Derivatives of carboxylic acids (variants), pharmaceutical composition and method fo selective binding α4β1-integrin in mammal

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of carboxylic acids of the formula: wherein Y is taken independently in each case among the group comprising C(O), N, CR1, C(R2)(R3), NR5, CH; q means a whole number from 3 to 10; A is taken among the group comprising NR6; E is taken among the group comprising NR7; J is taken among the group comprising O; T is taken among the group comprising (CH2)b wherein b = 0; M is taken among the group comprising C(R9)(R10), (CH2)u wherein u means a whole number from 0 to 3; L is taken among the group comprising NR11 and (CH2)n wherein n means 0; X is taken among the group comprising CO2H, tetrazolyl; W is taken among the group comprising C, CR15 and N; R1, R2, R3 and R15 are taken independently among th group comprising hydrogen atom, halogen atom, hydroxyl, alkyl, alkoxy-group, -CF3, amino-group, -NHC(O)N(C1-C3-alkyl)-C(O)NH-(C1-C3-alkyl), -NHC(O)NH-(C1-C6-alkyl), alkylamino-, alkoxyalkoxy-group, aryl, aryloxy-, arylamino-group, heterocyclyl, heterocyclylalkyl, heterocyclylamino-group wherein heteroatom is taken among N atom or O atom, -NHSO2-(C1-C3-alkyl), aryloxyalkyl; R4 is taken among the group comprising hydrogen atom, aryl, aralkyl, benzofuranyl, dihydrobenzofuranyl, dihydroindenyl, alkyl, benzodioxolyl, dihydrobenzodioxynyl, furyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, indolyl, thienyl, biphenyl, 2-oxo-2,3-dihydro-1H-benzimidazolyl, pyrimidinyl and carbazolyl. Other values of radicals are given in the claimed invention. Also, invention relates to pharmaceutical composition used for inhibition binding α4β1-integrin in mammal based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof in aims for treatment or prophylaxis of diseases associated with α4β1-integrin.

EFFECT: improved method for inhibition, valuable medicinal properties of compounds.

33 cl, 7 tbl, 42 ex

 

The technical field to which the invention relates.

The invention mainly relates to the inhibition of binding α4β1integrin with its receptor, for example with the receptor VCAM-1 (molecule-1 adhesion of the cells of the blood vessels) and fibronectin. The invention also relates to compounds which inhibit such binding, to pharmaceutically active compositions comprising such compounds and to the use of the above compounds separately, as described above, or in compositions for the treatment or prevention of diseases associated with α4β1the integrin.

The level of technology

When tissue damage by microorganism or damage a key role in the development of the inflammatory process belongs to white blood cells - leukocytes. One of the most important aspects of the inflammatory process is cell adhesion. Usually leukocytes circulate in the bloodstream. However, when the tissue becomes infected or damaged, white blood cells recognize the diseased or damaged tissue, contact with the capillary wall and migrate through the capillary to the affected tissue. These processes are mediated by a family of proteins called cell adhesion molecules.

There are three main types of leukocytes: granulocytes, monocytes and lymphocytes, α4β1integrin (very late in antigen-4 or VLA-4) is a heterodimeric protein, expressed on the surface of monocytes, lymphocytes, and two subclasses of granulocytes eosinophils and basophils. This protein plays a key role in cell adhesion through its ability to recognize and bind VCAM-1 and fibronectin, proteins associated with endothelial cells that line the inner wall of the capillaries.

After infection or damage to tissue surrounding the capillary, endothelial cells Express a number of adhesion molecules, including VCAM-1, responsible for binding of cells needed to fight infection. Before contact with VCAM-1 or fibronectin, leukocytes first interact with certain adhesion molecules in order to slow down their movement and to ensure the "rolling" of the cells along the activated endothelium. Monocytes, lymphocytes, basophils and eosinophils are closely associated with VCAM-1 or fibronectin on the wall of a blood vessel using α4β1integrin. It is established that such interaction is included in the migration process of these leukocytes to the damaged tissue, and in the process the primary "Rainha".

Although migration of leukocytes to the site of damage helps fight infection and leads to the degradation of foreign material, in many cases, this migration can be uncontrolled, with the influx of the loci is the inflammation of excess white blood cells, causing extensive tissue damage. Therefore, compounds capable of blocking this process can be useful as therapeutic agents. Thus, there is a need to develop inhibitors that may prevent the binding of cells with VCAM-1 and fibronectin.

Some of the diseases that can be treated by inhibiting the binding of α4β1include , without limitation, atherosclerosis, rheumatoid arthritis, asthma, allergies, multiple sclerosis, lupus, inflammatory bowel disease, graft rejection, contact allergies, and diabetes. In addition to the presence of integrin some leukocytes, α4β1also found in various tumor cells, including leukemia cells, melanoma cells, lymphoma and sarcoma. Assume that cell adhesion involving α4β1can accompany the process of metastasis of some tumors. Therefore, the inhibitors bind α4β1can find application in the treatment of some forms of cancer.

Isolation and purification of peptide that inhibits the binding of α4β1protein described in U.S. patent No. 5510332. Peptides that inhibit the binding described in applications WO 95/15973, EP 041915, EP 0422938 A1, U.S. patent No. 5192746 and the application WO 96/06108. New compounds that can be used for the inhibition and prevention of cell adhesion and mediate cell adhesion pathological conditions described in applications WO 96/22966, WO 98/04247 and WO 98/04913.

Therefore, the object of the invention is to develop new compounds inhibiting the binding of α4β1and pharmaceutical compositions comprising such new connections.

The invention

The present invention is directed to derivatives of carboxylic acids of the formula I

where Y in each case independently chosen from the group consisting of C(O), N, CR1C(R2)(R3), NR5, SN;

q denotes an integer from 3 to 10;

And chosen from the group consisting of NR6;

E is chosen from the group consisting of NR7;

J is chosen from the group consisting Of;

T is chosen from the group consisting of (CH2)bwhere b means 0;

M is chosen from the group consisting of C(R9)(R10) and (CH2)uwhere u represents an integer from 0 to 3;

L is chosen from the group consisting of NR11and (CH2)nwhere n stands for 0;

X is chosen from the group consisting of CO2H, tetrazolyl;

W is chosen from the group consisting of C, CR15and N,

R1, R2, R3and R15independent is selected from the group containing hydrogen, halogen, hydroxyl, alkyl, alkoxy, -CF3, amino, -NHC(O)N(C1-C3alkyl)C(O)NH-(C1-C3alkyl), -NHC(O)NH(C1-C6alkyl), alkylamino, alkoxyalkyl, cycloalkyl, aryl, aryloxy, arylamino, heterocyclyl, heterocyclisation, where the heteroatom is selected from N or O, -NHSO2(C1-C3alkyl), aryloxyalkyl;

where R1, R2, R3and R15not substituted or substituted by at least one electron-donating or electron-withdrawing group selected from the group consisting of carboxy, alkyl, alkoxy and aryl;

R4selected from the group consisting of hydrogen, aryl, aralkyl, benzofuranyl, dihydrobenzofuranyl, dihydroindeno, alkyl, benzodioxolyl, dihydroergotoxine, furyl, naphthyl, chinoline, ethenolysis, pyridinyl, indolyl, thienyl, biphenyl, 2-oxo-2,3-dihydro-1H-benzimidazolyl, pyrimidinyl and carbazolyl,

where R4may be not substituted or substituted by at least one electron-donating or electron-withdrawing group selected from the group consisting of alkyl, alkoxy, hydroxy, SO2(C1-C3alkyl), halogen, di(lower alkyl)amino, alkylthio, halogenated, -O-halogenated, alkoxyalkane, cycloalkyl, -NHSO2(C1-C3alkyl), -N(C1-C3alkyl)SO2(C1-C3alkyl), cycloalkane, pyrrolidinyl, -O-recloak salkil and piperidinyl;

R5selected from the group consisting of aralkyl, aryloxyalkyl, cycloalkyl and geterotsiklicheskikh, which heteroatom is selected from N, O and S, where R5may be not substituted or substituted by at least one electron-donating or electron-withdrawing group selected from the group consisting of aralkylamines, 3-aryl-1-ureido, halogen, -CN, alkoxy, alkyl, halogenated, aryl, hydroxy, -NO2, amino, -NH(aliphatic acyl), -NHSO2(C1-C3alkyl), alkylthio, -O-halogenated, -SO2(C1-C3alkyl), -SO2N(C1-C3alkyl)2, -SO2(1-pyrrolidinyl), -SO2(1-piperidinyl), -O-aralkyl, -O-cycloalkenyl, alkoxyalkane;

R6selected from the group consisting of hydrogen, alkyl;

R7and R11represent hydrogen;

where R9and R10represent hydrogen or alkyl;

and where, if a means NR6and at least one Y represents CR1, R1and R6can be combined with the formation of the loop, or their pharmaceutically acceptable salts.

In the preferred compounds of the formula I M can be C(R9)(R10), q can mean 4 or 5, L may indicate (CH2)nwhere n is 0, X may mean COOH, W is mean or CR15, a R15means hydrogen.

More specifically, the compounds according to the present image is meniu can be described by the formula II

where Y in each case independently chosen from the group consisting of C(O), N, CR1C(R2)(R3), NR5;

q denotes an integer from 3 to 7;

T is chosen from the group consisting of (CH2)bwhere b means 0;

L is chosen from the group consisting of NR11and (CH2)nwhere n stands for 0;

W is chosen from the group consisting of C, CR15and N,

In selected from the group consisting of hydrogen and alkyl;

R1, R2, R3and R15independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkyl, alkoxy, -CF3, amino, -NHC(O)N(C1-C3alkyl)C(O)NH(C1-C3alkyl), -NHC(O)NH(C1-C6alkyl), alkylamino, alkoxyalkyl, cycloalkyl, aryl, aryloxy, arylamino, heterocyclyl, heterocyclisation where heteroatom selected from N or O, -NHSO2(C1-C3alkyl), aryloxyalkyl;

where R1, R2, R3and R15not substituted or substituted by at least one electron-donating or electron-withdrawing group selected from the group consisting of carboxy, alkyl, alkoxy and aryl;

R4selected from the group consisting of hydrogen, aryl, aralkyl, benzofuranyl, dihydrobenzofuranyl, dihydroindeno, alkyl, benzodioxolyl, dihydroergotoxine, furyl, naphthyl, chinoline, ethenolysis, pyridinyl, indolyl, thienyl, Biff is Il, 2-oxo-2,3-dihydro-1H-benzimidazolyl, pyrimidinyl and carbazolyl, where R4may be not substituted or substituted by at least one electron-donating or electron-withdrawing group selected from the group consisting of alkyl, alkoxy, hydroxy, SO2(C1-C3alkyl), halogen, di(lower alkyl)amino, alkylthio, halogenated, -O-halogenated, alkoxyalkane, cycloalkyl, -NHSO2(C1-C3alkyl), -N(C1-C3alkyl)SO2(C1-C3alkyl), cycloalkane, pyrrolidinyl, -O-cycloalkenyl and piperidinyl;

R5selected from the group consisting of aralkyl, aryloxyalkyl, cycloalkyl and geterotsiklicheskikh, which heteroatom is selected from N, O and S, where R5may be not substituted or substituted by at least one electron-donating or electron-withdrawing group selected from the group consisting of aralkylamines, 3-aryl-1-ureido, halogen, -CN, alkoxy, alkyl, halogenated, aryl, hydroxy, -NO2, amino, -NH(aliphatic acyl), -NHSO2(C1-C3alkyl), alkylthio, -O-halogenated, -SO2(C1-C3alkyl), -SO2N(C1-C3alkyl)2, -SO2(1-pyrrolidinyl),-SO2(1-piperidinyl),-O-aralkyl,-O-cycloalkenyl, alkoxyalkane;

R6selected from the group consisting of hydrogen, alkyl;

R7and R11represent hydrogen;

and where R 9and R10represent hydrogen or alkyl;

or their pharmaceutically acceptable salts.

In preferred compounds of formula II q can mean 4 or 5, W mean or CR15L may indicate (CH2)nwhere n is 0, R15means hydrogen.

More specifically, the compounds of the present invention can be described by formula III

where Y in each case independently chosen from the group consisting of C(O), N, CR1C(R2)(R3), NR5CH;

q denotes an integer from 2 to 5;

T is chosen from the group consisting of (CH2)bwhere b means 0;

L is chosen from the group consisting of NR11and (CH2)nwhere n stands for 0;

In selected from the group consisting of hydrogen and alkyl;

R1, R2and R3independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkyl, alkoxy, -CF3, amino, -NHC(O)N(C1-C3alkyl)C(O)NH(C1-C3alkyl), -NHC(O)NH(C1-C6alkyl), alkylamino, alkoxyalkyl, cycloalkyl, aryl, aryloxy, arylamino, heterocyclyl, heterocyclisation, where the heteroatom is selected from N or O, -NHSO2(C1-C3alkyl), aryloxyalkyl;

where R1, R2and R3not substituted or substituted by at least one electron-donating or electron-withdrawing group, select the Noah group, containing carboxy, alkyl, alkoxy and aryl;

R4selected from the group consisting of hydrogen, aryl, aralkyl, benzofuranyl, dihydrobenzofuranyl, dihydroindeno, alkyl, benzodioxolyl, dihydroergotoxine, furyl, naphthyl, chinoline, ethenolysis, pyridinyl, indolyl, thienyl, biphenyl, 2-oxo-2,3-dihydro-1H-benzimidazolyl, pyrimidinyl and carbazolyl, where R4may be not substituted or substituted by at least one electron-donating or electron-withdrawing group selected from the group consisting of alkyl, alkoxy, hydroxy, SO2(C1-C3alkyl), halogen, di(lower alkyl)amino, alkylthio, halogenated, -O-halogenated, alkoxyalkane, cycloalkyl, -NHSO2(C1-C3alkyl), -N(C1-C3alkyl)SO2(C1-C3alkyl), cycloalkane, pyrrolidinyl, -O-cycloalkenyl and piperidinyl;

R5selected from the group consisting of aralkyl, aryloxyalkyl, cycloalkyl and geterotsiklicheskikh, which heteroatom is selected from N, O and S, where R5may be not substituted or substituted by at least one electron-donating or electron-withdrawing group selected from the group consisting of aralkylamines, 3-aryl-1-ureido, halogen, -CN, alkoxy, alkyl, halogenated, aryl, hydroxy, -NO2, amino, -NH(aliphatic acyl), -NHSO2(C1-C3alkyl), alkylthio, -O-halogenated, -SO2(C 1-C3alkyl), -SO2N(C1-C3alkyl)2, -SO2(1-pyrrolidinyl), -SO2(1-piperidinyl), -O-aralkyl, -O-cycloalkenyl, alkoxyalkane;

R6selected from the group consisting of hydrogen, alkyl;

R7and R11represent hydrogen;

R9and R10represent hydrogen or alkyl;

or their pharmaceutically acceptable salts.

In preferred compounds of formula III, R5may mean aralkyl and geterotsiklicheskikh, L may indicate (CH2)nwhere n is 0, Y can mean CR1and C(R2)(R3and q can mean 2 or 3.

In the formula III fragment molecules

may mean

where R18, R19, R20, R21and R28in each case, independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkyl, alkoxy, -CF3, amino, -NHC(O)N(C1-C3alkyl)C(O)NH(C1-C3alkyl), -NHC(O)NH(C1-C6alkyl), alkylamino, alkoxyalkyl, cycloalkyl, aryl, aryloxy, arylamino, heterocyclyl, heterocyclisation, where the heteroatom is selected from N or O, -NHSO2(C1-C3alkyl) and aryloxyalkyl,

with means an integer from zero to two,/p>

d is an integer from zero to three,

E. means an integer from zero to four,

f denotes zero or one.

In one variation of the embodiment of the invention R5means alkylaryl, R4means aryl, T mean (CH2)bwhere b is 0, L is (CH2)nwhere n is 0, and R6, R7, R9and R10each independently mean hydrogen.

More specifically, the compounds of the present invention can be described by the formula IV

in which T is chosen from the group consisting of (CH2)bwhere b means 0;

L is chosen from the group consisting of NR11and (CH2)nwhere n stands for 0;

g denotes an integer from 0 to 7;

R4selected from the group consisting of hydrogen, aryl, aralkyl, benzofuranyl, dihydrobenzofuranyl, dihydroindeno, alkyl, benzodioxolyl, dihydroergotoxine, furyl, naphthyl, chinoline, ethenolysis, pyridinyl, indolyl, thienyl, biphenyl, 2-oxo-2,3-dihydro-1H-benzimidazolyl, pyrimidinyl and carbazolyl, where R4may be not substituted or substituted by at least one electron-donating or electron-withdrawing group selected from the group consisting of alkyl, alkoxy, hydroxy, SO2(C1-C3alkyl), halogen, di(lower alkyl)amino, alkylthio, halogenated, -O-halogenated, alkoxyalkane, qi is loukil, -NHSO2(C1-C3alkyl), -N(C1-C3alkyl)SO2(C1-C3alkyl), cycloalkane, pyrrolidinyl, -O-cycloalkenyl and piperidinyl;

R6selected from the group consisting of hydrogen, alkyl;

In, R7and R11represent hydrogen;

R9, R10represent hydrogen or alkyl;

R23in each case independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, -CF3, -NH2, -OH, -NHC(O)N(C1-C3alkyl)C(O)NH(C1-C3alkyl), -NHC(O)NH(C1-C6alkyl), -NHSO2(C1-C3alkyl), alkylamino, alkoxyalkyl, cycloalkyl, aryl, aryloxy, arylamino, heterocyclyl, heterocyclisation, where the heteroatom is selected from N or O;

thus R23may be not substituted or substituted by at least one electrondonor or electron-withdrawing group selected from the group consisting of carboxy, alkyl, alkoxy and aryl;

R18selected from the group consisting of cycloalkyl, aralkyl, geterotsiklicheskikh, aryloxyalkyl,

where R18not substituted or substituted by at least one electrondonor or electron-withdrawing group selected from the group consisting of aralkylamines, 3-aryl-1-ureido, halogen, -CN, alkoxy, alkyl, halogenated, aryl, hydroxy, -NO2, amino, -NH(aliphatic acyl), -NHSO2 (C1-C3alkyl), alkylthio, -O-halogenated, -SO2(C1-C3alkyl), -SO2N(C1-C3alkyl)2, -SO2(1-pyrrolidinyl), -SO2(1-piperidinyl), -O-aralkyl, -O-cycloalkenyl, alkoxyalkane;

or their pharmaceutically acceptable salt.

Preferred in the present compounds of the present invention can also be described by the formula V

Formula V in which h stands for an integer from zero to five;

And R7mean hydrogen;

R6, R9and R10represents hydrogen or lower alkyl;

R24and R25in each case independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, -CF3HE, halogenated, cycloalkyl, aralkyl;

R27in each case independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkyl, alkoxy, -NHSO2(C1-C3alkyl), -N(C1-C3alkyl)SO2(C1-C3alkyl), di(nishiuchi)amino, halogenated, -O-halogenated, alkoxyalkane, cycloalkyl, cycloalkene, alkylthio, -O-cycloalkenyl, -SO2(C1-C3alkyl), pyrrolidinyl and piperidinyl;

R18in each case independently selected from the group containing alkylamino, arylamino, tiari, aralkyl, GE is erotically, where the heteroatom is selected from N and S, aryloxyalkyl, hydrogen, and

R26selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, aralkyl;

and R26may be unsubstituted or substituted by at least one electron-donating or electron-withdrawing group selected from the group consisting of alkoxy, alkoxyalkyl;

a R18, R24, R25not substituted or substituted by at least one electron-donating or electron-withdrawing group containing a lower alkyl, alkyloxy, hydroxy, sulfonyl, -SO2(C1-C3alkyl), halogen, di(lower alkyl)amino;

and R24and R25can be combined with the education cycle;

or their pharmaceutically acceptable salt.

In the preferred compounds of the present invention of the formula V of each of In, R6, R7, R9, R10, R24, R25and R26independently means hydrogen, and R18means substituted or unsubstituted aralkyl.

Other preferred compounds of the present invention can be described by formula VI

where Z in each case independently chosen from the group consisting of CR30C(R31)(R32) and SN;

z denotes an integer from 3 to 6;

k is an integer from 0 to 5;

T is selected from the group consisting of (CH 2)bwhere b means 0;

L is selected from the group consisting of NR11and (CH2)nwhere n stands for 0;

R6selected from the group consisting of hydrogen, alkyl;

R7and R11represent hydrogen;

R18selected from the group consisting of cycloalkyl, aralkyl, geterotsiklicheskikh, aryloxyalkyl;

R4selected from the group consisting of hydrogen, aryl, aralkyl, benzofuranyl, dihydrobenzofuranyl, dihydroindeno, alkyl, benzodioxolyl, dihydroergotoxine, furyl, naphthyl, chinoline, ethenolysis, pyridinyl, indolyl, thienyl, biphenyl, 2-oxo-2,3-dihydro-1H-benzimidazolyl, pyrimidinyl and carbazolyl, where R4may be not substituted or substituted by at least one electron-donating or electron-withdrawing group selected from the group consisting of alkyl, alkoxy, hydroxy, SO2(C1-C3alkyl), halogen, di(lower alkyl)amino, alkylthio, halogenated, -O-halogenated, alkoxyalkane, cycloalkyl, -NHSO2(C1-C3alkyl), -N(C1-C3alkyl)SO2(C1-C3alkyl), cycloalkane, pyrrolidinyl, -O-cycloalkenyl and piperidinyl;

R9and R10represent hydrogen or alkyl;

R29, R30, R31and R32in each case independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, -CF , -OH, -NH2, -NHC(O)N(C1-C3alkyl)C(O)NH(C1-C3alkyl), -NHC(O)NH(C1-C6alkyl), -NHSO2(C1-C3alkyl), alkylamino, alkoxyalkyl, cycloalkyl, aryl, aryloxy, arylamino, heterocyclyl, heterocyclisation, where the heteroatom is selected from N or O;

where R29, R30, R31and R32not substituted or substituted by at least one electron-donating or electron-withdrawing group selected from the group consisting of carboxy, alkyl, alkoxy and aryl;

or their pharmaceutically acceptable salt.

Some compounds of formulae I-VI can be obtained from the new intermediate compounds having the formula VII and formula VIII

where each of R24and R25independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, -CF3HE, halogenated, cycloalkyl, aralkyl, R24and R25not substituted or substituted by at least one electron-donating or electron-withdrawing group containing a lower alkyl, alkyloxy, hydroxy, sulfonyl, -SO2(C1-C3alkyl), halogen, di(lower alkyl)amino;

or R24and R25can be combined with the loop

provided that if R24and R25combined with the education cycle, the resulting cycle does not mean benzene;

R18selected from the group containing cycloalkenyl, aralkyl, geterotsiklicheskikh, aryloxyalkyl;

where R18not substituted or substituted by at least one electron-donating or electron-withdrawing group selected from the group consisting of aralkylamines, 3-aryl-1-ureido, halogen, -CN, alkoxy, alkyl, halogenated, aryl, hydroxy, -NO2, amino, -NH(aliphatic acyl), -NHSO2(C1-C3alkyl), alkylthio, -O-halogenated, -SO2(C1-C3alkyl), -SO2N(C1-C3alkyl)2, -SO2(1-pyrrolidinyl), -SO2(1-piperidinyl), -O-aralkyl, -O-cycloalkenyl, alkoxyalkane; a R34means hydrogen.

In preferred compounds of formula VII according to the present invention R34means hydrogen, R18means aralkyl, and each of R24and R25independently means hydrogen, lower alkyl or lower alkyl, in which R24and R25combined with the formation of the loop.

New preferred intermediate compounds of the present invention are represented by formula VIII

where each of R24and R25independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, -CF3HE, halogenated, cycloalkyl, aralkyl;

thus R24and R25not substituted or substituted by at least one electron-donating or power is accepting group, containing lower alkyl, alkyloxy, hydroxy, sulfonyl, -SO2(C1-C3alkyl), halogen, di(lower alkyl)amino;

or R24and R25can be combined with the loop

provided that if R24and R25combined with the education cycle, the resulting cycle does not mean benzene;

R34means hydrogen, and

R35in each case independently selected from the group consisting of halogen, hydroxyl, alkyl, alkylthio, alkoxy, NH(aliphatic acyl), -CN, -NO2, -NH2, -NHSO2(C1-C3alkyl), aralkylamines, 3-aryl-1-ureido, halogenated, -O-halogenated, alkoxyalkane, -O-cycloalkenyl, aryl, -O-aralkyl, -SO2(C1-C3alkyl), -SO2N(C1-C3alkyl)2, -SO2(1-pyrrolidinyl), -SO2(1-piperidinyl), a m means an integer from 0 to 5.

In preferred compounds of formula VIII according to the present invention R34means hydrogen, m means an integer from one to three, and R35in each case, means alkyl, halogen, alkoxy, halogenated, sulfonyl, HE or-CN.

Preferred at the present time are the following connections:

(3S)-3-[({[2-methyl-4-(2-methylpropyl)-6-oxo-1-(phenylmethyl)-1,6-dihydro-5-pyrimidinyl]amino}carbonyl)amino]-3-(4-were)propionic acid,

(3S)-3-(1,3-benzodioxol-yl)-3-[({[2-oxo-1 -(phenylmethyl)-4-propyl-1,2-dihydro-3-pyridinyl]amino}carbonyl)amino]propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-ethyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid, (3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid, (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid,

-N(C1-C3alkyl)C(O)(C1-C3alkyl), -NHC(O)N(C1-C3alkyl)C(O)NH(C1-C3alkyl), -NHC(O)NH(C1-C6alkyl), -NHSO2(C1-C3alkyl), -NHSO2(aryl), alkoxyalkyl, alkylamino, alkynylamino, di(C1-C3)amino, -C(O)O-(C1-C3alkyl), -C(O)NH(C1-C3alkyl), -C(O)N(C1-C3alkyl)2, -CH=NOH, -RO3H2, ORO3H2halogenated, alkoxyalkane, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl, aryl, aroyl, aryloxy, arylamino, biaryl, tiari, diarylamino, heterocyclyl, alkylaryl, aralkyl, aralkyl, Alkylglucoside, geterotsiklicheskikh, sulfonyl, -SO2-(C1-C3alkyl), -SO3-(C1-C3alkyl), sulfonamide, carbamate, aryloxyalkyl and-C(O)NH(benzyl) groups;

R34selected from the group consisting of alkyl, alkenyl, quinil, hydroxyalkyl, aliphatic acyl, alkylamino, aldoxycarb the sludge, heterocyclyl, -CH=NOH, halogenated, alkoxyalkane, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl, aryl, aroyl, aryloxy, arylamino, biaryl, tiari, diarylamino, heterocyclyl, alkylaryl, aralkyl, aralkyl, Alkylglucoside, geterotsiklicheskikh, carbamate, aryloxyalkyl, hydrogen and-C(O)NH(benzyl) group,

R35in each case independently selected from the group consisting of halogen, alkyl, alkenyl, quinil, alkoxy, alkenone, alkyloxy, dialkoxy, hydroxyalkyl, aliphatic acyl, -CF3, -CO2H, -SH, -CN, -NO2, -NH2HE, alkynylamino, alkoxycarbonyl, heterocyclyl, carboxy, -N(C1-C3alkyl)C(O)(C1-C3alkyl), -NHC(O)N(C1-C3alkyl)-C(O)NH(C1-C3alkyl), -NHC(O)NH(C1-C6alkyl), -NHSO2(C1-C3alkyl), -NHSO2(aryl), alkoxyalkyl, alkylamino, alkynylamino, di(C1-C3)amino, -C(O)O(C1-C3alkyl), -C(O)NH(C1-C3alkyl), -C(O)N(C1-C3alkyl)2, -CH=NOH, -RO3H2, ORO3H2halogenated, alkoxyalkane, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl, aryl, aroyl, aryloxy, arylamino, biaryl, tiari, diarylamino, heterocyclyl, alkylaryl, aralkyl, aralkyl, Alkylglucoside, heterotic illlil, sulfonyl, -SO2-(C1-C3alkyl), -SO3-(C1-C3alkyl), sulfonamide, carbamate, aryloxyalkyl and-C(O)NH(benzyl) group,

where R24, R25, R34and R35not substituted or substituted by at least one electron-donating or electron-withdrawing group, a m means an integer from 0 to 5.

In preferred compounds of formula VIII according to the present invention R34means hydrogen, m means an integer from one to three, and R35in each case, means alkyl, halogen, alkoxy, halogenated, sulfonyl, HE or-CN.

Preferred at the present time are the following connections:

(3S)-3-[({[2-methyl-4-(2-methylpropyl)-6-oxo-1-(phenylmethyl)-1,6-dihydro-5-pyrimidinyl]amino}carbonyl)amino]-3-(4-were)propionic acid,

(3S)-3-(1,3-benzodioxol-5-yl)-3-[({[2-oxo-1-(phenylmethyl)-4-propyl-1,2-dihydro-3-pyridinyl]amino}carbonyl)amino]propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-ethyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-{[({6-methyl-2-oxo-1-(phenylmethyl)--[(phenylmethyl)oxy]-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-2,4-dimethyl-6-oxo-1,6-dihydro-5-pyrimidinyl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-{[({4-amino-1-[(2-chlorophenyl)methyl]-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)-propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-[4-(metiloksi)phenyl]propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(3,4-dimetilfenil)propionic acid,

(3S)-3-{[({4-amino-1-[(2-chlorophenyl)methyl]-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-[({[1-[(2-chlorophenyl)methyl]-4-(1,4-oxazine-4-yl)-2-oxo-1,2-dihydro-3-pyridinyl]amino}carbonyl)amino]-3-(4-were)propionic acid,

(3S)-3-[({[1-[(2-chlorophenyl)methyl]-2-oxo-4-(propylamino)-1,2-dihydro-3-pyridinyl]amino}carbonyl)amino]-3-(4-were)propionic acid,

(3S)-3-{[({1-[(2-bromophenyl)methyl]-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-[3-methyl-4-(metiloksi)phenyl]-propionic acid,

(3S)-3-{[({1-[(2-chlorphen is)methyl]-2-oxo-4-phenyl-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-[(2-{[2-(metiloksi)ethyl]oxy}ethyl)oxy]-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-[(1,1-dimethylethyl)amino]-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)-propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-phenylpropionate acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-[4-methyltetrahydro-1(2H)-pyrazinyl]-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]-amino}-3-(4-were)propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-[4-(metiloksi)phenyl]propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(3, 5dimethylphenyl)propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(3-were)propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-[3-(metiloksi)phenyl]propionic acid,

(3S)-3-[3,5-bis(metiloksi)phenyl]-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl}aminocarbonyl]amino}propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-chinoline}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-[3-(trifluoromethyl)phenyl]propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-[({ethyl[(ethylamino)-carbonyl]amino}carbonyl)amino]-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-{[({4-(1-acetonyl)-1-[(2-chlorophenyl)methyl]-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-[({[1-[(2-chlorophenyl)methyl]-4-({2-[(2-{[2-(metiloksi)ethyl]oxy}ethyl)oxy]ethyl}oxy)-2-oxo-1,2-dihydro-3-pyridinyl]amino}carbonyl)amino]-3-(4-were)propionic acid,

(3S)-3-{[({1-[(2-forfinal)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-{[({1-[(2-chloro-6-forfinal)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-(1,3-benzodioxol-5-yl)-3-((((2-oxo-1-((4-(trifluoromethyl)phenyl)methyl)-1,2-dihydro-3-pyridinyl)amino)carbonyl)-amino)propionic acid,

(3S)-3-((((1-((2-chlorophenyl)methyl)-2-oxo-1,2-dihydro-3-pyridinyl)amino)carbonyl) - Amin is)-3-(4-were)propionic acid,

(3S)-3-((((1-((2-forfinal)methyl)-2-oxo-1,2-dihydro-3-pyridinyl)amino)carbonyl)amino)-3-(4-were)propionic acid,

(3S)-3-((((1-((2-bromophenyl)methyl)-2-oxo-1,2-dihydro-3-pyridinyl)amino)carbonyl)amino)-3-(4-were)propionic acid,

(3S)-3-((((1-((2,4-dichlorophenyl)methyl)-2-oxo-1,2-dihydro-3-pyridinyl)amino)carbonyl)amino)-3-(4-were)propionic acid,

(3S)-3-((((1-((2-chloro-6-forfinal)methyl)-2-oxo-1,2-dihydro-3-pyridinyl)amino)carbonyl)amino)-3-(4-were)propionic acid,

(3S)-3-((((1-((2-chlorophenyl)methyl)-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl)amino)carbonyl)amino)-3-(4-trifluoromethyl)-oxy)phenyl)-propionic acid,

(3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid,

4-{[3-[({[(1S)-2-carboxy-1-(4-were)ethyl]amino)carbonyl)amino]-1-(2-Chlorobenzyl)-2-oxo-1,2-dihydropyridines-4-yl]amino}benzoic acid,

(3S)-3-{[({1-(2-Chlorobenzyl)-4-[(2,2-dimethylpropanoyl)amino]-2-oxo-1,2-dihydropyridines-3-yl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-[({[4-{[(tert-butylamino)carbonyl]amino}-1-(2-Chlorobenzyl)-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid,

(3S)-3-[({[1-(2-cyanobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-12-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(7-methoxy-1,3-benzodioxol-5-yl)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3-ethoxy-4-methoxyphenyl)propionic acid,

(3S)-3-[(([1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3,4-acid)propionic acid,

(3S)-3-[({[1-(4-Chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid,

(3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid,

(3S)-3-[({[1-(2,6-diferensial)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid,

(3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3,5-acid)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3,4-dioxyphenyl)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroc and-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3-methoxy-4-were)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3,5-dimethoxy-4-were)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3,4-dimetilfenil)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid,

(3S)-3-{[({1-[2-chloro-5-(trifluoromethyl)benzyl]-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3-were)propionic acid,

(3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid,

(3S)-3-[({[1-(2,6-dimethoxybenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3-propoxyphenyl)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propionic acid,

3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3,4-dioxyphenyl)propionic acid,

(3S)-3-(3-butoxyphenyl)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]propionic acid,

(3S)-3-{[({1-[2-chloro-5-(methylsulphonyl)benzyl]-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-[3-(2-methoxyethoxy)phenyl]propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3,4-dibromobiphenyl)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-[3-(deformedarse)phenyl]propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3,4-dioxyphenyl)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propionic acid,

(3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3,4-dioxyphenyl)propionic acid,

(3S)-3-[({[1-(2-chloro-6-cyanobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic sour is a,

3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(2-naphthyl)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3,4-dioxyphenyl)propionic acid,

(3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3,4-dioxyphenyl)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-methoxyphenyl)propionic acid,

(3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b] pyridine-3-yl] amino}carbonyl)amino]-3-(3-ethoxyphenyl)propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}Carbo who yl)amino]-3-(1-methyl-1H-indol-5-yl)propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(2,3-dihydro-1-benzofuran-5-yl)propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl]amino}carbonyl)amino]-3-(3,5-dioxyphenyl)propionic acid,

(3S)-3-[({[5-chloro-1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl]amino}carbonyl)amino]-3-(3-propoxyphenyl)propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl]amino}carbonyl)amino]-3-phenylpropionate acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl]amino}carbonyl)amino]-3-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-yl)propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-[3-(triptoreline)phenyl]propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3-isopropoxide who yl)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl]amino}carbonyl)amino]-3-(1-methyl-1H-indol-5-yl)propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-5-cyclopropyl-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-5-cyclopropyl-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid,

(3S)-3-[({[1-(2-chloro-5-methoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-6-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(1-methyl-1H-indol-6-yl)propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl]amino}carbonyl)amino]-3-[3-(cyclopropylamino)phenyl]propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl]amino}carbonyl)amino]-3-[3-(cyclopropylmethoxy)phenyl]propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl]amino}carbonyl)amino]-3-[3-(cyclopropyl is hydroxy)phenyl]propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl]amino}carbonyl)amino]-3-(3, 5dimethylphenyl)propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl}amino)carbonyl]amino}-3-{3-[(deformity)oxy]phenyl}propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl}amino)carbonyl]amino}-3-{3-[(1,1,2,2-tetraborate)oxy]phenyl}propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl}amino)carbonyl]amino}-3-(1-ethyl-1H-indol-5-yl)propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl}amino)carbonyl]amino}-3-[3-(diethylamino)phenyl]propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propionic who Isleta,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino} carbonyl)amino]-3-(6-methoxy-2-naphthyl)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl]amino}carbonyl)amino]-3-(3-were)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-[3-(diethylamino)phenyl]propionic acid,

(3S)-3-{[({1-[(2-chloro-6-were)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl}amino)-carbonyl]amino}-3-(1-methyl-1H-indol-5-yl)propionic acid,

(3S)-3-{[({1[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl}amino)carbonyl]amino}-3-{3-[(methylsulphonyl)amino]phenyl}propionic acid,

(3S)-3-{[({1-[(2-chloro-6-were)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl}amino)carbonyl]amino}-3-{3-[(methylsulphonyl)amino]phenyl}-propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl}amino)carbonyl]amino}-3-{3-[methyl - (methylsulphonyl)amino]phenyl} propionic acid,

(3S)-3-{[({1-[(2-chloro-6-were)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-Cyclops the NTA[b]pyridine-3-yl}amino)carbonyl]amino}-3-{3-[methyl - (methylsulphonyl)amino]-phenyl} propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl}amino)carbonyl]amino}-3-{3-[ethyl(methylsulphonyl)amino]phenyl}propionic acid,

(3S)-3-{[({1-[(2-chloro-6-were)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl}amino)carbonyl]amino}-3-{3-[ethyl(methylsulphonyl)amino]-phenyl}propionic acid,

(3S)-3-{[({1-[(2-chloro-6-were)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl}amino)carbonyl]amino}-3-(1H-indol-5-yl)propionic acid

and their pharmaceutically acceptable salts.

Preferred compounds of formula VII include:

5-(2-Chlorobenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-Chlorobenzyl)-6-methyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-terbisil)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-chloro-6-terbisil)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-benzyl-6-methyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-benzyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2,5-dimethylbenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-methylbenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2,4-dichlorobenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-methoxybenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2,5-diferensial)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-[2-chloro-5-(methylthio)benzyl] - for 3,5-dihydro,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(4-terbisil)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-chloro-5-methoxybenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-[3,5-bis(trifluoromethyl)benzyl] - for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(4-tert-butylbenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(3-Chlorobenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(4-chlorbenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-[3-(trifluoromethyl)benzyl] - for 3,5-dihydro[1,3]oxazol[4,5-C]-pyridine-2,4-dione,

5-(2-bromobenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(3,4-dichlorobenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(4-methylbenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-chloro-6-methoxybenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-[4-(trifluoromethyl)benzyl] - for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(3-methylbenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(pyridine-2-yl-methyl) - for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-Chlorobenzyl)-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2,4-diferensial)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2,6-diferensial)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-[3-(triptoreline)benzyl] - for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-[4-(triptoreline)benzyl] - for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-[2-(trifluoromethyl)benzyl] - for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,/p>

5-(3-methoxybenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2,3-dichlorobenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(3,5-dimethylbenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-Chlorobenzyl)-7-pentyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2,4-dichlorobenzyl)-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-Chlorobenzyl)-7-ethyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

7-butyl-5-(2-Chlorobenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-[2-chloro-5-(trifluoromethyl)benzyl] - for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2,6-dichlorobenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-chloro-5-terbisil)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-chloro-6-methylbenzyl)-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(4-Chlorobenzyl)-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-Chlorobenzyl)-5,6,7,8-tetrahydro-2H-cyclopent[b][1,3]oxazol[5,4-d]-pyridine-2,4(3H)-dione,

7-methyl-5-[4-(methylsulphonyl)benzyl] - for 3,5-dihydro[1,3]oxazol[4,5-C]-pyridine-2,4-dione,

5-(4-methoxybenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-Chlorobenzyl)-7-propyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

4-[(2,4-dioxo-2,3-dihydro[1,3]oxazol[4,5-C]pyridine-5(4H)-yl)methyl]-N,N-dimethylbenzenesulfonamide,

5-(methicillin)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-Chlorobenzyl)-3,5,6,7,8,9-hexahydro[1,3]oxazol[4,5-C]quinoline-2,4-dio is,

5-(2-Chlorobenzyl)-7-ethyl-6-methyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-[2-(methylthio)benzyl] - for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

2-[(2,4-dioxo-2,3-dihydro[1,3]oxazol[4,5-C]pyridine-5(4H)-yl)methyl] - N,N-dimethylbenzenesulfonamide,

5-(2,6-dimethoxybenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-[2-(triptoreline)benzyl] - for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-Chlorobenzyl)-6,7-dimethyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-[2-chloro-5-(methylsulphonyl)benzyl] - for 3,5-dihydro[1,3]oxazol[4,5-C]-pyridine-2,4-dione,

5-(4-chloro-2-methoxybenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-Chlorobenzyl)-5,6,7,8,9,10-hexahydro-2H-cyclohepta[b][1,3]oxazol[5,4-c]-pyridine-2,4(3H)-dione,

5-[2-(deformedarse)benzyl] - for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

7-methyl-5-[(1R)-1-phenylethyl] - for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(4-Chlorobenzyl)-7-propyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-[2-(methylsulphonyl)benzyl] - for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2,6-dimethylbenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

3-chloro-2-[(2,4-dioxo-2,3-dihydro[1,3]oxazol[4,5-C]pyridine-5(4H)-yl)methyl]benzonitrile,

5-(2-chloro-6-methylbenzyl)-6,7-dimethyl-3,5-dihydro[1,3]oxazol[4,5-C]-pyridine-2,4-dione,

2-[(2,4-dioxo-2,3-dihydro[1,3]oxazol[4,5-C]pyridine-5(4H)-yl)methyl]-benzonitrile,

5-(2-chloro-6-methoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazol-[4,5-C]feast the Dean-2,4-dione,

5-[3-(methylthio)benzyl] - for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-Chlorobenzyl)-7-cyclopropyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(3-Chlorobenzyl)-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2,6-dichlorobenzyl)-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

7-methyl-5-(4-methylbenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(3,5-dimethoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2,6-diferensial)-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-[3-(methylsulphonyl)benzyl] - for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-chloro-6-ethoxybenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-chloro-6-ethoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-fluoro-6-methoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazol-[4,5-C]pyridine-2,4-dione,

5-(2-chloro-6-methoxybenzyl)-7-propyl-3,5-dihydro[1,3]oxazol-[4,5-C]pyridine-2,4-dione,

5-(5-chloro-2-terbisil)-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-Chlorobenzyl)-7-isopropyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(5-fluoro-2-methylbenzyl)-7-methyl-3,5-dihydro[1,3]oxazol-[4,5-C]pyridine-2,4-dione,

7-methyl-5-[(1S)-1-phenylethyl] - for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-chloro-5-isopropoxyphenyl)-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]-pyridine-2,4-dione,

5-(5-acetyl-2-methoxybenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-chlorine is benzyl)-7-methyl-3,5-dihydro[1,3]oxazol[4,5-d]pyridazin-2,4-dione,

5-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]-pyridine-2,4-dione,

5-(2-chloro-6-methylbenzyl)-5,6,7,8-tetrahydro-2H-cyclopent[b]-[1,3]oxazol[5,4-d]pyridine-2,4(3H)-dione,

5-(2-chloro-6-ethoxybenzyl)-7-ethyl-3,5-dihydro[1,3]oxazol-[4,5-C]pyridine-2,4-dione,

5-(2-chloro-6-propoxyphenyl)-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-chloro-6-salutogenesis)-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]-pyridine-2,4-dione,

5-(2-chloro-6-ethoxybenzyl)-5,6,7,8-tetrahydro-2H-cyclopent[b]-[1,3]oxazol[5,4-d]pyridine-2,4(3H)-dione,

5-(2-chloro-6-isopropoxyphenyl)-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]-pyridine-2,4-dione,

5-[2-chloro-6-(2,2,2-triptoreline)benzyl]-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-chloro-6-ethoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazol-[4,5-d]pyridazin-2,4-dione,

5-[2-chloro-6-(2-methoxyethoxy)benzyl]-5,6,7,8-tetrahydro-2H-cyclopent[b][1,3]oxazol[5,4-d]pyridine-2,4(3H)-dione,

5-(2-chloro-6-ethoxybenzyl)-6,7-dimethyl-3,5-dihydro[1,3]oxazol[4,5-C]-pyridine-2,4-dione,

5-(2-chloro-6-ethoxybenzyl)-7-ethyl-6-methyl-3,5-dihydro[1,3]oxazol[4,5-C]-pyridine-2,4-dione,

5-(2-Chlorobenzyl)-7-ethyl-3,5-dihydro[1,3]oxazol[4,5-d]pyridazin-2,4-dione,

5-(2-chloro-6-ethoxybenzyl)-7-propyl-3,5-dihydro[1,3]oxazol-[4,5-C]pyridine-2,4-dione,

5-(2-chloro-6-ethoxybenzyl)-7-cyclopropyl-3,5-dihydro[1,3]oxazol[4,5-C]-pyridine-2,4-dione,

5-(2-chloro-5-propoxyphenyl)-7-methyl-3,5-dihydro[1,3]-oxazol[4,5-C]-pyridine-2,4-dione,

5-(2-the ENT-5-methoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazol-[4,5-C]pyridine-2,4-dione,

5-(2-chloro-6-ethoxybenzyl)-6-methyl-3,5-dihydro[1,3]oxazol-[4,5-C]pyridine-2,4-dione,

5-(2-chloro-5-ethoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazol-[4,5-C]pyridine-2,4-dione,

5-[2-chloro-5-(piperidine-1-yl-sulfonyl)benzyl]-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-[2-chloro-5-(pyrrolidin-1-yl-sulfonyl)benzyl]-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-[2-chloro-6-(cyclopentyloxy)benzyl]-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-[2-(benzyloxy)-6-Chlorobenzyl]-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]-pyridine-2,4-dione,

5-(2,3-dichloro-6-ethoxybenzyl)-5,6,7,8-tetrahydro-2H-cyclopent[b][1,3]oxazol[5,4-d]pyridine-2,4(3H)-dione,

5-[2-chloro-5-(trifluoromethyl)benzyl]-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]-pyridine-2,4-dione and

5-(2-chloro-5-terbisil)-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione.

Assume also derivatives of these compounds, such as esters, carbamates, aminal, amides, optical isomers, and prodrugs.

The present invention relates also to pharmaceutical compositions comprising a physiologically acceptable diluent and at least one compound of the present invention.

The present invention relates also to a method of inhibiting the binding of α4β1integrin c VCAM-1, comprising contacting cells expressing α4β1integrin, tile is Oh, expressing VCAM-1, in the presence of an effective inhibiting amount of the compounds of the present invention. VCAM-1 may be present on the surface of endothelial cells of blood vessels, on antigen-presenting cells or other cell types, α4β1may be present on leukocytes, such as monocytes, lymphocytes, granulocytes, stem cells or any other cells that are able to Express the α4β1.

Information confirming the possibility of carrying out the invention

Definition of terms

The term "alkyl", alone or in combination, means1-C12linear or branched, substituted or unsubstituted saturated radical, formed from a saturated hydrocarbon with the removal of one hydrogen atom, provided that, if the term alkyl is not preceded by a symbol Withx-Cy. Typical examples of alkyl groups include, along with other methyl, ethyl, n-propyl, ISO-propyl, n-butyl, sec-butyl, ISO-butyl and tert-butyl.

The term "alkenyl", separately or in combination, means a substituted or unsubstituted linear, substituted or unsubstituted branched alkanniny radical containing from 2 to 10 carbon atoms. Examples of such radicals include, without limitation, ethynyl, E - and Z-pentenyl, decenyl the other

The term "quinil", separately or in combination, means a substituted or unsubstituted linear, substituted or unsubstituted branched alkynylaryl radical containing from 2 to 10 carbon atoms. Examples of such radicals include, without limitation, ethinyl, PROPYNYL, propargyl, butynyl, hexenyl, decenyl etc.

The term "lower" modified "alkyl", "alkenyl", "quinil" or "alkoxy" means1-C6link to a specific functional purpose. For example, the lower alkyl means1-C6alkyl.

The term "aliphatic acyl", alone or in combination, means a radical of the formula alkyl-C(O)-, alkenyl-C(O)- and quinil-C(O)-, formed from alkane-, alkene - and alkenylboronic acid, where the terms "alkyl", "alkenyl" and "quinil" have the meanings specified above. Examples of such aliphatic acyl radicals include, among others, without limitation, acetyl, propionyl, butyryl, valeryl, 4-methylallyl, acryloyl, crotyl, propionyl and methylpropionyl.

The term "cycloalkyl"means aliphatic cyclic system containing 3 to 10 carbon atoms and from 1 to 3 cycles, including, among others, without limitation, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl and substituted. Cycloalkyl groups can be unsubstituted or substituted one, two the or three substituents, are independently selected from the group comprising lower alkyl, halogenated, alkoxy, dialkoxy, amino, alkylamino, dialkylamino, hydroxy, halogen, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.

"Cycloalkyl includes CIS or TRANS form. In addition, the substituents in the bicyclic system with bridge connection can be in the endo - and Exo-positions.

The term "cycloalkenyl", separately or in combination, means a carbocyclic system containing from 4 to 8 carbon atoms and one or more double bonds. Examples of such cycloalkyl radicals include, without limitation, cyclopentenyl, cyclohexenyl, cyclopentadienyl, etc.

The term "cycloalkenyl"means cycloalkyl group attached to ness. alkylation, including, without limitation, cyclohexylmethyl.

The term "halogen" means I, Br, Cl or F.

The term "halogenated" means NISS. alkylation is attached to at least one halogen Deputy, for example, along with others, chloromethyl, foradil, trifluoromethyl and pentafluoroethyl.

The term "alkoxy", alone or in combination, means a simple alkylpyridine, where the term "alkyl" has the values listed above. Examples of typical radical simple alkyl ester include, but are not limited to methoxy, ethoxy, n-propoxy, ISO-propoxy, n-butoxy, out-butoxy, sec-butoxy, tert-butoxy etc.

The term "alconox", separately or in combination, means a radical of the formula of alkenyl-O, provided that the radical is not an enol ether, where the term "alkenyl" has the values listed above. Examples of typical altnetseattle include, without limitation, allyloxy, E - and Z - 3-methyl-2-propenoic etc.

The term "alkyloxy", separately or in combination, means a radical of the formula quinil-O, provided that the radical is not isalnum ether. Examples of typical alkyloxy radicals include, without limitation, propargyloxy, 2-butenyloxy etc.

The term "carboxyl" means a radical of carboxylic acid-C(O)HE.

The term "carboxy" means-C(O)O-.

The term "dialkoxy" means a radical of tiefer formula alkyl-S-, where "alkyl" has the values listed above.

The term "carboxaldehyde" means-C(O)R, where R is hydrogen.

The term "carboxamide" or "amide" means-C(O)NRaRbwhere Raand Rbeach independently means hydrogen, alkyl or any suitable substitute.

The term "alkoxyalkyl" means RcO-RdO-, where Rcmeans lower alkyl having values above and Rdmeans alkylen where alkylen means -(CH2)n'-where n' is the CE is th number from 1 to 6. Typical examples of alkoxyalkyl groups include among others methoxyethoxy, ethoxyethoxy, tert-butoxyethoxy.

The term "alkylamino" means ReNH-, where Remeans along with other lower alkyl, for example, ethylamino, butylamino.

The term "alkanolamine", separately or in combination, means a radical of the formula of alkenyl-NH - or (alkenyl)2N-, where the term "alkenyl" has the values specified above, provided that the radical is not an enamine. An example of this alkenylbenzene is allelomimetrical.

The term "alkynylamino", separately or in combination, means a radical of the formula quinil-NH-or (quinil)2N-, where the term "quinil" has the values specified above, provided that the radical is not an amine. An example of this alkylaminocarbonyl is propargylamines.

The term "dialkylamino" means RfRgN-, where Rfand Rgindependently selects, among others, from the group comprising lower alkyl, such as diethylamino, methylpropylamine.

The term "amino" means H2N.

The term "alkoxycarbonyl" means alkoxygroup with the values specified above, attached to the main fragment of the molecule via a carbonyl group. Examples alkoxycarbonyl groups include, among others, methoxycarbonyl, etoxycarbonyl and isopropoxide boil.

The term "aryl" or "aromatic", separately or in combination, means a substituted or unsubstituted carbocyclic aromatic group containing from about 6 to 12 carbon atoms, such as phenyl, naphthyl, indenyl, indanyl, azulene, fluorene and anthracene; or heterocyclic aromatic group containing at least one industrijski atom N, O or S, such as furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, 2-pyrazoline, pyrazolidine, isoxazole, isothiazole, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-tritional, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, 2,3-dihydrobenzofuranyl, benzo[b]thiophenyl, 1H-indazole, benzimidazole, benzthiazole, purinol, 4H-hemolysins, ethenolysis, cinnoline, phthalazine, hintline, honokalani, 1,8-naphthyridine, pteridine, carbazole, acridine, phenazine, phenothiazinyl, phenoxazines, pyrazolo[1,5-C]triazinyl, etc. In terms of "aralkyl and alkylaryl" the term "alkyl" has the values listed above. Cycles can have several deputies.

The term "aralkyl", separately or in combination, means an alkyl, substituted allrazolam, and the terms "alkyl" and "aryl" shall have the meanings specified above. Typical examples of radicals "aralkyl VK is ucaut, without limitation, phenylmethyl, phenethyl, phenylgesic, diphenylmethyl, pyridylmethyl, tetrazolyl, furylmethyl, imidazolidinyl, indolylmethane, tamiltamil etc.

The term "aralkyl", separately or in combination, means of alkenyl, replaced by allrazolam, and the terms "aryl" and "alkenyl" have the meanings specified above.

The term "arylamino", separately or in combination, means a radical of the formula aryl-NH-, where "aryl" has the values listed above. Examples of radicals of arylamino" include, without limitation, phenylamino(anilide), naphthylamine, 2-, 3 - and 4-pyridylamino etc.

The term "biaryl", separately or in combination, means a radical of the formula aryl-aryl, where the term "aryl" has the values listed above.

The term "tiari", separately or in combination, means a radical of the formula aryl-S-, where the term "aryl" has the values listed above. Example tiurilova radical is thiophenemethyl,

The term "aroyl", separately or in combination, means a radical of the formula aryl-CO-, where the term "aryl" has the values listed above. Examples of radicals of aromatic acyl include, without limitation, benzoyl, 4-halogenmethyl, 4-carboxybenzoyl, Naftoli, pyridylcarbonyl etc.

The term "heterocyclyl", separately or in combination, means a non-aromatic 3-10-membered cycle, which according to what ina least one industrijski atom, N, O or S. the Heterocycle can optionally be condensed with aryl. The heterocycle may be optionally substituted by at least one Deputy, which is independently chosen from the group that includes, along with other hydrogen, halogen, hydroxyl, amino, nitro, trifluoromethyl, triptoreline, alkyl, aralkyl, alkenyl, quinil, aryl, cyano, carboxy, carbalkoxy, carboxyethyl, oxo, arylsulfonyl and aralkylamines.

The term "alkylglycerol"means an alkyl group having values above, attached to the main fragment of the molecule through a heterocyclic group, including, without limitation, 2-methyl-6-thiazolyl, 2-methyl-1-pyrrolyl and 5-ethyl-2-thiophenyl.

The term "geterotsiklicheskikh" means a heterocyclic group, with the values specified above, attached to the main fragment of the molecule through an alkyl group, including, without limitation, 2-thienylmethyl, 2-pyridinylmethyl and 2-(1-piperidinyl)ethyl.

The term "aminal"means Polyacetal having the structure RhC(NRiRj)(NRkRl)-, where Rh, Ri, Rj, Rkand Rleach independently means hydrogen, alkyl or any suitable substitute.

The term "ester" means-C(O)Rmwhere Rmmeans hydrogen, alkyl or any suitable substitute.

The term "carbamate" means derivatives of carbamino acid NH2C(O)OH.

Use of these terms is intended to include substituted and unsubstituted fragments of the molecule. The substitution can be carried out by one or more groups such as alcohols, ethers, esters, amides, sulfones, sulfides, hydroxyl, nitro, cyano, carboxy, amines, heteroatoms, lower alkyl, lower alkoxy, lower alkoxycarbonyl, alkoxyalkyl, aryloxy, halogen, triptoreline, trifluoromethyl, alkyl, aralkyl, alkenyl, quinil, aryl, cyano, carboxy, carbalkoxy, carboxyethyl, cycloalkyl, cycloalkenyl, heterocyclyl, Alkylglucoside, geterotsiklicheskikh, oxo, arylsulfonyl and aralkylamines or any of the substituents mentioned in the preceding Chapter or any of those substituents that are attached directly or via an appropriate linking group. Usually bridging groups are short chain containing 1-3 atoms, represents the following structures, such as-S-, -C(O)-, -NH-, -S-, -S(O)-, -O-, -C(O)O - or-S(O)O-. Rings can have several deputies.

The term "electron-withdrawing or electron-donating" means the property of the Deputy to accept or give up electrons relative to the corresponding ability of the hydrogen atom, if it takes the molecule in the same position. E and terms known to experts in the art and are discussed in the article J.March, Advanced Organic Chemistry (Modern organic chemistry) (1985), pages 16-18, included as references in this text. Electron-withdrawing groups include, along with other halogen, nitro, carboxyl, lower alkenyl, lower quinil, carboxaldehyde, carboxamide, aryl, Quaternary ammonium, trifluoromethyl and sulfonyl and aryl-lower alkanoyl. Electron-donating groups include among others such as hydroxy, lower alkyl, amino, lower alkylamino, di(lower alkyl)amino, aryloxy, mercapto, lower alkylthio, lower allylmercaptan and disulfide. Specialist in the art should note that the above substituents may have an electron-donating or electron-withdrawing properties in different chemical conditions. Moreover, the present invention includes any combination of substituents selected from the aforementioned groups.

The most preferred electron-donating or electron-withdrawing substituents are halogen, nitro, alkanoyl, carboxaldehyde, arylalkyl, aryloxy, carboxyl, carboxamide, cyano, sulfonyl, sulfoxide, heterocyclyl, guanidine, Quaternary ammonium, lower alkenyl, lower quinil, salt sulfone, hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di(lower alkyl)amino, amino(lower alkyl)mercapto, mercaptomethyl, alkylthio, carboxylate alkyl), Allakaket, alkanolamine, alkanoyl(lower alkyl)amino, lower alkylsulfonyl, arylsulfonyl, alkylsulfonyl(lower alkyl)amino, arylsulfonyl(lower alkyl)amino, lower alkylcarboxylic, di(lower alkyl)carboxamide, sulfonamide, lower alkylsulfonyl, di(lower alkyl)sulfonamide, lower alkylsulfonyl, arylsulfonyl, acidity.

The term "composition (composition)" is intended to denote a product that contains certain componenet in certain amounts, as well as any product which is formed, directly or indirectly, from the combination of certain components in certain amounts.

Cycle Y defined in formulas I, II and III, can mean a monocyclic heterocycle or an aromatic ring, or a bicyclic system.

The dotted line in formulas I, II and III indicate the relationship between the atoms of Y and W, for example, it may be a single or double bond, when Y and/or W is a surrogate, such as N, C or CH. Hence, the cycle defined in the formula as Y, can be saturated or unsaturated, depending on the selected values of W and/or Y.

Suitable substituents for aryl groups, alkyl, cycloalkyl, heterocyclyl or cycles, defined as Y and W in formulas I and II, as defined above, include, if available, alcohols, amines, heteroatoms, or any combination of the following : GRU is p: alkyl, alkoxy, alkoxyalkyl, alkyl, cycloalkyl or heterocyclyl, prisoedinennykh directly or via an appropriate linking group. Usually bridging groups are short chain containing 1-3 atoms, represents the following structures, such as C, C=O, CO2, O, N, S, S=O, SO2as for example, along with other, ethers, amides, amines, derivatives of urea, sulfonamides, sulfonamides.

For example, R1, R2, R3, R5, R6, R7and R8in the above formulas I, II and III independently can mean, without limitation, the following groups: hydrogen, alkyl, phenyl, thienylmethyl, isobutyl, n-butyl, 2-thienylmethyl, 1,3-thiazol-2-yl-methyl, benzyl, thienyl, 3-pyridinylmethyl, 3-methyl-1-benzo-thiophene-2-yl, allyl, 3-methoxybenzyl, propyl, 2-ethoxyethyl, cyclopropylmethyl, benzylsulfamide, benzylmaleimide, phenylsulfanyl, geneticalgorithm, 3-phenylpropyl-sulfanilyl, 4-((2-toluenesulfonyl)amino)benzyl, 2-pyridinylmethyl, 2-(1H-indol-3-yl)ethyl 1H-benzimidazole-2-yl, 4-piperidinylmethyl, 3-hydroxy-4-methoxybenzyl, 4-hydroxyphenyl, 4-aminobenzyl, phenylsulfonyl, 4-(acetylamino)phenyl, 4-methoxyphenyl, 4-AMINOPHENYL, 4-chlorophenyl, (4-(benzylmethyl)amino)phenyl, (4-(methylsulphonyl)amino)phenyl, 2-AMINOPHENYL, 2-were, isopropyl, 2-oxo-1-pyrrolidinyl, 3-(methylsulfanyl)propyl, propylsulfonyl)methyl, octylaniline, 3-AMINOPHENYL, 4-((2-toluenesulfonyl)amino)phenyl, 2-((methylbenzyl)amino)benzyl, methylsulfonylmethyl, hydroxy, chlorine, fluorine, bromine, ureido, amino, methanesulfonamido, acetylamino or ethylsulfonyl.

Deputy R4in the above formulas I, II and III independently may mean, without limitation, the following groups: 1,3-benzodioxol-5-yl, 1-naphthyl, thienyl, 4-isobutoxide, 2,6-dimetilfenil, allyloxyphenyl, 3-bromo-4-methoxyphenyl, 4-butoxyphenyl, 1-benzofuran-2-yl, 2-thienylmethyl, phenyl, methylsulfonyl, phenylsulfonyl, penicillanic, 4-bromo-2-thienyl, 3-methyl-2-thienyl, 4-were, 3,5-bis(metiloksi)phenyl, 4-(metiloksi)phenyl, 4-forfinal, 3-(metiloksi)phenyl, 3,4,5-Tris(metiloksi)phenyl, 2,3-dihydro-1-benzofuran-5-yl, 3-forfinal, 4-(trifluoromethyl)phenyl, 4-fluoro-3-(trifluoromethyl)phenyl, 4-(1,1-dimethylethyl)phenyl, 3, 5dimethylphenyl, 4-hydroxyphenyl, 3,4-dimetilfenil, 3-methyl-4-(methoxy)phenyl, 4-hydroxy-3-were, 3-were, 2,3-dihydroindol-5-yl, 2-were, 2,6-bis(metiloksi)phenyl, 2,6-dihydroxyphenyl, 4-chlorophenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 4-((trifluoromethyl)oxy)phenyl, 4-ethylphenyl, 4-(ethyloxy)phenyl, methyl, 2-propyl or 4,5-dihydro-1,3-oxazol-2-yl.

Two independent groups of R1, R2, R3or R5can be combined with the formation of the loop.

R4and R11may be associated with education is receiving cycle, along with other, such as 1-pyrrolidino, 1-piperidino, 4-methyl-1-piperazine derivatives, 4-acetyl-1-piperazine derivatives and 4-morpholino.

R9and R10may be associated with the formation of the loop, along with other such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Reduction

In the schemes and in the examples the following abbreviations are used: SIDE by means of tert-butyloxycarbonyl, DMF means dimethylformamide, THF means tetrahydrofuran, DME means dimethoxyethane, DMSO means dimethylsulfoxide, NMM means N-methylmorpholin, DIPEA means diisopropylethylamine, the OED means 1,1'-carbonyldiimidazole, TBS means salt of TRIS-buffer solution, MS means methanesulfonyl, TMEDA means N,N,N',N'-tetramethylethylenediamine, EDC means 1,2-dichloroethane, NCS means N-chlorosuccinimide, NBS means of N-bromosuccinimide, DFFA means diphenylphosphinite, DEAD means diethylazodicarboxylate, TFW means anhydride by triperoxonane acid, DHM means dichloromethane, BCMAL means bis(trimethylsilyl)amide lithium CBS means benzyloxycarbonyl.

For amino acids following abbreviations are used: With means L-cysteine, D is L-aspartic acid, E means of L-glutamic acid, G denotes glycine, N means L-histidine, I mean L-isoleucine, L mean L-leucine, N means L-asparagine, R mean L-Proline, L Q means-glutamin, S means L-serine, T mean L-threonine, V means L-valine, W stands for L-tryptophan.

Examples of methods that can be used to obtain compounds of the above formulas on the following synthesis schemes. Detailed description of typical compounds of the present invention are described in the examples below.

The method described in example 1.

The method described below in example 2.

The method described below in example 3.

The method described below in example 4.

The method described below in example 5.

The method described below in example 6.

The method described below in example 7.

The method described below in example 8.

The method described below in example 9.

The method described below in example 10.

The method described below in example 11.

The method described below in example 12.

The method described below in example 13.

The method described below in example 14.

The method described below in example 15.

The method described below in example 16.

The method described below in example 17.

The method described below in example 18.

The method described below in example 19.

The method described below in example 20.

The method described below in example 21.

The method described below in example 22.

The method described below in example 23.

The method described below in example 24.

The method described below in example 25.

The method described below in example 26.

The method described below in example 27.

The method described below in example 28.

The method described below in example 29.

The method described below in example 30.

The method described lower the in example 31.

Compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from organic and inorganic acids. The definition of "pharmaceutically acceptable salt" refers to those salts which are, according to current medical opinion, suitable for contact with the tissues of humans and lower animals without causing visible signs of toxicity, irritation, allergic response and the like, and consistent with the acceptable value of benefit/risk. Pharmaceutically acceptable salts are known in the art. For example, S.M.Berge et al. describe pharmaceutically acceptable salts in the article J.Pharmaceutical Sciences, 1977, 66:1. Salt can be prepared in situ during the final phase of isolation and purification of the compounds according to the invention or on a separate stage by reacting the free base with a suitable organic acid. Typical acid additive salts include, without limitation, acetate, adipate, alginate, citrate, aspartate, benzoate, bansilalpet, bisulfate, butyrate, comfort, camphorsulfonate, digluconate, glycyrrhizinate, hemisulfate, heptanoate, hexane is at, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonic (isetionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluensulfonate, undecanoate. Additionally, basic nitrogen containing groups may form a Quaternary ammonium base with such agents as lower alkylhalogenide, such as methyl, ethyl, propyl and butylchloride, bromides and iodides, diallylsulfide, such as dimethyl, diethyl, dibutil and dimycolate, long chain halides such as decyl, lauryl, miriti and sterilgarda, bromides and iodides, arylalkylamine, such as benzyl and phenetermine and others With the help of this technique get water or oil-soluble or dispersible products. Examples of acids that can be used in the form of a pharmaceutically acceptable acid additive salts include such inorganic acids as hydrochloric acid, Hydrobromic acid, sulfuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.

Basically additive salts can be obtained in situ during the final phase of isolation and purification connect the deposits according to the invention by the interaction of the compounds carrying a carboxyl group with a suitable base such as the hydroxide, carbonate or bicarbonate pharmaceutically acceptable metal cation or ammonium, or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, without limitation, salts of cations of alkali or alkaline-earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum and the like, and nontoxic Quaternary cations amonia and Amina, including among other ammonium, Tetramethylammonium, tetraethylammonium, methylammonium, dimethylammonium, ammonium, triethylammonium, diethylammonium and ethylamine. Other typical organic amines used to obtain additive salts include Ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, etc.

Dosage forms for topical administration of the compounds of the present invention include powders, sprays, ointments and medicinal forms for inhalation. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffer substances and gases-displacers that may be required. In the scope of the present invention also includes compositions for use in ophthalmology, eye ointments, powders and solutions.

The actual dose levels the active components in pharmaceutical compositions according to the invention can be modified in such a way, to get the number of active connections (connections), effective to achieve a desired therapeutic effect for a particular patient, compositions, or as a way of introduction. The selected dose will depend on the activity of the particular compound, the route of administration, the severity of the disease to be treated, and the patient's condition and medical history of the patient to be treated. However, the initial dose of the active compounds below the level required to achieve a therapeutic effect, and gradually increasing doses to achieve the desired effect will be determined by a qualified technician.

When used for the above or other purposes therapeutically effective amount of one of the compounds of the present invention can be used in pure form or, if such form is available, in the form of a pharmaceutically acceptable salt of ester or prodrug.

Alternatively, the connection can be introduced in the form of pharmaceutical compositions that contain the compound in combination with one or more pharmaceutically acceptable excipients. The definition of "therapeutically effective amount" of the compounds according to the invention means an amount of compound sufficient for the treatment of disorders with an acceptable/benefit ratio for rice is, set for any kind of therapy. However, it should be understood that the total daily intake of the compounds and compositions of the present invention will be determined by the attending physician in accordance with current medical opinion. The specific level of therapeutically effective dose for any particular patient will depend on many factors: violations to be treated, the severity of the violation, the activity of the specific compound employed specific composition, age, body weight, General health, sex and diet of the patient, time of administration (drug), route of administration, rate of excretion of the specific compound, the duration of treatment, concomitant drugs used in combination or simultaneously with a specific connection, and other factors known in the medical practice. For example, the initial dose of active compound at the level below the required dose to achieve a therapeutic effect and gradually increase the dosage to achieve the desired effect will be determined by a qualified technician.

The total daily dose of the compounds according to the invention to be administered to a human or lower animal, is in the range from about 0.0001 to about 1000 mg/kg/day. When ingested is more preferred dose may be in the range of from about 0.001 to about 5 mg/kg/day. If necessary, the effective daily dose may be divided for introduction into several portions, respectively, single dose compositions may contain such number of doses or portions, which correspond to a daily dose.

The present invention relates also to the development of pharmaceutical compositions comprising compounds of the present invention, processed in a mixture with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions may be specially prepared for oral administration in solid or liquid form, for parenteral injection, or for rectal administration.

The pharmaceutical compositions of the present invention can be introduced into humans and other mammals orally, rectally, intracavitary, intravaginal, intraperitoneal, local (powders, ointments and drops), transbukkalno ways or in the form of an oral or nasal spray. The term "parenteral" refers to introduction methods (drugs), which includes intravenous, intramuscular, intraperitoneal, vnutrigrudne, subcutaneous and intraarticular injection and infusion.

Another aspect of the present invention to provide pharmaceutical compositions comprising a component according to the present izobreteniya physiologically tolerable diluent. The present invention includes one or more compounds described above, processed into compositions together with one or more non-toxic physiologically tolerable or acceptable diluents, carriers, adjuvantly or fillers, which are all together in this text are referred to as "diluents" and which are intended along with other introduction methods for parentrule injection, intranasal delivery, for oral administration in solid or liquid form, for rectal or topical administration.

The composition may also be introduced to the local way through the catheter directly to the site of the target via intracoronary stent (a tubular device composed of a thin wire mesh) or by using biodegradable (rasskazyvaemoe in the body of the polymer. Connections can also be obtained in the form of complexes with ligands such as antibodies, with the aim of delivering targeted.

Compositions for parenteral injection may include physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders intended for preparation of sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethane is l, polyols (propylene glycol, polyethylene glycol, glycerin and the like), vegetable oils (such as olive oil), injectable esters such as ethyl ester of oleic acid, and their suitable mixtures.

These compounds may also contain an adjuvant, such as preserving, wetting, emulsifying and dispersing agents. Prevention of the development of microflora can be achieved by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, etc. May also be needed for the introduction of isotonic agents such as sugars, sodium chloride, etc. Prolonged absorption of the injectable pharmaceutical form can be achieved through the use of agents that slow the absorption such as aluminum monostearate and gelatin.

Suspensions, in addition to the active compounds, may contain suspendresume agents, for example ethoxylated isostearyl alcohols, esters of polyoxyethylenesorbitan and sorbitan, microcrystalline cellulose, Metagalaxy aluminum, bentonite, agar-agar and tragakant, or mixtures of these compounds, etc.

In some cases, prolongation of drug action is necessary to slow down the absorption of drugs for subcutaneous or intramuscular, inyecci is. This can be achieved by applying a liquid suspension of crystalline or amorphous material with poor water-solubility. In this case, the speed of absorption of the medicinal product depends on the rate of dissolution, which in turn may depend on the size of the crystals and crystalline forms. Alternatively, delayed absorption of the drug form, introduced parenterally, is achieved by dissolving or suspendirovanie medicines in oil.

Injecting a prolonged form get in the form of microencapsulated matrix of the drug in biodegradable polymers such as polylactide-polyglycol. The rate of release of drug can be adjusted depending on the ratio of drug/polymer and the nature of the particular polymer. Examples of other biodegradable polymers include poly(orthoevra) and poly(anhydrides). Prolonged injectable formulations produce also the immersion of the drug in liposomes or microemulsions that are compatible with body tissues. Injectable formulations can be sterilized, for example, by filtration through a filter for retention of bacteria or incorporating sterilizing agents in the form of sterile solid compositions, which can dissolve the sludge is to dispergirujutsja in sterile water or other sterile injectable medium immediately before use.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms the active compound may be mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) carriers or extenders, such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and the Arabian gum, C) humectants such as glycerol, d) dezintegriruetsja agents, such as agar-agar, calcium carbonate, potato starch and starch from tapioca starches, alginic acid, certain silicates and sodium carbonate, e) agents, retarding dissolution such as paraffin, f) absorption accelerators such as Quaternary ammonium compounds Foundation, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and I) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills dosage form may also comprise buffering agents.

Solid compositions of a similar type can also COI is lesofat as fillers in soft and hard gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like

Solid dosage forms such as tablets, pills, capsules, pills and granules can be produced by coating and shell, such as intersolubility coating and other coatings known in the field of pharmaceutical compositions. By choice they may contain contrast agents or can be obtained in the form of compositions which release the active ingredient (s) only or preferably in a certain area of the gastrointestinal tract, optionally in the extended form. Examples of the enveloping compositions that may be used include polymers and waxes.

The active compounds can also be manufactured in microencapsulated form, if appropriate, with one or more of the above-mentioned fillers.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl ester benzoic acid, propylene glycol, 1,3-Buleleng icol, dimethylformamide, oils (primarily, cottonseed oil, peanut oil, corn oil, wheat germ oil, olive oil, castor oil and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycols and esters of fatty acids and sorbitan and mixtures thereof.

Besides inert diluents, the compositions for oral administration can also include an adjuvant, such as wetting agents, emulsifying and suspendresume agents, sweeteners, flavorings and fragrances.

Compositions for rectal and vaginal injection are preferably suppositories which can be obtained by mixing the compounds of the present invention with suitable, not causing irritation fillers or carriers such as cocoa butter, polyethylene glycol or a wax which is solid at room temperature, but melts at body temperature and therefore melt in the rectal or vaginal cavity and release the active compound.

Compounds of the present invention can also be introduced in the form of liposomes. As is known in the art, liposomes mainly derived from phospholipids or other lipids. Liposomes form a mono - or multi-layer hydrated liquid crystals that are dispersed in the aquatic environment. For these the oil can be used any non-toxic, physiologically acceptable and metabolisable a lipid capable of forming liposomes. The compositions of the present invention in liposomal form can contain, in addition to the compounds of the present invention, stabilizers, preservatives, fillers, etc. Preferred lipids are natural and synthetic phospholipids and phosphatidylcholine (lecithins), which can be used separately or in combination.

Methods of obtaining liposomes known in the art. See, for example, in the review of Methods in Cell Biology (Methods in cell biology) (1976), .XIV, ed Prescott, Academic Press, New York, N.Y., pages 33 and forth.

The term "pharmaceutically acceptable prodrugs"as used herein, means those prodrugs of the compounds of the present invention, which, according to current medical opinion, suitable for contact with the tissues of humans and lower animals without visible signs of toxicity, irritation, allergic response and the like, correspond to the acceptable value of benefit/risk and effective in use, and, if possible, indicate zwitter-ionic forms of the compounds according to the invention. Prodrugs of the present invention can quickly be transformed in vivo with the formation of the parent compound of the above formula, for example, hydrolysis in the blood. Detail is the first discussion of this issue is given in the publication .Higuchi, V.Stella, Pro-drugs as Novel Delivery Systems (Prodrugs as new delivery systems), t, A.C.S. Symposium Series, and in Bioreversible Carrirers in Drug Design (Bioapatite media in the construction of medicines), Ed. by Edward C. Roche, American Pharmaceutical Association and Pergamon Press (1987), included in the text of the application as references.

Compounds of the present invention, which are formed during the conversion in vivo of another connection, which was administered to a mammal, is included in the scope of the present invention.

Compounds of the present invention can exist in the form of stereoisomers, which contain asymmetric or chiral centers. Such stereoisomers are indicated by the symbols "R" or "S" depending on the configuration of the substituents at the chiral carbon atom. The present invention includes various stereoisomers and mixtures thereof. Stereoisomer include enantiomers and diastereoisomers, and also mixtures of enantiomers and diastereomers. Individual stereoisomers of compounds of the present invention can be obtained synthetically from commercially available preparatov parent compounds, which contain asymmetric or chiral centers or by obtaining racemic mixtures followed by their separation methods known to experts in this field of technology. These methods include, for example, (1) the linking of a mixture of enantiomers with hee the social auxiliary substance, separation of the resulting mixture of diastereomers by recrystallization or chromatography and the separation of the optically pure product from the auxiliary substances, (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.

Compounds according to the invention can exist in resolutiony, as well as in solvated forms, including hydrated forms, such as polyhydrate. Usually for the purposes of the invention solvated forms with pharmaceutically acceptable solvents such as water and ethanol, along with other solvents, identical nonsolvated forms.

Another aspect of the present invention includes a method of inhibiting the binding of α4β1integrin with VCAM-1. The method according to the present invention can be used in vitro or in vivo. In accordance with the method according to the present invention, a cell expressing α4β1integrin, enter in contact with the cell expressing VCAM-1, in the presence of an effective inhibiting amount of the compounds of the present invention.

Cell expressing α4β1integrin may be natural leukocyte, the fat cell (mastocytoma) or other cell type that expresses α4β1in the body at the cellular surface is, or a cell transformed (transfectional) expression vector containing polynucleotide (e.g., genomic DNA or cDNA)encoding α4β1integrin. In the most preferred variant of the embodiment of the invention α4β1integrin is present on the surface of a leukocyte, such as a monocyte, lymphocyte or granulocyte (for example, eosinophil or basophil).

Cell that expresses VCAM-1 may be natural cell (e.g., endothelial cell) or a cell transformed (transfectional) vector expresii containing polynucleotide that encodes VCAM-1. Methods of obtaining transfected cells expressing VCAM-1, are known in the art.

In the case when VCAM-1 is present on the cell surface, preferably expression is induced by inflammatory cytokines, such as αtumor necrosis factor, interleukin-4 and interleukin-1β.

If the body has cells expressing α4β1integrin and VCAM-1, in a living organism is administered an effective amount of the compounds of the present invention. The connection is preferably a pharmaceutical composition of the present invention. The method according to the present invention are primarily used in the treatment of diseases associated with h is controlled by the migration of leukocytes to the damaged tissue. Such diseases include, without limitation, asthma, atherosclerosis, rheumatoid arthritis, Allergy, multiple sclerosis, lupus, inflammatory bowel, graft rejection, contact allergies, diabetes, leukemia and brain tumor. The introduction is preferably intravascular way, subcutaneous, intranasal, transdermal or oral method.

The present invention relates also to a method of selective inhibition of binding α4β1integrin protein, comprising contacting the integrin protein in the presence of an effective inhibiting amount of the compounds of the present invention. In a preferred variant embodiment of the invention, α4β1integrin is expressed on the cell surface, natural or transformed with the aim expresii α4β1integrin.

Protein is associated with α4β1integrin, can be expressed either on the cell surface, or to be part of the extracellular matrix. Preferred proteins are primarily fibronectin or invasin.

Property of the compounds of the present invention to inhibit the binding is described in detail in the following premaraj. These examples are presented to describe preferably the x variants of the embodiment and fulfillment of the invention and, unless otherwise stated, do not limit the scope of the claims of the invention as it is claimed in the attached claims.

Example 1

Synthesis of (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-ethyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid (10).

Stage 1: Compound 1 (20,8 g, 135 mmol) was dissolved in methanol (270 ml) and added palladium on coal (10% Pd on dry weight, firm Degussa type E101 NE/W, ˜50% water, 5.75 g, 2.7 mmol Pd). The atmosphere in the flask was replaced with hydrogen (five switch the valve between the vacuum line and the balloon with hydrogen, the mixture is stirred overnight, then filtered. The filtrate was concentrated in vacuo, the residue is transferred into a mixture of hexane/ethyl acetate (1:1) and washed with a mixture of water/saturated solution of NaHCO3(4:1), saturated solution Manso3and a salt solution. The organic layer is dried over MgSO4, filtered, the filtrate is concentrated under reduced pressure to thus obtain compound 2 (12,43 g, 74%) as a solid white color. The compound obtained is used without purification.

Stage 2: Compound 2 (2.64 g, is 21.3 mmol) dissolved in dichloromethane (50 ml) and cooled to 0°C. the Cold solution was sequentially treated with triethylamine (3.6 ml, 25.6 mmol) and trimethylacetylchloride (2,90 ml of 23.4 mmol). The solution was stirred at room temperature for 6 h, and ZAT is m refluxed over night. The mixture is partitioned between dichloromethane and aqueous NaOH solution (2 BC). The organic layer was washed with brine, dried over MgSO4filter, concentrate the filtrate, while getting connection 3 (3.33 g, 75%).

Stage 3: Compound 3 (0.50 g, 2.4 mmol) dissolved in dry THF (9.6 ml) and TMEDA (1.1 ml, 7.2 mmol) in dry nitrogen atmosphere. The resulting solution was cooled to a temperature of from -20°-10°and sequentially treated with n-butyllithium (1.6 M solution in hexane, to 2.25 ml) and tert-butyllithium (1.7 M solution in pentane, 2.1 ml), adding reagents dropwise with a syringe. After 30 minutes the bath temperature was raised to-5-0°and treat ethyliodide (of 0.77 ml, 9.6 mmol), adding the reagent with a syringe. The solution was stirred at 0°C for 2 h and then at room temperature overnight. The reaction is stopped by the addition of methanol and the mixture concentrated to dryness. The residue is purified by filtration through silica gel, elute with a mixture of hexane/ethyl acetate 3:1 and then recrystallized from hexane, thus obtain compound 4 (0.32 g, 56%).

Stage 4: Compound 4 (0.32 g, 1.3 mmol) was dissolved in glacial acetic acid (4.5 ml) and treated with potassium iodide (0.65 g, 3.9 mmol). The resulting mixture is heated on an oil bath set at 115°With, for 1.0 hours the Mixture is cooled, diluted with water and using 2 N. NaOH and 2 N. HCl Dov is completed the pH to 6. The mixture is extracted with chloroform (4 times). The combined extracts are washed with aqueous sodium thiosulfate, dried over MgSO4and filtered. The filtrate is concentrated under reduced pressure, you get a connection 5 (0.25 g, 86%) as a solid white color. The compound obtained is used without further purification.

Stage 5: Compound 5 (0.25 g, 1.1 mmol) dissolved in THF (45 ml) and treated dropwise with a solution of bis(trimethylsilyl)amide potassium (0.5 M in toluene, 2.7 ml) at 0°C. the resulting solution was treated with 2-chlorobenzylamino (0.16 ml, 1.2 mmol) and incubated at room temperature overnight. The mixture is partitioned between 2 N. HCl and ethyl acetate. The organic layer was washed with brine, dried over MgSO4and filtered. The filtrate is concentrated under reduced pressure and the residue purified by chromatography (SiO2the elution is conducted with a mixture of hexane/ethyl acetate in a gradient from 4:1 to 2:1), you get a connection 6 (0.16 g, 41%).

Stage 6: Compound 6 (0.16 g, 0.46 mmol) is suspended in a mixture of water/concentrated HCl 1:1 (4.6 ml). The suspension is refluxed for 4 h, and the connection dissolves. The mixture is cooled, diluted with water and extracted with diethyl ether. The aqueous layer was alkalinized with an excess of a saturated solution of sodium bicarbonate and the mixture extracted with ethyl acetate. The extract is combined washed with brine, dried over MgSO4and filtered, the filtrate is concentrated under reduced pressure, you get a connection 7 (of 0.081 g, 67%).

Step 7: Compound 7 (0,080 g, 0.30 mmol) dissolved in 1,2-dichloroethane (1.2 ml) and DIPEA (0,115 ml, 0.66 mmol) and cooled to 0°C. the Cold solution is quickly treated with a solution of phosgene (1.93 and M in toluene, 0,170 ml, 0.33 mmol). After 30 minutes add quickly syringe compound 8 (0,068 g, 0.33 mmol) in 1,2-dichloroethane (0.5 ml). The resulting mixture was heated at 55°C for 1 h the Mixture was partitioned between dichloromethane and 2 N. HCl. The organic layer was washed with saturated aqueous Manso3and brine, dried over MgSO4and filtered. The filtrate is concentrated and thus obtain compound 9 (0,110 g, 74%).

Step 8: Compound 9 (0.11 g, 0.22 mmol) dissolved in a mixture of THF/N2About 2:1 (0,88 ml) and 2 N. NaOH solution (0.33 ml). Then added dropwise methanol to the formation of homogeneous solution. The mixture is stirred for 20 min, diluted with water and washed with ethyl ether. The aqueous layer was acidified with 2 N. HCl and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over MgSO4and filtered. The filtrate is concentrated and thus obtain (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-ethyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]-amino}-3-(4-were)propionic acid (compound 10, 0,095 g, 92%).

Example 2

Synthesis of (3S)-3-{[({6-methyl-2-oxo-1-(phenylmethyl)-4-[(phenylmethyl)oxy]-1,2-dihydro-3-pyridinyl}amino)carbonyl]-amino}-3-(4-were)-propionic acid (15).

Step 1: To a suspension of compound 11 (1.0 g, 5.9 mmol) and K2CO3(2,40 g, 17.6 mmol) in acetone (50 ml) add benzylbromide (2,31 g, 13.5 mmol). After heating under reflux overnight, the reaction mixture was cooled and distributed between ethyl acetate and saturated NaHCO3. The organic layer is washed with diluted HCl and brine, dried over MgSO4and filtered. The filtrate is concentrated and thus obtain compound 12 (1.60 g, 80%).

Stage 2: Compound 12 (0,30 g, 0.86 mmol), powdered zinc (0,30 g, 4.6 mmol) and saturated aqueous NH4Cl (0,30 ml) is stirred Meon (18 ml). The resulting mixture was stirred at room temperature for 1 h, and then add an additional amount of zinc (0,30 g, 4.6 mmol). The obtained heterogeneous mixture is heated under reflux during the night. After filtration of the hot mixture and concentrating the filtrate under reduced pressure the residue is dissolved in ethyl acetate and washed with saturated aqueous NaHCO3and a salt solution. The organic layer is dried over MgSO4and filtered, the filtrate is concentrated under reduced pressure, you get a connection 13 (0.18 g, 66%).

Stage 3: Compound 1 (0,30 g, to 0.94 mmol) and DIPEA (and 0.40 ml, 2.3 mmol) dissolved in CH2Cl2and cooled to 0°C. To the resulting solution was added dropwise phosgene (1.9m in toluene, of 0.55 ml, 1.0 mmol). The reaction mixture was stirred at 0°C for 15 min, and then added compound 8 (0,19 g of 0.94 mmol) in CH2Cl2(2 ml). The resulting solution was stirred at room temperature overnight and then poured into ethyl acetate and washed with saturated aqueous NaHCO3, 1 N. HCl and brine. The organic layer is dried over MgSO4and filtered, the filtrate is concentrated under reduced pressure. Purify the residue rapid chromatography on silica gel, elution is conducted with a mixture of hexane/ethyl acetate in a gradient from 1:1 to 1:2, you get a connection 14 (0.33 g, 64%).

Stage 4: a Solution of compound 14 (0.33 g, 0.6 mmol) in THF (6 ml) is treated with 2 N. NaOH (2 ml). Add Meon to obtain a homogeneous solution. The reaction mixture was stirred at room temperature for 30 min and poured into H2O (50 ml). The aqueous layer was washed with diethyl ether (twice), and then acidified with 1 N. HCl. The aqueous layer was extracted with ethyl acetate (twice). The combined ethyl acetate extracts washed with brine (twice), dried over MgSO4and filtered. The filtrate is concentrated under reduced pressure to thus obtain (3S)-3-{[({6-methyl-2-oxo-1-(phenylmethyl)-4-[(phenylmethyl)is XI]-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid (15, 0.26 g, 90%) as a solid off-white color, TPL 124-126°C.

Example 3

Synthesis of (3S)-3-{[({4-amino-1-[(2-chlorophenyl)methyl]-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid (22).

Step 1: To a solution of compound 11 (10,00 g, 58.8 mmol) in anhydrous DMF (120 ml) at 0°add NaH (60% dispersion in mineral oil, of 5.40 g, 135 mmol). The reaction mixture was stirred at 0°C for 15 min, and then add 2-chlorobenzylchloride (12.3 g, to 76.4 mmol). After stirring at 55°overnight the mixture was poured into ice-cold water and twice washed with Et2O. the Aqueous layer was acidified and the precipitate is filtered off, you get a connection 16 (14,7 g, 85%).

Stage 2: In a flask containing compound 16 (8.00 g, 28.6 mmol), tightly closed with a rubber septum and connected to the container with dry nitrogen at room temperature using a syringe add POCl3(30,0 ml, 322 mmol). Line nitrogen supply is cut off and the reaction mixture is stirred at 70°C overnight, then poured into ice (300 ml) and stirred for 30 minutes the reaction mixture is extracted with dichloromethane (300 ml) and the organic phase is dried over MgSO4and filtered. The filtrate is concentrated under reduced pressure, you get a connection 17 (7,3 g, 86%) as a solid dark brown color.

Stage 3: In a flask with a volume of 250 ml, equipped with a fridge and a rubber septum and connected to the container, add at room temperature a solution of compound 17 (2.1 g, 7.05 mmol), methanol (55 ml) and aqueous ammonium hydroxide (28-30%, 70,0 ml of 1.14 mol). The reaction mixture is heated at 65°C for 60 h, the flask is connected only to the cylinder. The mixture is filtered and the filtrate concentrated under reduced pressure, you get a connection 18 (1.5 g, 76%) as a solid brown color.

Stage 4: To a solution of compound 18 (0.3 g, of 1.02 mmol) in methanol (50 ml) successively added at room temperature, saturated aqueous ammonium chloride (2 ml) and zinc dust (0,30 g, 4.6 mmol). After stirring for 30 min at room temperature add an additional amount of zinc (0,30 g, 4.6 mmol) and the reaction mixture refluxed overnight. The reaction mixture is filtered while hot and the filtrate is concentrated under reduced pressure. The residue is distributed between ethyl acetate and 1 N. NaOH. The solution is filtered and the aqueous phase extracted with ethyl acetate. The combined organic phases are dried over MgSO4and filtered. The filtrate is concentrated under reduced pressure, you get a connection 19 (0.21 g, 78%) as a solid brown color.

Stage 5: a Solution of the compounds is of 19 (0.10 g, 0.38 mmol), NMM (0,040 ml, 0.38 mmol) and compound 20 (0.14 g, 0.38 mmol) in anhydrous DMF (5 ml) is heated at 50°With during the night. The mixture is cooled and diluted with ethyl acetate (60 ml). The organic layer is washed with 0.5 N. NaOH (3×30 ml) and brine, dried over MgSO4and filtered. The filtrate is concentrated under reduced pressure and the residue purified rapid chromatography on silica gel, elution is conducted with a mixture of CHCl3/Meon in a gradient from 9:1 to 17:3, you get a connection 21 (0,120 g, 65%) as a yellow foam.

Step 6: a Solution of compound 21 (0,120 g, 0.25 mmol) in THF (6 ml) is treated with 2 N. NaOH (2 ml). Add methanol to obtain a homogeneous solution. The reaction mixture was stirred at room temperature for 30 min and poured into H2About (50 ml). The aqueous layer was washed with diethyl ether (twice), and then acidified with 1 N. HCl. The aqueous layer was extracted with ethyl acetate (twice). The combined ethyl acetate extracts washed with brine (twice), dried over MgSO4and filtered. The filtrate is concentrated under reduced pressure to thus obtain (3S)-3-{[({4-amino-1-[(2-chlorophenyl)methyl]-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid (compound 22, 0,100 g, 89%) as a solid off-white color, TPL 145-147°C.

Example 4

Synthesis of (3S)-3-[({[1-[(2-chlorophenyl)methyl]-4-(metiloksi)2-oxo-1,2-dihydro-3-pyridinyl]amino}carbonyl)amino]-3-(4-were)propionic acid.

Step 1: To a solution of compound 23 (10,00 g, 64,0 mmol) in anhydrous DMF (130 ml) at 0°add NaH (60% dispersion in mineral oil, 5,90 g, 147 mmol). The reaction mixture was stirred at 0°C for 15 min, and then add 2-chlorobenzylchloride (13,4 g, and 83.3 mmol). After stirring at 55°overnight the mixture was poured into ice-cold water and twice washed with Et2O. the Aqueous layer was acidified and the precipitate filtered off, you get a connection 24 (13.5 g, 75%).

Stage 2: a Suspension of compound 24 (1.0 g, 3.6 mmol), K2CO3of 0.85 g, 6.2 mmol) and Mel (1.18 g, 8.3 mmol) in acetone (20 ml) is heated under reflux during the night. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous NaHCO3, 1 N. HCl and brine. The organic layer is dried over MgSO4and filtered. The filtrate is concentrated under reduced pressure, you get a connection 25 (0.74 g, 70%).

(3S)-3-[({[1-[(2-chlorophenyl)methyl]-4-(metiloksi)-2-oxo-1,2-dihydro-3-pyridinyl]amino}carbonyl)amino]-3-(4-were)propionic acid is obtained from compound 25 in accordance with the methods described in example 3. MS calculated: (M+N)+=469,93; found: (M+N)+=470,01.

Example 5

Synthesis of (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-fluoro-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)-propionic acid.

Stage 1: Connection 3 (0.65 g, 3.1 mm is l) dissolved in dry THF (12,4 ml) and TMEDA (0,90 ml, 6 mmol) in dry nitrogen atmosphere. The resulting solution was cooled to a temperature of from -15 to -10°and via syringe is added dropwise n-utility (1.6 M in hexane, of 7.75 ml, 12.4 mmol). After 1.5 h to a cold solution using a syringe quickly add a solution of N-forbindelseshastighed (1.07 g, 3.4 mmol) in THF (5 ml). The solution was stirred at 0°C for 1 h and then at room temperature for 3 hours the Reaction is stopped by the addition of water and the mixture extracted with chloroform (4 times). The combined organic extracts washed with brine, dried over MgSO4and filtered. The filtrate is concentrated under reduced pressure and the residue purified by chromatography (SiO2the layer of gel, the elution is conducted with a mixture of hexane/ethyl acetate 4:1 then 3:1), you get a connection 26 (0,177 g, 25%).

(3S)-3-{[({1-[(2-chlorophenyl) methyl]-4-fluoro-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid is obtained from compound 26 in accordance with the techniques described in example 1. MS calculated: (M+N)+=458,12; found: (M+N)+=458,01.

Example 6

Synthesis of (3S)-4-chloro-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid.

Stage 1: Connection 3 (0.65 g, 3.1 mmol) dissolved in THF (21 ml) and TMEDA 1,20 ml of 7.75 mmol), cooled to -15°C. the Solution is treated with n-buta what lithium (1.6 M in hexane, 4.8 ml, 7.8 mmol). The mixture was kept at a temperature of from -20° -10°S, and then cooled to -78°C. Add solid M-chlorosuccinimide (0.45 g, 3.4 mmol), and the device is rinsed with stream of nitrogen under pressure. The reaction mixture was gradually warmed to room temperature and then stirred overnight. The reaction is stopped by the addition of water and the mixture extracted with chloroform (4 times). The combined organic layers dried over MgSO4and filtered. The filtrate is concentrated under reduced pressure and the residue is recrystallized from hexane, thus receive the connection 27 (0.25 g, 33%).

(3S)-4-chloro-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid is obtained from compound 27 in accordance with the techniques described in example 1.

Example 7

Synthesis of (3S)-4-bromo-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)-propionic acid.

Stage 1: Connection 3 (2.00 g, 9.6 mmol) dissolved in dry THF (32 ml) and TMEDA (2.20 ml, 14.4 mmol) in dry nitrogen atmosphere. The resulting solution was cooled to a temperature of from -20° -10°and via syringe is added dropwise n-utility (1.60 M in hexane, to 18.0 ml, 28.8 mmol). After complete addition, the solution is cooled to -78°and using a syringe added dropwise bromine (0,49 ml, 10.5 mm is eh). The solution slowly warmed to room temperature and stand overnight and then the reaction stopped by the addition of water and the mixture extracted with chloroform. The organic layer is dried over MgSO4and filtered, and the filtrate concentrated under reduced pressure. The residue is recrystallized from hexane, thus receive the connection 28 (1,32 g, 48%) as a solid yellow color.

(3S)-4-bromo-3-{[({1-[(2-chlorophenyl) methyl]-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid is obtained from compound 28 in accordance with the techniques described in example 1.

Example 8

Synthesis of (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid (32).

Step 1: To a solution of compound 24 (1.5 g, 5.3 mmol) in methanol (50 ml) successively added at room temperature, saturated ammonium chloride (1.5 ml) and zinc dust (1.5 g, 23 mmol). After stirring for 30 min at room temperature add an additional amount of zinc (1.5 g, 23 mmol) and the reaction mixture refluxed overnight. The reaction mixture is filtered while hot and the filtrate is concentrated under reduced pressure. To the obtained residue, add HCl (1 BC) to a pH of approximately 4, and the formed precipitate collected f is trovanjem, you get a connection 29 (0,80 g, 57%) as a solid brown color.

Stage 2: a Solution of compound 29 (0.26 g, 1.0 mmol) and CBI (0.25 g, 1.6 mmol) in DMF (10 ml) is heated at 70°With during the night. After cooling to room temperature the reaction mixture was diluted with ethyl acetate and washed with 1 N. HCl (3 times) and brine. The organic layer is dried over MgSO4and filtered, and the filtrate concentrated under reduced pressure, you get a connection 30 (0.14 g, 50%) as a solid brown color.

Stage 3: a Solution of compound 30 (0.1 g, 0.36 mmol) and compound 8 (0,082 g, 0.40 mmol) in anhydrous DMF (5 ml) is heated at 70°With during the night. Then the reaction mixture is cooled, diluted with ethyl acetate, washed with 1 N. HCl (3 times) and brine. The organic layer is dried over MgSO4and filtered, and the filtrate concentrated under reduced pressure. The residue is purified Express chromatography (SiO2), elute with a mixture of CHCl3/Meon 9:1, you get a connection 31 (0.17 g, 97%).

Stage 4: a Solution of compound 31 (0,170 g, 0.35 mmol) in THF (6 ml) is treated with 2 N. NaOH (1 ml). Add methanol to obtain a homogeneous solution. The reaction mixture was stirred at room temperature for 30 min and poured into H2About (50 ml). The aqueous layer was washed with diethyl ether (twice), and then acidified with 1 N. HCl. Water is a layer extracted with ethyl acetate (twice). The combined ethyl acetate extracts washed with brine (twice), dried over MgSO4and filtered. The filtrate is concentrated under reduced pressure to thus obtain (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid (compound 32, 0,150 g, 94%) as a solid off-white color, TPL 113-115°C.

Example 9

Synthesis of (3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-4-phenyl-1,2-dihydro-Z-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid.

Stage 1: Connection 33 (obtained from compound 28 in accordance with the techniques described in example 1, 0.20 g, 0.50 mmol) dissolved in DMF (1.8 ml) and water (0.7 ml), treated To a3RHO4(0.39 g, of 1.86 mmol) and phenylboric acid (0,113 g of 0.93 mmol). From the obtained reaction mixture to remove oxygen (five switch the valve between the vacuum line and the container with nitrogen, and then add tetrakis(triphenylphosphine)palladium (0) (8.7 mg, 0,050 mmol). From the mixture again to remove the oxygen, as described above, and heated at 90°With during the night. Then the reaction mixture is cooled, diluted with water and extracted with ethyl acetate (2 times). The combined extracts washed with brine, dried over MgSO4and filtered through silica gel and then concentrated under reduced pressure. The remainder suspender is in a mixture of water/concentrated HCl 1:1 (2 ml) and acetonitrile (0.5 ml). The suspension is refluxed for 1 h, then cooled and distributed between ethyl acetate and saturated aqueous NaHCO3. The ethyl acetate layer was washed with brine, dried over MgSO4and filtered, and then concentrated under reduced pressure. The residue is purified Express chromatography (SiO2, hexane/ethyl acetate 3:1), you get a connection 34 (0,115 g, 94%). The resulting substance is used without purification.

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-4-phenyl-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid is obtained from compound 34 in accordance with the techniques described in example 1.1H NMR (400 MHz, CD3OD): δ of 2.25 (s, 3H), of 2.50 (m, 2H), 4,89 (t, J=5,9 Hz, 1H), of 5.34 (s, 2H), 6,40 (d, J=7,0 Hz, 1H), 7,0 (d, J=8.0 Hz, 2H), 7,10 (d, J=8.0 Hz, 2H), 7,18 (m, 1H), 7,28 (m, 2H), 7,35 (m, 3H), 7,43 (m, 1H), 7,49 (m, 3H).

Example 10

Synthesis of (3S)-3-[({[2-methyl)-4-(2-methylpropyl)-6-oxo-1-(phenylmethyl)-1,6-dihydro-5-pyrimidinyl]amino}carbonyl)amino]-3-(4-were)propionic acid (43).

Stage 1: Compound 35 (2.00 g, 18.2 mmol) dissolved in 30 ml of dry methanol. To the resulting solution add benzylamine (1.97 g, 18.2 mmol) and triethylamine (2.0 g, 20.0 mmol). The reaction mixture was stirred at 50°C for 3 h, and then concentrated under reduced pressure. The residue is partitioned between H2O and CH2Cl2. The organic layer is dried over MgSO4and Phil is trout, and the filtrate concentrated under reduced pressure, you get a connection 36 (2.3 g, 82%).

Stage 2: To a solution of compound 37 (3.50 g, of 26.5 mmol) in ethanol (10 ml) and pyridine (5 ml) add isovaleraldehyde (2.8 ml, 27 mmol) and piperidine (1 ml). The reaction mixture was refluxed for 3 h and concentrated under reduced pressure. The residue is partitioned between 2 N. HCl (15 ml) and ethyl acetate (30 ml). The organic layer is dried over MgSO4and filtered, and the filtrate concentrated under reduced pressure. The residue is purified by chromatography on silica gel, elute with a mixture of hexane/ethyl acetate 2:1, you get a connection 38 (3.6 g, 67%).

Stage 3: a Solution of compound 38 (2.5 g, 12,48 mmol) and compound 36 (2,52 g, 13.7 mmol) in dry methanol (25 ml) intensively refluxed for 3 h, cooled and concentrated under reduced pressure. The residue is purified by chromatography on silica gel, elute with a mixture of hexane/ethyl acetate 2:1, you get a connection 39 (2,75 g, 69%).

Stage 4: To a solution of compound 39 (2.5 g, 7.9 mmol) in CCl4(15 ml) is added NBS (1.4 g, 8.0 mmol), K2CO3(11,0 g, 80,0 mmol) and benzoyl peroxide (50 mg, 0.20 mmol). The reaction mixture was refluxed for 1 h, cooled to room temperature, diluted with H2O and extracted with CH2Cl2. The organic layer is dried over MgO 4and filtered, and the filtrate concentrated under reduced pressure. The residue is purified by chromatography on silica gel, elute with a mixture of hexane/ethyl acetate 3:1, you get a connection 40 (0,62 g, 25%).

Stage 5: Compound 40 (of 0.60 g, 1.9 mmol) is treated with 2 N. NaOH (5 ml) and THF (3 ml). The reaction mixture was stirred at room temperature for 2 h, acidified with 2 N. HCl and extracted with ethyl acetate. The organic layer is dried over MgSO4and filtered, and the filtrate concentrated under reduced pressure, you get a connection 41 (560 mg, 98%).

Step 6: To a solution of compound 41 (0.56 g of 1.86 mmol) in dry benzene (10 ml) add diphenylphosphinite (0.56 g, 2.0 mmol) and triethylamine (2,02 g, 2.0 mmol). The reaction mixture is heated at 90°C for 1 h, and then add a solution of compound 8 (0.39 g, 1.9 mmol) in benzene (2 ml). The reaction mixture was stirred at 90°C for 1 h, cooled to room temperature, diluted with 10% aqueous ammonium chloride and extracted with ethyl acetate. The organic layer is dried over MgSO4and filtered, and the filtrate concentrated under reduced pressure. The residue is purified by chromatography on silica gel, elute with a mixture of ethyl acetate/hexane 7:3, you get a connection 42 (0,38 g, 40%).

Step 7: To a solution of compound 42 (0.35 g, 0.7 mmol) in a mixture of THF/Meon 1:1 (8 ml) is added 2 N. NaOH (8 ml). The reaction mixture was paramesh what happens at room temperature for 3 h, acidified with 2 N. HCl (10 ml) and extracted with ethyl acetate (20 ml). The organic layer is dried over MgSO4and filtered, and the filtrate concentrated under reduced pressure to thus obtain (3S)-3-[({[2-methyl-4-(2-methylpropyl)-6-oxo-1-(phenylmethyl)-1,6-dihydro-5-pyrimidinyl]amino}carbonyl)amino]-3-(4-were)propionic acid (compound 43, 250 mg, 75%). MS calculated: (M+N)+=477,25 m/z; found: (M+H)+=477,17 m/z.

Example 11

Synthesis of (3S)-3-[({[2-methyl-6-oxo-1-(phenylmethyl)-1,6-dihydro-5-pyrimidinyl]amino}carbonyl)amino]-3-(4-were)propionic acid.

Stage 1: a Solution of compound 36 (2.3 g, a 15.5 mmol) and compound 44 (3,36 g of 15.5 mmol) in absolute ethanol (35 ml) is refluxed for 3 h and concentrated. The residue is purified by chromatography on silica gel, elute with a mixture of ethyl acetate/hexane 1:1, you get a connection 45 (1,87 g, 55%).

(3S)-3-[({[2-methyl-6-oxo-1-(phenylmethyl)-1,6-dihydro-5-pyrimidinyl]amino}carbonyl)amino]-3-(4-were)propionic acid is obtained from compound 45 in accordance with the methods described in example 10.1H NMR (400 MHz, CD3OD): δ of 2.28 (s, 3H), of 2.35 (s, 3H), 2.57 m (m, 2H), 5,16 (m, 1H), and 5.30 (s, 2H), 7,13 (m, 4H), 7,30 (m, 5H), and 8.50 (s, 1H).

Example 12

Synthesis of (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-[({ethyl[(ethylamino)carbonyl]amino}carbonyl)amino]-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid.

The study is 1: To a solution of compound 46 (obtained in accordance with methods, described in example 3, 0.50 g, 1.8 mmol) in THF (10 ml) at 0°add NaH (60% dispersion in mineral oil, 0,23 g, 5.1 mmol). The reaction mixture was stirred at 0°C for 10 min, and then add utilizationa (0.65 g, to 9.15 mmol). The mixture is stirred at room temperature for 2 days, the reaction stopped by the addition of 1 N. HCl and the mixture extracted with ethyl acetate. The organic layer is dried over MgSO4and filtered, and the filtrate concentrated under reduced pressure, you get a connection 47 (0,60 g). The resulting substance is used without purification.

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-[({ethyl[(ethylamino)carbonyl]-amino}carbonyl)amino]-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]-amino}-3-(4-were)propionic acid is obtained from compound 47 in accordance with the methods described in example 3, TPL 128-130°C.

Example 13

Synthesis of (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-chinoline}amino)carbonyl]amino}-3-(4-were)propionic acid.

Step 1: To a solution of compound 48 (2.00 g, to 9.70 mmol) in anhydrous DMF (25 ml) at 0°add NaH (60% dispersion in mineral oil, 0,89 g, 22 mmol). The reaction mixture was stirred at 0°C for 15 min, and then add 2-chlorobenzylchloride (2,03 g, 12.6 mmol). The mixture was stirred at 55°during the night, and then poured into ice water and washed with Et2O (d is every). The aqueous layer is acidified and filtered, the resulting precipitate is a compound 49 (3,45 g). The resulting substance is used without purification.

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-chinoline}amino)carbonyl]amino}-3-(4-were)propionic acid is obtained from compound 49 in accordance with the methods described in example 8, TPL 134-136°C.

Example 14

Synthesis of (3S)-3-{[({1-[(2-chlorophenyl)methyl]-5-methyl-2-oxo-1,2-dihydro-Z-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid (56).

Step 1: To a suspension of compound 51 (1,67 g, 9,81 mmol) in DMF (33 ml) at room temperature in an atmosphere of dry nitrogen was added sequentially 2-chlorobenzylamino (1,30 ml, about 10.8 mmol) and EDCl (2.35 g, 12.3 mmol). The resulting mixture was intensively stirred at room temperature for 5 h, diluted with ethyl acetate and washed with 2 N. HCl, H2O (3 times), saturated aqueous NaHCO3and a salt solution. The organic layer is dried over MgSO4and filtered, and the filtrate concentrated under reduced pressure, you get a connection 52 (2.55 g, 100%) as a solid pale yellow color.

Stage 2: a Solution of compound 52 (555 mg, 2,17 mmol) and 3-dimethylamino-2-methylpropanal (738 mg, 6.5 mmol) in absolute ethanol (4.3 ml) and glacial acetic acid (0,22 ml) is refluxed overnight. The mixture of laidout at room temperature, dilute with ethyl acetate and washed with 2 N. HCl (twice), N2O and brine. The organic layer is dried over MgSO4and filtered, and the filtrate concentrated under reduced pressure. The residue is purified by chromatography on silica gel, elute with a mixture of hexane/ethyl acetate in a gradient from 7:3 to 1:1, then hexane/ethyl acetate/methanol 19:19:2, you get a connection 53 (182 mg, 27%) as a yellow oil.

Stage 3: To a solution of compound 53 (167 mg, 0.55 mmol) in THF (3 ml) add 2 N. NaOH (1 ml) and methanol (2 ml). The resulting mixture was stirred for 15 min, diluted with H2O and extracted with ethyl ether. The aqueous layer was acidified with 2 N. HCl and extracted with ethyl acetate. The ethyl acetate layer was washed with H2O and brine, dried over MgSO4and filtered. The filtrate is concentrated under reduced pressure, you get a connection 54 (139 mg, 91%) as a solid white color.

Stage 4: To a suspension of compound 54 (175 mg, to 0.63 mmol) in THF (6,7 ml) and DIPEA (0,23 ml of 1.34 mmol) at room temperature in a dry nitrogen atmosphere added by syringe, DFFA (0,29 ml of 1.34 mmol). The resulting mixture was stirred at room temperature for 15 min, then heated under reflux for 3.5 hours the Mixture is cooled to room temperature and add a solution of compound 8 (278 mg, of 1.34 mmol) in THF (6.0 ml) with Tr the BCI, which was washed with THF (0.7 ml). The resulting mixture was stirred at room temperature overnight, diluted with ethyl acetate and washed with 2 N. HCl (twice), saturated aqueous NaHCO3and a salt solution. The organic layer is dried over MgSO4and filtered, and the filtrate concentrated under reduced pressure. The residue is purified by chromatography on silica gel, elute with a mixture of hexane/ethyl acetate 7:3, then 3:2 and finally 1:1, you get a connection 55 (60 mg, 20%) as a colourless oil.

Stage 5: To a solution of compound 55 (60 mg, 0.12 mmol) in THF (3 ml) is added 0,192 N. NaOH (0,65 ml, 0.12 mmol) and methanol (2 ml). The resulting mixture was stirred at room temperature for 24 h, and then diluted with N2O. the Organic solvents removed under reduced pressure and the resulting aqueous mixture is extracted with ethyl ether.

The aqueous phase lyophilized, you get a sodium salt of (3S)-3-{[({1-[(2-chlorophenyl)methyl]-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid (compound 56, 56 mg, 95%) as a solid off-white color. MS calculated for (C24H23ClN3O4)-=452,14 m/z; found: 451,99 m/z.

Example 15

Synthesis of (3S)-3-(1,3-benzodioxol-5-yl)-3-[({[2-oxo-1-(2-thienylmethyl)-1,2-dihydro-3-pyridinyl]amino}carbonyl)amino]propionic acid (62).

Step 1: To a solution of 2-t is fenoterol (1,015 g, 8,89 mmol)in CH2Cl2(17,8 ml), cooled to 0°C in an atmosphere of dry nitrogen, using a syringe add successively triethylamine (2,98 ml, with 21.4 mmol) and methanesulfonamide (0,69 ml, 8.9 mmol). The resulting mixture was stirred at 0°C for 15 min, and then add 2-hydroxy-3-nitropyridine (1,496 g of 10.7 mmol) and 4-dimethylaminopyridine (catalytic amount). The reaction mixture was gradually warmed to room temperature and then stirred overnight. The mixture is diluted with ethyl acetate and washed with 2 N. HCl, H2Oh, saturated NaHCO3and a salt solution. The organic phase is dried over MgSO4and filtered, and the filtrate concentrated under reduced pressure, you get a connection 58 (395 mg) as a waxy solid yellow color. The resulting substance is used without purification.

Stage 2: To a solution of compound 58 (330 mg, of 1.40 mmol) in glacial acetic acid (6.6 ml) at room temperature in a dry nitrogen atmosphere added iron powder (154 mg, 2.8 mmol, -325 mesh). The resulting solution was heated at 60°C in an oil bath with vigorous stirring for 20 minutes the Mixture is cooled to room temperature, diluted with ethyl acetate and filtered through a layer of celite. The filtrate was washed with N2Oh, saturated NaHCO3and a salt solution. The organic phase is dried over MgSO4/sub> and filtered, and the filtrate concentrated under reduced pressure. The residue is filtered through silica gel, elute with a mixture of hexane/ethyl acetate in a gradient from 1:1 to 1:3, you get a connection 59 (188 mg, 12% after two steps) as a solid green color.

Stage 3: To a solution of compound 59 (111 mg, 0.54 mmol) in CH2Cl2(2.7 ml), cooled to 0°C in an atmosphere of dry nitrogen, using a syringe added sequentially N,N-diisopropylethylamine (0,23 ml of 1.30 mmol) and phosgene (0,31 ml, 1.9 M in toluene, 0.59 mmol). The resulting mixture was stirred at 0°C for 15 min, and then add a solution β-aminoether 60 (167 mg, 0.70 mmol) in CH2Cl2(2.7 ml) using a tube, which was washed with CH2Cl2(1.0 ml). The reaction mixture is heated to room temperature, stirred for 2 h, diluted with ethyl acetate and washed with 2 N. HCl, H2O, saturated NaHCO3and a salt solution. The organic phase is dried over MgSO4and filtered, and the filtrate concentrated under reduced pressure. The residue is purified by chromatography on silica gel, elute with a mixture of hexane/ethyl acetate 1:1, you get a connection 61 (mg, 91%) as a purple foam.

Stage 4: To a solution of ester 61 (227 mg, 0.48 mmol) in THF (6 ml) at room temperature add NaOH (2 ml, 2 N. in H2O, 4 mmol) and methanol (enough is La prepare a transparent solution, approximately 2 ml). The resulting mixture was stirred for 15 min, and then diluted with water and extracted with ether. The aqueous phase is acidified with HCl (2 BC) and extracted with ethyl acetate. The organic phase is washed with saline, dried over MgSO4and filtered, and the filtrate concentrated under reduced pressure, you get a connection 62 (191 mg, 90%) as a solid white color.1H NMR (400 MHz, CD3SOCD3): δ 2,63 (d, J=7,3 Hz, 2H), 4,99 (dt, J=8,4, 7,3 Hz, 1H), and 5.30 (s, 2H), 5,98 (m, 2H), 6,21 (dd, J=7,5, 7,0 Hz, 1H), 6,78 (dd, J=8,1, 1,6 Hz, 1H), 6,85 (d, J=8,1 Hz, 1H), to 6.88 (d, J=1.6 Hz, 1H), 6,97 (dd, J=5,1, 3.5 Hz, 1H), 7,17 (dd, J=3,5, 1.1 Hz, 1H), 7,35 (dd, J=7,0, 1.8 Hz, 1H), 7,44 (dd, J=5,1, 1,1 Hz, 1H), to 7.67 (d, J=8,4 Hz, 1H), 7,94 (dd, J=7,5, 1.8 Hz, 1H), 8,40 (s, 1H).

Example 16

Synthesis of (3S)-3-(1,3-benzodioxol-5-yl)-3-[({[(3S)-2-oxo-1-(2-thienylmethyl)hexahydro-3-pyridinyl]amino}carbonyl)amino]propionic acid (68).

Step 1: To a solution of N-αtert-butoxycarbonyl-N-δ-benzyloxycarbonyl-L-ornithine 63 (1,00 g, 2,73 mmol) and cesium carbonate (1,33 g, 4.1 mmol) in DMF (10 ml) at room temperature in a dry nitrogen atmosphere using a syringe add itmean (0,22 ml, 3.3 mmol). The resulting mixture was stirred at room temperature for 18 h and then diluted with ethyl acetate and washed with N2Oh, 10%solution of Na2S2About5saturated NaHCO3and a salt solution. The organic phase is dried over MgSO4and f is trout, and the filtrate concentrated under reduced pressure, thus receive the ester 64 (1,21 g) in the form of oil pale yellow color. The resulting product contains DMF, but is used without purification.

Stage 2: To a solution of 64 (0,86 g of the crude product obtained in the previous phase, theoretically, 1.94 mmol) in methanol (10 ml) at 0°C in an atmosphere of dry nitrogen was added palladium on coal (300 mg, 10% Pd, Degussa type E101 NE/W, wet, 50% water by weight). The atmosphere in the flask was replaced with hydrogen (five switch the valve between the vacuum line and a balloon with hydrogen and the mixture stirred at 0°C for 30 min, and then filtered directly into a flask containing 2-thiophenecarboxaldehyde (177 mg, was 1.58 mmol). The mixture of concentrate (in a water bath at room temperature) and the residue is transferred in dichloroethane (6 ml). To the resulting solution add triacetoxyborohydride sodium (479 mg, and 2.26 mmol) and the resulting mixture stirred for 2 h, diluted with ethyl acetate and washed with saturated NaHCO3(2 times) and brine. The organic phase is dried over MgSO4and filtered, and the filtrate concentrated under reduced pressure. The residue is filtered through silica gel, elute with a mixture of hexane/ethyl acetate 7:3, you get a lactam 65 (75 mg, 12% after two steps) as a colourless oil.

Stage 3: In a flask containing compound 65 (89 mg,0.29 mmol) and closed with a rubber septum, at room temperature in a dry nitrogen atmosphere using a syringe add HCl (7.2 ml, 4.0 M in dioxane, 28.8 mmol). Needle for nitrogen supply and remove the mixture in a closed flask is stirred over night. The resulting mixture was diluted with CH2Cl2and washed with saturated NaHCO3. The organic phase is dried over MgSO4and filtered, and the filtrate concentrated under reduced pressure, thus receive Amin 66 (60 mg, 100%) as oil is light yellow in color. The resulting product is used without purification.

Stage 4: To a solution β-aminoether 60 (75 mg, 0.32 mmol) in CH2Cl2(0.6 ml) at room temperature in a dry nitrogen atmosphere add carbonyldiimidazole (51 mg, 0.32 mmol). The resulting mixture was stirred at room temperature for 5 min and using a tube, which was washed with CH2Cl2(0.2 ml)add a solution of amine 66 (60 mg, 0.29 mmol) in CH2Cl2(0, 6 ml). The resulting mixture was stirred at room temperature for 3 days and then diluted with ethyl acetate and washed with 2 N. HCl (2 times), H2O, saturated NaHCO3and a salt solution. The organic phase is dried over MgSO4and filtered, and the filtrate concentrated under reduced pressure. The residue is filtered through silica gel, elute with a mixture of hexane/ethyl acetate in a gradient from 1:1 to 2:3, you get a urea 67 (110 mg, 80%).

Stage 5: It is astory urea 67 (108 mg, 0.23 mmol) in THF (3 ml) at room temperature add NaOH (1 ml, 2 N. in N2Oh, 2 mmol) and methanol (quantity sufficient to prepare a transparent solution, approximately 2 ml). The resulting mixture was stirred for 15 min, and then diluted with water and extracted with ether. The aqueous phase is acidified with HCl (2 BC) and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over MgSO4and filtered, and the filtrate concentrated under reduced pressure, you get a connection 68 (92 mg, 90%) as a white foam.1H NMR (400 MHz, CD3SOCD3): δ to 1.45 (m, 1H), 1,76 (m, 2H), 2,62 (m, 2H), 3,25 (m, overlap, H2Oh, 2H), 4,01 (m, 1H), 4,59 (d, J=to 15.0 Hz, 1H), and 4.68 (d, J=to 15.0 Hz, 1H), 4,96 (m, 1H), 5,97 (s, 2H), 6,24 (d, J=6,6 Hz, 1H), of 6.71 (d, J=8,4 Hz, 1H), 6.75 in (dd, J=8,1, 1.5 Hz, 1H), PC 6.82 (d, J=8,1 Hz, 1H), 6,85 (d, J=1.5 Hz, 1H), 6,97 (dd, J=5,1, 3.3 Hz, 1H), 7,03 (dd, J=3.3V, 1.5 Hz, 1H), 7,42 (dd, J=5,1, 1.5 Hz, 1H), 12,06 (br. s, 1H).

Example 17

Synthesis of (3S)-3-(1,3-benzodioxol-5-yl)-3-[({[(3S)-2-oxo-1-(2-thienylmethyl)tetrahydro-1H-pyrrol-3-yl]amino}carbonyl)amino]propionic acid (74).

Step 1: To a solution α-benzyl ester of N-tert-butoxycarbonyl-L-aspartic acid (2.10 g, 6.5 mmol) in dimethoxyethane (15 ml), cooled to -15°C (bath temperature)in a dry nitrogen atmosphere using a syringe add sequentially 4-methylmorpholin (of 0.71 ml, 6.5 mmol) and isobutylparaben (from 0.84 ml, 6.5 mmol). The MCA is ü stirred for 2 min, then filtered and the solid residue in the form of a pellet washed with dimethoxyethane (10 ml). The filtrate is again cooled to -15°C (bath temperature) and after addition of N2O (100 ml) immediately add a solution of sodium borohydride (370 mg, 9.7 mmol) in H2O (3 ml). The resulting mixture was extracted with ethyl acetate (3 times), the organic layers are combined and washed with cold (0° (C) HCl (0,2 N.), N2Oh, saturated NaHCO3and a salt solution. The obtained organic layer is dried over MgSO4and filtered, and the filtrate concentrated under reduced pressure, you get a connection 69 (2.50 g) as a colourless oil. The resulting product contains a number of unrecovered mixed anhydride, but is used without purification.

Stage 2: To a solution of oxalicacid (2.4 ml, 2.0 M in CH2Cl2, 4.8 mmol) in CH2Cl2(30 ml), cooled to -65°C in an atmosphere of dry nitrogen, using a syringe add solution methylsulfoxide (0,55 ml, 7.8 mmol) in CH2Cl2(8 ml). The resulting mixture was stirred at -65°C for 15 min, and then add a solution of alcohol 69 (1,00 g, 3.2 mmol) in CH2Cl2(29 ml) using a tube, which was washed with CH2Cl2(3 ml). The reaction mixture was stirred at -65°C for 3 h, and then heated to -20°C (bath temperature). Type H2O (20 ml) and tritium is n (0,96 ml, 6,9 mmol). The aqueous layer was extracted with CH2Cl2and the combined organic phases are dried over MgSO4and filtered. The filtrate is concentrated under reduced pressure, thus receive aldehyde 70 in the form of a solid white color. The resulting product is immediately used without purification.

Stage 3: To a solution of the crude aldehyde 70 (theoretical quantity 3.2 mmol) and 2-aminomethylation (402 mg, 3,55 mmol) in dichloroethane (13 ml) at room temperature in a dry nitrogen atmosphere add triacetoxyborohydride sodium (959 mg, 4.5 mmol). The resulting mixture was stirred at room temperature overnight, and then diluted with ethyl acetate, washed with saturated NaHCO3and a salt solution. The organic phase is dried over MgSO4and filtered, and the filtrate concentrated under reduced pressure. The residue is purified by chromatography on silica gel, elute with a mixture of hexane/ethyl acetate 1:1, you get a lactam 71 (220 mg, 23% after two steps) as a solid white color.

Stage 4: To a solution of compound 71 (220 mg, of 0.74 mmol) in dioxane (1.5 ml), closed with a rubber septum, at room temperature in a dry nitrogen atmosphere using a syringe add HCl (1.50 ml, 4.0 M in dioxane, 6.0 mmol). Needle for nitrogen supply and remove the mixture in a closed flask is stirred for 5 hours the mixture is diluted with the H 2Cl2and washed with saturated NaHCO3. The organic phase is dried over MgSO4and filtered, and the filtrate concentrated under reduced pressure, thus receive Amin 72 (129 mg, 89%) as oil is light yellow in color. The resulting product is used without purification.

Stage 5: To a solution of amine 72 (123 mg, 0,63 mmol) in CH2Cl2(1.5 ml), at room temperature in a dry nitrogen atmosphere add carbonyldiimidazole (112 mg, 0.69 mmol). The resulting mixture was stirred at room temperature for 5 min and using a tube, which was washed with CH2Cl2(0.2 ml)add a solution β-amino ester 60 (164 mg, 0.69 mmol) in CH2Cl2(0.8 ml). The resulting mixture was stirred at room temperature overnight, and then diluted with ethyl acetate and washed with 2 N. HCl (2 times), N2Oh, saturated NaHCO3and a salt solution. The organic phase is dried over MgSO4and filtered, and the filtrate concentrated under reduced pressure. The residue is filtered through silica gel, elute with a mixture of chloroform/methanol 49:1, you get a urea 73 (230 mg, 80%) as a colourless oil which slowly solidified upon storage.

Step 6: To a solution of urea 73 (230 mg, 0.50 mmol) in THF (3 ml) at room temperature add NaOH (1 ml, 2 N. in N2Oh, 2 mmol) and methanol (1 ml). The resulting mixture was stirred for 1 h, then R is izbavlyayut water and extracted with ether. The aqueous phase is acidified with HCl (2 BC) and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over MgSO4and filtered, and the filtrate concentrated under reduced pressure, you get a connection 74 (181 mg, 84%) as a white foam.1H NMR (400 MHz, CD3CCA3): δ of 1.64 (m, 1H), 2,30 (m, 1H), 2,64 (m, 2H), 3,20 (m, 2H), 4,17 (dd, J=8,8, and 8.4 Hz, 1H), 4,56 (s, 2H), 4,96 (m, 1H), 5,97 (s, 2H), 6,30 (d, J=7,0 Hz, 1H), return of 6.58 (d, J=8,8 Hz, 1H), 6,77 (m, 1H), to 6.80-6.90 to (m, 2H), of 6.96? 7.04 baby mortality (m, 2H), 7,45 (dd, J=5,1, 0.7 Hz, 1H), 12,10 (br. s, 1H).

Example 18

Synthesis of (3S)-3-[({[5-chloro-2-hydroxy-3-(phenylmethyl)phenyl]-amino}carbonyl)amino]-3-(4-were)propionic acid.

Step 1: To a mixture of 2-phenylmethyl-3-chlorophenol (5,00 g is 22.9 mmol) in Et2O (20 ml) and 6 N. HCl (50 ml) are added sequentially KNO3(2.30 g, is 22.9 mmol) and NaNO2(20 mg, catalytic amount). The resulting mixture was stirred for 2 h, diluted with water and extracted with ethyl acetate. The organic layer is washed with water and brine, dried over MgSO4and filtered. The filtrate is concentrated under reduced pressure, you get a connection 99 (6.0 g, 100%).

Stage 2: To a solution of compound 99 (6.0 g, of 22.8 mmol) in methanol (360 ml) is added powdered zinc (6.0 g, 92 mmol) and saturated aqueous NH4Cl (6 ml). Received a heterogeneous mixture is refluxed over night. After filtration of the hot mixture and concentrated the I of the filtrate under reduced pressure the residue is dissolved in ethyl acetate and washed with saturated aqueous NaHCO 3and a salt solution. The organic layer is dried over MgSO4and filtered, the filtrate is concentrated under reduced pressure, you get a connection 100 (with 2.93 g, 55%).

Stage 3: To a solution of compound 25 (0.20 g, 0.96 mmol) in CH2Cl2when 0°add sequentially DIPEA (and 0.40 ml, 2.4 mmol) and phosgene (1,93 M in toluene, of 0.60 ml, 1.2 mmol). The resulting mixture was warmed to room temperature, stirred for 20 min and again cooled to 0°C. To the mixture is added dropwise a solution of compound 100 (0.25 g, 1.1 mmol) in CH2Cl2. The resulting mixture was warmed to room temperature overnight, diluted with water and extracted with CH2Cl2. The organic layer is washed with water and brine, dried over MgSO4and filtered. The filtrate is concentrated under reduced pressure, the residue is purified by chromatography on silica gel, elute with a mixture of hexane/ethyl acetate in a gradient from 9:1 to 5:1, you get a connection 101 (60 mg, 12%).

(3S)-3-[({[5-chloro-2-hydroxy-3-(phenylmethyl)phenyl]-amino}carbonyl)amino]-3-(4-were)propionic acid is obtained from compound 101 in accordance with the techniques described in example 1.1H NMR (400 MHz, CD3SO2CD3): δ and 2.26 (s, 3H), 2,58 (dd, J=15,8, and 6.6 Hz, 1H), to 2.67 (dd, J=15,8, and 8.4 Hz, 1H), 3,49 (s, 2H), 4,88 (m, 1H), 7,00-of 7.70 (m, 13H), 11,95 (br. s, 1H).

Example 19

Synthesis of (3S)-3-(1,3-benzodioxol-5-the l)-3-[({butyl[2,5-dioxo-1-(phenylethyl)tetrahydro-1H-pyrrol-3-yl]amino}carbonyl)amino]propionic acid.

Stage 1: the Solution imide N-benzylmaleimide acid (2,60 g, a 13.9 mmol) and n-butylamine (1,00 g, 13.7 mmol) in THF (15 ml) was stirred at room temperature overnight and concentrated under reduced pressure. The residue is purified by chromatography on silica gel, elute with a mixture of hexane/ethyl acetate in a gradient from 4:1 to 2:1, you get a connection 102 (3.25 g, 90%).

(3S)-3-(1,3-benzodioxol-5-yl)-3-[({butyl[2,5-dioxo-1-(phenylethyl)tetrahydro-1H-pyrrol-3-yl]amino}carbonyl)amino]-propionic acid is obtained from compound 102 in accordance with the techniques described in example 1, TPL 80-85°C.

Example 20

Synthesis of (3S)-3-(1,3-benzodioxol-5-yl)-3-[({[1-(cyclopentylmethyl)-2-oxo-1,2-dihydro-3-pyridinyl]amino}carbonyl)amino]propionic acid.

Step 1: To a solution of 2-hydroxy-3-nitropyridine (200 mg, 1.4 mmol) in CH2Cl2(14 ml) at 0°C in nitrogen atmosphere add triphenylphosphine (551 mg, 2.1 mmol), and then cyclopentanemethanol (178 mg, 1.78 mmol). The solution was stirred at 0°C for 15 min using a syringe added dropwise diethyl ester of azodicarboxylic acid (366 mg, 2.1 mmol). The resulting reaction mixture was stirred at 0°C for 1 h and then at room temperature overnight. The reaction is stopped by the addition of methanol (20 ml) and the mixture washed with water (twice). The aqueous layer was extracted with dichloromethane, and unite the military organic layers are dried over magnesium sulfate and filtered. The filtrate is concentrated and the residue purified by chromatography on silica gel, elute with a mixture of hexane/ethyl acetate 1:1, you get a connection 103 (299 mg, 96%) as a solid yellow color.

(3S)-3-(1,3-benzodioxol-5-yl)-3-[({[1-(cyclopentylmethyl)-2-oxo-1,2-dihydro-3-pyridinyl]amino}carbonyl)amino]propionic acid is obtained from compound 103 in accordance with the techniques described in example 1.1H NMR (400 MHz, CDCl3): δ 1,2-1,7 (m, 8H), was 2.34 (m, 1H), 2,81(dd, 1H), 2,95 (dd, 1H), 3,92 (d, J=7.7 Hz, 2H), and 5.30 (m, 1H), of 5.92 (m, 2H), 6,30 (t, J=7,1 Hz, 1H), 6,68-7,00 (m, 5H), with 8.33 (d, J=7.7 Hz, 1H), 8,89 (s, 1H).

Example 21

Synthesis of (3S)-3-(1,3-benzodioxol-5-yl)-3-{[({3-[(2-thienylmethyl)amino]phenyl}amino)carbonyl]amino}propionic acid.

Step 1: To a solution of 2-thiophenecarboxaldehyde (of 0.48 g, 4.0 mmol) in dichloromethane add 3-nitroaniline (0.51 g, 3.7 mmol). The solution is concentrated to dryness and transferred in 1,2-dichloroethane (16 ml). Then added NaBH(SLA)3(1.01 g, 4.8 mmol) and molecular sievesThe resulting solution was stirred at room temperature overnight, diluted with chloroform and washed with water. The organic layer is dried over MgSO4and filtered, and the filtrate concentrated under reduced pressure, you get a connection 104 (0,72 g, 84%).

Stage 2: To a solution of compound 104 (0,30 g, 1.3 mmol) in CH2Cl2(5.2 ml) and triethylamine (0,215 ml, 1.5 mmol) at ° To add triperoxonane anhydride (0,193 ml, 1.4 mmol). The solution was stirred at 0°C for 15 min, the ice bath removed and the mixture is stirred for 15 minutes the Mixture was diluted with CH2Cl2washed 2 N. HCl, water and brine. The organic layer is dried over Na2SO4and filtered, and the filtrate concentrated under reduced pressure, you get a connection 105 (0,38 g, 100%) as a solid yellow color.

Stage 3: To a solution of compound 105 (or 0.38 g, 1.4 mmol) in ethanol (2.6 ml) and acetic acid (2.6 ml) at room temperature add the Fe powder (0.36 g, 6.5 mmol) and the resulting suspension is intensively stirred at 40°until, while according to the TLC will not be a complete consumption of compound 105. The mixture is filtered through a layer of celite and washed with chloroform. The filtrate is diluted with saturated sodium bicarbonate, the chloroform layer is dried over Na2SO4and filtered. The filtrate is concentrated under reduced pressure and the residue purified by chromatography on silica gel (elute with a mixture of hexane/ethyl acetate in a gradient from 6:1 to 4:1), you get a connection 106 (is 0.102 g, 25%).

(3S)-3-(1,3-benzodioxol-5-yl)-3-{[({3-[(2-thienylmethyl)amino]-phenyl}amino)carbonyl]amino}propionic acid produced from compound 106 in accordance with the techniques described in example 1.1H NMR (400 MHz, CD3SO2 CD3): δ of 2.50 (m, 2H, overlapping, DMSO), 4,37 (d, J=5,9 Hz, 2H), 4,94 (m, 1H), 5,94 (m, 2H), 6,06 (t, J=5.8 Hz, 1H), 6,16 (m, 1H), 6,59 (d, J=8,8 Hz, 1H), 6,78 (m, 3H), 6,85 (dd, J=8,8, 7.7 Hz, 1H), 6.90 to (s, 1H), 6,94 (dd, J=5,2, and 3.7 Hz, 1H), 7,00 (d, J=3.3 Hz, 1H), 7,33 (dd, J=5,1, 1.1 Hz, 1H), 8,5 (s, 1H).

Example 22

Synthesis of 3-(1,3-benzodioxol-5-yl)-2,2-debtor-3-[({[2-oxo-1-(2-thienylmethyl)-1,2-dihydro-3-pyridinyl]amino}carbonyl)amino]propionic acid.

Step 1: To a solution of (1S,2R,5S)-(+)-mentolovogo ether (R)-p-toluensulfonate acid (3.00 g, 10.2 mmol) in THF (25,5 ml), cooled to -78°With added dropwise bis(trimethylsilyl)amidite (1.0 M in THF, 15.3 ml) for 15 min. the mixture was stirred at room temperature for 6 h, and then cooled to 0°C. Quickly add piperonal (a 3.06 g, 20,4 mmol) and CsF (3,10 g of 20.4 mmol)and the suspension is stirred at room temperature for 36 hours the Reaction is stopped by the addition of saturated NH4Cl and the mixture is extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4and filtered, and the filtrate concentrated under reduced pressure. The residue is recrystallized from hexane and dichloromethane, you get a connection 108 (1,36 g, 46%).

Stage 2: To a suspension of zinc dust (2.00 g, to 30.5 mmol) in THF (20.2 ml) is added ethyl ether bradypterus acid (0,78 ml, 6.1 mmol) and refluxed for 15 minutes Suspe is the Zia cooled to 0° And add the connection 108 (0.87 g, 3.0 mmol). The resulting suspension is warmed to room temperature and stirred over night. The reaction stopped by the addition of the minimum quantity of saturated NH4Cl and the mixture is extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaHCO3and brine, dried over Na2SO4and filtered. The filtrate is concentrated under reduced pressure and the residue purified by chromatography on silica gel (elute with a mixture of hexane/ethyl acetate in a gradient from 6:1 to 4:1), you get a connection 109 (0,607 g, 61% at 80%conversion).

Stage 3: To a solution of compound 109 (0,700 g, 1.70 mmol) in methanol (4.3 ml) at 0°add triperoxonane acid (0,26 ml, 3.4 mmol). The solution was stirred at 0°C for 2 h, then concentrated to dryness under reduced pressure and at a constant ambient temperature below 30°C. the Residue is transferred in diethyl ether and washed with 2 N. HCl (2 times). The combined aqueous layers carefully alkalinized with excess saturated NaHCO3and extracted with diethyl ether. The ether layer is dried over MgSO4and filtered, and the filtrate concentrated under reduced pressure, you get a connection 110 (0,326 g, 80%).

3-(1,3-benzodioxol-5-yl)-2,2-debtor-3-[({[2-oxo-1-(2-thienylmethyl)-1,2-dihydro-3-pyridinyl]amino}carbonyl)amino]propionic acid is obtained from the connection 110 in accordance with the methods described in example 1. MS: calculated (M-H)-=476,07; found (M-N)-=476,00.

Example 23

Synthesis of (3S)-3-(1,3-benzodioxol-5-yl)-3-({[9-oxo-8-(phenylmethyl)-2,3,4,5,8,9-hexahydro-1H-pyrido[3,4-b]azepin-1-yl]carbonyl}amino)-propionic acid.

Step 1: To a solution of compound 3 (0.74 g, 3.6 mmol) in THF (14.4 ml) and TMEDA (1.60 ml, about 10.8 mmol) at -20°via syringe dropwise added sequentially n-utility (1.6 M in hexane, 3.4 ml, 5.4 mmol) and tert-utility (1.7 M in pentane, 2.5 ml, 4.3 mmol). The temperature was raised to values in the interval from -10°0°and maintain the solution within 2 hours To the mixture quickly add 1,4-dibromobutane (1.75 ml, 14.7 mmol), the solution is heated to room temperature and stirred for 4 days. The reaction is stopped by the addition of water and the mixture extracted with CHCl3(3 times). The combined extracts washed with brine, dried over Na2SO4and filtered. The filtrate is concentrated under reduced pressure and the residue purified by chromatography on silica gel (elute with a mixture of hexane/ethyl acetate, 4:1), you get a connection 111 (0,41G, 44%).

(3S)-3-(1,3-benzodioxol-5-yl)-3-({[9-oxo-8-(phenylmethyl)-2,3,4,5,8,9-hexahydro-1H-pyrido[3,4-b]azepin-1-yl]carbonyl}amino)propionic acid is obtained from compound 111 in accordance with the techniques described in example 4. MS: calculated (M-H)-=488,18; found the (M-N) -=488,21.

Example 24

Synthesis of (3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-hydroxyphenyl)propionic acid.

Step 1: To a solution of compound 112 (obtained in accordance with the methods described in example 15, 0,19 g 0,39 mmol) in CH2Cl2when 0°C in an atmosphere of nitrogen added via syringe BBr3(1.0 M in CH2Cl2, 1.2 ml, 1.2 mmol). The mixture is gradually warmed to room temperature and stirred over night. The resulting mixture was diluted with water and stirred for 30 min, and then diluted with saturated aqueous NaHCO3. The organic layer is washed with water, aqueous layers are combined and acidified with 2 N. HCl, extracted with ethyl acetate (3 times). The combined ethyl acetate layers dried over MgSO4and filtered. The filtrate is concentrated under reduced pressure to thus obtain (3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-hydroxyphenyl)propionic acid (113, 120 mg, 70%).1H NMR (400 MHz, CD3SO2CD3): δ 2,95 (d, J=5,2 Hz, 2H), 5,28 (s, 2H), 5,35 (ddd, J=9,2, 4,8, and 4.4 Hz, 1H), 6,33 (t, J=7,1 Hz, 1H), 6,60 (d, J=8,8 Hz, 2H),? 7.04 baby mortality (m, 5H), 7,22 (m, 3H), 7,37 (dd, J=7,7, 1.5 Hz, 1H), 8,35 (dd, J=7,6 and 1.5 Hz, 1H), 8,80 (s, 1H).

Example 25

Synthesis of (3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid, compound 119.

4. The resulting mixture was filtered under vacuum through a large silica gel and the filtrate concentrated under reduced pressure, you get a connection 114 (of 8.27 g, 68%) as oil is light yellow in color. The resulting material was used without additional purification.

Stage 2: RA is Toru connection 114 (3,95 g, 25,0 mmol) in anhydrous methanol (225 ml) at room temperature dropwise using a dropping funnel add a solution of 2-chlorobenzylamino (4,2 g, 30 mmol) in anhydrous methanol (25 ml). The solution is heated at 45°C overnight, then refluxed for 2 hours, the Reaction mixture was cooled to room temperature and concentrated to dryness. The residue is transferred in dichloromethane and filtered. The solid is collected and dried in a vacuum, you get a connection 115 (2.20 g, 35%) as a solid light yellow color.

Stage 3: To a suspension of compound 115 (840 mg, 3.4 mmol) in glacial acetic acid (11 ml) at room temperature successively added NaNO2(46 mg, 0.67 mmol), water (0,92 ml) and HNO3(70%to 0.85 ml of 13.4 mmol). The resulting solution was bright yellow color was stirred at room temperature overnight, then diluted with CH2Cl2and water. The aqueous phase is extracted with CH2Cl2organic layers are combined and washed with water (3 times) and brine. The organic layer is dried over MgSO4and filtered, the filtrate is concentrated under reduced pressure, you get a connection 116 (910 mg, 92%) as a solid bright yellow. The resulting material was used without purification.

Stage 4: To a solution of compound 116 (910 mg, 3.1 mmol) in DMF (10.3 ml) at room t is mperature in dry nitrogen atmosphere add the powdered zinc (909 mg, a 13.9 mmol) and triethylamine hydrochloride (2340 mg of 17.0 mmol). The resulting mixture was heated at 55°C for 2 h, then cooled to room temperature. To the resulting mixture of solid CBI (1002 mg, 6,18 mmol). When this happens the gas.

Then the mixture is heated at 80°C for 1 h, cooled to room temperature, diluted with CH2Cl2and HCl (2 BC). The aqueous layer was extracted with CH2Cl2organic layers are combined and washed with water (4 times) and brine. The organic layer is dried over MgSO4and filtered, the filtrate is concentrated under reduced pressure, you get a connection 117 (920 mg) as a solid yellow color. The resulting material contains a small amount of DMF and used without purification.

Stage 5: a Suspension of compound 117 (920 mg of the crude material, theoretically, 3.1 mmol) and compound 8 (800 mg, 3,86 mmol) in ml THF in a dry nitrogen atmosphere heated at 55°C overnight, cooled to room temperature and diluted with ethyl acetate. The resulting mixture was twice washed with HCl (2 BC) and brine, the organic layer is dried over MgSO4and filtered. The filtrate is concentrated under reduced pressure and the resulting residue purified via chromatography on silica gel, elution is conducted with a mixture of hexane/ethyl acetate 7:3, it is connected to the e 118 (1098 mg, 71% after two steps) as a foam light yellow color.

Step 6: To a solution of compound 118 (1091 mg, 2,19 mmol) in THF (18 ml) at room temperature is added sodium hydroxide (2 N., 6 ml) and methanol (12 ml). The mixture is stirred for 20 min, then diluted with water and extracted with ethyl ether. The aqueous phase is acidified with HCl (2 BC) and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over MgSO4and filtered. The filtrate is concentrated under reduced pressure to thus obtain (3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid, 119 (1045 mg, yield quantitative) as a white foam. MS: calculated (M-H)-=468,13 m/z; found (M-N)-=467,99 m/z.

Example 26

Synthesis of (3S)-3-[({[4-hydroxy-2-oxo-1-(pyridine-2-yl-methyl)-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid.

Step 1: To a solution of compound 23 (0.50 g, 3.2 mmol) in DMSO (12.5 ml) at room temperature add powdered KOH (0,89 g, 16 mmol) and the mixture is stirred for 1.5 hours To the resulting mixture of solid hydrochloride of 2-picolylamine (0,63 g, 3.8 mmol) and the mixture is stirred over night. After that add the hydrochloride of triethylamine (3,52 g, 25.6 mmol) and DMF (5 ml), and then powdered zinc (1.04 g, 16.0 mmol). The mixture heating the Ute at 80° C for 2 h, then cooled to room temperature. To this mixture add the OED (1,00 g, 6.2 mmol) and the resulting mixture heated to 80°With during the night. The mixture is diluted with ethyl acetate and saturated aqueous NaHCO3. The organic layer is dried over MgSO4and filtered, the filtrate is concentrated under reduced pressure. The resulting residue is filtered through a layer of silica gel, elution is conducted with a mixture of CHCL3/CH3IT is 9:1, you get a connection 120 (0.14 g, 18%).

(3S)-3-[({[4-Hydroxy-2-oxo-1-(pyridine-2-yl-methyl)-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid is obtained from compound 120 in accordance with the method described in example 25. MS: calculated (M-H)-=421,15 m/z; found (M-N)-=421,06 m/z.

Example 27

Synthesis of (3S)-3-{[({1-[2-chloro-5-(methylsulphonyl)benzyl]-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl}amino)carbonyl]amino}-3-(4-were)propionic acid.

Step 1: To a solution of compound 121 (obtained from compound 23 according to the procedures described in example 4, 220 mg, 0.67 mmol) in anhydrous CH2Cl2(14 ml), cooled to 0°in dry nitrogen atmosphere, add m-HPBC (610 mg, 3.6 mmol). The resulting mixture was warmed to room temperature and stirred for 4 h, the Reaction mixture was diluted with water (50 ml)and the aqueous phase extracted with CH2Cl2(2 times). Merged the content of inorganic fillers layers dried over MgSO 4and filtered, the filtrate is concentrated under reduced pressure. The resulting residue is purified by means of chromatography on silica gel, elution is conducted with a mixture of CHCl3/Meon 9:1, you get a connection 122 (219 mg, yield 91%) as a solid yellow color.

(3S)-3-{[({1-[2-Chloro-5-(methylsulphonyl)benzyl]-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl}amino)carbonyl]amino}-3-(4-were)propionic acid is obtained from compound 122 according to the procedures described in example 25. MS: calculated (M-H)-=532,10 m/z; found (M-N)-=531,94 m/z.

Example 28

Synthesis of (3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3-were)propionic acid.

Step 1: To a solution of compound 123 (70 mg, 0.13 mmol) in anhydrous CH2Cl2(3 ml) under stirring in nitrogen atmosphere, add ZnBr2(200 mg, 0.82 mmol). The solution was stirred at 0°C for 1 h the resulting mixture was warmed to room temperature and stirred over night. Then the reaction mixture was added water (50 ml) and stirred for another 3 hours, the Layers separated and the aqueous layer was extracted with CH2Cl2(2 times). The combined organic layers dried over MgSO4and filtered, the filtrate is concentrated under reduced pressure to thus obtain (3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-4-hydroxy-2-oxo-1,2-dihydrospiro the Jn-3-yl]amino}carbonyl)amino]-3-(3-were)propionic acid, the connection 124 (60 mg, yield 95%). MS: calculated (M-H)-=484,13 m/z; found (M-N)-=484,00 m/z.

Example 29

Synthesis of (3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid.

Stage 1: a Mixture of malonaldehyde (25,0 g, 177 mmol) and valeronitrile (25,0 g to 300.7 mmol) in anhydrous atmosphere intensively stirred at room temperature for 24 hours To the resulting heterogeneous mixture is added diethyl ether (50 ml). The precipitate is collected and washed with diethyl ether, you get a connection 125·HCl in a solid white color (20.2 g, 64%).

Stage 2: To a suspension of compound 125·HCl (6,10 g of 27.2 mmol) in EtOH (100 ml), add triethylamine (5.8 g, 57,3 mmol) and palladium on coal (10% Pd per dry weight, Degussa type E101 Ne/W, water content ˜50%, 3.5 g, 1.6 mmol Pd). The atmosphere in the flask was replaced with hydrogen (five switch the valve between the vacuum line and a balloon with hydrogen and the mixture is stirred overnight, then filtered. The filtrate is concentrated under reduced pressure, you get a connection 126·2t3NHCl (11,0 g, 94%). This material is used without further purification.

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid is obtained from a connection 126·2SD3NHCl with the according methods described in example 25. MS: calculated (M-H)-=496,16 m/z; found (M-N)-=495,94 m/z.

Example 30

Synthesis of (3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid.

Step 1: To a solution of ethyl ester of 2-oxocyclopentanecarboxylate acid (3,30 g, 21.1 mmol) in toluene (45 ml) is added 4-chlorobenzylamino (2,56 ml, 21.1 mmol). The resulting mixture was refluxed overnight with removal of water azeotrope using traps Dean-stark. The reaction mixture was concentrated under reduced pressure, you get a connection 127 (5,90 g, 99%) as oil red. This material is used without purification.

Stage 2: To a solution of compound 127 (11,0 g, or 39.3 mmol)in anhydrous THF (75 ml), cooled to 0°in dry nitrogen atmosphere, add NaH (60%dispersion in mineral oil, 1.73 g, 43.2 mmol). The reaction mixture was stirred at 0°C for 10 min, then add acetylchloride (3.9 ml, 55 mmol). The reaction mixture is slowly warmed to room temperature and stirred over night. The resulting mixture was concentrated under reduced pressure and to the residue is added ice water (200 ml) and HCl (1N., 200 ml). This mixture is extracted with ethyl acetate (300 ml), an ethyl acetate layer is dried over MgSO4and filtered. The filtrate is concentrated at eigendom pressure, you get a connection 128 (13,4 g) as a brown oil. This material contains mineral oil, but it is used without purification.

Stage 3: To a solution of the crude compound 128 (13,4 g, theoretically at 39.3 mmol) in anhydrous THF (50 ml), cooled to 0°C in an atmosphere of dry nitrogen, using a syringe slowly added bis(trimethylsilyl)amide lithium (1.0 M in THF, 125 ml, 125 mmol). The reaction mixture is heated to room temperature and stirred overnight, the reaction mixture was concentrated under reduced pressure, the residue triturated with a mixture of ethyl acetate/hexane and filtered. The solid is washed with HCl (1N., 250 ml) and water (500 ml), you get a connection 129 (5,48 g, 48% after two steps) as a solid brown color.

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid synthesized from compound 129 according to the procedures described in example 25. MS: calculated (M+H)+=496,16 m/z; found (M+H)+=495,99 m/z.

Example 31

Synthesis of (3S)-3-[({[4-{[(tert-butylamino)carbonyl]amino}-1-(2-Chlorobenzyl)-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid.

Step 1: To a solution of compound 46 (500 mg, to 1.79 mmol) in anhydrous THF (10 ml), cooled to 0°C in an atmosphere of dry nitrogen, d is billaut NaH (60%dispersion in mineral oil, 210 mg, 5.37 mmol) and the resulting mixture is stirred for 20 minutes To this mixture is added tert-utilizationa (0,31 ml, 2.68 mmol), the reaction mixture is heated to room temperature and stirred for 2 days. The reaction is stopped by the addition of water and twice extracted with ethyl acetate. The organic layers are combined, dried over MgSO4and filtered, the filtrate is concentrated under reduced pressure, you get a connection 130 (600 mg, 97%) as a solid brown color.

(3S)-3-[({[4-{[(tert-butylamino)carbonyl]amino}-1-(2-Chlorobenzyl)-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid is obtained from a connection 130 according to the procedures described in example 3. MS: calculated (M-H)-=552,20 m/z; found (M-N)-=551,89 m/z.

To obtain the compounds listed in tables 2, 3, 4 and 5, can be used in methods of synthesis such as those described above.

Example 32

Synthesis of (3S)-3-[({[5-chloro-1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid.

Step 1: To a solution of compound 31 (350 mg, to 0.72 mmol) in CH2Cl2at room temperature in a dry nitrogen atmosphere using a syringe add sulfurylchloride (1.0 M in CH2Cl2, of 0.65 ml of 0.65 mmol). The resulting mixture was stirred at room temperature during the 1 h, then partitioned between CH2Cl2and water. The organic layer was washed with brine and dried over MgSO4the filtrate is concentrated under reduced pressure. The residue is purified using chromatography on silica gel, elution is conducted with a mixture of hexane/ethyl acetate 8:1, then 4:1 and finally 1:1, you get a connection 131 (240 mg, 64%).

(3S)-3-[({[5-chloro-1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid is obtained from compound 131 in accordance with the method described in example 1. MS: calculated (M-H)-=488,08 m/z; found (M-N)-=487,97 m/z.

Example 33

Synthesis of (3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(2',6'-dimethoxy-1,1'-biphenyl-4-yl)propionic acid.

Step 1: To a solution of (R)-(+)-N-benzyl-α-methylbenzylamine (5,07 g, 24 mmol) in THF (85 ml) under nitrogen atmosphere calcined in a vessel cooled to -78°With dropwise within 30 min add second-utility (1.3 M solution in cyclohexane and 18.0 ml of 23.4 mmol). The mixture was stirred at -78°C for 30 min, then added dropwise a solution of tert-butyl methyl ether 4-bromcresol acid (5.1 g, 20 mmol) in THF (20 ml), warmed to room temperature and incubated overnight. The reaction is stopped by adding a saturated solution of ammonium chloride (˜50 ml), organically the layer washed with a saturated solution of sodium chloride, dried over MgSO4and filtered. The filtrate is concentrated under reduced pressure and the residue purified via chromatography on silica gel, elution is carried out in a gradient from hexane to a mixture of hexane/ethyl acetate 3:1, you get a connection 132 (4,33 g, 47%) as oil is light yellow in color.

Stage 2: To a solution of compound 132 (7,4 g, 15 mmol) and 2,6-dimethoxyphenylacetic acid (4.9 g, 27 mmol) in DME (100 ml) at room temperature in a dry nitrogen atmosphere add fine powder of potassium phosphate (8.0 g, 37.5 mmol) and dichlorobis(triphenylphosphine)palladium (0) (0.5 g, 0.75 mmol). From the mixture to remove oxygen (by five-time replacement vacuum on the flow of gaseous nitrogen, and then heated under reflux for 8 hours Then the mixture is cooled and filtered through celite 521, the filtrate is concentrated under reduced pressure. The residue is purified using chromatography on silica gel, elution is carried out in a gradient from hexane to a mixture of hexane/ethyl acetate 3:1, you get a connection 133 (7.8 g, yield 95%).

Stage 3: To a solution of compound 133 (3,39 g, 6.1 mmol) in ethanol (80 ml) in a vessel with a capacity of 250 ml successively added acetic acid (0.5 ml) and palladium on coal (10% Pd per dry weight, Degussa type E101 Ne/W, water content ˜50%, 2.5 g, 1.2 mmol Pd). The reaction mixture was stirred in an atmosphere of nitrogen from a cylinder within 36 hours Reacciona the mixture is filtered through celite 521, and the filtrate concentrated under reduced pressure. The residue is recrystallized from ethyl acetate, thus receive the connection 134·SPLA (1.0 g, 71%) as a solid white color.

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(2',6'-dimethoxy-1,1'-biphenyl-4-yl)propionic acid synthesized from compound 134·SPLA according to the procedures described in example 25. MS: calculated (M+H)+=592,19; found (M+H)+=592,04.

Example 34

Synthesis of (3S)-3-[({[2-(2-chloro-6-ethoxybenzyl)-5-hydroxy-6-methyl-3-oxo-2,3-dihydropyridin-4-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propionic acid.

Step 1: To a solution of tert-butoxide sodium (65 g, 0,642 mol) in THF (1 l) at room temperature in a dry nitrogen atmosphere for 10 min add ethanol (250 ml) was 5.35 mol). To the resulting solution was added in several portions of 2-chloro-6-perbenzoate (100 g, 0,642 mol). The reaction mixture was stirred for 30 min at room temperature, and then reduce its volume under reduced pressure to approximately 250 ml of the resulting mixture was poured into chloroform and water, the layers separated. The organic layer was washed with water (twice) and brine, dried over MgSO4and filtered. The filtrate is concentrated under reduced pressure, you get a solid light yellow color. This material as stilizovala of hexane, you get 2-chloro-6-ethoxybenzonitrile, compound 135 (101 g, yield 87%) as a crystalline substance of white color.

Stage 2: To a solution of 2-chloro-6-ethoxybenzonitrile, compound 135 (93,2 g, 0,513 mol) in THF (350 ml) at room temperature in a dry nitrogen atmosphere add a solution of borane in THF (1.0 M, 620 ml of 0.62 mol). The resulting mixture was heated under reflux for 3 h, then cooled to room temperature. To a solution very slowly add water (250 ml) until the evolution of hydrogen. Then within a few minutes, add concentrated HCl (50 ml) and the solution heated at 50°C for 2 h and Then the solution is cooled and partitioned between chloroform and water. The aqueous layer was washed 6 times with chloroform. The combined organic fractions washed with HCl (1M) and the organic layer discarded. To the combined aqueous layers add chloroform and solid CON up until the aqueous phase will not have an alkaline reaction (pH>9). The aqueous layer was washed with chloroform another 5 times. The organic fractions are combined and washed with water, brine, dried over MgSO4and silica gel (2 g). This mixture is filtered and the filtrate concentrated under reduced pressure to thus obtain 2-chloro-6-ethoxybenzyl, compound 136 (60.1 g, yield 64%) as oil is light yellow in color.

Stage 3: To a solution of 2-chloro-6-this is cibenzoline, compound 136 (7.30 g, or 39.3 mmol) in glacial acetic acid (50 ml) and acetic anhydride (50 ml) at room temperature in small portions add sodium nitrite (6,00 g of 85.7 mmol). The resulting mixture was stirred at room temperature overnight, then poured into ice water and extracted with ethyl acetate. The organic layer was washed with aqueous solution of NaOH (1N., 2×100 ml) and brine (twice). The organic layer is dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure, you get a connection 137 (9.00 g, 100%) as a solid light yellow color.

Stage 4: To a solution of compound 137 (9.00 g, or 39.3 mmol) and tetrabutylammonium (1.0 g, 3.1 mmol) in THF (50 ml) at room temperature is added slowly an aqueous solution of NaOH (2 N., 50 ml, 100 mmol) and the mixture is heated at 45°With during the night. The reaction mixture is cooled to room temperature, then diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure, you get a connection 138 (7,08 g, yield 96%).

Stage 5: To a solution of compound 138 (7,08 g of 37.9 mmol) in CH2Cl2(55 ml) at room temperature in an atmosphere of dry nitrogen was added dropwise a solution of SOCl2(9.0 ml, 120 mmol) in CH Cl2(30 ml). The resulting mixture was stirred at room temperature overnight, then poured into ice water. The aqueous layer was extracted with CH2Cl2and the combined organic layers washed with aqueous solution of NaOH (1N., twice), water (3 times) and brine (2 times). The organic layer is dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure to thus obtain 2-chloro-6-ethoxybenzylidene, compound 139 (6,69 g, yield 86%) as a viscous brown oil.

Step 6: a Solution of 2-chloro-6-ethoxybenzaldehyde, compound 139 (6,90 g, or 33.7 mmol) and hydrazine (21,60 g, 673 mmol) in Meon (22 ml) was stirred at room temperature for 3 hours the Mixture was partitioned between CH2Cl2and water. The organic layer is dried over MgSO4and filtered, the filtrate is concentrated under reduced pressure, you get a connection 140 (6,18 g, 92%).

Step 7: To a suspension of ethyl ester of pyruvic acid (of 3.85 ml, or 33.7 mmol) and MgSO4in CHCl3(65 ml) is added slowly a solution of compound 140 (6,14 g of 30.6 mmol) in CHCl3(30 ml). The resulting mixture was stirred at room temperature overnight, then filtered and the filtrate concentrated under reduced pressure, you get a connection 141 (8,43 g, 92%). This material is used in the next stage without purification.

Step 8: To the races is the thief of compound 141(8,43 g, of 28.2 mmol) in dry THF (110 ml), cooled to 0°C in an atmosphere of dry nitrogen to one portion add sodium hydride (60%dispersion in mineral oil, 1.88 g, or 47.1 mmol). The resulting mixture was stirred at 0°C for 30 min, then slowly add methylmalonate (6,63 g, 47,10 mmol). The mixture is heated to room temperature, stirred overnight, the reaction gently stopped by the addition of water, then extracted with ethyl acetate (twice). The organic layers are combined, washed with saline, dried over MgSO4and filtered. The filtrate is concentrated under reduced pressure, you get a connection 142 (14,29 g). This material is used in the next stage without additional purification.

Step 9: To a solution of the crude compound 142 (14,29 g) in dry DMF (60 ml), cooled to 0°C in an atmosphere of dry nitrogen, one portion add sodium hydride (60%dispersion in mineral oil, 2,90 g, 72.2 mmol). The solution is heated to 60°C overnight, then cooled in an ice bath and shaken with hexane. The layers are separated and the layer of DMF was poured into ice-cold water. The mixture is acidified (pH 1) by adding HCl (2 BC). The precipitate is collected by filtration, dissolved in ethyl acetate material. The organic solution is dried over MgSO4and filtered, the filtrate is concentrated and thus receive the connection 143 (8,42 g, yield 85 after two steps).

Stage 10: a Solution of compound 143 (8,42 g of 23.9 mmol) in dioxane (100 ml) and aqueous HCl solution (60 ml, 5,2 BC) is refluxed overnight. The mixture is cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4and filtered. The filtrate is concentrated under reduced pressure, and the residue purified via chromatography on silica gel, elution is conducted with a mixture of ethyl acetate/hexane 1:1, then ethyl acetate and finally with a mixture of ethyl acetate/methanol 9:1, you get a connection 144 (2.0 g, 28%).

(3S)-3-[({[2-(2-chloro-6-ethoxybenzyl)-5-hydroxy-6-methyl-3-oxo-2,3-dihydropyridin-4-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propionic acid is obtained from compound 144 according to the procedures described in example 25. MS: calculated (M+H)+=545,18; found (M+H)+=545,05.

Example 35

Synthesis of (3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl]amino}carbonyl)amino]-3-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-yl)propionic acid.

Stage 1: a Mixture of sodium hydride (60%dispersion in mineral oil, 8.00 g, 200 mmol) and compound 145 (8,94 g of 66.6 mmol) in DMF (250 ml), cooled to 0°C in an atmosphere of dry nitrogen, gradually warmed to room temperature. To the resulting mixture add Iodate (16 ml, 200 mmol) and reacciona the mixture was stirred at room temperature overnight. The reaction mixture was poured into ice and extracted with ethyl acetate. The organic layer is washed with water and brine, dried over Na2SO4and filtered. The filtrate is concentrated under reduced pressure, the residue is transferred into hexane and filtered. The obtained solid brown dried under reduced pressure, you get a connection 146 (9.00 g, 71%yield). This material is used without purification.

Stage 2: a Mixture of DMF (3.6 g, 49 mmol) and POCl3(9.6 ml, 100 mmol) was stirred at room temperature in a dry nitrogen atmosphere for 1 h Then the mixture was placed in an oil bath at 45°and small portions add connection 146 (7.6 g, 40 mmol). The oil bath temperature was raised to 70°and the mixture is stirred overnight, then cooled to room temperature. The mixture is diluted with water and extracted with ethyl acetate. The organic layer is washed with water and brine, dried over Na2SO4and filtered. The filtrate is concentrated under reduced pressure, you get a mixture of compounds 147/146 in the ratio of 7:3 (6.69 in). This material is used without purification.

Stage 3: To a solution of the mixture of compounds 147/146 obtained at the previous stage (2.2 g)in ethanol (2.2 ml) is successively added malonic acid (1,16 g, and 11.2 mmol), pyridine (of 0.44 ml) and piperidine (0,99 ml). The resulting mixture is agreat under reflux for 6 h, then cooled to room temperature. The mixture is diluted with aqueous NaOH solution (1 BC) and extracted with ethyl acetate (4 times). The aqueous layer was acidified with HCl (1 BC) to pH 3 and the resulting suspension is filtered, the solid washed with water. Solid white is collected and dried under reduced pressure, you get a connection 148 (1,69 g, 49% after two steps).

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl]amino}carbonyl)amino]-3-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-yl)propionic acid is obtained from a connection 148 according to the procedures described in examples 33 and 25. MS: calculated (M+H)+=594,21; found (M+H)+=594,05.

Example 36

Synthesis of (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino} carbonyl)amino]-3-(4-were)propionic acid, compound 153.

Step 1: To a solution of compound 114 (20,3 g, 129 mmol) in anhydrous methanol (430 ml) at room temperature in a dry nitrogen atmosphere is added 2-chloro-6-ethoxybenzyl, compound 136 (31.1 g, 168 mmol). The solution is heated at 45°C for 1 h, then refluxed overnight. The reaction mixture is cooled to room temperature and concentrated to dryness. The residue is transferred in dichloromethane and filtered. The solid is collected and dried in vacuum, thus receive with the unity 149 (14,7 g, 39%).

Stage 2: To a suspension of compound 149 (11,02 g, 37.8 mmol) in glacial acetic acid (126 ml) at room temperature successively added NaNO2(522 mg, 7.6 mmol), water (10.5 ml) and HNO3(70%and 9.6 ml, 151,2 mmol). The resulting solution was bright yellow color was stirred at room temperature overnight, then diluted with CH2Cl2and water. The aqueous phase is extracted with CH2Cl2organic layers are combined and washed with water (3 times) and brine. The organic layer is dried over MgSO4and filtered, the filtrate is concentrated under reduced pressure. The residue is recrystallized from a mixture of CH2Cl2/ethyl acetate, thus receive the connection 150 (10,9 g, 85%) as a solid bright yellow color.

Stage 3: To a solution of compound 150 (10,9 g is 32.2 mmol) in DMF (107 ml) at room temperature in a dry nitrogen atmosphere add powdered zinc (9,48 g, 145 mmol) and triethylamine hydrochloride (24.4 g, 177 mmol). The resulting mixture was heated at 55°C for 1 h, then cooled to room temperature. To the resulting mixture add the OED (10.4 g, 64,4 mmol) as a solid. Adding observe the evolution of gas. The mixture is heated at 80°C for 2 h, cooled to room temperature and poured into HCl (2 ad, 1 l). The resulting suspension is stirred for 20 min, then diluted with water (1 l and filtered. Solid resuspended in water (1 l) and filtered. The solid is dried in vacuum, you get a connection 151 (10,78 g, yield 100%) as white powder.

Stage 4: a Mixture of compounds 151 (for 10.68 g, 31.9 per mmol) and 8 (of 8.27 g, and 39.9 mmol) in DMF (64 ml) in a dry nitrogen atmosphere heated at 55°C overnight, cooled to room temperature, then diluted with ethyl acetate. The resulting mixture was washed with HCl (2 B.C.), water (4 times) and brine, the organic layers dried over MgSO4and filtered. The filtrate is concentrated under reduced pressure and the resulting residue purified via chromatography on silica gel, elution is conducted with a mixture of hexane/ethyl acetate 7:3, you get a connection 152 (14.2 g, 82%) as a foam light yellow color.

Stage 5: To a solution of compound 152 (11,60 g, with 21.4 mmol) in THF (138 ml) at room temperature, add aqueous sodium hydroxide solution (2 N., 46 ml) and methanol (92 ml). The mixture is stirred for 20 min, then diluted with water and extracted with ethyl acetate. The aqueous layer was acidified with HCl (2 BC) and extracted with ethyl acetate. An ethyl acetate layer is washed with water and brine, dried over MgSO4and filtered. The filtrate is concentrated under reduced pressure to thus obtain (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)impregnated the new acid, compound 153 (10,82, yield 98%) as a foam light brown color. MS: calculated (M-H)-=512,16; found (M-N)-=512,03.

Example 37

Synthesis of (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propionic acid, compound 156.

Stage 1: a Mixture of compounds 151 (8,40 g, 28.8 mmol) and 154 (8,2 g, 35 mmol) in DMF (100 ml) is heated at 55°C in an atmosphere of dry nitrogen over night, cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with HCl (2 B.C.), water (4 times) and brine, the organic layer is dried over MgSO4and filtered. The filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel, elution is carried out in the gradient mixture of hexane/ethyl acetate 8:2 to 1:1, you get a connection 155 (11,1 g, yield 67%).

Stage 2: To a solution of compound 155 (9,12 g, 15.9 mmol) wtgf (100 ml) at room temperature, add aqueous sodium hydroxide solution (1N., 88 ml) and methanol (63 ml). The mixture is stirred for 20 min, then diluted with water and extracted with ethyl ether. The ether layer discarded. The aqueous phase is acidified with HCl (2 BC) and extracted with ethyl ether (4 times). The organic layers washed with water and brine, dried over MgSO4and filtered. The filtrate is concentrated under reduced pressure, the AI, thus obtain (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propionic acid, compound 156 (8,13 g, 93%) as a white foam. MS: calculated (M+H)+=544,19; found (M+H)+=544,04.

Example 38

Synthesis of (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(6-methoxy-2-naphthyl)propionic acid, compound 159.

Stage 1: a Mixture of compounds 151 (110 mg, 0.29 mmol), 157 (130 mg, 0.34 mmol) and NMM (0,50 ml, 4.5 mmol) in DMF (1.0 l) is heated at 55°C in an atmosphere of dry nitrogen over night, cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with HCl (2 B.C.), water (4 times) and brine, the organic layer is dried over MgSO4and filtered. The filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel, elution is conducted with a mixture of hexane/ethyl acetate 1:1, you get a connection 158 (130 mg, yield 73%).

Stage 2: To a solution of compound 158 (130 mg, 0.21 mmol) in THF (3 ml) at room temperature, add aqueous sodium hydroxide solution (1N., 1 ml) and methanol (2 ml). The mixture is stirred for 20 min, then diluted with water and extracted with ethyl ether. The aqueous phase is acidified with HCl (2 BC) and extracted with ethyl acetate. An ethyl acetate layer was washed with water is the first and saline, dried over MgSO4and filtered. The filtrate is concentrated under reduced pressure to thus obtain (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(6-methoxy-2-naphthyl)propionic acid, compound 159 (90 mg, yield 74%). MS: calculated (M+H)+=580,19; found (M+H)+=580,07.

Example 39

Synthesis of (3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propionic acid, compound 164.

Step 1: To a suspension of compound 129 (5.30 g, 19.2 mmol) in glacial acetic acid (64 ml) at room temperature successively added NaNO2(266 mg, 3.9 mmol), water (5.3 ml) and HNO3(70%, a 4.9 ml, 77 mmol). The resulting solution was bright yellow color was stirred at room temperature overnight, then poured into water and filtered, washed with water. Solid bright yellow dried under reduced pressure, you get a connection 160 (5.35 g, 87%).

Stage 2: To a solution of compound 160 (5.35 g, and 16.7 mmol) in DMF (56 ml) at room temperature in a dry nitrogen atmosphere add powdered zinc (4,88 g, to 74.7 mmol) and triethylamine hydrochloride (12,6 g of 91.5 mmol). The resulting mixture was heated at 55°C for 1 h, then cooled to room temperature. To the resulting mixture add the OED (5 41G, 33.4 mmol) in venom. Adding observe the evolution of gas. Then the mixture is heated at 80°C for 2 h, cooled to room temperature and poured into HCl (2 N., 500 ml). The resulting suspension is stirred for 20 min, then diluted with water (500 ml) and filtered. Solid resuspended in water (500 ml) and filtered. The solid is dried in vacuum, you get a connection 161 (5.0 g, yield 95%) as white powder.

Stage 3: a Mixture of compounds 161 (6,14 g, and 19.4 mmol) and 162 (5,12 g, 20.3 mmol) in DMF (90 ml) is heated at 80°C in an atmosphere of dry nitrogen over night, cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with HCl (2 B.C.), water (4 times) and brine, the organic layer is dried over MgSO4and filtered. The filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel, elution is conducted with a mixture of hexane/ethyl acetate 7:3, you get a connection 163 (8.90 g, 81%) as a foam light yellow color.

Stage 4: To a solution of compound 163 (8.69 g, and 15.3 mmol) in THF (35 ml) at room temperature, add aqueous sodium hydroxide solution (2 N., 30 ml) and methanol (30 ml). The mixture is stirred overnight, then diluted with water and extracted with ethyl ether. The aqueous phase is acidified with HCl (2 BC) and extracted with ethyl acetate. An ethyl acetate layer washed with water is saline, dried over MgSO4and filtered. The filtrate is concentrated under reduced pressure to thus obtain (3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propionic acid, compound 164 (7.50 g, yield 91%). MS: calculated (M+H)+=540,19; found (M+H)+=540,09.

Example 40

Synthesis of (3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl]amino}carbonyl)amino]-3-(4-chloro-3-isopropoxyphenyl)propionic acid.

Step 1: To a mixture of compound 162 (200 mg, 0.80 mmol) in glacial acetic acid (1.65 ml), cooled to 0°C in an atmosphere of dry nitrogen, using a syringe added dropwise a mixture of SO2Cl2(1.2 ml, 15 mmol) in glacial acetic acid (1.0 ml). The resulting mixture was stirred at 0°C for 30 min and warmed to room temperature. After stirring for another 4 h the mixture was again cooled to 0°and the reaction stopped by careful addition of saturated aqueous NaHCO3. The mixture is extracted with ethyl acetate and the organic layer was washed with saturated aqueous NaHCO3, dried over MgSO4and filtered. The filtrate is concentrated under reduced pressure, the residue is purified by chromatography on silica gel, elution is conducted with a mixture of hexane/ethyl acetate 2:1, you get a connection 165 (148 m is, 65%).

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl]amino}carbonyl)amino]-3-(4-chloro-3-isopropoxyphenyl)propionic acid is obtained from compound 165 according to the procedures described in examples 25 and 30. MS: calculated (M-H)-=586,15; found (M-N)-=585,92.

Example 41

Synthesis of (3S)-3-({[(1-{[2-chloro-6-tetrahydro-1(2H)-pyridinylmethyl]methyl}-4-hydroxy-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl)amino]carbonyl}amino)-3-(4-were)propionic acid.

Step 1: To a suspension of compound 166 (0.35 g, 1.06 mmol, obtained according to the procedures described in examples 34 and 25) in methanol (7 ml) and water (3.5 ml), cooled to 0°With, successively added glacial acetic acid (189 μl, 3.2 mmol) and sodium nitrite (178 mg, to 2.65 mmol). The mixture is slowly warmed to room temperature and stand overnight, then diluted with chloroform and water. The pH value of the aqueous phase support in the range of 4-5. The organic layer was washed with brine, dried over MgSO4and filtered, the filtrate is concentrated under reduced pressure, you get a connection 167 (0.35 g, 92%) as a solid yellow color.

(3S)-3-({[(1-{[2-chloro-6-tetrahydro-1(2H)-pyridinylmethyl]methyl}-4-hydroxy-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl)amino]carbonyl}amino)-3-(4-were)propionic acid synthesized from compound 167 according to m is codicum, described in example 25. MS: calculated (M-H)-=551,21; found (M-N)-=551,06.

Methods of synthesis, similar to the above, can be used to obtain the compounds listed in tables 1-7.

Example 42

To evaluate the effectiveness of the synthesized compounds using a method in which a 26-membered peptide containing a fragment of CSI fibronectin with N-terminal cysteine residue (CDELPQLVTLPHPNLHGPEILDVPST) condense with ovalbumin, activated by imida maleic acid. Polystyrene 96-well tablets are covered with a solution of bovine serum albumin and conjugate of ovalbumin and CSI at a concentration of 0.5 μg/ml in TBS buffer solution (50 mm TRIS, pH 7.5, 150 ml NaCl) at 4°C for 16 h Tablets washed three times with TBS and blocked TBS containing 3% BSA at room temperature for 4 h Before analysis blocked tablets washed three times with buffer solution for binding (TBS, 1 mm MgCl2, 1 mm CaCl2, 1 mm MnCl2). The Ramos cells labeled with fluorescent kalayna AM, resuspending in buffer solution for binding (107cells/ml) and diluted with the same buffer at a ratio of 1:2 in the presence or in the absence of connection. Connection type at a concentration of 100 M Cells immediately added to the wells (2,5×105of cells per well) and incubated at 37°during the course the e 30 minutes After three times washing with buffer to bind fused cells are lysed and measured fluorescence on fluorometry. The results are presented in tables 1-3. The value of the IC50defined as the dose required for 50%inhibition. The value of the IC50in microns are shown in tables 1 and 3. The lower the value of the IC50and the higher the degree (percentage) of inhibition, the higher the efficiency connections, which ensures the prevention of the coalescence of cells.

All cited publications are included in this description as a reference.

The present invention is illustrated by the above description and examples. The above description is not intended to limit the scope of the invention, since from the point of view of the described variants of the embodiment of the invention there are many options, obvious to a person skilled in the art. It should be understood that all such variations are included within the scope and essence of the invention claimed in the UNCTAD the accompanying claims.

Possible changes in the design, implementation and sequence of the method according to the present invention, described herein, without going beyond the concept and scope of the invention as defined in the following claims.

SEQUENCE LISTING

(1) GENERAL INFORMATION:

(i) APPLICANTS: BADIGER, Ronald; CHEN, Kai; HOLLAND, George, U.;

CASHIER, Jamal, M.; LEE, Yuen; MARKET, Robert, C.; Scott, Ian, L. and WU, Chengde

(ii) title of the INVENTION: Derivatives of carboxylic acids (options), pharmaceutical composition and method for selective inhibition of binding α4β1integrin in a mammal

(iii) NUMBER of SEQUENCES: 1

(iv) CORRESPONDENCE ADDRESS:

(A) ADDRESSEE: Rockey, Milnamow &Katz, Ltd.

(B) STREET: 180 N. Stetson Avenue, 2 Prudential Plaza, Suite 47

(B) CITY: Chicago

(G) STATE: Illinois

(E) COUNTRY: USA

(E) POSTAL CODE: 60601

(v) DATA FOR COMPUTER PROCESSING:

(A) MEDIUM TYPE: FLOPPY disk

(B) COMPUTER: IBM PC compatible

(B) OPERATING SYSTEM: PC-DOS/MS-DOS

(D) SOFTWARE: Patentin Release #1.0, Version #1.30

(vi) information ABOUT THIS APPLICATION:

(A) APPLICATION NUMBER:

(B) FILING DATE:

(B) CLASSIFICATION:

(viii) INFORMATION ABOUT the AGENT/REPRESENTATIVE of:

(A) NAME: Katz, Martin L.

(B) REGISTRATION NUMBER: 25,011

(B) the REFERENCE NUMBER/NUMBER DOSSIER: EX4542P0400US

(ix) INFORMATION FOR TELECOMMUNICATIONS:

(A) PHONE: (312) 616-5400

(B) TELEFAX: (312) 616-5460

(2) the INFORMATION ABOUT the SEQUENCE SEQ ID N0:1:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 26 amino acids

(B) TYPE: amino acid

(B) NUMBER of CIRCUITS: one

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: protein

(xi) SEQUENCE DESCRIPTION SEQ ID NO:1:

CysAspGluLeuProGlnLeuValThrLeuProHisProAsnLeuHis
151015
GlyProGluIleLeuAspValProSerThr
20 25

1. Derivatives of carboxylic acids, having the structure

where Y in each case independently chosen from the group consisting of C(O), N, CR1C(R2)(R3), NR5CH;

q denotes an integer from 3 to 10;

And chosen from the group consisting of NR6;

E is chosen from the group consisting of NR7;

J is chosen from the group consisting Of;

T is chosen from the group consisting of (CH2)bwhere b means 0;

M is chosen from the group consisting of C(R9)(R10) and (CH2)uwhere u represents an integer from 0 to 3;

L is chosen from the group consisting of NR11and (CH2)nwhere n stands for 0;

X is chosen from the group consisting of CO2N, tetrazolyl;

W is chosen from the group consisting of C, CR15and N, and

R1, R2, R3and R15independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkyl, alkoxy, -CF3, amino, -NHC(O)N(C1-C3alkyl)C(O)NH-(C1-C3alkyl), -NHC(O)NH(C1-C6alkyl), alkylamino, alkoxyalkyl, cycloalkyl, aryl, aryloxy, arylamino is, heterocyclyl, heterocyclisation, where the heteroatom is selected from N or O, -NHSO2(C1-C3alkyl), aryloxyalkyl;

where R1, R2, R3and R15unsubstituted or substituted by at least one electron-donating or electron-withdrawing group selected from the group consisting of carboxy, alkyl, alkoxy and aryl;

R4selected from the group consisting of hydrogen, aryl, aralkyl, benzofuranyl, dihydrobenzofuranyl, dihydroindeno, alkyl, benzodioxolyl, dihydroergotoxine, furyl, naphthyl, chinoline, ethenolysis, pyridinyl, indolyl, thienyl, biphenyl, 2-oxo-2,3-dihydro-1H-benzimidazolyl, pyrimidinyl and carbazolyl, where R4may be unsubstituted or substituted by at least one electron-donating or electron-withdrawing group selected from the group consisting of alkyl, alkoxy, hydroxy, SO2(C1-C3alkyl), halogen, di(lower alkyl)amino, alkylthio, halogenated, -O-halogenated, alkoxyalkane, cycloalkyl, -NHSO2(C1-C3alkyl), -N(C1-C3alkyl)SO2(C1-C3alkyl), cycloalkane, pyrrolidinyl, -O-cycloalkenyl and piperidinyl;

R5selected from the group consisting of aralkyl, aryloxyalkyl, cycloalkyl and geterotsiklicheskikh, which heteroatom is selected from N, O and S, where R5may be unsubstituted or substituted on the end is th least one electron-donating or electron-withdrawing group, selected from the group consisting of aralkylamines, 3-aryl-1-ureido, halogen, -CN, alkoxy, alkyl, halogenated, aryl, hydroxy, -NO2, amino, -NH(aliphatic acyl), -NHSO2(C1-C3alkyl), alkylthio, -O-halogenated, -SO2(C1-C3alkyl), -SO2N(C1-C3alkyl)2, -SO2(1-pyrrolidinyl), -SO2(1-piperidinyl), -O-aralkyl, -O-cycloalkenyl, alkoxyalkane;

R6selected from the group consisting of hydrogen, alkyl;

R7and R11represent hydrogen;

R9and R10represent hydrogen or alkyl;

and where, if a means NR6and at least one Y represents CR1, R1and R6can be combined with the loop

or their pharmaceutically acceptable salts.

2. The compound according to claim 1, characterized in that

M means C(R9)(R10);

q is 4 or 5;

L means (CH2)nwhere n is 0;

X is COOH;

W means With or CR15;

R15means hydrogen.

3. The compound according to claim 1, characterized in that it is a derivative selected from the group consisting of esters of formula-C(O)Rmwhere Rmmeans alkyl.

4. Derivatives of carboxylic acids, having the structure

where Y in each case independently chosen from the group consisting of C(O), N, CR1C(R2)(R3), NR5, SN;

q denotes an integer from 3 to 7;

T is chosen from the group consisting of (CH2)bwhere b means 0;

L is chosen from the group consisting of NR11and (CH2)nwhere n stands for 0;

W is chosen from the group consisting of C, CR15and N, and

In selected from the group consisting of hydrogen and alkyl;

R1, R2, R3and R15independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkyl, alkoxy, -CF3, amino, -NHC(O)N(C1-C3alkyl)C(O)NH(C1-C3alkyl), -NHC(O)NH(C1-C6alkyl), alkylamino, alkoxyalkyl, cycloalkyl, aryl, aryloxy, arylamino, heterocyclyl, heterocyclisation where heteroatom selected from N or O, -NHSO2(C1-C3alkyl), aryloxyalkyl;

where R1, R2, R3and R15unsubstituted or substituted by at least one electron-donating or electron-withdrawing group selected from the group consisting of carboxy, alkyl, alkoxy and aryl;

R4selected from the group consisting of hydrogen, aryl, aralkyl, benzofuranyl, dihydrobenzofuranyl, dihydroindeno, alkyl, benzodioxolyl, dihydroergotoxine, furyl, naphthyl, chinoline, ethenolysis,pyridine is l,indolyl,thienyl,biphenyl,2-oxo-2,3-dihydro-1H-benzimidazolyl, pyrimidinyl and carbazolyl,

where R4may be unsubstituted or substituted by at least one electron-donating or electron-withdrawing group selected from the group consisting of alkyl, alkoxy, hydroxy, SO2(C1-C3alkyl), halogen, di(lower alkyl)amino, alkylthio, halogenated, -O-halogenated, alkoxyalkane, cycloalkyl, -NHSO2(C1-C3alkyl), -N(C1-C3alkyl)SO2(C1-C3alkyl), cycloalkane, pyrrolidinyl, -O-cycloalkenyl and piperidinyl;

R5selected from the group consisting of aralkyl, aryloxyalkyl, cycloalkyl and geterotsiklicheskikh, which heteroatom is selected from N, O and S, where R5may be unsubstituted or substituted by at least one electron-donating or electron-withdrawing group selected from the group consisting of aralkylamines, 3-aryl-1-ureido, halogen, -CN, alkoxy, alkyl, halogenated, aryl, hydroxy, -NO2, amino, -NH(aliphatic acyl), -NHSO2(C1-C3alkyl), alkylthio, -O-halogenated, -SO2(C1-C3alkyl), -SO2N(C1-C3alkyl)2, -SO2(1-pyrrolidinyl), -SO2(1-piperidinyl), -O-aralkyl, -O-cycloalkenyl, alkoxyalkane;

R6selected from the group consisting of hydrogen, alkyl;

R7and R11represent hydrogen;

R9and R10

or their pharmaceutically acceptable salts.

5. The compound according to claim 4, characterized in that

q is 4 or 5;

W means With or CR15;

L means (CH2)nwhere n is 0;

R15means hydrogen.

6. The compound according to claim 4, characterized in that it is a derivative selected from the group consisting of esters of formula-C(O)Rmwhere Rmmeans alkyl.

7. Derivatives of carboxylic acids, having the structure

where Y in each case independently selected from the group consisting of C(O), N, CR1C(R2)(R3), NR5CH;

q denotes an integer from 2 to 5;

T is selected from the group consisting of (CH2)bwhere b means 0;

L is selected from the group consisting of NR11and (CH2)nwhere n stands for 0;

Selected from the group consisting of hydrogen and alkyl;

R1, R2and R3independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkyl, alkoxy, -CF3, amino, -NHC(O)N(C1-C3alkyl)C(O)NH(C1-C3alkyl), -NHC(O)NH(C1-C6alkyl), alkylamino, alkoxyalkyl, cycloalkyl, aryl, aryloxy, arylamino, heterocyclyl, heterocyclisation, where the heteroatom is selected from N or O, -NHSO2(C1-C3alkyl), aryloxyalkyl;/p>

where R1, R2and R3unsubstituted or substituted by at least one electron-donating or electron-withdrawing group selected from the group consisting of carboxy, alkyl, alkoxy and aryl;

R4selected from the group consisting of hydrogen, aryl, aralkyl, benzofuranyl, dihydrobenzofuranyl, dihydroindeno, alkyl, benzodioxolyl, dihydroergotoxine, furyl, naphthyl, chinoline, ethenolysis, pyridinyl, indolyl, thienyl, biphenyl, 2-oxo-2,3-dihydro-1H-benzimidazolyl, pyrimidinyl and carbazolyl, where R4may be unsubstituted or substituted by at least one electron-donating or electron-withdrawing group selected from the group consisting of alkyl, alkoxy, hydroxy, SO2(C1-C3alkyl), halogen, di(lower alkyl)amino, alkylthio, halogenated, -O-halogenated, alkoxyalkane, cycloalkyl, -NHSO2(C1-C3alkyl), -N(C1-C3alkyl)SO2(C1-C3alkyl), cycloalkane, pyrrolidinyl, -O-cycloalkenyl and piperidinyl;

R5selected from the group consisting of aralkyl, aryloxyalkyl, cycloalkyl and geterotsiklicheskikh, which heteroatom is selected from N, O and S, where R5may be unsubstituted or substituted by at least one electron-donating or electron-withdrawing group selected from the group consisting of aralkylamines, 3-aryl-1-ureido halogen, -CN, alkoxy, alkyl, halogenated, aryl, hydroxy, -NO2, amino, -NH(aliphatic acyl), -NHSO2(C1-C3alkyl), alkylthio, -O-halogenated, -SO2(C1-C3alkyl), -SO2N(C1-C3alkyl)2, -SO2(1-pyrrolidinyl), -SO2(1-piperidinyl), -O-aralkyl, -O-cycloalkenyl, alkoxyalkane;

R6selected from the group consisting of hydrogen, alkyl;

R7and R11represent hydrogen;

R9and R10represent hydrogen or alkyl,

or their pharmaceutically acceptable salts.

8. The connection according to claim 7, wherein R5selected from the group consisting of aralkyl and geterotsiklicheskikh, which heteroatom is selected from N, O and S, L means (CH2)nwhere n is 0, Y is chosen from the group consisting of CR1and C(R2)(R3), and q is 2 or 3.

9. The connection according to claim 7, characterized in that it is a derivative selected from the group consisting of esters of formula-C(O)Rmwhere Rmmeans alkyl.

10. The connection according to claim 7, characterized in that

selected from the group consisting of

,and

where R18, R19, R20, Rsup> 21and R28in each case, independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkyl, alkoxy, -CF3, amino, -NHC(O)N(C1-C3alkyl)C(O)NH(C1-C3alkyl), -NHC(O)NH(C1-C6alkyl), alkylamino, alkoxyalkyl, cycloalkyl, aryl, aryloxy, arylamino, heterocyclyl, heterocyclisation, where the heteroatom is selected from N or O, -NHSO2(C1-C3alkyl) and aryloxyalkyl;

with means an integer from zero to two;

d is an integer from zero to three;

E. means an integer from zero to four and

f denotes zero or one.

11. The connection according to claim 7, characterized in that

R5means alkylaryl;

R4means aryl;

T means (CH2)bwhere b is 0;

L means (CH2)nwhere n is 0, and

In, R6, R7, R9and R10each independently mean hydrogen.

12. The compound according to claim 4 or 7, characterized in that it is selected from the group consisting of

(3S)-3-[({[2-methyl-4-(2-methylpropyl)-6-oxo-1-(phenylmethyl)-1,6-dihydro-5-pyrimidinyl]amino}carbonyl)amino]-3-(4-were)propionic acid,

(3S)-3-(1,3-benzodioxol-5-yl)-3-[({[2-oxo-1-(phenylmethyl)-4-propyl-1,2-dihydro-3-pyridinyl]amino}carbonyl)amino]propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-ethyl-2-oxo-12-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-{[({6-methyl-2-oxo-1-(phenylmethyl)-4-[(phenylmethyl)oxy]-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-2,4-dimethyl-6-oxo-1,6-dihydro-5-pyrimidinyl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-{[({4-amino-1-[(2-chlorophenyl)methyl]-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)-propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl) methyl]-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-[4-(metiloksi)phenyl]propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(3,4-dimetilfenil)propionic acid,

(3S)-3-{[({4-amino-1-[(2-chlorophenyl)methyl]-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-[({[1-[(2-chlorophenyl)methyl]-4-(1,4-oxazine-4-yl)-2-oxo-1,2-dihydro-3-pyridinyl]amino}carbonyl)amino]-3-(4-methyl who enyl)propionic acid,

(3S)-3-[({[1-[(2-chlorophenyl)methyl]-2-oxo-4-(propylamino)-1,2-dihydro-3-pyridinyl]amino}carbonyl)amino]-3-(4-were)propionic acid,

(3S)-3-{[({1-[(2-bromophenyl)methyl]-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-[3-methyl-4-(metiloksi)phenyl]-propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-4-phenyl-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-[(2-{[2-(metiloksi)ethyl]oxy}ethyl)oxy]-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-[(1,1-dimethylethyl)amino]-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methyl-phenyl)propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-phenylpropionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-[4-methyltetrahydro-1(2H)-pyrazinyl]-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-the CSR-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-[4-(metiloksi)phenyl]propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(3, 5dimethylphenyl)propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(3-were)propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-[3-(metiloksi)phenyl]propionic acid,

(3S)-3-[3,5-bis(metiloksi)phenyl]-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-chinoline}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-[3-(trifluoromethyl)phenyl]propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-[({ethyl[(ethylamino)-carbonyl]amino}carbonyl)amino]-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-{[({4-(1-acetonyl)-1-[(2-chlorophenyl)methyl]-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-[({[1-[(2-chlorophenyl)methyl]-4-({2-[(2-{[2-(methyl-oxy)ethyl]oxy}ethyl)oxy]ethyl}oxy)-2-oxo-1,2-dihydro-3-pyridinyl]amino)carbonyl)amino]-3-(4-were)propionic acid,

(3S)-3-{({1-[(2-forfinal)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-{[({1-[(2-chloro-6-forfinal)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-(1,3-benzodioxol-5-yl)-3-((((2-oxo-1-((4-(trifter-methyl)phenyl)methyl)-1,2-dihydro-3-pyridinyl)amino)carbonyl)-amino)propionic acid,

(3S)-3-((((1-((2-chlorophenyl)methyl)-2-oxo-1,2-dihydro-3-pyridinyl)amino)carbonyl)amino)-3-(4-were)propionic acid,

(3S)-3-((((1-((2-forfinal)methyl)-2-oxo-1,2-dihydro-3-pyridinyl)amino)carbonyl)amino)-3-(4-were)propionic acid,

(3S)-3-((((1-((2-bromophenyl)methyl)-2-oxo-1,2-dihydro-3-pyridinyl)amino)carbonyl)amino)-3-(4-were)propionic acid,

(3S)-3-((((1-((2,4-dichlorophenyl)methyl)-2-oxo-1,2-dihydro-3-pyridinyl)amino)carbonyl)amino)-3-(4-were)propionic acid,

(3S)-3-((((1-((2-chloro-6-forfinal)methyl)-2-oxo-1,2-dihydro-3-pyridinyl)amino)carbonyl)amino)-3-(4-were)propionic acid,

(3S)-3-((((1-((2-chlorophenyl)methyl)-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl)amino)carbonyl)amino)-3-(4-trifluoromethyl)-oxy)phenyl)propionic acid

and their pharmaceutically acceptable salts.

13. The connection according claim 11, characterized in that it is a derivative that is selected is from the group containing esters of the formula-C(O)Rmwhere Rmmeans alkyl.

14. Derivatives of carboxylic acids, having the structure

in which T is selected from the group consisting of (CH2)bwhere b means 0;

L is selected from the group consisting of NR11and (CH2)nwhere n stands for 0;

g denotes an integer from 0 to 7;

R4selected from the group consisting of hydrogen, aryl, aralkyl, benzofuranyl, dihydrobenzofuranyl, dihydroindeno, alkyl, benzodioxolyl, dihydroergotoxine, furyl, naphthyl, chinoline, ethenolysis, pyridinyl, indolyl, thienyl, biphenyl, 2-oxo-2,3-dihydro-1H-benzimidazolyl, pyrimidinyl and carbazolyl, where R4may be unsubstituted or substituted by at least one electron-donating or electron-withdrawing group selected from the group consisting of alkyl, alkoxy, hydroxy, SO2(C1-C3alkyl), halogen, di(lower alkyl)amino, alkylthio, halogenated, -O-halogenated, alkoxyalkane, cycloalkyl, -NHSO2(C1-C3alkyl), -N(C1-C3alkyl)SO2(C1-C3alkyl), cycloalkane, pyrrolidinyl, -O-cycloalkenyl and piperidinyl;

R6selected from the group consisting of hydrogen, alkyl;

In, R7and R11represent hydrogen;

R9, R represent hydrogen or alkyl;

R23in each case independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, -CF3, -NH2, -OH, -NHC(O)N(C1-C3alkyl)C(O)NH(C1-C3alkyl), -NHC(O)NH(C1-C6alkyl), -NHSO2(C1-C3alkyl), alkylamino, alkoxyalkyl, cycloalkyl, aryl, aryloxy, arylamino, heterocyclyl, heterocyclisation, where the heteroatom is selected from N or O; R23may be unsubstituted or substituted by at least one electron-donating or electron-withdrawing group selected from the group consisting of carboxy, alkyl, alkoxy and aryl;

R18selected from the group consisting of cycloalkyl, aralkyl, geterotsiklicheskikh, aryloxyalkyl, where R18unsubstituted or substituted by at least one electron-donating or electron-withdrawing group selected from the group consisting of aralkylamines, 3-aryl-1-ureido, halogen, -CN, alkoxy, alkyl, halogenated, aryl, hydroxy, -NO2, amino, -NH(aliphatic acyl), -NHSO2(C1-C3alkyl), alkylthio, -O-halogenated, -SO2(C1-C3alkyl), -SO2N(C1-C3alkyl)2, -SO2(1-pyrrolidinyl), -SO2(1-piperidinyl), -O-aralkyl, -O-cycloalkenyl, alkoxyalkane,

or their pharmaceutically acceptable salts.

15. Soy is inania on 14 characterized in that it is a derivative selected from the group consisting of esters of formula-C(O)Rmwhere Rmmeans alkyl.

16. Derivatives of carboxylic acids, having the structure

in which h stands for an integer from zero to five;

And R7mean hydrogen;

R6, R9and R10represents hydrogen or lower alkyl;

R24and R25in each case independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, -CF3HE, halogenated, cycloalkyl, aralkyl;

R27in each case independently selected from the group consisting of halogen, hydroxyl, alkyl, alkoxy, -NHSO2(C1-C3alkyl), -N(C1-C3alkyl)SO2(C1-C3alkyl), di(lower alkyl)amino, halogenated, -O-halogenated, alkoxyalkane, cycloalkyl, cycloalkene, alkylthio, -O-cycloalkenyl, -SO2(C1-C3alkyl), pyrrolidinyl and piperidinyl;

R18in each case independently selected from the group containing alkylamino, arylamino, tiari, aralkyl, geterotsiklicheskikh, where the heteroatom is selected from N and S, aryloxyalkyl, hydrogen, and

R26selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, alkyl, and R26may be unsubstituted or substituted by at least one electron-donating or electron-withdrawing group selected from the group consisting of alkoxy, alkoxyalkyl, a R18, R24, R25unsubstituted or substituted by at least one electron-donating or electron-withdrawing group containing a lower alkyl, alkyloxy, hydroxy, sulfonyl, -SO2(C1-C3alkyl), halogen, di(lower alkyl)amino, and R24and R25can be combined with the loop

or their pharmaceutically acceptable salts.

17. Connection item 16, characterized In that, R6, R7, R9, R10, R24, R25and R26each independently mean hydrogen, and R18means substituted or unsubstituted aralkyl.

18. Connection item 16, characterized in that it is a derivative selected from the group consisting of esters of formula-C(O)Rmwhere Rmmeans alkyl.

19. Derivatives of carboxylic acids, having the structure

where Z in each case independently chosen from the group consisting of CR30C(R31)(R32) and SN;

z denotes an integer from 3 to 6;

k is an integer from 0 to 5;

T is chosen from the group consisting of (CH2 bwhere b means 0;

L is chosen from the group consisting of NR11and (CH2)nwhere n stands for 0;

R6selected from the group consisting of hydrogen, alkyl;

R7and R11represent hydrogen;

R18selected from the group consisting of cycloalkyl, aralkyl, geterotsiklicheskikh, aryloxyalkyl;

R4selected from the group consisting of hydrogen, aryl, aralkyl, benzofuranyl, dihydrobenzofuranyl, dihydroindeno, alkyl, benzodioxolyl, dihydroergotoxine, furyl, naphthyl, chinoline, ethenolysis, pyridinyl, indolyl, thienyl, biphenyl, 2-oxo-2,3-dihydro-1H-benzimidazolyl, pyrimidinyl and carbazolyl, where R4may be unsubstituted or substituted by at least one electron-donating or electron-withdrawing group selected from the group consisting of alkyl, alkoxy, hydroxy, SO2(C1-C3alkyl), halogen, di(lower alkyl)amino, alkylthio, halogenated, -O-halogenated, alkoxyalkane, cycloalkyl, -NHSO2(C1-C3alkyl), -N(C1-C3alkyl)SO2(C1-C3alkyl), cycloalkane, pyrrolidinyl, -O-cycloalkenyl and piperidinyl;

R9and R10represent hydrogen or alkyl;

R29, R30, R31and R32in each case independently selected from the group containing in the location, halogen, alkyl, alkoxy, -CF3, -OH, -NH2, -NHC(O)N(C1-C3alkyl)C(O)NH(C1-C3alkyl), -NHC(O)NH(C1-C6alkyl), -NHSO2(C1-C3alkyl), alkylamino, alkoxyalkyl, cycloalkyl, aryl, aryloxy, arylamino, heterocyclyl, heterocyclisation, where the heteroatom is selected from N or O;

where R29, R30, R31and R32unsubstituted or substituted by at least one electron-donating or electron-withdrawing group selected from the group consisting of carboxy, alkyl, alkoxy and aryl,

or their pharmaceutically acceptable salts.

20. The connection according to claim 19, characterized in that it is a derivative selected from the group consisting of esters of formula-C(O)Rmwhere Rmmeans alkyl.

21. The connection according to claim 19, characterized in that z is equal to three or four.

22. The compound having the structure

where R24and R25each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, -CF3HE, halogenated, cycloalkyl, aralkyl, R24and R25unsubstituted or substituted by at least one electron-donating or electron-withdrawing group containing a lower alkyl, alkyloxy, hydroxy, sulfonyl, -SO2(C1-C3alkyl), halogen, di(lower and the keel)amino, or R24and R25can be combined with the education cycle, provided that if R24and R25combined with the education cycle, the resulting cycle does not mean benzene;

R18selected from the group consisting of cycloalkyl, aralkyl, geterotsiklicheskikh, aryloxyalkyl, where R18unsubstituted or substituted by at least one electron-donating or electron-withdrawing group selected from the group consisting of aralkylamines, 3-aryl-1-ureido, halogen, -CN, alkoxy, alkyl, halogenated, aryl, hydroxy, -NO2, amino, -NH(aliphatic acyl), -NHSO2(C1-C3alkyl), alkylthio, -O-halogenated, -SO2(C1-C3alkyl), -SO2N(C1-C3alkyl)2, -SO2(1-pyrrolidinyl), -SO2(1-piperidinyl), -O-aralkyl, -O-cycloalkenyl, alkoxyalkane;

and R34means hydrogen.

23. The connection to item 22, wherein R34means hydrogen, R18means aralkyl, and R24and R25each independently selected from the group consisting of hydrogen, lower alkyl and lower alkyl, in which R24and R25combined with the formation of the loop.

24. Connection p.22, characterized in that it is represented by the structure

where R24and R25each independently selected from the group steriade is hydrogen, halogen, alkyl, alkoxy, -CF3HE, halogenated, cycloalkyl, aralkyl;

thus R24and R25unsubstituted or substituted by at least one electron-donating or electron-withdrawing group containing a lower alkyl, alkyloxy, hydroxy, sulfonyl, -SO2(C1-C3alkyl), halogen, di(lower alkyl)amino, or R24and R25can be combined with the education cycle, provided that if R24and R25combined with the education cycle, the resulting cycle does not mean benzene;

R34means hydrogen, and

R35in each case independently selected from the group consisting of halogen, hydroxyl, alkyl, alkylthio, alkoxy, NH(aliphatic acyl), -CN, -NO2, -NH2, -NHSO2(C1-C3alkyl), aralkylamines, 3-aryl-1-ureido, halogenated, -O-halogenated, alkoxyalkane, -O-cycloalkenyl, aryl, -O-aralkyl, -SO2(C1-C3alkyl), -SO2N(C1-C3alkyl)2, -SO2(1-pyrrolidinyl), -SO2(1-piperidinyl);

m means an integer from 0 to 5.

25. The connection point 24, wherein R34means hydrogen, m means an integer from one to three, and R35in each case selected from the group consisting of alkyl, halogen, alkoxy, halogenated, sulfonyl IT, and-CN.

26. Connected the e on p.22, characterized in that it is selected from the group consisting of

5-(2-Chlorobenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-Chlorobenzyl)-6-methyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-terbisil)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-chloro-6-terbisil)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-benzyl-6-methyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-benzyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2,5-dimethylbenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-methylbenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2,4-dichlorobenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-methoxybenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2,5-diferensial)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-[2-chloro-5-(methylthio)benzyl] - for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(4-terbisil)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-chloro-5-methoxybenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-[3,5-bis(trifluoromethyl)benzyl] - for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(4-tert-butylbenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(3-Chlorobenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(4-chlorbenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-[-(trifluoromethyl)benzyl] - for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-bromobenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(3,4-dichlorobenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(4-methylbenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-chloro-6-methoxybenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-[4-(trifluoromethyl)benzyl] - for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(3-methylbenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(pyridine-2-ylmethyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-Chlorobenzyl)-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2,4-diferensial)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2,6-diferensial)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-[3-(triptoreline)benzyl] - for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-[4-(triptoreline)benzyl] - for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-[2-(trifluoromethyl)benzyl] - for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(3-methoxybenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2,3-dichlorobenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(3,5-dimethylbenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-Chlorobenzyl)-7-pentyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2,4-dichlorobenzyl)-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-Chlorobenzyl)-7-the Teal-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

7-butyl-5-(2-Chlorobenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-[2-chloro-5-(trifluoromethyl)benzyl] - for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2,6-dichlorobenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-chloro-5-terbisil)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-chloro-6-methylbenzyl)-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(4-Chlorobenzyl)-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-Chlorobenzyl)-5,6,7,8-tetrahydro-2H-cyclopent[b][1,3]oxazol[5,4-d]-pyridine-2,4(3H)-dione,

7-methyl-5-[4-(methylsulphonyl)benzyl] - for 3,5-dihydro[1,3]oxazol[4,5-C]-pyridine-2,4-dione,

5-(4-methoxybenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-Chlorobenzyl)-7-propyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

4-[(2,4-dioxo-2,3-dihydro[1,3]oxazol[4,5-C]pyridine-5(4H)-yl)methyl]-N,N-dimethylbenzenesulfonamide,

5-(methicillin)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-Chlorobenzyl)-3,5,6,7,8,9-hexahydro[1,3]oxazol[4,5-C]quinoline-2,4-dione,

5-(2-Chlorobenzyl)-7-ethyl-6-methyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-[2-(methylthio)benzyl] - for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

2-[(2,4-dioxo-2,3-dihydro[1,3]oxazol[4,5-C]pyridine-5(4H)-yl)methyl]-N,N-dimethylbenzenesulfonamide,

5-(2,6-dimethoxybenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-24-dione,

5-[2-(triptoreline)benzyl] - for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-Chlorobenzyl)-6,7-dimethyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-[2-chloro-5-(methylsulphonyl)benzyl] - for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(4-chloro-2-methoxybenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-Chlorobenzyl)-5,6,7,8,9,10-hexahydro-2H-cyclohepta[b][1,3]oxazol[5,4-d]-pyridine-2,4(3H)-dione,

5-[2-(deformedarse)benzyl] - for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

7-methyl-5-[(1R)-1-phenylethyl] - for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(4-Chlorobenzyl)-7-propyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-[2-(methylsulphonyl)benzyl] - for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2,6-dimethylbenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

3-chloro-2-[(2,4-dioxo-2,3-dihydro[1,3]oxazol[4,5-C]pyridine-5(4H)-yl)methyl]benzonitrile,

5-(2-chloro-6-methylbenzyl)-6,7-dimethyl-3,5-dihydro[1,3]oxazol[4,5-C]-pyridine-2,4-dione,

2-[(2,4-dioxo-2,3-dihydro[1,3]oxazol[4,5-C]pyridine-5(4H)-yl)methyl]-benzonitrile,

5-(2-chloro-6-methoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazol-[4,5-C]pyridine-2,4-dione,

5-[3-(methylthio)benzyl] - for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-Chlorobenzyl)-7-cyclopropyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(3-Chlorobenzyl)-7-methyl-3,5-dihydro[1,3]oxazol[45-a]pyridine-2,4-dione,

5-(2,6-dichlorobenzyl)-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

7-methyl-5-(4-methylbenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(3,5-dimethoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2,6-diferensial)-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-[3-(methylsulphonyl)benzyl] - for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-chloro-6-ethoxybenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-chloro-6-ethoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazol(4,5-C]pyridine-2,4-dione,

5-(2-fluoro-6-methoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazol-[4,5-C]pyridine-2,4-dione,

5-(2-chloro-6-methoxybenzyl)-7-propyl-3,5-dihydro[1,3]oxazol-[4,5-C]-pyridine-2,4-dione,

5-(5-chloro-2-terbisil)-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-Chlorobenzyl)-7-isopropyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(5-fluoro-2-methylbenzyl)-7-methyl-3,5-dihydro[1,3]oxazol-[4,5-C]pyridine-2,4-dione,

7-methyl-5-[(1S)-1-phenylethyl] - for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-chloro-5-isopropoxyphenyl)-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]-pyridine-2,4-dione,

5-(5-acetyl-2-methoxybenzyl)for 3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-Chlorobenzyl)-7-methyl-3,5-dihydro[1,3]oxazol[4,5-d]pyridazin-2,4-dione,

5-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3,5-dihydro[1,3]is xazal[4,5-C]-pyridine-2,4-dione,

5-(2-chloro-6-methylbenzyl)-5,6,7,8-tetrahydro-2H-cyclopent[b]-[1,3]oxazol-[5,4-d]pyridine-2,4(3H)-dione,

5-(2-chloro-6-ethoxybenzyl)-7-ethyl-3,5-dihydro[1,3]oxazol-[4,5-C]pyridine-2,4-dione,

5-(2-chloro-6-propoxyphenyl)-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-chloro-6-salutogenesis)-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]-pyridine-2,4-dione,

5-(2-chloro-6-ethoxybenzyl)-5,6,7,8-tetrahydro-2H-cyclopent[b]-[1,3]oxazol[5,4-d]pyridine-2,4(3H)-dione,

5-(2-chloro-6-isopropoxyphenyl)-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]-pyridine-2,4-dione,

5-[2-chloro-6-(2,2,2-triptoreline)benzyl]-7-methyl-3,5-dihydro-[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-chloro-6-ethoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazol-[4,5-d]pyridazin-2,4-dione,

5-[2-chloro-6-(2-methoxyethoxy)benzyl]-5,6,7,8-tetrahydro-2H-cyclopent[b][1,3]oxazol[5,4-d]pyridine-2,4(3H)-dione,

5-(2-chloro-6-ethoxybenzyl)-6,7-dimethyl-3,5-dihydro[1,3]oxazol[4,5-C]-pyridine-2,4-dione,

5-(2-chloro-6-ethoxybenzyl)-7-ethyl-6-methyl-3,5-dihydro[1,3]oxazol[4,5-C]-pyridine-2,4-dione,

5-(2-Chlorobenzyl)-7-ethyl-3,5-dihydro[1,3]oxazol[4,5-d]pyridazin-2,4-dione,

5-(2-chloro-6-ethoxybenzyl)-7-propyl-3,5-dihydro(1,3]oxazol-[4,5-C]pyridine-2,4-dione,

5-(2-chloro-6-ethoxybenzyl)-7-cyclopropyl-3,5-dihydro[1,3]oxazol[4,5-C]-pyridine-2,4-dione,

5-(2-chloro-5-propoxyphenyl)-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-(2-chloro-5-methoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazol-[4,5-C]pyridine-2,4-dione,

5-(2-chloro-6-ethoxybenzyl)-6-methyl-3,5-dihydro[1,3]oxazol-[4,5-C]pyridine-2,4-dione,

5-(2-chloro-5-ethoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazol-[4,5-C]pyridine-2,4-dione,

5-[2-chloro-5-(piperidine-1-ylsulphonyl)benzyl]-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-[2-chloro-5-(pyrrolidin-1-ylsulphonyl)benzyl]-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-[2-chloro-6-(cyclopentyloxy)benzyl]-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione,

5-[2-(benzyloxy)-6-Chlorobenzyl]-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]-pyridine-2,4-dione,

5-(2,3-dichloro-6-ethoxybenzyl)-5,6,7,8-tetrahydro-2H-cyclopent[b][1,3]oxazol[5,4-d]pyridine-2,4(3H)-dione,

5-[2-chloro-5-(trifluoromethyl)benzyl]-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]-pyridine-2,4-dione and

5-(2-chloro-5-terbisil)-7-methyl-3,5-dihydro[1,3]oxazol[4,5-C]pyridine-2,4-dione.

27. A compound selected from the group consisting of

(3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid,

4-{[3-[({[(1S)-2-carboxy-1-(4-were)ethyl]amino}carbonyl)amino]-1-(2-Chlorobenzyl)-2-oxo-1,2-dihydropyridines-4-yl]amino}benzoic acid,

(3S)-3-{[({1-(2-Chlorobenzyl)-4-[(2,2-dimethylpropanoyl)amino]-2-oxo-1,2-dihydropyridines-3-yl}amino)carbonyl]amino}-3(4-were)propionic acid,

(3S)-3-[({[4-{[(tert-butylamino)carbonyl]amino}-1-(2-Chlorobenzyl)-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid,

(3S)-3-[({[1-(2-cyanobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(7-methoxy-1,3-benzodioxol-5-yl)propionic acid,

(3S)-3-[{{[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3-ethoxy-4-methoxyphenyl)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3,4-acid)propionic acid,

(3S)-3-[({[1-(4-Chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino)carbonyl)amino]-3-(4-were)propionic acid,

(3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid,

(3S)-3-[({[1-(2,6-diferensial)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}to bonil)amino]-3-(4-were)propionic acid,

(3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3,5-acid)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3,4-dioxyphenyl)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3-methoxy-4-were)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino)carbonyl)amino]-3-(3,5-dimethoxy-4-were)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3,4-dimetilfenil)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid,

(3S)-3-{[({1-[2-chloro-5-(trifluoromethyl)benzyl]-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3-were)propionic acid,

(3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}Carbo who yl)amino]-3-(4-were)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl]amino}carbonyl)amino]-3-(4-were)-propionic acid,

(3S)-3-[({[1-(2,6-dimethoxybenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3-propoxyphenyl)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3,4-dioxyphenyl)propionic acid,

(3S)-3-(3-butoxyphenyl)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]propionic acid,

(3S)-3-{[({1-[2-chloro-5-(methylsulphonyl)benzyl]-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl}amino)carbonyl]amino}-3-(4-were)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-[3-(2-methoxyethoxy)phenyl]propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}ka is bonyl)amino]-3-(3,4-dibromobiphenyl)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-[3-(deformedarse)phenyl]propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3,4-dioxyphenyl)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propionic acid,

(38)-3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3,4-dioxyphenyl)propionic acid,

(3S)-3-[({[1-(2-chloro-6-cyanobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid,

3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(2-naphthyl)propionic acid,

(3S)-3-[({[1 -(2-Chlorobenzyl)-4-hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3,4-dioxyphenyl)propionic acid,

(3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3,4-dioxyphenyl)-propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]while the Ino}carbonyl)amino]-3-(4-methoxyphenyl)propionic acid,

(3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)-propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)-propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)-propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(1-methyl-1H-indol-5-yl)-propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(2,3-dihydro-1-benzofuran-5-yl)propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl]amino}carbonyl)amino]-3-(3,5-dioxyphenyl)propionic acid,

(3S)-3-[({[5-chloro-1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3-isop epoxyphenol)propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl]amino}carbonyl)amino]-3-(3-propoxyphenyl)-propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl]amino}carbonyl)amino]-3-phenylpropionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent(b]pyridine-3-yl]amino}carbonyl)amino]-3-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-yl)propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-[3-(triptoreline)phenyl]-propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)-propionic acid,

(3S)-3-(({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl]amino}carbonyl)amino]-3-(1-methyl-1H-indol-5-yl)propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-5-cyclopropyl-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)-propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-5-cyclopropyl-4-hydroxy-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid,

(3S)-3-[({[1-(2-chloro-5-methoxybenzyl)-4-hydroxy-5-methyl-2-about the co-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-6-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)-propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(1-methyl-1H-indol-6-yl)-propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl]amino}carbonyl)amino]-3-[3-(cyclopropylamino)phenyl]propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl]amino}carbonyl)amino]-3-[3-(cyclopropylmethoxy)phenyl]propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl]amino}carbonyl)amino]-3-[3-(cyclopropylmethoxy)phenyl]propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl]amino}carbonyl)amino]-3-(3, 5dimethylphenyl)-propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl}amino)carbonyl]amino}-3-{3-((deformity)-hydroxy]phenyl}propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl}amino)carbonyl]amino}-3-{3-[(1,1,2,2-tetraborate)oxy]phenyl}propionic acid,

(3S)-3-{[({1-[(2-chlorine is phenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl}amino)carbonyl]amino}-3-(1-ethyl-1H-indol-5-yl)propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl}amino)carbonyl]amino}-3-[3-(diethylamino)-phenyl]propionic acid and their pharmaceutically acceptable salts.

28. (3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid and its pharmaceutically acceptable salts.

29. (3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl]amino}carbonyl)amino]-3-(4-were)-propionic acid and its pharmaceutically acceptable salts.

30. (3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-[3-(diethylamino)phenyl]-propionic acid and its pharmaceutically acceptable salts.

31. A compound selected from the group consisting of

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(4-were)propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propionic acid,

(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridines-3-yl]amino}carb the Nile)amino]-3-(6-methoxy-2-naphthyl)propionic acid,

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl]amino}carbonyl)amino]-3-(3-were)propionic acid,

(3S)-3-{[({1-[(2-chloro-6-were)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl}amino)carbonyl]amino}-3-(1-methyl-1H-indol-5-yl)propionic acid,

(3S)-3-{[({1-((2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl}amino)carbonyl]amino}-3-{3-[(methylsulphonyl)amino]phenyl}propionic acid,

(3S)-3-{[({1-[(2-chloro-6-were)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl}amino)carbonyl]amino}-3-{3-[(methylsulphonyl)amino]phenyl}propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl}amino)carbonyl]amino}-3-{3-[methyl - (methylsulphonyl)amino]phenyl}propionic acid,

(3S)-3-{[({1-[(2-chloro-6-were)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl}amino)carbonyl]amino}-3-{3-[methyl - (methylsulphonyl)amino]-phenyl} propionic acid,

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl}amino)carbonyl]amino}-3-{3-[ethyl(methylsulphonyl)amino]phenyl}propionic acid,

(3S)-3-{[({1-[(2-chloro-6-were)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl}amino)carbon is l]amino}-3-{3-[ethyl(methylsulphonyl)amino]-phenyl}propionic acid,

(3S)-3-{[({1-[(2-chloro-6-were)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopent[b]pyridine-3-yl}amino)carbonyl]amino}-3-(1H-indol-5-yl)propionic acid and their pharmaceutically acceptable salts.

32. Pharmaceutical composition for inhibiting the binding of α4β1integrin containing the compound according to claim 1 in a pharmaceutically acceptable carrier.

33. The method of selective inhibition of binding α4β1integrin in a mammal, wherein said mammal is administered a therapeutic amount of a compound according to claim 1.



 

Same patents:

FIELD: organic chemistry, biochemistry, medicine, pharmacology.

SUBSTANCE: invention relates to gyrase inhibitors that reduce amount of microorganisms in biological sample by contacting the indicated sample with compound of the formula (I): , to a method for treatment of bacterial infection by using compounds of the formula (I), compounds of the formula (I) and a pharmaceutical composition comprising compounds of the formula (I). Invention provides the enhanced effectiveness of treatment.

EFFECT: valuable medicinal properties of gyrase.

54 cl, 5 tbl, 13 ex

FIELD: organic chemistry, medicinal biochemistry, pharmacy.

SUBSTANCE: invention relates to substituted benzimidazoles of the formula (I): and/or their stereoisomeric forms, and/or their physiologically acceptable salts wherein one of substitutes R1, R2, R3 and R4 means a residue of the formula (II): wherein D means -C(O)-; R8 means hydrogen atom or (C1-C4)-alkyl; R9 means: 1. (C1-C6)-alkyl wherein alkyl is linear or branched and can be free of substituted by one-, bi- or tri-fold; Z means: 1. a residue of 5-14-membered aromatic system that comprises from 1 to 4 heteroatoms as members of the cycle that represent nitrogen and oxygen atoms wherein aromatic system is free or substituted; 1.1 a heterocycle taken among the group of oxadiazole or oxadiazolone that can be unsubstituted or substituted; 2. (C1-C6)-alkyl wherein alkyl is a linear or branched and monosubstituted with phenyl or group -OH; or 3. -C(O)-R10 wherein R10 means -O-R11, -N(R11)2 or morpholinyl; or R8 and R9 in common with nitrogen atom and carbon atom with that they are bound, respectively, form heterocycle of the formula (IIa): wherein D, Z and R10 have values given in the formula (II); A means a residue -CH2-; B means a residue -CH-; Y is absent or means a residue -CH2-; or X and Y in common form phenyl. The cyclic system formed by N, A, X, Y, B and carbon atom is unsubstituted or monosubstituted with (C1-C8)-alkyl wherein alkyl is monosubstituted with phenyl, and other substitutes R1, R2, R3 and R4 mean independently of one another hydrogen atom, respectively; R5 means hydrogen atom; R6 means the heteroaromatic cyclic system with 5-14 members in cycle that comprises 1 or 2 nitrogen atoms and can be unsubstituted or substituted. Also, invention relates to a medicinal agent for inhibition of activity of IkB kinase based on these compounds and to a method for preparing the indicated agent. Invention provides preparing new compounds and medicinal agents based on thereof for aims for prophylaxis and treatment of diseases associated with the enhanced activity of NFkB.

EFFECT: valuable medicinal properties of compounds and composition.

4 cl, 7 tbl, 224 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives if azaindole of the formula (I)

or its pharmaceutically acceptable salts wherein the formula is taken among the group consisting of , , and and wherein each among R1, R2, R3 and R4 is taken independently among the group consisting of hydrogen atom (H), (C1-C6)-alkyl, (C2-C6)-alkenyl, halogen atom, cyano-group (CN), phenyl, nitro-group, -OC(O)R15, -C(O)R15, -C(O)OR16, -OR19, -SR20 and NR21R22 wherein R15 is taken independently among the group including hydrogen atom (H),(C1-C6)-alkyl and (C2-C6)-alkenyl; each among R16, R19 and R0 is taken independently among the group including hydrogen atom (H), (C1-C6)-alkyl or (C1-C6)-alkyl substituted with from 1 to 3 halogen atoms; each among R21 and R22 is taken among the group including hydrogen atom(H), hydroxy-group (OH), (C1-C6)-alkyl; R5 represents the group (O)m wherein m = 0 or 1; n = 1 or 2; R6 is taken among the group including hydrogen atom (H), (C1-C6)-alkyl, -C(O)R24 and -C(O)OR5 under condition that carbon atoms comprising carbon-carbon double bond of indicated (C3-C6)-alkenyl are not the addition point to nitrogen atom to which R6 is joined; R24 is taken among the group consisting of hydrogen atom (H), and (C1-C6)-alkyl; R25 represents (C1-C6)-alkyl; each among R7, R8, R9, R10, R11, R12, R13 and R14 is taken independently among the group including hydrogen atom (H) and (C1-C6)-alkyl; Ar is taken among the group including:

, and . Compounds of the formula (I) inhibit HIV-1 that allows proposing their applying in medicine.

EFFECT: valuable medicinal and antiviral properties of compounds.

22 cl, 13 sch, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (1)

wherein A represents bicyclic or tricyclic azepine derivative; V1 and V2 both represent hydrogen atom (H) or one among V1 and V2 represents hydrogen atom (H), OMe, OBn, OPh, O-acyl, Br, Cl, F, N3, NH2, NHBn and another represents hydrogen atom (H); or V1 and V2 represent in common =O or -O(CH2)pO-; W1 represents oxygen (O) or sulfur (S) atom; X1 and X2 both represent hydrogen atom (H) or in common represent =O or =S; Y represents OR5 or NR6R7; R1 means hydrogen atom (H), lower alkyl, F, Cl and Br; R2 means lower alkoxy-group or values given for R1; R3 and R5 are taken independently among hydrogen atom (H) and lower alkyl; R4 means hydrogen atom (H); R6 and R7 are taken independently among hydrogen atom (H) and lower alkyl, or they in common mean -(CH2)n-; n = 3, 4, 5 or 6; p = 2 or 3. These compounds are agonists of vasopressin V2 receptors and useful as antidiuretic and procoagulants, and also to pharmaceutical compositions comprising these vasopressin agonists. These compositions are useful especially in treatment of diabetes insipidus of the central origin and night enuresis.

EFFECT: valuable medicinal properties of compounds, improved method for treatment.

26 cl, 1 tbl, 119 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new azaheterocycles comprising fragment of piperidin-2-yl- of the general formula (1):

as separate enantiomers or mixture of enantiomers, or their pharmaceutically acceptable salts, oxides or hydrates. In compounds of the formula (1) R1 represents hydrogen atom, inert substitute or NH-protecting substitute; W represents optionally substituted azaheterocycle, such as: pyridin-3-yl, pyrazolo[1,5-a]pyridin-6-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-7-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-9-yl, imidazo[1,2-a]pyrimidin-6-yl, imidazo[1,2-a]pyrimidin-8-yl or [1,8]naphthyridin-3-yl. Compounds elicit activity with respect to nicotine receptors and can be used in pharmaceutical industry. Also, invention relates to the focused library for search of physiologically active compound-leaders, and to pharmaceutical compositions based on new compounds of the formula (1).

EFFECT: valuable medicinal and pharmacological properties of compounds.

9 cl, 1 tbl, 15 sch, 22 ex

FIELD: organic chemistry, medicine, psychiatry, pharmacy.

SUBSTANCE: invention relates to medicinal agents used for prophylaxis and treatment of schizophrenia by inhibition or suppression of neurodegenerative disease caused by hypofunction of glutamic acid receptors. As an active component agents comprise derivative of 5-substituted 3-oxadiazolyl-1,6-naphthiridine-2(1H)-one of the formula (I):

wherein Het represents oxadiazolyl group; R1 represents hydrogen atom, lower alkyl group, lower cycloalkyl group, trifluoromethyl group, lower alkenyl group, lower alkynyl group, lower alkoxyl group, lower alkoxy-(lower)-alkyl group, lower hydroxyalkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group; R2 represents hydrogen atom, lower alkyl group, lower cycloalkyl group, lower cycloalkylmethyl group, lower alkenyl group, lower cycloalkenyl group, lower alkynyl group, substituted or unsubstituted aryl group and substituted or unsubstituted heteroaryl group wherein indicated groups represent phenyl or naphthyl and indicated heteroaryl groups represents furyl, thienyl or pyridyl, or their physiologically acceptable acid-additive salts.

EFFECT: valuable medicinal properties of agents.

10 cl, 1 tbl

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines of the general formula (1)

that are effective inhibitors if caspase-3 that can be used for preparing medicinal agents and for experimental (in vitro, in vivo) investigation of apoptosis processes as "pharmacological tools". Also, invention proposes pharmaceutical composition and a method for their preparing and applying. In the general formula (1) radicals R1, R2, R3 and R8 represent independently of one another hydrogen atom, halogen atom, CF3, CN, inert substitute, optionally substituted hydroxyl group, optionally substituted carboxy-(C1-C6)-alkyl group, optionally substituted carbamoyl group; R4 represents hydrogen atom, halogen atom, inert substitute, optionally substituted amino-group, substituted hydroxyl group; R5 represents hydrogen atom, inert substitute, optionally substituted hydroxy-(C1-C5)-alkyl, optionally substituted amino-(C1-C7)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group; R6 and R7 represent independently of one another hydrogen atom, inert substitute, optionally substituted amino-(C1-C7)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group; or R6 and R7 in common with nitrogen atom to which they are bound represent optionally substituted and optionally additionally including heteroatom taken among group: oxygen, nitrogen or sulfur, 3-10-membered cycle; or R6 and R7 in common with nitrogen atom to which they are bound represent condensed heterocycle being optionally substituted and optionally additionally including heteroatom taken among group: oxygen, nitrogen or sulfur.

EFFECT: improved preparing method and treatment.

9 cl, 19 sch, 7 tbl, 25 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyclic amide of the formula (I)

or its salt, or hydrate, or solvate wherein X represents (C1-C6)-alkyl, (C1-C6)-alkyl substituted with phenyl, (C2-C6)-alkenyl substituted with phenyl or halogenphenyl, (C2-C6)-alkynyl substituted with phenyl, phenyl that can be substituted with (C1-C6)-alkyl; one or more halogen atom, nitro-group, phenyl, (C1-C6)-alkoxy-group, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy-group, phenyl-(C1-C6)-alkyl, (C1-C6)-alkoxyphenyl-(C1-C6)-alkyl, amino-group, optionally substituted with (C1-C6)-alkyl, acetyl, (C1-C6)-alkoxy-group, substituted with phenyl, phenylcarbonyl, furanyl; 1- or 2-naphthyl, monocyclic (C3-C8)-cycloalkyl, amino-group substituted with one or more substitutes taken among phenyl, halogenphenyl, (C1-C6)-alkoxyphenyl, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl; 5- or 6-membered monocyclic heterocyclic group comprising 1 or 2 heteroatoms, such as nitrogen (N), oxygen (O), sulfur (S) atom optionally substituted with halogenphenyl, halogen atom, benzyl, (C1-C6)-alkyl, phenyl; 8-10-membered bicyclic heteroaryl group comprising 1 or 2 heteroatoms taken among N, O and optionally substituted with halogen atom; 8-10-membered polycyclic cycloalkyl group; Q means -CH2-, -CO-, -O-, -S-, -CH(OR7)- or -C(=NR8)- wherein R7 means hydrogen atom (H), (C1-C6)-alkyl; R8 means OH, (C1-C)-alkoxy-group, acylamino-group, (C1-C6)-alkoxycarbonylamino-group, phenyl-(C1-C6)-alkoxy-group; n = 0-5; B represents group or wherein each among R3, R4, R5 and R6 represents independently substitute taken among group consisting of hydrogen atom (H), halogen atom, NO2 (nitro-group), (C1-C6)-alkoxy-group, CN (cyano-group); m = 1 or 2; ring represents 5- or 6-membered aromatic heterocyclic ring comprising one or two heteroatoms taken among O, S, N. Compound of the formula (I) elicit activity inhibiting binding sigma-receptors that allows their using as component of medicinal agent.

EFFECT: valuable medicinal properties of compounds.

21 cl, 2 sch, 4 tbl, 183 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to a new improved method for preparing 6-methyl-2-(4-methylphenyl)-imidazolo[1,2-a]pyridine-3-(N,N-dimethylacetamide) of the formula (I) or its pharmaceutically acceptable acid additive salts. Method involves interaction of ester of the general formula (II) (wherein R is a lower alkyl or phenyl-lower alkyl) with dimethylamine in polar aproton solvent and if necessary conversion of synthesized compound of the formula (I) to pharmaceutically acceptable acid additive salt. Compound of the formula (I) is the known effective sedative agent used in therapy. Also, invention relates to intermediate compounds of the general formula (II) wherein R is a lower alkyl or phenyl-lower alkyl using in this method. Method provides preparing highly pure product for a single stage being without applying harmful and toxic reagents.

EFFECT: improved method for preparing.

16 cl, 15 ex

FIELD: organic chemistry, madicine.

SUBSTANCE: tricyclic benzodiazepines of formula I as well as their pharmaceutical acceptable salts, pharmaceutical composition containing the same and methods for hypertension treatment are disclosed. In formula A is -C(O)-; Y is CH2 or CH as olefinic site; X is CH2 or CH as olefinic site S, O or NR3 (R3 is C1-C8-alkyl) with the proviso that when Y is CH, X also is CH; Z is N or CH; R1 is hydrogen, C1-C8-alkyl, C1-C8-alkoxy or halogen; R2 is NR4COAr (R4 is hydrogen; Ar is phenyl optionally substituted with 1-3 substitutes independently selected from C1-C8-alkyl, halogen, hydroxyl, fluorinated C1-C8-alkylthio and another phenyl optionally substituted with substitute selected from C1-C4-alkyl, halogen, and hydroxyl); R5 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine, hydroxyl or di-(C1-C4)-alkylamino.

EFFECT: improved pharmaceutical composition for hypertension treatment.

12 cl, 5 tbl, 52 ex

FIELD: organic chemistry, medicinal biochemistry, pharmacy.

SUBSTANCE: invention relates to substituted benzimidazoles of the formula (I): and/or their stereoisomeric forms, and/or their physiologically acceptable salts wherein one of substitutes R1, R2, R3 and R4 means a residue of the formula (II): wherein D means -C(O)-; R8 means hydrogen atom or (C1-C4)-alkyl; R9 means: 1. (C1-C6)-alkyl wherein alkyl is linear or branched and can be free of substituted by one-, bi- or tri-fold; Z means: 1. a residue of 5-14-membered aromatic system that comprises from 1 to 4 heteroatoms as members of the cycle that represent nitrogen and oxygen atoms wherein aromatic system is free or substituted; 1.1 a heterocycle taken among the group of oxadiazole or oxadiazolone that can be unsubstituted or substituted; 2. (C1-C6)-alkyl wherein alkyl is a linear or branched and monosubstituted with phenyl or group -OH; or 3. -C(O)-R10 wherein R10 means -O-R11, -N(R11)2 or morpholinyl; or R8 and R9 in common with nitrogen atom and carbon atom with that they are bound, respectively, form heterocycle of the formula (IIa): wherein D, Z and R10 have values given in the formula (II); A means a residue -CH2-; B means a residue -CH-; Y is absent or means a residue -CH2-; or X and Y in common form phenyl. The cyclic system formed by N, A, X, Y, B and carbon atom is unsubstituted or monosubstituted with (C1-C8)-alkyl wherein alkyl is monosubstituted with phenyl, and other substitutes R1, R2, R3 and R4 mean independently of one another hydrogen atom, respectively; R5 means hydrogen atom; R6 means the heteroaromatic cyclic system with 5-14 members in cycle that comprises 1 or 2 nitrogen atoms and can be unsubstituted or substituted. Also, invention relates to a medicinal agent for inhibition of activity of IkB kinase based on these compounds and to a method for preparing the indicated agent. Invention provides preparing new compounds and medicinal agents based on thereof for aims for prophylaxis and treatment of diseases associated with the enhanced activity of NFkB.

EFFECT: valuable medicinal properties of compounds and composition.

4 cl, 7 tbl, 224 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: present invention relates to new 4-piperazinyl-(8-quinolinyl)-methyl)-benzamides of general formula I

1, wherein R1 is phenyl, pyridinyl, thiophenyl, furanyl, and inidazolyl, and each phenyl or heteroaromatic ring is optionally and independently substituted with 1, 2 or 3 substituents, selected from linear or branched C1-C6-alkyl, NO2, CF3, C1-C6-alkoxy, halogen, or pharmaceutically acceptable salts thereof. Compounds of present invention are useful in therapy, in particular for pain alleviation. Also disclosed are pharmaceutical composition based on compounds of formula I and method for pain treatment.

EFFECT: new compounds and compositions for pain treatment.

12 ck, 19 ex, 3 tbl

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to applying compounds of the general formula (1):

as inhibitors of caspase-3 that allows their applying as "molecular tools" and as active medicinal substances inhibiting selectively the scheduling cellular death (apoptosis). Also, invention relates to pharmaceutical compositions based on compounds of the formula (1), to a method for their preparing and a method for treatment or prophylaxis of diseases associated with enhanced activation of apoptosis. Also, invention relates to new groups of compounds of the formula 91), in particular, to compounds of the formulae (1.1):

and (1.2):

. In indicated structural formulae R1 represents inert substitute; R2, R3 and R4 represent independently of one another hydrogen atom, fluorine atom (F), chlorine atom (Cl), bromine atom (Br), iodine atom (J). CF3, inert substitute, nitro-group (NO2), CN, COOH, optionally substituted sulfamoyl group, optionally substituted carbamide group, optionally substituted carboxy-(C1-C6)-alkyl group; R5 represents oxygen atom or carbon atom included in optionally condensed, optionally substituted and optionally comprising one or some heteroatoms; R6 represents hydrogen atom or inert substitute; X represents sulfur atom or oxygen atom.

EFFECT: improved preparing and applying methods, valuable medicinal and biochemical properties of compounds.

3 cl, 1 dwg, 2 tbl, 1 sch, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new piperidine compounds of the general formula (I) wherein A means preferably ring of the formula:

wherein R1 means hydrogen atom (H), cyano-group (CN), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group; W means (C1-C6)-alkylene that can be substituted, ordinary bond; Z means optionally substituted aromatic hydrocarbon cyclic (C6-C14)-group; l means a number from 0 to 6. Compounds show the excellent activity directed for inhibition of sodium channels and selective inhibition of potassium channels.

EFFECT: improved preparing method, improved inhibiting method, valuable medicinal properties of compounds.

26 cl, 4 tbl, 476 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyclic amide of the formula (I)

or its salt, or hydrate, or solvate wherein X represents (C1-C6)-alkyl, (C1-C6)-alkyl substituted with phenyl, (C2-C6)-alkenyl substituted with phenyl or halogenphenyl, (C2-C6)-alkynyl substituted with phenyl, phenyl that can be substituted with (C1-C6)-alkyl; one or more halogen atom, nitro-group, phenyl, (C1-C6)-alkoxy-group, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy-group, phenyl-(C1-C6)-alkyl, (C1-C6)-alkoxyphenyl-(C1-C6)-alkyl, amino-group, optionally substituted with (C1-C6)-alkyl, acetyl, (C1-C6)-alkoxy-group, substituted with phenyl, phenylcarbonyl, furanyl; 1- or 2-naphthyl, monocyclic (C3-C8)-cycloalkyl, amino-group substituted with one or more substitutes taken among phenyl, halogenphenyl, (C1-C6)-alkoxyphenyl, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl; 5- or 6-membered monocyclic heterocyclic group comprising 1 or 2 heteroatoms, such as nitrogen (N), oxygen (O), sulfur (S) atom optionally substituted with halogenphenyl, halogen atom, benzyl, (C1-C6)-alkyl, phenyl; 8-10-membered bicyclic heteroaryl group comprising 1 or 2 heteroatoms taken among N, O and optionally substituted with halogen atom; 8-10-membered polycyclic cycloalkyl group; Q means -CH2-, -CO-, -O-, -S-, -CH(OR7)- or -C(=NR8)- wherein R7 means hydrogen atom (H), (C1-C6)-alkyl; R8 means OH, (C1-C)-alkoxy-group, acylamino-group, (C1-C6)-alkoxycarbonylamino-group, phenyl-(C1-C6)-alkoxy-group; n = 0-5; B represents group or wherein each among R3, R4, R5 and R6 represents independently substitute taken among group consisting of hydrogen atom (H), halogen atom, NO2 (nitro-group), (C1-C6)-alkoxy-group, CN (cyano-group); m = 1 or 2; ring represents 5- or 6-membered aromatic heterocyclic ring comprising one or two heteroatoms taken among O, S, N. Compound of the formula (I) elicit activity inhibiting binding sigma-receptors that allows their using as component of medicinal agent.

EFFECT: valuable medicinal properties of compounds.

21 cl, 2 sch, 4 tbl, 183 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tetrahydroisoquinoline of the formula [I] wherein R1 represents hydrogen atom or lower alkyl; R2 represents alkyl having optionally a substitute taken among alkoxycarbonyl and carboxy-group, cycloalkyl, cycloalkylalkyl, aryl having optionally a substitute taken among lower alkyl, arylalkyl having optionally a substitute taken among lower alkyl, lower alkoxy-group, halogen atom and acyl, alkenyl, alkynyl, or monocyclic heterocyclylalkyl wherein indicated heterocycle comprises 5- or 6-membered ring comprising nitrogen atom and having optionally a substitute taken among lower alkyl; R3 represents hydrogen atom or lower alkoxy-group; A represents a direct bond or >N-R5 wherein R5 represents lower alkyl; B represents lower alkylene; Y represents aryl or monocyclic or condensed heterocyclyl comprising at least one heteroatom taken among oxygen atom and nitrogen atom and having optionally a substitute taken among lower alkyl, carboxy-group, aryl, alkenyl, cycloalkyl and thienyl, or to its pharmaceutically acceptable salt. Also, invention relates to pharmaceutical composition eliciting hypoglycaemic and hypolipidemic effect based on these derivatives. Invention provides preparing new compounds and pharmaceutical agents based on thereof, namely, hypoglycaemic agent, hypolipidemic agent, an agent enhancing resistance to insulin, therapeutic agent used for treatment of diabetes mellitus, therapeutic agent against diabetic complication, agent enhancing the tolerance to glucose, agent against atherosclerosis, agent against obesity, an anti-inflammatory agent, agent for prophylaxis and treatment of PPAR-mediated diseases and agent used for prophylaxis and treatment of X-syndrome.

EFFECT: valuable medicinal properties of compounds and composition.

13 cl, 7 tbl, 75 ex

Indole derivatives // 2256659

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indole of the formula (I): wherein R1 means phenyl substituted or unsubstituted radical R2 and/or R4; R2, R4 R5 and R6 in each case and independently of one another mean Hal; R3 mean substituted or unsubstituted radical R5 and/or R6 or means Het wherein Het means 2-furyl, 3-furyl, 2-thienyl or 3-thienyl; Hal means fluorine atom (F), chlorine atom (Cl), bromine atom (Br) or iodine atom (J), and their physiologically acceptable salts and solvates also. Compounds of the formula (I) are prepared by interaction of compound of the formula (I): wherein L means Cl, Br, J or free or reactive functional modified group OH; R3 has value indicated in the formula (I) with compound of the formula (III): . Compounds of the formula (I) show affinity to 5-HT2A receptors that allow their using in the pharmaceutical composition.

EFFECT: valuable medicinal and pharmacological properties of compounds.

4 cl, 10 ex

The invention relates to benzimidazole derivative of the formula (I)

or its pharmaceutically acceptable salt, where Rrepresents a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents a group of formula-CO2R2where R2is hydroxyalkyl, alkoxyalkyl or toolboxitem, Rrepresents a group of the formula

where o is 0 or 1, n is 0, 1 or 2, X represents N or CH, Y is O, NR11or CHR11where R11represents hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl, or acyl, or a group of the formula -(alkyl)p-CN, -(alkyl)p-aryl, -(alkyl)p-O-aryl, -(alkyl)p-O-aralkyl, -(alkyl)p"heterocycle", -(alkyl)p-CO2"heterocycle" or -(alkyl-CO2)s-(alkyl)t-COR5and , in these formulas, R, s and t independently of each other 0 or 1, "heterocycle" represents a 5 the n heteroatom, represents a nitrogen, oxygen or sulfur, and which may substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl and oxo, R5represents a hydroxy, alkoxy, hydroxy-C1-8-alkoxy, C1-8-alkoxyalkane, Tiltonsville, aryl, or aralkyl, or a group of the formula-NR6R7or-O-alkyl-NR6R7and , in these formulas, R6and R7independently of one another represent hydrogen or alkyl, and R14and R15independently of one another represent hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl or acyl; or where R' is a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents fornillo group; and Rrepresents -(alkyl)m-CO2R8where m is 0 or 1, R8represents a group of formula -(alkyl)p-NR9R10where R is 0 or 1, and R9and R10together with the nitrogen atom to which they are attached, form a piperazinilnom group, possibly substituted by acyl

The invention relates to new N-heterocyclic derivatives of the formula (I):

where: A means-OR1-C(O)N(R1R2or-N(R1R21; each X, Y and Z independently represents N or C(R19); each U represents N or C(R5), provided that U is N only when X represents N, and Z and Y denote CR19; each W represents N or CH; V denotes: (1) N(R4); (2) C(R4)H; or (3) the groupdirectly related to the group -(C(R14R20)n-A,denotes a 5-6-membered N-heterocyclyl, optionally containing 6-membered ring additional heteroatom selected from oxygen, sulfur and NR6where R6denotes hydrogen, optionally substituted phenyl, 6-membered heterocyclyl containing 1-2 nitrogen atom, optionally substituted 5-membered heterocyclyl containing 1-2 nitrogen atom, aminosulfonyl, monoalkylammonium, dialkylaminoalkyl,1-6alkoxycarbonyl, acetyl, etc

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new taxanes of the general formula (I)

wherein R2 means benzoyloxy-group; R7 means hydroxyl (OH); R9 means keto-group; R10 means R10aCOO-; R10 means (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl or 5-6-membered heteroaromatic group wherein heteroatom represents oxygen atom (O), sulfur atom (S) or nitrogen atom (N); R14 means hydrogen atom (H); X3 means (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, phenyl substituted possibly with nitro-group (-NO2), 5-6-membered heteroaromatic group wherein heteroatom represents O, S or N; X5 means -COX10, -COOX10; X10 means (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, phenyl or 5-6-membered heteroaromatic group wherein heteroatom represents O, S, N; Ac means acetyl. Compounds of the formula (I) elicit antitumor activity.

EFFECT: valuable medicinal properties of compounds.

68 cl, 1 tbl, 6 ex

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