Azaindol derivatives as factor xa inhibitors

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the formula I and their pharmaceutically acceptable salts as factor Xa inhibitors, medicine based on them, as well as a method of their obtaining and application. In the general formula I R0 is monocyclical or bicyclical 6-9-membered heterocyclyl selected out of the group of benzothiophenyl, pyridyl or monocyclical 5-membered heterocyclyl containing 1, 2 heteroatoms selected out of nitrogen or oxygen, where the mentioned heterocyclyl is monosubstituted by R8 and additionally substituted by monocyclical 5-membered heterocyclyl containing 1 heteroatom of sulfur, where heterocyclyl is monosubstituted by R8; R8 is a halogen or substructure , which is 6-membered partially unsaturated or aromatic cyclical group in the formula I, containing 1 nitrogen heteroatom, and which is substituted by 1 R23 group or oxogroup under a condition that the mentioned cyclical group is not a phenyl residuum; Q is a direct link, -(C0-C2)-alkylene-C(O)-NR10-, -(C1-C6)-alkylene; -R1 is a hydrogen atom; R2 is a direct link, V is a 6-membered cyclical residuum with 1 heteroatom selected out of nitrogen, where the mentioned cyclical residuum is unsubstituted, bicyclical 12-membered heterocyclyl with 1-2 heteroatom selected out of nitrogen, where the mentioned cyclical residuum is unsubstituted; G is a direct link; M a hydrogen atom, -(C1-C8)-alkyl where alkyl is unsubstituted; R3 is a hydrogen atom; R23 is a hydrogen atom, -(C0-C4)-alkylene -O-R19 (where R19 is a) hydrogen atom, b) -(C1-C4)-alkyl where alkyl is unsubstituted or monosubstituted by R13), -(C0-C4)-alkylene-C(O)-R11, -(C0-C4)-alkylene-C(O)-O-R11; R11 and R12 can both or individually be hydrogen atom, -(C1-C6)-alkyl: -O-R17 or R13 is -C(O)-O-R10; R10 and R20 are hydrogen atoms or -(C1-C6)-alkyl independently from each other, R17 is -(C1-C6)-alkyl; and its pharmaceutically acceptable salts.

EFFECT: possible application in effecting blood coagulation, inflammation reaction or fibrinolysis, or in treatment and prophylactics of diseases caused by Xa factor, eg cardiovascular disorders, thromboembolic diseases or restenosis.

11 cl, 1 tbl, 15 ex

 

The present invention relates to compounds of the formula I:

where R0; R1; R2; R3; Q; V, G and M have the meanings specified below. The compounds of formula I are valuable pharmacologically active compounds. They have a strong antithrombotic effect and are suitable, for example, for the treatment and prevention of cardiovascular disorders, such thromboembolic diseases or restenoses. They are acting reversible inhibitors of enzymes of the blood coagulation factor Xa (FXa) and/or factor VIIa (FVIIA), and can in General be applied in conditions in which there is undesired activity of factor Xa and/or factor VIIa or for the treatment or prevention of which is expected inhibition of factor Xa and/or factor VIIa. The invention also relates to methods of preparing compounds of the formula I, their use, in particular as active ingredients in pharmaceuticals and to pharmaceutical preparations containing them.

Normal hemostasis is the result of a complex balance between the process of initiation of clotting and dissolution of the clot. The complex interaction between blood cells, specific plasma proteins and vascular surface to maintain the fluidity of blood up until not going is it damage and blood loss (EP-A-987274). Many significant pathological condition associated with abnormal hemostasis. For example, the local formation of a blood clot due to a rupture of atherosclerotic plaques is a major cause of acute myocardial infarction and unstable angina. Treatment of occlusal coronary thrombus either thrombolytic therapy or percutaneous angioplasty may be accompanied by acute thrombotic re-closure of the affected vessel.

A need remains in a safe and effective anticoagulant to limit or prevent the formation of thrombus. The most desirable to create tools that inhibit coagulation without direct inhibitory effect on thrombin, but by inhibiting other stages in the cascade of clotting, similar to the activity of factor XA and/or factor VIIa. Currently, it is believed that inhibitors of factor XA are associated with a lower risk of bleeding than thrombin inhibitors (A.E.P.Adang & J.B.M.Rewinkel, Drugs of the Future 2000, 25, 369-383).

Specific for factor XA inhibitors of blood coagulation with low molecular weight that are effective but do not cause adverse side effects have been described, for example, in document WO-A-95/29189. However, in addition to efficiency as a specific factor XA inhibitor of blood coagulation, it is desirable that such inhibi the ora also had an additional preferred properties for example, stability in plasma and liver and selectivity in comparison with other serine proteases, inhibition of which is not anticipated, such as thrombin. There remains a need to more specific for factor XA inhibitors of blood coagulation with low molecular weight that are effective and have the aforementioned advantages.

Specific inhibition of the catalytic complex of factor VIIa/tissue factor with monoclonal antibodies (WO-A-92/06711) or protein, such as factor VIIa, inactivated by chloromethylketone (WO-A-96/12800, WO-A-97/47651), is a highly effective means of combating the formation of a blood clot, caused by acute damage to the arteries or thrombotic complications associated with bacterial septicemia. There is also experimental evidence, indicating that the inhibition of factor VIIa/tissue factor inhibits restenosis after balloon angioplasty. Of bleeding studies conducted in baboons, indicate that the inhibition of the complex of factor VIIa/tissue factor has the widest range of security with regard to therapeutic efficacy and the risk of bleeding of any proven approach with the use of anticoagulants, including the inhibition of thrombin, platelets and factor XA. Op is edelenyi inhibitors of factor VIIa have been already described. In the document EP-A-987274, for example, disclosed compounds containing Tripeptide unit, which inhibit factor VIIa. However, the property profile of these compounds is still not perfect and needs further having a low molecular weight inhibitors of blood coagulation, anybrowser factor VIIa.

The present invention satisfies these needs by providing novel compounds of the formula I, which exhibit higher inhibitory activity against factor XA/factor VIIa and represent favorable tools with high biological availability.

(1) Thus, the present invention relates to compounds of formula I,

where R0represents a

1) monocyclic or bicyclic 6-14-membered aryl, where aryl is mono-, di - or tizamidine, independently from each other, R8,

2) monocyclic or bicyclic 4 to 15-membered heterocyclyl selected from the group benzimidazolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiophene, cinnoline, Romania, indazole, indoline, isopropanyl, isoindolyl, izochinolina, phenylpyridine, phthalazine, pteridine, purine, pyridyl, predominately, pyridopyrimidines, pyridopyrimidines, pyrimidinyl, heatline, ginoli is a, khinoksalinona or 1,4,5,6-tetrahydropyridine where specified heterocyclyl is mono-, di - or tizamidine, independently from each other, R8or

3) a monocyclic or bicyclic 4 to 15-membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, where indicated heterocyclyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R8, and which is optionally substituted monocyclic or bicyclic 4 to 15-membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, where

heterocyclyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R8,

R8represents a

1) halogen,

2) -NO2,

3) -CN,

4) -C(O)-NH2,

5) -OH,

6) -NH2,

7) -O-CF3

8) a monocyclic or bicyclic 6-14-membered aryl, where aryl is mono-, di - or tizamidine, independently of one another by halogen or-O-(C1-C8)-alkyl,

9) -(C1-C8)-alkyl, where alkyl is unsubstituted or mono-, di - or tizamidine, independently of one another, halogen, NH2HE or methoxyethanol,

10) -O-(C1-C8)-alkyl, where alkyl is unsubstituted or mono-, di - or tizamidine, independently of one another, halogen, NH2 HE or methoxyethanol,

11) -SO2-CH3or

12) -SO2-CF3,

provided that R8represents at least one halogen, -C(O)-NH2or-O-(C1-C8)-alkyl residue, if R0represents a monocyclic or bicyclic 6-14-membered aryl,

substructure

in the formula I represents a

4-8-membered saturated, partially unsaturated or aromatic cyclic group containing 0, 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, unsubstituted or substituted 1, 2, 3, 4, 5 or 6 R3or substituted 1 or 2, provided that the cyclic group is phenyl residue,

Q represents a direct bond, -(C0-C2-alkylen-C(O)-NR10-, -NR10-C(O)-NR10-, -NR10-C(O)-, -SO2-, -(C1-C6-alkylene, -(CH2)m-NR10-C(O)-NR10-(CH2)n-, -(CH2)m-NR10-C(O)-(CH2)n-, -(CH2)m-S-(CH2)n-, -(CH2)m-C(O)-(CH2)n-, -(CH2)m-SO2-NR10-(CH2)n-, -(CH2)m-NR10-SO2-(CH2)n-, -(CH2)m-NR10-SO2-NR10-(CH2)n-, -(CH2)m-CH(OH)-(CH2)n-, -(CH2)m-O-C(O)-NR10 2)n-, -(C2-C3-alkylen-O-(C0-C3-alkylene, -(C2-C3-alkylen-S(O)-, -(C2-C3-alkylen-S(O)2-, -(CH2)m-NR10-C(O)-O-(CH2)n-, -(C2-C3-alkylen-S(O)2-NH-(R10)-, -(C2-C3-alkylene-N(R10)- or -(C0-C3-alkylen-C(O)-O-(CH2)m-,

where R10has the values defined below, and n and m independently of one another are identical or different and represent integers 0, 1, 2, 3, 4, 5 or 6, where alkylene residues, which are formed by -(CH2)m- or -(CH2)n-are unsubstituted or mono-, di - or tizamidine independently of one another by halogen, -NH2or is HE; or(C3-C6-cycloalkenes where cycloalkyl is unsubstituted or mono-, di - or tizamidine, independently of one another, halogen, -NH2or is HE;

R1represents a hydrogen atom, -(C1-C4)-alkyl, where alkyl is unsubstituted or substituted 1-3 times R13; -(C1-C3-alkylen-C(O)-NH-R0, -(C1-C3-alkylen-C(O)-O-R10, monocyclic or bicyclic 6-14-membered aryl, where aryl is mono-, di - or tizamidine, independently from each other, R8where R8has the values defined above; a monocyclic or bicyclic 4 to 15 members of the hydrated heterocyclyl, containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen; -(C1-C3-perforacion, -(C1-C3-alkylen-S(O)-(C1-C4)-alkyl, -(C1-C3-alkylen-S(O)2-(C1-C3)-alkyl, -(C1-C3-alkylen-S(O)2-N(R4')-R5', -(C1-C3-alkylen-O-(C1-C4)-alkyl, -(C0-C3-alkylene-(C3-C8-cycloalkyl, or -(C0-C3-alkylene-het, where het represents a 3-7-membered cyclic residue, containing up to 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, where indicated cyclic residue is unsubstituted or mono-, di - or tizamidine, independently from each other, R14,

R4'and R5'independent from each other and are the same or different and represent a hydrogen atom or -(C1-C4)-alkyl,

R2represents a direct bond or -(C1-C4-alkylen, or

R1and R3together with the atoms to which they are linked, can form a 6-8 membered cyclic group, containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, where indicated cyclic group is unsubstituted or mono-, di - or tizamidine, independently from each other, R14or

R1-N-R2-V can form a 4-7-membered cyclic group, terzidou 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, where indicated cyclic group is unsubstituted or mono-, di - or tizamidine, independently from each other, one of R14,

R14represents a halogen, -OH, =O, -(C1-C8)-alkyl, -(C1-C4)-alkoxy, -NO2-, -C(O)-OH, -CN, -NH2, -C(O)-O-(C1-C4)-alkyl, -(C0-C8)-alkyl-SO2-(C1-C4)-alkyl, -(C0-C8)-alkyl-SO2-(C1-C3)-perfluoroalkyl, -(C0-C8)-alkyl-SO2-N(R18)-R21, -C(O)-NH-(C1-C8)-alkyl, -C(O)-N-[(C1-C8)-alkyl]2, NR18-C(O)-NH-(C1-C8)-alkyl, -C(O)-NH2, -S-R18or NR18-C(O)-NH-[(C1-C8)-alkyl]2,

where R18and R21represent, independently from each other hydrogen atom, -(C1-C3)-perfluoroalkyl or -(C1-C6)-alkyl,

V represents

1) 3-7-membered cyclic residue, containing 1-4 heteroatoms selected from nitrogen, sulfur or oxygen, where indicated cyclic residue is unsubstituted or mono-, di - or tizamidine, independently from each other, R14,

2) 6-14-membered aryl, where aryl is unsubstituted or mono-, di - or tizamidine, independently from each other, R14or

3) a monocyclic or bicyclic 4 to 15-membered hetero is iklil, where specified heterocyclyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R14,

G represents a direct bond, -(CH2)m-NR10-SO2-NR10-(CH2)n-, -(CH2)m-CH(OH)-(CH2)n-, -(CH2)m-, -(CH2)m-O-(CH2)n-, -(CH2)m-C(O)-NR10-(CH2)n-, -(CH2)-SO2-(CH2)n-, -(CH2)m-NR10-C(O)-NR10-(CH2)n-, -(CH2)m-NR10-C(O)-(CH2)n-, -(CH2)m-C(O)-(CH2)n-, -(CH2)-S-(CH2)n-, -(CH2)m-SO2-NR10-(CH2)n-, -(CH2)m-NR10-SO2-(CH2)n-, -(CH2)m-NR10-, -(CH2)m-O-C(O)-NR10-(CH2)n- or -(CH2)m-NR10-C(O)-O-(CH2)n-,

n and m independently of one another are identical or different and represent integers 0, 1, 2, 3, 4, 5 or 6,

M represents

1) a hydrogen atom,

2) -(C1-C8)-alkyl, where alkyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R14,

3) -C(O)-N(R11)-R12,

4) -(CH2)m-NR10,

5) 6-14-membered aryl, where aryl is unsubstituted or mono-, di - or tizamidine, independently of the other, R14,

6) a monocyclic or bicyclic 4 to 15-membered heterocyclyl where heterocyclyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R14,

7) -(C3-C8-cycloalkyl where specified cycloalkyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R14,

8) 3-7-membered cyclic residue, containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen, where indicated cyclic residue is unsubstituted or mono-, di - or tizamidine, independently from each other, R14where R14has the values defined above,

R3represents a

1) a hydrogen atom,

2) halogen,

3) -(C1-C4)-alkyl, where the specified alkyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R13,

4) -(C1-C3)-perfluoroalkyl,

5) phenyl, where phenyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R13,

6) -(C0-C4-alkylen-O-R19where R19represents a

(a) a hydrogen atom,

b) -(C1-C4)-alkyl, where alkyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R13,

C) -CF3or

d) -CHF2,

7) -NO2,

8) -CN,

9) -SOs-R11where s R is the set 1 or 2,

10) -SOt-N(R11)-R12where t is 1 or 2,

11) -(C0-C4-alkylen-C(O)-R11,

12) -(C0-C4-alkylen-C(O)-O-R11,

13) -(C0-C4-alkylen-C(O)-N(R11)-R12,

14) -(C0-C4-alkylene-N(R11)-R12,

15) -NR10-SO2-R10,

16) -S-R10,

17) -(C0-C2-alkylen-C(O)-O-(C2-C4-alkylen-O-C(O)-(C1-C4)-alkyl,

18) -C(O)-O-C(R15, R16)-O-C(O)-R17,

19) -(C0-C2-alkylen-C(O)-O-(C2-C4-alkylen-O-C(O)-O-(C1-C6)-alkyl,

20) -C(O)-O-C(R15, R16)-O-C(O)-O-R17,

21) -(C0-C4-alkylene-(C6-C14)-aryl, where aryl is mono-, di - or tizamidine, independently from each other, R13,

22) -(C0-C4-alkylene-(C4-C15)-heterocyclyl where heterocyclyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R13,

23) -(C0-C4-alkylene-(C3-C8-cycloalkyl where cycloalkyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R13,

24) -(C0-C4-alkylene-het where het is unsubstituted or mono-, di - or tizamidine, independently from each other, R13,

25) -(C0-C3-alkylen-O-CH2-(C1-C3-perforacion-CH2-O-(C0 -C4)-alkyl,

26) -SOw-N(R11)-R13where w is 1 or 2,

27) -(C0-C4-alkylen-C(O)-N(R11)-R13,

28) -(C0-C4-alkylene-N(R11)-R13or

29) a residue from the following list of

where Me represents methyl, or

if 2 balance-OR19attached to adjacent atoms they can form together with the atoms to which they are attached, a 5 - or 6-membered ring which is unsubstituted or substituted from 1 to 4 R13,

R11and R12independently of one another are identical or different and represent

1) a hydrogen atom,

2) -(C1-C6)-alkyl, where alkyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R13,

3) -(C0-C6)-alkyl-(C3-C6-cycloalkyl,

4) -SOt-R10where t is 1 or 2,

5) -(C0-C6)-alkyl-(C6-C14)-aryl, where alkyl and aryl independently from one another are unsubstituted or mono-, di - or tizamidine R13,

6) -(C1-C3)-perfluoroalkyl,

7) -O-R17or

8) -(C0-C6)-alkyl-(C4-C15)-heterocyclyl, where the alkyl and heterocyclyl have the meanings given above, and is what is carried out independently from each other unsubstituted or mono-, di - or tizamidine R13or

R11and R12together with the nitrogen atom to which they are bound, form a 4-7-membered monocyclic heterocyclic ring which, in addition to the nitrogen atom, may contain 1 or 2 identical or different ring heteroatoms selected from oxygen, sulfur and azoty; where the specified heterocyclic ring is unsubstituted or mono-, di - or tizamidine, independently from each other, R13,

R13represents a halogen, -NO2, -CN, =O, -OH, -CF3, -C(O)-O-R10, -C(O)-N(R10)-R20, -N(R10)-R20, -(C3-C8-cycloalkyl, -(C0-C3-alkylen-O-R10, -Si-(CH3)3, -N(R10)-S(O)u-R10where u is 1 or 2, -S-R10, -SOr-R10where r is 1 or 2, -S(O)v-N(R10)- R20where v is 1 or 2, -C(O)-R10, -(C1-C8)-alkyl, -(C1-C8)-alkoxy, phenyl, phenyloxy-, O-CF3, -(C0-C4)-alkyl-C(O)-O-C(R15, R16)-O-C(O)-R17, -(C1-C4)-alkoxyphenyl, -(C0-C4)-alkyl-C(O)-O-C(R15, R16)-O-C(O)-R17, -(C1-C3)-perfluoroalkyl, -O-R15, -NH-C(O)-NH-R10, -NH-C(O)-O-R10or a residue from the following list of

where Me represents methyl,

R10and R20represent, independently on the angle from each other, hydrogen, -(C1-C6)-alkyl, -(C0-C4)-alkyl-OH, -(C0-C4)-alkyl-O-(C1-C4)-alkyl or -(C1-C3)-perfluoroalkyl,

R15and R16represent, independently from each other hydrogen, -(C1-C6)-alkyl, or together with the carbon atom to which they are bound, may form a 3-6-membered carbocyclic ring which is unsubstituted or substituted from 1 to 3 R10and

R17represents -(C1-C6)-alkyl, -(C1-C6)-alkyl-OH, -(C1-C6)-alkyl-O-(C1-C6)-alkyl, -(C3-C8-cycloalkyl, -(C1-C6)-alkyl-O-(C1-C8)-alkyl-(C3-C8-cycloalkyl, -(C1-C6)-alkyl-(C3-C8-cycloalkyl, where the specified cycloalkyl ring is unsubstituted or substituted 1, 2 or 3-HE,

-O-(C1-C4)-alkyl, or R10,

in all its stereoisomeric forms in any ratio, and its physiologically acceptable salt.

(2) Thus, the present invention relates to compounds of formula I, where

R0represents a

1) monocyclic or bicyclic 6-14-membered aryl selected from phenyl, naphthyl, biphenylyl, antila or fluorenyl, where aryl is mono-, di - or tizamidine, independently from each other, R8.

2) heterocyclyl, SEL is p from benzimidazolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiophene, cinnoline, Romania, indazole, indoline, isopropanyl, isoindolyl, izochinolina, phenylpyridine, phthalazine, pteridine, purine, pyridyl, predominately, pyridopyrimidines, pyridopyrimidines, pyrimidinyl, heatline, chinoline, khinoksalinona or 1,4,5,6-tetrahydropyridine where specified heterocyclyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R8or

3) heterocyclyl where heterocyclyl selected from the group consisting of acridine, asianshemale, azaspirodecanedione, azepine, azetidine, aziridine, benzimidazolyl, benzofuranyl, benzothiophene, benzothiophene, benzoxazole, benzthiazole, benzotriazolyl, benzatropine, benzisoxazole, benzisothiazole, carbazolyl, an-carbazolyl, carboline, Romania, chromene, cinnoline, decahydroquinoline, 4,5-dihydroquinoline, dioxazine, dioxazine, 1,3-DIOXOLANYL, 1,3-DIOXOLANYL, 6N-1,5,2-detainee, dehydrator[2,3-b]-tetrahydrofuranyl, furanyl, furazane, imidazolidinyl, imidazolyl, imidazolyl, 1H-indazole, indoline, indolizine, indolyl, 3H-indolyl, isobenzofuranyl, isopropanyl, isoindolyl, isoindoline, isoindolyl, izochinolina, isothiazoline, ittia is olidine, isothiazoline, isoxazole, isoxazoline, isoxazolidine, 2-isoxazoline, cefoperazone, morpholinyl, naphthyridine, octahydronaphthalene, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2-oxathiane, 1,2-oxathiolane, 1,4-oxazepine, 1,2-oxazinyl, 1,3-oxazinyl, 1,4-oxazinyl, oxazolidinyl, oxazolyl, oxazolyl, phenanthridine, phenanthroline, phenazine, phenothiazine, femoxetine, phenoxazine, phthalazine, piperazinil, piperidinyl, pteridinyl, purinol, pyranyl, pyrazinyl, pyrazolidine, pyrazoline, pyrazolyl, pyridazinyl, paradoxically, predominately, peridotite, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidinone, pyrroline 2N-pyrrolyl, pyrrolyl, heatline, chinoline, 4H-chinoiserie, khinoksalinona, hinokitiol, tetrahydrofuranyl, tetrahydroisoquinoline, tetrahydroquinoline, 1,4,5,6-tetrahydropyridine, tetrahydropyridine, tetrahydrothiophene, tetrazine, tetrazole, 6N-1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrene, 1,2-teinila, 1,3-teinila, 1,4-teinila, 1,3-thiazolyl, thiazolyl, thiazolidine, thiazoline, tanila, tatania, tiantianriri, cyanoacetyl, tenomodulin, tatania, thiomorpholine, thiophene the sludge, thiophenyl, dipiradol, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanterra,

where specified heterocyclyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R8and

which is optionally substituted by heterocyclyl selected from the group consisting of acridine, asianshemale, azaspirodecanedione, azepine, azetidine, aziridine, benzimidazolyl, benzofuranyl, benzothiophene, benzothiophene, benzoxazole, benzthiazole, benzotriazolyl, benzatropine, benzisoxazole, benzisothiazole, carbazolyl, an-carbazolyl, carboline, Romania, chromene, cinnoline, decahydroquinoline, 4,5-dihydroquinoline, dioxazine, dioxazine, 1,3-DIOXOLANYL, 1,3-DIOXOLANYL, 6N-1,5,2-detainee, dehydrator[2,3-b]-tetrahydrofuranyl, furanyl, furazane, imidazolidinyl, imidazolyl, imidazolyl, 1H-indazole, indoline, indolizine, indolyl, 3H-indolyl, isobenzofuranyl, isopropanyl, isoindolyl, isoindoline, isoindolyl, izochinolina, isothiazoline, isothiazolinone, isothiazoline, isoxazole, isoxazoline, isoxazolidine, 2-isoxazoline, cefoperazone, morpholinyl, naphthyridine, octahydronaphthalene, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazol the La, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2-oxathiane, 1,2-oxathiolane, 1,4-oxazepine, 1,2-oxazinyl, 1,3-oxazinyl, 1,4-oxazinyl, oxazolidinyl, oxazolyl, oxazolyl, phenanthridine, phenanthroline, phenazine, phenothiazine, femoxetine, phenoxazine, phthalazine, piperazinil, piperidinyl, pteridinyl, purinol, pyranyl, pyrazinyl, pyrazolidine, pyrazoline, pyrazolyl, pyridazinyl, paradoxically, predominately, peridotite, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidinone, pyrroline 2N-pyrrolyl, pyrrolyl, heatline, chinoline, 4H-chinoiserie, khinoksalinona, hinokitiol, tetrahydrofuranyl, tetrahydroisoquinoline, tetrahydroquinoline, 1,4,5,6-tetrahydropyridine, tetrahydropyridine, tetrahydrothiophene, tetrazine, tetrazole, 6N-1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrene, 1,2-teinila, 1,3-teinila, 1,4-teinila, 1,3-thiazolyl, thiazolyl, thiazolidine, thiazoline, teinila, tatania, tiantianriri, cyanoacetyl, tenomodulin, tatania, thiomorpholine, thiophenolate, thiophenyl, dipiradol, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazole, 1,3,4-triazolyl and xanterra,

where heterocyclyl is unsubstituted or mono-, di - and tizamidine, independently from each other, R8,

R8represents a

1) halogen,

2) -NO2,

3) -CN,

4) -C(O)-NH2,

5) -OH,

6) -NH2,

7) -O-CF3,

8) a monocyclic or bicyclic 6-14-membered aryl, where aryl has meaning as defined above and aryl is mono-, di - or tizamidine, independently from each other, by halogen or-O-(C1-C8)-alkyl,

9) -(C1-C8)-alkyl, where alkyl is unsubstituted or mono-, di - or tizamidine, independently of one another, halogen, NH2, -OH or methoxyethanol, or

10) -O-(C1-C8)-alkyl, where alkyl is unsubstituted or mono-, di - or tizamidine, independently of one another, halogen, NH2, -OH or methoxyethanol,

11) -SO2-CH3or

12) -SO2-CF3,

provided that R8represents at least one halogen, -C(O)-NH2or-O-(C1-C8)-alkyl residue, if R0represents a monocyclic or bicyclic 6-14-membered aryl, where aryl has meaning as defined above,

substructure D is a residue selected from the group consisting of azetidine, asatina, asokan, asokan-2-it, cyclobutyl, cyclooctane, cyclooctene, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1,4-diazepine, 1,2-diazepine, 1,3-diazepine, 1,4-what iazepine, [1,4]diatkine, [1,2]diadakan-3-one, [1,3]diadakan-2-it, dioxazine, dioxazine, dioxole, 1,3-dioxolene, 1,3-dioxolane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazoline, isoxazol, isoxazoline, isoxazolidine, 2-isoxazoline, cefoperazone, research, 1,2-oxathiane, 1,2-oxathiolane, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, [1,4]oxazoline, [1,3]oxazolin-2-it, oxetane, oxolane, oxolan-2-it, piperazine, piperidine, Piran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, 5,6,7,8-tetrahydro-1H-Asotin-2-it, tetrahydrofuran, tetrahydropyran, tetrahydropyridine, tetrazine, thiadiazine, thiadiazole, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, 1,3-thiazole, thiazole, thiazolidine, thiazoline, Tatana, Ciocana, Ciocan-1,1-dioxide, Ciocan-1-oxide, Ciocan-2-it, thiomorpholine, thiophene, thiopyran, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole, and is unsubstituted or substituted from 1 to 6, R3or substituted by 1 or 2 =On,

Q represents a direct bond, -(C0-C2-alkylen-C(O)-NR10-, -NR10-C(O)-NR10-, -NR10-C(O)-, -SO2-, -(C1-C6-alkylene, -(CH2)m-NR10-C(O)-NR10-(CH2)n-, -(CH2)m-NR10-C(O)-(CH2)n-, -(CH2 )m-S-(CH2)n-, -(CH2)m-C(O)-(CH2)n-, -(CH2)m-SO2-NR10-(CH2)n-, -(CH2)m-NR10-SO2-(CH2)n-, -(CH2)m-NR10-SO2-NR10-(CH2)n-, -(CH2)m-CH(OH)-(CH2)n-, -(CH2)m-O-C(O)-NR10-(CH2)n-, -(C2-C3-alkylen-O-(C0-C3-alkylene, -(C2-C3-alkylen-S(O)-, -(C2-C3-alkylen-S(O)2-, -(CH2)m-NR10-C(O)-O-(CH2)n-, -(C2-C3-alkylen-S(O)2-NH-(R10)-, -(C2-C3-alkylene-N(R10)- or -(C0-C3-alkylen-C(O)-O-,

where R10has the values defined below, and where n and m independently of one another are identical or different and represent integers 0, 1, 2, 3, 4, 5 or 6, where alkylene residues formed -(CH2)m- or -(CH2)n-are unsubstituted or mono-, di - or tizamidine independently of one another by halogen, -NH2or is HE; or(C3-C6-cycloalkenes where cycloalkyl is unsubstituted or mono-, di - or tizamidine, independently of one another, halogen, -NH2or is HE;

R1represents a hydrogen atom, -(C1-C4)-alkyl, where alkyl is unsubstituted or substituted 1-3 times R13 ; -(C1-C3-alkylen-C(O)-NH-R0, -(C1-C3-alkylen-C(O)-O-R15, aryl selected from phenyl, naphthyl, biphenylyl, antila or fluorenyl, where aryl is unsubstituted or mono-, di - or tizamidine, independently from each other, R8where R8has the values defined above;

monocyclic or bicyclic 4 to 15-membered heterocyclyl, which has the values defined above;

-(C1-C3-perforacion, -(C1-C3-alkylen-S(O)-(C1-C4)-alkyl, -(C1-C3-alkylen-S(O)2-(C1-C3)-alkyl, -(C1-C3-alkylen-S(O)2-N(R4')-R5', -(C1-C3-alkylen-O-(C1-C4)-alkyl, -(C0-C3-alkylene-(C3-C8-cycloalkyl, or -(C0-C3-alkylene-het, where het is a residue selected from azepine, azetidine, aziridine, azirine, 1,4-diazepine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, diaziridine, diazirine, dioxazine, dioxazine, dioxole, 1,3-dioxolene, 1,3-dioxolane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazoline, isoxazol, isoxazoline, isoxazolidine, 2-isoxazoline, cefoperazone, research, 1,4-oxazepine, 1,2-oxathiane, 1,2-oxathiolane, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, oxazolidine, oxirane, piperazine, piperidine, n is wound, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydropyridine, tetrazine, tetrazole, thiadiazine, thiadiazole, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, 1,3-thiazole, thiazole, thiazolidine, thiazoline, teinila, Tatana, thiomorpholine, thiopyran, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole, where this cyclic group is unsubstituted or mono-, di - or tizamidine, independently other, R14,

R4'and R5'independent from each other and are the same or different and represent a hydrogen atom or -(C1-C4)-alkyl,

R2represents a direct bond or -(C1-C4-alkylen,

R1and R3together with the atoms to which they are linked, can form a 6-8 membered cyclic residue selected from the group consisting of asokan, asokan-2-it, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, [1,4]diatkine, [1,2]diadakan-3-one, [1,3]diadakan-2-it, dioxazine, [1,4]dioxolane, dioxole, cefoperazone, research, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, axokine, oxolan-2-it, piperazine, piperidine, Piran, pyrazine, pyridazine, pyridine or 5,6,7,8-tetrahydro-1H-Asotin-2-it, where this cyclic group is unsubstituted or mono-, di - or tizamidine, independently researched the mo from each other, R14or

R1-N-R2-V can form a 4-7-membered cyclic group, selected from the group of azepine, azetidine, dioxazine, dioxazine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazoline, isoxazol, isoxazoline, isoxazolidine, 2-isoxazoline, cefoperazone, research, oxazole, piperazine, piperidine, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydropyridine, tetrazine, tetrazole, thiazole, thiadiazole, thiazolidine, thiazoline, thiomorpholine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole, where this cyclic group is unsubstituted or mono-, di - or tizamidine, independently from each other, R14,

R14represents fluorine, chlorine, bromine, iodine, -OH, =O, -(C1-C8)-alkyl, -(C1-C4)-alkoxy, -NO2-, -C(O)-OH, -CN, -NH2, -C(O)-O-(C1-C4)-alkyl, -(C0-C8)-alkyl-SO2-(C1-C4)-alkyl, -(C0-C8)-alkyl-SO2-(C1-C3)-perfluoroalkyl, -(C0-C8)-alkyl-SO2-N(R18)-R21, -C(O)-NH-(C1-C8)-alkyl, -C(O)-N-[(C1-C8)-alkyl]2, NR18-C(O)-NH-(C1-C8)-alkyl, -C(O)-NH2, -S-R18or NR18-C(O)-NH-[(C 1-C8)-alkyl]2,

where R18and R21represent, independently from each other hydrogen atom, -(C1-C3)-perfluoroalkyl or -(C1-C6)-alkyl,

V represents

1) monocyclic or bicyclic 6-14-membered aryl selected from the group consisting of phenyl, naphthyl, biphenylyl, antila or fluorenyl, where aryl is unsubstituted or mono-, di - or tizamidine, independently from each other, R14,

2) heterocyclyl selected from the group of acridine, 8-azabicyclo[3,2,1]Oct-3-yl, azaindole(1H-pyrrolopyridine); asianshemale, azaspirodecanedione, azepine, azetidine, aziridine, benzimidazolyl, benzofuranyl, benzothiophene, benzothiophene, benzoxazole, benzthiazole, benzotriazolyl, benzatropine, benzisoxazole, benzisothiazole, carbazolyl, an-carbazolyl, carboline, Romania, chromene, cinnoline, decahydroquinoline, 1,4-diazepine, 4,5-dihydroquinoline, dioxazine, dioxazine, 1,3-DIOXOLANYL, 1,3-DIOXOLANYL, 6N-1,5,2-detainee, dehydrator[2,3-b]-tetrahydrofuranyl, furanyl, furazane, imidazolidinyl, imidazolyl, imidazolyl, 1H-indazole, indoline, indolizine, indolyl, 3H-indolyl, isobenzofuranyl, isopropanyl, isoindolyl, isoindoline, isoindolyl, izochinolina, isothiazoline, isothiazolinone, is sitesonline, isoxazolyl, isoxazoline, isoxazolidine, 2-isoxazoline, cefoperazone, morpholinyl, naphthyridine, octahydronaphthalene, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2-oxathiane, 1,2-oxathiolane, 1,4-oxazepine, 1,2-oxazinyl, 1,3-oxazinyl, 1,4-oxazinyl, oxazolidinyl, oxazolyl, oxazolyl, phenanthridine, phenanthroline, phenazine, phenothiazine, femoxetine, phenoxazine, phthalazine, piperazinil, piperidinyl, pteridinyl, purinol, pyranyl, pyrazinyl, pyrazolidine, pyrazoline, pyrazolyl, pyridazinyl, paradoxically, predominately, peridotite, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidinone, pyrroline 2N-pyrrolyl, pyrrolyl, heatline, chinoline, 4H-chinoiserie, khinoksalinona, hinokitiol, tetrahydrofuranyl, tetrahydroisoquinoline, tetrahydroquinoline, 1,4,5,6-tetrahydropyridine, tetrahydropyridine, tetrahydrothiophene, tetrazine, tetrazole, 6N-1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrene, 1,2-teinila, 1,3-teinila, 1,4-teinila, 1,3-thiazolyl, thiazolyl, thiazolidine, thiazoline, teinila, tatania, tiantianriri, cyanoacetyl, tenomodulin, tatania, thiomorpholine, 1λ6-thiomorpholine, t is openil, dipiradol, 1,2,3-triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanterra,

where specified heterocyclyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R14,

G represents a direct bond, -(CH2)m-NR10-SO2-NR10-(CH2)n-, -(CH2)m-CH(OH)-(CH2)n-, -(CH2)m-, -(CH2)m-O-(CH2)n-, -(CH2)m-C(O)-NR10-(CH2)n-, -(CH2)-SO2-(CH2)n-, -(CH2)m-NR10-C(O)-NR10-(CH2)n-, -(CH2)m-NR10-C(O)-(CH2)n-, -(CH2)m-C(O)-(CH2)n-, -(CH2)-S-(CH2)n-, -(CH2)m-SO2-NR10-(CH2)n-, -(CH2)m-NR10-SO2-(CH2)n-, -(CH2)m-NR10-, -(CH2)m-O-C(O)-NR10-(CH2)n- or -(CH2)m-NR10-C(O)-O-(CH2)n-,

n and m independently of one another are identical or different and represent integers 0, 1, 2, 3, 4, 5 or 6,

M represents

1) a hydrogen atom,

2) -(C1-C8)-alkyl, where alkyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R14,

3) -C(O)-N(R11)-R12,

4) -(CH2)m-NR10 ,

5) -(C6-C14)-aryl, where aryl has meaning as defined above and is unsubstituted or mono-, di - or tizamidine, independently from each other, R14,

6) -(C4-C15)-heterocyclyl where heterocyclyl has the values defined above and is unsubstituted or mono-, di - or tizamidine, independently from each other, R14or

7) -(C3-C8-cycloalkyl where specified cycloalkyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R14,

R3represents a

1) a hydrogen atom,

2) halogen,

3) -(C1-C4)-alkyl, where the specified alkyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R13,

4) -(C1-C3)-perfluoroalkyl,

5) phenyl, where phenyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R13,

6) -(C0-C4-alkylen-O-R19where R19represents a

(a) a hydrogen atom,

b) -(C1-C4)-alkyl, where alkyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R13,

C) -CF3or

d) -CHF2,

7) -NO2,

8) -CN,

9) -SOs-R11where s is 1 or 2,

10) -SOt-N(R11)-R12where t is 1 or 2,

11) -(C0-C4-alkylen-C(O)-R11,

12) -(C0-C4-alkylen-C(O)-O-R11,

13) -(C0-C4-alkylen-C(O)-N(R11)-R12,

14) -(C0-C4-alkylene-N(R11)-R12,

15) -NR10-SO2-R10,

16) -S-R10,

17) -(C0-C2-alkylen-C(O)-O-(C2-C4-alkylen-O-C(O)-(C1-C4)-alkyl,

18) -C(O)-O-C(R15, R16)-O-C(O)-R17,

19) -(C0-C2-alkylen-C(O)-O-(C2-C4-alkylen-O-C(O)-O-(C1-C6)-alkyl,

20) -C(O)-O-C(R15, R16)-O-C(O)-O-R17,

21) -(C0-C4-alkylene-(C6-C14)-aryl, where aryl is mono-, di - or tizamidine, independently from each other, R13,

22) -(C0-C4-alkylene-(C4-C15)-heterocyclyl where heterocyclyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R13,

23) -(C0-C4-alkylene-(C3-C8-cycloalkyl where cycloalkyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R13,

24) -(C0-C4-alkylene-het where het is unsubstituted or mono-, di - or tizamidine, independently from each other, R13,

25) -(C0-C4-alkylen-O-CH2-(C1-C3-perforacion-CH2-O-(C0-C3)-alkyl,

26) -SOw-N(R11)-R13where w is 1 or 2,

27) -(C0-C4)-al the ilen-C(O)-N(R 11)-R13,

28) -(C0-C4-alkylene-N(R11)-R13or

29) a residue from the following list of

where Me represents methyl, or

if 2 balance-OR19attached to adjacent atoms they can form together with the atoms to which they are attached, 1,3-dioxole or 2,3-dihydro-[1,4]dioxin ring, which is substituted by from 1 to 4 R13,

R11and R12independently of one another are identical or different and represent

1) a hydrogen atom,

2) -(C1-C6)-alkyl, where alkyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R13,

3) -(C0-C6)-alkyl-(C3-C6-cycloalkyl,

4) -SOt-R10where t is 1 or 2,

5) -(C0-C6)-alkyl-(C6-C14)-aryl, where alkyl and aryl independently from one another are unsubstituted or mono-, di - or tizamidine R13,

6) -(C1-C3)-perfluoroalkyl,

7) -O-R17or

8) -(C0-C6)-alkyl-(C4-C15)-heterocyclyl, where the alkyl and heterocyclyl are independently from each other unsubstituted or mono-, di - or tizamidine R13or

R11and R12together with the nitrogen atom to which they are bound, form heterocyclics the second ring, selected from the group of azepine, azetidine, dioxazine, dioxazine, 1,4-diazepine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazoline, isoxazol, isoxazoline, isoxazolidine, 2-isoxazoline, cefoperazone, research, [1,4]oxazepan, oxazole, piperazine, piperidine, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydropyridine, tetrazine, tetrazole, thiazole, thiadiazole, thiazolidine, thiazoline, thiomorpholine, thiophene, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole, where the aforementioned heterocyclic ring is unsubstituted or mono-, di - or tizamidine, independently from each other, R13,

R13represents a halogen, -NO2, -CN, =O, -OH, -CF3, -C(O)-O-R10, -C(O)-N(R10)-R20, -N(R10)-R20, -(C3-C8-cycloalkyl, -(C0-C3-alkylen-O-R10, -Si-(CH3)3, -N(R10)-S(O)u-R10where u is 1 or 2, -S-R10, -SOr-R10where r is 1 or 2, -S(O)v-N(R10)-R20where v is 1 or 2, -C(O)-R10, -(C1-C8)-alkyl, -(C1-C8)-alkoxy, phenyl, phenyloxy-, O-CF3, -(C0-C4)-alkyl-C(O)-O-C(R15, R16)-O-C(O)-R17, -(C1-C4 )-alkoxyphenyl, -(C0-C4)-alkyl-C(O)-O-C(R15, R16)-O-C(O)-O-R17, -(C1-C3)-perfluoroalkyl, -O-R15, -NH-C(O)-NH-R10, -NH-C(O)-O-R10or a residue from the following list of

where Me represents methyl,

R10and R20represent, independently from each other hydrogen, -(C1-C6)-alkyl, -(C0-C4)-alkyl-OH, -(C0-C4)-alkyl-O-(C1-C4)-alkyl or -(C1-C3)-perfluoroalkyl,

R15and R16represent, independently from each other hydrogen, -(C1-C6)-alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, where each ring is unsubstituted or substituted from 1 to 3 R10and

R17represents -(C1-C6)-alkyl, -(C1-C6)-alkyl-OH, -(C1-C6)-alkyl-O-(C1-C6)-alkyl, -(C3-C8-cycloalkyl, -(C1-C6)-alkyl-O-(C1-C8)-alkyl-(C3-C8-cycloalkyl, -(C1-C6)-alkyl-(C3-C8-cycloalkyl, where the specified cycloalkyl ring is unsubstituted or substituted 1, 2 or 3-HE,

-O-(C1-C4)-alkyl, or R10,

in all its stereoisomeric forms and mixtures in any ratio, and its physiologically acceptable salt.

(3) the Crust is ASEE the invention also relates to compounds of the formula I, where

where R0represents a

1) monocyclic or bicyclic 6-14-membered aryl selected from the group of phenyl, naphthyl, biphenyl, antila or fluorenyl, where aryl is mono-, di - or tizamidine, independently from each other, R8,

2) heterocyclyl selected from the group benzimidazolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiophene, cinnoline, Romania, indazole, indoline, isopropanyl, isoindolyl, izochinolina, phenylpyridine, phthalazine, pteridine, purine, pyridyl, predominately, pyridopyrimidines, pyridopyrimidines, pyrimidinyl, heatline, chinoline, khinoksalinona or 1,4,5,6-tetrahydropyridine where specified heterocyclyl is mono-, di - or tizamidine, independently from each other, R8or

3) heterocyclyl selected from the group asianshemale, benzimidazolyl, 1,3-benzodioxolyl, benzofuranyl, benzothiazolyl, benzothiophene, benzoxazole, Romania, indolinyl, 2-furil, 3-furil, imidazolyl, indolyl, indazole, isopropanyl, isoindolyl, izochinolina, isothiazoline, isoxazole, oxazoline, phthalazine, pteridine, purine, pyrazine, pyrazolyl, pyridazinyl, predominately, pyridopyrimidines, pyridopyrimidines, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrrolyl, 2-pyrrolyl is, 3-pyrrolyl, chinoline, heatline, khinoksalinona, tetrazolyl, thiazolyl, 2-tanila or 3-tanila,

which is optionally substituted by heterocyclyl selected from the group of acridine, asianshemale, azaspirodecanedione, azepine, azetidine, aziridine, benzimidazolyl, benzofuranyl, benzothiophene, benzothiophene, benzoxazole, benzthiazole, benzotriazolyl, benzatropine, benzisoxazole, benzisothiazole, carbazolyl, an-carbazolyl, carboline, Romania, chromene, cinnoline, decahydroquinoline, 4,5-dihydroquinoline, dioxazine, dioxazine, 1,3-DIOXOLANYL, 1,3-DIOXOLANYL, 6N-1,5,2-detainee, dehydrator[2,3-b]-tetrahydrofuranyl, furanyl, furazane, imidazolidinyl, imidazolyl, imidazolyl, 1H-indazole, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isopropanyl, isoindolyl, isoindoline, isoindolyl, izochinolina (benzimidazolyl), isothiazoline, isothiazolinone, isothiazoline, isoxazole, isoxazoline, isoxazolidine, 2-isoxazoline, cefoperazone, morpholinyl, naphthyridine, octahydronaphthalene, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2-oxathiane, 1,2-oxathiolane, 1,4-oxazepine, 1,2-oxazinyl, 1,3-oxazinyl, 1,4-oxazinyl, oxazolidinyl, oxazoline is a, oxazolyl, phenanthridine, phenanthroline, phenazine, phenothiazine, femoxetine, phenoxazine, phthalazine, piperazinil, piperidinyl, pteridinyl, purinol, pyranyl, pyrazinyl, pyrazolidine, pyrazoline, pyrazolyl, pyridazinyl, paradoxically, predominately, peridotite, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidinone, pyrroline 2N-pyrrolyl, pyrrolyl, heatline, chinoline, 4H-chinoiserie, khinoksalinona, hinokitiol, tetrahydrofuranyl, tetrahydroisoquinoline, tetrahydroquinoline, 1,4,5,6-tetrahydropyridine, tetrahydropyridine, tetrahydrothiophene, tetrazine, tetrazole, 6N-1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrene, 1,2-teinila, 1,3-teinila, 1,4-teinila, 1,3-thiazolyl, thiazolyl, thiazolidine, thiazoline, teinila, tatania, tiantianriri, cyanoacetyl, tenomodulin, tatania, thiomorpholine, thiophenyl, dipiradol, 1,2,3-triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanterra,

where specified heterocyclyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R8,

R8represents a

1. fluorine, chlorine or bromine,

2. -NO2,

3. -CN

4. -C(O)-NH2,

5. -OH,

6. -NH2,

7. -OCF3 ,

8. monocyclic or bicyclic 6-14-membered aryl, where aryl has meaning as defined above and is mono-, di - or tizamidine, independently from each other, by halogen or-O-(C1-C8)-alkyl,

9. -(C1-C8)-alkyl, where alkyl is unsubstituted or mono-, di - or tizamidine, independently of one another, halogen, NH2HE or methoxyethanol, or

10. -O-(C1-C8)-alkyl, where alkyl is unsubstituted or mono-, di - or tizamidine, independently of one another, halogen, NH2HE or methoxyethanol,

11. -SO2CH3or

12. -SO2CF3,

provided that R8represents at least one halogen, -C(O)-NH2or-O-(C1-C8)-alkyl residue, if R0represents aryl or heterocyclyl who have the meanings given above,

substructure D is a residue selected from the group of pyridyl, pyridyl-N-oxipurinol, pyrrolyl, furil, teinila, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, isothiazoline, thiadiazolyl, pyrimidinyl, pyridazinyl, pyrazinyl and is unsubstituted or substituted from 1 to 4 R3or substituted by 1 or 2 =On,

Q represents a direct bond, -(C0-C2-alkylen-C(O)-NR10-, -NR10-C(O)-NR10-, -NR10/sup> -C(O)-, -SO2-, -(C1-C6-alkylen,

R1represents a hydrogen atom, -(C1-C4)-alkyl, where alkyl is unsubstituted or substituted 1-3 times R13; -(C1-C3-alkylen-C(O)-NH-R0, -(C1-C3-alkylen-C(O)-O-R15, -(C1-C3-perforacion, -(C1-C3-alkylen-S(O)-(C1-C4)-alkyl, -(C1-C3-alkylen-S(O)2-(C1-C3)-alkyl, -(C1-C3-alkylen-S(O)2-N(R4')-R5', -(C1-C3-alkylen-O-(C1-C4)-alkyl, -(C0-C3-alkylene-(C3-C8-cycloalkyl, or -(C0-C3-alkylene-het, where het is a residue selected from the group of azepine, azetidine, aziridine, 1,4-diazepine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, diaziridine, diazirine, dioxazine, dioxazine, dioxole, 1,3-dioxolene, 1,3-dioxolane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazoline, isoxazol, isoxazoline, isoxazolidine, 2-isoxazoline, cefoperazone, research, 1,2-oxathiane, 1,2-oxylane, 1,4-oxazepine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, oxazolidine, oxirane, piperazine, piperidine, Piran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydropyridine is, tetrazine, tetrazole, thiadiazine, thiadiazole, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, 1,3-thiazole, thiazole, thiazolidine, thiazoline, teinila, Tatana, thiomorpholine, thiopyran, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole, where het is unsubstituted or mono-, di - or tizamidine, independently from each other, R14,

R4'and R5'independent from each other and are the same or different and represent a hydrogen atom or -(C1-C4)-alkyl,

R2represents a direct bond or -(C1-C4-alkylen, or

R1-N-R2-V form a 4-7-membered cyclic group, selected from the group of azepine, azetidine, 1,4-diazepine, dioxazine, dioxazine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazoline, isoxazol, isoxazoline, isoxazolidine, 2-isoxazoline, cefoperazone, research, 1,4-oxazepine, oxazole, piperazine, piperidine, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydropyridine, tetrazine, tetrazole, thiazole, thiadiazole, thiazolidine, thiazoline, thiomorpholine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole, where this cyclic group is asamese the Noi or mono-, di - or tizamidine, independently from each other, R14,

R14represents fluorine, chlorine, bromine, iodine, -OH, =O, -(C1-C8)-alkyl, -(C1-C4)-alkoxy, -NO2-, -C(O)-OH, -CN, -NH2, -C(O)-O-(C1-C4)-alkyl, -(C0-C8)-alkyl-SO2-(C1-C4)-alkyl, -(C0-C8)-alkyl-SO2-(C1-C3)-perfluoroalkyl, -(C0-C8)-alkyl-SO2-N(R18)-R21, -C(O)-NH-(C1-C8)-alkyl, -C(O)-N-[(C1-C8)-alkyl]2, NR18-C(O)-NH-(C1-C8)-alkyl, -C(O)-NH2, -S-R18or NR18-C(O)-NH-[(C1-C8)-alkyl]2,

where R18and R21represent independently from each other hydrogen atom, -(C1-C3)-perfluoroalkyl or -(C1-C6)-alkyl,

V represents

1) residue het is selected from the group azaindole(1H-pyrrolopyridine), azepine, azetidine, aziridine, azirine, 1,4-diazepine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, diaziridine, diazirine, dioxazine, dioxazine, dioxole, 1,3-dioxolene, 1,3-dioxolane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazoline, isoxazol, isoxazoline, isoxazolidine, 2-isoxazoline, cefoperazone, research, 1,2-oxathiane, 1,2-oxathiolane, 1,4-oxazepine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, oxazolidine, oxirane, Pieper is Zina, piperidine, Piran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydropyridine, tetrazine, tetrazole, thiadiazine, thiadiazole, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, 1,3-thiazole, thiazole, thiazolidine, thiazoline, teinila, Tatana, thiomorpholine, thiopyran, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole, which has the values defined above, and where het is unsubstituted or mono-, di - or tizamidine, independently from each other, R14or

2) phenyl, where phenyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R14,

G represents a direct bond, -(CH2)m-NR10-SO2-NR10-(CH2)n-, -(CH2)m-CH(OH)-(CH2)n-, -(CH2)m-, -(CH2)m-O-(CH2)n-, -(CH2)m-C(O)-NR10-(CH2)n-, -(CH2)-SO2-(CH2)n-, -(CH2)m-NR10-C(O)-NR10-(CH2)n-, -(CH2)m-NR10-C(O)-(CH2)n-, -(CH2)m-C(O)-(CH2)n-, -(CH2)-S-(CH2)n-, -(CH2)m-SO2-NR10-(CH2)n-, -(CH2)m-NR10-SO2-(CH2)n-, -(CH2)m-NR10-, -(CH2)m-O-C(O)-NR10 2)n- or -(CH2)m-NR10-C(O)-O-(CH2)n-,

n and m are independently of one another identical or different and represent integers 0, 1, 2, 3, 4, 5 or 6,

M represents

1) a hydrogen atom,

2) -(C1-C8)-alkyl, where alkyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R14,

3) -C(O)-N(R11)-R12,

4) -(CH2)m-NR10,

5) phenyl or naphthyl, where phenyl or naphthyl are unsubstituted or mono-, di - or tizamidine, independently from each other, R14,

6) heterocyclyl where heterocyclyl represents the balance of the group, which can be obtained from azepane, azepine, 1,4-diazepine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, imidazole, isothiazole, isoxazol, isoxazolidine, 2-isoxazoline, metamorphosen, cefoperazone, research, oxazole, [1,4]-oxazepan, piperazine, piperazinone, piperidine, piperidine, pyrazine, pyridazine, pyridazine, pyridine, pyridone, pyrimidine, pyrrolidine, pyrrolidinone, tetrahydropyran, 1,4,5,6-tetrahydropyridine, tetrazine, tetrazole, thiadiazole, thiazole, thiophene, thiomorpholine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole, where specified heterocyclyl is unsubstituted or mono-, di - or tizamidine, independently from others who ha R14or

7) -(C3-C8-cycloalkyl where specified cycloalkyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R14,

R3represents a

1) a hydrogen atom,

2) halogen,

3) -(C1-C4)-alkyl, where alkyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R13,

4) -(C1-C3)-perfluoroalkyl,

5) phenyl, where phenyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R13,

6) -(C0-C4-alkylen-O-R19where R19represents a

(a) a hydrogen atom,

b) -(C1-C4)-alkyl, where alkyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R13,

C) -CF3or

d) -CHF2,

7) -CN,

8) -(C0-C4-alkylene-(C4-C15)-heterocyclyl where heterocyclyl has the values defined above and is unsubstituted or mono-, di - or tizamidine, independently from each other, R13,

9) -SOs-R11where s is 1 or 2,

10) -SOt-N(R11)-R12where t is 1 or 2,

11) -(C0-C4-alkylen-C(O)-R11,

12) -(C0-C4-alkylen-C(O)-O-R11,

13) -(C0-C4-alkylen-C(O)-N(R11)-R12,

14) -(C0-C4-alkylene-N(R11)-R12 ,

15) -NR10-SO2-R10,

16) -(C0-C4-alkylene-het, where het has the meanings defined above and is unsubstituted or mono-, di - or tizamidine, independently from each other, R13,

17) -(C0-C2-alkylen-C(O)-O-(C2-C4-alkylen-O-C(O)-(C1-C4)-alkyl,

18) -C(O)-O-C(R15, R16)-O-C(O)-R17,

19) -(C0-C2-alkylen-C(O)-O-(C2-C4-alkylen-O-C(O)-O-(C1-C6)-alkyl,

20) -C(O)-O-C(R15, R16)-O-C(O)-O-R17,

21) -(C0-C4-alkylene-(C6-C14)-aryl, where aryl has meaning as defined above and is mono-, di - or tizamidine, independently from each other, R13,

22) -(C0-C4-alkylene-(C3-C8-cycloalkyl where cycloalkyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R13,

23) -(C0-C3-alkylen-O-CH2-CF2-CH2-O-(C0-C3)-alkyl,

24) -(C0-C3-alkylen-O-CH2-CF2-CF2-CH2-O-(C0-C3)-alkyl,

25) -(C0-C3-alkylen-O-CH2-(C1-C3-perforacion-CH2-OH,

26) -SOw-N(R11)-R13where w is 1 or 2,

27) -(C0-C4-alkylen-C(O)-N(R11)-R13,

28) -(C0-C4-alkylene-N(R11)-R13or

29) the rest of pursuing what about the list

where Me represents methyl, or

if 2 balance-OR19attached to adjacent atoms they can form together with the atoms to which they are attached, 1,3-dioxole ring or a 2,3-dihydro-[1,4]dioxin ring, substituted from 1 to 4 R13,

R11and R12independently of one another are identical or different and represent

1) a hydrogen atom,

2) -(C1-C6)-alkyl, where alkyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R13,

3) -(C0-C6)-alkyl-(C6-C14)-aryl, where aryl has meaning as defined above, and where alkyl and aryl are independently of one another, unsubstituted or mono-, di - or tizamidine R13,

4) -O-R17or

5) -(C0-C6)-alkyl-(C4-C15)-heterocyclyl, where the alkyl and heterocyclyl are, independently of one another, unsubstituted or mono-, di - or tizamidine R13or

R11and R12together with the nitrogen atom to which they are bound, may form a ring selected from the group of azepine, azetidine, 1,4-diazepine, dioxazine, dioxazine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazoline, isoxazol, isoxazoline, isoxazolidine, 2 from which Catalina, cefoperazone, research, [1,4]oxazepan, oxazole, piperazine, piperidine, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydropyridine, tetrazine, tetrazole, thiazole, thiadiazole, thiazolidine, thiazoline, thiomorpholine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole, that is unsubstituted or mono-, di - or tizamidine, independently from each other, R13,

R13represents fluorine, chlorine, bromine, iodine, -NO2, -CN, =O, -OH, -CF3, -C(O)-O-R10, -C(O)-N(R10)-R20, -N(R10)-R20, -(C0-C3-alkylen-O-R10, -Si-(CH3)3, -N(R10)-S(O)2-R10, -S-R10, -SO2-R10, -S(O)2-N(R10)-R20, -C(O)-R10, -(C1-C8)-alkyl, -(C1-C8)-alkoxy, phenyl, phenyloxy-, O-CF3, -(C1-C3)-perfluoroalkyl, -(C0-C4)-alkyl-C(O)-O-C(R15,R16)-O-C(O)-R17, -(C1-C4)-alkoxyphenyl, -(C0-C4)-alkyl-C(O)-O-C(R15,R16)-O-C(O)-O-R17, -O-R15, -NH-C(O)-NH-R10, -NH-C(O)-O-R10or a residue from the following list of

where Me represents methyl,

R10and R20before the represent, independently from each other hydrogen, -(C1-C6)-alkyl, -(C0-C4)-alkyl-OH, -(C0-C4)-alkyl-O-(C1-C4)-alkyl or -(C1-C3)-perfluoroalkyl,

R15and R16represent independently from each other hydrogen, -(C1-C6)-alkyl, or together form a ring selected from the group of cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, where each ring is unsubstituted or substituted from 1 to 3 R10and

R17represents -(C1-C6)-alkyl, -(C1-C6)-alkyl-OH, -(C1-C6)-alkyl-O-(C1-C6)-alkyl, -(C3-C8-cycloalkyl, -(C1-C6)-alkyl-O-(C1-C8)-alkyl-(C3-C8-cycloalkyl, -(C1-C6)-alkyl-(C3-C8-cycloalkyl, where the specified cycloalkyl ring is unsubstituted or substituted 1, 2 or 3-HE,

-O-(C1-C4)-alkyl, or R10,

in all its stereoisomeric forms and mixtures in any ratio, and its physiologically acceptable salt.

(4) the Present invention also relates to compounds of formula I, where

R0represents a

1) phenyl, where phenyl is unsubstituted or mono-, di - or trisemester, independently from each other, R8.

2) heterocyclyl selected from the group benzimidazolyl, 1,3-benzodioxolyl, benzo is uranyl, benzoxazolyl, benzothiazolyl, benzothiophene, cinnoline, Romania, indazole, indoline, isopropanyl, isoindolyl, izochinolina, phenylpyridine, phthalazine, pteridine, purine, pyridyl, predominately, pyridopyrimidines, pyridopyrimidines, pyrimidinyl, heatline, chinoline, khinoksalinona or 1,4,5,6-tetrahydropyridine where specified heterocyclyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R8or

3) heterocyclyl selected from the group of pyridyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, furil, 2-furil, 3-furil, teinila, 2-tanila, 3-tanila, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazoline, triazolyl, tetrazolyl, pyridazinyl and pyrazinyl where specified heterocyclyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R8,

and additionally substituted by a residue selected from the group of pyridyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, furil, 2-furil, 3-furil, teinila, 2-tanila, 3-tanila, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazoline, triazolyl, tetrazolyl, pyridazinyl and pyrazinyl, where the specified residue is unsubstituted or mono-, di - or tizamidine, n is independently from each other, R8,

R8represents a

1. F, Cl, Br or I,

2. -C(O)-NH2,

3. -(C1-C4)-alkyl, where alkyl is unsubstituted or mono-, di - or tizamidine, independently of one another, halogen, -OH or methoxyethanol, or

4. -O-(C1-C4)-alkyl, where alkyl is unsubstituted or mono-, di - or tizamidine, independently from each other, by halogen or methoxyethanol, provided that R8represents at least one halogen, -C(O)-NH2or-O-(C1-C8)-alkyl residue, if R0represents aryl or heterocyclyl who have the meanings given above,

substructure D is a residue selected from the group of pyridyl, pyridyl-N-oxide, pyrrolyl, furil, teinila, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazoline, thiadiazolyl, pyrimidinyl, pyridazinyl, pyrazinyl and is unsubstituted or substituted from 1 to 4 R3or substituted by 1 or 2 =On,

Q represents a direct bond, -C(O)-; -SO2- or -(C1-C6-alkylene, -(C0-C2-alkylen-C(O)-NR10-,

R1represents a hydrogen atom, -(C1-C2)-alkyl, -(C1-C3-alkylen-C(O)-NH-RO, -(C1-C3-perforacion, -(C1-C3-alkylen-C(O)-OR15, -(C1-C3-alkylen-S(O)2-C 1-C3)-alkyl or -(C1-C3-alkylen-S(O)2-N(R4')-R5'where R4'and R5'independent from each other and are the same or different and represent a hydrogen atom or -(C1-C4)-alkyl,

R2represents a direct bond or -(C1-C2-alkylen,

R1-N-R2-V can form a 4-7-membered cyclic group, selected from the group of azetidine, azetidinone, piperidine, piperazine, pyridine, pyrimidine, pyrrolidine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole, 1,2,4-triazole, tetrazine, tetrazole, 1,4-diazepine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, azepine, cefoperazone, 1,4-oxazepine, oxazole, isoxazol, isoxazolidine, 2-isoxazoline, research, thiazole, isothiazole, thiadiazole or thiomorpholine where the specified cyclic group is unsubstituted or mono-, di - or tizamidine, independently from each other, R14,

R14represents fluorine, chlorine, -OH, =O, -(C1-C8)-alkyl, -C(O)-OH, -CN, -NH2, -C(O)-O-(C1-C4)-alkyl, -C(O)-NH-(C1-C8)-alkyl, -C(O)-N-[(C1-C8)-alkyl]2, -C(O)-NH2or-N(R18)- R21,

where R18and R21represent, independently from each other hydrogen atom, -(C1-C3)-perfluoroalkyl or -(C1-C4)-alkyl,

V is particularly the

1. cyclic residue selected from the group consisting of compounds derived from azaindole(1H-pyrrolopyridine), aziridine, azirine, azetidine, azetidinone, 1,4-diazepine, pyrrole, pyrrolidine, pyridinyl, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyrimidine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, tetrazine, tetrazole, azepine, diazirine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, pyridazine, piperidine, piperazine, pyrrolidinone, cefoperazone, furan, Piran, dioxolan, 1,4-oxazepine, oxazole, isoxazol, 2-isoxazoline, isoxazolidine, research, oxirane, oxaziridine, 1,3-dioxolene, 1,3-dioxolane, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxaziridine, thiophene, thiopyran, Tatana, thiazole, isothiazole, isothiazoline, isothiazolinone, 1,2-oxathiolane, thiadiazole, thiopyran, 1,2-thiazine, 1,3-thiazole, 1,3-thiazine, 1,4-thiazine, thiadiazine or thiomorpholine where the specified cyclic residue is unsubstituted or mono-, di or tizamidine, independently from each other, R14or

2. phenyl, where phenyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R14or

G represents a direct bond, -(CH2)m- or -(CH2)m-NR10-where m is an integer 0, 1, 2, 3,or 4

M represents

1. a hydrogen atom,/p>

2. heterocyclyl where heterocyclyl represents a residue selected from the group which can be obtained from azepane, azepine, 1,4-diazepine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, imidazole, isothiazole, isoxazol, isoxazolidine, 2-isoxazoline, metamorphosen, cefoperazone, research, oxazole, [1,4]-oxazepan, piperazine, piperazinone, piperidine, piperidine, pyrazine, pyridazine, pyridazine, pyridine, pyridone, pyrimidine, pyrrolidine, pyrrolidinone, tetrahydropyran, 1,4,5,6-tetrahydropyridine, tetrazine, tetrazole, thiadiazole, thiazole, thiomorpholine, thiophene, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole, where specified heterocyclyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R14,

3. -(C1-C6)-alkyl, where alkyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R14,

4. -(C3-C6-cycloalkyl or

5. -C(O)-N(R11)-R12,

R3represents a

1) a hydrogen atom,

2) halogen,

3) -(C1-C4)-alkyl, where alkyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R13,

4) -(C1-C3)-perfluoroalkyl,

5) phenyl, where phenyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R13

6) -(C0-C4-alkylen-O-R19where R19represents a

(a) a hydrogen atom,

b) -(C1-C4)-alkyl, where alkyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R13,

C) -CF3or

d) -CF2,

7) -CN,

8) -NR10-SO2-R10,

9) -SOs-R11where s is 1 or 2,

10) -SOt-N(R11)-R12where t is 1 or 2,

11) -(C0-C4-alkylen-C(O)- R11,

12) -(C0-C4-alkylen-C(O)-O-R11,

13) -(C0-C4-alkylen-C(O)-N(R11)-R12,

14) -(C0-C4-alkylene-N(R11)-R12,

15) -(C0-C2-alkylen-C(O)-O-(C2-C4-alkylen-O-C(O)-(C1-C4)-alkyl,

16) -C(O)-O-C(R15, R16)-O-C(O)-R17,

17) -(C0-C2-alkylen-C(O)-O-(C2-C4-alkylen-O-C(O)-O-(C1-C6)-alkyl,

18) -C(O)-O-C(R15, R16)-O-C(O)-O-R17,

19) -(C0-C3-alkylen-O-CH2-CF2-CH2-O-(C0-C3)-alkyl,

20) -(C0-C3-alkylen-O-CH2-CF2-CF2-CH2-O-(C0-C3)-alkyl,

21) -(C0-C3-alkylen-O-CH2-(C1-C3-perforacion-CH2-OH,

22) -SOw-N(R11)-R13where w is 1 or 2,

23) -(C0-C4-alkylen-C(O)-N(R11)-R13,

24) -(C0-C4 11)-R13or

25) a residue from the following list of

where Me represents methyl,

if 2 balance-OR19attached to adjacent atoms they can form together with the atoms to which they are attached, 1,3-dioxole ring or a 2,3-dihydro-[1,4]dioxin ring, which is substituted by from 1 to 4 R13,

R11and R12together with the nitrogen atom to which they are bound, may form a ring selected from the group of azepine, azetidine, 1,4-diazepine, dioxazine, dioxazine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazoline, isoxazol, isoxazoline, isoxazolidine, 2-isoxazoline, cefoperazone, research, [1,4]-oxazepan, oxazole, piperazine, piperidine, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydropyridine, tetrazine, tetrazole, thiazole, thiadiazole, thiazolidine, thiazoline, thiomorpholine, thiophene, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole, where the specified ring is unsubstituted or mono-, di - or tizamidine, independently from each other, R13,

R13represents fluorine, chlorine, -NO2, -CN, =O, -OH, -CF3, -C(O)-O-R10, -C(O)-N(R10-R 20, -N(R10)-R20, -(C0-C3-alkylen-O-R10, -Si-(CH3)3, -N(R10)-S(O)2-R10, -S-R10, -SO2-R10, -S(O)2-N(R10)-R20, -C(O)-R10, -(C1-C8)-alkyl, -(C1-C8)-alkoxy, phenyl, phenyloxy-, O-CF3, perfluoroalkyl, -NH-C(O)-NH-R10, -(C0-C4)-alkyl-C(O)-O-C(R15, R16)-O-C(O)-R17, -(C1-C4)-alkoxyphenyl, -(C0-C4)-alkyl-C(O)-O-C(R15, R16)-O-C(O)-O-R17, -O-R15, -NH-C(O)-O-R10or a residue from the following list of

where Me represents methyl,

R10and R20represent independently from each other hydrogen, -(C1-C6)-alkyl, -(C0-C4)-alkyl-OH, -(C0-C4)-alkyl-O-(C1-C4)-alkyl or -(C1-C3)-perfluoroalkyl,

R15and R16represent independently from each other hydrogen, -(C1-C6)-alkyl, or together form a ring selected from the group of cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, where each ring is unsubstituted or substituted from 1 to 3 R10and

R17represents -(C1-C6)-alkyl, -(C1-C6)-alkyl-OH, -(C1-C6)-alkyl-O-(C1-C6)-alkyl, -(C3-C8-cycloalkyl, -(C1-C6)-alkyl-O-(C 1-C8)-alkyl-(C3-C8-cycloalkyl, -(C1-C6)-alkyl-(C3-C8-cycloalkyl, where the specified cycloalkyl ring is unsubstituted or substituted 1, 2 or 3-HE,

-O-(C1-C4)-alkyl, or R10,

in all its stereoisomeric forms and mixtures in any ratio, and its physiologically acceptable salt.

(5) the Present invention also relates to compounds of formula I, where

R0represents a

1) phenyl, where phenyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R8.

2) heterocyclyl selected from the group of indolyl, isoindolyl, benzofuranyl, benzothiophene, 1,3-benzodioxolyl, indazole, benzimidazole, benzoxazole, benzothiazole, chinoline, izochinolina, Romania, isopropanyl, cinnoline, heatline, khinoksalinona, phthalazine, predominately, pyridopyrimidines, pyridopyrimidines, pyridyl, purines and pteridines,

where specified heterocyclyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R8,

3) heterocyclyl selected from the group of pyridyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, furil, 2-furil, 3-furil, teinila, 2-tanila, 3-tanila, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl,isothiazoline, triazolyl, tetrazolyl, pyridazinyl and pyrazinyl where specified heterocyclyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R8,

and additionally substituted by a residue selected from the group of pyridyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, furil, 2-furil, 3-furil, teinila, 2-tanila, 3-tanila, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazoline, triazolyl, tetrazolyl, pyridazinyl and pyrazinyl, where the specified residue is unsubstituted or mono-, di - or tizamidine, independently from each other, R8,

R8represents a

1. F, Cl, Br or I,

2. -C(O)-NH2,

3. -(C1-C4)-alkyl, where alkyl is unsubstituted mono-, di - or tizamidine, independently of one another, halogen, -OH or methoxyethanol, or

4. -O-(C1-C4)-alkyl, where alkyl is unsubstituted or mono-, di - or tizamidine, independently from each other, by halogen or methoxyethanol, provided that R8represents at least one halogen, -C(O)-NH2or-O-(C1-C8)-alkyl residue, if R0represents aryl or heterocyclyl who have the meanings given above,

substructure D is a residue selected from the group status is the present from pyridyl, pyridyl-N-oxide, pyrrolyl, furil, teinila, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, isothiazoline, thiadiazolyl, pyrimidinyl, pyridazinyl, pyrazinyl and is unsubstituted or substituted from 1 to 4 R3or substituted by 1 or 2 =On,

Q represents a direct bond, -C(O)-; -SO2- or -(C1-C6-alkylene, -(C0-C2-alkylen-C(O)-NR10-,

R1represents a hydrogen atom or -(C1-C2)-alkyl,

R2represents a direct bond or -(C1-C2-alkylen, or

R1-N-R2-V can form a 4-7-membered cyclic group, selected from piperidine, pyridine, pyrimidine, pyrrolidine, pyrrolidinone, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole, 1,2,4-triazole, tetrazine, tetrazole, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, azepine, cefoperazone, oxazole, isoxazol, isoxazolidine, 2-isoxazoline, research, thiazole, isothiazole, thiadiazole or thiomorpholine where the specified cyclic group is unsubstituted or mono-, di - or tizamidine, independently other, R14,

R14represents fluorine, chlorine, =O, -(C1-C4)-alkyl or-NH2,

V represents

1. cyclic residue from the group consisting of compounds that are derived from azaindole(1H-pyrrolopyridine is), azetidine, azepine, aziridine, azirine, 1,4-diazepine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, diazirine, 1,3-dioxolane, dioxolane, furan, imidazole, isoquinoline, isothiazole, isothiazoline, isothiazoline, isoxazol, 2-isoxazoline, isoxazolidine, cefoperazone, research, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, 1,2-oxathiolane, piperidine, Piran, pyrazine, pyrazole, pyridazine, piperazine, pyridine, pyridone, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, heatline, quinoline, tetrazine, tetrazole, thiadiazine, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, 1,3-thiazole, Tatana, thiomorpholine, thiophene, thiopyran, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole,

where the specified cyclic residue is unsubstituted or mono-, di - or tizamidine, independently from each other, R14or

2. phenyl, where phenyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R14,

G represents a direct bond, -(CH2)m- or -(CH2)m-NR10-where m is an integer 0, 1, 2, 3,or 4

M represents

1. a hydrogen atom,

2. heterocyclyl where heterocyclyl represents the balance of the group, which can be obtained from 1,4-diazepan, metamorphosen, thiophene, pyridazine, piperidine, piperazine, pyridine, pyrimidine, PI is alidina, pyrrolidinone, pyridinyl, imidazole, pyridazine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole, 1,2,4-triazole, tetrazine, tetrazole, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, azepine, cefoperazone, oxazole, isoxazol, isoxazolidine, 2-isoxazoline, research, thiazole, isothiazole, tetrahydropyran, 1,4,5,6-tetrahydropyridine, thiadiazole or thiomorpholine where specified heterocyclyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R14,

3. -(C1-C6)-alkyl, where alkyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R14or

4. -(C3-C6-cycloalkyl,

R3represents a

1) a hydrogen atom,

2) halogen,

3) -(C1-C4)-alkyl, where alkyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R13,

4) -(C1-C3)-perfluoroalkyl,

5) phenyl, where phenyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R13,

6) -(C0-C4-alkylen-O-R19where R19represents a

(a) a hydrogen atom,

b) -(C1-C4)-alkyl, where alkyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R13,

C) -CF3or

d) -CHF2,

7) -CN,

8) -NR10,-SO 2-R10,

9) -SOs-R11where s is 1 or 2,

10) -SOt-N(R11)-R12where t is 1 or 2,

11) -(C0-C4-alkylen-C(O)-R11,

12) -(C0-C4-alkylen-C(O)-O-R11,

13) -(C0-C4-alkylen-C(O)-N(R11)-R12,

14) -(C0-C4-alkylene-N(R11)-R12,

15) -(C0-C2-alkylen-C(O)-O-(C2-C4-alkylen-O-C(O)-(C1-C4)-alkyl,

16) -C(O)-O-C(R15, R16)-O-C(O)-R17,

17) -(C0-C2-alkylen-C(O)-O-(C2-C4-alkylen-O-C(O)-O-(C1-C6)-alkyl,

18) -C(O)-O-C(R15, R16)-O-C(O)-O-R17or

19) a residue from the following list of

where Me represents methyl,

R11and R12are independently of one another identical or different and represent

1) a hydrogen atom,

2) -(C1-C6)-alkyl, where alkyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R13,

3) -(C0-C6)-alkyl-(C3-C6-cycloalkyl,

4) -O-R17or

5) -(C0-C6)-alkyl-(C4-C15)-heterocyclyl, where the alkyl and heterocyclyl independently of one another are unsubstituted or mono-, di - or tizamidine R13and where heterocyclyl selected from the group of azetidine, cyclopropyl, cyclobe the sludge, 4,5-dihydrooxazolo, imidazolidine, research, (1,4)-oxazepine, oxazolidine, piperidine, piperazine, pyrrolidine, tetrahydrothiophene, thiazolidine or thiomorpholine, or

R11and R12together with the nitrogen atom to which they are linked, form a heterocyclic ring selected from the group of azetidine, cyclopropyl, cyclobutyl, 4,5-dihydrooxazolo, imidazolidine, metrolina, (1,4)-oxazepine, oxazolidine, piperidine, piperazine, pyrrolidine, tetrahydrothiophene, thiazolidine or thiomorpholine,

R13represents a fluorine, -CN, =O, -OH, -CF3, -C(O)-O-R10, -C(O)-N(R10)-R20, -N(R10)-R20, -(C3-C6-cycloalkyl, -(C0-C3-alkylen-O-R10, -Si-(CH3)3, -S-R10, -SO2-R10, -(C1-C3)-perfluoroalkyl, or a residue from the following list of

where Me represents methyl,

R10and R20represent independently from each other hydrogen, -(C1-C4)-alkyl or -(C1-C3)-perfluoroalkyl,

R15and R16represent, independently from each other hydrogen, -(C1-C6)-alkyl, or together form a ring selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, where each ring is unsubstituted or substituted from 1 to 3 R10and

R17before the hat is -(C 1-C6)-alkyl, -(C1-C6)-alkyl-OH, -(C1-C6)-alkyl-O-(C1-C6)-alkyl, -(C1-C6)-alkyl-O-(C1-C8)-alkyl-(C3-C8-cycloalkyl, -(C0-C6)-alkyl-(C3-C8-cycloalkyl, where the specified cycloalkyl ring is unsubstituted or substituted 1, 2 or 3-HE,

-O-(C1-C4)-alkyl, or R10,

in all its stereoisomeric forms and mixtures in any ratio, and its physiologically acceptable salt.

(6) the Present invention also relates to compounds of formula I, where

R0represents a

1. phenyl, where phenyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R8.

2. pyridyl or benzothiophene where pyridyl or benzothiophenes are unsubstituted or mono-, di - or tizamidine, independently from each other, R8or

3. heterocyclyl selected from tanila, thiadiazolyl, isoxazolyl and thiazolyl where specified heterocyclyl substituted by a residue selected from tanila, 2-tanila and 3-tanila, where the specified residue is unsubstituted or mono-, di - or tizamidine, independently from each other, R8,

R8represents F, Cl, Br, -OCH3or-C(O)-NH2,

substructure D is a residue selected from pyridyl, pyridyl-N-oxide, pyrrolyl, thienyl is, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazoline, thiadiazolyl, pyrimidinyl, pyridazinyl or pyrazinyl and is unsubstituted or substituted 1, 2, 3, or 4 R3or substituted by 1 or 2 =On,

Q represents a direct bond, -C(O)-; -SO2-, CH2-C(O)-NH-, methylene or ethylene,

R1represents a hydrogen atom,

R2represents a direct bond or methylene,

R1-N-R2-V can form a 4-7-membered cyclic group, selected from azetidine, pyrrolidine, piperidine and

R14represents fluorine, chlorine, =O, methyl, ethyl, or-NH2,

V represents

1. cyclic residue from the group consisting of compounds that are derived from azaindole(1H-pyrrolopyridine), azetidine, 1,4-diazepine, isoxazol, isoquinoline, piperazine, piperidine, pyrazine, pyridazine, pyrimidine, pyrrolidine, heatline, quinoline or tetrahydropyrane,

where the specified cyclic residue is unsubstituted or mono-or disubstituted, independently of one another, R14, or

2. phenyl, where phenyl is unsubstituted or mono - or disubstituted, independently of one another, R14,

G represents a direct bond, -(CH2)m- or -(CH2)m-NR10-, where m represents the integer 1 or 2,

M represents Alamogordo, -(C2-C4)-alkyl, azepane, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, imidazolyl, geomorphology, [1,4]oxazepan, piperidinyl, piperidinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolidinyl, 1,4,5,6-tetrahydropyridine or tetrahydropyranyl, where the residues are unsubstituted or mono-or disubstituted independently of each R14

R3represents a

1) a hydrogen atom,

2) fluorine, chlorine,

3) -(C1-C4)-alkyl, where alkyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R13,

4) -(C1-C3)-perfluoroalkyl,

5) phenyl, where phenyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R13,

6) -(C0-C4-alkylen-O-R19where R19represents a

(a) a hydrogen atom,

b) -(C1-C4)-alkyl, where alkyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R13,

C) -CF3or

d) -CHF2,

7) -CN,

8) -NR10-SO2-R10,

9) -SOs-R11where s is 1 or 2,

10) -SOt-N(R11)-R12where t is 1 or 2,

11) -(C0-C4-alkylen-C(O)- R11,

12) -(C0-C4-alkylen-C(O)-O-R11,

13) -(C0-C4-alkylen-C(O)-N(R11)-R12,

14) -(C0C 4-alkylene-N(R11)-R12,

15) -(C0-C2-alkylen-C(O)-O-(C2-C4-alkylen-O-C(O)-(C1-C4)-alkyl,

16) -C(O)-O-C(R15, R16)-O-C(O)-R17,

17) -(C0-C2-alkylen-C(O)-O-(C2-C4-alkylen-O-C(O)-O-(C1-C6)-alkyl or

18) -C(O)-O-C(R15, R16)-O-C(O)-O-R17,

R11and R12are independently of one another identical or different and represent

1) a hydrogen atom,

2) -(C1-C4)-alkyl, where alkyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R13,

3) -(C0-C6)-alkyl-(C3-C6-cycloalkyl,

4) -O-R17or

5) -(C0-C6)-Alkylglucoside, where the alkyl and heterocyclyl are independently from each other unsubstituted or mono-, di - or tizamidine R13and where heterocyclyl selected from azetidine, imidazolidine, research, (1,4)-oxazepine or pyrrolidine, or

R11and R12together with the nitrogen atom to which they are bound, may form a ring which is selected from the group of azetidine, imidazolidine, research, (1,4)-oxazepine, piperazine, piperidine, pyrrolidine or thiomorpholine,

R13represents a fluorine, -CN, =O, -OH, -CF3, -C(O)-O-R10, -C(O)-N(R10)-R20, -N(R10)-R20, -(C3-C6-cycloalkyl, -(C0 -C3-alkylen-O-R10, -Si-(CH3)3, -S-R10, -SO2-R10or -(C1-C3)-perfluoroalkyl,

R10and R20represent, independently from each other hydrogen, -(C1-C4)-alkyl or -(C1-C3)-perfluoroalkyl,

R15and R16represent independently from each other hydrogen, -(C1-C4)-alkyl, or together form a ring selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, where each ring is unsubstituted or substituted from 1 to 3 R10and

R17represents -(C1-C6)-alkyl, -(C1-C6)-alkyl-OH, -(C1-C6)-alkyl-O-(C1-C6)-alkyl, -(C1-C6)-alkyl-O-(C1-C8)-alkyl-(C3-C8-cycloalkyl, -(C0-C6)-alkyl-(C3-C8-cycloalkyl, where the specified cycloalkyl ring is unsubstituted or substituted 1, 2 or 3-OH, -O-(C1-C4)-alkyl, or R10,

in all its stereoisomeric forms and mixtures in any ratio, and its physiologically acceptable salt.

(7) the Present invention also relates to compounds of formula I, where

R0represents a

1. pyridyl or benzothiophene where pyridyl or benzothiophenes are unsubstituted or mono - or disubstituted independently of each R8the sludge is

2. heterocyclyl selected from the group of tanila, thiadiazolyl, isoxazolyl and thiazolyl where specified heterocyclyl is substituted, independently of one another, a residue selected from tanila, 2-tanila and 3-tanila, where the specified residue is unsubstituted or mono - or disubstituted, independently of one another, R8,

R8represents F, Cl, Br, -OCH3or-C(O)-NH2,

substructure D is a pyridyl is unsubstituted or substituted 1, 2, 3, or 4 R3or substituted by one or two =O,

Q represents-CH2-C(O)-NH -, or a methylene,

R1represents a hydrogen atom,

R2represents a direct bond,

R14represents fluorine, chlorine, =O, methyl, ethyl, or-NH2,

V represents piperidine, where the piperidine is unsubstituted or mono - or disubstituted, independently of one another, R14, or

G represents a direct link,

M represents a hydrogen atom, -(C2-C4)-alkyl, isopropyl or pyridyl, where the residue is unsubstituted or mono - or di - substituted, independently from each other, R14,

R3represents a

1) a hydrogen atom,

2) fluorine, chlorine,

3) -(C1-C4)-alkyl, where alkyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R13,

4) -(Csub> 0-C2-alkylen-O-R19where R19represents a

(a) a hydrogen atom, or

b) -(C1-C4)-alkyl, where alkyl is unsubstituted or mono-, di - or tizamidine, independently from each other, R13,

5) -(C0-C4-alkylen-C(O)-R11,

6) -(C0-C4-alkylen-C(O)-N(R11)-R12,

R11and R12independent from each other and are the same or different and represent

1) hydrogen or

2) -(C1-C4)-alkyl, where alkyl is mono-, di - or tizamidine, independently from each other, R13or

R11and R12together with the nitrogen atom to which they are bound, may form a ring selected from the group of azetidine, imidazolidine, research, (1,4)-oxazepine, piperazine, piperidine, pyrrolidine or thiomorpholine,

R13represents fluorine, =O, -OH, -CF3, -C(O)-O-R10, -C(O)-N(R10)-R20, -N(R10)-R20or -(C0-C3-alkylen-O-R10,

R10and R20represent independently from each other hydrogen, -(C1-C4)-alkyl or -(C1-C3)-perfluoroalkyl,

in all its stereoisomeric forms and mixtures in any ratio, and its physiologically acceptable salt.

(8) the Present invention also relates to compounds of the formula I, which are

(1-isoprop piperidin-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-pyrrol[2,3-b]pyridine-2-carboxylic acid,

methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-pyrrol[2,3-b]pyridine-5-carboxylic acid,

1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-pyrrol[2,3-b]pyridine-5-carboxylic acid,

2-[(1-isopropylpiperazine-4-yl)amide] 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-pyrrol[2,3-b]pyridine-2,5-dicarboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-pyrrol[3,2-b]pyridine-2-carboxylic acid,

1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-pyrrol[3,2-b]pyridine-5-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-oxo-4,5-dihydro-1H-pyrrol[3,2-b]piperidine-2-carboxylic acid,

methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-ylcarbonyl)-1H-pyrrol[3,2-b]pyridine-2-carboxylic acid,

1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-ylcarbonyl)-1H-pyrrol[3,2-b]pyridine-5-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-(2-methoxyethoxy)-1H-pyrrol[2,3-c]pyridine-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-(2-hydroxyethoxy)-1H-pyrrol[2,3-c]pyridi the-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-5-(2-methoxyethoxy)-1H-pyrrol[2,3-c]pyridine-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-5-(2-hydroxyethoxy)-1H-pyrrol[2,3-c]pyridine-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[(6-chlorobenzo[b]thiophene-2-ylmethyl)-5-(2-methoxyethoxy)-1H-pyrrol[2,3-c]pyridine-2-carboxylic acid, or

(1-isopropylpiperazine-4-yl)amide 1-[(6-chlorobenzo[b]thiophene-2-ylmethyl)-5-(2-hydroxyethoxy)-1H-pyrrol[2,3-c]pyridine-2-carboxylic acid.

Used in the present description, the term "alkyl" should be understood in its broadest sense to denote a hydrocarbon residue which may be linear or branched, and which may be acyclic or cyclic residues, or include any combination of acyclic and cyclic subunits. In addition, used in the present description, the term "alkyl" includes clear saturated groups and unsaturated groups, where the latter groups contain one or more, e.g. 1, 2 or 3 double bonds and/or triple bonds with the proviso that the double bond is not located within the cyclic alkyl groups such that the obtained aromatic system. All these instructions also apply to the situation, if an alkyl group occurs as a Deputy on the other is the STATCOM, for example, in alkoxylate, alkoholitarbimine residue or arylalkyl residue. Examples of "-(C1-C8)-alkyl or-(C1-C8)-alkylene" are alkyl residues containing from 1 to 8 carbon atoms, are methyl, methylene, ethyl, ethylene, propyl, propylene, butyl, butylene, pentyl, pentile, hexyl, heptyl or octyl, n-isomers of all these residues, isopropyl, isobutyl, 1-methylbutyl, isopentyl, neopentyl, 2,2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, isohexyl, sec-butyl, tert-pentyl, tert-butyl, tert-pentyl. The term "-(C0-C6)-alkyl or-(C0-C8-alkylene" represents a hydrocarbon residue containing from 1 to 8 carbon atoms. The term "-C0-alkyl" or "C0-alkylene" represents a covalent bond.

Unsaturated alkyl residues are, for example, alkeline residues such as vinyl, 1-propenyl, 2-propenyl (=allyl), 2-butenyl, 3-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 5-hexenyl or 1,3-pentadienyl, or alkyline residues, such as ethinyl, 1-propinyl, 2-propinyl (=propargyl) or 2-butynyl. Alkyl residues may also be unsaturated when they replaced. Examples -(C3-C8)-cycloalkyl cyclic alkyl residues are cycloalkyl residues containing from 3 to 8 ring atoms of plastics technology : turning & the Yes, like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, which can also be substituted and/or unsaturated. Unsaturated cyclic alkyl groups and unsaturated cycloalkyl group, such, for example, cyclopentyl or cyclohexenyl can be connected through any carbon atom.

Assume that the terms "monocyclic or bicyclic 6-14-membered aryl or-(C6-C14)-aryl" means an aromatic hydrocarbon radicals containing from 6 to 14 atoms in the ring. Examples -(C6-C14)-aryl radicals are phenyl, naphthyl, such as 1-naphthyl and 2-naphthyl, biphenylyl, for example, 2-biphenylyl, 3-biphenylyl and 4-biphenylyl, antrel or fluorenyl. Biphenylene radicals, raftiline radicals and in particular phenyl radicals are preferred aryl radicals.

The terms "monocyclic or bicyclic 4 to 15-membered heterocyclyl or-(C4-C15)-heterocyclyl" refers to a heterocycle in which one or more of 4-15 carbon atoms substituted by heteroatoms, such as nitrogen, oxygen or sulphur.

Examples are acridines, 8-azabicyclo[3.2.1]Oct-3-yl, azaindole(1H-pyrrolopyridine), asianshemales, azaspiracid, azepine, azetidine, aziridine, benzimidazolyl, benzofuranyl, benzothiophene is l, benzothiophenes, benzoxazolyl, benzothiazolyl, benzotriazolyl, asterisell, benzisoxazole, benzisothiazole, carbazolyl, an-carbazolyl, carbolines, bromanil, bromanil, cinnoline, decahydroquinoline, 4,5-dihydrooxazolo, doxazosin, dioxazines, 1,3-DIOXOLANYL, 1,3-DIOXOLANYL, 6N-1,5,2-detainer, dehydrator[2,3-b]-tetrahydrofuranyl, furanyl, furutani, imidazolidinyl, imidazolyl, imidazolyl, 1H-indazole, indoline, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isopropanol, isoindolyl, isoindolines, isoindolyl, ethenolysis(benzimidazolyl), isothiazolin, isothiazolinones, isothiazolines, isoxazolyl, isoxazolyl, isoxazolidine, 2-isoxazoline, cefoperazone, morpholinyl, naphthyridine, octahydronaphthalene, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2-oxathiane, 1,2-oxathiolane, 1,4-oxazepine, 1,2-oxazinyl, 1,3-oxazinyl, 1,4-oxazinyl, oxazolidinyl, oxazolyl, oxazolyl, oxetanyl, axokine, phenanthridines, phenanthrolines, phenazines, phenothiazines, phenoxathiin, phenoxazines, phthalazine, piperazinil, piperidinyl, pteridinyl, purinol, pyranyl, pyrazinyl, pyrazolidine, pyrazoline, pyrazolyl, pyridazinyl, paradoxicaly, predominately, peridotites, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidinone, pyrroline 2N-pyrrolyl, Erroll, hintline, chinoline, 4H-hemolysins, honokalani, hinokitiol, tetrahydrofuranyl, tetrahydroisoquinoline, tetrahydroquinoline, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridine, tetrahydrothiophene, tetrazines, tetrazolyl, 6N-1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrene, 1,2-thiazines, 1,3-thiazines, 1,4-thiazines, 1,3-thiazolyl, thiazolyl, diazolidinyl, thiazolyl, thienyl, titanyl, theNational, cyanoacetyl, tenomodulin, titanyl, thiomorpholine, 1λ6-thiomorpholine, thiophenols thiophenyl, tiopronin, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xantinol.

Preferred are heterocyclic compounds, such as benzimidazolyl, 1,3-benzodioxolyl, benzofuranyl, benzothiazolyl, benzothiophene, benzoxazole, bromanil, indolinyl, 2-furyl, 3-furyl, imidazolyl, indolyl, indazoles, isopropanol, isoindolyl, ethenolysis, isothiazolin, isoxazolyl, oxazolyl, phthalazine, pteridine, purinol, pyrazinyl, pyrazolyl, paradisial, predominately, pyridopyrimidines, pyridopyrimidines, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrrolyl; 2-pyrrolyl, 3-pyrrolyl, chinoline, hintline, honokalani, tetrazolyl, thiazolyl, 2-thienyl and 3-thienyl.

Preferred are also:

The term "het" or "3-7-membered cyclic residue, containing up to 1, 2, 3 or 4 heteroatoms"refer to structures of heterocycles which can be derived from compounds such as azepine, azetidine, aziridine, asirin, 1,4-diazepan, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, diaziridine, diazirine, dixital, dioxazine, dioxole, 1,3-dioxolene, 1,3-dioxolane, furan, imidazole, imidazoline, imidazolidine, isothiazol, isothiazolin, isothiazolin, isoxazol, isoxazolin, isoxazolidine, 2-isoxazolin, metamorphosen, cefoperazon, morpholine, 1,2-exatape, 1,2-oxathiolan, 1,4-oxazepan, 1,2-oxazin, 1,3-oxazin, 1,4-oxazin, oxazol, oxaziridine, oxetan, oxiran, piperazine, piperidine, Piran, pyrazin, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrrolin, tetrahydrofuran, tetrahydropyran, tetrahydropyridine, tetrazine, tetrazole, thiadiazine, thiadiazole, 1,2-thiazin, 1,3-thiazin, 1,4-thiazin, 1,3-thiazole, the thiazole, thiazolidine, thiazoline, thienyl, tieton, thiomorpholine, thiopyran, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole.

The term "group R1-N-R2-V can form a 4-7-membered cyclic group, or R11and R12together with the nitrogen atom to which they are bound, may form a 4-7-membered monocyclic heterocyclic Kohl is about, which, in addition to the nitrogen atom, may contain 1 or 2 identical or different ring heteroatoms selected from oxygen, sulfur and nitrogen" refer to structures of heterocycles which can be derived from such compounds as ASEAN, azepin, azetidin, dixital, dioxazine, 1,4-diazepan, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, imidazole, imidazoline, imidazolidine, isothiazol, isothiazolin, isothiazolin, isoxazol, isoxazolin, isoxazolidine, 2-isoxazoline, cefoperazon, morpholine, [1,4]oxazepan, oxazole, piperazine, piperidine, pyrazin, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrrolin, tetrahydropyridine, tetrazine, tetrazole, thiazole, thiadiazole, thiazolidine, thiazoline, thiomorpholine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole.

The term "R15and R16together with the carbon atom to which they are bound, may form a 3-6-membered carbocyclic ring" refers to structures that can be derived from compounds such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The term "substructure

in the formula I or substructure D is a

4-8-membered saturated, partially unsaturated or aromatic cyclic group containing 0, 1, 2, 3 or 4 heteroatoms you the security of nitrogen, sulfur or oxygen" refers to structures that can be derived from compounds such as ASEAN, azetidin, azatin, asokan, asokan-2-it, cyclobutyl, cyclooctyl, cyclooctene, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1,2-diazepan, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, [1,4]diadakan, [1,2]diadakan-3-one, [1,3]diadakan-2-it, dixital, dioxazine, dioxole, 1,3-dioxolene, 1,3-dioxolane, furan, imidazol, imidazolin, imidazolidin, isothiazol, isothiazolin, isothiazolin, isoxazol, isoxazolin, isoxazolidine, 2-isoxazoline, cefoperazon, morpholine, 1,4-oxazepan, 1,2-exatape, 1,2-oxathiolan, 1,2-oxazin, 1,3-oxazin, 1,4-oxazin, oxazol, [1,4]oxytocin, [1,3]oxazolin-2-it, oxetan, oxacin, oxolan-2-it, piperazine, piperidine, phenyl, Piran, pyrazin, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidin, pyrrolidine, pyrrolin, 5,6,7,8-tetrahydro-1H-Asotin-2-it, tetrahydrofuran, tetrahydropyran, tetrahydropyridine, tetrazine, thiadiazine, thiadiazole, 1,2-thiazin, 1,3-thiazin, 1,4-thiazin, 1,3-thiazole, thiazole, thiazolidine, thiazoline, tieton, Ciocan, Ciocan-1,1-dioxide, Ciocan-1-oxide, Ciocan-2-it, thiomorpholine, thiopyran, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole.

The term "substructure D is a 5-6-membered saturated, partially unsaturated or aromatic cyclic group containing 0, 1,2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen" refers to structures that can be derived from compounds such as cyclopentyl, cyclohexyl, dixital, dioxazine, dioxole, 1,3-dioxolene, 1,3-dioxolane, furan, imidazole, imidazoline, imidazolidine, isothiazol, isothiazolin, isothiazolin, isoxazol, isoxazolin, isoxazolidine, 2-isoxazoline, metamorphosen, cefoperazon, morpholine, 1,2-oxathiolan, 1,2-oxazin, 1,3-oxazin, 1,4-oxazin, oxazole, piperazine, piperidine, phenyl, Piran, piratin, pyrazole, pyrazoline, pyrazolidine, pyrazin, pyrazine, pyridazine, pyridate, pyridine, pyridone, pyrimidine, pyrimidone, pyrrole, pyrrolidine, pyrrolidinone, pyrrolin, tetrahydrofuran, tetrahydropyran, tetrahydropyridine, tetrazine, tetrazole, thiadiazine, thiadiazole, 1,2-thiazin, 1,3-thiazin, 1,4-thiazin, 1,3-thiazole, thiazole, thiazolidine, thiazoline, thiomorpholine, thiopyran, tetrazine, tetrazole, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole.

The term "R1and R3together with the atoms to which they are linked, can form a 6-8 membered cyclic group, containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen" refers to structures of heterocycles which can be derived from compounds such as asokan, asokan-2-it, cycloheptyl, cyclohexyl, cyclooctyl, cyclooctene, 1,4-diazepan, 1,2-diazepine, 1,3-diazepine, 1,-diazepin, [1,4]diadakan, [1,2]diadakan-3-one, [1,3]diadakan-2-it, dioxazine, [1,4]dioxin, dioxole, cefoperazon, morpholine, 1,2-exatape, 1,4-oxazepan, 1,2-oxazin, 1,3-oxazin, 1,4-oxazin, [1,4]oxytocin, [1,3]oxazolin-2-it, oxacin, oxolan-2-it, phenyl, piperazine, piperidine, Piran, pyrazin, pyridazine, pyrimidine, 5,6,7,8-tetrahydro-1H-Asotin-2-he or thiomorpholine.

The fact that many of the above names heterocycles represent chemical names unsaturated or aromatic ring systems, does not imply that the 4-15 membered mono - or polycyclic group can be obtained only from the appropriate unsaturated ring system. Names in this description are used only to describe the ring system in relation to the ring size and the number of heteroatoms and their relative positions. As explained above, 4-15 membered mono - or polycyclic group may be saturated or partly unsaturated or aromatic, and thus, in the case of suitability can be obtained not only from themselves above heterocycles, but also from all their partially or completely hydrogenated analogs, as well as from their more highly unsaturated analogues. As examples of fully or partially hydrogenated analogues of the above heterocycles, which can be obtained from this group, can the following can be mentioned: pyrrolin, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, dihydropyridines, tetrahydropyridine, piperidine, 1,3-dioxolane, 2-imidazolin, imidazolidin, 4,5-dihydro-1,3-oxazole, 1,3-oxazolidin, 4,5-dihydro-1,3-thiazole, 1,3-thiazolidine, perhydro-1,4-dioxane, piperazine, perhydro-1,4-oxazin (=morpholine), perhydro-1,4-thiazin (=thiomorpholine), peligrosa, indolin, isoindoline, 1,2,3,4-tetrahydroquinoline or 1,2,3,4-tetrahydroisoquinoline.

The term "-(C1-C3)-perfluoroalkyl represents a partially or fully fluorinated alkyl residue, which can be obtained from residues such as-CF3, -CHF2, -CH2F, -CHF-CF3, -CHF-CHF2, -CHF,-CH2F, -CH2-CF3, -CH2-CHF2, -CH2-CH2F, -CF2-CF3, -CF2-CHF2, -CF2-CH2F, -CH2-CHF-CF3, -CH2-CHF-CHF2, -CH2-CHF-CH2F, -CH2-CH2-CF3, -CH2-CH2-CHF2, -CH2-CH2-CH2F, -CH2-CF2-CF3, -CH2-CF2-CHF2, -CH2-CF2-CH2F, -CHF-CHF-CF3, -CHF-CHF-CHF2, -CHF-CHF-CH2F, -CHF,-CH2-CF3, -CHF,-CH2-CHF2, -CHF,-CH2-CH2F, -CHF-CF2-CF3, -CHF-CF2-CHF2, -CHF-CF2-CH2F, -CF2-CHF-CF3, -CF2-CHF-CHF2, -CF2-CHF-CH2F, -CF2-CH2-CF3, -CF2-CH2-CHF2, -CF2-C 2-CH2F, -CF2-CF2-CF3, -CF2-CF2-CHF2or-CF2-CF2-CH2F.

The term "-(C1-C3-perforacion" represents a partially or fully fluorinated alkalinity residue, which can be obtained from residues such as-CF2-, -CHF-, -CHF-CHF2-, -CHF-CHF-, -CH2-CF2-, -CH2-CHF-, -CF2-CF2-, -CF2-CHF-, -CH2-CHF-CF2-, -CH2-CHF-CHF-, -CH2-CH2-CF2-, -CH2-CH2-CHF, -CH2-CF2-CF2-, -CH2-CF2-CHF-, -CHF-CHF-CF2-, -CHF-CHF-CHF-, -CHF-CH2-CF2-, -CHF-CH2-CHF-, -CHF-CF2-CF2-, -CHF-CF2-CHF-, -CF2-CHF-CF2-, -CF2-CHF-CHF-, -CF2-CH2-CF2-, -CF2-CH2-CHF-, -CF2-CF2-CF2- or-CF2-CF2-CHF.

The term "oxo-balance" or "=O" refers to the remains, such as carbonyl (-C(O)-) or nitroso (-N=O). Halogen represents fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, particularly preferably chlorine or bromine.

Optically active carbon atoms present in the compounds of formula I can independently of each other to have the R configuration or the configuration is S. Compounds of formula I may be present in the form of pure enantiomers or pure diastereomers or in the form of mixtures of enantiomers and/or diastereomers, for example in the form the of Azamatov. The present invention relates to the pure enantiomers and mixtures of enantiomers, as well as pure diastereomers and mixtures of diastereomers. The invention includes a mixture of two or more than two stereoisomers of the formula I, and it includes all ratios of the stereoisomers in the mixtures. When the compounds of formula I can be present as E isomers or Z isomers (or CIS isomers or TRANS isomers), the invention relates to the pure S-isomers, and to the pure Z-isomer and E/Z mixtures in all ratios. The invention also includes all tautomeric forms of compounds of formula I.

The diastereomers, E/Z isomers, can be separated into individual isomers, for example, chromatography. The racemates can be split into 2 enantiomers by conventional means, for example, by chromatography on chiral phases or by separation, for example, crystallization of the diastereomeric salts obtained with optically active acids or bases. Stereochemical homogeneous compounds of formula I can also be obtained by using stereochemical homogeneous starting materials or by using stereoselective reactions.

Physiologically acceptable salts of the compounds of formula I are non-toxic salts which are physiologically acceptable, in particular, pharmaceutically salts used. Such salts of compounds of formula I, operasie acid group, for example, a carboxyl group COOH, represents, for example, alkali metal salts or salts of alkaline earth metals such as sodium, potassium salts, magnesium salts and calcium salts, and also salts with physiologically acceptable Quaternary ammonium ions, such as Tetramethylammonium or tetraethylammonium, and acid additive salts with ammonia and physiologically acceptable organic amines, such as methylamine, dimethylamine, trimethylamine, ethylamine, triethylamine, ethanolamine or Tris-(2-hydroxyethyl)amine. Basic groups contained in the compounds of the formula I, for example, an amino group or guanidinium form an acid additive salt, for example, with inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, or with organic carboxylic acids and sulfonic acids, such as formic acid, acetic acid, oxalic acid, citric acid, lactic acid, malic acid, succinic acid, malonic acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonate acid or para-toluensulfonate acid. The compounds of formula I, which simultaneously contain a basic group and an acidic group, for example, guanidinium and carboxyls the th group, may also be present in the form of zwitterions (betaines), which are likewise included in the present invention.

Salts of compounds of formula I can be obtained by conventional means, well known to the experts in this field, for example, by combining the compounds of formula I with an inorganic or organic acid or base in a solvent or dispersing agent, or other salts of cationic or anionic exchange. The present invention also includes all salts of the compounds of the formula I which, owing to low physiological tolerability, are not directly suitable for use in medicines, but are suitable, for example, as intermediates for further chemical modifications of the compounds of formula I or as starting materials for producing the physiologically acceptable salts.

The present invention also includes any and all solvents are compounds of the formula I, for example hydrates or adducts with alcohols.

The invention also includes derivatives and modifications of the compounds of the formula I, for example, prodrugs, protected forms and other physiologically acceptable derivatives, as well as active metabolites of compounds of formula I. the Invention relates in particular to prodrugs and protected forms of the compounds of formula I which may be turned in with the organisations of the formula I under physiological conditions. Suitable prodrugs for the compounds of formula I, i.e. chemically modified derivatives of the compounds of formula I, having properties which are improved in the desired manner, for example with respect to solubility, bioavailability or duration of action, known to specialists in this field. More detailed information relating to prodrugs can be found in standard literature, such, for example, Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985; Fleisher et al., Advanced Drug Delivery Reviews 19 (1996) 115-130; or H. Bundgaard, Drugs of the Future 16 (1991) 443, which are all included in the present description by reference. Suitable prodrugs for the compounds of formula I are, in particular, acyl prodrugs and urethane prodrugs unilaterally nitrogen-containing groups such as amino groups and guanidinium and ester prodrugs and amide prodrugs of the group of carboxylic acids that may be present in compounds of the formula I. In the acyl prodrugs and urethane the prodrugs of one or more, e.g. 1 or 2 hydrogen atoms on the nitrogen atoms in these groups is substituted by an acyl group or a carbamate, preferably -(C1-C6)-allyloxycarbonyl group. Suitable acyl groups and urethane groups to acyl prodrugs and urethane prodrugs are, for example the EP, prodrugs Rp1-CO - and Rp2-O-CO-, where Rp1is a (C1-C18)-alkyl, (C1-C8-cycloalkyl, (C3-C8-cycloalkyl-(C1-C4)-alkyl, (C6-C14)-aryl, Het - (C6-C14)-aryl-(C1-C4)-alkyl, or Het-(C1-C4)-alkyl and in which Rp2matter listed for Rp1with the exception of hydrogen.

Especially preferred compounds of formula I are those in which 2 or more residues are defined as indicated above for the preferred compounds of formula I, or residues may have one or some of the specific definitions of residues presented in their General definitions or in the above definitions, the preferred compounds. All possible combinations of the definitions presented for the preferred definitions of certain signs residues are clearly the subject of the present invention.

Also in respect to all preferred compounds of the formula I, in all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts are definitely the subject of the present invention, and their prodrugs. Similarly, in all the preferred compounds of formula I, all the residues that are present more than once in the Molek is e, are independent from each other and can be identical or different.

The compounds of formula I can be obtained by using procedures and methodologies, which are in themselves known and understood by the person skilled in the art. The original materials or forming blocks for use in the General synthetic procedures that can be used for obtaining the compounds of formula I, easily accessible to the person skilled in the art. In many cases, they are commercially available or have been described in the literature. Otherwise they can be obtained from readily available compounds, the precursors analogous to the procedures described in the literature, or procedures or analogously to procedures described in this application.

In General, the compounds of formula I can be obtained, for example in the course of a convergent synthesis, by linking two or more fragments which can be obtained retrosynthetic of compounds of formula I. more Specifically, suitably substituted the original azaindole derivatives are used as forming units upon receipt of the compounds of formula I. Although various synthetic aspects of the chemistry of azaindole significantly different from the chemistry of indoles, many of the procedures that describe the synthesis and functionalization of indoles can be modified and adapted by the experts in this field. Therefore, the literature describing the Tr is nformatio and synthesis of indoles, highly instructive and applicable to chemistry azaindole. If such azaindole derivatives are not available for sale, you can get them in accordance with well known standard procedures for the formation of isoindoline ring system, such as, for example, indole synthesis, Fischer indole synthesis Bichler or indole synthesis Reissert. By selection of suitable precursor molecules, these kinds of indole synthesis provide the possibility of introducing a variety of substituents in different positions azaindole system, which can then be chemically modified for the final receipt of the molecule of formula I having the desired type of substituent. As one of the comprehensive reviews on the chemistry of indoles and synthetic procedures for their production, there is a link W.J. Houlihan (ed.), "Indoles, Part One", volume 25, 1972, from the series "The Chemistry of Heterocyclic Compounds", A. Weissberger and E.C. Taylor (ed.), John Wiley & Sons; R.E. Willette, Advances in Heterocyclic Chemistry 9 (1968) 27; J.-Y. Merour Curr. Org. Chem. 5 (2001) 471; h Döpp et al. in Houben-Weyl, "Methods der Organischen Chemie" (Methods of Organic Chemistry), Georg Thieme Verlag, Stuttgart, Germany 1994, Vol E6a,b part 2a Hetarene I.

If you are going to synthesize the original isoindoline derivatives, it can be done, for example, in accordance with well-known above azaindole synthesis. In the following description given a brief explanation, however, they are with undertie procedures extensively discussed in the literature, and they are well known specialist in this field.

Indole synthesis, Fischer includes acid cyclization of heteroarylboronic, for example, General formula 2,

which can be obtained in various ways, and in which R30, R31and R32can have a wide variety of definitions. In addition to hydrogen and alkyl, R31and R32may, in particular, to designate ester group, or a methyl or ethyl group, or a 2,2,2-triptoreline group, bearing ester group as a substituent, thus providing the possibility of introducing in isoindoline molecule of part (CH2)p-CO, occurring in groups of R2and/or R3in the compounds of formula I. as examples of numerous literary references describing the synthesis isoindoline derivatives, in accordance with the synthesis Fischer, in addition to the above-mentioned book, published Houlihan, referred to the following articles: F.G. Salituro et al., J. Med. Chem. 33 (1990) 2944; N.M. Gray et al., J. Med. Chem. 34 (1991) 1283; J. Sh. Chikvaidze et al., Khim. Geterotsikl. Soedin. (1991) 1508; S.P. Hiremath et al., Indian J. Chem. 19 (1980) 770; J. Bornstein, J. Amer. Chem. Soc. 79 (1957) 1745; S. Wagaw, B. Yang and S. Buchwald, J. Am. Chem. Soc. 121 (1999) 10251 or by Y. Murakami, Y. Yokoyama, T. Miura, H. Hirasawa Y. Kamimura and M. Izaki, Heterocycles 22 (1984) 1211; D. L. Hughes, Org. Prep. Proc. 25 (1993) 607.

Indole synthesis Reissert includes the replacement cycle is tion about-nitrophenylpyruvic acids or their esters, for example, General formula 3

in which R30can have a wide variety of definitions and may be present in all positions of the aromatic ring. Indole synthesis Reissert leads to deriving azaindole-2-carboxylic acid. Derivatives of pyruvic acid of formula 3 can be obtained by condensation of esters of oxalic acid substituted o-nitrotetrazolato. As a literary sources, in addition to the above-mentioned book, published Houlihan, and referred to in this description of the literary references are mentioned, for example, article: H.G. Lindwall and G.J. Mantell, J. Org. Chem. 18 (1953) 345 or H. Burton and J.L. Stoves, J. Chem. Soc. (1937) 1726 or W. Noland, F. Baude, Org. Synth Coll. Vol. V, J. Wiley, New York, (1973) 567.

Another way to achieve selective in relation to access azaindole structure includes palladium catalysis, for example, Galanina (X=Cl, Br, I) or o-triftoratsetilatsetonom (X=Otf) of General formula 4 can be cyklinowanie in azaindole using multiple alkynes making procedures J. Ezquerra, C Pedregal. C Lamas, J. Barluenga, M. Perez, M. Garcia-Martin, J. Gonzalez, J. Org. Chem. 61 (1996) 5805; or F. Ujjainwalla, D. Warner, Tetrahedron Lett. 39 (1998) 5355 and, in addition, A. Rodriguez, C. Koradin, W. Dohle, P. Knochel, Angew. Chem. 112 (2000) 2607; or R. Larock, E. Yum, M. Refvik, J. Org. Chem. 63 (1998) 7653; R. Larock, E. Yum, J. Am. Chem. Soc. 113 (1991) 6689; K. Roesch; R. Larock, J. Org. Chem. 66 (2001) 412.

Alternatively, isoindoline structure can be created using a variety of ketones in terms of palladium catalysis adoption and modification of the procedure described C.Chen, D. Liebermann, R.Larsen, T.Verhoeven and P.Reider J. Org. Chem. 62 (1997) 2676, as listed below, where X = Cl, Br, I or Otf:

In accordance with indole synthesis Bichler And-Aza-anilinction, for example, the General formula 10,

can be cyklinowanie in azaindole derivatives.

Another way to specifically substituted isoindolines derived passes through 2,3-dihydroindole (isoindoline), which can be easily obtained by reduction of azaindole, for example, by hydrogenation or by cyclization of the appropriate azaphenanthrene derivatives. Isoindoline may be subjected to various electrophilic aromatic substitution reactions, providing the possibility of introducing a variety of substituents in the aromatic nucleus, which cannot be directly introduced into the aromatic nucleus azaindole molecules. Then azaindole can be dehydrogenation in the appropriate azaindole, for example, reagents such as chloranil or palladium, together with the acceptor of hydrogen. And again, the details on these methods of synthesis can be found in the above book edited by Houlihan.

More t the th, 2-N-azaindole can be converted into the corresponding carboxylic acids or esters of carboxylic acids by introduction of lithium in position 2 azaindole General formula 13 and the subsequent interaction with carbon dioxide or alkylchlorosilanes in accordance with I. Hasan, E. Marinelli, L. Lin, F. Fowler, A. Levy, J. Org. Chem. 46 (1981) 157; T. Kline J. Heterocycl. Chem. 22 (1985) 505; J. R. Dormoy, A. Heymes, Tetrahedron 49, (1993) 2885; E. Desarbre, S. Coudret, C. Meheust, J.-Y. Merour, Tetrahedron 53 (1997) 3637, as follows:

where R45denotes hydrogen or a protective group, such, for example, benzosulfimide or tert-butoxycarbonyl.

Below are listed and briefly described in reference further procedures of particular interest for the implementation of the present invention, however, they represent a standard procedure, discussed in the literature, and they are well known specialist in this field.

1) T. Sakamoto et al., Chem. Pharm. Bull. 34 (1986) 2362.

a) I. Mahadevan et al., J. Heterocycl. Chem. 29 (1992) 359

b) J.-R. Dormoy et al., Tetrahedron 49 (1993) 2885

3) a) L. Estel et al., J. Org. Chem. 53 (1988) 2740

b) D. Hands et al., Synthesis (1996) 877

c) Kumiko T. et al., Bioorg. Med. Chem. Lett. 20 (2000) 2347

4) a) S. Clemo et al., J. Chem. Soc. (1945) 603

b) R. Okuda, J. Org. Chem. 24 (1959) 1008

c) J. Turner, J. Org. Chem. 48 (1983) 3401

5 (a) M. Davis et al., Tetrahedron 48 (1992) 939

b) C. Martin et al., Tetrahedron Lett. 30 (1989) 935

c) S. Ball et al., J. Were Obtained. Chem. 550 (1998) 457

Depending on the substituents in the original materials, in certain types of synthesis azaindole can be obtained mixture of positional isomers, which, however, can be separated modern methods of separation, such, for example, preparative HPLC.

In addition, to obtain the desired substituents in the nucleus azaindole ring system in formula I, the functional groups introduced into the ring system during azaindole synthesis can be chemically modified. For example, azaindole, bearing a hydrogen atom in position 2 and position 3, can also be obtained by saponification and subsequent decarboxylation of azaindole bearing ester group in the corresponding position. Groups, carboxylic acid groups and acetic acid in position 2 and position 3 can be transformed into their homologues conventional reactions for chain elongation of carboxylic acids. The halogen atoms can be introduced in position 2 and position 3, for example, the interaction of the corresponding isoindoline with halogenation agent such as pentachloride phosphorus, similar to the method described J.C.Powers, J. Org. Chem. 31 (1966) 2627. Source isoindoline for such synthesis can be obtained from 2-aminoheterocycles Ki the lot. Source isoindoline derivative to obtain the compounds of formula I bearing a halogen substituent in position 3 can be obtained in accordance with the procedures described in the literature, such as the following. For fluorination of complex derivatives ethyl ester 1H-isoindol-2-carboxylic acid in position 3 triplet N-fluoro-2,4,6-trimethylpyridine is a reagent of choice (T. Umemoto, S. Fukami, G. Tomizawa, K. Harasawa, K. Kawada, K. Tomita J. Am. Chem. Soc. 112 (1990) 8563 in order). Chlorination derivatives complex ethyl ester 1H-isoindol-2-carboxylic acid in position 3 the interaction of sulfurylchloride in benzene gives complex ethyl ester of 3-chloro-1H-isoindol-2-carboxylic acid (Chem. Abstr. 1962, 3441i-3442b); the same result can be obtained by means of NCS (D. Comins, M. Killpack, Tetrahedron Lett. 33 (1989) 4337; M. Brennan, K. Erickson, F. Szmlac, M. Tansey, J. Thornton, Heterocycles 24 (1986) 2879). Bromination of complex derivatives ethyl ester 1H-isoindol-2-carboxylic acid in position 3 can be achieved by interaction with NBS (M. Tani, H. Ikegami, M. Tashiro, T. Hiura, H. Tsukioka, Heterocycles 34 (1992) 2349). Similar to the procedures described above, the NIS can be used essentially for iodination derived complex ethyl ester 1H-isoindol-2-carboxylic acid in position 3. In addition, iodination derived complex ethyl ester 1H-isoindol-2-carboxylic acid in position 3, the effective use of iodine (T. Sakamoto, Nagano T, Y. Kondo, H. Yamanaka Chem. Pharm. Bull. 36 (1988) 2248).

In particular, the groups present azaindole ring system can be modified by a variety of reactions and thus can be obtained a desirable residues R3aand R30. For example, the nitro group can be restored in amino various reducing agents, such as sulfides, dithionite, a complex hydride, or by catalytic hydrogenation. The restoration of the nitro group can also be undertaken at a later stage of the synthesis of the compounds of formula I, and the restoration of the nitro group to the amino group can also occur spontaneously, the reaction is carried out on other functional groups, for example, the interaction of a group such as cyano, hydrogen sulphide, or by hydrogenation of the group. For inducing or receiving the remainder R3aand R30amino groups can then be modified in accordance with the standard procedures for alkylation, for example, by interaction with the (substituted) alkylhalogenide or by reductive amination of carbonyl compounds, in accordance with standard procedures for alkylation, for example, by interaction with activated derivatives of carboxylic acids, such as acid chlorides, anhydrides, activated esters, or interaction with the carboxylic key is lots in the presence of an activating agent, or in accordance with the procedures for sulfonylamine, for example, the interaction with sulphonylchloride. Carboxylic acid chlorides of carboxylic acids or esters of carboxylic acids can be introduced by procedures F. Santangelo, C. Casagrande, G. Norcini, F. Gerli, Synth. Commun. 23 (1993) 2717; P. Beswick, C. Greenwood, T. Mowlem, G. Nechvatal, D. Widdowson, Tetrahedron 44 (1988) 7325; V. Collot, M. Schmitt, P. Marwah, J. Bourguignon, Heterocylces 51 (1999) 2823. Halogen or hydroxy-group - by triflate or nonflat or primary amines via their diazonium salts or after interconversion to the corresponding stannane, or baronova acid present in azaindole structure, can be turned into a variety of other functional groups, for example, -CN, -CF3, ethers, acids, esters, amides, amines, alkyl or aryl groups, mediated by transition metals, namely, by catalysis with palladium or Nickel or copper salts and reagents, for example, the following (F. Diederich, P. Stang, Metal-catalyzed Cross-coupling Reactions, Wiley-VCH, 1998; or M. Beller, C. Bolm, Transition Metals for Organic Synthesis, Wiley-VCH, 1998; J. Tsuji, Palladium Reagents and Catalysts, Wiley, 1996; J. Hartwig, Angew. Chem. 110 (1998) 2154; B. Yang, S. Buchwald, J. Were Obtained. Chem. 576 (1999) 125; T. Sakamoto, K. Ohsawa, J. Chem. Soc. Perkin Trans I, (1999), 2323; D. Nichols, S. Frescas, D. Marona-Lewicka, X. Huang, B. Roth, Gudelsky G., J. Nash, J. Med. Chem, 37 (1994), 4347; P. Lam, C. Clark, S. Saubern, J. Adams, M. Winters, D. Chan, A. Combs, Tetrahedron Lett., 39 (1998) 2941; D. Chan, K. Monaco, R. Wang, M. Winters, Tetrahedron Lett. 39 (1998)2933; V. Farina, V. Krishnamurthy, W. Scott, The Stille Reaction, Wiley, 1994; A. Klaspars, X. Huang, S. Buchwald, J. Am. Chem. Soc. 124 (2002) 7421; F. Kwong, A. Klapars, S. Buchwald, Org. Lett. 4 (2002) 581; M Wolter, G. Nordmann, G. Job, S. Buchwald, 4 (2002) 973).

Ester groups present in azaindole core, can be hydrolyzed to the corresponding carboxylic acid, which after activation can then interact with amines or alcohols under standard conditions. In addition, these ester or acid groups can be restored into the corresponding alcohols of various standard procedures. Group of simple ether present in azaindole core, for example, benzyloxy or other easily split the group of ethers, can be broken down to obtain the hydroxy groups, which can then interact with a variety of agents, for example, by esterification agents or activating agents, providing the possibility of substitution of hydroxyl groups by other groups. Sulfur-containing groups can interact in the same way.

In the course of the synthesis to modify the groups R54or R8'attached to azaindole ring system, applying the methodology of parallel synthesis, in addition to a variety of reactions, it may be useful to catalysis salt of palladium or copper. Such reactions are described, for example, in F. Diederich, P. Stang, Metal-catalyzed Cross-coupling Reactions, Wiley-VCH,1998; or M. Beller, C. Bolm, Transition Metals for Organic Synthesis, Wiley-VCH, 1998; J. Tsuji, Palladium Reagents and Catalysts, Wiley, 1996; J. Hartwig, Angew. Chem. 110 (1998), 2154; B. Yang, S. Buchwald, J. Were Obtained. Chem. 576 (1999) 125; P. Lam, C Clark, S. Saubern, J.Adams, M. Winters, D. Chan, A. Combs, Tetrahedron Lett. 39 (1998) 2941; D.Chan, K. Monaco, R. Wang, M. Winters, Tetrahedron Lett. 39 (1998) 2933; J. Wolfe, H. Tomori, J. Sadight, J. Yin, S. Buchwald, J. Org. Chem. 65 (2000) 1158; V. Farina, V. Krishnamurthy, W. Scott, The Stille Reaction, Wiley, 1994; A. Klaspars, X. Huang, S. Buchwald, J. Am. Chem. Soc. 124 (2002) 7421; F. Kwong, A. Klapars, S. Buchwald, Org. Lett. 4 (2002) 581; M Wolter, G. Nordmann, G. Job, S. Buchwald, 4 (2002) 973).

The previously mentioned reactions for the conversion of functional groups, in addition, in General, exclusively described in the guidelines for organic chemistry, like M. Smith, J. March, March's Advanced Organic Chemistry, Wiley-VCH, 2001 and in textbooks, such Houben-Weyl, "Methods der Organischen Chemie" (Methods of Organic Chemistry), Georg Thieme Verlag, Stuttgart, Germany, or "Organic Reactions", John Wiley & Sons, New York, or R. C. Larock, "Comprehensive Organic Transformations", Wiley-VCH, 2nded (1999), B. Trost, I. Fleming (eds.), Comprehensive Heterocyclic Chemistry II, Elsevier Science, 1996), where you can find the details on the reactions and literary sources. Due to the fact that in the present case the functional groups attached to azaindole system, in certain cases, it may be necessary to perform a special device interaction conditions or to choose specific reagents from a variety of reagents that can in principle be used in the reaction of conversion, or to take specific measures to achieve the desired accepts the stop, for example, using methods of protective groups. However, the discovery of suitable interaction and reaction conditions in such cases does not cause any problems for professionals in this field.

The structural elements present in the residues in position 1 azaindole ring in the compounds of formula I, and in the group COR8'present in position 2 and/or at position 3 isoindoline rings, you can type in the source isoindoline derived, which can be obtained, as described above, the successive stages of interaction using the methodologies of synthesis, similar to the methodologies described below, using procedures, which themselves are well known specialist in this field.

The remains of R8'you can enter in formula 29, for example, by condensation of the corresponding carboxylic acid of formula 29 compound of the formula HR8'i.e. an amine of the formula HN(R1'R2'-V-G-M to obtain the compounds of formula 30. Thus obtained compound of formula 30 can already contain the desired final groups, i.e. groups of R8'and R54may represent a group-N(R1R2-V-G-M and R0-Q-as defined in the formula I, or optionally in the compound of formula 30, thus obtained; then the remainder or remainders R8'and the remainder R54turn with therefore, its remains in N(R 1R2-V-G-M and R0-Q to obtain the desired compounds of formula I.

Thus, the residues R8'and accordingly remains R1'and R2'-V-G-M that are contained in them, may have presented above indicate, respectively, R1and R2-V-G-M, or in addition to the remains of a functional group R1'and R2'-V-G-M may also be present in the form of groups that can subsequently be transformed into a nite group, R1and R2-V-G-M, i.e., functional groups can be present in the form of groups of precursors or derivatives, for example, in a protected form. In the course of obtaining the compounds of formula I may generally be preferable or necessary to introduce functional groups that restore or prevent unwanted interactions or adverse reactions at an appropriate stage of the synthesis, in the form of groups predecessors, who later converted into the desired functional groups, or to temporarily block functional groups by a strategy of protective groups suitable for problems of synthesis. Such strategies are well known to specialists in this field (see, for example, Greene and Wuts, Protective Groups in Organic Synthesis, Wiley, 1991, or P. Kocienski, Protecting groups, Thieme 1994). As examples of groups that preceded it, can be mentioned cyanoprop and nitro. Ceanography can at a later stage to be transformed into derivatives of carboxylic acids or restoration aminomethyl group, or the nitro group, which can be transformed recovery, similar to catalytic hydrogenation in the amino group. Protective groups can also be set to a solid phase, and cleavage from the solid phase means the removal of the protective group. The use of such techniques known to experts in this area (Burgess K (Ewd.) Solid Phase Organic Synthesis, New York; Wiley, 2000). For example, the phenolic hydroxy-group can be attached to trityl-polystyrene resin, which serves as a protective group, and the molecule is cleaved from the resin by TFA treatment (triperoxonane acid) at a later stage of the synthesis.

The remainder R54in the compounds of formulas 29 and 30 may denote a group-Q-R0as defined above, which ultimately must be present in the desirable molecule-target formula I, or it can refer to a group which can be subsequently transformed into the group-Q-R0for example, group-a precursor or derivative of the group-Q-R0in which functional groups are present in protected form, or R54may denote a hydrogen atom or a protective group for the nitrogen atom isoindoline rings. Similarly, the residues R3a and R30in formulas 29 and 30 have corresponding definitions R3in the formula I, as defined above, however, for the synthesis of compounds of formula I, these residues can also in principle be present at the stage of condensation of the compounds of formula 29 with the compound of the formula HR8'giving the compound of formula 30 in the form of groups predecessors or in a protected form.

The remains of R53in compounds of formula 29, which may be the same or different, can represent, for example, hydroxy or (C1-C4)-alkoxy, i.e COR53,present in the compounds of formula 29 can be, for example, the free carboxylic acids or their esters, such complex alkilany esters, which can be group COR8'in the compounds of the formula I. the Group COR53can also be any other activated carboxylic acid derivative, which enables the formation of amide, formation of ester or education complex tiefer with the compound of the formula HR8'. The group COR53may also represent, for example, acid chloride, activated ester, such substituted difficult phenyl ether, asolid, such imidazoline, azide or a mixed anhydride, for example, a mixed anhydride with a complex ether carboxylic sour is s or sulfonic acid, where all derivatives can be obtained from the carboxylic acid by standard procedures, and they can interact with an amine, alcohol or mercaptan of the formula HR8'under standard conditions. The carboxylic acid group COOH, representing COR53in connection 29, can be obtained, for example, from the group of ester, introduced in isoindoline the system during synthesis azaindole, standard hydrolysis procedures.

The compounds of formula I in which the group COR8is a group of ester can also be obtained from compounds of formula 29, in which COR53represents a group of the carboxylic acid, the usual reactions of esterification, such, for example, the interaction of the acid with an alcohol under conditions of acid catalysis, or alkylation of salts of carboxylic acids with an electrophile, such alkylhalogenide, or by transesterification from another of ester. The compounds of formula I in which the group COR8represents an amide group, can be obtained from amines and compounds of formula 29, in which COR53represents a group of the carboxylic acid or its ester, conventional amination reactions. In particular, for obtaining the amides of the compounds of formula 29, in which COR53represents a group of the carboxylic acid can be condensed under standard conditions with the connections of the formula HR 8'who are amines, via usual reagents compounds used in peptide synthesis. These chemicals compounds are, for example, carbodiimide like dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide, carbonylcyanide like carbonyldiimidazole (CDI) and similar reagents, propylphosphonic anhydride, tetrafluoroborate O-((cyano(etoxycarbonyl)methylene)amino)-N,N,N',N'-tetramethylurea (TOTU), diethylphosphoramidite (DEPC) or chloride bis-(2-oxo-3-oxazolidinyl)fostoria (BOP-Cl) and many others.

If the residue-Q-R0present in azaindole formula I, or a residue R54present in azaindole formula 29, or a residue in which functional groups within the residue-Q-R0or R54are present in protected form or in the form of group precursor that have not already been introduced during the previous stage, for example, during the synthesis isoindoline nucleus, these residues can, for example, be entered in position 1 azaindole the conventional system described in the literature procedures well known to the expert in the field of N-alkylation, reductive amination, N-arilirovaniya, N-acylation or N-sulfonylamine, the ring atoms of nitrogen heterocycles. Source isoindoline derived, which should be used in such a reaction, not who has the hydrogen atom in position 1. N-alkylation of the ring nitrogen atom can, for example, be performed under standard conditions, preferably in the presence of a base, using alkylating the compound of formula LG-Q-R0or of the formula R54-LG, where the atom in the group Q or R54related LG group, in this case represents an aliphatic carbon atom in the alkyl part, and LG represents a leaving group, e.g. halogen, like chlorine, bromine or iodine, or sulfonyloxy, such tosyloxy, mesilate or tripterocalyx. LG may, for example, also be a hydroxy-group, which is to achieve the alkylation reaction is activated with conventional activating agent. To obtain compounds in which a represents a direct bond, an aromatic group is directly related to the position 1 azaindole system can be used the usual procedure of arilirovaniya. For example, aristorod like perbenzoate of alkyl and methylsulfonyl 4-ftoheia, can be used as a progress agent. Such processes are described, for example, S. Stabler, Jahangir, Synth. Commun. 24 (1994) 123; I. Khanna, R. Weier, Y. Yu, X. Xu. F. Koszyk, J. Med. Chem. 40 (1997) 1634. Alternatively, a wide variety of substituted arisitide, the approach formulated above or aritifical can serve as progress agents in position 1 azaindole system during the reaction, posredovanje salt of copper or palladium in accordance with R. Sarges, H. Howard, K. Koe, A. Weissmann, J. Med. Chem, 32 (1989) 437; P. Unangst, D. Connor, R. Stabler, R. Weikert, J. Heterocycl. Chem, 24 (1987) 811; G. Tokmakov, I. Grandberg, Tetrahedron 51 (1995) 2091; D. Old, M. Harris, S. Buchwald, Org. Lett. 2 (2000) 1403, G. Mann, J. Hartwig, M. Driver, C. Fernandez-Rivas, J. Am. Chem. Soc. 120 (1998) 827; J. Hartwig, M. Kawatsura, S. Hauk, K. Shaughnessy, L J. Org. Chem. 64 (1999) 5575. Moreover, such reactions arilirovaniya can be carried out by the interaction of a wide range of substituted arylboronic acids, as demonstrated, for example, W. Mederski, M. Lefort, M. Germann, D. Kux, Tetrahedron 55 (1999) 12757.

In the course of synthesis in many cases, it may be beneficial or even required the use of microwave assistance to accelerate, facilitate, or enable interactions. Some of the reactions, for example, described J.L Krstenansky, I. Cotteril, Curr: Opin. Drug. Disc. & Development, 4(2000), 454; P. Lidstrom, J. Tierney, B. Wathey, J. Westman, Tetrahedron, 57(2001), 9225; M. Larhed, A. Hallberg, Drug Discovery Today, 8 (2001) 406; S. Caddick, Tetrahedron, 51 (1995) 10403.

Preferred methods include, but are not limited to, the methods described in the examples. Compounds of the present invention are inhibitors of serine protease, which inhibit the enzyme activity of blood coagulation factors factor XA and/or factor VII. In particular, they are highly active inhibitors of factor XA. They are specific inhibitors of serine protease, while they do not significantly inhibit the activity of other proteases, inhib is the testing which is undesirable. The activity of the compounds of formula I can be determined, for example, in the analysis described below, or other assays known to specialists in this field. Regarding the inhibition of factor XA, the preferred embodiment of the invention includes compounds that have a Ki<1 mm for the inhibition of factor XA, according to the definitions in the following analysis, with a concomitant inhibition of factor VIIa or without inhibition, and which is preferably essentially does not inhibit the activity of other proteases involved in coagulation and fibrinolysis, inhibition of which is undesirable (using the same concentration of the inhibitor). Compounds of the invention inhibit the catalytic activity of factor XA or right, within complex prothrombinase, or in the form of a soluble subunit, or indirectly by inhibition of the Assembly of factor XA in complex prothrombinase.

As inhibitors of factor XA and/or factor VIIa, the compounds of formula I and their physiologically acceptable salts and their prodrugs are generally suitable for the treatment and prophylaxis of conditions in which the activity of factor XA and/or factor VIIa plays a role or has an undesired extent, or which can have a beneficial effect of inhibition of factor XA and/or factor VIIa or decrease their activity, or to prevent, alleghany who or treatment which the doctor wishes to inhibit factor XA and/or factor VIIa or reduce their activity. Because the inhibition of factor XA and/or factor VIIa affects blood coagulation and fibrinolysis, the compounds of formula I and their physiologically acceptable salts and their prodrugs are generally suitable for reducing blood clotting, or for the treatment and prophylaxis of conditions in which the activity of factor XA and/or factor VIIa plays a role or has an undesired extent, or which can have a beneficial effect of reducing blood clotting, or for the prevention, mitigation or treatment which the doctor wants to decrease the activity of the blood coagulation system. Therefore, a specific object of the present invention is the reduction or inhibition of unwanted blood clotting, in particular the individual, the introduction of an effective amount of the compounds of formula I or its physiologically acceptable salts or prodrugs, as well as its pharmaceutical preparations.

The present invention also relates to compounds of formula I and their physiologically acceptable salts and/or their prodrugs for use as pharmaceuticals (or drugs), to the use of compounds of the formula I and their physiologically acceptable salts and/or their prodrugs for the production of pharmaceuticals for inhibition of factor XA and/or factor VIIa or for influencing the folding roof is, inflammatory response or fibrinolysis or for the treatment or prevention of the above diseases or below, for example, for the production of pharmaceuticals for the treatment and prevention of cardiovascular disorders, thromboembolic diseases or restenoses. The invention also relates to the use of compounds of the formula I and their physiologically acceptable salts and/or their prodrugs for the inhibition of factor XA and/or factor VIIa or for influencing blood coagulation or fibrinolysis or for the treatment or prevention of the above diseases or below, for example, for use in the treatment and prevention of cardiovascular disorders, thromboembolic diseases or restenoses, and to methods of treatment aimed at such goals, including how these types of treatment and prevention. The present invention also relates to pharmaceutical preparations (or pharmaceutical compositions)which contain an effective amount of at least one compound of the formula I and physiologically acceptable salts and/or its prodrugs in addition to customary pharmaceutically acceptable carrier, i.e. one or more pharmaceutically acceptable substances-carriers or excipients and/or auxiliary substances or additives.

The invention also relates to the treatment of pathologists is a mini-States, such as abnormal formation of thrombus, acute myocardial infarction, unstable angina, thromboembolism, acute occlusion of vessels associated with thrombolytic therapy or percutaneous transluminal coronary angioplasty (RTSA), transient ischemic attacks, stroke, intermittent claudication or coronary artery bypass grafting of the coronary or peripheral arteries, narrowing of the lumen of blood vessels, restenosis after coronary or venous angioplasty, maintenance of patency of vascular access in patients receiving long-term hemodialysis, pathological blood clot occurring in the veins of the lower limbs, after operations on abdominal, knee or hip joint, the risk of pulmonary thromboembolism, or disseminated systemic intravascular coagulopathy occurring in the vascular system during septic shock, certain viral infections or cancer. Compounds of the present invention can also be used to decrease the inflammatory response. Examples of specific disorders, for the treatment or prevention of which it is possible to apply the compounds of formula I are coronary heart disease, myocardial infarction, angina pectoris, vascular restenosis, for example restenosis after angioplasty, such RTSA, respiratory distress syndrome, adult, m is goorganga failure and disorder in the form of disseminated intravascular coagulation. Examples related to the issue of complications associated with operations that are thrombosis such as deep vein thrombosis and proximal veins, which may occur after the operation.

The compounds of formula I and their physiologically acceptable salts and their prodrugs, you can enter an animal, preferably a mammal, and in particular, people in the form of pharmaceutical preparations for treatment or prevention. They can be administered separately or in mixtures with one another or in the form of pharmaceutical preparations, which provide the opportunity for enteral or parenteral administration.

The pharmaceutical agents can be administered orally, for example in the form of pills, tablets, lacquered tablets, coated tablets, granules, hard and soft gelatine capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures. However, the introduction can be performed rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injection solutions or infusion solutions, microcapsules, implants or rods, or percutaneous or place, for example, in the form of ointments, solutions or tinctures, or in other ways, for example, in the form of aerosols or nasal sprays.

The pharmaceutical preparations according to the invention is produced by way known per se and familiar to the person skilled in the art, where pharmaceutically acceptable inert inorganic and/or organic media used in addition to the compound (compounds) of the formula I and/or their pharmaceutically acceptable salts and/or its (their) prodrugs. For the production of pills, tablets, coated tablets and hard gelatin capsules can be used, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. Carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, semisolid and liquid polyols, natural or hardened oils, etc. Suitable carrier materials for the production of solutions, such as solutions for injection, or of emulsions or syrups are, for example, water, saline, alcohols, glycerol, polyols, sucrose, invert sugar, glucose, vegetable oils, etc. Suitable carrier materials for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid. The pharmaceutical preparations normally contain about 0.5% to 90 wt.% compounds of the formula I and/or their physiologically acceptable salts and/or their prodrugs. The amount of the active ingredient of the formula I and/or physiologically acceptable salts and/or its prodrugs in the pharmaceutical preparations normally is about is about 0.5 mg to about 1000 mg, preferably, from about 1 mg to about 500 mg

In addition to the active ingredients of the formula I and/or their physiologically acceptable salts and/or prodrugs and to the substances-the media, the pharmaceutical preparations can contain additives such as, for example, fillers, disintegrating agents, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavorings, thickeners, diluents, buffer substances, solvents, soljubilizatory, agents for achieving a depot effect, salts for modifying the osmotic pressure, covering agents or antioxidants. They may also contain 2 or more compounds of the formula I and/or their physiologically acceptable salts and/or their prodrugs. When the pharmaceutical preparation contains 2 or more compounds of the formula I, the choice of individual compounds can be targeted to specific General pharmacological profile of a pharmaceutical product. For example, highly active connection with a shorter duration of action can be combined with long-acting connection with lower activity. The flexibility permitted in the selection of the substituents of the compounds of formula I, provides significant control of biological and physico-chemical properties is of soedinenii and thus, provides the possibility of selecting the desired compounds. In addition, in addition, at least one compound of the formula I and/or physiologically acceptable salts and/or its prodrug, the pharmaceutical preparations can also contain one or more other therapeutically or prophylactically active ingredients. When using compounds of formula I dose can be varied within wide limits, and, as is usually done, and it is known to the doctor, pick it up for individual conditions in each individual case. It depends on the specific compounds from nature and severity of the subject to treatment of the disease, the type and schemes, or from being treated whether acute or chronic condition, or whether prevention. The appropriate dosage can be set using clinical approaches that are well known in the field of medicine. In General, the daily dose to achieve the desired outcomes in an adult weighing about 75 kg is from 0.01 mg/kg to 100 mg/kg, preferably from 0.1 mg/kg to 50 mg/kg, in particular from 0.1 mg/kg to 10 mg/kg (in each case in mg per 1 kg of body weight). The daily dose can be divided, in particular, in the case of the introduction of relatively large quantities for several, for example 2, 3 or 4 partial injections. Usually, according to ofindividuals behavior, it may be necessary to deviate upward or downward from the specified daily dose.

The compound of the formula I can also preferably be used as anticoagulant outside of the individual. For example, the effective amount of the compounds of the invention may come in contact with viewsate the blood sample to prevent clotting of the blood sample. In addition, the compound of formula I or its salts can be used for diagnostic purposes, for example, in the diagnosis in vivo, and as an aid in biochemical research. For example, the compound of the formula I can be used in the analysis to identify the presence of factor XA and/or factor VIIa or for selection of factor XA and/or factor VIIa essentially in purified form. The compound of the invention can be labeled, for example, a radioisotope, and then labeled compound associated with factor XA and/or factor VIIa, detected using conventional method used to detect a specific label. Thus, the compound of formula I or its salt can be used as a probe to identify the localization of the amount of the activity of factor XA and/or factor VIIa in vivo, in vitro or ex vivo.

In addition, the compounds of formula I can be used as intermediates synthesis for the preparation of other compounds, in particular of other pharmaceutical the ski active ingredients, which can be obtained from compounds of the formula I, for example, the introduction of substituents or modification of functional groups.

In General, the synthetic sequence to produce compounds that can be used in the present invention, presented in the examples below. And explanation, and the real procedure of various aspects of the present invention are described in the appropriate places on the description. The following examples are intended merely to illustrate the present invention and not to limit either by volume or entity. Specialists in this field will readily understand that known variations of the conditions and methods described in the examples, can be used for the synthesis of compounds of the present invention.

It is clear that changes that do not significantly affect the activity of various embodiments of the invention, included in disclosed in the present description the invention. Thus, the following examples are intended to illustrate and not limit the present invention.

EXAMPLES

When at the final stage of synthesis of compounds were used acid, such as triperoxonane acid or acetic acid, for example, when triperoxonane acid was used to remove the tBu group, or when the compound was purified by chromatography using eluent is, which contain this acid, in some cases, depending on the procedure of development, for example, details of the method of freeze-drying, the compound was obtained partially or completely in the form of an acid salt used, for example, in the form of a salt of acetic acid or salt triperoxonane acid or salt of hydrochloric acid.

Used abbreviations:
Tert-butyltBu
2,2'-bis(diphenylphosphino-1,1'-binaphthylBinap
Chloride bis-(oxo-3-oxazolidinyl)phosphorylaBOP-Cl
Dibenzylideneacetonedba
DichloromethaneDCM
Carbodiimide of DICYCLOHEXYLDCC
Cyanide diethylphosphineDEPC
4-dimethylaminopyridineDMAP
N,N-dimethylformamideDMF
The sulfoxideDMSO
1,1'-bis(diphenylphosphino)ferroceneDPPF
Hexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylureaHATU
N-bromosuccinimideNBS
N-chlorosuccinimideNCS
N-idsktune the ID NIS
N-ethylmorpholineNEM
MethanolMeOH
The room temperature from 20°to 25°RT
RichSat.
TetrahydrofuranTHF
Triperoxonane acidTFA
Tetrafluoroborate O-((etoxycarbonyl)cyanomethylene)-N,N,N',N'-tetramethylureaTOTU

Example 1

(1-Isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-pyrrol[2,3-b]pyridine-2-carboxylic acid

(i) methyl ester 1H-pyrrol[2,3-b]pyridine-2-carboxylic acid

0,495 g (1,64 mmol) 1-benzazolyl-1H-pyrrol[2,3-b]pyridine-2-carboxylic acid are dissolved in 5 ml of methanol and 3 ml of 2 n aqueous sodium hydroxide. The reaction mixture was stirred at 40°C for 8 hours the Solvent is removed under reduced pressure. Residual volatiles are removed double joint distilling with toluene. The residue is suspended in methanolic hydrochloric acid and stirred for 16 h at RT. The solvent is removed under reduced pressure. The residue is dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic phase from the shat sodium sulfate, filtered and the solvent is removed under reduced pressure.

Output 0,201, MC (Cl+): m/e=177 (M+H-).

(ii) 1-[5-(5-Chlorothiophene-2-yl)-isoxazol-3-ylmethyl]-1H-pyrrol[2,3-b]pyridine-2-carboxylic acid

of € 0.195 g (1.1 mmol) of a compound methyl ester 1H-pyrrol[2,3-b]pyridine-2-carboxylic acid are dissolved in 4 ml of DMF and added to 48.7 mg (1.2 mmol) of sodium hydride (60% in mineral oil). The reaction mixture was stirred at RT for 20 min, cooled to -78°With, then add 324 mg (1.2 mmol) of 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol [obtained by adaptation of the procedure described by Ewing, William R.; Becker, Michael R.; Choi-Sledeski, Yong Mi; Pauls, Heinz W.; He, Wei; Condon, Stephen M.; Davis, Roderick S.; Hanney, Barbara A.; Spada, Alfred P.; Burns, Christopher J.; Jiang, John Z.; Li, Aiwen; Myers, Michael R.; Lau, Wan F.; Poli, Gregory B; PCT Int. Appl. (2001) 460 pp. WO 0107436 A2]. The reaction mixture is allowed the opportunity to warm up to CT during the night. Add 0.3 ml of 2 n aqueous sodium hydroxide and then the reaction mixture was stirred at RT for 24 hours the Product was then purified preparative HPLC in the reversed phase elwira gradient 0-100% acetonitrile in water (+0.01% of triperoxonane acid). After lyophilization the product is obtained in the form of solids.

Yield 280 mg of MC (MC TOF ES+): m/e=359 (M+).

(iii) a compound tert-butyl methyl ether (1-isopropylpiperazine-4-yl)carbamino acid

To a solution of 5.0 g of complex tert-butyl ether piperidine-4-ylcarbamate acid in 15 ml of methane is La add 7,34 ml of acetone, 3,14 g Na(CN)BH3and 0.3 ml of acetic acid. After stirring for 16 h at RT the solvent is removed under reduced pressure and the residue partition between water (30 ml) and 30 ml of ethyl acetate. The organic layer was washed with a saturated solution of Na2CO3, water and then dried over Na2SO4. After filtration the solvent is removed under reduced pressure to obtain a white solid.

Output: 4,8, MC (ES+): m/e=243.

(iv) 1-Isopropylpiperazine-4-ylamine

To 4.8 g complex tert-butyl methyl ether (1-isopropylpiperazine-4-yl)carbamino acid in 15 ml of methanol are added 20 ml of methanolic hydrochloric acid (8M) and the mixture is stirred for 16 hours the solvent under reduced pressure gives a white solid, which together evaporated twice with 20 ml of toluene. The product is obtained in the form of its hydrochloride.

Output: 5,42, MC (ES+): m/e=143.

(v)(1-Isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-pyrrol[2,3-b]pyridine-2-carboxylic acid

is 0.135 g (0.4 mmol) of 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-pyrrol[2,3-b]pyridine-2-carboxylic acid, 0,432 g (3.8 mmol) of NEM and 135 mg (0.4 mmol) of TOTU dissolved in 3 ml of DMF and stirred at RY for 20 minutes 89 mg (0.4 mmol) of the dihydrochloride of 1-isopropylpiperazine-4-ylamine added to the reaction solution and stirred at RT for 4 h Product cleaned the Ute preparative HPLC in the reversed-phase, elwira gradient 0-100% acetonitrile in water (+0.01% of triperoxonane acid). After lyophilization receive the product in the form of solids.

Yield: 156 mg MC (MC TOF ES+): m/e=484 (M+).

Example 2

Methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-pyrrol[2,3-b]piperidine-5-carboxylic acid

(i) methyl ester 6-aminonicotinic acid

To a solution of 10 g of 6-aminonicotinic acid in 100 ml Meon add 0.8 ml of concentrated H2SO4and the mixture is heated to 60°C for 12 h and Then the reaction mixture was concentrated under reduced pressure. After adding 50 ml of ice water, the pH of the mixture was adjusted to 8 by addition of K2CO3. The aqueous phase is extracted with ethyl acetate (3×100 ml) and the combined organic layers dried over MgSO4. Removal of solvent gives 5.5 g of the desired product, which is subjected to the next reaction without further purification.

Output: 5.5V,

(ii) methyl ester of 6-amino-5-iodonicotinate acid

To 5 g of complex methyl ester 6-aminonicotinic acid and 16.2 g of tetrafluoroborate bis(pyridine)iodine(I) in 250 ml of DCM is added dropwise to 7.6 ml triftormetilfullerenov acid at 0°C. the Mixture is stirred for 24 h at RT. Then add a further 3.2 g of tetrafluoroborate bis(pyridine)iodine(I) and 5 ml triftormetilfullerenov acid. After stirring for 2 h at RT, the reaction mixture was concentrated under reduced pressure and then collect a concentrated aqueous solution of Na2SO3and adjusted to pH 8 with concentrated aqueous ammonia. The mixture is extracted with ethyl acetate (2×150 ml). The combined organic layers washed with brine and then dried over MgSO4. After filtration the solvent is removed under reduced pressure and the residue distil together with 100 ml of toluene.

Output: 9,6,

(iii) Complex 5-methyl ester 1H-pyrrol[2,3-b]pyridine-2,5-dicarboxylic acid

A solution of 5.6 g of a complex of methyl ester of 6-amino-5-iodonicotinate acid, 5.3g 2-oxopropanoic acid, 11.1 g NEt3of 4.2 g of triphenylphosphine and 1.1 g of Pd(OAc)2in 100 ml of DMF is heated in argon atmosphere up to 100°C. After 10 h, the reaction mixture was concentrated under reduced pressure and the residue is stirred with 250 ml water for 1 h the Precipitated product is filtered and washed with water. The crude product is subjected to the next reaction stage without further purification.

Output: 10,

(iv) methyl ester of 2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-pyrrol[2,3-b]pyridine-5-carboxylic acid

To a solution of 9.5 g of complex 5-methyl ester 1H-pyrrol[2,3-b]pyridine-2,5-dicarboxylic acid in 120 ml of DMF and 23.9 ml Net3add to 9.2 g of the hydrochloride of 1-isopropylidene the DIN-4-ylamine and 11 g of BOP-Cl at RT and the mixture is stirred for 3 hours After adding 20 ml of water the reaction mixture is extracted with ethyl acetate (3×150 ml). The combined organic layers washed with brine (1×50 ml) and dried over MgSO4. After filtration the solvent is removed under reduced pressure and the residue purified by chromatography on silica gel, elwira EtOAc/MeOH 9:7→EtOAc/MeOH/NH3(aq.) 6:4:0,4. The fractions containing the product is evaporated and distil together with toluene.

The output of 7.2,

(v) methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpyridine-4-ylcarbonyl)-1H-pyrrol[2,3-b]pyridine-5-carboxylic acid

To a solution of 1.2 g of complex methyl ester 2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-pyrrol[2,3-b]pyridine-5-carboxylic acid in 20 ml of DMF add 91 mg of sodium hydride (95%) at 0°C. Then the reaction mixture was warmed up to CT and stirred for 30 minutes After cooling again to 0°add 967 mg 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol [obtained by adapting the procedures described Ewing, William R.; Becker, Michael R.; Choi-Sledeski, Yong Mi; Pauls, Heinz W.; He, Wei; Condon, Stephen M.; Davis, Roderick S.; Hanney, Barbara A.; Spada, Alfred P.; Burns, Christopher J.; Jiang, John Z.; Li, Aiwen; Myers, Michael R.; Lau, Wan F.; Poli, Gregory B; Int PQ. Appl. (2001), 460 pp. WO 0107436 A2] and the mixture is stirred for 2 h at RT. Then add 50 ml of water and the precipitate filtered off to obtain 630 mg of the pure product. The filtrate is concentrated under reduced pressure and and the residue purified preparative HPLC in the reversed-phase, elwira gradient 0-100% acetonitrile in water (+0.01% of triperoxonane acid). After lyophilization get another 371 mg of the product as a solid.

Output: 1,0, MC (ES+): m/e=542, chlorine-type.

Example 3

1-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-pyrrol[2,3-b]pyridine-5-carboxylic acid

To a solution of 630 mg of the complex of methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-pyrrol[2,3-b]pyridine-5-carboxylic acid in 60 ml Meon add to 8.7 ml of a 1M aqueous solution of NaOH. The reaction mixture is heated to 60°C for 3 hours After cooling to CT type of 8.8 ml of 1M aqueous HCl and the solvents removed under reduced pressure. The residue is stirred with water/MeCN 2:1 and precipitated product is filtered off.

Output: 276 mg. MC (ES+): m/e=528, chlorine-type.

Example 4

2-[(1-Isopropylpiperazine-4-yl)amide] 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-pyrrol[2,3-b]pyridine-2,5-dicarboxylic acid

To a solution of 100 mg 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-pyrrol[2,3-b]pyridine-5-carboxylic acid in 1 ml DMF added 62 mg TOTU, 0.2 ml DIPEA and 10 mg NH4Cl at RT and stirred for 16 h Then the solvent is removed under reduced pressure and the crude material purified preparative HPLC (C18 column obrasheniyashi, elution with a gradient of H2O/MeCN with 0.1% TFA). The fractions containing the product is evaporated and lyophilizer to obtain white solids. The product is obtained in the form of its triperoxonane salt.

Yield: 16 mg MC (ES+): m/e=527, chlorine-type.

Example 5

(1-Isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-pyrrol[3,2-b]pyridine-2-carboxylic acid

(i) 1H-Pyrrole[3,2-b]pyridine-2-carboxylic acid

1,22 ml of 2-oxopropanoic acid, 0.26 g of palladium acetate and 3,20 ml of triethylamine are added to a solution of 1.00 g of 2-bromopyridin-3-ylamine and to 1.21 g of triphenylphosphine in 10 ml of N,N-dimethylformamide. The reaction mixture was stirred for 4 h at 100°C. After removal of the solvent under reduced pressure the residue is purified column chromatography on silica gel with dichloromethane/methanol as eluent.

Yield: 260 mg MC (ES+): m/e=163.

1H-NMR (400 MHz, DMSO/TMS): δ = 13,30 (s, 1H); 12,00 (s, 1H); to 8.45 (d, 1H); of 7.82 (d, 1H); to 7.25 (DD, 1H); 7,14(s, 1H).

(ii) methyl ester 1H-pyrrol[3,2-b]pyridine-2-carboxylic acid

A solution of 130 mg of 1H-pyrrole[2,3-b]pyridine-2-carboxylic acid in 5 ml of 8 n hydrochloric acid in methanol is stirred at 60°C for 6 hours removing the solvent under reduced pressure gives a white solid, which together evaporated twice with 5 ml of toluene. The product is obtained in Vidiago hydrochloride.

Yield: 150 mg MC (ES+): m/e=177.

1H-NMR (400 MHz, DMSO/TMS): δ = 13,60 (s, 1H); 8,86 (d, 1H); 8,59 (d, 1H); of 7.82 (DD, 1H); 7,41 (s, 1H); 3,99 (s, 3H).

(iii) methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-pyrrol[3,2-b]pyridine-2-carboxylic acid

To a solution of 150 mg of complex methyl ester 1H-pyrrol[3,2-b]pyridine-2-carboxylic acid in 2 ml of N,N-dimethylformamide add to 20.4 mg of sodium hydride (95%) at 0°C. After stirring at 0°C for 10 min add 261 mg 3-bromacil-5-(5-chlorothiophene-2-yl)isoxazol. The reaction mixture allow to warm to room temperature and stirred for 2 hours After removal of the solvent under reduced pressure the residue is purified by chromatography on silica gel, elwira gradient dichloromethane/methanol.

Yield: 80 mg MC (ES+): m/e=374, chlorine-type.

1H-NMR (400 MHz, DMSO/TMS): δ = 8,54 (d, 1H); 8,13 (d, 1H); 7,58 (d, 1H); the 7.43 (s, 1H); 7,39 (DD, 1H); 7,26 (d, 1H); 7,73 (s, 1H); 5,98 (s, 2H); 3,90 (s, 3H),

(iv) 1-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-pyrrol[3,2-b]pyridine-2-carboxylic acid

A solution of 75 mg of complex methyl ester 1H-pyrrol[3,2-b]pyridine-2-carboxylic acid and 9.6 mg of lithium hydroxide in a mixture of 3 ml of tetrahydrofuran and 1 ml of water is stirred for 2 h at room temperature. After acidification of 6 n hydrochloric acid to pH 2 solvent mixture is removed under reduced pressure. Received the STATCOM purify by chromatography on silica gel, elwira gradient of ethyl acetate/methanol with 0.1% water.

Yield: 50 mg MC (ES+): m/e=360, chlorine-type.

1H-NMR (400 MHz, DMSO/TMS): δ = to 8.45 (d, 1H); to 7.84 (d, 1H); 7,53 (d, 1H); 7,22 (d, 1H); to 7.15 (DD, 1H); 6,94 (s, 1H); 6,60 (s, 1H); 6,14 (s, 2H).

(v) (1-Isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-pyrrol[3,2-b]pyridine-2-carboxylic acid

To a suspension of 50 mg 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-pyrrol[3,2-b]pyridine-2-carboxylic acid added 36 mg of the hydrochloride of 1-isopropylpiperazine-4-ylamine and 35 mg of bis(2-oxo-3-oxazolidinyl)phosphonic chloride in 1 ml of dichloromethane, 77 μl of triethylamine at room temperature and the mixture is stirred for 16 hours After removal of the solvent under reduced pressure the residue is purified preparative HPLC (column C18 reversed phase chromatography the gradient of water/acetonitrile with 0.1% triperoxonane acid). The fractions containing the product is evaporated and lyophilizer for white balance, which partition between 5 ml aqueous 0.1 n solution of sodium hydroxide and 5 ml of ethyl acetate. The organic layer was washed with additional water and then dried over sodium sulfate. After filtration and removal of solvent under reduced pressure to obtain white solid.

Yield: 10 mg MC (ES+): m/e=484, chlorine-type.

1H-NMR (500 MHz, DMSO/TMS): δ = 8,53 (d, 1H); 8,46 (d, 1H); 8,03 (d, 1H); EUR 7.57 (d, 1H); to 7.32 (s, 1H); 7,8 (DD, 1H); 7,26 (d, 1H); of 6.65 (s, 1H); to 5.93 (s, 2H); 3.75 to (m, 1H); 2,80 (m, 2H); 2,70 (m, 1H); 2,17 (m, 2H); of 1.80 (m, 2H); 1,53 (m, 2H); to 0.96 (d, 6H).

Example 6

1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-pyrrol[3,2-b]pyridine-5-carboxylic acid

(i) methyl ester of 5-amino-6-bromopyridin-2-carboxylic acid

To a solution of 5.00 g of complex methyl ester 5-aminopyridine-2-carboxylic acid in 75 ml of 48% aqueous Hydrobromic acid add 3,39 ml of 32% aqueous hydrogen peroxide solution. The mixture is stirred at room temperature for 2 h, then added to 0.80 ml of hydrogen peroxide solution. After stirring for 1 h the reaction mixture is cooled and its pH was adjusted to 8 by addition of concentrated aqueous ammonia. The mixture is extracted with 300 ml of ethyl acetate. The aqueous layer was washed with additional ethyl acetate and then the combined organic phases are dried over sodium sulfate. After filtration the solvent is removed under reduced pressure, and the residue purified by chromatography on silica gel, elwira gradient of n-heptane/ethyl acetate.

Output: 2,83, MC (ES+): m/e=231.

1H-NMR (400 MHz, DMSO/TMS): δ = 7,80 (d, 1H); 7,10 (d, 1H); 6,37 (s, 2H); of 3.80 (s, 3H).

(ii) Complex of 5-methyl ester 1H-pyrrol[3,2-b]pyridine-2,5-dicarboxylic acid

The following connection receive by analogy with example 5 with the use of the Finance complex methyl ester of 5-amino-6-bromopyridin-2-carboxylic acid instead of 2-bromopyridin-3-ylamine.

MC (ES+): m/e=221.

1H-NMR (400 MHz, DMSO/TMS): δ = RS 11.80 (s, 1H); 7,89 (d, 1H); to 7.84 (d, 1H); 6,93 (s, 1H); 3,88 (s, 3H).

(iii) methyl ester of 2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-pyrrol[3,2-b]pyridine-5-carboxylic acid

To a solution of 140 mg of complex 5-methyl ester 1H-pyrrol[3,2-b]pyridine-2,5-dicarboxylic acid, 1.4 ml of N,N-dimethylformamide and 0.35 ml of triethylamine added 164 mg of the hydrochloride of 1-isopropylpiperazine-4-ylamine and 161 mg of bis(2-oxo-3-oxazolidinyl)phosphonic chloride at room temperature and the mixture is stirred for 1 h After removal of the solvent under reduced pressure the residue is purified preparative HPLC (column C18 reversed phase elution gradient of water/acetonitrile with 0.1% triperoxonane acid). The fractions containing the product is evaporated and lyophilizer to obtain white solids. The product is obtained in the form of triperoxonane salt.

Yield: 112 mg MC (ES+): m/e=345.

1H-NMR (400 MHz, DMSO/TMS): δ = 12,20 (s, 1H); 9,10 (s, 1H); 8,79 (d, 1H); to 7.93 (m, 2H); 7,42 (s, 1H); to 4.14 (m, 1H); 3,90 (s, 3H); 3,47 (m, 3H); 3.15 in (m, 2H); to 2.15 (m, 2H); of 1.88 (m, 2H); of 1.28 (d, 6H).

(iv) methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-pyrrol[3,2-b]pyridine-5-carboxylic acid

To a solution of 60 mg of complex methyl ester 2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-pyrrol[3,2-b]pyridine-5-carboxylic acid in 2 N,N-dimethylformamide add 4 mg of sodium hydride (95%) at 0° C. After stirring at 0°C for 10 min add 53 mg of 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol and the mixture is stirred for 2 h at room temperature. After removal of the solvent under reduced pressure the residue is purified preparative HPLC (column C18 reversed phase elution gradient of water/acetonitrile with 0.1% triperoxonane acid). The fractions containing the product is evaporated and lyophilizer to obtain white solids. The product is obtained in the form of triperoxonane salt.

Yield: 50 mg MC (ES+): m/e=542, chlorine-type.

1H-NMR (400 MHz, DMSO/TMS): δ = 8,93 (m, 2H); of 8.25 (d, 1H); 8,04 (d, 1H); at 7.55 (d, 1H); 7,42 (s, 1H); 7,28 (d, 1H); 6,69 (s, 1H); 5,97 (s, 2H); 4,07 (m, 1H); 3,91 (s, 3H); to 3.45 (m, 2H); 3,10 (m, 2H); 2,10 (m, 3H); to 1.83 (m, 2H); 1,25 (m, 6H).

(v) 1-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-pyrrol[3,2-b]pyridine-5-carboxylic acid

To a solution of 50 mg of complex methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-pyrrol[3,2-b]pyridine-5-carboxylic acid in 2 ml of THF and 1 ml of water is added 3.6 mg of lithium hydroxide and the mixture is stirred at room temperature for 2 h Then the reaction mixture was acidified with 6 n hydrochloric acid to pH 3 and the solvent is removed under reduced pressure. The resulting residue is purified preparative HPLC (column C18 reversed phase, e is aerovane gradient of water/acetonitrile with 0.1% triperoxonane acid). The fractions containing the product is evaporated and lyophilizer to obtain white solids. The product is obtained in the form of triperoxonane salt.

Yield: 25 mg MC (ES+): m/e=528, chlorine-type.

1H-NMR (500 MHz, DMSO/TMS): δ = 13,00 (s, 1H); 8,90 (m, 2H); 8,23 (d, 1H); 8,03 (d, 1H); 7,56 (d, 1H); 7,42 (s, 1H); 7,28 (d, 1H); 6,69 (s, 1H); 5,98 (s, 2H); 4,07 (m, 1H); to 3.45 (m, 2H); 3,10 (m, 2H); 2,10 (m, 3H); to 1.83 (m, 2H); of 1.25 (d, 6H).

Example 7

(1-Isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-oxo-4,5-dihydro-1H-pyrrol[3,2-b]pyridine-2-carboxylic acid

(i) methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4-hydroxy-1H-pyrrole[3,2-b]pyridine-2-carboxylic acid

To a solution of 80 mg of complex methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-pyrrol[3,2-b]pyridine-2-carboxylic acid in 1 ml of dichloromethane add a solution of 52.8 mg 3-chloroperoxybenzoic acid (70%wet with water) in 1 ml dichloromethane at 0°C. After stirring at 0°C for 1 h the reaction mixture allow to warm to room temperature and stirred for 16 hours The solution was washed with aqueous 0.1 n solution of sodium hydroxide. The organic layer was washed with additional water and then dried over anhydrous sodium sulfate. After concentration under reduced pressure the residue is directly subjected to the subsequent interaction without further purification.

Yield: 100 mg MC (ES+): m/e=390, chlorine-type.

(ii) methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-oxo-4,5-dihydro-1H-pyrrol[3,2-b]pyridine-2-carboxylic acid

A solution of 100 mg of the complex of methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-4-hydroxy-1H-pyrrole[3,2-b]pyridine-2-carboxylic acid in 5 ml of acetic anhydride is heated for 4 h at 100°C. After cooling to room temperature, the solvent mixture is removed under reduced pressure. After co-evaporation twice with 5 ml of toluene, the residue is dissolved in 5 ml of methanol and add to 17.6 mg of potassium carbonate. The suspension is stirred for 16 h at room temperature. After concentration under reduced pressure the residue is purified preparative HPLC (column C18 reversed phase elution gradient of water/acetonitrile with 0.1% triperoxonane acid). The product is obtained in the form of triperoxonane salt.

Yield: 20 mg MC (ES+): m/e=390, chlorine-type.

1H-NMR (400 MHz, DMSO/TMS): δ = 11,65 (s, 1H), of 7.90 (d, 1H); of 7.60 (d, 1H); 7,28 (d, 1H); of 6.71 (s, 1H); to 6.67 (s, 1H); 6,35 (d, 1H); by 5.87 (s, 2H); 3,81 (s, 3H).

(iii) 1-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-oxo-4,5-dihydro-1H-pyrrol[3,2-b]pyridine-2-carboxylic acid

A solution of 20 mg of complex methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-oxo-4,5-dihydro-1H-pyrrol[3,2-b]pyridine-2-carboxylic acid and 1.9 mg of lithium hydroxide in a mixture of 2 ml of t is trageriemen and 1 ml of water is stirred for 2 h at room temperature. The solvent is removed under reduced pressure and the residue together evaporated twice with toluene. The residue is directly subjected to the subsequent interaction without further purification.

Yield: 20 mg MC (ES+): m/e=376, chlorine-type.

(iv) (1-Isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-oxo-4,5-dihydro-1H-pyrrol[3,2-b]pyridine-2-carboxylic acid

To a suspension of 19.9 mg 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-oxo-4,5-dihydro-1H-5-pyrrol[3,2-b]pyridine-2-carboxylic acid and 13.5 mg of bis(2-oxo-3-oxazolidinyl)phosphinic chloride in 1 ml of dichloromethane added to 7.4 μl of triethylamine at room temperature and the mixture is stirred for 2 hours, the Reaction mixture was treated with 5 ml of aqueous 0.1 n sodium hydroxide solution and washed with acetylaceton. The organic layer is dried over anhydrous sodium sulfate. After filtration and removal of solvent under reduced pressure the residue is dissolved in a mixture of 2 ml of acetonitrile and 1 ml of water. Lyophilization of the solution gives a white solid.

Yield: 8 mg MC (ES+): m/e=500, chlorine-type.

1H-NMR (500 MHz, DMSO/TMS): δ = 11,70 (s, 1H); at 8.36 (d, 1H); 7,83 (d, 1H); to 7.59 (d, 1H); 7,28 (d, 1H); 6,76 (s, 1H); 6,63 (s, 1H); from 6.22 (d, 1H); to 5.85 (s, 2H); 3,68 (s, 1H); 2,78 (m, 2H); in 2.68 (m, 1H); and 2.14 (m, 2H); to 1.75 (m, 2H); is 1.51 (m, 2H); and 0.98 (d, 6H).

Example 8

Methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(3,4,5,6-tetrahydro-2H-[1,4']BIP is Ridel-4-ylcarbonyl)-1H-pyrrol[3,2-b]pyridine-5-carboxylic acid

(i) methyl ester of 2-(3,4,5,6-tetrahydro-2H-[1,4']bipyridyl-4-ylcarbonyl)-1H-pyrrol[3,2-b]pyridine-5-carboxylic acid

To a solution of 450 mg of complex 5-methyl ester 1H-pyrrol[3,2-b]pyridine-2,5-dicarboxylic acid in 9 ml of dichloromethane and 1.13 ml of triethylamine added 614 mg of the dihydrochloride 3,4,5,6-tetrahydro-2H-[1,4']bipyridyl-4-ylamine and 520 mg of bis(2-oxo-3-oxazolidinyl)phosphonic chloride at room temperature and the mixture is stirred for 2 hours After treatment of the reaction mixture 5 ml of a saturated aqueous solution of potassium carbonate precipitate is filtered off and together evaporated twice with toluene. The precipitate directly defy the subsequent reaction without further purification.

Yield: 300 mg MC (ES+): m/e=380.

1H-NMR (400 MHz, DMSO/TMS): δ = 8,30 (m, 1H); 8,15 (d, 2H); to 7.68 (d, 2H);? 7.04 baby mortality (s, 1H); 6,85 (d, 2H); 4,10 (m, 1H); 3,95 (m, 2H); of 3.84 (s, 3H); 3,00 (m, 2H); 1.91 a (m, 2H); 1,53 (m, 2H).

(ii) methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(3,4,5,6-tetrahydro-2H-[1,4']bipyridyl-4-ylcarbonyl)-1H-pyrrol[3,2-b]pyridine-5-carboxylic acid

To a solution of 150 mg of complex methyl ester 2-(3,4,5,6-tetrahydro-2H-[1,4']bipyridyl-4-ylcarbonyl)-1H-pyrrol[3,2-b]pyridine-5-carboxylic acid add 2 ml of N,N-dimethylformamide, 9.5 mg of sodium hydride (96%) at 0°C. After stirring at 0°C for 10 min add 121 mg of 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol and a mixture of PE amerivault for 50 h at room temperature. 2 ml of water is added to the reaction mixture and the precipitate is filtered off. The residue is dissolved in 2 ml of N,N-dimethylformamide and purified preparative HPLC (column C18 reversed phase elution gradient of water/acetonitrile with 0.1% triperoxonane acid). The fractions containing the product is evaporated and lyophilizer to obtain white solids. The product is obtained in the form of triperoxonane salt.

Yield: 27 mg MC (ES+): m/e=577, chlorine-type.

Example 9

1-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(3,4,5,6-tetrahydro-2H-[1,4']bipyridyl-4-ylcarbonyl)-1H-pyrrol[3,2-b]pyridine-5-carboxylic acid

To a solution of complex methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-pyrrol[3,2-b]pyridine-5-carboxylic acid in 0.5 ml of tetrahydrofuran and 0.25 ml of water is added 2.4 mg of lithium hydroxide and the mixture is stirred at room temperature for 16 hours After removal of the solvent under reduced pressure the resulting residue is purified preparative HPLC (column C18 reversed phase elution gradient of water/acetonitrile with 0.1% triperoxonane acid). The fractions containing the product is evaporated and lyophilizer to obtain white solids. The product is obtained in the form of triperoxonane salt.

Output: 14,3 mg MC (ES+): m/e=563, chlorine-type.

1H-NMR (500 MHz, DMSO/TMS):δ = 13,25 (s, 1H); 13,00 (s, 1H); 8,73 (d, 1H); 8,24 (m, 3H); 8,03 (d, 1H); EUR 7.57 (d, 1H); 7,39 (s, 1H); 7,26 (m, 3H); 6,69 (s, 1H); 5,98 (s, 2H); 4.25 in (m, 3H); 2,00 (m, 2H); to 1.59 (m, 2H).

Example 10

(1-Isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-(2-methoxyethoxy)-1H-pyrrol[2,3-C]pyridine-2-carboxylic acid

(i) 2-(2-Methoxyethoxy)-4-methyl-5-nitropyridine

To 20 ml of 2-methoxyethanol add 243 mg NaH (6,09 mmol, 60% suspension in oil) and the mixture stirred for 15 min in argon atmosphere. Add 1 g (5.8 mmol) of 2-chloro-4-methyl-5-nitropyridine and the reaction mixture stirred for 3 h at room temperature. After adding 40 ml of water and simple methyl tert-butyl ether phases are separated and the organic phase is washed with a saturated solution of NaHCO3and water and dried over Na2SO4. After filtration the solvent is removed in vacuo and the residue purified flash chromatography on silica gel using heptane/ethyl acetate=8/2. 2-(2-methoxyethoxy)-4-methyl-5-nitropyridine isolated in the form of a colourless oil.

Output: 0,73,

(ii) Potassium salt complex ethyl ester 3-[2-(2-methoxyethoxy)-5-nitropyridine-4-yl]-2-oxopropanoic acid

To 265 mg (of 6.78 mmol) of potassium in 20 ml simple absolute diethyl ether is added slowly to 2.5 ml of ethanol. The mixture is cooled to 0°and add a solution of 720 mg (3,39 mmol) of 2-(2-methoxyethoxy)-4-methyl-5-nitropyridine 2.5 the l simple absolute diethyl ether and 0.5 ml of ethanol. Dropwise within 45 min add 3,966 g (27,14 mmol) diethyl ether complex of oxalic acid in 15 ml of toluene. The reaction mixture was stirred at room temperature for 4 hours the Precipitate is filtered, washed with simple diethyl ether/n-heptane 1/1 and dried in vacuum. Potassium salt of a complex of ethyl ether, 1.4 g of 3-[2-(2-methoxyethoxy)-5-nitropyridine-4-yl]-2-oxopropanoic acid is isolated in the form of a red solid and used in the next stage without further purification.

(iii) a Complex ethyl ester 5-(2-methoxyethoxy)-1H-pyrrol[2,3-C]pyridine-2-carboxylic acid

0.8 ml of acid acid are added to a solution of dried potassium salt complex ethyl ester 3-[2-(2-methoxyethoxy)-5-nitropyridine-4-yl]-2-oxopropanoic acid in 20 ml of methanol and the solution hydrogenizing using 199 mg of Pd(OH)2(20% on charcoal). After 3 h the mixture is concentrated and the residue partitioned between a saturated solution NaHC3and ethyl acetate. The phases are separated and the organic phase is dried over MgSO4. After filtration the solvent is removed in vacuum and produces the desired product as a pale yellow solid.

Output: 660 mg.

(iv) Complex ethyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-(2-methoxyethoxy)-1H-pyrrol[2,3-C]pyridine-2-carboxylic acid

105 mg (4,16 mmol) NaH (96%) are added to the Rast is switchyard complex ethyl ester 5-(2-methoxyethoxy)-1H-pyrrol[2,3-C]pyridine-2-carboxylic acid in 50 ml of absolute DMF and the mixture is stirred for 30 min at room temperature. To a mixture of 1.05 g (of 3.78 mmol) 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol and stirring is continued for 3 hours After adding 21 mg (0,832 mmol) NaH (96%) and 210 mg (0,756 mmol) 3-methyl bromide-5-(5-chlorothiophene-2-yl)isoxazol and standing overnight the mixture was concentrated in vacuo. The residue is dissolved in CH2Cl2and the solution is washed with saturated solution of NaHCO3. The solvent is removed in vacuo and the residue purified flash chromatography on silica gel using n-heptane/ethyl acetate=3/2 as solvent. The fractions containing the product are concentrated.

The output of 1.3,

(v) 1-[5-(5-Chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-(2-methoxyethoxy)-1H-pyrrol[2,3-C]pyridine-2-carboxylic acid

To a solution of 1.3 g (2,814 mmol) of a compound ethyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-(2-methoxyethoxy)-1H-pyrrol[2,3-C]pyridine-2-carboxylic acid in 30 ml of THF and 15 ml of MeOH type of 11.26 ml 1M LiOH and the mixture was stirred at 50°C for 3 hours the Organic solvents are removed in vacuo, add 50 ml of water and the pH adjusted to 2 with a solution of 1 n HCl. The desired product precipitated and filtered. Washed with water and dried over P2O5.

Output 1,11,

(vi) (1-Isopropylpiperazine-4-yl)amidogidrolaza 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-(2-methoxyethoxy)-1H-pyrrol[2,3-C]pyridine-2-carboxylic acid

To a solution of 1.11 g (2.55 mmol) of 1-[5-(5-chlorothiophene--yl)isoxazol-3-ylmethyl]-5-(2-methoxyethoxy)-1H-pyrrol[2,3-C]pyridine-2-carboxylic acid and 0.55 g (2.55 mmol) of the dihydrochloride of 1-isopropylpiperazine-4-ylamine in 20 ml of absolute DMF add 837 mg (2.55 mmol) of TOTU and 1.34 ml (to 7.67 mmol) and DIPEA mixture stirred at room temperature for 4 hours the Solvent is removed in vacuum, the residue is dissolved in CH2Cl2and the phase of the CH2Cl2washed with a saturated solution of NaHCO3. The organic phase is concentrated and the residue purified by chromatography through silica gel using CH2Cl2/MeOH/HOAc/H2O=90/10/1/1 as eluent. The fractions containing the product are combined and concentrated. The product is isolated in the form of its hydrochloride by lyophilizate using 2.5 equivalents of 1 n HCl in H2O/AcCN.

Output 1,2, MC (ES+): m/e=558, chlorine-type.

Example 11

(1-Isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-(2-hydroxyethoxy)-1H-pyrrol[2,3-C]pyridine-2-carboxylic acid

To a solution of 600 mg (1.01 mmol) (1-isopropylpiperazine-4-yl)americanled 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-(2-methoxyethoxy)-1H-pyrrol[2,3-C]pyridine-2-carboxylic acid (example 10 (vi)) in 50 ml of CH2Cl2add 2 ml (2.02 mmol) of 1M solution of BBr3in CH2Cl2. The mixture is stirred at room temperature for 6 hours After standing overnight the solvent is removed in vacuo and the residue purified preparative HPLC (eluent: CH3CN/H2O/0.1% of CF3COOH). The fractions containing the product are combined and concentrated in vacuo. The residue is dissolved in CH2Cl2and prom is provide a 0.1 n NaOH solution. The solution is removed under vacuum and the residue lyophilizer 2.5 equivalents of 1 n HCl, getting 464 mg (79%) of the hydrochloride of the desired product.

MC (LC-MC-ES+): m/e=544, chlorine-type.

Example 12

(1-Isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-5-(2-methoxyethoxy)-1H-pyrrol[2,3-C]pyridine-2-carboxylic acid

(i) 5-(2-Methoxyethoxy)-1H-pyrrol[2,3-C]pyridine-2-carboxylic acid

To a solution of 1 g (3,784 mmol) of a compound ethyl ester 5-(2-methoxyethoxy)-1H-pyrrol[2,3-C]pyridine-2-carboxylic acid (example 10 (iii)) in 50 ml THF and 25 ml MeOH add 15,14 ml of 1M LiOH. The mixture is stirred for 2 h at room temperature. Organic solvents are removed in vacuo, the solution is acidified and concentrated in vacuo. The residue is purified flash chromatography through silica gel using H2Cl2/MeOH/HOAc/H2O=90/10/1/1 as eluent. Fraction of the product combine, concentrated in vacuo and lyophilizers.

Yield: 820 mg

(ii) (1-Isopropylpiperazine-4-yl)amide 5-(2-methoxyethoxy)-1H-pyrrol[2,3-C]pyridine-2-carboxylic acid

To a solution of 820 mg (3,47 mmol) 5-(2-methoxyethoxy)-1H-pyrrol[2,3-C]pyridine-2-carboxylic acid and 745 mg (3,47 mmol) of the dihydrochloride of 1-isopropylpiperazine-4-ylamine in 30 ml of absolute DMF is added 1.13 g (3,47 mmol) of TOTU and is 1.81 ml (10,41 mmol) DIPEA and the mixture is stirred for 4 h at room temperature. The solvent is dilaut in vacuum, the residue is dissolved in H2Cl2and the phase of the CH2Cl2washed with a saturated solution of NaHCO3. The organic phase is concentrated and the residue purified by chromatography through silica gel using CH2Cl2/MeOH/HOAc/H2O=90/10/1/1 as eluent. The fractions containing the product are combined and concentrated. The residue is dissolved in H2Cl2and the phase of the CH2Cl2washed with a saturated solution of NaHCO3. The phases are separated and the organic phase is dried over Na2SO4. After filtration the solvent is removed in vacuum. Exit 461 mg

(iii) 2-Bromo-N-(5-chloropyridin-2-yl)ndimethylacetamide

To a solution of 5 g of 5-chloropyridin-2-ylamine and 1.5 ml of pyridine in 30 ml of toluene are added dropwise 8 g bromoacetamide dissolved in 10 ml of toluene under conditions of cooling with ice. After 2 h the precipitate are filtered and recrystallised of toluene to obtain a white solid.

Output: 12,

(iv) (1-Isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-5-(2-methoxyethoxy)-1H-pyrrol[2,3-C]pyridine-2-carboxylic acid

To a solution of 461 mg (1,27 µm) (1-isopropylpiperazine-4-yl)amide 5-(2-methoxyethoxy)-1H-pyrrol[2,3-C]pyridine-2-carboxylic acid in 20 ml of absolute DMF is added 46 mg (1,91 mmol) NaH (96%) in argon atmosphere. The mixture is stirred for 15 min at room temperature. Add 479 mg (1,91 mmol) 2-d is-N-(5-chloropyridin-2-yl)ndimethylacetamide and the mixture is stirred for 3 h at room temperature. The solvent is removed in vacuum, the residue is dissolved in H2Cl2and the phase of the CH2Cl2washed with N2Oh, and dried over Na2SO4. After filtration, the organic phase is concentrated and the residue purified by chromatography through silica gel using CH2Cl2/MeOH/HOAc/H2O=90/10/1/1 as eluent and subsequent preparative HPLC (eluent: CH3CN/H2O/0.1% of CF3COOH). The fractions containing the product are combined and concentrated in vacuo. The remainder lyophilizer 2 equivalents of 1 n HCl in a mixture of H2O/CH3CN, giving the hydrochloride of the desired product.

Output: 545 mg MC (LC-MC-ES+): m/e=529, chlorine-type.

Example 13

(1-Isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-5-(2-methoxyethoxy)-1H-pyrrol[2,3-C]pyridine-2-carboxylic acid

Connection receive, as described in example 11. Of 446 mg (0,789 mmol) (1-isopropylpiperazine-4-yl)americanled 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-5-(2-methoxyethoxy)-1H-pyrrol[2,3-C]pyridine-2-carboxylic acid get 286 mg of the desired product.

MC (LC-MC-ES+): m/e=515, chlorine-type.

Example 14

(1-Isopropylpiperazine-4-yl)amide 1-(6-chlorobenzo[b]thiophene-2-ylmethyl]-5-(2-methoxyethoxy)-1H-pyrrol[2,3-C]pyridine-2-carboxylic acid

(i) Complex ethyl ester 1-(6-chlorobenzo[b]thiophene-2-ylmethyl]-5-(2-methoxyethoxy)-1H-pyrrol[2,3-C]pyridine-karbonovoi acid

To a solution of 660 mg (2,497 mmol) of a compound ethyl ester 5-(2-methoxyethoxy)-1H-pyrrol[2,3-C]pyridine-2-carboxylic acid in 15 ml of absolute DMF is added 24 mg (2,497 mmol) NaH (96%) in argon atmosphere. The mixture is stirred for 30 min at room temperature. 623 mg (2,497 mmol) 2-methyl bromide-6-chlorobenzo[b]thiophene [obtained by adaptation of the procedure described by Ewing, William R. et al. in PCT Int. Appl. (1999), 300 pp. WO 9937304 A1; and Ewing, William R. et al. PCT Int. Appl. (2001), 460 pp. WO 0107436 A2] and the mixture is stirred for 1 h at room temperature. The solvent is removed in vacuo and the residue purified preparative HPLC (eluent: CH3CN/H2O/0.1% of CF3COOH). The fractions containing the product are pooled, concentrated in vacuo and lyophilizers.

Yield: 900 mg

(ii) 1-(6-Chlorobenzo[b]thiophene-2-ylmethyl]-5-(2-methoxyethoxy)-1H-pyrrol[2,3-C]pyridine-2-carboxylic acid

8 ml of a 1M solution of LiOH are added to a solution of 890 mg (2 mmol) of a compound ethyl ester 1-(6-chlorobenzo[b]thiophene-2-ylmethyl]-5-(2-methoxyethoxy)-1H-pyrrol[2,3-C]pyridine-2-carboxylic acid in 30 ml of THF and 15 ml of MeOH, and the mixture is stirred for 1 h at 50°C. Add 16 ml of 1 n HCl, the organic solvent is removed in vacuo, and the residue is extracted with ethyl acetate. The organic phase is dried over MgSO4. After filtration the solvent is evaporated, obtaining the desired product.

Yield: 810 mg

(iii) (1-Isopropylpiperazine-4-yl)amide 1-(6-CHL is benzo[b]thiophene-2-ylmethyl]-5-(2-methoxyethoxy)-1H-pyrrol[2,3-C]pyridine-2-carboxylic acid

To a solution of 800 mg (1.92 mmol) of 1-(6-chlorobenzo[b]thiophene-2-ylmethyl]-5-(2-methoxyethoxy)-1H-pyrrol[2,3-C]pyridine-2-carboxylic acid and 413 mg (1.92 mmol) of the dihydrochloride of 1-isopropylpiperazine-4-ylamine in 20 ml of absolute DMF add 628 mg (1.92 mmol) of TOTU and 1.0 ml (5,757 mmol) of DIPEA, and the mixture is stirred at room temperature for 1 h the Solvent is removed in vacuo and the residue purified preparative HPLC (eluent: CH3CN/H2O/0.1% of CF3COOH) and chromatography through silica gel using CH2Cl2/MeOH/HOAc/H2O=85/15/1,5/1,5 as eluent. The fractions containing the product are combined and concentrated. Output: 870 mg (69%), the corresponding triptorelin. 60 mg trifenatate lyophilizer using 2.5 equivalents of 1 n HCl in N2Oh and isolated in the form of hydrochloride.

MC (LC-MS-ES+): m/e=541, chlorine-type.

Example 15

(1-Isopropylpiperazine-4-yl)amide 1-(6-chlorobenzo[b]thiophene-2-ylmethyl]-5-(2-hydroxyethoxy)-1H-pyrrol[2,3-C]pyridine-2-carboxylic acid

To a solution of 810 mg (1,236 mmol) (1-isopropylpiperazine-4-yl)amidogidrolaza 1-(6-chlorobenzo[b]thiophene-2-ylmethyl]-5-(2-methoxyethoxy)-1H-pyrrol[2,3-C]pyridine-2-carboxylic acid in 80 ml of CH2Cl2add 2,472 ml of 1M solution of BBr3in CH2Cl2. The mixture is stirred at room temperature for 30 minutes the Solvent is removed in vacuum and lyophilizers. The remainder of imaut preparative HPLC (eluent: CH 3CN/H2O/0.1% of CF3COOH). The fractions containing the product are pooled, concentrated in vacuo and lyophilizers with 2.5 equivalents of 1 n HCl, receiving the hydrochloride of the desired product.

Output: 594 mg MC (LC-MC-ES+): m/e=527, chlorine-type.

Pharmacological testing

The ability of the compounds of formula I to inhibit factor XA or factor VIIa or other enzymes such as thrombin, plasmin, or trypsin can be estimated by determining the concentration of the compounds of formula I that inhibits enzyme activity by 50%, i.e. the IC50 value that was associated with the inhibition constant Ki. Purified enzymes are used in chromogenic assays. The concentration of inhibitor which causes a decrease by 50% the rate of hydrolysis of the substrate, determined by linear regression after plotting the graph of relative velocities of hydrolysis (compared to eingeborenen control) depending on the logarithm of the concentration of the compound of formula I. To calculate the inhibition constants Ki IC50 value correct on the competition with the substrate, using the formula

Ki=IC50/{1+(the substrate concentration/Km)},

where Km is a constant Michaelis-Menten (Chen and Prusoff, Biochem. Pharmacol. 22 (1973), 3099-3108; I. H. Segal, Enzyme Kinetics, 1975, John Wiley & Sons, New York, 100-125; which is incorporated into this description by reference).

A) analysis of the factor Ha

In the analysis to determine the population of inhibiting the activity of factor XA using the buffer TBS-PEG (50 mm Tris-HCl, pH of 7.8, 200 mm NaCl, 0,05% (wt./about.) PEG-8000, 0,02% (wt./about.) NaN3). IC50 is determined by combining the contents of the respective holes Mitrovice microplates half square Costar, comprising 25 μl human factor XA (Enzyme Research Laboratories, Inc.; South Bend, Indiana) in TBS-PEG; 40 ál of 10% (vol./about.) DMSO in TBS-PEG (inhibited control) or various concentrations of compounds to be tested, diluted in 10% (vol./about.) DMSO in TBS-PEG; and the substrate S-2765 (N(α)-benzyloxycarbonyl-D-Arg-Gly-L-Arg-para-nitroanilide, Kabi Pharmacia, Inc.; Franklin, Ohio) in TBS-PEG.

Analysis of pre-incubation of the compounds of formula I plus enzyme for 10 minutes Then the analysis begins by adding the substrate to obtain a final volume of 100 μl. The initial rate of hydrolysis of a chromogenic substrate is measured by the change in absorbance at 405 nm using instruments kinetic reading tablet (Cerer UV900HDi) at 25°C for the linear part of the flow of time (usually within 1.5 min after substrate addition). The concentration of the enzyme is 0.5 nm, and the substrate concentration is 140 ám.

b) Analysis of factor VIIa

Inhibitory activity of factor VIIa/tissue factor determined using a chromogenic assay. Essentially as described previously (publication J.A.Ostrem et al., Biochemistry 37 (1998) 1053-1059), which included in this is e description as a reference). Kinetic tests conducted at 25°in tetrofosmin microplate half square (Costar Corp., Cambridge, Massachusetts), using using kinetic device reader tablet (Molecular Devices Spectramax 250). A typical analysis consists of 25 μl human factor VIIa and TF (corresponding final concentration of 5 nm and 10 nm) in combination with 40 μl of dilutions of the inhibitor in the buffer 10% DMSO/TBS-PEG (50 mm Tris, 15 mm NaCl, 5 mm CaCl2, 0,05% PEG 8000, pH 8,15). After 15 min period prior incubation analysis start by adding 35 ál of chromogenic substrate S-2288 (D-Ile-Pro-Arg-para-nitroanilide, Pharmacia Hepar Inc., the final concentration of 500 μl). The results of the inhibition constants Ki (FXa) inhibition of factor XA) is shown in the table.

Table
ExampleKi(FXa) [µm]ExampleKi(FXa) [µm]
10,00670,023
20,05590,085
30,067110,047
40,070130,044
50,004
60,010

1. The compound of the formula I

where R0represents a

monocyclic or bicyclic 6-9-membered heterocyclyl selected from the group of benzothiophene, pyridyl, or

monocyclic 5-membered heterocyclyl containing 1 2 heteroatoms selected from nitrogen or oxygen, where indicated heterocyclyl is monogamist R8, and which is optionally substituted monocyclic 5-membered heterocyclyl containing 1 heteroatom selected from sulphur,

where heterocyclyl monogamist R8,

R8 represents a

halogen,

substructure

which in the formula I represents a 6-membered, partially unsaturated or aromatic cyclic group containing 1 heteroatom selected from nitrogen, and which is substituted by 1 group R23 or exography,

provided that the cyclic group is phenyl residue,

Q represents a direct bond, -(C0-C2-alkylen-C(O)-NR10-, -(C1-C6-alkylen,

R1represents a hydrogen atom,

R2represents a direct bond,

V represents

6-membered cyclic residue, containing 1 heteroatom selected from nitrogen, where MC is connected cyclic residue is unsubstituted,

bicyclic 12-membered heterocyclyl containing 1-2 heteroatoms selected from nitrogen, where the specified heterocyclyl is unsubstituted,

G represents a direct link,

M represents

a hydrogen atom,

-(C1-C8)-alkyl, where alkyl is unsubstituted,

R3 represents a

a hydrogen atom,

R23 represents a

a hydrogen atom,

-(C0-C4-alkylene-O-R19 where R19 represents a

(a) a hydrogen atom,

b) -(C1-C4)-alkyl, where alkyl is unsubstituted or monosubstituted R13,

-(C0-C4-alkylen-C(O)-R11,

-(C0-C4-alkylen-C(O)-O-R11,

R11 and R12 independently of one another are identical or different and represent

a hydrogen atom,

-(C1-C6)-alkyl,

-O-R17or

R13 represents-C(O)-O-R10,

R10and R20represent, independently from each other hydrogen, -(C1-C6)-alkyl,

R17 represents -(C1-C6)-alkyl, and physiologically acceptable salts.

2. The compound of formula I according to claim 1,

where R0represents a

heterocyclyl selected from the group of benzothiophene, pyridyl, or courtesans who were cilil, where heterocyclyl selected from the group of dehydrator[2,3-b]tetrahydrofuranyl, furanyl, imidazolidinyl, imidazolyl, imidazolyl, isoxazolyl, isoxazoline, isoxazolidine, 2-isoxazoline, oxazoline, oxazole, pyrazolidine, pyrazoline, pyrazolyl 2N-pyrrolyl, pyrrolyl, tetrahydrofuranyl where specified heterocyclyl monogamist R8, and

which is optionally substituted by heterocyclyl selected from the group of tanila where heterocyclyl monogamist R8,

R8 represents a

halogen,

substructure D is a residue selected from the group of pyridine, substituted 1 group R23, or exography,

Q represents a direct bond, -(C0-C2-alkylen-C(O)-NR10-, -(C1-C6-alkylen,

R1represents a hydrogen atom,

R2represents a direct bond,

V represents

heterocyclyl selected from the group of piperidinyl, pyridyl, chinoline, 4H-chinoiserie, tetrahydroisoquinoline, tetrahydroquinoline, tetrahydropyridine where specified heterocyclyl is unsubstituted,

M represents

a hydrogen atom,

-(C1-C8)-alkyl, where alkyl is unsubstituted,

R3 represents a

a hydrogen atom,

R23 pre what is a

a hydrogen atom,

-(C0-C4-alkylene-O-R19 where R19 represents a

(a) a hydrogen atom,

b) -(C1-C4)-alkyl, where alkyl is unsubstituted or monosubstituted R13,

-(C0-C4-alkylen-C(O)-R11,

-(C0-C4-alkylen-C(O)-O-R11,

R11 and R12 independently of one another are identical or different and represent

a hydrogen atom,

-(C1-C6)-alkyl,

-O-R17or

R13 represents-C(O)-O-R10,

R10and R20represent, independently from each other hydrogen, -(C1-C6)-alkyl,

R17 represents -(C1-C6)-alkyl.

3. The compound of formula I according to claim 1 or 2,

where R0represents a

heterocyclyl selected from the group of benzothiophene, pyridyl, or

heterocyclyl, selected from the group 2-furil, 3-furil, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, 2-pyrrolyl, 3-pyrrolyl,

which is optionally substituted by heterocyclyl selected from the group of tanila where heterocyclyl monogamist R8,

R8 represents a

fluorine, chlorine or bromine,

substructure D is a residue selected from the group of pyridyl, substituted 1 group R23, or oxagr is POI,

Q represents a direct bond, -(C0-C2-alkylen-C(O)-NR10-, (C1-C6-alkylen,

R1represents a hydrogen atom,

R2represents a direct bond,

V represents

heterocyclyl selected from piperidine, pyridine, tetrahydropyridine, and where heterocyclyl is unsubstituted,

M represents

a hydrogen atom,

-(C1-C8)-alkyl, where alkyl is unsubstituted, independently from each other, R14,

R3 represents a

a hydrogen atom,

R23 represents a

a hydrogen atom,

-(C0-C4-alkylene-O-R19 where R19 represents a

(a) a hydrogen atom,

b) -(C1-C4)-alkyl, where alkyl is unsubstituted or monogamist R13,

-(C0-C4-alkylen-C(O)-R11,

-(C0-C4-alkylen-C(O)-O-R11,

R11 and R12 independently of one another are identical or different and represent

a hydrogen atom,

-(C1-C6)-alkyl,

-O-R17or

R13 represents-C(O)-O-R10,

R10and R20represent, independently from each other hydrogen, -(C1-C6)-alkyl,

R17 represents -(C1-the 6)-alkyl.

4. The compound of formula I according to claim 1,

where R0represents a

heterocyclyl selected from the group of benzothiophene, pyridyl, or

heterocyclyl, selected from the group pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, furil, 2-furil, 3-furil, imidazolyl, pyrazolyl, oxazolyl and isoxazolyl where heterocyclyl is monogamist R8,

and additionally substituted by a residue of tanila, 2-tanila, 3-tanila, where the specified residue is monogamist R8,

R8 represents a

F, Cl, Br or I,

substructure D is a residue selected from the group of pyridyl, substituted 1 group R23, or exography,

Q represents a direct bond, -(C1-C6-alkylene or -(C0-C2-alkylen-C(O)-NR10-,

R1represents a hydrogen atom,

R2represents a direct bond,

V represents

cyclic residue from the group consisting of compounds that are derivatives of pyridine, where the specified heterocyclyl is unsubstituted, M is a hydrogen atom,

-(C1-C6)-alkyl, where alkyl is unsubstituted,

R3 represents a

1) a hydrogen atom,

R23 represents a

a hydrogen atom,

-(C0 4-alkylene-O-R19 where R19 represents a

(a) a hydrogen atom,

b) -(C0-C4)-alkyl, where alkyl is unsubstituted or monogamist R13,

-(C0-C4-alkylen-C(O)-R11,

-(C0-C4-alkylen-C(O)-O-R11,

R13 represents-C(O)-O-R10,

R10and R20represent, independently from each other hydrogen, -(C1-C6)-alkyl,

R17 represents -(C1-C6)-alkyl.

5. The compound of formula I according to claim 1,

where R0represents a

heterocyclyl selected from the group of benzothiophene, pyridyl, or

heterocyclyl, selected from the group pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, furil, 2-furil, 3-furil, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl and pyrazinyl where heterocyclyl monogamist R8,

and additionally substituted by a residue selected from the group of tanila, 2-tanila, 3-tanila, where the specified residue is monogamist R8,

R8 represents a

F, Cl, Br or I,

substructure D is a residue selected from the group of pyridyl, and is substituted by 1 group R23, or exography,

Q represents a direct bond, -(C1-C6-alkylene or -(C0-C2-alkylen-C(O)-NR10-,

R1represents the volume of hydrogen

R2represents a direct bond,

V represents

cyclic residue from the group consisting of compounds that are derived aziridine, isoquinoline, research, piperidine, pyridine, quinoline, where the specified cyclic residue is unsubstituted,

M represents

a hydrogen atom,

-(C1-C8)-alkyl, where alkyl is unsubstituted,

R3 represents a hydrogen atom,

R23 represents a

a hydrogen atom,

-(C0-C4-alkylene-O-R19 where R19 represents a

(a) a hydrogen atom,

b) -(C1-C4)-alkyl, where alkyl is unsubstituted or monogamist R13,

-(C0-C4-alkylen-C(O)-R11,

-(C0-C4-alkylen-C(O)-O-R11,

R11 and R12 independently of one another are identical or different and represent

a hydrogen atom,

-(C1-C6)-alkyl,

-O-R17or

R13 represents-C(O)-O-R10,

R10and R20represent, independently from each other hydrogen, -(C1-C6)-alkyl, and

R17 represents -(C1-C6)-alkyl.

6. The compound of formula I according to claim 1,

where R0represents a

pyridi is or benzothiophene, or

heterocyclyl selected from isoxazolyl where specified heterocyclyl is substituted by a residue selected from tanila, 2-tanila and 3-tanila, where the specified residue is monogamist R8,

R8 represents F, Cl, Br,

substructure D is a residue selected from pyridyl, substituted 1 group R23 or exography,

Q represents a direct bond, -CH2-C(O)-NH, methylene or ethylene,

R1represents a hydrogen atom,

R2represents a direct bond,

V represents

residue selected from the group consisting of compounds that are derivatives of piperidine, heatline, quinoline,

where the specified cyclic residue is unsubstituted,

M represents a hydrogen atom, (C2-C4)-alkyl, where alkyl is nesnesinin,

R3 represents a

a hydrogen atom,

R23 represents a

a hydrogen atom,

-(C0-C2-alkylene-O-R19 where R19 represents a

(a) a hydrogen atom,

b) -(C1-C4)-alkyl, where alkyl is unsubstituted or monogamist R13,

-(C0-C4-alkylen-C(O)-R11,

-(C0-C4-alkylen-C(O)-O-R11,

R11 and R12 independently of the other the other are equal or different and represent

a hydrogen atom,

-(C1-C4)-alkyl,

-O-R17or

R13 represents-C(O)-O-R10,

R10and R20represent, independently from each other hydrogen, -(C1-C6)-alkyl, R17 represents -(C1-C6)-alkyl.

7. The compound of formula I according to claim 1,

where R0represents a

pyridyl or benzothiophene, or

heterocyclyl selected from isoxazolyl where specified heterocyclyl is substituted by a residue selected from tanila, 2-tanila and 3-tanila, where the specified residue is monogamist R8,

R8 represents F, Cl, Br,

substructure D is a residue selected from pyridyl, substituted 1 group R23 or exography,

Q represents-CH2-C(O)-NH or methylene,

R1represents a hydrogen atom,

R2represents a direct bond,

V represents piperidine, where the piperidine is unsubstituted,

G represents a direct link,

M represents a hydrogen atom, (C2-C4)-alkyl, where alkyl is unsubstituted,

R3 represents a

a hydrogen atom,

R11 and R12 independently of one another are identical or different and represent the th

a hydrogen atom or

-(C1-C4)-alkyl,

R13 represents-C(O)-O-R10,

R10and R20represent, independently from each other hydrogen, -(C1-C4)-alkyl.

8. The compound of formula I according to claim 1, where the compound of formula I is a

(1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid,

methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid,

1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid,

2-[(1-isopropylpiperazine-4-yl)amide]5-amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-2,5-dicarboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid,

1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(1-isopropylpiperazine-4-ylcarbonyl)-1H-pyrrolo[3,2-b]pyridine-5-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-oxo-4,5-dihydro-1H-pyrrolo[3,2-b]piperidine-2-carboxylic acid,

methyl ester 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(3,4,5,6-Tetra the DRO-2H-[1,4']bipyridinyl-4-ylcarbonyl)-1H-pyrrolo[3,2-b]pyridine-5-carboxylic acid,

1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-2-(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-ylcarbonyl)-1H-pyrrolo[3,2-b]pyridine-5-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-(2-methoxyethoxy)-1H-pyrrolo[2,3-C]pyridine-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[5-(5-chlorothiophene-2-yl)isoxazol-3-ylmethyl]-5-(2-hydroxyethoxy)-1H-pyrrolo[2,3-C]pyridine-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-5-(2-methoxyethoxy)-1H-pyrrolo[2,3-C]pyridine-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[(5-chloropyridin-2-ylcarbonyl)methyl]-5-(2-hydroxyethoxy)-1H-pyrrolo[2,3-C]pyridine-2-carboxylic acid,

(1-isopropylpiperazine-4-yl)amide 1-[(6-chlorobenzo[b]thiophene-2-ylmethyl)-5-(2-methoxyethoxy)-1H-pyrrolo[2,3-C]pyridine-2-carboxylic acid, or

(1-isopropylpiperazine-4-yl)amide 1-[(6-chlorobenzo[b]thiophene-2-ylmethyl)-5-(2-hydroxyethoxy)-1H-pyrrolo[2,3-C]pyridine-2-carboxylic acid.

9. The method of obtaining the compounds of formula I according to any one of claims 1 to 8, which involves the condensation of the compounds of formula 29 with the compound of the formula HR8'obtaining the compounds of formula 30

where the remainder R8'has a value of-N(R1)-R2-V-G-M, where R1,R2,V,G and M have the values, as specified in claims 1 to 8, the remainder R54means the group-Q-R0or hydrogen, and where the group-C(O)-R53can be a carboxylic acid group or its ester, and the group R3ain formulas 29 and 30 have corresponding definitions R3in the formula I, as defined in claim 1 and the functional groups not participating in the reaction can, if necessary, be protected, and if the resulting connection R54means N, transform it in connection with the group-Q-R0; with removal if necessary, the protective groups.

10. The drug that has the property of an inhibitor of factor XA, comprising an effective amount of at least one of the compounds of formula I according to any one of claims 1 to 8 or its physiologically acceptable salt and a pharmaceutically acceptable carrier.

11. The use of the compounds of formula I according to any one of claims 1 to 8 and/or its physiologically acceptable salts for the manufacture of medicines that have the property of an inhibitor of factor XA.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention concerns new enantiomers of (+)-and(-)-trans-2,3,4,4a,5,9b-hexahydro-2,8-dimethyl-1H-pyrido[4,3-b]indol and method of its obtaining. Being optical antipodes for each other, enantiomers exhibit different biological activity and can be applied as an active component in pharmaceutical compositions of nootropic and sedative action for treatment of different individual status of patients.

EFFECT: obtaining of the claimed compound.

1 ex, 5 tbl, 5 cl

FIELD: chemistry.

SUBSTANCE: invention concerns pyrido[2,3-b]pyrazine derivatives of the general formula I where R1 and R2 are hydrogen, unsubstituted C1-C8 alkyl or substituted with hydroxy-, alkoxy-, nitro- or CO2-alkyl, aryl, heteroaryl selected out of the group of pyrinidile or benzodioxalyl, independently from each other; R4 is hydrogen, R3 is a NR9R10 group where R9 is hydrogen and R10 is a -C(Y)NR11R12 group where Y is O or S and R11 is hydrogen, R12 is an alkyl, alkenyl, alkinyl, cycloalkyl, aryl, possibly substituted by a haloid nitro-, trifluormethyl, alkyl, substituted aryl or heterocyclyl selected out of the group of furanyl or morpholinyl, alkyl or their salts endurable physiologically, their solvates, hydrates and polymorphous forms, where the mentioned compounds can be in the forms of theirs racemates, pure enantiomers and/or diastereomers, or anatiomer and/or diastereomer mixes, or tautomers. The invention also describes a medicine based on the compounds, a method of the medicine obtaining, and application of the medicine in treatment of diseases or abnormalities caused by misdirected cellular signal transduction processes.

EFFECT: possible application in cancer treatment.

12 cl, 2 tbl, 38 ex

FIELD: chemistry.

SUBSTANCE: invention concerns a new 1-(3,4-diethoxyphenyl)-2,3,5,6-tetrahydro-(3,4-diethoxybenzo)[g]quinoxalino[2,3-b]indolisine hudrochloride of the formula: which exhibits direct anticoagulation effect and credibly prolongs coagulation time for nitrate blood and coagulability change rate in the concentration of 1 mg/ml at 36.5%. LD50 for intraperitoneal introduction to white mice comprised 355.0 (310.0÷410.0) mg/kg. T"пл" 160-161°C (isopropanol).

EFFECT: obtaining of the claimed compound.

1 tbl

FIELD: chemistry.

SUBSTANCE: invention concerns malonamide derivatives of the formulae (IA) or (IB) , and pharmaceutically acceptable acid additive salts of them, where R1, R1',(R2)1,2,3, R3, R4, R14, L, and are such as described in this invention. Also the invention concerns a medicine with inhibition effect on γ-secretase, which can be applied in treatment of Alzheimer's disease.

EFFECT: obtaining new malonamide derivatives with beneficial biological properties.

17 cl, 188 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to compounds with general formulae (I) and (II) and their pharmaceutical salts, their use as inhibitors of HIV-integrase and to pharmaceutical salts based on them. In formula (I) , R1 represents H or NR2R5; R2 represents CH3; R5 represents 1) C(O)CH2SO2CH3, 2) C(O)C(O)N(CH3)2, 3) SO2N(CH3)2 or 4) SO2R20 where R20 represents , , or ; or alternatively, R2 and R5 together with a nitrogen atom, to which they are bonded, form or , R3 represents hydrogen; R4 represents 1) n-fluorobenzyl, 2) 4-fluro-3-methylbenzyl, 3) 3-chlorobenzyl or 4) 3-chloro-4-methylbenzyl; R12 and R14 both represent H, except that, when R5 represents C(O)C(O)N(CH3)2 and R4 represents n-fluorobenzyl, and n equals 1, then R12 and R14 both represent H, or both represent CH3; and n is an integer, equal to 0, 1 or 2.

EFFECT: compounds can be used for treating HIV-infection.

12 cl, 5 dwg, 1 tbl, 8 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to application as ligands of 5-NT6 receptor azaheterocyclic compositions of general formula 1 or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and/or hydrates , where R2 and R3 independently represent substitute of amides chosen from hydrogen; substituted carbonyl; substituted aminocarbonyl; substituted aminothiocarbonyl; substituted sulphonyl; C1-C5-alkyl, optionally substituted with C6-C10-aryl, optionally substituted with heterocyclil, C6-C10-arylaminocarbonyl, C6-C10- arylaminothiocarbonyl, C5-C10-azaheteroaryl, optionally substituted with carboxyl, nitrile group; optionally substituted with aryl; R1k are 1 to 3 independent substitutes to cyclic system chosen from hydrogen, optionally substituted C1-C5-alkyl, C1-C5-alkyloxy, C1-C5-alkenyl, C1-C5- alkenyl, halogen, trifluoromathyl, nitrile, carboxyl, optionally substituted heterocyclil, substituted sulphonyl, optionally substituted carboxyl; dashed line with accompanying continuous line () corresponds to single or double bond; n=1.2 or 3. Invention also concerns a pharmaceutical formulation, production method and tabletted, capsulated or injection medical product in pharmaceutically acceptable package.

EFFECT: agent has improved efficiency.

17 cl, 8 tbl, 5 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to producing the novel compounds with dipeptidyl peptidase IV (DPP-IV) inhibiting activity and particularly, it relates to the compounds with the condensed 1,3-dihydroimidazole cycle. The invention relates to the compounds represented by the common formula (II), or their pharmaceutically acceptable salts, where, Z3a means nitrogen atom or the group with formula -CR2a=; X3a means oxygen atom or sulfur atom; T1a means piperazine-1-yl group, 3-amino-piperidine-1-yl group, 3-methylamino-piperidine-1-yl group; X1a means oxygen atom hydrogen, C2-6-alkenyl group, C2-6-alkynyl group or benzyl group; each of R1a and R2a independently means hydrogen atom, halogenatom, C1-6-alkyl group, cyanogroup or group, represented with formula-A0a-A1a; A0a means oxygen atom, sulfur atom or group, represented with formula-NA2a-; Ala means hydrogen atom, C1-6-alkyl group, C1-6-alkenyl group, C2-6-alkynyl group, phenyl group, cyanophenyl group, carbamoylphenyl group, benzyl group; A2a means hydrogen atom or C1-6-alkyl group; X2a means hydrogen atom, C2-6-alkenyl group, C2-6-alkynyl group, 1H-piridine-2-onyl group, 1-methyl-1H-piridine-2-onyl group, C1-6-alkyl group, which can have a group, selected from the substitutes group specified below B, phenyl group, which can have a group, selected from the substitutes group specified below B, 5- or 6-membered heteroarylgroup, containing one or two nitrogen atoms, oxygen or sulfur, which can have a group, selected from the substitutes group specified below B, phenylC1-6-alkyl group, which can have a group, selected from the substitutes group specified below B: <Substitutes group B> substitutes group B is group, including chlorine atom, bromine atom; cyanogroup, C1-b-alkyl group, C2-b-alkenyl group, C2-6-alkynyl group, C3-8-cycloalkyl group, C1-6alcoxigroup, carbamoyl groupcarboxyl group and C1-6-alcoxicarbonyl group.

EFFECT: research and revealing compounds with DPP-IV inhibiting activity, useful as pharmaceutical agents which can be used as therapeutic and preventing medicines in such diseases as diabetes, obesity and hyperlipidemia.

12 cl, 84 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the novel compounds with the formula (I) or their pharmaceutically or veterinary-acceptable salts: where: R1 and R3 independently represent H; F; Cl; Br; C1-C6alkyl; R2 represents H or C3-C7cycloalkyl; Y represents -S- or -N(R5)-, where R5 represents H; X represents the bind; R4 represents -C(=O)NR6R7, where R6 represents H or radical of formula -(Alk)b-Q, where b is equal to 0 or 1, and Alk is not necessarily substituted with C1-C6alkyl, C1-C6alkoxi, F, Cl, Br, oxo, COOH, bivalent C1-C12alkylen, C2-C12alkenylen with direct or ramified chain, which can be disconnected with one ore several non-adjacent -O-, -S- or -N(R8)-, where R8 represents H or C1-C4alkyl, C3-C4alkenyl or C3-C6cycloalkyl, and Q represents H; -SH; -NR8R8, where each R8 can be similar or different; the complex ether group; or not necessarily substituted with C1-C6alkyl, C1-C6alkoxi, phenyl, benzyl, phenoxy, C3-C8cycloalkyl, amino, fluor, bromine, oxo, -COOH, -CORA, -COORA, NHRA, -NRARB, where RA and RB are independent (C1-C6)alkyl group, phenyl, C3-C7cycloalkyl, C5-C7cycloalkenyl or heterocyclilc ring containing 5 to 8 ring atoms; and R7 represents H or C1-C6alkyl; or, taken together with atom or atoms, they are bound with, R6 and R7 form not necessarily substituted with (C1-C6)alkyl, COORA, where RA is the (C1-C6)alkyl group, phenyl, not necessarily substituted with F, Cl, Br, heterocyclilc ring containing 5 to 8 ring atoms. The invention also relates to N-(3-dimethylaminopropyl)-4-(4-cyclopropyl-3-oxo-3,5-dihydropirazol[4,3-c]quinoline-2-il]benzamide; to application of the compounds; to the immunomodulation method and to the pharmaceutical and veterinary composition.

EFFECT: production of novel immunobiologic compounds.

14 cl, 173 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the novel substituted indoline phemylsulfamide derivatives with the common formula , where A means C-R11 group or nitrogen, and R11 means hydrogen or alkyl with 1-4 carbon atoms, X means oxygen, R1 means aryl with 6-10 carbon atoms, unsubstituted or once-triple substituted with the similar or different substitutes, selected from the group which includes halogen, zyano, alkyl with 1-6 carbon atoms, alkoxi with 1-6 carbon atoms, phenoxi, benziloxi, trifluoromethyl, trifluorometoxi, alkenil with 2-6 carbon atoms, phenyl, alkylthio with 1-6 carbon atoms, mono- and dialkylamino with 1-6 carbon atoms in each alkyl group, or means the group with formula , R2 and R3 similar or different and independently from each other mean hydrogen or alkyl with 1-6 carbon atoms, or with the carbon atom they are bound to form the 3-7-membered spiro-compound cycloalkylic ring, R4 means hydrogen or alkyl with 1-6 carbon atoms, R5 R4 means hydrogen or alkyl with 1-6 carbon atoms, R6 means hydrogen or alkyl with 1-6 carbon atoms, R7 means hydrogen, alkyl with 1-6 carbon atoms, R8 - R10 mean hydrogen; as well as to their pharmaceutically compatible salts.

EFFECT: compounds are designated for prevention and/or treatment of cardio-vascular diseases, particularly dislipidemia and ischemic heart disease.

4 cl, 1 dwg, 96 ex

FIELD: chemistry; medicine.

SUBSTANCE: invention pertains to derivatives of 7-phenylpyrazolopyridine with formula (I) ,where R1, R5, R6, R40, R41 and R42 represent different hydrocarbon substitutes or functional groups, its salts or hydrates, and especially to salts of N-cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyradin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine. The compound with formula (I), especially salts of N-cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyradin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine, act as antagonists of the receptor of corticotrophin release factor and can be used in medicine for treating various diseases of the nervous system and the gastrointestinal tract.

EFFECT: obtaining of new biologically active substances.

162 ex, 5 tbl

FIELD: chemistry.

SUBSTANCE: invention concerns a new 1-(3,4-diethoxyphenyl)-2,3,5,6-tetrahydro-(3,4-diethoxybenzo)[g]quinoxalino[2,3-b]indolisine hudrochloride of the formula: which exhibits direct anticoagulation effect and credibly prolongs coagulation time for nitrate blood and coagulability change rate in the concentration of 1 mg/ml at 36.5%. LD50 for intraperitoneal introduction to white mice comprised 355.0 (310.0÷410.0) mg/kg. T"пл" 160-161°C (isopropanol).

EFFECT: obtaining of the claimed compound.

1 tbl

FIELD: medicine; cardiology.

SUBSTANCE: individually prescribed low-calorie diet, reasonably graduated static and dynamic physical activities, and introduction of Metformin in dosage 500 mg 2 times a day after meal and Lisinopril in dosage 10 mg once a day within 8 months are applied.

EFFECT: method provides stable normalisation of thromboplastin formation.

1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: tricyclic bonds are substituted with heterocyclic ones, which have the formula (I), or its pharmaceutically acceptable salt or solvate in which: n denotes 0-2; Q denotes , R1 denotes H, R2 represents H or alkyl with 1-6 carbon atoms, R3 represents H, hydroxy-group, -NR22R23, Het denotes mono- or bycyclic heteroaryl group from 5 - 10 atoms, containing from 1 to 9 carbon atoms and 1 heteroatom N, where Het bonds with B through the cyclic carbon atom, and the group Het has a substitute W. W consists of from 1 to 4 substitutes, independently selected from the group containing H, halogen, R21-aryl and P21-heteroaryl, R4 and R5 are independently selected from the group containing H and alkyl with 1 - 6 carbon atoms, R7, R8, R10 and R11 denote R1, R9 represent H, B represents -(CH2)n3-. cis- or trans -(CH2)n4CR12=CR12a(CH2)n5 or -(CH2)n4C=C(CH2)n5, where n3 denotes 0-5, n4 and n5 independently denote 0-2, and R12 and R12a denote H, X represents -O-, Y represents =O, each R13 is independently selected from the group containing H, alkyl with 1-6 carbon atoms, -(CH2)n6NHC(O)OR16b, -(CH2)n6NHC(O)R16b, -(CH2)n6NHC(O)NR4R5, -(CH2)n6NHSO2R16, and -(CH2)n6C(O)NR28R29, where n6 denotes 0, each R14 is independently selected from the group containing H, alkyl with 1-6 carbon atoms, -(CH2)n6NHC(O)OR16b, -(CH2)n6NHC(O)R16b, -(CH2)n6NHC(O)NR4R5, -(CH2)n6NHSO2R16 and -(CH2)n6C(O)NR28R29, where n6 denotes 0, where, at least one of R13 and R14 is chosen from the group containing -(CH2)n6NHC(O)OR16b, -(CH2)n6NHC(O)R16b, -(CH2)n6NHC(O)NR4R5, -(CH2)n6NHSO2R16 and -(CH2)n6C(O)NR28R29, where n6 denotes 0, R16 represents an alkyl with 1-6 carbon atoms, R16b represents H, an alkyl with 1-6 carbonatoms, (an alkoxy with 1-6 carbon atoms)-(an alkyl with 1 - 6 carbon atoms)-, R22-O-C(O)-(an alkyl with 1 - 6 carbon atoms)-, a cycloalkyl with 3-6 carbon atoms, R21 represents from 1 to 3 substitutes, which are independently selected from a group comprising of H, -CN, -CF3, halogen, alkyl with 1 - 6 carbon atoms, -OH, alkoxy- group with 1 - 6 carbon atoms, -C(O)NR25R26 and -SR13, R22 represents H or an alkyl with 1-6 carbon atoms, R23 represents H, R25 and R26 are independently selected from a group comprising of H and an alkyl with 1 - 6 carbon atoms, and R28 and R29 are independently selected from a group comprising of H, an alkyl with 1 - 6 carbon atoms, heteroaryl, heterocyclil and also a pharmaceutical composition, containing these bonds.

EFFECT: application for getting medication for the treatment of diseases related to thrombosis, atherosclerosis, restenosis, hypertension, sternocardia, arrythmia, cardiac insufficiency and cancer, the way of administering is specified in the bonds Also therapy in combination with other cardiovascular agents is allowed.

23 cl, 7 tbl, 92 ex

FIELD: medicine.

SUBSTANCE: invention refers to biochemistry and medicine, namely to method of production of capture physiologically active substances, specifically blood anticoagulants used for prevention and treatment of thromboses, thrombophlebitis, thromboembolism, thromboembolic complications etc. Method of production of capture physiologically active substances is realised by reaction of physiologically active substance and N- acryloylhygidroxyphthamylide copolymer, of lower critical mixing temperature. Heparin and hirudin are used as physiologically active substance while N-acryloylhygidroxyphthamylide copolymer is copolymer of 1-5% mole N-acryloylhygidroxyphthamylide, 88-98% mole N- isopropylacrylamide or N,N-diethylacrylamide and 1-7 % mole acrylamide of molecular weight 8900-18000.

EFFECT: method provides possibility to produce polymeric derivatives of blood anticoagulants of lowered molecular weight.

24 ex, 3 tbl, 1 dwg

FIELD: medicine.

SUBSTANCE: beforehand system is introduced with heparin in amount 5 thousand UN/50 ml of physiologic saline. Blood is sampled at rate 25 ml per minute. Blood is irradiated in dish within 15-20 minutes. Then blood is dosed with heparin in amount 10 thousand UN/9 ml of physiologic saline during the whole period of blood return.

EFFECT: thrombosis and system occlusion prevention.

2 cl, 1 ex

FIELD: medicine.

SUBSTANCE: offered pharmaceutical formulation with anticoagulative and antiaggregatory action contains sodium heparin as reactant and carbomers 940 or 980, trisamine, lavender oil, neroli oil and water as adjuvants taken in specific proportions. Pharmaceutical formulation has gel consistency. Method of production of offered formulation includes sodium heparin aqueous solution, nypagin solution, ethanol solution of lavender and neroli oil, and trisamine sequentially added to water-dispersed carbomers.

EFFECT: new formulation is characterised by high pharmaceutical activity; does not have by-effects; stable for keeping; has optimal viscosity and applicable organoleptic property.

4 cl, 1 tbl, 3 ex

FIELD: medicine; pharmacology.

SUBSTANCE: this invention describes new crystal forms of tryazol[4,5-d]pyrimidine formula I , composition methods and based pharmaceutical formulations. Compounds develop high efficiency as antagonist P2T, can be applied for medical prevention and treatment of arterial thrombotic complication, as well as tumour growth and extension.

EFFECT: compounds show high metabolic stability and bioavailability.

22 cl, 5 ex, 6 dwg

FIELD: medicine.

SUBSTANCE: invention concerns glycoforms of VII factor and compositions of VII factor, characterized by modified configurations on basis of asparaginic oligosaccharide chains. In addition invention includes detection method applied for polypeptide glycoforms of VII factor, receiving method and disease treatment method as well.

EFFECT: identification of biologically active forms of recombinant VII factor.

53 cl, 5ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes a pharmaceutical composition possessing the fibrinolytic effect and comprising as an active substance a modified activator of plasminogen of urokinase type mAPUT22, mannitol and sodium chloride taken in the following ratio of components, wt.-%: mAPUT22, 2.8-4.2; mannitol, 31.1-38.8, and sodium chloride, up to 100. This pharmaceutical composition can be used in neurosurgery in treatment of intracranial hematomas arising in hemorrhagic insults. The composition possesses high specific fibrinolytic activity and doesn't cause dangerous adverse effects in removing intracranial hematomas.

EFFECT: valuable medicinal properties of pharmaceutical composition.

2 cl, 8 tbl, 6 dwg, 3 ex

FIELD: chemical-pharmaceutical industry.

SUBSTANCE: invention proposes a butylphthalide-containing soft capsule consisting of capsule wall and oil containing a drug wherein indicated oil consists of mainly butylphthalide and vegetable oil taken in the ratio about 1:10, not above. Material of capsule wall consists of mainly a base, plasticizing agent and water taken in the ratio about = 1:(0.2-0.4):(0.8-1.3), respectively. Soft gel capsules masks strong and specific odor of butylphthalide and solve problems associated with preparing oily active agents for oral using.

EFFECT: improved and valuable properties of capsules.

15 cl, 4 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new enantiomers of (+)-and(-)-trans-2,3,4,4a,5,9b-hexahydro-2,8-dimethyl-1H-pyrido[4,3-b]indol and method of its obtaining. Being optical antipodes for each other, enantiomers exhibit different biological activity and can be applied as an active component in pharmaceutical compositions of nootropic and sedative action for treatment of different individual status of patients.

EFFECT: obtaining of the claimed compound.

1 ex, 5 tbl, 5 cl

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