Isoserine derivatives applied as blood coagulation factor ixa inhibitors


FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula I

and/or to all isomer forms of a compound of formula I and/or to mixtures of these forms in any proportions, and/or to physiologically acceptable salts of the compound of formula I, wherein R1 represents 1) -(C6-C14)-aryl-Z, wherein Z represents aminomethylene, 2) Het-Z, wherein Z represents amino group, and wherein Het is unsubstituted or additionally monosubstituted by group T, R2 represents 1) -(C0)-alkylene-(C6-C14)aryl, wherein aryl is unsubstituted or mono- or disubstituted by group T or 2) -(C0)-alkylene-Het, wherein Het is unsubstituted or monosubstituted by group T, R3 represents 1) -(C0)-alkylene-(C6-C14)-aryl, wherein aryl is unsubstituted or mono- or disubstituted by group T, 2) -O-(C6-C14)-alkylene(C6-C14)-aryl, wherein aryl is unsubstituted or monosubstituted by group T, 3) -(C0)-alkylene-Het, wherein Het is unsubstituted or mono-, di- or trisubstituted by group T, 4) -(C0)-alkylene-(C6-C14)-aryl-Q-(C6-C14)-aryl, wherein both aryl radicals are unsubstituted, 5) -(C0)-alkylene-(C6-C14)-aryl-Q)-Het, wherein aryl and Het in each case are independently unsubstituted or disubstituted by group T, 6) -(C0)-alkylene-Het-Q-Het, wherein both radicals Het are unsubstituted, Q represents a covalent bond, -(C1-C4)-alkylene, -N((C1-C4)-alkyl)- or -O-, T represents 1) halogen, 2) -(C1-C6)-alkyl, wherein alkyl is unsubstituted disubstituted by group -(C1-C3)-fluoralkyl or -N-C(O)-(C1-C4)-alkyl, 3) -(C1-C3)-fluoralkyl, 4) -(C3-C8)-cycloalkyl, 5) -O-(C1-C4)-alkyl, 6) -O-(C1-C3)-fluoralkyl, 7) -N(R10)(R11), wherein R(10) and R(11) independently represent hydrogen atom or -(C1-C6)-alkyl, 8) -C(O)-NH-R10, 9) -SO2-(C1-C4)-alkyl, 10) -SO2-(C1-C3)-fluoralkyl, R4 and R5 are identical and represent hydrogen atom, and R6 represent hydrogen atom with said Het being 5-10-member ring system consisting of 1 or 2 coupled ring systems, and wherein one or two identical or different heteroatoms are selected from oxygen, nitrogen and sulphur. Also, the invention refers to the use of the compound of formula I for preparing a drug.

EFFECT: there are prepared new compounds exhibiting antithrombotic activity, which particularly inhibit blood coagulation factor lXa.

6 cl, 2 tbl, 9 ex

 

The present invention relates to new compounds of formula I, having antithrombotic activity, which, in particular, inhibit the coagulation factor IXa, to methods for their preparation and to their use as pharmaceuticals.

Blood clotting is a process control flow of blood, which is essential for the survival of mammals. The process of blood clotting and the subsequent dissolution of the clot after wound healing takes place immediately after vascular damage, and it can be divided into four phases:

1. Phase of vasoconstriction or narrowing of blood vessels: through loss of blood in the affected area is reduced.

2. The next phase is the activation of platelets by thrombin. Platelets attach to the injury of the vessel wall and form a unit of platelets. Protein fibrinogen is responsible for binding to platelets by appropriate surface receptors. Platelets are also linked with the available collagen extracellular matrix of the damaged walls of the vessel, and due to this their activation. After activation, platelets are secreted various substances-the messengers, which induce the activation of other platelets. At the same time, membrane lipid, phosphatidylserine, transported and the inside of the membrane of platelets on the outer side, where can accumulate complexes of coagulation factors. Platelets accelerate the clotting of blood through such a mechanism.

3. The formation of such complexes clotting factors leads to a massive formation of thrombin, which converts soluble fibrinogen into fibrin by the removal of two small peptides. Fibrin monomers spontaneously form a filamentary chain, of which, after cross-linking by coagulation factor XIII protein formed a stable structure. Initially even more free unit of platelets will stabilize this structure of fibrin; aggregates of platelets and structure of fibrin are the two essential components of a blood clot.

4. After healing wounds clot dissolves under the action of the key enzyme of endogenous system of fibrinolysis, plasmin.

Two alternative paths can lead to the formation of a fibrin clot, the internal and the external path. These pathways are triggered by different mechanisms, but in a later phase they converge with the formation of a common target path of the cascade of blood coagulation. To this end the path of blood coagulation is the activation of coagulation factor X. Activated factor X is responsible for the formation of thrombin from the inactive precursor of prothrombin, the CID is wirausaha in the blood. A blood clot at the base of the abnormality of the vessel wall in the absence of damage to the vessel is the result of an inner path. The formation of a fibrin clot in response to tissue damage or injury is the result of external paths. Both paths include a relatively large number of proteins, which are known as blood clotting factors.

For the inner journey the necessary coagulation factors V, VIII, IX, X, XI and XII, as well as prekallikrein, high kininogen, calcium ions and phospholipids of platelets.

Initiation inner path occurs when prekallikrein, high kininogen, factor XI and XII contact with a negatively charged surface. This time is designated as the contact phase. Availability for exposure of collagen in the walls of blood vessels is the main stimulus of the contact phase. The result of the processes of the contact phase is the transformation prekallikrein in kallickrein, which, in turn, activates factor XII. Under the influence of factor XIIa is further hydrolysis prekallikrein to kallikrein, resulting in activation. With increased activation of factor XII activates factor XI, which leads to the release of bradykinin, vasodilator. The result is the completion of the initial phase of vasoconstriction. Bradic the NIN is formed of high-molecular-weight kininogen. In the presence of ions of Ca2+factor XIa activates factor IX. Factor IX is a proferment, which contains vitamin K-dependent γ remains-carboxyglutamic acid (GLA). The activity of serine protease becomes noticeable after binding of Ca2+these GLA residues. Various serine protease cascade coagulation (factors II, VII, IX and X) contain vitamin K-dependent GLA residues. Factor IXa cleaves factor X and leads to activation of factor Xa. A necessary condition for the formation of the factor IXa is the formation of a complex of tenaz of Ca2+and factor VIIIa, IXa and X on the surface of activated platelets. One of the reactions of activated platelets is the presentation of phosphatidylserine and phosphatidylinositol on surfaces. The exposure of these phospholipids, above all, makes possible the formation of the complex of tenaz. Factor VIII in this way has the function of the receptor for factors IXa and X. Factor VIII therefore represents a cofactor in the cascade of blood coagulation. For activation of factor VIII with the formation of factor VIIIa, the actual receptor, requires only a minimal amount of thrombin. With increasing concentration of thrombin factor VIIIa, in the end, then cleaved and inactivated by thrombin. This dual action of thrombin in relation to factor VIII leads to with whom neogranichenniy education complex tenasi and thus, to limit blood clotting.

For external paths required tissue factor (TF) and coagulation factors V, VII, VIII, IX and X. In the case of damage to the vessel tissue factor (TF) is accumulated with coagulation factor VII and the activation of the latter. The complex of TF and coagulation factor VII have two of the substrate, the coagulation factors X and IX.

The coagulation factor IX can be activated through an inner path and the outer path. Activation of factor IXa, thus, provides a Central point of intersection between the two pathways of activation of blood coagulation.

Factor IXa plays an important role in blood coagulation. The lack of factor IXa causes hemophilia B, whereas higher concentrations of factor IXa in the blood lead to a significantly increased risk of formation of thrombosis (Weltermann A, et al., J Thromb Haemost. 2003; 1: 28-32). Regulation of the activity of factor IXa can reduce thrombus formation in animal models (Feuerstein GZ, et al., Thromb Haemost. 1999; 82: 1443-1445).

The compounds of formula I of the present invention are suitable for prophylactic and therapeutic injection of the person suffering from diseases accompanying thrombosis, embolism, the ability to hypercoagulability or fibrotic changes. They can be used for secondary prevention, and they are suitable for neotlojnoi, and for long-term therapy.

The present invention therefore relates to the compound of formula I

and/or all stereoisomeric forms of the compounds of formula I and/or mixtures of these forms in any ratio, and/or physiologically acceptable salts of the compounds of formula I, where

R1 represents

1) -(C6-C14)-aryl-Z, where Z is a basic nitrogen-containing group, and where the aryl is unsubstituted or mono-, di - or tizamidine group T,

2) -(C3-C12-cycloalkyl-Z, where Z is a basic nitrogen-containing group, and where cycloalkyl is unsubstituted or optionally mono-, di - or tizamidine group T,

3) four-pjatnadtsatiletny Het-Z, where Z is a basic nitrogen-containing group, and where Het is unsubstituted or optionally mono-, di - or tizamidine group T,

R2 represents

1) -(C0-C4-alkylene-(C6-C14)-aryl, where aryl is unsubstituted or mono-, di - or tizamidine group T,

2) -(C0-C4-alkylene-(C3-C8-cycloalkyl where cycloalkyl is unsubstituted or mono-, di - or tizamidine group T, or

3) -(C0-C4-alkylene-Het where Het is unsubstituted or mono-, di - or tizamidine group T,

R3 represents a

1) (C 0-C4-alkylene-(C6-C14)-aryl, where aryl is unsubstituted or mono-, di - or tizamidine group T,

2) -O-(C1-C4-alkylene-(C6-C14)-aryl, where aryl is unsubstituted or mono-, di - or tizamidine group T,

3) -(C0-C4-alkylene-Het where Het is unsubstituted or mono-, di - or tizamidine group T,

4) -O-(C1-C4-alkylene-Het where Het is unsubstituted or mono-, di - or tizamidine group T,

5) -(C0-C4-alkylene-(C6-C14)-aryl-Q-(C6-C14)-aryl, where two aryl radicals in each case independently of one another are unsubstituted or mono-, di - or tizamidine group T,

6) -(C0-C4-alkylene-(C6-C14)-aryl-Q-(C3-C12-cycloalkyl, where aryl and cycloalkyl in each case independently of one another are unsubstituted or mono-, di - or tizamidine group T,

7) -(C0-C4-alkylene-(C6-C14)-aryl-Q-Het, where aryl and Het in each case independently of one another are unsubstituted or mono-, di - or tizamidine group T,

8) -(C0-C4-alkylene-Het-Q-(C6-C14)-aryl, where aryl and Het in each case independently of one another are unsubstituted or mono-, di - or tizamidine group T, or

9) -(C0-C4-alkylene-Het-Q-Het, where the two radical Het, in each case independently of one another are unsubstituted or mono-, di - or tizamidine group T,

10) -N(R5)-(C1-C4-alkylene-(C6-C14)-aryl, where aryl is unsubstituted or mono-, di - or tizamidine group T, or

11) -N(R5)-(C1-C4-alkylene-Het where Het is unsubstituted or mono-, di - or tizamidine group T,

Q is a covalent bond, -(C1-C4-alkylene, -NH-, -N((C1-C4)-alkyl)-, -O-, -S-, or-SO2-,

T is a

1) halogen,

2) -(C1-C6)-alkyl, where alkyl is unsubstituted or mono -, di - or tizamidine group -(C1-C3-foralkyl, -N-C(O)-OH or-N-C(O)-(C1-C4)-alkyl,

3) -(C1-C3-foralkyl,

4) -(C3-C8-cycloalkyl,

5) -OH,

6) -O-(C1-C4)-alkyl,

7) -O-(C1-C3-foralkyl,

8) -NO2,

9) -CN,

10) -N(R10)(R11), where R10 and R11 independently from each other represent a hydrogen atom, -(C3-C8-cycloalkyl, halogen or -(C1-C6)-alkyl,

11) -C(O)-NH-R10,

12) -NH-C(O)-R10,

13) -NH-SO2R10,

14) -SO2-(C1-C4)-alkyl,

15) -SO2-NH-R10,

16) -SO2-(C1-C3-foralkyl,

17) -S-(C1-C4)-alkyl or

18) -S-(C1-C3-foralkyl,

R4 and R5 are the same or different from each other and independently from each other represent a hydrogen atom or -(C1 4)-alkyl, and

R6 represents a hydrogen atom, -C(O)-R12, -C(O)-O-R12, -C(O)-NH-R12, or -(C1-C4)-alkyl, where

R12 represents -(C1-C6)-alkyl, -(C3-C8-cycloalkyl, -(C6-C14)-aryl or Het.

The present invention also relates to the compound of formula I, and/or all stereoisomeric forms of the compounds of formula I and/or mixtures of these forms in any ratio, and/or physiologically acceptable salts of the compounds of formula I, where

R1 represents

1) -(C6-C14)-aryl-Z -, where aryl is selected from the group consisting of phenyl and naphthyl, and where aryl is unsubstituted or mono-, di - or tizamidine group T, and Z represents amino, amidino, aminomethyl, aminopyridines, azetidine, guanidino, piperidinyl, pyridinyl or pyrrolidinyl, or

2) four-pjatnadtsatiletny Het-Z, where Het is selected from the group consisting of acridine, azepine, azetidine, benzimidazolinyl, benzimidazolyl, benzofuranyl, benzothiophene, benzothiophene, benzoxazole, benzothiazole, benzotriazole, benzonitrile, benzisoxazole, benzisothiazole, carbazolyl, 4aH-carbazolyl, carboline, beta carboline, heatline, chinoline, chinoiserie, 4H-chinoiserie, khinoksalinona, hinokitiol, Romania, chromene, cinnoline, DECA-hydroxynonenal, dibenzofurane, is benzothiophene, dihydrofuro[2,3-b]-tetrahydrofuranyl, dihydrofurane, dioxole, dioxane, dioxolane, 2H, 6H-1,5,2-detainee, furanyl, furazane, imidazolidinyl, imidazolyl, imidazolyl, 1H-indazole, indoline, indolizine, indolyl, 3H-indolyl, isobenzofuranyl, izochinolina, isopropanyl, isoindolyl, isoindoline, isoindolyl, isothiazoline, 2-isothiazoline, isothiazoline, isoxazole, isoxazolidine, 2-isoxazoline, morpholine, naphthyridine, octahydronaphthalene, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, oxathiolane, phenanthridine, phenanthrene, phenanthroline, phenazine, phenothiazine, femoxetine, phenoxazine, phthalazine, piperazinil, piperidinyl, pteridinyl, purinol, pyranyl, pyrazinyl, pyrazolidine, pyrazoline, pyrazolyl, pyridazinyl, paradoxically, predominately, peridotite, peridotite, pyridyl, pyrimidinyl, pyrrolidinyl, pyrroline, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinoline, tetrahydroquinoline, tetrahydropyridine, 6H-1,2,5-thiadiazine, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrene, teinila, thiazolyl, teinila, tenomodulin, cyanoacetyl, thienopyridine the La, thienopyrrole, tiantianriri, thienothiophene, thiomorpholine, dipiradol, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl or xanterra, and where Het is unsubstituted or mono-, di - or tizamidine group T, and where Z has the meanings given above,

R2 represents

1) -(C0-C4-alkylene-(C6-C14)-aryl, where aryl has the meaning defined above and is unsubstituted or mono-, di - or tizamidine group T,

2) -(C0-C4-alkylene-(C3-C8-cycloalkyl where cycloalkyl is unsubstituted or mono-, di - or tizamidine group T, or

3) -(C0-C4-alkylene-Het, where Het has the meaning defined above and is unsubstituted or mono-, di - or tizamidine group T,

R3 represents a

1) -(C0-C4-alkylene-(C6-C14)-aryl, where aryl has the meaning defined above and is unsubstituted or mono-, di - or tizamidine group T,

2) -(C0-C4-alkylene-Het, where Het has the meaning defined above and is unsubstituted or mono-, di - or tizamidine group T,

3) -(C0-C4-alkylene-(C6-C14)-aryl-Q-(C6-C14)-aryl, where two aryl in each case independently of one another have the meanings given above, and in each case independently from the other are unsubstituted or mono-, di - or tizamidine group T,

4) -(C0-C4-alkylene-(C6-C14)-aryl-Q-(C3-C12-cycloalkyl, where aryl has the meaning given above, and cycloalkyl is unsubstituted or mono-, di - or tizamidine group T,

5) -(C0-C4-alkylene-(C6-C14)-aryl-Q-Het, where aryl and Het have the meanings given above, and in each case independently of one another are unsubstituted or mono-, di - or tizamidine group T,

6) -(C0-C4-alkylene-Het-Q-(C6-C14)-aryl, where aryl and Het have the meanings given above, and in each case independently of one another are unsubstituted or mono-, di - or tizamidine group T, or

7) -(C0-C4-alkylene-Het-Q-Het, where two radicals Het have the meanings given above, and in each case independently of one another are unsubstituted or mono-, di - or tizamidine group T,

Q is a covalent bond, -(C1-C4-alkylene, -NH-, -N((C1-C4)-alkyl)- or-O-,

T is a

1) halogen,

2) -(C1-C6)-alkyl, where alkyl is unsubstituted or is mono-, di - or tizamidine group -(C1-C3-foralkyl, -N-C(O)-OH or-N-C(O)-(C1-C4)-alkyl,

3) -(C1-C3-foralkyl,

4) -(C3-C6-cycloalkyl,

5) -OH,

6) -O-(C -C4)-alkyl,

7) -O-(C1-C3-foralkyl,

8) -NO2,

9) -CN,

10) -N(R10)(R11), where R10 and R11 independently from each other represent a hydrogen atom, -(C3-C6-cycloalkyl, halogen or -(C1-C6)-alkyl,

11) -C(O)-NH-R10,

12) -NH-C(O)-R10,

13) -NH-SO2R10,

14) -SO2-(C1-C4)-alkyl,

15) -SO2-NH-R10,

16) -SO2-(C1-C3-foralkyl,

17) -S-(C1-C4)-alkyl or

18) -S-(C1-C3-foralkyl,

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

R6 represents a hydrogen atom, -C(O)-R12, -C(O)-O-R12, -C(O)-NH-R12, or -(C1-C4)-alkyl, where

R12 represents -(C1-C6)-alkyl, -(C3-C6-cycloalkyl, -(C6-C14)-aryl or Het.

The present invention also relates to the compound of formula I, and/or all stereoisomeric forms of the compounds of formula I and/or mixtures of these forms in any ratio, and/or physiologically acceptable salts of the compounds of formula I, where

R1 represents a 4-benzamidine, aminomethylphenol or Het-Z, where Het is selected from the group consisting of benzimidazolyl, benzothiazolyl and izochinolina, and where Z represents amino,

R2 represents

1) phenyl, where phenyl is unsubstituted who passed or mono - or disubstituted by the group T, or

2) Het-1, Het-1 is selected from the group consisting of furanyl, pyrazolyl or tanila, and Het-1 is unsubstituted or mono - or disubstituted by the group T,

R3 represents a

1) phenyl, where phenyl is unsubstituted or mono - or disubstituted by the group T,

2) Het-2, where Het-2 is selected from the group consisting of benzimidazolyl, benzofuranyl, benzothiophene, chinoline, khinoksalinona, furanyl, indolyl, izochinolina, isoxazolyl, morpholinyl, piperidinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, teinila, thienopyrrole or thienothiophene, and where Het-2 is unsubstituted or mono - or disubstituted by the group T,

3) -phenyl-Q-phenyl, where two phenyl radical in each case independently of one another are unsubstituted or mono - or disubstituted by the group T,

4) phenyl-Q-(C3-C6-cycloalkyl, where phenyl and cycloalkyl in each case independently of one another are unsubstituted or mono - or disubstituted by the group T,

5) phenyl-Q-Het-2, where Het-2 has the meaning defined above, and phenyl and Het-2, in each case independently of one another are unsubstituted or mono - or disubstituted by the group T,

6) Het-2-Q-phenyl, where Het-2 has the meaning defined above, and phenyl and Het-2, in each case independently of one another are unsubstituted or mono - or disubstituted by the group T, or

7) Het-2-Q-Het-2, where the VA radical Het-2 have the meanings defined above are in each case independently of one another are unsubstituted or mono - or disubstituted by the group T,

Q is a covalent bond, -CH2-, -N(CH3)- or-O-,

T is a

1) F, Cl or Br,

2) -(C1-C4)-alkyl, where alkyl is unsubstituted or mono - or disubstituted by the group-CF3or-N-C(O)-CH3,

3) -CF3,

4) -O-(C1-C4)-alkyl,

5) -O-CF3,

6) -NO2,

7) -N(R10)(R11), where R10 and R11 independently from each other represent a hydrogen atom or -(C1-C4)-alkyl,

8) -SO2-CH3,

9) -S-CF3or

10) -S-(C1-C2)-alkyl,

R4, R5 and R6 in each case represent a hydrogen atom.

The term “(C1-C4)-alkyl or(C1-C6)-alkyl” is to be considered as meaning hydrocarbon radicals, the carbon chain which is linear or branched and contains from 1 to 4 or 1 to 6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, 2,3-dimethylbutan or neohexyl.

The term “-(C0-C4-alkylen” should be considered as meaning hydrocarbon radicals, the carbon chain which is linear or branched and contains from 1 to 4 carbon atoms, for example methylene, ethylene, n is cut isopropylene, isobutylene, butylene or tert-butylene. “-C0-Alkylene” represents a covalent bond. The term “-(C1-C4-alkylen” should be considered as meaning hydrocarbon radicals, the carbon chain which is linear or branched and contains from 1 to 4 carbon atoms, such as methylene (-CH2-), ethylene (-CH2-CH2-), propylene (-CH2-CH2-CH2-), isopropylene, isobutylene, butylene or tert-butylene.

The term “-(C3-C12-cycloalkyl” should be considered as meaning ring consisting of 3-12 carbon atoms, such as compounds that are formed from monociclo containing from 3 to 8 carbon atoms in the ring such as cyclopropane, CYCLOBUTANE, cyclopentane, cyclohexane, Cycloheptane or cyclooctane, which is formed from bicyclo bicyclo[4,2,0]octane, octahedrons, decahydronaphthalene, decahydrate, decahydronaphthalene or dodecahydrate, or from the associated bridge communication cycles, such as Spiro[2,5]octane, Spiro[3,4]octane, Spiro[3,5]nonan, bicyclo[3,1,1]heptane, bicyclo[2,2,1]heptane or bicyclo[2,2,2]octane.

The term “-(C3-C6-cycloalkyl or-(C3-C8-cycloalkyl” should be considered as meaning radicals which are formed from monociclo containing from 3 to 6 or 3 to 8 carbon atoms in the ring, that is their as cyclopropane, CYCLOBUTANE, cyclopentane, cyclohexane, cyclo-heptane or cyclooctane.

The term “-(C6-C14)-aryl” should be considered as meaning aromatic hydrocarbon radicals containing from 6 to 14 carbon atoms in the ring. -(C6-C14)-Aryl radicals are, for example, phenyl, naphthyl, for example 1-naphthyl, 2-naphthyl, antrel or fluorenyl. Raftiline radicals and in particular phenyl radicals are preferred aryl radicals.

The term “four-pjatnadtsatiletny Het” or “Het” should be considered as meaning ring systems containing from 4 to 15 carbon atoms, which are present in one, two or three ring systems connected together, and in which one, two, three or four identical or different from each other heteroatoms selected from the group comprising oxygen, nitrogen or sulfur, can replace the corresponding carbon atoms. Examples of such ring systems are radicals acridines, azepine, azetidine, benzimidazolinyl, benzimidazolyl, benzofuranyl, benzothiophene, benzothiophene, benzoxazole, benzothiazole, benzotriazole, betterall, benzisoxazole, benzisothiazole, carbazolyl, 4aH-carbazolyl, carbolines, beta-carbolines, hintline, chinoline, hemolysins, 4H-hemolysins, honokalani, hinokitiol, bromanil,bromanil, cinnoline, DECA-hydroxynonenal, dibenzofurans, dibenzothiophenes, dihydrofuro[2,3-b]-tetrahydrofuranyl, dihydrofurane, dioxole, dioxane, dioxolane, 2H, 6H-1,5,2-detainer, furanyl, furutani, imidazolidinyl, imidazolyl, imidazolyl, 1H-indazole, indoline, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, ethenolysis, isopropanol, isoindolyl, isoindolines, isoindolyl, isothiazoline, 2-isothiazoline, isothiazolin, isoxazolyl, isoxazolidine, 2-isoxazoline, morpholine, naphthyridine, octahydronaphthalene, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, oxathiolane, phenanthridines, phenanthrene, phenanthrolines, phenazines, phenothiazines, phenoxathiin, phenoxazines, phthalazine, piperazinil, piperidinyl, pteridinyl, purinol, pyranyl, pyrazinyl, pyrazolidine, pyrazoline, pyrazolyl, pyridazinyl, paradoxicaly, predominately, peridotites, peridotites, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinoline, tetrahydroquinoline, tetrahydropyridine, 6H-1,2,5-thiadiazine, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrene, triazinyl, thiazolyl, thienyl, tenomodulin, cyanoacetyl, thienopyridines, thienopyrrole, thieno azolyl, thienothiophene, thiomorpholine, tiopronin, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl or xantener.

The term “-(C1-C3-foralkyl” should be considered as meaning partially or fully fluorinated alkyl radical, which is formed, for example, of the following radicals: -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-CH2-CH2F, -CF2-CF2-CF3, -CF2-CF2-CHF2or-CF2-CF2-CH2F.

The term “halogen” is to be considered as meaning fluorine, chlorine, bromine or iodine; fluorine, chlorine or bromine is preferred, in particular the military chlorine or bromine.

The term “basic nitrogen-containing group” should be considered as meaning radicals, where appropriate this group acid has a pKa from about 5 to 15. Examples of such ό nitrogen-containing groups include amino, aminomethyl, amidino (carbamimidoyl), guanidino, azetidine, pyrrolidine, piperidinyl, pyridinyl or aminopyridines.

Functional groups used intermediate compounds, such as amino or carboxyl group may be protected with appropriate protective groups. Suitable protective groups for functional amino groups are, for example, tert-butoxycarbonyl, benzyloxycarbonyl, phthaloyl, or trailie or tselnye protective group. Suitable protective groups for the carboxyl functional groups are, for example, alkalemia, arrowie or arylalkylamine esters. Protective groups can be introduced and removed by methods that are well known or described in this application (see Green, T.W., Wutz, P.G.M.,Protective Groups in Organic Synthesis(1991), 2nd Ed., p.p 1-16 Wiley-Interscience, or Kocienski, P.,Protecting Groups(1994), Thieme). The term “protective group” may include associated with the polymer protective group. Such protected compounds of formula (I), where, for example, functional groups of the radicals R1, R2, R3, R4, R5 or R6, optionally, can also be protected, even though they themselves could the t and not to be pharmacologically active, optional can be converted, after the introduction of mammals, by metabolism in the pharmacologically active compounds of the present invention.

Compounds of the present invention can be well-known methods or in accordance with the methods described in this application.

The present invention also relates to a method for obtaining compounds of formula I, and/or stereoisomeric forms of the compounds of formula I and/or physiologically acceptable salts of the compounds of formula I, which includes obtaining the compounds of formula I according to scheme 1.

Scheme 1:

The radicals R1, R2, R3 and R4 used in figure 1 have the same meanings as in the compound of formula I, X represents an amino-protective group, BOC represents a protective group butoxycarbonyl, and Os is an OS.

In the method at the stage of a compound of formula II, for example (2R,3S)-3-(Boc-amino)-2-hydroxy-3-phenylpropane acid, dissolved in a solvent such as dimethylformamide (DMF), dichloromethane (CH2Cl2), tetrahydrofuran (THF), N-methylpyrrolidinone (NMP) or dioxane, and subjected to interaction with a suitable amine of formula NH(R1-BOC)-R4, for example, 6 - or 7-iminoisoindolin-1-yl)-N-dicarboximide tert-butyl ether, 2-amino-6-nitrobenzothiazole or tert-butyl 2,5-is aminobenzimidazole-1-carboxylate, to obtain the corresponding amide (III). For this purpose, as described above, using conventional condensing agent such as TOTU, PyBrop, PyBop, HATU or EDC, and a suitable base, such as amine bases, such as diisopropylethylamine (Hünig base), triethylamine (NEt3or 4-dimethylaminopyridine (4-DMAP).

Then obtain compound IV by removal of the protective groups such as tert-butyloxycarbonyl (BOC), in accordance with standard methods (for example, using TFA-CH2Cl2). (For alternative methods of removal of the protective groups, see z.B. Kocienski, P.J.,Protecting Groups, Thieme Verlag 1994).

By combining svojeobraznaja amide with a suitable carboxylic acids of the type R3-COOH in similar conditions as described in method A, the result is the desired connection type I.

In the case of compounds of type II that are not available, for example, R2=Het, connection type I can also be obtained by using the path (R6=H), outgoing from the corresponding cinnamic acids. Here, in the first stage is the interaction of cinnamic acids with obtaining relevant isopropylcarbamate, followed by aminohydroxylation, in accordance with the published standard methods. After subsequent removal of acid acetyl, two amide linkage (1. with R3-COOH and 2. with NH(R1)-R2) and UDA is placed BOC, using conditions similar to those described above, in the same way get a connection type I. For both the above methods, the compound (I), where R=H, in principle, can be converted by methods known from the literature (for example, the formation of ester or carbamoylethyl), directly in derivatives, where R6 is other than H.

The present invention also relates to a method for obtaining compounds of formula I, and/or stereoisomeric forms of the compounds of formula I and/or physiologically acceptable salts of the compounds of formula I, which includes

a) interaction of the compounds of formula II

where X represents an amino-protective group and the radicals R2 and R6 have the meanings given for formula I, with a compound NH(R1)(R4) to obtain the compounds of formula III,

where X represents an amino-protective group and the radicals R1, R2, R4 and R6 have the meanings given for formula I, and converting the compounds of formula III to the compound of formula IV by removal of the protective group,

where the radicals R1, R2, R4 and R6 have the meanings given for formula I, and interaction with the compound of the formula V

obtaining the compounds of formula I, or

(b) any allocation of the compounds of formula I, p is obtained in accordance with method a), in free form, or select it from physiologically acceptable salts, or in the presence of acidic or basic groups, converting it into physiologically acceptable salt, or

c) separation of the compounds of formula I obtained in accordance with method a), or a suitable precursor of the formula I, which due to their chemical structures exist in enantiomeric or diastereomeric forms, pure enantiomers or diastereomers by salt formation with enantiomerically pure acids or bases, chromatography with chiral stationary phases or derivatization by means of chiral enantiomerically pure compounds such as amino acids, separation of the thus obtained diastereomers and removal of the chiral auxiliary groups.

The compound of formula I obtained in accordance with Scheme 1, or a suitable precursor of the formula I which, because of their chemical structures exist in enantiomeric forms, can be divided into pure enantiomers (method c) by salt formation with enantiomerically pure acids or bases, chromatography with chiral stationary phases or derivatization by means of chiral enantiomerically pure compounds such as amino acids, separation of the thus obtained diastereomers and removal of the chiral auxiliary the groups, or

the compound of formula I obtained in accordance with Scheme 1, or may be isolated in free form or in the presence of acidic or basic groups, converted into a physiologically acceptable salt (method b).

In the method in stage c), the compound of formula I, if it exists in the form of mixtures of diastereomers or enantiomers, or if it is elected obtained by synthesis in the form of a mixture thereof, is separated into the pure stereoisomers, either by chromatography on an optionally chiral material carrier, or, if the racemic compound of the formula I is capable of salt formation, by fractionated crystallization of the formed diastereomeric salts with an optically active base or acid as an excipient. Suitable chiral stationary phase for the separation of enantiomers by the method of thin-layer or column chromatography represent, for example, the media based on the modified silica gel ("Pirkle phases) and high molecular weight carbohydrates, such as triacetylcellulose. For analytical purposes the methods of gas chromatography with chiral stationary phases can also be used after appropriate derivatization, as is well known to specialists in this field. For the separation of enantiomers of racemic carboxylic acids carry out the formation of diastereoisomeric salts with different solubility using optically active, typically, commercially available bases, such as (-)-nicotine, (+)- and (-)-phenylethylamine, quinine bases, L-lysine or L - and D-arginine, more poorly soluble component is isolated in the form of solids, more easily soluble diastereoisomer precipitated from the mother liquor and pure enantiomers is obtained from the thus obtained diastereomeric salts. By the way, which is, in principle, identical, racemic compounds of formula I which contain a basic group such as amino group, can be converted into pure enantiomers with an optically active acid such as (+)-camphor-10-sulfonic acid, D - and L-tartaric acid, D - and L-lactic acid and (+) and (-)-mandelic acid. Chiral compounds that contain the functional group of the alcohol or amine, can also be converted using a suitably activated or optionally N-protected enantiomerically pure amino acids to the corresponding esters or amides, or, on the contrary, chiral carboxylic acids can be converted using carboxy-protected enantiomerically pure amino acid amides, or using enantiomerically pure hydroxycarboxylic acids such as lactic acid, into the corresponding chiral esters. Then the chirality of the amino acid or alcohol radicals, BB is effected in enantiomerically pure form, can be used for separation of the isomers by implementing the present separation of diastereoisomers by crystallization or chromatography with suitable stationary phases and then remove trapped chiral groups are also using suitable methods.

In addition, in the case of some compounds according to the present invention it becomes possible to use diastereomers or enantiomerically pure starting products to obtain structures that make up the skeleton of the connection. This way you can use other simplified methods for purification of the final products. These initial products were received in advance in enantiomeric or diastereomeric pure form in accordance with the methods known from the literature. This means, in particular, that in the synthesis of the structures composing the skeleton of a connection, use either enantioselective methods, either enantiomeric (or diastereomers) separation carried out at an earlier stage of the synthesis, not only at the stage of final products. This results in simplification of the separation procedure in two or more stages.

Acidic or basic products of the compounds of formula I may be present in the form of their salts or in free form. Pharmacologically acceptable salts are preferred, nab is emer, salts of alkaline or alkaline-earth metals, such as hydrochloride, hydrobromide, sulphates, hemisulfate, all possible phosphates and salts of amino acids, natural substrates or carboxylic acids.

Obtaining physiologically acceptable salts of the compounds of the formula I is capable of salt formation, including their stereoisomeric forms, in accordance with method stage c), carried out by the method known per se. With ό reagents such as hydroxides, carbonates, bicarbonates, alkoxides and ammonia or organic bases, for example trimethyl - or triethylamine, ethanolamine, diethanolamine or triethanolamine, trometamol, or, alternatively, with ό amino acids, for example lysine, ornithine or arginine, the compounds of formula I form stable alkali metal salts, alkaline-earth metal or optionally substituted ammonium salts. If the compounds of formula I contain basic groups, stable acid salt additive can also be obtained with the use of strong acids. For this purpose suitable are inorganic and organic acids, such as hydrochloric, Hydrobromic, sulfuric, semiseria, phosphoric, methansulfonate, benzolsulfonat, p-toluensulfonate, 4-bromobenzophenone, cyclohexanesulfonyl, triftormetilfullerenov, 2-hydroxyethane Lifanova, acetic, oxalic, tartaric, succinic, glycerophosphoric, lactic, malic, adipic, citric, fumaric, maleic, gluconic, glucuronic, palmitic or triperoxonane acid.

The invention also relates to medicines, which include an effective amount of at least one of the compounds of formula I and/or physiologically acceptable salts of the compounds of formula I, and/or an optionally stereoisomeric form of the compounds of formula I, together with a pharmaceutically suitable and physiologically acceptable carrier, additive and/or other active and auxiliary substances.

Taking into account of their pharmacological properties, the compounds of the present invention are suitable, for example, for the prophylaxis, secondary prophylaxis and therapy of all those diseases that can be treated by inhibition of coagulation factor IXa. Thus, the compounds of the present invention are suitable as inhibitors for both prophylactic and therapeutic use in man. They are suitable for emergency treatment and for long-term therapy. The compounds of formula I can be used for patients suffering from disorders or diseases which are accompanied by thrombosis, embolism, the ability to hyperco is ulali or fibrotic changes. These include myocardial infarction, angina and other forms of acute coronary syndrome, stroke, peripheral vascular disease, deep vein thrombosis, embolism blood vessels of the lungs, embolic or thrombotic phenomena caused by cardiac arrhythmia, cardiovascular events such as restenosis after revascularization, angioplasty and similar procedures, such as stent implantation and operations associated with the bypass. In addition, the compounds of formula I can be used in all kinds of interventions that lead to contact of blood with foreign materials, as in patients with dialysis and in patients with permanent catheters. The compounds of formula I can also be used to reduce the risk of thrombosis after surgery, such as knee and hip joints.

The compounds of formula I are suitable for the treatment of patients with disseminated intravascular coagulation, sepsis and other intravascular phenomena that accompany inflammation. In addition, the compounds of formula I are suitable for the prophylaxis and treatment of patients with atherosclerosis, diabetes and metabolic syndrome and its complications. Disorders of the hemostatic system (e.g., fibrin deposits) is involved in the mechanisms that lead to tumor growth is to tumor metastasis, and in inflammatory and degenerative joint diseases such as rheumatoid arthritis and osteoarthritis. The compounds of formula I are suitable for the slowing or prevention of such processes.

Other indications for the use of compounds of formula I include fibrotic changes of the lung, such as chronic obstructive pulmonary disease, respiratory distress syndrome in adults (ARDS), and eyes, such as fibrin deposits after eye operations. The compounds of formula I are also suitable for the prophylaxis and/or treatment of scarring.

Medicines according to the present invention can be administered by oral administration, by inhalation, rectal or percutaneous injection or by subcutaneous, intravascular, intraperitoneally or intravenous injection. Oral administration is preferred. Possible coating of stents compounds of formula I, as well as other surfaces that come into contact with the blood in the body.

The present invention also relates to a method for obtaining a medicinal product, which comprises bringing at least one compound of formula I in a suitable introduction to the form using a pharmaceutically suitable and physiologically acceptable carrier and, optionally, other suitable active substances, add the to or excipients.

Suitable solid or herbal forms of drugs are, for example, granules, powders, coated tablets, tablets, (micro)capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions and drugs with prolonged release of the active substance, for which use conventional excipients, such as carriers, disintegrating agents, binders, coating agents, substances to create volume, slip agents or lubricants, flavors, sweeteners and soljubilizatory. You can specify such frequently used auxiliary substances, such as magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactose, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as oil of cod liver oil, sunflower, peanut or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and one - or polyhydric alcohols, such as glycerin.

Preferably the pharmaceutical drugs and get injected into dosage units, where each unit contains as active component a specific dose of a compound of formula I according to the present invention. In the case of solid dosage units such as tablets, capsules, coated tablets or suppositories, this dose can comp the manage about 1000 mg, but preferably from approximately 50 to 300 mg, and in the case of injection solutions in ampoules approximately 300 mg, but preferably approximately from 10 to 100 mg.

For the treatment of an adult patient weighing approximately 70 kg, depending on the effectiveness of the compounds of formula I, you can specify a daily dose of from about 2 mg to 1000 mg of active substance, preferably from about 50 mg to 500 mg. However, in some circumstances, a higher or lower dose may be appropriate. The daily dose can be administered by a single administration in a single dose or as several smaller dosage units and by multiple introductions of subdivided doses at specific intervals.

The compounds of formula I can be introduced as monotherapy, or in combination or together with all antithrombotic agents (anticoagulants and platelet aggregation inhibitors), thrombolytic (plasminogen activators any type), other profibrinolytic active agents, antihypertensive agents, regulators of sugar in the blood, means for reducing the level of lipids, and anti-arrhythmia.

Examples

The final products usually determine mass-spectroscopic methods (FAB, ESI-MS) and by the method1H-NMR, in each case specifies the primary peak or two of the main peak. Temperatures are in degrees Celsius, Yld. means output. Used abbreviations or decrypted, or are traditional symbols. Unless otherwise specified, the chromatographic separation was carried out on silica gel using mixtures of ethyl acetate/heptane as eluents. Preparative separation on silica gel (HPLC) with reversed phase (RP) was carried out, unless otherwise specified, the following conditions: column Merck Hibar RT 250-25 LiChrospher 100 RP-18e 5 m, Merck KGaA, Germany, Life Science & Analytics, 64293 Darmstadt; mobile phase A: H2O + 0.1% of TFA, B phase: 80% acetonitrile + 0.1% of TFA, flow rate 25 ml/min, from 0 to 7 min 100% A, 7 min to 22 min to 100% B, 22 min 30 min 100% B, 30 min 33 min to 100% A, 33 min to 35 min 100% A. the Evaporation of the solvent is usually carried out under reduced pressure at 35°C-45°C on a rotary evaporator. Unless otherwise stated, analyses LC/MS was carried out under the following conditions:

The way A:

Column: YMC Jshere H80 33×2.1 mm; Waters GmbH Helfmann-Park 10, 65760 Eschborn, Germany; filler 4 μm,

Solvent: ACN+0.05% of TFA:H2O is+0.05% TFA (flow rate 1.3 ml/min)

Gradient: 5:95 (0 min) to 95:5 (2.5 minutes) to 95:5 (3,0 min)

Ionization: ESI+

The way B:

Column: YMC Jshere H80 33×2.1 mm; filler 4 μm,

Solvent: ACN+0.05% of TFA:H2O is+0.05% TFA (flow rate 1 ml/min)

Gradient: 5:95 (0 min) to 95:5 (by 3.4 min) to 95:5 (4,4 min)

Ionization: ESI+

The method:

Column: YMC Jshere H80 33×2.1 mm, 4 μm,

Solvent: ACN+0,08% TFA:H2O+0,1% TFA (flow rate 1.3 ml/min)

Gradient: 5:95 (0 min) to 95:5 (2.5 minutes) to 95:5 (3 min)

Ionization: ESI+

The way D:

Column: YMC Jshere ODS H80 20×2.1 mm filler 4 μm,

Solvent: ACN:H2O is+0.05% TFA (flow rate 1 ml/min)

Gradient: 4:96 (0 min) to 95:5 (2 min) to 95:5 (2,4 min) 96:4 (2,45 min)

Ionization: ESI+

Preparative HPLC was carried out using the following method:

Column: Waters Atlantis dC18 OBD 30×100 mm 5 μm; Waters GmbH Helfmann-Park 10, 65760 Eschborn, Germany

Solvent: ACN:H2O+0,1%TFA (flow rate 60 ml/min)

Gradient: 10:90 (0 min) to 90:10 (10 min)

Used abbreviations:

td align="justify"> dimethylformamide
CANacetonitrile
Bocbutoxycarbonyl
DCMdichloromethane
(DHQ)2PHAL1-[(R)-((4S,5R)-5-ethyl-1-azabicyclo[2,2,2]Oct-2-yl)-(6-methoxyquinoline-4-yl)methoxy]-4-[(R)-((4R,5S)-5-ethyl-1-azabicyclo-[2,2,2]Oct-2-yl)-(6-methoxyquinoline-4-yl)methoxy]phthalazine
DIPEAN,N-diisopropylethylamine (base Chenega)
DMF
DMSOthe sulfoxide
EDCN'-(3-dimethylaminopropyl)-N-ethylcarbodiimide
HATUhexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea
HOAt1-hydroxy-7-asobancaria
K2[OsO2(OH)4]potassium osmate, dihydrate
LC/MSliquid chromatography/mass spectroscopy
MeOHmethanol
NMMN-methylmorpholin
PyBophexaphosphate 1-benzothiazolylsulfenamide
PyBrophexaphosphate postreperfusion
Rtretention time
TFAtriperoxonane acid
TOTUtetrafluoroborate O-((etoxycarbonyl)-cyan is methylaniline)-N,N,N',N'-tetramethylurea
RTroom temperature (21°C to 24°C)

Example 1

N-[(1S,2R)-2-(1-aminoisoquinoline-7-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-tert-butylbenzamide; connection with triperoxonane acid

Stage 1 method:

[7-((2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionylamino)isoquinoline-1-yl]-N-dicarboximide tert-butyl methyl ether

0,69 ml (6.26 mmol) of NMM was added to a solution of 0.75 g (of 2.08 mmol) 7-iminoisoindolin-1-yl-N-dicarboximide tert-butyl ester, (2R,3S)-3-(Boc-amino)-2-hydroxy-3-phenylpropane acid (0,587 g of 2.08 mmol) and HOAt (0,284 g of 2.08 mmol) in 10 ml of DMF under stirring for 10 minutes (min). After adding 0,973 g PyBrop (of 2.08 mmol) and the mixture was stirred at room temperature for 18 hours. Then to the reaction mixture were added water and the mixture was extracted with ethyl acetate, dried using sodium sulfate, filtered and concentrated under reduced pressure and the residue was purified using chromatography on silica gel (ethyl acetate:n-heptane 1:2).

Was obtained 0.56 g (yield: 43%) of purified specified in the connection header.

LC/MS (Method D) (M+H-BOC)+523

7-Iminoisoindolin-1-yl-N-dicarboximide tert-butyl ether was obtained in the same way as op is Sano in WO 00/71507, page 92.

Stage 2 method:

(2R,3S)-3-amino-N-(1-aminoisoquinoline-7-yl)-2-hydroxy-3-phenylpropionamide; connection with triperoxonane acid

3 ml of TFA was added 0.56 g (0.89 mmol) of the compound from stage 1 of the method in DCM (9 ml). Then the reaction mixture was stirred at room temperature for 3 hours. Solvents drove under reduced pressure and was carried out by absorption of the solid in MeOH and water, and in the end liofilizirovanny. Received 0,485 g (yield: 99%) of purified specified in the title compounds as white solids. LC/MS (Method D) (M+H)+323

Stage 3 method:

N-[(1S,2R)-2-(1-aminoisoquinoline-7-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-tert-butylbenzamide; connection with triperoxonane acid

0,038 ml (0.22 mmol) DIPEA was added to a solution of 40 mg (0,073 mmol) of the compound from stage 2 way, 4-tert-butylbenzoic acid (12.9 mg, 0,073 mmol), HOAt (9,89 mg, 0,073 mmol) and HATU (27,6 mg, 0,073 mmol) in DMF (1.5 ml). Then the reaction mixture was stirred for 42 hours at room temperature. The reaction mixture was filtered and purified using preparative high performance liquid chromatography (HPLC). Purified fractions of the product liofilizirovanny and received a white solid. Exit 53%

LC-MS (Method A) 482,23 (Rt=1,43 min, 100%)

1H NMR (500 MHz, DMSO-d6 ) δ (ppm): 1.28 (in s, 9H), of 4.54 (t, 1H), 5.56mm (DD, 1H), of 6.31 (d, 1H), 7,18 (d, 1H), 7,25 (m, 1H), 7,33 (t, 2H), 7,47 (d, 4H), 7,58 (d, 1H), 7,78 (d, 2H), to $ 7.91 (d, 1H), 8,01 (DD, 1H), 8,45 (d, 1H), total of 8.74 (, 1H), 8,91 (s, 2H), 10,36 (s, 1H), 12,90 (s, 1H)

Example 2:

N-[(1S,2R)-2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-diethylaminobenzoic; compound with HCl

Stage 1 method:

[6-((2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionylamino)-isoquinoline-1-yl]-N-dicarboximide tert-butyl methyl ether

6-Iminoisoindolin-1-yl-N-dicarboximide tert-butyl ester (1.5 g, of 4.17 mmol) was subjected to interaction similar to the method of producing example 1, stage 1. Received 0,82 g specified in the title compound; yield: 32% solids.

LC/MS (Method D) (M+H)+623

6-Iminoisoindolin-1-yl-N-dicarboximide tert-butyl ester was obtained as in the method described in WO2004/072101, page 108.

Stage 2 method:

(2R,3S)-3-amino-N-(1-aminoisoquinoline-6-yl)-2-hydroxy-3-phenylpropionamide; connection with triperoxonane acid

Connection with phase 1 of the method (0,82 g of 1.32 mmol) was subjected to interaction similar to the method of producing example 1, step 2. Received 0.71 g specified in the title compound (yield: 98%) as a solid.

LC/MS (Method D) (M+H)+323

Stage 3 method:

N-[(1S,2R)-2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroc the and-1-phenylethyl]-4-diethylaminobenzoic; connection with hydrochloric acid

The product obtained in stage 2 of the method (0.6 g, of 1.09 mmol), 4-diethylaminobenzoic acid (0.21 g, of 1.09 mmol), HOAt (148 mg, of 1.09 mmol) and HATU (415 mg, of 1.09 mmol) was dissolved in 10 ml of DMF and added to 0.56 ml of DIPEA (with 3.27 mmol). Then the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered and purified using preparative HPLC. Purified fractions of the product liofilizirovanny, was dissolved in 2 ml of MeOH and was then processed using 5 ml of 5 M HCl and liofilizirovanny again. Received 278 mg of a white solid. Yield: 45%

LC/MS (Method B) 497,24 (Rt=1,15 min, 100%)

1H NMR (500 MHz, DMSO-d6) δ (ppm): a 1.08 (t, 6H), to 3.38 (d, 4H), 4,56 (d, 1H), 5,54 (DD, 1H), 6,65 (s, 2H), 7,14 (d, 1H), 7,24 (t, 1H), 7,32 (m, 2H), 7,45 (d, 2H), to 7.59 (t, 1H), 7,71 (s, 2H), to $ 7.91 (DD, 1H), 8,15 (s, 1H), 8,29 (d, 1H), 8,49 (d, 1H), 8,90 (s, 2H), at 10.64 (s, 1H), 12,90 (s, 1H)

Example 3:

N-[(1S,2R)-2-(2-aminobenzothiazole-6-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-isopropylbenzene; connection with triperoxonane acid

Stage 1 method:

Benzothiazole-2,6-diamine

2-Amino-6-nitrobenzothiazole (1.0 g, 5,12 mmol) was dissolved in 100 ml MeOH was added palladium on charcoal (10%, 545 mg, 0.51 mmol). The reaction mixture was first made using hydrogen at room temperature (3 bar H2 ) for 2.5 hours. The mixture was filtered, the solvent was removed under reduced pressure and the residue was purified using chromatography on silica gel (ethyl acetate:n-heptane 1:2). Received 0,81 g (yield: 96%) of purified specified in the connection header.

LC/MS (Method D) (M+H)+166

Stage 2 method:

[(1S,2R)-2-(2-aminobenzothiazole-6-ylcarbonyl)-2-hydroxy-1-phenylethyl]carboxamido tert-butyl methyl ether

The compound obtained in stage 1 of the method (71 mg, 0.43 mmol)were subjected to interaction similar to the method of producing example 1, stage 1. Received 180 mg specified in the title compound; yield: 98% solids. LC/MS (Method D) (M+H)+429

Stage 3 method:

(2R,3S)-3-amino-N-(2-aminobenzothiazole-6-yl)-2-hydroxy-3-phenylpropionamide; connection with triperoxonane acid

Connection with stage 2 ways (180 mg, 0.42 mmol) was subjected to interaction similar to the method of producing example 1, step 2. Received 177 mg specified in the title compound; yield: 76% solids. LC/MS (Method D) (M+H)+329

Stage 4 method:

N-[(1S,2R)-2-(2-aminobenzothiazole-6-ylcarbonyl)-2-hydroxy-1-phenyl-ethyl]-4-isopropylbenzene; connection with triperoxonane acid

The product obtained in stage 3 of the method (78 mg, 0.14 mmol), 4-isopropylbenzoic acid (23 mg, 0.14 mmol), HOAt (19 mg, 0.14 mmol) and HATU (3 mg, 0.14 mmol) was dissolved in 2 ml DMF and added 0,046 ml of NMM (0.42 mmol). Then the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered and purified using preparative HPLC. Purified fractions of the product liofilizirovanny. Received 33 mg of a white solid. Yield: 40%

LC/MS (Method A) 474,17 (Rt=1,63 min, 100%)

1H NMR (500 MHz, DMSO-d6) δ (ppm): of 1.20 (d, 6H), 2,94 (hept, 1H), of 4.44 (d, 1H), 5,49 (DD, 1H), 7,24 (t, 1H), 7,28-7,34 (m, 5H), 7,38 (DD, 1H), 7,44 (d, 2H), to 7.77 (d, 2H), with 8.05 (d, 1H), 8,15 (s, 1H), 8,43 (d, 1H), 9,95 (s, 1H)

Example 4:

N-[(1R,2R)-2-(1-aminoisoquinoline-6-ylcarbonyl)-1-furan-2-yl-2-hydroxyethyl]-4-diethylaminobenzoic; connection with triperoxonane acid

Stage 1 method:

Isopropyl (E)-3-furan-2-ylacrylic

of 1.46 ml of thionyl chloride (20 mmol) was added to a solution of 1.38 g of 3-(2-furyl)acrylic acid (10 mmol) in 10 ml of chloroform and 0.1 ml of DMF. The solution was heated to 70°C and kept at this temperature for 1 hour, then the solvent was removed under reduced pressure and the residue was dissolved in 6.6 ml of DCM and 3.3 ml of pyridine and then cooled to 0°C. was Added to 0.96 ml of 2-propanol (12.5 mmol), the temperature was raised to room temperature and the reaction mixture was stirred for 2.5 hours. The mixture was acidified using 30 ml of 1 M chloritoid the Oh of the acid and were extracted using 150 ml of ethyl acetate. The organic phase was washed with an aqueous solution of sodium bicarbonate, dried over sodium sulfate, filtered and the solvents were removed under reduced pressure. Received 1,72 g (yield: 96%) specified in the connection header. LC/MS (Method D) (M+H-isopropyl)+139

Stage 2 method:

Isopropyl (2R,3R)-3-acetylamino-3-furan-2-yl-2-hydroxypropionate

The reaction was carried out as described in Sharpless et. al. Angew. Int. Ed. 1997,36, 1483.

14 ml of tert-butanol and 117 mg (DHQ)2PHAL (0.15 mmol) was added to a solution containing 128 mg of the monohydrate of lithium hydroxide (a 3.06 mmol) and 44.5 mg K2[OsO2(OH)4] (0.12 mmol) in 7 ml of water, and the solution was stirred at room temperature for 10 minutes After adding 14 ml of water and the mixture was cooled to 4°C and was added 0.54 g (3 mmol) of the compound in accordance with stage 1 of the method and 455 mg of N-bromoacetamide (3.3 mmol). The mixture was stirred at 4°C for 3.5 hours. Then added 1.2 g of sodium sulfite and the mixture was stirred for 30 minutes at room temperature. Added water and the aqueous phase was extracted with ethyl acetate. The organic phase was dried using sodium sulfate, filtered, the solvent was removed under reduced pressure and the residue was purified using chromatography on silica gel (ethyl acetate:n-heptane 2:3). Received 112 mg (yield: 15%) cleaned what about specified in the connection header.

LC/MS (Method D) (M+H)+256

Stage 3 method:

(2R,3R)-3-amino-3-furan-2-yl-2-hydroxypropionic acid; compound with hydrochloric acid

112 mg of the compound obtained in stage 2 of the method (0.44 mmol), was dissolved in 8 ml of hydrochloric acid (10%) and heated at 110°C for 3 hours. To the reaction mixture were added water and after lyophilization received 91 mg (yield 100%) of the net specified in the connection header.

LC/MS (Method D) (M+H-NH2)+155

Stage 4 method:

(2R,3R)-3-(4-diethylaminobenzylidene)-3-furan-2-yl-2-hydroxypropionic acid

89 mg of 4-diethylaminobenzoic acid (0.46 mmol) and 152 mg TOTU (0.46 mmol) was dissolved in 2 ml DMF and added 255 μl of NMM (2,31 mmol). The reaction mixture was stirred at room temperature for 30 minutes and was added 96 mg of the product from step 3 of the method (0.46 mmol). Then the reaction mixture was stirred for 18 hours at room temperature. The mixture was filtered and purified using preparative HPLC. Purified fractions of the product liofilizirovanny. Received 142 mg of a white solid. Yield: 89%

LC/MS (Method D) (M+H)+347

Stage 5 method:

{6-[(2R,3R)-3-(4-diethylaminobenzylidene)-3-furan-2-yl-2-hydroxy-propionamide]isoquinoline-1-yl}-N-dicarboxylic what about the tert-butyl methyl ether

48,2 mg of the product obtained at stage 4 way (0.14 mmol), 50 mg of 7-amino-isoquinoline-1-yl)-N-dicarboximide tert-butyl ester (0.14 mmol), 19 mg of HOAt (0.14 mmol) and 64,8 mg of PyBrop (0.14 mmol) was dissolved in 1.5 ml DMF and then added 61,3 μl of NMM (0,56 mmol) and the reaction mixture was then stirred at room temperature for 42 hours. The mixture was filtered and purified using preparative HPLC. Purified fractions of the product liofilizirovanny. Liofilizirovannoe the solid is then dissolved and purified using chromatography on silica gel (DCM:MeOH 30:1). Received 13 mg (yield: 14%) purified specified in the connection header.

LC/MS (Method D) (M+H)+688

Stage 6 method:

N-[(1R,2R)-2-(1-aminoisoquinoline-6-ylcarbonyl)-1-furan-2-yl-2-hydroxyethyl]-4-diethylaminobenzoic; connection with triperoxonane acid

The product obtained in stage 5 of the method (13 mg, of 18.9 mmol), was dissolved in 3 ml of DCM was added 1 ml of TFA. The reaction mixture then was stirred for 1 hour at room temperature. The reaction mixture was filtered and the solvents were removed under reduced pressure. The residue was dissolved in MeOH and water, liofilizirovanny and received 11 mg of a white solid. Yield: 97%. LC/MS (Method A) 487,22 (Rt=1,00 min, 100%)

1H NMR (500 MHz, DMSO-d6) δ (ppm): a 1.08 (t, 6H), 3,37 (square, 4H), with 4.64 (d, 1H), ,65 (DD, 1H), 6,32 (d, 1H), 6,40 (d, 1H), 6,63 (d, 2H), 7,15 (d, 1H), to 7.59 (m, 2H), to 7.67 (d, 2H), to $ 7.91 (DD, 1H), of 7.96 (d, 1H); 8,31 (d, 1H), 8,45 (d, 1H), 8,81 (s, 2H), 10,56 (s, 1H), of 12.73 (s, 1H)

Example 5:

N-[(1S,2R)-2-(2-aminobenzothiazole-6-ylcarbonyl)-1-(2-chlorophenyl)-2-hydroxyethyl]-4-isopropylbenzene; connection with triperoxonane acid

Stage 1 method:

Isopropyl (E)-3-(2-chlorophenyl)acrylate

1,83 g 2-harkerite acid (10 mmol) was subjected to interact the same way as the receive example 4, stage 1. Received 1.92 g specified in the title compound; yield: 86%. LC/MS (Method D) (M+H)+225

Stage 2 method:

Isopropyl (2R,3S)-3-acetylamino-3-(2-chlorophenyl)-2-hydroxypropionate

to 1.9 g of compound obtained in stage 1 of the method (8,46 mmol)were subjected to interaction the same way as the receiving of example 4, step 2 of the method. Received 1,93 g specified in the title compound; yield: 76%.

LC/MS (Method D) (M+H)+300

Stage 3 method:

(2R,3S)-3-amino-3-(2-chlorophenyl)-2-hydroxypropionic acid; compound with hydrochloric acid

of 1.93 g of compound obtained in stage 2 of the method (6,44 mmol)were subjected to interaction the same way as the receive example 4, stage 3. Received 1.6 g specified in the title compound was obtained; yield: 99%.

LC/MS (Method D) (M+H)+216

Stage 4 method:

<> (2R,3S)-3-(2-chlorophenyl)-2-hydroxy-3-(4-isopropylbenzylamine)propionic acid

525 mg of 4-isopropylbenzoic acid (3.2 mmol) and 525 mg of the product from step 3 (3.2 mmol) was subjected to interaction method similar to that described in example 4, stage 4. Received 630 mg specified in the title compound as a white solid; yield: 54%. LC/MS (Method D) (M+H)+362

Stage 5 method:

N-[(1S,2R)-2-(2-aminobenzothiazole-6-ylcarbonyl)-1-(2-chlorophenyl)-2-hydroxyethyl]-4-isopropylbenzene; connection with triperoxonane acid

77 mg of the compound obtained in stage 4 way (0.21 mmol)were subjected to interaction with 35 mg of the compound obtained in example 3, stage 1 (0.21 mmol), similar to the way an example 4, stage 5. Received 87 mg specified in the title compound; yield: 66%.

LC/MS (Method A) 508,13 (Rt=1,40 min, 100%)

1H NMR (400 MHz, DMSO-d6) δ (ppm): to 1.19 (d, 6H), 2,92 (hept, 1H), to 4.41 (d, 1H), of 5.89 (DD, 1H), 6.42 per (s, 1H), 7,27-7,34 (m, 5H), was 7.45 (m, 2H), 7,56 (DD, 1H), 7,76 (d, 2H), 8,07 (s, 1H), 8,10 (d, 1H), 8,39 (d, 1H), 9,85 (s, 1H)

Example 6:

N-[(1S,2R)-2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-1-(2-forfinal)-2-hydroxyethyl]-4-isopropylbenzene; connection with triperoxonane acid

Ethoxycarbonylmethylene received in accordance with the Patent application Germany 4238260, and tert-butyl 2,5-diamino Intimidator-1-carboxylate was obtained in accordance with the International application WO2002/042273.

Stage 1 method:

Isopropyl E-3-(2-forfinal)acrylate

400 mg of sodium hydride (60% in oil, 10 mmol) was added to a stirred solution of 4.4 g of ethoxycarbonylmethylene (10 mmol) in 20 ml DMF and the mixture was stirred further at room temperature for 10 minutes. Added 1.24 g of 2-fluoro-benzaldehyde (10 mmol) and the mixture was stirred for 5 hours at room temperature. The reaction mixture was taken for the absorption of 100 ml ethyl acetate and washed with normal saline, dried over sodium sulfate, filtered and concentrated under reduced pressure. Carried out the purification using chromatography on silica gel (ethyl acetate/heptane 1:1). Received 1,25 g specified in the connection header. Yield: 60%.

LC/MS (Method D) (M+H)+209.

Stage 2 method:

Isopropyl (1S,2R)-3-acetylamino-3-(2-forfinal)-2-hydroxypropionate

1,25 g of compound obtained in stage 1 of the method (6 mmol)were subjected to interaction the same way as the receiving of example 4, step 2. Received 1.18 g specified in the title compound; yield: 69%.

LC/MS (Method D) (M+H)+284

Stage 3 method:

(1S,2R)-3-amino-3-(2-forfinal)-2-hydroxypropionic acid; compound with hydrochloric acid

1.18 g of the compound obtained in stage 2 ways is a (4,11 mmol), were subjected to interaction the same way as the receive example 4, stage 3. Received 1 g specified in the title compound; yield: 99%.

LC/MS (Method D) (M+H)+200

Stage 4 method:

(2R,3S)-3-(2-Forfinal)-2-hydroxy-3-(4-isopropylbenzylamine)propionic acid

342 mg of 4-isopropylbenzoic acid (2.1 mmol) and 416 mg of the product from step 3 (2.1 mmol) was subjected to interaction method similar to that described in example 4, stage 4. Received 365 mg specified in the title compound as a white solid; yield: 50%. LC/MS (Method D) (M+H)+346

Stage 5 method:

tert-Butyl (2R,3S)-2-amino-5-[3-(2-forfinal)-2-hydroxy-3-(4-isopropylbenzylamine)propionamido]benzimidazole-1-carboxylate

65 mg of tert-butyl 2,5-diaminobenzidine-1-carboxylate and 92 mg of the compound obtained in stage 4 way (0,266 mmol), was dissolved in 2 ml of DMF. Then added 36 mg of HOAt (0,265 mmol), 130 mg of PyBrop (0.28 mmol) and 200 μl of DIPEA (1,17 mmol) in 1 ml DMF. After stirring at room temperature for 3 hours the mixture was diluted with ethyl acetate. The organic phase was washed with normal saline, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was used without further purification in the next stage of the way. LC/MS (Pic is b (D) (M+H) +576

Stage 6 method:

N-[(1S,2R)-2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-1-(2-forfinal)-2-hydroxyethyl]-4-isopropylbenzene; connection with triperoxonane acid

The residue from step 5 of the method in a mixture of 2 ml DCM and 2 ml of TFA. After stirring at room temperature for 2 hours the solvent is evaporated under reduced pressure and the residue was purified using preparative HPLC. Received 65 mg specified in the title compound as a white solid; yield: 44%. LC/MS (Method A) 475,20 (Rt=1,38 min, 100%)

1H NMR (400 MHz, DMSO-d6) δ (ppm): to 1.19 (d, 6H), 2,92 (hept, 1H), 4,40 (users, 1H), 5,79 (DD, 1H), 6,38 (users, 1H), 7,14-7,38 (m, 8H), 7,52 (dt, 1H), to 7.77 (d, 2H), 7,88 (s, 1H), 8,40 (s, 1H), 8,43 (d, 1H), 10,00 (s, 1H) 12,40 (users, 1H)

Example 7:

N-[(1S,2R)-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-tert-butylbenzamide; connection with triperoxonane acid

Stage 1 method:

tert-Butyl (1S,2R)-2-amino-6-(3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionylamino)benzimidazole-1-carboxylate

1.5 g of (1S,2R)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionic acid (5.3 mmol) and of 1.32 g of tert-butyl 2,5-diaminobenzidine-1-carboxylate (5.3 mmol) was dissolved in 30 ml of DMF. Added 798 mg of HOAt (5,86 mmol), 1,75 g PyBrop (5,86 mmol) and 2.8 ml of DIPEA (16 mmol) in 1 ml DCM and 15 ml of DMF and the mixture was stirred at room temperature for 5 hours. The organic phase was washed with an aqueous solution of sodium bicarbonate and common salt solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. After chromatography on silica gel (ethyl acetate/heptane 2:1) received 2 g specified in the title compounds as white solids. Yield: 74%.

LC/MS (Method D) (M+H-tBu)+456

Stage 2 method:

(1S,2R)-3-amino-N-(2-amino-3H-benzimidazole-5-yl)-2-hydroxy-3-phenyl-propionamide; connection with triperoxonane acid

The product obtained by the method in stage 1, was dissolved in 10 ml DCM and 10 ml of TFA was stirred for 2 hours at room temperature and obtained 2.1 g specified in the connection header in the form of a pink solid; yield 99%. LC/MS (Method D) (M+H)+312

Stage 3 method:

N-[(1S,2R)-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-tert-butylbenzamide; connection with triperoxonane acid

45 mg of 4-tert-butylbenzoic acid (0.25 mmol), 91 mg TOTU (0.28 mmol) and 150 μl of N-ethylmorpholine (1.5 mmol) was dissolved in 2 ml DMF and the solution was stirred for 30 minutes at room temperature. Added 132 mg of the product obtained in method stage 2 (0.25 mmol)and the mixture was stirred for 2 hours at room temperature. The mixture was diluted atilas what tatom. The organic phase was washed with an aqueous solution of sodium bicarbonate and common salt solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified using HPLC. Received 36 mg specified in the title compounds as white solids. Yield: 25%.

LC/MS (Method A) 472,31 (Rt=1,39 min, 100%)

1H NMR (400 MHz, DMSO-d6) δ (ppm): of 1.29 (s, 9H), 4,47 (users, 1H), 5,50 (DD, 1H), 6,11 (users, 1H), 7,20-to 7.35 (m, 5H), 7,40-of 7.48 (m, 5H), 7,76 (d, 2H), a 7.85 (s, 1H), 8,39 (users, 1H), 8,45 (d, 1H), 8,39 (d, 1H), 9,99 (s, 1H).

Example 8:

N-[(1S,2R)-2-(4-aminomethylpropanol)-2-hydroxy-1-phenylethyl]benzamide; connection with triperoxonane acid

Stage 1 method:

tert-Butyl [4-((2R,3S)-3-benzoylamino-2-hydroxy-3-phenylpropionylamino)benzyl]carbamate

By the way, is similar to that described in example 1, stage 1, 33 mg (0.15 mmol) of tert-butyl (4-aminobenzyl)carbamate and 43 mg (0.15 mmol) of (2R,3S)-3-benzoylamino-2-hydroxy-3-phenylpropionic acid was dissolved in 1 ml DCM and 1 ml of DMF and consistently processed using 78 μl DIPEA (0.45 mmol), the 22.5 mg of HOAt (0,165 mmol) and 76.9 mg (0,165 mmol) of PyBrop. Without any further processing of the received batch of product was filtered and then purified using HPLC. Containing the product fractions liofilizirovanny.

With the adiya 2 ways:

N-[(1S,2R)-2-(4-aminomethylpropanol)-2-hydroxy-1-phenylethyl]benzamide; connection with triperoxonane acid

The product obtained by the method in stage 1 were subjected to interaction method similar to that described in example 1, stage 3; the mixture was then concentrated, treated with water and liofilizirovanny.

Output: 31,5 mg (43% from 2 stages).

LC/MS (Method A) M-NH2=373,40 (Rt=1,09 min, 85%)

1H NMR (500 MHz, DMSO-d6) δ (ppm): of 3.97 (d, 2H), 4,47 (users, 1H), 5,50 (DD, 1H), 6,11 (DD, 1H), 7.23 percent (m, 1H), 7,30 and 7.36 (m, 4H), 7,42-of 7.48 (m, 4H), 7,53 (m, 1H), 7.62mm (d, 2H), to 7.84 (d, 2H), 8,05 (users, 3H), 8,53 (d, 1H), 9,99 (s, 1H).

Example 9:

N-[(1S,2R)-2-(2,4-diaminoquinazoline-6-ylcarbonyl)-2-hydroxy-1-phenylethyl]benzamide; connection with triperoxonane acid

By the way, is similar to that described in example 1, stage 1, 76 mg (0.44 mmol) hinzelin-2,4,6-analogue and 150 mg (0.52 mmol) of (2R,3S)-3-benzoylamino-2-hydroxy-3-phenylpropionic acid was dissolved in 3 ml of DMF and consistently processed using 153 μl DIPEA (0.86 mmol), 78,9 mg HOAt (or 0.57 mmol) and 251 mg (of 0.53 mmol) of PyBrop. Without any further processing of the received batch of product was filtered and purified using HPLC. Containing the product phase liofilizirovanny.

Yield: 114 mg (48%).

LC/MS (Method A) M+H=443,32 (Rt=1,10 min, 100%)

1H NMR (500 MHz, DMSO-d6 ) δ (ppm): 4,51 (m, 1H), 5,54 (m, 1H), and 6.25 (d, 1H), 7,22-7,51 (m, 9H), 7,75-7,83 (m, 4H), at 8.36 (users, 1H), 8,53 (d, 1H), 8,72 (users, 1H), 8,93 (users, 1H), 10,15 (users, 1H), 12,30 (users, 1H).

Compounds in table 1 below were obtained in the same way as described in the examples above.

Connection shall be in accordance with the rules of the International Union for Pure and Applied Chemistry (IUPAC). The absolute stereochemistry is not specified, and the connection in each case were obtained in the form of salts triperoxonane acid.

N-[2-(1-aminoisoquinoline-7-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-pyrrol-1-ylbenzene 0,97
Table 1
Example
No.
ConnectionWeight
according to LC-MS
Rt
according to LC-MS
Method LC-MS
104-amino-N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]benzamide431,230,81A
11[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenyl-ethyl]amide cinoxacin-2-carboxylic acid468,231,14A
12N-[2-(2-amino-3H-benzimidazol the-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-methoxybenzamide 446,231,08A
13[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenyl-ethyl]amide thiophene-3-carboxylic acid422,171A
14[(1S,2R)-2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 1-methyl-1H-pyrrole-2-carboxylic acid419,231,02A
15[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenyl-ethyl]amide of the quinoline-2-carboxylic acid467,231,23A
16N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-cyclohexylbenzene498,231,5A
17N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-isopropylbenzene458,21,33A
18N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-triptoreline-benzamid500,111,33A
19N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-diethylaminobenzoic487,281A
20N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-phenoxybenzamide508,241,4A
21N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-benzylbenzamide506,271,41A
22N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-isopropoxybenzoic474,271,47B
23N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-methylsulfanyl-benzamide462,22/td> 1,37B
24N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-metilsulfonilmetane476,23the 1.44B
25N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-[(4,6-dimethylpyrimidin-2-yl)methylamino]benzamide551,321,18B
26N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-pyridin-3-ylbenzene493,260,95B
274-(2-acetylamino-3,3,3-cryptochromes)-N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]benzamide569,291,32B
28[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 1-methyl-1H-indole-2-carboxylic acid469,261,45B
29[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 5-methoxy-1H-indole-2-carboxylic acid485,261,36B
30[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 5-ethyl-1H-indole-2-carboxylic acid483,281,58B
31[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide of 6-methoxy-1H-indole-2-carboxylic acid485,261,39B
32[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 4-methoxyquinoline-2-carboxylic acid497,251,5B
33[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 3-ethoxyphenoxy-2-carboxylic acid512,271,45B
34[2-(2-amino-3H-benzoni the azole-5-ylcarbonyl)-2-hydroxy-1-phenyl-ethyl]amide naphthalene-2-carboxylic acid 466,241,29A
35N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-pyrrol-1-ylbenzene481,261,3A
36N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-trifloromethyl-benzamid516,171,39A
37Biphenyl-4-carboxylic acid [2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenyl-ethyl]amide492,281,53B
38N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-(2,2,2-triptoreline)-benzamide514,25the 1.44B
39Benzyl [2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]carbamate446,251,27A
40 N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-ethylbenzamide444,231,4B
41N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-ethoxybenzene460,221,31B
42[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenyl-ethyl]amide 5-butylpyrazine-2-carboxylic acid473,241,62B
43[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide, benzo[b]thiophene-2-carboxylic acid472,171,42B
44[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide of 6-methoxynaphthalene-2-carboxylic acid496,221,45B
45[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 4-(2,2,2-thrift ratil)-4H-thieno[3,2-b]pyrrole-5-carboxylic acid 543,171,54B
464'-{[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenyl-ethyl]amide}3-methylamide biphenyl-3,4'-dicarboxylic acid549,261,28B
47N-[2-(1-aminoisoquinoline-7-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-diethylaminobenzoic497,241,09A
48N-[2-(1-aminoisoquinoline-7-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-isopropylbenzene468,221,37A
49N-[2-(1-aminoisoquinoline-7-ylcarbonyl)-2-hydroxy-1-phenylethyl]-6-pyrrolidin-1-yl-nicotinamide496,221,03A
50N-[2-(1-aminoisoquinoline-7-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-morpholine-4-yl-benzamide511,221,16A
51491,21,37A
52[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 1-ethyl-2,3-dimethyl-1H-indole-5-carboxylic acid511,351,4A
53N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-morpholine-4-yl-benzamide501,331,2A
54N-[2-(1-aminoisoquinoline-7-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-pyrrolidin-1-yl-benzamide495,23of 1.34A
55N-[2-(1-aminoisoquinoline-7-ylcarbonyl)-2-hydroxy-1-phenylethyl]-6-morpholine-4-yl-nicotinamide513,220,97A
56[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 5,6-dimethoxy-1H-indole-2-carboxylic acid 515,341,16A
57N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-pyrrolidin-1-yl-benzamide485,111,37A
58N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-isobutylbenzene472,31,65B
59N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-butylbenzamide472,31,67B
60N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-propylbenzamide458,281,36A
61[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 4H-thieno[3,2-b]pyrrole-5-carboxylic acid461,21,3B
62N-[2-(4-carbs is methylphenylcarbinol)-2-hydroxy-1-phenylethyl]-4-diethylaminobenzoic 473,240,98A
63[2-(1-aminoisoquinoline-7-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 5-methoxy-1H-indole-2-carboxylic acid495,191,32A
64[2-(1-amino-isoquinoline-7-ylcarbonyl)-2-hydroxy-1-phenyl-ethyl]amide 5-ethylthiophen-2-carboxylic acid460,161,31A
65[2-(1-aminoisoquinoline-7-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 5-tert-butylthiophene-2-carboxylic acid488,191,45A
66N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-phenylethyl]benzamide426,171,15A
67[2-(2-Amin-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide of 6-bromobenzophenone-2-carboxylic acid534,151,37A
68[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 5-ethylthiophen-2-carboxylic acid450,161,25A
69[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide thieno[3,2-b]thiophene-2-carboxylic acid478,151,3A
70[2-(2-Amin-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 5-methoxybenzophenone-2-carboxylic acid486,21,26A
71[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide, benzo[b]thiophene-3-carboxylic acid472,171,26A
72[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 4-methylthiophene-2-carboxylic acid436,141,18A
73N-[2-(2-aminobenzothiazole-6-ilk who rebamol)-2-hydroxy-1-phenylethyl]-4-diethylaminobenzoic; connection with triperoxonane acid503,21,42A
74[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenyl-ethyl]amide of 1H-indole-2-carboxylic acid455,221,21A
75N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-dimethylamino-benzamide; connection with triperoxonane acid459,251,06A
76[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 5-tert-butylthiophene-2-carboxylic acid478,21,38A
77N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-methoxy-3-methyl-benzamide460,191,2A
78N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-3-fluoro-4-methyl-benzamide448,17 1,22A
79[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 5-isopropylthio-3-carboxylic acid464,151,31A
805-Ethylthiophen-3-carboxylic acid [2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide450,121,24A
81[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide [2,2']bithiophene-5-carboxylic acid504,141,35A
82[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 5-methoxy-1H-indole-2-carboxylic acid; compound with triperoxonane acid495,191,26A
83N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-methoxybenzamide456,181,19 A
84N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-isopropylbenzene468,221,38A
85N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-diethylaminobenzoic497,241,05A
86N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-ethoxybenzene470,21,32A
87N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-ethylbenzamide454,21,37A
88N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-tert-butylbenzamide482,231,43A
89N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-phenylethyl]-3-dimethylaminobenzene469,21A
90N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-dimethylaminobenzene469,211,13A
91[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-phenyl-ethyl]amide 5-ethylthiophen-2-carboxylic acid460,161,32A
92[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-phenyl-ethyl]amide 5-ethylthiophen-3-carboxylic acid460,161,31A
93[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 5-tert-butylthiophene-2-carboxylic acid488,191,43A
94N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-phenylethyl]-3-ethylbenzamide454,21,36A
95N-[2-(1-aminoisoquinoline-6-ilk who rebamol)-2-hydroxy-1-phenylethyl]-3-ethoxybenzene 470,21,33A
96N-[2-(2-amino-1H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-(3-triptoreline)ethyl]-4-isopropylbenzene526,191,53A
97N-[2-(2-amino-1H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-(2-methoxyphenyl)ethyl]-4-isopropylbenzene488,351,4A
98N-[2-(2-amino-1H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-(3-triptoreline)ethyl]-4-diethylaminobenzoic555,391,23A
99N-[2-(2-amino-1H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-(2-methoxyphenyl)ethyl]-4-diethylaminobenzoic517,411,1A
100N-[2-(2-amino-1H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-(4-methoxyphenyl)ethyl]-4-ethylaminomethyl517,421,03A
101N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-1-(3-ethoxyphenyl)-2-hydroxyethyl]-4-diethyl-aminobenzamide541,271,28B
102N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-(4-isopropylphenyl)ethyl]-4-diethylaminobenzoic529,241,28A
103N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-1-(3-ethoxyphenyl)-2-hydroxyethyl]-4-isopropylbenzene502,161,46A
104N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-1-(3-ethoxyphenyl)-2-hydroxyethyl]-4-diethylaminobenzoic531,241,16A
105N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-m-triletal]-4-diethylaminobenzoic511,261,15A
106N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroc the and-1-(4-isopropylphenyl)ethyl]-4-isopropylbenzene 500,191,55A
107N-[2-(2-aminobenzothiazole-6-ylcarbonyl)-2-hydroxy-1-(4-triptoreline)ethyl]-4-isopropylbenzene542,161,53A
108N-[2-(2-aminobenzothiazole-6-ylcarbonyl)-2-hydroxy-1-m-triletal]-4-diethylaminobenzoic517,211,14A
109N-[2-(2-aminobenzothiazole-6-ylcarbonyl)-2-hydroxy-1-m-triletal]-4-isopropylbenzene488,191,42A
110N-[2-(2-aminobenzothiazole-6-ylcarbonyl)-2-hydroxy-1-(4-isopropylphenyl)ethyl]-4-diethylaminobenzoic545,251,27A
111N-[2-(2-aminobenzothiazole-6-ylcarbonyl)-1-(3-ethoxy-phenyl)-2-hydroxyethyl]-4-diethylaminobenzoic547,231,13A
N-[2-(2-aminobenzothiazole-6-ylcarbonyl)-2-hydroxy-1-(4-triptoreline)ethyl]-4-diethylaminobenzoic571,191,27A
113N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-1-(2-chlorophenyl)-2-hydroxyethyl]-4-diethylaminobenzoic521,191,06A
114N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-(4-triptoreline)ethyl]-4-isopropylbenzene526,141,5A
115N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-(4-triptoreline)ethyl]-4-diethylaminobenzoic555,241,29A
116N-[2-(2-aminobenzothiazole-6-ylcarbonyl)-1-(3-ethoxyphenyl)-2-hydroxyethyl]-4-isopropylbenzene518,21,46A
117N-[2-(2-aminobenzothiazole-6-ylcarbonyl)-1-(2-chlorophenyl)-2-hydroxic the l]-4-diethylaminobenzoic M + 1 =538/5400,93D
118N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-1-(3-bromophenyl)-2-hydroxyethyl]-4-diethylaminobenzoic575,151,35B
119N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-1-(3-bromophenyl)-2-hydroxyethyl]-4-ethylbenzamide532,111,63B
120N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-(4-isopropylphenyl)ethyl]-4-isopropylbenzene510,261,58A
121N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-1-(2-chlorophenyl)-2-hydroxyethyl]-4-isopropylbenzene502,18the 1.44B
122N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-m-triletal]-4-isopropylbenzene472,181,42A
123 N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-m-triletal]-4-diethylaminobenzoic501,231,09A
124N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-1-(4-bromophenyl)-2-hydroxyethyl]-4-diethylaminobenzoic575,151,37B
125N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-1-(4-bromophenyl)-2-hydroxyethyl]-4-isopropylbenzeneM + 1 =547/5481,24D
126N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-1-(3-bromophenyl)-2-hydroxyethyl]-4-isopropylbenzene546,131,66C
127N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-m-triletal]-4-isopropylbenzene482,231,42A
128N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-1-(3-ethoxyphenyl)-2-hydroxyethyl]-4-isopropylbenzene512,24 1,43A
129N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-(4-isopropylphenyl)ethyl]-4-diethylaminobenzoic539,291,32A
130N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-1-(2-chlorophenyl)-2-hydroxyethyl]-4-diethylaminobenzoic531,21,16A
131N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-(4-triptoreline)ethyl]-4-diethylaminobenzoic565,231,26A
132N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-(4-triptoreline)ethyl]-4-isopropylbenzene536,21,83B
133N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-1-(4-bromophenyl)-2-hydroxyethyl]-4-ethylbenzamide532,111,62C
134N-[2-(2-amino-3H-benzamid the evil-5-ylcarbonyl)-1-(3,5-acid)-2-hydroxyethyl]-4-isopropylbenzene 518,221,43A
135N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-1-(3,5-acid)-2-hydroxyethyl]-4-diethylaminobenzoic547,261,05A
136N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-propylbenzamide468,221,36A
137N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-1-(2-chlorophenyl)-2-hydroxyethyl]-4-isopropylbenzene491,171,35A
138N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-cyclopropylbenzene466,21,45B
139N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-1-(2-chlorophenyl)-2-hydroxyethyl]-4-ethylbenzamide488,161,53B
140 N-[2-(2-aminobenzothiazole-6-ylcarbonyl)-1-furan-2-yl-2-hydroxyethyl]-4-diethylaminobenzoic493,181,03B
141N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-1-(2-forfinal)-2-hydroxyethyl]-4-diethylaminobenzoic504,231,04A
142N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-1-(3,5-differenl)-2-hydroxyethyl]-4-isopropylbenzene493,191,58B
143N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-1-(3,5-differenl)-2-hydroxyethyl]-4-diethylaminobenzoic522,221,21B
144N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-1-(5-fluoro-2-methanesulfonyl)-2-hydroxy-ethyl]-4-diethylaminobenzoic582,211,36A
145N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-1-(5-fluoro-2-methanesulfonyl)-2-hydroxy-ethyl]-4-is ethylaminomethyl 553,181,54A
146N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-1-(3-chlorophenyl)-2-hydroxyethyl]-4-diethylaminobenzoic491,171,6A
147N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-1-(3-chlorophenyl)-2-hydroxyethyl]-4-diethylaminobenzoic520,21,43A
148N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-(2-trifloromethyl)ethyl]-4-isopropylbenzene541,191,6A
149N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-(2-trifloromethyl)ethyl]-4-diethylaminobenzoic570,221,47A
150N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-o-triletal]-4-diethylaminobenzoicM + 1=5120,93D
151N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-thiophene-2-ileti]-4-diethylaminobenzoic509,161,08A
1529H-fluoren-9-ylmethyl [(1S,2R)-2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenyl-ethyl]carbamate534,411,47A
1532 chlorbenzyl [2-(2-amino-3H-benzimidazole-5-yl-carbarnoyl)-2-hydroxy-1-phenylethyl]carbamate480,191,26A

The drugs examples

Method for the determination of factor IXa

Obtained in the examples of the substances tested for inhibition of enzyme activity of FIXa using substrate PEFA 3107 (Pentapharm/Loxo; via S. Black GmbH, Baumstrasse 41, 47198 Duisburg, Germany; Pr. No. 095-20) and factor IXa (Calbiochem, Merck KGaA supplies Calbiochem on the market in Germany, Life Science & Analytics, 64293 Darmstadt; Pr. No. 233290). In this way 28 μl of test buffer (50 mm α,α,α-Tris(hydroxymethyl)methylamine (TRIS), 100 mm NaCl, 5 mm CaCl2, 0.1% of bovine serum albumin, pH of 7.4) and 10 μl of factor IXa (final concentration in the test batch 277 nm) dobavlyali 2 ál of 10 mm solution of the respective test substance in dimethyl sulfoxide and the mixture is incubated for 15 minutes at room temperature in 96-polunochnom the microtiter plate. The enzymatic reaction was started by adding 10 μl of substrate (1 mm initial solution in water). The completion of the reaction was monitored at 405 nm in a reading device for microtiter plates (SpectraMax plus 384; Molecular Devices) for 15 minutes.

IR50was calculated from the average value (the determination in two repetitions of a series of dilutions of the test substances using the program Grafit 4 (Erithacus Software, UK). The inhibition constants (Ki) was calculated according to the equation of Cheng Prusoff Ki=IR50/(1+(S/Km), where S=concentration of the test substrate in the test and Km=constant Michaelis-Menten.

Table 2 presents the results.

0,17
Table 2
Connection exampleEnzymatic analysis of factor IXa
IR50[µm]
Connection exampleEnzymatic analysis of factor IXa
IR50[µm]
170,28810,57
53of 1.34870,14
680,73134

1. The compound of the formula I

and/or all isomeric forms of the compounds of formula I and/or mixtures of these forms in any ratio, and/or a physiologically acceptable salt of the compounds of formula I,
where R1 represents a
1) -(C6-C14)-aryl-Z, where Z is aminomethyl,
2) Het-Z, where Z is an amino group and where Het is unsubstituted or optionally monosubstituted by a group T,
R2 represents a
1) -(C0-alkylene-(C6-C14)-aryl, where aryl is unsubstituted or mono - or disubstituted by T, or
2) -(C0-alkylene-Het where Het is unsubstituted or monosubstituted by a group T,
R3 represents a
1) -(C0-alkylene-(C6-C14)-aryl, where aryl is unsubstituted or mono - or disubstituted by T,
2) -O-(C1-C4-alkylene-(C6-C14)-aryl, where aryl is unsubstituted or monosubstituted by a group T,
3) -(C0-alkylene-Het where Het is unsubstituted or mono-, di - or tizamidine group T,
4) -(C0-alkylene-(C6-C14)-aryl-Q-(C6-C14)-aryl, where the two aryl radicals are unsubstituted,
5) -(C0-alkylene-(C6-C14)-aryl-Q-Het, where aryl and Het in each case independently of one another are unsubstituted or disubstituted group is th T,
6) -(C0-alkylene-Het-Q-Het, where both radical Het are unsubstituted,
Q is a covalent bond, -(C1-C4-alkylene, -N((C1-C4)-alkyl)- or-O-,
T is a
1) halogen,
2) -(C1-C6)-alkyl, where alkyl is unsubstituted or disubstituted by a group -(C1-C3-foralkyl or-T-C(O)-(C1-C4)-alkyl,
3) -(C1-C3-foralkyl,
4) -(C3-C8-cycloalkyl,
5) -O-(C1-C4)-alkyl,
6) -O-(C1-C3-foralkyl,
7) -N(R10)(R11), where R10 and R11 independently from each other represent a hydrogen atom or -(C1-C6)-alkyl,
8) -C(O)-NH-R10,
9) -SO2-(C1-C4)-alkyl,
10) -SO2-(C1-C3-foralkyl,
R4 and R5 are the same and represent a hydrogen atom, and
R6 represents a hydrogen atom,
while the above Het represents a 5-to 10-membered ring system comprising 1 or 2 ring systems that are connected to each other, and in which one or two identical or different from each other heteroatoms selected from oxygen, nitrogen and sulphur.

2. The compound of formula I according to claim 1, where
R1 represents a
1) -(C6-C14)-aryl-Z -, where aryl is selected from the group consisting of phenyl and naphthyl, and Z represents aminomethyl, or
2) Het-Z, where Het is selected from the group consisting of iazepine, benzimidazolinyl, benzimidazolyl, benzofuranyl, benzothiophene, benzothiophene, benzoxazole, benzothiazole, benzisoxazole, benzisothiazole, heatline, chinoline, chinoiserie, 4H-chinoiserie, khinoksalinona, hinokitiol, Romania, chromene, cinnoline, decahydroquinoline, dihydrofuro[2,3-b]-tetrahydrofuranyl, dihydrofurane, dioxole, dioxane, dioxolane, furanyl, imidazolidinyl, imidazolyl, imidazolyl, 1H-indazole, indoline, indolizine, indoline, MN-indolyl, isobenzofuranyl, izochinolina, isopropanyl, isoindolyl, isoindoline, isoindolyl, isothiazoline, 2-isothiazoline, isothiazoline, isoxazole, isoxazolidine, 2-isoxazoline, morpholine, naphthyridine, octahydronaphthalene, oxazolidinyl, oxazolyl, oxazolidinyl, oxathiolane, phthalazine, piperazinil, piperidinyl, pyranyl, pyrazinyl, pyrazolidine, pyrazoline, pyrazolyl, pyridazinyl, peridotite, pyridyl, pyrimidinyl, pyrrolidinyl, pyrroline 2N-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinoline, tetrahydroquinoline, tetrahydropyridine, teinila, thiazolyl, teinila, thienopyridine, thienopyrrole, thienothiophene, thiomorpholine or dipiradol, and where Het is unsubstituted or monosubstituted by a group T, and where Z pre who is an amino group,
R2 represents a
1) -(C0-alkylene-(C6-C14)-aryl, where aryl has the meaning defined above and is unsubstituted or mono - or disubstituted by T, or
2) -(C0-alkylene-Het, where Het has the meaning defined above and is unsubstituted or monosubstituted by a group T,
R3 represents a
1) -(C0-alkylene-(C6-C14)-aryl, where aryl has the meaning defined above and is unsubstituted or mono - or disubstituted by T,
2) -(C0-alkylene-Het, where Het has the meaning defined above and is unsubstituted or mono-, di - or tizamidine group T,
3) -(C0-alkylene-(C6-C14)-aryl-Q-(C6-C14)-aryl, where two aryl in each case independently of one another have the meanings defined above, and both are unsubstituted,
4) -(C0-alkylene-(C6-C14)-aryl-Q-Het, where aryl and Het have the meanings given above, and in each case independently of one another are unsubstituted or disubstituted by T, or
5) -(C0-alkylene-Het-Q-Het, where two radicals Het have the meanings given above, and both are unsubstituted,
Q is a covalent bond, -(C1-C4-alkylene, -N((C1-C4)-alkyl)- or-O-,
T is a
1) halogen,
2) -(C1-C6)-alkyl, where alkyl is the tsya unsubstituted or disubstituted by a group -(C 1-C3-foralkyl or-N-C(O)-(C1-C4)-alkyl,
3) -(C1-C3-foralkyl,
4) -(C3-C6-cycloalkyl,
5) -O-(C1-C4)-alkyl,
6) -O-(C1-C3-foralkyl,
7) -N(R10)(R11), where R10 and R11 independently from each other represent a hydrogen atom or -(C1-C6)-alkyl,
8) -C(O)-NH-R10,
9) -SO2-(C1-C4)-alkyl or
10) -SO2-(C1-C3-foralkyl,
R4 and R5 are the same and represent a hydrogen atom, and
R6 represents a hydrogen atom.

3. The compound of formula I according to claim 1 or 2, where
R1 represents aminomethylphenol or Het-Z, where Het is selected from the group consisting of benzimidazolyl, benzothiazolyl and izochinolina, and where Z represents amino,
R2 represents (1) phenyl, where phenyl is unsubstituted or mono - or disubstituted by T, or
2) Het-1, Het-1 is selected from the group consisting of furanyl, pyrazolyl or tanila, and Het-1 is unsubstituted or monosubstituted by a group T,
R3 represents a
1) phenyl, where phenyl is unsubstituted or mono - or disubstituted by T,
2) Het-2, where Het-2 is selected from the group consisting of benzimidazolyl, benzofuranyl, benzothiophene, chinoline, khinoksalinona, furanyl, indolyl, izochinolina, isoxazolyl, morpholinyl, piperidinyl, pyridyl, pyrimidinyl, pyrrolidine is a, pyrrolyl, teinila, thienopyrrole or thienothiophene, and where Het-2 is unsubstituted or mono - or disubstituted by T,
3) -phenyl-Q-phenyl, where both the phenyl radicals are unsubstituted,
4) phenyl-Q-Het-2, where Het-2 has the meaning defined above, and phenyl and Het-2, in each case independently of one another are unsubstituted or disubstituted by T,
5) Het-2-Q-Het-2, where two radicals Het-2 have the meanings given above, and both are unsubstituted,
Q is a covalent bond, -CH2-, -N(CH3)- or-O-,
T is a
1) F, Cl or Br,
2) -(C1-C4)-alkyl, where alkyl is unsubstituted or disubstituted by the group-CF3or-N-C(O)-CH3,
3) -CF3,
4) -O-(C1-C4)-alkyl,
5) -O-CF3,
6) -N(R10)(R11), where R10 and R11 independently from each other represent a hydrogen atom or -(C1-C4)-alkyl or
7)-SO2-CH3,
R4, R5 and R6 in each case represent a hydrogen atom.

4. The compound of formula I according to claim 1, which represents the following connection
N-[(1S,2R)-2-(1-aminoisoquinoline-7-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-tert-butylbenzamide,
N-[(1S,2R)-2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-diethylaminobenzoic,
N-[(1S,2R)-2-(2-aminobenzothiazole-6-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-isopropylbenzene,
N-[(1R,2R)-2-(1-aminoazo inolin-6-ylcarbonyl)-1-furan-2-yl-2-hydroxyethyl]-4-diethylaminobenzoic,
N-[(1S,2R)-2-(2-aminobenzothiazole-6-ylcarbonyl)-1-(2-chlorophenyl)-2-hydroxyethyl]-4-isopropylbenzene,
N-[(1S,2R)-2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-1-(2-forfinal)-2-hydroxyethyl]-4-isopropylbenzene,
N-[(1S,2R)-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-tert-butylbenzamide,
N-[(1S,2R)-2-(4-aminomethylpropanol)-2-hydroxy-1-phenylethyl]benzamide,
N-[(1S,2R)-2-(2,4-diaminoquinazoline-6-ylcarbonyl)-2-hydroxy-1-phenylethyl]benzamide,
4-amino-N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]benzamide,
[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide cinoxacin-2-carboxylic acid,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-methoxybenzamide,
[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide thiophene-3-carboxylic acid,
[(1S,2R)-2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 1-methyl-1H-pyrrole-2-carboxylic acid,
[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide of the quinoline-2-carboxylic acid,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-cyclohexylbenzene,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-isopropylbenzene,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-triptoreline-benzamid,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)2-hydroxy-1-phenylethyl]-4-diethylaminobenzoic,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-phenoxybenzamide,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-benzyl-benzamide,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-isopropoxybenzoic,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-methylsulfonylbenzoyl,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-metilsulfonilmetane,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-[(4,6-dimethylpyrimidin-2-yl)methylamino]benzamide,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-pyridin-3-ylbenzene,
4-(2-acetylamino-3,3,3-cryptochromes)-N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]benzamide,
[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 1-methyl-1H-indole-2-carboxylic acid,
[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 5-methoxy-1H-indole-2-carboxylic acid,
[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 5-ethyl-1H-indole-2-carboxylic acid,
[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide of 6-methoxy-1H-indole-2-carboxylic acid,
[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 4-methoxyquinoline-2-carboxylic acid,
[2-(2-amino-3H-benzimidazole-5-ilıca bemail)-2-hydroxy-1-phenylethyl]amide 3-ethoxyphenoxy-2-carboxylic acid,
[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide naphthalene-2-carboxylic acid,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-pyrrol-1-ylbenzene,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-triftormetilfullerenov,
[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide biphenyl-4-carboxylic acid,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-(2,2,2-triptoreline)benzamid,
benzyl[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]carbamate,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-ethylbenzamide,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-ethoxybenzene,
[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 5-butylpyrazine-2-carboxylic acid,
[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide, benzo[b]thiophene-2-carboxylic acid,
[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide of 6-methoxynaphthalene-2-carboxylic acid,
[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 4-(2,2,2-triptorelin)-4H-thieno[3,2-b]pyrrole-5-carboxylic acid,
4'-{[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide}3-methylamide biphenyl-3,4'-dicarboxylic acid,
N-[2-(1-aminoisoquinoline-7-yl who carbamoyl)-2-hydroxy-1-phenylethyl]-4-diethylaminobenzoic,
N-[2-(1-aminoisoquinoline-7-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-isopropylbenzene,
N-[2-(3-aminoisoquinoline-7-ylcarbonyl)-2-hydroxy-1-phenylethyl]-6-pyrrolidin-1-iniatiated,
N-[2-(1-aminoisoquinoline-7-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-morpholine-4-ylbenzene,
N-[2-(1-aminoisoquinoline-7-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-pyrrol-1-ylbenzene,
[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 1-ethyl-2,3-dimethyl-1H-indole-5-carboxylic acid,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-morpholine-4-ylbenzene,
N-[2-(1-aminoisoquinoline-7-ylcarbonyl)-2-hydroxy-1-phenylethyl] -4-pyrrolidin-1-ylbenzene,
N-[2-(1-aminoisoquinoline-7-ylcarbonyl)-2-hydroxy-1-phenylethyl]-6-morpholine-4-yl-nicotinamide,
[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 5,6-dimethoxy-1H-indole-2-carboxylic acid,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-pyrrolidin-1-ylbenzene,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-isobutylbenzene,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-butylbenzamide,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-propylbenzamide,
4H-thieno[3,2-b]pyrrole-5-carboxylic acid [2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide,
[2-(1-aminoisoquinoline-7-ylcarbonyl-2-hydroxy-1-phenylethyl]amide 5-methoxy-1H-indole-2-carboxylic acid,
5-ethylthiophen-2-carboxylic acid [2-(1-aminoisoquinoline-7-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide,
[2-(1-aminoisoquinoline-7-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 5-tert-butyl-thiophene-2-carboxylic acid,
N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-phenylethyl]benzamide,
[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide of 6-bromobenzophenone-2-carboxylic acid,
[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 5-ethyl-thiophene-2-carboxylic acid,
[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide thieno[3,2-b]thiophene-2-carboxylic acid,
[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 5-methoxybenzophenone-2-carboxylic acid,
[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide, benzo[b]thiophene-3-carboxylic acid,
[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 4-methylthiophene-2-carboxylic acid,
N-[2-(2-amino-benzothiazole-6-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-diethylaminobenzoic,
[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide of 1H-indole-2-carboxylic acid,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-dimethylaminobenzene,
[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 5-tert-butylthiophene-2-carboxylic acid,
N-[2-(2-amino-3H-benzamid the evil-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-methoxy-3-methylbenzamide,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]-3-fluoro-4-methylbenzamide,
[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 5-isopropylthio-3-carboxylic acid,
[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 5-ethylthiophen-3-carboxylic acid,
[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide [2,2']bithiophene-5-carboxylic acid,
[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 5-methoxy-1H-indole-2-carboxylic acid,
N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-methoxybenzamide,
N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-isopropylbenzene,
N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-diethylaminobenzoic,
N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-ethoxybenzene,
N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-ethylbenzamide,
N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-tert-butylbenzamide,
N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-phenylethyl]-3-dimethylaminobenzene,
N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-dimethylaminobenzene,
[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 5-ethyl-thiophene-2-carboxylic acid,
[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-peneliti is]amide 5-ethylthiophen-3-carboxylic acid,
[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-phenylethyl]amide 5-tert-butylthiophene-2-carboxylic acid,
N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-phenylethyl]-3-ethylbenzamide,
N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-phenylethyl]-3-ethoxybenzene,
N-[2-(2-amino-1H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-(3-triptoreline)ethyl]-4-isopropylbenzene,
N-[2-(2-amino-1H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-(2-methoxyphenyl)ethyl]-4-isopropylbenzene,
N-[2-(2-amino-1H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-(3-triptoreline)ethyl]-4-diethylaminobenzoic,
N-[2-(2-amino-1H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-(2-methoxyphenyl)ethyl]-4-diethylaminobenzoic,
N-[2-(2-amino-1H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-(4-methoxyphenyl)ethyl]-4-diethylaminobenzoic,
N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-1-(3-ethoxyphenyl)-2-hydroxyethyl]-4-diethylaminobenzoic,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-(4-isopropylphenyl)ethyl]-4-diethylaminobenzoic,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-1-(3-ethoxyphenyl)-2-hydroxyethyl]-4-isopropylbenzene,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-1-(3-ethoxyphenyl)-2-hydroxyethyl]-4-diethylaminobenzoic,
N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-m-triletal]-4-diethylaminobenzoic,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-(4-isopropylphenyl)ethyl]-4-isoprop benzamid,
N-[2-(2-aminobenzothiazole-6-ylcarbonyl)-2-hydroxy-1-(4-triptoreline)ethyl]-4-isopropylbenzene,
N-[2-(2-aminobenzothiazole-6-ylcarbonyl)-2-hydroxy-1-m-triletal]-4-diethylaminobenzoic,
N-[2-(2-aminobenzothiazole-6-ylcarbonyl)-2-hydroxy-1-m-tolyl-ethyl]-4-isopropylbenzene,
N-[2-(2-aminobenzothiazole-6-ylcarbonyl)-2-hydroxy-1-(4-isopropylphenyl)ethyl]-4-diethylaminobenzoic,
N-[2-(2-aminobenzothiazole-6-ylcarbonyl)-1-(3-ethoxyphenyl)-2-hydroxyethyl]-4-diethylaminobenzoic,
N-[2-(2-aminobenzothiazole-6-ylcarbonyl)-2-hydroxy-1-(4-triptoreline)ethyl]-4-diethylaminobenzoic,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-1-(2-chlorophenyl)-2-hydroxyethyl]-4-diethylaminobenzoic,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-(4-triptoreline)ethyl]-4-isopropylbenzene,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-(4-triptoreline)ethyl]-4-diethylaminobenzoic,
N-[2-(2-aminobenzothiazole-6-ylcarbonyl)-1-(3-ethoxyphenyl)-2-hydroxyethyl]-4-isopropylbenzene,
N-[2-(2-aminobenzothiazole-6-ylcarbonyl)-1-(2-chlorophenyl)-2-hydroxyethyl]-4-diethylaminobenzoic,
N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-1-(3-bromophenyl)-2-hydroxyethyl]-4-diethylaminobenzoic,
N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-1-(3-bromophenyl)-2-hydroxyethyl]-4-ethylbenzamide,
N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-(4-isopropylphenyl)ethyl]-4-isopropylbenzene,
N-[2-1-aminoisoquinoline-6-ylcarbonyl)-1-(2-chlorophenyl)-2-hydroxyethyl]-4-isopropylbenzene,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-m-triletal]-4-isopropylbenzene,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-m-triletal]-4-diethylaminobenzoic,
N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-1-(4-bromophenyl)-2-hydroxyethyl]-4-diethylaminobenzoic,
N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-1-(4-bromophenyl)-2-hydroxyethyl]-4-isopropylbenzene,
N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-1-(3-bromophenyl)-2-hydroxyethyl]-4-isopropylbenzene,
N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-m-triletal]-4-isopropylbenzene,
N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-1-(3-ethoxyphenyl)-2-hydroxyethyl]-4-isopropylbenzene,
N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-(4-isopropylphenyl)ethyl]-4-diethylaminobenzoic,
N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-1-(2-chlorophenyl)-2-hydroxyethyl]-4-diethylaminobenzoic,
N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-(4-triptoreline)ethyl]-4-diethylaminobenzoic,
N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-(4-triptoreline)ethyl]-4-isopropylbenzene,
N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-1-(4-bromophenyl)-2-hydroxyethyl]-4-ethylbenzamide,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-1-(3,5-acid)-2-hydroxyethyl]-4-isopropylbenzene,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-1-(3,5-acid)-2-hydroxyethyl]-4-diethylaminobenzoic,
N-[2-(1-aminoisoquinoline-6-ilkar email)-2-hydroxy-1-phenylethyl]-4-propylbenzamide,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-1-(2-chlorophenyl)-2-hydroxyethyl]-4-isopropylbenzene,
N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-2-hydroxy-1-phenylethyl]-4-cyclopropylbenzene,
N-[2-(1-aminoisoquinoline-6-ylcarbonyl)-1-(2-chlorophenyl)-2-hydroxyethyl]-4-ethylbenzamide,
N-[2-(2-aminobenzothiazole-6-ylcarbonyl)-1-furan-2-yl-2-hydroxyethyl]-4-diethylaminobenzoic,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-1-(2-forfinal)-2-hydroxyethyl]-4-diethylaminobenzoic,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-1-(3,5-differenl)-2-hydroxyethyl]-4-isopropylbenzene,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-1-(3,5-differenl)-2-hydroxyethyl]-4-diethylaminobenzoic,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-1-(5-fluoro-2-methanesulfonyl)-2-hydroxyethyl]-4-diethylaminobenzoic,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-1-(5-fluoro-2-methanesulfonyl)-2-hydroxyethyl]-4-diethylaminobenzoic,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-1-(3-chlorophenyl)-2-hydroxyethyl]-4-diethylaminobenzoic,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-1-(3-chlorophenyl)-2-hydroxyethyl]-4-diethylaminobenzoic,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-3-(2-trifloromethyl)ethyl]-4-isopropylbenzene,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-(2-trifloromethyl)ethyl]-4-diethylaminobenzoic,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydrox the-1-o-triletal]-4-diethylaminobenzoic,
N-[2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-thiophene-2-ileti]-4-diethylaminobenzoic,
N-fluoren-9-ylmethyl [(1S,2R)-2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]carbamate or
2 chlorbenzyl [2-(2-amino-3H-benzimidazole-5-ylcarbonyl)-2-hydroxy-1-phenylethyl]carbamate.

5. The use of the compounds of formula I according to one or more of claims 1 to 4 to obtain drugs for the prophylaxis, secondary prophylaxis and therapy of all diseases that are accompanied by thrombosis, embolism, the ability to hypercoagulability or fibrotic changes.

6. The use according to claim 5, where the disease is a myocardial infarction, angina and other forms of acute coronary syndrome, stroke, peripheral vascular disease, deep vein thrombosis, embolism blood vessels of the lungs, embolic or thrombotic phenomena caused by cardiac arrhythmia, cardiovascular events such as restenosis after revascularization and angioplasty and similar procedures, such as stent implantation and operations associated with bypass surgery, or to reduce the risk of thrombosis after surgery, such as knee and hip joints, or disseminated intravascular coagulation, sepsis and other intravascular phenomena that accompany inflammation, atherosclerosis, diabetes, the metabolic syndrome and its complications, tumor growth and tumor metastasis, inflammatory and degenerative joint diseases such as rheumatoid arthritis and osteoarthritis, disorders of the hemostatic system, such as fibrin deposits, fibrotic changes of the lung, such as chronic obstructive pulmonary disease, respiratory distress syndrome of adults, or fibrin deposits in the eye after eye operations, or for prophylaxis and/or treatment of scarring.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and ,

where the ring X represents benzole or pyridine; R1 represents substituted alkyl; R2 represents optionally substituted aryl or optionally substituted 4-7-member monocyclic heterocyclic group or optionally substituted condensed group of heterocyclic group with the benzole ring where the substitutes of optionally substituted aryl, optionally substituted 4-7-member monocyclic heterocyclic group and optionally substituted condensed group of heterocyclic group with the benzole ring are selected from a group consisting of; (1) alkyl optionally substituted by a group selected from halogen and alkoxycarbonyl, (2) alkoxy optionally substituted by halogen, (3) halogen, (4) 4-7-member monocyclic heterocyclic group or (5) amino, optionally mono- or disubstituted alkyl, and (6) hydroxyl, R3 represents hydrogen or alkyl: R4 represents hydrogen, halogen or alkyl; R5 represents hydrogen or alkyl; R6 and R7 are identical or different, and each represents hydrogen or halogen; or pharmaceutically acceptable salt. Also, the invention refers to a IKur blocker containing the compounds described above as an active ingredient, and also to a preventive and therapeutic agent for cardiac arrhythmia and atrial fibrillation.

EFFECT: there are produced and described new compounds applicable as a IKur blocker effective for preventing or treating cardiac arrhythmia, such as atrial fibrillation.

12 cl, 13 ex

FIELD: chemistry.

SUBSTANCE: compounds can be used to treat such diseases as hypertension, congestive heart failure, cardiac hypertrophy and others. In formula I R1 denotes a) cyclohexyl or trifluoromethyl; or b) phenyl, 2-thienyl, 3-thienyl, 2-pyridyl, 2-imidazolyl, 2-thiazolyl, 2-benzothienyl, 4-benzofuryl, 4-benzothienyl, 7-benzofuryl, 2,3-dihydro-7-benzofuryl, 7-benzothienyl, 1,3-benzodioxol-4-yl, 7-indazolyl, or 8-quinolinyl, optionally substituted with 1-3 substitutes, and X and Y each denotes a single bond; R2 denotes methyl, ethyl, propyl, butyl, pentyl, hexyl, 5-pentenyloxy, 3,33-trifluoropropyl, 4,4-difluoropentyl, 3-(cyclopropyl)propyl, 4-(cyclopropyl)butyl, 3-hydroxypropyl, 4-hydroxybutyl, 4-hydroxypentyl, 4-hydroxyhexyl, 5-hydroxyhexyl, 2-hydroxyethoxy etc, given in the claim; R3 denotes H, F, OH, methoxy, ethoxy, 3-hydroxypropoxy, acetylamino, propionylamino, (2-methylpropionyl)amino, or butanoylamino; A denotes 2,4-disubstituted morpholine with R1XCR2R3Y, bonded on the second position and Q bonded on the fourth position, 1,3-disubstituted piperidine with R1XCR2R3Y bonded on the third position and Q bonded on the first position, 1,3-dibustituted-3-methylpiperidine with R1XCR2R3Y bonded on the third position and Q bonded on the first position, 1,3-disubstituted benzene or 1,3-disubstituted cyclohexane; Q denotes Q1, Q2, Q4, Q5, Q9, or Q10 given in the claim, to which A and N are bonded on cut-off bonds, R4 denotes H or methyl.

EFFECT: obtaining novel compounds having aspartic protease inhibitor properties, particularly renin inhibitor.

10 cl, 1 tbl, 166 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula I or their pharmaceutically acceptable salts exhibiting the properties of voltage-dependent sodium channel inhibitors, such as NaV1.8. The latter play a central role in generating the action potentials in all excitable cells such as neurons and myocytes, and can be used for treating such diseases as epilepsy, irritable bowel syndrome, chronic pain, etc. In the compounds of formula I: R1 and R2 together with nitrogen atom a substituted ring selected from: (A),(B),(C),(D) or (E), which are specified in the patent claim, where in the ring (A): each of m1 and n1 is independently equal to 0-3, provided m1+n1 is equal to 3-4; z1 is equal to 0-4; Sp1 represents -O-, -S-, -NR'- or C1-C4alkylidene linker in which one methylene ring is optionally or independently substituted by -O-, provided Sp1 is bound with carbonyl group through an atom different from carbon; the ring B1 represents a 5-6-members saturated or aromatic, monocyclic or heterocyclic ring containing 1-4 heteroatoms selected from O or N with the ring B1 is optionally substituted by w1 independent variants -R11 with w1 being equal to 0-1; where in the ring (B): G2 represents CH; each of m2 and n2 is independently equal to 0-3, provided m2+n2 is equal to 2-4; p2 is equal to 0-2; q2 is equal to 0 or 1; z2 is equal to 0-4; Sp2 represents a bond or C1-C6alkylidene linker in which up to two methylene links are optionally or independently substituted by -O-. The other radical values are specified in the patent claim.

EFFECT: making new compounds of formula I or to their pharmaceutically acceptable salts showing the properties of voltage-dependent sodium channel inhibitors.

67 cl, 4 tbl, 503 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described compounds of formula

as well as their pharmaceutically acceptable salts where the substitutes are those as described in the patent claim. The compounds of formula (I) are 11β-hydroxysteroid dehydrogenase (11β-HSD) enzyme inhibitors.

EFFECT: making the compounds effective for treating and preventing the diseases, such as insulin-independent diabetes and metabolic syndrome, particularly obesity, eating disorders or dislipidemia.

15 cl, 1 tbl, 28 ex

FIELD: chemistry.

SUBSTANCE: present invention is related to new quinolone derivatives of general formula (I) where R1: C3-6cycloalkyl or lower alkylene C3-6cycloalkyl, R2: -H or halogen, R3: -H, halogen, -OR0 or -O-(lower alkylene)-phenyl, R0: are the same or different from each other, and each represents -H or lower alkyl, R4: lower alkyl, halogen(lower alkyl), lower alkyleneC3-6cycloalkyl, C3-7cycloalkyl or a heterocyclic group, where cycloalkyl and the heterocyclic group specified in R4 can be respectively substituted, R5: -NO2, -CN, -L-Ra, -C(O)R0, -O-Rb, -N(R6)2, lower alkylene-N(R6)(Rc), -N(R6)C(O)-Rd, lower alkylene-N(R6)C(O)-Rd, lower alkylene-N(R0)C(O)O-(lower alkyl), -N(R0)C(O)N(R0)-Re, lower alkylene-N(R0)C(O)N(R0)-Re, -N(R0)S(O)2N(R0)C(O)-Rd, -CH=NOH, C3-6cycloalkyl, (2,4-dioxo-1,3-thiazolidin-5-yliden)methyl or (4-oxo-2-tioxo-1,3-thiazolidin-5-yliden)methyl where cycloalkyl specified in R5 can be respectively substituted, R6: H, lower alkyl, lower alkylene-CO2R0 or lower alkylene-P(O)((OPp)2, where lower alkylene specified in R6 can be substituted, L: lower alkylene or lower alkenylene which can be respectively substituted, Ra: -OR0, -O-(lower alkylene)-phenyl, -O-(lower alkylene)-CO2R0, -CO2R0, -C(O)NHOH, -C(O)N(R6)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-phenyl, -C(O)N(R0)-S(O)2-(heterocyclic group), -NH2OH, -OC(O)R0, -OC(O)-(halogen(lower alkyl)), -P(O)(ORp)2, phenyl or the heterocyclic group where phenyl or the heterocyclic group specified in Ra can be substituted, Rp: R0, lower alkylene-OC(O)-(lower alkyl), lower alkylene-OC(O)-C3-6cycloalkyl, lower alkylene-OC(O)O-(lower alkyl), Rb: H, lower alkylene-Rba or lower alkenylene-Rba where lower alkylene or lower alkenylene specified in Rb can be substituted, Rba: -OR0, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-[phenyl, -C(NH2)-NOH, -C(NH2)=NO-C(O)-(lower alkylene)-C(O)R0, -CO2-(lower alkylene)-phenyl, -P(O)(ORp)2, -C(O)R0, -C(O)-phenyl, C3-6cycloalkyl, phenyl or the heterocyclic group where phenyl and the heterocyclic group specified in Rba can be substituted, Rc: H, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-P(O)((OPp)2, phenyl where lower alkylene and phenyl are specified in Rd can be substituted, Rd: C1-7-alkyl, lower alkenyl, halogen(lower alkyl), lower alkylene-Rda, lower alkylenylene-Rda, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where lower alkylene, cycloalkyl, phenyl, naphthyl and the heterocyclic group specified in Rd can be substituted, Rda: -CN, -OR0, -O-(lower alkylene)-CO2R0, -O-naphthyl, -CO2R0, -CO2-(lower alkylene)-N(R0)2, -P(O)(ORp)2, -N(R6)2, -C(O)N(R0)-phenyl, -C(O)N(R0)-(lower alkylene which can be used by -CO2R0)-phenyl, -N(R0)C(O)-phenyl, -N(R0)C(O)-OR0, -N(R0)C(O)-O-(lower alkylene)-phenyl, -N(R0)S(O)2-phenyl, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where phenyl, naphthyl and heterocyclic group specified in Ra can be substituted, Re: lower alkylene-CO2R0, phenyl, -S(O)2-phenyl or -S(O)2-(heterocyclic group), where phenyl and the heterocyclic group specified in Re can be substituted, X: CH, A: C(R7), R7: -H, or R4 and R7 together can form lower alkylene, where the substituted groups have the substituted specified in cl.1, and provided 7-(cyclohexylamino)-1-ethyl-6-fluor-4-oxo-1,4-dohydroquinoline-3-carbonitryl is excluded. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I) and application of formula (I) for preparing a thrombocyte aggregation inhibitor or a P2Y12 inhibitor.

EFFECT: there are produced new quinol-4-one derivatives showing effective biological properties.

11 cl, 83 tbl, 71 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula

, where X denotes a 5-member heterocylic group bonded through a carbon atom, selected from thiophenyl, furanyl, pyrazolyl and pyrrolyl, which can be substituted with 1-3 Ra groups; T denotes O, S; B is as indicated in the claim; Z1 denotes an unsubstituted cyclopropyl; Z2 denotes a hydrogen atom, C1-C8alkyl; or C1-C8alkoxycarbonyl; Z3 independently denotes a hydrogen atom. The invention also relates to a fungicidal composition containing a compound of formula (I) as an active ingredient, and a plant pathogenic fungus control method in agricultural plants.

EFFECT: obtaining compounds of formula (I), having fungicidal activity.

9 cl, 3 dwg, 255 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula or pharmaceutically acceptable salt thereof, synthesis methods thereof, pharmaceutical compositions containing said compounds, and use thereof to prepare a medicinal agent having mTOR kinase and/or PI3K kinase inhibiting action.

EFFECT: improved properties of the derivatives.

15 cl, 72 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel C-phenyl glycitol compound which serves as a preventive or therapeutic agent for sugar diabetes by inhibiting SGLT1 activity, as well as SGLT2 activity; demonstrating inhibiting effect on glucose absorption, and also acts on release of glucose with urine. The C-phenyl glycitol compound has formula (I) given below, or pharmaceutically acceptable salt or hydrate thereof, where R1 and R2 are identical or different and denote a hydrogen atom, a hydroxyl group, a C1-6 alkyl group, a C1-6 alkoxy group or a halogen atom, R3 is a hydrogen atom, a C1-6 alkyl group or a C1-6 alkoxy group, Y is a C1-6 alkylene group, -O-(CH2)n- (n is a whole number which assumes values from 1 to 4), provided that when Z denotes -NHC(= NH)NH2 or -NHCON(RB)Rc, n not equal to 1, Z is -CONHRA, -NHC(=NH)NH2 or -NHCON(RB)Rc, or The invention also relates to a pharmaceutical composition based on compounds of formula I.

EFFECT: high efficiency of the compounds.

19 cl, 8 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel organic compounds of formula where R1 denotes H; halogen; -C0-C7-alkyl-O-R3; -NR4R5; R2 denotes phenyl, substituted with one or two substitutes selected from a group consisting of C1-7alkyl, halogen-C1-7alkyl, C1-7alkoxy, halogen-C1-7alkoxy, phenoxy, halogen, C1-7alkylpiperazinyl-C1-7alkyl, C3-C8-cyclalkyl, C1-7alkylpiperidinyl-C1-7alkyl and C1-7alkylimidazolyl; R3 denotes H or phenyl-lower alkyl; R4 and R5 are independently selected from a group consisting of H; lower alkyl; lower alkoxy-carbonyl and amino; A, B and X are independently selected from C(R7) or N, provided that not more than one or A, B and X denotes N; R7 denotes H; R8 denotes hydrogen; n equals 0; Y denotes O; Z denotes C; W is absent; K denotes N or C, and either a) if K denotes C, the bond shown by a wavy line () is a double bond, Q is selected from O-N, S-N, O-CH and S-CH, where in each case, the left-hand O or S atom is bonded through a bond shown in formula I to K, the right-hand N or carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by the dotted line, is a double bond with C; and the bond shown by a thick line () is a single bond; or b) if K denotes N, the bond shown by a wavy line () is a single bond; Q denotes N=CH, where the left-hand N atom is bonded through a bond shown in formula I to K, the right-hand carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by a dotted line, is a single bond with C; and the bond shown by thick line () is a double bond; or salt thereof (preferably pharmaceutically acceptable salt). The invention also relates to a pharmaceutical composition, having inhibiting action on protein kinase, containing a compound of formula I or salt thereof in an effective amount and at least one pharmaceutically acceptable carrier material.

EFFECT: heterocyclic carboxamides as kinase inhibitors.

12 cl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula (I) and pharmaceutically acceptable salt thereof, where m denotes a direct bond; n equals 0, 1, 2, 3 or 4 and n equals zero indicates a direct bond; p equals 1; s denotes a direct bond; t denotes a direct bond; R1 and R2 each independently denotes hydrogen; A denotes a radical selected from , where R4 and R5 are each independently selected from hydrogen or C1-6alkyloxy; Z denotes a radical (b-2), where R6 and R7 each independently denotes hydrogen. The invention also describes a pharmaceutical composition for treating cancer and preparation method thereof, based on compounds of formula I, use of these compounds to obtain a medicinal agent, as well as a method of producing said compounds.

EFFECT: novel compounds which can be used as p53-MDM2 interaction inhibitors are obtained and described.

10 cl, ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and ,

where the ring X represents benzole or pyridine; R1 represents substituted alkyl; R2 represents optionally substituted aryl or optionally substituted 4-7-member monocyclic heterocyclic group or optionally substituted condensed group of heterocyclic group with the benzole ring where the substitutes of optionally substituted aryl, optionally substituted 4-7-member monocyclic heterocyclic group and optionally substituted condensed group of heterocyclic group with the benzole ring are selected from a group consisting of; (1) alkyl optionally substituted by a group selected from halogen and alkoxycarbonyl, (2) alkoxy optionally substituted by halogen, (3) halogen, (4) 4-7-member monocyclic heterocyclic group or (5) amino, optionally mono- or disubstituted alkyl, and (6) hydroxyl, R3 represents hydrogen or alkyl: R4 represents hydrogen, halogen or alkyl; R5 represents hydrogen or alkyl; R6 and R7 are identical or different, and each represents hydrogen or halogen; or pharmaceutically acceptable salt. Also, the invention refers to a IKur blocker containing the compounds described above as an active ingredient, and also to a preventive and therapeutic agent for cardiac arrhythmia and atrial fibrillation.

EFFECT: there are produced and described new compounds applicable as a IKur blocker effective for preventing or treating cardiac arrhythmia, such as atrial fibrillation.

12 cl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

and pharmaceutically acceptable salts and solvates thereof, in which R1 is an optionally substituted alkyl or similar, R2 is a group of formula: -Y-R5, where Y is -O- or S; R5 is a substituted alkyl (the substitute is an optionally substituted cycloalkyl or similar), a branched alkyl or similar; R4 is hydrogen or C1-10 alkyl; R3 is a group of formula: -C(=O)-Z-R6, where Z is -NR7- or -NR7-W-; R6 is an optionally substituted cycloalkyl or similar; R7 is hydrogen or C1-10 alkyl, W is C1-10 alkylene; X is =N- provided that a compound in which R2 is 2-(4-morpholino)ethoxy, 2-, 3- or 4-pyridylmethoxy, 1-methylpiperidinyl-2-methoxy, benzyloxy or 4-substituted benzyloxy is excluded; and R3 is N-(1-adamantyl)carbamoyl, N-(2-adamantyl)carbamoyl and N-(3-noradamantyl)carbamoyl. Said compound is an 11β-hydroxysteroid dehydrogenase type 1 inhibitor. The invention also relates to a pharmaceutical composition containing said compound as an active ingredient.

EFFECT: improved properties of the compound.

23 cl, 72 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound of general formula I

,

and a pharmaceutically acceptable salt thereof, where X denotes CH2, CHF or S, Y denotes CN, R1, R2, R3 and R4 denotes hydrogen, n equals 1, m equals 0 or 1, R denotes R11, R12 or R13, where R11 includes at least one group selected from the following b) or c), where optionally substituted heterocyclic and heteroaryl groups are bonded with a noradamantyl part either directly or through a methylene adjacent group or a C-C bond or C-N bond; b) the substituted 5-member heteroaryl group, in which the heteroaryl ring is a monocyclic aromatic ring system, includes two or more heteroatoms selected from nitrogen and oxygen; c) the heterocyclic group is optionally substituted with a C1-C3 alkyl or oxo group, where the heterocyclic ring system is a 5-9-member mono- or bicyclic ring system with one or more heteroatoms selected from a group consisting of nitrogen and sulphur, where heteroatoms can also be present as functional groups, where the heterocyclic ring system can contain one or two double bonds, and where the monocyclic heterocyclic ring can be condensed with a phenyl ring, R12 is selected from hydrogen, halogen, hydroxy, amino and C1-C4 alkoxy; R13 is a substituted phenyl, where the substitutes, which can be identical or different, include at least one group selected from a) hydrogen; b) nitro, amino; c) the saturated or unsaturated monocyclic heterocyclic ring system is optionally substituted with one or more groups selected from C1-C3 alkyl and oxo, where the heterocyclic ring system is a 5-member ring with one or more heteroatoms selected from a group consisting of nitrogen and sulphur, where the heteroatoms can also be present as functional groups. The present invention also relates to a pharmaceutical composition having dipeptidyl peptidase IV inhibiting activity, methods of obtaining the novel compound of formula I and use in treating type II diabetes and diabetic complications as well as for treating dyslipidaemia, hypercholesteremia, obesity and hyperglycaemia.

EFFECT: novel dipeptidyl peptidase IV inhibitors.

10 cl, 1 tbl, 43 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new indazole derivants with the formula (1.0) or to their pharmaceutically acceptable salts and isomerides that act as inactivators in relation to ERK2. In formula (1.0): meanings of the chemical groups Q, R1, R2 are given in the invention formula. The invention also refers to the pharmaceutical composition containing the mentioned compounds and to application of the compounds with the formula (1.0) for production of crude drugs used in malignant growth treatment.

EFFECT: application of the compounds for production of crude drugs used in malignant growth treatment.

65 cl, 611 ex, 27 tbl

FIELD: chemistry.

SUBSTANCE: present invention refers to the compound 5-[3-[(2S)-1-(difluoromethoxy)-propane-2-yl]-oxy-5-[(5-methylpyrazin-2-yl)-carbamoyl]]phenoxy]-N,N-dimethyl-pyrazine-2-carboxamide. The invention also refers to a pharmaceutical composition, and also to application of the compound under cl.1.

EFFECT: making the new biologically active compounds showing GLK (glucokinase) activator activity.

5 cl, 6 ex, 2 tbl, 2 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula I or their pharmaceutically acceptable salts exhibiting the properties of voltage-dependent sodium channel inhibitors, such as NaV1.8. The latter play a central role in generating the action potentials in all excitable cells such as neurons and myocytes, and can be used for treating such diseases as epilepsy, irritable bowel syndrome, chronic pain, etc. In the compounds of formula I: R1 and R2 together with nitrogen atom a substituted ring selected from: (A),(B),(C),(D) or (E), which are specified in the patent claim, where in the ring (A): each of m1 and n1 is independently equal to 0-3, provided m1+n1 is equal to 3-4; z1 is equal to 0-4; Sp1 represents -O-, -S-, -NR'- or C1-C4alkylidene linker in which one methylene ring is optionally or independently substituted by -O-, provided Sp1 is bound with carbonyl group through an atom different from carbon; the ring B1 represents a 5-6-members saturated or aromatic, monocyclic or heterocyclic ring containing 1-4 heteroatoms selected from O or N with the ring B1 is optionally substituted by w1 independent variants -R11 with w1 being equal to 0-1; where in the ring (B): G2 represents CH; each of m2 and n2 is independently equal to 0-3, provided m2+n2 is equal to 2-4; p2 is equal to 0-2; q2 is equal to 0 or 1; z2 is equal to 0-4; Sp2 represents a bond or C1-C6alkylidene linker in which up to two methylene links are optionally or independently substituted by -O-. The other radical values are specified in the patent claim.

EFFECT: making new compounds of formula I or to their pharmaceutically acceptable salts showing the properties of voltage-dependent sodium channel inhibitors.

67 cl, 4 tbl, 503 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula

, where X denotes a 5-member heterocylic group bonded through a carbon atom, selected from thiophenyl, furanyl, pyrazolyl and pyrrolyl, which can be substituted with 1-3 Ra groups; T denotes O, S; B is as indicated in the claim; Z1 denotes an unsubstituted cyclopropyl; Z2 denotes a hydrogen atom, C1-C8alkyl; or C1-C8alkoxycarbonyl; Z3 independently denotes a hydrogen atom. The invention also relates to a fungicidal composition containing a compound of formula (I) as an active ingredient, and a plant pathogenic fungus control method in agricultural plants.

EFFECT: obtaining compounds of formula (I), having fungicidal activity.

9 cl, 3 dwg, 255 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula or pharmaceutically acceptable salt thereof, synthesis methods thereof, pharmaceutical compositions containing said compounds, and use thereof to prepare a medicinal agent having mTOR kinase and/or PI3K kinase inhibiting action.

EFFECT: improved properties of the derivatives.

15 cl, 72 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula where: R1 denotes COORa1, CONRa2Ra2', CONRa4ORa4', where: each of Ra1 and Ra4 denotes a hydrogen atom; each of Ra2 and Ra2' denotes a hydrogen atom; Ra4' denotes a lower alkyl; or R1 denotes a heterocyclic group selected from the following groups, where Y2 denotes a hydrogen atom or a lower alkyl: R2 denotes O, S, SO, SO2; R3 denotes a phenyl which is substituted with 2 substitutes selected from halogen, CF3; X2 denotes CH or N; W denotes the following residue: where: W1 denotes CH or S; W2 denotes CH; W3 denotes C or N; and at least one of W1, W2 and W3 denotes a carbon atom; or pharmaceutically acceptable salt or ester thereof. The invention also relates to a pharmaceutical composition having Avrora A selective inhibitory action, which, along with a pharmaceutically acceptable carrier or diluent, contains at least one compound of formula I a an active ingredient.

EFFECT: aminopyridine or aminopyrazine derivatives which inhibit growth of tumour cells based on Avrora A kinase selective inhibitory action.

11 cl, 3 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel organic compounds of formula where R1 denotes H; halogen; -C0-C7-alkyl-O-R3; -NR4R5; R2 denotes phenyl, substituted with one or two substitutes selected from a group consisting of C1-7alkyl, halogen-C1-7alkyl, C1-7alkoxy, halogen-C1-7alkoxy, phenoxy, halogen, C1-7alkylpiperazinyl-C1-7alkyl, C3-C8-cyclalkyl, C1-7alkylpiperidinyl-C1-7alkyl and C1-7alkylimidazolyl; R3 denotes H or phenyl-lower alkyl; R4 and R5 are independently selected from a group consisting of H; lower alkyl; lower alkoxy-carbonyl and amino; A, B and X are independently selected from C(R7) or N, provided that not more than one or A, B and X denotes N; R7 denotes H; R8 denotes hydrogen; n equals 0; Y denotes O; Z denotes C; W is absent; K denotes N or C, and either a) if K denotes C, the bond shown by a wavy line () is a double bond, Q is selected from O-N, S-N, O-CH and S-CH, where in each case, the left-hand O or S atom is bonded through a bond shown in formula I to K, the right-hand N or carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by the dotted line, is a double bond with C; and the bond shown by a thick line () is a single bond; or b) if K denotes N, the bond shown by a wavy line () is a single bond; Q denotes N=CH, where the left-hand N atom is bonded through a bond shown in formula I to K, the right-hand carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by a dotted line, is a single bond with C; and the bond shown by thick line () is a double bond; or salt thereof (preferably pharmaceutically acceptable salt). The invention also relates to a pharmaceutical composition, having inhibiting action on protein kinase, containing a compound of formula I or salt thereof in an effective amount and at least one pharmaceutically acceptable carrier material.

EFFECT: heterocyclic carboxamides as kinase inhibitors.

12 cl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and ,

where the ring X represents benzole or pyridine; R1 represents substituted alkyl; R2 represents optionally substituted aryl or optionally substituted 4-7-member monocyclic heterocyclic group or optionally substituted condensed group of heterocyclic group with the benzole ring where the substitutes of optionally substituted aryl, optionally substituted 4-7-member monocyclic heterocyclic group and optionally substituted condensed group of heterocyclic group with the benzole ring are selected from a group consisting of; (1) alkyl optionally substituted by a group selected from halogen and alkoxycarbonyl, (2) alkoxy optionally substituted by halogen, (3) halogen, (4) 4-7-member monocyclic heterocyclic group or (5) amino, optionally mono- or disubstituted alkyl, and (6) hydroxyl, R3 represents hydrogen or alkyl: R4 represents hydrogen, halogen or alkyl; R5 represents hydrogen or alkyl; R6 and R7 are identical or different, and each represents hydrogen or halogen; or pharmaceutically acceptable salt. Also, the invention refers to a IKur blocker containing the compounds described above as an active ingredient, and also to a preventive and therapeutic agent for cardiac arrhythmia and atrial fibrillation.

EFFECT: there are produced and described new compounds applicable as a IKur blocker effective for preventing or treating cardiac arrhythmia, such as atrial fibrillation.

12 cl, 13 ex

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