Benzene derivative or salt thereof

FIELD: chemistry.

SUBSTANCE: invention relates to novel benzene derivatives of general formula (I) or salts thereof: [Chem. 12]

(Symbols in the given formula have the following values X1:-NR12-C(=O)- or -C(=O)-NR12-, X2 : -NR13 -C(=O)-, Ring A is a 6-member ring, if necessary having 1 or 2 double bonds and if necessary having 1-3 heteroatoms selected from N, O, Ring B is a benzene ring or a 6-member heteroaryl ring having 1-3 heteroatoms selected from N, R is a hydrogen atom or a residue of β-D- glucopyranoside uronic acid; R1-R8 are identical or different and each denotes a hydrogen atom, a halogen atom, -O-(lower alkyl), R9-R11 are identical or different and each denotes a hydrogen atom, lower alkyl, -O-(lower alkyl), -(CH2)n-N(lower alkyl)2, -(CH2)n-NH(lower alkyl), -(CH2)n-N(lower alkyl) (if necessary substituted with -C=O; a 6-member heterocycle having 1-3 heteroatoms selected from N, S, O) -(CH2)n-(C=O)-N(lower alkyl)2, -(CH2)n-(C-O)-N(lower alkyl) (if necessary substituted with -C=O, alkyl, a 6-member heterocycle having 1-3 heteroatoms selected from N) -(CH2)n- if necessary substituted with alkyl, -COCH3, -SO2CH3, -COOCH3, -C=O, CF3, -OCH3, OH, halogen; 5-7-member heterocycle having 1-3 heteroatoms selected from N, S, O), -(CH2)n-O- (if necessary substituted with alkyl; 6-member heterocycle having 1-3 heteroatoms selected from N), n is an integer from 0 to 3, R12 and R13 denote a hydrogen atom, provided that in R1-R11, when two lower alkyls are bonded to a nitrogen atom, they can together form a 3-8-member nitrogen-containing heterocycle.) The invention also relates to benzene derivatives of general formula (II), to a pharmaceutical composition, as well as to use of the said compounds.

EFFECT: obtaining novel biologically active compounds which are active as inhibitors of activated blood-coagulation factor X.

16 cl, 365 ex, 42 tbl

 

Description

TECHNICAL AREA

The present invention relates to new derivatives of benzene or its salts, which can be used as medicines, particularly as an inhibitor of activated blood coagulation factor X.

PREREQUISITES TO the CREATION of INVENTIONS

Last time, the frequency of thromboembolic disorders, such as myocardial infarction, thrombosis of the brain and peripheral arteriograms increases from year to year due to the popularization of Western lifestyle and increase in the population share of older people, and there is an increasing social demand for treatment of such disorders. Anticoagulant therapy, as well as fibrinolysin therapy and antithrombotics therapy is part of medical therapy for treatment and prevention of thrombosis (Sogo Rinsho, 41: 2141-2145, 1989). In particular, antikoaguliruyuschee means for the prevention of thrombosis must meet the requirements of high security for long-term administration and possess the ability to reliable and adequate expression of anticoagulant activity. However, anticoagula the ability of warfarin potassium, which is the only oral anticoagulation means commonly used in the world at the present time, is difficult to control because of its features is, based on the action and its mechanism (J. Clinical Pharmacology, 32, 196-209, 1992; and N. Eng. J. Med., 324 (26), 1865-1875, 1991), and this drug is extremely difficult to use in a clinical setting; and a search antikoaguliruyuschee funds that would have been more useful and easy to use.

It is known that thrombin converts fibrinogen into fibrin in the final stages of coagulation, deep participating in activation and coagulation of platelets (Satoshi Matsuo's T-PA and Pro-UK, Gakusai Kikaku, pp. 5-40, Blood Coagulation, 1986)and its inhibitors for a long period of time were at the centre of research antikoaguliruyuschee funds for the development of medicines.

On the other hand, activated coagulation factor X represents the enzyme for the production of thrombin, which plays a key role in blood coagulation, and because it exists in the connection of internal and external reactions of the coagulation cascade, its inhibitors could effectively inhibit the blood clotting (THROMBOSIS RESEARCH (19), 339-349, 1980). Further, it was shown that, in contrast to inhibitors of thrombin, activated inhibitor of coagulation factor X has no inhibitory effect on the coagulation of platelets, but can specifically inhibit the clotting of blood, and that termicheskom test on animal models it shows antidromically effect, but the shows side effects such as bleeding, this inhibitor was, in particular, take note in the specified ratio (Circulation, 1991, 84, 1741).

As compounds capable of inhibiting the activated blood coagulation factor X, known derivatives of amidinotransferase or their salts (JP-A 5-208946; Thrombosis Haemostasis, 71 (3), 314-319, 1994; and Thrombosis Haemostasis, 72 (3), 393-396, 1994).

In Patent Reference 1 (WO 01/74791) derivatives of diazepan following General formula or their salts are described as compounds capable of inhibiting the activated blood coagulation factor X. However, they differ from the compounds according to the present invention, the structure in terms of the presence or absence of diazepan.

[Chem. 1]

(Ring A and ring B: the same or different, each denotes an aryl or heteroaryl, if necessary having from 1 to 3 substituents; for other characters see publication.)

In Patent Reference 2 (WO 02/42270) substituted benzene derivatives of the following General formula or their salts are described as compounds capable of inhibiting the activated blood coagulation factor X. However, they differ from the compounds according to the present invention on the structure of the ring B.

[Chem. 2]

(A ring: benzene ring or 5 - or 6-membered heterocycle containing 1 to 4 heteroatoms of the same type or the s types, selected from N, S and O. the Ring B: when R4denotes a hydrogen atom or-SO3H, it refers to the piperidine ring in which the nitrogen atom is substituted by an R7and so on for other characters, see publication.)

Further, in Patent Reference 3 (WO 03/26652) compounds of General formula P4-P-M-M4(M: 3-10-membered carbocycle, or 4-10-membered heterocycle. P: 5-7-membered carbocycle or a 5-7 membered heterocycle condensed with ring M or missing. One of the P4and M4represents-Z-A-B and the other-G1-G. for other characters, see the publication.) described as a compound capable of inhibiting the activated blood coagulation factor X. However, they differ from the compounds according to the present invention on the structure-Z-A-B, etc.

Patent Reference 1: international Publication WO 01/74791

Patent Reference 2: international Publication WO 02/42270

Patent Reference 3: international Publication WO 03/26652

DISCLOSURE of INVENTIONS

Objectives of the INVENTION

As described above, inhibitors of activated coagulation factor X effective anticoagulant therapy and is expected to provide specific inhibition of coagulation systems. Accordingly, there is a great need for the development of selective inhibitors of activated blood coagulation factor X, which would differ from you is upomjanutyh known compounds according to the chemical structure, for which it would be possible oral administration and which would show excellent effects.

MEANS of SOLVING the PROBLEM

The authors of the present invention have found that derivatives of benzene following General formula (I) or their salts, which are characterized by a chemical structure that the phenolic ring and the benzene ring are connected to each other by an amide bond, and that the phenolic ring is also associated with a benzene ring or heteroaryl ring amide bond, have an excellent effect of inhibiting activated blood coagulation factor X and are especially excellent oral activity that led to the creation of the present invention. In particular, the present invention relates to the derivatives of benzene following General formula (I) or (II) or their salts and pharmaceutical compositions containing these compounds as active ingredient, in particular as an inhibitor of activated blood coagulation factor X[1]-[18].

[1] Derived benzene following General formula (I) or salts thereof:

[Chem. 3]

(symbols in the formula have the following meanings:

X1: -NR12-C(=O)- or-C(=O)-NR12-,

X2: -NR13-C(=O)- or-C(=O)-NR13-,

Ring A: 5 - or 6-membered ring, if necessary with 1 or 2 double the communication and, if necessary, having from 1 to 3 heteroatoms, selected from N, S, O,

Ring B: benzene ring or 5 - or 6-membered heteroaryl ring having 1 to 3 heteroatoms selected from N, S, O,

R: a hydrogen atom or a sugar residue,

R1-R8: the same or different, each represents a hydrogen atom, halogen atom, if necessary substituted lower alkyl, -O-(if necessary substituted lower alkyl), -O-(if necessary substituted 4-to 8-membered heterocycle having from 1 to 3 heteroatoms selected from N, S, O), -CN, -NH2, -N(if necessary substituted lower alkyl)2, -NH(if necessary substituted lower alkyl), -NH(if necessary substituted 4-to 8-membered heterocycle having from 1 to 3 heteroatoms selected from N, S, O), -NHSO2(if necessary substituted lower alkyl), -N(if necessary substituted lower alkyl)SO2(if necessary substituted lower alkyl), -NO2, -COOH, -CO2(if necessary substituted lower alkyl), -CONH2, -CONH(if necessary substituted lower alkyl), -CON(if necessary substituted lower alkyl)2, -OH, -(CH2)n-NH2, -(CH2)n-N(if necessary substituted lower alkyl)2or -(CH2)n-NH(if necessary substituted lower alkyl),

R9-R11: the same or different, ka is each of which denotes a hydrogen atom, the halogen atom, if necessary substituted lower alkyl, -O-(if necessary substituted lower alkyl), -CN, -NH2, -N(if necessary substituted lower alkyl)2, -NH(if necessary substituted lower alkyl), -NHSO2(if necessary substituted lower alkyl), -N(if necessary substituted lower alkyl)SO2(if necessary substituted lower alkyl), -NO2, -COOH, -CO2(if necessary substituted lower alkyl), -CONH2, -CONH(if necessary substituted lower alkyl), -CON(if necessary substituted lower alkyl)2, -OH, -(CH2)n-N(if necessary substituted lower alkyl)2, -(CH2)n-NH(if necessary substituted lower alkyl), -(CH2)n-NH2, -(CH2)n-N(if necessary substituted 4-to 8-membered heterocycle having from 1 to 3 heteroatoms selected from N, S, O)2, -(CH2)n-NH(if necessary substituted 4-to 8-membered heterocycle having from 1 to 3 heteroatoms selected from N, S, O)- (CH2)n-N(if necessary substituted lower alkyl)(if necessary substituted 4-to 8-membered heterocycle having from 1 to 3 heteroatoms selected from N, S, O)- (CH2)n-(C=O)-N(if necessary substituted lower alkyl)2, -(CH2)n2)n-(C=O)-NH2, -(CH2)n-(C=O)-N(if necessary substituted 4-to 8-membered heterocycle having from 1 to 3 heteroatoms selected from N, S, O)2, -(CH2)n-(C=O)-NH(if necessary substituted 4-to 8-membered heterocycle having from 1 to 3 heteroatoms selected from N, S, O)- (CH2)n-(C=O)-N(if necessary substituted lower alkyl)(if necessary substituted 4-to 8-membered heterocycle having from 1 to 3 heteroatoms selected from N, S, O)- (CH2)n-O-(if necessary substituted lower alkyl), -(CH2)n-(if necessary substituted 4-to 8-membered heterocycle having from 1 to 3 heteroatoms selected from N, S, O)- (CH2)n-O-(if necessary substituted 4-to 8-membered heterocycle having from 1 to 3 heteroatoms selected from N, S, O) or -(CH2)n-(C=O)-(if necessary substituted 4-to 8-membered heterocycle having from 1 to 3 heteroatoms selected from N, S, O),

n: an integer from 0 to 6,

R12and R13: the same or different, each represents a hydrogen atom or lower alkyl,

provided that, in R1-R11when two lower alkyl linked to a nitrogen atom, then they may together form a 3-8-membered nitrogen-containing heterocycle).

[2] the Compound or its salt according to [1], in which in the formula (I) [1] group:

[Chem. ]

is a group selected from the following:

[3] the Compound or its salt according to [1], in which in the formula (I) [1] group:

[Chem. 5]

is a group selected from the following:

[4] the Compound or its salt according to [1], in which in the formula (I) [1] group:

[Chem. 6]

is a group selected from the following:

[5] the Compound or its salt according to [1]-[4], in which in the formula (I) [1] ring B represents a benzene ring or a pyridine ring.

[6] the Compound or its salt according to [1]-[5], in which in the formula (I) [1] R denotes a hydrogen atom or charigny residue of glucuronic acid.

[7] the Compound or its salt according to [1]-[6], in which, if necessary, substituted 4-to 8-membered heterocycle having from 1 to 3 heteroatoms selected from N, S, O, represents a heterocycle selected from azetidine, pyrrolidine, piperidine, azepane, asokan, piperazine, tetrahydrooxazolo, thiomorpholine, 1,4-diazepine, 1,4-oxathiane, 1,4-diazepine, 1,5-diatkine, 1,5-oxazoline, 1,5-thiazocine, imidazole, triazole, thiazole, oxazole, isoxazol, pyrazole, pyridine, pyrazine or pyrimidine.

[8] the Compound or its salt according to [7], in which oterom Deputy in if necessary substituted lower alkyl represents from 1 to 3 substituents, selected from-OH, CF3, -CN, =O, -NH2, -COOH, -COO-lower alkyl, -CONH2, -CONH(lower alkyl), -CON(lower alkyl)2, -O-lower alkyl, -NH(lower alkyl), -N(lower alkyl)2, -NHCO(lower alkyl), -N(lower alkyl)CO(lower alkyl), -NHCONH2, -NHCONH(lower alkyl), -NHCON(lower alkyl)2, -N(lower alkyl)CONH(lower alkyl), -N(lower alkyl), CON(lower alkyl)2, halogen atom, -NHSO2-(lower alkyl), -N(lower alkyl)SO2-(lower alkyl), or-SO2(lower alkyl), and Deputy in if necessary substituted 4-to 8-membered heterocycle having from 1 to 3 heteroatoms selected from N, S, O, represents from 1 to 3 substituents selected from lower alkyl, -OH, CF3, -CN, =O, -NH2, -COOH, -COO-lower alkyl, -CONH2, -CONH(lower alkyl), -CON(lower alkyl)2, -O-lower alkyl, -NH(lower alkyl), -N(lower alkyl)2, -NHCO(lower alkyl), -N(lower alkyl)CO(lower alkyl), -NHCONH2, -NHCONH(lower alkyl), -NHCON(lower alkyl)2, -N(lower alkyl)CONH(lower alkyl), -N(lower alkyl), CON(lower alkyl)2, halogen atom, -NHSO2-(lower alkyl), -N(lower alkyl)SO2-(lower alkyl), or-SO2(lower alkyl).

[9] Derived benzene following General formula (II) or its salt:

[Chem. 7]

(Symbols in the formula have the following meanings:

X1: -NH-C(=O)- or-C(=O)-NH-,

Y: N or CH,

Z: N, NH, CH is Li CH 2,

R: a hydrogen atom or a sugar residue,

R1-R8: the same or different, each represents a hydrogen atom, halogen atom, decreases alkyl, -O-lower alkyl, -O-(if necessary substituted 4-to 8-membered heterocycle having from 1 to 3 heteroatoms selected from N, S, O), -CN, -NH2, -N(lower alkyl)2, -NH(lower alkyl), -NHSO2(lower alkyl) or NO2,

R9-R11: the same or different, each represents a hydrogen atom, halogen atom, decreases alkyl, -(CH2)n-N(if necessary substituted lower alkyl)2, -(CH2)n-NH(lower alkyl), -(CH2)n-NH2, -(CH2)n-N(if necessary substituted 4-to 8-membered heterocycle having from 1 to 3 heteroatoms selected from N, S, O)2, -(CH2)n-NH(if necessary substituted 4-to 8-membered heterocycle having from 1 to 3 heteroatoms selected from N, S, O)- (CH2)n-N(lower alkyl)(if necessary substituted 4-to 8-membered heterocycle having from 1 to 3 heteroatoms selected from N, S, O)- (CH2)n-(C=O)-N(lower alkyl)2, -(CH2)n-(C=O)-NH(lower alkyl), -(CH2)n-(C=O)-NH2, -(CH2)n-(C=O)-N(4-to 8-membered heterocycle having from 1 to 3 heteroatoms selected from N, S, O)2, -(CH2)n-(C=O)-NH(4-to 8-membered heterocycle, having the th from 1 to 3 heteroatoms, selected from N, S, O)- (CH2)n-(C=O)-N(lower alkyl)( 4-8-membered heterocycle having from 1 to 3 heteroatoms selected from N, S, O)- (CH2)n-O-lower alkyl, -(CH2)n-(if necessary substituted 4-to 8-membered heterocycle having from 1 to 3 heteroatoms selected from N, S, O)- (CH2)n-O-(if necessary substituted 4-to 8-membered heterocycle having from 1 to 3 heteroatoms selected from N, S, O), or -(CH2)n-(C=O)-(if necessary substituted 4-to 8-membered heterocycle having from 1 to 3 heteroatoms selected from N, S, O),

n: an integer from 0 to 6,

provided that the dotted part in the formula are the same or different and each means a simple bond or double bond, and R1-R11when two lower alkyl groups linked to the nitrogen atom they may together form a 3-8-membered nitrogen-containing heterocycle).

[10] the Compound or its salt according to [9], in which in the formula (II) [9] R denotes a hydrogen atom or charigny residue of glucuronic acid.

[11] the Compound or its salt according to [1], is selected from the following compounds: N-(5-chloropyridin-2-yl)-3-hydroxy-2-{[4-(1-methyl-4-oxo-1,4-dihydropyridines-3-yl)benzoyl]amino}benzamide, N-(5-chloropyridin-2-yl)-2-[(4-{1-[2-(dimethylamino)ethyl]-2-oxo-1,2-dihydropyridines-3-yl}benzoyl)amino]-3-hydroxybenzamide, N-(5-chloropyridin-2-yl)-3-hydroxy-2-[(4-{1-[-(1,4-oxazepan-4-yl)ethyl]-2-oxo-1,2-dihydropyridines-3-yl}benzoyl)amino]benzamide, 5-chloro-N-(5-chloropyridin-2-yl)-3-hydroxy-2-{[4-(1-{2-[(1-methylpyridin-4-yl)oxy]ethyl}-2-oxo-1,2-dihydropyridines-3-yl)benzoyl]amino}benzamide, N-(5-chloropyridin-2-yl)-3-hydroxy-2-{[4-(1-methyl-2-oxo-1,2-dihydropyridines-3-yl)benzoyl]amino}benzamide, N-(5-chloropyridin-2-yl)-2-[(4-{1-[2-(dimethylamino)ethyl]-2-oxopiperidin-3-yl}benzoyl)amino]-3-hydroxybenzamide, 3-[(5-chloropyridin-2-yl)carbarnoyl]-2-[(4-{1-[2-(dimethylamino)ethyl]-2-oxo-1,2-dihydropyridines-3-yl}benzoyl)amino]phenyl-β-D-glucopyranoside acid, N-(5-chloropyridin-2-yl)-3-hydroxy-2-[(4-{1-[2-(4-methylpiperazin-1-yl)ethyl]-2-oxo-1,2-dihydropyridines-3-yl}benzoyl)amino]benzamide, 4-{1-[2-(dimethylamino)ethyl]-2-oxo-1,2-dihydropyridines-3-yl}-N-{2-hydroxy-6-[(4-methoxybenzoyl)amino]phenyl}benzamide, N-(5-chloropyridin-2-yl)-3-hydroxy-2-[(4-{1-[2-(4-hydroxypiperidine-1-yl)ethyl]-2-oxo-1,2-dihydropyridines-3-yl}benzoyl)amino]benzamide, 5-chloro-N-(5-chloropyridin-2-yl)-2-[(4-{1-[2-(dimethylamino)ethyl]-2-oxo-1,2-dihydropyridines-3-yl}benzoyl)amino]-3-hydroxybenzamide, 3-[(5-chloropyridin-2-yl)carbarnoyl]-2-[(4-{1-[2-(dimethylamino)ethyl]-2-oxopiperidin-3-yl}benzoyl)amino]phenyl-β-D-glucopyranoside acid.

[12] a Pharmaceutical composition comprising a compound or its salt according to [1] as an active ingredient.

[13] the Pharmaceutical composition according to [12], which is an inhibitor of activated blood coagulation factor X.

[14] Farmatsevticeski the composition [12], which is anticoagulation tool.

[15] Use of the compound or its salt according to [1] or [9] to obtain inhibitor of activated blood coagulation factor X.

[16] Use of the compound or its salt according to [1] or [9] to obtain anticoagulative tools.

[17] a Method of treating a patient suffering from a disease associated with activated coagulation factor X, which includes an introduction to the patient an effective amount of the compound or its salt according to [1] or [9].

[18] a Method of treating a patient suffering from a disease caused by thrombi or emboli, which includes an introduction to the patient an effective amount of a compound or salt according to this [1] or [9].

The compound (I) according to the present invention are described in detail below.

The term "lower" in the definition of the General formula in this description means a straight or branched carbon chain having from 1 to 6 carbon atoms, unless specifically stated otherwise. Accordingly, the "lower alkyl" includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dime rbutil, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl. Of them, preferred are groups having from 1 to 3 carbon atoms, and more preferably, methyl, ethyl.

"Halogen atom" includes fluorine atom, chlorine atom, bromine atom, iodine atom. Especially preferred are a chlorine atom and a bromine atom.

Ring A, "5 - or 6-membered ring having 1 or 2 double bonds and, if necessary, having from 1 to 3 heteroatoms selected from N, S, O" includes, for example, a saturated 6-membered cycle, such as cyclohexane, piperidine, piperazine, tetrahydrooxazolo, thiomorpholine, tetrahydro-2H-Piran, tetrahydro-2H-thiopyran, 1,4-Ossetian; containing a double bond 6-membered cycle, such as cyclohexene, 1,2,3,6-tetrahydropyridine, 1,2-dihydropyridines, 1,4-dihydropyrimidin, 1,2-dihydropyrazine, 1,2,3,6-tetrahydropyrazin, 3,6-dihydro-2H-Piran, 2H-Piran, 3,6-dihydro-2H-thiopyran, 2H-thiopyran; a saturated 5-membered cycle, such as cyclopentane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene; and containing a double bond 5-membered cycle, such as cyclopentadiene, 2,5-dihydro-1H-pyrrole, 2H-pyrrole, 2,5-dihydrofuran, 2.5-dihydrothiophene.

Ring A is a ketone, of course including the enol ring structure in the keto-enol tautomerizations. Ring A may have a double bond, and the ring A can have one is if two double bonds. If the ring A represents a 5-membered ring, R10and R11may be missing.

Ring B, "5 - or 6-membered heteroaryl ring having 1 to 3 heteroatoms selected from N, S, O" includes, for example, furan, thiophene, pyrrole, pyridine, oxazole, isoxazol, thiazole, isothiazol, furazan, imidazole, pyrazole, pyrazin, pyrimidine, pyridazine, triazine, triazole, tetrazole, which, however, do not limit the invention.

Deputy for "if necessary substituted lower alkyl" includes-OH, -CF3, -CN, =O, -NH2, -COOH, -COO-lower alkyl, -CONH2, -CONH(lower alkyl), -CON(lower alkyl)2, -O-lower alkyl, -NH(lower alkyl), -N(lower alkyl)2, -NHCO(lower alkyl), -N(lower alkyl)CO(lower alkyl), -NHCONH2, -NHCONH(lower alkyl), -NHCON(lower alkyl)2, -N(lower alkyl)CONH(lower alkyl), -N(lower alkyl), CON(lower alkyl)2, halogen atom, -NHSO2-(lower alkyl), -N(lower alkyl)SO2-(lower alkyl), or-SO2(lower alkyl).

"4-to 8-membered heterocycle" of the "4-to 8-membered heterocycle having from 1 to 3 heteroatoms selected from N, S, O" include saturated cycle, such as azetidin, pyrrolidine, piperidine, ASEAN, asokan, piperazine, tetrahydrooxazolo, thiomorpholine, 1,4-diazepan, 1,4-oxazepan, 1,4-thiazepan, 1,5-diadakan, 1,5-oxytocin, 1,5-tazocin; and unsaturated cycle, such as thiazole, imidazole, triazole, thiazole, ACS is angry isoxazol, pyrazol, pyridine, pyrazin, pyrimidine.

Deputy for "if necessary substituted 4-to 8-membered heterocycle having from 1 to 3 heteroatoms selected from N, S, O" includes lower alkyl, -OH, -CF3, -CN, =O, -NH2, -COOH, -COO-lower alkyl, -CONH2, -CONH(lower alkyl), -CON(lower alkyl)2, -O-lower alkyl, -NH(lower alkyl), -N(lower alkyl)2, -NHCO(lower alkyl), -N(lower alkyl)CO(lower alkyl), -NHCONH2, -NHCONH(lower alkyl), -NHCON(lower alkyl)2, -N(lower alkyl)CONH(lower alkyl), -N(lower alkyl), CON(lower alkyl)2, halogen atom, -NHSO2-(lower alkyl), -N(lower alkyl)SO2-(lower alkyl), or-SO2(lower alkyl).

In-N(if necessary substituted lower alkyl)2and-N(lower alkyl)2these two substituents on the same nitrogen atom may be different from each other.

-N(if necessary substituted lower alkyl)2and-N(lower alkyl)2together with the nitrogen atom can form a ring structure. Specifically, they may form a 3-8-membered nitrogen-containing heterocycle. Nitrogen-containing heterocycle may have from 1 to 3 heteroatoms.

Further, a ring and A benzene ring must always be connected to each other through a carbon atom on ring A, and the present invention does not include the case where the ring And connected with the benzene ring che is ez heteroatom in the ring A.

"Sugar residue" means the residue of sugar monosaccharide. This may be the residue of sugar obtained from sugar such as glucose, mannose, galactose, arabinose, xylose, ribose, N-acetylglucosamine, glucuronic acid, mannurone acid, removing one hydroxyl group, especially a hydroxyl group in position 1 of the sugar; however, the connection should not be limited to, but may include a sugar residue in which a hydroxyl group substituted by a lower alkoxy group, etc. is Preferred charigny residue of glucuronic acid.

Compounds according to the present invention include mixtures of various stereoisomers or isolated stereoisomers such as geometrical isomers, tautomeric isomers, optical isomers.

Compounds according to the present invention can form salts joining with acid. Depending on the type of substituent, the compounds can form salts with a base. Specifically, they include the salts of Association with an acid derived from an inorganic acid, such as hydrochloric acid, Hydrobromic acid, iodine-hydrogen acid, sulfuric acid, nitric acid, phosphoric acid; organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic who Isleta, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonate acid, econsultancy acid, or aspartic acid, glutamic acid; and salts with an inorganic base, such as sodium, potassium, magnesium, calcium, aluminum; organic base such as methylamine, ethylamine, ethanolamine; basic amino acid such as lysine, ornithine; and ammonium salts.

Further, the present invention includes hydrates, various pharmaceutically acceptable solvate and polymorph crystals of the compounds according to the present invention. Of course, not limited to the compounds described in the Examples which will be given below, the present invention covers all derivatives of benzene of formula (I) and (II) and their pharmaceutically acceptable salts.

In addition, the compounds according to the present invention include compounds which are metabolized in vivo to form compounds of formula (I) or their salts, or prodrugs. The emerging group of prodrugs of the compounds according to the present invention includes described in Prog. Med. 5:2157-2161 (1985); and is described in "Development of Medicines", Vol. 7, Planning Molecule, pp. 163-198, Hirokawa Publishing, 1990.

(Production method)

Typical methods for producing compounds according to the present invention are described below.

[Chem. 8]

(In the formula, ring A, ring B, X1X2, R1-R11have the same meanings as above; Q and W have values such that when Q represents-NH2or-NH-lower alkyl, then W represents-COOH, and when Q represents-COOH, then W represents-NH2or-NH-lower alkyl.)

Stage A:

This is the reaction of obtaining compound (Ia) by condensation of carboxylic acid and amine compounds (IIa) and compound (III). This reaction is carried out preferably in the presence of a condensing reagent according to conventional acylation with getting amide bond. As the condensing reagent, for example, preferred are N,N-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(N,N-dimethylamino)propyl]carbodiimide, carbonyldiimidazole, diphenylphosphoryl (DPPA), diethylphosphoramidite.

After converting carboxylic acids into the corresponding active derivative it can be condensed with the amine. Active carboxylic acid derivative includes active esters obtained by reaction with a derivative of phenol, such as p-NITROPHENOL or N-hydroxyamino, such as 1-hydroxysuccinimide or 1-hydroxybenzotriazole; monoalkyl esters of carboxylic acids; mixed acid anhydrides obtained by reaction with organic acid; mixed anhydrides sour the s-type phosphoric acid, obtained by reaction with diphenylphosphinylchloride and N-methylmorpholine; azides acids obtained by reaction of ester with hydrazine or alkylation; halides, such as acid anhydrides, bromohydrin acid; symmetric acid anhydrides. In General, the reaction can be conducted in a solvent with cooling or at room temperature; however, depending on the type of acylation, in some cases, it can occur in the absence of water.

The solvent is not involved in the reaction solvent, including, for example, dimethylformamide, dioxane, tetrahydrofuran, simple ether, dichloroethane, dichloromethane, chloroform, carbon tetrachloride, dimethoxymethane, dimethoxyethane, ethyl acetate, benzene, acetonitrile, dimethyl sulfoxide, ethanol, methanol, water and mixtures of these solvents. It can be appropriately selected depending on the way in which it is used.

Depending on the method used, the reaction can proceed in the presence of a base, such as N-methylmorpholine, triethylamine, trimethylamine, pyridine, sodium hydride, tert-piperonyl potassium, utility, sodium amide, potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, or when using a base as a solvent.

In addition to the reactions described herein can be used any which I have a different reaction, can lead to the formation of the amide bond.

The way to obtain the compounds of formula (Ia) can be changed in such a way that, after the formation of the amide bond X2formed amide bond X1. In addition, any other known alkylation, acylation, oxidation, reduction, hydrolysis, etc. that are frequently used by professionals, can be combined in any desired manner to obtain the compounds according to the present invention.

[Chem. 9]

(In the formula, ring A, ring B, X1X2, R1-R11have the same meanings as above; Z means the deleted group; R12means, if necessary, secure the remainder of the sugar.)

Stage B:

This is the stage of obtaining the compound (Ib)with, if necessary, secure the remainder of the sugar, by the reaction of phenol and donor sugar, compounds (Ia) and compound (IV), preferably in the presence of activator. This reaction can be conducted according to the normal glycosylation. Typical methods are described in Yuki Gousei Called Kyoukai shi, Vol. 50, No. 5 (1992), pp. 378-390; and "Jikken Depending Kouza, Vol. 26, Yuki Gousei VIII, pp. 267-354, 1992, Maruzen.

The sugar donor comprises, for example, sacharine derivative having the deleted group in position 1 of the sugar. Delete group includes halogen, thioalkyl, togetherall, acyloxy, try oraclenet, diarylphosphino, diarylphosphino, tetramethylphosphonium, dialkylphosphate.

Condensing reagent includes silver carbonate, triftorbyenzola silver, silver perchlorate, silver oxide, sodium hydroxide, potassium carbonate, sodium methylate, sodium hydride, databaseconnect, trimethylsilyl Tripura, boron TRIFLUORIDE, the methyl Tripura, silicon tetrachloride, tin chloride, paratoluenesulfonyl acid and its salts, anhydride triftormetilfullerenov acid, copper bromide, mercury bromide, N-bromosuccinimide.

Triphenylphosphine, diethylazodicarboxylate, etc. can be used as an activator, for example, for the sugar donor having a hydroxyl group in position 1.

In General, the reaction can be conducted in a solvent with cooling or at room temperature; however, depending on the type of glycosylation, in some cases, it can occur in the absence of water.

The solvent is an inert solvent not participating in the reaction, including, for example, dimethylformamide, dioxane, tetrahydrofuran, simple ether, dichloroethane, dichloromethane, chloroform, carbon tetrachloride, dimethoxymethane, dimethoxyethane, ethyl acetate, benzene, toluene, acetonitrile, dimethyl sulfoxide, methanol, ethanol and mixtures of these solvents. It can be appropriately selected depending on the FPIC of the BA.

In addition to the reactions described herein can also be used any other reaction leading to the formation of glycosidic bonds.

If R12in the compound (Ib) according to the present invention indicates, if necessary, secure the remainder of the sugar, and when the protective group is not cleaved at the stage B, the protective group can be cleaved according to method suitable for the cleavage of the protective group, for example, through hydrolysis with a base such as sodium carbonate, or through the restoration, such as catalytic hydrogenation, to obtain, thus, the compounds according to the present invention, where R12means unprotected sugar residue.

Without being specific, definite, the protective group may be any commonly used to protect the hydroxyl group or carboxyl group, and includes, for example, in case of need, substituted lower alkyl, aralkyl, more than three lowest alkylsilane, acyl. "Aralkyl" means a group derived from the specified alkyl group by replacement of a hydrogen atom of the aryl, specifically including benzyl. "Acyl" specifically includes acetyl, propionyl, Isopropenyl, benzoyl.

(Method of Obtaining the Source Connections)

Typical methods of obtaining the starting compounds for preparing compounds (I) of the present invention is described below./p>

[Chem. 10]

(In this formula, R6-R11have the same meanings as above; and U represents-COOH, -COOP1, -NH2, -NH-lower alkyl, -NH-P2, -N(P2)-lower alkyl, NO2; P1and P2each represents a protective group of carboxyl group or a protective group of amino group. When V means-B(Oh)2or-B(OL1)OL2then Y represents a group to delete; and when V means a group to delete, then Y represents-B(Oh)2or-B(OL1)OL2. L1and L2are the same or different and each represents lower alkyl, or L1and L2together form if necessary substituted lower alkylene.)

The method of Obtaining 1:

This method is the reaction of obtaining compound (IIIa) via the condensation of compound (IVa) and a compound (V). This reaction is carried out in a solvent inert to the reaction, in the presence of a base and a palladium catalyst, with cooling or under heating.

Remove group for Y or V includes halogen, methanesulfonate, p-toluensulfonate, tripterocalyx.

Palladium-based catalyst for use in the method according to the invention preferably represents tetranitropentaerithrite, dichlorobistriphenylphosphine, dichlorodiphenyltrichlorethane. The basis is the W preferably represents sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium ethylate, sodium methylate, potassium fluoride, cesium fluoride.

Without being specific, definite, the solvent includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene; ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; alcohols such as methanol, ethanol, 2-propanol, butanol, N,N-dimethylformamide (DMF), N-organic (NMP), dimethylsulfoxide (DMSO), water, or mixtures of these solvents.

If U in the compound (IIIa) indicates NO2connection, where U denotes-NH2, can then be obtained by recovering; and if U denotes-COOP1, -NH-P2or-N(P2)-lower alkyl, the compound, where U denotes-COOH, -NH2or-NH-lower alkyl can then be obtained according to a method suitable for the cleavage of the protective group, for example, cleavage by hydrolysis with a base such as sodium hydroxide, or acid, such as hydrochloric acid, or by splitting recovery, such as catalytic hydrogenation, or by cleavage with acid, such as triperoxonane acid.

To obtain can be used a process comprising combines the Yu usual stages, well-known specialist, for example, a method including obtaining a precursor of the compound (IIIa), where U represents-CN, or any other, it is easy to convert the compound (IIIa), with subsequent conversion of this precursor to the compound (IIIa) according to a method suitable for this predecessor.

[Chem. 11]

(In this formula, R4-R11, U, Q and W have the same meanings as described above).

A method of Obtaining a 2:

This method is the reaction of obtaining compound (VII) via the condensation of compound (VI) and compound (III). The reaction of this stage may be similar reaction from stage A.

Compounds according to the present invention, thus obtained, as described above, can be isolated and purified by known methods, for example, extraction, precipitation, chromatography separation, fractionation by crystallization, recrystallization, etc. Available compounds according to the present invention can be converted into a desired salt by a conventional salt formation.

If the compounds according to the present invention have asymmetric carbon, they may include optical isomers. The optical isomers can be separated in the usual manner fractionation crystallization to recrystallization from a suitable salt, or chrome what ografia on columns.

The EFFECT of the INVENTION

Compounds according to the present invention specifically inhibit the activated blood coagulation factor X and have a strong anticoagulatory activity. Accordingly, these compounds can be used as antikoaguliruyuschee tools or as a means for the prevention and treatment of disorders that are caused by thrombi or emboli.

Diseases for which the compounds according to the present invention are effective include cerebrovascular disorders such as cerebral infarction, thrombosis of the brain, brain embolism, transient brain ischemia (TIA), subarachnoid hemorrhage (vasospasm); ischemic cardiopathy, such as acute and chronic myocardial infarction, unstable angina, coronary thrombolysis; disorders of the blood vessels of the lungs, such as infarction, pulmonary embolism; and various other vascular disorders, such as occlusion of peripheral artery disease, deep vein thrombosis, disseminated intravascular coagulation, thrombophilia after artificial formation of blood vessels and after artificial valvoplasty, reocclusion and rekonstrukcija after surgery for coronary artery bypass surgery, reocclusion and rekonstrukcija after PTCA (percutaneous transluminal coronary angioplasty) or PTCR (percutaneous transluminal cor is stationary recanalization), thrombophilia during artificial blood circulation.

On the basis of their activity by inhibiting activated blood coagulation factor X and their activity on the inhibition of the reproduction of influenza viruses, the compounds according to the present invention are expected to be suitable for the prevention of infection by influenza viruses and for treatment of influenza (JP-A-6-22971).

The excellent activity of the compounds according to the present invention for inhibition of activated coagulation factor X was confirmed by the test methods shown below.

1) Test measuring the clotting time of blood with human activated blood coagulation factor X (human factor Xa):

10 ml of the test compounds, dissolved in DMSO, or only DMSO and 50 ml of human factor Xa (Enzyme Research Labs) was added to 90 ml of human plasma and incubated at 37°C for 3 minutes, and then added 100 μl of 20 mM CaCl2pre-heated to 37°C, and the time until coagulation was measured using coagulometer (Amelung KC10). The human plasma was prepared as follows: using sodium citrate as an anticoagulant, collected the blood of healthy individuals, centrifuged at 3000 rpm for 15 minutes at 4°C, the resulting plasma was pooled, frozen and preserved. The concentration of human factor Xa was determined thus the om, the coagulation time adding DMSO (control) was approximately 30 seconds. The CT value2(concentration 2-fold increase in time of coagulation with DMSO) was calculated by linear regression, ranking the relative value (ratio) time coagulation for control of the concentration of the tested compounds.

2) Test measuring the inhibition of the enzyme by the method of synthetic substrate:

25 ml of reaction buffer (pH 8,4), 5 ml of the test compounds, dissolved in DMSO, or only DMSO and 10 ml of a synthetic substrate, 2 mM S-2222 (Chromogenix) was added to a microplate with 96 wells, then add 10 ml of 0.025 U/ml of human factor Xa, and the reaction was carried out at 37°C for 10 minutes, and then the change in light absorption at 405 nm was measured using Spectramax 340PC384, Molecular Devices and calculate the value of the IC50.

The result of this test is IC50the compound of Example 1 was 6.7 nm, and the value of the IC50the compound of Example 30 was 8.3 nm.

3) External coagulation time (RT):

2 ml of the test compounds, dissolved in DMSO, or only DMSO, and 50 ml of physiological saline was added to 50 ml of human plasma, heated at 37°C for 1 minute, then add 100 ml of HemosIL RecombiPlasTin (Instrumentation Laboratory) and measured coagulation time. To measure the coagulation time using the and Amelung KC10A. The CT value2(concentration 2-fold increase in time of coagulation with DMSO) was calculated by linear regression, building relative value (ratio) time coagulation for control of the concentration of the tested compounds.

The result of this test is CT2connection Example 1, amounted to 0.34 mm, and the CT value2the compound of Example 42 was 0.65 mm.

The results of these measurements 1), 2) and 3) confirmed that the compounds according to the present invention inhibit the activated coagulation factor human X and demonstrate a strong anticoagulant effect.

4) Test time measurement of coagulation ex vivo with mice (oral administration):

Experimental male ICR mice (body weight of approximately 40 g, SLC), which had no access to food for 12 hours or longer, orally injected with a solution or suspension of the test compounds, dissolved in 0.5% methylcellulose (100 mg/kg), using a needle for feeding; and after 30 minutes and 2 hours, under anesthesia simple diethyl ether, 1 ml of blood was taken from mice through postavlenuyu vein 3.8% sodium citrate, 1/10 by volume, and centrifuged at 12000 rpm for 3 minutes to separate the plasma. External coagulation time (RT) and the inner coagulation time (APTT) for this plasma was measured according to the following methods a) and b).

a) External coagulation time (RT):

50 ml of mouse plasma was heated at 37°C for 1 minute, then add 100 ml of HemosIL RecombiPlasTin and measured coagulation time. To measure the coagulation time used Amelung KC10A. The coagulation time of plasma mouse without the introduction of the test compound served as a control; and the activity of the tested compounds against the prolongation of coagulation time of were represented as relative values compared to control 1.

As a result, after 30 minutes after administration of the compound of Example 10 and Example 78 prolonged coagulation time by 3.3 times and 3.9 times, respectively; that is, the compounds showed very high activity against prolongation of coagulation time of.

b) Internal coagulation time (APTT):

50 ml Hemoliance Synthasil APTT (Instrumentation Laboratory) was added to 50 ml of the indicated plasma was heated at 37°C for 3 minutes, then added 50 μl of a 20 mM solution of CaCl2pre-heated to 37°C and measured coagulation time. To measure the coagulation time used Amelung KC10A. The coagulation time of plasma mouse without the introduction of the test compound served as a control; and the activity of the tested compounds against the prolongation of coagulation time of were represented as relative values compared to control 1.

Dose-dependent and gramasevaka change an coagulating effect was investigated in the same way, as described above, but with a change in the dose and time of blood collection.

5) the Method of measurement of coagulation time of ex vivo with cynomolgus macaques (oral administration):

Experimental male cynomolgus macaque (weighing approximately 4 kg), which did not have access to food within 12 hours or longer, orally injected with a solution or suspension of the test compounds, dissolved in 0.5% methylcellulose, using a needle for feeding. Before the introduction of the test compound and after 1, 2, 4, 8 and 24 hours after injection of 1 ml of blood was taken from the thus-treated animals through the femoral vein in 3.8% of sodium citrate, 1/10 by volume, and centrifuged at 12000 rpm for 3 minutes to separate the plasma. External coagulation time (RT) and the inner coagulation time (APTT) for this plasma was measured according to the same methods as in (a) and (b). The test was not conducted under anesthesia.

Test results indicated 4) and (5) confirm the effect of prolongation of coagulation time of the compounds according to the present invention in oral administration.

Pharmaceutical compositions containing as active ingredient one or more compounds of the formula (I) and their pharmaceutically acceptable salts according to the present invention may be formulated with conventional pharmaceutical carriers based and other additives, in the form of t is bleak, powders, fine granules, granules, capsules, pills, liquid preparations, injections, suppositories, ointments, poultices and the like, and may be administered orally or parenterally.

Clinical dose for administration to man of the compounds according to the present invention can be appropriately determined depending on the condition, body weight, age and sex of patients, which they are introduced, but in General ranges from 0.1 to 500 mg/adult patient/day for oral administration and from 0.01 to 100 mg/adult patient/day for parenteral administration. This dose can be administered to the patient at one time or may be divided into several parts for injection at different points in time. As the dose may vary depending on various conditions, depending on the circumstances it can be used a smaller dose than the above-defined range.

As a solid composition for oral administration according to the present invention can be used in tablets, powders, granules, etc. Solid composition of these types contains one or more active substances, along with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metachromasy acid and magnesium aluminate. Typically, the composition can sod who can't make fun of any other additives in addition to the inert diluents, above, for example, lubricants such as magnesium stearate, a disintegrator such as glycolate, cellulose calcium, stabilizer such as lactose, and a solubilizer agent or accelerator dissolution, such as glutamic acid or aspartic acid. If desired, tablets and pills may be coated with a film soluble in the stomach or small intestine substances, such as sucrose, gelatin, hydroxypropylcellulose, phthalate of hydroxypropylmethylcellulose, etc.

Liquid composition for oral administration includes, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc. that contain normal inactive diluent such as purified water and ethanol. In addition to inert diluents, the compositions may further contain auxiliary pharmaceutical additives such as solubilization, dissolution accelerators, accelerators, wetting, accelerators suspension, as well as sweeteners, flavoring agents, fragrances and preservatives.

The injection for parenteral administration includes, for example, sterile aqueous or nonaqueous solutions, suspensions and emulsions. The solvent for the aqueous solutions and suspensions include, for example, distilled water and physiological saline for injection. The solvent for non-aqueous solutions, suspen the rd includes for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, Polysorbate 80 (trade name), etc.

These compositions may further contain additives, such as isotonic additives, preservatives, accelerators, wetting, emulsifying agents, dispersing agents, stabilizers (e.g., lactose), soljubilizatory, dissolution accelerators, etc. Their is sterilized by passing them through the breathtaking bacteria filters or adding thereto an antimicrobial agent, or exposing radiation. Sterile solid composition thus obtained may be dissolved before use in sterile water or a sterile solvent for injection.

If the compounds according to the present invention have low solubility, they can be treated to impart solubility. To impart solubility can be used any known methods applicable to pharmaceuticals. For example, there may be used a method of adding to the compounds of surfactants (for example, hardened by polyoxyethylene castor oils, esters of higher fatty acids and polyoxyethylene-sorbitan, polyoxyethylene-polyoxypropyleneglycol, fatty acid sucrose); and a method of forming a solid dispersion that includes joint is according to the invention and soljubilizatory, for example, polymers (water-soluble polymers, such as hypromellose (HPMC), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG); intersolubility polymers, such as karboksimetiltselljuloza (CMEC), the phthalate of hydroxypropylmethylcellulose (HPMCP), a copolymer of methacrylic acid and methyl methacrylate (Eudragit L, S, trademark, Rohm and Haas)). If desirable, can also be used a method of forming soluble salts, and methods of forming compounds include cyclodextrin, etc. Solubilizing means can be appropriately modified depending on the chemical compounds used in conjunction with them ("Recent Pharmaceutical Techniques and Their Applications", Isamu Utsumi, et al., in the Journal of Medicines, 157-159, 1983; and "Pharmacological Monograph No. 1, Bioavailability" by Koji Nagai, et al., published by Soft Science Co., 78-82, 1988). Of them, preferred is a method of forming a solid dispersion of chemical compounds and solubilization to improve the solubility of chemical compounds (JP-A 56-49314; FR 2 460 667).

The BEST WAY of carrying out the INVENTION

[Example]

Following specifically describes the method of obtaining the compounds according to the present invention with reference to the following Examples illustrating the formation of compounds. Some of the initial compounds for producing compounds according to the present invention are new, and the retrieval method is demonstriruetsya in the Reference Examples.

Reference Example 1:

3-Bromo-1-methylpyridin-4(1H)-he hydrobromide (640 mg) suspended in toluene (10 ml) and water (5 ml) was added [4-(methoxycarbonyl)phenyl]Bronevoy acid (642 mg), sodium carbonate (757 mg) and tetrakis(triphenylphosphine)palladium (0) (138 mg), followed by stirring under heating at an oil bath at 100°C for 3 hours. The reaction mixture was filtered through celite, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure and the residue was purified by chromatography on a column of silica gel (FUJI SILYSIA CHEMICAL Ltd., the same in subsequent cases) (chloroform:methanol = 90:10)to give 4-(1-methyl-4-oxo-1,4-dihydropyridines-3-yl)methylbenzoate (118 mg).

In the same manner as in Reference Example 1, there were obtained compounds of Reference Examples 4, 7, 10, 12, 14, 16, 18, 119, 132.

Reference Example 2:

1M NaOH (1,42 ml) was added to a suspension of 4-(1-methyl-4-oxo-1,4-dihydropyridines-3-yl)methylbenzoate (115 mg) in EtOH (3 ml) followed by stirring at room temperature for 8 hours. 1M HCl (1,42 ml) was added to the reaction solution, followed by concentration under reduced pressure. To the residue was added water (20 ml) followed by stirring for 20 minutes. The precipitate was collected by filtration and dried under reduced pressure at 60°C, receiving 4-(1-methyl-4-oxo-1,4-dihydropyridines-3-yl)benzo is you acid (92 mg).

In the same manner as in Reference Example 2, there were obtained compounds of Reference Examples 5, 9, 17, 22, 24, 31, 33, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 85, 87, 89, 91, 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 120, 123, 125, 127, 129, 133.

Reference Example 3:

5-Bromopyrimidine-4(3H)-he (578 mg) was dissolved in N,N-dimethylformamide (15 ml) was added potassium carbonate (685 mg) and methyliodide (247 ml) followed by stirring at room temperature for 24 hours. To the reaction mixture was added water, followed by extraction with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate 1:1)to give 5-bromo-3-methylpyrimidin-4(3H)-he (337 mg) in the form of a solid white color.

Reference Example 6:

5-Bromopyrimidine-4(3H)-he (459 mg) was dissolved in N,N-dimethylformamide (13 ml), then cooled on ice was added sodium hydride (55%, 137 mg) followed by stirring at the same temperature for 30 minutes. Then added 1-(chloromethyl)-4-methoxybenzo (392 ml) followed by stirring at room temperature for 15 hours. To the reaction mixture was added water, followed by extraction with chloroform. Organic with the Oh was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, and the obtained residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate is from 4:1 to 2:1)to give 5-bromo-3-(4-methoxybenzyl)pyrimidine-4(3H)-he (382 mg) in the form of a solid white color.

Reference Example 8:

4-[1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methylbenzoate (205 mg) was dissolved in triperoxonane acid (5 ml) followed by stirring at 70°C for 15 hours. The reaction mixture was evaporated under reduced pressure, followed two azeotropic treatment with toluene. To the obtained residue was added water, followed by three extractions with chloroform. The organic layer was dried over anhydrous sodium sulfate, then the solvent is evaporated and the obtained residue was purified by chromatography on a column of silica gel (methanol/chloroform equal to from 2% to 5%)to give 4-(6-oxo-1,6-dihydropyrimidin-5-yl)methylbenzoate (86 mg) in the form of a solid white color.

Reference Example 11:

Aqueous 6 n hydrochloric acid (5 ml) was added to 4-(2-oxo-2H-Piran-3-yl)methylbenzoate (72 mg), followed by stirring at 90°C for 15 hours. The reaction mixture was cooled to room temperature, added water, and the solid substance was collected by filtration. After washing with water is a solid substance was dried under reduced Yes the tion, getting 4-(2-oxo-2H-Piran-3-yl)benzoic acid (65 mg) in the form of a solid light brown color.

In the same manner as in Reference Example 11, were obtained the compounds of Reference Examples 13 and 15.

Reference Example 19:

Acetic acid (10 ml) and aqueous 30% hydrogen peroxide solution (452 ml) was added to 4-pyridine-3-imetelstat (708 mg), followed by stirring at 70°C for 18 hours. The reaction mixture was concentrated under reduced pressure, was added a saturated aqueous solution of sodium bicarbonate, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and the obtained residue was purified by chromatography on a column of silica gel (methanol/chloroform is from 0% to 10%)to give 4-(1-oxidability-3-yl)methylbenzoate (720 mg) in the form of a solid white color.

Reference Example 20:

Acetic anhydride (20 ml) was added to 4-(1-oxidability-3-yl)methylbenzoate (704 mg), followed by stirring at 130°C for 24 hours. The reaction mixture was concentrated under reduced pressure, followed two azeotropic treatment with toluene. The obtained residue was purified by chromatography on columns with NH-silica gel (methanol/chloroform is from 0% to 10%)to give 4-(2-oxo-1,2-dihydropyridines-3-yl)methylbenzoate(651 mg) in the form of a solid light brown color.

In the same manner as in Reference Example 20 was obtained the compound of Reference Example 25.

Reference Example 21:

4-(2-oxo-1,2-dihydropyridines-3-yl)methylbenzoate (1.04 g) was dissolved in N,N-dimethylformamide (20 ml) was added sodium carbonate (1.88 g) and (2-chloroethyl)dimethylamine hydrochloride (981 mg), followed by stirring at 80°C for 7 hours. Then was added potassium carbonate (628 mg), followed by stirring for 2 hours. The reaction mixture was concentrated under reduced pressure, to the residue was added water, followed by extraction with chloroform. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent evaporated under reduced pressure. The obtained residue was purified by chromatography on columns with NH-silica gel (hexane:ethyl acetate is from 9:1 to 1:1)to give 4-{1-[2-(dimethylamino)ethyl]-2-oxo-1,2-dihydropyridines-3-yl}methylbenzoate (954 mg) in the form of a yellow oil.

In the same manner as in Reference Example 21, were obtained the compounds of Reference Examples 23, 26, 28, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 118, 121, 122, 131.

Reference Example 27:

10%Pd-C (360 mg) was added to a solution of 1-{2-[3-{4-[(benzyloxy)carbonyl]phenyl}-2-oxopyridine-1(2H)-yl]ethyl}piperidine-4-ethylcarboxylate (1,647 g) in ethanol (30 ml), followed by stirring in an atmosphere of odor is Yes under normal pressure at room temperature for 27 hours. The reaction mixture was filtered through celite, washed with THF and ethanol, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (chloroform:methanol is from 100:0 to 80:20)to give 4-(1-{2-[4-(etoxycarbonyl)piperidine-1-yl]ethyl}-2-oxo-1,2-dihydropyridines-3-yl)benzoic acid (671 mg) as an amorphous solid light yellow color.

Reference Example 29:

While cooling on ice triethylamine (0,66 ml) and methanesulfonamide (0,29 ml) was added to a solution of 4-[1-(2-oxyethyl)-2-oxo-1,2-dihydropyridines-3-yl]methylbenzoate (841 mg) in dichloromethane (15 ml), followed by stirring, while cooling on ice for 1 hour. To the reaction mixture were added water (20 ml) followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure, obtaining a yellow oil (1.34 in). The obtained yellow oil (1,34 g) was dissolved in acetonitrile (10 ml) was added 2-piperazinone (1.55 g) and N,N-diisopropylethylamine (2,68 ml). The reaction mixture was stirred at 80°C for 6 hours, then allowed to cool to room temperature. To the reaction mixture were added water (50 ml) followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure is I. The obtained residue was purified by chromatography on a column of silica gel (chloroform:methanol is from 100:0 to 95:5)to give 4-{2-oxo-1-[2-(3-oxopiperidin-1-yl)ethyl]-1,2-dihydropyridines-3-yl}methylbenzoate (1020 mg) as a colorless amorphous solid.

In the same manner as in Reference Example 29 was obtained the compound of Reference Example 86.

Reference Example 30:

While cooling on ice, sodium hydride (60% suspension in oil, 50 mg) was added to a solution of 4-{2-oxo-1-[2-(3-oxopiperidin-1-yl)ethyl]-1,2-dihydropyridines-3-yl}methylbenzoate (380 mg) in N,N-dimethylformamide (10 ml) followed by stirring for 5 minutes and then added methyliodide (70 ml). While cooling on ice, the reaction mixture was stirred for 1.5 hours. To the reaction mixture was added ice water (20 ml) and saturated aqueous sodium hydrogen carbonate solution (10 ml) followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, then the solvent is evaporated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (chloroform:methanol is from 100:0 to 95:5)to give 4-{1-[2-(4-methyl-3-oxopiperidin-1-yl)ethyl]-2-oxo-1,2-dihydropyridines-3-yl}methylbenzoate (350 mg) in the form of a light yellow oil.

Reference Example 32:

4-{1-[2-(dimethylamino)ethyl]-2-oxo-1,2-dihydropyridines-3-yl}methylbenzoate (490 mg) Rast is oral in acetic acid (20 ml) was added platinum oxide (74 mg), followed by stirring in an atmosphere of hydrogen (1 ATM) at room temperature for 15 hours. The steam in the reactor was purged with argon, and then the reaction mixture was filtered through celite, followed by washing with methanol. The filtrate was concentrated under reduced pressure, followed two azeotropic treatment with toluene. A saturated aqueous solution of sodium bicarbonate was added to the residue, followed twice by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by chromatography on columns with NH-silica gel (hexane:ethyl acetate is from 2:1 to 1:2)to give 4-{1-[2-(dimethylamino)ethyl]-2-oxopiperidin-3-yl}methylbenzoate (439 mg) in the form of a colorless oil.

In the same manner as in Reference Example 32, there were obtained compounds of Reference Examples 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 126, 128.

Reference Example 124:

4-(2-oxo-1,2-dihydropyridines-3-yl)methylbenzoate (316 mg) suspended in toluene (7 ml) was added 1-methyl-4-piperidinol (318 mg) and cyanomethaemoglobin (317 mg), followed by stirring at 100°C for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was purified by chromatography on a column of silica gel (methanol/chloroform is from 0% to 10%)to give 4-[1-(1-methylpiperidin-4-yl)-2-oxo-1,2-dihydropyridines-3-yl]methylbenzoate (85 mg) in the form of a colorless oil.

Reference Example 130:

4-{1-[2-(dimethylamino)ethyl]-2-oxo-1,2-dihydropyridines-3-yl}benzoic acid (1,46 g) suspended in dichloroethane (15 ml)was added dimethylformamide (125 ml) and the acid chloride oxalic acid (367 ml) was added dropwise at room temperature. After stirring at room temperature for 30 minutes, the reaction mixture was evaporated under reduced pressure. To the obtained residue was added a solution of 2-amino-3-NITROPHENOL (499 mg) in a mixture of dichloromethane (10 ml) - pyridine (10 ml), followed by stirring overnight at room temperature. The reaction suspension was filtered and the filtrate was evaporated under reduced pressure. Substance, collected by filtration, and the residue after filtration was dissolved in a mixture of ethanol (14,6 ml) - water (14.6 ml) was added 1M aqueous solution of hydrochloric acid (3,24 ml) and iron (904 mg) followed by heating under reflux for 3 hours. To the reaction suspension was added saturated aqueous sodium hydrogen carbonate solution and chloroform, followed by vigorous stirring and filtered through celite. The filtrate was extracted with chloroform, the organic layer evaporated under reduced pressure, and the residue was purified by chromatography on columns with NH-silica gel (chloroform:methanol is from 100:0 to 95:5)to give N-(2-amino-6-hydroxyphenyl)-4-{1-[2-(dimethylamino)ethyl]-2-oxo-1,2-Digue is dropyridine-3-yl}benzamide (600 mg) in the form of a solid brown color.

In the same manner as in Reference Example 130 was produced compound of Reference Example 134.

Example 1:

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72 mg), 1-hydroxybenzotriazole (62 mg), triethylamine (64 ml) and 2-amino-N-(5-chloro-2-pyridinyl)-3-hydroxybenzamide (121 mg) was added to a solution of 4-(1-methyl-4-oxo-1,4-dihydropyridines-3-yl)benzoic acid (88 mg) in N,N-dimethylformamide (3 ml) followed by stirring at room temperature for 14 hours. Then to the reaction solution were added water (30 ml) and the precipitated insoluble solid was collected by filtration. The obtained solid substance was dried at 60°C under reduced pressure, then the solid substance was added tetrahydrofuran (5 ml), N,N-dimethylformamide (1 ml) and acetic acid (104 ml), followed by stirring under heating at 60°C for 2 days. After that, the reaction solution was concentrated under reduced pressure, to the residue was added saturated aqueous sodium hydrogen carbonate solution (30 ml) followed by extraction with ethyl acetate. The organic layer is washed with aqueous saturated sodium hydrogen carbonate solution and saturated aqueous solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on columns with NH-silica gel (chloroform:methanol equal to 97:3). Cleaned the config product is suspended in ethanol, added 1M hydrochloric acid (324 ml) followed by concentration under reduced pressure. The residue was recrystallized from ethanol, receiving N-(5-chloropyridin-2-yl)-3-hydroxy-2-{[4-(1-methyl-4-oxo-1,4-dihydropyridines-3-yl)benzoyl]amino}benzamide hydrochloride (123 mg).

In the same manner as in Example 1, there were obtained compounds of Examples 2-11, 20, 21, 24-70, 81-110, 113-119.

Example 12:

4-(1-{2-[4-(tert-butoxycarbonyl)piperazine-1-yl]ethyl}-2-oxo-1,2-dihydropyridines-3-yl)benzoic acid (731 mg) was dissolved in N,N-dimethylformamide (15 ml), was added 1-hydroxybenzotriazole (253 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (359 mg) and triethylamine (261 ml) was added 2-amino-N-(5-chloro-2-pyridinyl)-3-hydroxybenzamide (412 mg), followed by stirring at room temperature for 7 hours. To the reaction mixture were added water and the resulting precipitate was collected by filtration and washed with water. The obtained solid substance was dried under reduced pressure and was dissolved in tetrahydrofuran (15 ml) was added acetic acid (448 ml) followed by stirring at 60°C for 5 hours. The reaction mixture was concentrated under reduced pressure and then was twice subjected to azeotropic treatment with toluene. The residue was purified by chromatography on columns with NH-silica gel (methanol/chloroform is from 0% to 5%). The compound obtained was dissolved in ethyl is the Etat (10 ml) was added to a mixture of 4 N. hydrochloric acid/ethyl acetate (3,88 ml) followed by stirring at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure and saturated aqueous sodium hydrogen carbonate solution was added to the residue, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and the residue was purified by chromatography on columns with NH-silica gel (methanol/chloroform is from 0% to 5%)to give N-(5-chloropyridin-2-yl)-3-hydroxy-2-({4-[2-oxo-1-(2-piperazine-1-retil)-1,2-dihydropyridines-3-yl]benzoyl}amino)benzamide (867 mg) in the form of a solid yellow-white.

In the same manner as in Example 12, were obtained compounds of Examples 13, 71-76, 79, 111, 112.

Example 14:

N-(5-chloropyridin-2-yl)-3-hydroxy-2-({4-[2-oxo-1-(2-piperazine-1-retil)-1,2-dihydropyridines-3-yl]benzoyl}amino)benzamide (393 mg) was dissolved in tetrahydrofuran (10 ml) and added aqueous 37%formalin solution (134 ml) and triacetoxyborohydride sodium (436 mg), followed by stirring at room temperature for 9 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, then the solvent is evaporated under reduced pressure ostatok was purified by chromatography on columns with NH-silica gel (methanol/chloroform is from 0% to 5%). The compound obtained was dissolved in ethyl acetate and added to a mixture of 4 N. hydrochloric acid/ethyl acetate, followed by stirring at room temperature for 30 minutes. The precipitate was collected by filtration and dried under reduced pressure, obtaining N-(5-chloropyridin-2-yl)-3-hydroxy-2-[(4-{1-[2-(4-methylpiperazin-1-yl)ethyl]-2-oxo-1,2-dihydropyridines-3-yl}benzoyl)amino]benzamide the dihydrochloride (426 mg) in the form of a solid yellow-white in color.

In the same manner as in Example 14, were obtained compounds of Examples 15, 77, 78, 80.

Example 16:

N-(5-chloropyridin-2-yl)-3-hydroxy-2-({4-[2-oxo-1-(2-piperazine-1-retil)-1,2-dihydropyridines-3-yl]benzoyl}amino)benzamide (128 mg) was dissolved in pyridine (5 ml) was added acetic anhydride (21 ml), followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, then was twice subjected to azeotropic treatment with toluene. To the residue was added water, followed by extraction with chloroform and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and the residue was purified by chromatography on columns with NH-silica gel (methanol/chloroform is from 0% to 5%). The compound obtained was dissolved in ethyl acetate and added to a mixture of 4 N. hydrochloric acid/ethyl acetate. The precipitate was collected, filtracia was dried under reduced pressure, getting 2-[(4-{1-[2-(4-acetylpiperidine-1-yl)ethyl]-2-oxo-1,2-dihydropyridines-3-yl}benzoyl)amino]-N-(5-chloropyridin-2-yl)-3-hydroxybenzamide hydrochloride (109 mg) in the form of a solid yellow-white in color.

In the same manner as in Example 16, there was obtained the compound of Example 17.

Example 18:

N-(5-chloropyridin-2-yl)-3-hydroxy-2-({4-[2-oxo-1-(2-piperazine-1-retil)-1,2-dihydropyridines-3-yl]benzoyl}amino)benzamide (130 mg) was dissolved in pyridine (5 ml) and, while cooling on ice, was added methanesulfonamide (51 ml), followed by stirring at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, then subjected to azeotropic treatment with toluene. Saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure. The residue was purified by chromatography on a column with NH-silica gel (methanol/chloroform is from 0% to 5%), followed by chromatography on a column of silica gel (methanol/chloroform is from 0% to 5%). The compound obtained was dissolved in ethyl acetate and added to a mixture of 4 N. hydrochloric acid/ethyl acetate, followed by stirring at room temperature for 30 minutes. The precipitate was collected by filtration and dried under reduced pressure, p is the best N-(5-chloropyridin-2-yl)-3-hydroxy-2-{[4-(1-{2-[4-(methylsulphonyl)piperazine-1-yl]ethyl}-2-oxo-1,2-dihydropyridines-3-yl)benzoyl]amino}benzamide hydrochloride (47 mg) in the form of a solid yellow-white in color.

In the same manner as in Example 18 was obtained the compound of Example 19.

Example 22:

An aqueous solution of 1M sodium hydroxide (3.0 ml) was added to a solution of 1-{2-[3-(4-{[(2-{[(5-chloropyridin-2-yl)amino]carbonyl}-6-hydroxyphenyl)amino]carbonyl}phenyl)-2-oxopyridine-1(2H)-yl]ethyl}piperidine-4-ethylcarboxylate (392 mg) in a mixture of ethanol (5 ml) - tetrahydrofuran (5 ml) followed by stirring at room temperature for 19 hours. 1M hydrochloric acid (3.0 ml) and water (50 ml) was added to the reaction mixture followed by extraction with a mixture of chloroform-isopropanol. The organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure, obtaining 1-{2-[3-(4-{[(2-{[(5-chloropyridin-2-yl)amino]carbonyl}-6-hydroxyphenyl)amino]carbonyl}phenyl)-2-oxopyridine-1(2H)-yl]ethyl}piperidine-4-carboxylic acid (332 mg) in the form of a solid of light yellow color.

In the same manner as in Example 22 was obtained the compound of Example 23.

Examples 120, 121:

N-(5-chloropyridin-2-yl)-2-[(4-{1-[2-(dimethylamino)ethyl]-2-oxopiperidin-3-yl}benzoyl)amino]-3-hydroxybenzamide (72,2 g) optically separated and purified on a column of optical separation CHIRALPAK AD-H, using as solvent for elution of a mixture of n-hexane:ethanol:2-propanol:diethylamine is 20:80:0,1:0,1, thereby obtaining compounds of Examples 120 and 120, the number of 30.7 g and 29.8 g (s) is responsible.

Example 122:

N-(5-chloropyridin-2-yl)-2-[(4-{1-[2-(dimethylamino)ethyl]-2-oxo-1,2-dihydropyridines-3-yl}benzoyl)amino]-3-hydroxybenzamide (7.0 g) was dissolved in chloroform (70 ml) and, while cooling on ice, was added methanol (70 ml), 1,8-diazabicyclo[5.4.0]-7-undecene (4,90 ml) and methyl-1-bromo-1-deoxy-2,3,4-tri-O-acetyl-α-D-glucopyranoside (10,45 g), followed by stirring at room temperature for 2 hours. Added additional amount of 1,8-diazabicyclo[5.4.0]-7-undecene (4,90 ml) and methyl-1-bromo-1-deoxy-2,3,4-tri-O-acetyl-α-D-glucopyranoside (10,45 g), followed by stirring at room temperature for 2 hours. Added additional amount of 1,8-diazabicyclo[5.4.0]-7-undecene (5,94 ml) and methyl-1-bromo-1-deoxy-2,3,4-tri-O-acetyl-α-D-glucopyranoside (10,45 g), followed by stirring at room temperature for 2 hours. Then to the reaction solution was added water, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure. The obtained residue was dissolved in a mixture of methanol (100 ml) and water (50 ml) and at room temperature was added sodium carbonate (4,18 g), followed by stirring at room temperature for 1 hour. The reaction mixture was filtered and the filtrate was evaporated under reduced DAVLENIYa was added to the residue, followed by extraction with water. The aqueous layer was washed with ethyl acetate and then the aqueous layer was evaporated under reduced pressure. The residue was purified high-performance liquid chromatography on columns (DAISOPAK, SP-120-10-ODS-BP, acetonitrile:water is from 83:17 to 72:28). Ethanol (20 ml) was added to the resulting pure product (682 mg), followed by stirring overnight at room temperature. The precipitated solid was collected by filtration and dried under reduced pressure, obtaining 3-[(5-chloropyridin-2-yl) carbarnoyl]-2-[(4-{1-[2-(dimethylamino)ethyl]-2-oxo-1,2-dihydropyridines-3-yl}benzoyl)amino]phenyl β-D-glucopyranoside acid (444 mg) in the form of a solid white color.

In the same manner as in Example 122, the compound of Example 123 was obtained, based on the compound of Example 120, and the compound of Example 124 was received, based on the compound of Example 121.

Example 125:

N-(5-chloropyridin-2-yl)-2-[(4-{1-[2-(dimethylamino)ethyl]-2-oxopiperidin-3-yl}benzoyl)amino]-3-hydroxybenzamide (300 mg) was dissolved in dimethylformamide (6 ml) and, while cooling on ice, was added aqueous 32%solution of peracetic acid (135 ml), followed by stirring under cooling on ice for 30 minutes. The reaction solution was placed in a saturated aqueous solution of sodium bicarbonate (30 ml) followed by extraction with chloroform. The organic layer was dried over sodium sulfate and evaporated under pony is hinnon pressure, receiving N-(5-chloropyridin-2-yl)-2-[(4-{1-[2-(dimethylnitrosamine)ethyl]-2-oxopiperidin-3-yl}benzoyl)amino]-3-hydroxybenzamide (210 mg). The obtained N-(5-chloropyridin-2-yl)-2-[(4-{1-[2-(dimethylnitrosamine)ethyl]-2-oxopiperidin-3-yl}benzoyl)amino]-3-hydroxybenzamide (209 mg) was dissolved in dimethylformamide (3 ml), then at room temperature was added water (3 ml), benzoic acid (46 mg) and 1M aqueous solution of ferric chloride (38 ml), followed by stirring at room temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture followed by extraction with chloroform. The organic layer evaporated under reduced pressure and the residue was purified by chromatography on columns with NH-silica gel (chloroform:methanol is from 100:0 to 95:5). The purified product was dissolved in ethanol, and the solution was added a mixture of 4M hydrochloric acid/ethyl acetate (1 ml) followed by evaporation under reduced pressure. Ethyl acetate was added to the residue, followed by stirring at room temperature for 1 hour. The precipitate was collected by filtration and dried at 40°C under reduced pressure, obtaining N-(5-chloropyridin-2-yl)-3-hydroxy-2-[(4-{1-[2-(methylamino)ethyl]-2-oxopiperidin-3-yl}benzoyl)amino]benzamide hydrochloride (108 mg) in the form of a solid white color.

Example 126:

N-(2-amino-6-hydroxyphenyl)-4-{1-[2-(dimetilan the but)ethyl]-2-oxo-1,2-dihydropyridines-3-yl}benzamide (276 mg) was dissolved in pyridine (6 ml) and while cooling on ice, was added 4-chlorobenzylchloride (99 ml), followed by stirring overnight at room temperature. The reaction solution was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (chloroform:methanol:ammonia is from 100:0:0 to 95:5:0.5 to). The purified product (250 mg) was dissolved in ethyl acetate and the solution was added a mixture of 4M hydrochloric acid/ethyl acetate (129 ml), followed by stirring at room temperature for 1 hour. The precipitate was collected by filtration and dried at room temperature under reduced pressure, obtaining 4-chloro-N-{2-[(4-{1-[2-(dimethylamino)ethyl]-2-oxo-1,2-dihydropyridines-3-yl}benzoyl)amino]-3-hydroxyphenyl}benzamide hydrochloride (157 mg) in the form of a solid white color.

In the same manner as in Example 126, there were obtained compounds of Examples 127, 128.

Structural formulas and physical-chemical properties of the compounds of Reference Examples and the compounds of Examples are shown in the following Table 1-30. Acronyms in the Tables below. The compounds in Tables 31-42 can be easily obtained almost in the same manner as in the above Examples or the methods of obtaining, or by making some modifications, obvious to those skilled in relation to such methods.

Ref: the Reference Number of the Example, Note: the Number of the example Structure: Structural formula, DATA: physical data, NMR spectrum, nuclear magnetic resonance (TMS internal standard), FAB, ESI: data mass spectrometry. In the Structure of HCl includes monohydrochloride and the dihydrochloride.

[Table 1]

[Table 2]

[Table 3]

[Table 4]

[Table 5]

[Table 6]

[Table 7]

[Table 8]

[Table 9]
Etc.StructureData
1NMR (DMSO-d6):
4,10 (3H, s), 7,09-7,19 (2H, m), 7,26 (1H, t, J=7.9 Hz), 7,41 (1H, d, J=7,0 Hz), 7,73-7,79 (2H, m), 7,88 (1H, DD, J=2,8, and 8.9 Hz), 8,00-8,07 (2H, m), 8,11 (1H, d, J=8,9 Hz), a 8.34 (1H, d, J=2,8 Hz), 8,44-8,50 (1H, m), 8,71-8,77 (1H, m), 9,83 (1H, s), to 9.93 (1H, s), 10,54 (1H, s)
FAB+: 474
2NMR (DMSO-d6):
4,06 (3H, s), 7,16 (2H, s), 7,26 (1H, d, J=7,0 Hz), 7,76 (2H, d, J=8.5 Hz), 7,88 (1H, DD, J=2.7, and a 8.9 Hz), 801 (2H, d, J=8,4 Hz), 8,08 (1H, d, J=8,9 Hz), 8,33-8,44 (2H, m), 8,62-8,73 (1H, m), 9,80 (1H, s), of 10.47 (1H, s), a 10.74 (1H, s)
FAB+: 509
3FAB+:476
4ESI-:460
5ESI-:460
6FAB+:462
[Table 10]
7ESI-:462
8FAB+: 477
9FAB+: 511
10NMR (DMSO-d6):
of 2.86 (3H, s), 2,87 (3H, s), 3,40-to 3.49 (2H, m), 4,37 (2H, t, J=6.4 Hz), 6.48 in (1H, t, J=6.9 Hz), 7,11-7,17 (2H, m), 7,25 (1H, t, J=7.9 Hz), 7,75-7,98 (7H, m), 8,13 (1H, d, J=8,9 Hz), a 8.34 (1H, d, J=3.1 Hz), 9,71-10,20 (3H, m), 10,53 (1H, s)
ESI+: 532/td>
11NMR (DMSO-d6):
of 2.86 (3H, s), 2,87 (3H, s), 3,28-to 3.58 (2H, m), 4,37 (2H, t, J=6.4 Hz), 6.48 in (1H, t, J=6.9 Hz), 7,14-7,19 (2H, m), 7,75-of 7.96 (7H, m), 8,08 (1H, d, J=8,9 Hz), at 8.36 (1H, d, J=2.3 Hz), 9,72 (1H, s), 9,99 (1H, C)10,49 (1H, s), 10,71 (1H, s)
ESI+: 566
12NMR (DMSO-d6):
2,37 at 2.45 (4H, m), 2,58 (2H, t, J=6.4 Hz), 2,68 was 2.76 (4H, m), 4,08 (2H, t, J=6.4 Hz), 6.35mm (1H, t, J=6.9 Hz), was 7.08 (1H, d, J=8,8 Hz), 7,15-7,31 (2H, m), 7,66 to 7.75 (2H, m), 7,81 (2H, d, J=8,2 Hz), 7,86-to $ 7.91 (1H, m), to 7.99 (2H, d, J=8.0 Hz), 8,17 (1H, d, J=9.0 Hz), a 8.34 (1H, d, J=2,6 Hz)
FAB+:573
[Table 11]
13ESI+:607
14NMR (DMSO-d6):
and 2.83 (3H, s), 3,12-4,57 (12H, m), 6,46 (1H, t, J=6.9 Hz), 7,11-to 7.18 (2H, m), 7,25 (1H, t, J=7.8 Hz), 7,71-7,97 (7H, m), 8,13 (1H, d, J=9.0 Hz), 8,35 (1H, d, J=2,8 Hz), at 9.53-of 10.21 (2H, m), 10,54 (1H, s), up 11,86 (1H, s)
ESI+:587
15ESI+:621
16 NMR (DMSO-d6):
and 2.83 (3H, s), 2,85-4,56 (12H, m), 6,47 (1H, t, J=6.8 Hz), 7,11-to 7.18 (2H, m), 7.23 percent (1H, t, J=7.8 Hz), 7,73-7,98 (7H, m), 8,13 (1H, d, J=9.0 Hz), a 8.34 (1H, d, J=2.7 Hz), 9,56-10,23 (2H, m), 10,53 (1H, s), 11,14 (1H, s)
ESI+:615
17ESI+:649
18NMR (DMSO-d6):
to 3.02 (3H, s), is 3.08-3,96 (10H, m), 4,42 (2H, t, J=6.2 Hz), 6.48 in (1H, t, J=6.8 Hz), 7,09-to 7.18 (2H, m), 7,25 (1H, t, J=7.8 Hz), 7,73-7,98 (7H, m), 8,13 (1H, d, J=9.0 Hz), 8,35 (1H, d, J=2.6 Hz), 9,68-10,06 (2H, m), 10,53 (1H, s), of 10.73 (1H, s)
ESI+:651
[Table 12]
19ESI+:685
20FAB+: 644
21ESI+: 678
22NMR (DMSO-d6):
1,40 is 2.10 (4H, m), 2,60-of 3.00 (1H, m), 3.00 and is 3.40 (2H, m), 3,40-of 3.95 (4H, m), 3.95 to and 4.40 (2H, m), 6.30-in-6,50 (1H, m), 7,12 (1H, d, J=8.0 Hz), to 7.15 (1H, d, J=8.0 Hz) to 7.25 (1H, t, J=8.0 Hz), 7,60-8,06 (7H, m), 8,13 (1H, d, J=8,8 Hz), a 8.34 (1H, d, J=2,8 Hz), 9,74 (1H, is), 9,87 (1H, s)10,52 (1H, s)
ESI+: 616
23ESI+: 650
24NMR (DMSO-d6):
2,89 (3H, s), 3,20-3,70 (6H, m), 3,70-4,20 (2H, m), 4,30-4,60 (2H, m), 6.48 in (1H, t, J=6.9 Hz), 7,09-7,19 (2H, m), 7,25 (1H, t, J=7.8 Hz), to 7.77 (1H, DD, J=1,9, 7,1 Hz), 7,80-to $ 7.91 (4H, m), to $ 7.91-of 8.00 (2H, m), 8,13 (1H, d, J=9.0 Hz), a 8.34 (1H, d, J=2,8 Hz), 9,60-10,20 (2H, m), 10,53 (1H, s)
ESI+: 601
[Table 13]
25ESI+: 635
26NMR (DMSO-d6):
1,79-of 2.21 (4H, m), 2,75-2,84 (6H, m), 3,19-3,82 (7H, m), 7,09-to 7.18 (2H, m), 7,20-7,28 (1H, m), 7,33 (2H, d, J=8,3 Hz), 7,81-to $ 7.91 (3H, m), 8,13 (1H, d, J=9.0 Hz), a 8.34 (1H, d, J=2.4 Hz), RS 9.69 (1H, s)of 9.89 (1H with), 10,11 (1H, s), 10,51 (1H, s)
ESI+: 536
27NMR (DMSO-d6):
1,80-2,12 (4H, m), 2.77-to 2,84 (6H, m), 3,17-3,82 (7H, m), 7,13-7,16 (2H, m), 7,32 (2H, d, J=8,3 Hz), 7,83 (2H, d, J=8,3 Hz), 7,88 (1H, DD, J=8,9 and 2.5 Hz), 8,08 (1H, d, J=8,9 Hz), at 8.36 (1H, d, J=2.5 Hz), for 9.64 (1H, s), 9,87 (1H, s), 10,43 (1H, s), 10,70 (1H, s)
FAB+: 570
28 NMR (DMSO-d6):
6,33 (1H, t, J=6.4 Hz), 7,07-7,19 (2H, m), 7,21-7,29 (1H, m), 7,40-7,47 (1H, m), 7,71-7,99 (6H, m)to 8.14 (1H, d, J=8,9 Hz), 8,31-of 8.37 (1H, m), 9,74 (1H, s), 9,84 (1H, s)10,52 (1H, s), 11,88 (1H, s)
FAB-: 459
29NMR (DMSO-d6):
6,32 (1H, t, J=6,7 Hz), 7,09-7,19 (2H, m), 7,44 (1H, DD, J=6,4, 1.9 Hz), 7,74 (1H, DD, J=7,0, 2.0 Hz), 7,81-7,94 (5H, m), 8,10 (1H, d, J=8,9 Hz), at 8.36 (1H, d, J=2.6 Hz), RS 9.69 (1H, s), 10,37 (1H, s), 10,71 (1H, C)11,88 (1H, s)
FAB+: 495
30NMR (DMSO-d6):
to 3.52 (3H, s), 6.35mm (1H, t, J=6.9 Hz), 7,07-7,19 (2H, m), 7,25 (1H, t, J=7.8 Hz), 7,71 (1H, DD, J=7,0, 2.0 Hz), 7,75-7,97 (6H, m)to 8.14 (1H, d, J=8,9 Hz), 8,35 (1H, d, J=2,9 Hz), 9,74 (1H, s), 9,84 (1H, s), 10,53 (1H, s)
ESI+:475
[Table 14]
31FAB+:509
32NMR (DMSO-d6):
3,07-3,24 (2H, m), 3.40 in-a-3.84 (6H, m), 3,93-4,10 (2H, m)to 4.41 (2H, t, J=6.5 Hz), of 6.49 (1H, t, J=6.9 Hz), 7,09-to 7.18 (2H, m), 7,25 (1H, t, J=7.9 Hz), 7,78 (1H, DD, J=1,9, 7,2 Hz), 7,81-7,86 (3H, m), 7,88 (1H, DD, J=2.7, and a 8.9 Hz), 7,95 (2H, d, J=8,4 Hz m), 8,13 (1H, d, J=9.0 Hz), 8,35 (1H, d, J=2.3 Hz), 9,70-9,99 (2H, m), accounted for 10.39-10,57 (2H, m)
FAB+: 57
33NMR (DMSO-d6):
3,09-3,24 (2H, m), 3.46 in-3,82 (6H, m), 3.95 to 4,07 (2H, m), and 4.40 (2H, t, J=6.3 Hz), of 6.49 (1H, t, J=6.8 Hz), 7,15 (2H, s), 7,75-of 7.96 (7H, m), 8,08 (1H, d, J=9.0 Hz), at 8.36 (1H, d, J=3.0 Hz), 9,71 (1H, s), 10,45 (2H, s), of 10.72 (1H, s)
FAB+: 608
34NMR (DMSO-d6):
1,79 and 2.13 (4H, m), 2,60 is 2.80 (1H, m), 3.00 and-3,14 (2H, m), 3.33 and-with 3.79 (4H, m), 4,42 (2H, t, J=6,7 Hz), 6.48 in (1H, t, J=6.9 Hz), 7,14 (2H, t, J=7.8 Hz), 7,25 (1H, t, J=7.9 Hz), 7,74-to $ 7.91 (5H, m), 7,95 (2H, d, J=8,4 Hz), 8,13 (1H, d, J=9.0 Hz), a 8.34 (1H, d, J=2.5 Hz), RS 9.69-of 10.05 (2H, m), 10,41-of 10.58 (2H, m)
FAB+: 640
35NMR (DMSO-d6):
1,76-of 2.15 (4H, m), 2,60-2,78 (1H, m), 2,97-and 3.16 (2H, m), 3,32-of 3.80 (4H, m)to 4.41 (2H, t, J=6.5 Hz), 6.48 in (1H, t, J=6.9 Hz), 7,15 (2H, s), 7,75-7,98 (7H, m), 8,08 (1H, d, J=8,9 Hz), at 8.36 (1H, d, J=2.3 Hz), 9,72 (1H, s), 10,28-or 10.60 (2H, m), 10,71 (1H, s)
FAB+: 674
[Table 15]
36NMR (DMSO-d6):
of 1.26 (6H, t, J=7,3 Hz), 3,16-of 3.27 (4H, m), 3,37-of 3.46 (2H, m), to 4.38 (2H, t, J=6,7 Hz), 6.48 in (1H, t, J=6.9 Hz), 7,10-to 7.18 (2H, m), 7,21-7,28 (1H, m), 7,75-7,98 (7H, m), 8,13 (1H, d, J=9.0 Hz), a 8.34 (1H, d, J=2,5 Hz), 9,76 (1H, s), to 9.91 (1H, s), 10,32 (1H, s)10,52 (1H, s)
FAB+: 560
37NMR (DMSO-d6):
of 1.26 (6H, t, J=7.2 Hz), 3,16-of 3.27 (4H, m), 3,36-of 3.43 (2H, m), to 4.38 (2H, t, J=7,1 Hz), 6.48 in (1H, t, J=6.9 Hz), 7,12-7,19 (2H, m), 7,75-of 7.96 (7H, m), 8,08 (1H, d, J=9.0 Hz), at 8.36 (1H, d, J=2.5 Hz), 9,73 (1H, C), 10,28 (1H, s), 10,49 (1H, s), 10,71 (1H, s)
FAB+: 594
38NMR (DMSO-d6):
1,53-to 1.67 (1H, m), 1,83-of 1.94 (1H, m), 1,96 e 2.06 (1H, m), 2,12-of 2.23 (1H, m), 2,97-and 3.16 (2H, m), with 3.27 (3H, s), 3.33 and-to 3.67 (5H, m), 4,39 (2H, t, J=6.5 Hz), 6.48 in (1H, t, J=6.9 Hz), 7,09-to 7.18 (2H, m), 7,22-7,28 (1H, m), of 7.75-7,97 (7H, m), 8,13 (1H, d, J=8,9 Hz), a 8.34 (1H, d, J=2,8 Hz), 9,71-9,98 (3H, m), 10,52 (1H, s)
ESI+: 602
39NMR (DMSO-d6):
1,56 is 1.70 (1H, m), 1,86 e 2.06 (2H, m), 2,12-of 2.21 (1H, m), 2,96 is 3.15 (2H, m), 3,26 (3H, s), 3.40 in-the 3.65 (5H, m), and 4.40 (2H, t, J=6,7 Hz), 6,47 (1H, t, J=6.8 Hz), 7,11-7,19 (2H, m), 7,75-of 7.95 (7H, m), 8,08 (1H, d, J=8,9 Hz), at 8.36 (1H, d, J=2.5 Hz), 9,72 (1H, s), 10,10-10,30 (1H, m), 10,48 (1H, s), 10,71 (1H, s)
FAB+: 637
40NMR (DMSO-d6):
the 1.04 (3H, t, J=7.0 Hz), 1,24 (3H, t, J=7.0 Hz), 3,26-of 3.46 (4H, m), a 4.86 (2H, s)6,38 (1H, t, J=6.9 Hz), 7,07-7,19 (2H, m), 7,21-7,29 (1H, m), 7,66-7,71 (1H, m), 7,72-7,76 (1H, m), 7,78-7,97 (5H, m), 8,13 (1H, d, J=9.0 Hz), a 8.34 (1H, d, J=2.5 Hz), of 9.75 (1H, s), 9,84 (1H, s)10,52 (1H, s)
FAB+: 574
[Tab the Itza 16]
41NMR (DMSO-d6):
the 1.04 (3H, t, J=7,1 Hz)of 1.23 (3H, t, J=7,1 Hz), of 3.25 to 3.45 (4H, m), a 4.86 (2H, s), 6,37 (1H, t, J=6.8 Hz), 7,10-to 7.18 (2H, m), 7,65-7,71 (1H, m), 7,72-to 7.77 (1H, m), 7,78-7,94 (5H, m), of 8.09 (1H, d, J=9.0 Hz), at 8.36 (1H, d, J=2.7 Hz), to 9.70 (1H, s), 10,36 (1H, s), 10,70 (1H, s)
FAB+: 608
42ESI+: 588
43ESI+: 622
44NMR (DMSO-d6):
3,19-4,50 (12H, m), 6,40-6,51 (1H, m), 7,08-7,33 (3H, m), 7.68 per-8,04 (7H, m), 8,13 (1H, d, J=9.0 Hz), 8,31-to 8.40 (1H, m), of 9.75 (1H, s), 10,48-10,59 (1H, s)
ESI+: 622
45NMR (DMSO-d6):
3,12-4,50 (12H, m), 6,44 (1H, t, J=7.0 Hz),? 7.04 baby mortality-of 7.23 (2H, m), to 7.67-of 8.00 (7H, m), of 8.09 (1H, d, J=8,8 Hz), 8,31-to 8.41 (1H, m), 9,62-and 8.50 (1H, m), of 10.25-10,59 (1H, m), at 10.64-10,78 (1H, m)
ESI+: 656
46NMR (DMSO-d6):
1,13 of 1.28 (6H, m), 2,04-to 2.18 (2H, m), 3,01-of 3.25 (6H, m), 3,98-4,17 (2H, m), to 6.43 (1H, t, J=6.8 Hz), 7,11-to 7.32 (3H, m), 7,69-8,04 (7H, m), 8,10-8,19 (1H, m), 8,33-8,39 (1H, m), 9,76 (1H, s), 10,27 (1H, s), 10,54 (1H, s)
ESI+: 574
[Table 17]
47NMR (DMSO-d6):
to 1.19 (6H, t, J=7.5 Hz), 2,02-2,19 (2H, m), 2,97-up 3.22 (6H, m), 3,97-4,18 (2H, m), to 6.43 (1H, t, J=6.8 Hz), 7,16 (2H, s), 7,65-8,02 (7H, m), of 8.09 (1H, d, J=8,8 Hz), at 8.36 (1H, d, J=2.6 Hz), 9,72 (1H, s), 9,98 (1H, s), of 10.47 (1H, s), 10,71 (1H, s)
ESI+: 608

119
48ESI+: 576
49FAB+: 610
50FAB+: 620
51FAB+: 654
52FAB+: 590
53FAB+: 624
[Table 18]
54 FAB+: 602
55FAB+: 636
56FAB+: 602
57FAB+: 636
58FAB+: 588
59FAB+: 622
60NMR (DMSO-d6)
2,05-2,19 (2H, m), 2.70 height is 2.80 (6H, m), 3,03-3,17 (2H, m), 3,60-4,30 (2H, m), to 6.43 (1H, t, J=6.8 Hz), 7,08-7,20 (2H, m), 7,20-7,30 (1H, m), 7.68 per-8,03 (7H, m), 8,08-8,17 (1H, m), 8,27-8,39 (1H, m), 9,68-9,86 (1H, m,), 10,38 (1H, s), 10,54 (1H, d, J=3.1 Hz)
FAB+: 546
[Table 19]
61NMR (DMSO-d6)
2,02-of 2.21 (2H, 2,02), 2,64-of 2.86 (6H, m)3,00-3,20 (2H, m), 3,94-to 4.14 (2H, m), 6.42 per (1H, t, J=6.9 Hz), to 7.15 (1H, d, J=2.3 Hz), 7,21 (1H, d, J=2.3 Hz), of 7.64-8,02 (7H, m), of 8.09 (1H, d, J=8,9 Hz), at 8.36 (1H, d, J=2,5 Hz), of 9.75 (1H, s), 10,53 (1H, s), 1073 (1H, C)
FAB+: 580
62ESI+: 586
63ESI+: 620
64ESI+:588
65FAB+:622
66NMR (DMSO-d6):
1,86 is 2.01 (4H, m), 3.04 from-is 3.08 (2H, m), 3,51-3,62 (4H, m), 4,36-4,39 (2H, m), 6,46 (1H, t, J=6.9 Hz), 7,13-7,16 (2H, m), 7,25 (1H, t, J=7.9 Hz), 7,76-of 7.90 (5H, m), 7,95 (2H, d, J=8,4 Hz), 8,13 (1H, d, 9.0 Hz), a 8.34 (1H, d, J=2.6 Hz), made up 9.77 (1H, s), 10,53 (1H, s), is 10.68 (1H, users)
ESI+: 558
[Table 20]
67NMR (DMSO-d6):
1,86 is 2.01 (4H, m), 3,06-to 3.09 (2H, m), 3,51-3,62 (4H, m), 4,34-4,,37 (2H, m), 6,46 (1H, t, J=6.9 Hz), to 7.15 (1H, d, J=2.4 Hz), 7,17 (1H, d, J=2.4 Hz), 7,76 (1H, d, J=2.0 Hz), 7,78 (1H, d, J=2.0 Hz), 7,81-7,94 (5H, m), 8,08 (1H, d, J=9.0 Hz), at 8.36 (1H, d, J=2,9 Hz), 9,73 (1H, s), 10,42 (1H, users), 10,71 (1H, s)
ESI+: 592
68NMR (D. THE CO-d6):
1,37-of 1.85 (6H, m), 2,92-to 2.99 (2H, m), 3,41 is 3.57 (4H, m), of 4.38 was 4.42 (2H, m), 6.48 in (1H, t, J=6.8 Hz), 7,12-7,16 (2H, m), 7,25 (1H, t, J=7.9 Hz), to 7.77-of 7.90 (5H, m), 7,94 (2H, d, J=8,4 Hz), 8,13 (1H, d, J=9.1 Hz), a 8.34 (1H, d, J=2.4 Hz), of 9.75 (1H, s), to 9.93 (1H, users), 10,52 (1H, s)
ESI+: 572
69NMR (DMSO-d6):
1,37-of 1.84 (6H, m), 2,92-to 2.99 (2H, m), 3,36 is 3.57 (4H, m), 4,39 was 4.42 (2H, m), 6,47 (1H, t, J=6.9 Hz), to 7.15 (1H, d, J=2,2), 7,18 (1H, d, J=2.4 Hz), to 7.77 (1H, DD, J=1,9, 7,0), 7,81-7,89 (4H, m), to 7.93 (2H, d, J=8,4 Hz), of 8.09 (1H, d, J=8,8 Hz), 8,35 (1H, d, 3.2 Hz), 9,73 (1H, s), of 10.09 (1H, users), of 10.72 (1H, s)
ESI+: 606
70ESI+: 650
71ESI+: 587
72ESI+: 621
[Table 21]
73NMR (DMSO-d6)
at 2.59 (3H, t, J=2,8 Hz), 3,20-to 3.36 (2H, m), 4,30 (2H, t, J=5.5 Hz), 6,46 (1H, t, J=6.9 Hz), 7,09-7,19 (2H, m), 7,25 (1H, t, J=7.9 Hz), 7,72-7,99 (7H, m)to 8.12 (1H, d, J=9.3 Hz), 8,35 (1H, d, J=2.6 Hz), 8,76-8,97 (1H, m), 9,76 (1H, s), 10,49-of 10.58 (1H, m)
FAB+: 518
74 NMR (DMSO-d6)
2,55-of 2.64 (3H, m), 3,24-to 3.36 (2H, m), 4,23 is 4.36 (2H, m), 6,46 (1H, t, J=6,7 Hz), 7,10-7,22 (2H, m), 7,70-7,99 (7H, m), 8,08 (1H, d, J=8,8 Hz), at 8.36 (1H, d, J=2,8 Hz), 8,67-8,93 (1H, m), 9,73 (1H, s), 10,51 (1H, (C), of 10.72 (1H, s)
FAB+: 552
75ESI+:588
76ESI+:622
77ESI+:602
78NMR (DMSO-d6)
1,50-of 1.65 (1H, m), 1,80-of 1.93 (2H, m), 2,01-2,10 (1H, m), 2,63-by 2.73 (3H, m), 2,80-of 2.93 (2H, m), 3,13 is 3.23 (1H, m), 3,31-with 3.79 (4H, m), 4.09 to is 4.21 (2H, m), 6,33-6.42 per (1H, m), 7,13-7,19 (2H, m), 7.68 per-of 7.95 (7H, m), 8,09 (1H, d, J=8,9 Hz), at 8.36 (1H, d, J=2.3 Hz), 9,72 (1H, s), of 10.09-10,59 (2H, m), 10,71 (1H, s)
ESI+:636
[Table 22]
79FAB+: 587
80ESI+:601
81 ESI+: 587
82ESI+: 621
83NMR (DMSO-d6):
1,58-of 1.84 (2H, m), 1,88 e 2.06 (2H, m), 2,90-3,30 (2H, m), 3,30-4,00 (5H, m)to 4.41 (2H, DD, J=6.3, in the 12.8 Hz), 6,47 (1H, t, J=6.9 Hz), 7,09-7,19 (2H, m), 7,25 (1H, t, J=7.8 Hz), to 7.77 (1H, DD, J=1,9, 7,1 Hz), 7,80-to $ 7.91 (4H, m), to $ 7.91-of 8.00 (2H, m), 8,13 (1H, d, J=9.0 Hz), a 8.34 (1H, d, J=2,8 Hz), 9,76 (1H, s), 9,80-10,35 (1H, m), 10,53 (1H, s)
ESI+: 588
84MR (DMSO-d6):
1,54-of 1.84 (2H, m), 1,86 e 2.06 (2H, m), 2,90-3,30 (2H, m), 3,30-4,00 (5H, m), and 4.40 (2H, DD, J=6,2, to 12.8 Hz), 6,47 (1H, t, J=6.9 Hz), to 7.15 (1H, d, J=2.4 Hz), 7,18 (1H, d, J=2.4 Hz), 7,72-of 8.00 (7H, m), of 8.09 (1H, d, J=8,9 Hz), at 8.36 (1H, d, J=2.4 Hz), 9,73 (1H, s), 9,90-10,66 (1H, m), 10,71 (1H, s)
ESI+: 622
85NMR (DMSO-d6)
1,62-of 1.92 (3H, m), 1,98 and 2.13 (1H, m), 3,17-of 3.48 (2H, m), 7,10 (1H, d, J=7.8 Hz), 7,14 (1H, d, J=7.8 Hz), 7,20 was 7.36 (3H, m), 7,66 (1H, s), 7,79-7,94 (3H, m), 8,13 (1H, d, J=8.7 Hz), a 8.34 (1H, d, J=2,9 Hz), 9,67 (1H, s), 9,83 (1H, s), 10,51 (1H, s)
FAB+: 465
[Table 23]
86 NMR (DMSO-d6):
1,64-of 1.88 (3H, m), 1,99-of 2.09 (1H, m), 3,18-to 3.34 (2H, m), 3,53-3,61 (1H, m), 7,08-7,17 (2H, m), 7,28 (2H, d, J=8,3 Hz), 7,66 (1H, s)of 7.82 (2H, d, J=8,3 Hz), 7,87 (1H, DD, J=8,9 and 2.5 Hz), of 8.09 (1H, d, J=8,9 Hz), 8,35 (1H, d, J=2.5 Hz), 9,62 (1H, s), 10,34 (1H, s), 10,69 (1H, s)
FAB+: 499
87ESI+: 479
88FAB+:518
89NMR (DMSO-d6):
1,18-of 1.27 (6H, m), 1,76-2,12 (4H, m), is 3.08-3,78 (11H, m), 7,08-7,17 (2H, m), 7,20-7,27 (1H, m), 7,31 (2H, d, J=8,3 Hz), 7,81-of 7.90 (3H, m)to 8.12 (1H, d, J=9.0 Hz), a 8.34 (1H, d, J=2.4 Hz), 9,68 (1H, s), 9,80-9,96 (2H, m), 10,51 (1H, s)
FAB+: 564
90NMR (DMSO-d6):
1,19-of 1.27 (6H, m), 1,79-2,11 (4H, m), 3,06-of 3.77 (11H, m), 7,12-to 7.18 (2H, m), 7,31 (2H, d, J=8,4 Hz), 7,83 (2H, d, J=8,3 Hz), 7,87 (1H, DD, J=8,9, 2,8 Hz), 8,08 (1H, d, J=8,9 Hz), 8,35 (1H, d, J=2.5 Hz), 9,65 (1H, s), 10,18 (1H, s), of 10.47 (1H, s), 10,69 (1H, s)
FAB+: 598
91ESI+:606
[Table 24]
92 ESI+:640
93ESI+: 592
94ESI+: 626
95NMR (DMSO-d6)
1,74 with 2.14 (4H, m), 3,62-3,90 (15H, m), 7,13 (2H, DD, J=4,6, and 12.6 Hz), 7,24 (1H, t, J=7.8 Hz), 7,35 (2H, d, J=8.6 Hz), 7,78-of 7.96 (3H, m)to 8.12 (1H, d, J=8.1 Hz), a 8.34 (1H, d, J=2,9 Hz), 9,68 (1H, s), 10,49-10,54 (1H, m)
ESI+: 626
96NMR (DMSO-d6)
1,71-2,17 (4H, m), 3,26-4,16 (15H, m), 7,15 (2H, s), 7,35 (2H, d, J=8.6 Hz), to 7.77-a 7.92 (3H, m), of 8.09 (1H, d, J=9,2 Hz), at 8.36 (1H, d, J=2.4 Hz), for 9.64 (1H, s), 10,66-of 10.73 (1H, m)
ESI+: 660
97ESI+: 578
98ESI+: 612
[Table 25]
99FAB+: 578
100 NMR (DMSO-d6):
1,80-2,12 (4H, m), 3.00 and-4,05 (15H, m), 7,14 (2H, s), 7,32 (2H, d, J=8,2 Hz), 7,83 (2H, d, J=8,2 Hz), 7,88 (1H, DD, J=2.7, and 9.0 Hz), 8,08 (1H, d, J=9.0 Hz), 8,35 (1H, d, J=2.7 Hz), for 9.64 (1H, s), 10,43 (1H, s), 10,70 (2H, s)
FAB+: 612
101ESI+:578
102ESI+:612
103ESI+:562
104ESI+:596
105NMR (DMSO-d6):
1,30-2,11 (10H, m), 2,82-of 2.97 (2H, m), 3,18-3,76 (9H, m), 7,09-7,17 (2H, m), 7,20-7,28 (1H, m), 7,32 (2H, d, J=8,3 Hz), 7,81-to $ 7.91 (3H, m)to 8.12 (1H, d, J=9.0 Hz), a 8.34 (1H, d, J=2.5 Hz), 9,62-10,06 (3H, m), 10,51 (1H, s)
ESI+: 576
[Table 26]
106NMR (DMSO-d6):
1,28-2,11 (10H, m), 2,82-2,95 (2H, m), 3,18-3,76 (9H, m), 7,12-to 7.18 (2H, m), 7,31 (2H, d, J=8,3 Hz), 7,83 (2H, d, J=8,3 Hz), 7,88 (1H, DD, J=8,9, 2.7 Hz), 8,08 (1H, d, J=8,9 Hz),8,35 (1H, d, J=2.5 Hz), 9,65 (1H, s), 10,07 (1H, s), 10,48 (1H, s), 10,70 (1H, s)
ESI+: 610
107ESI+:592
108ESI+:626
109NMR (DMSO-d6):
1,28 of 1.46 (1H, m), 1,58-2,19 (11H, m), 2,74 totaling 3.04 (4H, m), 3,26-of 3.95 (7H, m), 7,09-to 7.18 (2H, m), 7,20 was 7.36 (3H, m), 7,79-of 7.95 (3H, m)to 8.12 (1H, d, J=9.0 Hz), a 8.34 (1H, d, J=2.6 Hz), to 9.70 (1H, s), 10,10 (1H, s), 10,52 (1H, s)
FAB+: 590
110NMR (DMSO-d6)
1,28-of 1.45 (1H, m), 1,62-2,11 (11H, m), was 2.76-to 3.02 (4H, m), 3,28-3,88 (7H, m), 7,12-7,19 (2H, m), 7,29 (2H, d, J=8.1 Hz), 7,78-7,94 (3H, m), 8,08 (1H, d, J=8,4 Hz), 8,35 (1H, d, J=2,9 Hz), to 9.66 (1H, s), to 9.91 (1H with), 10,48 (1H, s), 10,66-of 10.73 (1H, m)
FAB+: 624
111ESI+:577
112ESI+:611
[Table 27]
113 ESI+:576
114ESI+:610
115NMR (DMSO-d6):
to 2.85 (3H, s), 2,87 (3H, s), 3,47-3,55 (2H, m), 4,39 (2H, t, J=6.2 Hz), 7,11-to 7.18 (2H, m), 7,25 (1H, t, J=7.9 Hz), 7,81-to $ 7.91 (3H, m), 7,98 (2H, d, J=8,4 Hz)to 8.12 (1H, d, J=9.0 Hz), of 8.28 (1H, s), 8,35 (1H, d, J=2,8 Hz), 8,63 (1H, s), 9,74 of 10.05 (2H, m), 10,27 (1H, s), 10,54 (1H, s)
ESI+: 533
116NMR (DMSO-d6)
3,26 (3H, s), 3,63 (2H, t, J=5.3 Hz), is 4.15 (2H, t, J=5.3 Hz), 6.35mm (1H, t, J=6.9 Hz), 7,08-to 7.18 (2H, m), 7,25 (1H, t, J=7.9 Hz), 7.68 per-7,74 (2H, m), 7,78-of 7.96 (5H, m)to 8.14 (1H, d, J=8,9 Hz), 8,35 (1H, d, J=2,6 Hz), of 9.75 (1H, s), 9,85 (1H, s), 10,53 (1H, s)
FAB+: 519
117NMR (DMSO-d6)
2,01 is 2.10 (2H, m), 2.21 are a 2.36 (2H, m), 2,78 (3H, d, J=4,7 Hz), 3,15 to be 3.29 (2H, m), 3,41-3,68 (2H, m), 4,99-5,13 (1H, m), of 6.49 (1H, t, J=6.9 Hz), 7,09-7,19 (2H, m), 7,25 (1H, t, J=7.9 Hz), to 7.59-7,66 (1H, m), 7.68 per-7,74 (1H, m), 7,80 (2H, d, J=8,2 Hz), the 7.85-of 7.97 (3H, m), 8,13 (1H, d, J=8,9 Hz), 8,35 (1H, d, J=2.6 Hz), 9,72-10,00 (2H, m), 10,50-is 10.68 (2H, m)
ESI+: 558
[Table 28]
118FAB+: 591
ESI+: 591
120The HPLC conditions
Column: CHIRALPAK AS-H
(0,46 cm (ID) ×25 cm (L))
Eluent: Hexane/Ethanol/Diethylamine =
50/50/0,1
Flow rate: 1.0 ml/min
The pace. column: 40°C
Detection: UV 254 nm
Holding time: 5,97 min
121The HPLC conditions
Column: CHIRALPAK AS-H
(0,46 cm (ID)×25 cm (L))
Eluent: Hexane/Ethanol/Diethylamine =
50/50/0,1
Flow rate: 1.0 ml/min
The pace. column: 40°C
Detection: UV 254 nm
Holding time: to 8.57 min
122NMR (DMSO-d6 + D2O)
of 2.20 (6H, s), to 2.57 (2H, t, J=6.4 Hz), 3,18-to 3.38 (3H, m), 3,51 (1H, d, J=9.8 Hz), 4,07 (2H, t, J=6.4 Hz), 4,88 ( 1H, d, J=7.5 Hz), to 6.39 (1H, t, J=6.8 Hz), 7,32 is 7.50 (3H, m), to 7.67-7,74 (2H, m), 7,80 (2H, d, J=8,4 Hz), 7,87 (1H, DD, J=2.5 and 9.0 Hz), of 7.96 (2H, d, J=8,4 Hz)and 8.1 (1H, d, J=9,0), and 8.3 (1H, d, J=2.5 Hz)
ESI+: 708
[Table 29]
123NMR (DMSO-d6 + D2O)
1,69-to 1.87 (3H, m), 1,96-2,11 (1H, m), and 2.8 (6H, C)2,72 of 2.92 (2H, m), 3,20-3,76 (9H, m), 4,91 (1H, d, J=7,6 Hz), 7,27 (2H, d, J=8,2 Hz), 7,33-7,46 (3H, m), 7,80-of 7.90 (3H, m), 8,10 (1H, d, J=9.0 Hz), 8,31 (1H, d, J=2,8 Hz)
ESI+: 712
124NMR (DMSO-d6 + D2O)
1,55-to 1.98 (3H, m), 2,00-2,11 (1H, m)2,60 (6H, s), 2,90-of 3.06 (2H, m), 3,18-3,79 (9H, m)to 4.92 (1H, d, J=7,6 Hz), 7,30 (2H, d, J=8,2 Hz), 7,34 was 7.45 (3H, m), 7,82-of 7.90 (3H, m), 8,10 (1H, d, J=9.0 Hz), 8,31 (1H, d, J=2.5 Hz)
ESI+: 712
125NMR (DMSO-d6)
1,80-2,00 (3H, m), 2,01 and 2.13 (1H, m), 2,53-2,60 (3H, m), 3,01-3,19 (2H, m), 3,34-of 3.60 (3H, m), 3,63-of 3.77 (2H, m), 7,07-7,17 (2H, m), 7,24 (1H, t, J=7.8 Hz), 7,33 (2H, d, J=8,3 Hz), 7,79-to 7.93 (3H, m), 8,13 (1H, d, J=8,9 Hz), 8,35 (1H, d, J=2.4 Hz), a total of 8.74 (2H, s)to 9.70 (1H, s), for 9.90 (1H, s), 10,53 (1H, s)
ESI+: 522
126ESI+: 531
127NMR (DMSO-d6)
of 2.86 (6H, s), of 3.46 (2H, t, J=6.3 Hz), 3,81 (3H, s), to 4.38 (2H, t, J=6.3 Hz), 6,47 (1H, t, J=6.9 Hz), PC 6.82 (1H, d, J=7.8 Hz), 7,03 (2H, d, J=8,8 Hz), 7,16 (1H, t, J=8.1 Hz), 7,27 (1H, d, J=7.9 Hz), 7,74-7,94 (6H, m), of 8.04 (2H, d, J=8.1 Hz), 9,65 (1H, s)9,68 (1H, s), 9,80 (1H, s), 10,14 (1H, s)
ESI+: 527
[Table 30]
128 FAB+: 561

[Table 31]

[Table 32]

[Table 33]

[Table 34]

[Table 35]

[Table 36]

[Table 37]

[Table 38]

[Table 39]

[Table 40]

[Table 41]

[Table 42]

INDUSTRIAL APPLICABILITY

Compounds according to the present invention have an anticoagulant effect, based on their ability to inhibit the activated blood coagulation factor X, and can be used as inhibitors of coagulation or means for the prevention or treatment of diseases caused by thrombi or emboli, and therefore have industrial applicability.

1. A derivative of benzene following General formula (I) or its salt:
[Chem. 12]

(symbols in the formula have the following meanings:
X1:-NR12-C(=O)-or-C(=O)-NR12-,
X2:-NR12-C(=O)-,
Ring: 6-membered ring which, if necessary having 1 or 2 double bonds and, if necessary, having from 1 to 3 heteroatoms selected from N, O,
Ring: benzene ring or 6-membered heteroaryl ring having 1 to 3 heteroatoms selected from N,
R: a hydrogen atom or a residue of β-D-glucopyranoside acid;
R1-R8: the same or different, each represents a hydrogen atom, halogen atom, -O-(lower alkyl),
R9-R11: the same or different, each represents a hydrogen atom, a lower alkyl, -O-(lower alkyl), -(CH2)n-N(lower alkyl)2, -(CH2)n-NH-(lower alkyl), -(CH2)n-N(lower alkyl) (if necessary substituted by a group: -S=O; 6-membered heterocycle having from 1 to 3 heteroatoms selected from N, S, O), -(CH2)n-(C=O)-N(lower alkyl)2, -(CH2)n-(C=O)-N(lower alkyl)(if necessary substituted groups: -C=O, alkyl, 6-membered heterocycle having from 1 to 3 heteroatoms selected from N), -(CH2)n-(if necessary substituted by the groups: alkyl, -PINES3, -SO2CH3-SOON3, -C=O, CF3, -Och3HE, halogen; 5-7-membered heterocycle having from 1 to 3 heteroatoms selected from N, S, O), -(CH2)n-O-(if necessary substituted by the group: alkyl; 6-membered heterocycle having about the 1 to 3 heteroatoms, selected from N, n: an integer from 0 to 3,
R12and R13: denote a hydrogen atom,
provided that, in R1-R11when two lower alkyl linked to a nitrogen atom, then they may together form a 3-8-membered nitrogen-containing heterocycle).

2. The compound or its salt according to claim 1, in which in the formula (I) according to claim 1 group:
[Chem. 13]

is a group selected from the following:
,,,,,
,,,,,.

3. The compound or its salt according to claim 1, in which in the formula (I) according to claim 1 group:
[Chem. 14]

is a group selected from the following:
,,,,
,,or.

4. The compound or its salt according to claim 1, in which in the formula (I) according to claim 1 group:
[Chem. 15]

is a group selected from the following:
, or.

5. The compound or its salt according to claims 1 to 4, in which in the formula (I) according to claim 1 ring represents a benzene ring or a pyridine ring.

6. The compound or its salt according to claim 5, in which in the formula (I) according to claim 1, R denotes a hydrogen atom or charigny residue of β-D-glucopyranoside acid.

7. The compound or its salt according to claim 6, in which, if necessary, substituted 5-7-membered heterocycle having from 1 to 3 heteroatoms selected from N, S, O, represents a heterocycle selected from azetidine, pyrrolidine, piperidine, azepane, asokan, piperazine, tetrahydrooxazolo, thiomorpholine, 1,4-diazepine, 1,4-oxathiane, 1,4-diazepine, 1,5-diatkine, 1,5-oxazoline, 1,5-thiazocine, imidazole, triazole, thiazole, oxazole, isoxazol, pyrazole, pyridine, pyrazine or pyrimidine.

8. The compound or its salt according to claim 7, in which the Deputy if necessary substituted lower alkyl represents from 1 to 3 substituents selected from C=O, and the Deputy if necessary substituted 5-7-membered heterocycle having from 1 to 3 heteroatoms selected from N, S, O, represents from 1 to 3 substituents selected from lower alkyl, -HE, CF3, -COO-lower alkyl or-SO2(lower alkyl).

9. A derivative of benzene following General formula (II) or its salt:
[Chem. 16]

(symbols in the formula have the following meanings:
X1: -NH-C(=O)- or-C(=O)-NH-,
Y: N or CH,
Z:N, NH, CH or CH2,
R: a hydrogen atom or a residue of β-D-glucopyranoside acid,
R1-R8: the same or different, each represents a hydrogen atom, halogen atom, -O-lower alkyl,
R9-R11: the same or different, each represents a hydrogen atom, a lower alkyl, -(CH2)n-N(lower alkyl)2, -(CH2)n-NH(lower alkyl), -(CH2)n-N(lower alkyl)(if necessary substituted by a group: -S=O; 6-membered heterocycle having from 1 to 3 heteroatoms selected from N, S, O), -(CH2)n-(C=O)-N(lower alkyl)2, -(CH2)n-(C=O)-N(lower alkyl)(6-membered heterocycle having from 1 to 3 heteroatoms selected from N), -(CH2)n-O-lower alkyl,-(CH2)n-(if necessary substituted by the groups: alkyl, -PINES3, -SO2CH3-SOON3, -C=O, CF3, -Och3HE, halogen; 5-7-membered heterocycle having from 1 to 3 heteroatoms selected from N, S, O), -(CH2)n-O-(if necessary substituted by the group: alkyl; 6-membered heterocycle having from 1 to 3 heteroatoms selected from N),
n: an integer from 0 to 3,
provided that the dotted part in the formula are the same or different, and each is Aya means a simple link or a double bond, and R1-R11when two lower alkyl groups linked to the nitrogen atom they may together form a 3-8-membered nitrogen-containing heterocycle).

10. The compound or its salt according to claim 9, in which in the formula (II) according to claim 9 R denotes a hydrogen atom or a residue of β-D-glucopyranoside acid.

11. The compound or its salt according to claim 1, selected from the following compounds:
N-(5-chloropyridin-2-yl)-3-hydroxy-2-{[4-(1-methyl-4-oxo-1,4-dihydropyridines-3-yl)benzoyl]amino}benzamide, N-(5-chloropyridin-2-yl)-2-[(4-{1-[2-(dimetilamine)ethyl]-2-oxo-1,2-dihydropyridines-3-yl} benzoyl)amino]-3-hydroxybenzamide,
N-(5-chloropyridin-2-yl)-3-hydroxy-2-[(4-{1-[2-(1,4-oxazepan-4-yl)ethyl]-2-oxo-1,2-dihydropyridines-3-yl}benzoyl)amino]benzamide, 5-chloro-N-(5-chloropyridin-2-yl)-3-hydroxy-2-{[4-(1-{2-[(1-methylpyridin-4-yl)oxy]ethyl}-2-oxo-1,2-dihydropyridines-3-yl)benzoyl]amino}benzamide, N-(5-chloropyridin-2-yl)-3-hydroxy-2-{[4-(1-methyl-2-oxo-1,2-dihydropyridines-3-yl)benzoyl]amino}benzamide,
N-(5-chloropyridin-2-yl)-2-[(4-{1-[2-(dimetilamine)ethyl]-2-oxopiperidin-3-yl}benzoyl)amino]-3-hydroxybenzamide, 3-[(5-chloropyridin-2-yl)carbarnoyl]-2-[(4-{1-[2-(dimetilamine)ethyl]-2-oxo-1,2-dihydropyridines-3-yl}benzoyl)amino]phenyl-β-D-glucopyranoside acid, N-(5-chloropyridin-2-yl)-3-hydroxy-2-[(4-{1-[2-(4-methylpiperazin-1-yl)ethyl]-2-oxo-1,2-dihydropyridines-3-yl}benzoyl)amino]benzamide, 4-{1-[2-(dimetilamine)ethyl]-2-oxo-1,2-dihydropyridines-3-yl}-N-{2-Ki-the Roxy-6-[(4-methoxybenzoyl)amino]phenyl} benzamide, N-(5-chloropyridin-2-yl)-3-hydroxy-2-[(4-{1-[2-(4-hydroxypiperidine-1-yl)ethyl]-2-oxo-1,2-dihydropyridines-3-yl}benzoyl)amino]benzamide, 5-chloro-N-(5-chloropyridin-2-yl)-2-[(4-{1-[2-(dimetilamine)ethyl]-2-oxo-1,2-dihydropyridines-3-yl} benzoyl)amino]-3-hydroxybenzamide, 3-[(5-chloropyridin-2-yl)carbarnoyl]-2-[(4-{1-[2-(dimetilamine)ethyl]-2-oxopiperidin-3-yl}benzoyl)amino]phenyl-β-D-glucopyranoside acid.

12. Pharmaceutical composition, which has activity as an inhibitor of activated blood coagulation factor X, containing the compound or its salt according to claim 1 as an active ingredient.

13. The pharmaceutical composition according to item 12, which is an inhibitor of activated blood coagulation factor X.

14. The pharmaceutical composition according to item 12, which is anticoagulation tool.

15. The use of compound or its salt according to claim 1 or 9 to get the inhibitor of activated blood coagulation factor X.

16. The use of compound or its salt according to claim 1 or 9 to get anticoagulative funds.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: formula (I) compounds, radicals of which are defined in the formula of invention, are described. A pharmaceutical composition containing formula (I) compounds is also described.

EFFECT: obtaining compounds which have inhibitory activity on protein kinase MEK1/2 and are meant for use as a therapeutically active substance which is useful for treating MEK1/2 mediated diseases.

13 cl, 18 ex

FIELD: chemistry.

SUBSTANCE: benzamide derivatives are presented by the formula [1] or its salt, where Z is -O-, -NR5-, -S-, -SO-; 1 is 0 or 1; m is 0 or 1; R1 is hydrogen atom, C1-6-alkyl group, R2 is hydrogen atom, hydroxylic group, C1-6- alkyl group, carboxyl group, C1-6-alkoxycarbonyl group or -CONR10R11, or R2 and R1 together form =O; R3 is hydrogen atom or C1-6-alkyl group; R4 is hydrogen atom or halogen atom; V is direct bond or -(CR21R22)n-; P1 and P2 rings are the same or different, and each is aromatic or saturated carbocyclic group, or 5-10-member saturated or unsaturated heterocyclic group containing 1-3 heteroatoms selected out of N, O, S.

EFFECT: obtainment of compound with excellent inhibition effect on vanilloid receptor type 1 activity, efficiency in treatment of diseases involving vanilloid receptor type 1 activity.

17 cl, 56 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I , where R1 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl and lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl, which can be substituted with a halogen; R2 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl or lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl which can be substituted with a halogen; or R1 and R2 together with the nitrogen atom to which they are bonded form a 4-, 5- or 6-member saturated or partially unsaturated heterocyclic ring which optionally contains the same heteroatom selected from oxygen or sulphur, where the said saturated or partially heterocyclic ring is unsubstituted or substituted with one or two groups independently selected from a group consisting of lower alkyl, halogen, halogenalkyl, cyano group, hydroxy group, lower hydroxyalkyl, lower alkoxy group, oxo group; A is selected from , and , where m equals 0 or 1; R3 is a lower alkyl; n equals 0; R4 is a lower alkyl; p equals 1; q equals 0, 1 or 2; R5 is hydrogen; and their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition based on formula I compounds.

EFFECT: new quinoline derivatives are obtained, which have antagonistic effect on histamine 3 receptors (H3 receptors).

18 cl, 4 tbl, 86 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to benzazepin derivatives of formula (I), where R1 is unsubstituted cyclobutyl, R2 is 3-pyrazinyl, substituted CON(H)(Me) or 2-pyridinyl-M-pyrrolidinyl, where the said pyrrolidinyl group is substituted with a =O group; which is: methylamide 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy) pyrazine-2-carboxylic acid

or 1-{6-[(3-cyclbutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone

EFFECT: obtaining compounds which have affinity to histamine H3 receptor and pharmaceutical compositons containing said compounds.

11 cl, 288 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) and to their pharmaceutically acceptable salts, optical isomers or their mixture as glucokinase activators. In general formula (I) where R1 is C3-8-cycloalkyl, C3-8-cycloalkenyl, a 6-member heterocyclyl with 1 nitrogen atom, condensed phenyl-C3-8-cycloalkyl, each of which is possibly substituted with one or two substitutes R3, R4, R5 and R6; R2 is C3-8-cycloalkyl, a 5-6-member heterocyclyl with 1-2 heteroatoms selected from N, O, or S, each of which can be substituted with one or two substitutes R30, R31, R32 and R33, and R3, R4, R5, R6, R30, R31, R32 and R33 are independently selected from a group consisting of halogen, hydroxy, oxo, -CF3; or -NR10R12; or C1-6-alkyl, phenyl, C1-6-alkoxy, C1-6-alkyl-C(O)-O-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; or -C(O)-R27, -S(O)2-R27; or two substitutes selected from R3, R4, R5 and R6 or R30, R31, R32 and R33, bonded to the same atom or to neighbouring atoms, together form a -O-(CH2)2-O- radical; R10 and R11 independently represent hydrogen, C1-6-alkyl, -C(O)-C1-6-alkyl, -C(O)-O- C1-6-alkyl, -S(O)2- C1-6-alkyl; R27 is C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, phenyl, phenyl-C1-6-alkyl, a 5-6-member heteroaryl with 1-2 heteroatoms selected from N or S, a 6-member heteroaryl-C1-6-alkyl with 1 nitrogen atom, a 6-member heterocyclyl-C1-6-alkyl with 1-2 heteroatoms selected from N or O, R10R11-N- C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; R12 is a halogen, CF3, C1-6-alkoxy, -NR10R11; A is a 5-9-member heteroaryl with 1-3 heteroatoms selected from N, O or S, which is possibly substituted with one or two substitutes independently selected from R7, R8 and R9; R7, R8 and R9 are independently selected from halogen, cyano, -CF3; or C1-6-alkyl, C2-6-alkenyl, C1-6-alkoxy, C1-6-alkylthio, -C(O)-O-C1-6-alkyl, formyl, - C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-O-C(O)-C1-6-alkyl or hydroxy-C1-6-alkyl, each of which is possibly substituted with a substitute independently selected from R16; or phenyl, 5-member heteroaryl-C1-6-alkylthio with 2-4 nitrogen atoms, phenylthio, 5-6-member heteroarylthio with 1-2 nitrogen atoms, each of which is possibly substituted on the aryl or heteroaryl part with one or two substitutes independently selected from R17; or C3-8-cycloalkyl; or a 6-member heterocyclyl with 2 nitrogen atoms, 5-7-member heterocyclyl-C1-6-alkylthio with 1-2 heteroatoms selected from N or O, each of which is possibly substituted with one substitute independently selected from R16; or C1-6-alkyl-NR19R20, -S(O)2-R21 or -S(O)2-NR19R20; or -C(O)NR22R23; R16, R17 and R18 independently represent C1-6-alkyl, carboxy, -C(O)-O-C1-6-alkyl, -NR19R20, -C(O)NR19R20; R19 and R20 independently represent hydrogen, C1-6-alkyl, phenyl, 5-member heteroaryl with 2 heteroatoms selected from N or S, 6-member heterocyclyl with 1 nitrogen atom, -C(O)-O-C1-6-alkyl or -S(O)2-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R24; or R19 and R20 together with a nitrogen atom to which they are bonded form a 5-7-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring possibly contains one additional heteroatom selected from nitrogen, oxygen and sulphur, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R21 is selected from C2-6-alkenyl; or R22 and R23 are independently selected from hydrogen, -C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-S(O)2-C1-6-alkyl, C3-8-cycloalkyl; or R22 and R23 together with a nitrogen atom to which they are bonded form a 6-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R24 is oxo, C1-6-alkyl, carboxy- C1-6-alkyl, a 6-member heterocyclyl with 1 nitrogen atom, -NH-S(O)2R28 or -S(O)2R28, where each cyclic group is possibly substituted with one substitute independently selected from R29; R28 is C1-6-alkyl, -C1-6-alkyl-C(O)-O- C1-6-alkyl or -N(CH3)2; R29 is C1-6-alkyl.

EFFECT: obtaining compounds which can be used for treating and preventing diseases mediated by low glucokinase activity.

21 cl, 1 dwg, 608 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (XXI) where values of R1, Y, Ra and Rb are given in subparagraphs 1 and 2 of the formula of invention, as phosphatidylinositol-3-kinase inhibitors, a pharmaceutical composition based on said compounds and their use.

EFFECT: compounds can be used for treating and preventing diseases mediated by phosphatidylinositol-3-kinase.

5 cl, 5 tbl, 146 ex

FIELD: chemistry.

SUBSTANCE: described are compounds of formula (I)

Values of radicals R1-R6 are given in the formula of invention. The compounds inhibit protein kinase MEK1/2. Also described is a pharmaceutical composition for administration in diseases mediated by MEK1/2.

EFFECT: compounds are highly efficient.

16 cl, 27 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

or

or to their pharmaceutically acceptable salts, where ring A, R2, R3, R4 and X are as defined in the description. The disclosed compounds are useful as 11βHSD1 inhibitor. The invention also relates to a pharmaceutical composition, an agent for treating or preventing pathology related to glucocorticoids, a 11βHSD1 inhibitor containing the disclosed compound or its pharmaceutically acceptable salt, and use of the disclosed compounds.

EFFECT: compounds are highly effective.

40 cl, 48 tbl, 191 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula and their pharmaceutically acceptable salts and esters. The disclosed compounds have cdk4 inhibition properties. In formula (I) n equals 0 or 1; R1 and R2 are each independently selected from a group consisting of H, lower alkyl, CO2R5, SO2R6 and COR6; or alternatively, R1 and R2 can form a ring containing 5-6 atoms in the ring, where the said ring contains carbon atoms, where the said carbon atoms are optionally substituted with oxygen, and the said atoms in the ring are optionally substituted with OR6; R3 is selected from a group consisting of H, lower alkyl, O-lower alkyl, halogen, OH, CN, NO2 and COOH; R4 is selected from a group consisting of H, lower alkyl, C3-C6-cycloalkyl, O-lower alkyl, halogen, NO2, S-lower alkyl, NR5R6, CONR7R8, OH and CN; or alternatively R3 and R4, together with two carbon atoms and the bond between them from the benzene ring, to which R3 and R4 are bonded, can form a ring containing 5-7 atoms, where the said 5-7-member ring contains carbon atoms, where the said carbon atoms are optionally substituted with one or two heteroatoms selected from O and N, and the said atoms in the ring are optionally substituted with CO2R6; R4 represents H or halogen; R5 and R6 are each independently selected from a group consisting of H and lower alkyl; R7 and R8 each represents H. The invention also relates to a pharmaceutical composition for treating or controlling diseases progression of which can be enhanced by inhibiting cdk4, containing an effective amount of the disclosed compound as an active ingredient, to use of disclosed compounds for preparing medicinal agents and method of producing said compounds.

EFFECT: more effective treatment.

30 cl, 1 tbl, 142 ex

FIELD: medicine.

SUBSTANCE: invention refers to new compounds of formula I in the form of salt where J means a C1-C2 alkylene; R1 means cyclopentane, cyclohexyl, phenyl or thiophenes; R2 means hydroxy; R3 means a cyclopentane, cyclohexyl, phenyl or thiophenes; with R1 and R3 are not identical, or -CR1R2R3 together form a group of the formula , where Ra means a chemical bond, and Rb means hydroxy; R4 means methyl; R5 means C1 alkyl substituted with -CO-NH-R6; R6 means 5- or 6-membered heterocyclic group that contains in a cycle at least one heteroatom selected from nitrogen, oxygen and sulfur; or J means C1-C2 alkylene; R1 and R3 both mean phenyl; R2 means hydroxy; R4 means methyl, R5 means C1 alkyl substituted with -CO-NH-R9; and R9 means 5- or 6-membered heterocyclic group that contains in a cycle at least one heteroatom selected from nitrogen, oxygen and sulfur. The invention also refers to pharmaceutical composition, to application of compound according to any of clauses 1-3, as well as to method for obtaining a compound of formula I according to clause 1.

EFFECT: obtaining new biologically active compounds having antagonistic activity against muscarinic receptor M3.

7 cl, 21 ex

Cytokine inhibitors // 2394029

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) and their pharmaceutically acceptable salts and acids. In formula (I) , Ar1 is an aromatic carbocycle substituted with one R1 and where Ar1 is independently substituted with two R2; R1 is J-N(Ra)-(CH2)m-, N(J)2-(CH2)m-, NH2C(O)-, J-N(Ra)-C(O)-, J-S(O)m-N(Ra)-, J-N(Ra)-S(O)m-; Q is CRP; Y is -N(Rx)-; where Ra, Rp, Rx and Ry each independently denotes hydrogen or (C1-C5)alkyl; X is O-; W is N or CH, m independently equals 0, 1 or 2; J is selected from (C1-C10)alkyl, optionally substituted Rb; R2 is selected from (C1-C6)alkyl or (C1-C4)alkoxy, optionally partially or completely halogenated; R3, R4 and R5 are each independently selected from hydrogen or (C1-C6)alkyl; R6 is optionally bonded in the ortho- or meta-position to the nitrogen atom of the said ring and is selected from a bond, -O-, O-(CH2)1-5-, -NH-, -C(O)-NH-, branched or straight (C1-C5)alkyl; and where each R6 is further optionally covalently bonded to groups selected from hydrogen, -NR7R8, (C1-C3)alkyl, heteroaryl(C0-C4)alkyl, where the heteroaryl is pyrimidine, and heterocyclyl(C0-C4)alkyl, where the heterocyclyl is selected form morpholine, pyrrolidine, piperazinyl, optionally substituted with (C1-C6)alkyl; R7 and R8 each independently denote hydrogen or branched or straight (C1-C5)alkyl; and Rb is selected from hydrogen, (C1-C5)alkyl, amino, (C1-C5)alkylamino, (C1-C5)dialkylamino. The invention also relates to a pharmaceutical composition containing a pharmaceutically effective amount of the formula (I) compound, to use of the disclosed compounds to prepare a pharmaceutical composition and to a method of obtaining formula (I) compounds.

EFFECT: disclosed compounds have cytokine inhibiting properties.

13 cl, 3 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: novel 1,2,4-triazole derivatives - protein kinase inhibitors of formula (I) are described, where X - N; Y - CH2, NH, NR or 0; R1 and R2 each independently denote hydrogen; R3 is phenyl, substituted with -CN, 6-member heteroaryl containing 1-2 N atoms, possibly substituted with a 7-member heterocyclyl containing 2 nitrogen atoms, which in turn is substituted with C1-6alkylcarbonyl; R4 is hydrogen; R5 is hydrogen or -CN; and R is a C1-6alkyl group, C1-6alkylcarbonyl group substituted with -CN, or a C3-6cycloalkyl group, a method of inhibiting FLT-3 or c-KIT protein kinase.

EFFECT: obtaining novel compounds and their use in making a medicinal agent for treating or relieving acute myelogenic leucosis.

11 cl, 1 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: benzamide derivatives are presented by the formula [1] or its salt, where Z is -O-, -NR5-, -S-, -SO-; 1 is 0 or 1; m is 0 or 1; R1 is hydrogen atom, C1-6-alkyl group, R2 is hydrogen atom, hydroxylic group, C1-6- alkyl group, carboxyl group, C1-6-alkoxycarbonyl group or -CONR10R11, or R2 and R1 together form =O; R3 is hydrogen atom or C1-6-alkyl group; R4 is hydrogen atom or halogen atom; V is direct bond or -(CR21R22)n-; P1 and P2 rings are the same or different, and each is aromatic or saturated carbocyclic group, or 5-10-member saturated or unsaturated heterocyclic group containing 1-3 heteroatoms selected out of N, O, S.

EFFECT: obtainment of compound with excellent inhibition effect on vanilloid receptor type 1 activity, efficiency in treatment of diseases involving vanilloid receptor type 1 activity.

17 cl, 56 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention refers to novel method of obtaining [2S*[R*[R*[R*]]]] and [2R*[S*[S*[S*]]]]-(±)α,α'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyrane-2-methanol] racemate of the formula (I) (nebivolol) and its pharmaceutically acceptable salts , involving stages indicated in the claim, and to intermediate compounds and methods of obtainment thereof.

EFFECT: improved method.

106 cl, 12 tbl, 20 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I , where R1 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl and lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl, which can be substituted with a halogen; R2 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl or lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl which can be substituted with a halogen; or R1 and R2 together with the nitrogen atom to which they are bonded form a 4-, 5- or 6-member saturated or partially unsaturated heterocyclic ring which optionally contains the same heteroatom selected from oxygen or sulphur, where the said saturated or partially heterocyclic ring is unsubstituted or substituted with one or two groups independently selected from a group consisting of lower alkyl, halogen, halogenalkyl, cyano group, hydroxy group, lower hydroxyalkyl, lower alkoxy group, oxo group; A is selected from , and , where m equals 0 or 1; R3 is a lower alkyl; n equals 0; R4 is a lower alkyl; p equals 1; q equals 0, 1 or 2; R5 is hydrogen; and their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition based on formula I compounds.

EFFECT: new quinoline derivatives are obtained, which have antagonistic effect on histamine 3 receptors (H3 receptors).

18 cl, 4 tbl, 86 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new 4-substituted 3-(3-dialkylaminomethyl-indol-1-yl)maleimide derivatives of general formula

and ,

where: X1-X4 denote C; Z denotes H; R1 denotes alkyl, H, -(CH2)3-N-(C2H5)2; R2 and R3 denote alkyl, or together with the nitrogen atom to which they are bonded form a C4-7-monocyclic ring containing 1 or 2 heteroatoms, selected from O and N, possibly substituted with an alkyl; R4 denotes H; Y denotes S, -N-(C2H5); where in formula I compounds R5 and R6 together with the nitrogen atom to which they are bonded form a C9-10 a condensed bicyclic ring containing an N heteroatom, possibly substituted with R, where R denotes -N-(R2)-R3; in formula II compounds R5 denotes phenyl, optionally substituted with OCH3.

EFFECT: obtaining new compounds which can be used as protein kinase inhibiting agents.

2 cl, 6 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to benzazepin derivatives of formula (I), where R1 is unsubstituted cyclobutyl, R2 is 3-pyrazinyl, substituted CON(H)(Me) or 2-pyridinyl-M-pyrrolidinyl, where the said pyrrolidinyl group is substituted with a =O group; which is: methylamide 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy) pyrazine-2-carboxylic acid

or 1-{6-[(3-cyclbutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone

EFFECT: obtaining compounds which have affinity to histamine H3 receptor and pharmaceutical compositons containing said compounds.

11 cl, 288 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of structural formula I and their pharmaceutically acceptable salts. In structural formula I , X is oxygen; Y is oxygen; Y1 Y2, R7 and R4 represent H; X1 and X2 are independently selected from a group consisting of hydrogen, an alkyl group containing 1 to 5 carbon atoms, in which one or more hydrogen atoms of the alkyl group can be substituted with a halogen, aryl group containing 6 to 10 carbon atoms or a cycloalkyl group containing 3 to 9 carbon atoms, or a 5-9-member heterocyclic group with 2 heteroatoms selected from N and O, or a cycloalkyl group containing 5 to 9 carbon atoms; values of the rest of the radicals are given in the formula of invention. The invention also pertains to a pharmaceutical composition having properties of selective inhibitors of type IV phosphodiesterase, containing a therapeutically effective amount of the invented compound.

EFFECT: increased effectiveness of the compounds.

6 cl, 23 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to benzazepin derivatives of formula (I), where R1 is unsubstituted cyclobutyl, R2 is 3-pyrazinyl, substituted CON(H)(Me) or 2-pyridinyl-M-pyrrolidinyl, where the said pyrrolidinyl group is substituted with a =O group; which is: methylamide 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy) pyrazine-2-carboxylic acid

or 1-{6-[(3-cyclbutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone

EFFECT: obtaining compounds which have affinity to histamine H3 receptor and pharmaceutical compositons containing said compounds.

11 cl, 288 ex

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