Substituted pyridines and pyridazines with angiogenesis inhibition activity

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to substituted pyridines and pyridazines with angiogenesis inhibition activity of general formula I

(I)1, wherein ring containing A, B, D, E, and L represents phenyl or nitrogen-containing heterocycle; X and Y are various linkage groups; R1 and R2 are identical or different and represent specific substituents or together form linkage ring; ring J represents aryl, pyridyl or cycloalkyl; and G's represent various specific substituents. Also disclosed are pharmaceutical composition containing claimed compounds, as well as method for treating of mammalian with abnormal angiogenesis or treating of increased penetrability using the same.

EFFECT: new pyridine and pyridazine derivatives with angiogenesis inhibition activity.

26 cl, 6 tbl, 114 ex

 

The scope of the invention

The present invention relates to pharmaceutical preparations consisting of small heterocyclic molecules, and more particularly to substituted pyridinium and pyridazine with the ability to inhibit angiogenesis.

Prior art

Vasculogenic includes the formation of new blood vessels from endothelial precursors cells, or angioblasts. The first vascular structure of the embryo are formed by vasculogenesis. Angiogenesis involves the development of capillaries from existing blood vessels and is the main mechanism by which vascularization occurs in organs such as the brain and kidneys. While vasculogenic limited to embryonic development, angiogenesis can occur in adults, for example, during pregnancy, the menstrual cycle or healing of wounds.

One major regulator of angiogenesis and vasculogenesis as in embryonic development and in diseases dependent on angiogenesis is the growth factor vascular endothelial (VEGF, also known as vascular permeability factor, the Fund). The VEGF is a family of isoforms of mitogens, the resulting alternative stitching mRNA that exist in homodimeric forms. The receptor of VEGF RDK is highly specific in relation to glue the Cam vascular endothelium (see reviews in the works: Farrara et at. Endocr. Rev., 1992, of 13.18; Neufield et al. FASEB J., 1999,13, 9).

Expression of VEGF is induced by hypoxia (Shweiki et al. Nature, 1992, 359, 843), and various cytokines and growth factors such as interleukin-1, Jn-terleukin-6, a growth factor, epidermal and transforming growth factor - α and β.

To date, it is known that VEGF and members of the family of VEGF are associated with one or more of the three receptors transport through tyrosine kinase membrane (Mustonen et al. J. Cell Biol., 1995,129, 895), receptor-PRES (also known as the fit-1 (fms-like tyrosinekinase-1)); receptor-2, VEGF, also known as the receptor containing the domain of the kinase insert (RDK), a murine analogue of RDK known as kinase-1 in the liver of the fetus (flk-1), and receptor-3, VEGF (also known as the fit-4). It is shown that the RDK and fit-1 have different characteristics of signal transduction (Waltenberger et al. J. Biol. Chem., 1994, 269, 26988; Park et al. Oncogene, 1995,10, 135). Thus, in intact cells RDK subject strictly dependent ligand tyrosine phosphorylation, whereas fit-1 is characterized by a weaker response. Thus, the binding of SDC is a mandatory condition for receiving the full spectrum of biological response mediated by the VEGF.

In vivo, VEGF plays a major role in vasculogenesis and induces angiogenesis and gives resizemode blood vessels. Deregulated expression of VEGF contributes to the development of a number of diseases that are characterized by abnormal processes of angiogenesis and/or an increased permeability. Therefore, regulation of the transduction cascade of signals mediated by the VEGF, provides a convenient way to control abnormal processes of angiogenesis and/or an increased permeability.

Angiogenesis is considered absolutely necessary for the growth of tumors larger than 1-2 mm, Oxygen and nutrients can enter the tumor cells are smaller than the specified size limit, by diffusion. However, after reaching a certain size, further growth of each tumor depends on angiogenesis. Oncogenic cells in hypoxic areas of tumors respond to stimulation by the production of VEGF, which induces activation of resting endothelial cells, which stimulates the formation of new blood vessels (Shweiki et al. Proc. NAT'l. Acad. Sci., 1995, 92, 768). In addition, the production of VEGF on tumor sites, where there is no angiogenesis can occur along the path of signal transduction reflex of the current stimulus (Grugel et al. J. Biol. Chem., 1995, 270, 25915; Rak et al. Cancer Res., 1995, 55,4575). Research in situ hybridization showed that is producing excessive amounts of VEGF mRNA in various human cancers, is the key lung cancer (Mattern et al. VG. J. Cancer, 1996, 73, 931), thyroid gland (Viglietto et al. Oncogene, 1995,11,1569), breast cancer (Brown et al. Human Pathol., 1995, 26, 86), gastrointestinal tract (Brown et al. Cancer Res., 1993, 53,4727; Suzuki et al. Cancer Res., 1996, 56, 3004), kidney and urinary bladder (Brown et al. Am. J. Pathol., 1993, 1431,1255), ovary (Olson et al. Cancer Res., 1994, 54,1255) and cervix (Guidi et al. J. NAT'l. Cancer Inst., 1995, 87,12137), and angiosarcoma (Hashimoto et al. Lab. Invest., 1995, 73, 859) and some intracranial tumors (Plate et al. Nature, 1992, 359, 845; Phillips et al. Int. J. Oncol, 1993, 2, 913; Viglietto et al. J. Clin. Invest., 1993, 91,153). It is shown that neutralizing monoclonal antibodies against RDK effectively block the angiogenesis of tumors (Kim et al. Nature, 1993, 362, 841; Rockwell et al. Mol. Cell. Differ., 1995, 3, 315).

Excessive production of VEGF, for example, occur in conditions of extreme hypoxia, can lead to intraocular angiogenesis, calling hyperproliferative blood vessels, which ultimately leads to blindness. This cascade of events has been observed for a number of types of retinopathy, including diabetic retinopathy, ischemic blockage of the veins of the retina, retinopathy by prematurity (Aiello et al. New Engl. J. Med., 1994, 311,1480; Peer et al. Lab. Invest., 1995, 72, 638) and age-related macular degeneration (VJ; see Lopez et al. Invest. Ophthalmol. Vis. Sci, 1996, 37, 855).

In rheumatoid arthritis (PA), the expansion of the vascular keratitis can oposredovanie expression of angiogenic factors. Levels immunol the active VEGF are high in synovial fluid of patients suffering from RA, whereas the levels of VEGF are low in synovial fluid of patients suffering from other forms of arthritis degenerative joint diseases (Koch et al. J. Immunol., 1994, 152,4149). It is shown that angiogenesis inhibitor AGM-170 prevents neovascularization of the joints when the simulated rat collagen arthritis (Peacock et al. J... Med., 1992,175,1135).

Also it is shown that increased expression of VEGF may occur with psoriasis, as well as in bullous diseases involving subepidermal blistering, such as bullous pemphigoid, erythema multiforme, and dermatitis herpetiformis (Brown et al. J. Invest. Dermatol, 1995, 104, 744).

Because inhibition of signal transduction RDK leads to inhibition of angiogenesis and the appearance of increased permeability, mediated by the VEGF inhibitors RDK will be useful for the treatment of diseases characterized by abnormal processes of angiogenesis and/or an increased permeability, including the above diseases.

Examples phthalazines and other condensed pyridazines, which is structurally similar to the compounds of the present application, disclosed in the following patents and patent applications: WO 9835958 (Novartis), U.S. patent 5489741, U.S. patent 3753988, U.S. patent 3478028 and the Japan patent 03106875. Other publications on phthalazines: EI-Feky, S.A., Bayoumy, B.E., and Abd EI-Sami, Z.K., J. Egyt Chem. (1991), Volume Date 1990, 33 (2), 189 -197; Duhault, J., Gonnard, P., and Fenard, S., Bull. Soc. Chim. Biol., (1967), 49 (2), 177 0 190; and Holava, H.M. and Jr, Partyka, R. A., J. Med. Chem., (1969), 12,555 556. Compounds corresponding to the present invention differ from those described in all the above links and only publish Novartis describes such compounds as inhibitors of angiogenesis.

As shown above, compounds that inhibit angiogenesis, used in the treatment of various pathological conditions and are therefore necessary. Such substances are the subject of this application.

Brief description of the invention

In its broadest aspect the present invention relates to the combination of three sets of chemical compounds or their acceptable from a pharmaceutical point of view salts or proletarienne drugs, and in the scope of the invention, each set overlaps with the others. General structural formula of the compounds belonging to all three sets of connections is the same, however it should be noted that the definitions of the various groups within the overall structure, for each set are slightly different. Thus, these sets of chemical compounds differ from each other, but overlap in their scope.

The first set of compounds has the General structural formula:

where

R 1and R2

together form a bridge containing two fragments of the T2and one piece T3specified bridge in conjunction with the cycle to which it is attached, forms a bicyclic structure

where

each T2independently denotes N, CH or CG1;

T3means S, O, CR4G1C(R4or NR3.

In the above substructures G1means the Deputy, is independently selected from the group comprising-N(R6)2; -NR3COR6; halogen; alkyl; cycloalkyl; lower alkenyl; lower cycloalkenyl; halogen-substituted alkyl; aminosilanes alkyl; N-(lower alkyl)aminosilanes alkyl; N,N-di-(lower alkyl)aminosilanes alkyl; N-(lower alkanoyl)aminosilanes alkyl; replacement alkyl; lansley alkyl; carboxyterminal alkyl; missiologically alkyl; phenyl lower alkoxycarbonylmethyl alkyl; halogen-substituted, alkylamino-; aminosilane alkylamino-; N-(lower alkyl)aminosilane alkylamino-; N, N-di-(lower alkyl)aminosilane alkylamino-; N-(lower alkanoyl)aminosilane alkylamino-; replacement of alkylamino-; lanzamiento alkylamino-; CT-boxesandarrows alkylamino-; sessioncontroller alkylamino-; phenyl lower alkoxycarbonyl the th alkylamino; -OR6; -SR6; -S(O)R6; -S(O)2R6; halogenated lower alkoxy; halogenated lower alkylthio; halogenated lower alkylsulfonyl; -OCOR6; -COR6; -CO2R6; -CON(R6)2; -CH2OR3; -NO2; -CN; amedieval; guanidine; alphagroup;- (OH)2; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted saturated heterocyclic fragment; optionally substituted saturated heteroseksualci; optionally substituted partially unsaturated heterocyclic fragment; optionally substituted partially unsaturated heteroseksualci; -OCO2R3; optionally substituted heteroaromatic; optionally substituted heteroaromatics; -S(O)p(optional substituted heteroaryl); optionally substituted heteroaromatics; -S(O)p(optional substituted heteroaromatic); -Cho; - OCON(R6)2; -NR3CO2R6; and-NR3CON(R6)2.

The group R3means H or lower alkyl. R6independently selected from the group consisting of H; alkyl; cycloalkyl; optionally substituted aryl; optionally substituted aryl lower alkyl, lower alkyl-N(R3)2and lower alkyl-HE.

In the General structural formula (I) R4denotes H, halogen or lower al the sludge. The subscript p is 0,1 or 2 and X is selected from the group comprising O, S and NR3.

Connecting the Y fragment is selected from the group comprising lower alkylene; -CH2-O-; -CH2-S-; -CH2-NH-; -O-; -S-; -NH-; -O-CH2-; -S(O)-; -S(O)2-; -SCH2-; -S(O)CH2-; -S(O)2CH2-; -CH2S(O)-; -CH2S(O)2-; -(CR42)n-S(O)p-(5-membered heteroaryl)-(CR42)s- and -(CR42)n-C(G2)(R4)-(CR42)s-. In the last two connecting group Y n and s independently are 0 or an integer of 1-2. Deputy G2selected from the group comprising-CN, -CO2R3; -CON(R6)2and-CH2(R6)2.

Z means CR4or N.

For cycles a, b, D, E, and L the number of possible substituents G3in cycles indicated by the lower index q, which is equal to 0,1 or 2.

Replacement fragments G3represent a monovalent or divalent fragments selected from the group including: lower alkyl; or-NR3COR6; CT-bacisally alkyl; lower alkoxycarbonylmethyl alkyl; OR6; -SR6; -S(O)R6; -S(O)2R6; -OCOR6; -COR6; -CO2R6; -CH2OR3; -CON(R6)2; -S(O)2N(R6); -NO2; -CN; optionally substituted aryl; optionally substituted heteros is aryl; optionally substituted saturated heterocyclic fragment; optionally substituted partially unsaturated heterocyclic fragment; optionally substituted heteroaromatic; optionally substituted heteroaromatics; -S(O)p(optional substituted heteroaryl); optionally substituted heteroaromatics; -S(O)p(optional substituted heteroaromatic); -OCON(R6)2; -NR3CO2R6; -NR3CON(R6)2and bivalent bridge of structure T2=T2-T3. In this divalent bridge every T2independently denotes N, CH or CG3(and T3means S, O, CR4G3'C(R4)2; or NR3. G3'means any of the above defined fragments G3which are monovalent, and end group T2the bridge is associated with L, and T3linked to D, forming a 5-membered condensed cycle.

In the cycle, represented in the left part of the General structural formula (I), a and D independently denote N or CH; b and E independently denote N or CH; L is N or CH, provided that a) the total number of atoms N in a loop containing a, b, D, E, and L is 0, 1, 2 or 3; (b) if L is CH, and q=0 or any G3means monovalent Deputy, then at least one of a and D is an N atom and (C) if L is CH and G3oznachaet the bivalent bridge of structure T 2= T2-T3then a, b, D, and E. also mean SN.

J indicates cycle selected from the group comprising aryl; pyridyl and cycloalkyl. The subscript q' denotes the number of substituents G4in cycle J and equal to 0, 1, 2, 3, 4 or 5.

Possible substituents G4in cycle J represent a monovalent or divalent fragments selected from the group comprising-N(R6)2; -NR3COR6; halogen; alkyl; cycloalkyl; lower alkenyl; lower cycloalkenyl; halogen-substituted alkyl; aminosilanes alkyl; N-(lower alkyl)aminosilanes alkyl; N,N-di-(lower alkyl)aminosilanes alkyl; N-(lower alkanoyl)aminosilanes alkyl; replacement alkyl;

lansley alkyl; carboxyterminal alkyl; lower alkoxycarbonylmethyl alkyl; phenyl missiologically alkyl; halogen-substituted, alkylamino-; aminosilane alkylamino-; N-(lower alkyl)aminosilane alkylamino-; N,N-di-(lower alkyl)aminosilane alkylamino-; N-(lower alkanoyl)aminosilane alkylamino-; replacement of alkylamino-; lanzamiento alkylamino-; carboxyterminal alkylamino-; lower alkoxycarbonylmethyl alkylamino-; phenyl lower alkoxycarbonylmethyl alkylamino; -OR6; -SR6; -S(O)R6; -S(O)2R6; halogenated lower alkoxy; Galaganov the config lowest alkylthiol; halogenated lower alkylsulfonyl; -OCOR6; -COR6; -CO2R6; -CON(R6)2; -CH2OR3; -NO2; -CN; amedieval; guanidine; alphagroup;- (OH)2; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted saturated heterocyclic fragment; optionally substituted partially unsaturated heterocyclic fragment; -OCO2R3; optionally substituted heteroaromatic; optionally substituted heteroaromatics; -S(O)p(optional substituted heteroaryl); optionally substituted heteroaromatics; -S(O)p(optional substituted heteroaromatic); -Cho; -OCON(R6)2; -NR3CO2(R6)2; -NRCCON(R6)2; and forming a condensed cycle divalent bridges attached to adjacent positions of the cycle J and connecting these provisions, moreover, these bridges have the structure:

a)

where each T2independently denotes N, CH or CG4′; T3means S, O, CR4G4′C(R4)2or NR3; G4'means any of the above defined fragments G4which are monovalent, and the binding of cycle J occurs on the terminal atoms T2and T3;

b)

where each T2independently denotes N, CH or CG4'; G4'(meaning any of the above defined fragments G4which are monovalent; provided that not more than two bridging atoms T2can represent N; and the binding of cycle J occurs on the terminal atoms T2; and

c)

where all T4T5and T6independently denote O, S, CR4G4'C(R4)2or NR3; G4'(meaning any of the above defined fragments G4which are monovalent, and the binding of cycle J occurs on the terminal atoms T4or T5; under the following conditions:

i) if T4means O, S or NR3then the other T4mean CR4G4'(or C(R4)2;

ii) a bridge comprising atoms T5and T6may contain not more than two heteroatoms O, S or N;

iii) in the bridge, including the atoms T5and T6if one group T5and one group T6represent the atoms O, or two groups, T6represent the atoms Of specified atoms shared by at least one carbon atom.

If G4means alkyl group, located in the loop J near the bridge -(CR42)p-, and X is NR3where R3means alkyl the first Deputy, then G4and alkyl substituent R3if X can be connected to each other to form a bridge of the structure -(CR42)p'-where R' is 2, 3 or 4, provided that the sum of p and p' is 2, 3 or 4, which leads to the formation of 5-, 6-or 7-membered nitrogen cycle.

Additional the following conditions: 1) G1, G2, G3and G4if two groups of R3or R6mean alkyl and are in the same N atom they may be linked by communication, Oh, 8 or NR3with the formation of N-containing heterocycle with 5-7 atoms in the cycle; and 2) if the aryl, heteroaryl or heterocyclic ring optionally contains substituents, the ring may be up to 5 substituents that are independently selected from the group consisting of amino, mono(lower alkyl)substituted amino, di(lower alkyl)substituted amino, (lower alkanoyl)amino, halogen, lower alkyl, halogenated lower alkyl, hydroxyl, lower alkoxyl, lower alkylthio, halogenated lower alkoxy, halogenated lower alkylthio, lower alkanoyloxy, -CO2R3, -Cho, -CH2OR3, -OCO2R3, -CON(R6)2, -OCON(R6)2, -NR3CON(R6)2, nitro-, amedieval, guanidine, mercapto, sulfo and cyano; and 3) if there is any alkyl group PR is connected to On, S or N and contains hydroxyl Deputy, the hydroxyl Deputy separated from O, S or N, attached to an alkyl group, at least two carbon atoms.

The second set of compounds has the General structural formula:

where

R1and R2:

(i) independently denote H or lower alkyl;

ii) together form a bridge of the structure

in which the binding is established through the terminal carbon atoms;

iii) together form a bridge of the structure

in which the binding is established through the terminal carbon atoms;

iv) together form a bridge of the structure

where one or two fragments of the T1cycle mean N, and the others mean or CG CH1and the binding is established through the terminal carbon atoms; or

v) together form a bridge containing two fragments of the T2and one piece T3and this bridge together with the cycle to which it is attached, forms a bicyclic structure

where

each T2independently denotes N, CH or CG1;

T3means S, O, CR4G1With(R4)2or NR3.

In the above Nosticova is the substructures subscript m is 0 or an integer of 1-4, that shows that the obtained condensed cycles optionally can contain up to four substituents G1.

G1means the Deputy, is independently selected from the group comprising-N(R6)2; -NR3COR6; halogen; alkyl; cycloalkyl; lower alkenyl; lower cycloalkenyl; halogen-substituted alkyl; aminosilanes alkyl; N-(nishiuchi)aminosilanes alkyl; N,N-di-(nishiuchi)aminosilanes alkyl; N-(nissioner)aminosilanes alkyl; replacement alkyl; lansley alkyl; carboxyterminal alkyl; missiologically alkyl; phenylmethylsulfonyl alkyl; halogen-substituted, alkylamino-; aminosilane alkylamino-; N-(nishiuchi)aminosilane alkylamino-; N,N-di-(nishiuchi)aminosilane alkylamino-; N-(nissioner)aminosilane alkylamino-; replacement of alkylamino-; lanzamiento alkylamino-; carboxyterminal alkylamino-; sessioncontroller alkylamino-; phenylmethylsulfonyl alkylamino; -OR6; -SR6; -S(O)R6; -S(O)2R6; halogenated lower alkoxy; halogenated lower alkylthio; halogenated lower alkylsulfonyl; -OCOR6; -COR6; -CO2R6; -CON(R6)2; -CH2OR3; -NO2; -CN; amedieval; Guan is new; alphagroup;- (OH)2; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted saturated heterocyclic radical; optionally substituted saturated heteroseksualci; optionally substituted partially unsaturated heterocyclic radical; optionally substituted partially unsaturated heteroseksualci; -OCO2R3; optionally substituted heteroaromatic; optionally substituted heteroaromatics;-S(O)p(optional substituted heteroaryl); optionally substituted heteroaromatics; -S(O)p(optional substituted heteroaromatic); -Cho; -OCON(R6)2; -NR3CO2R6; and-NR3CON(R6)2.

The group R3means H or lower alkyl. R6independently selected from the group consisting of H; alkyl; cycloalkyl; optionally substituted aryl; optionally substituted arylnitrenes, lower alkyl-N(R3)2and lower alkyl-HE.

In the General structural formula (I) R4denotes H, halogen or lower alkyl; the subscript p is 0,1 or 2 and X is selected from the group comprising O, S and NR3.

Connecting the Y fragment is selected from the group comprising lower alkylene; CH2-O-; -CH2-S-; -CH2-NH-; -O-; -S-; -NH-; -O-CH2-; -S(O)-; -S(O)2-; -SCH2-; -S(O)CH2-; -S(O)2CH2-; -CH2 S(O)-; -CH2S(O)2-; -(CR42)n-S(O)p-(5-membered heteroaryl)-(CR42)sand -(CR42)n-C(G2)(R4)(CR42)s-. In the last two connecting fragments Y subscripts n and s independently are 0 or an integer of 1-2. G2selected from the group comprising-CN, -CO2R3; -CON(R6and-CH2N(R6)2.

Z denotes N or CR4.

For cycles a, b, D, E, and L the number of possible substituents G3in cycles indicated by the lower index q, which is equal to 0,1 or 2.

Deputy G3represent a monovalent or divalent fragments selected from the group comprising lower alkyl; -NR3OR6; carboxyterminal alkyl; lower alkoxycarbonylmethyl alkyl; OR6; -SR6; -S(O)R6; -S(O)2R6; -OCOR6; -COR6; -CO2R6; -CH2OR3; -CON(R6)2; -S(O)2N(R6)2; -NO2; -CN; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted saturated heterocyclic radical; optionally substituted partially unsaturated heterocyclic radical; optionally substituted heteroaromatic; optionally substituted heteroaromatics; -S(O)p(optional substituted heteroaryl); optional is tion substituted heteroaromatics; -S(O)p(optional substituted heteroaromatic); -OCON(R6)2; -NR3CO2R6; -NR3CON(R6)2and bivalent bridge of structure T2=T2-T3. In this divalent bridge every T2independently denotes N, CH or CG3'and T3means S, O, CR4G3'C(R4)2or NR3. G3'means any of the above defined fragments G3which are monovalent, and the limit T2associated with L, and T3linked to D, forming a 5-membered condensed cycle.

In the cycle, represented in the left part of the General structural formula (I), a and D independently denote SN; b and E independently mean CH; and L is CH, provided that formed in the phenyl ring by Deputy G3is specified bivalent bridge of structure T2=T2-T3.

J indicates cycle selected from the group comprising aryl; pyridyl and cycloalkyl. The subscript q' denotes the number of substituents G4in cycle J and is equal to 0,1, 2, 3,4 or 5.

G4means monovalent or bivalent fragment selected from the group comprising-N(R6)2; -NR3COR6; halogen; alkyl; cycloalkyl; lower alkenyl; lower cycloalkenyl; halogen-substituted alkyl; aminosilanes alkyl; N-(nishiuchi)aminosilanes alkyl; N,N-di-(nissia the keel)aminosilanes alkyl; N-(nissioner)aminosilanes alkyl; replacement alkyl; lansley alkyl; carboxyterminal alkyl; missiologically alkyl; phenylmethylsulfonyl alkyl; halogen-substituted, alkylamino-; aminosilane alkylamino-; N-(nishiuchi)aminosilane alkylamino-; N,N-di-(nishiuchi)aminosilane alkylamino-; N-(nissioner)aminosilane alkylamino-; replacement of alkylamino-; lanzamiento alkylamino-; carboxyterminal alkylamino-; sessioncontroller alkylamino-; phenylmethylsulfonyl alkylamino; -OR6; -SR6; -S(O)R6; -S(O)2R6; halogenated lower alkoxy; halogenated lower alkylthio; halogenated lower alkylsulfonyl; -OCOR6; -COR6; -CO2R6; -CON(R6)2; -CH2OR3; -NO2; -CH; amedieval; guanidine; alphagroup;- (OH)2; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted saturated heterocyclic radical; optionally substituted partially unsaturated heterocyclic radical; -OCO2R3; optionally substituted heteroaromatic; optionally substituted heteroaromatics; -S(O)p(optional substituted heteroaryl); optionally substituted hetaeras arylalkyl; -S(O)p(optional substituted heteroaromatic); -Cho; -OCON(R6)2; -NR3CO2R6; -NR3CON(R6)2; and forming a condensed cycle divalent bridges attached to adjacent positions of the cycle J and connecting these provisions, moreover, these bridges have the structure:

a)

where each T2independently denotes N, CH or CG4'; T3means S, O, CR4G4'C(R4)2or NR3; G4'means any of the above defined fragments G4which are monovalent, and the binding of cycle J occurs on the terminal atoms T2and T3;

b)

where each T2independently denotes N, CH or CG4'; G4'means any of the above defined fragments G4which are monovalent; provided that not more than two bridging atoms T2can represent N; and the binding of cycle J occurs on the terminal atoms T2; and

C)

where all T4T5and T6independently denote O, S, CR4G4'C(R4)2or NR3; G4'means any of the above defined fragments G4which are monovalent, and the binding of cycle J p is oshodi on the terminal atoms T 4or T5; under the following conditions:

i) if T4means O, S or NR3then the other T4mean CR4G4'(or C(R4)2,

ii) a bridge comprising atoms T5and T6may contain not more than two heteroatoms O, S or N;

iii) in the bridge, including the atoms T5and T6if one group T5and one group T6represent the atoms O, or two groups, T6represent the atoms Of specified atoms shared by at least one carbon atom.

If G4means alkyl group, located in the loop J near the bridge -(CR42)p-, and X is NR3where R3means alkyl substituent, G4and alkyl substituent R3if X can be connected to each other to form a bridge of the structure -(CR42)p'where R' is 2, 3 or 4, provided that the sum of p and p' is 2, 3 or 4, which leads to the formation of 5-, 6-or 7-membered nitrogen cycle.

Additional the following conditions: 1) G1, G2, G3and G4if two groups of R3or R6mean alkyl and are in the same N atom they may be linked by communication, O, S or NR3with the formation of N-containing heterocycle with 5-7 atoms in the cycle; and 2) if aryl, and heteroaryl and heterocyclic ring optionally contains substituents, the ring can be up to 5 substituents that are independently selected from the group consisting of amino, mono(lower alkyl)substituted amino, di(lower alkyl)substituted amino, (lower alkanoyl)amino, halogen, lower alkyl, halogenated lower alkyl, hydroxyl, lower alkoxyl, lower alkylthio, halogenated lower alkoxy. halogenated lower alkylthio, lower alkanoyloxy, -CO2R3, -Cho, -CH2OR3, -OCO2R3, -CONC(R6)2, -OCON(R6)2, -NR3CON(R6)2the nitro. amedieval, guanidine, mercapto, sulfo and cyano; and 3) if there is any alkyl group is attached to O, S or N and contains hydroxyl Deputy, the hydroxyl Deputy separated from O, S or N, attached to an alkyl group, at least two carbon atoms.

The third set of compounds has the General structural formula:

where R1and R2:

(i) independently denote H or lower alkyl;

ii) together form a bridge of the structure

in which the binding is established through the terminal carbon atoms;

iii) together form a bridge of the structure

in which the binding is established through the terminal carbon atoms;

iv) compatible with the IDT form a bridge structure

where one or two fragments of the T1cycle mean N, and the others mean or CG CH1and the binding is established through the terminal carbon atoms; or v) together form a bridge containing two fragments of the T2and one piece T3and this bridge together with the cycle to which it is attached, forms a bicyclic structure

where

each T2independently denotes N, CH or CG1;

T3means S, O, CR4G1C(R4)2or NR3.

In the above bridge structures subscript m is 0 or an integer of 1-4, which shows that the obtained condensed cycles optionally can contain up to four substituents G1.

G1means the Deputy, is independently selected from the group comprising-N(R6)2; -NR3COR6; halogen; alkyl; cycloalkyl; lower alkenyl; lower cycloalkenyl; halogen-substituted alkyl; aminosilanes alkyl; N-(nishiuchi)aminosilanes alkyl; N,N-di-(nishiuchi)aminosilanes alkyl; N-(nissioner)aminosilanes alkyl; replacement alkyl; lansley alkyl; carboxyterminal alkyl; missiologically alkyl; phenylmethylsulfonyl alkyl; halogen-substituted alkyl is Mino-; aminosilane alkylamino-; N-(nishiuchi)aminosilane alkylamino-; N,N-di-(nishiuchi)aminosilane alkylamino-; N-(nissioner)aminosilane alkylamino-; replacement of alkylamino-; lanzamiento alkylamino-; carboxyterminal alkylamino-; nissian-oxycarbonate alkylamino-; phenylmethylsulfonyl alkylamino; -OR6; -SR6; -S(O)R6; -S(O)2R6; halogenated lower alkoxy; halogenated lower alkylthio; halogenated lower alkylsulfonyl; -OCOR6; -COR6; -CO2R8; -CON(R6)2; -CH2OR3; -NO2; -CN; amedieval; guanidine; alphagroup;- (OH)2; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted saturated heterocyclic radical; optionally substituted saturated heteroseksualci; optionally substituted partially unsaturated heterocyclic radical; optionally substituted partially unsaturated heteroseksualci; -OCO2R3; optionally substituted heteroaromatic; optionally substituted heteroaromatics; -S(O)p(optional substituted heteroaryl); optionally substituted heteroaromatics; -S(O)p(optional substituted heteroaromatic); -Cho; -OCON(R6)2; -NR3 CO2R6; and-NR3CON(R6)2.

The group R3means H or lower alkyl. R6independently selected from the group consisting of H; alkyl; cycloalkyl; optionally substituted aryl; optionally substituted arylnitrenes, lower alkyl-N(R3)2and lower alkyl-HE.

In the General structural formula (I) R4denotes H, halogen or lower alkyl; the subscript p is 0,1 or 2 and X is selected from the group comprising O, S and NR3.

Connecting the Y fragment is selected from the group comprising lower alkylene; -CH2-O-; -CH2-S-; -CH2NH-; -O-; -S-; -NH-; -O-CH2; -S(O)-; -S(O)2-; -SCH2-; -S(O)CH2-; -S(O)2CH2-; -CH2S(O)-; -CH2S(O)2-; -(CH42)n-S(O)p-(5-membered heteroaryl)-(CR42)s- and -(CR42)n-C(G2)(R4)-(CR42)s-. In the last two connecting group Y subscripts n and s independently are 0 or an integer of 1-2. G2selected from the group comprising-CN, -CO2R3; -CON(R6)2and-CH2N(R6)2.

Z means CR4.

For cycles a, b, D, E, and L the number of possible substituents G3in cycles indicated by the lower index q, which is equal to 0,1 or 2.

Deputy G3represent a monovalent or divalent fragments, selected the s group, including-NR3COR6; carboxyterminal alkyl; lower approximability alkyl; OR6; -SR6; -S(O)R6; -S(O)2R6; -OCOR6; -COR6; -CO2R6; -CH2OR3; -CON(R6)2; -S(O)2N(R6)2; -NO2; -CN; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted saturated heterocyclic radical; optionally substituted partially unsaturated heterocyclic radical; optionally substituted heteroaromatic; optionally substituted heteroaromatics; -S(O)p(optional substituted heteroaryl); optionally substituted heteroaromatics; -S(O)p(optional substituted heteroaromatic); -OCON(R6)2; -NR3CO2R6; -NR3CON(R6)2and bivalent bridge of structure T2=T2-T3. In this divalent bridge every T2independently denotes N, CH or CG3'and T3means S, O, CR4G3'C(R4)2or NR3, G3'means any of the above defined fragments G3which are monovalent, and the limit T2associated with L, and T3linked to D, forming a 5-membered condensed cycle.

In the cycle, represented in the left part of the General structural formula (I), a and D independently mean is N or CH; B and E independently denote N or CH; L is N or CH, provided that a) the total number of atoms N in a loop containing a, b, D, E, and L is 0, 1, 2 or 3; (b) if L is CH and any G3means monovalent Deputy, then at least one of a and D is an N atom and (C) if L is CH and G3means a bivalent bridge of structure T2=T2-T3then a, b, D, and E. also mean SN.

J indicates cycle selected from the group comprising aryl; pyridyl and cycloalkyl. The subscript q' denotes the number of substituents G4in cycle J and is equal to 0,1, 2, 3, 4 or 5.

G4means monovalent or bivalent fragment selected from the group comprising-N(R6)2; -NR3COR6; halogen; alkyl; cycloalkyl; lower alkenyl; lower cycloalkenyl; halogen-substituted alkyl; aminosilanes alkyl; N-(nishiuchi)aminosilanes alkyl; N,N-di-(nishiuchi)aminosilanes alkyl; N-(nissioner)aminosilanes alkyl; replacement alkyl; lansley alkyl; carboxyterminal alkyl; missiologically alkyl; phenylmethylsulfonyl alkyl; halogen-substituted, alkylamino-; aminosilane alkylamino-; N-(nishiuchi)aminosilane alkylamino-; N,N-di-(nishiuchi)aminosilane alkylamino-; N-(nissioner)aminosilane alkylamino-; hydroxy is amestoy alkylamino-; lanzamiento alkylamino-carboxyterminal alkylamino-; sessioncontroller alkylamino-; phenylmethylsulfonyl alkylamino; -OR6; -SR6; -S(O)R6; -S(O)2R6; halogenated lower alkoxy; halogenated lower alkylthio; halogenated lower alkylsulfonyl; -OCOR6; -COR6; -CO2R6; -CON(R6)2; -CH2OR3; -NO2; -CN; amedieval; guanidine; alphagroup;- (OH)2; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted saturated heterocyclic radical; optionally substituted partially unsaturated heterocyclic radical; -OCO2R3; optionally substituted heteroaromatic; optionally substituted heteroaromatics; -S(O)p(optional substituted heteroaryl); optionally substituted heteroaromatics; -S(O)p(optional substituted heteroaromatic); -Cho; -OCON(R6)2; -NR3CO2R6; -NRCCON(R6)2; and forming a condensed cycle divalent bridges attached to adjacent positions of the cycle J and connecting these provisions, moreover, these bridges have the structure:

a)

where each T2independently denotes N, CH or CG4'; T3means S, O, C, R4G4'C(R4)2or NR3; G4'means any of the above defined fragments G4which are monovalent, and the binding of cycle J occurs on the terminal atoms T2and T3;

b)

where each T2independently denotes N, CH or CG4′; G4'means any of the above defined fragments G4which are monovalent; provided that not more than two bridging atoms T2can represent N; and the binding of cycle J occurs on the terminal atoms T2; and

C)

where all T4T5and T6independently denote O, S, CR4G4′C(R4)2; or NR3; G4'means any of the above defined fragments G4which are monovalent, and the binding of cycle J occurs on the terminal atoms T4or T5; under the following conditions:

i) if T4means O, S or NR3then the other T4mean CR4G4'(or C(R4)2

ii) a bridge comprising atoms T5and T6may contain not more than two heteroatoms O, S or N;

iii) in the bridge, including the atoms T5and T6if one group T5and one group T6imagine the battle atoms O or two groups T6represent the atoms Of specified atoms shared by at least one carbon atom.

If G4means alkyl group, located in the loop J near the bridge -(CR42)p-, and X is NR3where R3means alkyl substituent, G4and alkyl substituent R3if X can be connected to each other with the formation of a bridge structure (CR42)p′-where R' is 2, 3 or 4, provided that the sum of p' and p' is 2, 3 or 4, which leads to the formation of 5-, 6 - or 7-membered nitrogen cycle.

Additional the following conditions: 1) G1, G2, G3and G4if two groups of R3or R6mean alkyl and are in the same N atom they may be linked by communication, O, S or NR3with the formation of N-containing heterocycle with 5-7 atoms in the cycle; and 2) if the aryl, heteroaryl or heterocyclic ring optionally contains substituents, the ring may be up to 5 substituents that are independently selected from the group consisting of amino, mono(lower alkyl)substituted amino, di(lower alkyl) substituted amino, (lower alkanoyl)amino, halogen, lower alkyl, halogenated lower alkyl, hydroxyl, lower alkoxyl, lower alkylthio, halogenated Nissi paxil, halogenated lower alkylthio, lower alkanoyloxy, -CO2R3, -Cho, -CH2OR3, -OCO2R3, -CON(R6)2, -OCON(R6)2, -NR3CON(R6)2, nitro-, amedieval, guanidine, mercapto, sulfo and cyano; and 3) if there is any alkyl group is attached to O, S or N and contains hydroxyl Deputy, the hydroxyl Deputy separated from O, S or N, attached to an alkyl group, at least two carbon atoms.

In the scope of the present invention also includes acceptable from a pharmaceutical point of view salts of these compounds, as well as commonly used proletarienne preparations of these compounds, such as O-ACI-derivatives of compounds of the present invention, which contain hydroxyl groups.

The present invention also relates to pharmaceutical compositions comprising one or more compounds of the present invention, or their salts, or proletarienne drugs in acceptable from a pharmaceutical point of view of the media.

The present invention also relates to a method of use of these substances for the treatment of a mammal, in which there is a pathological condition characterized by abnormal processes of angiogenesis or the occurrence of a behavior is increased permeability, involving the introduction of this mammal in the number of connections corresponding to the present invention, or its salts, or procarcinogen of the drug, which is effective for the treatment of this condition.

DETAILED description of the INVENTION

Definitions:

The adjective "lower" denotes a radical containing a maximum of up to 7 atoms, inclusive, in particular, to a maximum of 5 carbon atoms inclusive, and these radicals are linear or branched with one or many branches.

"Alkyl" means a hydrocarbon radical, up to a maximum of 12 carbon atoms, inclusive, which may be linear or branched with single or multiple branching. Preferably, April was lower alkyl.

If to refer to compounds, salts, etc. used the plural, it also means one compound, salt, etc.

Asymmetric carbon atom is (R)-, (S) or (R, S)-configuration, preferably in the (R)-or (S)-configuration. The substituents on the double bond or the cycle can be in the CIS(=Z-) or TRANS(=E-) form. Thus, the connection may be present as mixtures of isomers or as pure isomers, preferably in the form of enantiomerically pure diastereoisomers and possess CIS-or TRANS configurations of double bonds.

ISSI alkylen Y may be linear or branched, but preferably linear, predominantly representing the methylene (-CH2), ethylene (-CH2-CH2), trimethylene (-CH2-CH2-CH2or tetramethylene (-CH2CH2CH2CH2). If Y is the lowest alkylene, it is most preferable that it represents a methylene.

"Aryl" means an aromatic radical containing from 6 to 14 carbon atoms, such as phenyl, naphthyl, fluorenyl or phenanthrene.

"Halogen" means fluorine, chlorine, bromine or iodine, but preferably fluorine, chlorine or bromine.

"Pyridyl" means 1-, 2-or 3-pyridyl, but preferably 2 or 3-pyridyl.

"Cycloalkyl" means a saturated carbocycle, which contains from 3 to 12 carbon atoms, but preferably from 3 to 8 carbon atoms.

"Cycloalkenyl" means directionspanel and non-aromatic unsaturated carbocycle, which contains from 3 to 12 carbon atoms, but preferably from 3 to 8 carbon atoms and up to three double bonds. Specialists in the art it is well known that cycloalkenyl groups that differ from aromatic compounds by the absence of only one double bond, such as cyclohexadiene, are not sufficiently directionspanel to be acceptable medicinal substances, and so using them as cover the oil is not included in the scope of the present invention.

Cycloalkyl and cycloalkenyl group may include branching points, so that they can contain as substituents alkyl or alkeneamine group. Examples of such branched cyclic groups are 3,4-dimethylcyclopentene, 4-allylcyclohexane and 3-ethylcyclopentane-3-enyl.

Preferably, the salt represented acceptable from a pharmaceutical point of view salts of compounds of formula I, such as, for example, molecular, acid salts, preferably organic and inorganic acids, formed by compounds of the formula I containing a basic nitrogen atom. Suitable inorganic acids are, for example, acid halides, such as hydrochloric acid, sulfuric acid and phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic, and sulfamic acids, for example acetic acid, propionic acid, octanoic acid, cekanova acid, dodekanisa acid, glycolic acid, lactic acid, 2-hydroxipropionic acid, gluconic acid, glucosamine-carboxylic acid, fumaric acid, succinic acid, adipic acid, Emelyanova acid, cork acid, azelaic acid, malic acid, tartaric acid, citric acid, glutaric acid, galactosemia acid, linakis is the notes, such as glutamic acid, aspartic acid, N-methylglycine, azetildigoxina acid, N-acetylaspartic or N-acetylcysteine, pyruvic acid, acetoacetic acid, phosphoserine, 2 or 3-glycerophosphoric acid.

In the definition of Y biradical "-(5-membered heteroaryl)-" means a 5-membered aromatic heterocycle containing 1-3 heteroatoms selected from the group comprising O, S and N, and the number of atoms N is 0-3 and the number of each of the atoms O and S is 0-1, and attached to the sulfur atom by a carbon atom, and -(CR42)satoms With or N. Examples of such diradicals include

In the definition of G1, G2, G3and G4States that if two groups of R3or R6attached to the same N atom, they may form a heterocycle containing 5-7 atoms. Examples of such heterocycles containing N atom to which they are attached, are:

"Heterocyclic radical" or "heterocycle" means a 5-7 membered heterocyclic system with 1-3 heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, which may be unsaturated or fully or partially saturated and unsubstituted or contain substituents, preferably lower alkyl, such as methyl, ethyl, 1-propyl, 2-propyl or tert-butyl.

If that aryl, heteroaryl or heterocyclic ring optionally substituted, that ring may contain up to 5 substituents that are independently selected from the group comprising amino, mono-or di(lower alkyl)substituted amino, lower alkanolamines, halogen, lower alkyl, halogenated lower alkyl, such as trifluoromethyl, hydroxyl, lower alkoxy, halogenated lower alkoxy, such as triptoreline, halogenated lower alkylthio, such as cryptomaterial, -CO2R3, -Cho, -CH2OR3, -OCO2R3, -CON(R6)2, -OCON(R6)2, -NR3CON(R6)2, nitro-, amedieval, guanidine, mercapto, sulfo and cyano.

In a loop that is attached to Y, the elements of the cycles a, b, D, E and L can represent N or CH, and it should be understood that the optional substituents should join with the carbon atom and not to the nitrogen atom, and that if this carbon atom by a Deputy G3then the group G3replaces the atom N, which should be at the carbon atom in the absence of G3.

Examples of cycle J together with two adjacent fragments G4, which together form a second condensed cycle are:

"Hetero is the Rila" means a monocyclic or condensed bicyclic aromatic system, containing from 5 to 10 atoms, 1-4 of which are heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, and the remainder are carbon atoms. Preferably, heteroaryl was a monocyclic system containing only 5 or 6 atoms, 1-3 of which are heteroatoms.

"Alkenyl" means an unsaturated radical containing up to 12 carbon atoms which may be linear or branched with single or multiple branching, and containing up to 3 double bonds. Preferably, alkenyl was a lower alkenyl containing up to 2 double bonds.

"Alkanoyl" means alkylsulphonyl, and preferably lower alkylsulphonyl.

Halogenated lower alkyl, halogenated lower alkoxy and halogenated lower alkylthio are substituents that the alkyl fragments are partially or fully substituted by Halogens, preferably chlorine and/or fluorine, and most preferably fluorine. Examples of such substituents are trifluoromethyl, trifloromethyl, cryptomaterial, 1,1,2,2-tetrafluoroethoxy, dichloromethyl, vermeil and deformity.

If the name of the Deputy provided in the form of a string of fragments, such as "familythiobacteriaceae alkylamino", it should be understood, is the place of connection is the last piece of this string (in this case, the amino group), and the remaining fragments of this string are connected to each other in the same sequence in which they are listed in the row. Thus, the example, "familythiobacteriaceae alkylamino"means:

If the name of the Deputy provided in the form of a string of fragments with communication at the beginning (usually depicted in the form of a hyphen, such as "-S(O)p(optional substituted heteroaromatic)", it should be understood that the connection point is the first atom of the string (in this case S, or sulfur), and the remaining fragments of this string are connected to each other in the same sequence in which they are listed in the row. Thus, the example, -S(O)p(optional substituted heteroaromatic)"means:

It should be understood that the leftmost plot in all variants of the connecting fragment Y is connected to a loop containing a, b, D, E and L, and that the rightmost section of the connecting fragment connected with pyridazinone fragment of the General formula. Thus, examples of usage of the connecting fragment-CH2O-or connecting slice-O-CH2-" presents the following compounds of the present invention is:

In the General structural formula (I) are preferred and most preferred groups are the following.

R1and R2preferably:

i) together form a bridge of the structure

in which the binding is established through the terminal carbon atoms;

ii) together form a bridge of the structure

where one or two fragments of the T1cycle mean N, and the remaining mean CH, and the binding is established through the terminal carbon atoms; or

iii) together form a bridge containing two fragments of the T2and one piece T3and this bridge together with the cycle to which it is attached, forms a bicyclic structure

where

each T2independently denotes N, CH or CG1;

T3means S, O, CH2or NR3; and

provided that, if T3means O or S, at least one T2means or CG CH1.

Most preferably, any group G1was the non-end atom of the bridge. Most preferably, the bridge iii) limit T2meant N or CH, reconcavo T2meant SN or CG1and T3meant S or O.

Preferably, the subscript m is 0 or an integer of 1-2, and preferably, the substituents G1were selected from a group comprising-N(R6)2; -NR6OR6; halogen; lower alkyl; replacement alkyl; aminosilane alkylamino-; N-(nishiuchi)aminosilane alkylamino-; N,N-di-(nishiuchi)aminosilane alkylamino-; replacement of alkylamino-; carboxyterminal alkylamino-; sessioncontroller alkylamino-; -OR6; -SR6; -S(O)R6; -S(O)2R6; halogenated lower alkoxy; halogenated lower alkylthio; halogenated lower alkylsulfonyl; -OCOR6; -COR6; -CO2R6; -CON(R6)2; -NO2; -CN; optionally substituted heteroaromatic; optionally substituted heteroaromatics; optionally substituted heteroaromatics; and-S(O)p(optional substituted heteroaromatic). Most preferably, m is equal to O and G1he was Deputy, is independently selected from the group comprising-N(R6)2; -NR3OR6; halogen; -OR6where R6means lower alkyl; NO2; optionally substituted heteroaromatics and optionally substituted heteroaromatics.

If R6means alkyl group, preferably, it represents a lower alkyl. Preferably, the group R4meant N, preferably, p is 0 or 1 and preferably X meant NR3.

Preferably, in the connecting cable Inc the m fragment Y subscripts n and s is 0 or 1, more preferably 0. It is preferable that Y was chosen from a group comprising lower alkylene; CH2-O-; -CH2-S-; -CH2-NH-; -S-; -NH-; -(CR42)n-S(O)pIs a 5-membered heteroaryl)-(CR42)s-and-(CR42)nWith(G2)(R4)- (CR42)s- and-O-CH2-. More preferably, Y has been selected from the group comprising-CH2-O-; -CH2-NH-; -S-; -NH-; -(CR42)n- S(O)p-(5-membered heteroaryl) (CR42)s- and-O-CH2-.

Preferably, in the cycle, represented in the left part of the structure (I), A, D, and E meant SN, a L meant N or CH, provided that when L is N, then preferably all the substituents G3was monovalent, and if L is CH, then preferably all the substituents G3were bivalent.

Preferably, the substituents G3were selected from a group comprising a monovalent fragments: lower alkyl; or-NR3COR6; -OR6; -SR6; -S(O)R6; -S(O)2R6; -CO2R6; -CON(R6)2; -S(O)2N(R6)2; -CN; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heteroaromatic; optionally substituted heteroaromatics; -S(O)p(NeoMaster is but substituted heteroaryl); optionally substituted heteroaromatics; -S(O)p(optional substituted heteroaromatic); and bivalent bridge of structure T2=T2-T3where T2means N or CH. Preferably, T3meant S, O, CR42H2or NR3.

Most preferably, G3were selected from a group comprising a monovalent fragments: lower alkyl; or-NR3OR6; -CO2R6; -CON(R6)2; -S(O)2N(R6)2; and bivalent bridge of structure T2=T2-T3where T2means N or CH. Most preferably, T3meant S, O, CH2or NR3.

Most preferably, the subscript q, which denotes the number of substituents G3amounted to 1.

Preferably, the cycle J meant benzene and preferably, subscript q′which denotes the number of substituents G4in the benzene cycle, equal to 0,1, 2 or 3. Most preferably, the subscript q' equal to 1 or 2.

Preferably, the fragments G4were selected from a group comprising-N(R6)2; -NR3COR6; halogen; alkyl; halogen-substituted alkyl; replacement alkyl; carboxyterminal alkyl; missiologically alkyl; aminotoluene-; N-(nishiuchi)aminosilane alkylamino-; N,N-di-(nishiuchi)aminosilane alkylamino-; N-(nissioner)aminosilane alkylamino-; replacement of alkylamino-; carboxyterminal alkylamino-; sessioncontroller alkylamino-; phenylmethylsulfonyl alkylamino; -OR6; -SR6; -S(O)R6; -S(O)2R6; halogenated lower alkoxy; halogenated lower alkylthio; halogenated lower alkylsulfonyl; -OCOR6; -COR6; -CO2R6; -CON(R6)2; -CH2OR3; -NO2; -CN; optionally substituted heteroaromatic; optionally substituted heteroaromatics; -S(O)p(optional substituted heteroaryl); optionally substituted heteroaromatics; -S(O)p(optional substituted heteroaromatic), and form a condensed cycle divalent bridges attached to adjacent positions of the cycle J and connecting these provisions, moreover, these bridges have the structure:

a)

where each T2independently denotes N or CH; T3means S or O and linking with the benzene ring cycle occurs on the terminal atoms T2and T3;

b)

where each T2independently denotes N, CH or CG4'; when the the condition, that not more than two bridging atoms T2can represent N; and linking with the benzene ring cycle occurs on the terminal atoms T2; and

C)

where all T5and T6independently denote O, S, or CH2; and the binding of cycle J occurs on the terminal atoms T5; under the following conditions:

i) a bridge comprising atoms T5and T6may contain not more than two heteroatoms O, S or N;

ii) in the bridge, including the atoms T5and T6if one group T5and one group T6represent the atoms O, or two groups, T6represent the atoms Of specified atoms shared by at least one carbon atom.

Preferably, alkyl groups forming the entire fragment G4or part thereof, was a lower alkyl.

If G4means alkyl group, located in the loop J near the bridge -(CR42)p-, and X is NR3where R3means alkyl substituent, G4and alkyl substituent R3if X can be connected to each other to form a bridge of the structure -(CH2)p'-where preferably R' is equal to 2 or 3, provided that the sum of p and p' is 2 or 3, which leads to the formation of 5-or 6-membered nitrogen cycle. Most p is edocfile, to the sum of R' and R' equal to 2, which leads to the formation of 5-membered cycle.

Most preferably, G1, G2, G3and G4if two groups of R3or R6mean alkyl and are in the same N atom they may be linked by communication, O, S or NR3with the formation of N-containing heterocycle of 5-6 atoms in the loop.

Preferably, if the aryl, heteroaryl or heterocyclic ring optionally contains substituents, the ring could be up to 2 substituents that are independently selected from the group consisting of amino, mono(lower alkyl)substituted amino, di(lower alkyl)substituted amino, (lower alkanoyl)amino, halogen, lower alkyl, halogenated lower alkyl, hydroxyl, lower alkoxyl, lower alkylthio, halogenated lower alkoxy, halogenated lower alkylthio, -CH2OR3, nitro and cyano.

The method corresponding to the present invention is intended for use in the treatment of VEGF-mediated conditions in humans and other mammals.

The compounds can be administered orally, dermal, parenteral, by injection, by inhalation or spray, or sublingually, rectally or vaginally in dosage form compositions. The term "administered by injection" includes intravenous, NR is chrysostomou, intramuscular, subcutaneous and parenteral injections, and the use of infusion techniques. Dermal introduction may include local application or percutaneous introduction. One or more compounds may be present together with one or more non-toxic pharmaceutically acceptable carriers and optionally other active ingredients.

Compositions intended for oral administration, can be manufactured in accordance with any method known in the manufacture of pharmaceutical compositions. In order to obtain palatable preparations, such compositions can contain one or more reagents selected from the group comprising diluents, sweeteners, flavorings, colorants and preservatives.

Tablets contain the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These fillers can be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate and sodium phosphate; granulating and loosening agents, for example corn starch and alginic acid; binding agents, for example magnesium stearate, stearic acid and talc. Tablets may not contain coatings or through the Yu known methods or can be coated, slow disintegration and absorption in the gastrointestinal tract and thereby provide a delayed action over a longer period. For example, you can use inhibiting substance, such as glycerylmonostearate or literallayout. These compositions can also be prepared in solid form with quick release.

Compositions intended for oral use may also be produced in the form of capsules of hard gelatin, in which the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules from which the active ingredient is mixed with water or oil, such as peanut oil, liquid paraffin or olive oil.

You can also use a water suspension containing the active substance in a mixture with excipients suitable for the preparation of aqueous suspensions. Such fillers are suspendresume reagents, such as sodium carboxymethyl cellulose, methylcellulose, hypromellose, sodium salt of alginate, polyvinylpyrrolidone, tragacanth gum and gum acacia; dispersing or wetting agents, which can be a natural phosphatides, for example lecithin, or condensation products of accelerated with fatty is a slot, for example polyoxyethylenated, or condensation products of ethylene oxide with aliphatic alcohols with long chain, such as geksametilentetramina, or condensation products of ethylene oxide with partial esters of fatty acids and exit, such as polyoxyethylenesorbitan, or condensation products of ethylene oxide with partial esters of fatty acids, and anhydrides of exit, such as polyethylenterephthalat. Aqueous suspensions can also contain one or more preservatives, for example ethyl or n-propyl-p-hydroxybenzoate, one or more colouring, one or more flavor additives and one or more sweeteners, such as sucrose and saccharin.

Dispersible powders and granules suitable for preparation of an aqueous suspension by adding water, contain the active ingredient mixed with dispersing or wetting agent, suspenders reagent and one or more preservatives. Examples of suitable dispersing or wetting agents and suspendida reagents listed above. There also may be additional excipients, for example sweetening, flavoring and coloring additives.

These compounds can also be in the form of non-aqueous liquid compositions, for example, the p oil suspensions, which can be prepared by suspension of active ingredients in a vegetable oil, such as olive oil, sesame oil or peanut oil, or in mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agents, for example beeswax, hard paraffin or cetyl alcohol. To obtain palatable compositions intended for oral use, you can add sweeteners, such as those mentioned above, and flavoring. These compositions can be given the ability for long-term storage by adding antioxidants such as ascorbic acid. Pharmaceutical compositions corresponding to the present invention, can also be an emulsion of the type oil-in-water. The oil phase may be a vegetable oil such as peanut oil or olive oil, or mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents may be natural gums, for example gum acacia and tragacanth gum, natural phosphatides, for example soy lecithin, and esters or partial esters of fatty acids, and anhydrides of exit, such as servicemanual, and condensation products of these partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. is mulshi may also contain sweeteners and flavorings.

Syrups and elixirs can be prepared with the addition of sweeteners, such as glycerol, propylene glycol, sorbitol and sucrose. Such compositions may also contain soothing agents, preservatives and flavoring and coloring additives.

These compounds can also be entered in the form of suppositories intended for rectal or vaginal administration of medical preparations. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal or vaginal temperature and therefore melt in the rectum or vagina, releasing the drug. Such substances include cocoa butter and polyethylene glycols.

Compounds corresponding to the present invention can also be entered using percutaneous methods known to experts in the art (see, for example: Chien, "Transdennal Controlled Systemic Medications", Marcel Dekker, Inc.; Lipp et al. WO 94/04157 dated March 3, 1994). For example, a solution or suspension of the compounds of formula I in a suitable volatile solvent, optionally containing reagents that increase permeability, can be combined with additional additives, known to experts in the art, such as matrix materials and bactericides. P the following sterilizing the mixture by known methods, can be made in the form of dosage forms. In addition, by processing using emulsifying reagent and water from the solution or suspension of the compounds of formula I can be prepared lotion or ointment. Suitable solvents intended to prepare systems for percutaneous introduction, known to experts in the art and include lower alcohols such as ethanol and isopropyl alcohol; lower ketones, such as acetone, esters of lower carboxylic acids, such as ethyl acetate, polar ethers such as tetrahydrofuran, lower hydrocarbons, such as hexane, cyclohexane and benzene, and halogenated hydrocarbons such as dichloromethane, chloroform, trichlorotrifluoroethane and trichloroethane. Suitable solvents can also be a mixture of one or more substances selected from the group comprising lower alcohols, lower ketones, esters of lower carboxylic acids, polar ethers, lower hydrocarbons, halogenated hydrocarbons.

Suitable materials that increase the permeability intended to prepare systems for percutaneous introduction, known to experts in the art and include, for example, monobasic and polybasic alcohols, such as ethanol, propylene glycol and benzyl alcohol, saturated and unsaturated fatty alcohols with 8 to 18 carbon atoms, such as La is relevy alcohol and cetyl alcohol, saturated and unsaturated fatty acids with 8 to 18 carbon atoms, such as stearic acid, esters of saturated and unsaturated fatty acids containing up to 24 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl or monoglyceride esters of acetic acid, Caproic acid, lauric acid, myristic acid, stearic acid and palmitic acid, and complex diesters of saturated and unsaturated dicarboxylic acids containing up to 24 carbon atoms, such as diisopropylamide, diisobutylamine, Diisopropylamine, and Diisopropylamine Diisopropylamine. Additional materials that increase the permeability include vospalitelnye derivatives, such as lecithin, cephalin, terpenes, amides, ketones, urea and derivatives thereof and ethers, such as dimetridazole and monotropy ether of diethylene glycol. Suitable compositions that increase the permeability may also include mixtures of one or more substances selected from the group comprising monobasic and polybasic alcohols, saturated and unsaturated fatty alcohols with 8 to 18 carbon atoms, saturated and unsaturated fatty acids with 8 to 18 carbon atoms, esters of saturated and unsaturated fatty acids containing up to 24 at the MOU carbon complex diesters of saturated and unsaturated dicarboxylic acids containing up to 24 carbon atoms, vospalitelnye derivatives, terpenes, amides, ketones, urea and derivatives thereof and ethers.

Suitable binders intended to prepare systems for percutaneous introduction, known to experts in the art and include polyacrylates, silicones, polyurethanes, block polymers, butadiene-styrene copolymers, natural and synthetic rubbers. As matrix components can also be used ethers of cellulose, substituted polyethylene and silicates. For increasing the viscosity of the matrix, you can add additional additives, such as viscous resin or oil.

For all modes of application disclosed in the present invention for compounds of formula I, preferably daily oral dose ranged from 0.01 to 200 mg/(kg full weight). Preferably, the daily dose in the introduction by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, as well as when using the procedures of infusion ranged from 0.01 to 200 mg/(kg full weight). Preferably, the daily rectal dose ranged from 0.01 to 200 mg/(kg full weight). Preferably, daily vaginal dose ranged from 0.01 to 200 mg/(kg floor is Oh body mass). Preferably, the daily dose of the local application ranged from 0.1 to 200 mg when applied one to four times per day. Preferably, the concentration of dermal introduction was so to support the daily dose is from 0.01 to 200 mg/kg, Preferably daily inhalation dose ranged from 0.01 to 10 mg/(kg full weight).

Specialists in the art should understand that the specific route of administration will depend on various factors, each of which is as usual taken into account by the treating physician. However, it should also be understood that the specific dose for each patient will depend on many factors, including (but not limited to) the activity of the specific compound, the age of the patient, the body weight of the patient, the General health of the patient, gender of the patient, the diet of the patient, time of administration, route of administration, rate of excretion, combination of drugs and the severity of the pathological condition being treated. In addition, the specialist in the art it should be clear that the optimal course of treatment, i.e. the route of administration and the daily number of doses of the compounds of formula I or its acceptable from a pharmaceutical point of view of salt taken within a certain amount the and days, must be installed by the specialists in the art using conventional methods of treatment trials.

GENERAL procedure for the synthesis of

Compounds corresponding to the present invention can be obtained by using known chemical reactions and procedures. However, below the General methods of synthesis are given to help the reader in the synthesis inhibitors RDK, and more detailed specific examples are provided below in the experimental section, which describes practical examples.

In these techniques, all group variables are described using generic names, unless they are specifically defined below. If in this structure, the variable group, or a Deputy designated by the symbol (i.e. R3, R4, R6, G1, G2, G3or G4), is used more than once, it should be understood that each of these groups or substituents may independently be any of the values from the range of definitions of the corresponding symbol. As defined above, the compounds corresponding to the present invention, containing cyclic fragments, each of which independently may contain from 0 to 5 substituents G1, G3or G4that are not defined as N. It should be noted that in contrast to the following General schemes, the substituents G1, G3and G4 used in this way, as if their definition included N to show in any provisions of these structures may contain such substituents G1, G3and G4and to simplify the drawings. However, such non-standard usage does not imply any change in the definition of G1, G3and G4. Thus, only the following diagrams General methods G1, G3and G4they can mean the N in addition to the structures specified in the definitions of G1, G3and G4.

Within these General methods, the variable M is equivalent to the fragment

in which any variable group and the Deputy can independently vary within the definitions given above for this character.

Within these General methods variable Q1equivalent fragment

in which L and N and any other variable group and the Deputy can independently vary within the definitions given above for this character.

Within these General methods variable Q2equivalent fragment

in which any variable group and the Deputy can independently vary within the definitions given above for this character.

It should be understood that the connection is to be placed, relevant to the present invention, each of the declared optional functional group cannot be obtained by using each of the following methods. Within the scope of each method are optional substituents, which are stable in the reaction conditions, or a functional group that can participate in the reaction and which, if presented in a protected form, and removing the respective protective groups is performed at appropriate stages by methods known to experts in this field of technology.

General procedure a Compound of the formula I-A in which X, M, Q1and Q2are as defined above, Y represents-CH2-O-, -CH2-S-, -CH2-NH-, -O-, -S-or-NH and R1and R2together with the carbon atoms to which they are attached, form a condensed 5-membered aromatic heterocycle, hal means a halogen (Cl, Br, F or I, preferably Cl, Br or F), usually obtained in accordance with the sequence of reactions shown below, entitled Method A. Thus, a specialist in the art can obtain a heterocycle of the formula II in which R signifies lower alkyl, in accordance with the published procedure specified in the reference table. In cases of thiophene-2,3-dicarboxylic acid (row 1 of the table) and pyrazole-3,4-d the carboxylic acid (row 10 of the table) carboxylic acid is transformed into methyl or ethyl esters by treating the corresponding alcohol and the catalyst is an inorganic acid (usually sulfuric acid) boiling under reflux. To obtain an intermediate product III fluids of formula II is treated with hydrazinehydrate (specific conditions of the reaction, see Robba, M.; Le Guen, Y., Bull. Soc. Chem. Fr., 1970 124317). Compound III is treated halogenation reagent such as phosphorus oxychloride, oxybromide phosphorus, pentabromide phosphorus or pentachloride phosphorus, and get dihalogenide intermediate product IV. Dichloride or dibromide intermediate products can be turned into differeny intermediate product (if necessary) by the reaction with hydrogen fluoride. When using the later stages of the iodine-containing reagents, such as potassium iodide or tetrabutylammonium, in the reaction mixtures without allocation of a pure substance is formed of ideny intermediate product. Dihalogenide intermediate product IV is treated with a nucleophilic reagent of the formula V by boiling under reflux with alcohol or other suitable solvent, such as tetrahydrofuran (THF), dimethoxyethane (DME), dimethyl formamide (DMF), dimethylsulfoxide (DMSO) and the like, and receive the intermediate product of formula VI. Such condensation can be carried out in the melt without a solvent and can be catalysed by acids such as HCL, or bases, such as triethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Sedimentary VI enter into reaction with compounds of formula VII in a suitable aprotic solvent, such as DMSO, DMF, or without solvent, often in the presence of a basic catalyst, such as DBU or CsCO4or a crown ether such as 18-crown-6, at temperatures usually in the range from room temperature up to the temperature phlegmy with obtaining the compounds of formula I-A, corresponding to the present invention. Specialist in the art should understand that the nature of the parent compounds will determine the selection of the suitable solvents, catalyst (if used) and temperature. Intermediates of formula V and VII are often commercially available or can easily be obtained by methods well known to specialists in this field of technology. Receiving VII in which Y represents-CH2-O-, and Q2means 4-pyridyl containing as a substituent 2-aminocarbonyl group (2-CONH2), in particular, described in the work of Martin, I., et al. Acta Chem. Scand. 1995 49 230.

Method And

General methods In the compounds of formula 1 in which M, X and Q2are as defined above, Y represents-CH2-O-, -CH2-S-, -CH2-NH-, -O-, -S-or-NH-, easy to get, as indicated in the methodology Century In accordance with the procedure described in the literature (Tomisawa and Wang, Chem. Pharm. Bull., 21,1973, 2607, 2612), isocarboxazid VIII is introduced into reaction with PBr5in the melt and the floor is with 1,4-dibromophenol IX. Intermediate IX is treated with a nucleophilic reagent of the formula V by boiling with alcohol under reflux and receive the intermediate product of formula X. This condensation can be carried out in the melt without a solvent and can be catalysed by acids such as HCL, or bases, such as triethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The compound of formula X is introduced into reaction with the compound of the formula VII in a suitable aprotic solvent such as DMSO, DMF, or without solvent, often using a basic catalyst, such as DBU or CsCO4at elevated temperatures and are appropriately present invention the compound of formula I-B. This technique is most appropriate when Y represents-CH2-S or-S-.

Method In

General procedure C - Compounds of formula I-C in which M, X, R1, R2, m and Q2are as defined above, is easily obtained using the sequence of reactions described in method C. In this method, preferably, m is 0, a R1and R2together with the carbon atoms to which they are attached, form a benzene or a 5-membered aromatic heterocycle. Starting material XI or commercially, or specialist in the art gets the go so, as indicated in the following reference table. Starting material XI is introduced into reaction with urea or ammonia, usually at elevated temperature and pressure (in the case of ammonia), and get imide XII. The imide is introduced into reaction with the aldehyde XIII in acetic acid and piperidine boiling under reflux and receive intermediate XIV. The reaction of XIV with sodium borohydride in methanol or other suitable solvent in accordance with the General procedure described I.W. Elliott and Y. Takekoshi {J. Heterocycl. Chem. 1976,13, 597), gives an intermediate product XV. Treatment of XV with a suitable halogenation reagent such as POCl3, POBr3, PCl2, PBr5or thionyl chloride, gives halide intermediate product XVI, which enter into reaction with the nucleophilic reagent of the formula V by boiling with alcohol under reflux and receive a corresponding present invention the compound of formula I-C. This condensation can be carried out in the melt without a solvent and can be catalysed by acids such as HCL, or bases, such as triethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Alternatively, the reagent V can be condensed with the intermediate product XV by heating the two components, with P2O5in the melt and to obtain a connection structure I-C. This last technique is particularly effective, is if X is amine connecting link.

Methods With

Checklist FOR OBTAINING INITIAL SUBSTANCES
Available.
Available.
D.E. Ames and 0. Riubeiro, J. Chem. Soc. Perkin Trans. 11975 1390.
J.R.Carson and S. Wong, J. Med. Chem. 1973,16,172.
K. Yasuyuki, et. al., J. Org. Chem. 1986, 51,4150.
Schneller, et. al., J. Med. Chem. 1978, 21, 990.
R.K. Robins, et. al., J. Org. Chem. 1963, 28, 3041.
P. Gupta, et. al., J. Heterocycl. Chem. 1986, 23, 59.
R. C. Meyer, et. al., J. Heterocycl. Chem. 1980, 17,159.

General method D-Compounds of formula I-D-1, in which R1, R2, R6, M, X, Y, G3and Z are as defined above, and q is 0 or 1, is easily obtained using the sequence of reactions described in method D. this technique pyridylamine pyridazine or pyridine (I-D-1) pravr who participate in 2-aminocarbonyl functional derivative pyridines of the formula (I-D-2) by using formamide (XVII) in the presence of hydrogen peroxide and iron salts in accordance with the methodology described in the literature (Minisci et al., Tetrahedron, 1985, 41, 4157). This technique gives the best results, if R1and R2together form a condensed aromatic heterocycle or a condensed aromatic carbocycle. In cases where Z denotes CH, and R1and R2do not form a condensed aromatic cycle can be formed isomeric by-product, in which Z signifies CCONHR6and, if it is formed, it is removed from the desired product by chromatography.

Procedure D

General method E - the compounds of formula I-E-1 and I-E-2, in which R1, R2, R6, M, X, Y, G3and Z are as defined above, and q is 0 or 1 and R3means lower alkyl, easily obtained using the sequence of reactions described in the method that this method pyridylamine pyridazine or pyridine (I-D-1) is transformed into 2-aminocarbonyl functional derivative pyridines of the formula (I-E-1) through the use of monoalkylation (XVIII) in the presence of S2O82-, acid and catalytic amounts of AgNO3in accordance with the methods described in the literature (Serra, F. et al., Tetrahedron Letters, 1992, 33 (21), 3057). Then the compounds of formula I-E-1, in which R3means N, obtained by hydrolysis of ester using a base, such as guide the oxide of sodium, in a mixture of methanol/water. The compounds of formula I-E-2, where R6independently are as defined above, but particularly including such compounds, in which none of the R6does not mean N., easily obtained from the acid (I-E-1, R3=H) by treatment with amine XIX in the presence of coupling reagent such as DCC (dicyclohexylcarbodiimide). This technique gives the best results, if R1and R2together form a condensed aromatic heterocycle or a condensed aromatic carbocycle. In cases where Z denotes CH, and R1and R2do not form a condensed aromatic cycle, the first stage can be formed isomeric by-product, in which Z means CO2R3and, if it is formed, it is removed from the desired product by chromatography.

Method E

General method F the compounds of formula I-F where M, Q2and X are as defined above, m is an integer equal to 1-5, and R1and R2together with the carbon atoms to which they are attached, form a condensed 5-membered aromatic heterocycle, can be obtained by using the sequence of reactions described in method F. Easily obtainable source of heterocyclic carboxylic acid XX is introduced into the reaction is July with butyllithium, and then with dimethylformamide and receive an aldehyde of structure XXI. The reaction XXI with hydrazine gives pyridazine XXII. Processing XXII suitable halogenation reagent such as POCl3, POBr3PCI5, PBr5or thionyl chloride, gives halide intermediate product, which is injected into reaction with a nucleophilic reagent of the formula V by boiling with alcohol under reflux and receive the intermediate compound of formula XXIII. Such condensation can be carried out in the melt without a solvent and can be catalysed by acids such as HCL, or bases, such as triethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Alternatively, the reagent V can be condensed with the intermediate product XXII by heating the two components, with P2O5in the melt and get XXIII. This latter technique is especially effective if X is amine connecting link. Formirovanie and alkylation of compounds of Reissert XXIII using halide XXIV carried out as described in the General method proposed by F.D. Popp, Heterocycles, 1980,14,1033, and receive the intermediate product structure XXV. Subsequent processing XXV base gives the corresponding present invention compound I-F.

Method F

General method G - Compounds of formula 1-G, where M, Q2and X is the tsya such as defined above, m is an integer equal to 1 to 4, and R1and R2together with the carbon atoms to which they are attached, form a condensed 5-membered aromatic heterocycle, can be obtained by using the sequence of reactions described in method G. Aldehyde XXI, obtained by the method of F can be recovered with sodium borohydride and get gidrokshikislotu, which turns into a lactone using methods known to experts in the art, for example, using toluensulfonate obtained lactone XXVI. Condensation of the intermediate product XXVI with the aldehyde XIII in the presence of a base such as sodium methoxide, usually in a solvent such as methanol, boiling under reflux gives the intermediate product structure XXVII. The reaction XXVII with hydrazine or, preferably, with hydrazinehydrate at 100 ° -150°gives intermediate product structure XXVIII. The transformation of the intermediate XXVIII in the corresponding present invention, the compound of structure I-G is carried out according to the procedures described in method C, using XXVIII instead of XV.

Method G

General procedure N - Compounds of formula I-N in which R1, R2, M, X, R6, q and G3are as defined above, can easily get help is through the sequence of reactions, described in method N. Thus, the techniques described in the work of Martin, I.; Anvelt, J.; Vares, L; Kuehn, I.; Claesson, A., Acta. Chem. Scand. 1995, 49, 230 232, or the above-described method D or E with the replacement I-D-1 on easily accessible ester pyridine-4-carboxylic acid XXX use for converting XXX XXXI. The restoration of this complex ester in accordance with the above description of Martin, et al. after this is carried out using a mild reducing reagent such as NaBH4, so amide Deputy remains unchanged, and get alcohol XXXII. Then the alcohol is heated with a base, such as DBU or CsCO4with halogenopyrimidines VI, obtained by the method And arid environment, and get the present invention the compound of formula I-H.

Methodology N

General procedure I is Relevant to the present invention the compounds of formula I-I in which R1, R2, M, X, R6, q and G3are as defined above, and W stands for a bond or-CH2-easily get by using the sequence of reactions described in method I. This method is particularly suitable, if q is 1 and XXXIII means 4-chloropyridin. Alternatively, in this method, you can use the other 4-halogenerator, such as 4-herperidin or 4-bromopyridin. It is thus easy to obtain 4-halogenfrei the s XXXIII converted into intermediates of formula XXXIV using the General procedures D and E with the replacement I-D-1 4-halogenerator. The reaction XXXIV with potassium hydrosulfide or sodium gives a thiol having the formula XXXV. Alternatively, the alcohol group of the intermediate product XXXII, obtained by the method of N into useplease group by reaction with methanesulfonanilide and a suitable base, such as triethylamine, in the cold, so that was minimized by the formation of polymeric substances, and the resulting intermediate product is introduced into reaction with sulphide of potassium or sodium with getting thiol having the formula XXXVI. The thiol of formula XXXV or formula XXXVI enter into reaction with the intermediate product VI, obtained by the method A, and a suitable base, such as diisopropylethylamine or CsCO4in DMF or other suitable anhydrous solvent or in the absence of solvent with obtaining I-D-9.

The method I

General method J Is Relevant to the present invention the compounds of formula I-J-1 or I-J-2, in which R1, R2, M, X, W and G3are as defined above, and contain in their structure sulfoxide or sulfonyl fragment easily get by using the sequence of reactions described in the methodology J. Compounds corresponding to the present invention, which contain a thioester group as part of the Deputy G1, G3or G4or as the e part Y, as shown in the typical structure I-I in method I, can be converted into the corresponding present invention compounds containing sulfoxide fragment, such as I-J-1, by treatment with one equivalent of m-chloroperbenzoic acid (MJPBK) in methylene chloride or chloroform (MJPBK, Synth. Commun., 26,10,1913-1920,1996) or by treatment with periodate sodium in methanol/water at a temperature of from 0°to room (J. Org. Sung., 58, 25, 6996 7000,1993). The expected by-products, representing a mixture of different N-oxides and sulfone I-J-2, can be removed by chromatography. Sulfon I-J-2 is obtained by adding an additional amount MJPBK or, preferably, by the use of potassium permanganate in a mixture of acetic acid/water (Eur. Med. Chem. Ther., 21,1, 5 8,1986), or by using hydrogen peroxide in acetic acid (Chem. Heterocycl. Compd., 15,1085-1088, 1979). In cases where unwanted N-oxides are products produced in large quantities, they can be turned back into the necessary sulfoxidov or sulfones by hydrogenation in a mixture of ethanol/acetic acid using a catalyst of palladium on coal (Yakugaku Zassi, 69, 545 548,1949, Chem.Abstr.1950, 4474).

Method J

A General method To Appropriate the present invention the compounds of formula I, in which R1, R2, M, X and Q1 are as defined above, is easily obtained using the sequence of reactions described in the methodology as a Specialist in the art gets the original substance structure XXXVII ways known in the literature. For example, XXXVII in which R1and R2together with the carbon atoms to which they are attached form a 2,3-substituted thiophene, furan, pyrrole, checkpointing, oxazole or thiazole, obtained using the General scheme of the synthesis described in J. Org. Chem. 1981, 46, 211, and conducting hydrolysis of the initially formed tert-Putilkovo of ester using triperoxonane acid. Source pyrazole can be obtained by reaction of 2-oxo-3-penten-1,5-dieval acid (J. Chem. Phys. 1974, 60,1597) with diazomethane. The original substance, in which R1and R2together with the carbon atoms to which they are attached, form phenyl, get methods work Cymerman-Craig et al., Aust. J. Chem. 1956, 9, 222, 225. The compounds of formula XXXVII in which R1and R2mean lower alkyl, easy to get in accordance with the methods described in patent CH 482415 (Chem. Abstr. 120261 u, 1970). The crude dicarboxylic acid of the formula XXXVII is then treated with hydrazine and get pyridazine XXXVIII (the conditions of the reaction are described in detail in the work of Vaughn, W. R.; Baird, S. L. J. Am. Chem. Soc. 1946, 68, 1314). Pyridazine XXXVIII process gloriou what they reagent, such as phosphorus oxychloride, and receive intermediate dichloropropane, which by treatment with water is subjected to hydrolysis to obtain chloropyridazine XXXIX. Chlorine substituted acid XXXIX process nucleophilic reagent of the formula V in the presence of a base such as sodium hydride, in a solvent such as DMF, or in the absence of solvent. The resulting acid XXXX restore using recovery reagent, such as BF3THF, in accordance with the methodology proposed by Tilley, J. W.; Coffen, D. L.; Schaer, C. H.; Lind, J. J. Org. Chem. 1987, 52, 2469. The resulting alcohol XXXXI enter into reaction with a base and optionally substituted 4-haloperidolum, optionally substituted 4-halogenopyrimidines or optionally substituted 4-halogenopyrimidines (XXXXII) and receive a corresponding present invention the compound of formula I-K (specific conditions of the reaction, see Barlow, J. J.; Block, M. H.; Hudson, J. A.; Leach, A.; Longridge, J. L.; Main, C. G.; Nicholson, S. J. Org. Chem. 1992, 57, 5158).

Methods To

A General method L Is Relevant to the present invention the compounds of formula I-L in which R1, R2, M, X and Q1are as defined above, is easily obtained using the sequence of reactions described in the method L. Thus, the alcohol of formula XXXXI, obtained by the method For introducing reacts the Yu with methanesulfonamide in the presence of a suitable base, and then with potassium hydrosulfide or sodium and receive thiol XXXXIII. Then the thiol is introduced into reaction with 4-halogenopyrimidines XXXXII, obtained by the method, in the presence of a suitable base, such as triethylamine, and get the present invention compound I-K. Alternative, XXXXI turn in the halogenated intermediate product of formula XXXXIV methods known to experts in the field of technology, and the halide is introduced into reaction with the thiol XXXXV and receive I-K. the Intermediate product XXXXIV also can be transformed into an intermediate product XXXXIII by treatment with KHS or NaHS. Reagents XXXXV or are commercially available, for example, 4-mercaptopyridine, or a specialist in the art and may be obtained for example by the method described above I.

The method L

EXPERIMENTAL SECTION

Conventions of the NMR spectrum: s - singlet, d - doublet, t - triplet, q - quadruplet, m - multiplet, b - wide.

Example 1: Obtain 1-(chlorpheniramine)-4-pyridylthio)-isoquinoline

Stage 1: obtain the intermediate product And the Mixture 2,90 g, 19,07 mmol isocurvature and 14,40 g, 33,68 mmol of pentabromide phosphorus alloys at 140°C. the Melt is transformed into a red liquid and after about 10 min the reaction mixture solidified and cooled. The reaction to shift the ü crushed and poured into ice-cold water. The obtained solid is filtered off and dried in air. Weight 5.50 g, yield 96%, so pl. 94-96°. Rf=0,66 40% solution of ethyl acetate in hexano.

Stage 2: a Mixture of 1.00 g, 3,49 mmol of 1,4-dibromothiophene (intermediate product (A)obtained in stage 1, with 4-Chloroaniline melted at 140°C. the Reaction mixture turned into a dark red liquid, and after about 10 min the reaction mixture solidified and ready for further processing. The reaction mixture is pulverized and triturated with a mixture of methanol/THF, 50/50, then filtered and dried in the air without additional purification. Weight 0.75 g, yield to 64.4%, so pl. 260-263°. Rf=0,58 40% solution of ethyl acetate in hexano.

Stage 3: a Mixture of 0.05 g, 0,1498 mmol 1-(4-Chloroaniline)-4-bromoisoquinoline with 0.02 g, 0.18 mmol 4-mercaptopyridine alloys 140°C for about 10 minutes the reaction mixture is purified through a plate with holes the size of 1000 μm using a 5% solution of methanol in hexano as solvent. Weight 0,0103 g, yield 19%, so pl. 192 -195°. Rf=0,50 40% solution of ethyl acetate in hexano.

Example 2: Obtain 1-(indan-5-ylamino)-4-(4-pyridylthio)-isoquinoline

To obtain the desired compound applied the methodology used to obtain the P is the iMER 1, but with substitution of 4-Chloroaniline 5-aminoindan in stage 2. So pl. 100 -103°, TLC (thin layer chromatography) Rf=0,40 (40% solution of ethyl acetate in hexano).

Example 3: Obtaining 1-(benzothiazole-5-ylamino)-4-(4-pyridylthio)-isoquinoline

To obtain the desired compound applied the methodology used to obtain in Example 1, but replacing 4-Chloroaniline-6-aminobenzothiazole in stage 2. TLC Rf=0,36 (5% methanol/methylene chloride); MS (mass spectroscopy)=387.

Example 4: Obtain 1-(4-chlorpheniramine)-4-(4-pyridylmethyl)-isoquinoline

Stage 1: a Mixture of hemophthalmia (770 mg, 4,78 mmol), 4-pyridinecarboxamide (0,469 ml, 4,78 mmol) and piperidine (0.5 ml) in acetic acid (25 ml) 1 h refluxed. The resulting solution was cooled to room temperature. The solid product is separated by filtration, washed with water (4x10 ml), dried in vacuum and obtain 920 mg (to 3.67 mmol, yield 77%) of a mixture of Z - and E-isomers of the above compounds. In1H NMR (DMSO-d6in the field of aromatic compounds observed complex proton signals due to the presence of Z - and E-isomers. MS ER (elektrorazpredelenie) 251 (M+N)+, 252 (M+2N)+.

Stage 2: To a suspension of the original substance (1.70 g, 6.8 mmol) in methanol (250 ml) at 0°with a slow gain of borohydride sodium (3.0 g, 79 mmol). Mixture is allowed to warm to room temperature and continue stirring for 1 h the resulting mixture was concentrated to remove solvent. To the residue was added ice water (100 ml) and 2 n HCI solution was adjusted pH to 2. Stirred for 10 min, add 2 n NaOH solution until the pH of the solution is equal to about 11. The resulting solution was extracted with CH2Cl2(4 × 100 ml). The organic layers collected, dried over MgSO4and concentrate. The residue is purified by chromatography on a column (1:10 vol/about. methanol dichloromethane) and receive 400 mg of the desired compound as a solid (1.70 mmol, yield 25%).1H NMR (Meon-d4) 8,33-8,39 (m, 4H), 7,50-to 7.68 (m, 3H), 7,30-7,31 (m, 2H), 7,14 (s, 1H), 4,15 (s, 2H); MS ER 237 (M+N)+, 238 (M+2N)+; TLC (1:10 vol/about. methanol dichloromethane) Rf=0,40.

Stage 3: a Mixture of 4-Chloroaniline (178 mg, of 1.40 mmol), phosphorous pentoxide (396 mg, of 1.40 mmol) and trietilenglikole (193 mg, of 1.40 mmol) is heated to 200°in an argon atmosphere and stirred for 1.5 h to obtain a homogeneous melt. To melt add the original substance (82 mg, 0.35 mmol). The reaction mixture was stirred 2 h at 200°C. the Obtained black solid mass is then cooled to 100°C. Add methanol (5 ml) and water (10 ml) and the reaction mixture is treated with ultrasound, while the black mass of n will become soluble. Add dichloromethane (40 ml) and to bring the pH of the mixture to 10 add concentrated ammonia solution (about 2 ml). The organic layer is separated, the aqueous layer was extracted with dichloromethane (3 × 20 ml). The combined organic layers dried over MgSO4filter and concentrate. Cleaning the plate for preparative TLC (1: 10 vol/about. methanol dichloromethane) to give 26 mg (0.08 mmol, yield 22%) of the desired compound as a yellow solid.1H NMR (Meon-d4) of 8.37 (d, J=7.8 Hz, 3H), 7,86 (s, 1H), 7,55-to 7.77 (m, 5H), 7,27-7,33 (m, 4H), or 4.31 (s, 2H); MS ER 346 (M+N)+; TLC (1:10 vol/about. methanol dichloromethane) Rf=0,45.

Example 5: Obtain 1-(benzothiazole-6-ylamino)-4-(4-pyridylmethyl)-isoquinoline

To obtain the desired compound applied the methodology used to obtain in Example 4, but replacing 4-Chloroaniline-6-aminobenzothiazole at stage 3.1H NMR (MeOH-d4) the remaining 9.08 (s, 1H), of 8.37 8,59 (m, 4H), 7,79 shed 8.01 (m, 2H), 7,60 for 7.78 (m, 4H), 7,30 (d, 2H), 4,34 (s, 2H); MS ER 369 (M+N)+; TLC (1:4 vol./about. hexane-ethyl acetate) Rf=0,20.

Example 6: Obtain 1-(indan-5-ylamino)-4-(4-pyridylmethyl)-isoquinoline

To obtain the desired compound applied the methodology used to obtain in Example 4, but replacing 4-Chloroaniline-6-aminoindan at stage 3.1HNMR (MeOH-d4) 8,35 (m, 3H), 7,46-to 7.77 (m, 5H), 7,1-7,27 (m, 4H), 4.26 deaths (s, 2H), 2,87-2,90 (m, 4H), 2.05 is is 2.10 (m, 2H); MS ER 352 (M+N)+TLC (1: 4 vol./about. hexane in ethyl acetate) Rf=0,25.

Example 7: Obtain 1-(3-fluoro-4-methylphenylimino)-4-(4-pyridylmethyl)-isoquinoline

To obtain the desired compound applied the methodology used to obtain in Example 4, but replacing 4-Chloroaniline 3-fluoro-4-methylaniline in stage 3.1H NMR (MeOH-d4) to 8.34 (d, 3H), 7.87 (s, 1H), 7,54-of 7.69 (m, 4H), 7,10-7,31 (m, 4H), 2,22 (s, 3H); MS ER 344 (M+N)+; TLC (1: 4 vol./about. hexane in ethyl acetate) Rf=0,20.

Example 8: Obtain 4-(4-chlorpheniramine)-7-(4-pyridyloxy)-thieno[2,3-d]pyridazine

Step 1: To a dry 3-necked round-bottom flask with a volume of 2 l attach a mechanical stirrer and addition funnel. Into the flask in an argon atmosphere was placed 2-thiencarbazone acid (25 g, 195 mmol) and anhydrous THF (500 ml). The mixture is cooled to -78°in a bath of solid carbon dioxide and isopropanol and stirred for 30 minutes Within 30 minutes added dropwise n-utility in hexano (2.5 M, 172 ml). The reaction mixture is still stirred for 1 h at -78°S, and then placed in an atmosphere of dry carbon dioxide. After the addition of carbon dioxide, the reaction mixture thickens. The reaction mixture for another 1 h and maintained at -78°and then heated to -10°C. the Reaction is stopped with 2 N. HCI (213 ml) and the mixture is allowed to warm to room temperature. The layers are separated and the aqueous layer was extracted with EtOAc (3×200 ml). The organic layers are combined, dried (Na2SO4) and concentrated on a rotary evaporator. The brown solid is crystallized from hot isopropanol and dried over night in vacuum. Get the desired thiophene-2,3-dicarboxylic acid (27,3 g, 159 mmol; yield 82%).1H NMR (DMSO-d6) of 7.69 (d, J=1,5, 1), 7,38 (d, J=4,8, 1); ER MS (M+H)+=173; TLC (chloroform Meon water, 6: 4:1); Rf=0,74.

Stage 1A: To obtain the same product alternative in stage 1 instead of 2-thiophencarboxylic acid to use 3-thiencarbazone acid.

Stage 2: To a round bottom flask with a volume of 1 l attach the reflux condenser and placed in a mixing rod. Into the flask, the product obtained in stage 1 (62 g, 360 mmol)in Meon (500 ml) and a catalytic amount of H2SO4(˜5 ml). The reaction mixture for 24 h refluxed under stirring. The reaction mixture is cooled to room temperature and concentrated on a rotary evaporator. The brown mixture was purified using chromatography on silica gel (hexane, EtOAc, gradient mode from 80:20 to 60:40). Get the desired dimethylthiophene-2,3, in primary forms (21.2 g, 106 mmol; yield 31%).1H NMR (DMSO-d6) to 7.93 (d, J=4,8,1), 7,35 (d, J=4,8, 1), and 3.8 (d, J=1, 6); MS ER (M+N)sup> +=201; TLC (hexane EtOAc, 70: 30); Rf=0,48.

Stage 3: To a round bottom flask of 250 ml attach the reflux condenser and placed in a mixing rod. Into the flask, the product obtained in stage 2 (16 g, 80 mmol), hydrazinehydrate (6,6 ml, 213 mmol) and EtOH (77 ml) and 2.5 h refluxed. The reaction mixture is cooled to room temperature and concentrated on a rotary evaporator. Add water (50 ml) and the filtrate is separated from the insoluble solids. The aqueous layer was concentrated on a rotary evaporator to obtain a pale yellow solid. The solid during the night is dried in a vacuum Cabinet at 50°C. Receive the desired thieno-[2,3-a]pyridazine-4,7-dione (12 g, 71 mmol; yield 89%).1H NMR (DMSO-d6) a 7.85 (d, J=5,1,1), 7,42 (d, J=5,1,1); MS ER (M+N)+=169; TLC (dichloromethane Meon, 60:40); Rf=0,58.

Stage 4: intermediate product: To a round bottom flask of 250 ml attach the reflux condenser and placed in a mixing rod. Into the flask, the product obtained in stage 3 (2.5 g, of 14.8 mmol), phosphorus oxychloride (45 ml, 481 mmol) and pyridine (4,57 ml, 55 mmol) and 2.5 h refluxed. The reaction mixture is cooled to room temperature and poured on ice. The mixture was separated and the aqueous layer is xtraceroute chloroform (4 × 75 ml). The organic layers are combined, dried (Na2SO4) and concentrated on a rotary evaporator, getting a dark yellow solid. Get the desired 4,7-dichlorethene[2,3]pyridazine (intermediate product; 1.5 g, 7,3 mmol; yield 49%); so pl. 260-263°C.1H NMR (DMSO-d6) 8,55 (d, J=5,7,1), 7,80 (d, J=5,1, 1); MS ER (M+N)+=206; TLC (hexane EtOAc, 70: 30); R=0,56. Cm. also Robba, M.; Bull. Soc. Chim. Fr.; 1967,4220 4235.

Stage 5: To a round bottom flask of 250 ml attach the reflux condenser and placed in a mixing rod. Into the flask, the product obtained in stage 4 (of 7.65 g of 37.3 mmol), 4-Chloroaniline (4,76 g of 37.3 mmol) in EtOH (75 ml). A mixture of 3 h refluxed. After 3 h of the reaction mixture falls precipitate an orange solid. The reaction mixture is cooled to room temperature and the solid is separated by filtration and washed with hexane. Get the desired 7-chloro-4-(4-chlorpheniramine)-thieno[2,3-d]pyridazin (6.5 g, 21.9 mmol; yield 60%); so pl. 139-142°; ER MS (M+N)+=297; TLC (hexane EtOAc, 60:40); Rf=0,48.

Step 6: To a round bottom flask with a volume of 150 ml attach the reflux condenser and placed in a mixing rod. Into the flask, the product obtained at stage 5 (0.33 g, 1.1 mmol), 4-pyridylcarbinol (1.2 g, and 11.2 mmol) in DBU (2.5 ml, and 16.7 mmol and a mixture of 24 h, heated at 125° C. the hot reaction mixture was added EtOAc (10 ml) and then the reaction mixture was poured into water (10 ml). The layers are separated and the aqueous layer was extracted with EtOAc (3×10 ml). The organic layers are combined, dried (MgSO4) and concentrated on a rotary evaporator. The resulting mixture was purified using chromatography on silica gel (dichloromethane-methanol-acetone (90:5:5) and obtain a pale yellow solid. Get the desired compound (0.03 g, 0.08 mmol; the yield of 7.3%); so pl. 203 -205°C, with decomposition; ER MS (M+N)+=369; TLC (dichloromethane-methanol-acetone, 95:2,5:2,5); Rf=0,56.

Example 9: Obtain 4-(4-chlorpheniramine)-7-(4-pyridyloxy)-furo[2,3-d]pyridazine

Stage 1: In a dry 3-necked flask with a volume of 3 l equipped with a dropping funnel, a pipe for supplying argon and mechanical stirrer, was placed n-utility (2.5 M in hexano, 196 ml, 491 mmol). The mixture is diluted with dry THF (500 ml) and cooled to -78°C. are added dropwise 2-frankenboob acid (25 g, 223 mmol) in solution in THF (500 ml). The mixture is stirred for 1.5 h, and then within 1 h after the reaction mixture is blown with dry carbon dioxide. Gradually heated to -10°and then, the resulting thick white suspension is treated with an aqueous solution of HCI (2 N., 446 ml). Two layers are separated and the aqueous layer was extracted with EtOAc (3 × 300 ml). The joint body is ical layers dried (Na2SO 4), filtered and concentrated, obtaining the crude furan-2,3-dicarboxylic acid as an orange solid (44 g), which is used without further purification.1H NMR (300 MHz, d6-acetone) δ 7,06 (d, J=1,7,1), of 7.97 (d, J=1,7,1)and 10.7 (bs, 2H); TLC (CHCl3/Meon/N2O 6:4:1); Rf=0,56.

Stage 2: To a dry round-bottom flask 500 ml attach the nozzle to supply argon and placed in a mixing rod. The flask crude acid obtained in stage 1 (44 g) and dissolved in Meon (250 ml). To the reaction mixture in portions added chlorotrimethylsilane (80 ml, 630 mmol). After stirring at room temperature for 15,5 h the solution is concentrated to obtain oil and add silica (5 g). The mixture is suspended in the Meon (100 ml) and removal of volatile substances repeat two more times. The remainder is injected directly into the upper part of the chromatographic column and elute with a mixture of hexane/EtOAc 60:40, getting dimethylfuran-2,3, in primary forms, in the form of an orange oil (38 g, the total output of stage 1 and stage 2 is equal to 93%).1H NMR (300 MHz, CDCl3) δ 3,81 (s, 3), of 6.71 (d, J=2,8, 1), 7,46 (d, J=2,8,1); TLC (hexane/EtOAc 60:40); Rf=0,46.

Stage 3: In a round bottom flask with a volume of 500 ml, equipped with a nozzle for supplying argon, a mixing degree of the press and reflux condenser, put di-methylfuran-2,3, in primary forms (44 g, 236 mmol)dissolved in EtOH (250 ml). To the solution is added hydrazinehydrate (55% N2H4, 40 ml, 3.0 mmol) and the reaction mixture is refluxed. For 5.5 h slowly precipitated yellow solid and after this time the mixture is cooled to room temperature. Volatiles are removed under reduced pressure and receives a yellow paste, which is suspended in water and filtered. The yellow solid is washed with water and transferred into a round bottom flask with a volume of 500 ml, equipped with a nozzle for supplying argon, reflux condenser and stirring rod. The solid is suspended in aqueous HCl (2 N., 200 ml) and the mixture refluxed. After boiling for 4 h orange suspension is cooled to room temperature and filtered. The solid is thoroughly washed with water and dried in vacuum, obtaining a 4.7-dioxo[2,3-d]herperidin as an orange solid (21,5 g, 60%).1H NMR (300 MHz, DMSO-d6) δ 7,00 (d, J=2,1,1H), 8,19 (d, J=2,1,1H), 11,7 (bs, 2H).

Stage 4: intermediate product: To a round bottom flask with a volume of 1 l attach the reflux condenser, a pipe for supplying argon and placed in a mixing rod. Furan obtained in stage 3 (15 g, 102 mmol)is added to a mixture of phosphorus oxychloride (300 ml) and pyridine (30 ml) and the resulting orange suspension is refluxed. After boiling the reaction mixture for 4 h volatiles removed on a rotary evaporator. The residue was poured on ice and the aqueous mixture extracted with CHCl3(4 × 250 ml). The combined organic layers are washed with saline, dried (MgSO4and concentrate, receiving 4,7-dichloro[2,3-d]herperidin (intermediate product, 11.3 g, 59%) as an orange-red solid, which is used without further purification. TLC (hexane/EtOAc 60:40); Rf=0,352.1H NMR (300 MHz, DMSO-d6) δ 7,40 (d, J=2, 0, 1), 8,63 (d, J=2, 0, 1).

Stage 5: In a round bottom flask of 100 ml, equipped with a mixing rod, a pipe for supplying argon and reflux condenser, was placed a product obtained in stage 4 (1.50 g, 7,98 mmol)dissolved in ethanol (100 ml). To this mixture is added Chloroaniline (1,02 g 7,98 mmol) and the resulting suspension is refluxed. After boiling for 4 h, the reaction mixture was concentrated on a rotary evaporator. The crude orange solid is injected directly into the upper part of the chromatographic column and elute with a mixture of CH2Cl2 /MeOH 97:3, obtaining a mixture of 4-MgSO-7-[N-(4-chlorophenyl)-amino]-[2,3]properidine and 7-chloro-4-[N-(4-chlorophenyl)-amino]-[2,3-d]properidine in the form of a yellow powder (1.2 g, 55%). TLC (CH2Cl2/MeOH 97: 3); Rf=0,7;1H NMR (300 MHz, DMSO-d6) δcontained in a larger amount of the isomer (A) 7,40 (d, J=8,9,2), 7.45 (d, J=8,9, 2), 7,87 (d, J=9,2, 2), a 8.34 (d, J=2.0 a, 1), 9,62 (s, 1); contained in a smaller amount of the isomer (B) 7,28 (d, J=2.0 a, 1), 7,40 (d, J=8,9, 2), 7,87 (d, J=9,2, 2), 8,48 (d, J=2.1 a, 1), 9,88 (s, 1).

Step 6: To a round bottom flask with a volume of 25 ml attach the nozzle to supply argon, the reflux condenser and placed in a mixing rod. The product obtained at stage 5 (400 mg, 1.4 mmol), mixed with 4-pyridylcarbinol (782 mg, 7,17 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-Yong (2.5 ml, and 16.7 mmol) and the suspension heated to 125°C. After stirring for 24 h the reaction mixture is cooled, injected directly into the top of a flash column and elute with a mixture of CH2Cl2/MeOH 95: 5. The obtained yellow oil re chromatographic under the same conditions and get the desired compound in the form of parts of a mixture of three components. Separation by HPLC (high performance liquid chromatography (column C18CH3CN/H2About gradient mode from 10: 90 to 100: 0) gives the desired compound in the form of an almost white solid (13,7 mg, 3%). TLC (CH2Cl2 /MeOH 95:5) Rf=0,19; so pl. 198°;1H NMR (300 MHz, CDCl2) δ the ceiling of 5.60 (s, 2), 6.6 (d, J=2,1,1), 7,18-7,20 (m, 2), 7,35-the 7.43 (m, 6), 7,66 (d, J=2,1,1), 8,54 (d, J=5,6, 2).

Stage 5A and 6A: Alternative 4,7-dibromo[2,3-d]properidine (intermediate G, below) is used to obtain the desired compounds through stage 5, but using diplomirovannyi intermediate product instead deklarirovannoe. Stage 6A is carried out by fusing the two components in the presence of CsCO4and not 1,8-diazabicyclo[5.4.0]undec-7-ene. The crude product was then purified as described above.

Intermediate products from D to G: other bicyclic 4,5-condensed-3,6-dehalogenating

Using the General method of Example 9, stage 2-4, substituting furan-2,3-dicarboxylic acid in a suitable heterocyclic dicarboxylic acid, and get replaced dichloropyridazine from D to G, are presented in the table below. Dibromopyridin G get, conducting steps 2-3 of Example 9 and then holding stage 4' as follows: 0.50 g (3,287 mmol) of product obtained in stage 3, was added 2.83 g (to 6.57 mmol) pentabromide phosphorus.

This mixture is heated to 125°C. At a temperature of about 115°the reaction mixture is melted and re-solidified until its temperature reaches 125°C. the Reaction with the ect is cooled and the solid residue is crushed and poured into ice-cold water. The obtained solid is filtered off and dried in vacuum. Weight=0.75 g (yield 82%). In some cases, as is shown in the links, dichloropyridazine are known substances. All these dehalogenation heterocycles can be used to obtain the claimed compounds of the present invention.

Table
DReceived in accordance with the methods cited in: Robba, M.; Bull. Soc. Chim. Fr.; 263, 1966, 1385-1387.1H NMR (DMSO-d6) 9,94 (s, 1); MS ER (M+N)+=207.
EReceived:1H NMR (DMSO-d6) 8685 (s, 1); MS ER (M+N)+=189.
FCan be obtained using methods described in the work: Robba, M., et al.; Bull. Soc. Chim. Fr.; 1957,4220 4235.
GTCX Rf=0,76 (5% Meon/methylene chloride).

The intermediate product N: Receive (2-methylaminomethyl-4-pyridyl)-methanol

Step 1: Mix a solution of utilitarianist (250 ml) of 1.64 mol) and concentrated sulfuric acid 92 ml, of 1.64 mol) in N-methylformamide (2.0 l) cooled to 0°in the bath with ice. Add the sulfate heptahydrate iron(II) (22,8 g 0,0812 mol, crushed with the pestle in a mortar, and then added dropwise a 30% aqueous hydrogen peroxide solution (56 ml, 0,492 mol). While maintaining the temperature of the reaction mixture below 22°With four more times add iron sulfate(II) and hydrogen peroxide. After stirring the reaction mixture for thirty minutes, add a solution of sodium citrate (2 l, 1 M) (pH of the mixture is about 5). The mixture is extracted with dichloromethane (1 l, 2×500 ml). The combined organic extracts washed with water (2×500 ml), 5% aqueous sodium bicarbonate solution (3×100 ml) and saline solution (500 ml). The resulting organic solution is then dried over sodium sulfate, filtered and concentrated in vacuo, obtaining a solid substance. The crude solid is triturated with hexane, filtered, washed with hexane and dried in vacuum, obtaining 270,35 g (79,2%) pastel-yellow solid.1H NMR (DMSO-d6, 300 MHz): δ 8,9 (d, 1H), 8,3 (m, 1H), and 8.0 (dd, 1H), 4,4 (q, 2H), and 2.8 (d, 3H)and 1.3 (t, 3H).

Stage 2: To a mechanically stirred suspension of the product obtained in stage 1 (51,60 g, 0,248 mol)in EtOH (1.3 l) was added to borohydride sodium (18.7 g, 0,495 mol). The reaction mixture was stirred for 18 h p is at room temperature. The reaction of the resulting solution gently stopped by adding saturated aqueous solution of ammonium hydrochloride (2 l). At the time of stopping the reaction observed gas evolution. The mixture is alkalinized with concentrated ammonium hydroxide solution (200 ml) to rn. Then extracted with EtOAc (8×400 ml). The combined organic layers are dried (MgSO4), filtered and concentrated in vacuo, obtaining the intermediate product N in the form of a transparent light-yellow oil (36,6 g, yield 89%).1H NMR (DMSO-d6, 300 MHz): δ a total of 8.74 (q, 1H), 8,53 (dd, 1H), 7,99 (m, 1H), of 7.48 (m, 1H), of 5.53 (t, 1H), 4,60 (d, 2H), 2,81 (d, 3H): MC m/z 167 [M+H]+.

Intermediate products from 1 to N: a General method of obtaining [2-(N-substituted)-aminocarbonyl-4-pyridyl]methanol intermediates

When 0°to a solution of amine 2 (3 equiv.) in benzene was added trimethylaluminum (3 EQ.). There is a gas and then the reaction mixture is allowed to warm to room temperature and stirred for 1 h (Lipton, M. F. et al. Org. Synth. Coil. Vol. 6,1988, 492 or Levin, J. I. et al. Synth. Comm., 1982,12, 989). Known carbinol 1 (1 EQ., Hadri, A. E., Leclerc, G. Heterocyclic Chem., 1993, 30, 631) was added to the aluminium reagent and a mixture of 1 h refluxed. The reaction is stopped by the water and the reaction mixture is concentrated. The crude product is usually purified by chromatographing column of silica gel (EtOAc 20/1/Meon) and get the connection 3. The composition of the final product is usually confirmed using LC/MS (LC - liquid chromatography) and NMR spectroscopy.

ExampleUsed Amin 2The call features 3
I(M+N)+223; Rf=0,17 (100% EtOAc)
J(M+N)+181; Rf=0,2 (9:1 EtOAc/Meon)
To(M+N)+224; Rf=0,14 (1:1 EtOAc/CH2Cl2)
L(M+N)+193; Rf=0,58 (100% EtOAc)
M(M+N)+311; Rf=0,34 (3/2 EtOAc/hexane)
N(M+H)+181; Rf=0,46 (100% EtOAc)
*Instead of benzene as the solvent used CH2Cl2.

Example 10: Obtain 4-(4-chlorpheniramine)-7-(2-aminocarbonyl-4-pyridyloxy)-thieno[2,3-d]pyridazine

To a 3-necked round-bottom flask with a volume of 25 ml attach thermometer and in it put eremacausis rod. Into the flask, the product obtained in Example 8 (value (0.475) g, 1,29 mmol), iron sulfate heptahydrate (0,179 g, 0.64 mmol), formamide (of 11.15 ml, 281 mmol) and concentrated H2SO4(0,14 ml). The mixture is stirred for 30 min at room temperature and at this time, to the mixture are added dropwise N2O2(0.2 ml, 6,44 mmol). The reaction mixture is still stirred for 1 h at room temperature and then for 30 min, heated to 55°C. the Reaction mixture is 3 hours and maintained at this temperature and then cooled to room temperature. To the reaction mixture was added an aqueous solution of sodium citrate (0.27 M, 1 ml) and then the layers are separated and the aqueous layer was extracted with EtOAc (4×5 ml). The organic layers are combined, dried (MgSO4) and concentrated on a rotary evaporator. The obtained solid is dissolved in hot acetone and filtration is separated from the remaining solids. Then the filtrate concentrated on a rotary evaporator, the residue is dissolved in hot Meon and the white solid collected by filtration. Get the desired compound (0,014 g 0,034 mmol; the yield of 2.7%); so pl.=233°; ER MS (M+N)+=412. TLC (dichloromethane-methanol-acetone, 95: 2,5: 2,5); Rf=0,20.

Example 11: Obtain 4-(4-chlorpheniramine)-7-(2-methylaminomethyl-4-pyridyloxy)-thieno[2,3-d]pyridazine

To obtain and komago connection use a technique, used to obtain in Example 10, but with the replacement of formamide on methylformamide.1H NMR (DMSO-d6) 8,80 (d, 1), to 8.62 (d, 1), 8,31 (d, 1), of 8.09 (d, 2), 7,86 (d, 2), the 7.65 (d, 1), 7,35 (d, 2), 5,74 (s, 2), 2,84 (d, 3); MS ER (M+N)+=426. Rf(95/2,5/2,5, dichloromethane/Meon/acetone)=0,469.

Example 12: Obtain 1-(4-chlorpheniramine)-4-(2-aminocarbonyl-4-pyridylmethyl)-isoquinoline

To obtain the desired compound applied the methodology used to obtain in Example 10, but replacing the product of Example 8 the product of Example 4. The crude product was then purified using plates for preparative TLC (1:4 vol./about. hexane-ethyl acetate, yield 19%) and get the desired compound as a yellow solid.1H NMR (MeOH-d4) 8,42 (d, 1H), 8.34 per (d, 1H), 7,94 (s, 1H),7,88 (s, 1H), 7,55-7,76 (m, 5H), 7,26 and 7.36 (m, 3H), 4,34 (s, 2H); MS ER 389 (M+N)+TLC (1: 4 vol./about. hexane-ethyl acetate) Rf=0,44.

Example 13: producing 1-(4-chlorpheniramine)-4-(2-methylaminomethyl-4-pyridylmethyl)-isoquinoline

To obtain the desired compound applied the methodology used to obtain in Example 11, but replacing the product of Example 8 the product of Example 4. The crude product is purified by chromatography on a column (2: 3 vol./about. hexane, ethyl acetate, yield 20%) and get the desired compound as a yellow solid.1H NMR (Meon-d4 ) 8,42 (d, 1H), with 8.33 (d, 1H), 7,88 (d, 2H), 7,55-to 7.77 (m, 5H), 7,28 and 7.36 (m, 3H), 4,34 (s, 2H), 2,89 (s, 3H); MS ER 403 (M+N)+; TLC (2:3 vol./about. hexane-ethyl acetate) Rf=0,30.

Examples 14 and 15: Obtain 4-(4-chlorpheniramine)-7-(2-methylaminomethyl-4-pyridyloxy)-furo[2,3-d]pyridazine and 4-(4-chlorpheniramine)-2-methylaminomethyl-7-(2-methylaminomethyl-4-pyridyloxy)-furo[2,3-d]pyridazine

To a suspension of the final product obtained in Example 9 (19,20 g of 54.4 mmol), N-methylformamide (200 ml) and distilled water (20 ml) at room temperature is added dropwise concentrated H2SO4(2,9 ml of 54.4 mmol). The mixture is stirred until it turned into a clear solution. To this solution in one portion add FeSO4·7H2O (1.51 g, 5.43 mmol), and then added hydroxylamine-O-sulfonic acid (GOSC, 1.84 g, 16.3 mmol). The addition of FeSO4.7H2O and GOSK repeat 11 times at 10-minute intervals. Analysis by HPLC indicates the magazine is empty, the greater part of the original substance. The reaction mixture is cooled in a bath of ice. With vigorous stirring, was added a solution of sodium citrate (600 ml, 1M, 600 mmol). The resulting suspension is vigorously stirred for further 10 minutes, the Solid is collected by filtration, washed with water (3 × 100 ml) and dried 16 h in vacuo at 50°C. the Crude product is t (21 g) purified by filtration through a layer of silica gel, elwira with 5% CH3HE/CH2Cl2. Obtained 3.7 g of product is recrystallized from CH3CN (125 ml, boiled for 1.5 h). The solid is collected by filtration, washed with CH3CN (2×15 ml) and dried 16 h in vacuo at 50°C. the Final product (4-(4-chlorpheniramine)-7-(2-methylaminomethyl-4-pyridyloxy)-furo[2,3-d]pyridazin) is a light yellow solid (3,38 g, 15.2 per cent). So pl. p.223-224°C.

The main by-product produce by using the above filtering through a layer of silica gel. The structure of the by-product 4-(4-chlorpheniramine)-2-methylaminomethyl-7-(2-methylaminomethyl-4-pyridyloxy)-furo[2,3-a]pyridazine) characterize using1H NMR, two-dimensional NMR, elemental analysis and MS.1H NMR (DMSO-d6, 300 MHz): δ to 9.32 (br s, 1H), 8.93 (q, 1H), 8,79 (q, 1H), 8,63 (dd, 1H), 8,12 (m, 1H), to $ 7.91 (m, 3H), of 7.70 (dd, 1H), 7,35 (m, 2H), USD 5.76 (br s, 2H), 2,81 (d, 6H). MC m/z 467 [M+H]+.

Example 14A: Obtain 4-(4-chlorpheniramine)-7-(2-methylaminomethyl-4-pyridyloxy)-furo[2,3-d]pyridazine-Method 2

To a mixture of the intermediate product obtained in Example 9, stage 5 (10.0 g, 35,7 mmol), the intermediate product H (12.4 g, 74,6 mmol) and 18-crown-6 (0,42 g of 1.59 mmol) in toluene (100 ml) in one portion at room temperature was added powdered KOH (4.4 g, 85%, from 66.7 mmol). Then reacts the traditional mixture with vigorous stirring and heated to 85± 2°C. the Reaction mixture was vigorously stirred at this temperature overnight. After cooling to room temperature, the toluene layer is decanted and the resinous residue is added water (100 ml). The resulting mixture was vigorously stirred until it becomes a fluid suspension. The solids are collected by filtration, washed with water (2×10 ml) and dried 16 h in vacuo at 45°C. a Yellow-brown solid is suspended in acetonitrile (70 ml) and suspendu 2 h refluxed. After cooling to room temperature, the solids are collected by filtration, washed with a small amount of acetonitrile and dried over night in vacuum at 45°C. the Desired allocate connection with the release of 46% (of 6.73 g) as a pale yellow solid.

Example 16: Obtain 4-(4-chlorpheniramine)-7-(2-aminocarbonyl-4-pyridyloxy)-furo[2,3-d]pyridazine

To obtain the desired compound applied the methodology used to obtain in Example 14, but replacing N-methylformamide on formamid. The reaction is carried out using 500 mg of the final product obtained in Example 9, and proportional amounts of solvents and reagents. The crude product is purified by HPLC on a column of 75 × 30 cm C18 using linear gradient the th mode of elution from 10% to 100% acetonitrile in water with addition of 0.1% triperoxonane acid at a rate of 10 ml/min for 10 min and obtain 18 mg of the desired compound as a yellow solid: HPLC (column 50 × 4.6 mm YMC CombiScreen® C18 using linear gradient elution mode from 10 to 100% acetonitrile in water with addition of 0.1% triperoxonane acid with a speed of 3 ml/min for 5 min, UV detection at 254 nm) to 2.35 min peak; MS ER 396 (M+N)+.

Example 17: Obtain 4-(4-chlorpheniramine)-7-(benzothiazol-6-ylamino)-thieno[2,3-d]pyridazine

The dichloride obtained in Example 8, step 4 (of 1.00 g of 4.90 mmol), was added p-Chloroaniline (622 mg, of 4.90 mmol) and absolute ethanol (10.0 ml). A mixture of 2 hours and refluxed at 95°S, and then cooled to room temperature. The resulting yellow precipitate (2) is filtered and washed with isopropyl alcohol, 4,0 N. a solution of KOH, H2O and then with hexane. Then the filtrate (2) is mixed with 6-aminobenzothiazole (883 mg, 5,88 mmol) in 10 ml of n-butanol and during the night is heated at 150°C. the Reaction mixture is allowed to cool to room temperature, and then the solvent is removed on a rotary evaporator. The residue is successively treated 4,0 N. water solution of KOH and extracted with dichloromethane (50 ml), dried (MgSO4) and the solvent evaporated. The crude product was then purified using flash chromatography on silica gel using 95% dichloromethane/methanol as eluent. The structure of the pure desired compound acknowledge the help of LC/MS and NMR: TLC (30% EtOAc/hexane) R f(3)=0,20;1H NMR (DMSO) δ to 7.2 (dd, 3H), 7,38 (dd, 3H), of 7.65 (d, 1H), 8.0 a (d, 1H), 8,45 (d, 1H), and 8.8 (s, 1H); LC/MS m/z 410, WU (retention time)=4,21 minutes

Example 18: Obtain 4-(indan-5-ylamino)-7-(benzothiazol-6-ylamino)-thieno[2,3-d]pyridazine

To obtain the desired compound applied the methodology used to obtain in Example 17, but replacing 4-Chloroaniline 5-aminoindan. The crude product was then purified using flash chromatography on silica gel using 30% ethyl acetate/hexane as eluent. The structure of the pure desired compound is confirmed using LC/MS and NMR: TLC (30% EtOAc/hexane) Rf(3)=0,20;1H NMR (DMSO) δ 2,0 (m, 2H), 2,85 (m, 4H), 7,18 (d, 1H), and 7.8 (d, 1H), 7,95 (d, 1H), 8,10 (d, 1H), 8,18 (d, 1H), and 8.7 (d, 2H), and 9.1 (d, 2H); LC/MS m/z 414. WU=4,43 minutes

Example 19: Obtaining 4-(5-bromoindole-1-yl)-7-(4-pyridyloxy)-furo[2,3-d]pyridazine

4,7-Dichloro[2,3-d]properidine obtained in Example 9, stage 4 (95 mg, 0.50 mmol)and 5-bromoindoline (100 mg, 0.50 mmol) for 2 hours and heated under reflux with 60 ml of absolute ethanol at 95°C. the Reaction mixture is allowed to cool to room temperature and the resulting precipitate is filtered and washed with isopropyl alcohol, 4,0 N. a solution of KOH, H2Oh and hexane, and then dried. Receive the intermediate product purity of about 95% (WU=4,72, (M+N)+350), which is used in the next stage without additional purification. 4-Pyridylcarbinol (28 mg, 0.26 mmol) and sodium hydride (60%, 50 mg, 1.25 mmol) and stirred for 20 min in 20 ml of anhydrous tetrahydrofuran at 0°in argon atmosphere, and then give 44 mg of the above intermediate product (0.13 mmol). The reaction mixture was stirred for 2 h at 0°and then the temperature is allowed to rise to room temperature. The mixture is stirred for another 12 h and the solvent is evaporated under reduced pressure. The obtained solid substance was dissolved in 50 ml dichloromethane and washed with a solution To a2CO3and H2O. the Organic layer is separated, dried (MgSO4) and evaporated under reduced pressure. The crude product was then purified by TLC (Rf=0,3) on silica gel using mixtures of dichloromethane/methanol (95: 5) as eluent. The structure of the pure desired compound is confirmed using LC/MS and NMR:1H NMR (CDCl3) δ 3,20 (m, 2H), 4,30 4,50 (m, 2H), ceiling of 5.60 (s, 2H), 6,9-8,0 (m, 6H), 860 (m. 2H); LC/MS (M+N)+423, WU=4,49 minutes

Example 20: Obtaining 4-(4-methoxyphenylazo)-7-(2-methylaminomethyl-4-pyridyloxy)-furo[2,3-d]pyridazine

To a suspension of 4,7-dichloro[2,3-d]properidine obtained in Example 9, stage 4 (400 mg, 2,12 mmol, 1 EQ.), and p-anisidine (p-MeO6H4NH2) (260 mg, 2,12 mmol, 1 EQ.) in DME (5 ml) was added water (1 ml). The resulting solution was 48 h and heated at 50°C. After the cooling gap is possible to room temperature, a brown precipitate is removed by filtration and the filtrate was concentrated in vacuo, receiving the crude product as a brown solid. Rubbing brown solid with CH2Cl2give 292 mg (50%) of the intermediate product 4-(4-methoxyphenylazo)-7-Harper[2,3-d]pyridazine, the structure of which is confirmed using LC/MS and NMR. A suspension of this intermediate product (292 mg, 1.06 mmol, 1 EQ.), (2-methylaminomethyl-4-pyridyl)-methanol (intermediate product N 529 mg, 3,18 mmol, 3 EQ.) and 18-crown-6 (42 mg, 0.16 mmol, 15 mol. %) in toluene (4 ml), stirred for 20 min at room temperature. Then add CON (178 mg, 3,18 mmol, 3 EQ.) and the reaction mixture 36 h heated at 80°C. After cooling to room temperature, add water (10 ml) and the mixture is vigorously stirred until it forms a white suspension. The suspension is filtered and washed with water and diethyl ether and receive 125 mg (29%) of the desired product as a pale yellow solid: (M+N)4406; Rf=0.50 In (100% EtOAc).

Example 21: Obtain 4-(4-methoxyphenylazo)-7-(4-pyridyloxy)-furo[2,3-d]pyridazine

To obtain the desired compound applied the methodology used to obtain in Example 20, but replacing (2-methylaminomethyl-4-pyridyl)-methanol 4-pyridinemethanol. Pure product produce by using chromatography on flash-column: (M+N)+349; Rf=0,3 (95: 5 CH2Cl2CH 3IT).

Example 22: Obtain 4-(4-methoxyphenylazo)-7-(2-aminocarbonyl-4-pyridyloxy)-furo[2,3-d]pyridazine

To obtain the desired compound applied the methodology used to obtain in Example 16, but replacing the product obtained in Example 9, the product obtained in Example 21. The reaction is carried out using 250 mg of the original substance and proportional amounts of solvents and reagents. The crude product is purified by HPLC on a column of 75 × 30 mm C18 using linear gradient elution mode from 10 to 100% acetonitrile in water with addition of 0.1% triperoxonane acid at a rate of 10 ml/min for 10 min and obtain 16 mg of the desired compound as a white solid: HPLC (column 50 × 4.6 mm YMC CombiScreen® C18 using linear gradient elution mode from 10 to 100% acetonitrile in water with addition of 0.1% triperoxonane acid with a speed of 3 ml/min for 5 min, UV detection at 254 nm) to 1.98 min peak; MS ER 392 (M+N)+.

Examples 23-80: Obtaining of the present invention compounds according to methods a-1, a-2 and a-3

Procedure a-1: an Equal number of equivalents of the dichloride (1) and M-NH22 hours and refluxed at 95°With a suitable quantity AB is autogo ethanol. The reaction mixture is allowed to cool to room temperature and the resulting precipitate (2) is filtered off and successively washed with isopropyl alcohol, 4,0 N. a solution of KOH, H2Oh and hexane, and then dried. Then at 150°C for 10 h carry out the reaction of the filtrate (2) with 1.2 equivalents of Q-NH2in a suitable amount of n-butyl alcohol. The reaction mixture is cooled to room temperature, and then the solvent is evaporated under reduced pressure. The residue is treated 4,0 N. water solution of KOH and extracted with dichloromethane. The organic layer is dried (MgSO4) and evaporated. The crude product (3) was purified using preparative thin-layer chromatography (TLC) or flash chromatography on silica gel using mixtures of dichloromethane/methanol (95:5) as eluent. The structure of the final product confirmed using LC/MS and/or NMR. Relevant to the present invention compounds of Examples 23-25,48 and 76-80, which are presented in the table below, the receive method a-1.

Procedure a-2: One equivalent dichloride (1) and 2.2 equivalent M-NH210 h refluxed at 150°with a suitable amount of n-butanol. The reaction mixture is allowed to cool to room temperature and the formed precipitate of (4) is filtered off and successively washed the t isopropyl alcohol, 4,0 N. a solution of KOH, H2O and hexane, and then dried. The crude product (4) purify using preparative TLC or flash chromatography on silica gel using mixtures of dichloromethane/methanol (95:5) as eluent. The structure of the final product confirmed using LC/MS and/or NMR. Relevant to the present invention compounds of Examples 26-33 and 75, which are presented in the table below, the receive method a-2.

Procedure a-3: One equivalent dichloride (1) and one equivalent of M-NH2suspended in DME (0.3 M) and add water to form a solution. The reaction mixture for 48 h, heated at 65°C. After cooling to room temperature the precipitate is filtered off and washed with DME with obtaining an intermediate product (2), the structure of which is confirmed using LC/MS and NMR. In some cases, the intermediate product (2) further purified using preparative TLC or washed with other solvents. The suspension (2) (1 EQ.), carbinol (3) (3 EQ.) and 18-crown-6 (10 mol.%) in toluene (0.3 M) stirred for 10 min at room temperature. Then add KOH (3 EQ.) and the reaction mixture for 24 h and heated at 80°C. After cooling to room temperature, added water and the mixture is vigorously stirred until the formation of the suspension. The suspension is filtered and about what to see and receive the desired product (4). In some Examples, additional purification of the final products using preparative TLC and/or washing other solvents. The final products are characterized using LC/MS and NMR spectroscopy. The structure of the final product confirmed using LC/MS and/or NMR. Relevant to the present invention compounds of Examples 34-47,49 74 and 81-82D, which are presented in the table below, get on methodology a-3.

Compounds that get similar methods a-1, a-2 or a-3

*All compounds listed in this table can be characterized using HPLC mass spectroscopy with elektrorazpredelenie positive ions (HPLC ER-MS conditions are listed below). In addition, some compounds were characterized by TLC on plates with silica gel and the above values Rf and solvents. For other examples presented in this table shows the retention times for HPLC;aHPLC-mass spectroscopy with elektrorazpredelenie (HPLC R-MS), make use of the device for HPLC Hewlett-Packard 1100, equipped with a Quaternary pump, a detector with variable DL is Noah waves, column YMC Pro C18 2.0 mm × 23 mm and a mass spectrometer with an ion trap and ionization elektrorazpredelenie Finnigan LCQ. For HPLC use elution in gradient mode from 90% a to 95% b for 4 min. Buffer solution And consists of 98% water, 2% acetonitrile and 0.02% TFA (triperoxonane acid). The buffer solution includes 98% acetonitrile, 2% water and 0,018% TFA. Spectra were scanned in the range 140-1200 at. unit mass with a variable time of ions in accordance with the number of ions in the source.bIn addition to the HPLC experiment ER-MS analyzed by HPLC with detection by UV peak under the following conditions: column 50×4.6 mm YMC CombiScreen® C18 using linear gradient elution mode from 10 to 100% acetonitrile in water with addition of 0.1% triperoxonane acid with a speed of 3 ml/min for 5 min, UV detection at 254 nm.cThe product was then purified by HPLC with a reversed phase C18 column using gradient elution mode with a mixture of water/acetonitrile with the addition of triperoxonane acid, so that upon evaporation of the pure product was triptorelin.dAs shown, in stage 2 methodology a-1 instead of the amine using 4-pyridinemethanol;eObtaining 5-amino-2,3-dihydrobenzofuran see Mitchell, H., Leblanc, Y. J. Org. Chem. 1994, 59, 682 687.fA link that describes the obtaining of you know what about the intermediate alcohol with protective tert-butyldimethylsilyl group (TBS): Parsons, A. F., Pettifer, R. M. J. Chem. Soc. Perkin Trans. 1,1998, 651.

The removal of the protective group from the

carried out as follows:

At room temperature to a solution of the alcohol protecting group in THF (0,05 M) was added three equivalents of 1.0 M solution of tetrabutylammonium in THF.

The reaction mixture was stirred for 1 h at room temperature, and then the reaction is stopped with water and extracted with EtOAc.

Examples 83-92: Getting isoquinolines by the method In-1

Procedure b-1: Dibromophenol (5, 29 mg, 0.1 mmol)obtained in Example 1, stage 1, and M-NH2(0.2 mmol) of 36 h heated at 90°With 1 ml of n-butanol in a bottle with a volume of 8 ml of the Reaction mixture is cooled to room temperature, and then the solvent is evaporated under reduced pressure. Into a vial was added 4-mercaptopyridine (23 mg, 0.2 mmol) and cesium carbonate (67 mg, 0.2 mmol). The mixture is heated 1 h at 180°and allow it to cool to room temperature. Into a vial was added methanol (2 ml) and the mixture 10 min, treated with ultrasound and filtered. A methanol solution of the reaction mixture is collected and evaporated under reduced pressure. The formation of the product is confirmed using LC/MS. Relevant to the present invention compounds of Examples 83-92, which are presented in the table below, get methods To-1.

Compounds that get by the method In-1

*HPLC mass spectroscopy with elektrorazpredelenie (HPLC R-MS), make use of the device for HPLC Hewlett-Packard 1100, equipped with a Quaternary pump, a detector with variable wavelength, column YMC Pro C18 2.0 mm × 23 mm and a mass spectrometer with an ion trap and ionization elektrorazpredelenie Finnigan LCQ. For HPLC use elution in gradient mode from 90% a to 95% b for 4 min. Buffer solution And consists of 98% water, 2% acetonitrile and 0.02% TFA. The buffer solution includes 98% acetonitrile, 2% water and 0,018% TFA. Spectra were scanned in the range 140-1200 at. unit mass with a variable time of ions in accordance with the number of ions in the source.

Examples 93-105: Getting new phthalazinone compounds of the present invention, similar methods of synthesis

For obtaining of the present invention of new phthalimide compounds 93-105 from 1,4-Dichlorotoluene (methodology of its receipt, see patent WO 98/35958 issued by Novartis 11.02.98), and not from dichloropropionic heterocyclic pyridazines together with suitable bicyclic and is substituted aniline methods a-1 And a-2 listed in the table.

New phthalazine that get in methods a-1 And a-2

*HPLC mass spectroscopy with elektrorazpredelenie (HPLC R-MS), make use of the device for HPLC Hewlett-Packard 1100, equipped with a Quaternary pump, a detector with variable wavelength, column YMC Pro C18 2.0 mm × 23 mm and a mass spectrometer with an ion trap and ionization elektrorazpredelenie Finnigan LCQ. For HPLC use elution in gradient mode from 90% a to 95% b for 4 min. Buffer solution And consists of 98% water, 2% acetonitrile and 0.02% TFA. The buffer solution includes 98% acetonitrile, 2% water and 0,018% TFA. Spectra were scanned in the range 140-1200 at. unit mass with a variable time of ions in accordance with the number of ions in the source.

Examples 106-114: obtain the salts of the compounds of Example 14

The product obtained in Example 14 (1.50 g, 3,66 mmol), stirred as a suspension in methanol (20 ml) and rapidly added dropwise a solution of hydrate toluensulfonate acid (0,701 g, to 3.67 mmol) in methanol (5 ml + 5 ml rinse). All materials dissolved within 5 min with the formation of a yellow solution. Add anhydrous ether (30 ml) and stirring is continued for another 5 minutes, until they begin to form a solid residue. The mixture for 45 min at AC is shivani cooled in a bath of ice water and then solid the desired substance (example 104) is collected by filtration, washed with ether and dried at 55°in a vacuum drying Cabinet until analysis using NMR does not indicate the absence of solvents (1.5 h). Other compounds have a similar way using different acids instead toluensulfonate acid. Scaling and the use of smaller amounts of methanol in the first stage usually leads to more rapid precipitation of salts and to promote crystallization of the corresponding salts instead of ether use different solvents in accordance with the instructions in the table. In some cases, first remove the methanol by evaporation in a vacuum. For the final drying, depending on the quality of the material and the specific acid used should be from 1.5 h to several days.

The salts of compounds of Example 14

*Secrete salt, contains two molecules model HC1, not salt composition of 1:1. This happens even if you use less than 2 equivalents of acid.

Biological methods and data from studies in vitro

Analysis RDK: Domain of cytosolic kinase RDK-kinase Express in cells Sf9 insect in the form of a fusion protein 6His. The fusion protein domain RDK-kinase purified on chelate column Ni++. Tablets with 96 holes for enzyme immunosorbent analysis cover 5 μg poly(Glu;Tyr1) (Sigma Chemical Co., St Louis, MO) in 100 μl of buffer rastv the RA HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic) (20 mm HEPES, pH 7,5,150 mm NaCl, With 0.02% Thimerosal) at 4° and incubated overnight. Before using the tablets is washed with HEPES, NaCl buffer solution and tablets are blocking with 1% bovine serum albumin, 0.1% of Tween 20 in HEPES, NaCl buffer solution.

The compounds are subjected to serial dilution in 100% DMSO from 4 mm to 0.12 mm using a semi-log diagram cultivation. These advanced breeding 20 times diluted with water to give solutions of the compounds in 5% DMSO. After placing it in a hole 85 μl of buffer solution for analysis (20 mm HEPES, pH 7,5,100 mm KCl, 10 mm MgCl2, 3 mm MnCl2, 0.05% glycerol, 0.005% of Triton X-100,1 mm mercaptoethanol with or without added 3,3 µm ATP), add 5 μl of the diluted compounds, so that the end of the analyzed volume is 100 μl. The final concentration range from 10 μm to 0.3 nm 0.25% DMSO. The analysis initiated by adding 10 μl (3 ng) domain RDK-kinase.

Samples incubated with the test compound or only the solution with gentle stirring for 60 minutes, the Wells are washed and perform the test phosphotyrosine (CFT) using antiphosphotyrosine (anti-CFT), mAb clone 4G10 (Upstate Biotechnology, Lake Placid, NY). Complexes CFT/anti-CFT detected using a conjugate of horseradish peroxidase with antibody to mouse IgG (Amersham International plc, Buckindhamshire, England). Phosphotyrosine number is also determined by incubation with 100 μl of a solution of 3,3',5,5'-tetramethylbenzidine (Kirkegaard and Perry, TMB Microwell Component 1 peroxidase substrate). The color development is stopped by adding 100 µl of 1% of the stopping solution-based HCI (Kirkegaard and Perry, TMB Component 1 stop solution).

The optical density determined spektrofotometrichesky at 450 nm using a reader for tablet with 96 holes, SpectraMax 250 (Molecular Devices). Of all values of OD (optical density) subtract background values OD (without ATP in the sample) and the inhibition percentage calculated according to equation:

Inhibition, %={[OP(control solution) OP(with the addition of compound)] × 100}/[ OP(control solution) OP (without addition of ATP)].

The values of the IC50determined using the method of least squares using the dependence of the concentration of the compound on the inhibition percentage. Compounds that according to this analysis have values IC50≤ 100 nm, include compounds of Examples 1, 2, 4, 6, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19, 20, 22, 23, 24, 34, 37, 38, 39, 40, 42, 43, 44, 47, 49, 51, 52, 53, 54, 56, 57, 59, 60, 62, 63, 65, 66, 68, 69, 70, 71, 72, 73, 74, 75, 78, 82V, S, 82D, 85, 88, 93, 96, 97, 98, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111 and 112. Compounds that have values IC50equal to from 100 nm to 1000 nm, include compounds of Examples 3, 5, 7, 21, 27, 28, 35, 36, 45, 46, 48, 50, 55, 58, 61, 64, 67, 76, 79, A, 89, 95, 99 and 100. Compounds for which the measured values IC50> 1000 nm, include compounds exampl is 26, 29, 30, 31, 32, 33, 41, 77, 80, 81 and 94. The number of Examples that are not included in this list correspond to the compounds for which we can assume that they are inactive and have values IC50in excess of 1 micron.

The study of the cellular mechanism of inhibition of Phosphorylation ZTZ RDK:

The NIH3T3 cells expressing polnocny receptor RDK, grown in DMEM (modified by way of Dulbecco environment Needle) (Life Technology, Inc., Grand Island, NY), to which is added 10% serum of newborn calves, little glucose, 25 mmol/l sodium pyruvate, piridoksingidrohlorid and 0.2 mg/ml G418 (Life Technology, Inc., Grand Island, NY). Cells stored at 37°in covered call gene-1 vials Kzt75 (Becton Dickinson Labware, Bedford, MA) in a humidified atmosphere containing 5% CO2.

Fifteen thousand cells are placed in each well coated with collagen-1 tablets containing 96 wells, the culture medium DMEM. After six hours, the wells are washed and the medium replaced with DMEM without serum. After culturing overnight to transfer cells into rest Wednesday, replace with a physiological solution with a phosphate buffer solution of Dulbecco (Life Technology, Inc., Grand Island, NY)containing 0.1% bovine albumin (Sigma Chemical Co., St Louis, MO). After addition to the cells of the studied compounds at various concentrations (0-300 nm) in solution with the final concentration of DMSO is 1%, the cells 30 mi is incubated at room temperature. The cells are then at room temperature for 10 min, treated with VEGF (30 ng/ml). After stimulation with VEGF buffer solution were removed and the cells for 30 min at 4°subjected to lysis by adding 150 µl of extraction buffer (50 mm Tris [Tris(hydroxymethylamino)methane], 7,8, to which was added 10% glycerol, 50 mm BGP (beta glycerolphosphate), 2 mm add (ethylenediaminetetraacetic acid), 10 mm NaF, 0.5 mm NaVO4and 0.3% TX-100).

To assess the phosphorylation of the receptor 100 μl of each lysate of cells added to the wells for enzyme immunosorbent analysis, pre-coated with 300 ng of antibody C20 (Santa Cruz Biotechnology, Inc., Santa Cruz, CA). After 60 min incubation tablet washed and perform the test phosphotyrosine for the associated RDK using anti-phosphotyrosine mAb clone 4G10 (Upstate Biotechnology, Lake Placid, NY). The tablet is washed and the wells incubated with a conjugate of horseradish peroxidase with antibody to mouse IgG (Amersham International plc, Buckindhamshire, England). The wells are washed and quantitative determination of phosphotyrosine carried out by adding to each well 100 μl of 3,3',5,5'-tetramethylbenzidine (Kirkegaard and Perry, TMB Microwell Component 1 peroxidase substrate). The color development is stopped by adding 100 µl of 1% of the stopping solution-based HCI (Kirkegaard and Perry, TMB Component 1 stop solution).

Optically the density determine spektrofotometrichesky at 450 nm using a reader for tablet with 96 wells (SpectraMax 250, Molecular Devices). Of all values of OD (optical density) subtract background values OD (without VEGF in the sample) and the inhibition percentage calculated according to equation:

Inhibition, %={[OP(control solution of VEGF) OP(with the addition of the compounds)] × 100}/[ OP(control solution of VEGF) OP (without addition of VEGF)].

The values of the IC50for some typical materials is determined using the method of least squares using the dependence of the concentration of compounds on the inhibition percentage. Compounds that according to this analysis have values IC50≤20 nm, include compounds of Examples 2, 6, 10, 11, 14, 23, 96, 101, 102, 103, 104, 105. Compounds that have values IC50equal to from 20 nm to 50 nm, include compounds of Examples 1, 4, 8, 9, 12, 13, 17, 24, 93, 98. Compounds that have values IC50equal to from 50 nm to 400 nm, include compounds of Examples 97, 99 and 100.

Model of angiogenesis in Matrigel®:

Preparation of macromolecular complexes of enzymes that form pores in the cell membrane Matrigel and phase in vivo:

Matrigel® (Collaborative Biomedical Products, Bedford, MA) is an extract of basement membrane tumor mice, composed primarily of laminin, collagen IV and heparansulfate. It is supplied as a sterile liquid at 4°C, but at 37°quickly Brazul solid gel.

Liquid Matrigel at 4°mixed with tumor cells of human SK-MEL2, which are subjected to transfection with a plasmid containing the gene of the mouse VEGF with breeding marker. Tumor cells grown in vitro with artificial selection, and cells are mixed with a cold liquid Matrigel at a ratio of 2×1060.5 ml With needle No. 25 0.5 ml implanted subcutaneously near the midline of the abdomen. The compounds dosed in the form of solutions in ethanol/Cremaphor EL/saline(12,5%/12,5%/75%) on 30,100 and 300 mg/kg oral once per day starting from the day of implantation. Mice killed after 12 days after implantation and Matrigel pellets are removed for determination of hemoglobin.

Determination of hemoglobin: Granules Matrigel at 4°put in 4 volumes (wt./about.) buffer solution for lysis (20 mm Tris, 1 mm EGTC (ethylene glycol-tetraoxane acid), 1 mm add, 1% Triton X-100 [EM Science, Gibbstown, N.J.], and the complete mixture containing add protease inhibitor [Mannheim, Germany]) and homogenized at 4°s Homogenizate incubated on ice for 30 min with shaking and centrifuged at 14K × g for 30 min at 4°C. the Supernatant is transferred into chilled tubes for microcentrifuge and to determination of hemoglobin stored at 4°C.

Mouse hemoglobin (Sigma Chemical Co., St Louis, MO) suspended in the treated in auto the lava water (BioWhittaker, Inc., Walkersville, MD) in an amount of 5 mg/ml. Receive a calibration curve for the range from 500 μg/ml to 30 μg/ml in buffer solution for lysis (see above). The number corresponding to the calibration curve and sample 5 µl lysate is placed in each of two wells of a standard plate with 96 holes, made of polystyrene. Using set for analysis of hemoglobin in plasma Sigma Plasma Hemoglobin Kit (Sigma Chemical Co., St Louis, MO) substrate TMB restore at room temperature in 50 ml of acetic acid. To each well at room temperature add 100 ál of the substrate, and then 100 μl of a solution of hydrogen peroxide. Tablet incubated 10 min at room temperature.

The optical density determined spektrofotometrichesky at 600 nm using a reader for tablet with 96 holes SpectraMax 250 Microplate Spectrophotometer System (Molecular Devices, Sunnyvale, CA). Of all the values of optical density subtract background values for the buffer solution for lysis.

The full content of hemoglobin in the sample is calculated by the following equation:

The full content of hemoglobin=(Volume of sample lysate) × (hemoglobin concentration).

From each value of the hemoglobin content in the Matrigel sample with cells subtract the average full the hemoglobin content in the Matrigel samples without cells. The inhibition percentage calculated after the ith equation:

The inhibition %=[(Average full content of hemoglobin in tumor lysates treated with drug) × 100]/(average full the hemoglobin content in the lysates of untreated tumors).

The compound of Example 8 when conducting this analysis reveals considerable activity at doses of 100 and 300 mg/kg orally once a day with inhibition > 60% of the total hemoglobin content in the Matrigel samples taken from infected animals compared to control animals, which impose only solution. Other typical materials in this model is not investigated.

From consideration of this description or disclosed here, the practical implementation of the present invention to a person skilled in the technical field will be obvious other embodiments of the present invention. Assume that the present description and examples be considered only as illustrative, and the true scope and essence of the present invention is indicated in the following claims.

1. The compound having the General structural formula

(I)

where R1and R2together form a bridge containing two fragments of the T2and one piece T3specified bridge in conjunction with the cycle to which it is attached, forms a bicyclic structure

img src="https://img.russianpatents.com/819/8192211-s.jpg" height="31" width="118" >

where each T2independently denotes N, CH or CG1;

T3means S, O, CR4G1C(R4)2or NR3;

and where G1means the Deputy, is independently selected from the group including

-N(R6)2;

-NR3COR6;

halogen;

alkyl;

cycloalkyl;

lower alkenyl;

lower cycloalkenyl;

halogen-substituted alkyl;

aminosilanes alkyl;

N-(nishiuchi)aminosilanes alkyl;

N,N-di-(nishiuchi)aminosilanes alkyl;

N-(nissioner)aminosilanes alkyl;

replacement alkyl;

tiananamen alkyl;

carboxyterminal alkyl;

missiologically alkyl;

phenylmethylsulfonyl alkyl;

halogensubstituted alkylamino-;

aminosilane alkylamino-;

N-(nishiuchi)aminosilane alkylamino-;

N,N-di-(nishiuchi)aminosilane alkylamino-;

N-(nissioner)aminosilane alkylamino-;

replacement of alkylamino-;

lanzamiento alkylamino-;

carboxyterminal alkylamino-;

sessioncontroller alkylamino-;

phenyldichloroarsine bersamaan alkylamino;

-OR6;

-SR6;

-S(O)R6;

-S(O)2R6;

halogenated lower alkoxy;

halogenated lower alkylthio;

halogenated lower alkylsulfonyl;

-OCOR6;

-COR6;

-CO2R6;

-CON(R6)2;

-CH2OR3;

-NO2;

-CN;

amedieval;

guanidine;

alphagroup;

-In(OH)2;

optionally substituted aryl represents an aromatic radical with 6 to 14 carbon atoms, including phenyl, naphthyl, fluorenyl or phenanthrene;

optionally substituted heteroaryl, which represents a monocyclic or condensed bicyclic aromatic system containing in total from 5 to 10 atoms, 1-4 of which are heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, with heteroaryl preferably represents a monocyclic system containing in the amount of 5 or 6 atoms, 1-3 of which are heteroatoms;

optionally substituted saturated heterocyclic fragment that represents a 5-7 membered heterocyclic system with 1-3 heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, which is may be unsaturated or fully or partially saturated, including pyridyl, pyrimidyl, furanyl, imidazolyl, isoquinoline,pyridazine;

optionally substituted saturated heteroseksualci;

optionally substituted partially unsaturated heterocyclic fragment that represents a 5-7 membered heterocyclic system with 1-3 heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, which may be unsaturated or fully or partially saturated, including pyridyl, pyrimidyl, furanyl, imidazolyl, isoquinoline, pyridazine;

optionally substituted partially unsaturated heteroseksualci;

-OCO2R3;

optionally substituted heteroaromatic;

optionally substituted heteroaromatics;

-S(O)p(optional substituted heteroaryl, which represents a monocyclic or condensed bicyclic aromatic system containing in total from 5 to 10 atoms, 1-4 of which are heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, with heteroaryl preferably represents a monocyclic system containing in the amount of 5 or 6 atoms, 1-3 of which are heteroatoms);

optionally substituted heteroaromatics;

-S(O)p(optional substituted heteroaromatic);

CH is;

-OCON(R6)2;

-NR3CO2R6; and

-NR3CON(R6)2;

R3means H or lower alkyl;

R6independently selected from the group including

N;

alkyl;

cycloalkyl;

optionally substituted aryl represents an aromatic radical with 6 to 14 carbon atoms, including phenyl, naphthyl, fluorenyl or phenanthrene ; and

optionally substituted allyssia;

lower alkyl-N(R3)2; and

lower alkyl-HE;

R4denotes H, halogen or lower alkyl;

p is 0,1 or 2;

X is selected from the group comprising O, S and NR3;

Y is selected from the group including

lowest alkylen;

-CH2-O-;

-CH2-S-;

-CH2-NH-;

-O-;

-S-;

-NH-;

-(CR42)n-S(O)p-(5-membered heteroaryl containing 1-3 heteroatoms selected from the group comprising O, S, N, and the number of atoms N is 0-3 and the number of each of the atoms O and S is 0-1)-(CR42)s-;

-(CR42)n-C(G2)(R4)-(CR42)s-;

where n and s are independently 0 or an integer 1, 2; and

G2selected from the group comprising-CN, -CO2 R3; -CON(R6)2;

-O-CH2-;

-S(O)-;

-S(O)2-;

-SCH2-;

-S(O)CH2-;

-S(O)2CH2-;

-CH2S(O)-; and

-CH2S(O)2-;

Z denotes N or CR4:

q is 0, 1 or 2;

G3means monovalent or bivalent fragment selected from the group including:

lower alkyl;

-NR3COR6;

carboxyterminal alkyl;

lower alkoxycarbonylmethyl alkyl;

-OR6;

-SR6;

-S(O)R6;

-S(O)2R6;

-OCOR6;

-COR6;

-CO2R6;

-CH2OR3;

-CO(R6)2;

-S(O)2N(R6)2

-NO2;

-CN;

optionally substituted aryl represents an aromatic radical with 6 to 14 carbon atoms, including phenyl, naphthyl, fluorenyl or phenanthrene;

optionally substituted heteroaryl, which represents a monocyclic or condensed bicyclic aromatic system containing in total from 5 to 10 atoms, 1-4 of which are heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, with heteroaryl preferably represents the FDS is th monocyclic system, containing in the amount of 5 or 6 atoms, 1-3 of which are heteroatoms;

optionally substituted saturated heterocyclic fragment that represents a 5-7 membered heterocyclic system with 1-3 heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, which may be unsaturated or fully or partially saturated, including pyridyl, pyrimidyl, furanyl, imidazolyl, isoquinoline, pyridazine;

optionally substituted partially unsaturated heterocyclic fragment that represents a 5-7 membered heterocyclic system with 1-3 heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, which may be unsaturated or fully or partially saturated, including pyridyl, pyrimidyl, furanyl, imidazolyl, isoquinoline, pyridazine;

optionally substituted heteroaromatic;

optionally substituted heteroaromatics;

S(O)p(optional substituted heteroaryl, which represents a monocyclic or condensed bicyclic aromatic system containing in total from 5 to 10 atoms, 1-4 of which are heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, with heteroaryl preferably represents a monocyclic system containing the sum of 5 and and 6 atoms, 1-3 of which are heteroatoms);

optionally substituted heteroaromatics;

S(O)p(optional substituted heteroaromatic);

-OCON(R6)2;

-NR3CO2R6;

-NR3CON(R6)2and

bivalent bridge of structure T2=T2-T3where each T2independently denotes N, CH or CG3and T3means S, O, CR4G3'(R4)2or NR3; where G3'means any of the above defined fragments G3which are monovalent; and a terminal group T2the bridge is associated with L, and T3linked to D, forming a 5-membered condensed cycle;

A and D independently denote N or CH;

B and E independently denote N or CH;

L is N or CH; and if

a) the total number of atoms N in a loop containing a, b, D, E, and L is 0, 1, 2 or 3; and

(b) if L is CH, and q=0 or any G3means monovalent Deputy, then at least one of a and D is an N atom; and

c) if L is CH and G3means a bivalent bridge of structure T2=T2-T3then a, b, D, and E. also mean SN;

J indicates cycle selected from the group including

aryl represents an aromatic radical with 614 carbon atoms, including phenyl, naphthyl, fluorenyl or phenanthrene;

pyridyl and

cycloalkyl;

q' represents the number of substituents G4in cycle J and equal to 0, 1, 2, 3, 4 or 5, and

G4means monovalent or bivalent fragment selected from the group including

-N(R6)2

-NR3COR6;

halogen;

alkyl;

cycloalkyl;

lower alkenyl;

lower cycloalkenyl;

halogen-substituted alkyl;

aminosilanes alkyl;

N-(nishiuchi)aminosilanes alkyl;

N,N-di-(nishiuchi)aminosilanes alkyl;

N-(nissioner)aminosilanes alkyl;

replacement alkyl;

tiananamen alkyl;

carboxyterminal alkyl;

missiologically alkyl;

phenylmethylsulfonyl alkyl;

halogensubstituted alkylamino-;

aminosilane alkylamino-;

N-(nishiuchi)aminosilane alkylamino-;

N,N-di-(nishiuchi)aminosilane alkylamino-;

N-(nissioner)aminosilane alkylamino-;

replacement of alkylamino-;

lanzamiento alkylamino-;

carboxyterminal alkylamino-;

sessioncontroller alcelam the but;

phenylmethylsulfonyl alkylamino;

-OR6;

-SR6;

-S(O)R6;

-S(O)2R6;

halogenated lower alkoxy;

halogenated lower alkylthio;

halogenated lower alkylsulfonyl;

-OCOR6;

-COR6;

-CO2R6;

-CON(R6)2

-CH2OR3;

-NO2;

-CN;

amedieval;

guanidine;

alphagroup;

-In(OH)2;

optionally substituted aryl represents an aromatic radical with 6 to 14 carbon atoms, including phenyl, naphthyl, fluorenyl or phenanthrene;

optionally substituted heteroaryl, which represents a monocyclic or condensed bicyclic aromatic system containing in total from 5 to 10 atoms, 1-4 of which are heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, with heteroaryl preferably represents a monocyclic system containing in the amount of 5 or 6 atoms, 1-3 of which are heteroatoms;

optionally substituted saturated heterocyclic fragment that represents a 5-7 membered heterocyclic system with 1 to 3 heteroatom is mi, selected from the group comprising nitrogen, oxygen and sulfur, which may be unsaturated or fully or partially saturated, including pyridyl, pyrimidyl, furanyl, imidazolyl, isoquinoline, pyridazine;

optionally substituted partially unsaturated heterocyclic fragment that represents a 5-7 membered heterocyclic system with 1-3 heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, which may be unsaturated or fully or partially saturated, including pyridyl, pyrimidyl, furanyl, imidazolyl, isoquinoline, pyridazine;

-OCO2R3;

optionally substituted heteroaromatic;

optionally substituted heteroaromatics;

-S(O)p(optional substituted heteroaryl, which represents a monocyclic or condensed bicyclic aromatic system containing in total from 5 to 10 atoms, 1-4 of which are heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, with heteroaryl preferably represents a monocyclic system containing in the amount of 5 or 6 atoms, 1-3 of which are heteroatoms);

optionally substituted heteroaromatics;

-S(O)p(optional substituted heteroaromatic);

-CHO;

-OCN(R 6)2;

-NR3CO2R6;

-NR3CON(R6)2and

forming a condensed cycle divalent bridges attached to adjacent positions of the cycle J and connecting these provisions, moreover, these bridges have the structure

a)

where each T2independently denotes N, CH or CG4';

T3means S, O, CR4G4'C(R4)2or NR3; where

G4'means any of the above defined fragments G4which are monovalent; and

the binding of cycle J occurs on the terminal atoms T2and T3;

b)

where each T2independently denotes N, CH or CG4'; where G4' means any of the above defined fragments G4which are monovalent; and

provided that not more than two bridging atoms T2can be a

N;

and linking to cycle J occurs on the terminal atoms T2; and

C)

where all T4T5and T6independently denote O, S, CR4G4', C(R4)2or NR3; where G4' means any defined above is Rahmanov G 4which are monovalent; and

the binding of cycle J occurs on the terminal atoms T4or T5;

if

i) if T4means O, S or NR3then the other T4mean CR4G4' or C(R4)2;

ii) a bridge comprising atoms T5and T6may contain not more than two heteroatoms O, S or N; and

iii) in the bridge, including the atoms T5and T6if one group T5and one group T6represent the atoms O, or two groups, T6represent the atoms Of specified atoms shared by at least one carbon atom;

if G4means alkyl group, located in the loop J near the bridge -(CR42)p-, and X is NR3where R3means alkyl substituent, G4and alkyl substituent R3if X can be connected to each other to form a bridge of the structure -(CH2)p'-where R' is 2, 3 or 4, provided that the sum of p and p' is 2, 3 or 4, which leads to the formation of 5-, 6 - or 7-membered nitrogen cycle;

and with the additional terms, namely, that G1, G2, G3and G4if two groups of R3or R6mean alkyl and are in the same N atom they may the be associated with communication, O, S or NR3with the formation of N-containing heterocycle with 5 to 7 atoms in the cycle;

if aryl, heteroaryl or heterocyclic ring optionally contains substituents, the ring may be up to 5 substituents that are independently selected from the group consisting of amino, mono(lower alkyl)substituted amino, di(lower alkyl)substituted amino, (lower alkanoyl)amino, halogen, lower alkyl, halogenated lower alkyl, hydroxyl, lower alkoxyl, lower alkylthio, halogenated lower alkoxy, halogenated lower alkylthio, lower alkanoyloxy, -CO2R3, -CHO, -CH2OR3, -OCO2R3, -CON(R6)2, -OCON(R6)2, -NR3CON(R6)2, nitro-, amedieval, guanidine, mercapto, sulfo and cyano; and

if there is any alkyl group is attached to O, S or N and contains hydroxyl Deputy, the hydroxyl Deputy separated from O, S or N, attached to an alkyl group, at least two carbon atoms;

or its pharmaceutically acceptable salt.

2. Connection on p. 1, wherein R1and R2together form a bridge containing two fragments of the T2and one piece T3and this bridge together with the cycle to which it is attached, forms biciklizes the structure

where each T2independently denotes N, CH or CG1;

T3means S, O, CH2or NR3;

provided that, if T3means O or S, at least one T2means or CG CH1.

3. The pharmaceutical composition inhibiting angiogenesis activity, including a connection on p. 1 and a pharmaceutically acceptable carrier.

4. A method of treating a mammal, in which there is a condition characterized by abnormal processes of angiogenesis or the occurrence of high permeability, including the introduction of a given mammal, the number of connections on p. 1, which is effective for the treatment of this condition.

5. The method according to p. 4, wherein the specified condition is a tumor growth, retinopathy, including diabetic retinopathy, ischemic blockage of the veins of the retina, retinopathy by prematurity and age-related macular degeneration; rheumatoid arthritis; psoriasis; or bullous disease accompanied subepidermal blistering, including bullous pemphigoid, erythema multiforme, and dermatitis herpetiformis.

6. The compound having the General structural formula

(I)

where R1and R2

i) ezavisimo mean H or lower alkyl;

ii) together form a bridge of the structure

in which the binding is established through the terminal carbon atoms;

iii) together form a bridge of the structure

in which the binding is established through the terminal carbon atoms;

together form a bridge of the structure

where one or two fragments of the T1cycle mean N, and the others mean or CG CH1and the binding is established through the terminal carbon atoms; or v) together form a bridge containing two fragments of the T2and one piece T3and this bridge together with the cycle to which it is attached, forms a bicyclic structure

where each T2independently denotes N, CH or CG1; and

T3means S, O, CR4G1C(R4)2or NR3;

and where m is 0 or an integer of 1 to 4; and

G1means the Deputy, is independently selected from the group including

-N(R6)2;

-NR3COR6;

halogen;

alkyl;

cycloalkyl;

lower alkenyl;

lower cycloalkenyl;

halogen-substituted alkyl;

aminosilanes alkyl;

N-(nishiuchi)aminosilanes alkyl;

N,N-di-(nishiuchi)aminosilanes alkyl;

N-(nissioner)aminosilanes alkyl;

replacement alkyl;

tiananamen alkyl;

carboxyterminal alkyl;

missiologically alkyl;

phenylmethylsulfonyl alkyl;

halogensubstituted alkylamino-;

aminosilane alkylamino-;

N-(nishiuchi)aminosilane alkylamino-;

N,N-di-(nishiuchi)aminosilane alkylamino-;

N-(nissioner)aminosilane alkylamino-;

replacement of alkylamino-;

lanzamiento alkylamino-;

carboxyterminal alkylamino-;

sessioncontroller alkylamino-;

phenylmethylsulfonyl alkylamino;

-OR6;

-SR6;

-S(O)R6;

-S(O)2R6;

halogenated lower alkoxy;

halogenated lower alkylthio;

halogenated lower alkylsulfonyl;

-OCOR6;

-COR6;

-CO2R6;

-CON(R6)2;

-CH2OR3;

-NO2;

-CN;

amedieval;

alphagroup;

-In(OH)2;

optionally substituted aryl represents an aromatic radical with 6 to 14 carbon atoms, including phenyl, naphthyl, fluorenyl or phenanthrene;

optionally substituted heteroaryl, which represents a monocyclic or condensed bicyclic aromatic system containing in total from 5 to 10 atoms, 1-4 of which are heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, with heteroaryl preferably represents a monocyclic system containing in the amount of 5 or 6 atoms, 1-3 of which are heteroatoms;

optionally substituted saturated heterocyclic fragment that represents a 5-7 membered heterocyclic system with 1-3 heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, which may be unsaturated or fully or partially saturated, including pyridyl, pyrimidyl, furanyl, imidazolyl, isoquinoline, pyridazine;

optionally substituted saturated heteroseksualci;

optionally substituted partially unsaturated heterocyclic fragment that represents a 5-7 membered heterocyclic system with 1-3 heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, to the which may be unsaturated or fully or partially saturated, including pyridyl, pyrimidyl, furanyl, imidazolyl, isoquinoline, pyridazine;

optionally substituted partially unsaturated heteroseksualci;

-OCO2R3;

optionally substituted heteroaromatic;

optionally substituted heteroaromatics;

-S(O)p(optional substituted heteroaryl, which represents a monocyclic or condensed bicyclic aromatic system containing in total from 5 to 10 atoms, 1-4 of which are heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, with heteroaryl preferably represents a monocyclic system containing in the amount of 5 or 6 atoms, 1-3 of which are heteroatoms);

optionally substituted heteroaromatics;

-S(O)p(optional substituted heteroaromatic);

-SNO;

-OCON(R6)2;

-NR3CO2R6and

-NR3CON(R6)2

R3means H or lower alkyl;

R6independently selected from the group including

N;

alkyl;

cycloalkyl;

optionally substituted aryl represents an aromatic radical with 6 to 14 carbon atoms, including phenyl, naphthyl, fluorenyl or phenanthrene;

and

optionally substituted allyssia;

lower alkyl-N(R3)2; and

lower alkyl-HE;

R4denotes H, halogen or lower alkyl;

p is 0,1 or 2;

X is selected from the group comprising O, S and NR3;

Y is selected from the group including

lowest alkylen;

-CH2-O-;

-CH2-S-;

-CH2-NH-;

-O-;

-S-;

-NH-;

-(CR42)n-S(O)p-(5-membered heteroaryl)-(CR42)s-;

-(CR42)n-C(G2)(R4)-(CR42)s-;

where n and s are independently 0 or an integer 1 to 2; and

G2selected from the group comprising-CN, -CO2R3; -CON(R6)2and-CH2N(R6)2;

-O-CH2-;

-S(O)-;

-S(O)2-;

-SCH2-;

-S(O)CH2-;

-S(O)2CH2-;

-CH2S(O)-; and

-CH2S(O)2-;

Z denotes N or CR4;

q is 1 or 2;

G3means monovalent or bivalent fragment selected from the group including

lower alkyl;

-NR3COR6;

carboxyterminal alkyl;

lower alkoxycarbonylmethyl alkyl;

-OR6 ;

-SR6;

-S(O)R6;

-S(O)2R6;

-OCOR6;

-COR6;

-CO2R6;

-CH2OR3;

-CON(R6)2;

-S(O)2N(R6)2

-NO2;

-CN;

optionally substituted aryl represents an aromatic radical with 6 to 14 carbon atoms, including phenyl, naphthyl, fluorenyl or phenanthrene;

optionally substituted heteroaryl, which represents a monocyclic or condensed bicyclic aromatic system containing in total from 5 to 10 atoms, 1-4 of which are heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, with heteroaryl preferably represents a monocyclic system containing in the amount of 5 or 6 atoms, 1-3 of which are heteroatoms;

optionally substituted saturated heterocyclic fragment that represents a 5-7 membered heterocyclic system with 1-3 heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, which may be unsaturated or fully or partially saturated, including pyridyl, pyrimidyl, furanyl, imidazolyl, isoquinoline, pyridazine;

optionally substituted partially unsaturated heterocyclic shall ragment, represents a 5-7 membered heterocyclic system with 1-3 heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, which may be unsaturated or fully or partially saturated, including pyridyl, pyrimidyl, furanyl, imidazolyl, isoquinoline, pyridazine;

optionally substituted heteroaromatic;

optionally substituted heteroaromatics:

-S(O)p(optional substituted heteroaryl, which represents a monocyclic or condensed bicyclic aromatic system containing in total from 5 to 10 atoms, 1-4 of which are heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, with heteroaryl preferably represents a monocyclic system containing in the amount of 5 or 6 atoms, 1-3 of which are heteroatoms);

optionally substituted heteroaromatics;

-S(O)p(optional substituted heteroaromatic);

-OCON(R6)2;

-NR3CO2R6;

-NR3CON(R6)2and

bivalent bridge of structure T2=T2-T3where

each T2independently denotes N, CH or CG3'; and T3means S, O, CR4G3', C(R4)2or NR3; where G3' Osnach is no any of the above defined fragments G 3which are monovalent; and

end group T2associated with L, and T3linked to D, forming a 5-membered condensed cycle;

A and D independently denote SN;

B and E independently denote SN;

L is CH; and provided that

formed in the phenyl ring by Deputy G3is specified bivalent bridge of structure T2=T2-T3;

J indicates cycle selected from the group including

aryl represents an aromatic radical with 6 to 14 carbon atoms, including phenyl, naphthyl, fluorenyl or phenanthrene;

pyridyl; and

cycloalkyl;

q' represents the number of substituents G4in cycle J and equal to 0, 1, 2, 3, 4 or 5, and G4means monovalent or bivalent fragment selected from the group including

-N(R6)2;

-NR3COR6;

halogen;

alkyl;

cycloalkyl;

lower alkenyl;

lower cycloalkenyl;

halogen-substituted alkyl;

aminosilanes alkyl;

N-(nishiuchi)aminosilanes alkyl;

N,N-di-(nishiuchi)aminosilanes alkyl;

N-(nissioner)aminosilanes alkyl;

replacement alkyl;

tiananamen alkyl;

carboxysome the military alkyl;

missiologically alkyl;

phenylmethylsulfonyl alkyl;

halogensubstituted alkylamino-;

aminosilane alkylamino-;

N-(nishiuchi)aminosilane alkylamino-;

N,N-di-(nishiuchi)aminosilane alkylamino-;

N-(nissioner)aminosilane alkylamino-;

replacement of alkylamino-;

lanzamiento alkylamino-;

carboxyterminal alkylamino-;

sessioncontroller alkylamino-;

phenylmethylsulfonyl alkylamino;

-OR6;

-SR6;

-S(O)R6;

-S(O)2R6;

halogenated lower alkoxy;

halogenated lower alkylthio;

halogenated lower alkylsulfonyl;

-OCOR6;

-COR6;

-CO2R6;

-CON(R6)2;

-CH2OR3;

-NO2;

-CN;

amedieval;

guanidine;

alphagroup;

-In(OH)2;

optionally substituted aryl represents an aromatic radical with 6 to 14 carbon atoms, including phenyl, naphthyl, fluorenyl or phenanthrene;

optionally substituted heteroaryl, predstavlyalsya monocyclic or condensed bicyclic aromatic system, containing in total from 5 to 10 atoms, 1-4 of which are heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, with heteroaryl preferably represents a monocyclic system containing in the amount of 5 or 6 atoms, 1-3 of which are heteroatoms;

optionally substituted saturated heterocyclic fragment that represents a 5-7 membered heterocyclic system with 1-3 heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, which may be unsaturated or fully or partially saturated, including pyridyl, pyrimidyl, furanyl, imidazolyl, isoquinoline, pyridazine;

optionally substituted partially unsaturated heterocyclic fragment that represents a 5-7 membered heterocyclic system with 1-3 heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, which may be unsaturated or fully or partially saturated, including pyridyl, pyrimidyl, furanyl, imidazolyl, isoquinoline, pyridazine;

-OCO2R3;

optionally substituted heteroaromatic;

optionally substituted heteroaromatics;

-S(O)p(optional substituted heteroaryl, which represents a monocyclic or condensed bicyclic aromatic with the system, containing in total from 5 to 10 atoms, 1-4 of which are heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, with heteroaryl preferably represents a monocyclic system containing in the amount of 5 or 6 atoms, 1-3 of which are heteroatoms);

optionally substituted heteroaromatics;

-S(O)p(optional substituted heteroaromatic);

-SNO;

-OCON(R6)2;

-NR3CO2R6

-NR3CON(R6)2and

forming a condensed cycle divalent bridges attached to adjacent positions of the cycle J and connecting these provisions, moreover, these bridges have the structure

a)

where each T2independently denotes N, CH or CG4';

T3means S, O, CR4G4', C(R4)2or NR3; where G4'means any of the above defined fragments G4which are monovalent; and linking with the cycle J occurs on the terminal atoms T2and T3;

b)

where each T2independently denotes N, CH or CG4'; where G4' means any of the above defined fragments G4that t is Auda monovalent; and

provided that not more than two bridging atoms T2can represent N;

and linking to cycle J occurs on the terminal atoms T2; and

C)

where all T4T5and T6independently denote O, S, CR4G4'C(R4)2or NR3; where G4'means any of the above defined fragments G4which are monovalent; and linking with the cycle J occurs on the terminal atoms T4or T5;

if

i) if T4means O, S or NR3then the other T4mean CR4G4' or C(R4)2;

ii) a bridge comprising atoms T5and T6may contain not more than two heteroatoms O, S or N; and

iii) in the bridge, including the atoms T5and T6if one group T5and one group T6represent the atoms O, or two groups, T6represent the atoms Of specified atoms shared by at least one carbon atom;

if G4means alkyl group, located in the loop J near the bridge -(CR42)p-, and X is NR3where R3means alkyl substituent, G4and alkyl substituent R3if X can be connected to each the other to form a bridge of the structure -(CH 2)p'-where R' is 2, 3 or 4, provided that the sum of p and p' is 2, 3 or 4, which leads to the formation of 5-, 6 - or 7-membered nitrogen cycle;

and with the additional terms, namely, that

in G1, G2, G3and G4if two groups of R3or R6mean alkyl and are in the same N atom they may be linked by communication, O, S or NR3with the formation of N-containing heterocycle with 5 to 7 atoms in the cycle;

if aryl, heteroaryl or heterocyclic ring optionally contains substituents, the ring may be up to 5 substituents that are independently selected from the group consisting of amino, mono(lower alkyl)substituted amino, di(lower alkyl)substituted amino, (lower alkanoyl)amino, halogen, lower alkyl, halogenated lower alkyl, hydroxyl, lower alkoxyl, lower alkylthio, halogenated lower alkoxy, halogenated lower alkylthio, lower alkanoyloxy, -CO2R3, -Cho, -CH2OR3, -OCO2R3, -CON(R6)2, -OCON(R6)2, -NR3CON(R6)2, nitro-, amedieval, guanidine, mercapto, sulfo and cyano; and

if there is any alkyl group is attached to O, S or N and contains hydroxyl Deputy, the hydroxyl Deputy is separated from Oh, S or N, attached to an alkyl group, at least two carbon atoms;

or its pharmaceutically acceptable salt.

7. Connection on p. 6, characterized in that, in a loop containing a, b, D, E, and L and bivalent bridge of structure T2=T2-T3, limit T2mean N and fragment T3the specified bridge means S, O, CR42or NR3.

8. The pharmaceutical composition inhibiting angiogenesis activity, including a connection on p. 6 and a pharmaceutically acceptable carrier.

9. A method of treating a mammal, in which there is a condition characterized by abnormal processes of angiogenesis or the occurrence of high permeability, including the introduction of a given mammal, the number of connections on p. 6, which is effective for the treatment of this condition.

10. The method according to p. 9, characterized in that the said pathological condition is a tumor growth, retinopathy, including diabetic retinopathy, ischemic blockage of the veins of the retina, retinopathy by prematurity and age-related macular degeneration; rheumatoid arthritis; psoriasis or bullous disease accompanied subepidermal blistering, including bullous pemphigoid, erythema multiforme, and dermatitis herpetiformis.

1. The compound having the General structural formula

where R1and R2

(i) independently denote H or lower alkyl;

ii) together form a bridge of the structure

in which the binding is established through the terminal carbon atoms;

iii) together form a bridge of the structure

in which the binding is established through the terminal carbon atoms;

iv) together form a bridge of the structure

where one or two fragments of the T1cycle mean N, and the others mean or CG CH1and the binding is established through the terminal carbon atoms; or v) together form a bridge containing two fragments of the T2and one piece T3and this bridge together with the cycle to which it is attached, forms a bicyclic structure

where each T2independently denotes N, CH or CG1; and

T3means S, O, CR4G1C(R4)2or NR3;

and where

m is 0 or an integer of 1 to 4; and

G1means the Deputy, is independently selected from the group including

-N(R6)2;

-NR3COR6;

halogen;

alkyl;

cycloalkyl;

lower alkenyl;

lower cycloalkenyl;

halogen-substituted alkyl;

aminosilanes alkyl;

N-(nishiuchi)aminosilanes alkyl;

N,N-di-(nishiuchi)aminosilanes alkyl;

N-(nissioner)aminosilanes alkyl;

replacement alkyl;

tiananamen alkyl;

carboxyterminal alkyl;

missiologically alkyl;

phenylmethylsulfonyl alkyl;

halogensubstituted alkylamino-;

aminosilane alkylamino-;

N-(nishiuchi)aminosilane alkylamino-;

N,N-di-(nishiuchi)aminosilane alkylamino-;

N-(nissioner)aminosilane alkylamino-;

replacement of alkylamino-;

lanzamiento alkylamino-;

carboxyterminal alkylamino-;

sessioncontroller alkylamino-;

phenylmethylsulfonyl alkylamino;

-OR6;

-SR6;

-S(O)R6;

-S(O)2R6;

halogenated lower alkoxy;

halogenated lower alkylthio;

halogenated lower alkylsulfonyl;

-OCOR6;

-COR6;

-CO2R6;

-CON(R6)2;

-CH2OR3;

-NO2;

-CN;

amedieval;

guanidine;

alphagroup;

-B(OH)2;

optionally substituted aryl represents an aromatic radical with 6 to 14 carbon atoms, including phenyl, naphthyl, fluorenyl or phenanthrene;

optionally substituted heteroaryl, which represents a monocyclic or condensed bicyclic aromatic system containing in total from 5 to 10 atoms, 1-4 of which are heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, with heteroaryl preferably represents a monocyclic system containing in the amount of 5 or 6 atoms, 1-3 of which are heteroatoms;

optionally substituted saturated heterocyclic fragment that represents a 5-7 membered heterocyclic system with 1-3 heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, which may be unsaturated or fully or partially saturated, including pyridyl, pyrimidyl, furanyl, imidazolyl, isoquinoline, pyridazine;

optionally substituted saturated heteroseksualci;

optionally substituted h is partially unsaturated heterocyclic fragment, represents a 5-7 membered heterocyclic system with 1-3 heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, which may be unsaturated or fully or partially saturated, including pyridyl, pyrimidyl, furanyl, imidazolyl, isoquinoline, pyridazine;

optionally substituted partially unsaturated heteroseksualci;

-OCO2R3;

optionally substituted heteroaromatic;

optionally substituted heteroaromatics;

-S(O)p(optional substituted heteroaryl);

optionally substituted heteroaromatics;

-S(O)p(optional substituted heteroaromatic);

-SNO;

-OCON(R6)2;

-NR3CO2R6and

-NR3CON(R6)2and

R3means H or lower alkyl:

R6independently selected from the group including

N;

alkyl;

cycloalkyl;

optionally substituted aryl represents an aromatic radical with 6 to 14 carbon atoms, including phenyl, naphthyl, fluorenyl or phenanthrene;

and

optionally substituted allyssia;

lower alkyl-N(R3)2; and

lower alkyl-HE;

R4denotes H, halogen or nishiuchi;

p is 0, 1 or 2;

X is selected from the group comprising O, S and NR3;

Y is selected from the group including

lowest alkylen;

-CH2-O-;

-CH2-S-;

-CH2-NH-;

-O-;

-S-;

-NH-;

-(CR42)n-S(O)p-(5-membered heteroaryl, which represents a monocyclic or condensed bicyclic aromatic system containing 1-4 heteroatoms selected from the group comprising nitrogen, oxygen and sulfur)-(CR42)s-;

-(CR42)n-C(G2)(R4)-(CR42)s-;

where n and s are independently 0 or an integer 1 to 2; and

G2selected from the group comprising-CN, -CO2R3; -CON(R6)2and

-CH2N(R6)2;

-O-CH2-;

-S(O)-;

-S(O)2-;

-SCH2-;

-S(O)CH2-;

-S(O)2CH2-;

-CH2S(O)-; and

-CH2S(O)2-;

Z means CR4;

q is 1 or 2;

G3means monovalent or bivalent fragment selected from the group including:

-NR3COR6;

carboxyterminal alkyl;

lower alkoxycarbonylmethyl alkyl;

-OR6 ;

-SR6;

-S(O)R6;

-S(O)2R6;

-OCOR6;

-COR6;

-CO2R6;

-CH2OR3;

-CON(R6)2

-S(O)2N(R6)2;

-NO2;

-CN;

optionally substituted aryl represents an aromatic radical with 6 to 14 carbon atoms, including phenyl, naphthyl, fluorenyl or phenanthrene;

optionally substituted heteroaryl, which represents a monocyclic or condensed bicyclic aromatic system containing in total from 5 to 10 atoms, 1-4 of which are heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, with heteroaryl preferably represents a monocyclic system containing in the amount of 5 or 6 atoms, 1-3 of which are heteroatoms;

optionally substituted saturated heterocyclic fragment that represents a 5-7 membered heterocyclic system with 1-3 heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, which may be unsaturated or fully or partially saturated, including pyridyl, pyrimidyl, furanyl, imidazolyl, isoquinoline, pyridazine;

optionally substituted partially unsaturated heterocycle which ical fragment, represents a 5-7 membered heterocyclic system with 1-3 heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, which may be unsaturated or fully or partially saturated, including pyridyl, pyrimidyl, furanyl, imidazolyl, isoquinoline, pyridazine;

optionally substituted heteroaromatic;

optionally substituted heteroaromatics;

-S(O)p(optional substituted heteroaryl, which represents a monocyclic or condensed bicyclic aromatic system containing in total from 5 to 10 atoms, 1-4 of which are heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, with heteroaryl preferably represents a monocyclic system containing in the amount of 5 or 6 atoms, 1-3 of which are heteroatoms);

optionally substituted heteroaromatics;

-S(O)p(optional substituted heteroaromatic);

-OCON(R6)2;

-NR3CO2R6

-NR3CON(R6)2and

bivalent bridge of structure T2=T2-T3where

each T2independently denotes N, CH or CG3'; and T3means S, O, CR4G3', C(R4)2or NR3; where G3' Osnach is no any of the above defined fragments G 3which are monovalent; and

end group T2associated with L, and T3linked to D, forming a 5-membered condensed cycle;

A and D independently denote N or CH;

B and E independently denote N or CH;

L is N or CH; and provided that

a) the total number of atoms N in a loop containing a, b, D, E, and L is 0, 1, 2 or 3; and

(b) if L is CH and any G3means monovalent Deputy, then at least one of a and D is an N atom; and

c) if L is CH and G3means a bivalent bridge of structure T2=T2-T3then a, b, D, and E. also mean SN;

J indicates cycle selected from the group including

aryl represents an aromatic radical with 6 to 14 carbon atoms, including phenyl, naphthyl, fluorenyl or phenanthrene;

pyridyl; and

cycloalkyl;

q' represents the number of substituents G4in cycle J and equal to 0, 1, 2, 3, 4 or 5, and

G4means monovalent or bivalent fragment selected from the group including

-N(R6)2;

-NR3COR6;

halogen;

alkyl;

cycloalkyl;

lower alkenyl;

lower cycloalkenyl;

halogen-substituted alkyl;

AMINOPHENYL;

N-(nishiuchi)aminosilanes alkyl;

N,N-di-(nishiuchi)aminosilanes alkyl;

N-(nissioner)aminosilanes alkyl;

replacement alkyl;

tiananamen alkyl;

carboxyterminal alkyl;

missiologically alkyl;

phenylmethylsulfonyl alkyl;

halogensubstituted alkylamino-;

aminosilane alkylamino-;

N-(nishiuchi)aminosilane alkylamino-;

N,N-di-(nishiuchi)aminosilane alkylamino-;

N-(nissioner)aminosilane alkylamino-;

replacement of alkylamino-;

lanzamiento alkylamino-;

carboxyterminal alkylamino-;

sessioncontroller alkylamino-;

phenylmethylsulfonyl alkylamino;

-OR6;

-SR6;

-S(O)R6;

-S(Oh)2R6;

halogenated lower alkoxy;

halogenated lower alkylthio;

halogenated lower alkylsulfonyl;

-OCOR6;

-COR6;

-CO2R6;

-CON(R6)2;

-CH2OR3;

-NO2;

-CN;

amedieval;

wandynowo;

alphagroup;

-In(OH)2;

optionally substituted aryl represents an aromatic radical with 6 to 14 carbon atoms, including phenyl, naphthyl, fluorenyl or phenanthrene;

optionally substituted heteroaryl, which represents a monocyclic or condensed bicyclic aromatic system containing in total from 5 to 10 atoms, 1-4 of which are heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, with heteroaryl preferably represents a monocyclic system containing in the amount of 5 or 6 atoms, 1-3 of which are heteroatoms;

optionally substituted saturated heterocyclic fragment that represents a 5-7 membered heterocyclic system with 1-3 heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, which may be unsaturated or fully or partially saturated, including pyridyl, pyrimidyl, furanyl, imidazolyl, isoquinoline, pyridazine;

optionally substituted partially unsaturated heterocyclic fragment that represents a 5-7 membered heterocyclic system with 1-3 heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, which may be unsaturated or fully or partially saturated, the including pyridyl, pyrimidyl, furanyl, imidazolyl, isoquinoline, pyridazine;

-OCO2R3;

optionally substituted heteroaromatic;

optionally substituted heteroaromatics;

-S(Oh)p(optional substituted heteroaryl);

optionally substituted heteroaromatics;

-S(Oh)p(optional substituted heteroaromatic);

-SNO;

-OCON(R6)2;

-NR3CO2R6

-NR3CON(R6)2and

forming a condensed cycle divalent bridges attached to adjacent positions of the cycle J and connecting these provisions, moreover, these bridges have the structure:

a)

where each T2independently denotes N, CH or CG4';

T3means S, O, CR4G4', C(R4)2or NR3; where G4' means any of the above defined fragments G4which are monovalent; and linking with the cycle J occurs on the terminal atoms T2and T3;

b)

where each T2independently denotes N, CH or CG4'; where G4' means any of the above defined fragments G4which are monovalent; and

the ri condition, that not more than two bridging atoms T2can represent N;

and linking to cycle J occurs on the terminal atoms T2; and

C)

where all T4T5and T6independently denote O, S, CR4G4', C(R4)2or NR3; where G4'means any of the above defined fragments G4which are monovalent; and linking with the cycle J occurs on the terminal atoms T4or T5;

if

i) if T4means O, S or NR3then the other T4mean CR4G4'or C(R4)2

ii) a bridge comprising atoms T5and T6may contain not more than two heteroatoms O, S or N; and

iii) in the bridge, including the atoms T5and T6if one group T5and one group T6represent the atoms O, or two groups, T6represent the atoms Of specified atoms shared by at least one carbon atom;

if G4means alkyl group, located in the loop J near the bridge -(CR42)p-, and X is NR3where R3means alkyl substituent, G4and alkyl substituent R3if X can be connected to each other with established who eat a bridge of the structure -(CH 2)p'-where R' is 2, 3 or 4, provided that the sum of p and p' is 2, 3 or 4, which leads to the formation of 5-, 6 - or 7-membered nitrogen cycle;

and with the additional terms, namely, that

in G1, G2, G3and G4if two groups of R3or R6mean alkyl and are in the same N atom they may be linked by communication, O, S or NR3with the formation of N-containing heterocycle with 5 to 7 atoms in the cycle;

if aryl, heteroaryl or heterocyclic ring optionally contains substituents, the ring may be up to 5 substituents that are independently selected from the group consisting of amino, mono(lower alkyl)substituted amino, di(lower alkyl)substituted amino, (lower alkanoyl)amino, halogen, lower alkyl, halogenated lower alkyl, hydroxyl, lower alkoxyl, lower alkylthio, halogenated lower alkoxy, halogenated lower alkylthio, lower alkanoyloxy, -CO2R3, -Cho, -CH2OR3, -OCO2R3, -CON(R6)2-OCON(R6)2, -NR3CON(R6)2, nitro-, amedieval, guanidine, mercapto, sulfo and cyano; and

if there is any alkyl group is attached to O, S or N and contains hydroxyl Deputy, the hydroxyl replace the ü is separated from Oh, S or N, attached to an alkyl group, at least two carbon atoms;

or its pharmaceutically acceptable salt.

12. Connection on p. 11, wherein R4means N.

13. The pharmaceutical composition inhibiting angiogenesis activity, including a connection on p. 11 and a pharmaceutically acceptable carrier.

14. A method of treating a mammal, in which there is a condition characterized by abnormal processes of angiogenesis or the occurrence of high permeability, including the introduction of a given mammal, the number of connections on p. 11, which is effective for the treatment of this condition.

15. The method according to p. 14, characterized in that the said pathological condition is a tumor growth, retinopathy, including diabetic retinopathy, ischemic blockage of the veins of the retina, retinopathy by prematurity and age-related macular degeneration; rheumatoid arthritis; psoriasis or bullous disease accompanied subepidermal blistering, including bullous pemphigoid, erythema multiforme, and dermatitis herpetiformis.

16. A compound selected from the group including

N-(4-chlorophenyl)-4-(4-pyridylsulfonyl)-1-ethanolamin,

N-(2,3-dihydro-1H-inden-5-yl)-4-(4-pyridylsulfonyl)-1-isoquinolines is h,

N-(1,3-benzothiazol-6-yl)-4-(4-pyridylsulfonyl)-1-ethanolamin,

N-(4-chlorophenyl)-4-(4-pyridinylmethyl)-1-ethanolamin,

N-(1,3-benzothiazol-6-yl)-4-(4-pyridinylmethyl)-1-ethanolamin,

N-(2,3-dihydro-1H-inden-5-yl)-4-(4-pyridinylmethyl)-1-N

ethanolamin,

N-(3-fluoro-4-were)-4-(4-pyridinylmethyl)-1-ethanolamin,

N-(4-chlorophenyl)-7-(4-pyridinylmethyl)thieno[2,3-d]pyridazin-4-amine,

N-(4-chlorophenyl)-7-(4-pyridinylmethyl)furo[2,3-d]pyridazin-4-amine,

4-[({4-[(4-chlorophenyl)amino]thieno[2,3-d]pyridazin-7-yl}oxy)methyl]-2-pyridinecarboxamide,

4-[({4-[(4-chlorophenyl)amino]thieno[2,3-d]pyridazin-7-yl}oxy)methyl]-N-methyl-2-pyridinecarboxamide,

4-({1-[(4-chlorophenyl)amino]-4-ethenolysis}methyl)-2-pyridinecarboxamide,

4-({1-[(4-chlorophenyl)amino]-4-ethenolysis}methyl)-N-methyl-2-pyridinecarboxamide,

4-[({4-[(4-chlorophenyl)amino]furo[2,3-d]pyridazin-7-yl}oxy)methyl]-N-methyl-2-pyridinecarboxamide,

4-[({4-[(4-chlorophenyl)amino]furo[2,3-d]pyridazin-7-yl}oxy)methyl]-2-pyridinecarboxamide,

N-(1,3-benzothiazol-6-yl)-N-{4-[(4-chlorophenyl)amino]thieno[2,3--d]pyridazin-7-yl}amine,

N-(1,3-benzothiazol-6-yl)-N-[4-(2,3-dihydro-1H-inden-5-

ylamino)thieno[2,3-d]pyridazin-7-yl]amine,

4-(5-bromo-2,3-dihydro-1H-indol-1-yl)-7-(4-

pyridinylmethyl)furo[2,3-d]pyridazin,

4-[({4-[(methoxyphenyl)amino]furo[2,3-d]pyridazin-7-yl}oxy)methyl]-N-methyl-2-pyridinecarboxamide,

N-(4-methoxyphenyl)-7-(4-pyridinylmethyl)furo[2,3-d]pyridazin-4-amine,

4-[({4-[(4-methoxyphenyl)amino]furo[2,3-d]pyridazin-7-yl}oxy)methyl]-2-pyridinecarboxamide,

N7-(1,3-benzothiazol-6-yl)-N4-(4-chlorophenyl)thieno[2,3-d]pyridazine-4,7-diamine,

N-(1,3-benzothiazol-6-yl)-N-[4-(2,3-dihydro-1H-inden-5-ylamino)thieno[2,3-d]pyridazin-7-yl]amine,

N-(1H-indazol-5-yl)-N-[4-(1H-indazol-5-ylamino)thieno[2,3-d]pyridazin-7-yl]amine,

N-(1,3-benzothiazol-6-yl)-N-[4-(1,3-benzothiazol-6-ylamino)furo[2,3-d]pyridazin-7-yl]amine,

4-[({4-[(4-methoxyphenyl)amino]furo[2,3-d]pyridazin-7-yl}oxy)methyl]-N-methyl-2-pyridinecarboxamide,

4-[({4-[(3-chlorophenyl)amino]furo[2,3-d]pyridazin-7-yl}oxy)methyl]-N-methyl-2-pyridinecarboxamide,

4-[({4-[(3-chloro-4-forfinal)amino]furo[2,3-d]pyridazin-7-yl}oxy)methyl]-N-methyl-2-pyridinecarboxamide,

4-[({4-[(4-forfinal)amino]furo[2,3-d]pyridazin-7-yl}oxy)methyl]-N-methyl-2-pyridinecarboxamide,

4-[({4-[(4-bromophenyl)amino]furo[2,3-d]pyridazin-7-yl}oxy)methyl]-N-methyl-2-pyridinecarboxamide,

N-methyl-4-[({4-[(4-were)amino]furo[2,3-d]pyridazin-7-yl}oxy)methyl]-2-pyridinecarboxamide,

N-methyl-4-[({4-[(3-were)amino]furo[2,3-d]pyridazin-7-yl}oxy)methyl]-2-pyridinecarboxamide,

N-methyl-4-{[(4-{[4-(trifluoromethyl)phenyl]amino}furo[2,3-d]pyridazin-7-yl)oxy]methyl}-2-pyridinecarboxamide,

N-methyl-{[(4-{[4-(triptoreline)phenyl]amino}furo[2,3-d]pyridazin-7-yl)oxy]methyl}-2-pyridinecarboxamide,

4-[({4-[(3-chloro-4-methoxyphenyl)amino]furo[2,3-d]pyridazin-7-yl}oxy)methyl]-N-methyl-2-pyridinecarboxamide,

4-({[4-({4-[acetyl(methyl)amino]phenyl}amino)furo[2,3-d]pyridazin-7-yl]oxy}methyl)-N-methyl-2-pyridinecarboxamide,

N-methyl-4-{[(4-{[4-(4-morpholinyl)phenyl]amino}furo[2,3-d]pyridazin-7-yl)oxy]methyl}-2-pyridinecarboxamide,

4[({4-[(3,4-differenl)amino)furo[3-pyridin]-yl}oxy)methyl]-N-methyl-2-pyridinecarboxamide,

N-(1,3-benzothiazol-6-yl)4-{4-[(4-chlorophenyl)amino]furo[2,3-d]pyridazin-7-yl}amine,

4-({[4-(2,3-dihydro-1H-inden-5-ylamino)furo[2,3-d]pyridazin-7-yl]oxy}methyl)-H-methyl-2-pyridinecarboxamide,

4-[({4-[(2-methoxyphenyl)amino]furo[2,d]pyridazin-7-yl}oxy)methyl]-N-methyl-2-pyridinecarboxamide,

4-[({4-[(3-methoxyphenyl)amino]furo[2,3-d]pyridazin-7-yl}oxy)methyl]-N-methyl-2-pyridinecarboxamide,

4-({[4-(1,3-benzodioxol-5-ylamino)furo[2,3-d]pyridazin-7-yl]oxy}methyl)-N-methyl-2-pyridinecarboxamide,

4-[({4-[(3,4-dichlorophenyl)amino]furo[2,3-d]pyridazin-7-yl}oxy)methyl]-N-methyl-2-pyridinecarboxamide,

4-[({4-[(3, 5dimethylphenyl)amino]furo[2,3-d]pyridazin-7-yl}oxy)methyl]-methyl-2-pyridinecarboxamide,

4-({[4-(1H-indazol-5-ylamino)furo[2,3-d]pyridazin-7-yl]oxy}methyl)-N-methyl-2-pyridinecarboxamide,

N-(4-methoxyphenyl)-7-(4-pyridinylmethyl)furo[2,3-d]-pyridazin-4-amine,

4-[({4-[(4-hydroxyphenyl)amino]furo[2,d]pyridazin-7-yl}oxy)methyl]-N-methyl-2-pyridinecarboxamide,

4-{[7-(4-pyridinylmethyl)furo[2,3-d]pyridazin-4-yl]amino}phenol,

4-{[(4-anilinophenol[2,3-d]pyridazin-7-yl)oxy]methyl}-N-methyl-2-pyridinecarboxamide,

4-[({4-[(3-methoxy-4-were)amino]furo[2,3-d]pyridazin-7-yl}oxy)methyl]-N-methyl-2-pyridinecarboxamide,

N-(4-chlorophenyl)-7-{[2-(4-morpholinylcarbonyl)-4-pyridinyl]methoxy}furo[2,3-d]pyridazine-4-amine,

N-methyl-4-[({4-[(2-methyl-1,3-benzothiazol-5-yl)amino]furo[2,3-d]pyridazin-7-yl}oxy)methyl]-2-pyridinecarboxamide,

4-({[4-(1,3-benzothiazol-6-ylamino)furo[2,3-d]pyridazin-7-yl]oxy}methyl)-N-methyl-2-pyridinecarboxamide,

{4-[({4-[(4-chlorophenyl)amino]furo[2,3-d]pyridazin-7-yl}oxy)methyl]-2-pyridinyl}methanol,

4-({[4-(2,3-dihydro-1-benzofuran-5-ylamino)furo[2,3-d]pyridazin-7-yl]oxy}methyl)-N-methyl-2-pyridinecarboxamide,

4-({[4-(2,3-dihydro-1-benzofuran-5-ylamino)thieno[2,3-d]pyridazin-7-yl]oxy}methyl)-N-methyl-2-pyridinecarboxamide,

4-[({4-[(4-forfinal)amino]thieno[2,3-d]pyridazin-7-yl}oxy)methyl]-N-methyl-2-pyridinecarboxamide,

N-methyl-4-[({4-[(3-were)amino]thieno[2,3-d]pyridazin-7-yl}oxy)methyl]-2-pyridinecarboxamide,

4-[({4-[(4-methoxyphenyl)amino]thieno[2,3-d]pyridazin-7-yl}oxy)methyl]-N-methyl-2-pyridinecarboxamide,

N-methyl-4-{[(4-{[4-(triptoreline)phenyl]amino}thieno[2,3-d]pyridazin-7-yl)oxy]methyl}-2-pyridinecarboxamide,

N-methyl-4{[(4-{[4-(trifluoromethyl)phenyl]amino}thieno[2,3-d]pyridazin-7-yl)oxy]methyl}-2-pyridinecarboxamide,

4-[({4-[(4-bromophenyl)amino]thieno[2,3-d]pyridazin-7-yl}oxy)methyl]-N-methyl-2-pyridinecarboxamide,

4-({[4-(2,3-dihydro-1H-inden-5-ylamino)thieno[2,3-d]pyridazin-7-yl]oxy}methyl)-N-methyl-2-pyridinecarboxamide,

4-({[4-(1,3-benzodioxol-5-ylamino)thieno[2,3-d]pyridazin-7-yl]oxy}methyl)-N-methyl-2-pyridinecarboxamide,

N-(1,3-benzothiazol-6-yl)-N-[4-(1,3-benzothiazol-6-ylamino)thieno[2,3-d]-pyridazin-7-yl]amine,

N-(1,3-benzothiazol-6-yl)-N-{4-[(4-bromophenyl)amino]thieno[2,3-d]pyridazin-7-yl}amine,

N-(1,3-benzothiazol-6-yl)-N-{4-[(2,4-dimetilfenil)amino]thieno[2,3-d]pyridazin-7-yl}amine,

N-(1,3-benzothiazol-6-yl)-N-{4-[(3-fluoro-4-were)amino]thieno[2,3-d]pyridazin-7-yl}amine,

4-[({4-[(4-chlorophenyl)amino]furo[2,3-d]pyridazin-7-yl}oxy)methyl]-N-[2-(dimethylamino)ethyl]-2-pyridinecarboxamide,

4-[({4-[(4-chlorophenyl)amino]furo[2,3-d]pyridazin-7-yl}oxy)methyl]-N-cyclopropyl-2-pyridinecarboxamide,

4-[({4-[(4-chlorophenyl)amino]furo[2,3-d]pyridazin-7-yl}oxy)methyl]-N-(2-hydroxyethyl)-2-pyridinecarboxamide,

4-[({4-[(4-chlorophenyl)amino]furo[2,3-d]pyridazin-7-yl}oxy)methyl]-N-ethyl-2-pyridinecarboxamide,

N-(4-chlorophenyl)-4-(4-pyridylsulfonyl)-1-ethanolamin,

N-(2,3-dihydro-1H-inden-5-yl)-4-(4-pyridylsulfonyl)-1-ethanolamin,

N-(1,3-benzothiazol-6-yl)-4-(4-pyridylsulfonyl)-1-ethanolamin,

N-(1,3-benzothiazol-6-yl)-N-[4-(1,benzothiazol-6-ylamino)-1-phthalazine]Amin,

N-(1H-benzimidazole-6-yl)-N-{4-[(4-chlorophenyl)amino]-1-phthalazine}amine,

N-(1H-1,2,3-benzotriazol-5-yl)-N-{4-[(4-chlorophenyl)amino]-1-phthalazine}amine,

N-(1,3-benzothiazol-6-yl)-4-(5-bromo-2,3-dihydro-1H-indol-1-yl)-1-phthalazinone,

N-(1,3-benzothiazol-6-yl)-N-{4-[(2,2-debtor-1,3-benzodioxol-5-yl)amino]-1-phthalazine}amine,

N-(1,3-benzothiazol-6-yl)-N-(4-{[4-(1-piperidinyl)phenyl]amino}-1-phthalazine)amine,

N-(1,3-benzothiazol-6-yl)-N-[4-({4-[ethyl(isopropyl)amino]phenyl}amino)-1-phthalazine]Amin,

N-(1,3-benzothiazol-6-yl)-N-{4-[(3-bromophenyl)amino]-1-phthalazine}amine,

N-(1,3-benzothiazol-6-yl)-N-{4-[(4-isopropylphenyl)amino]-1-phthalazine}amine,

N-(1,3-benzothiazol-6-yl)-N-{4-[(3-methoxyphenyl)amino]-1-phthalazine}amine,

N-(1,3-benzothiazol-6-yl)-N-{4-[(3-fluoro-4-were)amino]-1-phthalazine}amine,

N-(1,3-benzothiazol-6-yl)-N-{4-[(4-chlorophenyl)amino]-1-phthalazine}amine,

4-[({4-[(4-chlorophenyl)amino]furo[2,3-d]pyridazin-7-yl}oxy)methyl]-N-methyl-2-pyridinecarboxamide 4-methylbenzenesulfonate,

4-[({4-[(4-chlorophenyl)amino]furo[2,3-d]pyridazin-7-yl}oxy)methyl]-N-methyl-2-pyridinecarboxamide 4-chlorobenzenesulfonate,

4-[({4-[(4-chlorophenyl)amino]furo[2,3-d]pyridazin-7-yl}oxy)methyl]-N-methyl-2-pyridinecarboxamide,

4-[({4-[(4-chlorophenyl)amino]furo[2,3-d]pyridazin-7-yl}oxy)methyl]-N-methyl-2-pyridinecarboxamide econsultants Thonet,

4-[({4-[(4-chlorophenyl)amino]furo[2,3-d]pyridazin-7-yl}oxy)methyl]-N-methyl-2-pyridinecarboxamide the dihydrochloride,

4-[({4-[(4-chlorophenyl)amino]furo[2,3-d]pyridazin-7-yl}oxy)methyl]-N-methyl-2-pyridinecarboxamide hydrobromide,

4-[({4-[(4-chlorophenyl)amino]furo[2,3-d]pyridazin-7-yl}oxy)methyl]-N-methyl-2-pyridinecarboxamide sulfate

4-[({4-[(4-chlorphenyl)amino]furo[2,3-d]pyridazin-7-yl}oxy)methyl]-N-methyl-2-pyridinecarboxamide nitrate,

4-[({4-[(4-chlorophenyl)amino]furo[2,3-d]pyridazin-7-yl}oxy)methyl]-N-methyl-2-pyridinecarboxamide-2-hydroxyethanesulfonic,

4-[({4-[(4-chlorophenyl)amino]furo[2,3-d]pyridazin-7-yl}oxy)methyl]-N-methyl-2-pyridinecarboxamide bansilalpet.



 

Same patents:

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to applying compounds of the general formula (1):

as inhibitors of caspase-3 that allows their applying as "molecular tools" and as active medicinal substances inhibiting selectively the scheduling cellular death (apoptosis). Also, invention relates to pharmaceutical compositions based on compounds of the formula (1), to a method for their preparing and a method for treatment or prophylaxis of diseases associated with enhanced activation of apoptosis. Also, invention relates to new groups of compounds of the formula 91), in particular, to compounds of the formulae (1.1):

and (1.2):

. In indicated structural formulae R1 represents inert substitute; R2, R3 and R4 represent independently of one another hydrogen atom, fluorine atom (F), chlorine atom (Cl), bromine atom (Br), iodine atom (J). CF3, inert substitute, nitro-group (NO2), CN, COOH, optionally substituted sulfamoyl group, optionally substituted carbamide group, optionally substituted carboxy-(C1-C6)-alkyl group; R5 represents oxygen atom or carbon atom included in optionally condensed, optionally substituted and optionally comprising one or some heteroatoms; R6 represents hydrogen atom or inert substitute; X represents sulfur atom or oxygen atom.

EFFECT: improved preparing and applying methods, valuable medicinal and biochemical properties of compounds.

3 cl, 1 dwg, 2 tbl, 1 sch, 8 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to methods for treatment of diseases or syndromes associated with metabolism of fatty acids and glucose and to new compounds and their pharmaceutically acceptable salts. Invention relates to applying new compounds and pharmaceutical compositions for treatment of cardiovascular diseases, diabetes mellitus, cancer diseases, acidosis and obesity by inhibition of activity of enzyme malonyl-CoA-decarboxylase. Indicated compounds correspond to formulae (I) and (II) wherein Y, C, R1, R2, R6 and R7 have values given in the invention claim.

EFFECT: valuable medicinal and biochemical properties of azoles.

27 cl, 8 tbl

FIELD: organic chemistry, madicine.

SUBSTANCE: tricyclic benzodiazepines of formula I as well as their pharmaceutical acceptable salts, pharmaceutical composition containing the same and methods for hypertension treatment are disclosed. In formula A is -C(O)-; Y is CH2 or CH as olefinic site; X is CH2 or CH as olefinic site S, O or NR3 (R3 is C1-C8-alkyl) with the proviso that when Y is CH, X also is CH; Z is N or CH; R1 is hydrogen, C1-C8-alkyl, C1-C8-alkoxy or halogen; R2 is NR4COAr (R4 is hydrogen; Ar is phenyl optionally substituted with 1-3 substitutes independently selected from C1-C8-alkyl, halogen, hydroxyl, fluorinated C1-C8-alkylthio and another phenyl optionally substituted with substitute selected from C1-C4-alkyl, halogen, and hydroxyl); R5 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine, hydroxyl or di-(C1-C4)-alkylamino.

EFFECT: improved pharmaceutical composition for hypertension treatment.

12 cl, 5 tbl, 52 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

20 cl, 6 tbl, 192 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to oxazolo- and thiazolo-[4,5-c]-quinoline-4-amines of the general formula (I)

wherein R1 is taken among group consisting of oxygen and sulfur atoms; R2 is taken among hydrogen atom, alkyl, alkyl-OH (hydroxyalkyl), alkyl-X-alkyl, alkyl-O-C(O)-N(R5)2, morpholinyl, pyrrolidinyl, alkyl-X-aryl radical, alkenyl-X-aryl radical; each substitute R3 and R4 represents hydrogen atom or substitutes R3 and R4 taken in common form the condensed aromatic or [1,5]-naphthiridine system; X represents -O- or a single bond; R5 represents hydrogen atom. Also, invention describes intermediate compounds, pharmaceutical composition and a method for stimulating biosynthesis of cytokinins (cytokines) based on these compounds. Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable properties of compounds.

21 cl, 2 tbl, 64 ex

The invention relates to organic chemistry and can find application in medicine

The invention relates to the field of production of new heterocyclic o-dicarbonitriles

The invention relates to a new method for the preparation of 3-substituted cephalosporins of the formula (I):

where R1is a para-nitrobenzyl or allyl, X is a halogen; comprising the stage of: a) cyclization trimethylphosphine the compounds of formula (IIIA):

where R1is a para-nitrobenzyl or allyl, R2selected from the group comprising FROM1-6alkyl, C6-10aryl, C6-10arils1-6alkyl and dithienyl; in a solvent to form compounds of the formula (II):

where R1is a para-nitrobenzyl or allyl; R2selected from the group comprising FROM1-6alkyl, C6-10aryl, C6-10arils1-6alkyl and dithienyl; and (b) interaction of the compounds of the formula (II) with acid

The invention relates to polycyclic, thiazolidin-2 - ildenafil amines and their physiologically acceptable salts and physiologically functional derivatives

The invention relates to a method for producing [1,2,4]triazolo[3,4-b][1,3]benzothiazol-3(2H)-thione of the formula

including fusion [1,2,4]triazolo[3,4-b][1,3]benzothiazole with excess sulfur in for 5-20 minutes at a temperature of 180-200With subsequent isolation of the target product

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (1)

wherein A represents bicyclic or tricyclic azepine derivative; V1 and V2 both represent hydrogen atom (H) or one among V1 and V2 represents hydrogen atom (H), OMe, OBn, OPh, O-acyl, Br, Cl, F, N3, NH2, NHBn and another represents hydrogen atom (H); or V1 and V2 represent in common =O or -O(CH2)pO-; W1 represents oxygen (O) or sulfur (S) atom; X1 and X2 both represent hydrogen atom (H) or in common represent =O or =S; Y represents OR5 or NR6R7; R1 means hydrogen atom (H), lower alkyl, F, Cl and Br; R2 means lower alkoxy-group or values given for R1; R3 and R5 are taken independently among hydrogen atom (H) and lower alkyl; R4 means hydrogen atom (H); R6 and R7 are taken independently among hydrogen atom (H) and lower alkyl, or they in common mean -(CH2)n-; n = 3, 4, 5 or 6; p = 2 or 3. These compounds are agonists of vasopressin V2 receptors and useful as antidiuretic and procoagulants, and also to pharmaceutical compositions comprising these vasopressin agonists. These compositions are useful especially in treatment of diabetes insipidus of the central origin and night enuresis.

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

26 cl, 1 tbl, 119 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of piperazine of the general formula (I): wherein Y represents lower alkylene; R1 represents phenyl substituted with one or two similar or different substitutes taken among a group including lower alkoxy-group, mono- (or di-, or tri-)-halogen-lower)-alkyl, nitro-, amino-, lower alkylamino-, di-(lower)-alkylamino-, lower alkylthio-group,alkylsulfonyl, lower alkylaminosulfonyl, di-(lower)-alkylaminosulfonyl, and pyrrolyl; R2 means phenyl substituted with hydroxy-group at position 3 and with lower alkyl and halogen atom additionally; R3 means hydrogen atom; R4 represents (2,6-dimethylmorpholino)-(lower)-alkyl, (2-methoxymethylmorpholino)-(lower)-alkyl, (3-methoxymethylmorpholino)-(lower)-alkyl. Also, invention relates to their pharmaceutically acceptable salts, to method for their preparing, pharmaceutical composition and a method for vomiting inhibition. Proposed compounds are antagonists of tachykinin and can be used for vomiting inhibition.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

9 cl, 47 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new oxathiepino[6,5-b]dihydropyridines of the formula (I):

wherein: (a) R1, R2, R3, R4 and R5 are taken independently among group consisting of hydrogen atom (H), halogen atom, nitro-group (NO2); (b) R6 is taken among group consisting of unbranched or branched (C1-C5)-alkyl wherein indicated alkyl can be substituted with phenylacetyloxy-, hydroxy- carboalkoxy-group or group NR'R'' wherein R' and R'' are taken independently among group consisting of hydrogen atom (H), unbranched or branched (C1-C8)-alkyl, benzyl; (c) R7 is taken among group consisting of hydrogen atom (H), alkyl; (d) R9 represents oxygen atom; (e) n is a whole number from 1 to 2, or its pharmaceutically acceptable salt. Compounds are useful as antagonists of calcium channels and elicit cardiovascular, anti-asthmatic and anti-bronchoconstricting activity. Also, invention describes the pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds and composition.

28 cl, 2 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyclic amide of the formula (I)

or its salt, or hydrate, or solvate wherein X represents (C1-C6)-alkyl, (C1-C6)-alkyl substituted with phenyl, (C2-C6)-alkenyl substituted with phenyl or halogenphenyl, (C2-C6)-alkynyl substituted with phenyl, phenyl that can be substituted with (C1-C6)-alkyl; one or more halogen atom, nitro-group, phenyl, (C1-C6)-alkoxy-group, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy-group, phenyl-(C1-C6)-alkyl, (C1-C6)-alkoxyphenyl-(C1-C6)-alkyl, amino-group, optionally substituted with (C1-C6)-alkyl, acetyl, (C1-C6)-alkoxy-group, substituted with phenyl, phenylcarbonyl, furanyl; 1- or 2-naphthyl, monocyclic (C3-C8)-cycloalkyl, amino-group substituted with one or more substitutes taken among phenyl, halogenphenyl, (C1-C6)-alkoxyphenyl, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl; 5- or 6-membered monocyclic heterocyclic group comprising 1 or 2 heteroatoms, such as nitrogen (N), oxygen (O), sulfur (S) atom optionally substituted with halogenphenyl, halogen atom, benzyl, (C1-C6)-alkyl, phenyl; 8-10-membered bicyclic heteroaryl group comprising 1 or 2 heteroatoms taken among N, O and optionally substituted with halogen atom; 8-10-membered polycyclic cycloalkyl group; Q means -CH2-, -CO-, -O-, -S-, -CH(OR7)- or -C(=NR8)- wherein R7 means hydrogen atom (H), (C1-C6)-alkyl; R8 means OH, (C1-C)-alkoxy-group, acylamino-group, (C1-C6)-alkoxycarbonylamino-group, phenyl-(C1-C6)-alkoxy-group; n = 0-5; B represents group or wherein each among R3, R4, R5 and R6 represents independently substitute taken among group consisting of hydrogen atom (H), halogen atom, NO2 (nitro-group), (C1-C6)-alkoxy-group, CN (cyano-group); m = 1 or 2; ring represents 5- or 6-membered aromatic heterocyclic ring comprising one or two heteroatoms taken among O, S, N. Compound of the formula (I) elicit activity inhibiting binding sigma-receptors that allows their using as component of medicinal agent.

EFFECT: valuable medicinal properties of compounds.

21 cl, 2 sch, 4 tbl, 183 ex

FIELD: organic chemistry, medicine, hormones, pharmacy.

SUBSTANCE: invention relates to new biologically active compounds that act as agonists of peptide hormone vasopressin. Invention describes the compound of the general formula (1) or its pharmaceutically acceptable salt wherein V represents a covalent bond or NH; X is taken among CH2, oxygen atom (O) and N-alkyl; Z represents sulfur atom (S) or -CH=CH-; R1 and R2 are taken independently among hydrogen (H), fluorine (F), chlorine (Cl), bromine (Br) atom and alkyl; R3 is taken among hydroxyl group (OH), O-alkyl and NR4R5 wherein each R4 and R5 represents independently hydrogen atom (H) or alkyl, or both represent -(CH2)q-; p = 0, 1, 2, 3 or 4; q = 4 or 5. Also, invention describes a pharmaceutical composition eliciting agonistic activity with respect to V2-receptors, a method for treatment of enuresis, nicturia and diabetes insipidus, method for control of enuresis and a method for treatment of enuresis and a method for treatment of diseases associated with damage in blood coagulability. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: valuable medicinal properties of compounds.

17 cl, 31 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to a new derivative of bicyclic heteroaromatic compound of the general formula (I) or its pharmaceutically acceptable salt eliciting agonistic activity with respect to luteinizing hormone (LH). Compounds can be used for preparing medicinal agents for control ability for conception. In compounds of the general formula (I) R1 represents R7 wherein R7 represents (C6-C10)-aryl optionally substituted with halogen atom at ortho- and/or meta-position; NHR8, OR8 wherein R8 means (C1-C8)-alkyl that can be substituted with halogen atom, (C1-C8)-alkylcarbonyl, (C1-C8)-alkylcarbonyloxy-group, phenyl, (C6-C10)-arylcarbonylamino-group, 5-methyl-2-phenylimidazol-4-yl, (C6)-heterocycloalkyl wherein 1-2 heteroatoms are taken among nitrogen and oxygen atoms, ethyloxycarbonylmethylthio-(C1-C4)-alkoxy-group, amino-group, (C6-C7)-heteroaryl; or (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; R2 represents (C1-C8)-alkyl or (C6-C10)-aryl optionally substituted with one or more substitutes taken among (C1-C8)-alkoxy-group; or (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; R3 represents (C1-C8)-alkyl possibly substituted with (C6-C14)-aryl possibly substituted with halogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkoxycarbonyl, mono- or tri-(C6-C10)-cycloalkyl, (C6-C10)-aryl, (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; (C5-C7)-heterocycloalkyl comprising 2 heteroatoms taking among nitrogen or oxygen atom; (C3-C8)-cycloalkyl, (C2-C7)-heterocycloalkyl comprising 2 heteroatoms taking among nitrogen or oxygen atom; or (C6-C10)-aryl optionally substituted with one or more substitutes taken among (C1-C8)-alkoxy-group; X represents sulfur atom (S) or N(R4); Y represents nitrogen atom (N); R4 represents (C1-C8)-alkyl, phenyl-(C1-C8)-alkyl; or X represents sulfur atom (S), and Y represents CH; Z represents NH2 or OH; A represents sulfur (S), oxygen atom (O) or a bond. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable properties of compounds and composition.

14 cl, 1 tbl, 119 ex

The invention relates to compounds of the formula I

in which

R1, R2in each case, independently of one another represent H, A, HE, OA or Hal,

X is R4, R5or R6, monosubstituted R7,

R4is unbranched or branched alkylene with 1-10 atoms, in which one or two CH2groups can be substituted by a group-CH=CH-,

R5is cycloalkyl or cycloalkylation containing 5-12 With atoms

R6is phenyl or vinylmation,

R7is COOH, cooa, CONH2, CONHA, CON(A)2or CN,

And is alkyl having from 1 to 6 atoms

Hal represents F, Cl, Br or I,

where at least one of the radicals R1or R2HE is a,

and their pharmaceutically acceptable salts

New drug substances // 2237657
The invention relates to organic chemistry and can find application in medicine

New drugs // 2237057
The invention relates to organic chemistry and can find application in medicine

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyclic amide of the formula (I)

or its salt, or hydrate, or solvate wherein X represents (C1-C6)-alkyl, (C1-C6)-alkyl substituted with phenyl, (C2-C6)-alkenyl substituted with phenyl or halogenphenyl, (C2-C6)-alkynyl substituted with phenyl, phenyl that can be substituted with (C1-C6)-alkyl; one or more halogen atom, nitro-group, phenyl, (C1-C6)-alkoxy-group, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy-group, phenyl-(C1-C6)-alkyl, (C1-C6)-alkoxyphenyl-(C1-C6)-alkyl, amino-group, optionally substituted with (C1-C6)-alkyl, acetyl, (C1-C6)-alkoxy-group, substituted with phenyl, phenylcarbonyl, furanyl; 1- or 2-naphthyl, monocyclic (C3-C8)-cycloalkyl, amino-group substituted with one or more substitutes taken among phenyl, halogenphenyl, (C1-C6)-alkoxyphenyl, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl; 5- or 6-membered monocyclic heterocyclic group comprising 1 or 2 heteroatoms, such as nitrogen (N), oxygen (O), sulfur (S) atom optionally substituted with halogenphenyl, halogen atom, benzyl, (C1-C6)-alkyl, phenyl; 8-10-membered bicyclic heteroaryl group comprising 1 or 2 heteroatoms taken among N, O and optionally substituted with halogen atom; 8-10-membered polycyclic cycloalkyl group; Q means -CH2-, -CO-, -O-, -S-, -CH(OR7)- or -C(=NR8)- wherein R7 means hydrogen atom (H), (C1-C6)-alkyl; R8 means OH, (C1-C)-alkoxy-group, acylamino-group, (C1-C6)-alkoxycarbonylamino-group, phenyl-(C1-C6)-alkoxy-group; n = 0-5; B represents group or wherein each among R3, R4, R5 and R6 represents independently substitute taken among group consisting of hydrogen atom (H), halogen atom, NO2 (nitro-group), (C1-C6)-alkoxy-group, CN (cyano-group); m = 1 or 2; ring represents 5- or 6-membered aromatic heterocyclic ring comprising one or two heteroatoms taken among O, S, N. Compound of the formula (I) elicit activity inhibiting binding sigma-receptors that allows their using as component of medicinal agent.

EFFECT: valuable medicinal properties of compounds.

21 cl, 2 sch, 4 tbl, 183 ex

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