Quinoline-like compound substituted by phosphorus-containing group, method for preparing it, therapeutic composition containing this compound and using it

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to quinolines substituted by phosphorus-containing group of formula and applicable in medicine, wherein Z represents V1 and V2 are independently specified in hydrogen or halogen; one of R and R` represent phosphorus-containing substitute Q; the other one is specified in hydrogen or methoxyl; wherein the phosphorus-containing substitute Q represents A represents O; L represents C1-6alkyl; J represents NH or C3-6heterocycloalkyl and J is optionally substituted by G3; X is absent or represents -C(=O)-; X is absent or represents C1-6alkyl; each of R1 and R2 are independently specified in C1-6alkyl or C1-6alkoxy; G3 represents C1-6alkyl, R3S(=O)m-, R5C(=O)- or R3R4NC(=O)-; R3, R4 and R5 are independently specified in 3 or C1-6alkyl; m is equal to 0-2.

EFFECT: there are presented new protein kinase inhibitors effective for treating the diseases associated with abnormal protein kinase activity.

20 cl, 42 ex, 8 tbl, 3 dwg

 

Field of the invention

The present invention relates to the field of organic chemistry and medicinal chemistry, in particular to substituted phosphorous group of the quinoline, to methods for its preparation, pharmaceutical compositions containing this compound, and application.

Prior art

Protein kinase is a type phosphotransferase and has a function of transferring the γ-phosphate group of ATP to specific amino acid residue of the substrate, promoting the phosphorylation of the protein and the manifestation of their physiological and biochemical functions. Protein kinase plays an important role and has mainly the following two functions in signal transduction: from one side it regulates the activity of proteins by phosphorylation; on the other hand it step by step amplifies the signals by sequential phosphorylation of proteins, causing cell response.

Abnormal activity of protein kinases are not only closely associated with an abnormal condition at a certain stage in the sequence of intra - and extracellular signal transduction pathways, such as tumor cells proliferation, apoptosis, metastasis, but also is the main cause of several other human diseases associated with an inflammatory or proliferative response, NRA�emer rheumatoid arthritis, diseases of the cardiovascular or nervous system, asthma, psoriasis. At the moment we know about the existence of more than 400 species of human diseases that are directly or indirectly related protein kinase, which makes the protein kinase is another important target for drugs after coupled with G-protein receptor.

A large family of protein kinases consists of more than 500 members and is mainly divided into two types, i.e. proteincontaining (RTK) and serine-trionychidae. Location kinases in the cell are classified into receptor kinase and preceptories kinase, also called intracellular kinases. Receptor kinase mainly belong to tyrosinekinase, also called receptor tyrosinekinase (RTK); such receptor kinases are composed of parts that are from the outside of the cell membrane, the transmembrane domain and the part lying in the cytoplasm; part of the catalytic kinase located in the cytoplasm. Most serine-trainingin is inside the cell and belongs to preceptory kinase, otherwise known as cytosolic kinases.

The receptors of growth factors are typical representatives of the family RTK, with at least 19 subfamilies; the main subfamilies are as follows:

(a) the receptor tyrosine kinase family of HER that�exclude EGFR (the receptor of epithelial growth factor), HER2, HER3 and HER4. EGFR is a target of synthetic small molecule drugs, such as Tarceva®, Tykerb®and monoclonal antibodies Erbitux®for the treatment of non-small cell lung cancer;

(b) the collection consists of insulin the insulin receptor (IR), a receptor insulin-like growth factor 1 (IGF-1R) and its receptor, insulin related receptor (IRR); where IGF-1R is a well-known target of anticancer therapy; because it is extremely similar to IR, in particular inside the jail part of kinases, their amino acid sequences are 100% identical, then the inhibition of the activity of IGF-1R is usually also inhibited the activity of IR. It is proved that IR is also an effective target for cancer therapy, although the inhibition of IR may be risks of raising blood sugar levels, and need to find a balance between efficacy and acceptable risk when using the IR inhibitor as an anticancer agent;

() family of receptors platelet-derived growth factor (PDGFR), which includes PDGFR-α, PDGFR-β, CSF1R, c-KIT and c-fms; where c-KIT is a molecular target drugs for the treatment of leukemia, such as Gleevec®and also in the treatment of stromal tumors of the gastrointestinal tract;

(g) family of receptors, growth factor vascular endothelial (VEGFR), �AutoRAE includes FLT1 (Fms-like tyrosinekinase 1 or VEGFR1), KDR (or VEGFR-2) and FLT4 (or VEGFR3). Members of this family are the molecular target Sutent®and Naxavar®;

(d) family of receptors of fibroblast growth factor (FGFR), which includes FGFR1, FGFR2, FGFR3 and FGFR4 and 7 ligands, FGF1, fgf2 plasmid, FGF3, FGF4, FGF5, FGF6, and FGF7. Members of this family are the molecular targets of drugs currently undergoing clinical trials;

(e) family of METH, which includes c-Met, also called receptor growth factor hepatocyte (hHGFR), and RON; where c-Met plays an important role in the growth and metastasis of the primary tumor; drugs aimed at the members of a family of METH are currently undergoing clinical trials;

(g) the family of RET; RET receptors are members of the GDNF family and have the RET51 isoform, RET43 and RET9; drugs aimed at the members of the family RET currently undergoing clinical trials;

(h) the Eph family, which is the largest family of receptor tyrosine kinases consists of 16 receptors (EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA9, EPHA10, EPHB1, EPHB2, ERNW, ERNW, ERNW, ERNV) and 9 ligands (EFNA1, EFNA2, EFNA3, EFNA4, EFNA5, EFNB1, EFNB2, EFNB3). Members of this family play important roles in the development of animals, and some of them play a role in neoplastic processes.

Preceptory kinases do not have parts that are from the outside of the cell membrane, � transmembrane domain, and the whole kinase located in the cytoplasm. To date, it is known that there are at least 24 preceptory kinase, which is divided into 11 subfamilies, i.e. subfamily of Src, Frk, Btk, CsK, AbI, Zap70, Fes, Fps, Fak, Jak and AcK; where the Src subfamily is the largest and includes Src, Yes, Fyn, Lyn, Lck, BIk, Hck, Fgr, AUR1, AUR2 and Yrk kinase. For more information see: Neet, K.; Hunter, T. Genes Cells to 1996, 1, 147-169 and the documents referred to there. Although some preceptories kinases belong to tyrosinekinase, most preceptory kinases belong to the serine-trainingcenter; where some of their members are the molecular targets of drugs for the treatment of leukemia, such as Gleevec®and Sprycel®.

As stated above, the clinical and practical application has been fully proved that the receptor kinase and preceptories kinases are targets of anticancer therapy, and some anticancer drugs approved for sale in the market for use by patients. Besides the treatment of tumors, inhibition of abnormal activity of receptor kinases and preceptory kinases can also be used to treat the following diseases: psoriasis, cirrhosis, diabetes, associated with an angiogenesis-related diseases, restenosis disease, eye disease, age-related macular deg�neralu, rheumatoid arthritis and other inflammatory diseases, diseases of the immune system such as autoimmune disease, cardiovascular diseases such as atherosclerosis, or kidney disease, etc., but are not limited to. Thus, it is necessary to continue the development of the required inhibitors of these kinases.

Summary of the invention

One object of the present invention is to offer a substituted phosphorous group, a quinoline possessing inhibitory activity against protein kinases, and methods for its preparation.

Another object of the present invention is to propose the adoption of the above substituted phosphorous group of the quinoline in the manufacture of medicines for the treatment of diseases associated with abnormal protein kinase activity.

Another object of the present invention is to propose a pharmaceutical composition containing the above substituted phosphorous group, a quinoline, for the treatment of diseases associated with abnormal protein kinase activity.

The technical solution of the invention

Substituted phosphorous group, a quinoline having a molecular structure represented by the following formula (I):

in which

Z represents �Wallpapers each of V1and V2independently selected from hydrogen, halogen, -OCF3, -CF3, -NO2, -CN, -OH, -NH2, -NMe2, C1-6alkyl, C3-6cycloalkyl, C3-6geterotsiklicheskie, S6alkoxy, C3-6cycloalkane or C3-6heteroseksualci;

one of R and R' represents a phosphorus-containing Q Deputy, the other is selected from hydrogen, methoxyl, methoxyethoxy or phosphorous Deputy Q;

where phosphorous Deputy Q represents an,

A is absent or represents O, NH, S(=O)mor C1-6alkyl, and A possibly substituted G1;

L is absent or represents C1-6alkyl, C3-6cycloalkyl, S6aryl, C5-6heteroaryl or C3-6heteroseksualci, and L possibly substituted G2;

J is absent or represents O, NH, S(=O)m, C1-6alkyl, C3-6cycloalkyl, S6aryl, C5-6heteroaryl or C3-6heteroseksualci, and J possibly substituted G3;

X is absent or represents-C(=O)-, -S(O)m-, C1-6alkyl, C3-6cycloalkyl, S6aryl, C5-6heteroaryl or C3-6heteroseksualci, and X possibly substituted G4;

Y is absent or represents C1-6alkyl, C3-6cycloalkyl, S6aryl, C5-6heteroaryl or C3-6�heteroseksualci, and Y possibly substituted G5;

each of R1and R2independently selected from-OH, C1-6alkyl, C3-6cycloalkyl, S6aryl, C5-6heteroaryl, C3-6geterotsiklicheskie, S6alkoxy, C3-6cycloalkane, S6aryloxy, C5-6heteroaromatic or C3-6heteroseksualci, and each of R1and R2possibly substituted G6; R1and R2together with the phosphorus atom to which they are attached, can form a C3-6geteroseksualnoe ring, which may optionally contain heteroatom(s) selected(s) from O, N or S(=O)m;

where

each of G1G2G3G4G5and G6independently selected from H, -CN, -CF3, -CO2H, halogen, C1-6alkyl, C3-6cycloalkyl, C2-6alkenyl, C2-6alkynyl, S6aryl, C5-6heteroaryl, C3-6geterotsiklicheskie, R3O-, R3R4N-, R3S(=O)m-, R3R4NS(=O)m-, R5C(=O)-, R3R4NC(=O)-, R3OC(=O)-, R5C(=O)O-, R3R4NC(=O)O-, R5C(=O)NR3-, R3R4NC(=O)NR6-, R3OC(=O)NR6-, R3S(=O)mNR6-, R3R4NS(=O)mNR6-, R3R4NC(=NR7)NR6-, R3R4NC(=CHNO2)NR6-, R3R4NC(=N-CN)NR6-, R3R4NC(=NR7)-, R S(=O)(=NR7)NR6or R3R4NS(=O)(=NR7)-;

each of R3, R4, R5, R6and R7independently selected from H, C1-6alkyl, C3-6cycloalkyl, S6aryl, C5-6heteroaryl or C1-6geterotsiklicheskie; when R3and R4attached to the same nitrogen atom, then R3and R4together with the nitrogen to which they are attached, can form a C3-6geteroseksualnoe ring, which may optionally contain heteroatom(s) selected(s) from O, N or S(=O)m; and R3, R4, R5, R6and R7can be possibly substituted by halogen, CN, C1-6the alkyl or C3-6cycloalkyl;

m is equal to 0-2.

In this application proposed substituted phosphorous group, a quinoline, represented by the following formula (Ia):

where in the above formula

A represents O, NH or S(=O)mand A possibly substituted G1;

L represents C1-6alkyl or C3-6cycloalkyl, and L possibly substituted G2;

J represents O, NH or S(=O)mand J possibly substituted G3;

Y represents C1-6alkyl or C3-6cycloalkyl, and Y possibly substituted G5;

each of R1and R2independently selected from-OH, C1-6alkyl, C3-6cycloalkyl�, With6aryl, C5-6heteroaryl, C3-6geterotsiklicheskie, C1-6alkoxy, C3-6cycloalkane, S6aryloxy, C5-6heteroaromatic or C3-6heteroseksualci, and each of R1and R2possibly substituted G6;

m is equal to 0-2.

Substituted phosphorous group, a quinoline represented by the following formula (Ib):

,

where in the above formula

A represents O, NH or S(=O)mand A possibly substituted G1;

L represents C1-6alkyl, and substituted L can G2;

J represents C3-6cycloalkyl or C3-6heteroseksualci, and J possibly substituted G3;

X is absent or represents-C(=O)- or-S(O)m-;

Y represents C1-6alkyl or C3-6cycloalkyl, and Y possibly substituted G5;

each of R1and R2independently selected from-OH, C1-6alkyl, C3-6cycloalkyl, S6aryl, C5-6heteroaryl, C3-6geterotsiklicheskie, C1-6alkoxy, C3-6cycloalkane, S6aryloxy, C5-6heteroaromatic or C3-6heteroseksualci, and each of R1and R2possibly substituted G6;

m is equal to 0-2.

Substituted phosphorous group, a quinoline represented by the following formula (Ic):

g�e in the above formula

A represents O, NH or S(=O)mand A possibly substituted G1;

L represents C1-6alkyl or C3-6cycloalkyl, and L possibly substituted G2;

J represents O, NH or S(=O)mand J possibly substituted G3;

Y represents C1-6alkyl or C3-6cycloalkyl, and Y possibly substituted G5;

each of R1and R2independently selected from-OH, C1-6alkyl, C3-6cycloalkyl, S6aryl, C5-6heteroaryl, C3-6geterotsiklicheskie, C1-6alkoxy, C3-6cycloalkane, S6aryloxy, C5-6heteroaromatic or C3-6heteroseksualci, and each of R1and R2possibly substituted G6;

m is equal to 0-2.

In this application proposed substituted phosphorous group, a quinoline, represented by the following formula (Id):

,

where in the above formula

A represents O, NH or S(=O)mand A possibly substituted G1;

L represents C1-6alkyl, and substituted L can G2;

J represents C3-6cycloalkyl or C3-6heteroseksualci, and J possibly substituted G3;

X is absent or represents-C(=O)- or-S(O)m-;

Y represents C1-6alkyl or C3-6cycloalkyl, and Y possibly substituted G5;

each of R1 and R 2independently selected from-OH, C1-6alkyl, C3-6cycloalkyl, S6aryl, C5-6heteroaryl, C3-6geterotsiklicheskie, C1-6alkoxy, C3-6cycloalkane, S6aryloxy, C5-6heteroaromatic or C3-6heteroseksualci, and each of R1and R2possibly substituted G6;

m is equal to 0-2.

In this application proposed substituted phosphorous group, a quinoline, represented by the following formula (Ie):

where in the above formula

L represents C1-6alkyl or C3-6cycloalkyl, and L possibly substituted G2;

Y represents C1-6alkyl or C3-6cycloalkyl, and Y possibly substituted G5.

Substituted phosphorous group, a quinoline represented by the following formula (If):

where in the above formula

Y represents C1-6alkyl or C3-6cycloalkyl, and Y possibly substituted G5.

Substituted phosphorous group, a quinoline selected from the group consisting of one or more than one of the following connections:

N1-[4-[[7-[3-(diethoxyphosphoryloxy)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[7-[3-(diethoxyphosphoryloxy)ethoxyl]-6-methoxyl-4-chinolin]oxyl]-3-f�ofranil]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[7-[3-(diethoxyphosphoryloxy)(methyl)amino)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[7-[3-(diethoxyphosphoryloxy)(ethyl)amino)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[7-[3-(diethoxyphosphoryloxy)(n-propyl)amino)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[7-[3-(diethoxyphosphoryloxy)(ethyl)amino)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)tikopian-1,1-dicarboxamide;

N1-[4-[[7-[3-(diethoxyphosphoryloxy)(methyl)amino)ethoxyl]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[7-[3-(diethoxyphosphoryloxy)(ethyl)amino)ethoxyl]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[7-[3-(diethoxyphosphoryloxy)(n-propyl)amino)ethoxyl]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[7-[3-(diethoxyphosphoryloxy)(ethyl)amino)ethoxyl]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[7-[3-(acetyl(diethoxyphosphoryloxy)amino)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-Fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[7-[3-(formyl(diethoxyphosphoryl�lmutil)amino)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[7-[3-(propionyl(diethoxyphosphoryloxy)amino)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[7-[3-(Isopropenyl(diethoxyphosphoryloxy)amino)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[7-[3-(cyclopropylmethyl(diethoxyphosphoryloxy)amino)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[7-[3-(acetyl(diethoxyphosphoryloxy)amino)ethoxyl]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[7-[3-(formyl(diethoxyphosphoryloxy)amino)ethoxyl]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[7-[3-(propionyl(diethoxyphosphoryloxy)amino)ethoxyl]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[7-[3-(Isopropenyl(diethoxyphosphoryloxy)amino)ethoxyl]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[7-[3-(cyclopropylmethyl(diethoxyphosphoryloxy)amino)ethoxyl]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1'-[4-[[7-[3-(aminocarbonyl(diethoxyphosphoryloxy)amino)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1-(4-fluorophenyl)cyclopropane,1-dicarboxamide;

N1'-[4-[[7-[3-(diethoxyphosphoryloxy)(ethylaminomethyl)amino)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1'-[4-[[7-[3-(diethoxyphosphoryloxy)(methylaminomethyl)amino)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1'-[4-[[7-[3-(diethoxyphosphoryloxy)(N,N'-dimethylaminoethyl)amino)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1'-[4-[[7-[3-(aminocarbonyl(diethoxyphosphoryloxy)amino)ethoxyl]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1'-[4-[[7-[3-(diethoxyphosphoryloxy)(ethylaminomethyl)amino)ethoxyl]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1'-[4-[[7-[3-(diethoxyphosphoryloxy)(methylaminomethyl)amino)ethoxyl]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1'-[4-[[7-[3-(diethoxyphosphoryloxy)(N,N'-dimethylaminoethyl)amino)ethoxyl]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1'-[4-[[7-[3-(diethoxyphosphoryloxy)(methyl-sulfonyl)amino)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1'-[4-[[7-[3-(diethoxyphosphoryloxy)(ethylsulfonyl)amino)ProPak�yl]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[6-[3-(diethoxyphosphoryloxy)propoxy]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[6-[3-(diethoxyphosphoryloxy)ethoxyl]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[6-[3-(diethoxyphosphoryloxy)(methyl)amino)propoxy]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[6-[3-(diethoxyphosphoryloxy)(ethyl)amino)propoxy]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[6-[3-(diethoxyphosphoryloxy)(n-propyl)amino)propoxy]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[6-[3-(diethoxyphosphoryloxy)(ethyl)amino)propoxy]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[6-[3-(diethoxyphosphoryloxy)(methyl)amino)ethoxyl]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[6-[3-(diethoxyphosphoryloxy)(ethyl)amino)ethoxyl]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[6-[3-(diethoxyphosphoryloxy)(n-propyl)amino)ethoxyl]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[6-[3-(diethoxyphosphoryloxy)(ethyl)amino)e�oxyl]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)tikopian-1,1-dicarboxamide;

N1-[4-[[6-[3-(acetyl(diethoxyphosphoryloxy)amino)propoxy]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[6-[3-(formyl(diethoxyphosphoryloxy)amino)propoxy]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[6-[3-(propionyl(diethoxyphosphoryloxy)amino)propoxy]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[6-[3-(Isopropenyl(diethoxyphosphoryloxy)amino)propoxy]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[6-[3-(temporaryfolder(diethoxyphosphoryloxy)amino)propoxy]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[6-[3-(acetyl(diethoxyphosphoryloxy)amino)ethoxyl]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[6-[3-(formyl(diethoxyphosphoryloxy)amino)ethoxyl]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[6-[3-(propionyl(diethoxyphosphoryloxy)amino)ethoxyl]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[6-[3-(Isopropenyl(diethoxyphosphoryloxy)amino)ethoxyl]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;/p>

N1-[4-[[6-[3-(cyclopropylmethyl(diethoxyphosphoryloxy)amino)ethoxyl]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1'-[4-[[6-[3-(aminocarbonyl(diethoxyphosphoryloxy)amino)propoxy]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1'-[4-[[6-[3-(diethoxyphosphoryloxy)(ethylaminomethyl)amino)propoxy]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1'-[4-[[6-[3-(diethoxyphosphoryloxy)(methylaminomethyl)amino)propoxy]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1'-[4-[[6-[3-(diethoxyphosphoryloxy)(N,N'-dimethylaminoethyl)amino)propoxy]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1'-[4-[[6-[3-(aminocarbonyl(diethoxyphosphoryloxy)amino)ethoxyl]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1'-[4-[[6-[3-(diethoxyphosphoryloxy)(ethylaminomethyl)amino)ethoxyl]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1'-[4-[[6-[3-(diethoxyphosphoryloxy)(methylaminomethyl)amino)ethoxyl]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1'-[4-[[6-[3-(diethoxyphosphoryloxy)(N,N'-dimethylaminoethyl)amino)ethoxyl-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1'-[4-[[6-[3-(diethoxyphosphoryloxy)(methyl-sulfonyl)amino)propoxy]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1'-[4-[[6-[3-(diethoxyphosphoryloxy)(ethylsulfonyl)amino)propoxy]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[7-[[1-(diethoxyphosphoryloxy)-4-piperidinyl]methoxyl]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[7-[[1-(2-diethoxyphosphoryl)-4-piperidinyl]methoxyl]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[6-[[1-(diethoxyphosphoryloxy)-4-piperidinyl]methoxyl]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[6-[[1-(2-diethoxyphosphoryl)-4-piperidinyl]methoxyl]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.

Substituted phosphorous group, a quinoline selected from the group consisting of one or more than one of the following connections:

N1-[4-[[7-[3-(diethoxyphosphoryloxy)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[7-[3-(diethoxyphosphoryl(N-methyl)methylamino)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[7-[3-acetyl(diethoxyphosphoryloxy)amino)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[7-[[1-(2-diethoxyphosphoryl)-4-piperidinyl]methoxyl]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;

N1-[4-[[7-[[1-(diethoxyphosphoryloxy)-4-piperidinyl]methoxyl]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.

The racemate or enantiomer of the substituted phosphorous quinoline group.

In this application a method of producing substituted phosphorous quinoline group, consisting of stages, presented in the following scheme 1:

Scheme 1

where

t is equal to 0-4;

LG or GL are generally accepted in the field of organic chemistry leaving groups;

PG is conventional in the field of organic chemistry protecting groups;

each RR1, RR11, RR12, RR2, RR3, RR4or RR5selected from H, C1-6alkyl, C3-6cycloalkyl, S6aryl, C5-6heteroaryl or C3-6geterotsiklicheskie and possibly substituted by H, -CN, -CF3, -CO2H, halogen, C1-6the alkyl, C1-6cycloalkyl, C2-6alkenyl, C2-6ukinila, S6the aryl, C5-6heteroaryl, C3-6heteroseksualci, R3O-, R3R4N-, R3S(=O)m-, R3R4NS(=O)m-, R5C(=O)-, R3R4NC(=O)-, R3OC(=O)-, R C(=O)O-, R3R4NC(=O)O-, R5C(=O)NR3-, R3R4NC(=O)NR6-, R3OC(=O)NR6-, R3S(=O)mNR6-, R3R4NS(=O)mNR6-, R3R4NC(=NR7)NR6-, R3R4NC(=CHNO2)NR6-, R3R4NC(=N-CN)NR6-, R3R4NC(=NR7)-, R3S(=O)(=NR7)NR6or R3R4NS(=O)(=NR7), where each of R3, R4, R5, R6and R7independently selected from hydrogen, C1-6alkyl, C3-6cycloalkyl, S6aryl, C5-6heteroaryl or C3-6erotically; when R3and R4attached to the same nitrogen atom, then R3and R4together with the nitrogen to which they are attached, can form a C3-6geteroseksualnoe ring, which may optionally contain heteroatom(s) selected(s) from O, N, S(=O)m; and each of R3, R4, R5, R6and R7possibly substituted by halogen, CN, C1-6the alkyl or C3-6Cycloalkyl; m is 0-2.

In this application a method of producing substituted phosphorous quinoline group, consisting of stages, presented in the following scheme 2:

Scheme 2

where

PP' can be anywhere from PG, H and PP; and PG can be transformed into H by means of the removal of protection.

In the present application is a method of producing substituted phosphorous quinoline group, consisting of stages, presented in the following scheme 3:

Figure 3

In the present application is a method of producing substituted phosphorous quinoline group, consisting of stages, presented in the following scheme 4:

Scheme 4

In the present application is a method of producing substituted phosphorous quinoline group, consisting of stages, presented in the following scheme 5:

Scheme 5

In this application the proposed use of pharmaceutical compositions containing substituted phosphorous group, a quinoline, where the composition is used for treatment of diseases associated with abnormal protein kinase activity.

In this application the proposed use of pharmaceutical compositions containing substituted phosphorous group, a quinoline, where the protein kinase is c-Met, KDR or VEGFR2, RET, PDGFR-β, c-KIT, FIt3, MEK5, DDR1, LOK, CSF1R, EPHA7, EPHA8, EPHB6, MKNK2, BLK, HIPK4, HCK or FIt4.

In this application the proposed use of pharmaceutical compositions containing substituted phosphorous group, a quinoline, where the protein kinase is a RON, ALK or anaplastic lymphoma kinase), EGF1R, HER2, HER3, HER4, PDGR-α, c-fms, FLT1, Src, Frk, Btk, CsK, Abl, Fes, Fps, Fak, AcK, Yes, Fyn, Lyn, Lck, Hck, Fgr, Yrk, PDK1, TAK1, Tie-2, Tie-1, YSK4, TRKA, TRK B, TRK C, SLK, PKN2, PLK4, MST1R, MAP4K or DDR2.

In this application the proposed use of pharmaceutical compositions containing substituted phosphorous group, a quinoline, where the disease that is treated with this composition, is a psoriasis, cirrhosis, diabetes, mediated by angiogenesis diseases, eye diseases, diseases of the immune system, or cardiovascular disease.

In this application the proposed use of pharmaceutical compositions containing substituted phosphorous group, a quinoline, where the disease that is treated with this composition, is a tumor, including solid and liquid tumors.

In this application the proposed use of pharmaceutical compositions containing substituted phosphorous group, a quinoline, where the disease that is treated with this composition, is a tumor, including lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin melanoma or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, bowel cancer is cancer of the endocrine system, thyroid cancer, parathyroid cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, bladder cancer, cancer of the kidney or ureter, renal cell carcinomas, tumors of the Central nervous system (CNS), spinal cord tumors, pituitary adenomas, gastrointestinal stromal tumors, colorectal cancer, non-small cell lung cancer, small cell lung cancer, mastocytosis, glioma, sarcoma and lymphoma.

In this application of the proposed drug for the treatment of diseases associated with abnormal activity of protein kinase, which contains any of the above compounds or its pharmaceutically acceptable salt, a solvate, a prodrug, or a racemate or enantiomer of any of the above compounds or its pharmaceutically acceptable salt, solvate, prodrug.

The above mentioned medicinal product further comprises at least one pharmaceutically acceptable carrier.

The above medication is in the form of the following compositions: (1) oral composition; (2) injecting the composition; (3) rectal suppositories; (4) the composition for nasal inhalation; (5) eye drops; (6) skin patch.

A series of experiments confirms that the substituted phosphorous group quinolines p� the present invention have the following advantages: (1) screening tests of inhibition of the kinase show the connection of the present invention has a strong inhibitory effect on a number of protein kinases and their mutants; (2) tests for the inhibition of the tumor show that such substituted phosphorous group, a quinoline significantly inhibited tumor growth without apparent toxicity; (3) the compound of the present invention may be used in combination with other anticancer drugs and thus to provide a synergistic or additive effect; (4) the compound of the present invention may be used in conjunction with other types of tumor therapy, such as radiotherapy, interventional therapy, etc. It shows replaced the phosphorous group, a quinoline of the invention can be used as a medicament for the effective treatment of diseases associated with abnormal protein kinase activity.

Among the diseases associated with abnormal protein kinase activity, treating a compound of the invention, the forms of kidney cancer are cancer of the adrenal, renal cell carcinoma or carcinoma of the renal pelvis; glioma represent neuroglia of the brain stem, the neuroendocrine glioma and neuroglioma.

In addition to tumors, diseases associated with abnormal activity of prot�incense, for treatment using a compound of the invention optionally include psoriasis, cirrhosis, diabetes, associated with an angiogenesis-related diseases, restenosis disease, eye diseases such as AMD (age-related macular degeneration), rheumatoid arthritis and other inflammatory diseases, diseases of the immune system such as autoimmune disease (e.g. AIDS), cardiovascular diseases such as atherosclerosis, or kidney disease, etc.

Pharmaceutical composition containing the compound of the present invention may be used to treat diseases associated with abnormal activity of protein kinase, in a mammal, such as patients-people.

By means of the manufacturing method of (cooking) a compound of the invention (including the racemate, enantiomer or other stereoisomer or its pharmaceutically acceptable salt, hydrate, solvate or prodrug in combination with suitable pharmaceutically acceptable carriers and is usually used in medicine, adjuvants can be prepared in the form of a pharmaceutical composition, which is favorable for the introduction.

Route of administration of the drug containing the compound according to the invention, can be: (1) oral administration, for example �ableto, capsule, etc.; (2) injection, for example intravenous, subcutaneous, intramuscular, ocular injection, intraperitoneal injection, etc.; (3) rectal plugging mass, such as suppositories, gels, etc.; and (4) nasal inhalation, for example, a spray, an aerosol, etc.; (5) eye drops; (6) a dermal patch. The system of release of the drug; for example, liposome technology, slow release, etc. can also be applied where it is preferable to apply the oral administration and injection, in particular is more preferable to apply the oral administration.

Various dosage forms of the pharmaceutical composition containing the compound of the present invention, can be prepared using conventional in the medical industry methods, such as mixing, dissolving, granulating, grinding, emulsifying, encapsulating, coating sugar coating, freeze drying, freeze drying, etc.

The content of compounds of the present invention in the pharmaceutical composition is in the range of 0.001-100%. An effective amount of a pharmaceutical composition for administration to mammals, including humans, is 0.1-500 mg per kilogram of body weight per day, preferably in amounts of 1-100 mg per kilogram of body weight per day. In this range with an effective amount of�the unity of the present invention exhibits a pharmaceutical action to inhibition of the activity of protein kinases and treatment of diseases, associated with abnormal activity of protein kinase (e.g. cancer).

Frequency of administration of the drug of the present invention may vary depending on the compounds or pharmaceutical compositions and diseases that must be treated; a pharmaceutical composition of the present invention is generally administered 1-6 times a day, the optimal frequency is 1-3 times a day.

Packaging and storage of the medicinal product according to the present invention is similar to the packing and storage of conventional Western medicines, for example a medicament in the form of a solid drug can be directly placed in a bottle made of glass, plastic, paper or metal; in vial preferably contains desiccant to maintain the quality of the drug; usually the drug is in the form of a liquid composition is placed in a bottle made of glass, plastic or metal or a flexible tube; as a medicament in the form of a composition in the form of fog is usually placed resistant to high pressure container of plastic or metal and be equipped with a pressure reducing valve, etc.

Definition of terms

Following are definitions of terms referred to in the present invention. Group variables used in the present invention, e.g., R a, Rb, m, etc., apply only to this section (i.e. the section "Definition of terms").

In accordance with the General specialist knowledge in this area the majority of chemical reactions must be conducted in a solvent; usually used a solvent to obtain compounds of the invention include water, methanol, ethanol, isopropanol, n-propanol, n-butanol, Isobutanol, tert-butanol, 2-methoxyethanol, 2,2,2-triptoreline, dichloro methane, 1,2-dichloroethane, chloroform, THF, dioxane, DME, ethyl acetate, diethyl ether, methyl tert-butyl ether, hexane, cyclohexane, toluene, acetonitrile, DMF (dimethylformamide), DMSO or a mixture of any two or more of the above solvents, but are not limited to. In some cases, chemical interactions must be conducted in the presence of acids or bases; generally used a base to obtain compounds of the invention include the Et3N, Me3N, i-Pr2NEt, pyridine, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DABCO (1,4-diazabicyclo[2.2.2]octane), tetramethylguanidine, NaOH, KOH, Cs2CO3, Na2CO3, K2CO3, NaHCO3, KF, CsF, K3PO3, K2HPO4, KH2PO4, NaH, n-BuLi, sec-BuLi, tert-BuLi, NaN(SiMe3)2, LiN(SiMe3)2, KN(SiMe3)2or a mixture of any two or more of the reasons listed above, but not limited�ciaude them; and commonly used acids include HCO2H, Acoh, TFUK (trifluoroacetic acid), HCl (hydrochloric acid), H2SO4, HNO3, H3PO4p-TsOH (p-toluensulfonate acid), PhSO3H, CSA (camphorsulfacid), MsOH (methanesulfonic acid) or a Lewis acid such as ZnCl2, AlCl3, BF3·OEt2, but are not limited to. In some cases, the chemical reaction should be carried out in the presence of a binding reagent; usually used binding reagents to obtain compounds of the invention include DCC (N,N'-dicyclohexylcarbodiimide), EDC, HATU, TBTU (tetrafluoroborate O-benzotriazole-1-yl-N,N,N',N'-tetramethylurea), PyBOP (hexaflurophosphate (benzotriazole-1-yloxy)triprolidine), HCTU (hexaflurophosphate O-(1H-6-chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethylurea), BOP (hexaflurophosphate the benzotriazole-1-yloxytris(dimethylamino)phosphonium), DIC (N,N'-diisopropylcarbodiimide, HOBt (1-hydroxy-benzotriazole), HOAt (1-gidroksibenzotriazola), CDI (1,1'-carbonyldiimidazole), DEPBT (3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-he), etc., but are not limited to. At some stage of obtaining compounds according to the invention the necessary remedial response and reducing agents; reducing agents include H2+Pd/C, H2+Pd(OH)2, H2+PtO2, H2+Raney Ni, H2Needed to harm2+Raney Ni, Mg+MeOH, Fe+Fe AcOH+HCl Zn+AcOH, Zn+HCl, Zn+NH4OAc, SnCl2, LiAIH4, NaBH4, NaBH3(CN), NaB(OAc)3H, BH3etc., but are not limited to. At some stage of obtaining compounds of the invention necessary remove the protection; when the protective group is a Boc (tert-butoxycarbonyl), a commonly used reagent to remove the protecting include HCl, TFUK, H2SO4etc., but are not limited to; when the protective group is a CBZ (benzyloxycarbonyl), a commonly used reagent to remove the protecting include strong HCl, H2+Pd/C, etc., but are not limited to; when the protective group is a Bn (benzyl), a commonly used reagent to remove the protecting include H2+Pd/C, H2+Pd(OH)2, H2+Pd/C+HCl, etc., but are not limited to. The reaction of obtaining the compounds according to the invention is usually carried out at room temperature, but sometimes the temperature must be lowered to -78°C or increased to 200°C. typically the reaction is conducted in terms of the above mentioned solvents and temperatures typically with stirring, but sometimes must be done in the microwave; when the substrate, reagent, catalyst are sensitive to water or oxygen, the reaction should be carried out in an anhydrous and oxygen-free conditions; in such a case can not be used with proton solvents.

The term "solvate" means a stable substance, formed by the compound of the invention and is typically used in chemical reactions with the solvent by means of covalent bonds, hydrogen bonds, ionic bonds, van der Waals forces, complexation, inclusion, etc.; the solvent may be methanol, ethanol, propanol, butanol, ethylene glycol, PROPANEDIOL, polyethylene glycol, acetone, acetonitrile, diethyl ether, methyl tert-butyl ether, etc.

The term "hydrate" means a solvate in which the solvent is water.

The term "prodrug" means a compound which is obtained by conversion of compounds of the present invention by means of chemical synthesis or physical method and transforms it back to the connection present�Adamu to the invention in the body of a mammal after it has been administered to a mammal. Usually the technique of "prodrug" is used to overcome insufficient or inappropriate physical-chemical property or the ability to exercise the medicinal properties of the drug compounds.

The term "racemate, enantiomer or other stereoisomer" means compounds having the same molecular formula and molecular weight, but they differ due to the different types of bonding between atoms and different spatial locations, such compounds called isomer or stereoisomer. When these stereoisomers are mirror images of each other, i.e. they look similar, but cannot be completely superimposed on each other, like left hand and right hand, these compounds are called enantiomers. The absolute configuration of the enantiomers is usually represented as (R)- and (S)- or R - and S-. Detailed rules for the determination of absolute configurations, see Chapter 4 of "Advanced Organic Chemistry", edition 4th (J. March, John Wiley and Sons, New York, 1992). (R)- and (S)-enantiomers rotate the plane of polarized light in opposite directions, i.e., rotation left and rotation right. When (R)- and (S)-enantiomers or are mixed in the ratio 1:1, the mixture has a rotating action on polarized light, this mixture is called a racemate.

The connection according to the invention may have tautomers, rotamer, CIS-TRANS isomers, etc., aceponate can be found and explored in "Advanced Organic Chemistry", edition 4th, J. March. Since these isomers have the same function of inhibiting protein kinase activity, and the connection according to the invention, these isomers are covered by the present invention.

In accordance with the General knowledge in the art, after administration of the compounds of the present invention mammals (e.g. humans), it probably is metabolized into various metabolites in the body of a mammal using a variety of enzymes, since these metabolites have the function of inhibiting protein kinase activity, similar to the function of the compounds according to the invention, they are also covered by the present invention.

The term "pharmaceutical composition" means a mixture obtained by mixing one or more compounds according to the invention, its pharmaceutically acceptable salt, or solvate, or hydrate, or prodrug with other chemical ingredient (e.g. pharmaceutically acceptable carrier). The purpose of the preparation of the pharmaceutical composition is to facilitate the introduction of animals. The above pharmaceutical compositions in addition to the pharmaceutically acceptable carrier may further contain commonly used pharmaceutical excipients, for example, antibacterial agent, antifungal agent, antimicrobe� agent, preservative, colouring substance, solubilizer, thickener, surfactant, chelating agent, protein, amino acid, fat, carbohydrate, vitamins, minerals, trace elements, sweetener, colorant, flavor, or combination thereof.

The term "pharmaceutically acceptable carrier" refers to an inactive ingredient in the pharmaceutical composition; it may be the calcium carbonate, calcium phosphate, various sugars (e.g. lactose, mannitol, etc.), starch, cyclodextrin, magnesium stearate, cellulose, magnesium carbonate, polyacrylate, polymethylacrylate, gelatin, water, glycol, PROPANEDIOL, ethylene glycol, castor oil, hydrogenated castor oil, polyethoxysiloxane hydrogenated castor oil, sesame oil, corn oil, peanut oil, etc.

The term "alkyl" means linear or branched saturated hydrocarbon group having the specified number of carbon atoms, for example C1-12alkyl means a linear or branched group with 1-12 carbon atoms. With0alkyl means a single covalent bond. Used in the present invention the term "alkyl" includes methyl, ethyl, propyl, butyl, isopropyl, neopentyl, 2-methyl-1-hexyl, etc., but is not limited thereto. One or all of the hydrogen atoms and�Qila can be substituted by the following groups: cycloalkyl, aryl, heteroaryl, geteroseksualnoe ring, halogen, amino, hydroxyl, cyano, nitro, carboxyl, thio, oxo, alkoxy, aryloxy, alkylthio, aaltio, carbonyl, thiocarbonyl, C-amide, N-amide, O-aminocarbonyl, N-aminocarboxylate, O-diaminocarbenes, N-diaminocarbenes, C-ester, O-ester and-NRaRbwhere Raand Rbrespectively selected from hydrogen, alkyl, cycloalkyl, aryl, acetyl, carbonyl, sulfonyl and triftormetilfullerenov, and Raand Rbtogether with the nitrogen atom to which they are attached, may form a 5 - or 6-membered geteroseksualnoe ring.

The term "cycloalkyl" or "cyclic alkyl" means a one-, two - or multiring hydrocarbon group having the specified number of carbon atoms; in the case of two - or multiring groups, they can be joined together to condensed (two adjacent carbon atoms are common to two or more rings) or Spiro group (one carbon atom is common to two or more rings), such as C1-12cycloalkyl means a group of one-, two - or multiring hydrocarbon compounds having 1 to 12 carbon atoms. With0cycloalkyl means one single covalent bond. Cycloalkyl may contain unsaturated double or triple bond, but does not have a completely conjugated π-electro�Noah system. Used in the present invention, the term "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclohexyl, cyclopentenyl, cycloheptatriene, Adamantine, but not limited to (examples are shown in table 1):

Table 1
etc.

One or all of the hydrogen atoms of cycloalkyl or cycloalkane can be substituted by the following groups: alkyl, aryl, heteroaryl, geteroseksualnoe ring, halogen, amino, hydroxyl, cyano, nitro, carboxyl, thio, oxo, alkoxy, aryloxy, alkylthio, aaltio, carbonyl, thiocarbonyl, C-amide, N-amide, O-aminocarbonyl, N-aminocarboxylate, O-diaminocarbenes, N-diaminocarbenes, C-ester, O-ester and-NRaRb, where Raand Rbrespectively selected from hydrogen, alkyl, cycloalkyl, aryl, acetyl, carbonyl, sulfonyl, triftormetilfullerenov, and Raand Rbtogether with the nitrogen atom to which they are attached, may form a 5 - or 6-membered geteroseksualnoe ring.

The term "halogen" means fluorine, chlorine, bromine or iodine.

The term "alkoxy" or "alkoxyl" means alkyl having the specified number of carbon atoms attached to another group through the ATO� of oxygen. Used in the present invention the term "alkoxy" include methoxyl, ethoxyl, propoxy, butoxy, cyclopentyloxy, cyclohexyloxy, isopropoxy, neopentylene, 2-methyl-1-hexyloxy, etc., but is not limited thereto.

The term "cycloalkane" or "cycloalkyl" means that cycloalkyl having specific number of carbon atoms attached to another group through an oxygen atom. Used in the present invention, the term "cycloalkane" includes cyclopropane, CYCLOBUTANE, cyclohexane and the like, but is not limited thereto.

The term "aryl" means one-, two - or multiring group consisting of 6-12 carbon atoms, where at least one ring is fully conjugated π-electronic system and meets the rule N+2, i.e. possesses aromaticity; but the entire group need not be fully connected. The aryl may also be in the form of arylene, i.e. in the structure of the aryl contains two or more than two atoms, attached to other groups. Used in the present invention, the term "aryl" includes phenyl, naphthyl, indenyl, indanyl, tetrahydronaphthalene, etc., but is not limited thereto. One or all of the hydrogen atoms of the aryl can be substituted by the following groups: alkyl, cycloalkyl, heteroaryl, geteroseksualnoe ring, halogen, amino, hydroxyl, cyano, nitro, carbox�l, thio, oxo, alkoxy, aryloxy, alkylthio, aaltio, carbonyl, thiocarbonyl, C-amide, N-amide, O-aminocarbonyl, N-aminocarboxylate, O-diaminocarbenes, N-diaminocarbenes, C-ester, O-ester and-NRaRbwhere Raand Rbrespectively selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, acetyl, carbonyl, sulfonyl, triftormetilfullerenov, and Raand Rbtogether with the nitrogen atom to which they are attached, may form a 5 - or 6-membered geteroseksualnoe ring.

The term "heteroaryl" means one-, two - or multiring group consisting of 5-12 ring atoms, other than hydrogen atoms, where at least one atom is an O, N or S(=O)m(where m is 0-2) and where at least one ring is fully conjugated π-electronic system and meets the rule N+2, i.e. possesses aromaticity; but the entire group need not be completely coupled; for example, C5heteroaryl means an aromatic ring group, consisting of 5 ring atoms, where at least one ring atom selected from O, N or S(=O)m(where m is 0-2). Heteroaryl may also be in the form of heteroarenes, i.e. in the structure of heteroaryl there are two or more than two atoms, attached to other groups. Used in the infusion�eat the invention, the term "heteroaryl" includes pyridinyl, pyridinoyl, tetrahydropyridine, pyrimidine, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, thiophenyl, furanyl, indole, azaindole, benzimidazole, indolinyl, indolinyl, chinoline, etc., but not limited to (examples are shown in table 2):

Table 2

One or all of the hydrogen atoms of heteroaryl can be substituted by the following groups: alkyl, cycloalkyl, aryl, geteroseksualnoe ring, halogen, amino, hydroxyl, cyano, nitro, carboxyl, thio, oxo, alkoxy, aryloxy, alkylthio, aaltio, carbonyl, thiocarbonyl, C-amide, N-amide, O-aminocarbonyl, N-aminocarboxylate, O-diaminocarbenes, N-diaminocarbenes, C-ester, O-ester and-NRaRbwhere Raand Rbrespectively selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, acetyl, carbonyl, sulfonyl and triftormetilfullerenov, and Raand Rbtogether with the nitrogen atom to which they are attached, may form a 5 - or 6-membered geteroseksualnoe ring.

The term "heteroseksualci or geteroseksualnoe ring" means a one-, two - or multiring alkyl or alkane, consisting of 3-12 Col�of core atoms, different from hydrogen atoms, where at least one atom is an O, N or S(=O)m(where m is 0-2), such as6heteroseksualci means adnakolava group consisting of 6 ring atoms, where at least one ring atom selected from O, N or S(=O)m(where m is 0-2). Such a ring may optionally contain double or triple bonds than single relations, but these double or triple bonds do not form an aromatic structure. These one-, two - or multiring alkali or alkanes can be in the form of a condensed ring, bridged ring or a Spiro ring. Used in the present invention, the term "heteroseksualci" or "geteroseksualnoe ring" includes piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, indolinyl, tetrahydropyridine, tetrahydrofuranyl, trapidil, etc., but not limited to (examples are shown in table 3):

Table 3

One or all of the hydrogen atoms of geterotsiklicheskie or geteroseksualnoe rings can be substituted by the following groups: alkyl, cycloalkyl, aryl, heteroaryl, geteroseksualnoe ring, halogen, amine�, hydroxyl, cyano, nitro, carboxyl, thio, oxo, alkoxy, aryloxy, alkylthio, aaltio, carbonyl, thiocarbonyl, C-amide, N-amide, O-aminocarbonyl, N-aminocarboxylate, O-diaminocarbenes, N-diaminocarbenes, C-ester, O-ester and-NRaRbwhere Raand Rbrespectively selected from the group consisting of: hydrogen, alkyl, cycloalkyl, aryl, acetyl, carbonyl, sulfonyl, triftormetilfullerenov, and Raand Rbtogether with the nitrogen atom to which they are attached, may form a 5 - or 6-membered geteroseksualnoe ring.

The term "aryloxy" means that the aryl is attached to another group through an oxygen atom. Used in the present invention, the term "aryloxy" include phenoxy, naphthyloxy, etc., but is not limited thereto.

The term "heteroaromatic" means that heteroaryl attached to another group through an oxygen atom. Used in the present invention, the term "heteroaromatic" includes a 4-pyridyloxy, 2-titilate, etc., but is not limited thereto.

The term "amino" means H2N - or H2N-, in which the hydrogen atoms are substituted, i.e., RaHN and RaRbN-.

The term "oxo" or "Axel" means =O, i.e., the oxygen attached to the carbon or heteroatoms including N, S, P, through a double bond. Examples of substances substituted by oxilog include� substances shown in table 4, but are not limited to:

Table 4

"Hydroxyl" means-OH.

"Nitro" means-NO2.

"Carboxyl" means-CO2H.

"Thio" means-SH.

"Alkylthio" means alkyl-S-.

"Aristeo" means an aryl-S-.

"Carbonyl" means-C(=O)-.

"Thiocarbonyl" means-C(=S)-.

"C-amide" means-C(=O)NRaRb.

"N-amide" means C(=O)NRa-.

"O-aminocarbonyl" means-O-C(=O)NRaRb.

"N-aminocarbonyl" means O-C(=O)NRa-.

"Diaminocarbenes" means-O-C(=S)NRaRb.

"N-diaminocarbenes" means O-C(=S)NRa-.

"C-ester" means-C(=O)ORa.

"N-ester" means C(=O)O-.

"Acetyl" means CH3C(=O)-.

"Sulfonyl" means-SO2Ra.

"Triftormetilfullerenov" means CF3SO2-.

Brief description of graphic materials

Fig.1 is an image of tumors in models of murine xenograft GTL-16.

Fig.2 is a curve of the change in tumor size in models of murine xenograft GTL-16.

Fig.3 is a curve showing the change�tion of body weight in models of murine xenograft GTL-16.

Fig.4 represents the molecular structure of the compounds according to the invention.

Concrete implementation of

The present invention is additionally described in the following examples, so that the General public will be further understood method of obtaining the compounds according to the invention and their useful effect. But the examples should not be construed as limiting the present application.

Following are abbreviations used in examples and their corresponding values. If any abbreviation that is not included in the following list, appears in the examples, it has a generally accepted value.

DMSO: dimethyl sulfoxide

TMS: tetramethylsilane

DCM: dichloro methane

CDCl3: datastreamptr

CD3OD: watermethanol

DME: 1,2-dimethoxyethane

THF: tetrahydrofuran;

water.: the aqueous solution

TLC: thin layer chromatography

LC-MS: liquid chromatography-mass spectrometry

g: grams

mg: milligram

mmol: millimole

mcm: micromol

ál: microliter

nm: nanomole

M: molarity

N: normality (equivalent concentration)

m/z: mass-to-charge

δ: chemical shift

DMAP: 4-dimethylaminopyridine

DIPEA: diisopropylethylamine

HATU: hexaflurophosphate 2-(7-asobancaria)-N,N,N',N'-tetramethylurea

EDC.HCl: hydrochloride 1-ethyl-3-(3-dimethylaminopropyl)carb�of diimide.

General conditions of the experiment:

Hydrogen and carbon spectra of nuclear magnetic resonance were obtained using equipment Varian INOVA-500 NB, or Varian 400 MHz or Bruker 400 MHz (solvent is deutero-DMSO, datentraeger or watermethanol, etc., and the internal standard is TMS). The mass spectrum obtained by using a liquid chromatograph-mass spectrometer (ionization source ESI (elektrorazpredelenie ionization) or APCI (chemical ionization at atmospheric pressure) ZQ4000, Waters Corporation, USA). UV spectrum was measured using an ultraviolet spectrophotometer UV-3010, Hitachi Corporation, Japan. The infrared spectrum is measured by an infrared spectrometer NICOLET 6700 (KBr disks). The HPLC was performed on high performance liquid chromatograph, Waters 2695 ZORBAX column (BX-C8, 5 μm, 150×4.6 mm). The melting point measured by a device for determining the melting point of Electrothermal IA9100, without correction.

The source materials, reagents and solvents are commercially available from: Beta Pharma, Shanghai; Shanghai PI Chemicals; AndaChem, Taiyuan; Shanghai FWD Chemicals; Sigma-Aldrich, Milwaukee, Wisconsin (WI), USA; Acros, Morris plains, new Jersey (NJ), USA; Frontier Scientific, Logan, Utah, USA; Alfa Aesar, ward hill, Massachusetts (MA), USA and etc., or synthesized by methods described in the literature. Unless specified in�, usually the solvent from the supplier was used directly without drying or dried using molecular sieves.

Methods of obtaining various intermediate compounds (including intermediate A, intermediate B, intermediate C, intermediate compound D, the intermediate compound F, intermediate connection G of intermediate compound H, intermediate I, intermediate J intermediate K) necessary for obtaining the compounds according to the invention are as follows.

The method of obtaining the intermediate A: 4-(2-fluoro-4-nitrophenoxy)-6-methoxyindole-7-ol:

Intermediate a connection receive according to the method described in WO 2008/035209, and analytical data of the obtained product are as follows:1H NMR (400 MHz, DMSO-d6): δ=11.74 (s, user., 1H), 8.76 (d, J=6.8 Hz, 1H), 8.47 (dd, J=2.8 Hz, J=10.4 Hz, 1H), 8.23 (dd, J=1.2 Hz, J=8.8 Hz, 1H), 7.81 (m, 1H), 7.65 (s, 1H), 7.49 (s, 1H), 7.04 (d, J=6.4 Hz, 1H), 3.94 (s, 3H).

The method of obtaining the intermediate B: 4-(2-fluoro-4-nitrophenoxy)-7-methoxyindole-6-ol:

Intermediate compound B receive according to the methods described in documents WO 2003/033472 and WO 2004/039782, and analytical data of the obtained product are as follows: mass spectrum m/z: 331.12 [M+H].

Method semi�t) of the intermediate C: tert-butyl-4-[[4-(4-amino-2-pertenece)-6-methoxyl-7-chinolin]hydroxymethyl]piperidine-1-carboxylate:

Intermediate compound C receive according to the method described in document WO 2008/076415, and analytical data of the obtained product are as follows: mass spectrum m/z: 498.21 [M+H].

A method of producing an intermediate compound D: 1-[(4-fluorophenyl)carbamoyl]cyclopropanecarboxylic acid:

Intermediate compound C receive according to the method described in document WO 2005/030140, and analytical data of the obtained product are as follows:1H NMR (400 MHz, DMSO-d6): δ=13.0 (s, 1H), 10.6 (s, 1H), 7.62-7.57 (m, 2H), 7.15-7.09 (m, 2H), 1.39 (s, 4H).

A method of producing an intermediate compound E: N-benzyl-3-chloro-N-(diethoxyphosphoryloxy)propan-1-amine:

1.6 ml of 37% aqueous formaldehyde solution was added to a suspension of the hydrochloride of N-benzyl-3-chloropropane-1-amine (7.9 g, or of 35.9 mmol) in dioxane (60 ml), the mixture is gently heated until it turns into a solution. The solution was cooled to room temperature, it is added 3.2 ml of diethylphosphate, stirring at room temperature for 30 minutes and then stirring at 90-100°C for 3 hours, the reaction is stopped. The solvent was removed under reduced pressure, and the residue purified by column chromatography (eluent: 1-4% MeOH in DCM) to give 7.6 g of the target compound (o�d: 63%). The analytical data of the obtained product are as follows:1H NMR (400 MHz, DMSO-d6): δ=7.30-7.21 (m, 5H), 4.01-3.93 (m, 4H), 3.69 (s, 2H), 3.59 (t, J=6.8 Hz, 2H), 2.83 (d, J=10.0 Hz, 2H), 2.61 (t, J=6.8 Hz, 2H), 1.85-1.82 (m, 2H), 1.2 (t, J=7.2 Hz, 6H).

The method of obtaining intermediate compounds F: 4-[[7-[3-(benzyl(diethoxyphosphoryloxy)amino)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-ftorhinolona:

Stage 1: obtaining N-benzyl-N-(diethoxyphosphoryl)-3-[[4-(2-fluoro-4-nitrophenoxy)-6-methoxyl-7-chinolin]oxyl]propan-1-amine: potassium carbonate (7.3 g or 53.2 mmol) was added to a solution of intermediate E (7.6 g or 22.8 mmol) and intermediate compound A (5.0 g or 15.2 mmol) in DMF (100 ml). The resulting mixture was stirred at 110°C for 2 hours. The reaction mixture was diluted with 500 ml of ethyl acetate, an inorganic salt was removed through filtration, the filtrate concentrated, and the residue purified by column chromatography (eluent: 1-4% MeOH in DCM) to give 3.6 g of the target compound (yield: 38%). The analytical data of the obtained product are as follows:1H NMR (400 MHz, DMSO-d6): δ=8.57 (d, J=5.2 Hz, 1H), 8.47 (dd, J=2.4, 10.4 Hz, 1H), 8.21-8.18 (m, 1H), 7.63 (t, J=8.8 Hz, 1H), 7.41-7.18 (m, 8H), 6.78 (d, J=5.2 Hz, 1H), 4.17 (t, J=6.4 Hz, 2H), 4.04-3.96 (m, 4H), 3.86 (s, 3H), 3.78 (s, 2H), 2.91 (d, J=10.0 Hz, 2H), 2.73 (t, J=6.4 Hz, 2H), 2.00 (t, J=6.4 Hz, 2H), 1.24-1.19 (m, 6H).

Stage 2: obtaining 4-[[7-[3-(benzyl(diethoxymethylsilane) propoxy]-6-methoxyl-4-chinolin]oxyl]-3-ftorhinolona:

N-benzyl-N-(diethoxyphosphoryl)-3-[[4-(2-fluoro-4-nitrophenoxy)-6-methoxyl-7-chinolin]oxyl]propan-1-amine (3.6 g, or 28.7 mmol) obtained in stage 1, was dissolved in 300 ml of THF, there was added 5 g of Raney Nickel, the resulting mixture was stirred at 30°C under a hydrogen pressure of 30 f./square inch (about 206,8 kPa) for 2 hours. In the end the reaction mixture was filtered, and the filtrate concentrated under reduced pressure to obtain 2.9 g of the target compound (yield: 83%). The analytical data of the obtained product are as follows: mass spectrum m/z: 598.01 [M+H].

The method of obtaining the intermediate G: 4-[[6-[3-(benzyl(diethoxyphosphoryloxy)amino)propoxy]-7-methoxyl-4-chinolin]oxyl]-3-ftorhinolona:

Taking as a basis of the intermediate compound E and the intermediate B, intermediate connection G prepared in a manner analogous to the method of obtaining the intermediate compounds F. Analytical data of the obtained product are as follows: mass spectrum m/z: 598.08 [M+H].

The method of obtaining the intermediate H: 3-chloro-N-(diethoxyphosphoryloxy)-N-methylpropan-1-amine:

0.8 ml of 37% aqueous formaldehyde solution was added to a suspension of 3-chloro-N-methylpropan-1-amine (1.4 g or 1.3 mmol) in dioxane (30 ml), the mixture is gently heated until it turns into a solution. �Astor cooled to room temperature, it is added 1.6 ml of diethylphosphate, stirring at room temperature for 30 minutes and then stirring at 90-100°C for 3 hours, the reaction is stopped. The solvent was removed under reduced pressure, and the residue purified by column chromatography (eluent: 1-4% MeOH in DCM) to give 2.3 g of the target compound (yield: 81%). The analytical data of the obtained product are as follows:1H NMR (400 MHz, CDCl3): δ=4.17-4.10 (m, 4H), 3.74-3.53 (m, 4H), 3.28-3.08 (m, 2H), 2.80 (s, 3H), 2.25-2.09 (m, 2H), 1.29 (t, J=6.8 Hz, 6H).

A method of producing an intermediate of compound I: 4-[[7-[3-(diethoxyphosphoryloxy(methyl))amino)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-ftorhinolona:

Stage 1: obtaining N-(diethoxyphosphoryl)-3-[[4-(2-fluoro-4-nitrophenoxy)-6-methoxyl-7-chinolin]oxyl]-N-methyl-propane-1-amine: potassium carbonate (2.9 g or 21,0 mmol) was added to a solution of intermediate compound H (2.0 g or 6.0 mmol) and intermediate compound A (2.3 g or 9.0 mmol) in DMF (45 ml). The resulting mixture was stirred at 110°C for 2 hours. The reaction mixture was diluted with 100 ml of ethyl acetate, an inorganic salt was removed through filtration, the filtrate concentrated, and the residue purified by column chromatography (eluent: 1-5% MeOH in DCM) to give 1.8 g of the target compound (yield: 55%). The analytical data of the obtained product yavl�are as follows: 1H NMR (400 MHz, DMSO-d6): δ=8.55 (d, J=5.2 Hz, 1H), 8.46 (dd, J=2.4, 10.8 Hz, 1H), 8.22-8.15 (m, 1H), 7.62 (t, J=8.4 Hz, 1H), 7.43 (d, J=12.8 Hz, 2H), 6.76 (d, J=5.2 Hz, 1H), 4.20 (t, J=8.4 Hz, 2H), 4.01-3.95 (m, 4H), 3.91 (s, 3H), 2.82 (d, J=10.8 Hz, 2H), 2.64 (t, J=6.8 Hz, 2H), 2.34 (s, 3H), 1.96-1.93 (m, 3H), 1.21 (t, J=4.4 Hz, 6H).

Stage 2: obtaining 4-[[7-[3-(diethoxyphosphoryloxy(methyl))amino)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-ftorhinolona:

N-(diethoxyphosphoryl)-3-[[4-(2-fluoro-4-nitrophenoxy)-6-methoxyl-7-chinolin]oxyl]-N-methyl-propane-1-amine (1.8 g or 3.3 mmol), obtained in stage 1, was dissolved in 170 ml of THF, there was added 5 g of Raney Nickel, the resulting mixture was stirred at 30°C under a hydrogen pressure of 30 f./square inch (about 206,8 kPa) for 2 hours. In the end the reaction mixture was filtered, and the filtrate concentrated under reduced pressure to obtain 1.6 g of the target compound (yield: 97%). The analytical data of the obtained product are as follows: mass spectrum m/z: 522.10 [M+H].

The method of obtaining the intermediate J: 4-[[6-[3-(diethoxyphosphoryloxy)(methyl)amino)propoxy]-7-methoxyl-4-chinolin]oxyl]-3-ftorhinolona:

Taking as a basis the intermediate N and intermediate compound B, the intermediate compound J prepared in a manner analogous to the method of obtaining the intermediate compounds I. Analytical data of the obtained product are as follows: mass spectrum m/z: 52.12 [M+H].

The method of obtaining the intermediate K: dihydrochloride N1-[3-fluoro-4-[[6-methoxyl-7-(4-piperidinylmethyl)-4-chinolin]oxyl]phenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:

Stage 1: obtain tert-butyl-4-[[4-[2-fluorine-4-[[1-[(4-fluorophenyl)aminocarbonyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxyl-7-chinolin]hydroxymethyl]piperidine-1-carboxylate: a mixture of intermediate C (1.5 g or 3.0 mmol), intermediate D (1.7 g or 7.6 mmol), DIPEA (1.55 g or 12.0 mmol), HATU (2.3 g or 6.0 mmol), DMAP (0,183 g or 1.5 mmol) in DMF (60 ml) was stirred at 30-40°C during the night. The mixture is concentrated under reduced pressure, and the residue purified by column chromatography (eluent: 1-5% MeOH in DCM) to give 1.9 g of the target compound (yield: 90%). The analytical data of the obtained product are as follows: mass spectrum m/z: 703.30 [M+H].

Stage 2: obtain the dihydrochloride tert-butyl-N1-[3-fluoro-4-[[6-methoxyl-7-(4-piperidinylmethyl)-4-chinolin]oxyl]phenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide: at 0°C saturated solution (40 ml), HCl in EtOAc is added to a solution of tert-butyl-4-[[4-[2-fluorine-4-[[1-[(4-fluorophenyl)aminocarbonyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxyl-7-chinolin]hydroxymethyl]piperidine-1-carboxylate (1.6 g 2.3 mmol), obtained in stage 1, in EtOAc (40 ml), the resulting mixture was stirred at room� temperature for 4 hours. The mixture was filtered to collect the precipitate, followed by washing with EtOAc obtaining 1.0 g of the target compound (yield: 69%). The analytical data of the obtained product are as follows: mass spectrum m/z: 603.10 [M+H].

Example 1

Getting one replaced, the phosphorous group quinolines of the present invention, N1-[4-[[7-[3-(benzyl(diethoxyphosphoryloxy)amino)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:

A mixture of intermediate F (3.3 g or 5.5 mmol), intermediate D (3.1 g or 13,8 mmol), DIPEA (3.8 g 22.1 mmol), HATU (4.2 g or 11.0 mmol), DMAP (0,337 g or 2.8 mmol) dissolved in DMF (150 ml), stirred at 30-40°C during the night. The mixture is concentrated under reduced pressure, and the residue purified by column chromatography (eluent: 1-4% MeOH in DCM) to give 3.0 g of the compounds according to the invention (yield: 68%). The analytical data of the obtained product are as follows: mass spectrum m/z: 803.10 [M+H].

Example 2

Getting one replaced, the phosphorous group quinolines of the present invention, N1-[4-[[6-[3-(benzyl(diethoxyphosphoryloxy)amino)propoxy]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)tikopian-1,1-dicarboxamide:

Using an intermediate connection G and about�autocine compound D, the above compound obtained in the same manner as in example 1. The analytical data of the obtained product are as follows: mass spectrum m/z: 803.13 [M+H].

Example 3

Getting one replaced, the phosphorous group quinolines of the present invention, N1-[4-[[7-[3-(diethoxyphosphoryloxy)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:

N1-[4-[[7-[3-(benzyl(diethoxyphosphoryloxy)amino)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide obtained in example 1 (1.0 g or 1.2 mmol) was dissolved in EtOH/THF (1:1, 250 ml), there was added Pd(OH)2(1 g), and the resulting mixture was stirred at 45°C under a hydrogen pressure of 50 p./square inch (about 344,7 kPa) for 18 hours. In the end the reaction mixture was filtered, the filtrate is concentrated under reduced pressure, and the residue purified by column chromatography (eluent: 1-4% MeOH in DCM) to give 0,368 g of the compounds according to the invention (yield: 43%). The analytical data of the obtained product are as follows: mass spectrum m/z: 713.20 [M+H].

Example 4

Getting one replaced, the phosphorous group quinolines of the present invention, N1-[4-[[6-[3-(diethoxyphosphoryloxy)propoxy]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)qi�laplapan-1,1-dicarboxamide:

Using N1-[4-[[6-[3-(benzyl(diethoxyphosphoryloxy)amino)propoxy]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide obtained in example 2, the above compound obtained in the same manner as in example 3. The analytical data of the obtained product are as follows: mass spectrum m/z: 713.21 [M+H].

Example 5

Getting one replaced, the phosphorous group quinolines of the present invention, N1-[4-[[7-[3-(acetyl(diethoxyphosphoryloxy)amino)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)tikopian-1,1-dicarboxamide:

N1-[4-[[7-[3-(diethoxyphosphoryloxy)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)tikopian-1,1-dicarboxamide obtained in example 3 (1.0 g or 1.4 mmol), and DIPEA (0,544 g or 4.2 mmol) was dissolved in DCM (50 ml) there is added acetic anhydride (0,428 g or 4.2 mmol), and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM followed by washing with brine and then concentrated, and the residue purified by column chromatography (eluent: 1-3% MeOH in DCM) to give 0,856 g of the compounds according to the invention (yield: 81%). The analytical data of the obtained product are as follows: mass spectrum m/z: 755.18 [�+N].

Example 6

Getting one replaced, the phosphorous group quinolines of the present invention, N1-[4-[[6-[3-(acetyl(diethoxyphosphoryloxy)amino)propoxy]-7-methoxyl-4-quinol Il]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:

Using N1-[4-[[6-[3-(diethoxyphosphoryloxy)propoxy]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide obtained in example 4, the above compound is synthesized in the same manner as in example 5. The analytical data of the obtained product are as follows: mass spectrum m/z: 755.18 [M+H].

Example 7

Getting one replaced, the phosphorous group quinolines of the present invention, N1-[4-[[7-[3-(diethoxyphosphoryloxy)(methyl)amino)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:

A mixture of intermediate compound I (0.8 g (1.5 mmol), intermediate D (0,856 g or 7.6 mmol), DIPEA (1.1 ml or 6.1 mmol), HATU (1.2 g or 3.1 mmol), DMAP (0.093 g or 0.8 mmol) in DMF (60 ml) was stirred at 30-40°C during the night. The mixture is concentrated under reduced pressure, and the residue purified by column chromatography (eluent: 1-5% MeOH in DCM) to give 0,352 g of the compounds according to the invention (yield: 31%). Analytical data� of the obtained product are as follows: 1H NMR (400 MHz, DMSO-d6): δ=10.37 (s, 1H), 9.99 (s, 1H), 8.46 (d, J=5.2 Hz, 1H), 7.90 (dd, J=2.4, 13.2 Hz, 1H), 7.64-7.60 (m, 2H), 7.64-7.60 (m, 2H), 7.51-7.49 (m, 2H), 7.16-7.11 (m, 2H), 6.41 (t, J=4.4 Hz, 1H), 4.19 (t, J=6.0 Hz, 1H), 4.04-3.96 (m, 4H), 3.93 (s, 3H), 2.90-2.81 (m, 2H), 2.71-2.61 (m, 2H), 2.06 (s, 3H), 1.98-1.90 (m, 2H), 1.46-1.42 (m, 4H), 1.21 (t, J=7.2 Hz, 6H).

Example 8

Getting one replaced, the phosphorous group quinolines of the present invention, N1-[4-[[6-[3-(diethoxyphosphoryloxy)(methyl)amino)propoxy]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:

Using intermediate J and intermediate compound D, the above compound obtained in the same manner as in example 7. The analytical data of the obtained product are as follows: mass spectrum m/z: 727.20 [M+H].

Example 9

Getting one replaced, the phosphorous group quinolines of the present invention, N1-[4-[[7-[[1-(2-diethoxyphosphoryl)-4-piperidinyl]methoxyl]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:

A mixture of intermediate K (0.5 g or 0.8 mmol), 2-diethoxyphosphoryloxy acid (0,307 g or 1.6 mmol), DIPEA (0,404 g or 3.1 mmol), HATU (0,597 g or 1.6 mmol) in DMF (15 ml) was stirred at room temperature for 2 hours. The mixture is concentrated under reduced pressure�, and the residue purified by column chromatography (eluent: 1-5% MeOH in DCM) to give 0,237 g of the compounds according to the invention (yield: 39%). The analytical data of the obtained product are as follows:1H NMR (400 MHz, DMSO-d6): δ=10.37 (s, 1H), 9.99 (s, 1H), 8.45 (d, J=5.2 Hz, 1H), 7.90 (dd, J=2.0, 13.2 Hz, 1H), 7.64-7.60 (m, 2H), 7.50-7.48 (m, 2H), 7.42-7.37 (m, 2H), 7.16-7.11 (m, 2H), 6.40 (dd, J=1.2, 5.2 Hz, 1H), 4.45-4.35 (m, 1H), 4.05-3.98 (m, 7H), 3.93 (s, 3H), 3.20-3.00 (m, 3H), 2.65-2.55 (m, 1H), 2.20-2.00 (m, 1H), 1.88-1.78 (m, 2H), 1.45-1.44 (m, 4H), 1.42-1.28 (m, 1H), 1.23 (t, J=6.8 Hz, 6H), 1.18-1.08 (m, 1H).

Example 10

Getting one replaced, the phosphorous group quinolines of the present invention, N1-[4-[[7-[[1-(diethoxyphosphoryloxy)-4-piperidinyl]methoxyl]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)tikopian-1,1-dicarboxamide:

0,11 ml of 37% aqueous formaldehyde solution was added to a suspension of intermediate compound K (0.8 g or 1.3 mmol) in dioxane (10 ml), the mixture is gently heated until it turns into a solution. The solution was cooled to room temperature, add 0,21 ml of diethylphosphate with stirring at room temperature for 30 minutes and then stirring at 90-100°C for 3 hours, the reaction is stopped. The solvent was removed under reduced pressure, and the residue purified by column chromatography (eluent: 1-4% MeOH in DCM) to give 0,354 g is connected�I according to the invention (yield: 35%). The analytical data of the obtained product are as follows:1H NMR (400 MHz, DMSO-d6): δ=10.37 (s, 1H), 10.00 (s, 1H), 8.45 (d, J=5.2 Hz, 1H), 7.90 (dd, J=2.0, 13.2 Hz, 1H), 7.64-7.60 (m, 2H), 7.51-7.49 (m, 2H), 7.42-7.36 (m, 2H), 7.16-7.11 (m, 2H), 6.39 (d, J=5.2 Hz, 1H), 4.05-3.97 (m, 6H), 3.93 (s, 3H), 3.06-3.03 (m, 2H), 2.76-2.74 (m, 2H), 2.15-2.09 (m, 2H), 1.88-1.74 (n, 3H), 1.45-1.33 (m, 6H), 1.24 (t, J=6.8 Hz, 6H).

Example 11

Getting one replaced, the phosphorous group quinolines of the present invention, N1'-[4-[[7-[3-(aminocarbonyl(diethoxyphosphoryloxy)amino)propoxy]-6-methoxyl-4-quinol Il]oxyl]-3-fluorophenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:

N1-[4-[[7-[3-(diethoxyphosphoryloxy)propoxy]-6-methoxyl-4-quinol Il]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide obtained in example 3 (is 71.2 mg or 0.1 mmol) was dissolved in DCM (5 ml), and then there add Me3Si-NCO (23,0 mg or 0.20 mmol) and diisopropylethylamine (38,5 mg or 0.3 mmol), the resulting mixture was stirred at room temperature for 16 hours, the solvent was removed under reduced pressure, and the crude product is purified by column chromatography on silica gel (eluent: 1-4% MeOH in DCM) to give of 57.5 mg of the compounds according to the invention (yield: 76%). The analytical data of the obtained product are as follows: mass spectrum m/z: 756.12 [M+H].

Example 12

Getting one replaced the phospho�group containing quinolines of the present invention, N1'-[4-[[6-[3-(aminocarbonyl(diethoxyphosphoryloxy)amino)propoxy]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:

Using N1-[4-[[6-[3-(diethoxyphosphoryloxy)propoxy]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide obtained in example 4, the above compound obtained in the same manner as in example 11. The analytical data of the obtained product are as follows: mass spectrum m/z: 756.18 [M+H].

Example 13

Getting one replaced, the phosphorous group quinolines of the present invention, N1'-[4-[[7-[3-(diethoxyphosphoryloxy)(ethylaminomethyl)amino)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:

N1-[4-[[7-[3-(diethoxyphosphoryloxy)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide obtained in example 3 (is 71.2 mg or 0.1 mmol) was dissolved in DCM (5 ml), then there is added EtNCO (14.2 mg or 0.20 mmol) and diisopropylethylamine (38,5 mg or 0.3 mmol), the resulting mixture was stirred at room temperature for 16 hours, the solvent was removed under reduced pressure, and the crude product is purified by column chromatography on silica gel (eluent: 1-4% MeOH � DCM) to give 64.3 mg of the compounds according to the invention (yield: 82%). The analytical data of the obtained product are as follows: mass spectrum m/z: 784.22 [M+H].

Example 14

Getting one replaced, the phosphorous group quinolines of the present invention, N1'-[4-[[7-[3-(diethoxyphosphoryloxy)(propionyl)amino)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1-(4-fluorophenyl)tikopian-1,1-dicarboxamide:

N1-[4-[[7-[3-(diethoxyphosphoryloxy)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (is 71.2 mg or 0.1 mmol), obtained in example 3 was dissolved in DCM (5 ml), then there is added propionic acid (14,8 mg or 0.20 mmol), EDC.HCl (38.4 mg (0.2 mmol) and diisopropylethylamine (64,2 mg or 0.5 mmol), the resulting mixture was stirred at room temperature for 16 hours, the solvent was removed under reduced pressure, and the crude product is purified by column chromatography on silica gel (eluent: 1-4% MeOH in DCM) to give a reading of 50.7 mg of the compounds according to the invention (yield: 66%). The analytical data of the obtained product are as follows: mass spectrum m/z: 769.15 [M+H].

Example 15

Getting one replaced, the phosphorous group quinolines of the present invention, N1'-[4-[[7-[3-(diethoxyphosphoryloxy)(methyl-sulfonyl)amino)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1-(4-fluorophenyl)Cyclops�pan-1,1-dicarboxamide:

N1-[4-[[7-[3-(diethoxyphosphoryloxy)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide obtained in example 3 (is 71.2 mg or 0.1 mmol) was dissolved in DCM (5 ml), and then there was added methylsulfonylamino (22,9 mg or 0.20 mmol), EDC.HCl (38.4 mg (0.2 mmol) and diisopropylethylamine (64,2 mg or 0.5 mmol), the resulting mixture was stirred at room temperature for 16 hours, the solvent was removed under reduced pressure, and the crude product is purified by column chromatography on silica gel (eluent: 1-4% MeOH in DCM) to give 44,3 mg of the compounds according to the invention (yield: 56%). The analytical data of the obtained product are as follows: mass spectrum m/z: 791.28 [M+H].

Example 16

Screening test kinase inhibition:

In this example, the compound obtained in example 10, N1-[4-[[7-[[1-(diethoxyphosphoryloxy)-4-piperidinyl]methoxyl]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, tested for inhibitory effect on 442-kinase panel KinomeScan™ (http://www.kinomescan.com) from DiscoveRx Corporation (4215 Sorrento Valley Blvd, San Diego, California (CA) 92121), when the concentration of the compounds of 1000 nm, the results shown in the following table 5.

For detailed information on methods for screening, see Fabian, M. A. et al, Nat Biotechnol. 2005, 23, 329 and Karaman, M. W. et al, Nat Biotechnol. 2008, 26, 127 the following typical results you can see the connection of the present invention has a significant inhibitory effect on kinases, including c-Met, KDR or VEGFR2, RET, PDGFR-β, c-KIT, Flt3, MEK5, DDR1, LOK, CSF1R, EPHA7, EPHA8, EPHB6, MKNK2, BLK, HIPK4, HCK, FIt4 and their mutants.

LZK
Table 5
Kinase-targetExample 10Kinase-targetExample 10
The gene symbol for Ambit% Ctrl@1000 nmThe gene symbol for Ambit% Ctrl@1000 nm
AAK191MAPKAPK2100
ABL1 (E255K)-phosphorylated63MARKERS100
ABL1 (F317I)-nefosfaurilirovanna42MARK1100
ABL1 (F317I)-phosphorylated70MARK2100
ABL1 (F317L)-nefosfaurilirovanna10MARK3 100
ABL1 (F317L)-phosphorylated69MARK4100
ABL1 (H396P)-nefosfaurilirovanna1,9MAST1100
ABL1 (H396P)-phosphorylated63MEK124
ABL1 (M351T)-phosphorylated42MEK233
ABL1 (Q252H)-nefosfaurilirovanna2,4MAC100
ABL1 (Q252H)-phosphorylated84MEK4100
ABL1 (T315I)-nefosfaurilirovanna3,8MEK50,25
ABL1 (T315I)-75MEK687
phosphorylated
ABL1 (Y253F)-phosphorylated32MELK29
ABL1-nefosfaurilirovanna1,8MERTK2,1
ABL1-phosphorylated33METH7,7
ABL228METH (MT)3
ACVR1100MET (Y1235D)4,4
ACVR1B100MINK100
ACVR2A100MKK7100
ACVR2B100MKNK145
ACVRL1100MKNK20,05
ADCK367MLCK100
ADCK 100MLK183
AKT1100MLK278
AKT210MLK363
ACT100MRCKA100
ALK15MRCKB100
AMRS-alpha1100MST1100
AMRS-ALPHA2100MST1R4
ANKK1100MST2100
ARK5100MST3100
ASK1100MST480
ASK2100MTOR 100
AURKA100MUSK13
AURKB74MYLK100
AURKC66MYLK2100
AXL8MYLK4100
BIKE100MYO3A93
BLK0,5MYO3B100
BMPR1A100NDR1100
BMPR1B100NDR282
BMPR2100NEK1100
BMX92NEK11100
BRAF100 NEK2100
BRAF (V600E)100NEK358
BRK3,0NEK4100
BRSK1100NEK597
BRSK2100NEK6100
VTK51NEK7100
CAMK178NEK966
CAMK1D96NIM1100
CAMK1G88NLK100
CAMK2A100CSR196
CAMK2B100R38-alpha53
CAMK2D 9438-beta87
CAMK2G100R38-Delta53
CAMK4100R38-gamma100
CAMKK132PAK137
CAMKK281PAK254
CASK100REC32
CDC2L1100PAKL4100
CDC2L2100PAK687
CDC2L5100PKA7100
CDK1167PCTK1100
CDK2100PCTK200
CDK3100RSTC100
CDK4-cyclin D1100PDGFRA1,8
CDK4-cyclin D3100PDGFRB0
CDK5100PDPK1100
CDK715PFCDPK1 (P. falciparum)84
CDK876PFPK5100
(P. falciparum)
CDK9100PFTAIRE287
CDKL1100PFTK100
CDKL2100PHKG1100
CDKL3 100PHKG296
CDKL5100PIK3C2B100
CHEK1100PIK3C2G98
CHEK235PIK3CA100
CIT100PIK3CA (C420R)100
CLK189PIK3CA (E542K)100
CLK278PIK3CA (E545A)74
CLK3100PIK3CA (E545K)100
CLK446PIK3CA (H1047L)100
CSF1R0,25PIK3CA (H1047Y)63
CSK14PIK3CA (18DDL) 100
CSNK1A1100PIK3CA (M1043I)100
CSNK1A1L100PIK3CA (Q546K)100
CSNK1D100PIK3CB100
CSNK1E100PIK3CD100
CSNK1G1100PIK3CG100
CSNK1G2100PIK4CB100
CSNK1G3100PIM196
CSNK2A1100PIM267
CSNK2A2100PIM367
CTK100PIP5K1A100
DAPK1 100PIP5K1C100
DAPK2100PIP5K2B100
DAPK3100PIP5K2C38
DCAMKL191The RAX-alpha100
DCAMKL2100The RAX-beta100
DCAMKL3100PKMYT1100
DDR10PKN1100
DDR27,8PKN22,6
DLK52PKNB (M. tuberculosis)96
DMPK85PLK1100
DMPK276PLK2 83
DRAK1100PLK3100
DRAK2100PLK47,4
DYRK1A100PRKCD100
DYRK1B86PRKCE100
DYRK2100PRKCH100
EGFR100PRKCI100
EGFR (E746-A750del)92PRKCQ100
EGFR (G719C)75PRKD1100
EGFR (G719S)81PRKD2100
EGFR (L747-E749del, A750P)67PRKD388
EGFR (L747-S752del, P753S 67PRKG1100
EGFR (L747-T751del, Sins)72PRKG2100
EGFR (L858R)59PRKR100
EGFR (L858R, T790M)100PRKX81
EGFR (L861Q)84PRP476
EGFR (S752-1759del)82PYK219
EGFR (T790M)100QSK100
EIF2AK1100RAF1100
EPHA14,6RET0,1
EPHA24,8RET (M918T)0,05
EPHA360,35
EPHA44RET (V804M)0,6
EPHA53,5RIOK1100
EPHA64,8RIOK2100
EPHA70,8RIOK3100
EPHA80,15RIPK199
EPHB14,6RIPK230
EPHB22,8RIPK489
EPHB336RIPK582
EPHB412ROCK1100
EPHB60,9ROCK2100
ERBB2/td> 96ROS129
ERBB398RPS6KA4 (N-terminal kinase domain 1)76
ERBB4100RPS6KA4 (C-terminal kinase domain 2)100
ERK199RPS6KA5 (N-terminal kinase domain 1)100
ERK2100RPS6KA5 (C-terminal kinase domain 2)83
ERK3100RSK1 (N-terminal kinase domain 1)59
ERK4100RSK1 (C-terminal kinase domain 2)100
ERK5100RSK2 N-terminal kinase domain 1)100
ERK895RSK3 (N-terminal kinase domain 1)100
ERN181RSK3 (C-terminal kinase domain 2)100
FAK51RSK4 (N-terminal kinase domain 1)77
FER50RSKK4 (C-terminal91
kinase domain 2)
FES44S6K189
FGFR1100SBK1100
FGFR76SgK110100
FGFR369SGK375
FGFR3 (G697C)100SIK60
FGFR4100SIK2100
FGR 35SLK7,4
FLT17,3SNARK100
FLT32,3SNRK100
FLT3 (D835H)0,6SRC3,2
FLT3 (D835Y)2,4SRMS8,9
FLT3 (ITD)2,8SRPK170
FLT3 (K663Q)0,55SRPK2100
FLT3 (N841L)0SRPK3100
FLT3 (R834Q)16STK1677
FLT40,2STK3346
FRK8,8STK3582
FYN48STK36100
GAK100STK39100
GCM2 (kinase domain 2.S808G)100SYK58
GRK1100TAK175
GRK478TAOK1100
GRK7100TAOK270
GSK3A100TAOK3100
GSK3B100TBK179
HCK0,35TEC100
HIPK192TESK139
HIPK2100 TGFBR1100
HIPK366TGFBR2100
HIPK40,15TIE14
HPK140TIE22,4
HUNK100TLK188
ICK95TLK2100
IGF1R94TNIK70
IKK-alpha100TNK130
IKK-beta100TNK294
IKK-Epsilon94TNNI3K94
INSR54TRAK1,8
INSRR65TRKB4
IRAKI100TRKC2,2
IRAK333TRPM686
IRAK4100TSSK1B100
ITK34TTK84
JAK1 (catalytic JH1 domain)93TXK62
JAK1 (pseudobinary JH2 domain)100TYK2 (catalytic JH1 domain)92
JAK2 (catalytic JH1 domain)100TYK2 (pseudobinary JH1 domain)100
JAK3 (catalytic JH1 domain)100TYRO341
JNK180ULK 100
JNK293ULK2100
JNK395ULK382
KIT0,2VEGFR23,9
KIT (A829P)64VRK2100
KIT (D816H)63WEE1100
KIT (D816V)18WEE2100
KIT (L576P)0YANK1100
KIT (V559D)0,15YANK2100
KIT (V559D, T670I)1,4YANK3100
KIT (V559D, V654A)4,1YES20
LATS1100YSK157
LATS296YSK41,7
LCK2,2ZAK36
LIMK192ZAP7C81
LIMK2100
LKB1100
LOK0
LRRK2100
LRRK2(G2019S)100
LTK26
LYN18
47
MAC100
MAP3K180
MAP3K15100
MAP3K2100
MAP3K3100
MAP3K4100
MAP4K2100
MAP4K320
MAP4K4100
MAP4K52,8

Example 17

Inhibitory activity against kinases in tumor cells.

In this example, the compound obtained in example 10, N1-[4-[[7-[[1-(diethoxyphosphoryloxy)-4-piperidinyl]methoxyl]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)tikopian-1,1-dicarboxamide, tested on tumor cells from the Corporation ProQinase GmbH (Breisacher Str. 117, D-79106 Freiburg, Germany, http://www.proqinase.com) on the inhibitory activity against the following kinases: c-KIT, c-MET, VEGFR2 and PDGFR-β. The study includes the following stages.

First, the compound of the present invention was dissolved in dimethylsulfoxide (DMSO) to obtain a 10 mm stock solution, which was serially diluted according to the concentration ranges shown in table 6:

Table 6
ConnectionThe concentration of the initial solution [M]The investigated range [M]The investigated range [M]The investigated range [M]The investigated range [M]
c-KITc-METVEGFR2PDGFR-B
The compound obtained� in example 10 1,0×10-21,0×10-5Of -1.0×10-91,0×10-5Of -1.0×10-91,0×10-5Of -1.0×10-91,0×10-5Of -1.0×10-9

Cell culture

Kinase c-KIT: in a research experiment on the phosphorylation of KIT kinase in cells using the cell line of acute megakariocitarnogo human leukemia Me with endogenous vysokoagressivnyh c-KIT wild type. When these cells stimulate human stem cell factor (SCF), is autophosphorylated receptor tyrosine kinase KIT. M07e cells inoculated in RPMI containing 20% fetal calf serum (FCS) and 10 ng/ml GM-CSF (granulocyte-macrophage colony stimulating factor), multi-well tablet for cell cultures. The connection according to the invention is added to the cells after depletion during the night serum and growth factor, then the cells are cultured in a medium without serum.

Kinase c-MET: in a research experiment on the phosphorylation of the kinase c-MET in cells using the cell lines of gastric cancer MKN45 human with endogenous vysokoagressivnyh c-MET wild-type (c-MET wild type). Such a high expression of c-MET leads to continuous autophosphorylated receptor tyrosine Ki�AZ c-MET without ligands. The MKN45 cells inoculated into the culture medium DMEM (Wednesday Needle, modified by Dulbecco) containing 10% FCS, in multi-well tablet for cell cultures. The connection according to the invention is added to the cells after depletion during the night serum, then the cells are cultured in a medium without serum.

The VEGFR2 kinase: in a research experiment on the phosphorylation of VEGFR2 kinase in cells spontaneously use immortalizing line of endothelial cells from the human umbilical vein HUE with endogenous vysokoagressivnyh R (receptor) growth factor vascular endothelial-2 (VEGFR2). When these cells are stimulated with growth factor of vascular endothelium-A (VEGF-A) of a person, it leads to autophosphorylation receptor tyrosine kinases VEGFR2. Cells HUE is inoculated in the culture medium of endothelial cells (ECGM) containing 10% FCS, in multi-well tablet for cell cultures. The connection according to the invention is added to the cells after depletion in the culture medium of endothelial cells (ECGM) during the night serum, then the cells are cultured in a culture medium ECGM without serum.

Kinase PDGFR-β: in a research experiment on the phosphorylation of kinases PDGFR-beta in cells using the cell line of embryonic mouse fibroblasts NIH3T3 with endogenous vysokoagressivnyh PDGFR-β wild-type (PDGFR-β wild-type). When these to�etki stimulate murine platelet-derived growth factor BB (PDGF-BB), this leads to autophosphorylation receptor tyrosine kinases PDGFR-beta. NIH3T3 cells inoculated into the culture medium of DMEM containing 10% FCS, in multi-well tablet for cell cultures. The connection according to the invention is added to the cells after depletion during the night serum, then the cells are cultured in a medium without serum.

Method of research

A sample of the diluted stock solution of the compounds according to the invention is added to a solution of culture cells at a ratio of 1:100, until then, until you reach the final concentration of DMSO of 1%. After cultivation at 37°C for 90 minutes cells stimulate according to table 7 (quantitative method: sandwich ELISA (ELISA): quantitative analysis of substrate phosphorylation is carried out by the method of sandwich ELISA in 96-well plate using antibodies to capture specific substrate and antibodies for the detection of dephosphorylating tyrosine. The magnitude of IC50define when using the software GraphPad Prism 5.01):

SCF
Table 7
TargetLigandConcentrationTime
c-KIT100 ng/ml3 min
c-METwithout stimulation
PDGFR-βPDGF-BB100 ng/ml3 min
VEGFR2VEGF-A100 ng/ml3 min

The results of the study

When constructing the titration curve N1-[4-[[7-[[1-(diethoxyphosphoryloxy)-4-piperidinyl]methoxyl]-6-methoxyl-4-quinol Il]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)tikopian-1,1-dicarboxamide, inhibiting c-KIT, c-MET, VEGFR2 and PDGFR-β in the cells, get the value of IC50connection, four indicated inhibitory kinase; shown in table 8.

Table 8
ConnectionThe magnitude of IC50in the cell*
The compound obtained in example 10c-KITc-METVEGFR2PDGFR-β
27 nm17 nm0,43 nm 13 nm
*the average value of two results studies

From the above data it can be seen that the compound of the present invention has a significant inhibitory effect on some kinases, i.e., c-Met, c-KIT, VEGFR2 and PDGFR-β in tumor cells, their size Yo are in the range of 0.43-27 nm.

Example 18

Antitumor experiments: in this example, N1-[4-[[7-[3-(diethoxyphosphoryloxy)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide obtained in example 3, use in antitumor experiments xenotransplanted of gastric cancer cells human GTL-16 on animal models Nude thymus of mice with mutations in the nude, methods and results are as follows.

Materials

7-8-week-old female mice BALB/c-nu/nu, having the status of SPF (free of specific pathogens), weighing 16-20 g of the gain in the Center of experimental animals in Guangdong province (Experimental Animal Center of Guangdong Province), room control certificate: NO: 0072659. Of gastric cancer cells GTL-16 acquire in the Centre of the source cell of the Shanghai Institute of biological Sciences (Cell Source Center of Shanghai Institutes for Biological Sciences). Culture medium RPMI-1640, fetal calf serum (FBS) and trypsin digestive juice get from Gibco Corporation. All antibi�Tiki acquire from Sigma Company.

Methods

Initial cultivation of gastric cancer cells GTL-16: cell line GTL-16 is inoculated into the culture medium RPMI-1640 containing 10% FBS, 100 u/ml penicillin, 100 u/ml streptomycin, and cultured at 37°C, 5% CO2, 100% humidity in a carbon dioxide incubator cells, the cells are in logarithmic growth phase after 24 hours, 48 hours after inoculation, cells grow, covering the bottom of the culture vessel. Then the cells GTL-16, covering 80% of the bottom of the culture vessel, broken up, after 5 minutes centrifugation at 1000 rpm, the cells are diluted to 2×107cells/ml, and subcutaneously implanted into the front edge of the right axillary fossa in an amount of 0.1 ml per mouse. 12 days after implantation of tumor cells weighed Nude thymus of mice with mutations in the nude, carrying tumors, the tumor size was measured, and mice with tumor size in the range of 40-160 mm3randomly divided into a group of media (media, 0.2% aqueous solution of methylsulfonic acid) and subjected to the treatment group, which used the compound obtained in example 3, N1-[4-[[7-[3-(diethoxyphosphoryloxy)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (which was dissolved in a 0.2% aqueous solution of methylsulfonic acid to a concentration of 5 mg/ml), 8 mice per group; then b�stiasny mice with mutations in the nude weigh every day and orally administered in an amount of 0.1 ml/10 g body weight with a probe (50 mg/kg daily orally), the size of tumors in each animal was measured every two days, after 14 days the mice of tumor-bearing sacrificed by dislocation of the cervical spine, and tumors are removed for weighing. Method of counting the inhibition of tumor growth (TGI): the experimental data are expressed as mean values ±SD (standard deviation), TGI=[(Vgroup media-Vtreated group)÷Vgroup media]×100%.

Vgroup mediamean tumor volume in mice in the group of medium;

Vtreated groupmean tumor volume in mice in treated group.

Results

The effect of tumor inhibiting compounds of the present invention obtained in example 3 in the tumor of mice in treated group: the media group and treated group respectively give the media and the drug solution, after 14 days the mean tumor volumes in animals in the media group and treated group are 377,1±244,5 mm3(n=7) and 57.1±61,2 (n=8), respectively; thus, in TGI treated group is 85%. Compared with the initial tumor volume, the tumor size in the treated group are significantly reduced. Comparison of tumor tissues is shown in Fig.1, and compared�e experimental curves shown in Fig.2.

The change of body weight of mice in the group of medium and treated group is shown in Fig.3: after treatment for 14 days body weight of mice in treated group, which used the compound according to example 3 has changed slightly (less than 5%).

From the results of the above antitumor experiments can be seen that in animal models of xenograft Nude thymus of mice with mutations in the nude a typical compound of the present invention exhibits significant antitumor activity when administered orally at a dose of 50 mg/kg once daily; 14 days TGI reaches 85%. Body weight of animals in the treated group is essentially not reduced, it shows that the drug has no significant toxicity.

Example 19:

The ingredients and composition of the medicinal product

Tablet (mg/tablet)

The compound obtained in example 1: 100;

Lactose, Ph EUR (European Pharmacopoeia): 182,75;

Carboxymethylcellulose sodium: 12,0;

The slurry of corn starch (5 wt./vol.%): 2,25;

Magnesium stearate: 3,0.

The application is for people

Applicable to patients suffering from diseases associated with abnormal protein kinase activity.

Example 20:

The ingredients and composition of the medicinal product

Tablet (mg/tablet)

p> The compound obtained in example 5: 100; content of other substances is the same as in example 19.

The application is for people

Applicable to patients suffering from diseases associated with abnormal protein kinase activity.

Example 21:

The ingredients and composition of the medicinal product

Tablet (mg/tablet)

The compound obtained in example 1: 50;

Lactose, Ph EUR: 223,75;

Carboxymethylcellulose sodium: 6,0;

Corn starch: 15,0;

Polyvinylpyrrolidone (5 wt./vol.%): 2,25;

Magnesium stearate: 3,0.

The application is for people

Applicable to patients suffering from diseases associated with abnormal protein kinase activity.

Example 22:

The ingredients and composition of the medicinal product

Tablet (mg/tablet)

The compound obtained in example 3: 50; the content of other substances is the same as in example 21.

The application is for people

Applicable to patients suffering from diseases associated with abnormal protein kinase activity.

Example 23:

The ingredients and composition of the medicinal product

Tablet (mg/tablet)

The compound obtained in example 7: 1,0;

Lactose, Ph EUR: 93,25,

Carboxymethylcellulose sodium: 4,0;

The slurry of corn starch (5 wt./vol.%): 0,75;

Magnesium stearate: 76.

The application is for people

PR�minim for patients suffering from diseases associated with abnormal protein kinase activity.

Example 24:

The ingredients and composition of the medicinal product

Tablet (mg/tablet)

The compound obtained in example 5: 1,0; the content of other substances is the same as in example 23.

The application is for people

Applicable to patients suffering from diseases associated with abnormal protein kinase activity.

Example 25:

The ingredients and composition of the medicinal product

Capsule (mg/capsule)

The compound obtained in example 7: 10,0;

Lactose, Ph EUR: 488,5;

Magnesium: 1,5.

The application is for people

Applicable to patients suffering from diseases associated with abnormal protein kinase activity.

Example 26:

The ingredients and composition of the medicinal product

Capsule (mg/capsule)

The compound obtained in example 2: 10,0 mm; the content of other substances is the same as in example 25.

The application is for people

Applicable to patients suffering from diseases associated with abnormal protein kinase activity.

Example 27:

The ingredients and composition of the medicinal product

Injection (50 mg/ml)

The compound obtained in example 6: 5%;

1 M sodium hydroxide solution: 15%;

0.1 M hydrochloric acid solution (pH adjusted to 7.6);

Polietileno�ol 400: 5%;

Bring up to 100% with water for injection:

The application is for people

Applicable to patients suffering from diseases associated with abnormal protein kinase activity.

Example 28:

The ingredients and composition of the medicinal product

Injection (50 mg/ml)

The compound obtained in example 12: 5%; content of other substances is the same as in example 27; in the end brought to 100% with water for injection.

The application is for people

Applicable to patients suffering from diseases associated with abnormal protein kinase activity.

Example 29:

The ingredients and composition of the medicinal product

Injection (10 mg/ml)

The compound obtained in example 11: 1%;

Hydrophosphate denetria BP (British Pharmacopoeia): 3.6 percent;

A 0.1 M solution of sodium hydroxide: 15%;

Bring up to 100% with water for injection.

The application is for people

Applicable to patients suffering from diseases associated with abnormal protein kinase activity.

Example 30:

The ingredients and composition of the medicinal product

Injection (10 mg/ml)

The compound obtained in example 9: 1%; the content of other substances is the same as in example 29; bring to 100% with water for injection.

The application is for people

Applicable to patients suffering from diseases associated with abnormal active�STU protein kinase.

Example 31:

The ingredients and composition of the medicinal product

Injection (1 mg/ml) (pH adjusted to 6)

The compound obtained in example 6 is 0.1%;

Hydrophosphate denetria BP: 2,26%;

Citric acid: 0,38%;

Polyethylene glycol 400: 3,5%;

Water for injections (to bring to 100%).

The application is for people

Applicable to patients suffering from diseases associated with abnormal protein kinase activity.

Example 32:

The ingredients and composition of the medicinal product

Injection (1 mg/ml) (pH adjusted to 6)

The compound obtained in example 10: 0,1%; the content of other substances is the same as in example 31; at the end use water for injection to bring the contents up to 100%.

The application is for people

Applicable to patients suffering from diseases associated with abnormal protein kinase activity.

Example 33:

The ingredients and composition of the medicinal product

Aerosol (mg/ml)

The compound obtained in example 1:10;

Sorbitan oleate: 13,5;

Trichloromethane: 910,0;

DICHLORODIFLUOROMETHANE: 490,0.

The application is for people

Applicable to patients suffering from diseases associated with abnormal protein kinase activity.

Example 34:

The ingredients and composition of the medicinal product

Aerosol (mg/ml)

The compound obtained in example 10; the content of other substances is the same as in example 33.

The application is for people

Applicable to patients suffering from diseases associated with abnormal protein kinase activity.

Example 35:

The ingredients and composition of the medicinal product

Aerosol (mg/ml)

The compound obtained in example 4: 0,2;

Sorbitan oleate: 0,27;

Trichloromethane: 70,0;

DICHLORODIFLUOROMETHANE: 280,0;

Dichlorotetrafluoroethane: 1094,0.

The application is for people

Applicable to patients suffering from diseases associated with abnormal protein kinase activity.

Example 36:

The ingredients and composition of the medicinal product

Aerosol (mg/ml)

The compound obtained in example 7: 0,2; the content of other substances is the same as in example 35.

The application is for people

Applicable to patients suffering from diseases associated with abnormal protein kinase activity.

Example 37:

The ingredients and composition of the medicinal product

Aerosol (mg/ml)

The compound obtained in example 8: 2,5;

Sorbitan oleate: 3,38;

Trichloromethane: 67,5;

DICHLORODIFLUOROMETHANE: 1086,0;

Dichlorotetrafluoroethane: 191,60.

The application is for people

Applicable to patients suffering from diseases associated with abnormal protein kinase activity.

Example 38:

�ingredienti and composition of the medicinal product

Aerosol (mg/ml)

The compound obtained in example 11: 2,5; the content of other substances is the same as in example 37.

The application is for people

Applicable to patients suffering from diseases associated with abnormal protein kinase activity.

Example 39:

The ingredients and composition of the medicinal product

Aerosol (mg/ml)

The compound obtained in example 4: 2,5;

Soy lecithin: 2,7;

Trichloromethane: 67,5;

DICHLORODIFLUOROMETHANE: 1086,0;

Dichlorotetrafluoroethane: 191,60;

The application is for people

Applicable to patients suffering from diseases associated with abnormal protein kinase activity.

Example 40:

The ingredients and composition of the medicinal product

Aerosol (mg/ml)

The compound obtained in example 13: 2,5; the content of other substances is the same as in example 39.

The application is for people

Applicable to patients suffering from diseases associated with abnormal protein kinase activity.

Example 41:

The ingredients and composition of the medicinal product

Ointment (/ml)

The compound obtained in example 1: 40 mg;

Ethanol: 300 ál;

Water: 300 ál;

1-dodecylcyclobutanone: 50 µl;

Propandiol: to 1 ml.

The application is for people

Applicable to patients suffering from diseases associated with abnormal AK�ewnetu protein kinase.

Example 42:

The ingredients and composition of the medicinal product

Ointment (/ml)

The compound obtained in example 7: 40 mg; the content of other substances is the same as in example 41.

The application is for people

Applicable to patients suffering from diseases associated with abnormal protein kinase activity.

1. Substituted phosphorous group, a quinoline, represented by the following formula (I):

where in the formula (I)
Ζ is aeach of V1and V2independently selected from hydrogen or halogen;
one of R and R' represents a phosphorus-containing Q Deputy, the other chosen from hydrogen or methoxyl;
where phosphorous Deputy Q represents an
A represents O;
L represents C1-6alkyl;
J represents NH or C3-6heteroseksualci and J possibly substituted G3;
X is absent or represents-C(=O)-;
Υ is absent or represents C1-6alkyl;
each of R1and R2independently selected from C1-6alkyl or C1-6alkoxy;
G3represents C1-6alkyl, R3S(=O)m-, R5C(=O)- or R3R4NC(=O)-;
each of R3, R4and R5independently chosen� of Η or C 1-6alkyl;
m is equal to 0-2.

2. Substituted phosphorous group, a quinoline according to claim 1, wherein the compound represented by the following formula (Ia):

where in the above formula
A represents O;
L represents C1-6alkyl;
J represents NH and J possibly substituted G3;
Υ represents C1-6alkyl.

3. Substituted phosphorous group, a quinoline according to claim 1, wherein the compound represented by the following formula (Ib):

where in the above formula
A represents O;
L represents C1-6alkyl;
J represents C3-6heteroseksualci;
X is absent or represents-C(=O)-;
Υ represents C1-6alkyl.

4. Substituted phosphorous group, a quinoline according to claim 1, wherein the compound represented by the following formula (Ic):

where in the above formula
A represents O;
L represents C1-6alkyl;
J represents NH and J possibly substituted G3;
Υ represents C1-6alkyl.

5. Substituted phosphorous group, a quinoline according to claim 1, wherein the compound represented by the following formula (Id):

where in the above formula
A represents O;
L With a 1-6alkyl;
J represents C3-6heteroseksualci;
X is absent or represents-C(=O)-;
Υ represents C1-6alkyl.

6. Substituted phosphorous group, a quinoline according to claim 1, wherein the compound represented by the following formula (Ie):

where in the above formula
L represents C1-6alkyl;
Υ represents C1-6alkyl.

7. Substituted phosphorous group, a quinoline according to claim 1, wherein the compound represented by the following formula (If):

where in the above formula
X is absent or represents-C(=O)-;
Υ represents C1-6alkyl.

8. Substituted phosphorous group, a quinoline according to claim 1, wherein the compound is selected from the group consisting of one or more of the following compounds:
N1-[4-[[7-[3-(diethoxyphosphoryloxy)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
N1-[4-[[7-[3-(diethoxyphosphoryloxy)(methyl)amino)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
N1-[4-[[7-[3-(acetyl(diethoxyphosphoryloxy)amino)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
N1-[4-[[7-[3-(propionyl(diethoxyphosphoryloxy)amino)ethoxy�yl]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
N1'-[4-[[7-[3-(aminocarbonyl(diethoxyphosphoryloxy)amino)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
N1'-[4-[[7-[3-(diethoxyphosphoryloxy)(ethylaminomethyl)amino)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
N1'-[4-[[7-[3-(diethoxyphosphoryloxy)(ethylaminomethyl)amino)ethoxyl]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
N1'-[4-[[7-[3-(diethoxyphosphoryloxy)(methyl-sulfonyl)amino)propoxy]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
N1-[4-[[6-[3-(diethoxyphosphoryloxy)propoxy]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
N1-[4-[[6-[3-(diethoxyphosphoryloxy)(methyl)amino)propoxy]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
N1-[4-[[6-[3-(acetyl(diethoxyphosphoryloxy)amino)propoxy]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
N1-[4-[[6-[3-(propionyl(diethoxyphosphoryloxy)amino)ethoxyl]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
N1'-[4-[[6-[3-(aminocarbonyl(diethoxyphosphoryloxy)amino)propoxy]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxy�d;
N1'-[4-[[6-[3-(diethoxyphosphoryloxy)(ethylaminomethyl)amino)propoxy]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
N1'-[4-[[6-[3-(aminocarbonyl(diethoxyphosphoryloxy)amino)ethoxyl]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
N1'-[4-[[6-[3-(diethoxyphosphoryloxy)(methyl-sulfonyl)amino)propoxy]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
N1-[4-[[7-[[1-(diethoxyphosphoryloxy)-4-piperidinyl]methoxyl]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
N1-[4-[[7-[[1-(2-diethoxyphosphoryl)-4-piperidinyl]methoxyl]-6-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
N1-[4-[[6-[[1-(diethoxyphosphoryloxy)-4-piperidinyl]methoxyl]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide or
N1-[4-[[6-[[1-(2-diethoxyphosphoryl)-4-piperidinyl]methoxyl]-7-methoxyl-4-chinolin]oxyl]-3-fluorophenyl]-N1'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.

9. The method of obtaining substituted phosphorous group quinolines according to any one of claims. 1-8, consisting of stages, presented in the following scheme 1:

where method contains the following stages:
first stage: removal of the protective group PG of the N atom compounds �-2 to produce a compound A-3;
second stage: interaction of compound A-3 with the reagent to give product A-4, where the reagent is a:
(a) R3S(=O)mCl together with the base, then G3in the A-4 is an R3S(=O)m-;
(b) R5C(=O)Cl with a base or R5C(=O)OH together with a binding reagent, then G3in the A-4 is an R5C(=O)-;
(b) R3R4NCO with a base or R3R4NC(=O)Cl and base together, then G3in the A-4 is an R3R4NC(=O)-; or
(g)1-6alkyl-LG, together with the base or C1-6aldehyde or ketone with a reducing agent, then G3in the A-4 is a C1-6alkyl;
where
t is equal to 0-4;
LG is conventional in the field of organic chemistry leaving groups;
PG is conventional in the field of organic chemistry protecting groups;
define G3, R3, R4, R5and m are the same as shown in clause 1.

10. The method of obtaining substituted phosphorous group quinolines according to any one of claims. 1-8, consisting of stages, presented in the following scheme 2:

where method contains the following stages:
first stage: the restoration of the nitro group of compound A-10 with receipt of amine A-11;
second stage: exposure to compounds A-11 and the connection �-12 reactions combination with obtaining the compounds A-13;
third stage: the removal of the protective group of the N atom of the compounds A-13 to produce a compound A-14;
fourth stage: the interaction of compounds A-14 with a reagent to give product A-15,
where the reagent is a:
(a) R3S(=O)mCl together with the base, then G3in the A-15 is an R3S(=O)m-;
(b) R5C(=O)Cl with a base or R5C(=O)OH together with a binding reagent, then G3in the A-15 is an R5C(=O)-;
(b) R3R4NCO with a base or R3R4NC(=O)Cl and base together, then G3in the A-15 is an R3R4NC(=O)-; or
(g)1-6alkyl-LG, together with the base or With1-6aldehyde or ketone with a reducing agent, then G3in A-15 is a C1-6alkyl;
where
t=0-4;
PG is conventional in the field of organic chemistry protecting groups;
define G3, R3, R4, R5and m are the same as in item 1.

11. The method of obtaining substituted phosphorous group quinolines according to any one of claims. 1-8, consisting of stages, presented in the following scheme 5:

where method contains the following stages:
the interaction of the compounds A-23 with the reagent to give product A-17, where the reagent is a:
(a) diethylphosphate and formal�of digid, then X in A-17 missing and Υ represents C1-6alkyl; or
(b) 2-diethoxyphosphoryloxy acid together with a binding reagent or 2-diethoxymethylsilane together with the base, then X is in A-17 represents-C(=O) and Υ represents C1-6alkyl.

12. Use of pharmaceutical compositions containing substituted phosphorous group quinolines according to any one of claims. 1-8, where the composition is used for treatment of diseases associated with abnormal activity of protein kinases.

13. The use according to claim 12, wherein the protein kinase is c-Met, KDR or VEGFR2, RET, PDGFR-β, c-KIT, Flt3, MEK, DDR1, LOK, CSF1R, EPHA7, EPHA8, EPHB6, MKNK2, BLK, HIPK4, HCK or Flt4.

14. The use according to claim 12, wherein the protein kinase is an ALK or anaplastic lymphoma kinase), EGFR, PDGFR-α, FLT1, Src, Frk, Btk, Abl, Fes, Fak, Yes, Fyn, Lyn, Lck, Hck, Fgr, TAK1, Tie-2, Tie-1, YSK4, TRK B, TRK C, SLK, PKN2, PLK4, MST1R, MAP4K or DDR2.

15. The use according to claim 12, wherein the disease is a psoriasis, cirrhosis, diabetes, mediated by angiogenesis diseases, eye diseases, diseases of the immune system, or cardiovascular disease.

16. The use according to claim 12, wherein the disease is a tumor, including solid and liquid tumors.

17. The use according to claim 12, wherein the tumor comprises: lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, melanoma of the skin or �nutriglow melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, colon cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, bladder cancer, cancer of the kidney or ureter, renal cancer, tumors of the Central nervous system (CNS), spinal cord tumors, pituitary adenomas, gastrointestinal stromal tumors, colorectal cancer, non-small cell lung cancer, small cell lung cancer, mastocytosis, glioma, sarcoma, lymphoma or any combination of them.

18. A medicament for the treatment of diseases associated with abnormal activity of protein kinase containing a compound according to any one of claims. 1-8 or a pharmaceutically acceptable salt.

19. Medicament according to claim 18, further comprising at least one pharmaceutically acceptable carrier.

20. Medicament according to claim 18, which is in the form of the following songs:
(1) oral composition; (2) injecting the composition; (3) the composition for nasal inhalation; (4) eye drops.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compound of formula (I) or its racemate, enantiomer, diastereoisomer and their mixture, as well as to their pharmaceutically acceptable salt, where A is selected from the group, consisting of carbon atom or nitrogen atom; when A represents carbon atom, R1 represents C1-C6-alkoxyl; R2 represents cyano; when A represents nitrogen atom, R1 hydrogen atom or C1-C6-alkoxyl; where said C1-C6-alkoxyl is optionally additionally substituted with one C1-C6-alkoxyl group; R2 is absent; R3 represents radical, which has the formula given below: or , where D represents phenyl, where phenyl is optionally additionally substituted with one or two halogen atoms; T represents -O(CH2)r-; L represents pyridyl; R4 and R5 each represents hydrogen atom; R6 and R7 each is independently selected from hydrogen atom or hydroxyl; R8 represents hydrogen atom; R9 represents hydrogen atom or C1-C6-alkyl; r equals 1 and n equals 2 or 3. Invention also relates to intermediate compound of formula (IA), method of obtaining compound of formulae (I) and (IA), pharmaceutical composition based on formula (I) compound and method of its obtaining and to application of formula (I) compound.

EFFECT: novel heterocyclic compounds, inhibiting activity with respect to receptor tyrosine kinases EGFR or receptor tyrosine kinases HER-2 are obtained.

18 cl, 12 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of general formula 1 or their stereoisomers or pharmaceutically acceptable salts possessing the properties of inhibitors of RNA polymerase HCV NS5B, and to methods for producing them. In general formula 1 R1 represents C1-C4alkyl; R2 and R3 represents fluorine, or R2 represents fluorine, while R3 represents methyl; one of R4 and R5 represents hydrogen, and the other of R4 and R5 represents C1-C6acyl optionally substituted by α-aminoacyl specified in a group containing (dimethylamino)acetyl, 1-tert-butoxycarbonylamino-2-methyl-propylcarbonyl, 1-methylpyrrolidine-2-carbonyl, 1-methylpiperidine-3-carbonyl and 1-methylpiperidine-4-carbonyl, R6 represents hydrogen, methyl, methoxy and halogen.

EFFECT: compounds can be used for treating and preventing viral infections, including hepatitis C, optionally with additional agents specified in an inhibitor of inosin-5-monophosphate dehydrogenase, eg Ribamidine, an inhibitor of hepatitis C protease C NS3, eg Asunaprevir (BMS-650032), an inhibitor of hepatitis C protease C NS3/4A, eg Sofosbuvir (TMC435), an inhibitor of RNA-polymerase NS5A, eg Daclatasvir (BMS-790052) or Ledipasvir (GS-5885).

18 cl, 1 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to 2-amino-1-((phosphonoxy)methyl)-3-(3-((4-((2-pyridinyloxy)methyl)phenyl)methyl)-5-isoxazolyl)pyridinium of formula: and salts thereof effective as an antimycotic agent, and to pharmaceutical compositions and therapeutic agents based on it and the use thereof in treating mycotic diseases.

EFFECT: what is presented is the new effective antimycotic agent with improved water solubility and safety.

6 cl, 16 dwg, 3 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to derivatives of Ice formula and the use thereof in treating the diseases associated with thrombocyte aggregation ICE', wherein P(O)R5R8 is specified in R1 is specified in phenyl; W is specified in a bond, -O-, -NR3-; R2 is specified in alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, phenyl, heterocyclyl, or heteroaryl, alkoxycarbonyl alkyl, carboxyalkyl or phenyl alkyl; R3 is specified in hydrogen or alkyl; or R2 and R3 form a ring together with a nitrogen atom; Ra is specified in hydrogen or methyl; R4 is specified in alkoxy; n is from 0 to 3; m is from 0 to 1; V is specified in a bond and phenyl; R5 and R8 are specified in hydroxyl, phenyloxy, benzyloxy, -O-(CHR6)-O-C(=O)-R7, -O-(CHR6)-O-C(=O)-O-R7, -O-(CHR6)-C(=O)-O-R9, -NH-(CHR10)-C(=O)-O-R9, -NH-C(CH3)2-C(=O)-O-R9; q is equal to 2; R6 is specified in hydrogen and alkyl; R7 is specified in alkyl or cycloalkyl; R9 is specified in alkyl; R10 is specified in hydrogen, alkyl, phenyl or benzyl; and R11 is specified in hydrogen, alkyl or alkoxy.

EFFECT: new P2Y12 receptor antagonists are produced.

25 cl, 126 ex, 5 tbl

FIELD: chemistry.

SUBSTANCE: compounds under the present invention are characterised by properties of aurora-kinase-A and/or aurora-kinase-B inhibitor. In general formula (I) : A represents 5-merous heteroaryl containing two nitrogen atoms; X represents NR14; m represents 0, 1, 2 or 3; Z represents the group chosen from -NR1R2, and 4-7-merous saturated ring connected by carbon atom containing nitrogen atom and substituted at nitrogen atom with C1-C4alkyl substituted by phosphonoxy; R1 represents C1-C6-alkyl substituted by phosphonoxy; R2 represents the group chosen from hydrogen, C1-C6-alkyl where C1-C6-alkyl is optionally substituted with 1, 2 or 3 halogen or C1-C4-alkoxy groups, or R2 represents the group chosen from C2-C6-alkenyl, C2-C6-alkinyl, C3-C6-cycloalkyl and C3-C6-cycloalkyl-C1-C4alkyl; or R1 and R2 together with nitrogen atom whereto attached form 4-7-merous saturated ring substituted at carbon or nitrogen atom by the group chosen from phosphonoxy and C1-C4-alkyl where C1-C4alkyl is substituted by phosphonoxy; R3 represents the group chosen from hydrogen, halogen, C1-C6-alkoxy; R4 represents phenyl substituted with 1-2 halogens; R5, R6, R7 and R14 represent hydrogen. In addition, the invention concerns the pharmaceutical composition containing therapeutically active amount of the compound under the invention, to application of the compound for preparation of a medical product applied in therapy of disease wherefore inhibition of one or more aurora-kinases is efficient, to method treatment, as well as production of the compounds under the invention.

EFFECT: high-yield end product.

26 cl, 5 tbl, 50 ex

FIELD: medicine; pharmacology.

SUBSTANCE: subjects of invention are also pharmaceutical drugs or agents for prophylaxis and treatment of neuropathy, increase of production and treatment of the neurotrophic factor, for pain relief, for nerve protection, for prophylaxis and treatment of the neuropathic pain containing compound of the formula or of the formula . In the compounds of the formulas (I) and (II) symbols and radicals have the meanings mentioned in the invention formula. The specified agents have an excellent effect and low toxicity. There are also proposed ways of treatment and prophylaxis of the abovementioned conditions by means of the compounds of the formula (I) or (II) and application of these compounds for production of the abovementioned agents. Besides, one has proposed methods for production of the specified compounds and intermediate pyrazol compounds.

EFFECT: compound has an effect increasing production and secretion of the neurotrophic factor.

46 cl, 1 tbl, 233 ex

FIELD: chemistry.

SUBSTANCE: description is given of a hetero-aromatic compounds with a phosphonate group with formula (I) and their pharmaceutical salts, radicals of which are given in the formula of invention. The compounds are inhibitors of fructose-1,6-bisphosphotase. Description is also given of pharmaceutical compositions based on compounds with formula (I) and (X) and the method if inhibiting fructose-1,6-bisphosphotase, using the compound with formula (I).

EFFECT: obtaining of new biologically active substances.

184 cl, 52 tbl, 62 ex

FIELD: chemistry of organophosphorus compounds, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new bisamidate phosphonate compounds that are inhibitors of fructose 1,6-bis-phosphatase. Invention describes a compound of the formula (IA): wherein compound of the formula (IA) is converted in vivo or in vitro to compound of the formula M-PO3H2 that is inhibitor of fructose 1,6-bis-phosphatase and wherein M represents R5-X- wherein R5 is chosen from a group consisting of compounds of the formula or wherein each G is chosen from the group consisting of atoms C, N, O, S and Se and wherein only one G can mean atom O, S or Se and at most one G represents atom N; each G' is chosen independently from the group consisting of atoms C and N and wherein two G' groups, not above, represent atom N; A is chosen from the group consisting of -H, -NR42, -CONR42, -CO2R3, halide, -S(O)R3, -SO2R3, alkyl, alkenyl, alkynyl, perhaloidalkyl, haloidalkyl, aryl, -CH2OH, -CH2NR42, -CH2CN, -CN, -C(S)NH2, -OR2, -SR2, -N3, -NHC(S)NR42, -NHAc, or absent; each B and D is chosen independently from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclyl, aralkyl, alkoxyalkyl, -C(O)R11, -C(O)SR11, -SO2R11, -S(O)R3, -CN, -NR92, -OR3, -SR3, perhaloidalkyl, halide, -NO2, or absent and all groups except for -H, -CN, perhaloidalkyl, -NO2 and halide are substituted optionally; E is chosen from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclyl, alkoxyalkyl, -C(O)OR3, -CONR42, -CN, -NR92, -NO2, -OR3, -SR3, perhaloidalkyl, halide, or absent; all groups except for -H, -CN, perhaloidalkyl and halide are substituted optionally; J is chosen from the group consisting of -H, or absent; X represents optionally substituted binding group that binds R5 with phosphorus atom through 2-4 atoms comprising 0-1 heteroatom chosen from atoms N, O and S with exception that if X represents urea or carbamate then there are 2 heteroatoms that determine the shortest distance between R5 and phosphorus atom and wherein atom bound with phosphorus means carbon atom and wherein X is chosen from the group consisting of -alkyl(hydroxy)-, -alkynyl-, - heteroaryl-, -carbonylalkyl-, -1,1-dihaloidalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino- and -alkylaminocarbonylamino- and all groups are substituted optionally; under condition that X is not substituted with -COOR2, -SO3H or -PO3R22; n means a whole number from 1 to 3; R2 is taken among the group -R3 and -H; R3 is chosen from the group consisting of alkyl, aryl, alicyclyc and aralkyl; each R4 is chosen independently from the group consisting of -H and alkyl, or R4 and R4 form cycloalkyl group; each R9 is chosen independently from the group consisting of -H, alkyl, aryl, aralkyl and alicyclyl, or R9 and R9 form in common cycloalkyl group; R11 is chosen from the group consisting of alkyl, aryl, -NR22 and -OR2; each R12 and R13 is chosen independently from the group consisting of hydrogen atom (H), lower alkyl, lower aryl, lower aralkyl wherein all groups are substituted optionally, or R12 and R13 in common are bound through 2-5 atoms comprising optionally 1-2 heteroatoms chosen from the group consisting of atoms O, N and S to form cyclic group; each R14 is chosen independently from the group consisting of -OR17, -N(R17)2, -NHR17, -NR2OR19 and -SR17; R15 is chosen from the group consisting of -H, lower alkyl, lower aryl, lower aralkyl, or in common with R16 is bound through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; R16 is chosen from the group consisting of -(CR12R13)n-C(O)-R14, -H, lower alkyl, lower aryl, lower aralkyl, or in common with R15 is bound through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; each R17 is chosen independently from the group consisting of lower alkyl, lower aryl and lower aralkyl and all groups are substituted optionally, or R17 and R17 at atom N are bound in common through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; R18 is chosen independently among the group consisting of hydrogen atom (H), lower alkyl, aryl, aralkyl, or in common with R12 is bound through 1-4 carbon atoms forming cyclic group; each R19 is chosen independently from the group consisting of -H, lower alkyl, lower aryl, lower alicyclyl, lower aralkyl and -COR3; and under condition that when G' represents nitrogen atom (N) then the corresponding A, B, D or E are absent; at least one from A and B, or A, B, D and E is chosen from the group consisting of -H, or absent; when G represents nitrogen atom (N) then the corresponding A or B is not halide or group bound directly with G through a heteroatom; and its pharmaceutically acceptable salts. Also, invention describes a method for treatment or prophylaxis of diabetes mellitus, a method for inhibition of activity 0f fructose 1,6-bis-phosphatase, a method for decreasing blood glucose in animals, a method for treatment of diseases associated with glycogen deposition, a method for inhibition of gluconeogenesis in animal and a pharmaceutical composition based on compounds of the formula (IA).

EFFECT: valuable medicinal and biochemical properties of compounds.

69 cl, 7 tbl, 64 ex

The invention relates to 4-hydroxy-3-chinainternational and hydrazides of General formula (I), where a represents a-CH2- or-NH-, a R1, R2, R3and R4such as defined in the claims

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new N-[2-(adamant-2-yl)aminocarbonylmethyl]-N'-(dialkylamino)alkylnitrobenzamide of general formula and their physiologically acceptable salts, preferentially hydrochlorides, which possess antiarhythmic action. In formula I, R can be hydrogen, alkyl (C1-C6) or cycloalkyl; R1 can be hydrogen or aliphatic residue (C1-C2); R2 can be alkyl (C1-C2) or saturated heterocycle together with nitrogen with one or two heteroatoms, such as morpholine, pyrrolidine, piperidine; "n" can have a value of 2 or 3; a nitro group in benzamide can be found in any position of the cycle.

EFFECT: invention refers to a method for preparing the compounds of general formula I, specific compounds of formula I, as well as to using them antiarhythmic, particularly antifibrillation agents.

8 cl, 11 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: presented is using 2-morpholino-5-phenyl-6H-1,3,4-thiadiazine hydrobromide as an agent changing the total spectrum power of the heart rate variability and possessing anti-bradycardia properties. The effect of the invention can be used if it is necessary to increase the heart rate if it has dipped down, which can constitute an immediate risk of loss of the individual's life caused by a high risk of cardiac arrest emergency.

EFFECT: reducing the power of a high-frequency component of the cardiac rhythm spectrum by several times, reducing a RR interval variability factor by reducing the regulatory effect of the parasympathetic nervous system on the cardiac rhythm.

8 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, specifically to pharmaceutical compositions possessing prolonged antiarrhythmic actions and applicable to correct the cardiac arrhythmia, including that of the ischemic origin. What is presented is a pharmaceutical composition with the prolonged antiarrhythmic acitivity containing bis[2-(diethylamino)]-N-(2,6-dimethylphenyl)acetamide L-glutaminate, L-glutamic acid, 2-aminoethane sulpho-acid and excipients.

EFFECT: prolonged antiarrhythmic action and stability of the dosage form (tablets, capsules for oral application or solution for injections).

3 cl, 4 tbl

FIELD: medicine.

SUBSTANCE: invention represents a pharmaceutical formulation possessing an ability to inhibit cardiac arrhythmias, containing the type A botulinum toxin and mucopolysaccharide specified in a group containing chitosan, heparin, nadroparin, hyaluronic acid taken in a ratio of 1:(103-109), preferentially 1:(106-108) by weight respectively with the ingredients of the formulation taken in certain relations.

EFFECT: higher pharmacological activity, reduced required single dose for achieving the required therapeutic effect, prolonging the action of botulinum toxin and reduced side effects botulinum toxin.

8 cl

FIELD: medicine.

SUBSTANCE: invention refers to medicine. What is described is an adhesive plaster, wherein each of the elements of a carrier, a protective film and an adhesive layer has a flat rectangular shape, while a projecting portion is formed on a surface from the carrier of the adhesive plaster angularly. Besides, the adhesive plaster can be formed to have a middle portion and a periphery, while the projecting portion can be formed angularly after the rectangular middle portion. Besides, between adjoining, at least two projecting portions there can be presented a connective component element wherein the thickness of the adhesive plaster is lesser than that of the adhesive plaster in the projecting portion.

EFFECT: plaster prevents bisoprolol or its salt leakage from the adhesive layer thereby avoiding impoverishment of the therapeutic agent.

6 cl, 6 dwg, 4 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: drug preparation represents a composition containing: lappaconitine hydrobromide 0.02 - 0.06 g, pregelatinised starch 0.0335 - 0.0536 g, lactose monohydrate 0.058 - 0.122 g, hypromellose 0.078 - 0.161 g, calcium stearate 0.002 - 0.004 g and colloidal silicone dioxide 0.002 - 0.004 g.

EFFECT: prolonged antiarrhythmic action of the active ingredient lappaconitine hydrobromide with accessory alkaloids.

5 cl, 1 tbl

FIELD: medicine.

SUBSTANCE: invention represents a method for increasing biocidal and therapeutic action of a suspension-cream with linco-spectin consisting in detoxification and polymerisation of linco-spectin 100 g in water 300 ml by 0.15±0.05% glutaric aldehyde 0.15±0.05% alkyldimethyl benzylammonium chloride at 38-40°C for 2-3 days.

EFFECT: linco-spectin resistance to the enzymatic degradation of a microbial cell, lower toxicity, faster tissue regeneration and manifested biocidal action on the pathogenic bacteria, viruses, and moulds for 3 years.

5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 2'-bromoanilide of N-butylpyrrolidine-2-carboxylic acid hydrochloride of formula (I): , having antiarrhythmic activity. The compound is obtained through bromination of δ-chlorovaleric acid with subsequent conversion thereof into an acid chloride using thionyl chloride, further amination with 2-bromoaniline and then performing ring closure with butylamine to form 2'-bromoanilide of N-butylpyrrolidine-2-carboxylic acid and reacting the latter with hydrogen chloride. The compound has melting point of 196-198°C.

EFFECT: high activity of the compound.

1 dwg, 1 tbl

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