Imidasoquinolines as dual lipid kinase and mtor inhibitors

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of pharmaceutics and medicine and deals with application of 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydroimidaso[4,5-c]quinilin-1-yl)phenyl]propionitryl or 8-(6-methoxypyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethylphenyl)-1,3-dihydroimidaso[4,5-c]quinoline-2-on or its tautomer, pharmaceutically acceptable salt, hydrate or solvate for obtaining medication, intended for treatment of disease, connected with change or impairment of mTOR kinase regulation, selected from group, including glioma, disease transplant-against-host, for instance, after bone marrow transplantation, restenosis, tuberous sclerosis, lymphangioleimyomatosis, pigment retinitis, autoimmune diseases, including encephalomyelitis, insulin-dependent diabetes mellitus, dermatomyositis, rheumatoid diseases, steroid-resistant acute lymphoblastic leukemia, fibrous diseases, pulmonary hypertension, immunomodulation, Von Hippel-Lindau syndrome, Carney syndrome, familial adenomatous polyposis, juvenile polyposis syndrome, Birt-Hogg-Duke syndrome, familial hypertrophic cardiomyopathy, Wolff-Parkinson-White syndrome, neurodegenerative disorders, wet and dry macular degeneration, muscle dystrophy (atrophy, cachexia) and myopathies, such as Danone disease, bacterial and viral infections, including military tuberculosis, group A streptococcus, virus of type I herpes simplex, HIV-infection, neurofibromatosis, including type 1 neurofibromatosis, Peutz-Jeghers syndrome, or any their combinations.

EFFECT: invention ensures high efficiency.

9 cl

 

The present invention relates to the use of a specific derivative imidazoquinolines for the treatment of diseases dependent kinase target of rapamycin in mammals (mTOR), or to obtain pharmaceutical compositions intended for use in the treatment of these diseases, methods of use of specific imidazoquinolines for the treatment of the mentioned diseases in warm-blooded animals, especially humans, pharmaceutical preparations containing specific imidazoquinolines and intended for the treatment of these diseases.

Unexpectedly, it was found that specific derivatives imidazoquinolines that described in the application WO 2006/122806 as inhibitors of the activity lietkynes, such as PI3 kinase, inhibit the activity of Ser/Thr-kinase mTOR. Therefore, these compounds are dual inhibitors of PI3 kinase and mTOR and thus suitable for the treatment of diseases dependent kinase mTOR.

Syndromes, which, as installed or to be connected at the molecular level with rasagulla activity of mTOR kinase, for example, described in articles COC and other "Disregulation of the TSC-mTOR pathway in human disease", Nature Genetics, v.37, 19-24, D.M.Sabatini, "mTOR and cancer: insights into a complex relationship", Nature Reviews, Vol.6, 729-734, and ..Hennessy and other "Exploiting the PI3K/Akt pathway for cancer drug discovery", Nature Reviews, 4, 988-1004, and all these documents, including the I cited links, included in this description as a reference. These syndromes include:

- rejection of organ or tissue after transplantation, for example, for the treatment of recipients, for example, heart transplant, lung, heart-lung, liver, kidney, pancreatic, skin or corneal disease graft-versus-host, for example, after transplantation of bone marrow,

- restenosis,

- tuberose sclerosis,

- lymphangioleiomyomatosis,

- retinitis pigmentosa,

- autoimmune diseases, including encephalomyelitis, insulin-dependent diabetes mellitus, lupus, dermatomyositis, arthritis and rheumatoid diseases,

- resistant to steroids acute lymphoblastic leukemia,

- fibrotic diseases, including scleroderma, pulmonary fibrosis, renal fibrosis, cystic fibrosis,

pulmonary hypertension,

- immunomodulation,

multiple sclerosis,

syndrome of Hippel-Lindau,

syndrome Carney,

- familial adenomatous polyposis,

syndrome of juvenile polyposis,

- syndrome BIRT-Hogg-Duke,

- familial hypertrophic cardiomyopathy,

syndrome Wolff-Parkinson-white,

- neurodegenerative diseases such as Parkinson's disease, Huntington's disease, Alzheimer's disease and dementia caused by Tau mutations

- spinal-cerebral ataxia type 3, side amyotropic the ski sclerosis, caused by mutations in the SOD-1, neuronally ceroid-lipofuscinosis/disease batten (neurodegenerative disease in children),

- wet and dry macular degeneration,

- muscle wasting (atrophy, cachexia) and myopathy, such as Danon disease,

bacterial and viral infections, including miliary tuberculosis, group a Streptococcus, herpes simplex virus type I, HIV-infection,

- neurofibromatosis, including neurofibromatosis type 1

- syndrome Patna-Jeghers,

or any combination of them.

Recently described the effectiveness of a dual inhibitor of PI3 kinase/mTOR in malignant glioma (Cancer Cell, v.9, 341-349).

Specific derivatives of imidazoquinolines used in the present invention, receipt and suitable pharmaceutical compositions containing these compounds, described in the patent WO 2006/122806 and include the compounds of formula I

where

R1denotes a naphthyl or phenyl, where the specified phenyl substituted by one or two substituents, independently selected from the group comprising halogen, (ness.)alkyl, unsubstituted or substituted with halogen, cyano, imidazolyl or triazolyl, denotes cycloalkyl, amino group, substituted by one or two substituents, independently selected from the group comprising (ness.)alkyl, (ness.)alkylsulfonyl, (ness.)alkoxygroup the PU and (ness.)alkoxy(ness.)alkylamino, means piperazinil, unsubstituted or substituted by one or two substituents, independently selected from the group comprising (ness.)alkyl and (ness.)alkylsulfonyl, denotes the 2-oxopyrrolidin, (ness.)alkoxy(ness.)alkyl, imidazolyl, pyrazolyl and triazolyl,

R2denotes O or S,

R3means (ness.)alkyl,

R4denotes pyridyl, unsubstituted or substituted with halogen, cyano, (ness.)the alkyl, (ness.)alkoxygroup or piperazinil, unsubstituted or substituted (ness.)the alkyl, denotes pyrimidinyl, unsubstituted or substituted (ness.)alkoxygroup, denotes chinoline, unsubstituted or substituted with halogen, represents honokalani or phenyl substituted by alkoxygroup,

R5denotes hydrogen or halogen,

n is 0 or 1,

R6indicates oxide, provided that when n is 1, then the N atom contained in the radical R6, charged positively,

R7denotes hydrogen or an amino group,

or tautomer, or a pharmaceutically acceptable salt, or a hydrate or MES.

The radicals and symbols used in the definition of compounds of formula I have the meanings described in the patent WO 2006/122806, which is included in this description by reference.

Preferred compounds of the present invention are compounds, opisanie patent WO 2006/122806, selected from the group including:

2-methyl-2-[4-(3-methyl-2-oxo-8-pyridin-4-yl-2,3-dihydroimidazo[4,5-C]quinoline-1-yl)phenyl]propionitrile,

2-methyl-2-[4-(3-methyl-2-oxo-8-pyridin-3-yl-2,3-dihydroimidazo[4,5-C]quinoline-1-yl)phenyl]propionitrile,

2-{4-[8-(6-methoxypyridine-3-yl)-3-methyl-2-oxo-2,3-dihydroimidazo[4,5-C]quinoline-1-yl]phenyl}-2-methylpropionitrile,

2-{4-[8-(5-methoxypyridine-3-yl)-3-methyl-2-oxo-2,3-dihydroimidazo[4,5-C]quinoline-1-yl]phenyl}-2-methylpropionitrile,

2-methyl-2-{4-[3-methyl-2-oxo-8-(6-piperazine-1-espiridion-3-yl)-2,3-dihydroimidazo[4,5-C]quinoline-1-yl]phenyl}propionitrile,

2-methyl-2-(4-{3-methyl-8-[2-(4-methylpiperazin-1-yl)pyridine-4-yl]-2-oxo-2,3-dihydroimidazo[4,5-C]quinoline-1-yl}phenyl)propionitrile,

2-methyl-2-[4-(3-methyl-2-oxo-8-quinoline-3-yl-2,3-dihydroimidazo[4,5-C]quinoline-1-yl)phenyl]propionitrile,

2-{4-[8-(2-ftorhinolon-3-yl)-3-methyl-2-oxo-2,3-dihydroimidazo[4,5-C]quinoline-1-yl]phenyl}-2-methylpropionitrile,

2-methyl-2-[4-(3-methyl-2-oxo-8-quinoline-6-yl-2,3-dihydroimidazo[4,5-C]quinoline-1-yl)phenyl]propionitrile,

2-methyl-2-[4-(3-methyl-2-oxo-8-quinoline-5-yl-2,3-dihydroimidazo[4,5-C]quinoline-1-yl)phenyl]propionitrile,

2-methyl-2-[4-(3-methyl-2-oxo-8-quinoline-6-yl-2,3-dihydroimidazo[4,5-C]quinoline-1-yl)phenyl]propionitrile,

2-ethyl-2-[4-(3-methyl-2-oxo-8-pyridin-3-yl-2,3-dihydroimidazo[4,5-C]quinoline-1-yl)phenyl]butyronitrile,

2-ethyl-2-[4-(3-methyl-2-oxo-8-quinoline-3-yl-2,3-dihydroimidazo[4,5-C]quinoline-1-ylphenyl]butyronitrile,

1-[3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl]-3-methyl-8-pyridin-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-[3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl]-3-methyl-8-quinoline-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

3-methyl-1-[4-(2-oxopyrrolidin-1-yl)phenyl]-8-pyridin-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

3-methyl-1-[4-(2-oxopyrrolidin-1-yl)phenyl]-8-quinoline-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-{4-[bis-(2-methoxyethyl)amino]-3-forfinal}-3-methyl-8-pyridin-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-{4-[bis-(2-methoxyethyl)amino]-3-forfinal}-3-methyl-8-quinoline-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-{4-[bis-(2-methoxyethyl)amino]phenyl}-3-methyl-8-pyridin-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-{4-[bis-(2-methoxyethyl)amino]phenyl}-3-methyl-8-quinoline-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

3-methyl-1-naphthalene-2-yl-8-pyridin-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

3-methyl-1-naphthalene-2-yl-8-quinoline-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-(2-chlorophenyl)-3-methyl-8-pyridin-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-(2-chlorophenyl)-3-methyl-8-quinoline-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

3-methyl-8-pyridin-3-yl-1-ortho-tolyl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

3-methyl-8-quinoline-3-yl-1-ortho-tolyl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-(2-ethylphenyl)-3-methyl-8-pyridin-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-(2-ethylphenyl)-3-methyl-8-quinoline-3-yl-1,3-digidroid is zo[4,5-C]quinoline-2-it,

3-methyl-8-pyridin-3-yl-1-(2-triptoreline)-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

3-methyl-8-quinoline-3-yl-1-(2-triptoreline)-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-(4-fluoro-2-were)-3-methyl-8-pyridin-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-(4-fluoro-2-were)-3-methyl-8-quinoline-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-(2-chloro-4-forfinal)-3-methyl-8-pyridin-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-(2-chloro-4-forfinal)-3-methyl-8-quinoline-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-(3-chlorophenyl)-3-methyl-8-pyridin-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-(3-chlorophenyl)-3-methyl-8-quinoline-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

3-methyl-8-pyridin-3-yl-1-(3-triptoreline)-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

3-methyl-8-quinoline-3-yl-1-(3-triptoreline)-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-(4-methoxymethyl)-3-methyl-8-pyridin-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-(4-methoxymethyl)-3-methyl-8-quinoline-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-[2-chloro-4-(2-methoxyethyl)phenyl]-3-methyl-8-pyridin-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-[2-chloro-4-(2-methoxyethyl)phenyl]-3-methyl-8-[quinoline-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-[4-(2-methoxyethyl)phenyl]-3-methyl-8-quinoline-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-[4-(2-methoxyethyl)phenyl]-3-methyl-8-pyridin-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

2-methyl-2-[4-(3-IU the Il-2-oxo-5-hydroxy-8-pyridin-3-yl-2,3-dihydroimidazo[4,5-C]quinoline-1-yl)phenyl]propionitrile,

2-methyl-2-[4-(3-methyl-2-oxo-5-hydroxy-8-quinoline-3-yl-2,3-dihydroimidazo[4,5-C]quinoline-1-yl)phenyl]propionitrile,

2-[4-(7-fluoro-3-methyl-2-oxo-8-pyridin-3-yl-2,3-dihydroimidazo[4,5-C]quinoline-1-yl)phenyl]-2-methylpropionitrile,

2-[4-(7-fluoro-3-methyl-2-oxo-8-quinoline-3-yl-2,3-dihydroimidazo[4,5-C][quinoline-1-yl)phenyl]-2-methylpropionitrile,

N-methyl-N-[4-(3-methyl-2-oxo-8-pyridin-3-yl-2,3-dihydroimidazo[4,5-C]quinoline-1-yl)phenyl]methanesulfonamide,

tert-butyl ether methyl[4-(3-methyl-2-oxo-8-pyridin-3-yl-2,3-dihydroimidazo[4,5-C]quinoline-1-yl)phenyl]carbamino acid,

methyl[4-(3-methyl-2-oxo-8-pyridin-3-yl-2,3-dihydroimidazo[4,5-C]quinoline-1-yl)phenyl]amide econsultancy acid,

methyl[4-(3-methyl-2-oxo-8-quinoline-3-yl-2,3-dihydroimidazo[4,5-C]quinoline-1-yl)phenyl]amide econsultancy acid,

N-ethyl-N-[4-(3-methyl-2-oxo-8-pyridin-3-yl-2,3-dihydroimidazo[4,5-C]quinoline-1-yl)phenyl]methanesulfonamide,

N-ethyl-N-[4-(3-methyl-2-oxo-8-quinoline-3-yl-2,3-dihydroimidazo[4,5-C]quinoline-1-yl)phenyl]methanesulfonamide,

2-[4-(3-ethyl-2-oxo-8-pyridin-3-yl-2,3-dihydroimidazo[4,5-C]quinoline-1-yl)-phenyl]-2-methylpropionitrile,

1-[3-fluoro-4-(4-methanesulfonylaminoethyl-1-yl)phenyl]-3-methyl-8-quinoline-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-[3-fluoro-4-(4-methanesulfonylaminoethyl-1-yl)phenyl]-3-methyl-8-pyridin-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-(3-fluoro-4-piperazine-1-ylphenyl)-3-methyl-8-[quinoline-3-yl-1,3-digidroid is zo[4,5-C]quinoline-2-it,

1-(3-fluoro-4-piperazine-1-yl-phenyl)-3-methyl-8-pyridin-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

3-methyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-8-quinoline-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

3-methyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-8-pyridin-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-[2-chloro-4-(4-methylpiperazin-1-yl)phenyl]-3-methyl-8-quinoline-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-[2-chloro-4-(4-methylpiperazin-1-yl)phenyl]-3-methyl-8-pyridin-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]-3-methyl-8-quinoline-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]-3-methyl-8-pyridin-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-(4-imidazol-1-yl-2-were)-3-methyl-8-quinoline-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-(4-imidazol-1-yl-2-were)-3-methyl-8-pyridin-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

3-methyl-1-(4-(pyrazole-1-ylphenyl)-8-quinoline-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

3-methyl-1-(4-(pyrazole-1-ylphenyl)-8-pyridin-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

3-methyl-8-quinoline-3-yl-1-(4-[1,2,4]triazole-1-ylphenyl)-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

3-methyl-8-pyridin-3-yl-1-(4-[1,2,4]triazole-1-ylphenyl)-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

3-methyl-1-[4-(4-methylpiperazin-1-yl)-3-triptoreline]-8-quinoline-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

3-methyl-1-[4-(4-methylpiperazin-1-yl)-3-triptoreline-8-pyridin-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-(3-chloro-4-piperazine-1-ylphenyl)-3-methyl-8-quinoline-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-(3-chloro-4-piperazine-1-ylphenyl)-3-methyl-8-pyridin-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-(3-chloro-4-piperazine-1-ylphenyl)-8-(6-methoxypyridine-3-yl)-3-methyl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-(3-chloro-4-piperazine-1-ylphenyl)-8-(5-methoxypyridine-3-yl)-3-methyl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

8-(6-methoxypyridine-3-yl)-3-methyl-1-[4-(4-methylpiperazin-1-yl)-3-triptoreline]-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

8-(5-methoxypyridine-3-yl)-3-methyl-1-[4-(4-methylpiperazin-1-yl)-3-trifluoromethyl-phenyl]-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-[2-chloro-4-(4-methylpiperazin-1-yl)phenyl]-8-(6-methoxypyridine-3-yl)-3-methyl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-[2-chloro-4-(4-methylpiperazin-1-yl)phenyl]-8-(5-methoxypyridine-3-yl)-3-methyl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-(3-chloro-4-piperazine-1-ylphenyl)-3-methyl-8-cinoxacin-6-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

3-methyl-1-(4-piperazine-1-yl-3-triptoreline)-8-quinoline-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

3-methyl-1-(4-piperazine-1-yl-3-triptoreline)-8-pyridin-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

8-(6-methoxypyridine-3-yl)-3-methyl-1-(4-piperazine-1-yl-3-triptoreline)-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

8-(5-methoxypyridine-3-yl)-3-methyl-1-(4-piperazine-1-yl-3-triptoreline)-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

3-methyl-1-(4-piperazine-1-yl-3-triptoreline)-8-cinoxacin-6-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-[3-chloro-4-(CIS-3,5-dimethylpiperazine-1-yl)phenyl]-3-methyl-8-pyridin-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-[3-chloro-4-(CIS-3,5-dimethylpiperazine-1-yl)phenyl]-3-methyl-8-quinoline-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-[3-chloro-4-(4-ethylpiperazin-1-yl)phenyl]-3-methyl-8-pyridin-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-[3-chloro-4-(4-ethylpiperazin-1-yl)phenyl]-3-methyl-8-quinoline-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-[3-chloro-4-(4-isopropylpiperazine-1-yl)phenyl]-3-methyl-8-pyridin-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-[3-chloro-4-(4-isopropylpiperazine-1-yl)phenyl]-3-methyl-8-quinoline-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-[4-(4-ethylpiperazin-1-yl)-3-triptoreline]-3-methyl-8-pyridin-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-[4-(4-ethylpiperazin-1-yl)-3-triptoreline]-3-methyl-8-quinoline-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

3-methyl-8-(6-piperazine-1-espiridion-3-yl)-1-(3-triptoreline)-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

8-(6-methoxypyridine-3-yl)-3-methyl-1-(3-triptoreline)-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-(3-chloro-4-imidazol-1-ylphenyl)-3-methyl-8-pyridin-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-(3-chloro-4-imidazol-1-ylphenyl)-3-methyl-8-quinoline-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

2-methyl-2-[4-(3-methyl-8-quinoline-3-yl-2-thioxo-2,3-dihydroimidazo[4,5-C]quinoline-1-yl)-phenyl]propionitrile,

2-methyl-2-{4-[3-methyl-8-(2-methylpyridin-4-yl)-2-oxo-2,3-di is etomidate[4,5-C]quinoline-1-yl]-phenyl}propionitrile,

5-{1-[4-(centimetres)phenyl]-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-C]quinoline-8-yl}pyridine-2-carbonitrile,

2-[4-(4-amino-3-methyl-2-oxo-8-quinoline-3-yl-2,3-dihydroimidazo[4,5-C]quinoline-1-yl)phenyl]-2-methylpropionitrile,

1-[4-(3-methyl-2-oxo-8-pyridin-3-yl-2,3-dihydroimidazo[4,5-C]quinoline-1-yl)phenyl]cyclopropanecarbonitrile,

1-[4-(3-methyl-2-oxo-8-quinoline-3-yl-2,3-dihydroimidazo[4,5-C]quinoline-1-yl)phenyl]cyclopropanecarbonitrile,

1-{4-[8-(6-methoxypyridine-3-yl)-3-methyl-2-oxo-2,3-dihydroimidazo[4,5-C]quinoline-1-yl]phenyl}cyclopropanecarbonitrile,

1-[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]-8-(6-methoxypyridine-3-yl)-3-methyl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]-8-(5-methoxypyridine-3-yl)-3-methyl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]-3-methyl-8-cinoxacin-6-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-(3-chloro-4-piperazine-1-ylphenyl)-8-(2-methoxypyridine-5-yl)-3-methyl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-(3-chloro-4-piperazine-1-ylphenyl)-3-methyl-8-pyrimidine-5-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-(3-chloro-4-piperazine-1-ylphenyl)-8-(2-methoxypyridine-5-yl)-3-methyl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-(3-chloro-4-piperazine-1-ylphenyl)-3-methyl-8-pyrimidine-5-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-(3-chloro-4-piperazine-1-ylphenyl)-3-methyl-8-(2-methylpyridin-4-yl)-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-[3-chloro-4-(the IP-3,5-dimethylpiperazine-1-yl)phenyl]-8-(6-methoxypyridine-3-yl)-3-methyl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-[3-chloro-4-(CIS-3,5-dimethylpiperazine-1-yl)phenyl]-8-(5-methoxypyridine-3-yl)-3-methyl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-[4-(CIS-3,5-dimethylpiperazine-1-yl)-3-triptoreline]-8-(6-methoxypyridine-3-yl)-3-methyl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-[4-(CIS-3,5-dimethylpiperazine-1-yl)-3-triptoreline]-8-(5-methoxypyridine-3-yl)-3-methyl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

8-(2-methoxypyridine-5-yl)-3-methyl-1-(4-piperazine-1-yl-3-trifluoromethyl-phenyl)-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

3-methyl-1-(4-piperazine-1-yl-3-triptoreline)-8-pyrimidine-5-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

5-[3-methyl-2-oxo-1-(4-piperazine-1-yl-3-triptoreline)-2,3-dihydro-1H-imidazo[4,5-C]quinoline-8-yl]pyridine-2-carbonitrile,

3-methyl-8-(2-methylpyridin-4-yl)-1-(4-piperazine-1-yl-3-triptoreline)-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

8-(3,4-acid)-3-methyl-1-(4-piperazine-1-yl-3-triptoreline)-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

3-methyl-8-pyridin-3-yl-1-(4-[1,2,4]triazole-1-yl-3-triptoreline)-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

3-methyl-8-quinoline-3-yl-1-(4-[1,2,4]triazole-1-yl-3-triptoreline)-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

8-(6-methoxypyridine-3-yl)-3-methyl-1-(4-[1,2,4]triazole-1-yl-3-triptoreline)-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

8-(5-methoxypyridine-3-yl)-3-methyl-1-(4-[1,2,4]triazole-1-yl-3-triptoreline)-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

5-[3-methyl--oxo-1-(4-[1,2,4]triazole-1-yl-3-triptoreline)-2,3-dihydro-1H-imidazo[4,5-C]quinoline-8-yl]pyridine-2-carbonitrile,

8-(6-herperidin-3-yl)-3-methyl-1-(4-[1,2,4]triazole-1-yl-3-triptoreline)-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

8-(2,6-dimethoxypyridine-3-yl)-3-methyl-1-(4-[1,2,4]triazole-1-yl-3-triptoreline)-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

3-methyl-8-pyrimidine-5-yl-1-(4-[1,2,4]triazole-1-yl-3-triptoreline)-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

8-(2-methoxypyridine-5-yl)-3-methyl-1-(4-[1,2,4]triazole-1-yl-3-triptoreline)-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

8-(2,4-dimethoxypyrimidine-5-yl)-3-methyl-1-(4-[1,2,4]triazole-1-yl-3-triptoreline)-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

3-methyl-1-(4-(pyrazole-1-yl-3-triptoreline)-8-pyridin-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

3-methyl-1-(4-(pyrazole-1-yl-3-triptoreline)-8-quinoline-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

8-(6-methoxypyridine-3-yl)-3-methyl-1-(4-(pyrazole-1-yl-3-triptoreline)-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

8-(5-methoxypyridine-3-yl)-3-methyl-1-(4-(pyrazole-1-yl-3-triptoreline)-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-(3-chloro-4-[1,2,4]triazole-1-ylphenyl)-3-methyl-8-pyridin-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-(3-chloro-4-[1,2,4]triazole-1-ylphenyl)-3-methyl-8-quinoline-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-(4-imidazol-1-yl-3-triptoreline)-3-methyl-8-pyridin-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-(4-imidazol-1-yl-3-triptoreline)-3-methyl-8-quinoline-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-(4-imidazol-1-yl-3-triptoreline)-8-(6-methoxypyridine-3-yl)-3-methyl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-(4-imidazol-1-yl-3-triptoreline)-8-(5-methoxypyridine-3-yl)-3-methyl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

3-methyl-8-pyridin-3-yl-1-(4-[1,2,4]triazole-1-ylmethylene)-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

3-methyl-8-quinoline-3-yl-1-(4-[1,2,4]triazole-1-ylmethylene)-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

1-(4-imidazol-1-ylmethylene)-3-methyl-8-pyridin-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-he

1-(4-imidazol-1-ylmethylene)-3-methyl-8-quinoline-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-it,

or tautomer, or a pharmaceutically acceptable salt, or a hydrate or MES.

The preferred compound of the present invention is 2-methyl-2-[4-(3-methyl-2-oxo-8-quinoline-3-yl-2,3-dihydroimidazo[4,5-C]quinoline-1-yl)phenyl]propionitrile and his monotonical. Synthesis of 2-methyl-2-[4-(3-methyl-2-oxo-8-quinoline-3-yl-2,3-dihydroimidazo[4,5-C]quinoline-1-yl)phenyl]propionitrile described, for example, in patent WO 2006/122806 in example 1.

Another preferred compound of the present invention is 8-(6-methoxypyridine-3-yl)-3-methyl-1-(4-piperazine-1-yl-3-triptoreline)-1,3-dihydroimidazo[4,5-C]quinoline-2-it. Synthesis of 8-(6-methoxypyridine-3-yl)-3-methyl-1-(4-piperazine-1-yl-3-triptoreline)-1,3-dihydroimidazo[4,5-C]quinoline-2-it is described, for example, in patent WO 2006/122806 in example 86.

According to the present invention the preferred symptoms intended for the treatment of the Oia compounds of the formula I, include the following diseases:

- restenosis,

- tuberose sclerosis,

- lymphangioleiomyomatosis,

- retinitis pigmentosa,

- neurodegenerative diseases such as Parkinson's disease, Huntington's disease, Alzheimer's disease and dementia caused by toomuchtime,

- spinal-cerebral ataxia type 3, amyotrophic lateral sclerosis caused by mutations in the SOD-1, neuronally ceroid-lipofuscinosis/disease batten (neurodegenerative disease in children),

- wet and dry macular degeneration,

- neurofibromatosis, including neurofibromatosis type 1

- syndrome Patna-Jeghers.

The most preferred syndromes intended for the treatment of the present invention compounds of formula I include syndrome tuberose syndrome or syndrome Patna-Jeghers.

First of all, the present invention relates to a method of treatment of diseases dependent kinase mTOR, which consists of introducing a therapeutically effective amount of a specific derived imidazoquinolines formula I, especially preferably 2-methyl-2-[4-(3-methyl-2-oxo-8-quinoline-3-yl-2,3-dihydroimidazo[4,5-C]quinoline-1-yl)phenyl]propionitrile or 8-(6-methoxypyridine-3-yl)-3-methyl-1-(4-piperazine-1-yl-3-triptoreline)-1,3-dihydroimidazo[4,5-C]quinoline-2-it, a warm-blooded animal in need of such treatment.

In addition, the present invention relates to the use of compounds of the formula I, especially preferably 2-methyl-2-[4-(3-methyl-2-oxo-8-quinoline-3-yl-2,3-dihydroimidazo[4,5-C]quinoline-1-yl)phenyl]propionitrile or 8-(6-methoxypyridine-3-yl)-3-methyl-1-(4-piperazine-1-yl-3-triptoreline)-1,3-dihydroimidazo[4,5-C]quinoline-2-it, to obtain a pharmaceutical preparation intended for treatment of diseases dependent kinase mTOR, and including the specified compound or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, for use of the specified compound or its pharmaceutically acceptable salts for the treatment of diseases dependent kinase mTOR.

The treatment according to the present invention includes symptomatic or prophylactic treatment.

The compound of formula (I) can also be used for the treatment of diseases dependent kinase mTOR, in combination with other active compounds, for example, the combination of components described in the patent WO 2006/122806.

The compound of formula (I) can also be used effectively in combination with known methods of treatment, for example, with the introduction of hormones or primarily in combination with radiation therapy. The compound of formula (I) can also be used, primarily, as radiosensibility primarily to treat tumors that prowl who have weak sensitivity to radiation therapy.

The term "combination"used in this context denotes a fixed combination in one dosage form or a set of components for joint introduction, in which the compound of formula (I) and component combination is administered independently at the same time or separately in a certain period of time, thus primarily observed cooperative effect of the combination of components, i.e. a synergistic effect.

The compound of the formula I can be entered separately or in combination with one or more other therapeutic compounds, when combined treatment is carried out at the introduction of fixed combinations or the introduction of compounds according to the invention and one or more other therapeutic compounds or alternately with the introduction independently of each other, or when the joint introduction of fixed combinations and one or more other therapeutic compounds.

The dosage of the active ingredient depends on many different factors, including type, species, age, body weight, sex and condition of the patient, the severity of the condition intended for treatment, route of administration, the kidneys and the liver of the patient and, above all, the specific connection. A physician, Clinician or veterinarian of ordinary skill can determine and prescribe the effective amount is STV medicines necessary to prevent, slow or stop development of the state. Optimal precision dose, which is achieved by the concentration of drug in the effective range and observed the desired effect, it is necessary to determine the presence of drugs in the area of the target. This should take into account the distribution, balance and withdrawal of drugs from the body.

Compounds according to the invention can be entered by any standard method, primarily parenterally, for example, in the form of solutions or suspensions for injection, enteral, for example oral, for example in the form of tablets or capsules, local, i.e. in the form of lotions, gels, ointments or creams, or in a nasal form or in the form of a suppository. Local injection means, for example, applied to the skin. Another form of local introduction is an introduction to the eyes. Pharmaceutical compositions comprising the compound according to the invention in a mixture with at least one pharmaceutically acceptable carrier or diluent, can be obtained in a standard way mixing with a pharmaceutically acceptable carrier or diluent.

Pharmaceutical compositions for treatment of one of the above violations include an effective amount of the compounds of formula I, or its N-oxide, or tautomer in a mixture with a pharmaceutically p is yimlamai media suitable for local, enteral, for example oral or rectal, or parenteral administration and which are inorganic or organic, solid or liquid substances. The pharmaceutical composition used for oral administration, first of all, are tablets or gelatin capsules that include the active ingredient mixed with diluents, such as lactose, dextrose, mannitol, and/or glycerol, and/or oil and/or polyethylene glycol. Tablets can also include a binder such as silicate of magnesium, starches, such as corn, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone, and, if necessary, dezintegriruetsja agents, such as starches, agar, alginic acid or its salt, such as sodium alginate, and/or effervescent mixtures, or absorbents, colorants, flavors and sweeteners. Pharmaceutically active compounds of the present invention can also be used in the form of compositions for parenteral administration or in the form of solutions for injection. The pharmaceutical compositions can be sterilized and/or can include excipients, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilized the market, salts for regulating osmotic pressure and/or buffer substances. These pharmaceutical compositions may optionally include other pharmacologically active substances, receive a standard way, for example with a standard mixing, granulation, dissolution or lyophilization, and these pharmaceutical compositions comprise from approximately 1 to 99%, especially from approximately 1 to approximately 20%, active ingredient(s).

The effectiveness of compounds of the formula I and their salts were evaluated for their inhibitory activity against the kinase mTOR using the following methods.

Biochemical analysis

A kit for determining the activity of the K-LISA™ mTOR company Calbiochem (catalog number SWA) used for determining the activity of 2-methyl-2-[4-(3-methyl-2-oxo-8-quinoline-3-yl-2,3-dihydroimidazo[4,5-C]quinoline-1-yl)phenyl]propionitrile (compound 1) and 8-(6-methoxypyridine-3-yl)-3-methyl-1-(4-piperazine-1-yl-3-triptoreline)-1,3-dihydroimidazo[4,5-C]quinoline-2-she (compound 2). Compounds 1, 2 or wortmannin incubated in a mixture with the enzyme mTOR for 30 min in an ice bath. This mixture then was transferred into a 96-well plate coated with glutathione and pre-incubated with the recombinant protein GST-S6K1. Kinase reaction was initiated by adding kinase buffer solution, which contains asego 100 μm ATP, and incubated for 30 min at 30°C. the Activity of mTOR was quantified using the system detection conjugate antibodies against phospho-Thr389 and horseradish peroxidase. Wortmannin used as a reference compound for determining the activity of mTOR kinase.

Methyl-2-[4-(3-methyl-2-oxo-8-quinoline-3-yl-2,3-dihydroimidazo[4,5-C]quinoline-1-yl)phenyl]propionitrile (compound 1) inhibits the activity of mTOR kinase, and the value of the IC50is 20.7 nm.

8-(6-Methoxypyridine-3-yl)-3-methyl-1-(4-piperazine-1-yl-3-triptoreline)-1,3-dihydroimidazo[4,5-C]quinoline-2-on (compound 2) inhibits the activity of mTOR kinase, and the value of the IC50is 1.4 nm.

The analysis using cells

For the quantitative determination of the level of phosphorylation of ribosomal protein S6 used cell Western analysis in 96-well tablets after treatment with compounds in HeLa cells. HeLa cells were cultivated in 96-well plates (5000 cells per well)were cultured for 72 h, and then in depleted medium for 18 h in a humid environment containing 5% CO2at 37°C. Then cells were incubated in 200 μl of depleted environment within 180 min and the cells were stimulated for 60 min after addition of 200 μl of medium for analysis. All solutions are pre-heated for 30 min, 96-well tablets covered with a film (Millipore), and incubated in incubat the re in the atmosphere of CO 2at 37°C in accordance with the method of exhaustion and stimulation. The cells were fixed by adding 50 μl of fixative solution 5X Mirsky for 60 min, then washed (8×200 μl of Tris-saline buffer solution, Bio-Tek ELX405). After blocking for 48 h in Tris-saline buffer solution, pH of 7.2, containing 0.1% Triton-X100 and 0.1% bovine serum albumin at 4°C. fixed cells were incubated overnight at 4°C in the presence of primary antibodies against phospho(Ser235-236)S6 (Cell Signaling Technologies #2211, or they were replaced with antibodies firm Cell Signaling Technologies #2215) and determined the amount of phosphorylated S6 balance Ser240-244. To the wells were added 50 μl of antibody (dilution 1:300 in blocking solution), the cells were washed (8×200 μl of Tris-saline buffer solution)was then added 100 μl labeled with europium secondary anti-rabbit antibody (Perkin-Elmer, 2.4 μg/ml) and incubated for 90 min at room temperature in the dark. After the final stage of leaching (8×200 μl of Tris-saline buffer solution) into each well was added 100 μl of a solution-amplifier Delphia™ and after 120 min was determined by fluorescence on fluorimetry Envision 2101 (Perkin-Elmer).

A framework for analysis contained 1X nonessential amino acids and 1 mm L-glutamine ("medium") in the presence or absence of 100 nm insulin.

2-Methyl-2-[4-(3-methyl-2-oxo-8-quinoline-3-yl-2,3-dihydroimidazo[4,5-C]quinoline-1-the l)phenyl]propionitrile (compound 1) inhibits induced phosphorylation of S6 when the value of the IC 5017 nm. 8-(6-Methoxypyridine-3-yl)-3-methyl-1-(4-piperazine-1-yl-3-triptoreline)-1,3-dihydroimidazo[4,5-C]quinoline-2-on (compound 2) inhibits induced phosphorylation of S6 when the value of the IC5011 nm.

1. The use of the compounds of formula I, which represents a 2-methyl-2-[4-(3-methyl-2-oxo-8-quinoline-3-yl-2,3-dihydroimidazo[4,5-C]quinoline-1-yl)phenyl]propionitrile or 8-(6-methoxypyridine-3-yl)-3-methyl-1-(4-piperazine-1-yl-3-triptoreline)-1,3-dihydroimidazo[4,5-C]quinoline-2-he, or his tautomer, pharmaceutically acceptable salt, hydrate or MES for obtaining a medicinal product intended for the treatment of diseases associated with changing or rasagulla mTOR kinase selected from the group including glioma, disease graft-versus-host, for example, after bone marrow transplantation, restenosis, tuberose sclerosis, lymphangioleiomyomatosis, retinitis pigmentosa, autoimmune diseases, including encephalomyelitis, insulin-dependent diabetes mellitus, dermatomyositis, rheumatoid diseases, resistant to steroids acute lymphoblastic leukemia, fibrotic diseases, pulmonary hypertension, immunomodulation, syndrome Hippel-Lindau syndrome Carney, familial adenomatous polyposis syndrome juvenile polyposis syndrome the BIRT-Hogg-Duke, familial hypertrophic cardiomyopathy syndrome wolf-Perkins is on-white, neurodegenerative disorders, wet and dry macular degeneration, muscle wasting (atrophy, cachexia) and myopathy, such as Danon disease, bacterial and viral infections, including miliary tuberculosis, streptococ group a, herpes simplex virus type I, HIV infection, neurofibromatosis, including neurofibromatosis type 1 syndrome Patna-Jeghers or any combination of them.

2. The use according to claim 1, where the compound of formula I is 2-methyl-2-[4-(3-methyl-2-oxo-8-quinoline-3-yl-2,3-dihydroimidazo[4,5-C]quinoline-1-yl)phenyl]propionitrile.

3. The use according to claim 1, where the compound of the formula I is 8-(6-methoxypyridine-3-yl)-3-methyl-1-(4-piperazine-1-yl-3-triptoreline)-1,3-dihydroimidazo[4,5-C]quinoline-2-it.

4. The use according to any one of claims 1 to 3, where the fibrotic disease is a pulmonary fibrosis, renal fibrosis or cystic fibrosis.

5. The use according to any one of claims 1 to 3, where neurodegenerative infringement is Parkinson's disease, Huntington's disease, Alzheimer's disease and dementia caused by Tau mutations, spinal-cerebellar ataxia type 3, amyotrophic lateral sclerosis caused by mutations in the SOD-1, neuronally ceroid-lipofuscinosis/disease batten (neurodegenerative disease in children).

6. A method for the treatment of diseases dependent kinase mTOR, including the introduction of a therapeutically effective the number of the compounds of formula 1 according to any one of claims 1 to 3 man or animal, who needs it, where disease-dependent kinase mTOR, is a disease associated with modifying or rasagulla mTOR kinase selected from the group including glioma, disease graft-versus-host, for example, after bone marrow transplantation, restenosis, tuberose sclerosis, lymphangioleiomyomatosis, retinitis pigmentosa, autoimmune diseases, including encephalomyelitis, insulin-dependent diabetes mellitus, dermatomyositis, rheumatoid diseases, resistant to steroids acute lymphoblastic leukemia, fibrotic diseases, pulmonary hypertension, immunomodulation, syndrome Hippel-Lindau syndrome Carney, familial adenomatous polyposis syndrome of juvenile polyposis the syndrome BIRT-Hogg-Duke, familial hypertrophic cardiomyopathy syndrome Wolff-Parkinson-white,
neurodegenerative disorders, wet and dry macular degeneration, muscle wasting (atrophy, cachexia) and myopathy, such as Danon disease, bacterial and viral infections, including miliary tuberculosis, streptococ group a, herpes simplex virus type I, HIV infection, neurofibromatosis, including neurofibromatosis type 1 syndrome Patna-Jeghers or any combination of them.

7. The method according to claim 6, where the fibrotic disease is a pulmonary fibrosis, renal fibrosis or cystic fibrosis.

8. The method according to claim 6, where aeroderivative infringement is Parkinson's disease, Huntington's disease, Alzheimer's disease and dementia caused by Tau mutations, spinal-cerebellar ataxia type 3, amyotrophic lateral sclerosis caused by mutations in the SOD-1, neuronally ceroid-lipofuscinosis/disease batten (neurodegenerative disease in children).

9. The pharmaceutical preparation comprising the compound of formula I according to any one of claims 1 to 3, or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, effective to treat the condition-dependent kinase mTOR when administered to man or animal, where the disease-dependent kinase mTOR, is a disease associated with modifying or rasagulla mTOR kinase selected from the group including glioma, disease graft-versus-host, for example, after bone marrow transplantation, restenosis, tuberose sclerosis, lymphangioleiomyomatosis, retinitis pigmentosa, autoimmune diseases, including encephalomyelitis, insulin-dependent diabetes mellitus, dermatomyositis, rheumatoid diseases, resistant to steroids acute lymphoblastic leukemia, fibrotic diseases, pulmonary hypertension, immunomodulation, syndrome Hippel-Lindau syndrome Carney, familial adenomatous polyposis syndrome of juvenile polyposis syndrome the BIRT-Hogg-Duke, familial hypertrophic cardiomyopathy syndrome Wolff-Parkinson-white, naroda generative violations wet and dry macular degeneration, muscle wasting (atrophy, cachexia) and myopathy, such as Danon disease, bacterial and viral infections, including miliary tuberculosis, streptococ group a, herpes simplex virus type I, HIV infection, neurofibromatosis, including neurofibromatosis type 1 syndrome Patna-Jeghers or any combination of them.



 

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SUBSTANCE: invention relates to a compound of formula I:

,

where X1 denotes a bond, NR8 or S; Y1 denotes O or NR ; R1 denotes C1-10alkyl, C6-10aryl or a 5-10-member heteroaryl containing 1-3 heteroatoms which are independently selected from N or S; where said R1 is optionally substituted with 0-2 J1; R2 denotes H or C1-10alkyl; each of R3, R4, R5 and R6 independently denotes H or C1-10alkyl; and R7 denotes C1-10alkyl, C3-10cycloalkyl, phenyl, 5-6-member heterocyclyl containing 1-3 heteroatoms independently selected from O and N, - (C1-6alkyl) -(C3-10cycloalkyl), - (C1-6alkyl) - (phenyl) or -(C1-6alkyl)-(6-member heterocyclyl containing 2 heteroatoms selected from O and N); where said R7 is optionally substituted with 0-5 J7; or R3 and R4, together with a carbon atom with which they are bonded, optionally form a 3-4-member saturated or partially unsaturated monocyclic fragment; R3 and R5, together with carbon atoms with which they are bonded, optionally form a 5-member monocyclic fragment; R8 denotes H; R9 denotes H or unsubstituted C1-6alkyl; or R2 and R9, together with atoms with which they are bonded, optionally form a 5-member aromatic monocyclic fragment containing 3 nitrogen atoms; each J1 independently denotes C1-6halogenalkyl, halogen, NO2, CN, Q or -Z-Q; or two J1 together can optionally form =O; Z denotes C1-6alkyl, wherein 0-3 carbon atoms are optionally substituted with -NR-, -O-, -C(O)- or -SO2-; wherein each Z is optionally substituted with 0-2 J2; Q denotes H; C1-6alkyl; 3-8-member aromatic or non-aromatic monocyclic fragment containing 0-3 heteroatoms independently selected from O, N and S; or an 8-10-member aromatic bicyclic system; each Q is optionally substituted with 0-2 JQ; each J7 independently denotes C1-6alkyl or halogen(C1-4alkyl); each of JQ and J7 independently denotes M or -Y-M; each Y independently denotes an unsubstituted C1-6alkyl, wherein 0-3 carbon atoms are optionally substituted with -O-, -C(O)- or -SO2-; each M independently denotes H, C1-6alkyl, C3-6cycloalkyl; halogen (C1-6alkyl), phenyl, halogen, CN, OH, OR1; or two M together can optionally form =O; R denotes H or an unsubstituted C1-6alkyl; R' denotes an unsubstituted C1-6alkyl. The invention also relates to methods of producing said compounds and a pharmaceutical composition for inhibiting PLK based on said compounds.

EFFECT: novel compounds which can be used in medicine as inhibitors of protein kinase are obtained.

34 cl, 1 tbl, 279 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel derivatives of imidazo[4,5-c]chinoline of general formula or to its pharmaceutically acceptable salts, where R1 represents straight-chained C1-C6alkyl, possibly substituted with one substituent, selected from C1-C3alkoxy; Z1 represents C2-C6alkylene; X1 represents NR5 or >NCOR5; Y1 represents C1-C6alkylene; R3 represents C1-C6alkyl, possibly substituted with C1-C6alkoxy; R5 represents hydrogen, piperidinyl, possibly substituted by piperidinyl nitrogen with group R10, group C1-C6alkyl, where the last group is possibly substituted with one substituent, independently selected from NR7R8 or R9; or R5 represents C1-C6alkylene, which can be bound with carbon atom in C2-C6alkylene group Z1 with formation of piperidine ring; each of R7 and R8 independently represents tetrahydropyranyl, piperidinyl, possibly substituted by piperidinyl nitrogen atom with group R10a, C1-C6alkyl, where the last group is possibly substituted with one group, independently selected from OR12; or R7 and R8 together with nitrogen atom, to which they are bound, form 4-7-membered saturated heterocyclic ring, selected from asetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, 1,4-oxazepanyl and 1,4-diazepanyl, where heterocyclic ring is possibly substituted with one or two substituents, independently selected from S(O)qR15, OR15, CO2R15, COR15, CONR15R16, NR15CO2R16, pyrimidinyl and C1-C6alkyl, where the last group is possibly substituted with one group, independently selected from OR18 and CO2R18; R9 represents S(O)qR20; R10 and R10a independently represent COR2 or group C1-C6alkyl; each of R12, R15, R16, R18, R20 and R24 independently represents hydrogen or C1-C6alkyl; q equals 2; m and n both equal 0; and A represents phenyl. Invention also relates to method of obtaining formula (I) compound, based on it pharmaceutical composition, and to method of treating said pathological conditions.

EFFECT: obtained are novel derivatives of imidazo[4,5-c]chinoline, useful modulation of TLR7 activity.

17 cl, 18 dwg, 81 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to (R)-4-(heteroaryl)phenyl compounds of formula ,

where X represents heteroatom, selected from -S or O, Y represents H or residue, selected from group, consisting of - linear or branched C1-C4-alkyl, halogen-C1-C3-alkyl; Z represents heteroaryl ring, selected from group, consisting of unsubstituted tetrazole and triazole, pyrazole, thiazole, isoxazole, isothiazole, thiadiazole and oxadiazole, substituted with one hydroxyl group and optionally additionally substituted with linear C1-C4-alkyl. (R)-4-(heteroaryl)phenylethyl derivatives of formula (I), which can be used for application in treatment of diseases, into which C5a-induced human PMN-chemotaxis is involved. Formula (I) compounds, where Z represents tertazole, is obtained by interaction of formula

compound with trimethylsililazide.

EFFECT: obtaining (R)-4-(heteroaryl)phenylethyl derivatives, possessing high selectivity and activity in inhibition of C5a-induced chemotaxis of neutrophils.

7 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a piperidine derivative of general formula (I)

,

where R1 denotes hydrogen or a substitute selected from the following (b)-(i): b) acrylic acid (including alkyl ester and hydroxyalkyl amide), (c) ureide, (d) alkenyl, (e) aminoalkyl which can be substituted with alkyl carbonyl or aminocarbonyl, (f) carbonyl alkyl, substituted with hydroxy, alkoxy or hydroxyalkylamino, (g) carbonyl, substituted with hydroxy, morpholino, alkoxy, hydroxyalkyl aminoalkoxy or cyclohexyloxy carbonyloxyalkoxy, (h) carbonylamino, substituted with alkyl or alkoxy, (i) aminocarbonyl which can be substituted with one or two substitutes selected from amino, hydroxy, alkoxy, alkenyl and alkyl (which can be substituted with halogen, thiol, piperidino, amino, alkoxy, alkoxycarbonyl, aminocarbonyl or one or two hydroxy); R2 denotes hydrogen or a substitute selected from the following (j)-(r): (j) cyano, (k) acrylic acid, (l) alkyl, substituted with hydroxy or piperidino, (m) carbonyl alkyl, substituted with hydroxy, alkoxy (which can be substituted with cyclohexyloxy carbonyloxy) or hydroxyalkylamino, (n) carbonyl, substituted with hydroxy or alkoxy, (o) carbonyl alkoxy, substituted with alkoxy, (p) carbonyl alkyl sulphanyl, substituted with hydroxy or alkoxy, (q) alkoxy, (r) halogen; and R3 denotes hydrogen or a substitute selected from the following (s)-(w): (s) alkyl which can be substituted with carboxy, cyano, pyrrolidyl, piperidino, alkoxy, alkyl sulphanyl or one or two hydroxy, (t) carbonyl, substituted with alkyl or alkoxy, (u) carbonyl alkoxyalkyl, substituted with hydroxy or alkoxy, (v) carbonyl alkyl, substituted with alkyl, alkoxy or alkylphenyl, (w) aminoalkyl, substituted with aminocarbonyl or alkane sulphonyl, where one of said R1 and R2 denotes a substitute other than hydrogen, A is unsubstituted or is an oxo, B denotes carbon or oxygen, one of X and Y denotes carbon and the other denotes sulphur, the dotted line denotes a single bond or a double bond, under the condition that when R2 denotes halogen or alkoxy, A is unsubstituted, R1 denotes a substitute other than hydrogen and B denotes oxygen. The invention also relates to an antihistamine which contains a compound of formula I and use of the described compound for treatment and production of a medicinal agent.

EFFECT: novel compounds having antagonistic action on histamine receptors are obtained and described and can be suitable as active ingredients of a pharmaceutical composition, especially an antihistamine composition.

17 cl, 40 ex, 21 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine and deals with complex immunomodulator for prevention of malfunctions and regulation of immune system functioning (versions). Claimed is complex medication for prevention of malfunctions and regulation of immune system functioning, which is characterised by the fact, that it is made in form of capsules and contains human recombinant interferon of alpha, and/or beta, and/or gamma types, retinol palmitate, zinc sulphate monohydrate, additional substance - to 0.1 g. Also claimed is complex immunomodulator for prevention of malfunctions and regulation of immune system functioning, which is characterised by the fact that it is made in form of suppository on hydrophilic base and contains human recombinant interferon of alpha, and/or beta, and/or gamma types, retinol palmitate and/or substances, selected from a number of alpha, beta, gamma carotenes, zinc sulphate monohydrate, as well as additional substances.

EFFECT: invention insures extension of possibilities of prevention and correction of immunological malfunctions in healthy and ill people.

6 cl, 8 ex, 8 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to drug form with delayed release for delivery of medication into large intestine. Drug form includes part with core and core coating, where core includes medication and coating. Coating includes mixture of sensitive to influence of large intestine bacteria substance and film-forming polymeric substance, which is not soluble at Ph lower than 5 and soluble at pH higher than 5. As sensitive to influence of large intestine bacteria substance used is starch, containing not more than 75% of amilose. Invention also relates to method of obtaining said drug form, which lies in formation of core and covering core with covering composition, which includes mixture of starch, which contains not more than 75% of amilose, and film-forming polymeric substance.

EFFECT: invention relates to application of claimed drug form for production of medication for treatment of inflammatory disease of intestine and carcinoma, as well as to methods of treating said diseases by introduction of therapeutically efficient amount of claimed drug form.

28 cl, 17 dwg, 1 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: method of obtaining drug-containing composition of polymeric micelles includes: dissolution of poorly dissolved in water drug and amphiphilic block copolymer in organic solvent; and addition to obtained mixture in organic solvent of water solution with formation of polymeric micelles. Method does not require carrying out separate operation of organic solvent removal before formation of micelles. Method is simple, reduces technological time and amenable to scaling.

EFFECT: in accordance with invention method polymeric micelles preserve their stability.

14 cl, 9 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to medicine and describes pharmaceutical composition for injecting, based on homogeneous liquid, containing docetaxel, with controlled pH in the interval from 3 to 5, consisting of: (a) docetaxel or its pharmaceutically acceptable salt, (b) surfactant, selected from group, consisting of polysorbate, polyoxyethylene glycol ester and polyoxyethylene derivatives of castor oil, (c) water-free ethanol in concentration from 100 to 800 mg/ml, and (d) pH regulator, selected from citric acid, fumaric acid, lactic acid, stannic acid, succinic acid, maleic acid, acetic acid, tartaric acid and phosphoric acid.

EFFECT: composition is suitable for efficient introduction of docetaxel as it has improved pharmaceutical stability.

2 cl, 4 ex, 8 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: in formula (VIII):

X represents NR7; Y represents O or N-(CH2)nR19; n is equal to 1 or 2; m is equal to 1 or 2; R1 represents H or C1-6alkyl; R2 independently represents H, C1-6alkyl or C5-6cycloalkyl; each of R4 and R4 independently represents H or C1-6alkyl; or R4 and R4 together form spiro-C3-6cycloalkyl group; R19 represents H, C1-6alkyl, C6aryl or C3cycloalkyl group; R6 represents OR8 ; and each of R7 and R8 independently represents H or C1-6alkyl. The invention also refers to compounds of formula VI, VII, a pharmaceutical composition containing said compounds, and a method of treating a proliferative disease, such as cancer.

EFFECT: invention refers to new pyrimidine derivatives and their pharmaceutically acceptable salts possessing the properties of a PLK1 kinase inhibitor.

24 cl, 8 tbl, 9 ex

Scfv-binding sparc // 2477728

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to immunology. There are presented versions of anti-SPARC ScFv, as well as a composition for treating a condition associated with high expression of SPARC with KD making at least 7.8×10-5 M containing said antibody in the effective amount bound to a therapeutic agent, as well as a method of treating a mammal based on the use of said composition. What is described in a composition for diagnosing the condition associated with high expression of SPARC on the basis of the anti-SPARC ScFy antibody bound to the diagnostic agent.

EFFECT: use of the invention can find application in medicine for treating the diseases associated with high expression of SPARC.

9 cl, 19 dwg, 1 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to biotechnology and molecular genetics. There are disclosed the versions of disintegrin and their use in pharmacology. The version of disintegrin involves the recovered polypeptide which possesses αvβ3 receptor antagonist activity and substantially lower ability to block αIIbβ3 and/or α5β1 integrin receptor than wild-type disintegrin. The polypeptide is coded by a modified nucleotide sequence of disintegrin possessing lower ability to bind to αIIbβ3 and/or α5β1 integrin than wild-type disintegrin.

EFFECT: invention may be used for treating and/or preventing the αvβ3 integrin-associated diseases in a mammal, which include without limitation osteoporosis, bone tumor or cancer growth, angiogenesis-related tumor growth and metastasis, tumor metastasis in bone, malignancy-induced hypercalcemia, angiogenesis-related eye diseases, Paget's disease, rheumatoid arthritis, and osteoarthritis.

23 cl, 16 dwg, 1 tbl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new substituted phenoxyacetic acids of general formula 1 possessing the properties of a selective antagonist inhibiting A2a adenosine receptor activity. The compounds may be used in preventing and treating central nervous system diseases, such as cognitive disorders, Parkinson's disease, or depression, tumour diseases, inflammatory processes. The invention also refers to an agent for intensification of immune response or action of drug preparations in the combination treatment of the diseases. In general formula

, R1, R2 and R3, optionally simultaneously represent hydrogen. C1-C5alkyl, C3-C5alkenyl or C3-C5-alkynyl; R4 represents hydrogen, a halogen atom, hydroxyl, C1-C3alkyl, C1-C3alkyloxy; R5 represents hydrogen, C1-C3alkyl, the group -C(O)R6;R6 represents hydroxyl, C1-C5alkyloxy, C3-C5alkenyloxy, C3-C5alkynyloxy optionally substituted by an amino group wherein the substitutes optionally identical are specified in hydrogen, C1-C3alkyl optionally substituted by a mono- or dialkylaminogroup, an alkyloxygroup, 5-6-member saturated heterocyclyl containing 1-2 heteroatoms specified in nitrogen and oxygen: pyridyl, phenyl optionally substituted by 1-3 methoxygroups; or optionally substituted 6-member, optionally annulated with 5-member unsaturated heterocyclyl, saturated heterocyclyl containing 2 nitrogen atoms wherein the substitutes are specified in C1-C3alkyl optionally substituted by 5- member heteroaryl containing 1-3 heteroatoms specified in nitrogen and oxygen; or 6- member optionally saturated heterocyclyl containing 1-2 nitrogen atom optionally substituted by C1-C3alkyl, oxo, optionally substituted by phenyl; a dashed line with an accompanying continuous line represents a single, double or triple bond.

EFFECT: preparing new substituted phenoxyacetic acids of general formula 1 possessing the properties of the selective agonist inhibiting A2a adenosine receptor activity.

15 cl, 3 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

wherein m is equal to 0, 1, 2; n is equal to 0, 1, 2, 3; each p, s, t is equal to 0 or 1; X represents CHR8 wherein R8 represents hydrogen; represents -CR9=C<, and then a dash line represents a bond, R9 independently represents hydrogen or C1-6-alkyl, or wherein R9 together with one of R2 or R20 forms a direct bond; R1 represents hydrogen; R2 and R20 are specified in: halogen, cyano, polyhalogen-C1-6-alkyl, C1-6-alkyl, morpholinyl, C1-6-alkyloxy with any of said groups is optionally and independently substituted by hydroxy, NR21R22 wherein R21 and R22 are independently specified in hydrogen, C1-6-alkylcarbonyl; or R2 and R20 together with a phenyl cycle whereto attached form a naphthaline group; or one of R2 or R20 have the values specified above, and the other of R2 or R20 together with R9 form a direct bond; R3 represents hydrogen; R4 and R5 independently represent hydrogen, C1-6-alkyl, hydroxy-C1-6-alkyl, C2-6-alkenyl or C1-6-alkyloxy; or R6 represents hydrogen; when p is equal to 1, then R7 represents hydrogen; Z represents one of the radicals presented in the patent claim. Also, the invention refers to a based pharmaceutical composition, using the compounds of formula (I) for producing the drug preparation for treating the disorders medicated by p53-MDM2 interaction for treating cancer, and to methods for producing the compounds of formula (I).

EFFECT: preparing the compounds of formula (I) as p53-MDM2 interaction inhibitors.

13 cl, 5 tbl, 31 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and

possessing the protein kinase inhibitor property, their pharmaceutically acceptable salts, solvates and hydrates, as well as to the use thereof and a based pharmaceutical composition. In general formula (1) X1 represents N, CRt1; X2 represents N, CRt2, X3 represents N, CRt3, X4 represents N, CH and wherein X1, X2, X3 and X4 are independently specified; Rt1 represents -H, halogen, -COOH, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, -CH3OH; Rt2 represents -H, halogen, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, CH2OH, -NH2; Rt3 represents -H, -S(O)rR4, halogen, -CN, -COOH, -CONH2, -COOCH3, -COOCH2CH3; the cycle A represents phenyl or a 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R'; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb; Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5, -NR4SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -O-, -S-, -NR3-; L1 represents NR3C(O) or C(O)NR3; R3, R4 and R5 are independently specified and represent H, C1-C6-alkyl, and also the group NR4 R5 may represent a 5- or 6-member saturated or aromatic cycle; in each case R6 is independently specified and represents C1-C6-alkyl optionally substituted by C1-C6- alkyl or 5-6 merous heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; In general formula (II) Z represents CH; X, represents CRt1; X2 represents CRt2, X3 represents CRt3 X4 represents CH and wherein X1, X2, X3 and X4 are independently specified; Rt1 represents -H; Rt2 represents -H, -F; Rt3 represents -H, -F; the cycle A represents phenyl or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R3; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb, Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -NR3-; L represents NR3C(O) or C(O)NR3; R4 and R5 are independently specified and represent H, C1-C6-alkyl, also the group NR4R3 may represent a 6-member saturated cycle; in each case R6 is independently specified and represents, C1-C6-alkyl optionally substituted by C1-C6-alkyl or 5-6 member heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; m is equal to 1; p is equal to 1.2.

EFFECT: preparing the compounds possessing the protein kinase inhibitor property.

16 cl, 5 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly oncology and surgery, and may be used in treating rectal cancer. That is ensured by teleirradiation, oral administration of capecitabine, intrarectal administration of metronidazole, local SHF hyperthermia followed by a surgical intervention. Capecitabine is administered 2000 mg/m2 from the 1st to 14th days. Metronidazole 10 g/m2 is intrarectally administered on the 3rd and 5th therapeutic days as a part of a composite mixture having the following proportions, wt %: metronidazole 12-22, sodium alginate 4-6, dimethylsulphoxide 2, distilled water up to 100. The 5-hour exposure of metronidazole is followed by a session of teletherapy. The local SHF hyperthermia at temperature 41-45° for one hour follows a session of teletherapy on 3rd, 4th and 5th therapeutic days. The surgical intervention is conducted 4 weeks after the completion of the preoperative therapy.

EFFECT: method provides ensuring complete therapeutic pathomorphism of the tumour in 25% of patients, reducing toxic and post-therapeutic complications, as well as enables conducting sphincter-preserving surgical interventions.

3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to using a compound of formula (I):

wherein R represents a hydrogen atom or CH3, and X represents a physiologically acceptable counter ion for preparing a hepatoprotective agent for treating or preventing a liver injury. The invention also refers to a method for treating or preventing the liver injury which involves a therapeutically or preventive effective amount of said compound of formula (I).

EFFECT: declared group of inventions provides hepatoprotective activity ensured by an ability of the compounds of formula (I) to improve an endothelium function to release endogenic prostacyclin.

14 cl, 7 dwg, 3 tbl, 5 ex

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