Imidazoquinoline and pyrimidine derivatives as potential modulators of vbgf-stimulated angiogenic processes

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, and concerns using 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)phenyl]propionitrile or 8-(6-methoxypyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethylphenyl)-1,3-dihydroimidazol[4,5-c]quinolin-2-one.

EFFECT: preparing a pharmaceutical formulation for treating a VBGF-stimulated angiogenic disease, a method of treating a VBGF-stimulated angiogenic disease and using the above compounds for the high-efficacy treatment of the above diseases.

5 cl, 4 dwg, 4 ex

 

The present invention relates to the use of certain derivatives of imidazoquinolines and pyridine for the treatment of VEGF-dependent diseases or to obtain pharmaceutical compositions for use in the treatment of these diseases, and to methods of use of certain derivatives of imidazoquinolines and pyridine for treatment of these diseases in a warm-blooded animal, in particular human, to pharmaceutical compositions containing certain derivative imidazoquinolines and pyridine, for the treatment of these diseases and to certain derivative imidazoquinolines and pyridine for use in the treatment of these diseases.

It was discovered that certain derivatives of imidazoquinolines and pyrimidine described in W02006/122806 and W007/084786, respectively, as of modulating the biological activity R-kinases, capable of blocking the biological effects associated with activation of VEGF receptors, with related ligands. Thus, these compounds are suitable for the treatment of VEGF-driven angiogenic diseases.

Syndromes that have or assume a molecular bond with the axis of the VEGFR/VEGF described, for example, in "P.Carmeliet and RK Jain; Angiogenesis in cancer and other diseases, Nature 2000; 407: 249-257"and "SM Weiss and Cheresh DA; Pathophysiological consequences ofVEGF-induced vascular permeability. Nature 2005, 437:4697-50"that completely, including all mentioned in these references, clucene in the present application by reference, and represent the following:

- rheumatoid arthritis

- synovitis

- the destruction of bone and cartilage

- osteomyelitis

- growth of pannus

- formation of osteophytes

- hepatitis

- pneumonia

- glomerulonephritis

- asthma

- nasal polyps

- status after transplantation

education in the liver

- retinopathy of prematurity

- age-related macular degeneration

- diabetic retinopathy

- prodlenie and other eye diseases

- take

- thyroiditis

- hypertrophy of the thyroid gland

- lymphoproliferative disease

- Kaposi's sarcoma

hematological malignancies (e.g., hemangioma)

- obesity

- spinal cord injury

- acute myocardial infarction

- swelling of the lungs, brain and retina

or any other combination.

Modern antiangiogenic therapy targeting or binding ligands (through competition with the antagonist or commit endogenous ligand or the expression of a soluble form of the receptor) with cognate receptors expressed on the surface of endothelial cells forming blood vessels (for example, the binding of VEGF to VEGFR1, 2 or 3); or suppression by activating receptors using inhibitors of low molecular weight, lock the observed kinase activity of the receptor(s), tyrosine kinase (e.g., blockade of activation of VEGFR1, 2 or 3). Previously described other strategies aimed at activating endogenous and natural inhibitor of VEGF-induced path in endothelial cells, or to attack the existing vascular system of VEGF-toxin conjugate. The PI3K inhibitors exert its antiangiogenic properties in blocking the proliferation of VEGF-induced signal being associated with VEGFR1, 2, or 3, the path of the PI3K/Akt is an important underlying effector VEGFR, because it is required for survival and proliferation of endothelial cells in vitro and in vivo (HP Gerber et al.. Vascular Endothelial Growth Factor Regulates Endothelial Cell Survival through the Phosphatidylinositol 3'-kinase/Akt Signal Transduction Pathway, J Biol Chem 1998; 273(46); 30336-30343; Fujio Y and Y To Wash, Akt Mediates Cytoprotection of Endothelial Cells by Vascular Endothelial Growth Factor in an Anchorage-dependent Manner. J Biol Chem 1999; 274(23):16349 - 16354; Benjamin LE and E Keshet E. Conditional switching of vascular endothelial growth factor (VEGF) expression in tumors: Induction of endothelial cell shedding and regression ofhemangioblastoma-like vessels by VEGF withdrawal. PNAS 1997; 94(16):8761-8766; TL Phung et al. Pathological angiogenesis is induced by sustained ACT of signaling and inhibited by rapamycin. Cancer Cell 2006; 10(2); 159-170). It is shown that the PI3K inhibitors abrogate VEGF-induced proliferation and survival ("V Dayanir et al., Identification of Tyrosine Residues in Vascular Endothelial Growth Factor Receptor-2/FLK-l Involved in Activation ofPhosphatidylinositol 3-Kinase and Cell Proliferation. J Biol Chem 2001: 276(21): 17686-17692 "), since it is considered that the path interception PI3K has a significant impact on misaligned function of blood vessels (AK Olsso et al., Nature Review Molecular Cellular Biology, 2006; vol 7,359-371).

Certain derivatives of imidazoquinolines suitable for the present invention, the receiving and containing a suitable pharmaceutical compositions are described in WO 2006/122806 and include compounds of formula I:

,

in which

R1represents naphthyl or phenyl, where the said 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; cycloalkyl; an amino group substituted by one or two substituents, independently selected from the group comprising (ness.)alkyl, (ness.)alkylsulfonyl, (ness.)alkoxygroup and (ness.)alkoxy(ness.)alkylamino; piperazinil, unsubstituted or substituted by one or two substituents, independently selected from the group comprising (ness.)alkyl and (ness.)alkylsulfonyl; 2-oxopyrrolidin; (ness.)alkoxy(ness.)alkyl; imidazolyl; pyrazolyl; and triazolyl;

R2represents O or S;

R3represents (ness.)alkyl;

R4represents pyridyl, unsubstituted or substituted with halogen, cyano, (ness.)the alkyl, (ness.)alkoxygroup or piperazinil, unsubstituted or substituted (ness.)by alkyl; pyrimidinyl, unsubstituted or substituted the first (ness.)alkoxygroup; chinoline, unsubstituted or substituted with halogen; honokalani; or phenyl substituted by alkoxygroup;

R5represents hydrogen or halogen;

n is 0 or 1;

R6is axicorp;

provided that if n=1, N-atom containing radical R6has a positive charge;

R7represents hydrogen or an amino group;

or their tautomers, pharmaceutically acceptable salt, hydrate or solvate.

The radicals and symbols used to identify the compounds of formula I, have the same values as disclosed in the publication WO 2006/122806, which is incorporated into the present application by reference.

Preferred compounds of the present invention are compounds described in WO 2006/122806 and selected from the group comprising;

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-(5-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-cinoxacin-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-yl)phenyl]butyronitrile;

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

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

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

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

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

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

1-{4-[bis(2-methoxyethyl)amino]phenyl}-3-methyl-8-pyridin-3-yl-1,3-dihydr is imidazo[4,5-C]quinoline-2-he;

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

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

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

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

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

3-methyl-8-pyridin-3-yl-1-o-tolyl-1,3-dihydroimidazo[4,5-C]quinoline-2-he;

3-methyl-8-quinoline-3-yl-1-o-tolyl-1,3-dihydroimidazo[4,5-C]quinoline-2-he;

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

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

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

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

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

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

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

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

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

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

3-methyl-8-pyrid the n-3-yl-1-(3-triptoreline)-1,3-dihydroimidazo [4,5-C]quinoline-2-he;

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

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

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

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

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

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

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

2-methyl-2-[4-(3-methyl-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 acids;

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

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

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-he;

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

1-(3-fluoro-4-piperazine-1-ylphenyl)-3-methyl-8-quinoline-3-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-he;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

8-(5-methoxypyridine-3-yl)-3-methyl-1-[4-(4-methylpiperazin-1-yl)-3-triptoreline]- 1,3-dihydroimidazo [4,5-C]quinoline--he;

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

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

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

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

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

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

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

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

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-he;

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-he;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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-dihydroimidazo[4,5-C]quinoline-1-yl]phenyl}propionitrile;

5-{1-[4-(centimetres)phenyl]-3-meta the-2-oxo-2,3-dihydro-1-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-he;

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

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

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

1-[3-chloro-4-piperazine-1-yl)phenyl]-3-methyl-8-pyrimidine-6-yl-1,3-dihydroimidazo[4,5-C]quinoline-2-he;

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

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

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

1-[3-chloro-4-(CIS-3,5-dimethylpiperazine-1-yl)phenyl]-8-(6-methoxypyridine-3-yl)-3-methyl-1,3-dihydroimidazo[4,5-C]quinoline-2-he;

<> 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-he;

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-he;

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-he;

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

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

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-he;

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

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

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

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-he;

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-he;

5-[3-methyl-2-OK is about-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-he;

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-he;

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

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-he;

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-he;

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

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

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

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

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

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

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

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

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

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

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

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

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-he;

or their tautomers, pharmaceutically acceptable salt, hydrate or solvate.

Especially 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. 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 in example 1 application WO 2006/122806 (compound A).

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-RNA as described in example 86 application WO 2006/122806 (connection B).

Some is produced in the water pyrimidine, suitable for the present invention, the receiving and containing a suitable pharmaceutical compositions are described in WO 07/084786 and include compounds of formula II

,

or stereoisomers, tautomers or pharmaceutically acceptable salts, where W represents S, Rwor N, where Rwselected from the group including:

(1) hydrogen,

(2) cyano,

(3) halogen,

(4) methyl,

(5) trifluoromethyl,

(6) sulfamidihappo;

R1selected from the group including:

(1) hydrogen,

(2) cyano,

(3) the nitrogroup,

(4) halogen,

(5) substituted or unsubstituted alkyl,

(6) substituted or unsubstituted of alkenyl,

(7) substituted or unsubstituted quinil,

(8) substituted or unsubstituted aryl,

(9) substituted or unsubstituted, heteroaryl,

(10) substituted or unsubstituted heterocyclyl,

(11) substituted or unsubstituted, cycloalkyl,

(12) -COR1a,

(13) -CO2R1a,

(14) -CONR1aR1b,

(15) -NR1aR1b,

(16) -NR1aCOR1b,

(17) -NR1aSO2R1b,

(18) -OCOR1a,

(19) -OR1a,

(20) -SR1a,

(21) -SOR1a,

(22) -SO2R1aH

(23) -SO2NR1aR1b

where R1aand R1bindependently selected from the group including:

(a) hydrogen,

(b) substituted or unsubstituted Ala is l,

(C) substituted or unsubstituted aryl,

(g) substituted or unsubstituted, heteroaryl,

(d) substituted or unsubstituted heterocyclyl and (e) substituted or unsubstituted, cycloalkyl,

R2selected from the group including:

(1) hydrogen,

(2) cyano,

(3) the nitrogroup,

(4) halogen,

(5) a hydroxy-group,

(6) an amino group,

(7) substituted or unsubstituted alkyl,

(8) -R2Aand

(9) -NR2aCOR2b,

where R2aand R2bindependently selected from the group including:

(a) hydrogen and

(b) substituted or unsubstituted alkyl;

R3selected from the group comprising;

(1) hydrogen,

(2) cyano,

(3) the nitrogroup,

(4) halogen,

(5) substituted or unsubstituted alkyl,

(6) substituted or unsubstituted of alkenyl,

(7) substituted or unsubstituted quinil,

(8) substituted or unsubstituted aryl,

(9) substituted or unsubstituted, heteroaryl,

(10) substituted or unsubstituted heterocyclyl,

(11) substituted or unsubstituted, cycloalkyl,

(12) -R3A.

(13) -NR3aR3b,

(14) -NR3aCOR3b.

(15) -NR3aSO2R3b,

(16) -or SIG3A,

(17) -SR3a,

(18) -SOR3a,

(19) -SO2R3Aand

(20) -SO2NR3aR3b,

where R3Aand R3bindependently selected from the group including:

(a) hydrogen,

(b)substituted or unsubstituted alkyl,

(C) substituted or unsubstituted aryl,

(g) substituted or unsubstituted, heteroaryl,

(d) substituted or unsubstituted heterocyclyl and (e) substituted or unsubstituted, cycloalkyl and R4selected from the group including:

(1) hydrogen, and

(2) a halogen.

The radicals and symbols used to describe the compounds of formula II have the same values as disclosed in the publication W007/084786, which is incorporated into the present application by reference.

Preferred compounds of the present invention are compounds specifically described in WO 07/084786. Especially preferred compound of the present invention is 5-(2,6-dimorpholino-4-yl-pyrimidine-4-yl)-4-triptorelin-2-ylamine (compound). Synthesis of 5-(2,6-dimorpholino-4-yl-pyrimidine-4-yl)-4-triptorelin-2-ylamine described in example 10 application WO 07/084786.

In accordance with the present invention treatment:

- rheumatoid arthritis

- synovitis

- destruction of bone and cartilage

- osteomielitis

- growth of pannus

- the formation of osteophytes

- hepatitis

- pneumonia

- glomerulonephritis

- asthma

- nasal polyps

States after transplantation

- formations in the liver

- retinopathy of prematurity

- age-related macular degeneration

- diabetic retinopathy

- holodilnik and the other eye is of deseases

- leukomalacia

- Hashimoto

- hypertrophy of the thyroid gland

- lymphoproliferative disorders

- Kaposi's sarcoma

hematological malignancies (e.g., hemangiomas)

- obesity

- spinal cord injury

- acute myocardial infarction

- edema of the lungs, brain and retina

or any other combination thereof, compounds of formulas I and II is the most preferred.

In particular, the present invention relates to a method for the treatment of VEGF-induced angiogenic diseases, including introduction to the needy in a warm-blooded animal a therapeutically effective amount of a specific derivative 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 (compound A) or 8(6-methoxypyridine-3-yl)-3-methyl-1-(4-piperazine-1-yl-3-triptoreline)-1,3-dihydroimidazo[4,5-C]quinoline-2-she (compound B), or a specific pyridine derivative of the formula II, particularly preferably 5-(2,6-dimorpholino-4-yl-pyrimidine-4-yl)-4-triptorelin-2-ylamine (compound).

In addition, the present invention relates to the use of specific derivative imidazoquinolines formula I, especially preferably 2-methyl-2-[4-(3-methyl-2-oxo-8-quinoline-3-yl-2,3-Digue is toimitate[4,5-C]quinoline-1-yl)phenyl]propionitrile (compound A) or 8(6-methoxypyridine-3-yl)-3-methyl-1-(4-piperazine-1-yl-3-triptoreline)-1,3-dihydroimidazo[4,5-C]quinoline-2-she (compound B), or a specific pyridine derivative of the formula II, particularly preferably 5-(2,6-dimorpholino-4-yl-pyrimidine-4-yl)-4-triptorelin-2-ylamine (compound)to obtain a pharmaceutical composition for the treatment of VEGF-induced angiogenic diseases or tumors, or disease-resistant agents, aimed at representatives of the family of VEGF and/or VEGFR.

Resistance to treatment with modulators of VEGF and/or VEGFR may be acquired by different mechanisms when exposed to the specified VEGF and/or VEGFR-modulator.

In particular, the present invention relates to the treatment of diseases or tumors that are dependent on VEGF or with resistance in the treatment of the modulator axis VEGF/VEGFR, compound of formula I, particularly preferably 2-methyl-2-[4-(3-methyl-2-oxo-8-quinoline-3-yl-2,3-dihydroimidazo[4,5-C]quinoline-1-yl)phenyl]propionitrile (compound A) or 8(6-methoxypyridine-3-yl)-3-methyl-1-(4-piperazine-1-yl-3-triptoreline)-1,3-dihydroimidazo[4,5-C]quinoline-2-one (compound B), or formula II, particularly preferably 5-(2,6-dimorpholino-4-yl-pyrimidine-4-yl)-4-triptorelin-2-aluminum (compound) or their pharmaceutically acceptable salts. Possible agents directed at the axis of the VEGF/VEGFR, are, for example, bevacizumab, ranibizumab, AVE0005, HuMV833, 2C3, SVO-P11, sutent, sorafenib, vatalanib, zactima, lidosta is Rin, angiozyme,, AG-013736, lestaurtinib, CP-547,632, CEP-7055, KRN633, NVP-AEE, IMC-1211, ZK260253, semaxanib, E-7107, AS-3, Cand5 and PTC-299.

The compound of formula (I) or (II) can also be used for the treatment of VEGF-induced angiogenic diseases in combination with other active compounds, for example, in combination with auxiliary agents, as described in W02006/122806 and W007/084786, more preferably with agents directed at VEGF or VEGFR, such as, but without limitation, anti-VEGF bevacizumab, anti-VEGF ranibizumab, AVE0005, anti-VEGF HuMV833 anti-VEGF SS FREE-P11, sutent, sorafenib, vatalanib, zactima, midostaurin, angiozyme, AG-013736, lestaurtinib, CP-547,632, CEP-7055, KRN633, NVP-AEE788, IMC-1211, ZK260253, semaxanib, E-7107, AS-3, Cand5 and PTC-299; and inhibitors of HSP90 CNF1010, CNF2024, tanespimycin, alvespereira, IPI504, SNX5422 and NVP-AUY922.

The term "combination" in the context of the present invention is either a fixed combination in one dosage form, or a set of parts for joint introduction, in which the compound of formula (I) and partner combinations can be entered independently in the same time or separately during the period of time for which the partners of the combination will manifest joint, for example, a synergistic effect.

The compound of formula (I) can be entered by itself or in combination with one or more other therapeutic compounds. Possible the combinational therapy takes the form of fixed combinations, or administration of compounds of the present invention and one or more other therapeutic compounds, sequentially or independently from one another, or co-administration of fixed combinations and one or more other therapeutic compounds.

The dosage of the active ingredient depends on various factors, including species, age, weight, sex and medical condition of the patient, severity of illness, type of administration, functioning of kidney and human liver and concrete used for the connection. Physician, Clinician or veterinarian of the middle level will easily be able to determine and prescribe the effective amount of the drug required to prevent, counter or stop the development of the state. Optimal precision in the selection of the concentration of the drug in the range, providing efficiency, requires a regime based on the kinetics of the availability of drugs to the target sites, which includes consideration of distribution, of establishment of the equilibrium concentration and excretion of drugs.

Compounds of the present invention can be introduced by any conventional method, in particular, parenteral, for example, in the form of solutions or suspensions for injection, enterline, for example, orally in the form of tablets or capsules, topic the ski, for example, in the form of lotions, gels, ointments or creams, or in the form of a nasal or suppository form. Topical application, for example, is carried out on the skin. Another form of topical injection is applied to the eyes. Pharmaceutical compositions containing the compound of the present invention together with at least one pharmaceutically acceptable carrier or diluent, can be obtained in the usual way by mixing with a pharmaceutically acceptable carrier or diluent.

The pharmaceutical compositions contain an effective amount to treat one of the above disorders, the compounds of formula I or its N-oxide or tautomer, together with pharmaceutically acceptable carriers suitable for topical, enteral, for example oral or rectal, or parenteral administration and which can be organic or inorganic, solid or liquid. There are pharmaceutical compositions used for oral administration, especially tablets or gelatin capsules which contain the active ingredient together with diluents, for example lactose, dextrose, mannitol, and/or glycerol, and/or lubricants and/or polyethylene glycol. Tablets may also contain binders, for example, a silicate of magnesium, starches, so the e as wheat, corn or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if desired, substance-leavening agents, e.g. starches, agar, alginic acid or its salts, such as sodium alginate, and/or emit gas mixtures, or adsorbents, colorants, sweeteners and flavorings. It is also possible to use the pharmacologically active compounds of the present invention in the form of parenteral entered compositions or in the form of infusion solutions. The pharmaceutical compositions may be sterilized and/or may contain excipients, for example preservatives, stabilizers, moisturizers and/or emulsifiers, solvents, salts for regulating osmotic pressure and/or buffers. The pharmaceutical compositions of the present invention that, if desired, may contain other pharmacologically active substances, get in a known manner, for example, by simple mixing, granulating, obtain drugs with a sweet filling, dissolution or lyophilization processes, and contain from about 1% to 99%, particularly preferably from about 1% to about 20% of the active ingredient(s).

Brief description of figures

Figure 1 shows the effect of compound a on VEGF-induced proliferation. Cells HUVEC sown, soak in a little vortochny environment, contains (V) or not containing (0) VEGF and BrDU and incubated with increasing concentrations of compounds And within 24 hours the Proliferation of endothelial cells was measured by quantitative content entered BrDU. Spend four independent experiments with n=3 cells per group*p=<0,05 (ANOVA-Dunnett's) above the base line, processed VEGF-a comparison samples (represented by a horizontal line).

X-ray diffraction pattern.

Figure 2 shows the effect of compound a on VEGF-induced neovascularization in vivo. The FVB mice with implanted Teflon agar camera only with agar (agar) or with VEGF 165 (agar+VEGF) in a concentration of 2 mg/ml, administered orally, the compound a or placebo (Veh, all cells) for 4 days at the indicated doses and mode. Animals killed after 24 h after the last dose, for the quantitative determination of VEGF-induced neovascularization tissue (left panel), and content Tie-2 no ELISA (right panel). *, p=<0,05 (ANOVA-Dunnett's) compared with the processed VEGF reference samples,

Figure 3: Effect of compounds a, B and C on VEGF-induced permeability in vivo. The FVB mice, which pre-specified time, oral introduced or compound a (30 mg/kg), or compound B (7.5 mg/kg), or compound B (50 mg/kg), intravenously injected Evans blue and after 30 min inject VEGF in the ear. Then kill mice, and edit the accelerate the selection of the dye. *, p=<0,05.

Figure 4: Effect of compounds a and b on vnutritelostnoe pressure in the tumor. Rats with orthotopic transportirovannoy tumor BN472 having a pressure-sensitive catheter inserted into the tumor, lump sum orally administered compound a (30 mg/kg - upper panel, the dark line), or the connection In (2.5 mg/kg, bottom panel, dark line), or placebo (both panels - gray line). IFP register within 24 hours and build the schedule of deviations (Delta) (top panel, dark line: untreated animals; gray line/treatment was carried out as indicated above the graph).

Examples

The effectiveness of compounds of the formula (I) and (II) and their salts can be demonstrated as follows:

Example 1: analysis of the proliferation of HUVEC

Effect on VEGF-induced HUVEC proliferation are examined using a set for the introduction of BrdU (Biotrak Cell Proliferation Elisa System V.2, Amersham, England). Subconfluent layer HUVEC sown at a density of 5x10 cells per cell in 96-cell tablets, filled with 1.5% gelatin, and then incubated at 37°C in the presence of 5% CO2in a nutrient medium containing 5% FBS (PromoCell, Switzerland). After 24 HR culture medium replaced basal medium containing 1.5% FBS. After another 24 h, the medium update and add the connection or the control solvent. At the same time add human growth factor VEGFigs (10ng/ml). After 24 h incubation add BrdU-labeled solution and the cells incubated for another 24 h before fixation, the blockade and the addition of peroxidase labeled antibodies to BrdU. Binding of antibodies was determined using the substrate 3,3'5,5'-tetramethylbenzidine, which forms a colored product, the amount of which is measured on a spectrophotometer at 450 nm.

Example 2: analysis of angiogenesis camera-implant in vivo

Sterile tissue chamber, made of perforamce-Teflon®, filled with 500 µl of liquid agar (0.8% wt./vol.), containing 20 u/ml heparin (Novo Nordisk A/S, Bagsvaerd, Denmark), with or without growth factor (VEGF165; 2 μg/ml) and implanted under sterile conditions in the dorsal surface of female mice (FVB; Charles River Laboratories, les Oncins, France). Processing begins for 4-6 days prior to implantation of the camera, and then every day appointed by the dose over 3 days. After this the camera of the animals are removed, and the formed vascularized tissue is removed and weighed. Tissue samples homogenized in buffer RlPA (50 mm Tris-HCl, 121 mm NaCl, 1 mm EDTA, 6 mm EGTA, 1% NP-40, 20 mm NaF, 1 mm Pefabloc SC, 1 mm Na3V04), centrifuged 1 h at 7000 rpm and the supernatant is filtered using a 0.45 µm syringe filter (Acrodisc® GF, Gelman Sciences, Ann Arbor, MI, USA). To determine the level of Tie-2 96-cell tablets Nunc (Naperville, IL) Maxisorp fill breathtaking antibody - anti-Tie-2 AV (UBI Hauppauge, NY), with a concentration of 2 µg/ml (100 μl/cell)and incubated over night at 4°C. Then cells are washed with TPBS (Tween 80 PBS) and blocked by incubation with 3% Top-Block (Juro, Lucerne, Switzerland) for 2 h at room temperature. Add 300 mg of protein lysate and incubated for another 2 h, and then cells are washed three times before adding goat antimelanoma antibodies Tie-2 (R&D Systems, Minneapolis, MN; 0.5 μg/ml) and conjugated with alkaline phosphate antibodiesa antibody (Sigma, St. Louis, MO; diluted 1:6,000) in TPBS+0,1%Top-Block for 1 h at room temperature. Complexes of antibodies Tie-2 is determined at the end of incubation using p-nitrophenylphosphate substrate (Sigma). Absorptive capacity Spectro-photometric response determined using ELISA reader at 405 nm. As the standard use of recombinant human extracellular domain of Tie-2, combined with the constant regions IgGI (sTie-2Fc) man, dissolved in RIPA buffer solution in a concentration of from 0.1 to 300 ng/cell.

Example 3: analysis of VEGF-induced permeability analysis (miles)200 μl of Evans blue (0.5 percent) was injected into the tail vein of female mice of FVB. Thirty minutes later, mice anastasiou (3% izoflurana in O2, Forene, Abbott AG, Cham, Switzerland), and then placed on the operating table, the temperature of which is supported at the level of 39°C. the Ears is ISA stretch on a steel cone, equipped with double-sided sticker to highlight the dorsal surface. Then the microscope is injected under the skin hypodermal needle (30G) between the first and second neuro-vascular bundle of the ear and deepen 4-5 mm. then Microlitre syringe (250 µl, Hamilton, Bonaduz, Switzerland) was injected 2 μl of VEGF164(10 ng/ml), with the formation of subdermal bubble. The dye Evans blue, is associated with serum albumin, will follow in the areas of increased capillary permeability, generating a visible blue stain, allowing to measure the permeability of blood vessels. Region intradermal photograph 30 min after injection in all animals.

VEGF-mediated vascular permeability determined by measuring the area (mm2) dye leaked into the area of introduction of VEGF, using the support software for image analysis system (imaging KS-400 3.0, Zeiss, Germany).

Example 4: pressure of the interstitial fluid of the tumor IFP tumors BN472 measure of conscious, freely moving rats in his cell, using an adapted, fully implantable miniature radio telemetry system that includes 4 main components: an implantable transmitter (AM unit, model TLM-PAC10, volume: 1.1 cm, weight: 1.4 g), continuously reading and transmitting information to the animal, one receiving device is located beneath the cell-matrix interface to coordinate signals and the computer system receiving data for collection, analysis and storage of data. Transmitter implanted under sterile conditions in the flank of the animal under anesthesia isoflurane (3% izoflurana in O2). Animals unconscious placed on a heated surface and shave them the abdominal region. The ventral surface of the peritoneum get, lubricating the skin with a surgical scrub povidone-iodine. The animal lying on its back in the middle of the abdomen with an incision of about 30 mm and the skin is separated from the parietal muscles of the air pocket. Then placed in the pocket sterile transmitter, and measuring catheter is injected subcutaneously in the tumor region (the lower the fat layer of the mammary gland). A pressure-sensitive catheter is introduced into the tumor (to a depth of 4-5 mm), and fixed in the injection fabric glue Vetbond (3M company). The presence of fluid communication between the tip of the pressure-sensitive catheter and the tumor is determined by a weak ripple of the inlet tubes connecting the catheter with telemetry sensor using a clip. Implantation of the catheter is considered successful if the readings before and after this test differ by no more than 1 mm Hg, However, the majority of implanted tumors Volno brassie curves intratumoral IFP-pressure pulsation can be easily registered with high resolution, that only stronger confirms the touch location of the catheter. The total time of surgery for implanting telemetry sensor is about 20 minutes Postoperative analgesia performed using two subcutaneous injections of 0.05 mg/kg buprenorphine (Temgesic®, Reckitt and Colman), immediately after the operation and after 8-12 hours during the operation, the animal is unconscious placed on a soft material in a clean cage with an unlimited amount of water. To maintain the body temperature of the external heating lamp. Animals give 2 days to recover from surgery before you start collecting any physiological data, IFP for all animals recorded continuously for 24 hours to 10 days, and analyze a 10-second cycles with an interval of 1 min and a sampling frequency of 500 Hz. The area under the curve (PPC), recorded within 24 hours after the treatment, calculated using the method of line.

1. The use of a compound that is 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 or their pharmaceutically acceptable salts pharmaceutical composition for the treatment of VEGF-stimulirovannogo the angiogenic diseases, selected from the group consisting of rheumatoid arthritis, synovitis, bone destruction and cartilage, osteomyelitis, pannus overgrowth, formation of osteophytes, nasal polyps and lesions in the liver, retinopathy of prematurity, age-related macular degeneration, diabetic retinopathy, holodilnik and other ocular diseases, leukomalacia, thyroiditis, thyroid gland thyroid cancer, lymphoproliferative disease, Kaposi's sarcoma, hemangiomas, obesity, spinal cord injury, acute myocardial infarction, pulmonary edema, brain and retina, or any combinations thereof.

2. The use according to claim 1, where the compound is 2-methyl-2-[4-(3-methyl-2-oxo-8-quinoline-3-yl-2,3-dihydroimidazo[4,5-c]quinoline-1-yl)phenyl]propionitrile or its pharmaceutically acceptable salt.

3. The use according to claim 1, where the connection is a 8-(6-methoxypyridine-3-yl)-3-methyl-1-(4-piperazine-1-yl-3-triptoreline)-1,3-dihydroimidazo[4,5-c]quinoline-2-one or its pharmaceutically acceptable salt.

4. A method for the treatment of VEGF-induced angiogenic disease is selected from the group consisting of rheumatoid arthritis, synovitis, bone destruction and cartilage, osteomyelitis, pannus overgrowth, formation of osteophytes, nasal polyps and lesions in the liver, retinopathy of prematurity, age-related macular degeneration, diabetic the coy retinopathy, holodilnik and other ocular diseases, leukomalacia, thyroiditis, thyroid gland thyroid cancer, lymphoproliferative disease, Kaposi's sarcoma, hemangiomas, obesity, spinal cord injury, acute myocardial infarction, pulmonary edema, brain and retina, or any combinations thereof, comprising introducing a therapeutically effective amount of the compound 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-she according to claim 1 or their pharmaceutically acceptable salts to the needy in a warm-blooded animal.

5. The use of the compounds 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-she according to claim 1 or their pharmaceutically acceptable salts for the treatment of VEGF-stimulated angiogenic disease is selected from the group consisting of rheumatoid arthritis, synovitis, bone destruction and cartilage, osteomyelitis, pannus overgrowth, formation of osteophytes, nasal polyps and lesions in the liver, retinopathy of prematurity, age-related macular degeneration, diabetic retinopathy, holodilnik and other nutrigen the diseases, leukomalacia, thyroiditis, thyroid gland thyroid cancer, lymphoproliferative disease, Kaposi's sarcoma, hemangiomas, obesity, spinal cord injury, acute myocardial infarction, pulmonary edema, brain and retina, or any combinations thereof.



 

Same patents:

FIELD: biotechnologies.

SUBSTANCE: invention refers to a method for obtaining a compound of formula 682, which is in a crystalline form, where the above method involves the following: (i) treatment of the compound of formula 682-9 with palmitic anhydride mixed with H2O/dioxane so that the compound of formula 682 is formed; (ii) treatment of the product obtained at stage (i) with methanol so that the compound of formula 682 is obtained in the form of solvate with methanol (Form K); (iii) extraction of the compound of formula 682, which has been obtained at stage (ii) in the form of solvate with methanol (Form K); (iv) optional cleaning of the product of stage (iii) by recrystallisation. Besides, the invention proposes a method for obtaining the compound of formula 682-4, where the above method involves the following: (i) conversion of the compound of formula 682-1 to the compound of formula 682-2' by treatment of the above compound of formula 682-1 with 1,3-dichloro-1,1,4,4-tetraisopropyldisiloxane (CIPS) in pyridine; (ii) conversion of the above compound of formula 682-2' to the compound of formula 682-3 by treatment of the above compound of formula 682-2' with acetic anhydride to EtOH; and (iii) conversion of the above compound of formula 682-3 to the compound of formula 682-4 by treatment of the above compound of formula 682-3 with an oxidiser, preferably with free radical 2,2,6,6-tetramethylpiperidinyloxy (TEMPO) and NaOCl. Further aspects of the invention refer to use of the above methods for obtaining 2'-cyano-2'-deoxy-N4-palmitoyl-1-β-D-arabinofuranosylcytosine, pyrimidine nucleoside, and are suitable for treatment and/or prevention of cancer.

EFFECT: improvement of compounds.

22 cl, 1 tbl, 1 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to new purine compounds of formula I and their pharmaceutically acceptable salts that have properties of an inhibitor of lipidic kinases including p110 alpha and other isoforms of PI3K. In formula I , R1 is chosen from H, C1-C12alkyl and -(C1-C12alkene)-(C5-C6 heterocyclyl), where heterocyclyl can contain 1-2 heteroatoms in a cycle, which are chosen from nitrogen, and in which alkyl and heterocyclyl are optionally replaced with one or more groups independently chosen from -NHCOCH3, -NHS(O)2CH3, -OH, -S(O)2N(CH3)2 and -S(O)2CH3; R2 is chosen from C1-C12alkyl, -(C1-C6alkene)-(C5-C6heterocyclyl) or -(C1-C6alkene)-C(=O)-(C5-C6heterocyclyl), in each of which heterocyclyl contains 1-2 heteroatoms chosen from nitrogen and oxygen, -(C1-C6alkene)-(C6aryl), where aryl is chosen from phenyl, and -(C1-C6alkene)-(C5-C6heteroaryl), where heteroaryl contains 1 atom of nitrogen, in which alkyl, heterocyclyl, aryl and heteroaryl are optionally replaced with one or more groups independently chosen from F, Cl, Br, I, CH3, -CF3, -CO2H, -COCH3, -CO2CH3, -CONHCH3, -NHCOCH3, -NH(SO)2CH3, -OH, -OCH3, -S(O)2N(CH3)2 and -S(O)2CH3; and R3 represents monocyclic heteroaryl chosen from derivatives of pyridine and pyrimidine, which are specified in Claim 1 of the invention formula.

EFFECT: applicability of a compound for treatment of proliferative diseases, such as cancer.

7 cl, 2 dwg 1 tbl, 59 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I

or a pharmaceutically acceptable salt thereof, where R1 is H or R1 and R2 together with a nitrogen group can form where A, B, C and D are independently selected from a group consisting of CR1a and N; where at least one of A, B, C and D is CR1a; where R1a is selected from a group consisting of H, -ORi, -SRii, -S(O)Riii, -C(O)NRvRvi and CF3, where Ri is selected from a group consisting of methyl, ethyl, propyl, hydroxyethyl, hydroxypropyl, 2-oxo-2-phenylethyl, butyl, acetonitrile and benzyl; Rii, Riii and Riv denote methyl; Rv and Rvi are independently selected from a group consisting of H, methyl, ethyl, hydroxyethyl, hydroxypropyl, diethyalminoethyl, phenyl, pyridinyl, methoxyethyl, hydroxyethoxyethyl, benzyl, phenylethyl, 2-hydroxy-1-hydroxymethyl-2-phenylethyl and carbomoylethyl, or Rv and RVi together form morpholine or ethyl ester of piperazine; R2 is selected from a group consisting of phenyl, naphthyl, pyrazolyl and C1-C8alkylene phenyl; R3 is C1-C8alkylene; R4 is selected from a group consisting of H, C1-C8alkyl and -C=NH(NH2). The invention also relates to compounds of formulae I-A

I-B I-C

I-D I-E

values of radicals of which are given in the claim; a method of treating said pathological conditions, a pharmaceutical composition based on said compounds, a method of identifying a Trp-p8 agonist and specific compounds.

EFFECT: obtaining compounds which are useful as Trp-p8 modulators.

25 cl, 19 dwg, 8 tbl, 17 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to bicyclic heterocycles of formula I and formula II , in which radicals and symbols have values specified in the formula of the invention. These compounds have inhibiting activity in relation to MEK kinase. The invention also refers to a pharmaceutical composition for treatment of hyperproliferation disease or inflammatory disease, to a method for inhibition of abnormal growth of cells or treatment of hyperproliferation disorders and to a treatment method of inflammatory diseases of a mammal. Besides, the invention refers to use of a pharmaceutical composition for preparation of a medicinal agent for treatment of the above diseases of a mammal.

EFFECT: improving compound application efficiency.

19 cl, 29 ex

FIELD: biotechnologies.

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

,

where R1 represents NR7C(O)R8 or NR9R10; R2 represents hydrogen; R3 represents halogen; R4 represents hydrogen, halogen, cyano, hydroxy, C1-4alkyl, C1-4alkoxy, CF3, OCF3, C1-4alkylthio, S(O)(C1-4alkyl), S(O)2(C1-4alkyl), CO2H or CO2(C1-4alkyl); R5 represents C1-6alkyl (replaced with NR11R12 or heterocyclyl that represents nonaromatic 5-7-membered ring containing 1 or 2 heteroatoms independently chosen from a group containing nitrogen, oxygen or sulphur); R6 represents hydrogen, halogen, hydroxy, C1-4alkoxy, CO2H or C1-6alkyl (possibly replaced with NR15R16 group, morpholinyl or thiomorpholinyl); R7 represents hydrogen; R8 represents C3-6cycloalkyl (possibly replaced with NR24R25 group), phenyl or heteroaryl, which represents aromatic 5- or 6-membered ring containing 1 to 3 heteroatoms independently chosen from the group containing nitrogen, oxygen and sulphur, and which is probably condensed with one 6-membered aromatic or nonaromatic carbocyclic ring or with one 6-membered aromatic heterocyclic ring, where the above 6-membered aromatic heterocyclic ring includes 1 to 3 heteroatoms independently chosen from a group containing nitrogen, oxygen and sulphur; R9 represents hydrogen or C1-6alkyl (possibly replaced with pyrazolyl); R10 represents C1-6alkyl (possibly replaced with phenyl or heteroaryl group, which represents aromatic 5- or 6-membered ring containing 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur, and which is possibly condensed with one 6-membered heterocyclic ring, where the above 6-membered aromatic heterocyclic ring contains 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur; where the above phenyl and heteroaryl groups in R8, R9 and R10 are possibly independently replaced with the following group: halogen, hydroxy, C(O)R42, C1-6alkyl, C1-6hydroxyalkyl, C1-6halogenoalkyl, C1-6alkoxy(C1-6)alkyl or C3-10cycloalkyl; unless otherwise stated, heterocyclyl is possibly replaced with group of C1-6alkyl, (C1-6alkyl)OH, (C1-6alkyl)C(O)NR51R52 or pyrrolidinyl; R42 represents C1-6alkyl; R12, R15 and R25 independently represent C1-6alkyl (possibly replaced with hydroxy or NR55R56 group); R11, R16, R24, R51, R52, R55 and R56 independently represent hydrogen or C1-6alkyl; or to its pharmaceutically acceptable salts.

EFFECT: new compounds are obtained, which can be used in medicine for treatment of PDE4-mediated disease state.

10 cl, 2 tbl, 202 ex

FIELD: biotechnologies.

SUBSTANCE: pox virus of variolovaccine is proposed, which includes a defect F2L gene and a suicide gene. Pox virus has oncolytic activity. Besides, a reproduction method of such pox virus and its use for treatment of proliferative diseases or diseases with increased activity of osteoclasts is proposed.

EFFECT: improving compound application efficiency.

31 cl, 12 dwg, 3 tbl

FIELD: biotechnologies.

SUBSTANCE: an in vitro generation method of antigen-specific cytotoxic cells with activity against ovarian carcinoma cells is proposed. Simultaneously, a non-adhesive fraction of mononuclear cells (MNC) and mature dendritic cells (DC) are cultivated in presence of recombinant human interleukine-12 and recombinant human interleukine-18. MNC are extracted from peripheral blood of patients having ovarian carcinoma. Mature DC are obtained from monocytes of adhesive MNC fraction after two-day cultivation, and first, activation by lysate of autologous ovarian carcinoma cells, and then maturation of DC loaded with lysate during one day in presence of recombinant human TMF-α (tumor necrosis factor).

EFFECT: use of the invention provides reduction of a stage for obtaining mature DC, in vitro increases cytotoxicity of antigen-specific cytotoxic cells with antitumor activity and provides an immune response via T-helper to type 1 in respect to ovarian carcinoma, which can be used in ovarian carcinoma therapy.

2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to biotechnology. What is disclosed is a vaccine representing four RNAs coding a prostate-specific antigen (PSA), a prostate-specific membrane antigen (PSMA), a prostate stem cell antigen (PSCA) and a six-transmembrane epithelial antigen of the prostate (STEAP). The vaccine is applicable for treating prostate carcinoma, preferentially neo-adjuvant and/or hormone resistant prostate carcinoma, as well as related diseases or disorders. Using the vaccine and a kit are also disclosed. The invention can be used in medicine.

EFFECT: preparing the vaccine for treating prostate carcinoma.

16 cl, 23 dwg, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a kit for lung cancer cell sensitisation to cisplatin. The declared kit comprises a first composition containing a therapeutically effective amount of sodium metaarsenite, and a second composition containing a therapeutically effective amount of cisplatin. Also, the invention refers to using the therapeutically effective amount of sodium metaarsenite for lung cancer cell sensitisation in a patient treated with cisplatin.

EFFECT: invention provides increasing the therapeutic effectiveness with a reduced risk of side effects.

10 cl, 4 tbl, 3 dwg, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are presented: a combination for treating a proliferative disease containing (a) the phosphoinositide3-kinase inhibitor 5-(2,6-dimorpholin-4-yl-pyrimidin-4-yl)-4-trifluoromethylpyridin-2-ylamine (compound B) or a pharmaceutically acceptable salt thereof and (b) a compound that modulates the Ras/Raf/Mek pathaway specified in a group consisting of (i) a compound that modulates Raf kinase activity that is Raf265, SB590885, XL281 or PLX4032; (ii) a compound that modulates Mek kinase activity that is PD325901, PD-181461, ARRY142886/AZD6244, ARRY-509, XL518, JTP-74057, AS-701255, AS-701173, AZD8330, ARRY162, ARRY300, RDEA436, E6201, RO4987655/R-7167, GSK1120212 or AS703026, wherein the active ingredients in each case present in a free form or as a pharmaceutically acceptable salt or a hydrate thereof, and used simultaneously, separately or sequentially, a respective pharmaceutical composition or a combination drug, and a method of treating a proliferative disease in a homoithermic animal, principally a human.

EFFECT: what is shown is a synergism of the antineoplastic action of the declared combinations.

11 cl, 6 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to tranquilising compounds, contributing to reduction of anxiety, increase of cognitive and motor activity, namely to 4-(1-hydroxy-1-methyl-2-morpholinoethyl)benzoic acid (1) and 4-(1-hydroxy-2-morpholinocyclohexyl)benzoic acid (2), their pharmaceutically acceptable salts and esters. In addition, object of invention is also presented by method of obtaining and compounds.

EFFECT: compounds, possessing anxiolytic activity, which do not manifest considerable sedative action, hypotension and excitatory action on central nervous system.

2 cl, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds having the structure or pharmaceutically acceptable salts thereof, where Y is or ; A is -(CH2)6-, cis-CH2CH=CH-(CH2)3- or -CH2C=C-(CH2)3-, where 1 or 2 carbon atoms can be substituted with S or O; or A is -(CH2)m-Ar-(CH2)0-, where Ar is interarylene or heterointerarylene, the sum of m and o is equal to 1, 2, 3 or 4, and where one CH2 can be substituted with S or O; J is C=O, CHOH, CHF, CHCl, CHBr, CF2, CCl2, CBr2 or CHCN; and B is aryl or heteroaryl, substituted with C1-10 oxoalkyl. The invention also relates to a method of treating balding, which involves administering a therapeutically effective amount of said compound to a subject in need of such treatment.

EFFECT: high efficiency of using the compound.

11 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a water-soluble salicyl morpholide of formula .

EFFECT: derivative possesses nootropic activity in a combination with antidepressant action.

6 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: device refers to new styrene derivatives with the structure formula A in the form of geometrical isomers or tautomers and their pharmaceutical acceptable salts. In structural formula (A) R1 represents hydrogen; R2 represents hydrogen or C1-C6alkyl; R3, R4, R5 and R6 are identical or different and independently represent hydrogen, halogen, C1-C6alkyl or -OR12; R7 represents hydrogen or C1-C6alkyl; R8 represents hydrogen; R9 represents hydrogen, C1-C6alkyl, or -C(=O)R13; R10 represents hydrogen or C1-C6alkyl; Z represents W-Y, wherein W represents -C(R14)(R15)-; Y represents -C(R16)(R17)-; each R12 independently represents hydrogen or C1-C6alkyl; each R13 independently represents C1-C6alkyl; R14 and R15 are identical or different, and independently specified in hydrogen, fluoro, methyl, ethyl, trifluoromethyl, -OH, -OCH3 or -NH2; or R14 and R15 together form oxo; R16 and R17 are identical or different and independently represent hydrogen, halogen, C1-C6alkyl or -OR12. The other radical values are specified in the patent claim.

EFFECT: compounds may be used for treating an ophthalmic disease or disorder in an individual which can represent age-related macular degeneration or Stargardt macular degeneration.

17 cl, 14 tbl, 143 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), stereoisomers, trans- and cis-isomers, racemates or pharmaceutically acceptable salts thereof, having modulating activity on histamine H3-receptors. In formula (I) m equals 0; one of R1 and R2 is selected from a group which includes hydrogen, C1-10alkoxycarbonyl, amido-, carboxy-, C3-8cycloalkyl, halogen, -NRARB, (NRARB)carbonyl, or a group of formula -L2-R6; the other of R1 and R2 is selected from a group which includes hydrogen, halogen; each of R3a and R3b is independently selected from a group which includes hydrogen; each of R4 and R5 is independently selected from a group which includes C1-10alkyl and C1-10hydroxyalkyl; or R4 and R5, taken together with a nitrogen atom to which each is bonded, form a heteroaromatic ring of the type (a) or (b), where Q1 is O or C; Q2 is -N(R20)-; R20 is selected from a group which includes hydrogen and C1-10alkoxycarbonyl; each of p1 and p2 is independently equal to 1, 2 or 3; each of q1, q2, q3, q4 and q5 are independently equal to 0, 1 or 2; and wherein each carbon atom in the ring is substituted with hydrogen or 0, 1 or 2 substitutes, independently selected from a group which includes hydrogen, hydroxy group, fluorine, C1-10alkyl, C1-10hydroxyalkyl and C1-10fluoroalkyl; R6 is a phenyl, heterocycle or heterocycloC1-4alkyl, wherein the heterocycle is a 4-6-member aromatic or non-aromatic ring which contains 1 or 2 heteroatoms independently selected from N, O and S, optionally condensed with a benzene ring, wherein the phenyl or heterocycle can be unsubstituted or optionally substituted with one or more substitutes independently selected from a group which includes C1-4alkoxy, C1-4alkyl, cyano, halogen and oxo-; L is a bond or C1-4alkylene; L2 is a bond, C1-4alkylene, -C(=O)-, -SO2N(R14a)-, -N(R14a)SO2-, -C(O)N(R14a)-, -N(Rl4a)C(O)- or -N(R15)-; R10 is selected from a group which includes hydrogen; R14a is selected from a group which includes hydrogen; R15 is selected from a group which includes hydrogen; and RA and RB are independently selected from a group which includes hydrogen, C1-10alkyl, C1-10acyl, C1-4halogenalkyl, C1-10alkoxycarbonyl, C3-8cycloalkyl and C3-8cycloalkylcarbonyl. The invention also relates to a pharmaceutical composition which contains compounds of formula (I), a method for selective modulation of effects of histamine H3-receptors, use of said compounds in producing a medicament for treating a condition or disorder modulated by histamine H3-receptors, as well as specific compounds of formula (I).

EFFECT: improved properties of compounds.

18 cl, 2 tbl, 154 ex

FIELD: chemistry.

SUBSTANCE: invention relates to N-hydroxylsulphonamide derivatives of formula or , where R1 is H; R2 is H; n is 0; b is an integer in the range of 1-4; R3, R4, R5, R6 and R7 are independently selected from H, halogen, carboxyl, carboxyl ester selected from a group including -C(O)O-morpholino, -C(O)O-C1-C8alkyl and -C(O)O-substituted C1-C8alkyl, where the substitute is morpholino; acylamino, which is a -C(O)NRaRb group, where Ra and Rb are independently C1-C8alkyl, or Ra and Rb together with a nitrogen atom to which they are bonded form morpholino; and sulphonylamino, which is a SO2NR2 group, where two groups R, together with a nitrogen atom to which they are bonded, form morpholino; R8 is selected from halogen and carbonylamino, selected from a -CONH-substituted C1-C8alkyl, where the substitute is morpholino; and -CONR2, where two groups R, together with a nitrogen atom to which they are bonded, form morpholino; C is a heteroaromatic ring which contains cyclic fragments Q9, Q10, Q11, Q12, Q13 and Q14, which are independently selected from C, CH and S, under the condition that at least one of the fragments Q9, Q10, Q11, Q12, Q13 and Q14 is S. The invention also relates to a method of modulating nitroxyl levels, a method of treating diseases which respond to treatment with nitroxyl, a treatment set and a pharmaceutical composition containing compounds of formula (I) or (III).

EFFECT: compounds of formula (I) or (III) for treating diseases which respond to treatment with nitroxyl.

20 cl, 5 ex, 4 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to pediatric neurology, and can be used for rehabilitation of neurological disorders in children in case of neuroinfections. For this purpose, at the background of adequate complex and pathogenetic therapy, parenteral introduction of actovegin in acute period of disease additionally from the first days of disease cytoflavin is introduced intravenously by drop infusion in dose 0.6 ml/kg or 10 ml per day for 3-5 days, elcar perorally in dose 70-100 mg/kg of weight per day for 3-4 weeks. In the period of early reconvalescence pantogam is additionally introduced perorally in dose 50-70 mg/kg of weight per day for 4 weeks. In case if multifocal affection of brain substance is present, gliatilin is introduced intravenously by drop infusion in dose 1 ml per 5 kg of body weight per day in combination with intramuscular introduction of ipidacrine in dose 5-15 mg per day for 7-10 days, after that gliatilin perorally in dose 50 mg/kg of weight per day together with ipidacrine inside in dose 1 mg/kg per day for 4 weeks.

EFFECT: method makes it possible to improve disease outcome due to reduction of frequency of residual neurological deficiency formation with reduction of term of hospital treatment.

3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is presented is the use of the drug -2-(2-morpholinoethyl)thio-5-ethoxybenzimidazole dihydrochloride (the anxiolytic Afobazole) as a preparation with cardioprotective activity. It is shown that Afobazole (5-10 mg/kg intravenously or intraperitoneally) on various models of myocardial ischemia and heart rhythm disorder exhibits manifested cardioprotective activity observed primarily at the myocardium and may be related to a certain extent to its affinity for sigma1-receptors localised in cardiac myocytes. Antiarrhythmic action of Afobazole is preferentially conditioned by its ability to increase electrical stability of the maycardium directly.

EFFECT: findings entitle recommending the anxiolytic Afobazole to be used in clinical practice as a cardioprotector for the purpose of preventing and treating cardiovascular disorders in the patients suffering cardiophobic and/or asthenic-depressive syndromes burdened by cardiopathies.

1 dwg, 3 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of substituted sulphonamides of general formula (I) where R1 is CO or SO2, R2 is NH or O, R includes a tertiary diC1-4alkylamine group in which alkyl fragments are identical or different, or an amino group whose alkyl groups together form a 5, 6 or 7-member ring with saturated bonds or the ends of the alkyl fragments are bonded to an O heteroatom, or R is 4-(N,N-diethylaminoethoxy)benzyl, where R1 is SO; and R2 is NH; or R is 4-[N-(morpholinopropyl)sulphamoyl]phenyl, where R1 is CO and R2 is NH, n is the number of carbons in the connecting aliphatic chain, where n is equal to 0, 2 or 3; and/or physiologically acceptable salts thereof in production of a medicinal agent for treating glaucoma. The invention also relates to substituted sulphonamides of formula (Ia) (where values of radicals are given in the claim) and physiologically acceptable salts thereof, a method for production thereof and a medicinal agent based thereon, for treating eye diseases.

EFFECT: compounds can be used as carbonic anhydrase inhibitors.

11 cl, 3 dwg, 4 tbl, 19 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed is medication for prevention and/or treatment of diabetic neuropathy, which contains (+)2-[substituted-inden-7-yloxy)methyl]morpho-lyn (isomer of indeloxosin) or its pharmaceutically acceptable salt as the only active ingredient, its application for production of medication of the same purpose, respective method of treatment, its application for production of medication improving diabetic neuropathy pathophysiology, medication of the same purpose. It is demonstrated that invention ensures prevention and/or treatment of diabetic motor neuropathy (such as, malfunction with muscular weakness, including disability of independent walking), diabetic sensor neuropathy (such as paresthesia, including anomaly of vibration perception, allodynia, hypoesthesia such, as dumbness of extremities or sense of cold, or pain) or diabetic autonomic neuropathy (such as anomaly of stool: constipation or diarrhea, malfunction of urination, impotence, orthostatic hypotension, sudomotor dysfunction, anomalous variability of heart rate or slowing of evacuation of gastric contents).

EFFECT: invention ensures improvement of diabetic neuropathy pathophysiology: recovery of FGF-2, IGF-1 expression, reduction of rate of motor nerve conduction.

11 cl, 3 dwg, 3 tbl

FIELD: biotechnologies.

SUBSTANCE: new derivatives of triazolo[1,5-a]quinoline of general formula (I)

, where X means -NH-; R13-cyano; R1 and R2 mean H or methyl; R5-phenyl, possibly substituted, or 5- or 6-member heterocyclyl; R3 means phenyl or one atom of nitrogen containing 6-member heterocyclyl; R4 - one atom of nitrogen containing 6-member heterocyclyl or a group of the formula (a), , where R6 and R7 - independently mean C3-6cycloalkyl or C1-4alkyl; or a group of the formula (b) , where R8 and R9 mean C1-4alkyl; Z - oxygen or a group -NR12-, where R12 - hydrogen, C1-4alkyl, C3-6 cycloalkyl, benzyl, -CH2-acetyl, -CH2-CH2-O-CH2-CH3 or acetyl; W means nitrogen atom or a group -CH-; m and o mean 2; p and r mean zero or 1; t means zero; methods of their production, new intermediate compounds of described methods of production, a pharmaceutical composition containing these compounds, and application of compounds of common formula (I) and their pharmaceutical acceptable salts as ligands of adenosine A3 receptor in treatment of different diseases.

EFFECT: improved properties of compounds.

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