Pyrazole pyridine derivatives as nadph-oxidase

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the field of organic chemistry, namely to novel derivatives of pyrazole pyridine of formula , as well as to its tautomers, geometrical isomers, enantiomers, diastereomers, racemates and pharmaceutically acceptable salts, where G1 represents H; G2 represents -CHR1R2; R1 and R2 independently on each other are selected from H; C1C6-alkoxy-C1C6-alkyl; C1-C6-alkyl; optionally substituted phenyl; optionally substituted phenyl-C1-C6-alkyl; optionally substituted morpholine-C1-C6-alkyl; or -CHR1R2 together form a ring, selected from an optionally substituted C3-C8-cycloalkyl and substituted piperidine; G3 is selected from an optionally substituted C1C6-alkoxy -C1-C6-alkyl; C1-C6-alkyl; substituted phenyl; substituted phenyl-C1C6-alkyl; G4 is selected from a substituted acyl-C1C6-alkyl, where acyl represents a group -CO-R and R stands for H or morpholine; optionally substituted C1-C6-alkyl; optionally substituted phenyl or indene; substituted phenyl-C1-C6-alkyl; optionally substituted pyridine- or furanyl-C1C6-alkyl; morpholine- or piperidine-C1-C6-alkyl; G5 represents H; where the term "substituted" stands for the groups, substituted with 1 to 5 substituents, selected from the group, which includes a "C1-C6-alkyl," "morpholine", "C1-C6-alkylphenyl", "di-C1-C6-alkylamino", "acylamino", which stands for the group NRCOR", where R represents H and R" represents a C1-C6-alkyl, "phenyl", "fluorine-substituted phenyl", "C1-C6-alkoxy", "C1-C6-alkoxycarbonyl", "halogen". The invention also relates to a pharmaceutical composition based on the formula (I) compound and particular compounds.

EFFECT: obtained are the novel derivatives of pyrasole pyridine, useful for the treatment and/or prevention of disorders or states, associated with NADPH-oxidase.

12 cl, 3 tbl, 21 ex

 

The technical field to which the invention relates

The present invention relates to pyrazolopyrimidine derivatives of formula (I), their pharmaceutical compositions and their use for preparing medicines for the treatment and/or prophylaxis of cardiovascular diseases, respiratory diseases, diseases, violate the metabolism, diseases of the skin and/or bone, neurodegenerative diseases, kidney diseases, disorders of the reproductive system, inflammatory diseases and different types of cancer. In particular the present invention relates to pyrazolopyrimidinone derivatives suitable for preparation of pharmaceutical compositions for the modulation, in particular inhibition of the activity or function of (NADPH oxidase).

The level of technology

NADPH oxidase (NOX) are proteins that transfer electrons across biological membranes. Typically, the electron acceptor is oxygen, and the reaction product of electron transfer is superoxide. Thus, the biological function of NOX enzymes is the production of oxygen reactive oxygen species (ROS or ROS). Reactive oxygen species (ROS) are produced from oxygen and small molecules, including oxygen radicals (superoxide anion [O2- ], hydroxyl radical [BUT], peroxyl (peroxide) radical [ROO], alkoxyl-radical [RO] and hydroperoxyl (belonging) radical [NOO]), and certain non-radical molecules that are either oxidizing agents and/or are easily converted into radicals. Nitrogen-containing oxidizing agents, such as nitrogen oxide, also known as active forms of nitrogen (RNS or RNS). The generation of ROS is usually a cascade of reactions that start with the production of superoxide. Superoxide rapidly dismutase to hydrogen peroxide either spontaneously, particularly at low pH values, or with the participation of the enzyme superoxide dismutase. Other events in the cascade of reactions generating ROS include the reaction of superoxide with nitric oxide with the formation of peroxynitrite, catalyzed by peroxidase, the formation of hypochlorous acid from hydrogen peroxide and catalyzed by iron Fenton reaction leading to the generation of hydroxyl radical.

ROS avidly interact with a large number of molecules, including other small inorganic molecules as well as DNA, proteins, lipids, carbohydrates and nucleic acids. This initial reaction may generate a secondary radical, multiplying, thus, potential damage. ROS are involved not only in cell damage and destruction of pathogens, but also in Bo�lsoe the number of reversible regulatory processes in virtually all cells and tissues. However, despite the important role of ROS in the regulation of fundamental physiological processes, the production of ROS can also permanently damage or alter the function of target molecules. Consequently AFK more and more identified as major contributors to damage to biological organisms, the so-called "oxidative stress".

When inflammation of the NADPH-oxidase is one of the most important sources of ROS production in vascular cells under inflammatory conditions (Thabut et al., 2002, J. Biol. Chem., 277:22814-22821).

In the lung tissue is constantly exposed to oxidants generated either endogenously in metabolic reactions (for example, during respiration in the mitochondria or upon activation of recruited inflammatory cells) or exogenous in the air (e.g. cigarette smoke or air pollutants). In addition, the lungs are constantly exposed to high partial pressures of oxygen in comparison with other tissues, have a large surface area and is actively supplied with blood, and are especially susceptible to damage mediated by ROS (Brigham, 1986, Chest, 89(6): 859-863). Dependent on NADPH oxidase generation of ROS has been described in lung endothelial cells and in smooth muscle cells. It is assumed that the activation of NADPH oxidase in response to stimuli involved in the development of pulmonary for�of olivani, such as pulmonary hypertension and narrowing of the blood vessels in the lungs (Djordjevic et al., 2005, Arterioscler. Thromb. Vase. Biol., 25, 519-525; Liua et al., 2004, Am. J. Physiol. Lung, Cell. Mol. Physiol., 287: Llll-118). In addition, pulmonary fibrosis is characterized by pulmonary inflammation and excessive generation of ROS.

Osteoclasts, which are cells similar to macrophages, and play a key role in the reconstruction of bone tissue (e.g., bone resorption), generate ROS via NADPH-dependent oxidase mechanisms (Yang et al., 2002, J. Cell. Chem. 84, 645-654).

It is known that in diabetes, oxidative stress is increased (e.g., increased generation of ROS due to the oxidation of glucose) both in humans and in animals, and it is known that increased oxidative stress plays an important role in the development of complications associated with diabetes. It was shown that the increased peroxide accumulation and impaired function of the Central retina in diabetic rats coincide with the areas of activity of NADPH oxidase in the endothelial cells of the retina (Ellis et al., 2000, Free Rad. Biol. Med., 28:91-101). In addition, it has been suggested that controlling oxidative stress (ROS) in mitochondria and/or in the area of inflammation may be a useful approach for the treatment of diabetes (Pillarisetti et al., 2004, Expert Opin. Ther. Targets, 8(5: 401-408).

ROS is also actively involved in the pathogenesis of atherosclerosis, cell proliferation, g�bertonio and overall cardiovascular disease, associated with damage during reperfusion (Cai et al., 2003, Trends Pharmacol. Sci., 24:471-478). When all the risk factors of atherosclerosis not only increases the production of superoxide, for example, in the wall of the arteries, but ROS also induce many "proatherogenic" cellular responses in vitro. An important consequence of the formation of ROS in vascular cells is the consumption of nitric oxide (NO). NO inhibits the development of vascular diseases and the loss of NO is an important factor in the pathogenesis of cardiovascular diseases. It was reported about the increase in the activity of NADPH oxidase in the vascular wall after injury using a balloon catheter (Shietal., 2001, Throm. Vase. Biol., 2001, 21, 739-745).

It is believed that oxidative stress or caused by free radical damage is also a major factor in neurodegenerative diseases. Such damage may include mitochondrial abnormalities, demyelination of neurons, apoptosis, neuronal loss and reduced cognitive ability, potentially leading to the development of progressive neurodegenerative disease (Nunomura et al., 2001, J. Neuropathol. Exp.Neurol., 60:759 - 767; Girouard, 2006, J. Appl. Physiol. 100:328-33 (J).

In addition, we demonstrated the generation of ROS by sperm a great number of species, and it has been suggested that this is due to NADPH oxidase, present in the sperm (Vernet et al., Biol. Reprod., 2001, 65:1102-1113). Meanwhile�Xia, the increased generation of ROS is involved in the development of pathology of the sperm, including male infertility, as well as some diseases of the penis and prostate cancer.

NADPH oxidase are multi-subunit enzymes, consisting of associated with the membrane domain of cytochrome b558 and three cytoplasmic protein subunits, p47phox, p67phox and the small GTPase Rac. Seven isoforms of NOX enzymes, including NOX1, NOX2, NOX3, NOX4, NOX5 DUOX1 and DUOX2 (Leto et al., 2006, Antioxid Re6ox Signal, 8(9-10): 1549-61; Cheng et al., 2001, Gene, 16; 269(1-2): 131-40).

Thus formed from NADPH ROS contribute to the pathogenesis of many diseases, especially cardiovascular diseases or disorders, respiratory disorders or diseases, illnesses or disorders that affect the metabolism of bone diseases, neurodegenerative diseases, inflammatory diseases, reproductive disorders or diseases, pain, cancers, and diseases or disorders of the gastrointestinal tract. Thus, it would be highly desirable to create new active agents aimed at ROS-signaling cascade, especially on NADPH oxidase (NOX).

Disclosure of the invention

The present invention is directed to new molecules suitable for the treatment and/or prophylaxis of diseases associated with (NADPH-oxidase), such as with�techno disease, respiratory diseases, diseases, violate the metabolism, diseases of the skin and/or bone, neurodegenerative diseases, kidney disease, disorders of the reproductive system, inflammatory diseases, different types of cancer, allergic diseases, injuries, septic, hemorrhagic and anaphylactic shock, diseases and disorders of the gastrointestinal tract, angiogenesis and angiogenesis-dependent condition. In particular the present invention relates to new molecules suitable for inhibiting or reducing the production of ROS in cells.

The first aspect of the present invention provides pyrazolopyrimidine derivative of formula (I), where G1, G2, G3, G4and G5are as defined below, and its pharmaceutically acceptable salts and pharmaceutically active derivative.

The second aspect of the present invention relates pyrazolopyrimidine derivative of formula (I), where G1, G2, G3, G4and G5are as defined below, and its pharmaceutically acceptable salts and pharmaceutically active derivative for use as a medicine.

The third aspect of the present invention relates to pharmaceutical compositions containing at least one pyrazolopyrimidine derivative according to the present Fig�structure, and its pharmaceutically acceptable salts and pharmaceutically active derivative, and a pharmaceutically acceptable carrier, solvent or excipient.

A fourth aspect of the present invention relates to the use pyrazolopyrimidine derivative according to the present invention and its pharmaceutically acceptable salts and pharmaceutically active derivative to obtain a pharmaceutical composition for the treatment or prophylaxis of a disease or condition selected from cardiovascular diseases, respiratory diseases, diseases, violate the metabolism, skin diseases, bone diseases, neuro-inflammatory and/or neurodegenerative diseases, kidney diseases, diseases of reproductive system, diseases affecting the eye and/or the lens and/or conditions affecting the inner ear, inflammatory diseases, liver diseases, pain, different types of cancer, allergic diseases, injuries, septic diseases, hemorrhagic and anaphylactic shock, diseases or disorders of the gastrointestinal system, disorders of angiogenesis and dependent angiogenesis diseases and/or other diseases and disorders associated with (NADPH-oxidase).

A fifth aspect of the present invent�Oia relates to a method of treating a patient suffering from a disease or condition selected from cardiovascular diseases, respiratory diseases, diseases, violate the metabolism, skin diseases, bone diseases, neuro-inflammatory and/or neurodegenerative diseases, kidney diseases, diseases of reproductive system, diseases affecting the eye and/or the lens and/or conditions affecting the inner ear, inflammatory diseases, liver diseases, pain, different types of cancer, allergic diseases, injuries, septic, hemorrhagic and anaphylactic shock, diseases or disorders of the gastrointestinal tract, angiogenesis and dependent angiogenesis diseases and/or other diseases and disorders associated with (NADPH-oxidase). This method includes the introduction of pyrazolopyrimidinone derivative of formula (I), where G1, G2, G3, g4and G5are as defined below, and its pharmaceutically acceptable salts and pharmaceutically active derivative to a patient in need of such treatment.

The sixth aspect of the present invention relates pyrazolopyrimidine derivative of formula (I), where G1, G2, G3, g4and G5are as defined below, and pharmaceutical�ski acceptable salts and pharmaceutically active derivative, for the treatment of a disease or condition selected from cardiovascular diseases, respiratory diseases, diseases, violate the metabolism, skin diseases, bone diseases, neuro-inflammatory and/or neurodegenerative diseases, kidney diseases, diseases of reproductive system, diseases affecting the eye and/or the lens and/or conditions affecting the inner ear, inflammatory diseases, liver diseases, pain, different types of cancer, allergic diseases, injuries, septic diseases, hemorrhagic and anaphylactic shock, diseases or disorders of the gastrointestinal system, violations of dependent angiogenesis and angiogenesis diseases and other diseases and/or disorders associated with (NADPH-oxidase).

Other features and advantages of the present invention will be apparent from the following embodiment of the invention.

The implementation of the invention

The following paragraphs provide definitions of various chemical components, which are part of the compounds according to the present invention, and are intended for uniform application in the further text of the description and in the claims, except in those cases where a different definition of the trade�t a broader definition.

The term "alkyl" when used alone or in combination with other terms, comprises a straight chain or branched C1-C20-alkyl which refers to monovalent alkyl groups having from 1 to 20 carbon atoms. This term can be illustrated by groups such as methyl, ethyl, n-propyl, ISO-propyl, n-butyl, sec-butyl, ISO-butyl, tert-butyl, n-pentyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, n-heptyl, 2-etylhexyl, 3-etylhexyl, 4-etylhexyl, 5-etylhexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, tetrahydropyranyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-octadecyl, n-Needell, and n-eicosanol and the like. Preferably they include C1-C9alkyl, more preferably C1-C6-alkyl, particularly preferably1-C4-alkyl, which, by analogy, refer respectively to monovalent alkyl groups having 1 to 9 carbon atoms, monovalent alkyl group having from 1 to 6 carbon atoms and monovalent alkyl groups having 1 to 4 carbon atoms. In particular, they include the C1-C6-alkyl.

The term "alkenyl" when used alone or in combination with other terms, comprises a straight chain�ü or branched C 2-C30-alkenyl. He can have any possible number of double bonds in all possible positions, and the configuration of the double bond may be (E) or (Z) configuration. This term can be illustrated by groups such as vinyl, allyl, Isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl, geranyl, 1-decenyl, 1-tetrads azenil, 1-octadecenyl, 9-octadecenyl, 1-eicosene and 3, 7, 11, 15-tetramethyl-1-hexadecanol, and the like. Preferably they include With2-C8-alkenyl, more preferably C2-C6-alkenyl. Amongst the most preferred are vinyl or ethenyl (-CH=CH2), n-2-propenyl (allyl, -CH2CH=CH2), Isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and 3-methyl-2-butenyl and the like.

The term "alkynyl", when used by itself or in combination with other terms, comprises a straight chain or branched C2-C20-alkynyl. It can have any possible number of triple bonds in any possible position. This term can be illustrated by groups such as alkyline group, which may have 2-20 carbon and�Ohm and not necessarily, the double bond, such as ethinyl (-C=CH), 1-PROPYNYL, 2-PROPYNYL (propargyl: -CH2C=CH), 2-butinyl, 2-penten-4-inyl, and the like. Preferably they include With2-C8-alkynyl, more preferably2-C6alkynyl and the like. Preferably they include With2-C6-alkynyl which refers to groups having 2 to 6 carbon atoms and having at least 1 or 2 sites valkininkai unsaturation.

The term "heteroalkyl" refers to C1-C12-alkyl, preferably C1-C6-alkyl in which at least one carbon atom replaced by a heteroatom selected from O, N or S, including 2-methoxyethyl and the like.

The term "aryl" refers to an unsaturated aromatic carbocyclic group containing from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., indenyl, naphthyl). Aryl includes phenyl, naphthyl, antril, phenanthrene and the like.

The term "C1-C6-alkylaryl" refers to aryl groups having C1-C6-alkyl Deputy, including methylphenyl, ethylphenyl and the like.

The term "aryl-(C1-C6-alkyl" refers to C1-C6-alkyl groups having an aryl Deputy, including 3-of phenylpropyl, benzyl and�such.

The term "heteroaryl" denotes a monocyclic heteroaromatic, or bicyclic or tricyclic heteroaromatic group of condensed rings. Particular examples of heteroaromatic groups include optionally substituted pyridyl, pyrrolyl, pyrimidinyl, furyl, trienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,1,3,4-triazinyl, 1,2,3-triazinyl, benzofuran, [2,3-dihydro]benzofuran, isobenzofuran, benzothiazyl, benzotriazolyl, isobenzofuran, indole, isoindole, 3H-indole, benzimidazole, imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxazolyl, hemolysins, chinazoline, phthalazine, honokalani, cinnoline, naphthyridine, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, hinely, ethanolic, tetrazolyl, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, purinol, pteridinyl, carbazolyl, xantener or benzhydryl.

The term "C1-C6-alkylether" refers to heteroaryl groups having C1-C6-alkyl Deputy, including methylphenyl and the like.

The term "heteroaryl-C1-C6-alkyl" refers to C1-C6-alkyl groups having a heteroaryl Deputy, including furylmethyl and the like.

The term "C2-C6-alkynylaryl" refers to aryl groups having C2-C6-alkenyl Deputy, including vinylphenol and the like.

The term "aryl-C2-C6the alkenyl" refers to C2-C6-alkenyl group having the aryl Deputy, including fineliner and the like.

The term "C2-C6-alkenylamine" refers to heteroaryl groups having C2-C6-alkenyl Deputy, including vinylpyridine and the like.

The term "heteroaryl-C2-C6the alkenyl" refers to C1-C6-alkenyl groups having a heteroaryl Deputy, including pyridinoline and the like.

The term "C3-C8-cycloalkyl" denotes a saturated carbocyclic group of from 3 to 8 carbon atoms having a single ring (e.g., cyclohexyl) or multiple condensed rings (e.g., norbornyl). C3-C8-cycloalkyl includes cyclopentyl, cyclohexyl, norbornyl and the like.

The term "heteroseksualci" refers to C3-C8-cycloalkyl group according to the definition given above, in which up to 3 carbon atoms are replaced by heteroatoms selected from the group consisting of O, S, NR, where R represents hydrogen or methyl. Heteroseksualci include pyrrolidin�l, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl and the like.

The term "C1-C6-alkyl-C3-C8-cycloalkyl" refers to C3-C8-cycloalkyl group having C1-C6-alkyl Deputy, including Methylcyclopentane and the like.

The term "C3-C8-cycloalkyl-C1-C6-alkyl" refers to C1-C6is an alkyl group having a C3-C8-cycloalkenyl Deputy, including 3-cyclopentylpropionyl and the like.

The term "C1-C6-alkylchlorosilanes" means geterotsiklicheskie group having C1-C6-alkyl Deputy, including 4-methylpiperidine and the like.

The term "heteroseksualci-C1-C6-alkyl" refers to C1-C6is an alkyl group having heterologously Deputy, including (1-demerol-4-yl)methyl and the like.

The term "carboxy" refers to a group-C(O)HE.

The term "carboxy-C1-C6-alkyl" refers to C1-C6is an alkyl group having a carboxy Deputy, including 2-carboxyethyl and the like.

The term "acyl" denotes the group-C(O)R where R includes H, "alkyl", preferably "C1-C6-alkyl", "aryl", "heteroaryl", "C3-C8-cycloalkyl", "heteroseksualci", "aryl-C1-C6 -alkyl", "heteroaryl-C1-C6-alkyl", "C3-C8-cycloalkyl-C1-C6-alkyl" or "heteroseksualci-C1-C6-alkyl", including acetyl and the like.

The term "acyl-C1-C6-alkyl" refers to C1-C6-alkyl groups having an acyl Deputy, including 2-acetylethyl and the like.

The term "arylaryl" refers to aryl groups having an acyl Deputy, including 2-acetylphenyl and the like.

The term "acyloxy" denotes the group-OC(O)R where R includes H, "C1-C6-alkyl", "C2-C6-alkenyl", "C2-C6-alkynyl", "C3-C8-cycloalkyl", "heteroseksualci", "aryl", "heteroaryl", "aryl-C1-C6-alkyl", "heteroaryl-C1-C6-alkyl", "aryl-C2-C6-alkenyl", "heteroaryl-C2-C6-alkenyl", "aryl-C2-C6-alkynyl", "heteroaryl-C2-C6-alkynyl", "C3-C8-cycloalkyl-C1-C6-alkyl" or "heteroseksualci-C1-C6-alkyl", including acetyloxy and the like.

The term "acyloxy-C1-C6-alkyl" refers to C1-C6is an alkyl group having acyloxy-Deputy, including 2-(ethylcarboxylate)ethyl and the like.

The term "alkoxy" denotes the group-O-R where R includes "C1-C6-alkyl", "aryl", �heteroaryl", "aryl-C1-C6-alkyl" or "heteroaryl-C1-C6-alkyl". Preferred alkoxy groups include, for example, methoxy, ethoxy, phenoxy and the like.

The term "alkoxy-C1-C6-alkyl" refers to C1-C6-alkyl groups having an alkoxy-substituent including methoxyethyl and the like.

The term "alkoxycarbonyl" denotes the group-C(O)OR where R includes "C1-C6-alkyl", "aryl", "heteroaryl", "aryl-C1-C6-alkyl", "heteroaryl-C1-C6-alkyl" or "heteroalkyl".

The term "alkoxycarbonyl-C1-C6-alkyl" refers to C1-C6is an alkyl group having alkoxycarbonyl Deputy, including 2-(benzyloxycarbonyl)ethyl and the like.

The term "aminocarbonyl" denotes the group-C(O)NRR', where R and R' represent independently from each other H, C1-C6-alkyl, aryl, heteroaryl, "aryl-C1-C6-alkyl" or "heteroaryl-C1-C6-alkyl", including N-phenylcarbamoyl and the like.

The term "aminocarbonyl-C1-C6-alkyl" refers to alkyl groups having aminocarbonyl Deputy, including 2-(dimethylaminoethyl)ethyl, N-ethylacetamide, N,N-diethylacetamide and the like.

The term "acylamino" refers to the group-NRC(O)R', where R and R' represent independently from each other H, "C1 -C6-alkyl," "C2-C6-alkenyl," "C2-C6-alkynyl," "C3-C8-cycloalkyl," "heteroseksualci," "aryl," "heteroaryl," "aryl-C1-C6-alkyl", "heteroaryl-C1-C6-alkyl," "aryl-C2-C6-alkenyl," "heteroaryl-C2-C6-alkenyl," "aryl-C2-C6-alkynyl," "heteroaryl-C2-C6alkynyl," "cycloalkyl-C1-C6-alkyl" or "heteroseksualci-C1-C6-alkyl", including acetylamino and the like.

The term "acylamino-C1-C6-alkyl" refers to C1-C6alkyl group having acylamino-Deputy, including 2-(propionamido)ethyl and the like.

The term "ureido" refers to the group-NRC(O)NR'R", where R, R' and R" represent independently of each other H, "C1-C6-alkyl," "alkenyl," "alkynyl," "C3-C8-cycloalkyl," "heteroseksualci," "C1-C6-aryl," "heteroaryl," "aryl-C1-C6-alkyl", "heteroaryl-C1-C6-alkyl," "aryl-C2-C6-alkenyl," "heteroaryl-C2-C6-alkenyl," "aryl-C2-C6-alkynyl," "heteroaryl-C2-C6-alkynyl," "cycloalkyl-C1-C6-alkyl" or "heteroseksualci-C1-C6-alkyl, and where R' and R" together with the nitrogen atom to which they are attached, may not necessarily form a 3-8-membered heterocyclyl�ilen ring.

The term "ureido-C1-C6-alkyl" refers to C1-C6is an alkyl group having ureido-Deputy, including 2-(N'-methylurea)ethyl and the like.

The term "carbamate" refers to the group-NRC(O)OR', where R and R' represent independently from each other, "C1-C6-alkyl." "C2-C6-alkenyl," "C2-C6-alkynyl," "C3-C8-cycloalkyl," "heteroseksualci," "aryl," "heteroaryl," "C1-C6-alkylaryl", "heteroaryl-C1-C6-alkyl," "aryl-C2-C6-alkenyl," "heteroaryl-C2-C6-alkenyl," "aryl-C2-C6-alkynyl," "heteroaryl-C2-C6-alkynyl," "cycloalkyl-C1-C6-alkyl" or "heteroseksualci-C1-C6-alkyl", and do not necessarily R may also represent hydrogen.

The term "amino" denotes the group-NRR' where R and R' represent independently from each other H, "C1-C6-alkyl", "aryl", "heteroaryl", "C1-C6-alkylaryl", "C1-C6-alkylglycerol," "cycloalkyl" or "heteroseksualci," and where R and R' together with the nitrogen atom to which they are attached, may not necessarily form a 3-8-membered geteroseksualnoe ring.

The term "aminoalkyl" refers to alkyl groups having an amino substituent, including 2-(1-pyrrolidinyl)ethyl and the like.

The term "ammonium" is designated�et positively charged group-N +RR'R", where R, R' and R" represent independently of each other "C1-C6-alkyl", "C1-C6-alkylaryl", "C1-C6-alkylglycerol," "cycloalkyl," or "heteroseksualci," and where R and R', together with the nitrogen atom to which they are attached, may not necessarily form a 3-8-membered geteroseksualnoe ring.

The term "ammonium-alkyl" refers to alkyl groups having an ammonium substituent, including 1-of ethylpyrrolidin and the like.

The term "halogen" denotes fluorine, chlorine, bromine and iodine.

The term "sulfonyloxy" denotes the group-OSO2-R, where R is selected from C1-C6-alkyl," "C1-C6-alkyl" substituted with Halogens, e.g., -OSO2-CF3group, "C2-C6-alkenyl," "alkynyl," "C3-C8-cycloalkyl," "heteroseksualci," "aryl," "heteroaryl," "aryl-C1-C6-alkyl", "heteroaryl-C1-C6-alkyl," "aryl-C2-C6-alkenyl," "heteroaryl-C2-C6-alkenyl," "aryl-C2-C6-alkynyl," "heteroaryl-C2-C6-alkynyl," "cycloalkyl-C1-C6-alkyl" or "geterotsiklicheskie".

The term "sulfonyloxy-C1-C6-alkyl" refers to alkyl groups having sulfonyloxy-Deputy, including 2-(methylsulfonyl)ethyl and the like.

The term "su�honil" refers to a group "-SO 2-R", where R is selected from "aryl," "heteroaryl," "C1-C6-alkyl," "C1-C6-alkyl" substituted with Halogens, e.g., -SO2-CF3group "C2-C6-alkenyl," "C2-C6-alkynyl," "C3-C8-cycloalkyl," "heteroseksualci," "aryl," "heteroaryl," "aryl-C1-C6-alkyl", "heteroaryl-C1-C6-alkyl," "aryl-C2-C6-alkenyl," "heteroaryl-C2-C6-alkenyl," "aryl-C2-C6-alkynyl," "heteroaryl-C2-C6-alkynyl," "cycloalkyl-C1-C6-alkyl" or "heteroseksualci-C1-C6-alkyl".

The term "sulfonyl-C1-C6-alkyl" refers to alkyl groups having sulfanilyl Deputy, including 2-(methyl-sulfonyl)ethyl and the like.

The term "sulfinyl" refers to a group "-S(O)-R", where R is selected from "alkyl," "alkyl" substituted with Halogens, e.g., -SO-CF3group "C2-C6-alkenyl," "C2-C6-alkynyl," "C3-C8-cycloalkyl," "heteroseksualci," "aryl," "heteroaryl," "aryl-C1-C6-alkyl", "heteroaryl-C1-C6-alkyl," "aryl-C2-C6-alkenyl," "heteroaryl-C2-C6-alkenyl," "aryl-C2-C6-alkynyl," "heteroaryl-C2-C6-alkynyl," "C3-C8-cycloalkyl-C1-C6-alkyl" or "hetero�cycloalkyl-C 1-C6alkyl".

The term "sulfanilate" denotes an alkyl group having sulfanilyl Deputy, including 2-(methylsulfinyl)ethyl and the like.

The term "sulfanyl" refers to groups-S-R where R includes H, "C1-C6-alkyl," "C1-C6-alkyl" substituted with Halogens, e.g., -S-CF3group "C2-C6-alkenyl," "C2-C6-alkynyl," "C3-C8-cycloalkyl," "heteroseksualci," "aryl," "heteroaryl," "aryl-C1-C6-alkyl", "heteroaryl-C1-C6-alkyl," "aryl-C2-C6-alkenyl," "heteroaryl-C2-C6-alkenyl," "aryl-C2-C6-alkynyl," "alkynylaryl," "cycloalkyl-C1-C6-alkyl" or "heteroseksualci-C1-C6-alkyl". Preferred sulfanilimide groups include methylsulfanyl, ethylsulfanyl and the like.

The term "sulfanyl-C1-C6-alkyl" refers to C1-C5is an alkyl group having sulfanilyl Deputy, including 2-(ethylsulfanyl)ethyl and the like,

The term "sulfonylamino" refers to a group-NRSO2-R', where R and R' represent independently from each other, "C1-C6-alkyl," "C2-C6-alkenyl," "C2-C6-alkynyl," "C3-C8-cycloalkyl," "heteroseksualci," "aryl," "heteroaryl," "aryl-C1-C6-alkyl", "heteroaryl-C -C6-alkyl," "aryl-C2-C6-alkenyl," "heteroaryl-C2-C6-alkenyl," "aryl-C2-C6-alkynyl," "heteroaryl-C2-C6-alkynyl," "C3-C8-cycloalkyl-C1-C6-alkyl" or "heteroseksualci-C1-C6alkyl".

The term "sulfonylamino-C1-C6-alkyl" denotes an alkyl group having sulfonylamino-Deputy, including 2-(ethylsulfanyl)ethyl and the like.

The term "aminosulfonyl" refers to a group-SO2-NRR', where R and R' represent independently from each other H, "C1-C6-alkyl," "C2-C6-alkenyl," "C2-C6-alkynyl," "C3-C8-cycloalkyl," "heteroseksualci," "aryl," "heteroaryl," "aryl-C1-C6-alkyl", "heteroaryl-C1-C6-alkyl," "arylalkyl," "heteroaryl-C2-C6-alkenyl," "aryl-C2-C6-alkynyl," "heteroaryl-C2-C6-alkynyl," "C3-C8-cycloalkyl-C1-C6-alkyl" or "heteroseksualci-C1-C6-alkyl", and where R and R' together with the nitrogen atom to which they are attached, may not necessarily form a 3-8-membered geteroseksualnoe ring. Aminosulfonyl groups include cyclohexylsulfamic, piperidinylcarbonyl and the like.

The term "aminosulfonyl-C1-C6-alkyl" refers to C1-C 6alkyl group having aminosulfonyl Deputy, including 2-(cyclohexyloxycarbonyl)ethyl and the like.

Unless otherwise specified in the definition of the individual substituent, the substituents should be understood as not necessarily substituted.

Unless otherwise specified in the definition of the individual substituent, the term "substituted" refers to groups substituted with from 1 to 5 substituents selected from group, which includes "C1-C6-alkyl," "C2-C6-alkenyl," "C2-C6-alkynyl," "C3-C8-cycloalkyl," "heteroseksualci," "C1-C6-alkylaryl," "C1-C6-alkylglycerol," "C1-C6-alkylsilanes," "C1-C6-alkylchlorosilanes," "amino," "aminosulfonyl," "ammonium," "arylamino," "aminocarbonyl," "aryl," "heteroaryl," "sulfinyl," "sulfonyl," "alkoxy," "alkoxycarbonyl," "carbamate," "sulfonyl," "halogen," trihalomethyl, cyano, hydroxy, merkapto, nitro and the like.

The term "pharmaceutically acceptable salts or complexes" refers to salts or complexes shown below, compounds of formula (I). Examples of such salts include, but are not limited to, basic additive salts formed by reaction of a compound of formula (I) with organic or inorganic bases such as hydroxide, carbonate or BIC�rbonate cation of metals, such as metals selected from the group consisting of alkali metals (sodium, potassium or lithium), alkaline earth metals (e.g. calcium or magnesium), or with an organic primary, secondary or tertiary alkyl amine. Amine salts derived from methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, morpholine, N-Me-D-glucamine, N,N'-bis(phenylmethyl)-1,2-amandemen, tromethamine, ethanolamine, diethanolamine, Ethylenediamine, N-methylmorpholine, procaine, piperidine, piperazine and the like, are considered as included in the scope of the present invention.

Also in the present invention include salts, which are obtained from the acid-additive salts formed with inorganic acids (e.g. hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic (dikalova) acid, pamula acid (palmoic acid), alginic acid, polyglutamine acid, naphthalenesulfonate acid, naphthalenedisulfonic acid and polygalacturonic acid.

The term "pharmaceutically act�VNOM derivative" refers to any compound, which when administered to the recipient is capable of, directly or indirectly, disclosed to ensure the activity here. The term "not right" also includes prodrugs that can be converted to its active form of medication under the action of endogenous enzymes or metabolism. A prodrug is a derivative of the compounds according to the present invention, providing the inhibition of NADPH-oxidase activity, which comprises chemically or metabolically remove the group, and is a compound which can be converted into a pharmaceutically active compound in vivo by splitting the solvent (solvolysis) under physiological conditions. The present invention also includes all tautomers of the compounds according to the present invention.

The term "cardiovascular disorders or disease includes atherosclerosis, particularly diseases or disorders associated with endothelial dysfunction, including, but not limited to, hypertension, cardiovascular complications of diabetes Type I or Type II, intimal hyperplasia, coronary heart disease, spasms of cerebral vessels, coronary vessels or arteries, endothelial dysfunction, heart failure, including chronic heart failure, peripheral arterial disease, restenosis, trauma, wysw�nnye stent infarction, ischemic stroke, vascular complications, such as occurs after organ transplantation, myocardial infarction, hypertension, formation of atherosclerotic plaques, platelet aggregation, angina pectoris, aneurysm, aortic dissection, ischemic heart disease, heart hypertrophy, pulmonary embolism, thrombosis, including deep vein thrombosis, damage arising after ischemia resulting from restoration of blood flow or oxygen supply, as in the case of organ transplants, open-heart surgery, angioplasty, hemorrhagic shock, angioplasty of ischemic organs including the heart, brain, liver, kidney, retina, and intestines.

The term "violation or respiratory disease includes asthma, bronchitis, allergic rhinitis, respiratory syndrome adults, cystic fibrosis, viral lung infection (influenza), pulmonary hypertension, idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease (COPD).

The term "allergic disease" includes hay fever and asthma.

The term "injury" includes polychromatism.

The term "a disease or disorder affecting the metabolism includes obesity, metabolic syndrome, and diabetes Type II.

The term "skin disease" or "violation" includes psoriasis, eczema, dermatitis, wound healing R�n and the formation of scars.

The term "breach of bones" includes osteoporosis, osteoporos, osteosclerosis, periodontitis and hyperparathyroidism.

The term "neurodegenerative disease or disorder" includes a disease or condition characterized by degeneration or changes in the Central nervous system (CNS), particularly at the level of neurons, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), epilepsy and muscular dystrophy. It also includes neuro-inflammatory and associated with demyelination condition or disease, such as the cases and leukodystrophy.

The term "demyelination" refers to the condition or disease of the Central nervous system, including the degradation of the myelin sheath of axons. In the context of the present invention, the term "associated with a demyelination disease" is intended to refer to conditions that include the process, leading to demyelination of cells, such as multiple sclerosis, progressive multifocal (multifocal) leucoencephalopathy (progressive multifocal leukoencephalopathy, PML), myelopathy, any neuro-inflammatory condition involving autoreactive leukocytes within the CNS, congenital metabolic disorder, a neuropathy with abnormal myelination, demyelination, drug-induced, Daniel�the organization, induced by radiation, hereditary condition of demyelination, a condition of demyelination induced by prions, the demyelination-induced encephalitis or spinal cord injury. Preferably, the state represents a multiple sclerosis.

The term "disease or disorder of the kidneys includes diabetic nephropathy, renal failure, glomerulonephritis, nephrotoxicity of aminoglycosides and platinum compounds and overactive bladder. In a specific embodiment, the term according to the present invention includes chronic illnesses or disorders of the kidneys.

The term "abuse or the disease of the reproductive system" includes erectile dysfunction, fertility disorders, prostatic hypertrophy and benign hypertrophy of the prostate.

The term "abuse or disease affecting the eye and/or the lens includes cataracts, including diabetic cataracts, re-clouding of the lens after cataract surgery, diabetic and other forms of retinopathy.

The term "a condition that affects the inner ear includes presbyacusis (senile deafness), tinnitus (ringing in the ears, Meniere's disease (hydrops of the labyrinth of the inner ear) and other balance problems, tricomoniasis, vestibular migraine and induced noise sweat�th hearing and induced by drugs hearing loss (ototoxicity).

The term "inflammatory disorders or disease" refers to inflammatory bowel disease, sepsis (General blood poisoning), septic shock, acute respiratory distress syndrome in adults, pancreatitis, shock induced by trauma, bronchial asthma, allergic rhinitis, rheumatoid arthritis, chronic rheumatoid arthritis, arteriosclerosis, subarachnoid hemorrhage, ischemic stroke (cerebral infarction), heart failure, myocardial infarction, psoriasis, cystic fibrosis, stroke, acute bronchitis, chronic bronchitis, acute bronchiolitis, chronic bronchiolitis, osteoarthritis, gout, myelitis (inflammation of spinal cord), ankylosing spondylitis (Bechterew's disease-Strumpell-Marie), Reiter's syndrome, psoriatic arthritis, spondylitis (inflammation of the intervertebral joints), chronic polyarthritis (still's disease), or ankylosing spondylitis children, recurrent arthritis, infectious arthritis or arthritis after infection, gonococcal arthritis, syphilitic arthritis, Lyme disease, arthritis induced "vasculitis syndrome", nadasny (periarteritis) nodosa (Kussmaul disease), anaphylactic vasculitis, granulomatosis Lagreca, the rheumatoid polymyalgia, arthritis cells the joints, the arthritis associated with deposition of calcium crystals, pseudopodia, n� associated with arthritis rheumatism, bursitis, tenosynovitis, an inflammation of the epicondyle (tennis elbow or tennis elbow), carpal tunnel syndrome, diseases caused by repetitive actions like typing on a typewriter), mixed form of arthritis, neuropathic arthropathy, hemorrhagic arthritis, purple vessels, hypertrophic osteoarthropathy, mnogotsentrovye reticulohistiocytosis, arthritis induced by specific diseases, pigmentation of the blood, sickle-cell anemia and other abnormalities of hemoglobin, hyperlipoproteinemia, dysgammaglobulinemia, hyperparathyroidism, acromegaly, familial Mediterranean fever, Bechet disease, systemic autoimmune disease erythematous (lupus), multiple sclerosis and Crohn's disease (gerolimatos) or disease such recurrent polychondritis (syndrome of Meyenburg-Altherr-Olinger), chronic inflammatory bowel disease (inflammatory bowel diseases, IBD) or the related diseases which require the administration to a mammal a therapeutically effective dose of a compound of formula (I) in an amount sufficient to inhibit NADPH oxidase.

The term "diseases or disorders of the liver includes liver fibrosis, alcoholic liver fibrosis, fatty liver and nonalcoholic steatohepatitis.

The term "arthritis" means acute rheumatic arthritis, chronic rheumatoid arthritis, chlamydial arthritis, chronic absorptive arthritis, chylous (lymph) arthritis, arthritis associated with bowel disease, filariasis arthritis, gonococcal arthritis, gouty arthritis, hemophilic arthritis, hypertrophic arthritis, chronic arthritis in children, arthritis Lyme arthritis newborn foals, nadasny (nodular) arthritis, agronomically arthritis, psoriatic arthritis or suppurative arthritis, or the related diseases which require the administration to a mammal a therapeutically effective dose of a compound of formula (I) in an amount sufficient to inhibit NADPH oxidase.

The term "pain" includes hyperalgesia (increased pain sensitivity) associated with pain in inflammation.

The term "cancer" refers to a carcinoma (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, limfangioèndoteliomu, periosteum (osteophyte), mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, carcinoma of the colon, pancreatic cancer, breast cancer, ovarian cancer, kidney cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, carcinoma of the sweat glands, carcinoma of the sebaceous glands, papillary carcinoma, papillary adenocarcinoma, cyst�nocarcinoma, medullary carcinoma, bronchogenic carcinoma, carcinoma of the kidney cells, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms ' tumor, cervical cancer, tumor of the testis, lung cancer, small cell lung cancer, lung adenocarcinoma, bladder cancer, or cancer of the epithelium, or the related diseases which require the administration to a mammal a therapeutically effective dose of a compound of formula (I) in an amount sufficient to inhibit NADPH oxidase.

The term "disease or disorders of the gastrointestinal tract" includes violations of the gastric mucosa that occurs when ischemic bowel disease, enteritis/colitis, cancer chemotherapy or neutropenia.

The term "angiogenesis" includes the formation of new vessels by branching, intusseption (intussusceptive) angiogenesis, vasculogenesis, arteriogenesis and lymphangiogenesis. Angiogenesis represents the formation of new blood vessels from pre-existing capillaries or post-capillary venules and occurs in pathological conditions, such as different types of cancer, arthritis and inflammation. A large number of tissues or organs, including the developed tissues, can support angiogenesis in disease conditions including skin, muscle, gut, connective tissue, joints, �spine and similar fabrics, in which blood vessels can invade under the influence of angiogenic stimuli.

Used here meaning the term "angiogenesis-dependent condition" is intended to indicate the conditions under which the process of angiogenesis or vasculogenesis supports or enhances a pathological condition. Vasculogenesis is the formation of new blood vessels arising from angioblasts, which are the precursors of endothelial cells. Both processes lead to the formation of new blood vessel and enter into the meaning of the term "angiogenesis-dependent conditions." Similarly, the term "angiogenesis" is used here in the meaning involves the formation of blood vessels de novo, as occurs in vasculogenesis, and also the process of branching and expansion of existing vessels, capillaries and venules.

The term "inhibiting angiogenesis" means that the compound is effective in reducing the extent, amount or rate of formation of new vessels. Reduce the extent, amount or rate of proliferation or migration of endothelial cells into the tissue is a specific example of inhibition of angiogenesis. Inhibiting angiogenesis activity is particularly suitable in the treatment of any type of cancer because it is directed to the process of tumor growth � the lack of new blood vessel formation in the tumor tissue, resulting in tumor tissue does not receive the required nutrients, slows its growth, stops further growth, regresses and eventually becomes necrotic, resulting in the death of the tumor. In addition, inhibiting angiogenesis activity is particularly suitable in the treatment of any type of cancer, as it is particularly effective against the formation of metastases, as their education also requires masculinely primary tumor to metastatic cancer cells could exist in the primary tumor and their spread into the secondary phase requires the formation of new blood vessels to support growth of the metastases.

In used herein, the terms "treating", "treat" and the like generally mean obtaining a desired pharmaceutical or physiological effect. The effect may be prophylactic in terms of preventing or partially preventing a disease, symptom or condition in this disease, and/or may be therapeutic in terms of a partial or complete cure of a disease, condition, symptom or adverse effect associated with the disease. The term "treatment" used here in the meaning includes any treatment of a disease in a mammal, especially a human, and includes: (a) preventing the occur� disease in a subject which may be predisposed to the disease, but it had not yet diagnosed; (b) suppression of the disease, that is stopping the development, or relieving the disease, i.e. ensuring that the regression of the disease, and/or its symptoms or conditions.

The term "subject" is used here in the meaning refers to mammals. For example, mammals contemplated by the present invention include humans, primates, domestic animals such as cattle, sheep, pigs, horses and the like.

The term "inhibitor", as used in the context of the present invention, is defined as a molecule that partially or fully inhibits the activity of NADPH oxidase and/or inhibits or reduces the generation of reactive oxygen species (ROS).

Compounds according to the present invention

In one embodiment of the present invention provides pyrazolopyrimidine derivative of formula (I):

where G1is selected from H; optionally substituted acyl; optionally substituted acyl-C1-C6-alkyl, optionally substituted alkyl, such as aminocarbonylmethyl (e.g. phenylacetamide), optionally substituted C3-C8-cycloalkenyl, optionally substituted geterotsiklicheskie, optionally substituted Ari�alkyl, such as optionally substituted phenylalkyl, such as optionally substituted phenylmethyl (e.g. phenylmethyl, or 3-methylphenylethyl, or 4-tormentil, or 2-Chlorobenzyl, or 4-Chlorobenzyl, or 4-methylbenzyl, or 4-bromobenzyl); and optionally substituted heteroaromatic, such as optionally substituted pyridinyl, such as pyridin-2-ylmethyl; G2is selected from-CHR1R2and optionally substituted saturated ring system selected from optionally substituted C3-C8-cycloalkyl, such as optionally substituted cyclohexyl, and optionally substituted heteroseksualci, such as optionally substituted piperidine (e.g. 1-demerol-4-yl); R1and R2independently from each other selected from H; optionally substituted alkoxy; optionally substituted alkoxy-C1-C6-alkyl, such as optionally substituted methoxy (e.g. 2-methoxyethyl or 2-methoxy-4-chlorophenyl); optionally substituted amino; optionally substituted aminoalkyl, such as optionally substituted aminomethyl (for example, 2-diethylaminomethyl); optionally substituted acyl; optionally substituted C1-C6-alkyl, such as methyl, optionally substituted propyl (e.g., isopropyl); optionally substituted C2-C6 -alkenyl; optionally substituted C2-C6-alkynyl; optionally substituted aryl such as optionally substituted phenyl (e.g. phenyl, 4-chlorophenyl or 2,5-dichlorophenyl, or 2-chloro-4-fluorophenyl); optionally substituted C1-C6-alkylaryl; optionally substituted aryl-C1-C6-alkyl, such as optionally substituted phenyl-C1-C6-alkyl (e.g., optionally substituted phenylmethyl, such as 2-phenylmethyl); optionally substituted heteroaryl; optionally substituted C1-C6-alkylglycerol; optionally substituted heteroaryl-C1-C6-alkyl, such as optionally substituted morpholinyl-C1-C6-alkyl (e.g. 2-morpholine-4-retil); optionally substituted C2-C6-alkynylaryl; optionally substituted aryl-C2-C6-alkenyl; optionally substituted C2-C6alkenylphenol; optionally substituted heteroaryl-C2-C6-alkenyl; optionally substituted C3-C8-cycloalkyl, such as optionally substituted cyclohexyl (e.g. cyclohexyl); optionally substituted geterotsiklicheskie; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycle�alkyl-C 1-C6-alkyl; optionally substituted C1-C6-alkylchlorosilanes and optionally substituted heteroseksualci-C1-C6-alkyl, such as optionally substituted morpholinyl-C1-C6-alkyl (e.g., optionally substituted morpholinylmethyl, such as 2-morpholine-4-ylmethyl); or-CHR1R2together form an optionally substituted ring selected from optionally substituted C3-C8-cycloalkyl, such as optionally substituted cyclohexyl (e.g. cyclohexyl) and optionally substituted heteroseksualci, such as optionally substituted piperidine (e.g. 1-demerol-4-yl) or optionally substituted pyrrolidin; G3is selected from H; optionally substituted amino; optionally substituted aminoalkyl, such as benzyl(methyl)aminomethyl; optionally substituted aminocarbonyl; optionally substituted alkoxy; optionally substituted alkoxy-C1-C6alkyl, such as optionally substituted phenoxy-C1-C6-alkyl (e.g. 4-forfinancial, or 4-chlorphenoxamine, or 3-phenoxypropan, or 4-benzoyloxymethyl); optionally substituted acyl; optionally substituted C1-C6-alkyl, such as methyl, ethyl, butyl (e.g., 4-butyl); optionally samisen�With th 2-C6-alkenyl; optionally substituted C2-C6-alkynyl; optionally substituted aryl such as optionally substituted phenyl (e.g. phenyl, 3-chlorophenyl, 3,4-dichlorophenyl, or 4-chlorophenyl or 3,5-dichlorophenyl); optionally substituted C1-C6-alkylaryl; optionally substituted aryl-C1-C6-alkyl, such as optionally substituted phenyl-C1-C6-alkyl, such as optionally substituted benzyl (e.g. 3-methoxybenzyl); optionally substituted heteroaryl; optionally substituted C1-C6-alkylglycerol; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C2-C6-alkynylaryl; optionally substituted aryl-C2-C6-alkenyl; optionally substituted C2-C6-alkenylphenol; optionally substituted heteroaryl-C2-C6-alkenyl; optionally substituted C3-C8-cycloalkyl; optionally substituted geterotsiklicheskie, such as optionally substituted piperidine (e.g., demerol-1-carboxylate); optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted C1 -C6-alkylchlorosilanes and optionally substituted heteroseksualci-C1-C6-alkyl, such as optionally substituted morpholinyl-C1-C6-alkyl (for example, morpholine-4-ylmethyl); G4is selected from H; optionally substituted acyl; optionally substituted acylamino; optionally substituted acyl-C1-C6-alkyl, such as optionally substituted arylmethyl (for example, morpholino-4-acetyl-piperazine-1-acetyl-4-(phenylmethyl)-); optionally substituted C1-C6-alkyl, such as optionally substituted methyl (e.g. methyl), or optionally of substituted pentyl (e.g., isopentyl), or optionally substituted acylamino-C1-C6-alkyl, such as optionally substituted benzamide-C1-C6-alkyl (e.g. 4-fermentability), or optionally substituted heteroalkyl, such as a substituted alkoxy-C1-C6-alkyl, such as optionally substituted methoxy-C1-C6-alkyl (e.g. 2-methoxyethyl), optionally substituted ethoxy-C1-C6alkyl (e.g. 3-ethoxypropan), optionally substituted phenoxy-C1-C6-alkyl (e.g. 3-phenoxypropan); optionally substituted C2-C6-alkenyl; optionally substituted C2-C6-alkinyl; not necessarily samewe�tion of aryl, such as optionally substituted phenyl (e.g., three-formatexception or phenylacetamide); optionally substituted C1-C6-alkylaryl; optionally substituted aryl-C1-C6-alkyl, such as optionally substituted phenylmethyl (for example, methyl or benzyl benzoic acid (e.g., 2-benzyl), or dimethoxybenzyl, or 3.5 dimethoxybenzyl, or 3-methoxybenzyl, or 4-methoxybenzyl, or 4-Chlorobenzyl, or morpholine-4-iletileri, or phenylacetamide), or optionally substituted phenylethyl (e.g., 2-phenylethyl, 4-methoxyphenacyl); optionally substituted heteroaryl, such as optionally substituted dihydroindol (e.g., 2,3-dihydro-1H-indene-1-yl); optionally substituted C1-C6alkylglycerol; optionally substituted heteroaryl-C1-C6-alkyl, such as optionally substituted thiophenyl-C1-C6-alkyl, such as optionally substituted thienylmethyl (for example, thiophene-2-ylmethyl), or optionally substituted imidazolyl-C1-C6-alkyl, such as optionally substituted imidazolidinyl (e.g., imidazol-4-retil), or optionally substituted indole-C1-C6-alkyl, such as optionally substituted indolicidin (e.g., indol-3-yl ethyl) or optionally substituted furanyl-C1-C6 -alkyl, such as optionally substituted furylmethyl (e.g., furan-2-ylmethyl), or optionally substituted benzodioxolyl-C1-C6-alkyl, such as optionally substituted benzodioxolyl (for example, 1,3-benzodioxol-5-ylmethyl), or optionally substituted pyridinyl-C1-C6-alkyl, such as optionally substituted pyridinylmethyl (e.g., pyridin-3-ylmethyl, or pyridin-2-ylmethyl, or 1-acetylpiperidine-4-ylmethyl or tert-butylpiperazine-1-carboxylatomethyl), or such as optionally substituted pyridinylmethyl (for example, pyridine-2-retil), or optionally substituted morpholinyl-C1-C6-alkyl, such as optionally substituted morpholinylmethyl (for example, 4-benzylmorphine-2-ylmethyl), or optionally substituted pyrrolidin-C1-C6-alkyl, such as optionally substituted pyrrolidinyl (for example, 5-oxopyrrolidin-3-ylmethyl); optionally substituted C2-C6-alkynylaryl; optionally substituted aryl-C2-C6-alkenyl; optionally substituted alkenylphenol; optionally substituted heteroaryl-C2-C6-alkenyl; optionally substituted C3-C8-cycloalkyl; optionally substituted geterotsiklicheskie, such as optionally substituted morpholinyl (for example, 5-morpholine-4-yl), or not�certainly substituted piperazinyl (e.g., 4-methylpiperazine), or optionally substituted piperidinyl (for example, 4-methylbenzyl)piperidine-4-yl); optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted C1-C6-alkylchlorosilanes and optionally substituted heteroseksualci-C1-C6-alkyl, such as optionally substituted morpholinyl-C1-C6-alkyl, such as optionally substituted morpholinyl (for example, 3-(morpholine-4-yl)propyl)), optionally substituted morpholinyl (for example, 2-morpholine-4-retil); or optionally substituted piperazinyl-C1-C6-alkyl, such as optionally substituted piperazinylmethyl (for example, 2-(4-acetylpiperidine-1-yl)ethyl or 2-(4-exaniination-1-yl)ethyl) or optionally substituted pyrrolidinyl-C1-C6alkyl, such as optionally substituted pyrrolidinyl (for example, 3-(2-oxopyrrolidin-1-yl) propyl) or optionally substituted tetrahydrofuranyl-C1-C6-alkyl, such as optionally substituted tetrahydrofuranyl (e.g., tetrahydrofuran-2-ylmethyl); G5is selected from H; optionally substituted C1-C6-alkyl; optionally substituted C2-C6-alken�La; optionally substituted C2-C6-alkynyl; optionally substituted aryl; optionally substituted C1-C6-alkylaryl; optionally substituted aryl-C1-C6-alkyl; optionally substituted heteroaryl; optionally substituted C1-C6-alkylglycerol; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C2-C6-alkynylaryl; optionally substituted aryl-C2-C6-alkenyl; optionally substituted C2-C6-alkenylphenol; optionally substituted heteroaryl-C2-C6-alkenyl; optionally substituted C3-C8-cycloalkyl; optionally substituted geterotsiklicheskie; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted C1-C6-alkylchlorosilanes and optionally substituted heteroseksualci-C1-C6-alkyl; and its pharmaceutically acceptable salts and pharmaceutically active derivative.

Composition

The present invention provides pharmaceutical or therapeutic agents as compositions and methods for treating a patient, preferably a patient,being a mammal, and most preferably the patient who is the person who is suffering from medical diseases, particularly diseases mediated by NADPH oxidase, such as cardiovascular disorders or disease, respiratory disorders or disease, a disease or disorder affecting the metabolism, impaired skin, impaired bones, neuro-inflammatory violation, neurodegenerative violation, kidney disease, disorders of reproductive system, a disease or disorder affecting the eye and/or the lens, a condition lieudieu on the inner ear, inflammatory disorders or disease, liver disease, pain, cancer, angiogenesis, angiogenesis-dependent conditions and/or diseases or disorders of the gastrointestinal tract.

Pharmaceutical compositions of the present invention may contain one or more pyrazolopyrimidine derivative described here in any form. The compositions of the present invention may also include one or more pharmaceutically acceptable additional ingredient(s) such as alum, stabilizers, antimicrobial agents, buffers, colorants, flavors, excipients and the like.

Compounds of the present invention together with commonly used adjuvant, carrier, diluent or excipient may� be placed into the form of pharmaceutical compositions and their metered dosage forms and in this form can be used in solid form, such as tablets or filled capsules, or in liquid forms such as solutions, suspensions, emulsions, elixirs, or filled their capsules, for oral use, or in the form of sterile solutions for injection for parenteral (including subcutaneous) use. Such pharmaceutical compositions and dosages can include the ingredients in conventional proportions, with or without adding additional active compounds or components, and such metered dosage forms may contain any suitable effective amount of the active ingredient corresponding to the range used daily dosages. The compositions according to the present invention are preferably compositions for injection.

The compositions of the present invention may also be a liquid dosage form, including but not limited to, aqueous or oily suspensions, solutions, emulsions, syrups and elixirs. Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous media buffers, suspendresume and dispersing agents, colorants, flavors and the like. Compositions can also be prepared as a dry product for�the reason, it with water or other suitable medium before use. Such liquid dosage forms may contain additives including, but not limited to, suspendresume agents, emulsifying agents, non-aqueous vehicles and preservatives. Suspendresume agents include, but are not limited to, orbitally syrup, methylcellulose, glucose/sugar syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, gel, aluminum stearate, and hydrogenomonas dietary fats. Emulsifying agents include, but are not limited to, lecithin, servicemanuals and gum Arabic. Non-aqueous carriers include, but are not limited to, edible oils, almond oil, fractionated coconut oil, oily esters, propylene glycol and ethyl alcohol. Preservatives include, but are not limited to, methyl - or propyl-and-hydroxybenzoate and sorbic acid. Additional materials and methods of production and the like are provided in Part 5 of the publication Remington's Pharmaceutical Sciences, 21stEdition, 2005, University of the Sciences in Philadelphia, Lippincott Williams & Wilkins, which is included in the present invention by reference.

Solid compositions of the present invention can be in the form of tablets or pellets, prepared in the usual way. For example, tablets and capsules for oral administration may contain conventional excipients including, but not limited to, binders, fillers, Liu�recenty, dezintegriruetsja and moisturizing agents. Binding agents include, but are not limited to, syrup, acacia, gelatin, sorbitol, tragakant, vegetable starch adhesive and polyvinylpyrrolidone. Fillers include, but are not limited to, lactose, sugar(RAM), microcrystalline cellulose, corn starch, calcium phosphate, and sorbitol. The lubricants include, but are not limited to, magnesium stearate, stearic acid, talc, polyethylene glycol and silica. Dezintegriruetsja agents include, but are not limited to, potato starch and glycolate sodium starch. Wetting agents include, but are not limited to, sodium lauryl sulfate. Tablet may have a coating well known in the art.

Compositions for injection are usually prepared on a sterile solution for injection or phosphate buffer solution, or other solutions for injection, which are known in the art.

The compositions of the present invention can also be prepared in the form of suppositories which may contain a basis for suppositories, including, but not limited to, cocoa butter or glycerides. The compositions of the present invention can also be prepared for inhalation and to be in shape, including, but not limited to, solution, suspension or emulsion that may BB�be a dry powder or in the form of an aerosol with the use of a compressed fluid, such as DICHLORODIFLUOROMETHANE or trichloromethane. The compositions of the present invention can also be prepared in the form of compositions for transdermal administration, comprising an aqueous or non-aqueous carriers, including, but not limited to, creams, ointments, lotions, pastes, medical tape, a sticker or membrane.

The compositions of the present invention can also be prepared for parenteral administration, including, but not limited to, by injection or continuous infusion. Compositions for injection may be in the form of suspensions, solutions or emulsions in oily or aqueous vehicles and may contain additional agents, including, but not limited to, suspendida, stabilizing and dispersing agents. The composition may also be provided in the form of a powder for reconstitution in a suitable carrier, including, but not limited to, sterile, free from pyrogen free water.

The compositions of the present invention can also be prepared in the form of drugs to be deposited (sustained release), which may be administered by implantation or by intramuscular injection. Compositions can be prepared with suitable polymeric or hydrophobic materials (as an emulsion in a suitable oil, for example), ion exchange resins or in the form of poorly dissolving�imih derivatives (in the form of a poorly soluble salt, for example).

The compositions of the present invention can also be prepared in the form of liposomal drugs. Compositions in the form of liposome preparations may include liposomes, which penetrate in the targeted cells or through the Horny layer of the skin (stratum corneum) and merge with the cell membrane, delivering the contents of the liposome into the cell. Other suitable compositions can be applied niosomes. Niosomes are lipid vesicles similar to liposomes with membranes consisting largely of non-ionic lipids, some forms of which are effective for transporting compounds across the stratum corneum of the skin.

Compounds of the present invention can also be administered in the forms for extended release or using the systems for prolonged drug delivery. Description of representative material for long delivery can also be found in the incorporated by reference " Remington's Pharmaceutical Sciences.

Method of administration

The compositions of the present invention may be administered by any method, including, but not limited to, oral, parenteral introduction under the tongue, transdermal, rectal, transmucosal (through the mucous), topical, by inhalation, buccal or intranasal administration or a combination of both. Parenteral administration includes, but� not limited to, intravenous, intra-arterial, vnutriarterialno, subcutaneous, intramuscular, vnutriobolochechnoe introduction and introduction to the joint. The compositions of the present invention can also be administered in the form of an implant, which provides slow release of the compositions, as well as a slow controlled intravenous infusion. In a preferred embodiment pyrazolopyrimidinone derivatives according to the present invention are administered intravenously or subcutaneously.

The present invention is further illustrated by the following Examples which in no way limit the scope of the present invention.

Administered dose as a single or multiple dosages of the individual will vary depending on many factors, including pharmacokinetic properties, the condition and patient characteristics (gender, age, body weight, health, size), severity of symptoms, while ongoing treatment, frequency of administration and the desired effect.

Combination

According to one embodiment of the present invention compounds according to the present invention and their pharmaceutical compositions can be entered either by themselves or in combination with an additional agent suitable for the treatment of cancer, such as substances used in conventional chemotherapy directed� against solid tumors and for monitoring the formation of metastases, or substances used in hormone therapy, or any other molecule which acts triggering programmed cell death, for example, the additional agent selected from the category of drugs that stop the synthesis of building block molecules pre-DNA, such as methotrexate (Abitrexate®), fluorouracil (Adrucil®), hydroxyurea (Hydrea®), and mercaptopurine (Purinethol®), for example, an additional agent selected from the category of drugs that directly destroy DNA in the cell nucleus, such as cisplatin (Platinol®) and antibiotics - daunorubicin (Cerubidine®), doxorubicin (Adriamycin®) and etoposide (VePesid®), for example, an additional agent selected from the category of drugs that affect the synthesis or degradation of the mitotic spindle, such as Vinblastine (Velban®), Vincristine (Oncovin®) and Paclitaxel (Taxol®).

According to another embodiment of the present invention compounds according to the present invention and their pharmaceutical compositions may be administered in combination with agents directed at cell surface proteins, such as gene transport chain of the cytokine receptor, and can be entered cytotoxins directed to the receptor.

According to another embodiment of the present invention compounds according to the present invention and their pharmaceutical compositions may be administered in combination with radiation therapy.

Present and�the acquisition includes the introduction of compounds according to the present invention or its pharmaceutical composition, where the connection according to the present invention or its pharmaceutical composition is administered to the individual prior to, simultaneously or sequentially with respect to other therapeutic procedures or joint agents, suitable for treating different types of cancer (for example, when multiple schemas medication), in a therapeutically effective amount. Compounds according to the present invention or their pharmaceutical compositions, which are introduced simultaneously with said joint agents, can be administered in the same composition or different compositions, and by the same route or different routes of administration.

In another specific embodiment, the compounds and methods of the present invention are intended for use in the treatment of various types of cancer, where the introduction of compounds according to the present invention, as a rule, is carried out during or after chemotherapy, hormone therapy or radiotherapy.

In another specific embodiment, the compounds and methods of the present invention are intended for use in the treatment of various types of cancer, where the introduction of compounds according to the present invention, usually performed after a course of chemotherapy, hormonal therapy or radiotherapy in those moments of time when the tumor tissue will be responding to the toxic attack by John�the use of angiogenesis to restore the supply of tumor tissue with blood and nutrients.

In another embodiment, the introduction of the compounds according to the present invention is used after surgery, during which were removed solid tumors, and is a prophylaxis against metastases.

Patients

In one embodiment, patients according to the present invention are patients suffering from cardiovascular disorders or diseases.

In another embodiment, patients according to the present invention are patients suffering from respiratory disorders or diseases.

In another embodiment, patients according to the present invention are patients who suffer from diseases or disorders that affect the metabolism.

In another embodiment, patients according to the present invention are patients who suffer from skin disorders.

In another embodiment, patients according to the present invention are patients suffering from disorders of the bones.

In another embodiment, patients according to the present invention are patients suffering from neuro-inflammatory disorders and/or neurodegenerative disorders.

In another embodiment, patients according to the present invention are patients who suffer from kidney disease.

In another embodiment, patients according to the present invention are patients, CT�Adumim from reproductive disorders.

In another embodiment, patients according to the present invention are patients who suffer from diseases or disorders affecting the eye and/or the lens and/or the condition affecting the inner ear.

In another embodiment, patients according to the present invention are patients suffering from inflammatory disorders or diseases.

In another embodiment, patients according to the present invention are patients suffering from liver disease.

In another embodiment, patients according to the present invention are patients suffering from pain, such as pain in inflammation.

In another embodiment, patients according to the present invention are patients suffering from cancer.

In another embodiment, patients according to the present invention are patients suffering from angiogenesis or angiogenesis-dependent condition.

In another embodiment, patients according to the present invention are patients who suffer from allergic disorders.

In another embodiment, patients according to the present invention are patients who suffer from trauma.

In another embodiment, patients according to the present invention are patients suffering from septic, hemorrhagic or anaphylactic shock.

In another �opaseniy patients according to the present invention are patients who suffering from diseases or disorders of the gastrointestinal tract.

The use according to the present invention

In another embodiment, the present invention provides pyrazolopyrimidine derivative of formula (I); and its pharmaceutically acceptable salts and pharmaceutically active derivative for use as a medicine.

In an additional embodiment the present invention provides pyrazolopyrimidine derivative according to the present invention in which G1represents N.

In an additional embodiment the present invention provides pyrazolopyrimidine derivative according to the present invention in which G1represents an optionally substituted acyl.

In an additional embodiment the present invention provides pyrazolopyrimidine derivative according to the present invention in which G2represents-CHR1R2; R1and R2are as defined in carrying out the invention.

In an additional embodiment the present invention provides pyrazolopyrimidine derivative according to the present invention in which G2is an optionally substituted saturated ring system.

In another additional embodiment of the present invention providing�t pyrazolopyrimidine derivative according to the present invention, in which G2represents-CHR1R2; R1represents H; R2is such as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention in which G2represents-CHR1R2; R1is an optionally substituted C1-C6-alkyl; R2is such as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention in which G2represents-CHR1R2; R1represents optionally substituted aryl; R2is such as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention in which G2represents-CHR1R2; R1represents optionally substituted amino-C1-C6-alkyl; R2is such as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derived from�publicly to the present invention, in which G2represents-CHR1R2; R1is an optionally substituted C2-C6-cycloalkyl; R2is such as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention in which G2represents-CHR1R2; R1represents an optionally substituted heteroseksualci; R2is such as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention in which G2represents-CHR1R2; R1represents an optionally substituted heteroseksualci-C1-C6-alkyl; R2is such as defined in carrying out the invention.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention in which G2represents-CHR1R2; R1represents an optionally substituted alkoxy-C1-C6-alkyl; R2is such as defined in carrying out the invention.

In additional in�the polishing, the present invention provides pyrazolopyrimidine derivative according to the present invention, in which G2represents-CHR1R2; R1represents H; R2is such as defined in carrying out the invention.

In an additional embodiment the present invention provides pyrazolopyrimidine derivative according to the present invention in which G2represents-CHR1R2; R1and R2represent N.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention in which G2represents-CHR1R2; -CHR1R2together form an optionally substituted ring selected from optionally substituted C3-C8-cycloalkyl and optionally substituted geterotsiklicheskie.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention in which G3is an optionally substituted C1-C6-alkyl.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention in which G3represents optionally substituted amino.

In another additional embodiment of the present invention to provide�ing pyrazolopyrimidine derivative according to the present invention, in which G3represents optionally substituted amino-C1-C6-alkyl.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention in which G3represents an optionally substituted aminocarbonyl.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention in which G3represents an optionally substituted acyl.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention in which G3represents an optionally substituted alkoxy.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention in which G3represents an optionally substituted alkoxy-C1-C6-alkyl.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention in which G3represents optionally substituted aryl.

In another additional embodiment of the present invention provides pyrazolopyrimidine� derivative according to the present invention, in which G3represents an optionally substituted heteroaryl.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention in which G3is selected from optionally substituted geterotsiklicheskie and C2-C6-cycloalkyl.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention in which G4is selected from optionally substituted C1-C6-alkyl; optionally substituted C2-C6-alkenyl and optionally substituted C2-C6-alkynyl.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention in which G4represents an optionally substituted, acylamino-C1-C6-alkyl.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention in which G4represents an optionally substituted alkoxy-C1-C6-alkyl.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present izobreteny�, in which G4represents optionally substituted aryl.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention in which G4is selected from optionally substituted aryl-C1-C6of alkyl and substituted heteroaryl-C1-C6-alkyl.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention in which G4is an optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl and optionally substituted heteroseksualci-C1-C6-alkyl.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention in which G4represents an optionally substituted acyl.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention in which G4represents an optionally substituted, acylamino.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention in which G4is a fun� optionally substituted acyl-C 1-C6-alkyl.

In another additional embodiment of the present invention provides pyrazolopyrimidine derivative according to the present invention in which G5represents N.

In another embodiment, the present invention provides the use of pyrazolopyrimidine derivative of formula (I), where G1, G2, G3, G4and G5are as defined in carrying out the invention and its pharmaceutically acceptable salts and pharmaceutically active derivative, for the manufacture of pharmaceutical compositions for the treatment or prevention of diseases or disorders selected from cardiovascular disorders, respiratory disorders, metabolic disorders, skin disorders, bone disorders, neuro-inflammatory and/or neurodegenerative disorders, kidney diseases, disorders of the reproductive system, diseases affecting the eye and/or the lens and/or conditions affecting the inner ear, inflammatory disorders, liver diseases, pain, different types of cancer, allergic disorders, injuries, septic, hemorrhagic and anaphylactic shock, disorders of the gastrointestinal tract, angiogenesis, angiogenesis-dependent conditions and other diseases and disorders associated with �dazai (NADPH-oxidase).

In another embodiment, the present invention provides pyrazolopyrimidine derivative of formula (I), where G1, G2, G3, G4and G5are as defined in carrying out the invention and its pharmaceutically acceptable salts and pharmaceutically active derivative, for the treatment or prophylaxis of a disease or condition selected from cardiovascular disorders, respiratory disorders, metabolic disorders, skin disorders, bone disorders, neuro-inflammatory and/or neurodegenerative disorders, kidney diseases, disorders of the reproductive system, diseases affecting the eye and/or the lens and/or conditions affecting the inner ear, inflammatory disorders, liver diseases, pain, different types of cancer, allergic disorders, injuries, septic, hemorrhagic and anaphylactic shock, disorders of the gastrointestinal tract, angiogenesis, angiogenesis-dependent conditions and other diseases and disorders associated with (NADPH-oxidase).

Compounds of the present invention include in particular those selected from the following group:

2-benzyl-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(4-Chlorobenzyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-spiritin-3,6(2H,5H)-dione;

2-benzyl-4-methyl-5-[3-(triptoreline)phenyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2,4-dimethyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione

2,4,5-trimethyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

5-(furan-2-ylmethyl)-2,4-dimethyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

5-(4-Chlorobenzyl)-2,4-dimethyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-butyl-5-(4-chlorbenzyl)-2-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-butyl-2-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

5-(4-Chlorobenzyl)-4-methyl-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-benzyl-4-butyl-5-(3,5-dimethoxybenzyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-benzyl-4-butyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-cyclohexyl-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2,4-dimethyl-5-(2-pyridin-2-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-methoxyethyl)-4-methyl-5-(2-pyridin-2-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione; and

2,4-dimethyl-5-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione.

Compounds of the present invention include in particular those selected from the following group:

5-(2-methoxyethyl)-4-methyl-2-(2-phenylethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-methoxyethyl)-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]�of iridin-3,b(2H,5H)-dione;

N-{3-[2-(2-methoxyethyl)-4-methyl-3,6-diokso-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C] pyridin-5-yl]phenyl}acetamide;

2-(2-methoxyethyl)-4-methyl-5-(2-morpholine-4-yl-2-oxoethyl)-1H-pyrazolo[4,3-C] pyridine-3,6(2H,5H)-dione;

2-benzyl-4-(3-methoxybenzyl)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6 (2H,5H)-dione;

2-benzyl-4-(3-methoxybenzyl)-5-(2-methoxyethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2,5-dichlorobenzyl)-5-(2-methoxyethyl)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-[2-(4-chlorophenoxy)ethyl]-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2,5-dichlorobenzyl)-4-methyl-5-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6 (2H,5H)-dione;

2-(2,5-dichlorobenzyl)-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

5-(3,5-dimethoxybenzyl)-2-(2-methoxyethyl)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

N-(3-{[4-methyl-3,6-diokso-2-(2-phenylethyl)-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridin-5-yl]methyl}phenyl)acetamide;

4-methyl-5-(2-morpholine-4-retil)-2-(2-phenylethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione

4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-2-(2-phenylethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-methoxyethyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

N-[2-(2-benzyl-4-methyl-3,6-diokso-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridin-5-yl)ethyl]-4-fermentated;

N-[3-(2-benzyl-4-methyl-3,6-diokso-1,2,3,6-tetrahydro-5H-pyrazolo,3-C]pyridin-5-yl)phenyl]acetamide;

N-(3-{[2-(2-chloro-4-terbisil)-4-methyl-3,6-diokso-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridin-5-yl]methyl}phenyl)acetamide;

5-[2-(4-benzylpiperazine-1-yl)-2-oxoethyl]-2-(2-methoxyethyl)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2,5-dichlorobenzyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6 (2H,5H)-dione;

2-(2-chloro-4-terbisil)-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo [4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2,5-dichlorobenzyl)-4-methyl-5-(2-morpholine-4-yl-2-oxoethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-methyl-2-(2-phenylethyl)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-chloro-4-terbisil)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-fluoro-N-{2-[2-(2-methoxyethyl)-4-methyl-3,6-diokso-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridin-5-yl]ethyl}benzamide;

5-[2-(4-benzylpiperazine-1-yl)-2-oxoethyl]-2-(2-chloro-4-terbisil)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

5-benzyl-4-methyl-2-(1-demerol-4-yl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-methyl-2-(2-methylpropyl")-5-(pyridin-3-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-methyl-2-(2-methylpropyl")-5-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

5-(2,5-dichlorobenzyl)-4-methyl-2-(2-methylpropyl")-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

5-(2,4-dichlorobenzyl)-4-methyl-2-(2-methylpropyl")-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

5-(2,3-dihydro-1H-indene-1-yl)-4-methyl-2-(methylpropyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-(3-chlorophenyl)-5-(2-morpholine-4-retil)-2-(2-phenylethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-benzyl-4-(3-chlorophenyl)-5-(2-methoxyethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

5-(4-Chlorobenzyl)-4-[(4-pertenece)methyl]-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-[(4-pertenece)methyl]-5-(2-methoxyethyl)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

5-(4-Chlorobenzyl)-4-(3-chlorophenyl)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-(3-chlorophenyl)-2-(2-morpholine-4-retil)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

5-(4-Chlorobenzyl)-4-(4-chlorophenyl)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-(4-chlorophenyl)-5-(4-methoxybenzyl)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-(4-chlorophenyl)-5-(3-methoxybenzyl)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-(4-chlorophenyl)-2,5-bis(2-methoxyethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

5-(4-Chlorobenzyl)-4-(4-chlorophenyl)-2-(2-methoxyethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-(4-chlorophenyl)-5-(2-methoxyethyl)-2-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-[(4-pertenece)methyl]-5-(4-methoxybenzyl)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-[(4-pertenece)methyl]-2-(2-morpholine-4-retil)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-(4-chlorophenyl)-5-(2-morpholine-4-retil)-2-(2-FeNi�ethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-(4-chlorophenyl)-5-(3-methoxybenzyl)-2-(2-methoxyethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-(4-chlorophenyl)-2-(2-methoxyethyl)-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-(4-chlorophenyl)-2-(2-methoxyethyl)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-(4-chlorophenyl)-5-(3-ethoxypropan)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

5-(2-methoxyethyl)-4-methyl-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-(4-chlorophenyl)-5-(2-methoxyethyl)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-(3,4-dichlorophenyl)-2-(2-methoxyethyl)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-(3,4-dichlorophenyl)-5-(2-methoxyethyl)-2-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-(4-chlorophenyl)-5-methyl-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

5-methyl-2-(2-morpholine-4-ileti)-4-(3-phenoxypropan)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

5-(2-methoxyethyl)-2-(2-morpholine-4-ileti)-4-(3-phenoxypropan)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-[(4-pertenece)methyl]-2-(2-methoxyethyl)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-[(4-chlorophenoxy)methyl]-5-(2-methoxyethyl)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-(4-chlorophenyl)-2-(2-methoxyethyl)-5-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-(4-chlorophenyl)-2-(2-morpholine-4-retil)-5-(pyridin-2-ilmet�l)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-[(4-pertenece)methyl]-5-(3-methoxybenzyl)-2-(2-methoxyethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-methyl-2-(2-morpholine-4-retil)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-(4-chlorophenyl)-5-methyl-2-(1-demerol-4-yl)-1H-pyrazolo [4,3-C]pyridine-3,6(2H,5H)-dione;

4-(4-chlorophenyl)-2-[2-(dimethylamino)ethyl]-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

5-(3-methoxybenzyl)-4-methyl-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2-(2-morpholine-4-ileti)-4-(3-phenoxypropan)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-(3-chlorophenyl)-5-(3-ethoxypropan)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-[(4-pertenece)methyl]-5-methyl-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-[(4-chlorophenoxy)methyl]-5-(3-ethoxypropan)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione

4-[(benzyloxy)methyl]-5-(3-methoxybenzyl)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-[(benzyloxy)methyl]-5-(3-ethoxypropan)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

5-(3-ethoxypropan)-4-[(4-pertenece)methyl]-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-[(4-chlorophenoxy)methyl]-2-(2-morpholine-4-retil)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,b(2H,5H)-dione;

4-(4-chlorophenyl)-2-(2-morpholine-4-retil)-5-(2-pyridin-2-retil)-1H-pyrazolo[4,3-C]p�ridin-3,6(2H,5H)-dione;

4-[(4-pertenece)methyl]-2-(2-morpholine-4-retil)-5-(2-pyridin-2-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

2,5-bis(2-methoxyethyl)-4-(3-phenoxypropan)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-[(4-chlorophenoxy)methyl]-5-(3-methoxybenzyl)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

4-(3,5-dichlorophenyl)-5-(2-methoxyethyl)-2-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

5-[(4-benzylmorphine-2-yl)methyl]-4-(4-chlorophenyl)-2-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

5-[(1-acetylpiperidine-4-yl)methyl]-4-(4-chlorophenyl)-2-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;

tert-butyl 4-{[4-(4-chlorophenyl)-2-methyl-3,6-diokso-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridin-5-yl]methyl}piperidine-1-carboxylate; and

4-(4-chlorophenyl)-2-methyl-5-[(5-oxopyrrolidin-3-yl)methyl]-1H-pyrazolo[4,3-C] pyridine-3,6(2H,5H)-dione.

In another embodiment, the present invention provides a method of treatment of a patient suffering from a disease or condition selected from cardiovascular disorders, respiratory disorders, metabolic disorders, skin disorders, bone disorders, neuro-inflammatory and/or neurodegenerative disorders, kidney diseases, disorders of the reproductive system, diseases affecting the eye and/or the lens and/or conditions affecting the inner ear, inflammatory disorders, liver diseases, pain, different types of cancer, allergiesthere, injuries, septic, hemorrhagic and anaphylactic shock, disorders of the gastrointestinal tract, angiogenesis, angiogenesis-dependent conditions and other diseases and disorders associated with (NADPH-oxidase). The method includes introducing the compound of formula (I) to a patient in need.

In another embodiment, the present invention provides a method of inhibiting angiogenesis in a patient who needs it, where the method includes introduction of inhibiting angiogenesis dose of a compound of formula (I) to a patient in need.

In another embodiment, the present invention provides a method of inhibiting tumor neovascularization by inhibiting tumor angiogenesis according to the present methods. Similarly, the present invention provides a method of inhibiting tumor growth by applying the angiogenesis-inhibiting ways.

In a particular embodiment, the compounds and methods of the present invention are intended for use in the treatment of tumour tissue in a patient with a tumor, a solid tumor, metastases, cancer, melanoma, skin cancer, breast cancer, a hemangioma or angiofibroma and the like types of cancer, and inhibition of angiogenesis in neoplastic tissues, where there is neovascularization of a tumor tissue of a Typical fabric with solid tumors, which are susceptible to treatment by the compounds and methods of the present invention include, but are not limited to, skin tumors, melanoma, tumors of the lung, pancreas, breast, colon, laryngeal, ovarian, prostate, colorectal tumors, tumors of head, neck, testes, lymphoid tissue, bone marrow, bone, sarcoma, tumors of the kidneys, sweat glands and similar fabrics. Other examples of cancers that are affected by treatment, are of glioblastoma.

In another specific embodiment, the compounds and methods of the present invention are intended for use in the treatment of the inflamed tissue and the angiogenesis to inhibit angiogenesis in the inflamed tissue, where there is neovascularization of inflamed tissue. In this case, the compound and method according to the present invention designed for the inhibition of angiogenesis in arthritis tissue, such as in a patient with chronic articular rheumatism, in the inflamed tissues in immune or non-immune inflammation in tissues affected by psoriasis, and the like.

In embodiments of the present invention is intended for inhibiting angiogenesis in the tissue. The degree of angiogenesis in the tissue and, thus, the degree of inhibition achieved by the methods of the present invention can be evaluated by many methods, such to�to described here.

In another embodiment, the present invention provides a pharmaceutical composition comprising at least one pyrazolopyrimidine derivative of formula (I) and its pharmaceutically acceptable carrier, solvent or excipient.

Compounds of the present invention were named according to IUPAC standards used in the program ACD/Name product version 10.01).

Compounds according to the present invention include compound of formula (I), its tautomers, its geometrical isomers, its optically active forms as enantiomers, diastereomers and its racemate forms, and their pharmaceutically acceptable salts. In the present invention as examples of derivatives can be obtained from readily available starting materials with the use of the following standard methods and procedures. You should note that where are typical or preferred experimental conditions (i.e., temperature of reaction, time, moles of reagents, solvents, etc.), can also be used and other experimental conditions, unless expressly agreed. Optimum reaction conditions may vary in the case of the particular reactants or solvents used, but such conditions can be determined by an expert in the field of technology with the use of routine with�osobov optimization.

In the present invention references are incorporated by reference in its entirety. The present invention is not limited to the specific embodiments described here, since they are intended only to illustrate individual aspects of the present invention, therefore, functionally equivalent methods and components are within the present invention. Indeed, various modifications of the present invention in addition to those here shown and described will be apparent to those skilled in the art from the following description and the accompanying figures and Diagrams. Such modifications are within the appended claims,

The present invention already described, the following examples are intended to illustrate and not limit the scope of the present invention.

The synthesis of compounds of the present invention:

New derivatives of formula (I) can be obtained from readily available starting materials using conventional techniques and procedures. You need to understand that where are typical or preferred experimental conditions (i.e., temperature of reaction, time, moles of reagents, solvents, etc.), can also be used and other experimental conditions, unless expressly agreed. About�optimal reaction conditions may vary in the case of the use of specific reagents or solvents, but such conditions can be determined by a person skilled in the technical field with use of routine optimization methods.

A General approach to the synthesis for the preparation of compounds of formula (I) shown in the Diagram below, 1.

Scheme 1

Pyrazolopyrimidinone derivatives of formula (I) in which the substituents G1, G2, G3, G4and G5are as defined above, can be obtained in three chemical stages from custom made or commercially available substituted hydrazine derivatives of the formula (VI) derivatives of aceondeckmusic of formula (V), primary amine derivatives of formula (II) and derivatives trialkylamine of formula (III) according to the Protocol of the synthesis shown above in Scheme 1. More. a concrete method hydrazine derivative of formula (VI) in which G2is such as defined above, is reacted with a derivative of aceondeckmusic of formula (V), where G5and R3are as defined above, in a neutral environment and under reflux in a suitable solvent, such as benzene, toluene or other inert solvents, in the course of time, which depends on its own reactivity of compounds of the formula (VI), to obtain the corresponding 4-substituted derivatives of 2-hydroxypyrazolo of formula (IV). Intermediate�intramural compounds of formula (IV) is further reacted with the derivatives of trialkylamine of formula (III), in which G3and R4are as defined above, in the presence of acetic acid and a reflux condenser, with the formation of the intermediate of formula (VII). Intermediate compounds of formula (VII) is further processed primary amine derivatives of formula (II) in which G4is such as defined above, in solvents such as toluene or benzene under reflux, to obtain the intermediate compounds of formula (VIII). Derivatives of pyrazole of the formula (Ia), i.e. of formula (I) in which G1represents N, are allocated after cyclization of the intermediate compounds of formula (VIII), preferably in proton solvents in the presence of base, such as methanolate sodium, isopropanolate sodium or the like, using standard conditions with a reflux condenser, well known to those skilled in the art, as shown in figure 1.

This reaction can be carried out in solvents such as methanol, ethanol, isopropanol, or other inert solvents, at room temperature for a period of time, which depends on its own reactivity of compounds of the formula (VIII), but usually the reaction requires traditional heating methods or using microwave technology, using standard conditions well known to those skilled in the art, as �provided above in Scheme 1. At the next stage pyrazolopyrimidinone derivatives of the formula (Ia) were treated with alkylating agent such as alkylchloride, bromides, iodides or mesylate, where G1is such as defined above, in the presence of a suitable base, e.g. triethylamine, sodium hydride or potassium carbonate as a base in a suitable solvent, e.g. N,N-dimethylformamide or tetrahydrofuran, using conventional heating or using microwave technology. Alternative to this, pyrazolopyrimidinone derivatives of the formula (Ia) were treated with anhydrides, acylchlorides or carboxylic acids in the presence of binders, where G1is such as defined above, in the presence of a suitable base, such as triethylamine, sodium acetate in a suitable solvent, e.g. N,N-dimethylformamide or tetrahydrofuran, dichloromethane, using conventional heating or using microwave technology. After that pyrazolopyrimidinone derivatives of the formula (Ib) are allocated using standard conditions well known to those skilled in the art, as shown in figure 1.

Scheme 2

Pyrazolopyrimidinone derivatives of formula (I) in which the substituents G1, G2, G3, G4and G5�are such, as defined above, can be obtained in four or five chemical stages from custom made or commercially available substituted hydrazine derivatives of the formula (VI) derivatives of aceondeckmusic of formula (V), primary amine derivatives of formula (II) and derivatives acylchlorides of formula (IX) according to the Protocol of the synthesis shown above in Scheme 2. In a more specific method, a hydrazine derivative of formula (VI) in which G2is such as defined above, is reacted with a derivative of aceondeckmusic of formula (V), where G5and R8are as defined above, in a neutral environment and under reflux in a suitable solvent, such as benzene, toluene or other inert solvents, in the course of time, which depends on its own reactivity of compounds of the formula (VI), to obtain the corresponding 4-substituted derivatives of 2-hydroxypyrazolo of formula (IV). Intermediate compounds of formula (IV) is further reacted with the derivatives of acylchlorides of formula (IX) in which G3is such as defined above, in the presence of calcium hydroxide with a reflux condenser and with the formation of the intermediate of formula (X). Intermediate compounds of formula (X) is further processed primary amine derivatives of formula (II) in which G4is such as defined above, in a solvent�spruce such as toluene or benzene, under reflux, to obtain the intermediate compounds of formula (VIII). Derivatives of pyrazole of the formula (Ia), i.e. of formula (I) in which G1represents N, are allocated after cyclization of the intermediate compounds of formula (VIII), preferably in proton solvents in the presence of base, such as methanolate sodium, isopropanolate sodium or the like, using standard conditions with a reflux condenser, well known to those skilled in the art, as shown in figure 2.

At the next stage pyrazolopyrimidinone derivatives of the formula (Ia) were treated with alkylating agent such as alkylchloride, bromides, iodides or mesylate, where G1is such as defined above, in the presence of a suitable base, e.g. triethylamine, sodium hydride or potassium carbonate as a base in a suitable solvent, for example N,N-dimethylformamide or tetrahydrofuran, using conventional heating or using microwave technology. Alternative to this pyrazolopyrimidinone derivatives of the formula (Ia) were treated with anhydrides, acylchlorides or carboxylic acids in the presence of binding agents, where G1is such as defined above, in the presence of a suitable base, such as triethylamine, sodium acetate � a suitable solvent, for example N,N-dimethylformamide or tetrahydrofuran, dichloromethane, using conventional heating or using microwave technology. After that pyrazolopyrimidinone derivatives of the formula (Ib) are allocated using standard conditions well known to those skilled in the art, as shown above in Scheme 2.

These reactions can be carried out in solvents such as methanol, ethanol, isopropanol, or other inert solvents, at room temperature for a period of time, which depends on its own reactivity of compounds of the formula (VIII), but usually the reaction requires traditional heating methods or using microwave technology, using standard conditions well known to those skilled in the art, as shown above in Schemes 1 or 2.

The following definitions were used the following abbreviations:

Å (Angstrom), Ac2O (Acetic anhydride), EQ. (equivalent), min (minute) h (hour), g (grams), MHz (Megahertz), ml (milliliter), mm (millimeter), mmol (millimole), mm (millimolar), ng (nanogram), nm (nanometer), rt (room temperature), BLM (Bleomycin), BSA (Bovine serum albumin), DCF (2,7-DICHLORODIFLUOROMETHANE), DCM (dichloro methane), DIPEA (di-isopropylaniline), DMSO (Dimethylsulfoxide), DMF (N,N-Dimethylformamide), DAPI (4,6-Di�midino-2-phenylindole), DPI (Diphenyliodonium), they fixed (Cyclohexane), EDTA (ethylenediaminetetraacetic acid), EGF (Epidermal growth factor), EtOAc (ethyl Acetate), FC (Flash chromatography on silica gel), HBSS (Buffered salt solution Hanks), HPLC (high performance liquid chromatography), HiDCF-DA (2',7'-DICHLORODIFLUOROMETHANE), MEM (2-methoxyethoxymethyl), MS (Macc spectrometry), NADPH (Nicotinamide-dinucleotide, reduced form), NBT (Nitroblue tetrazolium), NMR (Nuclear magnetic resonance), PBS (Phosphate buffer saline), PetEther (Petroleum ether), TEA (Triethylamine), TFA (Trifluoroacetic acid), TGF-p (Factor of growth of tumors beta), THF (Tetrahydrofuran), tBuOK (Treat-butoxide potassium), ROS (reactive oxygen species), SOD (superoxide Dismutase), SPA (Scintillation analysis of convergence). TLC (Thin layer chromatography), UV (Ultraviolet).

If the above set of General methods for the synthesis is not suitable for obtaining compounds of formula (I) and/or necessary intermediates for the synthesis of compounds of formula (I), can be used appropriate methods for their production, are known to those skilled in the art. Typically, the synthesis pathway of any individual compound of formula (I) will depend on the specific substituents of each molecule and the availability of the necessary intermediates, again these factors are quite underst�NY specialist average level of skill in the art. For exploring all the ways of protecting groups and removal of protection, see Philip J. Kocienski, in the book "Protecting Groups", Georg Thieme Verlag Stuttgart, 2005 and Theodora W. Greene and Peter G. M. Wuts in the book "Protective Groups in Organic Synthesis", Wiley Interscience, 4thEdition 2006.

Compounds of the present invention can be isolated in the form of aggregates with solvent molecules by crystallization by evaporation of a suitable solvent. Pharmaceutically acceptable acid-additive salts of compounds of formula (I) which contain a basic center, may be obtained in the usual way. For example, a solution of the free base may be treated with a suitable acid, either in pure form or in a suitable solution, and the resulting salt can be isolated either by filtration or by evaporation of the reaction solvent under vacuum. Pharmaceutically acceptable basic additive salts can be obtained in a similar manner by treatment of a solution of a compound of formula (I) with a suitable base. Both types of salts may be derived or transformed into each other with techniques of ion-exchange resins.

Hereinafter the present invention will be illustrated with some examples, which should not be construed as limiting the scope of the present invention.

The data of HPLC, NMR and MS, are presented in the Examples described below were obtained following about�time: HPLC: column Waters Symmetry C8 50×4.6 mm, Conditions: MeCN/H2O, from 5 to 100% (8 min), registration of absorption at 230-400 nm; Mass spectra: PE-SCIEX API 150 EX (APCI and ESI), LC/MS spectra: Waters ZMD (ES);1H-NMR: Bruker DPX-300 MHz.

Purification using preparative HPLC was performed with HPLC Waters Prep LC 4000 System equipped with columns Prep Nova-Pak®HR 186 µm, 60A, 40×30 mm (up to 100 mg) or Chagga® Prep MS C8, 10 μm, 50×300 mm (up to 1 g). All cleaning was performed with a gradient elution MeCN/H2O and 0.09% TFA; UV registration at 254 nm and 220 nm; flow rate 20 ml/min (up to 50 mg). TLC analysis was performed on the plates Merck Precoated 60 F254. The purification using flash chromatography was carried out on the substrate SiO2using as allentow mixture cyclohexane/EtOAc or DCM/MeOH.

Example 1. Obtaining 2-benzyl-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C] pyridine-3,6(2H,5H)-dione (1) (Compound Ia, Scheme 1)

a) methyl(1-benzyl-5-hydroxy-1H-pyrazol-3-yl)acetate (Compound of formula (IV), Scheme 1).

To a suspension of benzylaminopurine (1,000 g, 5,126 mmol, 1 equivalent) in anhydrous toluene (25 ml) were added sequentially diisopropylethylamine (1,32 ml, 10,252 mmol, 2 equivalent) and dimethyl-3-oxopentanoate (0,893 g, 5,126 mmol, 1 equivalent). The resulting mixture was heated under reflux for 18 h before concentrated under vacuum. The obtained brown oil was purified by flash chromatography over SiO2(H 2Cl2:MeOH, 97:3). Received 0.810 g of pure methyl-(1-benzyl-5-hydroxy-1H-pyrazol-3-yl)acetate in the form of white solids. The yield was 64%. MS(ESI+): 247,1; MS(ESI-): 245,1.

b) methyl[(4E)-1-benzyl-4-(1-amoxicililin)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl] acetate (Compound of formula (VII), Scheme 1).

A mixture of the above methyl-(1-benzyl-5-hydroxy-1H-pyrazol-3-yl)acetate (Compound of formula (IV), 0,215 g, 0,873 mmol, 1 equiv), glacial acetic acid (5 μl, 0.1 equivalent) and Mo(OEt)3(5.5 ml, 5,48 mmol, 6.3 equivalent) was heated at 75°C for 1 hour and 15 min. the Obtained orange solution was concentrated under vacuum to obtain an orange syrup, which was washed with cyclohexane and then dried under vacuum. Due to its relative instability further purification of methyl[(4E)-1-benzyl-4-(1-amoxicililin)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]acetate was conducted (0,276 g, quantitative yield). MS(ESI+):317,1.

C) methyl[(4E)-1-benzyl-5-oxo-4-{1-[(pyridin-2-ylmethyl)amino]ethyliden}-4,5-dihydro-1H-pyrazol-3-yl]acetate (Compound of formula (VIII), Scheme 1).

The mixture obtained above methyl[(4E)-1-benzyl-4-(1-amoxicililin)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]acetate (Compound of formula (VII), 0,276 g, 0,873 mmol, 1 equivalent) and 1-pyridin-2-ylmethanone (0,061 ml, 0,873 mmol, 1 equivalent) was stirred at room temperature in t�luole (8.0 ml) for 15 min. The solvent was removed under vacuum. The resulting precipitate was dissolved in minimum amount of CH2Cl2and was added dropwise to a stirred solution of 150 ml of cyclohexane, resulting pale yellow precipitate, which was filtered. It was found that this residue represents the pure methyl[(4E)-1-benzyl-5-oxo-4-{1-[(pyridin-2-ylmethyl)amino]ethyliden}-4,5-dihydro-1H-pyrazol-3-yl]acetate (0,278 g). The yield was 84%. MS(ESI+): 379,2.

g), 2-benzyl-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (Compound of formula (Ia), Scheme 1)

A solution of i-PrONa in isopropanol, obtained by dissolving of sodium (0,017 g of 0.713 mmol, 1 equivalent) in i-PrOH (16 ml) was treated with methyl[(4E)-1-benzyl-5-oxo-4-{1-[(pyridin-2-ylmethyl)amino]ethyliden}-4,5-dihydro-1H-pyrazol-3-yl]acetate

(Compound of formula (VIII) (0,270 g, of 0.713 mmol, 1 equivalent). The reaction mixture was maintained under reflux for 1 h, then was cooled and neutralized to pH 7 by the addition of 0.12 ml of 20% aqueous solution of HCl. Under vacuum was removed 15 ml of i-PrOH was added 10 ml of N2Oh, and then the flask was placed overnight in a refrigerator. The resulting white precipitate was filtered, washed with water (2×3 ml), then with cyclohexane and dried under vacuum. Received 0,240 g of pure product 2-benzyl-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-36(2H,5H)-dione. The yield was 97%.1H NMR (500 MHz, DMSO-d6, ppm) 2,78 (s, 3H), to 4.81 (s, 2H), levels lower than the 5.37 (s, 2H), 5,59 (s, 1H), 7,31-7,26 (m, 5H), of 7.36 (m, 2H), 7,76 (td, 77,6, a 1.9 Hz, 1H), is 8.46 (dt, J4,2, 1.6 Hz, 1H), of 10.34 (s, 1H); MS (ESI+)=347,2.

Example 2. Obtaining 2-(4-Chlorobenzyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (2) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in example 1 on the basis of (4-Chlorobenzyl)hydrazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 1-pyridin-2-ylmethanone, the title compound (2) was isolated in a solid beige color with a yield of 48% (purity 99% according to HPLC). MS(ESI+): 381,5; MS(ESI-): 379,8.

Example 3. Obtaining 2-benzyl-4-methyl-5-[3-(triptoreline)phenyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (3) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in example 1 on the basis of benzylamine, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 3-(triptoreline)aniline, the title compound (3) was isolated as a solid substance of white color with a yield of 43% (purity of 98% according to HPLC). MS(ESI+): to $ 416.5; MS(ESI-): 414,5.

Example 4. Obtaining 2,4-dimethyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C] pyridine-3,6(2H,5H)-dione (4) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in the example , based on methylhydrazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 1-pyridin-2-ylmethanone, the title compound (4) was allocated in the form of a solid beige color with a yield of 35% (purity 99% according to HPLC). MS(ESI+): 271,3; MS(ESI-): EUR 269.5.

Example 5. Obtaining 2,4,5-trimethyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (5) (Compound 1A, Scheme 1)

According to the General methods of synthesis, as shown in example 1, based on methylhydrazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and methylamine, the title compound (5) was isolated in a solid beige color with a yield of 40% (purity 97% according to HPLC). MS(ESI+): 194,3; MS(ESI-): 192,5.

Example 6. Getting 5-(furan-2-ylmethyl)-2,4-dimethyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (6) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in example 1, based on methylhydrazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 1-furan-2-ylmethanone, the title compound (b) was allocated in the form of a solid beige color with a yield of 38% (purity of 98% according to HPLC). MS(ESI+): 260,4; MS(ESI-) : 258,3.

Example 7. Getting 5-(4-Chlorobenzyl)-2,4-dimethyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (7) (Compound Ia, Scheme 1)

According to the General methods of synthesis as in example 1 based on methylhydrazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and para-chlorobenzylamino, the title compound (7) was isolated in a solid beige color with a yield of 45% (purity 97% according to HPLC). MS (ESI+): 304,8; MS(ESI-): 302,7.

Example 8: Obtain 4-butyl-5-(4-chlorbenzyl)-2-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (8) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in Example 1, based on methylhydrazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxypropane and para-chlorobenzylamino, the title compound (8) was isolated in a solid beige color with a yield of 49% (purity of 98% according to HPLC). MS (ESI+): 346,8; MS(ESI-): 344,6.

Example 9. Getting 4-butyl-2-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C] pyridine-3,6(2H,5H)-dione (9) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in example 1, based on methylhydrazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxypropane and 1-pyridin-2-ylmethanone, the title compound (9) was isolated in a solid beige color with a yield of 48% (purity 96% according to HPLC). MS(ESI+): 313,5; MS(ESI-): 311.4,

Example 10. Getting 5-(4-Chlorobenzyl)-4-methyl-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (10) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in example 1 on the basis of 4-(2-hidradenitis)morpholine, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and para-chlorobenzylamino, the title compound (10) was allocated in the form of a solid substance of white color with a yield of 33% (purity 95% according to HPLC). MS(ESI+): 403,9; MS(ESI-): 401,8.

Example 11. Obtaining 2-benzyl-4-butyl-5-(3,5-dimethoxybenzyl)-1H-pyrazolo[4,3-C] pyridine-3,6(2H,5H)-dione (11) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in example 1, based on benzylpiperazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxypropane and 4.5-dimethoxyphenethylamine, the title compound (11) was isolated in a solid beige color with a yield of 31% (purity 99% according to HPLC). MS(ESI+): 448,5; MS(ESI-): 446,5.

Example 12. Obtaining 2-benzyl-4-butyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C] pyridine-3,6(2H,5H)-dione (12) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in example 1, based on benzylpiperazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxypropane and 1-pyridin-2-ylmethanone, the title compound (12) was isolated as a solid substance of white color with a yield of 38% (purity of 98% according to HPLC). MS(ESI+): 389,5; MS(ESI-): 387,6.

Example 13. Getting 2-cyclohexyl-4-methyl-5-[2-(morpholine-4-�lmutil)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (13) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in example 1, based on cyclohexylpiperazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 1-[2-(morpholine-4-ylmethyl)phenyl]methanamine, the title compound (13) was isolated in a solid beige color with a yield of 31% (purity 99% according to HPLC). MS(ESI+): 437,6; MS(ESI-): 435,6.

Example 14. Obtaining 2,4-dimethyl-5-(2-pyridin-2-retil)-1H-pyrazolo[4,3-C] pyridine-3,6(2H,5H)-dione (14) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in example 1, based on methylhydrazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 2-pyridin-2-retinamide, the title compound (14) was isolated in a solid yellow color with a yield of 43% (purity 96% according to HPLC). MS(ESI+): 285,3; MS(ESI-): 283,5.

Example 15. Obtaining 2-(2-methoxyethyl)-4-methyl-5-(2-pyridin-2-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione (15) (Compound Ia, Scheme 1)

According to the General methods of synthesis, as shown in example 1, based on (2-methoxyethyl)hydrazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 2-pyridin-2-retinamide, the title compound (15) was isolated in a solid beige color with a yield of 47% (purity 99% according to HPLC). MS(ESI+): 329,5; MS(ESI-): 327,4.

According to the General methods of synthesis, as shown in example 1, based on methylhydrazine, dimethyl-3-oxopentanoate, 1,1,1-triethoxysilane and 2-morpholine-4-retinamide, the title compound (16) was isolated as a solid substance of white color with a yield of 43% (purity 99% according to HPLC). MS(ESI+): 293,4; MS(ESI-): 291,3.

Example 17. 2-benzyl-4-(3-methoxybenzyl)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C] pyridine-3,6(2H,5H)-dione (21) (Compound 1A, Scheme 2)

a) methyl(1-benzyl-5-hydroxy-1H-pyrazol-3-yl)acetate (Compound of formula (IV), Scheme 2).

To a suspension of benzylaminopurine (1,000 g, 5,126 mmol, 1 equivalent) in anhydrous toluene (25 ml) were added sequentially diisopropylethylamine (1,32 ml, 10,252 mmol, 2 equivalent) and dimethyl-3-oxopentanoate (0,893 g, 5,126 mmol, 1 equivalent). The resulting mixture was heated under reflux for 18 h before concentrating under vacuum. The obtained brown oil was purified by flash chromatography over SiO2(CH2Cl2:MeOH, 97:3). Received 0.810 g of pure methyl-(1-benzyl-5-hydroxy-1H-pyrazol-3-yl)acetate in the form of white solids. The yield was 64%. MS(ESI+): 247,1;MS(ESI -): 245,1.

b) methyl{1-benzyl-4-[(3-methoxyphenyl)acetyl]-5-oxo-4,5-dihydro-1H-pyrazol-3-yl} acetate (Compound of formula (X), Scheme 2).

The mixture obtained above methyl(1-benzyl-5-hydroxy-1H-pyrazol-3-yl)acetate (Compound of formula (IV), 1 g, 3,76 mmol, 1 equivalent) and CA(Oh)2(2,78 g, 10 equivalents) was suspended in dioxane (30 ml). To the suspension in an atmosphere of nitrogen was added (3-methoxyphenyl)acetyl chloride (0,761 g, 1.1 equivalent). Thereafter, the mixture was heated at 100°C for 45-60 minutes. The obtained red solution was concentrated under vacuum to obtain a red syrup, which was distributed between ethyl acetate and cold 0.1 M HCl. The organic phase was washed with brine and dried over Na2SO4. After evaporation of the solvent there was obtained methyl {1-benzyl-4-[(3-methoxyphenyl)acetyl]-5-oxo-4,5-dihydro-1H-pyrazol-3-yl} acetate pink (1,09 g). The yield was 70%, purity 89% according to HPLC. MS(ESI+): 395,2; MS(ESI-): 393,2.

C) methyl[(4Z)-1-benzyl-4-{2-(3-methoxyphenyl)-1-[(pyridin-2-ylmethyl)amino]ethyliden}-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]acetate (Compound of formula (VIII), Scheme 2).

The mixture obtained above methyl{1-benzyl-4-[(3-methoxyphenyl)acetyl]-5-oxo-4,5-dihydro-1H-pyrazol-3-yl}acetate (Compound of formula (X), 394 mg, 1 equivalent), 1-pyridin-2-ylmethanone�a (119 mg, 1.1 equivalent) and Acoh (60 mg, 1 equivalent) was stirred at 80°C in a nitrogen atmosphere in a mixture of toluene/HMP(10/1)(10 ml) for 2 hours. The solvent was removed under vacuum. The obtained residue was distributed between ethyl acetate and saturated solution of NaHCO3. The organic phase was washed with brine and then was dried over Na2SO4. After evaporation of the solvent was obtained pure methyl[(4)-1-benzyl-4-{2-(3-methoxyphenyl)-1-[(pyridin-2-ylmethyl)amino]-ethyliden}-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]acetate (160 mg). The yield was 33%, which was used in next step without further purification.

g), 2-benzyl-4-(3-methoxybenzyl)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6 (2H,5H)-dione (Compound of formula (Ia), Scheme 2)

The above methyl[(4Z)-1-benzyl-4-{2-(3-methoxyphenyl)-1-[(pyridin-2-yl methyl)amino]ethyliden}-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]acetate (Compound of formula (VIII)) was treated with freshly prepared MeONa in MeOH (2 M, 20 ml). The solution was stirred at room temperature until the disappearance of the original enamine (t=0.5-2 hrs). The reaction mixture was concentrated under vacuum to remove MeOH, and the crude product was dissolved in ethyl acetate (80 ml) and preextraction water (30 ml×3). The combined organic layer was acidified to pH=6, preextraction ethyl acetate (30 ml×3), dried over Na2SO4and PTS�puppy by TLC to obtain the final product 2-benzyl-4-(3-methoxybenzyl)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione in the form of a yellow oil (65 mg, the yield was 43%).1H-NMR (400MHz, DMSO-d6): 3,635 (s, 3H); 4,702 (s, 2H); 4,860 (s, 2H); 5,274 (s, 2H), UAH 5,696 (s, 1H); 6,646-6,716 (m, 3H), 7,104-7,144 (m, 2H); 7,277-7,416 (m, 6H); 7,823-7,859 (t, 1H); 8,492-8,501 (d, 1H), MS(ESr): 453,2; MS(ESI): 451,2.

Structures of other compounds that were synthesized are shown in table 1 below.

MS(ESI+): 357,6
Table 1
ConnectionStructureNameDataMethod
175-(2-methoxyethyl)-4-methyl-2-(2-phenylethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 328,5Example 1, Scheme 1
182-(2-methoxyethyl)-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]Pyridine-3,6(2H,5H)-dioneMS(ESI+): 413,7Example 1, Scheme 1
19N-{3-[2-(2-methoxyethyl)-4-methyl-3,6-diokso-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridin-5-yl]phenyl}acetamideExample 1, Scheme 1
202-(2-methoxyethyl)-4-methyl-5-(2-morpholine-4-yl-2-oxoethyl)-1H-pyrazolo 4,3-C]pyridine-3,b(2H,5H)-dioneMS(ESf); 351,4Example 1, Scheme 1
212-benzyl-4-(3-methoxybenzyl)-5-(pyridin-2-yl methyl)-1H-pyrazolo[4,3-C] pyridine-3,6(2H,5H)-dioneMS(ESI+): 453,6Example 17, Scheme
222-benzyl-4-(3-methoxybenzyl)-5-(2-methoxyethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 420,5Example 17,Scheme
232-(2,5-dichlorobenzyl)-5-(2-methoxyethyl)-4-methyl-1H-pyrazolo[4,3-C] pyridine-3,6(2H,5H)-dioneMS(ESI+): 383,4Example 1, Scheme 1
242-[2-(4-chlorphenoxy)e�yl]-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione MS(ESI+): 411,9Example 1, Scheme 1

td align="center"> N-[3-(2-benzyl-4-methyl-3,6-diokso-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridin-5-yl)phenyl]acetamide
ConnectionStructureNameDataMethod
252-(2,5-dichlorobenzyl)-4-methyl-5-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 438,9Example 1, Scheme 1
262-(2,5-dichlorobenzyl)-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 514,6Example 1, Scheme 1
275-(3,5-dimethoxybenzyl)-2-(2-methoxyethyl)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 374,6Example 1, Scheme 1
28N-(3-{[4-methyl-3,6-diokso-2-2-phenylethyl)-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridin-5-yl]methyl}phenyl)acetamide MS(ESI+):417,5Example 1, Scheme 1
294-methyl-5-(2-morpholine-4-retil)-2-(2-phenylethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 383,5Example 1, Scheme 1
304-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-2-(2-phenylethyl)-1H-pyrazolo[4,3-C]pyridine-3,b(2H,5H)-dioneMS(ESI+): 459,7Example 1, Scheme 1
312-(2-methoxyethyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,b(2H,5H)-dioneMS(ESI+):315,3Example 1, Scheme 1
32N-[2-(2-benzyl-4-methyl-3,6-diokso-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridin-5-yl)ethyl]-4-perbenzoicMS(ESI+): 421,4Example 1, Scheme 1
33MS(ESI+): 389,5Example 1, Scheme 1
34N-(3-{[2-(2-chloro-4-terbisil)-4-methyl-3,6-diokso-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridin-5-yl] methyl}phenyl)acetamideMS(ESI+): 456,0Example 1, Scheme 1
355-[2-(4-benzylpiperazine-1-yl)-2-oxoethyl]-2-(2-methoxy ethyl)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 440,6Example 1, Scheme 1

ConnectionStructureNameDataMethod
362-(2,5-dichlorobenzyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 416,4Example 1, Scheme 1
372-(2-chloro-4-terbisil)-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 498,0Example 1, Scheme 1
382-(2,5-dichlorobenzyl)-4-methyl-5-(2-morpholine-4-yl-2-oxoethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 452,9Example 1, Scheme 1
394-methyl-2-(2-phenylethyl)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 361,4Example 1, Scheme 1
402-(2-chloro-4-terbisil)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 400,1Example 1, Scheme 1
414-fluoro-N-{2-[2-(2-methoxyethyl)-4-methyl-3,6-diokso-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridin-5-yl]�Teal}benzamide MS(ESI+): 389,5Example 1, Scheme 1
425-[2-(4-benzylpiperazine-1-yl)-2-oxoethyl]-2-(2-chloro-4-terbisil)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): RUB 525.1Example 1, Scheme 1
435-benzyl-4-methyl-2-(1-demerol-4-yl)-1H-pyrazolo[4,3-C]pyridine-3,b(2H,5H)-dioneMS(ESI+): 353,5Example 1, Scheme 1
444-methyl-2-(2-methylpropyl")-5-(pyridin-3-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+):313,5Example 1, Scheme 1
454-methyl-2-(2-methylpropyl")-5-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 335,6Example 1, Scheme 1

Compounds�s StructureNameDataMethod
465-(2,5-dichlorobenzyl)-4-methyl-2-(2-methylpropyl")-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 381,3Example 1, Scheme 1
475-(2,4-dichlorobenzyl)-4-methyl-2-(2-methylpropyl")-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 381,3Example 1, Scheme 1
485-(2,3-dihydro-1H-indene-1-yl)-4-methyl-2-(2-methylpropyl")-1H-pyrazolo[4,3-C pyridine-3,6(2H,5H)-dioneMS(ESI+): 338,5Example 1, Scheme 1
494-(3-chlorophenyl)-5-(2-morpholine-4-retil)-2-(2-phenylethyl)-1H-pyrazolo[4,3-C]Pyridine-3,6(2H,5H)-dioneMS(ESI+): of 480.2Example 17, Scheme
50 2-benzyl-4-(3-chlorophenyl)-5-(2-methoxyethyl)-1H-pyrazolo[4,3-C pyridine-3,6(2H,5H)-dioneMS(ESI+): 411,1Example 17, Scheme
515-(4-Chlorobenzyl)-4-[(4-pertenece)methyl]-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESf): 514,2Example 17, Scheme
524-[(4-pertenece)methyl]-5-(2-methoxyethyl)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 447,6Example 17, Scheme
535-(4-Chlorobenzyl)-4-(3-chlorophenyl)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,b(2H,5H)-dioneMS(ESI+): 500,8Example 17, Scheme

ConnectionStructureNameData�]
544-(3-chlorophenyl)-2-(2-morpholine-4-retil)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): RUB 467.2Example 17, Scheme 2
555-(4-Chlorobenzyl)-4-(4-chlorophenyl)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,b(2H,5H)-dioneMS(ESI+): 500,7Example 17, Scheme 2
564-(4-chlorophenyl)-5-(4-methoxybenzyl)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 496,1Example 17, Scheme
574-(4-chlorophenyl)-5-(3-methoxybenzyl)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 496,2Example 17, Scheme 2
584-(4-chlorophenyl)-2,5-bis(2-methoxyethyl)-1H-Pyra�olo[4,3-C]pyridine-3,6(2H,5H)-dione MS(ESI+): to 378.9Example 17, Scheme 2
595-(4-Chlorobenzyl)-4-(4-chlorophenyl)-2-(2-methoxy ethyl)-1H-pyrazolo[4,3-C] pyridine-3,6(2H,5H)-dioneMS(ESI+): 445,8Example 17, Scheme 2
604-(4-chlorophenyl)-5-(2-methoxyethyl)-2-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 334,9Example 17, Scheme 2
614-[(4-pertenece)methyl]-5-(4-methoxybenzyl)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 509,7Example 17, Scheme 2

ConnectionStructureNameDataMethod
624-[(4-pertenece)methyl�]-2-(2-morpholine-4-retil)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pidin-3,6(2H,5H)-dione MS(ESI+): 480,6Example 17, Scheme 2
634-(4-chlorophenyl)-5-(2-morpholine-4-retil)-2-(2-phenylethyl)-1H-pyrazolo[4,3-C]predin-3,6(2H,5H)-dioneMS(ESI+): 480,1Example 17, Scheme 2
644-(4-chlorophenyl)-5-(3-methoxybenzyl)-2-(2-methoxyethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 441,1Example 17, Scheme 2
654-(4-chlorophenyl)-2-(2-methoxyethyl)-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]predin-3,6(2H,5H)-dioneMS(ESI+):510,2Example 17, Scheme 2
664-(4-chlorophenyl)-2-(2-methoxyethyl)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]predin-3,6(2H,5H)-dioneMS(ESI+): 411,9Example 17, Scheme 2
67 4-(4-chlorophenyl)-5-(3-ethoxypropan)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+)462,0Example 17, Scheme 2
685-(2-methoxyethyl)-4-methyl-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C] pyridine-3,6(2H,5H)-dioneMS(ESI+):337,5Example 1, Scheme 1
694-(4-chlorophenyl)-5-(2-methoxyethyl)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]predin-3,6(2H,5H)-dioneMS(ESI+): 433,9Example 17, Scheme

ConnectionStructureNameDataMethod
704-(3,4-dichlorophenyl)-2-(2-methoxyethyl)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 446,4Example 17, Scheme 2
714-(3,4-dichlorophenyl)-5-(2-methoxyethyl)-2-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 369,7Example 17, Scheme 2
724-(4-chlorophenyl)-5-methyl-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,b(2H,5H)-dioneMS(ESI+): 390,1Example 17, Scheme 2
735 meters-2-(2-morpholine-4-ileti)-4-(3-phenoxy-propyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): to 413.5Example 17, Scheme 2
745-(2-methoxyethyl)-2-(2-morpholine-4-ileti)-4-(3-phenoxypropan)-1H-pyrazolo[4,3-C]Pyridine-3,6(2H,5H)-dioneMS(ESr): 457,6Example 17, Scheme 2
754-[(4-pertenece)methyl]-2-(2-methoxyethyl)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione MS(ESI+) 425,5Example 17, Scheme 2

ConnectionStructureNameDataMethod
764-[(4-chlorophenoxy)methyl]-5-(2-methoxyethyl)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 464,1Example 17, Scheme 2
774-(4-chlorophenyl)-2-(2-methoxyethyl)-5-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 334,9Example 17, Scheme 2
784-(4-chlorophenyl)-2-(2-morpholine-4-retil)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 466,8Example 17, Scheme 2
794-[(4-pertenece)methyl]-5-(3-methoxybenzyl-2-(2-methoxyethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione MS(ESI+): 454,6Example 17, Scheme 2
804-methyl-2-(2-morpholine-4-retil)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 370,5Example 1, Scheme 1
814-(4-chlorophenyl)-5-methyl-2-(1-demerol-4-yl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 373,9Example 17, Scheme 2
824-(4-chlorophenyl)-2[2-(dimethylamino)ethyl]-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,b(2H,5H)-dioneMS(ESI+) 425,3Example 17, Scheme

ConnectionStructureNameDataMethod
835-(3-methoxybenzyl)-methyl-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione MS(ESI+): 399,6Example 1, Scheme 1
842-(2-morpholine-4-ileti)-4-(3-phenoxypropan)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 490,7Primer, Scheme 2
854-(3-chlorophenyl)-5-(3-ethoxypropan)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 462,0Example 17, Scheme
864-[(4-pertenece)methyl]-5-methyl-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 403,5Example 17, Scheme 2
874-[(4-chlorophenoxy)methyl]-5-(3-ethoxypropan)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 492,0Example 17, Scheme 2
88 4-[(benzyloxy)methyl]-5-(3-methoxybenzyl)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,b(2H,5H)-dioneMS(ESI+): 505,6Example 17, Scheme 2
894-[(benzyloxy)methyl]-5-(3-ethoxypropan)-2-(2-morpholine-4-retil)-1 H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESr):471,7Example 17, Scheme
905-(3-ethoxypropan)-4-[(4-pertenece)methyl]-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 475,6Example 17, Scheme 2

ConnectionStructureNameDataMethod
914-[(4-chlorophenoxy)methyl]-2-(2-morpholine-4-retil)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 497,0
924-(4-chlorophenyl)-2-(2-morpholine-4-retil)-5-(2-pyridin-2-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 481,2Example 17, Scheme 2
934-[(4-pertenece)methyl]-2-(2-morpholine-4-retil)-5-(2-pyridin-2-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 494,6Example 17, Scheme 2
942,5-bis(2-methoxyethyl)-4-(3-phenoxypropan)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 402,5Example 17, Scheme
954-[(4-chlorophenoxy)methyl]-5-(3-methoxybenzyl)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+):526,4Example 17, Scheme 2
964-(3,5-dichlorophenyl)-5-(2-methods�Sitel)-2-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione MS(ESI+): 369,8Example 17, Scheme 2
975-[(4-benzylmorphine-2-yl)methyl]-4-(4-chlorophenyl)-2-methyl-1H-pyrazolo[4,3-C]Pyridine-3,6(2H,5H)-dioneMS(ESI+): 466,1Example 17, Scheme 2

ConnectionStructureNameDataMethod
985-[(1-acetylpiperidine-4-yl)methyl]-4-(4-chlorophenyl)-2-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dioneMS(ESI+): 415,9Example 17, Scheme 2
99tert-butyl 4-{[4-(4-chlorophenyl)-2-methyl-3,6-diokso-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridin-5-yl] methyl}piperidine-1-carboxylateMS(ESI+): 474,2Example 17, Scheme 2
100 4-(4-chlorophenyl)-2-methyl-5-[(5-oxopyrrolidin-3-yl)methyl]-1H-pyrazolo[4,3-C]Pervin-3,6(2H,5H)-dioneMS(ESI+):373,7Example 17, Scheme 2

Example 18. Measuring levels of reactive oxygen species in different cell cultures

The activity of compounds according to the present invention can be tested for their activity in inhibiting or reducing the production of reactive oxygen species (ROS) from oxygen in the cells. The activity of compounds was tested in the following cell cultures using different methods such as using nitroblue tetrazolium, Amplex Red, Chemiluminescence (Luminol) and 2',7'- (H2DCF-DA) according to the following detailed protocols.

Cell line of microglia of the person

Line of microglial cells (NMS, microglia human clone 3) (Janabi et al., 1995, Neurosci. Lett. 195:105) were cultured in MEM medium (minimal sufficient medium eagle containing 10% FBS with 50 U/ml of sodium salt of penicillin G and 50 µg/ml streptomycin sulfate, and were treated at 37°C for 24 hours. In culture medium was added to IFN-γ (IFN-γ of human rights, Roche. 11040596001) to final concentration of 10 ng/ml for 24 h before the definition of education O2-.

Endothelial cells from the human umbilical vein (HUVEC)

Cells HUVEC cultiv�grown in minimal endothelial environment supplemented with hydrocortisone (1 µg/ml, CalbioChem), an extract of the brain of a bull (12 µg/ml), gentamicin (50 µg/ml, CalbioChem), amphotericin b (50 ng/ml, CaIBioChem), EGF (10 ng/ml) and 10% FCS, until the fourth passage. Starting with the fifth passage cells were cultured at the lower concentration of FCS (2%) in the absence of EGF, unless otherwise specified. All experiments were performed with cells at the fifth passage. Cells were incubated with OxLDL (oxidized low-density lipoprotein) or an appropriate buffer as control for 24 h before the definition of education O2-.

Cells HL-60

Cell line acute myeloid leukemia human HL-60 were cultured in RPMI medium 1640 (Invitrogen) enriched with 10% thermoinactivation calf serum, 2 mm glutamine, 100 U/ml penicillin (Sigma) and 100 µg of streptomycin (Sigma) at 37°C in a humid atmosphere with 5% CO2. The differentiation of HL-60 in the phenotype of neutrophils was started by adding into the culture medium MezSO (final concentration of 1.25% (by volume) for 6 days).

1. Nitroblue tetrazolium (NBT)

Intracellular and extracellular superoxide was measured using the colorimetric method using a quantitative test using nitroblue tetrazolium (NBT). Inhibiting SOD the conversion of NBT to formazan, a thin blue precipitate in the presence of superoxide anion was measured on the spectrometer Fluostar Optima pectrometer (BMG labtech). After incubation with the appropriate stimulus, the cells were treated with trypsin (IX Trypsin-EDTA), were collected by centrifugation and washed with PBS to remove culture medium. In 48-well plates were placed on a 5×105cells and incubated them in a balanced salt Hanks solution containing 0.5 mg/ml NBT with or without the addition of 800 U/ml SOD in the presence or in the absence of the compounds according to the present invention. As a control, was injected DPI at final concentration of 10 μm. After 2.5 h, the cells were fixed and washed with methanol to remove any remaining not recovered NBT. The restored formazan was dissolved in 230 μl of 2 M potassium hydroxide and 280 μl of dimethyl sulfoxide. The absorption was measured at 630 nm. For calculations of the absorption at 630 nm normalized for each individual plate wells. The average value of four blank wells were subtracted from each of the adjusted values for each time point. The activity of NADPH oxidase was expressed as % of activity in control cells. The residual activity of DPI-treated cells was usually <10%.

2. Amplex Red

Extracellular hydrogen peroxide was measured using Amplex UltraRed (Molecular Probes). Cells were treated with trypsin (IX Trypsin-EDTA), collected by centrifugation and were resuspended in HBSS medium enriched with 1% glucose. Cell seeding�in black 96-well plates with a density of 50,000 cells in 200 ál of buffer (HBSS with 1% glucose, containing 0.005 U/ml horseradish peroxidase (Roche) and 50 µm Amplex Red) in the presence or in the absence of the compounds according to the present invention. As a control, was injected DPI at final concentration of 10 μm. The tablets were placed in a fluorescent Optima Fluorescent plate reader and kept at 37°C for 20 min, Fluorescence was measured for 15 minutes (hours?) at wavelengths of the exciting and emitted light 544 nm and 590 nm, respectively. The activity of NADPH oxidase was expressed as % of activity in control cells. The residual activity of DPI-treated cells was usually <10%.

The following table 2 shows the percentage inhibition of the activity of NADPH oxidase, measured using Amplex Red using differentiated under the action of DMSO cells HL-60, as described above:

Table 2
Compound No.Inhibition (%)
(1)67
(2)61
(3)63
(4)65
(5) 48
(6)74
(8)79
(10)77
(13)56
(15)72
(16)74
(18)75
(19)73
(20)75
(21)74
(24)79
(28)78
(30)77
(35)72
(44)78
(48)91
(51) 76
(58)95
(74)95
(77)90
(83)89
(86)87
(89)86
Compound No.Inhibition (%)
(94)90
(97)89
(98)92
(100)90

The following table 3 shows the values of IC50for the activity of NADPH oxidase, measured using Amplex Red using differentiated under the action of DMSO cells HL-60, as described above:

Table 3
Compound No.IC50(μm)
(1)<5
(2)<5
(3)<5
(4)<5
(5)<5
(6)<5
(8)<5
(10)<5
(13)<5
(15)<5
(16)<5
(18)<5
(19)<5
(20)<5
(21)<5
(24)<5
(28)<5
(30)<5
(35)<5
(44)<5
(48) <5
(51)<5
(58)<5
(74)<5
(77)<5
(83)<5
(86)<5
(89)<5
(94)<5

3. Chemiluminescence (Luminol)

ROS was measured using the chemiluminescent probe luminol. Cells were cultured and placed in tablets as described for Amplex Red, except that the Amplex Red was replaced with 10 mg/ml luminol (Sigma 09235). The light emission was recorded continuously at 37°C for 60 min, using the luminescence mode of the device FluoStar Optima fluorescent plate reader. The average value of four blank wells were subtracted from each of the adjusted values for each time point. The activity of NADPH oxidase was expressed as % of activity in control cells. The residual activity of DPI-treated cells was usually <10%.

4. 2',7'-DICHLORODIFLUOROMETHANE diacetate (H2DCF-DA)

The HUVEC cells were placed on a coverslip and left in dormancy�e overnight in 0.5% BSA prior to the stimulation of TGF-p. Cells were loaded for 10 min with 5 μm CM-H2DCFDA in phenol red-free medium in the dark, and then treated with TGF-(3 (R&D Systems) in the presence or in the absence of the compounds according to the present invention. Then the cells were visualized using immunofluorescence microscopy after fixation and staining of nuclei DAPI or evaluation of the living state using confocal microscopy. The DCF fluorescence was visualized at a wavelength of the exciting light of 488 nm and emission at 515-540 nm. To avoid photo-oxidation of the dye image was acquired with one quick scan, using identical settings for all samples. For calculations of the absorption at 540 nm normalized to the absorption at 540 nm for each individual hole. The average value of four blank wells were subtracted from each of the adjusted values for each time point. The activity of NADPH oxidase was expressed as % of activity in control cells. The residual activity of DPI-treated cells was usually <10%.

Example 19. The measurement of blood pressure in Spontaneously Hypertensive Rats (SHR)

To assess the possibility of using compounds according to the present invention for the treatment of hypertension was conducted the following experiment.

Were used rats of the SHR line age 11 weeks with systolic blood pressure above 170 MND. The connection according to the present invention was administered to rats orally at a dose of approximately 3, 10, 30 and 100 mg/kg in the period of time from about 10:00 and 12:00 h. the Mean, systolic and diastolic blood pressures and heart rate were measured after 2, 4, 6, 8, and 24 after the first injection of the compounds according to the present invention for carrying out the kinetic analysis in a single day. Thereafter, the pressure was measured every two days for two weeks in the morning at point 24 hours after insertion and at the point corresponding to the half-life of the connection.

After the last injection was controlled point 24 hours. Animals were monitored for an additional week without treatment to assess the excretion of compounds. Animals were treated once daily for two weeks with a probe with a special needle that is adapted for the probe, at a dose of 5 ml/kg. Before taking to the experiment the animals acclimatized for two days, and then coached for one week. Pressure was measured in awake rats using the plethysmography with tail cuff (6 Codas, Kent). Animals included in group after training for a few days and if the change in systolic pressure from them was ≤ 40 mm Hg, i.e. +/-20 mm Hg. Measure baseline spend at least two days before the experiment. Prior to�scarlet experiment animals randomizable to obtain homogeneous groups.

Example 20. Induced by bleomycin lung damage in mice

To assess the possibility of using compounds according to the present invention for the prevention or treatment of respiratory disorders or diseases was conducted the following experiment.

To get lung damage, which is comparable to those in violation or respiratory disease, such as idiopathic pulmonary fibrosis, animals were injected into the trachea of a single sublethal dose of bleomycin (BLM) (2.5 U/kg body weight, dissolved in 0.25 ml of 0.9% Nad). Control animals were subjected to similar treatment, but instead of bleomycin in the trachea were injected the same volume of saline. Infusion into the trachea was performed under anesthesia using ketamine (80 mg/kg body weight, intraperitoneally) and xylazine (20 mg/kg body weight, intraperitoneally).

2 weeks after insertion in the trachea of BLM or saline, animals were killed with a lethal injection of phenobarbital sodium with subsequent emission of blood from the abdominal aorta. Was performed bronchoalveolar washing, lungs were weighed and used separately for biochemical (right lung homogenate, n=10) and histological (left lung, n=10) studies, as described below. Animals were randomly divided into four groups: control - saline R�the target (n=8) and control + BLM (n=10); and the Connection Dose 1+BLM (n=10) and Compound Dose 2+BLM (N=10). Media or compound was administered within 2 weeks.

The mice in the course of treatment with daily oral was administered the compound according to the present invention, or physiological/reference solution starting from day 0 within two weeks. The accumulation in whole lung acid-soluble collagen was analyzed using the method of Sircol assay.

Example 21. Animal models of cancer

To assess the possibility of using compounds according to the present invention for the treatment of cancer, in particular for slowing tumor growth and/or angiogenesis, were conducted the following experiments.

The study of angiogenesis In vivo

The female mice of the C57BL6/J aged 7 to 10 weeks were injected subcutaneously with 400 μl full growth factor gel Matrigel (Matrigel) with addition of 500 ng/ml of the angiogenic factor (b-FGF or VEGF). One week after injection, mice were scanned using MicroCT (Skyscan). Mice retro-orbital injection was injected indicator (400 μl of labeled iodine liposomes) for the visualization of vessel density. Image scans then reconstructed using the program Recon, and the density of the shading in the area entered Matrigel was calculated for each side of the seal. Compounds of the present invention is administered orally in appropriate doses 1 and 2 once a day for 10 days. Results�s expressed in density dimming, which correlates with the density of blood vessels. The matrix of Matrices also were frozen and stained for CD31 to visualize blood vessels.

Measurement of tumor growth

Cells of Lewis lung carcinoma (LLC1) in an amount of 5×105were injected by subcutaneous injection in the back of the mice. Mice were injected daily connection according to the present invention, oral dose of 40 mg/kg control When the tumor reached approximately 1 cm in length, the mice were sacrificed, and the tumors excised, weighed and frozen. For analysis of therapeutic effects in mice by injection was administered LLC1 cells, and after the tumors had reached a size of approximately 0.5 cm, mice were treated was monitored daily and tumor size. After killing the mice tumor and frozen sections of tumors were stained with antibodies against CD31 and analyzed the level of ROS.

1. Pyrazolopyrimidine derivative of formula (I):

where G1represents H; G2represents-CHR1R2; R1and R2independently from each other selected from H; C1With6-alkoxy-C1With6-alkyl; C1-C6-alkyl; optionally substituted phenyl; optionally substituted phenyl-C1-C6-alkyl; optionally substituted morpholine-C1-C6-alkyl; or-CHR1R2along the way�t ring, selected from optionally substituted C3-C8-cycloalkyl and substituted piperidine; G3selected from optionally substituted C1With6-alkoxy-C1-C6-alkyl; C1-C6-alkyl; substituted phenyl; substituted phenyl-C1With6-alkyl; G4selected from substituted acyl-C1With6-alkyl, where acyl is a group-CO-R and R is H or a morpholine; optionally substituted C1-C6-alkyl; optionally substituted phenyl or indene; substituted phenyl-C1-C6-alkyl; optionally substituted pyridin - or furanyl-C1With6-alkyl; a morpholine or piperidine-C1-C6-alkyl; G5represents h, as well as its tautomers, its geometrical isomers, its optically active forms as enantiomers, its diastereoisomers and its racemate and pharmaceutically acceptable salts,
where the term "substituted" refers to groups substituted with from 1 to 5 substituents selected from group, which includes "C1-C6-alkyl," "morpholine", "C1-C6-alkylphenyl", "di-C1-C6-alkylamino", "arylamino" which means a group NRCOR', where R represents H and R' represents C1-C6-alkyl, phenyl, fluorine-substituted phenyl", "C1-C6-alkoxy", "C1-C6/sub> -alkoxycarbonyl", "halogen".

2. A derivative according to claim 1, wherein G2represents-CHR1R2; R1represents H; R2is such as defined in the preceding paragraphs.

3. A derivative according to claim 1, in which R1and R2represent N.

4. A derivative according to claim 1, in which R1represents optionally substituted phenyl.

5. A derivative according to claim 1, in which R1is a morpholine-C1-C6-alkyl.

6. A derivative according to claim 1, in which R1represents C1-C6-alkoxy-C1-C6-alkyl.

7. A derivative according to claim 1, wherein G2represents-CHR1R2and-CHR1R2together form a ring selected from optionally substituted C3-C8-cycloalkyl and substituted piperidine.

8. Derivative according to any one of the preceding paragraphs, in which G3represents C1-C6-alkyl.

9. Pyrazolopyrimidinone derivative selected from the following group:
2-benzyl-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(4-Chlorobenzyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridin,6(2H,5H)-dione;
2-benzyl-4-methyl-5-[3-(triptoreline)phenyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2,4-dimethyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-br/> 2,4,5-trimethyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
5-(furan-2-ylmethyl)-2,4-dimethyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
5-(4-Chlorobenzyl)-2,4-dimethyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-butyl-5-(4-chlorbenzyl)-2-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-butyl-2-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
5-(4-Chlorobenzyl)-4-methyl-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-benzyl-4-butyl-5-(3,5-dimethoxybenzyl)-1H-pyrazolo[4,3-C] pyridine-3,6(2H,5H)-dione;
2-benzyl-4-butyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-cyclohexyl-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2,4-dimethyl-5-(2-pyridin-2-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2-methoxyethyl)-4-methyl-5-(2-pyridin-2-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2,4-dimethyl-5-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
5-(2-methoxyethyl)-4-methyl-2-(2-phenylethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2-methoxyethyl)-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
N-{3-[2-(2-methoxyethyl)-4-methyl-3,6-diokso-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridin-5-yl]phenyl}acetamide;
2-(2-methoxyethyl)-4-methyl-5-(2-morpholine-4-yl-2-oxoethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-benzyl-4-(3-methoxybenzyl)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-benzyl-4-(3-�ethoxybenzyl)-5-(2-methoxyethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2,5-dichlorobenzyl)-5-(2-methoxyethyl)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-[2-(4-chlorophenoxy)ethyl]-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2,5-dichlorobenzyl)-4-methyl-5-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2,5-dichlorobenzyl)-4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
5-(3,5-dimethoxybenzyl)-2-(2-methoxyethyl)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
N-(3-{[4-methyl-3,6-diokso-2-(2-phenylethyl)-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridin-5-yl]methyl}phenyl)acetamide;
4-methyl-5-(2-morpholine-4-retil)-2-(2-phenylethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-methyl-5-[2-(morpholine-4-ylmethyl)benzyl]-2-(2-phenylethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2-methoxyethyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
N-[2-(2-benzyl-4-methyl-3,6-diokso-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridin-5-yl)ethyl]-4-fermentated;
N-[3-(2-benzyl-4-methyl-3,6-diokso-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridin-5-yl)phenyl]acetamide;
N-(3-{[2-(2-chloro-4-terbisil)-4-methyl-3,6-diokso-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridin-5-yl]methyl}phenyl)acetamide;
5-[2-(4-benzylpiperazine-1-yl)-2-oxoethyl]-2-(2-methoxyethyl)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2,5-dichlorobenzyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2-chloro-4-terbisil)-4-methyl-5-[2-(morpholine-4-ylmethyl)BAA�ZIL]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2,5-dichlorobenzyl)-4-methyl-5-(2-morpholine-4-yl-2-oxoethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione
4-methyl-2-(2-phenylethyl)-5-(pyridin-2-ylmethyl)-W-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2-(2-chloro-4-terbisil)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-fluoro--{2-[2-(2-methoxyethyl)-4-methyl-3,6-diokso-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridin-5-yl]ethyl}benzamide;
5-[2-(4-benzylpiperazine-1-yl)-2-oxoethyl]-2-(2-chloro-4-terbisil)-4-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
5-benzyl-4-methyl-2-(1-demerol-4-yl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-methyl-2-(2-methylpropyl")-5-(pyridin-3-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-methyl-2-(2-methylpropyl")-5-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
5-(2,5-dichlorobenzyl)-4-methyl-2-(2-methylpropyl")-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
5-(2,4-dichlorobenzyl)-4-methyl-2-(2-methylpropyl")-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
5-(2,3-dihydro-1H-indene-1-yl)-4-methyl-2-(2-methylpropyl")-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-(3-chlorophenyl)-5-(2-morpholine-4-retil)-2-(2-phenylethyl)-1H-pyrazolo[4,3-C] pyridine-3,6(2H,5H)-dione;
2-benzyl-4-(3-chlorophenyl)-5-(2-methoxyethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
5-(4-Chlorobenzyl)-4-[(4-pertenece)methyl]-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-[(4-pertenece)methyl]-5-(2-methoxyethyl)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
5-4-Chlorobenzyl)-4-(3-chlorophenyl)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-(3-chlorophenyl)-2-(2-morpholine-4-retil)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
5-(4-Chlorobenzyl)-4-(4-chlorophenyl)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-(4-chlorophenyl)-5-(4-methoxybenzyl)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-(4-chlorophenyl)-5-(3-methoxybenzyl)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-(4-chlorophenyl)-2,5-bis(2-methoxyethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
5-(4-Chlorobenzyl)-4-(4-chlorophenyl)-2-(2-methoxyethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-(4-chlorophenyl)-5-(2-methoxyethyl)-2-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-[(4-pertenece)methyl]-5-(4-methoxybenzyl)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-[(4-pertenece)methyl]-2-(2-morpholine-4-retil)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-(4-chlorophenyl)-5-(2-morpholine-4-retil)-2-(2-phenylethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-(4-chlorophenyl)-5-(3-methoxybenzyl)-2-(2-methoxyethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-(4-chlorophenyl)-2-(2-methoxyethyl)-5-[2-(morpholine-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-(4-chlorophenyl)-2-(2-methoxyethyl)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-(4-chlorophenyl)-5-(3-ethoxypropan)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
5 -(2-methoxyethyl)-4-methyl-2-(2-morpholine-4-retil)-1 H-pyrazolo [4,3-C] p�ridin-3,6(2H,5H)-dione;
4-(4-chlorophenyl)-5-(2-methoxyethyl)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-(3,4-dichlorophenyl)-2-(2-methoxyethyl)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-(3,4-dichlorophenyl)-5-(2-methoxyethyl)-2-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-(4-chlorophenyl)-5-methyl-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
5-methyl-2-(2-morpholine-4-ileti)-4-(3-phenoxypropan)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
5-(2-methoxyethyl)-2-(2-morpholine-4-ileti)-4-(3-phenoxypropan)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-[(4-pertenece)methyl]-2-(2-methoxyethyl)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-[(4-chlorophenoxy)methyl]-5-(2-methoxyethyl)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-(4-chlorophenyl)-2-(2-methoxyethyl)-5-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-(4-chlorophenyl)-2-(2-morpholine-4-retil)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-[(4-pertenece)methyl]-5-(3-methoxybenzyl)-2-(2-methoxyethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-methyl-2-(2-morpholine-4-retil)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-(4-chlorophenyl)-5-methyl-2-(1-demerol-4-yl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-(4-chlorophenyl)-2-[2-(dimethylamino)ethyl]-5-(pyridin-2-ylmethyl)-1H-pyrazolo-[4,3-C]pyridine-3,6(2H,5H)-dione;
5-(3-methoxybenzyl)-4-methyl-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridin,6(2H,5H)-dione;
2-(2-morpholine-4-ileti)-4-(3-phenoxypropan)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-(3-chlorophenyl)-5-(3-ethoxypropan)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-[(4-pertenece)methyl]-5-methyl-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-[(4-chlorophenoxy)methyl]-5-(3-ethoxypropan)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-[(benzyloxy)methyl]-5-(3-methoxybenzyl)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-[(benzyloxy)methyl]-5-(3-ethoxypropan)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
5-(3-ethoxypropan)-4-[(4-pertenece)methyl]-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-[(4-chlorophenoxy)methyl]-2-(2-morpholine-4-retil)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-(4-chlorophenyl)-2-(2-morpholine-4-retil)-5-(2-pyridin-2-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-[(4-pertenece)methyl]-2-(2-morpholine-4-retil)-5-(2-pyridin-2-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
2,5-bis(2-methoxyethyl)-4-(3-phenoxypropan)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-[(4-chlorophenoxy)methyl]-5-(3-methoxybenzyl)-2-(2-morpholine-4-retil)-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
4-(3,5-dichlorophenyl)-5-(2-methoxyethyl)-2-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
5-[(4-benzylmorphine-2-yl)methyl]-4-(4-chlorophenyl)-2-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
5-[(1-acetylpiperidine-4-yl)methyl]-4-(4-chlorophenyl)-2-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione;
tert-butyl-{[4-(4-chlorophenyl)-2-methyl-3,6-diokso-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-C]pyridin-5-yl]methyl}piperidine-1-carboxylate; and
4-(4-chlorophenyl)-2-methyl-5-[(5-oxopyrrolidin-3-yl)methyl]-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione.

10. Pharmaceutical composition having the ability to inhibit NADPH-oxidase containing at least one derivative according to any one of claims.1-9 and a pharmaceutically acceptable carrier, solvent or excipient.

11. Derivative according to any one of claims.1-9 for use as a medicinal product having the properties of an inhibitor of NADPH oxidase.

12. Pyrazolopyrimidinone derivative according to any one of claims.1-9 for the treatment of a disease or condition selected from cardiovascular disorders, respiratory disorders, metabolic disorders, skin disorders, bone disorders, neuro-inflammatory and/or neurodegenerative disorders, kidney diseases, reproduction disorders, diseases affecting the eye and/or the lens and/or conditions affecting the inner ear, inflammatory disorders, liver diseases, pain, different types of cancer, allergic disorders, injuries, septic, hemorrhagic and anaphylactic shock, diseases or disorders of the gastrointestinal tract, an�of oogeneza, angiogenesis-dependent conditions and other diseases and/or disorders associated with (NADPH-oxidase).



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to azoloazine salts of compounds of a fluoroquinolone line of formulae 4a-c , 5a-c , 7a-b and 8a-b , possessing antibacterial and antiviral properties. The claimed compounds can be applied for the creation of a medication for the emergency prevention and treatment of infections, caused by pathogens of both the bacterial and viral origin, including especially dangerous ones. In general formulae 4 and 5 R=CH3, R1=C2H5; R=H, R1=C2H5; R=C2H5, R1=cyclo-C3H7, in formulae 7 and 8 R=H (7a, 8a); R=CH3 (7b, 8b).

EFFECT: increased efficiency of the compound application.

8 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: given invention refers to new 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole derivatives, which can be used for modulating histamine receptors in individuals or for treating neurodegenerative diseases. The above derivatives have formula , wherein R1 is specified in an alkyl, substituted alkoxy or phenyl, and aralalkyl; R2 is specified in an alkyl, C6-C14-aryl optionally substituted by 1 to 5 substitutes specified in alkoxy and alkyl; R3 is an alkyl; and R4 is an alkyl.

EFFECT: presented are the new compounds effective as histamine receptor modulators, and a based pharmaceutical composition.

20 cl, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to new quinolin-4-one derivatives of formula (1) or to its pharmaceutically acceptable salt, wherein R1 represents: (1) hydrogen, (2) C1-C6 alkyl, (35) carbamoyl-C1-C6 alkyl optionally containing morpholinyl-C1-C6 alkyl, or (36) phosphonoxy-C1-C6 alkyl optionally containing one or two C1-C6 alkyl groups on a phosphonoxy group; R2 represents: (1) hydrogen or (2) C1-C6 alkyl; R3 represents phenyl, thienyl or furyl, wherein a phenyl ring presented by R3, can be substituted by one C1-C6 alkoxy group; R4 and R5 are bound to form a group presented by any of the following formulas: , , , , , , or a group presented by the following formula: a group optionally containing one or more substitutes specified in a group consisting of C1-C6 alkyl groups and oxogroups; R6 represents hydrogen; and R7 represents C1-C6 alkoxy group. The invention also refers to a pharmaceutical composition based on the compound of formula , to a preventive and/or therapeutic agent based on the compound of formula (1), using the compound of formula (1), a method for preparing the compound of formula , as well as to specific compounds.

EFFECT: there are prepared new quinolin-4-one derivatives effective in treating neurodegenerative diseases, diseases caused by neurological dysfunction, or diseases caused by mitochondrial dysfunction.

18 cl, 1 tbl, 257 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of general formula I, their pharmaceutically acceptable salts or N-oxides. In general formula , R1 represents C1-6alkoxy, such as methoxy or hydroxy; R2 represents C3-5cycloalkyl, which is optionally substituted by one substitute specified in R4, wherein R4 means C1-4alkyl, which is optionally substituted by hydroxy, C1-4alkoxy, group -OC(O)NR5R6, wherein each of R5 and R6 independently represents a hydrogen atom, C1-4alkyl, C3-6cycloalkyl, or R5 and R6 together with a nitrogen atom where they are attached to, form pyrrolidinyl, group -NHC(O)R7, wherein R7 means C1-4alkyl, C3-5cycloalkyloxy or pyrrolidinyl, or benzyloxygroup; -C(O)NR7R8, wherein each of R7 and R8 independently represents a hydrogen atom or C1-4alkyl, which in turn can be substituted by hydroxy, oxo, cyano, group -SO2C1-4alkyl, group -SO2NR11R12, wherein each of R11 and R12 independently represents a hydrogen atom or C1-4alkyl, group -NHSO2C1-4alkyl, group -NHC(O)C1-4alkyl, group -C(O)NR7R8, wherein R7 and R8 together with a nitrogen atom, where they are attached to, form morpholinyl, -OC(O)C2-6alkenyl, phenyl, pyridinyl or C3-6cycloalkyl, or R7 and R8 together with a nitrogen atom where they are attached to, form 5-6-merous cycle specified in morpholinyl, piperidinyl, piperazinyl substituted by C1-4alkyl, or pyrrolidinyl; -COOR7, wherein R7 means a hydrogen atom or C1-4alkyl; A represents phenyl optionally one or two-substituted by cyano, halogen, hydroxyl, C1-4alkyl, halogenC1-4alkyl, C1-4alkoxy, halogenC1-4alkoxy, C1-4alkoxyC1-4alkoxy, -SO2C1-4alkyl, group -C(O)OR3, wherein R3 means a hydrogen atom or C1-4alkyl, -C(O)R3, wherein R3 means C1-4alkyl, amino, C1-4alkylamino or diC1-4alkylamino, -NR5R6, wherein R5 and R6 independently mean hydrogen, -C(O)C1-4alkyl or -SO2C1-4alkyl, -C1-4alkylNR5R6, wherein R5 and R6 independently mean hydrogen or -SO2C1-4alkyl, or -C1-4alkylC(O)OR3, wherein R3 means C1-4alkyl, -SO2NR11R12, wherein R11 and R12 independently mean a hydrogen atom or C1-4alkyl substituted by hydroxy, or R11 and R12 together with a nitrogen atom where they are attached to, form morpholinyl; pyrrolidinyl optionally substituted by cyano; pyrimidinyl; thiophenyl optionally substituted by C1-4acyl; piperidinyl; 4,5-dihydro-2H-pyridazinone substituted by C1-4alkyl; dihydrobenzofuranone; oxoindanyl; or dihydro-oxoindolyl; X and Y represent either C and N, or N and C, respectively.

EFFECT: there are prepared new compounds, which possess the inhibitory activity on PDE4.

6 cl, 53 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compound of general formula (I) or to its pharmaceutically acceptable salt, acid salt or stereoisomer, where Y: NRa and N+R1R2X-; Z: bond, -(CH2)p, -CHOH, -CH=CH-, -C≡C-, -CONH- and -CO-; Rb: C1-C8 alkyl, C2-C8 alkenyl, C6-C10 aryl, -NR5R6,: , and ; with each alkyl, alkenyl and aryl, representing Rb, possibly, contains 1-3 substituents, selected from C1-C4 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C6-C10 aryl, 5-, 6- and 7-membered heterocyclyl, containing 1-3 heteroatoms, selected from nitrogen, oxygen and sulphur, halogen, -OH, -NH2, -CN and -NO2; Rc: halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkinyl, C3-C10 cycloalkyl, C3-C8 cycloalkenyl, C1-C4 alkoxy, C6-C10 aryl, 5-, 6-, 7- and 8-membered monocyclic heterocyclyl, containing 1-3 heteroatoms, selected from nitrogen, oxygen and sulphur, 9- and 10-membered bicyclic heterocyclyl, containing 1-3 heteroatoms, selected from nitrogen, oxygen and sulphur; with C1-C6 alkyl, C2-C6 alkenyl C2-C6 alkinyl, C3-C10 cycloalkyl, C3-C8 cycloalkenyl, C6-C10aryl, 5-, 6-, 7-, 8-membered monocyclic heterocyclyl and 9- and 10-membered bicyclic heterocyclyl, representing Rc, possibly contain 1-5 substituents, selected from the group, consisting of C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 cycloalkyl, C4-C8 cycloalkenyla, halogen, -OH, -NH2, C6-C10 (A)(A')(A")(A'")aryl, (A)(A')(A")(A'")heterocyclyl, containing 1-3 heteroatom, selected from nitrogen, oxygen and sulphur, NR14R15, (CH2)pNR14R15, -CN, -NO2, oxo, -COOR14, SOR14, SO2R14, SO2NR14R15, NR15SO2R16, COR14, CONR14R15 and NR15COR16; with each (A), (A'), (A") and (A'")independently absent or representing C1-C4 alkyl, and each heterocyclyl (A)(A')(A")(A'")heterocyclyl is independently selected from the group, consisting of 5-, 6-, 7- and 8-membered monocyclic heterocyclyl, containing 1-3 heteroatoms, selected from nitrogen, oxygen and sulphur, and 9- and 10-membered bicyclico heterocyclyl, containing 1-3 heteroatoms, selected from nitrogen, oxygen and sulphur; the remaining radicals have values given in i.1;and on condition that, if Rc represents heterocyclyl, said heterocyclyl is bound directly through carbon atom of heterocyclyl ring. Invention also relates to particular compounds and to pharmaceutical composition based on formula (I) compound.

EFFECT: obtained are novel imidazopyrazine and imidazodiazepine derivatives, useful for prevention or treatment of disease or condition, severity of which is reduced by receptors to cannabinoids.

21 cl, 5 dwg, 4 tbl, 71 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new cyclic indolysincarboxamides and azaindolysincarboxamides of formulas Ia and Ib:

presented below, wherein the values of R, Ra, R10, R20, R30, R40, Y, n, p and q are specified in cl. 1 of formula. What is described is a method for preparing them.

EFFECT: compounds exhibit rennin-inhibitory activity that enables using them in the pharmaceutical composition and for treating hypertension.

11 cl, 4 tbl, 17 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula , where R1 represents hydroxyadamantyl, methoxycarbonyladamantyl, carboxyadamantyl, aminocarbonyladamantyl or aminocarbonylbicyclo[2.2.2]octanyl and where A represents CR5R6; or phenyl, chlorobenzyl, benzyl, chlorophenylethyl, phenylethyl, difluorobenzyl, dichlorophenyl, trifluoromethylphenyl or difluorophenylethyl and where A represents CR5R6; R2 and R3 together with nitrogen atom N* and carbon atom C*, which they are bount to, form group or ; R4 represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, arylalkyl, arylalkoxygroup, arylalkoxyalkyl, hydroxyalkyl, aryl, heteroarylalkyl, heteroaryloxyalkyl, substituted aryl, substituted heteroarylalkyl or substituted heteroaryloxyalkyl, where substituted aryl, substituted heteroarylalkyl and substituted heteroaryloxyalkyl are substituted with 1-3 substituents, independently selected from alkyl, cycloalkyl, cyanogroup, halogen, halogenalkyl, hydroxygroup and alkoxygroup; R5 represents hydrogen; R6represents hydrogen; as well as to their pharmaceutically acceptable salts and esters, which can be used as 11b-HSD1 inhibitors.

EFFECT: obtaining compounds which can be used as 11b-HSD1 inhibitors.

9 cl, 1 tbl, 103 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a triazolopyridine compound of general formula [I] or a pharmaceutically acceptable salt, where the partial structural formula: is a group represented by any of the following formulae: or R1 is (1) a hydrogen atom, (2) C1-6alkyl group, (3) phenyl group or (4) C3-8cycloalkyl group; R2 is (1) a hydrogen atom, (2) C1-10alkyl group, (3) phenyl group, optionally substituted with identical or different 1-3 substitutes selected from the following groupB, (4) C3-8cycloalkyl group, (5) C3-8cycloalkenyl group, (6) thienyl group, optionally substituted with 1 substitute selected from halogen or C1-6alkyl group, (7) phenyl-C1-6alkyl group (wherein phenyl is optionally substituted with different or identical 1-2 substitutes selected from halogen, C3-8cycloalkyl or halogen-C1-6alkyl group) or (8) C3-8cycloalkyl-C1-6alkyl group; R3 is (1) a hydrogen atom, (2) a halogen atom, (3) C1-6alkyl group, (4) phenyl group (6) phenyl-C1-6alkyl group; and each of R4 and R5 are both hydrogen atoms or a group B: (a) a halogen atom, (b) C1-6alkyl group, (c) C3-8cycloalkyl group, (d) cyano group and (e) halogen-C1-6alkyl group. The invention also relates to the specific compounds, a pharmaceutical composition based on the compound of formula [I] and to use of the compound with the formula [I].

EFFECT: obtaining novel triazolopyrine compounds, having inhibitory activity on prolyl hydroxylase and capable of inducing erythropoietin production.

30 cl, 34 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

,

wherein pyridine rings A, B and C are independently unsubstituted or substituted by one or more substitutes independently specified in a group consisting of: C1-6-alkyl, halogen alkyl having 1-6 carbon atoms, Hal or OR13; L1 and L2 are independently specified in residues having formula or , wherein at least one of L1 or L2 has formula (b); R1 and R2 are independently specified in a group consisting of hydrogen, C1-6-alkyl and phenyl; R3 is specified in hydrogen and C1-6-alkyl; R4, R5, R6 and R7 are independently specified in a group consisting of hydrogen and C1-6-alkyl; R8, R9, R10 and R11 are independently specified in a group consisting of hydrogen and C1-6-alkyl; R12 is specified in a group consisting of hydrogen and C1-6-alkyl; R13 is independently specified in a group consisting of hydrogen, C1-6-alkyl and phenyl; p is equal to 1 or 2; q is equal to 0, 1 or 2, and Hal is specified in a group consisting of F, Cl, Br, and I, which can be used in treating a group of amyloid protein related disturbances and disorders.

EFFECT: preparing the compounds which can be used in treating a group of amyloid protein related disturbances and disorders.

17 cl, 1 dwg, 6 tbl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyrazolopyridine derivatives of formula (I) , a based pharmaceutical composition, and using them for treating and/or preventing disorders or conditions related to nictonamide adenine dinucleotide phosphatoxidase (NADPH-oxidase), as well as to a method for preparing them and an intermediate of formula (VIII) . In general formula (I), G1 is specified in H; and optionally substituted heteroaryl-C1-C6-alkyl; G2 is specified in H; optionally substituted C1-C6-alkyl; optionally substituted C2-C6-alkenyl; optionally substituted C2-C6-alkinyl; optionally substituted aryl; optionally substituted C1-C6-alkylaryl; optionally substituted aryl-C1-C6-alkyl; optionally substituted heteroaryl; optionally substituted C1-C6-alkylheteroaryl; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C2-C6-alkenylaryl; optionally substituted aryl-C2-C6-alkenyl; optionally substituted C2-C6-alkenylheteroaryl; optionally substituted heteroaryl-C2-C6-alkenyl; optionally substituted C3-C8-cycloalkyl; optionally substituted C3-C8-heterocycloalkyl; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted C1-C6-alkyl-C3-C8-heterocycloalkyl and optionally substituted C3-C8-heterocycloalkyl-C1-C6-alkyl; G3 is specified in H; optionally substituted amino; optionally substituted aminoalkyl; optionally substituted aminocarbonyl; optionally substituted alkoxy, optionally substituted alkoxy-C1-C6-alkyl; optionally substituted carbonyl; optionally substituted C1-C6-alkyl; optionally substituted C2-C6-alkenyl; optionally substituted C2-C6-alkinyl; optionally substituted aryl; optionally substituted aryl-C1-C6-alkyl; optionally substituted C1-C6-alkylaryl: optionally substituted heteroaryl; optionally substituted C1-C6-alkylheteroaryl; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C2-C6-alkenylaryl; optionally substituted aryl-C2-C6-alkenyl; optionally substituted C2-C6-alkenylheteroaryl; optionally substituted heteroaryl-C2-C6-alkenyl; optionally substituted C3-C8-cycloalkyl; optionally substituted C3-C8-heterocycloalkyl; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted C1-C6-alkyl-C3-C8-hterocycloalkyl and optionally substituted C3-C8-heterocycloalkyl-C1-C6-alkyl; G4 is specified in -NR2-C(O)-R1 and -(CHR3)m-(CH2)n-R4, G5 represents H.

EFFECT: preparing the pharmaceutical composition for treating and/or preventing the disorders and conditions related to nictonamide adenine dinucleotide phosphatoxidase.

16 cl, 3 tbl, 87 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a citrate of a compound described by formula (II) below, and a pharmaceutical composition containing said citrate.

EFFECT: experimental results of the present inventions prove that said citrate can inhibit activity of phosphodiesterase type 5 and can be used for treating erectile dysfunction, for inhibiting thrombocyte aggregation and treating thrombosis, for reducing pulmonary hypertension and treating cardiovascular diseases, asthma and diabetic gastroparesis.

2 cl

FIELD: medicine.

SUBSTANCE: group of inventions relates to field of therapy and/or prevention of diseases in mammals, in particular humans. Group of inventions includes medication for treatment and/or prevention of cardiovascular disease, and/or inflammatory disease, and/or liver disease, and/or neurological disease, and/or steatosis by increasing content of polyunsaturated fatty acids in mammal's blood, representing dairy product of ruminants with reduced cholesterol content, where cholesterol content constitutes from 10 mg/100 g of fat to 150 mg/100 g of fat, as well as application of dairy product of ruminants with reduced cholesterol content, in which cholesterol content constitutes from 10 mg/100 g of fat to 150 mg/100 g of fat, for treatment and/or prevention of cardiovascular disease, and/or inflammatory disease, and/or liver disease, and/or neurological disease, and/or steatosis by increasing content of polyunsaturated fatty acids in mammal's blood.

EFFECT: obtaining medication for treatment and/or prevention of cardiovascular disease, and/or inflammatory disease, and/or liver disease, and/or neurological disease, and/or steatosis.

18 cl, 5 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I, wherein R1 and R2 are identical or different and specified in an alkyl or alkenyl hydrocarbon chain; the R3 group values split by lipase are specified in the patient claim. R4 and R5 are independently hydrogen or C1-C7alkyl; R6 represents hydrogen or C1-C7alkyl; and R7 and R8 are independently hydrogen or C1-C7alkyl. The invention also refers to using compounds of formulas ,

which are introduced into the mammalian biological system and increase the cell concentrations of specific sn-2 substituted ethanolamine-plasmalogens.

EFFECT: compounds are applicable in treating or preventing the age-related disorders associated with high membrane cholesterol, high amyloids and low plasmalogens, such as neurodegeneration, cognitive disorder, dementia, cancer, osteoporosis, bipolar disorder and vascular diseases.

11 cl, 18 dwg, 7 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, in particular to cardiology, and represents a method of the drug treatment of patients in late rehabilitation period after aortocoronary bypass surgery, consisting in the combined administration to the patient of medications thrombo ASS 100 mg, atorvastatin 20 mg and additionally amlodipine in a daily dose from 5 to 10 mg and losartan in a daily dose from 25 to 100 mg.

EFFECT: invention ensures the long-term preservation of results of surgical myocardium revascularisation.

3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to fluorinated aminotriazole derivatives of formula

,

wherein A represents a group specified in furanyl, oxazolyl and thiazolyl, wherein two attachment points of the above group are found in 1,3-position; R1 represents phenyl, which is unsubstituted, mono- or disubstituted, wherein the substitutes are independently specified in a group consisting of halogen, methyl, methoxy group, trifluoromethyl, trifluormethoxy group and dimethylamino group; and R2 represents hydrogen, methyl, ethyl or cyclopropyl. Besides, the invention refers to a pharmaceutical composition containing the compound of formula (I), and to using the compound of formula (I) for preparing a therapeutic agent.

EFFECT: compounds of formula (I) possessing the agonist activity in relation to ALX receptor.

26 cl, 2 tbl, 36 ex

FIELD: medicine.

SUBSTANCE: method involves taking general baths and prescribing mud applications on lower extremities with underlying standard drug therapy. The patient takes prepared silicate-carbonate baths with the concentration of sodium salt of metasilicic acid of 100-150 mg/l and the content of carbon dioxide of 1.2 g/l. The bath water temperature is 36°-37°C. The length of the procedure is 10-15 minutes. Taking the baths is followed by having a 30-40-minute rest. Sulphide silt mud sock- or boot-like applications are performed. The mud temperature is 32°-36°C; the length of procedure is 8-20 minutes. The procedures are performed 2 days running, with a pause on the 3rd day. The therapeutic course makes 6-10 procedures.

EFFECT: method provides the further development of the symptom-free involvement of target organs: heart, kidneys, vessels by taking the antihypertensive, antianginal and antiarrhythmic effects, promotes the energetic and adaptation possibilities of the body.

5 ex

FIELD: medicine.

SUBSTANCE: invention refers to biotechnology and concerns a method for producing progenitor cells from mammalian myocardial samples. A presented method involves milling the samples, implanting them on culture dishes coated so that to provide adhesion; culturing the samples in the hypoxic environment so that to provide the sample adhesion to form a cell culture; recovering cells from the cell culture by enzymatic treatment; culturing the recovered cells until forming cell aggregates, and processing the cell aggregates with an enzyme solution to produce the progenitor cells of myocardium.

EFFECT: presented invention can be used in medicine and veterinary science for studying the myocardium regeneration mechanisms and stem cell biology, as well as for treating cardiac diseases.

10 cl, 2 dwg, 2 ex

FIELD: medicine.

SUBSTANCE: herbal tea has the hypolipidemic, antiaggregant, vasoprotective and adaptogenic action. The herbal tea contains common liquorice roots, blood-red hawthorn fruit, wild camomile blossom, blood-red hawthorn blossom, elevated part of meadow crane, elevated part of clump speedwell, clove tree flower buds, sweet flag rhizome, turmeric rhizome, anomalous peony root, common valerian rhizomes, elevated part of common sweet clover, common willow leaves, field caraway fruit, elevated part of tripartite bur-marigold, elevated part of common St. John's wort, elevated part of garden sage, meadowsweet blossom, elevated part of field mint, elevated part of cudweed in certain proportions. The above herbal tea extends the range of products for preventing primary ischemic stroke in the patients suffering cerebrovascular disease. It promotes mobilising all links of self-protection: immune protective, antioxidant and detoxification, neuroendocrine system.

EFFECT: more effective prevention.

1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to biotechnology, specifically to compositions for inducing angiogenesis in tissues, and can be used in medicine. The method provides transforming the strain E. coli TOP10 by the pCMV-VEGF165 plasmid, culturing the strain in an environment acceptable for the biomass collection followed by separating the superhelical pCMV-VEGF165 plasmid that is followed by the pCMV-VEGF165 plasmid lyophilisation, which is conducted in the necessary presence in the lyophilised solution of a cryoprotectant, a pH stabiliser, an antioxidant and other substances enabling producing normal saline for injections with the pure plasmid concentration of 0.1 to 10 mg/ml and pH 7.0 to 9.0 and providing t the superhelical form of the pCMV-VEGF165 plasmid storage retention. The method of treating an individual's tissue and/or organ ischemia consists in administering an effective amount of the prepared pharmaceutical composition intramuscularly into the individual.

EFFECT: invention enables preparing the therapeutically applicable pharmaceutical composition of the pCMV-VEGF165 plasmid DNA with preserving properties of the main substance at long-term storage at +2-+8°C.

3 cl, 2 dwg, 4 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to biotechnology and immunology.

EFFECT: bispecific anti-human vascular endothelial growth factor VEGF and human angiopoietin-2 ANG-2 antibodies, methods for producing them, pharmaceutical compositions containing the above antibodies, and using them are described.

13 cl, 26 dwg, 15 tbl, 19 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to biotechnology. What is presented is the strain Bifidobacterium longum NCIMB 41676 possessing the immunomodulatory action. The above strain is applicable as an anti-infectious probiotic strain. What is also presented is a probiotic formulation containing the above strain and a carrier for oral administration. What is also presented is using the formulation as a cognitive function enhancer for preventing the central nervous system disorders, such as Alzheimer disease, schizophrenia and/or mild cognitive disorders. Alternatively, what is used is the formulation for preventing an inflammation related to obesity, for preventing metabolic disorders related to obesity.

EFFECT: group of inventions provides increasing anti-inflammatory cytokine IL-10 and decreasing proinflammatory cytokines and lipopolysaccharide induced HfkB activity.

37 cl, 16 dwg, 6 tbl, 8 ex

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