The present invention is related to pyrazolo pyridine derivatives of Formula (I), pharmaceutical composition thereof and to their use for the treatment and/or prophylaxis of disorders or conditions related to Nicotinamide adenine dinucleotide phosphate oxidase (NADPH Oxidase).
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Claim 1:
Claim 2: . The derivative according towherein Gis H.
Claim 3: . The derivative according towherein Gis C-Calkyl.
Claim 4: . The derivative according towherein Gis a substituted C-Calkyl.
Claim 5: . The derivative according towherein Gis —(CHR)—(CH)—R; R, R, m and n are as defined in.
Claim 6: . The derivative according towherein Ris —C(O)R; Ris as defined in.
Claim 7: . The derivative according towherein Ris -A-B; A and B are as defined in.
Claim 8: . The derivative according towherein Ris —CHRR; Rand Rare as defined in.
Claim 9: . The derivative according towherein Ris —(CH)q-E; E and q are as defined in.
Claim 10: . The derivative according towherein Gis H.
Claim 11: . A pyrazolo pyridine derivative selected from the following compounds:
Claim 12: . A pharmaceutical composition containing at least one derivative according toand a pharmaceutically acceptable carrier, diluent or excipient thereof.
Claim 13: . The derivative according towherein Gis a substituted aryl.
Claim 14: . The derivative according towherein Ris —(CH)q-E; E is NRR; R, Rand q are as defined in.
Claim 15: . The derivative according towherein Ris —(CH)q-E; E is NRC(O)—R; R, Rand q are as defined in.
Claim 16: . The derivative according towherein Ris H.
Claim 17: . The derivative according towherein Gis —(CHR)—(CH)—R; Ris —(CH)q-E; E is optionally substituted C-C-cycloalkyl; m is an integer selected from 1 to 5; n is an integer selected from 1 to 5; and p and q are integers selected from 0 to 5.
Claim 18: . The derivative according towherein Gis —(CHR)—(CH)—R; Ris —(CH)q-E; E is optionally substituted C-Calkynyl; n is an integer selected from 1 to 5; and p and q are integers selected from 0 to 5.
Claim 19: . The derivative according to, wherein Ris selected from —C(O)R; -A-B; —CHRRor —(CH)q-E, and q is an integer selected from 1 to 5.
Claim 20: . The derivative according to, wherein E is selected from —NRR; and —NRC(O)—R.
Claim 21: . The derivative according to, wherein Gis an aryl.
Claim 22: . The derivative according to, wherein said substituted C-Calkyl is substituted with one to five groups selected from the group consisting of C-Calkyl, C-Calkenyl, C-Calkynyl, C-C-cycloalkyl, heterocycloalkyl, C-Calkyl aryl, C-Calkyl heteroaryl, C-Calkyl cycloalkyl, C-Calkyl heterocycloalkyl, amino, aminosulfonyl, ammonium, acyl amino, amino carbonyl, aryl, heteroaryl, sulfinyl, sulfonyl, alkoxy, alkoxy carbonyl, carbamate, sulfanyl, halogen, trihalomethyl, cyano, hydroxy, mercapto and nitro.
Claim 23: . The derivative according to claim, whereinGis substituted aryl andsaid substituted aryl is substituted with one to five groups selected from the group consisting of C-Calkyl, C-Calkenyl, C-Calkynyl, C-C-cycloalkyl, heterocycloalkyl, C-Calkyl aryl, C-Calkyl heteroaryl, C-Calkyl cycloalkyl, C-Calkyl heterocycloalkyl, amino, aminosulfonyl, ammonium, acyl amino, amino carbonyl, aryl, heteroaryl, sulfinyl, sulfonyl, alkoxy, alkoxy carbonyl, carbamate, sulfanyl, halogen, trihalomethyl, cyano, hydroxy, mercapto and nitro.
Claim 24: . The derivative according to, wherein Gis —(CHR)—(CH)—R, wherein Rand Rare H, m=0 and n=0-3 and Gis selected from H; optionally substituted C-Calkyl; optionally substituted C-Calkenyl; optionally substituted C-Calkynyl; optionally substituted aryl; optionally substituted C-Calkyl aryl; optionally substituted aryl C-Calkyl; optionally substituted heteroaryl; optionally substituted C-Calkyl heteroaryl; optionally substituted heteroaryl C-Calkyl; optionally substituted C-Calkenyl aryl; optionally substituted aryl C-Calkenyl: optionally substituted C-Calkenyl heteroaryl; optionally substituted heteroaryl C-Calkenyl; optionally substituted C-C-cycloalkyl; optionally substituted heterocycloalkyl; optionally substituted C-Calkyl C-C-cycloalkyl; optionally substituted C-C-cycloalkyl C-Calkyl; optionally substituted C-Calkyl heterocycloalkyl and optionally substituted heterocycloalkyl C-Calkyl.
Claim 25: . The derivative according to, wherein Gis —(CHR)—(CH)—R, wherein Ris selected from halogen; optionally substituted alkoxy; optionally substituted alkoxy C-Calkyl aryl; optionally substituted C-Calkyl aryl; optionally substituted aryl C-Calkyl; heteroaryl; optionally substituted C-Calkyl heteroaryl; optionally substituted heteroaryl C-Calkyl; optionally substituted C-C-cycloalkyl; optionally substituted C-Calkyl C-C-cycloalkyl; optionally substituted C-C-cycloalkyl C-Calkyl; optionally substituted heterocycloalkyl; optionally substituted C-Calkyl heterocycloalkyl; and optionally substituted heterocycloalkyl C-Calkyl; Ris selected from H; —C(O)R; -A-B; —CHRRand —(CH)q-E; Rand Rare independently selected from H; optionally substituted alkoxy C-Calkyl; optionally substituted aryl; optionally substituted C-Calkyl aryl; optionally substituted aryl C-Calkyl; optionally substituted heteroaryl; optionally substituted C-Calkyl heteroaryl; optionally substituted heteroaryl C-Calkyl; optionally substituted C-C-cycloalkyl; optionally substituted C-Calkyl C-C-cycloalkyl; optionally substituted C-C-cycloalkyl C-Calkyl; optionally substituted heterocycloalkyl; optionally substituted C-Calkyl heterocycloalkyl; and optionally substituted heterocycloalkyl C-Calkyl or —NRRform together a ring selected from optionally substituted heteroaryl and optionally substituted heterocycloalkyl; Ris selected from optionally substituted amino; optionally substituted alkoxy; optionally substituted aminoalkyl; optionally substituted alkoxy C-Calkyl; optionally substituted C-Calkyl; optionally substituted C-Calkenyl; optionally substituted C-Calkynyl; —NRR; optionally substituted aryl; optionally substituted C-Calkyl aryl; optionally substituted aryl C-Calkyl; optionally substituted heteroaryl; optionally substituted C-Calkyl heteroaryl; optionally substituted heteroaryl C-Calkyl; optionally substituted C-C-cycloalkyl; optionally substituted C-Calkyl C-C-cycloalkyl; optionally substituted C-C-cycloalkyl C-Calkyl; optionally substituted heterocycloalkyl; optionally substituted C-Calkyl heterocycloalkyl; and optionally substituted heterocycloalkyl C-Calkyl; Rand Rare independently selected from optionally substituted aryl; optionally substituted heteroaryl; optionally substituted C-C-cycloalkyl and optionally substituted heterocycloalkyl; Ris selected from optionally substituted aryl and optionally substituted heteroaryl; Rand Rare independently selected from H; optionally substituted acyl; optionally substituted C-Calkyl; optionally substituted C-Calkenyl; optionally substituted C-Calkynyl; optionally substituted aryl; optionally substituted C-Calkyl aryl; optionally substituted aryl C-Calkyl; optionally substituted heteroaryl; optionally substituted C-Calkyl heteroaryl; optionally substituted heteroaryl C-Calkyl; optionally substituted C-C-cycloalkyl; optionally substituted C-Calkyl C-C-cycloalkyl; optionally substituted C-C-cycloalkyl C-Calkyl; optionally substituted heterocycloalkyl; optionally substituted C-Calkyl heterocycloalkyl; and optionally substituted heterocycloalkyl C-Calkyl or —NRRform together a ring selected from optionally substituted heteroaryl and optionally substituted optionally substituted heterocycloalkyl; Ris selected from optionally substituted aryl; optionally substituted heteroaryl; optionally substituted C-C-cycloalkyl and optionally substituted heterocycloalkyl; R, Rand Rare independently selected from H and optionally substituted C-Calkyl; Ris selected from optionally substituted C-Calkyl; optionally substituted C-Calkenyl; optionally substituted C-Calkynyl; optionally substituted aryl; optionally substituted C-Calkyl aryl; optionally substituted aryl C-Calkyl; optionally substituted heteroaryl; optionally substituted C-Calkyl heteroaryl; optionally substituted heteroaryl C-Calkyl; optionally substituted C-C-cycloalkyl; optionally substituted C-Calkyl C-C-cycloalkyl; optionally substituted C-C-cycloalkyl C-Calkyl; optionally substituted heterocycloalkyl; optionally substituted C-Calkyl heterocycloalkyl; and optionally substituted heterocycloalkyl C-Calkyl; A is selected from optionally substituted aryl, and optionally substituted heteroaryl; B is selected from −OR, —NRRand a (CH)p-R; E is selected from optionally substituted C-C-cycloalkyl; optionally substituted C-Calkynyl; —NRR; and —NRC(O)—R; m is an integer selected from 1 to 5; n is an integer selected from 1 to 5; p and q are integers selected from 0 to 5; and Gis selected from H; optionally substituted C-Calkyl; optionally substituted C-Calkenyl; optionally substituted C-Calkynyl; optionally substituted aryl; optionally substituted C-Calkyl aryl; optionally substituted aryl C-Calkyl; optionally substituted heteroaryl; optionally substituted C-Calkyl heteroaryl; optionally substituted heteroaryl C-Calkyl; optionally substituted C-Calkenyl aryl; optionally substituted aryl C-Calkenyl; optionally substituted C-Calkenyl heteroaryl; optionally substituted heteroaryl C-Calkenyl; optionally substituted C-C-cycloalkyl; optionally substituted heterocycloalkyl; optionally substituted C-Calkyl C-C-cycloalkyl; optionally substituted C-C-cycloalkyl C-Calkyl; optionally substituted C-Calkyl heterocycloalkyl and optionally substituted heterocycloalkyl C-Calkyl.
Claim 26: . The derivative according to, wherein Gis —(CHR)—(CH)—R, wherein Ris selected from H; halogen; optionally substituted alkoxy; optionally substituted alkoxy C-Calkyl aryl; optionally substituted C-Calkyl aryl; optionally substituted aryl C-Calkyl; heteroaryl; optionally substituted C-Calkyl heteroaryl; optionally substituted heteroaryl C-Calkyl; optionally substituted C-C-cycloalkyl; optionally substituted C-Calkyl C-C-cycloalkyl; optionally substituted C-C-cycloalkyl C-Calkyl; optionally substituted heterocycloalkyl; optionally substituted C-Calkyl heterocycloalkyl; and optionally substituted heterocycloalkyl C-Calkyl; Ris selected from —C(O)R; -A-B; —CHRRand —(CH)q-E; Ris selected from optionally substituted amino; optionally substituted alkoxy; optionally substituted aminoalkyl; optionally substituted alkoxy C-Calkyl; optionally substituted C-Calkyl; optionally substituted C-Calkenyl; optionally substituted C-Calkynyl; —NRR, wherein Rand Rare independently selected from H; optionally substituted alkoxy C-Calkyl; optionally substituted aryl; optionally substituted C-Calkyl aryl; optionally substituted aryl C-Calkyl; optionally substituted heteroaryl; optionally substituted C-Calkyl heteroaryl; optionally substituted heteroaryl C-Calkyl; optionally substituted C-C-cycloalkyl; optionally substituted C-Calkyl C-C-cycloalkyl; optionally substituted C-C-cycloalkyl C-Calkyl; optionally substituted heterocycloalkyl; optionally substituted C-Calkyl heterocycloalkyl; and optionally substituted heterocycloalkyl C-Calkyl or —NRRform together a ring selected from optionally substituted heteroaryl and optionally substituted heterocycloalkyl; optionally substituted aryl; optionally substituted aryl; optionally substituted C-Calkyl aryl; optionally substituted aryl C-Calkyl; optionally substituted heteroaryl; optionally substituted C-Calkyl heteroaryl; optionally substituted heteroaryl C-Calkyl; optionally substituted C-C-cycloalkyl; optionally substituted C-Calkyl C-C-cycloalkyl; optionally substituted C-C-cycloalkyl C-Calkyl; optionally substituted heterocycloalkyl; optionally substituted C-Calkyl heterocycloalkyl; and optionally substituted heterocycloalkyl C-Calkyl; Rand Rare independently selected from optionally substituted aryl; optionally substituted heteroaryl; optionally substituted C-C-cycloalkyl and optionally substituted heterocycloalkyl; A is selected from optionally substituted aryl, and optionally substituted heteroaryl; B is selected from —OR, —NRRand —(CH2)p-R; Ris selected from optionally substituted aryl and optionally substituted heteroaryl; Rand Rare independently selected from H; optionally substituted acyl; optionally substituted C-Calkyl; optionally substituted C-Calkenyl: optionally substituted C-Calkynyl; optionally substituted aryl; optionally substituted C-Calkyl aryl; optionally substituted aryl C-Calkyl; optionally substituted heteroaryl; optionally substituted C-Calkyl heteroaryl; optionally substituted heteroaryl C-Calkyl; optionally substituted C-C-cycloalkyl; optionally substituted C-Calkyl C-C-cycloalkyl; optionally substituted C-C-cycloalkyl C-Calkyl; optionally substituted heterocycloalkyl; optionally substituted C-Calkyl heterocycloalkyl; and optionally substituted heterocycloalkyl C-Calkyl or —NRRform together a ring selected from optionally substituted heteroaryl and optionally substituted optionally substituted heterocycloalkyl; Ris selected from optionally substituted aryl; optionally substituted heteroaryl; optionally substituted C-C-cycloalkyl and optionally substituted heterocycloalkyl; E is selected from optionally substituted C-C-cycloalkyl; optionally substituted C-Calkynyl; —NRR; and —NRC(O)—R; R, Rand Rare independently selected from H and optionally substituted C-Calkyl; Ris selected from optionally substituted C-Calkyl; optionally substituted C-Calkenyl; optionally substituted C-Calkynyl: optionally substituted aryl; optionally substituted C-Calkyl aryl; optionally substituted aryl C-Calkyl; optionally substituted heteroaryl; optionally substituted C-Calkyl heteroaryl; optionally substituted heteroaryl C-Calkyl; optionally substituted C-C-cycloalkyl; optionally substituted C-Calkyl C-C-cycloalkyl; optionally substituted C-C-cycloalkyl C-Calkyl; optionally substituted heterocycloalkyl; optionally substituted C-Calkyl heterocycloalkyl; and optionally substituted heterocycloalkyl C-Calkyl; m is an integer selected from 1 to 5; n is an integer selected from 1 to 5; p and q are integers selected from 0 to 5; and Gis selected from H; optionally substituted C-Calkyl; optionally substituted C-Calkenyl; optionally substituted C-Calkynyl; optionally substituted aryl; optionally substituted C-Calkyl aryl; optionally substituted aryl C-Calkyl; optionally substituted heteroaryl; optionally substituted C-Calkyl heteroaryl; optionally substituted heteroaryl C-Calkyl; optionally substituted C-Calkenyl aryl; optionally substituted aryl C-Calkenyl; optionally substituted C-Calkenyl heteroaryl; optionally substituted heteroaryl C-Calkenyl; optionally substituted C-C-cycloalkyl; optionally substituted heterocycloalkyl; optionally substituted C-Calkyl C-C-cycloalkyl; optionally substituted C-C-cycloalkyl C-Calkyl; optionally substituted C-Calkyl heterocycloalkyl and optionally substituted heterocycloalkyl C-Calkyl.
Claim 27:
Claim 28: 28. The compound of, wherein the compound is 2-(2-Chlorophenyl)-4-[3-(dimethylamino)phenyl]-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione or a pharmaceutically acceptable salt thereof.
Claim 29: 29. The compound of, wherein the compound is 2-(2-Chlorophenyl)-4-[3-(dimethylamino)phenyl]-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione.
Claim 30: 30. The compound of, wherein the compound is a pharmaceutically acceptable salt of 2-(2-Chlorophenyl)-4-[3-(dimethylamino)phenyl]-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione.
Claim 31: 31. The derivative according to, wherein Gis selected from optionally substituted aryl and optionally substituted heteroaryl.
Claim 32: 32. The derivative according to, wherein Gis selected from optionally substituted aryl and optionally substituted heteroaryl.
Complete technical specification and implementation details from the patent document.
This application is the U.S. national stage application of International Patent Application No. PCT/IB2009/054156, filed Sep. 22, 2009.
The present invention relates to pyrazolo pyridine derivatives of Formula (I), pharmaceutical composition thereof and to their use for the preparation of a medicament for the treatment and/or prophylaxis of cardiovascular diseases, respiratory disorders, disorders affecting the metabolism, skin and/or bone diseases, neurodegenerative diseases, kidney diseases, reproduction disorders, inflammatory disorders and cancers. Specifically, the present invention is related to pyrazolo pyridine derivatives useful for the preparation of a pharmaceutical formulation for the modulation, notably the inhibition of the activity or function of the Nicotinamide adenine dinucleotide phosphate oxidase (NADPH Oxidase).
NADPH oxidases (NOX) are proteins that transfer electrons across biological membranes. In general, the electron acceptor is oxygen and the product of the electron transfer reaction is superoxide. The biological function of NOX enzymes is therefore the generation of reactive oxygen species (ROS) from oxygen. Reactive oxygen species (ROS) are oxygen-derived small molecules, including oxygen radicals (super-oxide anion[.O][O], hydroxyl[HO.][HO], peroxyl[ROO.][ROO], alkoxyl[RO.][RO]and hydroperoxyl[HOO.][HOO]) and certain non-radicals that are either oxidizing agents and/or are easily converted into radicals. Nitrogen-containing oxidizing agents, such as nitric oxide are also called reactive nitrogen species (RNS). ROS generation is generally a cascade of reactions that starts with the production of superoxide. Superoxide rapidly dismutates to hydrogen peroxide either spontaneously, particularly at low pH or catalyzed by superoxide dismutase. Other elements in the cascade of ROS generation include the reaction of superoxide with nitric oxide to form peroxynitrite, the peroxidase-catalyzed formation of hypochlorous acid from hydrogen peroxide, and the iron-catalyzed 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 second radical, thus multiplying the potential damage. ROS are involved not only in cellular damage and killing of pathogens, but also in a large number of reversible regulatory processes in virtually all cells and tissues. However, despite the importance of ROS in the regulation of fundamental physiological processes, ROS production can also irreversibly destroy or alter the function of the target molecule. Consequently, ROS have been increasingly identified as major contributors to damage in biological organisms, so-called “oxidative stress”.
During inflammation, 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, tissues are constantly exposed to oxidants that are generated either endogenously by metabolic reactions (e.g. by mitochondrial respiration or activation of recruited inflammatory cells) or exogenously in the air (e.g. cigarette smoke or air pollutants). Further, the lungs, constantly exposed to high oxygen tensions as compared to other tissues, have a considerable surface area and blood supply and are particularly susceptible to injury mediated by ROS (Brigham, 1986, Chest, 89(6): 859-863). NADPH oxidase-dependent ROS generation has been described in pulmonary endothelial cells and smooth muscle cells. NADPH oxidase activation in response to stimuli has been thought to be involved in the development of respiratory disorders such as pulmonary hypertension and enhancement of pulmonary vasoconstriction (Djordjevic et al., 2005, Arterioscler. Thromb. Vasc. Biol., 25, 519-525; Liua et al., 2004, Am. J. Physiol. Lung, Cell. Mol. Physiol., 287: L111-118). Further, pulmonary fibrosis has been characterized by lung inflammation and excessive generation of ROS.
Osteoclasts, which are macrophage-like cells that play a crucial role in bone turn-over (e.g. bone resorption), generate ROS through NADPH oxidase-dependent mechanisms (Yang et al., 2002, J. Cell. Chem. 84, 645-654).
Diabetes is known to increase oxidative stress (e.g. increased generation of ROS by auto-oxidation of glucose) both in humans and animals and increased oxidative stress has been said to play an important role in the development of diabetic complications. It has been shown that increased peroxide localization and endothelial cell dysfunction in the central retina of diabetic rats coincides with the areas of NADPH oxidase activity in the retinal endothelial cells (Ellis et al., 2000, Free Rad. Biol. Med., 28:91-101). Further, it has been suggested that controlling oxidative stress (ROS) in mitochondria and/or inflammation may be a beneficial approach for the treatment of diabetes (Pillarisetti et al., 2004, Expert Opin. Ther. Targets, 8(5):401-408).
ROS are also strongly implicated in the pathogenesis of atherosclerosis, cell proliferation, hypertension and reperfusion injury cardiovascular diseases in general (Cai et al., 2003, Trends Pharmacol. Sci., 24; 471-478). Not only is superoxide production, for example in the arterial wall, increased by all risk factors for atherosclerosis, but ROS also induce many “proatherogenic” in vitro cellular responses. 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 loss of NO is important in the pathogenesis of cardiovascular diseases. The increase in NADPH oxidase activity in vascular wall after balloon injury has been reported (Shi et al., 2001,Thrum. Vase.Throm. Vasc.Biol., 2001, 21, 739-745).
It is believed that oxidative stress or free radical damage is also a major causative factor in neurodegenerative diseases. Such damages may include mitochondrial abnormalities, neuronal demyelination, apoptosis, neuronal death and reduced cognitive performance, potentially leading to the development of progressive neurodegenerative disorders (Nunomura et al., 2001, J. Neuropathol. Exp. Neurol., 60: 759-767; Girouard, 2006, J. Appl. Physiol. 100:328-335).
Further, the generation of ROS by sperm has been demonstrated in a large number of species and has been suggested to be attributed to an NADPH oxidase within spermatozoa (Vernet et al., Biol. Reprod., 2001, 65:1102-1113). Excessive ROS generation has been suggested to be implicated in sperm pathology, including male infertility and also in some penile disorders and prostate cancer.
NADPH oxidases are multi-subunit enzymes made up of a membrane-bound cytochrome b558 domain and three cytosolic protein subunits, p47phox, p67phox and a small GTPase, Rac. Seven isoforms of NOX enzymes have been identified including NOX1, NOX2, NOX3, NOX4, NOX5, DUOX1 and DUOX2 (Leto et al., 2006, Antioxid Redox Signal, 8(9-10):1549-61; Cheng et al., 2001, Gene, 16; 269(1-2):131-40).
Thus, ROS derived from NADPH contribute to the pathogenesis of numerous diseases, especially cardiovascular diseases or disorders, respiratory disorder or disease, disease or disorder affecting the metabolism, bone disorders, neurodegenerative diseases, inflammatory diseases, reproduction disorder or disease, pain, cancer and disease or disorders of the gastrointestinal system. Therefore, it would be highly desirable to develop new active agents focusing on the ROS signaling cascade, especially on NADPH oxidases (NOX).
The present invention is directed towards new molecules useful in the treatment and/or prophylaxis of Nicotinamide adenine dinucleotide phosphate oxidase (NADPH Oxidase) related disorders such as cardiovascular diseases, respiratory disorders, disorders affecting the metabolism, skin and/or bone diseases, neurodegenerative diseases, kidney diseases, reproduction disorders, inflammatory disorders, cancers, allergic disorders, traumatisms, septic, hemorrhagic and anaphylactic shock, diseases or disorders of the gastrointestinal system, angiogenesis and angiogenesis-dependent conditions. Notably, the invention is related to new molecules useful in the inhibition or reduction of ROS production in cells.
A first aspect of the invention provides a pyrazolo pyridine derivative according to Formula (I), wherein G, G, G, Gand Gare as defined below, as well as pharmaceutically acceptable salts and pharmaceutically active derivative thereof.
A second aspect of the invention relates to a pyrazolo pyridine derivative according to Formula (I), wherein G, G, G, Gand Gare as defined below, as well as pharmaceutically acceptable salts and pharmaceutically active derivative thereof for use as a medicament.
A third aspect of the invention relates to a pharmaceutical composition containing at least one a pyrazolo pyridine derivative according to the invention, as well as pharmaceutically acceptable salts and pharmaceutically active derivative thereof and a pharmaceutically acceptable carrier, diluent or excipient thereof.
A fourth aspect of the invention resides in a use of a pyrazolo pyridine derivative according to the invention as well as pharmaceutically acceptable salts and pharmaceutically active derivative thereof for the preparation of a pharmaceutical composition for the treatment or prophylaxis of a disease or condition selected from cardiovascular disorders, respiratory disorders, metabolism disorders, skin disorders, bone disorders, neuroinflammatory 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, cancers, allergic disorders, traumatisms, septic, hemorrhagic and anaphylactic shock, diseases or disorders of the gastrointestinal system, angiogenesis and angiogenesis-dependent and/or other diseases and disorders associated with Nicotinamide adenine dinucleotide phosphate oxidase (NADPH Oxidase).
A fifth aspect of the invention relates to a method for treating a patient suffering from a disease or condition selected from cardiovascular disorders, respiratory disorders, metabolism disorders, skin disorders, bone disorders, neuroinflammatory 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, cancers, allergic disorders, traumatisms, septic, hemorrhagic and anaphylactic shock, diseases or disorders of the gastrointestinal system, angiogenesis and angiogenesis-dependent and other diseases and/or disorders associated with Nicotinamide adenine dinucleotide phosphate oxidase (NADPH Oxidase). The method comprises administering a pyrazolo pyridine derivative according to Formula (I), wherein G, G, G, Gand Gare as defined below, as well as pharmaceutically acceptable salts and pharmaceutically active derivative thereof in a patient in need thereof.
A sixth aspect of the invention relates to a pyrazolo pyridine derivative according to Formula (I), wherein G, G, G, Gand Gare as defined below, as well as pharmaceutically acceptable salts and pharmaceutically active derivative thereof, for the treatment of a disease or condition selected from cardiovascular disorders, respiratory disorders, metabolism disorders, skin disorders, bone disorders, neuroinflammatory 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, cancers, allergic disorders, traumatisms, septic, hemorrhagic and anaphylactic shock, diseases or disorders of the gastrointestinal system, angiogenesis and angiogenesis-dependent and other diseases and/or disorders associated with Nicotinamide adenine dinucleotide phosphate oxidase (NADPH Oxidase).
A seventh aspect of the invention relates to an intermediate of Formula (VIII), wherein G, G, Gand Rare as defined below.
An eighth aspect of the invention relates to an intermediate of Formula (X) wherein G, Gand Rare as defined below.
A ninth aspect of the invention relates to a processes for the preparation of intermediates compounds of Formulae (VIII) or (X) according to the invention.
A tenth aspect according to the invention relates to processes for the preparation of a compound of Formula (I) according to the invention.
Other features and advantages of the invention will be apparent from the following detailed description.
The following paragraphs provide definitions of the various chemical moieties that make up the compounds according to the invention and are intended to apply uniformly through-out the specification and claims, unless an otherwise expressly set out definition provides a broader definition.
The term “alkyl” when used alone or in combination with other terms, comprises a straight chain or branched C-Calkyl which refers to monovalent alkyl groups having 1 to 20 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, tetrahydrogeranyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-octadecyl, n-nonadecyl, and n-eicosanyl and the like. Preferably, these include C-Calkyl, more preferably C-Calkyl, especially preferably C-Calkyl, which, by analogy, refer respectively to monovalent alkyl groups having 1 to 9 carbon atoms, monovalent alkyl groups having 1 to 6 carbon atoms and monovalent alkyl groups having 1 to 4 carbon atoms. Particularly, those include C-Calkyl.
The term “alkenyl” when used alone or in combination with other terms, comprises a straight chain or branched C-Calkenyl. It may have any available number of double bonds in any available positions, and the configuration of the double bond may be the (E) or (Z) configuration. This term is exemplified 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-tetradecenyl, 1-octadecenyl, 9-octadecenyl, 1-eicosenyl, and 3,7,11,15-tetramethyl-1-hexadecenyl, and the like. Preferably, these include C-Calkenyl, more preferably C-Calkenyl. Among others, especially preferred are vinyl or ethenyl (—CH═CH), n-2-propenyl (allyl, —CHCH═CH), isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and 3-methyl-2-butenyl and the like.
The term “alkynyl” when used alone or in combination with other terms, comprises a straight chain or branched C-Calkynyl. It may have any available number of triple bonds in any available positions. This term is exemplified by groups such as alkynyl groups that may have a carbon number of 2-20, and optionally a double bond, such as ethynyl (—C≡CH), 1-propynyl, 2-propynyl (propargyl: —CHC≡CH), 2-butynyl, 2-pentene-4-ynyl, and the like. Particularly, these include C-Calkynyl, more preferably C-Calkynyl and the like. Preferably those include C-Calkynyl which refers to groups having 2 to 6 carbon atoms and having at least 1 or 2 sites of alkynyl unsaturation.
The term “heteroalkyl” refers to C-C-alkyl, preferably C-C-alkyl, wherein at least one carbon has been replaced by a heteroatom selected from O, N or S, including 2-methoxy ethyl and the like.
The term “aryl” refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., indenyl, naphthyl). Aryl include phenyl, naphthyl, anthryl, phenanthrenyl and the like.
The term “C-Calkyl aryl” refers to aryl groups having an C-Calkyl substituent, including methyl phenyl, ethyl phenyl and the like.
The term “aryl C-Calkyl” refers to C-Calkyl groups having an aryl substituent, including 3-phenylpropanyl, benzyl and the like.
The term “heteroaryl” refers to a monocyclic heteroaromatic, or a bicyclic or a tricyclic fused-ring heteroaromatic group. Particular examples of heteroaromatic groups include optionally substituted pyridyl, pyrrolyl, pyrimidinyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadia-zolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxa-zolyl, quinolizinyl, quinazolinyl, pthalazinyl, quinoxalinyl, cinnolinyl, napthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl, xanthenyl or benzoquinolyl.
The term “C-Calkyl heteroaryl” refers to heteroaryl groups having a C-Calkyl substituent, including methyl furyl and the like.
The term “heteroaryl C-Calkyl” refers to C-Calkyl groups having a heteroaryl substituent, including furyl methyl and the like.
The term “C-Calkenyl aryl” refers to an aryl groups having a C-Calkenyl substituent, including vinyl phenyl and the like.
The term “aryl C-Calkenyl” refers to a C-Calkenyl groups having an aryl substituent, including phenyl vinyl and the like.
The term “C-Calkenyl heteroaryl” refers to heteroaryl groups having a C-Calkenyl substituent, including vinyl pyridinyl and the like.
The term “heteroaryl C-Calkenyl” refers to C-Calkenyl groups having a heteroaryl substituent, including pyridinyl vinyl and the like.
The term “C-C-cycloalkyl” refers to 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). C-C-cycloalkyl includes cyclopentyl, cyclohexyl, norbornyl and the like.
The term “heterocycloalkyl” refers to a C-C-cycloalkyl group according to the definition above, in which up to 3 carbon atoms are replaced by heteroatoms chosen from the group consisting of O, S, NR, R being defined as hydrogen or methyl. Heterocycloalkyl include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl and the like.
The term “C-Calkyl C-C-cycloalkyl” refers to C-C-cycloalkyl groups having a C-Calkyl substituent, including methyl cyclopentyl and the like.
The term “C-C-cycloalkyl C-Calkyl” refers to C-Calkyl groups having a C-C-cycloalkyl substituent, including 3-cyclopentyl propyl and the like.
The term “C-Calkyl heterocycloalkyl” refers to heterocycloalkyl groups having a C-Calkyl substituent, including 4-methylpiperidinyl and the like.
The term “heterocycloalkyl C-Calkyl” refers to C-Calkyl groups having a heterocycloalkyl substituent, including (1-methylpiperidin-4-yl)methyl and the like.
The term “carboxy” refers to the group —C(O)OH.
The term “carboxy C-Calkyl” refers to C-Calkyl groups having a carboxy substituent, including 2-carboxyethyl and the like.
The term “acyl” refers to the group —C(O)R where R includes H, “alkyl,” preferably “C-Calkyl,” “aryl,” “heteroaryl,” “C-C-cycloalkyl,” “heterocycloalkyl,” “aryl C-Calkyl,” “heteroaryl C-Calkyl,” “C-C-cycloalkyl C-Calkyl” or “heterocycloalkyl C-Calkyl”, including acetyl and the like.
The term “acyl C-Calkyl” to C-Calkyl groups having an acyl substituent, including 2-acetylethyl and the like.
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May 5, 2026
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