WO2008113856A1 - Pyrazolo pyridine derivatives as nadph oxidase inhibitors - Google Patents

Pyrazolo pyridine derivatives as nadph oxidase inhibitors Download PDF

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Publication number
WO2008113856A1
WO2008113856A1 PCT/EP2008/053390 EP2008053390W WO2008113856A1 WO 2008113856 A1 WO2008113856 A1 WO 2008113856A1 EP 2008053390 W EP2008053390 W EP 2008053390W WO 2008113856 A1 WO2008113856 A1 WO 2008113856A1
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WO
WIPO (PCT)
Prior art keywords
pyrazolo
alkyl
pyridine
dione
methyl
Prior art date
Application number
PCT/EP2008/053390
Other languages
French (fr)
Inventor
Patrick Page
Mike Orchard
Laeticia Fioraso-Cartier
Bianca Mottironi
Original Assignee
Genkyo Tex Sa
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to PL08718102T priority Critical patent/PL2139477T3/en
Priority to SI200830863T priority patent/SI2139477T1/en
Priority to AU2008228186A priority patent/AU2008228186C1/en
Priority to RS20130060A priority patent/RS52640B/en
Priority to DK08718102.0T priority patent/DK2139477T3/en
Priority to EP08718102A priority patent/EP2139477B1/en
Priority to BRPI0808824A priority patent/BRPI0808824B8/en
Priority to US12/532,336 priority patent/US8389518B2/en
Application filed by Genkyo Tex Sa filed Critical Genkyo Tex Sa
Priority to CA2676954A priority patent/CA2676954C/en
Priority to ES08718102T priority patent/ES2398994T3/en
Priority to CN200880009282.4A priority patent/CN101686967B/en
Priority to JP2009554036A priority patent/JP5715340B2/en
Publication of WO2008113856A1 publication Critical patent/WO2008113856A1/en
Priority to IL201009A priority patent/IL201009A/en
Priority to HK10108322.0A priority patent/HK1141734A1/en
Priority to US13/734,205 priority patent/US9073919B2/en
Priority to HRP20130143AT priority patent/HRP20130143T1/en

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Definitions

  • 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.
  • 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 are proteins that transfer electrons across biological membranes.
  • 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 2 " ], hydroxyl [HO * ], peroxyl [ROO * ], alkoxyl [RO * ] and hydroperoxyl [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.
  • 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).
  • metabolic reactions e.g. by mitochondrial respiration or activation of recruited inflammatory cells
  • exogenously in the air e.g. cigarette smoke or air pollutants.
  • 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).
  • ROS Reactive oxygen species
  • 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. Vase. Biol, 25, 519-525; Liua et al, 2004, Am. J. Physiol. Lung, Cell. MoI. Physiol, 287: Llll-118). Further, pulmonary fibrosis has been characterized by lung inflammation and excessive generation of ROS.
  • 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 GTP ase, Rac.
  • 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 signalling cascade, especially on NADPH oxidases (NOX).
  • NOX NADPH oxidases
  • a first aspect of the invention provides a pyrazolo pyridine derivative according to Formula (I), wherein Gi, G 2 , G3, G 4 and G5 are 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 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 and/or other diseases and disorders associated with Nicotinamide adenine dinucleotide phosphate oxidase (NADPH Oxidase).
  • 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
  • a fourth 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 and other diseases and/or disorders associated with Nicotinamide adenine dinucleotide phosphate oxidase (NADPH Oxidase).
  • alkynyl when used alone or in combination with other terms, comprises a straight chain or branched C 2 -C 2O alkynyl. 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: -CH 2 C ⁇ CH), 2-butynyl, 2-pentene-4-ynyl, and the like. Preferably, these include C 2 -Cs alkynyl, more preferably C 2 -C 6 alkynyl and the like.
  • aryl alkyl refers to alkyl groups having an aryl substituent, including 3- phenylpropanyl, benzyl and the like.
  • heteroaryl refers to a monocyclic heteroaromatic, or a bicyclic or a tricyclic fused-ring heteroaromatic group.
  • 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, l,3,4-oxadiazolyl,l,3,4-triazinyl, 1,2,3- triazinyl, benzofuryl, [2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, iso
  • heteroaryl alkyl refers to alkyl groups having a heteroaryl substituent, including furyl methyl and the like.
  • aryl alkenyl refers to an alkenyl groups having an aryl substituent, including phenyl vinyl and the like.
  • alkenyl heteroaryl refers to heteroaryl groups having an alkenyl substituent, including vinyl pyridinyl and the like.
  • heterocycloalkyl refers to a Cs-Cs-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.
  • carboxy alkyl refers to alkyl groups having a carboxy substituent, including 2- carboxy ethyl and the like.
  • heteroaryl alkyl Cs-Cg-cycloalkyl alkyl
  • heterocycloalkyl alkyl including acetyl and the like.
  • acyloxy refers to the group -OC(O)R where R includes H, “alkyl”, “alkenyl,”
  • alkoxy refers to the group -0-R where R includes “alkyl”, “aryl”, “heteroaryl”,
  • acylamino refers to the group -NRC(O)R' where R and R' are independently
  • ureido refers to the group -NRC(0)NR'R" where R, R and R" are independently H, “alkyl,” “alkenyl,” “alkynyl,” “C 3 -C 8 -cycloalkyl,” “heterocycloalkyl,”
  • ureido alkyl refers to -alkyl groups having an ureido substituent, including 2-
  • amino alkyl refers to alkyl groups having an amino substituent, including 2-(l- pyrrolidinyl)ethyl and the like.
  • sulfonyloxy refers to a group -OSO 2 -R wherein R is selected from “alkyl,”
  • alkyl substituted with halogens, e.g., an -OSO 2 -CF 3 group, "alkenyl,” “alkynyl,” “C 3 -C 8 - cycloalkyl,” “heterocycloalkyl,” “aryl,” “heteroaryl,” “aryl alkyl”, “heteroaryl alkyl,” “aryl alkenyl,” “heteroaryl alkenyl,” “aryl alkynyl,” “heteroaryl alkynyl,” “cycloalkyl alkyl,” or
  • sulfonyloxy alkyl refers to alkyl groups having a sulfonyloxy substituent, including 2-(methylsulfonyloxy)ethyl and the like.
  • alkenyl "alkynyl,” “C 3 -C 8 -cycloalkyl,” “heterocycloalkyl,” “aryl,” “heteroaryl,” “aryl alkyl”, “heteroaryl alkyl,” “aryl alkenyl,” “heteroaryl alkenyl,” “aryl alkynyl,” “heteroaryl alkynyl,” “cycloalkyl alkyl,” or “heterocycloalkyl alkyl”.
  • sulfonyl alkyl refers to alkyl groups having a sulfonyl substituent, including 2-
  • heterocycloalkyl alkyl is a heterocycloalkyl alkyl
  • sulfonylamino refers to a group -NRSO 2 -R' where R and R' are independently
  • alkyl alkenyl
  • alkynyl alkynyl
  • C 3 -C 8 -cycloalkyl heterocycloalkyl
  • aryl heteroaryl
  • aminosulfonyl refers to a group -SO 2 -NRR' where R and R' are independently
  • salts which are formed from to acid addition salts formed with inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), as well as 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 acid, palmoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene disulfonic acid, and poly-galacturonic acid.
  • inorganic acids e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like
  • organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic
  • cardiovascular disorder or disease comprises atherosclerosis, especially diseases or disorders associated with endothelial dysfunction including but not limited to hypertension, cardiovascular complications of Type I or Type II diabetes, intimal hyperplasia, coronary heart disease, cerebral, coronary or arterial vasospasm, endothelial dysfunction, heart failure including congestive heart failure, peripheral artery disease, restenosis, trauma caused by a stent, stroke, ischemic attack, vascular complications such as after organ transplantation, or viral or bacterial infections, myocardial infarction, hypertension, formation of atherosclerotic plaques, platelet aggregation, angina pectoris, aneurysm, aortic dissection, ischemic heart disease, cardiac hypertrophy, pulmonary embolus, thrombotic events including deep vein thrombosis, injury caused after ischemia by restoration of blood flow or oxygen delivery as in organ transplantation, open heart surgery, angioplasty, hemorrhagic shock, angioplasty of ischemic organ
  • myelopathies any neuroinflammatory condition involving autoreactive leukocyte within the CNS, congenital metabolic disorder, a neuropathy with abnormal myelination, drug induced demyelination, radiation induced demyelination, a hereditary demyelinating condition, a prion induced demyelinating condition, encephalitis induced demyelination or a spinal cord injury.
  • the condition is multiple sclerosis.
  • treatment covers any treatment of a disease in a mammal, particularly a human, and includes: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; or relieving the disease, i.e., causing regression of the disease and/or its symptoms or conditions.
  • Solid compositions of this invention may be in the form of tablets or lozenges formulated in a conventional manner.
  • tablets and capsules for oral administration may contain conventional excipients including, but not limited to, binding agents, fillers, lubricants, disintegrants and wetting agents.
  • Binding agents include, but are not limited to, syrup, accacia, gelatin, sorbitol, tragacanth, mucilage of starch and polyvinylpyrrolidone.
  • Fillers include, but are not limited to, lactose, sugar, microcrystalline cellulose, maizestarch, calcium phosphate, and sorbitol.
  • compositions of this invention may also be formulated for parenteral administration, including, but not limited to, by injection or continuous infusion.
  • Formulations for injection may be in the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents including, but not limited to, suspending, stabilizing, and dispersing agents.
  • the composition may also be provided in a powder form for reconstitution with a suitable vehicle including, but not limited to, sterile, pyrogen-free water.
  • compositions of this invention may also be formulated as a depot preparation, which may be administered by implantation or by intramuscular injection.
  • the compositions may be formulated with suitable polymeric or hydrophobic materials (as an emulsion in an acceptable oil, for example), ion exchange resins, or as sparingly soluble derivatives (as a sparingly soluble salt, for example).
  • patients according to the invention are patients suffering from a respiratory disorder or disease.
  • patients according to the invention are patients suffering from a disease or disorder affecting the metabolism.
  • patients according to the invention are patients suffering from pain, such as inflammatory pain.
  • the invention provides a pyrazolo pyridine derivative according to Formula (I):
  • phenylacetamide optionally substituted C3-Cg-cycloalkyl alkyl, optionally substituted heterocycloalkyl alkyl, optionally substituted aryl alkyl such as optionally substituted phenyl alkyl like optionally substituted phenyl methyl (e.g. phenyl methyl or 3-methyl phenyl methyl or 4-fluorobenzyl or 2-chlorobenzyl or 4-chlorobenzyl or 4-methyl benzyl or 4-bromobenzyl); and optionally substituted heteroaryl alkyl such as optionally substituted pyridine alkyl like pyridine -2 -yl methyl;
  • G 2 is selected from H; optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted aryl such as optionally substituted phenyl (e.g. phenyl or 4-fluorophenyl or 4-methoxyphenyl or 4-nitrophenyl or 2- chlorophenyl or 2-methyl phenyl or 4-(trifluoromethyl) phenyl or 4-(trifluoromethoxy) phenyl or 2,5-difluorophenyl or 2-methoxyphenyl); optionally substituted alkyl aryl; optionally substituted aryl alkyl; optionally substituted heteroaryl, such as optionally substituted benzothiazolyl (e.g.
  • the invention provides a pyrazolo pyridine derivative according to the invention wherein G 4 is selected from optionally substituted alkyl; optionally substituted alkenyl and optionally substituted alkynyl.
  • the invention provides a use of a pyrazolo pyridine derivative according to Formula (I):
  • phenylacetamide optionally substituted cycloalkyl alkyl, optionally substituted heterocycloalkyl alkyl, optionally substituted aryl alkyl such as optionally substituted phenyl alkyl like optionally substituted phenyl methyl (e.g. phenyl methyl or 3-methyl phenyl methyl or 4-fluorobenzyl or 2-chlorobenzyl or 4-chlorobenzyl or 4-methyl benzyl or 4-bromobenzyl); and optionally substituted heteroaryl alkyl such as optionally substituted pyridine alkyl like pyridine -2 -yl methyl;
  • G 1 , G 2 , G 3 , G 4 and G 5 are as described herein; as well as pharmaceutically acceptable salts and pharmaceutically active derivative thereof, for use in 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, disorders of the gastrointestinal system and other diseases and disorders associated with Nicotinamide adenine dinucleotide phosphate oxidase (NADPH Oxidase).
  • 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
  • the compounds of invention have been named according the IUPAC standards used in the program ACD/Name (product version 10.01).
  • Example 7 a Following the general methods as outlined in Example 7 a), starting from (4- fluorophenyl)hydrazine, dimethyl 3-oxopentanedioate, 1,1,1-triethoxypropane and 1- pyridin-2-ylmethanamine, the title compound (49) was isolated as a yellowish solid in 77% yield (99% purity by HPLC). MS(ESI + ): 365.5; MS(ESF): 363.7.
  • Example 60 Measurement of levels of reactive oxygen species in different cell cultures
  • Human microglia cell line HMC3, human microglia clone 3 (Janabi et al, 1995, Neurosci Lett 195:105) were cultured in MEM (Eagle's minimum essential medium) containing 10% FBS with 50 U/ml penicillin G sodium 50 ⁇ g/ml streptomycin sulfate, and incubated at 37°C for 24 hours.
  • IFN- ⁇ human IFN- ⁇ , Roche. 11 040 596 001
  • NBT Nitroblue tetrazolium
  • ROS was measured using the chemiluminescent probe luminol.
  • Cells were cultured and plated as for Amplex Red except that the Amplex Red agent was replaced by 10 ⁇ g/mL luminol (Sigma 09235). Light emission was recorded continuously at 37 0 C for 60 minutes using the luminescence function of the FluoStar Optima fluorescent plate reader. The mean of the four blank values was substracted from each corrected value for each time point. NOX activities were expressed as % of the activity in control cells. Residual activity of DPI-treated cells was usually ⁇ 10%.

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Abstract

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 Nicotin amide adenine dinucleotide phosphate oxidase (NADPH Oxidase).

Description

Pyrazolo pyridine derivatives as NADPH Oxidase inhibitors
Field of the Invention
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).
Background of the Invention
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 [O2 "], hydroxyl [HO*], peroxyl [ROO*], alkoxyl [RO*] and hydroperoxyl [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. Vase. Biol, 25, 519-525; Liua et al, 2004, Am. J. Physiol. Lung, Cell. MoI. Physiol, 287: Llll-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. ScL, 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, Throm. Vase. 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 GTP ase, Rac. Seven isoforms of NOX enzymes have been identified including NOXl, N0X2, N0X3, N0X4, N0X5, DUOXl and DU0X2 (Leto et al, 2006, Antioxid Redox Signal, 8(9-10):1549-61; Cheng et al, 2001, Gene, 16;269(l-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 signalling cascade, especially on NADPH oxidases (NOX).
Summary of the Invention
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 and/or other diseases and disorders associated with Nicotinamide adenine dinucleotide phosphate oxidase (NADPH Oxidase). 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 Gi, G2, G3, G4 and G5 are as defined below, as well as pharmaceutically acceptable salts and pharmaceutically active derivative thereof for use as a medicament.
A second 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 third 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 and/or other diseases and disorders associated with Nicotinamide adenine dinucleotide phosphate oxidase (NADPH Oxidase).
A fourth 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 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 G1, G2, G3, G4 and G5 are as defined below, as well as pharmaceutically acceptable salts and pharmaceutically active derivative thereof in a patient in need thereof.
A fifth aspect of the invention relates to a pyrazolo pyridine derivative according to Formula (I), wherein G1, G2, G3, G4 and G5 are as defined below, as well as pharmaceutically acceptable salts and pharmaceutically active derivative thereof, for use in 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 and other diseases and/or disorders associated with Nicotinamide adenine dinucleotide phosphate oxidase (NADPH Oxidase).
Other features and advantages of the invention will be apparent from the following detailed description.
Detailed Description of the invention
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 throughout 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 C1-C20 alkyl 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 C1-C9 alkyl, more preferably Ci-C6 alkyl, especially preferably Ci -C4 alkyl, 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.
The term "alkenyl" when used alone or in combination with other terms, comprises a straight chain or branched C2-C20 alkenyl. 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-l-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-l-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 C2-Cs alkenyl, more preferably C2-C6 alkenyl. Among others, especially preferred are vinyl or ethenyl (- CH=CH2), n-2-propenyl (allyl, -CH2CH=CH2), isopropenyl, 1-propenyl, 2-methyl-l- 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 C2-C2O alkynyl. 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: -CH2C≡CH), 2-butynyl, 2-pentene-4-ynyl, and the like. Preferably, these include C2-Cs alkynyl, more preferably C2-C6 alkynyl and the like.
The term "heteroalkyl" refers to Ci-Ci2 -alkyl, preferably Ci-C6 -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 "alkyl aryl" refers to aryl groups having an alkyl substituent, including methyl phenyl, ethyl phenyl and the like.
The term "aryl alkyl" refers to alkyl 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, l,3,4-oxadiazolyl,l,3,4-triazinyl, 1,2,3- triazinyl, benzofuryl, [2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo[l,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 "alkyl heteroaryl" refers to heteroaryl groups having an alkyl substituent, including methyl furyl and the like.
The term "heteroaryl alkyl" refers to alkyl groups having a heteroaryl substituent, including furyl methyl and the like.
The term "alkenyl aryl" refers to an aryl groups having an alkenyl substituent, including vinyl phenyl and the like.
The term "aryl alkenyl" refers to an alkenyl groups having an aryl substituent, including phenyl vinyl and the like.
The term "alkenyl heteroaryl" refers to heteroaryl groups having an alkenyl substituent, including vinyl pyridinyl and the like.
The term "heteroaryl alkenyl" refers to alkenyl groups having a Heteroaryl substituent, including pyridinyl vinyl and the like.
The term "Cs-Cs-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).
C3-C8-cycloalkyl includes cyclopentyl, cyclohexyl, norbornyl and the like.
The term "heterocycloalkyl" refers to a Cs-Cs-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 "alkyl Cs-Cs-cycloalkyl" refers to Cs-Cs-cycloalkyl groups having an alkyl substituent, including methyl cyclopentyl and the like. The term "Cs-Cs-cycloalkyl alkyl" refers to alkyl groups having a Cs-Cs-cycloalkyl substituent, including 3-cyclopentyl propyl and the like.
The term "alkyl heterocycloalkyl" refers to heterocycloalkyl groups having an alkyl substituent, including 4-methylpiperidinyl and the like.
The term "heterocycloalkyl alkyl" refers to alkyl groups having a heterocycloalkyl substituent, including (l-methylpiperidin-4-yl) methyl and the like.
The term "carboxy" refers to the group -C(O)OH.
The term "carboxy alkyl" refers to alkyl groups having a carboxy substituent, including 2- carboxy ethyl and the like.
The term "acyl" refers to the group -C(O)R where R includes H, "alkyl," preferably
"alkyl," "aryl," "heteroaryl," "C3-C8-cycloalkyl," "heterocycloalkyl," "aryl alkyl,"
"heteroaryl alkyl," "Cs-Cg-cycloalkyl alkyl" or "heterocycloalkyl alkyl", including acetyl and the like.
The term "acyl alkyl" to alkyl groups having an acyl substituent, including 2-acetylethyl and the like.
The term "acyl aryl" refers to aryl groups having an acyl substituent, including 2- acetylphenyl and the like.
The term "acyloxy" refers to the group -OC(O)R where R includes H, "alkyl", "alkenyl,"
"alkynyl," "C3-C8-cycloalkyl," "heterocycloalkyl," "aryl," "heteroaryl," "aryl alkyl",
"heteroaryl alkyl," "aryl alkenyl," "heteroaryl alkenyl," "aryl alkynyl," "heteroaryl alkynyl," "Cs-Cs-cycloalkyl alkyl," or "heterocycloalkyl alkyl", including acetyloxy and the like.
The term "acyloxy alkyl" refers to alkyl groups having an acyloxy substituent, including 2-
(ethylcarbonyloxy)ethyl and the like.
The term "alkoxy" refers to the group -0-R where R includes "alkyl", "aryl", "heteroaryl",
"aryl alkyl" or "heteroaryl alkyl". Preferred alkoxy groups include for example, methoxy, ethoxy, phenoxy and the like.
The term "alkoxy alkyl" refers to alkyl groups having an alkoxy substituent, including methoxy ethyl and the like. The term "alkoxycarbonyl" refers to the group -C(O)OR where R includes "alkyl", "aryl",
"heteroaryl" , "aryl alkyl", "heteroaryl alkyl" or "heteroalkyl".
The term "alkoxycarbonyl alkyl" refers to alkyl groups having an alkoxycarbonyl substituent, including 2-(benzyloxycarbonyl)ethyl and the like.
The term "aminocarbonyl" refers to the group -C(O)NRR' where R and R' are independently H, alkyl, aryl, heteroaryl, "aryl alkyl" or "heteroaryl alkyl," including N- phenyl carbonyl and the like.
The term "aminocarbonyl alkyl" refers to alkyl groups having an aminocarbonyl substituent, including 2-(dimethylaminocarbonyl)ethyl, N-ethyl acetamidyl, N,N-Diethyl- acetamidyl and the like.
The term "acylamino" refers to the group -NRC(O)R' where R and R' are independently
H, "alkyl," "alkenyl," "alkynyl," "C3-C8-cycloalkyl," "heterocycloalkyl," "aryl,"
"heteroaryl," "aryl alkyl", "heteroaryl alkyl," "aryl alkenyl," "heteroaryl alkenyl," "aryl alkynyl," "heteroaryl alkynyl," "cycloalkyl alkyl," or "heterocycloalkyl alkyl", including acetylamino and the like.
The term "acylamino alkyl" refers to alkyl groups having an acylamino substituent, including 2-(propionylamino)ethyl and the like.
The term "ureido" refers to the group -NRC(0)NR'R" where R, R and R" are independently H, "alkyl," "alkenyl," "alkynyl," "C3-C8-cycloalkyl," "heterocycloalkyl,"
"aryl," "heteroaryl," "aryl alkyl", "heteroaryl alkyl," "aryl alkenyl," "heteroaryl alkenyl,"
"aryl alkynyl," "heteroaryl alkynyl," "cycloalkyl alkyl," or "heterocycloalkyl alkyl," and where R' and R," together with the nitrogen atom to which they are attached, can optionally form a 3-8-membered heterocycloalkyl ring.
The term "ureido alkyl" refers to -alkyl groups having an ureido substituent, including 2-
(/V'-methylureido)ethyl and the like.
The term "carbamate" refers to the group -NRC(O)OR' where R and R' are independently
"alkyl," "alkenyl," "alkynyl," "C3-C8-cycloalkyl," "heterocycloalkyl," "aryl," "heteroaryl,"
"alkyl aryl" , "heteroaryl alkyl," "aryl alkenyl," "heteroaryl alkenyl," "aryl alkynyl,"
"heteroaryl alkynyl," "cycloalkyl alkyl," or "heterocycloalkyl alkyl" and optionally R can also be hydrogen. The term "amino" refers to the group -NRR' where R and R' are independently H , "alkyl",
"aryl", "heteroaryl", "alkyl aryl", "alkyl heteroaryl," "cycloalkyl," or "heterocycloalkyl," and where R and R', together with the nitrogen atom to which they are attached, can optionally form a 3-8-membered heterocycloalkyl ring.
The term "amino alkyl" refers to alkyl groups having an amino substituent, including 2-(l- pyrrolidinyl)ethyl and the like.
The term "ammonium" refers to a positively charged group -N+RR5R" where R, R' and R" are independently "alkyl", "alkyl aryl", "alkyl heteroaryl," "cycloalkyl," or
"heterocycloalkyl," and where R and R', together with the nitrogen atom to which they are attached, can optionally form a 3-8-membered heterocycloalkyl ring.
The term "ammonium alkyl" refers to alkyl groups having an ammonium substituent, including 1-ethylpyrrolidinium and the like.
The term "halogen" refers to fluoro, chloro, bromo and iodo atoms.
The term "sulfonyloxy" refers to a group -OSO2-R wherein R is selected from "alkyl,"
"alkyl" substituted with halogens, e.g., an -OSO2-CF3 group, "alkenyl," "alkynyl," "C3-C8- cycloalkyl," "heterocycloalkyl," "aryl," "heteroaryl," "aryl alkyl", "heteroaryl alkyl," "aryl alkenyl," "heteroaryl alkenyl," "aryl alkynyl," "heteroaryl alkynyl," "cycloalkyl alkyl," or
"heterocycloalkyl alkyl".
The term "sulfonyloxy alkyl" refers to alkyl groups having a sulfonyloxy substituent, including 2-(methylsulfonyloxy)ethyl and the like.
The term "sulfonyl" refers to group "-SO2-R" wherein R is selected from "aryl,"
"heteroaryl," "alkyl," "alkyl" substituted with halogens, e.g., an -SO2-CF3 group,
"alkenyl," "alkynyl," "C3-C8-cycloalkyl," "heterocycloalkyl," "aryl," "heteroaryl," "aryl alkyl", "heteroaryl alkyl," "aryl alkenyl," "heteroaryl alkenyl," "aryl alkynyl," "heteroaryl alkynyl," "cycloalkyl alkyl," or "heterocycloalkyl alkyl".
The term "sulfonyl alkyl" refers to alkyl groups having a sulfonyl substituent, including 2-
(methylsulfonyl)ethyl and the like.
The term "sulfmyl" refers to a group "-S(O)-R" wherein R is selected from "alkyl," "alkyl" substituted with halogens, e.g., a -SO-CF3 group, "alkenyl," "alkynyl," "C3-C8-cycloalkyl,"
"heterocycloalkyl," "aryl," "heteroaryl," "aryl alkyl", "heteroaryl alkyl," "aryl alkenyl," "heteroaryl alkenyl," "aryl alkynyl," "heteroaryl alkynyl," "C3-C8-cycloalkyl alkyl," or
"heterocycloalkyl alkyl".
The term "sulfinyl alkyl" refers to alkyl groups having a sulfmyl substituent, including 2-
(methylsulfinyl)ethyl and the like.
The term "sulfanyl" refers to groups -S-R where R includes H, "alkyl," "alkyl" substituted with halogens, e.g., a -S-CF3 group, "alkenyl," "alkynyl," "C3-C8-cycloalkyl,"
"heterocycloalkyl," "aryl," "heteroaryl," "aryl alkyl", "heteroaryl alkyl," "aryl alkenyl,"
"heteroaryl alkenyl," "aryl alkynyl," "alkynylheteroaryl," "cycloalkyl alkyl," or
"heterocycloalkyl alkyl". Preferred sulfanyl groups include methylsulfanyl, ethylsulfanyl, and the like.
The term "sulfanyl alkyl" refers to Ci-Cs-alkyl groups having a sulfanyl substituent, including 2-(ethylsulfanyl)ethyl and the like.
The term "sulfonylamino" refers to a group -NRSO2-R' where R and R' are independently
"alkyl," "alkenyl," "alkynyl," "C3-C8-cycloalkyl," "heterocycloalkyl," "aryl," "heteroaryl,"
"aryl alkyl", "heteroaryl alkyl," "aryl alkenyl," "heteroaryl alkenyl," "aryl alkynyl,"
"heteroaryl alkynyl," "C3-C8-cycloalkyl alkyl," or "heterocycloalkyl alkyl".
The term "sulfonylamino alkyl" refers to alkyl groups having a sulfonylamino substituent, including 2-(ethylsulfonylamino)ethyl and the like.
The term "aminosulfonyl" refers to a group -SO2-NRR' where R and R' are independently
H, "alkyl," "alkenyl," "alkynyl," "C3-C8-cycloalkyl," "heterocycloalkyl," "aryl,"
"heteroaryl," "aryl alkyl", "heteroaryl alkyl," "aryl alkenyl," "heteroaryl alkenyl," "aryl alkynyl," "heteroaryl alkynyl," "C3-C8-cycloalkyl alkyl," or "heterocycloalkyl alkyl", and where R and R', together with the nitrogen atom to which they are attached, can optionally form a 3-8-membered heterocycloalkyl ring. Aminosulfonyl groups include cyclohexylaminosulfonyl, piperidinylsulfonyl and the like.
The term "aminosulfonyl alkyl" refers to alkyl groups having an aminosulfonyl substituent, including 2-(cyclohexylaminosulfonyl)ethyl and the like.
Unless otherwise constrained by the definition of the individual substituent, the term
"substituted" refers to groups substituted with from 1 to 5 substituents selected from the group consisting of "alkyl," "alkenyl," "alkynyl," "C3-C8-cycloalkyl," "heterocycloalkyl," "alkyl aryl," "alkyl heteroaryl," "alkyl cycloalkyl," "alkyl heterocycloalkyl," "amino," "aminosulfonyl," "ammonium," "acyl amino," "amino carbonyl," "aryl," "heteroaryl," "sulfϊnyl," "sulfonyl," "alkoxy," "alkoxy carbonyl," "carbamate," "sulfanyl," "halogen," trihalomethyl, cyano, hydroxy, mercapto, nitro, and the like.
The term "pharmaceutically acceptable salts or complexes" refers to salts or complexes of the below-specified compounds of Formula (I). Examples of such salts include, but are not restricted, to base addition salts formed by reaction of compounds of Formula (I) with organic or inorganic bases such as hydroxide, carbonate or bicarbonate of a metal cation such as those selected in 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)-l,2-ethanediamine, tromethamine, ethanolamine, diethanolamine, ethylenediamine, N-methylmorpholine, procaine, piperidine, piperazine and the like are contemplated being within the scope of the instant invention.
Also comprised are salts which are formed from to acid addition salts formed with inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), as well as 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 acid, palmoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene disulfonic acid, and poly-galacturonic acid. "Pharmaceutically active derivative" refers to any compound that upon administration to the recipient, is capable of providing directly or indirectly, the activity disclosed herein. The term "indirectly" also encompasses prodrugs which may be converted to the active form of the drug via endogenous enzymes or metabolism. The prodrug is a derivative of the compound according to the invention and presenting NADPH oxidase inhibiting activity that has a chemically or metabolically decomposable group, and a compound that may be converted into a pharmaceutically active compound in vivo by solvolysis under physiological conditions. The invention further encompasses any tautomers of the compounds according to the invention.
The term "cardiovascular disorder or disease" comprises atherosclerosis, especially diseases or disorders associated with endothelial dysfunction including but not limited to hypertension, cardiovascular complications of Type I or Type II diabetes, intimal hyperplasia, coronary heart disease, cerebral, coronary or arterial vasospasm, endothelial dysfunction, heart failure including congestive heart failure, peripheral artery disease, restenosis, trauma caused by a stent, stroke, ischemic attack, vascular complications such as after organ transplantation, or viral or bacterial infections, myocardial infarction, hypertension, formation of atherosclerotic plaques, platelet aggregation, angina pectoris, aneurysm, aortic dissection, ischemic heart disease, cardiac hypertrophy, pulmonary embolus, thrombotic events including deep vein thrombosis, injury caused after ischemia by restoration of blood flow or oxygen delivery as in organ transplantation, open heart surgery, angioplasty, hemorrhagic shock, angioplasty of ischemic organs including heart, brain, liver, kidney, retina and bowel.
The term "respiratory disorder or disease" comprises bronchial asthma, bronchitis, allergic rhinitis, adult respiratory syndrome, cystic fibrosis, lung viral infection (influenza), pulmonary hypertension and chronic obstructive pulmonary diseases (COPD).
The term "allergic disorder" includes hay fever and asthma.
The term "traumatism" includes polytraumatism.
The term "disease or disorder affecting the metabolism" includes obesity, metabolic syndrome and Type II diabetes.
The term "skin disease" or disorder" includes psoriasis, eczema, dermatitis, wound healing and scar formation.
The term "bone disorder" includes osteoporosis, osteoporasis, osteosclerosis, periodontitis, and hyperparathyroidism.
The term "neurodegenerative disease or disorder" comprises a disease or a state characterized by a central nervous system (CNS) degeneration or alteration, especially at the level of the neurons such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, epilepsy and muscular dystrophy. It further comprises neuro-inflammatory and demyelinating states or diseases such as leukoencephalopathies, and leukodystrophies.
The term "demyelinating" is referring to a state or a disease of the CNS comprising the degradation of the myelin around the axons. In the context of the invention, the term demyelinating disease is intended to comprise conditions which comprise a process that demyelinate cells such as multiple sclerosis, progressive multifocal leukoencephalopathy
(PML), myelopathies, any neuroinflammatory condition involving autoreactive leukocyte within the CNS, congenital metabolic disorder, a neuropathy with abnormal myelination, drug induced demyelination, radiation induced demyelination, a hereditary demyelinating condition, a prion induced demyelinating condition, encephalitis induced demyelination or a spinal cord injury. Preferably, the condition is multiple sclerosis.
The term "kidney disease or disorder" includes diabetic nephropathy, renal failure, glomerulonephritis, nephrotoxicity of aminoglycosides and platinum compounds and hyperactive bladder.
The term "reproduction disorder or disease" includes erectile dysfunction, fertility disorders, prostatic hypertrophy and benign prostatic hypertrophy.
The term "disease or disorder affecting the eye and/or the lens" includes cataract including diabetic cataract, re-opacification of the lens post cataract surgery, diabetic and other forms of retinopathy.
The term "conditions affecting the inner ear" includes presbyacusis, tinnitus, Meniere's disease and other balance problems, utriculolithiasis, vestibular migraine, and noise induced hearing loss and drug induced hearing loss (ototoxicity).
The term "inflammatory disorder or disease" means inflammatory bowel disease, sepsis, septic shock, adult respiratory distress syndrome, pancreatitis, shock induced by trauma, bronchial asthma, allergic rhinitis, rheumatoid arthritis, chronic rheumatoid arthritis, arteriosclerosis, intracerebral hemorrhage, cerebral infarction, heart failure, myocardial infarction, psoriasis, cystic fibrosis, stroke, acute bronchitis, chronic bronchitis, acute bronchiolitis, chronic bronchiolitis, osteoarthritis, gout, myelitis, ankylosing spondylitis,
Reuter syndrome, psoriatic arthritis, spondylarthritis, juvenile arthritis or juvenile ankylosing spondylitis, reactive arthritis, infectious arthritis or arthritis after infection, gonococcal arthritis, tuberculous arthritis, viral arthritis, arthritis by bacteria, syphilitic arthritis, Lyme disease, arthritis induced by "angiitis syndrome," polyarteritis nodosa, anaphylactic angiitis, Luegenec granulomatosis, rheumatoid polymyalgia, articular cell rheumatism, calcium crystal deposition arthritis, pseudogout, non-arthritic rheumatism, bursitis, tendosynovitis, epicondyle inflammation (tennis elbow), carpal tunnel syndrome, disorders by repetitive use (typing), mixed form of arthritis, neuropathic arthropathy, hemorrhagic arthritis, vascular peliosis, hypertrophic osteoarthropathy, multicentric reticulohistiocytosis, arthritis induced by specific diseases, blood pigmentation, sickle cell disease and other hemoglobin abnormality, hyperlipoproteinemia, dysgammaglobulinemia, hyperparathyroidism, acromegaly, familial Mediterranean fever, Bechet's disease, systemic autoimmune disease erythematosus, multiple sclerosis and Crohn's disease or diseases like relapsing polychondritis, chronic inflammatory bowel diseases (IBD) or the related diseases which require the administration to a mammal in a therapeutic effective dose of a compound expressed by Formula (I) in a sufficient dose to inhibit NADPH oxidase. The term liver diseases or disorders include liver fibrosis, alcohol induced fibrosis, steatosis and non alcoholic steatohepatitis.
The term "arthritis" means acute rheumatic arthritis, chronic rheumatoid arthritis, chlamydial arthritis, chronic absorptive arthritis, chylous arthritis, arthritis based on bowel disease, filarial arthritis, gonorrheal arthritis, gouty arthritis, hemophilic arthritis, hypertrophic arthritis, juvenile chronic arthritis, Lyme arthritis, neonatal foal arthritis, nodular arthritis, ochronotic arthritis, psoriatic arthritis or suppurative arthritis, or the related diseases which require the administration to a mammal in a therapeutic effective dose of a compound expressed by Formula (I) in a sufficient dose to inhibit NADPH oxidase.
The term "pain" includes hyperalgesia associated with inflammatory pain. The term "cancer" means carcinoma (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endothelium sarcoma, lymphangiosarcoma, lymphangioendothelioma, periosteoma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostatic carcinoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, orchioncus, lung cancer, small-cell lung cancer, bladder cancer or epithelial cancer) or the related diseases which require the administration to a mammal in a therapeutic effective dose of a compound expressed by the Formula (I) in a sufficient dose to inhibit NADPH oxidase.
The term "disease or disorders of the gastrointestinal system", includes gastric mucosa disorders ischemic bowel disease management, enteritis/colitis, cancer chemotherapy, or neutropenia.
As used herein, "treatment" and "treating" and the like generally mean obtaining a desired pharmacological and physiological effect. The effect may be prophylactic in terms of preventing or partially preventing a disease, symptom or condition thereof and/or may be therapeutic in terms of a partial or complete cure of a disease, condition, symptom or adverse effect attributed to the disease. The term "treatment" as used herein covers any treatment of a disease in a mammal, particularly a human, and includes: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; or relieving the disease, i.e., causing regression of the disease and/or its symptoms or conditions.
The term "subject" as used herein refers to mammals. For examples, mammals contemplated by the present invention include human, primates, domesticated animals such as cattle, sheep, pigs, horses and the like.
The term "inhibitor" used in the context of the invention is defined as a molecule that inhibits completely or partially the activity of NADPH oxidase and/or inhibit or reduce the generation of reactive oxygen species (ROS). Compositions
The invention provides pharmaceutical or therapeutic agents as compositions and methods for treating a patient, preferably a mammalian patient, and most preferably a human patient who is suffering from a medical disorder, and in particular a disorder mediated by NADPH oxidase, such as a cardiovascular disorder or disease, a respiratory disorder or disease, a disease or disorder affecting the metabolism, a skin disorder, a bone disorder, a neuroinflammatory disorder, a neurodegenerative disorder, a kidney disease, a reproduction disorder, a disease or disorder affecting the eye and/or the lens, a condition affecting the inner ear, an inflammatory disorder or disease, a liver disease, pain, a cancer and/or a disease or disorders of the gastrointestinal system.
Pharmaceutical compositions of the invention can contain one or more pyrazolo pyridine derivative in any form described herein. Compositions of this invention may further comprise one or more pharmaceutically acceptable additional ingredient(s), such as alum, stabilizers, antimicrobial agents, buffers, coloring agents, flavoring agents, adjuvants, and the like.
The compounds of the invention, together with a conventionally employed adjuvant, carrier, diluent or excipient may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. Compositions according to the invention are preferably injectable.
Compositions of this invention may also be liquid formulations, 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 vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. The compositions may also be formulated as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain additives, including, but not limited to, suspending agents, emulsifying agents, non-aqueous vehicles and preservatives. Suspending agents include, but are not limited to, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate gel, and hydrogenated edible fats. Emulsifying agents include, but are not limited to, lecithin, sorbitan monooleate, and acacia. Nonaqueous vehicles 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 p- hydroxybenzoate and sorbic acid. Further materials as well as processing techniques and the like are set out in Part 5 of Remington' s Pharmaceutical Sciences, 2(f Edition, 2000, Merck Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.
Solid compositions of this invention may be in the form of tablets or lozenges formulated in a conventional manner. For example, tablets and capsules for oral administration may contain conventional excipients including, but not limited to, binding agents, fillers, lubricants, disintegrants and wetting agents. Binding agents include, but are not limited to, syrup, accacia, gelatin, sorbitol, tragacanth, mucilage of starch and polyvinylpyrrolidone. Fillers include, but are not limited to, lactose, sugar, microcrystalline cellulose, maizestarch, calcium phosphate, and sorbitol. Lubricants include, but are not limited to, magnesium stearate, stearic acid, talc, polyethylene glycol, and silica. Disintegrants include, but are not limited to, potato starch and sodium starch glycollate. Wetting agents include, but are not limited to, sodium lauryl sulfate. Tablets may be coated according to methods well known in the art.
Injectable compositions are typically based upon injectable sterile saline or phosphate- buffered saline or other injectable carriers known in the art.
Compositions of this invention may also be formulated as suppositories, which may contain suppository bases including, but not limited to, cocoa butter or glycerides. Compositions of this invention may also be formulated for inhalation, which may be in a form including, but not limited to, a solution, suspension, or emulsion that may be administered as a dry powder or in the form of an aerosol using a propellant, such as dichlorodifluoromethane or trichlorofluoromethane. Compositions of this invention may also be formulated transdermal formulations comprising aqueous or non-aqueous vehicles including, but not limited to, creams, ointments, lotions, pastes, medicated plaster, patch, or membrane. Compositions of this invention may also be formulated for parenteral administration, including, but not limited to, by injection or continuous infusion. Formulations for injection may be in the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents including, but not limited to, suspending, stabilizing, and dispersing agents. The composition may also be provided in a powder form for reconstitution with a suitable vehicle including, but not limited to, sterile, pyrogen-free water.
Compositions of this invention may also be formulated as a depot preparation, which may be administered by implantation or by intramuscular injection. The compositions may be formulated with suitable polymeric or hydrophobic materials (as an emulsion in an acceptable oil, for example), ion exchange resins, or as sparingly soluble derivatives (as a sparingly soluble salt, for example).
Compositions of this invention may also be formulated as a liposome preparation. The liposome preparation can comprise liposomes which penetrate the cells of interest or the stratum corneum, and fuse with the cell membrane, resulting in delivery of the contents of the liposome into the cell. Other suitable formulations can employ 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. The compounds of this invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can also be found in the incorporated materials in Remington's Pharmaceutical Sciences. Mode of administration
Compositions of this invention may be administered in any manner, including, but not limited to, orally, parenterally, sublingually, transdermally, rectally, transmucosally, topically, via inhalation, via buccal or intranasal administration, or combinations thereof. Parenteral administration includes, but is not limited to, intravenous, intra-arterial, intraperitoneal, subcutaneous, intramuscular, intra-thecal, and intra-articular. The compositions of this invention may also be administered in the form of an implant, which allows slow release of the compositions as well as a slow controlled i.v. infusion. In a preferred embodiment, pyrazolo pyridine derivatives according to the invention are administered intravenously or subcutaneously.
This invention is further illustrated by the following examples that are not intended to limit the scope of the invention in any way.
The dosage administered, as single or multiple doses, to an individual will vary depending upon a variety of factors, including pharmacokinetic properties, patient conditions and characteristics (sex, age, body weight, health, size), extent of symptoms, concurrent treatments, frequency of treatment and the effect desired.
Patients
In an embodiment, patients according to the invention are patients suffering from a cardiovascular disorder or disease.
In another embodiment, patients according to the invention are patients suffering from a respiratory disorder or disease.
In another embodiment, patients according to the invention are patients suffering from a disease or disorder affecting the metabolism.
In another embodiment, patients according to the invention are patients suffering from a skin disorder.
In another embodiment, patients according to the invention are patients suffering from a bone disorder.
In another embodiment, patients according to the invention are patients suffering from a neuroinflammatory disorder and/or a neurodegenerative disorder. In another embodiment, patients according to the invention are patients suffering from a kidney disease.
In another embodiment, patients according to the invention are patients suffering from a reproduction disorder.
In another embodiment, patients according to the invention are patients suffering from a disease or disorder affecting the eye and/or the lens and/or a condition affecting the inner ear.
In another embodiment, patients according to the invention are patients suffering from an inflammatory disorder or disease.
In another embodiment, patients according to the invention are patients suffering from a liver disease.
In another embodiment, patients according to the invention are patients suffering from pain, such as inflammatory pain.
In another embodiment, patients according to the invention are patients suffering from a cancer.
In another embodiment, patients according to the invention are patients suffering from allergic disorders.
In another embodiment, patients according to the invention are patients suffering from traumatisms.
In another embodiment, patients according to the invention are patients suffering from septic, hemorrhagic and anaphylactic shock.
In another embodiment, patients according to the invention are patients suffering from a disease or disorders of the gastrointestinal system.
Use according to the invention
In one embodiment, the invention provides a pyrazolo pyridine derivative according to Formula (I):
Figure imgf000024_0001
(I) wherein Gi is selected from H, optionally substituted alkyl such as aminocarbonyl alkyl
(e.g. phenylacetamide), optionally substituted C3-Cg-cycloalkyl alkyl, optionally substituted heterocycloalkyl alkyl, optionally substituted aryl alkyl such as optionally substituted phenyl alkyl like optionally substituted phenyl methyl (e.g. phenyl methyl or 3-methyl phenyl methyl or 4-fluorobenzyl or 2-chlorobenzyl or 4-chlorobenzyl or 4-methyl benzyl or 4-bromobenzyl); and optionally substituted heteroaryl alkyl such as optionally substituted pyridine alkyl like pyridine -2 -yl methyl;
G2 is selected from H; optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted aryl such as optionally substituted phenyl (e.g. phenyl or 4-fluorophenyl or 4-methoxyphenyl or 4-nitrophenyl or 2- chlorophenyl or 2-methyl phenyl or 4-(trifluoromethyl) phenyl or 4-(trifluoromethoxy) phenyl or 2,5-difluorophenyl or 2-methoxyphenyl); optionally substituted alkyl aryl; optionally substituted aryl alkyl; optionally substituted heteroaryl, such as optionally substituted benzothiazolyl (e.g. l,3-benzothiazol-2-yl) or optionally substituted pyridinyl (e.g. pyridin-2-yl); optionally substituted alkyl heteroaryl; optionally substituted heteroaryl alkyl; optionally substituted alkenyl aryl; optionally substituted aryl alkenyl; optionally substituted alkenyl heteroaryl; optionally substituted heteroaryl alkenyl; optionally substituted C3-Cg-cycloalkyl; optionally substituted heterocycloalkyl; optionally substituted alkyl C3-Cg-cycloalkyl; optionally substituted C3-Cg-cycloalkyl alkyl; optionally substituted alkyl heterocycloalkyl and optionally substituted heterocycloalkyl alkyl; G3 is selected from H; optionally substituted alkyl such as methyl or ethyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted aryl such as optionally substituted phenyl (e.g. phenyl); optionally substituted alkyl aryl; optionally substituted aryl alkyl; optionally substituted heteroaryl; optionally substituted alkyl heteroaryl; optionally substituted heteroaryl alkyl; optionally substituted alkenyl aryl; optionally substituted aryl alkenyl; optionally substituted alkenyl heteroaryl; optionally substituted heteroaryl alkenyl; optionally substituted C3-C8-cycloalkyl; optionally substituted heterocycloalkyl; optionally substituted alkyl C3-Cg-cycloalkyl; optionally substituted C3-Cg-cycloalkyl alkyl; optionally substituted alkyl heterocycloalkyl and optionally substituted heterocycloalkyl alkyl;
G4 is selected from H, optionally substituted alkyl such as optionally substituted pentyl (e.g. isopentyl) or optionally substituted heteroalkyl such as optionally substituted methoxy (e.g. 2-methoxyethyl); optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted aryl; optionally substituted alkyl aryl; optionally substituted aryl alkyl such as optionally substituted phenyl methyl (e.g. benzoic acid methyl or benzyl) or optionally substituted phenyl ethyl (e.g. 2-phenyl ethyl, 4-methoxyphenyl ethyl); optionally substituted heteroaryl; optionally substituted alkyl heteroaryl; optionally substituted heteroaryl alkyl such as optionally substituted thiophenyl alkyl like optionally substituted thiophenyl methyl (e.g. thiophen-2-yl methyl) or optionally substituted imidazolyl alkyl like optionally substituted imidazolyl ethyl (e.g. imidazol-4-yl ethyl) or optionally substituted indolyl alkyl like optionally substituted indolyl ethyl (e.g. indol-3-yl ethyl) or optionally substituted furanyl alkyl like optionally substituted furanyl methyl (e.g. furan-2- yl methyl) or optionally substituted benzodioxolyl alkyl like optionally substituted benzodioxolyl methyl (e.g. l,3-benzodioxol-5-yl methyl) or optionally substituted pyridinyl alkyl like optionally substituted pyridinyl methyl (e.g. pyridine-3-yl methyl or pyridin-2-yl methyl); optionally substituted alkenyl aryl; optionally substituted aryl alkenyl; optionally substituted alkenyl heteroaryl; optionally substituted heteroaryl alkenyl; optionally substituted C3-Cg-cycloalkyl; optionally substituted heterocycloalkyl such as optionally substituted morpholinyl (e.g. 5-morpholin-4-yl) or optionally substituted piperazinyl (e.g. 4-methyl piperazinyl) or optionally substituted piperidinyl (e.g. 4-methylbenzyl)piperidin- 4-yl); optionally substituted alkyl C3-Cg-cycloalkyl; and optionally substituted C3-Cg- cycloalkyl alkyl; optionally substituted alkyl heterocycloalkyl and optionally substituted heterocycloalkyl alkyl such as optionally substituted morpholinyl alkyl like optionally substituted morpholinyl propyl (e.g. 3-(morpholin-4-yl) propyl)) optionally substituted morpholinyl ethyl (e.g. 2-morpholin-4-ylethyl); or optionally substituted piperazinyl alkyl like optionally substituted piperazinyl ethyl (e.g. 2-(4-acetylpiperazin-l-yl) ethyl or 2-(4- hexanoyl piperazin-1-yl) ethyl) or optionally substituted pyrrolidinyl alkyl like optionally substituted pyrrolidinyl propyl (e.g. 3-(2-oxopyrrolidin-l-yl) propyl) or optionally substituted tetrahydrofuranyl alkyl like optionally substituted tetrahydrofuranyl methyl (e.g. tetrahydrofuran-2-yl methyl);
G5 is selected from H, optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted aryl; optionally substituted alkyl aryl; optionally substituted aryl alkyl; optionally substituted heteroaryl; optionally substituted alkyl heteroaryl; optionally substituted heteroaryl alkyl; optionally substituted alkenyl aryl; optionally substituted aryl alkenyl; optionally substituted alkenyl heteroaryl; optionally substituted heteroaryl alkenyl; optionally substituted Cs-Cs-cycloalkyl; optionally substituted heterocycloalkyl; optionally substituted alkyl Cs-Cs-cycloalkyl; optionally substituted Cs-Cs-cycloalkyl alkyl; optionally substituted alkyl heterocycloalkyl and optionally substituted heterocycloalkyl alkyl; as well as pharmaceutically acceptable salts and pharmaceutically active derivative thereof, for use as a medicament.
In a further embodiment, the invention provides a pyrazolo pyridine derivative according to the invention wherein Gi is H.
In another further embodiment, the invention provides a pyrazolo pyridine derivative according to the invention wherein Gi is selected from optionally substituted aryl alkyl and optionally substituted heteroaryl alkyl.
In another further embodiment, the invention provides a pyrazolo pyridine derivative according to the invention wherein Gi is optionally substituted alkyl.
In another further embodiment, the invention provides a pyrazolo pyridine derivative according to the invention wherein G2 is selected from optionally substituted aryl and optionally substituted heteroaryl. In another further embodiment, the invention provides a pyrazolo pyridine derivative according to the invention wherein G3 is H.
In another further embodiment, the invention provides a pyrazolo pyridine derivative according to the invention wherein G3 is optionally substituted alkyl, such as optionally substituted methyl.
In another further embodiment, the invention provides a pyrazolo pyridine derivative according to the invention wherein G3 is optionally substituted aryl.
In another further embodiment, the invention provides a pyrazolo pyridine derivative according to the invention wherein G4 is selected from optionally substituted alkyl; optionally substituted alkenyl and optionally substituted alkynyl.
In another further embodiment, the invention provides a pyrazolo pyridine derivative according to the invention wherein G4 is selected from optionally substituted optionally substituted aryl alkyl and substituted heteroaryl alkyl.
In another further embodiment, the invention provides a pyrazolo pyridine derivative according to the invention wherein G4 is optionally substituted optionally substituted C3- Cg-cycloalkyl alkyl and optionally substituted heterocycloalkyl alkyl.
In another further embodiment, the invention provides a pyrazolo pyridine derivative according to the invention wherein G4 is optionally substituted heterocycloalkyl.
In another further embodiment, the invention provides a pyrazolo pyridine derivative according to the invention wherein G5 is H.
In another embodiment, the invention provides a use of a pyrazolo pyridine derivative according to Formula (I):
Figure imgf000028_0001
(I) wherein Gi is selected from H, optionally substituted alkyl such as aminocarbonyl alkyl
(e.g. phenylacetamide), optionally substituted cycloalkyl alkyl, optionally substituted heterocycloalkyl alkyl, optionally substituted aryl alkyl such as optionally substituted phenyl alkyl like optionally substituted phenyl methyl (e.g. phenyl methyl or 3-methyl phenyl methyl or 4-fluorobenzyl or 2-chlorobenzyl or 4-chlorobenzyl or 4-methyl benzyl or 4-bromobenzyl); and optionally substituted heteroaryl alkyl such as optionally substituted pyridine alkyl like pyridine -2 -yl methyl;
G2 is selected from H; optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted aryl such as optionally substituted phenyl (e.g. phenyl or 4-fluorophenyl or 4-methoxyphenyl or 4-nitrophenyl or 2- chlorophenyl or 2-methyl phenyl or 4-(trifluoromethyl) phenyl or 4-(trifluoromethoxy) phenyl or 2,5-difluorophenyl or 2-methoxyphenyl); optionally substituted alkyl aryl; optionally substituted aryl alkyl; optionally substituted heteroaryl, such as optionally substituted benzothiazolyl (e.g. l,3-benzothiazol-2-yl) or optionally substituted pyridinyl (e.g. pyridin-2-yl); optionally substituted alkyl heteroaryl; optionally substituted heteroaryl alkyl; optionally substituted alkenyl aryl; optionally substituted aryl alkenyl; optionally substituted alkenyl heteroaryl; optionally substituted heteroaryl alkenyl; optionally substituted Cs-Cs-cycloalkyl; optionally substituted heterocycloalkyl; optionally substituted alkyl Cs-Cs-cycloalkyl; optionally substituted Cs-Cs-cycloalkyl alkyl; optionally substituted alkyl heterocycloalkyl and optionally substituted heterocycloalkyl alkyl; G3 is selected from H; optionally substituted alkyl such as methyl or ethyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted aryl such as optionally substituted phenyl (e.g. phenyl); optionally substituted alkyl aryl; optionally substituted aryl alkyl; optionally substituted heteroaryl; optionally substituted alkyl heteroaryl; optionally substituted heteroaryl alkyl; optionally substituted alkenyl aryl; optionally substituted aryl alkenyl; optionally substituted alkenyl heteroaryl; optionally substituted heteroaryl alkenyl; optionally substituted C3-C8-cycloalkyl; optionally substituted heterocycloalkyl; optionally substituted alkyl C3-Cg-cycloalkyl; optionally substituted C3-Cg-cycloalkyl alkyl; optionally substituted alkyl heterocycloalkyl and optionally substituted heterocycloalkyl alkyl;
G4 is selected from H, optionally substituted alkyl such as pentyl (e.g. isopentyl) or optionally substituted heteroalkyl such as optionally substituted methoxy (e.g. 2- methoxy ethyl); optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted aryl; optionally substituted alkyl aryl; optionally substituted aryl alkyl such as optionally substituted phenyl methyl (e.g. benzoic acid methyl or benzyl) or optionally substituted phenyl ethyl (e.g. 2-phenyl ethyl, 2-(4-methoxyphenyl) ethyl); optionally substituted heteroaryl; optionally substituted alkyl heteroaryl; optionally substituted heteroaryl alkyl such as optionally substituted thiophenyl alkyl like optionally substituted thiophenyl methyl (e.g. thiophen-2-yl methyl) or optionally substituted imidazolyl alkyl like optionally substituted imidazolyl ethyl (e.g. imidazol-4-yl ethyl) or optionally substituted indolyl alkyl like optionally substituted indolyl ethyl (e.g. indol-3-yl ethyl) or optionally substituted furanyl alkyl like optionally substituted furanyl methyl (e.g. furan-2- yl methyl) or optionally substituted benzodioxolyl alkyl like optionally substituted benzodioxolyl methyl (e.g. l,3-benzodioxol-5-yl methyl) or optionally substituted pyridinyl alkyl like optionally substituted pyridinyl methyl (e.g. pyridine-3-yl methyl or pyridin-2-yl methyl); optionally substituted alkenyl aryl; optionally substituted aryl alkenyl; optionally substituted alkenyl heteroaryl; optionally substituted heteroaryl alkenyl; optionally substituted C3-Cg-cycloalkyl; optionally substituted heterocycloalkyl such as optionally substituted morpholinyl (e.g. 5-morpholin-4-yl) or optionally substituted piperazinyl (e.g. 4-methyl piperazinyl) or optionally substituted piperidinyl (e.g. 4-methylbenzyl)piperidin- 4-yl); optionally substituted alkyl C3-Cg-cycloalkyl; and optionally substituted C3-Cg- cycloalkyl alkyl; optionally substituted alkyl heterocycloalkyl and optionally substituted heterocycloalkyl alkyl such as optionally substituted morpholinyl alkyl like optionally substituted morpholinyl propyl (e.g. 3-(morpholin-4-yl) propyl)), optionally substituted morpholinyl ethyl (e.g. 2-morpholin-4-ylethyl); or optionally substituted piperazinyl alkyl like optionally substituted piperazinyl ethyl (e.g. 2-(4-acetylpiperazin-l-yl) ethyl or 2-(4- hexanoyl piperazin-1-yl) ethyl) or optionally substituted pyrrolidinyl alkyl like optionally substituted pyrrolidinyl propyl (e.g. 3-(2-oxopyrrolidin-l-yl) propyl) or optionally substituted tetrahydrofuranyl alkyl like optionally substituted tetrahydrofuranyl methyl (e.g. tetrahydrofuran-2-yl methyl);
G5 is selected from H, optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted aryl; optionally substituted alkyl aryl; optionally substituted aryl alkyl; optionally substituted heteroaryl; optionally substituted alkyl heteroaryl; optionally substituted heteroaryl alkyl; optionally substituted alkenyl aryl; optionally substituted aryl alkenyl; optionally substituted alkenyl heteroaryl; optionally substituted heteroaryl alkenyl; optionally substituted Cs-Cs-cycloalkyl; optionally substituted heterocycloalkyl; optionally substituted alkyl Cs-Cs-cycloalkyl; optionally substituted Cs-Cs-cycloalkyl alkyl; optionally substituted alkyl heterocycloalkyl and optionally substituted heterocycloalkyl alkyl; 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, disorders of the gastrointestinal system and other diseases and disorders associated with Nicotinamide adenine dinucleotide phosphate oxidase (NADPH Oxidase).
In another embodiment, the invention provides a pyrazolo pyridine derivative according to Formula (I):
Figure imgf000031_0001
(I) wherein G1, G2, G3, G4 and G5 are as described herein; as well as pharmaceutically acceptable salts and pharmaceutically active derivative thereof, for use in 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, disorders of the gastrointestinal system and other diseases and disorders associated with Nicotinamide adenine dinucleotide phosphate oxidase (NADPH Oxidase).
Compounds of the present invention include in particular those selected from the following group:
4-methyl-2-phenyl-5-(thiophen-2-ylmethyl)-lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;
2-(l,3-benzothiazol-2-yl)-5-[2-(lH-imidazol-4-yl)ethyl]-4-methyl-lH-pyrazolo[4,3-c] pyridine-3,6(2H,5H)-dione;
2-(l,3-benzothiazol-2-yl)-5-[2-(lH-indol-3-yl)ethyl]-4-methyl-lH-pyrazolo[4,3-c]pyridine-
3,6(2H,5H)-dione;
2-(l,3-benzothiazol-2-yl)-4-methyl-5-(3-morpholin-4-ylpropyl)-lH-pyrazolo[4,3-c] pyridine-3,6(2H,5H)-dione;
5-(furan-2-ylmethyl)-4-methyl-2-phenyl-lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;
4-{[2-(l,3-benzothiazol-2-yl)-4-methyl-3,6-dioxo-l,2,3,6-tetrahydro-5H-pyrazolo[4,3-c] pyridin-5-yl]methyl}benzoic acid;
4-methyl-2-phenyl-5-(pyridin-3-ylmethyl)-lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione; 4-methyl-2-phenyl-5-(2-phenylethyl)-lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;
5-[2-(4-acetylpiperazin-l-yl)ethyl]-2-(l,3-benzothiazol-2-yl)-4-methyl-lH-pyrazolo[4,3-c] pyridine-3,6(2H,5H)-dione;
2-(l,3-benzothiazol-2-yl)-4-methyl-5-(2-methylbutyl)-lH-pyrazolo[4,3-c]pyridine-3,6
(2H,5H)-dione;
2-(l,3-benzothiazol-2-yl)-5-[2-(4-methoxyphenyl)ethyl]-4-methyl-lH-pyrazolo[4,3-c] pyridine-3,6(2H,5H)-dione;
2-(l,3-benzothiazol-2-yl)-5-[2-(4-hexanoylpiperazin-l-yl)ethyl]-4-methyl-lH-pyrazolo
[4,3-c]pyridine-3,6(2H,5H)-dione;
2-(l,3-benzothiazol-2-yl)-l-benzyl-5-(furan-2-ylmethyl)-4-methyl-lH-pyrazolo[4,3-c] pyridine-3,6(2H,5H)-dione;
5-[2-(lH-indol-3-yl)ethyl]-4-methyl-l-(3-methylbenzyl)-2-phenyl-lH-pyrazolo[4,3-c] pyridine-3,6(2H,5H)-dione; l-(4-fluorobenzyl)-5-[2-(lH-indol-3-yl)ethyl]-4-methyl-2-phenyl-lH-pyrazolo[4,3-c] pyridine-3,6(2H,5H)-dione; l-(2-chlorobenzyl)-4-methyl-5-[3-(2-oxopyrrolidin-l-yl)propyl]-2-phenyl-lH-pyrazolo
[4,3-c]pyridine-3,6(2H,5H)-dione;
2-( 1 ,3 -benzothiazol-2-yl)- 1 -benzyl-4-methyl-5 -(tetrahydrofuran-2-ylmethyl)- 1 H-pyrazolo
[4,3-c]pyridine-3,6(2H,5H)-dione; l-(4-chlorobenzyl)-5-[2-(lH-imidazol-4-yl)ethyl]-4-methyl-2-phenyl-lH-pyrazolo[4,3- c]pyridine-3,6(2H,5H)-dione; and
5-(l,3-benzodioxol-5-ylmethyl)-4-methyl-2-phenyl-lH-pyrazolo[4,3-c]pyridine-3,6
(2H,5H)-dione;
5-benzyl-4-methyl-2 -phenyl- lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;
5-benzyl-2-(4-fluorophenyl)-4-methyl-lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;
5-benzyl-2-(4-methoxyphenyl)-4-methyl-lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;
2-(l,3-benzothiazol-2-yl)-4-methyl-5-morpholin-4-yl-lH-pyrazolo[4,3-c]pyridine-3,6
(2H,5H)-dione;
5-benzyl-4-methyl-2-(4-nitrophenyl)-lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione; 2-(l,3-benzothiazol-2-yl)-4-methyl-l-(3-methylbenzyl)-5-(3-morpholin-4-ylpropyl)-lH- pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;
2-(l,3-benzothiazol-2-yl)-l-(4-fluorobenzyl)-4-methyl-5-(3-morpholin-4-ylpropyl)-lH- pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;
2-(l,3-benzothiazol-2-yl)-4-methyl-l-(4-methylbenzyl)-5-(3-morpholin-4-ylpropyl)-lH- pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;
2-(l,3-benzothiazol-2-yl)-l-(2-chlorobenzyl)-4-methyl-5-morpholin-4-yl-lH-pyrazolo[4,3- c]pyridine-3,6(2H,5H)-dione;
2-(l,3-benzothiazol-2-yl)-l-(4-bromobenzyl)-4-methyl-5-(2-morpholin-4-ylethyl)-lH- pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;
2-[2-(l,3-benzothiazol-2-yl)-4-methyl-5-(3-morpholin-4-ylpropyl)-3,6-dioxo-2,3,5,6- tetrahydro- lH-pyrazolo[4,3-c]pyridin- 1 -yl]-N-phenylacetamide;
4-methyl-2-phenyl-5-(tetrahydrofuran-2-ylmethyl)-lH-pyrazolo[4,3-c]pyridine-3,6
(2H,5H)-dione;
2-(l,3-benzothiazol-2-yl)-4-methyl-5-(2-phenylethyl)-lH-pyrazolo[4,3-c]pyridine-
3,6(2H,5H)-dione;
5-[2-(lH-indol-3-yl)ethyl]-4-methyl-2-phenyl-lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)- dione;
4-methyl-5-morpholin-4-yl-2-phenyl-lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;
2-(l,3-benzothiazol-2-yl)-l-(2-chlorobenzyl)-4-methyl-5-(3-morpholin-4-ylpropyl)-lH- pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;
5-benzyl-4-ethyl-2-(4-fluorophenyl)-lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;
4-ethyl-2-(4-fluorophenyl)-5-(2-phenylethyl)-lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)- dione;
4-ethyl-2-(4-fluorophenyl)-5-morpholin-4-yl-lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)- dione;
4-methyl-5-(2-morpholin-4-ylethyl)-2-phenyl-lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)- dione;
4-ethyl-5-morpholin-4-yl-2-phenyl-lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione; 2-(2-chlorophenyl)-4-methyl-5-(pyridin-2-ylmethyl)-lH-pyrazolo[4,3-c]pyridine-3,6
(2H,5H)-dione;
4-methyl-2-(2-methylphenyl)-5 -(3 -morpholin-4-ylpropyl)- 1 H-pyrazolo [4,3 -c]pyridine-
3,6(2H,5H)-dione;
2-( 1 ,3 -benzothiazol-2-yl)-4-methyl- 1 -(pyridin-2-ylmethyl)-5 -(tetrahydrofuran-2-ylmethyl)- lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;
2-(l,3-benzothiazol-2-yl)-4-ethyl-5-(pyridin-2-ylmethyl)-lH-pyrazolo[4,3-c]pyridine-3,6
(2H,5H)-dione;
2-(l,3-benzothiazol-2-yl)-4-ethyl-5-(3-morpholin-4-ylpropyl)-lH-pyrazolo[4,3-c]pyridine-
3,6(2H,5H)-dione;
2-(l,3-benzothiazol-2-yl)-4-ethyl-5-(2-methoxyethyl)-lH-pyrazolo[4,3-c]pyridine-3,6
(2H,5H)-dione;
2-(l,3-benzothiazol-2-yl)-4-ethyl-5-(4-methylpiperazin-l-yl)-lH-pyrazolo[4,3-c]pyridine-
3,6(2H,5H)-dione;
2-(l,3-benzothiazol-2-yl)-4-ethyl-5-[l-(4-methylbenzyl)piperidin-4-yl]-lH-pyrazolo[4,3-c] pyridine-3,6(2H,5H)-dione;
4-ethyl-2-(4-fluorophenyl)-5-(pyridin-2-ylmethyl)-lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)- dione;
4-ethyl-2-(4-fluorophenyl)-5-(3-morpholin-4-ylpropyl)-lH-pyrazolo[4,3-c]pyridine-3,6
(2H,5H)-dione;
4-ethyl-2-(4-fluorophenyl)-5-(2-methoxyethyl)-lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)- dione;
5-(2-morpholin-4-ylethyl)-2-pyridin-2-yl-lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;
2,4-diphenyl-5-(pyridin-3-ylmethyl)-lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;
2-(2-chlorophenyl)-4-ethyl-5-(pyridin-3-ylmethyl)-lH-pyrazolo[4,3-c]pyridine-3,6
(2H,5H)-dione;
4-methyl-2-(2-methylphenyl)-5-(pyridin-2-ylmethyl)-lH-pyrazolo[4,3-c]pyridine-3,6
(2H,5H)-dione;
4-ethyl-5-(3-morpholin-4-ylpropyl)-2-[4-(trifluoromethyl)phenyl]-lH-pyrazolo[4,3-c] pyridine-3,6(2H,5H)-dione; 4-ethyl-5-(3-morpholin-4-ylpropyl)-2-[4-(trifluoromethoxy)phenyl]-lH-pyrazolo[4,3-c] pyridine-3,6(2H,5H)-dione;
2-(2,5-difluorophenyl)-4-ethyl-5-(3-morpholin-4-ylpropyl)-lH-pyrazolo[4,3-c]pyridine-3,6
(2H,5H)-dione; and
4-ethyl-2-(2-methoxyphenyl)-5-(3-morpholin-4-ylpropyl)-lH-pyrazolo[4,3-c]pyridine-3,6
(2H,5H)-dione.
In another embodiment, the invention provides 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, disorders of the gastrointestinal system and other diseases and disorders associated with Nicotinamide adenine dinucleotide phosphate oxidase (NADPH Oxidase). The method comprises administering a compound according to Formula (I) in a patient in need thereof.
In another embodiment, the invention provides a pyrazolo pyridine derivative according to the invention; 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, disorders of the gastrointestinal system and other diseases and disorders associated with Nicotinamide adenine dinucleotide phosphate oxidase (NADPH Oxidase). In another embodiment, the invention provides a pharmaceutical composition containing at least one derivative pyrazolo pyridine according to Formula (I) and a pharmaceutically acceptable carrier, diluent or excipient thereof.
The compounds of invention have been named according the IUPAC standards used in the program ACD/Name (product version 10.01).
Compounds according to the present invention also comprise its tautomers, its geometrical isomers, its optically active forms as enantiomers, diastereomers and its racemate forms, as well as pharmaceutically acceptable salts thereof. The derivatives exemplified in this invention may be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred experimental conditions (i.e. reaction temperatures, time, moles of reagents, solvents etc.) are given, other experimental conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by the person skilled in the art, using routine optimisation procedures.
References cited herein are hereby incorporated by reference in their entirety. The present invention is not to be limited in scope by the specific embodiments described herein, which are intended as single illustrations of individual aspects of the invention, and functionally equivalent methods and components are within the scope of the invention. Indeed, various modifications of the invention, in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.
The invention having been described, the following examples are presented by way of illustration, and not limitation.
Synthesis of compounds of the invention:
The novel derivatives according to Formula (I) can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred experimental conditions (i.e. reaction temperatures, time, moles of reagents, solvents etc.) are given, other experimental conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by the person skilled in the art, using routine optimisation procedures.
The general synthetic approach for obtaining compounds of Formula (I) is depicted in Scheme 1 below.
Scheme 1
Figure imgf000037_0001
R1 = Me, Et, Pr, iPr, Bu
,NH2 Toluene
(N)
Figure imgf000037_0002
G1 as described above G1 = H
(Ib) (Ia) (VIII)
Pyrazolo pyridine derivatives according to Formula (I), whereby the substituents G1, G2, G3, G4 and G5 are as above defined, may be prepared in three chemical steps, from custom made or commercially available substituted hydrazine derivatives according to Formula (VI), acetone dicarboxylate derivatives according to Formula (V), primary amine derivatives according to Formula (II) and trialkyl ortho ester derivatives according to Formula (III), following synthetic protocol highlighted as outlined in the Scheme 1 below. In a more specific method, a hydrazine derivative according to Formula (VI) wherein G2 is defined as above is reacted with an acetone dicarboxylate derivative according to Formula (V) wherein G5 and R1 are defined as above, in neutral and under refluxing conditions in a suitable solvents like benzene, toluene or other unreactive solvents over time depending of the intrinsic reactivity of compounds according to Formula (VI) to give the corresponding 4-substituted 2-hydroxyl pyrazole derivatives according to Formula (IV). The intermediate compounds according to Formula (IV) are further reacted with trialkyl ortho ester derivatives according to Formula (III) wherein G3 and R2 are defined as above, to allow formation of an intermediate of Formula (VII) in presence of acetic acid and under refluxing conditions. Intermediate compounds of Formula (VII) are further treated with primary amine derivatives according to Formula (II) wherein G4 is defined as above, in solvents such as toluene or benzene under refluxing conditions, to obtain the intermediate compounds of Formula (VIII). The pyrazolo derivatives according to Formula (Ia), i.e. of Formula (I) wherein Gi is H, are isolated after cyclisation of intermediate compounds of Formula (VIII), preferably in protic solvents in presence of base such as sodium methanolate, sodium isopropanolate or the like, using standard refluxing conditions well known to the person skilled in the art as shown in the Scheme 1.
This reaction may be performed in solvents like methanol, ethanol, isopropanol or other unreactive solvents at room temperature over time depending of the intrinsic reactivity of compounds according to Formula (VIII), but usually required the need of traditional thermic heating or microwave methods, using standard conditions well known to the person skilled in the art as shown in Scheme 1, above. In a subsequent step, the pyrazolo pyridine derivatives of Formula (Ia) were treated with an alkylating agent such as alkyl chlorides, bromides, iodides or mesylates, wherein Gi is defined as above, in 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, by traditional thermic method or using microwave technology. Following this process the pyrazolo pyridine derivatives according to Formula (I) are isolated, using standard conditions well known to the person skilled in the art as shown in the Scheme 1. The following abbreviations refer respectively to the definitions below:
A (Angstrom), Ac2O (Acetic anhydride), eq. (equivalent), min (minute), h (hour), g (gram), MHz (Megahertz), niL (milliliter), mm (millimetre), mmol (millimole), mM (millimolar), ng (nanogram), nm (nanometer), rt (room temperature), NADPH (Nicotinamide adenine dinucelotide diphosphate reduced form), BSA (Bovine serum albumin), DCF (2,7-dichlorodihydrofluorescein), DCM (dichloromethane), DIPEA (di- isopropyl ethylamine), DMSO (Dimethyl Sulfoxide), DMF (N,N-Dimethylformamide), DAPI (4,6 Diamidino-2-phenylindole), DPI (Diphenyl-iodonium), cHex (Cyclohexane), EDTA (ethylenediaminetetraacetic acid), EGF (Epidermal Growth Factor), EtOAc (Ethyl acetate), FC (Flash Chromatography on silica gel), HBSS (Hank's Buffered Salt Solution), HPLC (High performance liquid chromatography), H2DCF-DA (2',T- dichlorodihydrofluorescein diacetate), MEM (2-methoxyethoxymethyl), MS (Mass Spectrometry), NBT (Nitroblue tetrazolium), NMR (Nuclear magnetic resonance), PBS (Phosphate Buffered Saline), PetEther (Petroleum ether), TEA (Triethyl amine), TFA (Trifluoroacetic acid), TGF-β (Tumor Growth Factor beta), THF (Tetrahydrofuran), tBuOK (Potassium tert-butoxide), ROS (Reactive oxygen species), SOD (Superoxide dismutase), SPA (Scintillation proximity assay), TLC (Thin layer chromatography), UV (Ultraviolet).
If the above set of general synthetic methods is not applicable to obtain compounds according to Formula (I) and/or necessary intermediates for the synthesis of compounds of Formula (I), suitable methods of preparation known by a person skilled in the art should be used. In general, the synthesis pathways for any individual compound of Formula (I) will depend on the specific substituents of each molecule and upon the ready availability of intermediates necessary; again such factors being appreciated by those of ordinary skill in the art. For all the protection and deprotection methods, see Philip J. Kocienski, in "Protecting Groups", Georg Thieme Verlag Stuttgart, New York, 1994 and, Theodora W. Greene and Peter G. M. Wuts in "Protective Groups in Organic Synthesis", Wiley Interscience, 3rd Edition 1999. Compounds of this invention can be isolated in association with solvent molecules by crystallization from evaporation of an appropriate solvent. The pharmaceutically acceptable acid addition salts of the compounds of Formula (I), which contain a basic center, may be prepared in a conventional manner. For example, a solution of the free base may be treated with a suitable acid, either neat or in a suitable solution, and the resulting salt isolated either by filtration or by evaporation under vacuum of the reaction solvent. Pharmaceutically acceptable base addition salts may be obtained in an analogous manner by treating a solution of compound of Formula (I) with a suitable base. Both types of salts may be formed or interconverted using ion-exchange resin techniques.
In the following the present invention shall be illustrated by means of some examples, which are not to be viewed as limiting the scope of the invention.
The HPLC, NMR and MS data provided in the examples described below are obtained as followed: HPLC: column Waters Symmetry C8 50 x 4.6 mm, Conditions: MeCN/H2O, 5 to 100% (8 min), max plot 230-400 nm; Mass spectra: PE-SCIEX API 150 EX (APCI and ESI), LC/MS spectra: Waters ZMD (ES); 1H-NMR: Bruker DPX-300MHz.
The preparative HPLC purifications are performed with HPLC Waters Prep LC 4000 System equipped with columns Prep Nova-Pak®HR C 186 μm 6θA, 40x30 mm (up to 100 mg) or with XTerra® Prep MS C 8, 10 μm, 50x300 mm (up to Ig). All the purifications are performed with a gradient of MeCN/H2O 0.09% TFA; UV detection at 254 nm and 220 nm; flow 20 mL/min (up to 50 mg). TLC Analysis is performed on Merck Precoated 60 F254 plates. Purifications by flash chromatography are performed on SiO2 support, using cyclohexane/EtOAc or DCM/MeOH mixtures as eluents.
Example 1: Formation of 4-methyl-2-phenyl-5-(thiophen-2-ylmethyl)-lH-pyrazolo [4,3-clpyridine-3,6(2H,5H)-dione (l)(Compound Ia, Scheme 1)
Figure imgf000040_0001
Following the general methods as outlined in Example 7 below, starting from phenylhydrazine, dimethyl 3-oxopentanedioate, 1,1,1-triethoxy ethane and l-thiophen-2- ylmethanamine, the title compound (1) was isolated as a white solid in 70% yield (98% purity by HPLC). MS(ESI+): 338.6; MS(ESI ): 336.4.
Example 2: Formation of 2-(l,3-benzothiazol-2-yr)-5-r2-(lH-imidazol-4-ylkthyll-4- methyl-lH-pyrazolor4.,3-clpyridine-3.l6(2H.,5H)-dione (2HCompound Ia, Scheme 1)
Figure imgf000041_0001
Following the general methods as outlined in Example 7, starting from 2-hydrazino-l,3- benzothiazole, dimethyl 3-oxopentanedioate, 1,1,1-triethoxy ethane and 2-(lH-imidazol-5- yl)ethanamine, the title compound (2) was isolated as a yellow-beige solid in 75% yield (98% purity by HPLC). MS(ESI+): 393.5; MS(ESL): 391.6.
Example 3: Formation of 2-α,3-benzothiazol-2-yl)-5-[2-αH-indol-3-yl)ethyll-4-methyl -lH-pyrazolo[4,3-clpyridine-3.,6f2H,5H)-dione (3)(Compound Ia, Scheme 1)
Figure imgf000041_0002
Following the general methods as outlined in Example 7, starting from 2-hydrazino-l,3- benzothiazole, dimethyl 3-oxopentanedioate, 1,1,1-triethoxy ethane and 2-(lH-indol-3- yl)ethanamine, the title compound (3) was isolated as a white solid in 76% yield (98% purity by HPLC). MS(ESI+): 442.6; MS(ESL): 440.7.
Example 4: Formation of 2-(l.,3-benzothiazol-2-yl)-4-methyl-5-(3-morpholin-4-yl propyl)-lH-pyrazolor4,3-clpyridine-3,6(^H,5H)-dione (4)(Compound Ia, Scheme 1)
Figure imgf000041_0003
Following the general methods as outlined in Example 7, starting from 2-hydrazino-l,3- benzothiazole, dimethyl 3-oxopentanedioate, 1,1,1-triethoxy ethane and 3-morpholin-4- ylpropan-1 -amine, the title compound (4) was isolated as a white solid in 72% yield (96% purity by HPLC). MS(ESI+): 426.6; MS(ESF): 424.7.
Example 5: Formation of 5-ffuran-2-ylmethyl)-4-methyl-2-phenyl-lH-pyrazolo[4,3- clpyridine-3.,6(2H.,5H)-dione (5)(Compound Ia, Scheme 1)
Figure imgf000042_0001
Following the general methods as outlined in Example 7, starting from phenylhydrazine, dimethyl 3-oxopentanedioate, 1,1,1-triethoxy ethane and l-furan-2-ylmethanamine, the title compound (5) was isolated as a white solid in 79% yield (96% purity by HPLC). MS(ESI+): 322.5; MS(ESF): 320.4.
Example 6: Formation of 4-{[2-fl,3-benzothiazol-2-yl)-4-methyl-3.l6-dioxo-l.l2,3i6- tetrahydro-SH-pyrazolo [4,3-cl pyridin-5-yll methyljbenzoic acid (6)(Compound Ia, Scheme 1)
Figure imgf000042_0002
Following the general methods as outlined in Example 7, starting from 2-hydrazino-l,3- benzothiazole, dimethyl 3-oxopentanedioate, 1,1,1-triethoxy ethane and 4-(aminomethyl) benzoic acid, the title compound (6) was isolated as a white solid in 78% yield (99% purity by HPLC). MS(ESI+): 433.5; MS(ESF): 431.4. Example 7: Formation of 4-methyl-2-phenyl-5-fpyridin-3-ylmethyl)-lH-pyrazolo[4,3- cl pyridine-3.,6(2H.,5H)-dione (7)(Compound Ia, Scheme 1)
Figure imgf000043_0001
a) Methyl (S-hydroxy-l-phenyl-lH-pyrazol-S-ylJacetate (Compound of Formula (IV), Scheme 1). The mixture of dimethyl 3-oxopentanedioate (10 mmol, 1.74 g) and phenylhydrazine (10 mmol, 1.08 g) in dry benzene (50 ml) was refluxed for 8 h, then solvent was removed in vacuo and the title compound was separated by recrystallization from i-PrOH (20 ml). Yield: 80 %. 1HNMR (500 MHz, DMSO-d6, ppm): 3.49(2H, s), 3.68(3H, s), 5.43(1H, s), 7.12 (IH, t , 7.4Hz), 7.35(2H, t, 7.6Hz), 7.78(2H, d, 7.9Hz), I Ll(IH, bs)
b) Methyl [(4Z)-4-(l-ethoxyethylidene)-5-oxo-l-phenyl-4,5-dihydro-lH-pyrazol-3- yl] acetate (Compound of Formula (VII), Scheme 1). The mixture of the above obtained methyl (5 -hydroxy- 1 -phenyl- lH-pyrazol-3-yl)acetate (Compound of Formula (IV), 1.85 g), acetic anhydride (1.00 ml) and MeC(OEt)3 (2.50 ml) was refluxed for 1 h. and left overnight at an ambient temperature. Resulting precipitate was collected by filtration and washed with ethyl ether (10 ml) in order to obtain crude product methyl [(4Z)-4-(l- ethoxyethylidene)-5-oxo-l-phenyl-4,5-dihydro-lH-pyrazol-3-yl]acetate (1.20 g, 80 % purity) in 50 % yields. 1HNMR (400 MHz, CDC13, ppm): 1.42(3H, t, 7.1Hz), 2.78(3H, s), 3.73(3H, s), 3.76(2H, s), 4.31(2H, q, 6.9Hz), 7.16 (IH, t , 7.2Hz), 7.37(2H, t, 7.6Hz), 7.97(2H, d, 8.0Hz). MS(ESI+): 303.3; MS(ESI ): 301.2.
c) Methyl [(4Z)-5-oxo-l-phenyl-4-{l-[(pyridin-3-ylmethyl)amino]ethylidene}-4,5- dihydro-lH-pyrazol-3-yl] acetate (Compound of Formula (VIII), Scheme 1). The mixture of the above obtained methyl [(4Z)-4-(l-ethoxyethylidene)-5-oxo-l-phenyl-4,5- dihydro-lH-pyrazol-3-yl] acetate (Compound of Formula (VII), 1.20 g) and 3- aminomethylpyridine (0.45 g) was refluxed in toluene (20 ml) for 0.5 h and left overnight at an ambient temperature. Resulting expected product methyl [(4Z)-5-oxo-l-phenyl-4-{l- [(pyridin-3-ylmethyl)amino]ethylidene}-4,5-dihydro-lH-pyrazol-3-yl]acetate (0.87 g) was collected by filtration and washed with ethyl ether (20 ml). Yield 60 %. 1HNMR (400 MHz, CDC13, ppm): 2.38(3H, s), 3.71(3H, s), 3.82(2H, s), 4.71(2H, d, 5.9Hz), 7.18 (IH, t , 7.2Hz), 7.38(3H, m), 7.7O(1H, d, 7.7Hz), 7.97(2H, d, 8.0Hz), 8.63(2H, bs), 12.17QH, bs). MS(ESI+): 365.3; MS(ESI ): 363.5.
d) 4-methyl-2-phenyl-5-(pyridin-3-ylmethyl)-lH-pyrazolor4,3-cl pyridine-3,6(2H,5H)- dione (7)( Compound of Formula (Ia), Scheme 1)
An isopropanolic solution of NaOi-Pr, obtained by dissolving of sodium (0.055 g) in i- PrOH (50 ml), was treated with the above obtained methyl [(4Z)-5-oxo-l-phenyl-4-{l- [(pyridin-3-ylmethyl)amino]ethylidene}-4,5-dihydro-lH-pyrazol-3-yl]acetate (Compound of Formula (VIII), 0.87 g). The reaction mixture was refluxed for 9 h, then cooled and neutralized to pH 7 with aqueous HCl solution (20 %). The precipitate formed was filtered off, washed with water (20 ml) and air-dried. 0.46g of chromatographically pure product was obtained in yield of 58 %. 1HNMR (400MHz, DMSO-d6, ppm): 2.77(3H, s), 5.38(2H, s), 5.82(1H, s), 7.18 (IH, t , 7.5Hz), 7.36(1H, m), 7.45(2H, t, 7.6Hz), 7.56(1H, d, 7.7Hz), 7.73(2H, d, 8.0Hz), 8.49(2H, bs), 10.8(1H, bs) . MS(ESI+): 333.5; MS(ESF): 331.5.
Example 8: Formation of 4-methyl-2-phenyl-5-f2-phenylethyl)-lH-pyrazolo[4,3-cl pyridine-3.,6f2H,5H)-dione (8)(Compound Ia, Scheme 1)
Figure imgf000044_0001
Following the general methods as outlined in Example 7, starting from phenylhydrazine, dimethyl 3-oxopentanedioate, 1,1,1-triethoxy ethane and 2-phenylethanamine, the title compound (8) was isolated as a white solid in 80% yield (98% purity by HPLC). MS(ESI+): 346.7; MS(ESF): 344.5. Example 9: Formation of 5-[2-f4-acetylpiperazin-l-yl)ethyll-2-fl,3-benzothiazol-2-yl)- 4-methyl-lH-pyrazolo [4,3-cl pyridine-3.,6( 2H,5H)-dione (9)( Compound Ia, Scheme 1)
Figure imgf000045_0001
Following the general methods as outlined in Example 7, starting from 2-hydrazino-l,3- benzothiazole, dimethyl 3-oxopentanedioate, 1,1,1-triethoxy ethane and 2-(4- acetylpiperazin-l-yl)ethanamine, the title compound (9) was isolated as a white solid in 73% yield (94% purity by HPLC). MS(ESI+): 453.6; MS(ESF): 451.7.
Example 10: Formation of 2-q,3-benzothiazol-2-yl)-4-methyl-5-q-methylbutylMH- pyrazolo[4,3-clpyridine-3.,6f2H,5H)-dione (lOHCompound Ia, Scheme 1)
Figure imgf000045_0002
Following the general methods as outlined in Example 7, starting from 2-hydrazino-l,3- benzothiazole, dimethyl 3-oxopentanedioate, 1,1,1-triethoxy ethane and 2-methylbutan-l- amine, the title compound (10) was isolated as a white solid in 77% yield (99% purity by HPLC). MS(ESI+): 369.7; MS(ESF): 367.8.
Example 11: Formation of 2-fl,3-benzothiazol-2-yl)-5-[2-f4-methoxyphenyl)ethyll-4- methyl-lH-pyrazolor4,3-clpyridine-3,6(^H,5H)-dione (ll)(Compound Ia, Scheme 1)
Figure imgf000045_0003
Following the general methods as outlined in Example 7, starting from 2-hydrazino-l,3- benzothiazole, dimethyl 3-oxopentanedioate, 1,1,1-triethoxy ethane and 2-(4- methoxyphenyl)ethanamine, the title compound (11) was isolated as a white solid in 79% yield (97% purity by HPLC). MS(ESI+): 433.6; MS(ESF): 431.7.
Example 12: Formation of 2-fl,3-benzothiazol-2-yl)-5-[2-(4-hexanoylpiperazin-l- yl)ethyll-4-methyl-lH-pyrazolor4,3-clpyridine-3,6(2H,5H)-dione α2)(Compound Ia, Scheme 1)
Figure imgf000046_0001
Following the general methods as outlined in Example 7, starting from 2-hydrazino-l,3- benzothiazole, dimethyl 3-oxopentanedioate, 1,1,1-triethoxy ethane and 2-(4- hexanoylpiperazin-l-yl)ethanamine, the title compound (12) was isolated as a beige solid in 71% yield (95% purity by HPLC). MS(ESI+): 508.8; MS(ESF): 506.6.
Example 13: Formation of 2-d,3-benzothiazol-2-yl)-l-benzyl-5-(furan-2-ylmethyl)-4- methyl-lH-pyrazolo[4,3-clpyridine-3.,6(2H,5H)-dione (13)(Compound Ib, Scheme 1)
Figure imgf000046_0002
Following the general methods as outlined in Example 7, starting from 2-hydrazino-l,3- benzothiazole, dimethyl 3-oxopentanedioate, 1,1,1-triethoxy ethane, l-furan-2- ylmethanamine and alkylation with (chloromethyl)benzene (1 eq.) and the corresponding intermediate compound according to Formula (Ia) (1 eq.) in presence of triethylamine (1.5 eq.) in refluxing THF, the title compound (13) was isolated as a beige solid in 61% yield (97% purity by HPLC). MS(ESI+): 469.6; MS(ESF): 467.3. Example 14: Formation of 5-[2-flH-indol-3-yl)ethyll-4-methyl-l-f3-methylbenzyl)-2- phenyl-lH-pyrazolo[4,3-clpyridine-3.,6f2H,5H)-(iione (14)(Compound Ib, Scheme 1)
Figure imgf000047_0001
Following the general methods as outlined in Examples 7 and 13, starting from phenylhydrazine, dimethyl 3-oxopentanedioate, 1,1,1-triethoxy ethane, 2-(lH-indol-3-yl) ethanamine and l-(chloromethyl)-3-methylbenzene, the title compound (14) was isolated as a white solid in 58% yield (98% purity by HPLC). MS(ESI+): 489.6; MS(ESF): 487.5.
Example 15: Formation of l-(4-fluorobenzyl)-5-r2-qH-indol-3-ylkthyll-4-methyl-2- phenyl-lH-pyrazolo[4,3-clpyridine-3.,6(2H,5H)-dione (ISHCompound Ib, Scheme 1)
Figure imgf000047_0002
Following the general methods as outlined in Examples 7 and 13, starting from phenylhydrazine, dimethyl 3-oxopentanedioate, 1,1,1-triethoxy ethane, 2-(lH-indol-3-yl) ethanamine and l-(chloromethyl)-4-fluorobenzene, the title compound (15) was isolated as a white solid in 55% yield (95% purity by HPLC). MS(ESI+): 493.6; MS(ESF): 491.6. Example 16: Formation of l-f2-chlorobenzyl)-4-methyl-5-[3-f2-oxopyrrolidin-l-yl) propyll-2-phenyl-lH-pyrazolo[4,3-clpyridine-3.,6f2H,5H)-(iione (16) (Compound Ib, Scheme 1)
Figure imgf000048_0001
Following the general methods as outlined in Examples 7 and 13, starting from phenylhydrazine, dimethyl 3-oxopentanedioate, 1,1,1-triethoxy ethane, l-(3-aminopropyl) pyrrolidin-2-one and l-chloro-2-(chloromethyl)benzene, the title compound (16) was isolated as a white solid in 51% yield (98% purity by HPLC). MS(ESI+): 492.1; MS(ESF): 490.0.
Example 17: Formation of 2-(l,3-benzothiazol-2-yl)-l-benzyl-4-methyl-5-(tetrahvdro furan-2-ylmethyl)-lH-pyrazolo[4,3-clpyridine-3.,6(2H,5H)-dione (17) (Compound Ib, Scheme 1)
Figure imgf000048_0002
Following the general methods as outlined in Examples 7 and 13, starting from 2- hydrazino-l,3-benzothiazole, dimethyl 3-oxopentanedioate, 1,1,1-triethoxyethane, 1- (tetrahydrofuran -2-yl)methanamine and (chloromethyl)benzene, the title compound (17) was isolated as a beige solid in 61% yield (97% purity by HPLC). MS(ESI+): 473.7; MS(ESF): 471.6. Example 18: Formation of l-(4-chlorobenzyl)-5-r2-( lH-imidazol-4-yl)ethyll-4-methyl- 2-phenyl-lH-pyrazolo[4,3-clpyridine-3.,6f2H,5H)-(iione (18) (Compound Ib, Scheme 1)
Figure imgf000049_0001
Following the general methods as outlined in Examples 7 and 13, starting from phenylhydrazine, dimethyl 3-oxopentanedioate, 1,1,1-triethoxyethane, 2-(lH-imidazol-5- yl)ethanamine and l-chloro-4-(chloromethyl)benzene, the title compound (18) was isolated as a beige solid in 63% yield (98% purity by HPLC). MS(ESI+): 461.0; MS(ESI ): 459.0.
Example 19: Formation of 5-(l,3-benzodioxol-5-ylmethyl)-4-methyl-2-phenyl-lH- pyrazolo[4,3-clpyridine-3.,6(2H,5H)-dione (19) (Compound Ia, Scheme 1)
Figure imgf000049_0002
Following the general methods as outlined in Example 7 a), starting from phenylhydrazine, dimethyl 3-oxopentanedioate, 1,1,1-triethoxyethane and l-(l,3-benzodioxol-5-yl) methanamine, the title compound (19) was isolated as a beige solid in 78% yield (99% purity by HPLC). MS(ESI+): 376.5; MS(ESL): 374.5.
Example 20: Formation of 5-benzyl-4-methyl-2-phenyl-lH-pyrazolo[4,3-clpyridine- 3,6(2H,5H)-dione (20) (Compound Ia, Scheme 1)
Figure imgf000050_0001
Following the general methods as outlined in Example 7 a), starting from phenylhydrazine, dimethyl 3-oxopentanedioate, 1,1,1-triethoxy ethane and benzylamine, the title compound (20) was isolated as a beige solid in 79% yield (99% purity by HPLC). MS(ESI+): 332.5; MS(ESI ): 330.4.
Example 21: Formation of 5-benzyl-2-(4-fluorophenyl)-4-methyl-lH-pyrazolo[4,3- clpyridine-3.,6(2H,5H)-dione (21) (Compound Ia, Scheme 1)
Figure imgf000050_0002
Following the general methods as outlined in Example 7 a), starting from (4- fluorophenyl)hydrazine, dimethyl 3-oxopentanedioate, 1,1,1-triethoxy ethane and benzylamine, the title compound (21) was isolated as a white solid in 86% yield (99% purity by HPLC). MS(ESI+): 350.5; MS(ESL): 348.6. Example 22: Formation of 5-benzyl-2-f4-methoxyphenyl)-4-methyl-lH-pyrazolo[4,3- clpyridine-3.,6(2H.,5H)-dione (22) (Compound Ia, Scheme 1)
Figure imgf000051_0001
Following the general methods as outlined in Example 7 a), starting from (4- methoxyphenyl)hydrazine, dimethyl 3-oxopentanedioate, 1,1,1-triethoxy ethane and benzylamine, the title compound (22) was isolated as a beige solid in 78% yield (95% purity by HPLC). MS(ESI+): 362.6; MS(ESI ): 360.5.
Example 23: Formation of 2-(l,3-benzothiazol-2-yl)-4-methyl-5-morpholin-4-yl-lH- pyrazolo [4,3-cl pyridine-3.,6(2H,5H)-dione (23) (Compound Ia, Scheme 1)
Figure imgf000051_0002
Following the general methods as outlined in Example 7 a), starting from 2-hydrazino-l,3- benzothiazole, dimethyl 3-oxopentanedioate, 1,1,1-triethoxy ethane and morpholin-4-amine, the title compound (23) was isolated as a yellowish solid in 81% yield (99% purity by HPLC). MS(ESI+): 384.5; MS(ESL): 382.5.
Example 24: Formation of 5-benzyl-4-methyl-2-(4-nitrophenyl)-lH-pyrazolo[4,3- clpyridine-3.,6(2H,5H)-dione (24) (Compound Ia, Scheme 1)
Figure imgf000051_0003
Following the general methods as outlined in Example 7 a), starting from (4- nitrophenyl)hydrazine, dimethyl 3-oxopentanedioate, 1,1,1-triethoxy ethane and benzylamine, the title compound (24) was isolated as a yellow solid in 72% yield (96% purity by HPLC). MS(ESI+): 377.6; MS(ESF): 375.5.
Example 25: Formation of 2-fl,3-benzothiazol-2-yl)-4-methyl-l-(3-methylbenzyl)-5-(3- morpholin-4-ylpropyl)-lH-pyrazolo[4,3-clpyridine-3.,6(2H,5H)-(iione (25) (Compound Ib, Scheme 1)
Figure imgf000052_0001
Following the general methods as outlined in Examples 7 and 13, starting from 2- hydrazino-l,3-benzothiazole, dimethyl 3-oxopentanedioate, 1,1,1-triethoxyethane, 3- morpholin-4-ylpropan-l -amine and l-(chloromethyl)-3-methylbenzene, the title compound (25) was isolated as a white solid in 68% yield (98% purity by HPLC). MS(ESI+): 530.9; MS(ESF): 528.6.
Example 26: Formation of 2-(l,3-benzothiazol-2-yl)-l-(4-fluorobenzyl)-4-methyl-5-(3- morpholin-4-ylpropyl)-lH-pyrazolor4,3-clpyridine-3,6(2H,5H)-dione (26) (Compound Ib, Scheme 1)
Figure imgf000052_0002
Following the general methods as outlined in Examples 7 and 13, starting from 2- hydrazino-l,3-benzothiazole, dimethyl 3-oxopentanedioate, 1,1,1-triethoxyethane, 3- morpholin-4-ylpropan-l -amine and l-(chloromethyl)-4-fluorobenzene, the title compound (26) was isolated as a beige solid in 54% yield (98% purity by HPLC). MS(ESI+): 534.9; MS(ESI ): 532.6.
Example 27: Formation of 2-fl,3-benzothiazol-2-yl)-4-methyl-l-(4-methylbenzyl)-5-(3- morpholin-4-ylpropyl)-lH-pyrazolo[4,3-clpyridine-3.,6(2H,5H)-(iione (27) (Compound Ib, Scheme 1)
Figure imgf000053_0001
Following the general methods as outlined in Examples 7 and 13, starting from 2- hydrazino-l,3-benzothiazole, dimethyl 3-oxopentanedioate, 1,1,1-triethoxyethane, 3- morpholin-4-ylpropan-l -amine and l-(bromomethyl)-4-methylbenzene, the title compound (27) was isolated as a beige solid in 62% yield (98% purity by HPLC). MS(ESI+): 530.8; MS(ESL): 528.6.
Example 28: Formation of 2-(l,3-benzothiazol-2-yl)-l-(2-chlorobenzyl)-4-methyl-5- morpholin-4-yl-lH-pyrazolo[4,3-clpyridine-3.,6(2H,5H)-dione (28) (Compound Ib, Scheme 1)
Figure imgf000053_0002
Following the general methods as outlined in Examples 7 and 13, starting from 2- hydrazino-l,3-benzothiazole, dimethyl 3-oxopentanedioate, 1,1,1-triethoxyethane, morpholin-4-amine and l-chloro-2-(chloromethyl)benzene, the title compound (28) was isolated as a beige solid in 56% yield (98% purity by HPLC). MS(ESI+): 509.1; MS(ESL): 507.0. Example 29: Formation of 2-(l-,3-benzothiazol-2-yr)-l-(4-bromobenzyr)-4-methyl-5-(2- morpholin-4-ylethyl)-lH-pyrazolo[4,3-clpyridine-3.,6f2H,5H)-(iione (29) (Compound Ib, Scheme 1)
Figure imgf000054_0001
Following the general methods as outlined in Examples 7 and 13, starting from 2- hydrazino-l,3-benzothiazole, dimethyl 3-oxopentanedioate, 1,1,1-triethoxyethane, 2- morpholin-4-ylethanamine and l-bromo-4-(chloromethyl)benzene, the title compound (29) was isolated as a beige solid in 50% yield (98% purity by HPLC). MS(ESI+): 581.7; MS(ESF): 579.4.
Example 30: Formation of 2-[2-(l,3-benzothiazol-2-yl)-4-methyl-5-(3-morpholin-4- ylpropyl)-3.,6-dioxo-2,3i5.l6-tetrahvdro-lH-pyrazolo[4,3-clpyridin-l-yll-N- phenylacetamide (30) (Compound Ib, Scheme 1)
Figure imgf000054_0002
Following the general methods as outlined in Examples 7 and 13, starting from 2- hydrazino-l,3-benzothiazole, dimethyl 3-oxopentanedioate, 1,1,1-triethoxyethane, 3- morpholin-4-ylpropan-l -amine and 2-bromo-N-phenylacetamide, the title compound (30) was isolated as a beige solid in 67% yield (98% purity by HPLC). MS(ESI+): 559.8; MS(ESF): 557.4. Example 31: Formation of 4-methyl-2-phenyl-5-ftetrahvdrofuran-2-ylmethyl)-lH- pyrazolo [4,3-cl pyridine-3,6( 2H,5H)-dione (31) (Compound Ia, Scheme 1)
Figure imgf000055_0001
Following the general methods as outlined in Example 7 a), starting from phenylhydrazine, dimethyl 3-oxopentanedioate, 1,1,1-triethoxy ethane and l-(tetrahydrofuran-2- yl)methanamine, the title compound (31) was isolated as a white solid in 78% yield (99% purity by HPLC). MS(ESI+): 326.5; MS(ESF): 324.4.
Example 32: Formation of 2-(l,3-benzothiazol-2-yl)-4-methyl-5-(2-phenylethyl)-lH- pyrazolo [4,3-cl pyridine-3,6(2H,5H)-dione (32) (Compound Ia, Scheme 1)
Figure imgf000055_0002
Following the general methods as outlined in Example 7 a), starting from 2-hydrazino-l,3- benzothiazole, dimethyl 3-oxopentanedioate, 1,1,1-triethoxy ethane and 2- phenylethanamine, the title compound (32) was isolated as a beige solid in 64% yield (97% purity by HPLC). MS(ESI+): 403.7; MS(ESF): 401.5.
Example 33: Formation of 5-[2-(lH-indol-3-yl)ethyll-4-methyl-2-phenyl-lH- pyrazolo [4,3-cl pyridine-3,6(2H,5H)-dione (33) (Compound Ia, Scheme 1)
Figure imgf000055_0003
Following the general methods as outlined in Example 7 a), starting from phenylhydrazine, dimethyl 3-oxopentanedioate, 1,1,1-triethoxy ethane and 2-(lH-indol-3-yl)ethanamine, the title compound (33) was isolated as a beige solid in 82% yield (99% purity by HPLC). MS(ESI+): 335.5; MS(ESI ): 333.3.
Example 34: Formation of 4-methyl-5-morpholin-4-yl-2-phenyl-lH-pyrazolo[4,3- clpyridine-3,6(2H.,5H)-dione (34) (Compound Ia, Scheme 1)
Figure imgf000056_0001
Following the general methods as outlined in Example 7 a), starting from phenylhydrazine, dimethyl 3-oxopentanedioate, 1,1,1-triethoxy ethane and morpholin-4-amine, the title compound (34) was isolated as a white solid in 87% yield (99% purity by HPLC). MS(ESI+): 327.6; MS(ESL): 325.4.
Example 35: Formation of 2-(l,3-benzothiazol-2-yl)-l-(2-chlorobenzyl)-4-methyl-5-(3- morpholin-4-ylpropyl)-lH-pyrazolor4,3-clpyridine-3,6(2H,5H)-dione (35) (Compound Ib, Scheme 1)
Figure imgf000056_0002
Following the general methods as outlined in Examples 7 and 13, starting from 2- hydrazino-l,3-benzothiazole, dimethyl 3-oxopentanedioate, 1,1,1-triethoxyethane, 3- morpholin-4-ylpropan-l -amine and l-chloro-2-(chloromethyl)benzene, the title compound (35) was isolated as a beige solid in 61% yield (98% purity by HPLC). MS(ESI+): 551.2; MS(ESL): 549.4. Example 36: Formation of 5-benzyl-4-ethyl-2-f4-fluorophenyl)-lH-pyrazolo[4,3- clpyridine-3.,6(2H.,5H)-dione (36) (Compound Ia, Scheme 1)
Figure imgf000057_0001
Following the general methods as outlined in Example 7 a), starting from (4- fluorophenyl)hydrazine, dimethyl 3-oxopentanedioate, 1,1,1-triethoxy ethane and benzylamine, the title compound (36) was isolated as a yellowish solid in 80% yield (96% purity by HPLC). MS(ESI+): 364.5; MS(ESI ): 362.2.
Example 37: Formation of 4-ethyl-2-(4-fluorophenyl)-5-(2-phenylethyl)-lH- pyrazolo [4,3-cl pyridine-3.,6(2H,5H)-dione (37) (Compound Ia, Scheme 1)
Figure imgf000057_0002
Following the general methods as outlined in Example 7 a), starting from (4- fluorophenyl)hydrazine, dimethyl 3-oxopentanedioate, 1,1,1-triethoxypropane and 2- phenylethanamine, the title compound (37) was isolated as a white solid in 83% yield (97% purity by HPLC). MS(ESI+): 378.5; MS(ESL): 376.4.
Example 38: Formation of 4-ethyl-2-f4-fluorophenyl)-5-morpholin-4-yl-lH- pyrazolo [4,3-cl pyridine-3.,6( 2H,5H)-dione (38) (Compound Ia, Scheme 1)
Figure imgf000058_0001
Following the general methods as outlined in Example 7 a), starting from (4- fluorophenyl)hydrazine, dimethyl 3-oxopentanedioate, 1,1,1-triethoxypropane and morpholin-4-amine, the title compound (38) was isolated as a beige solid in 77% yield (99% purity by HPLC). MS(ESI+): 358.7; MS(ESF): 356.2.
Example 39: Formation of 4-methyl-5-(2-morpholin-4-ylethyl)-2-phenyl-lH- pyrazolo [4,3-cl pyridine-3.,6(2H,5H)-dione (39) (Compound Ia, Scheme 1)
Figure imgf000058_0002
Following the general methods as outlined in Example 7 a), starting from phenylhydrazine, dimethyl 3-oxopentanedioate, 1,1,1-triethoxy ethane and 2-morpholin-4-ylethanamine, the title compound (39) was isolated as a beige solid in 63% yield (95% purity by HPLC). MS(ESI+): 355.5; MS(ESF): 353.5.
Example 40: Formation of 4-ethyl-5-morpholin-4-yl-2-phenyl-lH-pyrazolo[4,3- clpyridine-3.,6(2H.,5H)-dione (40) (Compound Ia, Scheme 1)
Figure imgf000059_0001
Following the general methods as outlined in Example 7 a), starting from phenylhydrazine, dimethyl 3-oxopentanedioate, 1,1,1-triethoxypropane and morpholin-4-amine, the title compound (40) was isolated as a white solid in 89% yield (98% purity by HPLC). MS(ESI+): 341.8; MS(ESF): 339.4.
Example 41: Formation of 2-(2-chlorophenyl)-4-methyl-5-(pyridin-2-ylmethyl)-lH- pyrazolo[4,3-clpyridine-3.,6(2H,5H)-dione (41) (Compound Ia, Scheme 1)
Figure imgf000059_0002
Following the general methods as outlined in Example 7 a), starting from (2- chlorophenyl)hydrazine, dimethyl 3-oxopentanedioate, 1,1,1-triethoxy ethane and 1-pyridin- 2-ylmethanamine, the title compound (41) was isolated as a yellow solid in 81% yield (99% purity by HPLC). MS(ESI+): 367.9; MS(ESF): 365.7. Example 42: Formation of 4-methyl-2-f2-methylphenyl)-5-f3-morpholin-4-ylpropyl)- lH-pyrazolo[4,3-clpyridine-3.,6f2H,5H)-(iione f42) (Compound Ia, Scheme 1)
Figure imgf000060_0001
Following the general methods as outlined in Example 7 a), starting from (2- methylphenyl)hydrazine, dimethyl 3-oxopentanedioate, 1,1,1-triethoxy ethane and 3- morpholin-4-ylpropan-l -amine, the title compound (42) was isolated as a beige solid in 72% yield (98% purity by HPLC). MS(ESI+): 383.6; MS(ESF): 381.5.
Example 43: Formation of 2-(l,3-benzothiazol-2-yl)-4-methyl-l-(pyridin-2-ylmethyl)- 5-(tetrahvdrofuran-2-ylmethyl)-lH-pyrazolo[4,3-clpyridine-3.,6(2H,5H)-dione (43) (Compound Ib, Scheme 1)
Figure imgf000060_0002
Following the general methods as outlined in Examples 7 and 13, starting from 2- hydrazino-l,3-benzothiazole, dimethyl 3-oxopentanedioate, 1,1,1-triethoxyethane, 1- (tetrahydrofuran-2-yl)methanamine and 2-(chloromethyl)pyridine, the title compound (43) was isolated as a beige solid in 60% yield (98% purity by HPLC). MS(ESI+): 474.6; MS(ESF): 472.5. Example 44: Formation of 2-d,3-benzothiazol-2-yl)-4-ethyl-5-(pyridin-2-ylmethyl)- lH-pyrazolo [4,3-cl pyridine-3.,6( 2H,5H)-dione (44) (Compound Ia, Scheme 1)
Following the general methods as outlined in Example 7 a), starting from 2-hydrazino-l,3- benzothiazole, dimethyl 3-oxopentanedioate, 1,1,1-triethoxypropane and l-pyridin-2- ylmethanamine, the title compound (44) was isolated as a yellow solid in 83% yield (95% purity by HPLC). MS(ESI+): 404.6; MS(ESI ): 402.5.
Example 45: Formation of 2-(l,3-benzothiazol-2-yl)-4-ethyl-5-(3-morpholin-4- ylpropyl)-lH-pyrazolo[4,3-clpyridine-3.,6(2H,5H)-dione (45) (Compound Ia, Scheme
1)
Figure imgf000061_0002
Following the general methods as outlined in Example 7 a), starting from 2-hydrazino-l,3- benzothiazole, dimethyl 3-oxopentanedioate, 1,1,1-triethoxypropane and 3-morpholin-4- ylpropan-1 -amine, the title compound (45) was isolated as a beige solid in 82% yield (98% purity by HPLC). MS(ESI+): 440.5; MS(ESL): 438.4.
Example 46: Formation of 2-(l,3-benzothiazol-2-yl)-4-ethyl-5-(2-methoxyethyl)-lH- pyrazolo [4,3-cl pyridine-3.,6(2H,5H)-dione (46) (Compound Ia, Scheme 1)
Figure imgf000061_0003
Following the general methods as outlined in Example 7 a), starting from 2-hydrazino-l,3- benzothiazole, dimethyl 3-oxopentanedioate, 1,1,1-triethoxypropane and 2- methoxyethanamine, the title compound (46) was isolated as a white solid in 69% yield (97% purity by HPLC). MS(ESI+): 371.4; MS(ESF): 369.4.
Example 47: Formation of 2-(l,3-benzothiazol-2-yD-4-ethyl-5-(4-methylpiperazin-l- yl)-lH-pyrazolo[4,3-clpyridine-3.,6(2H,5H)-(iione (47) (Compound Ia, Scheme 1)
Figure imgf000062_0001
Following the general methods as outlined in Example 7 a), starting from 2-hydrazino-l,3- benzothiazole, dimethyl 3-oxopentanedioate, 1,1,1-triethoxypropane and A- methylpiperazin-1 -amine, the title compound (47) was isolated as a beige solid in 78% yield (98% purity by HPLC). MS(ESI+): 411.6; MS(ESF): 409.4.
Example 48: Formation of 2-(l,3-benzothiazol-2-yl)-4-ethyl-5-[l-(4-methylbenzyl) piperidin-4-yll -lH-pyrazolo [4,3-cl pyridine-3,6(2H.,5H)-dione (48) (Compound Ia, Scheme 1)
Figure imgf000062_0002
Following the general methods as outlined in Example 7 a), starting from 2-hydrazino-l,3- benzothiazole, dimethyl 3-oxopentanedioate, 1,1,1-triethoxypropane and l-(4- methylbenzyl)piperidin-4-amine, the title compound (48) was isolated as a yellow solid in 55% yield (92% purity by HPLC). MS(ESI+): 500.6; MS(ESF): 498.6. Example 49: Formation of 4-ethyl-2-(4-fluorophenyl)-5-(pyridin-2-ylmethyl)-lH- pyrazolo [4,3-cl pyridine-3,6( 2H,5H)-dione (49) (Compound Ia, Scheme 1)
Figure imgf000063_0001
Following the general methods as outlined in Example 7 a), starting from (4- fluorophenyl)hydrazine, dimethyl 3-oxopentanedioate, 1,1,1-triethoxypropane and 1- pyridin-2-ylmethanamine, the title compound (49) was isolated as a yellowish solid in 77% yield (99% purity by HPLC). MS(ESI+): 365.5; MS(ESF): 363.7.
Example 50: Formation of 4-ethyl-2-(4-fluorophenyl)-5-(3-morpholin-4-ylpropyl)-lH- pyrazolo [4,3-cl pyridine-3,6(2H,5H)-dione (50) (Compound Ia, Scheme 1)
Figure imgf000063_0002
Following the general methods as outlined in Example 7 a), starting from (4- fluorophenyl)hydrazine, dimethyl 3-oxopentanedioate, 1,1,1-triethoxypropane and 3- morpholin-4-ylpropan-l -amine, the title compound (50) was isolated as a beige solid in 78% yield (99% purity by HPLC). MS(ESI+): 401.5; MS(ESF): 399.3.
Example 51: Formation of 4-ethyl-2-(4-fluorophenyl)-5-(2-methoxyethyl)-lH- pyrazolo [4,3-cl pyridine-3,6(2H,5H)-dione (51) (Compound Ia, Scheme 1)
Figure imgf000063_0003
Following the general methods as outlined in Example 7 a), starting from (4- fluorophenyl)hydrazine, dimethyl 3-oxopentanedioate, 1,1,1-triethoxypropane and 2- methoxyethanamine, the title compound (51) was isolated as a white solid in 76% yield (98% purity by HPLC). MS(ESI+): 332.4; MS(ESF): 330.4.
Example 52: Formation of 5-(2-morpholin-4-ylethyl)-2-pyridin-2-yl-lH-pyrazolo[4,3- clpyridine-3,6(2H.,5H)-dione (52) (Compound Ia, Scheme 1)
Figure imgf000064_0001
Following the general methods as outlined in Example 7 a), starting from 2- hydrazinopyridine, dimethyl 3-oxopentanedioate, 1,1,1-triethoxymethane and 2-morpholin- 4-ylethanamine, the title compound (52) was isolated as a yellowish solid in 68% yield (97% purity by HPLC). MS(ESI+): 342.5; MS(ESF): 340.3.
Example 53: Formation of 2,4-diphenyl-5-(pyridin-3-ylmethyl)-lH-pyrazolo[4,3- clpyridine-3.,6(2H,5H)-dione (53) (Compound Ia, Scheme 1)
Figure imgf000064_0002
Following the general methods as outlined in Example 7 a), starting from phenylhydrazine, dimethyl 3-oxopentanedioate, (triethoxymethyl)benzene and l-pyridin-3-ylmethanamine, the title compound (53) was isolated as a beige solid in 79% yield (96% purity by HPLC). MS(ESI+): 395.5; MS(ESF): 393.2. Example 54: Formation of 2-(2-chlorophenyl)-4-ethyl-5-(pyridin-3-ylmethyl)-lH- pyrazolo [4,3-cl pyridine-3.,6( 2H,5H)-dione (54) (Compound Ia, Scheme 1)
Figure imgf000065_0001
Following the general methods as outlined in Example 7 a), starting from (2- chlorophenyl)hydrazine, dimethyl 3-oxopentanedioate, 1,1,1-triethoxypropane and 1- pyridin-3-ylmethanamine, the title compound (54) was isolated as a yellow solid in 74% yield (98% purity by HPLC). MS(ESI+): 381.8; MS(ESF): 379.6.
Example 55: Formation of 4-methyl-2-(2-methylphenyl)-5-(pyridin-2-ylmethyl)-lH- pyrazolo [4,3-cl pyridine-3.,6(2H,5H)-dione (55) (Compound Ia, Scheme 1)
Figure imgf000065_0002
Following the general methods as outlined in Example 7 a), starting from (2- methylphenyl)hydrazine, dimethyl 3-oxopentanedioate, 1,1,1-triethoxy ethane and 1- pyridin-2-ylmethanamine, the title compound (55) was isolated as a yellow solid in 63% yield (98% purity by HPLC). MS(ESI+): 347.5; MS(ESF): 345.6. Example 56: Formation of 4-ethyl-5-f3-morpholin-4-ylpropyl)-2-[4-ftrifluoromethyl) phenyll -lH-pyrazolo [4,3-cl pyridine-3.,6(2H.,5H)-dione (56) (Compound Ia, Scheme 1)
Figure imgf000066_0001
Following the general methods as outlined in Example 7 a), starting from [4- (trifluoromethyl)phenyl]hydrazine, dimethyl 3-oxopentanedioate, 1,1,1-triethoxypropane and 3-morpholin-4-ylpropan-l-amine, the title compound (56) was isolated as a yellow solid in 59% yield (96% purity by HPLC). MS(ESI+): 451.5; MS(ESF): 449.4.
Example 57: Formation of 4-ethyl-5-(3-morpholin-4-ylpropyl)-2-[4-(trifluoromethoxy) phenyll -lH-pyrazolo [4,3-cl pyridine-3.,6(2H,5H)-dione (57) (Compound Ia, Scheme 1)
Figure imgf000066_0002
Following the general methods as outlined in Example 7 a), starting from [4- (trifluoromethoxy)phenyl]hydrazine, dimethyl 3-oxopentanedioate, 1,1,1-triethoxypropane and 3-morpholin-4-ylpropan-l-amine, the title compound (57) was isolated as a yellow solid in 67% yield (97% purity by HPLC). MS(ESI+): 467.4; MS(ESF): 465.6. Example 58: Formation of 2-(2,5-difluorophenyl)-4-ethyl-5-(3-morpholin-4-ylpropyl)- lH-pyrazolo [4,3-cl pyridine-3.,6( 2H,5H)-dione (58) (Compound Ia, Scheme 1)
Figure imgf000067_0001
Following the general methods as outlined in Example 7 a), starting from (2,5- difluorophenyl)hydrazine, dimethyl 3-oxopentanedioate, 1,1,1-triethoxypropane and 3- morpholin-4-ylpropan-l -amine, the title compound (58) was isolated as a yellow solid in 71% yield (98% purity by HPLC). MS(ESI+): 419.7; MS(ESF): 417.3.
Example 59: Formation of 4-ethyl-2-(2-methoxyphenyl)-5-(3-morpholin-4-ylpropyl)- lH-pyrazolo [4,3-cl pyridine-3.,6(2H,5H)-dione (59) (Compound Ia, Scheme 1)
Figure imgf000067_0002
Following the general methods as outlined in Example 7 a), starting from (2- methoxyphenyl)hydrazine, dimethyl 3-oxopentanedioate, 1,1,1-triethoxypropane and 3- morpholin-4-ylpropan-l -amine, the title compound (59) was isolated as a yellowish solid in 67% yield (99% purity by HPLC). MS(ESI+): 413.6; MS(ESF): 411.7.
Example 60: Measurement of levels of reactive oxygen species in different cell cultures
The activity of the compounds according to the invention may be tested for their activity in the inhibition or reduction of formation of reactive oxygen species (ROS) from oxygen in cells. The activity of the compounds is tested in the following cell cultures by different techniques such as nitroblue tetrazolium, Amplex Red, Chemiluminescence (Luminol) and 2',7'-dichlorodihydrofluorescein diacetate (H2DCF-DA) according to the protocols detailed below.
Human microglia cell line
Human microglia cell line (HMC3, human microglia clone 3) (Janabi et al, 1995, Neurosci Lett 195:105) were cultured in MEM (Eagle's minimum essential medium) containing 10% FBS with 50 U/ml penicillin G sodium 50 μg/ml streptomycin sulfate, and incubated at 37°C for 24 hours. IFN-γ (human IFN-γ, Roche. 11 040 596 001) was added to the culture medium for a final concentration of 10 ng/ml 24 h, before detection Of O2 " formation.
Human umbilical vein endothelial cells (HUVEC)
HUVEC are cultured in endothelial basal medium supplemented with hydrocortisone (1 μg/mL, CalbioChem), bovine brain extract (12 μg/mL), gentamicin (50 μg/mL, CalbioChem), amphotericin B (50 ng/niL, CalBioChem EGF (10 ng/niL, and 10% FCS until the fourth passage. When the fifth passage was started, cells were cultured with a lower concentration of FCS (2%) in the absence of EGF, if not indicated otherwise. All experiments were done with cells of the fifth passage. The cells were incubated with OxLDL (oxidized low-density lipoprotein) or its buffer as control for 24 h, before detection of O2 " formation.
HL-60 cells
Human acute myeloid leukemia cell line HL-60 was cultured in RPMI 1640 (Invitrogen) supplemented with 10 % heat-inactivated calf serum, 2 mM glutamine, 100 U/mL penicillin (Sigma), and 100 μg streptomycin (Sigma) at 370C under a humidified atmosphere of 5% CO2. HL60 differentiation to the neutrophil phenotype was triggered by adding Me2SO (final concentration 1.25% v/v for 6 days) to the culture medium.
1. Nitroblue tetrazolium (NBT)
Intracellular and extracellular superoxide was measured by a colorimetric technique using a quantitative nitroblue tetrazolium (NBT) test. SOD-inhibitable conversion of NBT to formazan, a fine blue precipitate, in the presence of superoxide anion was measured using Fluostar Optima spectrometer (BMG labtech). Following incubation with appropriate stimuli, cells were trypsinized (IX Trypsin-EDTA), collected by centrifugation, and washed with PBS to remove medium. 5 X 105 cells were plated on 48-well plates and incubated in Hank's balanced salt solution containing 0.5 mg/mL NBT with or without 800 U/mL SOD in the presence or absence of compounds according to the invention. As a control, DPI was included at a final concentration of 10 μM. After 2.5 h, cells were fixed and washed with methanol to remove non reduced NBT. The reduced formazan was then dissolved in 230 μl of 2M potassium hydroxide and in 280 μl of dimethylsulfoxide. The absorption was measured at 630 nm. For calculation, the absorbance at 630 nm was normalized for each individual well. The mean of the four blank values was substracted from each corrected value for each time point. NOX activities were expressed as % of the activity in control cells. Residual activity of DPI-treated cells was usually <10%.
2. Amplex Red
Extracellular hydrogen peroxide was measured using Amplex UltraRed (Molecular Probes). Cells were trypsinized (IX Trypsin-EDTA), collected by centrifugation, and resuspended in HBSS supplemented with 1% glucose. Cells were seeded into black 96-well plates at a density of 50'000cells in 200 μl testing buffer (HBSS 1% glucose containing 0.005 U/mL horseradish peroxidase (Roche) and 50 μM Amplex Red in the presence or absence of compounds according to the invention. As a control, DPI was included at a final concentration of 10 μM The plates were placed in the fluorescent Optima Fluorescent plate reader and kept at 37°C during 20 min. Fluorescence was measured for 15 min hours with excitation and emission wavelengths of 544 nm and 590 nm respectively. NOX activities were expressed as % of the activity in control cells. Residual activity of DPI-treated cells was usually < 10%.
The Table 1 below summarizes the percentage of inhibition of NOX activity as measured by Amplex Red using DMSO-differentiated HL60 cells as described above: Table 1
Figure imgf000070_0001
The Table 2 below summarizes the IC50 of NOX activity as measured by Amplex Red using DMSO-differentiated HL60 cells as described above:
Table 2
Figure imgf000070_0002
3. Chemiluminescence (Luminol)
ROS was measured using the chemiluminescent probe luminol. Cells were cultured and plated as for Amplex Red except that the Amplex Red agent was replaced by 10 μg/mL luminol (Sigma 09235). Light emission was recorded continuously at 37 0C for 60 minutes using the luminescence function of the FluoStar Optima fluorescent plate reader. The mean of the four blank values was substracted from each corrected value for each time point. NOX activities were expressed as % of the activity in control cells. Residual activity of DPI-treated cells was usually <10%.
4. 2',7'-dichlorodihydrofluorescein diacetate (H2DCF-DA)
HUVEC were plated on coverslips and made quiescent overnight in 0.5% BSA before stimulation with TGF-β. Cells were loaded for 10 minutes with 5 μM CM-H2DCFDA in phenol-red-free medium in the dark and then treated with TGF-β (R&D Systems) in the presence or absence of compounds according to the invention. Cells were then visualized by immunofluorescence microscopy after fixation and staining of the nuclei with DAPI or examined live using confocal microscopy. DCF fluorescence was visualized at an excitation wavelength of 488 nm and emission at 515 to 540 nm. To avoid photo-oxidation of the indicator dye, images were collected with a single rapid scan using identical parameters for all samples. For calculation, the absorbance at 540 nm was normalized to absorbance at 540 nm for each individual well. The mean of the four blank values was subtracted from each corrected value for each time point. NOX activities were expressed as % of the activity in control cells. Residual activity of DPI-treated cells was usually <10%.

Claims

Claims
1. A pyrazolo pyridine derivative according to Formula (I):
Figure imgf000072_0001
(I) wherein Gi is selected from H, alkyl, C3-Cg-cycloalkyl alkyl, heterocycloalkyl alkyl, aryl alkyl and heteroaryl alkyl;
G2 is selected from H, alkyl, alkenyl, alkynyl, aryl, alkyl aryl, aryl alkyl, heteroaryl, alkyl heteroaryl, heteroaryl alkyl, alkenyl aryl, aryl alkenyl, alkenyl heteroaryl, heteroaryl alkenyl, C3-Cg-cycloalkyl, heterocycloalkyl, alkyl C3-Cg-cycloalkyl, C3-
C8-cycloalkyl alkyl, alkyl heterocycloalkyl and heterocycloalkyl alkyl;
G3 is selected from H, alkyl, alkenyl, alkynyl, aryl, alkyl aryl, aryl alkyl, heteroaryl, alkyl heteroaryl, heteroaryl alkyl, alkenyl aryl, aryl alkenyl, alkenyl heteroaryl, heteroaryl alkenyl, C3-Cg-cycloalkyl, heterocycloalkyl, alkyl C3-Cg-cycloalkyl, C3-
C8-cycloalkyl alkyl, alkyl heterocycloalkyl and heterocycloalkyl alkyl;
G4 is selected from H, alkyl, alkenyl, alkynyl, aryl, alkyl aryl, aryl alkyl, heteroaryl, alkyl heteroaryl, heteroaryl alkyl, alkenyl aryl, aryl alkenyl, alkenyl heteroaryl, heteroaryl alkenyl, C3-Cg-cycloalkyl, heterocycloalkyl, alkyl C3-Cg-cycloalkyl, C3-
Cg-cycloalkyl alkyl, alkyl heterocycloalkyl and heterocycloalkyl alkyl;
G5 is selected from H, alkyl, alkenyl, alkynyl, aryl, alkyl aryl, aryl alkyl, heteroaryl, alkyl heteroaryl, heteroaryl alkyl, alkenyl aryl, aryl alkenyl, alkenyl heteroaryl, heteroaryl alkenyl, C3-Cg-cycloalkyl, heterocycloalkyl, alkyl C3-Cg-cycloalkyl, C3-
Cg-cycloalkyl alkyl, alkyl heterocycloalkyl and heterocycloalkyl alkyl; as well as pharmaceutically acceptable salts and pharmaceutically active derivative thereof, for use as a medicament.
2. A derivative according to claim 1 wherein Gi is H.
3. A derivative according to claim 1 wherein Gi is aryl alkyl and heteroaryl alkyl.
4. A derivative according to claim 1 wherein Gi is alkyl.
5. A derivative according to any ones of claim 1 to 4 wherein G2 is selected from aryl and heteroaryl.
6. A derivative according to any one of claims 1 to 5 wherein G3 is H.
7. A derivative according to any one of claims 1 to 5 wherein G3 is alkyl.
8. A derivative according to any one of claims 1 to 5 wherein G3 is aryl.
9. A derivative according to any one of claims 1 to 8 wherein G4 is selected from alkyl, alkenyl and alkynyl.
10. A derivative according to any one of claims 1 to 8 wherein G4 is selected from aryl alkyl and heteroaryl alkyl.
11. A derivative according to any one of claims 1 to 8 wherein G4 is selected from heterocycloalkyl alkyl and Cs-Cs-cycloalkyl alkyl.
12. A derivative according to any one of claims 1 to 8 wherein G4 is heterocycloalkyl.
13. A derivative according to any one of claims 1 to 12 wherein G5 is H.
14. A derivative according to any one of claims 1 to 13 selected from the following group:
4-methyl-2-phenyl-5-(thiophen-2-ylmethyl)-lH-pyrazolo[4,3-c]pyridine-3,6 (2H,5H)-dione;
2-(l,3-benzothiazol-2-yl)-5-[2-(lH-imidazol-4-yl)ethyl]-4-methyl-lH-pyrazolo[4,3- c]pyridine-3,6(2H,5H)-dione; 2-( 1 ,3 -benzothiazol-2-yl)-5 - [2-( 1 H-indol-3 -yl)ethyl]-4-methyl- 1 H-pyrazolo [4,3 -c] pyridine-3,6(2H,5H)-dione;
2-(l,3-benzothiazol-2-yl)-4-methyl-5-(3-morpholin-4-ylpropyl)-lH-pyrazolo[4,3-c] pyridine-3,6(2H,5H)-dione;
5-(furan-2-ylmethyl)-4-methyl-2-phenyl-lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)- dione;
4-{[2-(l,3-benzothiazol-2-yl)-4-methyl-3,6-dioxo-l,2,3,6-tetrahydro-5H-pyrazolo
[4,3-c]pyridin-5-yl]methyl}benzoic acid;
4-methyl-2-phenyl-5-(pyridin-3-ylmethyl)-lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)- dione;
4-methyl-2-phenyl-5-(2-phenylethyl)-lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)- dione;
5-[2-(4-acetylpiperazin-l-yl)ethyl]-2-(l,3-benzothiazol-2-yl)-4-methyl-lH-pyrazolo
[4,3-c]pyridine-3,6(2H,5H)-dione;
2-(l,3-benzothiazol-2-yl)-4-methyl-5-(2-methylbutyl)-lH-pyrazolo[4,3-c]pyridine-
3,6(2H,5H)-dione;
2-(l,3-benzothiazol-2-yl)-5-[2-(4-methoxyphenyl)ethyl]-4-methyl-lH-pyrazolo[4,3- c]pyridine-3,6(2H,5H)-dione;
2-(l,3-benzothiazol-2-yl)-5-[2-(4-hexanoylpiperazin-l-yl)ethyl]-4-methyl-lH- pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;
2-( 1 ,3 -benzothiazol-2-yl)- 1 -benzyl-5 -(furan-2-ylmethyl)-4-methyl- 1 H-pyrazolo
[4,3-c]pyridine-3,6(2H,5H)-dione;
5-[2-(lH-indol-3-yl)ethyl]-4-methyl-l-(3-methylbenzyl)-2-phenyl-lH-pyrazolo[4,3- c]pyridine-3,6(2H,5H)-dione;
1 -(4-fluorobenzyl)-5 -[2-(I H-indol-3 -yl)ethyl] -4-methyl-2-phenyl- 1 H-pyrazolo [4,3 - c]pyridine-3,6(2H,5H)-dione; l-(2-chlorobenzyl)-4-methyl-5-[3-(2-oxopyrrolidin-l-yl)propyl]-2-phenyl-lH- pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;
2-( 1 ,3 -benzothiazol-2-yl)- 1 -benzyl-4-methyl-5 -(tetrahydrofuran-2-ylmethyl)- 1 H- pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione; l-(4-chlorobenzyl)-5-[2-(lH-imidazol-4-yl)ethyl]-4-methyl-2 -phenyl- lH-pyrazo Io
[4,3-c]pyridine-3,6(2H,5H)-dione;
5-(l,3-benzodioxol-5-ylmethyl)-4-methyl-2-phenyl-lH-pyrazolo[4,3-c]pyridine-
3,6(2H,5H)-dione;
5-benzyl-4-methyl-2 -phenyl- lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;
5-benzyl-2-(4-fluorophenyl)-4-methyl-lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)- dione;
5-benzyl-2-(4-methoxyphenyl)-4-methyl-lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)- dione;
2-(l,3-benzothiazol-2-yl)-4-methyl-5-morpholin-4-yl-lH-pyrazolo[4,3-c]pyridine-
3,6 (2H,5H)-dione;
5-benzyl-4-methyl-2-(4-nitrophenyl)-lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)- dione;
2-(l,3-benzothiazol-2-yl)-4-methyl-l-(3-methylbenzyl)-5-(3-morpholin-4-ylpropyl)
-lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;
2-(l,3-benzothiazol-2-yl)-l-(4-fluorobenzyl)-4-methyl-5-(3-morpholin-4-ylpropyl)- lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;
2-(l,3-benzothiazol-2-yl)-4-methyl-l-(4-methylbenzyl)-5-(3-morpholin-4-ylpropyl)
-lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;
2-(l,3-benzothiazol-2-yl)-l-(2-chlorobenzyl)-4-methyl-5-morpholin-4-yl-lH- pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;
2-(l,3-benzothiazol-2-yl)-l-(4-bromobenzyl)-4-methyl-5-(2-morpholin-4-ylethyl)- lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;
2-[2-(l,3-benzothiazol-2-yl)-4-methyl-5-(3-morpholin-4-ylpropyl)-3,6-dioxo-
2,3,5,6-tetrahydro-lH-pyrazolo[4,3-c]pyridin-l-yl]-N-phenylacetamide;
4-methyl-2-phenyl-5-(tetrahydrofuran-2-ylmethyl)-lH-pyrazolo[4,3-c]pyridine-3,6
(2H,5H)-dione;
2-(l,3-benzothiazol-2-yl)-4-methyl-5-(2-phenylethyl)-lH-pyrazolo[4,3-c]pyridine-
3,6(2H,5H)-dione; 5-[2-(lH-indol-3-yl)ethyl]-4-methyl-2-phenyl-lH-pyrazolo[4,3-c]pyridine-3,6
(2H,5H)-dione;
4-methyl-5-morpholin-4-yl-2-phenyl-lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)- dione;
2-(l,3-benzothiazol-2-yl)-l-(2-chlorobenzyl)-4-methyl-5-(3-morpholin-4-ylpropyl)- lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;
5-benzyl-4-ethyl-2-(4-fluorophenyl)-lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;
4-ethyl-2-(4-fluorophenyl)-5-(2-phenylethyl)-lH-pyrazolo[4,3-c]pyridine-3,6
(2H,5H)-dione;
4-ethyl-2-(4-fluorophenyl)-5-morpholin-4-yl-lH-pyrazolo[4,3-c]pyridine-3,6
(2H,5H)-dione;
4-methyl-5-(2-morpholin-4-ylethyl)-2-phenyl-lH-pyrazolo[4,3-c]pyridine-3,6
(2H,5H)-dione;
4-ethyl-5-morpholin-4-yl-2-phenyl-lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;
2-(2-chlorophenyl)-4-methyl-5-(pyridin-2-ylmethyl)-lH-pyrazolo[4,3-c]pyridine-
3,6 (2H,5H)-dione;
4-methyl-2-(2-methylphenyl)-5 -(3 -morpholin-4-ylpropyl)- 1 H-pyrazolo [4,3 -c] pyridine-3,6(2H,5H)-dione;
2-( 1 ,3 -benzothiazol-2-yl)-4-methyl- 1 -(pyridin-2-ylmethyl)-5 -(tetrahydrofuran-2- ylmethyl)-lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;
2-(l,3-benzothiazol-2-yl)-4-ethyl-5-(pyridin-2-ylmethyl)-lH-pyrazolo[4,3-c] pyridine-3,6 (2H,5H)-dione;
2-(l,3-benzothiazol-2-yl)-4-ethyl-5-(3-morpholin-4-ylpropyl)-lH-pyrazolo[4,3-c] pyridine-3,6(2H,5H)-dione;
2-(l,3-benzothiazol-2-yl)-4-ethyl-5-(2-methoxyethyl)-lH-pyrazolo[4,3-c]pyridine-
3,6 (2H,5H)-dione;
2-(l,3-benzothiazol-2-yl)-4-ethyl-5-(4-methylpiperazin-l-yl)-lH-pyrazolo[4,3-c] pyridine-3,6(2H,5H)-dione;
2-(l,3-benzothiazol-2-yl)-4-ethyl-5-[l-(4-methylbenzyl)piperidin-4-yl]-lH- pyrazolo[4,3-c] pyridine-3,6(2H,5H)-dione; 4-ethyl-2-(4-fluorophenyl)-5-(pyridin-2-ylmethyl)-lH-pyrazolo[4,3-c]pyridine-
3,6(2H,5H)-dione;
4-ethyl-2-(4-fluorophenyl)-5-(3-morpholin-4-ylpropyl)-lH-pyrazolo[4,3-c]pyridine-
3,6 (2H,5H)-dione;
4-ethyl-2-(4-fluorophenyl)-5-(2-methoxyethyl)-lH-pyrazolo[4,3-c]pyridine-3,6
(2H,5H)-dione;
5-(2-morpholin-4-ylethyl)-2-pyridin-2-yl-lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)- dione;
2,4-diphenyl-5-(pyridin-3-ylmethyl)-lH-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;
2-(2-chlorophenyl)-4-ethyl-5-(pyridin-3-ylmethyl)-lH-pyrazolo[4,3-c]pyridine-3,6
(2H,5H)-dione;
4-methyl-2-(2-methylphenyl)-5-(pyridin-2-ylmethyl)-lH-pyrazolo[4,3-c]pyridine-
3,6 (2H,5H)-dione;
4-ethyl-5 -(3 -morpholin-4-ylpropyl)-2- [4-(trifluoromethyl)phenyl] - 1 H-pyrazolo [4,3 - c] pyridine-3,6(2H,5H)-dione;
4-ethyl-5 -(3 -morpholin-4-ylpropyl)-2- [4-(trifluoromethoxy)phenyl] - 1 H-pyrazolo
[4,3-c] pyridine-3,6(2H,5H)-dione;
2-(2,5-difluorophenyl)-4-ethyl-5-(3-morpholin-4-ylpropyl)-lH-pyrazolo[4,3- c]pyridine-3,6 (2H,5H)-dione; and
4-ethyl-2-(2-methoxyphenyl)-5-(3-morpholin-4-ylpropyl)-lH-pyrazolo[4,3- c]pyridine-3,6 (2H,5H)-dione.
15. A pharmaceutical composition containing at least one derivative according to any one of claims 1 to 14 and a pharmaceutically acceptable carrier, diluent or excipient thereof.
16. A use of a pyrazolo pyridine derivative according to Formula (I), wherein G1, G2, G3, G4 and G5 are as defined in any one of the preceding claims, 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 and other diseases and disorders associated with Nicotinamide adenine dinucleotide phosphate oxidase (NADPH Oxidase).
17. A pyrazolo pyridine derivative according to Formula (I), wherein G1, G2, G3, G4 and G5 are as defined in any one of the preceding claims, as well as pharmaceutically acceptable salts and pharmaceutically active derivative thereof, for use in 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 and other diseases and/or disorders associated with Nicotinamide adenine dinucleotide phosphate oxidase (NADPH Oxidase).
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ES08718102T ES2398994T3 (en) 2007-03-22 2008-03-20 Pyrazol pyridine derivatives as inhibitors of NAPDH oxidase
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