WO2014128655A1 - Dérivés d'imidazo[4,5-c]quinoléine substituée utilisés comme inhibiteurs de bromodomaines - Google Patents

Dérivés d'imidazo[4,5-c]quinoléine substituée utilisés comme inhibiteurs de bromodomaines Download PDF

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WO2014128655A1
WO2014128655A1 PCT/IB2014/059152 IB2014059152W WO2014128655A1 WO 2014128655 A1 WO2014128655 A1 WO 2014128655A1 IB 2014059152 W IB2014059152 W IB 2014059152W WO 2014128655 A1 WO2014128655 A1 WO 2014128655A1
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methoxy
imidazo
quinolin
methyl
compound
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PCT/IB2014/059152
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English (en)
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Sanjita SASMAL
Subramanya Hosahalli
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Aurigene Discovery Technologies Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the present invention relates to compounds useful for the treatment and prevention of diseases or disorder, in particular their use in diseases or disorder associated where there is an advantage in inhibiting kinase enzyme activity, and more particularly bromodomain inhibitors.
  • the invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of diseases or disorder associated with bromodomain.
  • the acetylation of histone lysine is central to providing the dynamic regulation of chromatin-based gene transcription.
  • the bromodomain (BRD) which is the conserved structural module in chromatin-associated proteins and histone acetyl tranferases, is the sole protein domain known to recognize acetyl-lysine residues on proteins.
  • the BET family of bromodomain containing proteins comprises 4 proteins (BRD2, BRD3, BRD4 and BRD-t) which contain tandem bromodomains capable of binding to two acetylated lysine residues in close proximity, increasing the specificity of the interaction.
  • BRD2 and BRD3 are reported to associate with histones along actively transcribed genes and may be involved in facilitating transcriptional elongation (Leroy et al, Mol. Cell. 2008 30(1):51 -60), while BRD4 appears to be involved in the recruitment of the pTEF-[beta] complex to inducible genes, resulting in phosphorylation of RNA polymerase and increased transcriptional output (Hargreaves et al, Cell, 2009 138(1): 129-145).
  • BRD4 or BRD3 may fuse with NUT (nuclear protein in testis) forming novel fusion oncogenes, BRD4-NUT or BRD3- NUT, in a highly malignant form of epithelial neoplasia (French et al. Cancer Research, 2003, 63, 304-307 and French et al. Journal of Clinical Oncology, 2004, 22 (20), 4135-4139).
  • BRD-NUT fusion proteins contribute to carcinogenesis (Oncogene, 2008, 27, 2237-2242).
  • BRD-t is uniquely expressed in the testes and ovary.
  • Japanese patent application JP2008-156311 disclosed a benzimidazole derivative which is said to be a BRD2 bromodomain binding agent has utility with respect to virus infection / proliferation.
  • bromodomain inhibitors Certain quinoline derivatives have been found in the context of this invention to have a class of compounds that inhibit the binding of BET family bromodomains to acetylated lysine residues for controlling the gene expressions in human health and disease. Such compounds will hereafter be referred to as "bromodomain inhibitors".
  • the present invention relates to substituted imidazo[4,5-c]quinoline derivatives of formula (1) which are useful as kinase inhibitors.
  • the present invention relates to the compound of formula (1)
  • Cyi is an optionally substituted monocyclic ring having 1-3 heteroatoms independently selected from N and O; wherein the optional substituent is alkyl; Cy 2 is an optionally substituted monocyclic ring having 0-2 heteroatoms; wherein the heteroatom is N and the optional substituents are selected from alkyl, halogen and alkoxy;
  • Ri is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, cycloalkylalkyl and heterocyclylalkyl;
  • R 2 and R 3 are independently selected from the halogen, hydroxy or alkyl; or R 2 and R 3 combined together to form an oxo group;
  • R 2 and R 3 can be taken together with the carbon atom to which they are attached to form a 3-4 membered cycloalkyl ring;
  • R4 is selected from hydrogen, halogen and alkyl
  • R5 is selected from hydrogen, halogen, alkyl and alkoxy.
  • Embodiments of the present invention provide substituted imidazo[4,5-c]quinoline derivatives of formula ( 1) which are useful as bromodomain inhibitors.
  • Cyi is an optionally substituted monocyclic ring having 1-3 heteroatoms independently selected from N and O; wherein the optional substituent is alkyl;
  • Cy 2 is an optionally substituted monocyclic ring having 0-2 heteroatoms; wherein the heteroatom is N and the optional substituents are selected from alkyl, halogen and alkoxy;
  • Ri is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, cycloalkylalkyl and heterocyclylalkyl;
  • R 2 and R 3 are independently selected from the halogen, hydroxy or alkyl; or R 2 and R 3 combined together to form an oxo group;
  • R 2 and R 3 can be taken together with the carbon atom to which they are attached to form a 3-4 membered cycloalkyl ring;
  • R4 is selected from hydrogen, halogen and alkyl
  • R5 is selected from hydrogen, halogen, alkyl and alkoxy.
  • Cy 2 is selected from optionally substituted phenyl and optionally substituted pyridyl.
  • halogen is chloro and fluoro
  • alkoxy is methoxy
  • alkyl is methyl
  • Ri is selected from hydrogen, alkyl, hydroxyalkyl and alkoxyalkyl; in particular alkyl is methyl, hydroxyalkyl is -CH2CH2OH, and alkoxyalkyl is -CH 2 CH 2 OCH 3 .
  • Ri is selected from arylalkyl, cyaloalkylalkyl and heterocyclylalkyl.
  • Ri According to yet another embodiment, specifically provided are compounds of formula ( 1), wherein R 2 and R 3 are independently selected from halogen, hydroxy and alkyl; in particular halogen is fluoro, and alkyl is methyl and ethyl.
  • the compound of formula ( 1) is a compound of formula (la)
  • Ri and Cy 2 are same as defined in formula ( 1).
  • the compound of formula ( 1) is a compound of formula (lb)
  • Ri and Cy 2 are same as defined in formula (1).
  • the compound of formula (1) is a compound of formula (lc)
  • Ri and Cy 2 are same as defined in formula (1); and 'n' is an integer selected from 0 and 1.
  • the compound of formula (1) is selected from the group consisting of
  • the present invention provides process for preparation of compound of formula (1) and their pharmaceutical compositions.
  • the definition of "compounds of formula ( 1)" inherently includes all stereoisomers of the compound of formula ( 1) either as pure stereoisomer or as a mixture of two or more stereoisomers.
  • stereoisomers include enantiomers, diasteroisomers, racemates, cis or trans isomers and mixture thereof.
  • the absolute configuration at an asymmetric atom is specified by either R or S.
  • Resolved compounds whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light.
  • a specific stereoisomer is identified, this means that said stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 5%, in particularly less than 2% or 1 % of the other isomers.
  • Alkyl refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms; in particular alkyl is Ci-Cio alkyl group which may have 1 to 10 (inclusive) carbon atoms in it; in more particular alkyl is Ci-C 6 alkyl group which may have 1 to 6 (inclusive) carbon atoms in it and in more preferred particular alkyl is Ci- C 4 alkyl group which may have 1 to 4 (inclusive) carbon atoms in it.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec- butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.
  • An alkyl group can be unsubstituted or substituted with one or more suitable groups.
  • Alkoxy refers to the group alkyl-O- or -O-alkyl, where alkyl group is as defined above.
  • Ci-Cioalkyl group containing alkoxy groups include but are not limited to methoxy, ethoxy, n-propoxy, zso-propoxy, n-butoxy and i-butoxy.
  • An alkoxy group can be unsubstituted or substituted with one or more suitable groups.
  • Halogen or "halo” includes fluorine, chlorine, bromine or iodine.
  • Haldroxy refers to -OH group.
  • Oxo refers to -C(O)-.
  • Alkoxyalkyl refers to an alkyl group substituted with one or more alkoxy groups; the alkyl group and alkoxy group are same as defined above, wherein one or more of the alkyl group's hydrogen atom has been replaced with alkoxy group.
  • Representative examples of an alkoxyalkyl group include but are not limited to -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 OCH 2 CH 3 , -
  • Hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups; the alkyl group and hydroxy group are same as defined above, wherein one or more of the alkyl group's hydrogen atom has been replaced with hydroxy group.
  • Representative examples of an hydroxyalkyl group includes but are not limited to -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH(OH)CH 3 , -
  • Aryl refers to an optionally substituted monocylic, bicyclic or polycyclic aromatic hydrocarbon ring system of about 6 to 14 carbon atoms.
  • Examples of a C 6 -Ci4 aryl group include, but are not limited to phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl and acenaphthyl.
  • Aryl group can be unsubstituted or substituted with one or more suitable groups;
  • Arylalkyl refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atom has been replaced with an aryl group as defined above.
  • arylalkyl group include, but are not limited to benzyl, benzhydryl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl.
  • An arylalkyl group can be unsubstituted or substituted with one or more suitable groups.
  • Cycloalkyl refers to a non-aromatic, saturated, monocyclic, bicyclic or polycyclic hydrocarbon ring system.
  • Representative examples of a cycloalkyl include, but are not limited to cyclopropyl, cyclopentyl, cycloheptyl, cyclooctyl, decahydronaphthalen-l-yl, octahydro-lH- inden-2-yl and decahydro-lH-benzo[7] annulen-2-yl.
  • a cycloalkyl can be unsubstituted or substituted with one or more suitable groups.
  • Cyclyoalkylalkyl refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atom has been replaced with cycloalkyl group as defined above.
  • Representative examples of a cyclyoalkylalkyl group include, but are not limited to cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, cyclopentylmethyl, cyclohexylmethyl and the like.
  • a cycloalkylalkyl group can be unsubstituted or substituted with one or more suitable groups.
  • Heterocyclyl includes the definitions of "heterocycloalkyl” and “heteroaryl”.
  • the term “Heterocycloalkyl” refers to a non-aromatic, saturated or partially saturated, monocyclic or polycyclic ring system of 3 to 10 member having at least one heteroatom or hetero group selected from O, N, S, S(O), S(0) 2 , NH and C(O).
  • Exemplary heterocycloalkyl groups include piperdinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,3-dioxolanyl, 1,4-dioxanyl and the like.
  • a heterocycloalkyl group can be unsubstituted or substituted with one or more suitable groups.
  • Heteroaryl refers to an unsaturated, monocyclic, bicyclic, or polycyclic aromatic ring system containing at least one heteroatoms selected from oxygen, sulfur and nitrogen.
  • C5-C10 heteroaryl groups include furan, thiophene, indole, azaindole, oxazole, thiazole, thiadiazole, isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, 1-methyl- 1,2,4-triazole, lH-tetrazole, 1-methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, N-methylbenzimidazole, azabenzimidazo
  • Bicyclic heteroaryl groups include those where a phenyl, pyridine, pyrimidine or pyridazine ring is fused to a 5 or 6-membered monocyclic heterocyclyl ring having one or two nitrogen atoms in the ring, one nitrogen atom together with either one oxygen or one sulfur atom in the ring, or one O or S ring atom
  • a heteroaryl group can be unsubstituted or substituted with one or more suitable groups.
  • Heterocyclylalkyl refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atom has been replaced with heterocyclyl group as defined above.
  • Representative examples of a heterocyclylalkyl group include, but are not limited to tetrahydropyran-4yl-methyl-, thiazole-5yl-methyl-. 2-pyridinemethyl, 2-pyyrolidinemethyl and the like
  • a heterocyclylalkyl group can be unsubstituted or substituted with one or more suitable groups.
  • Hetero atom refers to a sulfur, nitrogen or oxygen atom.
  • Hetero group refers to -C(O), -S(O), -NH and -S(0) 2 .
  • “Monocyclic ring” refers to a saturated, partially saturated or unsaturated 3 to 7 membered ring, having 0-3 heteroatoms/heterogroups independently selected from N, O, S,-C(0), -S(O), - NH and -S(0) 2 .
  • Representative examples of a 3 to 7 membered ring include, but are not limited to cyclopropyl, cyclobutyl, cyclohexyl, azetidine, oxirane, phenyl, pyridyl, pyrazole, pyrimidine, piperizine, piperidine, morpholine, 1,2,3,6-tetrahydropyridine indazole and the like.
  • suitable groups
  • the compounds and pharmaceutically compositions of the present invention are used in the treatment and/or prevention of diseases and/or disorders in which aberrant, abnormal or deregulated activity of bromodomain containing proteins contribute to the pathology and/or symptomology of such diseases and/or disorders.
  • diseases and/or disorders mediated by one or more of these kinases are provided herein.
  • the compounds and pharmaceutically compositions of the present invention are used in the treatment and/or prevention of diseases and/or disorders in which aberrant, abnormal or deregulated activity of BET family of bromodomain containing proteins; in particular BRD2, BRD3, BRD4 and BRD-t proteins.
  • Bromodomain inhibitors are believed to be useful in the treatment of a variety of diseases or conditions related to systemic or tissue inflammation, inflammatory responses to infection or hypoxia, cellular activation and proliferation, lipid metabolism, fibrosis and in the prevention and treatment of viral infections.
  • Bromodomain inhibitors may be useful in the treatment of a wide variety of chronic autoimmune and inflammatory conditions such as rheumatoid arthritis, osteoarthritis, acute gout, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease (Crohn's disease and Ulcerative colitis), asthma, chronic obstructive airways disease, pneumonitis, myocarditis, pericarditis, myositis, eczema, dermatitis, alopecia, vitiligo, bullous skin diseases, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, depression, retinitis, uveitis, scleritis, hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing cholangitis, Addison's disease, hypophysitis, thyroiditis, type I diabetes and
  • Bromodomain inhibitors may be useful in the treatment of a wide variety of acute inflammatory conditions such as acute gout, giant cell arteritis, nephritis including lupus nephritis, vasculitis with organ involvement such as glomerulonephritis, vasculitis including giant cell arteritis, Wegener's granulomatosis, Polyarteritisnodosa, Behcet's disease, Kawasaki disease, Takayasu's Arteritis, vasculitis with organ involvement and acute rejection of transplanted organs.
  • acute inflammatory conditions such as acute gout, giant cell arteritis, nephritis including lupus nephritis, vasculitis with organ involvement such as glomerulonephritis, vasculitis including giant cell arteritis, Wegener's granulomatosis, Polyarteritisnodosa, Behcet's disease, Kawasaki disease
  • Bromodomain inhibitors may be useful in the prevention or treatment of diseases or conditions which involve inflammatory responses to infections with bacteria, viruses, fungi, parasites or their toxins, such as sepsis, sepsis syndrome, septic shock, endotoxaemia, systemic inflammatory response syndrome (SIRS), multi-organ dysfunction syndrome, toxic shock syndrome, acute lung injury, ARDS (adult respiratory distress syndrome), acute renal failure, fulminant hepatitis, burns, acute pancreatitis, post-surgical syndromes, sarcoidosis, Herxheimer reactions, encephalitis, myelitis, meningitis, malaria and SIRS associated with viral infections such as influenza, herpes zoster, herpes simplex and coronavirus.
  • diseases or conditions which involve inflammatory responses to infections with bacteria, viruses, fungi, parasites or their toxins, such as sepsis, sepsis syndrome, septic shock, endotoxaemia, systemic inflammatory response syndrome (SIRS),
  • Bromodomain inhibitors may be useful in the prevention or treatment of conditions associated with ischaemia-reperfusion injury such as myocardial infarction, cerebro- vascular ischaemia (stroke), acute coronary syndromes, renal reperfusion injury, organ transplantation, coronary artery bypass grafting, cardio-pulmonary bypass procedures, pulmonary, renal, hepatic, gastro -intestinal or peripheral limb embolism.
  • ischaemia-reperfusion injury such as myocardial infarction, cerebro- vascular ischaemia (stroke), acute coronary syndromes, renal reperfusion injury, organ transplantation, coronary artery bypass grafting, cardio-pulmonary bypass procedures, pulmonary, renal, hepatic, gastro -intestinal or peripheral limb embolism.
  • Bromodomain inhibitors may be useful in the treatment of disorders of lipid metabolism via the regulation of APO-A1 such as hypercholesterolemia, atherosclerosis and Alzheimer's disease.
  • Bromodomain inhibitors may be useful in the treatment of fibrotic conditions such as idiopathic pulmonary fibrosis, renal fibrosis, post-operative stricture, keloid formation, scleroderma and cardiac fibrosis.
  • Bromodomain inhibitors may be useful in the prevention and treatment of viral infections such as herpes virus, human papilloma virus, adenovirus and poxvirus and other DNA viruses. Bromodomain inhibitors may be useful in the treatment of cancer, including hematological, epithelial including lung, breast and colon carcinomas, midline carcinomas, mesenchymal, hepatic, renal and neurological tumors.
  • viral infections such as herpes virus, human papilloma virus, adenovirus and poxvirus and other DNA viruses.
  • Bromodomain inhibitors may be useful in the treatment of cancer, including hematological, epithelial including lung, breast and colon carcinomas, midline carcinomas, mesenchymal, hepatic, renal and neurological tumors.
  • the disease or condition for which a bromodomain inhibitor is indicated is selected from diseases associated with systemic inflammatory response syndrome, such as sepsis, burns, pancreatitis, major trauma, haemorrhage and ischaemia.
  • the bromodomain inhibitor would be administered at the point of diagnosis to reduce the incidence of: SIRS, the onset of shock, multi-organ dysfunction syndrome, which includes the onset of acute lung injury, ARDS, acute renal, hepatic, cardiac and gastro-intestinal injury and mortality.
  • the bromodomain inhibitor would be administered prior to surgical or other procedures associated with a high risk of sepsis, haemorrhage, extensive tissue damage, SIRS or MODS (multiple organ dysfunction syndrome).
  • the disease or condition for which a bromodomain inhibitor is indicated is sepsis, sepsis syndrome, septic shock and endotoxaemia.
  • the bromodomain inhibitor is indicated for the treatment of acute or chronic pancreatitis.
  • the bromodomain is indicated for the treatment of burns.
  • the disease or condition for which a bromodomain inhibitor is indicated is selected from herpes simplex infections and reactivations, cold sores, herpes zoster infections and reactivations, chickenpox, shingles, human papilloma virus, cervical neoplasia, adenovirus infections, including acute respiratory disease, poxvirus infections such as cowpox and smallpox and African swine fever virus.
  • a bromodomain inhibitor is indicated for the treatment of Human papilloma virus infections of skin or cervical epithelia.
  • a bromodomain inhibitor is intended to include each of or all of the above disease states. While it is possible that for use in therapy, a compound of formula (1) as well as pharmaceutically acceptable salts thereof may be administered as the raw chemical, it is common to present the active ingredient as a pharmaceutical composition.
  • Comprise or “Comprising” is generally used in the sense of include, that is to say permitting the presence of one or more features or components.
  • “Pharmaceutically acceptable salt” or “pharmaceutically acceptable derivatives” is taken to mean an active ingredient, which comprises a compound of the formula ( 1 ) in the form of one of its salts, in particular if this salt form imparts improved pharmacokinetic properties on the active ingredient compared with the free form of the active ingredient or any other salt form of the active ingredient used earlier.
  • the pharmaceutically acceptable salt form of the active ingredient can also provide this active ingredient for the first time with a desired pharmacokinetic property which it did not have earlier and can even have a positive influence on the pharmacodynamics of this active ingredient with respect to its therapeutic efficacy in the body.
  • terapéuticaally effective amount means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • the compounds and pharmaceutically compositions of the present invention may be used in combination with other drugs that are used in the treatment/pre vention/suppression or amelioration of the diseases or conditions for which compounds of the present invention may be useful.
  • Such other drugs may be administered, by a route and in an amount commonly used there for, contemporaneously or sequentially with a compound of the present invention.
  • a pharmaceutical composition containing such other drugs in addition to the compound of the present invention may also be preferred.
  • the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
  • a pharmaceutical composition of the invention may be formulated as being compatible with its intended route of administration, which may preferably be an oral administration.
  • the pharmaceutical compositions of the invention may be formulated for administration by inhalation, such as aerosols or dry powders; for oral administration, such in the form of tablets, capsules, gels, syrups, suspensions, emulsions, elixirs, solutions, powders or granules; for rectal or vaginal administration, such as suppositories; or for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular, or infusion) such as a sterile solution, suspension or emulsion.
  • the compounds of the present invention may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethyl cellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano -particles and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano -particles and nanocapsules
  • novel substituted imidazo[4,5-c]quinoline derivatives of formula (1) 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 optimization procedures. The specifics of the processes according to the present invention are detailed in the example section mentioned below.
  • the compounds of the present invention can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the present invention also embraces isotopically-labeled variants of the present invention which are identical to those recited herein, but for the fact that one or more atoms of the compound are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses.
  • Exemplary isotopes that can be incorporated in to compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as 2 H ("D"), 3 ⁇ 4, n C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 32 P, 33 P, 35 S, 18 F, 36 C1, 123 I and 125 I.
  • Isotopically labeled compounds of the present inventions can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • Another embodiment of the present invention provides methods useful for making the compounds of formula (1) are set forth in the examples below and generalized in below scheme.
  • One of skill in the art will recognize that the below scheme can be adapted to produce the compounds of formula ( 1) and pharmaceutically accepted salts of compounds of formula ( 1) according to the present invention. Wherein all symbols/variables are as defined earlier unless otherwise stated. The process is represented herein by below scheme.
  • the novel compounds of the present invention can be synthesized from formula ( 1.1).
  • Formula ( 1.1) undergoes chlorination by using chlorinating agents such as POCI3, SOCb and the like in presence of suitable solvents such as DCM, DMF and the like at appropriate conditions, followed by N-alkylation by using suitable alkylamines in presence of suitable base such as TEA at suitable conditions to give formula (1.2).
  • Formula ( 1.2) undergoes reduction in presence of catalyst such as 10% Pd-C/H 2 or SnCl 2 .2H 2 0/ Conc.HCl in presence of suitable solvents such as ethanol to give formula ( 1.3).
  • Formula (1.3) undergoes amide coupling with appropriate acids in presence of suitable coupling reagents such as EDC.HCl/ HOBt or HATU/DIEA in presence of suitable base like TEA, in suitable solvents such as DCM, DMF and the like to give formula (1.4), which undergoes further cyclisation reaction in presence of acetic acid or potassium phosphate tribasic in presence of suitable solvents such as tet-butanol at appropriate conditions to give formula (1.5).
  • Formula (1.5) undergoes oxidation in presence of Mn0 2 or Se0 2 in suitable solvents such as 1,4-dioxane at suitable conditions to give compounds of formula (la).
  • Formula (la) further undergoes fluorination in presence of D AST ((Diethylamino)sulfurtrifluoride) at suitable solvents such as DCM and the like in suitable conditions to give compound of formula (lb).
  • D AST Diethylamino)sulfurtrifluoride
  • suitable solvents such as DCM and the like in suitable conditions
  • Formula (la) undergoes alkylation of carbonyl group in presence of appropriate Grignard reagent such as ethylmagnesiumbromide or organolithium reagent such as methyl lithium in presence of suitable solvents at suitable temperatures to give compound of formula (lc).
  • Step-f 4-bromo-5-methoxy-2-((2-nitrovinyl)amino)benzoic acid
  • reaction mixture was cooled to 25-35°C and water was added and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated under vacuum to get the desired crude product. Crude product was purified by column chromatography using 60-120 mesh silica gel and 5% methanol-DCM as eluent to get the pure product as brown solid (2.3 g, 54%).
  • Step-a 4-(4-chloro-6-methoxy-3-nitroquinolin-7-yl)-3,5-dimethylisoxazole
  • this reaction can be performed by using other chlorinating agents such as thionyl chloride and the like.
  • Step-b 7-(3, 5-dimethylisoxazol-4-yl)-6-methoxy-N-(4-methoxybenzyl)-3-nitroquinolin-4-amine
  • 4-(4-chloro-6-methoxy-3-nitroquinolin-7-yl)-3,5- dimethylisoxazole 0.5 g, 1.5 mmol,
  • 4-methoxybenzylmine 0.122 mL, 1.65 mmol
  • Step-c 7-(3, 5-dimethylisoxazol-4-yl)-6-methoxy-N 4 -(4-methoxybenzyl)quinoline-3,4-diamine
  • this reaction can be performed by hydro genation in presence of 10% Pd- C/H 2 and the like.
  • Step-e 4-(8-methoxy-l-(4-methoxybenzyl)-2-(pyridin-3-ylmethyl)-lH-imidazo[4,5-clquinolin-7- yl)-3,5-dimethylisoxazole
  • Step-f 4-(8-methoxy-2-(pyridin-3-ylmethyl)-lH-imidazo[4,5-clquinolin-7-yl)-3,5-dimethyl isoxazole
  • Example-A Synthesis of (7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-lH-imidazor4,5-clquinolin- 2-yl)(pyridin-3-yl)methanone (Compound- 1 )
  • DAST Diethylamino sulfur trifluoride
  • Example-C Synthesis of l-(7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-l-methyl-lH-imidazor4, 5-clquinolin-2-yl)-l-(pyridin-3-yl)ethanol (Compound-32 & Compound-33) mer-1 mer-2
  • Example-D Synthesis of l-(4-chlorophenyl)-l-(7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-l- methyl- -imidazo[4,5-clquinolin-2-yl)propan-l-ol (Compound-34 & 35)
  • Example-D with appropriate starting compound, reagents under suitable reaction conditions.
  • the physiochemical characteristics of the compounds are summarized herein below table.
  • Example-E Synthesis of 4-(8-methoxy-l-methyl-2-(l-(pyridin-3-yl)cyclopropyl)-lH-imidazor4, 5-clquinolin-7-yl)-3,5-dimethylisoxazole (Compound-38)
  • step-d of Intermediate-II A process of this step was adopted from step-d of Intermediate-II to get the desired crude compound as brown oil (0.13 g); LC-MS: m/z 444.2 (M+l) + .
  • In-Vitro Biochemical Data of Imidazo[4,5-C]quinoline derivatives in time-resolved fluorescence resonance energy transfer (TR-FRET) assay.
  • TR-FRET time-resolved fluorescence resonance energy transfer
  • the reaction mixture was further incubated for 30mins at room temperature on a plate shaker. 2 nM of Europium labeled streptavidn and 10 nM of XL-665 labeled antibody diluted in detection buffer (50mM HEPES, P H : 7.5, 50 mM NaCl, 500 ⁇ CHAPS and 800 mM KF) were added to all the wells excluding the buffer blank wells. The reaction plate was incubated for additional 30mins at room temperature on plate shaker. The plate was read in Perkin Elmer WALLAC 1420 Multilabel Counter Victor 3 (Ex: 340 nm Em: 615& 665 nm). The amount of displacement of the peptide was measured as ratio of specific 665 nm energy transfer signal to 615 nm signals. The compound's IC50 was determined by fitting the dose response data to sigmoid curve fitting equation using Graph Pad Prism software V5.
  • the selected compounds were screened in the above mentioned assay and the results (IC50) are summarized in the below table.
  • the IC50 values are set forth in the below table wherein Group 'A' refers to an IC50 value of less than 200 nM, Group 'B' refers to an IC50 value in range of 200 to 500 nM and Group 'C refers to an IC50 value of greater than 500 nM.

Abstract

La présente invention porte sur de nouveaux dérivés d'imidazo[4,5-c]quinoléine substituée de formule (1), qui peuvent être thérapeutiquement utiles, plus particulièrement comme inhibiteurs de bromodomaines (1), dans laquelle formule Cy1, Cy2, R1, R2, R3, R4 et R5 ont les mêmes significations que celles données dans la description, et sur des sels pharmaceutiquement acceptables de ceux-ci, qui sont utiles dans le traitement et la prévention de maladies ou troubles, en particulier sur leur utilisation dans des maladies ou troubles associés en tant qu'inhibiteurs de bromodomaines. La présente invention porte également sur la préparation des composés et sur des formulations pharmaceutiques comprenant au moins l'un des composés d'imidazo[4,5-c]quinoléine substituée de formule (1) conjointement avec un véhicule, diluant ou excipient pharmaceutiquement acceptable à cet effet.
PCT/IB2014/059152 2013-02-25 2014-02-21 Dérivés d'imidazo[4,5-c]quinoléine substituée utilisés comme inhibiteurs de bromodomaines WO2014128655A1 (fr)

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US10189832B2 (en) 2016-06-20 2019-01-29 Incyte Corporation Crystalline solid forms of a BET inhibitor
US10231953B2 (en) 2014-12-17 2019-03-19 Zenith Epigenetics Ltd. Inhibitors of bromodomains
US10292968B2 (en) 2014-12-11 2019-05-21 Zenith Epigenetics Ltd. Substituted heterocycles as bromodomain inhibitors
US10329305B2 (en) 2015-10-29 2019-06-25 Incyte Corporation Amorphous solid form of a BET protein inhibitor
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011054846A1 (fr) * 2009-11-05 2011-05-12 Glaxosmithkline Llc Derives d'imidazo [4, 5-c] quinoline comme inhibiteurs de bromodomaine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011054846A1 (fr) * 2009-11-05 2011-05-12 Glaxosmithkline Llc Derives d'imidazo [4, 5-c] quinoline comme inhibiteurs de bromodomaine

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