WO2005000813A1 - Derives d'heteroarylamino-phenylcetone et leur utilisation en tant qu'inhibiteurs de kinases - Google Patents

Derives d'heteroarylamino-phenylcetone et leur utilisation en tant qu'inhibiteurs de kinases Download PDF

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WO2005000813A1
WO2005000813A1 PCT/US2004/017248 US2004017248W WO2005000813A1 WO 2005000813 A1 WO2005000813 A1 WO 2005000813A1 US 2004017248 W US2004017248 W US 2004017248W WO 2005000813 A1 WO2005000813 A1 WO 2005000813A1
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optionally substituted
compound
substituents selected
lower alkyl
sjo
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PCT/US2004/017248
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Evgueni Piatnitski
Alexander Kiselyov
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Imclone Systems Incorporated
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to heteroarylaminophenylketone derivatives that inhibit kinases, pharmaceutical compositions that contain the compounds, methods for making the compounds, and methods of treating kinase-dependent diseases and conditions in mammals by administering a therapeutically effective amount of the compounds to said mammals.
  • Angiogenesis is a highly complex process of developing new blood vessels 5 that involves the proliferation and migration of, and tissue infiltration by capillary endothelial cells from pre-existing blood vessels, cell assembly into tubular structures, joining of newly forming tubular assemblies to closed-circuit vascular systems, and maturation of newly formed capillary vessels.
  • Angiogenesis is important in normal physiological processes includingo embryonic development, follicular growth, and wound healing, as well as in pathological conditions such as tumor growth and in non-neoplastic diseases involving abnormal neovascularization, including neovascular glaucoma (Folkman, J. and Klagsbrun, M. Science 235:442-447 (1987).
  • Other disease states include but are not limited to, neoplastic diseases, including but not limited to solid tumors, 5 atherosclerosis and other inflammatory diseases such as rheumatoid arthritis, and ophthalmological conditions such as diabetic retinopathy and age-related macular
  • One means for controlling such diseases and pathological conditions comprises restricting the blood supply to those cells involved in mediating or causing the disease or condition, for example, by occluding blood vessels supplying portions of organs in which tumors are present.
  • Such approaches require the site of the tumor to be identified and are generally limited to treatment to a single site, or a small number of sits.
  • An additional disadvantage of direct mechanical restriction of a blood supply is that collateral blood vessels develop, often quite rapidly, restoring the blood supply to the tumor.
  • VEGF vascular endothelial proliferation
  • VEGF is a factor that has been implicated as a regulator of angiogenesis in vivo (Klagsbrun, M. and D'Amore, P. (1991) Annual Rev. Physiol. 53: 217-239).
  • VEGF acts as an angiogenesis inducer by specifically promoting the proliferation of endothelial cells. It is a homodimeric glycoprotein consisting of two 23 kD subunits. Four different monomeric isoforms of NEGF resulting from alternative splicing of mR ⁇ A have been identified. These include two membrane bound forms (VEGF206 and VEGF 189 ) and two soluble forms (VEGF ]65 and VEGF ⁇ 21 ). VEGF 165 is the most abundant isoform in all human tissues except placenta.
  • NEGF is expressed in embryonic tissues (Breier et al., Development (Camb.) 114:521 (1992)), macrophages, and proliferating epidermal keratinocytes during wound healing (Brown et al., J. Exp. Med., 176:1375 (1992)), and may be responsible for tissue edema associated with inflammation (Ferrara et al., Endocr. Rev. 13:18 (1992)).
  • VEGF expression in situ hybridization studies have demonstrated high levels of VEGF expression in a number of human tumor lines including glioblastoma multiforme, hemangioblastoma, other central nervous system neoplasms and AiDS-associated Kaposi's sarcoma (Plate, K. et al. (1992) Nature 359: 845-848; Plate, K. et al. (1993) Cancer Res. 53: 5822-5827; Berkman, R. et al. (1993) J. Clin. Invest. 91 : 153-159; Nakamura, S. et al. (1992) AIDS Weekly, 13 (1)). High levels of VEGF expression has also been found in atherosclerotic lesions, plaques and in inflammatory cells.
  • VEGF mediates its biological effect through high affinity VEGF receptors which are selectively expressed on endothelial cells during, for example, embryogenesis (Millauer, B., et al. (1993) Cell 72: 835-846) and tumor formation, and which have been implicated in modulating angiogenesis and tumor growth.
  • These receptors comprise a tyrosine kinase cytosolic domain that initiates the signaling pathway involved in cell growth.
  • VEGF receptors typically are class III receptor-type tyrosine kinases characterized by having several, typically 5 or 7, immunoglobulin-like loops in their amino-terminal extracellular receptor ligand-binding domains (Kaipainen et al., J. Exp. Med. 178:2077-2088 (1993)).
  • the other two regions include a transmembrane region and a carboxy-terminal intracellular catalytic domain interrupted by an insertion of hydrophilic interkinase sequences of variable lengths, called the kinase insert domain (Terman et al., Oncogene 6:1677-1683 (1991)).
  • VEGF receptors include VEGFR-1 (or flt-1), sequenced by Shibuya M. et al., Oncogene 5, 519-524 (1990); and VEGFR-2 (or flk-1/KDR).
  • KDR described in PCT/US92/01300, filed February 20, 1992, and in Terman et al., Oncogene 6:1677-1683 (1991), is the human homologue of flk-lk, sequenced by Matthews W. et al. Proc. Natl. Acad. Sci. USA, 88:9026-9030 (1991).
  • VEGF receptor molecules e.g., VEGFR-1 and VEGFR-2. It is generally believed that KDR/VEGFR- 2 is the main VEGF signal transducer that results in endothelial cell proliferation, migration, differentiation, tube formation, increase of vascular permeability, and maintenance of vascular integrity.
  • VEGFR-1 possesses a much weaker kinase activity, and is unable to generate a mitogenic response when stimulated by VEGF, although it binds to VEGF with an affinity that is approximately 10- fold higher than KDR. VEGFR-1 has also been implicated in VEGF and placenta growth factor (P1GF) induced migration of monocytes and macrophages and production of tissue factor.
  • P1GF placenta growth factor
  • VEGFR-2 High levels of VEGFR-2, for example, are expressed by endothelial cells that infiltrate gliomas (Plate, K. et al., (1992) Nature 359: 845-848), and are specifically upregulated by VEGF produced by human glioblastomas (Plate, K. et al. (1993)
  • VEGR-2 expression in glioblastoma associated endothelial cells suggests that receptor activity is induced during tumor formation, since VEGFR-2 transcripts are barely detectable in normal brain endothelial cells, indicating generation of a paracrine VEGF/VEGFR loop. This upregulation is confined to the vascular endothelial cells in close proximity to the tumor.
  • Blocking VEGF activity with neutralizing anti-VEGF monoclonal antibodies (mAbs) results in inhibition of the growth of human tumor xenografts in nude mice (Kim, K. et al.
  • VEGFR antagonists have been developed to treat vascularized tumors and other angiogenic diseases. These have included neutralizing antibodies that block signaling by VEGF receptors expressed on vascular endothelial cells to reduce tumor growth by blocking angiogenesis through an endothelial-dependent paracrine loop. See, e.g., U.S. Patent No.
  • VEGF receptors have also been found on some non-endothelial cells, such as tumor cells producing VEGF, wherein an endothelial-independent autocrine loop is generated to support tumor growth.
  • VEGF/human VEGFR-2 autocrine loop mediates leukemic cell survival and migration in vivo.
  • Dias et al. "Autocrine stimulation of VEGFR-2 activates human leukemic cell growth and migration," J. Clin. Invest. 106:511 -521 (2000); Witte et al., "Treatment of non-solid mammalian tumors with vascular endothelial growth factor receptor antagonsits;” and WO 01/74296 (Witte et al.).
  • VEGF production and VEGFR expression also have been reported for some solid tumor cell lines in vitro. (See Tohoku, Sato, J. Exp.
  • VEGFR-1 Mabs inhibit an autocrine VEGFR/human VEGFR-1 loop in breast carcinoma cells. Wu, et al., "Monoclonal antibody against VEGFRl inhibits fltl-positive DU4475 human breast tumor growth
  • the invention relates to heteroarylaminophenylketone derivatives, which are kinase inhibitors that have the following formula I:
  • Ri is selected from hydrogen, lower alkyl, lower alkenyl, lower alkynyl and aralkyl, wherein the lower alkyl, lower alkenyl, lower alkynyl and aralkyl may be unsubstituted or substituted with one or more substituents selected from R 2 ;
  • R 3 is selected from:
  • X is O, S, or N-R, a is 0 to 3, b is 0 to 2; c is 0 or 1 ; 0 R-i is selected from:
  • each R 2 is independently selected from:
  • lower alkyl which may be optionally substituted with one or more halogen, hydroxy, lower alkoxy, 0 3) lower alkenyl, which may be optionally substituted with one or more halogen, hydroxy, lower alkoxy,
  • a group of the formula -CO 2 R, -OR, -SR, -SO 2 R, -NH 2 , -NHR, -NRR,5 or R can occupy two adjacent positions to form a fused 5- or 6-membered carbocyclic or heterocychc ring, which may be substituted or unsubstituted and wherein the heterocychc ring may contain from 1 to 2 heteroatoms selected from N, O or S, o each R is independently selected from hydrogen, halogen, lower alkyl, lower alkoxy, aralkyl, aryl, and heteroaryl, and
  • each Y is independently selected from C-R and N.
  • the invention further relates to pharmaceutical compositions containing a therapeutically effective amount of the compounds of formula I.
  • the invention is also directed to methods of inhibiting VEGF receptor tyrosine kinases, especially KDR, and methods of treating VEGF receptor tyrosine kinase- dependent diseases and conditions in mammals using the VEGF receptor kinase inhibitors of Formula I.
  • the diseases and conditions that may be treated or prevented by the present methods include, for example, conditions or diseases in which pathogenic angiogenesis is implicated, including neoplastic diseases such as solid or liquid tumors, atherosclerosis, age related macular degeneration, retinal vascularization, inflammatory diseases, or cell proliferative disorders, in mammals.
  • the method includes administering to a mammal in need of such treatment a therapeutically effective amount of one or more compounds of the present invention.
  • the invention further relates to a method of making the compounds of formula I.
  • lower alkyl refers to a saturated hydrocarbon derived radical containing from 1 to 6 carbon atoms.
  • the lower alkyl group may be straight, branched or cyclic.
  • Straight or branched lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl, and the like.
  • Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • lower alkenyl refers to a non-aromatic hydrocarbon radical, straight, branched or cyclic, containing from 2 to 6 carbon atoms and at least one carbon to carbon double bond.
  • Lower alkenyl groups include ethenyl, propenyl, butenyl cyclohexenyl, and the like.
  • lower alkynyl refers to a hydrocarbon radical that is straight, or branched, containing from 2 to 6 carbon atoms and at least one carbon to carbon triple bond.
  • Lower alkynyl groups include ethynyl, propynyl and butynyl, and the like.
  • aralkyl as used herein contemplates a lower alkyl group which has as a substituent an aryl group.
  • aryl refers to unsubstituted or substituted 5- or 6- membered aromatic rings, such as, phenyl, substituted phenyl and the like, as well bicyclic rings such as naphthyl and heterocychc rings, such as pyridine, imidazole, oxazole, thiazole and the like.
  • aryl denotes a group containing at least one aromatic ring having at least 5 atoms, with up to two such rings being present, containing up to 10 atoms therein.
  • Preferred aryl groups are phenyl and naphthyl.
  • heterocycle heteroaryl or heterocychc
  • the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quatemized.
  • Heterocycle includes the abovementioned heteroaryls, as well as dihydro and tetrahydro analogs thereof.
  • Heterocycles include any bicyclic group in which any of the above-defined rings is fused to a benzene ring.
  • the heterocychc ring may be attached at any heteroatom or carbon atom, which results in the creation of a stable structure.
  • heterocychc components include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholin
  • alkoxy refers to a substituent with an alkyl group in either a straight-chained or branched configuration, and may include a double or a triple bond, which is attached via an oxygen atom.
  • the alkyl portion may be substituted or unsubstituted.
  • Substituents on the alkyl group may include for example, a phenyl ring, in which the alkoxy may be for example, a benzyloxy group.
  • alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy allyloxy, propargyloxy, vinyloxy, and the like.
  • halo or halogen as used herein is intended to include the halogen atoms fluorine, chlorine, bromine and iodine.
  • the terms "pharmaceutically acceptable salts” and “hydrates” refer to those salts and hydrated forms of the compound that would be apparent to those in the art, i.e., those which favorably affect the physical or pharmacokinetic properties of the compound, such as solubility, palatability, absorption, distribution, metabolism and excretion. Other factors, more practical in nature, which those skilled in the art may take into account in the selection include the cost of the raw materials, ease of crystallization, yield, stability, solubility, hygroscopicity and flowability of the resulting bulk drug.
  • a compound of the present invention is present as a salt or hydrate that is non-pharmaceutically acceptable, that compound can be converted in certain circumstances to a salt or hydrate form that is pharmaceutically acceptable in accordance with the present invention.
  • a counterion such as, an alkali metal cation such as sodium or potassium.
  • suitable counterions include calcium, magnesium, zinc, ammonium, or alkylammonium cations, such as tetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium, meglumine, triethanol-hydroammoniurn, and the like.
  • An appropriate number of counterions are associated with the molecule to maintain overall charge neutrality.
  • the compound is positively charged, e.g., protonated, an appropriate number of negatively charged counterions are present to maintain overall charge neutrality.
  • salts may be prepared by the addition of an appropriate acid.
  • the compound can be used in the form of salts derived from inorganic or organic acids. Examples include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, pamoate, pectinate, persulfate, 3-phenyl
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
  • the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl
  • diamyl sulfates long chain halides
  • the presence of pharmaceutically acceptable salts within the scope of the present compounds is not intended to limit the compounds of the present invention to those that are synthetically prepared.
  • the compounds of the present invention also include compounds that are converted within the body and prodrugs.
  • Pro-drug means a form of the compounds of the present invention suitable for administration to a patient without undue toxicity, irritation, allergic response, and the like, and effective for their intended use.
  • a pro-drug is transformed in vivo to yield the parent compound of the formula I herein, for example by hydrolysis in blood.
  • T. Higuchi and V. Stella Pro-drugs as Novel Delivery Systems Vol. 14 of the A. C. S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987.
  • the compounds of the present invention may have asymmetric centers and occur as racemates, mixtures of enantiomers and as individual enantiomers with all isomeric forms being included in the present invention.
  • the compounds of the invention have the following formula (II):
  • Y' is selected from CH and N;
  • Y is selected from C-R and N;
  • X is selected from O, S, and N-R;
  • Ri is selected from hydrogen, lower alkyl, lower alkenyl, lower alkynyl and aralkyl, wherein the lower alkyl, lower alkenyl, lower alkynyl and aralkyl may be unsubstituted or substituted with one or more substituents selected from R ;
  • R 3 is selected from:
  • X is O, S, or N-R, a is 0 to 3, b is 0 to 2; c is 0 or 1 ;
  • R 2 is independently selected from:
  • lower alkyl which may be optionally substituted with one or more halogen, hydroxy, lower alkoxy
  • lower alkenyl which may be optionally substituted with one or more halogen, hydroxy, lower alkoxy
  • Express Mail No. EV 331382753 US or R 2 can occupy two adjacent positions to form a fused 5- or 6-membered carbocyclic or heterocychc ring, which may be substituted or unsubstituted with R 3 and wherein the heterocychc ring may contain from 1 to 2 heteroatoms independently selected from N, O or S; and
  • R is independently selected from hydrogen, halogen, lower alkyl, lower alkoxy, aralkyl, aryl and heteroaryl.
  • the invention further relates to a method for making the compounds of formula II.
  • Method A The method entails reacting a compound of formula V with a benzyne intermediate as shown below, wherein R 3 , and Y are as defined above:
  • Method B The method entails reacting an N-protected arylamine of formula X with a strong base (RLi) such as n-BuLi, LDA, etc., followed by a heterocychc acid chloride of formula XI or XII, or other acylating agents, such as carbonyl derivatives, wherein R 2 , R 3 , X and Y are as defined above:
  • RLi strong base
  • XI or XII acylating agents
  • Method C The method entails reacting a orthonitrocarbonyl compound of formula IN with a bicycle of formula XIII as shown below, wherein R , R 4 , X and Y are as defined above (Org. Lett. 2000, 2/10, 1485; Synth. Commun. 1997, 27, 2125):
  • Tables 1 and 2 provide representative embodiments of compounds of Formula
  • Tyrosine kinase inhibition can be determined using well-known methods.
  • the compounds of the present invention generally involve inhibition or regulation of phosphorylation events. Accordingly, phosphorylation assays are useful in determining antagonists useful in the context of the present invention.
  • Tyrosine kinase inhibition may be determined by measuring the autophosphorylation level of recombinant kinase receptor, and/or phosphorylation of natural or synthetic substrates. Phosphorylation can be detected, for example, using an antibody specific for phosphotyrosine in an ELISA assay or on a Western blot.
  • Some assays for tyrosine kinase activity are described in Panek et al., J. Pharmacol. Exp. Thera., 283: 1433.44 (1997) and Batley et al., Life Sci., 62: 143-50 (1998).
  • methods for detection of protein expression can be utilized, wherein the proteins being measured are regulated by tyrosine kinase activity.
  • these methods include immunohistochemistry (IHC) for detection of protein expression, fluorescence in situ hybridization (FISH) for detection of gene amplification, competitive radioligand binding assays, solid matrix blotting techniques, such as Northern and Southern blots, reverse transcriptase polymerase chain reaction (RT- PCR) and ELISA.
  • IHC immunohistochemistry
  • FISH fluorescence in situ hybridization
  • RT- PCR reverse transcriptase polymerase chain reaction
  • ELISA solid matrix blotting techniques, such as Northern and Southern blots, reverse transcriptase polymerase chain reaction
  • VEGF receptor tyrosine kinase inhibition can be observed by mitogenic assays using HUVEC cells (Cornell University Medical College ) stimulated with VEGF in the presence and absence of inhibitor.
  • Another method involves testing for inhibition of growth of VEGF- expressing tumor cells, using for example, human tumor cells injected into a mouse.
  • VEGF receptor tyrosine kinases especially KDR
  • methods of inhibiting VEGF receptor tyrosine kinases, especially KDR and/or treating or preventing VEGF receptor kinase-dependent diseases and conditions in mammals using the VEGF receptor kinase inhibitors of Formula I.
  • the VEGF receptor is
  • Express Mail No. EV 331382753 US usually bound to a cell, such as an endothelial or tumor cell.
  • a cell such as an endothelial or tumor cell.
  • the VEGF receptor may be free from the cell, preferably in soluble form.
  • the diseases and conditions which may be treated or prevented by the present methods include, for example, those in which pathogenic angiogenesis or tumor growth is stimulated through a VEGF/NEGFR paracrine and/or autocrine loop.
  • pathogenic angiogenesis or tumor growth is stimulated through a VEGF/NEGFR paracrine and/or autocrine loop.
  • paracrine VEGFR stimulation of vascular endothelium is associated with angiogenic diseases and vascularization of tumors.
  • VEGF receptors are also found on non-endothelial cells, such as tumor cells, indicating the presence of an autocrine and/or paracrine loop in these cells.
  • the method is also useful for neutralizing VEGF receptors on such cells, thereby inhibiting autocrine and/or paracrine stimulation and inhibiting tumor growth.
  • Tumors and neoplasms include, for example, malignant tumors and neoplasms, such as blastemas, carcinomas or sarcomas, and highly vascular-dependent tumors and neoplasms.
  • Cancers that may be treated by the methods of the present invention include, for example, cancers of the brain, genitourinary tract, lymphatic system, stomach, renal, colon, larynx and lung and bone.
  • ⁇ on-limiting examples further include epidermoid tumors, squamous tumors, such as head and neck tumors, colorectal tumors, prostate tumors, breast tumors, lung tumors, including lung adenocarcinoma and small cell and non-small cell lung tumors, pancreatic tumors, thyroid tumors, ovarian tumors, and liver tumors.
  • the method is also used for treatment of vascularized skin cancers, including squamous cell carcinoma, basal cell carcinoma, and skin cancers that can be treated by suppressing the growth of malignant keratinocytes, such as human malignant keratinocytes.
  • cancers that can be treated include Kaposi's sarcoma, C ⁇ S neoplasms (neuroblastomas, capillary hemangioblastomas, meningiomas and cerebral metastases), melanoma, gastrointestinal and renal carcinomas and sarcomas, rhabdomyosarcoma, glioblastoma, including glioblastoma multiforme, histiocytic lymphoma, and leiomyosarcoma.
  • Kaposi's sarcoma C ⁇ S neoplasms (neuroblastomas, capillary hemangioblastomas, meningiomas and cerebral metastases), melanoma, gastrointestinal and renal carcinomas and sarcomas, rhabdomyosarcoma, glioblastoma, including glioblastoma multiforme, histiocytic lymphoma, and leiomyosarcoma.
  • a further aspect of the present invention includes methods of treating or preventing angiogenic diseases, inflammatory diseases or other diseases characterized by paracrine stimulation through VEGF receptors, by administering to a mammal in need of such treatment a therapeutically effective amount of one or more of the
  • non-neoplastic angiogenic diseases include diseases characterized by retinal vascularization, such as neovascular glaucoma, proliferative retinopathy, including diabetic retinopathy, retinopathy of prematurity (retrolental fibroplastic), macular degeneration, and corneal graft rejection.
  • retinal vascularization such as neovascular glaucoma, proliferative retinopathy, including diabetic retinopathy, retinopathy of prematurity (retrolental fibroplastic), macular degeneration, and corneal graft rejection.
  • inflammatory diseases examples include, but are not limited to, atherosclerosis, rheumatoid arthritis (RA), insulin-dependent diabetes mellitus, multiple sclerosis, myasthenia gravis, Chron's disease, autoimmune nephritis, primary biliary cirrhosis, psoriasis, acute pancreatitis, allograph rejection, allergic inflammation, contact dermatitis and delayed hypersensitivity reactions, inflammatory bowel disease, septic shock, osteoporosis, osteoarthritis, and cognition defects induced by neuronal inflammation.
  • angiogenic diseases are hemangiomas, angiofibromas, Osier- Weber syndrome, restinosis, and fungal, parasitic and viral infections, including cytomegaloviral infections.
  • the present invention also includes methods for treating tumors that express VEGF receptors, especially KDR, for example through inhibition of an autocrine VEGF/NEGFR loop, wherein one or more of the Formula I compounds are adminstered in an amount effective to reduce tumor growth or size.
  • the method is effective for treating a solid or liquid tumor that is not vascularized, or is not yet substantially vascularized.
  • solid tumors which may be accordingly treated include breast carcinoma, lung carcinoma, colorectal carcinoma, pancreatic carcinoma, glioma and lymphoma.
  • liquid tumors include leukemia, multiple myeloma and lymphoma.
  • leukemias include acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), erythrocytic leukemia or monocytic leukemia.
  • lymphomas include Hodgkin's and non-Hodgkin's lymphoma.
  • the compounds of formula I may be used for in vivo and in vitro investigative, diagnostic, or prophylactic methods, which are well known in the art.
  • a therapeutically effective amount of one or more of the Formula I compounds is administered to a mammal in need.
  • administering means delivering the compounds of the present invention to a mammal by any method that may achieve the result sought. They may be administered, for example, orally, parenterally (intravenously or intramuscularly),
  • compositions which include at least one compound of the present invention as described herein (that is, a compound of Formula I) or a pharmaceutically acceptable salt, hydrate or pro-drug thereof, in combination with a pharmaceutically acceptable carrier.
  • the compounds of the present invention may be employed in solid or liquid form including for example, powder or crystalline form, in solution or in suspension. They may be administered in numerous different ways, such as orally, parenterally (intravenously or intramuscularly), topically, transdermally or by inhalation.
  • the choice of carrier and the content of active compound in the carrier are generally determined in accordance with the solubility and chemical properties of the desired product, the particular mode of administration and the provisions to be observed in pharmaceutical practice.
  • the carrier employed may be, for example, either a solid or liquid.
  • One method of administering a solid dosage form is to form solid compositions for rectal administration, which include suppositories formulated in accordance with known methods and containing at least one compound of the present invention.
  • solid carriers include lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • liquid carriers include syrup, peanut oil, olive oil, water and the like.
  • emulsions, suspensions or solutions of the compounds according to the invention in vegetable oil for example sesame oil, groundnut oil or olive oil, or aqueous-organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well as sterile aqueous solutions of the pharmaceutically acceptable salts, are used.
  • Injectable forms must be fluid to the extent they can be easily syringed, and proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • compositions can be brought about by use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • the solutions of the salts of the products according to the invention are especially useful for administration by intramuscular or subcutaneous injection.
  • Solutions of the active compound as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropyl- cellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils.
  • aqueous solutions also including solutions of the salts in pure distilled water, may be used for intravenous administration with the proviso that their pH is suitably adjusted, that they are judiciously buffered and rendered isotonic with a sufficient quantity of glucose or sodium chloride and that they are sterilized by heating, irradiation, microfiltration, and/or by various antibacterial and antifungal agents, for example, Xparabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • injectable dosage forms include sterile injectable liquids, e.g., solutions, emulsions and suspensions.
  • Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • methods of preparation may include vacuum drying and a freeze-dry technique that yields a powder of the active ingredient plus any additional desired ingredient from previously sterile-filtered solution thereof.
  • injectable solids examples include powders that are reconstituted, dissolved or suspended in a liquid prior to injection.
  • the carrier typically includes sterile water, saline or another injectable liquid, e.g., peanut oil for intramuscular injections.
  • various buffering agents, preservatives and the like can be included within the compositions of the present invention.
  • the active compound may be administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or
  • oral solid dosage forms include tablets, capsules, troches, lozenges and the like.
  • oral liquid examples include tablets, capsules, troches, lozenges and the like.
  • 5 dosage forms include solutions, suspensions, syrups, emulsions, soft gelatin capsules and the like.
  • Carriers for oral use may include time delay materials known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
  • time delay materials known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
  • lactose and liquid carrier such as high molecular weight polyethylene glycols.
  • Topical administration in the form of gels (water or alcohol based), creams or ointments, for example, containing compounds of the invention may be used.
  • Topical applications may be formulated in carriers such as hydrophobic or hydrophilic bases to form ointments, creams, lotions, in aqueous, oleaginous or alcoholic liquids to form paints or in dry diluents to form powders.
  • Such topical formulations can be used fors example, to treat ocular diseases as well as inflammatory diseases such as rheumatoid arthritis, psoriasis, contact dermatitis, delayed hypersensitivity reactions and the like.
  • Compounds of the invention may be also incorporated in a gel or matrix base for application in a patch, which would allow a controlled release of compound through transdermal barrier.
  • compounds of the invention may be dissolved or suspended in a suitable carrier for use in a nebulizer or a suspension or solution aerosol, or may be absorbed or adsorbed onto a suitable solid carrier for use in a dry powder inhaler.
  • compositions according to the invention may also be formulated in a manner 5 that resists rapid clearance from the vascular (arterial or venous) wall by convection and/or diffusion, thereby increasing the residence time of the viral particles at the desired site of action.
  • a periadventitial depot comprising a compound according to the invention may be used for sustained release.
  • One such useful depot for administering a compound according to the invention may be a copolymer matrix,o such as ethylene-vinyl acetate, or a polyvinyl alcohol gel surrounded by a Silastic shell.
  • a compound according to the invention may be delivered locally from a silicone polymer implanted in the adventitia.
  • microparticles may be included a variety of synthetic polymers, such as polylactide for example, or natural substances, including proteins or polysaccharides. Such microparticles enable strategic manipulation of variables including total dose of drug and kinetics of its release. Microparticles can be injected efficiently into the arterial or venous wall through a porous balloon catheter or a balloon over stent, and are retained in the vascular wall and the periadventitial tissue for at least about two weeks. Formulations and methodologies for local, intravascular site-specific delivery of therapeutic agents are discussed in Reissen et al. (J. Am. Coll. Cardiol. 1994; 23: 1234-1244).
  • a composition according to the invention may also comprise a hydrogel which is prepared from any biocompatible or non-cytotoxic (homo or hetero) polymer, such as a hydrophilic polyacrylic acid polymer that can act as a drug absorbing sponge.
  • a hydrogel which is prepared from any biocompatible or non-cytotoxic (homo or hetero) polymer, such as a hydrophilic polyacrylic acid polymer that can act as a drug absorbing sponge.
  • biocompatible or non-cytotoxic (homo or hetero) polymer such as a hydrophilic polyacrylic acid polymer that can act as a drug absorbing sponge.
  • Another embodiment of the invention provides for a compound according to the invention to be administered by means of perfusion balloons.
  • perfusion balloons which make it possible to maintain a blood flow and thus to decrease the risks of ischaemia of the myocardium, on inflation of the balloon, also enable the compound to be delivered locally at normal pressure for a relatively long time, more than twenty minutes, which may be necessary for its optimal action.
  • a channeled balloon catheter such as “channelled balloon angioplasty catheter", Mansfield Medical, Boston Scientific Corp., Watertown, Mass.
  • This catheter includes a conventional balloon covered with a layer of 24 perforated channels that are perfused via an independent lumen through an additional infusion orifice.
  • Various types of balloon catheters such as double balloon, porous balloon, microporous balloon, channel balloon, balloon over stent and hydrogel catheters, all of which may be used to practice the invention, are disclosed in Reissen et al. (1994).
  • Another aspect of the present invention relates to a pharmaceutical composition including a compound according to the invention and poloxamer, such as
  • Poloxamer 407 which is a non-toxic, biocompatible polyol, commercially available (e.g., from BASF, Parsippany, N.J.).
  • a poloxamer impregnated with a compound according to the invention may be deposited for example, directly on the surface of the tissue to be treated, for example during a surgical intervention.
  • Poloxamer possesses essentially the same advantages as hydrogel while having a lower viscosity.
  • composition may also be administered to a patient via a stent device.
  • the composition is a polymeric material in which the compound of the invention is incorporated, which composition is applied to at least one surface of the stent device.
  • Polymeric materials suitable for incorporating the compound of the invention include polymers having relatively low processing temperatures such as polycaprolactone, poly(efhylene-co-vinyl acetate) or poly(vinyl acetate or silicone gum rubber and polymers having similar relatively low processing temperatures.
  • suitable polymers include non-degradable polymers capable of carrying and delivering therapeutic drugs such as latexes, urethanes, polysiloxanes, styrene- ethylene/butylene-styrene block copolymers (SEBS) and biodegradable, bioabsorbable polymers capable of carrying and delivering therapeutic drugs, such as poly-DL-lactic acid (DL-PLA), and poly-L-lactic acid (L-PLA), polyorthoesters, polyiminocarbonates, aliphatic polycarbonates, and polyphosphazenes.
  • DL-PLA poly-DL-lactic acid
  • L-PLA poly-L-lactic acid
  • polyorthoesters polyiminocarbonates
  • aliphatic polycarbonates aliphatic polycarbonates
  • polyphosphazenes polyphosphazenes.
  • compositions of the present invention optionally contain one or more excipients that are conventional in the art.
  • excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silica gels combined with lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for preparing tablets, troches, pills, capsules and the like.
  • Express Mail No. EV 331382753 US contain emulsifying agents or agents which facilitate suspension. Diluents such as sucrose, ethanol, polyols such as polyethylene glycol, propylene glycol and glycerol, and chloroform or mixtures thereof may also be used.
  • the active compound may be incorporated into sustained-release preparations and formulations. The percentage of active ingredient in the compositions of the invention may be varied. Several unit dosage forms may be administered at about the same time.
  • a suitable dose employed may be determined by a physician or qualified medical professional, and depends upon various factors including the desired therapeutic effect, the nature of the illness being treated, the route of administration, the duration of the treatment, and the condition of the patient, such as age, weight, general state of health and other characteristics, which can influence the efficacy of the compound according to the invention.
  • doses are generally from about 0.001 to about 50, preferably about 0.001 to about 5, mg/kg body weight per day by inhalation; from about 0.01 to about 100, preferably 0.1 to 70, more preferably 0.5 to 10, mg/kg body weight per day by oral administration; from about 0.1 to about 150 mg applied externally; and from about 0.001 to about 10, preferably 0.01 to 10, mg/kg body weight per day by intravenous or intramuscular administration.
  • the compounds and compositions according to the invention may be administered as frequently as necessary as determined by a skilled practitioner in order to obtain the desired therapeutic effect. Some patients may respond rapidly to a higher or lower dose and may find much weaker maintenance doses adequate. For other patients, it may be necessary to have long-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiological requirements of each particular patient. Generally, the active product may be administered orally 1 to 4 times per day. For other patients, it may be necessary to prescribe not more than one or two doses per day.
  • the compounds of the present invention may also be formulated for use in conjunction with other therapeutically active compounds or in connection with the application of therapeutic techniques to address pharmacological conditions, which may be ameliorated through the application of a compound according to the present invention.
  • the reaction mixture was sti ⁇ ed for 1 hr at - 78 °C and then allowed to warm upto room temperature. Sti ⁇ ed for another 3 hrs and then quenched with saturated NH 4 C1 solution. Allowed to stir for 10 mins and then took up the solution in a separatory funnel and worked up with water followed by sat. NaCl solution. Dried the organic layer with NaSO 4 , then filtered and concentrated theo solution to get a pale yellow oil that was purified via flash chromatography. The diacylated product was taken up in THF (35 mL) and 0.5M LiOH solution in methanol (152.4 mL, 72.6 mmol) was added to it. After stirring for 2 hours the reaction mixture was concentrated to one-third of the volume, neutralized with 10%
  • VEGFR tyrosine kinase inhibition is determined by measuring the phosphorylation level of poly-Glu-Ala-Tyr-biotin (pGAT-biotin) peptide in a Homogeneous Time-Resolved Fluorescence (HTRF) assay.
  • pGAT-biotin poly-Glu-Ala-Tyr-biotin
  • HTRF Homogeneous Time-Resolved Fluorescence
  • the kinase reaction is initiated by the addition of 10 ⁇ l of 10 ⁇ M ATP in reaction buffer, after which the plate is incubated at room temperature for 45 min.
  • the reaction is stopped by the addition of 50 ⁇ l of KF buffer (50 mM Hepes pH 7.5, 0.5 M KF, 1 mg/ml BSA) containing 100 mM EDTA and 0.36 ⁇ g/ml PY20K (Eu-cryptate labeled anti-phosphotyrosine antibody, CIS bio international).
  • SV-XL modified- APC-labeled Streptavidin, CIS bio international
  • DNA for transfection is diluted to a final concentration of 5 ⁇ g/ml DNA in IXBBS, 125 mM CaCk and incubated at room temperature for 30 min. 293 cells are seeded in 15 cm tissue culture plates using 2 x 10 7 cells per plate and incubated for 4 hrs, followed by dropwise addition of 3 ml of DNA solution. The plates are incubated overnight.
  • cells are trypsinized, seeded at 4 x 10 5 cell/ml into wells of 48 well tissue culture plates (1 ml/well) and incubated overnight.
  • Compounds of the invention are added to individual wells to a final concentration of 10-30 ⁇ M and incubated for 2 hours.
  • 10 mM stock solution are diluted 1/300-1/1000, yielding a final DMSO concentration of 0.1-0.3%.
  • the methods of synthesis of the present invention are not limited to the methods exemplified in the example.
  • the methods of the present invention include methods of making any of the compounds set forth in the present invention that those skilled would be able to make in view of the present disclosure, and are not limited to the exemplified method.
  • methods encompassed by the present invention may involve the use of a different starting material depending on the desired final compound, different amounts of various ingredients, or substitution of different ingredients such as other reactants or catalysts that would be suitable depending on the starting material and result to be achieved.

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  • Organic Chemistry (AREA)
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Abstract

La présente invention concerne des composés qui inhibent les tyrosines kinases du récepteur VEGF, notamment le KDR, des compositions pharmaceutiques qui contiennent lesdits composés, des méthodes de traitement de maladies et de pathologies dépendant des kinases du récepteur VEGF, chez des mammifères, à l'aide desdits composés et de ladite composition, ainsi que des méthodes de fabrication desdits composés.
PCT/US2004/017248 2003-05-30 2004-06-01 Derives d'heteroarylamino-phenylcetone et leur utilisation en tant qu'inhibiteurs de kinases WO2005000813A1 (fr)

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FR2880891A1 (fr) * 2005-01-19 2006-07-21 Aventis Pharma Sa Pyrazolo pyridines substituees, compositions les contenant, procede de fabrication et utilisation
DE102007002717A1 (de) 2007-01-18 2008-07-24 Merck Patent Gmbh Heterocyclische Indazolderivate
DE102007022565A1 (de) 2007-05-14 2008-11-20 Merck Patent Gmbh Heterocyclische Indazolderivate
DE102008038220A1 (de) 2008-08-18 2010-02-25 Merck Patent Gmbh Oxadiazolderivate
DE102008038221A1 (de) 2008-08-18 2010-02-25 Merck Patent Gmbh 7-Azaindolderivate
DE102008038222A1 (de) 2008-08-18 2010-02-25 Merck Patent Gmbh Indazol-5-carbonsäurehydrazid-derivate
US8188071B2 (en) 2007-01-31 2012-05-29 Vertex Pharmaceuticals Incorporated Amino substituted pyridines as potent kinase inhibitors
US8247421B2 (en) 2006-12-21 2012-08-21 Vertex Pharmaceuticals Incorporated 5-cyano-4-(pyrrolo [2,3B] pyridine-3-yl)-pyrimidine derivatives useful as protein kinase inhibitors
US8377926B2 (en) 2008-08-06 2013-02-19 Vertex Pharmaceuticals Incorporated Aminopyridine kinase inhibitors
US8541445B2 (en) 2009-05-06 2013-09-24 Vertex Pharmaceuticals Incorporated Pyrazolopyridines
US8563576B2 (en) 2008-07-23 2013-10-22 Vertex Pharmaceuticals Incorporated Tri-cyclic pyrazolopyridine kinase inhibitors
US8569337B2 (en) 2008-07-23 2013-10-29 Vertex Pharmaceuticals Incorporated Tri-cyclic pyrazolopyridine kinase inhibitors
US8809335B2 (en) 2010-01-27 2014-08-19 Vertex Pharmaceuticals Incorporated Pyrazolopyrimidine kinase inhibitors
US8829007B2 (en) 2009-06-17 2014-09-09 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US8871774B2 (en) 2010-12-16 2014-10-28 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US8895740B2 (en) 2010-01-27 2014-11-25 Vertex Pharmaceuticals Incorporated Pyrazolopyrazine kinase inhibitors
US9051319B2 (en) 2011-08-01 2015-06-09 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US9067932B2 (en) 2010-01-27 2015-06-30 Vertex Pharmaceuticals Incorporated Pyrazolopyridine kinase inhibitors
US9137973B2 (en) 2008-07-23 2015-09-22 Vertex Pharmaceuticals Incorporated Pyrazolopyridine kinase inhibitors
US9458110B2 (en) 2013-02-28 2016-10-04 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
US9771361B2 (en) 2013-11-13 2017-09-26 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US9828345B2 (en) 2013-02-28 2017-11-28 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
US10023569B2 (en) 2013-11-13 2018-07-17 Vertex Pharmaceuticals Incorporated Methods of preparing inhibitors of influenza viruses replication
US10273233B2 (en) 2015-05-13 2019-04-30 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US10533004B2 (en) 2015-05-13 2020-01-14 Vertex Pharmaceuticals Incorporated Methods of preparing inhibitors of influenza viruses replication

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2113343A1 (de) * 1971-03-19 1972-09-21 Thiemann Chem Pharm Fab Indolo[2,3-b] chinolone und Verfahren zu ihrer Herstellung

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2113343A1 (de) * 1971-03-19 1972-09-21 Thiemann Chem Pharm Fab Indolo[2,3-b] chinolone und Verfahren zu ihrer Herstellung

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FR2880891A1 (fr) * 2005-01-19 2006-07-21 Aventis Pharma Sa Pyrazolo pyridines substituees, compositions les contenant, procede de fabrication et utilisation
US8962642B2 (en) 2006-12-21 2015-02-24 Vertex Pharmaceuticals Incorporated 5-cyano-4- (pyrrolo [2,3B] pyridine-3-yl) -pyrimidine derivatives useful as protein kinase inhibitors
US8530489B2 (en) 2006-12-21 2013-09-10 Vertex Pharmaceuticals Incorporated 5-cyano-4-(pyrrolo [2,3B] pyridine-3-yl)-pyrimidine derivatives useful as protein kinase inhibitors
US8247421B2 (en) 2006-12-21 2012-08-21 Vertex Pharmaceuticals Incorporated 5-cyano-4-(pyrrolo [2,3B] pyridine-3-yl)-pyrimidine derivatives useful as protein kinase inhibitors
DE102007002717A1 (de) 2007-01-18 2008-07-24 Merck Patent Gmbh Heterocyclische Indazolderivate
WO2008086854A1 (fr) 2007-01-18 2008-07-24 Merck Patent Gmbh Dérivés de 5-( [1, 3, 4] oxadiazole-2-yl)-ih-indazole et 5-( [1, 3, 4] thiadiazole-2-yl)-ih-indazole comme inhibiteurs de la sgk pour le traitement de diabètes
US8188071B2 (en) 2007-01-31 2012-05-29 Vertex Pharmaceuticals Incorporated Amino substituted pyridines as potent kinase inhibitors
US8741931B2 (en) 2007-01-31 2014-06-03 Juan-Miguel Jimenez Kinase inhibitors
DE102007022565A1 (de) 2007-05-14 2008-11-20 Merck Patent Gmbh Heterocyclische Indazolderivate
US9137973B2 (en) 2008-07-23 2015-09-22 Vertex Pharmaceuticals Incorporated Pyrazolopyridine kinase inhibitors
US8569337B2 (en) 2008-07-23 2013-10-29 Vertex Pharmaceuticals Incorporated Tri-cyclic pyrazolopyridine kinase inhibitors
US8563576B2 (en) 2008-07-23 2013-10-22 Vertex Pharmaceuticals Incorporated Tri-cyclic pyrazolopyridine kinase inhibitors
US8815866B2 (en) 2008-08-06 2014-08-26 Vertex Pharmaceuticals Incorporated Aminopyridine kinase inhibitors
US8377926B2 (en) 2008-08-06 2013-02-19 Vertex Pharmaceuticals Incorporated Aminopyridine kinase inhibitors
DE102008038220A1 (de) 2008-08-18 2010-02-25 Merck Patent Gmbh Oxadiazolderivate
WO2010020305A1 (fr) 2008-08-18 2010-02-25 Merck Patent Gmbh Dérivés d'oxadiazol pour le traitement du diabète
DE102008038222A1 (de) 2008-08-18 2010-02-25 Merck Patent Gmbh Indazol-5-carbonsäurehydrazid-derivate
DE102008038221A1 (de) 2008-08-18 2010-02-25 Merck Patent Gmbh 7-Azaindolderivate
US8541445B2 (en) 2009-05-06 2013-09-24 Vertex Pharmaceuticals Incorporated Pyrazolopyridines
US9808459B2 (en) 2009-06-17 2017-11-07 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US9345708B2 (en) 2009-06-17 2016-05-24 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US10874673B2 (en) 2009-06-17 2020-12-29 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US10039762B2 (en) 2009-06-17 2018-08-07 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US9518056B2 (en) 2009-06-17 2016-12-13 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US8829007B2 (en) 2009-06-17 2014-09-09 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US8809335B2 (en) 2010-01-27 2014-08-19 Vertex Pharmaceuticals Incorporated Pyrazolopyrimidine kinase inhibitors
US9067932B2 (en) 2010-01-27 2015-06-30 Vertex Pharmaceuticals Incorporated Pyrazolopyridine kinase inhibitors
US8895740B2 (en) 2010-01-27 2014-11-25 Vertex Pharmaceuticals Incorporated Pyrazolopyrazine kinase inhibitors
US8871774B2 (en) 2010-12-16 2014-10-28 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US10875855B2 (en) 2011-08-01 2020-12-29 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US9394302B2 (en) 2011-08-01 2016-07-19 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US9908878B2 (en) 2011-08-01 2018-03-06 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US9051319B2 (en) 2011-08-01 2015-06-09 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US9458110B2 (en) 2013-02-28 2016-10-04 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
US9828345B2 (en) 2013-02-28 2017-11-28 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
US9771361B2 (en) 2013-11-13 2017-09-26 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US10640501B2 (en) 2013-11-13 2020-05-05 Vertex Pharmaceuticals Incorporated Methods of preparing inhibitors of influenza viruses replication
US10023569B2 (en) 2013-11-13 2018-07-17 Vertex Pharmaceuticals Incorporated Methods of preparing inhibitors of influenza viruses replication
US11345700B2 (en) 2013-11-13 2022-05-31 Vertex Pharmaceuticals Incorporated Methods of preparing inhibitors of influenza viruses replication
US10533004B2 (en) 2015-05-13 2020-01-14 Vertex Pharmaceuticals Incorporated Methods of preparing inhibitors of influenza viruses replication
US10273233B2 (en) 2015-05-13 2019-04-30 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication

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