WO2004089930A1 - Derives de 4- fluoroquinolone et leur utilisation comme inhibiteurs de kinase - Google Patents

Derives de 4- fluoroquinolone et leur utilisation comme inhibiteurs de kinase Download PDF

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WO2004089930A1
WO2004089930A1 PCT/US2004/010195 US2004010195W WO2004089930A1 WO 2004089930 A1 WO2004089930 A1 WO 2004089930A1 US 2004010195 W US2004010195 W US 2004010195W WO 2004089930 A1 WO2004089930 A1 WO 2004089930A1
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vegf
compounds
dmso
compound
nmr
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PCT/US2004/010195
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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
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to 4-fluoroquinolone 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 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 including 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).
  • neoplastic diseases including but not limited to solid tumors, atherosclerosis and other inflammatory diseases such as rheumatoid arthritis, and ophthalmological conditions such as diabetic retinopathy and age-related macular degeneration.
  • Conditions or diseases to which persistent or uncontrolled angiogenesis contribute have been termed angiogenic dependent or angiogenic associated diseases.
  • 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 VEGF resulting from alternative splicing of mRNA have been identified. These include two membrane bound forms (VEGF 206 and VEGF ⁇ 89 ) and two soluble forms (VEGF ⁇ 65 and VEGF ⁇ 2 ⁇ ). VEGF ⁇ 65 is the most abundant isoform in all human tissues except placenta. VEGF is expressed in embryonic tissues (Breier et al., Development (Camb.)
  • 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-temiinal 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. 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) Cancer Res.
  • P1GF placenta growth factor
  • 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. (1993) Nature 362: 841-844), suggesting a direct role for VEGF in tumor-related angiogenesis.
  • 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. For example, it has been demonstrated that a
  • 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.
  • the invention relates to 4-fluoroquinoline derivatives, which are
  • kinase inhibitors that have the following formula I: or pharmaceutically acceptable salts, stereoisomers, hydrates or pro-drugs thereof, wherein Ri and 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 may be substituted with one or more substituents selected from
  • R 2 ; R 3 is selected from:
  • tetrazole wherein X is O, S, or N-R, a is 0 to 3; b is 0 to 2; and c is 0 or 1 ; t is selected from:
  • X is O, S, or N-R, a is 0 to 3; b is 0 to 2; and c is O or 1; each R is independently selected from:
  • a group of the formula -CO 2 R, -OR, -SR, -SO 2 R, -NH 2 , -NHR, -NRR, or R 2 can occupy two adjacent positions when taken together form a fused 5- or 6- membered carbocyclic or heterocyclic ring, wherein heterocyclic ring may contain from 1 to 2 heteroatoms selected from N, O or S, and each R is independently selected from H, lower alkyl, aralkyl, aryl, and heteroaryl, and
  • 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 like, as well bicyclic rings such as naphthyl and heterocyclic 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 contemplates a stable 5- to 6-membered mono- or 7- to 10-membered bicyclic heterocyclic ring system, any ring of which may be saturated or unsaturated, aromatic or non-aromatic, and which includes carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • 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 heterocyclic ring may be attached at any heteroatom or carbon atom, which results in the creation of a stable structure.
  • heterocyclic 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, morpholiny
  • 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 individual isomers and mixtures thereof are intended to be encompassed by the formulae depicted herein.
  • 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.
  • solubility, palatability, absorption, distribution, metabolism and excretion include 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 When 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 allcylammonium cations, such as tetramethylammonium, tetrabutylammonium, choline, triethylhydro ammonium, meglumine, triethanol-hydroammonium, 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-phenylpropionate, pivalate, propionat
  • 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 or 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):
  • the invention further relates to a method for making the compounds of formula I.
  • the method entails reacting a compound of formula III with a compound of formula TV as shown below, wherein Ri, R , Ri, and Y are as defined above:
  • a compound of formula III is dissolved in a solvent, which may be any aprotic organic solvent, such as, tefrahydrofuran, methylene chloride, ether, diethyl ether, hexane, toluene, etc.
  • a solvent which may be any aprotic organic solvent, such as, tefrahydrofuran, methylene chloride, ether, diethyl ether, hexane, toluene, etc.
  • the solution is added with vigorous stirring to a mixture of a compound of formula IV and a strong base kept at low temperature, preferably between -78 °C to -10°C.
  • the reaction preferably takes place under anhydrous conditions, such as an argon atmosphere.
  • the strong base may be any strong base, for example, LDA, n- BuLi, Bu-Li, LHMDS, KHMDS, NaHMDS, sodium methoxide, sodium hydroxide, potassium methoxide, potassium hydroxide, sodium hydride, potassium hydride, lithium hydride, etc.
  • the reaction mixture is allowed to warm to between about 0-30 degrees Celcius, preferably room temperature, and stirred for about 4 hours.
  • the reaction product may then be recovered and purified by conventional techniques. For example, the reaction mixture may be concentrated and the residue partitioned between an organic solvent that is not miscible with water and a concentrated aqueous organic salt solution. The aqueous layer may then be extracted with an organic solvent that is not miscible with water. The extract may then be dried, concentrated and purified by, for example, column chromatography or recrystallization from various solvents.
  • Table 1 provides representative embodiments of compounds of Formula I.
  • 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
  • Grandis et al., Cancer, 78:1284-1292. (1996); Shimizu et al, Japan J. Cancer Res., 85:567-571 (1994); Sauter et al, Am. J.
  • 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. (See, U.S. Patent No. 6,365,157 to Rockwell et al.)
  • 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 usually bound to 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/VEGFR paracrine and/or autocrine loop.
  • pathogenic angiogenesis or tumor growth is stimulated through a VEGF/VEGFR 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 rumor growth.
  • Tumors and neoplasms include, for example, malignant tumors and neoplasms, such as blastomas, 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.
  • Non-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, CNS 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 CNS 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 compounds set forth herein.
  • 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.
  • 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 cytomegalo viral infections.
  • the present invention also includes methods for treating tumors that express VEGF receptors, especially KDR, for example through inhibition of an autocrine
  • the method is effective for treating a solid or liquid tumor that is not vascularized, or is not yet substantially vascularized.
  • solid tumors that may be 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 fonnula 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), topically, transdennally or by inhalation.
  • mammal as used herein is intended to include, but is not limited to, humans, laboratory animals, domestic pets and farm animals.
  • “Therapeutically effective amount” means an amount of compound of the present invention that when administered to a mammal is effective in producing the desired therapeutic effect, such as inhibiting kinase activity.
  • 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 examples 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
  • 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.
  • Prolonged absorption of the injectable compositions can be brought about by use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • 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, maybe 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, parabens, 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 it may be incorporated directly with the food of the diet, or may be incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • oral solid dosage forms include tablets, capsules, troches, lozenges and the like.
  • oral liquid 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 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 for 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 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, 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.
  • Such polymers have been described, for example, in application WO93/08845. Certain of them, such as, in particular, those obtained from ethylene and/or propylene oxide are commercially available.
  • 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 “channeled 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 maybe 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.).
  • poloxamer such as Poloxamer 407
  • 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.
  • a channel balloon catheter with a poloxamer impregnated with a compound according to the invention may be advantageous in that it may keep the balloon inflated for a longer period of time, while retaining the properties of facilitated sliding, and of site-specificity of the poloxamer.
  • 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(ethylene-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, dicalcmm 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.
  • 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.
  • Example 1 Synthesis of 4-fluoro-3-(l -methyl- lH-indol-3-yl)-lH-quinolin-2-one A solution of 2-(trifluoromethyl)aniline (161 mg, 1 mmol) in 5 ml of dry tefrahydrofuran was added via syringe to a vigorously stirred mixture of (1-methyl-lH- indol-3-yl)-acetic acid methyl ester (4 mmol) and LDA (4 mmol, freshly prepared from diisopropylamine and ra-BuLi) in 20 ml of dry T ⁇ F at -78°C under argon.
  • VEGFR tyrosine kinase inhibition is determined by measuring the phosphorylation of a poly-EY peptide substrate. Costar 96 wells ELISA plate is coated over-night at 4°C with 50 ⁇ l/well of 5 ⁇ g/ml poly EY peptide in PBS (final amount of poly-EY is 250 ng/well).
  • the coated plates are washed three times with PBS + 0.1% Tween-20, followed by addition of 25 ⁇ l/well of 2X reaction buffer (100 mM Hepes pH 7.5, 10 mM MgC12, 10 mM MnC12, 1 mM DTT). Then 2.5 ⁇ l/well of 200 ⁇ M compound in 100% DMSO are added to each plate (final compound concentration in the reaction is 10 ⁇ M). Next 20 ⁇ l of 500 ng/ml KDR are added per well, to get a final KDR concentration of 10 ng/well.
  • 2X reaction buffer 100 mM Hepes pH 7.5, 10 mM MgC12, 10 mM MnC12, 1 mM DTT.
  • 2X reaction buffer 100 mM Hepes pH 7.5, 10 mM MgC12, 10 mM MnC12, 1 mM DTT.
  • 2.5 ⁇ l/well of 200 ⁇ M compound in 100% DMSO are added to each plate (final compound
  • Example 3 Cell-based assay for VEGFR-2 (KDR) Kinase hibition
  • An FGFR1 :KDR chimeric receptor composed of an extracellular FGFR1 domain and the cytoplasmic domain of KDR is transfected into 293 primary human embryonal kidney cells. This receptor is constitutively active and able to phosphorylated both itself and downstream signaling molecules via its KDR cytoplasmic domain.
  • the transfected 293 cells (4 x 10 5 cell/ml) are divided 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. Generally, 10 mM stock solution are diluted 1/300-1/1000, yielding a final DMSO concentration of 0.1- 0.3%.
  • Cells are lysed by resuspension in 100 ⁇ l lysis buffer (150 mM NaCl, 50 mM Hepes pH 7.5, 0.5% Trition X-100, 10 mM NaPPi, 50 mM NaF, 1 mM Na 3 VO 4 and protease inhibitors) and rocked for lhr at 4°C.
  • 100 ⁇ l lysis buffer 150 mM NaCl, 50 mM Hepes pH 7.5, 0.5% Trition X-100, 10 mM NaPPi, 50 mM NaF, 1 mM Na 3 VO 4 and protease inhibitors
  • ELISA for detection of tyrosine-phosphorylated chimeric receptor 96 well ELISA plates are coated using 100 ⁇ l/well of 10 ⁇ g/ml ⁇ FGFRl, and incubated overnight at 4°C.
  • ⁇ FGFRl is prepared in a buffer containing 16 ml 0.2M Na 2 CO 3 and 34 ml 0.2M NaHCO 3 and the pH adjusted to 9.6.
  • Concurrent with lysis of the transfected cells, ⁇ FGFRl coated ELISA plates are washed three times with PBS+0.1% Tween-20, blocked by addition of 200 ⁇ l/well of 3% BSA in PBS and incubated for lhr. Blocking solution is removed from the wells. 80 ⁇ l of lysate is then transferred to the coated and blocked wells and incubated for lhr at 4°C. The plates are washed three times with PBS+0.1% Tween-20.
  • 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.

Abstract

L'invention concerne des composés qui inhibent la tyrosine kinase du récepteur de VEGF, notamment KDR, des compositions pharmaceutiques contenant ces composés, des procédés de traitement de maladies et états liés à la kinase du récepteur VEGF chez les mammifères au moyen de ces composés et compositions, ainsi que leurs procédés de fabrication.
PCT/US2004/010195 2003-04-02 2004-04-02 Derives de 4- fluoroquinolone et leur utilisation comme inhibiteurs de kinase WO2004089930A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8044062B2 (en) 2005-10-07 2011-10-25 Exelixis, Inc. Substituted pyrido[2,3-d]pyrimidin-7(8H)-one inhibitors of phospatidylinositol 3-kinase alpha
US8101622B2 (en) 2008-09-30 2012-01-24 Exelixis, Inc. Pyridopyrimidinone inhibitors of PI3Kα and mTOR
US8247408B2 (en) 2005-10-07 2012-08-21 Exelixis, Inc. Pyridopyrimidinone inhibitors of PI3Kα for the treatment of cancer
US8273755B2 (en) 2006-09-15 2012-09-25 Pfizer Inc 4-methylpyridopyrimidinone compounds
US8389514B2 (en) 2007-09-11 2013-03-05 Kyorin Pharmaceutical Co., Ltd. Cyanoaminoquinolones and tetrazoloaminoquinolones as GSK-3 inhibitors
US8476261B2 (en) 2007-09-12 2013-07-02 Kyorin Pharmaceutical Co., Ltd. Spirocyclic aminoquinolones as GSK-3 inhibitors
US8901137B2 (en) 2010-02-09 2014-12-02 Exelixis, Inc. Methods of treating cancer using pyridopyrimidinone inhibitors of PI3K and mTOR in combination with autophagy inhibitors

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001029025A2 (fr) * 1999-10-19 2001-04-26 Merck & Co., Inc. Inhibiteurs de tyrosine kinases

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001029025A2 (fr) * 1999-10-19 2001-04-26 Merck & Co., Inc. Inhibiteurs de tyrosine kinases

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8044062B2 (en) 2005-10-07 2011-10-25 Exelixis, Inc. Substituted pyrido[2,3-d]pyrimidin-7(8H)-one inhibitors of phospatidylinositol 3-kinase alpha
US8247408B2 (en) 2005-10-07 2012-08-21 Exelixis, Inc. Pyridopyrimidinone inhibitors of PI3Kα for the treatment of cancer
US8273755B2 (en) 2006-09-15 2012-09-25 Pfizer Inc 4-methylpyridopyrimidinone compounds
US8633204B2 (en) 2006-09-15 2014-01-21 Pfizer Inc. 4-methylpyridopyrimidinone compounds
US8389514B2 (en) 2007-09-11 2013-03-05 Kyorin Pharmaceutical Co., Ltd. Cyanoaminoquinolones and tetrazoloaminoquinolones as GSK-3 inhibitors
US8476261B2 (en) 2007-09-12 2013-07-02 Kyorin Pharmaceutical Co., Ltd. Spirocyclic aminoquinolones as GSK-3 inhibitors
US8901112B2 (en) 2007-09-12 2014-12-02 Kyorin Pharmaceutical Co., Ltd. Spirocyclic aminoquinolones as GSK-3 inhibitors
US8101622B2 (en) 2008-09-30 2012-01-24 Exelixis, Inc. Pyridopyrimidinone inhibitors of PI3Kα and mTOR
US8901137B2 (en) 2010-02-09 2014-12-02 Exelixis, Inc. Methods of treating cancer using pyridopyrimidinone inhibitors of PI3K and mTOR in combination with autophagy inhibitors

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