WO2002076985A1 - Composes utiles en tant qu'inhibiteurs de kinases pour le traitement des maladies hyperproliferatives - Google Patents

Composes utiles en tant qu'inhibiteurs de kinases pour le traitement des maladies hyperproliferatives Download PDF

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WO2002076985A1
WO2002076985A1 PCT/US2002/008915 US0208915W WO02076985A1 WO 2002076985 A1 WO2002076985 A1 WO 2002076985A1 US 0208915 W US0208915 W US 0208915W WO 02076985 A1 WO02076985 A1 WO 02076985A1
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group
galkyl
conr
nitrogen
cancer
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PCT/US2002/008915
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William E. Bondinell
Dennis A. Holt
Maria Amparo Lago
Michael J. Neeb
Marcus A. Semones
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Smithkline Beecham Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems

Definitions

  • the present invention relates to kinase enzyme inhibitors, pharmaceutical compositions comprising these compounds and methods for identifying these compounds and methods of using these compounds to treat various diseases including forms of cancer and hyperproliferative diseases.
  • Protein kinases play a critical role in the control of cell growth and differentiation, and are key members of cellular signals leading to the production of growth factors and cytokines.
  • a partial non-limiting list of such kinases includes CDK2, CDK4, cdc2, CHK1, CSBP/p38, EGF, Erb B2, Erb B3, Erb B4, FGF, Mytl, PDGF, PLK1, Tie, src, and wee-1 kinase.
  • Protein kinases play a critical role in the control of cell growth and differentiation and are key mediators of cellular signals leading to the production of growth factors and cytokines. See, for example, Schlessinger and Ullrich, Neuron 1992, 9, 383.
  • a partial non- limiting list of such kinases includes abl, ARaf, ATK, ATM, bcr-abl, Blk, BRaf, Brk, Btk, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, cfms, c-fms, CHK1, c-kit, c-met, cRafl, CSF1R, CSK, c-src, EGFR, ErbB2, ErbB3, ErbB4, ERK, ERK1, ERK2, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, Fp
  • Protein kinases have been implicated as targets in central nervous system disorders such as Alzheimer's (Mandelkow, E. M. et al. FEBS Lett. 1992, 314, 315. Sengupta, A. et al. Mol. Cell. Biochem. 1997, 167,99), pain sensation (Yashpal, K. J. Neitrosci. 1995, 15, 3263-72), inflammatory disorders such as arthritis ( Badger, J. Phartn. Exp. Ther. 1996, 279, 1453), psoriasis (Dvir, et al, J. Cell Biol.
  • M phase-promoting factor a complex containing the cdc2 protein kinase and cyclin B.
  • MPF M phase-promoting factor
  • Proper regulation of MPF ensures that mitosis occurs only after earlier phases of the cell cycle are complete.
  • Phosphorylation of cdc2 at Tyr-15 and Thr-14 suppresses this activity during interphase (Gl, S, and G2).
  • G2-M transition cdc2 is dephosphorylated at Tyr-15 and Thr-14 allowing MPF to phosphorylate its mitotic substrates.
  • a distinct family of cdc-regulatory kinases (Weel) is known to be responsible for phosphorylation of the cdc Tyr-15.
  • cdc2 A new member of this family, Mytl, was recently described as the Thr-14 and Tyr-15-specific cdc2 kinase, and shown to be an important regulator of cdc2/cyclin B kinase activity (Science 270:86-90, 1995; Mol. Cell. Biol. 17:571, 1997).
  • the inhibitory phosphorylation of cdc2 is important for the timing of entry into mitosis. Studies have shown that premature activation of cdc2 leads to mitotic catastrophe and cell death. Inhibition of Mytl is predicted to cause premature activation of cdc2, and thus would kill rapidly proliferating cells.
  • Mytl inhibition is predicted to reduce resistance to conventional DNA-damaging chemotherapeutics, because the mechanisms by which cells avoid death involve arrest in the G2 phase of the cell cycle, and repair or DNA damage prior to division. That arrest should be prevented by blocking Mytl inhibitory phosphorylation of cdc2. Thus forcing the cell to enter mitosis prematurely.
  • Mytl kinase is an important cell cycle regulator, particularly at the G2/M phase.
  • Inhibitors would therefore be attractive for the treatment of cancer.
  • Current cancer therapies including surgery, radiation, and chemotherapy, are often unsuccessful in curing the disease.
  • the patient populations are large. For example, in colon cancer alone there are 160,000 new cases each year in the US, and 60,000 deaths. There are 600,000 new colon cancer cases each year worldwide.
  • the number for lung cancer is twice that of colon cancer.
  • the largest deficiency of chemotherapies for major solid tumors is that most patients fail to respond. This is due to cell cycle regulation and subsequent repair of damage to DNA or mitotic apparatus, the targets for most effective chemotherapeutic agents.
  • Mytl kinase offers a point of intervention downstream from these mechanisms by which tumor cells develop resistance. Inhibition of Mytl could in and of itself have therapeutic benefit in reducing tumor proliferation, and in addition, could be used in conjunction with conventional chemotherapies to overcome drug resistance.
  • the present invention involves compounds represented by Formula (I) hereinbelow, pharmaceutical compositions comprising such compounds, methods of antagonizing kinase receptors, and methods of treating diseases using these compounds.
  • Ri' selected from the group consisting of NRR 1 , OR, SR, SOR, SO2R, and halo;
  • R, Rl, R!4 5 and R ⁇ are independently selected from the group consisting of hydrogen, Cj.galkyl, Ci .galkanoyl, C2_8 l e yl, C2-g lkynyl, C3_ ⁇ ocycloalkyl, Co_3alkylaryl, C ⁇ alkylheterocyclyl, and Co-3alkylheteroaryl, wherein any of the foregoing carbon containing values may be optionally substituted by one or more of group A, on any position;
  • Y is selected from an inorganic or organic anion
  • D is selected from the group consisting of Cj.galkyl, Ci.galkanoyl, C2- galkenyl, C2_galkynyl, C3_ ⁇ o c y Ci ⁇ a lkyl, Co-3 a lkylaryl, Co-3alkylheterocyclyl, CQ.
  • R and R! together with the nitrogen to which they are attached and R ⁇ 4 and R!5 together with the nitrogen to which they are attached may optionally and independently may form a ring having 3 to 7 carbon atoms, optionally containing 1,
  • R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, C galkyl, Ci.galkanoyl, C2-galkenyl, C2_galkynyl, Co-3alkylaryl, C()-3alkylheterocyclyl, and Co_3alkylheteroaryl; or R 2 and R 3 taken together with the nitrogen to which they are attached may optionally form a ring having 3 to 7 carbon atoms optionally containing 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur, and nitrogen substituted with hydrogen, C ].
  • R 5 , R", and R are independently selected from the group consisting of hydrogen, C ⁇ . alkyl, C ⁇ _galkanoyl, C2_galkenyl, C2-galkynyl, C3_ ⁇ ⁇ ocycloalkyl, Co-3alkylaryl, Co-3alkylheterocyclyl, and Co_3alkylheteroaryl; or R 5 and R6 taken together with the nitrogen to which they are attached may optionally form a ring having 3 to 7 carbon atoms and optionally containing 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, sulfur, or nitrogen substituted with hydrogen, .galkyl or (CH 2 )o-3aryl; R 2 ' is selected from the group consisting of hydrogen, Ci.galkyl, COR 8 ,
  • R 8 , R 9 , and RlO are independently selected from the group consisting of hydrogen, Cj.galkyl, C ⁇ _galkanoyl, C2_galkenyl, C2-8alkynyl, C3_ ⁇ o c y c l° a lkyl, Co_3alkylaryl, Co_3alkylheterocyclyl, and Co_3alkylheteroaryl; or R 8 and R 9 taken together with the nitrogen to which they are attached may optionally form a ring having 3 to 7 carbon atoms, optionally containing 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, sulfur, and nitrogen substituted with hydrogen, Cj .galkyl, or
  • R 3 is selected from the group consisting of hydrogen, Ci.galkyl, 03. gcycloalkyl, aryl and heteroaryl, optionally substituted with one or more of group E, cyano, CONHR 1 1, CONR 8 R 9 CO2R 8 , NR 8 R 9 , nitro, OR 8 , or halogen;
  • R! 1 is selected from the group consisting of 2-hydroxy ethyl, 2-(Cj_ galkoxy)ethyl, or 2-(R 12 R 13 N)ethyl; R! 2 and R 3 are independently hydrogen or Ci.galkyl;
  • Y' is nitrogen or CR 2 ; • ⁇ • ⁇ . ;.
  • Rl6 is selected from the group consisting of Ci .galkyl, C2_galkenyl, C2_ galkynyl, C3_ ⁇ o c y c ⁇ oa lkyl, Co-3alkylaryl, Co_3alkylheterocyclyl, and CQ. 3alkylheteroaryl, wherein any of the foregoing carbon containing values may be optionally substituted by one or more of group E, on any position.
  • Preferred Y values include, but are not limited to, bisulfate, chloride, fumarate, iodide, maleate, methanesulfonate, nitrate and sulfate.
  • Preferred compounds of the present invention are selected from the group consisting of:
  • Rl' is NRR 1 ;
  • R is preferably hydrogen
  • R! is C ⁇ _3alkylaryl, preferably C ⁇ alkylaryl, more preferably phenyl;
  • A is OR 2 , preferably located at the 4-position;
  • R 2 is Ci.galkyl, preferably ethyl substituted on the 2-position with E;
  • R 5 and R° are independently Ci.galkyl, preferably ethyl;
  • R 2 is preferably hydrogen
  • R 3 is aryl, preferably phenyl, optionally substituted with one or more of group E, wherein E is one or more of Ci.galkyl, trifluoromethyl, or halo, preferably disubstituted at the 2,6-positions, more preferably 2,6-dichloro;
  • Z' is NR 14 Rl5 0 r OR 16 ;
  • R! and R 5 are independently hydrogen or Ci.galkyl
  • R1" is Ci.galkyl, preferably methyl
  • Y' is nitrogen or CR 2 ; preferably Y' is nitrogen, and a pharmaceutically acceptable salt thereof.
  • Z' is NH2 or OCH3, and a pharmaceutically acceptable salt thereof.
  • alkanoyl is used herein at all occurrences to mean a C(0)alkyl group, wherein the alkyl portion is as defined below, including, but not limited to, acetyl, pivaloyl, and the like.
  • alkenyl is used herein at all occurrences to mean a straight or branched chain radical, wherein there is at least one double bond between two of the carbon atoms in the chain, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l- propenyl, 1-butenyl, 2-butenyl, and the like.
  • alkoxy is used herein at all occurrences to mean a straight or branched chain radical bonded to an oxygen atom, including, but not limited to, methoxy, ethoxy, n- propoxy, isopropoxy, and the like.
  • alkyl refers to a saturated hydrocarbon group joined together by single carbon-carbon bonds.
  • the alkyl hydrocarbon group may be linear, or branched, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.
  • alkylaryl is used herein at all occurrences to mean a aryl group as defined below attached to an alkyl group as defined above, including, but not limited to, benzyl and phenethyl, and the like.
  • alkylheterocyclyl is used herein at all occurrences to mean a heterocyclic group as defined below attached to an alkyl group as defined above, including, but not limited to, (tetrahydro-3-furanyl)methyl and 3-(4-morpholinyl)propyl, and the like.
  • alkylheteroaryl is used herein at all occurrences to mean a heteroaryl group as defined below attached to an alkyl group as defined above, including, but not limited to, 3-(furanyl)methyl and (2-pyridinyl)propyl, and the like.
  • alkynyl is used herein at all occurrences to mean a straight or branched chain radical, wherein there is at least one triple bond between two of the carbon atoms in the chain, including, but not limited to, acetylene, 1- propylene, 2-propylene, and the like.
  • aralkyl is used herein at all occurrences to mean an aryl moiety as defined below, which is connected to an alkyl moiety as defined above, including, but not limited to, benzyl or phenethyl, and the like.
  • alkylaryl is used herein at all occurrences to mean a aryl group as defined below attached to an alkyl group as defined above, including, but not limited to, benzyl and phenethyl, and the like.
  • alkylheteocyclyl is used herein at all occurrences to mean a heterocyclic group as defined below attached to an alkyl group as defined above, including, but not limited to, (tetrahydro-3-furanyl)methyl and 3-(4- morpholinyl)propyl, and the like.
  • alkylheteroaryl is used herein at all occurrences to mean a heteroaryl group as defined below attached to an alkyl group as defined above, including, but not limited to, 3-(furanyl)methyl and (2-pyridinyl)propyl, and the like.
  • alkynyl is used herein at all occurrences to mean a straight or branched chain radical, wherein there is at least one triple bond between two of the carbon atoms in the chain, including, but not limited to, acetylene, 1- propylene, 2- propylene, and the like.
  • aralkyl is used herein at all occurrences to mean an aryl moiety as defined below, which is connected to an alkyl moiety as defined above, including, but not limited to, benzyl or phenethyl, and the like.
  • aryl is used herein at all occurrences to mean 6-14-membered substituted or unsubstituted aromatic ring(s) or ring systems which may include bi- or tri- cyclic systems, including, but not limited to phenyl, naphthalenyl, biphenyl, phenanthryl, anthracenyl, and the like.
  • aryloxy is used herein at all occurrences to mean an aryl group as defined above linked via an oxy group, including, but not limited to, phenoxy, and the like.
  • cycloalkyl is used herein at all occurrences to mean cyclic radicals, which may be mono- or bicyclo- fused ring systems which may additionally include unsaturation, including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, 1,2,3,4- tetrahydronaphthalenyl, and the like.
  • halo or halogen are used interchangeably herein at all occurrences to mean radicals derived from the elements chlorine, fluorine, iodine and bromine.
  • heteroaryl is used herein at all occurrences to mean a 5-14-membered substituted or unsubstituted aromatic ring(s) or ring systems which may include bi- or tri- cyclic systems, which ring or ring systems contain 1 to 4 heteroatoms selected from nitrogen, which may be optionally substituted with hydrogen or C galkyl, oxygen, and sulfur, including, but not limited to, indolyl, benzofuranyl, thianaphthenyl, quinolyl, isoquinolyl, pyrrolyl, furanyl, thienyl, pyridyl, and the like.
  • heteroaryloxy is used herein at all occurrences to mean an heteroaryl group as defined above linked via an oxy group, including, but not limited to, 2- pyridinyloxy, and the like.
  • heterocyclic is used herein at all occurrences to mean a saturated or wholly or partially unsaturated 5-10-membered ring system (unless the cyclic ring system is otherwise limited) in which one or more rings contain one or more heteroatoms selected from nitrogen, which may be optionally substituted with hydrogen or Ci.galkyl, oxygen, and sulfur, including, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, imidazolidine, pyrazolidine, 1,2,3,6-tetrahydropyridine, hexahydroazepine, and the like.
  • the compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol, and the like, are equivalent to the unsolvated forms for purposes of this invention.
  • the compounds of the present invention may contain one or more asymmetric 0 carbon atoms and may exist in racemic and optically active forms.
  • the stereocenters may be of any combination of R and S configuration, for example, (R,R), (R,S), (S,S) or (S,R). All of these compounds and diastereomers are contemplated to be within the scope of the present invention.
  • Geometric isomers and tautomers of the present compounds are also within the 5 scope of the present invention.
  • the present compounds can also be formulated as pharmaceutically acceptable salts and complexes thereof.
  • Pharmaceutically acceptable salts are non-toxic salts in the amounts and concentrations at which they are administered.
  • Pharmaceutically acceptable salts include acid addition salts such as those " containing sulfate, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate.
  • Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
  • acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
  • Pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ⁇ ammonium, alkylamine, and zinc, when acidic functional groups, such as carboxylic acid or phenol are present.
  • Preferred salts include sulfate, bisulfate, hydrochloride, fumarate, maleate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and sodium.
  • the compounds of formula (I) can be prepared by art-recognized procedures from known or commercially available starting materials. If the starting materials are unavailable from a commercial source, their synthesis is described herein, or they can be prepared by procedures known in the art. Specifically, compounds of formula (I) wherein Y' is nitrogen, R!
  • R 2 ', R 3 ', and Z' are as defined for formula (I), are prepared by methods known to the art.
  • Compounds of formula (I) can be prepared from appropriately substituted pyrimidine 1-1, which is commercially available or is prepared by methods known to the art.
  • pyrimidine 1-1 is commercially available or is prepared by methods known to the art.
  • 2-chloro-4,5- diaminopyrimidine 1-1 is reacted with an appropriately substituted ⁇ -oxo carboxylic acid ester, for example ethyl ⁇ -oxobenzeneacetate, in an appropriate solvent, for example, water or ethanol, at an appropriate temperature, for example room temperature or reflux, to afford the substituted pteridin-7-ol 1-2.
  • Treatment of 1-2 with a suitable amine for example an appropriately substituted alkyl amine or an appropriately substituted aniline, for example 4-[2-a suitable amine, for example an appropriately substituted alkyl amine or an appropriately substituted aniline, for example
  • a present compound or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • the present ligands can be administered by different routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, topical, transdermal, or transmucosal administration.
  • oral administration is preferred.
  • the compounds can be formulated into conventional oral dosage forms such as capsules, tablets and liquid preparations such as syrups, elixirs and concentrated drops.
  • injection parenteral administration
  • the compounds of the invention are formulated in liquid solutions, preferably, in physiologically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution.
  • the compounds may be formulated in solid form and redissolved or suspended immediately prior to use. Lyophilized forms can also be produced.
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives.
  • detergents may be used to facilitate permeation.
  • Transmucosal administration for example, may be through nasal sprays, rectal suppositories, or vaginal suppositories.
  • the compounds of the invention can be formulated into ointments, salves, gels, or creams, as is generally known in the art.
  • the amounts of various compounds to be administered can be determined by standard procedures taking into account factors such as the compound IC 50 , EC 50 , the biological half- life of the compound, the age, size and weight of the patient, and the disease or disorder
  • Amounts administered also depend on the routes of administration and the degree of oral bioavailability. For example, for compounds with low oral bioavailability, relatively higher doses will have to be administered.
  • the composition is in unit dosage form.
  • a tablet, or capsule may be administered, for nasal application, a metered aerosol dose may be administered, for transdermal application, a topical formulation or patch may be administered and for transmucosal delivery, a buccal patch may be administered. In each case, dosing is such that the patient may administer a single dose.
  • Each dosage unit for oral administration contains suitably from 0.01 to 500 mg/Kg, and preferably from 0.1 to 50 mg/Kg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.
  • the daily dosage for parenteral, nasal, oral inhalation, transmucosal or transdermal routes contains suitably from 0.01 mg to 100 mg/Kg, of a compound of Formula(I).
  • a topical formulation contains suitably 0.01 to 5.0%
  • the active ingredient may be administered from 1 to 6 times per day, preferably once, sufficient to exhibit the desired activity, as is readily apparent to one skilled in the art.
  • the present invention also provides compounds of formula (I) and pharmaceutically acceptable salts thereof (hereafter collectively referred to as the "active compounds") for use in medical therapy, and particularly in the treatment of disorders mediated by a Kinase, such as Mytl kinase.
  • a further aspect of the invention provides a method of treatment of a human or animal suffering from a disorder mediated by a protein kinase, said treatment comprising administering an effective amount of an active compound of formula (I) to the human or animal patient.
  • the present invention comprises a method for inhibiting a kinase comprising bringing said kinase into contact with a compound of formula (I).
  • Another aspect of the present invention provides a method for using an active compound of formula (I), in the preparation of a medicament for the treatment of malignant tumors, or for the treatment of disorders involving abnormal angiogenesis, such as arthritis, diabetic retinopathy, macular degeneration and psoriasis.
  • compounds of formula (I) can be used in the preparation of a medicament for the treatment of a disease mediated by a kinase selected from the group consisting of: abl, ARaf, ATK, ATM, bcr-abl, Blk, BRaf, Brk, Btk, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, cfms, c-fms, CHK1, c-kit, c-met, cRafl, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK, ERK1, ERK2, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, Fps, Frk, Fyn, GSK, gsk3a, gsk3b, Hck, IGF-1R, IKK, IKK1,
  • compounds of formula (I) can be used in the preparation of a medicament for the treatment of organ transplant rejection, tumor growth, chemotherapy- induced mucositis, radiation-induced mucositis, plantar-palmar syndrome, chemotherapy- induced alopecia, chemotherapy-induced thrombocytopenia, chemotherapy-induced leukopenia and hirsutism or of treating a disease state selected from the group consisting of: mucocitis, restenosis, atherosclerosis, rheumatoid arthritis, angiogenesis, hepatic cirrhosis, glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, chronic obstructive pulmonary disease, thrombotic microangiopathy, aglomerulopathy, psoriasis, diabetes mellitus, inflammation, a neurodegenerative disease, macular degeneration, actinic keratosis and hyperproliferative disorders.
  • Another aspect of the present invention provides the use of an active compound of
  • Another aspect of the present invention provides the use of an active compound of 5 formula (I) in the preparation of a medicament for the treatment of viral or eukaryotic infections.
  • treatment includes, but is not limited to prevention, retardation and prophylaxis of the disease.
  • diseases treatable using the present compounds include, but are not limited to leukemias, solid tumor cancers, 0 metastases, soft tissue cancers, brain cancer, esophageal cancer, stomach cancer, pancreatic cancer, liver cancer, lung cancer, bladder cancer, bone cancer, prostate cancer, ovarian cancer, cervical cancer, uterine cancer, testicular cancer, kidney cancer, head cancer and neck cancer, chronic inflammatory proliferative diseases such as psoriasis and rheumatoid arthritis; proliferative cardiovascular diseases such as restenosis; proliferative ocular disorders such as 5 diabetic retinopathy; and benign hyperproliferative diseases such as hemangiomas.
  • Composition of Formula (I) and their pharmaceutically acceptable salts which are active when given orally- can be formulated as syrups-, tablets, capsules and lozenge ' s.
  • a - . syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil. olive oil, glycerine or water with a ⁇ flavoring or coloring agent.
  • a liquid carrier for example, ethanol, peanut oil. olive oil, glycerine or water with a ⁇ flavoring or coloring agent.
  • any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose.
  • composition is in the form of a capsule
  • any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell.
  • composition is in the form of a soft gelatin shell capsule
  • any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils, and are incorporated in a soft gelatin capsule shell.
  • Typical parenteral compositions consist of a solution or suspension of a compound " or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.
  • Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane.
  • a typical suppository formulation comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa- butter or other low melting vegetable waxes or fats or their synthetic analogs.
  • a binding and/or lubricating agent for example polymeric glycols, gelatins, cocoa- butter or other low melting vegetable waxes or fats or their synthetic analogs.
  • Typical dermal and transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
  • the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer a single dose.
  • a GST-Mytl expression construct was constructed which has the glutathione-S- transf erase gene fused to the amino terminus of Mytl kinase via a linker containing a thrombin cleavage site. This clone has been truncated at amino acid 362 of Mytl, just prior to the to the transmembrane domain. This construct was cloned into the Baculovirus expression vector, pFASTBAC, and this was used to make the viral stock for the subsequent infection. Spodoptera frugiperda cells (Sf21) were infected with the virus expressing the GST-Mytl and the cells were grown for 3 days, then harvested and frozen down.
  • the GST-Mytl protein was purified as follows: An Sf21 cell pellet expressing GST-Mytl was resuspended on ice in lOmls of lysis buffer (50mM Tris-Cl, pH 7.5, 250mM NaCl2, lmM dithiothreitol (DTT), 0.1%NP-40, 5% (v/v) protease inhibitor cocktail, lmM sodium orthovanadate), cells were lysed by sonication and centrifuged at 100,000xg for 30min.
  • lysis buffer 50mM Tris-Cl, pH 7.5, 250mM NaCl2, lmM dithiothreitol (DTT), 0.1%NP-40, 5% (v/v) protease inhibitor cocktail, lmM sodium orthovanadate
  • the supernatant was added to 5mls (packed volume) of Glutathione Sepharose 4B, equilibrated in wash buffer (20mM Tris-Cl, pH 7.0, lOmM MgCl2, lOOmM NaCl2, lmM DTT, 0.5%(v/v) protease inhibitor cocktail, lmM sodium orthovanadate).
  • wash buffer 20mM Tris-Cl, pH 7.0, lOmM MgCl2, lOOmM NaCl2, lmM DTT, 0.5%(v/v) protease inhibitor cocktail, lmM sodium orthovanadate.
  • wash buffer 20mM Tris-Cl, pH 7.0, lOmM MgCl2, lOOmM NaCl2, lmM DTT, 0.5%(v/v) protease inhibitor cocktail, lmM sodium orthovanadate.
  • the mixture was rocked for 30min.
  • the GST-Mytl was eluted from the column with lOmls of lOmM Glutathione in 50mM Tris-Cl, pH 8.0 in 500ul fractions. Protein concentrations were determined on the fractions using Bio-Rad's Protein assay kit as per instructions.
  • Delayed fluorescent immunoassays were performed in 96well NUNC maxisorp plates, at 50ul/well with 0.25ug GST-Mytl, in BufferA (50mM HEPES, pH 7.4, 2mM Mn(OAc) 2 , 5uM ATP, lmM DTT). For determination of pH optimum, divalent cation usage and K m of ATP, the appropriate component was varied as indicated in the figures. Autophosphorylation reactions were initiated by the addition of GST-Mytl in buffer and were allowed to proceed at room temperature with shaking for 20min. The reactions were stopped with the addition of EDTA to a 20mM final concentration, and the protein was allowed to continue to bind to the wells for an additional 40min.
  • BufferA 50mM HEPES, pH 7.4, 2mM Mn(OAc) 2 , 5uM ATP, lmM DTT.
  • pH optimum, divalent cation usage and K m of ATP the appropriate component was varied as indicated in the figures.
  • TBS/Tween 50mM Tris, pH 7.4, 150mM NaCl 2 , 0.2% Tween-20. After washing, the plate was blocked using Pierce's Superblock in TBS at lOOul/well. This was immediately decanted and the blocking was repeated two more times. The plate was then washed again with three washes of 300ul/well of TBS-Tween. Then lOOul of Eu- labeled anti-phosphotyrosine antibody diluted to 0.125ug/ml in TBS/Tween containing 0.15mg/ml BSA was added to the wells and allowed to incubate for 30min. with shaking at room temperature.
  • Synchronized cells were then returned to complete media containing a DNA-damaging drug such as 50nM topotecan (a dosage we have found to be sufficient to arrest cells in early G2 phase without inducing apoptosis) alone and in combination with test compounds for up to 18 hours.
  • Cell Cycle profiles were then performed cytometrically using a procedure for propidium iodide staining ofnuclei. (Vindelov et al, Cytometry Vol.3, No.5, 1983, 323- :" 327)
  • Mytl inhibitors would be expected to reverse the G2 arrest caused by the DNA damaging agent. Typical concentration ranges for such activity would be 0.001 to 10 uM.
  • Proliferation studies were performed in a variety of adherent and non-adherent cell lines including Hela S3, HT29, and Jurkat.
  • the proliferation assay utilized a colorimetric change resulting from reduction of the tetrazolium reagent XTT into a formazan product by metabolically active cells (Scudiero et al. Cancer Research, 48, 1981, 4827-4833) Cells ⁇ were seeded in lOOuls in 96 well plates to roughly 10% confluence (cell concentration varied with cell lines) and grown for 24 hours. Compounds were then added with or without sufficient vehicle- containing media to raise the cells to a 200ul final volume containing chemical reagents in 0.2% DMSO.
  • Mytl inhibitors are expected to inhibit the proliferation of such cancer cell lines and/or enhance the cytotoxicity of DNA-damaging chemotherapeutic drugs. Typical concentration ranges for such activity would be 0.001 to 10 uM.
  • Other assays for cellular proliferation or cytotoxicity could also be used with test compounds, and these assays are known to those skilled in the art.
  • CDK1 and CDK2 Cyclin dependent protein kinase assays utilized the peptides Biotin-aminohexyl-
  • CDK1 and CDK2 were both expressed utilizing a baculovirus expression system and were partially purified to comprise 20-80% of total protein, with no detectable competing reactions present.
  • assays were performed by incubating either enzyme (0.2-10 nM), with and without inhibitor, one of the two peptide substrates (1-10 nM), [ « 32 P]ATP (1-20 nM), and 10-20 mM Mg 2+ for periods of time generally within the range 10-120 min.
  • Reactions were terminated with 0.2-2 volumes of either 20% acetic acid or 50-100 mM EDTA buffered to pH 7 (substrate consumption ⁇ 20%).
  • the buffer employed in enzyme assays was either 30 mM HEPES 7.4 containing 0.15 M NaCl and 5% DMSO, the buffer 50 mM MOPS 7.0 containing 0.15 M NaCl and 5% DMSO, or the buffer 100 mM HEPES pH 7.5 containing 0.1 mg/mL BSA and 5% DMSO.
  • Inhibitors were diluted in 100% DMSO prior to addition into the assay.
  • Detection of peptide phosphorylation was accomplished by scintillation counting following either collection of peptide onto phosphocellulose filters (for reactions stopped with acetic acid), collection of peptide in wells of 96 well plates coated with Streptavidin (Pierce) (reactions were stopped with EDTA), or addition of Avidin coated Scintillant impregnated beads (Scintillation Proximity Assays from Amersham, reactions were stopped with EDTA).
  • the peptide substrate used in the Tie-2 assay was biotin-ammohexyl- LEAREYRWLGGKKKamide.
  • the kinase domain of the enzyme was purified to homogeneity from a baculovirus expression system.
  • the enzyme was diluted to 10 nM into a 60 ⁇ l reaction containing 100 mM HEPES, pH 7.5, 500 ⁇ M ATP, 10 mM MgCl 2 , 2 ⁇ M peptide, 1 mM DTT, 0.05 mg/ml BSA, and an inhibitor at varying concentrations.
  • the controls were reactions in the presence (negative controls) or absence (positive controls) of 50 mM EDTA.
  • Reactions were incubated for 30 min at room temperature, and then quenched by stopped by 80 ⁇ l of 0.15 M EDTA.
  • the quenched samples (125 ⁇ l) were transferred to a Neutravidin plates # 15128 and incubated at room temperature for 30-60 minutes, allowing the biotinylated peptide to bind to the neutravidin on the plates.
  • the neutravidin plates were then washed with water for 5 times.
  • Europium conjugated anti- ' ⁇ , phosphotyrosine antibody, (EG & G Wallac, # CR04- 100) ( 1 mg/ml) was diluted 1 : 10,000 in l%BSA-0.05% Tween 20-TBS, and 150 ⁇ l of the diluted antibody was added to each well of the neutravidin plate, so the phosphorylated peptide was bound with the Europium labelled antibody. After another 30-60 min incubation at room temperature, the plates were washed again with water for 5 times.
  • Enhancemant solution 150 ul of Enhancemant solution was then added to each well, dissociating Eu 3+ from solid phase bound antibodies to form a homogeneous and highly fluorescent Eu-(2-NTA) 3 (TOPO) 23 micellar chelate solution.
  • the plates were incubated for 10 minutes at room temperature to allow the above process, and fluorescent signal for each well was determined in a Wallac 1420 Victor Multilabel Counter with "Europium” protocol.
  • the kinase activity of all wells was calculated as %S, the percentage of the fluorescent counts vs. positive controls after substraction of negative controls, as in eq. 1.
  • Counts sample -Counts negative % S 100* (1)
  • CountSp OS j t j ve -Counts ne g at i ve Plots of compound concentration versus %S were constructed.
  • IC50s (K, expressed in units of molarity), the compound concentration at which the enzyme activity was inhibited by 50%, were determined from nonlinear least squares fits of the data to the simple competitive binding model of eq. 2.
  • %S is the experimentally observed count rate at sample compound concentration X
  • %S max is the best fit value for the maximum amplitude of the concentration-response curve
  • Y is the count rate observed at infinitely high inhibitor concentration.
  • CSBP/p38 Kinase Assay Compounds capable of inhibiting CSBP/p38 kinase can be identified with in vitro assays and cellular assays as described below. Variations of these assays would be obvious to those skilled in the art.
  • This assay measures the CSBP/p38-catalyzed transfer of 32 P from [a- 32 P]ATP to threonine residue in an epidermal growth factor receptor (EGFR)-derived peptide (T669) with the following sequence: KRELVEPLT SGEAPNQALLR (residues 661-681).
  • EGFR epidermal growth factor receptor
  • KRELVEPLT SGEAPNQALLR Residues 661-681.
  • Reactions were carried in round bottom 96 well plate (from Corning) in a 30 mL volume. Reactions contained (in final concentration): 25 mM Hepes, pH 7.5; 8 mM MgCl 2 ; 0.17 mM ATP (the K ⁇ i[ AT p] of p38 (see Lee et. al., Nature 300, n72 pg. 639-746 (Dec. 1994)); 2.5 uCi of [g-32P]ATP; 0.2 mM sodium orthovanadate; 1 mM DTT; 0.1% BSA; 10% glycerol; 0.67 mM T669 peptide; and 2-4 nM of yeast-expressed, activated and purified p38.
  • Reactions were initiated by the addition of [gamma-32P]Mg/ATP, and incubated for 25 min. at 37 °C. Inhibitors (dissolved in DMSO) were incubated with the reaction mixture on ice for 30 minutes prior to adding the 32P-ATP. Final DMSO concentration was 0.16%. Reactions were terminated by adding 10 uL of 0.3 M phosphoric acid, and phosphorylated peptide was isolated from the reactions by capturing it on p81 phosphocellulose filters. Filters were washed with 75 mM phosphoric acids, and incorporated 32P was quantified using beta scintillation counter.
  • NEN standard flashplate is coated with 1 ug/100 uL/well GST-cdc25c in PBS overnight at 4°C. The plate is washed 2 times with PBS at 250 uL/well and dried 5 to 15 minutes at 37°C. A mixture of 0.5 uCi 33P-ATP and 50 uM ATP are added as 10 uL/well to the dried flashplate. A pre-incubated mixture containing GST-PLK in Kinase Buffer is added as 40 uL/well with a final PLK concentration of 0.5 ug/well (pre-incubation occurs for 1 hour at 37°C).
  • reaction was initiated by addition of GST-CHKl (0.5 ug/well) and was allowed to proceed for a time predetermined to be linear on a time vs. phosphorylation plot. Reaction is terminated with the addition of an equal volume (50 uL) of 50-mM EDTA. Plates were washed four times in PBS, dried for 30 minutes at 30°C and quantitated by liquid scintillation counting. Typical concentration ranges in which test compounds are expected to inhibit CHK1 activity are 0.001 to 10 uM.
  • the present invention includes but is not limited to the examples below.
  • Nuclear magnetic resonance spectra were recorded at 300 MHz using a Bruker AM 300 spectrometer.
  • CDCI3 is deuteriochloroform
  • DMSO-d6 is hexadeuteriodimethylsulfoxide
  • CD3OD is tetradeuteriomethanol. Chemical shifts are reported in parts per million downfield from the internal standard tetramethylsilane.
  • ODS refers to an octadecylsilyl derivatized silica gel chromatographic support. 5 ⁇ Apex-ODS indicates an octadecylsilyl derivatized silica gel chromatographic support having a nominal particle size of 5 ⁇ , made by Jones Chromatography, Littleton, Colorado.
  • YMC ODS-AQ® is an ODS chromatographic support and is a registered trademark of YMC Co. Ltd., Kyoto, Japan.
  • PRP-1® is a polymeric (styrene-divinylbenzene) chromatographic support, and is a registered trademark of Hamilton Co., Reno, Nevada)
  • Celite® is a filter aid composed of * acid- washed diatomaceous silica, and is a registered trademark of Manville Corp., Denver, Colorado.
  • Example 1(b) 7-chloro-2-[[4-( ⁇ ethylamino)butyl]amino]-6-phenyl-pteridine
  • the compound of Example 1(b) is treated with thionyl chloride and a trace of dimethylformamide in chloroform to give the title compound.
  • 2-[[4-(diethylamino)butyl]amino]-7-methoxy-6-phenyl-pteridine The compound of Example 1(c) is treated with sodium methoxide in methanol and warmed to give the title compound.

Abstract

L'invention se rapporte à de nouveaux inhibiteurs de kinases et à des méthodes d'utilisation de tels inhibiteurs.
PCT/US2002/008915 2001-03-23 2002-03-22 Composes utiles en tant qu'inhibiteurs de kinases pour le traitement des maladies hyperproliferatives WO2002076985A1 (fr)

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