WO2000078299A2 - Composition et procede pour prevenir les effets secondaires de chimiotherapie et/ou de radiotherapie ou pour en reduire la gravite - Google Patents

Composition et procede pour prevenir les effets secondaires de chimiotherapie et/ou de radiotherapie ou pour en reduire la gravite Download PDF

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WO2000078299A2
WO2000078299A2 PCT/US2000/005186 US0005186W WO0078299A2 WO 2000078299 A2 WO2000078299 A2 WO 2000078299A2 US 0005186 W US0005186 W US 0005186W WO 0078299 A2 WO0078299 A2 WO 0078299A2
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alkyl
cyclin
inhibitor
dependent kinase
aryl
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PCT/US2000/005186
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WO2000078299A3 (fr
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Stephen Thomas Davis
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Glaxo Group Limited
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Priority to EP00970426A priority Critical patent/EP1177016A2/fr
Priority to AU79811/00A priority patent/AU7981100A/en
Priority to JP2001504363A priority patent/JP2003502362A/ja
Priority to US09/914,392 priority patent/US6620818B1/en
Publication of WO2000078299A2 publication Critical patent/WO2000078299A2/fr
Publication of WO2000078299A3 publication Critical patent/WO2000078299A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates generally to cyclin-dependent kinase II inhibitor compounds having utility as pharmacological agents for preventing/reducing the severity of epithelial cytotoxicity side effects of chemotherapy and/or radiation therapy, including alopecia, plantar-palmar syndrome and/or mucositis.
  • the invention also relates to a corresponding method of preventing/reducing the severity of such side effects, by administration of such a pharmalogical agent to a patient subjected to chemotherapy and/or radiation therapy treatment.
  • 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, c-kit, c-met, cRa l , CSF1 R, CSK, c-src, EGFR, ErbB2, ErbB3, ErbB4, ERK, ERK1 , ERK2, Fak, fes, FGFR1 , FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4
  • 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, 767,99), pain sensation (Yashpal, K. J. Neurosci. 1995, 15, 3263-72), inflammatory disorders such as arthritis ( Badger, J. Pharm. Exp. Ther. 1996, 279, 1453), psoriasis (Dvir, et al. J. Cell Biol.
  • osteoporosis (Tanaka et al, Nature, 1996, 383, 528), cancer (Hunter and Pines, Cell 1994, 79, 573), atherosclerosis (Hajjar and Pomerantz, FASEB J. 1992, 6, 2933), thrombosis (Salari, FEBS 1990, 263, 104), metabolic disorders such as diabetes (Borthwick, A.C. et al. Biochem. Biophys. Res. Commun. 1995, 210, 738), blood vessel proliferative disorders such as angiogenesis (Strawn et al Cancer Res. 1996, 56, 3540; Jackson et al J.
  • Chemotherapeutic techniques and radiation therapy techniques are well- established in the treatment of neoplastic conditions of various types.
  • patients commonly experience severe host epithelial cell toxicity.
  • the consequences of damage to the proliferating epithelium induced by chemotherapy frequently include hair loss (alopecia), plantar-palmar syndrome and mucositis; such side effects, especially mucositis, are also known to occur as a result of radiation therapy.
  • hair loss alopecia
  • plantar-palmar syndrome and mucositis
  • mucositis are also known to occur as a result of radiation therapy.
  • These side-effects may be of varying severity, depending on the type, dosages and dosing schedule of the respective chemotherapy and/or radiation therapy involved.
  • the present invention provides a novel approach to preventing/reducing the severity of epithelial cytotoxicity side effects such as alopecia, plantar-palmar syndrome and/or mucositis in a subject receiving chemotherapy and/or radiation therapy, by administering to such subject an effective amount of a cyc n- dependent kinase II inhibitor
  • a cyc n- dependent kinase II inhibitor A wide variety of particular cyclin-dependent kinase II inhibitor species useful in the broad practice of the present invention are hereinafter more fully described
  • the cyclin-dependent kinase inhibitor is preferably non-systemically administered to the subject, more preferably topically
  • the cyclin-dependent kinase II inhibitor may be administered topically to prevent/reduce the severity of alopecia incident to chemotherapy and/or radiation therapy, by application of the inhibitor compound, or a formulation containing same, to a corporeal locus susceptible to alopecia
  • a topical formulation may be made up with the cyclin-dependent kinase II inhibitor present in an effective amount and such topical formulation may then be administered to the subject's scalp and/or facial areas, to combat alopecia incident to chemotherapy and/or radiation therapy treatment
  • the cyclin-dependent kinase II inhibitor may be topically administered to the plantar and/or palmar regions that are susceptible to lesioning as a concomitant condition of such therapeutic treatment
  • the cyclin-dependent kinase II inhibitor is preferably administered topically to mouth and throat mucosa of the oral cavity
  • the patient receiving chemotherapy and/or radiation therapy may be contemporaneously administered the cyclin-dependent kinase II inhibitor in accordance with a selected dosage regimen that is effective to prevent/reduce the severity of two or more of the aforementioned side effects.
  • administration is desirably of a non-systemic character, being topically applied to head regions susceptible to occurrence or progression of alopecia, being topically applied to plantar and/or palmar regions susceptible to the occurance or progression of plantar-palmar lesions, and/or being topically administered to oral cavity mucosa in the mouth and throat areas susceptible to occurrence or progression of mucositis.
  • the invention in another aspect relates to a cytoprotective composition for preventing/reducing the severity of epithelial cytotoxicity side effects incident to the administration of chemotherapy and/or radiation therapy, e.g., alopecia, plantar-palmar syndrome and/or mucositis.
  • a cytoprotective composition for preventing/reducing the severity of epithelial cytotoxicity side effects incident to the administration of chemotherapy and/or radiation therapy, e.g., alopecia, plantar-palmar syndrome and/or mucositis.
  • Such composition is suitably formulated to comprise an effective amount of a cyclin-dependent kinase II inhibitor for the prevention or reduction in the severity of the epithelial cytotoxicity side effects of the chemotherapy and/or radiation therapy.
  • the composition may be formulated for such purpose with one or more pharmaceutically acceptable carriers, excipients or diluents.
  • the present invention provides a method and composition for preventing/reducing the severity of epithelial cytotoxicity side effects, e.g., alopecia, plantar-palmar syndrome and/or mucositis, in a subject receiving chemotherapy and/or radiation therapy, involving administration to the subject of an effective amount of a cyclin-dependent kinase II inhibitor.
  • epithelial cytotoxicity side effects e.g., alopecia, plantar-palmar syndrome and/or mucositis
  • Cyclin-dependent kinase II (sometimes hereinafter referred to as "CDK2") is a protein senne/threonine kinase that is required for progression of cells through the G1 and S phases of the cell cycle. Inhibition of CDK2 in normal cells results in a reversible cell cycle arrest and can therefore protect cells from antineoplastic agents with cytotoxic activity dependent on progression through the cell cycle.
  • the present invention exploits this characteristic.
  • an inhibitor of CDK2 is topically applied to the scalp and optionally other hirsute areas to prevent alopecia, one of the most common and distressing side effects of chemotherapy and/or radiation therapy.
  • the CDK2 inhibitor is topically applied to the hands and/or feet of a patient, to prevent or reduce the severity of plantar-palmar syndrome, and/or is topically applied to the mouth and throat mucosa of the oral cavity to prevent or reduce the severity of mucositis incident to chemotherapy and/or radiation therapy treatment
  • the cyclin-dependent kinase II inhibitor of the invention may comprise any suitable compound having inhibitory action on cyclin-dependent kinase II activity, i.e.
  • cyclin-dependent kinase II inhibitors that may be employed in the broad practice of the invention to prevent/reduce the severity of epithelial cytotoxicity side effects of chemotherapy and/or radiation therapy, such as alopecia, plantar-palmar syndrome and/or mucositis, include the cyclin- dependent kinase II inhibitor compounds described in the following references, as well as in the references identified in the Bibliography set forth hereinafter, the disclosures of all of which are hereby incorporated herein by reference in their respective entireties:
  • the present invention also extends to the use of pharmaceutically acceptable salts, soivates, biohydrolyzable carbonates, biohydrolyzable ureides, biohydrolyzable esters, biohydrolyzable amides, biohydrolyzable carbamates, affinity reagents or prodrugs thereof in either crystalline or amorphous form
  • the therapeutic compositions of the present invention may include one or more than one cyclin-dependent kinase II inhibitor agent, as suitable to achieve the desired efficacy in a given end use application of the invention.
  • X is N, CH, CCF 3l or C(C ⁇ . , 2 aliphatic);
  • R 1 is selected from the group consisting of: hydrogen, C ⁇ - ⁇ 2 aliphatic, thioi, hydroxy, hydroxy-d-12 aliphatic, Aryl, Aryl-C ⁇ -1 2 aliphatic, R 6 -Aryl-C ⁇ .
  • R 6 , Aryl, Cyc and Het are as defined below;
  • R 2 is selected from the group consisting of hydrogen, C 1 - 12 aliphatic, N- hydroxyimino-Ci-12 aliphatic, C1-12 alkoxy, hydroxy-d-12 aliphatic, d-1 2 alkoxycarbonyl, carboxyl d- 1
  • R 1 and R 2 are optionally joined to form a fused ring selected from the group as defined for Het below, and said fused ring is optionally substituted by d- 12 aliphatic, halogen, nitro, cyano, C ⁇ _ 12 alkoxy, amino, hydroxyl, carbo- C1- 12 alkoxy, or oxo;
  • R 3 is selected from the group consisting of: hydrogen, d- 12 aliphatic, hydroxy, hydroxy C ⁇ _ 12 aliphatic, di-d-12 aliphatic amino, di-C ⁇ - 12 aliphatic aminocarbonyl, di-d.
  • R 2 and R 3 are optionally joined to form a fused ring selected from the group as defined for Het below, and said fused ring is optionally substituted by C- ⁇ - 6 aliphatic or C ⁇ _ 6 aliphatic-carbonyl; with the proviso that R 1 , R 2 and R 3 cannot simultaneously be hydrogen;
  • R 4 is selected from the group consisting of: sulfonic acid, C 1 - 12 aliphatic-sulfonyl, sulfonyl-d-1 2 aliphatic, C1-6 aliphatic-amino, R 7 -sulfonyl, R 7 -sulfonyl-C ⁇ - ⁇ 2 aliphatic, R 7 -aminosuifony
  • R 7 , R 8 , Aryl and Het are as defined below;
  • R 5 is hydrogen; and further wherein R 4 and R 5 are optionally joined to form a fused ring, said ring being selected from the group as defined for Het below, or any of said fused rings optionally substituted by C - 12 aliphatic, oxo or dioxo;
  • R 6 is selected from the group consisting of C ⁇ . 1 aliphatic, hydroxy, d. 12 alkoxy, or halogen;
  • R 7 is selected from the group consisting of: hydrogen, C 1-12 aliphatic, C ⁇ - ⁇ 2 alkoxy, hydroxy-C ⁇ - ⁇ 2 alkoxy, hydroxy-C ⁇ _ 12 aliphatic, carboxylic acid, C ⁇ - ⁇ 2 aliphatic-carbonyl, Het, Het-C ⁇ . 12 aliphatic, Het-C 1- 2 alkoxy, di-Het- d_ ⁇ 2 alkoxy Aryl, Aryl-d. ⁇ 2 aliphatic, Aryl-C 1-12 alkoxy, Aryl-carbonyl, C ⁇ - ⁇ 8 alkoxyalkoxyalkoxyalkoxyaliphatic, or hydroxyl where Het and Aryl are as defined below;
  • R 8 is selected from the group consisting of: hydrogen, nitro, cyano, C 1 - 12 alkoxy, halo, carbo- C ⁇ - ⁇ 2 alkoxy and halo- d_ ⁇ 2 aliphatic;
  • Aryl is selected from the group consisting of: phenyl, naphthyl, phenanthryl or anthracenyl;
  • Cyc is selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, and optionally has one or more degrees of unsaturation;
  • Het is a saturated or unsaturated heteroatom ring system selected from the group consisting of: benzimidazole, dihydrothiophene, dioxin, dioxane, dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan, imidazole, isoquinoline, morpholine, oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxadiazine, piperazine, piperidine, pyran, pyrazine, pyrazole, pyridine, pyrimidine, pyrrole, pyrrolidine, quinoline, tetrahydrofuran, tetrazine, thiadiazine, thiadiazole, thiatriazole, thiazine, thiazole, thiomorpholine, thiophene, thiopyran, triazine and tri
  • esters, amides and carbamates are preferably hydrolyzable and more preferably are biohydrolyzable.
  • Illustrative species of cyclin-dependent kinase II inhibitors that may be usefully employed in the practice of the present invention include the following compounds within the foregoing formula (A) (of formulae (A1 ), (A2), and (A3) respectively):
  • the CDK2 inhibitor compound that is selected for use in a given application of the methodology of the present invention may then be formulated as the active ingredient in a pharmaceutically acceptable composition, for topical or otherwise non-systemic administration to a subject (e.g., a mammalian subject such as a human subject), to prevent/reduce the severity of epithelial cytotoxicity side effects (e.g., alopecia, plantar-palmar syndrome, and/or mucocitis) induced by chemotherapy and/or radiation therapy contemporaneously being administered to the subject.
  • a subject e.g., a mammalian subject such as a human subject
  • epithelial cytotoxicity side effects e.g., alopecia, plantar-palmar syndrome, and/or mucocitis
  • the CDK2 inhibitor compound is preferably administered topically to the corporeal locus that is susceptible to alopecia, such as the head (e.g., the scalp, eyebrow regions, beard and mustache areas, etc.).
  • the head e.g., the scalp, eyebrow regions, beard and mustache areas, etc.
  • the cyclin dependant kinase II inhibitor compound may be formulated in a topical administration formulation, by combination of the compound with a selected pharmaceutically acceptable vehicle (carrier, diluent or excipient), so that the amount of the compound in the formulation is sufficient to achieve the prevention or reduction in severity of the alopecia side effect, when administered in accordance with an appropriately designed treatment protocol.
  • a selected pharmaceutically acceptable vehicle carrier, diluent or excipient
  • the formulation can be in any useful dosage unit form for corresponding administration.
  • Formulations of the thiazole-oxindole compound may be constituted and administered in any suitable manner, such as in a liquid formulation for aerosolized spray administration to the head region of a subject susceptible to chemotherapy-induced alopecia, or by a dermal patch or dressing containing the CDK2 inhibitor formulation in a releasable form, for positioning on the head in contact with the area of susceptibility
  • the formulation may alternatively be prepared as a lotion, salve, gel, foam, paste, oil, creme, or other suitable form, for administration to the appropriate corporeal locus, e.g., to the scalp or other area of the head for preventing/reducing the severity of alopecia, with initial administration being followed by massage, brushing, or toweling to distribute the formulation on the scalp evenly for uniformity of therapeutic effect
  • compositions that may be uced for topical adminstration of the CDK2 inhibitor agents of the invention to the corporeal locus of a subject receiving chemotherapy and/or radiation therapy
  • a formulation of the type described in Tata, S , et al , Relative Influence of Ethanol and Propylene Glycol Cosolvents on Deposition of Minoxidil into the Skin, Journal of Pharmaceutical Sciences, Vol. 83, No 10, October 1994, pp 1508-1510 may be employed
  • Such a formulation may comprise a 2% solution of the active ingredient in 60% ethanol, 20% propylene glycol and 20% water, for topical administration of the solution to the scalp
  • compositions identified in U S. Patents 5,849,733, 5,807,698; 5,625,031 , and 5,486,509 include the formulations identified in U S. Patents 5,849,733, 5,807,698; 5,625,031 , and 5,486,509, the disclosures of which are incorporated herein by reference in their entireties
  • the formulation may be constituted to provide an appropriate dose for a desired dosing schedule.
  • the dosage and dosage schedule may be readily determined for a given subject, within the skill of the art, based on the character of the chemotherapy and/or radiation therapy being employed.
  • Analogous considerations apply to the formulation and administration of the CDK2 inhibitor for preventing/reducing the severity of plantar-palmar syndrome, involving topical administration to the areas of the hands and feet susceptible to the syndrome as a side-effect of chemotherapy and/or radiation therapy.
  • the cyclin-dependent kinase II inhibitor may be formulated in a suitable topical formulation for application to the oral cavity mucosa.
  • Illustrative delivery systems for the cyclin-dependent kinase II inhibitor of the invention, as used to combat mucositis, include the formulations and delivery techniques described in Cullinan U.S.
  • Useful formulations may include the active ingredient and excipients, diluents, or carriers, formed into tablets, capsules, sprays, mouthwashes, lozenges, troches, pastilles, lollipops, suspensions, powders and the like, for application to the mucosa of the oral cavity.
  • Acceptable daily dosages of the CDK2 inhibitor for preventing/reducing the severity of epithtelial cytotoxicity side effects induced by chemotherapy and/or radiation therapy may be from about 0.1 to about 1000 mg/day, and preferably from about 0.2 to about 100 mg/day.
  • the cyclin-dependent kinase II inhibitor in the preferred practice of the invention is administered contemporaneously with the chemotherapy and/or radiation therapy treatment (i.e., simultaneously with, or sufficiently near in time to, the chemotherapy and/or radiation therapy, so as to achieve a preventative or ameliorative effect on the epithelial cytotoxicity side effect that would otherwise be presented in the absence of the CDK2 inhibitor).
  • the chemotherapy and/or radiation therapy may be of any appropriate type for the neoplastic condition, or other disease state or condition, of the patient being treated.
  • the chemotherapy may comprise administration of chemotherapeutic agents, including cycle-specific agents (such as cytosine arabinoside (ARA-C)) and non-cycle-specific agents (such as Cytoxan), individually or in combination with one another.
  • cycle-specific agents such as cytosine arabinoside (ARA-C)
  • non-cycle-specific agents such as Cytoxan
  • the cyclin-dependent kinase II inhibitor in one embodiment of the invention is administered 1-4 times in a chemotherapeutic cycle, as a cytoprotective composition for preventing/reducing the severity of epithelial cytotoxicity side effects such as alopecia, plantar-palmar syndrome and/or mucositis, in a subject receiving chemotherapy and/or radiation therapy.
  • the cyclin-dependent kinase II inhibitor effects a desired temporary arrest of the hair follicle cell cvcle by inhibition of cyclin-dependent kinase II activity.
  • the inhibitor agent formulated in a suitable topically administerable formulation, may be applied 1 -2 times per chemotherapeutic cycle prior to and during the time of administration of chemotherapy, in one specific preferred illustrative embodiment
  • cyclin-dependent kinase I I inhibitor agents that are topically administerable to prevent/reduce the severity of chemotherapy-induced alopecia, are assessed for efficacy and selected for use based on one or more of the following characteristics:
  • cytotoxic regimens one of which includes an alkylating agent (e.g., a regimen involving doxorubicin/cyclophosphamide (anthracyclin/alkylating agent), etoposide (topoisomerase II inhibitor), taxol, etc.);
  • an alkylating agent e.g., a regimen involving doxorubicin/cyclophosphamide (anthracyclin/alkylating agent), etoposide (topoisomerase II inhibitor), taxol, etc.
  • a topical dose of 10 mg/kg of body weight of the subject yielding a plasma concentration of less than 15 nanoMolar, and preferably a systemic exposure to less than 0.01 of the IC50 concentration for protection of the HT29 tumour cell line;
  • the compound of the invention may be formulated for topical administration in any suitable manner to prevent/ reduce the severity of plantar/palmar syndrome, involving a suitable dosing and treatment regimen for the patient receiving chemotherapy and/or radiation therapy.
  • the compound of the invention in an appropriate form is most preferably formulated for topical administration to the oral cavity mucosa, in a mouthwash, lozenge or lollipop.
  • the invention may be practiced with a wide variety of CDK2 inhibitor compounds, some of which are described more fully below.
  • R may comprise a substituent such as:
  • X is oxygen or sulfur
  • R 1 is hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, -(CH 2 ) q -NR 7 R 8 , alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkoxycarbonyl, arylalkyloxycarbonyl or aryloxycarbonyl;
  • R 2 is hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, hydroxy, alkoxy, arylalkoxy, aryloxy, alkylcarbonyloxy, arylalkylcarbonyloxy, arylcarbonyloxy, carboxy, alkyloxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl, ammo, -NR 7 R 8 , thiol, alkylthio, arylalkylthio, or arylthio;
  • R 3 is alkyl, cycloalkyl,
  • R 6 is hydrogen, alkyl, arylalkyl, aryl, cycloalkyl, hydroxy, alkoyy, arylalkoxy, aryloxy, alkylcarbonyloxy, arylalkylcarbonyloxy, arylcarbonyloxy, carboxy, alkyloxycarbonyl, arylalkoxycarbonyl, amino, cyano, nitro, -NR 7 R 8 , halogen, alkylhalo, -CHO, alkylS(0) m - or -OC(0)NR 7 R 8 , NR 7 R 8 thiol, alkylthio, arylalkylthio or arylthio,
  • R 7 and R 8 are independently hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, heterocycle or alkylcarbonyl; or R 7 and R 8 together with a nitrogen atom to which they are bonded can form a heterocycle, m is an integer of 0 to 2, n is an integer of 0 to 3, p is an integer of 1 to 3, and q is an integer of 2 to 5
  • X is O, S or CHR X where R x is H or d 4 alkyl, D is H, halo or NZi Z 2 where Z-, and Z 2 are each independently H or d 4 alkyl or d 4 hydroxyalkyl
  • B is selected from H, alkyl, alkoxy, CF 3 , an optionally substituted aryl (e.g. phenyl) or an optionally substituted aralkyl (e.g.
  • Y is or includes an optionally substituted 4- to 8-membered carbocyclic or heterocyclic ring; or comprises an optionally substituted linear or branched hydrocarbon chain.
  • CDK2 inhibitor compounds useful in preventing epithelial cytotoxicity incident to chemotherapy and/or radiation therapy in accordance with the present invention include the compounds described in International Publication WO 98/33798 published August 6, 1998 and entitled, "PYRIDO [2,3- D] PYRIMIDINES AND 4-AMINOPYRIMIDINES AS INHIBITORS OF CELLULAR PROLIFERATION" (WARNER LAMBERT COMPANY), which discloses 7,8-dihydro-2-(amino and thio)pyrido[2,3-d]pyrimidines and 2,4- diaminopyrimidines that are potent inhibitors of cyclin-dependent kinases (cdks) and growth factor-mediated kinases, and are described as being useful for treating cell proliferatives disorders, such as cancer and restenosis.
  • Such compounds are of Formula D1 and Formula D2 below:
  • W is NH, S, SO, or S0 2
  • Ri includes phenyl and substituted phenyl
  • R 2 includes alkyl and cycloalkyl
  • R 3 includes alkyl and hydrogen
  • R 8 and R 9 include hydrogen and alkyl
  • Z is carboxy
  • a further class of CDK2 inhibitors includes tyrphostins, such as for example tyrphostins from the AG555/AG494 family as described in N Klemberger-Doron, et al., Inhibition of Cdk2 Activation by Selected Tyrphostins Causes Cell Cycle Arrest at Late G1 and S Phases, Experimental Cell Research 241 , 340-351 (1998).
  • tyrphostins such as for example tyrphostins from the AG555/AG494 family as described in N Klemberger-Doron, et al., Inhibition of Cdk2 Activation by Selected Tyrphostins Causes Cell Cycle Arrest at Late G1 and S Phases, Experimental Cell Research 241 , 340-351 (1998).
  • CDK2 inhibitors that may be usefuiiy employed in the practice of the invention include the 2, 6, 9-trisubstituted purine compounds described in International Publication WO 98/05335 published February 12, 1998, "PURINE INHIBITORS OF CYCLIN DEPENDENT KINASE 2 AND I" (CV THERAPEUTICS, INC.) of the formulae:
  • Another aspect of the present invention relates to the use of a CDK2 inhibitor species, in coadministration or alternating administration with previously known anti-alopecia and/or anti-mucositis therapies for more effective treatment of the patient undergoing chemotherapy.
  • the CDK2 inhibitor agent may be administered to a patient undergoing chemotherapy, concurrently with administration to the patient of an anti-mucositis agent, such as the mucositis-preventing/reducing the severity of compounds of the formula:
  • R 1 and R 3 are independently hydrogen, -CH 3 , -C(0)-(C ⁇ . 6 alkyl), or -C(0)-Ar, wherein Ar is optionally substituted phenyl, R 2 is selected from the group consisting of pyrro dine, hexamethyleneamino, and pipe ⁇ dino, and pharmaceutically acceptable salts and solvates thereof, as more fully described in U.S. Patent 5,496,828.
  • solvate is a complex of variable stoichiometry formed by a solute and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Solvents may be, by way of example, water, ethanol, or acetic acid.
  • biohydrolyzable carbonate As used herein, the terms “biohydrolyzable carbonate”, “biohydrolyzable ureide” and “biohydrolyzable carbamate” include carbonates, ureides, and carbamates, respectively, of a CDK2 inhibitor compound, which carbonates, ureides, and carbamates, do not completely dimmish the biological activity of the parent substance
  • Such carbonates, ureides, and carbamates may confer on the parent compound advantageous properties in vivo, such as improved duration of action, onset of action, and the like
  • An advantage of such biohydrolyzable forms is that, for example, they facilitate improved oral administration because the carbonates, ureides, and carbamates are more readily absorbed from the gut and are then transformed to an active compound in plasma
  • biohydrolyzable compounds are known in the art and include, by way of example, lower alkyl carbamates
  • biohydrolyzable ester is an ester of an active compound which does not completely dimmish the biological activity of the parent substance. Such esters may confer on the parent compound advantageous p opert ⁇ es in vivo, such as improved duration of action, onset of action, and the like. Also included are esters which are relatively biologically inactive but which are converted in vivo by the subject to the biologically active principle.
  • biohydrolyzable forms are that, for example, they facilitate improved oral administration because they are more readily absorbed from the gut and are then transformed to an active compound in plasma
  • biohydrolyzable esters include, by way of example, lower alkyl esters, lower acyloxy-alkyl esters, lower alkoxyacyloxyalkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters and cho ne esters.
  • biohydrolyzable amide is an amide of an active parent compound which does not completely dimmish the biological activity of the parent compound Such amides may confer on the parent compound advantageous properties in vivo, such as improved duration of action, onset of action, and the like Also included are amides which are relatively biologically inactive but which are converted in vivo by the subject to the biologically active principle An advantage of such biohydrolyzable forms is that, for example, they facilitate improved oral administration because they are more readily absorbed from the gut and are then transformed to an active compound in plasma.
  • biohydrolyzable include, by way of example, lower alkyl amides, -ammo acid amides, alkoxyacyl amides and alkyiaminoalkylcarbonyl amides
  • prodrug includes compounds which are hydrolyzable in vivo to yield an active compound, including for example, biohydrolyzable amides, biohydr
  • affinity reagent means a group attached to the active compound which does not affect its in vitro biological activity, allowing the compound to bind to a target, yet such a group binds strongly to a third component allowing a) characterization of the target as to localization within a cell or other organism component, perhaps by visualization by fluorescence or radiography, or b) facile separation of the target from an unknown mixture of targets, whether proteinaceous or not protemaceous
  • An example of an affinity reagent according to b) would be biotm either directly attached to the active compound or linked with a spacer of one to 50 atoms selected from the group consisting of: C, H, O, N, S, or P in any combination
  • An Example of an affinity reagent according to a) above would be fluorescem, either directly attached to the active compound or linked with a spacer of one to 50 atoms selected from the group consisting of C, H, O, N, S, or P in any combination
  • the term "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician
  • the term "therapeutically effective amount' means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease or disorder, or a decrease in the rate of advancement of a disease or disorder, and also includes amounts effective to enhance normal physiological function
  • the CDK2 inhibitor agents in the practice of the present invention via topical application to susceptible skin areas for preventing/reducing the severity of alopecia incident to chemotherapy and/or radiation therapy, and via mouthwash formulation or lozenge for preventing/reducing the severity of mucositis incident to chemotherapy and/or radiation therapy
  • the CDK2 inhibitor agents in the practice of the invention can be otherwise administered in oral (including buccal and sublingual) dosage forms as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules
  • they may also be administered in nasal, ophthalmic, otic, rectal, intravenous (both bolus and infusion), intrapentoneal, mtraarticular, subcutaneous or intramuscular inhalation or insufflation form, all using forms well known to those of ordinary skill in the pharmaceutical arts.
  • the dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
  • An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to combat the alopecia and/or mucositis condition.
  • Oral dosages in the practice of the present invention when used for the indicated effects, will range between about 0 01 to about 100 mg/kg of body weight per day, and particularly about 0 1 to 10 mg/kg of body weight per day.
  • Oral dosage units will generally be administered in the range of from 0 1 to about 250 mg and more preferably from about 25 to about 250 mg
  • the daily dosage for a 70 kg mammal will generally be in the range of about 70 mg to 7 grams of a CDK2 inhibitor compound
  • the dosage to be administered is based on the usual conditions such as the physical condition of the patient, age, body weight, past medical history, route of administrations, severity of the conditions and the like.
  • Topical application may be once or more than once per day depending on the course of chemotherapy and/or radiation therapy treatment
  • compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • the compounds for use according to the present invention can be prepared in a range of concentrations for topical use of about 0.1 to about 5mg/ml of suitable solvent.
  • a preferred volume for application to the scalp is about 2 to 20 ml, resulting in an effective dosage delivered to the patient of about 0.2 to about 100 mg.
  • preferred compounds for the present invention can be administered in mtranasal form via topical use of suitable mtranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen
  • the compounds herein described in detail can form the active ingredient and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier” materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • carrier suitable pharmaceutical diluents, excipients or carriers
  • suitable pharmaceutical diluents, excipients or carriers suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.
  • a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.
  • Capsules are made by preparing a powder mixture as described above, and filling formed gelatin sheaths.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aligmate, gelatin, or polyvmyl pyrrohdone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate
  • the powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules The granules, the
  • Oral fluids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compounJ Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle Suspensions can be formulated by dispersing the compound in a non-toxic vehicle Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added
  • dosage unit formulations for oral administration can be microencapsulated The formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like
  • Liposome delivery systems such as small unilar ⁇ ellar vesicles, large unilamellar vesicles and multilamellar vesicles
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamme or phosphatidylcholmes
  • Compounds for use according to the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled
  • the compounds may also be coupled with soluble polymers as targetable drug carriers
  • Such polymers can include polyvinylpyrro done, pyran copolymer, polyhydroxypropylmethacrylamide- phenol, polyhydroxyethylaspartamidephenol, or polyethyieneoxidepolylysine substituted with palmitoyl residues
  • the compounds may be coupled to a class of biodegradable polymers useful achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels
  • Parenteral administration can be effected by utilizing liquid dosage unit forms such as sterile solutions and suspensions intended for subcutaneous, intramuscular or intravenous injection These are prepared by suspending or dissolving a measured amount of the compound in a non-toxic liquid vehicle suitable for injection such as aqueous oleaginous medium and sterilizing the suspension or solution Alternatively, a measured amount of the compound is placed in a vial and the vial and its contents are sterilized and sealed An accompanying vial or vehicle can be provided for mixing prior to administration Non-toxic salts and salt solutions can be added to render the injection isotonic Stabilizers, preservations and emulsifiers can also be added
  • Rectal administration can be effected utilizing suppositories in which the compound is admixed with low-melting water-soluble or insoluble solids such as polyethylene glycol, cocoa butter, higher ester as for example flavored aqueous solution, while elixirs are prepared through my ⁇ styl palmitate or mixtures thereof
  • Topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams
  • the formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions Such carriers may be present as from about 1 % up to about 98% of the formulation More usually they will form up to about 80% of the formulation
  • the compounds for use according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e g dichlorodifluoromethane, t ⁇ chlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane, heptafluoropropane, carbon dioxide or other suitable gas
  • a suitable propellant e g dichlorodifluoromethane, t ⁇ chlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane, heptafluoropropane, carbon dioxide or other suitable gas
  • a suitable propellant e g dichlorodifluoromethane, t ⁇ chlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane, heptafluoropropan
  • the inhibitory activity of various illustrative compounds may be determined against CDK2 kinase by the assay technique described below; the inhibitory activity may be determined as well against other kinases for comparison purposes (such as, for example, VEGFR2, Tie-2, and c-fms).
  • CDK1 and CDK2 Cyclin dependent protein kinase assays utilized the peptides Biotin-aminohexyl- AAKAKKTPKKAKK and Biotin-aminohexyl-ARRPMSPKKKA-NH 2 as phosphoryl group acceptors.
  • 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 NaCI and 5% DMSO, the buffer 50 mM MOPS 7.0 containing 0.15 M NaCI 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 phosphocelluiose 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).
  • Table 1 illustrate the inhibitory activity of the illustrative compounds of formulae (A1 ), (A2) and (A3), as hereinbefore defined, against CDK2 and CDK1.
  • Protection from chemotherapy-induced alopecia may, for example, be determined in 7-day old Sprague-Dawley rat pups Treatment is carried out by administering the compounds topically to the head of the animal in doses from 0 01 to 10 mg/kg 2h before and 2h after the administration of a single dose of 6 mg/kg etoposide intrape ⁇ toneally Six days after dosing, animals are scored visually for hair loss using a grading scale from 1 (complete hair loss) to 4 (no apparent hair loss) In this assay, the prior treatment of the animal with a CDK2 inhibitor compound according to the present invention results in a marked reduction in the severity of alopecia compared to vehicle treated controls When the CDK2 inhibitor compounds are used to combat alopecia and/or mucositis in conjunction with the administration of chemotherapeutic agents or radiation therapy for cancer treatment, the CDK2 inhibitor compounds may be utilized to provide a secondary means of suppressing tumor growth either when administered simultaneously with the chemotherapeutic agents, or in an chemo
  • Flavopiridol (L86 82875; NSC 649890), a new kinase inhibitor for tumor therapy, International Journal of Oncology 9: 1143-1168, 1996.

Abstract

L'invention concerne une composition et un procédé pour prévenir les effets secondaires de cytotoxicité épithéliale (tels que l'alopécie, le syndrome plantaire-palmaire et/ou la mucosite) ou pour en réduire la gravité, lesdits effets secondaires apparaissant chez un sujet soumis à une chimiothérapie et/ou une radiothérapie; selon ce procédé, on administre simultanément au patient une quantité efficace d'un inhibiteur de kinase II dépendant de la cycline.
PCT/US2000/005186 1999-03-04 2000-03-01 Composition et procede pour prevenir les effets secondaires de chimiotherapie et/ou de radiotherapie ou pour en reduire la gravite WO2000078299A2 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP00970426A EP1177016A2 (fr) 1999-03-04 2000-03-01 Composition et procede pour prevenir les effets secondaires de chimiotherapie et/ou de radiotherapie ou pour en reduire la gravite
AU79811/00A AU7981100A (en) 1999-03-04 2000-03-01 Composition and method for preventing/reducing the severity of side effects of chemotherapy and/or radiation therapy
JP2001504363A JP2003502362A (ja) 1999-03-04 2000-03-01 化学療法および／または放射線療法の副作用の苛酷さを防止／軽減するための組成物および方法
US09/914,392 US6620818B1 (en) 2000-03-01 2000-03-01 Method for reducing the severity of side effects of chemotherapy and/or radiation therapy

Applications Claiming Priority (2)

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GBGB9904932.2A GB9904932D0 (en) 1999-03-04 1999-03-04 Composition and method for preventing/reducing the severity of side effects of chemotherapy and/or radiation therapy
GB9904932.2 1999-03-04

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001080813A2 (fr) * 2000-04-27 2001-11-01 Bristol-Myers Squibb Company Methodes de prevention et de traitement de l'alopecie provoquee par la chimiotherapie ou la radiotherapie
US6369086B1 (en) * 1997-09-05 2002-04-09 Smithkline Beecham Corporation Substituted oxidole derivatives as protein tyrosine and as protein serine/threonine kinase inhibitors
US6482842B2 (en) 2000-02-07 2002-11-19 Bristol-Myers Squibb Company 3-aminopyrazole inhibitors of cyclin dependent kinases
JP2006508186A (ja) * 2002-11-06 2006-03-09 サイクラセル・リミテッド ドセタキセル及びｃｄｋ阻害剤を含む組合せ
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
KR101432171B1 (ko) 2013-01-22 2014-08-22 한국원자력의학원 Ｃｄｋ11ａ를 측정하는 제제를 포함하는 방사선 저항성 또는 민감성 진단용 조성물 및 이의 용도

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996012506A1 (fr) * 1994-10-24 1996-05-02 Baylor College Of Medecine Inhibiteurs de synthese d'adn produits dans des cellules senescentes
WO1997027297A1 (fr) * 1996-01-23 1997-07-31 Mitotix, Inc. Inhibiteurs de la progression du cycle cellulaire et leurs utilisations
WO1998050356A1 (fr) * 1997-05-07 1998-11-12 Sugen, Inc. Derives de 2-indolinone utilises en tant que modulateurs de l'activite de la proteine kinase
WO1999010325A1 (fr) * 1997-08-06 1999-03-04 Glaxo Group Limited Derives de benzylidene-1,3-dihydro-indol-2-one utilises comme inhibiteurs des tyrosine-recepteur-kinases, notamment des raf-kinases
WO1999015500A1 (fr) * 1997-09-05 1999-04-01 Glaxo Group Limited Derives substitues d'oxindole en tant qu'inhibiteurs de la tyrosine kinase et de la serine/threonine kinase
WO1999052869A1 (fr) * 1998-04-15 1999-10-21 Boehringer Ingelheim Pharma Kg Indolinones substituees a effet inhibiteur sur des kinases et des complexes cycline/cdk

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996012506A1 (fr) * 1994-10-24 1996-05-02 Baylor College Of Medecine Inhibiteurs de synthese d'adn produits dans des cellules senescentes
WO1997027297A1 (fr) * 1996-01-23 1997-07-31 Mitotix, Inc. Inhibiteurs de la progression du cycle cellulaire et leurs utilisations
WO1998050356A1 (fr) * 1997-05-07 1998-11-12 Sugen, Inc. Derives de 2-indolinone utilises en tant que modulateurs de l'activite de la proteine kinase
WO1999010325A1 (fr) * 1997-08-06 1999-03-04 Glaxo Group Limited Derives de benzylidene-1,3-dihydro-indol-2-one utilises comme inhibiteurs des tyrosine-recepteur-kinases, notamment des raf-kinases
WO1999015500A1 (fr) * 1997-09-05 1999-04-01 Glaxo Group Limited Derives substitues d'oxindole en tant qu'inhibiteurs de la tyrosine kinase et de la serine/threonine kinase
WO1999052869A1 (fr) * 1998-04-15 1999-10-21 Boehringer Ingelheim Pharma Kg Indolinones substituees a effet inhibiteur sur des kinases et des complexes cycline/cdk

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6369086B1 (en) * 1997-09-05 2002-04-09 Smithkline Beecham Corporation Substituted oxidole derivatives as protein tyrosine and as protein serine/threonine kinase inhibitors
US6482842B2 (en) 2000-02-07 2002-11-19 Bristol-Myers Squibb Company 3-aminopyrazole inhibitors of cyclin dependent kinases
US6610724B2 (en) 2000-02-07 2003-08-26 Bristol-Myers Squibb Company 3-Aminopyrazole inhibitors of cyclin dependent kinases
WO2001080813A2 (fr) * 2000-04-27 2001-11-01 Bristol-Myers Squibb Company Methodes de prevention et de traitement de l'alopecie provoquee par la chimiotherapie ou la radiotherapie
WO2001080813A3 (fr) * 2000-04-27 2002-02-07 Bristol Myers Squibb Co Methodes de prevention et de traitement de l'alopecie provoquee par la chimiotherapie ou la radiotherapie
JP2006508186A (ja) * 2002-11-06 2006-03-09 サイクラセル・リミテッド ドセタキセル及びｃｄｋ阻害剤を含む組合せ
JP4764165B2 (ja) * 2002-11-06 2011-08-31 サイクラセル リミテッド ドセタキセル及びｃｄｋ阻害剤を含む組合せ
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
KR101432171B1 (ko) 2013-01-22 2014-08-22 한국원자력의학원 Ｃｄｋ11ａ를 측정하는 제제를 포함하는 방사선 저항성 또는 민감성 진단용 조성물 및 이의 용도

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WO2000078299A3 (fr) 2001-10-18
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AU7981100A (en) 2001-01-09
GB9904932D0 (en) 1999-04-28

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