Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/04—Ortho-condensed systems
• • 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
• • 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
  • A61P39/00—General protective or antinoxious agents

Definitions

• the present invention relates generally to thiazolindolinone compounds having utility as cyclin dependent kinase II inhibitors useful, inter alia, for preventing/reducing the severity of epithelial cytotoxic effects (e.g., alopecia, plantar-palmar syndrome, and mucositis) incident to chemotherapy and/or radiation therapy.
• the present invention also relates to the synthesis of such compounds, and to formulations containing such compounds as pharmacological compositions for preventing/reducing the severity of epithelial cytotoxic effects in a patient subjected to corresponding 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, FL
• 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. 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.
• Chemotherapeutic techniques and radiation therapy techniques are well- established in the treatment of neoplastic conditions of various types.
• the patient may 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.
• These side-effect conditions 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 relates to the compound:
• the present invention provides a novel approach to preventing/reducing the severity of epithelial cytotoxicity side-effects of chemotherapy and/or radiation therapy, in a subject receiving such therapy, by administering to the subject an effective amount of one or more of such variant forms of the above thiazolindolinone compound, as hereinafter more fully described.
• Epithelial cytotoxicity side-effects that can be prevented/reduced in severity in this manner include alopecia, plantar-palmar syndrome and/or mucositis induced by chemotherapy and/or radiation therapy.
• the invention also relates in another aspect to methods for preparing various forms of such thiazolindolinone compound.
• a further aspect of the invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising (a) at least one of the aforementioned forms of such thiazolindolinone compound, in an amount that is effective in preventing/reducing the severity of epithelial cell toxicity side effects induced by the administration of chemotherapy and/or radiation therapy, and (b) one or more pharmaceutically acceptable carriers, excipients or diluents.
• the present invention provides a thiazolindolinone compound having various forms that are useful as cyclin dependent kinase inhibitors.
• the thiazolindolinone compound has the formula:
• the resulting form of the compound 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 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 thiazolindolinone compound of the invention in a suitable variant form 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 CDK2 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), with the amount of the compound being 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 thiazolindolinone compound may be constituted and administered in any other 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 formulated 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 used 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, the entire disclosure of which is incorporated herein by reference.
• 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 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 prevention/reduction in 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 50 to about 200 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 therapy-induced 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 cycle by inhibition of cyclin dependent kinase II activity.
• the inhibitor agent formulated in a suitable topically administerable formulation, may be applied 1-2 times or more per chemotherapeutic cycle prior to and during the time of administration of chemotherapy, in one preferred specific embodiment.
• cyclin dependent kinase II 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 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 in a suitable variant form, may correspondingly be formulated for topical administration to prevent/reduce the severity of plantar/palmar syndrome, in 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 preferably formulated for topical administration to the oral cavity mucosa, in a mouthwash, lozenge or lollipop.
• the thiazolindolinone compound of the present invention has the ability to crystallize in more than one form, a characteristic known as polymorphism, and all such polymorphic forms (“polymorphs”) are encompassed within the scope of the invention.
• Polymorphism generally can occur as a response to changes in temperature or pressure or both, and can also result from variations in the crystallization process.
• Polymorphs can be distinguished by various physical characteristics, and typically the x-ray diffraction patterns, solubility behavior, and melting point of the compound are used to distinguish polymorphs.
• the phrase "in the vicinity of in reference to a specified value of melting point temperature means a temperature (measured in degrees Centigrade) in the range of the specified value + 2°C.
• Recrystallization procedures for the respective forms were carried out in each case with the compound being dissolved in the selected solvent and stored at ambient temperature (e.g., 25°C) until the solvent evaporated. The solid residue was then analyzed by x-ray diffraction.
• the compound was dissolved in a selected solvent at 25°C, and water or alcohol was added to precipitate a solid.
• the solid was analyzed by x-ray diffraction.
• the powdered compound was sprinkled on a quartz zero background plate and scanned from 5-40° 2-Theta using a Scintag PADV or XDS2000.
• Form A Specific forms of the thiazolindolinone compound of the invention illustratively described hereinafter are denoted for ease of reference as Form A, Form B and Form C, respectively.
• Form A Specific forms of the thiazolindolinone compound of the invention illustratively described hereinafter are denoted for ease of reference as Form A, Form B and Form C, respectively.
• Form A is a thiazolindolinone compound with the formula:
• the melting point of Form A determined by the previously described melting point determination procedure is 235°C.
• X-ray diffraction characterisation of Form A showed such polymorph to have the x-ray diffraction spectra shown in Figure 1 (spectra A1 and curve A2), wherein the respective curves are generated from different lots of the compound.
• X-ray diffraction values of Form A are tabulated below in Table I.
• Form B is a thiazolindolinone compound with the formula:
• the melting point of Form B determined by the previously described melting point determination procedure is 247°C.
• Form C is a thiazolindolinone compound with the formula:
• the melting point of Form C determined by the previously described melting point determination procedure is 243°C.
• X-ray diffraction characterization of Form C showed such form of the compound to have the x-ray diffraction spectra shown in Figure 2 (curve C).
• X-ray diffraction values for Form C are tabulated below in Table III.
• Table III X-ray diffraction characteristics for Form C: 2-Theta and Relative Intensity Values
• Example 1 Preparation of 4-amino-N-(4-aminomethylpyridinyl) benzene- sulfonamide.
• DMSO dimethylsulfoxide
• DMF dimethylformamide
• PEG 400 polyethylene glycol having a molecular weight of 400
• PXRD powder x-ray diffraction.

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• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
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• 1999
  • 1999-03-04 GB GBGB9904930.6A patent/GB9904930D0/en not_active Ceased
• 2000
  • 2000-03-01 JP JP2000602239A patent/JP2003532620A/ja active Pending
  • 2000-03-01 HU HU0200376A patent/HUP0200376A3/hu unknown
  • 2000-03-01 TR TR2001/02557T patent/TR200102557T2/xx unknown
  • 2000-03-01 CN CN00804616A patent/CN1355807A/zh active Pending
  • 2000-03-01 AU AU36110/00A patent/AU3611000A/en not_active Abandoned
  • 2000-03-01 KR KR1020017011094A patent/KR20020005606A/ko not_active Application Discontinuation
  • 2000-03-01 CA CA002361580A patent/CA2361580A1/en not_active Abandoned
  • 2000-03-01 MX MXPA01008910A patent/MXPA01008910A/es not_active Application Discontinuation
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• 2001
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• 2002
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