Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-08-28
2002-12-10
Dentz, Bernard (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S276100
Reexamination Certificate
active
06492398
ABSTRACT:
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-paimar 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.
BACKGROUND OF THE INVENTION
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, Bik, BRaf, Brk, Btk, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, cfms, c-fms, c-kit, c-met, cRaf1, CSF1R, CSK, c-src, EGFR, ErbB2, ErbB3, ErbB4, ERK, ERK1, ERK2, Fak, fes, FGFRI, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK4, Fps, Frk, Fyn, GSK, gsk3a, gsk3b, Hck, IGF-1R, IKK, IKK1, IKK2, IKK3, INS-R, Integrin-linkedkinase, Jak, JAK1, JAK2, JAK3, JNK, JNK, Lck, Lyn, MEK, MEK1, MEK2, p38, PDGFR, PIK, PKB1, PKB2, PKB3, PKC, PKCa, PKCb, PKCd, PKCe, PKCg, PKCI, PKCm, PKCz, PLK1, Polo-like kinase, PYK2, tie
1
, tie
2
, TrkA, TrkB, TrkC, UL13, UL97, VEGF-R1, VEGF-R2, Yes and Zap70. Protein kinases have been implicated as targets in central nervous system disorders such as Alzheimers (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
. 1991, 113, 857), and chronic obstructive pulmonary disease, bone diseases such as 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. Pharm. Exp
. Ther. 1998, 284, 687), restenosis (Buchdunger et al,
Proc, Nat Acad. Sci USA
1991, 92, 2258), autoimmune diseases and transplant rejection (Bolen and Brugge,
Ann. Rev. Immunol
. 1997, 15, 371) and infectious diseases such as viral (Littler, E.
Nature
1992, 358, 160), and fungal infections (Lum, R. T. PCT Int. Appl., WO 9805335 A1 980212).
Chemotherapeutic techniques and radiation therapy techniques are well established in the treatment of neoplastic conditions of various types. As concomitant side-effects to the administration of chemotherapy and/or radiation therapy, 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.
SUMMARY OF THE INVENTION
The present invention relates to the compound:
in one or more of the variant forms hereinafter more fully described.
In one aspect, 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 thiazoliridolinone compound, as hereinafter more fully described.
Epithelial cytotoxicity side-effects that can be preventedir educed in severity in this manner include alopecia, plantar-palmar syndrome and/or mucositis is induced by chemotherapy and/or radiation therapy.
Variant species of such thiazolindolinone compound
include the various forms, which are described in the ensuing discussion and characterised with reference to their melting points, x-ray diffraction crystallographic spectra, solubilities in solvent media, and methods of synthesis.
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 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.
Other aspects, features and advantages of the invention will be more fully apparent from the ensuing disclosure and appended claims.
DETAILED DESCRIPTION OF THE INVENTION, AND PREFERRED EMBODIMENTS THEREOF
The present invention provides a thiazolindolinone compound having various forms that are useful as cyclin dependent kinase inhibitors.
The thiazolindotinone compound has the formula:
and may be prepared in variant forms, Forms A, B and C, as described more fully hereinafter.
A generalized synthesis scheme (Scheme 1) is set out below for the thiazolindolinone compound of the invention, and is described more fully in the subsequent Examples herein.
The resulting product of such synthesis, 4-{[7-oxo-6,7-dihydro-8H-[1,3]thiazolo[5,4-e]indol-8-ylidene)methyl]amino}N-(4-pyridinylmethyl)-benzene sulfonamide, can be recovered from the synthesis reaction system and thereafter submitted to recrystallization using a specific solvent species, to yield a corresponding desired form of the compound for ultimate use, as hereinafter described.
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.
To prevent/reduce the severity of alopecia induced by chemotherapy and/or radiation therapy in a subject receiving such therapy, 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.).
For such topical application, 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. 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 lot
Dentz Bernard
Lemanowicz John L.
SmithKline Beechman Corporation
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