JP2003502362A - Compositions and methods for preventing / reducing the severity of side effects of chemotherapy and / or radiation therapy - Google Patents

Abstract

  (57) [Summary] Compositions and methods for preventing / reducing the severity of epithelial cytotoxic side effects such as alopecia, plantar-palm syndrome, and / or mucositis in patients undergoing chemotherapy and / or radiation therapy. And co-administering an effective amount of a cyclin dependent kinase II inhibitor.

Description

Detailed Description of the Invention

The present invention generally relates to alopecia, plantar-palmar syndrome.
And / or cyclin-dependent kinase II inhibitor compounds useful as pharmacological compounds to prevent / reduce the severity of epithelial cytotoxic side effects of chemotherapy and / or radiotherapy such as mucositis. The invention also relates to a corresponding method of preventing / reducing the severity of the above side effects by administering a pharmacological compound as described above to a patient undergoing treatment with chemotherapy and / or radiation therapy.

BACKGROUND Protein kinases invention plays an important role in the control of cell growth and differentiation, are important mediators of cell signaling that produce growth factors and cytokines. See, for example, Schlessinger and Ullrich, Neuron 1992, 9, 383. A partial, non-limiting list of such kinases is 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, cRaf1, CSF1R, CSK, c-src
, EGFR, ErbB2, ErbB3, ErbB4, ERK, ERK1, ERK2, Fak, fes, FGFR1, FGFR2, FG
FR3, FGFR4, FGFR5, Fgr, FLK-4, Fps, Frk, Fyn, GSK, gsk3a, gsk3b, Hck, IG
F-1R, IKK, IKK1, IKK2, IKK3, INS-R, integrin-binding kinase, Jak, JAK1
, JAK2, JAK3, JNK, JNK, Lck, Lyn, MEK, MEK1, MEK2, p38, PDGFR, PIK, PKB1
, PKB2, PKB3, PKC, PKCα, PKCβ, PKCδ, PKCε, PKCγ, PKCλ, PKCμ, PKC
ζ, PLK1, Polo-like kinase, PYK2, tie1, tie2, TrkA, TrkB, TrkC, UL13, UL97
, VEGF-R1, VEGF-R2, Yes, and Zap70. Protein kinase
Alzheimer's disease (Mandelkow, EM et al. FEBS Lett. 1992, 314, 315; Sengu
pta, A. et al. Mol. Cell. Biochem. 1997, 167, 99), sensation of pain (Yashpal, K
.J. Neurosci. 1995, 15, 3263-72), inflammatory diseases such as arthritis (Badger, J. Ph.
arm. 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, AC
et al. Biochem. Biophys. Res. Commun. 1995, 210, 738), vascular 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 organ transplant rejection (Bol.
en and Brugge, Ann. Rev. Immunol. 1997, 15, 371), and viral infections.
(Littler, E. Nature 1992, 358, 160) and fungal infections (Lum, RT PCT Int.
It has been implicated as a target in diseases of the central nervous system such as infectious diseases such as Appl., WO 9805335 A1 980212).

Chemotherapy and radiotherapy techniques are fully established in the treatment of various types of neoplastic diseases. As a side effect with the application of chemotherapy and / or radiation therapy, patients generally experience severe epithelial cytotoxicity of the host. Chemotherapy-induced damage to the proliferating epithelium often results in hair loss (alopecia), plantar-palmar syndrome, and mucositis. In particular, mucositis can be of varying severity depending on the type, dosage and regimen of the respective chemotherapy and / or radiation therapy involved.

SUMMARY OF THE INVENTION The present invention provides for the treatment of alopecia, plantar-palm in such patients by administering to a patient undergoing chemotherapy and / or radiation therapy an effective amount of a cyclin dependent kinase II inhibitor. Provided are novel methods of preventing / reducing the severity of epithelial cytotoxic side effects such as plantar-palmar syndrome and / or mucositis.

A wide variety of specific cyclin dependent kinase inhibitors II used in the broad practice of the present invention are described in further detail below.

The cyclin dependent kinase inhibitor is preferably administered non-systemically to the patient, more preferably locally.

A cyclin-dependent kinase II inhibitor is used for the purpose of preventing / reducing the severity of alopecia that often occurs in chemotherapy and / or radiation therapy, by treating the inhibitor compound or a prescription containing the same with the alopecia of hair loss. It can be given locally by administration to an easily accessible part of the body. For example, a topical formulation included in an effective amount can consist of a cyclin-dependent kinase II inhibitor, which is then administered to the patient's scalp and / or facial area to provide a chemo Hair loss, which is likely to occur with therapy and / or radiation therapy, can be performed.

In order to prevent / reduce the severity of the plantar-palm syndrome that often occurs with chemotherapy and / or radiation therapy, cyclin-dependent kinase II inhibitors are used as a symptom associated with such therapeutic treatment to treat injury. It can be administered locally to the prone part of the plantar and / or palm.

In the prevention / alleviation of the severity of mucositis, which is a side effect of chemotherapy and / or radiation therapy, topical administration of cyclin-dependent kinase II inhibitors to the oral and throat mucosa preferable.

A combination therapy according to one aspect of the present invention provides a patient undergoing chemotherapy and / or radiation therapy according to a selected dosing regimen effective to prevent / alleviate more than one of the above-mentioned side effects. A cyclin-dependent kinase II inhibitor can be administered at the same time. Such administration is preferably non-systemic and is typically applied to the head, which is prone to hair loss or prone to baldness, and is typically plantar-the sole of the foot prone to palm injury or prone to tendencies and tendencies. It is applied to the palm area and / or is typically administered to the oral mucosa in the areas of the mouth and throat where mucositis is prone or prone to develop.

In another aspect, the present invention provides, in another aspect, epithelial cytotoxic side effects that tend to occur with the treatment of chemotherapy and / or radiation therapy, such as alopecia, plantar-palm syndrome and / or
Alternatively, it relates to a cytoprotective composition for preventing / reducing the severity of mucositis. Such compositions are suitably formulated to comprise an effective amount of a cyclin dependent kinase II inhibitor to prevent / alleviate the severity of epithelial cytotoxic side effects of chemotherapy and / or radiation therapy. . The composition can be formulated for such purposes with one or more pharmaceutically acceptable carriers, excipients or diluents.

Other aspects and features of the invention will be more fully apparent from the ensuing disclosure and claims.

Detailed Description of the Invention and Preferred Embodiments of the Invention The present invention comprises the administration of an effective amount of a cyclin-dependent kinase II inhibitor to a patient undergoing chemotherapy and / or radiation therapy in this patient. Methods and compositions for preventing / reducing epithelial cytotoxic side effects such as alopecia, plantar-palm syndrome and / or the severity of mucositis are provided.

Cyclin-dependent kinase II (hereinafter sometimes referred to as “CDK2”) is a protein serine / threonine kinase required for cell development through the G1 and S phases of the cell cycle. Inhibition of CDK2 in normal cells results in a reversible arrest of the cell cycle, and development during the cell cycle can protect the cells from anti-tumor compounds with cytotoxic effects. The present invention utilizes this feature.

In a preferred embodiment of the invention, the inhibitor of CDK2 is typically a scalp to prevent hair loss, which is one of the most common and distressing side effects of chemotherapy and / or radiation therapy, It is sometimes applied to other hairy parts. By delivering the CDK2 inhibitor directly to the target of the pores, systemic exposure of this compound is minimized and does not diminish the antitumor effect of the chemotherapeutic agent.

In another aspect of the invention, the CDK2 inhibitor is typically applied to the patient's hands and / or feet to prevent / alleviate the severity of plantar-palm syndrome, and / or It is typically applied to the oral and throat mucous membranes of the mouth to prevent / reduce the severity of mucositis that tends to occur with treatment with chemotherapy and / or radiation therapy.

The cyclin-dependent kinase II inhibitor of the present invention is a cyclin-dependent kinase II.
Any suitable compound having an activity-inhibiting effect, ie alopecia, plantar-palm syndrome and / or mucous membrane, which suppresses or ameliorates cyclin-dependent kinase II activity and tends to occur in treatment with chemotherapy and / or radiation therapy. It is a compound effective in preventing / reducing the severity of epithelial cytotoxic side effects such as flames.

Use in the broad practice of the present invention to prevent / reduce the severity of epithelial cytotoxic side effects of chemotherapy and / or radiation therapy such as alopecia, plantar-palm syndrome and / or mucositis. Representative cyclin-dependent kinase II inhibitors that can be, include cyclin-dependent kinase II inhibitor compounds described in the following documents and documents identified in the following references, the content of the above documents , Incorporated herein by reference as part of its disclosure. (A) “Substituted Oxindole Derivatives” Substituted oxindole derivatives described in International Patent Application No. PCT / EP98 / 05559 filed on September 3, 1998, (B) CNRS Center Natural Research International Publication No. WO97 / 20842 Purine Derivatives, (C) Ciba-Geigy (Novartis) International Publication No. WO95 / 09852, Pyridylpyrimidineamine Derivatives, (D) CV Therapeutics International Publication No. WO98 / 05335 2.
6,9-trisubstituted compounds, (E) 4H-1- as described in Hoechst AG German Patent 3836676
Benzopyran-4-one derivatives, (F) US Pat. No. 5,705,350 and US Pat. No. 5,849,7
2-thiol and 2-oxo-flavopiridol analogues described in US Pat. No. 33, (G) Warner Lambert Company International Publication WO98 / 33798, and US Pat. Nos. 5,776,942, 5 , 733, 913, No. 5,223,
No. 503, No. 4,628,089, No. 4,536,575, No. 4,431
805, and pyrido [2,3-D] described in 4,252,946.
Pyrimidines and 4-aminopyrimidines, (H) Antiviral CDK2 inhibitor compounds described in International Publication WO98 / 39007 of the University of Texas, (I) International Publication WO97 / 27297 of Mitotix Inc. Chimera C described in the book
DK2 inhibitor, (J) Imbach, P., et al., “2,6,9-trisubstituted Purines: Optimization of 2,6,9-trisubstituted purines: extremely potent and selective CDK2 inhibitors Towards
Highly Potent and Selective CDK1 Inhibitors) '', Bioorganic and Medicinal
Chemistry Letters, 9 (1999), 91-96, 2,6,9-trisubstituted purines, (K) KR Webster, et al., US Pat. No. 5, issued on April 29, 1997.
, 625, 031, (L) US Pat. No. 5,8, issued to Viktor J. Dzau on October 13, 1998.
No. 21,234, CDK2 inhibitor antisense sequences, (M) Legraverend, M., et al., "Synthesis of C2 alkynylated purines, a novel group of potent inhibitors of cyclin-dependent kinases ( Synthesis of C2 Alkynylated
Purines, a New Family of Potent Inhibitors of Cyclin-Dependent Kinases)
, Bioorganic & Medicinal Chemistry Letters 8 (1998), 793-798.
2. Alkynylated purines, and (N) Legraverend, N., et al. “Inhibition of Cdk2 activation by selected tyrphosphines causes cell cycle arrest in late G1 and S phases (Inhibition
of Cdk2 Activation by Selected Tyrphostins Causes Cell Cycle Arrest at L
ate G1 and S Phase), Experimental Cell Research 241, 340-351 (1998).

In addition to the use of certain compounds shown to be CDK2 inhibitors, the present invention provides pharmaceutically acceptable salts, solvates, biohydrolyzable salts in crystalline or amorphous form. Carbonate, biohydrolyzable ureido, biohydrolyzable ester, biohydrolyzable amide,
It also extends to the use of biohydrolyzable carbamates, affinity reagents or prodrugs thereof.

The therapeutic compositions of the present invention may include one or more cyclin dependent kinase II inhibitor compounds as appropriate to achieve the desired effect in a given end use of the present invention.

The types of compounds that can be effectively used in the practice of the present invention are described in International Patent Application PC
T / EP98 / 05559, the content of which is incorporated herein by reference in its entirety. This kind of thing
Formula (A)

[Chemical 12] (In the above formula,   X is N, CH, CCF_Three, Or C (C_1-12(Aliphatic),   R¹Is hydrogen, C_1-12Aliphatic, thiol, hydroxy, hydroxy-C_{1 to 12} Aliphatic, Aryl, Aryl-C_1-12Aliphatic, R⁶-ArylC_{1-1 Two} Aliphatic, Cyc, Cyc-C_1-6Aliphatic, Het, Het-C_1-12fat
Tribe, C_1-12Alkoxy, Aryl oxy, amino C_1-12Aliphatic amino,
The-C_1-12Aliphatic amino, di-C_1-12Aliphatic aminocarbonyl, di-C _1-12 Aliphatic aminosulfonyl, C_1-12Alkoxycarbonyl, halogen
(Eg, fluoro, bromo, iodo), cyano, sulfonamide, or nit
B, R⁶, Aryl, Cyc and Het are as defined below.
Selected from the group consisting of   R^TwoIs hydrogen, C_1-12Aliphatic, N-hydroxyimino-C_1-12Aliphatic,
C_1-12Alkoxy, hydroxy-C_1-12Aliphatic, C_1-12Alkoxy
Carbonyl, carbonyl C_1-12Aliphatic, Aryl, R⁶-Aryl-oxy
Carbonyl, R⁶-Oxycarbonyl-Aryl, Het, aminocarbonyl,
C_1-12Aliphatic-aminocarbonyl, Aryl-C_1-12Aliphatic-Aminoca
Lebonil, R⁶-Aryl-C_1-12Aliphatic-aminocarbonyl, Het-C _1-12 Aliphatic-aminocarbonyl, hydroxy-C_1-12Aliphatic-Aminoca
Lubonyl, C_1-12-Alkoxy-C_1-12Aliphatic-amino, di-C_{1-1 Two} Aliphatic amino, di-C_1-12Aliphatic aminocarbonyl, di-C_1-12fat
Group aminosulfonyl, halogen, hydroxy, nitro, C_1-12Aliphatic-sul
Honyl, aminosulfonyl, and C_1-12Aliphatic-aminosulfonyl
Selected from the group consisting of Aryl and Het as defined below.
Is   R¹And R^TwoAre optionally combined as defined below for Het
Forming a fused ring selected from the group of:_1-12Fat
Aliphatic, halogen, nitro, cyano, C_1-12-Alkoxy, amino, hydroxy
Sill, Carbo-C_1-12-Substituted by alkoxy or oxo,   R^ThreeIs hydrogen, C_1-12Aliphatic, hydroxy, hydroxy C_1-12Aliphatic,
The-C_1-12Aliphatic amino, di-C_1-12Aliphatic aminocarbonyl, di-C _1-12 Aliphatic aminosulfonyl, aminosulfonyl, C_1-12-Alkoxy
, Aryl, Aryl oxy, hydroxy-Aryl, Het, hydroxy-H
selected from the group consisting of et, Het-oxy, or halogen, provided that Ary
l and Het are as presented below,   Furthermore R^TwoAnd R^ThreeIs sometimes combined and defined for Het below.
Form a fused ring selected from the group consisting of_1-6 Aliphatic or C_1-6Aliphatic-substituted by carbonyl,   However, R¹, R^TwoAnd R^ThreeCannot be hydrogen at the same time,   R^FourIs sulfonic acid, C_1-12Aliphatic-sulfonyl, sulfonyl-C_1-12 Aliphatic, C_1-6Aliphatic-amino, R⁷-Sulfonyl, R⁷-Sulfonyl-C_{1 ~ 12} Aliphatic, R⁷-Aminosulfonyl, R⁷-Sulfonylamino-C_1-12 Aliphatic, aminosulfonylamino, di-C_1-12Aliphatic amino, di-C_{1-1 Two} Aliphatic aminocarbonyldi-C_1-12Aliphatic aminosulfonyl, di-C_{1 to 12} Aliphatic amino, di-C_1-12Aliphatic aminocarbonyl, di-C_1-12Fat
Aliphatic aminosulfonyl-C_1-12Aliphatic, (R⁸)_1-3-Aryl amino,
(R⁸)_1-3-Aryl sulfonyl, (R⁸)_1-3-Aryl aminosulfo
Nil, (R⁸)_1-3-Aryl sulfonylamino, Het-amino, Het-
Sulfonyl, Het-aminosulfonyl, aminoiminoamino, or aminoimine
Minoaminosulfonyl, wherein R⁷, R⁸, Aryl and Het are determined below
Selected from the group consisting of what is justified,   R⁵Is hydrogen,   Furthermore, R^FourAnd R⁵Is optionally combined and defined for Het below
Forming a fused ring selected from the group consisting of
C_1-12Substituted by aliphatic, oxo or dioxo,   R⁶Is C_1-12Aliphatic, hydroxy, C_1-12-Alkoxy, or halo
Selected from the group consisting of Gen,   R⁷Is hydrogen, C_1-12Aliphatic, C_1-12-Alkoxy, hydroxy-C_{1 ~ 12} Alkoxy, hydroxy-C_1-12Aliphatic, carboxylic acid, C_1-12Fat
Aliphatic-carbonyl, Het, Het-C_1-12Aliphatic, Het-C_1-12−
Alkoxy, di-Het-C_1-12-Alkoxy, Aryl, Aryl-C_{1 ~ 12} Aliphatic, Aryl-C_1-12-Alkoxy, Aryl-carbonyl, C _1-18 Alkoxyalkoxyalkoxyalkoxy aliphatic or hydroxy
A group of Het and Aryl as defined below.
Selected from   R⁸Is hydrogen, nitro, cyano, C_1-12-Alkoxy, halo, carbo-C_{1 ~ 12} -Alkoxy, and halo-C_1-12Selected from the group consisting of aliphatic,   Aryl is derived from phenyl, naphthyl, phenanthryl, or anthracenyl.
Selected from the group   Cyc is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Selected from the group consisting of cycloheptyl, and cyclooctyl, optionally
Has a degree of unsaturation of 1 or more,   Het is benzimidazole, dihydrothiophene, dioxine, dioxane
, Dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan,
Imidazole, isoquinoline, morpholine, oxazole, oxadiazole,
Oxathiazole, oxathiazolidine, oxazine, oxadiazine, pipera
Gin, piperidine, pyran, pyrazine, pyrazole, pyridine, pyrimidine, pi
Roll, pyrrolidine, quinoline, hitorahydrofuran, tetrazine, thiadiadi
, Thiadiazole, thiatriazole, thiazine, thiazole, thiomorpholi
From the group consisting of amines, thiophenes, thiopyrans, triazines, and triazoles
Selected) And a pharmaceutically acceptable salt thereof in crystalline or amorphous form,
Stells, amides, carbamates, solvates, hydrates, affinity reagents and
Comprises a prodrug. Esters, amides and carbamates are preferred
Is hydrolyzable, and more preferably biohydrolyzable.

Representative types of cyclin-dependent kinase II inhibitors that are effectively used in the practice of the present invention are within the range of formula (A) above ((A1), (A2) and (A3, respectively). )) Compounds.

[Chemical 13]

Next, the CDK2 inhibitor compound selected for use in a given application of the method of the invention is treated with chemotherapy and / or co-administration to a patient (eg, a mammalian patient, such as a human patient). The purpose of local or other non-systemic administration to a patient to prevent / reduce the severity of radiation-induced epithelial cytotoxic side effects (eg, alopecia, plantar-palm syndrome, and / or mucositis). Can be formulated as the active ingredient of a pharmaceutically acceptable composition.

To prevent / reduce the severity of alopecia induced by such therapy in patients undergoing chemotherapy and / or radiation therapy, a CDK2 inhibitor compound is preferably prone to hair loss, such as in the head Topical administration to body parts (eg, scalp, eyebrows, beards and mustaches).

For such topical administration, a cyclin-dependent kinase II inhibitor compound is combined with a pharmaceutically acceptable vehicle (carrier, diluent or excipient) of choice and formulated for topical administration. When formulated into a drug and administered according to an appropriately designed therapeutic regimen, the amount of compound in the drug can be sufficient to prevent / reduce the severity of the side effects of alopecia. . The formulation can be in any useful dosage unit form for comparable administration.

Formulations of thiazole-oxindole compounds are liquid formulations for aerosolized administration to the head of patients susceptible to chemotherapy-induced hair loss, or heads in contact with susceptible areas. In releasable form for placement in
It can be constructed and administered in any suitable manner, such as by dermal patch or dressing containing a CDK2 inhibitor compound.

Alternatively, the formulation is a lotion, ointment, gel, foam, paste, oil,
Prepared as a cream or other suitable form and administered to a suitable body part, such as the scalp or other parts of the head, for the purpose of preventing / reducing the severity of hair loss, followed by massage and brushing after the first administration Or, the toothing can be performed and the prescription agent can be evenly distributed on the scalp to even out the therapeutic effect.

One example of a composition that can be used for topical administration of the CDK2 inhibitor compounds of the present invention to a site on the body of a patient undergoing chemotherapy and / or radiation therapy is Ta
ka, S., et al., "Relative Influence of Ethanol and P
ropylene Glycol Cosolvents on Deposition of Minoxidil into the Skin), ''
Journal of Pharmaceutical Sciences, Vol. 83, No. 10, October 1994, pp. 1
Formulations of the type described in 508-1510 can be used. Such a formulation may comprise 2% of the active ingredient in 60% ethanol, 20% propylene glycol and 20% water for topical administration of the solution to the scalp.

Still other prescription agents that can be effectively used for topical administration of the CDK2 inhibitor compound of the present invention include US Pat. Nos. 5,849,733, 5,807,698 and 5,625. , 031 and 5,486,509, the contents of which are incorporated herein by reference.

Another example of a formulation that can be effectively used for topical administration of the CDK2 inhibitor compound of the present invention is Hoffman, RM, et al. Can be specifically directed to hair follicles (Liposomes Can Spe
cifically Target Entrapped Melanin To Hair Follicles in Histocultured Sk
in) '', In Vivo Cell. Dev. Biol., Vol. 29A: 192-194, March 1993, and Ni.
emiec, SM, et al. "Effect of nonionic liposome composition on local delivery of peptide drugs to the pilosebaceous unit: an in vivo study using the hamster ear model (I
nfluence of Nonionic Liposomal Composition on Topical Delivery of Peptid
e Drugs into Pilosebaceous Units: Anb in Vivo Study Using the Hamster Ea
r Model) '', Pharmaceutical Research, Vol. 12, No. 8, 1995, pp. 1184-1188.
And lipid-based formulations described in Rolland, A., et al., “Site-Specific Drug Delivery to the pilosebaceous structures using polymeric microspheres”.
ry to Pilosebaceous Structures Using Polymeric Microspheeres), Pharmac
eutical Research, Vol. 10, No. 12, 1993, pp. 1738-1744.

The formulation can be configured to provide the appropriate volume for the desired dosing regimen. Dosing and dosing regimens can be readily determined for a given patient within the skill of the art based on the characteristics of the chemotherapy and / or radiation therapy used.

Similar considerations prevent / mitigate the severity of plantar-palm syndrome, including local administration to the parts of the hands and feet susceptible to plantar-palm syndrome as a side effect of chemotherapy and / or radiation therapy. For prescribing and administering a CDK2 inhibitor.

To prevent / reduce the severity of mucositis, cyclin-dependent kinase II inhibitors can be formulated in suitable topical formulations for the purpose of application to the oral mucosa. Examples of delivery systems for cyclin-dependent kinase II inhibitors of the present invention, such as those used in the treatment of mucositis, include "Methods of Inhibiting Ulcerative Mucinitis.
Cullinan, US Pat. No. 5, issued March 5, 1996.
Formulations and delivery methods described in 496,828. Useful formulations include active ingredients formed into tablets, capsules, sprays, mouthwashes, lozenges, troches, fragrances, lollipops, suspensions, powders and the like, and excipients for application to the mucous membranes of the oral cavity. Molding agents, diluents or carriers can be included.

An acceptable daily dosage of a CDK2 inhibitor to prevent / reduce the severity of epithelial cytotoxic side effects induced by chemotherapy and / or radiation therapy is about 0.1.
To about 1000 mg / day, preferably about 0.2 to about 1000 mg / day.

A cyclin-dependent kinase II inhibitor in a preferred practice of the invention is used to protect against epithelial cytotoxic side effects that are necessarily presented at the same time as chemotherapy and / or radiation therapy (ie, in the absence of a CDK2 inhibitor). Alternatively, it is administered at the same time as, or sufficiently close to, chemotherapy and / or radiation therapy so as to obtain an improving effect. Chemotherapy and / or radiation therapy can be of any suitable type for the neoplastic disease or other disease state or condition of the patient being treated. For example, chemotherapy may include (cytosine arabinoside (ARA
It may comprise administering chemotherapeutic agents such as cycle-specific agents (such as -C) and non-cycle specific agents (such as cytoxane) individually or in combination with each other.

A cyclin-dependent kinase II inhibitor according to one aspect of the present invention is used to treat epidermal cells such as alopecia, plantar-palm syndrome and / or mucositis in patients receiving Kaga chestnut and / or radiation therapy. It is administered 1 to 4 times in the chemotherapy cycle as a cytoprotective composition to prevent / reduce the severity of toxic side effects.

In a particular application for the prevention / alleviation of the severity of alopecia induced by chemotherapy,
Inhibition of cyclin-dependent kinase II activity desirably arrests the hair follicle cell cycle. To this end, the inhibitor, formulated in a suitable topically administrable formulation, is administered, in one particular preferred illustrative embodiment, 1-2 times per chemotherapy cycle prior to and during chemotherapy. Can be applied.

In a preferred embodiment of the present invention, a cyclin-dependent kinase II inhibitor that can be administered locally to prevent / reduce the severity of alopecia induced by chemotherapy is characterized by the following characteristics (1) IC50 for CDK2: A value of less than 2.5 nanomolar, preferably less than 20 nanomolar, (2) an IC50 value in the G1 checkpoint assay of less than 1.5 micromolar, preferably less than 5 micromolar, (3) at least two types Of the cytotoxic regimen of which one comprises an alkylating agent (eg doxorubicin / cyclophosphamide (anthracycline / alkylating agent), etoposide (topoisomerase II inhibitor)
, Taxol, etc.), a reproducible indication of protection in a rat rat alopecia model, (4) at a local dose of 10 mg / kg of subject body weight, plasma concentration is less than 15 nanomolar, preferably for protection of the HT29 tumor cell line. Therefore, systemic exposure should be an IC50 concentration of less than 0.01, (5) an acceptable skin irritation profile, and (6) one or more of the suitability (with regard to miscibility, bioavailability, etc.) for the particular topical formulation used. Evaluate effects based on and select for use.

The compounds of the present invention are formulated for topical administration to patients undergoing chemotherapy and / or radiation therapy in any suitable manner, including appropriate dosages and treatment regimens, to achieve foot / palm syndrome Severity can be prevented / reduced.

To prevent / alleviate the severity of mucositis in patients undergoing chemotherapy and / or radiation therapy, the compounds of the invention in a suitable form are most preferably administered by mouth rinse, lozenge or lollipop. Formulated for topical administration to mucosa.

The present invention can be practiced with a wide variety of CDK2 inhibitor compounds, some of which are described in further detail below.

One class of compounds that can be effectively used in the practice of the present invention is the following formula (B)

[Chemical 14] C2 alkynylated purines, such as the CDK2 inhibitor compounds of E. coli, and their other saturated derivatives, R is Legraverend, M., et al., “Synthesis of C2 alkynylated purines, a potent cyclin-dependent kinase A new family of inhibitors (Synthesis of C2 Alkynylat
ed Purines, a New Family of Potent Inhibitors of Cyclin-Dependent Kinase
s) '', Bioorganic & Medicinal Chemistry Letters 8 (1998) 793-798, as described in more detail below.

[Chemical 15] Can comprise substituents such as

Other purine compounds that can be effectively used in the broad practice of the present invention include:
"Novel Purine Derivatives With Especially Antiproliferative Properties, And Their Biological Uses"
(NOVEL PURINE DERIVATIVES HAVING, IN PARTICULAR, ANTIPROLIFERATIVE PROPE
RTIES, AND BIOLOGICAL USES THE REOF) '' (CENTRE NATIONAL DE LA RECHERCHE SC
IENTIFIQUE (CNRS)), which is disclosed in International Publication No. WO97 / 20842, published on June 12, 1997, including 2-, 6-
-And 9-substituted purine derivatives, such as 2- (1-R-hydroxymethylpropylamino) -6-benzylamino-9-isopropyl-purine, and the formula is

[Chemical 16] and

[Chemical 17] , Roscovitine, olomoucine, etc. are described.

Another class of CDK2 inhibitor compounds that can be effectively used in the practice of the present invention is, for example, compounds of the formula:

[Chemical 18] (In the above formula, X is oxygen or sulfur, R ¹ is hydrogen, alkyl, aryl, arylalkyl, cycloalkyl,-(
_{^{CH 2) q -NR 7 R 8}} , alkylcarbonyl, arylcarbonyl, arylalkyl carbonyl, alkoxycarbonyl, aryl alkyloxycarbonyl or aryloxycarbonyl,, ^{R 2} is hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, Hydroxy, alkoxy, arylalkoxy, aryloxy, alkylcarbonyloxy, arylalkylcarbonyloxy, arylcarbonyloxy, carboxy, alkyloxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl, amino, -NR ⁷ R ⁸ , thiol, alkylthio, aryl. Alkylthio or arylthio, R ³ is alkyl, cycloalkyl, aryl, arylalkyl, heterocycle,
Or heterocycloalkyl, R ⁴ is hydrogen, alkyl, aryl, arylalkyl, nitro, amino,-(
_{^{CH 2) p -NR 7 R 8}} , halogen, hydroxy, alkoxy, carboxy, a heterocyclic or alkyloxycarbonyl,, ^{R 5} is hydrogen, alkyl, arylalkyl, aryl, cycloalkyl, hydroxy, alkoxy, arylalkoxy, Aryloxy, alkylcarbonyloxy, arylalkylcarbonyloxy, arylcarbonyloxy, carboxy, alkyloxycarbonyl, arylalkoxycarbonyl, cyano, nitro, —NR ⁷ R ⁸ , halogen, alkylhalo, —CHO, alkylS (O
) _M -, or -OC (O) a ^NR 7 ^{R 8, R 6} is hydrogen, alkyl, arylalkyl, aryl, cycloalkyl, hydroxy, alkoxy, arylalkoxy, aryloxy, alkylcarbonyloxy, aryl alkylcarbonyloxy , arylcarbonyloxy, carboxy, alkyloxycarbonyl, aryl alkoxycarbonyl, amino, cyano, nitro, ^-NR 7 ^{R 8,} halogen, alkylhalos, -CHO, alkyl S _{(O) m} - or -OC (O) NR ^7, R ^{8, NR} 7 ^{R 8,} thiol, alkylthio, aryl alkyl thio or arylthio,, ^{R 7} and ^{R 8} are independently hydrogen, alkyl, aryl, arylalkyl,
Cycloalkyl, heterocycle, or alkylcarbonyl, or R ⁷ and R ⁸ can form, together with the nitrogen atom to which they are attached, a heterocycle, m is an integer from 0 to 2 Wherein n is an integer from 0 to 3, p is an integer from 1 to 3 and q is an integer from 2 to 5) 2-thio or 2-oxo flavopyridol analogues such as Is mentioned.

Such flavopiridol derivatives are disclosed in US Pat. No. 5,849,733 and International Publication No. WO 97/42949 published on Nov. 20, 1997.
Specification "2-thio or 2-oxo flavopiridol analogue (2-THIO OR 2-OXO
FLAVOPIRIDOL ANALOGS) "(BRISTOL-MYERS SQUIBB COMPANY).

[0046]   Another example of a class of CDK2 inhibitor compounds is the formula

[Chemical 19] (In the above formula,   X is O, S or CHR_x(However, R_xIs H or C_1-4Is alkyl)
And D is H, halo, or NZ₁Z_Two(However, Z₁And Z_TwoRespectively
Independently H or C_1-4Alkyl or C_1-4Hydroxy alk
And A is H, C_1-4Alkyl, C_1-4Alkoxy, hydroxy
Si, CH_Two(CH_Two)_nOH (n = 1 to 4), and NR_a1R_a2(However, R _a1 And R_a2Are each independently H or C_1-4Is alkyl)
Selected, B is H, C_1-4Alkyl, C_1-4Alkoxy, CF_Three, In some cases
Substituted aryl (eg, phenyl) or an optionally substituted aryl
Ralalkyl (eg, benzyl), and hydroxy that provide the C = O tautomer.
Selected from the groups, Y being an optionally substituted 4- to 8-membered carbocycle or heterocycle
Linear or branched, which is or contains a ring, or is optionally substituted
Comprising a hydrocarbon chain) Compounds of

Such purine derivatives are disclosed in “CYCLIN DEPENDENT KINASE INHIBITING PURINE” published on January 21, 1999.
DERIVATIVES) "(NEW CASTLE UNIVERSITY VENTURES LIMITED) in International Publication No. WO 99/02162.

Another class of CDK2 inhibitor compounds useful in preventing epithelial cytotoxicity prone to chemotherapy and / or radiation therapy according to the present invention is August 6, 6
"PyRIDO [2,3-D] PYRIMIDINES AND 4-AMINOPYRIMIDINE as inhibitors of cell proliferation
S AS INHIBITORS OF CELLULAR PROLIFERATION) "(WARNER LAMBERT COMPANY) and the compounds described in International Publication No. WO98 / 33798.
This specification describes 7,8-dihydro-2- (amino and thio) pyrido [, which are potent inhibitors of cyclin-dependent kinases (cdks) and growth factor-dependent kinases.
2,3-d] pyrimidines and 2,4-diaminopyrimidines are disclosed,
It has been described to be useful in the treatment of cell proliferative disorders such as cancer and restenosis. Such compounds have the formulas D1 and D2 below:

[Chemical 20] and

[Chemical 21] (Wherein W is NH, S, SO or SO ₂ , R ¹ 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, and Z is carboxy).

Another category of compounds that can be effectively used in the practice of the present invention is:
The 4H-1-benzopyran-4-one derivatives described in German Patent DE 38366676 (Hoechst AG) are mentioned.

As another kind of CDK2 inhibitor compound, “Inhibition of Cdk2 activation by selected tyrphosphines causes inhibition of cell cycle in late G1 and S phase (Inhibition of Cdk2 Activation by Selected Tyrphostins Causes Cell C
ycle Arrest at Late G1 and S Phase), Experimental Cell Research 241, 3
40-351 (1998) and tyrphostins such as tyrphostins from AG555 / AG494.

Still another CDK2 inhibitor that can be effectively used in the practice of the present invention is 19
International Publication No. WO 98/05335, published on February 12, 1998, purine inhibitors of cyclin dependent kinases 2 and 1 (PURIN INHIBITORS OF CYCLIN
DEPENDENT KINASE 2 AND 1) '' (CV THERAPEUTIC, INC.)

[Chemical formula 22] (In the above formula, R is halogen, XR ¹ (where X = NH, O, S, SO ₂ ; R ¹ = alkyl,
Cycloalkyl, heterocyclyl, aryl, heteroalkyl) and R ² =
H, alkyl, cycloalkyl, aryl, heteroalkyl, R ³ = halogen, OH, SH, alkoxy, alkylthio, amino, heterocyclyl linked to N), and a 2,6,9-trisubstituted purine compound. To be

Another aspect of the present invention is co-administration or alternation with previously known anti-hair loss and / or anti-mucositis therapeutic agents for more effective treatment of patients undergoing chemotherapy. For the use of CDK2 inhibitor species in.

In a specific example, a CDK2 inhibitor compound is administered to a patient undergoing chemotherapy in

[Chemical formula 23] (In the above formula, R ¹ and R ³ are independently hydrogen, —CH ₃ , —C (O) — (C _1-6 alkyl) or —C (O) —Ar, where Ar is optionally Is a substituted phenyl, R ² is selected from the group consisting of pyrrolidine, hexamethyleneamino, and piperidino), and pharmaceutically acceptable salts and solvates thereof. 5,496,
Those described in more detail in 828 may be administered at the same time as they are administered to a patient to prevent mucositis / reduce severity.

Various other co-administered active compounds can be used in combination with the CDK2 inhibitor compound (s) in the course of treatment or dosing regimens to enhance the therapeutic effect.

The term “solvate” as used herein is a variable stoichiometric complex formed by a solute and a bait. Such a solvent for the purposes of the present invention should not interfere with the biological activity of the solute. The solvent can be, for example, water, ethanol, or acetic acid.

The terms “biohydrolyzable carbonate”, “biohydrolyzable ureido”, and “biohydrolyzable carbamate” as used herein refer to the carbonate, ureido and carbamate of the CDK2 inhibitor compound, respectively. Thus, the carbonates, ureides and carbamates include those that do not completely reduce the biological activity of the parent substance. Such carbonates, ureides and carbamates can impart advantageous properties in vivo to the parent compound, such as increased duration of action, onset of action and the like. Also included are compounds that are relatively biologically inactive, but that are converted by the subject in vivo to the biologically active ingredient. The advantage of such biohydrolyzable forms is that, for example, carbonates, ureides and carbamates are more easily absorbed from the gastrointestinal tract and then converted to active compounds in plasma, facilitating improved oral administration. That is. Many examples of such biohydrolyzable compounds are known in the art and include, for example, lower alkyl carbamates.

The term “biohydrolyzable ester” as used herein is an ester of an active compound which does not completely reduce the biological activity of the parent substance. Such esters may impart advantageous properties to the parent compound in vivo, such as increased duration of action, initiation of action, and the like. Also included are esters that are relatively biologically inactive but that are converted by the subject in vivo to the biologically active ingredient.
The advantage of such biohydrolyzable forms is, for example, that they are more easily absorbed from the gastrointestinal tract and then converted to the active compound in plasma, facilitating improved oral administration. Many examples of such biohydrolyzable esters are known in the art and include, for example, lower alkyl esters, lower acyloxy-alkyl esters, lower alkoxyacyloxyalkyl esters, alkoxyacyloxy esters, alkylacylaminoalkyl esters, and Examples include choline ester.

The term “biohydrolyzable amide” as used herein is an amide of the active parent compound that does not completely reduce the biological activity of the parent compound. Such amides can impart advantageous properties in vivo to the parent compound, such as increased duration of action, onset of action, and the like. Also included are amides that are relatively biologically inactive, but that are converted by the subject in vivo to the biologically active ingredient. The advantage of such biohydrolyzable forms is, for example, that they are more easily absorbed from the gastrointestinal tract and then converted to the active compound in plasma, facilitating improved oral administration. Many examples of such biohydrolyzable amides are known in the art and include, for example, lower alkyl amides, α-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.

As used herein, the term “prodrug” is a compound that is hydrolyzable in vivo to produce an active compound, such as biohydrolyzable amides, biohydrolyzable esters, and organisms. Includes hydrolyzable carbamates and the like. The term "prodrug" also includes compounds where a biohydrolyzable functional group is included in the active compound.

The term “affinity reagent” as used herein refers to a group attached to an active compound that does not affect biological activity in vitro, which allows the active compound to bind to a target, and further The group is strongly bound to the third component and a) characterizes the target such that it is localized within the cell or other biological component, such as by visualization by fluorescence or radiography, or b) proteinaceous or It facilitates separation of targets from unknown mixtures of targets, whether proteinaceous or not. An example of an affinity reagent according to b) is C, H, O, directly attached to the active compound or in any combination.
Biotin linked using a spacer of 1 to 50 atoms selected from the group consisting of N, S, or P. An example of an affinity reagent according to a) above is of 1 to 50 atoms directly bonded to the active compound or selected from the group consisting of C, H, O, N, S or P in any combination. Fluorescein bound using a spacer.

The term “effective amount” refers to the tissue, system, which is being investigated by a researcher or clinician,
By an amount of a drug or pharmaceutical compound that elicits a biological or medical response in an animal or human. The term "therapeutically effective amount" enhances the treatment, cure, prevention or amelioration of a disease or disorder or the rate of progression of the disease or disorder as compared to a comparable subject who has not been administered such an amount. It means any amount that decreases and also includes an amount effective to enhance normal physiological function.

In the practice of the present invention, a CDK2 inhibitor compound is applied topically to a sensitive area of skin for the purpose of preventing / reducing the severity of alopecia that is likely to occur with chemotherapy and / or radiation therapy, and For the purpose of preventing / reducing the severity of mucositis, which is likely to occur in chemotherapy and / or radiation therapy, it is preferable to administer by mouthwash formulation or lozenge, but in the practice of the present invention, the CDK2 inhibitor compound is a tablet, a capsule. It can also be administered in oral (oral and sublingual) dosage forms such as pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions (such as timed-release and sustained-release formulations, respectively). Similarly, they are nose, eyes, ears,
Rectal, intravenous (bolus and infusion), intraperitoneal, intraarticular, subcutaneous or intramuscular inhalation or insufflation forms, all of which can also be administered using forms well known to those of ordinary skill in the pharmaceutical arts.

Dosing regimens using the compounds of the present invention will include patient type, species, age, weight, sex,
And the medical condition, the severity of the disease to be treated, the route of administration, the patient's renal and hepatic function,
And the particular compound used or a salt thereof. A clinician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the drug required for the treatment of alopecia and / or mucosal inflammation conditions.

Oral dosages in the practice of the present invention, when used for the suggested effects,
It ranges from about 0.01 to about 100 mg / kg body weight per day, especially about 0 per day.
． It is in the range of 1 to 10 mg / kg body weight. Oral dosage units are generally 0.1 to about 250 m
g, more preferably in the range of about 25 to about 250 mg. The daily dosage for a 70 kg mammal will generally range from about 70 mg to 7 g of the CDK2 inhibitor compound.

The dosage administered is based on the usual conditions such as the physical condition of the patient, age, weight, past medical history, route of administration, severity of symptoms. In some cases, relatively low doses may be sufficient, and in some cases, relatively high doses or increased frequency of dosing may be necessary. A typical administration can be one or more times daily depending on the route of treatment by chemotherapy and / or radiation therapy. Advantageously, the compounds of the 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 used according to the invention can be prepared in a concentration range for topical use of a suitable solvent of about 0.1 to about 5 mg / ml. The preferred volume for application to the scalp is about 2-20 ml, and the effective dosage delivered to the patient is about 0.2 to about 100 mg.

For the treatment of alopecia induced by chemotherapy, 1 to 2 prior to the administration of chemotherapy
A single dose is preferred, with further application as needed. A similar dosing regimen may be involved in the treatment of radiation-induced alopecia. In addition, the compounds of this invention may be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using the forms of transdermal patches well known to those of ordinary skill in that art. Of course, to administer in the form of a transdermal delivery system, dosing is continuous rather than intermittent.

In the method of the present invention, the compounds described in detail herein are capable of forming the active ingredient and are typically suitable for the intended dosage form, ie oral tablets, capsules, elixirs, syrups and the like. And is administered in admixture with a suitable pharmaceutical diluent, excipient or carrier (collectively referred to herein as "carrier" material) consistent with normal pharmaceutical practice.

For example, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water. Powders may be prepared by milling the compound to a suitable fine particle size and mixing with a similarly milled pharmaceutical carrier such as an edible carbohydrate, eg starch or mannitol. Seasonings, preservatives,
A dispersant and a colorant can also be included.

Capsules are manufactured by preparing a powder mixture as described above and filling shaped gelatine sheaths. After adding glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol to the powder mixture, a filling operation can be carried out. A disintegrant or solubilizer such as agar, calcium carbonate, or sodium carbonate can also be added to improve the effectiveness of the drug when inoculating the capsule.

Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners,
Mention may be made of gum arabic, gum tragacanth or natural and synthetic gums such as 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, but are not limited to, 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. The powder mixture is prepared by mixing an appropriately ground compound with a diluent or base as described above, and optionally carboxymethylcellulose, alginate, gelatin, or polyvinylpyrrolidone, a dissolution retarder such as paraffin, a quaternary salt. Resorption promoters such as and / or bentonites,
It is prepared by mixing with an absorbent such as kaolin or dicalcium phosphate. The powder mixture may be syrup, starch paste, gum arabic solution (acadia mu
cilage), or a solution of cellulosic or polymeric material, and granulated by passing through a screen. As an alternative granulation method, the powder mixture can be moved through a tablet press and the incompletely formed sludge is divided into granules. Lubricity can be imparted to the granules by adding stearic acid, stearate salts, talc or mineral oils to prevent sticking to the tableting dies. The lubricated mixture is then compressed into tablets. The compounds of the present invention may also be combined with a free flowing inert carrier and compressed into tablets directly without any granulating or slugging steps. A clear or opaque protective coating consisting of a seal coat of shellac, a coating of sugar or polymeric material, and a brightener coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.

Oral fluids such as solution, syrups and elixirs are prepared in dosage unit form,
An aliquot can include a predetermined amount of compound. Syrups can be prepared by dissolving the compound in an appropriately flavored aqueous solution, elixirs being prepared using a non-toxic alcoholic vehicle. Suspensions may be formulated by dispersing the compound in a nontoxic vehicle. Solubilizers and emulsifiers such as isostearyl alcohol and polyoxyethylene sorbitol ether, preservatives, flavoring additives such as peppermint oil, or natural sweeteners, or saccharin or other artificial sweeteners may also be added. .

When appropriate, 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.

The compounds used according to the invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

The compounds used according to the invention can also be delivered by using monoclonal antibodies as individual carriers for coupling these compound molecules. The compounds can also be coupled with soluble polymers as targetable drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamidophenol, or polyethylene oxide polylysine substituted with palmitoyl residues. In addition, these compounds represent a class of biohydrolyzable polymers useful in providing controlled release of drugs, such as polylactic acid, borebucilone caprolactone (polepsilon).
caprolactone), polyhydroxybutyric acid, polyorthoester, polyacetal,
It can be coupled to crosslinked or amphiphilic block copolymers of polydihydropyrans, polycyanoacrylates, and hydrogels.

Parenteral administration can be carried out by using liquid dosage unit forms such as sterile solutions and suspensions 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 an aqueous oil medium, and sterilizing the suspension or solution.

Alternatively, a metered amount of the compound is placed in a vial and the vial and its contents are sterilized and sealed. An accompanying vial or vehicle may be provided and mixed prior to administration. Non-toxic salts and salt solutions can be added to make the injection solution isotonic. Stabilizers, preservatives and emulsifiers can also be added.

Rectal administration may be carried out using a suppository in which the compound is mixed with a water-soluble or insoluble solid substance having a constant temperature melting property, such as polyethylene glycol, cocoa butter, a higher ester such as a flavored aqueous solution, and elixir is palmitin. Prepared with myristyl acid or a mixture thereof.

The topical formulations of the present invention may be presented as ointments, creams or lotions, eye ointments, and eye or ear drops, impregnated dressings and aerosols, preservatives, penetration-enhancing solvents, and ointments. And suitable conventional additives such as cream emollients. The formulation may also contain compatible conventional carriers, such as cream or ointment bases, and ethanol or oleyl alcohol for lotions. Such carriers may comprise, for example, from about 1% to about 98% of the formulation. More usually they will make up up to about 80% of the formulation.

For administration by inhalation, the compounds used according to the invention may be administered in a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane, heptafluoropropane, carbon dioxide, or other It is conveniently delivered in the form of an aerosol spray from pressure packs or nebulizers using suitable gases. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges such as gelatin for use in inhalation or infusion devices can be formulated containing a powder mixture of a compound of the invention with a suitable powder base such as lactose or starch.

The inhibitory activity of various exemplified compounds can be determined for CDK2 kinase by the following assay, and the inhibitory activity can also be determined for other kinases for comparison purposes (eg VEGRR2, Tie-2 and c-fms).

For the CDK1 and CDK2 cyclin dependent protein kinase assays, the peptides biotin-aminohexyl-AAKAKKTPKKAKK, and biotin-aminohexyl-A were used.
The RRPMSPKKKA-NH ₂ was used as the phosphoryl group acceptor. CDK1 and
CDK2 was expressed using the baculovirus expression system and partially purified to contain 20-80% of the total protein, and no competitive reaction was detected. Typically, enzymes with and without inhibitors (0.2-10 nM), one of two peptide bases (1-
10 nM), [γ- ³² P] ATP (1-20 nM), and 10-20 mM Mg ^2+.
Was generally performed by incubating for a time in the range of 10 to 120 minutes. The reaction consisted of 50-100 buffered to 0.2-2 volumes of 20% acetic acid or pH 7.
Stopped with mM EDTA (Substrate consumption <20%). The buffer used for enzyme analysis was 0.1
30 mM HEPES 7.4 with 5 M NaCl and 5% DMSO, 0.15 M NaCl and 5%
50 mM MOPS 7.0 with DMSO or 10 with 0.1 mg / ml BSA and 5% DMSO
It was 0 mM HEPES pH 7.5. The inhibitor was diluted in 100% DMSO and then added to the analyte. Accompanying the detection of peptide phosphorylation, the peptide was collected on a phosphocellulose filter (the reaction was stopped with acetic acid), the peptide was collected into the wells of a 96-well plate coated with Streptavidin (Pierce) (the reaction was stopped with EDTA), Or
Add beads impregnated with Avidin-coated Scintillant (Amersham Sci
ntillation Proximity Assays, the reaction was stopped with EDTA) followed by scintillation counting. Assuming that the counts detected by any of these minus appropriate background (analysis with additional 40 mM EDTA or lacking peptide base) was proportional to the initial reaction rate, the IC50 was calculated as CPM = Vmax (
1-([I] / (K + [I]))) + nsb determined by the least squares method, or pIC50 is given by the formula CPM
= nsb + (V _max -nsb) / (1+ (x / 10 ^x -pIC50)) (where nsb is the background count).

The results shown in Table 1 below show the inhibitory activity of the exemplary compounds of formulas (A1), (A2) and (A3) as defined above on CDK2 and CDK1.

[0084] Table 1 Compound CDK2 CDK1 A1 ++++ ++++ A2 +++ ++ A3 ++++ +++ symbol _{(IC 50, nM) 1-10:} ++++ 11-50: +++ 51-100: ++> 100: +

Protection from chemotherapy-induced alopecia is described, for example, in 7-day-old Spraque-Da.
It can be measured in the paw of wley rats. Treatment is 6 mg of etoposide on the animal's head
Compounds were administered 0.01 to 2 hours before and 2 hours after intraperitoneal administration of a single dose of
It is performed by topical administration at a dose of 10 mg / kg. 6 days after dosing 1 animal
Hair loss is visually scored using a rating scale of (complete hair loss) to 4 (no apparent hair loss). In this analysis, pretreatment of animals with a CDK2 inhibitor compound of the invention results in a significant reduction in hair loss severity compared to vehicle-treated controls.

When a CDK2 inhibitor compound is used to treat alopecia and / or mucositis associated with the administration of a chemotherapeutic agent for the treatment of cancer or radiation therapy, the CDK2 inhibitor compound is used concurrently with a chemotherapeutic agent. Alternative regimens to administer or suppress tumor growth during chemotherapy or radiation treatment may provide a secondary means of suppressing tumor growth.

Although the present invention has been described and illustrated with respect to certain preferred embodiments, those skilled in the art can make various changes, modifications and substitutions without departing from the spirit and scope of the invention. It will be understood that you can. For example, applying effective dosages other than the preferred dosages described above as a result of variability in responsiveness of a mammal undergoing treatment for a cancer disease or other indications for a compound of the invention as described above. You can Similarly, the particular pharmacological response observed will vary according to and depending on the particular active compound selected or certain pharmaceutical carrier, as well as the type of prescription drug used and mode of administration. Such expected variations or differences in outcome are contemplated by the objectives and practice of the invention. Accordingly, the invention is limited only by the claims, which are to be construed as reasonably broad.

Although the present invention has been described in terms of specific features, aspects and embodiments, it is understood that the scope of the present invention is not limited thereby and is intended to be extended and encompassed by other variations, modifications and other embodiments. It Accordingly, the present invention should be construed and constructed to include all variations, modifications and other aspects within the spirit and scope of the appended claims.

Cited Documents Various documents are cited in the present specification, and the disclosure contents of all the documents and the following documents are incorporated herein as part of the disclosure thereof. Cline, BW, "Preventing Chemotherapy-induced Alopecia: A Review of the Literature (Prev
ention of chemotherapy-induced alopecia: A review of the literature), ''
Cancer Nursing / June 1984, pp. 221-227. Gray, NS, et al., “Exploiting Chemical Literatures, Structures, and Ge
nomics in the Search for Kinase Inhibitors) '', Science, Vol. 284, 24 Jul
y 1998, pp. 533-538. Hussein, AM, "Chemotherapy-induced alopecia: new development (Chemothe
rapy-Induced Alopecia: New Developments) '', Southern Medical Journal, Ma
y 1993, Vol. 86, No. 5, pp. 489-496. Hussein, AM, et al., `` Protection from Chemotherapy-Induced Alopecia in a Rat.
Model) '', Science, Vol. 249, September 28, 1990, pp. 1564-1566. Lauer, AC, et al., `` Transfollicular Drug Delivery ''
, Pharmaceutical Research, Vol. 12, No. 2, 1995, pp. 179-188. Li, L., et al., "Ease of targeted gene therapy of hair follicles (The feasi
bility of targeted selective gene therapy of the hair follicle), Natur
e Medicine, Volumme 1, No. 7, July 1995, pp. 705-706. Palumbo, Giuseppe A., et al., "Tyrphostin AG17 Apoptosis and Inhibition of cdk2 Activity in Lymphoma Cell Lines Overexpressing bcl-2." Trigger the (The Tyr
phostin AG17 Induces Apoptosis and Inhibition of cdk2 Activity in a Lymp
homa Cell Line That Overexpresses bcl-2), Cancer Research 57, 2434-233.
9, June 15, 1997. Roberts, James M., et al., US Pat. No. 5,8, issued Jan. 19, 1999.
61,259 specification. Sawaya, ME, "Alopecia-the search for new compounds continues (Alopecia-the search
for novel agents continues) '', Exp. Opin. Ther. Patents (1997) 7 (8): 859.
-872, Ashley Publications Ltd. Sedlacek, Hans H., et al., "Flavopiridol (L86 82875: NSC 649890)
, A novel kinase inhibitor for the treatment of tumors (Flavopiridol (L86 82875; NSC 649890
), a new kinase inhibitor for tumor therapy) '', International Journal of
Oncology 9: 1143-1168, 1996. Toledo, Leticia M., et al., "Structure of staurosporine bound to CDK2 and cAPK-a novel tool for the structure-based design of protein kinase inhibitors (Struc
tures of staurosporine bound to CDK2 and cAPK-new tools for structure-
based design of protein kinase inhibitors) '', Structure 1997, Vol. 5, No
. 12, pp. 1551-1556.

The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of products, prescription drugs, methods or uses of the claims, including, for example, but not limited to, one or more of the claims. Absent.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 29/00 A61P 29/00 43/00 111 43/00 111 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY) , KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC , LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Steven, Thomas, Davis, North Carolina, USA, Research, Triangle, Park, Pea ． Oh. Box, 13398, Five, Moore, Drive, F term in GlaxoSmithKline (reference) 4C084 AA17 NA14 ZA892 ZA922 ZB112 ZC202 ZC372 4C086 AA01 AA02 BC21 CB07 CB09 MA01 MA04 MA56 MA63 NA07 NA14 ZA89 ZA92 ZC20 ZC37

Claims (24)

[Claims] 1. A method of preventing / mitigating the severity of epithelial cytotoxic side effects of such treatment in a patient undergoing chemotherapy and / or radiation therapy, said patient comprising a cyclin dependent kinase II inhibitor. Is administered, but does not include the case where the cyclin dependent kinase inhibitor is a compound of formula (A) as defined herein. 2.   The method of claim 1, wherein the epithelial cytotoxic side effect is alopecia. 3. The side effect of epithelial cytotoxicity is plantar-palmar syndrome.
The method of claim 1. 4.   The method of claim 1, wherein the epithelial cytotoxic side effect is mucositis. 5. The method of claim 1, wherein the cyclin-dependent kinase II inhibitor is administered in a locally administered formulation at a location in the body susceptible to epithelial cytotoxicity induced by chemotherapy and / or radiation therapy. . 6. The method of claim 1, wherein the cyclin-dependent kinase II inhibitor is topically administered to the scalp to prevent / alleviate the severity of chemotherapy-induced alopecia. 7. The method of claim 1, wherein the cyclin-dependent kinase II inhibitor is locally administered to the hands and / or feet to prevent / alleviate the severity of the chemotherapy-induced plantar-palm syndrome. Method. 8. The method of claim 1, wherein the cyclin-dependent kinase II inhibitor is administered topically to the oral mucosa to prevent / alleviate the severity of chemotherapy-induced mucositis. 9. The method of claim 1, wherein the cyclin-dependent kinase II inhibitor is topically administered to the scalp to prevent / alleviate the severity of radiation-induced alopecia. 10. The method of claim 1, wherein the cyclin-dependent kinase II inhibitor is administered topically to the oral mucosa to prevent / reduce the severity of radiotherapy-induced mucositis. 11.   Cyclin-dependent kinase II inhibitor   (a) IC50 value for CDK2 is less than 2.5 nmol, and   (b) IC50 value in G1 checkpoint assay is less than 1.5 micromolar The method of claim 1, characterized by at least one of the IC50 characteristics of: 12. The method of claim 1, wherein the administration of the cyclin dependent kinase II inhibitor is non-systemic. 13. The above-mentioned cyclin-dependent kinase II inhibitor is a substituted oxindole derivative, a purine derivative, a pyridylpyrimidine amine derivative, a 4H-1-benzopyran-4-one derivative, a pyrido [2,3-D] pyrimidine, A type selected from the group consisting of 4-aminopyrimidine, CDK2 inhibitor antisense sequence, 2-thioflavopyridol analog, 2-oxo-flavopiridol analog, C2 alkynylated purine, and tyrphostins. The method according to claim 1, comprising the above-mentioned agents. 14.   Cyclin-dependent kinase inhibitors have the formula (I) C2 alkynylated purines of formula (B) as defined herein and their
At least a partially saturated derivative, (II) 2- (1-R-hydroxymethylpropylamino) -6-benzylamino
-9-isopropyl-purine, (III) formula [Chemical 1] Purine compound, (IV) formula [Chemical 2] Purine compound, (V) formula [Chemical 3] (In the above formula,   X is oxygen or sulfur,   R¹Is hydrogen, alkyl, aryl, arylalkyl, cycloalkyl,-(
CH_Two)_q-NR⁷R⁸, Alkylcarbonyl, arylcarbonyl, aryl
Alkyl carbonyl, alkoxy carbonyl, arylalkyl oxycarboni
Or aryloxycarbonyl,   R^TwoIs hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, hydr
Roxy, alkoxy, arylalkoxy, aryloxy, alkyl carbonate
Luoxy, arylalkylcarbonyloxy, arylcarbonyloxy,
Ruboxi, alkyloxycarbonyl, arylalkoxycarbonyl, aryl
Luoxycarbonyl, amino, -NR⁷R⁸, Thiol, alkylthio, ally
Is alkylthio or arylthio,   R^ThreeIs alkyl, cycloalkyl, aryl, arylalkyl, heterocycle,
Or heterocycloalkyl,   R^FourIs hydrogen, alkyl, aryl, arylalkyl, nitro, amino,-(
CH_Two)_p-NR⁷R⁸, Halogen, hydroxy, alkoxy, carboxy,
A telocycle, or alkyloxycarbonyl,   R⁵Is hydrogen, alkyl, arylalkyl, aryl, cycloalkyl, hydr
Roxy, alkoxy, arylalkoxy, aryloxy, alkyl carbonate
Luoxy, arylalkylcarbonyloxy, arylcarbonyloxy,
Ruboxy, alkyloxycarbonyl, arylalkoxycarbonyl, cyano
, Nitro, -NR⁷R⁸, Halogen, alkylhalo, —CHO, alkylS (O
)_m-Or-OC (O) NR⁷R⁸And   R⁶Is hydrogen, alkyl, arylalkyl, aryl, cycloalkyl, hydr
Roxy, alkoxy, arylalkoxy, aryloxy, alkyl carbonate
Luoxy, arylalkylcarbonyloxy, arylcarbonyloxy,
Ruboxy, alkylcarbonyl, arylalkoxycarbonyl, amino, sia
No, nitro, -NR⁷R⁸, Halogen, alkylthio, —CHO, alkyl S (
O)_m-Or-OC (O) NR⁷R⁸, NR⁷R⁸, Thiol, alkyl
O, arylalkylthio, or arylthio,   R⁷And R⁸Are independently hydrogen, alkyl, aryl, arylalkyl,
Cycloalkyl, heterocycle, or alkylcarbonyl, or R⁷Oh
And R⁸Form a heterocycle with the nitrogen atom to which they are attached
It is possible,   m is an integer from 0 to 2,   n is an integer of 0 to 3,   p is an integer of 1 to 3,   q is an integer of 2 to 5) Flavopiridol analogues of (VI) formula [Chemical 4] (In the above formula,   X is O, S or CHR_x(However, R_xIs H or C_1-4Is alkyl)
And D is H, halo, or NZ₁Z_Two(However, Z₁And Z_TwoRespectively
Independently H or C_1-4Alkyl or C_1-4Hydroxy alk
And A is H, C_1-4Alkyl, C_1-4Alkoxy, hydroxy
Si, CH_Two(CH_Two)_nOH (n = 1 to 4), and NR_a1R_a2(However, R _a1 And R_a2Are each independently H or C_1-4Is alkyl)
Selected, B is H, C_1-4Alkyl, C_1-4Alkoxy, CF_Three, In some cases
Substituted aryl or optionally substituted aralkyl, and C =
Selected from a hydroxy group that provides an O tautomer, and Y is optionally substituted
A 4- to 8-membered carbocycle or heterocycle, or containing, or
Thus comprising substituted linear or branched hydrocarbon chains) Purine derivative of (VII) formula [Chemical 5] (In the above formula,   W is NH, S, SO or SO_TwoAnd R¹Is phenyl and substituted phenyl
And R^TwoIncludes alkyl and cycloalkyl, R^ThreeIs alkyl and
And hydrogen, R⁸And R⁹Includes hydrogen and alkyl, Z is carboxy
It is shi) Of 7,8-dihydro-2- (amino and thio) pyrido [2,3-d] pyrimidi
The (VIII) formula [Chemical 6] (In the above formula,   W is NH, S, SO or SO_TwoAnd R¹Is phenyl and substituted phenyl
And R^TwoIncludes alkyl and cycloalkyl, R^ThreeIs alkyl and
And hydrogen, R⁸And R⁹Includes hydrogen and alkyl, Z is carboxy
It is shi) 2,4-diaminopyrimidine, (IX) 4H-1-benzopyran-4-one derivative, (X) expression [Chemical 7] (In the above formula,   R is halogen, XR¹(However, X = NH, O, S, SO_Two; R¹= Alkyl,
Cycloalkyl, heterocyclyl, aryl, heteroalkyl), R^Two=
H, alkyl, cycloalkyl, aryl, heteroalkyl, R^Three= Halo
Heterocycles linked to gen, OH, SH, alkoxy, alkylthio, amino, N
Kuril) A 2,6,9-trisubstituted purine compound of (XI) expression [Chemical 8] 2,6,9-trisubstituted purine compounds The method of claim 1, comprising selected from the compounds of: 15. A cyclin-dependent kinase II inhibitor has the formula: And [Chemical 10] The method of claim 1, comprising selected from the compounds of: 16. A cyclin dependent kinase II inhibitor has the formula: (In the above formula, X is oxygen or sulfur, R ¹ is hydrogen, alkyl, aryl, arylalkyl, cycloalkyl,-(
_{^{CH 2) q -NR 7 R 8}} , alkylcarbonyl, arylcarbonyl, arylalkyl carbonyl, alkoxycarbonyl, aryl alkyloxycarbonyl or aryloxycarbonyl,, ^{R 2} is hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, Hydroxy, alkoxy, arylalkoxy, aryloxy, alkylcarbonyloxy, arylalkylcarbonyloxy, arylcarbonyloxy, carboxy, alkyloxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl, amino, -NR ⁷ R ⁸ , thiol, alkylthio, aryl. Alkylthio or arylthio, R ³ is alkyl, cycloalkyl, aryl, arylalkyl, heterocycle,
Or heterocycloalkyl, R ⁴ is hydrogen, alkyl, aryl, arylalkyl, nitro, amino,-(
_{^{CH 2) p -NR 7 R 8}} , halogen, hydroxy, alkoxy, carboxy, a heterocyclic or alkyloxycarbonyl,, ^{R 5} is hydrogen, alkyl, arylalkyl, aryl, cycloalkyl, hydroxy, alkoxy, arylalkoxy, Aryloxy, alkylcarbonyloxy, arylalkylcarbonyloxy, arylcarbonyloxy, carboxy, alkyloxycarbonyl, arylalkoxycarbonyl, cyano, nitro, —NR ⁷ R ⁸ , halogen, alkylhalo, —CHO, alkylS (O
) _M -, or -OC (O) a ^NR 7 ^{R 8, R 6} is hydrogen, alkyl, arylalkyl, aryl, cycloalkyl, hydroxy, alkoxy, arylalkoxy, aryloxy, alkylcarbonyloxy, aryl alkylcarbonyloxy , arylcarbonyloxy, carboxy, alkyloxycarbonyl, aryl alkoxycarbonyl, amino, cyano, nitro, ^-NR 7 ^{R 8,} halogen, alkylhalos, -CHO, alkyl S _{(O) m} - or -OC (O) NR ^7, R ^{8, NR} 7 ^{R 8,} thiol, alkylthio, aryl alkyl thio or arylthio,, ^{R 7} and ^{R 8} are independently hydrogen, alkyl, aryl, arylalkyl,
Cycloalkyl, heterocycle, or alkylcarbonyl, or R ⁷ and R ⁸ can form, together with the nitrogen atom to which they are attached, a heterocycle, m is an integer from 0 to 2 Wherein n is an integer from 0 to 3, p is an integer from 1 to 3 and q is an integer from 2 to 5). 17. The method of claim 1, wherein the cyclin-dependent kinase II inhibitor is administered concurrently with treatment with radiation therapy having epithelial cytotoxic side effects. 18. The method of claim 1, wherein the cyclin-dependent kinase II inhibitor is administered concurrently with treatment with chemotherapy having epithelial cytotoxic side effects. 19. The method of claim 1, wherein the cyclin dependent kinase II inhibitor is administered 1-4 times in the chemotherapy cycle. 20. A cytoprotective composition for preventing / reducing the severity of alopecia and / or mucositis in patients undergoing chemotherapy and / or radiation therapy, comprising:
10. The composition as described above, which comprises a formulation comprising an effective amount of the cyclin-dependent kinase II inhibitor according to any one of 9 above. 21. The cyclin-dependent kinase II according to any one of claims 1 to 20, in the manufacture of a medicament for preventing / reducing the severity of epithelial cytotoxic side effects of chemotherapy and / or radiation therapy. Use of inhibitors. 22. In the manufacture of a medicament for preventing / alleviating the severity of alopecia and / or mucositis in patients undergoing chemotherapy and / or radiation therapy.
Use of the cyclin-dependent kinase II inhibitor according to any one of 1. 23. A method according to any one of claims 1 to 22 in the manufacture of a medicament for preventing / alleviating the severity of chemo-induced chemo-induced plantar-palm syndrome. Use of cyclin dependent kinase II inhibitors. 24. A method of treating a patient with a neoplastic disease, wherein the patient is treated with chemotherapy and / or
Alternatively, the patient is subjected to radiation therapy, and at the same time, the cyclin-dependent kinase II inhibitor is administered to the patient in an effective amount to prevent / reduce the severity of epithelial cytotoxic side effects likely to occur in the above chemotherapy and / or radiation therapy. how to.