TW202227097A - Use of uridine derivatives in preparation of a drug - Google Patents

Abstract

The present application provides a use of a uridine derivative in the preparation of a drug, said drug is used for preventing or treating a limb disease associated with the administration of a chemotherapeutic drug in a subject. The present application also provides pharmaceutical composition or a kit comprising a chemotherapeutic drug and said uridine derivative.

Description

Application of uridine derivatives in the preparation of medicines

The present application relates to the use of a uridine derivative in the preparation of a medicament for preventing or treating a disease or condition associated with the administration of a chemotherapeutic drug.

Administration of chemotherapeutic drugs is one of the most commonly used methods for the clinical treatment of tumors. However, the administration of chemotherapy drugs can cause serious side effects, some of which are extremity disorders, mainly in the hands and feet. These extremity disorders include: exudative hyperthyroidism, hand-foot syndrome (HFS), polyperiungual Suppurative granulomatous lesions, alopecia areata, nail bed separation, paronychia, etc. These side effects can lead to discontinuation or dose reduction of chemotherapy drugs, and can impair a patient's quality of life.

There are no successful treatment regimens in the prior art to control the side effects associated with the administration of chemotherapeutic drugs. Therefore, there is an urgent need for therapeutic regimens that can successfully control these side effects.

The present application relates to methods or uses for the prevention or treatment of diseases associated with the administration of chemotherapeutic drugs. The application provides a compound, or the use of a pharmaceutically acceptable salt, solvent, hydrate, prodrug form and stereoisomer thereof in the preparation of a medicament for the preparation of prevention and treatment of subjects with Shi Medications for extremity disorders associated with chemotherapy drugs (eg, hand-foot syndrome). The present application also provides medicaments, pharmaceutical combinations or kits comprising the compounds, methods of using the compounds to prevent or treat diseases or conditions associated with the administration of chemotherapeutic drugs, and the like. It has been found in the present application that the use of the compounds can effectively prevent or treat diseases or conditions associated with the administration of chemotherapeutic drugs. The present application also found that uridine derivatives comprising NSAIDs can relieve, prevent and/or treat extremity disorders (eg, hand-foot syndrome) associated with the administration of chemotherapeutic drugs, relieve pain, reduce inflammation, and preserve urine The functions of the glycoside part and the NSAID part have a synergistic effect.

In one aspect, the application provides the use of uridine derivatives or pharmaceutically acceptable salts, solvents, hydrates, prodrug forms and stereoisomers thereof in the manufacture of a medicament for prophylaxis and/or treatment Limb disease associated with administration of a chemotherapeutic drug in a subject, the uridine derivative comprising a compound represented by formula (I):

，式(I)，其中當R₁，R₂，R₄，R₅均為氫時，R₃不為-OH。

, formula (I), wherein when R ₁ , R ₂ , R ₄ , R ₅ are all hydrogen, R ₃ is not -OH.

，其中該X_s為氧或硫， R_s包含選自下組中的一種或多種基團：氫、取代或未取代的羥基、取代或未取代的巰基、取代或未取代的胺基、C1至C5的取代或未取代的烷基、C1至C5的取代或未取代的炔基、C1至C5的取代或未取代的環烷基、取代或未取代的雜環 烷基、取代或未取代的芳基以及取代或未取代的芳烷基。在某些實施方式中，X_s為氧。 In certain embodiments, the R1 is hydrogen or

, wherein the X _s is oxygen or sulfur, and R _s comprises one or more groups selected from the group consisting of hydrogen, substituted or unsubstituted hydroxy, substituted or unsubstituted mercapto, substituted or unsubstituted amine, C1 to C5 substituted or unsubstituted alkyl, C1 to C5 substituted or unsubstituted alkynyl, C1 to C5 substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aralkyl. In certain embodiments, _Xs is oxygen.

，其中該X_g為氧或硫，R_g 包含選自下組中的一種或多種基團：氫、取代或未取代的羥基、取代或未取代的巰基、取代或未取代的胺基、C1至C5的取代或未取代的烷基、C1至C5的取代或未取代的炔基、C1至C5的取代或未取代的環烷基、取代或未取代的雜環烷基、取代或未取代的芳基以及取代或未取代的芳烷基。在某些實施方式中，X_g為氧。 In certain embodiments, R ₂ is hydrogen or

, wherein the X _g is oxygen or sulfur, and R _g comprises one or more groups selected from the group consisting of hydrogen, substituted or unsubstituted hydroxyl, substituted or unsubstituted mercapto, substituted or unsubstituted amine, C1 to C5 substituted or unsubstituted alkyl, C1 to C5 substituted or unsubstituted alkynyl, C1 to C5 substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aralkyl. In certain embodiments, X _g is oxygen.

或氫，其中該R₇為氫或

，其中該X₁為氧或硫，R₆包含選自下組中的一種或多種基團：氫、取代 或未取代的羥基、取代或未取代的巰基、取代或未取代的胺基、C1至C5的取代或未取代的烷基、C1至C5的取代或未取代的炔基、C1至C5的取代或未取代的環烷基、取代或未取代的雜環烷基、取代或未取代的芳基以及取代或未取代的芳烷基。 In certain embodiments, the _R is

or hydrogen, wherein the R ₇ is hydrogen or

, wherein the X ₁ is oxygen or sulfur, and R ₆ comprises one or more groups selected from the group consisting of hydrogen, substituted or unsubstituted hydroxy, substituted or unsubstituted mercapto, substituted or unsubstituted amine, C1 to C5 substituted or unsubstituted alkyl, C1 to C5 substituted or unsubstituted alkynyl, C1 to C5 substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aralkyl.

，該R₇為

，其中，R₆ 包含選自下組中的一種或多種基團：選自下組中的一種或多種基團：氫、C1至C6烷基、C1至C6烷氧基、C3至C10環烷基、C3至C10環烷基氧基、C4至C10芳基烷基、C4至C10芳基烷氧基或C4至C10芳香基。 In certain embodiments, _R is

, the _R7 is

, wherein R ₆ comprises one or more groups selected from the group consisting of: one or more groups selected from the group consisting of hydrogen, C1 to C6 alkyl, C1 to C6 alkoxy, C3 to C10 cycloalkane group, C3 to C10 cycloalkyloxy, C4 to C10 arylalkyl, C4 to C10 arylalkoxy, or C4 to C10 aryl.

In certain embodiments, the _R3 is hydrogen.

，其中，R_s包含選自下組中的一 種或多種基團：氫、C1至C6烷基、C1至C6烷氧基、C3至C10環烷基、C3至C10環烷基氧基、C4至C10芳基烷基、C4至C10芳基烷氧基或C4至C10芳香基。 In certain embodiments, R ₁ is

, wherein R _s comprises one or more groups selected from the group consisting of hydrogen, C1 to C6 alkyl, C1 to C6 alkoxy, C3 to C10 cycloalkyl, C3 to C10 cycloalkyloxy, C4 to C10 arylalkyl, C4 to C10 arylalkoxy, or C4 to C10 aryl.

，其中，R_g包含選自下組中的一 種或多種基團：氫、C1至C6烷基、C1至C6烷氧基、C3至C10環烷基、C3至C10環烷基氧基、C4至C10芳基烷基、C4至C10芳基烷氧基或C4至C10芳香基。 In certain embodiments, R ₂ is

, wherein R _g comprises one or more groups selected from the group consisting of hydrogen, C1 to C6 alkyl, C1 to C6 alkoxy, C3 to C10 cycloalkyl, C3 to C10 cycloalkyloxy, C4 to C10 arylalkyl, C4 to C10 arylalkoxy, or C4 to C10 aryl.

_In certain embodiments, R4 is hydrogen.

_In certain embodiments, R5 is hydrogen.

，R₁包含選自下組的一中或多種基團：氫、

、

、

、

和

，R₂包含選自下組的一中或多 種基團：氫、

、

、

、

、

、

、

、

、

和

， R₁包含選自下組的一中或多種基團：氫、

、

、

、

和

，且R₂和R₁不同時為氫。 In certain embodiments, in the structure shown in formula (I), R ₄ and R ₅ are both hydrogen, and R ₃ is

, R ₁ comprises one or more groups selected from the group consisting of hydrogen,

,

,

,

and

, R ₂ comprises one or more groups selected from the group consisting of hydrogen,

,

,

,

,

,

,

,

,

and

, R ₁ contains one or more groups selected from the group consisting of hydrogen,

,

,

,

and

, and R ₂ and R ₁ are not both hydrogen.

In certain embodiments, the uridine derivative is selected from one or more of the following group:

、

和

。

,

and

.

，式(II)，其中，該R₁、R₂和/或R₇中的至少一個(例如，R₁，R₂， R₇，R₁和R₂，R₂和R₇，R₁和R₇，或R₁、R₂和R₇)包含非甾體抗炎藥(NSAID)部分。 In certain embodiments, the uridine derivative comprises a compound of formula (II):

, formula (II), wherein at least one of the R ₁ , R ₂ and/or R ₇ (eg, R ₁ , R ₂ , R ₇ , R ₁ and R ₂ , R ₂ and R ₇ , R ₁ and R ₇ , or R ₁ , R ₂ and R ₇ ) comprises a non-steroidal anti-inflammatory drug (NSAID) moiety.

In certain embodiments, the NSAID comprises salicylic acid or derivatives thereof, arylacetic acid or derivatives thereof, heteroarylacetic acid or derivatives thereof, indoleacetic acid or derivatives thereof, indeneacetic acid or derivatives thereof, Anthranilic acid or its derivatives and/or enolic acid or its derivatives.

In certain embodiments, R ₁ , R ₂ or R ₇ is hydrogen.

In certain embodiments, R ₁ , R ₂ and R ₇ are not simultaneously hydrogen.

， 其中，R₈為R_s ²或

，其中，R_s ¹為氫或甲基，R_s ²為

，其中，該 環A為C4至C7芳基、C4至C7雜芳基、茚環、萘環、吲哚啉環、不飽和多環烴和/或雜環多環，R_s ³和/或R_s ⁴獨立地選自：氫、C1至C6烷基、C1至C6烷基 酯、鹵素、C4至C7芳香基、C4至C7雜芳基和

，其中，環B為C4至 C7芳香基、C4至C7雜芳基，X為-CH₂、-NH-、-O-或

；其中，該C4至 C7芳香基、C4至C7雜芳基可選地被一個或多個選自下組的取代基取代：鹵素、C1至C6烷基、C1至C6炔基和C1至C6烯基。 In certain embodiments, any one of R ₁ , R ₂ and R ₇ is independently

, where R ₈ is R _s ² or

, where R _s ¹ is hydrogen or methyl, and R _s ² is

, wherein, the ring A is a C4 to C7 aryl group, a C4 to C7 heteroaryl group, an indene ring, a naphthalene ring, an indoline ring, an unsaturated polycyclic hydrocarbon and/or a heterocyclic polycyclic ring, R _s ³ and/or R _s ⁴ are independently selected from: hydrogen, C1 to C6 alkyl, C1 to C6 alkyl ester, halogen, C4 to C7 aryl, C4 to C7 heteroaryl and

, wherein Ring B is a C4-C7 aryl group, a C4-C7 heteroaryl group, and X is -CH ₂ , -NH-, -O- or

; wherein, the C4 to C7 aryl, C4 to C7 heteroaryl groups are optionally substituted by one or more substituents selected from the group consisting of halogen, C1 to C6 alkyl, C1 to C6 alkynyl and C1 to C6 alkenyl.

，其中，X為

，環B為苯環，該環B可選地被一個或多個C1至 C6烷基取代。 In certain embodiments, Ring A is a pyrrole ring, R _s ³ is C1-C6 alkyl, and R _s ⁴ is

, where X is

, ring B is a benzene ring, and the ring B is optionally substituted with one or more C1 to C6 alkyl groups.

，其中，該R_s ³為 C1至C6烷基或鹵素。 In certain embodiments, R _s ¹ and/or R _s ² are

, wherein the R _s ³ is C1 to C6 alkyl or halogen.

，其中，R_s ³和/或R_s ⁴ 選自：氫、C1至C6烷基、C1至C6烷基酯、鹵素、C4至C7芳香基、C4至C7 雜芳基、

，環B為C4至C7芳香基、C4至C7雜芳基，X為-CH₂、- NH-、-O-或

；其中，該C4至C7芳香基、C4至C7雜芳基可選地被一個 或多個選自下組的取代基取代：鹵素、C1至C6烷基、C1至C6炔基和C1至C6烯基。 In certain embodiments, R _s ¹ and/or R _s ² are

, wherein R _s ³ and/or R _s ⁴ are selected from: hydrogen, C1 to C6 alkyl, C1 to C6 alkyl ester, halogen, C4 to C7 aryl, C4 to C7 heteroaryl,

, Ring B is C4 to C7 aryl, C4 to C7 heteroaryl, X is -CH ₂ , -NH-, -O- or

; wherein, the C4 to C7 aryl, C4 to C7 heteroaryl groups are optionally substituted by one or more substituents selected from the group consisting of halogen, C1 to C6 alkyl, C1 to C6 alkynyl and C1 to C6 alkenyl.

，其中，R_s ³和/或R_s ⁴選自：氫、 C1至C6烷基、

、氟、氯、溴、苯環和

，其中，環B為苯環， X為-CH₂、-NH-、-O-或

；該苯環可選地被一個或多個選自下組的取代基取 代：氟、氯和溴。 In certain embodiments, R _s ² is

, wherein R _s ³ and/or R _s ⁴ are selected from: hydrogen, C1 to C6 alkyl,

, fluorine, chlorine, bromine, benzene ring and

, wherein Ring B is a benzene ring, X is -CH ₂ , -NH-, -O- or

; the benzene ring is optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine and bromine.

，R_s ¹為氫或甲基，R_s ²選自

、

、

、

、

和

In certain embodiments, R ₈ is

, R _s ¹ is hydrogen or methyl, R _s ² is selected from

,

,

,

,

and

，R_s ¹為氫或甲基，R_s ²為

，其中，環A₁為C4至C7環烷基、C4至C7雜環烷基、C4至C7芳香 基和/或C4至C7雜芳基，環B₁為C4至C7環烷基、C4至C7雜環烷基、C4至 C7芳香基、C4至C7雜芳基或

，其中，環B₂為C4至C7環烷基、C4 至C7雜環烷基、C4至C7芳香基和/或C4至C7雜芳基，環B₃為C4至C7環烷基、C4至C7雜環烷基、C4至C7芳香基和/或C4至C7雜芳基，其中，該C4至C7環烷基、C4至C7雜環烷基、C4至C7芳香基和/或C4至C7雜芳基可選 地被鹵素、

、

、

、C1至C6烷基、C1至C6烷基取代的酯 基和/或C1至C6烷基取代的醛基取代，其中，環C為苯環，Y為-CH₂、-NH-、 -O-或

；該苯環可選地被一個或多個選自下組的取代基取代：氟、氯、溴和

；該Y可以與環B₂或環B₃上的環原子形成雙鍵。 In certain embodiments, R ₈ is

, R _s ¹ is hydrogen or methyl, R _s ² is

, wherein Ring A ₁ is C4 to C7 cycloalkyl, C4 to C7 heterocycloalkyl, C4 to C7 aryl and/or C4 to C7 heteroaryl, and Ring B ₁ is C4 to C7 cycloalkyl, C4 to C7 C7 heterocycloalkyl, C4 to C7 aryl, C4 to C7 heteroaryl or

, wherein, ring B ₂ is C4 to C7 cycloalkyl, C4 to C7 heterocycloalkyl, C4 to C7 aryl and/or C4 to C7 heteroaryl, and ring B ₃ is C4 to C7 cycloalkyl, C4 to C7 C7 heterocycloalkyl, C4 to C7 aryl and/or C4 to C7 heteroaryl, wherein the C4 to C7 cycloalkyl, C4 to C7 heterocycloalkyl, C4 to C7 aryl and/or C4 to C7 Heteroaryl is optionally halo,

,

,

, C1 to C6 alkyl, C1 to C6 alkyl substituted ester group and/or C1 to C6 alkyl substituted aldehyde group substitution, wherein, ring C is a benzene ring, and Y is -CH ₂ , -NH-, -O -or

; the benzene ring is optionally substituted by one or more substituents selected from the group consisting of fluorine, chlorine, bromine and

; The Y may form a double bond with a ring atom on ring B ₂ or ring B ₃ .

，其中，該R_s ⁶ 為氟、氯或溴、

，M為氮或碳，X為碳或

，X與M間可選地形成雙 鍵，R_s ⁷為氟、氯、溴或

。 In certain embodiments, R _s ² is

, wherein, the R _s ⁶ is fluorine, chlorine or bromine,

, M is nitrogen or carbon, X is carbon or

, X and M can optionally form a double bond, R _s ⁷ is fluorine, chlorine, bromine or

.

，R_s ¹為氫或甲基，R_s ²為

或

。 In certain embodiments, R ₈ is

, R _s ¹ is hydrogen or methyl, R _s ² is

or

.

，R_s ¹為氫或甲基，R_s ²為

In certain embodiments, R ₈ is

, R _s ¹ is hydrogen or methyl, R _s ² is

，該環A₁為苯環，環B₁為

，且環B₂為吡咯環，B₃為吡喃環，該吡喃環可選地被一個或多個C1 至C6烷基和/或C1至C6烷基取代的醛基取代。 In certain embodiments, R _s ² is

, the ring A ₁ is a benzene ring, and the ring B ₁ is

, and ring B ₂ is a pyrrole ring, B ₃ is a pyran ring, and the pyran ring is optionally substituted with one or more C1 to C6 alkyl and/or C1 to C6 alkyl substituted aldehyde groups.

，R_s ¹為氫或甲基，R_s ²為

In certain embodiments, R ₈ is

, R _s ¹ is hydrogen or methyl, R _s ² is

或

。 In certain embodiments, R ₈ ¹ is

or

.

In certain embodiments, any one of R ₁ , R ₂ and R ₇ is independently

In certain embodiments, the R ₁ is selected from the group consisting of:

、

、

、

、

、

和

。 hydrogen,

,

,

,

,

,

and

.

In certain embodiments, the R ₁ is selected from the group consisting of:

、

、

、

、

和

。 hydrogen,

,

,

,

,

and

.

_In certain embodiments, the R is selected from the group consisting of:

、

、

、

、

、

、

、

和

。 hydrogen,

,

,

,

,

,

,

,

and

.

_In certain embodiments, the R is selected from the group consisting of:

、

、

、

、

和

。 hydrogen,

,

,

,

,

and

.

_In certain embodiments, the R is selected from the group consisting of:

、

、

和

。

,

,

and

.

_In certain embodiments, the R is selected from the group consisting of:

、

、

、

、

和

。 hydrogen,

,

,

,

,

and

.

In certain embodiments, at least one of R ₁ , R ₂ and R ₇ is selected from the group consisting of:

、

、

、

、

、

、

、

和

，並且R₁、R₂和R₇ 中不同時為氫。 hydrogen,

,

,

,

,

,

,

,

and

, and R ₁ , R ₂ and R ₇ are not hydrogen at the same time.

In certain embodiments, the uridine derivative is selected from one or more of the following group:

和

。

and

.

In certain embodiments, the chemotherapeutic drug is used to treat cancer.

In certain embodiments, the chemotherapeutic agent comprises a pyrimidine nucleoside analog or a prodrug thereof.

In some embodiments, the chemotherapeutic agent comprises a compound selected from the group consisting of capecitabine, cytarabine, docetaxel, doxorubicin, fluorouracil (5-FU), floxuridine, tegafur , Idarubicin, Paclitaxel, Epirubicin, Doxorubicin, Acelarin (NUC-1031), Leucovorin, Cisplatin, Taxanes, Cyclophosphamide, Vincristine and 5-FU prodrugs.

In certain embodiments, the 5-FU prodrugs include furanfluridine, 5'-deoxyfluridine, floxuridine, 2'-deoxyfluridine, prodrug derivatives of floxuridine Or prodrug derivatives of 2'-deoxyfluridine, trifluoro-methyl-2'-deoxyuridine, 6-azauridine and/or 3-deazauridine.

In certain embodiments, the chemotherapeutic agent comprises fluorouracil (5-FU), capecitabine, floxuridine, tegafur and/or cytarabine.

In certain embodiments, the chemotherapy and the administration of the chemotherapeutic drug-related extremity disease include a chemotherapeutic drug-related nail disease and/or a chemotherapeutic drug-related skin disease.

In certain embodiments, the extremity disease associated with administration of a chemotherapeutic agent comprises exudative hyperthyroid dermatitis associated with administration of a chemotherapeutic agent, multiple pyogenic granulomatous lesions associated with administration of a chemotherapeutic agent, dethyroidism associated with administration of a chemotherapeutic agent, Nail bed separation associated with the administration of chemotherapy drugs, nail changes associated with the administration of chemotherapy drugs, pigmentary degeneration associated with the administration of chemotherapy drugs, brittle nails associated with the administration of chemotherapy drugs, cracks in the fingers and heels associated with the administration of chemotherapy drugs, Black nails associated with the administration of chemotherapeutics, hand-foot syndrome (HFS) associated with the administration of chemotherapeutics and/or paronychia associated with the administration of chemotherapeutics.

In certain embodiments, the extremity disease associated with administration of a chemotherapeutic agent comprises hand-foot syndrome (HFS) associated with administration of a chemotherapeutic agent and/or paronychia associated with administration of a chemotherapeutic agent.

In certain embodiments, the severity of the limb disease associated with administration of the chemotherapeutic agent is grade 1 or above, grade 2 or above, grade 3 or above, or above in NCI-CTCAE V5.0. Level 4 or above and/or Level 5 or above.

In certain embodiments, the medicament is formulated for topical administration.

In certain embodiments, the medicament is formulated for transdermal administration.

In certain embodiments, the medicament is formulated for external administration.

In certain embodiments, the site of administration of the topical administration is not the site of occurrence of the cancer or the site of potential metastases of the cancer.

In certain embodiments, the medicament is formulated as creams, lotions, gels, oils, ointments, sprays, foams, liposomal formulations, liniments, aerosols and transdermal devices for transdermal absorption.

In certain embodiments, the medicament further includes one or more other active ingredients.

In certain embodiments, the concentration of the uridine compound in the medicament is from about 0.0001% (w/w) to about 50% (w/w). For example, the concentration of the uridine compound in the drug is about 0.1% (w/w) to about 30% (w/w), about 0.1% (w/w) to about 10% (w/w), about 0.1% (w/w) % (w/w) to about 5% (w/w), about 0.2% (w/w) to about 2% (w/w), about 0.5% (w/w) to about 5% (w/w) ), or from about 1% (w/w) to about 5% (w/w). For example, the concentration of the uridine compound in the drug is about 0.3% (w/w).

In certain embodiments, the uridine compound in the medicament is administered at a dose of from about 0.01 [mu]M to about 1000 [mu]M. For example, the uridine compound in the drug is administered in a dose of about 0.1 μM to about 500 μM, the uridine compound in the drug is administered in a dose of about 0.01 μM to about 400 μM, and the uridine compound in the drug is administered in a dose of about 0.01 μM to about 400 μM The dose is about 0.1 μM to about 400 μM, the uridine compound in the drug is administered at a dose of about 0.8 μM to about 400 μM, the uridine compound in the drug is administered at a dose of about 1 μM to about 400 μM, or the drug is administered in a dose of about 1 μM to about 400 μM The uridine compound is administered at a dose of about 1 μM to about 200 μM.

In certain embodiments, the drug does not substantially affect the therapeutic effect of the chemotherapeutic drug.

In certain embodiments, the subject includes a cancer patient.

In certain embodiments, the subject has been, is and/or will be administered the chemotherapeutic drug.

In certain embodiments, the subject has or is susceptible to the extremity disease associated with administration of the chemotherapeutic drug.

In certain embodiments, the severity of the limb disease associated with administration of the chemotherapeutic drug increases after administration of the chemotherapeutic drug.

In certain embodiments, the subject does not have the extremity disease associated with administration of the chemotherapeutic drug prior to administration of the chemotherapeutic drug.

In another aspect, the present application also provides a pharmaceutical combination or kit comprising: 1) the chemotherapeutic drug described in the present application; and 2) the uridine compound described in the present application.

In certain embodiments, in the pharmaceutical combination or kit, the chemotherapeutic agent and the compound of formula (I) are not mixed with each other.

In certain embodiments, the chemotherapeutic drug and the compound in the pharmaceutical combination or kit are each independently present in separate containers.

In certain embodiments, the compound in the pharmaceutical combination or kit is formulated for topical administration.

In certain embodiments, the compound of the pharmaceutical combination or kit is formulated for topical administration.

In certain embodiments, the compound of the pharmaceutical combination or kit is formulated for transdermal administration.

In certain embodiments, the compound in the pharmaceutical combination or kit is formulated to include creams, lotions, gels, oils, ointments, sprays, foams, liposomal formulations, liniments, aerosols and transdermal devices that are absorbed through the skin.

In certain embodiments, the concentration of the uridine derivative in the drug in the drug combination or kit is from about 0.0001% (w/w) to about 50% (w/w). For example, the concentration of the uridine compound in the drug is about 0.1% (w/w) to about 30% (w/w), about 0.1% (w/w) to about 10% (w/w), about 0.1% (w/w) % (w/w) to about 5% (w/w), about 0.2% (w/w) to about 2% (w/w), about 0.5% (w/w) to about 5% (w/w) ), or from about 1% (w/w) to about 5% (w/w). For example, the concentration of the uridine compound in the drug is about 0.3% (w/w).

In certain embodiments, the uridine compound in the pharmaceutical combination or kit is administered at a dose of about 0.01 μM to about 1000 μM. For example, the uridine compound in the drug is administered in a dose of about 0.1 μM to about 500 μM, the uridine compound in the drug is administered in a dose of about 0.01 μM to about 400 μM, and the uridine compound in the drug is administered in a dose of about 0.01 μM to about 400 μM The dose is about 0.1 μM to about 400 μM, the uridine compound in the drug is administered at a dose of about 0.8 μM to about 400 μM, the uridine compound in the drug is administered at a dose of about 1 μM to about 400 μM, or the drug is administered in a dose of about 1 μM to about 400 μM The uridine compound is administered at a dose of about 1 μM to about 200 μM.

In certain embodiments, the uridine derivative in 2) of the pharmaceutical combination or kit can prevent or treat a limb disease associated with the administration of the chemotherapeutic drug in 1).

In certain embodiments, the uridine derivative in 2) of the drug combination or kit does not substantially affect the therapeutic effect of the chemotherapeutic drug in 1).

In certain embodiments, the uridine derivative in 2) of the pharmaceutical combination or kit is administered before, concurrently with, or after the subject receives administration of the chemotherapeutic agent in 1).

In another aspect, the present application also provides a method for preventing or treating a limb disease associated with the administration of a chemotherapeutic drug, comprising administering the uridine derivative having a therapeutic effect to a subject in need thereof.

In another aspect, the present application also provides a method of preventing or treating a disease or disorder comprising administering to a subject susceptible to or suffering from the disease or disorder a combination comprising a chemotherapeutic drug and a uridine derivative, wherein the disease Or the condition is hand-foot syndrome.

In another aspect, the present application also provides a method of preventing or treating a disease or disorder comprising administering to a subject susceptible to or suffering from the disease or disorder a combination comprising a chemotherapeutic drug and a uridine derivative, wherein the disease Or the condition is paronychia.

Other aspects and advantages of the present application can be readily appreciated by those of ordinary skill in the art from the following detailed description. Only exemplary embodiments of the present application are shown and described in the following detailed description. As those skilled in the art will recognize, the content of this application enables those skilled in the art to make changes to the disclosed embodiments without departing from the spirit and scope of the inventions involved in this application. Accordingly, the drawings and descriptions in the specification of the present application are exemplary only and not restrictive.

The specific features of the invention to which this application relates are set forth in the appended claims. A better understanding of the features and advantages of the inventions involved in this application can be obtained by reference to the exemplary embodiments and drawings described in detail hereinafter. A brief description of the drawings is as follows:

Figure 1 shows a synthetic scheme for an exemplary compound of the present application.

Figures 2A and 2B show the structures of the compounds U1 to U13 of the present application.

Figures 3 to 6 show the toxicity mitigation of 5-FU with different concentrations of uridine derivatives in Hacat.

Figure 7 shows the toxicity mitigation of 5-FU by different concentrations of uridine derivatives in HFF.

Figure 8 shows capecitabine in a rat model of hand-foot syndrome.

Figure 9 shows that exemplary uridine derivatives of the present application prevent and/or treat capecitabine-induced hand-foot syndrome in a rat model.

Figure 10 shows the structures of the compounds U14 to U21 of the present application.

Figures 11-12 show the toxicity mitigation of exemplary NSAID-containing uridine derivatives against 5-FU in Hacat.

Figure 13 shows exemplary NSAID-containing uridine derivatives attenuating inflammatory responses in rats with hand-foot syndrome following chemotherapeutic drug administration.

Figure 14 shows an exemplary combination of uridine derivatives comprising NSAIDs to relieve pain in rats with hand-foot syndrome following chemotherapeutic drug administration.

The embodiments of the invention of the present application are described below by specific specific examples, and those who are familiar with the technology can easily understand other advantages and effects of the invention of the present application from the contents disclosed in this specification.

Chemotherapy drugs

In this application, the term "chemotherapeutic drug" generally refers to a chemotherapeutic drug or formulation. Chemotherapy drugs or preparations can kill tumor cells. These drugs can act on different links of tumor cell growth and reproduction, inhibit or kill tumor cells, and are currently one of the main methods for treating tumors. For example, chemotherapy drugs can act directly on DNA to prevent cancer cells from regenerating. For example, chemotherapy drugs can interfere with DNA and RNA synthesis. For example, chemotherapeutic drugs can block cancer cell proliferation by inhibiting the action of enzymes or mitosis. The types of chemotherapeutic drugs include, but are not limited to: alkylating agents, antimetabolites, antitumor antibiotics, plant anticancer drugs, hormones, and immunological agents.

In some embodiments, the chemotherapeutic agent may include a pyrimidine nucleoside analog or a prodrug thereof. Herein, the term "pyrimidine nucleoside analog" refers to a nucleoside analog metabolite that is structurally similar to pyrimidine, which normally inhibits cancer by interfering with DNA synthesis. The pyrimidine analogs may be cytosine analogs, 5-fluorocytosine analogs, uridine analogs, 5-fluorouridine analogs, thymidine analogs, and the like. The terms "prodrug" and "prodrug" are used interchangeably and are generally precursors of a specified compound that, after administration to a subject, undergo chemical or physiological processes such as solvolysis or enzymatic cleavage, or Under physiological conditions, the compound is produced in vivo. For example, chemotherapeutic drugs may include drugs that are metabolized to form floxuridine nucleotides. Flouridine nucleotides in cells can cause cytotoxicity by interfering with normal uridine nucleotide metabolism.

In this application, the term "cancer" generally refers to any medical condition that is mediated by the growth, proliferation or metastasis of a tumor or malignant cells, and that gives rise to solid and non-solid tumors (eg, leukemia). Cancers described in this application may include, but are not limited to: epithelial malignancies (cancers of epithelial origin), lung cancer (eg, non-small cell lung cancer), breast cancer, skin cancer, bladder cancer, colon cancer, intestinal cancer ( GI) cancer, prostate cancer, pancreatic cancer, uterine cancer, cervical cancer, ovarian cancer, esophageal cancer, head and neck cancer, stomach cancer and laryngeal cancer.

In this application, the term "disease or disorder associated with the administration of a chemotherapeutic drug" generally refers to a disease or disorder associated with the administration of a chemotherapeutic drug to a subject. For example, the disease or disorder can be a disease or disorder caused by administering the chemotherapeutic drug to the subject. the disease or condition may be Occurs or worsens with chemotherapy drugs. For example, the disease or disorder associated with the administration of a chemotherapeutic drug may be hand-foot syndrome.

In this application, the term "skin tissue disease or disorder" generally refers to pathological changes in the form, structure and/or function of the skin (including hair and nails). For example, the skin tissue disease or disorder may include, but is not limited to, rash, hand-foot syndrome, pruritus, erythema, dry skin, alopecia, paronychia, pigmentation disorders, and the like.

In this application, the term "rash" generally refers to changes in the skin that affect the color, appearance or texture of the skin. The rash can be limited to only one part of the body, or it can affect the entire skin. The rash can also include hives.

In this application, the term "hand-foot syndrome" is also referred to as Hand Foot Syndrome (HFS), or Palmar Plantar Erythrodysesthesia (PPE) or Hand-foot skin reaction (HFSR), which was developed by Harvard Medical School New England Dakennis Hospital First described by Jacob Lokich and Cery Moor in 1984. The typical clinical manifestations are progressive, and the main clinical manifestations are finger (toe) heat, pain, erythematous swelling, and severe cases can develop to desquamation, ulcers, and severe pain. Pathological manifestations of HFS can include basal keratinocyte vacuolar degeneration, perivascular lymphocyte infiltration, keratinocyte apoptosis, and skin edema. For example, HFS may include palmar, plantar hypoesthesia, or chemotherapy-induced acral erythema, among others. In this application, cancer patients may experience corresponding symptoms during chemotherapy.

In this application, the term "uridine derivative" generally refers to a product derived from the substitution of the hydrogen atom in uridine by other atoms or atomic groups. In some embodiments, at least one hydroxyl hydrogen on the deoxyribose sugar of the uridine derivative can be substituted. In some embodiments, the uridine derivative can prevent and /or to treat a disease or condition that has been, is and/or will be administered a chemotherapeutic agent and has or is susceptible to suffering from that is associated with the administration of the chemotherapeutic agent.

In this application, the term "alkyl" generally refers to a straight or branched chain saturated hydrocarbyl substituent (eg, a substituent obtained from a hydrocarbon by removal of a hydrogen) containing 1-20 carbon atoms; eg, 1-12 carbon atoms; in other embodiments, the number of carbon atoms is 1-10; in other embodiments, 1-6 carbon atoms, in other embodiments, 1-4 carbon atoms (such as 1, 2, 3 or more carbon atoms). Examples of substituents include: for example, methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl and tert-butyl), Amyl, isopentyl, hexyl, etc. In some cases, the number of carbon atoms in a hydrocarbyl substituent (ie, alkyl, alkenyl, cycloalkyl, aryl, etc.) is represented by the prefix "C _a -C _b ", where a is the smallest and b is the largest the number of carbon atoms in the substituent. Thus, for example, "Ci- _C6 alkyl" refers to an alkyl substituent containing from ₁ to 6 carbon atoms.

In this application, the term "cycloalkyl" generally refers to carbocyclic substituents obtained by removing hydrogen from saturated carbocyclic molecules and having carbon atoms of 3-14 carbon atoms. In some embodiments, a cycloalkyl substituent has 3-10 carbon atoms. Cycloalkyl groups may be monocyclic rings, which typically contain 4-7 ring atoms. Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cycloalkyl can also be 2-3 rings fused together, such as bicyclo[4.2.0]octane and decalin, also known as "bicycloalkyl".

In the present application, the term "cycloalkyl" also includes substituents fused to a _C6 - _C10 aromatic ring or a 5-10 membered heteroaromatic ring, wherein a group having such a fused cycloalkyl as a substituent The group is bound to a carbon atom of the cycloalkyl group. When such a fused cycloalkyl group is substituted with one or more substituents, unless otherwise specified, the one or more substituents are each bonded to a carbon atom of the cycloalkyl. The fused _C6 - _C10 aromatic ring or the 5-10 membered heteroaromatic ring may be further substituted as required.

In this application, the term "hydrogen" generally refers to a hydrogen substituent, possibly described as -H.

In this application, the term "oxygen" generally refers to an oxygen substituent, possibly described as -O-.

In this application, the term "hydroxyl" generally refers to -OH. The prefix "hydroxy" when used in conjunction with another term generally means that the substituent to which the prefix is attached is substituted with one or more hydroxy substituents. Compounds with carbons to which one or more hydroxyl substituents are attached include, for example, alcohols, enols, and phenols.

In this application, the terms "substituent", "radical" and "group" are used interchangeably.

If a substituent is described as "optionally substituted," the substituent may be: (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more substituents, then one or more hydrogens on that carbon (to the extent present) may be independently selected separately and/or together as desired Substituent substitution. If a nitrogen of a substituent is described as being optionally substituted with one or more substituents, one or more hydrogens on that nitrogen (to the extent present) may each be substituted with an independently selected optional substituent. An exemplary substituent may be described as -NR'R", wherein R' and R", taken together with the nitrogen atom to which they are attached, may form a heteroatom containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur. Heterocycle wherein the heterocycloalkyl moiety may be optionally substituted. The heterocycle formed by R' and R" together with the nitrogen atom to which they are attached can be partially or fully saturated, or aromatic. In some embodiments, the heterocycle consists of 4 to 10 atoms.

If a substituent is described as being "independently selected from" a group of groups, each substituent is selected independently of the other substituents. Thus, each substituent can be the same or different from the other substituents.

In this application, the term "formula (I)" or "formula (II)" may be referred to as "compound of formula (I)" or "compound of formula (II)", "compound of formula (I)" or "compound of formula (I)" The compound represented by formula (II)". Such terms are also defined to include all forms of compounds of formula (I) or compounds of formula (II), including hydrates, solvates, isomers, crystalline and amorphous forms, isomorphs, polymorphs and metabolites thing. For example, compounds of formula (I), or a pharmaceutically acceptable salt thereof, and compounds of formula (II), or a pharmaceutically acceptable salt thereof, may be available in unsolvated and solvated forms exist. When the binding force of the solvent or water is strong, the complex has a well-defined stoichiometry, which is not affected by humidity. However, when solvent or water binding is weak, such as in channel solvates and hygroscopic compounds, the water/solvent content will depend on humidity and drying conditions, in which case non-stoichiometry is the norm.

Compounds of formula (I) and/or compounds of formula (II) may have asymmetric carbon atoms. In the present application, the carbon-carbon bonds of compounds of formula (I) and/or compounds of formula (II) can be represented by solid lines, solid wedges or dotted wedges. The use of a solid line to depict a bond to an asymmetric carbon atom is meant to include all possible stereoisomers at that carbon atom (eg, specific enantiomers, racemic mixtures, etc.). The compounds of the present application may contain more than one asymmetric carbon atom. In these compounds, the use of solid lines to indicate bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers are to be included. For example, unless otherwise stated, it is meant that compounds of formula (I) and/or compounds of formula (II) may exist as enantiomers and diastereomers or as racemates and mixtures. Represents the use of solid lines to depict bonds to one or more asymmetric carbon atoms in compounds of formula (I) and/or compounds of formula (II), and the use of solid or dashed wedges to depict bonds to other asymmetric carbon atoms in the same compound. A mixture of diastereomers exists.

The compounds of the present application may exist in the form of clathrates or other complexes. Included within the scope of the invention are complexes, such as inclusion complexes, drug-host inclusion complexes, wherein the drug and host are present in stoichiometric or non-stoichiometric amounts, as opposed to the solvates described above. Also included are compounds of formula (I) and/or complexes of compounds of formula (II) containing two or more organic and/or inorganic components, which may be stoichiometric or non-stoichiometric. The resulting complexes can be ionized, partially ionized or not.

Stereoisomers of compounds of formula (I) and/or compounds of formula (II) include cis and trans isomers, optical isomers such as R and S enantiomers, diastereomers, Geometric isomers, rotational isomers, conformational isomers and tautomers, compounds of formula (I) and/or compounds of formula (II), including compounds exhibiting more than one type of isomerism; and mixtures thereof ( such as racemates and diastereomeric pairs). also package These include acid or base addition salts in which the counterion is optical, such as D-lactate or L-lysine, or racemates such as DL-tartrate or DL-arginine.

When any racemate crystallizes, there may be two different types of crystals. The first category is the above-mentioned racemic compounds (true racemates), in which a homogeneous form of crystals is produced containing equimolar amounts of the two enantiomers. The second type is a racemic mixture or agglomerate, in which two forms of crystals are produced in equimolar amounts, each form containing a single enantiomer.

Compounds of formula (I) and/or compounds of formula (II) may exhibit tautomerism and structural isomerism. For example, compounds of formula (I) and/or compounds of formula (II) may exist in several tautomeric forms, including enol and imine forms, and keto and enamine forms, as well as geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of compounds of formula (I) and/or compounds of formula (II). Tautomers exist in solution as a mixture of tautomers. In solid form, usually one tautomer predominates. Even if one tautomer can be described, the present invention includes all tautomers of compounds of formula (I) and/or compounds of formula (II).

The present invention also includes isotopically-labeled compounds which are the same as compounds of formula (I) and/or compounds of formula (II) but in which one or more atoms have been replaced by an atom having an atomic mass or mass number different from that found in nature. Compounds of formula (I) or isotopes to which compounds of formula (I) may be added include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as but not limited to: 2H, 3H, 13C, 14C, 15N, 18O, 17O , 31P, 32P, 35S, 18F and 36Cl. Certain isotopically-labeled compounds of formula (I) and/or compounds of formula (II), for example into which radioactive isotopes such as 3H and 14C are added, are useful for drug and/or substrate tissue distribution due to their ease of preparation and detectability Determination. Heavier isotopes such as 2H may offer certain therapeutic advantages due to their greater metabolic stability, eg, prolonged in vivo half-life or reduced dosage requirements. isotope label Compounds of formula (I) and/or compounds of formula (II) as described can generally be prepared by substituting an isotopically-labeled reagent for a non-isotopically-labeled reagent.

The compounds of the present application may be used in the form of salts derived from inorganic or organic acids. Certain compounds have advantages such as enhanced drug stability at different temperatures and humidity, or desired solubility in water/oil due to the physical properties of one or more salts. In some cases, salts of compounds can also be used as aids in the isolation, purification and/or resolution of compounds.

In the present application, the term "prodrug" is generally a precursor of a designated compound, which, after administration to a subject, undergoes chemical or physiological processes such as solvolysis or enzymatic cleavage, or under physiological conditions , the compound is produced in the body. "Prodrug" generally refers to a prodrug that is nontoxic, biologically tolerable, and biologically suitable for administration to a subject. Exemplary methods of selecting and preparing suitable prodrug derivatives are described in, eg, "Design of Prodrugs", H. Bundgaard (ed.), Elsevier, 1985.

In this application, the term "non-steroidal anti-inflammatory drug (NSAID)" generally refers to a class of drugs that have antipyretic and analgesic effects. Most NSAIDs inhibit the activity of cyclooxygenases (COX, eg, COX-1 and COX-2), thereby reducing the synthesis of prostaglandins and thromboxanes. Non-steroidal means non-glucocorticoid. In the present application, the uridine derivative may comprise an NSAID moiety, and the NSAID may be a commonly used NSAID, eg, a COX-1 and/or COX-2 inhibitor. The NSAID moiety can be linked to the uridine via an ester bond. The NSAIDs may include, but are not limited to, pyrazolidines, salicylates, acetic acid derivatives, xicams, propionic acid derivatives, profen and/or fenamic acids. For example, the NSAID can include aminoantipyrine, azapyrone, clofezone, ketobutazone, fepradone, diphenhydramine, monophenylbutazone, niphenazone, hydroxybutazone , phenylbutazone, antipyrine, isoantipyrine, sulfinpyrazone, succinamide, aspirin (acetylsalicylic acid), alumina acetylsalicylic acid, benoxylate, carbasalate Calcium, difluorobenzenesalicylic acid, diethyl ether salicylic acid, disalicylamine, acesalicylate, magnesium salicylate, methyl salicylate, salsalate, salicin, salicylic acid amide, sodium salicylate, aceclofenac, acemetacin, allofenac, amfenac, benzylic acid, bromfenac, bumadizone, benzoic acid, diclofenac sodium, diphenacetamide, etodolac, felbinac, fenac for acid, indomethacin, farnesindomethacin, ketorolac, lonazolic acid, oxamethacin, progomethacin, sulindac, tolmetin, zometac, ampiroxicam, dross oxicam, isoxicam, lornoxicam, meloxicam, piroxicam, tenoxicam, aminprofen, benoxiprofen, carbuprofen, dextroibuprofen, dextromethorphan Spinketoprofen, fenbufen, phenoxybuprofen, flunoprofen, flubuprofen, ibuprofen, ibuprofen, indoprofen, ketoprofen, loxoprofen, Miprofen, naproxen, oxaprozin, pirprofen, suprofen, darrenforbi, tepoxalin, tiaprofenic acid, vildaprofen, naproxenol, azapyrone, etofen Naftate, Flufenamic acid, Flufenamic acid, Meclofenamic acid, Mefenamic acid, Morniflumate, Niflufenamic acid, Tofenamic acid, Parecoxib, Celecoxib, Cimicol dexamethasone, delacoxib, etoricoxib, filocoxib, lumiracoxib, movacoxib, parecoxib, robecoxib, rofecoxib, valdecoxib, propionitrile, benzyl Damin, Chondroitin Sulfate, Diacerein, Fluproquinone, Glucosamine, Glycosaminoglycan, Magnesium Salicylate, Nabumetone, Nimesulide, Oxacitor, Proquinone, Ultra Oxide dismutase (ogurin) and/or tenidap.

The compound represented by the formula (I) or the compound represented by the formula (II)

The present application provides the use of a uridine derivative in the preparation of a medicament that can be used to prevent or treat a disease or disorder (eg, hand-foot syndrome) associated with the administration of a chemotherapeutic drug in a subject, wherein the uridine derivative The compound may be an acetyl derivative of uridine (eg, a mono-acetyl-derivative of uridine, a di-acetyl-derivative of uridine, or a tri-acetyl-derivative of uridine).

In the present application, the uridine derivatives may include compounds represented by formula (I) or compounds represented by formula (II), or pharmaceutically acceptable salts, solvents, hydrates, prodrug forms and stereoisomers thereof. Construct:

，式(I)，其中

, formula (I), where

When R ₁ , R ₂ , R ₄ and R ₅ are all hydrogen, R ₃ is not -OH.

In the present application, the R ₁ and R ₂ may be hydrogen.

，其中該X_s可以為氧或硫， R_s可以包括選自下組中的一種或多種基團：氫、取代或未取代的羥基、取代或未取代的巰基、取代或未取代的胺基、C1至C5的取代或未取代的烷基、C1至C5的取代或未取代的炔基、C1至C5的取代或未取代的環烷基、取代或未取代的雜環烷基、取代或未取代的芳基以及取代或未取代的芳烷基。例如，X_s可以為氧。 In this application, the R ₁ can be hydrogen or

, wherein the X _s can be oxygen or sulfur, and R _s can include one or more groups selected from the group consisting of hydrogen, substituted or unsubstituted hydroxy, substituted or unsubstituted thiol, substituted or unsubstituted amine , C1 to C5 substituted or unsubstituted alkyl, C1 to C5 substituted or unsubstituted alkynyl, C1 to C5 substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted Unsubstituted aryl and substituted or unsubstituted aralkyl. For example, _Xs can be oxygen.

，其中該X_g可以為氧或 硫，R_g可以包括選自下組中的一種或多種基團：氫、取代或未取代的羥基、取代或未取代的巰基、取代或未取代的胺基、C1至C5的取代或未取代的烷基、C1至C5的取代或未取代的炔基、C1至C5的取代或未取代的環烷基、取代或未取代的雜環烷基、取代或未取代的芳基以及取代或未取代的芳烷基。例如，X_g可以為氧。 In this application, the R ₂ can be hydrogen or

, wherein the X _g can be oxygen or sulfur, and R _g can include one or more groups selected from the group consisting of hydrogen, substituted or unsubstituted hydroxyl, substituted or unsubstituted thiol, substituted or unsubstituted amine , C1 to C5 substituted or unsubstituted alkyl, C1 to C5 substituted or unsubstituted alkynyl, C1 to C5 substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted Unsubstituted aryl and substituted or unsubstituted aralkyl. For example, _Xg can be oxygen.

For example, the _R3 can be hydrogen. For example, the R ₃ can be -OR ₇ . For example, the _R7 can be hydrogen.

，其中該X₁可以為氧或硫，R₆可以包 括選自下組中的一種或多種基團：氫、取代或未取代的羥基、取代或未取代的巰基、取代或未取代的胺基、C1至C5的取代或未取代的烷基、C1至C5的取代或未取代的炔基、C1至C5的取代或未取代的環烷基、取代或未取代的雜環烷基、取代或未取代的芳基以及取代或未取代的芳烷基。例如，R₆可以選自氫、C1至C6烷基、C1至C6烷氧基、C3至C10環烷基、C3至C10環烷基氧基、C4至C10芳基烷基、C4至C10芳基烷氧基以及C4至C10芳香基。 For example, the _R7 can be

, wherein the X ₁ can be oxygen or sulfur, and R ₆ can include one or more groups selected from the group consisting of hydrogen, substituted or unsubstituted hydroxy, substituted or unsubstituted thiol, substituted or unsubstituted amine , C1 to C5 substituted or unsubstituted alkyl, C1 to C5 substituted or unsubstituted alkynyl, C1 to C5 substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted Unsubstituted aryl and substituted or unsubstituted aralkyl. For example, R6 can be selected from hydrogen, C1 to _C6 alkyl, C1 to C6 alkoxy, C3 to C10 cycloalkyl, C3 to C10 cycloalkyloxy, C4 to C10 arylalkyl, C4 to C10 aryl alkoxy and C4 to C10 aryl groups.

可以為-(C=O)-R₆ ¹、-(C=O)-OR₆ ²、-(C=O)- NR₆ ³R₆ ⁴、-(C=S)-R₆ ⁵、-(C=S)-OR₆ ⁶、-(C=S)-NR₆ ⁷R₆ ⁸，其中R₆ ¹、R₆ ²、R₆ ³、R₆ ⁴、R₆ ⁵、R₆ ⁶、R₆ ⁷和R₆ ⁸中的任意一個可以獨立地包括選自下組中的一種或多種基團：氫、取代或未取代的烷基、取代或未取代的炔基、取代或未取代的環烷基、取代或未取代的雜環烷基、取代或未取代的芳基，取代或未取代的雜芳基。 For example, this

Can be -(C=O)-R ₆ ¹ , -(C=O)-OR ₆ ² , -(C=O)-NR ₆ ³ R ₆ ⁴ , -(C=S)-R ₆ ⁵ , - (C=S)-OR ₆ ⁶ , -(C=S)-NR ₆ ⁷ R ₆ ⁸ , wherein R ₆ ¹ , R ₆ ² , R ₆ ³ , R ₆ ⁴ , R ₆ ⁵ , R ₆ ⁶ , R Any of ₆ ⁷ and R ₆ ⁸ may independently include one or more groups selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, substituted or unsubstituted ring Alkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

For example, wherein any one of R ₆ ¹ , R ₆ ² , R ₆ ³ , R ₆ ⁴ , R ₆ ⁵ , R ₆ ⁶ , R ₆ ⁷ and R ₆ ⁸ may independently include one selected from the group consisting of or Various groups: hydrogen, C1 to C5 alkyl, C1 to C5 cycloalkyl, C1 to C5 heterocycloalkyl, phenyl or benzyl. In some embodiments, the R ₆ ¹ can be selected from hydrogen, C1 to C5 alkyl, C1 to C5 cycloalkyl, C1 to C5 heterocycloalkyl, phenyl, or benzyl. In some embodiments, the R ₆ ² can be selected from hydrogen, C1 to C5 alkyl, C1 to C5 cycloalkyl, C1 to C5 heterocycloalkyl, phenyl, or benzyl. In some embodiments, the R ₆ ³ can be selected from hydrogen, C1 to C5 alkyl, C1 to C5 cycloalkyl, C1 to C5 heterocycloalkyl, phenyl, or benzyl. In some embodiments, the R ₆ ⁴ can be selected from hydrogen, C1 to C5 alkyl, C1 to C5 cycloalkyl, C1 to C5 heterocycloalkyl, phenyl, or benzyl. In some embodiments, the R ₆ ⁵ can be selected from hydrogen, C1 to C5 alkyl, C1 to C5 cycloalkyl, C1 to C5 heterocycloalkyl, phenyl, or benzyl. In some embodiments, the R ₆ ⁶ can be selected from hydrogen, C1 to C5 alkyl, C1 to C5 cycloalkyl, C1 to C5 heterocycloalkyl, phenyl, or benzyl. In some embodiments, the R ₆ ⁷ can be selected from hydrogen, C1 to C5 alkyl, C1 to C5 cycloalkyl, C1 to C5 heterocycloalkyl, phenyl, or benzyl. In some embodiments, the R ₆ ⁸ can be selected from hydrogen, C1 to C5 alkyl, C1 to C5 cycloalkyl, C1 to C5 heterocycloalkyl, phenyl, or benzyl.

In some embodiments, the R ₁ can be selected from:

_In some embodiments, the R can be selected from:

_In some embodiments, the R can be selected from:

For example, the R ₆ ¹ may be selected from C1 to C5 alkyl, C1 to C5 cycloalkyl, phenyl or benzyl.

For example, the compound represented by the formula (I) may be any one or more of compounds U1 to U13.

，式(II)，其中，該R₁、R₂和/或R₇中的至少一個(例 如，R₁，R₂，R₇，R₁和R₂，R₂和R₇，R₁和R₇，或R₁、R₂和R₇)包含非甾體抗炎藥(NSAID)部分。例如，R₁包含NSAID，R₂和R₇為氫。例如，R₂包含NSAID，R₁和R₇為氫。例如，R₇包含NSAID，R₂和R₁為氫。例如，R₁和R₇各自獨立地包含NSAID，R₂為氫。例如，R₁和R₂各自獨立地包含NSAID，R₇為氫。例如，R₂和R₇各自獨立地包含NSAID，R₇為氫。例如，R₁、R₂和R₇各自獨立地包含NSAID。 In the present application, the uridine derivative may comprise an NSAID moiety, and the NSAID may be linked to the uridine moiety via an amide bond. In the present application, the uridine derivative may comprise a compound represented by formula (II):

, formula (II), wherein at least one of the R ₁ , R ₂ and/or R ₇ (eg, R ₁ , R ₂ , R ₇ , R ₁ and R ₂ , R ₂ and R ₇ , R ₁ and R ₇ , or R ₁ , R ₂ and R ₇ ) comprises a non-steroidal anti-inflammatory drug (NSAID) moiety. For example, _R1 contains NSAID, and R2 and _R7 are _hydrogen . For example, R2 contains _NSAIDs , and R1 and _R7 are _hydrogen . For example, _R7 contains _an NSAID, and R2 and R1 are _hydrogen . For example, R1 and _R7 each independently comprise _an NSAID and R2 is _hydrogen . For example, R ₁ and R ₂ each independently comprise an NSAID, and R ₇ is hydrogen. For example, R2 and _R7 each independently comprise an NSAID, and _R7 is _hydrogen . For example, R ₁ , R ₂ and R ₇ each independently comprise an NSAID.

In the present application, the NSAID may comprise salicylic acid or its derivatives, arylacetic acid or its derivatives, heteroarylacetic acid or its derivatives, indoleacetic acid or its derivatives, indeneacetic acid or its derivatives, ortho- Aminobenzoic acid or derivatives thereof and/or enolic acid or derivatives thereof.

For example, R ₁ , R ₂ or R ₇ can be hydrogen. For example, R ₁ , R ₂ and R ₇ may not simultaneously be hydrogen.

For example, at least one of R ₁ , R ₂ and R ₇ can be selected from the group consisting of:

、

、

和

，並且R₁、R₂和R₇ 中未選自上組的那些為氫。例如，R₁選自上組中的任意一個，R₂和R₇為氫。例如，R₂選自上組中的任意一個，R₁和R₇為氫。例如，R₇選自上組中的任意一個，R₂和R₁為氫。例如，R₁和R₇各自獨立地選自上組中的任意一個，R₂為氫。例如，R₁和R₂各自獨立地選自上組中的任意一個，R₇為氫。例如，R₂和R₇各自獨立地選自上組中的任意一個，R₇為氫。例如，R₁、R₂和R₇各自獨立地選自上組中的任意一個。

,

,

and

, and those of R ₁ , R ₂ and R ₇ not selected from the above group are hydrogen. For example, R1 is selected from any _of the above groups, and R2 and _R7 are _hydrogen . For example, R2 is selected from any _of the above groups, and R1 and _R7 are _hydrogen . For example, _R7 is selected from any _of the above groups, and R2 and R1 are _hydrogen . For example, R ₁ and R ₇ are each independently selected from any of the above groups, and R ₂ is hydrogen. For example, R ₁ and R ₂ are each independently selected from any of the above groups, and R ₇ is hydrogen. For example, R ₂ and R ₇ are each independently selected from any of the above groups, and R ₇ is hydrogen. For example, R ₁ , R ₂ and R ₇ are each independently selected from any one of the above groups.

For example, R ₁ , R ₂ and R ₇ may all be the same group. For example, R ₁ , R ₂ and R ₇ may all be different groups. For example, two of R ₁ , R ₂ and R ₇ can all be the same group, eg, R ₁ and R ₂ can be the same, R ₁ and R ₇ can be the same, or R ₂ and R ₇ can be the same.

For example, the uridine derivative comprising the NSAID may be selected from one or more of U14 to U21:

和

。

and

.

In the present application, the NSAID-containing uridine derivatives can be used to prevent or treat a disease or disorder associated with administration of a chemotherapeutic drug (eg, hand-foot syndrome) in a subject.

Limb disease associated with chemotherapy drug administration

In the present application, "diseases associated with the administration of chemotherapeutic drugs" generally refer to the related diseases and disorders in subjects caused by the administration of chemotherapeutic drugs. Clinically used anticancer chemotherapy drugs all have different degrees of toxic and side effects, and some serious toxic and side effects are the direct reasons for limiting the dose or use of drugs. While killing tumor cells, they also kill cells in normal tissues, especially the vigorously growing blood and lymphoid tissue cells in the human body. These cells and tissues are an important immune defense system of the human body. If the immune system of the human body is destroyed, cancer may develop rapidly and cause serious consequences.

In the present application, the disease associated with the administration of chemotherapeutic drugs may be limb disease.

In the present application, the term "limb disease" generally refers to diseases caused by pathological changes of limb tissue and/or cells (eg, tissue/cell pathology of the limb site associated with the administration of chemotherapeutic drugs).

In some embodiments, the extremity disease associated with administration of a chemotherapeutic drug may be a disease of the nails associated with administration of a chemotherapeutic drug and/or a skin disease associated with administration of a chemotherapeutic drug.

In some embodiments, the extremity disease associated with the administration of a chemotherapeutic agent may be exudative hyperthyroid dermatitis associated with the administration of a chemotherapeutic agent, multiple pyogenic granulomatous lesions associated with the administration of a chemotherapeutic agent, dethyroidism associated with the administration of a chemotherapeutic agent, Nail bed separation associated with the administration of chemotherapy drugs, nail changes associated with the administration of chemotherapy drugs, pigmentary degeneration associated with the administration of chemotherapy drugs, brittle nails associated with the administration of chemotherapy drugs, cracks in the fingers and heels associated with the administration of chemotherapy drugs, Black nails associated with the administration of chemotherapeutics, hand-foot syndrome (HFS) associated with the administration of chemotherapeutics and/or paronychia associated with the administration of chemotherapeutics.

In some embodiments, the extremity disease associated with administration of a chemotherapeutic agent is hand-foot syndrome (HFS) associated with administration of a chemotherapeutic agent. In some embodiments, the extremity disease associated with administration of a chemotherapeutic agent is paronychia associated with administration of a chemotherapeutic agent.

In this application, the term "hand foot syndrome" is also referred to as Hand Foot Syndrome (HFS). It was first described in 1984 by Jacob Lokich and Cery Moor of Harvard Medical School's New England Dakenneth Hospital. The typical clinical manifestations are progressive, and the main clinical manifestations are finger (toe) heat, pain, erythematous swelling, and in severe cases, it develops to desquamation, ulcers, and severe pain. The pathological manifestations of HFS mainly include, for example, basal keratinocyte vacuolar degeneration, perivascular lymphocyte infiltration, keratinocyte apoptosis, and skin edema. For example, HFS can include palmar, plantar hypoesthesia, or chemotherapy-induced acral erythema, among others. Cancer patients may experience corresponding symptoms during chemotherapy or molecular targeted therapy (eg, EGFR inhibitors).

Hand-foot syndrome (HFS) currently has a variety of grading methods, among which the National Cancer Institute (NCI) grading standard is more commonly used, which divides hand-foot syndrome into three grades: grade 1 is mild skin changes or dermatitis with paresthesia. (such as disappearance of fingerprints, pigmentation, erythema, peeling, paresthesia, hypoesthesia, skin numbness, etc.), but does not affect daily activities; grade 2 is the same as grade 1, accompanied by pain, mildly affecting daily activities, and the skin surface Complete; grade 3 is ulcerative dermatitis or skin changes with severe pain, which seriously affects daily life, with obvious tissue damage (such as desquamation, blisters, bleeding, edema, etc.).

In addition, the World Health Organization (WHO) classifies HFS as 4 grades: 1 is hypoesthesia, paresthesia or tingling in the hands and feet; 2 is discomfort, painless swelling or erythema when holding objects and walking; Grade 3 was painful erythema and edema on palms and soles, erythema and swelling around the nail; Grade 4 was peeling, ulceration, blistering and severe pain.

In this application, the term "paronychia" refers to an inflammatory reaction involving the periungual skin folds, manifested by acute or chronic suppurative, tender, and painful swelling of the periungual tissue, caused by a nail fold abscess. When the infection becomes chronic, transverse ridges appear at the base of the methyl groups, and new ridges appear with recurrence. The fingers are more commonly affected than the toes. Cancer patients may experience corresponding symptoms during chemotherapy or molecular targeted therapy.

The current general grading standard for paronychia is the grading standard formulated by NCI for skin adverse reactions. The grading refers to the CTCAE 5.0 standard grading released by NCI in 2017, which divides the severity of paronychia into 3 grades: grade 1 is paronychia. Swelling or erythema, damaged periungual skin; Grade 2 requires topical treatment, oral administration is required, paronychia swelling or erythema with pain, separation or detachment of the nail plate, limited use of tools in daily life; Grade 3 requires surgical treatment, Intravenous antibiotics are required, and self-care abilities are limited.

prevention and treatment

In another aspect, the present application provides the use of a uridine derivative in the manufacture of a medicament for preventing or treating a disease or condition associated with the administration of a chemotherapeutic drug in a subject. For example, the uridine derivative may comprise a compound of formula (I) herein. For example, the uridine derivative may comprise compounds U1 to U13. For example, the uridine derivative may comprise a compound of formula (II) herein. For example, and the uridine derivative may comprise compounds U14 to U21.

In the present application, the uridine derivatives can be used to prevent or treat hand-foot syndrome caused by chemotherapeutic drugs. For example, the uridine derivatives can be used for hand-foot syndrome caused by 5-FU or 5-FU prodrugs. For example, the uridine derivative can be used for preventing or treating hand-foot syndrome caused by capecitabine or 5-FU.

In the present application, the uridine derivative may comprise an NSAID moiety, and the uridine derivative comprising an NSAID moiety may alleviate, treat and/or prevent pyrimidine nucleoside analogs or prodrugs thereof (eg, 5- FU or capecitabine), compared with uridine derivatives that do not contain NSAIDs, can simultaneously reduce the pain and inflammatory response of the subjects, indicating that the dual effects of the uridine part and the NSAID part are retained and have a synergistic effect.

The methods of the present application comprise administering to a subject in need thereof an effective amount of a compound of formula (I) or a compound of formula (II), thereby preventing or treating a limb disease associated with administration of a chemotherapeutic drug in the subject . In the present application, the NSAID-containing uridine derivatives can be used to prevent or treat a disease or disorder associated with administration of a chemotherapeutic drug (eg, hand-foot syndrome) in a subject.

In this application, the term "prevention" generally refers to preventing the onset, recurrence or spread of a disease or one or more symptoms thereof. "Prevention" is used interchangeably with "prophylactic treatment" in this application. In certain embodiments, "prevention" generally refers to providing a patient suffering from a disease or condition described herein, with or without other drugs described herein, prior to the onset of symptoms treatment with the mentioned drugs. In certain embodiments, patients with a family history of a particular disease may be candidates for preventive regimens. In certain embodiments, patients with a history of recurrent symptoms are also potential prophylactics.

In this application, the term "subject" generally refers to a human or non-human animal (including mammals) in need of diagnosis, prognosis, amelioration, prevention and/or treatment of a disease, especially a compound represented by formula (I) is required or those subjects treated or prevented by a compound of formula (II). In some embodiments, the subject can include a cancer patient. For example, the cancer patient may have been, is, and/or will be administered a chemotherapeutic drug. For example, the chemotherapeutic drug can be the chemotherapeutic drug described in this application.

In some embodiments, the subject can be a human or a non-human mammal. Non-human mammals can include any mammalian species other than humans, such as livestock animals (eg, cattle, pigs, sheep, chickens, rabbits, or horses), or rodents (eg, rats and mice), or Primates (eg, gorillas and monkeys), or domestic animals (eg, dogs and cats). "Subjects" can be male or female, and can be of different ages.

After administration of the compound represented by the formula (I) or the compound represented by the formula (II) of the present application, the severity of the limb disease of the subject is alleviated. In some embodiments, the remission can be judged according to the grading scale of NCI-CTCAE V5.0, eg, the severity of the limb disease in the subject is reduced from grade 5 to grade 1 (eg, grade 5 to Level 4, Level 5 reduced to Level 3, Level 5 reduced to Level 2, Level 4 reduced to Level 3, Level 4 reduced to Level 2, Level 4 reduced to Level 1, Level 3 reduced to Level 2, Level 3 reduced to Level 1 level or level 2 down to level 1). In some embodiments, the remission can generally refer to a delay in the onset or progression of the subject's limb disease.

In some embodiments, administering an effective amount of a compound of formula (I) or a compound of formula (II) described in the present application to a subject in need can make the severity of the subject's limb disease from Level 5 reduced to Level 1 (e.g. Level 5 reduced to Level 4, Level 5 reduced to Level 3, Level 5 reduced to Level 2, Level 4 reduced to Level 3, Level 4 reduced to Level 2, Level 4 reduced to Level 1 , 3 to 2, 3 to 1, or 2 to 1).

In this application, the term "effective amount" generally refers to an amount of a drug that can alleviate or eliminate a disease or symptom in a subject, or prevent or prevent the occurrence of a disease or symptom prophylactically. An effective amount can be that amount of a drug that alleviates to a certain extent one or more diseases or symptoms in a subject; can restore partially or completely to normal one or more physiological or biochemical parameters associated with the cause of the disease or symptoms and/or the amount of the drug that reduces the likelihood of a disease or symptom.

The therapeutically effective dose of the compound of formula (I) or the compound of formula (II) provided in this application may depend on various factors known in the art, such as the activity, body weight, age, gender, diet, Excretion rate, past medical history, current treatments, time of administration, dosage form, method of administration, route of administration, drug combination, health status of the item and potential for cross-infection, allergies, hypersensitivity and side effects, and/or extent of epithelial tissue disease progression. One skilled in the art (eg, a physician or veterinarian) can proportionally lower or increase the dose according to these or other conditions or requirements.

The effective amount in humans can be extrapolated from the effective amount in experimental animals. For example, Freireich et al. describe the correlation of doses (based on milligrams per square meter of body surface) in animals and humans (Freireich et al., Cancer Chemother. Rep. 50, 219 (1966)). Body surface area can be approximately determined from the patient's height and weight. See, eg, Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 537 (1970).

In some embodiments, a compound of formula (I) or a compound of formula (II) provided herein can be administered at a therapeutically effective dose of between about 0.0001 mg/kg to about 10 mg/kg (eg, about 0.0001 mg/kg to about 10 mg/kg, about 0.005 mg/kg to about 10 mg/kg, about 0.01 mg/kg to about 10 mg/kg, about 0.02 mg/kg to about 10 mg/kg, about 0.05 mg/kg to about 10 mg/kg, about 0.1 mg/kg to about 10 mg/kg, about 0.15 mg/kg to about 10 mg/kg, about 0.2 mg/kg to about 10 mg/kg, about 0.25 mg/kg to about 10 mg/kg, about 0.3 mg/kg to about 10 mg/kg, about 0.35 mg/kg to about 10 mg/kg, about 0.4 mg/kg to about 10 mg/kg, about 0.45 mg/kg to about 10 mg/kg, about 0.5 mg/kg to about 10 mg /kg, about 0.55 mg/kg to about 10 mg/kg, about 0.6 mg/kg to about 10 mg/kg, about 0.65 mg/kg to about 10 mg/kg, about 0.7 mg/kg to about 10 mg/kg, about 0.75 mg /kg to about 10 mg/kg, about 0.8 mg/kg to about 10 mg/kg, about 0.85 mg/kg to about 10 mg/kg, about 0.9 mg/kg to about 10 mg/kg, about 0.95 mg/kg to about 10 mg/kg kg, about 1 mg/kg to about 10 mg/kg, about 2 mg/k to about 10 mg/kg, about 5 mg/k to about 10 mg/kg, about 6 mg/kg to about 10 mg/kg, about 8 mg/kg to about 10 mg/kg kg or about 9 mg/kg to about 10 mg/kg). In some embodiments, the compound of formula (I) or the compound of formula (II) is administered at a dose of about 5 mg/kg or less. In some embodiments, the dose administered is 1 mg/kg or less, 0.5 mg/kg or less, 0.1 mg/kg or less, 0.05 mg/kg or less or 0.01 mg/kg or less. A given dose may be administered at multiple intervals, such as once a day, twice a day or more, once a week, once every two weeks, once every three weeks, once a month, or once every two or more months . In some embodiments, the dose administered may vary over the course of treatment. For example, in some embodiments, the initially administered dose may be higher than the subsequently administered dose. In some embodiments, the administered dose is adjusted over the course of treatment based on the response of the drug administration device. In improving the condition of the subject, the nitric oxide releasing agents of the present application may be administered in maintenance doses as needed. Subsequently, the dose or frequency of administration, or both, can be reduced to a level that maintains improvement when symptoms are relieved to the desired level. In some embodiments, dosing may be spaced according to the disease state of the subject.

In the present application, the concentration of the uridine derivative (eg, the compound represented by the formula (I) or the compound represented by the formula (II)) may be about 0.0001% (w/w) to about 50% (w/w) w), for example, may be about 0.0001% (w/w) to about 90% (w/w), about 0.0001% (w/w) to about 80% (w/w), about 0.0001% (w/w) ) to about 70% (w/w), about 0.0001% (w/w) to about 60% (w/w), about 0.0001% (w/w) to about 50% (w/w), about 0.0001% (w/w) to about 40% (w/w), about 0.0001% (w/w) to about 30% (w/w), about 0.0001% (w/w) to about 20% (w/w) , about 0.0001% (w/w) to about 10% (w/w), about 0.0001% (w/w) to about 5% (w/w), about 0.0001% (w/w) to about 4% ( w/w), from about 0.0001% (w/w) to about 3% (w/w), from about 0.0001% (w/w) to about 2% (w/w), from about 0.0001% (w/w) to about 1% (w/w), about 0.0001% (w/w) to about 0.5% (w/w), about 0.0001% (w/w) to about 0.1% (w/w), about 0.0001% (w) /w) to about 0.05% (w/w), about 0.0001% (w/w) to about 0.01% (w/w), about 0.0001% (w/w) to about 0.005% (w/w), about 0.0001% (w/w) to about 0.005% (w/w) or about 0.0001% (w/w) to about 0.0001% (w/w).

In the present application, the concentrated administration dose of the uridine derivative (eg, the compound represented by formula (I) or the compound represented by formula (II)) may be about 0.0001 μM to about 1500 μM, eg, about 0.001 μM to about 1500 μM, about 1 μM to about 1500 μM, about 1 μM to about 500 μM, about 1 μM to about 100 μM, about 30 μM to about 900 μM, about 10 μM to about 1000 μM, about 10 μM to about 500 μM, about 10 μM to about 400 μM, or about 100 μM to about 100 μM to about 400 μM.

The compound represented by formula (I) or the compound represented by formula (II) described in this application can be administered by means of administration known in the art, such as injection administration or non-injection administration (eg, oral, nasal , sublingual, vaginal, rectal or topical). The compound represented by formula (I) or the compound represented by formula (II) disclosed in this application can be administered in the form of the pharmaceutical combination or kit described in this application.

In some embodiments, the administration of the compound of formula (I) or the compound of formula (II) can be topical. In some embodiments, the site of administration of the topical administration may not be the site of occurrence of the cancer or the site of potential metastases of the cancer. For example, the administered moiety may not be the primary site of cancer. For another example, the administered moiety may not be the metastatic site of the cancer. For example, the metastatic site may include the site of cancer metastasis resulting from lymphatic metastasis, vascular metastasis and/or implanted metastasis. In some embodiments, the metastatic site can include bone, brain, liver, stomach, and/or lung. For another example, the administered portion may not be the recurrence site of the cancer.

In some embodiments, the compound of formula (I) or the compound of formula (II) can be administered transdermally.

In some embodiments, the compound of formula (I) or the compound of formula (II) described herein can be co-administered with a chemotherapeutic agent. In some embodiments, the compound of formula (I) or the compound of formula (II) can be administered before, at the same time as, or after the subject receives a chemotherapeutic drug. In certain embodiments, the compound of formula (I) or the compound of formula (II) may be administered separately from the chemotherapeutic agent as part of a multiple dose regimen. In some embodiments, the compound of formula (I) or the compound of formula (II) can be administered concurrently with a chemotherapeutic agent. In embodiments of simultaneous administration, these The compound of formula (I) or the compound of formula (II) may be part of a single dosage form, which is mixed with the presently disclosed chemotherapeutic agents into a single composition. In other embodiments, these compounds of formula (I) or compounds of formula (II) may be administered as separate doses at about the same time as the chemotherapeutic agent. In the embodiment in which the compound represented by the formula (I) or the compound represented by the formula (II) and the chemotherapeutic drug are administered at intervals, the compound represented by the formula (I) or the compound represented by the formula (II) may be in Dosing is given at intervals before or after the chemotherapy drug is administered. The interval can be 1 minute, 2 minutes, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 18 hours , 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months or longer.

In some embodiments, the chemotherapeutic drugs described herein can be administered by the same route of administration or by a different route of administration as the compound of formula (I) or the compound of formula (II). In some embodiments, the chemotherapeutic drug is administered systemically or locally. In some embodiments, the chemotherapeutic agent is administered by a mode of administration other than transdermal, eg, by oral administration about 1 to about 6 times per day, or by continuous infusion. In some embodiments, the chemotherapeutic agents described herein are administered systemically and the compound of formula (I) or the compound of formula (II) is administered locally. In some embodiments, the chemotherapeutic agents described herein are administered intravenously and the compound of formula (I) or the compound of formula (II) is administered transdermally. In some embodiments, the chemotherapeutic agents described herein may be administered orally, and the compound of formula (I) or the compound of formula (II) may be administered transdermally.

Compounds of formula (I) or compounds of formula (II) used in combination with other therapeutic substances

In some embodiments, a compound of formula (I) or a compound of formula (II) described herein can be co-administered with one or more other therapeutic agents. The meaning of "combination" or "co-administration" in this application also includes compounds of formula (I) or compounds of formula (II) administered before or after another therapeutic substance are also considered to be Therapeutic substances are used "in combination", even if the compound of formula (I) or the compound of formula (II) The compound and the second substance are administered by different modes of administration. If possible, other therapeutic substances used in combination with the compound represented by formula (I) or the compound represented by formula (II) disclosed in this application can be administered by referring to the method in the product manual of the other therapeutic substance, or referring to a doctor of a desk reference, or by reference to other methods known in the art.

In certain embodiments, the one or more additional therapeutic agents may be administered separately (eg, sequentially) from a compound of formula (I) or a compound of formula (II) disclosed herein as part of a multiple dose regimen , eg, administering a compound of formula (I) or a compound of formula (II) in different overlapping regimens). In other embodiments, the therapeutic agents may be part of a single dosage form that is combined with the presently disclosed compound of formula (I) or compound of formula (II) into a single composition. In another embodiment, these agents may be administered as separate doses at about the same time as the compound of formula (I) or the compound of formula (II).

Medications for treating extremity disorders may include: anti-inflammatory agents, analgesics, local anesthetics, antihistamines, antiseptics, immunosuppressants and/or anti-bleeding agents and mixtures thereof.

drug combination or kit

In some embodiments, the compound of formula (I) or the compound of formula (II) can be administered as part of a drug or drug combination.

In some embodiments, the medicament may include a compound of formula (I) or a compound of formula (II) and one or more pharmaceutically acceptable carriers.

In some embodiments, the pharmaceutical combination or kit may comprise 1) a chemotherapeutic drug; and 2) a compound of formula (I) or a compound of formula (II). In some embodiments, the chemotherapeutic agent and the compound of formula (I) or the compound of formula (II) may not be mixed with each other. For example, the chemotherapeutic drug may be present in a separate container with the compound represented by the formula (I) or the compound represented by the formula (II) each independently. in the device. For example, the chemotherapeutic drug can be dispensed in one reagent bottle, and the compound of formula (I) or the compound of formula (II) can be dispensed in another reagent bottle.

In this application, the term "pharmaceutically acceptable" generally means suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction or other problems or complications within the scope of sound medical judgment, Those compounds, materials, compositions and/or dosage forms with a reasonable benefit/risk ratio. In some embodiments, pharmaceutically acceptable compounds, materials, compositions and/or dosage forms are those approved by a regulatory agency (eg, the US Food and Drug Administration, the Chinese Food and Drug Administration, or the European Medicines Agency) or listed in a generally recognized Those in a pharmacopoeia, such as the US Pharmacopoeia, the Chinese Pharmacopoeia or the European Pharmacopoeia, for use in animals, more particularly in humans.

Pharmaceutically acceptable excipients that can be used in the medicaments, pharmaceutical combinations or kits of the present application can include, but are not limited to, for example, pharmaceutically acceptable liquid, gel or solid carriers, aqueous media, non-aqueous media , antimicrobial substances, isotonic substances, buffers, antioxidants, anesthetics, suspending/dispersing agents, chelating agents, emulsifiers, diluents, adjuvants, excipients, non-toxic auxiliary substances, other components known in the art or above of various combinations. Suitable components may include, for example, fillers, binders, disintegrants, buffers, preservatives, lubricants, flavoring agents, thickening agents, coloring agents or emulsifiers. Oral liquid preparations may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, elixirs, and the like.

In some embodiments, the drug or the compound represented by the formula (I) or the compound represented by the formula (II) is an oral preparation. Oral formulations may include, but are not limited to, capsules, sachets, pills, tablets, lozenges (bases for flavor, usually sucrose and acacia or tragacanth), powders, granules, water or non-aqueous solutions or suspensions , water-in-oil or oil-in-water emulsions, elixirs or syrups, lozenges and/or mouthwashes and the like.

Oral solid preparations (for example, capsules, tablets, pills, dragees, powders or granules, etc.) can include the active substance and one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate, and/or or the following substances: (1) fillers or extenders; (2) adhesives; (3) wetting agents; (4) splitting agents; (5) retarder solutions; (6) accelerating absorption agents; (7) lubricants ; (8) absorbent; (9) glidant; and (10) colorant.

In some embodiments, the drug or the compound represented by the formula (I) or the compound represented by the formula (II) can be an injection preparation. Injectable preparations may include sterile aqueous solutions, dispersions, suspensions or emulsions. In all cases, the injectable preparation should be sterile and should be liquid to facilitate injection. It should be stable under the conditions of manufacture and storage and should be resistant to contamination by microorganisms (eg, bacteria and fungi). The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol, or suitable mixtures thereof, and/or vegetable oils. The injectable formulation should maintain proper fluidity, which can be maintained in a variety of ways, for example, by the use of coatings such as lecithin, the use of surfactants, and the like. Antimicrobial contamination can be achieved by the addition of various antibacterial and antifungal agents.

In the present application, the drug or the compound represented by the formula (I) or the compound represented by the formula (II) can be prepared for transdermal administration. In the present application, the drug or the compound represented by the formula (I) or the compound represented by the formula (II) may be prepared for topical administration. In some embodiments, the medicament or the compound of formula (I) or the compound of formula (II) is prepared for topical skin administration. For example, in the present application, the drug or the compound represented by the formula (I) or the compound represented by the formula (II) can be prepared as an ointment. For example, the compound of formula (I) or the compound of formula (II) can be suspended or dissolved in a mixture of one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene Compound, Emulsifying Wax and Water. The compound of formula (I) or the compound of formula (II) can also be formulated into a suitable lotion or cream and suspended or dissolved in a mixture of one or more of the following: Minerals Oil, Sorbitan Monostearate, Polyethylene Glycol, Liquid Paraffin, Polysorbate 60, Cetyl Esters Wax Cetearyl Alcohol, 2-Octyldodecanol, Benzyl Alcohol and water.

In the present application, in the drug, drug combination or kit, the concentration of the compound represented by formula (I) or the compound represented by formula (II) may be about 0.0001% (w/w) to about 50% ( w/w), for example, may be about 0.0001% (w/w) to about 90% (w/w), about 0.0001% (w/w) to about 80% (w/w), about 0.0001% (w/w) /w) to about 70% (w/w), about 0.0001% (w/w) to about 60% (w/w), about 0.0001% (w/w) to about 50% (w/w), about 0.0001% (w/w) to about 40% (w/w), about 0.0001% (w/w) to about 30% (w/w), about 0.0001% (w/w) to about 20% (w/w) w), about 0.0001% (w/w) to about 10% (w/w), about 0.0001% (w/w) to about 5% (w/w), about 0.0001% (w/w) to about 1 % (w/w), about 0.0001% (w/w) to about 0.5% (w/w), about 0.0001% (w/w) to about 0.1% (w/w), about 0.0001% (w/w) ) to about 0.05% (w/w), about 0.0001% (w/w) to about 0.01% (w/w), about 0.0001% (w/w) to about 0.005% (w/w), about 0.0001% (w/w) to about 0.005% (w/w) or about 0.0001% (w/w) to about 0.001% (w/w).

In the pharmaceutical combination or kit described in this application, the compound represented by the formula (I) or the compound represented by the formula (II) in 2) can prevent or treat the disease or condition caused by the chemotherapeutic drug in 1) .

In the present application, the term "substantially does not affect" may refer to the use of the compound represented by the formula (I) or the formula in 2) of the drug combination or kit compared with the therapeutic effect of the chemotherapeutic drug alone The compound shown in (II) and the chemotherapeutic drug in 1) have the same therapeutic effect, or do not produce significant disadvantage. For example, for any subject, the compound represented by the formula (I) or the compound represented by the formula (II) in 2) of the drug combination or kit is used compared with the therapeutic effect of the chemotherapeutic drug alone. The compound and the chemotherapeutic drug in 1) cause the same degree of tumor volume reduction, or, the degree of reduction is not less than about 5%, not less than about 4%, not less than about 3%, not less than about 2%, not less than about 1%, not less than about 0.5%, not less than about 0.1%, not less than about 0.01%, not less than about 0.001% or smaller.

In the pharmaceutical combination or kit described in this application, the compound represented by the formula (I) or the compound represented by the formula (II) in 2) is used before, at the same time or after the administration of the chemotherapeutic drug in 1) apply.

therapeutic use

In one aspect, the application provides the use of a compound represented by formula (I) or a compound represented by formula (II) in the preparation of a medicament for the prevention or treatment of a disease or condition associated with the administration of a chemotherapeutic drug (eg, with Chemotherapy-related extremity disorders, e.g., hand-foot syndrome).

In another aspect, the present application provides a compound represented by formula (I) or a compound represented by formula (II) for use in the prevention or treatment of a disease or condition associated with the administration of a chemotherapeutic drug (such as a limb associated with the administration of a chemotherapeutic drug) diseases such as hand-foot syndrome).

In another aspect, the present application provides a method of treating and/or preventing hand-foot syndrome associated with the administration of chemotherapeutic drugs by compounds of U1 to U13, the compounds being for external use. For example, the chemotherapeutic drug is 5-FU. For example, the compounds of U1 to U13 are administered at a concentration of from about 0.5 μM to about 1500 μM, for example, from about 1 μM to about 1000 μM, from about 10 μM to about 1000 μM, from about 10 μM to about 500 μM, from about 50 μM to about 500 μM, From about 100 μM to about 500 μM.

In another aspect, the present application provides a method of treating and/or preventing hand-foot syndrome associated with the administration of chemotherapeutic drugs by compounds of U1 to U13, the compounds being for external use. For example, the chemotherapy drug is capecitabine. For example, the U1 to U13 compounds are administered at a concentration of about 0.1% (wt%) to about 10.0% (wt%), eg, about 0.1% (wt%) to about 5.0% (wt%), about 0.5% (wt%) to about 5.0% (wt%), is about 0.5% (wt%) to about 3.0% (wt%), is about 1.0% (wt%) to about 3.0% (wt%), is From about 1.0% (wt%) to about 5.0% (wt%).

In another aspect, the present application provides a method of treating and/or preventing hand-foot syndrome associated with the administration of chemotherapeutic drugs by compounds of U14 to U21, the compounds being for external use. For example, the chemotherapeutic drug is 5-FU. For example, the compounds of U14 to U21 are administered at a concentration of from about 0.5 μM to about 1500 μM, for example, from about 1 μM to about 1000 μM, from about 10 μM to about 1000 μM, from about 10 μM to about 500 μM, from about 50 μM to about 500 μM, From about 100 μM to about 500 μM. For example, the U14 to U21 compounds are administered at a concentration of about 1 μM to about 400 μM, about 1 μM to about 200 μM, about 5 μM to about 400 μM, or about 5 μM to about 200 μM.

In another aspect, the present application provides a method of treating and/or preventing hand-foot syndrome associated with the administration of chemotherapeutic drugs by compounds of U14 to U21, the compounds being for external use. For example, the chemotherapeutic agent is 5-FU, capecitabine, cytarabine, doxorubicin, or Acelarin (NUC-1031). For example, the U14 to U21 compounds are administered at a concentration of about 0.5% (wt%) to about 5.0% (wt%), eg, about 0.5% (wt%) to about 3.0% (wt%). For example, the administration concentration is from about 1.0% (wt%) to about 5.0% (wt%). For example, the administration concentration is from about 1.0% (wt%) to about 3.0% (wt%). For example, the administration concentration is from about 1% (wt%) to about 5.0% (wt%). For example, the administration concentration is about 3% (wt %).

Without intending to be limited by any theory, the following examples are only used to illustrate the compounds, preparation methods, uses, etc. of the present application, and are not intended to limit the scope of the invention of the present application.

[Example]

Example 1 Compound represented by formula (I) [carbonic acid (2R,3R,4R,5R)-3,4-II(2,2-dimethylpropoxycarbonyloxy)-5-(2,4 Synthesis of -Di-oxypyrimidin-1-yl)tetrahydrofuran-2-yl]methyl 2,2-dimethylpropyl ester (U13)

The synthetic route of the compound represented by formula (I) is shown in Figure 1. Uridine (500 mg, 2.95 mmol) and triethylamine (1.04 g, 103 mmol) were dissolved in 5 mL of dichloromethane, and chloroformic acid was added at 0 degrees Celsius. Isoamyl ester (1.54 g, 10.3 mmol). The reaction mixture was stirred at 25 degrees Celsius for 2 hours. TLC chromatography showed that the reaction was complete. The reaction mixture was added to 20 ml of water and 20 ml of dichloromethane, and after extraction, the organic phase was separated. It was then washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and rotary evaporated to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain the product [(2R,3R,4R,5R)-3,4-bis(2,2-dimethylpropoxycarbonyloxy)-5-(2,4-dioxopyimidin-1-yl)tetrahydrofuran-2- yl]methyl 2,2-dimethylpropyl carbonate (1.0 g, 1.67 mmol, 81.49% yield, 98% purity). Structure detection results ¹ H NMR(400MHz, DMSO-d6)δ 11.50(s,1H), 7.75(d,1H, J =8.4Hz), 5.95(d,1H, J =4.8Hz), 5.69(d,1H) , J =8.0Hz),5.47(dd,1H, J =5.2,6.2Hz),5.33(t,1H, J =5.6Hz),4.3-4.5(m,3H),3.8-3.9(m,6H) , 0.9-0.9 (m, 27H). LCMS (M+H) ⁺ , 587.5.

U1-U12 provided in Figure 2A in this application were prepared using the same reaction conditions with the corresponding reagents.

Example 2-15 Uridine derivatives alleviate the proliferative toxicity of 5-FU on skin cell HaCaT

The cultured skin cells were digested with HaCaT, counted, and seeded into 96-well plates, with 5,000 to 10,000 cells per well. After the cells have adhered, discard the supernatant. Each well was divided into blank control group, chemotherapeutic drug group, chemotherapeutic drug+compound group represented by formula (I) and blank solvent control group. Chemotherapy drug group: add 100 μL of chemotherapeutic drug solution; chemotherapeutic drug + compound represented by formula (I) group: add chemotherapeutic drug and compound represented by formula (I) solution (chemotherapy drug and compound represented by formula (I) group The final concentration is shown in Table 1, according to the solubility of the compound group shown in formula (I), the compound group solution shown in formula (I) is an ethanol solution or an aqueous solution); blank control group: except for the normal replacement of the basal medium Do not add any solution; a variety of blank solvent control group: add the same volume as the corresponding chemotherapeutic drug group or chemotherapeutic drug+compound group represented by formula (I) the same kind of solution. The blank solvent control group was used for data correction, so as to exclude the effect of the solvent in the chemotherapeutic drug group and the chemotherapeutic drug+compound group represented by formula (I) on the results. After culturing for 48 hours, use the Cell Counting Kit-8 (CCK-8) detection kit (C0037, purchased from Shanghai Beyotime Biotechnology Co., Ltd., Beyotime Biotechnology) to measure the survival rate of cells, thereby calculating the proliferation of chemotherapeutic drugs on cells Toxicity and alleviation of proliferative toxicity by compounds of formula (I). Results were statistically analyzed and plotted using GraphPad Prism 6.0 software, t-test.

Table 1 lists the combination of 5-FU and uridine derivatives, and the corresponding experimental results (wherein, the data in the column of cell viability indicates that compared with the 5-FU group, the corresponding 5-FU + uridine derivative group has increased percentage of viable cells). Figure 3-6 lists typical experimental results.

Table 1: Experimental Conditions and Experimental Results of Examples 2-15

From the results in Table 1 and Figures 3 to 6, it can be seen that 5-FU has proliferation toxicity to skin cell HaCaT, while the compound represented by formula (I) has obvious alleviation effect on the proliferation toxicity caused by chemotherapeutic drugs. After the compound represented by formula (I) is added, the cell survival rate is increased, and at the same time, it has certain advantages over uridine.

Example 16-19 Uridine derivatives alleviate the proliferative toxicity of fluorine-based drugs on human foreskin fibroblasts HFF

The cultured human foreskin fibroblasts HFF were digested, counted, and seeded into 96-well plates, with 5,000 to 10,000 cells per well. After the cells have adhered, discard the supernatant. Chemotherapy drug group: add 100 μL of chemotherapeutic drug solution; chemotherapeutic drug + compound represented by formula (I) group: add chemotherapeutic drug and compound represented by formula (I) solution (chemotherapy drug and compound represented by formula (I) group The final concentration is shown in Table 2, according to the solubility of the compound group shown in formula (I), the compound group solution shown in formula (I) is an ethanol solution or an aqueous solution); blank control group: except for the normal replacement of the basal medium No additional solution was added; a variety of blank solvent control groups: the same volume of solution as the corresponding chemotherapeutic drug group and chemotherapeutic drug+compound group represented by formula (I) was added. The blank solvent control group was used for data correction, so as to exclude the effect of the solvent in the chemotherapeutic drug group and the chemotherapeutic drug+compound group represented by formula (I) on the results. After culturing for 48 hours, use the Cell Counting Kit-8 (CCK-8) detection kit (C0037, purchased from Shanghai Beyotime Biotechnology Co., Ltd., Beyotime Biotechnology) to measure the survival rate of cells, thereby calculating the proliferation of chemotherapeutic drugs on cells Toxicity and alleviation of proliferative toxicity by compounds of formula (I). Results were statistically analyzed and plotted using GraphPad Prism 6.0 software, t-test.

Table 2 lists the combination of 5-FU and uridine derivatives, and the corresponding experimental results (wherein, the data in the column of cell viability indicates that compared with the 5-FU group, the corresponding 5-FU + uridine derivative group has increased percentage of viable cells). Figure 7 lists the more typical experimental results.

Table 2: Experimental Conditions and Experimental Results of Examples 16-19

From the results in Table 2 and Figure 7, it can be seen that 5-FU has proliferation toxicity to HFF, while the compound represented by formula (I) has obvious alleviation effect on the proliferation toxicity caused by chemotherapeutic drugs. obvious advantage.

Example 20-27 Uridine derivatives prevent capecitabine-induced hand-foot syndrome in a rat model

A rat animal model was constructed. Female SD rats were given capecitabine by daily gavage for 6 weeks, and after several days, hand-foot syndrome appeared in the paws of the rats (the photo is shown in Fig. 8 ). There is no difference between the left and right paws in the hands and feet, and the degree of hand-foot syndrome is similar in the two paws. Similar to humans, rats develop hand-foot syndrome in the paws following oral capecitabine. Both have exactly the same cause, and the symptoms are very similar. Therefore, the rat is a very good animal model for simulating capecitabine-induced hand-foot syndrome.

After SD rats were acclimated for a week (about 200 g), the rats were divided into groups of 10, and then the rats were administered by gavage. Capecitabine was dissolved in a mixed solution of castor oil:ethanol=1:1, and diluted three times with PBS buffer solution. After gavage, the rats were fixed with a fixation cylinder, and the uridine derivative gel was applied to the double hind paws (about 1cm*3cm) of the rats in the drug application group (the frequency and concentration are shown in Table 3), and the blank group was applied Blank gel (blank control); about 4 hours after application, the rats were released after 4 hours, and the residual drug at the application site was wiped off with water, and then returned to the rat cage. The gavage frequency of capecitabine is shown in Table 3, and the uridine derivative is applied by gavage every day. The gavage and smear tests were repeated every day until obvious hand-foot syndrome appeared in the blank group. At this time, the number of rats with normal paw skin or with significantly lighter symptoms than the blank group with hand-foot syndrome was calculated as the effective inhibition of hand-foot syndrome. number of syndromic rats.

Table 3 lists the animal experimental combination of capecitabine and uridine derivative gel, and the corresponding experimental results (wherein, the value in the control rate column = the mold rate of hand-foot syndrome in the blank group - the hand-foot syndrome in the applicator group mold release rate).

Table 3: Experimental Conditions and Experimental Results for Examples 20-27

It can be seen from the results in Table 3 and Figure 9 that the compound gel represented by formula (I) can prevent capecitabine-induced hand-foot syndrome to a certain extent.

Example 28 Influence of the compound represented by formula (I) on the therapeutic effect of chemotherapeutic drugs

A BALB/C nude mouse model (human colon cancer cell HCT116 transplanted tumor) model was established. After the model was stabilized, the model mice were divided into 4 groups (the average tumor size of the 4 groups of mice was as consistent as possible), except for the blank group (5 mice), other There were 10 animals in each group, and they were given intragastric administration and drug application experiments.

Dissolve capecitabine in a mixed solution of castor oil: ethanol = 1:1 (volume ratio), dilute to the desired concentration with PBS before gavage (diluted about 3 times with PBS solution), and the gavage volume does not exceed 0.2 mL, administered by gavage for 5 days per week, and the dose was gradually increased. Except for the blank group, the other three groups of mice with tumor were orally administered capecitabine to control or shrink the tumor. At the same time, the gel containing derivatives as the main component was applied to the back of the mice by transdermal administration. The specific implementation is as follows:

A blank group: 5 tumor-bearing mice, without gavage and no drug application; B blank matrix group: 10 tumor-bearing mice, orally gavaged with capecitabine (1.5mmol/kg), and smeared with blank gel (smeared every day) on the back once for 14 days); C 0.5% U1 group: 10 tumor-bearing mice, orally gavaged with capecitabine, and coated with 0.5% U1 gel (administration method and frequency are the same as group B); D 2% U1 group : 10 tumor-bearing mice were orally gavaged with capecitabine and smeared with 1% U1 gel (the administration method and frequency were the same as group B); the smeared area of about 5.8 square centimeters was marked with a marker, and it should be smeared The area cannot be touched by the mouse's mouth, nor can it be next to the tumor. After the daily gavage of experimental groups B, C and D, the corresponding ointment was applied to the area marked on the back of the model mouse with a cotton swab, and the ointment was applied evenly to ensure that the skin was moistened; after applying the medicine, each mouse was placed in a relatively independent Keep the ointment on the back of the mouse for 4 hours to ensure the transdermal absorption of the drug applied on the back; after 4 hours, gently wipe off the residual ointment on the back of the mouse with a paper towel or a paper towel moistened with water; then the mouse can return to the previous cage. normal activity. Tumor size was measured and recorded every 2 days. After 14 days of experiment, the mice were dissected, the tumors were taken out, weighed and recorded, and the changes of tumor volume in different experimental groups were observed.

It can be seen from the results: the volume of tumor tissue in groups B, C, and D (capecitabine gavage group) was significantly smaller than that in group A (capecitabine non-gavage group); Group D) The tumor volume was similar to or slightly smaller than that of the blank gel group (group B). It can be seen that the transdermal gel of the compound of formula (I) does not affect the therapeutic effect of capecitabine on tumors.

Examples 29-36 Uridine Derivatives Containing NSAIDs Mitigate the Proliferative Toxicity of 5-FU on Skin Cell HaCaT

According to the methods of Examples 2-15, the effects of uridine derivatives containing NSAIDs in alleviating the proliferative toxicity of chemotherapeutic drugs (5-FU) on HaCaT cells were examined. See Table 4 for the final concentrations of uridine derivatives tested and test compounds.

Table 4 lists the combination of 5-FU and uridine derivatives, and the corresponding experimental results (wherein, the data in the column of cell viability indicates that the corresponding 5-FU + uridine derivatives were administered compared with the 5-FU group group increased percentage of viable cells). Figures 11 and 12 list the experimental results of several uridine derivatives containing NSAIDs to alleviate the toxicity of 5-FU.

Table 4: Experimental Conditions and Experimental Results for Examples 29-36

From the results in Table 4 and Figure 11 and Figure 12, it can be seen that 5-FU has proliferative toxicity to skin cell HaCaT, while uridine derivatives have obvious alleviation effects on the proliferative toxicity caused by 5-FU. After the uridine derivatives were obtained, the cell viability was increased, and it also had certain advantages over uridine. And the uridine derivatives of U14-U21 can show a strong relieving effect at a lower concentration, and at a concentration of about 50uM, the cell proliferation rate can be increased by more than 50% compared with the control group, or even increased by more than 100%.

Examples 37-49 Uridine derivatives prevent chemotherapeutic drug-induced hand-foot syndrome in a rat model

According to the methods of Examples 20-27, the effect of uridine derivatives on the rat model of chemotherapeutic drug-induced hand-foot syndrome was examined. At the same time, the rat paws after drug treatment were collected, and the inflammation was observed by hematoxylin-eosin staining (HE) and immunohistochemical staining (IHC).

See Table 5 for the uridine derivatives tested and their final concentrations. Table 5 lists the animal experimental combinations of chemotherapeutic drugs and uridine derivative gels, as well as the corresponding experimental results (wherein, the numerical value in the control rate column = the mold release rate of hand-foot syndrome in the blank group - the release of the hand-foot syndrome in the applicator group Rate).

The experimental conditions and experimental results of table 5 embodiment 37-49

It can be seen from the results in Table 5 that different concentrations or different types of uridine derivatives can alleviate the hand-foot syndrome to a certain extent. At the same time, the results of HE and IHC (Fig. 13) showed that the uridine derivatives containing NSAIDs improved the inflammation of the diseased site better than other uridine derivatives that did not contain NSAIDs and the control model group; therefore, the uridine derivatives containing NSAIDs remained With the dual functions of NSAIDs and uridine derivatives, it has more obvious advantages in the treatment and prevention of hand-foot syndrome.

Example 50 Uridine Derivatives Containing NSAIDs Relieve Pain in Chemotherapy Drug-Induced Hand-Foot Syndrome

Under the experimental conditions of Examples 37-47, pain analysis was performed on rats after administration of uridine derivatives (3% concentration) in a rat model of hand-foot syndrome constructed with 4000 mg/kg capecitabine for a period of time. , the pain assessment model is the mechanical sensitivity of rats (von Frey); the experimental steps are as follows: first let the rats adapt to the room for 1 hour, then put the rats into an observation box with a metal mesh floor, let the mice Stay in the box for 20 minutes to acclimate to the environment of the experimental platform. Then the von Frey device was used to detect the pain of the paw, and the surface of the palm of the rat was stimulated with special cilia to detect the mechanical sensitivity of the animal. , 10 g and 20 g (IITC Life Science, Woodland Hills, Series 2390). Immediately withdrawing the paw or licking after a specific pressure was applied was defined as responsive, while failure to withdraw the paw within 6 seconds was defined as unresponsive. The rat movement response was considered an ambiguous response, in which case the stimulus experiment was repeated.

The results are shown in Figure 14, uridine derivatives (U1 and U4) without NSAIDs did not significantly improve the pain in rats; uridine derivatives (U14, U16, U18 and U20) containing NSAIDs in rats The above can be significantly improved. In Fig. 14, Cape400 represents capecitabine at a concentration of 4000 mg/kg.

Example 51 Compound preparation

This example lists the preparation methods of several representative compounds in U14 to U21, and other unlisted compounds are prepared by using corresponding reactants under the same conditions.

(1)((2R,3S,4R,5R)-5-(2,4-Dioxy-3,4-dihydropyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2 -yl)methyl-2-(6-methoxynaphthalen-2-yl)propionate (U14)

The first step, 1-((3aR,4R,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxol-4 Synthesis of -yl)pyrimidine-2,4(1H,3H)-dione

To a solution of uridine (750.0g, 0.5mol, 1.0eq) and p-toluenesulfonic acid (52.9g, 51.2mmol, 0.1eq) in acetone (18.0L) at 0°C was added 2,2-dimethoxy Propane (352.0 g, 563.0 mmol, 68.9 mL, 1.1 eq). The mixture was stirred at 56°C for 1 hour. The reaction solution was cooled to room temperature, sodium bicarbonate (46.4 g, 92.1 mmol) was added, and the mixture was stirred at 25° C. for 0.5 hour. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to obtain 1-[(3aR,4R,6R,6aR)-6-(hydroxymethyl)-2,2 -Dimethyl-3a,4,6,6a-tetrahydrofuran[3,4-d][1,3]dioxol-4-yl]pyrimidine-2,4-dione (800.0g).LC-MS : (M+H) ⁺ , 284.9.

The second step, ((3aR,4R,6R,6aR)-6-(2,4-dioxy-3,4-dihydropyrimidin-1(2H)-yl)-2,2-dimethyltetrahydrofuran Synthesis of [3,4-d][1,3]Dioxy-4-yl)methyl-2-(6-methoxynaphthalen-2-yl)propanoate

-30℃ to 1-[(3aR,4R,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuran[3,4-d] To a solution of [1,3]dioxol-4-yl]pyrimidine-2,4-dione (188g, 662mmol, 1.0eq) in pyridine (2.0L) was added (2S)-2-(6-methyl) dropwise A solution of oxy-2-naphthyl)propionium chloride (168 g, 676 mmol, 1.02 eq) in dichloromethane (500 mL). The reaction solution was stirred at -30 °C for 4 hours, heated to 25 °C, quenched by adding water (10 mL), concentrated under reduced pressure, the crude product was added with ethyl acetate (400 mL), washed with aqueous hydrochloric acid (200 mL*3, 1M), and washed with anhydrous sodium sulfate. Dry, filter, and concentrate under reduced pressure to give crude product. Isopropyl acetate (4.0L) was recrystallized to give [(3aR,4R,6R,6aR)-4-(2,4-dioxopyrimidine-1-yl)-2,2-dimethyl-3a,4, 6,6a-Tetrahydrofuran[3,4-d][1,3]dioxy-6-yl]methyl(2S)-2-(6-methoxy-2-naphthyl)propionate (160g ,96.4% purity).

The third step, ((2R,3S,4R,5R)-5-(2,4-dioxy-3,4-dihydropyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran- Synthesis of 2-yl)methyl-2-(6-methoxynaphthalen-2-yl)propionate

At 25 °C, to [(3aR,4R,6R,6aR)-4-(2,4-dioxopyrimidine-1-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuran[ 3,4-d][1,3]Dioxy-6-yl]methyl(2S)-2-(6-methoxy-2-naphthyl)propionate (150g, 302mmol , 1.0eq) To a solution of water (225 mL) was added trifluoroacetic acid (225 mL). Stir at 25°C for 1 hour. The mixture was diluted with water (500 mL) and filtered to obtain a solid crude product. Recrystallization from isopropyl acetate to give (2R,3S,4R,5R)-5-(2,4-dioxy-3,4-dihydropyrimidin-1(2H)-yl)-3,4-dihydroxy Tetrahydrofuran-2-yl)methyl-2-(6-methoxynaphthalen-2-yl)propionate (95 g, 98.6% purity). White solid. LC-MS: (M+H) ⁺ , 457.1. ¹ H NMR: (400MHz, DMSO-d6) δ (ppm) 11.33(d, J =2.0Hz, 1H), 7.77(d, J =8.0Hz, 2H), 7.72(s, 1H), 7.35-7.41( m, 2H), 7.28(d, J =2.0Hz, 1H), 7.20-7.10(m, 1H), 5.80-5.58(M, 1H), 5.62-5.47(m, 1H), 4.41-4.20(m, 2H), 3.94-4.00(m, 2H), 3.84-3.89(m, 4H), 3.79-3.82(m, 1H), 1.48(d, J = 8.0Hz, 3H).

(2) 2-Ethylbutyl((S)-(2R,3S,4R,5R)-5-(2,4-dioxy-3,4-dihydropyrimidin-1(2H)-yl) -3,4-Dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine ester (U21) synthesis

The first step, 1-((3aR,4R,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxol-4 Synthesis of -yl)pyrimidine-2,4(1H,3H)-dione

Sulfuric acid (0.5 mL) was added dropwise to a solution of uracil-1-B-D-ribofuranoside (1.0 g, 4.1 mmol) in acetone (50 mL), and the mixture was stirred at 25° C. for 1 hour. The reaction solution was neutralized with triethylamine, concentrated to obtain the crude product, and purified by silica gel column chromatography (dichloromethane/methanol=10/1) to obtain 1-((3aR,4R,6R,6aR)-6-(hydroxymethyl) yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxol-4-yl)pyrimidine-2,4(1H,3H)-dione (1.2 g).

The second step, 2-ethylbutyl((S)-(3aR,4R,6R,6aR)-6-(2,4-dioxy-3,4-dihydropyrimidin-1(2H)-yl )-2,2-dimethyltetrahydrofurfural[3,4-d][1,3]dioxy-4-yl)methoxy)(phenoxy)phosphoryl)-L-alanine Synthesis of Esters

To N-[(S)-(2,3,4,5,6-pentafluorophenoxy)phenoxyphosphoryl]-L-alanine isopropyl ester (418 mg, 0.84 mmol, 1.2 eq) and 1-((3aR,4R,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxol-4- base)pyrimidine-2,4(1H,3H)-dione (200mg, 0.70mmol, 1.0eq) in acetonitrile (20mL) was added anhydrous magnesium chloride (67mg, 0.70mmol, 1.0eq). The reaction solution was stirred at 50°C After 1 hour, N,N-dimethylethylenediamine (227 mg, 1.76 mmol, 2.5 eq) was added dropwise. The reaction solution was stirred at 50°C for 2 hours. Water (50 mL) was added to quench, and ethyl acetate (30 mL*3) was used for extraction. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, evaporated under reduced pressure to remove the solvent, and purified by silica gel column chromatography (dichloromethane/methanol=10/1) to obtain 2-ethylbutyl ( (S)-(3aR,4R,6R,6aR)-6-(2,4-Dioxy-3,4-dihydropyrimidin-1(2H)-yl)-2,2-dimethyltetrahydro Furfural [3,4-d][1,3]dioxy-4-yl)methoxy)(phenoxy)phosphoryl)-L-alanine ester (400 mg).

The third step, 2-ethylbutyl ((S)-(2R,3S,4R,5R)-5-(2,4-dioxy-3,4-dihydropyrimidin-1(2H)-yl )-3,4-Dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine ester

To 2-ethylbutyl((S)-(3aR,4R,6R,6aR)-6-(2,4-dioxy-3,4-dihydropyrimidin-1(2H)-yl)-2 ,2-Dimethyltetrahydrofurfural[3,4-d][1,3]dioxy-4-yl)methoxy)(phenoxy)phosphoryl)-L-alanine ester (400mg , 67.2 mmol, 1.0 eq) in water (1 mL) was added trifluoroacetic acid (4 mL). The reaction solution was stirred at 25°C for 2 hours. After that, the reaction solution was concentrated under reduced pressure, and purified by preparative HPLC to obtain 2-ethylbutyl ((S)-(2R,3S,4R,5R)-5-(2,4-dioxy-3,4-dioxy) Hydropyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine ester (99.8 mg). LCMS: MS(ESI) m/z [M+H] ⁺ =556.1. ¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.36(d, J =2.0Hz, 1H), 7.58(d, J =8.0Hz, 1H), 7.48-7.32(m, 2H), 7.32-7.17(m ,3H),6.22-6.00(m,1H),5.77(d, J =6.0Hz,1H),5.59-5.48(m,1H),5.47(d, J =6.0Hz,1H),5.37-5.10( m, 1H), 4.20(m, 1H), 4.10(m, 1H), 4.04-3.81(m, 6H), 1.45(m, 1H), 1.35-1.19(m, 7H), 0.82(t, J = 8.0Hz, 6H).

The structure detection results of each compound are shown in Table 6.

Table 6 Structure test results of uridine derivatives

Claims (63)

Use of a uridine derivative or a pharmaceutically acceptable salt, solvent, hydrate, prodrug form and stereoisomer thereof in the manufacture of a medicament for use in the prevention and/or treatment of a subject and administration A chemotherapeutic drug-related limb disease, the uridine derivative comprising a compound represented by formula (I),

, formula (I), wherein, when R ₁ , R ₂ , R ₄ , and R ₅ are all hydrogen, R ₃ is not -OH. The use as claimed in claim 1, wherein R ₁ is hydrogen or

, wherein the X _s is oxygen or sulfur, and R _s comprises one or more groups selected from the group consisting of hydrogen, substituted or unsubstituted hydroxy, substituted or unsubstituted mercapto, substituted or unsubstituted amine, C1 to C5 substituted or unsubstituted alkyl, C1 to C5 substituted or unsubstituted alkynyl, C1 to C5 substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aralkyl. The use as claimed in claim 2, wherein _Xs is oxygen. The use as claimed in any one of claims 1 to ₃ , wherein R is hydrogen or

, wherein the X _g is oxygen or sulfur, and R _g comprises one or more groups selected from the group consisting of hydrogen, substituted or unsubstituted hydroxyl, substituted or unsubstituted mercapto, substituted or unsubstituted amine, C1 to C5 substituted or unsubstituted alkyl, C1 to C5 substituted or unsubstituted alkynyl, C1 to C5 substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aralkyl. The use as claimed in claim 4, wherein X _g is oxygen. The use as claimed in any one of claims 1 to 5, wherein _R is

or hydrogen, wherein the R ₇ is hydrogen or

, wherein the X ₁ is oxygen or sulfur, and R ₆ comprises one or more groups selected from the group consisting of hydrogen, substituted or unsubstituted hydroxy, substituted or unsubstituted mercapto, substituted or unsubstituted amine, C1 to C5 substituted or unsubstituted alkyl, C1 to C5 substituted or unsubstituted alkynyl, C1 to C5 substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aralkyl. The use as claimed in any one of claims 1 to 6, wherein _R is

, the _R7 is

, wherein R ₆ comprises one or more groups selected from the group consisting of hydrogen, C1 to C6 alkyl, C1 to C6 alkoxy, C3 to C10 cycloalkyl, C3 to C10 cycloalkyloxy, C4 to C10 arylalkyl, C4 to C10 arylalkoxy, and C4 to C10 aryl. The use as claimed in any one of claims 1 to 6, wherein the R ₃ is hydrogen. The use as claimed in any one of claims 1 to 8, wherein the R ₁ is

, wherein R _s comprises one or more groups selected from the group consisting of hydrogen, C1 to C6 alkyl, C1 to C6 alkoxy, C3 to C10 cycloalkyl, C3 to C10 cycloalkyloxy, C4 to C10 arylalkyl, C4 to C10 arylalkoxy, and C4 to C10 aryl. The use as claimed in any one of claims 1 to 8, wherein the R ₂ is

, wherein R _g comprises one or more groups selected from the group consisting of hydrogen, C1 to C6 alkyl, C1 to C6 alkoxy, C3 to C10 cycloalkyl, C3 to C10 cycloalkyloxy, C4 to C10 arylalkyl, C4 to C10 arylalkoxy, and C4 to C10 aryl. The use as claimed in any one of claims 1 to 9, wherein R ₄ is hydrogen. The use as claimed in any one of claims 1 to 10, wherein R ₅ is hydrogen. The use according to any one of claims 1 to 12, wherein the uridine derivative is selected from one or more of the following group:

,

and

. The use as claimed in claim 1, wherein the uridine derivative comprises a compound represented by formula (II):

, formula (II), wherein at least one of the R ₁ , R ₂ and R ₇ comprises a non-steroidal anti-inflammatory drug (NSAID) moiety. The use of claim 14, wherein the NSAID moiety comprises salicylic acid or a derivative thereof, arylacetic acid or a derivative thereof, heteroarylacetic acid or a derivative thereof, indoleacetic acid or a derivative thereof, indeneacetic acid or Its derivatives, anthranilic acid or its derivatives and/or enolic acid or its derivatives. The use as claimed in claim 14 or 15, wherein R ₁ , R ₂ or R ₇ is hydrogen. The use of any one of claims 14 to 16, wherein R ₁ , R ₂ and R ₇ are not simultaneously hydrogen. The use as claimed in any one of claims 14 to 16, wherein any one of R ₁ , R ₂ and R ₇ is independently

, where R ₈ is R _s ² or

,in, R _s ¹ is hydrogen or methyl, R _s ² is

,in, The ring A is a C4 to C7 aryl group, a C4 to C7 heteroaryl group, an indene ring, a naphthalene ring, an indoline ring, an unsaturated polycyclic hydrocarbon and/or a heterocyclic polycyclic ring, Rs ³ and/or Rs ⁴ are independently selected from: hydrogen, C1 to C6 alkyl, C1 to C6 alkyl ester, halogen, C4 to C7 aryl, C4 to C7 heteroaryl and

, wherein Ring B is a C4-C7 aryl group, a C4-C7 heteroaryl group, and X is -CH ₂ , -NH-, -O- or

wherein, the C4 to C7 aryl, C4 to C7 heteroaryl group is optionally substituted by one or more substituents selected from the group consisting of halogen, C1 to C6 alkyl, C1 to C6 alkynyl and C1 to C6 alkenyl. The use as claimed in any one of claims 14 to 18, wherein _R8 is

, R _s ¹ is hydrogen or methyl, and R _s ² is selected from

,

,

,

,

and

. The use as claimed in any one of claims 14 to 19, wherein _R8 is

, R _s ¹ is hydrogen or methyl, R _s ² is

,in, Ring A ₁ is C4 to C7 cycloalkyl, C4 to C7 heterocycloalkyl, C4 to C7 aryl and/or C4 to C7 heteroaryl, Ring B ₁ is C4 to C7 cycloalkyl, C4 to C7 heterocycloalkyl, C4 to C7 aryl, C4 to C7 heteroaryl or

,in, Ring B ₂ is C4 to C7 cycloalkyl, C4 to C7 heterocycloalkyl, C4 to C7 aryl and/or C4 to C7 heteroaryl, and Ring B ₃ is C4 to C7 cycloalkyl, C4 to C7 heterocycle alkyl, C4 to C7 aryl and/or C4 to C7 heteroaryl, Wherein, the C4 to C7 cycloalkyl, C4 to C7 heterocycloalkyl, C4 to C7 aryl and/or C4 to C7 heteroaryl are optionally halogenated,

,

,

, C1 to C6 alkyl, C1 to C6 alkyl substituted ester group and/or C1 to C6 alkyl substituted aldehyde group, Wherein, ring C is a benzene ring, and Y is -CH ₂ , -NH-, -O- or

; the benzene ring is optionally substituted by one or more substituents selected from the group consisting of fluorine, chlorine, bromine and

; the Y may form a double bond with a ring atom on ring B ₂ or ring B ₃ . The use as claimed in any one of claims 14 to 20, wherein _R8 is

, R _s ¹ is hydrogen or methyl, R _s ² is

or

. The use as claimed in any one of claims 14 to 21, wherein _R8 is

, R _s ¹ is hydrogen or methyl, R _s ² is

. The use as claimed in any one of claims 14 to ₂₂ , wherein R is

, R _s ¹ is hydrogen or methyl, R _s ² is

. The use as claimed in any one of claims 14 to 23, wherein R ₈ ¹ is

or

. The use of any one of claims 14 to 24, wherein any one of R ₁ , R ₂ and R ₇ is independently

. The use of any one of claims 14 to 25, wherein any one of R ₁ , R ₂ and R ₇ is independently selected from the group consisting of hydrogen,

,

,

,

,

,

,

,

and

The use according to any one of claims 1 to 26, wherein the uridine derivative is selected from one or more of the following group:

and

. The use of any one of claims 1 to 27, wherein the chemotherapeutic agent is for the treatment of cancer. The use of any one of claims 1 to 28, wherein the chemotherapeutic agent comprises a pyrimidine nucleoside analog or a prodrug thereof. The use of any one of claims 1 to 29, wherein the chemotherapeutic agent comprises one or more compounds selected from the group consisting of capecitabine, cytarabine, docetaxel, doxorubicin, Fluorouracil (5-FU), Floxuridine, Tegafur, Idarubicin, Paclitaxel, Epirubicin, Doxorubicin, Acelarin (NUC-1031), Leucovorin, Cisplatin , taxanes, cyclophosphamide, vincristine and 5-FU prodrugs. The use as claimed in claim 30, wherein the 5-FU prodrugs comprise the pro-drugs of furanfluridine, 5'-deoxyfluridine, floxuridine, 2'-deoxyfluridine, and floxuridine Derivatives or prodrug derivatives of 2'-deoxyfluridine, trifluoro-methyl-2'-deoxyuridine, 6-azauridine and/or 3-deazauridine. The use of any one of claims 1 to 31, wherein the chemotherapeutic agent comprises fluorouracil (5-FU), capecitabine, floxuridine, tegafur and/or cytarabine. The use according to any one of claims 1 to 32, wherein the extremity disease associated with the administration of chemotherapeutic drugs comprises nail diseases associated with the administration of chemotherapeutics and/or skin diseases associated with the administration of chemotherapeutics. The use of any one of claims 1 to 33, wherein the limb disease associated with administration of a chemotherapeutic drug comprises the disease or disorder associated with epithelial cell lesions. The use of claim 34, wherein the epithelial cells comprise skin epithelial cells. The use of any one of claims 1 to 35, wherein the extremity disease associated with the administration of a chemotherapeutic drug comprises exudative hyperthyroid dermatitis, multiple perithyroidal pyogenic granuloma-like lesions associated with the administration of a chemotherapeutic drug, and thyroid disease associated with administration of chemotherapy drugs, onychomycosis associated with administration of chemotherapy drugs Bed Separation, Nail Changes Associated With Chemotherapy, Pigmented Degeneration Associated With Chemotherapy, Nail Weaknesses Associated With Chemotherapy, Finger and Heel Cracks Associated With Chemotherapy, Melanosis Associated With Chemotherapy N, Hand-foot syndrome associated with administration of chemotherapeutics and/or paronychia associated with administration of chemotherapeutics. The use of any one of claims 1 to 36, wherein the extremity disease associated with the administration of a chemotherapeutic drug comprises hand-foot syndrome associated with the administration of a chemotherapeutic drug. The use according to any one of claims 1 to 37, wherein the severity of the limb disease associated with the administration of a chemotherapeutic drug is grade 1 or above, grade 2 or its according to NCI-CTCAE V5.0 Above, Level 3 or above, Level 4 or above, and/or Level 5 or above. The use of any one of claims 1 to 38, wherein the medicament is prepared for topical administration. The use of any one of claims 1 to 39, wherein the medicament is prepared for transdermal administration. The use of any one of claims 1 to 40, wherein the medicament is prepared for external administration. The use according to any one of claims 39 to 41, wherein the administration site of the local administration is not the site of occurrence of cancer or the site of potential metastasis of cancer. The use of any one of claims 1 to 42, wherein the medicament is prepared as a cream, lotion, gel, oil, ointment, spray, foam, liposomal formulation, liniment, aerosol and transdermal devices that are absorbed through the skin. The use of any one of claims 1 to 43, wherein the medicament further comprises one or more other active ingredients. The use of any one of claims 1 to 44, wherein the concentration of the uridine derivative in the medicament is from about 0.0001% (w/w) to about 50% (w/w). The use of any one of claims 1 to 45, wherein the uridine derivative in the medicament is administered at a concentration of about 0.01 μM to about 1000 μM. The use of any one of claims 1 to 46, wherein the drug does not substantially affect the therapeutic effect of the chemotherapeutic drug. The use of any one of claims 1 to 47, wherein the subject comprises a cancer patient. The use of any one of claims 1 to 48, wherein the subject has been, is and/or will be administered the chemotherapeutic drug. The use of any one of claims 1 to 49, wherein the subject has or is susceptible to the limb disease associated with administration of a chemotherapeutic drug. The use of any one of claims 1 to 50, wherein the severity of the limb disease associated with administration of a chemotherapeutic drug increases after administration of the chemotherapeutic drug. The use of any one of claims 1 to 51, wherein the subject does not have the limb disease associated with the administration of the chemotherapeutic drug prior to the administration of the chemotherapeutic drug. A pharmaceutical combination or kit comprising: 1) the chemotherapeutic drug according to any one of claims 1 to 52; and 2) the uridine derivative according to any one of claims 1 to 52. The drug combination or kit of claim 53, wherein the chemotherapeutic drug and the uridine derivative are not mixed with each other. The pharmaceutical combination or kit of claim 53 or 54, wherein the chemotherapeutic drug and the uridine derivative are each independently present in separate containers. The pharmaceutical combination or kit of any one of claims 53 to 55, wherein the uridine derivative is prepared for external administration. The pharmaceutical combination or kit of any one of claims 53 to 56, wherein the uridine derivative is prepared for topical administration. The pharmaceutical combination or kit of any one of claims 53 to 57, wherein the uridine derivative is prepared for transdermal administration. The pharmaceutical combination or kit of any one of claims 53 to 58, wherein the uridine derivative is prepared to include a cream, lotion, gel, oil, ointment, spray, foam, liposome Formulations, liniments, aerosols and transdermal devices for dermal absorption. The pharmaceutical combination or kit of any one of claims 53 to 59, wherein the concentration of the uridine derivative is from about 0.0001% (w/w) to about 50% (w/w). The pharmaceutical combination or kit according to any one of claims 53 to 60, wherein the uridine derivative in 2) can prevent or treat limb diseases related to the administration of the chemotherapeutic drug in 1). The pharmaceutical combination or kit according to any one of claims 53 to 61, wherein the uridine derivative in 2) does not substantially affect the therapeutic effect of the chemotherapeutic drug in 1). The pharmaceutical combination or kit of any one of claims 53 to 62, wherein the uridine derivative in 2) is administered before, simultaneously with or after the subject receives the chemotherapeutic drug in 1).

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