WO2022089612A1

WO2022089612A1 - Use of uridine derivative in preparation of medicament

Info

Publication number: WO2022089612A1
Application number: PCT/CN2021/127670
Authority: WO
Inventors: 刘世岚; 张诗宜; 吴兆宇
Original assignee: 上海岸阔医药科技有限公司
Priority date: 2020-10-30
Filing date: 2021-10-29
Publication date: 2022-05-05
Also published as: CN116437930A; TW202227097A

Abstract

Use of a uridine derivative in preparation of a medicament. The medicament is used for preventing or treating a limb disease associated with administration of a chemotherapy drug in a subject. Further provided is a pharmaceutical combination or kit comprising the chemotherapy drug and the uridine derivative.

Description

Application of uridine derivatives in the preparation of medicines

technical field

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.

Background technique

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), polythyroidism Peripheral pyogenic granulomatous lesions, hypothyroidism, nail bed separation, paronychia, etc. These side effects can lead to chemotherapy drug discontinuation or dose reductions, 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.

SUMMARY OF THE INVENTION

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 use of a pharmaceutically acceptable salt, solvent, hydrate, prodrug form and stereoisomer thereof in the preparation of a medicament for the preparation of a subject for prevention and treatment Drugs for extremity disorders associated with administration of chemotherapy drugs (eg, hand-foot syndrome). The 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 agents, and the like. It has been discovered in the present application that diseases or conditions associated with the administration of chemotherapeutic agents can be effectively prevented or treated using the compounds. The present application has also discovered 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 Treating a limb disease associated with the administration of a chemotherapeutic drug in a subject, the uridine derivative comprises a compound of formula (I):

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

In certain embodiments, the R1 is hydrogen or

wherein 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 amino, 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 Substituted aryl and substituted or unsubstituted aralkyl. In certain embodiments, _Xs is oxygen.

In certain embodiments, R ₂ is hydrogen or

wherein X _g is oxygen or sulfur, and R _g comprises one or more groups selected from the group consisting of hydrogen, substituted or unsubstituted hydroxy, substituted or unsubstituted mercapto, substituted or unsubstituted amino, 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 Substituted aryl and substituted or unsubstituted aralkyl. In certain embodiments, X _g is oxygen.

In certain embodiments, the R ₃ is

or hydrogen, wherein said _R7 is hydrogen or

wherein X ₁ is oxygen or sulfur, 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 amino, 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 Substituted aryl and substituted or unsubstituted aralkyl.

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 cycloalkyl, C3 to C10 cycloalkyloxy, C4 to C10 arylalkyl, C4 to C10 arylalkoxy, or C4 to C10 aryl.

In certain embodiments, the _R3 is hydrogen.

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.

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.

In certain embodiments, in the structure shown in formula (I), R ₄ and R ₅ are both hydrogen, and R ₃ is

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

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

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:

In certain embodiments, the uridine derivative comprises a compound of formula (II):

Formula (II), wherein at least one of said 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.

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

where R ₈ is R _s ² or

Wherein, 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, Rs ³ and/or Rs ⁴ is 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 with one or more substituents selected from the group consisting of halogen, C1 to C6 alkyl, C1 to C6 alkynyl, and C1 to C6 alkenyl.

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, which is optionally substituted with one or more C1 to C6 alkyl groups.

In certain embodiments, R _s ¹ and/or R _s ² are

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

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

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 rings and

wherein, ring B is a benzene ring, and 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.

In certain embodiments, R ₈ is

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

In certain embodiments, R ₈ is

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

Wherein, ring A ₁ is C4-C7 cycloalkyl, C4-C7 heterocycloalkyl, C4-C7 aryl and/or C4-C7 heteroaryl, and ring B ₁ is C4-C7 cycloalkyl, C4-C7 Heterocycloalkyl, C4 to C7 aryl, C4 to C7 heteroaryl or

Wherein, ring B ₂ is C4-C7 cycloalkyl, C4-C7 heterocycloalkyl, C4-C7 aryl and/or C4-C7 heteroaryl, and ring B ₃ is C4-C7 cycloalkyl, C4-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 group, 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 with 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 .

In certain embodiments, R _s ² is

Wherein, described R _s ⁶ is fluorine, chlorine or bromine,

M is nitrogen or carbon, X is carbon or

A double bond is optionally formed between X and M, and R _s ⁷ is fluorine, chlorine, bromine or

In certain embodiments, R ₈ is

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

In certain embodiments, R ₈ is

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

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.

In certain embodiments, R ₈ is

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

In certain embodiments, R ₈ ¹ is

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:

hydrogen,

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

hydrogen,

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

hydrogen,

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

hydrogen,

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

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

hydrogen,

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

hydrogen,

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

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, tega Fluoride, Idarubicin, Paclitaxel, Epirubicin, Doxorubicin, Acelarin (NUC-1031), Leucovorin, Cisplatin, Taxanes, Cyclophosphamide, Vincristine, and 5-FU Predrug body.

In certain embodiments, the 5-FU prodrug comprises fluoropyridine, 5'-deoxyfluridine, floxuridine, 2'-deoxyfluridine, a prodrug derivative 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 comprise a chemotherapeutic drug-related nail disease and/or a chemotherapeutic drug-related skin disease.

In certain embodiments, the extremity disease associated with the administration of a chemotherapeutic drug comprises exudative hyperthyroid dermatitis associated with the administration of a chemotherapeutic drug, multiple pyogenic granulomatous lesions associated with the administration of a chemotherapeutic drug, and dethyroidism associated with the administration of a chemotherapeutic drug Symptoms, Nail Bed Separation Associated with Chemotherapy, Nail Changes Associated with Chemotherapy, Pigmented Degeneration Associated with Chemotherapy, Nail Weakness Associated with Chemotherapy, Fingers and Heels Associated with Chemotherapy Fissures, black nails associated with administration of chemotherapeutics, hand-foot syndrome (HFS) associated with administration of chemotherapeutics and/or paronychia associated with 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 the administration of the chemotherapeutic agent is grade 1 or above, grade 2 or above, grade 3 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 skin absorption device.

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) 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) 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 μM to about 1000 μM. For example, the uridine compound in the drug is administered at a dose of about 0.1 μM to about 500 μM, the uridine compound in the drug is administered at a dose of about 0.01 μM to about 400 μM, and the uridine compound in the drug is administered at a dose of about 0.01 μM to about 400 μM The administered dose of the uridine compound in the drug is about 0.1 μM to about 400 μM, the administered dose of the uridine compound in the drug is about 0.8 μM to about 400 μM, and the administered dose of the uridine compound in the drug is about 1 μM to about 400 μM , or the uridine compound in the drug 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 the administration of the chemotherapeutic drug.

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

In certain embodiments, the subject does not have the extremity disease associated with the administration of the chemotherapeutic drug prior to the 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 compounds of the pharmaceutical combination or kit are formulated for topical administration.

In certain embodiments, the compounds of the pharmaceutical combination or kit are formulated for transdermal administration.

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

In certain embodiments, the concentration of the uridine derivative in the drug in the pharmaceutical 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) 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) 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 at a dose of about 0.1 μM to about 500 μM, the uridine compound in the drug is administered at a dose of about 0.01 μM to about 400 μM, and the uridine compound in the drug is administered at a dose of about 0.01 μM to about 400 μM The administered dose of the uridine compound in the drug is about 0.1 μM to about 400 μM, the administered dose of the uridine compound in the drug is about 0.8 μM to about 400 μM, and the administered dose of the uridine compound in the drug is about 1 μM to about 400 μM , or the uridine compound in the drug 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 the limb diseases associated with the administration of the chemotherapy 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, at the same time as, or after the subject is administered the chemotherapeutic drug 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 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 disorder is hand-foot syndrome.

In another aspect, the 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 disorder is paronychia.

Other aspects and advantages of the present application can be readily appreciated by those skilled 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 specific embodiments disclosed without departing from the spirit and scope of the invention to which this application relates. Accordingly, the drawings and descriptions in the specification of the present application are only exemplary and not restrictive.

Description of drawings

The invention to which this application relates is set forth with particularity characteristic of the appended claims. The features and advantages of the inventions involved in this application can be better understood by reference to the exemplary embodiments described in detail hereinafter and the accompanying drawings. 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-2B show the structures of compounds U1 to U13 described in this application.

Figures 3-6 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 compounds U14 to U21 described in this 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.

Detailed ways

The embodiments of the invention of the present application are described below with specific specific examples, and those skilled in the art 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, chemotherapy 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 comprise a pyrimidine nucleoside analog or a prodrug thereof. Among them, the term "pyrimidine nucleoside analog" refers to a nucleoside analog metabolite that is structurally similar to pyrimidine, which usually inhibits cancer by interfering with DNA synthesis. The pyrimidine analogs may be cytosine analogs, 5-fluorocytosine analogs, uridine analogs, 5-fluorouracil analogs, thymidine analogs, and the like. The term "prodrug" is used interchangeably with "prodrug" and is generally a precursor of a named compound that, 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 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 may be a disease or disorder caused by administration of the chemotherapeutic drug to a subject. The disease or disorder may develop or be exacerbated after administration of the chemotherapeutic drug. 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 Dakinis Hospital was 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 hydroxy hydrogen on the deoxyribose sugar of the uridine derivative can be substituted. In some embodiments, the uridine derivatives can prevent and/or treat a disease or condition that has been, is and/or will be administered with a chemotherapeutic agent and suffers from or is susceptible to a disease or condition 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), pentyl , isopentyl, hexyl, etc. In some cases, the number of carbon atoms in a hydrocarbyl substituent (ie, alkyl, alkenyl, cycloalkyl, aryl, etc.) is indicated 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 a carbocyclic substituent obtained by removing hydrogen from a saturated carbocyclic molecule and having carbon atoms ranging from 3 to 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 optionally further substituted.

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. When used in conjunction with another term, the prefix "hydroxy" 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 can 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 and/or together selected optional optional 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 can be described as -NR'R", wherein R' and R", taken together with the nitrogen atom to which they are attached, can 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, a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a compound of formula (II), or a pharmaceutically acceptable salt thereof, can exist in unsolvated and solvated forms. 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 (eg racemates and diastereomeric pairs). Also included are acid or base addition salts in which the counterion is optically active, 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, as well as 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 wherein one or more atoms are replaced by atoms having atomic masses or mass numbers different from those 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. Isotopically labeled compounds of formula (I) and/or formula (II) 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 this 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, This 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 through 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 may include aminoantipyrine, azapyrone, clofezone, ketobutazone, fepradone, diphenhydramine, monophenylbutazone, niphenazone, hydroxybutazone Pine, phenylbutazone, antipyrine, isoantipyrine, sulfinpyrazone, succinamide, aspirin (acetylsalicylic acid), alumina acetylsalicylic acid, benoxylate, carbasalate calcium , Difluorophenylsalicylic acid, Diacetylsalicylic acid, Ethsalicylamine, Acetylsalicylate, Magnesium salicylate, Methyl salicylate, Salicyl ester, Salicin, Salicylamide, Salicylic acid Sodium, aceclofenac, acemetacin, alclofenac, amfenac, benzylic acid, bromfenac, bumadizone, buprofen, diclofenac sodium, dibenzapamide, etoric Doxic acid, felbinac, fentenic acid, indomethacin, farnesindomethacin, ketorolac, lonazolic acid, oxamethacin, progmethacin, sulindac, tolmetin, zomet acid, ampiroxicam, droxicam, isoxicam, lornoxicam, meloxicam, piroxicam, tenoxicam, aminprofen, phenoxprofen, carbuprofen, dextromethorphan Robuprofen, Dexketoprofen, Fenbufen, Phenoxybuprofen, Flunoprofen, Flubuprofen, Ibuprofen, Ibuprofen, Indoprofen, Ketoprofen , Loxoprofen, Miprofen, Naproxen, Oxaprozin, Piprofen, Suprofen, Dalianfobi, Tepoxalin, Tioprofenic acid, Vidalprofen, Naprocino, Azapyrone, etofenamate, flufenamic acid, fluminamic acid, meclofenamic acid, mefenamic acid, moniflumate, niflufenac, tolfenamate, parecoxib, celecoxib coxib, simecoxib, delacoxib, etoricoxib, filocoxib, lumiracoxib, movacoxib, parecoxib, robecoxib, rofecoxib, valdecoxib, Aminopropionitrile, benzydamine, chondroitin sulfate, diacerein, fluproquinone, glucosamine, glycosaminoglycan, magnesium salicylate, nabumetone, nimesulide, oxacicrol, Proquinone, superoxide 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 manufacture of a medicament that can be used to prevent or treat a disease or condition (eg, hand-foot syndrome) associated with the administration of a chemotherapeutic drug in a subject, wherein the The uridine derivative may be an acetyl derivative of uridine (eg, a monoacetyl derivative of uridine, a diacetyl derivative of uridine, or a triacetyl 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:

in

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

In this application, the R ₁ and R ₂ can be hydrogen.

In this application, the R ₁ can be hydrogen or

wherein the _Xs may be oxygen or sulfur, and _Rs may include one or more groups selected from the group consisting of hydrogen, substituted or unsubstituted hydroxy, substituted or unsubstituted mercapto, substituted or unsubstituted Amino, 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. For example, _Xs can be oxygen.

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 hydroxy, substituted or unsubstituted mercapto, substituted or unsubstituted Amino, 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. 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.

For example, the _R7 can be

wherein the X ₁ may be oxygen or sulfur, and R ₆ may include one or more groups selected from the group consisting of hydrogen, substituted or unsubstituted hydroxy, substituted or unsubstituted mercapto, substituted or unsubstituted Amino, 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. 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.

For example, the

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 , where 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 cycloalkyl, 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 groups: hydrogen, C1 to C5 alkyl, C1 to C5 cycloalkyl, C1 to C5 heterocycloalkyl, phenyl or benzyl. In some embodiments, the R ₆ ¹ may 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 may 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 may 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 may 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 may 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.

In the present application, the uridine derivative may comprise an NSAID moiety, and the NSAID may be linked to the uridine moiety through 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 said 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, Anthranilic acid or its derivatives and/or enolic acid or its derivatives.

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:

And those of R ₁ , R ₂ and R ₇ which are 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 NSAID-containing uridine derivative may be selected from one or more of U14 to U21:

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

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 the administration of a chemotherapeutic drug may be a nail disease associated with the administration of a chemotherapeutic drug and/or a skin disease associated with the administration of a chemotherapeutic drug.

In some embodiments, the extremity disease associated with the administration of a chemotherapeutic drug may be exudative hyperthyroid dermatitis associated with the administration of a chemotherapeutic drug, multiple perithyroidal pyogenic granulomatosis, and dethyroidism associated with the administration of a chemotherapeutic drug Symptoms, Nail Bed Separation Associated with Chemotherapy, Nail Changes Associated with Chemotherapy, Pigmented Degeneration Associated with Chemotherapy, Nail Weakness Associated with Chemotherapy, Fingers and Heels Associated with Chemotherapy Fissures, black nails associated with administration of chemotherapeutics, hand-foot syndrome (HFS) associated with administration of chemotherapeutics and/or paronychia associated with administration of chemotherapeutics.

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

There are currently several grading methods for hand-foot syndrome (HFS), among which the National Cancer Institute (NCI) grading standard is more commonly used, which divides the hand-foot syndrome into three grades: grade 1 is mild skin changes or dermatitis with sensation Abnormalities (such as disappearance of fingerprints, hyperpigmentation, erythema, peeling, paresthesia, hypoesthesia, skin numbness, etc.), but do not affect daily activities; grade 2 is the same as grade 1 skin changes, accompanied by pain, mildly affecting daily activities, skin The surface is intact; grade 3 is ulcerative dermatitis or skin changes with severe pain, seriously affecting 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 is painful erythema and edema of palms and soles, erythema and swelling around the nail; Grade 4 is 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 derivatives can be used to prevent or treat 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 a pyrimidine nucleoside analog or a prodrug thereof (eg, 5-FU or capecitabine). citabine), compared with uridine derivatives that do not contain NSAID, it can simultaneously reduce the pain and inflammatory response of the subject, indicating that the dual effects of the uridine part and the NSAID part are retained, and there is 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 (eg, hand-foot syndrome) in a subject associated with the administration of chemotherapeutic drugs.

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 subjects for prevention.

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 may 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 criteria of NCI-CTCAE V5.0, eg, the severity of the limb disease of the subject is reduced from grade 5 to grade 1 (eg, grade 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, level 3 reduced to level 2, level 3 reduced to level 1 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 partially or fully restore one or more physiological or biochemical parameters associated with the cause of the disease or symptoms the amount of the drug to normal; and/or the amount of the drug that reduces the likelihood of the disease or symptoms.

The therapeutically effective dose of the compound of formula (I) or the compound of formula (II) provided in this application may depend on a variety of factors known in the art, such as the activity, body weight, age, gender, diet of the specific compound , excretion rate, past medical history, current treatment, time of administration, dosage form, method of administration, route of administration, drug combination, subject's health status and potential for cross-infection, allergies, hypersensitivity and side effects, and/or epithelial tissue disease degree of development. 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 administered subject. 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 the amelioration 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 formula (I) or the compound represented by formula (II)) may be about 0.0001% (w/w) to about 50% (w/w) /w), for example, 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) ), 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), about 0.0001% (w/w) to about 3% (w/w), about 0.0001% (w/w) to about 2% (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), From about 0.0001% (w/w) to about 0.005% (w/w) or from 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, for example, 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 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 of formula (I) or the compound of formula (II) disclosed in this application can be administered in the form of a 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. As another example, the administered moiety may not be a metastatic site of cancer. For example, the metastatic site may include the site of cancer metastasis caused by lymphatic metastasis, vascular metastasis and/or implanted metastasis. In some embodiments, the metastatic site may 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) may 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) can 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) may be administered concurrently with a chemotherapeutic drug. In concurrent administration embodiments, these compounds of formula (I) or compounds of formula (II) may be part of a single dosage form that is combined 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) The administration of the chemotherapeutic agent may be administered at intervals before or after administration. 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 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 means 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, while 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 A therapeutic substance is "combined", even if the compound of formula (I) or the compound of formula (II) 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 from a compound of formula (I) or a compound of formula (II) disclosed herein as part of a multiple dose regimen (eg, , sequentially, eg, administering a compound of formula (I) or a compound of formula (II) in different overlapping regimens). In other embodiments, these 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 drug and the compound of formula (I) or the compound of formula (II) may not be mixed with each other. For example, the chemotherapeutic agent may be present in a separate container independently of the compound of formula (I) or the compound of formula (II). 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 well known in the art Or a combination of the above. 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 formula (I) or the compound represented by 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 diphosphate. Calcium, and/or the following: (1) fillers or extenders; (2) binders; (3) wetting agents; (4) splitting agents; (5) retarder solutions; (6) absorption accelerating agents; (7) Lubricants; (8) Absorbents; (9) Glidants; and (10) Colorants.

In some embodiments, the drug or the compound represented by the formula (I) or the compound represented by the formula (II) may be an injection preparation. Injectable preparations may include sterile aqueous solutions, dispersions, suspensions or emulsions. In all cases, the injectable preparations 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 medicament 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 Oxypropylene compound, emulsifying wax and water. The compound represented by formula (I) or the compound represented by 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: mineral oil, sorbitan Sugar alcohol monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl ester 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, can 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 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), From about 0.0001% (w/w) to about 0.005% (w/w) or from 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 caused by the chemotherapeutic drug in 1) or disease.

In the present application, the term "substantially does not affect" may refer to the use of the compound represented by the formula (I) in 2) of the drug combination or kit compared with the therapeutic effect of the chemotherapeutic drug alone. The therapeutic effect of the compound or the compound represented by formula (II) and the chemotherapeutic drug in 1) is equivalent, or does not produce significant disadvantage. For example, for any subject, the compound represented by the formula (I) or the formula (II) in 2) of the drug combination or kit is used compared with the therapeutic effect of the chemotherapeutic drug alone. The indicated 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 less.

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 and at the same time as the chemotherapeutic drug in 1) is administered or later.

therapeutic use

In one aspect, the application provides the use of a compound of formula (I) or a compound of formula (II) in the preparation of a medicament for preventing or treating a disease or condition associated with the administration of a chemotherapeutic drug (such as Limb disorders associated with chemotherapy drugs (eg, 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 using compounds of U1 to U13 for topical use. For example, the chemotherapeutic drug is 5-FU. For example, the compounds of U1 to U13 are administered at a concentration of about 0.5 μM to about 1500 μM, eg, about 1 μM to about 1000 μM, about 10 μM to about 1000 μM, about 10 μM to about 500 μM, about 50 μM to 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 using compounds of U1 to U13 for topical use. For example, the chemotherapeutic drug is capecitabine. For example, the compounds of U1 to U13 are administered at a concentration of from about 0.1% (wt%) to about 10.0% (wt%), eg, from about 0.1% (wt%) to about 5.0% (wt%), as from about 0.5% (wt%) to about 5.0% (wt%), from about 0.5% (wt%) to about 3.0% (wt%), from about 1.0% (wt%) to about 3.0% (wt%), 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 using compounds U14 to U21 for topical use. For example, the chemotherapeutic drug is 5-FU. For example, the compounds of U14 to U21 are administered at a concentration of about 0.5 μM to about 1500 μM, eg, about 1 μM to about 1000 μM, about 10 μM to about 1000 μM, about 10 μM to about 500 μM, about 50 μM to about 50 μM to about 500 μM, from about 100 μM to about 500 μM. For example, the compounds of U14 to U21 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 using compounds U14 to U21 for topical 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, a concentration of about 3% (wt %) is administered.

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) [(2R,3R,4R,5R)-3,4-bis(2,2-dimethylpropoxycarbonyloxy)-5-(2,4-dioxopyrimdin-1-yl)tetrahydrofuran- Synthesis of 2-yl]methyl 2,2-dimethylpropyl carbonate(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)δ11.50(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 represented by formula (I) group 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 represented by formula (I), the solution of the compound group represented by formula (I) is ethanol solution or aqueous solution); blank control group: except for normal replacement of basal medium No additional solution is added; multiple blank solvent control group: add the same volume of solution as the corresponding chemotherapeutic drug group or chemotherapeutic drug+compound group represented by formula (I). The blank solvent control group was used for data correction to exclude the effect of the solvent in the chemotherapeutic drug group and the chemotherapeutic drug + compound of formula (I) group 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 determine the survival rate of cells, thereby calculating the proliferation of cells by chemotherapeutic drugs Toxicity and the alleviating effect of compounds of formula (I) on proliferation toxicity. Results were statistically analyzed and plotted using GraphPad Prism 6.0 software, t-test.

Table 1 lists the combinations of 5-FU and uridine derivatives, as well as the corresponding experimental results (wherein, the data in the cell viability column indicates that the corresponding 5-FU + uridine derivatives group compared with the 5-FU group. 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 3-6, it can be seen that 5-FU has proliferation toxicity to skin cells 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 a 96-well plate, 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 normal replacement of 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 the 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 determine the survival rate of cells, thereby calculating the proliferation of cells by chemotherapeutic drugs Toxicity and the alleviating effect of compounds of formula (I) on proliferation toxicity. 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, as well as the corresponding experimental results (wherein, the data in the cell viability column 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 Figure 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.

Capecitabine was dissolved in a mixed solution of castor oil:ethanol=1:1 (volume ratio), and the volume was adjusted to the desired concentration with PBS before gavage (diluted about 3 times with PBS solution), and the gavage volume did 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 the derivative as the main component was applied to the back of the mouse 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 consecutive 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 combinations of 5-FU and uridine derivatives, as well as the corresponding experimental results (wherein, the data in the cell viability column indicates that the corresponding 5-FU + uridine derivatives were administered compared with the 5-FU group group increased percentage of viable cells). Figures 11-12 list the experimental results of several NSAID-containing uridine derivatives in mitigating the toxicity of 5-FU.

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

From the results in Table 4 and Figures 11 to 12, it can be seen that 5-FU has proliferative toxicity to skin cell HaCaT, while uridine derivatives have a significant alleviation effect 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 the cell proliferation rate can be increased by more than 50% or even more than 100% at a concentration of about 50uM compared with the control group.

Example 37-49 Uridine derivatives prevent hand-foot syndrome induced by chemotherapeutic drugs 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 combination of chemotherapeutic drugs and uridine derivative gels in animal experiments, and 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 mold-out rate of 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-Induced Hand-Foot Syndrome

Under the experimental conditions of Examples 37-47, pain analysis was performed on rats after administration of uridine derivatives (at a concentration of 3%) for a period of time in a rat model of hand-foot syndrome constructed with 4000 mg/kg capecitabine , 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 (800.0 g). 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°C 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) propionyl 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 sulfuric acid. Dry over sodium, 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)propanoate (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) Synthesis of -3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine ester (U21)

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 crude product, and purified by silica gel column chromatography (dichloromethane/methanol=10/1) to obtain 1-((3aR, 4R, 6R, 6aR)-6-(hydroxymethyl) )-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. for ten minutes, after which 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-dihydro) Pyrimidine-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=2.0 Hz, 1H), 7.58 (d, J=8.0 Hz, 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

衍生物结构Derivative structure	Ms(M+H ⁺) Ms(M+H ⁺ )
U14U14	457.0457.0
U15U15	471.1471.1
U16U16	407.0407.0
U17U17	484.1484.1
U18U18	669.2669.2
U19U19	719.1719.1
U20U20	881.2881.2
U21U21	556.2556.2

Claims

Use of uridine derivatives or pharmaceutically acceptable salts, solvents, hydrates, prodrug forms and stereoisomers thereof in the manufacture of a medicament for the prevention and/or treatment of a A limb disease associated with administration of a chemotherapeutic drug, the uridine derivative comprising a compound represented by formula (I),

Wherein, when R 1 , R 2 , R 4 and R 5 are all hydrogen, R 3 is not -OH.
Use according to claim 1, wherein R 1 is hydrogen or
wherein 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 amino, 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 Substituted aryl and substituted or unsubstituted aralkyl.
The use according to claim 2, wherein Xs is oxygen.
Use according to any one of claims 1-3, wherein R is hydrogen or
wherein X g is oxygen or sulfur,

R g contains one or more groups selected from the group consisting of hydrogen, substituted or unsubstituted hydroxy, substituted or unsubstituted mercapto, substituted or unsubstituted amino, C1 to C5 substituted or unsubstituted alkanes 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 according to claim 4, wherein X g is oxygen.
The use according to any one of claims 1-5, wherein R is
or hydrogen, wherein said R7 is hydrogen or
wherein 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 amino, 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 Substituted aryl and substituted or unsubstituted aralkyl.
The use according to any one of claims 1-6, 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 according to any one of claims 1-6, wherein the R3 is hydrogen.
The use according to any one of claims 1-8, 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 according to any one of claims 1-8, 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 according to any one of claims 1-9, wherein R4 is hydrogen.
The use according to any one of claims 1-10, wherein R5 is hydrogen.
Use according to any one of claims 1-12, wherein the uridine derivative is selected from one or more of the following group:
The use according to claim 1, wherein the uridine derivative comprises a compound of formula (II):

Wherein, at least one of said 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 derivatives thereof, arylacetic acid or derivatives thereof, heteroarylacetic acid or derivatives thereof, indoleacetic acid or derivatives thereof, indeneacetic acid or its derivatives, anthranilic acid or its derivatives and/or enolic acid or its derivatives.
The use according to any one of claims 14-15, wherein R1, R2 or R7 is hydrogen .
The use of any one of claims 14-16, wherein R1, R2 and R7 are not simultaneously hydrogen .
The use according to any one of claims 14-16, 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 groups are optionally substituted with one or more substituents selected from the group consisting of halogen, C1 to C6 alkyl, C1 to C6 alkynyl, and C1 to C6 alkenyl.
Use according to claims 14-18 , wherein R is
R s 1 is hydrogen or methyl, and R s 2 is selected from
The use according to any one of claims 14-19, wherein R is
R s 1 is hydrogen or methyl, and 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 heterocycle Alkyl, 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 said C4 to C7 cycloalkyl, C4 to C7 heterocycloalkyl, C4 to C7 aryl and/or C4 to C7 heteroaryl base is optionally halogen,
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 with 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 according to any one of claims 14-20, wherein R is
R s 1 is hydrogen or methyl, and R s 2 is
The use according to any one of claims 14-21, wherein R is
R s 1 is hydrogen or methyl, and R s 2 is
The use according to any one of claims 14-22, wherein R is
R s 1 is hydrogen or methyl, and R s 2 is
The use according to any one of claims 14-23, wherein R 8 1 is
The use according to any one of claims 14-24, wherein any one of R 1 , R 2 and R 7 is independently
The use of any one of claims 14-25, wherein any one of R 1 , R 2 and R 7 is independently selected from the group consisting of hydrogen,
Use according to any one of claims 1-26, wherein the uridine derivative is selected from one or more of the following group:
The use of any one of claims 1-27, wherein the chemotherapeutic agent is for the treatment of cancer.
The use of any one of claims 1-28, wherein the chemotherapeutic agent comprises a pyrimidine nucleoside analog or a prodrug thereof.
The use of any one of claims 1-29, wherein the chemotherapeutic agent comprises one or more compounds selected from the group consisting of capecitabine, cytarabine, docetaxel, Mycin, Fluorouracil (5-FU), Floxuridine, Tegafur, Idarubicin, Paclitaxel, Epirubicin, Doxorubicin, Acelarin (NUC-1031), Leucovorin, Cisplatin, Taxane Alkane, cyclophosphamide, vincristine and 5-FU prodrugs.
The use according to claim 30, wherein the 5-FU prodrugs comprise prodrugs of furanfluridine, 5'-deoxyfluridine, floxuridine, 2'-deoxyfluridine, 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 1-31, wherein the chemotherapeutic agent comprises fluorouracil (5-FU), capecitabine, floxuridine, tegafur and/or cytarabine.
The use according to any one of claims 1-32, wherein the extremity disease associated with the administration of a chemotherapeutic drug comprises a nail disease associated with the administration of a chemotherapeutic drug and/or a skin disease associated with the administration of a chemotherapeutic drug.
The use of any one of claims 1-33, 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 according to any one of claims 1-35, wherein the extremity disease associated with the administration of a chemotherapeutic drug comprises exudative hyperthyroid dermatitis, multiple perithyroidal pyogenic granulomatous lesions associated with the administration of a chemotherapeutic drug , Deonailia associated with administration of chemotherapeutics, Nail bed separation associated with administration of chemotherapeutics, Nail changes associated with administration of chemotherapeutics, Pigmentation associated with administration of chemotherapeutics, Nail brittleness associated with administration of chemotherapeutics, and Cleft fingers and heels associated with chemotherapy, black nails associated with chemotherapy, hand-foot syndrome associated with chemotherapy, and/or paronychia associated with chemotherapy.
The use of any one of claims 1-36, wherein the extremity disease associated with administration of a chemotherapeutic drug comprises hand-foot syndrome associated with administration of a chemotherapeutic drug.
The use according to any one of claims 1-37, wherein the severity of the limb disease associated with administration of a chemotherapeutic drug is grade 1 or above, grade 2 or according to NCI-CTCAE V5.0 above, 3rd grade or above, 4th grade or above, and/or 5th grade or above.
The use of any one of claims 1-38, wherein the medicament is formulated for topical administration.
The use of any one of claims 1-39, wherein the medicament is formulated for transdermal administration.
The use of any one of claims 1-40, wherein the medicament is formulated for external administration.
The use according to any one of claims 39-41, wherein the site of administration of the topical administration is not the site of occurrence of cancer or the site of potential metastases of cancer.
The use of any one of claims 1-42, wherein the medicament is formulated as a cream, lotion, gel, oil, ointment, spray, foam, liposomal formulation, liniment, gas Aerosols and transdermal devices for absorption through the skin.
The use of any one of claims 1-43, wherein the medicament further comprises one or more other active ingredients.
The use of any one of claims 1-44, 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 1-45, 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 1-46, wherein the drug does not substantially affect the therapeutic effect of the chemotherapeutic drug.
The use of any one of claims 1-47, wherein the subject comprises a cancer patient.
The use of any one of claims 1-48, wherein the subject has been, is and/or will be administered the chemotherapeutic drug.
The use of any one of claims 1-49, wherein the subject has or is susceptible to the extremity disease associated with administration of a chemotherapeutic drug.
The use of any one of claims 1-50, wherein the severity of the limb disease associated with administration of a chemotherapeutic drug increases following administration of the chemotherapeutic drug.
The use of any one of claims 1-51, wherein the subject does not have the limb disease associated with administration of the chemotherapeutic drug prior to administration of the chemotherapeutic drug.
A pharmaceutical combination or kit comprising: 1) the chemotherapeutic drug of any one of claims 1-52; and 2) the uridine derivative of any one of claims 1-52.
The pharmaceutical 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 any one of claims 53-54, 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 53-55, wherein the uridine derivative is formulated for topical administration.
The pharmaceutical combination or kit of any one of claims 53-56, wherein the uridine derivative is formulated for topical administration.
The pharmaceutical combination or kit of any one of claims 53-57, wherein the uridine derivative is formulated for transdermal administration.
The pharmaceutical combination or kit of any one of claims 53-58, wherein the uridine derivative is prepared to include a cream, lotion, gel, oil, ointment, spray, foam, fat Plasmid preparations, liniments, aerosols and transdermal devices for transdermal absorption.
The pharmaceutical combination or kit of any one of claims 53-59, 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 53-60, wherein the uridine derivative in 2) can prevent or treat a limb disease associated with the administration of the chemotherapeutic drug in 1).
The pharmaceutical combination or kit according to any one of claims 53-61, 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 53-62, wherein the uridine derivative in 2) is administered to the subject before, concurrently with, or after administration of the chemotherapeutic agent in 1). dosing.