WO2022089614A1 - 胸苷衍生物在制备药物中的应用 - Google Patents

胸苷衍生物在制备药物中的应用 Download PDF

Info

Publication number
WO2022089614A1
WO2022089614A1 PCT/CN2021/127683 CN2021127683W WO2022089614A1 WO 2022089614 A1 WO2022089614 A1 WO 2022089614A1 CN 2021127683 W CN2021127683 W CN 2021127683W WO 2022089614 A1 WO2022089614 A1 WO 2022089614A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
unsubstituted
administration
group
hydrogen
Prior art date
Application number
PCT/CN2021/127683
Other languages
English (en)
French (fr)
Inventor
张诗宜
吴兆宇
刘世岚
Original Assignee
上海岸阔医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 上海岸阔医药科技有限公司 filed Critical 上海岸阔医药科技有限公司
Priority to US18/250,709 priority Critical patent/US20230405003A1/en
Priority to CN202180071369.XA priority patent/CN116367842A/zh
Priority to EP21885340.6A priority patent/EP4238571A1/en
Publication of WO2022089614A1 publication Critical patent/WO2022089614A1/zh

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/545—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present application relates to the field of biomedicine, in particular to a combination of thymidine derivatives, uridine derivatives and thymidine derivatives for the treatment of side effects caused by chemotherapeutic drugs.
  • Chemotherapy drugs can also damage normal tissues of patients while killing cancer cells, so chemotherapy often causes serious side effects, especially in the skin, facial features, hematopoietic tissues and gastrointestinal tract. Severe side effects caused by chemotherapy can impair the quality of life of patients and cause a decrease in the patient's tolerance to medication, which adversely affects the therapeutic effect, leads to disease progression, and affects the patient's survival.
  • the present application relates to the use of a thymidine derivative, a uridine derivative, and a thymidine derivative in combination in the preparation of a medicament for preventing or treating a disease or condition associated with the administration of a chemotherapeutic drug in a subject.
  • the present application relates to the use of thymidine derivatives and uridine derivatives, thymidine derivatives to prevent or treat diseases or conditions associated with the administration of chemotherapeutic drugs in a subject, which can effectively control the effects of chemotherapy drugs Side effects, such as skin tissue diseases or disorders, facial diseases or disorders, and/or gastrointestinal diseases or disorders, etc., associated with the administration of chemotherapeutic drugs.
  • the uridine derivatives and/or thymidine derivatives of the present application may contain an NSAID moiety, which has analgesic and anti-inflammatory effects while treating and/or preventing chemotherapy-related diseases or conditions, and further improves the symptoms of the subject.
  • the application provides the use of a thymidine 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, wherein the thymidine derivative is in At least one hydroxyl hydrogen on deoxyribose is substituted.
  • the thymidine derivative comprises the structure of formula (I): Formula (I)
  • R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are not hydrogen at the same time.
  • R 7 is In certain embodiments, R 7 is
  • R 6 is hydrogen
  • R 6 is wherein said R 6 1 is a C1 to C6 alkyl group. In certain embodiments, R 6 is
  • R 1 is wherein M 1 is oxygen or sulfur, and R 8 comprises one or more groups selected from the group consisting of hydrogen, substituted or unsubstituted hydroxy, substituted or unsubstituted mercapto, substituted or unsubstituted amino, Substituted or unsubstituted C1 to C5 alkyl, substituted or unsubstituted C1 to C5 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and, substituted or unsubstituted aralkyl; M 2 is silicon or carbon, and R 9 is selected from the group consisting of hydrogen, substituted or unsubstituted hydroxy, substituted or unsubstituted mercapto, substituted or unsubstituted amino, substituted or unsubstituted C1
  • R 2 is wherein M 1 is oxygen or sulfur, and R 8 comprises one or more groups selected from the group consisting of hydrogen, substituted or unsubstituted hydroxy, substituted or unsubstituted mercapto, substituted or unsubstituted amino, Substituted or unsubstituted C1 to C5 alkyl, substituted or unsubstituted C1 to C5 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and, substituted or unsubstituted aralkyl; M 2 is silicon or carbon, and R 9 is selected from the group consisting of hydrogen, substituted or unsubstituted hydroxy, substituted or unsubstituted mercapto, substituted or unsubstituted amino, substituted or unsubstituted C1
  • R is wherein M 1 is oxygen or sulfur, and R 8 comprises one or more groups selected from the group consisting of hydrogen, substituted or unsubstituted hydroxy, substituted or unsubstituted mercapto, substituted or unsubstituted amino, Substituted or unsubstituted C1 to C5 alkyl, substituted or unsubstituted C1 to C5 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and, substituted or unsubstituted aralkyl; M 2 is silicon or carbon, and R 9 is selected from the group consisting of hydrogen, substituted or unsubstituted hydroxy, substituted or unsubstituted mercapto, substituted or unsubstituted amino, substituted or unsubstituted C1 to
  • any one of R 8 1 , R 8 2 , R 8 3 , R 8 4 , R 8 5 , R 8 6 , R 8 7 and R 8 8 independently comprises selected from the group consisting of One or more groups of : hydrogen, C1 to C5 alkyl, C1 to C5 cycloalkyl, C1 to C5 heterocycloalkyl, phenyl or benzyl.
  • R 8 1 is selected from the group consisting of C 1 to C 5 alkyl, C 1 to C 5 cycloalkyl, phenyl and benzyl. In certain embodiments, R 8 1 is selected from the group consisting of methyl, ethyl, propyl, butyl, cyclopentyl, cyclopropanyl, and benzyl.
  • R 8 2 is selected from the group consisting of C1 to C5 alkyl, C1 to C5 cycloalkyl, phenyl and benzyl. In certain embodiments, R 8 2 is selected from the group consisting of cyclopropyl, propyl, butyl, pentyl, phenyl, and benzyl.
  • R 8 3 is hydrogen
  • R 8 4 is selected from the group consisting of: C1 to C5 alkyl, C1 to C5 cycloalkyl, phenyl, and benzyl.
  • R84 is selected from the group consisting of cyclopropyl, cyclopentyl, and phenyl.
  • R 9 is butyl
  • R3 is hydrogen. In certain embodiments, R4 is hydrogen. In certain embodiments, R5 is hydrogen.
  • R 1 is wherein R 8 1 contains one or more groups selected from the group consisting of C1 to C6 alkyl, C1 to C6 silyl, C1 to C6 alkoxy, C1 to C6 alkylnitro, C3 to C7 Cycloalkyl, C3 to C7 cycloalkylnitro, C4 to C7 aryl, C4 to C7 alkoxyaryl and/or C4 to C7 heteroaryl.
  • R 2 is wherein R 8 1 contains one or more groups selected from the group consisting of C1 to C6 alkyl, C1 to C6 silyl, C1 to C6 alkoxy, C1 to C6 alkylnitro, C3 to C7 Cycloalkyl, C3 to C7 cycloalkylnitro, C4 to C7 aryl, C4 to C7 alkoxyaryl and/or C4 to C7 heteroaryl.
  • R 3 , R 4 , R 5 and R 6 are all hydrogen, and R 7 is R 1 is selected from the group consisting of hydrogen, R is selected from the group consisting of hydrogen , And R 2 and R 1 are not both hydrogen.
  • the thymidine derivative is selected from one or more of compounds T1 to T24 of the following group:
  • the thymidine derivative comprises the structure of formula (II): Formula ( II ), wherein R1 and/or R2 comprise a non-steroidal anti-inflammatory drug (NSAID) moiety.
  • R1 contains an NSAID moiety
  • R2 is hydrogen
  • R1 is hydrogen
  • R1 contains the NSAID part
  • R2 contains the NSAID part.
  • 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 derivatives thereof compounds, anthranilic acid or its derivatives and/or enolic acid or its derivatives.
  • R 1 or R 2 is hydrogen
  • R 1 and R 2 are not both hydrogen.
  • R 1 and/or R 2 are 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
  • Ring A is a pyrrole ring
  • R s 3 is C1-C6 alkyl
  • 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.
  • R s 1 and/or R s 2 are Wherein, the R s 3 is C1 to C6 alkyl or halogen.
  • R s 1 and/or R s 2 are Wherein, R s 3 and/or R s 4 are selected from: hydrogen, C1 to C6 alkyl, C1 to C6 alkyl ester, halogen, C4 to C7 aryl, C4 to C7 heteroaryl, Ring B is C4 to C7 aryl, C4 to C7 heteroaryl, X is -CH 2 , -NH-, -O- or wherein the C4 to C7 aryl, C4 to C7 heteroaryl groups are optionally substituted 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.
  • 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.
  • R 8 is R s 1 is hydrogen or methyl, and R s 2 is selected from
  • R 8 is R s 1 is hydrogen or methyl
  • 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
  • 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
  • R 8 is R s 1 is hydrogen or methyl
  • R s 2 is
  • R 8 is R s 1 is hydrogen or methyl
  • R s 2 is
  • R s 2 is The ring A 1 is a benzene ring, and the ring B 1 is And ring B 2 is a pyrrole ring, B 3 is a pyran ring, and the pyran ring is optionally substituted with one or more C1 to C6 alkyl and/or C1 to C6 alkyl substituted aldehyde groups.
  • R 8 is R s 1 is hydrogen or methyl
  • R s 2 is
  • R 8 1 is
  • R 1 and/or R 2 are identical to each other.
  • the R 1 comprises an NSAID moiety
  • R 2 is hydrogen
  • the R 1 is any one group selected from the group consisting of:
  • R 2 is hydrogen
  • the R 2 comprises an NSAID moiety, and R 1 is hydrogen.
  • the R 2 is any one group selected from the group consisting of:
  • R 1 is hydrogen
  • both R 1 and R 2 comprise the NSAID moiety.
  • the R 1 and R 2 are each independently any one group selected from the group consisting of:
  • the thymidine derivative is selected from one or more of the following compounds T25 to T50:
  • the chemotherapeutic drug is used to treat cancer.
  • the chemotherapeutic agent comprises a pyrimidine nucleoside analog or a prodrug thereof.
  • the chemotherapeutic agent comprises one or more selected from the group consisting of capecitabine, cytarabine, docetaxel, doxorubicin, fluorouracil (5-FU), Floxuridine, Tegafur, Idarubicin, Paclitaxel, Epirubicin, Acelarin (NUC-1031), Doxorubicin, Leucovorin, Cisplatin, Paclitaxel, Cyclophosphamide, Vincristine, and 5- FU prodrugs (eg, prodrug derivatives of fluoropyridine and 5'-deoxyfluridine, floxuridine, 2'-deoxyfluridine, prodrug derivatives of floxuridine, or 2'-deoxyfluridine precursor derivatives, trifluoro-methyl-2'-deoxyuridine, 6-azauridine, 3-deazauridine).
  • capecitabine ecitabine
  • cytarabine docetaxel
  • doxorubicin fluorouracil
  • the use is where the disease or disorder is caused by administration of the chemotherapeutic drug.
  • the disease or disorder associated with the administration of a chemotherapeutic drug includes a skin tissue disease or disorder associated with the administration of a chemotherapeutic drug, a disease or disorder of hematopoietic tissue associated with the administration of a chemotherapeutic drug, limbs associated with the administration of a chemotherapeutic drug Disease or disorder, Cardiac disease or disorder associated with the administration of a chemotherapeutic drug, Nervous system disease or disorder associated with the administration of a chemotherapeutic drug, Disease or disorder of the five sense organs associated with the administration of a chemotherapeutic drug, and/or Gastrointestinal disease associated with the administration of a chemotherapeutic drug or disease.
  • the hematopoietic disease or disorder associated with the administration of a chemotherapeutic agent includes a bone marrow disease or disorder associated with the administration of a chemotherapeutic agent and a blood disease or disorder associated with the administration of a chemotherapeutic agent.
  • the hematopoietic disease or disorder associated with administration of a chemotherapeutic agent comprises a disease or disorder of abnormal blood cell proliferation associated with administration of a chemotherapeutic agent.
  • the disease or disorder associated with the administration of a chemotherapeutic agent includes a disease or disorder of epithelial tissue in the skin, extremities, facial features, and/or gastrointestinal tract associated with the administration of a chemotherapeutic agent.
  • the disease or disorder of epithelial tissue in the skin, extremities, five senses, and/or gastrointestinal tract associated with administration of a chemotherapeutic drug includes the disease or disorder associated with endothelial cell pathology, and/or with epithelial cells The disease or disorder to which the lesion is associated, and wherein the endothelial and/or epithelial lesion is associated with the administration of a chemotherapeutic agent.
  • the endothelial cells comprise vascular endothelial cells.
  • the epithelial cells include skin epithelial cells, oral epithelial cells, nasal cavity epithelial cells, gastric epithelial cells, and/or intestinal epithelial cells.
  • the disease or condition associated with the administration of a chemotherapeutic drug in the use includes rash associated with the administration of a chemotherapeutic drug, hand-foot syndrome associated with the administration of a chemotherapeutic drug, pruritus associated with the administration of a chemotherapeutic drug, Erythema associated with administration of chemotherapeutics, Dry skin associated with administration of chemotherapeutics, Hair loss associated with administration of chemotherapeutics, Paronychia associated with administration of chemotherapeutics, Pigmentation disorders associated with administration of chemotherapeutics, Administration of chemotherapeutics oral ulcers, dry mouth associated with administration of chemotherapy drugs, epistaxis associated with administration of chemotherapy drugs, nasopharyngitis associated with administration of chemotherapy drugs, cheilitis associated with administration of chemotherapy drugs, esophageal mucositis associated with administration of chemotherapy drugs, Gastric mucositis associated with administration of chemotherapeutics, gastric ulcers associated with administration of a chemo
  • the disease or disorder associated with the administration of a chemotherapeutic drug comprises hand-foot syndrome associated with the administration of a chemotherapeutic drug.
  • the disease or condition associated with administration of a chemotherapeutic agent comprises paronychia associated with administration of a chemotherapeutic agent.
  • the disease or disorder associated with the administration of a chemotherapeutic drug comprises a gastrointestinal disease associated with the administration of a chemotherapeutic drug.
  • the disease or condition associated with administration of a chemotherapeutic agent comprises diarrhea associated with administration of a chemotherapeutic agent.
  • the severity of the disease or condition associated with the administration of a chemotherapeutic agent is grade 1 or above, grade 2 or above, grade 3 or above, grade 3 or above, according to NCI-CTCAE V5.0 Level 4 or above, and/or Level 5.
  • the medicament is formulated for topical administration. In certain embodiments, the medicament is formulated for topical administration. In certain embodiments, the medicament is formulated for oral administration.
  • the medicament is formulated for oral administration.
  • Oral formulations may include, but are not limited to, capsules, sachets, pills, tablets, lozenges, powders, granules, aqueous or non-aqueous solutions or suspensions, water-in-oil or oil-in-water emulsions, elixirs or syrups, confectionery Lozenges and/or mouthwashes and the like.
  • the medicament is formulated as a cream, lotion, gel, oil, ointment, spray, foam, liposomal formulation, liniment, lotion, aerosol and/or transdermal absorption transdermal agent.
  • the concentration of the thymidine derivative in the drug is from about 0.0001% (w/w) to about 50% (w/w). In certain embodiments, the concentration of the thymidine derivative in the drug is from about 0.1% (w/w) to about 5% (w/w). In certain embodiments, the concentration of the thymidine derivative in the drug is from about 0.5% (w/w) to about 3% (w/w).
  • the thymidine derivative is administered at a dose of about 0.5 [mu]M to about 1000 [mu]M. In certain embodiments, the thymidine derivative is administered at a dose of from about 1 [mu]M to about 500 [mu]M.
  • the thymidine derivative is administered at a dose of from about 15 mpk to about 300 mpk. In certain embodiments, the thymidine derivative is administered at a dose of from about 10 mpk to about 500 mpk.
  • the medicament further comprises one or more active ingredients.
  • the drug does not substantially affect the therapeutic effect of the chemotherapeutic drug.
  • the use of the subject comprises a cancer patient.
  • the subject has been, is and/or will be administered the chemotherapeutic drug.
  • the subject has or is susceptible to the disease or condition associated with administration of the chemotherapeutic agent.
  • the use of said disease or condition increases in severity following administration of said chemotherapeutic agent.
  • the subject does not have the disease or condition prior to administration of the chemotherapeutic drug.
  • the present application provides a pharmaceutical combination or kit comprising: 1) the chemotherapeutic drug; and 2) the thymidine derivative.
  • the chemotherapeutic drug and the thymidine derivative in the drug combination or kit are not mixed with each other.
  • the chemotherapeutic drug and the thymidine derivative in the pharmaceutical combination or kit are each independently present in separate containers.
  • the thymidine derivative in 2) of the pharmaceutical combination or kit is capable of preventing or treating a disease or condition associated with administration of the chemotherapeutic drug in 1).
  • the thymidine derivative in 2) of the pharmaceutical combination or kit does not substantially affect the therapeutic effect of the chemotherapeutic drug in 1).
  • the thymidine derivative of 2) is administered in the pharmaceutical combination or kit before, concurrently with, or after administration of the chemotherapeutic drug of 1).
  • the application provides a method comprising administering a thymidine derivative to a subject, wherein the subject has been, is and/or will be administered a chemotherapeutic agent and has or is susceptible to and the administration The disease or condition associated with the chemotherapeutic agent.
  • the application provides a method for preventing or treating a disease or disorder, comprising administering a thymidine derivative to a subject susceptible to or suffering from a disease or disorder associated with administration of the chemotherapeutic agent, wherein The subject has been, is and/or will be administered a chemotherapeutic drug.
  • the application 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 thymidine derivative and a uridine derivative, wherein the disease or disorder is a disease or disorder associated with administration of a chemotherapeutic drug.
  • the method wherein the subject has been is and/or will be administered the chemotherapeutic drug. .
  • the application provides the use of a combination comprising a thymidine derivative and a uridine derivative in the manufacture of a medicament for preventing or treating a disease or condition associated with administration of a chemotherapeutic drug in a subject , wherein the thymidine derivative has at least one hydroxy hydrogen on deoxyribose substituted.
  • the thymidine derivative comprises the structure of formula (I): Formula (I)
  • R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are not hydrogen at the same time.
  • R 7 is In certain embodiments, R 7 is
  • R 6 is hydrogen
  • R 6 is wherein said R 6 1 is a C1 to C6 alkyl group. In certain embodiments, R 6 is
  • R 1 is wherein M 1 is oxygen or sulfur, and R 8 comprises one or more groups selected from the group consisting of hydrogen, substituted or unsubstituted hydroxy, substituted or unsubstituted mercapto, substituted or unsubstituted amino, substituted or unsubstituted or unsubstituted C1 to C5 alkyl, substituted or unsubstituted C1 to C5 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted Unsubstituted heteroaryl, and, substituted or unsubstituted aralkyl; M 2 is silicon or carbon, and R 9 is selected from the group consisting of hydrogen, substituted or unsubstituted hydroxy, substituted or unsubstituted mercapto, substituted or unsubstituted amino, substituted or unsub
  • R 2 is wherein M 1 is oxygen or sulfur, and R 8 comprises one or more groups selected from the group consisting of hydrogen, substituted or unsubstituted hydroxy, substituted or unsubstituted mercapto, substituted or unsubstituted amino, substituted or unsubstituted or unsubstituted C1 to C5 alkyl, substituted or unsubstituted C1 to C5 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted Unsubstituted heteroaryl, and, substituted or unsubstituted aralkyl; M 2 is silicon or carbon, and R 9 is selected from the group consisting of hydrogen, substituted or unsubstituted hydroxy, substituted or unsubstituted mercapto, substituted or unsubstituted amino, substituted or unsub
  • R is wherein M 1 is oxygen or sulfur, and R 8 comprises one or more groups selected from the group consisting of hydrogen, substituted or unsubstituted hydroxy, substituted or unsubstituted mercapto, substituted or unsubstituted amino, substituted or unsubstituted or unsubstituted C1 to C5 alkyl, substituted or unsubstituted C1 to C5 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted Unsubstituted heteroaryl, and, substituted or unsubstituted aralkyl; M 2 is silicon or carbon, and R 9 is selected from the group consisting of hydrogen, substituted or unsubstituted hydroxy, substituted or unsubstituted mercapto, substituted or unsubstituted amino, substituted
  • any one of R 8 1 , R 8 2 , R 8 3 , R 8 4 , R 8 5 , R 8 6 , R 8 7 and R 8 8 independently comprises a One or more of the groups: hydrogen, C1 to C5 alkyl, C1 to C5 cycloalkyl, C1 to C5 heterocycloalkyl, phenyl or benzyl.
  • R 8 1 comprises one or more groups selected from the group consisting of C 1 to C 5 alkyl, C 1 to C 5 cycloalkyl, phenyl, and benzyl. In certain embodiments, R 8 1 comprises one or more groups selected from the group consisting of methyl, ethyl, propyl, butyl, cyclopentyl, cyclopropanyl, and benzyl.
  • R 8 2 comprises one or more groups selected from the group consisting of C1 to C5 alkyl, C1 to C5 cycloalkyl, phenyl, and benzyl. In certain embodiments, R 8 2 comprises one or more groups selected from the group consisting of cyclopropyl, propyl, butyl, pentyl, phenyl, and benzyl.
  • R 8 3 is hydrogen
  • R 8 4 comprises one or more groups selected from the group consisting of C1 to C5 alkyl, C1 to C5 cycloalkyl, phenyl, and benzyl. In certain embodiments, R 8 4 comprises one or more groups selected from the group consisting of cyclopropyl, cyclopentyl, and phenyl.
  • R 9 is butyl
  • R3 is hydrogen. In certain embodiments, R4 is hydrogen. In certain embodiments, R5 is hydrogen.
  • R 1 is wherein, R 8 1 contains one or more groups selected from the group consisting of C1 to C6 alkyl, C1 to C6 silyl, C1 to C6 alkoxy, C1 to C6 alkylnitro, C3 to C7 ring Alkyl, C3 to C7 cycloalkylnitro, C4 to C7 aryl, C4 to C7 alkoxyaryl and/or C4 to C7 heteroaryl.
  • R 2 is wherein, R 8 1 contains one or more groups selected from the group consisting of C1 to C6 alkyl, C1 to C6 silyl, C1 to C6 alkoxy, C1 to C6 alkylnitro, C3 to C7 ring Alkyl, C3 to C7 cycloalkylnitro, C4 to C7 aryl, C4 to C7 alkoxyaryl and/or C4 to C7 heteroaryl.
  • R 3 , R 4 , R 5 and R 6 are all hydrogen, and R 7 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.
  • the thymidine derivative comprises one or more of compounds T1 to T24 selected from the group consisting of:
  • the thymidine derivative comprises the structure of formula (II): Formula ( II ), wherein R1 and/or R2 comprise a non-steroidal anti-inflammatory drug (NSAID) moiety.
  • NSAID non-steroidal anti-inflammatory drug
  • 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 derivatives thereof compounds, anthranilic acid or its derivatives and/or enolic acid or its derivatives.
  • R 1 or R 2 is hydrogen
  • R 1 and R 2 are not both hydrogen.
  • R 1 and/or R 2 are 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
  • Ring A is a pyrrole ring
  • R s 3 is C1-C6 alkyl
  • 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.
  • R s 1 and/or R s 2 are Wherein, the R s 3 is C1 to C6 alkyl or halogen.
  • R s 1 and/or R s 2 are Wherein, R s 3 and/or R s 4 are selected from: hydrogen, C1 to C6 alkyl, C1 to C6 alkyl ester, halogen, C4 to C7 aryl, C4 to C7 heteroaryl, Ring B is C4 to C7 aryl, C4 to C7 heteroaryl, X is -CH 2 , -NH-, -O- or wherein the C4 to C7 aryl, C4 to C7 heteroaryl groups are optionally substituted 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.
  • 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.
  • R 8 is R s 1 is hydrogen or methyl, and R s 2 is selected from
  • R 8 is R s 1 is hydrogen or methyl
  • 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
  • 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
  • R 8 is R s 1 is hydrogen or methyl
  • R s 2 is
  • R 8 is R s 1 is hydrogen or methyl
  • R s 2 is
  • R s 2 is The ring A 1 is a benzene ring, and the ring B 1 is And ring B 2 is a pyrrole ring, B 3 is a pyran ring, and the pyran ring is optionally substituted with one or more C1 to C6 alkyl and/or C1 to C6 alkyl substituted aldehyde groups.
  • R 8 is R s 1 is hydrogen or methyl
  • R s 2 is
  • R 8 1 is
  • R 1 and/or R 2 are identical to each other.
  • the R 1 comprises the NSAID moiety, and R 2 is hydrogen.
  • the R 1 comprises any one group selected from the group consisting of:
  • R 2 is hydrogen
  • the R 2 comprises the NSAID moiety, and R 1 is hydrogen.
  • the R 2 is selected from any one of the following groups:
  • R 1 is hydrogen
  • both R 1 and R 2 comprise the NSAID moiety.
  • the R 1 and R 2 are each independently selected from any one of the following groups:
  • the thymidine derivative is selected from one or more of the following group:
  • the uridine derivative can comprise the structure of formula (III):
  • X 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.
  • Xs is oxygen.
  • X 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.
  • 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, C
  • X is or hydrogen, wherein said X 7 is hydrogen or wherein said X 1 ' is oxygen or sulfur, and X 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 Unsubstituted aryl and substituted or unsubstituted aralkyl.
  • X 1 ' is oxygen.
  • X is The C7 is wherein X 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, or C4 to C10 aryl.
  • the X3 is hydrogen
  • the X 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.
  • the X 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.
  • X4 is hydrogen. In certain embodiments, X5 is hydrogen.
  • the uridine derivative is selected from one or more of U1 to U13.
  • the uridine derivative comprises a compound of formula (IV): Formula (IV), wherein at least one of said X 1 , X 2 and X 7 comprises a non-steroidal anti-inflammatory drug (NSAID) moiety.
  • NSAID non-steroidal anti-inflammatory drug
  • 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 derivatives thereof compounds, anthranilic acid or its derivatives and/or enolic acid or its derivatives.
  • X 1 , X 2 or X 7 is hydrogen. In certain embodiments, X 1 , X 2 and X 7 are not simultaneously hydrogen.
  • any one of X 1 , X 2 and X 7 is independently where X 8 is X s 2 or Wherein, X s 1 is hydrogen or methyl, and X 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, Xs 3 and/or Xs 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
  • X8 is X s 1 is hydrogen or methyl, and X s 2 is selected from
  • X8 is X s 1 is hydrogen or methyl
  • X s 2 is
  • ring A 1 ' is C4 to C7 cycloalkyl, C4 to C7 heterocycloalkyl, C4 to C7 aryl and/or C4 to C7 heteroaryl
  • ring B 1 ' is C4 to C7 cycloalkyl, C4 to C7 heterocycloalkyl, C4 to C7 aryl, C4 to C7 heteroaryl or
  • ring B 2 ' is C4 to C7 cycloalkyl, C4 to C7 heterocycloalkyl, C4 to C7 aryl and/or C4 to C7 heteroaryl
  • ring B 3 ' is C4 to C7 cycloalkyl, C4 to C7 heterocycloalkyl, C4 to C7 aryl and/or C4 to C7 heteroaryl, wherein the C4 to C7 cycloalkyl, C4 to
  • X8 is X s 1 is hydrogen or methyl, and X s 2 is
  • X8 is X s 1 is hydrogen or methyl, and X s 2 is
  • X8 is X s 1 is hydrogen or methyl, and X s 2 is
  • X 8 1 is
  • any one of X 1 , X 2 and X 7 is independently
  • At least one of X 1 , X 2 , and X 7 (eg, X 1 , X 2 , X 7 , X 1 and X 2 , X 2 and X 7 , X 1 and X 7 , or , X 1 , X 2 and X 7 ) contain the NSAID moiety, the remainder being hydrogen.
  • the X is selected from the group consisting of:
  • the X is selected from the group consisting of:
  • the X is selected from the group consisting of:
  • the X is selected from the group consisting of:
  • the X is selected from the group consisting of:
  • the X is selected from the group consisting of:
  • X 1 , X 2 or X 7 when one or more of X 1 , X 2 or X 7 are each independently selected from a specific group in the above-mentioned group, X 1 , X 2 or X 2 are not selected from the above-mentioned group. Those in X 7 are hydrogen, but X 1 , X 2 or X 7 are not simultaneously hydrogen. In certain embodiments, X 1 X 2 or X 7 may both be the same group. In certain embodiments, two of X 1 , X 2 or X 7 are the same group. In certain embodiments, X 1 , X 2 or X 7 are each different group.
  • the uridine derivative is selected from one or more of the following group:
  • the use of the chemotherapeutic agent is for the treatment of cancer.
  • the chemotherapeutic agent comprises a pyrimidine nucleoside analog or a prodrug thereof.
  • the chemotherapeutic agent comprises one or more selected from the group consisting of capecitabine, cytarabine, docetaxel, doxorubicin, fluorouracil (5-FU), Floxuridine, Tegafur, Idarubicin, Paclitaxel, Epirubicin, Acelarin (NUC-1031), Doxorubicin, Leucovorin, Cisplatin, Paclitaxel, Cyclophosphamide, Vincristine, and 5- FU prodrugs (eg, prodrug derivatives of fluoropyridine and 5'-deoxyfluridine, floxuridine, 2'-deoxyfluridine, prodrug derivatives of floxuridine, or 2'-deoxyfluridine precursor derivatives, trifluoro-methyl-2'-deoxyuridine, 6-azauridine or 3-deazauridine).
  • capecitabine ecitabine
  • cytarabine docetaxel
  • doxorubicin fluorouracil
  • the use is where the disease or disorder is caused by administration of the chemotherapeutic drug.
  • the disease or disorder associated with the administration of a chemotherapeutic drug includes a skin tissue disease or disorder associated with the administration of a chemotherapeutic drug, a disease or disorder of hematopoietic tissue associated with the administration of a chemotherapeutic drug, limbs associated with the administration of a chemotherapeutic drug Disease or disorder, Cardiac disease or disorder associated with the administration of a chemotherapeutic drug, Nervous system disease or disorder associated with the administration of a chemotherapeutic drug, Disease or disorder of the five sense organs associated with the administration of a chemotherapeutic drug, and/or Gastrointestinal disease associated with the administration of a chemotherapeutic drug or disease.
  • the hematopoietic disease or disorder associated with the administration of a chemotherapeutic agent includes a bone marrow disease or disorder associated with the administration of a chemotherapeutic agent and a blood disease or disorder associated with the administration of a chemotherapeutic agent.
  • the hematopoietic disease or disorder associated with administration of a chemotherapeutic agent comprises a disease or disorder of abnormal blood cell proliferation associated with administration of a chemotherapeutic agent.
  • the disease or disorder associated with the administration of a chemotherapeutic drug comprises an epithelial tissue disease or disorder associated with the administration of a chemotherapeutic drug.
  • the epithelial tissue disease or disorder associated with administration of a chemotherapeutic agent includes the disease or disorder associated with endothelial cell pathology, and/or the disease or disorder associated with epithelial cell pathology, and wherein The endothelial cell pathology and/or epithelial cell pathology is associated with the administration of the chemotherapeutic agent.
  • the endothelial cells comprise vascular endothelial cells.
  • the epithelial cells include skin epithelial cells, oral epithelial cells, nasal cavity epithelial cells, gastric epithelial cells, and/or intestinal epithelial cells.
  • the disease or condition associated with administration of a chemotherapeutic agent comprises rash associated with administration of a chemotherapeutic agent, hand-foot syndrome associated with administration of a chemotherapeutic agent, pruritus associated with administration of a chemotherapeutic agent, chemotherapy associated with administration of a chemotherapeutic agent erythema, dry skin associated with administration of chemotherapy drugs, alopecia associated with administration of chemotherapy drugs, paronychia associated with administration of chemotherapy drugs, pigmentation disorders associated with administration of chemotherapy drugs, oral ulcers associated with administration of chemotherapy drugs, Dry mouth associated with administration of chemotherapeutics, epistaxis associated with administration of chemotherapeutics, nasopharyngitis associated with administration of chemotherapeutics, cheilitis associated with administration of chemotherapeutics, esophageal mucositis associated with administration of chemotherapeutics, and administration of chemotherapeutics Gastric mucositis, gastric ulcer associated with administration of chemotherapeutics, and
  • the disease or condition associated with the administration of a chemotherapeutic drug comprises hand-foot syndrome associated with the administration of a chemotherapeutic drug and/or paronychia associated with the administration of a chemotherapeutic drug.
  • the severity of the disease or condition associated with the administration of a chemotherapeutic agent is grade 1 or above, grade 2 or above, grade 3 or above, grade 3 or above, according to NCI-CTCAE V5.0 Level 4 or above, and/or Level 5.
  • the use of the medicament is formulated for topical administration. In certain embodiments, the use of the medicament is formulated for oral administration. In certain embodiments, the use of the medicament is formulated for topical administration.
  • the concentration of the thymidine derivative in the drug is from about 0.0001% (w/w) to about 50% (w/w). In certain embodiments, the concentration of the thymidine derivative in the drug is from about 0.1% (w/w) to about 5% (w/w). In certain embodiments, the concentration of the thymidine derivative in the drug is from about 0.5% (w/w) to about 3% (w/w).
  • the thymidine derivative is administered at a dose of about 0.5 [mu]M to about 1000 [mu]M. In certain embodiments, the thymidine derivative is administered at a dose of from about 1 [mu]M to about 500 [mu]M. In certain embodiments, the thymidine derivative is administered at a dose of about 20 [mu]M to about 300 [mu]M. In certain embodiments, the thymidine derivative is administered at a dose of about 20 [mu]M to about 200 [mu]M. In certain embodiments, the thymidine derivative is administered at a dose of about 30 [mu]M to about 200 [mu]M.
  • the uridine derivative is administered at a dose of about 100 [mu]M to about 500 [mu]M. In certain embodiments, the uridine derivative is administered at a dose of from about 0.5 [mu]M to about 50 [mu]M. In certain embodiments, the uridine derivative is administered at a dose of about 1 ⁇ M to about 50 ⁇ M. In certain embodiments, the uridine derivative is administered at a dose of about 1 ⁇ M to about 30 ⁇ M. In certain embodiments, the uridine derivative is administered at a dose of about 10 [mu]M to about 50 [mu]M.
  • the thymidine derivatives and uridine derivatives are administered at a dose of about 0.5 [mu]M to about 1000 [mu]M. In certain embodiments, the thymidine derivatives and uridine derivatives are administered at a dose of from about 1 [mu]M to about 500 [mu]M. In certain embodiments, the thymidine derivatives and uridine derivatives are administered at a dose of from about 0.5 [mu]M to about 25 [mu]M. In certain embodiments, the thymidine derivatives and uridine derivatives are administered at a dose of about 0.8 [mu]M to about 25 [mu]M.
  • the thymidine derivative is administered at a dose of from about 15 mpk to about 300 mpk. In certain embodiments, the thymidine derivative is administered at a dose of from about 10 mpk to about 500 mpk.
  • the thymidine derivative is administered at a dose of from about 10 mpk to about 100 mpk. In certain embodiments, the thymidine derivative is administered at a dose of about 50 mpk to about 100 mpk.
  • the thymidine derivatives and uridine derivatives are administered at a dose of from about 50 mpk to about 1000 mpk. In certain embodiments, the thymidine derivatives and uridine derivatives are administered at a dose of about 300 mpk to about 1000 mpk.
  • the medicament further comprises one or more active ingredients.
  • the drug does not substantially affect the therapeutic effect of the chemotherapeutic drug.
  • the use of the subject comprises a cancer patient.
  • the subject has been, is and/or will be administered the chemotherapeutic drug.
  • the subject has or is susceptible to the disease or condition associated with administration of the chemotherapeutic agent.
  • the use of said disease or condition increases in severity following administration of said chemotherapeutic agent.
  • the subject does not have the disease or condition prior to administration of the chemotherapeutic drug.
  • the present application provides a pharmaceutical combination or kit comprising: 1) the chemotherapeutic drug; and 2) the combination comprising a thymidine derivative and a uridine derivative.
  • the chemotherapeutic drug and the combination comprising the thymidine derivative and the uridine derivative in the pharmaceutical combination or kit are not mixed with each other.
  • the chemotherapeutic agent and the combination comprising the thymidine derivative and the uridine derivative are each independently present in separate containers.
  • the combination comprising a thymidine derivative and a uridine derivative in the pharmaceutical combination or kit 2) is capable of preventing or treating a disease associated with administration of the chemotherapeutic drug in 1). disease or condition.
  • the combination comprising a thymidine derivative and a uridine derivative in 2) of the pharmaceutical combination or kit does not substantially affect the therapeutic effect of the chemotherapeutic drug in 1).
  • the combination comprising a thymidine derivative and a uridine derivative of 2) is administered in the pharmaceutical combination or kit before, concurrently with, or after administration of the chemotherapeutic drug of 1).
  • the application provides a method comprising administering to a subject a combination comprising a thymidine derivative and a uridine derivative, wherein the subject has been, is and/or will be administered a chemotherapeutic agent and Suffering from or susceptible to a disease or disorder associated with administration of the chemotherapeutic agent.
  • the application 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 thymidine derivative and a uridine derivative, wherein the disease or disorder is a disease or disorder associated with administration of a chemotherapeutic drug.
  • the method wherein the subject has been is and/or will be administered the chemotherapeutic drug.
  • Figures 1A-1D show the thymidine derivative compounds and their numbers described in the present application
  • FIGS. 2A-2B show the uridine derivative compounds described in this application and their numbers
  • Fig. 3-Fig. 10 show exemplary thymidine derivatives and the combination of thymidine derivatives and uridine derivatives, in Hacat cells, to alleviate the toxicity of fluorine drugs; at the same time, the results show that the derivatives series The relieving effect of the compound is superior to that of uridine.
  • Figure 11 shows a model of hand-foot syndrome induced by capecitabine in rats. As can be seen from the photos, the model features are obvious.
  • Figure 12 shows the exemplary results of the thymidine derivatives described in the present application and the combined use of thymidine derivatives and uridine derivatives to prevent and/or treat capecitabine in rats with hand-foot syndrome. It can be seen from the figure that the symptoms after applying the drug can be significantly relieved compared with the model group.
  • Figure 13 shows a model of hand-foot syndrome induced by capecitabine in mice.
  • Figure 14 shows the exemplary results of the thymidine derivatives described in the present application and the combined use of thymidine derivatives and uridine derivatives to prevent and/or treat capecitabine in mice with hand-foot syndrome. It can be seen from the figure that the symptoms after applying the drug can be significantly relieved compared with the model group.
  • Fig. 15-Fig. 20 show the relieving effect of thymidine derivatives containing NSAIDs on the toxicity of fluorine drugs in Hacat cells; at the same time, the results show that the relieving effect of uridine derivatives is better than that of thymidine effect.
  • Figure 21 shows the combined use of an exemplary NSAID-containing thymidine derivative and an NSAID-containing uridine derivative in Hacat cells to alleviate the toxicity of fluorine drugs.
  • Figure 22 shows exemplary NSAID-containing thymidine derivatives attenuating inflammatory responses in rats with hand-foot syndrome following chemotherapeutic drug administration.
  • Figure 23 shows exemplary NSAID-containing thymidine derivatives, and the combination of NSAID-containing thymidine derivatives and NSAID-containing uridine derivatives relieve pain in rats with hand-foot syndrome following chemotherapeutic drug administration.
  • Figure 24 shows an exemplary NSAID-containing thymidine derivative, and a combination of an NSAID-containing thymidine derivative and an NSAID-containing uridine derivative to relieve diarrhea following chemotherapy drug administration.
  • chemotherapeutic drugs generally refers to drugs that can act on different links of tumor cell growth and reproduction, and inhibit or kill tumor cells.
  • chemotherapeutic agents may include pyrimidine nucleoside analogs or prodrugs thereof.
  • the chemotherapeutic agent may include one or more selected from the group consisting of capecitabine, cytarabine, docetaxel, doxorubicin, fluorouracil (5-FU), floxuridine, tega Fluorine, idarubicin, paclitaxel, epirubicin, Acelarin (NUC-1031), doxorubicin, folinic acid, cisplatin, paclitaxel, cyclophosphamide, and vincristine.
  • chemotherapy drugs can act directly on DNA to prevent cancer cells from regenerating.
  • chemotherapy drugs can interfere with DNA and RNA synthesis.
  • chemotherapy drugs can block cancer cell proliferation by inhibiting the action of enzymes or mitosis.
  • the term "cancer” usually refers to a new organism formed by the proliferation of local tissue cells under the action of various carcinogenic factors. Because this new organism is mostly a space-occupying lump, it is also called a neoplasm. .
  • the cancer can be selected from the group consisting of lung cancer, pancreatic cancer, skin cancer, bladder cancer, colon cancer, uterine cancer, breast cancer, intestinal cancer, prostate cancer, cervical cancer, ovarian cancer, esophageal cancer, head and neck cancer , gastric and laryngeal cancers.
  • the cancer can be colon cancer.
  • 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.
  • 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.
  • the disease or disorder associated with the administration of a chemotherapeutic drug can be hand-foot syndrome.
  • the disease or condition associated with administration of a chemotherapeutic drug may be diarrhea.
  • skin tissue disease or disorder generally refers to pathological changes in the form, structure and/or function of the skin (including hair and nails).
  • 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.
  • 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.
  • HFS Hand Foot Syndrome
  • PPE Palmar Plantar Erythrodysesthesia
  • HFSR Hand-foot skin reaction
  • 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.
  • HFS may include palmar, plantar hypoesthesia, or chemotherapy-induced acral erythema, among others.
  • cancer patients may experience corresponding symptoms during chemotherapy.
  • thymidine derivative generally refers to a product derived from thymidine in which the hydrogen atom is replaced by other atoms or atomic groups.
  • the thymidine derivative may have at least one hydroxy hydrogen on the deoxyribose sugar substituted.
  • the Thymidine 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.
  • 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).
  • 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.
  • the number of carbon atoms in a hydrocarbyl substituent ie, alkyl, alkenyl, cycloalkyl, aryl, etc.
  • C a -C b the prefix
  • a is the smallest and b is the largest The number of carbon atoms in the substituent.
  • Ci- C6 alkyl refers to an alkyl substituent containing from 1 to 6 carbon atoms.
  • 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".
  • 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.
  • 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.
  • hydrogen generally refers to a hydrogen substituent, possibly described as -H.
  • oxygen generally refers to an oxygen substituent, possibly described as -O-.
  • hydroxyl generally refers to -OH.
  • 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.
  • 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.
  • each substituent is selected independently of the other substituents.
  • each substituent can be the same or different from the other substituents.
  • a compound represented by formula (I), a compound represented by formula (II), a compound represented by formula (III) or a compound represented by formula (IV) or a pharmaceutically acceptable salt thereof formula (I)
  • the compound shown, the compound shown in formula (II), the compound shown in formula (III) or the compound shown in formula (IV) or a pharmaceutically acceptable salt thereof can exist in unsolvated and solvated forms .
  • the binding force of the solvent or water is strong, the complex has a well-defined stoichiometry, which is not affected by humidity.
  • 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.
  • the "compound represented by formula (I)”, “compound represented by formula (II)”, “compound represented by formula (III)” or “compound represented by formula (IV)” may have an asymmetric carbon atom.
  • the carbon-carbon bond of the compound represented by the formula (I), the compound represented by the formula (II), the compound represented by the formula (III) or the compound represented by the formula (IV) can be represented by a solid line and a solid Wedge or point wedge representation.
  • 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.
  • 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), compounds of formula (II), compounds of formula (III) or complexes of compounds of formula (IV), which contain two or more compounds that can Stoichiometric or non-stoichiometric organic and/or inorganic components. The resulting complexes can be ionized, partially ionized or not.
  • Stereoisomers of the compound represented by the formula (I), the compound represented by the formula (II), the compound represented by the formula (III) or the compound represented by the formula (IV) include cis and trans isomers, Optical isomers, such as R and S enantiomers, diastereomers, geometric isomers, rotamers, conformers and tautomers, of formula (I)
  • Compounds, compounds of formula (II), compounds of formula (III), or compounds of formula (IV) include compounds that exhibit more than one type of isomerism; and mixtures thereof (such as racemates) and diastereomeric pairs).
  • 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.
  • 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.
  • the compound represented by the formula (I), the compound represented by the formula (II), the compound represented by the formula (III) or the compound represented by the formula (IV) may exhibit tautomerism and structural isomerism.
  • compounds of formula (I) or compounds of formula (I) may exist in several tautomeric forms, including enol and imine forms, and keto and enamine forms, as well as geometric isomers and mixtures thereof. All of these tautomeric forms are included within the scope of compounds of formula (I), compounds of formula (II), compounds of formula (III) or compounds of formula (IV).
  • 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 compounds of formula (I), compounds of formula (II), compounds of formula (III) or compounds of formula (IV) All tautomers.
  • the present invention also includes isotopically labeled compounds, which are the same as those described in the compounds of formula (I), the compounds of formula (II), the compounds of formula (III), or the compounds of formula (IV) , but one or more of its atoms are replaced by atoms with atomic masses or mass numbers different from those found in nature.
  • the compound represented by formula (I), the compound represented by formula (II), the compound represented by formula (III) or the compound represented by formula (IV) can be added.
  • Isotopes of the compound include hydrogen, carbon, nitrogen, oxygen, phosphorus , isotopes of fluorine and chlorine, such as but not limited to: 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl.
  • Isotopically-labeled compounds of formula (I), compounds of formula (II), compounds of formula (III), or compounds of formula (IV) can generally be prepared by substituting isotopically-labeled reagents for non-isotopically-labeled reagent preparation.
  • 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.
  • 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.
  • non-steroidal anti-inflammatory drug 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.
  • COX cyclooxygenases
  • Non-steroidal means non-glucocorticoid.
  • the thymidine derivative and/or 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 thymidine or 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.
  • 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,
  • chemotherapeutic drugs can treat cancer.
  • the chemotherapeutic agent may include a pyrimidine nucleoside analog or a prodrug thereof.
  • chemotherapeutic drugs can include drugs that can be metabolized to form floxuridine nucleotides. Flouridine nucleotides in cells can cause cytotoxicity by interfering with normal uridine nucleotide metabolism.
  • the chemotherapeutic drug may include one or more selected from the group consisting of capecitabine, cytarabine, docetaxel, doxorubicin, fluorouracil (5-FU), floxuridine, Fluoride, idarubicin, paclitaxel, epirubicin, Acelarin (NUC-1031), doxorubicin, leucovorin, cisplatin, paclitaxel, cyclophosphamide, vincristine, and 5-FU prodrugs ( For example, furanfluridine and 5'-deoxyfluridine, floxuridine, 2'-deoxyfluridine, prodrug derivatives of floxuridine or prodrug derivatives of 2'-deoxyfluridine, Trifluoro-methyl-2'-deoxyuridine, 6-azauridine, 3-deazauridine).
  • chemotherapeutic agents may include alkylating agents such as nitrogen mustard, nitrogen mustard N-oxide hydrochloride, chlorambucil, cyclophosphamide, ifosfamide, thietipide, isothiocyanates, white Zulfan, Nimustine Hydrochloride, Mitropium Bromide, Melphalan, dacarbazine, Ramustine, Imiphene Sodium Phosphate, Ethylene Triamine, Carmustine, Lomustine, Chain Utozotocin, pipobroman, ethoglucid, carboplatin, cisplatin, meplatin, nedaplatin, tenetamide, olimustine, dichloropyridine, flupix Tan, prednipoxitine, pumitepa, bendamustine hydrochloride (Ribomustin), temozolomide, diclofenac, trovafloxacin, zinostatin, simvastatin,
  • the chemotherapeutic drug may be a hormonal therapeutic anticancer agent, which may include fustatin, diethylstilbestrol, chlorostilbene, medroxyprogesterone acetate, megestrol acetate, cyproterone acetate, cyproterone acetate ketones, danazol, allylestradiol, progesterone, mepartricin, raloxifene or meloxifene, levofloxacin, antiestrogens (eg, tamoxifen citrate , toremifene citrate, etc.), contraceptives, prostacyclanes, testosterone lactones, aminosuccinimide, LH-RH agonists (eg, goserelin acetate, buserelin, leucovorin Prorelin, etc.), droloxifene, epiandrostanol, ethinyl estradiol sulfonate, furoxazole hydroch
  • the chemotherapeutic drug may also be an immunotherapy anticancer agent, which may include bubinenib, cristatin, etofuram, lentinan, ubenmetacin, interferon, interleukin, macrophage Phage colony stimulating factor, granulocyte colony stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, corynebacterium, everolimus, levamisole and/or polysaccharide K, etc.
  • an immunotherapy anticancer agent may include bubinenib, cristatin, etofuram, lentinan, ubenmetacin, interferon, interleukin, macrophage Phage colony stimulating factor, granulocyte colony stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, corynebacterium, everolimus, levamisole and/or polysaccharide K, etc.
  • the chemotherapeutic drug may be administered in combination with one or more other therapies.
  • the one or more other therapies can include one or more other anti-tumor therapies.
  • other anti-tumor therapies may also include radiation therapy or surgery.
  • chemotherapeutic drugs are used in combination with other anti-tumor therapies, they may be administered to the subject at the same time, or they may be administered separately at intervals.
  • the other anti-tumor therapy may be part of a single agent, which is mixed with the chemotherapeutic drug into a single composition.
  • the other anti-tumor therapy may be a single agent administered separately from the chemotherapeutic drug.
  • the chemotherapeutic drug may be administered at about 1-99% (eg, about 5-95%, about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or about 99%) dosage levels present and/or administered.
  • the disease or condition associated with the administration of a chemotherapeutic drug may be statistically significantly associated with the administration of a chemotherapeutic drug.
  • the disease or condition associated with the administration of a chemotherapeutic drug may be caused by the action of the chemotherapeutic drug.
  • the disease or disorder associated with administration of a chemotherapeutic drug may include a disease or disorder of skin tissue associated with administration of a chemotherapeutic drug, a disease or disorder of hematopoietic tissue associated with administration of a chemotherapeutic drug, a disease or disorder of extremities associated with administration of a chemotherapeutic drug, Cardiac disease or disorder associated with administration of a chemotherapeutic drug, neurological disease or disorder associated with administration of a chemotherapeutic drug, disease or disorder of the five senses associated with administration of a chemotherapeutic drug, and/or gastrointestinal disease or disorder associated with the administration of a chemotherapeutic drug.
  • the skin tissue disease or disorder, the disease or disorder of the extremities, the five sense organs, and/or the gastrointestinal tract disease or disorder associated with the administration of a chemotherapeutic drug may include a disease or disorder in the skin, limbs, five sense organs, and/or the gastrointestinal tract associated with the administration of a chemotherapeutic drug the disease or disorder.
  • the disease or disorder of epithelial tissue in the skin, extremities, five senses, and/or gastrointestinal tract associated with the administration of chemotherapeutic drugs includes the disease or disorder associated with endothelial cell pathology, and/or the disease or disorder associated with epithelial cell pathology.
  • a disease or disorder, and wherein said endothelial cell pathology and/or epithelial cell pathology is associated with said administration of a chemotherapeutic agent.
  • the endothelial cells can include vascular endothelial cells.
  • Pathological changes in vascular endothelial cells can include endothelial dysfunction.
  • the vascular endothelial cell lesions may include degenerative vascular diseases (eg, atherosclerosis, medial sclerosis, and arterioles (eg, hyaline degeneration and proliferative arterioles)), inflammatory Vascular disease (eg, infectious arteritis, syphilitic arteritis, giant cell arteritis, thromboangiitis obliterans, and rheumatic arteritis), functional vascular disease (eg, Raynaud's disease, cyanosis of the hands and feet, and erythematous limbs) pain) and/or congenital vascular disease (eg, congenital arteriovenous fistula), etc.
  • degenerative vascular diseases eg, atherosclerosis, medial sclerosis, and arterioles (eg,
  • the epithelial cells can include skin epithelial cells, oral epithelial cells, nasal cavity epithelial cells, gastric epithelial cells and/or intestinal epithelial cells.
  • the epithelial lesions can include skin epithelial lesions (eg, rash, acne, rosacea, atopic dermatitis, contact dermatitis, seborrheic dermatitis, lupus, scleroderma, pemphigus, hyperpigmentation, Melasma, vitiligo, urticaria, tinea corporis, pruritus, alopecia, hair changes, erythema, paronychia and onychomycosis, dry skin, hypersensitivity, and psoriasis), oral epithelial lesions (eg, pemphigus, Cold sores, herpetic stomatitis, granulomatous cheilitis, oral ulcers, pemphigoid, S
  • the skin tissue disease or disorder associated with the administration of a chemotherapeutic drug may include side effects or adverse reactions resulting from the administration of the chemotherapeutic drug.
  • the skin tissue disease or condition associated with administration of a chemotherapeutic drug may include rash associated with administration of a chemotherapeutic drug, hand-foot syndrome associated with administration of a chemotherapeutic drug, pruritus associated with administration of a chemotherapeutic drug, erythema associated with administration of a chemotherapeutic drug , Skin dryness associated with administration of chemotherapeutics, Hair loss associated with administration of chemotherapeutics, Paronychia associated with administration of chemotherapeutics, Pigmentation disorders associated with administration of chemotherapeutics, Oral ulcers associated with administration of chemotherapeutics, Drug-related dry mouth, epistaxis associated with administration of chemotherapeutics, nasopharyngitis associated with administration of chemotherapeutics, cheilitis associated with administration
  • the skin tissue disease or disorder, the five sense disease or disorder, and/or the gastrointestinal tract disease or disorder associated with the administration of chemotherapeutic drugs may include those in the skin tissue, the five sense organs, and/or the gastrointestinal tract that are associated with the administration of chemotherapeutic drugs Associated epithelial tissue disease or disorder.
  • skin tissue disease or disorder generally refers to pathological changes in the form, structure and/or function of the skin (including hair and nails).
  • 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.
  • 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.
  • Rashes also include hives.
  • HFS Hand Foot Syndrome
  • PPE Palmar Plantar Erythrodysesthesia
  • HFSR Hand-foot skin reaction
  • the pathological manifestations of HFS mainly include, for example, basal keratinocyte vacuolar degeneration, perivascular lymphocyte infiltration, keratinocyte apoptosis, and skin edema.
  • HFS can include palmar, plantar hypoesthesia, or chemotherapy-induced acral erythema, among others. Cancer patients may experience symptoms during chemotherapy or molecularly targeted therapy (such as chemotherapy drugs).
  • HFS hand-foot syndrome
  • NBI National Cancer Institute
  • 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.).
  • HFS World Health Organization
  • 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 the palms and soles, erythema and swelling around the nail
  • Grade 4 is peeling, ulceration, boils and severe pain.
  • gastrointestinal disease or disorder generally refers to pathological changes in the morphology, structure and/or function of stomach or intestinal tissue (eg, tissue of the digestive tract from the stomach pylorus to the anus).
  • the gastrointestinal disease or disorder may include, but is not limited to, diarrhea, vomitting, nausea, anorexia, constipation, and/or abdominal pain, and the like.
  • the hematopoietic disease or disorder associated with the administration of a chemotherapeutic drug may include a bone marrow disease or disorder associated with the administration of a chemotherapeutic drug and a blood disease or disorder associated with the administration of a chemotherapeutic drug.
  • the hematopoietic disease and disorder associated with the administration of a chemotherapeutic drug may include a disease or disorder of abnormal blood cell proliferation associated with the administration of a chemotherapeutic drug.
  • the hematopoietic disease associated with administration of a chemotherapeutic drug may include leukemia associated with administration of a chemotherapeutic drug, myeloproliferative disease associated with administration of a chemotherapeutic drug, myelosuppression associated with administration of a chemotherapeutic drug, anemia associated with administration of a chemotherapeutic drug , leukopenia associated with administration of a chemotherapeutic drug, and/or thrombocytopenia associated with administration of a chemotherapeutic drug.
  • the hematopoietic disease associated with the administration of a chemotherapeutic drug may be thrombocytopenia associated with the administration of a chemotherapeutic drug.
  • thrombocytopenia generally refers to the inhibitory effect of antitumor chemotherapeutic drugs on bone marrow megakaryocytes, resulting in the platelet count in peripheral blood being lower than 100 ⁇ 10 9 /L.
  • thrombocytopenia is usually classified into four grades.
  • 7.5x10 10 /L-the lower limit of normal value is grade 1
  • 5x10 10 /L-7.5x10 10 /L is grade 2
  • 2.5x10 10 /L-5x10 10 /L is grade 3
  • less than 2.5x10 10 /L is grade 3 level 4.
  • myelosuppression generally refers to the phenomenon that chemotherapy drugs can kill many normal bone marrow cells while killing a large number of tumor cells.
  • certain tumor patients have a progressive increase in myelosuppression during chemotherapy as the cumulative amount of chemotherapeutic drugs in the body increases.
  • myelosuppression can include, but is not limited to, leukopenia.
  • myeloproliferative disease generally refers to a group of related diseases caused by abnormal hematopoietic cells growing in the bone marrow. In some cases, these cells can become cancerous and become a type of leukemia. The incidence and severity of anemia increases and worsens with the accumulation of chemotherapy drugs.
  • NCI National Cancer Institute
  • WHO World Health Organization
  • anemia generally refers to a common clinical symptom of decreased peripheral blood red blood cell volume in humans, below the lower limit of the normal range.
  • chemotherapeutic drugs can directly affect bone marrow hematopoiesis by blocking the synthesis of erythroid precursor cells.
  • the heart disease or disorder associated with the administration of a chemotherapeutic drug may include the disease or disorder of the heart associated with the administration of a chemotherapeutic drug.
  • the heart disease or condition associated with administration of a chemotherapeutic drug may include nonspecific chest pain associated with administration of a chemotherapeutic drug, angina pectoris associated with administration of a chemotherapeutic drug, palpitations associated with administration of a chemotherapeutic drug, dyspnea associated with administration of a chemotherapeutic drug , Diffuse pleuritic chest pain associated with administration of chemotherapeutics, Supraventricular arrhythmias associated with administration of chemotherapeutics, Myocardial infarction associated with administration of chemotherapeutics, Bradycardia associated with administration of chemotherapeutics, Arrhythmias associated with administration of chemotherapeutics, ventricular fibrillation associated with administration of chemotherapeutics, ventricular tachycardia associated with administration of chemotherapeutic drugs
  • the chemotherapeutic drugs can be used to treat tumors.
  • the disease or condition is affected differently than the tumor.
  • the severity of the disease or condition associated with the administration of chemotherapeutic drugs may be grade 1 or above, grade 2 or above, grade 3 or above, grade 4 according to NCI-CTCAE V5.0 Grade or above, and/or Grade 5.
  • the disease or condition may develop or be exacerbated following administration of the chemotherapeutic drug.
  • the present application provides the use of a thymidine derivative in the preparation of a medicament for preventing or treating a disease or condition associated with the administration of a chemotherapeutic drug in a subject, wherein the thymidine can be the acetyl group of thymidine Derivatives (eg, monoacetyl derivatives of thymidine, diacetyl derivatives of thymidine, or triacetyl derivatives of thymidine).
  • thymidine can be the acetyl group of thymidine Derivatives (eg, monoacetyl derivatives of thymidine, diacetyl derivatives of thymidine, or triacetyl derivatives of thymidine).
  • the thymidine derivative may comprise the structure shown in formula (I): Wherein, R 2 , R 3 , R 4 , R 5 and/or R 6 may be hydrogen.
  • the thymidine derivative can be selected from any one or more of T1 to T24.
  • the application provides the use of a thymidine derivative comprising an NSAID moiety in the manufacture of a medicament for the prevention or treatment of a disease or condition associated with administration of a chemotherapeutic drug (eg, hand-foot syndrome, or diarrhea)
  • a chemotherapeutic drug eg, hand-foot syndrome, or diarrhea
  • the thymidine derivative comprises the structure shown in formula (II): Formula (II), wherein at least one of R 1 and R 2 comprises a non-steroidal anti-inflammatory drug (NSAID) moiety.
  • R1 in formula (II) contains an NSAID moiety.
  • R2 in formula ( II ) comprises an NSAID moiety.
  • the other can be hydrogen.
  • R1 and R2 in formula ( II ) both comprise NSAID moieties, and may comprise the same or different NSAID moieties.
  • the NSAID moiety may include, but is not limited to, pyrazolidines, salicylates, acetic acid derivatives, xicams, propionic acid derivatives, profen and/or fenamic acids.
  • the NSAID moiety may comprise 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.
  • the NSAID can be linked to thymidine through an ester bond.
  • the NSAID-containing thymidine derivative may be selected from one or more of T25 to T50.
  • the Thymidine Derivatives can be used together with the Uridine Derivatives to treat a disease or disorder in a subject associated with the administration of a chemotherapeutic drug.
  • the disease or disorder may be hand-foot syndrome or diarrhea.
  • the uridine derivative comprises the structure of formula (III):
  • X 4 and X 5 are both hydrogen, X 1 , X 2 and X 3 are not hydrogen or CH 3 CO- at the same time.
  • the uridine derivative is selected from one or more of U1 to U13.
  • the thymidine derivative may comprise an NSAID moiety
  • the thymidine derivative comprising an NSAID moiety may comprise a compound represented by formula (IV):
  • X 1 , X 2 and X 7 comprises a non-steroidal anti-inflammatory drug (NSAID) moiety.
  • X 1 in formula (IV) may contain an NSAID moiety.
  • X2 in formula ( II ) contains an NSAID moiety.
  • NSAID non-steroidal anti-inflammatory drug
  • X1 and X2 in formula (IV ) both comprise NSAID moieties, and may comprise the same or different NSAID moieties.
  • the NSAID moiety may include, but is not limited to, pyrazolidines, salicylates, acetic acid derivatives, xicams, propionic acid derivatives, profen and/or fenamic acids.
  • the NSAID moiety may comprise 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.
  • the NSAID can be linked to thymidine through an ester bond.
  • the NSAID-containing uridine derivative may be selected from one or more of U14 to U21.
  • the NSAID-containing thymidine derivatives and the NSAID-containing uridine derivatives can be used to prevent or treat diseases or conditions associated with the administration of chemotherapeutic drugs in a subject (eg, hand-foot syndrome and / or diarrhea).
  • the application provides the use of a thymidine derivative in the manufacture of a medicament for preventing or treating a disease or disorder (eg, diarrhea or hand-foot syndrome) associated with administration of a chemotherapeutic drug in a subject .
  • a disease or disorder eg, diarrhea or hand-foot syndrome
  • the thymidine derivative may comprise a compound of formula (I) herein.
  • the thymidine derivative may comprise compounds T1 to T24 herein.
  • the thymidine derivative may comprise a compound of formula (II) herein.
  • the thymidine derivative may comprise compounds T25 to T50 herein.
  • the present application provides the use of a thymidine derivative and 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.
  • the thymidine derivative may comprise a compound represented by formula (I) herein, and the thymidine derivative may comprise a compound represented by formula (III) herein.
  • the thymidine derivative may comprise compounds T1 to T24 herein, and the thymidine derivative may comprise compounds U1 to U13.
  • the thymidine derivative may comprise a compound represented by formula (II) herein
  • the thymidine derivative may comprise a compound represented by formula (IV) herein.
  • the thymidine derivative may comprise compounds T25 to T50 herein, and the thymidine derivative may comprise compounds U14 to U21.
  • the thymidine derivatives and/or uridine derivatives can be used to prevent or treat hand-foot syndrome caused by chemotherapeutic drugs.
  • the thymidine derivatives and/or uridine derivatives can be used for hand-foot syndrome caused by 5-FU or 5-FU prodrugs.
  • the thymidine derivatives and/or uridine derivatives can be used to prevent or treat hand-foot syndrome caused by capecitabine or 5-FU.
  • the thymidine derivatives and/or uridine derivatives can be used to prevent or treat diarrhea caused by chemotherapy drugs.
  • the thymidine derivatives and/or uridine derivatives can be used for diarrhea caused by 5-FU or 5-FU prodrugs.
  • the thymidine derivatives and/or uridine derivatives can prevent or treat diarrhea caused by 5-FU.
  • the thymidine derivative and/or uridine derivative may comprise an NSAID moiety
  • the thymidine derivative and/or uridine derivative comprising the NSAID moiety may alleviate, treat and/or prevent pyrimidine nucleoside analogs Drugs or their prodrugs (eg, 5-FU or capecitabine), compared with thymidine derivatives and/or uridine derivatives that do not contain NSAIDs, are able to reduce both pain and inflammatory responses in subjects, indicating retention
  • the dual effect of the uridine and/or thymidine moiety and the NSAID moiety has a synergistic effect.
  • the medicament may be prepared for external or oral administration.
  • the administration site of the topical administration may not be the site of occurrence of cancer or the site of potential metastases of cancer.
  • the administered moiety may not be the primary site of cancer.
  • the administered moiety may not be a metastatic site of cancer.
  • the metastatic site may include the site of cancer metastasis caused by lymphatic metastasis, vascular metastasis and/or implanted metastasis.
  • the metastatic site may include bone, brain, liver, stomach and/or lung.
  • the administered portion may not be the recurrence site of the cancer.
  • the concentration of the thymidine derivative may be about 0.0001% (w/w) to about 50% (w/w), for example, it may be about 0.0001% (w/w) to about 0.0001% (w/w) about 10% (w/w), about 0.0001% (w/w) to about 9.5% (w/w), about 0.0001% (w/w) to about 9% (w/w), about 0.0001% (w/w) /w) to about 8.5% (w/w), about 0.0001% (w/w) to about 8% (w/w), about 0.0001% (w/w) to about 7.5% (w/w), about 0.0001% (w/w) to about 7% (w/w), about 0.0001% (w/w) to about 6.5% (w/w), about 0.0001% (w/w) to about 6% (w/w) w), about 0.0001% (w/w) to about 5.5% (w/w), about 0.0001% (w/w) to about 5% (w/w), about 0.0001% (w
  • the concentration of the thymidine derivative may be about 0.0001% (w/w) to about 1% (w/w), about 0.0001% (w/w) to about 0.9% ( w/w), from about 0.0001% (w/w) to about 0.6% (w/w), from about 0.05% (w/w) to about 0.5% (w/w), from about 0.05% (w/w) to about 0.4% (w/w), about 0.05% (w/w) to about 0.3% (w/w), about 0.05% (w/w) to about 0.2% (w/w), about 0.1% (w/w) /w) to about 0.2% (w/w) or less.
  • the concentration of the thymidine derivative may be about 0.2% (w/w).
  • the concentration of the thymidine derivative may be about 0.1% (w/w).
  • the drug containing the thymidine derivative and/or the uridine derivative may not substantially affect the therapeutic effect of the chemotherapeutic drug.
  • administration of the drug comprising the thymidine derivative and/or uridine derivative does not substantially necessitate an increase in the dose of the chemotherapeutic drug administered to achieve substantially the same therapeutic effect.
  • the medicament can be formulated for oral administration.
  • 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 (for an inert base such as gelatin, glycerol, sucrose or acacia) and/or mouthwashes and the like.
  • Oral solid preparations 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 such as starch, lactose, sucrose, glucose, mannitol and/or silicic acid; (2) binders such as carboxymethylcellulose, alginic acid Salt, gelatin, polyvinylpyrrolidone, sucrose and/or acacia; (3) wetting agents, such as glycerol; (4) splitting agents, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicon acid salts and/or sodium carbonate; (5) blocker solutions, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) lubricants, such as acetol and/or glyceryl monostearate; (
  • Oral liquid preparations may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, elixirs, and the like.
  • liquid dosage forms may contain customary inert diluents, for example, water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzene ( Benzyl formate, propylene glycol, 1,3-butanediol, oils (in particular, cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acids Sorbitan esters, and mixtures of two or more of the above.
  • liquid preparations for oral administration can also contain adjuvants such as wetting agents,
  • the medicament can be formulated for topical administration.
  • the medicament can be formulated for topical skin administration.
  • the medicament can be an ointment, lotion or cream.
  • the medicament may further comprise one or more active ingredients.
  • the active ingredient may refer to a monomeric compound having medical utility or physiological activity.
  • the other active ingredients may be selected from the group consisting of anti-inflammatory agents, analgesics, local anesthetics, antibiotics, antihistamines, antiseptics, immunosuppressants and anti-bleeding agents.
  • the medicament may also include a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier may be selected from the group consisting of fillers, binders, disintegrants, buffers, preservatives, lubricants, flavoring agents, thickening agents, coloring agents and emulsifiers.
  • the subject may comprise a cancer patient.
  • the subject has been, is and/or will be administered the chemotherapeutic drug.
  • the subject may have or be susceptible to the disease or condition associated with the administration of the chemotherapeutic drug.
  • the severity of the disease or condition may increase after administration of the chemotherapeutic drug.
  • the subject did not have the disease or condition prior to administration of the chemotherapeutic drug.
  • the thymidine derivative may be administered at a dose of about 0.0001 ⁇ M to about 1500 ⁇ M, eg, about 0.001 ⁇ M to about 1500 ⁇ M, about 1 ⁇ M to about 1500 ⁇ M, about 1 ⁇ M to about 500 ⁇ M, about 1 ⁇ M to about 100 ⁇ M , about 30 ⁇ M to about 900 ⁇ M, about 10 ⁇ M to about 1000 ⁇ M, about 10 ⁇ M to about 500 ⁇ M.
  • the uridine derivative may be administered at a dose of about 0.0001 ⁇ M to about 1500 ⁇ M, for example, about 0.001 ⁇ M to about 1500 ⁇ M, about 1 ⁇ M to about 1500 ⁇ M, about 1 ⁇ M to about 500 ⁇ M, about 1 ⁇ M to about 100 ⁇ M , about 30 ⁇ M to about 900 ⁇ M, about 10 ⁇ M to about 1000 ⁇ M, about 10 ⁇ M to about 500 ⁇ M.
  • the thymidine derivatives and uridine derivatives may be administered at a dose of about 0.0001 ⁇ M to about 1500 ⁇ M, for example, about 0.001 ⁇ M to about 1500 ⁇ M, about 1 ⁇ M to about 1500 ⁇ M, about 1 ⁇ M to about 500 ⁇ M, About 1 ⁇ M to about 100 ⁇ M, about 30 ⁇ M to about 900 ⁇ M, about 10 ⁇ M to about 1000 ⁇ M, about 10 ⁇ M to about 500 ⁇ M.
  • the ratio of the concentration of the thymidine derivative to the concentration of the uridine derivative is about 1:10 to about 10:1, for example, about 1:8 to about 8:1 1, about 1:6 to about 6:1, about 1:4 to about 4:1, about 1:2 to about 2:1.
  • the ratio of the concentration of the compounds from T1 to T24 to the concentration of the compounds from U1 to U13 is about 1:10, about 1:8, about 1:6, about 1:4, about 1:2, about 2 : 1, about 4:1, about 6:1, about 8:1 or about 10:1.
  • the ratio of the administered dose of the thymidine derivative to the administered dose of the uridine derivative is about 1:10 to about 10:1, eg, about 1:1: 8 to about 8:1, about 1:6 to about 6:1, about 1:4 to about 4:1, about 1:2 to about 2:1.
  • the ratio of the concentration of the compounds from T1 to T24 to the concentration of the compounds from U1 to U13 is about 1:10, about 1:8, about 1:6, about 1:4, about 1:2, about 2 : 1, about 4:1, about 6:1, about 8:1 or about 10:1.
  • the present application provides a method of treating and/or preventing hand-foot syndrome associated with the administration of chemotherapeutic drugs with a compound of T1 to T24 for topical use.
  • the chemotherapeutic agent is 5-FU or capecitabine.
  • the T1 to T24 compounds are administered at a concentration of about 0.5% (wt%) to about 5.0% (wt%), or about 0.5% (wt%) to about 2.0% (wt%).
  • the present application provides a method of treating and/or preventing hand-foot syndrome associated with the administration of chemotherapeutic drugs with a compound of T1 to T24 for topical use.
  • the chemotherapeutic agent is 5-FU or capecitabine.
  • the T1 to T24 compounds are administered at a concentration of about 1 ⁇ M to about 1000 ⁇ M, about 10 ⁇ M to about 1000 ⁇ M, about 30 ⁇ M to about 500 ⁇ M, about 1 ⁇ M to about 10 ⁇ M, about 1 ⁇ M to about 100 ⁇ M, about 1 ⁇ M to about 200 ⁇ M, or About 10 ⁇ M to about 500 ⁇ M.
  • the application provides a method of treating and/or preventing diarrhea associated with the administration of a chemotherapeutic drug of a compound of T1 to T24, the compound being administered orally.
  • the chemotherapeutic agent is 5-FU or capecitabine.
  • the T1 to T24 compounds are administered at a concentration of from about 30 mpk to about 150 mpk.
  • the present application provides a method for treating and/or preventing hand-foot syndrome associated with the administration of chemotherapeutic drugs in combination with a compound of T1 to T24 and a compound of U1 to U13, wherein the compound is for external use.
  • the chemotherapeutic agent is 5-FU or capecitabine.
  • the ratio of the concentration of the compound of T1 to T24 to the concentration of the compound of U1 to U13 is about 1:10 to about 10:1, eg, about 1:8 to about 8:1, about 1:6 to About 6:1, about 1:4 to about 4:1, about 1:2 to about 2:1.
  • the ratio of the concentration of the compounds from T1 to T24 to the concentration of the compounds from U1 to U13 is about 1:10, about 1:8, about 1:6, about 1:4, about 1:2, about 2 : 1, about 4:1, about 6:1, about 8:1 or about 10:1.
  • the present application provides a method for treating and/or preventing hand-foot syndrome associated with the administration of chemotherapeutic drugs in combination with a compound of T1 to T24 and a compound of U1 to U13, wherein the compound is for external use.
  • the chemotherapeutic agent is 5-FU or capecitabine.
  • the compounds of T1 to T24 are administered at a concentration of about 0.5% (wt%) to about 5.0% (wt%)
  • the compounds of U1 to U13 are administered at a concentration of about 0.5% (wt%) to About 5.0% (wt%), and the concentration ratio is 1:10 to about 10:1.
  • the compounds of T1 to T24 are administered at a concentration of about 1.0% (wt%) to about 5.0% (wt%), and the compounds of U1 to U13 are administered at a concentration of about 1.0% (wt%) to About 5.0% (wt%), and the concentration ratio is 1:10 to about 10:1.
  • the application provides a method of treating and/or preventing hand-foot syndrome or diarrhea associated with the administration of chemotherapeutic drugs in combination with a compound of T1 to T24 and a compound of U1 to U13, the compound being administered orally.
  • the chemotherapeutic agent is 5-FU or capecitabine.
  • the T1 to T24 compounds are administered at a concentration of about 100 mpk to about 300 mpk
  • the U1 to U13 compounds are administered at a concentration of about 200 mpk to about 300 mpk in a concentration ratio of 1:3 to about 3:1.
  • the present application provides a method of treating and/or preventing diarrhea associated with administration of a chemotherapeutic drug in combination with a compound of T1 to T24 and a compound of U1 to U13, the compound being administered orally.
  • the chemotherapeutic agent is 5-FU or capecitabine.
  • the T1 to T24 compounds are administered at a concentration of about 30 mpk to about 150 mpk
  • the U1 to U13 compounds are administered at a concentration of about 1 mpk to about 50 mpk in a concentration ratio of 1:3 to about 3:1.
  • the application provides a method of treating and/or preventing hand-foot syndrome associated with the administration of chemotherapeutic drugs in combination with a compound of T1 to T24 and a compound of U1 to U13, the compound being administered orally.
  • the chemotherapeutic agent is 5-FU or capecitabine.
  • the T1 to T24 compounds are administered at a concentration of about 30 mpk to about 150 mpk
  • the U1 to U13 compounds are administered at a concentration of about 1 mpk to about 50 mpk in a concentration ratio of 1:1 to about 2:1.
  • the present application provides a method of treating and/or preventing hand-foot syndrome associated with the administration of chemotherapeutic drugs with a compound from T25 to T50 for topical use.
  • the chemotherapeutic agent is 5-FU or capecitabine.
  • the concentration of the compound from T25 to T50 is about 0.5 ⁇ M to about 12.5 ⁇ M, about 0.5 ⁇ M to about 50 ⁇ M, 0.5 ⁇ M to about 100 ⁇ M, 3 ⁇ M to about 100 ⁇ M, 10 ⁇ M to about 100 ⁇ M, 5 ⁇ M to about 200 ⁇ M, 2 ⁇ M to about 1000 ⁇ M , or 5 ⁇ M to about 500 ⁇ M.
  • the present application provides a method of treating and/or preventing hand-foot syndrome associated with the administration of chemotherapeutic drugs with a compound from T25 to T50 for topical use.
  • the chemotherapeutic agent is 5-FU or capecitabine.
  • the T25 to T50 compounds are administered at a concentration of from about 0.01% (wt%) to about 5.0% (wt%).
  • the T25 to T50 compounds are administered at a concentration of from about 0.1% (wt%) to about 5.0% (wt%).
  • the T25 to T50 compounds are administered at a concentration of from about 1.01% (wt%) to about 5.0% (wt%).
  • the T25 to T50 compounds are administered at a concentration of from about 3.0% (wt%) to about 5.0% (wt%).
  • the T25 to T50 compounds are administered at a concentration of from about 1.0 (wt%) to about 3.0% (wt%).
  • the application provides a method of treating and/or preventing hand-foot syndrome associated with administration of a chemotherapeutic drug with a compound of T25 to T50, the compound being administered orally.
  • the chemotherapeutic agent is 5-FU or capecitabine.
  • the T251 to T50 compounds are administered at a concentration of from about 100 mpk to about 500 mpk.
  • the T251 to T50 compounds are administered at a concentration of from about 200 mpk to about 300 mpk.
  • the application provides a method of treating and/or preventing diarrhea associated with administration of a chemotherapeutic drug of a compound of T25 to T50, the compound being administered orally.
  • the chemotherapeutic agent is 5-FU or capecitabine.
  • the T25 to T50 compound is administered at a concentration of from about 10 mpk to about 50 mpk.
  • the T25 to T50 compounds are administered at a concentration of from about 1 mpk to about 100 mpk.
  • the present application provides a method for treating and/or preventing hand-foot syndrome associated with the administration of chemotherapeutic drugs in combination with a compound of T25 to T50 and a compound of U14 to U21, wherein the compound is for external use.
  • the chemotherapeutic agent is 5-FU or capecitabine.
  • the ratio of the concentration of the compound of T25 to T50 to the concentration of the compound of U14 to U21 is about 1:10 to about 10:1, eg, about 1:8 to about 8:1, about 1:6 to About 6:1, about 1:4 to about 4:1, about 1:2 to about 2:1.
  • the ratio of the concentration of the compounds from T1 to T24 to the concentration of the compounds from U1 to U13 is about 1:10, about 1:8, about 1:6, about 1:4, about 1:2, about 2 : 1, about 4:1, about 6:1, about 8:1 or about 10:1.
  • the application provides a method of treating and/or preventing hand-foot syndrome associated with the administration of chemotherapeutic drugs in combination with a compound of T25 to T50 and a compound of U14 to U21, the compound being administered orally.
  • the chemotherapeutic agent is 5-FU or capecitabine.
  • the T25 to T50 compound is administered at a concentration of about 0.5 ⁇ M to about 25 ⁇ M
  • the U14 to U21 compound is administered at a concentration of about 0.5 ⁇ M to about 25 ⁇ M
  • the T25 to T50 compound and U14 to U21 The concentration ratio of the compounds is about 1:10 to about 10:1.
  • the T25 to T50 compound is administered at a concentration of about 0.5 ⁇ M to about 15 ⁇ M
  • the U14 to U21 compound is administered at a concentration of about 0.5 ⁇ M to about 15 ⁇ M
  • the T25 to T50 compound and U14 to U21 The concentration ratio of the compounds is about 1:3 to about 3:1.
  • the present application provides a method for treating and/or preventing hand-foot syndrome associated with the administration of chemotherapeutic drugs in combination with a compound of T25 to T50 and a compound of U14 to U21, wherein the compound is for external use.
  • the chemotherapeutic agent is 5-FU or capecitabine.
  • the compounds of T25 to T50 are administered at a concentration of about 0.01% (wt%) to about 5.0% (wt%)
  • the compounds of U14 to U21 are administered at a concentration of about 1% (wt%) to About 5.0% (wt %) and the concentration ratio of the compound of T25 to T50 and the compound of U14 to U21 is about 1:3 to about 3:1.
  • the chemotherapeutic agent is 5-FU or capecitabine.
  • the T25 to T50 compounds are administered at a concentration of about 1.0% (wt%) to about 5.0% (wt%)
  • the U14 to U21 compounds are administered at a concentration of about 1.0% (wt%) to about 5.0% (wt%)
  • the concentration ratio of the compounds of T25 to T50 and the compounds of U14 to U21 is about 1:3 to about 3:1.
  • the application provides a method of treating and/or preventing hand-foot syndrome associated with administration of a chemotherapeutic drug in combination with a compound of T25 to T50 and a compound of U14 to U21, the compound being administered orally.
  • the chemotherapeutic agent is 5-FU or capecitabine.
  • the T25 to T50 compound is administered at a concentration of about 30 mpk to about 150 mpk
  • the U14 to U21 compound is administered at a concentration of about 1 mpk to about 100 mpk
  • the T25 to T50 compound and the U14 to U21 compound are administered at a concentration of about 1 mpk to about 100 mpk
  • the concentration ratio is from about 1:3 to about 3:1.
  • the application provides a method of treating and/or preventing diarrhea associated with the administration of a chemotherapeutic drug in combination with a compound of T25 to T50 and a compound of U14 to U21, the compound being administered orally.
  • the chemotherapeutic agent is 5-FU or capecitabine.
  • the T25 to T50 compound is administered at a concentration of about 10 mpk to about 50 mpk
  • the U14 to U21 compound is administered at a concentration of about 1 mpk to about 100 mpk
  • the T25 to T50 compound and the U14 to U21 compound are administered at a concentration of about 1 mpk to about 100 mpk
  • the concentration ratio is from about 1:3 to about 3:1.
  • the present application provides a pharmaceutical combination or kit comprising: 1) the chemotherapeutic drug; and 2) the thymidine derivative and/or the uridine derivative.
  • the chemotherapeutic drug and the thymidine derivative in the drug combination or kit may be independently present in separate containers.
  • the thymidine derivative in 2) of the pharmaceutical combination or kit may be able to prevent or treat a disease or condition associated with the administration of the chemotherapeutic drug in 1).
  • the thymidine derivative in 2) of the drug combination or kit does not substantially affect the therapeutic effect of the chemotherapeutic drug in 1).
  • the thymidine derivative of 2) may be administered before, simultaneously with or after the administration of the chemotherapeutic drug of 1) in the pharmaceutical combination or kit.
  • the application provides a method comprising administering a thymidine derivative to a subject, wherein the subject has been, is and/or will be administered a chemotherapeutic agent and has or is susceptible to and the administration The disease or condition associated with the chemotherapeutic agent.
  • the subject has been, is and/or will be administered the chemotherapeutic drug.
  • the subject may include a human or a non-human animal.
  • the non-human animal may be selected from the group consisting of monkey, chicken, goose, cat, dog, mouse and rat.
  • non-human animals may also include any animal species other than humans, such as livestock animals, or rodents, or primates, or domestic animals, or poultry animals.
  • the thymidine derivative and/or uridine derivative may be administered before, concurrently with, or after administration of the chemotherapeutic agent to the subject.
  • the thymidine derivative and/or uridine derivative may be administered before or after administration of the chemotherapeutic drug Dosing at intervals.
  • 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.
  • ** means P ⁇ 0.01; * means P ⁇ 0.05; *** means P ⁇ 0.001, and t-test statistical test is used.
  • Uridine thymidine (2.0 g, 8.26 mmol) and triethylamine (1.67 g, 16.5 mmol) were dissolved in 10 mL of dichloromethane and butyryl chloride (1.76 g, 16.5 mmol) was added at 0 degrees Celsius.
  • 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 purified by reverse phase HPLC (column: Xtimate C18 150 x 40 mm x 10 um; mobile phase: water (0.225% FA)-ACN; B%: 20-50; 10 min) to give the product T6 (40.0 mg, 98.14% purity) ).
  • Example 2-29 Effects of thymidine derivatives or thymidine derivatives combined with uridine derivatives on alleviating the proliferation toxicity of chemotherapeutic drugs on HaCaT cells
  • 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 24 hours of culture, each well was divided into blank solvent control group, 5-FU group, 5-FU+thymidine derivative group, and 5-FU+thymidine derivative and uridine derivative combined administration group.
  • 5-FU group add 1 ⁇ L of 5-FU solution (the final concentration is shown in Table 3, all 5-FU solutions are DMSO solutions);
  • 5-FU+thymidine derivative group add 5-FU solution and thymidine derivative Solution (the final concentrations of 5-FU and thymidine derivatives are shown in Table 3, except that thymidine is an aqueous solution, the solutions of thymidine derivatives are all DMSO solutions);
  • Combined administration group add 5-FU solution and thymidine derivative and uridine derivative mixed solution (the final concentration of 5-FU and thymidine derivative + uridine derivative mixed solution is shown in Table 3, except that thymidine is In addition to the aqueous solution, the mixed solutions of thymidine derivatives + uridine derivatives are all DMSO solutions); blank solvent control group: add the corresponding 5-FU group or 5-FU + thymidine derivatives (or thymidine derivatives + urine Glycoside
  • the blank solvent control group was used as a control, so as to exclude the effect of the solvent on the results in the 5-FU group and the 5-FU+thymidine derivative (or thymidine derivative+uridine derivative mixed solution) group.
  • the cell survival rate was determined using the Cell Counting Kit-8 (CCK-8) detection kit (C0037, purchased from Shanghai Biyuntian Biotechnology Co., Ltd.), thereby calculating the proliferative toxicity of 5-FU to cells and Relief effect of thymidine derivatives (or thymidine derivatives + uridine derivatives mixed solution) on proliferation toxicity. Results were statistically analyzed and plotted using GraphPad Prism 6.0 software, t-test.
  • Table 3 lists the combination of 5-FU and thymidine derivatives (or thymidine derivatives + uridine derivatives mixed solution), as well as the corresponding experimental results (wherein, the data in the cell viability column represents the same as the 5-FU group Compared with the corresponding 5-FU + thymidine derivative group or 5-FU + thymidine derivative and uridine derivative co-administration group increased the percentage of viable cells).
  • Figures 3-10 list experimental results for several representative compounds.
  • fluorine drugs have certain proliferation toxicity to skin cell HaCaT, and thymidine derivatives or thymidine derivatives combined with uridine derivatives have obvious alleviation effects on the proliferation toxicity caused by fluorine drugs ; After adding thymidine derivatives or thymidine derivatives and uridine derivatives in combination, the cell survival rate is increased, and it also has certain advantages over thymidine.
  • Example 30-40 Thymidine derivatives or thymidine derivatives combined with uridine derivatives can prevent/treat chemotherapeutic drug-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 11 ).
  • the degree of hand-foot syndrome was similar in both paws, with no difference between the left and right paws.
  • 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.
  • Example 41-52 Thymidine derivatives or thymidine derivatives combined with uridine derivatives can prevent/treat chemotherapeutic drug-induced hand-foot syndrome in mouse models
  • mice Male Balb/c mice were given capecitabine by daily gavage for several days, and after several days, the paws of the mice developed symptoms of hand-foot syndrome (similar to the results of the rat model, Figure 13). Similar to humans, mice develop hand-foot syndrome in the front and hind paws following oral capecitabine. Both have exactly the same cause, and the symptoms are very similar. Therefore, mice are very good animal models for simulating capecitabine-induced hand-foot syndrome.
  • mice were divided into 10 groups.
  • After gavage apply blank gel to the front paws and hind paws (about 4*0.5cm*0.5cm) of the blank ointment group, and apply the blank gel to the front paws and hind paws (about 4*0.5cm*0.5cm) of the administration group Gels with different drugs. After applying the medicine, the mice were immobilized with an Elizabethan circle for 4 hours.
  • mice After 4 hours, the mice were released, and the residual medicine 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 5.
  • the gavage and smear tests were repeated every day until obvious hand-foot syndrome appeared in the blank control group. At this time, the number of mice whose paws in the smeared group remained normal or were significantly lighter than those in the non-medicated group was calculated as the effective inhibition of hand-foot syndrome. number of mice.
  • the remission of hand-foot syndrome was observed by oral administration of thymidine derivatives and the combination of thymidine derivatives and uridine derivatives. Examples 41-48 are the application of thymidine derivatives and/or uridine derivatives, and Examples 49-52 are the oral administration of thymidine derivatives and/or uridine derivatives.
  • Example 53-61 Relief effect of thymidine derivatives or thymidine derivatives and uridine derivatives in combination on 5-FU-induced diarrhea model in mice
  • mice Male Balb/c mice (7-8 weeks, 23-25 g) were injected with 70 mg/kg/d by intraperitoneal injection for three days.
  • the mice in the blank group were injected with 0.9% NaCl, and the effect was judged by observing the changes of diarrhea grade, food intake and body weight.
  • the severity of diarrhea was scored on the following scale, 0: normal stools, 1: soft stools, 2: slightly moist and soft stools, 3: moist, unformed stools with moderate perianal staining, and 4: watery stools with severe Perianal hair staining.
  • the severity of diarrhea was evaluated by the incidence of diarrhea (0-4 points) and the average diarrhea score. Finally, it was found that the diarrhea models after modeling were all about grade 3, and the models were stable and met the experimental needs.
  • mice The male Balb/c mice (7-8 weeks, 23-25 g) were reared and acclimatized for one week, and then divided into groups of 10 mice for administration experiments.
  • 5-FU was dissolved in 0.9% NaCl solution, and the mice in the model group and the treatment group were given an intraperitoneal injection of 70 mg/kg/d.
  • the dosage is shown in Table 6.
  • the modeling was completed three days later. Simultaneously with the modeling of 5-FU by injection, thymidine derivatives or thymidine derivatives and uridine derivatives were administered by gavage, and the series of compounds were dissolved in PBS solution of 5% DMSO + 1% HPMC.
  • the dosing frequency and dosage of the selected compounds are shown in Table 6.
  • Information such as diarrhea, food intake, and body weight change ( ⁇ %BW) (the body weight change in the table is recorded as the value on the 9th day) was observed and counted every day. 12 After the end of the experiment, the results were statistically analyzed.
  • Table 6 Statistical table of diarrhea, food intake, survival number and body weight change ( ⁇ %BW) in mice after thymidine derivatives or thymidine derivatives and uridine derivatives are administered in combination
  • the 5-FU control group and experimental group mice were taken from the ocular sinuses, and blood cells were counted. It was found that 5-FU could reduce the detected blood cells, while the use of thymidine derivatives or thymidine derivatives After the combined treatment of glycoside derivatives and uridine derivatives, the neutrophils and platelets of the animals were significantly higher than those of the 5-FU single-administration group.
  • Example 62 The effect of thymidine derivatives on the therapeutic effect of capecitabine
  • a BALB/C nude mouse model human colon cancer cell HCT116 transplanted tumor
  • 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.
  • the specific implementation is as follows:
  • a blank group 5 tumor-bearing mice, no gavage and no drug application;
  • B blank matrix group 10 tumor mice, oral gavage of capecitabine (1.5mmol/kg), blank gel on the back (smear once a day) , smeared continuously for 14 days);
  • C 0.5% T1 gel group 10 tumor mice, orally gavaged with capecitabine, and coated with 0.5% T1 gel (the administration method and frequency are the same as group B);
  • D 2% T1 gel Gel group 10 tumor mice, orally gavaged with capecitabine, and coated with 2% T1 gel (the administration method and frequency are the same as group B);
  • the smeared area of about 5.8 square centimeters was marked with a marker, and the coating The smeared area cannot be the area that the mouse's mouth can touch, nor the area next to the tumor.
  • Example 63-90 Effects of thymidine derivatives or thymidine derivatives combined with uridine derivatives on alleviating the proliferative toxicity of chemotherapeutic drugs on HaCaT cells
  • thymidine derivatives or the combination of thymidine derivatives and uridine derivatives, on relieving chemotherapeutic drugs (5-FU) on the proliferation of HaCaT cells were examined. See Table 7 for a protocol for the tested thymidine derivatives, or a combination of thymidine derivatives and uridine derivatives, as well as the final concentrations of test compounds.
  • Table 7 lists the combination of 5-FU and thymidine derivatives (or thymidine derivatives + uridine derivatives mixed solution), and the corresponding experimental results (wherein, the data in the cell viability column represents the same as the 5-FU group Compared with the corresponding 5-FU + thymidine derivative group or 5-FU + thymidine derivative and uridine derivative co-administration group increased the percentage of viable cells).
  • Figures 15-21 list experimental results for several exemplary compounds.
  • fluorine drugs have certain proliferation toxicity to skin cells HaCaT, and thymidine derivatives or thymidine derivatives combined with uridine derivatives can significantly alleviate the proliferation toxicity caused by fluorine drugs ; After adding thymidine derivatives or thymidine derivatives and uridine derivatives in combination, the cell survival rate is increased, and it also has certain advantages over thymidine.
  • Thymidine derivatives and uridine derivatives containing NSAIDs still have the effect of alleviating the cytotoxicity caused by 5-FU, and the alleviating effect is better than thymidine derivatives and uridine derivatives that do not contain NSAIDs: At the same concentration, containing NSAIDs The thymidine derivatives and uridine derivatives have higher cellular remission rates, or higher remission rates can be achieved at lower concentrations.
  • Example 91-117 Thymidine derivatives or thymidine derivatives combined with uridine derivatives can prevent/treat chemotherapeutic drug-induced hand-foot syndrome in a rat model
  • thymidine derivatives or the combined use of thymidine derivatives and uridine derivatives, on a rat model of hand-foot syndrome induced by chemotherapeutics were examined.
  • the rat paws after drug treatment were collected, and the inflammation was observed by hematoxylin-eosin staining (HE) and immunohistochemical staining (IHC).
  • HE hematoxylin-eosin stain stain stain staining
  • IHC immunohistochemical staining
  • Figure 22 is a graph of staining results of representative thymidine derivatives containing NSAIDs and thymidine derivatives not containing NSAIDs, showing that thymidine derivatives containing NSAIDs (eg, T25 to T50 compounds), or NSAID-containing thymidine derivatives in combination with NSAID-containing uridine derivatives ameliorates paw inflammation in rats better than NSAID-containing thymidine derivatives (eg, compounds from T1 to T24) and controls in a hand-foot syndrome model group, indicating that thymidine derivatives containing NSAIDs can simultaneously produce dual effects of NSAIDs and thymidine derivatives, and have more obvious advantages in the treatment and prevention of hand-foot syndrome.
  • thymidine derivatives containing NSAIDs eg, T25 to T50 compounds
  • NSAID-containing thymidine derivatives ameliorates paw inflammation in rats better than NSAID-containing thymidine derivatives (eg,
  • Example 118 Thymidine Derivatives and/or Uridine Derivatives Containing NSAIDs Relieve Pain in Chemotherapy Drug-Induced Hand-Foot Syndrome
  • thymidine derivatives (3% concentration) were administered to the rat model of hand-foot syndrome constructed by 4000 mg/kg capecitabine, and thymidine derivatives (1% concentration) were administered in urine
  • the glycoside derivatives concentration of 36% were combined for a period of time
  • the rats were subjected to pain analysis, and the pain evaluation model was the mechanical sensitivity of rats (von Frey); the experimental steps were as follows: first, let the rats adapt to 1 hours, and then the rats were placed in an observation box with a metal mesh floor, and the mice were allowed to stay in the box for 20 minutes to acclimate to the environment of the experimental platform.
  • 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.
  • thymidine derivatives (T1 and T4, both at a concentration of 3%) without NSAIDs did not significantly improve pain in rats; thymidine derivatives containing NSAIDs (T25, T26, T27, T50, T36, T32, T37, T41, T45, all at 3%) and thymidine derivatives containing NSAIDs and uridine derivatives containing NSAIDs (T25+U14, T25+U16, and T45+U20, all at concentrations 1%+3%) in combination can significantly improve the pain in rats.
  • Cape4000 represents 4000 mg/kg of capecitabine
  • the concentration of thymidine derivative is 3% when used alone, and the concentration of thymidine derivative is 1% when thymidine derivative is used in combination with uridine derivative, and the concentration of uridine derivative is 1%.
  • Derivative concentrations were all 3%.
  • Example 119-123 Thymidine derivatives or thymidine derivatives combined with uridine derivatives can prevent/treat chemotherapeutic drug-induced hand-foot syndrome in mouse models
  • Examples 41-52 the effects of thymidine derivatives, or the combined use of thymidine derivatives and uridine derivatives on the mouse model of hand-foot syndrome induced by chemotherapeutic drugs (capecitabine) were examined.
  • Examples 119-120 are for transdermal administration
  • Examples 121-123 are for oral administration.
  • Example 124-131 The relieving effect of thymidine derivatives or thymidine derivatives and uridine derivatives in combination on 5-FU-induced diarrhea model in mice
  • a 5-FU-induced diarrhea model was established using 7-8 week male Balb/c mice, and the alleviating effect of thymidine derivatives or thymidine derivatives and uridine derivatives on diarrhea was detected.
  • 5-Fu modeling dose 175mg/kg; single administration, intraperitoneal injection (ip.);
  • Administration of the compound to be tested (thymidine derivative or combination of thymidine derivative and uridine derivative) : single administration, intragastric administration, pre-administered at each time point before intraperitoneal injection of 5-FU compound.
  • the compound to be tested was administered 1 h before the administration of 5-FU, and then a certain amount of 5-FU was intraperitoneally injected at 1 h, and the compound to be tested was administered again 7 h after the injection of 5-FU.
  • mice After the mice were acclimatized for one week, they were divided into groups of 10 mice for administration test.
  • mice in the blank group were injected with 0.9% NaCl, and the effect was judged by observing the changes of diarrhea grade, food intake and body weight.
  • the severity of diarrhea was scored on the following scale, 0: normal stools, 1: soft stools, 2: slightly moist and soft stools, 3: moist, unformed stools with moderate perianal staining, and 4: watery stools with severe Perianal hair staining.
  • the severity of diarrhea was evaluated by the incidence of diarrhea (0-4 points) and the average diarrhea score. Finally, it was found that the diarrhea models after modeling were all about grade 3, and the models were stable and met the experimental needs.
  • 5-FU was dissolved in 0.9% NaCl solution, and the mice in the model group and the treatment group were given an intraperitoneal injection of 175 mg/kg/d. The modeling was completed three days later. Simultaneously with the injection of 5-FU for modeling, thymidine derivatives or thymidine derivatives and uridine derivatives were administered by gavage, and the compounds to be tested were dissolved in PBS solution of 5% DMSO+1% HPMC. The dosing frequency and dosage of the selected compounds are shown in Table 10. The body weight was weighed every day, and the body weight change was counted ( ⁇ %BW, the body weight change in the table was recorded as the value on the 6th day); the food weight was weighed every day to calculate the food intake. The clinical status of each mouse, such as activity, diarrhea, hair, fighting, etc., was observed every day. After 6 days, the experiment ended, and the results were statistically analyzed.
  • Table 10 Statistical table of diarrhea, food intake, survival number and body weight change ( ⁇ %BW) in mice after thymidine derivatives or thymidine derivatives and uridine derivatives are administered in combination
  • the results are shown in Table 10 and FIG. 24 .
  • the concentrations of the compounds in each group in FIG. 24 correspond to the concentrations in Table 10. From the results (Table 10 and Figure 25), it can be seen that the use of thymidine derivatives alone or the combination of thymidine derivatives and uridine derivatives can effectively reduce the level of diarrhea caused by 5FU drugs, and the mice in the simultaneous administration group Compared with the model group without thymidine derivatives and/or thymidine derivatives, the survival status, food intake and body weight changes were significantly improved.
  • This example lists the preparation methods of several representative compounds from T25 to T50 and U14 to U21, and other unlisted compounds are prepared by using corresponding reactants under the same conditions.
  • 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.
  • 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
  • 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.
  • reaction solution was quenched with saturated aqueous ammonium chloride solution (30 mL), extracted with ethyl acetate (20 mL*3), the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product .

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

涉及一种胸苷衍生物，或尿苷衍生物与胸苷衍生物联用在制备药物中的用途，所述药物用于预防或治疗受试者中与施用化疗药物相关的疾病或病症。还提供预防或治疗受试者中与施用化疗药物相关的疾病或病症的方法，所述方法可包括向有需要的受试者施用预防或治疗有效量的胸苷衍生物或尿苷和胸苷衍生物。

Description

胸苷衍生物在制备药物中的应用 技术领域
本申请涉及生物医药领域，具体的涉及一种胸苷衍生物和尿苷衍生物、胸苷衍生物联用治疗化疗药物引起的副作用。
背景技术
目前，化疗是癌症治疗的主要手段之一。化疗药物在杀伤癌细胞的同时也会伤害患者的正常组织，因此化疗往往会引起严重的副作用，特别是在皮肤，五官，造血组织和胃肠道发生的副作用。化疗引起的严重副作用会损害患者的生活质量，引起患者用药的耐受性降低，从而对治疗效果产生不利的影响，导致疾病进展，进而影响患者的生存期。
目前，尚没有有效的治疗方案来控制施用化疗药物相关的副作用，因此，迫切需要新的方案来填补这一空白。
发明内容
本申请涉及一种胸苷衍生物和尿苷衍生物、胸苷衍生物联用在制备药物中的用途，所述药物用于预防或治疗受试者中与施用化疗药物相关的疾病或病症。具体而言，本申请涉及使用胸苷衍生物和尿苷衍生物、胸苷衍生物来预防或治疗受试者中与施用化疗药物相关的疾病或病症，其可有效控制由化疗药物所引起的副作用，如与施用化疗药物相关的皮肤组织疾病或病症、五官疾病或病症和/或胃肠道疾病或病症等。本申请的尿苷衍生物和/或胸苷衍生物可包含NSAID部分，在治疗和/或预防化疗药物相关的疾病或病症的同时，具有镇痛抗炎效果，进一步改善受试者的症状。
一方面，本申请提供了一种胸苷衍生物在制备药物中的用途，所述药物用于预防或治疗受试者中与施用化疗药物相关的疾病或病症，其中所述胸苷衍生物在脱氧核糖上的至少一个羟基氢被取代。
在某些实施方式中，所述胸苷衍生物包含式(I)的结构：
Figure PCTCN2021127683-appb-000001
式(I)
其中，R 2、R 3、R 4、R 5、R 6和R 7不同时为氢。
在某些实施方式中，R 7为
Figure PCTCN2021127683-appb-000002
在某些实施方式中，R 7为
Figure PCTCN2021127683-appb-000003
在某些实施方式中，R 6为氢。
在某些实施方式中，R 6为
Figure PCTCN2021127683-appb-000004
其中所述R 6 1为C1至C6的烷基。在某些实施方式中，R 6为
Figure PCTCN2021127683-appb-000005
在某些实施方式中，R 1为
Figure PCTCN2021127683-appb-000006
其中，M 1为氧或硫，并且R 8包含选自下组中的一种或多种基团：氢、取代或未取代的羟基、取代或未取代的巯基、取代或未取代的氨基、取代或未取代的C1至C5烷基、取代或未取代的C1至C5炔基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基，以及，取代或未取代的芳烷基；M 2为硅或碳，并且R 9选自下组：氢、取代或未取代的羟基、取代或未取代的巯基、取代或未取代的氨基、取代或未取代的C1至C5烷基、取代或未取代的C1至C5炔基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基，以及，取代或未取代的芳烷基；R 9包含选自下组中的一种或多种基团：C1至C5烷基、C1至C5的环烷基、苯基或苯甲基。
在某些实施方式中，R 2为
Figure PCTCN2021127683-appb-000007
其中，M 1为氧或硫，并且R 8包含选自下组中的一种或多种基团：氢、取代或未取代的羟基、取代或未取代的巯基、取代或未取代的氨基、取代或未取代的C1至C5烷基、取代或未取代的C1至C5炔基、取代或未取代的 环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基，以及，取代或未取代的芳烷基；M 2为硅或碳，并且R 9选自下组：氢、取代或未取代的羟基、取代或未取代的巯基、取代或未取代的氨基、取代或未取代的C1至C5烷基、取代或未取代的C1至C5炔基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基，以及，取代或未取代的芳烷基；R 9包含选自下组中的一种或多种基团：C1至C5烷基、C1至C5的环烷基、苯基或苯甲基。
在某些实施方式中，R 3为
Figure PCTCN2021127683-appb-000008
其中，M 1为氧或硫，并且R 8包含选自下组中的一种或多种基团：氢、取代或未取代的羟基、取代或未取代的巯基、取代或未取代的氨基、取代或未取代的C1至C5烷基、取代或未取代的C1至C5炔基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基，以及，取代或未取代的芳烷基；M 2为硅或碳，并且R 9选自下组：氢、取代或未取代的羟基、取代或未取代的巯基、取代或未取代的氨基、取代或未取代的C1至C5烷基、取代或未取代的C1至C5炔基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基，以及，取代或未取代的芳烷基；R 9包含选自下组中的一种或多种基团：C1至C5烷基、C1至C5的环烷基、苯基或苯甲基。
在某些实施方式中，R 1选自下组：–(C＝O)–R 8 1、–(C＝O)–OR 8 2、–(C＝O)–NR 8 3R 8 4、–(C＝S)–R 8 5、–(C＝S)–OR 8 6和–(C＝S)–NR 8 7R 8 8，其中R 8 1、R 8 2、R 8 3、R 8 4、R 8 5、R 8 6、R 8 7和R 8 8中的任意一个独立地包含选自下组中的一种或多种基团：氢、取代或未取代的烷基、取代或未取代的炔基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基以及取代或未取代的杂芳基。
在某些实施方式中，R 2选自下组：–(C＝O)–R 8 1、–(C＝O)–OR 8 2、–(C＝O)–NR 8 3R 8 4、–(C＝S)–R 8 5、–(C＝S)–OR 8 6和–(C＝S)–NR 8 7R 8 8，其中R 8 1、R 8 2、R 8 3、R 8 4、R 8 5、R 8 6、R 8 7和R 8 8中的任意一个独立地包含选自下组中的一种或多种基团：氢、取代或未取代的烷基、取代或未取代的炔基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基以及取代或未取代的杂芳基。
在某些实施方式中，R 3选自下组：–(C＝O)–R 8 1、–(C＝O)–OR 8 2、–(C＝O)–NR 8 3R 8 4、–(C＝S)–R 8 5、–(C＝S)–OR 8 6和–(C＝S)–NR 8 7R 8 8，其中R 8 1、R 8 2、R 8 3、R 8 4、R 8 5、R 8 6、R 8 7和R 8 8中的任意一个独立地包含选自下组中的一种或多种基团：氢、取代或未取代的烷基、取代或未取代的炔基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基以及取代 或未取代的杂芳基。
在某些实施方式中，R 8 1、R 8 2、R 8 3、R 8 4、R 8 5、R 8 6、R 8 7和R 8 8中的任意一个独立地包含选自下组中的一种或多种基团：氢、C1至C5烷基、C1至C5的环烷基、C1至C5的杂环烷基、苯基或苯甲基。
在某些实施方式中，R 8 1选自下组：C 1至C 5烷基、C 1至C 5的环烷基、苯基和苯甲基。在某些实施方式中，R 8 1选自下组：甲基、乙基、丙基、丁基、环戊烷基、环丙烷基和苯甲基。
在某些实施方式中，R 8 2选自下组：C1至C5烷基、C1至C5的环烷基、苯基和苯甲基。在某些实施方式中，R 8 2选自下组：环丙基、丙基、丁基、戊基、苯基和苯甲基。
在某些实施方式中，R 8 3为氢。
在某些实施方式中，R 8 4选自下组：：C1至C5烷基、C1至C5的环烷基、苯基和苯甲基。在某些实施方式中，R 8 4选自下组：环丙基、环戊基和苯基。
在某些实施方式中，R 9为丁基。
在某些实施方式中，R 3为氢。在某些实施方式中，R 4为氢。在某些实施方式中，R 5为氢。
在某些实施方式中，R 1为
Figure PCTCN2021127683-appb-000009
其中，R 8 1包含选自下组中的一种或多种基团：C1至C6烷基、C1至C6硅烷基、C1至C6烷氧基、C1至C6烷基硝基、C3至C7环烷基、C3至C7环烷基硝基、C4至C7芳香基、C4至C7烷氧基芳香基和/或C4至C7杂芳基。在某些实施方式中，R 2为
Figure PCTCN2021127683-appb-000010
其中，R 8 1包含选自下组中的一种或多种基团：C1至C6烷基、C1至C6硅烷基、C1至C6烷氧基、C1至C6烷基硝基、C3至C7环烷基、C3至C7环烷基硝基、C4至C7芳香基、C4至C7烷氧基芳香基和/或C4至C7杂芳基。
在某些实施方式中，在式(I)所示的结构中，R 3、R 4、R 5和R 6均为氢，R 7为
Figure PCTCN2021127683-appb-000011
R 1选自下组：氢、
Figure PCTCN2021127683-appb-000012
Figure PCTCN2021127683-appb-000013
Figure PCTCN2021127683-appb-000014
Figure PCTCN2021127683-appb-000015
R 2选自下组：氢、
Figure PCTCN2021127683-appb-000016
Figure PCTCN2021127683-appb-000017
Figure PCTCN2021127683-appb-000018
且R 2和R 1不同时为氢。
在某些实施方式中，所述胸苷衍生物选自下组的化合物T1至化合物T24中的一种或多种：
Figure PCTCN2021127683-appb-000019
Figure PCTCN2021127683-appb-000020
Figure PCTCN2021127683-appb-000021
在某些实施方式中，所述胸苷衍生物包含式(II)所示的结构：
Figure PCTCN2021127683-appb-000022
式(II)，其中，R 1和/或R 2包含非甾体抗炎药(NSAID)部分。例如，R 1包含NSAID部分，且R 2为氢。例如，R 2包含NSAID部分，且R 1为氢。例如，R 1包含NSAID部分，且R 2包含NSAID部分。
在某些实施方式中，所述NSAID部分包含水杨酸或其衍生物、芳基乙酸或其衍生物、杂芳基乙酸或其衍生物、吲哚乙酸或其衍生物、茚乙酸或其衍生物、邻氨基苯甲酸或其衍生物和/或烯醇酸或其衍生物。
在某些实施方式中，R 1或R 2为氢。
在某些实施方式中，R 1和R 2不同时为氢。
在某些实施方式中，R 1和/或R 2为
Figure PCTCN2021127683-appb-000023
其中，R 8为R s 2或
Figure PCTCN2021127683-appb-000024
其中，R s 1为 氢或甲基，R s 2为
Figure PCTCN2021127683-appb-000025
其中，所述环A为C4至C7芳基、C4至C7杂芳基、茚环、萘环、吲哚啉环、不饱和多环烃和/或杂环多环，Rs 3和/或Rs 4独立地选自：氢、C1至C6烷基、C1至C6烷基酯、卤素、C4至C7芳香基、C4至C7杂芳基和
Figure PCTCN2021127683-appb-000026
其中，环B为C4至C7芳香基、C4至C7杂芳基，X为-CH 2、-NH-、-O-或
Figure PCTCN2021127683-appb-000027
其中，所述C4至C7芳香基、C4至C7杂芳基可选地被一个或多个选自下组的取代基取代：卤素、C1至C6烷基、C1至C6炔基和C1至C6烯基。
在某些实施方式中，环A为吡咯环，R s 3为C1-C6烷基，R s 4为
Figure PCTCN2021127683-appb-000028
其中，X为
Figure PCTCN2021127683-appb-000029
环B为苯环，所述环B可选地被一个或多个C1至C6烷基取代。
在某些实施方式中，R s 1和/或R s 2为
Figure PCTCN2021127683-appb-000030
其中，所述R s 3为C1至C6烷基或卤素。
在某些实施方式中，R s 1和/或R s 2为
Figure PCTCN2021127683-appb-000031
其中，R s 3和/或R s 4选自：氢、C1至C6烷基、C1至C6烷基酯、卤素、C4至C7芳香基、C4至C7杂芳基、
Figure PCTCN2021127683-appb-000032
环B为C4至C7芳香基、C4至C7杂芳基，X为-CH 2、-NH-、-O-或
Figure PCTCN2021127683-appb-000033
其中，所述C4至C7芳香基、C4至C7杂芳基可选地被一个或多个选自下组的取代基取代：卤素、C1至C6烷基、C1至C6炔基和C1至C6烯基。
在某些实施方式中，R s 2为
Figure PCTCN2021127683-appb-000034
其中，R s 3和/或R s 4选自：氢、C1至C6烷基、
Figure PCTCN2021127683-appb-000035
氟、氯、溴、苯环和
Figure PCTCN2021127683-appb-000036
其中，环B为苯环，X为-CH 2、-NH-、-O-或
Figure PCTCN2021127683-appb-000037
所述苯环可选地被一个或多个选自下组的取代基取代：氟、氯和溴。
在某些实施方式中，R 8为
Figure PCTCN2021127683-appb-000038
R s 1为氢或甲基，R s 2选自
Figure PCTCN2021127683-appb-000039
Figure PCTCN2021127683-appb-000040
在某些实施方式中，R 8为
Figure PCTCN2021127683-appb-000041
R s 1为氢或甲基，R s 2为
Figure PCTCN2021127683-appb-000042
其中，环A 1为C4至C7环烷基、C4至C7杂环烷基、C4至C7芳香基和/或C4至C7杂芳基，环B 1为C4至C7环烷基、C4至C7杂环烷基、C4至C7芳香基、C4至C7杂芳基或
Figure PCTCN2021127683-appb-000043
其中，环B 2为C4至C7环烷基、C4至C7杂环烷基、C4至C7芳香基和/或C4至C7杂芳基，环B 3为C4至C7环烷基、C4至C7杂环烷基、C4至C7芳香基和/或C4至C7杂芳基，其中，所述C4至C7环烷基、C4至C7杂环烷基、C4至C7芳香基和/或C4至C7杂芳基可选地被卤素、
Figure PCTCN2021127683-appb-000044
C1至C6烷基、C1至C6烷基取代的酯基和/或C1至C6烷基取代的醛基取代，其中，环C为苯环，Y为-CH 2、-NH-、-O-或
Figure PCTCN2021127683-appb-000045
所述苯环可选 地被一个或多个选自下组的取代基取代：氟、氯、溴和
Figure PCTCN2021127683-appb-000046
所述Y可以与环B 2或环B 3上的环原子形成双键。
在某些实施方式中，R s 2为
Figure PCTCN2021127683-appb-000047
其中，所述R s 6为氟、氯或溴、
Figure PCTCN2021127683-appb-000048
M为氮或碳，X为碳或
Figure PCTCN2021127683-appb-000049
X与M间可选地形成双键，R s 7为氟、氯、溴或
Figure PCTCN2021127683-appb-000050
在某些实施方式中，R 8为
Figure PCTCN2021127683-appb-000051
R s 1为氢或甲基，R s 2为
Figure PCTCN2021127683-appb-000052
Figure PCTCN2021127683-appb-000053
在某些实施方式中，R 8为
Figure PCTCN2021127683-appb-000054
R s 1为氢或甲基，R s 2为
Figure PCTCN2021127683-appb-000055
在某些实施方式中，R s 2为
Figure PCTCN2021127683-appb-000056
所述环A 1为苯环，环B 1为
Figure PCTCN2021127683-appb-000057
且环B 2为吡咯环，B 3为吡喃环，所述吡喃环可选地被一个或多个C1至C6烷基和/或C1至C6烷基 取代的醛基取代。
在某些实施方式中，R 8为
Figure PCTCN2021127683-appb-000058
R s 1为氢或甲基，R s 2为
Figure PCTCN2021127683-appb-000059
在某些实施方式中，R 8 1为
Figure PCTCN2021127683-appb-000060
在某些实施方式中，R 1和/或R 2为
Figure PCTCN2021127683-appb-000061
在某些实施方式中，所述R 1包含NSAID部分，且R 2为氢。
在某些实施方式中，所述R 1为选自下组中的任意一种基团：
Figure PCTCN2021127683-appb-000062
Figure PCTCN2021127683-appb-000063
且R 2为氢。
在某些实施方式中，所述R 2包含NSAID部分，且R 1为氢。
在某些实施方式中，所述R 2为选自下组中的任意一种基团：
Figure PCTCN2021127683-appb-000064
Figure PCTCN2021127683-appb-000065
且R 1为氢。
在某些实施方式中，所述R 1和R 2均包含所述NSAID部分。
在某些实施方式中，所述R 1和R 2各自独立地为选自下组中的任意一种基团：
Figure PCTCN2021127683-appb-000066
Figure PCTCN2021127683-appb-000067
在某些实施方式中，所述胸苷衍生物选自下组化合物T25至化合物T50中的一种或多种：
Figure PCTCN2021127683-appb-000068
Figure PCTCN2021127683-appb-000069
Figure PCTCN2021127683-appb-000070
在某些实施方式中，所述化疗药物用于治疗癌症。
在某些实施方式中，所述化疗药物包括嘧啶核苷类似物或其前药。
在某些实施方式中，所述化疗药物包括选自下组中的一种或多种：卡培他滨、阿糖胞苷、多西他赛、阿霉素、氟尿嘧啶(5-FU)、氟尿苷、替加氟、伊达比星、紫杉醇、表柔比星、Acelarin(NUC-1031)、多柔比星、亚叶酸、顺铂、紫杉醇、环磷酰胺、长春新碱和5-FU药物前体(例如，喃氟啶和5’-脱氧氟尿苷、氟尿苷、2’-脱氧氟尿苷、氟尿苷的药物前体衍生物或2’-脱氧氟尿苷的药物前体衍生物、三氟-甲基-2’-脱氧尿苷、6-氮杂尿苷、3-脱氮杂尿苷)。
在某些实施方式中，所述的用途中所述疾病或病症由施用所述化疗药物引起。
在某些实施方式中，所述与施用化疗药物相关的疾病或病症包括与施用化疗药物相关的皮肤组织疾病或病症、与施用化疗药物相关的造血组织疾病或病症、与施用化疗药物相关的四肢疾病或病症、与施用化疗药物相关的心脏疾病或病症、与施用化疗药物相关的神经系统疾病或病症、与施用化疗药物相关的五官疾病或病症和/或与施用化疗药物相关的胃肠道疾病或病症。
在某些实施方式中，所述与施用化疗药物相关的造血组织疾病或病症包括与施用化疗药物相关的骨髓疾病或病症和与施用化疗药物相关的血液疾病或病症。
在某些实施方式中，所述与施用化疗药物相关的造血组织疾病或病症包括与施用化疗药物相关的血液细胞增殖异常疾病或病症。
在某些实施方式中，所述与施用化疗药物相关的疾病或病症包括皮肤、四肢、五官和/或胃肠道中与施用化疗药物相关的上皮组织疾病或病症。
在某些实施方式中，所述皮肤、四肢、五官和/或胃肠道中与施用化疗药物相关的上皮组织疾病或病症包括与内皮细胞病变相关的所述疾病或病症，和/或与上皮细胞病变相关的所述疾病或病症，且其中所述内皮细胞病变和/或上皮细胞病变与所述施用化疗药物相关。
在某些实施方式中，所述内皮细胞包括血管内皮细胞。
在某些实施方式中，所述上皮细胞包括皮肤上皮细胞、口腔上皮细胞、鼻腔上皮细胞、胃上皮细胞和/或肠上皮细胞。
在某些实施方式中，所述的用途中所述与施用化疗药物相关的疾病或病症包括与施用化疗药物相关的皮疹、与施用化疗药物相关的手足综合征、与施用化疗药物相关的瘙痒、与施用化疗药物相关的红斑、与施用化疗药物相关的皮肤干燥、与施用化疗药物相关的脱发、与施用化疗药物相关的甲沟炎、与施用化疗药物相关的色素沉积紊乱、与施用化疗药物相关的口腔溃疡、与施用化疗药物相关的口干、与施用化疗药物相关的鼻衄、与施用化疗药物相关的鼻咽炎、与施用化疗药物相关的唇炎、与施用化疗药物相关的食管黏膜炎、与施用化疗药物相关的胃黏膜炎、与施用化疗药物相关的胃溃疡、与施用化疗药物相关的腹泻、与施用化疗药物相关的呕吐、与施用化疗药物相关的恶心、与施用化疗药物相关的厌食、与施用化疗药物相关的便秘、与施用化疗药物相关的腹痛、与施用化疗药物相关的非特异性胸痛、与施用化疗药物相关的心绞痛、与施用化疗药物相关的心悸、与施用化疗药物相关的呼吸困难、与施用化疗药物相关的与施用化疗药物相关的弥漫性胸膜炎性胸痛、与施用化疗药物相关的室上性心率失常、与施用化疗药物相关的低血压、与施用化疗药物相关的心肌梗死、与施用化疗药物相关的心动过缓、与施用化疗药物相关的心律失常、与施用化疗药物相关的室颤、与施用化疗药物相关的室性心动过速、与施用化疗药物相关的心肌炎、与施用化疗药物相关的心力衰竭、与施用化疗药物相关的急性肺水肿、与施用化疗药物相关的心搏骤停、与施用化疗药物相关的心包炎、与施用化疗药物相关的白血病、与施用化疗药物相关的骨髓增殖性疾病、与施用化疗药物相关的骨髓抑制、与施用化疗药物相关的贫血、与施用化疗药物相关的白细胞减少、与施用化疗药物相关的血小板减少、与施用化疗药物相关的远端感觉异常、 与施用化疗药物相关的肌肉收缩，和/或与施用化疗药物相关的四肢僵硬。
在某些实施方式中，所述与施用化疗药物相关的疾病或病症包括与施用化疗药物相关的手足综合征。在某些实施方式中，所述与施用化疗药物相关的疾病或病症包括与施用化疗药物相关的甲沟炎。在某些实施方式中，所述与施用化疗药物相关的疾病或病症包括与施用化疗药物相关的胃肠道疾病。在某些实施方式中，所述与施用化疗药物相关的疾病或病症包括与施用化疗药物相关的腹泻。
在某些实施方式中，所述与施用化疗药物相关的疾病或病症的严重程度为依据NCI-CTCAE V5.0中的第1级或以上、第2级或以上、第3级或以上、第4级或以上，和/或第5级。
在某些实施方式中，所述药物被制备为适用于外用给药。在某些实施方式中，所述药物被制备为适用于局部给药。在某些实施方式中，所述药物被制备为适用于口服给药。
在某些实施方式中，所述药物被制备为适用于口服给药。口服制剂可以包括但不限于，胶囊、囊剂、药丸、片剂、锭剂、粉末、颗粒剂、水或非水溶液或悬浮液、油包水或水包油的乳剂、酏剂或糖浆、糖果锭剂和/或漱口药及其类似物。
在某些实施方式中，所述药物被制备为乳膏、乳液、凝胶、油、软膏、喷雾剂、泡沫、脂质体制剂，搽剂，洗剂、气雾剂和/或经皮肤吸收的透皮剂。
在某些实施方式中，所述胸苷衍生物在所述药物中的浓度为约0.0001％(w/w)至约50％(w/w)。在某些实施方式中，所述胸苷衍生物在所述药物中的浓度为约0.1％(w/w)至约5％(w/w)。在某些实施方式中，所述胸苷衍生物在所述药物中的浓度为约0.5％(w/w)至约3％(w/w)。
在某些实施方式中，所述胸苷衍生物的给药剂量为约0.5μM至约1000μM。在某些实施方式中，所述胸苷衍生物的给药剂量为约1μM至约500μM。
在某些实施方式中，所述胸苷衍生物的给药剂量为约15mpk至约300mpk。在某些实施方式中，所述胸苷衍生物的给药剂量为约10mpk至约500mpk。
在某些实施方式中，所述药物中进一步包含一种或多种活性成分。
在某些实施方式中，所述药物基本上不影响所述化疗药物的治疗效果。
在某些实施方式中，所述的用途中所述受试者包含癌症患者。
在某些实施方式中，所述受试者曾经、正在和/或将来被施用所述化疗药物。
在某些实施方式中，所述受试者患有或易患有所述与施用所述化疗药物相关的疾病或病症。
在某些实施方式中，所述的用途中所述疾病或病症的严重程度在施用所述化疗药物之后增加。
在某些实施方式中，在施用所述化疗药物之前，所述受试者未患有所述疾病或病症。
另一方面，本申请提供了一种药物组合或试剂盒，其包含：1)所述的化疗药物；以及2)所述的胸苷衍生物。
在某些实施方式中，所述的药物组合或试剂盒中所述化疗药物与所述胸苷衍生物彼此不混合。
在某些实施方式中，所述的药物组合或试剂盒中所述化疗药物与所述胸苷衍生物各自独立地存在于单独的容器中。
在某些实施方式中，所述的药物组合或试剂盒中2)中的所述胸苷衍生物能够预防或治疗与施用1)中的所述化疗药物相关的疾病或病症。
在某些实施方式中，所述的药物组合或试剂盒中2)中的所述胸苷衍生物基本上不影响1)中的所述化疗药物的治疗效果。
在某些实施方式中，所述的药物组合或试剂盒中在施用1)的所述化疗药物之前、同时或者之后施用2)的所述胸苷衍生物。
另一方面，本申请提供了一种方法，其包含向受试者施用胸苷衍生物，其中所述受试者曾经、正在和/或将来被施用化疗药物且患有或易患有与施用所述化疗药物相关的疾病或病症。
另一方面，本申请提供了一种用于预防或治疗疾病或病症的方法，包含向易患有或患有施用所述化疗药物相关的疾病或病症的受试者施用胸苷衍生物，其中所述受试者曾经、正在和/或将来被施用化疗药物。
另一方面，本申请提供了一种预防或治疗疾病或病症的方法，包含向易患有或患有所述疾病或病症的受试者施用包含胸苷衍生物和尿苷衍生物的组合，其中所述疾病或病症为与施用化疗药物相关的疾病或病症。
在某些实施方式中，所述的方法中所述受试者曾经、正在和/或将来被施用所述化疗药物。。
另一方面，本申请提供了一种包含胸苷衍生物和尿苷衍生物的组合在制备药物中的用途，所述药物用于预防或治疗受试者中与施用化疗药物相关的疾病或病症，其中所述胸苷衍生物在脱氧核糖上的至少一个羟基氢被取代。
在某些实施方式中，所述胸苷衍生物包含式(I)的结构：
Figure PCTCN2021127683-appb-000071
式(I)
其中，R 2、R 3、R 4、R 5、R 6和R 7不同时为氢。
在某些实施方式中，R 7为
Figure PCTCN2021127683-appb-000072
在某些实施方式中，R 7为
Figure PCTCN2021127683-appb-000073
在某些实施方式中，R 6为氢。
在某些实施方式中，R 6为
Figure PCTCN2021127683-appb-000074
其中所述R 6 1为C1至C6的烷基。在某些实施方式中，R 6为
Figure PCTCN2021127683-appb-000075
在某些实施方式中，R 1为
Figure PCTCN2021127683-appb-000076
其中，M 1为氧或硫，并且R 8包含选自下组的一中或多种基团：氢、取代或未取代的羟基、取代或未取代的巯基、取代或未取代的氨基、取代或未取代的C1至C5烷基、取代或未取代的C1至C5炔基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基，以及，取代或未取代的芳烷基；M 2为硅或碳，并且R 9选自下组：氢、取代或未取代的羟基、取代或未取代的巯基、取代或未取代的氨基、取代或未取代的C1至C5烷基、取代或未取代的C1至C5炔基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基，以及，取代或未取代的芳烷基；R 9选自下组：C1至C5烷基、C1至C5的环烷基、苯基或苯甲基。
在某些实施方式中，R 2为
Figure PCTCN2021127683-appb-000077
其中，M 1为氧或硫，并且R 8包含选自下组的一中或多种基团：氢、取代或未取代的羟基、取代或未取代的巯基、取代或未取代的氨基、取代或未取代的C1至C5烷基、取代或未取代的C1至C5炔基、取代或未取代的环 烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基，以及，取代或未取代的芳烷基；M 2为硅或碳，并且R 9选自下组：氢、取代或未取代的羟基、取代或未取代的巯基、取代或未取代的氨基、取代或未取代的C1至C5烷基、取代或未取代的C1至C5炔基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基，以及，取代或未取代的芳烷基；R 9选自下组：C1至C5烷基、C1至C5的环烷基、苯基或苯甲基。
在某些实施方式中，R 3为
Figure PCTCN2021127683-appb-000078
其中，M 1为氧或硫，并且R 8包含选自下组的一中或多种基团：氢、取代或未取代的羟基、取代或未取代的巯基、取代或未取代的氨基、取代或未取代的C1至C5烷基、取代或未取代的C1至C5炔基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基，以及，取代或未取代的芳烷基；M 2为硅或碳，并且R 9选自下组：氢、取代或未取代的羟基、取代或未取代的巯基、取代或未取代的氨基、取代或未取代的C1至C5烷基、取代或未取代的C1至C5炔基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基，以及，取代或未取代的芳烷基；R 9选自下组：C1至C5烷基、C1至C5的环烷基、苯基或苯甲基。
在某些实施方式中，R 1选自下组：–(C＝O)–R 8 1、–(C＝O)–OR 8 2、–(C＝O)–NR 8 3R 8 4、–(C＝S)–R 8 5、–(C＝S)–OR 8 6和–(C＝S)–NR 8 7R 8 8，其中R 8 1、R 8 2、R 8 3、R 8 4、R 8 5、R 8 6、R 8 7和R 8 8中的任意一个独立地包含选自下组的一中或多种基团：氢、取代或未取代的烷基、取代或未取代的炔基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基以及取代或未取代的杂芳基。
在某些实施方式中，R 2选自下组：–(C＝O)–R 8 1、–(C＝O)–OR 8 2、–(C＝O)–NR 8 3R 8 4、–(C＝S)–R 8 5、–(C＝S)–OR 8 6和–(C＝S)–NR 8 7R 8 8，其中R 8 1、R 8 2、R 8 3、R 8 4、R 8 5、R 8 6、R 8 7和R 8 8中的任意一个独立地包含选自下组中的一种或多种基团：氢、取代或未取代的烷基、取代或未取代的炔基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基以及取代或未取代的杂芳基。
在某些实施方式中，R 3选自下组：–(C＝O)–R 8 1、–(C＝O)–OR 8 2、–(C＝O)–NR 8 3R 8 4、–(C＝S)–R 8 5、–(C＝S)–OR 8 6和–(C＝S)–NR 8 7R 8 8，其中R 8 1、R 8 2、R 8 3、R 8 4、R 8 5、R 8 6、R 8 7和R 8 8中的任意一个独立地包含选自下组中的一种或多种基团：氢、取代或未取代的烷基、取代或未取代的炔基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基以及取代 或未取代的杂芳基。
在某些实施方式中，R 8 1、R 8 2、R 8 3、R 8 4、R 8 5、R 8 6、R 8 7和R 8 8中的任意一个独立地包含选自下组的一中或多种基团：氢、C1至C5烷基、C1至C5的环烷基、C1至C5的杂环烷基、苯基或苯甲基。
在某些实施方式中，R 8 1包含选自下组的一中或多种基团：C 1至C 5烷基、C 1至C 5的环烷基、苯基和苯甲基。在某些实施方式中，R 8 1包含选自下组的一中或多种基团：甲基、乙基、丙基、丁基、环戊烷基、环丙烷基和苯甲基。
在某些实施方式中，R 8 2包含选自下组的一中或多种基团：C1至C5烷基、C1至C5的环烷基、苯基和苯甲基。在某些实施方式中，R 8 2包含选自下组的一中或多种基团：环丙基、丙基、丁基、戊基、苯基和苯甲基。
在某些实施方式中，R 8 3为氢。
在某些实施方式中，R 8 4包含选自下组的一中或多种基团：C1至C5烷基、C1至C5的环烷基、苯基和苯甲基。在某些实施方式中，R 8 4包含选自下组的一中或多种基团：环丙基、环戊基和苯基。
在某些实施方式中，R 9为丁基。
在某些实施方式中，R 3为氢。在某些实施方式中，R 4为氢。在某些实施方式中，R 5为氢。
在某些实施方式中，R 1为
Figure PCTCN2021127683-appb-000079
其中，R 8 1包含选自下组的一中或多种基团：C1至C6烷基、C1至C6硅烷基、C1至C6烷氧基、C1至C6烷基硝基、C3至C7环烷基、C3至C7环烷基硝基、C4至C7芳香基、C4至C7烷氧基芳香基和/或C4至C7杂芳基。在某些实施方式中，R 2为
Figure PCTCN2021127683-appb-000080
其中，R 8 1包含选自下组的一中或多种基团：C1至C6烷基、C1至C6硅烷基、C1至C6烷氧基、C1至C6烷基硝基、C3至C7环烷基、C3至C7环烷基硝基、C4至C7芳香基、C4至C7烷氧基芳香基和/或C4至C7杂芳基。
在某些实施方式中，在式(I)所示的结构中，R 3、R 4、R 5和R 6均为氢，R 7为
Figure PCTCN2021127683-appb-000081
R 1包含选自下组的一中或多种基团：氢、
Figure PCTCN2021127683-appb-000082
Figure PCTCN2021127683-appb-000083
Figure PCTCN2021127683-appb-000084
R 2包含选自下组的一中或多种基团：氢、
Figure PCTCN2021127683-appb-000085
Figure PCTCN2021127683-appb-000086
Figure PCTCN2021127683-appb-000087
且R 2和R 1不同时为氢。
在某些实施方式中，所述胸苷衍生物包含选自下组的化合物T1至化合物T24中的一种或多种：
Figure PCTCN2021127683-appb-000088
Figure PCTCN2021127683-appb-000089
在某些实施方式中，所述胸苷衍生物包含式(II)所示的结构：
Figure PCTCN2021127683-appb-000090
式(II)，其中，R 1和/或R 2包含非甾体抗炎药(NSAID)部分。
在某些实施方式中，所述NSAID部分包含水杨酸或其衍生物、芳基乙酸或其衍生物、杂芳基乙酸或其衍生物、吲哚乙酸或其衍生物、茚乙酸或其衍生物、邻氨基苯甲酸或其衍生物和/或烯醇酸或其衍生物。
在某些实施方式中，R 1或R 2为氢。
在某些实施方式中，R 1和R 2不同时为氢。
在某些实施方式中，R 1和/或R 2为
Figure PCTCN2021127683-appb-000091
其中，R 8为R s 2或
Figure PCTCN2021127683-appb-000092
其中，R s 1为氢或甲基，R s 2为
Figure PCTCN2021127683-appb-000093
其中，所述环A为C4至C7芳基、C4至C7杂芳基、茚环、萘环、吲哚啉环、不饱和多环烃和/或杂环多环，Rs 3和/或Rs 4独立地选自：氢、C1至C6烷基、C1至C6烷基酯、卤素、C4至C7芳香基、C4至C7杂芳基和
Figure PCTCN2021127683-appb-000094
其中，环B为C4至C7芳香基、C4至C7杂芳基，X为-CH 2、-NH-、-O-或
Figure PCTCN2021127683-appb-000095
其中，所述C4至C7芳香基、C4至C7杂芳基可选地被一个或多个选自下组的取代基取代：卤素、C1至C6烷基、C1至C6炔基和C1至C6烯基。
在某些实施方式中，环A为吡咯环，R s 3为C1-C6烷基，R s 4为
Figure PCTCN2021127683-appb-000096
其中，X为
Figure PCTCN2021127683-appb-000097
环B为苯环，所述环B可选地被一个或多个C1至C6烷基取代。
在某些实施方式中，R s 1和/或R s 2为
Figure PCTCN2021127683-appb-000098
其中，所述R s 3为C1至C6烷基或卤素。
在某些实施方式中，R s 1和/或R s 2为
Figure PCTCN2021127683-appb-000099
其中，R s 3和/或R s 4选自：氢、C1至C6烷基、C1至C6烷基酯、卤素、C4至C7芳香基、C4至C7杂芳基、
Figure PCTCN2021127683-appb-000100
环B为C4至C7芳香基、C4至C7杂芳基，X为-CH 2、-NH-、-O-或
Figure PCTCN2021127683-appb-000101
其中，所述C4至C7芳香基、C4至C7杂芳基可选地被一个或多个选自下组的取代基取代：卤素、C1至C6烷基、C1至C6炔基和C1至C6烯基。
在某些实施方式中，R s 2为
Figure PCTCN2021127683-appb-000102
其中，R s 3和/或R s 4选自：氢、C1至C6烷基、
Figure PCTCN2021127683-appb-000103
氟、氯、溴、苯环和
Figure PCTCN2021127683-appb-000104
其中，环B为苯环，X为-CH 2、-NH-、-O-或
Figure PCTCN2021127683-appb-000105
所述苯环可选地被一个或多个选自下组的取代基取代：氟、氯和溴。
在某些实施方式中，R 8为
Figure PCTCN2021127683-appb-000106
R s 1为氢或甲基，R s 2选自
Figure PCTCN2021127683-appb-000107
Figure PCTCN2021127683-appb-000108
在某些实施方式中，R 8为
Figure PCTCN2021127683-appb-000109
R s 1为氢或甲基，R s 2为
Figure PCTCN2021127683-appb-000110
其中，环A 1为C4至C7环烷基、C4至C7杂环烷基、C4至C7芳香基和/或C4至C7杂芳基，环B 1为C4至C7环烷基、C4至C7杂环烷基、C4至C7芳香基、C4至C7杂芳基或
Figure PCTCN2021127683-appb-000111
其中，环B 2为C4至C7环烷基、C4至C7杂环烷基、C4至C7芳香基和/或C4至C7杂芳基，环B 3为C4至C7环烷基、C4至C7杂环烷基、C4至C7芳香基和/或C4至C7杂芳基，其中，所述C4至C7环烷基、C4至C7杂环烷基、C4至C7芳香基和/或C4至C7杂芳基可选地被卤素、
Figure PCTCN2021127683-appb-000112
C1至C6烷基、C1至C6烷基取代的酯基和/或C1至C6烷基取代的醛基取代，其中，环C为苯环，Y为-CH 2、-NH-、-O-或
Figure PCTCN2021127683-appb-000113
所述苯环可选地被一个或多个选自下组的取代基取代：氟、氯、溴和
Figure PCTCN2021127683-appb-000114
所述Y可以与环B 2或环B 3上的环原子形成双键。
在某些实施方式中，R s 2为
Figure PCTCN2021127683-appb-000115
其中，所述R s 6为氟、氯或溴、
Figure PCTCN2021127683-appb-000116
M为氮或碳，X为碳或
Figure PCTCN2021127683-appb-000117
X与M间可选地形成双键，R s 7为氟、氯、溴或
Figure PCTCN2021127683-appb-000118
在某些实施方式中，R 8为
Figure PCTCN2021127683-appb-000119
R s 1为氢或甲基，R s 2为
Figure PCTCN2021127683-appb-000120
Figure PCTCN2021127683-appb-000121
在某些实施方式中，R 8为
Figure PCTCN2021127683-appb-000122
R s 1为氢或甲基，R s 2为
Figure PCTCN2021127683-appb-000123
在某些实施方式中，R s 2为
Figure PCTCN2021127683-appb-000124
所述环A 1为苯环，环B 1为
Figure PCTCN2021127683-appb-000125
且环B 2为吡咯环，B 3为吡喃环，所述吡喃环可选地被一个或多个C1至C6烷基和/或C1至C6烷基取代的醛基取代。
在某些实施方式中，R 8为
Figure PCTCN2021127683-appb-000126
R s 1为氢或甲基，R s 2为
Figure PCTCN2021127683-appb-000127
在某些实施方式中，R 8 1为
Figure PCTCN2021127683-appb-000128
在某些实施方式中，R 1和/或R 2为
Figure PCTCN2021127683-appb-000129
在某些实施方式中，所述R 1包含所述NSAID部分，且R 2为氢。
在某些实施方式中，所述R 1包含选自下组中的任意一种基团：
Figure PCTCN2021127683-appb-000130
Figure PCTCN2021127683-appb-000131
且R 2为氢。
在某些实施方式中，所述R 2包含所述NSAID部分，且R 1为氢。
在某些实施方式中，所述R 2选自下组中的任意一种基团：
Figure PCTCN2021127683-appb-000132
Figure PCTCN2021127683-appb-000133
Figure PCTCN2021127683-appb-000134
且R 1为氢。
在某些实施方式中，所述R 1和R 2均包含所述NSAID部分。
在某些实施方式中，所述R 1和R 2各自独立地选自下组中的任意一种基团：
Figure PCTCN2021127683-appb-000135
在某些实施方式中，所述胸苷衍生物选自下组中的一种或多种：
Figure PCTCN2021127683-appb-000136
Figure PCTCN2021127683-appb-000137
Figure PCTCN2021127683-appb-000138
在某些实施方式中，所述尿苷衍生物可以包含式(III)的结构：
Figure PCTCN2021127683-appb-000139
式(III)，其中，当X 4和X 5均为氢时，X 1、X 2和X 3不同时为氢或不同时为CH 3CO–。
在某些实施方式中，X 1为氢或
Figure PCTCN2021127683-appb-000140
其中所述X s为氧或硫，R s包含选自下组中的一种或多种基团：氢、取代或未取代的羟基、取代或未取代的巯基、取代或未取代的氨基、C1至C5的取代或未取代的烷基、C1至C5的取代或未取代的炔基、C1至C5的取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基以及取代或未取代的芳烷基。在某些实施方式中，X s为氧。
在某些实施方式中，X 2为氢或
Figure PCTCN2021127683-appb-000141
其中所述X g为氧或硫，R g包含选自下组中的一种或多种基团：氢、取代或未取代的羟基、取代或未取代的巯基、取代或未取代的氨基、C1至C5的取代或未取代的烷基、C1至C5的取代或未取代的炔基、C1至C5的取代或未取 代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基以及取代或未取代的芳烷基。在某些实施方式中，X g为氧。
在某些实施方式中，X 3为
Figure PCTCN2021127683-appb-000142
或氢，其中所述X 7为氢或
Figure PCTCN2021127683-appb-000143
其中所述X 1’为氧或硫，X 6包含选自下组中的一种或多种基团：氢、取代或未取代的羟基、取代或未取代的巯基、取代或未取代的氨基、C1至C5的取代或未取代的烷基、C1至C5的取代或未取代的炔基、C1至C5的取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基以及取代或未取代的芳烷基。在某些实施方式中，X 1’为氧。
在某些实施方式中，X 3为
Figure PCTCN2021127683-appb-000144
所述C 7为
Figure PCTCN2021127683-appb-000145
其中，X 6包含选自下组中的一种或多种基团：氢、C1至C6烷基、C1至C6烷氧基、C3至C10环烷基、C3至C10环烷基氧基、C4至C10芳基烷基、C4至C10芳基烷氧基或C4至C10芳香基。
在某些实施方式中，所述X 3为氢。
在某些实施方式中，所述X 1为
Figure PCTCN2021127683-appb-000146
其中，R s包含选自下组中的一种或多种基团：氢、C1至C6烷基、C1至C6烷氧基、C3至C10环烷基、C3至C10环烷基氧基、C4至C10芳基烷基、C4至C10芳基烷氧基或C4至C10芳香基。
在某些实施方式中，所述X 2为
Figure PCTCN2021127683-appb-000147
其中，R g包含选自下组中的一种或多种基团：氢、C1至C6烷基、C1至C6烷氧基、C3至C10环烷基、C3至C10环烷基氧基、C4至C10芳基烷基、C4至C10芳基烷氧基或C4至C10芳香基。
在某些实施方式中，X 4为氢。在某些实施方式中，X 5为氢。
在某些实施方式中，所述尿苷衍生物选自U1至U13中的一种或多种。
在某些实施方式中，所述尿苷衍生物包含如式(IV)所示的化合物：
Figure PCTCN2021127683-appb-000148
式(IV)，其中，所述X 1、X 2和X 7中的至少一个包含非甾体抗炎药(NSAID)部分。
在某些实施方式中，所述NSAID部分包含水杨酸或其衍生物、芳基乙酸或其衍生物、杂芳基乙酸或其衍生物、吲哚乙酸或其衍生物、茚乙酸或其衍生物、邻氨基苯甲酸或其衍生物和/或烯醇酸或其衍生物。
在某些实施方式中，X 1、X 2或X 7为氢。在某些实施方式中，X 1、X 2和X 7不同时为氢。
在某些实施方式中，X 1、X 2和X 7中的任意一个独立地为
Figure PCTCN2021127683-appb-000149
其中，X 8为X s 2或
Figure PCTCN2021127683-appb-000150
其中，X s 1为氢或甲基，X s 2为
Figure PCTCN2021127683-appb-000151
其中，所述环A’为C4至C7芳基、C4至C7杂芳基、茚环、萘环、吲哚啉环、不饱和多环烃和/或杂环多环，Xs 3和/或Xs 4独立地选自：氢、C1至C6烷基、C1至C6烷基酯、卤素、C4至C7芳香基、C4至C7杂芳基和
Figure PCTCN2021127683-appb-000152
其中，环B’为C4至C7芳香基、C4至C7杂芳基，X’为-CH 2、-NH-、-O-或
Figure PCTCN2021127683-appb-000153
其中，所述C4至C7芳香基、C4至C7杂芳基可选地被一个或多个选自下组的取代基取代：卤素、C1至C6烷基、C1至C6炔基和C1至C6烯基。
在某些实施方式中，X 8为
Figure PCTCN2021127683-appb-000154
X s 1为氢或甲基，X s 2选自
Figure PCTCN2021127683-appb-000155
Figure PCTCN2021127683-appb-000156
在某些实施方式中，X 8为
Figure PCTCN2021127683-appb-000157
X s 1为氢或甲基，X s 2为
Figure PCTCN2021127683-appb-000158
其中，环A 1’为C4至C7环烷基、C4至C7杂环烷基、C4至C7芳香基和/或C4至C7杂芳基，环B 1’为C4至C7环烷基、C4至C7杂环烷基、C4至C7芳香基、C4至C7杂芳基或
Figure PCTCN2021127683-appb-000159
其中，环B 2’为C4至C7环烷基、C4至C7杂环烷基、C4至C7芳香基和/或C4至C7杂芳基，环B 3’为C4至C7环烷基、C4至C7杂环烷基、C4至C7芳香基和/或C4至C7杂芳基，其中，所述C4至C7环烷基、C4至C7杂环烷基、C4至C7芳香基和/或C4至C7杂芳基可选地被卤素、
Figure PCTCN2021127683-appb-000160
C1至C6烷基、C1至C6烷基取代的酯基和/或C1至C6烷基取代的醛基取代，其中，环C’为苯环，Y’为-CH 2、-NH-、-O-或
Figure PCTCN2021127683-appb-000161
所述苯环可选地被一个或多个选自下组的取代基取代：氟、氯、溴和
Figure PCTCN2021127683-appb-000162
所述Y’可以与环B 2或环B 3上的环原子形成双键。
在某些实施方式中，X 8为
Figure PCTCN2021127683-appb-000163
X s 1为氢或甲基，X s 2为
Figure PCTCN2021127683-appb-000164
在某些实施方式中，X 8为
Figure PCTCN2021127683-appb-000165
X s 1为氢或甲基，X s 2为
Figure PCTCN2021127683-appb-000166
在某些实施方式中，X 8为
Figure PCTCN2021127683-appb-000167
X s 1为氢或甲基，X s 2为
Figure PCTCN2021127683-appb-000168
在某些实施方式中，X 8 1为
Figure PCTCN2021127683-appb-000169
在某些实施方式中，X 1、X 2和X 7中的任意一个独立地为
Figure PCTCN2021127683-appb-000170
在某些实施方式中，X 1、X 2和X 7中的至少一个(例如，X 1，X 2，X 7，X 1和X 2，X 2和X 7，X 1和X 7，或者，X 1、X 2和X 7)包含NSAID部分，剩下的为氢。
在某些实施方式中，所述X 1选自下组：
Figure PCTCN2021127683-appb-000171
Figure PCTCN2021127683-appb-000172
在某些实施方式中，所述X 1选自下组：
Figure PCTCN2021127683-appb-000173
在某些实施方式中，所述X 2选自下组：
Figure PCTCN2021127683-appb-000174
Figure PCTCN2021127683-appb-000175
在某些实施方式中，所述X 2选自下组：
氢、
Figure PCTCN2021127683-appb-000176
Figure PCTCN2021127683-appb-000177
在某些实施方式中，所述X 7选自下组：
Figure PCTCN2021127683-appb-000178
Figure PCTCN2021127683-appb-000179
在某些实施方式中，所述X 7选自下组：
Figure PCTCN2021127683-appb-000180
在某些实施方式中，当X 1、X 2或X 7中的一种或多种各自独立地选自上述组中的具体基团时，不选自上述组中的X 1、X 2或X 7中的那些为氢，但X 1、X 2或X 7不同时为氢。在某些实施方式中，X 1X 2或X 7可以均为相同的基团。在某些实施方式中，X 1、X 2或X 7中的两种为相同的基团。在某些实施方式中，X 1、X 2或X 7为各不相同的基团。
在某些实施方式中，所述尿苷衍生物选自下组中的一种或多种：
Figure PCTCN2021127683-appb-000181
在某些实施方式中，所述的用途中所述化疗药物用于治疗癌症。
在某些实施方式中，所述化疗药物包括嘧啶核苷类似物或其前药。
在某些实施方式中，所述化疗药物包括选自下组中的一种或多种：卡培他滨、阿糖胞苷、多西他赛、阿霉素、氟尿嘧啶(5-FU)、氟尿苷、替加氟、伊达比星、紫杉醇、表柔比星、Acelarin(NUC-1031)、多柔比星、亚叶酸、顺铂、紫杉醇、环磷酰胺、长春新碱和5-FU药物前体(例 如，喃氟啶和5’-脱氧氟尿苷、氟尿苷、2’-脱氧氟尿苷、氟尿苷的药物前体衍生物或2’-脱氧氟尿苷的药物前体衍生物、三氟-甲基-2’-脱氧尿苷、6-氮杂尿苷或3-脱氮杂尿苷)。
在某些实施方式中，所述的用途中所述疾病或病症由施用所述化疗药物引起。
在某些实施方式中，所述与施用化疗药物相关的疾病或病症包括与施用化疗药物相关的皮肤组织疾病或病症、与施用化疗药物相关的造血组织疾病或病症、与施用化疗药物相关的四肢疾病或病症、与施用化疗药物相关的心脏疾病或病症、与施用化疗药物相关的神经系统疾病或病症、与施用化疗药物相关的五官疾病或病症和/或与施用化疗药物相关的胃肠道疾病或病症。
在某些实施方式中，所述与施用化疗药物相关的造血组织疾病或病症包括与施用化疗药物相关的骨髓疾病或病症和与施用化疗药物相关的血液疾病或病症。
在某些实施方式中，所述与施用化疗药物相关的造血组织疾病或病症包括与施用化疗药物相关的血液细胞增殖异常疾病或病症。
在某些实施方式中，所述与施用化疗药物相关的疾病或病症包括与施用化疗药物相关的上皮组织疾病或病症。
在某些实施方式中，所述与施用化疗药物相关的上皮组织疾病或病症包括与内皮细胞病变相关的所述疾病或病症，和/或与上皮细胞病变相关的所述疾病或病症，且其中所述内皮细胞病变和/或上皮细胞病变与所述施用化疗药物相关。
在某些实施方式中，所述内皮细胞包括血管内皮细胞。
在某些实施方式中，所述上皮细胞包括皮肤上皮细胞、口腔上皮细胞、鼻腔上皮细胞、胃上皮细胞和/或肠上皮细胞。
在某些实施方式中，所述与施用化疗药物相关的疾病或病症包括与施用化疗药物相关的皮疹、与施用化疗药物相关的手足综合征、与施用化疗药物相关的瘙痒、与施用化疗药物相关的红斑、与施用化疗药物相关的皮肤干燥、与施用化疗药物相关的脱发、与施用化疗药物相关的甲沟炎、与施用化疗药物相关的色素沉积紊乱、与施用化疗药物相关的口腔溃疡、与施用化疗药物相关的口干、与施用化疗药物相关的鼻衄、与施用化疗药物相关的鼻咽炎、与施用化疗药物相关的唇炎、与施用化疗药物相关的食管黏膜炎、与施用化疗药物相关的胃黏膜炎、与施用化疗药物相关的胃溃疡、与施用化疗药物相关的腹泻、与施用化疗药物相关的呕吐、与施用化疗药物相关的恶心、与施用化疗药物相关的厌食、与施用化疗药物相关的便秘、或与施用化疗药物相关的腹痛、与施用化疗药物相关的非特异性胸痛、与施用化疗药物相关的心绞痛、与施用化疗药物相关的心悸、与施用化疗药物相关的呼吸困难、与施用化疗 药物相关的与施用化疗药物相关的弥漫性胸膜炎性胸痛、与施用化疗药物相关的室上性心率失常、与施用化疗药物相关的低血压、与施用化疗药物相关的心肌梗死、与施用化疗药物相关的心动过缓、与施用化疗药物相关的心律失常、与施用化疗药物相关的室颤、与施用化疗药物相关的室性心动过速、与施用化疗药物相关的心肌炎、与施用化疗药物相关的心力衰竭、与施用化疗药物相关的急性肺水肿、与施用化疗药物相关的心搏骤停、与施用化疗药物相关的心包炎、与施用化疗药物相关的白血病、与施用化疗药物相关的骨髓增殖性疾病、与施用化疗药物相关的骨髓抑制、与施用化疗药物相关的贫血、与施用化疗药物相关的白细胞减少、与施用化疗药物相关的粒细胞减少、与施用化疗药物相关的血小板减少、与施用化疗药物相关的远端感觉异常、与施用化疗药物相关的肌肉收缩，和/或与施用化疗药物相关的四肢僵硬。
在某些实施方式中，所述与施用化疗药物相关的疾病或病症包括与施用化疗药物相关的手足综合征和/或与施用化疗药物相关的甲沟炎。
在某些实施方式中，所述与施用化疗药物相关的疾病或病症的严重程度为依据NCI-CTCAE V5.0中的第1级或以上、第2级或以上、第3级或以上、第4级或以上，和/或第5级。
在某些实施方式中，所述的用途中所述药物被制备为适用于外用给药。在某些实施方式中，所述的用途中所述药物被制备为适用于口服给药。在某些实施方式中，所述的用途中所述药物被制备为适用于局部给药。
在某些实施方式中，所述胸苷衍生物在所述药物中的浓度为约0.0001％(w/w)至约50％(w/w)。在某些实施方式中，所述胸苷衍生物在所述药物中的浓度为约0.1％(w/w)至约5％(w/w)。在某些实施方式中，所述胸苷衍生物在所述药物中的浓度为约0.5％(w/w)至约3％(w/w)。
在某些实施方式中，所述胸苷衍生物的给药剂量为约0.5μM至约1000μM。在某些实施方式中，所述胸苷衍生物的给药剂量为约1μM至约500μM。在某些实施方式中，所述胸苷衍生物的给药剂量为约20μM至约300μM。在某些实施方式中，所述胸苷衍生物的给药剂量为约20μM至约200μM。在某些实施方式中，所述胸苷衍生物的给药剂量为约30μM至约200μM。
在某些实施方式中，所述尿苷衍生物的给药剂量为约100μM至约500μM。在某些实施方式中，所述尿苷衍生物的给药剂量为约0.5μM至约50μM。在某些实施方式中，所述尿苷衍生物的给药剂量为约1μM至约50μM。在某些实施方式中，所述尿苷衍生物的给药剂量为约1μM至约30μM。在某些实施方式中，所述尿苷衍生物的给药剂量为约10μM至约50μM。
在某些实施方式中，所述胸苷衍生物和尿苷衍生物的给药剂量为约0.5μM至约1000μM。 在某些实施方式中，所述胸苷衍生物和尿苷衍生物的给药剂量为约1μM至约500μM。在某些实施方式中，所述胸苷衍生物和尿苷衍生物的给药剂量为约0.5μM至约25μM。在某些实施方式中，所述胸苷衍生物和尿苷衍生物的给药剂量为约0.8μM至约25μM。
在某些实施方式中，所述胸苷衍生物的给药剂量为约15mpk至约300mpk。在某些实施方式中，所述胸苷衍生物的给药剂量为约10mpk至约500mpk。
在某些实施方式中，所述胸苷衍生物的给药剂量为约10mpk至约100mpk。在某些实施方式中，所述胸苷衍生物的给药剂量为约50mpk至约100mpk。
在某些实施方式中，所述胸苷衍生物和尿苷衍生物的给药剂量为约50mpk至约1000mpk。在某些实施方式中，所述胸苷衍生物和尿苷衍生物的给药剂量为约300mpk至约1000mpk。
在某些实施方式中，所述药物中进一步包含一种或多种活性成分。
在某些实施方式中，所述药物基本上不影响所述化疗药物的治疗效果。
在某些实施方式中，所述的用途中所述受试者包含癌症患者。
在某些实施方式中，所述受试者曾经、正在和/或将来被施用所述化疗药物。
在某些实施方式中，所述受试者患有或易患有所述与施用所述化疗药物相关的疾病或病症。
在某些实施方式中，所述的用途中所述疾病或病症的严重程度在施用所述化疗药物之后增加。
在某些实施方式中，在施用所述化疗药物之前，所述受试者未患有所述疾病或病症。
另一方面，本申请提供了一种药物组合或试剂盒，其包含：1)所述的化疗药物；以及2)所述的包含胸苷衍生物和尿苷衍生物的组合。
在某些实施方式中，所述的药物组合或试剂盒中所述化疗药物与所述包含胸苷衍生物和尿苷衍生物的组合彼此不混合。
在某些实施方式中，所述化疗药物与所述包含胸苷衍生物和尿苷衍生物的组合各自独立地存在于单独的容器中。
在某些实施方式中，所述的药物组合或试剂盒中2)中的所述包含胸苷衍生物和尿苷衍生物的组合能够预防或治疗与施用1)中的所述化疗药物相关的疾病或病症。
在某些实施方式中，所述的药物组合或试剂盒中2)中的所述包含胸苷衍生物和尿苷衍生物的组合基本上不影响1)中的所述化疗药物的治疗效果。
在某些实施方式中，所述的药物组合或试剂盒中在施用1)的所述化疗药物之前、同时或者之后施用2)的所述包含胸苷衍生物和尿苷衍生物的组合。
另一方面，本申请提供了一种方法，其包含向受试者施用包含胸苷衍生物和尿苷衍生物的组合，其中所述受试者曾经、正在和/或将来被施用化疗药物且患有或易患有与施用所述化疗药物相关的疾病或病症。
另一方面，本申请提供了一种预防或治疗疾病或病症的方法，包含向易患有或患有所述疾病或病症的受试者施用包含胸苷衍生物和尿苷衍生物的组合，其中所述疾病或病症为与施用化疗药物相关的疾病或病症。
在某些实施方式中，所述的方法中所述受试者曾经、正在和/或将来被施用所述化疗药物。
本领域技术人员能够从下文的详细描述中容易地洞察到本申请的其它方面和优势。下文的详细描述中仅显示和描述了本申请的示例性实施方式。如本领域技术人员将认识到的，本申请的内容使得本领域技术人员能够对所公开的具体实施方式进行改动而不脱离本申请所涉及发明的精神和范围。相应地，本申请的附图和说明书中的描述仅仅是示例性的，而非为限制性的。
附图说明
本申请所涉及的发明的具体特征如所附权利要求书所显示。通过参考下文中详细描述的示例性实施方式和附图能够更好地理解本申请所涉及发明的特点和优势。对附图简要说明书如下：
图1A-图1D显示的是本申请所述的胸苷衍生物化合物及其编号；
图2A-图2B显示的是本申请所述的尿苷衍生物化合物及其编号
图3-图10显示的是示例性的胸苷衍生物及胸苷衍生物与尿苷衍生物联用，在Hacat细胞中，对氟类药物产生毒性的缓解作用；同时结果显示，衍生物系列化合物缓解作用优于尿苷的缓解作用。
图11显示的是卡培他滨在大鼠产生手足综合症的模型。从照片可以看出，模型特征明显。
图12显示的是本申请所述胸苷衍生物及胸苷衍生物与尿苷衍生物联用预防和/或治疗卡培他滨在大鼠产生手足综合征的示例性结果。从图中可以看出，涂药后症状相较于模型组可以显著缓解。
图13显示的是卡培他滨在小鼠产生手足综合症的模型。
图14显示的是本申请所述胸苷衍生物及胸苷衍生物与尿苷衍生物联用预防和/或治疗卡培他滨在小鼠产生手足综合症的示例性结果。从图中可以看出，涂药后症状相较于模型组可 以显著缓解。
图15-图20显示的是示例性的包含NSAID的胸苷衍生物在Hacat细胞中，对氟类药物产生毒性的缓解作用；同时结果显示，尿苷衍生物化合物缓解作用优于胸苷的缓解作用。
图21显示的是示例性的包含NSAID的胸苷衍生物和包含NSAID的尿苷衍生物联用在Hacat细胞中，对氟类药物产生毒性的缓解作用。
图22显示的是示例性的包含NSAID的胸苷衍生物缓解化疗药物施用后的手足综合征大鼠的炎症反应。
图23显示的是示例性的包含NSAID的胸苷衍生物，以及包含NSAID的胸苷衍生物和包含NSAID的尿苷衍生物联用缓解化疗药物施用后的手足综合征大鼠的疼痛。
图24显示的是示例性的包含NSAID的胸苷衍生物，以及包含NSAID的胸苷衍生物和包含NSAID的尿苷衍生物联用缓解化疗药物施用后的腹泻。
具体实施方式
以下由特定的具体实施例说明本申请发明的实施方式，熟悉此技术的人士可由本说明书所公开的内容容易地了解本申请发明的其他优点及效果。
术语定义
在本申请中，术语“化疗药物”通常是指能作用在肿瘤细胞生长繁殖的不同环节上，抑制或者杀死肿瘤细胞的药物。在某些实施方式中，化疗药物可以包括嘧啶核苷类似物或其前药。例如，化疗药物可以包括选自下组中的一种或多种：卡培他滨、阿糖胞苷、多西他赛、阿霉素、氟尿嘧啶(5-FU)、氟尿苷、替加氟、伊达比星、紫杉醇、表柔比星、Acelarin(NUC-1031)、多柔比星、亚叶酸、顺铂、紫杉醇、环磷酰胺和长春新碱。例如，化疗药物可以直接作用于DNA上，防止癌细胞再生。例如，化疗药物可以干扰DNA和RNA的合成。例如，化疗药物可以通过抑制酶的作用或者有丝分裂来阻断癌细胞增殖。
在本申请中，术语“癌症”通常是指机体在各种致癌因子作用下，局部组织细胞增生所形成的新生物，由于这种新生物多呈占位性块状凸起，也称赘生物。所述的癌症可以选自下组：肺癌、胰腺癌、皮肤癌、膀胱癌、结肠癌、子宫癌、乳腺癌、肠道癌、前列腺癌、宫颈癌、卵巢癌、食管癌、头颈部癌、胃癌和喉癌。例如，所述的癌症可以是结肠癌。
在本申请中，术语“与施用化疗药物相关的疾病或病症”通常是指与向受试者施用化疗药物存在一定相关性的疾病或病症。例如，所述疾病或病症可以是因向受试者施用所述化疗药物而引起的疾病或病症。所述疾病或病症可能在施用化疗药物后产生或加重。例如，所述 与施用化疗药物相关的疾病或病症可以为手足综合征。例如，所述与施用化疗药物相关的疾病或病症可以为腹泻。
在本申请中，术语“皮肤组织疾病或病症”通常是指皮肤(包括毛发和甲)的形态、结构和/或功能发生的病理性变化。例如，所述皮肤组织疾病或病症可以包括但不限于皮疹、手足综合征、瘙痒、红斑、皮肤干燥、脱发、甲沟炎、色素沉积紊乱等。
在本申请中，术语“皮疹”通常是指会影响皮肤颜色、外观或纹理的皮肤变化。皮疹可以仅局限在身体的一部分，或影响整个皮肤。皮疹还可以包括荨麻疹。
在本申请中，术语“手足综合征”又称为Hand Foot Syndrome(HFS)，或Palmar Plantar Erythrodysesthesia(PPE)或Hand-foot skin reaction(HFSR)，其是由哈佛医学院新英格兰戴肯尼斯医院的Jacob Lokich和Cery Moor于1984年首次描述的。典型的临床表现呈进展性，临床主要可以表现为指(趾)热、痛、红斑性肿胀，严重者可以发展至脱屑、溃疡和剧烈疼痛等。HFS的病理表现可以包括基底角质细胞空泡变性、皮肤血管周围淋巴细胞浸润、角质细胞凋亡和皮肤水肿等。例如，HFS可以包括手掌、足底感觉迟钝或化疗引起的肢端红斑等。在本申请中，癌症患者在接受化疗的过程中可能出现相应症状。
在本申请中，术语“胸苷衍生物”通常是指胸苷中的氢原子被其它原子或原子团取代而衍生的产物。在一些实施方式中，所述胸苷衍生物在脱氧核糖上的至少一个羟基氢可以被取代。在一些实施方式中，所述胸苷衍生物可以预防和/或治疗曾经、正在和/或将来被施用化疗药物且患有或易患有与施用所述化疗药物相关的疾病或病症。
在本申请中，术语“烷基”通常指包含1-20个碳原子的直链或支链饱和烃基取代基(例如，通过除去氢而从烃中获得的取代基)；例如1-12个碳原子；在另一些实施方案中，碳原子数为1-10；在另一些实施方案中，为1-6个碳原子，在另一些实施方案中，为1-4个碳原子(比如1，2，3或更多碳原子)。取代基的实例包括：例如，甲基、乙基、丙基(包括正丙基和异丙基)，丁基(包括正丁基，异丁基，仲丁基和叔丁基)，戊基，异戊基，己基等。在某些情况下，烃基取代基(即烷基，烯基，环烷基，芳基等)中的碳原子数用前缀“C a-C b”表示，其中a为最小，b为最大的取代基中的碳原子数。因此，例如，“C 1-C 6烷基”是指含有1至6个碳原子的烷基取代基。
在本申请中，术语“环烷基”通常指通过从饱和碳环分子中除去氢并具有3-14个碳原子的碳原子而获得的碳环取代基。在一些实施方案中，一个环烷基取代基具有3-10个碳原子。环烷基可以是单环，其通常包含4-7个环原子。环烷基包括环丙基、环丁基、环戊基和环己基。环烷基也可以是稠合在一起的2-3个环，例如双环[4.2.0]辛烷和十氢化萘基，也可以称为 “双环烷基”。
在本申请中，术语“环烷基”还包括稠合至C 6-C 10芳环或5-10元杂芳族环的取代基，其中具有这种稠合的环烷基作为取代基的基团结合至环烷基的碳原子上。当这种稠合的环烷基被一个或多个取代基取代时，除非另有说明，一个或多个取代基各自键合至环烷基的碳原子上。稠合的C 6-C 10芳环或5-10元杂芳环可任选被进一步取代。
在本申请中，术语“氢”通常指氢取代基，可能被描述为-H。
在本申请中，术语“氧”通常指氧取代基，可能被描述为-O-。
在本申请中，术语“羟基”通常指-OH。当与另一个术语结合使用时，前缀“羟基”通常表示该前缀所连接的取代基被一个或多个羟基取代基取代。带有连接有一个或多个羟基取代基的碳的化合物包括：例如，醇，烯醇和苯酚。
在本申请中，术语“取代基”“自由基”和“基团”可以互换使用。
如果取代基被描述为是“任选取代的”，则该取代基可以是：(1)未取代的或(2)取代的。如果取代基的碳被描述为任选地被一个或多个取代基取代，则该碳上的一个或多个氢(就存在的程度而言)可以分别和/或一起被独立选择的任选取代基取代。如果取代基的氮被描述为任选地被一个或多个取代基取代，则该氮上的一个或多个氢(就存在的程度而言)可以各自被独立选择的任选取代基取代。一个示例性的取代基可以被描述为–NR’R”，其中R’和R”与它们所连接的氮原子一起可以形成包含1或2个独立地选自氧、氮和硫的杂原子的杂环，其中所述杂环烷基部分可以任选地被取代。由R’和R”与它们所连接的氮原子一起形成的杂环可以是部分或完全饱和的，或者是芳香族的。在一些实施方式中，杂环由4至10个原子组成。
如果取代基被描述为“独立地选自”一组基团，则每个取代基均独立于其他取代基进行选择。因此，每个取代基可以与其他取代基相同或不同。
在本申请中，术语“式(I)”、“式(II)”、“式(III)”、“式(IV)”可以称为“式(I)所示的化合物”、“式(II)所示的化合物”、“式(III)所示的化合物”或“式(IV)所示的化合物”。这样的术语也被定义为包括式(I)所示的化合物、式(II)所示的化合物、式(III)所示的化合物或式(IV)所示的化合物的所有形式，包括水合物，溶剂合物，异构体，结晶和非结晶形式，同晶型，多晶型和代谢物。例如，式(I)所示的化合物、式(II)所示的化合物、式(III)所示的化合物或式(IV)所示的化合物或其药学上可接受的盐，式(I)所示的化合物、式(II)所示的化合物、式(III)所示的化合物或式(IV)所示的化合物或其药学上可接受的盐，可以未溶剂化和溶剂化地形式存在。当溶剂或水的结合力较强时，配合物具有 明确地化学计量，其不受湿度影响。但是，当溶剂或水的结合力较弱时，例如在通道溶剂化物和吸湿性化合物中，水/溶剂的含量将取决于湿度和干燥条件，在这种情况下，非化学计量是常态。
“式(I)所示的化合物”、“式(II)所示的化合物”、“式(III)所示的化合物”或“式(IV)所示的化合物”可具有不对称碳原子。在本申请中，式(I)所示的化合物、式(II)所示的化合物、式(III)所示的化合物或式(IV)所示的化合物的碳-碳键可用实线，实心楔形或点状楔形表示。使用实线描绘与不对称碳原子的键表示包括该碳原子上的所有可能的立体异构体(例如特定对映异构体，外消旋混合物等)。本申请的化合物可能包含一个以上的不对称碳原子。在这些化合物中，使用实线表示与不对称碳原子的键意在表明所有可能的立体异构体均应包括在内。例如，除非另有说明，否则意指式(I)所示的化合物、式(II)所示的化合物、式(III)所示的化合物或式(IV)所示的化合物可以对映体和非对映体或作为外消旋体和混合物存在。表示使用实线描绘与式(I)所示的化合物、式(II)所示的化合物、式(III)所示的化合物或式(IV)所示的化合物中一个或多个不对称碳原子的键，以及使用实心或虚线楔形描述与同一化合物中其他不对称碳原子的键表明存在非对映异构体的混合物。
本申请的化合物可以以包合物或其他配合物的形式存在。在本发明的范围内包括复合物，例如包合物，药物-宿主包合复合物，其中与上述溶剂化物相反，药物和主体以化学计量或非化学计量的量存在。还包括式(I)所示的化合物、式(II)所示的化合物、式(III)所示的化合物或式(IV)所示的化合物的配合物，其含有两种或更多种可以化学计量或非化学计量的有机和/或无机组分。所得的络合物可以被电离，部分被电离或未被电离。
式(I)所示的化合物、式(II)所示的化合物、式(III)所示的化合物或式(IV)所示的化合物的立体异构体包括顺式和反式异构体，光学异构体，例如R和S对映异构体，非对映异构体，几何异构体，旋转异构体，构象异构体和互变异构体，式(I)所示的化合物、式(II)所示的化合物、式(III)所示的化合物或式(IV)所示的化合物包括表现出一种以上类型异构性的化合物；及其混合物(例如外消旋体和非对映体对)。还包括其中抗衡离子具有旋光性的酸加成盐或碱加成盐，例如D-乳酸酯或L-赖氨酸，或外消旋体，例如DL-酒石酸酯或DL-精氨酸。
当任何外消旋物结晶时，可能有两种不同类型的晶体。第一类是上述外消旋化合物(真正的外消旋体)，其中产生了一种均质形式的晶体，其中含有等摩尔量的两种对映异构体。第二类是外消旋混合物或团聚体，其中以等摩尔量产生两种形式的晶体，每种形式包含单个对映体。
式(I)所示的化合物、式(II)所示的化合物、式(III)所示的化合物或式(IV)所示的化合物可以表现出互变异构现象和结构异构现象。例如，式(I)化合物或式(I)化合物可以几种互变异构形式存在，包括烯醇和亚胺形式，以及酮和烯胺形式，以及几何异构体及其混合物。所有这些互变异构形式都包括在式(I)所示的化合物、式(II)所示的化合物、式(III)所示的化合物或式(IV)所示的化合物的范围内。互变异构体以互变异构体的混合物形式存在于溶液中。在固体形式中，通常一个互变异构体占主导。即使可以描述一个互变异构体，本发明也包括式(I)所示的化合物、式(II)所示的化合物、式(III)所示的化合物或式(IV)所示的化合物的所有互变异构体。
本发明还包括同位素标记的化合物，其与式(I)所示的化合物、式(II)所示的化合物、式(III)所示的化合物或式(IV)所示的化合物中所述相同，但其一个或多个原子被具有不同于自然界已发现的原子质量或质量数的原子取代。可加入式(I)所示的化合物、式(II)所示的化合物、式(III)所示的化合物或式(IV)所示的化合物化合物的同位素包括氢，碳，氮，氧，磷，氟和氯的同位素，例如但不限于：2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F,和36Cl。某些同位素标记的式(I)所示的化合物、式(II)所示的化合物、式(III)所示的化合物或式(IV)所示的化合物，例如其中加入放射性同位素(如3H和14C)，由于其易于制备和可检测性，可用于药物和/或底物组织分布测定。较重的同位素如2H，由于其较大的代谢稳定性，例如在体内半衰期延长或剂量要求降低，可以提供某些治疗上的优势。同位素标记的式(I)所示的化合物、式(II)所示的化合物、式(III)所示的化合物或式(IV)所示的化合物通常可通过用同位素标记的试剂代替非同位素标记的试剂制备。
本申请的化合物可以以衍生自无机或有机酸的盐的形式使用。某些化合物由于具有一种或多种盐的物理性质，具有如在不同温度和湿度下增强的药物稳定性，或在水/油中的所需溶解度的优势。在某些情况下，化合物的盐也可以用作化合物的分离，纯化和/或解析的助剂。
在本申请中，术语“药物前体”通常是指定化合物的前体，其在施用给受试者后，通过诸如溶剂分解或酶促裂解之类的化学或生理过程，或者在生理条件下，体内产生该化合物。“药物前体”通常是指无毒的、生物学上可耐受的，以及在生物学上适于施用给受试者的前药。选择和制备合适的药物前体衍生物的示例性方法在以下文献中有所描述：例如“Design of Prodrugs”，H.Bundgaard(编辑)，Elsevier，1985。
在本申请中，术语“非甾体抗炎药(NSAID)”通常是指一类具有解热镇痛效果的药物。大多数NSAID可以抑制环氧合酶(COX，例如，COX-1和COX-2)的活性，进而减少前列腺素和血栓素的合成。非甾体表示非糖皮质激素。在本申请中，所述胸苷衍生物和/或尿苷衍 生物可以包含NSAID部分，所述NSAID可以是常用的NSAID，例如，COX-1和/或COX-2抑制剂。所述NSAID部分可通过酯键与胸苷或尿苷连接。所述NSAID可包括但不限于吡唑烷类、水杨酸类、乙酸衍生物、昔康类、丙酸衍生物、洛芬类和/或芬那酸类。例如，所述NSAID可以包括氨基安替比林、阿扎丙酮、氯非宗、酮保泰松、非普拉酮、安乃近、单苯基保泰松、尼芬那宗、羟基保泰松、保泰松、安替比林、异安替比林、苯磺唑酮、琥保松、阿司匹林(乙酰水杨酸)、氧化铝缩乙酰水杨酸、贝诺酯、卡巴匹林钙、二氟苯水杨酸、双乙酰水杨酸、乙水杨胺、醋柳愈酯、水杨酸镁、水杨酸甲酯、双水杨酯、水杨苷、水杨酰胺、水杨酸钠、醋氯芬酸、阿西美辛、阿氯芬酸、氨芬酸、芐达酸、溴芬酸、布马地宗、丁苯羟酸、双氯芬酸钠、双苯哌醋胺、依托度酸、联苯乙酸、芬替酸、吲哚美辛、法呢吲哚美辛、酮咯酸、氯那唑酸、奥沙美辛、丙谷美辛、舒林酸、托美丁、佐美酸、安吡昔康、屈昔康、伊索昔康、氯诺昔康、美洛昔康、吡罗昔康、替诺昔康、阿明洛芬、苯恶洛芬、卡布洛芬、右旋布洛芬、右旋酮洛芬、芬布芬、苯氧布洛芬、氟诺洛芬、氟布洛芬、布洛芬、布洛新、吲哚布洛芬
Figure PCTCN2021127683-appb-000182
酮基布洛芬、洛索洛芬、咪洛芬、萘普生、奥沙普秦、吡洛芬、舒洛芬、达连福比、替泊沙林
Figure PCTCN2021127683-appb-000183
噻洛芬酸、维达洛芬、萘普西诺、阿扎丙酮、依托芬那酯、氟灭酸、氟胺烟酸、甲氯灭酸、甲芬那酸、吗尼氟酯、尼氟灭酸、托芬那酸、帕瑞昔布、塞来昔布、西咪考昔、地拉考昔、艾托考昔、非罗考昔、罗美昔布、吗瓦考昔、帕瑞考昔、罗贝考昔、罗非昔布、伐地考昔、氨基丙腈、芐达明、硫酸软骨素、双醋瑞因、氟丙喹宗、氨基葡萄糖、糖胺聚糖、水杨酸镁、萘丁美酮、尼美舒利、奥沙西罗、普罗喹宗、超氧化物歧化酶(奥古蛋白)和/或替尼达普。
发明详述
化疗药物
在本申请中，化疗药物可以治疗癌症。例如，所述化疗药物可以包括嘧啶核苷类似物或其前药。又例如，化疗药物可以包括可代谢形成氟尿苷核苷酸的药物。细胞中的氟尿苷核苷酸可以通过干扰正常的尿苷核苷酸代谢而引起细胞毒性。又例如，化疗药物可以包括选自下组中的一种或多种：卡培他滨、阿糖胞苷、多西他赛、阿霉素、氟尿嘧啶(5-FU)、氟尿苷、替加氟、伊达比星、紫杉醇、表柔比星、Acelarin(NUC-1031)、多柔比星、亚叶酸、顺铂、紫杉醇、环磷酰胺、长春新碱和5-FU药物前体(例如，喃氟啶和5’-脱氧氟尿苷、氟尿苷、2’-脱氧氟尿苷、氟尿苷的药物前体衍生物或2’-脱氧氟尿苷的药物前体衍生物、三氟-甲基-2’-脱氧尿苷、6-氮杂尿苷、3-脱氮杂尿苷)。
例如，化疗药物可以包括烷基化剂如氮芥、氮芥N-氧化物盐酸盐、苯丁酸氮芥、环磷酰 胺、异环磷酰胺、噻替派、异硫氰酸酯、白消安、盐酸尼莫司汀、米托溴铵、美法仑、达卡巴嗪、雷莫司汀、丙米酚磷酸钠、亚乙基三胺、卡莫司汀、洛莫司汀、链脲佐菌素、哌泊溴烷(pipobroman)、依托格鲁(ethoglucid)、卡铂、顺铂、米铂、奈达铂、替奈特胺、奥莫司汀、二氯吡啶、氟匹司坦、泼尼匹昔汀、嘌嘧替派(pumitepa)、盐酸苯达莫司汀(Ribomustin)、替莫唑胺、双氯芬酸、曲伐沙星、津诺他汀、辛伐他汀、青霉烯素、半胱胺亚硝脲(cystemustine)和比折来新(bizelesin)；抗代谢药物如巯嘌呤、6-巯基嘌呤核糖苷、硫代肌苷、甲氨蝶呤、培美曲塞、恩替西汀、阿糖胞苷、奥沙利铂、盐酸替沙巴汀、5-FU及其衍生物(例如，氟尿嘧啶、替加氟、UFT、多西葫芦、卡莫氟、卡培他滨等)、氨基喋呤、奈唑硫胺、甲酰四氢叶酸钙、小叶菌、叶酸钙、左派芬酸钙、克拉屈滨、埃米特福尔、氟达拉滨、吉西他滨、羟基脲、喷司他丁、吡曲克辛(piritrexim)、碘尿苷、米托胍酮、噻唑呋喃、维马司他和苯达莫司汀；抗肿瘤抗生素如放线菌素D、放线菌素C、丝裂霉素C、色霉素A3、博来霉素盐酸盐、硫酸博莱霉素、盐酸西替霉素、盐酸柔比星、盐酸米托蒽醌和盐酸伊达比星；和/或，依托泊苷、依托泊甙磷酸盐、硫酸长春碱、硫酸长春新碱、替尼泊苷、紫杉醇、多西他赛和长春瑞滨等植物来源的细胞毒抗癌药物。
例如，化疗药物可以是激素治疗抗癌剂，其可以包括夫司他丁、己烯雌酚、氯代木香烯、醋酸甲羟孕酮、乙酸甲地孕酮、乙酸环丙孕酮、醋酸环丙孕酮、丹那唑、烯丙雌醇、孕酮、美帕曲星(mepartricin)、雷洛昔芬或美洛昔芬、左旋氧氟沙星、抗雌激素(例如，他莫昔芬柠檬酸盐、托瑞米芬柠檬酸盐等)、避孕药、前列环烷烷、睾酮内酯、氨基丁二酰亚胺、LH-RH激动剂(例如，醋酸戈舍瑞林、布舍瑞林、亮丙瑞林等)、屈洛昔芬、表雄甾烷醇、炔雌醇磺酸酯、盐酸呋苯唑、阿那曲唑、来曲唑、依西美坦、伏罗唑、抗雄激素(例如，氟他胺、比卡鲁胺、尼鲁他胺等)、5α-还原酶抑制剂(例如，非那雄胺、爱普列特(Epristeride))、皮质类固醇(例如，地塞米松、泼尼松龙、倍他米松、曲安奈德等)和/或雄激素合成抑制剂(例如，阿比特龙等)。
例如，在某些情形中，化疗药物还可以是免疫治疗抗癌剂，其可以包括布比奈尼、克雷司汀、依托呋喃、香菇多糖、乌苯美辛、干扰素、白细胞介素、巨噬细胞集落刺激因子、粒细胞集落刺激因子、红细胞生成素、淋巴毒素、BCG疫苗、小棒状杆菌、依维莫司、左旋咪唑和/或多糖K等。
在本申请中，所述化疗药物可以与一种或多种其它疗法联合施用。例如，所述一种或多种其它疗法可以包括一种或多种其它抗肿瘤疗法。例如，其它抗肿瘤疗法也可以包括放射治疗或手术治疗。
在本申请中，在将化疗药物与其他抗肿瘤疗法组合使用的情况下，它们可以同时施用于受试者，或者以一定间隔分开施用。例如，所述其他抗肿瘤疗法可以是单一药剂的一部分，其与所述的化疗药物混合成为单一组合物。又例如，所述其他抗肿瘤疗法可以是单独的药剂，其与所述的化疗药物分别施用。在本申请中，如果所述其他抗肿瘤疗法与所述化疗药物作为单一组合物，所述化疗药物可以以相对于总剂量约1-99％(例如约5-95％、约1％、约5％、约10％、约20％、约30％、约40％、约50％、约60％、约70％、约80％、约90％、约95％或约99％)的剂量水平存在和/或被施用。
与施用化疗药物相关的疾病或病症
在本申请中，所述与施用化疗药物相关的疾病或病症可以与化疗药物的施用存在统计学上显著的相关性。在本申请中，所述与施用化疗药物相关的疾病或病症可以是由化疗药物的作用引起的。例如，所述与施用化疗药物相关的疾病或病症可以包括与施用化疗药物相关的皮肤组织疾病或病症、与施用化疗药物相关的造血组织疾病或病症、与施用化疗药物相关的四肢疾病或病症、与施用化疗药物相关的心脏疾病或病症、与施用化疗药物相关的神经系统疾病或病症、与施用化疗药物相关的五官疾病或病症和/或与施用化疗药物相关的胃肠道疾病或病症。
例如，所述与施用化疗药物相关的皮肤组织疾病或病症、四肢、五官疾病或病症和/或胃肠道疾病或病症可以包括皮肤、四肢、五官和/或胃肠道中与施用化疗药物相关的所述疾病或病症。例如，所述皮肤、四肢、五官和/或胃肠道中与施用化疗药物相关的上皮组织疾病或病症包括与内皮细胞病变相关的所述疾病或病症，和/或与上皮细胞病变相关的所述疾病或病症，且其中所述内皮细胞病变和/或上皮细胞病变与所述施用化疗药物相关。
例如，所述的内皮细胞可以包括血管内皮细胞。血管内皮细胞的病变可包括内皮功能障碍。例如，所述血管内皮细胞病变可以包括退行性变性血管疾病(例如，动脉粥样硬化、动脉中层硬化以及小动脉硬化(例如，透明变性型小动脉硬化和增生型小动脉硬化))、炎症性血管疾病(例如，感染性动脉炎、梅毒性动脉炎、巨细胞性动脉炎、血栓闭塞性脉管炎以及风湿性动脉炎)、功能性血管疾病(例如，雷诺氏病、手足发绀以及红斑肢痛症)和/或先天性血管疾病(例如，先天性动静脉瘘)等。
例如，所述的上皮细胞可以包括皮肤上皮细胞、口腔上皮细胞、鼻腔上皮细胞、胃上皮细胞和/或肠上皮细胞。例如，所述上皮细胞病变可以包括皮肤上皮细胞病变(例如，皮疹、痤疮、酒糟鼻、异位性皮炎、接触性皮炎、脂溢性皮炎、狼疮、硬皮病、天胞疮、色素沉淀、黑斑病、白癜风、荨麻疹、体癣、皮肤瘙痒、脱发、毛发改变、红斑、甲沟炎及甲裂、皮肤干 燥、超敏反应以及牛皮癣)、口腔上皮细胞病变(例如，天疱疮、唇疱疹、疱疹性口炎、肉芽肿性唇炎、口腔溃疡、类天疱疮、舍格林氏综合征、贝赫切特综合征以及口腔结节病等)、鼻腔上皮细胞病变(鼻衄、鼻窦炎、鼻疖以及鼻息肉等)、胃上皮细胞病变(例如，胃炎、肠化生、胃穿孔、胃瘘、胃溃疡以及胃肠道息肉)和/或小肠上皮细胞病变(例如，肠炎、克罗恩病、肠穿孔、肠瘘、肠溃疡、溃疡性结肠炎以及NSAIDs肠病)等。
例如，所述与施用化疗药物相关的皮肤组织疾病或病症可以包括因施用化疗药物而引起的副作用或不良反应。例如，所述与施用化疗药物相关的皮肤组织疾病或病症可以包括与施用化疗药物相关的皮疹、与施用化疗药物相关的手足综合征、与施用化疗药物相关的瘙痒、与施用化疗药物相关的红斑、与施用化疗药物相关的皮肤干燥、与施用化疗药物相关的脱发、与施用化疗药物相关的甲沟炎、与施用化疗药物相关的色素沉积紊乱、与施用化疗药物相关的口腔溃疡、与施用化疗药物相关的口干、与施用化疗药物相关的鼻衄、与施用化疗药物相关的鼻咽炎、与施用化疗药物相关的唇炎、与施用化疗药物相关的食管黏膜炎、与施用化疗药物相关的胃黏膜炎、与施用化疗药物相关的胃溃疡、与施用化疗药物相关的腹泻、与施用化疗药物相关的呕吐、与施用化疗药物相关的恶心、与施用化疗药物相关的厌食、与施用化疗药物相关的便秘、和/或与施用化疗药物相关的腹痛、与施用化疗药物相关的远端感觉异常、与施用化疗药物相关的肌肉收缩，和/或与施用化疗药物相关的四肢僵硬。
在本申请中，所述与施用化疗药物相关的皮肤组织疾病或病症、五官疾病或病症和/或胃肠道疾病或病症可以包括所述皮肤组织、五官和/或胃肠道中与施用化疗药物相关的上皮组织疾病或病症。
在本申请中，术语“皮肤组织疾病或病症”通常是指皮肤(包括毛发和甲)的形态、结构和/或功能发生的病理性变化。例如，所述皮肤组织疾病或病症可包括但不限于皮疹、手足综合征、瘙痒、红斑、皮肤干燥、脱发、甲沟炎、色素沉积紊乱等。
在本申请中，术语“皮疹”通常是指会影响皮肤颜色、外观或纹理的皮肤变化。皮疹可以仅局限在在身体的一部分，或影响整个皮肤。皮疹还包括荨麻疹。
在本申请中，术语“手足综合征”又称为Hand Foot Syndrome(HFS)，或Palmar Plantar Erythrodysesthesia(PPE)或Hand-foot skin reaction(HFSR)，其是由哈佛医学院新英格兰戴肯尼斯医院的Jacob Lokich和Cery Moor于1984年首次描述的。典型的临床表现呈进展性，临床主要表现为指(趾)热、痛、红斑性肿胀，严重者发展至脱屑、溃疡和剧烈疼痛等。HFS的病理表现主要包括，例如基底角质细胞空泡变性、皮肤血管周围淋巴细胞浸润、角质细胞凋亡和皮肤水肿等。例如，HFS可包括手掌、足底感觉迟钝或化疗引起的肢端红斑等。肿瘤 患者在接受化疗或者分子靶向治疗(如化疗药物)的过程中可能出现相应症状。
手足综合征(HFS)目前有多种分级方法，其中以美国国立癌症研究所(NCI)分级标准较为常用，该分级将手足综合征分为3级：1级为轻微的皮肤改变或皮炎伴感觉异常(如指纹消失、色素沉着、红斑、脱皮、感觉异常、感觉迟钝、皮肤麻木等)，但不影响日常活动；2级为皮肤改变同1级，并伴疼痛，轻度影响日常活动，皮肤表面完整；3级为溃疡性皮炎或皮肤改变伴剧烈疼痛，严重影响日常生活，具有明显的组织破坏，(如脱屑、水疱、出血、水肿等)。
此外，世界卫生组织(WHO)对HFS的分级则为4级：1级为手和脚感觉迟钝、感觉异常或刺痛感；2级为在持物和走路时的不舒适、无痛肿胀或红斑；3级为疼痛的红斑和水肿的手掌和脚底，甲周的红斑和肿胀；4级为脱皮、溃烂、起庖及剧烈的疼痛。
在本申请中，术语“胃肠道疾病或病症”通常是指胃或肠道组织(例如，从胃幽门至肛门的消化管组织)的形态、结构和/或功能发生的病理性变化。例如，所述胃肠道疾病或病症可包括但不限于腹泻(diarrhea)、呕吐(vomitting)、恶心(nausea)、厌食(anorexia)、便秘(constipation)和/或腹痛(abdominal pain)等。
例如，所述与施用化疗药物相关的造血系统疾病或病症可以包括与施用化疗药物相关的骨髓疾病或病症和与施用化疗药物相关的血液疾病或病症。例如，所述与施用化疗药物相关的造血组织疾病与病症可以包括与施用化疗药物相关的血液细胞增殖异常疾病或病症。例如，所述与施用化疗药物相关的造血系统疾病可以包括与施用化疗药物相关的白血病、与施用化疗药物相关的骨髓增殖性疾病、与施用化疗药物相关的骨髓抑制、与施用化疗药物相关的贫血、与施用化疗药物相关的白细胞减少、和/或与施用化疗药物相关的血小板减少。
在本申请中，所述与施用化疗药物相关的造血系统疾病可以是与施用化疗药物相关的血小板减少。在本申请中，术语“血小板减少”通常是指抗肿瘤化疗药物对骨髓巨核细胞产生抑制作用，导致的外周血中血小板计数低于100×10 9/L。参照常见不良反应术语标准5.0版(2017年11月)，血小板减少通常分为四级。其中，7.5x10 10/L-正常值下限为1级，5x10 10/L-7.5x10 10/L为2级，2.5x10 10/L-5x10 10/L为3级，小于2.5x10 10/L为4级。
在本申请中，术语“骨髓抑制”通常是指化疗药物在杀死大量肿瘤细胞的同时也可以杀死不少正常骨髓细胞的现象。在一些实施方式中，某些肿瘤病人在化疗中，随着化疗药物在体内累积量的增加，其骨髓抑制也逐渐加重。例如，骨髓抑制可包括但不限于白细胞减少。
在本申请中，术语“骨髓增殖性疾病”通常是指骨髓中生长的异常造血细胞引起的一组相关疾病。在一些情况下，这些细胞可能发生癌变，变成一种类型的白血病。随着化疗药物 的累积，贫血的发生率和严重程度会增加和加重。
参照美国国家癌症研究所(NCI)和世界卫生组织(WHO)贫血分级标准，同时结合中国国情，对肿瘤化疗相关贫血进行分级和贫血严重程度评估(正常值下限：男性120g/L；女性110g/L)，见表1。
表1肿瘤贫血严重程度分级(g/L)
血红蛋白 中国标准 NCI标准 WHO标准
0级(正常) >正常值下限 ≥正常值下限 ≥110
1级(轻度) 90～正常值下限 100～正常值下限 95～110
2级(中度) 60～90 80～100 80～95
3级(重度) 30～60 <80 65～80
4级(极重度) <30 威胁生命 <65
在本申请中，术语“贫血”通常是指人体外周血红细胞容量减少，低于正常范围下限的一种常见的临床症状。在一些实施方式中，化疗药物可通过阻断红系前体细胞的合成直接影响骨髓造血。
例如，所述与施用化疗药物相关的心脏疾病或病症可以包括心脏与施用化疗药物相关的所述疾病或病症。例如，所述与施用化疗药物相关的心脏疾病或病症可以包括与施用化疗药物相关的非特异性胸痛、与施用化疗药物相关的心绞痛、与施用化疗药物相关的心悸、与施用化疗药物相关的呼吸困难、与施用化疗药物相关的与施用化疗药物相关的弥漫性胸膜炎性胸痛、与施用化疗药物相关的室上性心率失常、与施用化疗药物相关的心肌梗死、与施用化疗药物相关的心动过缓、与施用化疗药物相关的心律失常、与施用化疗药物相关的室颤、与施用化疗药物相关的室性心动过速、与施用化疗药物相关的心肌炎、与施用化疗药物相关的心力衰竭、与施用化疗药物相关的心搏骤停和/或与施用化疗药物相关的心包炎。
在本申请中，所述化疗药物可用于治疗肿瘤。例如，所述疾病或病症的患处与肿瘤的患处不同。
在本申请中，所述与施用化疗药物相关的疾病或病症的严重程度可为依据NCI-CTCAE V5.0中的第1级或以上、第2级或以上、第3级或以上、第4级或以上，和/或第5级。
在施用所述化疗药物后，所述疾病或病症可能产生或加重。
胸苷衍生物和尿苷衍生物
本申请提供了一种胸苷衍生物在制备药物中的用途，所述药物用于预防或治疗受试者中 与施用化疗药物相关的疾病或病症，其中所述胸苷可以为胸苷的乙酰衍生物(例如，胸苷的一乙酰衍生物、胸苷的二乙酰衍生物或胸苷的三乙酰衍生物)。
在本申请中，所述胸苷衍生物可以包含式(I)所示的结构：
Figure PCTCN2021127683-appb-000184
其中，R 2、R 3、R 4、R 5和/或R 6可以为氢。
在本申请中，所述胸苷衍生物可以选自T1至T24中的任意一种或多种。
本申请提供了包含NSAID部分的胸苷衍生物在制备药物中的用途，其中，所述药物用于预防或治疗受试者中与施用化疗药物相关的疾病或病症(例如，手足综合征，或腹泻)
在本申请中，所述胸苷衍生物包含式(II)所示的结构：
Figure PCTCN2021127683-appb-000185
式(II)，其中，R 1和R 2中的至少一个包含非甾体抗炎药(NSAID)部分。例如，式(II)中的R 1包含NSAID部分。例如，式(II)中的R 2包含NSAID部分。当R 1和R 2中的一个包含非甾体抗炎药(NSAID)部分时，另一个可以为氢。
例如，式(II)中的R 1和R 2均包含NSAID部分，且可以包含相同或不同的NSAID部分。
在本申请中，所述NSAID部分可以包括但不限于吡唑烷类、水杨酸类、乙酸衍生物、昔康类、丙酸衍生物、洛芬类和/或芬那酸类。在本申请中，所述NSAID部分可以包含水杨酸或其衍生物、芳基乙酸或其衍生物、杂芳基乙酸或其衍生物、吲哚乙酸或其衍生物、茚乙酸或其衍生物、邻氨基苯甲酸或其衍生物和/或烯醇酸或其衍生物。所述NSAID可以通过酯键与胸苷连接。
例如，所述包含NSAID的胸苷衍生物可以选自T25至T50中的一种或多种。
在本申请中，所述胸苷衍生物可以和尿苷衍生物一起使用治疗受试者中与施用化疗药物 相关的疾病或病症。例如，所述疾病或病症可以是手足综合征或腹泻。
在本申请中，所述尿苷衍生物包含式(III)的结构：
Figure PCTCN2021127683-appb-000186
其中，当X 4和X 5均为氢时，X 1、X 2和X 3不同时为氢或不同时为CH 3CO–。例如，所述尿苷衍生物选自U1至U13中的一种或多种。
在本申请中，所述胸苷衍生物可以包含NSAID部分，例如，所述包含NSAID部分的胸苷衍生物可以包含式(IV)所示的化合物：
Figure PCTCN2021127683-appb-000187
其中，所述X 1、X 2和X 7中的至少一个包含非甾体抗炎药(NSAID)部分。例如，式(IV)中的X 1可以包含NSAID部分。例如，式(II)中的X 2包含NSAID部分。当X 1和X 2中的一个包含非甾体抗炎药(NSAID)部分涉及，另一个可以为氢。
例如，式(IV)中的X 1和X 2均包含NSAID部分，且可以包含相同或不同的NSAID部分。
在本申请中，所述NSAID部分可以包括但不限于吡唑烷类、水杨酸类、乙酸衍生物、昔康类、丙酸衍生物、洛芬类和/或芬那酸类。在本申请中，所述NSAID部分可以包含水杨酸或其衍生物、芳基乙酸或其衍生物、杂芳基乙酸或其衍生物、吲哚乙酸或其衍生物、茚乙酸或其衍生物、邻氨基苯甲酸或其衍生物和/或烯醇酸或其衍生物。所述NSAID可以通过酯键与胸苷连接。
例如，所述包含NSAID的尿苷衍生物可以选自U14至U21中的一种或多种。
在本申请中，所述包含NSAID的胸苷衍生物和所述包含NSAID的尿苷衍生物可以用于预防或治疗受试者中与施用化疗药物相关的疾病或病症(例如，手足综合征和/或腹泻)。
预防和/或治疗疾病的方法及相关用途
一方面，本申请提供了一种胸苷衍生物在制备药物中的用途，所述药物用于预防或治疗受试者中与施用化疗药物相关的疾病或病症(例如，腹泻或手足综合征)。例如，所述胸苷衍生物可包含本文中式(I)所示的化合物。例如，所述胸苷衍生物可包含本文中的化合物T1至T24。例如，所述胸苷衍生物可包含本文中式(II)所示的化合物。例如，所述胸苷衍生物可包含本文中的化合物T25至T50。
另一方面，本申请提供了一种胸苷衍生物和尿苷衍生物在制备药物中的用途，所述药物用于预防或治疗受试者中与施用化疗药物相关的疾病或病症。例如，所述胸苷衍生物可包含本文中式(I)所示的化合物，且所述胸苷衍生物可包含本文中式(III)所示的化合物。例如，所述胸苷衍生物可包含本文中的化合物T1至T24，且所述胸苷衍生物可包含化合物U1至U13。例如，所述胸苷衍生物可包含本文中式(II)所示的化合物，且所述胸苷衍生物可包含本文中式(IV)所示的化合物。例如，所述胸苷衍生物可包含本文中的化合物T25至T50，且所述胸苷衍生物可包含化合物U14至U21。
在本申请中，所述胸苷衍生物和/或尿苷衍生物可以用于预防或治疗化疗药物引起的手足综合征。例如，所述胸苷衍生物和/或尿苷衍生物可用于5-FU或5-FU前药引起的手足综合征。例如，所述胸苷衍生物和/或尿苷衍生物可用于预防或治疗卡培他滨或5-FU引起的手足综合征。在本申请中，所述胸苷衍生物和/或尿苷衍生物可以用于预防或治疗化疗药物引起的腹泻。例如，所述胸苷衍生物和/或尿苷衍生物可用于5-FU或5-FU前药引起的腹泻。例如，所述胸苷衍生物和/或尿苷衍生物可以预防或治疗5-FU引起的腹泻。
在本申请中，所述胸苷衍生物和/或尿苷衍生物可以包含NSAID部分，包含NSAID部分的胸苷衍生物和/或尿苷衍生物可以缓解、治疗和/或预防嘧啶核苷类似物或其前药(例如，5-FU或卡培他滨)，和不包含NSAID的胸苷衍生物和/或尿苷衍生物相比，能够同时减轻受试者疼痛和炎症反应，说明保留了尿苷和/或胸苷部分和NSAID部分的双重效果，具有协同效果。
在本申请中，所述药物可以被制备为适用于外用或口服给药。例如，所述局部给药的给药部位可以不为癌症的发生部位或癌症的潜在转移部位。例如，所述给药部分可以不为癌症的原发部位。又例如，所述给药部分可以不为癌症的转移部位。例如，所述转移部位可以包括淋巴转移、血管转移和/或种植性转移导致的癌症转移的发生部位。例如，所述转移部位可以包括骨、脑、肝、胃和/或肺。又例如，所述给药部分可以不为癌症的复发部位。在本申请的所述药物中，所述胸苷衍生物的浓度可以为约0.0001％(w/w)至约50％(w/w)，例如，可以在约0.0001％(w/w)至约10％(w/w)、约0.0001％(w/w)至约9.5％(w/w)、约0.0001％ (w/w)至约9％(w/w)、约0.0001％(w/w)至约8.5％(w/w)、约0.0001％(w/w)至约8％(w/w)、约0.0001％(w/w)至约7.5％(w/w)、约0.0001％(w/w)至约7％(w/w)、约0.0001％(w/w)至约6.5％(w/w)、约0.0001％(w/w)至约6％(w/w)、约0.0001％(w/w)至约5.5％(w/w)、约0.0001％(w/w)至约5％(w/w)、约0.0001％(w/w)至约4.5％(w/w)、约0.0001％(w/w)至约4％(w/w)、约0.0001％(w/w)至约3.5％(w/w)、约0.0001％(w/w)至约3％(w/w)、约0.0001％(w/w)至约2.5％(w/w)、约0.0001％(w/w)至约2％(w/w)、约0.0001％(w/w)至约1.5％(w/w)、约0.0001％(w/w)至约1％(w/w)、约0.0001％(w/w)至约0.5％(w/w)、约0.0001％(w/w)至约0.01％(w/w)或更小的范围内变动。在本申请的所述药物中，所述胸苷衍生物的浓度可以为约0.0001％(w/w)至约1％(w/w)、约0.0001％(w/w)至约0.9％(w/w)、约0.0001％(w/w)至约0.6％(w/w)、约0.05％(w/w)至约0.5％(w/w)、约0.05％(w/w)至约0.4％(w/w)、约0.05％(w/w)至约0.3％(w/w)、约0.05％(w/w)至约0.2％(w/w)、约0.1％(w/w)至约0.2％(w/w)或更小的范围内变动。例如，所述胸苷衍生物的浓度可以为约0.2％(w/w)。或者，所述胸苷衍生物的浓度可以为约0.1％(w/w)。
在本申请中，包含所述胸苷衍生物和/或尿苷衍生物的所述药物可基本上不影响所述化疗药物的治疗效果。例如，施用包含所述胸苷衍生物和/或尿苷衍生物的所述药物基本上不会使得需要增加施用所述化疗药物的剂量，以达到基本上相同的治疗效果。
例如，所述药物可以被制备为适用于口服给药。
在本申请中，所述药物为口服制剂。口服制剂可以包括但不限于，胶囊、囊剂、药丸、片剂、锭剂(用于味道的基底，通常是蔗糖和阿拉伯胶或黄芪胶)、粉末、颗粒剂、水或非水溶液或悬浮液、油包水或水包油的乳剂、酏剂或糖浆、糖果锭剂(适用惰性基质，如白明胶、甘油、蔗糖或者阿拉伯胶)和/或漱口药及其类似物。
口服的固体制剂(例如，胶囊、片剂、丸剂、糖衣丸、粉末或颗粒等)中可以包括所述的活性物质与一种或多种药学上可接受的辅料，如柠檬酸钠或磷酸二钙，和/或以下物质：(1)填料或者补充剂，例如淀粉、乳糖、蔗糖、葡萄糖、甘露糖醇和/或硅酸；(2)粘合剂，例如羧甲基纤维素、藻朊酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和/或阿拉伯胶；(3)湿润剂，例如丙三醇；(4)分裂剂，例如琼脂、碳酸钙、马铃薯或者木薯淀粉、海藻酸、某些硅酸盐和/或碳酸钠；(5)阻滞剂溶液，例如石蜡；(6)加速吸收剂，例如季铵化合物；(7)润滑剂，例如乙酰醇和/或单硬脂酸甘油酯；(8)吸收剂，例如高岭土和/或皂土；(9)助流剂，例如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠及其混合物；与(10)着色剂。
口服的液体制剂可以包括药学可接受的乳剂、微乳剂、溶液剂、悬浮剂、糖浆剂和酏剂 等。除了活性物质之外，液体剂型还可以含有常用的惰性稀释剂，例如，水或其他溶剂、增溶剂和乳化剂，如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯(甲)酸苄酯、丙二醇、1,3-丁二醇、油类(特别地，棉籽油、花生油、玉米油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇和脂肪酸山梨醇酯、以及以上两种或多种的混合物。除了惰性稀释液之外，口服的液体制剂也可以添加佐剂例如，润湿剂、乳化剂、悬浮剂、甜味剂、调味剂、颜料、香料或防腐剂。
例如，所述药物可以被制备为适用于外用给药。
例如，所述药物可以被制备为适于局部皮肤施用。例如，所述药物可以为软膏剂，洗剂或霜剂。
在本申请中，所述药物中可以进一步包含一种或多种活性成分。例如，所述活性成分可以指具有医疗效用或者生理活性的单体化合物。例如，所述其他活性成分可以选自下组：抗炎剂、止痛剂、局部麻醉剂、抗生素、抗组胺剂、防腐剂、免疫抑制剂和抗出血剂。
在本申请中，所述药物还可以包括药学上可接受的载体。例如，所述药学上可接受的载体可以选自下组：填充剂、粘合剂、崩解剂、缓冲液、防腐剂、润滑剂、搅味剂、增稠剂、着色剂和乳化剂。
在本申请中，所述受试者可以包含癌症患者。
在本申请中，所述受试者曾经、正在和/或将来可以被施用所述化疗药物。
在本申请中，所述受试者可以患有或易患有所述与施用所述化疗药物相关的疾病或病症。
在本申请中，所述疾病或病症的严重程度可以在施用所述化疗药物之后增加。
在本申请中，在施用所述化疗药物之前，所述受试者未患有所述疾病或病症。
在本申请中，所述胸苷衍生物的给药剂量可以为约0.0001μM至约1500μM，例如，约0.001μM至约1500μM，约1μM至约1500μM，约1μM至约500μM，约1μM至约100μM，约30μM至约900μM，约10μM至约1000μM，约10μM至约500μM。
在本申请中，所述尿苷衍生物的给药剂量可以为约0.0001μM至约1500μM，例如，约0.001μM至约1500μM，约1μM至约1500μM，约1μM至约500μM，约1μM至约100μM，约30μM至约900μM，约10μM至约1000μM，约10μM至约500μM。
在本申请中，所述胸苷衍生物和尿苷衍生物的给药剂量可以为约0.0001μM至约1500μM，例如，约0.001μM至约1500μM，约1μM至约1500μM，约1μM至约500μM，约1μM至约100μM，约30μM至约900μM，约10μM至约1000μM，约10μM至约500μM。
在本申请中，在所述药物中，所述胸苷衍生物的浓度与所述尿苷衍生物的浓度比例为约 1：10至约10：1，例如，约1：8至约8：1，约1：6至约6：1，约1：4至约4：1，约1：2至约2：1。例如，所述T1至T24的化合物的浓度与所述U1至U13的化合物的浓度比例为约1：10，约1：8，约1：6，约1：4，约1：2，约2：1，约4：1，约6：1，约8：1或约10：1。
在本申请中，在所述方法中，所述胸苷衍生物的给药剂量与所述尿苷衍生物的给药剂量的比例为约1：10至约10：1，例如，约1：8至约8：1，约1：6至约6：1，约1：4至约4：1，约1：2至约2：1。例如，所述T1至T24的化合物的浓度与所述U1至U13的化合物的浓度比例为约1：10，约1：8，约1：6，约1：4，约1：2，约2：1，约4：1，约6：1，约8：1或约10：1。
另一方面，本申请提供了T1至T24的化合物治疗和/或预防与施用化疗药物相关的手足综合征的方法，所述化合物为外用。例如，所述化疗药物为5-FU或卡培他滨。例如，所述T1至T24的化合物的给药浓度为约0.5％(wt％)至约5.0％(wt％)，或约0.5％(wt％)至约2.0％(wt％)。
另一方面，本申请提供了T1至T24的化合物治疗和/或预防与施用化疗药物相关的手足综合征的方法，所述化合物为外用。例如，所述化疗药物为5-FU或卡培他滨。例如，所述T1至T24的化合物的给药浓度为约1μM至约1000μM，约10μM至约1000μM，约30μM至约500μM，约1μM至约10μM，约1μM至约100μM，约1μM至约200μM或约10μM至约500μM。
另一方面，本申请提供了T1至T24的化合物治疗和/或预防与施用化疗药物相关的腹泻的方法，所述化合物为口服施用。例如，所述化疗药物为5-FU或卡培他滨。例如，所述T1至T24的化合物的给药浓度为约30mpk至约150mpk。
另一方面，本申请提供了T1至T24的化合物和U1至U13的化合物联用治疗和/或预防与施用化疗药物相关的手足综合征的方法，所述化合物为外用。例如，所述化疗药物为5-FU或卡培他滨。例如，所述T1至T24的化合物的浓度与所述U1至U13的化合物的浓度比例为约1：10至约10：1，例如，约1：8至约8：1，约1：6至约6：1，约1：4至约4：1，约1：2至约2：1。例如，所述T1至T24的化合物的浓度与所述U1至U13的化合物的浓度比例为约1：10，约1：8，约1：6，约1：4，约1：2，约2：1，约4：1，约6：1，约8：1或约10：1。
另一方面，本申请提供了T1至T24的化合物和U1至U13的化合物联用治疗和/或预防与施用化疗药物相关的手足综合征的方法，所述化合物为外用。例如，所述化疗药物为5-FU 或卡培他滨。例如，所述T1至T24的化合物的给药浓度为约0.5％(wt％)至约5.0％(wt％)，所述U1至U13的化合物的给药浓度为约0.5％(wt％)至约5.0％(wt％)，且浓度比为1：10至约10：1。例如，所述T1至T24的化合物的给药浓度为约1.0％(wt％)至约5.0％(wt％)，所述U1至U13的化合物的给药浓度为约1.0％(wt％)至约5.0％(wt％)，且浓度比为1：10至约10：1。
另一方面，本申请提供了T1至T24的化合物和U1至U13的化合物联用治疗和/或预防与施用化疗药物相关的手足综合征或腹泻的方法，所述化合物为口服施用。例如，所述化疗药物为5-FU或卡培他滨。例如，所述T1至T24的化合物的给药浓度为约100mpk至约300mpk，所述U1至U13的化合物的给药浓度约200mpk至约300mpk，且浓度比为1：3至约3：1。
另一方面，本申请提供了T1至T24的化合物和U1至U13的化合物联用治疗和/或预防与施用化疗药物相关的腹泻的方法，所述化合物为口服施用。例如，所述化疗药物为5-FU或卡培他滨。例如，所述T1至T24的化合物的给药浓度为约30mpk至约150mpk，所述U1至U13的化合物的给药浓度约1mpk至约50mpk，且浓度比为1：3至约3：1。
另一方面，本申请提供了T1至T24的化合物和U1至U13的化合物联用治疗和/或预防与施用化疗药物相关的手足综合征的方法，所述化合物为口服施用。例如，所述化疗药物为5-FU或卡培他滨。例如，所述T1至T24的化合物的给药浓度为约30mpk至约150mpk，所述U1至U13的化合物的给药浓度约1mpk至约50mpk，且浓度比为1：1至约2：1。
另一方面，本申请提供了T25至T50的化合物治疗和/或预防与施用化疗药物相关的手足综合征的方法，所述化合物为外用。例如，所述化疗药物为5-FU或卡培他滨。例如，T25至T50的化合物的浓度为约0.5μM至约12.5μM，约0.5μM至约50μM，0.5μM至约100μM，3μM至约100μM，10μM至约100μM，5μM至约200μM，2μM至约1000μM，或5μM至约500μM。
另一方面，本申请提供了T25至T50的化合物治疗和/或预防与施用化疗药物相关的手足综合征的方法，所述化合物为外用。例如，所述化疗药物为5-FU或卡培他滨。例如，所述T25至T50的化合物的给药浓度为约0.01％(wt％)至约5.0％(wt％)。例如，所述T25至T50的化合物的给药浓度为约0.1％(wt％)至约5.0％(wt％)。例如，所述T25至T50的化合物的给药浓度为约1.01％(wt％)至约5.0％(wt％)。例如，所述T25至T50的化合物的给药浓度为约3.0％(wt％)至约5.0％(wt％)。例如，所述T25至T50的化合物的给药浓度为约1.0(wt％)至约3.0％(wt％)。
另一方面，本申请提供了T25至T50的化合物治疗和/或预防与施用化疗药物相关的手足 综合征的方法，所述化合物为口服施用。例如，所述化疗药物为5-FU或卡培他滨。例如，所述T251至T50的化合物的给药浓度为约100mpk至约500mpk。例如，所述T251至T50的化合物的给药浓度为约200mpk至约300mpk。
另一方面，本申请提供了T25至T50的化合物治疗和/或预防与施用化疗药物相关的腹泻的方法，所述化合物为口服施用。例如，所述化疗药物为5-FU或卡培他滨。例如，所述T25至T50的化合物的给药浓度为约10mpk至约50mpk。例如，所述T25至T50的化合物的给药浓度为约1mpk至约100mpk。
另一方面，本申请提供了T25至T50的化合物和U14至U21的化合物联用治疗和/或预防与施用化疗药物相关的手足综合征的方法，所述化合物为外用。例如，所述化疗药物为5-FU或卡培他滨。例如，所述T25至T50的化合物的浓度与所述U14至U21的化合物的浓度比例为约1：10至约10：1，例如，约1：8至约8：1，约1：6至约6：1，约1：4至约4：1，约1：2至约2：1。例如，所述T1至T24的化合物的浓度与所述U1至U13的化合物的浓度比例为约1：10，约1：8，约1：6，约1：4，约1：2，约2：1，约4：1，约6：1，约8：1或约10：1。
另一方面，本申请提供了T25至T50的化合物和U14至U21的化合物联用治疗和/或预防与施用化疗药物相关的手足综合征的方法，所述化合物为口服施用。例如，所述化疗药物为5-FU或卡培他滨。例如，所述T25至T50的化合物的给药浓度为约0.5μM至约25μM，所述U14至U21的化合物的给药浓度为约0.5μM至约25μM，且T25至T50的化合物和U14至U21的化合物的浓度比为约1：10至约10：1。例如，所述T25至T50的化合物的给药浓度为约0.5μM至约15μM，所述U14至U21的化合物的给药浓度为约0.5μM至约15μM，且T25至T50的化合物和U14至U21的化合物的浓度比为约1：3至约3：1。
另一方面，本申请提供了T25至T50的化合物和U14至U21的化合物联用治疗和/或预防与施用化疗药物相关的手足综合征的方法，所述化合物为外用。例如，所述化疗药物为5-FU或卡培他滨。例如，所述T25至T50的化合物的给药浓度为约0.01％(wt％)至约5.0％(wt％)，所述U14至U21的化合物的给药浓度为约1％(wt％)至约5.0％(wt％)且T25至T50的化合物和U14至U21的化合物的浓度比为约1：3至约3：1。例如，所述化疗药物为5-FU或卡培他滨。例如，所述T25至T50的化合物的给药浓度为约1.0％(wt％)至约5.0％(wt％)，所述U14至U21的化合物的给药浓度为约1.0％(wt％)至约5.0％(wt％)，且T25至T50的化合物和U14至U21的化合物的浓度比为约1：3至约3：1。
另一方面，本申请提供了T25至T50的化合物和U14至U21的化合物联用治疗和/或预 防与施用化疗药物相关的手足综合征的方法，所述化合物为口服施用。例如，所述化疗药物为5-FU或卡培他滨。例如，所述T25至T50的化合物的给药浓度为约30mpk至约150mpk，所述U14至U21的化合物的给药浓度约1mpk至约100mpk，且T25至T50的化合物和U14至U21的化合物的浓度比为约1：3至约3：1。
另一方面，本申请提供了T25至T50的化合物和U14至U21的化合物联用治疗和/或预防与施用化疗药物相关的腹泻的方法，所述化合物为口服施用。例如，所述化疗药物为5-FU或卡培他滨。例如，所述T25至T50的化合物的给药浓度为约10mpk至约50mpk，所述U14至U21的化合物的给药浓度约1mpk至约100mpk，且T25至T50的化合物和U14至U21的化合物的浓度比为约1：3至约3：1。
另一方面，本申请提供了一种药物组合或试剂盒，其包含：1)所述的化疗药物；以及2)所述的胸苷衍生物和/或尿苷衍生物。
在本申请中，所述的药物组合或试剂盒中所述化疗药物与所述胸苷衍生物可以各自独立地存在于单独的容器中。
在本申请中，所述的药物组合或试剂盒中2)中的所述胸苷衍生物可以能够预防或治疗与施用1)中的所述化疗药物相关的疾病或病症。
在本申请中，所述的药物组合或试剂盒中2)中的所述胸苷衍生物基本上不影响1)中的所述化疗药物的治疗效果。
在本申请中，所述的药物组合或试剂盒中可以在施用1)的所述化疗药物之前、同时或者之后施用2)的所述胸苷衍生物。
另一方面，本申请提供了一种方法，其包含向受试者施用胸苷衍生物，其中所述受试者曾经、正在和/或将来被施用化疗药物且患有或易患有与施用所述化疗药物相关的疾病或病症。
在本申请中，所述受试者曾经、正在和/或将来可以被施用所述化疗药物。
在本申请中，所述受试者可以包括人或非人动物。例如，所述非人动物可以选自下组：猴、鸡、鹅、猫、狗、小鼠和大鼠。此外，非人动物也可以包括任何除人以外的动物物种，例如家畜动物，或啮齿类动物，或灵长类动物，或家养动物，或家禽动物。
例如，可以在向所述受试者施用所述化疗药物之前、同时或者之后施用所述胸苷衍生物和/或尿苷衍生物。在所述胸苷衍生物和/或尿苷衍生物与所述化疗药物间隔给药的实施方式中，所述胸苷衍生物和/或尿苷衍生物可以在施用所述化疗药物之前或之后间隔给药。所述间隔的时间可以为1分钟、2分钟、5分钟、10分钟、20分钟、30分钟、45分钟、1小时、2小时、3小时、4小时、5小时、6小时、12小时、18小时、1天、2天、3天、1周、2周、3周、1 个月、2个月、3个月或更长。
不欲被任何理论所限，下文中的实施例仅仅是为了阐释本申请的融合蛋白、制备方法和用途等，而不用于限制本申请发明的范围。
实施例
在本申请实施例的结果中，**表示P<0.01；*表示P<0.05；***表示P<0.001，利用t-test统计检验。
实施例1 T6(((2R,3S,5R)-3-(butyryloxy)-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methyl butyrate)的合成
Figure PCTCN2021127683-appb-000188
将尿苷胸苷(2.0g，8.26mmol)和三乙胺(1.67g，16.5mmol)溶解于10mL的二氯甲烷中，在0摄氏度下加入丁酰氯(1.76g，16.5mmol)。反应混合物在25摄氏度下搅拌2小时。TLC色谱显示反应完成。反应混合物加入到20ml的水和20ml的二氯甲烷中，萃取后，分出有机相。再用饱和食盐水洗涤(20ml)，无水硫酸钠干燥后，旋转蒸发得到粗品。粗产物通过反相HPLC纯化(柱：Xtimate C18 150×40mm×10um；流动相：水(0.225％FA)-ACN；B％：20-50；10min),得到产物T6(40.0mg,98.14％purity)。结构检测结果1H NMR(400MHz,DMSO-d6)δ11.34(br s,1H),7.40(d,1H,J＝7.6Hz),6.18(br t,1H,J＝6.8Hz),5.45(br s,1H),4.26(br d,2H,J＝3.6Hz),4.19(br s,1H),3.9-3.9(m,1H),3.60(td,1H,J＝7.2,10.9Hz),3.39(s,1H),2.5-2.6(m,1H),2.48(br s,1H),2.0-2.2(m,2H),1.7-1.8(m,4H),1.4-1.5(m,2H),0.7-0.9(m,6H).LCMS(M+H)+,383.0。
下列化合物合成方法和T6相似，结构检测结果如表2所示。
表2胸苷衍生物结构检测结果
Figure PCTCN2021127683-appb-000189
Figure PCTCN2021127683-appb-000190
Figure PCTCN2021127683-appb-000191
Figure PCTCN2021127683-appb-000192
Figure PCTCN2021127683-appb-000193
Figure PCTCN2021127683-appb-000194
实施例2-29胸苷衍生物或胸苷衍生物与尿苷衍生物联用缓解化疗药物对HaCaT细胞增殖毒性的效果
将培养的皮肤细胞HaCaT消化下来，计数，接种到96孔板中，每孔种植5000～10000个细胞。培养24h后，将各孔分成空白溶剂对照组、5-FU组、5-FU+胸苷衍生物组、5-FU+胸苷衍生物与尿苷衍生物联合给药组。5-FU组：加1μL的5-FU溶液(最终浓度如表3所示，5-FU溶液均为DMSO溶液)；5-FU+胸苷衍生物组：加入5-FU溶液和胸苷衍生物溶液(5-FU和胸苷衍生物的最终浓度如表3所示，除thymidine为水溶液之外，胸苷衍生物的溶液均为DMSO溶液)；5-FU+胸苷衍生物与尿苷衍生物联合给药组：加入5-FU溶液和胸苷衍生物 与尿苷衍生物混合溶液(5-FU和胸苷衍生物+尿苷衍生物混合溶液的最终浓度如表3所示，除thymidine为水溶液之外，胸苷衍生物+尿苷衍生物混合溶液均为DMSO溶液)；空白溶剂对照组：加入与对应的5-FU组或5-FU+胸苷衍生物(或胸苷衍生物+尿苷衍生物混合溶液)组等体积相同种类的溶液。空白溶剂对照组作为对照，从而排除5-FU组和5-FU+胸苷衍生物(或胸苷衍生物+尿苷衍生物混合溶液)组中溶剂对结果的影响。继续培养48小时后，使用Cell Counting Kit-8(CCK-8)检测试剂盒(C0037，购自上海碧云天生物科技有限公司)测定细胞的存活率，从而计算5-FU对细胞的增殖毒性以及胸苷衍生物(或胸苷衍生物+尿苷衍生物混合溶液)对增殖毒性的缓解作用。使用GraphPad Prism 6.0软件、t检验对结果进行统计分析和画图。
表3列出了5-FU和胸苷衍生物(或胸苷衍生物+尿苷衍生物混合溶液)的组合，以及相应的实验结果(其中，细胞存活率栏的数据表示与5-FU组相比，相应的5-FU+胸苷衍生物组或5-FU+胸苷衍生物与尿苷衍生物联合给药组所增加的存活细胞的百分比)。图3-10列出了几种代表性化合物的实验结果。
表3实施例2-29的实验条件和实验结果
Figure PCTCN2021127683-appb-000195
Figure PCTCN2021127683-appb-000196
Figure PCTCN2021127683-appb-000197
Figure PCTCN2021127683-appb-000198
Figure PCTCN2021127683-appb-000199
Figure PCTCN2021127683-appb-000200
从表3可以看出，氟类药物对皮肤细胞HaCaT具有一定的增殖毒性，而胸苷衍生物或胸苷衍生物与尿苷衍生物联用对氟类药物引起的增殖毒性有明显的缓解作用；加入胸苷衍生物或胸苷衍生物与尿苷衍生物联用后，细胞存活率有增加，同时相对胸苷也有一定的优势。
实施例30-40胸苷衍生物或胸苷衍生物与尿苷衍生物联用能够在大鼠模型上预防/治疗化疗药物引起的手足综合征
构建大鼠动物模型。通过每日灌胃的方式给予6周雌性SD大鼠卡培他滨，若干天后，大鼠的爪部出现手足综合症(照片如图11所示)。两爪出现手足综合症的程度相似，没有左右爪的差异。与在人体上类似，大鼠在口服卡培他滨之后爪部会产生手足综合症。两者病因完全相同，而病症也非常相似。因此，大鼠是非常好的用于模拟卡培他滨引起的手足综合症的动物模型。
SD大鼠饲养适应一周(约200g)后，将大鼠分成每组10只，然后进行灌胃给药试验。卡培他滨溶解在蓖麻油：乙醇＝1:1的混合溶液中，用PBS缓冲溶液稀释三倍，每只鼠灌胃量1mL/100g，给药剂量如表4所示。灌胃后，用固定筒将大鼠固定，对涂药组大鼠的双后爪(约 1cm*3cm)涂抹胸苷衍生物(或胸苷衍生物与尿苷衍生物复方凝胶)的凝胶(种类和浓度如表4所示)，空白组涂抹空白凝胶(做空白对照)；涂药后约4小时，4小时后放出大鼠，并用清水擦去涂药部位残留药物，放回鼠笼。卡培他滨的灌胃频率如表4所示，胸苷衍生物凝胶(或胸苷衍生物与尿苷衍生物复方凝胶)每天伴随灌胃进行涂药。每日重复灌胃和涂抹试验，直到空白组出现明显的手足综合症，此时将涂药组爪部皮肤保持正常或症状明显轻于空白组手足综合症的大鼠只数计算为有效抑制手足综合症大鼠的只数。
表4列出了卡培他滨和胸苷衍生物凝胶(或胸苷衍生物与尿苷衍生物复方凝胶)的动物实验组合，以及相应的实验结果(其中，控制率栏的数值＝空白组手足综合症出模率－涂药组手足综合症出模率)。
表4实施例30-40的实验条件和实验结果
Figure PCTCN2021127683-appb-000201
从结果可以看出(表4和图12)，不同浓度或不同种类的胸苷衍生物或胸苷衍生物与尿苷衍生物联用复方均可在一定程度上对手足综合症有一定的缓解作用。
实施例41-52胸苷衍生物或胸苷衍生物与尿苷衍生物联用能够在小鼠模型上预防/治疗化疗药物引起的手足综合征
构建小鼠动物模型。通过每日灌胃的方式给予6周雄性Balb/c小鼠卡培他滨，若干天后， 小鼠的爪子出现手足综合征症状(与大鼠模型结果类似，如图13)。与在人体上类似，小鼠在口服卡培他滨之后前爪和后爪会产生手足综合征。两者病因完全相同，而病症也非常相似。因此，小鼠是非常好的用于模拟卡培他滨引起的手足综合征的动物模型。
Balb/c小鼠饲养适应一周(约20g)后，将小鼠分成每组10只。进行灌胃给药试验。卡培他滨溶解在pH＝8的生理盐水中，每次灌胃剂量不超过0.3mL，给药剂量如表5所示。灌胃后，对空白软膏组的前爪和后爪(约4*0.5cm*0.5cm)涂抹空白凝胶，对给药组的前爪和后爪(约4*0.5cm*0.5cm)涂抹含不同药物的凝胶。涂药后用伊丽莎白圈将小鼠固定4小时，4小时后放出小鼠，并用清水擦去涂药部位残留药物，放回鼠笼。卡培他滨的灌胃频率如表5所示。每日重复灌胃和涂抹试验，直到空白对照组出现明显的手足综合征，此时将涂药组爪子保持正常或明显轻于非涂药组的小鼠只数计算为有效抑制手足综合征小鼠的只数。另通过口服给药胸苷衍生物及胸苷衍生物与尿苷衍生物联用，观察手足综合症的缓解情况。实施例41-48为涂抹胸苷衍生物和/或尿苷衍生物，实施例49-52为口服胸苷衍生物和/或尿苷衍生物。
表5列出了卡培他滨和胸苷衍生物(或胸苷衍生物与尿苷衍生物联用)的动物实验组合，以及相应的实验结果(其中，控制率栏的数值＝空白组手足综合症出模率－涂药组手足综合症出模率)。
表5实施例41-52的实验条件和实验结果
Figure PCTCN2021127683-appb-000202
Figure PCTCN2021127683-appb-000203
从结果可以看出(表5和图14)，不同浓度或不同种类的胸苷衍生物以及胸苷衍生物和尿苷衍生物联用均可在一定程度上对手足综合症有一定的缓解作用；同时口服胸苷衍生物及胸苷衍生物与尿苷衍生物联合给药，均可降低使用卡培他滨时的手足综合症的发生；同时实验中发现模型组中有部分实验鼠也出现甲沟炎等症状，而在口服给药组中未发现甲沟炎等其他严重皮肤副作用症状(非手足综合症)的出现。
实施例53-61胸苷衍生物或胸苷衍生物与尿苷衍生物联用对5-FU诱导的小鼠腹泻模型的缓解效果
通过腹腔注射的方式，给雄性Balb/c小鼠(7-8周，23-25g)注射70mg/kg/d，持续注射三天。空白组小鼠注射0.9％NaCl，通过观察腹泻等级变化、摄食量、体重变化来判断效果。腹泻的严重程度按以下标准评分，0：正常大便，1：软便，2：微湿软便，3：湿润、未成形大便，有中度的肛周染色，4：水样大便伴严重的肛周毛染色。以各腹泻发生率评分(0～4分)和平均腹泻评分评价腹泻的严重程度；最终发现建模后腹泻模型均在3级左右，模型稳定，符合实验需求。
将所述雄性Balb/c小鼠(7-8周，23-25g)饲养适应一周后，将其分组，每组10只，进行给药试验。将5-FU溶解在0.9％NaCl溶液中，模型组及治疗组的小鼠均腹腔注射给药量为70mg/kg/d，给药剂量如表6所示，三天后建模完成。在注射给药5-FU建模的同时，灌胃给 药胸苷衍生物或胸苷衍生物与尿苷衍生物联合给药，系列化合物用5％DMSO+1％HPMC的PBS溶液溶解。选用化合物的给药频率及给药剂量如表6所示，每天观察统计腹泻情况、摄食量、体重变化(Δ％BW)(表中体重变化记录的是第9日的数值)等信息，12天后试验结束，统计分析结果。
表6胸苷衍生物或胸苷衍生物与尿苷衍生物联合给药后小鼠腹泻情况、摄食量、存活数和体重变化(Δ％BW)统计表
Figure PCTCN2021127683-appb-000204
Δ％BW＝(BW(day0)-BW(day9))/BW(day0)，结果显示出腹泻、存活数、摄食量与体 重(BW)的均值±SEM，其中*P＜0.05，**P＜0.01，***P＜0.001；即治疗组大鼠与模型组大鼠进行比较。因为9天后会陆续出现动物死亡，导致数据不稳定，故选择9天进行体重变化分析。
从结果可以看出，胸苷衍生物单用或者胸苷衍生物和尿苷衍生物联合应用，均可有效地降低5-FU药物引起的腹泻等级，同时给药组小鼠的生存状态、摄食量也较模型组有明显改善；从数据可以看出，口服胸苷衍生物单药或胸苷衍生物及尿苷衍生物联用后，小鼠的体重变化也得到了明显的缓解。
在试验结束后，对5-FU对照组及实验组小鼠进行眼窦取血，进行血细胞计数，结果发现5-FU可以使检测到的血细胞都有所下降，而使用胸苷衍生物或者胸苷衍生物和尿苷衍生物联合治疗后，动物的嗜中性粒细胞、血小板等都显著高于5-FU单独给药组。
实施例62胸苷衍生物对卡培他滨治疗效果的影响
建立BALB/C裸鼠(人结肠癌细胞HCT116移植瘤)模型，模型稳定后，将模型鼠分成4组(4组鼠肿瘤大小平均值尽可能保持一致)，空白组(5只)除外，其他组每组10只，进行灌胃给药及涂抹药物实验。
卡培他滨溶解在蓖麻油:乙醇＝1:1(体积比)的混合溶液中，灌胃前用PBS定容至所需浓度(用PBS溶液稀释约3倍)，灌胃量不超过0.2mL，每周灌胃给药5天，给药剂量逐渐增加。除空白组外，其他三组带瘤鼠口服卡培他滨来控制或缩小肿瘤。同时通过透皮给药的方式，在小鼠背部涂抹衍生物为主要成分的凝胶，具体实施如下：
A空白组：带瘤鼠5只，不灌胃不涂药；B空白基质组：肿瘤鼠10只，口服灌胃卡培他滨(1.5mmol/kg)，背部涂空白凝胶(每天涂抹一次，连续涂抹14天)；C 0.5％T1凝胶组：肿瘤鼠10只，口服灌胃卡培他滨，涂0.5％T1凝胶(给药方式和频次同B组)；D 2％T1凝胶组：肿瘤鼠10只，口服灌胃卡培他滨，涂2％T1凝胶(给药方式和频次同B组)；用记号笔标记出约为5.8平方厘米涂抹面积，并且，该被涂抹的区域不能是小鼠嘴能触碰到的区域，也不能是紧挨着肿瘤的区域。B、C、D实验组在每日灌胃结束后，在模型鼠背部标定的区域，用棉签涂抹相应药膏，涂抹均匀，保证皮肤润湿即可；涂药后，每只老鼠在一个相对独立的空间中保持4小时，保证背部涂抹的药物透皮吸收；4小时后，用纸巾，或者沾水的纸巾轻轻擦去小鼠背部残留的药膏；然后小鼠可以回到之前饲养的笼子中正常活动。每2天测量并记录肿瘤的尺寸。实验14天结束后，解剖老鼠，取出肿瘤，称量并记录，观察不同实验组瘤体积变化情况。
从结果可知，B、C、D组(卡培他滨灌胃给药组)肿瘤组织的体积明显小于A组(卡培 他滨未灌胃给药组)；涂T1凝胶组(C、D组)肿瘤体积接近或略小于涂空白凝胶组(B组)。由此可见胸苷衍生物凝胶不会影响卡培他滨对肿瘤的治疗效果。
实施例63-90胸苷衍生物或胸苷衍生物与尿苷衍生物联用缓解化疗药物对HaCaT细胞增殖毒性的效果
按照实施例2-29的方法，检测胸苷衍生物，或胸苷衍生物与尿苷衍生物联用缓解化疗药物(5-FU)对HaCaT细胞增殖毒性的效果。测试的胸苷衍生物，或胸苷衍生物与尿苷衍生物联用方案，以及测试化合物的最终浓度请见表7。
表7列出了5-FU和胸苷衍生物(或胸苷衍生物+尿苷衍生物混合溶液)的组合，以及相应的实验结果(其中，细胞存活率栏的数据表示与5-FU组相比，相应的5-FU+胸苷衍生物组或5-FU+胸苷衍生物与尿苷衍生物联合给药组所增加的存活细胞的百分比)。图15-21列出了几种示例性化合物的实验结果。
表7实施例63-90的实验条件和实验结果
Figure PCTCN2021127683-appb-000205
Figure PCTCN2021127683-appb-000206
Figure PCTCN2021127683-appb-000207
Figure PCTCN2021127683-appb-000208
Figure PCTCN2021127683-appb-000209
Figure PCTCN2021127683-appb-000210
Figure PCTCN2021127683-appb-000211
从表7可以看出，氟类药物对皮肤细胞HaCaT具有一定的增殖毒性，而胸苷衍生物或胸苷衍生物与尿苷衍生物联用对氟类药物引起的增殖毒性有明显的缓解作用；加入胸苷衍生物或胸苷衍生物与尿苷衍生物联用后，细胞存活率有增加，同时相对胸苷也有一定的优势。包含NSAID的胸苷衍生物和尿苷衍生物仍具有缓解5-FU引起的细胞毒性的作用，且缓解效果好于不包含NSAID的胸苷衍生物和尿苷衍生物：相同浓度下，包含NSAID的胸苷衍生物和尿苷衍生物的细胞缓解率更高，或在较低浓度下即可达到较高缓解率。
实施例91-117胸苷衍生物或胸苷衍生物与尿苷衍生物联用能够在大鼠模型上预防/治疗化疗药物引起的手足综合征
按照实施例30-40的方法，检测胸苷衍生物，或胸苷衍生物与尿苷衍生物联用在化疗剂诱导手足综合征的大鼠模型上的效果。同时对给药治疗后的大鼠爪子进行取材，做苏木精-伊红染色(HE)及免疫组化染色(IHC)观察炎症情况。
测试的胸苷衍生物，或胸苷衍生物与尿苷衍生物联用方案，以及测试化合物的最终浓度请见表8。表8列出了化疗药物和胸苷衍生物凝胶(或胸苷衍生物与尿苷衍生物复方凝胶)的动物实验组合，以及相应的实验结果(其中，控制率栏的数值＝空白组手足综合症出模率－涂药组手足综合症出模率)。
表8实施例91-117的的实验条件和实验结果
Figure PCTCN2021127683-appb-000212
Figure PCTCN2021127683-appb-000213
从结果可以看出(表8)，不同浓度或不同种类的胸苷衍生物或胸苷衍生物与尿苷衍生物联用复方均可在一定程度上对手足综合症有一定的缓解作用，说明包含NSAID的胸苷衍生物和尿苷衍生物仍具有缓解化疗药诱导的手足综合征的效果。图22是有代表性的包含NSAID的胸苷衍生物和不包含NSAID的胸苷衍生物的一个染色结果图，结果显示，包含NSAID的胸苷衍生物(例如，T25至T50的化合物)、或包含NSAID的胸苷衍生物和包含NSAID的尿 苷衍生物联用改善大鼠爪子炎症的效果优于不包含NSAID的胸苷衍生物(例如，T1至T24的化合物)及对照的手足综合征模型组，说明包含NSAID的胸苷衍生物能够同时产生NSAID和胸苷衍生物的双重效果，在治疗及预防手足综合征方面优势更明显。
实施例118包含NSAID的胸苷衍生物和/或尿苷衍生物缓解化疗药物引起的手足综合征的疼痛
按照实施例91-115的方法，在4000mg/kg的卡培他滨构建的大鼠手足综合征模型给药胸苷衍生物(浓度为3％)，胸苷衍生物(浓度为1％)尿苷衍生物(浓度为3％)联用一段时间后，对大鼠进行疼痛分析，疼痛评估模型为大鼠的机械敏感性(von Frey)；实验步骤如下：首先让大鼠在房间内适应1小时，然后将大鼠放入带有金属网地板的观察箱中，让小鼠在箱中待20分钟，以适应实验平台的环境。然后用von Frey设备来检测爪子的疼痛情况，用特制的纤毛刺激大鼠掌心表面，以检测动物的机械敏感性，其力度为0.4克、0.8克、1.5克、2.5克、4克、8克、10克和20克(IITC Life Science，Woodland Hills，2390系列)。在被施以特定的压力后，大鼠立即抽出爪子或舔舐被定义为有反应，而在6秒内没有撤回爪子被定义为无反应。大鼠移动反应被认为是一种模糊的反应，在这种情况下会重复刺激实验。
结果如图23所示，不包含NSAID的胸苷衍生物(T1和T4，浓度均为3％)对大鼠的疼痛没有明显的改善；包含NSAID的胸苷衍生物(T25、T26、T27、T50、T36、T32、T37、T41、T45，浓度均为3％)以及包含NSAID的胸苷衍生物和包含NSAID的尿苷衍生物(T25+U14、T25+U16和T45+U20，浓度均为1％+3％)联用在大鼠疼痛上面能够明显改善。图23中，Cape4000表示4000mg/kg的卡培他滨，胸苷衍生物单用时浓度均为3％，胸苷衍生物与尿苷衍生物联用时，胸苷衍生物浓度为1％，尿苷衍生物浓度均为3％。
实施例119-123胸苷衍生物或胸苷衍生物与尿苷衍生物联用能够在小鼠模型上预防/治疗化疗药物引起的手足综合征
按照实施例41-52的方法，检测胸苷衍生物，或胸苷衍生物与尿苷衍生物联用在化疗药(卡培他滨)诱导手足综合征的小鼠模型上的效果。其中，实施例119-120为透皮给药，实施例121-123为口服给药。
测试的胸苷衍生物，或胸苷衍生物与尿苷衍生物联用方案，以及测试化合物的最终浓度请见表9。表9列出了卡培他滨和胸苷衍生物凝胶(或胸苷衍生物与尿苷衍生物复方凝胶)的动物实验组合，以及相应的实验结果(其中，控制率栏的数值＝空白组手足综合症出模率－涂药组手足综合症出模率)。
表9实施例119-123的实验条件和实验结果
Figure PCTCN2021127683-appb-000214
表9的结果显示，不同浓度或不同种类的胸苷衍生物或胸苷衍生物与尿苷衍生物联用复方均可在一定程度上对手足综合症有一定的缓解作用。
实施例124-131胸苷衍生物或胸苷衍生物与尿苷衍生物联用对5-FU诱导的小鼠腹泻模型的缓解效果
使用7-8周雄性Balb/c小鼠检测建立5-FU诱导腹泻模型，检测胸苷衍生物或胸苷衍生物与尿苷衍生物联用对腹泻的缓解效果。
5-Fu造模剂量：175mg/kg；单次给药，腹腔注射(ip.)；
待测试化合物(胸苷衍生物或胸苷衍生物与尿苷衍生物联用)的给药方式：单次给药，灌胃给药，于腹腔注射5-FU前各时间点提前给待测试化合物。5-FU给药前1h给药待测试化合物，然后1h时腹腔注射一定量的5-FU，注射5-FU后7h，再一次给药待测试化合物。
将所述小鼠饲养适应一周后，将其分组，每组10只，进行给药试验。
空白组小鼠注射0.9％NaCl，通过观察腹泻等级变化、摄食量、体重变化来判断效果。腹泻的严重程度按以下标准评分，0：正常大便，1：软便，2：微湿软便，3：湿润、未成形大便，有中度的肛周染色，4：水样大便伴严重的肛周毛染色。以各腹泻发生率评分(0～4分) 和平均腹泻评分评价腹泻的严重程度；最终发现建模后腹泻模型均在3级左右，模型稳定，符合实验需求。
将5-FU溶解在0.9％NaCl溶液中，模型组及治疗组的小鼠均腹腔注射给药量为175mg/kg/d，三天后建模完成。在注射给药5-FU建模的同时，灌胃给药胸苷衍生物或胸苷衍生物与尿苷衍生物联合给药，待测试化合物用5％DMSO+1％HPMC的PBS溶液溶解。选用化合物的给药频率及给药剂量如表10所示。每天称体重，统计体重变化(Δ％BW，表中体重变化记录的是第6日的数值)；每天称取食物重量，以计算摄食量。每天观察各小鼠的临床状态，例如活动、腹泻、毛发、打架情况等。6天后试验结束，统计分析结果。
表10胸苷衍生物或胸苷衍生物与尿苷衍生物联合给药后小鼠腹泻情况、摄食量、存活数和体重变化(Δ％BW)统计表
Figure PCTCN2021127683-appb-000215
Figure PCTCN2021127683-appb-000216
结果如表10和图24所示，图24中各组的化合物的浓度对应表10的浓度。从结果(表10和图25)可以看出，胸苷衍生物单用或者胸苷衍生物和尿苷衍生物联合应用，均可有效地降低5FU药物引起的腹泻等级，同时给药组小鼠的生存状态、摄食量和体重变化上也较未使用胸苷衍生物和/或胸苷衍生物的模型组有明显改善。
实施例132化合物制备
本实施例列举了T25至T50、U14至U21中代表性的几种化合物的制备方法，其他未列举的化合物制备采用相应的反应物，在相同的条件下制备。
(1)((2R，3S，5R)-3-羟基-5-(5-甲基-2,4-二氧基-3,4-二氢嘧啶-1(2H)-基)四氢呋喃-2-基)2-(3-苯氧基苯基)丙酸甲酯(T27)的合成
Figure PCTCN2021127683-appb-000217
向2-[3-(苯氧基)苯基]丙酸(0.5g,2.1mmol)的二氯甲烷(10mL)溶液中逐滴加入草酰氯(310mg,2.5mmol)。25℃下搅拌3小时。减压蒸馏除去溶剂得到黄色固体。0℃下向β-胸苷(1.0g,4.2mmol)的二氯甲烷(10mL)和吡啶(10mL)溶液中加入上述黄色固体，搅拌1小时。25℃搅拌12小时。旋蒸去除溶剂，加入水(50mL)，用乙酸乙酯(30mL*3)萃取。有机相收 集，无水硫酸钠干燥，过滤，旋蒸去除溶剂。硅胶柱层析(石油醚/乙酸乙酯＝5/1)后得到粗产物，进一步通过制备HPLC纯化得到化合物((2R，3S，5R)-3-羟基-5-(5-甲基-2,4-二氧基-3,4-二氢嘧啶-1(2H)-基)四氢呋喃-2-基)2-(3-苯氧基苯基)丙酸甲酯(192.9mg)。LCMS:MS(ESI)m/z[M+H] +＝476.2。 1H NMR(400MHz,DMSO-d 6)δ11.46–11.16(m,1H),7.43–7.27(m,4H),7.22-7.10(m,1H),7.04(t,J＝7.2Hz,1H),7.05-6.90(m,3H),6.96-6.80(m,1H),6.24-6.09(m,1H),4.28–4.13(m,3H),4.08–4.01(m,1H),3.94–3.80(m,3H),2.13–1.99(m,1H),1.75(d,J＝12.0Hz,3H),1.45-1.35(m,3H)。
(2)((2R，3S，4R，5R)-5-(2,4-二氧基-3,4-二氢嘧啶-1(2H)-基)-3,4-二羟基四氢呋喃-2-基)甲基-2-(6-甲氧基萘-2-基)丙酸酯(U14)
Figure PCTCN2021127683-appb-000218
第一步，1-((3aR，4R，6R，6aR)-6-(羟甲基)-2,2-二甲基四氢呋喃[3,4-d][1,3]二氧醇-4-基)嘧啶-2,4(1H，3H)-二酮的合成
0℃下向β-胸苷(750.0g,0.5mol,1.0eq)和对甲基苯磺酸(52.9g,51.2mmol,0.1eq)的丙酮(18.0L)溶液中加入2,2-二甲氧基丙烷(352.0g,563.0mmol,68.9mL,1.1eq)。混合物56℃下搅拌1小时。反应液冷却至室温，加入碳酸氢钠(46.4g,92.1mmol)，25℃下搅拌0.5小时。混合物减压浓缩，粗产物经硅胶柱层析(二氯甲烷/甲醇＝10/1)纯化得到1-[(3aR，4R，6R，6aR)-6-(羟甲基)-2,2-二甲基-3a，4,6,6a-四氢呋喃[3,4-d][1,3]二氧醇-4-基]嘧啶-2,4-二酮(800.0g).LC-MS:(M+H) +,284.9。
第二步，((3aR，4R，6R，6aR)-6-(2,4-二氧基-3,4-二氢嘧啶-1(2H)-基)-2,2-二甲基四氢呋喃[3,4-d][1,3]二氧基-4-基)甲基-2-(6-甲氧基萘-2-基)丙酸酯的合成
-30℃下向1-[(3aR，4R，6R，6aR)-6-(羟甲基)-2,2-二甲基-3a，4,6,6a-四氢呋喃[3,4-d][1,3]二氧醇-4-基]嘧啶-2,4-二酮(188g,662mmol,1.0eq)的吡啶(2.0L)溶液中逐滴加入(2S)-2-(6-甲氧基-2-萘基)丙酰氯(168g,676mmol,1.02eq)的二氯甲烷(500mL)溶液。反应液-30℃搅拌4小时，升温至25℃，加入水(10mL)淬灭，减压浓缩，粗产物加入乙酸乙酯(400mL)， 盐酸水溶液(200mL*3,1M)清洗，无水硫酸钠干燥，过滤，减压浓缩得到粗产物。醋酸异丙酯(4.0L)重结晶得到[(3aR，4R，6R，6aR)-4-(2,4-二氧嘧啶-1-基)-2,2-二甲基-3a，4,6,6a-四氢呋喃[3,4-d][1,3]二氧基-6-基]甲基(2S)-2-(6-甲氧基-2-萘基)丙酸酯(160g,96.4％purity)。
第三步，((2R，3S，4R，5R)-5-(2,4-二氧基-3,4-二氢嘧啶-1(2H)-基)-3,4-二羟基四氢呋喃-2-基)甲基-2-(6-甲氧基萘-2-基)丙酸酯的合成
25℃下，向[(3aR，4R，6R，6aR)-4-(2,4-二氧嘧啶-1-基)-2,2-二甲基-3a，4,6,6a-四氢呋喃[3,4-d][1,3]二氧基-6-基]甲基(2S)-2-(6-甲氧基-2-萘基)丙酸酯(150g,302mmol,1.0eq)的水(225mL)溶液中加入三氟乙酸(225mL)。25℃搅拌1小时。混合物加水(500mL)稀释后过滤得到固体粗产品。乙酸异丙酯重结晶得到(2R，3S，4R，5R)-5-(2,4-二氧基-3,4-二氢嘧啶-1(2H)-基)-3,4-二羟基四氢呋喃-2-基)甲基-2-(6-甲氧基萘-2-基)丙酸酯(95g,98.6％purity)。白色固体。LC-MS:(M+H) +,457.1。 1H 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)。
(3)2-乙基丁基((S)-(2R，3S，4R，5R)-5-(2,4-二氧基-3,4-二氢嘧啶-1(2H)-基)-3,4-二羟四氢呋喃-2-基)甲氧基)(苯氧基)磷酰基)-L-丙氨酸酯(U21)的合成
Figure PCTCN2021127683-appb-000219
第一步，1-((3aR，4R，6R，6aR)-6-(羟甲基)-2,2-二甲基四氢呋喃[3,4-d][1,3]二氧醇-4-基)嘧啶-2,4(1H，3H)-二酮的合成
在尿嘧啶-1-Β-D-呋喃核糖苷(1.0g,4.1mmol)的丙酮(50mL)溶液中逐滴加入硫酸(0.5mL)，25℃下搅拌1小时。反应液用三乙胺中和，浓缩得到粗产品，硅胶柱层析(二氯甲烷/甲醇＝10/1) 纯化得到1-((3aR，4R，6R，6aR)-6-(羟甲基)-2,2-二甲基四氢呋喃[3,4-d][1,3]二氧醇-4-基)嘧啶-2,4(1H，3H)-二酮(1.2g)。
第二步，2-乙基丁基((S)-(3aR，4R，6R，6aR)-6-(2,4-二氧基-3,4-二氢嘧啶-1(2H)-基)-2,2-二甲基四氢糠醛[3,4-d][1,3]二氧基-4-基)甲氧基)(苯氧基)磷酰基)-L-丙氨酸酯的合成
25℃下向N-[(S)-(2,3,4,5,6-五氟苯氧基)苯氧基磷酰基]-L-丙氨酸异丙酯(418mg,0.84mmol,1.2eq)和1-((3aR，4R，6R，6aR)-6-(羟甲基)-2,2-二甲基四氢呋喃[3,4-d][1,3]二氧醇-4-基)嘧啶-2,4(1H，3H)-二酮(200mg,0.70mmol,1.0eq)的乙腈(20mL)溶液中加入无水氯化镁(67mg,0.70mmol,1.0eq)。反应液50℃下搅拌十分钟，之后N,N-二甲基乙二胺(227mg,1.76mmol,2.5eq)逐滴滴入。反应液50℃下搅拌2小时。加入水(50mL)淬灭，乙酸乙酯(30mL*3)萃取。有机相用饱和食盐水(20mL)清洗，无水硫酸钠干燥，过滤，减压旋蒸除去溶剂，硅胶柱层析(二氯甲烷/甲醇＝10/1)纯化得到2-乙基丁基((S)-(3aR，4R，6R，6aR)-6-(2,4-二氧基-3,4-二氢嘧啶-1(2H)-基)-2,2-二甲基四氢糠醛[3,4-d][1,3]二氧基-4-基)甲氧基)(苯氧基)磷酰基)-L-丙氨酸酯(400mg)。
第三步，2-乙基丁基((S)-(2R，3S，4R，5R)-5-(2,4-二氧基-3,4-二氢嘧啶-1(2H)-基)-3,4-二羟四氢呋喃-2-基)甲氧基)(苯氧基)磷酰基)-L-丙氨酸酯
向2-乙基丁基((S)-(3aR，4R，6R，6aR)-6-(2,4-二氧基-3,4-二氢嘧啶-1(2H)-基)-2,2-二甲基四氢糠醛[3,4-d][1,3]二氧基-4-基)甲氧基)(苯氧基)磷酰基)-L-丙氨酸酯(400mg,67.2mmol,1.0eq)的水(1mL)中加入三氟乙酸(4mL)。反应液25℃搅拌2小时。之后反应液减压浓缩，通过制备HPLC纯化得到2-乙基丁基((S)-(2R，3S，4R，5R)-5-(2,4-二氧基-3,4-二氢嘧啶-1(2H)-基)-3,4-二羟四氢呋喃-2-基)甲氧基)(苯氧基)磷酰基)-L-丙氨酸酯(99.8mg)。LCMS:MS(ESI)m/z[M+H] +＝556.1。 1H NMR(400MHz,DMSO-d 6)δ11.36(d,J＝2.0Hz,1H),7.58(d,J＝8.0Hz,1H),7.48–7.32(m,2H),7.32-7.17(m,3H),6.22-6.00(m,1H),5.77(d,J＝6.0Hz,1H),5.59-5.48(m,1H),5.47(d,J＝6.0Hz,1H),5.37-5.10(m,1H),4.20(m,1H),4.10(m,1H),4.04–3.81(m,6H),1.45(m,1H),1.35–1.19(m,7H),0.82(t,J＝8.0Hz,6H)。
(4)2-乙基丁基((S)-(2R，3S，5R)-3-羟基-5-(5-甲基-2,4-二氧基-3,4-二氢嘧啶-1(2H)-基)四氢呋喃-2-基)甲氧基)(苯氧基)磷酰基)-L-丙氨酸酯(T48)和2-乙基丁基((S)-(2R，3S，5R)-2-(羟甲基)-5-(5-甲基-2,4-二氧基-3,4-二氢嘧啶-1(2H)-基)四氢呋喃-3-基)氧基)(苯氧基)磷酰基)-L-丙氨酸酯(T49)的合成
Figure PCTCN2021127683-appb-000220
0℃下向β-胸苷(200mg,0.82mmol,1.0eq)的DMF(10mL)溶液中缓慢加入叔丁基氯化酶(0.8mL,1M)。反应液0℃下搅拌0.5小时，室温搅拌30分钟。之后缓慢加入N-[(S)-(2,3,4,5,6-五氟苯氧基)苯氧基磷酰基]-L-丙氨酸异丙酯(409mg,0.83mmol,1.0eq)的DMF(1mL)溶液。反应液25℃下搅拌12小时。之后反应液用饱和氯化铵水溶液(30mL)淬灭，乙酸乙酯(20mL*3)萃取，有机相用饱和食盐水(10mL)清洗，无水硫酸钠干燥，过滤，减压浓缩得到粗产品。经制备HPLC和制备SFC得到2-乙基丁基((S)-(2R，3S，5R)-3-羟基-5-(5-甲基-2,4-二氧基-3,4-二氢嘧啶-1(2H)-基)四氢呋喃-2-基)甲氧基)(苯氧基)磷酰基)-L-丙氨酸酯(95.7mg)LCMS：MS(ESI)m/z＝554.3[M+H] + 。 1H NMR:(400MHz,DMSO-d 6)δ11.31(s,1H),7.49(t,J＝2.0Hz,1H),7.41–7.31(m,2H),7.30-7.17(m,3H),6.18(t,J＝8.0Hz,1H),6.10-5.97(M,1H),5.39(d,J＝4.0Hz,1H),4.30–4.14(m,2H),4.13–4.03(m,1H),4.00–3.77(m,4H),2.14–1.98(m,2H),1.78-1.70(M,3H),1.44(m,1H),1.34–1.18(m,7H),0.82(t,J＝8.0Hz,6H).
2-乙基丁基((S)-(2R，3S，5R)-2-(羟甲基)-5-(5-甲基-2,4-二氧基-3,4-二氢嘧啶-1(2H)-基)四氢呋喃-3-基)氧基)(苯氧基)磷酰基)-L-丙氨酸酯(57.0mg)。LCMS：MS(ESI)m/z＝554.3[M+H] + 。 1H NMR:(400MHz,DMSO-d 6)δ11.32(s,1H),7.71(dd,J＝5.2,1.2Hz,1H),7.38(t,J＝8.0Hz,2H),7.25–7.08(m,3H),6.22–6.04(m,2H),5.21(t,J＝5.2Hz,1H),4.98(t,J＝6.0Hz,1H),4.09–3.79(m,4H),3.66–3.54(m,2H),2.36–2.20(m,2H),1.77(d,J＝1.2Hz,3H),1.46(m,1H),1.36–1.19(m,7H),0.89–0.77(m,6H)。
各化合物的结构检测结果如表11所示。
表11衍生物结构检测结果
衍生物结构 Ms(M+H +) 衍生物结构 Ms(M+H +) 衍生物结构 Ms(M+H +)
T25 455.1 T38 582.1 U14 457.0
T26 540.2 T39 519.9 U15 471.1
T27 467.0 T40 581.1 U16 407.0
T28 469.0 T41 455.0 U17 484.1
T29 469.0 T42 455.0 U18 669.2
T30 431.2 T43 467.2 U19 719.1
T31 431.2 T44 431.1 U20 881.2
T32 431.2 T45 482.0 U21 556.2
T33 479.1 T46 691.2    
T34 480.1 T47 619.2    
T35 518.5 T48 554.1    
T36 482.0 T49 554.0    
T37 405.1 T50 479.1    

Claims (127)

  1. 胸苷衍生物在制备药物中的用途，所述药物用于预防或治疗受试者中与施用化疗药物相关的疾病或病症，其中所述胸苷衍生物在脱氧核糖上的至少一个羟基氢被取代。
  2. 根据权利要求1中所述的用途，其中所述胸苷衍生物包含式(I)的结构，或其药学上可接受的盐、溶剂、水合物、前药形式及其立体异构体：
    Figure PCTCN2021127683-appb-100001
    其中，R 2、R 3、R 4、R 5、R 6和R 7不同时为氢。
  3. 根据权利要求2所述的用途，其中，R 7为
    Figure PCTCN2021127683-appb-100002
  4. 根据权利要求2-3中任一项所述的用途，其中，R 6为氢。
  5. 根据权利要求2-3中任一项所述的用途，其中，R 6为
    Figure PCTCN2021127683-appb-100003
    其中所述R 6 1为C1至C6的烷基。
  6. 根据权利要求2-5中任一项所述的用途，其中，R 1，R 2和R 3中的任意一个独立地为
    Figure PCTCN2021127683-appb-100004
    其中，M 1为氧或硫，并且R 8包含选自下组的一中或多种基团：氢、取代或未取代的羟基、取代或未取代的巯基、取代或未取代的氨基、取代或未取代的C1至C5烷基、取代或未取代的C 1至C 5炔基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基，以及，取代或未取代的芳烷基；M 2为硅或碳，并且R 9包含选自下组的基团：氢、取代或未取代的羟基、取代或未取代的巯基、取代或未取代的氨基、取代或未取代的C1至C5烷基、取代或未取代的C1至C5炔基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基，以及，取代或未取代的芳烷基，
    R 9选自下组：C1至C5烷基、C1至C5的环烷基、苯基或苯甲基。
  7. 根据权利要求2-6中任一项所述的用途，其中R 1，R 2或R 3各自独立地选自下组：–(C＝O)–R 8 1、–(C＝O)–OR 8 2、–(C＝O)–NR 8 3R 8 4、–(C＝S)–R 8 5、–(C＝S)–OR 8 6和–(C＝S)–NR 8 7R 8 8，其中R 8 1、R 8 2、R 8 3、R 8 4、R 8 5、R 8 6、R 8 7和R 8 8中的任意一个独立地选自氢、取代或未取代的烷基、取代或未取代的炔基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基以及取代或未取代的杂芳基。
  8. 根据权利要求7所述的用途，其中R 8 1、R 8 2、R 8 3、R 8 4、R 8 5、R 8 6、R 8 7和R 8 8中的任意一个独立地选自氢、C1至C5烷基、C1至C5的环烷基、C1至C5的杂环烷基、苯基和苯甲基。
  9. 根据权利要求7-8中任一项所述的用途，其中R 8 1选自下组：甲基、乙基、丙基、丁基、环戊烷基、环丙烷基和苯甲基。
  10. 根据权利要求7-9中任一项所述的用途，其中R 8 2选自下组：环丙基、丙基、丁基、戊基、苯基和苯甲基。
  11. 根据权利要求7-10中任一项所述的用途，其中R 8 3为氢。
  12. 根据权利要求7-11中任一项所述的用途，其中R 8 4选自下组：环丙基、环戊基和苯基。
  13. 根据权利要求6-12任一项所述的用途，其中R 9为丁基。
  14. 根据权利要求2-13任一项所述的用途，其中R 3为氢。
  15. 根据权利要求2-14任一项所述的用途，其中R 4为氢。
  16. 根据权利要求2-15任一项所述的用途，其中R 5为氢。
  17. 根据权利要求2-16中任一项所述的用途，其中R 1和/或R 2为
    Figure PCTCN2021127683-appb-100005
    其中，R 8 1包含选自下组的一中或多种基团：C1至C6烷基、C1至C6硅烷基、C1至C6烷氧基、C1至C6烷基硝基、C3至C7环烷基、C3至C7环烷基硝基、C4至C7芳香基、C4至C7烷氧基芳香基和/或C4至C7杂芳基。
  18. 根据权利要求1-17中任一项所述的用途，其中所述胸苷衍生物为选自下组中的一种或多种：
    Figure PCTCN2021127683-appb-100006
    Figure PCTCN2021127683-appb-100007
  19. 根据权利要求1-18中任一项所述的用途，其中所述胸苷衍生物包含式(II)所示的结 构：
    Figure PCTCN2021127683-appb-100008
    其中，R 1和R 2中的至少一个包含非甾体抗炎药(NSAID)部分。
  20. 根据权利要求19所述的用途，其中所述NSAID部分包含水杨酸或其衍生物、芳基乙酸或其衍生物、杂芳基乙酸或其衍生物、吲哚乙酸或其衍生物、茚乙酸或其衍生物、邻氨基苯甲酸或其衍生物和/或烯醇酸或其衍生物。
  21. 根据权利要求19-20中任一项所述的用途，其中R 1或R 2为氢。
  22. 根据权利要求19-21中任一项所述的用途，其中R 1为选自下组中的任意一种基团：
    Figure PCTCN2021127683-appb-100009
    且R 2为氢。
  23. 根据权利要求19-22中任一项所述的用途，其中R 2为选自下组中的任意一种基团：
    Figure PCTCN2021127683-appb-100010
    且R 1为氢。
  24. 根据权利要求19-23中任一项所述的用途，其中R 1和R 2各自独立地为选自下组中的任意一种基团：
    Figure PCTCN2021127683-appb-100011
    Figure PCTCN2021127683-appb-100012
  25. 根据权利要求1-24中任一项所述的用途，其中所述胸苷衍生物为选自下组中的一种或多种：
    Figure PCTCN2021127683-appb-100013
    Figure PCTCN2021127683-appb-100014
    Figure PCTCN2021127683-appb-100015
  26. 根据权利要求1-25中任一项所述的用途，其中所述化疗药物用于治疗癌症。
  27. 根据权利要求1-26中任一项所述的用途，其中所述化疗药物包括嘧啶核苷类似物或其前药。
  28. 根据权利要求1-27中任一项所述的用途，其中所述化疗药物包括选自下组中的一种或多种：卡培他滨、阿糖胞苷、多西他赛、阿霉素、氟尿嘧啶(5-FU)、氟尿苷、替加氟、伊达比星、紫杉醇、表柔比星、Acelarin(NUC-1031)、多柔比星、亚叶酸、顺铂、紫杉醇、环磷酰胺、长春新碱和5-FU药物前体。
  29. 根据权利要求28所述的用途，其中所述5-FU药物前体包括喃氟啶、5’-脱氧氟尿苷、氟尿苷、2’-脱氧氟尿苷、氟尿苷的药物前体衍生物或2’-脱氧氟尿苷的药物前体衍生物、三氟-甲基-2’-脱氧尿苷、6-氮杂尿苷和/或3-脱氮杂尿苷。
  30. 根据权利要求1-29中任一项所述的用途，其中所述疾病或病症由施用所述化疗药物引起。
  31. 根据权利要求1-30中任一项所述的用途，其中所述与施用化疗药物相关的疾病或病症包 括与施用化疗药物相关的皮肤组织疾病或病症、与施用化疗药物相关的造血组织疾病或病症、与施用化疗药物相关的四肢疾病或病症、与施用化疗药物相关的心脏疾病或病症、与施用化疗药物相关的神经系统疾病或病症、与施用化疗药物相关的五官疾病或病症和/或与施用化疗药物相关的胃肠道疾病或病症。
  32. 根据权利要求31所述的用途，其中所述与施用化疗药物相关的皮肤组织疾病或病症包括皮肤、四肢、五官和/或胃肠道中与施用化疗药物相关的上皮组织疾病或病症。
  33. 根据权利要求32所述的用途，其中所述皮肤、四肢、五官和/或胃肠道中与施用化疗药物相关的上皮组织疾病或病症包括与内皮细胞病变相关的所述疾病或病症，和/或与上皮细胞病变相关的所述疾病或病症，且其中所述内皮细胞病变和/或上皮细胞病变与所述施用化疗药物相关。
  34. 根据权利要求33所述的用途，其中所述上皮细胞包括皮肤上皮细胞、口腔上皮细胞、鼻腔上皮细胞、胃上皮细胞和/或肠上皮细胞。
  35. 根据权利要求1-34中任一项所述的用途，其中所述与施用化疗药物相关的疾病或病症包括与施用化疗药物相关的手足综合征和/或与施用化疗药物相关的腹泻。
  36. 根据权利要求1-35中任一项所述的用途，其中所述与施用化疗药物相关的疾病或病症的严重程度为依据NCI-CTCAE V5.0中的第1级或以上、第2级或以上、第3级或以上、第4级或以上，和/或第5级。
  37. 根据权利要求1-36中任一项所述的用途，其中所述药物被制备为适用于外用给药或口服给药。
  38. 根据权利要求1-37中任一项所述的用途，其中所述胸苷衍生物在所述药物中的浓度为约0.0001％(w/w)至约50％(w/w)。
  39. 根据权利要求1-38中任一项所述的用途，其中所述胸苷衍生物的给药剂量为约0.5μM至约1000μM。
  40. 根据权利要求1-38中任一项所述的用途，其中所述胸苷衍生物的给药剂量为约15mpk至约300mpk。
  41. 根据权利要求1-40中任一项所述的用途，其中所述药物中进一步包含一种或多种活性成分。
  42. 根据权利要求1-41中任一项所述的用途，其中所述药物基本上不影响所述化疗药物的治疗效果。
  43. 根据权利要求1-42中任一项所述的用途，其中所述受试者包含癌症患者。
  44. 根据权利要求1-43中任一项所述的用途，其中所述受试者曾经、正在和/或将来被施用所述化疗药物。
  45. 根据权利要求1-44中任一项所述的用途，其中所述受试者患有或易患有所述与施用所述化疗药物相关的疾病或病症。
  46. 根据权利要求1-45中任一项所述的用途，其中所述疾病或病症的严重程度在施用所述化疗药物之后增加。
  47. 根据权利要求1-46中任一项所述的用途，其中在施用所述化疗药物之前，所述受试者未患有所述疾病或病症。
  48. 药物组合或试剂盒，其包含：1)权利要求1-47中任一项所述的化疗药物；以及2)权利要求1-47中任一项所述的胸苷衍生物。
  49. 根据权利要求48所述的药物组合或试剂盒，其中所述化疗药物与所述胸苷衍生物彼此不混合。
  50. 根据权利要求48-49中任一项所述的药物组合或试剂盒，其中所述化疗药物与所述胸苷衍生物各自独立地存在于单独的容器中。
  51. 根据权利要求48-50中任一项所述的药物组合或试剂盒，其中2)中的所述胸苷衍生物能够预防或治疗与施用1)中的所述化疗药物相关的疾病或病症。
  52. 根据权利要求48-51中任一项所述的药物组合或试剂盒，其中2)中的所述胸苷衍生物基本上不影响1)中的所述化疗药物的治疗效果。
  53. 根据权利要求48-52中任一项所述的药物组合或试剂盒，其中在施用1)的所述化疗药物之前、同时或者之后施用2)的所述胸苷衍生物。
  54. 包含胸苷衍生物和尿苷衍生物的组合在制备药物中的用途，所述药物用于预防或治疗受试者中与施用化疗药物相关的疾病或病症，其中所述胸苷衍生物包含式(I)的结构：
    Figure PCTCN2021127683-appb-100016
    其中，R 2、R 3、R 4、R 5、R 6和R 7不同时为氢。
  55. 根据权利要求54所述的用途，其中，R 7为
    Figure PCTCN2021127683-appb-100017
  56. 根据权利要求54-55中任一项所述的用途，其中，R 6为氢。
  57. 根据权利要求54-56中任一项所述的用途，其中，R 6为
    Figure PCTCN2021127683-appb-100018
    其中所述R 6 1为C1至C6的烷基。
  58. 根据权利要求54-57任一项所述的用途，其中，R 1、R 2和R 3中的任意一个独立地为
    Figure PCTCN2021127683-appb-100019
    其中，M 1为氧或硫，并且R 8包含选自下组的一中或多种基团：氢、取代或未取代的羟基、取代或未取代的巯基、取代或未取代的氨基、取代或未取代的C1至C5烷基、取代或未取代的C 1至C 5炔基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基，以及，取代或未取代的芳烷基；M 2为硅或碳，并且R 9选自下组：氢、取代或未取代的羟基、取代或未取代的巯基、取代或未取代的氨基、取代或未取代的C1至C5烷基、取代或未取代的C1至C5炔基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基，以及，取代或未取代的芳烷基，R 9选自下组：C1至C5烷基、C1至C5的环烷基、苯基或苯甲基。
  59. 根据权利要求54-58中任一项所述的用途，其中R 1、R 2或R 3各自独立地选自下组：–(C＝O)–R 8 1、–(C＝O)–OR 8 2、–(C＝O)–NR 8 3R 8 4、–(C＝S)–R 8 5、–(C＝S)–OR 8 6和–(C＝S)–NR 8 7R 8 8，其中R 8 1、R 8 2、R 8 3、R 8 4、R 8 5、R 8 6、R 8 7和R 8 8中的任意一个独立地包含选自下组的一中或多种基团：氢、取代或未取代的烷基、取代或未取代的炔基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基以及取代或未取代的杂芳基。
  60. 根据权利要求59所述的用途，其中R 8 1、R 8 2、R 8 3、R 8 4、R 8 5、R 8 6、R 8 7和R 8 8中的任意一个独立地选自氢、C1至C5烷基、C1至C5的环烷基、C1至C5的杂环烷基、苯基和苯甲基。
  61. 根据权利要求59-60中任一项所述的用途，其中R 8 1包含选自下组的一中或多种基团：甲基、乙基、丙基、丁基、环戊烷基、环丙烷基和苯甲基。
  62. 根据权利要求59-61中任一项所述的用途，其中R 8 2包含选自下组的一中或多种基团：环 丙基、丙基、丁基、戊基、苯基和苯甲基。
  63. 根据权利要求59-62中任一项所述的用途，其中R 8 3为氢。
  64. 根据权利要求59-63中任一项所述的用途，其中R 8 4选自下组：环丙基、环戊基和苯基。
  65. 根据权利要求59-64中任一项所述的用途，其中R 9为丁基。
  66. 根据权利要求59-65中任一项所述的用途，其中R 3为氢。
  67. 根据权利要求59-66中任一项所述的用途，其中R 4为氢。
  68. 根据权利要求59-67中任一项所述的用途，其中R 5为氢。
  69. 根据权利要求59-68中任一项所述的用途，其中R 1和/或R 2为
    Figure PCTCN2021127683-appb-100020
    其中，R 8 1包含选自下组中的一种或多种基团：C1至C6烷基、C1至C6硅烷基、C1至C6烷氧基、C1至C6烷基硝基、C3至C7环烷基、C3至C7环烷基硝基、C4至C7芳香基、C4至C7烷氧基芳香基和/或C4至C7杂芳基。
  70. 根据权利要求54-69中任一项所述的用途，其中所述胸苷衍生物为选自下组中的一种或多种：
    Figure PCTCN2021127683-appb-100021
    Figure PCTCN2021127683-appb-100022
    Figure PCTCN2021127683-appb-100023
  71. 根据权利要求54-63中任一项所述的用途，其中所述胸苷衍生物包含式(II)所示的结构
    Figure PCTCN2021127683-appb-100024
    其中，R 1和R 2中的至少一个包含非甾体抗炎药(NSAID)部分。
  72. 根据权利要求71所述的用途，其中所述NSAID包含水杨酸或其衍生物、芳基乙酸或其衍生物、杂芳基乙酸或其衍生物、吲哚乙酸或其衍生物、茚乙酸或其衍生物、邻氨基苯甲酸或其衍生物和/或烯醇酸或其衍生物。
  73. 根据权利要求71-72中任一项所述的用途，其中R 1或R 2为氢。
  74. 根据权利要求71-73中任一项所述的用途，其中R 1和R 2不同时为氢。
  75. 根据权利要求71-74中任一项所述的用途，其中R 1为选自下组中的任意一种基团：
    Figure PCTCN2021127683-appb-100025
    且R 2为氢。
  76. 根据权利要求71-74所述的用途，其中R 2为选自下组中的任意一种基团：
    Figure PCTCN2021127683-appb-100026
    Figure PCTCN2021127683-appb-100027
    且R 1为氢。
  77. 根据权利要求71-74中任一项所述的用途，其中R 1和R 2各自独立地为选自下组中的任意一种基团：
    Figure PCTCN2021127683-appb-100028
  78. 根据权利要求54-77中任一项所述的用途，其中所述胸苷衍生物选自下组中的一种或多种：
    Figure PCTCN2021127683-appb-100029
    Figure PCTCN2021127683-appb-100030
    Figure PCTCN2021127683-appb-100031
  79. 根据权利要求54-78中任一项所述的用途，其中所述尿苷衍生物包含式(III)的结构：
    Figure PCTCN2021127683-appb-100032
    其中，当X 4和X 5均为氢时，X 1、X 2和X 3不同时为氢或不同时为CH 3CO–。
  80. 根据权利要求79所述的用途，其中X 1为氢或
    Figure PCTCN2021127683-appb-100033
    其中所述X s为氧或硫，R s选自氢、取代或未取代的羟基、取代或未取代的巯基、取代或未取代的氨基、C1至C5的取代或未取代的烷基、C1至C5的取代或未取代的炔基、C1至C5的取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基以及取代或未取代的芳烷基。
  81. 根据权利要求80所述的用途，其中X s为氧。
  82. 根据权利要求79-81中任一项所述的用途，其中X 2为氢或
    Figure PCTCN2021127683-appb-100034
    其中所述X g为氧或硫，R g选自氢、取代或未取代的羟基、取代或未取代的巯基、取代或未取代的氨基、C1至C5的取代或未取代的烷基、C1至C5的取代或未取代的炔基、C1至C5的取代或未取代 的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基以及取代或未取代的芳烷基。
  83. 根据权利要求82所述的用途，其中X g为氧。
  84. 根据权利要求79-83中任一项所述的用途，其中X 3为
    Figure PCTCN2021127683-appb-100035
    或氢，其中所述X 7为氢
    Figure PCTCN2021127683-appb-100036
    其中所述X 1’为氧或硫，X 6选自氢、取代或未取代的羟基、取代或未取代的巯基、取代或未取代的氨基、C1至C5的取代或未取代的烷基、C1至C5的取代或未取代的炔基、C1至C5的取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基以及取代或未取代的芳烷基。
  85. 根据权利要求79-84中任一项所述的用途，其中X 3为
    Figure PCTCN2021127683-appb-100037
    所述C 7为
    Figure PCTCN2021127683-appb-100038
    其中，X 6选自氢、C1至C6烷基、C1至C6烷氧基、C3至C10环烷基、C3至C10环烷基氧基、C4至C10芳基烷基、C4至C10芳基烷氧基或C4至C10芳香基。
  86. 根据权利要求79-85中任一项所述的用途，其中所述X 3为氢。
  87. 根据权利要求79-86中任一项所述的用途，其中所述X 1为
    Figure PCTCN2021127683-appb-100039
    其中，R s选自氢、
    C1至C6烷基、C1至C6烷氧基、C3至C10环烷基、C3至C10环烷基氧基、C4至C10芳基烷基、C4至C10芳基烷氧基或C4至C10芳香基。
  88. 根据权利要求79-87中任一项所述的用途，其中所述X 2为
    Figure PCTCN2021127683-appb-100040
    其中，R g选自氢、C1至C6烷基、C1至C6烷氧基、C3至C10环烷基、C3至C10环烷基氧基、C4至C10芳基烷基、C4至C10芳基烷氧基或C4至C10芳香基。
  89. 根据权利要求79-88中任一项所述的用途，其中X 4为氢。
  90. 根据权利要求79-89中任一项所述的用途，其中X 5为氢。
  91. 根据权利要求79-90中任一项所述的用途，其中所述尿苷衍生物选自下组中的一种或多种：
    Figure PCTCN2021127683-appb-100041
  92. 根据权利要求54-91中任一项所述的用途，其中所述尿苷衍生物包含如式(IV)所示的化合物：
    Figure PCTCN2021127683-appb-100042
    其中，所述X 1、X 2和X 7中的至少一个包含非甾体抗炎药(NSAID)部分。
  93. 根据权利要求92所述的用途，其中所述NSAID部分包含水杨酸或其衍生物、芳基乙酸或其衍生物、杂芳基乙酸或其衍生物、吲哚乙酸或其衍生物、茚乙酸或其衍生物、邻氨基苯甲酸或其衍生物和/或烯醇酸或其衍生物。
  94. 根据权利要求92-93中任一项所述的用途，其中X 1、X 2或X 7为氢。
  95. 根据权利要求92-94中任一项所述的用途，其中X 1、X 2和X 7不同时为氢。
  96. 根据权利要求92-95中任一项所述的用途，其中X 1、X 2和X 7中的任意一个独立地选自下组：
    Figure PCTCN2021127683-appb-100043
    Figure PCTCN2021127683-appb-100044
  97. 根据权利要求54-96中任一项所述的用途，其中所述尿苷衍生物选自下组中的一种或多种：
    Figure PCTCN2021127683-appb-100045
  98. 根据权利要求54-97中任一项所述的用途，其中所述化疗药物用于治疗癌症。
  99. 根据权利要求54-98中任一项所述的用途，其中所述化疗药物包括嘧啶核苷类似物或其前药。
  100. 根据权利要求54-99中任一项所述的用途，其中所述化疗药物包括选自下组中的一种或多种：卡培他滨、阿糖胞苷、多西他赛、阿霉素、氟尿嘧啶(5-FU)、氟尿苷、替加 氟、伊达比星、紫杉醇、表柔比星、Acelarin(NUC-1031)、多柔比星、亚叶酸、顺铂、紫杉醇、环磷酰胺、长春新碱和5-FU药物前体。
  101. 根据权利要求100所述的用途，其中所述5-FU药物前体包括喃氟啶5’-脱氧氟尿苷、氟尿苷、2’-脱氧氟尿苷、氟尿苷的药物前体衍生物或2’-脱氧氟尿苷的药物前体衍生物、三氟-甲基-2’-脱氧尿苷、6-氮杂尿苷和3-脱氮杂尿苷。
  102. 根据权利要求54-101中任一项所述的用途，其中所述疾病或病症由施用所述化疗药物引起。
  103. 根据权利要求54-102中任一项所述的用途，其中所述与施用化疗药物相关的疾病或病症包括与施用化疗药物相关的皮肤组织疾病或病症、与施用化疗药物相关的造血组织疾病或病症、与施用化疗药物相关的四肢疾病或病症、与施用化疗药物相关的心脏疾病或病症、与施用化疗药物相关的神经系统疾病或病症、与施用化疗药物相关的五官疾病或病症和/或与施用化疗药物相关的胃肠道疾病或病症。
  104. 根据权利要求54-103所述的用途，其中所述与施用化疗药物相关的造血组织疾病或病症包括与施用化疗药物相关的骨髓疾病或病症和与施用化疗药物相关的血液疾病或病症。
  105. 根据权利要求54-104所述的用途，其中所述与施用化疗药物相关的疾病或病症包括与施用化疗药物相关的上皮组织疾病或病症。
  106. 根据权利要求105所述的用途，其中所述与施用化疗药物相关的上皮组织疾病或病症包括与内皮细胞病变相关的所述疾病或病症，和/或与上皮细胞病变相关的所述疾病或病症，且其中所述内皮细胞病变和/或上皮细胞病变与所述施用化疗药物相关。
  107. 根据权利要求106所述的用途，其中所述内皮细胞包括血管内皮细胞。
  108. 根据权利要求106-107中任一项所述的用途，其中所述上皮细胞包括皮肤上皮细胞、口腔上皮细胞、鼻腔上皮细胞、胃上皮细胞和/或肠上皮细胞。
  109. 根据权利要求54-108中任一项所述的用途，其中所述与施用化疗药物相关的疾病或病症包括与施用化疗药物相关的手足综合征和/或与施用化疗药物相关的腹泻。
  110. 根据权利要求54-109中任一项所述的用途，其中所述与施用化疗药物相关的疾病或病症的严重程度为依据NCI-CTCAE V5.0中的第1级或以上、第2级或以上、第3级或以上、第4级或以上，和/或第5级。
  111. 根据权利要求54-110中任一项所述的用途，其中所述药物被制备为适用于外用或口服给药。
  112. 根据权利要求54-111中任一项所述的用途，其中所述胸苷衍生物和尿苷衍生物在所述药物中的浓度为约0.0001％(w/w)至约50％(w/w)。
  113. 根据权利要求54-112中任一项所述的用途，其中所述胸苷衍生物和尿苷衍生物的给药剂量为约0.5μM至约1000μM。
  114. 根据权利要求54-113中任一项所述的用途，其中所述胸苷衍生物和尿苷衍生物的给药剂量为约10mpk至约1000mpk。
  115. 根据权利要求54-114中任一项所述的用途，其中所述药物中进一步包含一种或多种活性成分。
  116. 根据权利要求54-115中任一项所述的用途，其中所述药物基本上不影响所述化疗药物的治疗效果。
  117. 根据权利要求54-116中任一项所述的用途，其中所述受试者包含癌症患者。
  118. 根据权利要求54-117中任一项所述的用途，其中所述受试者曾经、正在和/或将来被施用所述化疗药物。
  119. 根据权利要求54-118中任一项所述的用途，其中所述受试者患有或易患有所述与施用所述化疗药物相关的疾病或病症。
  120. 根据权利要求54-119中任一项所述的用途，其中所述疾病或病症的严重程度在施用所述化疗药物之后增加。
  121. 根据权利要求54-120中任一项所述的用途，其中在施用所述化疗药物之前，所述受试者未患有所述疾病或病症。
  122. 药物组合或试剂盒，其包含：1)权利要求54-121中任一项所述的化疗药物；以及2)权利要求54-121中任一项所述的包含胸苷衍生物和尿苷衍生物的组合。
  123. 根据权利要求122所述的药物组合或试剂盒，其中所述化疗药物与所述包含胸苷衍生物和尿苷衍生物的组合彼此不混合。
  124. 根据权利要求122-123中任一项所述的药物组合或试剂盒，其中所述化疗药物与所述包含胸苷衍生物和尿苷衍生物的组合各自独立地存在于单独的容器中。
  125. 根据权利要求122-124中任一项所述的药物组合或试剂盒，其中2)中的所述包含胸苷衍生物和尿苷衍生物的组合能够预防或治疗与施用1)中的所述化疗药物相关的疾病或病症。
  126. 根据权利要求122-125中任一项所述的药物组合或试剂盒，其中2)中的所述包含胸苷衍生物和尿苷衍生物的组合基本上不影响1)中的所述化疗药物的治疗效果。
  127. 根据权利要求122-126中任一项所述的药物组合或试剂盒，其中在施用1)的所述化疗药物之前、同时或者之后施用2)的所述包含胸苷衍生物和尿苷衍生物的组合。
PCT/CN2021/127683 2020-10-30 2021-10-29 胸苷衍生物在制备药物中的应用 WO2022089614A1 (zh)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US18/250,709 US20230405003A1 (en) 2020-10-30 2021-10-29 Application of thymidine derivative in preparation of drugs
CN202180071369.XA CN116367842A (zh) 2020-10-30 2021-10-29 胸苷衍生物在制备药物中的应用
EP21885340.6A EP4238571A1 (en) 2020-10-30 2021-10-29 Application of thymidine derivative in preparation of drugs

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202011192954.9 2020-10-30
CN202011192954 2020-10-30

Publications (1)

Publication Number Publication Date
WO2022089614A1 true WO2022089614A1 (zh) 2022-05-05

Family

ID=81383580

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/127683 WO2022089614A1 (zh) 2020-10-30 2021-10-29 胸苷衍生物在制备药物中的应用

Country Status (5)

Country Link
US (1) US20230405003A1 (zh)
EP (1) EP4238571A1 (zh)
CN (1) CN116367842A (zh)
TW (1) TW202227098A (zh)
WO (1) WO2022089614A1 (zh)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022265964A1 (en) * 2021-06-14 2022-12-22 VenatoRx Pharmaceuticals, Inc. Orally-bioavailable nucleoside analogs
CN116199730A (zh) * 2023-04-24 2023-06-02 南京颐媛生物医学研究院有限公司 4-硫代尿嘧啶核糖核苷磷酸酯化合物及其制备方法和应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013096680A1 (en) * 2011-12-22 2013-06-27 Alios Biopharma, Inc. Substituted phosphorothioate nucleotide analogs
CN103209987A (zh) * 2010-09-22 2013-07-17 艾丽奥斯生物制药有限公司 取代的核苷酸类似物
CN111789956A (zh) * 2011-04-27 2020-10-20 耶鲁大学 用于抑制化疗引起副作用的药物治疗、筛选技术和试剂盒

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103209987A (zh) * 2010-09-22 2013-07-17 艾丽奥斯生物制药有限公司 取代的核苷酸类似物
CN111789956A (zh) * 2011-04-27 2020-10-20 耶鲁大学 用于抑制化疗引起副作用的药物治疗、筛选技术和试剂盒
WO2013096680A1 (en) * 2011-12-22 2013-06-27 Alios Biopharma, Inc. Substituted phosphorothioate nucleotide analogs

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
"Design of Prodrugs", 1985, ELSEVIER
CHIH-LANG LIN, RONG-NAN CHIEN, CHARISSE YEH, CHAO-WEI HSU, MING-LING CHANG, YI-CHENG CHEN , CHAU-TING YEH: "Significant renoprotective effect of telbivudine during preemptive antiviral therapy in advanced liver cancer patients receiving cisplatin-based chemotherapy: a case-control study", SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY, vol. 49, no. 12, 6 October 2014 (2014-10-06), UK , pages 1456 - 1464, XP009536185, ISSN: 0036-5521, DOI: 10.3109/00365521.2014.962604 *
HARTINGER J., VESELÝ P., MATOUŠKOVÁ E., ARGALACSOVÁ S., PETRUŽELKA L., NETÍKOVÁ I.: "Local Treatment of Hand-Foot Syndrome with Uridine/Thymidine: In Vitro Appraisal on a Human Keratinocyte Cell Line HaCaT", THE SCIENTIFIC WORLD JOURNAL, vol. 2012, 1 January 2012 (2012-01-01), pages 1 - 6, XP055925078, DOI: 10.1100/2012/421325 *
JAVAID SUMAIRA; ISHTIAQ MARIUM; SHAIKH MUNIZA; HAMEED ABDUL; CHOUDHARY M. IQBAL: "Thymidine esters as substrate analogue inhibitors of angiogenic enzyme thymidine phosphorylasein vitro", BIOORGANIC CHEMISTRY, vol. 70, 23 November 2016 (2016-11-23), US , pages 44 - 56, XP029957265, ISSN: 0045-2068, DOI: 10.1016/j.bioorg.2016.11.007 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022265964A1 (en) * 2021-06-14 2022-12-22 VenatoRx Pharmaceuticals, Inc. Orally-bioavailable nucleoside analogs
US11638715B2 (en) 2021-06-14 2023-05-02 VenatoRx Pharmaceuticals, Inc. Orally-bioavailable nucleoside analogs
CN116199730A (zh) * 2023-04-24 2023-06-02 南京颐媛生物医学研究院有限公司 4-硫代尿嘧啶核糖核苷磷酸酯化合物及其制备方法和应用

Also Published As

Publication number Publication date
TW202227098A (zh) 2022-07-16
CN116367842A (zh) 2023-06-30
EP4238571A1 (en) 2023-09-06
US20230405003A1 (en) 2023-12-21

Similar Documents

Publication Publication Date Title
WO2022089614A1 (zh) 胸苷衍生物在制备药物中的应用
AU2016269491B2 (en) Systems, methods, and formulations for treating cancer
WO2021147879A1 (zh) Shp2抑制剂及其应用
EP2812324B1 (en) Heteroaryl compounds and methods of use thereof
EA021196B1 (ru) Ингибиторы вирусов flaviviridae
CN111801339A (zh) 5-氟尿嘧啶化合物
JP2022169800A (ja) 細菌の排出ポンプ阻害剤
EP3880680A1 (en) A crystalline spirocyclic compound inhibitor of tryptophan hydroxylase 1 (tph1) for treating diseases or disorders associated with peripheral serotonin
EP2928466B1 (en) Use of maleimide derivatives for preventing and treating leukemia
US9669003B2 (en) Use of flavone and flavanone derivatives in preparation of sedative and hypnotic drugs
JP2001520174A (ja) 心血管疾患および脳血管疾患に関するリスクを低下させる併用療法
JP2013515766A (ja) イマチニブジクロロ酢酸塩及びそれを含む抗癌剤組成物
JP6215484B2 (ja) がん治療のための短鎖脂肪酸およびゼブラリンまたは１’−シアノ−シタラビンを含む相互プロドラッグ
JP6212831B2 (ja) ゲムシタビン誘導体、該誘導体を含む組成物及び該誘導体の製薬用途
WO2022089612A1 (zh) 尿苷衍生物在制备药物中的应用
JP2012504588A (ja) ピリミド誘導体およびその製薬学的用途
JP2012500222A (ja) 金属酵素阻害剤の設計および開発のための組成物および方法
WO2012055169A1 (zh) C-芳基葡糖苷衍生物及其制备方法和应用
WO2022066864A1 (en) Shmt inhibitors
JP2023524230A (ja) 腫瘍微小環境における免疫調節のためのヒストンデアセチラーゼ阻害剤
CN108368117B (zh) 一种取代的咪唑并喹唑啉化合物及其药物组合物
EP3674303A1 (en) Novel tryptophan hydroxylase inhibitor and pharmaceutical composition including same
JPWO2003024950A1 (ja) クマリン誘導体
JP5955531B2 (ja) 抗癌剤
EP4186503A1 (en) Anti-inflammatory composition comprising benzofuran-based n-acylhydrazone derivatives

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21885340

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2021885340

Country of ref document: EP

Effective date: 20230530