Drug combinations and their uses

Abstract

A pharmaceutical combination for preventing and / or treating tumors, comprising: a) a preventively and / or therapeutically effective amount of ascorbic acid or a derivative thereof; and b) a preventively and / or therapeutically effective amount of a PDE4 selective inhibitor.

Description

Technical Field

[0001] The present application relates to the field of biomedicine, and specifically to a drug combination and its use. Background Art

[0002] Malignant tumors are currently a serious threat to human health. Global cancer statistics for 2018 show 18.19 million new cancer cases and 9.6 million cancer deaths worldwide. Taking colorectal cancer as an example, colorectal cancer accounts for 10.2% of all cancer cases and 9.2% of all cancer deaths, resulting in approximately 1.85 million new cases and 880,000 deaths annually. In my country, approximately 370,000 new cases of colorectal cancer occur annually. Oxaliplatin is the primary treatment for colorectal cancer, with chemotherapy regimens including oxaliplatin + Xeloda and oxaliplatin + fluorouracil. However, these chemotherapy regimens are associated with significant side effects, such as damage to the digestive and hematologic systems, and drug resistance is common. Furthermore, over 30% of colorectal cancer patients are insensitive to platinum-based chemotherapy drugs. This suggests that while chemotherapy drugs offer anti-tumor effects, they also exhibit varying degrees of toxic side effects or resistance, particularly in some cancer patients. Therefore, the search for more effective anti-tumor drugs and approaches is a pressing challenge for the global medical community. Summary of the Invention

[0003] The present application provides a drug combination and its use or administration method, which mainly includes combining a PDE4 selective inhibitor with ascorbic acid or its derivatives as a drug combination for treating tumors, or administering a PDE4 selective inhibitor and ascorbic acid or its derivatives in combination to treat tumors. In addition, a PDE4 selective inhibitor and ascorbic acid or its derivatives and a platinum compound can also be used as a drug combination for treating tumors, or administering a PDE4 selective inhibitor and ascorbic acid or its derivatives and a platinum compound in combination to treat tumors. It has at least one of the following technical effects:

[0004] 1) A drug combination consisting of a PDE4 selective inhibitor and ascorbic acid or its derivatives can be used as an alternative therapy to traditional chemotherapy drugs to avoid the toxic side effects of traditional chemotherapy on the human body.

[0005] 2) A drug combination consisting of a PDE4 selective inhibitor and ascorbic acid or its derivatives is used to treat tumor patients who are insensitive to or resistant to traditional chemotherapy drugs to achieve therapeutic effects.

[0006] 3) The drug combination consisting of a PDE4 selective inhibitor and ascorbic acid or its derivatives can be used in combination with traditional chemotherapy drugs (such as platinum compounds) to reduce the dosage of chemotherapy drugs, thereby reducing the toxic side effects of traditional chemotherapy drugs.

[0007] 4) The combination of a PDE4 selective inhibitor and ascorbic acid or its derivatives achieved an unexpected inhibitory effect on tumors, significantly reduced the dosage of a single drug with the same effect, and improved the safety of the drug.

[0008] 5) The drug combination specifically inhibits tumor or tumor cell growth and has no effect on other physiological indicators of the subjects (such as body weight), demonstrating the safety of the drug.

[0009] The present application provides a pharmaceutical combination comprising:

[0010] a) a prophylactically and / or therapeutically effective amount of ascorbic acid or a derivative thereof; and

[0011] b) a prophylactically and / or therapeutically effective amount of a PDE4 selective inhibitor.

[0012] In certain embodiments, the pharmaceutical combination further comprises a prophylactically and / or therapeutically effective amount of a platinum compound.

[0013] In certain embodiments, the platinum compound comprises oxaliplatin, cisplatin and / or carboplatin.

[0014] In certain embodiments, the PDE4 selective inhibitor comprises Apremilast, Crisaborole, Drotaverine, CC-1088, BPN14770, GSK356278, HT-0712, TAK-648, Zembrin, ASP9831, Etazolate, Piclamilast, Rolipram, Cilomilast, GSK256066, AWD 12-281, Quinolyloxazole, DC-TA-46, Filaminast, and / or Glaucine.

[0015] In certain embodiments, the PDE4 selective inhibitor comprises a compound represented by Formula I or a pharmaceutically acceptable salt thereof:

[0016]

[0017] wherein one of R1 and R2 is hydrogen, C1-C6 alkoxy, C3-C7 cycloalkyloxy, C3-C7 cycloalkylmethoxy, benzyl

[0018] Oxy, or a C1-C4 alkoxy group substituted entirely or partially by fluorine, and the other of R1 and R2 is entirely or partially

[0019] C1-C4 oxy group substituted by fluorine, and

[0020] R3 is phenyl, pyridyl, phenyl substituted by R31, R32 and R33, or pyridyl substituted by R34, R35, R36 and R37, wherein:

[0021] R31 is hydroxy, halogen, cyano, carboxyl, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonyloxy, amino, mono- or di-C1-C4 alkylamino or C1-C4 alkylcarbonylamino,

[0022] R32 is hydrogen, hydroxy, halogen, amino, trifluoromethyl, C1-C4 alkyl or C1-C4 alkoxy,

[0023] R33 is hydrogen, halogen, C1-C4 alkyl or C1-C4 alkoxy,

[0024] R34 is hydroxy, halogen, cyano, carboxyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl or amino, R35 is hydrogen, halogen, amino or C1-C4 alkyl,

[0025] R36 is hydrogen or halogen, and

[0026] R37 is hydrogen or halogen.

[0027] In certain embodiments, the PDE4 selective inhibitor comprises Roflumilast or a derivative thereof.

[0028] In certain embodiments, the derivative of Roflumilast comprises benzamide and / or 4-Methylbenzanilide.

[0029] In certain embodiments, the ascorbic acid derivative comprises dehydroascorbic acid and / or a pharmaceutically acceptable ascorbate salt.

[0030] In certain embodiments, the pharmaceutically acceptable ascorbate comprises sodium ascorbate.

[0031] In certain embodiments, the ratio of the effective amount of the PDE4 selective inhibitor to the effective amount of ascorbic acid or a derivative thereof is from about 1:50 to about 1:500.

[0032] In certain embodiments, the mass ratio of the PDE4 selective inhibitor to the ascorbic acid or its derivative is from about 1:50 to about 1:500.

[0033] In certain embodiments, the effective amount ratio of the PDE4 selective inhibitor, the ascorbic acid or a derivative thereof, and the platinum compound is from about 1:50:1 to about 1:500:1.

[0034] In certain embodiments, the PDE4 selective inhibitor and the ascorbic acid or its derivative are each present in different containers.

[0035] In certain embodiments, the PDE4 selective inhibitor, the ascorbic acid or its derivative, and the platinum compound are each present in different containers.

[0036] In certain embodiments, the pharmaceutical combination comprises a first formulation comprising the ascorbic acid or a derivative thereof and a first pharmaceutically acceptable carrier, and a second formulation comprising the PDE4 selective inhibitor and a second pharmaceutically acceptable carrier.

[0037] In certain embodiments, the pharmaceutical combination comprises a first formulation, a second formulation, and a third formulation, wherein the first formulation comprises the ascorbic acid or a derivative thereof and a pharmaceutically acceptable first carrier, the second formulation comprises the PDE4 selective inhibitor and a pharmaceutically acceptable second carrier, and the third formulation comprises the platinum compound and a pharmaceutically acceptable third carrier.

[0038] In certain embodiments, the pharmaceutical combination comprises a pharmaceutical composition, and the pharmaceutical composition comprises the PDE4 selective inhibitor and the ascorbic acid or a derivative thereof.

[0039] In certain embodiments, the pharmaceutical composition further comprises a platinum compound.

[0040] In certain embodiments, the content of the PDE4 selective inhibitor in the pharmaceutical composition is about 1% to about 5% (w / w).

[0041] In certain embodiments, the content of ascorbic acid or a derivative thereof in the pharmaceutical composition is about 90% to about 98% (w / w).

[0042] In certain embodiments, the content of the platinum compound in the pharmaceutical composition is about 1% to about 5% (w / w).

[0043] On the other hand, the present application also provides a kit comprising the pharmaceutical combination described in the present application.

[0044] In certain embodiments, the pharmaceutical combination or kit described herein is used to prevent and / or treat tumors.

[0045] In certain embodiments, the tumor comprises a solid tumor and / or a non-solid tumor.

[0046] In certain embodiments, the tumor comprises colon cancer and / or melanoma.

[0047] In certain embodiments, the tumor comprises tumors or tumor cells that are unresponsive to a platinum compound.

[0048] On the other hand, the present application also provides use of a combination of ascorbic acid or a derivative thereof and a PDE4 selective inhibitor in the preparation of a medicament for preventing and / or treating tumors.

[0049] In certain embodiments, the present application also provides use of a combination of ascorbic acid or a derivative thereof, a PDE4 selective inhibitor, and a platinum compound in the preparation of a medicament for preventing and / or treating tumors.

[0050] In certain embodiments, the platinum compound comprises oxaliplatin, cisplatin and / or carboplatin.

[0051] In certain embodiments, the PDE4 selective inhibitor comprises Apremilast, Crisaborole, Drotaverine, CC-1088, BPN14770, GSK356278, HT-0712, TAK-648, Zembrin, ASP9831, Etazolate, Piclamilast, Rolipram, Cilomilast, GSK256066, AWD 12-281, Quinolyloxazole, DC-TA-46, Filaminast, and / or Glaucine.

[0052] In certain embodiments, the PDE4 selective inhibitor comprises a compound represented by Formula I or a pharmaceutically acceptable salt thereof:

[0053]

[0054] wherein one of R1 and R2 is hydrogen, C1-C6 alkoxy, C3-C7 cycloalkoxy, C3-C7 cycloalkylmethoxy, benzyloxy, or C1-C4 alkoxy substituted in whole or in part by fluorine, and the other of R1 and R2 is C1-C4 alkoxy substituted in whole or in part by fluorine, and

[0055] R3 is phenyl, pyridyl, phenyl substituted by R31, R32 and R33, or pyridyl substituted by R34, R35, R36 and R37, wherein:

[0056] R31 is hydroxy, halogen, cyano, carboxyl, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonyloxy, amino, mono- or di-C1-C4 alkylamino or C1-C4 alkylcarbonylamino,

[0057] R32 is hydrogen, hydroxy, halogen, amino, trifluoromethyl, C1-C4 alkyl or C1-C4 alkoxy,

[0058] R33 is hydrogen, halogen, C1-C4 alkyl or C1-C4 alkoxy,

[0059] R34 is hydroxy, halogen, cyano, carboxyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl or amino, R35 is hydrogen, halogen, amino or C1-C4 alkyl,

[0060] R36 is hydrogen or halogen, and

[0061] R37 is hydrogen or halogen.

[0062] In certain embodiments, the PDE4 selective inhibitor comprises Roflumilast or a derivative thereof.

[0063] In certain embodiments, the derivative of Roflumilast comprises Benzanilide and / or 4-Methylbenzanilide.

[0064] In certain embodiments, the ascorbic acid derivative comprises dehydroascorbic acid and / or a pharmaceutically acceptable ascorbate salt.

[0065] In certain embodiments, the pharmaceutically acceptable ascorbate comprises sodium ascorbate.

[0066] In certain embodiments, the tumor comprises a solid tumor and / or a non-solid tumor.

[0067] In certain embodiments, the tumor comprises colon cancer and / or melanoma.

[0068] In certain embodiments, the tumor comprises tumors or tumor cells that are unresponsive to a platinum compound.

[0069] In certain embodiments, the PDE4 selective inhibitor and the ascorbic acid or a derivative thereof are formulated to be administered to the subject simultaneously.

[0070] In certain embodiments, the PDE4 selective inhibitor and the ascorbic acid or a derivative thereof are formulated to be administered separately to the subject.

[0071] In certain embodiments, the PDE4 selective inhibitor, the ascorbic acid or a derivative thereof, and the platinum compound are configured to be administered to the subject simultaneously.

[0072] In certain embodiments, the PDE4 selective inhibitor, the ascorbic acid or a derivative thereof, and the platinum compound are formulated to be administered separately to a subject.

[0073] In certain embodiments, the medicament is formulated such that the PDE4 selective inhibitor is administered at a dose of about 1 mg / kg to about 10 mg / kg.

[0074] In certain embodiments, the medicament is formulated such that the ascorbic acid or a derivative thereof is administered at a dose of about 0.5 g / kg to about 2 g / kg.

[0075] In certain embodiments, the medicament is formulated such that the platinum compound is administered at a dose of about 1 mg / kg to about 10 mg / kg.

[0076] In certain embodiments, the medicament is formulated such that the PDE4 selective inhibitor and the ascorbic acid or a derivative thereof are administered in a mass ratio of about 1:50 to about 1:500.

[0077] In certain embodiments, the medicament is formulated such that the PDE4 selective inhibitor and the ascorbic acid or a derivative thereof are administered in an effective amount ratio of about 1:50 to about 1:500.

[0078] In certain embodiments, the medicament is formulated such that the PDE4 selective inhibitor, the ascorbic acid or a derivative thereof, and the platinum compound are administered in a mass ratio of about 1:50:1 to about 1:500:1.

[0079] In certain embodiments, the medicament is formulated such that the PDE4 selective inhibitor and the ascorbic acid or a derivative thereof are administered in an effective amount ratio of about 1:50 to about 1:500.

[0080] In certain embodiments, the medicament is formulated such that the PDE4 selective inhibitor, the ascorbic acid or a derivative thereof, and the platinum compound are administered in an effective amount ratio of about 1:50:1 to about 1:500:1.

[0081] On the other hand, the present application also provides a method for preventing and / or treating tumors, comprising administering to a subject in need thereof:

[0082] a) an effective amount of ascorbic acid or a derivative thereof; and

[0083] b) an effective amount of a PDE4 selective inhibitor.

[0084] In certain embodiments, the method further comprises administering to the subject in need thereof an effective amount of a platinum compound.

[0085] In certain embodiments, the platinum compound comprises oxaliplatin, cisplatin and / or carboplatin.

[0086] In certain embodiments, the PDE4 selective inhibitor comprises Apremilast, Crisaborole, Drotaverine, CC-1088, BPN14770, GSK356278, HT-0712, TAK-648, Zembrin, ASP9831, Etazolate, Piclamilast, Rolipram, Cilomilast, GSK256066, AWD 12-281, Quinolyloxazole, DC-TA-46, Filaminast, and / or Glaucine.

[0087] In certain embodiments, the PDE4 selective inhibitor comprises a compound represented by Formula I or a pharmaceutically acceptable salt thereof:

[0088]

[0089] wherein one of R1 and R2 is hydrogen, C1-C6 alkoxy, C3-C7 cycloalkoxy, C3-C7 cycloalkylmethoxy, benzyloxy, or C1-C4 alkoxy substituted in whole or in part by fluorine, and the other of R1 and R2 is C1-C4 alkoxy substituted in whole or in part by fluorine, and

[0090] R3 is phenyl, pyridyl, phenyl substituted by R31, R32 and R33, or pyridyl substituted by R34, R35, R36 and R37, wherein:

[0091] R31 is hydroxy, halogen, cyano, carboxyl, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonyloxy, amino, mono- or di-C1-C4 alkylamino or C1-C4 alkylcarbonylamino,

[0092] R32 is hydrogen, hydroxy, halogen, amino, trifluoromethyl, C1-C4 alkyl or C1-C4 alkoxy,

[0093] R33 is hydrogen, halogen, C1-C4 alkyl or C1-C4 alkoxy,

[0094] R34 is hydroxy, halogen, cyano, carboxyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl or amino, R35 is hydrogen, halogen, amino or C1-C4 alkyl,

[0095] R36 is hydrogen or halogen, and

[0096] R37 is hydrogen or halogen.

[0097] In certain embodiments, the PDE4 selective inhibitor comprises Roflumilast or a derivative thereof.

[0098] In certain embodiments, the derivative of Roflumilast comprises Benzanilide and / or 4-Methylbenzanilide.

[0099] In certain embodiments, the ascorbic acid derivative comprises dehydroascorbic acid and / or a pharmaceutically acceptable ascorbate salt.

[0100] In certain embodiments, the pharmaceutically acceptable ascorbate comprises sodium ascorbate.

[0101] In certain embodiments, the subject is a patient with a tumor that is unresponsive to a platinum compound.

[0102] In certain embodiments, the tumor comprises a solid tumor and / or a non-solid tumor.

[0103] In certain embodiments, the tumor comprises colon cancer and / or melanoma.

[0104] In certain embodiments, the tumor comprises tumors or tumor cells that are unresponsive to a platinum compound.

[0105] In certain embodiments, the PDE4 selective inhibitor and the ascorbic acid or a derivative thereof are administered to the subject simultaneously.

[0106] In certain embodiments, the PDE4 selective inhibitor and the ascorbic acid or a derivative thereof are administered to the subject sequentially.

[0107] In certain embodiments, the PDE4 selective inhibitor, the ascorbic acid or a derivative thereof, and the platinum compound are administered to the subject simultaneously.

[0108] In certain embodiments, the PDE4 selective inhibitor, the ascorbic acid or a derivative thereof, and the platinum compound are administered to the subject sequentially.

[0109] In certain embodiments, the PDE4 selective inhibitor is administered at a dose of about 1 mg / kg to about 10 mg / kg.

[0110] In certain embodiments, the ascorbic acid or a derivative thereof is administered at a dose of about 0.5 g / kg to about 2 g / kg.

[0111] In certain embodiments, the platinum compound is administered at a dose of about 1 mg / kg to about 10 mg / kg.

[0112] In certain embodiments, the PDE4 selective inhibitor and the ascorbic acid or a derivative thereof are administered in a mass ratio of about 1:50 to about 1:500.

[0113] In certain embodiments, the PDE4 selective inhibitor and the ascorbic acid or a derivative thereof are administered in an effective amount ratio of about 1:50 to about 1:500.

[0114] In certain embodiments, the PDE4 selective inhibitor, the ascorbic acid or a derivative thereof, and the platinum compound are administered in a mass ratio of about 1:50:1 to about 1:500:1.

[0115] In certain embodiments, the PDE4 selective inhibitor, the ascorbic acid or a derivative thereof, and the platinum compound are administered in an effective amount ratio of about 1:50:1 to about 1:500:1.

[0116] Those skilled in the art can easily discern other aspects and advantages of the present application from the detailed description below. In the detailed description below, only exemplary embodiments of the present application are shown and described. As will be appreciated by those skilled in the art, the content of this application enables those skilled in the art to modify the disclosed specific embodiments without departing from the spirit and scope of the invention to which this application relates. Accordingly, the descriptions in the drawings and specification of this application are merely exemplary and not restrictive. BRIEF DESCRIPTION OF THE DRAWINGS

[0117] The specific features of the invention involved in this application are shown in the appended claims. The features and advantages of the invention involved in this application can be better understood by referring to the exemplary embodiments described in detail below and the accompanying drawings. A brief description of the drawings is as follows:

[0118] Figure 1 Shown are the results of luciferin fluorescence imaging of mouse colon cancer treated with Roflumilast in combination with sodium ascorbate as described in the present application.

[0119] Figure 2 Shown are the quantitative statistical results of Luciferin fluorescence imaging of colon cancer in mice treated with Roflumilast in combination with sodium ascorbate as described in the present application.

[0120] Figure 3 Shown are the statistical results of the volume changes of colon cancer in mice treated with Roflumilast and sodium ascorbate in combination as described in the present application.

[0121] Figure 4 Shown are the effects of Roflumilast and sodium ascorbate described herein on body weight in mice.

[0122] Figure 5 Shown are the statistical results of the volume changes of colon cancer in mice treated with Roflumilast, sodium ascorbate, and oxaliplatin as described in the present application.

[0123] Figure 6 Shown are the effects of Roflumilast, sodium ascorbate, and oxaliplatin described herein on mouse body weight. DETAILED DESCRIPTION

[0124] The following describes the implementation of the present invention through specific embodiments. People familiar with this technology can easily understand other advantages and effects of the present invention from the contents disclosed in this specification.

[0125] Definition of terms

[0126] In this application, the term "unresponsive to platinum compounds" generally refers to situations in the field of anti-tumor treatment where traditional platinum compound chemotherapy fails to achieve the expected anti-tumor effect, as well as situations where platinum compounds are unable to inhibit tumor cell proliferation. This may include instances where platinum compounds fail to achieve an anti-tumor effect from the beginning to the end, and may also include instances where resistance to platinum compounds develops during treatment as the treatment progresses. The traditional platinum compound chemotherapy may be known or readily known to those skilled in the art. The platinum compounds may include cisplatin, carboplatin, oxaliplatin, nedaplatin, and the like.

[0127] In this application, the term "sequentially administering to the subject" generally means that when the active ingredients of a drug combination are administered to a subject, the time interval between the administration of the first active ingredient and the administration of the last active ingredient is greater than one hour. For example, the active ingredients of the drug combination may include the PDE4 selective inhibitor of this application, ascorbic acid and its derivatives, and a platinum compound.

[0128] In this application, the term "simultaneously administered to the subject" generally refers to the simultaneous administration of the active ingredients of the drug combination to the subject in the form of a composition / mixture, or, when the active ingredients of the drug combination are administered to the subject, the interval between the administration of the first active ingredient and the administration of the last active ingredient is no more than one hour. For example, the active ingredients of the drug combination may include the PDE4 selective inhibitor of this application, ascorbic acid and its derivatives, and a platinum compound.

[0129] In this application, the term "PDE4" generally refers to members of the PDE4 subfamily of phosphodiesterases (PDEs) that break phosphodiester bonds, or their functional variants. Phosphodiesterases (PDEs) hydrolyze intracellular second messengers (cAMP, cyclic adenosine monophosphate or cGMP, cyclic guanosine monophosphate), degrading cAMP or cGMP, thereby terminating the biochemical effects mediated by these second messengers. PDEs are a large, multigene family. In mammals, they can be divided into 12 families, namely PDE1-PDE12, based on 1) amino acid sequence, 2) substrate specificity, 3) regulatory properties, 4) pharmacological properties, and 5) tissue distribution. PDE nomenclature uses an Arabic numeral to denote the PDE family, followed by a capital letter to denote the gene within the family, and a second Arabic numeral to denote a splice variant derived from a single gene (e.g., PDE1C3: family 1, gene C, splice variant 3). Different PDEs within the same family may exhibit significant amino acid sequence differences but are functionally related. PDEs have different substrate specificities. For example, PDE4 is a cAMP-selective hydrolase. In humans, PDE4 can be divided into four subtypes: PDE4A, 4B, 4C, and 4D.

[0130] As used herein, the term "PDE4 selective inhibitor" generally refers to an inhibitor that selectively acts against the PDE4 subfamily within the PDE family. Among all members of the PDE family, these inhibitors primarily inhibit PDE4, while having little inhibitory effect on other PDE family members besides PDE4. In other words, PDE4 selective inhibitors are primarily specific to other members of the PDE family, and their potential inhibitory effects on other molecules outside the PDE family are not excluded. PDE4 selective inhibitors may have an inhibitory effect on one or more subtypes within the PDE4 family.

[0131] In this application, the term "drug combination" generally refers to a combination of at least two active ingredients / therapeutic agents. In some embodiments, each active ingredient / therapeutic agent can be prepared as an independent formulation (solid, liquid, gel, etc.), in some embodiments, each active ingredient / therapeutic agent can be present in different containers and can also be formulated into a desired formulation simultaneously or separately with a suitable carrier when needed; in some embodiments, each active ingredient / therapeutic agent can be from different sources (e.g., prepared, produced, or sold by different merchants); in some embodiments, each active ingredient / therapeutic agent can be mixed to form a pharmaceutical composition.

[0132] As used herein, the term "pharmaceutical composition" generally refers to a mixture comprising at least two active ingredients that are administered to a subject to treat a specific disease or condition affecting that individual. This mixture allows the active ingredients to be in an effective form and does not contain additional components that would be unacceptably toxic to the subject to which the composition is to be administered. Such compositions may be sterile and may also contain a pharmaceutically acceptable carrier.

[0133] In this application, the term "inhibitor" generally refers to a compound / substance or composition that can completely or partially prevent or reduce the physiological function of one or more specific biomolecules (e.g., proteins, polypeptides, lipopolysaccharides, glycoproteins, ribonucleoprotein complexes, etc.). The physiological function of reducing one or more specific proteins can include a reduction in the activity of the protein itself (e.g., the ability to bind to other molecules, etc.) or a reduction in the amount of the protein itself. In certain embodiments, the inhibitor can exist as different crystals, amorphous substances, pharmaceutically acceptable salts, hydrates, and solvates. In certain embodiments, the inhibitor can hinder the activation of cell signaling pathways.

[0134] In the present application, the term "functional variant" generally refers to a molecule that can include amino acid modifications (e.g., group substitutions, etc.) or insertions, substitutions, and / or deletions of one or more amino acids in the original protein sequence, while retaining the original sequence function. For example, the functional variant can have better biological activity (function) than the original sequence. For example, the retention does not have to be complete retention. For example, the functional variant can retain the original sequence function substantially, for example, retaining at least 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of the function of the original sequence. For example, the amino acid sequence of the functional variant can be at least 50%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the original amino acid sequence.

[0135] In this application, the term "effective amount" or "effective dose" generally refers to an amount sufficient to achieve or at least partially achieve the desired effect. A "therapeutically effective amount" or "therapeutically effective dose" of a drug or therapeutic agent is generally any amount of the drug that promotes disease regression (as evidenced by a reduction in the severity of disease symptoms, an increase in the frequency and duration of disease symptom-free periods, or the prevention of damage or disability caused by the disease) when used alone or in combination with another therapeutic agent. A "prophylactic effective amount" or "prophylactic effective dose" of a drug generally refers to an amount of the drug that inhibits the development or recurrence of the disease when administered to a subject at risk of disease development or disease recurrence, either alone or in combination with another therapeutic agent. The ability of therapeutic or prophylactic agents to promote disease regression or inhibit disease development or recurrence can be assessed using a variety of methods known to those skilled in the art, such as in human subjects during clinical trials, predicting efficacy in humans in animal model systems, or by measuring the activity of the agent in in vitro assays.

[0136] In this application, the term "ascorbic acid derivative" generally refers to a compound that releases ascorbic acid (vitamin C) in vivo or in vitro, and its solvates, hydrates or salts. The term also includes ascorbic acid analogs in which one or more hydroxyl groups of ascorbic acid are replaced by another structural moiety and wherein the ascorbic acid analog substantially retains the stabilizing activity of ascorbic acid in vitro or in vivo.

[0137] In this application, the term "container" generally refers to any vessel or device suitable for containing a drug, such as a medicine box, a medicine bottle, a medicine bag, a blister, a tube, a syringe, etc.

[0138] In this application, the term "administer" generally refers to introducing the drug combination into the subject's body by any introduction or delivery route. Any method known to those skilled in the art for contacting cells, organs, or tissues with the drug combination can be used. Including but not limited to intra-arterial, intranasal, intraperitoneal, intravenous, intramuscular, subcutaneous transdermal, or oral administration. The daily dose can be divided into one, two, or more suitable dosage forms to be administered at one, two, or more times during a certain time period.

[0139] In this application, the term "subject" generally refers to humans or non-human animals, including but not limited to cats, dogs, horses, pigs, cows, sheep, rabbits, mice, rats or monkeys.

[0140] In this application, the term "carrier" generally refers to any substance other than the active ingredient. For example, a pharmaceutically acceptable substance, composition, or vehicle for carrying or transporting a chemical agent. Examples include buffers, surfactants, stabilizers, preservatives, absorption enhancers for enhancing bioavailability, liquid or solid fillers, diluents, excipients, solvents, encapsulating materials, and / or other conventional solubilizers or dispersants. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not causing harm to the patient. For example, in this application, a suitable carrier is selected based on the form in which each active ingredient (e.g., ascorbic acid, a PDE4 selective inhibitor, or a platinum-based chemotherapeutic drug) is present (combination or separate formulations). For example, when each different active ingredient is present independently, it can be combined with a suitable carrier (i.e., the first carrier, second carrier, or third carrier described in this application) to form a formulation suitable for administration.

[0141] In this application, the term "preparation", also referred to as a pharmaceutical preparation, generally refers to a drug that is prepared in accordance with certain dosage form requirements and can be provided to a subject for treatment or prevention. For example, a preparation may include an active ingredient and a carrier.

[0142] In this application, the term "prevention" generally refers to the prophylactic administration of a combination to healthy subjects to prevent the occurrence of a disease or condition. It can also include the prophylactic administration of a combination to a patient in the early stages of an allergic disease to be treated. "Prevention" does not require 100% elimination of the possibility of the disease or condition occurring. In other words, "prevention" generally refers to a reduction in the likelihood or degree of occurrence of the disease or condition in the presence of the administered combination.

[0143] In this application, the term "treatment" generally refers to clinical intervention used to change the natural course of the treated individual or cell in the clinical pathological process. It may include improving the disease state, eliminating the lesion or improving the prognosis.

[0144] In this application, the term "tumor" generally refers to a growth or solid lesion formed by abnormal cell growth. In this application, a tumor can be a solid tumor or a non-solid tumor. In certain embodiments, a tangible mass that can be detected by clinical examination such as x-ray film, CT scan, B-ultrasound or palpation can be called a solid tumor, and a tumor such as leukemia that cannot be seen or palpated by X-ray, CT scan, B-ultrasound or palpation can be called a non-solid tumor.

[0145] In this application, the term "alkoxy" generally refers to a -OR group, where R can be an optionally substituted alkyl group.

[0146] In the present application, the term "alkyl" generally refers to straight-chain and branched saturated hydrocarbon groups. Non-limiting examples thereof may include methyl, ethyl, and straight-chain and branched propyl and butyl groups.

[0147] In the present application, the term "halogen" refers to the halogens of Group VIIA of the periodic table, such as F, Cl, Br and I.

[0148] In the present application, the term "amino" generally refers to a -NH group, wherein one or both hydrogen atoms may be optionally substituted, for example, by an alkyl group, a substituted alkyl group, a cycloalkyl group, an aryl group or a heteroaryl group.

[0149] In this application, the terms "comprises" or "comprising" generally mean that the features specifically stated are included, but other elements are not excluded.

[0150] In this application, the term "about" generally refers to a variation within a range of 0.5%-10% above or below the specified value, for example, a variation within a range of 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% above or below the specified value.

[0151] In this application, as known to those skilled in the art, terms such as "alkyl", "alkenyl", "cycloalkyl", etc. may be preceded by an identifier to indicate the number of atoms present in the group in a particular case, for example, C1-C4 alkyl, C3-C7 cycloalkyloxy, C1-C4 alkylcarbonylamino, etc., and the subscript number after "C" indicates the number of carbon atoms present in the group. For example, C3 alkyl refers to an alkyl group with three carbon atoms (e.g., n-propyl, isopropyl); C 1-10 In the examples, the members of the group may have any number of carbon atoms falling within the range of 1-4. Detailed Description of the Invention

[0153] In one aspect, the present application provides a pharmaceutical combination, which may comprise:

[0154] a) a prophylactically and / or therapeutically effective amount of ascorbic acid or a derivative thereof; and

[0155] b) a prophylactically and / or therapeutically effective amount of a PDE4 selective inhibitor.

[0156] For example, the pharmaceutical combination may further comprise a prophylactically and / or therapeutically effective amount of a platinum compound.

[0157] In another aspect, the present application further provides the use of a combination of ascorbic acid or a derivative thereof and a PDE4 selective inhibitor in the preparation of a medicament for preventing and / or treating tumors. The present application further provides the use of a combination of ascorbic acid or a derivative thereof, a PDE4 selective inhibitor, and a platinum compound in the preparation of a medicament for preventing and / or treating tumors.

[0158] On the other hand, the present application also provides a method for preventing and / or treating tumors, comprising administering to a subject in need thereof:

[0159] a) an effective amount of ascorbic acid or a derivative thereof; and

[0160] b) an effective amount of a PDE4 selective inhibitor.

[0161] In certain embodiments, the method further comprises administering to the subject in need thereof an effective amount of a platinum compound.

[0162] On the other hand, the present application also provides a kit, which may include the drug combination described in the present application.

[0163] Drug combinations

[0164] The pharmaceutical combination of the present application comprises: a) a preventive and / or therapeutically effective amount of ascorbic acid or a derivative thereof; and

[0165] b) A preventive and / or therapeutically effective amount of a PDE4 selective inhibitor. The pharmaceutical combination of the present application may further comprise a preventive and / or therapeutically effective amount of a platinum compound.

[0166] In the present application, the PDE4 selective inhibitor may include substances that can at least partially destroy or block the activity of one or more PDE4 subfamily members.

[0167] For example, the PDE4 subfamily member may include PDE4A, PDE4B, PDE4C and / or PDE4D.

[0168] For example, the PDE4 selective inhibitor may include a substance that at least partially destroys or blocks the activity of PDE4A, PDE4B, PDE4C, or PDE4D.

[0169] For example, the PDE4 selective inhibitor may include a substance that at least partially destroys or blocks the activity of PDE4C and PDE4D. For example, the PDE4 selective inhibitor may include a substance that at least partially destroys or blocks the activity of PDE4B and PDE4C. For example, the PDE4 selective inhibitor may include a substance that at least partially destroys or blocks the activity of PDE4B and PDE4D. For example, the PDE4 selective inhibitor may include a substance that at least partially destroys or blocks the activity of PDE4A and PDE4B. For example, the PDE4 selective inhibitor may include a substance that at least partially destroys or blocks the activity of PDE4A and PDE4C. For example, the PDE4 selective inhibitor may include a substance that at least partially destroys or blocks the activity of PDE4A and PDE4D.

[0170] For example, the PDE4 selective inhibitor can include a substance that at least partially destroys or blocks the activity of PDE4A, PDE4B, and PDE4C. For example, the PDE4 selective inhibitor can include a substance that at least partially destroys or blocks the activity of PDE4A, PDE4C, and PDE4D. For example, the PDE4 selective inhibitor can include a substance that at least partially destroys or blocks the activity of PDE4A, PDE4B, and PDE4D. For example, the PDE4 selective inhibitor can include a substance that at least partially destroys or blocks the activity of PDE4B, PDE4C, and PDE4D.

[0171] For example, the PDE4 selective inhibitors may include substances that at least partially destroy or block the activities of PDE4A, PDE4B, PDE4C, and PDE4C.

[0172] For example, the at least partial disruption or obstruction may include at least 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% disruption or obstruction.

[0173] For example, the PDE4 selective inhibitor does not substantially destroy or hinder the activity of other members of the PDEs family (except PDE4). For example, the substantially no destruction or hindrance can include up to 30%, 25%, 20%, 18%, 15%, 13%, 10%, 8%, 5%, 3%, 1% destruction or hindrance.

[0174] For example, other members of the PDEs family may include PDE1 subfamily members, PDE2 subfamily members, PDE3 subfamily members, PDE5 subfamily members, PDE6 subfamily members, PDE7 subfamily members, PDE8 subfamily members, PDE9 subfamily members, PDE10 subfamily members, PDE11 subfamily members, and PDE12 subfamily members.

[0175] For example, the activity may include the activity of hydrolyzing cAMP and / or cGMP. For example, the activity of hydrolyzing cAMP and / or cGMP may be measured by any method known to those skilled in the art.

[0176] For example, the PDE4 selective inhibitor may comprise Apremilast, Crisaborole, Drotaverine, CC-1088, BPN14770, GSK356278, HT-0712, TAK-648, Zembrin, ASP9831, Etazolate, Piclamilast, Rolipram, Cilomilast, GSK256066, AWD 12-281, Quinolyl oxazole, DC-TA-46, Filaminast and / or Glaucine.

[0177] For example, the PDE4 selective inhibitor comprises a compound represented by Formula I or a pharmaceutically acceptable salt thereof:

[0178]

[0179] wherein one of R1 and R2 is hydrogen, C1-C6 alkoxy, C3-C7 cycloalkyloxy, C3-C7 cycloalkylmethoxy, benzyl

[0180] Oxy, or a C1-C4 alkoxy group substituted entirely or partially by fluorine, and the other of R1 and R2 is entirely or partially

[0181] C1-C4 oxy group substituted by fluorine, and

[0182] R3 is phenyl, pyridyl, phenyl substituted by R31, R32 and R33, or pyridyl substituted by R34, R35, R36 and R37, wherein:

[0183] R31 is hydroxy, halogen, cyano, carboxyl, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonyloxy, amino, mono- or di-C1-C4 alkylamino or C1-C4 alkylcarbonylamino,

[0184] R32 is hydrogen, hydroxy, halogen, amino, trifluoromethyl, C1-C4 alkyl or C1-C4 alkoxy,

[0185] R33 is hydrogen, halogen, C1-C4 alkyl or C1-C4 alkoxy,

[0186] R34 is hydroxy, halogen, cyano, carboxyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl or amino, R35 is hydrogen, halogen, amino or C1-C4 alkyl,

[0187] R36 is hydrogen or halogen, and

[0188] R37 is hydrogen or halogen.

[0189] For example, the PDE4 selective inhibitor comprises Roflumilast or a derivative thereof.

[0190] For example, the derivative of Roflumilast comprises benzamide and / or bezafibrate.

[0191] For example, the ratio of the effective amount of the PDE4 selective inhibitor to the effective amount of ascorbic acid or a derivative thereof is from about 1:10 to about 1:5000.

[0192] For example, the ratio of the effective amount of the PDE4 selective inhibitor to the effective amount of ascorbic acid or a derivative thereof is from about 1:1 to about 1:20, from about 1:5 to about 1:20, from about 1:10 to about 1:20, from about 1:10 to about 1:25, from about 1:10 to about 1:50, from about 1:10 to about 1:100, from about 1:10 to about 1:150, from about 1:10 to about 1:200, from about 1:10 to about 1:250, from about 1:10 to about 1:300, from about 1:10 to about 1:400, from about 1:10 to about 1:500. about 1:450, about 1:10 to about 1:500, about 1:10 to about 1:550, about 1:10 to about 1:600, about 1:10 to about 1:650, about 1:10 to about 1:700, about 1:10 to about 1:800, about 1:10 to about 1:900, about 1:10 to about 1:1000, about 1:10 to about 1:1500, about 1:10 to about 1:2000, about 1:10 to about 1:3000, about 1:10 to about 1:4000, about 1:10 to about 1:5000, about 1:10 to about 1:650 5 to about 1:20, about 1:5 to about 1:25, about 1:5 to about 1:35, about 1:5 to about 1:50, about 1:5 to about 1:100, about 1:5 to about 1:150, about 1:5 to about 1:200, about 1:25 to about 1:50, about 1:25 to about 1:100, about 1:25 to about 1:150, about 1:25 to about 1:200, about 1:25 to about 1:1000, about 1:25 to about 1:5000, about 1:50 to about 1:100, about 1:50 to about 1:150, about 1:5 From about 1:50 to about 1:200, from about 1:50 to about 1:300, from about 1:50 to about 1:500, from about 1:50 to about 1:1000, from about 1:50 to about 1:2000, from about 1:50 to about 1:4000, or from about 1:50 to about 1:5000, from about 1:4500 to about 1:5000, from about 1:100 to about 1:2000, from about 1:1000 to about 1:4000, from about 1:1000 to about 1:3000, from about 1:500 to about 1:5000, from about 1:500 to about 1:2000.

[0193] For example, the ratio of the effective amount of the PDE4 selective inhibitor to the effective amount of ascorbic acid or a derivative thereof is from about 1:50 to about 1:500.

[0194] For example, the effective amount ratio may include an effective amount molar ratio and / or an effective amount mass ratio.

[0195] For example, the mass ratio of the PDE4 selective inhibitor to the ascorbic acid or its derivative is about 5000:1 to about 1:5000.

[0196] For example, the mass ratio of the PDE4 selective inhibitor to the ascorbic acid or its derivative is from about 20:1 to 1:1, from about 20:1 to about 5:1, from about 20:1 to about 10:1, from about 25:1 to about 10:1, from about 50:1 to about 10:1, from about 100:1 to about 10:1, from about 150:1 to about 10:1, from about 200:1 to about 10:1, from about 250:1 to about 10:1, from about 300:1 to about 10:1, from about 400:1 to about 10:1, from about 450:1 to about 10:1, from about 10:1 to about 500:1, from about 10:1 to about 550:1, from about 10:1 to about 600:1, from about 10:1 to about 650:1, from about 700:1 to about 10:1, from about 800:1 to about 10:1, from about 900:1 to about 10:1, from about 1000:1 to about 10:1, from about 1100:1 to about 1110 1 to about 10:1, about 900:1 to about 10:1, about 1000:1 to about 10:1, about 1500:1 to about 10:1, about 2000:1 to about 10:1, about 3000:1 to about 10:1, about 4000:1 to about 10:1, about 5000:1 to about 10:1, about 20:1 to about 5:1, about 1000:1 to about 50:1, about 2000:1 to about 50:1, about 3000:1 to about 50:1, about 4000:1 to about 50:1, about 5000:1 to about 1:50, about 20:1 to 1:20, about 20:1 to about 1:20, about 20:1 to about 1:25, about 25:1 to about 50:1, about 50:1 to about 1:100, about 100:1 to about 1:100, about 150:1 to about 1:100, about 200:1 to about 1:200, about 250:1 to about 1:500, about 300:1 to about 1:1000, about 400:1 to about 1:100, about 450:1 to about 1:500, about 10:1 to about 1:500, about 10:1 to about 1:550, about 10:1 to about 1:600, about 10:1 to about 1:650, about 700:1 to about 1:650, about 800:1 to about 1:800, about 900:1 to about 1:900, about 1000:1 to about 1:1000, about 1500:1 to about 1:1000, about 2000:1 to about 1:1500, about 3000:1 to about 1:1 1 to about 1:500, about 1:10 to about 1:20, about 1:5 to about 1:20, about 1:10 to about 1:20, about 1:10 to about 1:25, about 1:10 to about 1:50, about 1:10 to about 1:100, about 1:10 to about 1:150, about 1:10 to about 1:200, about 1:10 to about 1:25, about 1:10 to about 1:50, about 1:10 to about 1:100, about 1:10 to about 1:150, about 1:10 to about 1:200, about 1:10 to about 1:250, about 1:10 to about 1:300, about 1:10 to about 1:400, about 1:10 to about 1:450, about 1:10 to about 1:500,about 1:10 to about 1:550, about 1:10 to about 1:600, about 1:10 to about 1:650, about 1:10 to about 1:700, about 1:10 to about 1:800, about 1:10 to about 1:900, about 1:10 to about 1:1000, about 1:10 to about 1:1500, about 1:10 to about 1:2000, about 1:10 to about 1:3000, about 1:10 to about 1:4000, about 1:10 to about 1:5000, about 1:5 to about 1:20, about 1:5 to about 1:25, about 1:5 to about 1:35, about 1:5 to about 1:50, about 1:5 to about 1:10, about 1:5 to about 1:15 0, about 1:5 to about 1:200, about 1:25 to about 1:50, about 1:25 to about 1:100, about 1:25 to about 1:150, about 1:25 to about 1:200, about 1:25 to about 1:1000, about 1:25 to about 1:5000, about 1:50 to about 1:100, about 1:50 to about 1:150, about 1:50 to about 1:200, about 1:50 to about 1:300, about 1:50 to about 1:500, about 1:50 to about 1:1000, about 1:50 to about 1:2000, about 1:50 to about 1:3000, about 1:50 to about 1:4000, or about 1:50 to about 1:5000.

[0197] For example, the mass ratio of the PDE4 selective inhibitor to the ascorbic acid or its derivative is about 1:50 to about 1:500.

[0198] In certain embodiments, the mass ratio of the PDE4 selective inhibitor to the ascorbic acid or its derivative is from about 1:300 to about 1:500.

[0199] For example, the effective amount ratio of the PDE4 selective inhibitor, the ascorbic acid or its derivative, and the platinum compound is about 1:10:0.1 to about 1:5000:10.

[0200] For example, the effective amount ratio of the PDE4 selective inhibitor, the ascorbic acid or its derivative, and the platinum compound is about 1:1:0.1 to about 1:20:1, about 1:5:0.5 to about 1:20:1, about 1:10:0.1 to about 1:20:0.5, about 1:10:2 to about 1:25:0.5, about 1:10:0.5 to about 1:50:0.5, about 1:10:0.5 to about 1:100:0.5, about 1:10:0.5 to about 1:150:0.5, about 1:10:0.5 to about 1:200:0.5, about 1:10 to about 1:250:0.5, about 1:10:0.5 to about 1:300:0.5, about 1:10 to about 1:300:0.5 :400:0.5, about 1:10:1 to about 1:450:1, about 1:10:2 to about 1:500:0.5, about 1:10:2 to about 1:550:2, about 1:10:0.5 to about 1:600:5, about 1:10:0.5 to about 1:650:1, about 1:10:1 to about 1:700:5, about 1:10:1 to about 1:800:2, about 1:10:0.5 to about 1:900:5, about 1:10:0.5 to about 1:1000:1, about 1:100:1 to about 1:1500:3, about 1:10:0.1 to about 1:2000:1, about 1:10:0.1 to about 1:3000:2, about 1:10:1 to about 1:400 0:1, about 1:10:0.5 to about 1:5000:1, about 1:5:0.5 to about 1:20:1, about 1:5:0.5 to about 1:25:1, about 1:50.5 to about 1:35:1, about 1:5:0.5 to about 1:50:1, about 1:5:0.5 to about 1:100:1, about 1:5:1 to about 1:150:2, about 1:5:0.5 to about 1:200:1, about 1:25:1 to about 1:50:1, about 1:25:1 to about 1:100:1, about 1:25:1 to about 1:150:2, about 1:25:1 to about 1:200:5, about 1:25:2 to about 1:1000:2, about 1:25:0.5 to about 1:5000: 1, about 1:50:0.5 to about 1:100:1, about 1:50:0.5 to about 1:150:2, about 1:50:0.5 to about 1:200:2, about 1:50:0.5 to about 1:300:5, about 1:50:0.5 to about 1:500:5, about 1:50:0.5 to about 1:1000:5, about 1:50:0.5 to about 1:2000:10, about 1:50:1 to about 1:4000:10, or about 1:50:5 to about 1:5000:10, about 1:4500:1 to about 1:5000:5, about 1:100:1 to about 1:2000:5, about 1:1000:0.5 to about 1:4000:5, about 1:1000:0.5 to about 1:5000:55 to about 1:3000:5, about 1:500:1 to about 1:5000:1, about 1:500:1 to about 1:2000:1. .

[0201] For example, the effective amount ratio of the PDE4 selective inhibitor, the ascorbic acid or its derivative, and the platinum compound is about 1:50:1 to about 1:500:1.

[0202] For example, the effective amount ratio of the PDE4 selective inhibitor, the ascorbic acid or its derivative, and the platinum compound is about 1:300:1 to about 1:500:1.

[0203] For example, the PDE4 selective inhibitor, the ascorbic acid or its derivatives, and the platinum compound can each be from different sources, such as prepared, produced, or sold by different merchants. For example, the ascorbic acid or its derivatives prepared, produced, or sold do not have to be single-component or pure, as long as they contain a compound capable of releasing ascorbic acid (vitamin C) in vivo or in vitro, or a solvate, hydrate, or salt thereof, and / or an analog containing ascorbic acid (e.g., wherein one or more hydroxyl groups of ascorbic acid are substituted with another structural moiety, and wherein the ascorbic acid analog substantially retains the stable activity of ascorbic acid in vitro or in vivo), all are within the scope of the present application. Similarly, the PDE4 selective inhibitors or platinum compounds prepared, produced or sold do not have to be single-ingredient or pure, as long as they contain any one or more of the PDE4 selective inhibitors or platinum compounds described in this application that can release in vivo or in vitro, or their solvates, hydrates, salts, and / or analogs containing any one or more of the PDE4 selective inhibitors or platinum compounds (for example, they contain group modifications or substitutions, and the analogs substantially maintain the stable activity of any PDE4 selective inhibitor or platinum compound in vitro or in vivo) are within the scope of this application.

[0204] For example, the PDE4 selective inhibitor and the ascorbic acid or its derivative are each present in different containers.

[0205] For example, the PDE4 selective inhibitor and the platinum compound are present in the same container, and the PDE4 selective inhibitor and the ascorbic acid or its derivative are present in separate containers.

[0206] For example, the ascorbic acid or its derivative and the platinum compound are present in the same container, and the ascorbic acid or its derivative and the PDE4 selective inhibitor are present in separate containers.

[0207] For example, the PDE4 selective inhibitor, the ascorbic acid or its derivative, and the platinum compound are each present in different containers.

[0208] For example, the amount of the PDE4 selective inhibitor, the amount of the ascorbic acid or its derivative, and the platinum compound may be set according to their effective amount ratio, or may not be set according to their effective ratio.

[0209] For example, the PDE4 selective inhibitor may be present in 1 or more containers, e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more.

[0210] For example, the ascorbic acid or derivative thereof may be present in 1 or more containers, such as 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more.

[0211] For example, the platinum compound can be present in 1 or more containers, such as 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, or 12 or more.

[0212] For example, the container may include a medicine box, a medicine box, a medicine bottle, a medicine bag, a blister, a tube, a syringe, etc.; for example, the medicine bottle may include a sealed glass ampoule, a test tube, a vial, a flask, a bottle, etc.; for example, the container may be made of an organic polymer such as glass, polycarbonate, polystyrene, or a packaging material lined with foil such as ceramic, metal, composite film, cellophane, aluminum or alloy, etc., and any other appropriate material that can generally be used to hold reagents.

[0213] For example, the PDE4 selective inhibitor, the platinum compound, and the ascorbic acid or its derivative can be present in different containers, and can be formulated into preparations with appropriate carriers simultaneously or separately when necessary.

[0214] For example, the PDE4 selective inhibitor, the platinum compound and the ascorbic acid or its derivative are mixed to prepare a suitable preparation.

[0215] For example, the PDE4 selective inhibitor, the platinum compound, and the ascorbic acid or its derivative are each formulated into different suitable preparations.

[0216] For example, the PDE4 selective inhibitor, the platinum compound, and the ascorbic acid or its derivative may be present in different containers in the form of preparations.

[0217] For example, the pharmaceutical combination comprises a first formulation comprising the ascorbic acid or a derivative thereof and a pharmaceutically acceptable first carrier, and a second formulation comprising the PDE4 selective inhibitor and a pharmaceutically acceptable second carrier.

[0218] For example, the pharmaceutical combination comprises a first formulation, a second formulation and a third formulation, wherein the first formulation comprises the ascorbic acid or its derivative and a pharmaceutically acceptable first carrier, the second formulation comprises the PDE4 selective inhibitor and a pharmaceutically acceptable second carrier, and the third formulation comprises the platinum compound and a pharmaceutically acceptable third carrier.

[0219] For example, the first preparation and the second preparation may be in the same dosage form or in different dosage forms.

[0220] For example, the second preparation and the third preparation may be in the same dosage form or in different dosage forms.

[0221] For example, the first preparation and the third preparation may be in the same dosage form or in different dosage forms.

[0222] For example, the first formulation, the second formulation, and the third formulation may be in the same dosage form.

[0223] For example, the first formulation, the second formulation, and the third formulation may be in different dosage forms.

[0224] For example, the first preparation, the second preparation, and the third preparation can all be in the form of a pill, a powder, a tablet, a granule, a gel, a hard capsule, a soft capsule, a syrup, a mixture, a dew, an injection, an aerosol, an ointment, a film, a suppository, a pill, or any combination thereof. For example, the first preparation, the second preparation, and the third preparation are all injections. For example, the first preparation and the second preparation are tablets, and the third preparation is an injection. For example, the first preparation and the third preparation are injections, and the second preparation is a tablet. For example, the second preparation and the third preparation are injections, and the first preparation is a tablet. For example, the first preparation is a tablet, the second preparation is a granule, and the third preparation is an injection.

[0225] For example, the first preparation, the second preparation and the third preparation can be present in the form of preparations suitable for the same mode of administration. For example, the first preparation, the second preparation and the third preparation can all be tablets, granules, hard capsules, soft capsules, syrups suitable for oral administration. For example, the first preparation, the second preparation and the third preparation can all be injections suitable for injection.

[0226] For example, the first preparation, the second preparation and the third preparation can be in the form of preparations suitable for different modes of administration. For example, the first preparation and the second preparation can be tablets, granules, hard capsules, soft capsules, syrups suitable for oral administration, and the third preparation can be an injection suitable for injection. For example, the first preparation and the third preparation can be injections suitable for injection, and the second preparation can be tablets, granules, hard capsules, soft capsules, syrups for oral administration. For example, the second preparation and the third preparation can be injections suitable for injection, and the first preparation can be tablets, granules, hard capsules, soft capsules, syrups for oral administration. For example, the first preparation can be an injection suitable for injection, and the second preparation can be tablets, granules, hard capsules, soft capsules, syrups for oral administration, and the third preparation can be a sustained-release preparation suitable for embedding sustained-release encapsulated in microcapsules, etc.

[0227] For example, the pharmaceutical combination comprises a pharmaceutical composition, and the pharmaceutical composition comprises the PDE4 selective inhibitor and the ascorbic acid or a derivative thereof.

[0228] For example, the pharmaceutical composition further comprises a platinum compound.

[0229] For example, the content of the PDE4 selective inhibitor in the pharmaceutical composition is about 0.01% to about 20% (w / w).

[0230] For example, the content of the PDE4 selective inhibitor in the pharmaceutical composition is about 0.01% (w / w) to about 0.5% (w / w), about 0.05% (w / w) to about 5% (w / w), about 0.5% (w / w) to about 5% (w / w), about 10% (w / w) to about 20% (w / w), about 1% (w / w) to about 10% (w / w), about 5% (w / w) to about 20% (w / w), about 0.2% (w / w) to about 4% (w / w), about 0.1% (w / w) to about 5% (w / w), about 3% (w / w) to about 20% (w / w), about 5% to about 20% (w / w), and about 1% (w / w) to about 15% (w / w).

[0231] For example, the content of the PDE4 selective inhibitor in the pharmaceutical composition is about 1% to about 5% (w / w).

[0232] For example, the content of the ascorbic acid or its derivative in the pharmaceutical composition is about 30% to about 99% (w / w).

[0233] For example, the content of the ascorbic acid or its derivatives is from about 30% (w / w) to about 60% (w / w), from about 40% (w / w) to about 60% (w / w), from about 30% (w / w) to about 50% (w / w), from about 50% (w / w) to about 60% (w / w), from about 50% (w / w) to about 70% (w / w), from about 60% (w / w) to about 80% (w / w), from about 50% (w / w) to about 90% (w / w), from about 60% (w / w) to about 90% (w / w), from about 55% (w / w) to about 75% (w / w), from about 70% (w / w) to about 90% (w / w), and from about 80 to about 95% (w / w).

[0234] For example, the content of the ascorbic acid or its derivative in the pharmaceutical composition is about 90% to about 98% (w / w).

[0235] For example, the content of the platinum compound in the pharmaceutical composition is about 0.01% (w / w) to about 0.5% (w / w), about 0.05% (w / w) to about 5% (w / w), about 0.5% (w / w) to about 5% (w / w), about 10% (w / w) to about 20% (w / w), about 1% (w / w) to about 10% (w / w), about 5% (w / w) to about 20% (w / w), about 0.2% (w / w) to about 4% (w / w), about 0.1% (w / w) to about 5% (w / w), about 3% (w / w) to about 20% (w / w), about 5% to about 20% (w / w), and about 1% (w / w) to about 15% (w / w).

[0236] For example, the content of the platinum compound in the pharmaceutical composition is about 1% to about 5% (w / w).

[0237] Reagent test kit

[0238] The kit of the present application may include the drug combination described in the present application. The drug combination may be provided in the form of a kit, wherein the different components of the drug combination may be packaged in different containers and mixed before administration, or administered separately without mixing.

[0239] For example, separate packaging may be used to allow long-term storage without losing the functionality of the active ingredients.

[0240] For example, the preparation contained in the kit can be present in any type of container in which the preparation components remain active for a long time, are not adsorbed by the container material, and are not easily deteriorated. For example, a sealed glass ampoule, for example, can be made of glass, polycarbonate, polystyrene and other organic polymers, ceramics, metal, or any other suitable material that can be commonly used to hold reagents. Other examples of suitable containers include simple bottles made of materials similar to ampoules and packaging materials lined with foil such as aluminum or alloys. Other containers include test tubes, vials, flasks, bottles, syringes, or the like. The container has a sterile access port such as a bottle, and the bottle has a stopper that can be penetrated by a hypodermic needle.

[0241] For example, the kit may also contain a buffer packaged in the presence of a neutral and non-reactive gas such as nitrogen.

[0242] For example, the kit may also include auxiliary administration devices, such as measuring cups and measuring spoons suitable for oral administration, and syringes, infusion tubes, and infusion needles suitable for injection.

[0243] For example, the kit may also include instructions for use. Instructions for use of the kit comprising the drug combination may be printed on paper or other materials, and / or provided on an electrically or electromagnetically readable medium such as a Floppy (registered trademark) disk, CD-ROM, DVD-ROM, Zip disk, videotape, or audiotape. Detailed instructions for use may be physically included in the kit or posted on a website designated by the kit manufacturer or distributor or notified by email, etc.

[0244] For example, the instructions for use may record the drug combination provided by the present application.

[0245] For example, the instructions for use may record the uses or methods provided by the present application.

[0246] Uses and methods

[0247] The present application provides the use of a combination of ascorbic acid or a derivative thereof and a PDE4 selective inhibitor in the preparation of a medicament for preventing and / or treating tumors. The present application also provides the use of a combination of ascorbic acid or a derivative thereof, a PDE4 selective inhibitor, and a platinum compound in the preparation of a medicament for preventing and / or treating tumors.

[0248] The present application also provides a method for preventing and / or treating tumors, comprising administering to a subject in need thereof:

[0249] a) an effective amount of ascorbic acid or a derivative thereof; and

[0250] b) an effective amount of a PDE4 selective inhibitor.

[0251] For example, the method further comprises administering to the subject in need thereof an effective amount of a platinum compound.

[0252] For example, the tumor includes solid tumors and / or non-solid tumors.

[0253] For example, the solid tumor can be selected from the group consisting of liver cancer, stomach cancer, lung cancer, breast cancer, colon cancer, rectal cancer, renal cell carcinoma, hepatocellular carcinoma, non-small cell lung cancer, small intestine cancer, esophageal cancer, melanoma, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, solid tumors in children, bladder cancer, kidney or ureter cancer, renal pelvis cancer, central nervous system (CNS) tumors, primary CNS lymphoma, tumor angiogenesis, spinal vertebral tumors, brain stem gliomas, pituitary adenomas, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, and metastatic lesions of the aforementioned cancers.

[0254] For example, the non-solid tumor can be selected from the group consisting of chronic lymphocytic leukemia (CLL), acute leukemia, acute lymphoid leukemia (ALL), B-cell acute lymphoid leukemia (B-ALL), T-cell acute lymphoid leukemia (T-ALL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell or large cell follicular lymphoma, malignant lymphoproliferative disorders, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin lymphoma, Hodgkin lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, and Waldenstrom macroglobulinemia.

[0255] For example, the tumor includes colon cancer and / or melanoma.

[0256] For example, the tumor includes tumors or tumor cells that are unresponsive to platinum compounds.

[0257] For example, the PDE4 selective inhibitor and the ascorbic acid or a derivative thereof are formulated to be administered to the subject simultaneously.

[0258] For example, the PDE4 selective inhibitor and the ascorbic acid or a derivative thereof are administered to the subject simultaneously.

[0259] For example, the simultaneous administration to the subject can include administering the PDE4 selective inhibitor and the ascorbic acid or its derivative to the subject within an interval of no more than 1 hour, for example, 60 minutes, 55 minutes, 50 minutes, 45 minutes, 40 minutes, 35 minutes, 30 minutes, 25 minutes, 20 minutes, 15 minutes, 10 minutes, 8 minutes, 5 minutes, 3 minutes, 2 minutes, 1 minute, or administering them together in a mixed form.

[0260] For example, the PDE4 selective inhibitor and the ascorbic acid or its derivative are formulated to be administered separately to a subject.

[0261] For example, the PDE4 selective inhibitor and the ascorbic acid or a derivative thereof are administered sequentially to the subject.

[0262] For example, the separate administrations to the subject can include administering the PDE4 selective inhibitor and the ascorbic acid or a derivative thereof to the subject with a time interval greater than 1 hour, for example, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 15 hours, 18 hours, 21 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or longer.

[0263] For example, the sequential administration to the subject can include administering the PDE4 selective inhibitor and the ascorbic acid or a derivative thereof to the subject with a time interval greater than 1 hour, for example, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 15 hours, 18 hours, 21 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or longer.

[0264] For example, the PDE4 selective inhibitor, the ascorbic acid or a derivative thereof, and the platinum compound are configured to be administered to the subject simultaneously.

[0265] For example, the PDE4 selective inhibitor, the ascorbic acid or a derivative thereof, and the platinum compound are administered to the subject simultaneously.

[0266] For example, the simultaneous administration to the subject may include administering the PDE4 selective inhibitor, the ascorbic acid or its derivative, and the platinum compound together in a mixed form.

[0267] For example, the PDE4 selective inhibitor, the ascorbic acid or its derivatives, and the platinum compound are configured to be administered to the subject in any order, and the order of administration may include the PDE4 selective inhibitor, the ascorbic acid or its derivatives, the platinum compound, or the PDE4 selective inhibitor, the platinum compound, the ascorbic acid or its derivatives, or the ascorbic acid or its derivatives, the PDE4 selective inhibitor, the platinum compound, or the ascorbic acid or its derivatives, the platinum compound, the PDE4 selective inhibitor, or the platinum compound, the ascorbic acid or its derivatives, the PDE4 selective inhibitor, or the platinum compound, the PDE4 selective inhibitor, or the platinum compound, the PDE4 selective inhibitor, or the platinum compound, the PDE4 selective inhibitor, and the ascorbic acid or its derivatives. The simultaneous administration to the subject may include the first administration of the PDE4 selective inhibitor, the ascorbic acid or its derivatives, and the platinum compound to the subject and the last administration to the subject being no more than 1 hour apart. For example, the time interval is 60 minutes, 55 minutes, 50 minutes, 45 minutes, 40 minutes, 35 minutes, 30 minutes, 25 minutes, 20 minutes, 15 minutes, 10 minutes, 8 minutes, 5 minutes, 3 minutes, 2 minutes, or 1 minute.

[0268] For example, the PDE4 selective inhibitor, the ascorbic acid or its derivative, and the platinum compound are formulated to be administered separately to a subject.

[0269] For example, the PDE4 selective inhibitor, the ascorbic acid or a derivative thereof, and the platinum compound are sequentially administered to the subject.

[0270] For example, the PDE4 selective inhibitor, the ascorbic acid or its derivatives, and the platinum compound are configured to be administered to the subject in any order, and the order of administration may include the PDE4 selective inhibitor, the ascorbic acid or its derivatives, the platinum compound, or the PDE4 selective inhibitor, the platinum compound, the ascorbic acid or its derivatives, or the ascorbic acid or its derivatives, the PDE4 selective inhibitor, the platinum compound, or the ascorbic acid or its derivatives, the platinum compound, the PDE4 selective inhibitor, or the platinum compound, the ascorbic acid or its derivatives, the PDE4 selective inhibitor, or the platinum compound, the PDE4 selective inhibitor, or the platinum compound, the PDE4 selective inhibitor, or the platinum compound, the PDE4 selective inhibitor, and the ascorbic acid or its derivatives. The separate administration to the subject may include a time interval of more than 1 hour between the first administration of the PDE4 selective inhibitor, the ascorbic acid or its derivatives, and the last administration of the platinum compound to the subject. For example, the time interval is 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 15 hours, 18 hours, 21 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or longer. The sequential administration of the PDE4 selective inhibitor, the ascorbic acid or its derivative, and the platinum compound to the subject may be performed with a time interval of more than 1 hour between the first administration and the last administration to the subject. For example, the time interval is 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 15 hours, 18 hours, 21 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or longer.

[0271] For example, the administering of the PDE4 selective inhibitor may include administering once.

[0272] For example, the administration of the PDE4 selective inhibitor may include consecutive administration for 2 or more times, e.g., 3 or more times, 4 or more times, 5 or more times, 6 or more times, 7 or more times, 8 or more times, 9 or more times, 10 or more times, followed by the administration of the ascorbic acid or its derivative or the platinum compound.

[0273] For example, the administering of the ascorbic acid or a derivative thereof may include administering once.

[0274] For example, the administration of the ascorbic acid or its derivative may comprise consecutive administration for 2 or more times, e.g., 3 or more times, 4 or more times, 5 or more times, 6 or more times, 7 or more times, 8 or more times, 9 or more times, 10 or more times, followed by the administration of the PDE4 selective inhibitor or the platinum compound.

[0275] For example, the administering of the platinum compound may include administering once.

[0276] For example, the administering of the platinum compound may include administering the compound 2 or more times, e.g., 3 or more times, 4 or more times, 5 or more times, 6 or more times, 7 or more times, 8 or more times, 9 or more times, 10 or more times in succession, followed by administering the PDE4 selective inhibitor or the platinum compound.

[0277] For example, the medicament is formulated such that the PDE4 selective inhibitor is administered at a dose of about 0.05 mg / kg to about 40 mg / kg.

[0278] For example, the PDE4 selective inhibitor is administered at a dose of about 0.05 mg / kg to about 40 mg / kg.

[0279] For example, the PDE4 selective inhibitor is administered at a dose of about 1 mg / kg to about 30 mg / kg, about 1 mg / kg to about 20 mg / kg, about 1 mg / kg to about 40 mg / kg, about 5 mg / kg to about 20 mg / kg, about 10 mg / kg to about 40 mg / kg, about 5 mg / kg to about 30 mg / kg, about 0.1 mg / kg to about 30 mg / kg, about 0.5 mg / kg to about 20 mg / kg, about 0.5 mg / kg to about 30 mg / kg, about 10 mg / kg to about 30 mg / kg, about 20 mg / kg to about 40 mg / kg.

[0280] For example, the PDE4 selective inhibitor is administered at a dose of about 1 mg / kg to about 30 mg / kg, about 1 mg / kg to about 20 mg / kg, about 1 mg / kg to about 40 mg / kg, about 5 mg / kg to about 20 mg / kg, about 10 mg / kg to about 40 mg / kg, about 5 mg / kg to about 30 mg / kg, about 0.1 mg / kg to about 30 mg / kg, about 0.5 mg / kg to about 20 mg / kg, about 0.5 mg / kg to about 30 mg / kg, about 10 mg / kg to about 30 mg / kg, about 20 mg / kg to about 40 mg / kg.

[0281] For example, the medicament is formulated such that the PDE4 selective inhibitor is administered at a dose of about 1 mg / kg to about 10 mg / kg.

[0282] For example, the PDE4 selective inhibitor is administered at a dose of about 1 mg / kg to about 10 mg / kg.

[0283] For example, the medicament is formulated such that the ascorbic acid or a derivative thereof is administered at a dose of about 0.05 g / kg to about 2.5 g / kg.

[0284] For example, the ascorbic acid or a derivative thereof is administered at a dose of about 0.05 g / kg to about 2.5 g / kg.

[0285] For example, the ascorbic acid or its derivatives are administered at a dosage of about 0.05 g / kg to about 0.1 g / kg, about 0.1 g / kg to about 0.2 g / kg, about 0.15 g / kg to about 0.25 g / kg, about 0.05 g / kg to about 0.15 g / kg, about 0.05 g / kg to about 2.5 g / kg, about 0.25 g / kg to about 1 g / kg, about 0.35 g / kg to about 0.5 g / kg, about 0.5 g / kg Doses of from about 1 g / kg to about 1 g / kg, from about 0.5 g / kg to about 2.5 g / kg, from about 0.5 g / kg to about 2 g / kg, from about 1 g / kg to about 2 g / kg, from about 1 g / kg to about 2.5 g / kg, from about 1.5 g / kg to about 2.5 g / kg, from about 0.1 g / kg to about 2.5 g / kg, from about 0.5 g / kg to about 2 g / kg, and from about 0.05 g / kg to about 0.2 g / kg are administered.

[0286] For example, about 0.05 g / kg to about 0.1 g / kg, about 0.1 g / kg to about 0.2 g / kg, about 0.15 g / kg to about 0.25 g / kg, about 0.05 g / kg to about 0.15 g / kg, about 0.05 g / kg to about 2.5 g / kg, about 0.25 g / kg to about 1 g / kg, about 0.35 g / kg to about 0.5 g / kg, about 0.5 g / kg to about 1 g / kg , about 0.5 g / kg to about 2.5 g / kg, about 0.5 g / kg to about 2 g / kg, about 1 g / kg to about 2 g / kg, about 1 g / kg to about 2.5 g / kg, about 1.5 g / kg to about 2.5 g / kg, about 0.1 g / kg to about 2.5 g / kg, about 0.5 g / kg to about 2 g / kg, about 0.05 g / kg to about 0.2 g / kg.

[0287] For example, the medicament is formulated such that the ascorbic acid or a derivative thereof is administered at a dose of about 0.5 g / kg to about 2 g / kg.

[0288] For example, the ascorbic acid or a derivative thereof is administered at a dose of about 0.5 g / kg to about 2 g / kg.

[0289] For example, the medicament is formulated such that the platinum compound is administered at a dose of about 0.05 mg / kg to about 40 mg / kg.

[0290] For example, the platinum compound is administered at a dose of about 0.05 mg / kg to about 40 mg / kg.

[0291] For example, the platinum compound is administered at a dose of about 1 mg / kg to about 30 mg / kg, about 1 mg / kg to about 20 mg / kg, about 1 mg / kg to about 40 mg / kg, about 5 mg / kg to about 20 mg / kg, about 10 mg / kg to about 40 mg / kg, about 5 mg / kg to about 30 mg / kg, about 0.1 mg / kg to about 30 mg / kg, about 0.5 mg / kg to about 20 mg / kg, about 0.5 mg / kg to about 30 mg / kg, about 10 mg / kg to about 30 mg / kg, about 20 mg / kg to about 40 mg / kg.

[0292] For example, the platinum compound is administered at a dose of about 1 mg / kg to about 30 mg / kg, about 1 mg / kg to about 20 mg / kg, about 1 mg / kg to about 40 mg / kg, about 5 mg / kg to about 20 mg / kg, about 10 mg / kg to about 40 mg / kg, about 5 mg / kg to about 30 mg / kg, about 0.1 mg / kg to about 30 mg / kg, about 0.5 mg / kg to about 20 mg / kg, about 0.5 mg / kg to about 30 mg / kg, about 10 mg / kg to about 30 mg / kg, about 20 mg / kg to about 40 mg / kg.

[0293] For example, the medicament is formulated such that the platinum compound is administered at a dose of about 1 mg / kg to about 10 mg / kg.

[0294] For example, the platinum compound is administered at a dose of about 1 mg / kg to about 10 mg / kg.

[0295] For example, the medicament is formulated such that the PDE4 selective inhibitor and the ascorbic acid or its derivative are administered in a mass ratio of about 1:5 to about 1:5000.

[0296] For example, the PDE4 selective inhibitor and the ascorbic acid or its derivative are administered in a mass ratio of about 1:5 to about 1:5000.

[0297] For example, the drug is formulated such that the PDE4 selective inhibitor and the ascorbic acid or its derivative are in a ratio of about 1:1 to about 1:20, about 1:5 to about 1:20, about 1:10 to about 1:20, about 1:10 to about 1:25, about 1:10 to about 1:50, about 1:10 to about 1:100, about 1:10 to about 1:150, about 1:10 to about 1:200, about 1:10 to about 1:250, about 1:10 to about 1:300, about 1:10 to about 1:400, about 1:10 to about 1:450. 0, about 1:10 to about 1:500, about 1:10 to about 1:550, about 1:10 to about 1:600, about 1:10 to about 1:650, about 1:10 to about 1:700, about 1:10 to about 1:800, about 1:10 to about 1:900, about 1:10 to about 1:1000, about 1:10 to about 1:1500, about 1:10 to about 1:2000, about 1:10 to about 1:3000, about 1:10 to about 1:4000, about 1:10 to about 1:5000, about 1:10 to about 1:2 0, about 1:5 to about 1:25, about 1:5 to about 1:35, about 1:5 to about 1:50, about 1:5 to about 1:100, about 1:5 to about 1:150, about 1:5 to about 1:200, about 1:25 to about 1:50, about 1:25 to about 1:100, about 1:25 to about 1:150, about 1:25 to about 1:200, about 1:25 to about 1:1000, about 1:25 to about 1:5000, about 1:50 to about 1:100, about 1:50 to about 1:150, about 1:50 to about 1: In some embodiments, the present invention relates to a method for preparing an aqueous solution of at least one alkyl amine, wherein the aqueous solution is preferably at least 1:200, about 1:50 to about 1:200, about 1:50 to about 1:4000, or about 1:50 to about 1:5000, about 1:4500 to about 1:5000, about 1:100 to about 1:2000, about 1:1000 to about 1:4000, about 1:100 to about 1:2000, about 1:1000 to about 1:4000, about 1:1000 to about 1:3000, about 1:500 to about 1:5000, about 1:500 to about 1:2000.

[0298] For example, from about 1:1 to about 1:20, from about 1:5 to about 1:20, from about 1:10 to about 1:20, from about 1:10 to about 1:25, from about 1:10 to about 1:50, from about 1:10 to about 1:100, from about 1:10 to about 1:150, from about 1:10 to about 1:200, from about 1:10 to about 1:250, from about 1:10 to about 1:300, from about 1:10 to about 1:400, from about 1:10 to about 1:450, from about 1:10 to about 1:500, from about 1:10 to about 1:550, from about 1:10 to about 1:5 10 to about 1:600, about 1:10 to about 1:650, about 1:10 to about 1:700, about 1:10 to about 1:800, about 1:10 to about 1:900, about 1:10 to about 1:1000, about 1:10 to about 1:1500, about 1:10 to about 1:2000, about 1:10 to about 1:3000, about 1:10 to about 1:4000, about 1:10 to about 1:5000, about 1:5 to about 1:20, about 1:5 to about 1:25, about 1:5 to about 1:35, about 1:5 to about 1:50, about 1:5 to about 1:100, about 1:5 to about 1:150, about 1:5 to about 1:200, about 1:25 to about 1:50, about 1:25 to about 1:100, about 1:25 to about 1:150, about 1:25 to about 1:200, about 1:25 to about 1:1000, about 1:25 to about 1:5000, about 1:50 to about 1:100, about 1:50 to about 1:150, about 1:50 to about 1:200, about 1:50 to about 1:300, about 1:50 to about 1: The PDE4 selective inhibitor and the ascorbic acid or a derivative thereof are administered in a mass ratio of about 1:50 to about 1:500, about 1:50 to about 1:1000, about 1:50 to about 1:2000, about 1:50 to about 1:4000, or about 1:50 to about 1:5000, about 1:4500 to about 1:5000, about 1:100 to about 1:2000, about 1:1000 to about 1:4000, about 1:1000 to about 1:3000, about 1:500 to about 1:5000, or about 1:50 to about 1:2000.

[0299] For example, the medicament is formulated such that the PDE4 selective inhibitor and the ascorbic acid or its derivative are administered in a mass ratio of about 1:50 to about 1:500.

[0300] For example, the PDE4 selective inhibitor and the ascorbic acid or its derivative are administered in a mass ratio of about 1:50 to about 1:500.

[0301] For example, the medicament is formulated such that the PDE4 selective inhibitor and the ascorbic acid or its derivative are administered in an effective amount ratio of about 1:5 to about 1:5000.

[0302] For example, the PDE4 selective inhibitor and the ascorbic acid or its derivative are administered in an effective amount ratio of about 1:5 to about 1:5000.

[0303] For example, the drug is formulated such that the PDE4 selective inhibitor and the ascorbic acid or its derivative are in a ratio of about 1:1 to about 1:20, about 1:5 to about 1:20, about 1:10 to about 1:20, about 1:10 to about 1:25, about 1:10 to about 1:50, about 1:10 to about 1:100, about 1:10 to about 1:150, about 1:10 to about 1:200, about 1:10 to about 1:250, about 1:10 to about 1:300, about 1:10 to about 1:400, about 1:10 to about 1:450. , about 1:10 to about 1:500, about 1:10 to about 1:550, about 1:10 to about 1:600, about 1:10 to about 1:650, about 1:10 to about 1:700, about 1:10 to about 1:800, about 1:10 to about 1:900, about 1:10 to about 1:1000, about 1:10 to about 1:1500, about 1:10 to about 1:2000, about 1:10 to about 1:3000, about 1:10 to about 1:4000, about 1:10 to about 1:5000, about 1:20 , about 1:5 to about 1:25, about 1:5 to about 1:35, about 1:5 to about 1:50, about 1:5 to about 1:100, about 1:5 to about 1:150, about 1:5 to about 1:200, about 1:25 to about 1:50, about 1:25 to about 1:100, about 1:25 to about 1:150, about 1:25 to about 1:200, about 1:25 to about 1:1000, about 1:25 to about 1:5000, about 1:50 to about 1:100, about 1:50 to about 1:150, about 1:50 to about 1:20 In some embodiments, an effective amount ratio of about 1:0, about 1:50 to about 1:300, about 1:50 to about 1:500, about 1:50 to about 1:1000, about 1:50 to about 1:2000, about 1:50 to about 1:4000, or about 1:50 to about 1:5000, about 1:4500 to about 1:5000, about 1:100 to about 1:2000, about 1:1000 to about 1:4000, about 1:1000 to about 1:3000, about 1:500 to about 1:5000, about 1:500 to about 1:2000 is administered.

[0304] For example, from about 1:1 to about 1:20, from about 1:5 to about 1:20, from about 1:10 to about 1:20, from about 1:10 to about 1:25, from about 1:10 to about 1:50, from about 1:10 to about 1:100, from about 1:10 to about 1:150, from about 1:10 to about 1:200, from about 1:10 to about 1:250, from about 1:10 to about 1:300, from about 1:10 to about 1:400, from about 1:10 to about 1:450, from about 1:10 to about 1:500, from about 1:10 to about 1:550, from about 1:10 to about 1:1 0 to about 1:600, about 1:10 to about 1:650, about 1:10 to about 1:700, about 1:10 to about 1:800, about 1:10 to about 1:900, about 1:10 to about 1:1000, about 1:10 to about 1:1500, about 1:10 to about 1:2000, about 1:10 to about 1:3000, about 1:10 to about 1:4000, about 1:10 to about 1:5000, about 1:5 to about 1:20, about 1:5 to about 1:25, about 1:5 to about 1:35, about 1:5 to about 1:5 about 1:50, about 1:5 to about 1:100, about 1:5 to about 1:150, about 1:5 to about 1:200, about 1:25 to about 1:50, about 1:25 to about 1:100, about 1:25 to about 1:150, about 1:25 to about 1:200, about 1:25 to about 1:1000, about 1:25 to about 1:5000, about 1:50 to about 1:100, about 1:50 to about 1:150, about 1:50 to about 1:200, about 1:50 to about 1:300, about 1:50 to about 1:5 The PDE4 selective inhibitor and the ascorbic acid or a derivative thereof are administered in an effective amount ratio of about 1:00, about 1:50 to about 1:1000, about 1:50 to about 1:2000, about 1:50 to about 1:4000, or about 1:50 to about 1:5000, about 1:4500 to about 1:5000, about 1:100 to about 1:2000, about 1:1000 to about 1:4000, about 1:1000 to about 1:3000, about 1:500 to about 1:5000, about 1:500 to about 1:2000.

[0305] For example, the medicament is formulated such that the PDE4 selective inhibitor and the ascorbic acid or its derivative are administered in an effective amount ratio of about 1:50 to about 1:500.

[0306] For example, the PDE4 selective inhibitor and the ascorbic acid or its derivative are administered in an effective amount ratio of about 1:5 to about 1:5000.

[0307] For example, the drug is formulated such that the PDE4 selective inhibitor, the ascorbic acid or its derivative, and the platinum compound are administered in a mass ratio (or effective amount ratio) of about 1:10:0.1 to about 1:5000:10.

[0308] For example, the PDE4 selective inhibitor, the ascorbic acid or its derivative, and the platinum compound are administered in a mass ratio (or effective amount ratio) of about 1:10:0.1 to about 1:5000:10.

[0309] For example, the drug is formulated such that the PDE4 selective inhibitor, the ascorbic acid or its derivative, and the platinum compound are in a ratio of about 1:1:0.1 to about 1:20:1, about 1:5:0.5 to about 1:20:1, about 1:10:0.1 to about 1:20:0.5, about 1:10:2 to about 1:25:0.5, about 1:10:0.5 to about 1:50:0.5, about 1:10:0.5 to about 1:100:0.5, about 1:10:0.5 to about 1:150:0.5, about 1:10:0.5 to about 1:200:0.5, about 1:10 to about 1:250:0.5, about 1:10:0.5 to about 1:300:0.5, about 1:10 to about about 1:400:0.5, about 1:10:1 to about 1:450:1, about 1:10:2 to about 1:500:0.5, about 1:10:2 to about 1:550:2, about 1:10:0.5 to about 1:600:5, about 1:10:0.5 to about 1:650:1, about 1:10:1 to about 1:700:5, about 1:10:1 to about 1:800:2, about 1:10:0.5 to about 1:900:5, about 1:10:0.5 to about 1:1000:1, about 1:100:1 to about 1:1500:3, about 1:10:0.1 to about 1:2000:1, about 1:10:0.1 to about 1:3000:2, about 1:10:1 to about 1:40 00:1, about 1:10:0.5 to about 1:5000:1, about 1:5:0.5 to about 1:20:1, about 1:5:0.5 to about 1:25:1, about 1:50.5 to about 1:35:1, about 1:5:0.5 to about 1:50:1, about 1:5:0.5 to about 1:100:1, about 1:5:1 to about 1:150:2, about 1:5:0.5 to about 1:200:1, about 1:25:1 to about 1:50:1, about 1:25:1 to about 1:100:1, about 1:25:1 to about 1:150:2, about 1:25:1 to about 1:200:5, about 1:25:2 to about 1:1000:2, about 1:25:0.5 to about 1:5000: 1, about 1:50:0.5 to about 1:100:1, about 1:50:0.5 to about 1:150:2, about 1:50:0.5 to about 1:200:2, about 1:50:0.5 to about 1:300:5, about 1:50:0.5 to about 1:500:5, about 1:50:0.5 to about 1:1000:5, about 1:50:0.5 to about 1:2000:10, about 1:50:1 to about 1:4000:10, or about 1:50:5 to about 1:5000:10, about 1:4500:1 to about 1:5000:5, about 1:100:1 to about 1:2000:5, about 1:1000:0.5 to about 1:4000:5, about 1:1000:0.5 to about 1:5000:55 to about 1:3000:5, about 1:500:1 to about 1:5000:1, about 1:500:1 to about 1:2000:1 mass ratio (or effective amount ratio) is applied.

[0310] For example, the mixture is prepared at a concentration of about 1:1:0.1 to about 1:20:1, about 1:5:0.5 to about 1:20:1, about 1:10:0.1 to about 1:20:0.5, about 1:10:2 to about 1:25:0.5, about 1:10:0.5 to about 1:50:0.5, about 1:10:0.5 to about 1:100:0.5, about 1:10:0.5 to about 1:150:0.5, about 1:10:0.5 to about 1:200:0.5, about 1:10 to about 1:250:0.5, about 1:10:0.5 to about 1:300:0.5, about 1:10 to about 1:400:0.5, about 1:10:1 to about 1:450:1, about 1:10: :2 to about 1:500:0.5, about 1:10:2 to about 1:550:2, about 1:10:0.5 to about 1:600:5, about 1:10:0.5 to about 1:650:1, about 1:10:1 to about 1:700:5, about 1:10:1 to about 1:800:2, about 1:10:0.5 to about 1:900:5, about 1:10:0.5 to about 1:1000:1, about 1:100:1 to about 1:1500:3, about 1:10:0.1 to about 1:2000:1, about 1:10:0.1 to about 1:3000:2, about 1:10:1 to about 1:4000:1, about 1:10:0.5 to about 1:5000 :1, about 1:5:0.5 to about 1:20:1, about 1:5:0.5 to about 1:25:1, about 1:50.5 to about 1:35:1, about 1:5:0.5 to about 1:50:1, about 1:5:0.5 to about 1:100:1, about 1:5:1 to about 1:150:2, about 1:5:0.5 to about 1:200:1, about 1:25:1 to about 1:50:1, about 1:25:1 to about 1:100:1, about 1:25:1 to about 1:150:2, about 1:25:1 to about 1:200:5, about 1:25:2 to about 1:1000:2, about 1:25:0.5 to about 1:5000:1, about 1:50:0.5 to about 1:100:1, about 1:50:0.5 to about 1:150:2, about 1:50:0.5 to about 1:200:2, about 1:50:0.5 to about 1:300:5, about 1:50:0.5 to about 1:500:5, about 1:50:0.5 to about 1:1000:5, about 1:50:0.5 to about 1:2000:10, about 1:50:1 to about 1:4000:10, or about 1:50:5 to about 1:5000:10, about 1:4500:1 to about 1:5000:5, about 1:100:1 to about 1:2000:5, about 1:1000:0.5 to about 1:4000:5, or about 1:50:5 to about 1:5000:10.The PDE4 selective inhibitor, the ascorbic acid or its derivative, and the platinum compound are administered in a mass ratio (or effective amount ratio) of about 1:5 to about 1:3000:5, about 1:500:1 to about 1:5000:1, or about 1:500:1 to about 1:2000:1.

[0311] For example, the drug is formulated such that the PDE4 selective inhibitor, the ascorbic acid or its derivative, and the platinum compound are administered in a mass ratio (or effective amount ratio) of about 1:50:1 to about 1:500:1.

[0312] For example, the PDE4 selective inhibitor, the ascorbic acid or its derivative, and the platinum compound are administered in a mass ratio (or effective amount ratio) of about 1:50:1 to about 1:500:1.

[0313] For example, the effective amount ratio may include an effective amount molar ratio and / or an effective amount mass ratio.

[0314] For example, the administration may include intravenous, arterial, subcutaneous, intramuscular, intradermal, intracavitary, intratumoral, or peritumoral administration. For example, oral administration, application, etc. The mode of administration depends on various factors. For example, to achieve an effective concentration at the tumor site, the drug can be administered via various routes, such as selective arterial perfusion, intracavitary perfusion (intracavitary), intraperitoneal or intrapleural, and intraspinal administration. For example, local administration, such as selective arterial, intratumoral, or peritumoral injection or placement, for example, administration in the form of slow release within the tumor, peritumoral, or tumor cavity.

[0315] PDE4 selective inhibitors

[0316] In the present application, the PDE4 selective inhibitor may include substances that can at least partially destroy or block the activity of one or more PDE4 subfamily members.

[0317] For example, the PDE4 subfamily member may include PDE4A, PDE4B, PDE4C and / or PDE4D.

[0318] For example, the PDE4 selective inhibitor may include a substance that at least partially destroys or blocks the activity of PDE4A, PDE4B, PDE4C, or PDE4D.

[0319] For example, the PDE4 selective inhibitor may include a substance that at least partially destroys or blocks the activity of PDE4C and PDE4D. For example, the PDE4 selective inhibitor may include a substance that at least partially destroys or blocks the activity of PDE4B and PDE4C. For example, the PDE4 selective inhibitor may include a substance that at least partially destroys or blocks the activity of PDE4B and PDE4D. For example, the PDE4 selective inhibitor may include a substance that at least partially destroys or blocks the activity of PDE4A and PDE4B. For example, the PDE4 selective inhibitor may include a substance that at least partially destroys or blocks the activity of PDE4A and PDE4C. For example, the PDE4 selective inhibitor may include a substance that at least partially destroys or blocks the activity of PDE4A and PDE4D.

[0320] For example, the PDE4 selective inhibitor can include a substance that at least partially destroys or blocks the activity of PDE4A, PDE4B, and PDE4C. For example, the PDE4 selective inhibitor can include a substance that at least partially destroys or blocks the activity of PDE4A, PDE4C, and PDE4D. For example, the PDE4 selective inhibitor can include a substance that at least partially destroys or blocks the activity of PDE4A, PDE4B, and PDE4D. For example, the PDE4 selective inhibitor can include a substance that at least partially destroys or blocks the activity of PDE4B, PDE4C, and PDE4D.

[0321] For example, the PDE4 selective inhibitors may include substances that at least partially destroy or block the activities of PDE4A, PDE4B, PDE4C, and PDE4C.

[0322] For example, the at least partial disruption or obstruction may include at least 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% disruption or obstruction.

[0323] For example, the PDE4 selective inhibitor does not substantially destroy or hinder the activity of other members of the PDEs family (except PDE4). For example, the substantially no destruction or hindrance can include up to 30%, 25%, 20%, 18%, 15%, 13%, 10%, 8%, 5%, 3%, 1% destruction or hindrance.

[0324] For example, other members of the PDEs family may include PDE1 subfamily members, PDE2 subfamily members, PDE3 subfamily members, PDE5 subfamily members, PDE6 subfamily members, PDE7 subfamily members, PDE8 subfamily members, PDE9 subfamily members, PDE10 subfamily members, PDE11 subfamily members, and PDE12 subfamily members.

[0325] For example, the activity may include the activity of hydrolyzing cAMP and / or cGMP. For example, the activity of hydrolyzing cAMP and / or cGMP may be measured by any method known to those skilled in the art.

[0326] For example, the PDE4 selective inhibitor may comprise Apremilast, Crisaborole, Drotaverine, CC-1088, BPN14770, GSK356278, HT-0712, TAK-648, Zembrin, ASP9831, Etazolate, Piclamilast, Rolipram, Cilomilast, GSK256066, AWD 12-281, Quinolyl oxazole, DC-TA-46, Filaminast and / or Glaucine.

[0327] For example, the PDE4 selective inhibitor comprises a compound represented by Formula I or a pharmaceutically acceptable salt thereof:

[0328]

[0329] wherein one of R1 and R2 is hydrogen, C1-C6 alkoxy, C3-C7 cycloalkyloxy, C3-C7 cycloalkylmethoxy, benzyl

[0330] Oxy, or a C1-C4 alkoxy group substituted entirely or partially by fluorine, and the other of R1 and R2 is entirely or partially

[0331] a C1-C4 oxy group substituted by fluorine, and

[0332] R3 is phenyl, pyridyl, phenyl substituted by R31, R32 and R33, or pyridyl substituted by R34, R35, R36 and R37, wherein:

[0333] R31 is hydroxy, halogen, cyano, carboxyl, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonyloxy, amino, mono- or di-C1-C4 alkylamino or C1-C4 alkylcarbonylamino,

[0334] R32 is hydrogen, hydroxy, halogen, amino, trifluoromethyl, C1-C4 alkyl or C1-C4 alkoxy,

[0335] R33 is hydrogen, halogen, C1-C4 alkyl or C1-C4 alkoxy,

[0336] R34 is hydroxy, halogen, cyano, carboxyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl or amino, R35 is hydrogen, halogen, amino or C1-C4 alkyl,

[0337] R36 is hydrogen or halogen, and

[0338] R37 is hydrogen or halogen.

[0339] For example, the PDE4 selective inhibitor comprises Roflumilast or a derivative thereof.

[0340] For example, the derivatives of Roflumilast include benzamide, bezafibrate and / or 4-Methylbenzanilide.

[0341] For example, the compound having the structure shown in Formula I may include compounds described in patent application (US5712298A), which is incorporated herein by reference.

[0342] For example, in formula I: R1 is hydrogen, C1-C6 alkoxy, C3-C7 cycloalkoxy, C3-C7 cycloalkylmethoxy, benzyloxy or C1-C4 alkoxy substituted entirely or partially by fluorine,

[0343] R2 is a C1-C4 alkoxy group which is fully or partially substituted by fluorine, and

[0344] R3 is phenyl, pyridyl, phenyl substituted by R31, R32 and R33, or pyridyl substituted by R34, R35, R36 and R37, wherein:

[0345] R31 is hydroxy, halogen, cyano, carboxyl, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonyloxy, amino, mono- or di-C1-C4 alkylamino or C1-C4 alkylcarbonylamino, R32 is hydrogen, hydroxy, halogen, amino, trifluoromethyl, C1-C4 alkyl or C1-C4 alkoxy, R33 is hydrogen, halogen, C1-C4 alkyl or C1-C4 alkoxy, R34 is hydroxy, halogen, cyano, carboxyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl or amino, R35 is hydrogen, halogen, amino or C1-C4 alkyl, R36 is hydrogen or halogen, and R37 is hydrogen or halogen.

[0346] For example, in formula I: R1 is hydrogen, C1-C6 alkoxy, C3-C7 cycloalkyloxy, C3-C7 cycloalkylmethoxy, benzyloxy or C1-C4 alkoxy substituted entirely or partially by fluorine, R2 is methoxy substituted entirely or partially by fluorine, and R3 is phenyl, pyridyl, phenyl substituted by R31, R32 and R33 or pyridyl substituted by R34, R35, R36 and R37, wherein: R31 is hydroxy, halogen, cyano, carboxyl, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonyloxy, amino, mono- or di-C1-C4 alkylamino or C1-C4 alkylcarbonylamino, R32 is hydrogen, hydroxy, halogen, amino, trifluoromethyl, C1-C4 alkyl or C1-C4 alkoxy, R33 is hydrogen, halogen, C1-C4 alkyl or C1-C4 alkoxy, R34 is hydroxy, halogen, cyano, carboxyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl or amino, R35 is hydrogen, halogen, amino or C1-C4 alkyl, R36 is hydrogen or halogen, and R37 is hydrogen or halogen.

[0347] For example, in Formula I: R1 is C3-C7 cycloalkyloxy, C3-C7 cycloalkylmethoxy or benzyloxy, R2 is C1-C4 alkoxy substituted in whole or in part by fluorine, and R3 is phenyl, pyridyl, phenyl substituted by R31, R32 and R33 or pyridyl substituted by R34, R35, R36 and R37, wherein:

[0348] R31 is hydroxy, halogen, cyano, carboxyl, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonyloxy, amino, mono- or di-C1-C4 alkylamino or C1-C4 alkylcarbonylamino, R32 is hydrogen, hydroxy, halogen, amino, trifluoromethyl, C1-C4 alkyl or C1-C4 alkoxy, R33 is hydrogen, halogen, C1-C4 alkyl or C1-C4 alkoxy, R34 is hydroxy, halogen, cyano, carboxyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl or amino, R35 is hydrogen, halogen, amino or C1-C4 alkyl, R36 is hydrogen or halogen, and R37 is hydrogen or halogen.

[0349] For example, in Formula I: R1 is a C1-C4 alkoxy group which is fully or partially substituted by fluorine, R2 is hydrogen, C1-C6 alkoxy, C3-C7 cycloalkoxy, C3-C7 cycloalkylmethoxy, benzyloxy or a C1-C4 alkoxy group which is fully or partially substituted by fluorine, and R3 is phenyl, pyridyl, phenyl substituted by R31, R32 and R33 or pyridyl substituted by R34, R35, R36 and R37, wherein:

[0350] R31 is hydroxy, halogen, cyano, carboxyl, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyl, C1-C4-alkylcarbonyloxy, amino, mono- or di-C1-C4 alkylamino or C1-C4 alkylcarbonylamino, R32 is hydrogen, hydroxy, halogen, amino, trifluoromethyl, C1-C4 alkyl or C1-C4 alkoxy, R33 is hydrogen, halogen, C1-C4 alkyl or C1-C4 alkoxy, R34 is hydroxy, halogen, cyano, carboxyl, 1-4C-alkyl, 1-4C-alkoxy, C1-C4 alkoxycarbonyl or amino, R35 is hydrogen, halogen, amino or 1-4C-alkyl, R36 is hydrogen or halogen, and R37 is hydrogen or halogen.

[0351] For example, in Formula I: R1 is a C1-C4 alkoxy group which is fully or partially substituted with fluorine, R2 is a C3-C7 cycloalkylmethoxy group or a benzyloxy group, and R3 is a phenyl group, a pyridyl group, a phenyl group substituted with R31, R32 and R33, or a pyridyl group substituted with R34, R35, R36 and R37, wherein:

[0352] R31 is hydroxy, halogen, cyano, carboxyl, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonyloxy, amino, mono- or di-C1-C4 alkylamino or C1-C4 alkylcarbonylamino, R32 is hydrogen, hydroxy, halogen, amino, trifluoromethyl, C1-C4 alkyl or C1-C4 alkoxy, R33 is hydrogen, halogen, C1-C4 alkyl or C1-C4 alkoxy, R34 is hydroxy, halogen, cyano, carboxyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl or amino, R35 is hydrogen, halogen, amino or C1-C4 alkyl, R36 is hydrogen or halogen, and R37 is hydrogen or halogen.

[0353] For example, in Formula I: R1 is C1-C4 alkoxy, C3-C5 cycloalkoxy, C3-C5 cycloalkylmethoxy, benzyloxy or C1-C4 alkoxy substituted entirely or partially by fluorine, R2 is C1-C4 alkoxy substituted entirely or partially by fluorine, and R3 is phenyl, pyridyl, phenyl substituted by R31, R32 and R33 or pyridyl substituted by R34, R35, R36 and R37, wherein:

[0354] R31 is halogen, cyano, carboxyl, C1-C4 alkyl, C1-C4 alkoxy or C1-C4 alkoxycarbonyl, R32 is hydrogen, halogen, C1-C4 alkyl or C1-C4 alkoxy, R33 is hydrogen, halogen, C1-C4 alkyl or C1-C4 alkoxy, R34 is halogen or C1-C4 alkyl, R35 is hydrogen or halogen, R36 is hydrogen or halogen, and R37 is hydrogen or halogen.

[0355] For example, in Formula I: R1 is C1-C4 alkoxy, C3-C5 cycloalkoxy, C3-C5 cycloalkylmethoxy, benzyloxy, or C1-C4 alkoxy substituted entirely or partially by fluorine, R2 is methoxy substituted entirely or partially by fluorine, and R3 is phenyl, pyridyl, phenyl substituted by R31, R32, and R33, or pyridyl substituted by R34, R35, R36, and R37, wherein:

[0356] R31 is halogen, cyano, carboxyl, C1-C4 alkyl, C1-C4 alkoxy or C1-C4 alkoxycarbonyl, R32 is hydrogen, halogen, C1-C4 alkyl or C1-C4 alkoxy, R33 is hydrogen, halogen, C1-C4 alkyl or C1-C4 alkoxy, R34 is halogen or C1-C4 alkyl, R35 is hydrogen or halogen, R36 is hydrogen or halogen, and R37 is hydrogen or halogen.

[0357] For example, in Formula I: R1 is C3-C5 cycloalkyloxy, C3-C5 cycloalkylmethoxy or benzyloxy, R2 is C1-C4 alkoxy substituted in whole or in part by fluorine, and R3 is phenyl, pyridyl, phenyl substituted by R31, R32 and R33 or pyridyl substituted by R34, R35, R36 and R37, wherein:

[0358] R31 is halogen, cyano, carboxyl, C1-C4 alkyl, C1-C4 alkoxy or C1-C4 alkoxycarbonyl, R32 is hydrogen, halogen, C1-C4 alkyl or C1-C4 alkoxy, R33 is hydrogen, halogen, C1-C4 alkyl or C1-C4 alkoxy, R34 is halogen or C1-C4 alkyl, R35 is hydrogen or halogen, R36 is hydrogen or halogen, and R37 is hydrogen or halogen.

[0359] For example, in Formula I: R1 is a C1-C4 alkoxy group which is fully or partially substituted by fluorine, R2 is a C1-C4 alkoxy group, a C3-C5 cycloalkoxy group, a C3-C5 cycloalkylmethoxy group, a benzyloxy group or a C1-C4 alkoxy group which is fully or partially substituted by fluorine, and R3 is a phenyl group, a pyridyl group, a phenyl group substituted by R31, R32 and R33 or a pyridyl group substituted by R34, R35, R36 and R37, wherein:

[0360] R31 is halogen, cyano, carboxyl, C1-C4 alkyl, C1-C4 alkoxy or C1-C4 alkoxycarbonyl, R32 is hydrogen, halogen, C1-C4 alkyl or C1-C4 alkoxy, R33 is hydrogen, halogen, C1-C4 alkyl or C1-C4 alkoxy, R34 is halogen or C1-C4 alkyl, R35 is hydrogen or halogen, R36 is hydrogen or halogen, and R37 is hydrogen or halogen.

[0361] For example, in Formula I: R1 is a C1-C4 alkoxy group which is fully or partially substituted with fluorine, R2 is a C3-C5 cycloalkylmethoxy group or a benzyloxy group, and R3 is a phenyl group, a pyridyl group, a phenyl group substituted with R31, R32 and R33, or a pyridyl group substituted with R34, R35, R36 and R37, wherein:

[0362] R31 is halogen, cyano, carboxyl, C1-C4 alkyl, C1-C4 alkoxy or C1-C4 alkoxycarbonyl, R32 is hydrogen, halogen, C1-C4 alkyl or C1-C4 alkoxy, R33 is hydrogen, halogen, C1-C4 alkyl or C1-C4 alkoxy, R34 is halogen or C1-C4 alkyl, R35 is hydrogen or halogen, R36 is hydrogen or halogen, and R37 is hydrogen or halogen.

[0363] For example, in formula I: R1 is C1-C4 alkoxy, C1-C4 cycloalkyloxy, C1-C4 cycloalkylmethoxy, benzyloxy or C1-C4 alkoxy substituted entirely or partially by fluorine, R2 is C1-C4 alkoxy substituted entirely or partially by fluorine, and R3 is 2-bromophenyl, 2,6-dichloro-4-ethoxycarbonylphenyl, 2,6-dimethoxyphenyl, 4-cyano-2-fluorophenyl, 2,4,6-trifluorophenyl, 2-chloro-6-methyl phenyl, 2,6-dimethylphenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 3,5-dichloropyridin-4-yl, 3-methylpyridin-2-yl, 2-chloropyridin-3-yl, 3,5-dibromopyridin-2-yl, 2,3,5,6-tetrafluoropyridin-4-yl, 3-chloro-2,5,6-trifluoropyridin-4-yl, 3,5-dichloro-2,6-difluoropyridin-4-yl or 2,6-dichloropyridin-3-yl.

[0364] For example, in formula I: R1 is C1-C4 alkoxy, C3-C5 cycloalkyloxy, C3-C5 cycloalkylmethoxy, benzyloxy or C1-C4 alkoxy substituted entirely or partially by fluorine, R2 is methoxy substituted entirely or partially by fluorine, and R3 is 2-bromophenyl, 2,6-dichloro-4-ethoxycarbonylphenyl, 2,6-dimethoxyphenyl, 4-cyano-2-fluorophenyl, 2,4,6-trifluorophenyl, 2-chloro-6-methylphenyl phenyl, 2,6-dimethylphenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 3,5-dichloropyridin-4-yl, 3-methylpyridin-2-yl, 2-chloropyridin-3-yl, 3,5-dibromopyridin-2-yl, 2,3,5,6-tetrafluoropyridin-4-yl, 3-chloro-2,5,6-trifluoropyridin-4-yl, 3,5-dichloro-2,6-difluoropyridin-4-yl or 2,6-dichloropyridin-3-yl.

[0365] For example, in formula I: R1 is C3-C5 cycloalkyloxy, C3-C5 cycloalkylmethoxy or benzyloxy, R2 is C1-C4 alkoxy substituted in whole or in part by fluorine, and R3 is 2-bromophenyl, 2,6-dichloro-4-ethoxycarbonylphenyl, 2,6-dimethoxyphenyl, 4-cyano-2-fluorophenyl, 2,4,6-trifluorophenyl, 2-chloro-6-methylphenyl, 2,6-dimethylphenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 3,5-dichloropyridin-4-yl, 3-methylpyridin-2-yl, 2-chloropyridin-3-yl, 3,5-dibromopyridin-2-yl, 2,3,5,6-tetrafluoropyridin-4-yl, 3-chloro-2,5,6-trifluoropyridin-4-yl, 3,5-dichloro-2,6-difluoropyridin-4-yl or 2,6-dichloropyridin-3-yl.

[0366] For example, in formula I: R1 is a C1-C4 alkoxy group which is completely or partially substituted by fluorine, R2 is a C1-C4 alkoxy group, a C3-C5 cycloalkyloxy group, a C3-C5 cycloalkylmethoxy group, a benzyloxy group or a C1-C4 alkoxy group which is completely or partially substituted by fluorine, and R3 is 2-bromophenyl, 2,6-dichloro-4-ethoxycarbonylphenyl, 2,6-dimethoxyphenyl, 4-cyano-2-fluorophenyl, 2,4,6-trifluorophenyl, 2-chloro-6-methylphenyl phenyl, 2,6-dimethylphenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 3,5-dichloropyridin-4-yl, 3-methylpyridin-2-yl, 2-chloropyridin-3-yl, 3,5-dibromopyridin-2-yl, 2,3,5,6-tetrafluoropyridin-4-yl, 3-chloro-2,5,6-trifluoropyridin-4-yl, 3,5-dichloro-2,6-difluoropyridin-4-yl or 2,6-dichloropyridin-3-yl.

[0367] For example, in formula I: R1 is a C1-C4 alkoxy group which is fully or partially substituted with fluorine, R2 is a C3-C5 cycloalkylmethoxy group or a benzyloxy group, and R3 is a 2-bromophenyl group, a 2,6-dichloro-4-ethoxycarbonylphenyl group, a 2,6-dimethoxyphenyl group, a 4-cyano-2-fluorophenyl group, a 2,4,6-trifluorophenyl group, a 2-chloro-6-methylphenyl group, a 2,6-dimethylphenyl group, a 2,6-dimethylphenyl group, a Fluorophenyl, 2,6-dichlorophenyl, 3,5-dichloropyridin-4-yl, 3-methylpyridin-2-yl, 2-chloropyridin-3-yl, 3,5-dibromopyridin-2-yl, 2,3,5,6-tetrafluoropyridin-4-yl, 3-chloro-2,5,6-trifluoropyridin-4-yl, 3,5-dichloro-2,6-difluoropyridin-4-yl or 2,6-dichloropyridin-3-yl.

[0368] For example, in formula I: R1 is difluoromethoxy, R2 is methoxy, ethoxy, isopropyloxy, isobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, difluoromethoxy or 2,2,2-trifluoroethoxy, and R3 is 2-bromophenyl, 2,6-dichloro-4-ethoxycarbonylphenyl, 2,6-dimethoxyphenyl, 4-cyano-2-fluorophenyl, 2,4,6-trifluorophenyl, 2-chloro-6-methylphenyl, 2 ,6-dimethylphenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 3,5-dichloropyridin-4-yl, 3-methylpyridin-2-yl, 2-chloropyridin-3-yl, 3,5-dibromopyridin-2-yl, 2,3,5,6-tetrafluoropyridin-4-yl, 3-chloro-2,5,6-trifluoropyridin-4-yl, 3,5-dichloro-2,6-difluoropyridin-4-yl or 2,6-dichloropyridin-3-yl.

[0369] For example, in Formula I: R1 is difluoromethoxy, R2 is methoxy, cyclopropylmethoxy, cyclobutylmethoxy or difluoromethoxy, and R3 is 2-bromophenyl, 2,6-dichloro-4-ethoxycarbonylphenyl, 2,6-dimethoxyphenyl, 4-cyano-2-fluorophenyl, 2,4,6-trifluorophenyl, 2-chloro-6-methylphenyl, 2,6-dimethylphenyl, 2,6-difluorophenyl phenyl, 2,6-dichlorophenyl, 3,5-dichloropyridin-4-yl, 3-methylpyridin-2-yl, 2-chloropyridin-3-yl, 3,5-dibromopyridin-2-yl, 2,3,5,6-tetrafluoropyridin-4-yl, 3-chloro-2,5,6-trifluoropyridin-4-yl, 3,5-dichloro-2,6-difluoropyridin-4-yl or 2,6-dichloropyridin-3-yl.

[0370] For example, in formula I: R1 is methoxy, n-propyloxy, n-butoxy, cyclopropylmethoxy or 2,2,2-trifluoroethoxy, R2 is difluoromethoxy, and R3 is 2-bromophenyl, 2,6-dichloro-4-ethoxycarbonylphenyl, 2,6-dimethoxyphenyl, 4-cyano-2-fluorophenyl, 2,4,6-trifluorophenyl, 2-chloro-6-methylphenyl, 2,6-dimethylphenyl, 2, 6-difluorophenyl, 2,6-dichlorophenyl, 3,5-dichloropyridin-4-yl, 3-methylpyridin-2-yl, 2-chloropyridin-3-yl, 3,5-dibromopyridin-2-yl, 2,3,5,6-tetrafluoropyridin-4-yl, 3-chloro-2,5,6-trifluoropyridin-4-yl, 3,5-dichloro-2,6-difluoropyridin-4-yl or 2,6-dichloropyridin-3-yl.

[0371] For example, in Formula I: R1 is difluoromethoxy, R2 is cyclopropylmethoxy, and R3 is 2-bromophenyl, 2,6-dichloro-4-ethoxycarbonylphenyl, 2,6-dimethoxyphenyl, 4-cyano-2-fluorophenyl, 2,4,6-trifluorophenyl, 2-chloro-6-methylphenyl, 2,6-dimethylphenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 3,5-dichloropyridin-4-yl, 3-methylpyridin-2-yl, 2-chloropyridin-3-yl, 3,5-dibromopyridin-2-yl, 2,3,5,6-tetrafluoropyridin-4-yl, 3-chloro-2,5,6-trifluoropyridin-4-yl, 3,5-dichloro-2,6-difluoropyridin-4-yl or 2,6-dichloropyridin-3-yl.

[0372] For example, the compound having the structure of formula I may include N-(3,5-dichloropyridin-4-yl)-4-difluoromethoxy-3-methoxybenzamide (melting point: 170° C.), N-(3,5-dichloropyridin-4-yl)-3,4-bis-difluoromethoxybenzamide (melting point: 134° C.), N-(3,5-dichloropyridin-4-yl)-3-cyclobutylmethoxy-4-difluoromethoxybenzamide (melting point: 155° C.), N-(3,5-dichloropyridin-4-yl)-3,4-bis-difluoromethoxybenzamide (melting point: 134° C.), chloropyridin-4-yl)-3-cyclopentyloxy-4-difluoromethoxybenzamide (melting point: 128.5-129°C), N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide (melting point: 158°C), N-(3,5-dichloro-2,6-difluoropyridin-4-yl)-3-difluoromethoxy-4-methoxybenzamide (melting point: 218°C), N-(2,6-dichlorophenyl)-3-difluoromethoxybenzamide 1-Methoxy-4-methoxybenzamide (melting point: 164°C), N-(2,6-dimethylphenyl)-3-difluoromethoxy-4-methoxybenzamide (melting point: 164°C), N-(2-chloropyridin-3-yl)-3-difluoromethoxy-4-methoxybenzamide (melting point: 165°C), N-(3,5-dibromopyridin-2-yl)-3-difluoromethoxy-4-methoxybenzamide (melting point: 143°C), N-(3,5-dichloropyridin-2-yl)-3-difluoromethoxy-4-methoxybenzamide (melting point: 143°C), pyridin-4-yl)-3-difluoromethoxy-4-methoxybenzamide (melting point: 178°C), N-(3,5-dichloropyridin-4-yl)-3-difluoromethoxy-4-propoxybenzamide (melting point: 159°C), N-(3,5-dichloropyridin-4-yl)-3-ethoxy-4-difluoromethoxybenzamide (melting point: 134°C), N-(3,5-dichloropyridin-4-yl)-benzyloxy-3-difluoromethoxybenzamide (melting point: 1 52°C), N-(3,5-dichloropyridin-4-yl)-4-butoxy-3-difluoromethoxybenzamide (melting point: 146°C), N-(3,5-dichloropyridin-4-yl)-4-cyclopropylmethoxy-3-difluoromethoxybenzamide (melting point: 159°C), N-(3,5-dichloropyridin-4-yl)-4-difluoromethoxy-3-(1-methylethoxy)benzamide (melting point: 99.5°C), N-(3,5-dichloropyridin-4-yl)-4-difluoromethoxy-3-(2,2,2-trifluoroethoxy)-benzamide (melting point: 147°C), N-(3,5-dichloropyridin-4-yl)-4-difluoromethoxy-3-(2-methylpropoxy)benzamide (melting point: 153°C), N-(2,3,5,6-tetrafluoropyridin-4-yl)-4-difluoromethoxy-3-methoxybenzamide (melting point: 146°C), N-(2,4,6-trifluorophenyl)-4-difluoromethoxy N-(2,6-dichloro-4-ethoxycarbonylphenyl)-4-difluoromethoxy-3-methoxybenzamide (melting point: 176°C), N-(2,6-dichlorophenyl)-4-difluoromethoxy-3-methoxybenzamide (melting point: 186°C), N-(2,6-difluorophenyl)-4-difluoromethoxy-3-methoxybenzamide (melting point: 139°C), N-(2,6-dimethylphenyl)-4-difluoromethoxy-3-methoxybenzamide amide (melting point: 143°C), N-(2-bromophenyl)-4-difluoromethoxy-3-methoxybenzamide (melting point: 121°C), N-(2-chloro-6-methylphenyl)-4-difluoromethoxy-3-methoxybenzamide (melting point: 144°C), N-(2-chloropyridin-3-yl)-4-difluoromethoxy-3-methoxybenzamide (melting point: 137.5°C), N-(2-methylphenyl)-4-difluoromethoxy-3-methoxybenzamide (melting point: 125°C), N-(3,5-difluorophenyl)-4-difluoromethoxy-3-methoxybenzamide (melting point: 137.5°C), N-(3-Bromopyridin-2-yl)-4-difluoromethoxy-3-methoxybenzamide (melting point: 141°C), N-(3,5-dichloro-2,6-difluoropyridin-4-yl)-4-difluoromethoxy-3-methoxybenzamide (melting point: 174°C), N-(3-chloro-2,5,6-trifluoropyridin-4-yl)-4-difluoromethoxy-3-methoxybenzamide (melting point: 141°C), N-(3-methylpyridin-2-yl)-4-difluoromethoxy-3-methoxybenzamide (melting point: 96°C).

[0373] Suitable salts of the compounds of formula I include, for example, all acid addition salts or all salts formed with bases, depending on the substitution reaction. Particularly noteworthy are salts prepared from pharmacologically tolerable inorganic and organic acids and bases commonly used in pharmacy. Pharmacologically intolerable salts, such as those which, when preparing the compounds of the present invention, must first be precipitated as intermediates on an industrial scale and then converted into pharmacologically tolerable salts using methods familiar to those skilled in the art. On the one hand, the suitable salt is a water-soluble and water-insoluble acid addition salt formed with an acid. Acids suitable for this aspect include, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)-benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, pamoic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid. Here, when preparing the salt, the acid used can be a monobasic or polybasic acid as needed, and the feeding ratio can be a molar quantitative ratio or a ratio deviating from the quantitative ratio depending on the type of salt required.

[0374] For example, salts can also be formed with bases. Examples of basic salts include lithium, sodium, potassium, calcium, aluminum, magnesium, titanium, ammonium, methylglucamine or guanidinium salts. In this case, the base can be added in a molar amount or in a deviating ratio when preparing the salt.

[0375] Platinum compounds

[0376] In the present application, the platinum compound may include a class of platinum-containing substances, for example, cisplatin (cisplatin, DDP), carboplatin (Carboplatin), heptaplatin, dernaplatin, enloplatin, cyclothiaplatin (cycloethylenediamine sulfate platinum), cisspiroplatin (spirosulfplatinamide), dexormaplatin, iproplatin, lobaplatin, miboplatin, nedaplatin, ormaplatin, oxaliplatin, sebriplatin, spiroplatin and / or zeniplatin.

[0377] Ascorbic acid and its derivatives

[0378] In the present application, the ascorbic acid and its derivatives include members selected from ascorbic acid (vitamin C), ascorbic acid derivatives and combinations thereof.

[0379] For example, the ascorbic acid derivative may further include ascorbic acid salt or a salt of an ascorbic acid derivative.

[0380] For example, the ascorbic acid derivative may further include dehydroascorbate or a salt thereof.

[0381] Ascorbic acid is sensitive to environmental factors (e.g., light, heat, oxygen) due to its α-ketolactone structure. It can be unstable in water or other aqueous solutions. Chemical stabilization of the ascorbic acid molecule has been used to prepare ascorbic acid derivatives that are more stable than the parent compound (e.g., see U.S. Patents Nos. 5,137,723A and 5,078,989A), the contents of which are incorporated herein by reference.

[0382] For example, the ascorbic acid derivative can be an ascorbic acid analog. Typical ascorbic acid derivatives include following compounds: at least one of the hydroxyl groups of the ascorbic acid molecule (e.g., 2-OH, 3-OH, 5-OH, 6-OH) is derived by a modified group (e.g., referring to U.S. Patent No. 5,078,989A of Ando et al.). For example, one or more of the hydroxyl groups can be substituted by another structural part. For example, the ascorbic acid and its derivatives include ascorbic acid and at least one ascorbic acid derivative.

[0383] For example, the ascorbic acid derivative may include a free 2-OH group and a free 3-OH group.

[0384] For example, the ascorbic acid derivatives include esters of ascorbic acid derived from at least one of 5-OH and 6-OH.

[0385] For example, the ascorbic acid derivatives include esters such as 6-O-octanoyl-ascorbic acid, 6-O-dodecanoyl-ascorbic acid, 6-O-tetradecanoyl-ascorbic acid, 6-O-octadecanoyl-ascorbic acid, 6-O-dodecandioyl-ascorbic acid, 6-O-docosandioyl-ascorbic acid, 6-O-thapsoyl-ascorbic acid, 6-O-sebacoyl-ascorbic acid, and 6-O-adipoyl-ascorbic acid.

[0386] For example, the ascorbic acid derivatives may also include esters wherein the lipophilic moiety of the molecule is a mono- or polyunsaturated fatty acid. For example, the unsaturated fatty acid may include essential fatty acids associated with health, such as ω-3 (α-linolenic acid), ω-6, or ω-9 fatty acids. Esters containing amino acid residues may also be included.

[0387] For example, the ascorbic acid derivatives may also include 2-O-alkyl or 3-O-alkyl derivatives of ascorbic acid. 3-O-alkyl-ascorbic acid was reported by Nihro et al. in Chem. Pharm. Bull. 1991, 39: 1731-1735, which is incorporated herein by reference.

[0388] For example, the ascorbic acid derivative may include glycosides of ascorbic acid; such as ascorbic acid 1-glycoside, ascorbic acid 2-glycoside, ascorbic acid 3-glycoside, ascorbic acid 5-glycoside and ascorbic acid 6-glycoside.

[0389] For example, the ascorbic acid derivatives may include 2-O-(α-D-glucopyranosyl)-ascorbic acid (see, for example, U.S. Pat. No. 5,137,723A) and 2-O-(β-D-glucopyranosyl)-ascorbic acid (see, for example, U.S. Patent Application No. US20050113312A1). The above documents are incorporated herein by reference.

[0390] For example, the ascorbic acid derivative may include a difunctionalized derivative of ascorbic acid, such as, for example, 6-O-acyl-2-O-(α-D-glucopyranosyl)ascorbic acid (see, for example, Yamamoto et al., J. Med. Chem. 2002, 45(2): 462-468. This document is incorporated herein by reference.

[0391] For example, ascorbic acid derivatives can include phosphates of ascorbic acid. For example, ascorbic acid phosphate is an alkali metal salt, an alkaline earth metal salt or a transition metal salt. For example, magnesium ascorbyl phosphate, sodium ascorbyl phosphate (e.g., sodium ascorbyl-2-monophosphate), calcium ascorbyl phosphate, potassium ascorbyl phosphate and mixed salts, for example, sodium magnesium ascorbyl phosphate, sodium calcium ascorbyl phosphate, aminopropyl ascorbyl phosphate.

[0392] For example, ascorbic acid phosphate can exist as a hydrate, of which dihydrate is common. A typical dihydrate can be purchased from DSM under the product name STAY-C50.

[0393] In the present application, the ascorbic acid derivative comprises a pharmaceutically acceptable ascorbate.

[0394] For example, the pharmaceutically acceptable ascorbate salts include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, basic amino acid salts such as arginine, and organic amine salts such as triethanolamine.

[0395] For example, the salt of ascorbate or an ascorbic acid derivative may be an edible (eg, pharmaceutically acceptable) salt, such as calcium, sodium, magnesium, potassium, and zinc salts, and mixed salts of ascorbic acid or an ascorbic acid derivative.

[0396] For example, the pharmaceutically acceptable salt of ascorbate comprises sodium ascorbate.

[0397] Other well-known ascorbic acid derivatives are also useful for the purposes of this application.

[0398] Carriers and formulations

[0399] The ascorbic acid or its derivatives, the PDE4 selective inhibitors, and the platinum compounds described herein can each be an independent preparation (i.e., the first preparation, the second preparation, and the third preparation), or can be prepared as a suitable preparation in the form of a composition, for example, a combination of the ascorbic acid or its derivatives described herein and the PDE4 selective inhibitors described herein, for example, a combination of the ascorbic acid or its derivatives described herein and the platinum compounds described herein, for example, a combination of the PDE4 selective inhibitors described herein and the platinum compounds described herein, for example, a combination of the ascorbic acid or its derivatives described herein, the PDE4 selective inhibitors described herein, and the platinum compounds described herein. Regardless of whether the preparation is prepared independently or as a composition, it can be combined with any suitable carrier to obtain the desired preparation type.

[0400] For example, the dosage form of the first preparation, the second preparation, the third preparation or the pharmaceutical composition may include tablets, capsules, granules, powders, syrups, suspensions, suppositories, ointments, creams, gels, patches, inhalants, injections, etc. These preparations can be prepared according to conventional methods.

[0401] For example, in the case of liquid preparations, the preparations may be dissolved or suspended in water or other appropriate solvents at the time of use.

[0402] For example, tablets and granules can be coated by a known method.

[0403] For example, in the case of an injection, the active ingredient (including the ascorbic acid or its derivatives described in the present application, the PDE4 selective inhibitor described in the present application, and the platinum compound described in the present application) can be dissolved in water for preparation, or dissolved in physiological saline or glucose solution as needed. For example, a buffer or preservative can also be added.

[0404] For example, the drug can be provided in any dosage form for oral or parenteral administration. For example, the drug can be prepared as a preparation for oral administration in the form of granules, fine granules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions, or liquids.

[0405] For example, the drug may be in the form of a parenteral preparation for intravenous administration, intramuscular administration, intradermal administration, intracavitary administration, intratumoral administration, peritumoral administration or subcutaneous administration, such as an injection, a drip, a transdermal absorption agent, a transmucosal absorption agent, a nasal drop, an inhaler, a suppository, or the like.

[0406] For example, injections, drips, and the like can be prepared in a powdered dosage form such as a freeze-dried form, and dissolved in a suitable aqueous medium such as physiological saline before use.

[0407] For example, a sustained-release preparation covered with a polymer or the like can also be directly administered to an organ tissue or tumor such as the brain, blood, or lymph. For example, the sustained-release preparation can include a sustained-release pump, a sustained-release capsule, a sustained-release agent, an implant, or a sustained-release implant.

[0408] Regarding the type of pharmaceutical additive (carrier) used in the manufacture of pharmaceutical preparations, the ratio of the pharmaceutical additive (carrier) to the active ingredient, or the method for manufacturing the preparation, those skilled in the art can appropriately select according to the form of the preparation. For example, as a pharmaceutical additive (carrier), an inorganic or organic substance, or a solid or liquid substance can be used, for example, and can be blended in an amount of 1% to 90% by weight relative to the weight of the active ingredient. For example, the carrier can include lactose, glucose, mannitol, dextrin, cyclodextrin, starch, sucrose, magnesium aluminum metasilicate, synthetic aluminum silicate, sodium carboxymethylcellulose, hydroxypropyl starch, calcium carboxymethylcellulose, ion exchange resin, methylcellulose, gelatin, gum arabic, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, polyvinyl alcohol, light anhydrous silicic acid, magnesium stearate, talc, tragacanth gum, bentonite, propolis, titanium oxide, sorbitan fatty acid esters, sodium lauryl sulfate, glycerin, fatty acid glycerides, purified lanolin, glyceryl gelatin, polysorbate, polyethylene glycol, vegetable oil, wax, liquid paraffin, white petrolatum, fluorocarbons, nonionic surfactants, propylene glycol, water, etc.

[0409] For example, when manufacturing a solid preparation for oral administration, the active ingredient (including the ascorbic acid or its derivatives described in the present application, the PDE4 selective inhibitor described in the present application, and the platinum compound described in the present application) can be mixed with a carrier component such as lactose, starch, crystalline cellulose, calcium lactate, anhydrous silicic acid, etc. to prepare a powder; for example, a binder such as sucrose, hydroxypropyl cellulose, polyvinyl pyrrolidone, a disintegrant such as carboxymethyl cellulose, carboxymethyl cellulose calcium, etc. can be further added as needed and wet or dry granulation can be performed to prepare granules; for example, when manufacturing tablets, the powder and / or granules can be directly tableting; for example, lubricants such as magnesium stearate and talc can be added for tableting; for example, the granules or tablets can be coated with enteric solvent matrices such as hydroxypropyl methylcellulose phthalate, methacrylic acid-methyl methacrylate polymer to prepare enteric solvent preparations; for example, ethyl cellulose, carnauba wax, hydrogenated oil, etc. can be coated to prepare long-acting preparations; for example, when manufacturing capsules, powders or granules can be filled in hard capsules, for example, the active ingredients can be directly or dissolved in glycerol, polyethylene glycol, sesame oil, olive oil, etc. and then covered with gelatin film to prepare soft capsules.

[0410] For example, when preparing an injection, the active ingredient can be dissolved in distilled water for injection along with a pH adjuster such as hydrochloric acid, sodium hydroxide, lactose, lactic acid, sodium, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium chloride, glucose, or an isotonic agent as needed. For example, the active ingredient can be further sterile-filtered and filled into an ampoule. For example, mannitol, dextrin, cyclodextrin, gelatin, etc. can be further added and vacuum-freezed to produce a disintegrating injection. For example, lecithin, polysorbate 80, polyoxyethylene hydrogenated castor oil, etc. can be added to the active ingredient and emulsified in water to produce an injection emulsion.

[0411] For example, when producing a formulation for rectal administration, the active ingredient can be moistened and dissolved together with a suppository base material such as cocoa butter, fatty acid triglycerides, fatty acid diglycerides, fatty acid monoglycerides, or polyethylene glycol, and then poured into a mold and cooled. Alternatively, the active ingredient can be dissolved in polyethylene glycol, soybean oil, or the like and then coated with a gelatin film.

[0412] For example, when manufacturing external preparations for skin use, the active ingredient can be added to white petrolatum, beeswax, liquid paraffin, polyethylene glycol, etc., moistened and kneaded as needed to make an ointment; for example, it can also be kneaded with an adhesive such as rosin or alkyl acrylate polymer and then extended on a non-woven fabric such as polyalkyl to make a tape-shaped preparation.

[0413] For example, it can also be used as an implant or a sustained-release formulation such as a delivery system encapsulated in a microcapsule, which can be prepared using a carrier that can prevent immediate removal from the body. For example, biodegradable and biocompatible polymers such as ethylene-vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Those skilled in the art can easily prepare these materials. For example, a liposomal suspension can also be used as a pharmaceutically acceptable carrier. The liposome can include a lipid composition made containing phosphatidylcholine, cholesterol, and PEG-derivatized phosphatidylethanolamine (PEG-PE), which can be prepared by a filter of appropriate pore size and purified by reverse phase evaporation.

[0414] In the present application, the dosage and the number of administrations can be appropriately selected according to the purpose of preventing and / or treating the progression of the disease of the subject (subject), the type of disease, the patient's weight, age and other conditions. For example, oral administration can be divided into once a day or several times, or can be administered every few days. When used as an injection, it can be administered continuously or intermittently.

[0415] Without intending to be bound by any theory, the following examples are merely intended to illustrate the drug combination, method of use and application of the present application, and are not intended to limit the scope of the invention of the present application.

[0416] Example

[0417] C57 mice used in this application were purchased from Weitonglihua Laboratory Animal Technology Co., Ltd.; MC38 cells were purchased from ATCC; roflumilast was purchased from Aladdin, Catalog No. R126602; oxaliplatin was purchased from Aladdin, Catalog No. O124003; and sodium ascorbate was purchased from Aladdin, Catalog No. S105024. Oxaliplatin and roflumilast were used in DMSO, while sodium ascorbate was used in PBS.

[0418] Data processing: All data are expressed as mean ± standard deviation (mean ± SD) and analyzed by one-way ANOVA using GraphPad Prism 7.0 software. P < 0.05 indicates statistical significance. * indicates P < 0.05, ** indicates P < 0.01, and *** indicates P < 0.001.

[0419] The drug interaction coefficient (CDI) was used to evaluate the nature of drug interactions. The cells were divided into a control group, a drug A group, a drug B group, and a drug AB combination group. The cell viability of the A, B, and AB groups was tested.

[0420] CDI = cell activity of group AB / cell activity of group A * cell activity of group B. If CDI < 1, it proves that the nature of the drug effect is synergistic. When CDI < 0.7, the synergistic effect of the drug is very significant. If CDI = 1, the nature of the drug effect is additive. If CDI > 1, the nature of the drug effect is antagonistic.

[0421] Example 1 Effects of Roflumilast and Sodium Ascorbate on Inhibiting Colon Cancer

[0422] (1) Tumor formation in mice. 6-8 week old female C57 mice were selected and MC38 cells were cultured in vitro to the logarithmic phase. The cells were collected and resuspended in PBS buffer solution. The collected cells were injected subcutaneously into the mammary gland of mice. Each mouse was injected with 5×10 5 MC38 cells were used to establish an orthotopic tumor model.

[0423] (2) After tumor formation, the mice were divided into four experimental groups: blank control, Roflumilast group, sodium ascorbate group, and Roflumilast + sodium ascorbate group. Every 3 days, mice in the Roflumilast + sodium ascorbate group were intraperitoneally injected with 4 mg / kg of Roflumilast and intravenously injected with 1.5 g / kg of sodium ascorbate for a total of 5 times. At the same time, the Roflumilast group and the sodium ascorbate group were injected with the same dose of Roflumilast and sodium ascorbate in the same manner, and the blank control was injected with the same dose of normal saline. The day of the first injection was designated as day 1, and the weight and tumor size of the mice were recorded thereafter: tumor volume (mm 3 ) = length (L) × width (W) 2 / 2, and luciferin fluorescence imaging of the tumor was performed by intraperitoneal injection of 100 μL of a 1 mg / mL D-luciferin potassium aqueous solution into each mouse. 10 minutes after injection, luciferin fluorescence imaging was performed using a small animal in vivo imaging system (model: IVISLumina XRMS Series III).

[0424] The results are as follows Figure 1-4 shown. Figure 1 The Luciferin fluorescence imaging results of each group on the 18th day. Figure 2 This is a statistical graph of Luciferin fluorescence imaging results. Figure 1 and Figure 2 All showed that compared with the blank control, Roflumilast group, and sodium ascorbate group, the combination of Roflumilast and sodium ascorbate group significantly inhibited tumor growth. Figure 3The figure shows the statistical change of tumor volume over time. Compared with the blank control, Roflumilast group and sodium ascorbate group, the combination of Roflumilast and sodium ascorbate group significantly inhibited tumor growth. The significant difference analysis between the combination group and Roflumilast alone group on day 18 showed P < 0.001. Figure 4 The results showed that Roflumilast and sodium ascorbate had no effect on the body weight of mice compared with the control group, whether in the single-drug group or the combination group, indicating good safety.

[0425] Example 2 Roflumilast and sodium ascorbate enhance the tumor inhibition effect of oxaliplatin

[0426] The effect of Roflumilast and sodium ascorbate on the tumor inhibition effect of oxaliplatin was verified in the manner of Example 1. Mice were divided into 5 experimental groups: blank control, Roflumilast group, sodium ascorbate group, oxaliplatin group, Roflumilast+sodium ascorbate+oxaliplatin. Every 3 days, mice in the Roflumilast+sodium ascorbate+oxaliplatin group were injected intraperitoneally with 4 mg / kg of Roflumilast and 4 mg / kg of oxaliplatin, and intravenously injected with 1.5 g / kg of sodium ascorbate, for a total of 6 doses. At the same time, the Roflumilast group, sodium ascorbate group, and oxaliplatin group were injected with the same dose of Roflumilast, ascorbic acid, and oxaliplatin respectively, and the blank control was injected with the same dose of normal saline. The day of the first injection was taken as day 0, and the body weight and tumor size of the mice were detected and recorded afterwards: tumor volume (mm 3 ) = length (L) × width (W) 2 / 2.

[0427] The results are as follows Figure 5 and Figure 6 As shown, Roflumilast and sodium ascorbate can significantly enhance the tumor inhibition effect of oxaliplatin and have no effect on the body weight of mice, showing good safety. Figure 5 The results showed that the significant difference between the combination of Roflumilast + sodium ascorbate + oxaliplatin group and the oxaliplatin group on day 21 was P < 0.001.

[0428] Example 3 Inhibitory Effects of Combination of PDE4 Selective Inhibitor and Sodium Ascorbate on Colon Cancer Cells / Melanoma Cells

[0429] 1.1 Cell lines and cell culture

[0430] MC38 human colon cancer cells, HCT116 human colon cancer cells, and A375 cells were subcultured using RPMI-1640 medium containing 10% fetal bovine serum (FBS) in an incubator at 37°C and 5% carbon dioxide.

[0431] 1.2 Cell viability assay after single-drug administration

[0432] (1) After the cells plated on a 10 cm culture plate have grown to a density of about 90%, remove the culture medium and wash the adherent cells with PBS buffer. Add 1 mL of trypsin, mix well, and immediately discard. Place in an incubator to digest for about 5 minutes. Then, add about 10 mL of fresh culture medium and aspirate 10 μL for counting.

[0433] (2) After counting, dilute the cells to 1*10 per mL. 5 The diluted cells were plated into a 96-well plate at a rate of 100 μL per well, i.e., approximately 10,000 cells per well.

[0434] (3) After the cells were plated in a 96-well plate and cultured for 24 hours, different concentration gradients of PDE4 selective inhibitors were added thereto, including Benzanilide, 4-Methylbenzanilide, Apremilast, Crisaborole, and Drotaverine.

[0435] (4) 24 hours after drug addition, add 10 μL of CCK-8 solution and incubate in an incubator for 1-2 hours. Use a microplate reader to measure the absorbance (OD value) of each well at 490 nm and record the results. Calculate the relative cell activity:

[0436] Cell activity = (absorbance of experimental group - absorbance of blank group) / (absorbance of control group - absorbance of blank group) × 100%

[0437] The experimental group consisted of cells treated with varying concentrations of drug, the control group consisted of cells treated with only solvent, and the blank group consisted of cells treated with only solvent. The cell activity results were calculated using the formula: drug cell inhibition rate = 100% - cell activity. The cell activity of the control group, calculated using this formula, was 100%.

[0438] 1.3 Drug combination cell counting

[0439] (1) After the cells plated on a 10 cm culture plate have grown to a density of about 90%, remove the culture medium and wash the adherent cells with PBS buffer. Add 1 mL of trypsin, mix well, and immediately discard. Place in an incubator to digest for about 5 minutes. Then, add about 10 mL of fresh culture medium and aspirate 10 μL for counting.

[0440] (2) Pipette 10uL of the mixed cells into 10uL of trypan blue solution and count.

[0441] (3) After counting, dilute the cells to 1*10 per mL. 5 After the diluted cells are mixed, 500uL / well is pipetted into a 24-well plate, i.e., approximately 50,000 cells per well.

[0442] (4) After culturing cells plated in 24-well plates for approximately 24 hours, drugs were added. The experimental groups were as follows: 1) PDE4 selective inhibitor monotherapy, 2) sodium ascorbate, 3) PDE4 selective inhibitor combined with sodium ascorbate. The drug concentrations in the combination groups were the same as those in the monotherapy groups. 4) Control group: cells were treated with the same volume of solvent as in the PDE4 selective inhibitor monotherapy group. The PDE4 selective inhibitors were: Benzanilide, 4-Methylbenzanilide, Apremilast, Crisaborole, and Drotaverine.

[0443] (5) About 24 hours after drug addition, discard the culture medium, add about 150 μL of trypsin and discard it, and digest for about 5 minutes;

[0444] (6) After digestion, add the same amount of PBS to each well and mix thoroughly. Then, add 10 μL / well of trypan blue solution and mix thoroughly. Pipet 10 μL of the mixed solution and count the cells. Calculate the cell viability of each group according to the formula "Cell viability = number of cells in experimental group / number of cells in control group x 100%."

[0445] 1.4 Data Processing

[0446] Data are expressed as mean ± standard deviation (mean ± SD) and analyzed by one-way ANOVA using GraphPad Prism 7.0 software. P < 0.05 indicates statistical significance. * indicates P < 0.05, ** indicates P < 0.01, and *** indicates P < 0.001.

[0447] The drug interaction coefficient (CDI) was used to evaluate the nature of drug interactions. The cells were divided into a control group, a drug A group, a drug B group, and a drug AB combination group. The cell viability of the A, B, and AB groups was tested.

[0448] CDI = cell activity of group AB / cell activity of group A * cell activity of group B. If CDI < 1, it proves that the nature of the drug effect is synergistic. When CDI < 0.7, the synergistic effect of the drug is very significant. If CDI = 1, the nature of the drug effect is additive. If CDI > 1, the nature of the drug effect is antagonistic.

[0449] The results showed that the inhibitory effects of the above drugs combined with sodium ascorbate on colon cancer cells / melanoma cells were significantly better than those of the corresponding single-drug groups, and the two had a synergistic effect.

[0450] Example 4 Effect of Combination of PDE4 Selective Inhibitor and Sodium Ascorbate on the Inhibitory Effect of Platinum Compounds on Colon Cancer Cells / Melanoma Cells

[0451] The effect of a PDE4 selective inhibitor combined with sodium ascorbate on the inhibitory activity of platinum compounds against colon cancer cells and melanoma cells was examined using the method described in Example 3. The platinum compounds included oxaliplatin, cisplatin, and carboplatin, and the PDE4 selective inhibitors included benzanilide, 4-Methylbenzanilide, apremilast, crisaborole, and drotaverine. The experimental groups were as follows: 1) a PDE4 selective inhibitor alone; 2) a sodium ascorbate group; 3) a platinum compound alone; 4) a PDE4 selective inhibitor combined with sodium ascorbate; 5) a PDE4 selective inhibitor, sodium ascorbate, and platinum compound combination group, with the drug concentrations in these combination groups being the same as those in the monotherapy groups; and 6) a control group, consisting of cells treated with the same volume of solvent as in the PDE4 selective inhibitor alone group.

[0452] The results showed that the above drugs and sodium ascorbate can significantly enhance the inhibitory effect of various platinum compounds on tumor cells.

[0453] Example 5 Inhibitory Effects of Combination of PDE4 Selective Inhibitor and Dehydroascorbic Acid on Colon Cancer Cells / Melanoma Cells

[0454] The inhibitory effects of PDE4 selective inhibitors combined with dehydroascorbic acid on colon cancer cells and melanoma cells were tested using the methods described in Example 3. The PDE4 selective inhibitors were: roflumilast, benzamide, 4-Methylbenzanilide, apremilast, crisaborole, and drotaverine. The results showed that the inhibitory effects of each of these drugs combined with dehydroascorbic acid on colon cancer cells and melanoma cells were significantly greater than those of the corresponding drugs alone, and the two drugs exhibited a synergistic effect.

[0455] Example 6 Effect of PDE4 selective inhibitor combined with dehydroascorbic acid on the inhibitory effect of platinum compounds on colon cancer cells / melanoma cells

[0456] The effects of combining a PDE4-selective inhibitor with dehydroascorbic acid on the inhibitory effects of platinum compounds on colon cancer cells and melanoma cells were examined using the same method as in Example 4. The platinum compounds used were oxaliplatin, cisplatin, and carboplatin, and the PDE4-selective inhibitors were roflumilast, benzanilide, 4-Methylbenzanilide, apremilast, crisaborole, and drotaverine. The results showed that the combination of these drugs and sodium ascorbate significantly enhanced the inhibitory effects of the platinum compounds on tumor cells.

Claims

1. Use of a combination of ascorbic acid or a derivative thereof and a PDE4 selective inhibitor in the preparation of a medicament for preventing and / or treating tumors, wherein: The ascorbic acid derivative is dehydroascorbic acid and / or pharmaceutically acceptable ascorbic acid salt, the PDE4 selective inhibitor is Roflumilast, Benzanilide and / or 4-Methylbenzanilide, and the tumor is colon cancer.

2. Use of a combination of ascorbic acid or its derivatives, a PDE4 selective inhibitor and a platinum compound in the preparation of a medicament for preventing and / or treating tumors, wherein: The ascorbic acid or its derivative is dehydroascorbic acid and / or pharmaceutically acceptable ascorbic acid salt, the PDE4 selective inhibitor is Roflumilast, Benzanilide and / or 4-Methylbenzanilide, and the tumor is colon cancer.

3. The method according to claim 2, wherein the platinum compound comprises oxaliplatin, cisplatin and / or carboplatin.

4. The use according to claim 1 or 2, wherein the pharmaceutically acceptable ascorbate comprises sodium ascorbate.

5. The use according to claim 1 or 2, wherein the tumor comprises a tumor or tumor cells that are unresponsive to a platinum compound.

6. The use according to claim 1 or 2, wherein the PDE4 selective inhibitor and the ascorbic acid or a derivative thereof are formulated to be administered to the subject simultaneously.

7. The use according to claim 1 or 2, wherein the PDE4 selective inhibitor and the ascorbic acid or a derivative thereof are formulated to be administered to a subject separately.

8. The use according to claim 2, wherein the PDE4 selective inhibitor, the ascorbic acid or a derivative thereof, and the platinum compound are configured to be administered to the subject simultaneously.

9. The use according to claim 2, wherein the PDE4 selective inhibitor, the ascorbic acid or a derivative thereof, and the platinum compound are formulated to be administered to a subject separately.

10. The use according to claim 1 or 2, wherein the medicament is formulated such that the PDE4 selective inhibitor is administered at a dose of 1 mg / kg to 10 mg / kg.

11. The use according to claim 1 or 2, wherein the medicament is formulated so that the ascorbic acid or a derivative thereof is administered at a dose of 0.5 g / kg to 2 g / kg. 12 . The use according to claim 2 , wherein the medicament is formulated so that the platinum compound is administered at a dose of 1 mg / kg to 10 mg / kg.

13. The use according to claim 1 or 2, wherein the medicament is formulated such that the PDE4 selective inhibitor and the ascorbic acid or a derivative thereof are administered in a mass ratio of 1:50 to 1:

500.

14. The use according to claim 1 or 2, wherein the medicament is formulated such that the PDE4 selective inhibitor and the ascorbic acid or a derivative thereof are administered in an effective amount ratio of 1:50 to 1:

500. 15 . The use according to claim 2 , wherein the medicament is formulated such that the PDE4 selective inhibitor, the ascorbic acid or its derivative, and the platinum compound are administered in a mass ratio of 1:50:1 to 1:500:

1. 16 . The use according to claim 2 , wherein the medicament is formulated such that the PDE4 selective inhibitor, the ascorbic acid or its derivative, and the platinum compound are administered in an effective amount ratio of 1:50:1 to 1:500:1.

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