WO2018010674A1 - 一种有机硒化合物、其制备方法、包含其的药物组合物及其用途 - Google Patents

一种有机硒化合物、其制备方法、包含其的药物组合物及其用途 Download PDF

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WO2018010674A1
WO2018010674A1 PCT/CN2017/092784 CN2017092784W WO2018010674A1 WO 2018010674 A1 WO2018010674 A1 WO 2018010674A1 CN 2017092784 W CN2017092784 W CN 2017092784W WO 2018010674 A1 WO2018010674 A1 WO 2018010674A1
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group
cancer
substituted
alkyl
pharmaceutically acceptable
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PCT/CN2017/092784
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English (en)
French (fr)
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贺贤然
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深圳福山生物科技有限公司
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Priority claimed from CN201610552858.8A external-priority patent/CN106146372B/zh
Priority claimed from CN201610552859.2A external-priority patent/CN106176721B/zh
Application filed by 深圳福山生物科技有限公司 filed Critical 深圳福山生物科技有限公司
Publication of WO2018010674A1 publication Critical patent/WO2018010674A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C391/00—Compounds containing selenium
    • C07C391/02—Compounds containing selenium having selenium atoms bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
    • C07D209/28—1-(4-Chlorobenzoyl)-2-methyl-indolyl-3-acetic acid, substituted in position 5 by an oxygen or nitrogen atom; Esters thereof

Definitions

  • the present invention belongs to the field of medical technology, and in particular to an organic selenium compound for preventing and/or treating cancer, a preparation method thereof, and a pharmaceutical composition comprising the same.
  • cancer is the leading cause of illness and death worldwide, and cancer is expected to increase as modern technology prolongs life expectancy. Occasionally, small changes in DNA called “mutations” occur during the life of a cell. Among these mutations, certain mutations (called “silent mutations”) do not cause any essential changes in cellular function, while others can alter how cells function. A variety of mechanisms can prevent cells that have been mutated from continuing into the cell cycle, and if genetic errors are not corrected, these cells will "suicide” through a process called “apoptosis.” However, if mutations occur in proteins involved in cell cycle regulation, this can lead to uncontrolled cell proliferation (referred to as tumor formation), which can further develop into cancer.
  • tumor formation uncontrolled cell proliferation
  • Cancer cells usually have an adverse effect on the body. Cancer can spread through the invasion of malignant cells into adjacent tissues, or through a process known as "metastasis" in which malignant cells detach from the tumor mass and spread to distant sites. In many different types of tissues, cancer manifests itself in a variety of forms and can be characterized by its degree of invasion and invasion.
  • Cancer occurs as an abnormal tissue mass in a living host organism that receives nutrients from the host without relying on hyperproliferation of the host and destroying the host organism.
  • Human organs are made up of a large number of cells. Cancer occurs when normal cells of the human body become abnormal cells and the abnormal cells divide and proliferate without examination.
  • genetic factors are closely related to the pathogenesis of cancer, environmental factors also have an important impact on whether an individual has cancer. Cancer is especially prevalent in developed countries. It has been reported that the cause of cancer is increased use of pesticides, pesticides, etc. (and therefore increased residues in foods), and consumption of processed foods containing additives such as food preservatives and colorants.
  • Surgical treatment effectively removes cancer at an early stage, but the disadvantage is that sometimes organs have to be removed, which can lead to side effects and uncertainty about the spread of cancer to other organs.
  • Radiation therapy is beneficial for the effective treatment of cancer occurring in a specific organ, but has the following disadvantages: the exposure of the patient to other cancers due to radiation does not prevent the spread of cancer cells to other organs, and the patient has to withstand a large amount during the treatment. pain of.
  • Chemotherapy is usually carried out using an anticancer drug, but it is known that the toxicity of an anticancer drug acts not only on cancer cells but also on normal cells of a patient, causing side effects. Therefore, it is necessary to develop new anticancer drugs with higher cancer cell selectivity and as little toxicity as possible.
  • Selenium is an indispensable trace element in the life of the body.
  • studies have been conducted on selenium compounds, particularly organic selenium compounds, in an attempt to find compounds having anticancer or antitumor activity.
  • EI-Bayoumy et al [K El-Bayoumy, Drugs Future, 1997, 22(5): 539-545] found that benzyl selenide cyanide showed an anti-tumor effect in a DMBA-induced breast cancer mouse model.
  • benzyl selenide cyanide Compared with sodium selenite, benzyl selenide cyanide has a higher anticancer activity, but has a strong odor itself, and has side effects that cause a significant decrease in body weight of the patient.
  • Ebselen ebselen, 2-phenyl-1,2-benzoisoselazole-3(2H)-one
  • ethaneselen 1,2-[bis(1,2-benziso selenium) Oxazol-3(2H)-one)]ethane is two organic selenium compounds that have entered clinical trials. Studies have shown that the mechanism of action of ebselen is mainly through inhibition of target enzyme-thioxoxin reductase activity. Regulates its downstream signaling pathway and its anti-tumor pathway to achieve anti-tumor effects of drugs.
  • Biological activity and low toxicity may be related to its cyclic selenoamide structure or benzoisoxazolon-containing selenium heterocycle (H J Reich, et al. J. Am. Chem. Soc., 1987, 109(18): 5549-5551); ethaneselen is a thioredoxin reductase inhibitor, and the ethaneselen molecule contains two benzo-isoindoles.
  • the structure of selenazolidone has received synergistic effect and its activity is better than that of ebselen.
  • the inventors have unexpectedly discovered a class of organic compounds containing selenium through extensive experimental research, and have unexpected biological activities for preventing and/or treating cancer.
  • the compounds are useful for the treatment and/or prevention of a variety of cancers.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,
  • Ar 1 and Ar 2 each represent an aryl group or a heteroaryl group which may be the same or different, wherein any of Ar 1 and Ar 2 may be optionally substituted by one or more substituents selected from the group consisting of halogen , C 1-8 alkyl, C 1-8 alkoxy, halo C 1-8 alkoxy, amino, acyl, alkyl acyl (eg C 1-8 alkyl acyl), acyloxy, alkyl Acyloxy (eg C 1-8 alkyl acyloxy), carboxyl, nitro, cyano, C 1-8 alkylamino, halo C 1-8 alkyl, C 1-8 alkylamino An alkyl group, a hydroxyl group, a hydroxy C 1-8 alkyl group, a hydroxy C 1-8 alkylamino group, a C 3-6 cycloalkyl group, and a C 2-4 alkenyl group;
  • M is selected from O, S or Se;
  • A is a linear or branched alkylene chain or an alkenylene chain of 1 to 4 carbon atoms, or a direct covalent bond.
  • Ar 2 is phenyl or phenyl substituted by a halogen: C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, Halogenated C 1-4 alkoxy, amino and hydroxy.
  • Ar 1 is selected from unsubstituted or substituted phenyl, naphthyl and heteroaryl groups, wherein the substituent is selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, halogen C a 1-4 alkyl group, a halogenated C 1-4 alkoxy group, an amino group and a hydroxyl group; and wherein the heteroaryl group is selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, and isomeric Azyl, thiazolyl, pyridyl, pyrimidinyl, thienyl, benzothienyl, benzofuranyl, fluorenyl, azaindole, carbazolyl, benzimidazolyl, azabenzimidazolyl , benzoxazolyl, benzothiazolyl, benzothiadiazolyl
  • Ar 1 is selected from the group consisting of phenyl acyloxy, C 1-4 alkylcarbonyloxy, C 1-4 alkyl, C 1-4 alkoxy, benzoyl, a phenyl group, a biphenyl group, and a halogen-substituted biphenyl group;
  • Ar 1 is selected from C 1 -C 4 alkyl-substituted phenyl (4 isopropylphenyl), C 1 -C 4 alkanoyloxy substituted phenyl (eg 2-acetoxy substitution) Phenyl), halogen-substituted biphenyl (eg 2-fluoro-4 biphenyl), benzoyl substituted phenyl (eg 3-benzoyl substituted phenyl), hydroxybenzoyloxy substituted Phenyl (eg 2-hydroxybenzoyloxy substituted phenyl), substituted hydrazine (eg 2-methyl-1-4 chlorobenzoyl-5methoxy-1H hydrazine) and C 1 - An alkoxy-substituted naphthyl group of C 4 .
  • C 1 -C 4 alkyl-substituted phenyl (4 isopropylphenyl), C 1 -C 4 alkanoyloxy substituted phenyl
  • M is O.
  • Ar 1 is selected from C 1 -C 4 alkyl-substituted phenyl (eg, 4 isopropylphenyl), C 1 -C 4 alkanoyloxy substituted phenyl (eg 2-acetoxy substituted phenyl), halogen substituted biphenyl (eg 2-fluoro-4 biphenyl), benzoyl substituted phenyl (eg 3-benzoyl substituted phenyl) a hydroxybenzoyloxy substituted phenyl group (e.g., a 2-hydroxybenzoyloxy substituted phenyl group), a substituted hydrazine (e.g., 2-methyl-1-4 chlorobenzoyl-5 methoxy-) 1H ⁇ ) and C 1 -C 4 alkoxy-substituted naphthyl.
  • C 1 -C 4 alkyl-substituted phenyl eg, 4 isopropylphenyl
  • Ar 2 is a phenyl group or a phenyl group substituted by a halogen group or a C 1-4 alkyl group.
  • M is O
  • a straight or branched alkylene chain of 1 to 4 carbon atoms or a direct covalent bond is A straight or branched alkylene chain of 1 to 4 carbon atoms or a direct covalent bond.
  • the compound is selected from the group consisting of
  • the present invention provides a process for the preparation of the above compound, which comprises arylselenohalide or heteroarylselenohalide represented by X-Se-Ar 2 and Ar 1 -AC(M) a step of reacting COOH in an organic solvent, wherein Ar 1 , Ar 2 , M, and A are as defined above, and X is a halogen.
  • the preparation method comprises the presence of an arylselenohalide halide or a heteroarylselenohalide represented by X-Se-Ar 2 and Ar 1 -AC(M)-COOH in the presence of a catalyst tributylphosphine
  • the reaction is carried out in an organic solvent.
  • the molar ratio of the Ar 1 -AC(M)-COOH to the arylselenohalide or heteroarylselenohalide represented by X-Se-Ar 2 is 1:1 to 4.
  • the molar ratio of the tributylphosphine to Ar 1 -AC(M)-COOH is 1:1 to 3.
  • the reaction is carried out at a temperature below -5 °C, for example at a temperature of -15 °C.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof, a compound prepared by the preparation method of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt An acceptable carrier or excipient.
  • the pharmaceutical composition is a tablet, a pill, a powder, a lozenge, a suspension, an emulsion, a solution, a syrup, an aerosol, an ointment, a cream, a lotion, a capsule, a suppository, and a drip. Eye drops, injections and powder injections.
  • the pharmaceutically acceptable carrier is selected from one or more of the group consisting of water, salt solution, alcohol, polyethylene glycol, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, Lower alkyl ethers of lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or cellulose , silicic acid, fatty acids, fatty acid amines, fatty acid mono- and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethyl cellulose and polyvinylpyrrolidone.
  • the excipient is selected from one or more of the following: syrup, gum arabic, gel, sorbitol, lignan, polyvinylpyrrolidone (PVP), lactose, sugar, corn flour, phosphoric acid Calcium, sorbitol or glycine; tablet lubricants such as magnesium stearate, silica, talc, polyethylene glycol or silica, potato starch, sodium lauryl sulfate.
  • PVP polyvinylpyrrolidone
  • lactose lactose
  • sugar corn flour
  • phosphoric acid Calcium sorbitol or glycine
  • tablet lubricants such as magnesium stearate, silica, talc, polyethylene glycol or silica, potato starch, sodium lauryl sulfate.
  • the above pharmaceutical composition may further comprise another active pharmaceutical ingredient, ie a second drug, which is suitable for therapeutically indicating the same condition or associated treatment that can be treated by administering a compound of the invention. Illness.
  • the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof, a compound prepared by the preparation method of the present invention or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition of the present invention is prevented and/or Treating cancer or preventing, treating and/or alleviating complications associated with it and/or Use in symptoms;
  • the cancer is selected from the group consisting of brain cancer, breast cancer, colon cancer, rectal cancer, skin cancer, head and neck cancer, cervical cancer, kidney cancer, lung cancer, liver cancer, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer, gastric cancer, leukemia. Lymphoma, sarcoma and melanoma; cervical cancer, prostate cancer, colon cancer and gastric cancer are preferred.
  • the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof, a compound prepared by the preparation method of the present invention or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition of the present invention is prepared for prevention And/or use in a medicament for treating cancer, preventing and/or treating and/or alleviating complications and/or symptoms associated therewith;
  • the cancer is selected from the group consisting of brain cancer, breast cancer, colon cancer, rectal cancer, skin cancer, head and neck cancer, cervical cancer, kidney cancer, lung cancer, liver cancer, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer, gastric cancer, leukemia. Lymphoma, sarcoma and melanoma; cervical cancer, prostate cancer, colon cancer and gastric cancer are preferred.
  • the present invention provides a method of preventing and/or treating cancer or preventing, treating and/or alleviating complications and/or symptoms associated therewith, the method comprising administering to the patient in need thereof the present invention A compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition.
  • Various embodiments of the invention provide methods of using a compound, composition or combination of the invention, comprising administering to a patient in need of treatment for a condition in which they are in a dose, frequency and duration sufficient to provide a beneficial effect to the patient.
  • a compound, composition or combination comprising administering to a patient in need of treatment for a condition in which they are in a dose, frequency and duration sufficient to provide a beneficial effect to the patient.
  • treatment is defined as the treatment and care of a patient for the purpose of combating a disease, disorder or disorder, such as one of a plurality of types of disorders collectively referred to as "cancer,” which includes administering a compound of the invention.
  • cancer a disease, disorder or disorder, such as one of a plurality of types of disorders collectively referred to as “cancer,” which includes administering a compound of the invention.
  • Treatment in the context of the present invention means alleviating the symptoms associated with a condition or disease, or inhibiting the further development or progression of these symptoms, or preventing or preventing the disease or condition.
  • an "effective amount” or “therapeutically effective amount” of a compound of the invention as used herein refers to the complete or partial alleviation of symptoms associated with the condition or condition, or the cessation or slowing of further development or Or the amount of a compound that prevents or provides for the prevention of the condition or condition.
  • cancer refers to any malignant solid tumor, metastatic tumor or other condition in which cell division is uncontrolled and cells lose differentiation.
  • a group is defined as a "covalent bond”, it means that a group directly adjacent to the specified group is linked to each other by a covalent bond.
  • the compounds of the invention are intended to include all chiral, diastereomeric, racemic forms of the structure.
  • the compounds used in the present invention may include any enriched optical isomers enriched or resolved of any or all of the asymmetric atoms as apparent from the description. It is within the scope of the invention to isolate or synthesize racemic and diastereomeric mixtures as well as the individual optical isomers so as to be substantially free of their enantiomers or diastereomers.
  • substituted means that an organic group, as defined herein, which contains one or more bonds bonded to a hydrogen atom, is replaced by one or more bonds bonded to a non-hydrogen atom, said non-hydrogen An atom is a substituent.
  • the substituent of the compound of the present invention includes a halogen, an alkyl group (preferably a C 1-8 alkyl group, more preferably a C 1-4 alkyl group), and an alkane.
  • An oxy group (preferably a C 1-8 alkoxy group, more preferably a C 1-4 alkoxy group), a halogenated C 1-8 alkoxy group (preferably a halogenated C 1-4 alkoxy group), an amino group, an acyl group, C a 1-8 alkyl acyl group (preferably a C 1-4 alkylalkyl acyl group), an acyloxy group, a C 1-8 alkyl acyloxy group (preferably a C 1-4 alkyl acyloxy group), a carboxyl group, a nitro group, Cyano, C 1-8 alkylamino (preferably C 1-4 alkylamino), halogenated C 1-8 alkyl (preferably halogenated C 1-4 alkyl), C 1-8 alkylamine a C 1-8 alkyl group (preferably a C 1-4 alkylamino group C 1-4 alkyl group), a hydroxyl group, a hydroxy C 1-8 alkyl group (preferably a hydroxy
  • Alkyl groups include straight-chain and branched alkyl groups having from 1 to about 20 carbon atoms, typically from 1 to 12 carbon atoms or, in certain embodiments, from 1 to 8 or even more preferably from 1 to 4 carbon atoms.
  • Examples of the linear alkyl group include those having 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl groups.
  • branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl.
  • a representative substituted alkyl group may be substituted one or more times with any of the above groups such as an amino group, a hydroxyl group, a cyano group, a carboxyl group, a nitro group, a thio group, an alkoxy group, and a halogen group.
  • the cycloalkyl group is a cyclic alkyl group such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • the cycloalkyl group has from 3 to 8 ring members, while in other embodiments, the number of ring carbon atoms is from 3 to 5, 6 or 7.
  • Cycloalkyl further includes polycyclic cycloalkyl such as, but not limited to, norbornyl, adamantyl, borneol, decenyl, isodecenyl and decenyl, and fused rings such as, but not limited to, decahydronaphthyl Wait.
  • the cycloalkyl group also includes a ring substituted with a linear or branched alkyl group as defined above.
  • Representative substituted cycloalkyl groups can be monosubstituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4-, 2,5- or 2,6-disubstituted Cyclohexyl or mono-, di- or tri-substituted norbornyl or cycloheptyl, which may be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy and halo groups.
  • cycloalkenyl alone or in combination, means a cyclic alkenyl group.
  • the aryl group is a cyclic aromatic hydrocarbon which does not contain a hetero atom.
  • aryl groups include, but are not limited to, phenyl, indenyl, heptalenyl, biphenyl, indacenyl, indenyl, phenanthryl, triphenylenyl. , fluorenyl, naphthacenyl, biphenylene, anthracenyl and naphthyl.
  • an aryl group contains 6-14 carbons in the ring portion of the group.
  • the aryl group can be unsubstituted or substituted as defined above.
  • substituted aryl groups can be monosubstituted or substituted more than once, such as, but not limited to, 2-, 3-, 4-, 5- or 6-substituted phenyl or 2-8 substituted naphthyl, It may be substituted by carbon or a non-carbon group such as those described above.
  • a heteroaryl group is an aromatic ring compound containing 5 or more ring members, wherein one or more ring members are heteroatoms such as, but not limited to, N, O, and S.
  • the heteroaryl group designated as a C2-heteroaryl group may be a 5-membered ring having two carbon atoms and three hetero atoms, a 6-membered ring having two carbon atoms and four hetero atoms, and the like.
  • the C4-heteroaryl group may be a 5-membered ring having one hetero atom, a 6-membered ring having 2 hetero atoms, or the like. The sum of the number of carbon atoms plus the number of heteroatoms is equal to the total number of ring atoms.
  • Heteroaryl groups include, but are not limited to, the following groups: pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, thienyl, benzothienyl , benzofuranyl, fluorenyl, azaindole, carbazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, Imidazopyridyl, isoxazolopyridyl, thionaphthyl, anthracenyl, xanthyl, adenyl, guanyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, quinoxaline And quinazolinyl.
  • the heteroaryl group may be unsubstituted or
  • aryl and heteroaryl groups include, but are not limited to, phenyl, biphenyl, anthryl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl , N-hydroxyimidazolyl, fluorenyl (1-indenyl, 2-indenyl, 3-indenyl), thienyl (2-thienyl, 3-thienyl), furyl (2-furanyl, 3- Furyl), fluorenyl, oxadiazolyl, isoxazolyl, quinazolinyl, anthracenyl, xanthene, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl 2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl,
  • the aryl and heteroaryl groups may include phenyl, isoindolidinyl, Imidazolyl, oxazolyl, benzimidazolyl and benzoxazolyl; wherein any aryl or heteroaryl may be unsubstituted, monosubstituted or independently polysubstituted, for example with a J group as defined herein Replaced by the regiment.
  • alkoxy refers to an oxygen atom attached to an alkyl group, as defined above, including a cycloalkyl group.
  • linear alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy and the like.
  • branched alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like.
  • cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • halogen as used herein includes fluoro, chloro, bromo and iodo.
  • Haloalkyl includes monohaloalkyl and polyhaloalkyl (wherein all halogen atoms may be the same or different).
  • Partially halogenated alkyl is a "haloalkyl” group as used herein. Examples of the haloalkyl group include a trifluoromethyl group, a 1,1-dichloroethyl group, a 1,2-dichloroethyl group, a 1,3-dibromo-3,3-difluoropropyl group and the like.
  • acyl refers to a group containing a carbonyl moiety, wherein the group is bonded via the carbonyl carbon atom.
  • the carbonyl carbon atom is also bonded to other carbon atoms, which may be alkyl, aryl, aralkylcycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaryl A part of an alkyl group or the like.
  • the group is a "formyl" which is an acyl group (the term is as defined herein).
  • haloacyl group When a group containing a carbon atom bonded to a carbonyl carbon atom contains a halogen, the group is referred to as a "haloacyl group".
  • a group containing a carbon atom bonded to a carbonyl carbon atom contains a halogen, the group is referred to as a "haloacyl group”.
  • An example is trifluoroacetyl.
  • Salts well known in the art include organic compounds such as carboxylic acids, sulfonic acids or combinations of amines and counterions in ionic form.
  • an anionic form of the acid may form a salt with a cation such as a metal cation such as sodium, potassium or the like; an ammonium salt such as NH4+ or a cation of a plurality of amines, including a tetraalkylammonium salt such as tetramethylammonium or other cation Such as trimethyl sulfonium and so on.
  • a “pharmaceutically acceptable” salt is a salt formed from an ion that has been approved for human use and is generally non-toxic, such as a hydrochloride or sodium salt.
  • a “zwitterion” is an internal salt, for example it can be formed in a molecule having at least two ionizable groups, one forming an anion and the other forming a cation which are in equilibrium with each other. For example, an amino acid such as glycine may exist as a zwitterion.
  • “Zwitterionic” is a salt within the meaning of this document.
  • “Hydrate” is a compound that is present in combination with water molecules.
  • the composition may comprise a stoichiometric amount of water, such as a monohydrate or a dihydrate, or may contain any amount of water.
  • Solvate is a similar composition, except that a solvent other than water is used instead of water.
  • a solvent other than water for example, methanol or ethanol can form an "alcoholate” which can also be stoichiometric or non-stoichiometric.
  • a “tautomer” is two forms of a substance that differ only in the position of a hydrogen atom in the molecular structure.
  • Ar 1 and Ar 2 each represent an aryl group or a heteroaryl group which may be the same or different, wherein any of Ar 1 and Ar 2 may be optionally substituted by one or more substituents selected from the group consisting of halogen, C 1-8 alkyl, C 1-8 alkoxy, halogenated C 1-8 alkoxy, amino, acyl, C 1-8 alkyl acyl, acyloxy, C 1-8 alkyl acyloxy, Carboxyl, nitro, cyano, C 1-8 alkylamino, halo C 1-8 alkyl, C 1-8 alkylaminoalkyl, hydroxy, hydroxy C 1-8 alkyl, hydroxy C 1 An -8 alkylamino group, a C 3-6 cycloalkyl group, and a C 2-4 alkenyl group;
  • M is selected from O, S or Se;
  • A is a linear or branched alkylene chain or an alkenylene chain of 1 to 4 carbon atoms, or a direct covalent bond.
  • the Ar 2 is a phenyl group or a phenyl group substituted with a halogen: a C 1-4 alkyl group, a C 1-4 alkoxy group, a halogenated C 1-4 alkyl group. , halogenated C 1-4 alkoxy, amino and hydroxy.
  • the Ar 1 is selected from the group consisting of unsubstituted or substituted phenyl, naphthyl and heteroaryl groups,
  • substituent is selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, halo C 1-4 alkoxy, amino and hydroxy;
  • heteroaryl group is selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyrimidinyl, thienyl, benzothienyl, benzene And furyl, fluorenyl, azaindole, carbazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazo Pyridyl, isoxazolopyridinyl, thionaphthyl, anthryl, xanthyl, adenyl, guanyl, quinolyl, isoquinolyl, tetrahydroquinolyl, quinoxalinyl and Quinazoline group.
  • Ar 1 is selected from the group consisting of: phenylacyloxy, C 1-4 alkylformyloxy, C 1-4 alkyl, C 1-4 alkoxy, benzoyl Acyl, phenyl, biphenyl and halogen substituted biphenyl.
  • M represents a divalent atom attached to a carbon atom, which is an O, S or Se atom. In another preferred embodiment, M is O.
  • the compound of the invention is a specific compound selected from the group consisting of:
  • compositions of the present invention can be prepared by conventional techniques, for example as described in Remington: The Science and Practice of Pharmacy, 19th edition, 1995. The method described is hereby incorporated by reference.
  • the compositions may take such forms as conventional forms such as capsules, tablets, aerosols, solutions, suspensions or topical application.
  • a typical composition comprises a compound of the invention and an excipient or carrier.
  • the active compound is usually mixed with the carrier, or diluted by the carrier, or enclosed in a carrier which may be in the form of an ampule, capsule, sachet, paper or other container.
  • the carrier can be a solid, semi-solid or liquid material that serves as a carrier, excipient or medium for the active compound.
  • the active compound can be adsorbed onto a particulate solid carrier (e.g., contained in a sachet).
  • suitable carriers are water, saline solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, rings. Dextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and glycerol Diester, pentaerythritol fatty acid ester, polyoxyethylene, hydroxymethyl cellulose and polyvinylpyrrolidone.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or a mixture thereof with a wax.
  • the formulation may be admixed with adjuvants that do not adversely react with the active compound.
  • adjuvants may include wetting agents, emulsifying and suspending agents, salts which affect the osmotic pressure, buffers and/or coloring materials, preservatives, sweeteners or flavoring agents.
  • the composition can also be sterilized if desired.
  • the route of administration may be any route that effectively delivers the active compound of the invention to a suitable or desired site of action, such as oral, nasal, pulmonary, buccal, subcutaneous, intradermal, transdermal or parenteral routes, such as the rectum. Oral routes are preferred, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solutions or ointments.
  • the preparation may be tabletted, placed in a hard gelatin capsule in the form of a powder or pellet, or it may be in the form of a troche or lozenge. If a liquid carrier is employed, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid, such as an aqueous or nonaqueous liquid suspension or solution.
  • Injectable formulations usually comprise aqueous suspensions or oily suspensions, which may be prepared using suitable dispersing or wetting agents and suspending agents.
  • the injectable form can be in the solution phase or dissolved A suspension or a diluent prepared in the form of a suspension.
  • Acceptable solvents or vehicles include sterile water, Ringer's solution or isotonic saline solution.
  • a sterile oil can be employed as a solvent or suspending agent.
  • the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, monoglycerides, diglycerides or triglycerides.
  • the formulation may also be a powder suitable for reconstitution with a suitable solution as described above. Examples of these include, but are not limited to, freeze-dried, spin-dried or spray-dried powders, amorphous powders, granules, precipitates or microparticles.
  • the formulations may optionally contain stabilizers, pH adjusting agents, surfactants, bioavailability modifiers, and combinations of these agents.
  • the compounds can be formulated for parenteral administration by injection, such as by bolus injection or continuous infusion.
  • the unit dosage form for injection can be in ampoules or in multi-dose containers.
  • the formulations of the invention can be designed to provide rapid, sustained or delayed release of the active ingredient after administration to a patient by methods well known in the art.
  • the formulation can also be formulated for controlled release or slow release.
  • the compounds of the invention are effective over a wide dosage range.
  • a dose of from about 0.05 to about 5000 mg, preferably from about 1 to about 2000 mg, more preferably from about 2 to about 2000 mg per day may be used.
  • a typical dosage is from about 10 mg to about 1000 mg per day.
  • the precise dose will depend on the activity of the compound, the mode of administration, the desired treatment, the form of administration, the subject to be treated and the weight of the subject to be treated, and the preferences and experience of the physician or veterinarian.
  • the compounds of the present invention are formulated in unit dosage form containing from about 0.05 mg to about 1000 mg of the active ingredient per unit dose and a pharmaceutically acceptable carrier.
  • dosage forms suitable for oral, nasal, pulmonary or transdermal administration comprise from about 125 [mu]g to about 1250 mg, preferably from about 250 [mu]g to about 500 mg, more preferably from about 2.5 mg to about 250 mg, in admixture with a pharmaceutically acceptable carrier or diluent. Said compound.
  • the dosage form can be administered once daily, or more than once a day, for example twice daily or three times daily. Alternatively, the dosage form can be administered less frequently than once a day, such as every other day or week, if the prescribing physician deems it appropriate.
  • the pharmaceutical compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquids or gums.
  • Tablets and capsules for oral administration may be in the form of a unit dosage, and may contain conventional shaping Agents, examples of which are: binding agents such as syrup, gum arabic, gel, sorbitol, lignan, polyvinylpyrrolidone (PVP); fillers such as lactose, sugars, corn flour, calcium phosphate, sorbitol or glycine; Lubricants such as magnesium stearate, silica, talc, polyethylene glycol or silica; disintegrants such as potato starch; acceptable lubricants such as sodium lauryl sulfate.
  • binding agents such as syrup, gum arabic, gel, sorbitol, lignan, polyvinylpyrrolidone (PVP); fillers such as lactose, sugars, corn flour, calcium phosphate, sorbitol or
  • Oral liquid preparations may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or they may be formulated as a dry material which may be reconstituted with water or other suitable vehicle before use.
  • These liquid preparations may contain conventional additives such as suspending agents (e.g., sorbitol, syrup, methylcellulose, glucose syrup, gelatin, hydrogenated edible fats and oils).
  • Emulsifier such as hatching phospholipids, sorbitol monooleate or gum arabic
  • non-aqueous carrier including edible oils such as almond oil, rectified coconut oil, oils such as glycerin, propylene glycol or ethanol
  • preservatives such as The base or propyl p-hydroxybenzoic acid or sorbic acid may, if desired, also contain conventional flavoring or coloring agents.
  • the percentage of active ingredient in the pharmaceutical compositions of the invention is variable because the dosage of the drug must be formulated to a suitable ratio to achieve the desired therapeutic effect.
  • the pharmaceutical preparation of the present invention should be administered orally or by injection in an amount of from 1 to 15 mg of active substance per 70 kg of body weight per day.
  • the present invention provides, in various embodiments, methods of synthesizing the compounds of the invention herein.
  • the general method includes a step of reacting an arylselenohalide or a heteroarylselenohalide represented by X-Se-Ar 2 with Ar 1 -AC(M)-COOH in an organic solvent.
  • the reaction can be carried out at a low temperature, under a catalyst such as tributylphosphine.
  • the benzene selenyl chloride or the phenylselenyl bromide may be dissolved in tetrahydrofuran or dichloromethane, cooled at a low temperature, and tributylphosphine is added, and the formula Ar 1 -AC(M) is added with stirring.
  • the compound of -COOH was subjected to inert gas protection and continued to be stirred under low temperature to give the target compound Ar 1 -AC(M)-Se-Ar 2 .
  • the experimental methods in the following examples are conventional methods unless otherwise specified.
  • the raw materials, reagent materials, etc. used in the following examples can be obtained from the conventional biochemical reagent store unless otherwise specified. Or the drug business enterprise can buy it.
  • phenylselenium chloride (0.40 g, 2.10 mmol) and anhydrous tetrahydrofuran (20 ml) were added, and the mixture was cooled to -15 ° C in an ice salt bath, and then tributylphosphine (0.57 g, 2.80 mmol), 2-methyl- 1-(4-Chlorobenzoyl)-5-methoxy-1H-indole-3-acetic acid (0.50 g, 1.40 mmol), which was subjected to high-purity argon, and kept stirring at -15 ° C for 4.0 hours.
  • HeLa cervical cancer cells
  • PC3 prostate cancer cells
  • HCT-116 colon cancer cells
  • SGC-7091 gastric cancer cells
  • the cells in the log phase were inoculated into 96-well plates at 3 ⁇ 104 per well. After 12 hours, the supernatant was discarded and administered in the following groups: normal control group and dosing group (concentration 0-100 ⁇ M), each group Six replicate wells were cultured for 24 hours, the supernatant was discarded, and 50 ⁇ L of the culture medium containing MTT was added for 5 hours (0.5 mg/mL), 100 ⁇ L of DMSO was added, and the mixture was shaken for 1 hour, and the absorbance was measured at 570 nm on a microplate reader. In addition, paclitaxel was used as a positive control.
  • Table 1 In vitro growth inhibition of tumor cell lines (using human embryonic kidney cell 293T as a control)
  • IC 50 value is the average of three independent experiments
  • the logarithmic phase of hepatocarcinoma cell line Hepa 1c1c7 (purchased from ATCC) was seeded on a 96-well plate at 2 ⁇ 104 per well.
  • the culture medium contained 10% (v/v) fetal bovine serum, 0.01% penicillin G, 0.15% sodium bicarbonate, 0.01% streptomycin, cultured in an environment of 37 ° C, 5% carbon dioxide incubator for 24 hours, then dissolved in a known concentration of the test compound in DMSO, added to each well and maintained for 24 hours .
  • the final concentration of DMSO should be ⁇ 0.5% (V/V) after adding DMSO to each well. Thereafter, the supernatant was discarded, digoxigenin was added to digest the cells, and finally the culture medium containing MTT was added thereto, and gently shaken for 5 minutes, and the absorbance was measured at 550 nm.

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Abstract

提供了一种有机硒化合物、其制备方法、包含其的药物组合物及其用途。所述的有机硒化合物具有式(I)所示的结构： Ar 1-A-C(M)-Se-Ar 2 (I) 其中，A、Ar 1、Ar 2和M的定义如说明书所述，所述化合物或其药物可接受的盐以及包含其的药物组合物可以用于预防和/或治疗癌症或预防和/或治疗和/或缓解与其相关的并发症和/或症状。

Description

一种有机硒化合物、其制备方法、包含其的药物组合物及其用途 技术领域
本发明属于医药技术领域，具体涉及用于预防和/或治疗癌症的有机硒化合物、其制备方法及包含所述化合物的药物组合物。
背景技术
癌症是全世界罹患疾病和导致死亡的首要原因，并且由于现代技术延长了预期寿命，因此预计癌症仍会增加。在细胞的生命期中，偶尔会发生被称为“突变”的DNA微小变化。在这些突变中，某些突变(称为“沉默突变”)不会导致细胞功能的任何本质变化，而另一些突变则可改变细胞的作用方式。多种机制均可以阻止已发生突变的细胞继续进行细胞周期，并且如果遗传错误得不到纠正，这些细胞将通过被称为“细胞凋亡”的过程而“自杀”。然而，如果突变发生在参与细胞周期调控的蛋白质中，这可导致失控的细胞增殖(称为肿瘤形成)，其可进一步发展成癌症。
癌细胞通常对机体具有不利影响。癌症可通过恶性肿瘤细胞侵入邻近组织来扩散，也可通过已知为“转移”的过程来扩散，在“转移”过程中恶性细胞从肿瘤块脱离并扩散至较远的部位。在许多不同类型的组织中，癌症表现为多种形式，并可以其侵入和侵袭程度来表征。
癌症作为活宿主生物中的异常组织块而发生，它从宿主中接收营养而不依赖于宿主地过度增殖，并且破坏宿主机体。人体器官由大量细胞构成。当人体的正常细胞变成异常细胞并且该异常细胞不加检查地分裂和增殖时，就发生癌症。尽管遗传因素与癌症的发病密切相关，但环境因素也对个体是否发生癌症产生重要影响。癌症在发达国家尤其普遍。有报道称，导致癌症的原因是对农药、杀虫剂等的使用增加(因此这类物质在食品中的残留量增加)，对包含添加剂(如食品防腐剂和着色剂)的加工食品的消费增加，对水、土壤和空气的污染的增加，现代生活的压力，活动的减少，油腻的饮食习惯所引起的肥胖，等等。近年来，还有人指出，当正常细胞的细胞信号系 统发生故障，当癌症基因被激活，或当抑癌基因发生故障时，就引发癌症。
目前存在多种癌症治疗方法，如手术治疗，化学疗法和放射疗法。手术治疗方法在早期阶段有效地去除癌症，但是，缺点是有时不得不摘除器官，这会导致副作用，并且具有癌症扩散至其他器官的不确定性。放射治疗有利于有效地治疗在一个特定器官发生的癌症，但是有以下缺点：因为辐射而使患者暴露于其他癌症风险，无法防止癌细胞扩散到其他器官，并且在治疗过程中患者要承受很大的痛苦。化学疗法通常使用抗癌药物进行，但是已知抗癌药物的毒性不仅作用于癌细胞，也作用于患者的正常细胞，造成副作用。因此，要开发有更高的癌细胞选择性和尽可能小的毒性的新抗癌药物。
硒是机体生命活动不可缺少的一种微量元素。近年来，人们对硒化合物特别是有机硒化合物进行了研究，试图从中发现有抗癌或抗肿瘤活性的化合物。例如，EI-Bayoumy等[K El-Bayoumy，Drugs Future,1997，22(5):539～545]研究发现，苄基硒氰化物在DMBA诱导的乳腺癌小鼠模型中表现出抗肿瘤作用。与亚硒酸钠相比，苄基硒氰化物的抗癌活性更高，但其本身具有强烈的异味，且存在导致患者体重显著下降的副作用。
依布硒啉(ebselen，2-苯基-1,2-苯并异硒唑-3(2H)-酮)和乙烷硒啉(1,2-[二(1,2-苯并异硒唑-3(2H)-酮)]乙烷是两个已经进入临床试验阶段的有机硒化合物。研究表明，依布硒啉的作用机制主要是通过抑制靶酶-硫氧环蛋白还原酶的活性，调节其下游信号传导通路及其抗肿瘤凋亡通路，实现药物的抗肿瘤作用，生物活性和低毒性则可能与其环状硒酰胺结构或苯并异硒唑酮含硒杂环有关(H J Reich，等J.Am.Chem.Soc.，1987，109(18):5549-5551)；乙烷硒啉是硫氧还蛋白还原酶抑制剂，乙烷硒啉分子中含有2个苯并异硒唑酮结构，收到了协同增效的效果，活性优于依布硒啉。
尽管发现了上述有机硒化合物，但现有的有机硒化合物仍存在抗癌效力有待进一步提高、抗癌谱有限，以及化合物结构类型有限等问题，远远不能满足人类对于癌症预防和治疗的日益增长的需求。因此，开发出更好效果的抗癌药物，特别是有机硒化合物已成为迫切的需要。
发明简述
本发明人经过大量实验研究，意外发现了一类含硒的有机化合物，具有出乎意料的预防和/或治疗癌症的生物活性。所述化合物可有效用于多种癌症的治疗和/或预防。
本发明采用的技术方案如下：
一方面，本发明提供一种式(I)所示的化合物或其药物可接受的盐，
Ar1-A-C(M)-Se-Ar2
(I)
其中，Ar1和Ar2各自代表芳基或杂芳基，其可以相同或不同，其中Ar1和Ar2中任一个都可以任选地被一个或多个选自以下的取代基取代：卤素、C1-8烷基、C1-8烷氧基、卤代C1-8烷氧基、氨基、酰基、烷基酰基(例如C1-8烷基酰基)、酰氧基、烷基酰氧基(例如C1-8烷基酰氧基)、羧基、硝基、氰基、C1-8烷基胺基、卤代C1-8烷基、C1-8烷基胺基烷基、羟基、羟基C1-8烷基、羟基C1-8烷基胺基、C3-6环烷基和C2-4链烯基；
M选自O、S或Se；
A为1至4个碳原子的直链或支链化的亚烷基链或亚烯基链，或者为直接的共价键。
在本发明的优选实施方案中，Ar2为苯基或被以下取代基取代的苯基：卤素、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、卤代C1-4烷氧基、氨基和羟基。
优选地，Ar1选自未取代或取代的苯基、萘基和杂芳基，其中，所述取代基选自卤素、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、卤代C1-4烷氧基、氨基和羟基；并且其中所述杂芳基选自吡咯基、吡唑基、三唑基、四唑基、噁唑基、异噁唑基、噻唑基、吡啶基、嘧啶基、噻吩基、苯并噻吩基、苯并呋喃基、吲哚基、氮杂吲哚基、吲唑基、苯并咪唑基、氮杂苯并咪唑基、苯并噁唑基、苯并噻唑基、苯并噻二唑基、咪唑并吡啶基、异噁唑并吡啶基、硫杂萘基、嘌呤基、黄嘌呤基、腺嘌呤基、鸟嘌呤基、喹啉基、异喹啉基、四氢喹啉基、喹喔啉基和喹唑啉基。
在本发明的优选实施方案中，Ar1选自：苯基酰氧基、C1-4烷基甲酰氧 基、C1-4烷基、C1-4烷氧基、苯甲酰基、苯基、联苯基和卤素取代的联苯基；
优选地，Ar1选自C1-C4的烷基取代的苯基(4异丙基苯基)、C1-C4的烷酰氧基取代的苯基(例如2-乙酰氧基取代的苯基)、卤素取代的联苯基(例如2-氟-4联苯基)、苯甲酰基取代的苯基(例如3-苯甲酰基取代的苯基)、羟基苯甲酰氧基取代的苯基(例如2-羟基苯甲酰氧基取代的苯基)、取代吲哚(例如2-甲基-1-4氯苯甲酰基-5甲氧基-1H吲哚)和C1-C4的烷氧基取代的萘基。
在本发明的优选实施方案中，M为O。
在本发明的某些实施方案中，Ar1选自C1-C4的烷基取代的苯基(例如4异丙基苯基)、C1-C4的烷酰氧基取代的苯基(例如2-乙酰氧基取代的苯基)、卤素取代的联苯基(例如2-氟-4联苯基)、苯甲酰基取代的苯基(例如3-苯甲酰基取代的苯基)、羟基苯甲酰氧基取代的苯基(例如2-羟基苯甲酰氧基取代的苯基)、取代吲哚(例如2-甲基-1-4氯苯甲酰基-5甲氧基-1H吲哚)和C1-C4的烷氧基取代的萘基。
Ar2为苯基或被以下取代基取代的苯基：卤素、C1-4烷基。
M为O；
A为1至4个碳原子的直链或支链化的亚烷基链或者为直接的共价键。
在本发明的具体实施方案中，所述化合物选自：
Figure PCTCN2017092784-appb-000001
Figure PCTCN2017092784-appb-000002
另一方面，本发明提供一种上述化合物的制备方法，该方法包括将X-Se-Ar2所代表的芳基硒基卤化物或杂芳基硒基卤化物与Ar1-A-C(M)-COOH在有机溶剂中反应的步骤，其中，Ar1、Ar2、M、A的定义如前所述，X为卤素。
优选地，所述制备方法包括将X-Se-Ar2所代表的芳基硒基卤化物或杂 芳基硒基卤化物与Ar1-A-C(M)-COOH在催化剂三丁基膦的存在下在有机溶剂中反应。
优选地，所述Ar1-A-C(M)-COOH与X-Se-Ar2所代表的芳基硒基卤化物或杂芳基硒基卤化物的摩尔比为1：1～4。
优选地，所述三丁基膦与Ar1-A-C(M)-COOH的摩尔比为1：1～3。
优选地，所述反应在低于-5℃的温度下进行，例如在-15℃的温度下进行。
又一方面，本发明还提供一种药物组合物，其包含本发明所述化合物或其药学上可接受的盐、本发明所述制备方法制备的化合物或其药学上可接受的盐，以及药学上可接受的载体或赋形剂。
优选地，所述药物组合物为片剂、丸剂、粉末、锭剂、混悬剂、乳剂、溶液剂、糖浆剂、气雾剂、软膏剂、乳膏剂、洗剂、胶囊剂、栓剂、滴眼剂、注射剂和粉针剂。
优选地，所述药学上可接受的载体选自下述的一种或多种：水、盐溶液、醇、聚乙二醇、聚羟基乙氧基化蓖麻油、花生油、橄榄油、明胶、乳糖、白土、蔗糖、糊精、碳酸镁、糖、环糊精、直链淀粉、硬脂酸镁、滑石、明胶、琼脂、果胶、阿拉伯胶、硬脂酸或纤维素的低级烷基醚、硅酸、脂肪酸、脂肪酸胺、脂肪酸甘油单酯和甘油二酯、季戊四醇脂肪酸酯、聚氧乙烯、羟甲基纤维素和聚乙烯吡咯烷酮。
优选地，所述赋形剂选自下述的一种或多种：糖浆、阿拉伯树胶、凝胶、山梨醇、黄著胶、聚乙烯吡咯烷酮(PVP)、乳糖、糖类、玉米粉、磷酸钙、山梨醇或甘氨酸；片剂润滑剂如硬脂酸镁、二氧化硅、滑石、聚乙二醇或二氧化硅、马铃薯淀粉、月桂基硫酸钠。
在本发明的一些实施方案中，上述药物组合物还可包含另一种活性药物成分，即第二药物，所述第二药物适于治疗医学上表明施用本发明化合物可治疗的相同病症或相关病症。
再一方面，本发明提供本发明所述化合物或其药物可接受的盐、本发明所述制备方法制备的化合物或其药学上可接受的盐、本发明所述药物组合物在预防和/或治疗癌症或预防、治疗和/或缓解与其相关的并发症和/或 症状中的用途；
优选地，所述癌症选自脑癌、乳癌、结肠癌、直肠癌、皮肤癌、头颈癌、宫颈癌、肾癌、肺癌、肝癌、卵巢癌、胰腺癌、前列腺癌、甲状腺癌、胃癌、白血病、淋巴瘤、肉瘤和黑素瘤；优选宫颈癌、前列腺癌、结肠癌和胃癌。
又一方面，本发明提供本发明所述化合物或其药物可接受的盐、本发明所述制备方法制备的化合物或其药学上可接受的盐、本发明所述药物组合物在制备用于预防和/或治疗癌症，预防和/或治疗和/或缓解与其相关的并发症和/或症状的药物中的用途；
优选地，所述癌症选自脑癌、乳癌、结肠癌、直肠癌、皮肤癌、头颈癌、宫颈癌、肾癌、肺癌、肝癌、卵巢癌、胰腺癌、前列腺癌、甲状腺癌、胃癌、白血病、淋巴瘤、肉瘤和黑素瘤；优选宫颈癌、前列腺癌、结肠癌和胃癌。
再又一方面，本发明还提供了一种预防和/或治疗癌症或预防、治疗和/或缓解与其相关的并发症和/或症状的方法，该方法包括向有需要的患者施用本发明所述的化合物或其药物可接受的盐或所述药物组合物。
本发明的多个实施方案提供了使用本发明的化合物、组合物或组合的方法，包括向需要治疗其不良状况的患者以足以向所述患者提供有益效果的剂量、频率和持续时间来施用所述化合物、组合物或组合。
发明详述
本发明中，术语“治疗”定义为为了对抵抗疾病、病症或障碍(例如统称为“癌症”的多种类型病症中的一种)而对患者进行的处理和护理，其包括施用本发明化合物以预防症状或并发症的发作、或者减轻症状或并发症、或者治愈或消除疾病、病症或障碍。
在本发明上下文中的“治疗”意指减轻与病症或疾病相关的症状，或者抑制这些症状的进一步发展或恶化，或者防止或预防所述疾病或病症。类似地，本文中使用的本发明化合物的“有效量”或“治疗有效量”指完全或部分减轻与所述病症或状况相关的症状、或者停止或减缓这些症状的进一步发展或恶 化，或者预防或提供对所述病症或状况之预防的化合物的量。
本文中使用的术语“癌症”指任何恶性实体肿瘤、转移性瘤或其中细胞分裂不受控制和细胞丧失分化的其它病症。
当将基团定义为“共价键”时，意指直接邻接该指定基团的基团通过共价键彼此连接。
除非具体指出特定的立体化学或异构体形式，否则本发明化合物旨在包括结构的所有手性、非对映体、外消旋形式。在本发明中使用的化合物可以包括根据描述显而易见的任何或所有不对称原子的经富集或拆分的任何富集程度的光学异构体。可以分离或合成外消旋和非对映体混合物以及单独的光学异构体，以便基本上不含其对映体或非对映体，这些都在本发明的范围内。
通常，“取代的”指本文中所定义的有机基团(其中包含有与氢原子键合的一个或多个键)被一个或多个与非氢原子键合的键取代，所述非氢原子即为取代基。
本发明化合物的取代基(包括Ar1和Ar2的芳基或杂芳基上的取代基)包括卤素、烷基(优选C1-8烷基，更优选C1-4烷基)、烷氧基(优选C1-8烷氧基，更优选C1-4烷氧基)、卤代C1-8烷氧基(优选卤代C1-4烷氧基)、氨基、酰基、C1-8烷基酰基(优选C1-4烷基烷基酰基)、酰氧基、C1-8烷基酰氧基(优选C1-4烷基酰氧基)、羧基、硝基、氰基、C1-8烷基胺基(优选C1-4烷基胺基)、卤代C1-8烷基(优选卤代C1-4烷基)、C1-8烷基胺基C1-8烷基(优选C1-4烷基胺基C1-4烷基)、羟基、羟基C1-8烷基(优选羟基C1-4烷基)、羟基C1-8烷基胺基(优选羟基C1-4烷基胺基)、C3-6环烷基、C2-4链烯基。
烷基包括具有1至约20个碳原子、通常为1至12个碳原子或在某些实施方案中为1至8个甚至更优选为1至4个碳原子的直链和支链烷基。直链烷基的实例包括具有1至8个碳原子的那些，比如甲基、乙基、正丙基、正丁基、正戊基、正己基、正庚基和正辛基。支链烷基的实例包括但不限于异丙基、异丁基、仲丁基、叔丁基、新戊基、异戊基和2,2-二甲基丙基。代表性的取代烷基可以被任何上述基团取代一次或多次，所述上述基团例如氨基、羟基、氰基、羧基、硝基、硫基、烷氧基和卤素基团。
环烷基为环状烷基，例如但不限于环丙基、环丁基、环戊基、环己基、环庚基和环辛基。在优选的实施方案中，所述环烷基具有3至8个环成员，而在其它一些实施方案中，环碳原子的数目为3至5、6或7个。环烷基进一步包括多环环烷基，例如但不限于降冰片基、金刚烷基、冰片基、莰烯基、异莰烯基和蒈烯基，以及稠环例如但不限于十氢萘基等。环烷基还包括被如上定义的直链或支链烷基取代的环。代表性的取代环烷基可以是单取代的或多于一次取代的，例如但不限于2,2-、2,3-、2,4-、2,5-或2,6-二取代的环己基或单-、二-或三-取代的降冰片基或环庚基，其可以被例如氨基、羟基、氰基、羧基、硝基、硫基、烷氧基和卤素基团取代。术语“环烯基”单独或组合时表示环状烯基。
芳基为不包含杂原子的环状芳族烃。因此，芳基包括但不限于苯基、薁基、庚搭烯基(heptalenyl)、联苯基、二环戊二烯并苯基(indacenyl)、芴基、菲基、三亚苯基(triphenylenyl)、芘基、萘并萘基(naphthacenyl)、亚联苯基、蒽基和萘基。在某些实施方案中，芳基在该基团的环部分中包含6-14个碳。芳基可以是未取代或取代的，如上所定义。代表性的取代芳基可以是单取代的或多于一次取代的，例如但不限于2-、3-、4-、5-或6-取代的苯基或2-8取代的萘基，其可以被碳或非碳基团(如上述那些)取代。
杂芳基是含有5个或更多个环成员的芳环化合物，其中一个或更多个环成员是杂原子，例如但不限于N、O和S。命名为C2-杂芳基的杂芳基可以是具有两个碳原子和三个杂原子的5元环、具有两个碳原子和四个杂原子的6元环等。同样地，C4-杂芳基可以是具有一个杂原子的5元环、具有2个杂原子的6元环等。碳原子数目加杂原子数目的总和等于环原子的总数。杂芳基包括但不限于例如以下的基团：吡咯基、吡唑基、三唑基、四唑基、噁唑基、异噁唑基、噻唑基、吡啶基、噻吩基、苯并噻吩基、苯并呋喃基、吲哚基、氮杂吲哚基、吲唑基、苯并咪唑基、氮杂苯并咪唑基、苯并噁唑基、苯并噻唑基、苯并噻二唑基、咪唑并吡啶基、异噁唑并吡啶基、硫杂萘基、嘌呤基、黄嘌呤基、腺嘌呤基、鸟嘌呤基、喹啉基、异喹啉基、四氢喹啉基、喹喔啉基和喹唑啉基。杂芳基可以是未取代的，或者可以是被如上所述基团取代的。代表性的取代杂芳基可以被如上所述的那些基团取代一次或多次。
芳基和杂芳基的其它实例包括但不限于苯基、联苯基、茚基、萘基(1-萘基、2-萘基)、N-羟基四唑基、N-羟基三唑基、N-羟基咪唑基、蒽基(1-蒽基、2-蒽基、3-蒽基)、噻吩基(2-噻吩基、3-噻吩基)、呋喃基(2-呋喃基、3-呋喃基)、吲哚基、噁二唑基、异噁唑基、喹唑啉基、芴基、呫吨基、异茚满基、二苯甲基、吖啶基、噻唑基、吡咯基(2-吡咯基)、吡唑基(3-吡唑基)、咪唑基(1-咪唑基、2-咪唑基、4-咪唑基、5-咪唑基)、三唑基(1,2,3-三唑-1-基、1,2,3-三唑-2-基、1,2,3-三唑-4-基、1,2,4-三唑-3-基)、噁唑基(2-噁唑基、4-噁唑基、5-噁唑基)、噻唑基(2-噻唑基、4-噻唑基、5-噻唑基)、吡啶基(2-吡啶基、3-吡啶基、4-吡啶基)、嘧啶基(2-嘧啶基、4-嘧啶基、5-嘧啶基、6-嘧啶基)、吡嗪基、哒嗪基(3-哒嗪基、4-哒嗪基、5-哒嗪基)、喹啉基(2-喹啉基、3--喹啉基、4-喹啉基、5-喹啉基、6-喹啉基、7-喹啉基、8-喹啉基)、异喹啉基(1-异喹啉基、3-异喹啉基、4-异喹啉基、5-异喹啉基、6-异喹啉基、7-异喹啉基、8-异喹啉基)、苯并[b]呋喃基(2-苯并[b]呋喃基、3-苯并[b]呋喃基、4-苯并[b]呋喃基、5-苯并[b]呋喃基、6-苯并[b]呋喃基、7-苯并[b]呋喃基)、2,3-二氢-苯并[b]呋喃基(2-(2,3-二氢-苯并[b]呋喃基)、3-(2,3-二氢-苯并[b]呋喃基)、4-(2,3-二氢-苯并[b]呋喃基)、5-(2,3-二氢-苯并[b]呋喃基)、6-(2,3-二氢-苯并[b]呋喃基)、7-(2,3-二氢-苯并[b]呋喃基)、苯并[b]噻吩基(2-苯并[b]噻吩基、3-苯并[b]噻吩基、4-苯并[b]噻吩基、5-苯并[b]噻吩基、6-苯并[b]噻吩基、7-苯并[b]噻吩基)、2,3-二氢-苯并[b]噻吩基、(2-(2,3-二氢-苯并[b]噻吩基)、3-(2,3-二氢-苯并[b]噻吩基)、4-(2,3-二氢-苯并[b]噻吩基)、5-(2,3-二氢-苯并[b]噻吩基)、6-(2,3-二氢-苯并[b]噻吩基)、7-(2,3-二氢-苯并[b]噻吩基)、吲哚基(1-吲哚基、2-吲哚基、3-吲哚基、4-吲哚基、5-吲哚基、6-吲哚基、7-吲哚基)、吲唑(1-吲唑基、3-吲唑基、4-吲唑基、5-吲唑基、6-吲唑基、7-吲唑基)、苯并咪唑基(1-苯并咪唑基、2-苯并咪唑基、4-苯并咪唑基、5-苯并咪唑基、6-苯并咪唑基、7-苯并咪唑基、8-苯并咪唑基)、苯并噁唑基(1-苯并噁唑基、2-苯并噁唑基)、苯并噻唑基(1-苯并噻唑基、2-苯并噻唑基、4-苯并噻唑基、5-苯并噻唑基、6-苯并噻唑基、7-苯并噻唑基)、咔唑基(1-咔唑基、2-咔唑基、3-咔唑基、4-咔唑基)等。
更特别地，芳基和杂芳基可以包括苯基、异吲哚烷基(isoindolidinyl)、 咪唑基、噁唑基、苯并咪唑基和苯并噁唑基；其中任何芳基或杂芳基可以是未取代的、单取代的或者独立地多取代的，例如用如本文定义的J基团取代。
术语“烷氧基”指氧原子连接到如上述定义的包括环烷基在内的烷基上。直链烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基等。支链烷氧基的实例包括但不限于异丙氧基、仲丁氧基、叔丁氧基、异戊氧基、异己氧基等。环烷氧基的实例包括但不限于环丙氧基、环丁氧基、环戊氧基、环己氧基等。
本文使用的术语“卤素”包括氟、氯、溴和碘。“卤代烷基”包括单卤代烷基和多卤代烷基(其中所有卤原子可以相同或不同)。部分卤代的烷基是本文含义内的“卤代烷基”。卤代烷基的实例包括三氟甲基、1,1-二氯乙基、1,2-二氯乙基、1,3-二溴-3,3-二氟丙基等。
本文中使用的术语“酰基”指包含羰基部分的基团，其中该基团经由该羰基碳原子键合。该羰基碳原子还键合至其它碳原子，其可以是烷基、芳基、芳烷基环烷基、环烷基烷基、杂环基、杂环基烷基、杂芳基、杂芳基烷基等的一部分。在其中羰基碳原子键合至氢的特定情况下，该基团是“甲酰基”，其为一种酰基(该术语如本文所定义)。其它的实例包括乙酰基、苯甲酰基、苯乙酰基、吡啶基乙酰基、肉桂酰基和丙烯酰基等。当包含键合至羰基碳原子的碳原子的基团包含卤素时，该基团称为“卤代酰基”。一个实例为三氟乙酰基。
本领域众所周知的“盐”包括有机化合物，例如离子形式的羧酸、磺酸或胺与反离子的组合。例如，阴离子形式的酸可以与下述物质形成盐：阳离子如金属阳离子，例如钠、钾等；铵盐如NH4+或多种胺的阳离子，包括四烷基铵盐如四甲铵，或其它阳离子如三甲基硫鎓等。“可药用”盐是由已批准用于人使用且通常无毒的离子形成的盐，比如盐酸盐或钠盐。“两性离子”是内盐，例如其可以在具有至少两个可电离基团的分子中形成，一个形成阴离子，另一个形成阳离子，其彼此达到平衡。例如，氨基酸(如甘氨酸)可以以两性离子形式存在。“两性离子”是本文含义内的盐。
“水合物”是以与水分子组合存在的化合物。所述组合物可以包含化学计量量的水，例如一水合物或二水合物，或者可以包含任意量的水。
“溶剂化物”是类似的组合物，不同点在于用不同于水的溶剂代替水。例如，甲醇或乙醇可以形成“醇化物”，其也可以是化学计量的或非化学计量的。
“互变异构体”是物质的两种形式，其仅仅在分子结构中的氢原子位置不同。
在本发明的第一个方面，提供了式(I)的化合物:
Ar1-A-C(M)-Se-Ar2
(I)
或其可药用盐；
其中
Ar1和Ar2各自代表芳基或杂芳基，其可以相同或不同，其中Ar1和Ar2中任一个都可以任选地被一个或多个选自以下的取代基取代：卤素、C1-8烷基、C1-8烷氧基、卤代C1-8烷氧基、氨基、酰基、C1-8烷基酰基、酰氧基、C1-8烷基酰氧基、羧基、硝基、氰基、C1-8烷基胺基、卤代C1-8烷基、C1-8烷基胺基烷基、羟基、羟基C1-8烷基、羟基C1-8烷基胺基、C3-6环烷基和C2-4链烯基；
M选自O、S或Se；
A为1至4个碳原子的直链或支链化的亚烷基链或亚烯基链，或者为直接的共价键。
在一个优选的实施方案中，所述Ar2为苯基或被以下取代基取代的苯基：卤素、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、卤代C1-4烷氧基、氨基和羟基。
在另一个优选的实施方案中，所述Ar1选自未取代或取代的苯基、萘基和杂芳基，
其中，所述取代基选自卤素、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、卤代C1-4烷氧基、氨基和羟基；并且
其中所述杂芳基选自吡咯基、吡唑基、三唑基、四唑基、噁唑基、异噁唑基、噻唑基、吡啶基、嘧啶基、噻吩基、苯并噻吩基、苯并呋喃基、吲哚基、氮杂吲哚基、吲唑基、苯并咪唑基、氮杂苯并咪唑基、苯并噁唑基、苯并噻唑基、苯并噻二唑基、咪唑并吡啶基、异噁唑并吡啶基、硫杂萘基、嘌呤基、黄嘌呤基、腺嘌呤基、鸟嘌呤基、喹啉基、异喹啉基、四氢喹啉基、 喹喔啉基和喹唑啉基。在本发明的特别优选的实施方案中，Ar1选自：苯基酰氧基、C1-4烷基甲酰氧基、C1-4烷基、C1-4烷氧基、苯甲酰基、苯基、联苯基和卤素取代的联苯基。
在本发明的化合物中，M代表与碳原子相连的二价原子，其为O、S或Se原子。在另一个优选的实施方案中，M为O。
优选地，本发明化合物是选自以下的具体化合物或其可药用盐：
Figure PCTCN2017092784-appb-000003
本发明的另一个方面提供了包含本发明化合物和赋形剂或载体的药物组合物或者包含除本发明化合物外还另外包含其他药物活性成分以及赋形剂或载体的药物组合物。本发明的药物组合物可以通过常规技术制备，例如在Remington：The Science and Practice of Pharmacy,第19版，1995中所描 述的方法，其通过引用并入本文。所述组合物可以以常规形式出现，例如胶囊、片剂、气雾剂、溶液剂、混悬剂或局部施用形式。
典型的组合物包含本发明化合物和赋形剂或载体。例如，活性化合物通常与载体混合，或者被载体稀释，或者被密封在可以为安瓿、胶囊、小药囊(sachet)、纸或其它容器形式的载体内。当将活性化合物与载体混合时，或者当载体充当稀释剂时，所述载体可以为充当活性化合物的载体、赋形剂或介质的固体、半固体或液体材料。所述活性化合物可以吸附在颗粒状固体载体上(例如容纳在小药囊中)。合适的载体的一些实例为水、盐溶液、醇、聚乙二醇、聚羟基乙氧基化蓖麻油、花生油、橄榄油、明胶、乳糖、白土、蔗糖、糊精、碳酸镁、糖、环糊精、直链淀粉、硬脂酸镁、滑石、明胶、琼脂、果胶、阿拉伯胶、硬脂酸或纤维素的低级烷基醚、硅酸、脂肪酸、脂肪酸胺、脂肪酸甘油单酯和甘油二酯、季戊四醇脂肪酸酯、聚氧乙烯、羟甲基纤维素和聚乙烯吡咯烷酮。类似地，所述载体或稀释剂可以包括任何本领域已知的持续释放材料，例如单独的单硬脂酸甘油酯或二硬脂酸甘油酯或者其与蜡的混合物。
所述制剂可以与不与所述活性化合物发生有害反应的辅助剂混合。这些添加剂可以包括润湿剂、乳化剂和助悬剂、影响渗透压的盐、缓冲剂和/或着色物质、防腐剂、甜味剂或调味剂。如果需要，还可以对所述组合物进行灭菌。
施用途径可以是将本发明活性化合物有效地转运到适当的或期望的作用部位的任何途径，例如口服、经鼻、肺部、口含、皮下、皮内、透皮或肠胃外途径，例如直肠、贮库(depot)、皮下、静脉内、尿道内、肌内、鼻内、眼用溶液或软膏剂的途径，口服途径是优选的。
如果使用固体载体用于口服施用，则该制剂可以是压片的，以粉剂或小丸形式置于硬明胶胶囊中，或者其可以是糖锭(troche)或锭剂的形式。如果使用液体载体，则所述制剂可以是糖浆剂、乳剂、软明胶胶囊或无菌可注射液体的形式，例如水性或非水性液体混悬剂或溶液剂。
可注射的剂型通常包括水性混悬剂或油性混悬剂，其可以使用合适的分散剂或润湿剂和助悬剂来制备。可注射的形式可以是在溶液相中或者是用溶 剂或稀释剂制备的混悬剂的形式。可接受的溶剂或载体包括无菌水、林格溶液或等渗盐水溶液。或者，可以应用无菌油作为溶剂或助悬剂。优选地，所述油或脂肪酸是不挥发性的，包括天然油或合成油、脂肪酸、甘油单酯、甘油二酯或甘油三酯。
对于注射而言，所述制剂还可以是适于用上述的合适溶液重构的粉末。这些的实例包括但不限于冷冻干燥的、旋转干燥的或喷雾干燥的粉末，无定形粉末、颗粒、沉淀物或微粒。对于注射剂而言，所述制剂可以任选地包含稳定剂、pH调节剂、表面活性剂、生物利用度调节剂和这些试剂的组合。可以将所述化合物配制为用于通过注射进行胃肠外施用，例如通过推注或连续输注。用于注射的单位剂型可以在安瓿中或多剂量容器中。
可以将本发明的制剂设计成在通过本领域熟知的方法施用至患者后能提供活性成分的快速、持续或延迟释放。因此，还可以将所述制剂配制成用于控释释放或缓慢释放。
本发明的化合物在宽的剂量范围都是有效的。例如，在成年人的治疗中，可以使用每天约0.05至约5000mg、优选约1至约2000mg、更优选约2至约2000mg的剂量。典型的剂量为每天约10mg至约1000mg。在选择患者治疗方案时，其可常常须从较高的剂量开始，并且当病症得到控制时减少剂量。精确的剂量将取决于化合物的活性、施用方式、期望的治疗、施用的形式、待治疗的对象和待治疗对象的体重、及主管医师或兽医的偏好和经验。
通常，将本发明化合物分配在单位剂型中，其每单位剂量包含约0.05mg至约1000mg活性成分和可药用载体。
通常，适于口服、经鼻、肺部或透皮施用的剂型包括约125μg至约1250mg、优选约250μg至约500mg、更优选约2.5mg到约250mg的与可药用载体或稀释剂混合的所述化合物。
剂型可以是每日一次、或每日一次以上例如每日两次或每日三次施用。或者，剂型可以少于每日一次的频率施用，例如每隔一天或每周，如果开处方的医师认为合适的话。
药物组合物可以片剂、胶囊、粉剂、颗粒剂、锭剂、液体或胶状物形式。供口服的片剂和胶囊可以适于单位剂量用药的形式，并且可以含常规的赋形 剂，这些例子有：结合剂如糖浆、阿拉伯树胶、凝胶、山梨醇、黄著胶、聚乙烯吡咯烷酮(PVP)；填料如乳糖、糖类、玉米粉、磷酸钙、山梨醇或甘氨酸；片剂润滑剂如硬脂酸镁、二氧化硅、滑石、聚乙二醇或二氧化硅；崩解剂如马铃薯淀粉；可接受的润滑剂如月桂基硫酸钠。片剂可按照已知的常规制药实践中的方法进行包衣。口服液体制剂可以使水状或油状悬浮液、溶液、乳剂、糖浆或酊剂，也可制成一种干物质，在使用之前再用水或其它合适的载体重新调制。这些液体制剂可含有常规的添加剂，例如悬浮剂(如：山梨醇、糖浆、甲基纤维素、葡萄糖浆、明胶、经氢化的食用油脂)。乳化剂(如孵磷脂，山梨醇单油酸盐或阿拉伯树胶)，非水相载体(包括食用油如杏仁油、精馏的椰子油、油脂如甘油、丙二醇或乙醇),防腐剂(如甲基或丙基对羟基苯甲酸或山梨酸)，如果需要也可含有常规的风味剂或着色剂。
本发明药物组合物中活性物质的百分比是可变的，因为必须使药物调剂制成一定合适比例的剂量，以获得理想的疗效。总之，本发明的药物制剂经口服或注射给药应按每70kg体重每天1至15毫克活性物质。以下说明性的而不是限制性的给出一些实施实施例。
本发明在多个实施方案中提供了合成本文中本发明化合物的方法。通用方法包括使X-Se-Ar2所代表的芳基硒基卤化物或杂芳基硒基卤化物与Ar1-A-C(M)-COOH在有机溶剂中反应的步骤。所述反应可以在低温下反应，在催化剂(例如三丁基膦)下进行。在一些优选的实施方案中，可将苯硒基氯或苯硒基溴溶于四氢呋喃或二氯甲烷中，低温冷却，加入三丁基磷，搅拌下加入通式为Ar1-A-C(M)-COOH的化合物，通入惰性气体保护，继续低温搅拌，生成目标化合物Ar1-A-C(M)-Se-Ar2。
实施发明的最佳方式
根据下述实施例可以更好地理解本发明，然而实施例中所描述的具体的物料配比，工艺条件及结果仅用于说明本发明，而不应当对本发明进行限制。
下述实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的药材原料、试剂材料等，如无特殊说明，均可自常规生化试剂商店 或药品经营企业购买得到。
实施例1：制备2-乙酰氧基苯甲酸苯硒酯
反应式如下：
Figure PCTCN2017092784-appb-000004
在50ml烧瓶中加入苯硒氯(1.51g，6.67mmol)和无水二氯甲烷20ml，冰盐浴冷却至-15℃搅拌,依次加入三丁基磷(1.12g，5.56mmol)，2-乙酰氧基苯甲酸(1.00g，5.56mmol)，通入高纯氩气保护，保持-15℃搅拌反应2.0小时，TLC监测反应完全，减压蒸馏除去溶剂，硅胶柱层析分离，用乙酸乙酯(V)：石油醚(V)＝1:20作为流动相，得白色针状晶体I1.1g，产率61％。
核磁共振1H NMR(400MHz,CDCl3)：2.33(s,3H,CH3),7.16(d,J＝8.00Hz,1H,ArH),7.35-7.43(m,4H,ArH),7.56-7.59(m,3H,ArH),7.97(d,J＝8.00Hz,1H,ArH).13C NMR(100Hz,CDCl3):21.4,124.3,126.5,129.3,129.5,129.9,131.6,134.1,136.4,147.6,169.3,190.9.
ESI-MS:343.5([M+Na]+).
实施例2：制备2-(4-异丁基苯基)-丙酸苯硒酯
反应式如下：
在50ml烧瓶中加入苯硒氯(0.77g,4.04mmol)和无水二氯甲烷30ml，冰盐 浴冷却至-15℃搅拌,依次加入三丁基磷(0.82g，4.04mmol)，2-(4-异丁基苯基)-丙酸(0.50g，2.69mmol)，通入高纯氩气保护，保持-15℃搅拌反应2.0小时，TLC监测反应完全，减压蒸馏除去溶剂，硅胶柱层析分离，用乙酸乙酯(V)：石油醚(V)＝1:20作为流动相，得无色油状液体II0.72g，产率74％。
核磁共振1H NMR(400MHz,CDCl3)：0.90(s,3H,CH3),0.92(s,3H,CH3)，1.55(d,J＝8.00Hz,3H,CH3),1.85(m,1H,CH),2.48(d,2H,CH2),3.96(q,J＝8.00Hz,1H,CH),7.14(d,J＝8.00Hz,2H,ArH),7.23-7.25(m,2H,ArH),7.32-7.35(m,3H,ArH),7.42-7.44(m,2H,ArH).13C NMR(100Hz,CDCl3):18.3,22.5,30.3,45.3,57.4,127.1,128.4,128.8,129.3,129.7,135.9,136.0,141.6,202.8.
ESI-MS:385.5([M+K]+).
实施例3：制备(+)-α-甲基-6-甲氧基-2-萘乙酸苯硒酯
反应式如下：
Figure PCTCN2017092784-appb-000006
在50ml烧瓶中加入苯硒溴(0.77g,3.26mmol)和无水四氢呋喃20ml，冰盐浴冷却至-15℃搅拌,依次加入三丁基磷(0.88g，4.34mmol)，(+)-α-甲基-6-甲氧基-2-萘乙酸(0.50g，2.17mmol)，通入高纯氩气保护，保持-15℃搅拌反应3.0小时，TLC监测反应完全，减压蒸馏除去溶剂，硅胶柱层析分离，用乙酸乙酯(V)：石油醚(V)＝1:8作为流动相，得白色固体III0.66g，产率83％。
核磁共振1H NMR(400MHz,CDCl3)：1.63(d,J＝8.00Hz,3H,CH3),3.92(s,3H,CH3)，4.12(q,J＝8.00Hz,1H,CH),7.14-7.18(m,2H,ArH),7.30-7.34(m,3H,ArH),7.39-7.43(m,3H,ArH),7.73-7.75(m,3H,ArH).13C NMR(100Hz,CDCl3):18.2,55.3,57.6,105.7,119.2,126.7,126.9,127.4,127.5,128.7,128.9,129.2,129.4,133.8,134.1,135.8,157.9,202.6.
ESI-MS:393.5([M+Na]+).
实施例4：制备2-(2-羟基苯甲酰氧基)苯甲酸苯硒酯
反应式如下：
Figure PCTCN2017092784-appb-000007
在50ml烧瓶中加入苯硒氯(1.11g,5.82mmol)和无水四氢呋喃20ml，冰盐浴冷却至-15℃搅拌,依次加入三丁基磷(1.57g，7.76mmol)，2-(2-羟基苯甲酰氧基)苯甲酸(0.50g，1.94mmol)，通入高纯氩气保护，保持-15℃搅拌反应3.0小时，TLC监测反应完全，减压蒸馏除去溶剂，硅胶柱层析分离，用乙酸乙酯(V)：石油醚(V)＝1:8作为流动相，得白色固体IV0.62g，产率80％。
核磁共振1H NMR(400MHz,CDCl3):6.94(t,J＝8.00Hz,1H,ArH),7.02(d,J＝8.00Hz,1H,ArH),7.28(d,J＝8.00Hz,1H,ArH),7.35-7.37(m,3H,ArH),7.43-7.47(m,2H,ArH),7.50-7.60(m,2H,ArH),7.64-7.66(m,1H,ArH),8.09(dd,J1＝8.00Hz,J2＝3.2Hz,2H,ArH),10.3(s,1H,OH).13C NMR(100Hz,CDCl3):111.7,117.9,119.7,124.2,126.2,127.0,129.3,129.6,129.9,131.0,132.1,134.1,136.2,136.8,146.7,162.3,168.6,190.9.
ESI-MS:421.4([M+Na]+).
实施例5：制备2-甲基-1-(4-氯苯甲酰基)-5-甲氧基-1H-吲哚-3-乙酸苯硒酯
反应式如下：
Figure PCTCN2017092784-appb-000008
在50ml烧瓶中加入苯硒氯(0.40g,2.10mmol)和无水四氢呋喃20ml，冰盐浴冷却至-15℃搅拌,依次加入三丁基磷(0.57g，2.80mmol)，2-甲基-1-(4-氯苯甲酰基)-5-甲氧基-1H-吲哚-3-乙酸(0.50g，1.40mmol)，通入高纯氩气保护，保持-15℃搅拌反应4.0小时，TLC监测反应完全，减压蒸馏除去溶剂，硅胶柱层析分离，用乙酸乙酯(V)：石油醚(V)＝1:10作为流动相，得白色固体V0.53g，产率76％。
核磁共振1H NMR(400MHz,CDCl3):2.45(s,1H,CH3),3.85(s,1H,OCH3),3.95(s,2H,CH2),6.71(dd,J1＝8.00Hz,J2＝4.00Hz,1H,ArH),6.92(d,J＝12.00Hz,1H,ArH),6.95(d,J＝4.00Hz,1H,ArH),7.35-7.37(m,3H,ArH),7.44-7.49(m,4H,ArH),7.68-7.70(m,2H,ArH).13C NMR(100Hz,CDCl3):13.8,42.6,55.8,101.0,111.2,112.1,115.1,126.4,128.9,129.2,129.3,130.5,130.9,131.3,133.7,135.7,137.4,139.5,156.3,168.3,198.7.
ESI-MS:520.2([M+Na]+).
实施例6：制备2-(3-苯甲酰苯基)-丙酸苯硒酯
反应式如下：
Figure PCTCN2017092784-appb-000009
在50ml烧瓶中加入苯硒溴(0.70g,2.95mmol)和无水四氢呋喃30ml，冰盐浴冷却至-15℃搅拌,依次加入三丁基磷(0.80g，3.94mmol)，2-(3-苯甲酰苯基)-丙酸(0.50g，1.97mmol)，通入高纯氩气保护，保持-15℃搅拌反应4.0小时，TLC监测反应完全，减压蒸馏除去溶剂，硅胶柱层析分离，用乙酸乙酯(V)：石油醚(V)＝1:8作为流动相，得白色固体VI0.55g，产率71％。
核磁共振1H NMR(400MHz,CDCl3):1.59(d,3H,CH3),4.08(q,J＝4.00Hz,1H,CH),7.33-7.36(m,3H,ArH),7.43-7.49(m,5H,ArH),7.57-7.62(m,2H,ArH),7.74-7.77(m,2H,ArH),7.81-7.84(m,2H,ArH).13C NMR(100Hz,CDCl3):18.2,57.3,126.5,128.4,128.8,128.9,129.3,129.6,130.1,130.2,132.3,132.6,135.8,137.4,138.1,139.1,196.3,201.9.
ESI-MS:417.5([M+Na]+).
实施例7：制备(S)-(+)-2-(4-异丁苯基)丙酸苯硒酯
反应式如下：
Figure PCTCN2017092784-appb-000010
在50ml烧瓶中加入苯硒氯(1.54g,8.08mmol)和无水二氯甲烷30ml，冰盐浴冷却至-15℃搅拌,依次加入三丁基磷(1.64g，8.08mmol)，(S)-(+)-2-(4-异丁苯基)丙酸(1.00g，5.38mmol)，通入高纯氩气保护，保持-15℃搅拌反应3.0小时，TLC监测反应完全，减压蒸馏除去溶剂，硅胶柱层析分离，用乙酸乙酯(V)：石油醚(V)＝1:20作为流动相，得无色油状液体VII1.35g，产率56％。
核磁共振1H NMR(400MHz,CDCl3)：0.90(s,3H,CH3),0.92(s,3H,CH3)，1.55(d,J＝8.00Hz,3H,CH3),1.85(m,1H,CH),2.48(d,2H,CH2),3.96(q,J＝8.00Hz,1H,CH),7.14(d,J＝8.00Hz,2H,ArH),7.23-7.25(m,2H,ArH),7.32-7.35(m,3H,ArH),7.42-7.44(m,2H,ArH).13C NMR(100Hz,CDCl3): 18.3,22.5,30.3,45.3,57.4,127.1,128.4,128.8,129.3,129.7,135.9,136.0,141.6,202.8.
ESI-MS:385.5([M+K]+).
实施例8：制备2-(2-氟-4-联苯)丙酸苯硒酯
反应式如下：
Figure PCTCN2017092784-appb-000011
在50ml烧瓶中加入苯硒氯(0.23g,1.23mmol)和无水二氯甲烷30ml，冰盐浴冷却至-15℃搅拌,依次加入三丁基磷(0.33g，1.64mmol)，2-(2-氟-4-联苯)丙酸(0.20g，0.82mmol)，通入高纯氩气保护，保持-15℃搅拌反应3.0小时，TLC监测反应完全，减压蒸馏除去溶剂，硅胶柱层析分离，用乙酸乙酯(V)：石油醚(V)＝1:8作为流动相，得白色固体VIII0.23g，产率73％。
核磁共振1H NMR(400MHz,CDCl3)：1.56(d,J＝4.00Hz,3H,CH3),3.79(q,J＝8.00Hz,1H,CH)，7.14(d,J＝2.00Hz,2H,ArH),7.34-7.44(m,6H,ArH),7.52-7.55(m,5H,ArH),13C NMR(100Hz,CDCl3):18.0,44.8,115.3,123.7,127.9,128.3,128.6,129.1(J＝12Hz),130.9,135.4,140.9,158.5,160.9,179.6.
ESI-MS:406.3([M+Na]+).
实施例9：制备2-(4-异丁基苯基)-丙酸-4’-氯苯硒酯
反应式如下：
Figure PCTCN2017092784-appb-000012
Figure PCTCN2017092784-appb-000013
在50ml烧瓶中加入4-氯苯硒氯(0.34g,1.51mmol)和无水四氢呋喃30ml，冰盐浴冷却至-15℃搅拌,依次加入三丁基磷(0.46g，2.27mmol)，2-(4-异丁苯基)丙酸(0.30g，1.21mmol)，通入高纯氩气保护，保持-15℃搅拌反应2.0小时，TLC监测反应完全，减压蒸馏除去溶剂，硅胶柱层析分离，用乙酸乙酯(V)：石油醚(V)＝1:6作为流动相，得无色透明液体IX0.35g，产率66％。
核磁共振1H NMR(400MHz,CDCl3)：0.91(s,3H,CH3),0.93(s,3H,CH3)，1.56(d,J＝8.12Hz,3H,CH3),1.87(m,1H,CH),2.50(d,2H,CH2),3.98(q,J＝8.12Hz,1H,CH),7.16(d,J＝8.00Hz,2H,ArH),7.19-7.23(m,2H,ArH),7.33-7.36(m,2H,ArH),7.41-7.45(m,2H,ArH).13C NMR(100Hz,CDCl3):18.5,22.3,29.3,44.8,58.2,127.1,128.6,128.9,129.7,129.9,136.5,138.2,143.2,201.4.
ESI-MS:402.5([M+Na]+).
实施例10：制备2-(4-异丁基苯基)-丙酸-4’-甲基苯硒酯
反应式如下：
Figure PCTCN2017092784-appb-000014
在50ml烧瓶中加入4-甲基苯硒氯(0.46g,2.40mmol)和无水二氯甲烷30ml，冰盐浴冷却至-15℃搅拌,依次加入三丁基磷(0.48g，2.40mmol)，乙酰水杨酸(0.22g，1.20mmol)，通入高纯氩气保护，保持-15℃搅拌反应3.0小时，TLC监测反应完全，减压蒸馏除去溶剂，硅胶柱层析分离，用乙酸乙酯(V)：石油醚(V)＝1:6作为流动相，得白色固体X0.30g，产率75％。
核磁共振1H NMR(400MHz,CDCl3)：2.31(s,3H,CH3),3.22(s,3H,CH3)，7.10(d,J＝8.04Hz,1H,ArH),7.34-7.41(m,4H,ArH),7.52-7.54(m,2H,ArH),8.01(d,J＝8.04Hz,1H,ArH).13C NMR(100Hz,CDCl3):22.3,32.5,124.6,127.1,129.6,129.9,130.1,131.4,134.7,136.8,148.2,170.4,192.3.
ESI-MS:341.2([M+Na]+).
实施例11：生物活性评价
以下内容评价了本发明所述化合物抗培养基中几种人肿瘤细胞系生长的抑制活性，所述肿瘤细胞系包括HeLa(宫颈癌细胞)、PC3(前列腺癌细胞)、HCT-116(结肠癌细胞)、SGC-7091(胃癌细胞)。
1、体外细胞实验
(1)本发明所述化合物I-VIII的体外抗肿瘤作用实验
取对数期的各细胞按每孔3×104接种于96孔板上，12小时后弃去上清，按以下分组给药：正常对照组和加药组(浓度0-100μM)，每组设6个复孔，培养24小时，弃上清，加入含有MTT的培养液50μL培养4小时(0.5mg/mL),加入100μL DMSO，振荡1小时，在酶标仪上570nm处测吸光度。另外采用紫杉醇作为阳性对照药。
结果显示，加药后肿瘤细胞活性明显下降，而且肿瘤细胞活性随着药物浓度的增加而降低。结果见表1。
表1：肿瘤细胞系的体外生长抑制(采用人胚肾细胞293T作为对照)
Figure PCTCN2017092784-appb-000015
Figure PCTCN2017092784-appb-000016
aIC50值为三次独立实验的平均值
结果表明：本发明所述化合物I-VIII均能够不同程度地抑制多种肿瘤细胞生长，显示出本发明所述化合物具有明显的抗肿瘤活性。
(2)本发明所述化合物I-VIII的醌还原酶诱导活性实验
取对数期的鼠肝癌细胞株Hepa 1c1c7细胞(购自ATCC)，按每孔2×104接种于96孔板上，培养液含有10％(v/v)胎牛血清、0.01％青霉素G、0.15％碳酸氢钠、0.01％链霉素，于环境条件为37℃、5％二氧化碳培养箱中培养24小时，然后将已知浓度的待测化合物溶解在DMSO中，加入各孔并保持24小时。每孔加入DMSO后应保证DMSO的终浓度＜0.5％(V/V)。之后弃去上清液，加入洋地黄毒苷以消化细胞，最后加入含有MTT的培养液轻轻振荡5分钟，在550nm处测吸光度。
结果见表2。结果显示，给药组的化合物均显示出明显的醌还原酶诱导活性，表明对于本发明所述化合物具有癌症化学预防作用。
表2：本发明所述化合物I-VIII的醌还原酶诱导活性测试结果
Figure PCTCN2017092784-appb-000017
Figure PCTCN2017092784-appb-000018
a4′-溴黄酮为阳性对照。

Claims (10)

  1. 一种式(I)所示的化合物，
    Ar1-A-C(M)-Se-Ar2
    (I)
    或其药物可接受的盐；
    其中，Ar1和Ar2各自代表芳基或杂芳基，其可以相同或不同，其中Ar1和Ar2中任一个都可以任选地被一个或多个选自以下的取代基取代：卤素、C1-8烷基、C1-8烷氧基、卤代C1-8烷氧基、氨基、酰基、C1-8烷基酰基、酰氧基、C1-8烷基酰氧基、羧基、硝基、氰基、C1-8烷基胺基、卤代C1-8烷基、C1-8烷基胺基烷基、羟基、羟基C1-8烷基、羟基C1-8烷基胺基、C3-6环烷基和C2-4链烯基；
    M为O、S或Se；
    A为1至4个碳原子的直链或支链化的亚烷基链或亚烯基链，或者为直接的共价键。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于，所述Ar2为苯基或被以下取代基取代的苯基：卤素、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、卤代C1-4烷氧基、氨基和羟基。
  3. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其特征在于，所述Ar1选自未取代或取代的苯基、萘基和杂芳基，其中，所述取代基选自卤素、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、卤代C1-4烷氧基、氨基和羟基；并且其中所述杂芳基选自吡咯基、吡唑基、三唑基、四唑基、噁唑基、异噁唑基、噻唑基、吡啶基、嘧啶基、噻吩基、苯并噻吩基、苯并呋喃基、吲哚基、氮杂吲哚基、吲唑基、苯并咪唑基、氮杂苯并咪唑基、苯并噁唑基、苯并噻唑基、苯并噻二唑基、咪唑并吡啶基、异噁唑并吡啶基、硫 杂萘基、嘌呤基、黄嘌呤基、腺嘌呤基、鸟嘌呤基、喹啉基、异喹啉基、四氢喹啉基、喹喔啉基和喹唑啉基；
    优选地，所述Ar1选自：苯基酰氧基、C1-4烷基甲酰氧基、C1-4烷基、C1-4烷氧基、苯甲酰基、苯基、联苯基和卤素取代的联苯基；
    更优选地，Ar1选自C1-C4的烷基取代的苯基(4异丙基苯基)、C1-C4的烷酰氧基取代的苯基(例如2-乙酰氧基取代的苯基)、卤素取代的联苯基(例如2-氟-4联苯基)、苯甲酰基取代的苯基(例如3-苯甲酰基取代的苯基)、羟基苯甲酰氧基取代的苯基(例如2-羟基苯甲酰氧基取代的苯基)、取代吲哚(例如2-甲基-1-4氯苯甲酰基-5甲氧基-1H吲哚)和C1-C4的烷氧基取代的萘基。
  4. 根据权利要求1至3中任一项所述的化合物或其药学上可接受的盐，其特征在于，所述M为O。
  5. 根据权利要求1至4中任一项所述的化合物或其药学上可接受的盐，其特征在于，Ar2为苯基或被以下取代基取代的苯基：卤素、C1-4烷基；
    Ar1选自C1-C4的烷基取代的苯基(例如4异丙基苯基)、C1-C4的烷酰氧基取代的苯基(例如2-乙酰氧基取代的苯基)、卤素取代的联苯基(例如2-氟-4联苯基)、苯甲酰基取代的苯基(例如3-苯甲酰基取代的苯基)、羟基苯甲酰氧基取代的苯基(例如2-羟基苯甲酰氧基取代的苯基)、取代吲哚(例如2-甲基-1-4氯苯甲酰基-5甲氧基-1H吲哚)和C1-C4的烷氧基取代的萘基；
    M选自O；
    A为1至4个碳原子的直链或支链化的亚烷基链或者为直接的共价键；
    优选地，所述化合物选自：
    Figure PCTCN2017092784-appb-100001
    Figure PCTCN2017092784-appb-100002
  6. 一种权利要求1至5中任一项所述的化合物制备方法，该方法包括将X-Se-Ar2所代表的芳基硒基卤化物或杂芳基硒基卤化物与Ar1-A-C(M)-COOH在有机溶剂中反应的步骤；
    优选地，所述制备方法包括将X-Se-Ar2所代表的芳基硒基卤化物或杂芳基硒基卤化物与Ar1-A-C(M)-COOH在催化剂三丁基膦的存在下在有机溶剂中反应；
    优选地，所述Ar1-A-C(M)-COOH与X-Se-Ar2所代表的芳基硒基卤化物或杂芳基硒基卤化物的摩尔比为1：1～4；
    优选地，所述三丁基磷与Ar1-A-C(M)-COOH的摩尔比为1：1～3；
    优选地，所述反应在低于-5℃的温度下进行，例如在-15℃的温度下进行；
    其中，Ar1、Ar2、M、A的定义如权利要求1至5中任一项所述，X为卤素。
  7. 一种药物组合物，其包含根据权利要求1至5中任一项所述的化合物或其药学上可接受的盐以及药学上可接受的载体或赋形剂；
    优选地，所述药物组合物为片剂、丸剂、粉末、锭剂、混悬剂、乳剂、溶液剂、糖浆剂、气雾剂、软膏剂、乳膏剂、洗剂、胶囊剂、栓剂、滴眼剂、注射剂和粉针剂；
    优选地，所述药学上可接受的载体包括下述的一种或多种：水、盐溶液、醇、聚乙二醇、聚羟基乙氧基化蓖麻油、花生油、橄榄油、明胶、乳糖、白土、蔗糖、糊精、碳酸镁、糖、环糊精、直链淀粉、硬脂酸镁、滑石、明胶、琼脂、果胶、阿拉伯胶、硬脂酸或纤维素的低级烷基醚、硅酸、脂肪酸、脂肪酸胺、脂肪酸甘油单酯和甘油二酯、季戊四醇脂肪酸酯、聚氧乙烯、羟甲基纤维素和聚乙烯吡咯烷酮；
    优选地，所述药学上可接受的赋形剂包括下述的一种或多种：糖浆、阿拉伯树胶、凝胶、山梨醇、黄著胶、聚乙烯吡咯烷酮(PVP)、乳糖、糖类、玉米粉、磷酸钙、山梨醇或甘氨酸；片剂润滑剂如硬脂酸镁、二氧化 硅、滑石、聚乙二醇或二氧化硅、马铃薯淀粉、月桂基硫酸钠。
  8. 根据权利要求1至5中任一项所述的化合物或其药物可接受的盐、根据权利要求7所述的药物组合物在预防和/或治疗癌症或预防、治疗和/或缓解与其相关的并发症和/或症状中的用途；
    优选地，所述癌症选自脑癌、乳癌、结肠癌、直肠癌、皮肤癌、头颈癌、宫颈癌、肾癌、肺癌、肝癌、卵巢癌、胰腺癌、前列腺癌、甲状腺癌、胃癌、白血病、淋巴瘤、肉瘤和黑素瘤；优选宫颈癌、前列腺癌、结肠癌和胃癌。
  9. 根据权利要求1至5中任一项所述的化合物或其药物可接受的盐、根据权利要求7所述的药物组合物在制备用于预防和/或治疗癌症或预防、治疗和/或缓解与其相关的并发症和/或症状的药物中的用途；
    优选地，所述癌症选自脑癌、乳癌、结肠癌、直肠癌、皮肤癌、头颈癌、宫颈癌、肾癌、肺癌、肝癌、卵巢癌、胰腺癌、前列腺癌、甲状腺癌、胃癌、白血病、淋巴瘤、肉瘤和黑素瘤；优选宫颈癌、前列腺癌、结肠癌和胃癌。
  10. 一种预防和/或治疗癌症或预防、治疗和/或缓解与其相关的并发症和/或症状的方法，该方法包括向有需要的患者施用治疗有效量的权利要求1至5中任一项所述的化合物或其药物可接受的盐或权利要求7所述的药物组合物。
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