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WO2015081867A1 - 吉西他滨衍生物、含该衍生物的组合物及所述衍生物的制药用途 - Google Patents

吉西他滨衍生物、含该衍生物的组合物及所述衍生物的制药用途 Download PDF

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WO2015081867A1
WO2015081867A1 PCT/CN2014/093005 CN2014093005W WO2015081867A1 WO 2015081867 A1 WO2015081867 A1 WO 2015081867A1 CN 2014093005 W CN2014093005 W CN 2014093005W WO 2015081867 A1 WO2015081867 A1 WO 2015081867A1
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compound
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formula
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French (fr)
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吴耀东
单佳祺
沈锡明
吴春霞
黄滨南
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HANGZHOU MINSHENG INSTITUTES FOR PHARMA RESEARCH Co Ltd
Hangzhou Minsheng Pharmaceutical Co Ltd
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HANGZHOU MINSHENG INSTITUTES FOR PHARMA RESEARCH Co Ltd
Hangzhou Minsheng Pharmaceutical Co Ltd
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Priority to US15/101,816 priority Critical patent/US9944670B2/en
Priority to EP14867802.2A priority patent/EP3078671A4/en
Priority to JP2016536956A priority patent/JP6212831B2/ja
Publication of WO2015081867A1 publication Critical patent/WO2015081867A1/zh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives

Definitions

  • the invention belongs to the field of medicine, and particularly relates to a gemcitabine derivative, a composition containing the same, and the use of the compound in pharmaceutical, in particular, preparation of antitumor drugs.
  • Tumors are a kind of disease that seriously threatens human health. Thanks to the progress of life science research technology and deep understanding of tumor pathology in the past 30 years, breakthroughs in the development of anti-tumor drugs have made breakthroughs in various types of new molecules. The successful development of targeted anti-tumor drugs has played an important role in improving the level of cancer treatment. At this stage, tumor resistance is a difficult point in cancer treatment. The heterogeneity of tumors and the susceptibility to mutation are the main causes of drug resistance. Therefore, drug research and development for the mechanism of tumor resistance has a very important clinical significance.
  • Anti-metabolite drugs are an important component of anti-tumor drugs. In 2010, anti-metabolites accounted for 15.75% of the market share in the entire anti-tumor drug hospital market, ranking third. Anti-metabolic anti-tumor drugs are mainly composed of nucleoside drugs, among which gemcitabine, cytarabine, decitabine, azacytidine, cladribine, fludarabine, nairabine, etc. are most commonly used.
  • Gemcitabine is a cytosine analog, which is a cycle-specific antitumor drug; it mainly acts on the DNA synthesis phase, and also blocks the progression of the tumor cell cycle from DNA synthesis to DNA synthesis; gemcitabine is in deoxycytidine kinase. It is converted into active gemcitabine diphosphate and triphosphate, which inhibits tumor cell division and induces tumor cell apoptosis by affecting DNA synthesis and repair. It is suitable for the treatment of middle and late stage non-small cell lung cancer. Or pancreatic cancer that has metastasized.
  • Gemcitabine can be used in the treatment of paclitaxel and steroid-resistant breast cancer.
  • deoxycytidine kinase which increases the accumulation of gemcitabine triphosphate (dFdCTP) in tumor cells and promotes the binding of gemcitabine to the DNA strands of tumor cells, thereby increasing the drug sensitivity of drug-resistant tumor cells.
  • dFdCTP gemcitabine triphosphate
  • the present invention is different from the existing gemcitabine modification or modification idea, and uses gemcitabine as a lead compound to introduce a multi-target multi-action mechanism to synergistically act and simultaneously protect the synthesis mechanism of gemcitabine active pharmacophores.
  • Structural optimization optimizes the introduction of new reactive groups with specific molecular targeting, thereby preparing a class of gemcitabine compounds with novel structure, CDK inhibition and DNA synthesis inhibition, especially for gemcitabine compounds.
  • the purpose of tumor cell proliferation inhibitory activity is used to use gemcitabine as a lead compound to introduce a multi-target multi-action mechanism to synergistically act and simultaneously protect the synthesis mechanism of gemcitabine active pharmacophores.
  • Structural optimization optimizes the introduction of new reactive groups with specific molecular targeting, thereby preparing a class of gemcitabine compounds with novel structure, CDK inhibition and DNA synthesis inhibition, especially for gemcitabine compounds.
  • the purpose of tumor cell proliferation inhibitory activity is used to use gemcitabine as a lead compound
  • the present invention provides a gemcitabine derivative having the following structural formula I:
  • R 1 is selected from unsubstituted or substituted C 1-10 alkyl, unsubstituted or substituted C 2-10 alkenyl, unsubstituted or substituted C 2-10 alkynyl, unsubstituted or substituted C 3-7 ring
  • R 1 is an optionally substituted aryl group, wherein the substituent is selected from one of hydrogen, a hydroxyl group, a carboxyl group, a nitro group, a halogen atom, a C 1-6 alkyl group, and a C 1-6 alkoxy group or Several.
  • the optionally substituted aryl group is phenyl, benzyl or naphthyl.
  • R 1 is preferably from unsubstituted or substituted C 3-10 alkyl, unsubstituted or substituted C 3-10 alkenyl, unsubstituted or substituted C 3-10 alkynyl, unsubstituted or substituted a C 3-7 cycloalkyl group, an unsubstituted or substituted C 3-7 cycloalkoxy group, or an optionally substituted aryl group selected from a phenyl group, a benzyl group or a naphthyl group; wherein the substituent Is a halogen atom, a cyano group, a nitro group, an amino group, a trifluoromethyl group, a decyl group, a hydroxyl group, a carboxyl group, a carbonyl group, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 1-6 One or more of an alkyl,
  • the halogen atom is F, Cl, Br or I.
  • R 1 is preferably from unsubstituted or substituted C 4-9 alkyl, unsubstituted or substituted C 4-9 alkenyl, unsubstituted or substituted C 4-9 alkynyl, unsubstituted or Substituted C 3-7 cycloalkyl, unsubstituted or substituted C 3-7 cycloalkoxy; said substituent being selected from the group consisting of F and Cl.
  • No. GI-01 N-(5-((5-(tert-butyl)oxazol-2-yl)methyl)sulfonyl)thiazol-2-yl)-N'-(1-((2R, 4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)oxamide;
  • No. GI-02 N-(5-((5-(tert-butyl)oxazol-2-yl)methyl)sulfonyl)thiazol-2-yl)-N'-(1-((2R, 4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)malonamide;
  • No. GI-04 N-(5-((5-(tert-butyl)oxazol-2-yl)methyl)sulfonyl)thiazol-2-yl)-N'-(1-((2R, 4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)glutaramide;
  • No. GI-05 N-(5-((5-(tert-butyl)oxazol-2-yl)methyl)sulfonyl)thiazol-2-yl)-N'-(1-((2R, 4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)adipamide;
  • No. GI-06 N-(5-((5-(tert-butyl)oxazol-2-yl)methyl)sulfonyl)thiazol-2-yl)-N'-(1-((2R, 4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)pimelamide;
  • No. GI-08 N-(5-((5-(tert-butyl)oxazol-2-yl)methyl)sulfonyl)thiazol-2-yl)-N'-(1-((2R, 4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carboxamide;
  • No. GI-09 N-(5-((5-(tert-butyl)oxazol-2-yl)methyl)sulfonyl)thiazol-2-yl)-N'-(1-((2R, 4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carboxamide.
  • the invention also provides a preparation method of a gemcitabine derivative, comprising the following steps:
  • Y and Z each independently represent -OH, -F, -Cl, -Br or -I;
  • R 1 is selected from unsubstituted or substituted C 1-10 alkyl, unsubstituted or substituted C 2-10 alkenyl, unsubstituted or substituted C 2-10 alkynyl, unsubstituted or substituted C 3-7 ring alkyl, unsubstituted or substituted alkoxy group a C 3-7 cycloalkyl, wherein said substituent is a halogen atom, cyano, nitro, amino, trifluoromethyl, mercapto, hydroxy, carboxy, carbonyl, C One or more of 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, -NH-; or R 1 is an optionally substituted aryl group, wherein the substituent is selected from one or more of hydrogen, a hydroxyl group, a carboxyl group, a nitro group, a halogen atom, a C 1-6
  • the reaction temperature of the step (1) and the step (2) is from 0 ° C to 150 ° C; preferably from 20 ° C to 120 ° C.
  • the condensing agents of the step (1) and the step (2) are 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, 3-hydroxy-1,2,3-benzotriazine- 4(3H)-ketone, 1-ethyl-(3-dimethylaminopropyl)carbodiimide, N,N-dicyclohexylcarbodiimide, N,N-diisopropylcarbal One or more of the imines; preferably one or a combination of 1-hydroxybenzotriazole, 1-ethyl-(3-dimethylaminopropyl)carbodiimide;
  • the reaction solvent of the step (1) and the step (2) is benzene, toluene, chloroform, n-hexane, cyclohexane, dichloromethane, 1,2-dichloroethane, methyl tert-butyl ether, carbon tetrachloride.
  • the invention also provides another method for preparing a gemcitabine derivative, comprising the steps of:
  • Y and Z each independently represent -OH, -F, -Cl, -Br or -I;
  • R 1 is selected from unsubstituted or substituted C 1-10 alkyl, unsubstituted or substituted C 2-10 alkenyl, unsubstituted or substituted C 2-10 alkynyl, unsubstituted or substituted C 3-7 ring
  • the reaction temperature of the step (1) and the step (2) is from 0 ° C to 150 ° C; preferably from 20 ° C to 120 ° C.
  • the condensing agents of the step (1) and the step (2) are 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, 3-hydroxy-1,2,3-benzotriazine- 4(3H)-ketone, 1-ethyl-(3-dimethylaminopropyl)carbodiimide, N,N-dicyclohexylcarbodiimide, N,N-diisopropylcarbal One or more of the imines; preferably one or a combination of 1-hydroxybenzotriazole, 1-ethyl-(3-dimethylaminopropyl)carbodiimide;
  • the reaction solvent of the step (1) and the step (2) is benzene, toluene, chloroform, n-hexane, cyclohexane, dichloromethane, 1,2-dichloroethane, methyl tert-butyl ether, carbon tetrachloride.
  • the condensing agent of step (1) and step (2) is 1-hydroxybenzotriazole, 1- One or a combination of ethyl-(3-dimethylaminopropyl)carbodiimide;
  • the reaction solvent in the step (1) is N,N-dimethylformamide, and the reaction in the step (2)
  • the solvent is one of N,N-dimethylformamide, dimethyl sulfoxide or a combination thereof.
  • the compound of the formula VII involved in the above two preparation methods is commercially available, for example, from Alfa Aesar.
  • the compound of the formula VII can also be prepared by itself, and the preparation method is as follows: an appropriate amount of a di-C 1-6 alkoxycarbonyl compound is dissolved in acetic anhydride, and the mixture is heated under reflux for 4 hours, and then concentrated in a concentrated liquid. Add appropriate amount of xylene, concentrate and dry.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically effective amount of a gemcitabine derivative of formula I and a pharmaceutically acceptable excipient or additive.
  • the form of the pharmaceutical composition may be in the form of a usual preparation.
  • the invention also provides the use of a compound of formula I for the preparation of an anti-tumor drug.
  • the tumor is a drug resistant tumor.
  • tumor resistance means that an anti-tumor drug is either ineffective or otherwise effective to treat a tumor recurrence or metastasis.
  • the compound of the formula I of the present invention is mainly used for the preparation of a medicament for treating a tumor-resistant disease caused by a tumor cell to a cytotoxic drug, a targeted small molecule drug, a macromolecular antibody, and an immunomodulator antitumor drug.
  • the present invention also provides the use of a gemcitabine derivative of the general structure I as a prodrug for the preparation of an antitumor drug. That is, the gemcitabine derivative provided by the present invention can be administered orally by a prodrug for the treatment of gemcitabine indication-related tumors.
  • the invention also provides a method of treating a tumor comprising administering a compound of formula (I) of the invention to a subject in need thereof.
  • the tumor is a drug resistant tumor.
  • the present invention further provides a method for treating a tumor-resistant disease caused by a tumor cell to a cytotoxic drug, a targeted small molecule drug, a macromolecular antibody, and an immunomodulator antitumor drug, comprising administering to a subject in need thereof Inventive compounds of formula (I).
  • the invention uses gemcitabine as a lead compound, and through structural modification thereof, a series of novel compounds are obtained, and the compounds are screened for activity, and most of the compounds have significant antitumor activity and inhibit the activity of drug-resistant tumor cells. Far superior to gemcitabine, the toxicity is extremely low, and the effect is amazing.
  • the compound of the present invention has a reasonable structural design, and the optimized screening compound has both a dual-target mechanism of CDK inhibition and DNA synthesis inhibition, and the preparation source is widely available, the preparation method is simple and easy to operate, the reaction condition is mild, and the yield of the product is obtained. High, conducive to industrial scale production.
  • the compounds numbered GI-01 to GI-03 can be synthesized by the following reaction route:
  • step 1
  • n 0 or 1 or 2
  • Step 1 5-(((5-tert-butyl)oxathiazol-2-yl)methyl)sulfonyl)thiazol-2-amine (1.35 g, 9.5 mmol, 1.1 eq.), oxalic acid (0.774) g, 8.6 mmol, 1 eq.), 1-hydroxybenzotriazole monohydrate (1.46 g, 9.5 mmol), N-methylmorpholine (0.961 g, 9.5 mmol) dissolved in 15 mL of N,N- To dimethylformamide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.154 g, 11.2 mmol, 1.3 eq.) was added.
  • Step 2 7-((5-((2-tert-butyl)oxyoxazol-5-yl)methyl)sulfonyl)thiazol-2-yl)amino-7-oxoacetic acid (1.50 g, 4.4 mmol, 1 equivalent), gemcitabine (1.32 g, 4.4 mmol, 1 equivalent), 1-hydroxybenzotriazole monohydrate (0.674 g, 4.4 mmol), N-methylmorpholine (0.445 g, 4.4 mmol) was dissolved in 6 mL of a mixed solvent of N,N-dimethylformamide/dimethyl sulfoxide (3:1), and 1-(3-dimethylaminopropyl)-3-ethyl carbon was added.
  • the title compound was prepared in the same manner as in Example 1, except that in the first step, oxalic acid was replaced with malonic acid as a starting material, and the reaction was carried to the residue by TLC.
  • the title compound was prepared according to the method of Example 1, except that in step 1, succinic acid was replaced with succinic acid as a starting material, and the reaction was traced to the end by TLC to give a pale-yellow solid as the compound of number GI-03.
  • the compounds numbered GI-04 and GI-05 can be synthesized by the following reaction routes:
  • step 1
  • n 3 or 4
  • Step 1 glutaric acid (0.32 g, 2.42 mmol, 1.1 equivalents), gemcitabine (0.66 g, 2.2 mmol, 1 eq.), 1-hydroxybenzotriazole monohydrate (0.337 g, 2.2 mmol) N-methylmorpholine (0.223 g, 2.2 mmol) was dissolved in 4 mL of N,N-dimethylformamide, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide was added. Hydrochloride (0.548 g, 2.8 mmol, 1.3 eq.).
  • Step 2 5-((1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1, 2-Dihydropyrimidin-4-yl)amino)-5-oxopentanoic acid (1.51 g, 4 mmol, 1.0 eq.), 5-((5-tert-butyl)oxazol-2-yl )methyl)thio)thiazol-2-amine (1.08 g, 4 mmol, 1.0 eq.), 1-hydroxybenzotriazole monohydrate (0.613 g, 4.0 mmol), N-methylmorpholine (0.404) g, 4.0 mmol) dissolved in 6 mL of a mixed solvent of N,N-dimethylformamide / dimethyl sulfoxide (3:1), added 1-(3-dimethylaminopropyl)-3-ethyl
  • reaction solution was quenched by adding 20 mL of saturated brine, and extracted with dichloromethane (50 mL ⁇ 5). The organic layer was combined, and then saturated aqueous sodium carbonate, water, and saturated The organic layer was washed with EtOAc EtOAc m.
  • Example 4 The method of Example 4 was followed, except that in step 1, glutaric acid was replaced with adipic acid as a starting material, and the reaction was traced to the end by TLC to give a pale yellow solid which was a compound of the number GI-05.
  • the compounds numbered GI-06 to GI-07 can be synthesized by the following reaction route:
  • step 1
  • n 5 or 6
  • Step 1 pimelic anhydride (2.33 g, 8.6 mmol, 1 eq.) and 5-(((5-tert-butyl)oxathiazol-2-yl)methyl)thio)thiazol-2-amine (1.35) g, 9.5 mmol, 1.1 eq.) was dissolved in 15 mL of N,N-dimethylformamide and warmed to 100 ° C. After 16 hours, 30 mL of water was added to the reaction mixture to quench the reaction mixture, ethyl acetate (50 mL ⁇ 4) The extract is combined, and the organic layer is washed with brine, dried over anhydrous sodium sulfate.
  • Step 2 7-((5-(((2-tert-butyl))oxazol-5-yl)methyl)thio)thiazol-2-yl)amino-7-oxoheptanoic acid (1.815 g) , 4.4 mmol, 1 equivalent), gemcitabine (1.32 g, 4.4 mmol, 1 equivalent), 1-hydroxybenzotriazole monohydrate (0.674 g, 4.4 mmol), N-methylmorpholine (0.445 g) , 4.4 mmol) dissolved in 6 mL of a mixed solvent of N,N-dimethylformamide / dimethyl sulfoxide (3:1), added 1-(3-dimethylaminopropyl)-3-ethyl
  • the carbodiimide hydrochloride (1.096 g, 5.7 mmol, 1.3 eq.) was argon, warmed to 55 ° C and stirred for 19 hours. The reaction mixture was quenched by the addition of 20 mL of
  • the compounds numbered GI-08 to GI-09 can be synthesized by the following reaction route:
  • step 1
  • n 7 or 8.
  • Step 1 Dissolve sebacic anhydride (0.376 g, 2.0 mmol, 1 eq.), gemcitabine (0.66 g, 2.2 mmol, 1.1 eq.) in 15 mL of N,N-dimethylformamide and warm to 100 ° C.
  • Step 2 The preparation method is the same as Step 2 in Example 4, with 5-((1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2 5-(1-((2R,4R,5R)-3) is replaced by 5-yl-1,2-dihydropyrimidin-4-yl)amino)-5-oxodecanoic acid as a starting material.
  • step 1 the azelaic acid is replaced by sebacic acid as a raw material, and the reaction is traced to the end point by TLC to obtain a compound of the number GI-09.
  • Example 10 Effect of gemcitabine and its derivatives on cytotoxic activity of tumor-resistant cell lines
  • MATERIALS AND METHODS Human breast cancer adriamycin-resistant cell line MCF-7-ADR was cultured in 1640 medium containing 5% fetal bovine serum; gemcitabine and derivative GI-06 were dissolved in DMSO and frozen at -20 °C. Dilute to the corresponding concentration in PBS medium containing 5% fetal bovine serum before use, the final concentration of DMSO is 0.5%; activity test: take MCF-7-ADR cells in logarithmic growth stage, according to 3 ⁇ 10 3 per The wells were inoculated into a 96-well culture plate, and after 24 hours of incubation, the culture solution was changed, and the test solution was added at different concentrations.
  • Inhibition rate (%) (1 - (absorbance of blank control group - absorbance of administration group) / absorbance of blank control group) ⁇ 100%; calculation method of IC50: Rliss method was used.
  • the gemcitabine derivatives numbered GI-01 to GI-09 provided by the present invention significantly enhanced the proliferation inhibitory activity against the human breast cancer resistant cell line MCF-7-ADR relative to gemcitabine; especially the number The compound of GI-06 has the strongest antitumor activity.
  • Example 11 Experimental study on the effect of test compounds on the growth of subcutaneous xenografts of HCT-116 colon cancer in nude mice
  • Test samples GI-04, GI-05, GI-06, GI-09;
  • mice nude mice, female, 4-5 weeks old, 60
  • Cell line HCT-116 colon cancer cells.
  • mice Five mice were inoculated by cell suspension inoculation before the experiment, and passaged in nude mice for 4 times, and subcutaneous modeling was performed by tumor block plugging method.
  • Grouping Modeling to tumor volume growth to about 100 mm 3 , nude mice that met the criteria were randomly divided into 6 groups: solvent control group, gemcitabine hydrochloride group, GI-04, GI-05, GI-06, GI- 09.
  • the dose of gemcitabine hydrochloride was 160 mg/kg; the dose of GI-04, GI-05, GI-09 was 15 mg/kg; the dose of GI-06 was 15 mg/kg.
  • the GI-06 medium dose group was administered at a dose of 10 mg/kg, and the GI-06 low dose group was administered at a dose of 5 mg/kg.
  • the "solvent control" was given a corresponding solvent for GI-06 (0.1% Tween 80 plus 0.9% hydroxypropyl). Aqueous methylcellulose solution).
  • Dosing frequency Gemcitabine hydrochloride was administered twice a week (D1 and D4) for 2 times; GI-04, GI-05, GI-09 group was administered continuously for 5 days per week, and the drug was stopped for 2 days. A total of 10 doses were administered; the GI-06 high-dose group was administered continuously for 5 days per week, discontinued for 2 days, and administered a total of 10 times. The GI-06 medium dose group was administered for 7 days in the first week, and the second week was administered for 5 days due to animal status, and a total of 12 doses were administered. The frequency of low dose administration of GI-06 was the same as that of the GI-06 medium dose group.
  • GI-06 at 5 mg/kg, 10 mg/kg, and 15 mg/kg had significant inhibitory effects on tumor growth in HCT-116 colon cancer xenografts in all four compounds, with T/C of 27% and 13 respectively. % and 12%, while the control drug gemcitabine hydrochloride was administered by intraperitoneal injection of 160 mg/kg, and there was significant growth inhibition after 2 administrations, with a T/C of 5.8%.
  • Example 12 Experimental study on the effect of GI-06 compound on the growth of subcutaneous xenografts of A2780 ovarian cancer in nude mice
  • OBJECTIVE The effect of GI-06 compound on the growth of subcutaneous xenografts in A2780 ovarian cancer nude mice.
  • Test sample GI-06; positive control: gemcitabine hydrochloride
  • mice nude mice, female, 4-5 weeks old, 40 animals.
  • Cell line A2780 ovarian cancer cells were purchased from Shanghai Institute of Cell.
  • Grouping Modeling to tumor volume growth to about 100 mm 3 , nude mice that met the criteria were randomly divided into 5 groups: solvent control group (solvent control), gemcitabine hydrochloride group, GI-06 high, medium and low. Dose group, 6 animals per group.
  • the dose of gemcitabine hydrochloride was 160 mg/kg, the dose of GI-06 high dose was 12 mg/kg, and the dose of GI-06 was 8 mg/kg, GI-06 low dose group.
  • the dose was 4 mg/kg, and the "solvent control" was given the corresponding solvent of GI-06 (0.1% Tween 80 plus 0.9% hydroxypropylmethylcellulose aqueous solution).
  • Gemcitabine hydrochloride was administered by intraperitoneal injection, and the other groups were administered orally.
  • Dosing frequency Gemcitabine hydrochloride was administered twice a day (D1, D4, D15, D18) for 4 times; GI-06 was administered once a day for 21 days. .
  • the model used in the experiment was the A2780 ovarian cancer xenograft model.
  • the results of this experiment showed that GI-06 administration of 4mg/kg, 8mg/kg and 12mg/kg inhibited the growth of A2780 tumors in a dose-dependent manner, with T/C of 39.55%, 2.11% and 0.46%, respectively. .
  • the T/C of the gemcitabine group in the control group was 1.32%.
  • the three dose groups in this experiment did not show significant toxicity after continuous administration, and had no effect on animal body weight.

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Abstract

本发明提供了式（I）吉西他滨衍生物及其制备方法。本发明还涉及包含药物有效量的所述吉西他滨衍生物以及药学上可接受的赋形剂或添加剂的药物组合物。本发明进一步提供了所述衍生物在制备抗肿瘤药物中的应用。本发明设计的化合物结构新颖，具有显著的抗肿瘤活性。本发明涉及的化合物制备原料来源广泛易获取，制备方法简便易操作，产物的收率高，利于工业化规模生产。

Description

吉西他滨衍生物、含该衍生物的组合物及所述衍生物的制药用途 技术领域
本发明属于医药领域，具体涉及一种吉西他滨衍生物、含该类化合物的组合物及所述化合物的在制药，特别是制备抗肿瘤药物中的应用。
背景技术
肿瘤是严重威胁人类健康的一类疾患，得益于近三十年来生命科学研究技术的进步及对肿瘤病理学的深入认识，抗肿瘤药物的研发获得突破性的进展，各种类型的新型分子靶向抗肿瘤药物的研发成功在提高肿瘤治疗水平上发挥了重要作用。现阶段，肿瘤耐药是肿瘤治疗的难点所在，肿瘤的异质性及易于突变的特点是其容易产生耐药的主要原因，因此针对肿瘤耐药作用机制的药物研究和开发具有非常重要的临床意义。
抗代谢类药物是抗肿瘤药物重要组成部分，2010年在整个抗肿瘤药物医院市场中抗代谢药占据15.75％的市场份额，居第3位。抗代谢类抗肿瘤药物主要由核苷类药物组成，其中，吉西他滨、阿糖胞苷、地西他滨、氮杂胞苷、克拉屈滨、氟达拉滨、奈拉滨等最为常用。
吉西他滨(Gemcitabine)为氟胞苷类似物，属于周期特异性抗肿瘤药物；主要作用于DNA合成期，也可阻断肿瘤细胞周期由DNA合成前期向DNA合成期的进展；吉西他滨在脱氧胞苷激酶的作用下被转化为具有活性的吉西他滨二磷酸盐及三磷酸盐，通过影响DNA合成和修复，从而抑制肿瘤细胞分裂，诱导肿瘤细胞凋亡；适用于治疗中、晚期非小细胞肺癌，局部晚期或已转移的胰腺癌。
吉西他滨可用于紫杉醇及蒽醌类耐药的乳腺癌治疗，有研究表明耐药基因P-gp及MRP的过表达是相关耐药肿瘤细胞对吉西他滨敏感的重要原因，其可能的机制为：多药耐药引起脱氧胞苷激酶的表达升高，从而增加肿瘤细胞内吉西他滨三磷酸盐(dFdCTP)的积累，并可促进吉西他滨结合到肿瘤细胞DNA链，由此提高耐药肿瘤细胞的药物敏感性。
目前对吉西他滨及其衍生物的研究，主要通过在胞嘧啶环上胺基的修饰、改造，来合成出具有高抗肿瘤活性的化合物，但其不足之处在于：仅针对抑制肿瘤细胞DNA合成这样的单一靶点作用，限于客观的技术难度并未考虑多靶点作用机制的方式，以合成出具有高抗肿瘤活性的化合物。
发明内容
本发明迥异于现有的吉西他滨修饰或改造思路，以吉西他滨为先导化合物，引入多靶点多作用机制协同起效并同时保护吉西他滨活性药效基团的合成思路，通 过结构优化引入新的具有特定分子靶向作用的活性基团，从而制备得到一类结构新颖、CDK抑制和DNA合成抑制双靶点作用的吉西他滨类化合物，尤其能进一步提高吉西他滨类化合物对耐药肿瘤细胞增殖抑制活性的目的。
本发明通过如下技术方案实现：
本发明提供一种吉西他滨衍生物，具有如下结构通式I：
Figure PCTCN2014093005-appb-000001
式中
R1选自未取代或取代的C1-10烷基、未取代或取代的C2-10烯基、未取代或取代的C2-10炔基、未取代或取代的C3-7环烷基、未取代或取代的C3-7环烷氧基，其中所述的取代基选自卤原子、氰基、硝基、氨基、三氟甲基、巯基、羟基、羧基、羰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷氧基羰基和-NH-中的一种或几种；
或者R1为任选取代的芳基，其中所述的取代基选自氢、羟基、羧基、硝基、卤原子、C1-6烷基和C1-6烷氧基中的一种或几种。
优选的，任选取代的芳基为苯基、苄基或萘基。
在一个实施方案中，R1优选自未取代或取代的C3-10烷基、未取代或取代的C3-10烯基、未取代或取代的C3-10炔基、未取代或取代的C3-7环烷基、未取代或取代的C3-7环烷氧基，或是任选取代的选自苯基、苄基或萘基的芳基；其中，所述的取代基为卤原子、氰基、硝基、氨基、三氟甲基、巯基、羟基、羧基、羰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷氧基羰基、-NH-中的一种或几种。
优选的，卤原子为F、Cl、Br或I。
在另一个实施方案中，R1优选自未取代或取代的C4-9烷基、未取代或取代的C4-9烯基、未取代或取代的C4-9炔基、未取代或取代的C3-7环烷基、未取代或取代的C3-7环烷氧基；所述取代基选自F和Cl。
本发明最优选的化合物以编号GI-01到GI-09依次命名：
编号GI-01：N-(5-(((5-(叔丁基)氧杂唑-2-基)甲基)硫)噻唑-2-基)-N’-(1-((2R，4R，5R)-3，3-二氟-4-羟基-5-(羟甲基)四氢呋喃-2-基)-2-氧-1，2-二氢嘧啶-4-基)草酰胺；
编号GI-02：N-(5-(((5-(叔丁基)氧杂唑-2-基)甲基)硫)噻唑-2-基)-N’-(1-((2R，4R，5R)-3，3-二氟-4-羟基-5-(羟甲基)四氢呋喃-2-基)-2-氧-1，2-二氢嘧啶-4-基)丙二酰胺；
编号GI-03：N-(5-(((5-(叔丁基)氧杂唑-2-基)甲基)硫)噻唑-2-基)-N’-(1-((2R，4R，5R)-3，3-二氟-4-羟基-5-(羟甲基)四氢呋喃-2-基)-2-氧-1，2-二氢嘧啶-4-基)琥珀酰胺；
编号GI-04：N-(5-(((5-(叔丁基)氧杂唑-2-基)甲基)硫)噻唑-2-基)-N’-(1-((2R，4R，5R)-3，3-二氟-4-羟基-5-(羟甲基)四氢呋喃-2-基)-2-氧-1，2-二氢嘧啶-4-基)戊二酰胺；
编号GI-05：N-(5-(((5-(叔丁基)氧杂唑-2-基)甲基)硫)噻唑-2-基)-N’-(1-((2R，4R，5R)-3，3-二氟-4-羟基-5-(羟甲基)四氢呋喃-2-基)-2-氧-1，2-二氢嘧啶-4-基)己二酰胺；
编号GI-06：N-(5-(((5-(叔丁基)氧杂唑-2-基)甲基)硫)噻唑-2-基)-N’-(1-((2R，4R，5R)-3，3-二氟-4-羟基-5-(羟甲基)四氢呋喃-2-基)-2-氧-1，2-二氢嘧啶-4-基)庚二酰胺；
编号GI-07：N-(5-(((5-(叔丁基)氧杂唑-2-基)甲基)硫)噻唑-2-基)-N’-(1-((2R，4R，5R)-3，3-二氟-4-羟基-5-(羟甲基)四氢呋喃-2-基)-2-氧-1，2-二氢嘧啶-4-基)辛二酰胺；
编号GI-08：N-(5-(((5-(叔丁基)氧杂唑-2-基)甲基)硫)噻唑-2-基)-N’-(1-((2R，4R，5R)-3，3-二氟-4-羟基-5-(羟甲基)四氢呋喃-2-基)-2-氧-1，2-二氢嘧啶-4-基)壬二酰胺；
编号GI-09：N-(5-(((5-(叔丁基)氧杂唑-2-基)甲基)硫)噻唑-2-基)-N’-(1-((2R，4R，5R)-3，3-二氟-4-羟基-5-(羟甲基)四氢呋喃-2-基)-2-氧-1，2-二氢嘧啶-4-基)癸二酰胺。
本发明还提供了一种吉西他滨衍生物的制备方法，包括如下步骤：
(1)在缩合剂存在下，将下式IV的化合物与式V或式VII的化合物混合，经酰胺化反应后得到式III的中间产物，条件是，当式IV化合物与式VII化合物反应时，所得的式III化合物中Z为OH。反应式如下：
Figure PCTCN2014093005-appb-000002
(2)在缩合剂存在下，使中间产物III与式II的化合物混合，经酰胺化反应后 得到式I的目标产物，反应式如下：
Figure PCTCN2014093005-appb-000003
其中，Y、Z各自独立地代表-OH、-F、-Cl、-Br或-I；
R1选自未取代或取代的C1-10烷基、未取代或取代的C2-10烯基、未取代或取代的C2-10炔基、未取代或取代的C3-7环烷基、未取代或取代的C3-7环烷氧基，其中，所述的取代基为卤原子、氰基、硝基、氨基、三氟甲基、巯基、羟基、羧基、羰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷氧基羰基、-NH-中的一种或几种；或者R1是任选取代的芳基，其中所述的取代基选自氢、羟基、羧基、硝基、卤原子、C1-6烷基、C1-6烷氧基中的一种或几种；
步骤(1)和步骤(2)的反应温度为0℃到150℃；优选20℃-120℃。
步骤(1)和步骤(2)的缩合剂为1-羟基苯并三唑、1-羟基-7-偶氮苯并三氮唑、3-羟基-1，2，3-苯并三嗪-4(3H)-酮、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺、N，N-二环己基碳二亚胺、N，N-二异丙基碳二亚胺中的一种或几种；优选1-羟基苯并三唑、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺中的一种或其组合；
步骤(1)和步骤(2)的反应溶剂为苯、甲苯、氯仿、正己烷、环己烷、二氯甲烷、1，2-二氯乙烷、甲基叔丁基醚、四氯化碳、乙酸乙酯、乙酸丙酯、乙酸丁酯、甲醇、乙醇、丙酮、四氢呋喃、乙醚、乙腈、N，N-二甲基甲酰胺、二甲亚砜中的一种或几种。
本发明还提供了另一种制备吉西他滨衍生物的方法，包括如下步骤：
(1)在缩合剂存在下，使式II化合物与式V化合物或式VII化合物混合，经酰胺化反应后得到式VI的中间产物，条件是，当式II化合物与式VII化合物反应时，所得的式VI化合物中Z为OH。反应式如下：
Figure PCTCN2014093005-appb-000004
(2)在缩合剂存在下，使中间产物VI与式IV的化合物混合，经酰胺化反应后得到式I的目标产物，反应式如下：
Figure PCTCN2014093005-appb-000005
其中，Y、Z各自独立地代表-OH、-F、-Cl、-Br或-I；
R1选自未取代或取代的C1-10烷基、未取代或取代的C2-10烯基、未取代或取代的C2-10炔基、未取代或取代的C3-7环烷基、未取代或取代的C3-7环烷氧基，其中，所述的取代基为卤原子、氰基、硝基、氨基、三氟甲基、巯基、羟基、羧基、羰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷氧基羰基、-NH-中的一种或几种；或者R1是任选取代的芳基，其中所述的取代基选自氢、羟基、羧基、硝基、卤原子、C1-6烷基、C1-6烷氧基中的一种或几种；
步骤(1)和步骤(2)的反应温度为0℃到150℃；优选20℃-120℃。
步骤(1)和步骤(2)的缩合剂为1-羟基苯并三唑、1-羟基-7-偶氮苯并三氮唑、3-羟基-1，2，3-苯并三嗪-4(3H)-酮、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺、N，N-二环己基碳二亚胺、N，N-二异丙基碳二亚胺中的一种或几种；优选1-羟基苯并三唑、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺中的一种或其组合；
步骤(1)和步骤(2)的反应溶剂为苯、甲苯、氯仿、正己烷、环己烷、二氯甲烷、1，2-二氯乙烷、甲基叔丁基醚、四氯化碳、乙酸乙酯、乙酸丙酯、乙酸丁酯、甲醇、乙醇、丙酮、四氢呋喃、乙醚、乙腈、N，N-二甲基甲酰胺、二甲亚砜中的一种或几种。
在一个实施方案中，步骤(1)和步骤(2)的缩合剂为1-羟基苯并三唑、1- 乙基-(3-二甲基氨基丙基)碳酰二亚胺中的一种或其组合；步骤(1)中反应溶剂为N，N-二甲基甲酰胺，步骤(2)中反应溶剂为N，N-二甲基甲酰胺、二甲亚砜中的一种或其组合。
上述两种制备方法中所涉及的式VII化合物，可以通过市售获得，例如，可购自阿法埃莎(Alfa Aesar)。所述的式VII化合物还可以自行制备得到，制备方法如下：将适量的二C1-6烷氧基羰基类化合物溶解于乙酸酐中，升温回流4小时，浓缩反应液后，在浓缩液中加入适量二甲苯，浓缩干燥即得。
本发明还提供了一种药物组合物，它包含药物有效量的通式I的吉西他滨衍生物以及药学上可接受的赋形剂或添加剂。药物组合物的形式可以是常用制剂形式。
本发明还提供了式I化合物在制备抗肿瘤药物中的应用。
在一个实施方案中，所述的肿瘤为耐药肿瘤。术语“肿瘤耐药”是指：抗肿瘤药物直接或间接治疗无效或原先有效的药物用于治疗肿瘤复发或转移病症无效。
具体而言，本发明式I化合物主要是用于制备治疗因肿瘤细胞对细胞毒药物、靶向小分子药物、大分子抗体类及免疫调节剂类抗肿瘤药物产生的肿瘤耐药疾患的药物。
进一步的是，本发明还提供了通式结构I的吉西他滨衍生物作为前药在制备抗肿瘤药物中的应用。即，本发明所提供的吉西他滨衍生物，可通过前药的方式经口服途径给药用于吉西他滨适应症相关的肿瘤治疗。
本发明还提供了一种治疗肿瘤的方法，包括对需要的对象给予本发明的式(I)化合物。
在一个实施方案中，所述的肿瘤为耐药肿瘤。
本发明进一步提供了一种治疗因肿瘤细胞对细胞毒药物、靶向小分子药物、大分子抗体类及免疫调节剂类抗肿瘤药物产生的肿瘤耐药疾患的方法，包括对需要的对象给予本发明的式(I)化合物。
本发明以吉西他滨为先导化合物，通过对其结构修饰，得到了一系列结构新颖的化合物，并对这些化合物进行活性筛选，发现多数化合物具有显著的抗肿瘤活性，而且抑制耐药肿瘤细胞活性的作用远优于吉西他滨，毒性也极低，效果惊人。
总之，本发明的化合物结构设计合理，优化筛选的化合物兼具CDK抑制和DNA合成抑制的双靶点作用机制，制备原料来源广泛易获取，制备方法简便易操作，反应条件温和，产物的收率高，利于工业化规模生产。
具体实施方式
下面结合具体实施例对本发明进行进一步说明，但本发明的保护范围不囿于如下实施例公开的范围，需要说明的是，下述实施例不能作为对本发明保护范围的限制，在本发明基础上做出的任何改进都不违背本发明的精神。
制备例：制备式VII的化合物(如庚二酸酐)
Figure PCTCN2014093005-appb-000006
将3.2g庚二酸溶解于65mL乙酸酐中，升温回流4小时，将反应液浓缩，向浓缩液中加入二甲苯20mL，浓缩至干，定量得到粉色固体。
本发明中，编号为GI-01到GI-03的化合物，可以通过如下反应路线合成：
步骤1：
Figure PCTCN2014093005-appb-000007
步骤2：
Figure PCTCN2014093005-appb-000008
其中，n为0或1或2
实施例1：制备编号为GI-01的化合物
步骤1：将5-(((5-叔丁基)氧杂唑-2-基)甲基)硫)噻唑-2-胺(1.35g，9.5毫摩尔，1.1当量)、乙二酸(0.774g，8.6毫摩尔，1当量)、1-羟基苯并三唑一水合物(1.46g，9.5毫摩尔)、N-甲基吗啉(0.961g，9.5毫摩尔)溶解于15mL N，N-二甲基甲酰胺中，加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(2.154g，11.2毫摩尔，1.3当量)，氮气保护，室温搅拌2小时。向反应液中加入40mL饱和食盐水淬灭反应，二氯甲烷(50mL×5)萃取，合并有机层，无水硫酸钠干燥，浓缩，硅胶柱层析(石油醚∶乙酸乙酯＝10∶1到2∶1)得1.41g白色固体，7-((5-(((2-叔丁基)氧杂唑-5-基)甲基)硫)噻唑-2-基)胺基-7-氧代乙酸，收率82％。
1H NMR(CDCl 3，300MHz)：7.27(s，1H)，6.61(s，1H)，3.89(s，2H)，1.26(s， 9H).HRMS(ESI)[C13H15N3O4S2-H]+的计算值：342.4133，测定值：342.4129.
步骤2：将7-((5-(((2-叔丁基)氧杂唑-5-基)甲基)硫)噻唑-2-基)胺基-7-氧代乙酸(1.50g，4.4毫摩尔，1当量)、吉西他滨(1.32g，4.4毫摩尔，1当量)、1-羟基苯并三唑一水合物(0.674g，4.4毫摩尔)、N-甲基吗啉(0.445g，4.4毫摩尔)溶解于6mL N，N-二甲基甲酰胺/二甲基亚砜(3∶1)的混合溶剂中，加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(1.096g，5.7毫摩尔，1.3当量)，氩气保护，升温至55℃，搅拌19小时。向反应液中加入20mL饱和食盐水淬灭反应，二氯甲烷(50mL×5)萃取，合并有机层，依次饱和碳酸钠水溶液、水、饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱层析(二氯甲烷∶甲醇＝50∶1到10∶1)得712mg的GI-01化合物，为白色固体，收率27％。
1H NMR(DMSO-d6，300MHz)：12.29(s，1H)，10.88(s，1H)，8.23(d，J＝7.6Hz，1H)，7.34(s，1H)，7.26(d，J＝7.6Hz，1H)，6.70(s，1H)，6.31(d，J＝6.4Hz，1H)，6.19(t，J＝7.3，1H)，5.31(t，J＝5.2，1H)，4.18(m，1H)，4.09(s，2H)，3.91(d，J＝8.2，1H)，3.82(d，br，1H)，3.65(m，1H)，1.33(s，9H).HRMS(ESI)[C22H24F2N6O7S2-H]+计算值：587.5962，测定值：587.5960。
实施例2：制备编号为GI-02的化合物
按实施例1的方法制备标题化合物，但步骤1中以丙二酸为原料替换乙二酸，TLC跟踪反应至终点，得淡黄色固体即为编号GI-02的化合物。
1H NMR(DMSO-d6，300MHz)：12.24(s，1H)，10.93(s，1H)，8.25(d，J＝7.6Hz，1H)，7.36(s，1H)，7.23(d，J＝7.6Hz，1H)，6.77(s，1H)，6.33(d，J＝6.4Hz，1H)，6.16(t，J＝7.3，1H)，5.31(t，J＝5.2，1H)，4.13(m，1H)，4.02(s，2H)，3.91(d，J＝8.2，1H)，3.84(d，br，1H)，3.66(m，1H)，1.28(s，2H)，1.34(s，9H).HRMS(ESI)[C23H26F2N6O7S2-H]+计算值：601.6227，测定值：601.6230。
实施例3：制备编号为GI-03的化合物
按照实施例1的方法制备标题化合物，但步骤1中以丁二酸为原料替换乙二酸，TLC跟踪反应至终点，得淡黄色固体即为编号GI-03的化合物。
1H NMR(DMSO-d6，300MHz)：12.25(s，1H)，10.91(s，1H)，8.22(d，J＝7.6Hz，1H)，7.33(s，1H)，7.21(d，J＝7.6Hz，1H)，6.79(s，1H)，6.32(d，J＝6.4Hz，1H)，6.15(t，J＝7.3，1H)，5.38(t，J＝5.2，1H)，4.12(m，1H)，4.12(s，2H)，3.81(d，J＝8.2，1H)，3.85(d，br，1H)，3.69(m，1H)，1.28(m，4H)，1.34(s，9H).HRMS(ESI)[C24H28F2N6O7S2-H]+计算值：615.6493，测定值：615.6499。
本发明中，编号为GI-04和GI-05的化合物，可以通过如下反应路线合成：
步骤1：
Figure PCTCN2014093005-appb-000009
步骤2：
Figure PCTCN2014093005-appb-000010
其中n为3或4
实施例4：制备编号为GI-04的化合物
步骤1：将戊二酸(0.32g，2.42毫摩尔，1.1当量)、吉西他滨(0.66g，2.2毫摩尔，1当量)、1-羟基苯并三唑一水合物(0.337g，2.2毫摩尔)、N-甲基吗啉(0.223g，2.2毫摩尔)溶解于4mL N，N-二甲基甲酰胺中，加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.548g，2.8毫摩尔，1.3当量)，氮气保护，室温搅拌3小时。向反应液中加入20mL饱和食盐水淬灭反应，二氯甲烷(10mL×5)萃取，合并有机层，无水硫酸钠干燥，浓缩，硅胶柱层析(石油醚∶乙酸乙酯＝10∶1到2∶1)得0.89g白色固体，5-((1-((2R，4R，5R)-3，3-二氟-4-羟基-5-(羟甲基)四氢呋喃-2-基)-2-氧-1，2-二氢嘧啶-4-基)胺基)-5-氧代戊酸，收率94％。
HRMS(ESI)[C14H17F2N3O7-H]+计算值：378.3049，测定值：378.3055。
步骤2：将5-((1-((2R，4R，5R)-3，3-二氟-4-羟基-5-(羟甲基)四氢呋喃-2-基)-2-氧-1，2-二氢嘧啶-4-基)胺基)-5-氧代戊酸(1.51g，4毫摩尔，1.0当量)、5-(((5-叔丁基)氧杂唑-2-基)甲基)硫)噻唑-2-胺(1.08g，4毫摩尔，1.0当量)、1-羟基苯并三唑一水合物(0.613g，4.0毫摩尔)、N-甲基吗啉(0.404g，4.0毫摩尔)溶解于6mL N，N-二甲基甲酰胺/二甲基亚砜(3∶1)的混合溶剂中，加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(1.00g，5.2毫摩尔，1.3当量)，氩气保护，升温至55℃，搅拌16小时。向反应液中加入20mL饱和食盐水淬灭反应，二氯甲烷(50mL×5)萃取，合并有机层，依次饱和碳酸钠水溶液、水、饱和 食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱层析(二氯甲烷∶甲醇＝50∶1到10∶1)得811mg的标题化合物，为白色固体，收率32％。
HRMS(ESI)[C25H30F2N6O7S2-H]+计算值：629.6759，测定值629.6762。
实施例5：制备编号为GI-05的化合物
按照实施例4的方法，但步骤1中以己二酸为原料替换戊二酸，TLC跟踪反应至终点，得淡黄色固体即为编号GI-05的化合物。
HRMS(ESI)[C26H32F2N6O7S2-H]+计算值：643.7025，测定值：643.7030。
本发明中，编号为GI-06到GI-07的化合物，可以通过如下反应路线合成：
步骤1：
Figure PCTCN2014093005-appb-000011
步骤2：
Figure PCTCN2014093005-appb-000012
其中n为5或6
实施例6：制备编号为GI-06的化合物
步骤1：将庚二酸酐(2.33g，8.6毫摩尔，1当量)和5-(((5-叔丁基)氧杂唑-2-基)甲基)硫)噻唑-2-胺(1.35g，9.5毫摩尔，1.1当量)溶解于15mL N，N-二甲基甲酰胺中，升温至100℃，16小时后向反应液中加入30mL水淬灭反应液，乙酸乙酯(50mL×4)萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，
浓缩，硅胶柱层析(石油醚∶乙酸乙酯＝10∶1到2∶1)得1.8g淡黄色固体，
7-((5-(((2-叔丁基)氧杂唑-5-基)甲基)硫)噻唑-2-基)胺基-7-氧代庚酸，收率
51％。
1H NMR(CDCl3，300MHz)：7.25(s，1H)，6.60(s，1H)，3.96(s，2H)，2.50(五重峰，J＝7.2Hz，2H)，2.38(t，J＝7.2Hz，1H)，2.09(s，2H)，1.79(五重峰，J＝7.1Hz，2H)，1.69(五重峰，J＝8.1Hz，1H)，1.46(五重峰，J＝7.0Hz，2H)，1.26(s， 9H)。HRMS(ESI)[C18H25N3O4S2-H]-计算值：410.1214，测定值：410.1219。
步骤2：将7-((5-(((2-叔丁基)氧杂唑-5-基)甲基)硫)噻唑-2-基)胺基-7-氧代庚酸(1.815g，4.4毫摩尔，1当量)、吉西他滨(1.32g，4.4毫摩尔，1当量)、1-羟基苯并三唑一水合物(0.674g，4.4毫摩尔)、N-甲基吗啉(0.445g，4.4毫摩尔)溶解于6mL N，N-二甲基甲酰胺/二甲基亚砜(3∶1)的混合溶剂中，加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(1.096g，5.7毫摩尔，1.3当量)，氩气保护，升温至55℃，搅拌19小时。向反应液中加入20mL饱和食盐水淬灭反应，二氯甲烷(50mL×5)萃取，合并有机层，依次饱和碳酸钠水溶液、水、饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱层析(二氯甲烷∶甲醇＝50∶1到10∶1)得608mg的标题化合物，为白色固体，收率21％。
1H NMR(DMSO-d6，300MHz)：12.20(s，1H)，10.98(s，1H)，8.25(d，J＝7.6Hz，1H)，7.38(s，1H)，7.29(d，J＝7.6Hz，1H)，6.71(s，1H)，6.32(d，J＝6.4Hz，1H)，6.18(t，J＝7.3，1H)，5.30(t，J＝5.2，1H)，4.17(m，1H)，4.06(s，2H)，3.90(d，J＝8.2，1H)，3.82(d，br，1H)，3.66(m，1H)，2.42(t，J＝7.1Hz，4H)，1.58(m，4H)，1.28(m，2H)，1.3(s，9H).13C NMR(DMSO-d6，75MHz)：174.42，171.98，163.33，161.67，161.32，159.17，154.68，145.48，145.16，123.45，120.51，118.97，96.40，81.54，69.17，68.89，68.56，59.27，36.69，35.06，34.44，31.36，28.74，28.36，24.84，24.48。LC-MS(Q-TOF，100μg/mL)m/z[M+H+]测定值：657.19635。
实施例7：制备编号为GI-07的化合物
按照实施例6的方法制备，但步骤1中以辛二酸为原料替换庚二酸，TLC跟踪反应至终点，得白色固体即为编号GI-07的化合物。
HRMS(ESI)[C28H36F2N6O7S2-H]+的计算值：671.7556，测定值：671.7560。
本发明中，编号为GI-08到GI-09的化合物，可以通过如下反应路线合成：
步骤1：
Figure PCTCN2014093005-appb-000013
步骤2：
Figure PCTCN2014093005-appb-000014
其中，n为7或8。
实施例8：制备编号为GI-08的化合物
步骤1：将壬二酸酐(0.376g，2.0毫摩尔，1当量)、吉西他滨(0.66g，2.2毫摩尔，1.1当量)溶解于15mL N，N-二甲基甲酰胺中，升温至100℃，19小时后向反应液中加入30mL水淬灭反应液，乙酸乙酯(50mL×4)萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱层析(石油醚∶乙酸乙酯＝10∶1～2∶1)得796mg淡黄色固体，5-((1-((2R，4R，5R)-3，3-二氟-4-羟基-5-(羟甲基)四氢呋喃-2-基)-2-氧-1，2-二氢嘧啶-4-基)胺基)-5-氧代壬酸，收率91％。
HRMS(ESI)[C18H20F5N3O7-H]+计算值：434.4112，测定值：434.4120。
步骤2：制备方法同实施例4中步骤2，以5-((1-((2R，4R，5R)-3，3-二氟-4-羟基-5-(羟甲基)四氢呋喃-2-基)-2-氧-1，2-二氢嘧啶-4-基)胺基)-5-氧代壬酸为原料替换5-((1-((2R，4R，5R)-3，3-二氟-4-羟基-5-(羟甲基)四氢呋喃-2-基)-2-氧-1，2-二氢嘧啶-4-基)胺基)-5-氧代戊酸，TLC跟踪反应至终点，得白色固体即为编号GI-08的化合物。
HRMS(ESI)[C29H38F2N6O7S2-H]+计算值：685.7822，测定值：685.7830。
实施例9：制备编号为GI-09的化合物
本实施例的制备方法同实施例8，步骤1中以癸二酸为原料替换壬二酸，TLC跟踪反应至终点，得淡黄色固体即为编号GI-09的化合物。
HRMS(ESI)[C30H40F2N6O7S2-H]+计算值：699.8088，测定值：699.8090。
实施例10：吉西他滨及其衍生物对肿瘤耐药细胞株的细胞毒活性的影响试验
实验目的：对比吉西他滨衍生物(本发明实施例1-9的化合物)与吉西他滨(公知化合物，下表中为“对比例”)对肿瘤耐药细胞株的细胞毒活性差异。
材料及方法：人乳腺癌阿霉素耐药细胞株MCF-7-ADR培养于含5％胎牛血清的1640培养基中；吉西他滨及衍生物GI-06溶解于DMSO中，-20℃冻存，临用前以 含5％胎牛血清的1640培养基稀释至相应浓度，DMSO终浓度为0.5％；活性测试：取处于对数生长阶段的MCF-7-ADR细胞，按3×103每孔接种于96孔培养板，孵育24小时后更换培养液，加入不同浓度的供试品溶液，对照组加入含0.5％的DMSO培养液，继续孵育48小时后，MTT法测定细胞活性。抑制率(％)＝(1-(空白对照组的吸光度-给药组的吸光度)/空白对照组的吸光度)×100％；IC50的计算方法：采用Rliss法。
实验结果：见表1
表1吉西他滨及其衍生物对耐药肿瘤细胞活性的影响
Figure PCTCN2014093005-appb-000015
从表1可以看出，相对于吉西他滨，本发明提供的编号GI-01到GI-09的吉西他滨衍生物对人乳腺癌耐药细胞株MCF-7-ADR的增殖抑制活性明显增强；尤其是编号GI-06的化合物，抗肿瘤活性最强。
实施例11：测试化合物对HCT-116结肠癌裸小鼠皮下移植瘤生长影响的实验研究
实验目的：四个化合物对HCT-116结肠癌裸小鼠皮下移植瘤生长的影响
材料及方法：
供试样品：GI-04、GI-05、GI-06、GI-09；
阳性对照：盐酸吉西他滨。
实验动物：裸小鼠，雌性，4-5周龄，60只
细胞株：HCT-116结肠癌细胞。
造模：实验前采用细胞悬液接种法接种5只种鼠，经裸鼠体内传代4次后，采用肿瘤块插块法接种皮下造模。
分组：造模至肿瘤体积生长至100mm3左右，选取符合标准的裸小鼠随机分为6组，分别为溶剂对照组、盐酸吉西他滨组，GI-04、GI-05、GI-06、GI-09。
给药剂量：对照药盐酸吉西他滨给药剂量为160mg/kg；GI-04、GI-05、GI-09组给药剂量为15mg/kg；GI-06高剂量组给药剂量为15mg/kg，GI-06中剂量组给药剂量为10mg/kg，GI-06低剂量组给药剂量为5mg/kg，“溶剂对照”给予GI-06的对应溶剂(0.1％吐温80加0.9％羟丙甲基纤维素水溶液)。
给药途径：盐酸吉西他滨采用腹腔注射给药，其余各组采用口服灌胃给药。给药体积：0.1ml/10g
给药频率：盐酸吉西他滨第一周给药2次(D1和D4)，共给药2次；GI-04、GI-05、GI-09组每周连续给药5天，停药2天，共给药10次；GI-06高剂量组每周连续给药5天，停药2天，共给药10次。GI-06中剂量组第一周给药7天，第二周由于动物状态原因给药5天，共给药12次。GI-06低剂量给药频率与GI-06中剂量组相同。
观察时间：给药开始后连续观察15日，每周测量肿瘤体积2次。第15天停止给药。
统计方法：Excel统计软件包，单因素方差分析法。
实验结果：见表2
Figure PCTCN2014093005-appb-000016
实验结果显示四个化合物中GI-06在5mg/kg、10mg/kg、15mg/kg对HCT-116结肠癌裸鼠移植瘤均具有显著性抑制肿瘤生长作用，T/C分别为27％、13％和12％，而对照药盐酸吉西他滨采用腹腔注射160mg/kg，给药2次后也有显著生长抑制作用，T/C为5.8％。
本次实验结果显示即使低剂量组5mg/kg，采用连续给药的方式也能获得较好的抑制肿瘤生长的作用，提示下批实验还可以再降低剂量，以获得最低起效剂量。
实施例12：GI-06化合物对A2780卵巢癌裸小鼠皮下移植瘤生长影响的实验研究
实验目的：GI-06化合物对A2780卵巢癌裸小鼠皮下移植瘤生长的影响。
材料和方法：
供试样品：GI-06；阳性对照：盐酸吉西他滨
实验动物：裸小鼠，雌性，4-5周龄，40只。
细胞株：A2780卵巢癌细胞购于上海细胞所。
造模：实验前采用细胞悬液接种法接种5只种鼠，并经裸鼠体内传代2次后，采用肿瘤块插块法接种皮下造模。
分组：造模至肿瘤体积生长至100mm3左右，选取符合标准的裸小鼠随机分为5组，分别为溶剂对照组(溶剂对照)、盐酸吉西他滨组，GI-06高、中、低三个剂量组，每组6只动物。
给药剂量：对照药盐酸吉西他滨给药剂量为160mg/kg，GI-06高剂量组给药剂量为12mg/kg，GI-06中剂量组给药剂量为8mg/kg，GI-06低剂量组给药剂量为4mg/kg，“溶剂对照”给予GI-06的对应溶剂(0.1％吐温80加0.9％羟丙甲基纤维素水溶液)。
给药途径：盐酸吉西他滨采用腹腔注射给药，其余各组采用口服灌胃给药。
给药体积：0.1ml/10g
给药频率：盐酸吉西他滨分别于第一、三周给药2次(D1、D4、D15、D18)，共给药4次；GI-06各剂量组每天给药1次，共给药21天。
观察时间：给药开始后连续观察21日，每周测量肿瘤体积2次。第22天处死动物，剥离肿瘤称重。
统计方法：Excel统计软件包，单因素方差分析法。
实验结果：见表4
Figure PCTCN2014093005-appb-000017
实验采用的模型为A2780卵巢癌裸鼠移植瘤模型。本次实验结果显示，GI-06给药4mg/kg、8mg/kg以及12mg/kg对A2780肿瘤生长的抑制作用显著，且呈剂量依赖性，T/C分别为39.55％、2.11％和0.46％。而对照组吉西他滨腹腔注射组T/C为1.32％。本次实验的3个剂量组连续给药未出现明显的毒性，对动物体重无影响。

Claims (16)

  1. 一种化合物，它具有如下结构通式I：
    Figure PCTCN2014093005-appb-100001
    式中
    R1选自未取代或取代的C1-10烷基、未取代或取代的C2-10烯基、未取代或取代的C2-10炔基、未取代或取代的C3-7环烷基、未取代或取代的C3-7环烷氧基，其中所述的取代基选自卤原子、氰基、硝基、氨基、三氟甲基、巯基、羟基、羧基、羰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷氧基羰基和-NH-中的一种或几种；
    或者R1为任选取代的芳基，其中所述的取代基选自氢、羟基、羧基、硝基、卤原子、C1-6烷基和C1-6烷氧基中的一种或几种。
  2. 如权利要求1所述的化合物，其中所述的任选取代的芳基为苯基、苄基或萘基。
  3. 如权利要求1所述的化合物，其中R1选自未取代或取代的C3-10烷基、未取代或取代的C3-10烯基、未取代或取代的C3-10炔基、未取代或取代的C3-7环烷基、未取代或取代的C3-7环烷氧基，或是任选取代的选自苯基、苄基或萘基的芳基；其中，所述的取代基为卤原子、氰基、硝基、氨基、三氟甲基、巯基、羟基、羧基、羰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷氧基羰基、-NH-中的一种或几种。
  4. 如权利要求1所述的化合物，其中所述的卤原子为F、Cl、Br或I。
  5. 如权利要求1所述的化合物，其中R1选自未取代或取代的C4-9烷基、未取代或取代的C4-9烯基、未取代或取代的C4-9炔基、未取代或取代的C3-7环烷基、未取代或取代的C3-7环烷氧基；所述取代基选自F和Cl。
  6. 如权利要求1所述的化合物，其中所述的化合物选自下组：
    N-(5-(((5-(叔丁基)氧杂唑-2-基)甲基)硫)噻唑-2-基)-N’-(1-((2R，4R，5R)-3，3-二氟-4-羟基-5-(羟甲基)四氢呋喃-2-基)-2-氧-1，2-二氢嘧啶-4-基)草酰胺；
    N-(5-(((5-(叔丁基)氧杂唑-2-基)甲基)硫)噻唑-2-基)-N’-(1-((2R，4R，5R)-3，3-二氟-4-羟基-5-(羟甲基)四氢呋喃-2-基)-2-氧-1，2-二氢嘧啶-4-基)丙二酰胺；
    N-(5-(((5-(叔丁基)氧杂唑-2-基)甲基)硫)噻唑-2-基)-N’-(1-((2R，4R，5R)-3，3-二氟-4-羟基-5-(羟甲基)四氢呋喃-2-基)-2-氧-1，2-二氢嘧啶-4-基)琥珀酰胺；
    N-(5-(((5-(叔丁基)氧杂唑-2-基)甲基)硫)噻唑-2-基)-N’-(1-((2R，4R，5R)-3，3-二氟-4-羟基-5-(羟甲基)四氢呋喃-2-基)-2-氧-1，2-二氢嘧啶-4-基)戊二酰胺；
    N-(5-(((5-(叔丁基)氧杂唑-2-基)甲基)硫)噻唑-2-基)-N’-(1-((2R，4R，5R)-3，3-二氟-4-羟基-5-(羟甲基)四氢呋喃-2-基)-2-氧-1，2-二氢嘧啶-4-基)己二酰胺；
    N-(5-(((5-(叔丁基)氧杂唑-2-基)甲基)硫)噻唑-2-基)-N’-(1-((2R，4R，5R)-3，3-二氟-4-羟基-5-(羟甲基)四氢呋喃-2-基)-2-氧-1，2-二氢嘧啶-4-基)庚二酰胺；
    N-(5-(((5-(叔丁基)氧杂唑-2-基)甲基)硫)噻唑-2-基)-N’-(1-((2R，4R，5R)-3，3-二氟-4-羟基-5-(羟甲基)四氢呋喃-2-基)-2-氧-1，2-二氢嘧啶-4-基)辛二酰胺；
    N-(5-(((5-(叔丁基)氧杂唑-2-基)甲基)硫)噻唑-2-基)-N’-(1-((2R，4R，5R)-3，3-二氟-4-羟基-5-(羟甲基)四氢呋喃-2-基)-2-氧-1，2-二氢嘧啶-4-基)壬二酰胺；和
    N-(5-(((5-(叔丁基)氧杂唑-2-基)甲基)硫)噻唑-2-基)-N’-(1-((2R，4R，5R)-3，3-二氟-4-羟基-5-(羟甲基)四氢呋喃-2-基)-2-氧-1，2-二氢嘧啶-4-基)癸二酰胺。
  7. 一种制备如权利要求1-5任一所述化合物的方法，包括如下步骤：
    (1)在缩合剂存在下，将下式IV的化合物
    Figure PCTCN2014093005-appb-100002
    与式V或式VII的化合物混合，
    Figure PCTCN2014093005-appb-100003
    经酰胺化反应后得到式III的中间产物，
    Figure PCTCN2014093005-appb-100004
    其中，R1、Y和Z的定义与权利要求1-5中任一所述的相同，条件是，当式IV化合物与式VII化合物反应时，所得的式III化合物中Z为OH：及
    (2)在缩合剂存在下，使步骤(1)得到的中间产物III与下式II化合物混合，
    Figure PCTCN2014093005-appb-100005
    经酰胺化反应后得到权利要求1-5任一所述的化合物。
  8. 一种制备如权利要求1-5任一所述化合物的方法，包括如下步骤：
    (1)在缩合剂存在下，使式II化合物
    Figure PCTCN2014093005-appb-100006
    与式V化合物或式VII化合物混合，
    Figure PCTCN2014093005-appb-100007
    经酰胺化反应后得到式VI的中间产物，条件是，当式II化合物与式VII化合物反应时，所得的式VI化合物中Z为OH；
    Figure PCTCN2014093005-appb-100008
    其中，R1、Y和Z的定义与权利要求1-5中任一所述的相同，
    (2)在缩合剂存在下，使步骤(1)所得的中间产物VI与式IV的化合物混合，
    Figure PCTCN2014093005-appb-100009
    经酰胺化反应后得到如权利要求1-5任一所述的化合物。
  9. 如权利要求7或8所述的方法，其中所述步骤(1)和(2)在0℃到150℃下进行反应，优选20℃到120℃。
  10. 如权利要求7或8所述的方法，其中所述的缩合剂为1-羟基苯并三唑、1-羟基-7-偶氮苯并三氮唑、3-羟基-1，2，3-苯并三嗪-4(3H)-酮、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺、N，N-二环己基碳二亚胺、N，N-二异丙基碳二亚胺中的一种或几种。
  11. 如权利要求7或8所述的方法，其中所述步骤(1)和步骤(2)在选自苯、甲苯、氯仿、正己烷、环己烷、二氯甲烷、1，2-二氯乙烷、甲基叔丁基醚、四氯化碳、乙酸乙酯、乙酸丙酯、乙酸丁酯、甲醇、乙醇、丙酮、四氢呋喃、乙醚、乙腈、N，N-二甲基甲酰胺、二甲亚砜中的一种或几种的溶剂中进行反应。
  12. 如权利要求10所述的方法，其中所述缩合剂为1-羟基苯并三唑、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺中的一种或其组合；步骤(1)中的反应在N，N-二甲基甲酰胺中进行，步骤(2)的反应在选自N，N-二甲基甲酰胺、二甲亚砜中的一种或其组合的溶剂中进行。
  13. 一种药物组合物，它包含药物有效量的如权利要求1-6任一所述的化合物以及药学上可接受的赋形剂或添加剂。
  14. 如权利要求1-6任一所述的化合物在制备抗肿瘤药物中的应用。
  15. 如权利要求14所述的应用，其中所述的肿瘤为耐药肿瘤。
  16. 如权利要求1-6任一所述的化合物在制备治疗因肿瘤细胞对细胞毒药 物、靶向小分子药物、大分子抗体类及免疫调节剂类抗肿瘤药物产生的肿瘤耐药疾患的药物中的应用。
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