WO2019041733A1 - 具有协同抗癌活性的中间体药物和聚乙二醇偶联协同抗癌药物、及其制备方法和应用 - Google Patents

具有协同抗癌活性的中间体药物和聚乙二醇偶联协同抗癌药物、及其制备方法和应用 Download PDF

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WO2019041733A1
WO2019041733A1 PCT/CN2018/073662 CN2018073662W WO2019041733A1 WO 2019041733 A1 WO2019041733 A1 WO 2019041733A1 CN 2018073662 W CN2018073662 W CN 2018073662W WO 2019041733 A1 WO2019041733 A1 WO 2019041733A1
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drug
derivative
group
pki
mmol
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PCT/CN2018/073662
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English (en)
French (fr)
Inventor
李高全
汪斌
李大军
张倩
黄蕾
陈毛芬
吴晓丹
彭良艳
何婷婷
张艳艳
唐云
刘欢
税举媛
张翠芳
李建环
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重庆阿普格雷生物科技有限公司
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Priority to US16/643,245 priority Critical patent/US11484600B2/en
Priority to CN201880003668.8A priority patent/CN109843333B/zh
Priority to JP2020533331A priority patent/JP2020531591A/ja
Priority to EP18851929.2A priority patent/EP3677284A4/en
Publication of WO2019041733A1 publication Critical patent/WO2019041733A1/zh

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Definitions

  • the invention relates to the field of cancer treatment, in particular to an intermediate drug having synergistic anticancer activity and a polyethylene glycol coupled synergistic anticancer drug, a preparation method thereof, an application and a cancer treatment method.
  • Cancer is a very complex and deadly disease and a huge health crisis that is currently experiencing in developed and developing countries.
  • 2012 there were more than 14 million new cancer cases worldwide.
  • 2020 there will be more than 15 million new cancer patients worldwide, which will bring serious social, economic and medical problems to any country. influences.
  • a first aspect of the present invention provides an intermediate drug or derivative thereof having synergistic anticancer activity as shown in Formula I, or a pharmaceutically acceptable salt thereof, and a process for the preparation, use and treatment thereof.
  • a second aspect of the present invention provides a polyethylene glycol-coupled synergistic anticancer drug or a derivative thereof, or a pharmaceutically acceptable salt thereof, as shown in Formula II, and a process for the preparation, use and treatment thereof.
  • Z is selected from the group consisting of a dicarboxylic acid having an amino group, a polycarboxylic acid or a corresponding acyl substituent thereof; N is selected from an amino acid, a dipeptide or a polypeptide; An anticancer drug with a hydroxyl group, a carboxyl group or an acyl group.
  • PEG is selected from the group consisting of a single or multi-armed polyethylene glycol or a derivative of polyethylene glycol;
  • Y is selected from carboxylic acids bearing an amino group or their corresponding acyl substitutions;
  • An anticancer drug comprising an intermediate drug having a synergistic anticancer activity as shown in Formula I or a derivative thereof, or a pharmaceutically acceptable salt thereof.
  • An anticancer drug comprising a polyethylene glycol-coupled synergistic anticancer drug or derivative as shown in Formula II, or a pharmaceutically acceptable salt thereof.
  • a method of treating cancer which employs the present invention to provide an anticancer drug.
  • the invention uses a dicarboxylic acid or a polycarboxylic acid having an amino group and an amino acid or a polypeptide as a connecting member, and combines at least two anticancer drugs having synergistic effects to obtain an anticancer drug or an anticancer drug.
  • Such intermediate drugs are useful in the preparation of anti-cancer drugs, such as the preparation of multi-target payloads in a single nanomedicine.
  • the present invention uses polyethylene glycol as a carrier, and since the end of the polyethylene glycol polymer chain has only one grafting position, it is difficult to graft multiple anticancer drugs at the same time.
  • the combination of dual or multiple drugs is necessary to solve the multidrug resistance of tumors.
  • the inventor solved the problem of how to graft multiple anticancer drugs at the end of the polyethylene glycol polymer chain through multi-step organic synthesis, and can easily synthesize polyethylene glycol.
  • Coupling anti-cancer drugs or even polyethylene glycol-conjugated anti-cancer drugs to achieve multi-target, multi-therapy simultaneous administration can greatly reduce toxicity, and is conducive to overcoming multi-drug resistance of cancer, with synergy
  • the effect can be used to prepare anticancer drugs, with great clinical value and broad market prospects.
  • Figure 1 is a synthetic route diagram of the compound I-c provided in the fifth embodiment
  • Figure 2 is a synthetic route diagram of the compound II-c provided in the sixth embodiment
  • Figure 3 is a synthetic route diagram of the compound I-d provided in the seventh embodiment
  • Figure 4 is a synthetic route diagram of the compound II-d provided in the eighth embodiment.
  • the present embodiment provides an intermediate drug having a synergistic anticancer activity as shown in Formula I or a derivative thereof, or a pharmaceutically acceptable salt thereof;
  • Z is selected from the group consisting of a dicarboxylic acid having an amino group, a polycarboxylic acid or a corresponding acyl substituent thereof; N is selected from an amino acid, a dipeptide or a polypeptide; An anticancer drug with a hydroxyl group, a carboxyl group or an acyl group.
  • the intermediate drug is a linker of an amino acid or a polypeptide, and a dicarboxylic acid or a polycarboxylic acid having an amino group is used as a bridge to couple at least two anticancer drugs having synergistic effects.
  • a linker of an amino acid or a polypeptide and a dicarboxylic acid or a polycarboxylic acid having an amino group is used as a bridge to couple at least two anticancer drugs having synergistic effects.
  • N is selected from amino acids (eg, glycine, serine, threonine, tyrosine, cysteine, aspartic acid, etc.), dipeptides (eg, GG, ie, glycine-glycine; GS, glycine-serine; RE, That is, arginine and glutamic acid), or a polypeptide such as a tripeptide or a tetrapeptide.
  • amino acids eg, glycine, serine, threonine, tyrosine, cysteine, aspartic acid, etc.
  • dipeptides eg, GG, ie, glycine-glycine; GS, glycine-serine; RE, That is, arginine and glutamic acid
  • a polypeptide such as a tripeptide or a tetrapeptide.
  • a tripeptide for example, GLG, ie, glycine-leucine-glycine; GFA, glycine-phenylalanine-alanine; GLA, glycine-leucine-alanine
  • a tetrapeptide for example, GFLG
  • the amino acid or the polypeptide is used as a linking chain, and the amino group and the carboxyl group in the molecular structure are used as a linking group to carry out amidation reaction with an anticancer drug and an amino group-containing dicarboxylic acid or a polycarboxylic acid, respectively, and the reaction activity is strong, and the biological phase is active. Good solubility.
  • Z is selected from dicarboxylic acids, polycarboxylic acids or their corresponding acyl substituents bearing an amino group.
  • Z may be a dicarboxylic acid having an amino group
  • Z may also be a polycarboxylic acid having an amino group
  • Z may also be a corresponding acyl substituent of a dicarboxylic acid having an amino group
  • Z may also be a polycarboxylate having an amino group.
  • the corresponding acyl substituent of the acid When Z is a tricarboxylic acid having an amino group, three anticancer drugs having synergistic effects can be coupled thereto by an acyl group to form an anticancer drug. Similarly, when Z is a tetracarboxylic acid having an amino group, an anticancer drug can be formed.
  • the number of binding sites carried by Z is smaller than the number of anticancer drugs.
  • a binding site (such as a carboxyl group) can bind to one or an anticancer drug, but if two or two anticancer drugs are first combined, then two or two anticancer drugs will be combined.
  • the organic substances bind to the same site, so that the same binding site can be formed to combine two or two anticancer drugs.
  • the same binding site can also combine three or more than three or more types of anticancer drugs.
  • Z is a dicarboxylic acid having an amino group
  • Z is selected from the group consisting of glutamic acid, a derivative of glutamic acid, a derivative of aspartic acid, aspartic acid, glutaric acid having an amino group or Any one of derivatives of glutaric acid having an amino group.
  • glutamic acid and aspartic acid are natural amino acids with two carboxyl groups, which are highly reactive and can couple two amidated anticancer drugs via highly active acyl groups.
  • AC is selected from an anticancer drug having an amino group, a hydroxyl group, a carboxyl group or an acyl group.
  • the anticancer drug can form an amide bond with an amino acid through an amino group, a hydroxyl group, a carboxyl group or an acyl group to obtain an amino acid modified anticancer drug; the anticancer drug can also pass through an amino group.
  • a hydroxyl group, a carboxyl group or an acyl group forms an amide bond with an amino acid and a polypeptide to obtain a polypeptide-modified anticancer drug, which facilitates coupling using Z.
  • the anticancer drug comprises an immunotherapeutic cancer drug, a chemotherapeutic drug or a targeted drug, and more preferably, at least one AC is selected from the group consisting of immunotherapeutic cancer drugs, and at least one AC is selected from the group consisting of a chemotherapeutic drug or a targeted drug, and is immunized Therapeutic cancer drugs have synergistic effects with chemotherapeutic drugs or targeted drugs.
  • at least one of the ACs is selected from the chemotherapeutic drugs, at least one of the ACs is selected from the targeted drugs, and the selected chemotherapeutic drugs have a synergistic effect with the targeted drugs.
  • At least one AC is selected from the group consisting of immunotherapeutic cancer drugs, at least one AC is selected from the group consisting of chemotherapeutic drugs, at least one AC is selected from the group consisting of targeted drugs, and at least two of the immunotherapy cancer drugs, chemotherapeutic drugs, and targeted drugs are selected. Synergistic; further optionally, three of the immunotherapeutic cancer drugs, chemotherapeutic drugs, and targeted drugs have synergistic effects.
  • an anti-cancer drug that is combined with an immunotherapeutic cancer drug-chemotherapeutic drug, or an anticancer drug that is combined with an immunotherapeutic cancer drug-targeted drug, or a cancer drug-targeted drug combination anticancer A dual-drug, or immunotherapeutic cancer drug-chemotherapy drug-targeted drug combination of anti-cancer drugs to achieve multi-therapeutic combination of anticancer drugs.
  • the drug for immunotherapy of cancer may be selected from the group consisting of: lenalidomide, imiquimod, resiquimod, NLG919, Epacadostat;
  • the chemotherapeutic drug may be selected from the group consisting of: paclitaxel, doxorubicin, 5-fluorouracil (5-FU), SB-743921, belototecan, etoposide;
  • the targeted drug may be selected from the group consisting of: darafinib, trimetinib, palbociclib, ABT-888, Niraparib, PKI-587 with terminal bismethyl, allosteric PKI-587, AZD -5363, MK-2206, Lapatinib ditosylate, Dovetinib, Quisinostat, BIIB021.
  • Anticancer drugs can also be selected from: Linifanib, MK-2206, TAK-580, SMK-17, JNJ-7706621, SNS-032, Ribociclib, Niraparib, HSP-990, XL-019, NVP-BSK805, Golitimod, Indoximod, PD-1/PD-L1 inhibitor 2, PD-1/PD-L1 inhibitor 1, Voreloxin, imatinib, Ponatinib, Dasatinib, Bosutinib, gefitinib, Vandetanib, Suntinib, Nintedanib, Crizotinib, and Ceritinib.
  • BIIB021 The structure of BIIB021 is:
  • ABT-888 The structural formula of ABT-888 is:
  • Linifanib (ABT-869) is:
  • Lapatinib ditosylate The structural formula of Lapatinib ditosylate is:
  • TAK-580 (MLN2480) is:
  • SMK-17 The structural formula of SMK-17 is:
  • JNJ-7706621 The structural formula of JNJ-7706621 is:
  • HSP-990 The structural formula of HSP-990 is:
  • NVP-BSK805 The structural formula of NVP-BSK805 is:
  • the structure of the NLG919 is:
  • Imatinib including imatinib to the terminal methyl group, has the structural formula:
  • Ponatinib including Ponatinib with a terminal methyl group, has the structural formula:
  • Bosutinib which includes Bosutinib with a methyl group on the terminal tertiary amine, has the structural formula:
  • Gefitinib including gefitinib, which has been transformed into a terminal amine by a terminal morpholine ring, has the structural formula:
  • Vandetanib including Vandetanib, which has a terminal methyl group, has the structural formula:
  • Sunitinib which includes Sunitinib, which has a terminal tertiary amine which is a primary amine, and has the structural formula:
  • Nintedanib which includes Nintedanib, which has a terminal tertiary amino group, and has the structural formula:
  • the anticancer drug may also be selected from the group consisting of benzobutyric acid, melphalan, nitrite, lomustine, semustine, streptozin, chloramphenicol, carboplatin, oxaliplatin, Lobaplatin, tegafur, carmofur, fluoroiron, cytarabine, enoxabine, palmitoyl cytarabine, ancitabine, azacytidine, guanidine, thioguanine, squirt Statins, methotrexate, actinomycin D, bleomycin, daunorubicin, epirubicin, zorubicin, arubicin, mitoxantrone, specific group, mitosis Mycin C, hydroxycamptothecin, camptothecin, irinotecan, topotecan, rubitatecan, vinblastine, vincristine, vindesine, vinorelbine, docetaxe
  • AC is selected from the group consisting of Veliparib and allosteric PKI-587, Pabucicol (English name: Palbociclib, PCB for short) and allosteric PKI-587 a group consisting of lapatinib and a terminal bismethyl PKI-587, a group consisting of lapatinib and AZD5363, a group consisting of imiquimod and paclitaxel, or lenalidomide and a terminal bismethyl group.
  • the group consisting of PKI-587 are selected from the group consisting of Veliparib and allosteric PKI-587, Pabucicol (English name: Palbociclib, PCB for short) and allosteric PKI-587 a group consisting of lapatinib and a terminal bismethyl PKI-587, a group consisting of lapatinib and AZD5363, a group consisting of imiquimod and paclitaxel, or lenalidomide and a terminal bismethyl group.
  • the structure of the allosteric PKI-587 is The structure of PKI-587 with a terminal bismethyl group is The structural formula of AZD5363 is
  • the intermediate drug can be any of the following compounds:
  • ABT is ABT-888
  • PKI is allosteric PKI-587
  • the PCB is pabucilil and the PKI is an allosteric PKI-587;
  • LPT lapatinib and AZD is AZD5363;
  • LPT lapatinib and PKI is allosteric PKI-587;
  • LPT lapatinib
  • PKI a PKI-587 which is a terminal bismethyl group.
  • Step S1 amidating at least two of the anticancer drugs having synergistic effects with a derivative of an amino acid, an amino acid derivative, a dipeptide, a derivative of a dipeptide, a polypeptide or a polypeptide, respectively, to obtain the formula The first intermediate of the N-AC structural unit in I.
  • the method for synthesizing the first intermediate comprises: presenting an amino acid having an amino protecting group, a derivative of an amino acid, a dipeptide, a derivative of a dipeptide, a derivative of a polypeptide or a polypeptide in the presence of a polypeptide condensation reagent The amino group is deprotected after amidation with an anticancer drug.
  • the polypeptide condensation reagent includes HBTU, HOBT, HBTU.
  • the alkaloid DIEA N,N-diisopropylethylamine is also added to the reaction at a reaction temperature of -10 to 10 ° C, preferably -4 to 4 ° C.
  • the amino group on the amino acid or polypeptide and its derivative is protected with an amino protecting group before the reaction, and the amino protecting group is an alkyl-like carbonyl-based amino protecting group, for example, a tert-butoxycarbonyl group (Boc) ), fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), trimethylsilyloxycarbonyl (Teoc), and the like.
  • an amino protecting group is an alkyl-like carbonyl-based amino protecting group, for example, a tert-butoxycarbonyl group (Boc) ), fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), trimethylsilyloxycarbonyl (Teoc), and the like.
  • Step S2 Corresponding to any one of the first intermediates with an amino group-containing dicarboxylic acid, an amino group-containing polycarboxylic acid, an amino group-containing dicarboxylic acid, or an amino group-containing polycarboxylic acid
  • the amidation of the acyl substituent undergoes an amidation reaction to give a second intermediate having the ZN-AC structural unit of the formula I.
  • the method for synthesizing the second intermediate comprises: combining the first intermediate with the amino group-containing dicarboxylic acid, polycarboxylic acid or the corresponding amino group having a protecting group and a carboxyl protecting group After acylation of the acyl substituent with the first intermediate in the presence of PyAOP, the carboxyl group is deprotected.
  • a further option is to use amino-protected t-butyl glutamate, t-butyl aspartate, or Fmoc-protected t-butyl glutamate, Fmoc-protected tert-butyl aspartate. Simultaneous protection of the amino group and the carboxyl group is beneficial to increase the reaction rate, reduce by-products, and reduce the difficulty of coupling.
  • Step S3 amidating the second intermediate with the remaining first intermediate to obtain an intermediate drug represented by Formula I
  • the method for synthesizing the intermediate drug of Formula I further comprises: presenting the second intermediate with at least one of the first intermediates in the presence of PyAOP and 2,4,6-trimethylpyridine The amidation reaction occurs at -10 ° C to 10 ° C, and the amino group is deprotected.
  • At least two or two anticancer drugs are first combined together, and then an organic substance combined with at least two or two anticancer drugs is amidated with an amino acid or a peptide and a derivative thereof, wherein At least one binding site of the pharmaceutical intermediate represented by I is linked to at least two or two anticancer drugs.
  • the amino acid or the polypeptide is selected as a linking chain, and an amidated anticancer drug, that is, the first intermediate, is obtained, and the steric hindrance of at least two anticancer drugs simultaneously coupled with the polycarboxylic acid having an amino group is reduced. , reduce the difficulty of the reaction.
  • the types of reactions involved in the intermediate drug are amidation reactions, the selectivity of the amidation reaction is high, the reaction rate block, and the isomer by-products are small, so the yield of the product obtained by the synthesis method is high, and the reaction rate is high. fast.
  • the intermediate drug having a synergistic anticancer activity or a derivative thereof, or a pharmaceutically acceptable salt thereof, prepared by the method can be used for the preparation of an anticancer drug, such as a multi-target payload in the preparation of a single nanomedicine.
  • an excipient may be added or a variety of dosage forms suitable for administration may be prepared.
  • the above intermediate drug having a synergistic anticancer activity or a derivative thereof, or a pharmaceutically acceptable salt thereof, or a corresponding anticancer drug can be used for the treatment of cancer.
  • the present embodiment also provides a polyethylene glycol-coupled synergistic anticancer drug or a derivative thereof, or a pharmaceutically acceptable salt thereof, as shown in Formula II;
  • PEG is selected from the group consisting of a single or multi-armed polyethylene glycol or a derivative of polyethylene glycol; Y is selected from carboxylic acids bearing an amino group or their corresponding acyl substitutions; An intermediate drug, or derivative, or a pharmaceutically acceptable salt thereof, having synergistic anticancer activity as shown in Formula I;
  • the compound of the formula II provided by the present embodiment which is obtained by using the polyethylene glycol as a carrier, by extending the chain (Y) and the intermediate drug prepared by the above Coupling to obtain a polyethylene glycol-conjugated synergistic anticancer drug or derivative, which not only retains the respective properties of the anticancer drug, but also has a synergistic effect, together with a single anticancer drug or
  • the anticancer drug when combined with polyethylene glycol, the anticancer drug has a markedly reduced toxicity, improved water solubility and biostability, and has significant passive targeting and extremely low multidrug resistance.
  • PEG is selected from a single arm or a multi-armed polyethylene glycol or a derivative of polyethylene glycol, and the PEG may be a one-arm polyethylene glycol or a one-arm polyethylene glycol derivative, or may be a multi-armed Derivatives of polyethylene glycol or multi-arm polyethylene glycol.
  • the PEG is a single-arm, two-arm, four-arm or eight-arm polyethylene glycol, or the PEG is a single-arm, two-arm, four-arm or eight-arm polyethylene glycol derivative; more preferably,
  • the molecular weight of PEG is 12,000, 20,000, or 40,000 Daltons.
  • Y is an extended chain, which is beneficial to increase the number of branches, reduce the difficulty of coupling with polyethylene glycol, and improve the release efficiency of anticancer drugs in polyethylene glycol-coupled synergistic anticancer drugs or derivatives.
  • polyethylene glycol-coupled synergistic anticancer drug or derivative, or a pharmaceutically acceptable salt thereof is any of the following compounds:
  • ABT is ABT-888
  • PKI is allosteric PKI-587
  • the PCB is pabucilil and the PKI is an allosteric PKI-587;
  • LPT lapatinib and AZD is AZD5363;
  • LPT lapatinib and PKI is allosteric PKI-587;
  • LPT lapatinib
  • PKI a PKI-587 which is a terminal bismethyl group.
  • Step S1 Amidation reaction of the intermediate drug represented by Formula I with an amino group-containing carboxylic acid or its corresponding acyl substituent to obtain Formula II
  • the fourth intermediate of the structural unit
  • the method for synthesizing the fourth intermediate comprises: the amino group-containing carboxylic acid having an amino protecting group or a corresponding acyl substituent thereof in the presence of a polypeptide condensation reagent, and the third After the intermediate is amidated, the amino group is deprotected.
  • Step S2 The fourth intermediate is coupled with polyethylene glycol or a derivative thereof via an amide bond to give a product of the formula II.
  • the preparation method provided by the embodiment provides synthesis of an anti-cancer drug or an anti-cancer drug, and then is coupled to the polyethylene glycol through an extended chain, and the preparation method is simple, the reaction is mild, and the reaction rate is fast. High rate, suitable for industrial production.
  • the polyethylene glycol-conjugated anti-cancer drug or even the polyethylene glycol-conjugated anti-cancer drug can achieve multi-target and multi-therapy simultaneous administration, can greatly reduce toxicity, and is beneficial for overcoming cancer.
  • Drug resistance, synergistic effect, can be used to prepare anticancer drugs, with significant clinical value and broad market prospects.
  • polyethylene glycol-conjugated anti-cancer drug or even the polyethylene glycol-conjugated anti-cancer multidrug or its derivative, or a pharmaceutically acceptable salt thereof can be further processed into other forms of anticancer drugs, which can be added Excipients, or a variety of dosage forms that are convenient for administration.
  • the above polyethylene glycol-conjugated anticancer drug or even a polyethylene glycol-conjugated anticancer drug or a derivative thereof, or a pharmaceutically acceptable salt thereof, or a corresponding anticancer drug can be used for the treatment of cancer.
  • the aqueous phase was extracted with ethyl acetate (150 ml ⁇ 5), and the organic phase was combined, and the organic phase was dried over anhydrous sodium sulfate, filtered, filtered and evaporated.
  • A500-888 (4.8448 g, 19.831 mmol, Shanghai Lou), Compound A-1 (4.1691 g, 23.7962 mmol), HBTU (11.2806 g, 29.7452 mmol), HOBT (4.0192 g, 29.7452 mmol) were added to a 500 ml round bottom flask. ), dissolved in N,N-dimethylformamide (80 ml). The solution was cooled in a constant temperature reaction bath at 0 ° C for 20 minutes, then DIEA (15.53 ml, 89.2356 mmol) was slowly added dropwise. After 2 hours, it was moved to room temperature and stirred overnight.
  • reaction solution was transferred to a 2 L round bottom flask, and then about 800 ml of diethyl ether was added to precipitate. After the sedimentation, silica gel powder was added as a solid solution. Dry-up, column chromatography, gradient elution with 1% MeOH / m.
  • reaction solution was poured into saturated NaHCO 3 solution (200mL) and extracted with ethyl acetate (200mL ⁇ 3).
  • the organic phase was combined, and the organic phase was added with silica gel powder as a solid solution, dry-loaded, column chromatography, 1% methanol/dichloromethane to 5% methanol/dichloromethane gradient elution to 3% ammonia/6% methanol / dichloromethane elution. Evaporation to give compound F-1 in 100% yield.
  • the compound F-1 (12.7314 g, 17.4307 mmol) was added to a 500 ml round bottom flask, and dissolved in 100 ml of dichloromethane. TFA (26.7 ml, 348.614 mmol) was added under stirring, and the reaction was stirred at room temperature overnight, and the reaction was completed.
  • the magnet was added to a 1 L round bottom flask, and H 2 NCH 2 CH 2 OCH 2 CH 2 OH (9.542 ml, 95.1113 mmol) was added, dissolved in 150 ml of dichloromethane, and triethylamine (26.5133 ml, 190.2226 mmol) was added and stirred. Boc anhydride (24.9096 g, 114.1335 mmol) was added under the conditions.
  • reaction solution was transferred to a rotary evaporator to concentrate, dissolved in methanol, and sodium hydrogencarbonate powder (13 g) was added to neutralize triethylamine under stirring, and suction-filtered, and silica gel powder was added to make a solid solution. Dry-packing, column chromatography eluting with 10% EtOAc /EtOAcEtOAcEtOAcEtOAcEtOAc Collect the product and evaporate to obtain the compound 16.3341 g, yield 83.77%.
  • reaction solution was transferred to a 1 L sep. funnel, and water (100 ml, The organic phase was dried over anhydrous sodium sulfate, suction filtered, and then evaporated to silica gel to dry solids, dry, column chromatography, eluting with 10% ethyl acetate / petroleum ether to 35% ethyl acetate / petroleum ether Take off. Collect the product and evaporate the compound 15.0g, yield 68.13%
  • reaction solution was transferred to a 2 L round bottom flask, and then diethyl ether was poured, and the diethyl ether phase was removed.
  • the precipitate was dissolved in an appropriate amount of methanol/dichloromethane, and dried.
  • MALDI-TOF-MS [25000-60000] 42124-45870; the highest peak: 44322
  • reaction solution was poured into saturated NaHCO 3 solution (200mL), the combined organic phase was extracted with ethyl acetate (200mL ⁇ 2), the organic phase dried over anhydrous MgSO4, filtered off with suction. Evaporated dry compound The product was 8.4 g and the yield was 100%.
  • reaction solution was transferred to a 2 L round bottom flask, and then about 500 ml of diethyl ether was added to carry out sedimentation. After the sedimentation, silica gel powder was added as a solid solution. Dry loading, column chromatography, gradient elution with 1% methanol/dichloromethane to 7% methanol/dichloromethane. The yield of 7.9 g was 86.7%.
  • reaction solution was transferred to a 2 L round bottom flask, and then diethyl ether was poured, and the diethyl ether phase was removed.
  • the precipitate was dissolved in an appropriate amount of methanol/dichloromethane, and dried.
  • the compound A-4 (6.1 g, 4.0893 mmol) was added to a 500 ml round bottom flask, and dissolved in 20 ml of dichloromethane, and TFA (6.3 ml, 81.7859 mmol) was added under stirring, and the reaction was stirred at room temperature overnight, and the reaction was completed.
  • reaction was stopped, the reaction solution was transferred to a 2 L scooping funnel, 300 mL of a saturated NaHCO 3 solution was added, and then extracted three times with ethyl acetate.
  • the organic phases were combined and washed once with saturated NaHCO 3 solution and saturated brine, respectively.
  • the organic phase was dried over anhydrous MgSO 4 and filtered with suction. 12.70 g, yield 100%.
  • reaction solution was transferred to a 1 L separatory funnel, and then about 300 ml of saturated brine was added thereto, and the mixture was extracted three times with ethyl acetate.
  • the organic phase was combined and washed twice with saturated brine, , dissolved in an appropriate amount of dichloromethane, wet-loaded, column chromatography, eluted with dichloromethane, and then gradient eluted with 1% methanol / dichloromethane to 6% methanol / dichloromethane, concentrated product Compound 14.7 g, yield 99%.
  • the light red solid (3 g, 4.36 mmol) was placed in a reaction flask, 45 ml of dioxane was added, and 5 M HCl (15 ml) was added dropwise thereto in an ice bath. After the addition was completed, the reaction was allowed to stand at room temperature for 48 h, and the reaction was stopped and filtered. The filter cake was washed with sodium bicarbonate solution, washed with methanol to give a white solid, and dried in vacuo to give PKI a 2.2g, yield 85%.
  • reaction solution was transferred to a 2 L separatory funnel, and 200 ml of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was extracted three times with ethyl acetate.
  • the organic phase was combined and washed twice with saturated brine, and the organic phase was combined.
  • the water was dried over magnesium sulfate, filtered, and the filtrate was evaporated to dryness. Collecting and concentrating to obtain a pure product compound 1.6293 g, yield 100%.
  • the compound F-5 (500 mg, 0.6716 mmol) was placed in a 200 ml round bottom flask, dissolved in about 10 ml of dichloromethane, and TFA (0.5 ml, 6.716 mmol) was added under stirring, and the reaction was stirred at room temperature overnight.
  • the reaction solution is concentrated, and an appropriate amount of methanol is added to dissolve the crude product, and an appropriate amount of sodium hydrogencarbonate solid powder is added to neutralize the excess TFA. After the neutralization is completed, the mixture is filtered, and the filtrate is concentrated to dryness, and then dissolved with an appropriate amount of dichloromethane.
  • reaction solution was precipitated with anhydrous diethyl ether, and the diethyl ether phase was poured out twice.
  • the precipitate was dissolved with an appropriate amount of dichloromethane, and the mixture was applied to the column, and the column was chromatographed with 2% methanol/dichloromethane to 8 Gradient elution with % methanol/dichloromethane, and finally eluted with 3% aqueous ammonia/8% methanol/dichloromethane.
  • the concentrated product was collected to give compound H-5 4 g, yield 100%.
  • reaction mixture was transferred to a saturated aqueous solution of sodium bicarbonate (400 mL), and extracted with ethyl acetate (300 mL ⁇ 3), and the organic phase was washed twice with saturated sodium hydrogen carbonate solution (200 mL ⁇ 2), dried over magnesium sulfate, concentrated, and separated on a silica gel column, eluting with 10%-50% ethyl acetate- petroleum ether. 16.1 grams.
  • reaction solution was transferred to a filled with saturated NaHCO 3 solution (300 mL) and extracted with ethyl acetate (500 mL), the organic phase was dried over magnesium sulfate, filtered, concentrated and silica gel column with 15% -60% ethyl acetate-petroleum ether and 4-5% methanol-ethyl acetate were purified 7.5 grams.
  • the reaction solution is precipitated with anhydrous diethyl ether, and the diethyl ether phase is poured out twice.
  • the precipitate is dissolved with an appropriate amount of methanol and dichloromethane, and an appropriate amount of silica gel powder is added to prepare a solid solution, which is ready for dry loading, and the column layer is prepared.
  • the precipitate was first eluted with 2% dichloromethane, and then eluted with 3% ammonia/7% methanol/dichloromethane to 5% aqueous ammonia/9% methanol/dichloromethane.
  • the concentrated product was collected and the amino group was protected by Boc. E-6, compound D-6, 1.6 g, yield 72%.
  • AZD5363 100 mg, 0.2335 mmol, Shanghai Lou
  • Boc-Gly 40.9041 mg, 0.2335 mmol
  • HBTU 131.4439 mg, 0.3502 mmol
  • HOBT 47.3253 mg, 0.3502 mmol
  • reaction solution was transferred to a 0.25 L separatory funnel, and 30 ml of a saturated sodium hydrogencarbonate solution was added thereto, and then extracted twice with ethyl acetate (20 ml ⁇ 2), and the organic phases were combined, and then saturated with sodium hydrogen carbonate solution Wash twice (20ml ⁇ 2l) of the organic phase, combine the organic phase, dry the organic phase with anhydrous sodium sulfate, suction filtration, concentrate the filtrate, wet sample, column chromatography, 3% methanol / ethyl acetate to 4 The mixture was eluted with a gradient of EtOAc/EtOAc (EtOAc)EtOAc.
  • reaction solution was transferred to a 0.25 L separatory funnel, and then about 20 ml of saturated brine was added thereto, and the mixture was extracted four times with ethyl acetate. The organic phase was combined, evaporated to dryness, and dissolved with methylene chloride. Sample, column chromatography, collection of concentrated products, to obtain compounds 250.92 mg, yield 99%.
  • the compound C-7 (128 mg, 0.08235 mmol) was placed in a 50 ml round bottom flask, dissolved in about DMF (1.2 ml), and morpholine (0.144 ml, 1.6470 mmol) was added under stirring, and the reaction was stirred at room temperature for 3 h. At the end of the reaction, the reaction solution was precipitated with diethyl ether to remove a large amount of UV impurities, and the diethyl ether phase was poured out.
  • reaction solution was transferred to a 1 L round bottom flask, and the mixture was precipitated with n-hexane, and the n-hexane phase was poured out.
  • the precipitate was dissolved in methanol and dichloromethane, and an appropriate amount of silica gel powder was added to prepare a solid solution. kind.
  • the raw materials Boc-NH-GFLG-OBn (3.0054 g, 5.148 mmol, purchased from Nanjing Pharmaceutical Co., Ltd.) and 10% palladium/carbon catalyst (75 mg) were added to the hydrogenation reactor, and then DMF (30 ml) was added thereto. Dissolve, and let the solvent not pass the stirrer, block the hydrogenation reaction device, use the water pump to pump out the air in the reaction system for about 3 minutes, and then charge the hydrogen. After repeating this three times, the pressure on the hydrogenation reaction device is 18 psi, then at room temperature. The reaction was stirred overnight.
  • Boc-NH-GFLG-OH (5.149 mmol), lapatinib (2.601 g, 4.477 mmol, Wuhan Yuancheng Co-creation Technology Co., Ltd.), HBTU (2.547 g, 6.715 mmol) and HOBT (0.907 g, 6.715 mmol) was placed in a 250 ml round bottom flask and then DMF (90 ml) was added to dissolve, and the mixture was stirred at -5 ° C for 30 min.
  • A-9 (7.3782 g, 6.889 mmol) was dissolved in a 250 ml round-bottomed flask, which was dissolved in dichloromethane (75 ml), and then the mixture was stirred at room temperature overnight with TFA (5.192 ml, 69.89 mmol).
  • Fmoc-Glu-OH (0.54 g, 1.27 mmol) was placed in a 100 ml round bottom flask, then DMF (21 mL) was added to dissolve it, followed by the addition of compound C-9, LC-GFLG-LPT (1.0 g , 0.908 mmol), PyAOP (0.66 g, 1.27 mmol), stirred at 0 ° C for 30 min, then slowly added 2,4,6-trimethylpyridine (0.12 ml, 0.908 mmol), after the addition was completed. The reaction was carried out at this low temperature for 3 days. After the reaction is completed, the post-treatment gives a pure product. 0.388 g, combined to give the product 1.419, yield 94.2%.
  • reaction mixture was transferred to a 1 L sep. funnel, EtOAc (EtOAc) After washing once, then removing the water with saturated sodium chloride (100 ml), the organic phase was collected in a 2 L round bottom flask, crystallized overnight in a refrigerator, and filtered to give a compound. 9.1019 g, yield 96.98%.
  • the product obtained above (2.02 g, 1.69 mmol) was dissolved in methylene chloride (21 ml) in a 100 ml round bottom flask, and then the mixture was stirred at room temperature for 4 days. The reaction was stopped, and the reaction solution was concentrated to dryness vacuolly evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, The product in the aqueous phase was extracted with ethyl acetate, extracted three times (150 ml * 3), and the organic phase was combined and dried over anhydrous sodium sulfate, filtered, concentrated, dried, The product was collected by /2% aqueous ammonia/dichloromethane. The product was collected, concentrated and evaporated to dryness.
  • reaction solution was transferred to a 1000 ml separatory funnel, washed with deionized water (200 ml), the reaction flask was washed with ethyl acetate, and the mixed phase in the separatory funnel was shaken vigorously to separate the organic phase with acetic acid.
  • the ethyl ester was extracted three times (200 ml * 3) and the organic phases were combined and washed three times with saturated sodium chloride (100 ml).
  • step S1 the compound of formula A-10 is treated for use.
  • Boc-NH-GLG-OBn (6.0045g, 13.7873mmol, Nanjing Stone) was added to the hydrogenation reactor, 10% Pd/C (0.1005g) was added, DMF (30mL) was added to dissolve it, and hydrogen gas was introduced. The hydrogen pressure was 14 psi and the reaction was stirred at room temperature overnight. After completion of the reaction, the reaction solution was filtered through a pad of celite, and filtered cake was washed with DMF (20mL ⁇ 3) and the filtrate was transferred to a 250 mL round bottom flask.
  • step S2 a compound of formula B-10 is prepared.
  • reaction solution was transferred to a 2 L beaker, 800 mL of a saturated sodium hydrogencarbonate solution was added thereto, and a solid was precipitated, which was filtered with suction, and the filter cake was separated from water with toluene (100 mL ⁇ 5) and dried to give a compound of the formula B-10: 12.1 g The yield was 93.91%.
  • step S3 a compound of formula C-10 is prepared.
  • the compound of the formula B-10 (7.0271 g, 9.0681 mmol) was poured into a 250 mL flask, dissolved in dichloromethane (20 mL), then TFA (5.3873 mL, 72.5492 mmol) was added and the reaction was stirred at room temperature overnight. After the reaction was completed, the reaction liquid was evaporated to dryness, then dissolved with an appropriate amount of methanol, and a small amount of sodium hydrogencarbonate solid powder was added to neutralize the TFA, suction filtration, and the filtrate was evaporated to dryness, and the column was applied to the column.
  • step S4 a compound of formula D-10 is prepared.
  • Fmoc-Glu-OtBu (2.6402 g, 6.2055 mmol) was placed in a 250 mL flask, dissolved in about 70 mL of DMF, placed in a constant temperature reaction bath at 0 ° C, and a compound of formula C-10 (3.0176) was added with stirring. g, 4.4325 mmol), PyAoP (3.2354 g, 6.2055 mmol). After about 30 minutes, TMP (0.589 mL, 4.4325 mmol) was slowly added dropwise, and the reaction was stirred at 0 ° C overnight. After the reaction was completed, the reaction solution was transferred to a 2 L sep.
  • step S5 a compound of formula E-10 is prepared.
  • the compound of the formula D-10 (4.8342 g, 4.4584 mmol) was poured into a 100 mL flask, and about 35 mL of dichloromethane was added thereto to dissolve. TFA (4.1779 mL, 56.259 mmol) was added under stirring, and the reaction was stirred at room temperature overnight. After the completion of the reaction, the reaction mixture was evaporated to dryness, and then a mixture was evaporated to dryness, and the mixture was dissolved in n-hexane (100 mL ⁇ 3), and the solid was evaporated to give a compound of formula E-10: 5.78 g, yield 100%.
  • step S6 the compound of formula F-10 is treated for use.
  • Boc-NH-GLG-OBn (3g, 6.6149mmol, Nanjing Stone) was added to the hydrogenation reactor, 10% Pd/C (0.0500g) was added, DMF (30mL) was added, hydrogen gas was introduced, and the hydrogen pressure was 14 psi.
  • the reaction was stirred at room temperature overnight. After completion of the reaction, the reaction solution was suction filtered, and the filter cake was washed three times with DMF (20 mL ⁇ 3), and the filtrate was placed in a 250 mL round bottom flask to obtain F-10.
  • step S7 a compound of the formula G-10 is prepared.
  • reaction mixture was transferred to a 1 L sep. funnel, and a saturated sodium hydrogen carbonate aqueous solution (200 mL) and ethyl acetate (300 mL) were added to extract to give an organic phase, ethyl acetate (200 mL ⁇ 3) After washing, the organic phase was combined, and the organic phase was washed with saturated brine (100 mL ⁇ 3), dried over anhydrous sodium sulfate and filtered, and filtrated, and the filtrate was evaporated to dryness.
  • step S8 a compound of the formula H-10 is prepared.
  • the compound of formula G-10 (3.6483 g, 3.6791 mmol) was added to a 100 mL flask, dichloromethane (25 mL) was added and dissolved, then TFA (2.1857 mL, 29.4328 mmol) was added and stirred at room temperature overnight. After completion of the reaction, the reaction solution was evaporated to dryness, and then evaporated with methanol, and then, and then, and then, the mixture was dissolved in methanol (20 g), and the remaining TFA was added and filtered, and the filtrate was evaporated to dryness, and then applied to the column and column chromatography (0.5% ammonia water: The elution was carried out with 5% methanol: 94.5% dichloromethane.
  • step S9 a compound of formula I-10 is prepared.
  • the compound of formula E-10 (2.8900 g, 2.8108 mmol) was added to a 250 mL straight-tube reaction flask, dissolved in DMF (40 mL), the reaction was placed at 0 ° C, and the compound of formula H-10 (2.0921 g, 2.8108 mmol), PyAOP (1.7585 g, 3.3729 mmol). After about 30 minutes, 2,4,6-trimethylpyridine (0.3700 ml, 2.8108 mmol) was slowly added dropwise, and the reaction was stirred at 0 ° C overnight.
  • reaction solution was transferred to a 2 L separatory funnel, and extracted with deionized water (300 mL) and ethyl acetate (250 mL) to obtain an organic phase.
  • the aqueous phase was washed with EA (150 mL ⁇ 4), organic phase, organic
  • the phase was washed with saturated brine (200 m ⁇ 3), and then the organic phase was dried over anhydrous sodium sulfate and filtered, and then filtrated, and the filtrate was concentrated to dryness, dry-up, column chromatography, and Elution with % dichloromethane, concentration was concentrated to give the compound of formula I-10: 2.8780 g, yield 58.36%.
  • step S11 a compound of the formula J-10 is prepared.
  • the compound of formula I-10 (2.8725 g, 1.6373 mmol) was added to a 250 mL flask, dissolved in DMF (20 mL), then morpholine (4.2792 mL, 49.1190 mmol) was added, and the reaction was stirred at room temperature, about 1 After the reaction, the reaction was completed, diethyl ether (150 mL) was added under stirring, and the mixture was allowed to stand for about 30 minutes, and the supernatant was poured. The lower solid was precipitated with n-hexane (150 mL ⁇ 3) to give a solid, evaporated, and dried.
  • step S12 a compound of the formula K-10 is prepared.
  • the reaction mixture was transferred to a 1 L sep. funnel, and a saturated sodium hydrogen carbonate aqueous solution (250 mL) and ethyl acetate (200 mL) were added to extract to give an organic phase.
  • the organic phase is washed with saturated brine (150 mL ⁇ 3), dried over anhydrous sodium sulfate and filtered, filtered, evaporated, evaporated, evaporated, evaporated, evaporated Elution was carried out by using 1% aqueous ammonia + 6% methanol + 95.5% dichloromethane), and the product was collected and concentrated to dryness to give the compound of formula K-10: 1.4322 g, yield 84.20%.
  • step S13 a compound of the formula L-10 is prepared.
  • the compound of the formula K-10 (1.4108 g, 0.8351 mmol) was added to a 250 mL flask, dichloromethane (10 mL) was added to dissolve, and then TFA (0.6175 mL, 8.3510 mmol) was added, and the reaction was stirred at room temperature overnight.
  • step S14 a compound of the formula M-10 is prepared.
  • the compound of the formula L-10 (0.8398 g, 0.5293 mmol) was poured into a 250 mL flask, and dichloromethane (25 mL) and DMF (4 mL) were added to dissolve, and then M-SCM-10K (4.6715 g, 0.4410 mmol, Beijing Key Kai), the reaction is kept away from light at room temperature. After the reaction was completed, the reaction solution was concentrated to about 20 mL, and dichloromethane (10 mL) was added to dissolve, and diethyl ether (150 mL) was added to precipitate a solid, which was filtered and washed with diethyl ether (150 mL ⁇ 4) to give a crude product.
  • mice Balb/c nude nude mice, SPF grade; source is Shanghai Lingchang Biotechnology Co., Ltd.; license number is SCXK (Shanghai) 2013-0018, certificate number 2013001828988; week age is 16-18 weeks, female.
  • Experimental group test drug Compound of the formula 11 as prepared in the eleventh embodiment, molecular weight 12066, yellow powder, storage conditions 4 ° C; weighed the compound shown by formula M-10, added physiological saline ultrasound After dissolution, the drug was administered twice, and the remaining drug was stored at 4 ° C.
  • Blank control group reagent normal saline, purchased from Shandong Kangning Pharmaceutical, batch No. A16071105.
  • FCS Sciencell, item number 0500.
  • nude mice were inoculated subcutaneously on the right side, 0.1 ml/only, that is, the number of cells per nude mouse was 2 ⁇ 10 6 ; 20 were inoculated.
  • the size of the tumor under Colo-205 was measured, and 16 tumor-bearing mice were randomly divided into 2 groups according to the tumor volume, 8 in each group. The day of the grouping was recorded as Day1, and the administration started on the same day.
  • the grouping and dosing schedule are shown in Table 1:
  • Tumor size and body weight were measured every three days, and animal status was observed and recorded.
  • TV 1/2 ⁇ a ⁇ b 2 , where a and b represent length and width, respectively.
  • RTV TV 1 /TV t ⁇ 100, where TV 1 is the tumor volume when administered in a cage (ie Day 1), and TV t is the tumor volume at each measurement.
  • T/C(%) (T RTC /C RTV ) ⁇ 100
  • T TW tumor weight of treatment group
  • C TW tumor weight of blank control group
  • TW (timor weight) tumor weight.
  • Test data were expressed as mean ⁇ standard deviation (mean ⁇ SD), and body weight and tumor volume were determined using Student's t-test. P ⁇ 0.05 indicates a significant difference, and P ⁇ 0.01 indicates a very significant difference.
  • mice were recorded as Day1 on the day of grouping, and the body weight of each group was about 20 g at the time of grouping, and the body weight of the animals was measured every three days from the day of grouping (Day1) to the end point of the experiment (Day11).
  • the results are shown in Table 2.
  • the body weight of the Control group grew normally after the grouping, and the body weight of the M-10 group showed a gradual decline. At the end of the experiment, there was a significant difference between the weight of the drug-administered group and the Control group. On Day10 measurement, it was found that the weight loss of the 4 # mice in the administration group was severe, only 12.45 g, and Day11 died.
  • the tumors were randomly divided into tumor volume by 100-200 mm3.
  • the tumor volume of each group was about 210 mm3, and the tumors were measured every three days from the day of grouping (Day1) to the end of the experiment (Day11). volume.
  • the results showed (Table 3) that at the end of the experiment, the tumor volume of the Cortrol group was 1411.47 mm3 and the RTV was 680.32%.
  • the tumor model worked normally.
  • the tumor volume of the Control group was 1411.47 mm3 at the end of the experiment.
  • the tumor volume of the mice in the M-10 administration group grew slowly after the first administration, and then gradually decreased.
  • the tumor volume at the end of the experiment was 41.95 mm 3 , tumor volume (TV) and relative tumor volume (RTV) and Control. There was a significant difference in the comparison between the groups.
  • the tumor-bearing mice were euthanized with carbon dioxide, and the tumor was photographed and weighed after the tumor was removed.
  • the results showed (Table 4) that the tumor weight of the Control group was 0.90 g, and the tumor weight of the M-10 administration group was 0.013 g; the tumor inhibition rate was 98.5%.
  • the tumor weight and tumor inhibition rate of the drug-administered group were significantly different from those of the Control group.
  • the effect of the compound on tumors in Colo205 tumor-bearing mice was visually observed from Figure 4.
  • Colo205 tumor-bearing mice were administered.
  • the subcutaneous tumors were as long as 200 mm 3 , they were randomly grouped according to the tumor volume, and administration was started on the same day.
  • the tumor volume of each group was about 210 mm3 at the time of grouping.
  • the tumor volume of the Cortrol group was 1411.47 mm3 and the RTV was 680.32%.
  • the tumor model worked normally.
  • the tumor volume of the Control group was 1411.47 mm 3 at the end of the experiment.
  • the tumor volume of the mice in the M-10 administration group increased first and then decreased.
  • the tumor volume at the end of the experiment was 41.95 mm3.
  • the tumor volume (TV) and relative tumor volume (RTV) were significantly different from those of the Control group.
  • the tumor weight of the Control group was 0.90 g, and the tumor weight of the M-10 administration group was 0.013 g, respectively; the tumor inhibition rate was 98.5%.
  • the tumor weight and tumor inhibition rate of the drug-administered group were significantly different from those of the Control group.
  • mice showed weight loss, dry and chapped skin, low surface temperature and slight loose stools.
  • the intermediate drug or derivative thereof provided by the present invention, or a pharmaceutically acceptable salt thereof can be used for preparing an anticancer drug, for example, preparing a multi-target payload in a single nano drug, and can be used for treating cancer.
  • the preparation method provided by the invention can easily synthesize a polyethylene glycol-conjugated anti-cancer double drug or even a polyethylene glycol-conjugated anti-cancer multi-drug, thereby realizing simultaneous multi-target and multi-therapy administration, and can greatly reduce toxicity.
  • it is beneficial to overcome the multi-drug resistance of cancer has a synergistic effect, can be used for preparing anticancer drugs, can be used for treating cancer, has great clinical value and broad market prospect.

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Abstract

具有协同抗癌活性的中间体药物和聚乙二醇偶联协同抗癌药物，其制备方法和应用。该中间体药物的结构通式为（I），聚乙二醇偶联协同抗癌药物的结构通式为（II），上述药物能够实现多种抗癌药物之间的联合用药，避免在单独服用多种抗癌药物时由于药物之间的相互影响以及药代动力学而导致的毒性反应，且有利于克服癌症的多药耐药性，具有协同增效的作用，可用于制备抗癌药物及用于治疗癌症。

Description

具有协同抗癌活性的中间体药物和聚乙二醇偶联协同抗癌药物、及其制备方法、应用和癌症治疗方法
本申请要求于2017年08月30日提交中国专利局的申请号为CN201710761572.5、名称为“具有协同抗癌活性的中间体药物和聚乙二醇偶联协同抗癌药物、及其制备方法和应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及癌症治疗领域，具体而言，涉及一种具有协同抗癌活性的中间体药物和聚乙二醇偶联协同抗癌药物、及其制备方法、应用和癌症治疗方法。
背景技术
癌症是一种非常复杂和致命的疾病，是发达国家和发展中国家目前正在经历的一个巨大的健康危机。在2012年，全球有超过1400万例新的癌症病例发生，到2020年，世界范围内将有1500万多个新增癌症患者，这对任何国家的社会、经济和医疗都将带来严重的影响。
癌症治疗的临床结果普遍令人失望，在很大程度上归因于这种毁灭性疾病的异质性和复杂性。传统的手术和放疗仅用于局部疾病的治疗，而激素治疗、化疗、免疫治疗和靶向治疗用于单独治疗或与别的治疗方法联用。多年来，包括化疗在内的单一和组合疗法已经发展成为有效治疗方法。当然，联合治疗的临床效果并不像预期的那样好，通常都有更高的毒性，还受限于药物成分无法以自由分子形式达到所需时空分布，也就是说，在适当的时机将药物成分运送到正确的位置。除非使用有效的药物载体，否则药物成分之间的物理化学和药代动力学性质的固有差异会阻止这种情况的发生。目前，肿瘤化疗耐药性或多药耐药性的出现已经成为肿瘤化疗研究者面临的主要挑战。
发明内容
本发明的第一方面目的在于提供一种如式I所示的具有协同抗癌活性的中间体药物或其衍生物、或其药学上可接受的盐及其制备方法、应用和治疗方法。
本发明的第二方面目的在于提供一种如式II所示的聚乙二醇偶联协同抗癌药物或其衍生物、或其药学上可接受的盐及其制备方法、应用和治疗方法。
为了实现本发明的上述目的，特采用以下技术方案：
一种如式I所示的具有协同抗癌活性的中间体药物或衍生物、或其药学上可接受的盐；
Figure PCTCN2018073662-appb-000001
其中，i＝2、3、4或5；Z选自带有氨基的二羧酸、多羧酸或其相应的酰基取代物；N选自氨基酸、二肽或多肽；AC选自带有氨基、羟基、羧基或者酰基的抗癌药物。
一种如式II所示的聚乙二醇偶联协同抗癌药物或衍生物、或其药学上可接受的盐；
Figure PCTCN2018073662-appb-000002
其中，PEG选自单臂或多臂的聚乙二醇或聚乙二醇的衍生物；X选自
Figure PCTCN2018073662-appb-000003
Figure PCTCN2018073662-appb-000004
Y选自带有氨基的羧酸或其相应的酰基取代物；
Figure PCTCN2018073662-appb-000005
如权利要求1～3任一项如式I所示的具有协同抗癌活性的中间体药物，或衍生物、或其药学上可接受的盐；
m＝0、1或2；n＝1～5；j＝PEG的臂数。
一种式I所示的具有协同抗癌活性的中间体药物或衍生物、或其药学上可接受的盐的制备方法，其包括：
将具有协同作用的至少两个抗癌药物分别与氨基酸或肽及其衍生物发生酰胺化反应，得到具有式I中N-AC结构单元的第一中间体；
将任意一个第一中间体与带有氨基的二羧酸、多羧酸或其相应的酰基取代物发生酰胺化反应，得到具有式I中Z-N-AC结构单元的第二中间体；以及将第二中间体与剩余的第一中间体发生酰胺化反应，得到式I所示的中间体药物
Figure PCTCN2018073662-appb-000006
一种如式II所示的聚乙二醇偶联协同抗癌药物或衍生物、或其药学上可接受的盐的制备方法，其包括：
将式I所示的中间体药物与带有氨基的羧酸或其相应的酰基取代物发生酰胺化反应，得到具有式II中
Figure PCTCN2018073662-appb-000007
结构单元的第四中间体；以及将第四中间体与聚乙二醇或其衍生物通过酰胺键偶联，得到式II所示的产品。
如式I所示的具有协同抗癌活性的中间体药物或衍生物、或其药学上可接受的盐在制备抗癌药物中的应用。
如式I所示的具有协同抗癌活性的中间体药物或其衍生物、或其药学上可接受的盐在治疗癌症中的应用。
一种抗癌药物，包括如式I所示的具有协同抗癌活性的中间体药物或其衍生物、或其药学上可接受的盐。
如式II所示的聚乙二醇偶联协同抗癌药物或衍生物、或其药学上可接受的盐在制备抗癌药物中的应用。
如式II所示的聚乙二醇偶联协同抗癌药物或衍生物、或其药学上可接受的盐在治疗癌症中的应用。
一种抗癌药物，包括如式II所示的聚乙二醇偶联协同抗癌药物或衍生物、或其药学上可接受的盐。
一种癌症的治疗方法，其采用本发明提供抗癌药物。
与现有技术相比，本发明的有益效果例如包括：
本发明以带有氨基的二羧酸或多羧酸以及氨基酸或多肽为连接件，将具有协同增效作用的至少两个抗癌药物联用，得到抗癌双药或抗癌多药，形成多种抗癌药物之间的联合用药，避免在单独服用多种抗癌药物时由于药物之间的相互影响以及药代动力学而导致的毒性反应。这种中间体药物可用于制备抗癌药物，例如制备单一的纳米药物中的多靶点有效载荷。
在上述基础上，本发明以聚乙二醇为载体，由于聚乙二醇高分子链的末端只有一个接枝位置，难以同时接枝多个抗癌药。而双药或多药联用又是解决肿瘤多药耐药性所必须的。发明人 经过多年的研究，通过多步有机合成手段，解决了“如何在聚乙二醇高分子链的末端接枝多个抗癌药物”的这一难题，可以较容易地合成聚乙二醇偶联抗癌双药甚至聚乙二醇偶联抗癌多药，实现多靶点、多疗法同时给药，可以大幅度降低毒性，且有利于克服癌症的多药耐药性，具有协同增效的作用，可用于制备抗癌药物，具有重大的临床价值和广阔的市场前景。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，以下将对实施例或现有技术描述中所需要使用的附图作简单地介绍。
图1为第五实施例中提供的化合物I-c的合成路线图；
图2为第六实施例中提供的化合物II-c的合成路线图；
图3为第七实施例中提供的化合物I-d的合成路线图；
图4为第八实施例中提供的化合物II-d的合成路线图。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限制本发明的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售购买获得的常规产品。
本实施方式提供一种如式I所示的具有协同抗癌活性的中间体药物或其衍生物、或其药学上可接受的盐；
Figure PCTCN2018073662-appb-000008
其中，i＝2、3、4或5；Z选自带有氨基的二羧酸、多羧酸或其相应的酰基取代物；N选自氨基酸、二肽或多肽；AC选自带有氨基、羟基、羧基或者酰基的抗癌药物。
由式I可知，这种中间体药物，以氨基酸或多肽为连接链，以带有氨基的二羧酸或多羧酸为连接桥，将具有协同增效作用的至少两个抗癌药物偶联在一起，形成抗癌双药或抗癌多药，与同时使用单一抗癌药相比，毒性降低，药效增强。
N选自氨基酸(例如甘氨酸、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、天冬氨酸等)、二肽(例如GG，即甘氨酸-甘氨酸；GS，即甘氨酸-丝氨酸；RE，即精氨酸和谷氨酸)、或者多肽，比如三肽或四肽。其中，三肽(例如GLG，即甘氨酸-亮氨酸-甘氨酸；GFA，即甘氨酸-苯丙氨酸-丙氨酸；GLA，即甘氨酸-亮氨酸-丙氨酸)，四肽(例如GFLG，即甘氨酸-苯丙氨酸-亮氨酸-甘氨酸)。采用氨基酸或多肽为连接链，利用其分子结构中的氨基和羧基作为连接基团分别与抗癌药物和带有氨基的二羧酸或多羧酸进行酰胺化反应，反应活性强，且生物相溶性好。
Z选自带有氨基的二羧酸、多羧酸或其相应的酰基取代物。Z可以是带有氨基的二羧酸，Z也可以是带有氨基的多羧酸，Z还可以是带有氨基的二羧酸相应的酰基取代物，Z还可以是带有氨基的多羧酸相应的酰基取代物。当Z为带有氨基的三羧酸时，可在其上通过酰基偶联3个具有协同增效作用的抗癌药物，形成抗癌三药。同理，当Z为带有氨基的四羧酸时，可形成抗癌四药。
进一步地，Z带有的结合位点数量小于抗癌药物的数量。通常一个结合位点(例如一个羧基)可以结合一个或者一种抗癌药物，但是如果先将两个或者两种抗癌药物先结合到一起，再 将结合了两个或者两种抗癌药物的有机物结合到同一个位点上，这样就可以形成同一个结合位点结合两个或两种抗癌药物。同理，同一个结合位点也可以结合三个及三个以上数量或者种类的抗癌药物。
进一步地，当Z为带有氨基的二羧酸时，Z选自谷氨酸、谷氨酸的衍生物、天冬氨酸、天冬氨酸的衍生物、带有氨基的戊二酸或带有氨基的戊二酸的衍生物中的任意一种。谷氨酸和天冬氨酸均为带有两个羧基的天然氨基酸，反应活性强，能够通过高活性的酰基偶联两个酰胺化的抗癌药物。
AC选自带有氨基、羟基、羧基或者酰基的抗癌药物，抗癌药物可以通过氨基、羟基、羧基或者酰基与氨基酸形成酰胺键，得到氨基酸修饰的抗癌药物；抗癌药物也可以通过氨基、羟基、羧基或者酰基与氨基酸与多肽形成酰胺键，得到多肽修饰的抗癌药物，便于使用Z进行偶联。
进一步地，抗癌药物包括免疫治疗癌症药物、化疗药物或靶向药物，更为优选的，至少一种AC选自免疫治疗癌症药物，至少一种AC选自化疗药物或靶向药物，且免疫治疗癌症药物与化疗药物或靶向药物具有协同作用。可选的，至少一种所述AC选自所述化疗药物，至少一种所述AC选自所述靶向药物，且所选的所述化疗药物与所述靶向药物具有协同作用。可选的，至少一种AC选自免疫治疗癌症药物，至少一种AC选自化疗药物，至少一种AC选自靶向药物，且免疫治疗癌症药物、化疗药物和靶向药物中的至少两者具有协同作用；进一步可选的，免疫治疗癌症药物、化疗药物和靶向药物中的三者具有协同作用。
由此，即可得到免疫治疗癌症药物-化疗药物联用的抗癌双药，或者免疫治疗癌症药物-靶向药物联用的抗癌双药，或者化疗药物-靶向药物联用的抗癌双药，或者免疫治疗癌症药物-化疗药物-靶向药物联用的抗癌三药，以此实现抗癌药物的多疗法联合用药。
其中，免疫治疗癌症的药物可以选自：来那度胺(Lenalidomide)、咪喹莫特(Imiquimod)、雷西莫特(Resiquimod)、NLG919，Epacadostat；
化疗药物可以选自：紫杉醇、多柔比星、5-氟脲嘧啶(5-FU)、SB-743921、贝洛替康、埃托泊苷；
靶向药物可以选自：达拉非尼、曲美替尼、帕布昔利布(Palbociclib)、ABT-888、Niraparib、去末端双甲基的PKI-587、变构的PKI-587、AZD-5363、MK-2206、拉帕替尼(Lapatinib ditosylate)、多韦替尼、Quisinostat、BIIB021。
抗癌药物还可以选自：Linifanib、MK-2206、TAK-580、SMK-17、JNJ-7706621、SNS-032、Ribociclib、Niraparib、HSP-990、XL-019、NVP-BSK805、Golotimod、Indoximod、PD-1/PD-L1inhibitor 2、PD-1/PD-L1inhibitor 1、Voreloxin、伊马替尼、Ponatinib、Dasatinib、Bosutinib、吉非替尼、Vandetanib、Sunitinib、Nintedanib、Crizotinib、和Ceritinib。
SB-743921的结构式为：
Figure PCTCN2018073662-appb-000009
MK-2206的结构式为：
Figure PCTCN2018073662-appb-000010
BIIB021的结构式为：
Figure PCTCN2018073662-appb-000011
ABT-888的结构式为：
Figure PCTCN2018073662-appb-000012
Linifanib(ABT-869)的结构式为：
Figure PCTCN2018073662-appb-000013
Lapatinib ditosylate的结构式为：
Figure PCTCN2018073662-appb-000014
MK-2206 2HCl的结构式为：
Figure PCTCN2018073662-appb-000015
TAK-580(MLN2480)的结构式为：
Figure PCTCN2018073662-appb-000016
SMK-17的结构式为：
Figure PCTCN2018073662-appb-000017
JNJ-7706621的结构式为：
Figure PCTCN2018073662-appb-000018
SNS-032(BMS-387032)的结构式为：
Figure PCTCN2018073662-appb-000019
HSP-990的结构式为：
Figure PCTCN2018073662-appb-000020
XL-019的结构式为：
Figure PCTCN2018073662-appb-000021
NVP-BSK805的结构式为：
Figure PCTCN2018073662-appb-000022
PD-1/PD-L1inhibitor 2的结构式为：
Figure PCTCN2018073662-appb-000023
PD-1/PD-L1inhibitor 1的结构式为：
Figure PCTCN2018073662-appb-000024
NLG919的结构式为：
Figure PCTCN2018073662-appb-000025
伊马替尼，包括去末端甲基的伊马替尼，其结构式为：
Figure PCTCN2018073662-appb-000026
Ponatinib，包括去末端甲基的Ponatinib，其结构式为：
Figure PCTCN2018073662-appb-000027
Bosutinib，包括去末端三级胺上甲基的Bosutinib，其结构式为：
Figure PCTCN2018073662-appb-000028
吉非替尼，包括将末端吗啉环变构为一级胺的吉非替尼，其结构式为：
Figure PCTCN2018073662-appb-000029
Vandetanib，包括去末端甲基的Vandetanib，其结构式为：
Figure PCTCN2018073662-appb-000030
Sunitinib，包括将末端三级胺变构为一级胺的Sunitinib，其结构式为：
Figure PCTCN2018073662-appb-000031
Nintedanib，包括去末端三级胺甲基的Nintedanib，其结构式为：
Figure PCTCN2018073662-appb-000032
进一步地，抗癌药物还可以选自由苯丁酸氮介、美法仑、氮甲、洛莫司汀、司莫司汀、链佐星、 氯脲霉素、卡铂、奥沙利铂、洛铂、替加氟、卡莫氟、氟铁龙、阿糖胞苷、依诺他宾、棕榈酰阿糖胞苷、安西他宾、氮杂胞苷、巯嘌呤、硫鸟嘌呤、喷司他丁、甲氨蝶呤、放线菌素D、博来霉素、柔红霉素、表柔比星、佐柔比星、阿柔比星、米托蒽醌、比生群、丝裂霉素C、羟喜树碱、喜树碱、伊立替康、拓扑替康、鲁比替康、长春碱、长春新碱、长春地辛、长春瑞滨、多西他赛、尼洛替尼、厄诺替尼、埃克替尼、阿法替尼、索拉非尼、帕唑替尼、凡德他尼、维罗非尼、克唑替尼、鲁索利替尼、阿西替尼、瑞戈非尼、卡博替尼、曲美替尼、达拉非尼、依鲁替尼、伊德利赛、乐伐替尼、硼替佐米、卡非佐米、依维莫司、西罗莫司、托法替尼、奥拉帕尼、阿帕西普、罗米地辛、贝利司他、帕比司他、帕利夫明、坦西莫司、伏立诺他、idelalisib,AZD9291,Cobimetinib,vismodegib,ixazomib,sonidegib,omacetaxine mepesuccinate,Venetoclax,Enzalutamide,Calicheamicins,Autistatins,Maytansinoids、雌二醇、他莫昔芬、己烯雌酚、托瑞米芬、艾多昔芬、米普昔芬、屈洛昔芬、雷洛昔芬、阿佐昔芬、氟他胺、尼鲁米特、比卡鲁胺、睾酮、5α-二氢睾酮、甲睾酮、非那雄胺、度他雄胺、地塞米松、视黄酸、烟酸、烟酰胺、替莫唑胺、达卡巴嗪、依托泊苷、小白菊内脂、白藜芦醇、吉西他滨、二甲双胍、三氟拉嗪、甲硫哒嗪、盐霉素、姜黄素、BKM120、BYL719、pictilisib、XL765、PF-05212384、PF-04691502、GS-9820、dactolisib、copanlisib、GDC-0941、GSK2141795、RG7422、BGT226、XL147、SAR260301、GSK2636771、GSK2269557、GSK2126458、GSK1059615、RG7604、RG7666、AMG 319、MLN1117、AZD5363、AZD8186、AZD6482、MK-8669、BGT226、GSK1059615、AZD8055、ipatasertib、GSK2110183、GSK690693、RG7440、Vemurafenib、LGX818、RG7304、MLN2480、Trametinib、MEK162、pimasertib、RG7167,TAK-733、Gefitinib、erlotinib、afatinib、dacomitinib、AZD8931、AEE788、BGJ398、LY2874455、AZD4547、TKI258、motesanib、Fostamatinib、GS-9973、TAK-659、MLN8237、AZD1152、tozasertib、AMG 900、MK-5108、TAK-901、GSK1070916、PF-03814735、LDK378、RG7853、RG7601、ABT-199、ABT-737、ABT-263、SAR405838、RG7388、JNJ-26854165、Tofacitinib、ruxolitinib、momelotinib、baricitinib、LY2784544、GSK2586184、GLPG0634、AZD1480、foretinib、LY2801653,SAR125844,AMG208,AMG 337、Vorinostat,romidepsin,LBH589,JNJ-26481585、erismodegib,BMS-833923,LY2940680,PF-04449913、MK-8776,LY2603618,RG7741,AZD7762、olaparib,rucaparib,AZD2461、dinaciclib,LEE011,LY2835219,BAY 1000394,AZD5438、losmapimod,dilmapimod,LY2228820、MK-0752,PF-03084014，LY3039478，
Figure PCTCN2018073662-appb-000033
Figure PCTCN2018073662-appb-000034
Figure PCTCN2018073662-appb-000035
Figure PCTCN2018073662-appb-000036
组成的组中的至少两种。
更进一步地，式I中i＝2，AC选自Veliparib和变构的PKI-587组成的组、帕布昔利布(英文名：Palbociclib，简称PCB)和变构的PKI-587组成的组、拉帕替尼和去末端双甲基的PKI-587组成的组、拉帕替尼和AZD5363组成的组、咪喹莫特和紫杉醇组成的组、或来那度胺和去末端双甲基的PKI-587组成的组。这几组抗癌药物均表现出一定的协同增效性，可用于制备抗癌双药。
其中，变构的PKI-587的结构为
Figure PCTCN2018073662-appb-000037
去末端双甲基的PKI-587的结构为
Figure PCTCN2018073662-appb-000038
AZD5363的结构式为
Figure PCTCN2018073662-appb-000039
优选地，该中间体药物可以是如下任一化合物：
Figure PCTCN2018073662-appb-000040
其中，ABT为ABT-888，PKI为变构的PKI-587；
Figure PCTCN2018073662-appb-000041
其中，PCB为帕布昔利布，PKI为变构的PKI-587；
Figure PCTCN2018073662-appb-000042
其中，LPT为拉帕替尼，AZD为AZD5363；
Figure PCTCN2018073662-appb-000043
其中，LPT为拉帕替尼，PKI为变构的PKI-587；
Figure PCTCN2018073662-appb-000044
其中，LPT为拉帕替尼，PKI a为去末端双甲基的PKI-587。
上述如式I所示的中间体药物的制备方法，其包括：
步骤S1:将具有协同作用的至少两个所述抗癌药物分别与氨基酸、氨基酸的衍生物、二肽、二肽的衍生物、多肽或多肽的衍生物发生酰胺化反应，得到具有所述式I中N-AC结构单元的第一中间体。
优选地，所述第一中间体的合成方法包括：将带有氨基保护基团的氨基酸、氨基酸的衍生物、二肽、二肽的衍生物、多肽或多肽的衍生物在多肽缩合试剂的存在下，与抗癌药物进行酰胺化连接后，氨基去保护。
其中，多肽缩合试剂包括HBTU、HOBT、HBTU。反应中还加入了生物碱DIEA(N,N-二异丙基乙胺)，反应温度为-10～10℃，优选为-4～4℃。
为了增强反应的特异性，氨基酸或多肽及其衍生物上的氨基在反应前使用氨基保护基团进行保护，氨基保护基团为烷样羰基类氨基保护基，例如可以是叔丁氧羰基(Boc)、笏甲氧羰基(Fmoc)、苄氧羰基(Cbz)、三甲基硅乙氧羰基(Teoc)等。
步骤S2:将任意一个所述第一中间体与带有氨基的二羧酸、带有氨基的多羧酸、带有氨基的二羧酸相应的酰基取代物或者带有氨基的多羧酸相应的酰基取代物发生酰胺化反应，得到具有所述式I中Z-N-AC结构单元的第二中间体。
优选的，所述第二中间体的合成方法包括：将第一中间体与同时带有氨基保护基团和羧基保护基团的所述带有氨基的二羧酸、多羧酸或其相应的酰基取代物在PyAOP的存在下与第一中间体进行酰胺化连接后，羧基去保护。
更进一步的选择使用氨基被保护的谷氨酸叔丁酯、天冬氨酸叔丁酯，或者使用Fmoc保护的谷氨酸叔丁酯、Fmoc保护的天冬氨酸叔丁酯。同时保护氨基和羧基，有利于提高反应速率，减少副产物，降低偶联难度。
步骤S3:将所述第二中间体与剩余的所述第一中间体发生酰胺化反应，得到式I所示的中间体药物
Figure PCTCN2018073662-appb-000045
优选的，式I所示的所述中间体药物的合成方法还包括：将所述第二中间体与至少一个所述第一中间体在PyAOP以及2，4，6-三甲基吡啶的存在下于-10℃～10℃发生酰胺化反应，氨基去保护。
进一步地，先将至少两个或者两种抗癌药物先结合到一起，再将结合了至少两个或者两种抗癌药物的有机物与氨基酸或肽及其衍生物发生酰胺化反应，所述式I所示的药物中间体至少一个结合位点连接有至少两个或者两种抗癌药物。
该制备方法中选择氨基酸或多肽为连接链，制得酰胺化的抗癌药物，即第一中间体，降低至少两个抗癌药物同时与带有氨基的多羧酸偶联时的空间位阻，降低反应难度。且在该中间体药物中涉及的反应类型均为酰胺化反应，酰胺化反应的选择性高、反应速率块、异构体副产物少，因此使用该合成方法所得产品的收率高、反应速度快。由该方法制备的该具有协同抗癌活性的中间体药物或其衍生物、或其药学上可接受的盐，可用于制备抗癌药物，如制备单一的纳米药物中的多靶点有效载荷。制备抗癌药物时，可以添加赋形剂、或者制成各种便于给药的剂型。
上述具有协同抗癌活性的中间体药物或其衍生物、或其药学上可接受的盐，或者相应的抗癌药物可以用于治疗癌症。
本实施方式还提供一种如式II所示的聚乙二醇偶联协同抗癌药物或其衍生物、或其药学上可接受的盐；
Figure PCTCN2018073662-appb-000046
其中，PEG选自单臂或多臂的聚乙二醇或聚乙二醇的衍生物；X选自
Figure PCTCN2018073662-appb-000047
Figure PCTCN2018073662-appb-000048
Y选自带有氨基的羧酸或其相应的酰基取代物；
Figure PCTCN2018073662-appb-000049
如式I所示的具有协同抗癌活性的中间体药物，或衍生物、或其药学上可接受的盐；
m＝0、1或2；n＝1～5；j＝PEG的臂数。
本实施方式提供的式II化合物，以聚乙二醇为载体，通过延长链(Y)与上述制备得到的 中间体药物
Figure PCTCN2018073662-appb-000050
偶联，制得聚乙二醇偶联协同抗癌药物或衍生物，其不仅保留了抗癌药物各自的性能，还具有协同增效的作用，与单一的抗癌药物或者与
Figure PCTCN2018073662-appb-000051
相比，与聚乙二醇偶联后抗癌药物联用后毒性大幅度降低、水溶性和生物稳定性提高，且具有显著的被动靶向性，以及极低的多药耐药性。
PEG选自单臂或多臂的聚乙二醇或聚乙二醇的衍生物，PEG可以是单臂的聚乙二醇或者单臂的聚乙二醇的衍生物，也可以是多臂的聚乙二醇或者多臂的聚乙二醇的衍生物。优选地，PEG为单臂、双臂、四臂或八臂的聚乙二醇，或者PEG为单臂、双臂、四臂或八臂的聚乙二醇的衍生物；更为优选的，PEG的分子量为12000、20000、或40000道尔顿。
进一步的，Y选自
Figure PCTCN2018073662-appb-000052
其中，a＝0～8；b＝0～8；a、b不同时为0。可选的，a和b均为整数。Y为延长链，有利于增加支链的数量，降低与聚乙二醇偶联的难度，提高聚乙二醇偶联协同抗癌药物或衍生物中抗癌药物的释放效率。
更为优选地，所述Y选自
Figure PCTCN2018073662-appb-000053
(n＝1～1000)、
Figure PCTCN2018073662-appb-000054
Figure PCTCN2018073662-appb-000055
较为具体的，该聚乙二醇偶联协同抗癌药物或衍生物、或其药学上可接受的盐，其为如下任一化合物：
Figure PCTCN2018073662-appb-000056
其中，ABT为ABT-888，PKI为变构的PKI-587；
Figure PCTCN2018073662-appb-000057
其中，PCB为帕布昔利布，PKI为变构的PKI-587；
Figure PCTCN2018073662-appb-000058
其中，LPT为拉帕替尼，AZD为AZD5363；
Figure PCTCN2018073662-appb-000059
其中，LPT为拉帕替尼，PKI为变构的PKI-587；
Figure PCTCN2018073662-appb-000060
其中，LPT为拉帕替尼，PKI a为去末端双甲基的PKI-587。
一种如式II所示的聚乙二醇偶联协同抗癌药物或其衍生物、或其药学上可接受的盐的制备方法，其包括：
步骤S1：将式I所示的中间体药物与带有氨基的羧酸或其相应的酰基取代物发生酰胺化反应，得到具有式II中
Figure PCTCN2018073662-appb-000061
结构单元的第四中间体。
优选的，所述第四中间体的合成方法包括：将带有氨基保护基团的所述带有氨基的羧酸或其相应的酰基取代物在多肽缩合试剂的存在下，与所述第三中间体进行酰胺化连接后，氨基去保护。
步骤S2：将第四中间体与聚乙二醇或其衍生物通过酰胺键偶联，得到式II所示的产品。
从反应路线上分析，合成这种聚乙二醇偶联协同抗癌药物或衍生物还有一种方式，即先将一种抗癌药物偶联到聚乙二醇上之后，得到抗癌药物-聚乙二醇复合物；再将另一种或几种抗癌药物与所得到的抗癌药物-聚乙二醇复合物反应偶联得到以聚乙二醇为载体的抗癌双药或者抗癌多药。发明人经多年研究，发现在得到抗癌药物-聚乙二醇复合物后，由于空间位阻及反应的能垒高，很难在其结构上再引入第二个抗癌药物，采用这种方法合成时，产物收率低、副产物多，难以在工业上放大生产。而本实施方式提供的这种制备方法，即先合成抗癌双药或者抗癌多药，再将其通过延长链与聚乙二醇偶联，制法简单、反应温和、反应速率快、产率高，适合于工业化生产。
这种聚乙二醇偶联抗癌双药甚至聚乙二醇偶联抗癌多药，能够实现多靶点、多疗法同时给药，可以大幅度降低毒性，且有利于克服癌症的多药耐药性，具有协同增效的作用，可用于制 备抗癌药物，具有重大的临床价值和广阔的市场前景。
聚乙二醇偶联抗癌双药甚至聚乙二醇偶联抗癌多药或其衍生物、或其药学上可接受的盐，还可以进一步被加工成其他形式的抗癌药物，可以添加赋形剂、或者制成各种便于给药的剂型。
上述聚乙二醇偶联抗癌双药甚至聚乙二醇偶联抗癌多药或其衍生物、或其药学上可接受的盐，或者相应的抗癌药物可以用于治疗癌症。
以下结合实施例对本发明的特征和性能作进一步的详细描述：
第一实施例
合成如式I-1所示的具有协同抗癌活性的中间体药物：
Figure PCTCN2018073662-appb-000062
实施例1-1
制备：
Figure PCTCN2018073662-appb-000063
将甘氨酸(11.1194g，148.12mmol)加入1L圆底烧瓶中，加入1,4-二氧六环(150ml)溶解，加入磁子，加入2N NaOH(88.88ml，177.78mmol)，搅拌条件下加入Boc酸酐(48.5g，222.22mmol)。反应结束，将反应液移至旋转蒸发仪下浓缩，将浓缩液转移到1L分液漏斗中，加入乙醚100ml洗涤，重复两次。分离水相及有机相，水相加入1mol/L盐酸调pH至pH＝4。乙酸乙酯萃取水相(150ml×5),合并有机相，有机相加入无水硫酸钠干燥，抽滤，甲苯除水，蒸干，得化合物A-1，产率为100％。
实施例1-2
制备：
Figure PCTCN2018073662-appb-000064
在500ml圆底烧瓶中加入ABT-888(4.8448g，19.8301mmol，上海楼岚)，化合物A-1(4.1691g，23.7962mmol)，HBTU(11.2806g，29.7452mmol)，HOBT(4.0192g，29.7452mmol)，用N,N-二甲基甲酰胺(80ml)溶解。将溶液在0℃低温恒温反应浴中冷却20分钟，然后缓慢滴加DIEA(15.53ml，89.2356mmol)。2小时后移至室温，搅拌过夜。将反应液倒入饱和NaHCO 3溶液(200mL)中，用乙酸乙酯萃取(200mL×3)。然后用饱和碳酸氢钠溶液(200mL×2)淋洗，有机相用无水MgSO 4干燥，抽滤，加入硅胶粉做固体溶液。干法上样，柱层析二氯甲烷至7％甲醇/3％氨水/二氯甲烷梯度洗脱。收集产品，蒸干得化合物B-1 9.7g，产率100％。
实施例1-3
制备
Figure PCTCN2018073662-appb-000065
向500ml圆底烧瓶中加入化合物B-1(7.8g，19.4271mmol),加入二氯甲烷80ml溶解，搅拌条件下加入TFA(29.77ml，388.5430mmol)，室温过夜搅拌反应，反应结束，将反应液浓缩， 加入适量甲醇，使粗品溶解，并加入适量碳酸氢钠固体粉末中和多余的TFA，中和结束后，抽滤，滤液中加入适量硅胶粉做成固体溶液，干法上样，柱层析，1％甲醇/二氯甲烷至5％甲醇/二氯甲烷梯度洗脱，至1％氨水/5％甲醇/二氯甲烷至4％氨水/8％甲醇/二氯甲烷梯度洗脱。收集产品，蒸干得化合物C-1 4.8740g，产率87％。
实施例1-4
制备
Figure PCTCN2018073662-appb-000066
将化合物C-1(4.7g,15.5887mmol)、Fmoc保护的谷氨酸叔丁酯(9.2862g,21.8242mmol)、PyAOP(11.3787g,21.8242mmol)置于250ml圆底烧瓶中，然后加入100ml DMF，将混合液置于-5℃条件下搅拌30min，在此条件下缓慢滴加2,4,6-三甲基吡啶(2.06ml,15.5887mmol)，滴加完毕后，低温下反应2h，然后将反应液转移至零度冰箱中搅拌反应1天。反应结束，将反应液转移至2L的圆底烧瓶中，然后加入约800ml乙醚进行沉降，沉降后加入硅胶粉做固体溶液。干法上样，柱层析，1％甲醇/二氯甲烷至7％甲醇/二氯甲烷进行梯度洗脱，收集浓缩产品，得化合物D-1 9.6957g，产率为85.6％。
实施例1-5
制备
Figure PCTCN2018073662-appb-000067
向300ml圆底烧瓶中加入化合物D-1(9.6957g，13.3366mmol),加入二氯甲烷50ml溶解，搅拌条件下加入TFA(20.5ml，266.7318mmol)，室温过夜搅拌反应，反应结束，将反应液浓缩，加入适量甲醇，使粗品溶解，并加入适量碳酸氢钠固体粉末中和多余的TFA，中和结束后，抽滤，滤液中加入适量硅胶粉做成固体溶液，干法上样，柱层析，3％甲醇/二氯甲烷至8％甲醇/二氯甲烷梯度洗脱。蒸干，得化合物E-1 8.4g，产率93.9％。
ITMS+c ESI Full ms[120.00-1000.00][M+H +]：653.40，[M+Na +]：675.40，[M+K +]：691.32。
1H-NMR(400Hz，DMSO-d 6)δ12.70-12.00(m,1H),9.52-8.25(m,1H),8.25-7.75(m,4H),7.80-7.52(m,4H),7.49-7.10(m,4H),4.35-4.15(m,3H),4.15-3.90(m,3H),3.90-3.70(m,4H),2.75-2.60(m,1H),2.20-2.15(m,1H),2.15-1.95(m,2H),1.95-1.88(m,3H),1.86-1.81(m,1H),1.76-1.65(m,1H)。
实施例1-6
制备
Figure PCTCN2018073662-appb-000068
在500ml圆底烧瓶中加入变构的PKI-587(10g，17.43071mmol，长沙康鹏)，化合物A-1(3.665g，20.9169mmol)，HBTU(9.9156g，26.1461mmol)，HOBT(3.533g，26.1461mmol)，用N,N-二甲基甲酰胺(80ml)溶解。将溶液在0℃低温恒温反应浴中冷却20分钟，然后缓慢滴加DIEA(13.65ml，78.4382mmol)。2小时后移至室温，搅拌过夜。将反应液倒入饱和NaHCO 3溶液(200mL)中，用乙酸乙酯萃取(200mL×3)。合并有机相，有机相中加入硅胶粉做固体溶液，干法上样，柱层析，1％甲醇/二氯甲烷至5％甲醇/二氯甲烷梯度洗脱，至3％氨水 /6％甲醇/二氯甲烷洗脱。蒸干得化合物F-1，产率100％。
实施例1-7
制备
Figure PCTCN2018073662-appb-000069
向500ml圆底烧瓶中加入化合物F-1(12.7314g，17.4307mmol),加入二氯甲烷100ml溶解，搅拌条件下加入TFA(26.7ml，348.614mmol)，室温过夜搅拌反应，反应结束，将反应液浓缩，加入适量甲醇，使粗品溶解，并加入适量碳酸氢钠固体粉末中和多余的TFA，中和结束后，抽滤，滤液中加入适量硅胶粉做成固体溶液，干法上样，柱层析，二氯甲烷至3％甲醇/二氯甲烷梯度洗脱，至2％氨水/5％甲醇/二氯甲烷至6％氨水/7％甲醇/二氯甲烷梯度洗脱。收集产品，蒸干得化合物G-1 6.6g，产率60.1％
实施例1-8
制备
Figure PCTCN2018073662-appb-000070
将化合物E-1(3.8784g,5.9458mmol)、化合物G-1(2.5g,3.9638mmol)、PyAOP(3.10g,5.9458mmol)置于200ml圆底烧瓶中，然后加入20ml DMF，将混合液置于-5℃条件下搅拌30min，在此条件下缓慢滴加2,4,6-三甲基吡啶(0.52ml,3.9638mmol)，滴加完毕后，低温下反应2h，然后将反应液转移至零度冰箱中搅拌反应1天。第二天，追加11-58(1.0g，1.5855mmol)，2,4,6-三甲基吡啶(0.208ml,1.5855mmol)，将反应液转移至零度冰箱中反应，反应结束，将反应液转移至2L的圆底烧瓶中，然后加入无水乙醚进行沉降，加入硅胶粉做固体溶液，干法上样，柱层析，1％甲醇/二氯甲烷至6％甲醇/二氯甲烷进行梯度洗脱，至2％氨水/6％甲醇/二氯甲烷至4％氨水/7％甲醇/二氯甲烷梯度洗脱收集浓缩产品，得化合物H-1 3.3g，产率78％。
实施例1-9
制备
Figure PCTCN2018073662-appb-000071
向500ml圆底烧瓶中加入化合物H-1(3.25g，2.5700mmol),加入DMF(15ml)溶解，搅拌条件下加入吗啉(3.7ml，77.0995mmol)，室温条件下搅拌3小时，反应结束。将反应液转移至2L圆底烧瓶中，加入无水乙醚沉降，除去乙醚相，沉降物用适量的甲醇/二氯甲烷溶解，抽干。湿法上样，柱层析，5％甲醇/二氯甲烷，至4％氨水/9％甲醇/二氯甲烷洗脱。蒸干，得化合物I-1 2.7g，产率100％。
ITMS+c ESI Full ms[300.00-1600.00][M+H +]:1043.61,[M+Na +]:1065.64
1H-NMR(400Hz，DMSO-d 6)δ12.70-12.30(m,1H),9.35-9.20(m,1H),9.10-8.95(m,2H),8.35-8.25(m,2H),8.15-8.05(m,1H),7.85-7.75(m,1H),7.70-7.65(m,1H),7.60-7.50(m,4H),7.40-7.35(m,2H),7.30-7.20(m,1H),4.15-4.05(m,6H),4.03-3.95(m,2H),3.96-3.90(m,2H),3.90-3.70(m,11H),3.54-3.43(m,7H),3.42-3.40(m,1H),3.15-3.10(m,1H),2.25-2.14(m,3H),2.14-2.06(m,2H),2.06-1.97(m,3H),1.96-1.92(m,1H),1.90-1.86(m,3H),1.85-1.80(m,1H), 1.62-1.50(m,1H)。
第二实施例
合成如式D-2所示的聚乙二醇偶联协同抗癌药物或衍生物：
Figure PCTCN2018073662-appb-000072
实施例2-1
制备
Figure PCTCN2018073662-appb-000073
向1L圆底烧瓶中加入磁子，加入H 2NCH 2CH 2OCH 2CH 2OH(9.542ml，95.1113mmol)，加入二氯甲烷150ml溶解，加入三乙胺(26.5133ml，190.2226mmol)，搅拌条件下加入Boc酸酐(24.9096g，114.1335mmol)。反应结束，将反应液转移至旋转蒸发仪下浓缩，加入甲醇溶解，搅拌条件下加入碳酸氢钠粉末(13g)中和三乙胺，抽滤，加入硅胶粉做固体溶液。干法上样，柱层析10％乙酸乙酯/石油醚至50％乙酸乙酯/石油醚梯度洗脱，3％甲醇/乙酸乙酯至6％甲醇/乙酸乙酯梯度洗脱。收集产品，蒸干得到化合物
Figure PCTCN2018073662-appb-000074
16.3341g，产率83.77％。
将化合物
Figure PCTCN2018073662-appb-000075
(16.334g，75.581mmol)放入1L圆底烧瓶中，加入四氢呋喃200ml，将反应液置于-5℃条件下搅拌，通氮气保护下通过分液器逐滴滴加叔丁醇钾(75.58ml，75.581mmol)，40min后，加入溴乙酸乙酯(10.56ml，95.4972mmol)，将温度调至0℃，搅拌三小时后，将反应液转移至室温搅拌过夜。反应完毕，向反应液中加入100ml水，置于旋转蒸发仪下浓缩。将反应液转移至1L的分液漏斗中，加入100ml水，乙酸乙酯萃取(100ml×2)，合并有机相。有机相用无水硫酸钠干燥，抽滤，加入硅胶粉做成固体溶液，干法上样，柱层析，用10％乙酸乙酯/石油醚至35％乙酸乙酯/石油醚进行梯度洗脱。收集产品，蒸干得化合物
Figure PCTCN2018073662-appb-000076
15.0g，产率68.13％
将化合物
Figure PCTCN2018073662-appb-000077
(15g，51.4862mmol)放入500ml圆底烧瓶中，加入1,4-二氧六环(100ml)，在搅拌条件下加入氢氧化锂(5.28g，113.2697mmol)，滴加水，直至溶液呈现澄清的黄色。反应完成后，将反应液置于旋转蒸发仪下旋转浓缩，将反应液转移至1L分液漏斗中，加入50ml水，加入正己烷:乙醚1:1(200ml×2)萃取。分液后，向水相中滴加盐酸(1mol/L)直至pH＝1.乙酸乙酯萃取水相(100ml×4)，合并有机相，无水硫酸钠干燥有机相，抽滤，甲苯除水，于旋转蒸发仪上旋转蒸干，得化合物A-2。
实施例2-2
制备
Figure PCTCN2018073662-appb-000078
在500ml圆底烧瓶中加入化合物I-1(2.5g，2.3965mmol)，化合物A-2(0.9458g，3.5974mmol)，HBTU(1.3633g，3.5974mmol)，HOBT(0.4857g，3.5974mmol)，用N,N-二甲基甲酰胺(30ml)溶解。将溶液在0℃低温恒温反应浴中冷却20分钟，然后缓慢滴加DIEA(1.9ml，10.7481mmol)。2小时后移至室温，搅拌过夜。反应结束，将反应液转移至2L圆底烧瓶中，加入无水乙醚沉降，除去乙醚相，沉降物用适量的甲醇/二氯甲烷溶解，抽干。湿法上样，柱层析，4％甲醇/二氯甲烷，至2％氨水/4％甲醇/二氯甲烷至3％氨水/8％甲醇/二氯甲烷洗脱。蒸干，化合物B-2 3.0g，产率97％。
实施例2-3
制备
Figure PCTCN2018073662-appb-000079
向500ml圆底烧瓶中加入化合物B-2(2.95g，2.2890mmol),加入二氯甲烷20ml溶解，搅拌条件下加入TFA(3.5ml，45.7932mmol)，室温过夜搅拌反应，反应结束，将反应液浓缩，加入适量甲醇，使粗品溶解，并加入适量碳酸氢钠固体粉末中和多余的TFA，中和结束后，抽滤，湿法上样，柱层析，5％甲醇/二氯甲烷洗脱，至2％氨水/6％甲醇/二氯甲烷至3％氨水/8％甲醇/二氯甲烷梯度洗脱。收集产品，蒸干得化合物C-2 2.6229g，产率96.5％
ITMS+c ESI Full ms[400.00-1800.00][M+H +]:1188.78,[M+Na +]:1210.69。
1H-NMR(400Hz，DMSO-d 6)δ12.60-12.40(m,1H),9.45-9.20(m,3H),8.30-8.25(m,2H),8.20-8.10(m,1H),8.00-7.92(m,1H),7.80-7.75(m,2H),7.75-7.70(m,1H),7.70-7.60(m,1H),7.60-7.50(m,5H),7.40-7.35(m,2H),4.40-4.35(m,1H),4.15-4.00(m,3H),4.00-3.85(m,6H),3.88-3.75(m,8H),3.75-3.70(m,2H),3.70-3.60(m,9H),3.60-3.55(m,7H),3.55-3.40(m,2H),3.20-3.10(m,4H),3.00-2.90(m,2H),2.20-2.05(m,4H),2.05-1.95(m,3H),1.90-1.85(m,4H),1.80-1.70(m,1H)。
实施例2-4
制备
Figure PCTCN2018073662-appb-000080
向200ml圆底烧瓶中加入化合物C-2(2.3766g，2mmol)，加入二氯甲烷15ml溶解，并加入DMF(15ml)助溶。加入高分子聚乙二醇4ARM-SCM-40K(10g，0.25mmol，北京键凯)， 加入磁子，搅拌器12转/min条件下搅拌。反应完成，将反应液转移至2L圆底烧瓶中，加入无水乙醚沉降，抽滤。抽滤物加入二氯甲烷溶解，湿法上样。柱层析，二氯甲烷至5％甲醇/二氯甲烷，至4％氨水/8％甲醇/二氯甲烷梯度洗脱。收集产品，蒸干得化合物D-2 10.2g。
MALDI-TOF-MS[25000-60000]42124-45870；最高峰：44322
1H-NMR(400Hz，DMSO-d 6)δ12.60-12.40(m,4H),9.30-9.20(m,4H),9.10-9.05(m,4H),9.05-8.95(m,4H),8.30-8.25(m,10H),8.17-8.05(m,4H),7.95-7.90(m,2H),7.73-7.75(m,5H),7.75-7.65(m,5H),7.65-7.58(m,5H),7.58-7.52(m,17H),7.40-7.35(m,9H),7.23-7.18(m,4H),7.15-7.06(m,3H),4.40-4.30(m,5H),4.10-4.00(m,5H),4.00-3.90(m,5H),3.90-3.85(m,24H),3.80-3.70(m,20H),3.60-3.45(m,9130H),3.45-3.40(m,44H),3.40-3.35(m,64H),3.20-3.15(m,4H),3.06-2.85(m,9H),2.40-2.30(m,15H),2.05-1.95(m,12H),1.80-1.70(m,9H)。
第三实施例
合成如式I-3所示的具有协同抗癌活性的中间体药物：
Figure PCTCN2018073662-appb-000081
实施例3-1
制备
Figure PCTCN2018073662-appb-000082
在500ml圆底烧瓶中加入帕布昔利布(6.0g，13.4078mmol，北京安司莫森)，化合物A-1(2.8189g，16.0894mmol)，HBTU(7.6272g，20.1117mmol)，HOBT(2.7191g，20.1117mmol)，用N,N-二甲基甲酰胺(75ml)溶解。将溶液在0℃低温恒温反应浴中冷却20分钟，然后缓慢滴加DIEA(10.5ml，60.3351mmol)。2小时后移至室温，搅拌过夜。将反应液倒入饱和NaHCO 3溶液(200mL)中，用乙酸乙酯萃取(200mL×2)合并有机相，有机相用无水MgSO4干燥，抽滤。蒸干得化合物
Figure PCTCN2018073662-appb-000083
产品8.4g，产率100％。
向300ml圆底烧瓶中加入化合物B-3(8.1077g，13.4078mmol),加入二氯甲烷80ml溶解，搅拌条件下加入TFA(20.5ml，268.156mmol)，室温过夜搅拌反应，反应结束，将反应液浓缩，加入适量甲醇，使粗品溶解，并加入适量碳酸氢钠固体粉末中和多余的TFA，中和结束后，抽滤，滤液中加入适量硅胶粉做成固体溶液，干法上样，柱层析，1％甲醇/二氯甲烷至2％甲醇/二氯甲烷梯度洗脱，至1％氨水/4％甲醇/二氯甲烷至5％氨水/7％甲醇/二氯甲烷梯度洗脱。收集产品，蒸干得化合物C-3 5.0428g，产率75％
实施例3-2
制备
Figure PCTCN2018073662-appb-000084
将化合物C-3(5.0428g,9.9917mmol)、Fmoc保护的谷氨酸叔丁酯(5.9520g,13.9884mmol)、PyAOP(7.2933g,13.9884mmol)置于300ml圆底烧瓶中，然后加入100ml DMF，将混合液置于-5℃条件下搅拌30min，在此条件下缓慢滴加2,4,6-三甲基吡啶(1.32ml,9.9917mmol)，滴加 完毕后，低温下反应2h，然后将反应液转移至零度冰箱中搅拌反应1天。反应结束，将反应液转移至2L的圆底烧瓶中，然后加入约500ml乙醚进行沉降，沉降后加入硅胶粉做固体溶液。干法上样，柱层析，1％甲醇/二氯甲烷至7％甲醇/二氯甲烷进行梯度洗脱，收集浓缩产品，得化合物
Figure PCTCN2018073662-appb-000085
7.9g产率86.7％。
向500ml圆底烧瓶中加入化合物D-3(7.9g，8.6637mmol),加入二氯甲烷80ml溶解，搅拌条件下加入TFA(13.3ml，170.3274mmol)，室温过夜搅拌反应，反应结束，将反应液转移至旋转蒸发仪下浓缩，加入少量二氯甲烷溶解，加入正己烷沉降，反复沉降三次，可除去大部分杂质。产品加入适量甲醇，使粗品溶解，并加入适量碳酸氢钠固体粉末中和多余的TFA，中和结束后，抽滤。蒸干化合物E-3 7g，产率94.4％
ITMS+c ESI Full ms[200.00-1600.00][M+H +]:856.61,[M+Na +]:878.53,[M+K +]:894.52
1H-NMR(400Hz，DMSO-d 6)δ12.30-11.85(m,1H),10.30-10.20(m,1H),9.00-8.95(m,1H),8.10-8.05(m,1H),8.05-7.95(m,1H),7.85-7.80(m,1H),7.75-7.70(m,2H),7.65-7.60(m,1H),7.60-7.50(m,1H),7.50-7.40(m,2H),7.40-7.30(m,2H),5.90-5.75(m,1H),4.15-4.05(m,2H),4.05-3.95(m,1H),3.25-3.15(m,3H),2.65-2.60(m,2H),2.45-2.40(m,4H),2.35-2.30(m,5H),2.28-2.15(m,2H),2.00-1.83(m,3H),1.82-1.70(m,4H),1.65-1.52(m,2H),1.30-1.20(m,1H)。
实施例3-3
制备
Figure PCTCN2018073662-appb-000086
将化合物E-3(6.1075g,7.1349mmol)、化合物G-1(2.5g,3.9639mmol)、PyAOP(3.10g,5.9459mmol)置于200ml圆底烧瓶中，然后加入40ml DMF，将混合液置于-5℃条件下搅拌30min，在此条件下缓慢滴加2,4,6-三甲基吡啶(0.52ml,3.9639mmol)，滴加完毕后，低温下反应2h，然后将反应液转移至零度冰箱中搅拌反应1天。第二天，追加11-58(0.5g，0.7928mmol)，2,4,6-三甲基吡啶(0.10ml,0.7928mmol)，将反应液转移至零度冰箱中反应，反应结束，将反应液转移至2L的圆底烧瓶中，然后加入无水乙醚进行沉降，沉降抽干，湿法上样，柱层析，3％甲醇/二氯甲烷至6％甲醇/二氯甲烷进行梯度洗脱，至2％氨水/5％甲醇/二氯甲烷至3％氨水/6％甲醇/二氯甲烷梯度洗脱收集浓缩产品，得化合物
Figure PCTCN2018073662-appb-000087
1.5g，产率100％。
向500ml圆底烧瓶中加入H-3(6.4g，4.3606mmol),加入DMF15ml溶解，搅拌条件下加入吗啉(11.5ml，0.1308mmol)，室温条件下搅拌3小时，反应结束。将反应液转移至2L圆底烧瓶中，加入无水乙醚沉降，除去乙醚相，沉降物用适量的甲醇/二氯甲烷溶解，抽干。湿法上样，柱层析，4％甲醇/二氯甲烷至5％甲醇/二氯甲烷洗脱，至2％氨水/5％甲醇/二氯甲烷至4％氨水/8％甲醇/二氯甲烷洗脱。蒸干，得化合物I-3 5.9g，产率100％。
ITMS+c ESI Full ms[200.00-1600.00][M+H +]:1246.82,[M+Na +]:1268.76
1H-NMR(400Hz，DMSO-d 6)δ10.20-10.00(m,1H),9.10-9.00(m,1H),9.05-8.90(m,2H),8.35-8.25(m,2H),8.10-8.00(m,2H),7.90-7.80(m,1H),7.60-7.45(m,5H),7.45-7.35(m,2H),5.85-5.80(m,1H),4.17-4.12(m,1H),4.06-4.02(m,1H),4.00-3.97(m,1H),3.97-3.90(m,2H),3.90-3.70(m,8H),3.70-3.55(m,13H),3.55-3.40(m,8H),3.30-3.27(m,3H),3.25-3.20(m,3H), 3.15-3.10(m,2H),2.30-2.20(m,4H),1.95-1.85(m,3H),1.84-1.72(m,3H),1.70-1.50(m,3H)。
第四实施例
合成如式C-4所示的聚乙二醇偶联协同抗癌药物或衍生物：
Figure PCTCN2018073662-appb-000088
实施例4-1
制备
Figure PCTCN2018073662-appb-000089
在500ml圆底烧瓶中加入化合物I-3(5.8g，4.6564mmol)，化合物A-2(1.8376g，6.9846mmol)，HBTU(2.4688g，6.9846mmol)，HOBT(1.3086g，6.9846mmol)，用N,N-二甲基甲酰胺(50ml)溶解。将溶液在0℃低温恒温反应浴中冷却20分钟，然后缓慢滴加DIEA(3.65ml，20.9538mmol)。2小时后移至室温，搅拌过夜。反应结束，将反应液转移至2L圆底烧瓶中，加入无水乙醚沉降，除去乙醚相，沉降物用适量的甲醇/二氯甲烷溶解，抽干。湿法上样，柱层析，4％甲醇/二氯甲烷，至2％氨水/4％甲醇/二氯甲烷至3％氨水/8％甲醇/二氯甲烷洗脱。蒸干，得化合物
Figure PCTCN2018073662-appb-000090
6.2g，产率89.8％
向500ml圆底烧瓶中加入化合物A-4(6.1g，4.0893mmol),加入二氯甲烷20ml溶解，搅拌条件下加入TFA(6.3ml，81.7859mmol)，室温过夜搅拌反应，反应结束，将反应液浓缩，加入适量甲醇，使粗品溶解，并加入适量碳酸氢钠固体粉末中和多余的TFA，中和结束后，抽滤，湿法上样，柱层析，5％甲醇/二氯甲烷，至2％氨水/5％甲醇/二氯甲烷至4％氨水/8％甲醇/二氯甲烷梯度洗脱。收集产品，蒸干化合物B-4 4.9g，产率86％
ITMS+c ESI Full ms[300.00-1600.00][M+H +]:1391.84,[M+Na +]:1413.77
1H-NMR(400Hz，DMSO-d 6)δ10.15-10.05(m,1H),9.15-9.05(m,1H),9.05-8.90(m,2H),8.35-8.20(m,3H),8.10-8.00(m,2H),7.75-7.60(m,2H),7.60-7.55(m,4H),7.45-7.30(m,2H),5.85-5.80(m,1H),4.45-4.35(m,1H),4.25-4.10(m,1H),4.10-3.90(m,4H),3.90-3.85(m,3H),3.85-3.70(m,7H),3.70-3.55(m,29H),3.40-3.35(m,6H),3.30-3.25(m,3H),3.25-3.10(m,3H),2.60-2.57(m,1H),2.45-2.40(m,2H),2.35-2.30(m,2H),2.30-2.18(m,3H),2.05-1.75(m,5H),1.65-1.45(m,2H).
实施例4-2
制备
Figure PCTCN2018073662-appb-000091
向200ml圆底烧瓶中加入化合物A-4(2.7832g，2mmol)，加入二氯甲烷15ml溶解，并加入DMF(15ml)助溶。加入高分子4ARM-SCM-40K(10g，0.25mmol，北京键凯)，加入磁子缓慢搅拌。反应完成，将反应液转移至2L圆底烧瓶中，加入无水乙醚沉降，抽滤。抽滤物加入二氯甲烷溶解，湿法上样。柱层析，二氯甲烷至5％甲醇/二氯甲烷，至4％氨水/8％甲醇/二氯甲烷梯度洗脱。收集产品，蒸干得化合物C-4 10.8g。
MALDI-TOF-MS[25000-60000]45172-48292，最高峰：46670
1H-NMR(400Hz，DMSO-d 6)δ10.15-10.05(m,4H),9.15-9.05(m,4H),9.05-8.90(m,8H),8.35-8.25(m,12H),8.10-8.05(m,8H),7.90-7.85(m,4H),7.75-7.62(m,8H),7.60-7.50(m,16H),7.40-7.30(m,8H),5.90-5.80(m,4H),4.45-4.35(m,5H),4.20-4.10(m,6H),4.10-3.95(m,16H),3.95-3.85(m,26H),3.85-3.70(m,38H),3.70-3.60(m,78H),3.60-3.58(m,39H),3.58-3.40(m,3559H),3.40-3.35(m,25H),3.25-3.10(m,14H),2.30-2.20(m,13H),2.00-1.70(m,22H),1.65-1.53(m,8H)。
第五实施例
合成如式I-5所示的具有协同抗癌活性的中间体药物：
Figure PCTCN2018073662-appb-000092
合成路线如图1所示：
实施例5-1
制备
Figure PCTCN2018073662-appb-000093
将化合物A-1(3.0148g，17.2099mmol)，拉帕替尼(10g,17.2099mmol，武汉远成共创科技有限公司)，HBTU(9.6881g,25.8149mmol)，HOBT(3.4881g,25.8149mmol)加入至500mL的圆底烧瓶中,用DMF(150mL)溶解，将溶液在-5℃低温恒温反应仪中冷却20分钟，然后缓慢滴加DIEA(13.4902mL,77.4447mmol)。反应2h后移至室温搅拌，过夜。反应停止，将反应液转移至2L得分液漏斗中，加入300mL饱和NaHCO 3溶液，然后用乙酸乙酯萃取三次，合并有机相，再用饱和NaHCO 3溶液和饱和食盐水分别淋洗一次，将最终有机相用无水MgSO 4干燥，抽滤，然后减压浓缩将液体蒸干得化合物
Figure PCTCN2018073662-appb-000094
12.70g，产率100％。
将化合物B-5(12.7g,17.2099mmol)置于圆底烧瓶中，用50ml CH 2Cl 2溶解，搅拌条件下加入TFA(26.4mL，344.1985mmol)，室温搅拌过夜。反应结束，减压浓缩，用适量无水甲醇溶解，加入NaHCO 3固体粉末中和剩余的TFA。中和完全，过滤，滤液中加入适量硅胶粉，做成固体溶液，干法上样。柱层析，先用5％甲醇/二氯甲烷洗脱，再用2.5％氨水/7％甲醇/二氯甲 烷至5％氨水/10％甲醇/二氯甲烷进行梯度洗脱。收集产品，减压浓缩蒸干得化合物
Figure PCTCN2018073662-appb-000095
(C-5):10.98g,产率99.6％.
将化合物C-5(9g,14.1013mmol)、Fmoc保护的谷氨酸叔丁酯(8.40g,19.7418mmol)、PyAOP(10.2930g,19.7418mmol)置于1L圆底烧瓶中，然后加入260ml DMF，将混合液置于-5℃条件下搅拌30min，在此条件下缓慢滴加2,4,6-三甲基吡啶(1.86ml,14.1013mmol)，滴加完毕后，低温下反应2h，然后将反应液转移至零度冰箱中搅拌反应2天。反应结束，将反应液转移至1L的分液漏斗中，然后加入约300ml饱和食盐水，用乙酸乙酯萃取三次，合并有机相，并用饱和食盐水淋洗两次，合并有机相，浓缩蒸干，用适量二氯甲烷溶解，湿法上样，柱层析，先用二氯甲烷洗脱，再用1％甲醇/二氯甲烷至6％甲醇/二氯甲烷进行梯度洗脱，收集浓缩产品，得化合物
Figure PCTCN2018073662-appb-000096
14.7g,产率99％。
在烧瓶中加入化合物D-5(14.7g,28.6884mmol)用100ml二氯甲烷溶解，在室温下搅拌，然后再搅拌条件下缓慢滴加三氟乙酸(TFA)(44mL，573.7674mmol)，置于室温搅拌过夜。反应结束，停止反应，用旋转蒸发仪减压旋蒸蒸干，将蒸干的粗品用二氯甲烷溶解，用正己烷沉降，倒去正己烷相，重复三次，出去大量杂质，收集产品，减压浓缩蒸干得化合物E-5:13.9g,产率99.6％。
ITMS-c ESI Q 1MS[200.00-1100.00][M-H +]:987.41
ITMS+c ESIQ 1MS[200.00-1100.00][M+H +]:989.32
实施例5-2
制备去末端双甲基的PKI-587(即PKI a)的过程：
将P-5(4.2g，8.31mmol)投入反应瓶中，加入NMP(40ml),再依次加入DIEA(6.44g,49.86mmol)和HBTU(15.76g，41.35mmol),室温搅拌溶解1小时，加入tert-butyl piperidin-4-ylcarbamate(6.66g，33.23mmol),室温条件下反应三夜，停止反应，加入水和DCM，分层，水层用DCM萃取两次，合并有机相，水洗四次，饱和碳酸氢钠水溶液和饱和食盐水各洗涤一次，无水硫酸镁干燥，减压浓缩得油状物，室温下加入甲醇42ml，析晶半小时，过滤，滤液干燥得浅红色固体4.2g，产率73.5％。
ITMS+c ESI Full ms[150.00-1200.00][M+H +]688.35。
将上述浅红色固体(3g，4.36mmol)投入反应瓶中，加入二氧六环45ml，冰浴下滴加5M HCl(15ml)，滴加完毕后，室温条件下反应48h，停止反应，过滤，滤饼用碳酸氢钠溶液洗涤，甲醇洗涤得白色固体，真空干燥得PKI a 2.2g，产率85％。
1H-NMR(400Hz，DMSO-d 6)δ9.60-9.40(m,2H),8.45-8.25(m,2H),7.80-7.60(m,1H),7.60-7.51(m,4H),7.40-7.25(m,2H),4.00-3.55(m,18H),3.40-2.98(m,3H),1.90-1.60(m,2H),1.50-1.30(m,3H)
ITMS+c ESI Full ms[150.00-1200.00][M+H +]588.37。
实施例5-3
制备
Figure PCTCN2018073662-appb-000097
将PKI a(1g,1.7027mmol)、化合物A-1(328.11mg,1.8730mmol)、HBTU(958.51mg,2.5541mmol)和HOBT(345.10mg,2.5541mmol)置于500ml圆底烧瓶中，然后加入15ml DMF，将混合液置于-5℃条件下搅拌，在此条件下缓慢滴加DIEA(1.33ml,7.6622mmol)，滴加完毕后，低温下反应2h，然后将反应液转移至室温搅拌过夜反应。反应结束，将反应液转移至2L的分液漏斗中，加入200ml的饱和碳酸氢钠溶液，用乙酸乙酯萃取三次，合并有机相，用饱和食盐水淋洗两次，合并有机相，用无水硫酸镁干燥，过滤，滤液浓缩蒸干，然后用适量二氯甲烷溶解，准备湿法上样，柱层析，用3％甲醇/二氯甲烷至8％甲醇/二氯甲烷梯度洗脱，收集浓缩，得纯产品化合物
Figure PCTCN2018073662-appb-000098
1.6293g,产率100％。
将化合物F-5(500mg，0.6716mmol)置于200ml圆底烧瓶中，加入约10ml二氯甲烷使其溶解，在搅拌条件下加入TFA(0.5ml,6.716mmol)，室温过夜搅拌反应，反应结束，将反应液浓缩，加入适量甲醇，使粗品溶解，并加入适量碳酸氢钠固体粉末中和多余的TFA，中和结束后，抽滤，滤液浓缩蒸干，然后用适量二氯甲烷溶解，湿法上样，柱层析，先用4％甲醇/二氯甲烷至7％甲醇/二氯甲烷进行梯度洗脱，最后用3％氨水/6％甲醇/二氯甲烷至4％氨水/8％甲醇/二氯甲烷梯度洗脱，收集产品，浓缩蒸干得化合物G-5:360mg。产率84％。
实施例5-4
制备
Figure PCTCN2018073662-appb-000099
将化合物G-5(2g,3.1011mmol)、化合物E-5(3.3761g,3.4112mmol)、PyAOP(2.2643g,4.3429mmol)置于100ml圆底烧瓶中，然后加入50ml DMF，将混合液置于-5℃条件下搅拌30min，在此条件下缓慢滴加2,4,6-三甲基吡啶(0.41ml,3.1011mmol)，滴加完毕后，低温下反应2h，然后将反应液转移至-2℃条件下搅拌过夜反应。反应结束，将反应液用无水乙醚沉降，倒去乙醚相，重复两次，沉降物用适量二氯甲烷溶解，湿法上样，柱层析，先用2％甲醇/二氯甲烷至8％甲醇/二氯甲烷进行梯度洗脱，最后用3％氨水/8％甲醇/二氯甲烷洗脱，收集浓缩产品，得化合物H-5 4g,产率100％。
将化合物H-5(4g，2.4745mmol)置于500ml圆底烧瓶中，加入约20mlDMF使其溶解，在搅拌条件下加入吗啉(6.5ml,74.2364mmol)，室温搅拌反应3h，反应结束，将反应液用乙醚沉降，出去大量紫外杂质，倒去乙醚相，然后将沉淀物用甲醇和二氯甲烷混合液溶解，准备湿法上样，柱层析，先用3％甲醇/二氯甲烷至8％甲醇/二氯甲烷进行梯度洗脱，最后用3％氨水/8％甲醇/二氯甲烷梯度洗脱，收集产品，浓缩蒸干得化合物I-5 2.23g。产率70％。
1H-NMR(400Hz，DMSO-d 6)δ9.95-9.85(m,1H),9.10-9.00(m,1H),8.97-8.88(m,1H),8.76-8.70(m,1H),8.60-8.50(m,1H),8.40-8.33(m,1H),8.32-8.25(m,2H),8.24-8.16(m,1H),8.05-7.95(m,2H),7.92-7.83(m,1H),7.82-7.78(m,1H),7.75-7.65(m,1H),7.59-7.43(m,5H),7.37-7.25(m,4H),7.21-7.15(m,1H),7.15-7.03(m,1H),6.70-6.55(m,1H),5.35-5.20(m,2H),4.80-4.64(m,2H),4.40-4.10(m,3H),3.90-3.65(m,13H),3.64-3.58(m,9H),3.40-3.32(m,2H),3.10-3.00(m,3H),2.28-2.10(m,2H),1.90-1.67(m,6H),1.65-1.56(m,1H),1.40-1.28(m,2H)
ITMS+c ESI Full ms[200.00-2000.00][M+H +]:1394.38
第六实施例
合成如式F-6所示的聚乙二醇偶联协同抗癌药物或衍生物：
Figure PCTCN2018073662-appb-000100
合成路线如图2所示：
实施例6-1
制备
Figure PCTCN2018073662-appb-000101
将谷氨酸双苯甲酯(42.0g,128.2795mmol),Boc保护的谷氨酸(14.4122g,58.3089mmol),HBTU(65.6482g,174.9266mmol)和HOBT(23.6361g,174.9266mmol)的混合物溶于DMF(300mL)中，在-5℃的低温恒温反应浴冷却30分钟，滴加DIEA(91.41mL，524.7799mmol),滴加完毕后在-5℃的反应浴中继续反应1小时，然后将反应瓶转移至室温，反应两天后，将反应混合物转移至饱和碳酸氢钠溶液(400mL)，用乙酸乙酯萃取(300mL×3)，合并有机相用饱和碳酸氢钠溶液清洗两次(200mL×2)，用硫酸镁干燥，浓缩，在层析硅胶柱上，以10％-50％乙酸乙酯-石油醚洗脱液进行分离，得到
Figure PCTCN2018073662-appb-000102
16.1克。
将化合物A-6(16g,18.4760mmol)置于500mL的圆底烧瓶中，然后加入约二氯甲烷(50mL)使其溶解，搅拌条件下加入TFA(14.2mL,184.7596mmol)。室温条件下搅拌过夜，将反应液在旋转蒸发仪上浓缩，除去大量TFA，然后将粗品用甲醇溶解，加入NaHCO 3固体粉末，中和，过滤，浓缩干燥，通过10％-90％的乙酸乙酯-石油醚和5％的甲醇-乙酸乙酯完成柱层析分离，得到化合物
Figure PCTCN2018073662-appb-000103
24克。
将化合物B-6(14g,18.2796mmol)，BocNHCH 2CH 2OCH 2CH 2OCH 2COOH(7.2113g,27.4194mmol)，HBTU(13.7203g,76.5593mmol)和HOBT(4.9399g,36.5593mmol)置于500mL圆底烧瓶中，然后加入DMF(150mL)，在-5℃条件下搅拌20分钟，开始缓慢滴加DIEA(19.10mL, 109.6778mmol)，滴完后在-5℃继续反应2小时，置于室温，搅拌反应过夜，将反应液转移至盛有饱和NaHCO 3溶液(300mL)中，用乙酸乙酯(500mL)萃取，有机相溶液以硫酸镁干燥，过滤，浓缩，在硅胶柱上以15％-60％乙酸乙酯-石油醚和4-5％甲醇-乙酸乙酯纯化，得到
Figure PCTCN2018073662-appb-000104
7.5克。
实施例6-2
制备化合物E-6，结构见图2
将化合物I-5(2.23g,1.6014mmol)、化合物C-6(0.2588g,0.4mmol)、HBTU(0.9g,2.4mmol)、HOBT(0.3243g,2.4mmol)置于500ml圆底烧瓶中，然后加入30ml DMF，将混合液置于-5℃条件下搅拌30min，在此条件下缓慢滴加DIEA(1.25ml,7.2mmol)，滴加完毕后，低温下反应2h，然后将反应液转移至-2℃条件下搅拌过夜反应。反应结束，将反应液用无水乙醚沉降，倒去乙醚相，重复两次，沉降物用适量甲醇和二氯甲烷溶解，加入适量硅胶粉，做成固体溶液，准备干法上样，柱层析，先用2％二氯甲烷进行洗脱，再用3％氨水/7％甲醇/二氯甲烷至5％氨水/9％甲醇/二氯甲烷洗脱，收集浓缩产品，得氨基被Boc保护的E-6，即化合物D-6，1.6g,产率72％。
将化合物D-6(1.4g，0.2277mmol)置于200ml圆底烧瓶中，加入约15ml二氯甲烷使其溶解，在搅拌条件下加入TFA(0.52ml,6.8314mmol)，室温过夜搅拌反应，反应结束，将反应液用旋转蒸发仪浓缩，除去大量TFA，然后用甲醇和二氯甲醇溶解，用固体碳酸氢钠中和剩余的TFA，中和完毕后，过滤，滤液中加入适量硅胶粉，做成固体溶液，干法上样，柱层析，先用200ml二氯甲烷洗脱，然后用5％甲醇/二氯甲烷等度洗脱，最后用加入适量甲醇，使粗品溶解，并加入适量碳酸氢钠固体粉末中和多余的TFA，中和结束后，抽滤，滤液中加入适量硅胶粉做成固体溶液，干法上样，柱层析，用2％氨水/5％甲醇/二氯甲烷至3％氨水8％甲醇/二氯甲烷梯度洗脱，收集产品，浓缩蒸干得化合物E-6 1.09g。产率80％。
1H-NMR(400Hz，DMSO-d 6)δ9.95-9.75(m,4H),9.20-9.06(m,5H),89.06-8.95(m,4H),8.80-8.69(m,4H),8.64-8.50(m,4H),8.35-8.15(m,14H),8.15-8.06(m,3H),8.05-7.98(m,7H),7.94-7.85(m,4H),7.85-7.75(m,5H),7.75-7.66(m,4H),7.64-7.42(m,20H),7.40-7.22(m,19H),7.20-7.12(m,4H),7.10-7.00(m,3H),6.72-6.65(m,2H),6.60-6.50(m,2H),6.50-6.40(m,3H),5.35-5.15(m,8H),4.85-4.65(m,8H),4.40-4.00(m,26H),4.00-3.72(m,46H),3.71-3.53(m,45H),3.52-3.48(m,3H),3.45-3.40(m,4H),3.200-3.15(m,16H),3.10-2.95(m,14H),2.30-2.10(m,8H),2.05-1.85(m,6H),1.85-1.65(m,14H)
MALDI-TOF MS[5500-6500][M+H +]:6052,[M+Na +]:6079
实施例6-3
制备化合物F-6
将化合物E-6(1.09g,0.1802mmol)于200ml圆底烧瓶中，然后加入约30ml二氯甲烷和10mlDMF使化合物M-3溶解，最后加入Y-NHS-40K(5.0466g,0.1201mmol),室温条件下搅拌遮光反应，反应停止，用无水乙醚沉降，过滤，滤饼用二氯甲烷溶解，准备湿法上样，柱层析， 用二氯甲烷洗脱，再用5％甲醇/二氯甲烷洗脱，最后用3％氨水/8％甲醇/二氯甲烷洗脱，得F-6:5.7g。
MALDI-TOF MS：41503-43007
第七实施例
合成如式D-7所示的具有协同抗癌活性的中间体药物：
Figure PCTCN2018073662-appb-000105
合成路线如图3所示：
实施例7-1
制备
Figure PCTCN2018073662-appb-000106
将AZD5363(100mg,0.2335mmol，上海楼岚)、Boc-Gly(40.9041mg,0.2335mmol)、HBTU(131.4439mg,0.3502mmol)和HOBT(47.3253mg,0.3502mmol)置于100ml圆底烧瓶中，然后加入DMF(6ml)，使其溶解，将混合液置于-5℃条件下搅拌30min，然后缓慢滴加DIEA(0.183ml,1.0507mmol)，滴加完毕后，低温下反应2h，然后将反应温度升到0℃搅拌过夜反应。反应结束，将反应液转移至0.25L的分液漏斗中，加入30ml饱和碳酸氢钠溶液，然后用乙酸乙酯萃取两次(20ml×2)，合并有机相，再用饱和碳酸氢钠溶液淋洗两次(20ml×2l)有机相，合并有机相，将有机相用无水硫酸钠干燥，抽滤，滤液浓缩，湿法上样，柱层析，用3％甲醇/乙酸乙酯至4％甲醇/乙酸乙酯梯度洗脱，最后用4％三乙胺/甲醇/乙酸乙酯洗脱，收集浓缩，得化合物A-7 75.8mg,产率56％.
ITMS+c ESI Full MS[200.00-1100.00][M+H +]：586.31,[M+Na +]:608.27
将化合物A-7(1g，1.7080mmol)于100mL的圆底烧瓶中，用二氯甲烷(15mL)溶解，然后加入TFA(2.6mL,34.1618mmol)。室温条件下搅拌反应过夜。反应停止，将反应液减压浓缩蒸干，然后用适量甲醇溶解，搅拌条件下加入碳酸氢钠固体粉末中和剩余的TFA，中和结束后，过滤，滤液中加入适量硅胶粉，做成固体溶液，干法上样，柱层析，用2％氨水/5％甲醇/二氯甲烷至4％氨水/9％甲醇/乙二氯甲烷收集产品，浓缩蒸干得化合物B-7 763.8mg，产率100％。
ITMS+c ESI Full MS[120.00-1000.00][M+H +]:486.20，[M+Na +]:508.17
实施例7-2
制备
Figure PCTCN2018073662-appb-000107
将化合物B-7(83.58mg,0.1722mmol)、化合物E-3(170.4mg,0.1722mmol)、PyAOP(125.7mg,0.2410mmol)置于25ml圆底烧瓶中，然后加入DMF(3ml)，将混合液置于-5℃条件下搅拌30min，在此条件下缓慢滴加2,4,6-三甲基吡啶(0.06ml,0.1722mmol)，滴加完毕后，低温下反应2h，然后将反应液转移至零度冰箱中搅拌反应2天。反应结束，将反应液转移至0.25L的分液漏斗中，然后加入约20ml饱和食盐水，用乙酸乙酯萃取四次，合并有机相，浓缩蒸干，用 适量二氯甲烷溶解，湿法上样，柱层析，收集浓缩产品，得化合物
Figure PCTCN2018073662-appb-000108
250.92mg,产率99％。
将化合物C-7(128mg，0.08235mmol)置于50ml圆底烧瓶中，加入约DMF(1.2ml)使其溶解，在搅拌条件下加入吗啉(0.144ml,1.6470mmol)，室温搅拌反应3h，反应结束，将反应液用乙醚沉降，出去大量紫外杂质，倒去乙醚相，然后将沉淀物用二氯甲烷混合液溶解，准备湿法上样，柱层析，先用5％甲醇/二氯甲烷进行洗脱，再用3％氨水/8％甲醇/二氯甲烷洗脱，收集产品，浓缩蒸干得化合物D-7 108mg，产率99％。
1H-NMR(400Hz，DMSO-d 6)δ11.85-11.60(m,1H),10.00-9.80(m,1H),8.80-8.70(m,1H),8.60-8.50(m,1H),8.40-8.25(m,2H),8.25-8.15(m,2H),8.15-8.10(m,1H),8.02-7.98(m,1H),7.96-7.92(m,1H),7.85-7.76(m,1H),7.75-7.65(m,1H),7.51-7.44(m,1H),7.35-7.25(m,6H),7.24-7.12(m,2H),7.12-7.05(m,1H),6.73-6.65(m,1H),6.62-6.55(m,1H),.30-5.25(m,2H),4.91-4.82(m,1H),4.80-4.69(m,1H),4.65-4.50(m,1H),4.49-4.36(m,3H),4.34-4.26(m,1H),3.90-3.80(m,1H),3.80-3.70(m,3H),3.68-3.60(m,1H),3.40-3.30(m,3H),3.10-3.00(m,3H),2.35-2.20(m,2H),2.15-2.03(m,3H),2.20-1.85(m,2H),1.70-1.55(m,6H)
MALDI-TOF MS[1200-1300][M+Na+]:1256.6
ITMS+c ESIQ 1MS[300.00-1300.00][M+H +]:1234.76，[M+Na +]:1256.63
第八实施例
合成如式C-8所示的聚乙二醇偶联协同抗癌药物或衍生物：
Figure PCTCN2018073662-appb-000109
合成路线如图4所示：
将化合物D-7(0.95g,0.7702mmol)、化合物B-2(0.2026g,0.7702mmol)、HBTU(0.4336g,1.1554mmol)和HOBT(0.1561g,1.1554mmol)置于500ml圆底烧瓶中，然后加入DMF(80ml)，将混合液置于-5℃条件下搅拌，在此条件下缓慢滴加DIEA(0.6ml,3.4661mmol)，滴加完毕后，低温下反应1h，然后将反应液转移至室温搅拌过夜反应。反应结束，将反应液转移至1L的圆底烧瓶中，用正己烷沉降，倒去正己烷相，沉降物用甲醇和二氯甲烷溶解，加入适量硅胶粉，做成固体溶液，准备干法上样。柱层析，用2％氨水/4％甲醇/二氯甲烷至3％氨水/6％甲醇/二氯甲烷梯度洗脱，收集浓缩，得化合物A-8 660mg,产率58％。
将化合物A-8(650mg，0.4397mmol)置于100ml圆底烧瓶中，加入约15ml二氯甲烷使其溶解，在搅拌条件下加入TFA(0.67ml,8.7934mmol)，室温搅拌反应3h，反应结束，将反应液浓缩抽干，然后用适量得甲醇溶解，搅拌条件下加入固体碳酸氢钠粉末中和剩余的TFA，中和结束，过滤，滤液中加入适量硅胶粉，做成固体溶液，准备干法上样。柱层析，先用2％甲醇/二氯甲烷进行洗脱，再用2％氨水/5％甲醇/二氯甲烷至3％氨水/8％甲醇/二氯甲烷进行梯度洗脱，收集产品，浓缩蒸干得化合物B-8 550mg。产率91％。
将化合物B-8(550mg，0.3986mmol)置于100ml圆底烧瓶中，加入二氯甲烷(30ml)和DMF(6ml)使其溶解，然后加入4ARM-SCM-40K(2.8972g,0.06643mmol)，室温搅拌反应2周，反应结束，将反应液用无水乙醚沉降，过滤，滤饼用二氯甲烷溶解，湿法上样，柱层析，先用二氯甲烷进行洗脱，再用5％甲醇/二氯甲烷洗脱，最后用3％氨水/8％甲醇/二氯甲烷进行洗脱，收集产品，浓缩蒸干得化合物C-8 9-140 2.0g。产率71％。
1H-NMR(400Hz，DMSO-d 6)δ11.70-11.60(m,4H),10.00-9.75(m,4H),8.80-8.60(m,4H),8.60-8.50(m,4H),8.37-8.25(m,8H),8.25-8.15(m,4H),8.15-8.05(m,8H),8.04-7.98(m,4H),7.98-7.83(m,8H),7.82-7.78(m,4H),7.77-7.70(m,4H),7.38-7.25(m,32H),7.25-7.12(m,8H),7.11-7.05(m,4H),6.80-6.12(m,4H),6.70-6.55(m,4H),5.38-5.22(m,8H),4.91-4.82(m,4H),4.80-4.69(m,4H),4.58-4.50(m,4H),4.49-4.33(m,12H),4.30-4.15(m,8H),3.98-3.90(m,8H),3.85-3.74(m,16H),3.65-3.58(m,8H),3.59-3.48(m,4192.68H),3.40-3.35(m,24H),3.10-3.00(m,20H),2.30-2.18(m,8H),2.15-2.04(m,8H),2.04-1.92(m,12H),1.90-1.75(m,24H)
MALDI-TOF MS[40000-50000]最高峰46130.8。
第九实施例
合成如式J-9所示的药物中间体：
Figure PCTCN2018073662-appb-000110
实施例9-1
制备化合物
Figure PCTCN2018073662-appb-000111
将原料Boc-NH-GFLG-OBn(3.0054g,5.148mmol，购于南京药石科技股份有限公司)、10％钯/碳催化剂(75mg)加入到氢化反应装置中，然后加入DMF(30ml)使其溶解，并使溶剂没过搅拌子，封闭氢化反应装置，使用水泵抽出反应体系中的空气约3分钟，再充氢气，如此重复三次后，使氢化反应装置上的压力读数为18psi，然后在常温下搅拌反应过夜。通过TLC点板发现反应完成后进行后处理，取出反应液均匀滴加到装有压实硅澡土的抽滤漏斗，用DMF(20ml)清洗反应装置，直至反应器被清洗干净不含产物为止，得到
Figure PCTCN2018073662-appb-000112
(Boc-NH-GFLG-OH)的反应产物的DMF溶液，直接供下一步使用。
将上述产物Boc-NH-GFLG-OH(5.149mmol)、拉帕替尼(2.601g,4.477mmol，武汉远成共创科技有限公司)、HBTU(2.547g,6.715mmol)和HOBT(0.907g,6.715mmol)置于250ml圆底烧瓶中然后加入DMF(90ml)，使其溶解，将混合液置于-5℃条件下搅拌30min。然后缓慢滴加DIEA(3.33ml,20.147mmol)，滴加完毕后低温下反应2h，然后将反应装置放到室温条件下搅拌过夜反应。反应结束后，后处理得到化合物
Figure PCTCN2018073662-appb-000113
3.7347g，产率 79.025％。
将A-9(7.3782g,6.989mmol)于250ml的圆底烧瓶中，用二氯甲烷(75ml)溶解，然后加入TFA(5.192ml,69.89mmol)室温下搅拌反应过夜。反应停止，将反应液减压浓缩蒸干，然后加入适量乙酸乙酯溶解，转移到500ml的分液漏斗中，加入饱和碳酸氢钠(100ml)中和剩余的TFA，中和结束后分离有机相，用乙酸乙酯萃取水相中的产物，萃取3次(150ml*3)，合并有机相再用无水硫酸钠干燥，抽滤，浓缩，干法上样，柱层析，用4％甲醇/1％氨水/二氯甲烷洗脱，收集产品，浓缩，蒸干得到化合物B-9，4.7308g，产率70.85％。
1H NMR(400MHz,DMSO-d 6)δ9.86(s,1H),8.75-8.74(m,1H),8.56(s,1H),8.22-8.01(m,5H),7.82-7.73(m,2H),7.53-7.49(m,1H),7.33-7.11(m,11H),6.70-6.55(m,2H),5.27(s,2H),4.76-4.60(m,3H),4.38-4.26(m,3H),3.77-3.62(m,3H),3.39-3.37(m,1H),3.07-3.02(m,6H),2.86-2.82(m,1H),1.82(s,2H),1.61-1.49(m,3H),0.88-0.80(m,6H).
实施例9-2
制备化合物
Figure PCTCN2018073662-appb-000114
将化合物B-9，即GFLG-LPT(4.6g,4.81mmol)、Boc-NHCH 2CH 2O-CH 2CH 2OCH 2COOH(1.52g,5.772mmol,购于长沙康鹏医药有限公司)、HBTU(2.74g,7.22mmol)和HOBT(0.976g,7.22mmol)置于500ml圆底烧瓶中然后加入DMF(138ml)，使其溶解，将混合液置于-5℃条件下搅拌30min。然后缓慢滴加DIEA(3.58ml,21.65mmol)，滴加完毕后低温下反应2h，然后将反应装置放到室温条件下搅拌过夜反应。反应结束后，后处理得到化合物
Figure PCTCN2018073662-appb-000115
3.19g，产率55.38％。
将上述化合物(3.13g,2.61mmol)于100ml的圆底烧瓶中，用二氯甲烷(45ml)溶解，然后加入TFA(1.94ml,26.1mmol)室温下搅拌反应4天。反应停止，将反应液减压浓缩蒸干，然后加入适量乙酸乙酯溶解，转移到500ml的分液漏斗中，加入饱和碳酸氢钠(100ml)中和剩余的TFA，中和结束后分离有机相，用乙酸乙酯萃取水相中的产物，萃取3次(150ml*3)，合并有机相再用无水硫酸钠干燥，抽滤，浓缩，干法上样，柱层析，用4％甲醇/2％氨水/二氯甲烷洗脱，收集产品，浓缩，蒸干得到化合物C-9 2.072g，产率72.1％。
1H NMR(400MHz,DMSO-d6)δ8.75-8.74(m,1H),8.56(s,1H),8.14-8.12(m,3H),8.02-8.01(m,2H),7.82-7.73(m,3H),7.50-7.47(m,1H),7.35-7.11(m,11H),6.70-6.55(m,2H),5.27(s,2H),4.76-4.70(m,2H),4.59-4.53(m,1H),4.38-4.13(m,3H),3.89-3.75(m,5H),3.58-3.52(m,7H),3.37-3.34(m,1H),3.07-3.03(m,5H),2.80-2.77(m,1H),2.64-2.61(m,2H),1.98-1.47(m,5H),0.88-0.80(m,6H)；MALDI-TOF MS:[M+H +]1100.30,[M-H +]1098.25,[M+Na +]1122.25.
实施例9-3
制备化合物
Figure PCTCN2018073662-appb-000116
将Fmoc-Glu-OH(OtBu)(0.54g,1.27mmol)置于100ml圆底烧瓶中，然后加入DMF(21mL)使其溶解，随后加入化合物C-9,即LC-GFLG-LPT(1.0g,0.908mmol)、PyAOP(0.66g,1.27mmol)后置于0℃条件下搅拌30min，然后缓慢滴加2,4,6-三甲基吡啶(0.12ml,0.908mmol)，滴加完毕后在此低温下反应3天。反应结束后，后处理得到纯产物
Figure PCTCN2018073662-appb-000117
0.388g，合并得到产物1.419，产率94.2％。
MALDI-TOF MS:[M+H +]1507.45,[M-H +]1505.40,[M+Na +]1529.45.
将化合物D-9(1.35g,0.895mmol)置于100ml的圆底烧瓶中，用二氯甲烷(15ml)溶解，然后加入TFA(4.5ml)室温下搅拌反应过夜。反应停止，将反应液减压浓缩蒸干，然后加入二氯甲烷(5ml)溶解，加入正己烷(50ml)摇匀，使产物析出，放入冰箱中静止30min后，倒掉上清液，再次用二氯甲烷(5ml)溶解，加入正己烷(50ml)摇匀，使产物析出，放入冰箱中静止30min，重复此操作两次。将析出的产物减压浓缩蒸干，收集产品，得到E-9 1.585g。MALDI-TOF MS:[M-H +]1449.40.
实施例9-4
制备化合物
Figure PCTCN2018073662-appb-000118
将Boc-NH-GFLG-OH(10.297mmol)、变构的PKI-587(5.136g,8.954mmol，长沙康鹏)、HBTU(5.094g,13.431mmol)和HOBT(1.8149g,13.431mmol)置于250ml圆底烧瓶中然后加入DMF(95ml)，使其溶解，将混合液置于-5℃条件下搅拌30min。然后缓慢滴加DIEA(6.659ml,40.293mmol)，滴加完毕后低温下反应2h，然后将反应装置放到室温条件下搅拌过夜反应。反应结束后，将反应液转移到1L的分液漏斗中，加入饱和碳酸氢钠溶液(200ml)，用乙酸乙酯萃取三次(200ml*3)，合并有机相，再用饱和碳酸氢钠(100ml)清洗一次，然后用饱和氯化钠(100ml)除水后将有机相收集于2L的圆底烧瓶中，于冰箱中过夜放置结晶，抽滤，得到化合物
Figure PCTCN2018073662-appb-000119
9.1019g，产率96.98％。
1H NMR(400MHz,DMSO-d 6)δ9.43(d,J＝16.0Hz,2H),8.29-8.27(m,3H),7.95-7.88(m,2H),7.58-7.54(m,4H),7.40-7.38(m,2H),7.24-7.22(m,5H),6.93(t,J＝8.0Hz,1H),4.55-4.35(m,2H),3.98-3.51(m,28H),3.04-3.00(m,1H),2.89-2.69(m,1H),1.64-1.50(m,3H),1.36(s,9H),0.90-0.83(m,6H).MALDI-TOF MS:[M+H +]1048.50,[M-H +]1046.40,[M+Na +]1070.45.
将化合物F-9(3.007g,2.862mmol)于250ml的圆底烧瓶中，用二氯甲烷(35ml)溶解，然后加入TFA(2.125ml,28.62mmol)室温下搅拌反应过夜。反应停止，将反应液减压浓缩蒸干， 然后加入适量乙酸乙酯溶解，转移到500ml的分液漏斗中，加入饱和碳酸氢钠(100ml)中和剩余的TFA，中和结束后分离有机相，用乙酸乙酯萃取水相中的产物，萃取3次(150ml*3)，合并有机相发现有固体析出，抽滤，点TLC板发现析出的固体为产物，收集产品，得到化合物G-9 2.2522g，产率83.001％。 1H NMR(400MHz,DMSO-d 6)δ＝9.20(d,J＝12.0Hz,2H),8.30-8.27(m,4H),7.96-7.94(t,J＝8.0Hz,1H),7.58-7.54(m,4H),7.40-7.38(m,2H),7.26-7.24(m,5H),5.23(s,2H),4.63(s,1H),4.38-4.37(m,1H),3.99-3.50(m,28H),3.07-3.03(m,1H),2.80-2.77(m,1H),1.62-1.49(m,3H),0.91-0.84(m,6H).MALDI-TOF MS:[M+H +]948.40.
实施例9-5
制备化合物
Figure PCTCN2018073662-appb-000120
将化合物G-9，即GFLG-PKI(2.18g,2.299mmol)、Boc-NHCH 2CH 2O-CH 2CH 2OCH 2COOH(0.73g,2.759mmol)、HBTU(1.31g,3.449mmol)和HOBT(0.47g,3.449mmol)置于250ml圆底烧瓶中然后加入DMF(66ml)，使其溶解，将混合液置于-5℃条件下搅拌30min。然后缓慢滴加DIEA(1.71ml,10.346mmol)，滴加完毕后低温下反应2h，然后将反应装置放到室温条件下搅拌过夜反应。反应结束后，后处理得到产品，1.2286g，产率34.4％。 1H NMR(400MHz,DMSO-d 6)δ＝9.08(s,1H),8.98(s,1H),8.30-8.11(m,4H),7.89-7.77(m,2H),7.58-7.53(m,4H),7.40-7.38(m,2H),7.23-7.17(m,5H),6.79-6.77(t,J＝8.0Hz,1H),4.56-4.55(t,J＝4.0Hz,1H),4.36-4.34(m,1H),3.89-3.51(m,34H),3.36-3.33(m,2H),3.06-3.05(m,3H),2.78-2.76(m,1H),1.62-1.50(m,3H),1.36(s,9H),0.90-0.83(m,6H).
将上述所得产品(2.02g,1.69mmol)于100ml的圆底烧瓶中，用二氯甲烷(21ml)溶解，然后加入TFA(1.25ml,16.9mmol)室温下搅拌反应4天。反应停止，将反应液减压浓缩蒸干，然后加入适量乙酸乙酯溶解，转移到500ml的分液漏斗中，加入饱和碳酸氢钠(100ml)中和剩余的TFA，中和结束后分离有机相，用乙酸乙酯萃取水相中的产物，萃取3次(150ml*3)，合并有机相再用无水硫酸钠干燥，抽滤，浓缩，干法上样，柱层析，用6％甲醇/2％氨水/二氯甲烷洗脱，收集产品，浓缩，蒸干得到化合物H-9 1.057g，产率56.4％。
1H NMR(400MHz,DMSO-d 6)δ9.08(s,1H),9.05(s,1H),8.30-8.12(m,4H),7.90-7.82(m,2H),7.58-7.53(m,4H),7.40-7.38(m,2H),7.25-7.20(m,5H),4.56-4.55(t,J＝4.0Hz,1H),4.36-4.34(m,1H),3.89-3.51(m,34H),3.05-3.02(m,1H),2.79-2.62(m,3H),1.63-1.48(m,5H),0.90-0.83(m,6H).MALDI-TOF MS:[M+H +]1093.45,[M-H +]1091.40,[M+Na +]1115.40.
实施例9-6
制备化合物J-9：
将化合物E-9(1.30g,0.895mmol)置于100ml圆底烧瓶中，然后加入DMF(20ml)使其溶解，随后加入化合物H-9，即LC-GFLG-PKI(0.979g,0.895mmol)、PyAOP(0.56g,1.2mmol) 后置于0℃条件下搅拌30min，然后缓慢滴加2,4,6-三甲基吡啶(0.45ml,3.41mmol)，滴加完毕后在此低温下反应2天。反应结束后，将反应液转移到1000ml的分液漏斗中，加入去离子水(200ml)清洗，用乙酸乙酯洗反应瓶，用力摇匀分液漏斗中的混合相，分离有机相，用乙酸乙酯萃取三次(200ml*3)，合并有机相，再用饱和氯化钠(100ml)清洗三次。加入甲醇和二氯甲烷溶解附在瓶壁上的反应产物，合并产物，抽滤，滤液浓缩，干法上样，柱层析，用10％甲醇/二氯甲烷进行洗脱，收集浓缩，得到化合物
Figure PCTCN2018073662-appb-000121
1.123g，产率72.9％。
将化合物I-9(1.07g,0.423mmol)于100ml的圆底烧瓶中，用DMF(13ml)溶解，然后加入吗啉(1.11ml,12.7mmol)室温下搅拌反应2.5h，反应停止。将反应液转移到1000ml的分液漏斗中，加入饱和氯化钠(100ml)，用乙酸乙酯洗反应瓶，用力摇匀分液漏斗中的混合相，分离有机相，用乙酸乙酯萃取三次(200ml*3)，合并有机相，再用饱和氯化钠(100ml)清洗三次。加入甲醇和二氯甲烷溶解附在瓶壁上的反应产物，合并有机相产物，抽滤，滤液浓缩，干法上样，柱层析，用8％甲醇/2％氨水/二氯甲烷进行洗脱，收集浓缩，得到化合物J-9 0.5664g，产率74.9％。
第十实施例
合成如式C-9所示的聚乙二醇偶联抗癌药物或衍生物：
Figure PCTCN2018073662-appb-000122
将化合物J-9(0.55g,0.239mmol)、Boc-Gly(0.05g,0.286mmol)、HBTU(0.14g,0.359mmol)和HOBT(0.048g,0.359mmol)置于100ml圆底烧瓶中然后加入DMF(12ml)，使其溶解，将混合液置于-5℃条件下搅拌30min。然后缓慢滴加DIEA(0.18ml,1.08mmol)，滴加完毕后低温下反应2h，然后将反应装置放到室温条件下搅拌过夜反应。反应结束后，将反应液转移到1L的分液漏斗中，用乙酸乙酯洗反应瓶，加入去离子水(200ml)，摇匀，分离有机相，用乙酸乙酯萃取三次(200ml*3)，合并有机相，然后用饱和氯化钠(100ml)除水，抽滤，滤液浓缩，干法上样，柱层析，用6％甲醇/2％氨水/二氯甲烷进行洗脱，收集浓缩，得到化合物
Figure PCTCN2018073662-appb-000123
0.5723g,产率97.3％。
将化合物A-9(0.55g,0.223mmol)于100ml的圆底烧瓶中，用二氯甲烷(11mL)溶解，然后加入TFA(1.85ml,24.91mmol)室温下搅拌反应1天。反应停止，将反应液减压浓缩蒸干，然后加入适量乙酸乙酯溶解，转移到500ml的分液漏斗中，加入饱和碳酸氢钠(100mL)中和剩余的TFA，中和结束后分离有机相，用乙酸乙酯萃取水相中的产物，萃取5次(100mL×5)，合并有机相再用无水硫酸钠干燥，抽滤，浓缩，干法上样，柱层析，用6％甲醇/2％氨水/二氯甲烷洗脱，收集产品，浓缩，蒸干得到化合物
Figure PCTCN2018073662-appb-000124
0.474g，产率90.0％。 1H NMR(400MHz,DMSO-d 6)δ＝9.89-9.87(m,1H),9.13(s,1H),9.04(s,1H),8.75-8.74(m,1H),8.56(s,1H),8.50(d,J＝8.0Hz,1H),8.29(d,J＝12.0Hz,2H),8.22-8.12(m,5H),8.01-8.00(m,2H),7.91-7.87(m,2H),7.82-7.71(m,4H),7.55(t,J＝20.0Hz,4H),7.48(dd,J＝16.0,12.0Hz,2H),7.40-7.28(m,6H),7.23-7.06(m,12H),6.20(d,J＝4.0Hz,1H),5.27(s,2H),4.75-4.70(m,2H),4.58-4.54(m,2H),4.36-4.11(m,7H),3.98-3.74(m,21H),3.66-3.41(m,29H),3.22-3.16(m,5H),3.07-3.02(m,5H),2.76-2.67(m,3H),2.08(t,J＝8.0Hz,2H),1.84-1.74(m,2H),1.62-1.61(m,2H),1.52-1.49(m,3H),1.25-1.03(m,1H),0.90-0.79(m,12H).
将化合物B-9(0.400g,0.169mmol)置于100ml圆底烧瓶中，然后加入约二氯甲烷(20mL)和DMF(6mL)溶解，最后加入M-SCM-10K(1.495g,0.141mmol),室温条件下搅拌遮光反应3天，反应停止，浓缩，用无水乙醚沉降，过滤，滤饼用二氯甲烷溶解，准备湿法上样，柱层析，用二氯甲烷洗脱，再用5％甲醇/二氯甲烷洗脱，最后用3％氨水/8％甲醇/二氯甲烷洗脱，得化合物C-9 1.70g。 1H NMR(400MHz,DMSO-d 6)δ＝9.88-9.86(m,1H),9.10(s,1H),9.00(s,1H),8.75-8.73(m,1H),8.56(s,1H),8.29(d,J＝8.0Hz,2H),8.24-7.95(m,10H),7.87-7.71(m,6H),7.55(t,J＝16.0Hz,4H),7.48(dd,J＝16.0,8.0Hz,2H),7.40-7.06(m,16H),5.26(s,2H),4.75-4.70(m,2H),4.58-4.53(m,2H),4.35-4.34(m,3H),4.23-4.20(m,4H),3.98-3.41(m,992H),3.24-3.16(m,6H),3.06-3.02(m,5H),2.89-2.67(m,5H),2.07-1.93(m,2H),1.62-1.49(m,5H),1.24-1.07(m,1H),0.89-0.79(m,12H).MALDI-TOF MS范围：12100-13500。
第十一实施例
合成如式M-10的化合物的抗癌药物：
Figure PCTCN2018073662-appb-000125
步骤S1，对式A-10的化合物进行处理备用。
Figure PCTCN2018073662-appb-000126
将Boc-NH-GLG-OBn(6.0045g,13.7873mmol，南京药石)加入到氢化反应釜中，加入10％的Pd/C(0.1005g)，加入DMF(30mL)使其溶解，通入氢气，氢气压力为14psi，反应在室温下搅拌过夜。反应结束后，将反应液通过压紧的硅藻土层过滤，滤饼用DMF(20mL×3)清洗，滤液转移至250mL的圆底烧瓶中。
步骤S2，制备式B-10的化合物。
Figure PCTCN2018073662-appb-000127
将Palbociclib(7.1547g,15.9870mmol，简称PCB，北京安司莫森)、HBTU(9.0944g，23.9805mmol)、HOBT(3.2405g，23.9805mmol)加入到含有式A-10(6.3500g,18.3851mmol)DMF溶液的250mL烧瓶中，将反应置于-5℃条件下搅拌约20分钟,然后缓慢滴加DIEA(11.8906mL,71.9415mmol)，滴加完毕后，反应在-5℃搅拌1小时后，然后将反应置于室温下搅拌过夜。反应结束，将反应液转移到2L的烧杯中，加入800mL饱和碳酸氢钠溶液,析出固体，抽滤，滤饼用甲苯(100mLx5)除水，干燥，得到产品式B-10的化合物:12.1g,产率93.91％。 1H-NMR(400MHz,DMSO-d 6)δ10.17(s,1H),8.96(s,1H),8.10(dd,J＝12.0,4.2Hz,2H),7.88(t,J＝7.8Hz,2H),7.52(dd,J＝9.1,3.0Hz,1H),6.97(s,1H),5.94-5.61(m,1H),4.39(s,1H),4.00(d,J＝5.4Hz,2H),3.58(dd,J＝16.1,5.4Hz,4H),3.16(d,J＝19.0Hz,4H),2.43(s,3H),2.31(s,3H),2.25(s,2H),1.89(s,2H),1.82-1.70(m,2H),1.66-1.56(m,3H),1.52-1.43(m,2H),1.38(s,9H),1.24(d,J＝6.4Hz,2H),0.86(dd,J＝15.4,6.5Hz,6H)；MALDI-TOF MS:[M+H +]775.25,[M +]774.45
步骤S3，制备式C-10的化合物。
Figure PCTCN2018073662-appb-000128
将式B-10的化合物(7.0271g,9.0681mmol)投入到250mL的烧瓶中，加入二氯甲烷(20mL)溶解，然后加入TFA(5.3873mL,72.5492mmol)，反应在室温下搅拌过夜。反应结束，将反应液蒸干，然后用适量甲醇溶解，加入少量碳酸氢钠固体粉末中和TFA，抽滤，滤液蒸干，干法上样，柱层析，用(5％甲醇:1％氨水:94％二氯甲烷)洗脱，收集浓缩，得产品式C-10的化合物:5.2531g,产率：85.60％。 1H-NMR(400MHz,DMSO-d 6)δ10.17(s,1H),8.96(s,1H),8.16(t,J＝5.5Hz,1H),8.08(d,J＝2.9Hz,1H),7.98(d,J＝8.9Hz,1H),7.89(d,J＝9.0Hz,1H),7.52(dd,J＝9.1,3.0Hz,1H),5.83(p,J＝8.6Hz,1H),4.43(d,J＝ 5.9Hz,1H),4.00(d,J＝5.5Hz,2H),3.60(s,4H),3.23-3.07(m,6H),2.42(s,3H),2.31(s,3H),2.24(s,2H),2.05(s,1H),1.89(s,2H),1.81-1.71(m,2H),1.60(dd,J＝12.3,6.2Hz,3H),1.47(ddd,J＝19.4,13.3,6.1Hz,2H),1.23(s,1H),0.88(dd,J＝11.5,6.5Hz,6H)；MALDI-TOF MS:[M+H +]675.30
步骤S4，制备式D-10的化合物。
Figure PCTCN2018073662-appb-000129
将Fmoc-Glu-OtBu(2.6402g,6.2055mmol)投入到250mL的烧瓶里，加入约70mL的DMF使其溶解，置于0℃恒温反应浴中，在搅拌状态下加入式C-10化合物(3.0176g,4.4325mmol)、PyAoP(3.2354g,6.2055mmol),约30分钟后，缓慢滴加TMP(0.589mL,4.4325mmol)，反应在0℃下搅拌过夜。反应结束，将反应液转移到2L的分液漏斗中，加入去离子水(300mL)和乙酸乙酯(300mL)进行萃取，得有机相，水相用乙酸乙酯(200mL×4)清洗，合并有机相，用无水硫酸钠干燥，过滤，滤液蒸干浓缩，干法上样，柱层析，用(5％甲醇：95％二氯甲烷)进行洗脱，收集产品，蒸干浓缩，得产品式D-10的化合物:4.8342g，产率：100％。 1H-NMR(400MHz,DMSO-d 6)δ10.17(s,1H),8.96(s,1H),8.14-7.99(m,4H),7.89(d,J＝7.7Hz,3H),7.73(d,J＝7.5Hz,3H),7.51(dd,J＝9.1,2.8Hz,1H),7.42(t,J＝7.4Hz,2H),7.33(t,J＝7.4Hz,2H),5.84(dd,J＝17.8,8.9Hz,1H),4.49-4.19(m,4H),4.05-3.83(m,3H),3.79-3.54(m,6H),3.16(d,J＝19.6Hz,5H),2.42(s,3H),2.31(s,3H),2.27-2.20(m,3H),1.93(dd,J＝20.8,7.7Hz,4H),1.77(s,2H),1.66-1.47(m,5H),1.39(s,9H),0.86(dd,J＝16.0,6.5Hz,6H)；MALDI-TOF MS:[M-H +]1080.60
步骤S5，制备式E-10的化合物。
Figure PCTCN2018073662-appb-000130
将式D-10化合物(4.8342g,4.4584mmol)投入到100mL烧瓶中，加入约35mL二氯甲烷使其溶解，在搅拌状态下加入TFA(4.1779mL,56.259mmol),反应在室温下搅拌过夜。反应结束，将反应液蒸干，加入少量二氯甲烷使其溶解，加入正己烷(100mL×3)进行沉降，固体蒸干，得产品式E-10化合物:5.78g，产率100％。 1H-NMR(400MHz,DMSO-d 6)δ10.91(s,1H),8.99(s,1H),8.15-8.00(m,4H),7.87(t,J＝11.9Hz,3H),7.72(t,J＝7.2Hz,3H),7.55(dt,J＝8.4,7.8Hz,1H),7.42(d,J＝7.1Hz,2H),7.33(t,J＝7.4Hz,2H),5.93-5.80(m,1H),4.27(dd,J＝6.9,2.8Hz,4H),3.99(d,J＝5.2Hz,3H),3.75(dd,J＝16.8,5.9Hz,2H),3.61(s,4H),3.19(d,J＝21.3Hz,4H),3.02(td,J＝6.6,3.9Hz,1H),2.44(s,3H),2.34(s,3H),2.25(d,J＝7.6Hz,3H),1.93(s,2H),1.83(dd,J＝15.5,8.3Hz,4H),1.61(dd,J＝12.7,6.4Hz,3H),1.50(d,J＝6.9Hz,2H),0.86(dd,J＝16.3,6.5Hz,6H)；MALDI-TOF MS:[M-H +]1024.35
步骤S6，对式F-10的化合物进行处理备用。
Figure PCTCN2018073662-appb-000131
将Boc-NH-GLG-OBn(3g,6.6149mmol，南京药石)加入到氢化反应釜中，加入10％的Pd/C(0.0500g)，加入DMF(30mL),通入氢气，氢气压强为14psi,反应在室温下搅拌过夜。反应结束后，将反应液抽滤，滤饼用DMF(20mL×3)清洗3次，滤液装入250mL的圆底烧瓶中,得到F-10。
步骤S7，制备式G-10的化合物。
Figure PCTCN2018073662-appb-000132
将SB-743921(2.8503g,5.5124mmol，简称SB7，南京药石)、HBTU(2.7223g，8.2686mmol)、HOBT(1.1172g，8.2686mmol)加入到含有F-10(2.2834g,6.6149mmol)的DMF溶液的250mL烧瓶中，将反应置于-5℃搅拌约20分钟,然后缓慢滴加DIEA(4.0999mL,24.8058mmol),滴加完毕后，在-5℃反应1小时后，然后将反应置于室温下搅拌过夜。反应结束，将反应液转移到1L的分液漏斗中，加入饱和碳酸氢钠溶液(200mL)和乙酸乙酯(300mL)，进行萃取，得有机相，水相用乙酸乙酯(200mL×3)清洗，合并有机相，有机相用饱和食盐水(100mL×3)清洗，再用无水硫酸钠干燥，过滤，得滤液，滤液浓缩蒸干，干法上样，柱层析，用(1％氨水：3.5％甲醇：95.5％二氯甲烷)进行洗脱，收集产品，浓缩蒸干，得产品式G-10化合物:3.6983g，产率79.45％。 1H-NMR(400MHz,DMSO-d 6)δ8.09(dd,J＝9.3,5.2Hz,3H),7.89(d,J＝7.5Hz,1H),7.65-7.42(m,2H),7.42-7.06(m,8H),6.98(s,1H),5.75(d,J＝6.8Hz,1H),4.39-4.11(m,2H),3.90(d,J＝14.5Hz,1H),3.58(dd,J＝25.3,6.0Hz,4H),3.15(dd,J＝11.9,7.5Hz,1H),2.89(s,1H),2.64(s,2H),2.33(s,3H),1.57(d,J＝6.6Hz,1H),1.47(d,J＝7.0Hz,2H),1.36(s,9H),1.23(dd,J＝21.9,9.2Hz,5H),0.96(d,J＝6.3Hz,3H),0.84(dd,J＝14.8,6.4Hz,6H),0.53(d,J＝4.8Hz,2H)；MALDI-TOF MS:[M+H +]844.25,[M-H +]842.30,[M+Na +]866.25
步骤S8，制备式H-10的化合物。
Figure PCTCN2018073662-appb-000133
将式G-10的化合物(3.6483g,3.6791mmol)加入到100mL的烧瓶中，加入二氯甲烷(25mL)使其溶解，再加入TFA(2.1857mL,29.4328mmol)，在室温下搅拌过夜。反应结束，将反应液蒸干，用甲醇溶解，加入碳酸氢钠固体粉末(20g)中和剩余的TFA，过滤，滤液浓缩蒸干，干法上样，柱层析，用(0.5％氨水：5％甲醇：94.5％二氯甲烷)进行洗脱，收集浓缩蒸干，得产品式H-10的化合物：2.4881g,产率90.86％。 1H-NMR(400MHz,DMSO-d 6)δ8.17(dt,J＝11.4,8.0Hz,4H),7.57(dd,J＝8.6,2.0Hz,2H),7.43-6.96(m,9H),6.24(s,2H),5.76(s,1H),4.34(d,J＝6.7Hz,1H),4.17(d,J＝14.4Hz,1H),3.90(d,J＝14.8Hz,1H),3.53(d,J＝11.5Hz,2H),2.85-2.53(m,3H),2.33(s,3H),1.52(dd,J＝38.0,6.6Hz,3H),1.32(s,1H),1.15(dd,J＝38.5,6.6Hz,5H),0.96(d,J＝6.4Hz,3H),0.86(dd,J＝11.2,6.5Hz,6H),0.53(d,J＝5.2Hz,3H)；MALDI-TOF MS:[M+H +]744.25,[M-H +]742.25,[M+Na +]766.25
步骤S9，制备式I-10的化合物。
Figure PCTCN2018073662-appb-000134
Figure PCTCN2018073662-appb-000135
将式E-10的化合物(2.8900g,2.8108mmol)加入到250mL的直筒反应瓶中，加入DMF(40mL)使其溶解,将反应置于0℃，加入式H-10的化合物(2.0921g，2.8108mmol)、PyAOP(1.7585g,3.3729mmol),反应约30分钟后,缓慢滴加2,4,6-三甲基吡啶(0.3700ml,2.8108mmol)，反应在0℃搅拌过夜。反应结束，将反应液转移到2L分液漏斗中，加入去离子水(300mL)和乙酸乙酯(250mL)萃取，得有机相，水相用EA(150mL×4)清洗，合并有机相，有机相用饱和食盐水(200m×3)清洗，再用无水硫酸钠干燥有机相,抽滤，得滤液,将滤液浓缩蒸干，干法上样，柱层析，用(7％甲醇+93％二氯甲烷)洗脱，收集浓缩，得式I-10的化合物：2.8780g，产率58.36％。 1H-NMR(400MHz,DMSO-d 6)δ10.16(s,1H),8.96(s,1H),8.24(d,J＝5.7Hz,1H),8.17-7.98(m,7H),7.89(d,J＝9.5Hz,4H),7.79-7.64(m,3H),7.61-7.10(m,16H),5.94-5.68(m,2H),4.46-4.12(m,6H),3.98(dd,J＝12.4,7.2Hz,3H),3.77-3.56(m,9H),3.24-3.13(m,4H),3.01(td,J＝6.6,3.9Hz,7H),2.42(s,3H),2.36-2.21(m,10H),1.90(d,J＝11.0Hz,3H),1.83-1.72(m,7H),1.67-1.43(m,8H),1.19(dd,J＝18.9,11.8Hz,1H),0.88(ddt,J＝13.5,9.7,7.8Hz,13H),0.52(s,2H)；MALDI-TOF MS:[M+H +]1751.90,[M +]1750.75
步骤S11，制备式J-10的化合物。
Figure PCTCN2018073662-appb-000136
将式I-10的化合物(2.8725g,1.6373mmol)加入到250mL的烧瓶中，加入DMF(20mL)使其溶解，再加入吗啉(4.2792mL,49.1190mmol),反应在室温下搅拌，约1小时后，反应结束，在搅拌状态下加入乙醚(150mL)，沉降约30分钟，倾倒上清液，下层固体用正己烷(150mL×3)进行沉降，得到固体，蒸干，干法上样，柱层析，用(1％氨水：6％甲醇+93％二氯甲烷)进行洗脱，收集滤液，浓缩蒸干，得产品式J-10化合物:1.5427g,产率61.49％。 1H-NMR(400MHz,DMSO-d 6)δ10.16(s,1H),8.96(s,1H),8.36-8.02(m,10H),7.89(d,J＝9.0Hz,1H),7.53(ddd,J＝12.1,8.8,2.4Hz,3H),7.20(dd,J＝28.1,13.3Hz,10H),5.82(dt,J＝24.3,12.1Hz,2H),4.48-4.22(m,2H),4.13(dd,J＝22.6,10.2Hz,1H),4.08-3.89(m,3H),3.81-3.50(m,11H),3.23-3.09(m,6H),2.81-2.67(m,3H),2.42(s,3H),2.39-2.18(m,10H),1.91-1.75(m,5H),1.67-1.43(m,10H),1.19(dd,J＝18.9,11.8Hz,1H),0.88(ddd,J＝19.8,16.3,4.3Hz,16H),0.52(s,2H)；MALDI-TOF MS:[M +]1528.85
步骤S12，制备式K-10的化合物。
Figure PCTCN2018073662-appb-000137
将式J-10的化合物(1.5427g,1.0068mmol)、Boc-Gly-0H(0.2117g,1.2082mmol)、HBTU(0.5727g,5102mmol)、HOBT(0.2041g,1.5102mmol)加入到250mL烧瓶中，加入DMF(25mL)使其溶解，将反应置于-5℃条件下搅拌约30分钟,然后缓慢滴加DIEA(0.7488mL,4.5306mmol),滴加完毕后，在-5℃反应1小时后，然后将反应置于室温下搅拌过夜。反应结束，将反应液转移到1L的分液漏斗中，加入饱和碳酸氢钠溶液(250mL)和乙酸乙酯(200mL)，进行萃取，得到有机相，水相用乙酸乙酯(150 mL×3)清洗，合并有机相，有机相用饱和食盐水(150mL×3)清洗，再用无水硫酸钠干燥，抽滤，得滤液，滤液浓缩蒸干，干法走柱，柱层析，用(1％氨水+6％甲醇+95.5％二氯甲烷)进行洗脱，收集产品，浓缩蒸干，得产品式K-10的化合物:1.4322g，产率84.20％。 1H-NMR(400MHz,DMSO-d 6)δ10.16(s,1H),8.96(s,1H),8.27(s,1H),8.15-7.86(m,10H),7.53(ddd,J＝12.0,8.9,2.4Hz,3H),7.36-7.09(m,9H),6.92(t,J＝5.7Hz,1H),5.90-5.74(m,2H),4.46-4.16(m,4H),3.96(dd,J＝23.4,9.8Hz,3H),3.81-3.50(m,12H),3.24-3.06(m,6H),2.86-2.61(m,3H),2.42(s,3H),2.35-2.15(m,10H),1.83(d,J＝44.8Hz,5H),1.69-1.40(m,10H),1.36(s,9H),1.18(d,J＝18.9Hz,1H),1.01-0.79(m,16H),0.52(d,J＝4.8Hz,2H)；MALDI-TOF MS:[M+H +]1686.95,[M +]1685.95,[M+Na +]1708.95
步骤S13，制备式L-10的化合物。
Figure PCTCN2018073662-appb-000138
将式K-10的化合物(1.4108g,0.8351mmol)加入到250mL的烧瓶中，加入二氯甲烷(10mL)使其溶解，再加入TFA(0.6175mL,8.3510mmol),反应在室温下搅拌过夜。反应结束，将反应液蒸干，用乙酸乙酯溶解，将反应液转移到1L得分液漏斗中，加入饱和碳酸氢钠溶液(250mL)和乙酸乙酯(200mL)萃取，得有机相，水相用乙酸乙酯(150mL×4)清洗，合并有机相，用无水硫酸钠干燥，进行抽滤，滤液浓缩蒸干，干法上样，柱层析，用(1％氨水+6％甲醇+93％二氯甲烷)和(1％氨水+7％甲醇+93％二氯甲烷)进行洗脱，收集浓缩蒸干，得产品式L的化合物：1.2235g,产率92.33％。 1H-NMR(400MHz,DMSO-d 6)δ10.16(s,1H),8.96(s,1H),8.33(t,J＝5.5Hz,1H),8.21-7.78(m,10H),7.65-7.41(m,3H),7.41-7.06(m,9H),5.92-5.71(m,2H),4.48-4.12(m,4H),4.01-3.83(m,3H),3.80-3.56(m,11H),3.15(dd,J＝18.0,5.7Hz,7H),2.81-2.60(m,3H),2.42(s,3H),2.37-2.16(m,10H),1.95-1.45(m,15H),1.36-1.09(m,3H),0.87(ddd,J＝21.2,16.1,6.4Hz,16H),0.53(d,J＝5.1Hz,2H)；MALDI-TOF MS:[M +]1585.70,[M+Na +]1608.70
步骤S14，制备式M-10的化合物。
Figure PCTCN2018073662-appb-000139
将式L-10的化合物(0.8398g,0.5293mmol)投入到250mL烧瓶中，加入二氯甲烷(25mL)和DMF(4mL)使其溶解，再加入M-SCM-10K(4.6715g,0.4410mmol，北京键凯)，反应在常温下避光搅拌。反应结束，将反应液浓缩约20mL，加入二氯甲烷(10mL)使其溶解，加入乙醚(150mL)，析出固体，过滤，滤饼用乙醚(150mL×4)清洗，得到粗产品，将固体用二氯甲烷溶解，浓缩蒸干，干法上样，柱层析，用(1％氨水+6％甲醇+93％二氯甲烷)洗脱，收集产品，浓缩蒸干，得固体产品，将固体用少量无水乙醇溶解，用乙醚(150mL×2)进行沉降，抽滤，滤饼用乙醚(150mL×4)清洗，将固体蒸干得产品式M-10的化合物:4.9270g，产率：92.59％。 1H-NMR(400MHz,DMSO-d 6)δ10.15(d,J＝6.3Hz,1H),8.96(s,1H),8.24(d,J＝24.7Hz,2H),8.17-7.81(m,10H),7.53(ddd,J＝12.0,8.8,2.3Hz,3H),7.20(d,J＝41.3Hz,9H),5.90-5.70(m,2H),4.47-4.16(m,7H),4.08-3.44(m,920H),3.14(dd,J＝22.7,9.9 Hz,7H),2.66(d,J＝7.7Hz,3H),2.42(s,3H),2.35-2.15(m,10H),1.80(dd,J＝47.2,23.2Hz,5H),1.52(d,J＝50.5Hz,10H),1.22(d,J＝13.7Hz,1H),0.98-0.74(m,16H),0.51(s,2H)
试验例
一、试验方案
1、试验对象及材料
实验动物：Balb/c nude裸鼠，SPF级；来源是上海灵畅生物科技有限公司；许可证号为SCXK(沪)2013-0018，合格证号2013001828988；周龄为16-18周，雌性。
实验组受试药物：第十一实施例制备的如式M-10所示的化合物，分子量12066，黄色粉末，储存条件4℃；称取如式M-10所示的化合物，加入生理盐水超声溶解后给药，每次配两次药量，剩余药物4℃保存。
空白对照组试剂：生理盐水，购买自山东康宁药业，批号A16071105。
1460培养液：上海源培生物，货号L210KJ。
FCS:Sciencell，货号0500。
100*青霉素链霉素双抗：Gibco，货号10378-016。
2、实验方案
2.1模型建立
a)复苏并扩增Colo-205细胞；
b)待扩增到足够的细胞，收集细胞，用不含血清的1640培养基配置成浓度为2×10 7cell/ml的细胞悬液；
c)裸鼠右侧皮下接种，0.1ml/只，即每只裸鼠接种细胞数为2×10 6个；接种20只。
2.2分组与给药
测量Colo-205皮下肿瘤大小，挑选16只荷瘤鼠，根据肿瘤体积随机分成2组，每组8只。分组当天记为Day1，当天开始给药。分组及给药方案见表1：
表1.动物分组与给药
Figure PCTCN2018073662-appb-000140
2.3观察和监测
每三天测量肿瘤大小及体重，观察并记录动物状态。
2.4实验终点
最后一次测量后次日，动物二氧化碳安乐死。荷瘤小鼠拍照、剥瘤、瘤体拍照并称重后结束实验。
3、检测指标及计算、统计分析方法
3.1肿瘤体积(tumor volume,TV)
TV＝1/2×a×b 2，其中a、b分别表示长、宽。
3.2相对肿瘤体积(Relative Tumor Volume，RTV)
RTV＝TV 1/TV t×100，其中TV 1为分笼给药时(即Day1)肿瘤体积，TV t为每一次测量时的肿瘤体积。
3.3相对肿瘤增值率T/C(％)
T/C(％)＝(T RTC/C RTV)×100
T RTC治疗组RTC；C RTV空白对照组RTV。
3.4瘤重抑瘤率IR(％)
IR(％)＝(C TW-T TW)/C TW×100
T TW：治疗组瘤重；C TW：空白对照组瘤重；TW(timor weight)：肿瘤重量。
3.5统计分析
试验数据采用平均值±标准差(mean±SD)表示，体重及肿瘤体积采用Student’s t-test检验。P<0.05表示具有显著性差异，P<0.01表示具有极显著性差异。
二、试验结果
1、体重
小鼠分组当天记为Day1,分组时每组动物体重均为20g左右，从分组当天(Day1)至实验终点(Day11)每三天一次测量动物体重。结果如表2所示，自分组后Control组小鼠的体重正常增长，M-10给药组动物体重呈现逐渐下降趋势。实验终点时，给药组体重与Control组之间有极显著性差异。Day10测量时发现给药组4 #小鼠体重下降严重，仅12.45g，Day11该小鼠死亡。
表2 受式化合物对Colo-205荷瘤小鼠体重的影响(数据采用mean±SD表示)
Figure PCTCN2018073662-appb-000141
vs Control,**p<0.01
2、肿瘤体积
小鼠接种后待皮下瘤长至100-200mm3时依肿瘤体积随机分组，分组时各组小鼠肿瘤体积约为210mm3，从分组当天(Day1)至实验终点(Day11)每三天测量一次动物肿瘤体积。结果显示(表3)，试验终点时，Cortrol组小鼠的肿瘤体积为1411.47mm3，RTV为680.32％，肿瘤模型正常工作。
由肿瘤生长曲线可见，试验终点时，Control组肿瘤体积为1411.47mm3。M-10给药组小鼠的肿瘤体积在第一次给药后增长缓慢，之后逐渐减小，实验终点时肿瘤体积为41.95mm 3，肿瘤体积(TV)及相对肿瘤体积(RTV)与Control组相比均有极显著性差异。
表3 受试化合物对Colo205裸鼠皮下移植瘤的抑制作用(数据采用Mean±SD表示)
Figure PCTCN2018073662-appb-000142
vs Control，**p<0.01
3、实验终点肿瘤重量
完成药效试验后，将荷瘤小鼠采用二氧化碳安乐死，剥瘤后对瘤体进行拍照、称重。结果显示(表4)，Control组瘤重为0.90g，M-10给药组的瘤重为0.013g；抑瘤率为98.5％。给药组的瘤重和抑瘤率与Control组相比均有显著差异。由图4可直观的观察到化合物对Colo205荷瘤小鼠肿瘤的影响。
表4实验实验终点各组肿瘤重量(数据采用Mean±SD表示，n＝8)
组别 瘤重TW(g) 抑瘤率IR(％)
Control 0.90±0.31 —
M-10 0.013±0.004** 98.5
vs Control，**p<0.01
4、结果分析
1)本次试验，为考察化合物的药效，对Colo205荷瘤小鼠进行了给药治疗。待皮下瘤长至200mm 3时依肿瘤体积随机分组，当天开始给药。分组时各组小鼠肿瘤体积约为210mm3，试验终点时，Cortrol组小鼠的肿瘤体积为1411.47mm3，RTV为680.32％，肿瘤模型正常工作。
2)由肿瘤生长曲线可见，试验终点时，Control组肿瘤体积为1411.47mm 3。M-10给药组小鼠的肿瘤体积先增长后减少，实验终点时肿瘤体积为41.95mm3，肿瘤体积(TV)及相对肿瘤体积(RTV)与Control组相比均有显著性差异。
3)实验终点时，Control组瘤重为0.90g，M-10给药组的瘤重分别为0.013g；抑瘤率为98.5％。给药组的瘤重和抑瘤率与Control组相比有显著差异。
4)由体重增长曲线可见，自分组后Control组小鼠的体重呈先下降后上升的趋势，M-10给药组动物体重呈逐渐下降趋势。实验终点时，给药组体重与Control组之间有极显著性差异。Day10测量时发现给药组4#小鼠体重下降严重，仅12.45g，Day11该小鼠死亡。
5)在实验过程中我们发现，给药M-10组后小鼠出现体重下降，皮肤干燥皲裂，体表温度低以及轻微稀便等现象。
本实验成功建立了裸鼠Colo205皮下移植瘤模型并考察了受试化合物对该肿瘤生长的影响。在本实验体系及所设剂量下，化合物M-10对该动物模型肿瘤生长的具有较强的抑制作用。
尽管已用具体实施例来说明和描述了本发明，然而应意识到，在不背离本发明的精神和范围的情况下可以作出许多其它的更改和修改。因此，这意味着在所附权利要求中包括属于本发明范围内的所有这些变化和修改。
工业实用性
本发明提供的中间体药物或其衍生物、或其药学上可接受的盐，可用于制备抗癌药物，例如制备单一的纳米药物中的多靶点有效载荷，可用于治疗癌症。本发明提供的制备方法，可以较容易地合成聚乙二醇偶联抗癌双药甚至聚乙二醇偶联抗癌多药，实现多靶点、多疗法同时给药，可以大幅度降低毒性，且有利于克服癌症的多药耐药性，具有协同增效的作用，可用于制备抗癌药物，可用于治疗癌症，具有重大的临床价值和广阔的市场前景。

Claims (29)

  1. 一种如式I所示的具有协同抗癌活性的中间体药物或其衍生物、或其药学上可接受的盐；
    Figure PCTCN2018073662-appb-100001
    其中，i＝2、3、4或5；Z选自带有氨基的二羧酸、多羧酸或其相应的酰基取代物；N选自氨基酸、二肽或多肽；AC选自带有氨基、羟基、羧基或者酰基的抗癌药物。
  2. 根据权利要求1所述的具有协同抗癌活性的中间体药物或其衍生物、或其药学上可接受的盐，其特征在于，所述N选自二肽、三肽或四肽。
  3. 根据权利要求1或2所述的具有协同抗癌活性的中间体药物或其衍生物、或其药学上可接受的盐，其特征在于，
    所述N选自甘氨酸-甘氨酸GG、甘氨酸-亮氨酸-甘氨酸GLG、甘氨酸-苯丙氨酸-丙氨酸GFA、甘氨酸-亮氨酸-丙氨酸GLA或甘氨酸-苯丙氨酸-亮氨酸-甘氨酸GFLG。
  4. 根据权利要求1至3任一项所述的具有协同抗癌活性的中间体药物或其衍生物、或其药学上可接受的盐，其特征在于，
    所述Z选自谷氨酸、谷氨酸的衍生物、天冬氨酸、天冬氨酸衍生物、带有氨基的戊二酸或带有氨基的戊二酸的衍生物中的任意一种。
  5. 根据权利要求1至4任一项所述的具有协同抗癌活性的中间体药物或其衍生物、或其药学上可接受的盐，其特征在于，
    所述抗癌药物选自由：来那度胺、咪喹莫特、雷西莫特、NLG919，Epacadostat、紫杉醇、多柔比星、5-氟脲嘧啶、SB-743921、贝洛替康、埃托泊苷、达拉非尼、曲美替尼、帕布昔利布、Veliparib、Niraparib、去末端双甲基的PKI-587、变构的PKI-587、AZD-5363、MK-2206、拉帕替尼、多韦替尼、Quisinostat、BIIB021、Linifanib、MK-2206、TAK-580、SMK-17、JNJ-7706621、SNS-032、Ribociclib、Niraparib、HSP-990、XL-019、NVP-BSK805、Golotimod、Indoximod、PD-1/PD-L1inhibitor 2、PD-1/PD-L1inhibitor 1、SB-743921、Voreloxin、伊马替尼、Ponatinib、Dasatinib、Bosutinib、吉非替尼、Vandetanib、Sunitinib、Nintedanib、Crizotinib、和Ceritinib中的至少两种组成的组中的任一组。
  6. 根据权利要求1至5任一项所述的具有协同抗癌活性的中间体药物或其衍生物、或其药学上可接受的盐，其特征在于，
    所述式I中i≥2，至少一种所述AC选自免疫治疗癌症药物，至少一种所述AC选自所述化疗药物或所述靶向药物，且所述免疫治疗癌症药物与所述化疗药物或所述靶向药物具有协同作用。
  7. 根据权利要求1至5任一项所述的具有协同抗癌活性的中间体药物或其衍生物、或其药学上可接受的盐，其特征在于，
    所述式I中i≥2，至少一种所述AC选自所述化疗药物，至少一种所述AC选自所述靶向药物，且所选的所述化疗药物与所述靶向药物具有协同作用。
  8. 根据权利要求1至5任一项所述的具有协同抗癌活性的中间体药物或其衍生物、或其药学上可接受的盐，其特征在于，
    至少一种AC选自免疫治疗癌症药物，至少一种AC选自化疗药物，至少一种AC选自靶向药物，且所选的所述免疫治疗癌症药物、所述化疗药物和所述靶向药物中的至少两者具有协同作用；优选的，所选的所述免疫治疗癌症药物、所述化疗药物和所述靶向药物中的三者具有协同作用。
  9. 根据权利要求1至8所述的具有协同抗癌活性的中间体药物或其衍生物、或其药学上可接受的盐，其特征在于，
    所述式I中i＝2，所述AC选自由Veliparib和变构的PKI-587组成的组、帕布昔利布和变构的PKI-587组成的组、拉帕替尼和去末端双甲基的PKI-58 7组成的组、拉帕替尼和AZD5363组成的组、咪喹莫特和紫杉醇组成的组、或来那度胺和去末端双甲基的PKI-587组成的组中的任一组；
    其中，变构的PKI-587的结构为
    Figure PCTCN2018073662-appb-100002
    去末端双甲基的PKI-587的结构为
    Figure PCTCN2018073662-appb-100003
    AZD5363的结构式为
    Figure PCTCN2018073662-appb-100004
  10. 根据权利要求1至9任一项所述的具有协同抗癌活性的中间体药物或其衍生物、或其药学上可接受的盐，其特征在于，其包括如下任一结构式的化合物：
    Figure PCTCN2018073662-appb-100005
    其中，ABT为Veliparib，PKI为变构的PKI-587；
    Figure PCTCN2018073662-appb-100006
    其中，PCB为帕布昔利布，PKI为变构的PKI-587；
    Figure PCTCN2018073662-appb-100007
    其中，LPT为拉帕替尼，AZD为AZD5363；
    Figure PCTCN2018073662-appb-100008
    其中，LPT为拉帕替尼，PKI为变构的PKI-587；
    Figure PCTCN2018073662-appb-100009
    其中，LPT为拉帕替尼，PKI a为去末端双甲基的PKI-587。
  11. 一种如式II所示的聚乙二醇偶联协同抗癌药物或其衍生物、或其药学上可接受的盐；
    Figure PCTCN2018073662-appb-100010
    其中，PEG选自单臂或多臂的聚乙二醇或聚乙二醇的衍生物；X选自
    Figure PCTCN2018073662-appb-100011
    Figure PCTCN2018073662-appb-100012
    Y选自带有氨基的羧酸或其相应的酰基取代物；
    Figure PCTCN2018073662-appb-100013
    为如权利要求1至9任一项所述如式I所示的具有协同抗癌活性的中间体药物、或其衍生物、或其药学上可接受的盐；
    m＝0、1或2；n＝1～5；j＝PEG的臂数。
  12. 根据权利要求11所述的聚乙二醇偶联协同抗癌药物或其衍生物、或其药学上可接受的盐，其特征在于，所述PEG为单臂、双臂、四臂或八臂的聚乙二醇，或者所述PEG为单臂、双臂、四臂或八臂的聚乙二醇的衍生物。
  13. 根据权利要求11或12所述的具有协同抗癌活性的中间体药物或其衍生物、或其药学上可接受的盐，其特征在于，
    所述Y选自
    Figure PCTCN2018073662-appb-100014
    其中，a＝0～8；b＝0～8；a、b不同时为0。
  14. 根据权利要求11至13任一项所述的具有协同抗癌活性的中间体药物或其衍生物、或其药学上可接受的盐，其特征在于，
    所述Y选自
    Figure PCTCN2018073662-appb-100015
    其中n＝1～1000、
    Figure PCTCN2018073662-appb-100016
    Figure PCTCN2018073662-appb-100017
  15. 根据权利要求11至14任一项所述的聚乙二醇偶联协同抗癌药物或其衍生物、或其药学上可接受的盐，其特征在于，其为如下任一化合物：
    Figure PCTCN2018073662-appb-100018
    其中，ABT为Veliparib，PKI为变构的PKI-587；
    Figure PCTCN2018073662-appb-100019
    其中，PCB为帕布昔利布，PKI为变构的PKI-587；
    Figure PCTCN2018073662-appb-100020
    其中，LPT为拉帕替尼，AZD为AZD5363；
    Figure PCTCN2018073662-appb-100021
    其中，LPT为拉帕替尼，PKI为变构的PKI-587；
    Figure PCTCN2018073662-appb-100022
    其中，LPT为拉帕替尼，PKI a为去末端双甲基的PKI-587。
  16. 一种如权利要求1至10任一项所述的如式I所示的具有协同抗癌活性的中间体药物或其衍生物、或其药学上可接受的盐的制备方法，其特征在于，其包括：
    将具有协同作用的至少两个所述抗癌药物分别与氨基酸或肽及其衍生物发生酰胺化反应，得到具有所述式I中N-AC结构单元的第一中间体；
    将任意一个所述第一中间体与带有氨基的二羧酸、多羧酸或其相应的酰基取代物发生酰胺化反应，得到具有所述式I中Z-N-AC结构单元的第二中间体；以及
    将所述第二中间体与剩余的所述第一中间体发生酰胺化反应，得到式I所示的中间体药物
    Figure PCTCN2018073662-appb-100023
  17. 根据权利要求16所述的制备方法，其特征在于，
    所述第一中间体的合成方法包括：将带有氨基保护基团的所述氨基酸或多肽及其衍生物在多肽缩合试剂的存在下，与抗癌药物进行酰胺化连接后，氨基去保护。
  18. 根据权利要求16或17所述的制备方法，其特征在于，
    所述第二中间体的合成方法包括：将第一中间体与同时带有氨基保护基团和羧基保护基团的所述带有氨基的二羧酸、多羧酸或其相应的酰基取代物在PyAOP的存在下与第一中间体进行酰胺化连接后，羧基去保护。
  19. 根据权利要求16至18任一项所述的制备方法，其特征在于，
    式I所示的所述中间体药物的合成方法还包括：将所述第二中间体与至少一个所述第一中间体在PyAOP以及2，4，6-三甲基吡啶的存在下于-10℃～10℃发生酰胺化反应，氨基去保护。
  20. 根据权利要求16至19任一项所述的制备方法，其特征在于，先将至少两个或者两种抗癌药物先结合到一起，再将结合了至少两个或者两种抗癌药物的有机物与氨基酸或肽及其衍生物发生酰胺化反应，所述式I所示的药物中间体至少一个结合位点连接有至少两个或者两种抗癌药物。
  21. 一种如权利要求11至15任一项所述的如式II所示的聚乙二醇偶联协同抗癌药物或其衍生物、或其药学上可接受的盐的制备方法，其特征在于，其包括：
    将式I所示的所述中间体药物与带有氨基的羧酸或其相应的酰基取代物发生酰胺化反应，得到具有所述式II中
    Figure PCTCN2018073662-appb-100024
    结构单元的第四中间体；以及
    将第四中间体与聚乙二醇或其衍生物通过酰胺键偶联，得到式II所示的产品。
  22. 根据权利要求21所述的制备方法，其特征在于，
    所述第四中间体的合成方法包括：将带有氨基保护基团的所述带有氨基的羧酸或其相应的酰基取代物在多肽缩合试剂的存在下，与所述第三中间体进行酰胺化连接后，氨基去保护。
  23. 一种如权利要求1至10任一项所述的如式I所示的具有协同抗癌活性的中间体药物或其衍生物、或其药学上可接受的盐在制备抗癌药物中的应用。
  24. 一种如权利要求11至15任一项所述的如式II所示的聚乙二醇偶联协同抗癌药物或其衍生物、或其药学上可接受的盐在制备抗癌药物中的应用。
  25. 一种抗癌药物，其特征在于，包括如权利要求1至10任一项所述的如式I所示的具有协同抗癌活性的中间体药物或其衍生物、或其药学上可接受的盐。
  26. 一种抗癌药物，其特征在于，包括如权利要求11至15任一项所述的如式II所示的具有协同抗癌活性的中间体药物或其衍生物、或其药学上可接受的盐。
  27. 一种如权利要求1至10任一项所述的如式I所示的具有协同抗癌活性的中间体药物或其衍生物、或其药学上可接受的盐在治疗癌症上的应用。
  28. 一种如权利要求11至15任一项所述的如式II所示的具有协同抗癌活性的中间体药物或其衍生物、或其药学上可接受的盐在治疗癌症上的应用。
  29. 一种癌症治疗方法，其特征在于，其采用的抗癌药物为根据权利要求25或26所述抗癌药物。
PCT/CN2018/073662 2017-08-30 2018-01-22 具有协同抗癌活性的中间体药物和聚乙二醇偶联协同抗癌药物、及其制备方法和应用 WO2019041733A1 (zh)

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