WO2015096553A1 - 抗多药耐药紫杉烷类抗肿瘤化合物及其制备方法 - Google Patents

抗多药耐药紫杉烷类抗肿瘤化合物及其制备方法 Download PDF

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WO2015096553A1
WO2015096553A1 PCT/CN2014/090135 CN2014090135W WO2015096553A1 WO 2015096553 A1 WO2015096553 A1 WO 2015096553A1 CN 2014090135 W CN2014090135 W CN 2014090135W WO 2015096553 A1 WO2015096553 A1 WO 2015096553A1
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compound
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于跃
陈敏
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于跃
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems

Definitions

  • the invention belongs to the field of medicine, and particularly relates to an anti-multidrug resistant taxane antitumor compound and a preparation method thereof.
  • Paclitaxel and docetaxel are the most widely used anti-tumor drugs in clinical chemotherapy, and are mainly used in the treatment of ovarian cancer, breast cancer, lung cancer and melanoma. Although paclitaxel and docetaxel have good anti-tumor effects on sensitive tumors, they have almost no anti-tumor effect on multidrug-resistant tumors, especially the P-glycoprotein encoded by multidrug resistance gene (MDR-1). (P-gp) Overexpressing tumor cells have almost no inhibitory effect.
  • MDR-1 multidrug resistance gene
  • paclitaxel and docetaxel since the introduction of paclitaxel and docetaxel in the 1990s, until June 2010, more paclitaxel C-7, C-10 bismethyl etherified derivative, Cabazitaxel, was approved by the US FDA. In combination with prednisone, patients with hormone-resistant metastatic prostate cancer who have been treated with excessive paclitaxel are not only active against docetaxel-sensitive tumors, but also have pharmacological activities in tumor models that are insensitive to other chemotherapeutic drugs.
  • taxanes generally have low water solubility, and some toxic side effects and drug resistance are caused after administration. Therefore, the development of taxane anticancer drugs with low toxicity and good pharmacological properties, especially for multidrug resistant tumors, has become a research hotspot for pharmaceutical chemists at home and abroad.
  • the present invention provides a taxane compound of the formula I, a stereoisomer, solvate, crystal, prodrug or pharmaceutically acceptable salt thereof, wherein the compound of formula I has the structure:
  • R 1 and R 2 are each independently selected from a C1-C3 alkyl group, a C1-C3 halogenated alkyl group
  • R 6 is selected from a C1-C4 alkyl group, a C2-C4 alkenyl group, a C1-C4 haloalkyl group, a halogenated alkenyl group of C2-C4 or an optionally halogenated phenyl group
  • R 4 is selected from the group consisting of a C1-C3 alkoxy group, a halogen, a hydrogen, and -N 3 ; the precondition is that when R 4 is hydrogen, R 6 is not It is optionally a halogenated phenyl group.
  • the "halo" in the above substituents R 1 , R 2 and R 6 is preferably a monofluoro substitution, a difluoro substitution or a trifluoro substitution.
  • the substituents R 1 and R 2 in the compound of the formula I are each independently selected from the group consisting of methyl, ethyl, propyl, halomethyl, haloethyl, and the halo is a fluorine. Substitution, difluoro substitution, trifluoro substitution, monochloro substitution, dichloro substitution, trichloro substitution. Preferably, R 1 and R 2 are each selected from a methyl group or a halogenated methyl group.
  • the "alkyl group” is preferably a methyl group, an ethyl group or a propyl group
  • the "alkenyl group” is preferably a vinyl group, a propenyl group, an allyl group, a 2-methylpropenyl group, a 1-methylpropenyl group or the like, and a halogen.
  • Preferred are fluorine, chlorine, bromine and iodine.
  • pharmaceutically acceptable salt in the present invention means an addition salt of a non-toxic inorganic or organic acid and/or base. See “Salt selection for basic drugs”, Int. J. Pharm. (1986), 33, 201-217.
  • R 1 , R 2 , R 4 , R 6 in the compound of formula I are the specific groups at the corresponding positions in the specific compounds 11-54 of claim 5.
  • the compound of formula I is selected from the group consisting of compounds 11-54 of claim 5, stereoisomers, solvates, crystals, prodrugs thereof or pharmaceutically acceptable salts thereof.
  • the present invention provides an antitumor drug characterized by using the compound of the above formula I, a stereoisomer, a solvate, a crystal, a prodrug or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the above formula I, a stereoisomer, solvate, crystal, prodrug or a pharmaceutically acceptable salt thereof, and at least one other antitumor drug and pharmaceutically acceptable An acceptable carrier or excipient.
  • the pharmaceutical composition is preferably an injection, an oral preparation, a lyophilized powder injection, a suspension, or the like.
  • the present invention provides the use of a compound of the above formula I, a stereoisomer, a solvate, a crystal, a prodrug or a pharmaceutically acceptable salt thereof for the preparation of an antitumor drug, in particular for the preparation of a drug against multidrug resistance the use of.
  • the drug resistance mechanism is the drug efflux pump effect caused by P-glycoprotein overexpression.
  • the present invention provides the use of a compound of the above formula I, a stereoisomer, solvate, crystal, prodrug or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of paclitaxel and/or docetaxel Drug-resistant tumors.
  • A549/Pac, MCF-7/Doc, PC-3/Doc and the like are preferred.
  • the present invention provides the use of a compound of the above formula I, a stereoisomer, solvate, crystal, prodrug or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of ovarian cancer, breast cancer, lung cancer, Melanoma, prostate cancer, leukemia, etc.
  • the present invention provides the use of a compound of the above formula I, a stereoisomer, solvate, crystal, prodrug or pharmaceutically acceptable salt thereof for the preparation of an anti-tumor lead compound.
  • the present invention provides the use of a compound of the above formula I, a stereoisomer, solvate, crystal, prodrug or a pharmaceutically acceptable salt thereof for the preparation of an antitumor drug candidate.
  • the object of the present invention is to provide a Cabazitaxel analog having significant cytotoxic activity against a multidrug resistant tumor cell line, the compound of the formula I, a stereoisomer, a solvate, a crystal, a prodrug or a pharmaceutically thereof thereof provided by the present invention.
  • the acceptable salt has stronger antitumor activity against drug-resistant tumors than Cabazitaxel, and its toxic side effect is less than Cabazitaxel.
  • the invention provides a preparation method of the above compound of formula I, comprising the following steps:
  • the compound of the formula III can be purchased commercially or according to the literature (CN102241648A, CN1482251A, Bioorganic & Medicinal Chemistry Letters, Vol. 7, No. 2. pp. 133-138, 1997, ChemBioChem 2004, 5, Has been reported in 628-635, J. Org. Chem. 1993, 58, 1068-1075, CHIRALITY, 2000, 12, 431-441, Acc. Chem. Res.
  • the compound of the formula III in the present invention is an optically active single configuration of ⁇ -lactam, and is not a racemic ⁇ -lactam used in some literatures (such as CN102241648A), which is derived from commercial use. Custom purchase or prepared by:
  • Method 1 The substituted aldehyde 1 and p-methoxyaniline are formed under the action of a suitable dehydrating agent (for example, MgSO 4 , Na 2 SO 4 ) to form the compound of the formula II-1, directly with the acetoxyacetyl halide.
  • a suitable dehydrating agent for example, MgSO 4 , Na 2 SO 4
  • acetoxyacetyl chloride or acetoxyacetyl bromide is cyclized under the catalysis of an organic base such as triethylamine, pyridine or imidazole to obtain a racemic ⁇ -lactam intermediate compound III- 2, trypsin resolution to obtain a single configuration of the compound of formula III-3, under basic conditions to remove the acetyl group to obtain the compound of formula III-4 after the use of silicon (such as TBS, TES, TMS, TIPS, TBDPS) Or an alkoxyalkylene group (such as 1-ethoxyethyl (EE), methoxymethyl (MOM)) to protect the hydroxyl group to obtain the compound of the formula III-5, and the removal of the PMP protecting group by CAN oxidation is obtained.
  • silicon such as TBS, TES, TMS, TIPS, TBDPS
  • an alkoxyalkylene group such as 1-ethoxyethyl (EE), methoxymethyl (MOM)
  • Method 2 The compound III-5 is formed by oxidizing (such as ozone, OsO 4 , KMnO 4 ) to form a aldehyde compound III-8, followed by a wittig reaction with a halogenated methane (for example, difluorodibromomethane).
  • oxidizing such as ozone, OsO 4 , KMnO 4
  • a wittig reaction with a halogenated methane (for example, difluorodibromomethane).
  • the compound of formula III-9 is then oxidized by CAN to remove the PMP protecting group to give the compound of formula III-10, and then with Boc-anhydride ((Boc) 2 O), an organic base (such as triethylamine, pyridine or DCC)
  • Boc-anhydride ((Boc) 2 O)
  • an organic base such as triethylamine, pyridine or DCC
  • the compound of the formula III-11 is obtained by the action of the catalyst DMAP; wherein the compound of the formula III-11 can be reduced by the double bond under the action of H 2 to form the compound of the formula III-12.
  • Method 3 The compound of the formula III-8 is reacted with a fluorinating agent (for example, DAST) to form the compound of the formula III-13, and then the PMP protecting group is removed by oxidation with CAN to obtain the compound of the formula III-14, and then with the Boc-anhydride (( Boc) 2 O), an organic base such as triethylamine, pyridine or DCC gives the compound of the formula III-15 under the action of the catalyst DMAP.
  • a fluorinating agent for example, DAST
  • CAN oxidation with CAN
  • Boc-anhydride (( Boc) 2 O)
  • an organic base such as triethylamine, pyridine or DCC gives the compound of the formula III-15 under the action of the catalyst DMAP.
  • Method 4 Compound 2 is directly cyclized with an acetoxyacetyl halide (for example, acetoxyacetyl chloride or acetoxyacetyl bromide) under the catalysis of an organic base such as triethylamine, pyridine or imidazole to obtain racemization.
  • an organic base such as triethylamine, pyridine or imidazole to obtain racemization.
  • the ⁇ -lactam intermediate compound III-16 is subjected to trypsin resolution to obtain a compound of the formula III-17 in a single configuration, and then the acetyl group is removed under basic conditions to obtain the compound III-18.
  • racemic compound III-16 can also be removed from racemic compound 3 (prepared by the method described in Bioorganic & Medicinal Chemistry Letters, Vol. 7, No. 2. pp. 133-138, 1997) under the action of Pd/H 2 .
  • the benzyl group is then subjected to an acetylation reaction (Ac 2 O or AcCl).
  • R 7 and R 8 in each formula are each independently H, methyl or halomethyl;
  • R 5 is a silicon or alkoxyalkylene group, preferably TBS, TES, TMS, TIPS, TBDPS, EE, MOM;
  • R 6 is as defined in the compounds of formula I of the present invention.
  • a compound of the formula II-4 can be prepared according to the method described in the patents WO9630355A1, WO9630356A1, [10-deacetylbaccatin III (10-DAB) as a raw material and an alkylhalosilane (such as TBSCl, TESCl, TIPSCl) , TBDPSCl, TMSCl) react to form a compound of formula II-1, followed by basic conditions (such as NaH, LiH, KH) and C1-C3 haloalkyl (such as methyl iodide, ethyl bromide, 1-iodo-2chloroethyl)
  • the alkane or the like is reacted to obtain a compound of II-2, and the silicon-based protecting group is removed under suitable conditions (such as TBAF or HF) to obtain a compound of II-3, and under basic conditions (such as NaH, LiH, KH) and C1.
  • a compound of formula II-4 a compound of formula II-4 with a compound of formula III in a base such as LiHMDS Under the action of NaHMDS, the compound of formula II-5 is obtained, and then the R 5 protecting group is removed under suitable conditions such as fluoroquaternary ammonium salt (preferably TBAF), HF, acetic acid/methanol or acetic acid/zinc.
  • fluoroquaternary ammonium salt preferably TBAF
  • HF acetic acid/methanol
  • acetic acid/zinc acetic acid/zinc
  • the compound of the formula II-5 is removed by the action of Red-Al or a basic quaternary ammonium salt (preferably benzyltrimethylammonium hydroxide (Triton B)) to form a compound of the formula II-6.
  • a compound of the formula II-6 is condensed with a benzoic acid substituted at a meta position by R 4 under suitable conditions (a carbodiimide condensing agent (preferably DCC, DIC or EDCI) and DMAP) to form a compound of the formula II-7, removal of the protecting group R 5 down under suitable conditions (e.g., fluorinated quaternary ammonium salts (preferably TBAF), HF, acetic acid / acetic acid or methanol / zinc), to give a compound of formula-2 I.
  • suitable conditions e.g., fluorinated quaternary ammonium salts (preferably TBAF), HF, acetic acid / acetic acid or methanol / zinc
  • Method 2 Compound 5 (prepared according to the method described in the patent CN103012329A) and the compound of the formula III under the action of a base (such as LiHMDS, NaHMDS) to obtain a compound of the formula II-8, followed by suitable conditions (such as Raneynickel/ Removal of methylthio in methylthiomethylidene (MTM) by H 2 to give a compound of formula II-9, followed by suitable conditions (eg fluoroquaternary ammonium salt (preferably TBAF), HF, Removal of the R 5 protecting group by acetic acid/methanol or acetic acid/zinc) affords the compound of formula 1-3.
  • a base such as LiHMDS, NaHMDS
  • suitable conditions such as Raneynickel/ Removal of methylthio in methylthiomethylidene (MTM) by H 2 to give a compound of formula II-9
  • suitable conditions eg fluoroquaternary ammonium salt (preferably TBAF), HF, Removal of the R 5 protecting group by ace
  • the compound of formula II-9 is removed by the action of Red-Al or a basic quaternary ammonium salt (preferably benzyltrimethylammonium hydroxide (Triton B)) to form a compound of formula II-10.
  • a compound of the formula II-10 is condensed with a benzoic acid substituted at a meta position by R 4 under suitable conditions (under the action of a carbodiimide condensing agent (preferably DCC, DIC or EDCI) and DMAP) to form a compound of the formula II-11
  • the R 5 protecting group is removed under suitable conditions (such as fluoroquaternary ammonium salt (preferably TBAF), HF, acetic acid/methanol or acetic acid/zinc) to give the compound of formula 1-4.
  • the compound of the formula II-9 can also be obtained from the compound 6 (prepared according to the method described in the patent CN103012328A) and the compound of the formula III under the action of a base such as LiHMDS, NaHMDS.
  • R 1 , R 2 , R 4 and R 6 are the same as those of the compound of the formula I of the present invention
  • R 5 is a silicon group or an alkoxyalkylene group, preferably TBS, TES. , TMS, TIPS, TBDPS, EE, MOM (ie, the definition is the same as defined in the general formula III)
  • R 9 represents a silicon-based protecting group, preferably TMS, TES, TIPS, TBS, TBDPS.
  • the invention provides an intermediate for the preparation of a compound of formula I, characterized in that said intermediate is selected from the group consisting of compounds of formula II-5, wherein R 1 and R 2 are each independently selected from C1-C3 alkyl, C1-C3 haloalkyl.
  • R 6 is selected from the group consisting of C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C2-C4 haloalkenyl, and R 5 is selected from silyl or alkoxyalkylene, preferably TBS, TES, TMS, TIPS, TBDPS, EE, MOM.
  • an intermediate for the preparation of a compound of formula I characterized in that said intermediate is selected from the group consisting of compounds of formula II-7, wherein R 1 , R 2 , R 4 , R 6 are as defined in the formula Compound I, R 5 is as defined above for the compound of formula II-5.
  • Another aspect of the present invention to provide the intermediate compound of formula I, wherein the intermediate is selected from compounds of formula II-9, wherein R 5, R 6 defined above with a compound of formula II-5.
  • an intermediate for the preparation of a compound of formula I characterized in that the intermediate is selected from the group consisting of compounds of formula II-11, wherein R 4 , R 5 , R 6 are as defined above for the compound of formula II-7 .
  • an intermediate for the preparation of a compound of formula I characterized in that the intermediate is selected from the group consisting of compounds 62, 63, 65, 66, 80, 71, 72, 73, 74.
  • an intermediate for the preparation of a compound of formula I characterized in that said intermediate further comprises a TBS group of compounds 62, 63, 65, 66, 80, 71, 72, 73, 74 Replaced with intermediates of TES, TMS, TIPS, TBDPS, EE, MOM.
  • Synthetic compounds 21, 22 were obtained according to the methods in Examples 9, 10, 11, and 12.
  • ⁇ -lactam compounds 101, 102, 103, 104, 105 used in Examples 1-16 are commercially available or according to the literature (Journal of Fluorine Chemistry 125 (2004) 487-500, Journal of Fluorine Chemistry 2008, 129(9). Prepared by the method in 817-828, J. Med. Chem. 2008, 51, 3203-3221, WO2008021242A2), and the structural confirmation data are shown in Table 1.
  • the compounds of the present invention were tested against paclitaxel (Pac)-resistant human lung cancer cells (A549/Pac), docetaxel (Doc)-resistant human breast cancer cells (MCF-7/Doc), and docetaxel resistance.
  • paclitaxel Pac-resistant human lung cancer cells
  • Doc docetaxel-resistant human breast cancer cells
  • MCF-7/Doc docetaxel resistance
  • PC-3/Doc drug human prostate cancer cells
  • test samples were respectively composed of compounds 11, 13, 14, 15, 16, I-2a (compounds in CN102241648A), Cabazitaxel, and a suspension of 1.5 mg/mL (made of sterile water for injection and the above compounds). ), the blank control is the same dose of sterile water for injection.
  • Test method 32 Beagle dogs were divided into 8 groups, 2 females and 2 males in each group, and the test samples containing the compounds 11, 13, 14, 15, 16, I-2a, Cabazitaxel and the blank control were injected sequentially. 2 mL/kg once daily for 5 days. After 3 days, 2 of the Beagle dogs injected with compound I-2a died, 2 had muscle weakness and nausea, and all died after half a day; Beagle was injected with Cabazitaxel 5 days later. Two of the dogs died, but no death occurred in the other test groups, but nausea, limb convulsions, and weakness were observed. There were no obvious abnormal symptoms in the blank control group.
  • Compounds of the formula I in addition to the compounds of the invention may also be synthesized according to the methods described in Examples 1-16.
  • the compounds of the formula I according to the invention are resistant to tumor cell lines (A549/Pac, MCF- 7/Doc, PC-3/Doc) has an IC 50 ranging from 0.7 to 144 nM, and its toxic side effects are less than Cabazitaxel and Compound I-2a, which are limited in length and are not described here.
  • the invention has the advantages that: (1) the compound of the formula I of the invention has significant antitumor activity against paclitaxel and docetaxel-resistant tumor cell lines (A549/Pac, MCF-7/Doc, PC-3/Doc), Its activity is superior to Cabazitaxel, Larotaxel and Larotaxel analogues (I-2a); (2) The compound of formula I of the present invention not only has significant antitumor activity, but also has low toxic side effects, and its toxic side effect is less than Cabazitaxel, Compound I- 2a; (3) The compound of the formula I according to the invention belongs to the me-better drug of Cabazitaxel.

Abstract

本发明属于药物领域，涉及一种抗多药耐药紫杉烷类抗肿瘤化合物及其制备方法，具体涉及一种式Ⅰ结构的紫杉烷类化合物、其立体异构体、溶剂化物、晶体、前药或其药学上可接受的盐，其特征在于该化合物具有如式Ⅰ结构。其中R1、R2各自独立地选自C1-C3的烷基、C1-C3的卤代烷基，R6选自C1-C4的烷基、C2-C4的烯基、C1-C4的卤代烷基、C2-C4的卤代烯基或任选卤代的苯基，R4选自C1-C3的烷氧基、卤素、氢、-N3；前提条件是当R4为氢时，R6不为任选卤代的苯基。

Description

抗多药耐药紫杉烷类抗肿瘤化合物及其制备方法 技术领域
本发明属于药物领域，具体涉及一种抗多药耐药紫杉烷类抗肿瘤化合物及其制备方法。
背景技术
紫杉醇(paclitaxel)及多西紫杉醇(docetaxel)是当今临床化疗应用最广泛的抗肿瘤药物，主要应用于卵巢癌、乳腺癌、肺癌、黑色素瘤等的治疗。虽然紫杉醇和多西紫杉醇对敏感肿瘤具有很好的抗肿瘤效果，但是其对多药耐药肿瘤几乎没有抗肿瘤效果，尤其是对多药耐药基因(MDR-1)编码的P-糖蛋白(P-gp)过表达的肿瘤细胞几乎没有抑制效果。
自上世纪九十年代，紫杉醇及多西紫杉醇上市以来，直到2010年6月多西紫杉醇C-7、C-10位双甲醚化的衍生物——Cabazitaxel被美国FDA批准上市，该药可与泼尼松联合用于曾经接受过多西紫杉醇治疗的激素抵抗型转移性前列腺癌患者，不仅对多西紫杉醇敏感型肿瘤具有活性，同时对其他化疗药不敏感的肿瘤模型也具药理活性。
目前，紫杉烷类药物普遍存在水溶性低，用药后产生一些毒副作用及耐药性等问题。因此，开发低毒副作用、良好药理学性质尤其是对多药耐药肿瘤具有较高活性的紫杉烷类抗肿瘤药物成为国内外药物化学家的研究热点。
发明内容
本发明提供一种式I结构的紫杉烷类化合物、其立体异构体、溶剂化物、晶体、前药或其药学上可接受的盐，其特征在于式Ⅰ化合物具有如下结构：
Figure PCTCN2014090135-appb-000001
其中R1、R2各自独立地选自C1-C3的烷基、C1-C3的卤代烷基，R6选自C1-C4的烷基、C2-C4的烯基、C1-C4的卤代烷基、C2-C4的卤代烯基或任选卤代的苯基，R4选自C1-C3的烷氧基、卤素、氢、-N3；前提条件是当R4为氢时，R6不为任选卤代的苯基。上述取代基R1、R2、R6中的“卤代”优选一氟取代、二氟取代、三氟取代。
本发明的另一技术方案中，式I化合物中取代基R1、R2各自独立地选自甲基、乙基、丙基、卤代甲基、卤代乙基，所述卤代为一氟取代、二氟取代、三氟取代、一氯取代、二氯取代、三氯取代。优选R1、R2均选自甲基或卤代甲基。
本发明中所述“烷基”优选甲基、乙基、丙基，“烯基”优选乙烯基、丙烯基、烯丙基、2-甲基丙烯基、1-甲基丙烯基等，卤素优选氟、氯、溴、碘。
本发明中术语“药学上可接受的盐”是指非毒性的无机或有机酸和/或碱的加成盐。可参见“Salt selection for basic drugs”,Int.J.Pharm.(1986),33,201–217。
在另一优选例中，式I化合物中R1、R2、R4、R6是如权利要求5中具体化合物11-54中相应位置的具体基团。
在另一优选例中，所述的式I化合物选自权利要求5中的化合物11-54、其立体异构体、溶剂化物、晶体、前药或其药学上可接受的盐。
应理解，上述优选基团可相互组合以形成本发明的各种优选化合物，限于篇幅，在此不一一累述。
本发明提供一种抗肿瘤药物，其特征在于以上述式I化合物、其立体异构体、溶剂化物、晶体、前药或其药学上可接受的盐作为有效成分。
本发明提供一种药物组合物，其特征在于包含上述式I化合物、其立体异构体、溶剂化物、晶体、前药或其药学上可接受的盐，和至少一种其他抗肿瘤药物以及药学上可接受的载体或赋形剂。该药物组合物优选注射剂、口服制剂、冻干粉针剂、悬浮剂等。
本发明提供上述式I化合物、其立体异构体、溶剂化物、晶体、前药或其药学上可接受的盐在制备抗肿瘤药物中的用途，尤其是在制备抗多药耐药肿瘤药物中的用途。其中肿瘤的耐药机制为P-糖蛋白过表达引起的药物外排泵作用。
本发明提供上述式I化合物、其立体异构体、溶剂化物、晶体、前药或其药学上可接受的盐在制备药物中的用途，所述药物用于治疗对紫杉醇和/或多西紫杉醇耐药的肿瘤。优选A549/Pac、MCF-7/Doc、PC-3/Doc等。
本发明提供上述式I化合物、其立体异构体、溶剂化物、晶体、前药或其药学上可接受的盐在制备药物中的用途，所述药物用于治疗卵巢癌、乳腺癌、肺癌、黑色素瘤、前列腺癌、白血病等。
本发明提供上述式I化合物、其立体异构体、溶剂化物、晶体、前药或其药学上可接受的盐在制备抗肿瘤先导化合物中的应用。
本发明提供上述式I化合物、其立体异构体、溶剂化物、晶体、前药或其药学上可接受的盐在制备抗肿瘤候选药物中的应用。
本发明的目的在于提供一种针对多药耐药肿瘤细胞株具有显著细胞毒活性的Cabazitaxel类似物，本发明提供的式I化合物、其立体异构体、溶剂化物、晶体、前药或其药学上可接受的盐对耐药肿瘤的抗肿瘤活性强于Cabazitaxel，同时其毒副作用小于Cabazitaxel。
本发明提供上述式I化合物的制备方法，包括如下步骤：
(一)β-内酰胺的侧链——通式化合物III(
Figure PCTCN2014090135-appb-000002
)的制备：
通式化合物III可通过商业渠道进行购买或根据文献(CN102241648A、CN1482251A、Bioorganic&Medicinal Chemistry Letters,Vol.7,No.2.pp.133-138,1997、ChemBioChem 2004,5, 628–635、J.Org.Chem.1993,58,1068-1075、CHIRALITY,2000,12,431–441、Acc.Chem.Res.1995,28,383-389、CHIRALITY,1997,9,487-494)中已经报道的类似方法进行合成，本发明中通式化合物III为具有光学活性的单一构型的β-内酰胺，并非是一些文献(如CN102241648A)中采用的外消旋体β-内酰胺，其来源于商业定制购买或通过如下方法制备：
方法一：将取代的醛1与对甲氧基苯胺在适当的脱水剂(例如MgSO4、Na2SO4)作用下，形成烯夫碱通式化合物III-1，直接与乙酰氧基乙酰卤(例如乙酰氧基乙酰氯或乙酰氧基乙酰溴)在有机碱(例如三乙胺、吡啶或咪唑)催化下发生环合反应，获得外消旋的β-内酰胺中间体通式化合物III-2，经胰蛋白酶拆分得到单一构型的通式化合物III-3，碱性条件下脱除乙酰基得到通式化合物III-4后采用硅基(如TBS、TES、TMS、TIPS、TBDPS)或烷氧基亚烷基(如1-乙氧基乙基(EE)、甲氧甲基(MOM))对羟基进行保护得到通式化合物III-5，用CAN氧化脱除PMP保护基得到通式化合物III-6，再与Boc-酸酐((Boc)2O)、有机碱(如三乙胺、吡啶或DCC)在催化剂DMAP的作用下得到通式化合物III-7；其中通式化合物III-7可在H2作用下将其双键还原形成通式化合物III-22。
Figure PCTCN2014090135-appb-000003
方法二：通式化合物III-5通过氧化(如臭氧、OsO4、KMnO4)断裂双键形成醛通式化合物III-8，接下来与卤代甲烷(例如二氟二溴甲烷)发生wittig反应形成通式化合物III-9，然后用CAN氧化脱除PMP保护基得到通式化合物III-10，再与Boc-酸酐((Boc)2O)、有机碱(如三乙胺、吡啶或DCC)在催化剂DMAP的作用下得到通式化合物III-11；其中通式化合物III-11可在H2作用下将其双键还原形成通式化合物III-12。
方法三：通式化合物III-8与氟化剂(例如DAST)反应形成通式化合物III-13，然后用CAN 氧化脱除PMP保护基得到通式化合物III-14，再与Boc-酸酐((Boc)2O)、有机碱(如三乙胺、吡啶或DCC)在催化剂DMAP的作用下得到通式化合物III-15。
Figure PCTCN2014090135-appb-000004
方法四：化合物2直接与乙酰氧基乙酰卤(例如乙酰氧基乙酰氯或乙酰氧基乙酰溴)在有机碱(例如三乙胺、吡啶或咪唑)催化下发生环合反应，获得外消旋的β-内酰胺中间体通式化合物III-16，经胰蛋白酶拆分得到单一构型的通式化合物III-17后，再在碱性条件下脱除乙酰基得到通式化合物III-18后，采用硅基(如TBS、TES、TMS、TIPS、TBDPS)或烷氧基亚烷基(如1-乙氧基乙基(EE)、甲氧甲基(MOM))对羟基进行保护得到通式化合物III-19，用CAN氧化脱除PMP保护基得到通式化合物III-20，再与Boc-酸酐((Boc)2O)、有机碱(如三乙胺、吡啶或DCC)在催化剂DMAP的作用下得到通式化合物III-21。
Figure PCTCN2014090135-appb-000005
其中外消旋化合物III-16亦可由外消旋化合物3(可由Bioorganic&Medicinal Chemistry Letters,Vol.7,No.2.pp.133-138,1997记载的方法制备)在Pd/H2作用下脱除苄基后进行乙酰化反应(Ac2O或AcCl)得到。
Figure PCTCN2014090135-appb-000006
上述四种合成方法中，各通式中R7、R8各自独立地为H、甲基、卤代甲基；R5为硅基或烷氧基亚烷基，优选TBS、TES、TMS、TIPS、TBDPS、EE、MOM；R6与本发明式I化合物中的定义相同。
由于通式化合物III可通过商业渠道购买，而且现有技术(CN102241648A、CN1482251A、Bioorganic&Medicinal Chemistry Letters,Vol.7,No.2.pp.133-138,1997、ChemBioChem 2004,5,628–635、J.Org.Chem.1993,58,1068-1075、CHIRALITY,2000,12,431–441、Acc.Chem.Res.1995,28,383-389、CHIRALITY,1997,9,487-494)中对通式化合物III的合成方法已比较成熟，因此，以上仅列举通式化合物III中的几个代表性化合物III-7、III-11、III-12、III-15、III-21、III-22的合成方法。本领域的技术人员可以按照上述合成方法或现有技术中类似的方法对通式化合物III涉及的具体化合物进行一一合成，限于篇幅，在此不一一累述。
(二)母核与侧链的对接形成式I化合物：
方法一：可按照专利WO9630355A1、WO9630356A1中记载的方法制备得到式II-4化合物，【以10-去乙酰巴卡亭III(10-DAB)为原料与烷基卤硅烷(如TBSCl、TESCl、TIPSCl、TBDPSCl、TMSCl)反应形成式II-1化合物，接下来在碱性条件下(如NaH、LiH、KH)与C1-C3卤代烷基(如碘甲烷、溴乙烷、1-碘-2氯乙烷等)反应得到II-2化合物，在适当条件下(如TBAF或HF作用下)脱除硅基保护基得到II-3化合物，再在碱性条件下(如NaH、LiH、KH)与C1-C3卤代烷基(如碘甲烷、碘乙烷、溴乙烷、1-碘-2氯乙烷等)反应得到式II-4化合物】式II-4化合物与通式化合物III在碱(如LiHMDS、NaHMDS)的作用下，得到式II-5化合物，接下来在合适的条件下(如氟代季铵盐(优选TBAF)、HF、醋酸/甲醇或醋酸/锌)脱除R5保护基，得到式I-1化合物。
或者式II-5化合物在Red-Al或碱性季铵盐(优选苄基三甲基氢氧化铵(Triton B))的作用下，脱除2-位苯甲酰基，形成式II-6化合物，式II-6化合物与间位被R4取代的苯甲酸在合适的条件下(碳二亚胺类缩合剂(优选DCC、DIC或EDCI)及DMAP)进行缩合形成式II-7化合物，接下来在合适的条件下(如氟代季铵盐(优选TBAF)、HF、醋酸/甲醇或醋酸/锌)脱除R5保护基，得到式I-2化合物。
Figure PCTCN2014090135-appb-000007
方法二：化合物5(按照专利CN103012329A中记载的方法制备)与通式化合物III在碱(如LiHMDS、NaHMDS)的作用下，得到式II-8化合物，接下来在合适的条件下(如Raneynickel/H2作用下)脱除甲硫基亚甲基(MTM)中的甲硫基，得到式II-9化合物，接下来在合适的条件下(如氟代季铵盐(优选TBAF)、HF、醋酸/甲醇或醋酸/锌)脱除R5保护基，得到式I-3化合物。
或者式II-9化合物在Red-Al或碱性季铵盐(优选苄基三甲基氢氧化铵(Triton B))的作用下，脱除2-位苯甲酰基，形成式II-10化合物，式II-10化合物与间位被R4取代的苯甲酸在合适的条件下(碳二亚胺类缩合剂(优选DCC、DIC或EDCI)及DMAP作用下)进行缩合形成式II-11化合物，接下来在合适的条件下(如氟代季铵盐(优选TBAF)、HF、醋酸/甲醇或醋酸/锌)脱除R5保护基，得到式I-4化合物。
Figure PCTCN2014090135-appb-000008
其中式II-9化合物也可以由化合物6(按照专利CN103012328A中记载的方法制备)与通式化合物III在碱(如LiHMDS、NaHMDS)的作用下得到。
上述方法一、方法二中各通式中，R1、R2、R4、R6的定义与本发明式I化合物相同，R5为硅基或烷氧基亚烷基，优选TBS、TES、TMS、TIPS、TBDPS、EE、MOM(即其定义与通式化合物III中的定义相同)，R9表示硅基保护基，优选TMS、TES、TIPS、TBS、TBDPS。
上述合成方法中给出了包含在式I化合物范围内的式I-1、式I-2、式I-3、式I-4的合成方法。
本发明提供制备式I化合物的中间体，其特征在于所述中间体选自式II-5化合物，其中R1、R2各自独立地选自C1-C3的烷基、C1-C3的卤代烷基，R6选自C1-C4的烷基、C2-C4的烯基、C1-C4的卤代烷基、C2-C4的卤代烯基，R5选自硅基或烷氧基亚烷基，优选TBS、TES、TMS、TIPS、TBDPS、EE、MOM。
本发明的另一技术方案中提供制备式I化合物的中间体，其特征在于所述中间体选自式II-7化合物，其中R1、R2、R4、R6的定义同本发明式I化合物，R5的定义同上述式II-5化合物。
本发明的另一技术方案中提供制备式I化合物的中间体，其特征在于所述中间体选自式II-9化合物，其中R5、R6的定义同上述式II-5化合物。
本发明的另一技术方案中提供制备式I化合物的中间体，其特征在于所述中间体选自式II-11化合物，其中R4、R5、R6的定义同上述式II-7化合物。
本发明的另一技术方案中提供制备式I化合物的中间体，其特征在于所述中间体选自化合物62、63、65、66、80、71、72、73、74。
本发明的另一技术方案中提供制备式I化合物的中间体，其特征在于所述中间体还包括将化合物62、63、65、66、80、71、72、73、74中的TBS基团替换为TES、TMS、TIPS、TBDPS、EE、MOM的中间体。
应理解，在本发明范围内，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
为了便于对本发明的进一步理解，下面提供的实施例对其做了更详细的说明。但是这些实施例仅供更好的理解发明而并非用来限定本发明的范围或实施原则，本发明的实施方式不限于以下内容。
实施例1
Figure PCTCN2014090135-appb-000009
称取化合物5(1.0g,1.5mmol)、化合物101(1.07g,3.0mmol)溶于干燥的THF(30mL)中氩气保护下冷却至-40℃，加入LiHMDS(3.45mL,2.3mmol,1.0M in THF)，反应0.5～3h后，加入饱和NH4Cl(5mL)，EtOAc(100mL×3)萃取，合并有机相，饱和NaCl(50mL×3)洗涤，无水Na2SO4干燥，过滤减压浓缩，经硅胶柱层析(石油醚/EtOAc＝6/1)或重结晶得到白色固体(1.31g,85％)，即为化合物61；1H NMR(400MHz,CDCl3):δ8.10(d,J＝7.3Hz,2H,Ph-H),7.61(t,J＝7.5Hz,1H,Ph-H),7.47(t,J＝7.7Hz,2H,Ph-H),6.16(t,J＝9.0Hz,1H,H-13),5.67(d,J＝7.1Hz,1H,H-2),5.59(s,1H,H-10),5.25(d,J＝8.5Hz,1H,CH＝C),4.97(d,J＝8.3Hz,1H,H-5),4.78–4.59(m,6H,H-3′,CONH,OCH 2S×2),4.32(d,J＝8.4Hz,1H,H-20),4.26(q,J＝6.8Hz,2H,H-7,H-2′),4.20(d,J＝8.5Hz,1H,H-20),3.90(d,J＝6.9Hz,1H,H-3),2.88–2.78(m,1H,CH 2-6),2.42(s,3H,CH 3CO),2.29(d,J＝7.3Hz,2H,CH 2-14),2.20(s,3H,CH 3S),2.16(s,3H,CH 3S),2.01(s,3H,CH3),1.92–1.82(m,1H,CH 2-6),1.79(s,3H,CH3),1.76(s,3H,CH3),1.74(s,3H,CH3),1.36(s,9H,t-Bu-Boc),1.21(s,3H,CH3-16),1.19(s,3H,CH3-17),0.96(s,9H,t-Bu-TBS),0.15(s,3H,CH3-TBS),0.11(s,3H,CH3-TBS)；13C NMR(100MHz,CDCl3):δ204.57,171.89,170.05,167.00,166.89,155.04,140.69,133.79,133.58,130.13,129.31,128.57,121.88,116.09,83.99,81.11,79.49,78.93,78.56,77.63,76.49,75.12,74.89,73.84,72.02,71.70,60.41,57.11,47.05,43.28,35.30,32.97,28.26,27.76,26.36,25.79,25.68,22.70,21.08,21.00,18.64,18.42,15.53,14.29,14.20,14.08,13.95,13.88,10.81,-0.00,-4.84,-5.29.
实施例2
Figure PCTCN2014090135-appb-000010
称取化合物61(500mg,0.49mmol)溶于EtOH(30ml)中，加入雷铌镍(Raney-Nickel，5.0g)，在1atm H2作用下，于20～30℃下搅拌反应20h后，TLC检测显示生成两个与原料的极性极为接近的产物，过滤除去雷铌镍,减压浓缩后，经硅胶柱层析(石油醚/EtOAc＝6/1)得到化合物63(68mg,15％)and化合物62(317mg,70％)均为白色固体；
化合物63：1H NMR(400MHz,CDCl3)δ8.10(d,J＝7.9Hz,2H,Ph-H),7.60(t,J＝7.1Hz,1H,Ph-H),7.46(t,J＝7.2Hz,2H,Ph-H),6.15(t,J＝8.9Hz,1H,H-13),5.64(d,J＝7.0Hz,1H,H-2),5.00(d,J＝9.5Hz,1H,H-5),4.81(s,1H,H-10),4.64(broad d,J＝9.7Hz,1H,CONH),4.30(d,J＝8.1Hz,1H,H-20),4.20(s,2H,H-2′,H-3′),4.16(d,J＝8.1Hz,1H,H-20),3.90–3.80(m,2H,H-3,H-7),3.44(s,3H,CH 3O),3.30(s,3H,CH 3O),2.78–2.62(m,1H,H-6),2.39(s,3H,CH 3CO),2.34(d,J＝8.9Hz,2H,H-14),1.96(s,3H,CH3-18),1.83–1.76(m,1H,H-6),1.74(s,3H,CH3-19),1.67–1.57(m,2H,CH 2CH(CH3)2),1.60–1.50(m,1H,CH2CH(CH3)2),1.34(s,9H,t-Bu-Boc),1.19(s,6H,CH3-16,CH3-17),0.99(s,3H,CH2CH(CH 3)2),0.96(s,12H,t-Bu-TBS,CH2CH(CH 3)2),0.14(s,3H,CH3-TBS),0.10(s,3H,CH3-TBS)；13C NMR(100MHz,CDCl3):δ205.18,174.01,170.35,167.07,155.70,139.23,135.56,133.76,130.35,129.47,128.78,84.29,82.80,81.84,80.91,79.95,78.93,74.85,73.24,73.00,57.45,57.25,57.04,51.49,47.55,43.48,41.28,35.40,32.24,29.88,28.37,26.79,24.88,23.49,22.79,22.07,20.97,14.87,10.55,1.21,0.18.
化合物62：1H-NMR(400MHz,CDCl3):δ8.10(d,J＝7.3Hz,2H,Ph-H),7.60(t,J＝7.4Hz,1H,Ph-H),7.47(t,J＝7.7Hz,2H,Ph-H),6.18(t,J＝8.9Hz,1H,H-13),5.64(d,J＝7.1Hz,1H,H-2),5.25(d,J＝8.4Hz,1H,CH＝C),4.99(d,J＝8.5Hz,1H,H-5),4.81(s,2H,H-10,H-3′),4.75(broad d,J＝10.0Hz,1H,CONH),4.31(d,J＝8.4Hz,1H,H-20),4.25(d,J＝3.4Hz,1H,H-2′),4.19(d,J＝8.4Hz,1H,H-20),3.93–3.83(m,2H,H-7,H-3),3.44(s,3H,CH3 O),3.30(s,3H,CH 3O),2.76–2.64(m,1H,CH2-6),2.42(s,3H,CH 3CO),2.38–2.23(m,2H,CH 2-14),1.94(s,3H,CH3),1.79(s,3H,CH3),1.75(s,3H,CH3),1.72(s,3H,CH3),1.44–1.39(m,1H,CH2-6),1.36(s,9H,t-Bu-Boc),1.21(s,3H,CH3-16),1.19(s,3H,CH3-17),0.95(s,9H,t-Bu-TBS),0.14(s,3H,CH3-TBS),0.10(s,3H,CH3-TBS)；13C NMR(100MHz,CDCl3):δ205.12,171.98,170.31,167.06,155.22,139.85,135.05,133.73,130.31,129.55,128.74,122.11,84.40,82.69,81.66,80.85,79.16,76.66,75.38,75.03,71.84,60.60,57.35,57.28,56.95,51.85,47.49,43.50,35.48,32.15,28.45,26.71,25.97,25.89,22.93,21.28,18.84,18.63,14.67,14.39,10.61,0.19,-4.67,-5.09.
实施例3
Figure PCTCN2014090135-appb-000011
称取化合物62(22mg,0.023mmol)溶于THF(0.5mL)中，加入1mL新配制的pH 7.0左右的Bu4NF的THF溶液(用AcOH调pH 7.0,Bu4NF的浓度为1.0mol/L)，室温反应0.5～2h，加水(0.5mL)终止反应，减压蒸除THF，EtOAc(20mL)萃取，有机层用无水Na2SO4干燥，过滤、浓缩，经重结晶或硅胶柱层析(石油醚/EtOAc,1:1)得到白色固体，即为化合物16(16mg,85％)；1H NMR(400MHz,CDCl3):δ8.09(d,J＝8.0Hz,2H,Ph-H),7.60(t,J＝7.4Hz,1H,Ph-H),7.47(t,J＝7.5Hz,2H,Ph-H),6.17(t,J＝8.8Hz,1H,H-13),5.63(d,J＝7.1Hz,1H,H-2),5.31(d,J＝8.5Hz,1H,CH＝C),4.99(d,J＝9.1Hz,1H,H-5),4.85–4.80(m,2H,H-10,H-3′),4.77(d,J＝9.8Hz,1H,CONH),4.30(d,J＝8.4Hz,1H,H-20),4.23(s,1H,H-2′),4.18(d,J＝8.4Hz,1H,H-20),3.90–3.80(m,2H,H-3,H-7),3.64(t,J＝6.6Hz,1H,OH-2′),3.45(s,3H,CH 3O),3.30(s,3H,CH 3O),2.78–2.62(m,1H,H-6),2.42–2.36(m,1H,H-14),2.35(s,3H,CH 3CO),2.30(m,1H,H-14),1.96(s,3H,CH3),1.77(s,6H,CH3×2),1.72(s,3H,CH3),1.62–1.52(m,1H,H-6),1.37(s,9H,t-Bu-Boc),1.21(s,6H,CH3-16,CH3-17)；13C NMR(100MHz,CDCl3):δ205.19,170.53,167.07,155.57,146.33,139.25,135.56,134.76,133.81,130.29,129.43,128.78,84.29,82.82,80.91,78.95,77.40,76.70,74.76,73.91,72.58,63.29,57.45,57.26,57.08,47.58,43.45,35.46,32.96,32.27,29.88,29.57,28.43,28.16,26.86,25.96,22.84,22.67,20.82,18.80,14.97,14.30,10.53；ESI-MS(m/z):814.5[M+H]+,836.3[M+Na]+.
实施例4
Figure PCTCN2014090135-appb-000012
称取化合物63(20mg,0.022mmol)溶于THF(0.5mL)中，加入1mL新配制的pH 7.0左右的Bu4NF的THF溶液(用AcOH调pH 7.0,Bu4NF的浓度为1.0mol/L)，室温反应0.5～2h，加水(0.5mL)终止反应，减压蒸除THF，EtOAc(20mL)萃取，有机层用无水Na2SO4干燥，过滤、浓缩，经重结晶或硅胶柱层析(石油醚/EtOAc,1:1)得到白色固体，即为化合物11(16mg,90％)；1H NMR(400MHz,CDCl3):δ8.10(d,J＝7.5Hz,2H,Ph-H),7.60(t,J＝7.3Hz,1H,Ph-H),7.47(t,J＝7.6Hz,2H,Ph-H),6.18(t,J＝9.0Hz,1H,H-13),5.63(d,J＝6.9Hz,1H,H-2),4.99(d,J＝9.1Hz,1H,H-5),4.81(s,1H,H-10),4.62(d,J＝9.6Hz,1H,CONH),4.30(d,J＝8.4Hz,1H, H-20),4.22–4.17(m,2H,H-3′,H-2′),4.12(d,J＝8.4Hz,1H,H-20),3.90–3.81(m,2H,H-3,H-7),3.64(t,J＝6.6Hz,1H,OH-2′),3.45(s,3H,CH 3O),3.30(s,3H,CH 3O),2.75–2.65(m,1H,H-6),2.37(s,3H,CH 3CO),2.36–2.25(m,2H,H-14),1.96(s,3H,CH3-18),1.84–1.75(m,1H,H-6),1.72(s,3H,CH3-19),1.68(s,2H,CH 2CH(CH3)2),1.60–1.50(m,1H,CH2CH(CH3)2),1.33(s,9H,t-Bu-Boc),1.25(s,3H,CH3-16),1.20(s,3H,CH3-17),0.99(d,J＝2.5Hz,3H,CH2CH(CH 3)2),0.97(d,J＝2.3Hz,3H,CH2CH(CH 3)2)；13C NMR(100MHz,CDCl3):δ205.18,174.01,170.35,167.07,155.70,139.23,135.56,133.76,130.35,129.47,128.78,105.03,84.29,82.80,81.84,80.91,79.95,78.93,74.85,73.24,73.00,57.45,57.25,57.04,51.49,47.55,43.48,41.28,35.40,32.24,29.88,28.37,26.79,24.88,23.49,22.79,22.07,20.97,14.87,10.55；ESI-MS(m/z):816.4[M+H]+,838.5[M+Na]+.
实施例5
Figure PCTCN2014090135-appb-000013
称取化合物5(160mg,0.24mmol)、化合物102(175mg,0.48mmol)溶于干燥THF(8mL)，氩气保护下冷却至-20℃，加入LiHMDS(400μL,0.4mmol,1.0M in THF)，反应0.5h后，加入饱和NH4Cl(2mL)，EtOAc(50mL×3)萃取，合并有机相，饱和NaCl(20mL×3)洗涤，无水Na2SO4干燥，过滤、减压浓缩，经硅胶柱层析(石油醚/EtOAc＝6/1))或重结晶得到白色固体(149mg,60％)，即为化合物64；1H NMR(400MHz,CDCl3):δ8.11(d,J＝7.3Hz,2H,Ph-H),7.61(t,J＝7.4Hz,1H,Ph-H),7.51(t,J＝7.5Hz,2H,Ph-H),6.22(t,J＝8.9Hz,1H,H-13),5.67(d,J＝6.9Hz,1H,H-2),5.58(s,1H,H-10),4.97(d,J＝9.4Hz,2H,CONH,H-5),4.88(broad s,1H,H-3′),4.74(dd,J＝24.6,11.7Hz,2H,OCH 2S),4.64(dd,J＝23.5,11.8Hz,2H,OCH 2S),4.43(dd,J＝24.6,9.8Hz,1H,CH＝CF2),4.32(broad s,2H,H-2′,H-20),4.29–4.21(m,1H,H-7),4.19(d,J＝8.0Hz,1H,H-20),3.89(d,J＝7.0Hz,1H,H-3),2.82–2.72(m,1H,H-6),2.41(s,3H,CH 3CO),2.37–2.32(m,1H,H-14),2.24–2.19(m,1H,H-14),2.20(s,3H,CH 3S),2.17(s,3H,CH 3S),2.02(s,3H,CH3-18),1.90–1.83(m,1H,H-6),1.74(s,3H,CH3-19),1.33(s,9H,t-Bu-Boc),1.21(s,3H,CH3-16),1.20(s,3H,CH3-17),0.97(s,9H,t-Bu-TBS),0.17(s,3H,CH3-TBS),0.12(s,3H,CH3-TBS)；13C NMR(100MHz,CDCl3):δ204.68,171.13,170.37,167.23,155.03,140.32,134.30,133.80,130.38,129.35,128.86,84.11,81.38,80.41,79.01,77.84,77.40,76.75,76.70,74.97,74.00,72.26,72.22,71.96,60.60,57.33,47.23,43.54,35.35,33.12,29.89,28.33,26.65,25.84,22.70,21.18,18.55,15.77,14.23,14.15,10.98,-4.56,-5.25；19F NMR(376MHz,CDCl3):δ-84.7(dd,J＝36.5,24.4Hz,1F),-86.5(d,J＝36.5Hz,1F)；ESI-MS(m/z):1028.4[M+H]+,1050.3[M+Na]+.
实施例6
Figure PCTCN2014090135-appb-000014
称取化合物64(110mg,0.107mmol)溶于EtOH(20ml)中，加入雷铌镍(Raney-Nickel，1.0g)，在1atm H2作用下，于25℃下搅拌反应15h后，TLC检测显示原料消失生成一个产物，过滤除去雷铌镍,减压浓缩后，得到白色固体(90mg,90％)；称取该固体(25mg,0.028mmol)溶于THF(0.5mL)中，加入1mL新配制的pH 7.0左右的Bu4NF的THF溶液(用AcOH调pH 7.0,Bu4NF的浓度为1.0mol/L)，室温反应2h，加水(0.5mL)终止反应，减压蒸除THF，EtOAc(15mL)萃取，有机层用无水Na2SO4干燥，过滤、浓缩，经重结晶或硅胶柱层析(石油醚/EtOAc,1:1.5)得到白色固体(16mg,73％)，经结构确证该固体为化合物17；1H NMR(400MHz,CDCl3):δ8.10(d,J＝7.4Hz,2H,Ph-H),7.59(d,J＝7.4Hz,1H,Ph-H),7.50(d,J＝7.7Hz,2H,Ph-H),6.19(t,J＝8.9Hz,1H,H-13),5.64(d,J＝6.6Hz,1H,H-2),4.99(d,J＝9.3Hz,1H,H-5),4.81(s,1H,H-10),4.68(d,J＝9.6Hz,1H,CONH),4.35–4.25(m,2H,H-20,H-2′),4.17(d,J＝8.3Hz,1H,H-20),4.01–3.91(m,1H,H-3′),3.90–3.79(m,2H,H-7,H-3),3.64(t,J＝6.6Hz,1H,OH-2′),3.45(s,3H,CH 3O),3.30(s,3H,CH 3O),2.74–2.63(m,1H,H-6),2.39(s,3H,CH 3CO),2.36–2.26(m,2H,H-14),1.95(s,3H,CH3-18),1.83–1.77(m,1H,H-6),1.71(s,3H,CH3-19),1.67–1.60(m,2H,CH 2CH3),1.33(s,9H,t-Bu-Boc),1.25(s,3H,CH3-16),1.20(s,3H,CH3-17),1.01(t,J＝7.3Hz,3H,CH2CH 3)；13C NMR(100MHz,CDCl3):δ205.19,174.24,170.61,170.43,167.17,157.58,157.45,155.84,139.25,135.52,133.65,130.38,129.35,128.83,112.87,84.31,82.80,81.86,80.91,79.99,78.86,74.76,71.91,57.45,57.25,57.06,54.64,47.54,43.53,35.28,32.27,29.89,28.36,26.83,25.26,22.84,20.97,14.83,14.25,11.00,10.53；ESI-MS(m/z):788.3[M+H]+、810.4[M+Na]+.
化合物64在Raneynickel/H2的作用下，不仅将甲硫基脱除，而且还将二氟乙烯基脱氟还原为乙基，得到化合物66，其质谱数据(ESI-MS(m/z):924.4[M+Na]+)可证实。
实施例7
Figure PCTCN2014090135-appb-000015
称取化合物5(123mg,0.18mmol)、化合物103(130mg,0.37mmol)溶于干燥THF(6mL)，氩气保护下冷却至-30℃，加入LiHMDS(296μL,0.30mmol,1.0M in THF)，反应1.5h后，加入饱和NH4Cl(2mL)，EtOAc(30mL×3)萃取，合并有机相，饱和NaCl(10mL×3)洗涤，无水Na2SO4干燥，过滤、减压浓缩，经硅胶柱层析(石油醚/EtOAc＝6/1))或重结晶得到白色固体(158mg,83％)，即为化合物68；1H NMR(400MHz,CDCl3):δ8.12(d,J＝7.5Hz,2H,Ph-H),7.61(t,J＝7.5Hz,1H,Ph-H),7.51(t,J＝7.5Hz,2H,Ph-H),6.19(t,J＝8.9Hz,1H,H-13),5.92–5.60(m,2H,CF2 H,H-2),5.58(s,1H,H-10),5.02(broad d,J＝10.4Hz,1H,CONH),4.95(broad d,J＝9.3Hz,1H,H-5),4.78–4.62(m,5H,OCH 2S×2,H-2′),4.51–4.40(m,1H,H-3′),4.32(d,J＝8.2Hz,1H,H-20),4.25(dd,J＝10.4,6.7Hz,1H,H-7),4.18(d,J＝8.1Hz,1H,H-20),3.88(d,J＝6.7Hz,1H,H-3),2.84–2.73(m,1H,H-6),2.41(s,3H,CH 3CO),2.35–2.28(m,1H,H-14),2.26–2.18(m,1H,H-14),2.20(s,3H,CH 3S),2.16(s,3H,CH 3S),2.02(s,3H,CH3-18),1.90–1.82(m,1H,H-6),1.74(s,3H,CH3-19),1.32(s,9H,t-Bu-Boc),1.20(s,3H,CH3-16),1.17(s,3H,CH3-17),0.95(s,9H,t-Bu-TBS),0.18(s,3H,CH3-TBS),0.12(s,3H,CH3-TBS)；13C NMR(100MHz,CDCl3):δ204.67,171.04,170.50,167.28,155.36,140.13,134.39,133.78,130.41,129.30,128.90,84.12,81.43,80.98,78.86,77.85,76.73,74.90,73.96,72.25,72.06,62.89,57.38(m),47.29,43.53,35.27,33.14,29.88,28.17,26.55,25.77,22.91,21.09,18.41,15.77,14.24,14.14,10.97,-4.51,-5.45；19F NMR(376MHz,CDCl3):δ-125.9(ddd,J＝285.4,54.9,9.4Hz,1F),-129.4(ddd,J＝285.0,56.4,9.0Hz,1F)；ESI-MS(m/z):1016.4[M+H]+,1038.3[M+Na]+.
实施例8
Figure PCTCN2014090135-appb-000016
称取化合物68(60mg,0.059mmol)溶于EtOH(20ml)中，加入雷铌镍(Raney-Nickel，1.0g)，在1atm H2作用下，于25℃下搅拌反应12h后，过滤除去雷铌镍,减压浓缩后，得到白色固体80(49mg,90％)，ESI-MS(m/z):924.4[M+Na]+；称取化合物80(25mg,0.027mmol)溶于THF(0.5mL)中，加入1mL新配制的pH 7.0左右的Bu4NF的THF溶液(用AcOH调pH 7.0, Bu4NF的浓度为1.0mol/L)，室温反应2h，加水(0.5mL)终止反应，减压蒸除THF，EtOAc(15mL)萃取，有机层用无水Na2SO4干燥，过滤、浓缩，经重结晶或硅胶柱层析(石油醚/EtOAc,1:1.5)得到白色固体(19mg,87％)，即为化合物14；1H NMR(400MHz,CDCl3):δ8.11(d,J＝7.5Hz,2H,Ph-H),7.61(t,J＝6.9Hz,1H,Ph-H),7.50(t,J＝7.7Hz,2H,Ph-H),6.24(t,J＝9.0Hz,1H,H-13),5.88(td,J＝54.6,5.2Hz,1H,CF2 H),5.63(d,J＝7.0Hz,1H,H-2),5.07(broad d,J＝9.8Hz,1H,CONH),4.98(broad d,J＝9.5Hz,1H,H-5),4.80(s,1H,H-10),4.63(s,1H,H-2′),4.52–4.39(m,1H,H-3′),4.31(d,J＝8.1Hz,1H,H-20),4.17(d,J＝8.1Hz,1H,H-20),3.92–3.78(m,2H,H-3,H-7),3.54(s,1H,OH-2′),3.46(s,3H,CH 3O),3.30(s,3H,CH 3O),2.76–2.66(m,1H,H-6),2.41(s,3H,CH 3CO),2.32–2.22(m,2H,H-14),1.94(s,3H,CH3-18),1.71(s,3H,CH3-19),1.33(s,9H,t-Bu-Boc),1.25(s,3H,CH3-16),1.20(s,3H,CH3-17)；13C NMR(100MHz,CDCl3):δ205.11,172.45,170.78,167.25,155.25,138.53,135.97,133.75,130.36,129.28,128.88,84.31,82.74,81.87,81.17,80.91,78.87,77.40,76.71,74.72,73.35,68.62,57.24(m)47.56,43.52,35.24,32.23,29.89,28.21,26.91,22.82,20.98,14.76,10.54；19F NMR(376MHz,CDCl3):δ-126.3(ddd,J＝286.5,56.4,12.0Hz,1F),-128.1(ddd,J＝288.4,56.4,9.4Hz,1F)；ESI-MS(m/z):810.4[M+H]+,832.5[M+Na]+.
实施例9
Figure PCTCN2014090135-appb-000017
称取化合物6(500mg,0.87mmol)、化合物104(495mg,1.31mmol)溶于干燥THF(30mL)，氩气保护下冷却至-40℃，加入LiHMDS(120μL,1.2mmol,1.0M in THF)，反应1.5h后，加入饱和NH4Cl(3mL)，EtOAc(100mL×3)萃取，合并有机相，饱和NaCl(30mL×3)洗涤，无水Na2SO4干燥，过滤、减压浓缩，经硅胶柱层析(石油醚/EtOAc＝10/1))或重结晶得到白色固体(761mg,92％)，即为化合物69；1H NMR(400MHz,CDCl3):δ8.11(d,J＝7.4Hz,2H,Ph-H),7.59(t,J＝7.4Hz,1H,Ph-H),7.48(t,J＝7.6Hz,2H,Ph-H),7.37(t,J＝7.4Hz,2H,Ph-H),7.30–7.26(m,3H,Ph-H),6.31(t,J＝9.2Hz,1H,H-13),5.65(d,J＝7.1Hz,1H,H-2),5.45(broad d,J＝9.8Hz,1H,CONH),5.31(broad d,J＝8.9Hz,1H,H-3′),5.00(d,J＝10.0Hz,1H,H-5),4.80(s,1H,H-10),4.52(s,1H,H-2′),4.32(d,J＝8.3Hz,1H,H-20),4.19(d,J＝8.3Hz,1H,H-20),3.94–3.83(m,2H,H-3,H-7),3.45(s,3H,CH 3O),3.31(s,3H,CH 3O),2.76–2.62(m,1H,H-6),2.56(s,3H,CH 3CO),2.40–2.30(m,1H,H-14),2.22–2.14(m,1H,H-14),1.95(s,3H,CH3-18),1.84–1.76(m,1H,H-6),1.72(s,3H,CH3-19),1.32(s,9H,t-Bu-Boc),1.24(s,3H,CH3-16),1.20(s,3H,CH3-17),0.75(s,9H,t-Bu-TBS),-0.12(s,3H,CH3-TBS),-0.30(s,3H,CH3-TBS)；13C NMR(100MHz,CDCl3):δ 205.10,171.77,170.35,167.18,139.58,135.16,133.74,130.34,129.39,128.82,128.75,127.90,126.61,84.36,82.63,81.78,80.88,80.17,79.14,76.66,75.88,74.94,71.80,57.41,57.28,56.93,47.44,43.56,35.41,32.16,29.88,28.33,26.85,25.65,23.28,21.44,18.37,14.70,10.61,-5.26,-5.72；ESI-MS(m/z):950.4[M+H]+,972.5[M+Na]+.
实施例10
Figure PCTCN2014090135-appb-000018
称取化合物69(250mg,0.26mmol)溶于CH2Cl2(12mL)中于-30℃下，加入Triton B(40％w/w in MeOH,200μL)，反应5分钟后，加入饱和NH4Cl(2mL)，CH2Cl2(50mL×3)萃取，合并有机相，饱和NaCl(30mL×3)洗涤，无水Na2SO4干燥，过滤、减压浓缩，经硅胶柱层析(石油醚/EtOAc＝2/1)，回收化合物69(80mg,32％)，得到化合物70(125mg,56％)；1H NMR(400MHz,CDCl3):δ7.35(t,J＝7.0Hz,2H,Ph-H),7.29(d,J＝7.0Hz,1H,Ph-H),7.20(d,J＝7.5Hz,2H,Ph-H),6.23(t,J＝9.0Hz,1H,H-13),5.50(broad d,J＝9.9Hz,1H,CONH),5.20(d,J＝8.5Hz,1H,H-3′),5.02(broad d,J＝9.4Hz,1H,H-5),4.74(s,1H,H-10),4.68–4.59(m,2H,H-20),4.44(s,1H,H-2′),3.90(d,J＝3.4Hz,1H,H-3),3.84(dd,J＝9.8,6.0Hz,1H,H-7),3.50(d,J＝6.4Hz,1H,H-2),3.41(s,3H,CH 3O),3.29(s,3H,CH 3O),2.75–2.62(m,1H,H-6),2.41(s,3H,CH 3CO),2.24–2.08(m,2H,H-14),1.90(s,3H,CH3-18),1.80–1.66(m,1H,H-6),1.68(s,3H,CH3-19),1.42(s,9H,t-Bu-Boc),1.23(s,3H,CH3-16),1.07(s,3H,CH3-17),0.74(s,9H,t-Bu-TBS),-0.15(s,3H,CH3-TBS),-0.32(s,3H,CH3-TBS)；13C NMR(100MHz,CDCl3)δ205.71,171.85,169.97,155.53,139.27,138.83,135.43,128.72,127.93,126.63,83.99,83.02,82.71,81.06,80.30,78.43,78.10,75.63,74.55,72.40,57.28,56.94,47.39,43.09,35.69,32.26,29.88,28.42,26.44,25.66,23.27,21.30,18.36,14.66,10.79,-5.28,-5.73；ESI-MS(m/z):868.5[M+Na]+.
实施例11
Figure PCTCN2014090135-appb-000019
称取3-甲氧基苯甲酸(216mg,1.42mmol)溶于干燥的甲苯(3mL)中，加入DCC(292mg,1.42mmol)、DMAP(6mg,0.05mmol)，室温下搅拌5分钟，加入化合物70(40mg,0.05mmol)，加热至65℃反应48小时后，过滤、减压浓缩后，经硅胶柱层析(石油醚/EtOAc＝10/1)，回收化 合物70(8mg,20％)，得到化合物71(34mg；74％)，ESI-MS(m/z):980.5[M+H]+,1002.5[M+Na]+；称取化合物71(26mg,0.026mmol)，溶于THF(1.0mL)中，加入1mL新配制的pH 7.0左右的Bu4NF的THF溶液(用AcOH调pH 7.0,Bu4NF的浓度为1.0mol/L)，室温反应2h，加水(0.5mL)终止反应，减压蒸除THF，EtOAc(20mL)萃取，有机层用无水Na2SO4干燥，过滤、浓缩，经重结晶或硅胶柱层析(石油醚/EtOAc,1:1)得到白色固体(21mg,91％)，即为化合物20；1H NMR(400MHz,CDCl3):δ7.68(d,J＝7.0Hz,1H,Ph-H),7.61(s,1H,Ph-H),7.41–7.36(m,5H,Ph-H),7.35–7.30(m,1H,Ph-H),7.16-7.12(m,1H,Ph-H),6.20(t,J＝8.7Hz,1H,H-13),5.61(d,J＝7.0Hz,1H,H-2),5.44(d,J＝10.7Hz,1H,CONH),5.25(d,J＝9.0Hz,1H,H-3′),4.97(d,J＝9.3Hz,1H,H-5),4.79(s,1H,H-10),4.61(s,1H,H-2′),4.34(d,J＝8.3Hz,1H,H-20),4.16(d,J＝8.4Hz,1H,H-20),3.87(s,3H,CH 3O),3.86–3.76(m,2H,H-3,H-7),3.45(s,3H,CH 3O),3.30(s,3H,CH 3O),2.74–2.65(m,1H,H-6),2.35(s,3H,CH 3CO),2.31–2.21(m,2H,H-14),1.87(s,3H,CH3-18),1.82–1.75(m,1H,H-6),1.71(s,3H,CH3-19),1.35(s,9H,t-Bu-Boc),1.25(s,3H,CH3-16),1.21(s,3H,CH3-17)；13C NMR(100MHz,CDCl3):δ205.14,172.86,170.61,167.02,159.77,155.47,138.90,135.70,130.56,129.84,129.00,128.25,126.99,122.68,120.24,114.78,84.25,82.78,81.93,80.90,78.85,76.72,74.74,73.86,72.74,57.49,57.24,57.07,56.36,55.59,47.52,43.45,35.37,32.29,29.89,28.36,26.99,22.85,20.85,14.82,10.52；ESI-MS(m/z):866.3[M+H]+,888.3[M+Na]+.
实施例12
Figure PCTCN2014090135-appb-000020
称取3-叠氮基苯甲酸(300mg,1.84mmol)溶于干燥的甲苯(3mL)中，加入DCC(379mg,1.84mmol)、DMAP(7mg,0.06mmol)，室温下搅拌5分钟，加入化合物70(52mg,0.06mmol)，加热至65℃反应48小时后，过滤、减压浓缩后，经硅胶柱层析(石油醚/EtOAc＝10/1)，得到化合物72(56mg；93％)，ESI-MS(m/z):991.5[M+H]+,1013.5[M+Na]+；称取化合物72(30mg,0.03mmol)，溶于THF(1.0mL)中，加入1mL新配制的pH 7.0左右的Bu4NF的THF溶液(用AcOH调pH 7.0,Bu4NF的浓度为1.0mol/L)，室温反应0.5h，加水(0.5mL)终止反应，减压蒸除THF，EtOAc(20mL)萃取，有机层用无水Na2SO4干燥，过滤、浓缩，经重结晶或硅胶柱层析(石油醚/EtOAc,1:1)得到淡黄色固体(19mg,73％)，即为化合物19；1H NMR(400MHz,CDCl3):δ7.87(d,J＝7.5Hz,1H,Ph-H),7.78(s,1H,Ph-H),7.47(t,J＝7.9Hz,1H,Ph-H),7.39(m,4H,Ph-H),7.35–7.30(m,1H,Ph-H),7.25–7.22(m,1H,Ph-H),6.18(t,J＝8.7Hz,1H,H-13), 5.62(d,J＝6.9Hz,1H,H-2),5.41(d,J＝8.5Hz,1H,H-3′),5.24(d,J＝9.4Hz,1H,CONH),4.98(d,J＝8.9Hz,1H,H-5),4.79(s,1H,H-10),4.60(s,1H,H-2′),4.31(d,J＝8.4Hz,1H,H-20),4.15(d,J＝8.3Hz,1H,H-20),3.92–3.80(m,2H,H-3,H-7),3.45(s,3H,CH 3O),3.30(s,3H,CH 3O),2.75–2.64(m,1H,H-6),2.36(s,3H,CH 3CO),2.33–2.17(m,2H,H-14),1.88(s,3H,CH3-18),1.82–1.76(m,1H,H-6),1.71(s,3H,CH3-19),1.35(s,9H,t-Bu-Boc),1.25(s,3H,CH3-16),1.21(s,3H,CH3-17)；13C NMR(100MHz,CDCl3):δ205.10,173.01,170.65,166.19,155.46,140.88,139.02,138.49,135.67,131.08,130.34,129.00,128.26,127.05,126.94,124.46,120.30,84.30,82.78,81.86,80.86,80.39,78.92,76.63,75.14,73.79,72.83,57.51,57.25,57.05,56.43,47.49,43.44,35.32,32.25,29.89,28.36,26.94,22.90,20.84,14.81,10.50；ESI-MS(m/z):877.3[M+H]+,899.3[M+Na]+.
实施例13
Figure PCTCN2014090135-appb-000021
按照实施例1、5、7、9中的方法，化合物6与化合物105反应合成化合物73后，接下来按照实施例3、4中的方法合成化合物15。
实施例14
Figure PCTCN2014090135-appb-000022
按照实施例1、5、7、9中的方法，化合物6与化合物102反应合成化合物74后，接下来按照实施例3、4中的方法合成化合物13，化合物13在Pt-C/H2或PtO2/H2作用下，得到化合物12及约20％的脱一氟化合物18。
实施例15
按照实施例9、10、11、12中的方法得到合成化合物21、22。
实施例16
由于紫杉烷类药物的合成技术在现有技术中已相对成熟，采用本发明中式I化合物的通用制备方法(或现有技术中类似的方法)，本领域的技术人员可以按照实施例1-15中记载的合成方法，以类似的收率合成得到化合物23～54，限于篇幅，在此不再一一累述。
实施例1-16中所用β内酰胺化合物101、102、103、104、105是通过商业购买或按照文献(Journal of Fluorine Chemistry 125(2004)487–500、Journal of Fluorine Chemistry 2008,129(9):817-828、J.Med.Chem.2008,51,3203–3221、WO2008021242A2)中的方法制备，其结构确证数据见表1。
表1
Figure PCTCN2014090135-appb-000023
实施例1-16中制备的化合物11～54的结构确证数据，见表2
表2
Figure PCTCN2014090135-appb-000024
Figure PCTCN2014090135-appb-000025
生物活性测试
测试本发明化合物对紫杉醇(Paclitaxel,Pac)耐药的人肺癌细胞(A549/Pac)、多西紫杉醇(Docetaxel,Doc)耐药的人乳腺癌细胞(MCF-7/Doc)、多西紫杉醇耐药的人前列腺癌细胞(PC-3/Doc)以及上述非耐药细胞株的体外抗肿瘤活性。
耐药细胞株的获得：按照萧畔博士，2012年《山东大学博士学位论文》中记载的方法分别以紫杉醇、多西紫杉醇为诱导药物，对A549、MCF-7、PC-3进行诱导，直至上述肿瘤细胞株能够在含2μmol/mL药物浓度的培养基中稳定生长并传代。
按照CN102241648A中记载的方法对上述肿瘤细胞株A549、A549/Pac、MCF-7、MCF-7/Doc、PC-3、PC-3/Doc进行体外抗肿瘤活性测试，结果见表3。
表3
Figure PCTCN2014090135-appb-000026
Figure PCTCN2014090135-appb-000027
上表中“-”表示未进行测试。
采用32只Beagle犬(雌雄各一半，雌性5.6～8.0kg,雄性6.5～7.8kg)，测试化合物11、13、14、15、16、I-2a、Cabazitaxel的毒性。
供试品分别为含化合物11、13、14、15、16、I-2a(CN102241648A中的化合物)、Cabazitaxel，浓度为1.5mg/mL的混悬液(由无菌注射用水与上述化合物制成)，空白对照品为相同剂量的无菌注射用水。
试验方法：将32只Beagle犬雌雄均等分成8组，每组2雌2雄，依次注射含化合物11、13、14、15、16、I-2a、Cabazitaxel的供试品与空白对照品，剂量为2mL/kg，每天一次，连续注射5天，3天后，注射化合物I-2a的Beagle犬中有2只死亡，2只出现肌无力、恶心症状，半天后全部死亡；5天后注射Cabazitaxel的Beagle犬中有2只死亡，其他供试组中未出现死亡，但均出现恶心、四肢抽搐、无力症状；空白对照组无明显异常症状。
除本发明化合物11-54外的其他式I结构范围内的化合物亦可按照实施例1-16记载的方法进行合成，本发明式I化合物对耐药的肿瘤细胞株(A549/Pac、MCF-7/Doc、PC-3/Doc)的IC50范围为0.7～144nM范围内，其毒副作用均小于Cabazitaxel和化合物I-2a，限于篇幅，在此不一一累述。
本发明的优点在于：(1)本发明式I化合物对紫杉醇、多西紫杉醇耐药的肿瘤细胞株(A549/Pac、MCF-7/Doc、PC-3/Doc)具有显著的抗肿瘤活性，其活性优于Cabazitaxel、Larotaxel及Larotaxel类似物(I-2a)；(2)本发明式I化合物不仅具有显著的抗肿瘤活性，同时具有较低的毒副作用，其毒副作用小于Cabazitaxel、化合物I-2a；(3)本发明式I化合物属于Cabazitaxel的me-better药物。
在本发明提及的所有文献都在本申请中引用作为参考文献，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述内容之后，本领域的技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (22)

  1. 一种式I结构的紫杉烷类化合物、其立体异构体、溶剂化物、晶体、前药或其药学上可接受的盐，其特征在于式Ⅰ化合物具有如下结构：
    Figure PCTCN2014090135-appb-100001
    其中R1、R2各自独立地选自C1-C3的烷基、C1-C3的卤代烷基，R6选自C1-C4的烷基、C2-C4的烯基、C1-C4的卤代烷基、C2-C4的卤代烯基或任选卤代的苯基，R4选自C1-C3的烷氧基、卤素、氢、-N3；前提条件是当R4为氢时，R6不为任选卤代的苯基。
  2. 权利要求1所述的式I化合物，其特征在于所述取代基R1、R2、R6中的“卤代”优选一氟取代、二氟取代、三氟取代。
  3. 权利要求1-2任一项所述的式I化合物，其特征在于R1、R2各自独立地选自甲基、乙基、丙基、卤代甲基、卤代乙基，所述卤代为一氟取代、二氟取代、三氟取代、一氯取代、二氯取代、三氯取代。
  4. 权利要求3所述的式I化合物，其特征在于R1、R2均选自甲基或卤代甲基。
  5. 权利要求4所述的式I化合物选自具有如下结构的化合物11-54：
    Figure PCTCN2014090135-appb-100002
    Figure PCTCN2014090135-appb-100003
    Figure PCTCN2014090135-appb-100004
    Figure PCTCN2014090135-appb-100005
    Figure PCTCN2014090135-appb-100006
    及其立体异构体、溶剂化物、晶体、前药或其药学上可接受的盐。
  6. 一种抗肿瘤药物，其特征在于以权利要求1-5任一项所述的式I化合物、其立体异构体、溶剂化物、晶体、前药或其药学上可接受的盐作为有效成分。
  7. 一种药物组合物，其特征在于包含权利要求1-5任一项所述的式I化合物、其立体异构体、溶剂化物、晶体、前药或其药学上可接受的盐，和至少一种其他抗肿瘤药物和/或药学上可接受的载体或赋形剂。
  8. 权利要求7所述的药物组合物，其特征在于该药物组合物优选注射剂、口服制剂、冻干粉针剂、悬浮剂。
  9. 权利要求1-5任一项所述的式I化合物、其立体异构体、溶剂化物、晶体、前药或其药学上可接受的盐以及权利要求6所述的药物或权利要求7所述的药物组合物在制备抗肿瘤药物中的用途。
  10. 权利要求9所述的用途，其特征在于所述抗肿瘤药物为抗多药耐药肿瘤药物。
  11. 权利要求1-5任一项所述的式I化合物、其立体异构体、溶剂化物、晶体、前药或其药学上可接受的盐以及权利要求7所述的药物组合物在制备药物中的用途，所述药物用于治疗对紫杉醇和/或多西紫杉醇耐药的肿瘤。
  12. 权利要求10-11所述的用途，其特征在于肿瘤的耐药机制为P-糖蛋白过表达引起的药物外排泵作用。
  13. 权利要求1-5任一项所述的式I化合物、其立体异构体、溶剂化物、晶体、前药或其药学上可接受的盐以及权利要求7所述的药物组合物在制备药物中的用途，所述药物用于治疗卵巢癌、乳腺癌、肺癌、黑色素瘤、前列腺癌、白血病。
  14. 权利要求1-5任一项所述的式I化合物、其立体异构体、溶剂化物、晶体、前药或其药学上可接受的盐在制备抗肿瘤先导化合物中的应用。
  15. 权利要求1-5任一项所述的式I化合物、其立体异构体、溶剂化物、晶体、前药或其药学上可接受的盐在制备抗肿瘤候选药物中的应用。
  16. 权利要求4或5所述的式I化合物的制备方法，包括如下步骤：
    Figure PCTCN2014090135-appb-100007
    化合物5与式III化合物在碱(如LiHMDS、NaHMDS)的作用下，得到式II-8化合物，接下来在合适的条件下(如Raneynickel/H2作用下)脱除甲硫基亚甲基(MTM)中的甲硫基，得到式II-9化合物，接下来在合适的条件下(如氟代季铵盐(优选TBAF)、HF、醋酸/甲醇或醋酸/锌)脱除R5保护基，得到式I-3化合物；其中式II-9化合物也可由化合物6与式III化合物在碱(如LiHMDS、NaHMDS)的作用下得到；
    或者式II-9化合物在Red-Al或碱性季铵盐(优选苄基三甲基氢氧化铵(Triton B))的作用下，脱除2-位苯甲酰基，形成式II-10化合物，式II-10化合物与间位被R4取代的苯甲酸在合适的条件下(碳二亚胺类缩合剂(优选DCC、DIC或EDCI)及DMAP作用下)进行缩合形成式II-11化合物，接下来在合适的条件下(如氟代季铵盐(优选TBAF)、HF、醋酸/甲醇或醋酸/锌)脱除R5保护基，得到式I-4化合物；
    其中R5为硅基或烷氧基亚烷基，优选TBS、TES、TMS、TIPS、TBDPS、EE(1-乙氧基乙基)、MOM(甲氧甲基)；R4、R6与权利要求4或5所述的式I化合物中的定义相同。
  17. 权利要求1-5任一项所述的式I化合物的制备方法，包括如下步骤：
    Figure PCTCN2014090135-appb-100008
    以10-去乙酰巴卡亭III(10-DAB)为原料与烷基卤硅烷(如TBSCl、TESCl、TIPSCl、TBDPSCl、TMSCl)反应形成式II-1化合物，接下来在碱性条件下(如NaH、LiH、KH)与C1-C3卤代烷基(如碘甲烷、溴乙烷、1-碘-2氯乙烷等)反应得到II-2化合物，在适当条件下(如TBAF或HF作用下)脱除硅基保护基得到II-3化合物，再在碱性条件下(如NaH、LiH、KH)与C1-C3卤代烷基(如碘甲烷、碘乙烷、溴乙烷、1-碘-2氯乙烷等)反应得到式II-4化合物，式II-4化合物与式III化合物在碱(如LiHMDS、NaHMDS)的作用下，得到式II-5化合物，接下来在合适的条件下(如氟代季铵盐(优选TBAF)、HF、醋酸/甲醇或醋酸/锌)脱除R5保护基，得到式I-1化合物；
    或者式II-5化合物在Red-Al或碱性季铵盐(优选苄基三甲基氢氧化铵(Triton B))的作用下，脱除2-位苯甲酰基，形成式II-6化合物，式II-6化合物与间位被R4取代的苯甲酸在合适的条件下(碳二亚胺类缩合剂(优选DCC、DIC或EDCI)及DMAP)进行缩合形成式II-7 化合物，接下来在合适的条件下(如氟代季铵盐(优选TBAF)、HF、醋酸/甲醇或醋酸/锌)脱除R5保护基，得到式I-2化合物；
    其中R1、R2、R4、R6的定义与权利要求1-5任一项对式I化合物的定义相同，R5为硅基或烷氧基亚烷基，优选TBS、TES、TMS、TIPS、TBDPS、EE、MOM，R9表示硅基保护基，优选TMS、TES、TIPS、TBS、TBDPS。
  18. 一种制备权利要求1-5任一项所述的式I化合物的中间体，具有式II-5所示的结构：
    Figure PCTCN2014090135-appb-100009
    其中R1、R2各自独立地选自C1-C3的烷基、C1-C3的卤代烷基，R6选自C1-C4的烷基、C2-C4的烯基、C1-C4的卤代烷基、C2-C4的卤代烯基，R5选自硅基或烷氧基亚烷基，优选TBS、TES、TMS、TIPS、TBDPS、EE、MOM。
  19. 一种制备权利要求1-5任一项所述的式I化合物的中间体，具有式II-7所示的结构：
    Figure PCTCN2014090135-appb-100010
    其中R1、R2、R4、R6的定义同权利要求1-5任一项对式I化合物的定义，R5的定义同权利要求18对式II-5化合物的定义。
  20. 一种制备权利要求1-5任一项所述的式I化合物的中间体，具有式II-9所示的结构：
    Figure PCTCN2014090135-appb-100011
    其中R5、R6的定义同权利要求18对式II-5化合物的定义。
  21. 一种制备权利要求1-5任一项所述的式I化合物的中间体，具有式II-11化合物：
    Figure PCTCN2014090135-appb-100012
    其中R4、R5、R6的定义同权利要求19对式II-7化合物的定义。
  22. 权利要求18-21任一项所述的中间体选自如下化合物：
    Figure PCTCN2014090135-appb-100013
    ，该权利要求所述的中间体还包括将化合物62、63、65、66、80、71、72、73、74中TBS基团替换为TES、TMS、TIPS、TBDPS、EE、MOM的中间体。
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