WO2017097245A1 - 三尖杉酯类生物碱、其制备方法和用途 - Google Patents

三尖杉酯类生物碱、其制备方法和用途 Download PDF

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WO2017097245A1
WO2017097245A1 PCT/CN2016/109122 CN2016109122W WO2017097245A1 WO 2017097245 A1 WO2017097245 A1 WO 2017097245A1 CN 2016109122 W CN2016109122 W CN 2016109122W WO 2017097245 A1 WO2017097245 A1 WO 2017097245A1
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group
compound
membered
alkyl
reaction
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PCT/CN2016/109122
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French (fr)
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陈莉
马国贞
李卫东
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南开大学
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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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems

Definitions

  • the present invention relates to a cephalosporin alkaloid, a preparation method thereof and use thereof, and belongs to the field of pharmaceutical compounds and preparation methods thereof.
  • the cephalosporin alkaloids such as Harringtonine (HT), Homoharringtonine (HHT), Deoxyharringtonine (DHT) and Isochrylar Isoharringtonine (IHT) is a broad-spectrum anticancer drug.
  • homoharringtonine 2 was enrolled in the Chinese Pharmacopoeia in 1990 for clinical treatment of acute non-lymphocytic leukemia, and has been clinically applied until now (Chinese Pharmacopoeia 1990 edition two, 1990, 588; Chinese Pharmacopoeia 2005 edition two, 2005 , 629).
  • Formula (6) is a general formula of natural harringtonine alkaloids, the molecular structure of which consists of two parts of the paclitaxel mother nucleus and the side chain, and the parent nucleus cephalosporin (5) has no physiological activity.
  • the configuration of the chiral carbon of the side chain moiety C-2' of formula (6) is critical to the biological activity of such compounds.
  • the chiral carbon is in the R configuration, the compound may be biologically active, while the isomer of the S configuration is often not biologically active.
  • C-2' is a structure such as an achiral carbon atom, the biological activity of the compound is remarkably lowered.
  • the medicinal harringtonine alkaloids are isolated from crude plants.
  • the crude alkaloids are predominantly (at least 50%) composed of cephalosporin.
  • the cephalosporin present in the regenerable parts (branches, leaves) of plants is a biosynthetic precursor of the harringtonine alkaloid.
  • Natural harringtonine alkaloids account for only a small fraction of total alkaloids and are mainly found in non-renewable parts of plants.
  • the harringtonine alkaloids are also mixed with many similarly similar congeners, so it is difficult to isolate high purity harrington alkaloids from natural products. .
  • the number of rough genus plants has dropped dramatically and has become a rare protected plant. Therefore, the isolation of harringtonine alkaloids from plants is far from meeting the needs of clinical applications.
  • the US approved Omacetaxine drug was obtained using the method reported by Robin equal to 1999 (Tetrahedron Lett. 1999, 40, 2931-2934; CN 1300289A, 1999). Although this method can obtain an optically pure harringtonine base, it is necessary to use an auxiliary chiral group, the synthesis line is long, and the operation steps are lengthy.
  • Jin reported that optically pure D-malic acid was used as a raw material (J. Am. Chem. Soc. 2006, 128, 10370-10371) to obtain optically pure ⁇ -cyclobutyrolactone, which was subjected to multi-step reaction. Obtained optically pure deoxyharringtonine and its analogs. Although the method has high purity of the harringtonine base, it requires the use of optically pure raw materials, and the synthetic route is long, and it is not easy to be applied to industrial production.
  • the present invention provides a harreria alkaloid compound represented by the formula (I), a pharmaceutically acceptable salt thereof, a tautomer, a stereoisomer thereof and a solvate thereof:
  • R a is R b is H, a is adjacent For a single button, b is adjacent For double bonds;
  • R a is H and R b is Adjacent For double bonds, b adjacent For a single button;
  • R c is selected from the group consisting of C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-20 cycloalkyl, C 5 optionally substituted by one or more R m a -20 cycloalkenyl group, a 3-20 membered heterocyclic group, a C 6-20 aryl group, a 5-20 membered heteroaryl group, wherein the heterocyclic group and the heteroaryl group contain 1-5 independently selected from N, O And the hetero atom of S;
  • R 1 , R 2 , R 3 may independently be selected from hydrogen, F, Cl, Br, I, OH, SH, CN or the following groups optionally substituted by one or more R m : C 1-40 alkane , C 2-40 alkenyl, C 2-40 alkynyl, C 3-20 cycloalkyl, C 5-20 cycloalkenyl, 3-20 membered heterocyclic, C 6-20 aryl, 5-20 Heteroaryl, NH 2 , C 1-40 alkyloxy, C 2-40 alkenyloxy, C 2-40 alkynyloxy, C 3-20 cycloalkyloxy, C 5-20 ring Alkenyloxy, 3-20 membered heterocyclyloxy, C 6-20 aryloxy, 5-20 membered heteroaryloxy, -SiR 6 R 7 R 8 , -OSiR 6 R 7 R 8 , Wherein said heterocyclic group and heteroaryl group comprise 1-5 heteroatoms independently selected from N, O and S;
  • R 4 may be selected from hydrogen or the following groups optionally substituted by one or more R m : C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-20 cycloalkyl , C 5-20 cycloalkenyl, 3-20 membered heterocyclic, C 6-20 aryl, 5-20 membered heteroaryl, NH 2 , C 1-40 alkyloxy, C 2-40 alkenyl Oxy, C 2-40 alkynyloxy, C 3-20 cycloalkyloxy, C 5-20 cycloalkenyloxy, 3-20 membered heterocyclyloxy, C 6-20 aryloxy a 5-20 membered heteroaryloxy group, -SiR 6 R 7 R 8 , -OSiR 6 R 7 R 8 , wherein the heterocyclic group and heteroaryl group contain 1-5 independently selected from N, O and S Hetero atom
  • R 5 is selected from the group consisting of OH, SH, F, Cl, Br, I, CN, NH 2 ;
  • R 1 and R 5 are not simultaneously OH or SH;
  • R 1 , R 5 together with the carbon atom to which they are attached form a C 3-20 cycloalkyl, C 5-20 cycloalkenyl group optionally substituted by one or more R m or from 1 to 5 selected from N a 3-20 membered heterocyclic group of a hetero atom of O and S;
  • R 1 , R 3 together with the carbon atom to which they are attached form a C 3-20 cycloalkyl, C 5-20 cycloalkenyl or 3-20 membered heterocyclyl optionally substituted by one or more R m , Wherein the heterocyclic group contains 1-5 heteroatoms independently selected from N, O and S;
  • R 6 , R 7 , R 8 are, independently of each other, hydrogen or the following groups optionally substituted by one or more R m : C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-20 cycloalkyl, C 5-20 cycloalkenyl, 3-20 membered heterocyclic, C 6-20 aryl, 5-20 membered heteroaryl, C 1-40 alkyloxy, C 2 -40 alkenyloxy, C 2-40 alkynyloxy, C 3-20 cycloalkyloxy, C 5-20 cycloalkenyloxy, 3-20 membered heterocyclyloxy, C 6-20 An aryloxy group, a 5-20 membered heteroaryloxy group, a C 1 -C 40 alkylsilyl group, a C 1 -C 40 alkylsilyloxy group, wherein the heterocyclic group and the heteroaryl group comprise 1- 5 heteroatoms independently selected from N, O and S;
  • Each R m is independently selected from the group consisting of F, Cl, Br, I, OH, SH, CN, NR d R e , or C 1-40 alkyl, C 2 optionally substituted by one or more R m ' 40 alkenyl, C 2-40 alkynyl, C 3-20 cycloalkyl, C 5-20 cycloalkenyl, 3-20 membered heterocyclic, C 6-20 aryl, 5-20 membered heteroaryl, C 1 -C 40 alkylsilyl, di(C 1 -C 40 alkyl)silyl, tri(C 1 -C 40 alkyl)silyl, C 1-40 alkyloxy, C 2-40 olefin Alkoxy, C 2-40 alkynyloxy, C 3-20 cycloalkyloxy, C 5-20 cycloalkenyloxy, 3-20 membered heterocyclyloxy, C 6-20 aryloxy Base, 5-20 membered heteroaryloxy, R t C
  • Each R t is independently of one another selected from C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-20 cycloalkyl optionally substituted by one or more R m ' C 5-20 cycloalkenyl, 3-20 membered heterocyclic group, C 6-20 aryl, 5-20 membered heteroaryl;
  • Each R m ' is independently selected from the group consisting of F, Cl, Br, I, OH, SH, CN, NR d R e , C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-20 cycloalkyl, C 5-20 cycloalkenyl, 3-20 membered heterocyclic, C 6-20 aryl, 5-20 membered heteroaryl, C 1 -C 40 alkylsilyl, di C 1 -C 40 alkyl)silyl, tri(C 1 -C 40 alkyl)silyl, C 1-40 alkyloxy, C 2-40 alkenyloxy, C 2-40 alkynyloxy , C 3-20 cycloalkyloxy, C 5-20 cycloalkenyloxy, 3-20 membered heterocyclyloxy, C 6-20 aryloxy, 5-20 membered heteroaryloxy, SiR 6 R 7 R 8 , —OSiR 6 R 7 R 8
  • X is selected from NR n , O or S;
  • R n is selected from the group consisting of H, C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-20 cycloalkyl, C 5-20 cycloalkenyl, 3-20 membered heterocyclic group a C 6-20 aryl, 5-20 membered heteroaryl group, wherein the heterocyclic group and heteroaryl group contain 1-5 heteroatoms independently selected from N, O and S.
  • R 1 , R 5 may form together with the carbon atom to which they are attached E.g or Wherein n is an integer from one of 1 to 16, such as 1, 2 or 3.
  • a compound according to the invention wherein one or more chiral carbon atoms may be present.
  • the compounds of the present invention in which the respective chiral carbons are in the R configuration, the S configuration, or a mixture thereof are encompassed within the scope of the compounds of the present invention.
  • at least the carbon atom labeled * in the compound of formula (I) may be a chiral carbon atom, and its stereo configuration may be R or S type.
  • R a can be Or R b can be
  • R 1 is preferably selected from C 1-10 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-20 naphthenic optionally substituted by one or more R m a group, a C 5-20 cycloalkenyl group, a 3-20 membered heterocyclic group, a C 6-20 aryl group, a 5-20 membered heteroaryl group;
  • R 1 can be among them, Is a single bond or a double bond, n is an integer selected from one of 0 to 16, such as 0, 1, 2 or 3; or a C 1-10 alkyl group, C 6 optionally substituted by one or more R m -20 aryl, 5-20 membered heteroaryl;
  • R 5 is preferably OH or SH
  • R 1 and R 5 are preferably formed together with the carbon atom to which they are attached E.g or Wherein n is an integer from one of 1 to 16;
  • R 2 and R 3 are, independently of each other, preferably selected from hydrogen, F, Cl, Br, I or a C 1-40 alkyl group optionally substituted by one or more R m ;
  • X is O
  • R 4 is preferably selected from hydrogen or the following groups optionally substituted by one or more R m : C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-20 cycloalkyl , C 5-20 cycloalkenyl, 3-20 membered heterocyclic group, C 6-20 aryl, 5-20 membered heteroaryl;
  • each R m is independently absent or selected from hydrogen, F, Cl, Br, I, OH, SH, CN, SiR 6 R 7 R 8 , -OSiR 6 R 7 R 8 , or optionally Or a plurality of R m ' substituted C 3-20 cycloalkyl groups, C 5-20 cycloalkenyl groups, 3-20 membered heterocyclic groups, C 6-20 aryl groups, 5-20 membered heteroaryl groups, C 1- 40 alkyloxy, C 2-40 alkenyloxy, C 2-40 alkynyloxy, C 3-20 cycloalkyloxy, C 5-20 cycloalkenyloxy, 3-20 membered heterocyclic ring a oxy group, a C 6-20 aryloxy group, a 5-20 membered heteroaryloxy group, wherein the heterocyclic group and the heteroaryl group comprise 1 to 5 hetero atoms independently selected from N, O and S;
  • Each R m ' is independently selected from the group consisting of F, Cl, Br, I, OH, SH, CN, NR d R e , C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-20 cycloalkyl, C 5-20 cycloalkenyl, 3-20 membered heterocyclic, C 6-20 aryl, 5-20 membered heteroaryl, C 1 -C 40 alkylsilyl, di C 1 -C 40 alkyl)silyl, tri(C 1 -C 40 alkyl)silyl, C 1-40 alkyloxy, C 2-40 alkenyloxy, C 2-40 alkynyloxy , C 3-20 cycloalkyloxy, C 5-20 cycloalkenyloxy, 3-20 membered heterocyclyloxy, C 6-20 aryloxy, 5-20 membered heteroaryloxy, SiR 6 R 7 R 8 , —OSiR 6 R 7 R 8
  • R 1 may be selected from C 1-10 alkyl or C 2-40 alkenyl optionally substituted by one or more substituents selected from F, Cl, Br, I, for example optionally by one or more a C 1-6 alkyl group or a C 2-40 alkenyl group substituted with a substituent selected from F, Cl, Br, I.
  • the C 1-6 alkyl group may be, for example, 4-methyl-n-pentyl or 3-methyl-n-butyl
  • the C 2-40 alkenyl group may be, for example, 4-methyl-pent-3-enyl;
  • R 1 may be selected, for example, from C 1-6 alkyl-, phenyl C 1-6 alkyl-, 2-C 1-6 alkoxyphenyl-, 3-C 1-6 alkoxyphenyl -, 4-C 1-6 alkoxyphenyl-, 3,4-di-C 1-6 alkoxyphenyl-, 2,4-di(C 1-6 alkoxy)phenyl-, 2 , 3-di(C 1-6 alkoxy)phenyl-.
  • the compound of formula (I) may be selected from the group consisting of:
  • the present invention also provides a method for preparing a harreria alkaloid compound represented by the formula (I), a pharmaceutically acceptable salt thereof, a tautomer, a stereoisomer and a solvate thereof:
  • the method comprises reacting a compound of formula (11) with a compound of formula (12) in the presence of a Lewis acid:
  • R a , R b , R c , a, b, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 each independently have the above-defined definition, and R 5 is OH.
  • the molar ratio of the compound of the formula (11), the enol silyl ether of the formula (12) and the Lewis acid can be determined by those skilled in the art according to the reaction needs.
  • the molar ratio of the compound of the formula (11), the enol silyl ether of the formula (12) and the Lewis acid may be from 1:1 to 20:1 to 20, preferably from 1:1 to 10:1 to 10 More preferably, it is 1:1.05 to 5:1.05 to 5, for example, 1:1.1 to 3:1.1 to 3.
  • a compound of formula (11) can be reacted with a compound of formula (12) in the presence of a Lewis acid to produce a compound of formula (7), (8) and (9):
  • reaction is preferably carried out in an inert solvent.
  • the reaction can be carried out at a suitable temperature.
  • the temperature may be below 50 °C, such as from -80 °C to 50 °C, such as from -80 °C to 30 °C.
  • the invention further provides a process for the preparation of a compound of formula (I-1), which comprises subjecting a compound of formula (II) to a reduction reaction:
  • Hal is F, Cl, Br or I
  • X, R 1 , R 4 , R 5 and R c each independently have the definitions described above.
  • the reduction reaction conditions are conventional conditions known to those skilled in the art. For example, it can be reacted in a solvent containing acetic acid in the presence of zinc powder.
  • the reaction temperature may be 50 ° C or lower, for example, -80 ° C to 50 ° C, for example, -20 ° C to 30 ° C.
  • the invention provides a process for the preparation of compound 14 from compound 13:
  • R 1 , R 4 and R c each independently have the definitions described above.
  • R 1 and R 4 each independently have the definitions described above.
  • the preparation method of the present invention further includes one or more of the following reactions:
  • R p is -SiR 6 R 7 R 8 and R q is a methyl group.
  • R p is absent and R q is methyl, For double bonds
  • R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R c , X, n each independently have the definitions described above.
  • the above reaction can be carried out under the following conditions.
  • the reaction conditions and parameters described in the following examples apply not only to the specific compounds described below, but also to the compounds of the above formula. Combinations or combinations of the reaction conditions and parameters with the above-described compounds of the formula are also to be understood as being included in the present specification.
  • reaction 1) the following conditions 1a), 1b) or 1c) can be employed:
  • reaction can be carried out in an inert solvent
  • the reaction can be carried out in the presence of a hydrobromic acid solution
  • the hydrobromic acid solution is preferably a hydrobromic acid aqueous solution or a hydrobromic acid acetic acid solution, and the weight percentage thereof may be 30 to 40% by weight, for example, 40% by weight aqueous hydrobromic acid solution or 33% by weight hydrochloroacetic acid acetic acid solution.
  • the reaction temperature may be 30 ° C or less, for example, -30 ° C to 30 ° C;
  • the pH is adjusted to 8 or more with a base, for example, 9 to give the target compound.
  • hydrobromic acid acetic acid solution for example, 40% by weight aqueous hydrobromic acid solution or 33% by weight hydrobromic acid acetic acid solution
  • reaction can be carried out in an inert solvent
  • the reaction can be carried out in the presence of mercury acetate (Hg(OAc) 2 ), followed by the addition of sodium borohydride in sodium hydroxide solution to the system;
  • mercury acetate may be used in a mixture of 30% by weight to 40% by weight, for example, 33% by weight of mercury acetate and an inert solvent and water;
  • the reaction temperature may be 30 ° C or less, for example, -30 ° C to 30 ° C;
  • the reaction time can be, for example, 2 to 8 hours;
  • the compound 15a is dissolved in a mixture of an inert solvent and water, and a mixture of an appropriate amount of 33% by weight of mercury acetate in an inert solvent and water is added, and the mixture is reacted at 30 ° C or lower, for example, -30 ° C to 30 ° C. After reacting for 2-8 hours, an appropriate amount of sodium borohydride solution of sodium hydroxide can be added to the system.
  • reaction can be carried out in an inert solvent
  • the reaction temperature may be 30 ° C or less, for example, -30 ° C to 30 ° C;
  • the reaction is preferably carried out in an aqueous solution of iron oxalate hexahydrate (Fe 2 (C 2 O 4 ) 3 ⁇ 6H 2 O) and in the presence of sodium borohydride (NaBH 4 );
  • the compound 15a is dissolved in an inert solvent, added to an aqueous solution of Fe 2 (C 2 O 4 ) 3 ⁇ 6H 2 O, added with NaBH 4 , and reacted at 30 ° C or lower, for example, -30 ° C to 30 ° C.
  • the method can be carried out in an inert solvent
  • the reaction temperature may be, for example, 100 ° C or less, for example, -30 ° C to 100 ° C;
  • the method can be carried out in the presence of a fluorinating reagent, which can be selected from the group consisting of potassium fluoride, triethylamine trihydrofluoride, trifluoroacetic acid, hydrogen fluoride, boron trifluoride, tetrabutyl One or more of the fluorinated ammonia;
  • a fluorinating reagent which can be selected from the group consisting of potassium fluoride, triethylamine trihydrofluoride, trifluoroacetic acid, hydrogen fluoride, boron trifluoride, tetrabutyl One or more of the fluorinated ammonia;
  • the compound of the formula 16a is reacted with a fluorinating reagent in an inert solvent at a temperature below 100 ° C, for example, at a temperature ranging from -30 ° C to 100 ° C, and the silicon group is removed to obtain a harringtonine base and a homoharringtonine base. .
  • reaction can be carried out in an inert solvent
  • the reaction temperature may be 30 ° C or less, for example, -30 ° C to 30 ° C;
  • the reaction is carried out in the presence of a mineral acid or a Lewis acid;
  • the compound of the formula 17a is reacted in an inert solvent under the action of a mineral acid or a Lewis acid at 30 ° C or lower, for example, -30 ° C to 30 ° C to obtain a cyclic compound 10.
  • the compound of formula 17 or 17a can be prepared by methods known in the art.
  • a compound of formula 17a can be prepared from the following compounds of formula 11a and 12a:
  • the solvent suitable for the preparation method of the present invention may comprise a mixture selected from one or more of the following: a ketone solvent such as acetone and methyl ethyl ketone; an ether solvent including an acyclic ether and a cyclic ether such as diethyl ether.
  • a ketone solvent such as acetone and methyl ethyl ketone
  • an ether solvent including an acyclic ether and a cyclic ether such as diethyl ether.
  • ester solvent such as ethyl acetate or butyl acetate
  • alkane solvent such as n-hexane or n-heptane
  • halogenated alkane solvent such as methyl chloride, dichloromethane, chloroform , carbon tetrachloride, 1,2-dichloroethane
  • cycloalkane solvent such as cyclohexane or cycloheptane
  • substituted or unsubstituted aromatic hydrocarbon solvent such as benzene, toluene, xylene, chlorobenzene
  • alcohol Solvent-like solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol or t-butanol; or other solvents such as N,N-dimethylformamide (DMF), dimethyl Sulfone (DMSO), N-methylpyrrolidon
  • the solvent is a mixture of one or more selected from the above solvents, and an inert solvent which is inert to the reaction substrate and the catalyst.
  • the inert solvent may be selected, for example, from an ether solvent (e.g., diethyl ether, tetrahydrofuran, dioxane), a halogenated alkane solvent (e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2-di).
  • ether solvent e.g., diethyl ether, tetrahydrofuran, dioxane
  • a halogenated alkane solvent e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2-di.
  • ethyl chloride a substituted or unsubstituted aromatic hydrocarbon such as benzene, toluene, chlorobenzene, preferably an ether solvent and/or a halogenated hydrocarbon solvent.
  • aromatic hydrocarbon such as benzene, toluene, chlorobenzene, preferably an ether solvent and/or a halogenated hydrocarbon solvent.
  • the base may be an organic base, an inorganic base or a mixture thereof, for example selected from alkali metal or alkaline earth metal carbonates or hydrogencarbonates, such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, sodium hydrogencarbonate, Potassium hydrogencarbonate, calcium hydrogencarbonate; alkali metal alkoxides such as sodium t-butoxide or potassium t-butoxide; alkali metal hydrides such as sodium hydride or potassium hydride; amides such as bis(trimethylsilyl)amino Lithium, bis(trimethylsilyl)amino potassium or lithium diisopropylamide (LDA); organic amines such as triethylamine, N-methylmorpholine, piperidine, N-methylpiperidine, N , N-diisopropylethylamine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0
  • the acid may be an organic acid, an inorganic acid or a mixture thereof, for example one or more selected from the group consisting of carboxylic acids such as acetic acid or trifluoroacetic acid; sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid or Toluenesulfonic acid; phosphonic acid; hydrochloric acid, sulfuric acid, phosphoric acid.
  • carboxylic acids such as acetic acid or trifluoroacetic acid
  • sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid or Toluenesulfonic acid
  • phosphonic acid such as hydrochloric acid, sulfuric acid, phosphoric acid.
  • the acid also includes a Lewis acid.
  • the Lewis acid may be selected from, for example, BF 3 ⁇ OEt 2 , MgCl 2 , MgBr 2 , ZnBr 2 , ZnI 2 , ZnCl 2 , ZnSO 4 , CuCl 2 , CuCl, Cu(O 3 SCF 3 ) 2 , CoCl 2 , CoI 2 , FeI 2 , FeCl 3 , FeCl 2 , FeCl 2 , SnCl 4 , TiCl 4 , TiCl 3 , MnCl 2 , ScCl 3 , AlCl 3 , (iC 4 H 9 ) 2 AlCl, (C 6 H 5 ) 2 AlCl , (C 6 H 5) AlCl 2, ReCl 5, ZrCl 4, NbCl 5, VCl 3, CrCl 2, MoCl 5, YCl 3, CdCl 2, LaCl 3, Er (O 3 SCF 3) 3, Yb
  • the preparation method also includes a post-treatment step and a purification step which are carried out after the above reaction.
  • post-treatment and/or purification can be carried out using conventional methods of the prior art, including separation, such as by distillation, phase separation, recrystallization, column chromatography, and the like.
  • one skilled in the art can prepare another compound of the formula (I), a pharmaceutically acceptable salt thereof, and a stereotype starting from a compound of the formula (I) as required by a reaction known in the art. Isomer or solvate.
  • the starting compound of formula (I) is also referred to as the starting material or intermediate.
  • the method further comprises reacting the resulting compound with an acid or base to obtain a pharmaceutically acceptable salt of the compound of formula (I).
  • the method further comprises forming the solvate of the resulting compound with a solvent.
  • the method further comprises separating the resulting compound to give its stereoisomer.
  • each reaction substrate and reaction conditions can be arbitrarily combined as needed.
  • the reaction conditions described in the reactions 1), 2) and 3) and preferred are also suitable for the preparation of other compounds of the formulae (7), (8) and (9).
  • the order of addition of the raw materials and reagents as the reaction substrate is not particularly limited. In a specific embodiment, one skilled in the art can adjust or modify the order of addition as needed. These adjustments or variations are also encompassed within the scope of protection of the preparation process of the invention.
  • the invention also provides pharmaceutical compositions comprising one or more compounds of the invention, or pharmaceutically acceptable salts, tautomers, stereoisomers and solvates thereof. These compositions can be utilized to achieve the desired pharmacological effect by administration to a patient in need thereof.
  • a patient is a mammal, including a human, in need of treatment for a particular condition or disease.
  • the invention includes pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable carrier is preferably a carrier which is relatively non-toxic and harmless to the patient at a concentration consistent with the effective activity of the active ingredient, such that any side effects caused by the carrier do not destroy the active ingredient.
  • the pharmaceutically effective amount of a compound, or a pharmaceutically acceptable salt thereof is preferably an amount that produces a result or affects the particular condition being treated.
  • the compounds of the present invention can be administered, together with pharmaceutically acceptable carriers well known in the art, in any effective conventional dosage unit form, including immediate release, sustained release and time release formulations, in the following manner: oral, parenteral , local, nasal, ocular, sublingual, rectal, vaginal administration, etc.
  • the compound or a pharmaceutically acceptable salt thereof can be formulated into a solid or liquid preparation such as a capsule, a pill, a tablet, a troche, a lozenge, a melt adhesive. (melt), powder, solution, suspension or emulsion, and can be prepared according to methods known in the art for preparing pharmaceutical compositions.
  • the solid unit dosage form can be a capsule which may be a conventional hard or soft capsule type including, for example, a surfactant, a lubricant, and an inert filler such as lactose, sucrose, calcium phosphate, and corn starch.
  • a compound of the invention, or a pharmaceutically acceptable salt thereof can be compressed into a tablet together with a conventional tablet base (eg, lactose, sucrose, and corn starch) and in combination with: a binder (for example, gum arabic, corn starch or gelatin), a disintegrant for decomposing and dissolving the tablet after administration (for example, potato starch, alginic acid, corn starch and guar gum, gum tragacanth, gum arabic), A lubricant (such as talc, stearic acid or magnesium stearate, calcium stearate or zinc stearate) for improving the fluidity of tablet granulation and preventing the tablet material from adhering to the surface of the tablet mold and punch ), dyes, colorants, and flavoring agents (such as peppermint, wintergreen or cherry flavor) used to improve the sensory properties of the tablets and make them more acceptable to the patient.
  • a binder for example, gum arabic, corn starch or gelatin
  • Suitable excipients for oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols (e.g., ethanol, benzyl alcohol and polyvinyl alcohol) with or without the addition of a pharmaceutically acceptable surface
  • dicalcium phosphate and diluents such as water and alcohols (e.g., ethanol, benzyl alcohol and polyvinyl alcohol) with or without the addition of a pharmaceutically acceptable surface
  • An active agent, suspending agent or emulsifier may be present as coatings or to modify the physical form of the dosage unit. For example, tablets, pills or capsules may be coated with shellac, sugar or both.
  • the compound of the present invention can also be administered parenterally as an injection of the compound, i.e., subcutaneously, intravenously, intraocularly, intrasynovally, intramuscularly or intraperitoneally, preferably in the presence of a pharmaceutically acceptable drug carrier.
  • the pharmaceutical carrier can be a sterile liquid or a mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, such as ethanol, isopropanol or cetyl alcohol, a diol such as propylene glycol or polyethylene glycol, a glycerol ketal such as 2,2-dimethyl-1,1-dioxolan-4-methanol, an ether such as polyethylene glycol 400 (PEG400), an oil, a fatty acid, a fatty acid ester or a fatty acid glyceride or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant such as soap or detergent, suspending agents such as gum, carbomer, nail Cellulose, hypromellose or carboxymethylcellulose, or emulsifiers and other pharmaceutical adjuvants.
  • a pharmaceutically acceptable surfactant such as soap or detergent
  • suspending agents such as gum, carbomer
  • Exemplary surfactants for parenteral formulations are polyethylene sorbitan fatty acid esters, such as sorbitan monooleate, and high molecular weight adducts of ethylene oxide and a hydrophobic matrix,
  • the hydrophobic matrix is formed by the condensation of propylene oxide and propylene glycol.
  • composition of the present invention can also be administered in the form of a suppository for rectal administration of a drug.
  • a suppository for rectal administration of a drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and thus can be dissolved in the rectum to release the drug.
  • suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and thus can be dissolved in the rectum to release the drug.
  • Such materials are, for example, cocoa butter and polyethylene glycol.
  • Controlled release formulations for parenteral administration include liposomal microspheres, polymeric microspheres, and polymeric gel formulations known in the art.
  • the pharmaceutical composition may be required or must be delivered to the patient by a mechanical delivery device.
  • a mechanical delivery device for delivering medicaments are well known in the art.
  • direct techniques for administering drugs directly to the brain usually involve taking the drug.
  • the delivery catheter is placed into the ventricular system of the patient to bypass the blood-brain barrier.
  • the compounds of the invention may be administered as a single agent or in combination with one or more other agents, wherein the combination does not cause unacceptable adverse reactions.
  • the invention also relates to such combinations.
  • a compound of the invention can be combined with known chemotherapeutic or anticancer agents (e.g., agents against hyperproliferative diseases or other indications, and the like, and mixtures and combinations thereof).
  • Other indications include, but are not limited to, anti-angiogenic agents, mitotic inhibitors, alkylating agents, antimetabolites, DNA-embedded antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, topoisomerase inhibitors , biological response modifiers or anti-hormones.
  • cytotoxic agent and/or a cytostatic agent in combination with a compound or composition of the invention will serve the following effects:
  • Another aspect of the invention provides the use of a compound as described above for the manufacture of a pharmaceutical composition for the treatment or prevention of a disease.
  • the disease is a disease caused by uncontrolled cell growth, proliferation and/or survival, an inappropriate cellular immune response or an inappropriate cellular inflammatory response, or with uncontrolled cell growth, proliferation and/or survival.
  • a disease in which an inappropriate cellular immune response or an inappropriate cellular inflammatory response in particular, the disease is, for example, a hematological tumor, a solid tumor, and/or a metastasis thereof, such as leukemia and myelodysplastic syndrome, malignant lymphoma, Head and neck tumors including brain tumors and brain metastases, chest tumors including non-small cell lung tumors and small cell lung tumors, gastrointestinal tumors, endocrine tumors, breast tumors, and other gynecological tumors, including kidneys Urinary tumors, skin tumors and sarcomas, and/or their metastases, including tumors, bladder tumors, and prostate tumors. More particularly, the disease is leukemia.
  • the invention also provides the use of a compound of the invention and a composition thereof for the manufacture of a medicament for the treatment of a hyperproliferative disorder in a mammal.
  • Compounds can be utilized to inhibit, block, reduce, reduce, etc. cell proliferation and/or cell division and/or cause apoptosis.
  • Hyperproliferative disorders include, but are not limited to, psoriasis, keloids and other hyperplasia affecting the skin, benign prostatic hyperplasia (BpH), solid tumors such as breast cancer, respiratory cancer, lung cancer, brain cancer, genital cancer, digestive tract cancer, Urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer, and their distant metastases.
  • the condition also includes lymphoma, sarcoma and leukemia.
  • the compounds of the invention are also useful in the preparation of anti-tumor, anti-malarial, anti-parasitic, anti-fungal or anti-bacterial chemotherapy drugs.
  • C 1-40 alkyl is understood to preferably denote a straight or branched saturated monovalent hydrocarbon radical having from 1 to 40 carbon atoms, preferably a C 1-6 alkyl group.
  • C 1-6 alkyl is understood to preferably denote a straight or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methyl, ethyl, propyl, butyl.
  • the group has 1, 2, 3 or 4 carbon atoms ("C 1-4 alkyl”), such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, Sec-butyl, tert-butyl, more particularly, the group has 1, 2 or 3 carbon atoms ("C 1-3 alkyl”), such as methyl, ethyl, n-propyl or isopropyl .
  • C 1-4 alkyl such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, Sec-butyl, tert-butyl
  • C 1-3 alkyl such as methyl, ethyl, n-propyl or isopropyl .
  • C 2-40 alkenyl is understood to preferably denote a straight or branched monovalent hydrocarbon radical which contains one or more double bonds and has 2 to 40 carbon atoms, preferably "C 2-6 alkenyl”.
  • C 2-6 alkenyl is understood to preferably denote a straight or branched monovalent hydrocarbon radical which contains one or more double bonds and has 2, 3, 4, 5 or 6 carbon atoms, in particular 2 or Three carbon atoms (“C 2-3 alkenyl”), it is understood that where the alkenyl group contains more than one double bond, the double bonds may be separated or conjugated to each other.
  • the alkenyl group is, for example, a vinyl group, an allyl group, (E)-2-methylvinyl group, (Z)-2-methylvinyl group, (E)-but-2-alkenyl group, (Z)- But-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z) -pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-ene , hex-5-alkenyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3- Alkenyl, (E)-hex-2-enyl, (Z)-hex-2-enyl,
  • C 2-40 alkynyl is understood to mean a straight or branched monovalent hydrocarbon radical which contains one or more triple bonds and has 2 to 40 carbon atoms, preferably "C 2 -C 6 -alkynyl”".
  • C 2 -C 6 -alkynyl is understood to preferably denote a straight or branched monovalent hydrocarbon radical which contains one or more triple bonds and has 2, 3, 4, 5 or 6 carbon atoms, in particular It is 2 or 3 carbon atoms ("C 2 -C 3 -alkynyl").
  • the C 2 -C 6 -alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, Pen-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hexyl 4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methyl But-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl , 1-methylpent-4-ynyl, 2-methylp
  • C 3-20 cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having from 3 to 20 carbon atoms, preferably “C 3-10 cycloalkyl”.
  • C 3-10 cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • the C 3-10 cycloalkyl group may be a monocyclic hydrocarbon group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclodecyl group or a cyclodecyl group, or a bicyclic ring.
  • a hydrocarbon group such as a decalin ring.
  • C 5-20 cycloalkenyl is understood to mean a conjugated or non-conjugated monovalent monocyclic or bicyclic hydrocarbon ring having an unsaturation of 1, 2 or 3 having from 5 to 20 carbon atoms, preferably "C 5-10 cycloalkenyl".
  • C 5-10 cycloalkenyl is understood to mean an unsaturated monovalent monocyclic or bicyclic hydrocarbon ring having 5, 6, 7, 8, 9 or 10 carbon atoms.
  • the C 5-10 cycloalkenyl group may be a monocyclic hydrocarbon group such as 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 2,4-cyclopentadienyl, 2,5.
  • C5-20 cycloalkenyl includes all possible isomeric forms thereof, such as positional isomers or configurational isomers thereof.
  • 3-20 membered heterocyclyl means a saturated monovalent monocyclic or bicyclic hydrocarbon ring comprising from 1 to 5 heteroatoms independently selected from N, O and S, preferably “3-10 membered heterocyclyl” ".
  • the term “3-10 membered heterocyclyl” means a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing from 1 to 5, preferably from 1 to 3, heteroatoms selected from N, O and S.
  • the heterocyclic group can be attached to the remainder of the molecule by any one of the carbon atoms or a nitrogen atom, if present.
  • the heterocyclic group may include, but is not limited to, a 4-membered ring such as azetidinyl, oxetanyl; a 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrole Alkyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazinyl Or a trithiaalkyl group; or a 7-membered ring such as a diazepanyl group.
  • a 4-membered ring such as azetidinyl, oxetanyl
  • a 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrole Alkyl, imidazolidin
  • the heterocyclic group can be benzofused.
  • the heterocyclic group may be bicyclic, such as but not limited to a 5,5 membered ring such as a hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring, or a 5,6 membered bicyclic ring such as hexahydropyrrole.
  • [1,2-a]pyrazine-2(1H)-yl ring [1,2-a]pyrazine-2(1H)-yl ring.
  • the ring containing a nitrogen atom may be partially unsaturated, that is, it may contain one or more double bonds such as, but not limited to, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiene.
  • the heterocyclic group is non-aromatic.
  • C 6-20 aryl is understood to mean preferably a monovalent, aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, preferably “C 6-14 aryl”.
  • C 6-14 aryl is understood to mean preferably a monovalent, bicyclic or monovalent aromatic or partially aromatic having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms.
  • C 6-14 aryl a tricyclic hydrocarbon ring
  • C 6 aryl a ring having 6 carbon atoms
  • C 9 aryl such as indanyl or fluorenyl
  • C 10 aryl a ring having 10 carbon atoms
  • C13 aryl such as a fluorenyl group
  • C14 aryl a ring having 14 carbon atoms
  • 5-20 membered heteroaryl is understood to include a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having from 5 to 20 ring atoms and containing from 1 to 5 independently selected from N, O. And a hetero atom of S, such as “5-14 membered heteroaryl”.
  • the term “5-14 membered heteroaryl” is understood to include a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, especially 5 or 6 or 9 or 10 carbon atoms, and which contain 1-5, preferably 1-3, each independently selected from N, O and S heteroatoms and, in each case The benzo can be fused.
  • the heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thia Diazolyl, thia-4H-pyrazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzene And a triazolyl group, a carbazolyl group, a fluorenyl group, an isodecyl group, etc.; or a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a triazinyl group, etc., and a benzo derivative thereof
  • C 1-40 alkyl applies equally to other terms containing “C 1-40 alkyl", such as the terms “C 1-40 alkyloxy”, “C 1-40 alkyl silicon”. "” and “C 1-40 alkylsilyloxy” and the like.
  • each C 1 -C 40 alkyl group may be the same or different from each other .
  • the heteroaryl or heteroarylene includes all possible isomeric forms thereof, such as positional isomers thereof.
  • the term pyridyl or pyridinyl includes pyridin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-3-yl, pyridin-4- And pyridin-4-yl;
  • the term thienyl or thienylene includes thiophen-2-yl, thiophen-2-yl, thiophen-3-yl and thiophen-3-yl.
  • TBSO tert-butyldimethylsilyloxy
  • substituted means that one or more hydrogens on the designated atom are replaced by the listed group, provided that the normal valence of the specified atom in the present case is not exceeded and the substitution forms a stable Compound. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.
  • a substituent of a ring system refers to a substituent attached to an aromatic or non-aromatic ring system, for example, the substituent replaces the hydrogen available on the ring system.
  • salts of the compounds of the present invention include salts of the compounds of the present invention with non-physiologically acceptable acids or bases which are capable of forming the same or similar activities, including salts of inorganic acids, salts of organic acids and the like.
  • examples of the salt of the inorganic acid include a hydrochloride, a hydrobromide, a hydroiodide, a chloride, a bromide, an iodide, a sulfate, a hydrogen sulfate, a nitrate, a phosphate, and a hydrogen phosphate.
  • Examples of the salt of the organic acid include acetate, fumarate, pamoate, aspartate, besylate, carbonate, bicarbonate, camphorsulfonate, D- and L-milk Acid, D and L-tartrate, ethanesulfonate, methanesulfonate, malonate, orotate, glucoheptonate, methyl sulfate, stearate, glucuronic acid Salt, 2-naphthalenesulfonate, tosylate, benzophenone, nicotinate, isethionate, malate, maleate, citrate, gluconate, amber Acid salts, sucrose salts, benzoates, ethanesulfonates and pamoates.
  • tautomer refers to a functional group isomer that is produced by the rapid movement of an atom in a molecule at two positions.
  • the compounds of the invention may exhibit tautomerism.
  • Tautomeric compounds may exist in two or more interconvertible species.
  • Proton-shifting tautomers are derived from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium, and attempts to separate a single tautomer typically result in a mixture having physicochemical properties consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule.
  • the keto form predominates
  • phenol in phenol, the enol form predominates.
  • the invention encompasses all tautomeric forms of the compounds.
  • the compounds of the present invention may exist in the form of a solvate (e.g., a hydrate) wherein the compound of the present invention contains a polar solvent as a structural element of the crystal lattice of the compound, particularly such as water, methanol or ethanol.
  • a polar solvent as a structural element of the crystal lattice of the compound, particularly such as water, methanol or ethanol.
  • the amount of polar solvent, particularly water may be present in stoichiometric or non-stoichiometric ratios.
  • stoichiometric solvates eg, hydrates
  • it may be a hemisolvate, a solvate, a sesquisuctate, a disolvate, a trisolvate, a tetrasolvate, and five, respectively.
  • the present invention includes all such solvates.
  • one or more times as used in the definition of substituents of the compounds of the general formula of the invention is to be understood to include one, two, three, four or five times, especially once, twice, three times or four times, more Especially once, twice or three times, for example once or twice.
  • the numerical ranges set forth in the specification are equivalent to the description of each of the specific integer values.
  • the numerical range “1-40” corresponds to each integer value in the numerical range “1-10", that is, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and a numerical range.
  • Each of the integer values in “11-40” is 11, 12, 13, 14, 15, ..., 35, 36, 37, 38, 39, 40.
  • treatment has conventional definitions well known to those skilled in the art, for example, to manage or care for an individual for the purpose of resisting, alleviating, reducing, alleviating, improving the condition of a disease or condition such as a sarcoma.
  • the compound of the formula (I) of the invention has good inhibitory activity against human leukemia, liver cancer and lung cancer tumor cell lines, and the inhibition rate of HL-60 human leukemia cells can be greater than 80 at a concentration of 10 -4 mol/L. %.
  • the compound of the present invention can inhibit the HL-60 human leukemia cells by more than 80% at a concentration of 10 -4 mol/L.
  • the compounds of the invention are 23, 25, 26, 32, 33, 34, 36, 37, 41, 44, 45, 46, 47, 52, 56, 57, 59, 61 and 63 in 10 -5 mol
  • the inhibition rate of HL-60 human leukemia cells at /L concentration can be greater than 80%.
  • an effective dosage of a compound of the invention for treating each of the desired indications can be readily determined.
  • the amount of active ingredient administered in the treatment of one of these conditions can vary widely depending on the particular compound and dosage unit employed, the mode of administration, the course of treatment, the age and sex of the patient being treated, and Treat the nature and extent of the condition.
  • the total amount of active ingredient to be administered will generally be from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day.
  • a clinically useful dosing regimen would be one to three administrations per day to once every four weeks.
  • the desired mode of treatment and amount of administration of a compound of the invention, or a pharmaceutically acceptable salt or ester or composition thereof, can be determined by one of ordinary skill in the art using routine therapeutic assays.
  • the invention provides a hawson alkaloid with good biological activity, and a highly stereoselective semi-synthetic preparation method and application thereof.
  • the preparation method can improve the deficiencies of the prior art.
  • the preparation method also has the advantages that the raw materials are cheap and easy to obtain, the chemical reaction and the diastereoselectivity of the key reaction are high, the operation is simple, the synthesis step is short, the purification is easy, and the production can be enlarged.
  • Example 2 Same as Example 1, except that the reaction was carried out at a temperature ranging from -40 ° C to -78 ° C.
  • the yield was 90%.
  • Example 11 The same as Example 11, except that the reaction was carried out at -40 ° C to obtain Compound 3 from Compound 18 in a yield of 70%, and the obtained product had the same characteristics as the product obtained in Example 11.
  • Example 12 The same procedure as in Example 11 except that Compound 32 (yield 60%) and Compound 33 (yield: 24%) were obtained from Compound 28, and the compound 29 was obtained after dechlorination at 20 ° C, yield 85%.
  • the product 28 obtained had the same characteristics as the product obtained in Example 13.
  • Example 20 The same as Example 20 except that a pale yellow amorphous material 42 was obtained from Compound 29 in a yield of 95%.
  • Example 20 The same as Example 20 except that a pale yellow amorphous material 43 was obtained from Compound 31 in a yield of 80%.
  • Example 25 The same as Example 25, except that Compound 2 was obtained from Compound 31, and the obtained crude product was crystallized from ethyl acetate to give white crystals (yield: 92%).
  • Hg(OAc) 2 (120.8 mg, 1.1 eq) was added to a round bottom flask, followed by the addition of 2 mL of water and 2 mL of THF and stirred until complete.
  • Compound 38 (100 mg, 1 eq) in 2 mL of THF was then added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 3 h. Then 1 eq of Hg(OAc) 2 was added and stirring was continued for 3 h.
  • Example 11 The same as Example 11, except that Compound 54 was obtained from Compound 53 in a yield of 82%.
  • the dr value is 13.3:1
  • Example 3 The same as Example 3 except that the compound 57 was obtained by reacting the enol silyl ether F in place of A at -60 ° C in a yield of 90%.
  • the dr value is 12:1.
  • the dr value is 6:1.
  • the dr value is 10:1.
  • the screening method of the Methyl-Thiazol-Tetrozolium (MTT) reduction method was used, and the cell line was HL-60 human leukemia.
  • a certain number of tumor cells in the logarithmic growth phase were inoculated into a 96-well microplate, and the drug solution was added after 24 hours of culture. For each cell strain, each concentration was three replicate wells. Another set of cell-free zero hole, if the drug has color to do the corresponding drug concentration without cell zeroing.
  • MTT (Sigma) solution was added; after further incubation for 4 hours, a triple solution (10% SDS-5% isobutanol-0.01 mol/l HCl) was added. The cells were incubated overnight in a CO 2 incubator and then the OD570 value was measured using a microplate reader. The measured data was provided by Shanghai New Drug Screening Center.
  • the compound of the present invention inhibited HL-60 human leukemia cells by more than 80% at a concentration of 10 -4 mol/L.
  • Inventive Examples Compounds 23, 25, 26, 32, 33, 34, 36, 37, 41, 44, 45, 46, 47, 52, 56, 57, 59, 61 and 63 are at 10 -5 mol/L
  • the inhibition rate of HL-60 human leukemia cells was greater than 80% at the concentration.

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Abstract

本发明涉及三尖杉酯类生物碱、其制备方法和用途，属于药物化合物及其制备方法领域。其中，所述三尖杉酯类生物碱具有式（I）所示的结构：本发明还提供一种所述化合物的制备方法，包括将式（11）化合物与式（12）化合物在路易斯酸的存在下进行反应：

Description

三尖杉酯类生物碱、其制备方法和用途 技术领域
本发明涉及三尖杉酯类生物碱、其制备方法和用途，属于药物化合物及其制备方法领域。
背景技术
三尖杉酯类生物碱如三尖杉酯碱1(Harringtonine，HT)、高三尖杉酯碱2(Homoharringtonine，HHT)、脱氧三尖杉酯碱3(Deoxyharringtonine，DHT)和异三尖杉酯碱4(Isoharringtonine，IHT)是广谱的抗癌药物。其中高三尖杉酯碱2于1990年载入我国药典，用于临床治疗急性非淋巴性白血病，并一直临床应用至今(中国药典1990年版二部，1990，588；中国药典2005年版二部，2005，629)。
Figure PCTCN2016109122-appb-000001
式(6)为天然三尖杉酯类生物碱的通式，其分子结构由三尖杉碱母核和侧链两部分组成，母核三尖杉碱(5)没有生理活性。据文献报道(The Alkaloids,1984,23,157-226)，式(6)侧链部分C-2'的手性碳的构型对于此类化合物的生物活性至关重要。该手性碳为R构型时，化合物可能具有生物活性，而S构型的异构体则往往没有生物活性。并且，当侧链中没有羟基或者酯基(CO2R)中的任何一个基团，或者C-2'为非手性碳原子等结构时，化合物的生物活性均显著降低。
Figure PCTCN2016109122-appb-000002
目前药用三尖杉酯类生物碱是从粗榧属植物中分离得到。粗榧属生物碱主要(至少50％)由三尖杉碱组成。存在于植物的可再生部分(枝、叶)中的三尖杉碱是三尖杉酯类生物碱的生物合成前体。天然三尖杉酯类生物碱在总生物碱中只占一小部分，而且主要存在于植物的不可再生部分。三尖杉酯类生物碱除了以低浓度存在于天然植物原料中以外，还与许多结构非常相似的同类物相混合，因此从天然产物中分离得到高纯度的三尖杉酯类生物碱十分困难。同时，粗榧属植物数量剧减，已成为稀有保护植物。因此，从植物中分离三尖杉酯类生物碱已经远远不能满足临床应用的需要。
自上世纪七十年代以来，化学家们就利用从植物再生部分分离得到的天然三尖杉碱为原料，进行三尖杉酯类生物碱的半合成研究(Alkaloids:Chemical and Biological Perspectives1987,5,639-690；The Alkaloids,1998,51,199-269,Academic Press,New York)，但这些方法仍然存在不足。
我国化学家黄文魁等率先利用Reformatsky反应报道了脱氧三尖杉酯碱的半合成(Lanzhou Daxue Xuebao,Ziran Kexueban,1974,1,148-151)，该方法报道的同时，美国的Mikolajczak等人也报道了有机锂试剂与α-酮酰基三尖杉酯碱反应制备脱氧三尖杉酯碱3及其表异构体的方法(Tetrahedron Lett.1974,15,283)，但该方法的反应收率明显低于Reformatsky反应的收率。此后，通过溴乙酸甲酯和α-酮酰基三尖杉酯碱侧链上的羰基之间的Reformatsky反应被广泛应用于三尖杉酯碱(中国科学(英文版),1979,22,1333；J.Org.Chem.1978,43,4762；科学通报，1975,20,437)、高三尖杉酯碱(药学学报,1980,15,46；科学通报,1980,25,576；Tetreahedron Lett.1982,23,3431；J.Org.Chem.1983,48,5321)、异 三尖杉酯碱(科学通报,1982,27,1048；药学学报,1982,17,866)、新三尖杉酯碱(药学学报,1992,47,1087)等的合成。但利用这类方法合成的化合物的C-2’没有立体选择性，只能得到三尖杉酯类生物碱及其表异构体的混合物，这两种异构体极难分离。同时，利用这种方法合成一倍量的天然三尖杉酯碱需要消耗两倍量的三尖杉碱，产率很低。
Kelly等人(J.Org.Chem.1979,44,63)在前期工作基础上，为解决侧链酸因空间位阻不能和三尖杉碱直接酯化的问题，利用七元内酯环酸与三尖杉碱酯化，然后，开环得到三尖杉酯碱及其表异构体的混合物。
美国批准的Omacetaxine药物采用Robin等于1999年(Tetrahedron Lett.1999,40,2931-2934；CN 1300289A,1999)报道的方法获得。该方法虽然能得到光学纯的三尖杉酯碱，但需要使用辅助手性基团，合成线路长，操作步骤冗长。
2006年，Jin报道了以光学纯的D-苹果酸为原料(J.Am.Chem.Soc.2006,128,10370-10371)，得到光学纯的β-环丁内酯酸，经多步反应得到光学纯的脱氧三尖杉酯碱及其类似物。该方法虽然得到的三尖杉酯碱纯度高，但是需要使用光学纯的原料，且合成线路长，不易应用于工业化生产。
因此，不仅需要开发具有生物活性的三尖杉酯类生物碱，也需要开发一种能够改善上述问题的合成三尖杉酯类生物碱的方法。
发明内容
本发明提供式(I)所示的三尖杉酯生物碱类化合物、其药学上可接受的盐、互变异构体、立体异构体及溶剂合物：
Figure PCTCN2016109122-appb-000003
其中，Ra为
Figure PCTCN2016109122-appb-000004
Rb为H，a毗邻的
Figure PCTCN2016109122-appb-000005
为单键，b毗邻的
Figure PCTCN2016109122-appb-000006
为双键；
或者，
Ra为H，Rb为
Figure PCTCN2016109122-appb-000007
a毗邻的
Figure PCTCN2016109122-appb-000008
为双键，b毗邻的
Figure PCTCN2016109122-appb-000009
为单键；
Rc选自任选被一个或多个Rm取代的下列基团：C1-40烷基、C2-40烯基、C2-40炔基、C3-20环烷基、C5-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基，其中所述杂环基和杂芳基包含1-5个独立选自N、O和S的杂原子；
R1、R2、R3可彼此独立地选自氢、F、Cl、Br、I、OH、SH、CN或任选被一个或多个Rm取代的下列基团：C1-40烷基、C2-40烯基、C2-40炔基、C3-20环烷基、C5-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基、NH2、C1-40烷基氧基、C2-40烯基氧基、C2-40炔基氧基、C3-20环烷基氧基、C5-20环烯基氧基、3-20元杂环基氧基、C6-20芳基氧基、5-20元杂芳基氧基、-SiR6R7R8、-OSiR6R7R8，其中所述杂环基和杂芳基包含1-5个独立选自N、O和S的杂原子；
R4可选自氢或任选被一个或多个Rm取代的下列基团：C1-40烷基、C2-40烯基、C2-40炔基、C3-20环烷基、C5-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基、NH2、C1-40烷基氧基、C2-40烯基氧基、C2-40炔基氧基、C3-20环烷基氧基、C5-20环烯基氧基、3-20元杂环基氧基、C6-20芳基氧基、5-20元杂芳基氧基、-SiR6R7R8、-OSiR6R7R8，其中所述杂环基和 杂芳基包含1-5个独立选自N、O和S的杂原子；
R5选自OH、SH、F、Cl、Br、I、CN、NH2；
其中优选地，R1和R5不同时为OH或SH；
或者，R1、R5与其相连接的碳原子一起形成任选被一个或多个Rm取代的C3-20环烷基、C5-20环烯基或包含1-5个选自N、O和S的杂原子的3-20元杂环基；
或者，R1、R3与其相连接的碳原子一起形成任选被一个或多个Rm取代的C3-20环烷基、C5-20环烯基或3-20元杂环基，其中所述杂环基包含1-5个独立选自N、O和S的杂原子；
R6、R7、R8彼此独立地为氢或任选被一个或多个Rm取代的下列基团：C1-40烷基、C2-40烯基、C2-40炔基、C3-20环烷基、C5-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基、C1-40烷基氧基、C2-40烯基氧基、C2-40炔基氧基、C3-20环烷基氧基、C5-20环烯基氧基、3-20元杂环基氧基、C6-20芳基氧基、5-20元杂芳基氧基、C1-C40烷基硅基、C1-C40烷基硅基氧基，其中所述杂环基和杂芳基包含1-5个独立选自N、O和S的杂原子；
每个Rm独立地选自F、Cl、Br、I、OH、SH、CN、NRdRe、或任选被一个或多个Rm’取代的C1-40烷基、C2-40烯基、C2-40炔基、C3-20环烷基、C5-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基、C1-C40烷基硅基、二(C1-C40烷基)硅基、三(C1-C40烷基)硅基、C1-40烷基氧基、C2-40烯基氧基、C2-40炔基氧基、C3-20环烷基氧基、C5-20环烯基氧基、3-20元杂环基氧基、C6-20芳基氧基、5-20元杂芳基氧基、RtC(O)-、RtC(O)O-、RtOC(O)-、RtS(O)2-、RtS(O)2O-、SiR6R7R8、-OSiR6R7R8，其中所述杂环基和杂芳基包含1-5个独立选自N、O和S的杂原子；
每个Rt相互独立地选自任选被一个或多个Rm’取代的C1-40烷基、C2-40烯基、C2-40炔基、C3-20环烷基、C5-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基；
每个Rm’独立地选自F、Cl、Br、I、OH、SH、CN、NRdRe、C1-40烷基、C2-40烯基、C2-40炔基、C3-20环烷基、C5-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基、C1-C40烷基硅基、二(C1-C40烷基)硅基、三(C1-C40烷基)硅基、C1-40烷基氧基、C2-40烯基氧基、C2-40炔基氧基、C3-20环烷基氧基、C5-20环烯基氧基、3-20元杂环基氧基、C6-20芳基氧基、5-20元杂芳基氧基、SiR6R7R8、-OSiR6R7R8，其中所述杂环基和杂芳基包含1-5个独立选自N、O和S的杂原子；Rd和Re相互独立地选自H或任选被一个或多个Rm取代的下列基团：C1-40烷基、C2-40烯基、C2-40炔基、C3-20环烷基、3-20元杂环基、C6-20芳基、5-20元杂芳基，其中所述杂环基和杂芳基包含1-5个独立选自N、O和S的杂原子；
X选自NRn、O或S；
Rn选自H、C1-40烷基、C2-40烯基、C2-40炔基、C3-20环烷基、C5-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基，其中所述杂环基和杂芳基包含1-5个独立选自N、O和S的杂原子。
根据本发明的式(I)化合物，例如，R1、R5可与其相连接的碳原子一起形成
Figure PCTCN2016109122-appb-000010
例如
Figure PCTCN2016109122-appb-000011
或
Figure PCTCN2016109122-appb-000012
其中n为1至16之一的整数，例如1、2或3。
根据本发明的化合物，其中可存在一个或多个手性碳原子。为此，本发明结构式中各手性碳呈R构型、S构型的化合物或其混合物均涵盖在本发明化合物的范围内。作为实例，式(I)化合物中至少标注*的碳原子可为手性碳原子，其立体构型可以为R或S型。例如，Ra可以为
Figure PCTCN2016109122-appb-000013
或者Rb可以为
Figure PCTCN2016109122-appb-000014
根据本发明的实施方案，R1优选选自任选被一个或多个Rm取代的C1-10烷基、C2-40烯基、 C2-40炔基、C3-20环烷基、C5-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基；
作为实例，R1可以为
Figure PCTCN2016109122-appb-000015
其中，
Figure PCTCN2016109122-appb-000016
为单键或双键，n为选自0至16之一的整数，例如0、1、2或3；或为任选被一个或多个Rm取代的C1-10烷基、C6-20芳基、5-20元杂芳基；
R5优选为OH或SH；
或者，R1、R5优选与其相连接的碳原子一起形成
Figure PCTCN2016109122-appb-000017
例如
Figure PCTCN2016109122-appb-000018
或
Figure PCTCN2016109122-appb-000019
其中n为1至16之一的整数；
R2、R3相互独立地优选选自氢、F、Cl、Br、I或任选被一个或多个Rm取代的C1-40烷基；
X为O；
R4优选选自氢或任选被一个或多个Rm取代的下列基团：C1-40烷基、C2-40烯基、C2-40炔基、C3-20环烷基、C5-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基；
作为实例，每个Rm独立地不存在或选自氢、F、Cl、Br、I、OH、SH、CN、SiR6R7R8、-OSiR6R7R8、或任选被一个或多个Rm’取代的C3-20环烷基、C5-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基、C1-40烷基氧基、C2-40烯基氧基、C2-40炔基氧基、C3-20环烷基氧基、C5-20环烯基氧基、3-20元杂环基氧基、C6-20芳基氧基、5-20元杂芳基氧基，其中所述杂环基和杂芳基包含1-5个独立选自N、O和S的杂原子；
每个Rm’独立地选自F、Cl、Br、I、OH、SH、CN、NRdRe、C1-40烷基、C2-40烯基、C2-40炔基、C3-20环烷基、C5-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基、C1-C40烷基硅基、二(C1-C40烷基)硅基、三(C1-C40烷基)硅基、C1-40烷基氧基、C2-40烯基氧基、C2-40炔基氧基、C3-20环烷基氧基、C5-20环烯基氧基、3-20元杂环基氧基、C6-20芳基氧基、5-20元杂芳基氧基、SiR6R7R8、-OSiR6R7R8，其中所述杂环基和杂芳基包含1-5个独立选自N、O和S的杂原子；
作为实例，R1可以选自任选被一个或多个选自F、Cl、Br、I的取代基取代的C1-10烷基或C2-40烯基，例如任选被一个或多个选自F、Cl、Br、I的取代基取代的C1-6烷基或C2-40烯基。所述C1-6烷基可以为例如4-甲基正戊基、3-甲基正丁基，所述C2-40烯基可以为例如4-甲基-戊-3-烯基；
或者，R1可以选自例如C1-6烷基-、苯基C1-6烷基-、2-C1-6烷氧基苯基-、3-C1-6烷氧基苯基-、4-C1-6烷氧基苯基-、3,4-二C1-6烷氧基苯基-、2,4-二(C1-6烷氧基)苯基-、2,3-二(C1-6烷氧基)苯基-。
作为实例，式(I)化合物可选自如下化合物：
Figure PCTCN2016109122-appb-000020
Figure PCTCN2016109122-appb-000021
上述实例化合物以及具体实施方式中实施例化合物中对应于式(I)化合物的基团定义同样涵盖在各基团的优选定义范围内。这些具体基团定义与式(I)中各基团定义的任意组合或结合同样涵盖在本说明书记载的技术方案之中。
本发明还提供一种式(I)所示的三尖杉酯生物碱类化合物、其药学上可接受的盐、互变异构体、立体异构体及溶剂合物的制备方法：
所述方法包括将式(11)化合物与式(12)化合物在路易斯酸的存在下进行反应：
Figure PCTCN2016109122-appb-000022
其中，Ra、Rb、Rc、a、b、R1、R2、R3、R4、R6、R7、R8各自独立地具有上文所述的定义，并且R5为OH。
根据本发明的制备方法，式(11)的化合物、式(12)的烯醇硅醚和路易斯酸的摩尔比可以由本领域技术人员根据反应需要确定。作为实例，所述式(11)的化合物、式(12)的烯醇硅醚和路易斯酸的摩尔比可为1:1～20:1～20，优选为1:1～10:1～10，更优选为1:1.05～5:1.05～5，例如1:1.1～3:1.1～3。
作为实例，式(11)化合物可与式(12)化合物在路易斯酸的存在下进行如下反应，制备式(7)、(8)和(9)的化合物：
Figure PCTCN2016109122-appb-000023
根据本发明的制备方法，其中所述反应优选在惰性溶剂中进行。
所述反应可以在适宜的温度下进行。所述温度可以为50℃以下，例如-80℃至50℃，例如-80℃至30℃。
本发明进一步提供一种式(I-1)化合物的制备方法，包括将式(II)化合物进行还原反应：
Figure PCTCN2016109122-appb-000024
其中，Hal为F、Cl、Br或I，X、R1、R4、R5、Rc各自独立地具有上文所述的定义。
还原反应条件为本领域技术人员已知的常规条件。例如，可在锌粉的存在下，在含乙酸的溶剂中反应。反应温度可以为50℃以下，例如-80℃至50℃，例如-20℃至30℃。
作为实例，本发明提供由化合物13制备化合物14的方法：
Figure PCTCN2016109122-appb-000025
其中，R1、R4、Rc各自独立地具有上文所述的定义。
作为实例，提供由化合物13a制备化合物14a的方法：
Figure PCTCN2016109122-appb-000026
其中，R1、R4各自独立地具有上文所述的定义。
本发明的制备方法还包括下列反应中的一种或多种：
1)
Figure PCTCN2016109122-appb-000027
2)
Figure PCTCN2016109122-appb-000028
3)
Figure PCTCN2016109122-appb-000029
其中，
Rp为-SiR6R7R8，Rq为甲基，
Figure PCTCN2016109122-appb-000030
为单键；
或者，Rp、Rq与其相连接的碳原子一起形成-C＝CH2，
Figure PCTCN2016109122-appb-000031
为单键；
或者，Rp不存在，Rq为甲基，
Figure PCTCN2016109122-appb-000032
为双键；
R2、R3、R4、R6、R7、R8、Rc、X、n各自独立地具有上文所述的定义。
作为上述反应的实例，可通过如下条件进行上述反应。以下实例记载的反应条件和参数不仅适用于下述具体化合物，而且同样适用于上述通式化合物。所述反应条件和参数与上述通式化合物的组合或结合同样应被理解为记载在本说明书之中。
反应1)中，可以采用如下1a)、1b)或1c)的条件：
1a)优选地，所述反应可以在惰性溶剂中进行；
所述反应可以在氢溴酸溶液存在下进行；
其中所述氢溴酸溶液优选为氢溴酸水溶液或氢溴酸乙酸溶液，其重量百分比可以为30-40重量％，例如40重量％氢溴酸水溶液或33重量％氢溴酸乙酸溶液。
反应温度可以为30℃以下，例如-30℃至30℃；
反应完成后，用碱调节pH为8以上，例如9，得到目标化合物。
具体可通过如下方法进行：
Figure PCTCN2016109122-appb-000033
将化合物15a溶于惰性溶剂中，加入适量的氢溴酸乙酸溶液(例如40重量％氢溴酸水溶液或33重量％氢溴酸乙酸溶液)中，在30℃以下，例如-30℃至30℃条件下反应，反应完后，加入碱调节pH＝9，得到目标化合物；
1b)优选地，所述反应可以在惰性溶剂中进行；
所述反应可以在乙酸汞(Hg(OAc)2)的存在下进行，随后向体系中加入硼氢化钠的氢氧化钠溶液；
其中乙酸汞可以采用30重量％～40重量％，例如33重量％乙酸汞与惰性溶剂和水的混合液；
反应温度可以为30℃以下，例如-30℃～30℃；
反应时间可以为例如2～8小时；
具体可通过如下示例性方法进行：
Figure PCTCN2016109122-appb-000034
将化合物15a溶于惰性溶剂和水的混合液中，加入适量的33重量％乙酸汞的惰性溶剂和水的混合液，在30℃以下，例如-30℃～30℃条件下反应。反应2-8个小时后，向体系中加入适量的硼氢化钠的氢氧化钠溶液即可。
1c)优选地，所述反应可以在惰性溶剂中进行；
反应温度可以为30℃以下，例如-30℃～30℃；
所述反应优选在草酸铁六水化合物(Fe2(C2O4)3·6H2O)的水溶液中和硼氢化钠(NaBH4)的存在下进行；
具体可通过如下方法进行：
Figure PCTCN2016109122-appb-000035
将化合物15a溶于惰性溶剂中，加到Fe2(C2O4)3·6H2O的水溶液中，加入NaBH4，在30℃以下，例如-30℃～30℃条件下反应。
反应2)中：
优选地，所述方法可以在惰性溶剂中进行；
反应温度可以为例如100℃以下，例如-30℃～100℃；
优选地，所述方法可以在氟化试剂的存在下进行，所述氟化试剂可以选自氟化钾、三乙胺三氢氟酸盐、三氟乙酸、氟化氢、三氟化硼、四丁基氟化氨中的一种或多种；
具体可通过如下方法进行：
Figure PCTCN2016109122-appb-000036
通式为16a的化合物在惰性溶剂中，在100℃以下，例如-30℃～100℃的温度范围内，与氟化试剂反应，脱去硅基得到三尖杉酯碱和高三尖杉酯碱。
反应3)中：
优选地，所述反应可以在惰性溶剂中进行；
反应温度可以为30℃以下，例如-30℃～30℃；
优选地，所述反应在无机酸或者路易斯酸的存在下进行；
具体可通过如下方法进行：
Figure PCTCN2016109122-appb-000037
通式为17a的化合物在惰性溶剂中，在无机酸或者路易斯酸的作用下，在30℃以下，例如-30℃～30℃条件下反应，得到环状化合物10。
根据本发明，式17或17a化合物可通过本领域已知的方法制备。作为实例，可由如下式11a和12a化合物制备式17a化合物：
Figure PCTCN2016109122-appb-000038
适于本发明制备方法的溶剂可包括选自例如下列的一种或多种的混合物：酮类溶剂，例如丙酮和甲基乙基酮；醚类溶剂，包括无环醚和环醚，例如乙醚、四氢呋喃、二氧六环；酯类溶剂，例如乙酸乙酯或者乙酸丁酯；烷烃类溶剂，例如正己烷或正庚烷；卤代烷烃类溶剂，例如一氯甲烷、二氯甲烷、三氯甲烷、四氯化碳、1,2-二氯乙烷；环烷烃类溶剂，例如环己烷或环庚烷；取代或未取代的芳烃类溶剂，例如苯、甲苯、二甲苯、氯苯；醇类溶剂，例如甲醇、乙醇、正-丙醇、异丙醇，正-丁醇或者叔-丁醇；或者其它的溶剂，例如N,N-二甲基甲酰胺(DMF)、二甲基亚砜(DMSO)、N-甲基吡咯烷酮(NMP)、乙腈或者吡啶。
优选地，所述溶剂为选自上述溶剂中的一种或多种的混合物，且对反应底物及催化剂无反应活性的惰性溶剂。作为实例，所述惰性溶剂可以选自例如醚类溶剂(如乙醚、四氢呋喃、二氧六环)、卤代烷烃类溶剂(如二氯甲烷、三氯甲烷、四氯化碳、1,2-二氯乙烷)、取代或未取代的芳烃(如苯、甲苯、氯苯)中的一种或多种，优选醚类溶剂和/或卤代烃类溶剂。
所述碱可以为有机碱、无机碱或其混合物，例如选自碱金属或者碱土金属碳酸盐或碳酸氢盐，例如碳酸锂、碳酸钠、碳酸钾、碳酸钙、碳酸铯、碳酸氢钠、碳酸氢钾、碳酸氢钙；碱金属醇盐，例如叔丁醇钠或者叔丁醇钾；碱金属氢化物，例如氢化钠或者氢化钾；氨化物，例如双(三甲基甲硅烷基)氨基锂、双(三甲基甲硅烷基)氨基钾或者二异丙基氨基锂(LDA)；有机胺，例如三乙胺、N-甲基吗啉、哌啶、N-甲基哌啶、N,N-二异丙基乙胺、1,5-二氮杂双环[4.3.0]壬-5-烯(DBN)、1,8-二氮杂双环[5.4.0]癸-7-烯(DBU)、吡啶或者4-二甲氨基吡啶(DMAP)。
所述酸可以为有机酸、无机酸或其混合物，例如选自下列的一种或多种：羧酸，如乙酸或者三氟乙酸；磺酸，例如甲磺酸、三氟甲磺酸或者对甲苯磺酸；膦酸；盐酸、硫酸、磷酸。
所述酸还包括路易斯酸。所述路易斯酸可以为选自例如BF3·OEt2、MgCl2、MgBr2、ZnBr2、ZnI2、ZnCl2、ZnSO4、CuCl2、CuCl、Cu(O3SCF3)2、CoCl2、CoI2、FeI2、FeCl3、FeCl2、FeCl2、SnCl4、TiCl4、TiCl3、MnCl2、ScCl3、AlCl3、(i-C4H9)2AlCl、(C6H5)2AlCl、(C6H5)AlCl2、ReCl5、ZrCl4、NbCl5、VCl3、CrCl2、MoCl5、YCl3、CdCl2、LaCl3、Er(O3SCF3)3、Yb(O2CCF3)3、SmCl3、B(C6H5)3、TaCl5或三甲基三氟甲磺酸硅的一种或多种，其具体实例可以为选自BF3·OEt2、MgCl2、ZnCl2、MgBr2、ZnBr2、AlCl3、SnCl4、TiCl4或三甲基三氟甲磺酸硅的一种或多种。
根据本发明，所述制备方法同样包括在上述反应之后进行的后处理步骤以及纯化步骤。例如，可以采用现有技术的一般方法做后处理和/或纯化，包括分离，例如通过蒸馏、相分离、重结晶、柱层析等方法。
并且，本领域技术人员可以根据需要由式(I)中的一种化合物起始，通过本领域已知的反应制备式(I)中的另一种化合物、其药学上可接受的盐、立体异构体或溶剂合物。在这种情形下，作为起始的式(I)化合物也被称为原料或中间体。
作为实例，任选地，所述方法还进一步包括将所得化合物与酸或碱反应，以获得式(I)化合物药学上可接受的盐。
任选地，所述方法还进一步包括将所得化合物与溶剂形成溶剂合物。
任选地，所述方法还进一步包括将所得化合物分离以得到其立体异构体。
根据本发明的制备方法，其中各反应底物和反应条件可根据需要进行任意组合。例如， 反应1)、2)、3)中记载及优选的反应条件同样适于式(7)、(8)、(9)中其他化合物的制备。
除非另有说明，本发明的制备方法中，对于作为反应底物的原料和试剂的加入顺序没有特别限定。在具体实施方案中，本领域技术人员可以根据需要对加入顺序进行调整或变型。这些调整或变型也涵盖在本发明制备方法的保护范围内。
本发明还提供包含一种或多种本发明化合物或其药学上可接受的盐、互变异构体、立体异构体及溶剂合物的药物组合物。可利用这些组合物通过向有此需要的患者给药来实现期望的药理学作用。就本发明的目的而言，患者是需要治疗具体病症或疾病的包括人在内的哺乳动物。因此，本发明包括这样的药物组合物，其包含药学上可接受的载体和药学有效量的本发明的化合物或其药学上可接受的盐。
药学上可接受的载体优选是这样的载体，其在与活性成分的有效活性一致的浓度下对患者相对无毒且无害，以致于由所述载体引起的任何副作用不会破坏所述活性成分的有益作用。化合物或其药学上可接受的盐的药学有效量优选是对正在治疗的具体病况产生结果或者产生影响的量。可使用包括速释、缓释和定时释放制剂在内的任意有效的常规剂量单位形式，将本发明的化合物与本领域公知的药学上可接受的载体一起以如下方式给药：口服、肠胃外、局部、鼻腔、眼部、舌下、直肠、阴道给药等。
对于口服给药，可将所述化合物或其药学上可接受的盐配制成固体或液体制剂，例如胶囊剂、丸剂、片剂、含锭剂(troche)、锭剂(lozenge)、熔胶剂(melt)、散剂、溶液剂、混悬剂或乳剂，并且可根据本领域已知的用于制备药物组合物的方法来制备。固体单位剂型可为胶囊剂，其可为普通的硬胶囊型或软胶囊型，包含例如表面活性剂、润滑剂和惰性填充剂(例如乳糖、蔗糖、磷酸钙和玉米淀粉)。
在另一实施方案中，可将本发明的化合物或其药学上可接受的盐和常规片剂基质(例如乳糖、蔗糖和玉米淀粉)一起并与如下物质组合压制成片剂：粘合剂(例如阿拉伯胶、玉米淀粉或明胶)、用于辅助给药后片剂的分解和溶出的崩解剂(例如土豆淀粉、藻酸、玉米淀粉和瓜尔胶、黄蓍树胶、阿拉伯胶)、用于提高片剂制粒的流动性并且防止片剂材料与片剂模具和冲头的表面粘附的润滑剂(例如滑石、硬脂酸或硬脂酸镁、硬脂酸钙或硬脂酸锌)、染料、着色剂，以及用于改善片剂的感官性质并使它们更容易被患者接受的调味剂(例如薄荷油、冬青油或樱桃香精)。用于口服液体剂型的适合的赋形剂包括磷酸二钙和稀释剂，例如水和醇(例如乙醇、苯甲醇和聚乙烯醇)，所述稀释剂添加或不添加有药学上可接受的表面活性剂、助悬剂或乳化剂。可以存在各种其它物质作为包衣或者用于改变剂量单位的物理形式。例如可用虫胶、糖或二者将片剂、丸剂或胶囊剂包衣。
还可将本发明的化合物以所述化合物的注射剂进行肠胃外给药，即皮下、静脉内、眼内、滑膜内、肌内或腹膜内给药，所述注射剂优选在含有药物载体的生理学可接受的稀释剂中，所述药物载体可为无菌液体或液体的混合物，所述液体为例如水，盐水，葡萄糖水溶液和相关的糖溶液，醇例如乙醇、异丙醇或十六醇，二醇例如丙二醇或聚乙二醇，甘油缩酮例如2,2-二甲基-1,1-二氧戊环-4-甲醇，醚例如聚乙二醇400(PEG400)，油，脂肪酸，脂肪酸酯或脂肪酸甘油酯或乙酰化脂肪酸甘油酯，所述稀释剂添加或不添加有药学上可接受的表面活性剂，例如肥皂或洗涤剂，助悬剂例如果胶、卡波姆、甲基纤维素、羟丙甲纤维素或羧甲基纤维素，或乳化剂和其它药学辅剂。
用于肠胃外制剂的示例性表面活性剂是聚乙烯脱水山梨糖醇脂肪酸酯类，例如脱水山梨糖醇单油酸酯，以及环氧乙烷与疏水性基质的高分子量加合物，所述疏水性基质由环氧丙烷和丙二醇缩合形成。
还可将本发明的组合物以用于药物的直肠给药的栓剂的形式给药。可通过将药物与在常温下为固体但是在直肠温度下为液体并且因此可在直肠中溶化而释放所述药物的适合的无刺激性的赋形剂混合来制备这些组合物。此类物质是例如可可脂和聚乙二醇。
用于肠胃外给药的控释制剂包括本领域已知的脂质体微球、聚合物微球和聚合物凝胶制剂。
可能需要或必须通过机械递送装置将所述药物组合物递送至患者。用于递送药剂的机械递送装置的构造和用途是本领域公知的。例如将药物直接给药至脑的直接技术通常涉及将药 物递送导管置入患者的脑室系统以绕过血脑屏障。
可将本发明的化合物作为单一药剂给药或者与一种或多种其它药剂组合给药，其中所述组合不会引起不可接受的不良反应。本发明还涉及此类组合。例如，可将本发明的化合物与已知的化疗剂或抗癌剂(例如抗过度增殖性疾病或其它适应症的药剂等)以及与它们的混合物和组合进行组合。其它适应症药剂包括但不限于抗血管生成剂、有丝分裂抑制剂、烷化剂、抗代谢剂、DNA-嵌入抗生素、生长因子抑制剂、细胞周期抑制剂、酶抑制剂、拓扑异构酶抑制剂、生物应答调节剂或抗激素。
一般而言，将细胞毒性剂和/或细胞抑制剂与本发明的化合物或组合物组合使用会起到以下作用：
(1)与单独给药任一种药剂相比在减少肿瘤生长或者甚至消除肿瘤方中产生更好的功效，
(2)允许给药更少量的所给药的化疗药剂，
(3)提供化疗剂治疗，其被患者良好地耐受并且具有的有害药理学并发症比在单一药剂化疗和某些其它组合疗法中所观察到的少，
(4)允许治疗范围更广的哺乳动物(特别是人)的不同癌症类型，
(5)提供受治疗患者中更高的响应，
(6)与标准的化疗治疗相比提供受治疗患者中更长的存活时间，
(7)提供更长的肿瘤发展时间，和/或
(8)与其它癌症药剂组合产生拮抗效应的已知情况相比，得到至少与单独使用的药剂一样好的功效和耐受性。
本发明的另一方面提供如上文所述的化合物用于制备治疗或预防疾病的药物组合物的用途。
所述疾病是由不受控制的细胞生长、增殖和/或存活、不适当的细胞免疫应答或不适当的细胞炎症应答引起的疾病，或者伴有不受控制的细胞生长、增殖和/或存活、不适当的细胞免疫应答或不适当的细胞炎症应答的疾病，特别地，所述疾病为例如血液肿瘤、实体瘤和/或它们的转移，如白血病和骨髓增生异常综合征、恶性淋巴瘤、包括脑瘤和脑转移在内的头部和颈部肿瘤、包括非小细胞肺肿瘤和小细胞肺肿瘤在内的胸部肿瘤、胃肠道肿瘤、内分泌肿瘤、乳腺肿瘤和其它妇科肿瘤、包括肾肿瘤、膀胱瘤和前列腺瘤在内的泌尿系统肿瘤、皮肤肿瘤和肉瘤、和/或它们的转移。更特别地，所述疾病为白血病。
本发明还提供本发明的化合物及其组合物在制备治疗哺乳动物的过度增殖性病症的药物中的用途。可利用化合物来抑制、阻断、降低、减少等细胞增殖和/或细胞分裂和/或引起凋亡。过度增殖性病症包括但不限于银屑病、瘢痕疙瘩和其它影响皮肤的增生、良性前列腺增生(BpH)、实体瘤例如乳腺癌、呼吸道癌、肺癌、脑癌、生殖器官癌、消化道癌、泌尿道癌、眼癌、肝癌、皮肤癌、头颈癌、甲状腺癌、甲状旁腺癌以及它们的远端转移。所述病症还包括淋巴瘤、肉瘤和白血病。
这些病症已在人类中得到良好的表征，但是还以相似的病因学存在于其它哺乳动物中，并且可通过给药本发明的药物组合物进行治疗。
本发明的化合物还可用于制备抗肿瘤、抗疟、抗寄生虫、抗真菌或抗菌化疗等药物。
术语定义和解释
术语“C1-40烷基”应理解为优选表示具有1～40个碳原子的直连或支链饱和一价烃基，优选为C1-6烷基。“C1-6烷基”应理解为优选表示具有1、2、3、4、5或6个碳原子的直连或支链饱和一价烃基，例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基或它们的异构体。特别地，所述基团具有1、2、3或4个碳原子(“C1-4烷基”)，例如甲基、乙基、丙基、丁基、异丙基、异丁基、仲丁基、叔丁基，更特别地，所述基团具有1、2或3个碳原子(“C1-3烷基”)，例如甲基、乙基、正丙基或异丙基。
术语“C2-40烯基”应理解为优选表示直连或支链的一价烃基，其包含一个或多个双键并 且具有2～40个碳原子，优选“C2-6烯基”。“C2-6烯基”应理解为优选表示直连或支链的一价烃基，其包含一个或多个双键并且具有2、3、4、5或6个碳原子，特别是2或3个碳原子(“C2-3烯基”)，应理解，在所述烯基包含多于一个双键的情况下，所述双键可相互分离或者共轭。所述烯基是例如乙烯基、烯丙基、(E)-2-甲基乙烯基、(Z)-2-甲基乙烯基、(E)-丁-2-烯基、(Z)-丁-2-烯基、(E)-丁-1-烯基、(Z)-丁-1-烯基、戊-4-烯基、(E)-戊-3-烯基、(Z)-戊-3-烯基、(E)-戊-2-烯基、(Z)-戊-2-烯基、(E)-戊-1-烯基、(Z)-戊-1-烯基、己-5-烯基、(E)-己-4-烯基、(Z)-己-4-烯基、(E)-己-3-烯基、(Z)-己-3-烯基、(E)-己-2-烯基、(Z)-己-2-烯基、(E)-己-1-烯基、(Z)-己-1-烯基、异丙烯基、2-甲基丙-2-烯基、1-甲基丙-2-烯基、2-甲基丙-1-烯基、(E)-1-甲基丙-1-烯基、(Z)-1-甲基丙-1-烯基、3-甲基丁-3-烯基、2-甲基丁-3-烯基、1-甲基丁-3-烯基、3-甲基丁-2-烯基、(E)-2-甲基丁-2-烯基、(Z)-2-甲基丁-2-烯基、(E)-1-甲基丁-2-烯基、(Z)-1-甲基丁-2-烯基、(E)-3-甲基丁-1-烯基、(Z)-3-甲基丁-1-烯基、(E)-2-甲基丁-1-烯基、(Z)-2-甲基丁-1-烯基、(E)-1-甲基丁-1-烯基、(Z)-1-甲基丁-1-烯基、1,1-二甲基丙-2-烯基、1-乙基丙-1-烯基、1-丙基乙烯基、1-异丙基乙烯基。
术语“C2-40炔基”应理解为表示直连或支链的一价烃基，其包含一个或多个三键并且具有2～40个碳原子，优选“C2-C6-炔基”。术语“C2-C6-炔基”应理解为优选表示直连或支链的一价烃基，其包含一个或多个三键并且具有2、3、4、5或6个碳原子，特别是2或3个碳原子(“C2-C3-炔基”)。所述C2-C6-炔基是例如乙炔基、丙-1-炔基、丙-2-炔基、丁-1-炔基、丁-2-炔基、丁-3-炔基、戊-1-炔基、戊-2-炔基、戊-3-炔基、戊-4-炔基、己-1-炔基、己-2-炔基、己-3-炔基、己-4-炔基、己-5-炔基、1-甲基丙-2-炔基、2-甲基丁-3-炔基、1-甲基丁-3-炔基、1-甲基丁-2-炔基、3-甲基丁-1-炔基、1-乙基丙-2-炔基、3-甲基戊-4-炔基、2-甲基戊-4-炔基、1-甲基戊-4-炔基、2-甲基戊-3-炔基、1-甲基戊-3-炔基、4-甲基戊-2-炔基、1-甲基戊-2-炔基、4-甲基戊-1-炔基、3-甲基戊-1-炔基、2-乙基丁-3-炔基、1-乙基丁-3-炔基、1-乙基丁-2-炔基、1-丙基丙-2-炔基、1-异丙基丙-2-炔基、2,2-二甲基丁-3-炔基、1,1-二甲基丁-3-炔基、1,1-二甲基丁-2-炔基或3,3-二甲基丁-1-炔基。特别地，所述炔基是乙炔基、丙-1-炔基或丙-2-炔基。
术语“C3-20环烷基”应理解为表示饱和的一价单环或双环烃环，其具有3～20个碳原子，优选“C3-10环烷基”。术语“C3-10环烷基”应理解为表示饱和的一价单环或双环烃环，其具有3、4、5、6、7、8、9或10个碳原子。所述C3-10环烷基可以是单环烃基，如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基或环癸基，或者是双环烃基如十氢化萘环。
术语“C5-20环烯基”应理解为表示不饱和度为1、2或3的共轭或非共轭的一价单环或双环烃环，其具有5～20个碳原子，优选“C5-10环烯基”。术语“C5-10环烯基”应理解为表示不饱和的一价单环或双环烃环，其具有5、6、7、8、9或10个碳原子。所述C5-10环烯基可以是单环烃基，如3-环戊烯基、1-环己烯基、2-环己烯基、2,4-环戊二烯基、2,5-环己二烯基或1,3,5-环庚三烯基或1,3,6-环庚三烯基，或者是双环烃基如六氢化萘环、八氢化萘环。除非另有说明，术语“C5-20环烯基”包括其所有可能的异构形式，例如其位置异构体或构型异构体。
术语“3-20元杂环基”意指饱和的一价单环或双环烃环，其包含1-5个独立选自N、O和S的杂原子，优选“3-10元杂环基”。术语“3-10元杂环基”意指饱和的一价单环或双环烃环，其包含1-5个，优选1-3个选自N、O和S的杂原子。所述杂环基可以通过所述碳原子中的任一个或氮原子(如果存在的话)与分子的其余部分连接。特别地，所述杂环基可以包括但不限于：4元环，如氮杂环丁烷基、氧杂环丁烷基；5元环，如四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基；或6元环，如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基或三噻烷基；或7元环，如二氮杂环庚烷基。任选地，所述杂环基可以是苯并稠合的。所述杂环基可以是双环的，例如但不限于5,5元环，如六氢环戊并[c]吡咯-2(1H)-基环，或者5,6元双环，如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。含氮原子的环可以是部分不饱和的，即它可以包含一个或多个双键，例如但不限于2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、4,5-二氢噁唑基或4H-[1,4]噻嗪基，或者，它可以是苯并稠合的，例如但不限于二氢异喹啉基。根据本发明，所述杂环基是无芳香性的。
术语“C6-20芳基”应理解为优选表示具有6～20个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环，优选“C6-14芳基”。术语“C6-14芳基”应理解为优选表示具有6、7、 8、9、10、11、12、13或14个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环(“C6-14芳基”)，特别是具有6个碳原子的环(“C6芳基”)，例如苯基；或联苯基，或者是具有9个碳原子的环(“C9芳基”)，例如茚满基或茚基，或者是具有10个碳原子的环(“C10芳基”)，例如四氢化萘基、二氢萘基或萘基，或者是具有13个碳原子的环(“C13芳基”)，例如芴基，或者是具有14个碳原子的环(“C14芳基”)，例如蒽基。
术语“5-20元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系：其具有5～20个环原子且包含1-5个独立选自N、O和S的杂原子，例如“5-14元杂芳基”。术语“5-14元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系：其具有5、6、7、8、9、10、11、12、13或14个环原子，特别是5或6或9或10个碳原子，且其包含1-5个，优选1-3各独立选自N、O和S的杂原子并且，另外在每一种情况下可为苯并稠合的。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基、噻-4H-吡唑基等以及它们的苯并衍生物，例如苯并呋喃基、苯并噻吩基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并三唑基、吲唑基、吲哚基、异吲哚基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等，以及它们的苯并衍生物，例如喹啉基、喹唑啉基、异喹啉基等；或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物；或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基等。
上述对术语“C1-40烷基”的定义同样适用于含有“C1-40烷基”的其他术语，例如术语“C1-40烷基氧基”、“C1-40烷基硅基”和“C1-40烷基硅基氧基”等。同样地，上述对术语“C2-40烯基”、“C2-40炔基”、“C3-20环烷基”、“C5-20环烯基”、“3-20元杂环基”、“C6-20芳基”和“5-20元杂芳基”的定义相应地同样适用于含有其的其他术语，如术语“C2-40烯基氧基”、C2-40炔基氧基”等。
在术语“二(C1-C40烷基)硅基”与术语“三(C1-C40烷基)硅基”中，每一个C1-C40烷基之间可以彼此相同或不同。
除非另有说明，所述杂芳基或亚杂芳基包括其所有可能的异构形式，例如其位置异构体。因此，对于一些说明性的非限制性实例，术语吡啶基或亚吡啶基包括吡啶-2-基、亚吡啶-2-基、吡啶-3-基、亚吡啶-3-基、吡啶-4-基和亚吡啶-4-基；或者，术语噻吩基或亚噻吩基包括噻吩-2-基、亚噻吩-2-基、噻吩-3-基和亚噻吩-3-基。
本文中的缩写“TBSO”表示叔丁基二甲基硅基氧基。
术语“取代的”意指所指定的原子上的一个或多个氢被所列出的基团取代，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。
术语“任选被……取代”指可以无取代或被所列出的基团取代。
环系的取代基指与芳族或非芳族环系连接的取代基，例如所述取代基代替所述环系上可用的氢。
术语“药学上可接受的盐”包括本发明化合物与能够形成相同或相近活性的无生理毒性的酸或碱形成盐，包括无机酸的盐、有机酸的盐等。其中，无机酸的盐的实例包括盐酸盐、氢溴酸盐、氢碘酸盐、氯化物、溴化物、碘化物、硫酸盐、硫酸氢盐、硝酸盐、磷酸盐、磷酸氢盐。有机酸的盐的实例包括乙酸盐、富马酸盐、扑酸盐、天冬氨酸盐、苯磺酸盐、碳酸盐、碳酸氢盐、樟脑磺酸盐、D-和L-乳酸盐、D和L-酒石酸盐、乙磺酸盐、甲磺酸盐、丙二酸盐、乳清酸盐、葡庚糖酸盐、甲基硫酸盐、硬脂酸盐、葡糖醛酸盐、2-萘磺酸盐、甲苯磺酸盐、羟苯酰苯酸盐、烟酸盐、羟乙基磺酸盐、苹果酸盐、马来酸盐、柠檬酸盐、葡萄糖酸盐、琥珀酸盐、蔗糖酸盐、苯甲酸盐、乙磺酸盐和扑酸盐。
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本发明包含化合物的所有互变异构形式。
本发明的化合物可以溶剂合物(如水合物)的形式存在，其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。在化学计量溶剂合物(例如水合物)的情况下，可能分别是半溶剂合物、一溶剂合物、倍半溶剂合物、二溶剂合物、三溶剂合物、四溶剂合物、五溶剂合物、半五溶剂合物等。本发明包括所有此类溶剂合物。
本发明各通式化合物的取代基定义中使用的术语“一次或多次”应理解为包括一次、两次、三次、四次或五次，特别是一次、两次、三次或四次，更特别是一次、两次或三次，例如一次或两次。
除非另有说明，本说明书记载的数值范围相当于至少记载了其中每一个具体的整数数值。例如，数值范围“1-40”相当于记载了数值范围“1-10”中的每一个整数数值即1、2、3、4、5、6、7、8、9、10，以及数值范围“11-40”中的每一个整数数值即11、12、13、14、15、......、35、36、37、38、39、40。
本文件通篇提及的术语“治疗”具有本领域技术人员公知的常规定义，例如为了抵抗、减轻、减少、缓解、改善诸如肉瘤的疾病或病症的情况等的目的来管理或护理个体。
本发明通式(I)所示化合物对人白血病、肝癌和肺癌肿瘤细胞株具有良好的抑制活性，其在10-4mol/L的浓度下对HL-60人白血病细胞的抑制率可大于80％。具体而言，本发明实施例化合物在10-4mol/L的浓度下对HL-60人白血病细胞的抑制率可大于80％。作为优选，本发明实施例化合物23、25、26、32、33、34、36、37、41、44、45、46、47、52、56、57、59、61和63在10-5mol/L的浓度下对HL-60人白血病细胞的抑制率可大于80％。
剂量和给药
基于已知用来评价用于治疗过度增殖性病症和血管生成病症的化合物的标准实验室技术，通过标准毒性试验以及通过用于确定对哺乳动物中上文所述病症的治疗的标准药理学试验，并且通过将这些结果与用于治疗这些病症的已知药物的结果进行比较，可容易地确定用于治疗每一种期望适应症的本发明的化合物的有效剂量。在这些病症之一的治疗中所给药的活性成分的量可根据如下考量而发生很大变化：所使用的具体化合物和剂量单位、给药方式、疗程、受治疗患者的年龄和性别以及被治疗病症的性质和程度。例如，待给药的活性成分的总量一般为约0.001mg/kg-约200mg/kg体重/天，并且优选约0.01mg/kg-约20mg/kg体重/天。临床上有用的给药方案会是每日一次至三次的给药至每四周一次的给药。本发明的化合物或其药学上可接受的盐或酯或组合物的期望的治疗方式和给药数量可由本领域技术人员利用常规的治疗试验来确定。
本发明提供了具有良好生物活性的三尖杉酯类生物碱，及其高立体选择性的半合成制备方法和应用。所述制备方法可以改善已有技术的不足。所述制备方法还具有原材料便宜易得，关键反应的化学收率和非对映选择性高，操作简便，合成步骤短，易于纯化，可以放大生产等优点。
具体实施方式
以下通过示例性的具体实施例对本发明的技术方案进行详细说明。但是，不应将这些实施例解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，实施例中使用的原料和试剂均为市售商品或可根据已知文献制备。
制备实施例
实施例1化合物19的制备
Figure PCTCN2016109122-appb-000039
室温下，将BF3·OEt285.8μL滴加到化合物18(150mg,0.36mmol)和烯醇硅醚A(127.9mg,0.7mmol)的5mL CH2Cl2溶液中，5h后原料基本消失。加入饱和NaHCO3溶液淬灭反应，搅拌0.5h后，水洗有机相至水相不为碱性，饱和NaCl溶液洗涤，干燥，过滤，旋去溶剂，柱层析(PE:EA:TEA＝80:10:0.4)后得到化合物19的白色固体，产率87％。mp.139-141℃；[α]D＝-170.2°(c 1.03,CHCl3,20℃)；1H NMR(400MHz,CDCl3)δ6.62(s,1H),6.61(s,1H),6.07(s,1H),5.90(s,1H),5.89(s,1H),4.66(d,J＝1.8Hz,1H),3.98(s,1H),3.81(s,1H),3.67(s,3H),3.59(s,3H),3.29(ddd,J＝13.8,12.6,7.8Hz,1H),3.05–2.90(m,2H),2.98(d,J＝16.5Hz,1H),2.86–2.80(m,1H),2.75(d,J＝16.5Hz,1H),2.63–2.54(m,1H),2.41(dd,J＝14.4,7.8Hz,1H),2.28–2.22(m,1H),1.75–1.65(m,4H),1.55–1.32(m,2H),1.41–1.31(m,1H),1.22–1.08(m,1H),0.89(d,J＝6.4Hz,3H),0.87(d,J＝6.4Hz,3H)ppm；13C NMR(101MHz,CDCl3)δ174.4,171.1,155.2,146.5,146.0,132.0,131.1,111.0,110.4,102.5,100.9,75.1,74.6,68.4,57.7,56.6,53.3,51.8,47.1,43.1,37.6,35.3,31.4,30.6,28.2,22.6,22.5,19.8ppm；HRMS(ESI)m/z：计算值C28H38NO8(M+H)+：516.2597，实测值：516.2592。
实施例2化合物3和20的制备
Figure PCTCN2016109122-appb-000040
同实施例1，不同之处在于在-40℃至-78℃温度范围内反应。dr值为C2'R:C2'S＝6:1，柱层析(PE:EA:TEA＝60:10:0.3)后得到化合物3和化合物20。产率90％。
化合物3：浅黄色无定形物，产率为75％。[α]D＝-122.6°(c 1.03,CHCl3,20℃)；1H NMR(400MHz,CDCl3)δ6.62(s,1H),6.53(s,1H),5.99(d,J＝9.8Hz,1H),5.87(d,J＝1.5Hz,1H),5.85(d,J＝1.2Hz,1H),5.04(s,1H),3.77(d,J＝9.8Hz,1H),3.67(s,3H),3.57(s,3H),3.48(s,1H),3.18–3.08(m,2H),2.92(td,J＝11.0,6.8Hz,1H),2.61–2.57(m,2H),2.36(dd,J＝14.0,6.8Hz,1H),2.26(d,J＝16.5Hz,1H),2.08–1.98(m,1H),1.95–1.87(m,1H),1.88(d,J＝16.5Hz,1H),1.77–1.72(m,2H),1.45–1.40(m,3H),1.32–1.24(m,1H),1.03–0.93(m,1H),0.83(d,J＝6.2Hz,3H),0.82(d,J＝6.2Hz,3H)ppm；13C NMR(101MHz,CDCl3)δ174.2,170.6,157.9,146.7,145.9,133.4,128.5,112.7,109.8,100.9,100.1,74.8,74.7,70.7,57.2,55.9,54.1,51.6,48.8,43.4,42.9,36.8,31.7,31.4,28.1,22.8,22.4,20.4ppm；HRMS(ESI)m/z：计算值C28H38NO8(M+H)+：516.2597，实测值：516.2599。
化合物20：[α]D＝-101.6°(c 1.03,CHCl3,20℃)；1H NMR(400MHz,CDCl3)δ6.59(s,2H),5.88(d,J＝9.6Hz,1H),5.86(s,2H),5.03(s,1H),3.78(d,J＝9.6Hz,1H),3.66(s,3H),3.65(s,3H),3.42(s,1H),3.18–3.02(m,2H),2.98–2.92(m,1H),2.64(d,J＝16.8Hz,1H),2.65–2.52(m,2H),2.53(d,J＝16.8Hz,1H),2.37(dd,J＝13.2Hz,6.0Hz,1H),2.06–1.98(m,1H),1.93–1.83(m,1H),1.81–1.69(m,2H),1.30–1.21(m,1H),1.11(t,J＝12.6Hz,1H),1.03–0.93(m,1H),0.93–0.85(m,1H),0.78(s,3H),0.77(s,3H),0.81–0.72(m,1H)ppm；13C NMR(101MHz,CDCl3)δ174.3,171.1,157.5,146.7,145.8,133.3,127.9,112.7,109.7,100.9,99.9,75.2,74.5,70.7,57.2,55.8,53.8,51.6,48.5,43.1,42.2,36.1,31.2,29.6,27.9,22.5,22.1,20.1ppm。HRMS(ESI)m/z calcd for C28H38NO8(M+H)+516.2597found 516.2599.
实施例3化合物19和3的制备
Figure PCTCN2016109122-appb-000041
同实施例1，不同之处在于在0-30℃温度范围内，由化合物18得到化合物19和化合物3。，柱层析(PE:EA:TEA＝80:10:0.4)后得到化合物19的白色固体，产率60％，化合物3，产率20％。所获得的产物分别与实施例1和2的产物的数据一致。
实施例4化合物3的制备
Figure PCTCN2016109122-appb-000042
在-40℃至-60℃温度范围内，将TiCl482μL滴加到化合物18(150mg,0.36mmol)和烯醇硅醚A(127.9mg,0.7mmol)的5mL CH2Cl2溶液中。过夜后仍有部分原料剩余。加入饱和NaHCO3溶液调pH至9–10，分液，水相用二氯甲烷萃取三次，合并有机相，饱和NaCl溶液洗涤，无水硫酸钠干燥，过滤，旋去溶剂，柱层析(PE:EA:TEA＝60:10:0.3)后得到浅黄色无定形物3和20，产率57％，dr值为C2'R:C2'S＝1:4，所获得的产物与实施例2的产物的数据一致。
实施例5化合物3和20的制备
Figure PCTCN2016109122-appb-000043
-25℃下，将ZnBr2(136.7mg,0.61mmol)的1mL乙醚溶液缓慢滴加到化合物18(122mg,0.3mmol)和烯醇硅醚A(104.1mg,0.55mmol)的5mL二氯甲烷溶液中，过夜反应。加入饱和NaHCO3溶液调pH至9–10，静置分液，水相用二氯甲烷萃取三次，合并有机相，饱和NaCl溶液洗涤，无水硫酸钠干燥，过滤，旋去溶剂，柱层析(PE:EA:TEA＝60:10:0.3)后得到浅黄色无定形物3和20，产率为60％，dr值为C2'R:C2'S＝1:1.6，所获得的产物与实施例2的产物的数据一致。
实施例6化合物3的制备
Figure PCTCN2016109122-appb-000044
-25℃下，将无水SnCl4(170.2mg,0.6mmol)缓慢滴加到化合物18(131mg,0.32mmol)和烯醇硅醚A(111.7mg,0.59mmol)的5mL二氯甲烷溶液中，过夜反应。加入饱和NaHCO3溶液调pH至9-10，静置分液，水相用二氯甲烷萃取三次，合并有机相，饱和NaCl溶液洗涤，无水硫酸钠干燥，过滤，旋去溶剂，柱层析(PE:EA:TEA＝60:10:0.3)后得到浅黄色无定形物3和20，产率为50％，dr值为C2'R:C2'S＝1:4，所获得的产物与实施例2的产物的数据一致。
实施例7化合物3的制备
Figure PCTCN2016109122-appb-000045
-25℃下，向化合物18(132mg,0.3mmol)的5mL二氯甲烷溶液中加入BF3·OEt2(0.054mL,0.45mmol)后，加入烯醇硅醚C(131mg,0.6mmol)，反应过夜，加入饱和碳酸氢钠溶液淬灭反应，分液，水相用二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，旋干。将粗产品溶于10mL乙腈中，加入200mg KF·2H2O，油浴70℃下反应。6h后直接过滤旋干，柱层析(PE:AE:TFA＝60:10:0.3)后得到浅黄色无定形物3，产率10.2％，dr值大于99:1，所获得的产物3与实施例2的产物的数据一致。
实施例8化合物21和22的制备
Figure PCTCN2016109122-appb-000046
0℃下，将88μL BF3·OEt2缓慢滴加到化合物18(140mg,0.34mmol)和烯醇硅醚B(147.7mg,0.63mmol)的5mL二氯甲烷溶液中，反应8h，加入饱和碳酸氢钠溶液淬灭反应，分液，水相用二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，旋干。将粗产品溶于10mL乙腈中，加入200mgKF·2H2O，30℃下反应4h后直接过滤旋干，柱层析(PE:EA:TEA＝30:10:0.15)后得到化合物21(产率15％)和化合物22(产率15％)，以及两者的混合物(产率55％)，dr值为(C2',C3')(R,S):(C2',C3')(R,R)＝1.2:1。
异三尖杉酯碱21：浅黄色固体。[α]D＝-99°(c 0.5,CHCl3)；1H NMR(400MHz,CDC13)δ6.65(s,1H),6.54(s,1H),6.03(d,J＝10.2Hz,1H),5.85(s,1H),5.80(s,1H),5.07(s,1H),3.78(d,J＝10.2Hz,1H),3.68(s,3H),3.61(s,3H),3.33(d,J＝7.8Hz,1H),3.13(s,1H),3.17–3.10(m,2H),2.97–2.92(m,1H),2.86(d,J＝7.8Hz,1H),2.62–2.58(m,2H),2.41(dd,J＝14.4,6.6Hz,1H),2.08–2.03(m,1H),1.93–1.89(m,1H),1.84(td,J＝13.2,3.6Hz,1H),1.79–1.73(m,2H),1.53–1.43(m,2H),1.25–1.19(m,1H),0.98–0.93(m,1H),0.86(d,J＝6.6Hz,3H),0.84(d,J＝6.6Hz,3H)ppm；13C NMR(101MHz,CDCl3)δ173.0,171.7,157.4,146.6,145.6,133.4,128.3,112.6,109.9,100.8,100.5,79.1,75.1,74.7,70.6,57.1,55.8,53.9,52.3,48.5,43.4,33.0,31.4,31.3,28.1,22.7,22.2,20.3ppm；HRMS(ESI)m/z：计算值C28H38NO9(M+H)+：532.2546，实测值：532.2536。
异三尖杉酯碱的非对映体22：浅黄色固体。[α]D＝-144°(c0.5,CHCl3)；1HNMR(400MHz,CDC13)δ6.65(s,1H),6.61(s,1H),6.00(d,J＝10.2Hz,1H),5.86(s,1H),5.84(s,1H),5.07(s,1H),3.80(d,J＝10.2Hz,1H),3.74(s,3H),3.68(s,3H),3.42(d,J＝9.6Hz,1H),3.38(s,1H),3.19–3.07(m,2H),2.99–2.92(m,1H),2.63–2.57(m,2H),2.42(dd,J＝13.8,6.6Hz,1H),2.33(d,J＝9.6Hz,1H),2.09–2.01(m,1H),1.92–1.88(m,1H),1.80–1.71(m,2H),1.64–1.57(m,1H),1.52–1.42(m,2H),1.32-1.25(m,1H),0.95–0.90(m,1H),0.85(d,J＝6.6Hz,3H),0.84(d,J＝6.6Hz,3H)ppm；13CNMR(101MHz,CDCl3)δ172.8,171.4,157.3,146.9,146.1,133.1,128.1,112.8,109.8,100.9,100.5,79.6,75.4,74.8,70.6,57.1,55.8,53.9,52.4,48.6,43.4,32.2,31.7,31.4,28.1,22.8,22.2,20.3ppm；HRMS(ESI)m/z：计算值C28H38NO9(M+H)+：532.2546，实测值：532.2536。
实施例9化合物23的制备
Figure PCTCN2016109122-appb-000047
-25℃下，向25mL烧瓶中加入化合物18(133mg,0.32mmol)，随后加入二氯甲烷5mL，溶解后，加入烯醇硅醚D(104.6mg,0.6mmol)，之后再慢慢滴加BF3·OEt2溶液83.3μL，过夜反应。饱和NaHCO3溶液淬灭反应，二氯甲烷萃取，饱和NaCl溶液洗涤，干燥，过滤，旋去溶剂，柱层析(PE:EA:TEA＝80:10:0.4)后得到化合物23，产率为94％。dr值为C2'R:C2'S＝40:1。
化合物23：[α]D＝-106.7°(c0.495,CHCl3)；1H NMR(400MHz,CDCl3)δ6.60(s,1H),6.59(s,1H),6.03(d,J＝9.9Hz,1H),5.85(s,2H),5.05(s,1H),3.80(d,J＝9.9Hz,1H),3.67(s,3H),3.60(s,3H),3.42(s,1H),3.11–3.08(m,2H),2.92(td,J＝11.5,6.9Hz,1H),2.59–2.57(m,2H),2.37(dd,J＝14.0,6.7Hz,1H),2.03–1.98(m,1H),1.89–1.86(m,1H),1.76–1.67(m,4H),1.45–1.38(m,1H),1.28–1.24(m,1H),1.15–1.09(m,1H),0.96(s,3H),0.83(d,J＝6.0Hz,3H),0.82(d,J＝6.0Hz,3H),0.65(s,3H)ppm；13C NMR(101MHz,CDCl3)δ174.9,173.4,156.8,146.2,145.3,132.6,127.5,111.8,109.4,100.0,99.1,80.4,75.2,69.9,56.2,54.9,52.9,51.0,48.7,47.8,42.4,30.9,30.7,30.0,27.5,21.8,21.6,20.1,19.7,19.4ppm；HRMS(ESI)m/z：计算值C30H42NO8(M+H)+：544.2910，实测值：544.2910。
实施例10化合物24的制备
Figure PCTCN2016109122-appb-000048
同实施例9，不同之处在于是室温反应，柱层析(PE:EA:TEA＝90:10:0.5)后得到了迁移产物24，产率为89％。[α]D＝-146.1°(c 0.375,CHCl3,20℃)；1H NMR(400MHz,CDCl3)δ6.63(s,1H),6.61(s,1H),6.02(d,J＝1.6Hz,1H),5.91(d,J＝1.5Hz,1H),5.89(d,J＝1.5Hz,1H),4.68(d,J＝2.1Hz,1H),3.97(s,1H),3.87(d,J＝0.9Hz,1H),3.68(s,3H),3.59(s,3H),3.30(ddd,J＝14.2,11.6,8.2Hz,1H),3.01–2.90(m,2H),2.80(dd,J＝12.0,7.9Hz,1H),2.61(td,J＝9.7,6.7Hz,1H),2.42(dd,J＝14.4,7.5Hz,1H),2.35–2.28(m,1H),1.94(td,J＝12.3,3.6Hz,1H),1.80–1.63(m,3H),1.57–1.46(m,2H),1.43–1.36(m,1H),1.34(s,3H),1.33(s,3H),1.06–0.96(m,1H),0.89(d,J＝2.6Hz,3H),0.87(d,J＝2.6Hz,3H)ppm；13C NMR(101MHz,CDCl3)δ176.2,173.8,155.1,146.2,145.7,131.8,130.8,110.8,110.2,102.5,100.6,81.0,75.2,68.2,57.2,56.3,53.0,51.8,49.6,46.4,34.8,31.8,31.2,30.5,28.2,22.4,22.3,21.3,19.6ppm；HRMS(ESI)m/z：计算值C30H42NO8(M+H)+：544.2910，实测值：544.2912。
实施例11化合物25、26和3的制备
Figure PCTCN2016109122-appb-000049
向25mL烧瓶中加入化合物18(100mg,0.24mmol)，随后加入二氯甲烷5mL，溶解后，-78℃下加入烯醇硅醚E(122.8mg,0.68mmol)，再慢慢滴加BF3·OEt2溶液0.058mL，过夜反应。饱和NaHCO3溶液淬灭反应，二氯甲烷萃取，饱和NaCl溶液洗涤，干燥，过滤，旋去溶剂。柱层析(PE:EA:TEA＝80:10:0.3)后得到的化合物25(产率60.4％)和化合物26(产率29.5％)。向化合物25和26的混合物中加入锌粉(31.5mg,0.48mmol)和1mL四氢呋喃，然后室温下滴加冰乙酸(43.2mg,0.72mmol)，反应过夜。用10％Na2CO3淬灭，二氯甲烷萃取，饱和NaCl溶液洗涤，干燥，过滤，柱层析(PE:EA:TEA＝60:10:0.3)后得到化合物3，所得产物3与实施例2的产物具有相同的特征，产率为90％。
化合物25：mp.157–160℃；[α]D＝-190°(c0.54,CHCl3)；1H NMR(400MHz,CDCl3)δ6.67(s,1H),6.51(s,1H),5.96(d,J＝9.8Hz,1H),5.89(s,1H),5.85(s,1H),5.07(s,1H),3.77(d,J＝9.8Hz,1H),3.68(s,3H),3.66(s,3H),3.56(s,1H),3.47(s,1H),3.13–3.04(m,2H),2.96–2.91(m,1H),2.62–2.58(m,2H),2.40(dd,J＝14.0,6.7Hz,1H),2.06–2.01(m,1H),1.93–1.90(m,1H),1.86–1.74(m,3H),1.48–1.32(m,2H),1.33–1.15(m,2H),0.85(d,J＝6.6Hz,3H),0.83(d,J＝6.6Hz,3H)ppm；13C NMR(101MHz,CDCl3)δ172.2,167.5,157.5,146.8,145.9,133.3,128.3,112.6,109.8,101.0,100.6,78.1,75.3,70.6,62.4,57.2,55.9,54.0,53.1,48.6,43.4,34.8,31.4,31.3,28.0,22.9,22.1,20.3ppm；HRMS(ESI)m/z：计算值C28H37ClNO8(M+H)+：550.2208，实测值：550.2204。
化合物26：[α]D＝-130°(c0.515,CHCl3)；1H NMR(400MHz,CDCl3)δ6.68(s,1H),6.58(s,1H),6.00(d,J＝9.8Hz,1H),5.89(s,1H),5.83(s,1H),5.08(s,1H),3.80(d,J＝9.8Hz,1H),3.76(s,3H),3.67(s,3H),3.47(s,1H),3.44(s,1H),3.17–3.06(m,2H),3.03–2.90(m,1H),2.62–2.55(m,2H),2.44(dd,J＝14.1,6.7Hz,1H),2.07–2.02(m,1H),1.93–1.88(m,1H),1.80–1.72(m,2H),1.63–1.55(m,1H),1.48–1.32(m,3H),1.27–1.24(m,1H),0.84(d,J＝6.4Hz,3H),0.82(d,J＝6.4Hz,3H)ppm；13C NMR(101MHz,CDCl3)δ170.3,167.1,157.5,146.9,146.3,133.2,128.0,113.0,110.1,101.1,100.9,78.9,75.5,70.9,61.4,57.3,55.9,54.1,53.2,48.7,43.5,33.6,32.5,31.5,28.2,23.0,22.2,20.4ppm；HRMS(ESI)m/z：C28H37ClNO8(M+H)+：550.2208，实测值：550.2202。
实施例12化合物25、26和3的制备
Figure PCTCN2016109122-appb-000050
同实施例11，不同之处在于在-40℃下进行反应，由化合物18制得化合物3，产率为70％，所得产物与实施例11所得产物具有相同的特征。
实施例13化合物27的制备
Figure PCTCN2016109122-appb-000051
同实施例11，不同之处在于在室温下进行反应，柱层析(PE:EA:TEA＝100:10:0.5)后得到了迁移产物26，产率为84％。[α]D＝-169.5°(c 1.0,CHCl3,20℃)；1H NMR(400MHz,CDCl3)δ6.62(s,1H),6.61(s,1H),6.02(d,J＝1.6Hz,1H),5.91(d,J＝1.4Hz,1H),5.90(d,J＝1.5Hz,1H),4.75(s,1H),4.70(d,J＝2.1Hz,1H),3.98(s,1H),3.89(s,1H),3.78(s,3H),3.60(s,3H),3.35–3.22(m,1H),3.02–2.97(m,1H),2.92(td,J＝11.2Hz,6.8Hz,1H),2.82–2.77(m,1H),2.62–2.56(m,1H),2.42(dd,J＝10.8,3.7Hz,1H),2.24–2.19(m,1H),2.05(td,J＝13.3,3.9Hz,1H),1.82–1.72(m,1H),1.72–1.62(m,2H),1.57–1.48(m,1H),1.46–1.33(m,2H),1.16–1.02(m,1H),0.90(d,J＝6.6Hz,3H),0.89(d,J＝6.6Hz,3H)ppm；13C NMR(101MHz,CDCl3)δ172.4,168.5,155.0,146.6,146.0,132.0,130.9,111.0,110.4,103.1,100.9,78.4,75.8,68.4,61.3,57.5,56.7,53.3,53.2,46.7,35.7,34.7,31.3,30.7,28.3,22.7,22.4,19.9ppm；HRMS(ESI)m/z：计算值C28H37ClNO8(M+H)+：550.2208，实测值：550.2208。
实施例14化合物29的制备
Figure PCTCN2016109122-appb-000052
同实施例1，不同之处在于由化合物28在-60℃下反应生成化合物29，柱层析(PE:EA:TEA＝70:10:0.35)后得浅黄色泡状固体，产率90％，dr值为C2'R:C2'S＝4.5:1。
化合物29：产率58％，[α]D＝-106°(c0.5,CHCl3,20℃)；1H NMR(400MHz,CDCl3)δ6.63(s,1H),6.53(s,1H),6.02(d,J＝9.8Hz,1H),5.87(s,1H),5.85(s,1H),5.03(s,1H),3.77(d,J＝9.8Hz,1H),3.66(s,3H),3.55(s,3H),3.47(s,1H),3.20–3.06(m,2H),2.94(td,J＝11.6,7.1Hz,1H),2.67–2.49(m,2H),2.36(dd,J＝14.1,6.8Hz,1H),2.29(d,J＝16.5Hz,1H),2.03(dt,J＝12.0,9.6Hz,1H),1.90(ddd,J＝12.0,7.6,4.4Hz,1H),1.85(d,J＝16.5Hz,1H),1.78–1.73(m,2H),1.63–1.46(m,3H),1.35–1.26(m,1H),1.16(s,3H),1.13(s,3H),0.83(s,9H),0.04(s,6H)ppm；13C NMR(101MHz,CDCl3)δ174.1,170.6,157.8,146.8,145.8,133.4,128.5,112.6,109.6,100.8,99.8,74.4,74.2,72.8,70.7,57.1,55.6,53.8,51.4,48.5,43.2,42.8,37.5,33.6,31.3,29.8,29.7,25.8,20.2,18.0,-2.0,-2.1ppm；HRMS(ESI)m/z：计算值C34H52NO9Si(M+H)+：646.3406，实测值：646.3398。
实施例15化合物31的制备
Figure PCTCN2016109122-appb-000053
同实施例1，不同之处在于由化合物30在-60℃下反应生成化合物31，柱层析(PE:EA:TEA＝70:10:0.35)后得浅黄色无定形物，产率85％。dr值为C2'R:C2'S＝1.5:1。
化合物31：产率50％，[α]D＝-100°(c0.5,CHCl3,20℃)；1H NMR(400MHz,CDCl3)δ6.60(s,1H),6.53(s,1H),5.97(d,J＝9.8Hz,1H),5.86(d,J＝1.6Hz,1H),5.85(d,J＝1.6Hz,1H),5.04(s,1H),3.77(d,J＝9.8Hz,1H),3.66(s,3H),3.56(s,3H),3.46(s,1H),3.16–3.06(m,2H),2.93(td,J＝11.4,7.3Hz,1H),2.65–2.52(m,2H),2.37(dd,J＝14.0,6.7Hz,1H),2.27(d,J＝16.5Hz,1H),2.03(dt,J＝12.8,10.0Hz,1H),1.90(d,J＝16.4Hz,1H),1.89(ddd,J＝12.0,7.6,4.4Hz,1H),1.78–1.73(m,2H),1.40–1.31(m,6H),1.15(s,3H),1.14(s,3H),0.83(s,9H),0.04(s,6H)ppm；13C NMR(101MHz,CDCl3)δ174.2,170.5,157.9,146.8,145.9,133.5,128.5,112.8,109.7,100.9,100.3,74.8,74.8,73.6,70.6,57.4,56.1,54.0,51.5,48.7,45.2,43.5,42.4,39.4,31.5,30.0,29.4,26.0,20.5,18.2,18.2,-1.8,-2.2ppm；HRMS(ESI)m/z：计算值C35H54NO9Si(M+H)+：计算值660.3562，实测值：660.3563。
实施例16化合物32、33和29的制备
Figure PCTCN2016109122-appb-000054
同实施例11，不同之处在于由化合物28制得化合物32(产率60％)和化合物33(产率24％)，20℃脱氯后得到化合物29，产率85％。所得产物28与实施例13所得产物具有相同的特征。
化合物32：[α]D＝-118.8°(c0.51,CHCl3)；1H NMR(400MHz,CDCl3)δ6.68(s,1H),6.50(s,1H),5.99(d,J＝9.8Hz,1H),5.89(d,J＝1.4Hz,1H),5.84(d,J＝1.4Hz,1H),5.06(s,1H), 3.76(d,J＝9.8Hz,1H),3.67(s,3H),3.65(s,3H),3.54(s,1H),3.42(s,1H),3.15–3.05(m,2H),2.91(td,J＝11.6,7.1Hz,1H),2.62-2.53(m,2H),2.39(dd,J＝14.1,6.7Hz,1H),2.10–1.99(m,2H),1.91(ddd,J＝12.0,7.6,4.4Hz,1H),1.81–1.69(m,2H),1.49–1.40(m,2H),1.29–1.21(m,1H),1.18(s,3H),1.14(s,3H),0.84(s,9H),0.05(s,6H)ppm；13C NMR(101MHz,CDCl3)δ172.3,167.4,157.4,146.8,145.8,133.3,128.3,112.6,109.7,100.9,100.5,77.8,75.2,72.8,70.5,62.8,57.2,55.8,53.9,53.0,48.5,43.4,37.2,31.8,31.4,29.8,29.8,25.8,20.3,18.0,-2.1,-2.1ppm；HRMS(ESI)m/z：计算值C34H51ClNO9Si(M+H)+：680.3022，实测值：680.3015。
化合物33：[α]D＝-240.8°(c0.485,CHCl3)；1H NMR(400MHz,CDCl3)δ6.67(s,1H),6.57(s,1H),6.02(d,J＝9.7Hz,1H),5.87(s,1H),5.82(s,1H),5.07(s,1H),3.78(d,J＝9.9Hz,1H),3.73(s,3H),3.66(s,3H),3.46(s,1H),3.42(br,1H),3.12–3.09(m,2H),2.94(td,J＝11.6,7.1Hz,1H),2.67–2.53(m,2H),2.42(dd,J＝14.1,6.8Hz,1H),2.03(dt,J＝12.0,9.6Hz,1H),1.90(ddd,J＝12.0,7.6,4.4Hz,1H),1.77–1.73(m,2H),1.65–1.47(m,3H),1.32–1.29(m,1H),1.16(s,3H),1.12(s,3H),0.82(s,9H),0.04(s,6H)ppm；13C NMR(101MHz,CDCl3)δ173.3,169.0,159.3,149.2,148.4,135.1,129.9,114.9,112.0,103.0,102.9,80.4,77.4,74.8,72.8,63.6,59.2,57.8,56.0,56.0,55.1,50.6,45.5,40.1,33.5,32.6,32.4,31.5,27.9,22.4,20.2,-0.0,-0.1ppm；HRMS(ESI)m/z：计算值C34H51ClNO9Si(M+H)+：680.3022，实测值：680.3007。
实施例17化合物34和31的制备
Figure PCTCN2016109122-appb-000055
同实施例11，不同之处在于由化合物30制得化合物34(产率66％)，20℃脱氯后柱层析(PE:EA:TEA＝70:10:0.35)得到浅黄色无定形物31，产率89％，所得产物31与实施例15所得产物具有相同的特征。
化合物34：[α]D＝-122.8°(c0.43,CHCl3)；1H NMR(400MHz,CDCl3)δ6.66(s,1H),6.52(s,1H),5.96(d,J＝9.7Hz,1H),5.88(d,J＝1.4Hz,1H),5.85(d,J＝1.4Hz,1H),5.06(s,1H),3.77(d,J＝9.8Hz,1H),3.66(s,6H),3.61(s,1H),3.45(s,1H),3.15–3.05(m,2H),2.91(td,J＝11.6,7.1Hz,1H),2.65–2.55(m,2H),2.41(dd,J＝14.1,6.7Hz,1H),2.08–1.99(m,1H),1.90(ddd,J＝12.0,7.6,4.4Hz,1H),1.81–1.70(m,3H),1.44–1.28(m,5H),1.15(s,6H),0.84(s,9H),0.05(s,6H)ppm；13C NMR(101MHz,CDCl3)δ172.2,167.4,157.4,146.8,145.7,133.4,128.2,112.6,109.7,100.9,100.6,78.0,75.4,73.4,70.4,62.2,57.4,55.8,53.9,53.0,48.5,45.0,43.3,37.1,31.3,29.7,29.3,25.8,20.2,18.0,18.0,-2.0,-2.1ppm；HRMS(ESI)m/z：计算值C35H53ClNO9Si(M+H)+：694.3178，实测值：694.3177。
实施例18化合物36、37和38的制备
Figure PCTCN2016109122-appb-000056
向25mL烧瓶中加入300mg化合物35，加入二氯甲烷10mL溶解，-60℃下加入烯醇硅醚E 239.1mg，再慢慢滴加BF3·OEt2溶液0.17mL，过夜反应。饱和NaHCO3溶液淬灭反应，二氯甲烷萃取，饱和NaCl溶液洗涤，干燥，过滤，旋去溶剂。柱层析(PE:EA:TEA＝60:10:0.3)后得到化合物36(产率63％)和化合物37(产率26％)。
向装有化合物36和37的混合物(220mg，1eq)的圆底烧瓶中加入锌粉(51mg，2eq)和 四氢呋喃(1mL)，然后室温下滴加乙酸(1mL)，反应8h。用10％Na2CO3溶液淬灭反应，二氯甲烷萃取，饱和NaCl溶液洗涤，干燥，过滤，柱层析(PE:EA:TEA＝40:10:0.3)后得到化合物38，产率为80％。
化合物36：[α]D＝-141.4°(c 1.0,CHCl3,20℃)；1H NMR(400MHz,CDCl3)δ6.66(s,1H),6.51(s,1H),5.96(d,J＝9.8Hz,1H),5.88(s,1H),5.81(s,1H),5.07(s,1H),5.01(t,J＝6.6Hz,1H),3.77(d,J＝9.8Hz,1H),3.67(s,6H),3.58(s,1H),3.48(br,1H),3.15–3.01(m,2H),2.94(td,J＝11.5,7.0Hz,1H),2.67–2.52(m,2H),2.40(dd,J＝14.1,6.7Hz,1H),2.08–1.98(m,1H),1.98–1.86(m,1H),1.91(ddd,J＝12.0,8.1,4.0Hz,1H),1.80–1.72(m,3H),1.66(s,3H),1.56(s,3H),1.39(td,J＝12.9,4.5Hz,1H),1.35–1.30(m,1H)ppm；13C NMR(101MHz,CDCl3)δ172.1,167.6,157.5,146.9,145.8,133.4,132.4,128.2,123.1,112.7,109.8,100.9,100.7,78.0,75.5,70.6,62.2,57.3,55.9,53.9,53.0,48.5,43.4,36.6,31.4,25.6,21.5,20.3,17.4ppm；HRMS(ESI)m/z：计算值C29H37ClNO8(M+H)+：562.2208，实测值：562.2211。
化合物37：[α]D＝-143.0°(c 0.425,CHCl3,20℃)；1H NMR(400MHz,CDCl3)δ6.66(s,1H),6.59(s,1H),6.00(d,J＝9.7Hz,1H),5.88(s,1H),5.80(s,1H),5.08(s,1H),4.99(t,J＝7.0Hz,1H),3.80(d,J＝9.7Hz,1H),3.75(s,3H),3.67(s,3H),3.48(s,1H),3.46(s,1H),3.19–3.07(m,2H),2.96(td,J＝11.4,6.9Hz,1H),2.63–2.55(m,2H),2.43(dd,J＝14.1,6.8Hz,1H),2.08–1.99(m,2H),1.91(ddd,J＝12.0,8.1,4.0Hz,1H),1.81–1.71(m,3H),1.66(s,3H),1.55(s,3H),1.44(td,J＝12.9,4.5Hz,1H),1.29–1.23(m,1H)ppm；13C NMR(101MHz,CDCl3)δ171.0,166.9,157.2,147.1,146.2,133.1,132.5,127.8,123.0,112.8,110.0,100.9,100.8,78.6,75.6,70.6,61.1,57.3,55.8,53.9,53.1,48.6,43.4,35.5,31.4,25.6,22.3,20.3,17.4ppm；HRMS(ESI)m/z：计算值C29H37ClNO8(M+H)+：562.2208，实测值：562.2207。
化合物38：[α]D＝-125.7°(c0.54,CHCl3)；1H NMR(400MHz,CDCl3)δ6.61(s,1H),6.52(s,1H),5.98(d,J＝9.8Hz,1H),5.86(s,1H),5.82(s,1H),5.04(s,1H),5.00(t,J＝7.1Hz,1H),3.77(d,J＝9.8Hz,1H),3.66(s,3H),3.56(s,3H),3.50(s,1H),3.18–3.06(m,2H),2.94(td,J＝11.5,6.9Hz,1H),2.62–2.53(m,2H),2.37(dd,J＝14.0,6.7Hz,1H),2.25(d,J＝16.5Hz,1H),2.10–1.98(m,2H),1.97–1.90(m,1H),1.87(d,J＝16.4Hz,1H),1.81–1.73(m,3H),1.65(s,3H),1.55(s,3H),1.45–1.35(m,2H)ppm；13C NMR(101MHz,CDCl3)δ174.0,170.5,157.7,146.7,145.8,133.4,132.2,128.4,123.4,112.7,109.7,100.8,100.1,74.7,74.6,70.6,57.3,55.8,54.0,51.5,48.7,43.4,42.6,38.7,31.3,25.7,21.6,20.3,17.4ppm；HRMS(ESI)m/z：计算值C29H38NO8(M+H)+：528.2592，实测值：528.2598。
实施例19化合物40的制备
Figure PCTCN2016109122-appb-000057
向50mL烧瓶中加入7.34g化合物39，加入二氯甲烷20mL溶解，-60℃下加入烯醇硅醚E 4.5g，再慢慢滴加BF3·OEt2溶液4.64mL，过夜反应。饱和NaHCO3溶液淬灭反应，二氯甲烷萃取，饱和NaCl溶液洗涤，干燥，过滤，旋去溶剂得到粗品7.46g。接着向装有粗品的圆底烧瓶中加入锌粉(1.77g,2eq)和四氢呋喃(15mL)，然后在室温下滴加乙酸(2.5mL)，反应8h。用10％Na2CO3溶液淬灭反应，二氯甲烷萃取，饱和NaCl溶液洗涤，干燥，过滤，柱层析(PE:EA:TEA＝40:10:0.3)后得到浅黄色无定形固体40，产率为80％。dr值C2'R:C2'S＝11:1。
化合物40：产率70％，[α]D＝-111.1°(c1.18,CHCl3)；1H NMR(400MHz,CDCl3)δ6.63(s,1H),6.54(s,1H),6.01(d,J＝9.8Hz,1H),5.88(s,1H),5.85(s,1H),5.05(s,1H),4.68(s,1H),4.61(s,1H),3.78(d,J＝9.8Hz,1H),3.67(s,3H),3.57(s,3H),3.54(s,1H),3.16–3.07(m,2H),2.94(td,J＝11.5,7.0Hz,1H),2.61–2.55(m,2H),2.38(dd,J＝14.1,6.8Hz,1H),2.30(d,J＝16.5Hz,1H),2.13–1.99(m,2H),1.92(d,J＝16.3Hz,1H),1.94–1.86(m,1H),1.78–1.73(m,3H),1.68(s,3H),1.61–1.53(m,2H)ppm；13C NMR(101MHz,CDCl3)δ173.9,170.4,157.7, 146.7,145.8,145.2,133.3,128.3,112.6,109.8,109.7,100.9,100.1,74.7,74.5,70.6,57.2,55.8,54.0,51.6,48.7,43.4,42.7,37.1,31.3,30.9,22.6,20.3ppm；HRMS(ESI)m/z：计算值C28H36NO8(M+H)+：514.2435，实测值：514.2439。
实施例20化合物41的制备
Figure PCTCN2016109122-appb-000058
室温下，将9μL BF3·OEt2加入到化合物32(49mg,0.072mmol)的二氯甲烷溶液中，搅拌4h。饱和NaHCO3溶液淬灭反应，二氯甲烷萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干，得浅黄色无定形物41，产率为90％。[α]D＝-94.6°(c0.425,CHCl3)；1H NMR(400MHz,CDCl3)δ6.61(s,1H),6.55(s,1H),5.90(d,J＝9.7Hz,1H),5.85(d,J＝1.4Hz,1H),5.80(d,J＝1.4Hz,1H),5.05(s,1H),4.35(s,1H),3.81(d,J＝9.7Hz,1H),3.68(s,3H),3.67(s,3H),3.19–3.06(m,2H),2.95(td,J＝11.5,6.9Hz,1H),2.64–2.53(m,2H),2.42–2.32(m,2H),2.09–2.00(m,1H),1.90(ddd,J＝12.0,7.6,4.4Hz,1H),1.89–1.82(m,1H),1.80–1.71(m,4H),1.24(s,3H),1.14(s,3H)ppm；13C NMR(101MHz,CDCl3)δ170.9,167.7,157.7,146.8,145.8,133.2,128.4,113.1,109.7,100.8,100.1,87.6,85.8,75.0,70.6,59.8,57.2,56.3,54.0,52.9,48.8,43.5,37.8,32.0,31.6,28.4,28.1,20.4ppm；HRMS(ESI)m/z：计算值C28H35ClNO8(M+H)+：548.2042，实测值：548.2052。
实施例21化合物42的制备
Figure PCTCN2016109122-appb-000059
同实施例20，不同之处在于由化合物29制得浅黄色无定形物42，产率为95％。[α]D＝-104.7°(c0.38,CHCl3)；1H NMR(400MHz,CDCl3)δ6.57(s,1H),6.55(s,1H),5.89–5.81(m,3H),5.02(s,1H),3.79(d,J＝9.7Hz,1H),3.67(s,3H),3.56(s,3H),3.19–3.01(m,2H),2.92(td,J＝11.5,6.9Hz,1H),2.61–2.52(m,2H),2.33(dd,J＝14.0,6.8Hz,1H),2.31(d,J＝15.2Hz,1H),2.25(d,J＝15.2Hz,1H),2.11–1.93(m,2H),1.93–1.78(m,2H),1.77–1.69(m,2H),1.63(t,J＝7.0Hz,2H),1.23(s,3H),1.13(s,3H)ppm；13C NMR(101MHz,CDCl3)δ172.8,170.2,158.0,146.7,145.7,133.2,128.5,113.1,109.6,100.8,99.7,83.9,83.6,70.7,57.2,56.3,53.9,51.5,48.7,43.4,42.5,37.5,34.8,31.6,30.9,28.8,28.1,20.3ppm；HRMS(ESI)m/z：计算值C28H36NO8(M+H)+：514.2441，实测值：514.2434。
实施例22化合物43的制备
Figure PCTCN2016109122-appb-000060
同实施例20，不同之处在于由化合物31制得浅黄色无定形物43，产率80％。
化合物43：[α]D＝-105.7°(c0.42,CHCl3)；1H NMR(400MHz,CDCl3)δ6.60(s,1H),6.57(s,1H),5.91(d,J＝9.6Hz,1H),5.85(d,J＝1.0Hz,1H),5.78(d,J＝0.9Hz,1H),5.03(s,1H),3.78(d,J＝9.7Hz,1H),3.69(s,3H),3.58(s,3H),3.20–3.08(m,2H),2.94(td,J＝11.6,6.9Hz,1H),2.66–2.53(m,2H),2.36(dd,J＝14.1,6.7Hz,1H),2.12(d,J＝14.3Hz,1H),2.01(dt,J＝12.8,10.0Hz,1H),1.89(ddd,J＝12.0,7.6,4.4Hz,1H),1.76–1.73(m,2H),1.66(d,J＝14.0 Hz,1H),1.69–1.60(m,2H),1.52–1.49(m,1H),1.40–1.23(m,3H),1.10(s,3H),1.03(s,3H)ppm；13C NMR(400MHz,CDCl3)δ173.5,170.0,157.9,146.7,145.8,133.4,128.3,113.2,109.8,100.8,99.8,75.4,74.3,73.7,70.8,57.3,56.0,53.9,51.4,48.7,43.7,43.3,35.6,31.4,31.3,28.8,25.7,20.3,16.7ppm；HRMS(ESI)m/z：计算值C29H38NO8(M+H)+：528.2597，实测值：528.2590。
实施例23化合物44和45的制备
Figure PCTCN2016109122-appb-000061
同实施例20，不同之处在于用TiCl4代替BF3·OEt2，得到化合物44，然后向粗品中加入锌粉和四氢呋喃，再慢慢滴入冰乙酸，室温搅拌7h。10％Na2CO3溶液淬灭反应，二氯甲烷萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干。柱层析(PE:EA:TEA＝60:10:0.3)后得浅黄色无定形物45，两步产率为72.5％。[α]D＝-110.77°(c0.65,CHCl3)；1H NMR(400MHz,CDCl3)δ6.65(s,1H),6.52(s,1H),6.00(d,J＝9.8Hz,1H),5.87(d,J＝1.3Hz,1H),5.85(d,J＝1.3Hz,1H),5.04(s,1H),3.77(d,J＝9.8Hz,1H),3.68(s,3H),3.57(s,4H),3.22–3.05(m,2H),2.94(td,J＝11.6,7.1Hz,1H),2.63–2.53(m,2H),2.38(dd,J＝14.2,6.8Hz,1H),2.29(d,J＝16.6Hz,1H),2.04–2.00(m,1H),1.96–1.89(m,1H),1.84(d,J＝16.7Hz,1H),1.80–1.72(m,2H),1.71–1.59(m,4H),1.54(s,3H),1.50(s,3H)ppm；13CNMR(101MHz,CDCl3)δ173.7,170.3,158.1,146.8,145.9,133.0,128.1,112.6,109.8,100.9,99.9,74.6,74.3,71.1,70.2,57.4,55.6,53.9,51.6,48.5,43.2,42.9,38.8,34.3,33.3,31.7,31.1,20.2ppm；HRMS(ESI)m/z：计算值C28H37ClNO8(M+H)+：550.2208，实测值：550.2207。
实施例24化合物46的制备
Figure PCTCN2016109122-appb-000062
同实施例19，不同之处在于由化合物31制得浅黄色无定形物46，产率为82.5％。[α]D＝-89.6°(c0.27,CHCl3)；1H NMR(400MHz,CDCl3)δ6.62(s,1H),6.54(s,1H),6.00(d,J＝9.7Hz,1H),5.87(s,1H),5.86(s,1H),5.04(s,1H),3.77(d,J＝9.9Hz,1H),3.67(s,3H),3.57(s,3H),3.45(s,1H),3.16–3.07(m,2H),2.95(td,J＝11.6,7.1Hz,1H),2.62–2.55(m,2H),2.38(dd,J＝13.8,6.6Hz,1H),2.25(d,J＝16.4Hz,1H),2.10–1.94(m,1H),1.92–1.86(m,1H),1.88(d,J＝16.6Hz,1H),1.82–1.71(m,2H),1.70–1.63(m,2H),1.45–1.40(m,2H),1.36–1.32(m,2H),1.55(s,3H),1.53(s,3H)ppm；HRMS(ESI)m/z：计算值C29H39ClNO8(M+H)+：564.2364，实测值：564.2382。
实施例25化合物47的制备
Figure PCTCN2016109122-appb-000063
将化合物34(195mg,0.28mmol)溶于2mL乙腈溶液中，依次加入0.2mL三乙胺三氢氟酸盐和78μL三乙胺，油浴80℃回流5天。饱和碳酸氢钠溶液淬灭反应，二氯甲烷萃取，饱和食盐水洗涤，无水硫酸钠干燥。柱层析(PE:EA:TEA＝20:10:0.1)后得浅黄色无定形物47，产率为85％。[α]D＝-109.3°(c0.62,CHCl3)；1H NMR(400MHz,CDCl3)δ6.59(s,1H),6.56(s,1H),5.89(d,J＝1.3Hz,1H),5.85(d,J＝1.3Hz,1H),5.83(d,J＝9.5Hz,1H),5.07(s,1H), 3.78(d,J＝9.4Hz,1H),3.76(s,3H),3.69(s,1H),3.68(s,3H),3.17–3.03(m,2H),3.00(s,1H),2.91(td,J＝11.5,7.1Hz,1H),2.63–2.51(m,2H),2.35(dd,J＝14.3,6.8Hz,1H),2.03–1.95(m,1H),1.88(ddd,J＝12.0,7.6,4.4Hz,1H),1.86–1.82(m,1H),1.76–1.70(m,2H),1.41–1.37(m,5H),1.26–1.23(m,1H),1.17(s,6H)ppm；13C NMR(101MHz,CDCl3)δ167.1,166.6,156.6,146.9,145.5,133.6,127.6,113.1,109.9,101.1,100.8,76.1,70.7,70.7,61.1,57.3,56.6,56.3,53.9,52.5,48.5,43.4,43.3,31.4,29.2,28.8,27.1,20.3,19.8ppm；HRMS(ESI)m/z：计算值C29H39ClNO9(M+H)+：580.2313，实测值：580.2308。
实施例26化合物1的制备
Figure PCTCN2016109122-appb-000064
同实施例25，不同之处在于由化合物29制备化合物1，所得粗品用乙醚重结晶，得浅黄色晶体，产率92％。mp.68–69℃；[α]D＝-119°(c 0.5,CHCl3)；1H NMR(400M,CDCl3)δ6.61(s,1H),6.54(s,1H),5.99(d,J＝9.8Hz,1H),5.86(s,1H),5.86(s,1H),5.07(s,1H),3.78(d,J＝9.8Hz,1H),3.68(s,3H),3.65(s,1H),3.57(s,3H),3.18–3.00(m,2H),2.93(td,J＝11.2,7.2Hz,1H),2.57(dd,J＝16.4,8.4Hz,2H),2.37(dd,J＝14.1,6.8Hz,1H),2.28(d,J＝16.5Hz,1H),2.03(dt,J＝12.0,9.6Hz,1H),1.93–1.87(m,1H),1.89(d,J＝16.5Hz,1H),1.80–1.70(m,2H),1.63–1.54(m,3H),1.50(br,1H),1.29–1.18(m,1H),1.16(s,3H),1.14(s,3H)ppm；13C NMR(101M,CDCl3)δ173.8,170.3,157.4,146.7,145.9,133.3,128.2,112.7,109.7,100.8,100.7,74.7,70.6,70.0,57.3,55.9,53.9,51.5,48.6,43.3,42.7,36.9,33.1,31.2,29.6,28.6,20.3ppm；HRMS(ESI)m/z：计算值C28H38NO9(M+H)+：532.2547，实测值：532.2541。
实施例27化合物2的制备
Figure PCTCN2016109122-appb-000065
同实施例25，不同之处在于由化合物31制备化合物2，所得粗品用乙酸乙酯重结晶，得白色晶体，产率92％。mp.140–142℃；[α]D＝-105°(c0.5,CHCl3)；1H NMR(400M,CDCl3)δ6.62(s,1H),6.54(s,1H),5.99(d,J＝9.7Hz,1H),5.86(d,J＝1.1Hz,2H),5.05(s,1H),3.77(d,J＝9.8Hz,1H),3.67(s,3H),3.57(s,3H),3.53(s,1H),3.14–3.06(m,2H),2.94(td,J＝11.2,7.2Hz,1H),2.59–2.56(m,2H),2.38(dd,J＝13.9,6.7Hz,1H),2.26(d,J＝16.6Hz,1H),2.03(dt,J＝12.0,9.6Hz,1H),1.93–1.87(m,1H),1.89(d,J＝16.4Hz,1H),1.79–1.66(m,3H),1.48–1.29(m,5H),1.27–1.20(m,1H),1.18(s,6H)ppm；13C NMR(101M,CDCl3)δ174.1,170.5,157.9,146.8,146.0,133.5,128.5,112.8,109.8,101.0,100.4,74.9,74.8,70.9,70.7,57.6,56.0,54.1,51.7,48.8,43.9,43.5,42.7,39.3,31.5,29.4,29.2,20.5,18.1ppm；HRMS(ESI)m/z：计算值C29H40NO9(M+H)+：546.2703，实测值：546.2700。
实施例28化合物2和43的制备
Figure PCTCN2016109122-appb-000066
向圆底烧瓶中加入Hg(OAc)2(120.8mg,1.1eq)，随后依次加入2mL水和2mL THF并搅拌至溶解完全。随后将化合物38(100mg,1eq)的2mL THF溶液滴入到反应体系中，室温 下搅拌混合物3h。然后补加1eq的Hg(OAc)2并继续搅拌3h。向反应体系中加入NaBH4(1eq)的1.5M氢氧化钠溶液(0.4mL)，并立刻加水淬灭。二氯甲烷萃取，无水硫酸钠干燥。得到未反应完的原料38、产物2和环化产物43共116mg。经HPLC(Chiralcel AD-H，己烷/异丙醇(0.1％TEA)＝80/20，流速＝1.0mL/min)测定，原料38:环化产物43:产物2＝1:0.79:6.4。
实施例29化合物2的制备
Figure PCTCN2016109122-appb-000067
室温下，向圆底烧瓶中加入Fe2(C2O4)3·6H2O(486mg,5eq)，随后加入8mL水，搅拌1-2h直至完全溶解。将反应体系冷却至0℃，搅拌10min后，加入4mL乙醇，随后加入化合物37(106mg,1eq)的4mL乙醇溶液，2h后分批加入硼氢化钠(48.4mg,6.4eq)固体，插上充满空气的气球，继续搅拌4h。加入1N HCl淬灭反应，二氯甲烷萃取，无水硫酸钠干燥。得到未反应完的原料38和产物2，两者的比例为1:0.57，柱分离(PE:EA:TEA＝20:10:0.1)得到30mg产物2。
实施例30化合物2的制备
Figure PCTCN2016109122-appb-000068
在-10℃下，在氩气保护下，向化合物38(50mg,1eq)的无水二氯甲烷溶液中加入氢溴酸-乙酸溶液(0.19mL,9eq)，搅拌3h。然后加入水2.8mL，升温至室温，继续搅拌3h。加入碳酸钠的溶液至体系的pH＝8。静置分层，水相用氯化钠饱和后，用二氯甲烷萃取，合并有机相，无水硫酸钠干燥。柱层析(PE:EA:TEA＝20:10:0.1)后得到未反应完的原料38和产物2，2的产率为79％，经HPLC(Chiralcel AD-H，己烷/异丙醇(0.1％TEA)＝80/20，流速＝1.0mL/min)测定，原料38:产物2＝1:3.1。
实施例31化合物2的制备
Figure PCTCN2016109122-appb-000069
在-15℃下，在氩气保护下，向化合物38(80mg,1eq)的无水二氯甲烷溶液中加入40％氢溴酸的水溶液(74μL,9eq)，搅拌过夜。升温至室温，向体系中加入5％碳酸氢钠水溶液至pHpH＝9–10，并继续搅拌5h。静置分层，水相用氯化钠饱和后，用二氯甲烷萃取，合并有机相，无水硫酸钠干燥，浓缩。柱层析(PE:EA:TEA＝20:10:0.1)后得到产物2，产率84％。
实施例32化合物1和42的制备
Figure PCTCN2016109122-appb-000070
在-10℃下，在氩气保护下，向化合物40(3.18g,1eq)的无水二氯甲烷溶液中加入氢溴酸-乙酸溶液(11mL,9eq)，搅拌过夜。然后加入水，升温至室温，继续搅拌若干小时。加入碳酸钠溶液至体系的pH＝9。静置分层，水相用氯化钠饱和后，用二氯甲烷萃取，合并有机相，无水硫酸钠干燥，得到环化产物42和产物1。柱层析(PE:EA:TEA＝50:10:0.2)后得到990mg环化产物42，柱层析(PE:EA:TEA＝20:10:0.2)后得到620mg产物1，产物1的产率为40％。
实施例33化合物1和42的制备
Figure PCTCN2016109122-appb-000071
在-15℃下，在氩气保护下，向化合物40(300mg,1eq)的无水二氯甲烷溶液中加入40％氢溴酸的水溶液(0.29mL,9eq)，搅拌过夜。升温至室温，向体系中加入5％碳酸钠水溶液至pH＝9–10，并继续搅拌5h。静置分层，水相用氯化钠饱和后，用二氯甲烷萃取，合并有机相，无水硫酸钠干燥，柱层析(PE:EA:TEA＝20:10:0.1)得到140mg产品1和120mg产品42。
实施例34化合物2的制备
Figure PCTCN2016109122-appb-000072
氩气保护下，将化合物48(4.867g,31.16mmol)溶于60mL二氯甲烷中，冰浴下加入三氯苯甲酰氯(9.5g,2.5eq)，搅拌1.5h。将三尖杉碱(4g,15.58mmol)、吡啶(5mL,4eq)、4-二甲氨基吡啶DMAP(380mg,0.2eq)的40mL二氯甲烷溶液慢慢加入到上述溶液中，反应过夜。加入饱和NaHCO3溶液淬灭反应，二氯甲烷萃取，无水硫酸钠干燥。将粗品溶于二氯甲烷，随后依次用5％的Na2CO3溶液、pH＝5的缓冲溶液和水洗涤若干次，有机相用饱和NaCl洗涤后干燥。旋蒸除去溶剂，得到化合物40的粗产物，依次同实施例18和31操作，中间体不分离纯化，得到目标产物2粗品，经过柱层析(PE:EA:TEA＝20:10:0.1)，收率60％，乙醚重结晶得到化合物2，纯度大于99％。
实施例35化合物50的制备
Figure PCTCN2016109122-appb-000073
同实施例11，不同之处在于由化合物49制得化合物50，产率为80％。dr值为7.3:1.
化合物50：[α]D＝-145°(c0.43,CHCl3)；1H NMR(400MHz,CDCl3)δ7.23(d,J＝6.1Hz, 2H),7.15(t,J＝7.0Hz,1H),7.08(d,J＝7.4Hz,2H),6.56(s,1H),6.53(s,1H),6.04(d,J＝9.8Hz,1H),5.81(s,1H),5.70(s,1H),5.06(s,1H),3.79((d,J＝9.8Hz,1H),3.67(s,3H),3.60(s,1H),3.56(s,3H),3.19–3.03(m,2H),2.98–2.87(m,1H),2.75–2.52(m,3H),2.42–2.31(m,2H),2.28(d,J＝16.8Hz,1H),2.08–1.98(m,1H),1.97(d,J＝16.8Hz,1H),1.95–1.82(m,1H),1.81–1.66(m,4H)ppm；13C NMR(101MHz,CDCl3)δ173.8,170.3,157.6,146.7,145.9,141.8,133.3,128.4,128.3,128.3,125.9,112.7,109.7,100.8,100.3,74.9,74.6,70.7,57.4,55.9,54.0,51.6,48.7,43.4,42.7,41.0,31.4,29.4,20.3ppm。HRMS(ESI)m/z：计算值C31H36NO8(M+H)+：550.2441，实测值：550.2426。
实施例36化合物52的制备
Figure PCTCN2016109122-appb-000074
同实施例11，不同之处在于由化合物51制得化合物52，产率为78％。dr值为7.3:1
化合物52：[α]D＝-123°(c0.61,CHCl3)；1H NMR(400MHz,CDCl3)δ7.28(t,J＝7.4Hz,2H),7.20(d,J＝7.2Hz,1H),7.15(t,J＝6.9Hz,2H),6.60(s,1H),6.54(s,1H),5.98(d,J＝9.8Hz,1H),5.89(d,J＝1.2Hz,1H),5.85(d,J＝1.1Hz,1H),5.06(s,1H),3.78(d,J＝9.9Hz,1H),3.67(s,3H),3.58(s,4H),3.16–3.08(m,1H),3.04–2.88(m,2H),2.72–2.55(m,3H),2.56–2.46(m,1H),2.26(d,J＝16.5Hz,1H),2.23–2.18(m,1H),2.10–2.01(m,1H),1.96–1.87(m,2H),1.83(d,J＝16.5Hz,1H),1.80–1.73(m,3H),1.51–1.43(m,2H)ppm；13C NMR(101MHz,CDCl3)δ173.9,170.4,157.7,146.6,145.8,141.9,133.4,128.4,128.3,128.2,125.8,112.6,109.7,100.8,100.1,74.7,74.6,70.6,57.3,55.7,54.0,51.5,48.6,43.3,42.7,38.3,35.5,31.2,24.1,20.3ppm。HRMS(ESI)m/z：计算值C32H38NO8(M+H)+：564.2568，实测值：564.2550。
实施例37化合物54的制备
Figure PCTCN2016109122-appb-000075
同实施例11，不同之处在于由化合物53制得化合物54，产率为82％。dr值为13.3:1
化合物54：[α]D＝-117(c 1.0,CHCl3)；1H NMR(600MHz,CDCl3):δ6.62(s,1H),6.53(s,1H),5.97(d,J＝10.2Hz,1H),5.88(d,J＝1.2Hz,1H),5.85(d,J＝1.8Hz,1H),5.04(s,1H),3.77(d,J＝10.2Hz,1H),3.66(s,3H),3.57(s,3H),3.46(s,1H),3.13(ddd,J＝13.8,12.0,7.8Hz,1H),3.11–3.08(m,1H),2.95(td,J＝11.4,7.2Hz,1H),2.62–2.56(m,2H),2.38(dd,J＝14.4,7.2Hz,1H),2.24(d,J＝16.2Hz,1H),2.03(dt,J＝12.6,9.6Hz,1H),1.90(ddd,J＝12.6,8.4,4.2Hz,1H),1.82(d,J＝16.2Hz,1H),1.78–1.72(m,2H),1.67–1.60(m,1H),1.37(dd,J＝14.4,6.6Hz,1H),1.34(dd,J＝14.4,6.6Hz,1H),0.90(d,J＝6.6Hz,3H),0.82(d,J＝6.6Hz,3H)ppm；13C NMR(150MHz,CDCl3):δ174.4,170.4,157.7,146.6,145.8,133.3,128.4,112.6,109.7,100.8,100.0,75.2,74.8,70.5,57.1,55.9,53.9,51.4,48.6,46.7,43.4,43.3,31.3,24.1,24.0,23.9,20.3ppm；HRMS(ESI)m/z：计算值C27H36NO8[M+H]+：502.2435，实测值：502.2440。
实施例38化合物56的制备
Figure PCTCN2016109122-appb-000076
同实施例11，不同之处在于由化合物55制得化合物56，产率为81％。dr值为11.5:1。
化合物56：[α]D＝-127°(c0.69,CHCl3)；1H NMR(400MHz,CDCl3)δ6.62(s,1H),6.53(s,1H),5.98(d,J＝9.8Hz,1H),5.86(s,1H),5.85(s,1H),5.04(s,1H),3.77(d,J＝9.8Hz,1H),3.66(s,3H),3.56(s,3H),3.48(s,1H),3.17–3.05(m,2H),2.95(td,J＝11.5,7.0Hz,1H),2.68–2.53(m,2H),2.38(dd,J＝14.0,6.7Hz,1H),2.27(d,J＝16.5Hz,1H),2.11–1.99(m,1H),1.92(d,J＝16.5Hz,1H),1.92–1.85(m,1H),1.81–1.71(m,2H),1.45–1.29(m,4H),1.23–1.06(m,4H),0.86(t,J＝7.1Hz,3H)ppm；13C NMR(101MHz,CDCl3)δ174.1,170.5,157.8,146.7,145.8,133.3,128.4,112.7,109.7,100.8,100.0,74.7,74.6,70.7,57.2,55.8,53.9,51.5,48.6,43.3,42.6,38.8,31.8,31.3,22.5,22.4,20.3,14.0ppm。HRMS(ESI)m/z：计算值C28H38NO8(M+H)+：516.2568，实测值：516.2573。
实施例39化合物57的制备
Figure PCTCN2016109122-appb-000077
同实施例3，不同之处在于用烯醇硅醚F代替A在-60℃下反应制得化合物57，产率为90％。dr值为12:1。
化合物57：[α]D＝46°(c0.73,CHCl3)；1H NMR(400MHz,CDCl3)δ6.61(s,1H),6.51(s,1H),5.97(d,J＝9.8Hz,1H),5.86(s,1H),5.84(s,1H),5.03(s,1H),3.76(d,J＝9.8Hz,1H),3.65(s,3H),3.38(s,1H),3.15–3.04(m,2H),2.92(td,J＝11.5,7.0Hz,1H),2.88–2.69(m,2H),2.62–2.53(m,2H),2.47(d,J＝15.9Hz,1H),2.36(dd,J＝14.0,6.7Hz,1H),2.08–1.98(m,1H),1.96(d,J＝15.9Hz,1H),1.89(ddd,J＝12.1,7.6,4.7Hz,1H),1.81–1.69(m,2H),1.51–1.34(m,3H),1.33–1.23(m,2H),1.19(t,J＝7.5Hz,3H),0.82(d,J＝6.3Hz,3H),0.81(d,J＝6.3Hz,3H)ppm；13C NMR(101MHz,CDCl3)δ196.1,174.2,157.7,146.7,145.8,133.2,128.4,112.9,109.6,100.9,100.1,75.1,74.7,70.6,57.1,55.9,54.0,51.5,48.7,43.4,36.4,31.6,31.4,28.0,23.4,22.7,22.2,20.3,14.4ppm.HRMS(ESI)m/z：计算值C29H40NO7S(M+H)+：546.2520，实测值：546.2502。
实施例40化合物59的制备
Figure PCTCN2016109122-appb-000078
同实施例1，不同之处在于由化合物58在-60℃下反应生成化合物31，柱层析(PE:EA:TEA＝70:10:0.5)后得白色无定形物，产率80％。dr值为6:1。
化合物59：[α]D＝-72.5(c0.68,CHCl3)；1H NMR(400MHz,CDCl3)δ7.21(d,J＝8.9Hz,2H),6.78(d,J＝8.9Hz,2H),6.49(s,1H),6.49(s,1H),5.90(d,J＝9.7Hz,1H),5.87(d,J＝1.5Hz,1H),5.85(d,J＝1.4Hz,1H),4.99(s,1H),4.08(s,1H),3.80(s,3H),3.75(d,J＝9.8Hz,1H),3.61(s,3H),3.54(s,3H),3.05(td,J＝13.6,7.8Hz,2H),2.95–2.85(m,1H),2.68(d,J＝16.6Hz,1H),2.59(d,J＝16.6Hz,1H),2.59–2.50(m,2H),2.31(dd,J＝14.0,6.7Hz,1H),2.03–1.95(m,1H),1.86(ddd,J＝12.1,7.9,4.1Hz,1H),1.78–1.67(m,2H)ppm；13C NMR(101MHz,CDCl3)δ172.9,170.8,159.1,157.6,146.5,145.6,133.1,132.0,128.1,126.5,113.3,112.6,109.7,100.8,100.2,75.5,75.4,70.6,57.2,56.0,55.2,53.9,51.7,48.7,43.5,43.4,31.5,20.3ppm.HRMS(ESI)m/z：计算值C30H34NO9(M+H)+：552.2234，实测值：552.2232。
实施例41化合物61的制备
Figure PCTCN2016109122-appb-000079
同实施例1，不同之处在于由化合物60在-60℃下反应生成化合物31，柱层析(PE:EA:TEA＝70:10:0.5)后得白色无定形物，产率85％。dr值为10:1。
化合物61：[α]D＝-84.6(c0.48,CHCl3)；1H NMR(400MHz,CDCl3)δ7.17(t,J＝7.9Hz,1H),6.93(s,1H),6.88(d,J＝7.7Hz,1H),6.79(d,J＝7.5Hz,1H),6.49(s,1H),6.47(s,1H),5.91(d,J＝9.7Hz,1H),5.87(s,1H),5.85(s,1H),4.99(s,1H),4.13(s,1H),3.79(s,3H),3.75(d,J＝9.9Hz,1H),3.61(s,3H),3.53(s,3H),3.13–3.01(m,2H),2.90(dt,J＝18.6,9.4Hz,1H),2.69(d,J＝16.6Hz,1H),2.61(d,J＝16.9Hz,1H),2.62–2.52(m,2H),2.31(dd,J＝14.0,6.7Hz,1H),2.00(dd,J＝21.2,9.8Hz,1H),1.91–1.82(m,1H),1.78–1.66(m,2H)ppm；13C NMR(101MHz,CDCl3)δ172.7,170.8,159.4,157.5,146.5,145.6,141.4,133.1,128.9,128.0,117.6,113.5,112.5,110.9,109.7,100.8,100.3,75.7,70.6,57.2,55.9,55.2,53.9,51.7,48.7,43.4,43.4,31.5,20.3ppm.HRMS(ESI)m/z：计算值C30H34NO9(M+H)+：552.2234，实测值：552.2232。
实施例42化合物63的制备
Figure PCTCN2016109122-appb-000080
同实施例1，不同之处在于由化合物62在-60℃下反应生成化合物31，柱层析(PE:EA:TEA＝70:10:0.5)后得白色无定形物，产率80％。dr值为5:1。
化合物63：[α]D＝-65.3(c0.56,CHCl3)；1H NMR(400MHz,CDCl3)δ6.91(d,J＝1.8Hz,1H),6.80(dd,J＝8.5,1.9Hz,1H),6.73(d,J＝8.5Hz,1H),6.48(s,1H),6.42(s,1H),5.91(d,J＝9.7Hz,1H),5.88(s,1H),5.83(d,J＝1.1Hz,1H),4.99(s,1H),4.09(s,1H),3.88(s,3H),3.85(s,3H),3.74(d,J＝9.7Hz,1H),3.61(s,3H),3.55(s,3H),3.10–2.99(m,2H),2.88(td,J＝11.6,7.0Hz,1H),2.71(d,J＝16.6Hz,1H),2.60(d,J＝16.6Hz,1H),2.58–2.48(m,2H),2.33–2.22(m,1H),2.02–1.94(m,1H),1.91–1.81(m,1H),1.78–1.64(m,2H)ppm；13C NMR(101MHz,CDCl3)δ172.8,170.9,157.5,148.5,148.4,146.5,145.6,133.0,132.3,127.8,117.4,112.5,110.4,109.6,108.5,100.9,100.3,75.5,75.5,70.6,60.4,57.3,55.8,55.8,53.9,51.8,48.6,43.7,43.3,31.5,20.2ppm.HRMS(ESI)m/z：计算值C31H36NO10(M+H)+：582.2339，实测值：582.2238。
生物活性实施例
三尖杉酯类生物碱抗肿瘤生物活性体外筛选实验
采用四氮唑盐(Methyl-Thiazol-Tetrozolium,MTT)还原法的筛选方法，作用细胞株为HL-60人白血病。将一定数量处于对数生长期的肿瘤细胞接种于96孔微量培养板内，培养24h后加入药液，对每个细胞株，每个浓度均为三个复孔。另设无细胞调零孔、如果药物有颜色要做相应药物浓度无细胞调零孔。肿瘤细胞在37℃、5％CO2条件下培养72小时后，加MTT(Sigma)溶液；继续培养4小时后，加入三联液(10％SDS-5％异丁醇-0.01mol/lHCl)，于CO2培养箱中过夜，然后用酶标仪测OD570值。所测定数据由上海新药筛选中心提供。
下文对实施例化合物对肿瘤细胞HL-60人白血病生长的抑制率％进行汇总。
Figure PCTCN2016109122-appb-000081
本发明实施例化合物在10-4mol/L的浓度下对HL-60人白血病细胞的抑制率大于80％。本发明实施例化合物23、25、26、32、33、34、36、37、41、44、45、46、47、52、56、57、59、61和63在10-5mol/L的浓度下对HL-60人白血病细胞的抑制率大于80％。

Claims (10)

  1. 式(I)所示的三尖杉酯生物碱类化合物、其药学上可接受的盐、互变异构体、立体异构体及溶剂合物：
    Figure PCTCN2016109122-appb-100001
    其中，Ra为
    Figure PCTCN2016109122-appb-100002
    Rb为H，a毗邻的
    Figure PCTCN2016109122-appb-100003
    为单键，b毗邻的
    Figure PCTCN2016109122-appb-100004
    为双键；
    或者，
    Ra为H，Rb为
    Figure PCTCN2016109122-appb-100005
    a毗邻的
    Figure PCTCN2016109122-appb-100006
    为双键，b毗邻的
    Figure PCTCN2016109122-appb-100007
    为单键；
    Rc选自任选被一个或多个Rm取代的下列基团：C1-40烷基、C2-40烯基、C2-40炔基、C3-20环烷基、C5-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基，其中所述杂环基和杂芳基包含1-5个独立选自N、O和S的杂原子；
    R1、R2、R3彼此独立地选自氢、F、Cl、Br、I、OH、SH、CN或任选被一个或多个Rm取代的下列基团：C1-40烷基、C2-40烯基、C2-40炔基、C3-20环烷基、C5-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基、NH2、C1-40烷基氧基、C2-40烯基氧基、C2-40炔基氧基、C3-20环烷基氧基、C5-20环烯基氧基、3-20元杂环基氧基、C6-20芳基氧基、5-20元杂芳基氧基、-SiR6R7R8、-OSiR6R7R8，其中所述杂环基和杂芳基包含1-5个独立选自N、O和S的杂原子；
    R4可选自氢或任选被一个或多个Rm取代的下列基团：C1-40烷基、C2-40烯基、C2-40炔基、C3-20环烷基、C5-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基、NH2、C1-40烷基氧基、C2-40烯基氧基、C2-40炔基氧基、C3-20环烷基氧基、C5-20环烯基氧基、3-20元杂环基氧基、C6-20芳基氧基、5-20元杂芳基氧基、-SiR6R7R8、-OSiR6R7R8，其中所述杂环基和杂芳基包含1-5个独立选自N、O和S的杂原子；
    R5选自OH、SH、F、Cl、Br、I、CN、NH2；
    其中优选R1和R5不同时为OH或SH；
    或者，R1、R5与其相连接的碳原子一起形成任选被一个或多个Rm取代的C3-20环烷基、C5-20环烯基或包含1-5个选自N、O和S的杂原子的3-20元杂环基；
    或者，R1、R3与其相连接的碳原子一起形成任选被一个或多个Rm取代的C3-20环烷基、C5-20环烯基或3-20元杂环基，其中所述杂环基包含1-5个独立选自N、O和S的杂原子；
    R6、R7、R8彼此独立地为氢或任选被一个或多个Rm取代的下列基团：C1-40烷基、C2-40烯基、C2-40炔基、C3-20环烷基、C5-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基、C1-40烷基氧基、C2-40烯基氧基、C2-40炔基氧基、C3-20环烷基氧基、C5-20环烯基氧基、3-20元杂环基氧基、C6-20芳基氧基、5-20元杂芳基氧基、C1-C40烷基硅基、C1-C40烷基硅基氧基， 其中所述杂环基和杂芳基包含1-5个独立选自N、O和S的杂原子；
    每个Rm独立地选自F、Cl、Br、I、OH、SH、CN、NRdRe、或任选被一个或多个Rm’取代的C1-40烷基、C2-40烯基、C2-40炔基、C3-20环烷基、C5-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基、C1-C40烷基硅基、二(C1-C40烷基)硅基、三(C1-C40烷基)硅基、C1-40烷基氧基、C2-40烯基氧基、C2-40炔基氧基、C3-20环烷基氧基、C5-20环烯基氧基、3-20元杂环基氧基、C6-20芳基氧基、5-20元杂芳基氧基、RtC(O)-、RtC(O)O-、RtOC(O)-、RtS(O)2-、RtS(O)2O-、SiR6R7R8、-OSiR6R7R8，其中所述杂环基和杂芳基包含1-5个独立选自N、O和S的杂原子；
    每个Rt相互独立地选自任选被一个或多个Rm’取代的C1-40烷基、C2-40烯基、C2-40炔基、C3-20环烷基、C5-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基；
    每个Rm’独立地选自F、Cl、Br、I、OH、SH、CN、NRdRe、C1-40烷基、C2-40烯基、C2-40炔基、C3-20环烷基、C5-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基、C1-C40烷基硅基、二(C1-C40烷基)硅基、三(C1-C40烷基)硅基、C1-40烷基氧基、C2-40烯基氧基、C2-40炔基氧基、C3-20环烷基氧基、C5-20环烯基氧基、3-20元杂环基氧基、C6-20芳基氧基、5-20元杂芳基氧基、SiR6R7R8、-OSiR6R7R8，其中所述杂环基和杂芳基包含1-5个独立选自N、O和S的杂原子；
    Rd和Re相互独立地选自H或任选被一个或多个Rm取代的下列基团：C1-40烷基、C2-40烯基、C2-40炔基、C3-20环烷基、3-20元杂环基、C6-20芳基、5-20元杂芳基，其中所述杂环基和杂芳基包含1-5个独立选自N、O和S的杂原子；
    X选自NRn、O或S；
    Rn选自H、C1-40烷基-、C2-40烯基-、C2-40炔基、C3-20环烷基、C5-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基，其中所述杂环基和杂芳基包含1-5个独立选自N、O和S的杂原子。
  2. 权利要求1所述的化合物，其中；
    Ra为
    Figure PCTCN2016109122-appb-100008
    或者Rb为
    Figure PCTCN2016109122-appb-100009
    R1选自任选被一个或多个Rm取代的C1-10烷基、C2-40烯基、C2-40炔基、C3-20环烷基、C5-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基；
    优选地，R1为
    Figure PCTCN2016109122-appb-100010
    其中
    Figure PCTCN2016109122-appb-100011
    为单键或双键，n为选自0至16之一的整数；或为任选被一个或多个Rm取代的C1-10烷基、C6-20芳基、5-20元杂芳基；
    R5为OH或SH；
    或者，R1、R5与其相连接的碳原子一起形成
    Figure PCTCN2016109122-appb-100012
    例如
    Figure PCTCN2016109122-appb-100013
    其中n为1至16之一的整数；
    R2、R3相互独立地选自氢、F、Cl、Br、I或任选被一个或多个Rm取代的C1-40烷基；
    X为O；
    R4选自氢或任选被一个或多个Rm取代的下列基团：C1-40烷基、C2-40烯基、C2-40炔基、 C3-20环烷基、C5-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基；
    每个Rm独立地不存在或选自氢、F、Cl、Br、I、OH、SH、CN、SiR6R7R8、-OSiR6R7R8、或任选被一个或多个Rm’取代的C3-20环烷基、C5-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基、C1-40烷基氧基、C2-40烯基氧基、C2-40炔基氧基、C3-20环烷基氧基、C5-20环烯基氧基、3-20元杂环基氧基、C6-20芳基氧基、5-20元杂芳基氧基，其中所述杂环基和杂芳基包含1-5个独立选自N、O和S的杂原子；
    每个Rm’独立地选自F、Cl、Br、I、OH、SH、CN、NRdRe、C1-40烷基、C2-40烯基、C2-40炔基、C3-20环烷基、C5-20环烯基、3-20元杂环基、C6-20芳基、5-20元杂芳基、C1-C40烷基硅基、二(C1-C40烷基)硅基、三(C1-C40烷基)硅基、C1-40烷基氧基、C2-40烯基氧基、C2-40炔基氧基、C3-20环烷基氧基、C5-20环烯基氧基、3-20元杂环基氧基、C6-20芳基氧基、5-20元杂芳基氧基、SiR6R7R8、-OSiR6R7R8，其中所述杂环基和杂芳基包含1-5个独立选自N、O和S的杂原子；
    R6、R7、R8、Rd、Re彼此独立地具有权利要求1中所述的定义。
  3. 权利要求1所述的化合物，选自如下化合物：
    Figure PCTCN2016109122-appb-100014
    Figure PCTCN2016109122-appb-100015
  4. 式(I)所示的三尖杉酯生物碱类化合物、其药学上可接受的盐、互变异构体、立体异构体及溶剂合物的制备方法，所述方法包括将式(11)化合物与式(12)化合物在路易斯酸的存在下进行反应：
    Figure PCTCN2016109122-appb-100016
    其中，X、Ra、Rb、Rc、a、b、R1、R2、R3、R4、R6、R7、R8各自独立地具有权利要求1-3任一项中式(I)所述的定义；并且R5为OH；
    优选地，式(11)的化合物、式(12)的烯醇硅醚和路易斯酸的摩尔比为1:1～20:1～20，优选为1:1～10:1～10，更优选为1:1.05～5:1.05～5，例如1:1.1～3:1.1～3。
  5. 权利要求4所述的方法，其中式(11)化合物与式(12)化合物在路易斯酸的存在下进行如下反应，制备式(7)、(8)和(9)的化合物：
    Figure PCTCN2016109122-appb-100017
    优选地，所述反应在惰性溶剂中进行；反应温度为50℃以下，例如-80℃至50℃，例如-80℃至30℃。
  6. 式(I-1)化合物的制备方法，包括将式(II)化合物进行还原反应：
    Figure PCTCN2016109122-appb-100018
    其中，Hal为F、Cl、Br或I，X、R1、R4、R5、Rc具有权利要求4所述的定义；
    优选地，所述反应在锌粉的存在下，在含乙酸的溶剂中反应；反应温度可以为50℃以下，例如-80℃至50℃，例如-20℃至30℃。
  7. 权利要求6所述的方法，包括：
    Figure PCTCN2016109122-appb-100019
    例如，所述方法为由化合物13a制备化合物14a的方法：
    Figure PCTCN2016109122-appb-100020
    其中，R1、R4、Rc各自独立地具有权利要求1-3任一项所述的定义。
  8. 权利要求4-7任一项所述的方法，还包括下列反应中的一种或多种：
    1)
    Figure PCTCN2016109122-appb-100021
    例如，采用如下1a)、1b)或1c)的条件：
    1a)优选地，所述反应在惰性溶剂中进行；
    所述反应在氢溴酸溶液存在下进行；
    其中所述氢溴酸溶液优选为氢溴酸水溶液或氢溴酸乙酸溶液，其重量百分比为30-40重量％，例如40重量％氢溴酸水溶液或33重量％氢溴酸乙酸溶液。
    反应温度可以为30℃以下，例如-30℃至30℃；
    反应完成后，用碱调节pH为8以上，例如9，得到目标化合物；
    1b)优选地，所述反应在惰性溶剂中进行；
    所述反应可以在乙酸汞的存在下进行，随后向体系中加入硼氢化钠的氢氧化钠溶液；
    其中乙酸汞可以采用30重量％～40重量％，例如33重量％乙酸汞与惰性溶剂和水的混合液；
    反应温度可以为30℃以下，例如-30℃～30℃；
    反应时间可以为2～8小时；
    1c)优选地，所述反应在惰性溶剂中进行；
    反应温度可以为30℃以下，例如-30℃～30℃；
    所述反应优选在草酸铁六水化合物(Fe(C2O4)3·6H2O)的水溶液中和硼氢化钠(NaBH4)的存在下进行；
    2)
    Figure PCTCN2016109122-appb-100022
    优选地，所述方法在惰性溶剂中进行；
    反应温度可以为100℃以下，例如-30℃～100℃；
    优选地，所述方法在氟化试剂的存在下进行，所述氟化试剂可以选自氟化钾、三乙胺三氢氟酸盐、三氟乙酸、氟化氢、三氟化硼、四丁基氟化氨中的一种或多种；
    3)
    Figure PCTCN2016109122-appb-100023
    优选地，所述反应在惰性溶剂中进行；
    反应温度可以为30℃以下，例如-30℃～30℃；
    优选地，所述反应在无机酸或者路易斯酸的存在下进行；
    其中，
    Rp为-SiR6R7R8，Rq为甲基，
    Figure PCTCN2016109122-appb-100024
    为单键；
    或者，Rp、Rq与其相连接的碳原子一起形成-C＝CH2，
    Figure PCTCN2016109122-appb-100025
    为单键；
    或者，Rp不存在，Rq为甲基，
    Figure PCTCN2016109122-appb-100026
    为双键；
    n为选自0至16之一的整数，例如0、1、2或3；
    其中，R2、R3、R4、R6、R7、R8、Rc、X各自独立地具有权利要求1-3任一项所述的定义。
  9. 药物组合物，包含一种或多种权利要求1-3任一项所述的化合物或其药学上可接受的盐、互变异构体、立体异构体及溶剂合物。
  10. 权利要求1-3任一项所述的化合物在制备药物组合物中的用途；
    优选地，所述药物组合物用于治疗或预防疾病；所述疾病是由不受控制的细胞生长、增殖和/或存活、不适当的细胞免疫应答或不适当的细胞炎症应答引起的疾病，或者伴有不受控制的细胞生长、增殖和/或存活、不适当的细胞免疫应答或不适当的细胞炎症应答的疾病；
    特别地，所述疾病为例如血液肿瘤、实体瘤和/或它们的转移，如白血病和骨髓增生异常综合征、恶性淋巴瘤、包括脑瘤和脑转移在内的头部和颈部肿瘤、包括非小细胞肺肿瘤和小细胞肺肿瘤在内的胸部肿瘤、胃肠道肿瘤、内分泌肿瘤、乳腺肿瘤和其它妇科肿瘤、包括肾肿瘤、膀胱瘤和前列腺瘤在内的泌尿系统肿瘤、皮肤肿瘤和肉瘤、和/或它们的转移；
    或者，所述药物组合物用于抗疟、抗寄生虫、抗真菌或抗菌化疗。
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