CN1307580A - 各种片螺素化合物和类似物的合成 - Google Patents
各种片螺素化合物和类似物的合成 Download PDFInfo
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- CN1307580A CN1307580A CN99807867A CN99807867A CN1307580A CN 1307580 A CN1307580 A CN 1307580A CN 99807867 A CN99807867 A CN 99807867A CN 99807867 A CN99807867 A CN 99807867A CN 1307580 A CN1307580 A CN 1307580A
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- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
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- 239000002243 precursor Substances 0.000 description 1
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- 125000001725 pyrenyl group Chemical group 0.000 description 1
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- ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Natural products C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- HBMUMVMGBLMQJT-UHFFFAOYSA-N pyrrolo[2,1-a]isoquinoline Chemical compound C12=CC=CC=C2C=CN2C1=CC=C2 HBMUMVMGBLMQJT-UHFFFAOYSA-N 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- MCJGNVYPOGVAJF-UHFFFAOYSA-N quinolin-8-ol Chemical compound C1=CN=C2C(O)=CC=CC2=C1 MCJGNVYPOGVAJF-UHFFFAOYSA-N 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 239000011669 selenium Substances 0.000 description 1
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- 238000007493 shaping process Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
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- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 1
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- ZYXPMOIHQRKWGT-UHFFFAOYSA-N silver;2,2,2-trifluoroacetic acid Chemical compound [Ag].OC(=O)C(F)(F)F ZYXPMOIHQRKWGT-UHFFFAOYSA-N 0.000 description 1
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- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
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- KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical compound [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 description 1
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- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
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- 239000000375 suspending agent Substances 0.000 description 1
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- 229910052623 talc Inorganic materials 0.000 description 1
- 229910052714 tellurium Inorganic materials 0.000 description 1
- PORWMNRCUJJQNO-UHFFFAOYSA-N tellurium atom Chemical compound [Te] PORWMNRCUJJQNO-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YMBCJWGVCUEGHA-UHFFFAOYSA-M tetraethylammonium chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC YMBCJWGVCUEGHA-UHFFFAOYSA-M 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
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- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical class C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
- 125000000297 undecanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006216 vaginal suppository Substances 0.000 description 1
- 229940120293 vaginal suppository Drugs 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
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- 239000005019 zein Substances 0.000 description 1
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- 239000002076 α-tocopherol Substances 0.000 description 1
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Classifications
-
- 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
- C07D491/02—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 two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
-
- 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
- C07D491/14—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pyrrole Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及经合成的中间体制备各种各种片螺素化合物和类似物的方法,该方法包括进行式(Ⅰ)化合物的分子内环化而生产式(Ⅱ)化合物,其中的可变因素在说明书中给出。
Description
发明领域
本发明一般性地涉及可用于治疗的化合物的中间体。更具体地,本发明涉及制备一类稠多环生物碱的中间体。本发明也涉及制备稠多环生物碱及其类似物和衍生物的方法。
发明背景
潜在地显示有益的药理性质的天然存在分子可以从自然界,如海洋,植物和微生物分离出来。这类分子的一个例子是以片螺素(Lamellarins)已知的化合物的总类。这些多芳香生物碱从海洋中分离出来,并包括稠合的多芳香结构。片螺素C和D已经显示出在受精海胆分析中引起细胞分裂的抑制,而片螺素I,K和L在培养时都显示出对P388和A549细胞系有相当明显的细胞毒性。最近,片螺素N已经通过作为IV型微管毒物在肺癌细胞系中显示出活性。而且,这些化合物也已经显示出对多药耐受细胞具有细胞毒性,并可作为多药耐受表型的无毒调节剂,并因此提供一种有吸引力的化疗剂的潜在来源。
但是,片螺素的潜在临床应用受到其有限天然产量,以及分离困难的严重限制。
因此,人们对于开发这类分子的合成途径具有很高的积极性,对于这些分子的方法包括1,3,4-三芳基-2,5-二羧基取代的吡咯环的依次双环化(Steglich等,Angew.Chem.Int.Ed.Eng.1997,36,155),和N-叶立德-介导的吡咯环形成,安装该分子的吡咯和内酯部分(Banwell等,Chem.Commun.,1997,2259;Ishibashi等,Tetrahedron,1997,53,5951)。
本发明现在提供经合成中间体的另一方法,该方法允许取代类型范围的掺杂,并默许各种片螺素化合物和含有稠多环-吡咯核心的同系物。
发明公开
其中RA1-A4各自独立地选自氢,非强制性取代的烷基,非强制性取代的烯基,非强制性取代的炔基,非强制性保护的羟基,非强制性取代的氨基,非强制性取代的烷氧基,非强制性取代的烯氧基,非强制性取代的炔氧基,非强制性取代的芳基,非强制性取代的杂环基,羧基,羧基酯基,酰胺基,酰基,酰氧基,巯基,非强制性取代的烷硫基,卤素,硝基,硫酸根,磷酸根和氰基;或RA2和RA3一起非强制性地形成一根键,而RA1和RA4如上定义或与其所连接的碳原子一起形成非强制性取代的饱和或不饱和碳环或杂环基;或RA2和RA3非强制性地与其所连接的碳原子一起形成非强制性取代的碳环或杂环基;或RA1RA2C-CRA3RA4形成非强制性取代的芳基或芳香杂环基;Y选自氢,非强制性取代的烷基,非强制性取代的烯基,非强制性取代的炔基,非强制性保护的羟基,非强制性取代的氨基,非强制性取代的烷氧基,非强制性取代的烯氧基,非强制性取代的炔氧基,非强制性取代的芳基,非强制性取代的杂环基,羧基,羧基酯基,酰胺基,酰基,酰氧基,巯基,非强制性取代的烷硫基,卤素,硝基,硫酸根,磷酸根和氰基;W和X如Y的定义,或者与其所连接的氮和碳原子一起形成饱和或不饱和的含氮杂环基,该杂环基可以非强制性地被取代,或非强制性地与饱和或不饱和的碳环基,芳基或杂环基稠合;V表示卤素或氢原子;Z是-(CH2)n-U-(CH2)o-其中U选自CH2,NH或杂原子,n和o独立地选自0,1,2或3。
RA1-A4各自独立地选自氢,非强制性取代的烷基,非强制性取代的烯基,非强制性取代的炔基,非强制性保护的羟基,非强制性取代的氨基,非强制性取代的烷氧基,非强制性取代的烯氧基,非强制性取代的炔氧基,非强制性取代的芳基,非强制性取代的杂环基,羧基,羧基酯,酰胺基,酰基,酰氧基,巯基,非强制性取代的烷硫基,卤素,硝基,硫酸根,磷酸根和氰基;或RA2和RA3一起非强制性地形成一根键,而RA1和RA4如上定义或与其所连接的碳原子一起形成非强制性取代的碳环或杂环基;或RA2和RA3非强制性地与其所连接的碳原子一起形成非强制性取代的饱和或不饱和碳环或杂环基;或RA1RA2C-CRA3RA4形成非强制性取代的芳基或芳香杂环基;Y选自氢,非强制性取代的烷基,非强制性取代的烯基,非强制性取代的炔基,非强制性保护的羟基,非强制性取代的氨基,非强制性取代的烷氧基,非强制性取代的烯氧基,非强制性取代的炔氧基,非强制性取代的芳基,非强制性取代的杂环基,羧基,羧基酯基,酰胺基,酰基,酰氧基,巯基,非强制性取代的烷硫基,卤素,硝基,硫酸根,磷酸根和氰基;W和X如Y的定义,或者与其所连接的氮和碳原子一起形成饱和或不饱和的含氮杂环基,该杂环基可以非强制性地被取代,或非强制性地与饱和或不饱和的碳环基,芳基或杂环基稠合;V表示卤素或氢原子;Z是-(CH2)n-U-(CH2)o-其中U选自CH2,NH或杂原子,n和o独立地选自0,1,2或3。
本发明还一方面涉及通过本文所述的方法制备的式(II)化合物。
本文所用的术语“烷基”指直链,支链或环状全饱和烃基。除非碳原子数是特定的,否则该术语优选地指C1-20烷基或环烷基。直链或支链烷基的例子包括甲基,乙基,丙基,异丙基,丁基,异丁基,仲丁基,叔丁基,戊基,异戊基,仲戊基,1,2-二甲基丙基,1,1-二甲基丙基,己基,4-甲基戊基,1-甲基戊基,2-甲基戊基,3-甲基戊基,1,1-二甲基丁基,2,2-二甲基丁基,3,3-二甲基丁基,1,2-二甲基丁基,1,3-二甲基丁基,1,2,2-三甲基丙基,1,1,2-三甲基丙基,庚基,5-甲氧基己基,1-甲基己基,2,2-二甲基戊基,3,3-二甲基戊基,4,4-二甲基戊基,1,2-二甲基戊基,1,3-二甲基戊基,1,4-二甲基戊基,1,2,3-三甲基丁基,1,1,2-三甲基丁基,1,1,3-三甲基丁基,辛基,6-甲基庚基,1-甲基庚基,1,1,3,3-四甲基丁基,壬基,1-,2-,3-,4-,5-,6-或7-甲基辛基,1-,2-,3-,4-或5-乙基庚基,1-,2-或3-丙基己基,癸基,1-,2-,3-,4-,5-,6-,7-或8-甲基壬基,1-,2-,3-,4-,5-或6-乙基辛基,1-,2-,3-或4-丙基庚基,十一烷基,1-,2-,3-,4-,5-,6-,7-,8-或9-甲基癸基,1-,2-,3-,4-,5-,6-或7-乙基壬基,1-,2-,3-,4-或5-丙基辛基,1-,2-或3-丁基庚基,1-戊基己基,十二烷基,1-,2-,3-,4-,5-,6-,7-,8-,9-或10-甲基十一烷基,1-,2-,3-,4-,5-,6-,7-或8-乙基癸基,1-,2-,3-,4-,5-或6-丙基壬基,1-,2-,3-或4-丁基辛基,1-,2-戊基庚基等等。环烷基的例子包括单-或多环烷基,如环丙基,环丁基,环戊基,环己基,环庚基,环辛基,环壬基,环癸基等等。
本文所用的术语“烯基”指从直链,支链或环状烃基形成的,含有至少一个碳-碳双键的基团,包括烯化的单-,二-或多-不饱和的如前定义的烷基或环烷基。除非碳原子数是特定的,否则该术语优选地指C1-20烯基。烯基的例子包括乙烯基,烯丙基,1-甲基乙烯基,丁烯基,异丁烯基,3-甲基-2-丁烯基,1-戊烯基,环戊烯基,1-甲基环戊烯基,1-己烯基,3-己烯基,环己烯基,1-庚烯基,3-庚烯基,1-辛烯基,环辛烯基,1-壬烯基,2-壬烯基,3-壬烯基,1-癸烯基,3-癸烯基,1,3-丁二烯基,1,4-戊二烯基,1,3-环戊二烯基,1,3-己二烯基,1,4-己二烯基,1,3-环己二烯基,1,4-环己二烯基,1,3-环庚二烯基,1,3,5-环庚三烯基和1,3,5,7-环辛四烯基。
本文所用的术语“炔基”指从含有至少一个碳-碳三键的直链,支链或环状烃基产生的基团,包括炔化的如前定义的单-,二-或多-不饱和烷基或环烷基。除非碳原子数是特定的,否则该术语优选地指C1-20炔基。例子包括乙炔基,1-丙炔基,2-丙炔基,和丁炔基异构体,和戊炔基异构体。
术语“烷氧基”,“烯氧基”和“炔氧基”分别指与氧连接的如前定义的烷基,烯基和炔基。
术语“卤素”指氟,氯,溴或碘。
术语“芳基”指单,多核,共轭和稠合的芳香环系的残基。芳基的例子包括苯基,联苯基,三联苯基,四联苯基,萘基,四氢萘基,蒽基,二氢蒽基,苯并蒽基,二苯并蒽基,菲基,芴基,芘基,idenyl,薁基,窟基。
术语“杂环”指其中至少一个碳原子被优选地选自氮,硫和氧的杂原子置换的单-或多碳环基。其中至少一个碳原子被杂原子置换的单-或多碳环基是芳基时,被称为芳香杂环基。
合适的杂环基包括含氮杂环基,如含有1至4个氮原子的不饱和的3至6员杂单环,例如,吡咯基,吡咯啉基,咪唑基,咪唑啉基,吡唑基,吡啶基,嘧啶基,吡嗪基,哒嗪基,三唑基或四唑基;含有1至4个氮原子的饱和的3至6员杂单环,例如,吡咯烷基,咪唑烷基,哌啶基,吡唑烷基或哌嗪基;含有1至5个碳原子的稠合饱和或不饱和杂环基,如吲哚基,异吲哚基,二氢吲哚基,二氢异吲哚基,中氮茚基,异中氮茚基,苯并咪唑基,喹啉基,异喹啉基,吲唑基,苯并三唑基,嘌呤基,喹唑啉基,喹喔啉基,菲啶基,菲咯啉基,2,3-二氮杂萘基,1,5-二氮杂萘基,噌啉基,喋啶基,萘嵌间二氮杂苯基或四唑并哒嗪基;含有1至3个氧原子的饱和的3至6员杂单环,如四氢呋喃基,四氢吡喃基,二氧杂环己烷基,含有一个氧原子的不饱和3至6员杂单环基,如吡喃基,氧杂环己二烯基或呋喃基;含有1至3个氧原子的稠合饱和或不饱和杂环基,如苯并呋喃基,色烯基或呫吨基;含有1至2个硫原子的不饱和3至6员杂单环基,如噻吩基或二硫吩基;含有1至2个氧原子和1至3个氮原子的不饱和3至6员杂单环基,如噁唑基,噁唑啉基,异噁唑基,呋咱基或噁二唑基;含有1至2个氧原子和1至3个氮原子的饱和3至6员杂单环基,如吗啉基;含有1至2个氧原子和1至3个氮原子的不饱和稠杂环基,如苯并噁唑基或苯并噁二唑基;含有1至2个硫原子和1至3个氮原子的不饱和3至6员杂单环基,如噻唑基,噻唑啉基或噻二唑基;含有1至2个硫原子和1至3个氮原子的饱和3至6员杂单环基,如噻唑烷基;和含有1至2个硫原子和1至3个氮原子的不饱和稠杂环基,如苯并噻唑基或苯并噻二唑基。
术语“酰基”指其中OH被例如对W,X,和Y定义的残基置换的羧酸残基,具体地可以指氨基甲酰基,脂族酰基或含有芳香环的酰基,被称为芳族酰基,或含有杂环的酰基,被称为杂环酰基,优选C1-20酰基。合适的酰基的例子包括氨基甲酰基;直链或支链烷酰基如甲酰基,乙酰基,丙酰基,丁酰基,2-甲基丙酰基,戊酰基,2,2-二甲基丙酰基,己酰基,庚酰基,辛酰基,壬酰基,癸酰基,十一烷酰基,十二烷酰基,十三烷酰基,十四烷酰基,十五烷酰基,十六烷酰基,十七烷酰基,十八烷酰基,十九烷酰基和二十烷酰基;烷氧羰基如甲氧羰基,乙氧羰基,叔丁氧羰基,叔戊氧羰基和庚氧羰基;环烷基羰基如环丙基羰基,环丁基羰基,环戊基羰基和环己基羰基;烷基磺酰基如甲磺酰基和乙磺酰基;烷氧基磺酰基如甲氧基磺酰基和乙氧基磺酰基;芳酰基如苯甲酰基,甲苯甲酰基和萘甲酰基;芳烷氧基如苯基烷酰基(例如苯基乙酰基,苯基丙酰基,苯基丁酰基,苯基异丁酰基,苯基戊酰基和苯基己酰基)和萘基烷酰基(例如萘基乙酰基,萘基丙酰基和萘基丁酰基);芳烯酰基如苯基烯酰基(例如苯基丙烯酰基,苯基丁烯酰基,苯基异丁烯酰基,苯基戊烯酰基和苯基己烯酰基和萘基烯酰基(例如萘基丙烯酰基,萘基丁烯酰基和萘基戊烯酰基);芳烷氧羰基如苯基烷氧羰基(例如苄氧羰基);芳氧羰基如苯氧羰基和萘氧羰基;芳氧基烷酰基如苯氧基乙酰基和苯氧基丙酰基;芳基氨基甲酰基如苯基氨基甲酰基;芳硫基氨基甲酰基如苯硫基氨基甲酰基;芳基乙醛酰基如苯基乙醛酰基和萘基乙醛酰基;芳基磺酰基如苯基磺酰基和萘基磺酰基;杂环羰基;杂环烷酰基如噻吩基乙酰基,噻吩基丙酰基,噻吩基丁酰基,噻吩基戊酰基,噻吩基己酰基,噻唑基乙酰基,噻二唑基乙酰基和四唑基乙酰基;杂环烯酰基如杂环丙烯酰基,杂环丁烯酰基,杂环戊烯酰基和杂环己烯酰基;和杂环乙醛酰基如噻唑基乙醛酰基和噻吩基乙醛酰基。
术语“酰氧基”指与氧连接的如前定义的酰基。
在本说明书中,“非强制性取代的”意思是被一个或多个选自由烷基,烯基,炔基,芳基,卤素,卤代烷基,卤代烯基,卤代炔基,卤代芳基,羟基,烷氧基,烯氧基,芳氧基,苄氧基,卤代烷氧基,卤代烯氧基,卤代芳氧基,硝基,硝基烷基,硝基烯基,硝基炔基,硝基芳基,硝基杂环基,氨基,烷基氨基,二烷基氨基,烯基氨基,炔基氨基,芳基氨基,二芳基氨基,苄基氨基,二苄基氨基,酰基,烯基酰基,炔基酰基,芳基酰基,酰基氨基,二酰基氨基,酰氧基,烷基磺酰氧基,芳基磺酰氧基,杂环基、杂环氧基、杂环氨基、卤代杂环基、烷基亚磺酰基、芳基亚磺酰基,烷氧羰基,芳氧羰基,巯基,烷硫基,苄硫基,酰硫基,氰基,硝基,硫酸根和磷酸根组成的一组基团进一步取代,或不取代或稠合(形成稠多环基团)。术语“非强制性保护”指诸如羟基的基团可以被保护基保护或可以不保护。合适的保护基团是已知的,其例子在Protective Groups inOrganic Synthesis,由T.W.Greene(1981),John Wiley & Son中描述。
本文所用的“杂原子”指可以是环状有机化合物成员的除碳原子之外的任何原子。合适杂原子的例子包括氮,氧,硫,磷,硼,硅,砷,硒和碲,尤其是氮,氧和硫。
在式(I)和(II)化合物的优选方案中,U,如Z中定义,选自CH2,NH,氧或硫中之一。更优选地,U是NH或氧。最优选地,U是氧。在Z的另一优选方案中,n+o=0,1,2,3或4。Z的合适的例子包括-O-CH2-,-CH2-N-,-O-CH2-O-,-(CH2)3-,-CH2-NH-CH2-或-CH2-O-CH2-。在另一优选方案中,n和o都是0。
在另一优选的形式中,V是氢,碘或溴。
在另一式(I)和(II)的方案中,当W和X与它们所连接的氮和碳原子一起形成饱和或不饱和杂环基时,该基团优选地是非强制性取代的喹啉基,非强制性取代的异喹啉基,非强制性取代的二氢喹啉基,非强制性取代的二氢异喹啉基,非强制性取代的吡啶基或其二氢或四氢同系物,或非强制性取代的菲啶。优选地,W和X与它们所连接的氮和碳原子一起形成式(i)的非强制性取代的异喹啉基或非强制性取代的二氢异喹啉基:其中R1-R4和R14如上面Y定义,而
表示单键或双键。
优选地,式(i)的R1-R4是氢;羟基;非强制性取代的烷基;非强制性取代的烷氧基;酰氧基;羧基;羧酸酯基,其中该酯优选地是甲基,乙基,丙基或丁基酯;非强制性取代的氨基;酰胺基,其中其氮原子被一个或两个独立地选自甲基,乙基,丙基或丁基的烷基非强制性地取代;或硫酸根。最优选地,它们是氢,羟基,甲氧基,乙氧基,异丙氧基,甲基,乙基,丙基,乙酰氧基或硫酸根。优选地,R14是氢或羟基。
在式(I)和(II)化合物的另一方案中,当RA1RA2C-CRA3RA4形成芳基或芳香杂环基时,它可以是一个非强制性取代的苯或萘环,或非强制性取代的芳香杂环基如吡啶,呋喃,吡咯或噻吩和其苯-稠合的同系物,例如,喹啉,吲哚,苯并呋喃和苯并噻吩。双环杂环基可以经苯或杂环连接。优选地RA1RA2C-CRA3RA4形成非强制性取代的苯基。取代基优选地是氢;羟基;非强制性取代的烷基;非强制性取代的烷氧基;酰氧基;羧基;羧酯基,其中该酯优选地是甲基,乙基,丙基或丁基酯;非强制性取代的氨基;甲酰胺基,其中其氮原子被一个或两个独立地选自甲基,乙基,丙基或丁基的烷基非强制性地取代;或硫酸根。最优选地,它们是氢,羟基,甲氧基,乙氧基,异丙氧基,甲基,乙基,丙基,乙酰氧基或硫酸根。
在另一方案中,RA1-A4优选地独立地选自氢,非强制性取代的烷基,非强制性保护的羟基,非强制性取代的烷氧基,非强制性取代的苯基或酰氧基。在另一优选的方案中,RA1或RA3的至少一个可以是氢。在另一方案中,RA1和RA3都是氢。在另一方案中,RA1-A4中的三个或四个是氢。
在另一方案中,当RA2和RA3一起形成一根键,从而形成RA1C=CRA4时,RA1和RA4可以独立地选自氢;羟基;非强制性取代的烷基;非强制性取代的烷氧基;酰氧基;羧基;羧酯基,其中该酯优选地是甲基,乙基,丙基或丁基酯;非强制性取代的氨基;甲酰胺基,其中其氮原子被一个或两个独立地选自甲基,乙基,丙基或丁基的烷基非强制性地取代。在特别优选的形式中,RA1和RA4中的一个或两者是氢。
当RA2和RA3与其所连接的碳原子一起形成如前定义的碳环或杂环基时,优选地形成3至8-员环状基团,优选5至6-员环状基团。优选地,它们形成环戊烷,环己烷,环戊烯,环己烯,环戊二烯,环己二烯,四氢呋喃,二氢呋喃,吡咯烷,吡咯啉,吡喃,二氢吡喃,四氢吡喃或哌啶基。优选地,RA1和RA4是氢。
更优选地,R9-R13是氢;羟基;非强制性取代的烷基;非强制性取代的烷氧基;酰氧基;羧基;羧酯基,其中该酯优选地是甲基,乙基,丙基或丁基酯;非强制性取代的氨基;酰胺基,其中其氮原子被一个或两个独立地选自甲基,乙基,丙基或丁基的烷基非强制性地取代;或硫酸根。最优选地,R9-R13选自氢,羟基,甲氧基,乙氧基,异丙氧基,甲基,乙基,正丙基,异丙基,乙酰氧基或硫酸根。
另一优选的式(I)方案是其中X是氢而W是式(iii)基团的式(Ia)化合物:其中V是氢或卤素;RB1-B4相应地如本文前面对RA1-A4定义;而m选自1,2,3或4。
其中RA1-A4,V,Y,Z如前定义;
RB1-B4各自独立地选自氢,非强制性取代的烷基,非强制性取代的烯基,非强制性取代的炔基,非强制性保护的羟基,非强制性取代的氨基,非强制性取代的烷氧基,非强制性取代的烯氧基,非强制性取代的炔氧基,非强制性取代的芳基,非强制性取代的杂环基,羧基,羧基酯,酰胺基,酰基,酰氧基,巯基,非强制性取代的烷硫基,卤素,硝基,硫酸根,磷酸根和氰基;或
RB2和RB3一起非强制性地形成一根键,而RA1和RA4如上定义或与其所连接的碳原子一起形成非强制性取代的碳环或杂环基;或
RB2和RB3与其所连接的碳原子一起形成非强制性取代的饱和或不饱和碳环或杂环基;或
RB1RB2C-CRB3RB4形成非强制性取代的芳基或芳香杂环基;而
m选自1,2,3或4。
本发明另一优选的方案提供式(Ia)的中间体化合物其中:
RA1-A4,RB1-B4,V,Y,Z和m如前定义,并且非强制性地,在式(iii)中定义的(CH2)m中的一个或多个(CH2)可以非强制性地被如前定义的基团R14取代。
在另一优选的方案中,m是1或2。更优选地,m是2。
在式(Ia)和(IIa)化合物的另一方案中,当RB1RB2C-CRB3RB4形成芳基或芳香杂环基时,它可以是一个非强制性取代的苯或萘环,或非强制性取代的芳香杂环基如吡啶,呋喃,吡咯或噻吩和其苯-稠合的类似物,例如,喹啉,吲哚,苯并呋喃和苯并噻吩。双环杂环基可以经苯或杂环连接。优选地RB1RB2C-CRB3RB4形成非强制性取代的苯基。当RB1RB2C-CRB3RB4形成苯基(含有取代基V)时,环化可以给出如本文上面所述的式(i)基团。取代基优选地是氢;羟基;非强制性取代的烷基;非强制性取代的烷氧基;酰氧基;羧基;羧基酯,其中该酯优选地是甲基,乙基,丙基或丁基酯;非强制性取代的氨基;甲酰胺基,其中其氮原子被一个或两个独立地选自甲基,乙基,丙基或丁基的烷基非强制性地取代;或硫酸根。最优选地,它们是氢,羟基,甲氧基,乙氧基,异丙氧基,甲基,乙基,丙基,乙酰氧基或硫酸根。
在另一方案中,RB1-B4优选地独立地选自氢,非强制性取代的烷基,非强制性保护的羟基,非强制性取代的烷氧基,非强制性取代的苯基或酰氧基。在另一优选的方案中,RB1或RB3的至少一个可以是氢。在另一方案中,RB1和RB3都是氢。在另一方案中,RB1-B4中的三个或四个是氢。
在另一方案中,当RB2和RB3一起形成一根键,从而形成RB1C=CRB4时,RB1和RB4可以独立地选自氢;羟基;非强制性取代的烷基;非强制性取代的烷氧基;酰氧基;羧基;羧基酯,其中该酯优选地是甲基,乙基,丙基或丁基酯;非强制性取代的氨基;甲酰胺基,其中其氮原子被一个或两个独立地选自甲基,乙基,丙基或丁基的烷基非强制性地取代。在特别优选的形式中,RA1和RA4中的一个或两者是氢。
当RB2和RB3与其所连接的碳原子一起形成如前定义的碳环或杂环基时,优选地形成3至8-员环状基团,优选5至6-员环状基团。优选地,它们形成环戊烷,环己烷,环戊烯,环己烯,环戊二烯,环己二烯,四氢呋喃,二氢呋喃,吡咯烷,吡咯林,吡喃,二氢吡喃,四氢吡喃或哌啶基。优选地,RB1和RB4是氢。
特别优选的式(I)化合物具有如下式(Ib)的结构:其中R1-14独立地选自氢,非强制性取代的烷基,非强制性取代的烯基,非强制性取代的炔基,非强制性保护的羟基,非强制性取代的氨基,非强制性取代的烷氧基,非强制性取代的烯氧基,非强制性取代的炔氧基,非强制性取代的芳基,非强制性取代的杂环基,羧基,羧基酯,酰胺基,酰基,酰氧基,巯基,非强制性取代的烷硫基,卤素,硝基,硫酸根,磷酸根和氰基。优选的R1-14选自氢;羟基;非强制性取代的烷基;非强制性取代的烷氧基;酰氧基;羧基;羧基酯,其中该酯优选地是甲基,乙基,丙基或丁基酯;非强制性取代的氨基,如一或二烷基氨基;酰胺基,其中其氮原子被一个或两个独立地选自甲基,乙基,丙基或丁基的烷基非强制性地取代;或硫酸根。最优选地,R1-13选自氢;羟基;非强制性取代的烷基,如甲基,乙基或丙基;非强制性取代的烷氧基如甲氧基,乙氧基,正丙氧基,异丙氧基;酰氧基如乙酰氧基;或硫酸根,而R14优选地是氢或羟基。V如前定义,优选地是氢,碘或溴。
式(I),优选式(Ia)或(Ib)化合物的分子内环化,形成式(II),优选式(IIa)或式(IIb)的多环稠合化合物的步骤可以通过本专业技术人员已知的任何适当的手段进行。合适的方法在下面描述,但是,能够实施所需的环化的任何其他方法也形成本发明的部分。应该理解,基团V,W,X,Y,Z,RA1-A4,RB1-B4,和R1-4应为不干扰环化过程的形式。
当V表示氢原子时,氧化性分子内环化法,如Black等,Tetrahedron Lett.,1989,30,5807和Kita等,Chem.Commun.,1996,1481中所述的,可以被用于实施环化。
另外,当V是卤原子时,分子内环化可以经与Antonio等,Can.J.Chem.,1994,72,15和Moody等,Tetrahedron Lett.,1995,36,9501中所述的方法类似的方式产生合适的基团而进行。
当V是卤素时,用于式(I)化合物分子内环化的另一方法包括Pd[O]-介导的环化。分子内Pd[O]-催化的有机卤化物的烯化(分子内Heck反应)对于本专业技术人员是已知的,并且可以通过能够提供零价钯(Pd[O])的试剂的任意合适的组合而进行。
用于实施Pd[O]-催化的环化的合适的试剂组合例如在Burwood等,Tetrahedron Lett.,1995,36,9503;Desarbe等,Heterocycles,1995,41,1987;Harayoma等,Chem.Pharm.Bull.,1997,45,1723;和Grigg等,Tetrahedron,1995,50,359。
因此,在本发明的一个方案中,式(I)的Pd[O]-催化的环化可以通过Pd[II]试剂和“配体”组合而就地产生Pd[O]而进行,并进一步提供用于Pd[O]催化剂再生的碱。
合适的Pd[II]/Pd[O]试剂的例子包括,但不限于:Pd(OAc)2,PdCl2(CH3CN)2,PdCl2(PPh3)2,Pd(C6H5CN)2Cl2,Pd(二亚苄基丙酮)3。
提供试剂的“配体”的合适的例子包括,但不限于:PPh3,P(邻甲苯基)3;1,3-二[二苯基膦基]丙烷和1,3-二[二苯基膦基]乙烷。
用于从Pd[O]-催化的环化期间形成的Pd[II]再生Pd[O]的合适的碱包括,但不限于:烷基胺,如三乙胺和二异丙基乙胺;醋酸盐,如醋酸钠和醋酸钾;碳酸盐如碳酸钾,碳酸钠,碳酸银;和氢氧化物如氢氧化钠和氢氧化钾。
当式(Ia)或(Ib)化合物被处理而进行双环化,形成式(Ia)或(IIb)化合物时,环化可以通过基团,如上所述的氧化性或Pd-介导的环化工艺实现,各环化可以以相同,相似或不同的方式进行。
因此,在一个方案中,两个环化可以连续地,以任何顺序进行,并可以非强制性地应用不同的试剂和条件,例如如上所述的。非强制性地,在一次环化后进行,单环化产物可以被分离,然后在合适的条件下处理而进行第二次分子内环化。作为另一种形式,“双环化”可以“一锅煮”的进行,优选地在单套反应条件下进行。
作为更优选的形式,使式(Ia),优选(Ib)的化合物在Pd[O]-催化条件下进行“双环化”形成式(IIa),优选(IIb)化合物。
作为还更优选的形式,两次环化都在单套反应条件下以“一锅煮”方式进行。
式(I),(Ia)和(Ib)化合物可以通过本专业技术人员已知的进行吡咯核心碳原子取代的标准工艺,从吡咯核心制备,例如通过亲电芳香取代或卤代吡咯核,并用锡烷,硼酸或锌化合物如芳基锡烷,芳基硼酸和芳基锌化合物通过Stile,Suzuki,或Negishi交叉偶联反应而进行取代。N-原子的取代可以通过标准工艺进行。
没有任何限制意义,一个合适的方法在图解1中描绘,该图解用于举例说明取代吡咯核的合适的方法。
应该理解,通过在用于向吡咯核心引入1-,2-,4-取代类型的步骤中使用适当的试剂,例如,用于步骤(d),(e)和(f)的含有苯基试剂,其中苯基部分进一步如前所述被取代,取代类型和取代基可被引入以形成能够进行环化过程的中间体,并形成相应的环化过的化合物。
图解1图解1:试剂和条件:(a)Cl3CCOCl(1摩尔当量),Et2O,35℃,1小时(80%);(b)I2(1摩尔当量),AgO2CCF3(1摩尔当量),CHCl3,18℃,1小时(82%);(c)K2CO3(2M H2O),DMSO,18℃,32小时(92%);(d)(i)(COCl)2(1.1摩尔当量),DMF(催化量),CH2Cl2,18℃,2小时;(ii)邻溴苯酚(1摩尔当量),DMAP(催化量),CH2Cl2,18℃,1小时(92%);(e)K2CO3(1.14摩尔当量),Bu4NCl(0.1摩尔当量),DMF,80℃,2小时(90%);(f)PhZnCl(1.3摩尔当量),PdCl2(PPh3)2(0.05摩尔当量),THF/DMF,18℃,1小时(95%);(g)Pd(OAc)2(0.5摩尔当量),PPh3(1当量),NaOAc(4当量),DMF,130℃,6小时(16%);(h)TsCl(2.4摩尔当量),KOH(2.4摩尔当量),Et2O,0-18℃,2小时(98%)。
当可有可无的双键存在时,如含有式(I)部分的式(II)化合物如式(IIb)化合物中,可以通过环化产物的脱氢,或者,通过在其前体中掺入相应的双键而引入该双键。合适的方法是本专业技术人员已知的(参见例如,Advanced Organic Chemistry,Reactions.Mechanisms.andStructure,Jerry March,第三版,Wiley Interscience)。一种合适的方法包括用DDQ(2,3-二氯-5,6-二氰基-1,4-苯醌)处理环化的式(IIb)化合物。例如,片螺素T二异丙基醚(表2中的化合物37)可以通过用DDQ在干燥的氯仿中,于60-65℃处理而转化为片螺素W二异丙基醚(表1中的化合物11)(参见WO98/50365中的实施例11)。
WO97/01336(其整个内容以参考文献的形式掺入本文)描述了一类具有抗多药物耐受型肿瘤的抑制和/或细胞毒性活性的化合物。
因此,本发明再一方面提供治疗方法,包括对需要的动物,包括人施用有效量的如本文所述的方法制备的通式(II)化合物作为活性成分。
本文所用的术语“有效量”指当根据所需的剂量模式给药时,提供所需的治疗活性的化合物的量。剂量给药可以在分,小时,天,周,月或年的间隔发生,或超越这些周期的任何一个连续进行。合适的剂量在每剂量约每kg体重0.1ng至每kg体重1g的范围内。优选地,剂量在每剂量每kg体重1μg至每kg体重1g的范围。更优选地,剂量在每剂量每kg体重1mg至每kg体重1g的范围。合适地,剂量在每剂量每kg体重1mg至每kg体重500mg的范围,如1mg至250mg或1mg至100mg。
在优选的方案中,治疗方法涉及治疗多药物耐受的肿瘤。
在另一方案中,治疗方法涉及改善多药物耐受影响药物的抗肿瘤化疗效果。
在另一优选的方案中,治疗方法是诱导细胞凋亡的方法。更优选地,治疗方法是对多药物耐受细胞诱导细胞凋亡的方法。
在另一方案中,治疗方法涉及调节免疫功能。
活性成分可以由单剂量或一系列剂量给药。在活性成分可以被单独给药的同时,优选地是以组合物,优选药物组合物的形式存在。
本发明还一方面涉及包括根据本发明方法制备的通式(II)化合物与药用载体,赋形剂或稀释剂一起的组合物。
载体必须是药学上“可接受的”,即可以与组合物中的其他成分共容,并且不伤害主体。组合物包括适合于口服,直肠,鼻内,局部(包括颊内和舌下),阴道内或肠胃外(包括皮下,肌内,静脉内和真皮内)给药的组合物。该组合物可以方便地以单位剂量形式存在,并可以通过制药行业公知的任何方法制备。这类方法包括使活性成分与由一种或多种辅助成分组成的载体混合的步骤。一般说来,组合物通过使活性成分与液体载体或很细的固体载体或者它们两者均匀和密切地混合,如果需要,然后将产品成形。
适合于口服给药的本发明组合物可以以分离的单元如各自含有预定量的活性成分的胶囊,药囊或片剂;以粉剂或颗粒剂;以在水溶液或非水溶液中的溶液或悬浮液;或以水包油乳剂或油保水乳剂存在。活性成分也可以以丸剂,药糖剂或糊剂存在。
片剂可以通过压片或压模,非强制性地加以一种或多种辅助成分制造。压制的片剂可以通过在合适地机器中将活性成分以自由流动的形式如粉末或颗粒,非强制性地与粘合剂(例如惰性稀释剂,防腐剂,崩解剂(例如淀粉乙醇酸钠,交联聚乙烯吡咯烷酮,交联羧甲基纤维素钠),表面活性剂或分散剂混合,压片而制备。模制的片剂可以通过在合适的机器中,将用惰性液体稀释剂润湿的粉末状化合物的混合物压模而制造。该片剂可以非强制性地包衣或刻痕,并被配制以提供活性成分的缓释或受控释放,其中以不同的比例使用,例如羟丙基甲基纤维素,提供所需的释放形式。片剂可以非强制性地用肠衣包裹,使其在肠内而不是胃中释放。
适合于在口内局部给药的组合物包括在调味基,一般为蔗糖和阿拉伯胶或黄蓍胶中包含活性成分的锭剂;在惰性基质如明胶或甘油,或蔗糖和阿拉伯胶中包含活性成分的软锭剂;和在合适的液体载体中包含活性成分的漱口剂。
用于直肠内给药的组合物可以以带有合适的基质,包含,例如可可脂的栓剂存在。
适合于阴道内给药的组合物可以以含有除活性成分之外的,如本领域已知的载体的阴道栓,塞子,软膏,凝胶,糊剂,泡沫或喷雾制剂存在。
适合于肠胃外给药的组合物包括水或非水的等渗无菌注射液,它可含有抗氧化剂,缓冲剂,杀菌剂和使组合物与受体的血液等渗的溶质;可以包括悬浮剂和增稠剂的水和非水无菌悬浮液。该组合物可以存在于单剂量或多剂量密封容器,例如安瓿和小瓶中,并可在冷冻-干燥(冻干)条件下贮存,只需要在使用前加入无菌液体载体,例如注射用水。现场的注射溶液和悬浮液可以从前述种类的无菌粉剂,颗粒剂和片剂制备。
优选的单位剂量组合物是含有如上所述日剂量或单元,日亚剂量,或其适当部分的活性成分的组合物。
应该明白,除了上面具体提到的活性成分之外,本发明的组合物可以包括其他与所讨论的组合物类型有关的本领域普通的药剂,例如,适合于口服给药的组合物可包括诸如粘合剂,甜味剂,增稠剂,调味剂,崩解剂,包衣剂,防腐剂,润滑剂和/或延时剂的药剂。合适的甜味剂包括蔗糖,乳糖,葡萄糖,阿斯巴甜或糖精。合适的崩解剂包括玉米淀粉,甲基纤维素,聚乙烯基吡咯烷酮,黄原胶,膨润土,藻酸或琼脂。合适的调味剂包括薄荷油,冬青油,樱桃,橙子或覆盆子调味品。合适的包衣剂包括丙烯酸和/或异丁烯酸和/或其酯的聚合物或共聚物,蜡,脂肪醇,玉米醇溶蛋白,紫胶或谷蛋白。合适的防腐剂包括苯甲酸钠,维生素E,α-生育酚,抗坏血酸,对羟基苯甲酸甲酯,对羟基苯甲酸丙酯或亚硫酸氢钠。合适的润滑剂包括硬脂酸镁,硬脂酸,油酸钠,氯化钠或滑石。合适的延时剂包括甘油一硬脂酸酯或甘油二硬脂酸酯。
本发明也提供根据本发明方法制备的通式(II)化合物的在生产用于治疗有这种需要的动物或人的医药方面的用途。
本发明另一方面涉及包含根据本发明方法制备的通式(II)化合物用于治疗有这种需要的动物或人的药剂。
在第一方案中,药剂是用于治疗多药物耐受肿瘤的。
在另一方案中,药剂是用于对多药物耐受细胞诱导细胞凋亡的。
还一方案中,药剂是用于改善多药物耐受影响的药物的抗肿瘤化疗效果的。
另一方案是用于调节免疫功能的药剂。
本发明还一方面涉及通式(I)化合物用于治疗有这种需要的动物或人的用途。优选地,通式(I)化合物通过如前所述的方法制备。
在优选的方案中,该用途是治疗多药物耐受肿瘤。
在另一方案中,用途是改善多药物耐受影响的药物的抗肿瘤化疗效果。
还一方案是用于调节免疫功能。
优选地,没有限制意义,可以经本发明中间体制备的化合物的例子在下面表1和表2中描绘。下表及下文中,“Commpound”表示化合物,“Lamellarin”即片螺素,“Sulfate”为硫酸盐,“acctate,diacctate,triacetate”分别为醋酸盐,二醋酸盐,三醋酸盐。表1
Compound | R1 | R2 | R3 | R4R5 | R6 | R7 | R8R9 | R10 | R11 | R12R13 |
1 | H | H | H | H | H | H | H | H | H | H |
2(Lamellarin B) | OMe | OMe | OMe | H | OMe | OH | H | OMe | OH | H |
3(Lamellarin D) | H | OH | OMe | H | OMe | OH | H | OMe | OH | H |
4(Lamellarin D-triacetate) | H | OAc | OMe | H | OMe | OAc | H | OMe | OAc | H |
5(Lamellarin M) | OH | OMe | OMe | H | OMe | OH | H | OMe | OH | H |
6(Lamellarin M-triacetate) | OAc | OMe | OMe | H | OMe | OAc | H | OMe | OAc | H |
Compound | R1 | R2 | R3 | R4R5 | R6 | R7 | R8R9 | R10 | R11 | R12R13 |
7(Lamellarin N) | H | OH | OMe | H | OMe | OH | H | OH | OMe | H |
8(Lamellarin N-triacetate) | H | OAc | OMe | H | OMe | OAc | H | OAc | OMe | H |
9(Lamellarin W) | OMe | OMe | OMe | H | OMe | OH | H | OH | OMe | H |
10(Lamellarin X) | OH | OMe | OMe | H | OMe | OH | H | OH | OMe | H |
11 | OMe | OMe | OMe | H | OMe | OiPr | H | OiPr | OMe | H |
表2
Compound | R1 | R2 | R3 | R4R5 | R6 | R7 | R8R9 | R10 | R11 | R12R13 | R14 |
12(Lamellarin A) | OMe | OMe | OMe | H | OMe | OH | H | OMe | OH | H | OH |
13(Lamellarin C) | OMe | OMe | OMe | H | OMe | OH | H | OMe | OH | H | H |
14(Lamellarin E) | OH | OMe | OMe | H | OMe | OH | H | OH | OMe | H | H |
15(Lamellarin F) | OH | OMe | OMe | H | OMe | OH | H | OMe | OMe | H | H |
16(Lamellarin G) | H | OH | OMe | H | OH | OMe | H | OH | OMe | H | H |
17(Lamellarin H) | H | OH | OH | H | OH | OH | H | OH | OH | H | H |
Compound | R1 | R2 | R3 | R4R5 | R6 | R7 | R8R9 | R10 | R11 | R12R13 | R14 |
18(Lamellarin I) | OMe | OMe | OMe | H | OMe | OH | H | OMe | OMe | H | H |
19(Lamellarin I-acetate) | OMe | OMe | OMe | H | OMe | OAc | H | OMe | OMe | H | H |
20(Lamellarin J) | H | OH | OMe | H | OMe | OH | H | OMe | OMe | H | H |
21(Lamellarin K) | OH | OMe | OMe | H | OMe | OH | H | OMe | OH | H | H |
22(Lamellarin K-triacetate) | OAc | OMe | OMe | H | OMe | OAc | H | OMe | OAc | H | H |
23(Lamellarin L) | H | OH | OMe | H | OMe | OH | H | OH | OMe | H | H |
24 (Lamellarin L-triacetate) | H | OAc | OMe | H | OMe | OAc | H | OAc | OMe | H | H |
25(Lamellarin S) | H | OH | OMe | H | OH | OH | H | OH | OH | H | H |
26(Lamellarin T) | OMe | OMe | OMe | H | OMe | OH | H | OH | OMe | H | H |
Compound | R1 | R2 | R3 | R4R5 | R6 | R7 | R8R9 | R10 | R11 | R12R13 | R14 |
27(LamellarinT20-sulfate) | OMe | OMe | OMe | H | OMe | OSO3Na | H | OMe | OH | H | H |
28 | H | OMe | OMe | H | H | H | H | H | H | H | H |
29(Lamellarin U) | H | OMe | OMe | H | OMe | OH | H | OH | OMe | H | H |
30(LamellarinU20-sulfate) | H | OMe | OMe | H | OMe | OSO3Na | H | OH | OMe | H | H |
31(Lamellarin V) | OMe | OMe | OMe | H | OMe | OH | H | OH | OMe | H | OH |
32 (LamellarinV20-sulfate) | OMe | OMe | OMe | H | OMe | OSO3Na | H | OH | OMe | H | OH |
33(LamellarinY20-sulfate) | H | OMe | OH | H | OMe | OSO3Na | H | OH | OMe | H | H |
34 | H | OMe | OMe | H | OMe | OiPr | H | OMe | OiPr | H | H |
35 | H | OMe | OMe | H | OMe | OH | H | OMe | OH | H | H |
Compound | R1 | R2 | R3 | R4R5 | R6 | R7 | R8R9 | R10 | R11 | R12R13 | R14 |
36 | OiPr | OMe | OMe | H | OMe | OiPr | H | OMe | OiPr | H | H |
37 | OMe | OMe | OMe | H | OMe | OiPr | H | OiPr | OMe | H | H |
38 | H | OMe | OMe | H | OMe | OiPr | H | OiPr | OMe | H | H |
39(Lamellarin Tdiacetate) | OMe | OMe | OMe | H | OMe | OAc | H | OAc | OMe | H | H |
本发明现在参考下列实施例进行说明。但是,应该理解,这些与前面说明书的一般说明不矛盾。下文中“broad”或“broadened”表示“宽”或“变宽”的,“lit”表示文献值。“Found”为实测值,“requires”为理论值,“Mass Spectrum”为质谱。
实施例
实施例12-(三氯乙酰基)吡咯
根据Bailey等,Org.Synth.,1971,100的方法,从吡咯(12.5g,186mmol)和三氯乙酰氯(36.5g,200mmol)制备2-(三氯乙酰基)吡咯。在此方法中,以膏状固体形式得到标题化合物,m.p.73-74℃(lit.m.p.73-75℃).1H n.m.r.d9.30,broad s,1H;7.39,m,1H;7.17,m,1H;6.40,dt,J3.9and2.4Hz,1H.(参见J.Org.Chem.,1972,37,3618;1993,58,7245).4-碘-2-(三氯乙酰基)吡咯
根据Belanger,Tetrahedron Lett.,1979,2505的方法,从2-(三氯乙酰基)吡咯制备标题化合物。在磁力搅拌下,将碘(12.0g,47.2mmol)用0.17小时分批(每批约1g)加入三氟乙酸银(11.0g,49.8mmol)和2-(三氯乙酰基)吡咯(10.0g,47.1mmol)在干燥氯仿(70ml)中的混合物,保持0℃(冰浴)。加完后,使反应混合物温热至18℃,并在此温度下再搅拌2小时。用烧结的玻璃漏斗(No.3孔隙率)过滤产生的悬浮液,滤液用Na2S2O5(1×80ml 5%w/v水溶液)和水(2×80ml)洗涤,然后干燥(硫酸镁),过滤并减压浓缩。所得的固体残余物用己烷/乙醚(50ml 4∶1v/v混合物)处理,产生的悬浮液在18℃搅拌5小时,然后滤出固体,给出标题化合物(13.1g,82%)膏状固体,
m.p.129-130℃(lit.m.p.128-130℃).1H n.m.r.d 9.45,broad s,1H;7.44,dd,J2.6and1.3Hz,1H;7.19,dd,J 2.6and1.3Hz,1H.4-碘吡咯-2-羧酸
将碳酸钾(100ml 2M水溶液)加入4-碘-2-(三氯乙酰基)吡咯(8.5g,2.5mmol)的DMSO(30ml)溶液中,产生的混合物在18℃搅拌3小时,然后用水(200ml)稀释。所得的溶液用乙酸乙酯(2×100ml)洗涤,然后通过滴加盐酸(2M水溶液)酸化至pH3。产生的浆状物用乙酸乙酯(3×100ml)萃取,将合并的有机部分干燥(硫酸镁),过滤并减压浓缩,给出标题化合物(8)(5.51g,92%)白色固体,m.p.200℃(实测:M+-,236.9285.C5H4INO2计算值M+-,236.9287)
nmax(KBr)3287,3129,3035,1703,1544,1430,1300,1212,1122cm-1.1H n.m.r.[300 MHz,3∶1(CD3)2SO/CDCl3]d 11.98,broad s,1H;6.98,t,J1.5Hz,1H;6.76,宽s,1H(未观察到N-H的共振).13C n.m.r.[75.5MHz,3∶1(CD3)2SO/CDCl3]d 159.0(C),126.0(CH),123.3(C),118.8(CH),59.0(C).Mass spectrumm/z 237(100%)(M+-);219(87)[(M-H2O)+-].4-碘吡咯-2-羧酸2-溴苯基酯
在磁力搅拌下,将草酰氯(203ml,2.32mmol)加入4-碘吡咯-2-羧酸(8)(500mg,2.11mmol)在含有DMF(1滴)的干燥二氯甲烷(15.0ml)中的悬浮液。产生的溶液在18℃搅拌2小时后,将其在磁力搅拌下加入o-溴苯酚(363mg,2.11mmol),三乙胺(660ml,4.73mmol)和4-(N,N-二甲基氨基)吡啶(DMAP,几粒晶体)在二氯甲烷(10ml)中的溶液。1小时后,反应混合物浓缩到硅胶(5g)上,将残余物进行快速层析(硅胶,3∶1己烷/乙醚洗脱)。将适当的级分(Rf 0.2)浓缩,给出标题化合物(761mg,92%)白色晶状固体,m.p.126-127℃
(Found:C,33.9;H,1.7;Br,20.4;I,32.4;N,4.0.C11H7BrINO2 requires C,33.7;H,1.8;Br,20.4;I,32.4;N,3.6%).nmax(KBr)3383,2969,1709,1580,1541,1472,1444,1377,1312,1218,1169,1133,1043 cm-1.1H n.m.r.d 9.57,broad s,1H;7.65,dd,J8.1and1.5Hz,1H;7.37,td,J8.1and1.5Hz,1H;7.27,m,2H;7.18,td,J8.1and1.5Hz,1H;7.08,m,1H.13C n.m.r.d 158.0(C),148.3(C),134.0(CH),129.8(CH),129.1(CH),128.1(CH),124.4(CH),124.3(CH),123.6(C),116.9(C),62.9(C).Mass spectrum m/z 393(24%)391(22)(M+-);220(100)[(M-C6H4BrO)+-].4-甲苯磺酸2-(2-溴苯基)乙基酯(13)
在磁力搅拌下,将2-溴苯乙醇(5.00g,24.9mmol,ex ALDRICH)和4-甲苯磺酰氯(11.20g,59.7mmol)的乙醚(50ml)溶液冷却至0℃(冰浴),然后用粉末状氢氧化钾(3.2g,2.4摩尔当量)处理。所得的反应混合物被温热至18℃,在此温度下搅拌2.0小时,然后用水(100ml)稀释。分出的有机相用水(1×100ml)洗涤,然后干燥(硫酸镁),过滤并减压浓缩,给出白色固体。因为该物质含有残余的4-甲苯磺酰氯,所以将其溶于吡啶(75ml),产生的溶液在18℃搅拌0.16小时,然后用水(500ml)稀释,并用乙醚(1×500ml)萃取。分出的有机相用盐酸(1×250ml 5M水溶液)洗涤,然后用碳酸氢钠(1×250ml 0.5M水溶液)洗涤,然后干燥(硫酸镁),过滤并减压浓缩,给出标题化合物(8.66g,98%)白色晶状物质,m.p.39-39.5℃
(Found:C,50.9;H,4.2;Br,22.6;S,8.8.C15H15BrO3S requires C,50.7;H,4.3;Br,22.5;S,9.0%).nmax(KBr)1356,1177,1021,980,962,895,812,769,752,665,557cm-1.1H n.m.r.d7.68,d,J8.3Hz,2H;7.45,d,J7.7Hz,1H;7.27,d,J8.3Hz,2H;7.17,m,2H;7.07,m,1H;4.25,t,J7.0Hz,2H;3.09,t,J7.0Hz,2H;2.43,s,3H.13C n.m.r.d144.5(C),135.3(C),132.7(CH),132.8(C),131.3(CH),129.7(CH),128.5(CH),127.6(CH),127.4(CH),124.2(C),68.6(CH2),35.5(CH2),21.5(CH3).Mass spectrum m/z 356(0.7%)354(0.7)(M+-);184(98)182(100)[M-H3CC6H4SO3H)+-];171(49)169(51);155(45);103(32);91(80)(C7H7+).1-[2’-(2”-溴苯基)乙基]-4-碘吡咯-2-羧酸2-溴苯基酯
将化合物(13)(700mg,1.97mmol),氯化四乙基铵(30mg,0.18mmol)和碳酸钾(278mg,2.0mmol)加入化合物(11)(700mg,1.79mmol)在干燥的DMF(30ml)中的溶液,产生的浆状物在80℃搅拌2小时。冷却过的反应混合物用乙酸乙酯(150ml)稀释,并用水(3×150ml)洗涤。然后将分出的有机相干燥(硫酸镁),过滤并减压浓缩。所得的固体残余物进行快速层析(硅胶,4∶1己烷/乙醚洗脱),浓缩所需的级分(Rf 0.5,3∶1己烷/乙醚洗脱)给出标题化合物(14)(920mg,89%)白色晶状固体,m.p.122-123℃
(Found:C,39.5;H,2.1;Br,27.6;I,22.1;N,2.3.C19H14Br2INO2 requires C,39.7;H,2.5;Br,27.8;I,22.1;N,2.4%).nmax(KBr)2949,1716,1517,1468,1438,1411,1374,1326,1232,1216,1191,1055,1028 cm-1.1H n.m.r.d 7.65,dd,J7.8and1.8Hz,1H;7.55,dd,J7.8and1.8Hz,1H;7.37,m,2H;7.28-7.04,m,5H;6.70,d,J2.1Hz,1H;4.55,t,J7.5Hz,2H;3.20,t,J7.5Hz,2H.13C n.m.r.d 157.0(C),147.8(C),136.9(C),134.5(CH),133.3(CH),132.7(CH),131.2(CH),128.6(CH),128.4(CH),127.6(CH),127.3(CH),126.7(CH),124.4(C),124.0(CH),122.0(C),116.6(C),59.6(C),49.0(CH2),38.0(CH2).Mass spectrumm/z 577(1%)575(2)573(1)(M+-);496(10)494(11)[(M-Br-)+];404(98)402(100)[(M-C6H4BrO-)+].1-[2’-(2”-溴苯基)乙基]-4苯基吡咯-2-羧酸2-溴苯基酯(4)
在磁力搅拌下,2分钟内将苯基氯化锌[通过将无水氯化锌(540mg,3.96mmol)加入苯基锂(2.0ml 1.8M的环己烷/乙醚溶液,3.6mmol)的THF(4.0ml)溶液而制备]滴加到化合物(14)(1.75g,3.04mmol)和Pd(PPh3)2Cl2(106mg,0.152mmol)的DMF(15ml)溶液中。在18℃继续搅拌1小时,然后将反应混合物转移到分液漏斗中,用乙酸乙酯(100ml)稀释,并用氯化铵(100ml饱和水溶液)洗涤,然后用水(2×100ml)洗涤。将分出的有机相干燥(硫酸镁),过滤并减压浓缩,给出浅黄色油状物,将其进行快速层析(硅胶,2∶1己烷/二氯甲烷洗脱)。浓缩所需的级分(Rf 0.5)给出标题化合物(1.52g,95%)微晶固体,m.p.90-92℃
(Found:C,57.1;H,3.4;Br,30.7;N,2.5.C25H19Br2NO2 requires C,57.2;H,3.7;Br,30.4;N,2.7%).nmax(KBr)2958,2930,1718,1603,1580,1562,1472,1397,1215,1196,1066,1024 cm-1.1H n.m.r.d 7.70,dd,J8.0and1.5Hz,1H;7.60-7.00,m,14H;4.63,t,J6.9Hz,2H;3.32,t,J6.9Hz,2H.13C n.m.r.(75.5MHz,CDCl3)d 158.4(C),148.3(C),137.5(C),134.2(C),133.5(CH),132.9(C),131.5(CH),128.9(CH),128.6(3)(CH),128.6(1)(CH),127.8(CH),127.4(CH),127.3(CH),126.5(CH),125.4(CH),124.8(C),124.6(C),124.4(CH),120.9(C),117.5(CH),116.9(C),49.3(CH2),38.2(CH2).Mass spectrum m/z527(3%)525(6)523(3)(M+-);446(12)444(11)[(M-Br)+;354(100)352(96)[(M-C6H4BrO-)+].14-苯基-8,9-二氢-6H-[1]苯并吡喃并[4’,3’:4,5]吡咯并[2,1-a]异喹啉-6-酮
在磁力搅拌下,将Pd(OAc)2(32mg,0.143mmol)加入在Schlenk管中的化合物(4)(148mg,0.282mmol),NaOAc(92.7mg,1.13mmol)和PPh3(74.0mg,0.282mmol)的DMF(2ml)溶液中。产生的混合物被抽真空(1.0mmHg),并用N2(气体)回充3次(除去溶解的氧),然后在氮气氛中于135℃加热6小时。冷却的反应混合物用乙醚(25ml)稀释,并用食盐水(2×20ml)洗涤,然后用水(20ml)洗涤,干燥(硫酸镁),过滤并浓缩到硅胶(2g)上。残余物进行快速层析(硅胶,1∶2,1∶1,然后2∶1二氯甲烷/己烷洗脱),减压浓缩所需的级分(Rf 0.3,2∶1二氯甲烷/己烷洗脱)给出标题化合物(16mg,16%)乳白色微晶,
m.p.259-260℃(Found:M+-,363.1257.C25H17NO2 requires M+-,363.1259).nmax(KBr)2925,2853,1708,1449,1420,1396,1339,1281,1241,1198,1151,1133,1106,1085,1047 cm-1.1H n.m.r.d 7.58-7.55,m,2H;7.51-7.50,m,2H;7.40,dd,J7.5and0.9Hz,1H;7.32-7.18,m,4H;7.10,dd,J7.8and1.2Hz,1H;7.01-6.97,m,3H;4.88,t,J6.9Hz,2H;3.21,t,J6.9Hz,2H.13C n.m.r.d 155.3(C),151.2(C),135.6(C),135.3(C),133.8(C),130.7(CH),129.4(CH),128.3(CH),128.1(CH),127.5(C),127.4(CH),126.9(CH),125.7(CH),123.7(CH),123.3(CH),118.2(C),117.5(C),117.1(CH),42.3(CH2),29.3(CH2)(模糊或重叠的三个峰)、Mass spectrum m/z 363(100%)(M+-).5,6-二氢-1-苯基吡咯并[2,1-a]异喹啉-3-羧酸2’-溴苯基酯(16)和溴{2’-(5”,6”-二氢-1”-苯基吡咯并[2”,1”-a]异喹啉-3”-羧基)苯基}双(三苯膦)合钯(17)
将Pd(OAc)2(197mg,0.88mmol)加入化合物(4)(230mg,0.438mmol),NaOAc(80mg,0.975mmol)和PPh3(460mg,1.75mmol)的DMF(20ml)溶液中。产生的溶液被抽真空(1.0mmHg),并用N2(气体)回充3次以除去溶解的氧,然后在氮气氛中于110℃加热19小时。冷却的反应混合物用乙醚(25ml)稀释,并用食盐水(2×20ml)洗涤,然后用水(1×20ml)洗涤。分出的有机相被干燥(硫酸镁),过滤并减压浓缩到硅胶(2g)上。残余物进行快速层析(硅胶,1∶2然后1∶1二氯甲烷/己烷,接着4∶1二氯甲烷/乙酸乙酯洗脱),给出级分A和B。
浓缩级分A(Rf 0.6,2∶1二氯甲烷/己烷洗脱)给出化合物(16)(34mg,17%)米色晶状物质,m.p.130-131℃(Found:M+-,443.0529.C25H1879BrNO2 requires M+-,443.0521).nmax(KBr)2950,1710,1471,1439,1418,1240,1212,1176,1046cm-1.1H n.m.r.d 7.57,dd,J8.1and1.5Hz,1H;7.45-7.05,m,12H;6.95,br t,J8.1Hz,1H;4.57,t,J6.3Hz,2H;3.05,t,J6.3Hz,2H.13C n.m.r.d 158.5(C),148.1(C),136.1(C),133.4(C),133.3(CH),132.9(C),129.1(CH),128.6(C),128.4(CH),128.1(C),127.9(CH),127.7(CH),127.1(CH),126.9(CH),126.7(CH),125.5(CH),124.2(CH),123.5(C),121.3(CH),119.4(C),116.7(C),42.4(CH2),29.5(CH2).Mass spectrumm/z 445(10%)443(9)(M+-);272(100)[(M-C6H4BrO-)+].
浓缩级分B(Rf 0.1,2∶1二氯甲烷洗脱)给出化合物(17)(40mg,8.5%)米色晶状物质,m.p.159-162℃.nmax(KBr)3052,2923,1705,1481,1435,1416,1238,1172,1095,1058,1024cm-1.1H n.m.r.d 7.65-7.40,m,18H;7.30-7.05,m,22H;6.58,m,1H;6.52,t,J6.6Hz,1H;6.39,m,1H;6.07,q,J6.6Hz,1H;4.73,m,2H;3.05,m,2H.13C n.m.r.d 159.2(C),151.8(C),138.3(CH),136.5(C),134.8(CH),133.2(C),131.8(C),131.5(C),131.0(C),129.9(CH),129.8(CH),129.5(CH),129.0(CH),128.7(C),127.8(CH),127.5(CH),127.2(CH),127.0(CH),125.7(CH),125.0(CH),123.2(C),123.0(CH),121.9(CH),121.1(C),120.5(CH),42.2(CH2),29.7(CH2).Mass spectrum m/z 365(6)[(M-Pd(PPh3)2Br+H)+-];277(26);272(32){[M-C6H4OPd(PPh3)2Br]+};262(100)(Ph3P+-).1-苯基吡咯并[2,1-a]异喹啉(18)和1-[2’-(2”-溴苯基)乙基]-4-苯基吡咯(19)
将二溴化物(4)(13mg,25mmol),反式-二(m-乙酰基)-双[o-(二-o-甲苯基膦基)苄基]二钯(II)(Chem.,Eur.,J.,1997,3,1357,)(2.5mg,2.5mmol)和无水醋酸钠(6.2mg,75mmol)在脱气的N,N-二甲基乙酰胺(0.25ml)中的溶液在氮气氛中于140℃加热72小时。然后将冷却的反应混合物用乙醚(5ml)稀释,产生的溶液用食盐水/水(3×5ml的1∶1v/v混合物)洗涤。然后将有机相干燥(硫酸镁),过滤并减压浓缩,给出浅黄色油状物。使该物质进行快速层析(硅胶,3∶7然后7∶3二氯甲烷/己烷洗脱),将所需的级分(Rf0.7,3∶7二氯甲烷/己烷洗脱)后,给出化合物(18)和(19)的1∶3混合物(4mg,52%合并的产率)浅黄色不稳定的油状物。 nmax(KBr)1705,41.2,1555,1500,1471,1441,1359,1202,1071,1027,751,694,655cm-1.1H n.m.r.d[compound(18)]7.60-6.95,complex m,9H;6.92,t,J2.0Hz,1H,H-2;6.63,t,J1.6Hz,1H,H-5;6.43,broadened t,J2.3Hz,1H,H-4;4.14,t,J7.7Hz,2H;3.22,t,J7.7Hz,2H;[compound(19)] 7.60-6.95,complex m,9H;6.73,d,J2.7Hz,1H,H-3;6.23,d,J2.7Hz,1H,H-2;4.08,t,J7.7Hz,2H;3.10,t,J7.7Hz,2H.G.c./m.s.[compound(18)]Rf 4.52 min.)245(100)(M+-),167(21),149(28),120(6);[compound(19)](Rf 5.85 min.)327(12)325(12)(M+-),246(100)[(M-Br-)+].
在整个说明书和权利要求书中,除非上下文需要,“包括”一词,和其变化形式如“包含”,将被理解为用于包括所述的整体或步骤或整体的一组,但不排除然后其他整体或步骤或整体的一组。
本专业技术人员应该理解,本文所述的本发明除了特别描述的部分外,容易被改变和改进。应该理解本发明包括所有的这类改变和改进。本发明也包括在本说明书中单独或累积给出的所有的步骤,特征,组合物和化合物,以及任意两个或多个所说的步骤或特征和组合。
Claims (32)
其中RA1-A4各自独立地选自氢,非强制性取代的烷基,非强制性取代的烯基,非强制性取代的炔基,非强制性保护的羟基,非强制性取代的氨基,非强制性取代的烷氧基,非强制性取代的烯氧基,非强制性取代的炔氧基,非强制性取代的芳基,非强制性取代的杂环基,羧基,羧酯基,酰胺基,酰基,酰氧基,巯基,非强制性取代的烷硫基,卤素,硝基,硫酸根,磷酸根和氰基;
或RA2和RA3一起非强制性地形成一根键,而RA1和RA4如上定义或与其所连接的碳原子一起形成非强制性取代的碳环或杂环基;或
RA2和RA3非强制性地与其所连接的碳原子一起形成非强制性取代的饱和或不饱和碳环或杂环基;或
RA1RA2C-CRA3RA4形成非强制性取代的芳基或芳香杂环基;
Y选自氢,非强制性取代的烷基,非强制性取代的烯基,非强制性取代的炔基,非强制性保护的羟基,非强制性取代的氨基,非强制性取代的烷氧基,非强制性取代的烯氧基,非强制性取代的炔氧基,非强制性取代的芳基,非强制性取代的杂环基,羧基,羧酯基,酰胺基,酰基,酰氧基,巯基,非强制性取代的烷硫基,卤素,硝基,硫酸根,磷酸根和氰基;
W和X如Y的定义,或者与其所连接的氮和碳原子一起形成饱和或不饱和的含氮杂环基,该杂环基可以非强制性地被取代,或非强制性地与饱和或不饱和的碳环基,芳基或杂环基稠合;
V表示卤素或氢原子;
Z是-(CH2)n-U-(CH2)o-其中U选自CH2,NH或杂原子,n和o独立地选自0,1,2或3。
2.根据权利要求1的方法,其中W和X与它们所连接的氮和碳原子一起形成饱和或不饱和含氮杂环基,该杂环基可以非强制性地被取代或非强制性地与饱和或不饱和碳环基,芳基或杂环基稠合。
3.根据权利要求2的方法,其中W和X与它们所连接的氮和碳原子一起形成选自非强制性取代的喹啉基,非强制性取代的异喹啉基,非强制性取代的二氢喹啉基,非强制性取代的二氢异喹啉基,非强制性取代的吡啶基或其二氢或四氢同系物,或非强制性取代的菲啶。
4.根据权利要求3的方法,其中W和X与它们所连接的氮和碳原子一起形成式(i)的非强制性取代的异喹啉基或非强制性取代的二氢异喹啉基:其中R1-R4和R14如权利要求1对Y的定义,而
表示单键或双键。
5.根据权利要求4的方法,其中R1-R4独立地选自氢;羟基;非强制性取代的烷基;非强制性取代的烷氧基;酰氧基;羧基;羧基酯;非强制性取代的氨基;酰胺基;或硫酸根;而R14是氢或羟基。
其中:
RA1-A4,V,Y,Z如权利要求1定义;
RB1-B4各自独立地选自氢,非强制性取代的烷基,非强制性取代的烯基,非强制性取代的炔基,非强制性保护的羟基,非强制性取代的氨基,非强制性取代的烷氧基,非强制性取代的烯氧基,非强制性取代的炔氧基,非强制性取代的芳基,非强制性取代的杂环基,羧基,羧基酯,酰胺基,酰基,酰氧基,巯基,非强制性取代的烷硫基,卤素,硝基,硫酸根,磷酸根和氰基;或
RB2和RB3一起非强制性地形成一根键,而RA1和RA4如上定义或与其所连接的碳原子一起形成非强制性取代的碳环或杂环基;或
RB2和RB3与其所连接的碳原子一起形成非强制性取代的饱和或不饱和碳环或杂环基;或
RB1RB2C-CRB3RB4形成非强制性取代的芳基或芳香杂环基;而
m选自1,2,3或4。
7.根据权利要求6的方法,其中m是1或2,优选2。
8.根据权利要求1或权利要求6的方法,其中RA1RA2C-CRA3RA4形成芳基或芳香杂环基,所说的基团选自:非强制性取代的苯或萘环,或非强制性取代的吡啶,非强制性取代的呋喃,非强制性取代的吡咯或非强制性取代的噻吩和其苯-稠合的类似物。
9.根据权利要求8的方法,其中RA1RA2C-CRA3RA4形成非强制性取代的苯基。
10.根据权利要求9的方法,其中取代基选自:氢;羟基;非强制性取代的烷基;非强制性取代的烷氧基;酰氧基;羧基;羧基酯;非强制性取代的氨基;酰胺基;或硫酸根。
11.根据权利要求1或6的方法,其中Y是式(ii)的非强制性取代的苯基:
其中R9-R13如权利要求4中对R1-R4定义。
12.根据权利要求11的方法,其中R9-R13独立地选自氢;羟基;非强制性取代的烷基;非强制性取代的烷氧基;酰氧基;羧基;羧基酯;非强制性取代的氨基;酰胺基;或硫酸根。
13.根据权利要求10的方法,其中R9-R13独立地选自氢,羟基,甲氧基,乙氧基,异丙氧基,甲基,乙基,正丙基,异丙基,乙酰氧基或硫酸根。
15.根据权利要求14的方法,其中R1-14独立地选自:氢;羟基;非强制性取代的烷基;非强制性取代的烷氧基;酰氧基;羧基;羧基酯;非强制性取代的氨基;酰胺基;或硫酸根,优选地,R1-13选自氢;羟基;非强制性取代的烷基,如甲基,乙基或丙基;非强制性取代的烷氧基如甲氧基,乙氧基,正丙氧基,异丙氧基;酰氧基如乙酰氧基;或硫酸根,而R14优选地是氢或羟基,V是溴,碘或氢。
16.根据权利要求1或6的方法,其中U如在Z中定义,选自CH2,NH或氧,优选氧,而n+o=0,1,2,3或4,优选0。
17.根据权利要求1或6或14的方法,其中各个V独立地是氢,溴或碘。
18.根据权利要求1的方法,其中V是氢,而环化在氧化条件下进行。
19.根据权利要求1的方法,其中V是卤原子,优选溴或碘,而环化经式(I)基团的产生而进行。
20.根据权利要求1的方法,其中V是卤原子,优选溴或碘,而环化经Pd[O]-催化的方法而进行。
21.根据权利要求6或14的方法,其中两个V都是卤素,优选溴或碘,而两次环化在一锅内进行。
22.根据权利要求21的方法,其中一锅双环化是Pd[O]-催化的。
其中:
RA1-A4各自独立地选自氢,非强制性取代的烷基,非强制性取代的烯基,非强制性取代的炔基,非强制性保护的羟基,非强制性取代的氨基,非强制性取代的烷氧基,非强制性取代的烯氧基,非强制性取代的炔氧基,非强制性取代的芳基,非强制性取代的杂环基,羧基,羧基酯,酰胺基,酰基,酰氧基,巯基,非强制性取代的烷硫基,卤素,硝基,硫酸根,磷酸根和氰基;或
RA2和RA3一起非强制性地形成一根键,而RA1和RA4如上定义或与其所连接的碳原子一起形成非强制性取代的碳环或杂环基;或
RA2和RA3非强制性地与其所连接的碳原子一起形成非强制性取代的饱和或不饱和碳环或杂环基;或
RA1RA2C-CRA3RA4形成非强制性取代的芳基或芳香杂环基;
Y选自氢,非强制性取代的烷基,非强制性取代的烯基,非强制性取代的炔基,非强制性保护的羟基,非强制性取代的氨基,非强制性取代的烷氧基,非强制性取代的烯氧基,非强制性取代的炔氧基,非强制性取代的芳基,非强制性取代的杂环基,羧基,羧基酯,酰胺基,酰基,酰氧基,巯基,非强制性取代的烷硫基,卤素,硝基,硫酸根,磷酸根和氰基;
W和X如Y的定义,或者与其所连接的氮和碳原子一起形成饱和或不饱和的含氮杂环基,该杂环基可以非强制性地被取代,或非强制性地与饱和或不饱和的碳环基,芳基或杂环基稠合;
V表示卤素或氢原子;
Z是-(CH2)n-U-(CH2)o-其中U选自CH2,NH或杂原子,n和o独立地选自0,1,2或3。
24.根据权利要求23的化合物,其中W和X如权利要求2至5任意一项中定义。
26.根据权利要求23或25的化合物,其中RA1RA2C-CRA3RA4形成非强制性取代的苯基。
27.式(Ib)化合物:
其中R1-14独立地选自氢,非强制性取代的烷基,非强制性取代的烯基,非强制性取代的炔基,非强制性保护的羟基,非强制性取代的氨基,非强制性取代的烷氧基,非强制性取代的烯氧基,非强制性取代的炔氧基,非强制性取代的芳基,非强制性取代的杂环基,羧基,羧基酯,酰胺基,酰基,酰氧基,巯基,非强制性取代的烷硫基,卤素,硝基,硫酸根,磷酸根和氰基;和
V是卤素或氢。
28.根据权利要求27的化合物,其中R1-14独立地选自:氢;羟基;非强制性取代的烷基;非强制性取代的烷氧基;酰氧基;羧基;羧基酯;非强制性取代的氨基;酰胺基;或硫酸根,优选地R1-13独立地选自氢;羟基;非强制性取代的烷基,如甲基,乙基或丙基;非强制性取代的烷氧基如甲氧基,乙氧基,正丙氧基,异丙氧基;酰氧基如乙酰氧基;或硫酸根,而R14优选地是氢或羟基;V是溴,碘或氢。
29.治疗多药物耐受的肿瘤的方法,包括对需要的动物,包括人施用治疗有效量的如本文所述的方法制备的,根据权利要求1,6或14任意一项的式(II),(IIa)或(IIb)化合物。
30.如本文所述的方法制备的,根据权利要求1,6或14任意一项的式(II),(IIa)或(IIb)化合物在生产用于治疗多药物耐受的肿瘤的药物中的用途。
31.一种治疗多药物耐受肿瘤的药剂,包含如本文所述的方法制备的,根据权利要求1,6或14任意一项的式(II),(IIa)或(IIb)化合物。
32.治疗多药物耐受肿瘤的组合物,包括如本文所述的方法制备的,根据权利要求1,6或14任意一项的式(II),(IIa)或(IIb)化合物,以及药用载体,稀释剂或赋形剂。
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AU (1) | AUPP433398A0 (zh) |
BR (1) | BR9911559A (zh) |
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CN108059634A (zh) * | 2016-11-08 | 2018-05-22 | 华中师范大学 | 片螺素类化合物及其中间体的制备方法 |
CN112225745A (zh) * | 2020-11-16 | 2021-01-15 | 烟台大学 | 一种具有抗肿瘤活性的异片螺素类化合物、制备方法及用途 |
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US20060151335A1 (en) * | 2005-01-07 | 2006-07-13 | Combimatrix Corporation | Process for performing an isolated Pd(0) catalyzed reaction electrochemically on an electrode array device |
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PE20120003A1 (es) * | 2009-01-30 | 2012-02-12 | Glaxosmithkline Llc | Hidrocloruro de n-{(1s)-2-amino-1-[(3-fluorofenil)metil)etil}-5-cloro-4-(4-cloro-1-metil-1h-pirazol-5-il)-2-tiofenocarboxamida cristalino |
KR20120117905A (ko) | 2010-01-28 | 2012-10-24 | 프레지던트 앤드 펠로우즈 오브 하바드 칼리지 | 프로테아좀 활성을 향상시키는 조성물 및 방법 |
CN103635230B (zh) | 2011-05-12 | 2017-10-31 | 普罗蒂斯特斯治疗公司 | 蛋白内稳态调节剂 |
WO2014116228A1 (en) | 2013-01-25 | 2014-07-31 | President And Fellows Of Harvard College | Usp14 inhibitors for treating or preventing viral infections |
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CN110483510A (zh) * | 2019-09-05 | 2019-11-22 | 南京信息工程大学 | 一种片螺素类衍生物的制备方法 |
CN112300232B (zh) * | 2020-11-03 | 2021-11-09 | 浙江大学 | Lamellarin D糖基化衍生物及其制备和应用 |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN108059634A (zh) * | 2016-11-08 | 2018-05-22 | 华中师范大学 | 片螺素类化合物及其中间体的制备方法 |
CN108059634B (zh) * | 2016-11-08 | 2019-05-07 | 华中师范大学 | 片螺素类化合物及其中间体的制备方法 |
CN112225745A (zh) * | 2020-11-16 | 2021-01-15 | 烟台大学 | 一种具有抗肿瘤活性的异片螺素类化合物、制备方法及用途 |
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Publication number | Publication date |
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HUP0102784A3 (en) | 2003-03-28 |
JP2002518503A (ja) | 2002-06-25 |
EP1090008A4 (en) | 2003-01-02 |
NZ508652A (en) | 2003-09-26 |
HUP0102784A2 (hu) | 2001-11-28 |
RU2250209C2 (ru) | 2005-04-20 |
CA2334322A1 (en) | 1999-12-29 |
EP1090008A1 (en) | 2001-04-11 |
WO1999067250A1 (en) | 1999-12-29 |
KR100711996B1 (ko) | 2007-05-02 |
US6469171B1 (en) | 2002-10-22 |
KR20010053119A (ko) | 2001-06-25 |
BR9911559A (pt) | 2001-03-20 |
WO1999067250A8 (en) | 2001-06-14 |
CN1132836C (zh) | 2003-12-31 |
AUPP433398A0 (en) | 1998-07-16 |
PL345099A1 (en) | 2001-12-03 |
PL200164B1 (pl) | 2008-12-31 |
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