CN1094041A - 6,7-位修饰的红豆杉醇 - Google Patents
6,7-位修饰的红豆杉醇 Download PDFInfo
- Publication number
- CN1094041A CN1094041A CN93120068A CN93120068A CN1094041A CN 1094041 A CN1094041 A CN 1094041A CN 93120068 A CN93120068 A CN 93120068A CN 93120068 A CN93120068 A CN 93120068A CN 1094041 A CN1094041 A CN 1094041A
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- CN
- China
- Prior art keywords
- compound
- taxol
- group
- furyl
- hydroxyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229930012538 Paclitaxel Natural products 0.000 title claims description 34
- 229960001592 paclitaxel Drugs 0.000 title claims description 34
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- 150000001875 compounds Chemical class 0.000 claims abstract description 93
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- -1 acetoxyl group Chemical group 0.000 claims description 38
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 238000006356 dehydrogenation reaction Methods 0.000 claims description 9
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- 150000003839 salts Chemical class 0.000 claims description 8
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 7
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 6
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- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
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- 230000002829 reductive effect Effects 0.000 description 5
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- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 4
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- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 4
- CYGDSXFTXXFMNI-OTYYAQKOSA-N hydrofuramide Chemical compound C=1C=COC=1/C=N/C(C=1OC=CC=1)\N=C\C1=CC=CO1 CYGDSXFTXXFMNI-OTYYAQKOSA-N 0.000 description 4
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
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- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
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Abstract
本发明涉及式Ⅰ的红豆杉醇衍生物,其中,R1,
R2,Ra,Rb和Rc,R和R0的定义见说明书,和其药
物组合物以及用通式I的化合物治疗哺乳动物肿瘤
的方法。
Description
本发明给出的化合物具有抗肿瘤活性。
红豆杉醇(paclitaxel)首次从短叶红豆杉(红豆杉科)的树皮中分离出来,它具有如下的结构(标明了(C)2′-6-,7-和12-位)。
近来证实了它能治疗卵巢癌;对乳腺癌、结肠癌和肺癌也有显著的作用,见D.K.,and Donehower,R.C.Ann.Int.Med.,1989,111,P273。
在抗肿瘤药中,红豆杉醇的独特之处在于它能在其它不利的条件下促使微管蛋白组合成微管。此药与微管结合,稳定微管,防止其解聚,进而破坏了微管蛋白与微管之间的平衡,所以抑制了有丝分裂。红豆杉醇的作用机理、毒理、临床功效等有许多文章进行了综述,如由Rowinsky等著的文章中,关于红豆杉醇:A Novel Investigational Antimicrotubule Agent,J.Natl Caneer.Inst,82:pp1247-1259(1990)。
自从发现了红豆杉醇在癌症治疗方面有显著的疗效,为了寻找药理活性更好的化合物,许多实验室开始了设计红豆杉醇类似物的计划。例如,从中发现了通式如下的Taxotere
见,Biologically Active Taxol Analogues with Deleted A-Ring Side Chain Substititutents and Variable C-Z′Configurations,J.Med.Chem.34,pp1176-1184(1991);Relationships between the structure of Taxol Analogues and their Antimitotic Activity,J.Med.Chem.,34 pp992-998(1991)。
本发明涉及具有抗肿瘤活性的结构新颖的红豆杉醇类衍生物。
本发明给出了通式Ⅰ的红豆杉醇衍生物
其中R1为-CORz,其中的Rz为RO-或R;
R2为C1-6烷基,C2-6烯基,C2-6炔基,C3-6环烷基,或为通式是-W-Rx的基团,其中W为一键,C2-6链烯二基,或-(CH2)t-,
其中t为1到6;Rx为萘基,苯基或杂芳基,而且Rx还可被1-3个相同或不同的C1-6烷氧基、卤素或-CF3基团任意取代;
Ra为-OCOR,H,OH,-OR,-OSO2R,-OCONR0R,-O-CONHR,-OCOO(CH2)tR或-OCOOR;
Rb和Rc均为羟基,或者通过碳原子共同形成键而连结起来;且
R和R0独立是C1-6烷基、C2-6烯基、C3-6环烷基、C2-6炔基,或苯基,还可被1到3个相同或不同的C1-6烷基、C1-6烷氧基、卤素或-CF3基团任意取代。
本发明还给出药物组合物以及用通式Ⅰ的化合物治疗哺乳动物肿瘤的方法。
本发明给出了通式Ⅰ的红豆杉醇衍生物
其中R1为-CORz,Rz为RO-或R;
R2为C1-6烷基,C2-6烯基、C2-6炔基、C3-6环烷基、或者为通式是-W-Rx的基团,其中W可为键,C2-6链烯二基,或-(CH2)t,t为1-6;Rx为萘基、苯基、或杂芳基,而且Rx还可被1-3个相同或不同的C1-6烷基、C1-6烷氧基、卤素或-CF3基团任意取代。
Ra为-OCOR,H,OH,-OR,-OSO2R,-OCONR0R,-O-CONHR,-OCOO(CH2)tR或-OCOOR;
Rb和Rc均为羟基,或者通过碳原子共同形成键而连结起来;且
R和R0独立是C1-6烷基、C2-6烯基、C3-6环烷基、C2-6炔基,或苯基,还可被1到3个相同或不同的C1-6烷基、C1-6烷氧基、卤素或-CF3基团任意取代。
在本申请中,“C”符号后下标的数字表示每个特定基团所含碳原子的数目。例如,C1-6烷基指的是含有1到6个碳原子的直链或支链烷基,如甲基、乙基、正丙基、异丙基、正丁基、叔丁基、正戊基、正己基、3-甲基戊基及类似烷基;C2-6烯基指的是直链或支链烯基基团,如乙烯基,烯丙基,1-丙烯基,异丙烯基,1-丁烯基,2-丁烯基,3-丁烯基,甲代烯丙基,1,1-二甲基烯丙基,1-己烯基,2-己烯基或类似基团;C3-6环烷基指的是环丙基、环丁基、环戊基或环己烯;C3-6炔基指的是直链或支链的炔基,如乙炔基炔丙基(2-丙炔基),1-丙炔基,1-丁炔基,2-丁炔基,3-丁炔基,1-己炔基,4-甲基-2-戊炔基或类似基团;链烯二基指的是乙烯-1,2-二基(1,2-乙烯基),2-甲基-2-丁烯-1,4-二基,2-己烯-1,6-二基或类似基团;C1-6烷基氧基(烷氧基)指的是直链或支链的烷氧基,如甲氧基,乙氧基,正丙氧基,异丙氧基,正丁氧基,叔丁氧基,正戊氧基,正己氧基,或3-甲基戊氧基等等;杂芳基指的是至少含有氧、硫、氮中的一个杂原子的五员芳环,但至多含有一个硫、一个氧或4个氮原子;杂芳基还可为含有1-4个氮原子的六员芳香环;卤原子指的是氟、氯、溴、碘;杂芳基例子包括噻吩基、呋喃基、吡咯基、咪唑基、吡唑基、噻唑基、异噻唑基,噁唑基、异噁唑基、三唑基、噻三唑基、噁二唑基、四唑基、噻三唑基、噁三唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、三嗪基、四嗪基及类似基团。氮杂环丁酮为氮杂环丁烷-2-酮,在本申请中同一符号除非重新说明表示相同的含义。
通式Ⅰ的化合物可经多种方法进行合成。下面的合成方法,叙述和具体的实施例仅仅是为了说明的目的,而不解释为用任何方法的限制,如用任何其他方法合成本发明化合物的限制。在此公开的方法能够很容易地修改用来合成没有具体公开的通式Ⅰ的其它化合物。
在一种实施中,通式Ⅰa的化合物可经图Ⅰ的路线合成。在图中,通式Ⅱa的化合物与DAST反应,得到了通式Ⅲa的化合物,DAST反应可在多种溶剂中进行,如二氯甲烷,四氢呋喃(THF),乙醚,甲苯及其它混合溶剂,除了化合物Ⅲa外,通式Ⅳa和Ⅴa的化合物在DAST反应中可作为付产物得到。观察到当反应在四氢呋喃和乙醚的混合溶剂中进行时,得到了化合物Ⅲa,相对于化合物Ⅵa和Ⅴa来说有较高的收率。脱去化合物Ⅲa中的cbz,得到了通式Ⅰa的化合物。
在图Ⅱ的更普通的实施中,当通式Ⅰa的化合物与酯还原剂如四丁基氢硼化氨反应,C-13侧链被还原除去,得到了通式Ⅵa的化合物。以图Ⅳ中(a)步(见下)基本相同的方法,将通式Ⅵa的化合物与通式Ⅶ的氨杂环丁酮连结起来,得到通式Ⅷ的化合物,除去其羟基保护基R3,得到通式Ⅰ1的化合物。
象这里所用的,羟基保护基是用于阻止或保护羟基功能基的部分且它们对本技术领域人员来说是熟知的,上述的保护基最好是那些能通过不引起被保护分子明显破坏的方法除去的基团。这种易除去的羟基保护基例如包括氯乙酰基、甲氧基甲基、2,2,2-三氯乙氧基甲基,2,2,2-三氯乙氧基羰基、四氢吡喃基、四氢呋喃基、叔丁基、苄基、对硝基苄基、对甲氧基苄基、二苯基甲基、三C1-6烷基硅甲烷基,三苯基硅甲烷基,1-乙氧基乙基等。对于红豆杉醇及其衍生物的2′-羟基,优选的保护基有:1-乙氧基乙基,三乙基甲硅烷基,2,2,2-三氯乙氧基羰基和苄氧基羰基;更优选的基团是苄氧基羰基,其可容易地用催化氢解的方法除去。其它能应用的适宜的保护基见Theodora W.Greene and Peter,G.M.Wuts著《Protecting G roups in Organic Synthesis》第二版动第2章(1991,John Wiley &Sons),其公开说明书通过参考并入本文。
在另一种一般实施方案中,象按图Ⅰ(a)步的方法,通式Ⅱ的化合物能与DAST反应,得到图Ⅲ中通式Ⅲ的化合物。这里所用的,Rj为-OCOR,H,-OR,-OR3,-OSO2R,-OCONR0R,-O-CONHR,-OCOO(CH2)tR或-OCOOR。除去其羟基保护基R3,得到通式Ⅰ2的化合物。
通式Ⅱ表示的许多化合物在已有技术中是公知的或可用已知的方法(有或没有小的修改)容易地制得,例如,通式Ⅱ中Rj为H的化合物,可按1993.4.1公开PCT申请,WO 93/06093中的一般方法制得,此方法全部通过参考并入本文。
又如,通式Ⅱ的化合物可容易地由图Ⅳ的方法制备。在此图中的步骤a中,氮杂环丁酮Ⅶ与通式Ⅹ的一种化合物(浆果赤霉素Ⅲ的衍生物)反应,其中R4为羟基保护基,一般通式Ⅶ的氮杂环丁酮类化合物是已知的,它们及其前体的合成已有报道。如Halton的European Patent Application 0.400,971,A2,公开于1990.12.5;Holton的European Patent Application 0,534,709A1;0,534,708A1;and 0534,707A1,所有这三篇报道公开于1993,3,31;另外,Hotton在PCT申请,WO.93/06079公开于1993,4,1;Ojima等,Tefrahedron,48,No.34,pp6985-7012(1992);Journal of Organic Chemistny,56,pp1681-1683(1991);Tetrahedrrn Letters,33,No.39,pp5737-5740(1992);Brieva等,J.Org Chem,58,pp1068-1075;Palomo等,Tetrahedron Letters,31.No.44,pp6429-6432(1990);European Application552041,公开于1993,7,21,及我们美国专利申请No.092,170,于1993,7,14申请。所有十二篇公开说明全部通过参考并入本文。这些方法易被修改,用来合成Ⅶ范围内的其他的氮杂环丁酮类化合物,而且在此处或上述12篇参考文献或别入没有具体公开,对本领域技术人员是显而易见的。
European Patcnt Apptication 0,400,971,A2,0,534,709A1,0,534,708A1,ey 0,534,707A1;和Tetrahedron,48,No34,pp6985-7012(1992)和Tetrahedron Letters34,No.26,pp4149-4152(1993)也报道了由通式Ⅶ的氮杂环丁酮类化合物和浆果赤霉素Ⅲ衍生物的C13羟基或其金属烷氧化物反应得到(C)-13位上有不同侧链的红豆杉醇类似物,在图Ⅳ的(a)步中,成键前先将(C)13位C上的羟基转变为醇金属盐是有利的,上述的醇金属盐的金属阳离子最好选自Ⅰa或Ⅱa族金属。通式Ⅱ的化合物与强金属碱反应,得到需要的醇金属盐。如二异丙基酰胺锂,C1-6烷基锂,双(三甲基甲硅烷基)酰胺锂,苯基锂,氢化钠,氢化钾、氢化锂等类似的碱。例如,在惰性溶剂如四氢呋喃中,通式Ⅱ的化合物与正丁基锂反应,得到希望的醇锂盐。
通式Ⅹ的化合物或者是在先有技术中已知的,或者由已知的方法(有或没有改变)而容易制得。例如,Denis等1990年5月8日申请的U.S.Patent.No.4,924,011,报道于通式Ⅹ的化合物,其中R4为三乙基甲硅烷基,Rj为乙酰氧基。另外,在图Ⅴ中,通式Ⅸ的化合物与RL,RC(=O)L,R(CH2)tO(C=O)L,ROC(=O)L,LSO2R,LCONR0R,LCO2HR,O=C=N-R及其酸酐衍生物反应,其中L是典型的离去基如氯、溴、甲磺酰基、三氟甲基磺酰基及甲苯磺酰基,得到通式为Ⅹ1的化合物,此化合物在通式Ⅹ的范围内。此处Rm为-OR,-OCOR,-OSO2R,-OCONR0R,-OCONHR,-COCC(CH2)tR,或-OCOOR。在图Ⅴ的过程中,要求用碱引发脱去C10位羟基上的一个质子。步骤(a)中较有用的是强碱,如C1-6烷基锂。双(三甲基硅烷基)酰胺锂或其约1.1当量的类似碱,碱脱质子的反应最好在非质子溶剂中,如四氢呋喃,低温下,通常为-40℃至0℃的范围内,Denis等1990,5,8申请的U.S.Patent No.4,924,011说明了通式Ⅸ化合物的合成,其中R4为三乙基甲硅烷基,通式Ⅸ的化合物,其中R4不是三烷基甲硅烷基,或者是已知的,或者能很容易地由本技术领域熟练人员熟悉的方法合成得到。
图4说明了通式ⅩⅢ化合物与四氧化锇及4-甲基吗啡-N-氧化物(NMO)反应,接着脱去通式Ⅻ化合物中的羟基保护基,得到通式Ⅰ3的化合物。
图Ⅰ
图Ⅱ
图Ⅱ(续)
图Ⅲ
图Ⅳ
图Ⅴ
图Ⅵ
在本申请中列出的结构式想必最好地表示了本发明的化合物的结构,但是,在本发明范围内的一些化合物可以其它互变异构体的形式存在,其中氢原子转移到分子中的其它部位,结果导致了分子中原子之间化学键重排。应该知道,结构式表示它们可能存在的所有互变异构体。
下面讲到的具体实施例用以说明本发明中典型化合物的合成,不能理解成对本发明的范围限制。这些方法可加以改变,用来合成包括在本发明范围内而没有具体列出的化合物,而且,能用不同的方法,以稍微不同的方式产生同一化合物,对本技术领域熟练人员是显而易见的。
除非注明,所有的温度指的是摄氏温度(C),核磁共振谱特征用化学位移(δ)表示,以ppm为单位,四甲基硅烷为内标,在质子NMR谱数据中,不同位移时的相对面积,对应于分子中某一特定功能基的氢原子数目。复杂位移的特征用宽单峰(bs),宽双峰(bd),宽三峰(bt),宽四峰(bq),单峰(s),多重峰(m),双峰(d),四重峰(q),三重峰(t),双两峰(dd),双三峰(dt),双四峰(dq)表示;测定NMR所用的溶剂为DMSO-D6(全氟代二甲基亚砜),D2O(氘代水),CDCl3(氘代氯仿)及其它一些常用的氯代溶剂,红外(IR)图谱仅仅给出了那些具有鉴别官能团价值的吸收峰的波数(cm-1)。
Celite是Johns-Manville商品公司生产硅澡土注册商标。
此处的缩写是那些广泛应用的缩写,其中一些为:
MS:质谱,
HRMS:高分辨质谱,
DAST:二乙胺基三氟化硫,
AC:乙酰基;
PH:苯基;
Ar:芳基;
DCI:解吸化学电离
Y:产率;
V/V:体积/体积;
FAB:快速原子轰击;
NOBA:间-硝基苄醇;
min:分钟
h:小时
tBu:叔丁基
CbZ:苄氧基羰基
Bz:苯甲酰基
TES:三乙基甲硅烷基
实施例1
2′-O-(苄氧基羰基)红豆杉醇(Ⅱa)
室温搅拌下,向红豆杉醇(150mg,0.176mmol)与N,N-二异丙基乙酸(93μL,0.534mmol,3eq.)的4ml无水CH2Cl2混合液中加入氯甲酸苄酯(75μL,0.525mmol,3eq.),此反应液室温搅拌3h,浓缩至体积为2ml,产物过硅胶柱纯化,用1∶1的乙酸乙酯/己烷为洗脱剂,得到150mg(0.152mmol,收率:86%)化合物Ⅱa,为白色粉末,mp.140-150℃,(分解);〔d〕20D-53.5°(C=0.2,95%乙醇);
1H-NMR(300MHz,acetone-d6)δ ppm:1.18(3H,s,17-H3),1.92(3H,s,16-H3),1.66(3H,s,19-H3),1.96(3H,s,18-H3),2.16(3H,s,10-OAc),2.5(3H,s,4-OAc),3.53(1H,d,J=5.89Hz,7-OH,exchanged with D2O),3.85(1H,d,J=7.19Hz,3-H),3.9(1H,s,1-OH,exchanged with D2O),4.17(2H,ABq,20-H2),4.25(1H,m,7-H),4.97(1H,d;J=9.56Hz,5-H),5.19(2H,ABq,OCH2C6H5),5.54(1H,d,J=5.5Hz,2′-H),5.68(1H,d,J=7.13Hz,2-H),6.01(1H,dd,J=5.5,9.05Hz,3′-H),6.17(1H,bt,J=9.0Hz,13-H),6.42(1H,s,10-H),7.28-7.69(16H,m),7.87(2H,“d”,J=8Hz,3′-NHCOPh),8.14(2H,“d”,J=8Hz,2-CO2Ph),8.55(1H,d,J=9.06Hz,NH,exchanged with D2O);MS(FAB-NOBA/NaI+KI)m/e:988(M+H)+,1010(M+Na)+,1026(M+K)+;IR(KBr) ν max:3448,1748(C=O),1726(CONH),1250(C-O)cm-1;UV(MeOH∶H2O,1∶1) λ max:198(ε 7.3 x104),230nm(ε 2.7 x 104);HRMS calcd for C55H58NO16(MH+):988.3756,found:988.3766.
Anal.calcd for C55H57NO16·H2O:C,65.67;H,5.92;N,1.40.Found:C,65.99;H,5.64;N,1.33.
实施例2
2′-O-苄氧基羰基-6,7-脱氢红豆杉醇(Ⅲa)
2′-O-(苄氧基羰基)红豆杉醇(Ⅱa)(514mg,0.521mmol)溶于3ml四氢呋喃和6ml乙醚中。此溶液冷至-78℃,滴加DAST(0.134ml,1.040mmol)。反应液于-78℃下搅拌3h,然后放置室温过夜。反应完全后,减压浓缩,蒸除部分溶剂,残留物用色谱法分离,以含有30-40%乙酸乙酯的正己烷为洗脱剂,得到73mg(收率:14.5%)所需化合物。
1H-NMR(CDCl3,300MHz)δ ppm:8.15(d,J=7.1Hz,2H),7.71(d,J=7.1Hz,2H)7.63-7.24(m,16H)6.90(d,exch,J=9.3Hz,1H)6.25(bt,1H)6.21(s,1H)6.05(dd,J1=9.9Hz,J2=5.6Hz,1H)5.96(dd,J1=9.9Hz,J2=2.7Hz,1H)5.86-5.82(m,2H)5.42(d,J=2.5Hz,1H)5.18-5.09(m,3H)4.37(AB q,J=8.2Hz,2H)4.00(d,J=6.6Hz,1H)2.48-1.12(m,21H,includings at 2.44,3H;2.18,3H;1.86,3H;1.84,3H;1.23 3H;1.13,3H);13C-NMR(CDCl3,75MHz)δ ppm:205.5,169.5,169.1,167.8,167.1,167.0,154.1,141.9,139.9,136.8,134.3,133.7,133.5,132.0,130.2,129.2,129.1,128.9,128.7,128.4,127.2,126.6,126.2,81.2,81.1,78.8,76.9,76.3,75.9,75.7,71.9,70.7,55.4,52.7,43.1,41.4,35.8,26.4,22.8,22.1,21.0,20.8,20.5,14.5.
实施例3
6,7-脱氢红豆杉醇(Ⅰa)
2′-O-苄氧基羰基-6,7-脱氢红豆杉醇(Ⅲa)(19.6mg,0.020mmol)溶于0.5ml乙酸乙酯中,催化量的Pd/c(6.4mg,10%,0.006mmol)加入到上面的反应液中,在大气压下发生氢解反应。4h后,过滤,滤液蒸发剂,粗品以色谱法纯化(洗脱剂为含60%乙酸乙酯的正己烷),得16.7mg(收率:98.8%)所需化合物Ⅰa。
1H-NMR(CDCl3,300MHz)δ ppm:8.14(d,J=8.7Hz,2H),7.73(d,J=8.7Hz,2H),7.71-7.24(m,11H),7.00(d,exch,J=9.0Hz,1H),6.18(m,2H),6.04(dd,J1=9.9Hz,J2=5.6Hz,1H),5.86-5.76(m,3H),5.07(d,J=5.6Hz 1H),4.75(m,1H),4.35(ABq,J=8.2Hz,2H),3.97(d,J=6.4Hz,1H),3.53(d,J=4.8Hz,1H),2.37-1.12(m,21H,including s at 1.36,3H;2.21,3H;1.85,3H;1.71,3H;1.22,3H;1.13,3H);13C-NMR(CDCl3,75MHz):δ ppm:205.3,172.5,169.7,169.6,167.9,141.1,139.9,138.0,133.9,133.8,133.7,132.0,130.2,129.2,129.0,128.7,2,128.7,128.3,127.0,126.9,126.3,81.2,78.6,77.2,76.4,75.8,75.5,73.2,72.2,55.5,54.8,43.0,41.6,35.9,26.4,22.7,21.6,20.8,20.3,14.6;MS(FAB):836(MH).
实施例4
6,7-脱氢浆果赤霉素Ⅲ(Ⅵa)
向6,7-脱氢红豆杉醇(1.13g,1.35mmol)的60ml二氯甲烷/2%甲醇溶液中加入四丁基氢硼化胺(694mg,2.7mmol),反应液室温搅拌5h,加入10ml饱和的氯化铵水溶液使反应停止。有机层用硫酸镁干燥,浓缩。粗品以硅胶柱分离(洗脱剂为含10%乙酸乙酯的正己烷),再从甲醇中重结晶,得白色固体(630mg,收率:82%),mp.224-230℃(分解);
1H-NMR(300MHz,CDCl3):δ 8.15-8.09(m,2H),7.64-7.58(m,1H),7.51-7.45(m,2H),6.46(s,1H),6.05(dd,1H,J=6.0,9.0Hz),5.86(d,1H,12.0Hz),5.79(d,1H,J=6.0Hz),5.11(d,1H,J=6.0Hz),4.89-4.82(m,1H),4.35(ABq,2H,J=6.0,36.0Hz),4.09(d,1H,J=6.0Hz),2.35-2.18(m,10H,including singlets at 2.26,2.21),2.01(s,3H),1.83(s,3H),1.10-1.07(m,6H);13C-NMR(75.6MHz,CDCl3):δ 205.4,170.2,169.5,166.8,145.3,139.7,133.5,132.4,129.9,129.2,128.5,126.1,81.1,80.9,78.9,78.6,76.3,76.2,75.3,67.7,55.4,44.1,42.5,41.6,38.9,26.2,22.6,20.9,20.7,20.1,14.8,14.5.
实施例5
6,7-脱氢-2′-O-三乙基甲硅烷基-3′-(2-呋喃基)-3′-N-脱苯甲酰基-N-叔-丁氧基羰基红豆杉醇(Ⅷa)
6,7-脱氢浆果赤霉素Ⅲ(42mg,0.074mmol)溶于5ml干燥的四氢呋喃中,用惰性气体洗,于干冰/丙酮中冷至-55℃,用注射器向上述溶液中加入六甲基二硅氮烷基锂(溶于四氢呋喃的0.5M溶液,0.24ml,0.8mmol),得到浅黄色反应液,搅拌5min。然后,在5min内加入外消旋的N-叔丁氧基羰基-4-(2-呋喃基)-氮杂环丁酮(Ⅶa)(130.8mg,0.35mmol)的2ml四氢呋喃溶液。用冰水浴代替上面的冷浴,使反应液于0°搅拌1h,加入饱和NH4Cl浴液(2ml)使反应停止。然后再加入25乙酸乙酯稀释,水洗(2×10ml),有机层干燥(MgSO4),浓缩,得到所需化合物粗品,为一无色油状物粗品。该粗品用硅胶柱纯化,己烷/乙酸乙酯(7∶3)为洗脱剂,得所需化合物,为无色玻璃状物(59.5mg,收率86%)。
1H-NMR(300MHz,CDCl3):δ 8.14(d,2H,J=9.0Hz),7.60-7.37(m,3H),6.35-6.33(m,1H),6.24-6.20(m,3H),6.06(dd,1H,J=6.0,9.0Hz),5.87-5.84(m,2H),5.30(d,2H,J=6.0Hz),5.11(d,1H,J=3.0Hz),4.75(s,1H),4.36(ABq,2H,J=6.0,39.0Hz),4.04(d,1H,J=6.0Hz),2.47(s,3H),2.45-2.25(m,2H),2.22(s,3H),1.90-1.14(m,23H,including singlets at 1.86,1.82,1.34,1.25,1.14),0.87-0.73(m,9H),0.55-0.37(m,6H);13C-NMR(75.6MHz,CDCl3):δ 2.5.5,171.1,169.5,166.9,155.3,152.0,142.0,141.8,139.9,133.6,133.4,130.1,129.1,128.6,126.1,110.6,107.2,81.2,80.9,80.1,78.6,76.5,76.3,75.9,75.6,72.3,71.9,55.4,52.7,43.0,41.3,35.6,28.1,26.0,22.8,21.9,20.7,20.3,14.5,6.4,4.2.
实施例6
6,7-脱氢-3′-(2-呋喃基)-3′-N-脱苯甲酰基-N-叔丁氧基羰基红豆杉醇(Ⅰb)
2′-O-甲硅烷基保护的底物Ⅷa(59.5mg,0.063mmol)的2ml乙腈溶液,于冰水浴中冷至0℃,加入1NHCl(0.05ml,6eq.),此反应液在此温度下搅拌1h,减压蒸除部分溶剂,残留物用乙酸乙酯(25ml)和水(10ml)萃取,干燥(MgSO4)有机层,浓缩,得到白色泡沫状物。粗品用硅胶柱层析化,洗脱剂为含10%CH3CN的CH2Cl2溶液。分离得到所需产品,为一白色泡沫状物(46mg,收率:88%)。
1H-NMR(300MHz,CDCl3):δ 8.14(d,2H,J=6.0Hz),7.62-7.46(m,3H),6.37-6.30(m,2H),6.31-6.20(m,2H),6.06(dd,1H,J=6.0,12.0Hz),5.87-5.83(m,2H),5-35-5.23(m,2H),5.10(d,1H,J=6.0Hz),4.70(s,1H),4.37(ABq,2H,J=9.0,42.0Hz),4.02(d,1H,J=6.0Hz),3.31(bs,1H),2.40-1.15(m,31H,including singlets at 2.40,2.23,1.85,1.79,1.35,1.25,1.15);13C-NMR(75.6MHz,CDCl3):δ 205.2,169.4,166.9,142.3,141.3,139.7,133.5,130.0,129.0,128.5,126.1,110.5,107.2,81.1,80.9,78.5,76.2,75.7,75.4,72.2,71.6,55.3,51.5,42.9,41.4,35.5,28.0,26.0,2.5,21.6,20.6,20.1,14.4;HRMS Calcd for MH+C43H52NO15:822.3337;Found:822.3364
实施例7
6,7-脱氢-3′-(2-呋喃基)红豆杉醇(Ⅰc)
6,7-脱氢浆果赤霉素Ⅲ(Ⅵa)(191.4mg,0.33mmol)于5mL干燥的四氢呋喃溶液中,用惰性气体洗,用干冰/丙酮浴冷至-55℃。用注射器向上述液中滴加六甲基二硅氮烷基锂(在己烷中的1M溶液,0.4ml,0.4mmol),得到浅黄色溶液,搅拌5min,然后在5min内加入(3R,4S)-N-苯甲酰基-4-(2-呋喃基)氮杂环丁酮(Ⅶ′a)(150.0mg,0.4mmol)的2ml四氢呋喃溶液。用冰水浴代替上面的冷却浴,使反应液于0℃搅拌1h。加入2ml饱和NH4Cl溶液使反应停止,然后再加入25ml乙酸乙酯稀释,水洗(2×10ml),干燥有机相(MgSO4)浓缩,得到6,7-脱氢-2′-O-三乙基硅烷基-3′-(2-呋喃基)红豆杉醇的粗品,为一无色油状物。
6,7-脱氢-2′-O-三乙基硅烷基-3′(2-呋喃基)红豆杉醇的粗品(189mg)溶于2ml乙腈中,用冰水浴冷至0℃,加入1NHCl(0.5ml),反应液在此温度下搅拌1h,减压浓缩蒸除溶剂,残留物用乙酸乙酯(25ml)和水(10ml)萃取。干燥有机层(MgSO4),浓缩,得到白色泡沫状物,粗品用硅酸柱层析纯化,洗脱剂为含20%CH3CN的CH2Cl2溶液,分离,得所需化合物,为一白色泡沫状物(140mg,收率:51%)
1H-NMR(300MHz,CDCl3)δ 8.15(d,2H,J=9.0Hz),7.73(d,2H,J=9.0Hz),7.61-7.37(m,6H),6.92(d,1H,J=9.0Hz),6.38(d,2H,J=1.3Hz),6.21(s,2H),6.06(dd,1H,J=6.0,9.0Hz),5.89-5.84(m,2H),5.10(d,1H,J=6.0Hz),4.80(dd,1H,J=3.0,6.0Hz),4.36(ABq,2H,J=9.0,36.0Hz),4.01(d,1H,J=6.0Hz),3.58(d,1H,J=6.0Hz),2.43-1.74(m,17H,including singlets at 2.42,2.22,1.99,1.86,1.76),1.23-1.10(m,6H,including singlets at 1.23,1.14);13C-NMR(75.6MHz,CDCl3)δ 205.1,172.0,169.6,169.4,166.9,166.8,150.7,142.5,141.0,139.7,133.8,133.6,133.2,131.9,130.0,129.1,128.5,126.9,126.1,110.6,107.8,81.1,81.0,78.4,76.3,75.7,75.4,72.1,71.5,55.3,50.0,42.9,41.5,35.7,26.9,26.2,22.5,21.5,20.6,20.2,14.4.
实施例8
6,7-脱氢-2′-O-三乙基甲硅烷基-3′-(2-噻吩基)-3′-N-脱苯甲酰基-N-叔丁氧基羰基红豆杉醇(Ⅷb)
此主题化合物可按照实施例5中化合物Ⅷa的类似方法来制备1H-NMR(300MHz,CDCl3)δ 8.14(d,2H,J=9.0Hz),7.63-7.58(m,1H),7.49(t,2H,J=9.0Hz),7.26-7.23(m,1H),6.99-6.93(m,2H),6.23-6.19(m,2H),6.06(dd,1H,J=3.0,9.0Hz),5.87-5.84(m,2H),5.52-5.40(m,2H),5.10(d,1H,J=6.0Hz),4.55(d,1H,J=1.8Hz),4.38(ABq,2H,J=9.0,42.0Hz),4.03(d,1H,J=6.0Hz),2.47-2.20(m,8H,including singlets at 2.42,2.22),1.88-1.73(m,7H,including singlets at 1.86,1.81),1.43-1.14(m,15H,including singlets at 1.32,1.26,1.14),0.90-0.81(m,9H),0.59-0.42(m,6H);13C-NMR(75.6MHz,CDCl3):δ 205.4,171.0,169.5,169.2,166.9,141.9,139.9,133.6,133.4,130.1,129.1,128.6,126.8,126.1,124.6,124.5,81.2,81.0,80.1,78.7,76.2,75.8,75.7,75.2,71.2,55.3,53.7,43.0,41.3,35.7,28.1,26.1,22.9,22.0,20.7,20.4,14.5,6.5,4.4.
实施例9
6,7-脱氢-3′-(2-噻吩基)-3′-N-脱苯甲酰基-N-叔丁氧基羰基红豆杉醇(Ⅰd)
此化合物可采用像在实施例6中化合物Ⅰb的类似方法得到
1H-NMR(300MHz,CDCl3)δ 8.13(d,2H,J=6.0Hz),7.63-7.58(m,1H),7.49(t,2H,J=6.0Hz),7.26-7.24(m,1H),7.06(d,1H,J=6.0Hz),6.99-6.96(m,1H),6.22-6.19(m,2H),6.04(dd,1H,J=3.0,10.0Hz),5.86-5.81(m,2H),5.47-5.37(m,2H),5.08(d,1H,J=6.0Hz),4.61(dd,1H,J=2.1,5.4Hz),4.35(ABq,2H,J=8.1,39.0Hz),4.00(d,1H,J=6.0Hz),3.56-3.53(m,1H),2.37-2.20(m,8H,including singlets at 2.37,2.22),1.98-1.72(m,7H,including singlets at 1.96,1.86,1.75),1.39-1.14(m,15H,including singlets at 1.33,1.24,1.14);13C-NMR(75.6MHz,CDCl3)δ 205.2,169.5,169.4,166.9,154.9,141.3,139.8,133.7,133.6,133.5,130.1,129.9,129.1,128.6,126.9,126.2,125.3,125.2,81.1,81.0,80.3,78.5,76.3,75.8,75.5,73.3,72.3,55.4,52.7,43.0,41.5,35.6,28.1,26.2,22.6,21.6,20.7,20.2,14.4.
实施例10
三苯甲醛缩二氨phCH(-N=CHph)2的制备
在装有一个机械搅拌器和一个温度计的3升的三口圆底烧瓶中,加入1升浓氨水(大约30%)(14.8moles),一次加入苯甲醛(265g,2.5mol)的500ml 2-丙醇溶液。混合液于约22℃剧烈搅拌43h。得浆状液,过滤,用1升水洗滤出的块状物。真空干燥,得242.4g三苯甲醛缩二氨,为白色固体(mp.100-102℃),收率:97.4%。
上述步骤可用来制备通式为R2CH(-N=CHR2)2的二亚胺如:二氨缩三糠醛(R2=2-呋喃基)
三噻吩甲醛缩二氨(R2=2-呋喃基)
实施例11
(±)Cis-3-乙酰氧基-1-〔(苯基)(苯亚甲基亚胺基)甲基〕4-苯基氮杂环丁烷-2-酮(ⅩⅣa)
在一个装有温度计,电磁搅拌、滴液漏斗的1000ml的三颈圆底烧瓶中,加入三苯甲醛缩二氨(30.00g,100.5mmol)和150ml乙酸乙酯,在通氩气下搅拌,反应液冷至-5℃,加入三乙胺(16.8ml,121mmol)。然后在90min内逐滴加入乙酸乙酰氯(124ml,116mmol)的300ml乙酸乙酯溶液,在此温度下反应16h,将混合液温度升至20℃(1.5h),并转移至分液漏斗中,有机层连续用饱和NH4Cl水溶液(150ml,100ml),饱和NaHCO3水溶液(120ml)和盐水(120ml)洗,为了表示特性,用MgSO4干燥有机层,过滤,减压蒸去溶剂,目的化学物可在此阶段分离,这时可得到目的化合物,此法可得到定量的所需化合物粗品,为红色玻璃状物
HPLC纯(面积):87.9%(1∶1非对映异构体混合物)
1H-NMR(CDCl3,200MHz):δ 8.45(s,1H,N=CH),7.80-7.85(m,1H,Ph),7.60-7.65(m,1H,Ph),7.26-7.50(m,9H,Ph),7.00-7.10(m,4H,Ph),6.28(s,0.5H,NCHN),6.23(s,0.5H,NCHN),5.81(d,J=4.8Hz,0.5H,H-3),5.76(d,J=4.8Hz,0.5H,H-3),5.30(d,J=4.8Hz,0.5H,H-4),4.75(d,J=4.8Hz,0.5H,H-4),1.63(s,3H,CH3CO);IR(KBr):ν(cm-1)=1763(C=O),1641(C=N);UV(methanol):λ max(nm)=216,252.
实施例12
(±)-Cis-3-乙酰氧基-4-苯基氮杂环丁烷-2-酮(ⅩⅤa)
将上述实施例11中的化合物的500ml乙酸乙酯溶液在通氩气下小心转移到2.0升的Parr烧瓶中,其中含有10%Pa/c(6.00g)。此混合液通氢气(4atm)反应20h,催化剂用硅藻土填塞过滤除去。滤块与200ml乙酸乙酯混合成泥浆,搅拌(10min)然后过滤滤块用100ml乙酸乙酯洗,合并滤液,有机层用10%HCl洗(300ml),两层通过熔融玻璃漏斗除去白色沉淀(二苄基胺盐酸盐),并用乙酸乙酯(100ml)洗沉淀,分压,有机层用另外10%HCl(200ml)洗,合并10HCl洗液,用乙酸乙酯(200ml)再萃取,合并有机层,用饱和NaHCO3水溶液(300ml),盐水(250ml)洗,用MgSO4干燥有机层,过滤,浓缩至最后体积为75ml。将此混合物冷至-4℃,过滤得沉淀物,用200ml己烷洗,得所需化合物16.12g(从三苯甲醛缩二胺算,总收率为78.1%),为白色针状结晶,mp.150-151℃,HPLC纯(面积):99.8%
1H-NMR(CDCl3,200MHz):δ=7.30-7.38(m,5H,Ph),6.54(bs,exchangeable,1H,NH),5.87(dd,J=2.7,4.7Hz,1H,H-3),5.04(d,J=4.7Hz,1H,H-4),1.67(s,3H,CH3CO);IR(KBr):ν(cm-1)=3210(N-H),1755,1720(C=O);KF:0.17%.
Anal.Calcd.for C11H11NO3:C,64.38;H,5.40;N,6.83.Found:C,64.07;H,5.34;N,6.77.
实施例13
(±)-Cis-3-乙酰氧基-1-〔(2-呋喃基)(2-呋喃亚甲基亚氨基)甲基〕-4-(2-呋喃基)氮杂环丁烷-2-酮(ⅩⅣb)
除将二氨缩三糠醛代替三苯甲醛缩二胺,该主题化合物可按照实施例11中的步骤来制备。反应可按18.6mmol(相对于100mmol)的量进行。因而,二氨缩三糠醛(5.00g,18.6mmol),三乙胺(3.11ml,22.3mol)和乙酸乙酰氯(2.30ml,21.4mmol)给出6.192g(收率90.4%)的所需化合物。为一浅红色糖浆,得到的产物为1∶1的非对映体的混合物
1H-NMR(CDCl3;200MHz):δ 8.211(s,0.5H,N=CH),8.208(s,0.5H,N=CH),7.14-7.59(m,3H,furyl),6.90(d,J=3.5Hz,0.5H,furyl),6.83(d,J=3.5Hz,0.5H,furyl),6.10-6.53(m,6H,furyl,NCHN),5.90(d,J=4.9Hz,0.5H,H-3),5.86(d,J=4.8Hz,0.5H,H-3),5.35(d,J=4.8Hz,0.5H,H-4),4.90(d,J=4.9Hz,0.5H,H-4),1.91(s,1.5H,CH3CO),1.88(s,1.5H,CH3CO);IR(film):ν(cm-1)=1778,1753(C=O),1642(C=N);UV(methanol):λmax(nm)=220,278.
实施例14
(±)-Cis-3-(乙酰氧基)-4-(2-呋喃基)氮杂环丁烷-2-酮(ⅩⅤb)
该标题化合物按照实施例12中的步骤来制备,除非产物用制备性薄层色谱分离。反应以二氨缩三糠醛最初量为2.7mmol的量进行。因而,实施例13的化合物粗品(1.00g)重新溶解在50ml乙酸乙酯中,加入10%Pd/c(150mg),以制备性薄层色谱(2mm硅胶,洗脱剂如乙酸乙酯/己烷1∶1)纯化固体粗品,得到386mg的该标题化合物(以二氨缩三糖醛算,为65.8%校正的总收率),为一黄色固体,从乙酸乙酯/己烷中重结晶,mp.118-119℃,HPLC纯(面积):99.4%
1H-NMR(CDCl3,200MHz):δ 7.44(t,J=1.3Hz,2H,furyl),6.39(d,J=1.3Hz,1H,furyl),6.21(bs,exchangeable,1H,NH),5.88(dd,J=2.2,4.6Hz,1H,H-3),5.05(d,J=4.6Hz,1H,H-4),1.92(s,3H,CH3CO);IR(KBr):ν(cm-1)=3203(N-H),1756,1726(C=O);UV(methanol):λmax(nm)=222.
实施例15
(±)-Cis-3-乙酰氧基-1-〔(2-噻吩基)(2-噻吩基亚甲基亚氨基)甲基)-4-(2-噻吩基)氮杂环丁烷-2-酮(ⅩⅣc)
除以三噻吩甲醛缩二氨代替三苯甲醛基缩二氨,该标题化合物可按实施例11中描述的方法制备,因而,用三噻吩甲醛缩二氨(30g,94.7mmol),三乙胺(15.84ml,11.4mmol)及乙酸乙酯氯(1.6ml,108mmol)反应,得到该标题化合物,为粘稠状油状物。所得产品为含有作对映体的混合物。
1H-NMR(CDCl3):δ 8.52(s,1H),8.502(s,1H),7.51(d,J=4.9Hz,1H),7.45(d,J=4.4Hz,1H),7.41(d,J=3.1Hz,1H),7.37(d,1H),7.30(m,3H),7.16(m,1H),7.16(m,3H),7.09(m,2H),6.94(m,1H),6.89(m,1H),6.81-6.74(m,4H),6.48(s,1H),6.43(s,1H),5.85(m,2H),5.59(d,J=4.8Hz,1H),5.17(d,J=4.8Hz,1H),1.87(s,3H),1.86(s,3H).
实施例16
(±)-Cis-3-(乙酰氧基)-4-(2-噻吩基)氮杂环丁烷-2-酮(ⅩⅤc)
于25℃搅拌下,向化合物ⅩⅣc(0.431g,1.03mmol)的2.93ml CH2Cl2溶液中一次加入70%冰醋酸水溶液(0.35mL冰醋酸和0.15ml水)。反应液同流搅2.5h,加入50ml CH2Cl2稀释,然后用两份75ml饱和NaHCO3洗两次,50ml饱和盐水洗一次,有机层真空浓缩,得棕色油状物,溶于少量CH2Cl2中,过硅胶柱,每隔0.5″测一次,共测4″,用含10-60%乙酸乙酯的己烷进行梯废洗脱,得到少量的极性付产物而且得到了该标题化合物(0.154g,收率:75%,为白色固体。
1H-NMR(CDCl3):δ 7.32(dd,J=4.7,1.5Hz,1H),7.03(m,2H),6.75(bs,1H),5.86(dd,J=4.6,2.7Hz,1H),5.27(d,J=5.3Hz,1H),1.83(s,3H);13C-NMR(CDCl3):δ 169.3,165.5,138.4,127.1,127.07,126.2,78.3,54.0,20.0.
实施例17
(±)-Cis-3-三乙基甲硅烷氧基-4-(2-呋喃基)氮杂环丁烷-2-酮(ⅩⅥa)
乙酰氧基内酰胺ⅩⅤb(3.78g,19.4mmol)的60ml甲醇溶液与K2CO3(20mg,0.14mmol)搅拌反应90min,用Dowex 50W-Ⅹ8中和反应液,过滤,滤液浓缩,残留物溶于80ml无水四氢呋喃中,在0℃下与咪唑(1.44g,21.2mmol)及TEScl(氯代三甲基硅烷3.4ml,20.2mmol)搅拌反应30min。反应液用乙酸乙酯稀释,用盐水洗,MgSO4干燥,浓缩,残留物用硅胶层析分离(洗脱剂为3∶1己烷/乙酸乙酯),得4.47g(收率:86%)的该标题化合物,为一无色油状物。
IR(film)3276(broad),1768,1184,732cm-1;1H-NMR(CDCl3,300MHz)δ 7.38(s,1H),6.39(bs,1H),6.35(s,2H),5.05(dd,J=4.6,2.3Hz,1H),4.78(d,J=4.6Hz,1H),0.82(t,J=8.5Hz,6H),0.50(dq,J=8.5,1.8Hz,9H);13C-NMR(CDCl3,75.5Hz)δ 169.6,150.4,142.6,110.5,109.1,79.6,53.2,6.4,4.4;FABMS(DCI)M+H calcd for C13H21NO3Si:268,Found:268.
实施例18
(±)-Cis-3-三乙基甲硅烷氧基-4-(2-呋喃基)-N-叔丁氧基羰基氮杂环丁烷-2-酮(Ⅶa)
氮杂环丁酮ⅩⅥa(2.05g,7.7mmol)的30ml二氯甲烷溶液与二异丙基乙胺(1.5mL,8.6mmol)和甲酸二叔丁酯(2.0g,9.2mmol)及催化量的二甲基氨基吡啶(DMAP)于0℃搅拌反应,加入CH2Cl2稀释,盐水洗,用MgSO4干燥,浓缩,残留物用硅胶柱层析分离(洗脱剂为己烷/乙酸乙酯8∶1),得2.0g(收率:70%)该标题化合物,为蜡状固体
IR(KBr)1822,1806,1712,1370,1348,1016 cm-1;1H-NMR(CDCl3,300MHz)δ 7.38(m,1H),6.34(m,2H),5.04(ABq,J=12.4,5.5Hz,2H),1.39(s,9H),0.82(t,9H),0.50(m,6H);13C-NMR(CDCl3,75.5Hz)δ 165.7,148.0,147.7,142.8,110.5,109.7,83.4,77.4,56.0,27.8,6.3,4.4;DCIMS M+H calcd for C18H29NO5Si:368,Found:368.
实施例19
(±)-Cis-3-三乙基甲硅烷氧基-4-(2-噻吩基)-氮杂环丁烷-2-酮(ⅩⅥb)
3-乙酰氧基内酰胺ⅩⅤc(2.5g,11.8mmol)溶于10ml甲醇中,加入10ml饱和NaHCO3水溶液,得一浆状溶液,室温搅拌3h,加入20ml乙酸乙酯稀释,水洗(15ml),水层用乙酸乙酯萃到几次,合并有机层,干燥(MgSO4),浓缩,得黄色固体(产量:1.7g)、粗品溶于20ml无水四氢呋喃中,用冰/水浴冷至5℃,加入咪唑(752mg,1.1eq),搅拌5min后,逐滴加入三乙基氯硅烷(1.85ml,1.1eq),悬浮液于5℃搅拌反应3h,然后过滤除去固体,有机层用水洗(2×20ml),干燥(MgSO4),浓缩。粗品通过硅胶柱色谱纯化(洗脱剂:己烷/乙酸乙酯7∶3);得所需化合物(1.5g,收率:45%),为一无色固体。 m.p.70-71℃;1H-NMR(300MHz,CDCl3):δ 7.32-7.30(m,1H);7.05-6.98(m,2H),5.06-5.05(m,2H),0.82(t,9H,J=8Hz),0.55-0.46(m,6H);13C-NMR(75.6MHz,CDCl3):δ 169.1,139.7,126.5,126.4,125.8,79.4,55.1,6.3,4.4.
另一种方法:
乙酰氧基内酰胺ⅩⅤc(2.0g,9.37mmol)的40ml甲醇溶液与K2CO3(60mg,0.43mmol)搅拌30min,用Dowex 50W-X8中和反应液,过滤,滤液浓缩。残留物溶于50ml无水四氢呋喃中,在0℃下与咪唑(0.85g,11.3mmol)和TEScl(1.9ml,12,5mmol)搅拌30min。加入乙酸乙酸稀释,用盐水洗,用MgSO4干燥,浓缩。残留物用硅胶层析分离,(洗脱剂为己烷/乙酸乙酯3∶1),得所需化合物2.13g(收率:86%),为无色油状物。
实施例20
(±)-Cis-3-三乙基甲硅烷氧基-4-(2-噻吩基)-N-叔丁氧基羰基氮杂环丁烷-2-酮(Ⅶb)
甲硅烷基氮杂环丁酮ⅩⅥb(425.7mg,1.48mmol),溶于10ml CH2Cl2中,于冰水浴冷至5℃。向反应液中加入催化量的DMAP,TEScl(0.025ml,1.0eq),然后再加入甲酸二叔丁酯(388.4mg,1.2eq)。于此温度下搅拌2h。加入饱和NaHCO3水溶液(5ml)使反应停止,有机相用5ml水洗,干燥(MgSO4),通过一根短的硅胶柱,浓缩,得到所需化合物(525.3mg,收率:93%),为一无色油状物。
1H-NMR(300MHz,CDCl3):δ 7.31-7.29(m,1H),7.08-7.07(m 1H),7.00-6.58(m,1H),5.31(d,1H,J=6Hz),5.03(d,1H,J=6Hz),1.40(s,9H),0.83(t,9H,J=8Hz),0.56-0.47(m,6H);13C-NMR(75.6MHz,CDCl3):δ 165.5,147.5,136.4,127.6,126.2,126.1,83.3,77.3,57.9,27.7,6.2,4.3.
实施例21
代表实施例用来选择性合成10-脱乙酰基浆果赤霉素Ⅲ的C-10位衍生物
10-苯甲酰基-10-脱乙酰基-7-三乙基甲硅烷基浆果赤霉素Ⅲ(Ⅹ′a)
通氩气下,通式Ⅸ的浆果赤霉素的衍生物,其中R4为SiEt3(43.5mg,0.066mmol)溶于1.0mL干燥的四氢呋喃中,冷至-40℃,缓缓加入正丁基锂(0.050mL,0.82mmol,1.6M溶液)。搅拌5min后,加入苯甲酰氯(0.030ml,0.26mmol)。将反应液升温至0℃,搅拌反应1.5h,加入饱和NH4Cl水溶液(2ml)使反应停止。用乙酸乙酯(2×5mL)萃取水相,干燥(MgSO4),浓缩得到油状物,以闪式硅胶层析分离(洗脱剂:50%乙酸乙酯的己烷液),得该标题化合物(30mg,收率:60%,通式Ⅹ′的化合物,其中R4为Si(Et)3,Rm为OCOC6H5),为一泡沫状物1H-NMR(CDCl3):δ 8.17-8.05(m,4H),7.64-7.42(m,6H),6.67(s,1H),5.67(d,1H),4.95(d,1H),4.81(m,1H),4.56(dd,1H),4.30(d,1H),4.14(d,1H),3.92(d,1H),2.50(m,1H),2.30-2.0(m,18H),1.92-1.80(m,1H),1.72-1.62(bs,4H),1.30(s,3H),1.00(s,3H),0.89(t,3H),0.56(q,6H);HRMS(FAB/NOBA):Calculated for C42H54O11Si(MH+):762.3435.Found 762.3427.
应用此方法,可制得C10为甲酸酯,磺酸酯,氨基甲酸酯,醚等化合物。当用六甲基二硅烷锂进行反应,收率较好。
实施例22
2′-O-苄氧基羰基-6a-羟基-7a-羟基红豆杉醇(Ⅻa)
2′-O-苄氧基羰基-6,7-脱氢红豆杉醇(100mg,0.1mmol)溶于3ml干燥的四氢呋喃中,用冰/水浴冷却至5℃,加入吡啶(24μl,0.3mmol)和4-甲基吗啡啉-N-氧化物(12mg,0.1mmol),当固体完全溶解后,加入催化量的四氧化锇(2.5mg,0.01mmol),得黄色溶液,于冰箱中放置96h,加入10ml乙酸乙酯稀释,用饱和NaHCO3(5ml),水(10ml)洗,有机层用MgSO4干燥,浓缩,得到无色泡沫状粗品,由硅胶层析纯化(洗脱剂为含20%CH3CN的CH2Cl2溶液),得到所需产品,为白色泡沫状物(47mg,收率:47%)。
1H-NMR(CDCl3,300MHz):δ 8.12(d,2H,J=6.0Hz),7.68(d,2H,J=6.0Hz),7.60-7.29(m,16H),6.93(d,1H,J=9.0Hz),6.80(s,1H),6.24(t,1H,J=9.0Hz),5.99(dd,1H,J=3.0,9.0Hz),5.71(d,1H,J=6.0Hz),5.45(d,1H,J=3.0Hz),5.27-5.13(m,2H),4.67-4.63(m,2H),4.33(s,2H),4.16-4.12(m,1H),3.85(d,1H,J=6.0Hz),3.65(dd,1H,J=3.0,12.0Hz),2.87-2.84(m,1H),2.52(s,3H),2.42-2.33(m,1H),2.20-2.12(m,4H),2.01(s,1H),1.89(s,3H),1.61(s,3H),1.16(s,3H),1.11(s,3H);13C-NMR(CDCl3,75.6MHz):δ 205.9,172.3,169.3,167.6,167.1,166.9,154.0,140.5,136.6,134.2,133.7,133.4,132.9,132.0,130.2,129.1,128.9,128.8,128.7,128.6,128.5,128.4,127.1,126.4,91.5,84.1,79.1,77.9,77.7,77.6,76.8,76.6,74.8,72.0,71.8,70.7,60.4,57.6,52.6,42.6,39.7,36.0,25.9,22.5,21.4,21.0,20.8,15.4,14.7,14.1;HRMS calcd for C55H58NO17:1004.3705,found:1004.3691.
实施例23
6a-羟基-7a-羟基红豆杉醇(Ⅰe)
通氩气下,将2′-O-苄氧基羰基-6a-羟基-7a-羟基红豆杉醇(47mg,0.047mmol)的3ml乙酸乙酯溶液置于Parn烧瓶中,加入Pd/c(20mg),此悬浮液通40Psi的氢气,振摇,3h后,放气,将悬浮液过一个短的硅胶塞过滤,浓缩,粗品以硅胶层析法纯化(洗脱剂为含20%CH3CN的CH2Cl2溶液),得到所需化合物,为一白色泡沫状物(20.2mg按所得支的原料计算收率:99%)
1H-NMR(CDCl3,300MHz):δ 8.15(dd,2H,J=0.9,8.0Hz),7.72(dd,2H,J=0.9,9.0Hz),7.76-7.26(m,11H),7.02(d,1H,J=9Hz),6.79(s,1H),6.23(t,1H,J=9.0Hz),5.80(dd,1H,J=2.1,8.7Hz),5.73(d,1H,J=7.2Hz),4.82-4.79(m,1H),4.68-4.64(m,2H),4.34(s,2H),4.15(apparentt,1H,J=5.4Hz),3.85(d,1H,J=9.0Hz),3.69-3.60(m,2H),2.83(d,1H,J=8.1Hz),2.50(s,3H),2.43-2.35(m,1H),2.28-2.23(m,1H),2.19(s,3H),2.00(s,1H),1.80(s,3H),1.63(s,3H),1.19(s,3H),1.13(s,3H);13C-NMR(CDCl3,75.6MHz):δ 205.6,172.6,172.5,139.9,137.8,133.6,133.1,131.8,130.1,128.9,128.7,128.5,128.2,126.9,126.7,91.4,83.9;78.9,77.7,77.5,74.6,73.0,72.0,71.8,57.5,54.7,42.5,39.5,36.0,25.9,22.4,21.1,20.7,15.2,14.6.
实施例24
按照本发明所讲述的方法和实施例,可合成下述通式Ⅰ2的特定红豆杉醇衍生物:
实施例25
按照本申请所讲述的方法和实施例,可合成下述通式Ⅰ3的特定红豆杉醇衍生物
实施例26
生物数据
小鼠M109模型
象由Willam Rose在评价Madison109肺癌作为筛选抗癌药模型中所讲述的Cancer Treatment Reports,65,No.3-4(1981),用0.5ml的2%(W/V)的M109肺癌浆对Balb/c XDBA/2F1杂种小鼠进行腹膜内移植。
植玫肿瘤后1,5,9天或5,8天,给小鼠腹腔注射不同剂量的待测化合物,每天观察小鼠存活状况,直到植入肿瘤后大约75-90天。每次实验时,留有一组小鼠不给药,作为对照组。
给药组小鼠的平均存活时间(T)与对照组小鼠的平均存活时间(C)相比较,小鼠的每个给药组的这两个数字的比值乘以100%,以百分数表示,(即:%T/C),表1列出了一个代表化合物
表Ⅰ
(IP M109 data)
本发明的化合物对哺乳动物的肿瘤具有抑制作用,因此,本发明涉及的另一个方面是抑制对通式Ⅰ化合物敏感的哺乳动物肿瘤的方法。
本发明还给出了包含式Ⅰ的化合物在内的药物组合物,它能与一个或多个可药用的惰性或生理活性的载体,赋形剂、稀释剂或辅料组合,组合红豆杉醇及其相关衍生物(包括可能的剂量)的例子在许多文献中有过报道。下列如美国专利Nos.4,960,790及4,814,470,可遵循从这些例子组合本发明的化合物。例如,新化合物的片剂,丸剂,乳剂,分散剂,fooel premix以及其它适宜的形式给药,含有本发明化合物的药物制剂可容易地与无毒的有机药物载体或无毒的无机药物载体混合,通常药物含量为0.01mg-2500mg或更高剂量单位,最好50-500mg。典型的药用载体是,例如甘露糖醇manitol),脲、葡聚糖,乳糖,马铃薯和玉米淀粉,硬脂酸镁,滑石粉,植物油,聚二醇,乙基纤维素,聚乙烯吡咯烷酮,碳酸钙,油酸乙酯,肉豆冠酸异丙酯、苯甲酸苄酯、碳酸钠、明胶、碳酸钾、硅酸及其它一些常用的载体药物制剂,也可含有无毒的辅助物质,如乳化剂,防腐剂,润温剂以及如单月桂酸脱水山梨醇酯,三乙醇胺油酸盐,聚氧乙烯单硬脂酸酯,三棕榈酸甘油酸,二辛基硫代琥珀酸钠等等类似物。
本发明的化合物可冷冻干燥,如果需要的话,它们与另外的药用赋形剂结合制成适于非肠道给药,注射给药的组合物。对这种给药方式,药物可重新溶解在水中(标准水,生理盐水),或有机溶剂如丙二醇,乙醇等与水的混合物。
本发明的化合物作为红豆杉醇类可用于治疗哺乳动物肿瘤,红豆杉治醇治疗癌症病人给药方式,剂量及计划已得到广泛的研究。例如,见Ann.Int Med.111,pp272-279(1989);对于本发明的化合物,给药剂量,不管是单一剂量,多剂量还是每日剂量,当然都将随着所用的具体化合物的不同而改变,因为化合物不同的效价,给药途径、受体的大小及病人的健康状况不同,给药的剂量没有明确的范围,但它通常将是一个有效量,或者从剂型产生的药理活性游离形式的摩尔当量,在代谢释放出活性药物时达到其理想的药理及生理效果。给药的剂量通常为体重的0.8-8mg/kg之间或病人的约50-275mg/m2,一个在肿瘤治疗方面熟练的肿瘤学家,不用凭过多的经验,如通过参考红豆杉醇及其衍生物的早期研究,将能查明关于本发明的化合物的有效给药方法的适当的原始记录材料。
Claims (11)
1、通式Ⅰ的化合物
其中:
R1为CORZ,其中RZ为RO或R;
R2为C1-6烷基,C2-6烯基,C2-6炔基,C3-6环烷基,或通式是-W-RX的基团,其中W可为键,C2-6链烯二基,或-(CH2)-基,其中t为1-6;Rx为萘基、苯基,或杂芳基,而且Rx还可被1-3个相同或不同的C1-6烷基,C1-6烷氧基,卤素或-CF3基团任意取代。
Ra为-OCOR,H,OH,-OR,-OSO2R,-OCONR0R,-O-CONHR,-OCOO(CH2)tR,或-OCOOR;
Rb和Rc均为羟基,或者通过碳原子共同形成而连结起来。
R和R0独立为C1-6烷基,C2-6烯基,C3-6环烷基,C2-6炔基,或苯基,还可被1-3个相同或不同的C1-6烷基,C1-6烷氧基、卤素或-CF3基团任意取代。
2、权利要求1的化合物,其中R1为苯甲酰基或叔丁氧基羰基;R2为苯基,呋喃基或噻吩基;Ra为乙酰氧基;Rb和Rc通过碳原子形成键而相互连结。
3、权利要求2的化合物,其为6,7-脱氢红豆杉醇。
4、权利要求2的化合物,其为6,7-脱氢-3′-(2-呋喃基)-3′-N-脱苯甲酰基-N-叔丁氧基羰基红豆杉醇。
5、权利要求2的化合物,其为6,7-脱氢-3′-(2-呋喃基)红豆杉醇。
6、权利要求2的化合物,其为6,7-脱氢-3′-(2-噻吩基)-3′-N-脱苯甲酰基-N-叔丁氧基羰基红豆杉醇。
7、权利要求1的化合物,其中R1为苯甲酰基或叔丁氧基羰基;R2为苯基,呋喃基,或噻吩基;Ra为乙酰氧基;Rb和Rc为羟基。
8、权利要求7的化合物,其为6a-羟基-7a-羟基红豆杉醇。
9、一种药物组合物,其包括包含权利要求1-8任何一个中要求的一种化合物或其药用盐作为活性成份,以及有关的一种或多种药用的载体、赋形剂或稀释剂。
10、一种治疗哺乳动物肿瘤的方法,其包括以权利要求1-8任何一个中要求的化合物的肿瘤敏感剂量对哺乳动物给药。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US98576192A | 1992-12-04 | 1992-12-04 | |
US07/985,761 | 1992-12-04 | ||
US08/128,619 US5380751A (en) | 1992-12-04 | 1993-09-28 | 6,7-modified paclitaxels |
US08/128,619 | 1993-09-28 |
Publications (2)
Publication Number | Publication Date |
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CN1094041A true CN1094041A (zh) | 1994-10-26 |
CN1049433C CN1049433C (zh) | 2000-02-16 |
Family
ID=26826766
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN93120068A Expired - Fee Related CN1049433C (zh) | 1992-12-04 | 1993-12-03 | 6,7-位修饰的红豆杉醇以及含有该化合物的药物组合物 |
Country Status (20)
Country | Link |
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EP (1) | EP0600517B1 (zh) |
JP (1) | JP3360186B2 (zh) |
CN (1) | CN1049433C (zh) |
AT (1) | ATE195939T1 (zh) |
AU (1) | AU668777B2 (zh) |
CA (1) | CA2109861C (zh) |
CZ (1) | CZ287599B6 (zh) |
DE (1) | DE69329327T2 (zh) |
DK (1) | DK0600517T3 (zh) |
ES (1) | ES2149188T3 (zh) |
FI (1) | FI109795B (zh) |
GR (1) | GR3034686T3 (zh) |
HU (2) | HU222347B1 (zh) |
IL (1) | IL107819A (zh) |
MX (1) | MX9307555A (zh) |
NO (1) | NO305756B1 (zh) |
NZ (1) | NZ250343A (zh) |
PL (1) | PL178135B1 (zh) |
PT (1) | PT600517E (zh) |
SG (1) | SG55014A1 (zh) |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100448872C (zh) * | 2004-02-13 | 2009-01-07 | 佛罗里达州立大学研究基金有限公司 | C10环戊基酯取代的紫杉烷 |
WO2015074605A1 (zh) * | 2013-11-22 | 2015-05-28 | 天士力控股集团有限公司 | 一种紫杉烷类化合物、其制备方法和用途 |
Families Citing this family (45)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5998656A (en) | 1991-09-23 | 1999-12-07 | Florida State University | C10 tricyclic taxanes |
IL107950A (en) | 1992-12-15 | 2001-04-30 | Upjohn Co | b 7, b 8 - Matano - Taxols, their preparation and pharmaceutical preparations against malignant tumors containing them |
IL108316A (en) * | 1993-01-15 | 2006-10-31 | Univ Florida State | History of C-10 Texan and pharmaceuticals containing them |
ES2219968T3 (es) * | 1993-06-11 | 2004-12-01 | PHARMACIA & UPJOHN COMPANY | Uso antineoplasico de delta 6,7-taxoles y composiciones farmaceuticas que los contienen. |
IL127597A (en) * | 1994-01-28 | 2003-07-31 | Upjohn Co | Iso-taxol analogs |
US5395850A (en) * | 1994-03-10 | 1995-03-07 | Bristol-Myers Squibb Company | 6,7-epoxy paclitaxels |
GB9409131D0 (en) * | 1994-05-09 | 1994-06-29 | Erba Carlo Spa | Unsaturated taxane compounds |
FR2721026B1 (fr) * | 1994-06-09 | 1996-07-12 | Rhone Poulenc Rorer Sa | Nouveaux taxoïdes, leur préparation et les compositions pharmaceutiques qui les contiennent. |
FR2721025B1 (fr) * | 1994-06-09 | 1996-07-12 | Rhone Poulenc Rorer Sa | Nouveaux taxoïdes, leur préparation et les compositions pharmaceutiques qui les contiennent. |
US5840929A (en) * | 1995-04-14 | 1998-11-24 | Bristol-Myers Squibb Company | C4 methoxy ether derivatives of paclitaxel |
FR2742753B1 (fr) * | 1995-12-22 | 1998-01-30 | Rhone Poulenc Rorer Sa | Nouveaux taxoides, leur preparation et les compositions pharmaceutiques qui les contiennent |
US5773461A (en) * | 1996-06-06 | 1998-06-30 | Bristol-Myers Squibb Company | 7-deoxy-6-substituted paclitaxels |
US5635531A (en) * | 1996-07-08 | 1997-06-03 | Bristol-Myers Squibb Company | 3'-aminocarbonyloxy paclitaxels |
US5773464A (en) * | 1996-09-30 | 1998-06-30 | Bristol-Myers Squibb Company | C-10 epoxy taxanes |
US5977386A (en) * | 1996-12-24 | 1999-11-02 | Bristol-Myers Squibb Company | 6-thio-substituted paclitaxels |
US5902822A (en) * | 1997-02-28 | 1999-05-11 | Bristol-Myers Squibb Company | 7-methylthiooxomethyl and 7-methylthiodioxomethyl paclitaxels |
US5912264A (en) * | 1997-03-03 | 1999-06-15 | Bristol-Myers Squibb Company | 6-halo-or nitrate-substituted paclitaxels |
US6017935A (en) * | 1997-04-24 | 2000-01-25 | Bristol-Myers Squibb Company | 7-sulfur substituted paclitaxels |
IT1317731B1 (it) * | 2000-01-18 | 2003-07-15 | Indena Spa | Tassani semisintetici con attivita' antitumorale ed antiangiogenetica. |
US6649632B2 (en) | 2000-02-02 | 2003-11-18 | Fsu Research Foundation, Inc. | C10 ester substituted taxanes |
PL350331A1 (en) | 2000-02-02 | 2002-12-02 | Univ Florida State Res Found | C10 carbamoyloxy substituted taxanes as antitumor agents |
RU2264400C2 (ru) | 2000-02-02 | 2005-11-20 | Флорида Стейт Юниверсити Рисерч Фаундейшн, Инк. | Таксан, фармацевтическая композиция на его основе и способ ингибирования роста опухоли |
CN1362956A (zh) | 2000-02-02 | 2002-08-07 | 佛罗里达州立大学研究基金有限公司 | C7氨基甲酰氧基取代的紫衫烷抗肿瘤剂 |
KR100607612B1 (ko) | 2001-06-20 | 2006-08-02 | 제넨테크, 인크. | 종양의 진단 및 치료를 위한 방법 및 이를 위한 조성물 |
EP2153843B1 (en) | 2001-09-18 | 2012-08-15 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
US20030228305A1 (en) | 2002-01-02 | 2003-12-11 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
EP1571968A4 (en) | 2002-04-16 | 2007-10-17 | Genentech Inc | COMPOSITIONS AND METHODS FOR DIAGNOSIS AND TREATMENT OF TUMORS |
JP2005528905A (ja) | 2002-06-07 | 2005-09-29 | ジェネンテック・インコーポレーテッド | 腫瘍の診断と治療のための組成物と方法 |
SI2161283T1 (sl) | 2003-11-17 | 2014-10-30 | Genentech, Inc. | Sestavki, ki obsegajo protitelesa proti CD79b, konjugirana na sredstvo, ki inhibira rast, ali na citotoksično sredstvo, in postopki za zdravljenje tumorja hematopoetskega izvora |
PE20050693A1 (es) * | 2004-02-13 | 2005-09-27 | Univ Florida State Res Found | Taxanos sustituidos con esteres de ciclopentilo en c10 |
EP2230517A1 (en) | 2005-01-07 | 2010-09-22 | Diadexus, Inc. | OVR110 antibody compositions and methods of use |
EP2614839A3 (en) | 2006-04-05 | 2015-01-28 | Genentech, Inc. | Method for using BOC/CDO to modulate hedgehog signaling |
WO2008067283A2 (en) | 2006-11-27 | 2008-06-05 | Diadexus, Inc. | Ovr110 antibody compositions and methods of use |
WO2008103962A2 (en) | 2007-02-22 | 2008-08-28 | Genentech, Inc. | Methods for detecting inflammatory bowel disease |
CN111499748A (zh) | 2007-07-16 | 2020-08-07 | 健泰科生物技术公司 | 抗cd79b抗体和免疫偶联物及使用方法 |
PE20090481A1 (es) | 2007-07-16 | 2009-05-18 | Genentech Inc | Anticuerpos anti-cd79b e inmunoconjugados humanizados y metodos de uso |
EP3269737B1 (en) | 2008-01-31 | 2024-06-19 | Genentech, Inc. | Anti-cd79b antibodies and immunoconjugates and methods of use |
WO2009145981A1 (en) | 2008-03-31 | 2009-12-03 | Florida State University Research Foundation, Inc. | C(10) ethyl ester and c(10) cyclopropyl ester substituted taxanes |
JP6132548B2 (ja) | 2009-04-01 | 2017-05-24 | ジェネンテック, インコーポレイテッド | 抗FcRH5抗体および免疫接合体および使用方法 |
CN102711826B (zh) | 2009-10-22 | 2017-03-29 | 霍夫曼-拉罗奇有限公司 | 用于调控巨噬细胞刺激性蛋白的hepsin活化的方法和组合物 |
PE20121584A1 (es) | 2009-11-30 | 2012-11-29 | Genentech Inc | Composiciones y metodos para el diagnostico y el tratamiento de tumores |
AR080243A1 (es) | 2010-02-23 | 2012-03-21 | Genentech Inc | Composiciones y metodos para el diagnostico y tratamiento de tumores |
MA34291B1 (fr) | 2010-05-03 | 2013-06-01 | Genentech Inc | Compositions et méthodes de diagnostic et de traitement d'une tumeur |
WO2015116902A1 (en) | 2014-01-31 | 2015-08-06 | Genentech, Inc. | G-protein coupled receptors in hedgehog signaling |
KR20210003147A (ko) | 2018-04-13 | 2021-01-11 | 제넨테크, 인크. | 안정된 항-cd79b 면역접합체 제제 |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2601675B1 (fr) * | 1986-07-17 | 1988-09-23 | Rhone Poulenc Sante | Derives du taxol, leur preparation et les compositions pharmaceutiques qui les contiennent |
US4876399A (en) * | 1987-11-02 | 1989-10-24 | Research Corporation Technologies, Inc. | Taxols, their preparation and intermediates thereof |
US5175315A (en) * | 1989-05-31 | 1992-12-29 | Florida State University | Method for preparation of taxol using β-lactam |
US5015744A (en) * | 1989-11-14 | 1991-05-14 | Florida State University | Method for preparation of taxol using an oxazinone |
MX9102128A (es) * | 1990-11-23 | 1992-07-08 | Rhone Poulenc Rorer Sa | Derivados de taxano,procedimiento para su preparacion y composicion farmaceutica que los contiene |
US5227400A (en) * | 1991-09-23 | 1993-07-13 | Florida State University | Furyl and thienyl substituted taxanes and pharmaceutical compositions containing them |
US5272171A (en) * | 1992-02-13 | 1993-12-21 | Bristol-Myers Squibb Company | Phosphonooxy and carbonate derivatives of taxol |
ES2219968T3 (es) * | 1993-06-11 | 2004-12-01 | PHARMACIA & UPJOHN COMPANY | Uso antineoplasico de delta 6,7-taxoles y composiciones farmaceuticas que los contienen. |
-
1993
- 1993-11-24 CA CA002109861A patent/CA2109861C/en not_active Expired - Fee Related
- 1993-11-26 NO NO934277A patent/NO305756B1/no unknown
- 1993-12-01 MX MX9307555A patent/MX9307555A/es not_active IP Right Cessation
- 1993-12-01 IL IL10781993A patent/IL107819A/xx not_active IP Right Cessation
- 1993-12-01 CZ CZ19932603A patent/CZ287599B6/cs not_active IP Right Cessation
- 1993-12-01 FI FI935381A patent/FI109795B/fi not_active IP Right Cessation
- 1993-12-02 NZ NZ250343A patent/NZ250343A/en unknown
- 1993-12-03 EP EP93119554A patent/EP0600517B1/en not_active Expired - Lifetime
- 1993-12-03 JP JP34215393A patent/JP3360186B2/ja not_active Expired - Fee Related
- 1993-12-03 DE DE69329327T patent/DE69329327T2/de not_active Expired - Fee Related
- 1993-12-03 DK DK93119554T patent/DK0600517T3/da active
- 1993-12-03 PT PT93119554T patent/PT600517E/pt unknown
- 1993-12-03 SG SG1996002081A patent/SG55014A1/en unknown
- 1993-12-03 AU AU52121/93A patent/AU668777B2/en not_active Ceased
- 1993-12-03 PL PL93301305A patent/PL178135B1/pl not_active IP Right Cessation
- 1993-12-03 CN CN93120068A patent/CN1049433C/zh not_active Expired - Fee Related
- 1993-12-03 ES ES93119554T patent/ES2149188T3/es not_active Expired - Lifetime
- 1993-12-03 HU HU9303428A patent/HU222347B1/hu not_active IP Right Cessation
- 1993-12-03 HU HU0103602A patent/HU221817B1/hu not_active IP Right Cessation
- 1993-12-03 AT AT93119554T patent/ATE195939T1/de not_active IP Right Cessation
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100448872C (zh) * | 2004-02-13 | 2009-01-07 | 佛罗里达州立大学研究基金有限公司 | C10环戊基酯取代的紫杉烷 |
WO2015074605A1 (zh) * | 2013-11-22 | 2015-05-28 | 天士力控股集团有限公司 | 一种紫杉烷类化合物、其制备方法和用途 |
US10253007B2 (en) | 2013-11-22 | 2019-04-09 | Jiangsu Tasly Diyi Pharmaceutical Co., Ltd. | Taxanes compounds, preparation method therefor, and uses thereof |
Also Published As
Publication number | Publication date |
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FI109795B (fi) | 2002-10-15 |
JP3360186B2 (ja) | 2002-12-24 |
MX9307555A (es) | 1995-01-31 |
CZ260393A3 (en) | 1994-07-13 |
SG55014A1 (en) | 1998-12-21 |
DK0600517T3 (da) | 2000-10-30 |
PL301305A1 (en) | 1994-06-13 |
PL178135B1 (pl) | 2000-03-31 |
PT600517E (pt) | 2000-12-29 |
IL107819A (en) | 2000-06-29 |
HU222347B1 (hu) | 2003-06-28 |
AU668777B2 (en) | 1996-05-16 |
NZ250343A (zh) | 1996-11-26 |
CA2109861C (en) | 1999-03-16 |
NO305756B1 (no) | 1999-07-19 |
EP0600517A1 (en) | 1994-06-08 |
HU221817B1 (hu) | 2003-01-28 |
AU5212193A (en) | 1994-06-16 |
GR3034686T3 (en) | 2001-01-31 |
CA2109861A1 (en) | 1994-06-05 |
HUT65640A (en) | 1994-07-28 |
HU9303428D0 (en) | 1994-04-28 |
EP0600517B1 (en) | 2000-08-30 |
DE69329327D1 (de) | 2000-10-05 |
JPH06211823A (ja) | 1994-08-02 |
NO934277D0 (no) | 1993-11-26 |
FI935381A (fi) | 1994-06-05 |
ES2149188T3 (es) | 2000-11-01 |
NO934277L (no) | 1994-06-06 |
CN1049433C (zh) | 2000-02-16 |
CZ287599B6 (en) | 2001-01-17 |
DE69329327T2 (de) | 2001-04-05 |
IL107819A0 (en) | 1994-04-12 |
ATE195939T1 (de) | 2000-09-15 |
FI935381A0 (fi) | 1993-12-01 |
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