CN100349845C - 隐杯伞素类抗肿瘤剂 - Google Patents
隐杯伞素类抗肿瘤剂 Download PDFInfo
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- CN100349845C CN100349845C CNB971978093A CN97197809A CN100349845C CN 100349845 C CN100349845 C CN 100349845C CN B971978093 A CNB971978093 A CN B971978093A CN 97197809 A CN97197809 A CN 97197809A CN 100349845 C CN100349845 C CN 100349845C
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- halogen atom
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- 229930190064 illudin Natural products 0.000 title abstract description 15
- 239000002246 antineoplastic agent Substances 0.000 title description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 92
- -1 ethylenedioxy Chemical group 0.000 claims abstract description 37
- 125000003118 aryl group Chemical group 0.000 claims abstract description 25
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 13
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 11
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims abstract description 10
- 125000006529 (C3-C6) alkyl group Chemical group 0.000 claims abstract description 9
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 9
- 229910052727 yttrium Inorganic materials 0.000 claims abstract description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 8
- 125000000539 amino acid group Chemical group 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 5
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- 206010028980 Neoplasm Diseases 0.000 claims description 44
- 125000005843 halogen group Chemical group 0.000 claims description 38
- 125000000217 alkyl group Chemical group 0.000 claims description 33
- 238000002360 preparation method Methods 0.000 claims description 28
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- 238000011282 treatment Methods 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 14
- 125000001072 heteroaryl group Chemical group 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
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- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 claims description 9
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 9
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- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims description 6
- 230000012010 growth Effects 0.000 claims description 6
- LPQOADBMXVRBNX-UHFFFAOYSA-N ac1ldcw0 Chemical compound Cl.C1CN(C)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN3CCSC1=C32 LPQOADBMXVRBNX-UHFFFAOYSA-N 0.000 claims description 5
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
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- 125000000753 cycloalkyl group Chemical group 0.000 claims 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 8
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- FZQXMGLQANXZRP-UHFFFAOYSA-N 1-(3,4-dimethoxyphenyl)-3-(3-imidazol-1-ylpropyl)thiourea Chemical compound C1=C(OC)C(OC)=CC=C1NC(=S)NCCCN1C=NC=C1 FZQXMGLQANXZRP-UHFFFAOYSA-N 0.000 description 5
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 5
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Abstract
本发明提供了通式(Ⅰ)的隐杯伞素类似物,其中R1是(CH2)n-(X)-(Y)或H,其中n是0-4;X是O或S或N或不存在;而Y是任选取代的(C1-C8)烷基,(C6-C10)芳基,(C6-C10)芳基(C1-C4)烷基或环(C3-C6)烷基,其中任选含有一个或多个杂原子;单糖,氨基酸残基,或当n为2至4时,Y为H;R2不存在;或R1和R2一起构成5-7元环;R3是(C1-C4)烷基或H;R4是H、SCH2CO2(C1-C4)烷基、O-(C5-C12)芳基或S-(C5-C12)芳基;R5是H、OH或不存在;R6是(C1-C4)烷基或不存在;R7是OH或OSi((C1-C4)烷基)3;或R6和R7一起为亚乙二氧基;R8是任选取代的(C1-C4)烷基;而由…代表的键分别存在或不存在。本发明进一步提供了含式(Ⅰ)类似物的二聚体。
Description
发明背景
在延长患者生命、满足患者过正常生活的期望方面,化疗起主要作用的人肿瘤包括伯基特氏淋巴瘤、急性淋巴细胞白血病、何杰金氏病以及约10至15种其它类型的肿瘤。例如,见A.Golden等,Eur.J.Cancer,17,129(1981)(表1)。虽然,这些肿瘤的治愈率表明了筛选系统在选择对人有效的抗肿瘤剂方面的成功,但是,这些有代表性的肿瘤仅代表了各种类型肿瘤的一小部分,特别是对临床实体瘤有高度活性的药物极少。这些药物包括环磷酰胺、阿霉素、5-FU、六甲基密胺等。因此,多种类型恶性肿瘤的患者的复发率和死亡率仍很高。
复发后,用原来的治疗方案可使一些患者病情缓解。但是,通常需要高剂量的初始化疗剂或使用附加试剂,这表明产生了至少部分抗药性。最近有证据表明可同时对几种药物产生抗药性,包括患者并未接触过的药物。多重抗药性(mdr)肿瘤的出现可能是肿瘤物质的机能并构成了治疗失败的主要原因。为了克服此抗药性,可采用带有或没有放射的高剂量化疗法并进行同种异体或自体骨髓移植。高剂量化疗可使用原来的药物(一种或多种)或可包括附加试剂。需要开发与mdr亚型不交叉耐药的新药以增进治疗方案的治疗潜力并便于原治疗患者的调整治疗。
最近,Kelner,M.等,Cancer Res.,47,3186(1987)检测了称为隐杯伞素的一类新天然产物的体外抗肿瘤活性。隐杯伞素M纯化后送到国家癌症研究所癌症治疗室(NCI DCT)进行体内药物筛选。隐杯伞素M显著增加了患Dunning白血病鼠的生命,但是对实体瘤体系其治疗指数低。隐杯伞素极高的毒性妨碍了其在人肿瘤治疗中的应用。近来,已开发了隐杯伞素的合成类似物,它们具有一定的抗肿瘤活性,文献包括美国专利5439936和5523490。
但是,仍需要抑制肿瘤特别是实体瘤生长的化疗剂,该化疗剂具有适当的治疗指数,能有效地进行体内治疗。
发明概述
本发明提供了通式(I)的隐杯伞素类似物及其药用盐:
其中R1是(CH2)n-(X)-(Y)或H;n是0-4,X是O或S或N,而Y是CH2OC(O)(C1-C4)烷基,被1至2个OH或1至2个卤原子(Cl、Br、I或F)任选取代的(C1-C8)烷基;糖类,优选单糖,更优选果糖;CH2C(O)-O-(CH2)2-O-C(O)CH2SH,(CH2)2-O-(CH2)2W,其中W是卤原子;(C1-C8)烷基-O-(C1-C8)烷基;(C6-C10)芳基,(C6-C10)芳基(C1-C4)烷基或C(O)O(C6-C10)芳基,其中芳基部分被1至2个OH、卤原子、(C1-C4)烷基或O(C1-C4)烷基任选取代;CH2CO2(C1-C4)烷基,CH2CO2H,Si((C1-C4)烷基)3,氨基酸残基,优选丙氨酰基;或者H,其条件是当Y是H,n是2至4;或者
X不存在,而Y是CHO、NO2、COOH、OAc、(C2-C4)链烯基-CHO、CH(O(C1-C4)烷基)2;环(C3-C6)烷基或任选地含1-3个选自N、S或非过氧化物O杂原子的(C5-C12)芳基,该芳基被1至2个(C1-C4烷基)、CHO、OH或卤原子任选取代;
R2是不存在;或者R1-C-C-R2一起构成5至7元环,该环任选含有一个或多个,优选1至2个,选自N、S或非过氧化物O的杂原子,并被(C1-C4)烷基、OH或卤原子任选取代;
R3是H或(C1-C4)烷基;
R4是H、SCH2CO2(C1-C4)烷基、O-(C5-C12)芳基或S-(C5-C12)芳基,其中芳基被卤原子、OH或(C1-C4)烷基任选取代;
R5是H、OH或不存在;
R6是(C1-C4)烷基或H;
R7是OH或Si((C1-C4)烷基)3;或
R6和R7一起为亚乙二氧基;
R8是(C1-C4)烷基,该烷基被OH或卤原子任选取代;
由…代表的键可存在或不存在。
优选X不存在,n是2至4。
本发明还提供了式(I)的化合物,其中环丙基被-(CH2)2OH代替,而其羰基氧被羟基代替,即式(II)的化合物:
其中R1-R4定义如式(I),…表示的键分别存在或不存在。但是,优选R1是Z为OH或卤原子的(C1-C4)烷基-Z、或-S-(C5-C12)芳基,优选-S-苯基,该芳基被1至2个OH任选取代;R2不存在;R3是(C1-C4)烷基,优选甲基;R4是-S-(CH2)n-COOH,其中n、卤原子或(C1-C4)烷基是1至4,或R4是-S-芳基,优选-S-苯基,该芳基被1至2个OH、卤原子或(C1-C4)烷基任选取代。
本发明也提供了含式(I)化合物的二聚物,其中隐杯伞素类单体相同或不同。例如,在式(I)中,R1和R4可以是X和Y都不存在的式(I)化合物。因此,本发明也提供了其中单体结构相同或不同的含式(I)化合物的二聚物。一般来说,二聚物为式(III):
其中L是连接基。例如,L可以是烷基或酯连接基团。适宜的连接基团的例子包括-CH2-O-CH2-,-(CH2)n-,其中n是1至8,以及-CH2-S-CH2C(O)-O-(CH2)2-O-C(O)CH2-S-CH2-。其它连接基团对本领域技术人员是显而易见的。虽然显示了通过每个类似物的5位碳原子连接,但是应理解此类似物可通过其它位置连接,例如3、5或7位碳原子的任意结合。连接位置不是5位时,将存在R1取代基,其定义如式(I)。连接通过3位时,应意识到环丙基部分将不存在。连接是通过每个类似物的5位时,L优选-CH2-O-CH2-或-CH2-S-CH2C(O)-O-(CH2)2-O-C(O)CH2-S-CH2-。
这些化合物用作抗肿瘤剂,即在体外或在哺乳动物宿主如人或驯养动物体内抑制肿瘤细胞生长,并对实体瘤和多重抗药性肿瘤有特殊效果。
因此,本发明提供了治疗肿瘤,即在体外或优选在体内抑制肿瘤细胞生长的治疗方法,该方法通过给哺乳动物如肿瘤病人使用抑制所述癌细胞,即肿瘤细胞生长的有效量的式(I)化合物实现。实体瘤的治疗手段相对较少,而本发明化合物特别适于实体瘤的治疗。这些肿瘤包括表皮样肿瘤和急性(AML)或慢性(CML)髓细胞样肿瘤,以及肺、卵巢、乳腺和直肠癌。本发明化合物也可直接用来治疗子宫内膜肿瘤、膀胱癌、胰腺癌、淋巴瘤、何杰金氏病、前列腺癌、肉瘤及睾丸癌,还可治疗中枢神经系统肿瘤,如脑肿瘤、成神经细胞瘤和造血细胞癌症如B细胞白血病/淋巴瘤、骨髓瘤、T细胞白血病/淋巴瘤,及小细胞白血病/淋巴瘤。这些白血病/淋巴瘤可以是急性(ALL)或慢性(CLL)的。
本发明化合物也可通过将该化合物与能结合肿瘤相关抗原的试剂连接靶向于特定的肿瘤。此抗原可位于肿瘤上或在肿瘤细胞区域内。适宜的试剂包括多克隆和单克隆抗体。该化合物-试剂复合物可进一步包括将化合物连接于试剂上的连接剂。
本发明还提供了药物组合物,如药物单剂量形式,其中含有与药用载体结合的、抗肿瘤有效量的、本发明的一种或多种隐杯伞素类似物。
在本文中,考虑到本发明的方法,术语“抑制”指与不治疗时相比降低肿瘤细胞生长速度,或引起肿瘤细胞块体积缩小。抑制也包括使治疗彻底退化。因此,本发明类似物可以是肿瘤细胞的细胞抑制剂或细胞毒物质。
被治疗对象可以是易患癌症即恶性细胞群体的或患有肿瘤的任何哺乳动物。该类似物对体内人肿瘤细胞及体外人肿瘤细胞系有效。
附图简述
图1是本发明代表性化合物的略图。
图2A是化合物33合成的略图。
图2B是化合物35合成的略图。
发明详述
本发明提供了通式(I)的隐杯伞素类似物及其药用盐:
其中R1是(CH2)n-(X)-(Y)或H;n是0-4,当X不存在时优选n是2-4;X是O或S或N,而Y是CH2OC(O)(C1-C4)烷基、被1至2个OH或1至2个卤原子任选取代的(C1-C8)烷基、糖类,优选单糖,更优选果糖、CH2C(O)-O-(CH2)2-O-C(O)CH2SH,(CH2)2-O-(CH2)2W,其中W是卤原子;(C1-C8)烷基-O-(C1-C8)烷基,优选(C1-C4)烷基-O-(C1-C4)烷基;(C6-C10)芳基、(C6-C10)芳基(C1-C4)烷基或C(O)O(C6-C10)芳基,其中芳基部分被1至2个OH、卤原子、(C1-C4)烷基或O(C1-C4)烷基任选取代;CH2CO2(C1-C4)烷基、CH2CO2H、Si((C1-C4)烷基)3、氨基酸残基,优选丙氨酰基;或者H,其条件是当Y是H,n是2至4;或者
X不存在,而Y是CHO、NO2、NH2、OH、COOH、OAc、(C2-C4)链烯基-CHO、CH(O(C1-C4)烷基)2;环(C3-C6)烷基或(C5-C12)芳基,优选C5芳基,该芳基任选地含1-3个选自N、S或非过氧化物O杂原子,并被1至2个(C1-C4烷基)、CHO、OH或卤原子任选取代;
R2不存在;或者R1-C-C-R2一起构成5至7元环,所述环任选含有一个或多个选自N、S或非过氧化物O的杂原子,并被(C1-C4)烷基、OH或卤原子任选取代;
R3是H或(C1-C4)烷基;
R4是H、SCH2CO2(C1-C4)烷基、O-(C5-C12)芳基或S-(C5-C12)芳基,其中芳基被卤原子、OH或(C1-C4)烷基任选取代;
R5是H、OH或不存在;
R6是(C1-C4)烷基或H;
R7是OH或Si((C1-C4)烷基)3;或
R6和R7一起为亚乙二氧基;
R8是(C1-C4)烷基,该烷基任选含有OH或卤原子;
由…代表的键可存在或不存在。
在进一步优选的实例中,X不存在,n是2至4,而Y是OH或OAc。
在特别优选的实例中,R1是(CH2)n-X-Y,其中n是1,X是O或S,而Y是被1至2个OH或1至2个卤原子任选取代的(C1-C8)烷基,或-(CH3)2O(C1-C4)烷基;优选R2和R5不存在;R3、R6和R8为CH3;R4是H;而R7是OH。
按照本发明的另一个优选实例,R6和R7一起为亚乙二氧基,而R1是H;R2和R5不存在;R3和R4是H,而R8是CH3。
在另一个实例中,R1是CH2OH而R7是-OSi((C1-C4)烷基)3。
在本文中,术语“烷基”包括支链或直链烷基。
在本文中,术语“糖类”包括最多含8个碳,优选最多含6个碳的单糖,以及二糖。该术语包括葡萄糖、果糖和核糖,以及脱氧糖如脱氧核糖等。
图1中所示化合物是本发明的代表化合物。
本发明化合物可衍生自隐杯伞素S,6-羟基甲基酰基亚甲基环戊二烯(HMAF,即R1是CH2OH,R2不存在,R3是甲基,R4是H,R5不存在,R6是甲基,R7是OH而R8是甲基的式(I)化合物)及亚甲基环戊二烯(即R1是H,R2不存在,R3是甲基,R4是H,R5不存在,R6是甲基,R7是OH而R8是甲基的式(I)化合物)。它们的合成是本领域已知的(例如,见WO91/04754;WO94/18151)。
除非另外说明,X是S或O的下列式(I)化合物可通过向HMAF的酸性溶液中加入适当试剂制备。
当Y是(C1-C8)烷基时,使用烷基醚。例如,化合物16(其中Y是乙基)用乙醚制备。当Y是被1至2个OH或1至2个卤原子取代的(C1-C8)烷基时,加入适宜的醇或硫醇(如果需要,加以卤化)。例如,化合物19、20和22,其中X是O而Y是2,3-二羟基丙基、2-溴乙基及2-羟乙基,分别使用甘油、2-溴乙醇和乙二醇卤化。Y是CH2OC(O)(C1-C4)烷基的化合物,通过R1为(CH2)nOCH2OH的化合物与(C1-C4)烷基C(O)Cl在碱存在下反应制备。化合物53是合成化合物20的副产物。对X为S而Y是2,3-二羟基丙基的化合物32,使用硫代甘油作为试剂。
适宜的糖类用于合成Y是单糖的式(I)化合物。例如,用果糖制备化合物18。
当Y是CH2C(O)-O(CH2)2-O-C(O)CH2SH时,即化合物51,使用一定量的二巯基乙酸乙二醇酯作为试剂。
当Y是(CH2)2-O-(CH2)2W,其中W是卤原子时,使用适当卤代的醇。例如,通过加入2-溴乙醇得到化合物53。
Y是(C1-C8)烷基-O-(C1-C8)烷基,其中(C1-C8)烷基是直链烷基的式(I)化合物,可使用与制备化合物53类似的方法制备。当(C1-C8)烷基是支链时,可通过向HMAF中加入适当的烯烃和催化量的POCl3得到所需的产物。例如,Y是2-甲氧基-2-丙基的化合物21可通过向HMAF中加入2-甲氧基丙烯制备。
当Y是(C6-C10)芳基或(C6-C10)芳基(C1-C4)烷基时,可使用硫代芳基或芳基硫醇作为试剂制备。例如,Y是(C6H4)OH的化合物23通过加入4-羟基苯硫酚制备。化合物55是合成化合物23过程中得到的副产物。通过向HMAF的酸性溶液中加入苄基硫醇制备化合物24。X是S而Y是4-甲基苯的化合物26通过向HMAF的酸性溶液中加入对甲苯硫酚制备。Y是4-甲基苯而R4是甲苯硫酚的化合物48是使用一定量的对甲苯硫酚制备化合物26时的副产物。n=O,X是S,Y是4-甲基苯而R4分别是H或甲苯硫酚的化合物49和50可通过向酰基亚甲基环戊二烯的酸性溶液中加入对甲苯硫酚制备。Y是C(O)O(C6-C10)芳基的化合物可通过向HMAF的碱性溶液中加入适当的芳基氯甲酸酯制备。例如,Y是苯基乙酸酯的化合物27是通过向HMAF溶液中加入苯基氯甲酸酯和吡啶制备的。
Y是CH2CO2(C1-C4)烷基而X是S的化合物可通过向HMAF酸性溶液中加入适当的硫醇制备。例如,Y是CH2CO2Me而R4和R5是H的化合物25,是通过向HMAF在丙酮中的酸性溶液中加入甲基硫代羟乙酸酯制备的。Y是CH2CO2Me,R4是CH2CO2Me而R5分别是H和OH的化合物30和31,是通过向HMAF在丙酮和THF中的中性溶液中加入甲基硫代羟乙酸酯制备的。化合物45是形成的副产物。
Y是CH2CO2H的化合物可通过相应的酯水解制备。例如,化合物29是上述化合物25合成过程中的副产物。CO2H基团的碱金属、碱土金属及胺盐也在本发明的范围内。
Y是Si((C1-C4)烷基)3时,将适当的硅烷化试剂加入到HMAF和咪唑的溶液中。例如,R1是三乙基甲硅烷氧基而R7分别是OH或三乙基甲硅烷氧基的化合物43和44,都可通过将三乙基甲硅烷基氯加到HMAF和咪唑的DMF溶液中得到。
当Y是氨基酸残基,例如,甘氨酰基或丙氨酰基时,可使用含氨基酸类似物的适当的硫醇,例如半胱氨酸及其类似物。例如,Y是甘氨酰基的化合物37是通过将半胱氨酸加到HMAF的酸性溶液中制备的。
X不存在的式(I)化合物可制备如下。n是2而Y是CHO的化合物,即化合物10,可通过将丙烯醛加到亚甲基环戊二烯的酸性溶液中制备。n是1而Y是CHO的化合物11,是通过用Dess Martin试剂将HMAF氧化制备的。
Y是CH(O(C1-C4)烷基)2的化合物,可通过在适当溶剂中将化合物10还原制备。例如,Y是CH(OMe)2的化合物39是通过在甲醇中化合物10与硼氢化钠反应制备的。Y是CH(OEt)2的化合物40是通过化合物10在乙醇中与硼氢化钠反应制备的。
Y是-(C2-C4)链烯基-CHO的化合物可通过将适当的链炔基醛加到HMAF的酸性溶液中制备。例如Y是-CH=CHCH(O)的化合物41是通过用丙炔基醛处理HMAF的酸性溶液制备的。
Y是环(C3-C6)烷基的化合物可通过本领域已知方法制备。例如,在合成化合物10过程中制备化合物13。
当Y是(C5-C12)芳基或杂芳基时,适当取代的芳基或杂芳基试剂被加到酸性、碱性或中性HMAF中。例如,Y是咪唑基的化合物36是通过用咪唑处理HMAF的中性THF溶液制备的。
X不存在而n是2至4的化合物可制备如下。Y是OH的化合物可通过用适当的还原试剂将相应的醛或酸还原获得。例如,用氰基硼氢化钠和乙酸将醛化合物10还原制备化合物9。乙酸存在时,得到Y是OAc的化合物。例如,化合物46是化合物10还原反应的副产物。
R1-C-C-R2构成5至7元环的化合物可通过本领域的已知方法制备。例如,通过将隐杯伞素S加到多聚甲醛的酸性溶液中制备化合物14。
R1是CH2OH而R7是((C1-C8)烷基)3SiO-的化合物可通过用适当的硅烷化试剂处理HMAF和咪唑制备。例如,化合物42是通过向HMAF和咪唑中加入三乙基甲硅烷基氯制备的。
Y是COOH的化合物38是通过用Jones试剂将化合物10氧化制备的。
可通过本领域已知的方法制备式(III)的二聚化合物。例如,通过将乙醚加到HMAF和丙酮的酸性溶液中制备化合物17。当丙烯腈被加到HMAF和丙酮的酸性溶液中时得到副产物化合物47。化合物54是合成HMAF过程中的副产物,在合成化合物51时得到化合物52。
使用的药用盐包括盐,如胺的酸加成盐和自由羟基的一、二及三磷酸酯。胺盐包括无机酸和有机酸的盐,包括盐酸盐、硫酸盐、磷酸盐、柠檬酸盐、酒石酸盐、苹果酸盐、马来酸盐、碳酸氢盐等。可通过羟基芳基与金属氢氧化物、胺或铵反应形成碱金属胺或铵盐。
本发明的化合物可制成药物组合物并以适于所选给药途径的不同形式给哺乳动物如癌症病人施用,给药途径如口服或非肠道给药,后者如静脉内、腹膜内、肌肉内或皮下途径。
因此,本发明化合物可与药用载体如惰性稀释剂或可同化的食用载体结合口服给药。它们可包封于硬或软明胶胶囊中,可压制成片剂,或可直接与病人的食物混和。对于口服治疗给药,该活性化合物可与一种或多种赋形剂混和并以可消化的片剂、口含片、锭剂、胶囊、酏剂、混悬剂、糖浆、糯米纸囊剂等形式使用。这些组合物及制剂应含有至少0.1%的活性化合物。当然,该组合物及制剂的此百分比可以变化并一般占所给单位剂型重量的2至约60%。在这些治疗用组合物中,活性化合物的量为获得有效量浓度的量。
此片剂、锭剂、丸剂、胶囊等也可含有以下成分:粘合剂如黄蓍胶、阿拉伯胶、玉米淀粉或明胶;赋形剂如磷酸二氢钙;崩解剂如玉米淀粉、马铃薯淀粉、藻酸等;润滑剂如硬脂酸镁;以及甜味剂如蔗糖、乳糖或糖精,或矫味剂如薄荷、冬青油,或草莓香料。当该单位剂型是胶囊时,除上述物质外其中还可含有液体载体,例如植物油或聚乙二醇。可存在多种其它物质作为包衣或以其它方式修饰固体单位剂型的物理形式。例如,可用明胶、蜡、虫胶或糖等包衣片剂、丸剂或胶囊。糖浆或酏剂可含有活性化合物,蔗糖甜味剂、对羟基苯甲酸甲酯或丙酯防腐剂,着色剂及矫味剂如草莓或橘味香料。当然,用于制备任何单位剂型的任何物质应是药用的并且其使用量基本无毒。此外,可将此活性化合物掺混进缓释制剂和药具中。
也可通过输液或注射将此活性化合物静脉内或腹膜内施用。此活性化合物的溶液可在水中制备,其中水任选地与无毒表面活性剂混和。也可在甘油、液体聚乙二醇、甘油三乙酸酯及其混合物以及在油中制备分散剂。在贮存和使用的普通条件下,这些制剂含有防腐剂以防止微生物生长。
适于注射或输液用的药物剂型可含有含活性组分的灭菌水溶液或分散液或灭菌粉末,该活性组分适于灭菌可注射难溶溶液或分散液的即时制备。在所有情况下,最终剂型必须灭菌,并且在制备和保存条件下为流质并稳定。该液体载体可以是溶剂或液体分散介质,例如,水、乙醇、多元醇(如甘油、丙二醇、液体聚乙二醇等)、植物油、无毒甘油酯及其适当的混合物。例如,通过形成脂质体、通过维持所需颗粒粒度或通过使用表面活性剂以保持适当的流动性。可使用多种抗细菌和抗真菌剂防止微生物作用,例如,对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸、硫汞撒等。在很多情况下,应优选包括等渗剂,例如,糖、缓冲剂或氯化钠。通过在组合物中使用延迟吸收试剂如单硬脂酸铝和明胶可使此注射组合物的吸收延长。通过将活性化合物以所需量与所需的、上述列举的多种其它组分一起在适当的溶剂中混和,然后过滤除菌制备灭菌注射溶液。对于用于制备灭菌注射溶液的灭菌粉末,优选的制备方法是真空干燥和冻干技术,该技术可得到活性组分与在上述过滤灭菌溶液中存在的任何所需附加组分的粉末。
图(I)化合物的使用剂量可通过下述方法确定:联系其体外活性及在动物模型中的体内活性,如鼠科动物或狗模型,见美国专利5439936和5523490有关隐杯伞素类似物部分,对于较高等的哺乳动物,如儿童和成人,例如,见Borch等的美国专利4938949。
该类似物的治疗有效剂量需要随被治疗对象和肿瘤变化。但是,现已发现由于与隐杯伞素S和M相比毒性低,因此可使用较高剂量的该类似物。30至112000μg每千克体重是特别有效的静脉给药治疗剂量,如果腹膜内给药,则300至112000μg每千克体重是有效的。本领域技术人员会意识到该剂量可根据给药方法变化。
本发明将通过参照下列详细的实施例进一步描述。
实施例
实施例I:隐杯伞素类似物的合成
总论:熔点未校正。1H和13C NMR在300和75MHz检测。高分辨质谱在University of Minnesota Mass Spectrometry ServiceLaboratory测定。所有色谱使用硅胶(Davisil 230-425目,FisherScientific),而除非特别说明溶剂为乙酸乙酯和己烷。分析TLC在Whatman 4420222硅胶板上进行。通过TLC常规控制反应。
隐杯伞素S、羟基甲基酰基亚甲基环戊二烯(HMAF)和亚甲基环戊二烯的合成是本领域已知的(例如,见WO91/04754;WO94/18151)。
化合物11:向搅拌的103.5mg HMAF(MW 246,0.406mmol)的15ml二氯甲烷溶液中加入327mg Dess-Martin试剂。将此混合物室温搅拌1小时并在乙醚和饱和硫酸氢钠及碳酸氢钠溶液(1∶1)之间进行萃取。用盐水将此有机萃取物洗涤至中性。用硫酸镁干燥后,将此溶液浓缩并进行色谱纯化,得到65.7mg(64.0%)化合物11,是黄色胶状物。
1H NMR(CDCl3)δ0.83(m,1H),1.19(m,1H),1.41(s,3H),1.45(m,1H),1.67(m,1H),2.31(s,3H),2.50(s,3H),3.80(s,1H),7.08(s,1H),10.25(s,1H);MS m/z 244(M+);UVλmax 241nm(∈14000),293nm(∈12000).
化合物12(6-硝基酰基亚甲基环戊二烯):将酰基亚甲基环戊二烯(99mg,0.46mmol)溶解于二氯甲烷(20ml)并在氮气氛下向此溶液中加入四氟硼酸硝(141mg,1.1mmol)。形成暗棕色沉淀;将此化合物搅拌4小时,再加入四氟硼酸硝(53mg)并继续搅拌2小时。加入水(5ml)并用二氯甲烷(3×25ml)萃取此混合物。将合并的萃取物用饱和碳酸氢钠溶液、水洗涤,然后用硫酸镁干燥。除去溶剂并将此残余物用己烷-乙酸乙酯洗脱进行色谱纯化,得到硝基化合物12,为黄色固体(30mg)。
1H NMRδ0.90(ddd,1H),1.23(ddd,1H),1.50(ddd,1H),1.69(ddd,1H),1.46(s,3H),2.02(s,3H),2.34(s,3H),6.97(s,1H).MS m/z 261(M+-CH3),244(M+-OH),215(M+-NO2).
化合物14:向250ml 1M硫酸和200ml丙酮的溶液中加入40g多聚甲醛(MW 30,1.33mmol)。将此溶液加热至澄清,然后冷却至室温。向上述溶液中加入1g隐杯伞素S(MW 264,3.79mmol)。将此混合物室温搅拌72小时并在乙酸乙酯和水之间萃取。用饱和碳酸氢钠和盐水分别洗涤此萃取物至中性。用硫酸镁干燥后,浓缩此溶液并进行色谱纯化,得到245mg化合物14(23.4%)和226mg HMAF(24.3%)。化合物14是白色结晶。
mp 100.5-102.5;IR(KBr)3469,2966,2858,1703,1656,1596,1172cm-1;1H NMR(CDCl3)δ0.48(m,1H),0.84(m,1H),0.99(m,1H),1.10(s,3H),1.17(m,1H),1.32(s,3H),1.67(s,3H),3.61(s,1H),3.73(d,J=11.7Hz,1H),3.96(d,J=11.7Hz,1H),4.56(s,1H),4.75 (d,J=5.4Hz,1H),4.91(d,J=5.4Hz,1H),6.52(s,1H);13C NMR(CDCl3)δ199.7,141.4,136.5,135.9,134.7,90.0,80.3 75.9,70.8,46.8,32.3,24.7,22.5,13.8,8.9,5.6;MSm/z 276(M+),217,201,173;HRMS for C16H20O4理论值276.1362,实测值276.1364;UVλmax305nm(∈3148).
化合物23:向170mg HMAF(MW 246,0.691mmol)的15ml丙酮和1M硫酸溶液(1∶1)中加入63mg 4-羟基噻吩(MW 126,0.5mmol)。将此混合物在室温搅拌2小时并在乙酸乙酯和水之间萃取。用饱和碳酸氢钠和盐水分别洗涤有机萃取物至中性。用硫酸镁干燥后,浓缩此溶液并进行色谱纯化得到128mg(72.3%)化合物23黄色胶状物。
IR(KBr)3360,2974,1646,1592,1588,1495cm-1;1HNMR(CDCl3)δ0.75(m,1H),1.09(m,1H),1.38(m,1H),1.42(s,3H),1.52(m,1H),1.70(s,3H),2.14(s,1H),3.96(q,JAB=13.2Hz,2H),6.77(d,J=8.4Hz,2H),7.07(s,1H),7.20(d,J=8.4Hz,1H);13C NMR(CDCl3)δ197.9,159.6,156.7,142.4,138.2,136.0,135.9,132.9,131.5,125.8,123.6,116.1,115.9,76.2,37.6,34.2,27.8,16.3,14.2,12.5,9.5;MS m/z 354(M+),298,270.229;HRMS for C21H22O3S理论值354.1296,实测值354.1286;UVλmax(甲醇)332nm(∈7844).
化合物24:向117mg HMAF(MW 246,0.475mmol)的15ml丙酮和1M硫酸溶液(1∶1)中加入46mg苄基硫醇(MW 124,0.371mmol)。将此混合物在室温搅拌过夜并在乙酸乙酯和水之间萃取。用饱和碳酸氢钠和盐水分别洗涤有机萃取物至中性。用硫酸镁干燥后,浓缩此溶液并进行色谱纯化得到100mg(76.6%)化合物24黄色胶状物。
IR(KBr)3451,
2980,1659,1598,1496,1097cm-1,1H NMR(CDCl3)δ0.64(m,1H),1.02(m,1H),1.29(m,1H),1.33(s,3H),1.46(m,1H),1.91(s,3H),1.98(s,3H),3.62(s,2H),3.71(s,2H),7.06(s,1H),7.29(m,5H);13C NMR(CDCl3)δ197.2,159.5,141.8,138.4,137.8,134.9,130.1,128.7,128.3,126.9,126.0,75.9,37.5,36.8,28.6,27.5,15.7,14.1,12.8,9.3;MS m/z 352(M+),294,229;HRMS forC22H24O2S理论值352.1497,实测值352.1488;UVλmax(甲醇)332nm(∈8431).
化合物25和29:向166mg HMAF(MW 246,0.675mmol)的15ml丙酮和1M硫酸溶液(1∶1)中加入51mg巯基乙酸甲酯(MW 106,0.481mmol)。将此混合物在室温搅拌过夜并在乙酸乙酯和水之间萃取。用饱和碳酸氢钠和盐水分别洗涤有机萃取物至中性。用硫酸镁干燥后,浓缩此溶液并进行色谱纯化得到59mg化合物25(36.7%)和94mg(61.1%)化合物29。化合物25是黄色胶状物:
IR(KBr)3451,2944,1731,1665,1592,1496,1278cm-1;1H NMR(CDCl3)δ0.72(m,1H),1.07(m,1H),1.35(m,1H),1.37(s,3H),1.49(m,1H),2.12(s,3H),2.16(s,3H),3.23(s,2H),3.74(s,3H),3.92(q,JAB=12.3Hz,2H),7.09(s,1H);13C NMR(CDCl3)δ197.5,170.7,159.6,142.5,138.3,134.7,129.1,126.5,76.1,52.3,37.6,33.2,29.6,27.5,16.1,14.2,12.9,9.5;UVλmax(methanol)334nm(∈8093).化合物29也是黄色胶状物:1H NMR(CDCl3)δ0.73(m,1H),1.09(m,1H),1.32(m,1H),1.37(s,3H),1.50(m,1H),2.12(s,3H),2.16(s,3H),3.25(s,2H),3.93(m,2H),7.11(s,1H);13C NMR(CDCl3)δ197.8,174.7,159.8,142.7,138.2,135.1,129.4,126.4,76.1,37.7,33.2,29.6,27.6,16.2,14.3,12.9,9.5
化合物26:向125mgHMAF(MW 246,0.508mmol)的20ml丙酮和1M硫酸溶液(1∶1)中加入59mg对甲苯硫酚(MW 124,0.476mmol)。将此混合物在室温搅拌5小时并在乙酸乙酯和水之间萃取。用饱和碳酸氢钠和盐水分别洗涤有机萃取物至中性。用硫酸镁干燥后,浓缩此溶液并进行色谱纯化得到127mg(75.8%)化合物26黄色胶状物:
IR(KBr)3456,2972,1663,1596,1500,1092cm-1;1H NMR(CDCl3)δ0.71(m,1H),1.07(m,1H),1.32(m,1H),1.38(s,3H),1.50(m,1H),1.82(s,3H),2.14(s,3H),2.31(s,3H),3.97(s,1H),4.04(q,JAB=12.9Hz,2H),7.05(s,1H),7.07(d,q=8.1Hz,2H),7.23(d,q=7.8Hz,2H);13C NMR(CDCl3)δ197.3,159.2,142.3,138.4,137.3,135.0,132.2,131.3,129.8,129.5,126.1,76.0,37.5,33.1,27.6,21.0,16.1,14.1,12.6,9.4;MS m/z 352(M+),297,250,229;HRMS for C22H24O2S理论值352.1497,实测值352.1499;UVλmax(甲醇)333nm(∈6598).
化合物32:向195mgHMAF(MW246,0.793mmol)的10ml丙酮和1M硫酸溶液(1∶1)中加入70.2mg硫代甘油(MW 92,0.763mmol)。将此混合物在室温搅拌20小时并在乙酸乙酯和水之间萃取。用饱和碳酸氢钠和盐水分别洗涤有机萃取物至中性。用硫酸镁干燥后,浓缩此溶液并进行色谱纯化得到147mg(78.3%)化合物32黄色胶状物。
IR(KBr)3385,2908,1658,1586,1495,1284cm-1;1H NMR(CDCl3)δ0.72(m,1H),1.09(m,1H),1.26(m,1H),1.36(s,3H),1.49(m,1H),2.10(s,3H),2.16(s,3H),2.65(m,3H),3.81(m,5H),4.03(s,1H),7.10(s,1H);13C NMR(CDCl3)δ197.6,159.6,141.8,138.2,135.1,130.4,126.2,76.1,70.7,70.6,65.2,37.6,35.2,35.1,29.5,29.4,27.6,16.3,14.2,13.1,9.5;MS m/z 336(M+),261,229,201;HRMSfor C18H24O4S理论值336.1395实测值336.1395;UVλmax(甲醇)332nm(∈6893).
化合物16:向22mg HMAF(MW 246,0.089mmol)的3ml丙酮和1M硫酸溶液(1∶1)中加入7.5ml乙醚。将此混合物在室温搅拌24小时并在乙酸乙酯和水之间分配。用饱和碳酸氢钠和盐水分别洗涤有机萃取物至中性。用硫酸镁干燥后,浓缩此溶液并进行色谱纯化得到17mg(80.2%)化合物16黄色胶状物。
IR(KBr)3457,2968,1659,1592,1502,1284,1097cm-1;1H NMR(CDCl3)δ0.72(m,1H),1.08(m,1H),1.23(t,J=6.9Hz,3H),1.33(m,1H),1.38(s,3H),1.48(m,1H),2.11(s,3H),2.14(s,3H),3.53(q,J=6.9Hz,2H),3.91(s,1H),4.42(q,JAB=10.7,2H),7.10(s,1H);13C NMR(CDCl3)δ197.4,159.5,142.2,138.8,134.3,130.0,126.4,75.8,65.0,63.5,37.2,27.2,15.6,14.8,13.8,12.7,9.0;MS m/z 274(M+),261,228.200,185;HRMS for C17H22O3理论值274.1569实测值274.1568;UVλmax(甲醇)330nm(∈7225)
化合物17:向36mgHMAF(MW246,0.146mmol)的3ml丙酮和1M硫酸溶液(1∶1)中加入0.5ml乙醚。将此混合物在室温搅拌30小时并在乙酸乙酯和水之间分配。用饱和碳酸氢钠和盐水分别洗涤有机萃取物至中性。用硫酸镁干燥后,浓缩此溶液并进行色谱纯化得到5mg(14.4%)化合物17,11mg化合物16和13mg HMAF。化合物17是黄色胶状物:
IR(KBr)3433,2920,1659,1592,1502,1350,1163cm-1;1H NMR(CDCl3)δ0.67(m,1H),1.08(m,1H),1.31(m,1H),1.37(s,3H),1.48(m,1H),2.07(s,3H),2.11(s,3H),4.48(s,2H),7.10(s,1H);13C NMR(CDCl3)δ197.9,159.9,143.3,139.1,134.6,129.6,126.8,76.1,63.2,37.6,27.5,15.9,14.2,13.1,9.4;MS m/z 475(M+H),391,307,229;HRMS for C30H34O5(M+H)理论值475.2535实测值475.2467;UVλmax(甲醇)330nm(∈12905).
化合物18:向1.5gHMAF(MW 246,6.098mmol)的66ml丙酮和40ml 1M硫酸溶液(1∶1)中加入20g果糖。将此混合物在室温搅拌过夜并在乙酸乙酯和水之间分配。用饱和碳酸氢钠和盐水分别洗涤有机萃取物至中性。用硫酸镁干燥后,浓缩此溶液并进行色谱(用二氯甲烷和甲醇作溶剂)纯化得到350mg化合物18(14.1%,混合物)黄色胶状物(其中含有回收的701mg HMAF);
IR(KBr)3397,2932,1659,1574,1369,1085cm-1;MS m/z 409(M+H),307,229,203;HRMS for C21H28O8(M+H)理论值409.1863,实测值409.1869;UVλmax(甲醇)332nm(∈4745).
化合物19:向110mgHMAF(MW246,0.447mmol)的15ml丙酮和1M硫酸溶液(1∶1)中加入5ml甘油。将此混合物在室温搅拌22小时并在乙酸乙酯和水之间分配。用饱和碳酸氢钠和盐水分别洗涤有机萃取物至中性。用硫酸镁干燥后,浓缩此溶液并进行色谱(向一般溶剂系统中加入5%甲醇)纯化得到79mg化合物19(55.2%)黄色胶状物(其中含有回收的40mg HMAF):
IR(KBr)3415,2926,1659,1586,1103cm-1;1H NMR(CDCl3)δ0.72(m,1H),1.08(m,1H),1.26(m,1H),1.37(s,3H),1.50(m,1H),2.10(s,3H),2.15(s,3H),2.57(s,1H),3.58(m,4H),3.86(m,1H),3.91(s,1H),4.51(q,JAB=12.9Hz,2H),7.10(s,1H);13C NMR(CDCl3)δ198.0,160.1,143.2,138.8,134.6,129.4,126.9,76.2,70.9,70.6,64.4,63.8,37.6,27.4,16.1,14.2,13.1,9.4;MS m/z 320(M+),277,228,185;HRMS C18H24O5理论值320.1623,实测值320.1616;UVλmax(甲醇)331nm(∈7920).
化合物20和53:向188mg HMAF(MW 246,0.764mmol)的10ml丙酮和1M硫酸溶液(1∶1)中加入5ml 2-溴代乙醇。将此混合物在室温搅拌4.5小时并在乙酸乙酯和水之间萃取。用饱和碳酸氢钠和盐水分别洗涤有机萃取物至中性。用硫酸镁干燥后,浓缩此溶液并进行色谱纯化得到179.2mg化合物20(66.4%)黄色胶状物。
IR(KBr)3445,2914,1650,1592,1502.1097cm-1;1HNMR(CDCl3)δ0.71(m,1H),1.07(m,1H),1.35(m,1H),1.38(s,3H),1.48(m,1H),2.15(s,3H),3.47(t,J=6.0Hz,2H),3.77(t,J=6.0Hz,2H),3.91(s,1H),4.54(q,JAB=12Hz,2H),7.09(s,1H);13C NMR(CDCl3)δ198.1,160.6,143.2,138.9,134.4,129.3,127.0,76.3,69.4,64.1,37.7,30.6,27.6,16.4,14.3,13.2,9.5;MS m/z 352(M-H),326,228,285;HRMS for C17H21BrO3(M-H)理论值352.0674实测值352.0671;UVλmax(甲醇)332nm(∈7777).产物化合物53为黄色胶状物:
1H NMR(CDCl3)δ0.72(m,1H),1.05(m,1H),1.32(m,1H),1.37(s,3H),1.50(m,1H),2.13(s,3H),2.15(s,3H),3.46(t,J=6.3Hz,2H),3.65(m,4H),3.79(t,J=6.3Hz,2H),3.90(s,1H),4.51(q,JAB=12Hz,2H),7.09(s,1H).
化合物21:向260mg HMAF(MW 246,1.057mmol)的6ml 2-甲氧基丙烯溶液中加入2滴三氯氧磷。将此混合物在室温搅拌6天并在乙酸乙酯和水之间萃取。用饱和碳酸氢钠和盐水分别洗涤有机萃取物至中性。用硫酸镁干燥后,浓缩此溶液并进行色谱纯化得到133mg化合物21(39.6%)黄色胶状物(其中含有回收的87mg HMAF):
IR(KBr)3457,2980,1665,1598,1502,1091cm-1,1H NMR(CDCl3)δ0.72(m,1H),1.06(m,1H),1.25(m,1H),1.38(s,3H),1.41,(s,3H),1.42(s,3H),1.49(m,1H),2.15(s,3H),3.25(s,6H),3.95(s,1H),4.43(s,2H),7.11(s,1H);13C NMR(CDCl3)δ197.7,159.5,142.2,134.9,134.8,130.5,126.7,100.3,76.1,54.4,48.6,37.4,27.5,24.4,24.3,15.9,14.0,13.0,9.3;MS m/z 318(M+),260,229,185,73;HRMS for C19H26O4理论值318.1831,实测值318.1823;UVλmax(甲醇)330nm(∈8728).
化合物22:向9.0mg HMAF(MW 246,0.037mmol)的9ml丙酮和1M硫酸溶液(1∶1)中加入4.5ml乙二醇。将此混合物在室温搅拌2小时并在乙酸乙酯和水之间萃取。用饱和碳酸氢钠和盐水分别洗涤有机萃取物至中性。用硫酸镁干燥后,浓缩此溶液并进行色谱纯化得到11mg化合物22(100%)黄色胶状物:
IR(KBr)3439,2914,1665,1598,1508,1344,1103cm-1,1H NMR(CDCl3)δ0.71(m,1H),1.06(m,1H),1.32(m,1H),1.36(s,3H),1.47(m,1H),2.11(s,3H),2.14(s,3H),2.55(s,1H),3.57(t,J=4.5Hz,2H),3.73(t,J=4.5Hz,2H),3.98(s,1H),4.50(q,JAB=12Hz,2H),7.09(s,1H);13C NMR(CDCl3)δ197.9,160.0,142.9,138.9,134.5,129.6,126.8,76.1,70.9,64.2,61.6,37.5,27.4,16.0,14.1,13.1,9.3;MS m/z 290(M+),250,228,185;HRMS C17H22O4理论值290.1518,实测值190.1515;UVλmax(甲醇)331nm(∈9404)
化合物10和13:向1g亚甲基环戊二烯(MW 216,4.63mmol)的5ml丙酮和2.5ml 2M硫酸溶液中加入2.5ml丙烯醛。将此混合物在室温搅拌7小时并在乙酸乙酯和水之间萃取。用饱和碳酸氢钠和盐水分别洗涤有机萃取物至中性。用硫酸镁干燥后,浓缩此溶液并进行色谱纯化得到378mg化合物10(30.0%)和241mg化合物13(13.6%)。化合物10是黄色胶状物:
0.68(m,1H),1.07(m,1H),1.32(m,1H),1.36(s,3H),1.46(m,1H),2.01(s,3H),2.06(s,3H),2.65(t,J=7.8Hz,2H),3.00(m,2H),3.93(s,1H),7.12(s,1H),9.83(s,1H);13C NMR(CDCl3)δ200.4,196.3,157.3,139.4,138.3,135.4,133.7,125.3,75.4,43.5,36.9,27.0,19.5,15.4,13.4,12.4,8.6;MS m/z 272(M+),244,215,201;HRMSfor C17H20O3理论值272.1413,实测值272.1416;UVλmax(甲醇)332nm(∈8500)化合物13也是黄色胶状物(混合物):HRMS C23H28O5理论值384.1937,实测值384.1947;UVλmax(甲醇)329nm(∈6000).
化合物30、31和45:向108mg HMAF(MW 246,0.439mmol)的40ml丙酮和THF(1∶1)中加入1.5ml巯基乙酸甲酯。将此混合物在室温搅拌4天并在乙酸乙酯和水之间萃取。用饱和碳酸氢钠和盐水分别洗涤有机萃取物至中性。用硫酸镁干燥后,浓缩此溶液并进行色谱纯化得到44mg化合物30、20mg化合物31和29mg化合物45。化合物30是黄色胶状物:
1H NMR(CDCl3)δ0.70(m,1H),1.09(m,1H),1.33(s,3H),1.35(m,1H),1.50(m,1H),2.14(s,3H),2.15(s,3H),3.23(s,2H),3.67(s,3H),3.74(s,3H),3.92(s,2H),4.08(m,3H);MS m/z 438(M+),424,333,315;HRMS C21H26O6S2理论值438.1172,实测值438.1188;UVλmax(甲醇)372nm(∈10760),243nm(∈14364).化合物31为谈黄色胶:1HNMR(CDCl3)δ0.46(m,1H),0.88(m,1H),1.04(m,1H),1.32(s,3H),1.38(m,1H),1.87(s,3H),2.03(s,3H),3.13(m,2H),3.44(m,3H),3.73(s,3H),3.77(s,3H),4.02(s,1H),4.41(q,2H);MS m/z 456(M+),425,351,333;HRMSC21H28O7S2理论值456.1277,实测值456.1288;UVλmax(甲醇)263nm(∈17264),204nm(∈8648).化合物45也是黄色胶 MS m/z 352(M+),334,263,244,229,201;HRMS C18H24O5S理论值352.1345,实测值352.1333;UVλmax(甲醇)328nm(∈2692),238nm(∈11099).
化合物9:向30mg化合物10(MW 27 2,0.110mmol)的5ml THF溶液中加入5滴乙酸和一些氰基硼氢化钠。将此混合物室温搅拌1小时并在乙酸乙酯和水之间萃取。用饱和氯化铵和盐水分别洗涤有机萃取物。用硫酸镁干燥后,浓缩此溶液并进行色谱纯化得到21mg化合物9(69.5%)黄色胶状物:
1HNMR(CDCl3)δ0.67(m,1H),1.06(m,1H),1.26(m,1H),1.36(s,3H),1.46(m,1H),1.73(m,2H),2.06(s,3H),2.07(s,3H),2.74(m,2H),3.70(t,J=6.3Hz,2H),3.96(s,1H),7.14(s,1H);13C NMR(CDCl3)δ197.0,157.7,139.6,139.0,136.6,136.5,128.2,75.9,62.0,37.3,33.0,27.5,24.0,15.9,13.8,12.8,9.0;MSm/z 274(M+),246,215,187;HRMS C17H22O3理论值274.1569,实测值274.1557;UVλmax(甲醇)330nm(∈6700)
化合物27:在0℃氩气氛下,向163mg HMAF(MW 246,0.663mmol)的10ml二氯甲烷溶液中加入0.18ml吡啶和0.34ml氯代甲酸苯基酯。将此混合物搅拌3小时并在乙酸乙酯和水之间萃取。用盐水洗涤有机萃取物。用硫酸镁干燥后,浓缩此溶液并进行色谱纯化得到20mg化合物27黄色胶状物:
1H NMR(CDCl3)δ0.85(m,1H),1.18(m,1H),1.43(m,1H),1.52(s,3H),1.61(m,1H),2.12(s,3H),2.28(s,3H),4.04(s,1H),5.06(q,JAB=11.1Hz,2H),6.93-7.47(m,6H)
化合物28:在氩气氛下,向116mg HMAF(MW 246,0.447mmol)的10ml二氯甲烷溶液中加入0.10ml吡啶和0.25ml苄基氯。将此混合物浓缩并进行色谱纯化得到152mg化合物28(92.1%)黄色胶状物(其中含回收的13mg HMAF):
1H NMR(CDCl3)δ0.65(m,1H),1.02(m,1H),1.18(m,1H),1.32(s,3H),1.44(m,1H),2.03(s,3H),2.16(s,3H),3.86(s,1H),5.28(q,JAB=13.2Hz,2H),7.06(s,1H).
化合物33:按照图2A所示的方案制备化合物33。化合物A按照文献制备,为白色固体:
mp 134-6℃;IR(KBr)2993,2952,1757,1743,1454cm-1;1H NMR(CDCl3)d 0.74(m,1H),1.03(m,1H),1.13(m,1H),1.25(s,3H),1.32(m,1H),2.08(m,2H),2.27(m,2H),2.54(d,J=7.5 Hz,1H),2.92(m,1H),4.45(s,1H);13C NMR(CDCl3)d 216.6,211.4,87.7,87.4,57.6,41.3,39.2,38.3,25.1.14.1,13.4,11.9;MS m/z 206(M+),177,149,124;HRMS C12H14O3理论值206.0943,实测值206.0941.
化合物B——在25℃,向搅拌的化合物A(2.83g,13.7mmol)的2-丙醇(500ml)溶液中,加入碳酸钾(8g,58.0mmol)。将此混合物搅拌7天,然后在乙酸乙酯和水之间萃取。用饱和氯化铵洗涤有机萃取物并硫酸镁干燥。然后将此粗品浓缩并进行色谱纯化得到1.88g化合物A和0.78g化合物B(82.1%)。化合物B是白色固体:
mp 183-5℃;IR(KBr)3369,2995,1696,1616,1407,1367,1226cm-1;1H NMR(CDCl3)d 1.24(m,1H),1.38(m,1H),1.68(m,1H),1.88(m,1H),2.00(s,3H),2.16(m,2H),2.46(m,2H),3.21(m,1H),4.06(d,J=2.7Hz,1H);13C NMR(CDCl3)d 206.1,204.8,147.5,128.0,72.0,42.2,39.5,32.1,21.7,19.4,18.6,11.7;MS m/z 206(M+),177,150,147;HRMS C12H14O3理论值206.0943,实测值206.0944.
化合物C——在25℃,将对甲苯磺酸(12mg,0.063mmol)加到搅拌的化合物B(107mg,0.519mmol)和乙二醇(3.04g,49mmol)的苯(10ml)溶液中,将其随后搅拌24小时。将此混合物在乙酸乙酯和饱和碳酸氢钠之间萃取。用盐水洗涤合并的有机层,用硫酸镁干燥并浓缩为油状物,将其色谱纯化得到5mg化合物B和118mg化合物C(95.3%),化合物C为无色油状物:
IR(KBr)3469,2952,2892,1757,1690,1616,1374,1159,1085cm-1;1H NMR(CDCl3)d 1.00(m,3H),1.36(m,1H),1.88(d,J=2.7Hz,3H),1.96(m,2H),2.36(m,2H),3.19(t,J=3.9Hz,1H),3.78(t,J=3.9Hz,1H),4.00(m,4H);13C NMR(CDCl3)d 205.4,148.3,128.3,108.9,67.9,65.6,64.5,41.9,39.3,26.8,20.8,12.8,11.5,6.22;MS m/z 250(M+),221,193,177;HRMSC14H18O4理论值250.1205实测值250.1201.
化合物D——在氮气氛下,向搅拌的化合物C(8.0mg,0.032mmol)的吡啶(0.5ml)溶液中加入TESCl(0.1ml,0.25mmol)。将此混合物在60℃搅拌30分钟,然后浓缩为油状物。通过色谱将此粗品纯化得到13mg化合物D(定量),为无色油状物:
IR(KBr)2959,2885,1710,1610,1454,1414,1381,1219cm-1;1H NMR(CDCl3)d 0.62(q,J=7.8Hz,6H),0.94(m,11H),1.28(m,1H),1.83(m,1H),1.87(d,J=2.4Hz,3H),2.35(m,2H),3.13(m,2H),3.75(d,J=3.3Hz,1H),4.01(m,4H);13C(CDCl3)d 205.6,148.8,128.8,109.5,69.1,65.3,64.7,43.3,39.5,27.4,21.5,12.9,11.6,6.8,6.5,4.8;MS m/z 364(M+),336,291,219,161;HRMS C20H32O4Si理论值364.2070实测值364.2070.
化合物E——在氮气氛下,将化合物D(13mg,0.0357mmol)和苯基亚硒酸酐(13mg,0.0361mol)的氯代苯(0.5ml)溶液在95℃搅拌0.5小时。然后将此溶液浓缩并进行色谱纯化得到4.9mg化合物D和7.0mg化合物E(78.2%),化合物E为无色油状物:
IR(KBr)2959,2878,1716,1683、1622,1454,1381,1213cm-1;1H NMR(CDCl3)d 0.54(q,J=6.3Hz,6H),0.89(m,10H),1.27(m,2H),1.57(m,1H),1.93(m,3H),3.79(s,1H),4.00(m,4H),6.30(dd,J=2.4,6Hz,1H),7.28(dd,J=2.1,6Hz,1H);13C NMR(CDCl3)d 195.9,154.7,146.9,137.7,127.5,109.5,69.2,65.5,64.6,47.4,28.0,12.8,11.1,7.1,6.7,5.0;MS m/z 362(M+),333,289,187,159,87;HRMS C20H30O4Si理论值362.1913实测值362.1919.
化合物I——向化合物E(20mg,0.055mmol)和CeCl3·7H2O(35mg,0.094mmol)的甲醇(1ml)溶液中加入硼氢化钠(过量)。将此混合物在25℃搅拌15分钟后,再加入硼氢化钠。搅拌15分钟后,将此混合物在乙醚和饱和氯化铵之间萃取。用硫酸镁干燥此醚萃取物并浓缩得到粗品化合物F,为淡黄色油状物。
向上述粗品化合物F的二氯甲烷(1ml)溶液中,在25℃分别加入Et3N(20ml,0.143mmol)和MsCl(20ml,0.258mmol)。搅拌5分钟。然后将此混合物在乙醚和饱和碳酸氢钠之间萃取。用盐水洗涤此醚萃取物并用硫酸镁干燥。浓缩后,色谱纯化得到化合物H和化合物I,为黄色胶状物。
室温向上述化合物H的丙酮(2ml)和水(1ml)溶液中加入一些对苯甲磺酸。将此混合物放置5分钟并在乙醚和饱和碳酸氢钠之间萃取。然后用盐水洗涤此醚萃取物并用硫酸镁干燥。浓缩并色谱纯化后,与上述产物I混合得到10.5mg化合物I,为黄色胶状物:
IR(KBr)3456,2912,2885,1730,1636,1441,1367cm-1;1H NMR(CDCl3)d 0.75(m,1H),1.10(m,2H),1.24(m,1H),1.88(s,3H),2.34(d,J=6.9Hz,1H),3.95(m,2H),4.06(m,2H),4.68(d,J=5.7Hz,1H),6.34(m,1H),6.42(m,2H):13C NMR(CDCl3)d 152.0,139.8,134.6,130.5,125.3,117.9,111.9,71.3,67.0,66.1,31.5,16.4,9.5,6.6;MS m/z 232(M+),215,189,160,145;HRMS for C14H16O3理论值232.1099实测值232.1093.
化合物33——将化合物I(7.3mg,31mmol)和重铬酸吡啶(26mg,69mmol)的二氯甲烷(1ml)溶液在25℃搅拌1小时。用乙醚稀释此混合物并随后过滤。将此浓缩的粗品色谱纯化得到5.2mg化合物33(71.9%),为黄色结晶:
mp138-140℃;IR(KBr)2959,2892,1683,1616,1549,1441,1360cm-1;1H NMR(CDCl3)d 1.14(m,2H),1.35(m,2H),2.06(s,3H),4.02(m,2H),4.16(m,2H),6.63(dd,J=2.4,4.8Hz,1H),6.76(d,J=4.8Hz,1H),7.39(s,1H);13C NMR(CDCl3)d 187.6,159.6,140.3,135.4,131.0,127.9,124.8,106.2,66.0,33.4,16.9,12.9;MS m/z 230(M+),202,158;HRMS C14H14O3理论值230.0942,实测值230.0948;UVlmax(甲醇)230nm(e6543),330(e3484).
化合物35:按照图2B所示的方案制备化合物35。化合物J——向化合物B(37mg,0.18mmol)的吡啶(3ml)溶液中加入TESCl(0.25ml,0.624mmol)。将此混合物在氮气氛下在60℃搅拌0.5小时。浓缩并色谱纯化后,得到50mg化合物J(87%),为无色油状物:
IR(KBr)2952,2872,1703,1622,1461,1414,1226cm-1;1H NMR(CDCl3)d 0.58(q,J=7.8Hz,6H),0.97(m,10H),1.25(m,2H),1.58(m,1H),1.85(m,2H),1.98(s,3H),2.42(m,2H),3.09(b,1H),4.01(d.J=3Hz,1H);13C NMR(CDCl3)d 206.0,205.0,147.0,128.6,72.6,43.0,39.6,32.1,21.4,19.6,18.0,11.5,6.5,4.5;MS m/z 320(M+),291,259,HRMS C18H28O3Si理论值320.1808实测值320.1803.
化合物K——在氮气氛下,将化合物J(278mg,0.869mmol)和苯基亚硒酸酐(320mg,0.889mmol)的氯代苯(2.5ml)溶液在95℃搅拌0.5小时。然后将此溶液浓缩并进行色谱纯化得到58.7mg化合物J和131.2mg化合物K(60.2%),为无色胶状物:
IR(KBr)2952,2878,1730,1690,1636,1454,1240cm-1;1H NMR(CDCl3)d 0.52(q,J=7.8Hz,6H),0.85(t,J=7.8Hz,9H),1.20(m,1H),1.36(m,1H),1.69(m,1H),1.82(m,1H),2.06(s,3H),3.58(s,1H),4.26(d,J=2.4Hz,1H),6.45(dd,J=2.1,6Hz,1H),7.33(dd,J=2.1,6Hz,1H);13C NMR(CDCl3)d 205.9,195.3,153.2,144.3,139.4,127.7,72.1,47.3,32.4 , 20.1,19.7,11.4,6.4,4.4;MS m/z 318(M+),289,261;HRMS C18H26O3Si理论值318.1651实测值318.1658.
化合物N——在25℃,向化合物K(9.5mg,0.0299mmol)和CeCl3·7H2O(58.5mg,0.157mmol)的甲醇(0.3ml)溶液中加入硼氢化钠(过量)。搅拌30分钟。将此混合物在乙醚和饱和氯化铵之间萃取。用硫酸镁干燥此醚萃取物并浓缩得到粗品化合物L,为淡黄色油状物。
向上述粗品化合物L的二氯甲烷(0.2ml)溶液中,在25℃分别加入Et3N(5ml,0.036mmol)和MsCl(5ml,0.965mmol)。将此混合物搅拌5分钟,然后将此混合物在乙醚和饱和碳酸氢钠之间分离。用盐水洗涤此醚萃取物并用硫酸镁干燥。浓缩后,色谱纯化得到8.2mg化合物N(90.3%),为黄色胶状物。
IR(KBr)3557,3449,2946,2878,1716,1643,1461.1112cm-1;1H NMR(CDCl3)d 0.66(q,J=7.8Hz,6H),0.87(m,2H),0.98(t,J=7.8Hz,9H),1.26(m,2H),1.86(s,3H),2.55(d,J=3.9Hz,1H),3.24(s,1H),4.94(d,J=2.1Hz,1H),6.35(m,2H),6.46(m,1H);13C NMR(CDCl3)d 148.9,140.0,130.4,117.8,117.5,77.0,68.6,61.9,16.1,11.6,7.8,6.8,5.0;MS m/z 304(M+),287,275;HRMS C18H28O2Si理论值304.1859实测值304.1860.
化合物O——在25℃,将化合物N(1.2mg,3.95mmol)和Dess-Martin试剂(2.2mg,5.19mmol)的二氯甲烷(0.2ml)溶液搅拌30分钟。将此混合物在乙醚和10%亚硫酸钠之间分离。然后用盐水洗涤此醚萃取物并用硫酸镁干燥。浓缩后,进行色谱纯化得到1.1mg化合物O(92.3%),为黄色胶状物:
IR(KBr)2952,2872,1690,1610,1549,1354,1132cm-1;1H NMR(CDCl3)d 0.71(q,J=7.8Hz,6H),0.85(m,1H),0.97(t,J=7.8Hz,9H),1.21(m,2H),1.45(m,1H),2.08(s,3H),4.50(s,1H),6.66(dd,J=2.4,4.8Hz,lH),6.72(d,J=5.1Hz,1H),7.25(s,1H);13C NMR(CDCl3)d 193.3,161.2,140.7,131.8,131.2,128.3,122.8,32.9,17.1,12.5,10.3,6.9,5.2;MS m/z 302(M+),273,245;HRMSC18H26O2Si理论值302.1702.实测值302.1710;UVlmax227nm(e 15612),323nm(e 10720).
化合物35——向化合物O(9.0mg,0.0298mmol)的丙酮(0.8ml)和水(0.4ml)溶液中加入一些对苯甲磺酸。将此混合物搅拌30分钟。在乙醚和饱和碳酸氢钠之间萃取。然后用盐水洗涤此醚萃取物并用硫酸镁干燥。浓缩后,进行色谱纯化得到定量的化合物35,为黄色胶状物:
IR(KBr)3449,3013,2925,1663,1609,1441,1367,1260cm-1;1H NMR(CDCl3)d 0.81(m,1H),1.25(m,1H),1.36(m,1H),1.44(m,1H),2.12(s,3H),3.82(d,J=2.4Hz,1H),4.55(d,J=2.1Hz,1H),6.70(dd,J=2.7,5.1Hz,1H),6.81(t,1H),7.32(s,1H);13CNMR(CDCl3)d 194.2,162.2,140.9,132.7,131.4,126.5,124.1,74.6,32.8.17.0,12.7,10.3;MS m/z 188(M+),160,145;HRMS C12H12O2理论值188.0837实测值188.0840;UVlmax(甲醇)227nm(e 13626),323nm(e(7474).
化合物42、43和44:向340mg HMAF(MW 246,1.38mmol)和110mg咪唑(MW 68,1.62mmol)的4ml DMF溶液中加入0.7ml三乙基甲硅烷基氯(d 0.898,MW 360,1.75mmol)。将此混合物室温搅拌1.5小时。在乙醚和饱和碳酸氢钠之间萃取此混合物。用盐水洗涤此醚萃取物并用硫酸镁干燥。过滤并浓缩后,进行色谱纯化得到90.3mg化合物42、30mg化合物43和41.7mg化合物44。化合物42是黄色胶状物:
1H NMR(CDCl3)δ0.74(m,10H),0.94(t,J=7.8Hz,6H),1.08(m,1H),1.26(m,1H),1.37(s,3H),1.46(m,1H),2.11(s,3H),2.17(s,3H),4.62(s,2H),7.02(s,1H).化合物43是黄色胶:1H NMR(CDCl3)δ0.62(m,10H),0.94(t,J=7.5Hz,6H),1.06(m,1H),1.34(m,1H),1.38(s,3H),1.47(m,1H),2.12(s,3H),2.18(s,3H),3.92(s,1H),4.63(q,JAB=12.6Hz,2H),7.09(s,1H).化合物44也是黄色胶:1H NMR(CDCl3)δ0.65(m,19H),0.87(t,J=7.8Hz,12H),1.00(m,1H),1.17(m,1H),1.30(d,3H),1.36(m,1H),2.03(d,3H),2.09(s,3H),4.55(q,2H),6.96(s,1H).
化合物38:用Jones试剂将化合物10氧化得到化合物38,为黄色胶状物:
1H NMR(CDCl3)δ0.69(m,1H),0.88(m,1H),1.05(m,1H),1.36(s,3H),1.47(m,1H),2.06(s,3H),2.07(s,3H),2.52(m,2H),3.03(m,2H),7.13(s,1H).
化合物46:化合物46是化合物10还原为化合物9时的副产物,为黄色胶状物:
1H NMR(CDC3)δ 0.68(m,1H),1.06(m,1H),1.25(m,1H),1.36(s,3H),1.47(m,1H),2.04(s,3H),2.05(s,3H),2.06(s,3H),2.27(m,2H),2.72(m,2H),3.95(s,1H),4.10(m,2H),7.13(s,1H).
化合物39:当在甲醇中用硼氢化钠处理化合物10时,得到少量的化合物39。化合物39是黄色胶状物:
1HNMR(CDCl3)δ0.67(m,1H),1.06(m,1H),1.32(m,1H),1.36(s,3H),1.46(m,1H),1.78(m,2H),2.05(s,3H),2.06(s,3H),2.70(m,2H),3.33(s,3H),3.34(s,3H),3.95(s,1H),4.35(t,J=2.4Hz,1H),7.14(s,1H).
化合物40:当在乙醇中用硼氢化钠处理化合物10时,得到少量的化合物40。化合物40是黄色胶状物:
1H NMR(CDCl3)δ0.67(m,1H),1.04(m,1H),1.21(m,6H),1.29(m,1H),1.36(s,3H),1.46(m,1H),1.77(m,2H),2.05(s,3H),2.06(s,3H),2.71(m,2H),3.50(q,2H),3.65(q,2H),3.95(s,1H),4.48(t,J=5.4Hz,2H),7.13(s,1H).
化合物15:当在-78℃,在乙酸酐中用BF3·Et2O处理HMAF时,得到低收率的化合物15,为黄色胶状物:
1H NMR(CDCl3)δ0.97(m,1H),1.16(m,2H),1.46(m,1H),1.51(s,3H),2.10(s,3H),2.14(s,3H),2.19(s,3H),4.60(s,1H),4.65(s,2H),7.18(s,1H).
化合物47:当在硫酸和丙酮中用丙烯腈处理HMAF时,得到副产物化合物47,为黄色胶状物:
MS m/z 432(M+),414,399,386,371,217;HRMSC28H32O4理论值432.2302,实测值432.2312.
化合物48:当使用限量的巯基化合物制备化合物26时,形成副产物化合物48,为黄色胶状物:
1H NMR(CDCl3)δ0.64(m,1H),1.05(m,1H),1.26(m,1H),1.37(s,3H),1.48(m,1H),1.84(s,3H),2.16(s,3H),2.28(s,3H),2.32(s,3H),4.04(s,2H),6.87-7.27(m,8H);HRMSC28H28O2S2理论值460.1532实测值160.1504.
化合物49和50:室温向酰基亚甲基环戊二烯的丙酮和1M硫酸溶液(1∶1)中加入对甲苯硫酚。将此混合物搅拌过夜并在乙酸乙酯和水之间萃取。用饱和碳酸氢钠和盐水分别洗涤此有机萃取物。用硫酸镁干燥后,将其浓缩并进行色谱纯化得到低收率的化合物49和50。化合物49是黄色胶状物:
1H NMR(CDCl3)δ0.69(m,1H),0.88(m,1H),1.06(m,1H),1.25(m,1H),1.37(s,3H),2.16(s,3H),2.22(s,3H),2.28(s,3H),3.90(s,1H),6.90-7.30(m,5H).化合物50也是黄色胶:1H NMR(CDCl3)δ0.63(m,1H),1.06(m,1H),1.25(m,1H),1.37(s,3H),1.45(m,1H),1.83(s,3H),2.16(s,3H),2.28(s,3H),2.32(s,3H),4.04(s,1H),6.87-7.30(m,8H).
化合物41:当用丙炔基醛在丙酮和1M硫酸(1∶1)中处理HMAF时,得到化合物41,为黄色胶状物:
1H NMR(CDCl3)δ0.72(m,1H),1.14(m,1H),1.31(m,1H),1.38(s,3H),1.42(m,1H),2.05(s,3H),2.13(s,3H),3.96(s,1H),6.55(s,1H),7.16(s,1H),7.17(s,1H),9.68(d,1H).
化合物54:当制备HMAF时得到副产物化合物54,为黄色胶状物:
1H NMR(CDCl3)δ0.67(m,2H),1.01(m,2H),1.22(m,2H),1.34(s,3H),1.48(m,2H),1.71(s,3H),1.79(s,3H),2.04(s,3H),2.18(s,3H),3.86-4.21(m,4H),4.60(s,2H),7.15(s,1H).
化合物55:当形成化合物23时得到副产物化合物55,为黄色胶状物:
1H NMR(CDCl3)δ1.70(s,3H),2.29(s,3H),2.37(s,3H),2.95(t,3H),3.74(t,3H),4.22(s,1H),4.91(s,2H),6.40-7.15(m,8H).
化合物36:室温在THF中用咪唑处理HMAF得到化合物36,为黄色胶状物:
1H NMR(CD3OD)δ0.65(m,1H),1.06(m,1H),1.23(m,1H),1.34(s,3H),1.49(m,1H),1.74(s,3H),2.05(s,3H),5.08(d,2H),6.78-7.47(m,4H).
化合物51和52:室温向HMAF的丙酮和1M硫酸(1∶1)溶液中加入限量的二巯基乙酸乙二醇酯。将此混合物搅拌n小时并按照以前方法处理得到化合物51,为黄色胶状物:
1H NMR(CDCl3)δ0.72(m,1H),1.09(m,1H),1.35(m,1H),1.36(s,3H),1.50(m,1H),2.12(s,3H),2.15(s,3H),3.28(t,J=7.8Hz,4H),3.87(s,1H),3.92(q,JAB=13.2,2H),4.36(s,4H),7.08(s,1H).化合物52也是黄色胶:1H NMR(CDCl3)δ0.72(m,2H),1.10(m,2H),1.37(s,6H),1.53(m,2H),2.14(s,6H),2.19(s,6H),3.25(m,4H),3.87(s,2H),4.37(m,4H),4.65(s,4H),7.09(s,2H).
化合物37:向HMAF的丙酮和1M硫酸溶液(1∶1)中加入等量的半胱氨酸。将此混合物室温搅拌过夜。加入大量乙酸乙酯并加入硫酸镁除去水层。再加入固体碳酸氢钠以中和硫酸。然后将此溶液过滤、浓缩并进行色谱纯化得到化合物37,为黄色胶状物:
1H NMR(CD3OD)δ0.78(m,1H),0.89(m,1H),1.06(m,1H),1.31(s,3H),1.43(m,1H),2.15(s,3H),2.21(s,3H),2.91-4.02(m,8H),7.04(s,1H).
化合物56、57和58:向HAMF的丙酮和1M硫酸(1∶1)溶液中加入大量的对羟基硫酚。将此混合物室温搅拌过夜。用乙酸乙酯萃取此混合物。然后用饱和碳酸氢钠和盐水分别洗涤有机萃取物。用硫酸镁干燥后,将此溶液浓缩并进行色谱纯化得到化合物56、57和58。化合物56是黄色胶状物:
1H NMR(CDCl3)0.70(m,1H),0.89(m,1H),1.05(m,1H),1.36(s,3H),1.51(m,1H),2.16(s,3H),2.21(s,3H),3.92(s,1H),6.74(d,J=8.4Hz,1H),6.94(d,J=8.4Hz,1H),7.25(s,1H);化合物57是黄色胶:0.67(m,1H),1.07(m,1H),1.24(m,1H),1.37(s,3H),1.51(m,1H),1.67(s,3H),1.95(s,3H),4.08(s,1H),6.45(s,1H),6.78(d,J=8.4Hz,1H),7.33(d,J=8.4Hz,1H);化合物58也是黄色胶:δ0.62(m,1H),1.04(m,1H),1.24(m,1H),1.34(s,3H),1.47(m,1H),1.79(s,3H),2.15(s,3H),4.07(s,1H),6.72(d,J=8.4Hz,1H),6.77(d,J=8.4Hz,1H),6.88(d,J=8.4Hz,1H),7.26(d,J=8.4Hz,1H).
实施例II:体外研究
为了评价细胞毒性作用,将不同浓度的隐杯伞素加到MV522(人肺癌细胞系)和8392(B细胞白血病/淋巴瘤)细胞的培养基中,放置48小时,然后通过台盼蓝排除测定细胞生长/变化。作为此48小时联系接触研究的替代形式,将细胞加到96孔板中的培养基中,与不同浓度的隐杯伞素接触2小时,脉冲加入[3H]-胸苷1至2小时后,在玻璃过滤器上收获。将滤纸放入含闪烁液体的小瓶中并用β粒子(闪烁)计数器测定残余的放射性。
2小时IC50(nm/l) | 48小时C50(nm/l) | |||
化合物 | MV522 | 8392 | MV522 | 8392 |
8 | 870±90 | 12200±740 | 630=80 | 15100±2200 |
9 | 500±33 | 47100±10950 | 850±180 | 15100±2200 |
10 | 8900±1500 | 29400±1600 | 165±55 | 14450±1650 |
13 | 5120±650 | 11900±1300 | 270±130 | 4200±400 |
11 | 4900±900 | >100000 | 1200a | 40400±6700 |
14 | 115±30 | 9650±1200 | 460±120 | 1100±250 |
21 | 2400±940 | 34300±9400 | 930±250 | NT |
22 | 660±180 | 31700±1400 | 680±180 | NT |
23 | 2920±1140 | 138200=13000 | 2750±510 | NT |
24 | 1780±200 | 12780±2140 | 1210±260 | NT |
25 | 1300±310 | >25μm/l | 1180±120 | NT |
32 | 595±185 | >50μm/l | 205±30 | NT |
33 | >4000 | 29900±3300 | 4600±200 | NT |
由于不稳定性aN=2
如上所示,隐杯伞素类似物8-33是有效的抗肿瘤剂。
实施例III:体内研究
选择若干类似物剂型进行体内研究。抗癌试剂丝裂霉素C用作药物对照。每天通过IP(腹膜内)途径连续接种5天后,第10天开始药物治疗。开始治疗后,监视动物3周。对于所用的所有类似物,都未达到最大耐受剂量(MTD)。
由Simonsen,Inc.(Gilroy,CA)得到重18-22g的BALB/c nu/nu4周龄小鼠并放养于加利福尼亚大学(San Diego,CA)的无胸腺小鼠群落中,用高效微粒空气过滤器(HEPA)过滤通风橱保持无病原体条件。随意给在用聚酯纤维过滤盖通风的塑料笼中饲养的5组动物提供灭菌食物和水。所有接触动物的人员都穿戴清洁的、灭菌大衣,手套,口罩和鞋及头罩。所有研究按照NIH“动物护理和使用指南”的指导进行并得到大学学会动物护理和使用委员会的许可(条例3-006-2)。
用于异种皮移植研究的MV522肺癌细胞系按照Kelner等的描述(Anticancer Res.,15:867-872;873-878(1995))得到并保持在无抗生素的RPMI 1640培养基(Mediatech,Herndon,VA)中,该培养基中还添加了10%胎牛血清和2mM谷酰胺,并放置于37℃潮湿的二氧化碳孵育箱中。
将小鼠随机分为有5只动物的进行初始研究的治疗组和有16至20只动物的证明类似物效果的治疗组。将每只动物作耳标记并在整个实验中用此标记。在小鼠肩部通过s.c.(皮下)注射亲代细胞系MV522接种,每次接种1千万个细胞。s.c.埋植MV522细胞10天后,当s.c.肿瘤约3×3mm大小时,给动物实验所需药物和剂量。由存活的中间值计算药物对寿命的作用。
虽然MV522细胞通过转移使小鼠死亡,原s.c.肿瘤在肩部生长在治疗的第一天和此后一周内受到监视。以两个垂直的直径测量肿瘤大小。肿瘤重量按照式W=(宽度)2×长度/2)估算。用公式RW=Wt/Wi计算相对重量(RW)来对实验组中开始治疗时肿瘤大小的变化进行标准化,其中Wi是药物治疗开始时实验动物的肿瘤重量,而Wt是随后时间内肿瘤的重量。给动物进行尸体解剖,检查器官寻找转移的证据。
通过Kaplan和Meir方法比较动物组之间的存活曲线。为了比较多个动物组之间的相对肿瘤重量,进行普通ANOVA,然后进行Tukey-Kramer多重比较后ANOVA分析(Kelner等,Anticancer Res.,867-872;873-878(1995))。概率值(p)小于0.05的具有统计学显著性差异。
化合物 | 剂量(mg/kg) | p 值(肿瘤重量) |
HMAF | 6 | <0.01 |
8 | <0.01 | |
10 | <0.001 | |
9 | 4 | <0.001 |
8 | <0.001 | |
16 | <0.001 | |
10 | 3 | <0.001 |
6 | <0.001 | |
11 | 1.2 | <0.001 |
12 | 3.75 | <0.001 |
7.5 | <0.001 | |
16 | 4 | <0.001 |
8 | <0.01 | |
16 | <0.01 | |
18 | 18 | <0 001 |
20 | <0.001 | |
24 | <0.001 | |
32 | <0.001 | |
19 | 4 | <0.05 |
8 | <0.001(毒性) | |
16 | <0.001(毒性) | |
21 | 4 | <0.01 |
8 | <0.001 | |
16 | <0.001 | |
22 | 4 | <0.001 |
化合物 | 剂量(mg/kg) | p 值(肿瘤重量) |
8 | <0.001 | |
16 | 毒性 | |
23 | 4 | <0.001 |
8 | <0.001 | |
16 | <0.001 | |
24 | 0.2 | <0.001 |
25 | 4 | <0.001 |
8 | <0.001 | |
16 | <0.001 | |
26 | 0.4 | <0.001 |
29 | 4 | <0.001 |
8 | <0.001 | |
16 | <0.001 | |
32 | 4 | <0.05 |
8 | >0.05 | |
16 | <0.001 | |
20 | <0.001 | |
24 | <0.001 | |
33 | 4 | <0.01 |
8 | <0.01 | |
16 | <0.05 | |
丝裂霉素C | 1.6 | >0.05 |
2.0 | 毒性 |
类似物21似乎比HMAF更有效,特别是基于MTD未达到这一事实。类似物16、32和33也是有效的。高剂量的丝裂霉素C对肿瘤大小有作用。但是,该剂量带来毒性,因为所有动物在31天内最终死亡。低剂量的丝裂霉素C基本不起作用。
本发明已参考多种特定和优选实例和技术进行了描述。但是,应理解:在保持本发明精神和范围的同时可作出很多变化和修改。
Claims (59)
1.下式的化合物或其药用盐:
其中R1是(CH2)n-(X)-(Y),
其中n是0-4;
X是O或S或N,
而Y是CH2OC(O)(C1-C4)烷基,被2个OH或1至2个卤原子任选取代的(C1-C8)烷基;单糖,CH2C(O)-O-(CH2)2-O-C(O)CH2SH,(CH2)2-O-(CH2)2W,其中W是卤原子;-(C1-C8)烷基-O-(C1-C8)烷基;(C6-C10)芳基,(C6-C10)芳基(C1-C4)烷基或C(O)O(C6-C10)芳基,其中芳基部分被1至2个OH、卤原子、(C1-C4)烷基或O(C1-C4)烷基任选取代;CH2CO2(C1-C4)烷基,-CH2CO2H,Si((C1-C4)烷基)3或氨基酸残基;
R3是H或(C1-C4)烷基;
R4是SCH2CO2(C1-C4)烷基、S-(C6-C10)芳基,其中芳基被卤原子、OH或(C1-C4)烷基任选取代,或者是H;
R5是H、OH或不存在;
R6是(C1-C4)烷基或不存在;
R7是OH或-O(Si((C1-C4)烷基)3,或
R6和R7一起为亚乙二氧基;
R8是(C1-C4)烷基,该烷基任选含有OH或卤原子;
由...代表的键可存在或不存在。
2.权利要求1所述的化合物,其中n是1,...表示的键存在,而R5不存在。
3.权利要求2所述的化合物,其中R3是甲基,R4是H,R6是甲基,R7是OH而R8是甲基。
4.权利要求3所述的化合物,其中X是O。
5.权利要求4所述的化合物,其中Y是CH2OC(O)CH3。
6.权利要求4所述的化合物,其中Y是(C1-C4)烷基。
7.权利要求6所述的化合物,其中Y是乙基。
8.权利要求4所述的化合物,其中Y是被2个OH取代的(C1-C8)烷基。
9.权利要求8所述的化合物,其中Y是-CH2CH(OH)CH2OH。
10.权利要求4所述的化合物,其中Y是果糖。
11.权利要求4所述的化合物,其中Y是-(CH2)2Br。
12.权利要求4所述的化合物,其中Y是-C(CH3)2-O-(C1-C4)烷基。
13.权利要求12所述的化合物,其中Y是-C(CH3)2-O-CH3。
14.权利要求4所述的化合物,其中Y是-C(O)-O-苯基。
15.权利要求3所述的化合物其中X是S。
16.权利要求15所述的化合物,其中Y是被OH或甲基取代的苯基。
17.权利要求15所述的化合物,其中Y是苄基。
18.权利要求15所述的化合物,其中Y是-CH2CO2CH3。
19.权利要求15所述的化合物,其中Y是-CH2CO2H。
20.权利要求15所述的化合物,其中Y是被2个OH取代的(C1-C8)烷基。
21.权利要求20所述的化合物,其中Y是-CH2CH(OH)CH2OH。
22.权利要求1所述的化合物,其中n是1,...表示的键不存在,X是S;Y是-CH2CO2CH3;R3是甲基;R4是SCH2CO2CH3;R6是甲基而R7是OH。
23.权利要求22的化合物,其中R5是H。
24.权利要求22所述的化合物,其中R5是OH。
25.下式的化合物或其药用盐:
其中R1是(CH2)n(Y);
n是0-4;
Y是CHO、NO2、NH2、COOH、(C2-C4)链烯基-CHO、CH(O(C1-C4)烷基)2;环(C3-C6)烷基或5元杂芳基,其中含有一个或多个选自N、S或非过氧化物O杂原子,其中环烷基或杂芳基被1至2个(C1-C4)烷基、CHO、OH或卤原子任选取代;
R3是(C1-C4)烷基或H;
R4是SCH2CO2(C1-C4)烷基或H;
R5是H、OH或不存在;
R6是(C1-C4)烷基;
R7是OH;
R6和R7一起为亚乙二氧基;
R8是(C1-C4)烷基,该烷基任选被OH或卤原子取代;
由...代表的键可存在或不存在;
条件是n是0时Y不是NO2。
26.权利要求25所述的化合物,其中...表示的键存在。
27.权利要求26所述的化合物,其中R3是甲基;R4是H;R6是甲基;R7是OH而R8是甲基。
28.权利要求27所述的化合物,其中n是1。
29.权利要求28所述的化合物,其中Y是CHO。
30.权利要求29所述的化合物,其中Y是环己基。
31.权利要求27所述的化合物,其中n是2而Y是CHO。
34.权利要求33所述的化合物,其中R1、R3和R4是H,...表示的键存在;且R5不存在。
35.权利要求33所述的化合物,其中R6是H而R7是OH。
36.权利要求34所述的化合物,其中R6和R7是亚乙二氧基。
38.权利要求37所述的化合物,其中L是-(CH2)m-O-(CH2)n-,其中m和n独立地是1至4。
39.权利要求37所述的化合物,其中L是-CH2-S-CH2C(O)-O-(CH2)2-O-C(O)CH2-S-CH2-。
4O.权利要求37所述的化合物,其中A和B通过5位和3位连接。
41.权利要求39所述的化合物,其中A和B通过5位和7位连接。
44.一种药物单位剂型,其中含有抑制肿瘤生长有效量的权利要求1、25、32、33、37、42或43所述的化合物和药用载体。
45.权利要求44所述的药物单位剂型,其中载体是液体载体。
46.权利要求45所述的药物单位剂型,其中载体适于非肠道给药。
47.权利要求46所述的药物单位剂型,其中载体适于静脉给药。
48.权利要求44所述的药物单位剂型,其中载体适于口服给药。
49.权利要求48所述的药物单位剂型是片剂或胶囊。
50.权利要求1、25、32、33、37、42或43所述的化合物在制备一种抑制需此治疗的患者的肿瘤细胞生长的药物中的用途。
51.权利要求50所述的用途,其中患者是癌症病人。
52.权利要求51所述的用途,其中该患者患有实体瘤。
53.下式的化合物或其药用盐:
其中R1是(CH2)n(Y);
n是0-4;
Y是CHO、NH2、COOH、-(C2-C4)链烯基-CHO、CH(O(C1-C4)烷基)2;环(C3-C6)烷基或5元杂芳基,其中含有一个或多个选自N、S或非过氧化物O杂原子,其中环烷基或杂芳基被1至2个(C1-C4)烷基、CHO、OH或卤原子任选取代;
R3是(C1-C4)烷基或H;
R4是SCH2CO2(C1-C4)烷基或H;
R5是H、OH或不存在;
R6是(C1-C4)烷基;
R7是OH;
R6和R7一起为亚乙二氧基;
R8是(C1-C4)烷基,该烷基任选被OH或卤原子取代;
由...代表的键可存在或不存在。
54.下式的化合物或其药用盐:
其中R1是(CH2)n(Y);
n是2-4;
Y是CHO、NO2、NH2、COOH、(C2-C4)链烯基-CHO、CH(O(C1-C4)烷基)2;环(C3-C6)烷基或5元杂芳基,其中含有一个或多个选自N、S或非过氧化物O杂原子,其中环烷基或杂芳基被1至2个(C1-C4)烷基、CHO、OH或卤原子任选取代;
R3是(C1-C4)烷基或H;
R4是SCH2CO2(C1-C4)烷基或H;
R5是H、OH或不存在;
R6是(C1-C4)烷基;
R7是OH;
R6和R7一起为亚乙二氧基;
R8是(C1-C4)烷基,该烷基任选被OH或卤原子取代;
由...代表的键可存在或不存在。
55.下式的化合物或其药用盐:
其中R1是(CH2)n(Y);
n是0-4;
Y是CHO、NO2、NH2、COOH、(C2-C4)链烯基-CHO、CH(O(C1-C4)烷基)2;环(C3-C6)烷基或5元杂芳基,其中含有一个或多个选自N、S或非过氧化物O杂原子,其中环烷基或杂芳基被1至2个(C1-C4)烷基、CHO、OH或卤原子任选取代;
R3是(C1-C4)烷基或H;
R4是SCH2CO2(C1-C4)烷基;
R5是H、OH或不存在;
R6是(C1-C4)烷基;
R7是OH;
R6和R7一起为亚乙二氧基;
R8是(C1-C4)烷基,该烷基任选被OH或卤原子取代;
由...代表的键可存在或不存在。
56.下式的化合物或其药用盐:
其中R1是(CH2)n(Y);
n是0-4;
Y是CHO、NO2、NH2、COOH、(C2-C4)链烯基-CHO、CH(O(C1-C4)烷基)2;环(C3-C6)烷基或5元杂芳基,其中含有一个或多个选自N、S或非过氧化物O杂原子,其中环烷基或杂芳基被1至2个(C1-C4)烷基、CHO、OH或卤原子任选取代;
R3是(C1-C4)烷基或H;
R4是SCH2CO2(C1-C4)烷基或H;
R5是H、OH或不存在;
R6是(C1-C4)烷基;
R7是OH;
R6和R7一起为亚乙二氧基;
R8是(C1-C4)烷基,该烷基任选被OH或卤原子取代;
由...代表的键不存在。
59.式(I)化合物及其可药用盐:
其中R1是(CH2)n-(X)-(Y);n是0-4,X是O或S或N,和Y是氨基酸残基;
R3是H或(C1-C4)烷基;
R4是H、SCH2CO2(C1-C4)烷基、O-(C5-C12)芳基或S-(C5-C12)芳基,其中芳基任选被卤素、OH或(C1-C4)烷基取代;
R5是H、OH或不存在;
R6是(C1-C4)烷基或H;和
R7是OH或OSi((C1-C4)烷基)3;或
R6和R7一起为亚乙基二氧基;
R8是(C1-C4)烷基,它任选被OH或卤素取代;
...所代表的键可以存在或不存在。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/683,687 | 1996-07-18 | ||
US08/683,687 US5932553A (en) | 1996-07-18 | 1996-07-18 | Illudin analogs useful as antitumor agents |
Publications (2)
Publication Number | Publication Date |
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CN1230166A CN1230166A (zh) | 1999-09-29 |
CN100349845C true CN100349845C (zh) | 2007-11-21 |
Family
ID=24745052
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB971978093A Expired - Fee Related CN100349845C (zh) | 1996-07-18 | 1997-07-14 | 隐杯伞素类抗肿瘤剂 |
Country Status (24)
Country | Link |
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US (7) | US5932553A (zh) |
EP (2) | EP1454893B1 (zh) |
JP (1) | JP4372843B2 (zh) |
KR (1) | KR100627746B1 (zh) |
CN (1) | CN100349845C (zh) |
AP (2) | AP1251A (zh) |
AT (2) | ATE372976T1 (zh) |
AU (1) | AU738991B2 (zh) |
BR (1) | BR9710486A (zh) |
CA (1) | CA2260926C (zh) |
CZ (1) | CZ297803B6 (zh) |
DE (2) | DE69729302T2 (zh) |
DK (1) | DK0915819T3 (zh) |
ES (2) | ES2293122T3 (zh) |
HK (2) | HK1019873A1 (zh) |
HU (1) | HU226890B1 (zh) |
IL (1) | IL128058A (zh) |
NO (1) | NO316444B1 (zh) |
NZ (1) | NZ333857A (zh) |
OA (1) | OA10957A (zh) |
PL (1) | PL189726B1 (zh) |
PT (1) | PT915819E (zh) |
WO (1) | WO1998003458A1 (zh) |
ZA (1) | ZA976242B (zh) |
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US5932553A (en) | 1996-07-18 | 1999-08-03 | The Regents Of The University Of California | Illudin analogs useful as antitumor agents |
US5723632A (en) | 1996-08-08 | 1998-03-03 | Mgi Pharma, Inc. | Total synthesis of antitumor acylfulvenes |
US6608061B2 (en) * | 1997-05-22 | 2003-08-19 | Kyoma Hakko Kogyo Co., Ltd. | Bisaryl compound and medicament for cancer treatment comprising the same |
US6025328A (en) * | 1998-02-20 | 2000-02-15 | The Regents Of The University Of California | Antitumor agents |
US7141603B2 (en) * | 1999-02-19 | 2006-11-28 | The Regents Of The University California | Antitumor agents |
US7015247B2 (en) * | 2000-10-12 | 2006-03-21 | Alvin Guttag | Ibuprofen-aspirin, hydroxymethylacylfulvene analogs and L-sugar illudin analogs |
US6436916B1 (en) | 2000-10-12 | 2002-08-20 | Alvin Guttag | Ibuprofen-aspirin and hydroxymethylacylfulvene analogs |
US7718385B2 (en) * | 2003-10-17 | 2010-05-18 | The Johns Hopkins University | Bioactivation of alkylating agents for cancer treatment |
US20050274274A1 (en) * | 2004-06-14 | 2005-12-15 | Gore Makarand P | Methods and compositions for dying a substrate |
JP4989648B2 (ja) * | 2005-08-03 | 2012-08-01 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | 抗癌剤として有用なイルジン類似体 |
DE102005052501A1 (de) * | 2005-11-03 | 2007-05-16 | Univ Ernst Moritz Arndt | Neue Leitstrukturen für zytostatische Verbindungen auf Basis von Spiroverbindungen |
US8895667B2 (en) | 2009-07-17 | 2014-11-25 | Tyco Electronics Corporation | Methods of making reversible crosslinked polymers and related methods |
US10285955B2 (en) | 2014-04-10 | 2019-05-14 | Af Chemicals, Llc | Affinity medicant conjugate |
US11135182B2 (en) | 2014-04-10 | 2021-10-05 | Af Chemicals, Llc | Affinity medicant conjugates |
KR20160142885A (ko) | 2014-04-10 | 2016-12-13 | 에이에프 케미칼스, 엘엘씨 | 친화성 약제 컨쥬게이트 |
BR112021006710A2 (pt) | 2018-09-04 | 2021-08-10 | Lantern Pharma Inc. | composto análogos de iludina, usos dos mesmos e métodos para sintetizar os mesmos |
EP3667323A1 (en) | 2018-12-11 | 2020-06-17 | Kelner, Michael | Methods, compositions and devices for treating cancer with illudofulvenes |
US11591295B2 (en) | 2019-11-25 | 2023-02-28 | Af Chemicals Llc | Affinity illudofulvene conjugates |
EP4035684A1 (en) | 2019-11-25 | 2022-08-03 | AF Chemical LLC | Affinity illudofulvene conjugates |
CN112972443A (zh) * | 2021-03-29 | 2021-06-18 | 杭州添帆生物科技有限公司 | 一种抗癌药物及其应用 |
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-
1996
- 1996-07-18 US US08/683,687 patent/US5932553A/en not_active Expired - Lifetime
-
1997
- 1997-07-14 IL IL128058A patent/IL128058A/en not_active IP Right Cessation
- 1997-07-14 ES ES04012220T patent/ES2293122T3/es not_active Expired - Lifetime
- 1997-07-14 PL PL97331151A patent/PL189726B1/pl not_active IP Right Cessation
- 1997-07-14 NZ NZ333857A patent/NZ333857A/xx unknown
- 1997-07-14 AP APAP/P/2001/002315A patent/AP1251A/en active
- 1997-07-14 BR BR9710486-8A patent/BR9710486A/pt not_active Application Discontinuation
- 1997-07-14 AU AU36004/97A patent/AU738991B2/en not_active Ceased
- 1997-07-14 JP JP50700998A patent/JP4372843B2/ja not_active Expired - Fee Related
- 1997-07-14 CA CA002260926A patent/CA2260926C/en not_active Expired - Fee Related
- 1997-07-14 AT AT04012220T patent/ATE372976T1/de not_active IP Right Cessation
- 1997-07-14 AT AT97932586T patent/ATE267791T1/de not_active IP Right Cessation
- 1997-07-14 DE DE69729302T patent/DE69729302T2/de not_active Expired - Fee Related
- 1997-07-14 CN CNB971978093A patent/CN100349845C/zh not_active Expired - Fee Related
- 1997-07-14 PT PT97932586T patent/PT915819E/pt unknown
- 1997-07-14 KR KR1019997000333A patent/KR100627746B1/ko not_active IP Right Cessation
- 1997-07-14 EP EP04012220A patent/EP1454893B1/en not_active Expired - Lifetime
- 1997-07-14 ES ES97932586T patent/ES2222517T3/es not_active Expired - Lifetime
- 1997-07-14 DK DK97932586T patent/DK0915819T3/da active
- 1997-07-14 CZ CZ0012999A patent/CZ297803B6/cs not_active IP Right Cessation
- 1997-07-14 EP EP97932586A patent/EP0915819B1/en not_active Expired - Lifetime
- 1997-07-14 HU HU9904290A patent/HU226890B1/hu not_active IP Right Cessation
- 1997-07-14 AP APAP/P/1999/001465A patent/AP1250A/en active
- 1997-07-14 WO PCT/US1997/012143 patent/WO1998003458A1/en active IP Right Grant
- 1997-07-14 DE DE69738145T patent/DE69738145T2/de not_active Expired - Lifetime
- 1997-07-15 ZA ZA9706242A patent/ZA976242B/xx unknown
-
1999
- 1999-01-14 NO NO19990164A patent/NO316444B1/no not_active IP Right Cessation
- 1999-01-15 OA OA9900008A patent/OA10957A/en unknown
- 1999-02-01 US US09/241,172 patent/US6069283A/en not_active Expired - Fee Related
- 1999-11-05 HK HK99105065A patent/HK1019873A1/xx not_active IP Right Cessation
-
2000
- 2000-02-09 US US09/501,151 patent/US6380403B1/en not_active Expired - Lifetime
-
2002
- 2002-04-29 US US10/134,260 patent/US6639105B2/en not_active Expired - Lifetime
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2003
- 2003-10-27 US US10/694,533 patent/US6987193B2/en not_active Expired - Lifetime
-
2005
- 2005-03-08 HK HK05101976A patent/HK1068210A1/xx not_active IP Right Cessation
- 2005-12-20 US US11/312,236 patent/US7329759B2/en not_active Expired - Fee Related
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2007
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5439942A (en) * | 1989-10-03 | 1995-08-08 | The Regents Of The University Of California | Method of treating certain tumors using illudin analogs |
US5523490A (en) * | 1989-10-03 | 1996-06-04 | The Regents Of The University Of California | Illudin analogs |
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