CN1780630A - 具有免疫调节活性的膦酸酯化合物 - Google Patents
具有免疫调节活性的膦酸酯化合物 Download PDFInfo
- Publication number
- CN1780630A CN1780630A CN 200480011231 CN200480011231A CN1780630A CN 1780630 A CN1780630 A CN 1780630A CN 200480011231 CN200480011231 CN 200480011231 CN 200480011231 A CN200480011231 A CN 200480011231A CN 1780630 A CN1780630 A CN 1780630A
- Authority
- CN
- China
- Prior art keywords
- conjugate
- general formula
- following general
- group
- independently
- 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.)
- Pending
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及具有免疫调节活性的膦酸酯取代的化合物,含有该化合物的组合物,和包括施用该化合物的治疗方法,和涉及用于制备该化合物的方法和中间体。
Description
依据35U.S.C.§119(e),本非临时申请要求享有下列申请的优先权的利益:美国临时专利申请序列号No.60/465424,60/465373,60/465420,60/465380,60/465433,60/465481,60/465377,60/465581,60/465532,60/465844,60/465531和60/465574,全部于2003年4月25日提出申请;和美国临时专利申请序列号No.60/493303,60/493310,60/493309和60/493302,全部于2003年8月7日提出申请;和美国临时专利申请序列号No.60/495533,60/495529,60/495455,60/495537,60/495456,60/495398,60/495425,60/495427,60/495661,60/495393,60/495416,60/495614和60/495417,全部于2003年8月15日提出申请;和美国临时专利申请序列号No.60/514054,60/513971,60/514394,60/513975,60/514453,60/514202,60/513948,60/514424,60/514280,60/514144,60/513979,60/514075,60/513946,60/514051,60/514161,60/514325,60/514044,60/514201,60/514522,60/514140,60/514175,60/514113,60/513562,60/513592,60/513563,60/513579,60/513561,60/513589,60/513593,60/513588,60/514258,60/514021和60/514298,全部于2003年10月24日提出申请;和美国临时专利申请序列号No.60/532230,60/531960,60/532160,60/531940和60/531932,全部于2003年12月1日提出申请;和美国临时专利申请序列号No.60/532591,于2003年12月23日提出申请;和美国临时专利申请序列号No.60/536005,于2004年1月12日提出申请。以上列举的全部临时申请的全部内容被引入这里供参考。
本发明的领域
本发明一般性涉及具有免疫调节(例如,免疫抑制)活性的化合物。
本发明的背景
许多年来改善药物和其他药剂到靶细胞和组织的输送一直是大量研究的焦点。尽管进行了许多尝试以开发将生物活性分子输入细胞的方法,既有体内的和也有体外的,但是没有一种方法证实是完全让人满意的。优化抑制药物与其细胞内靶的结合,而最小化药物细胞间重新分布到例如邻近细胞,常常是困难的或无效力的。
当前胃肠道外给予患者的大部分药剂不是靶向的,导致了药剂全身性输送到机体的细胞和组织,在这些地方它是非必要的并通常是不希望的。这可能导致不利的药物副作用,并常常限制可能被施用的药物的剂量(例如糖皮质类固醇和其他抗炎药)。相比较,尽管口服给药被普遍认为是一种方便和经济的给药方法,但口服给药可能导致(a)药物通过细胞和组织屏障,例如血/脑、上皮细胞、细胞膜的吸收,导致不希望的的全身分布,或(b)药物在胃肠道内的短暂停留。因此,一个主要的目标是开发将药剂特异性靶向细胞和组织的方法。这类治疗的益处包括避免了这类药剂的不适当输送至其它细胞和组织,例如未感染的细胞的全身性生理效应。
自身免疫疾病和移植排斥成仍然是世界范围内的主要公众健康问题。虽然具有免疫抑制活性的药物在广泛地使用并显示出有效性,但由于它们的毒性和其它副作用而已经限制了临床应用。目前,仍然需要新的免疫抑制剂,即具有改进的免疫抑制剂活性和药物动力学性能,改进的口服生物利用度,更大的效价和延长的活体内有效半衰期的药物。新的免疫抑制剂应具有更少的副作用,更不复杂的给药方案,和/或是口服有效的。
本发明的概述
细胞内靶向可通过允许生物活性剂蓄积或停留在细胞内的方法和组合物来实现。本发明提供免疫调节(例如,免疫抑制)化合物的新型含膦酸酯的类似物。这些混合物具有相关的免疫调节化合物的用途,但由于膦酸酯基团的存在,它们典型地提供了膦酸酯化合物的细胞蓄积。因而,本发明的化合物显示出了改善的免疫调节性能,药物动力学性质,口服生物利用度,效价,或延长的活体内有效半衰期,或这些性能的结合。本发明的化合物还具有明显的抗性特征,更少的副作用,更不复杂的给药方案,或具有提高的口服活性。
本发明一般性涉及治疗化合物在细胞内的蓄积或保留。本发明更具体地涉及在靶细胞中达到含膦酸酯的分子的高浓度。这类有效靶向可以适用于各种治疗制剂和程序。
因此,在一个实施方案中本发明提供本发明的化合物,它是包含连接于一个或多个膦酸酯基团上的免疫调节化合物(例如免疫抑制化合物)的共轭物。
本发明的组合物包含具有至少一个膦酸酯基团的免疫调节化合物。因此,在一个实施方案中本发明提供一种共轭物,它包含连接于一个或多个膦酸酯基团上的免疫调节化合物(例如免疫抑制化合物)或它的药物学上可接受的盐。
在另一个实施方案中,本发明提供了通式500-547之中的任何一个的化合物:
它直接或间接地通过连接体被一个或多个膦酸酯基团所取代;和它任选地被一个或多个基团A0取代;或它们的药物学上可接受的盐,
其中:
A0是A1,A2或W3,条件是所述共轭物包括至少一个A1;
A1是:
A2是:
A3是:
Y1独立地是
,
,
,
,
,
或
;
Y2独立地是键,
,
,
,
,
,
,
或
;和当Y2联接两个亚磷原子时,Y2也可以是
;
Rx独立地是
,R1,R2,W3,保护基,或如下通式:
其中:
Ry独立地是
,W3,R2或保护基;
R1独立地是
或1到18个碳原子的烷基;
R2独立地是
,R1,R3或R4,其中各R4独立地被0到3个R3基团取代或一起连在碳原子上,两个R2基团形成具有3到8个碳的环和该环可以被0到3个R3基团取代;
R3是R3a,R3b,R3c或R3d,条件是当R3结合到杂原子上时,则R3是R3c或R3d;
R3a是
,
,
,
,
,
或
;
R3b是Y1;
R3d是
,
或
;
R4是1到18个碳原子的烷基,2到18个碳原子的链烯基,或2到18个碳原子的炔基;
R5是R4,其中各R4被0到3个R3基团取代;
W3是W4或W5;
W4是R5,
,
,
或
;
W5是碳环或杂环,其中W5独立地被0到3个R2基团取代;
W6是独立地被1、2或3个A3基团取代的W3;
M2是0,1或2;
M12a是1,2,3,4,5,6,7,8,9,10,11或12;
M12b是0,1,2,3,4,5,6,7,8,9,10,11或12;
M1a,M1c和M1d独立地是0或1;和
M12c是0,1,2,3,4,5,6,7,8,9,10,11或12。
在另一个实施方案中,本发明提供以下通式的化合物:
[DRUG]-(A0)nn
或它的药物学上可接受的盐;其中
DRUG是具有通式500-547之中的任何一个通式的化合物;
nn是1,2,或3;
其中:
A0是A1,A2或W3,条件是所述共轭物包括至少一个A1;
A1是:
A2是:
A3是:
Y1独立地是
,
,
,
,
,
或
;
Y2独立地是键,
,
,
,
,
,
,
或
;和当Y2联接两个亚磷原子时,Y2也可以是
;
Rx独立地是
,R1,R2,W3,保护基,或如下通式:
其中:
Ry独立地是
,W3,R2或保护基;
R1独立地是
或1到18个碳原子的烷基;
R2独立地是
,R1,R3或R4,其中各R4独立地被0到3个R3基团取代或一起连在碳原子上,两个R2基团形成具有3到8个碳的环和该环可以被0到3个R3基团取代;
R3是R3a,R3b,R3c或R3d,条件是当R3结合到杂原子上时,则R3是R3c或R3d;
R3a是
,
,
,
,
,
或
;
R3b是Y1;
R3c是-Rx,
,
,
,
,
,
,
,
,
,
,
,
,
,
或
;
R3d是
,
或
;
R4是1到18个碳原子的烷基,2到18个碳原子的链烯基,或2到18个碳原子的炔基;
R5是R4,其中各R4被0到3个R3基团取代;
W3是W4或W5;
W4是R5,
,
,
,或
;
W5是碳环或杂环,其中W5独立地被0到3个R2基团取代;
W6是独立地被1、2或3个A3基团取代的W3;
M2是0,1或2;
M12a是1,2,3,4,5,6,7,8,9,10,11或12;
M12b是0,1,2,3,4,5,6,7,8,9,10,11或12;
M1a,M1c和M1d独立地是0或1;和
M12c是0,1,2,3,4,5,6,7,8,9,10,11或12。
在另一个实施方案中,本发明提供了通式1-151之中的任何一个的化合物:
其中:
A0是A1;
A1是:
A3是:
Y1独立地是
,
,
,
,
,
或
;
Y2独立地是键,
,
,
,
,
,
,
或
;和当Y2联接两个亚磷原子时,Y2也可以是
;
Rx独立地是
,R2,W3,保护基,或如下通式:
Ry独立地是
,W3,R2或保护基;
R1独立地是
或1到18个碳原子的烷基;
R2独立地是
,R3或R4,其中各R4独立地被0到3个R3基团取代;
R3是R3a,R3b,R3c或R3d,条件是当R3结合到杂原子上时,则R3是R3c或R3d;
R3a是
,
,
,
,
,
或
;
R3b是Y1;
R3c是-Rx,
,
,
,
,
,
,
,
,
,
,
,
,
,
或
;
R3d是
,
或
;
R4是1到18个碳原子的烷基,2到18个碳原子的链烯基,或2到18个碳原子的炔基;
R5是R4,其中各R4被0到3个R3基团取代;
R5a独立地是1-18个碳原子的亚烷基,2-18个碳原子的亚链烯基,或2-18个碳原子亚炔基,所述亚烷基、亚链烯基或亚炔基中的任何一个可以被0-3个R3基团取代;
W3是W4或W5;
W4是R5,
,
,
或
;
W5是碳环或杂环,其中W5独立地被0到3个R2基团取代;
W6是独立地被1、2或3个A3基团取代的W3;
M2是0,1或2;
M12a是1,2,3,4,5,6,7,8,9,10,11或12;
M12b是0,1,2,3,4,5,6,7,8,9,10,11或12;
M1a,M1c和M1d独立地是0或1;
M12c是0,1,2,3,4,5,6,7,8,9,10,11或12;
各X50独立地是氢,
,
,
,
,甲基或叔丁基;
X51是氢,卤素,三氟甲基,(C1-C3)烷基,氰基,或(C1-C3)烷氧基;
X52是氢,氟,氯,溴,甲基或三氟甲基;
X53是
,或
;
X54和X55独立地选自氢或C1-C18酰基;
X56是氢,C1-C18酰基,或
或X54是氢以及X55和X56一起是
X57是
,氨基,羟基,或选自
和
中的卤素;
X58是氢,
,
,
,氰基,甲基或叔丁基;
X59是氢,
;
X60是
;
X62是甲基,氯,或三氟甲基;
X63是
,甲基,乙基,环丙基,乙烯基,或三氟甲基;
X64是
,甲基,乙基,环丙基,氯,乙烯基,烯丙基,3-甲基-1-丁烯-1-基;
X65是氢或
;和
Ar是芳基或杂芳基。
本发明提供药物组合物,它包含有效量的本发明的化合物,或它的药物学上可接受的盐,和药物学上可接受的稀释剂或载体结合。
本发明涉及一种增加药物化合物的细胞蓄积和保留,因此改进它们的治疗和诊断价值的方法,它包括将该化合物连接到一个或多个膦酸酯基团上。
本发明还提供了免疫抑制的维持的方法,例如在移植外科手术之后,它包括对动物(例如哺乳动物)施用有效量的本发明化合物。
本发明还提供了活体外或活体内调节免疫应答的方法,它包括使需要这样处理的样品与本发明的化合物接触。
本发明还提供了抑制动物(例如哺乳动物)中免疫应答的方法,它包括对所述动物施用有效量的本发明化合物。
本发明还提供了治疗动物(例如哺乳动物)中自身免疫病(例如牛皮癣,类风湿性关节炎,红斑狼疮,多发性硬化,糖尿病,局限性回肠炎,等等)的症状或效应的方法,它包括对所述动物施用有效量的本发明的化合物。
本发明还提供了治疗动物(例如哺乳动物)中移植排斥的症状或效应的方法,它包括对所述动物施用有效量的本发明化合物。
本发明还提供了抑制人T细胞的增殖和/或下调在动物(例如哺乳动物)中Th1或Th2类型细胞因子的产生,它包括对所述动物施用本发明的化合物。
本发明还提供了治疗动物(例如哺乳动物)中特异性皮炎的方法,它包括对所述动物施用有效量的本发明化合物。
本发明还提供了抑制动物(例如哺乳动物)中一种或多种T-淋巴细胞功能的方法,它包括对所述动物施用有效量的本发明化合物。
本发明还提供了抑制动物(例如哺乳动物)中二氢乳清酸脱氢酶的方法,它包括对动物施用有效量的本发明化合物。
本发明还提供用于医学治疗(优选用于在移植手术后的免疫抑制的维持,抑制免疫应答,治疗自身免疫病,治疗特异性皮炎,抑制人T细胞的增殖,下调Th1或Th2类型细胞因子的产生)的本发明化合物,以及本发明的化合物用于制造药物的用途,该药物用于在动物(例如哺乳动物)的移植手术之后维持免疫抑制。本发明还提供了本发明化合物在制造适用于抑制动物(例如哺乳动物)的免疫应答的药物中的用途。本发明还提供了本发明化合物在制造适用于治疗动物(例如哺乳动物)的自身免疫病的药物中的用途。本发明还提供了本发明化合物在制备适用于抑制人T细胞的增殖或下调动物的Th1或Th2类型细胞因子的产生的药物中的用途。
本发明还提供了免疫抑制的维持的方法,例如在移植手术之后,它包括对动物(例如哺乳动物)施用有效量的本发明化合物。
本发明还提供了在这里公开的用于制备本发明化合物的方法和新型中间体。本发明的化合物中的一些可用于制备本发明的其它化合物。
示范性权利要求的详细描述
下面详细参照本发明的某些权利要求,在附随的结构和式中举例说明了它们的实例。虽然将结合列举的权利要求描述本发明,但将要理解的是它们并不意旨将本发明限制于那些权利要求。相反,本发明意旨覆盖全部替代方案、修饰和等同物,它们可以被包括在权利要求限定的本发明的范围内。
定义
除非另作陈述,否则下述本文应用的术语和短语意旨具有如下含义:
当本文使用商品名称时,申请意指独立包括商品名称产品和商品名称产品的活性药物成分。
“生物利用度”是在药物活性物质进入体内后,靶组织对所述物质可利用的程度。药物活性物质的生物利用度的增加能够对患者提供更有效率和更有效的治疗,因为对于给定的剂量,在靶组织位点将有更多的药物活性物质被利用。
术语“膦酸酯”和“膦酸酯基团”包括分子内的官能团或部分,所述分子包含三价磷,该三价磷1)单键连接到碳上,2)双键连接到杂原子上,3)单键连接到杂原子上,和4)单键连接到另一个杂原子上,其中每个杂原子可以是相同的或不同的。术语“膦酸酯”和“膦酸酯基团”也包括官能团或部分,其包含呈与上面所述三价磷相同的氧化状态的三价磷,以及包含前药部分的官能团或部分,前药部分能与化合物分开以便化合物保留具有上面描述的特性的三价磷。例如,术语“膦酸酯”和“膦酸酯基团”包括膦酸、膦酸单酯、膦酸二酯、膦酸酰胺化物、硫代膦酸酯(phosphonthioate)官能团。在本发明的一个特殊实施方案中,术语“膦酸酯”和“膦酸酯基团”包括分子内的官能团或部分,所述分子包含三价磷,该三价磷1)单键连接到碳上,2)双键连接到氧上,3)单键连接到氧上,和4)单键连接到另一个氧上,以及官能团或部分,该官能团或部分包含前药部分,该前药部分能与化合物分开以便化合物保留具有如此特性的三价磷。在本发明的另一个特殊实施方案中,术语“膦酸酯”和“膦酸酯基团”包括分子内的官能团或部分,所述分子包含三价磷,该三价磷1)单键连接到碳上,2)双键连接到氧上,3)单键连接到氧或氮上,和4)单键连接到另一个氧或氮上,以及官能团或部分,该官能团或部分包含前药部分,该前药部分能与化合物分开以便化合物保留具有如此特性的三价磷。
本发明应用的术语“前药”指当被给予生物系统时,由于自发的化学反应、酶催化的化学反应、光解作用,和/或代谢化学反应而产生药物物质,即活性成分的任何化合物。因此前药是治疗活性化合物的共价修饰类似物或潜在形式。
“前药部分”是指不稳定的官能团,它在通过水解作用、酶促裂解或通过一些其他过程的细胞内系统地新陈代谢的过程中与活性抑制化合物分离(Bundgaard,Hans,“Design and Application of Prodrugs”in A Textbook of Drug Design and Development(1991),P.Krogsgaard-Larsen and H.Bundgaard,Eds.Harwood AcademicPublishers,pp.113-191)。能与本发明的膦酸酯前药化合物酶激活机制的酶包括但不限于酰胺酶、酯酶、微生物的酶、磷酯酶、胆碱酯酶、和磷酸酶(phosphases)。前药部分能够起增加溶解度、吸收和亲脂性的作用,以优化药物递送、生物利用度和功效。前药部分可以包括活性代谢产物或药物自身。
示范性的前药部分包括水解敏感的或不稳定的酰氧甲基酯
和酰氧甲基碳酸酯
,其中R9是C1-C6烷基,C1-C6取代的烷基,C6-C20芳香基或C6-C20取代的芳香基。酰氧烷基酯首先被用作羧酸的前药策略,之后被Farquhar等.(1983)J.Pharm.Sci. 72:324;也被美国专利号4816570,4968788,5663159和5792756用于磷酸酯和膦酸酯。之后,酰氧烷基酯被用于递送膦酸穿过细胞膜和增加口服生物利用度。酰氧烷基酯的一个接近的变体,烷氧基羰基氧烷基酯(碳酸酯),作为发明组合的化合物中的前药部分,也可以增加口服生物利用度。示范性的酰氧基甲酯是新戊酰氧甲氧基,
。示范性的酰氧甲基碳酸酯前药部分是新戊酰氧甲基碳酸酯
。
膦酸酯基团可以是一种膦酸酯前药部分。该前药部分可能对水解敏感,例如但不限于新戊酰氧甲基碳酸酯(POC)或POM基团。可选择的是,该前药部分可能对酶加强的裂解敏感,例如乳酸酯或膦酸酰胺酯基团。
磷基团的芳基酯,特别是苯基酯,被报道具有提高口服生物利用度的作用(De Lombaert et al.(1994)J.Med.Chem.37:498)。含有邻位于磷酸酯的羧酸酯的苯基酯也有描述(Khamnei and Torrence,(1996)J.Med.Chem.39:4109-4115)。苯甲基酯被报道能够产生母体膦酸。在一些情况下,邻位或对位的取代基可以加速水解作用。具有酰化苯酚或烷基化苯酚的苯甲基类似物可通过酶如脂酶、氧化酶等的作用,产生酚类化合物,其依次经历在苯甲基的
键处的分裂产生磷酸和醌甲基化物中间体。这类前药的例子被Mitchell等(1992)J.Chem.Soc.Perkin Trans.II 2345;Glazier WO 91/19721描述。含有与苯甲基亚甲基连接的含羧酸酯基团的其他苯甲基前药也已被描述(Glazier WO 91/19721)。含硫的前药被报道适用于膦酸酯药物的细胞内递送。这些前酯类含有乙硫基,其中硫醇基或被酰基酯化,或与另一个硫醇基结合形成一个二硫化物。二硫化物的脱脂化或还原产生游离的硫中间体,该中间体随后分解为磷酸和环硫化物(Puech等(1993)Antiviral Res.,22:155-174;Benzaria等(1996)J.Med.Chem.39:4958)。环膦酸酯也被描述为含磷化合物的前药(Erion等,美国专利No.6312662)。
“保护基团”指掩盖或改变官能团的性质或整体化合物的性质的化合物的部分。用于保护/脱保护的化学保护基团和策略是本领域公知的。例如参见,Protective Groups in Organic Chemistry,Theodora W.Greene,John Wiley & Sons,Inc.,New York,1991。保护基团通常被用作掩盖某些官能团的反应性,以有助于想要的化学反应的效率,例如以有次序和计划的方式生成和断裂化学键。化合物官能团的保护改变了除受保护的官能团的反应性以外的其它物理性质,例如极性,亲脂性(疏水性),以及可以通过普通分析工具测量的其他性质。化学保护的中间体它们自身可以是生物学活性的或非活性的。
受保护的化合物也可以呈现改变的,并且在一些情况下,优化的体外和体内性质,诸如通过细胞膜和抗酶的降解作用或多价螯合作用。在这种角色中,具有预期疗效的受保护的化合物可被称作为前药。保护基团的另一种功能是将母体药物转变为前药,由此前药在体内转化时释放母体药物。因为活性药物比母体药物可被更有效地吸收,所以前药在体内比母体药物具有更大的效价。在化学中间体的情况下,在体外除去保护基团,或在前药的情况下,在体内除去保护基团。对于化学中间体,脱保护后得到的产物,例如醇是生理学上可以接受的,并不特别重要,尽管通常更理想的是该产物是药理学上无害的。
任何提到本发明的任何化合物也包括提到它的生理学上可以接受的盐。本发明化合物的生理学上可以接受的盐的示例包括源于适宜碱的盐,所述碱例如碱金属(如,钠)、碱土金属(如,镁)、铵和
(其中X是C1-C4烷基)。生理学上可接受的氢原子或氨基的盐包括有机羧酸的盐,所述有机羧酸例如乙酸、苯甲酸、乳酸、反丁烯二酸、酒石酸、马来酸、丙二酸、苹果酸、羟乙磺酸、乳糖醛酸和琥珀酸;有机的磺酸,例如甲磺酸、乙磺酸、苯磺酸和p-甲苯磺酸;和无机酸,例如盐酸、硫酸、磷酸和氨基磺酸。羟基化合物的生理学上可接受的盐包括所述化合物的阴离子与适合的阳离子,例如
和
(其中X独立选自
或C1-C4烷基)结合。
为了治疗用途,本发明化合物的活性成分的盐将是生理学上可以接受的,亦即它们将是源于生理学上可接受的酸或碱的盐。然而,不是生理学上可接受的酸或碱的盐也可能发现是有用的,例如,在生理学上可接受的化合物的制备或纯化中。所有的盐,不论是否源于生理学上可接受的酸或碱,都在本发明的范围内。
“烷基”是C1-C18烃,包含正、仲、叔或环碳原子。例子是甲基(Me,
),乙基(Et,
),1-丙基(n-Pr,n-丙基,
),2-丙基(i-Pr,i-丙基,
),1-丁基(n-Bu,n-丁基,
),2-甲基-1-丙基(i-Bu,i-丁基,
),2-丁基(s-Bu,s-丁基,
),2-甲基-2-丙基(t-Bu,t-丁基,
),1-戊基(n-戊基,
),2-戊基(
),3-戊基(
),2-甲基-2-丁基(
),3-甲基-2-丁基(
),3-甲基-1-丁基(
),2-甲基-1-丁基(
),1-己基(
),2-己基(
),3-己基(
),2-甲基-2-戊基(
),3-甲基-2-戊基(
),4-甲基-2-戊基(
),3-甲基-3-戊基(
),2-甲基-3-戊基(
),2,3-二甲基-2-丁基(
),3,3-二甲基-2-丁基(
。
“烯基”是C2-C18烃,包含正、仲、叔或环碳原子,具有至少一个不饱和位置,亦即碳-碳,sp2双键。实例包括但不限于,亚乙基或乙烯基(
),烯丙基(
),环戊烯基(
)和5-己烯基(
)。
“炔基”是C2-C18烃,包含正、仲、叔或环碳原子,具有至少一个不饱和位置,亦即碳-碳,sp三键。实例包括但不限于,炔(
)和炔丙基(
)。
“亚烷基”指的是1-18个碳原子的饱和的、支链或直链或环状烃基,并具有两个单价的基团中心,其源自从母体烷烃的同一个或两个不同的碳原子上除去两个氢原子。典型的亚烷基包括但不限于,亚甲基(
)1,2-乙基(
),1,3-丙基(
),1,4-丁基(
),及其类似的基团。
“亚烯基”指的是2-18个碳原子的不饱和的、支链或直链或环状烃基,并具有两个单价的基团中心,其源自从母体烯烃的同一个或两个不同的碳原子上除去两个氢原子。典型的亚烯基包括但不限于1,2-亚乙基(
)。
“亚炔基”指的是2-18个碳原子的不饱和的、支链或直链或环状烃基,并具有两个单价的基团中心,其源自从母体炔的同一个或两个不同的碳原子上除去两个氢原子。典型的亚炔基包括但不限于,乙炔(
),炔丙基(
),和4-戊炔基(
)。
“芳基”指6-20个碳原子的一价芳烃基,源自从母体芳环系统的单一碳原子上除去1个氢原子。典型的芳基包括但不限于,源自于苯、被取代的苯、萘、蒽、联苯和类似基团的基团。
“芳基烷基”指非环状烷基,其中与碳原子,典型的是末端或sp3碳原子连接的氢原子中的一个被芳基取代。典型的芳基烷基包括,但不限于,苯甲基,2-苯基乙-1-基,萘甲基,2-萘乙-1-基,萘并苯甲基,2-萘并苯乙-1-基和类似基团。芳基烷基包含6-20个碳原子,例如芳基烷基的烷基部分,包括烷基,烯基或炔基,是1到6个碳原子,并且芳基部分是5到14碳原子。
“取代的烷基”,“取代的芳香基”,和“取代的芳基烷基”各自代表着烷基、芳基,和芳基烷基,其中一个或多个氢原子分别独立被非氢取代基取代。典型的取代基包括,但不限于,-X,-R,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,其中每一X独立地是卤素:
,
,
,或
;并且每一R独立地是
,烷基,芳香基,杂环,保护基团或前药部分。亚烷基,亚烯基,和亚炔基基团也可以被相似地取代。
此处使用的“杂环”包括,作为例子而不限于Paquette,Leo A.;Principles of Modern Heterocyclic Chemistry(W.A.Benjamin,NewYork,1968),特别地第1、3、4、6、7和9章;The Chemistry of Heterocvclic Compounds,A Series of Monographs”(John Wiley &Sons,New York,1950 to present),尤其是第13、14、16、19和28卷;和J.Am.Chem.Soc.(1960)82:5566中描述的这些杂环。在本发明的一个特别的实施方案中,“杂环”包括本申请中定义的“碳环”,其中一个或多个(例如1、2、3、或4)碳原子被杂原子(例如
、
或
)取代。
杂环的例子包括,作为例子而不限于,吡啶基、二氢吡啶基、四氢吡啶(哌啶基),噻唑基,四氢苯硫基(tetrahydrothiophenyl),硫氧化的四氢苯硫基,嘧啶基,呋喃基,噻吩基,吡咯基,吡唑基,咪唑基,四唑基,苯并呋喃基,噻萘基,吲哚基,假吲哚基(indolenyl),喹啉基,异喹啉,苯并咪唑基,哌啶基,4-哌啶酮基,吡咯烷基,2-吡咯烷酮基,吡咯啉基,四氢呋喃基,四氢喹啉基,四氢异喹啉基,十氢喹啉基,八氢异喹啉基,吖辛因,三嗪基,6H-1,2,5-噻二嗪基,2H,6H-1,5,2-二噻嗪基,噻吩基,噻蒽基,吡喃基,异苯并呋喃基,苯并吡喃基,呫吨基,phenoxathinyl,2H-吡咯基,异噻唑基,异噁唑基,吡嗪基,哒嗪基,中氮茚基,异吲哚基,3H-吲哚基,1H-吲唑基,嘌呤基,4H-喹嗪基,2,3-二氮杂萘基,萘啶基,喹喔啉基,喹唑啉基,肉啉基,喋啶基,4aH-咔唑基,咔唑基,β-咔啉基,菲啶基,吖啶基,嘧啶基,菲咯啉基,吩嗪基,吩噻嗪基,呋咱基,吩噁嗪基,异苯并二氢吡喃基,苯并二氢吡喃基,咪唑烷基,咪唑啉基,吡唑烷基,吡唑啉基,哌嗪基,二氢吲哚基,异二氢吲哚基,奎宁啶基,吗啉基,噁唑烷基,苯并三唑基,苯并异噁唑基,羟吲哚基,苯并噁唑啉基,靛红酰(isatinoyl),和双-四氧呋喃:
举例但不限于,碳键合的杂环是在吡啶的2,3,4,5,或6位,哒嗪的3,4,5,或6位,嘧啶的2,4,5,或6位,吡嗪的2、3、5或6位,呋喃,四氢呋喃,硫代呋喃,噻吩,吡咯或四氢吡咯的2,3,4,或5位,噁唑,咪唑或噻唑的2,4,或5位,异噁唑,吡唑,或异噻唑的3,4,或5位,氮丙啶的2或3位,吖丁啶的2,3,或4位,喹啉的2,3,4,5,6,7,或8位或异喹啉的1,3,4,5,6,7,或8位被键合。然而更典型地,碳键合的杂环包括2-吡啶基,3-吡啶基,4-吡啶基,5-吡啶基,6-吡啶基,3-哒嗪基,4-哒嗪基,5-哒嗪基,6-哒嗪基,2-嘧啶基,4-嘧啶基,5-嘧啶基,6-嘧啶基,2-吡嗪基,3-吡嗪基,5-吡嗪基,6-吡嗪基,2-噻唑基,4-噻唑基,或5-噻唑基。
举例和不限于,氮键合的杂环是在吖丁啶,吡咯,吡咯烷,2-吡咯啉,3-吡咯啉,咪唑,咪唑烷,2-咪唑啉,3-咪唑啉,吡唑,吡唑啉,2-吡唑啉,3-吡唑啉,哌啶,哌嗪,吲哚,二氢吲哚,1H-吲唑,氮丙啶的1位,异吲哚或异吲哚啉的2位,吗啉的4位,和咔唑,或β-咔啉的9位。然而更典型地,氮键合的杂环包括1-氮丙啶基,1-吖丁啶基,1-吡咯基,1-咪唑基,1-吡唑基和1-哌啶基。
“碳环”指饱和的、不饱和的或芳环,作为单环具有3到7个碳原子,作为双环有7到12个碳原子,作为多环至多约20个碳原子。单环碳环具有3到6个环原子,更加典型地,5或6个环原子。双环碳环具有7到12个环原子,例如,排列为双环-[4,5],[5,5],[5,6]或[6,6]系统,或排列为双环-[5,6]或[6,6]系统的9或10个环原子。单环碳环的例子包括环丙基,环丁基,环戊基,1-环戊-1-烯基,1-环戊-2-烯基,1-环戊-3-烯基,环己基,1-环己基-1-烯基,1-环己基-2-烯基,1-环己基-3-烯基,苯,螺烷基(spiryl)和萘基。
“连接体”或“连接基”指包括共价键的化学结构部分或以共价键将膦酸酯基团连接于药物上的原子基团的。连接体包括取代基A1和A3的一部分,它包括结构部分如:烷氧基的重复单元(例如,聚乙烯氧基(polyethylenoxy),PEG,聚亚甲基氧基)和烷基氨基的重复单元(例如,聚乙烯氨基,杰夫胺JeffamineTM);和二酸酯和酰胺,其中包括琥珀酸盐,琥珀酰胺,二乙醇酸盐,丙二酸盐,和己酰胺。
术语“手性的”是指具有镜像配偶体的不可叠加性质的分子,而术语“非手性的”是指可以在其镜像配偶体上可叠加的分子。
术语“立体异构体”指具有同一化学构成,但是原子或基团在空间的排列不同的化合物。
“非对映体”指具有两个或更多个手性中心并且其分子互相不是镜像的立体异构体。非对映体具有不同的物理性质,例如熔点,沸点,光谱性质,和反应性。非对映体的混合物在高分辨率的分析方法下,例如电泳和色谱法,可以分离。
“对映体”指为互相非可叠加镜像的化合物的两种立体异构体。
术语“治疗”或“治疗”,在某种程度上它涉及一种疾病或状况,包括预防疾病或状况发生,抑制疾病或状况,消除疾病或状况,和/或解除疾病或状况的一种或多种症状。
此处应用的立体化学的定义和惯例一般遵循S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill出版公司,纽约;和Eliel,E.和Wilen,S.,Stereochemistry of Organic Compounds(1994)John Wiley & Sons,Inc.,纽约。许多有机化合物以光学活性形式存在,亦即它们具有旋转平面偏振光的平面的能力。在描述光学活性化合物中,字首D和L或R和S被用于指代有关分子手性中心的分子绝对构型。字首的d和l或(+)和(-)被用于指示平面偏振光的被化合物旋转的标志,(-)或l表示化合物是左旋的。字首带(+)或d的化合物是右旋的。对于给定的化学构造来说,除了它们是互为镜像之外,这些立体异构体是相同的。一种特殊的立体异构体也被称为对映异构体,并且这类异构体的混合物常被称作对映异构体混合物。对映异构体的50∶50混合物被称为外消旋混合物或外消旋化物,当在化学反应或过程中没有立体选择性或立体特异性时,它可以产生。术语“外消旋混合物”和“外消旋化物”指的是两种对映异构体物种的等摩尔混合物,缺乏旋光性。
保护基团
在本发明的上下文中,保护基团包括前药部分和化学保护基团。
保护基团是可以获得的,通常是已知的和被使用过的,并且在合成过程中,亦即制备本发明化合物的途径与方法,被任选用于阻止受保护的基团发生副反应。对于大部分情况,对于要保护哪个基团的决定,何时实施,和化学保护基团“PG”的性质将取决于要被对抗的反应的化学(例如,酸性的,碱性的,氧化的,还原的或其他条件)和合成的预期方向。PG基团不需要相同,并且通常不相同,如果化合物被多个PG取代。通常,PG将被用于保护官能团诸如羧基,羟基,硫代,或氨基的基团,并且因此被用于阻止副反应或者另外促进合成的效率。脱保护产生游离的、脱保护基团的顺序取决于合成的预期方向和将要遇到的反应条件,并且可以本领域技术人员决定的任何顺序发生。
本发明化合物的不同的官能团可以被保护。例如,
基的保护基团(不论是羟基,羧酸,膦酸,还是其他官能)包括“醚-或酯-形成基团”。醚-或酯-形成基团在本申请提出的合成方案中能够起化学保护基团的功能。然而,正如本领域技术人员熟知的,一些羟基和硫代保护基团既不是醚-形成基团,也不是酯-形成基团,并且包括在下面讨论的酰胺。
非常大量的羟基保护基团和酰胺-形成基团和相应的化学裂解反应都被描述在Protective Groups in Organic Synthesis,Theodora W.Greene(John Wiley & Sons,Inc.,New York,1991,ISBN0-471-62301-6)(“Greene”)。也可见于Kocienski,Philip J.;protecting group(Georg Thieme Verlag Stuttgart,New York,1994),通过引用以其整体将它并入本申请。特别是第1章,保护基团:概述第1-20页,第2章,羟基保护基团,第21-94页,第3章,二醇保护基团,第95-117页,第4章,羧基保护基团,第118-154页,第5章,羰基保护基团,第155-184页。关于羧酸、膦酸、膦酸酯、磺酸保护基团和关于酸的其他保护基团见下面开始叙述的Greene。这样的基团包括,举例和不限于酯类、酰胺类、酰肼类等。
醚-和酯-形成保护基团
酯-形成基团包括:(1)膦酸酯-形成基团,例如膦酸酰胺化物酯、磷硫酰酯、膦酸酯,和膦酸-二-酰胺化物;(2)羧基酯-形成基团,和(3)硫酯-形成基团,例如磺酸酯、硫酸酯和亚磺酸酯。
本发明化合物的膦酸酯部分可以是或可以不是前药部分,亦即它们可以或可能对水解或酶解或修饰敏感。某些膦酸酯部分在大部分或几乎全部代谢条件下是稳定的。例如,二烷基膦酸酯,当烷基是两个或多个碳时,由于慢速水解,可能具有可察觉的体内稳定性。
在膦酸酯前药部分的上下文中,大量关于膦酸的结构多样的前药已经被描述,(Freeman and Ross in Progress in Medicinal Chemistry34:112-147(1997))并且被包括在本发明的保护范围内。示范性膦酸酯-形成基团是具有下式的亚结构A3中的苯基碳环,:
其中R1可以是
或C1-C12烷基;m1是1,2,3,4,5,6,7或8,并且苯基碳环被0到3个R2基团取代。当Y1是
时,形成乳酸酯,和当Y1是
,、
或
时,得到膦酸酰胺化物酯。
在其酯-形成的角色中,保护基团典型地与任意酸性基团结合,例如,举例和不限制于,
或
基团,因此导致 其中Rx如本申请中所定义。同样,Rx例如包括WO 95/07920中列举的酯基。
保护基团的例子包括:
C3-C12杂环(上面描述的)或芳基。这些芳基可以任选是多环的或单环的。例子包括苯基、螺基、2-和3-吡咯基、2-和3-噻吩基、2-和4-咪唑基、2-,4-和5-噁唑基、3-和4-异噁唑基、2-,4-和5-噻唑基,3-,4-和5-异噻唑基、3-和4-吡唑基、1-,2-,3-和4-吡啶基,和1-,2-,4-和5-嘧啶基,
被卤素取代的C3-C12杂环或芳基,R1,R1-O-C1-C12亚烷基,C1-C12烷氧基,
,
,
,羧基,羧基酯,硫醇,硫酯,C1-C12卤代烷基(1-6个卤素原子),C2-C12链烯基或C2-C12炔基。这类基团包括2-,3-和4-烷氧基苯基(C1-C12烷基),2-,3-和4-甲氧苯基,2-,3-和4-乙氧苯基,2,3-,2,4-,2,5-,2,6-,3,4-和3,5-二乙氧苯基,2-和3-碳乙氧基(carboethoxy)-4-羟苯基,2-和3-乙氧基-4-羟苯基,2-和3-乙氧基-5-羟苯基,2-和3-乙氧基-6-羟苯基,2-,3-和4-O-乙酰苯基,2-,3-和4-二甲基氨基苯基,2-,3-和4-甲基巯基苯基,2-,3-和4-卤代苯基(包括2-,3-和4-氟苯基和2-,3-和4-氯苯基),2,3-,2,4-,2,5-,2,6-,3,4-和3,5-二甲苯基,2,3-,2,4-,2,5-,2,6-,3,4-和3,5-双羧基乙基苯基,2,3-,2,4-,2,5-,2,6-,3,4-和3,5-二甲氧苯基,2,3-,2,4-,2,5-,2,6-,3,4-和3,5-二卤苯基(包括2,4-二氟苯基和3,5-二氟苯基),2-,3-和4-卤代烷基苯基(1到5个卤素原子,C1-C12烷基包括4-三氟甲基苯基),2-,3-和4-氰基苯基,2-,3-和4-硝基苯基,2-,3-和4-卤代烷基苯基(1到5个卤素原子,C1-C12烷基包括4-三氟甲基苯基和2-,3-和4-三氯甲苯基和2-,3-和4-三氯甲苯基),4-N-甲基哌啶基,3-N-甲基哌啶基,1-乙基哌嗪基,苯甲基,烷基水杨基苯基(C1-C4烷基,包括2-,3-和4-乙基水杨基苯基),2-,3-和4-乙酰苯基,1,8-二-羟基萘基(
)和芳氧基乙基[C6-C9芳基(包括苯氧基乙基)],2,2′-二羟基联苯基,2-,3-和4-N,N-二烷基氨基酚,
,三甲氧苯甲基,三乙氧苯甲基,2-烷基吡啶基(C1-4烷基);
2-羧基苯基的C4-C8酯;和C1-C4亚烷基-C3-C6芳基(包括苯甲基,-CH2-吡咯基,-CH2-噻吩基,-CH2-咪唑基,-CH2-噁唑基,-CH2-异噁唑基,-CH2-噻唑基,-CH2-异噻唑基,-CH2-吡唑基,-CH2-吡啶基和-CH2-嘧啶基),其在芳基部分被3到5卤原子取代或被1到2个选自下述的原子或基团取代:卤素,C1-C12烷氧基(包括甲氧基和乙氧基),氰基,硝基,
,C1-C12卤代烷基(1到6个卤原子;包括
),C1-C12烷基(包括甲基和乙基),C2-C12链烯基或C2-C12炔基;烷氧基乙基[C1-C6烷基包括
(甲氧基乙基)];被关于芳基的上述基团的任一种,特别是
或被1到3个卤原子取代的烷基(包括
,
,
,
,
,
,
,
,
,
,
,和
);
-N-2-丙基吗啉代,2,3-二氢-6-羟基茚,芝麻酚,儿茶酚单酯,
,
,
,
,胆甾烯基,烯醇丙酮酸酯(
),丙三醇;
5或6碳单糖,二糖或低聚糖(3到9个单糖基);
甘油三酯,例如α-D-β-甘油二酯(其中包含甘油酯脂类的脂肪酸通常是天然地存在的饱和的或不饱和的C6-26,C6-18或C6-10脂肪酸,诸如亚油酸,月桂酸,肉豆蔻酸,棕榈酸,硬脂酸,油酸,棕榈油酸,亚麻酸和类似的脂肪酸),其通过甘油三酯的甘油基氧被连接到此处的母体化合物的酰基上;
通过磷脂的磷酸酯连接到羧基上的磷脂;
2-苯并[c]呋喃酮基(显示在Clayton et a1.,Antimicrob.AgentsChemo.(1974)5(6):670-671的图1中;
环状碳酸酯,例如(5-Rd-2-氧-1,3-二氧杂环戊烯(dioxolen)-4-基)甲基酯(Sakamoto et al.,Chem.Pharm.Bull.(1984)32(6)2241-2248)其中Rd是R1,R4或芳基;和
本发明化合物的羟基任选被WO 94/21604中公开的基团III,IV或V中的一个或被异丙基取代。
表A列举了保护基团酯部分的例子,该部分例如可以通过氧被连接到
和
基团上。也显示了几个酰胺化物,其直接连接到
或
上。结构1-5,8-10和16,17,19-22的酯通过使本文具有游离羟基的化合物与相应的卤化物(氯化物或酰氯和类似物)和N,N-二环己基-N-吗啉羧基脒(carboxamidine)(或另一种碱诸如DBU,三乙胺,
,N,N-二甲基苯胺和类似物)在DMF(或其它溶剂诸如乙腈或N-甲基吡咯烷酮)中反应来合成。当被保护的化合物是一种膦酸酯时,结构5-7,11,12,21,和23-26的酯是通过醇或醇盐(或在化合物例如13,14和15的情况下为相应的胺)与一氯膦酸酯或二氯膦酸酯(或另一个激活的膦酸酯)的反应而合成的。
表A
1.-CH2-C(O)-N(R1)2 * | 10.-CH2-O-C(O)-C(CH3)3 |
2.-CH2-S(O)(R1) | 11.-CH2-CCl3 |
3.-CH2-S(O)2(R1) | 12.-C6H5 |
4.-CH2-O-C(O)-CH2-C6H5 | 13.-NH-CH2-C(O)O-CH2CH3 |
5.3-胆甾烯基 | 14.-N(CH3)-CH2-C(O)O-CH2CH3 |
6.3-吡啶基 | 15.-NHR1 |
7.N-乙基吗啉基 | 16.-CH2-O-C(O)-C10H15 |
8.-CH2-O-C(O)-C6H5 | 17.-CH2-O-C(O)-CH(CH3)2 |
9.-CH2-O-C(O)-CH2CH3 | 18.-CH2-C#H(OC(O)CH2R1)-CH2--(OC(O)CH2R1)* |
#-手性中心是(R),(S)或外消旋化物。
其它适合此处应用的酯类被描述在EP 632048中。
保护基团也包括形成前官能度(profunctionalities)的“双酯”(“double ester”),例如
,
,
,或结构式-CH(R1或W5)O((CO)R37)或-CH(R1或W5)((CO)OR38)的烷基-或芳基-酰氧烷基(其结合到酸性基团的氧上),其中R37和R38是烷基,芳基,或烷基芳基(见美国专利No.4,968,788)。经常地R37和R38是大体积基团(bulky groups),例如分枝的烷基,邻-取代的芳香基,间位-取代的芳香基,或它们的组合,包括1-6个碳原子的正、仲、异和叔烷基。一个例子就是新戊酰氧甲基基团。对于口服给药的前药,这些特别有用。此类有用的保护基团的例子是烷基酰氧甲基酯和它们的衍生物,包括
,
,
,
,
,
,
,
,
,
,
,
和
。
在一些权利要求中,被保护的酸性基团是酸性基团的酯和包含羟基的官能度的残基。在其它的权利要求中,氨基化合物被用于保护酸性官能度。适宜的含有羟基的或含有氨基的官能度的残基在上面被阐明或可见于WO95/07920。特别感兴趣的是氨基酸、氨基酸酯、多肽、或芳基醇的残基。典型的氨基酸、多肽和羧基酯化的氨基酸残基作为基团L1或L2被描述在WO95/07920的第11-18页与相关的文本中。WO95/07920清楚地教导了膦酸的酰胺化物,但是将要理解的是此类酰胺化物是与本文所阐述的任意酸基团和WO95/07920中阐述的氨基酸残基一起形成。
典型的用于保护酸性官能度的酯也被描述在WO95/07920中,再次理解用此处讨论的酸性基团以及与′920公开物的膦酸酯能够形成同样的酯类。典型的酯类基团至少在WO95/07920第89-93页(在R31或R35之下),第105页的表格,和第21-23页(如R)被定义。特别感兴趣的是未取代的芳香基的酯,诸如苯基或芳基烷基如苯甲基,或羟基,卤素-,烷氧基-,羧基和/或烷基酯羧基取代的芳香基或烷基芳基,特别地苯基,邻-乙氧苯基,或C1-C4烷基酯羧基苯基(水杨酸酯C1-C12烷基酯)。
受保护的酸性基团,特别地当使用WO95/07920中的酯类或酰胺时,适用作口服给药的前药。然而,为了使本发明的化合物通过口服途径给药有效,保护酸性基团不是必需的。当具有受保护的基团,特别地氨基酸酰胺化物或取代的和未取代的芳香基酯的本发明的化合物,被全身或口服地给药时,它们能够在体内水解裂解产生游离酸。
一种或多种酸性羟基是受保护的。如果超过一种酸性羟基是受保护的,那么相同的或不同的保护基团被应用,例如,酯类可以是不同的或相同的,或混合的酰胺化物和酯可以被应用。
在Greene(第14-118页)中描述的典型羟基保护基团包括取代的甲基和烷基醚,取代的苯甲基醚,甲硅烷基醚,酯类包括磺酸酯,和碳酸酯。例如:
·醚(甲基,叔丁酰基,烯丙基);
·取代的甲基醚(甲氧甲基,甲硫甲基,叔丁基硫甲基,(苯二甲基甲硅烷基)甲氧甲基,苄氧甲基,对甲氧基苄氧甲基,(4-甲氧苯氧基)甲基,邻甲氧基苯酚甲基,叔丁氧甲基,4-戊烯氧甲基,甲硅烷氧甲基,2-甲氧基乙氧甲基,2,2,2-三氯乙氧甲基,双(2-氯乙氧基)甲基,2-(三甲基甲硅烷基)乙氧甲基,四氢化吡喃基,3-溴四氢化吡喃基,四氢硫化吡喃基,1-甲氧环己基,4-甲氧四氢吡喃基,4-甲氧基四氢硫代吡喃基,甲氧基四氢硫代吡喃基S,S-二氧桥,1-[(2-氯-4-甲基)苯基]-4-甲氧哌啶-4-基,1,4-二噁烷-2-基,四氢呋喃基,四氢呋硫代喃基,2,3,3a,4,5,6,7,7a-八氢-7,8,8-三甲基-4,7-亚甲基苯并呋喃-2-基));
·取代的乙基醚(1-乙氧乙基,1-(2-氯乙氧基)乙基,1-甲基-1-甲氧乙基,1-甲基-1-苄氧乙基,1-甲基-1-苄氧基-2-氟代乙基,2,2,2-三氯乙基,2-三甲基甲硅烷乙基,2-(苯氧氢硒基)乙基,
·对-氯苯基,对甲氧苯基,2,4-二硝基苯基,苄基);
·取代的苄基醚(对甲氧苯甲基,3,4-二甲氧苯甲基,邻-硝基苄基,对硝基苄基,对卤代苯甲基,2,6-二氯苯甲基,对氰苯甲基,对苯基苯甲基,2-和4-吡咯甲基,3-甲基-2-吡咯甲基N-氧桥,二苯甲基,p,p′-二硝基二苯甲基,5-二苯并环庚基,三苯甲基,α-萘基二苯甲基,对甲氧苯基二苯甲基,二(对甲氧苯基)苯基甲基,三(对甲氧苯基)甲基,4-(4′-溴苯甲酰甲氧基)苯基二苯甲基,4,4′,4”-三(4,5-二氯苯二甲酰亚氨基苯基)甲基,4,4′,4”-三(乙酰丙酰氧基苯基)甲基,4,4′,4”-三(苯甲酰苯基)甲基,3-(咪唑-1-基甲基)双(4′,4”-二甲氧苯基)甲基,1,1-双(4-甲氧苯基)-1′-芘基甲基,9-蒽基,9-(9-苯基)呫吨基,9-(9-苯基-10-氧)蒽基,1,3-苯并二硫戊环-2-基,苯并异噻唑基S,S-二氧桥);
·甲硅烷基醚(三甲基甲硅烷基,三乙基甲硅烷基,三异丙基甲硅烷基,二甲基异丙基甲硅烷基,二乙基异丙基甲硅烷基,二甲基1,1,2-三甲基丙甲硅烷基基,叔丁基二甲基甲硅烷基,叔丁基二苯基甲硅烷基,三苯甲基甲硅烷基,三-对-二甲苯基甲硅烷基,三苯基甲硅烷基,二苯基甲基甲硅烷基,叔丁基甲氧苯基甲硅烷基);
·酯(甲酸酯,苯甲酰甲酸酯,乙酸酯,氯乙酸酯,二氯乙酸酯,三氯乙酸酯,三氟乙酸酯,甲氧乙酸酯,三苯基甲氧乙酸酯,苯氧乙酸酯,对氯苯氧乙酸酯,对聚乙酸苯酯,3-苯基丙酸酯,4-氧代戊酸酯(乙酰丙酸酯),4,4-(亚乙基二硫代)戊酸酯,新戊酸酯(Pivaloate),金刚烷酸酯(Adamantoate),巴豆酸酯,4-甲氧基丁烯酸酯,苯甲酸酯,对苯甲酸苯酯,2,4,6-三甲基苯甲酸酯(间-三甲苯甲酸酯));
·碳酸酯(甲基,9-芴基甲基,乙基,2,2,2-三氯乙基,2-(三甲基甲硅烷基)乙基,2-(苯基磺酰基)乙基,2-(三苯基磷鎓基)乙基,异丁基,乙烯基,烯丙基,对硝基苯基,苯甲基,对甲氧苯甲基,3,4-二甲氧苯甲基,邻-硝基苄基,对硝基苄基,S-苯甲基硫代碳酸酯,4-乙氧基-1-萘基,甲基二硫代碳酸酯);
·具有辅助裂解的基团(2-碘苯甲酸酯,4-叠氮基丁酸基,4-硝基-4-甲基戊酸酯,邻-(二溴甲基)苯甲酸酯,2-甲酰苯磺酸酯,2-(甲基硫代甲氧基)乙基碳酸酯,4-(甲基硫代甲氧基)丁酸酯,2-(甲基硫代甲氧基甲基)苯甲酸酯);其它酯类(2,6-二氯-4-甲基苯氧乙酸酯,2,6-二氯-4-(1,1,3,3四甲基丁基)苯氧乙酸酯,2,4-二(1,1-二甲丙基)苯氧乙酸酯,氯二苯基乙酸酯,异丁酸酯,单琥珀酸酯,(E)-2-甲基-2-丁烯酸酯(Tigloate),邻-(甲氧基羰基)苯甲酸酯,对-聚-苯甲酸酯,α-萘甲酸酯,硝酸酯,烷基N,N,N′,N′-四甲基磷二酰胺,N-苯基氨基甲酸酯,硼酸酯,二甲基硫膦基,2,4-二硝基苯基次磺酸酯);和
·磺酸酯(硫酸酯,甲磺酸酯(甲磺酸酯),苯甲基磺酸酯,甲苯磺酸酯)。
典型的1,2-二醇保护基团(因此,通常两个
与保护官能度连在一起)被记述在Greene第118-142页,和包括环状的缩醛和缩酮(亚甲基,亚乙基,1-叔-丁基亚乙基,1-苯基亚乙基,(4-甲氧苯基)亚乙基,2,2,2-三氯亚乙基,丙酮化合物(异亚丙基),亚环戊基,亚环己基,亚环庚基,苯亚甲基,对-甲氧苯亚甲基,2,4-二甲氧基苯亚甲基,3,4-二甲氧基苯亚甲基,2-硝基苯亚甲基);环状原酸酯(甲氧基亚甲基,乙氧基亚甲基,二甲氧基亚甲基,1-甲氧基亚乙基,1-乙氧基亚乙基,1,2-二甲氧基亚乙基,α-甲氧基苯亚甲基,1-(N,N-二甲氨基)亚乙基衍生物,α-(N,N-二甲氨基)苯亚甲基衍生物,2-噁亚环戊基);甲硅烷基衍生物(二-叔-丁基亚甲硅基),1,3-(1,1,3,3-四异丙基二亚硅氧烷基),和四-叔-丁氧基二硅氧烷-1,3-二亚基),环碳酸酯,环硼酸酯,乙基硼酸酯和苯基硼酸酯。
更加典型地,1,2-二醇保护基团包括那些表B中列举的,还更加典型地,环氧化物,丙酮化合物,环状的缩酮和芳基缩醛。
表B
其中R9是C1-C6烷基。
氨基保护基团
另一套护基团包括Greene第315-385页中记述的任意一种典型的氨基保护基团。它们包括:
·氨基甲酸酯:(甲基和乙基,9-芴基甲基,9(2-硫)芴基甲基,9-(2,7-二溴)芴基甲基,2,7-二-叔-丁基-[9-(10,10-二氧-10,10,10,10-四氢硫氧杂蒽基)]甲基,4-甲氧苯甲酰甲基);
·取代的乙基:(2,2,2-三氯乙基,2-三甲基甲硅烷乙基,2-苯乙基,1-(1-金刚烷基)-1-甲基乙基,1,1-二甲基-2-卤代乙基,1,1-二甲基-2,2-二溴乙基,1,1-二甲基-2,2,2-三氯乙基,1-甲基-1-(4-联苯基)乙基,1-(3,5-二-叔-丁基苯基)-1-甲基乙基,2-(2′-和4′-吡啶基)乙基,2-(N,N-二环己基甲酰胺基)乙基,叔-丁基,1-金刚烷基,乙烯基、烯丙基,1-异丙基烯丙基,桂皮酰基,4-硝基桂皮酰基,8-喹啉基,N-羟基哌啶基,烷基二硫基,苯甲基,对-甲氧苯甲基,对-硝基苄基,对-溴苯甲基,对-氯苯甲基,2,4-二氯苯甲基,4-甲基亚磺酰基苯甲基,9-蒽基甲基,二苯甲基);
·具有辅助裂解的基团:(2-甲基硫乙基,2-甲基磺酰基乙基,2-(对-甲苯磺酰基)乙基,[2-(1,3-二噻烷基)]甲基,4-甲基苯硫基,2,4-二甲基苯硫基,2-磷鎓基乙基,2-三苯基磷鎓基异丙基,1,1-二甲基-2-氰乙基,间-氯-对-酰氧苯甲基,对-(二羟基硼烷基)苯甲基,5-苯基异噁唑基甲基,2-(三氟甲基)-6-色酮基甲基);
·能够光解裂解的基团:(间-硝基苯基,3,5-二甲氧苯甲基,邻-硝基苄基,3,4-二甲氧基-6-硝基苄基,苯基(邻-硝基苯基)甲基);脲-型衍生物(吩噻嗪基-(10)-羰基,N′-对-甲苯磺酰基氨基羰基,N′-苯基氨基硫羰基);
·其它氨基甲酸酯类:(叔-戊基,S-苯甲基硫代氨基甲酸酯,对-氰基苯甲基,环丁基,环己基,环戊基,环丙基甲基,对-癸氧基苯甲基,二异丙甲基,2,2-二甲氧基羰基乙烯基,邻-(N,N-二甲基甲酰胺基)苯甲基,1,1-二甲基-3-(N,N-二甲基甲酰胺基)丙基,1,1-二甲基丙炔基,二(2-吡啶基)甲基,2-呋喃甲基,2-碘乙基,异冰片基,异丁基,异烟酰基,对-(p′-甲氧苯偶氮基)苯甲基,1-甲基环丁基,1-甲基环己基,1-甲基-1-环丙甲基,1-甲基-1-(3,5-二甲氧苯基)乙基,1-甲基-1-(对-苯偶氮基苯基)乙基,1-甲基-1-苯乙基,1-甲基-1-(4-吡啶基)乙基,苯基,对-(苯偶氮基)苯甲基,2,4,6-三-叔-丁基苯基,4-(三甲基铵)苯甲基,2,4,6-三甲基苯甲基);
·酰胺:(N-甲酰基,N-乙酰基,N-氯乙酰基,N-三氯乙酰基,N-三氟乙酰基,N-苯乙酰基,N-3-苯基丙酰基,N-picolinoyl,N-3-吡啶基甲酰胺,N-苯甲酰基苯丙氨酰基,N-苯甲酰基,N-对-苯基苯酰基);
·具有辅助裂解的酰胺:(N-邻-硝基苯基乙酰基,N-邻-硝基苯氧基乙酰基,N-乙酰乙酰基,(N′-二硫苄氧羰基氨基)乙酰基,N-3-(对-羟苯基)丙酰,N-3-(邻-硝基苯基)丙酰,N-2-甲基-2-(邻-硝基苯氧基)丙酰,N-2-甲基-2-(邻-苯基偶氮苯氧基)丙酰,N-4-氯丁酰,N-3-甲基-3-硝基丁酰,N-邻-硝基肉桂酰,N-乙酰蛋氨酸,N-邻-硝基苯甲酰,N-邻-(苯甲酰氧基甲基)苯甲酰,4,5-联苯-3-噁唑啉-2-酮);
·环酰亚胺衍生物:(N-邻-苯二甲酰亚胺,N-二硫杂琥珀酰,N-2,3-二苯基顺丁烯二酰基,N-2,5-二甲基吡咯基,N-1,1,4,4-四甲基二甲硅烷基氮杂环戊烷加合物,5-取代的1,3-二甲基-1,3,5-三氮杂环己-2-酮,5-取代的1,3-二苄基-1,3-5-三氮杂环己-2-酮,1-取代的3,5-二硝基-4-吡啶酮基);
·N-烷基和N-芳基胺:(N-甲基,N-烯丙基,N-[2-(三甲基甲硅烷基)乙氧基]甲基,N-3-乙酰氧基丙基,N-(1-异丙基-4-硝基-2-氧-3-吡咯啉-3-基),季铵盐,N-苯甲基,N-二(4-甲氧苯基)甲基,N-5-二苯并环庚基,N-三苯甲基,N-(4-甲氧苯基)二苯甲基,N-9-苯基芴基,N-2,7-二氯-9-芴基亚甲基,N-二茂铁基甲基,N-2-吡啶甲胺N′-氧化物);
·亚胺衍生物:(N-1,1-二甲基硫亚甲基,N-苯亚甲基,N-对-甲氧基亚苯基,N-二苯亚甲基,N-[(2-吡啶基)2,4,6-三甲苯基]亚甲基,N,(N′,N′-二甲基氨基亚甲基,N,N′-异亚丙基,N-对-硝基苯亚甲基,N-亚水杨基,N-5-氯亚水杨基,N-(5-氯-2-羟苯基)苯基亚甲基,N-亚环己基);
·烯胺衍生物:(N-(5,5-二甲基-3-氧-1-环己烯基));
·N-金属衍生物(N-甲硼烷衍生物,N-二苯基borinic acid衍生物,N-[苯基(五羰基铬-或-钨)]碳烯基,N-铜或N-锌螯合物);
·N-N衍生物:(N-硝基,N-亚硝基,N-氧化物);
·N-P衍生物:(N-二苯基氧膦基,N-二甲硫代氧膦基,N-二苯基硫代氧膦基,N-二烷基磷酰基,N-二苄基磷酰基,N-联二苯磷酰基);
·N-Si衍生物,N-S衍生物,和N-亚氧硫基衍生物:(N-苯亚氧硫基,N-邻-硝基苯亚氧硫基,N-2,4-二硝基苯亚氧硫基,N-五氯苯亚氧硫基,N-2-硝基-4-甲氧苯亚氧硫基,N-三苯甲基亚氧硫基,N-3-硝基吡啶亚氧硫基);和N-磺酰基衍生物(N-对-甲苯磺酰基,N-苯磺酰基,N-2,3,6-三甲基-4-甲氧苯磺酰基,N-2,4,6-三甲氧苯磺酰基,N-2,6-二甲基-4-甲氧苯磺酰基,N-五甲基苯磺酰基,N-2,3,5,6,-四甲基-4-甲氧苯磺酰基,N-4-甲氧苯磺酰基,N-2,4,6-三甲基苯磺酰基,N-2,6-二甲氧基-4-甲苯磺酰基,N-2,2,5,7,8-五甲基苯并二氢吡喃-6-磺酰基,N-甲磺酰基,N-β-三甲基甲硅烷基乙磺酰基,N-9-蒽磺酰基,N-4-(4′,8′-二甲氧基萘甲基)苯磺酰基,N-苯甲基磺酰基,N-三氟甲基磺酰基,N-苯甲酰磺酰基)
更加典型地,受保护的氨基包括氨基甲酸酯和酰胺,更典型地,
或
。另-个保护基团,也适用作氨基或
的前药,是:
见例如Alexander,J.et al.(1996)J.Med.Chem.39:480-486。
氨基酸和多肽保护基团和共轭物
本发明化合物的氨基酸或多肽保护基团具有 结构,其中R15是
、氨基酸或多肽残基,或R5,和R16是下面定义的。
R16是低级烷基或被氨基取代的低级烷基(C1-C6),羧基,酰胺,羧基酯,羟基,C6-C7芳基,胍基,咪唑基,吲哚基,巯基,亚砜,和/或烷基磷酸酯。R10也与氨基酸αN共同形成一个脯氨酸残基(R10
)。然而,R10通常是天然形成的氨基酸的侧基例如
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
和
。R10也包括1-胍基丙-3-基,苯甲基,4-羟基苯甲基,咪唑-4-基,吲哚-3-基,甲氧苯基和乙氧苯基。
另一组保护基团包括含氨基化合物残基,特别是一种氨基酸,多肽,保护基团,
,
,
,
或
,其中例如羧酸,与胺反应,亦即偶合,形成酰胺,如在
。膦酸可以与胺反应形成膦酰胺,如在
。
通常,氨基酸具有结构
,其中R17是
,
,氨基酸或多肽残基。氨基酸是低分子量化合物,约为少于大约1000MW并且它包含至少一个氨基或亚氨基和至少一个羧基。通常氨基酸是自然状态被发现,亦即,能够在生物材料中被检测到例如细菌或其它微生物,植物,动物或人。适宜的氨基酸典型地是α-氨基酸,亦即特征在于一个氨基或亚氨基氮原子通过单个的取代的或未取代的α-碳原子与一个羧基的碳原子分离的化合物。特别感兴趣的是疏水残基例如一或二烷基或芳基氨基酸,环烷基氨基酸和类似物。这些残基通过增加母体药物的分配系数促进细胞渗透性。典型地,该残基不包括巯基或胍基取代基。
天然形成的氨基酸残基是那些天然地在植物、动物或微生物中发现的残基,特别是它的蛋白质。多肽最典型地是基本上由那些天然形成的氨基酸残基组成。这些氨基酸是甘氨酸,丙氨酸,缬氨酸,亮氨酸,异亮氨酸,丝氨酸,苏氨酸,半胱氨酸,甲硫氨酸,谷氨酸,天冬氨酸,赖氨酸,羟基赖氨酸,精氨酸,组氨酸,苯丙氨酸,酪氨酸,色氨酸,脯氨酸,天门冬酰胺,谷氨酰胺和羟基脯氨酸。另外,非天然的氨基酸,例如,valanine,苯基甘氨酸和高精氨酸也被涵盖在内。通常遇到的不是基因编码的氨基酸也可以用于本发明。用于本发明的所有氨基酸可以或者是D-或L-旋光异构体。另外,其它肽模拟物也适用于本发明。有关的一般性综述,见Spatola,A.F.,在Chemistry and Biochemistry of amino acids,Peptides and Proteins,B.Weinstein,eds.,Marcel Dekker,New York,p.267(1983)。
当保护基团是单个氨基酸残基或多肽时,它们在本发明化合物取代基A1,A2或A3的R3被任选取代。这些共轭物通过在氨基酸的羧基(或例如多肽的C-端氨基酸)间形成酰胺键而产生。相似地,共轭物形成于R3和氨基酸或多肽的氨基基团之间。通常,母体分子任意位置中仅有一个被此处描述的氨基酸酰胺化,尽管在超过一个允许的位点引入氨基酸也落在本发明的保护范围内。通常,R3基团的羧基被氨基酸酰胺化。通常,氨基酸的α-氨基或α-羧基或多肽的末端氨基或羧基被键合到母体官能度上,亦即,在氨基酸侧链上的羧基或氨基通常不用于生成与母体化合物之间的酰胺键(尽管在下面进一步描述的共轭物的合成过程中这些基团可能需要被保护)。
关于氨基酸或多肽的包含羧基的侧链,可以理解的是羧基将任选例如,被R1封闭,用R5酯化,或被酰胺化。相似地,氨基侧链R16将任选用R1封闭或用R5取代。
与侧链氨基或羧基的这样的酯或酰胺键,像与母体分子的酯或酰胺,在体内或在体外在酸(pH<3)或碱(pH>10)条件下可任选是水解的。可选择地,在人类胃肠道中它们是充分稳定的,但是在血液中或细胞内环境中它们被酶促水解。酯或氨基酸或多肽酰胺化物也适用作制备包含游离氨基或羧基的母体分子的中间体。母体化合物游离的酸或碱,例如,可以通过常规的水解程序从本发明的酯或氨基酸或多肽的共轭物容易地生成。
当氨基酸残基包含一个或多个手性中心,D,L,内消旋,苏型或赤型(作为适当的)外消旋物,scalemates或它的混合物中的任意一种可以被使用。通常,如果中间体被非酶促水解(当酰胺被用作游离酸或游离胺的化学中间体是也将是这种情况),D异构体是有用的。在另一方面,L异构体具有更多用途,原因是它们对非酶水解和酶水解都敏感并且能更有效率地在胃肠道通过氨基酸或二肽基转运系统转运。
它的残基通过Rx或Ry表示的适宜的氨基酸的例子,包括以下氨基酸:
甘氨酸;
氨基多羧酸,例如,天冬氨酸,β-羟基天冬氨酸,谷氨酸,β-羟基谷氨酸,β-甲基天冬氨酸,β-甲基谷氨酸,β,β-二甲基天冬氨酸,γ-羟基谷氨酸,β,γ-二羟基谷氨酸,β-苯基谷氨酸,γ-亚甲基谷氨酸,3-氨基己二酸,2-氨基庚二酸,2-氨基辛二酸和2-氨基癸二酸;
氨基酸酰胺如谷氨酰胺和天门冬酰胺;
多氨基-或多碱基-一元羧酸如精氨酸,赖氨酸,β氨基丙氨酸,γ氨基丁酸,鸟氨酸,瓜氨酸(citruline),高精氨酸,高瓜氨酸,羟基赖氨酸,别羟赖氨酸(allohydroxylsine)和二氨基丁酸;
其它碱性的氨基酸残基例如组氨酸;
二氨基二羧酸例如α,α′-二氨基琥珀酸,α,α′-二氨基戊二酸,α,α′-二氨基己二酸,α,α′-二氨基庚二酸,α,α′-二氨基-β-羟基庚二酸,α,α′-二氨基辛二酸,α,α′-二氨基壬二酸,和α,α′-二氨基癸二酸;
亚氨基酸例如脯氨酸,羟基脯氨酸,别羟脯氨酸,γ-甲基脯氨酸,哌可酸,5-羟基哌扣立酸,和铃兰氨酸;
一-或二-烷基(典型地C1-C8支链的或正)氨基酸,例如丙氨酸,缬氨酸,亮氨酸,烯丙基甘氨酸,α-氨基丁酸,正缬氨酸,正亮氨酸,heptyline,α-甲基丝氨酸,α-氨基-α-甲基-γ-羟基戊酸,α-氨基-α-甲基-δ-羟基戊酸,α-氨基-α-甲基-ε-羟基己酸,异缬氨酸,α-甲基谷氨酸,α-氨基异丁酸,α-氨基二乙基乙酸,α-氨基二异丙基乙酸,α-氨基二-正-丙基乙酸,α-氨基二异丁基乙酸,α-氨基二-正-丁基乙酸,α-氨基乙基异丙基乙酸,α-氨基-正-丙基乙酸,α-氨基异戊基乙酸,α-甲基天冬氨酸,α-甲基谷氨酸,1-氨基环丙烷-1-羧酸,异亮氨酸,别异亮氨酸,叔-亮氨酸,β-甲基色氨酸和α-氨基-β-乙基-β-苯基丙酸;
β-苯基丝氨酸基(phenylserinyl);
脂肪族的α-氨基-β-羟基酸例如丝氨酸,β-羟基亮氨酸,β-羟基正亮氨酸,β羟基正缬氨酸,和α-氨基-β-羟硬脂酸;
α-氨基,α-,γ-,δ-或ε-羟基酸例如高丝氨酸,δ羟基正缬氨酸,γ-羟基正缬氨酸和ε-羟基正亮氨酸残基;刀豆氨酸(canavine)和副刀豆氨酸;γ羟基鸟氨酸;
2-氨基己糖酸例如D-氨基葡糖酸或D-氨基半乳糖酸;
α-氨基-β-硫醇,例如青霉胺,β-巯基正缬氨酸或β-巯基氨基丁酸;
其它含硫的氨基酸残基包括半胱氨酸;高胱氨酸,β-苯基甲硫氨酸,甲硫氨酸,S-烯丙基-L-半胱氨酸亚砜,2-巯基组氨酸,胱硫醚,和半胱氨酸或高胱氨酸的巯基醚;
苯丙氨酸,色氨酸和环-取代的α-氨基酸,例如苯基-或环己基氨基酸α-氨基苯乙酸,α-氨基环己乙酸和α-氨基-β-环己基丙酸;苯丙氨酸类似物和衍生物,包含芳基,低级烷基,羟基,胍基,氧基烷基醚,硝基,硫或卤素取代的苯基(例如,酪氨酸,甲基酪氨酸和邻-氯-,对-氯-,3,4-二氯,邻-,间-或对-甲基-,2,4,6-三甲基-,2-乙氧基-5-硝基-,2-羟基-5-硝基-和对-硝基-苯丙氨酸);呋喃基-,噻吩基-,吡啶基-,嘧啶基-,嘌呤基-或萘基-丙氨酸;和色氨酸类似物和衍生物包括犬尿素,3-羟基犬尿氨酸,2-羟色氨酸和4-羧基色氨酸;
α-氨基取代的氨基酸包括肌氨酸(N-甲基甘氨酸),N-苯甲基甘氨酸,N-甲基丙氨酸,N-苯甲基丙氨酸,N-甲基苯丙氨酸,N-苯甲基苯丙氨酸,N-甲基缬氨酸和N-苯甲基缬氨酸;和
α-羟基和取代的α羟基氨基酸,包括丝氨酸,苏氨酸,别苏氨酸,磷酸丝氨酸和磷酸苏氨酸。
多肽是氨基酸的聚合物,其中一个氨基酸单体的羧基通过一个酰胺键被键合到邻近氨基酸单体的氨基或亚氨基上。多肽包括二肽,低分子量多肽(大约1500-5000MW)和蛋白质。蛋白质任选包含3,5,10,50,75,100或更多残基,并且适宜地人,动物,植物或微生物的蛋白质基本上是序列同源。它们包括酶(例如,过氧化氢酶)也包括免疫原,例如KLH,或对抗希望产生免疫应答的任何类型的抗体或蛋白质。多肽的性质和同一性具有很大程度的不同。
多肽酰胺化物在产生抗体中适用作免疫原,所树抗体对抗多肽(如果它在给药动物体内不是致免疫的)或对抗在本发明化合物残余部分上的表位。
能够连接到母体非-肽基化合物的抗体被用于从混合物中分离母体化合物,例如在母体化合物的诊断或制造中。母体化合物和多肽的共轭物在接近地同源的动物体内通常比多肽更加容易致免疫的,并且因此使多肽更能致免疫,有利于产生对抗它的抗体。相应地,多肽或蛋白可能不需要是致免疫的,在通常被用于产生抗体的动物中,例如,兔,小鼠,马,或大鼠,但是最终产物共轭物在这些动物中的至少一种中应该是致免疫的。多肽在邻近酸性杂原子的第一和第二残基之间的肽键上任选包含一个解肽酶切割位点。这样的切割位点在侧面具有酶的识别结构,例如,被解肽酶识别的残基的特殊序列。
裂解本发明多肽共轭物的解肽酶是公知的,并且特别是包括羧肽酶。羧肽酶通过除去C-末端残基消化多肽,并且在许多情况下对特殊的C-末端序列是特异的。此类酶和它们的底物要求通常是公知的。例如,二肽(具有给定的残基对和游离的羧基端)通过它的α-氨基被共价键合到此处的化合物的磷原子或碳原子上。在权利要求中W1是膦酸酯,该肽将通过适宜的解肽酶被裂解是意料之中的,保留邻近的氨基酸残基的羧基自动催化地裂解膦酸酰胺键。
适宜的二肽基基团(用它们单个的字母代码表示)是AA,AR,AN,AD,AC,AE,AQ,AG,AH,AI,AL,AK,AM,AF,AP,AS,AT,AW,AY,AV,RA,RR,RN,RD,RC,RE,RQ,RG,RH,RI,RL,RK,RM,RF,RP,RS,RT,RW,RY,RV,NA,NR,NN,ND,NC,NE,NQ,NG,NH,NI,NL,NK,NM,NF,NP,NS,NT,NW,NY,NV,DA,DR,DN,DD,DC,DE,DQ,DG,DH,DI,DL,DK,DM,DF,DP,DS,DT,DW,DY,DV,CA,CR,CN,CD,CC,CE,CQ,CG,CH,CI,CL,CK,CM,CF,CP,CS,CT,CW,CY,CV,EA,ER,EN,ED,EC,EE,EQ,EG,EH,EI,EL,EK,EM,EF,EP,ES,ET,EW,EY,EV,QA,QR,QN,QD,QC,QE,QQ,QG,QH,QI,QL,QK,QM,QF,QP,QS,QT,QW,QY,QV,GA,GR,GN,GD,GC,GE,GQ,GG,GH,GI,GL,GK,GM,GF,GP,GS,GT,GW,GY,GV,HA,HR,HN,HD,HC,HE,HQ,HG,HH,HI,HL,HK,HM,HF,HP,HS,HT,HW,HY,HV,IA,IR,IN,ID,IC,IE,IQ,IG,IH,II,IL,IK,IM,IF,IP,IS,IT,IW,IY,IV,LA,LR,LN,LD,LC,LE,LQ,LG,LH,LI,LL,LK,LM,LF,LP,LS,LT,LW,LY,LV,KA,KR,KN,KD,KC,KE,KQ,KG,KH,KI,KL,KK,KM,KF,KP,KS,KT,KW,KY,KV,MA,MR,MN,MD,MC,ME,MQ,MG,MH,MI,ML,MK,MM,MF,MP,MS,MT,MW,MY,MV,FA,FR,FN,FD,FC,FE,FQ,FG,FH,FI,FL,FK,FM,FF,FP,FS,FT,FW,FY,FV,PA,PR,PN,PD,PC,PE,PQ,PG,PH,PI,PL,PK,PM,PF,PP,PS,PT,PW,PY,PV,SA,SR,SN,SD,SC,SE,SQ,SG,SH,SI,SL,SK,SM,SF,SP,SS,ST,SW,SY,SV,TA,TR,TN,TD,TC,TE,TQ,TG,TH,TI,TL,TK,TM,TF,TP,TS,TT,TW,TY,TV,WA,WR,WN,WD,WC,WE,WQ,WG,WH,WI,WL,WK,WM,WF,WP,WS,WT,WW,WY,WV,YA,YR,YN,YD,YC,YE,YQ,YG,YH,YI,YL,YK,YM,YF,YP,YS,YT,YW,YY,YV,VA,VR,VN,VD,VC,VE,VQ,VG,VH,VI,VL,VK,VM,VF,VP,VS,VT,VW,VY和VV。
三肽残基也适用作保护基团。当膦酸酯是被保护的,序列X200-脯氨酸-X201-(其中X200是任意氨基酸残基并且X201是氨基酸残基,脯氨酸的羧基酯,或氢)被鲁米那羧肽酶裂解生成具有游离羧基的X200,依次自动催化地裂解膦酸酰胺键是可预料的。X201的羧基任选用苯甲基酯化。
二肽或三肽类是基于已知的对能够影响到肠粘膜或其它细胞类型的转运的肽酶的转运性能和/或易感性进行选择的。缺少α-氨基的二肽和三肽是在肠粘膜细胞的刷状缘膜发现的肽转运蛋白的转运底物(Bai,J.P.F.,(1992)Pharm Res.9:969-978)。有转运能力的肽因此能够被用于增加酰胺化合物的生物利用度。含有一个或多个D构型氨基酸的二肽或三肽也是与肽转运相容并且能被用在本发明的酰胺化合物中。D构型氨基酸能够被用于降低二肽或三肽对蛋白酶水解的敏感性,所述蛋白酶对刷状缘,例如氨肽酶N是共同的。另外,二肽或三肽可替代地是基于它们对在肠腔中发现的的蛋白酶水解的相对抗性而被选择的。例如,缺少天冬氨酸和/或谷氨酸的三肽或多肽是氨肽酶A的不良底物,在疏水氨基酸(亮氨酸,酪氨酸,苯丙氨酸,缬氨酸,色氨酸)的N-端一侧的缺少氨基酸残基的二肽或三肽是内肽酶的不良底物,和在游离羧基末端的倒数第二位置缺少脯氨酸残基的肽是羧肽酶P的不良底物。类似的考虑也被应用到肽的选择中,该肽对胞液的、肾脏的、肝脏的、血清的或其它肽酶水解是或相对抵抗的或相对敏感的。这类不良裂解的多肽酰胺化物就是免疫原或适用于连接到蛋白上用以制备免疫原。
本发明特定实施方案
描述根、取代基和范围的特定值,和这里描述的本发明特定实施方案一样仅为举例说明;他们不排除其他确定值或其他确定范围内的值。
在本发明一特定实施方案中,共轭物是被一个或多个膦酸酯基团直接或间接通过连接体取代;而且任选被一个或多个A0基团取代的化合物;或者它的药学上可接受的盐,其中:
A0是A1、A2或W3;
A1是:
A2是:
A3是:
Y1独立地是
、
、
、
、
、
或
;
Y2独立地是键,
、
、
、
、
、
、
或
;
Rx独立地是
、R1、W3、保护基团或如下通式:
其中:
Ry独立地是
、W3、R2或保护基团;
R1独立地是
或1到18个碳原子的烷基;
R2独立地是
、R1、R3或R4,其中每一R4独立地被0到3个R3基团取代或两个R2基团在碳原子位置被结合到一起,形成一个3到8个碳的环并且该环可被0到3个R3基团取代;
R3是R3a、R3b、R3c或R3d,条件是当R3与杂原子结合时,那么R3是R3c或R3d;
R3a是
、
、
、
、
、
或
;
R3b是Y1;
R3c是
、
、
、
、
、
、
、
、
、
、
、
、
、
、
或
;
R3d是
、
或
;
R4是1到18个碳原子的烷基,2到18个碳原子的链烯基,或2到18个碳原子的炔基;
R5是R4,其中每个R4被0到3个R3基团取代;
R5a独立地是1到18个碳原子的亚烷基、2到18个碳原子的亚烯基、或2到18个碳原子的亚炔基,所述亚烷基、亚烯基或亚炔基中的任意一个被0到3个R3基团取代;
W3是W4或W5;
W4是R5、
、
、
或
;
W5是碳环或杂环,其中W5独立地被0到3个R2基团取代;
W6是W3,独立地被1、2或3个A3基团取代;
M2是0、1或2;
M12a是1、2、3、4、5、6、7、8、9、10、11或12;
M12b是0、1、2、3、4、5、6、7、8、9、10、11或12;
M1a、M1c、和M1d独立地是0或1;并且
M12c是0、1、2、3、4、5、6、7、8、9、10、11或12。
在本发明另一特定实施方案中A1具有以下通式:
在本发明另一特定实施方案中A1具有以下通式:
在本发明另一特定实施方案中A1具有以下通式:
在本发明另一特定实施方案中A1具有以下通式:
在本发明另一特定实施方案中A1具有以下通式:
而且W5是碳环或杂环,其中W5独立地被0到1个R2基团取代。M12a的特定值(velue)是is 1。
在本发明另一特定实施方案中A1具有以下通式:
在本发明另一特定实施方案中A1具有以下通式:
在本发明另一特定实施方案中A1具有以下通式:
其中W5a是独立被0或1个R2基团取代的碳环;
在本发明另一特定实施方案中A1具有以下通式:
其中Y2b是
或
;并且M12d是1、2、3、4、5、6、7或8。
在本发明另一特定实施方案中A1具有以下通式:
其中W5a是取代被0或1个R2基团独立的碳环;
在本发明另一特定实施方案中A1具有以下通式:
其中W5a是碳环或杂环,其中W5a独立地被0或1个R2基团取代;
在本发明另一特定实施方案中A1具有以下通式:
其中Y2b是
或
;并且M12d是1、2、3、4、5、6、7或8。
在本发明另一特定实施方案中A2具有以下通式:
在本发明另一特定实施方案中A2具有以下通式:
在本发明另一特定实施方案中M12b是1。
在本发明另一特定实施方案中M12b是0,Y2是键而且W5a是碳环或杂环,其中W5a任选和独立地被1、2或3个R2基团取代。
在本发明另一特定实施方案中A2具有以下通式:
其中W5a是碳环或杂环,其中W5a任选和独立地被1、2或3的R2基团取代。
在本发明另一特定实施方案中M12a是1。
在本发明另一特定实施方案中A2从苯基、取代的苯基、苯甲基、取代的苯甲基、吡啶基和取代的吡啶基中选择。
在本发明另一特定实施方案中A2具有以下通式:
在本发明另一特定实施方案中A2具有以下通式:
在本发明另一特定实施方案中M12b是1。
在本发明另一特定实施方案中A3具有以下通式:
在本发明另一特定实施方案中A3具有以下通式:
在本发明另一特定实施方案中A3具有以下通式:
其中Y1a是
或
;并且Y2a是
、
或
。
在本发明另一特定实施方案中A3具有以下通式:
其中Y2b是
或
。
在本发明另一特定实施方案中A3具有以下通式:
其中Y2b是
或
;并且M12d是1、2、3、4、5、6、7或8。
在本发明另一特定实施方案中A3具有以下通式:
其中Y2b是
或
;并且M12d是1、2、3、4、5、6、7或8。
在本发明另一特定实施方案中M12d是1。
在本发明另一特定实施方案中A3具有以下通式:
在本发明另一特定实施方案中A3具有以下通式:
在本发明另一特定实施方案中W5是碳环。
在本发明另一特定实施方案中A3具有以下通式:
在本发明另一特定实施方案中W5是苯基。
在本发明另一特定实施方案中A3具有以下通式:
其中Y1a是
或
;并且Y2a是
、
或
。
在本发明另一特定实施方案中A3具有以下通式:
其中Y2b是
或
。
在本发明另一特定实施方案中A3具有以下通式:
其中Y2b是
或
;且M12d是1、2、3、4、5、6、7或8。
在本发明另一特定实施方案中R1是
。
在本发明另一特定实施方案中A3具有以下通式:
其中苯基碳环被0、1、2或3个R2基团取代。
在本发明另一特定实施方案中A3具有以下通式:
在本发明另一特定实施方案中A3具有以下通式:
在本发明另一特定实施方案中A3具有以下通式:
在本发明另一特定实施方案中A3具有以下通式:
在本发明另一特定实施方案中A3具有以下通式:
其中Y1a是
或
;且Y2a是
、
或
。
在本发明另一特定实施方案中A3具有以下通式:
其中Y1a是
或
;Y2b是
或
;且Y2c是
、
或
。
在本发明另一特定实施方案中A3具有以下通式:
其中Y1a是
或
;Y2b是
或
;Y2d是
或
;且M12d是1、2、3、4、5、6、7或8。
在本发明另一特定实施方案中A3具有以下通式:
其中Y2b是
或
;且M12d是1、2、3、4、5、6、7或8。
在本发明另一特定实施方案中A3具有以下通式:
其中Y2b是
或
。
在本发明另一特定实施方案中A3具有以下通式:
在本发明另一特定实施方案中A3具有以下通式:
在本发明另一特定实施方案中A3具有以下通式:
其中Y1a是
或
;且Y2a是
、
或
。
在本发明另一特定实施方案中A3具有以下通式:
其中Y1a是
或
;Y2b是
或
;且Y2c是
、
或
。
在本发明另一特定实施方案中A3具有以下通式:
其中Y1a是
或
;Y2b是
或
;Y2d是
或
;且M12d是1、2、3、4、5、6、7或8。
在本发明另一特定实施方案中A3具有以下通式:
其中Y2b是
或
;且M12d是1、2、3、4、5、6、7或8。
在本发明另一特定实施方案中A3具有以下通式:
其中Y2b是
或
。
在本发明另一特定实施方案中A3具有以下通式:
其中:Y2b是
或
;且M12d是1、2、3、4、5、6、7或8。
在本发明另一特定实施方案中A3具有以下通式:
其中苯基碳环被0、1、2或3个R2基团取代。
在本发明另一特定实施方案中A3具有以下通式:
其中苯基碳环被0、1、2或3个R2基团取代。
在本发明另一特定实施方案中A3具有以下通式:
在本发明另一特定实施方案中A0具有以下通式:
其中每一R独立地是(C1-C6)烷基。
在本发明另一特定实施方案中Rx独立地是
、R1、W3、保护基团或以下通式:
其中:
Ry独立地是
、W3、R2或保护基团;
R1独立地是
或1到18个碳原子的烷基;
R2独立地是
、R1、R3或R4其中每一R4独立地被0到3个R3基团取代或二个R2基团在一碳原子上结合到一起,形成3到8个碳原子的环且该环可被0到3个R3基团取代;
在本发明另一特定实施方案中Rx具有以下通式:
其中Y1a是
或
;且Y2c是
、
或
。
在本发明另一特定实施方案中Rx具有以下通式:
其中Y1a是
或
;且Y2d是
或
。
在本发明另一特定实施方案中Rx具有以下通式:
在本发明另一特定实施方案中Ry是氢或1到10个碳的烷基。
在本发明另一特定实施方案中Rx具有以下通式:
在本发明另一特定实施方案中Rx具有以下通式:
在本发明另一特定实施方案中Rx具有以下通式:
在本发明另一特定实施方案中Y1是
或
在本发明另一特定实施方案中Y2是
、
或
。
在本发明另一特定实施方案中Rx具有以下通式:
其中:
m1a、m1b、m1c、m1d和m1e独立地是0或1;
m12c是0、1、2、3、4、5、6、7、8、9、10、11或12;
Ry是
、W3、R2或保护基团;
条件是:
如果m1a、m12c和m1d是0,那么m1b、m1c和m1e是0;
如果m1a和m12c是0且m1d不是0,那m1b和m1c是0;
如果m1a和m1d是0且m12c不是0,那么m1b和m1c和m1e中至少一个是0;
如果m1a是0且m12c和m1d不是0,那么m1b是0;
如果m12c和m1d是0且m1a不是0,那么m1b、m1c和m1e中至少二个是0;
如果m12c是0且m1a和m1d不是0,那么m1b和m1c中至少一个是0;并且
如果m1d是0且m1a和m12c不是0,那么m1c和m1e中至少一个是0。
在另一特定实施方案中,本发明提供如下通式的化合物:
[DRUG]-(A0)nn
或者它的药学上可接受的盐,其中,
DRUG是通式500-547之中的任何一个通式的化合物;
nn是1,2,或3;
A0是A1,A2,或W3,是所述化合物包括至少一个A1;
A1是:
A2是:
A3是:
Y1独立地是
,
,
,
,
,
或
;
Y2独立地是键,
,
,
,
,
,
,
或
;
Rx独立地是
,R1,W3,保护基,或如下通式:
其中:
Ry独立地是
,W3,R2或保护基;
R1独立地是
或1到18个碳原子的烷基;
R2独立地是
,R1,R3或R4,其中各R4独立地被0到3个R3基团取代或一起连在碳原子上,两个R2基团形成具有3到8个碳的环和该环可以被0到3个R3基团取代;
R3是R3a,R3b,R3c或R3d,条件是当R3结合到杂原子上时,则R3是R3c或R3d;
R3a是
,
,
,
,
,
或
;
R3b是Y1;
R3c是-Rx,
,
,
,
,
,
,
,
,
,
,
,
,
,
或
;
R3d是
,
或
;
R4是1到18个碳原子的烷基,2到18个碳原子的链烯基,或2到18个碳原子的炔基;
R5是R4,其中各R4被0到3个R3基团取代;
R5a独立地是1-18个碳原子的亚烷基,2-18个碳原子的亚链烯基,或2-18个碳原子亚炔基,所述亚烷基、亚链烯基或亚炔基中的任何一个可以被0-3个R3基团取代;
W3是W4或W5;
W4是R5,
,
,
或
;
W5是碳环或杂环,其中W5独立地被0到3个R2基团取代;
W6是独立地被1、2或3个A3基团取代的W3;
M2是0,1或2;
M12a是1,2,3,4,5,6,7,8,9,10,11或12;
M12b是0,1,2,3,4,5,6,7,8,9,10,11或12;
M1a,M1c和M1d独立地是0或1;和
M12c是0,1,2,3,4,5,6,7,8,9,10,11或12。
在另一个实施方案中,本发明提供了通式1-151之中的任何一个的化合物,其中:
A0是A1;
A1是:
A3是:
Y1独立地是
,
,
,
,
,
或
;
Y2独立地是键,
,
,
,
,
,
,
或
;
Rx独立地是
,W3,保护基,或如下通式:
Ry独立地是
,W3,R2或保护基;
R1独立地是
或1到18个碳原子的烷基;
R2独立地是
,R3或R4,其中各R4独立地被0到3个R3基团取代;
R3是R3a,R3b,R3c或R3d,条件是当R3结合到杂原子上时,则R3是R3c或R3d;
R3a是
,
,
,
,
,
或
;
R3b是Y1;
R3c是-Rx,
,
,
,
,
,
,
,
,
,
,
,
,
,
或
;
R3d是
,
或
;
R4是1到18个碳原子的烷基,2到18个碳原子的链烯基,或2到18个碳原子的炔基;
R5是R4,其中各R4被0到3个R3基团取代;
R5a独立地是1-18个碳原子的亚烷基,2-18个碳原子的亚链烯基,或2-18个碳原子亚炔基,所述亚烷基、亚链烯基或亚炔基中的任何一个可以被0-3个R3基团取代;
W3是W4或W5;
W4是R5,
,
,
或
;
W5是碳环或杂环,其中W5独立地被0到3个R2基团取代;
W6是独立地被1、2或3个A3基团取代的W3;
M2是0,1或2;
M12a是1,2,3,4,5,6,7,8,9,10,11或12;
M12b是0,1,2,3,4,5,6,7,8,9,10,11或12;
M1a,M1c和M1d独立地是0或1;和
M12c是0,1,2,3,4,5,6,7,8,9,10,11或12。
在另一个特定的实施方案中,本发明提供了以下通式的化合物:[DRUG]-[L-P(=Y1)-Y2-Rx]nn
或它的药物学上可接受的盐,其中
DRUG是具有通式500-547之中的任何一个通式的化合物;
Y1独立地是
,
,
,
,
,
或
;
Y2独立地是键,
,
,
,
,
,
,
或
;
Rx独立地是
,W3,保护基,或如下通式:
Ry独立地是
,W3,R2或保护基;
R2独立地是
,R3或R4,其中各R4独立地被0到3个R3基团取代;
R3是R3a,R3b,R3c或R3d,条件是当R3结合到杂原子上时,则R3是R3c或R3d;
R3a是
,
,
,
,
,
或
;
R3b是Y1;
R3c是-Rx,
,
,
,
,
,
,
,
,
,
,
,
,
,
或
;
R3d是
,
或
;
R4是1到18个碳原子的烷基,2到18个碳原子的链烯基,或2到18个碳原子的炔基;
R5是R4,其中各R4被0到3个R3基团取代;
W3是W4或W5;
W4是R5,
,
,
或
;
W5是碳环或杂环,其中W5独立地被0到3个R2基团取代;
M2是1,2,或3;
M1a,M1c和M1d独立地是0或1;
M12c是0,1,2,3,4,5,6,7,8,9,10,11或12;
nn是1,2,或3;和
L是连接基团。
在另一个特定的实施方案中,本发明提供了以下通式的化合物:[DRUG]-(A0)nn
或它的药物学上可接受的盐,其中
DRUG是具有通式500-547之中的任何一个通式的化合物;
nn是1,2,或3;
A0是A1,A2,或W3,条件是所述化合物包括至少一个A1;
A1是:
A2是:
A3是:
Y1独立地是
,
,
,
,
,
或
;
Y2独立地是键,
,
,
,
,
,
,
或
;
Rx独立地是
,W3,保护基,或如下通式:
Ry独立地是
,W3,R2或保护基;
R2独立地是
,R3或R4,其中各R4独立地被0到3个R3基团取代;
R3是R3a,R3b,R3c或R3d,条件是当R3结合到杂原子上时,则R3是R3c或R3d;
R3a是
,
,
,
,
,
或
;
R3b是Y1;
R3c是-Rx,
,
,
,
,
,
,
,
,
,
,
,
,
,
或
;
R3d是
,
或
;
R4是1到18个碳原子的烷基,2到18个碳原子的链烯基,或2到18个碳原子的炔基;
R5是R4,其中各R4被0到3个R3基团取代;
W3是W4或W5;
W4是R5,
,
,
或
;
W5是碳环或杂环,其中W5独立地被0到3个R2基团取代;
W6是独立地被1、2或3个A3基团取代的W3;
M2是0,1或2;
M12a是1,2,3,4,5,6,7,8,9,10,11或12;
M12b是0,1,2,3,4,5,6,7,8,9,10,11或12;
M1a,M1c和M1d独立地是0或1;和
M12c是0,1,2,3,4,5,6,7,8,9,10,11或12。
在本发明的化合物中,W5碳环和W5杂环独立地被0到3个R2基团取代。W5可以是包括单环-或双环碳环或杂环的饱和的,不饱和的或芳族的环。W5可具有3到10个环上原子,例如,3到7个环上原子。W5环在含有3个环上原子时是饱和的,在含有4个环上原子时是饱和的或单-不饱的,或在含有5个环原子时是饱和的、单-或二-不饱和的,和在含有6个环上原子时是饱和的,单-或二-不饱和的,或芳族的。
W5杂环可以是具有3到7个环上成员(2到6个碳原子和选自
,
,
和
中的1到3个杂原子)的单环或具有7到10个环上成员(4到9个碳原子和选自
,
,
和
中的1到3个杂原子)的双环。W5杂环单环可以具有3到6个环上原子(2到5个碳原子和选自
,
,和
中的1到2个杂原子);或具有5或6个环上原子(3到5个碳原子和选自
和
中的1到2个杂原子)。W5杂环族双环具有作为双环[4,5],[5,5],[5,6],或[6,6]体系排列的7-10个环上原子(6到9个碳原子和选自
,
和
中的1到2个杂原子);或作为双环[5,6]或[6,6]体系排列的9-10个环上原子(8到9个碳原子和选自
和
中的1到2个杂原子)。W5杂环可以经由碳,氮,硫或其它原子由稳定的共价键连接到Y2上。
W5杂环包括例如:吡啶基,二氢吡啶基异构体,哌啶基,哒嗪基,嘧啶基,吡嗪基,s-三嗪基,噁唑基,咪唑基,噻唑基,异噁唑基,吡唑基,异噻唑基,呋喃基,硫代呋喃基,噻吩基,和吡咯基。W5还包括,但不限于,例如下列实例:
W5碳环和杂环可以独立地被0到3个R2基团(如以上所定义)取代。例如,取代的W5碳环包括:
取代的苯基碳环的例子包括:
连接基团和连接体
本发明提供共轭物,它包含直接(例如通过共价键)或经由连接基团(即连接体)连接于一个或多个膦酸酯基团上的免疫调节化合物。连接基的性质不是关键的,只要它不干涉含有膦酸酯的化合物用作治疗剂的能力就行。膦酸酯或连接体能够,通过除去该化合物的氢或任何位置来提供为膦酸酯或连接体的连接所用的开放化合价,在任何合成可行的位置上连接到该化合物(例如通式500-547的化合物)上。
在本发明的一个实施方案中该连接基团或连接体(它能可能被标识“L”)能够包括这里所述的基团A0,A1,A2或W3的全部或一部分。
在本发明的另一个实施方案中,连接基团或连接体具有约20道尔顿到约400道尔顿的分子量。
在本发明的另一个实施方案中该连接基团或连接体具有约5埃到约300埃的长度。
在本发明的另一个实施方案中,连接基团或连接体以约5埃到约200埃(包括范围的端值)的长度分开DRUG和P(=Y1)残基。
在本发明的另一个实施方案中,连接基团或连接体是具有2到25个碳原子的二价的,支化或未支化的,饱和或不饱和的烃链,其中所述碳原子中的一个或多个(例如1,2,3或4个)任选地被(
)替代,和其中该链任选在碳上被一个或多个(例如1,2,3或4个)取代基取代,该取代基选自(C1-C6)烷氧基,(C3-C6)环烷基,(C1-C6)烷酰基,(C1-C6)烷酰基氧基,(C1-C6)烷氧基羰基,(C1-C6)烷硫基,叠氮基,氰基,硝基,卤素,羟基,氧代(
),羧基,芳基,芳氧基,杂芳基,和杂芳氧基。
在本发明的另一个实施方案中该连接基团或连接体具有通式W-A,其中A是(C1-C24)烷基,(C2-C24)链烯基,(C2-C24)炔基,(C3-C8)环烷基,(C6-C10)芳基或它们的组合,其中W是
,
,
,
,
,
,
,
,
,
,或直接的键;其中各R独立地是
或(C1-C6)烷基。
在本发明的另一个实施方案中该连接基团或连接体是从肽形成的二价基团。
在本发明的另一个实施方案中该连接基团或连接体是从氨基酸形成的二价基团。
在本发明的另一个实施方案中,连接基团或连接体是从聚-L-谷氨酸,聚-L-天冬氨酸,聚-L-组氨酸,聚-L-鸟氨酸,聚-L-丝氨酸,聚-L-苏氨酸,聚-L-酪氨酸,聚-L-亮氨酸,聚-L-赖氨酸-L-苯基丙氨酸,聚-L-赖氨酸或聚-L-赖氨酸-L-酪氨酸形成的二价基团。
在本发明的另一个实施方案中该连接基团或连接体具有通式
,其中,n在约1和约10之间;和W是
,
,
,
,
,
,
,
,
,
,或直接的键;其中各R独立地是
或(C1-C6)烷基。
在本发明的另一个实施方案中该连接基团或连接体是亚甲基,亚乙基或亚丙基。
在本发明的另一个实施方案中该连接基团或连接体经由连接体的碳原子连接到膦酸酯基团上。
化合物
本发明的化合物包括具有免疫调节活性的那些。本发明的化合物可以携带一个或多个(例如1,2,3或4个)膦酸酯基团,它可以是前药结构部分。
典型地,本发明的化合物具有约400原子质量单位到约10,000原子质量单位的分子量;在本发明的特定的实施方案中,化合物具有小于约5000原子质量单位的分子量;在本发明的另一个特定的实施方案中,化合物具有小于约2500原子质量单位的分子量;在本发明的另一个特定的实施方案中,化合物具有小于约1000原子质量单位的分子量;在本发明的另一个特定的实施方案中,化合物具有小于约800原子质量单位的分子量;在本发明的另一个特定的实施方案中,化合物具有小于约600原子质量单位的分子量;和在本发明的另一个特定的实施方案中,化合物具有小于约600原子质量单位和大于约400原子质量单位的分子量。
本发明的化合物还典型地具有小于约5的logD(极性)。在一个实施方案中本发明提供logD小于约4的化合物;在另一个实施方案本发明提供logD小于约3的化合物;在另一个实施方案本发明提供logD大于约-5的化合物;在另一个实施方案本发明提供logD大于约-3的化合物;和在另一个实施方案本发明提供logD大于约0和小于约3的化合物。
在本发明化合物中的所选择的取代基是在递归的程度上出现。在这一方面,“递归的取代基”意指取代基能够列举它本身的另一种情况。因为该取代基的递归性质,理论上,大量可以存在于任何给出的权利要求中。例如,Rx含有Ry取代基。Ry能够是R2,它进而能够是R3。如果R3被选择是R3c,则Rx的第二种情况能够选择。在药物化学领域中的普通技术人员会理解,此类取代基的总数合理地由预定化合物的所需性能来限制。此类性能包括,举例但无限制意味,物理性能如分子量,溶解度或log P,应用性能如对于预定靶的活性,和实际性能如合成的难易。
举例但无限制意味,W3,Ry和R3在某些权利要求中全部是递归的取代基。典型地,这些取代基中的每一种可以独立地在给定的权利要求中出现20,19,18,17,16,15,14,13,12,11,10,9,8,7,6,5,4,3,2,1,或0次。更典型地,这些中的每一个可以独立地在给定的权利要求中出现12或12以下的次数。仍然更典型地,在给定的权利要求中W3将出现0到8次,Ry将出现0到6次和R3将出现0到10次。甚至更典型地,在给定的权利要求中W3将出现0到6次,Ry将出现0到4次和R3将出现0到8次。
递归的取代基是本发明的预定方面。药物化学领域中的普通技术人员会理解此类取代基的多变性。在递归取代基存在于本发明的权利要求中的程度上,总数按照以上所述来确定。
每当在这里描述的化合物被一个以上的相同标识的基团(例如,“R1”或“R6a”)取代时,则应该理解,这些基团可以是相同的或不同的,即,各基团是独立地选择的。波形线表示共价键连接于相邻基团、结构部分或原子上的位点。
术语免疫调节化合物还包括吡美莫司,依维莫司,西罗莫司,他克莫司,泼尼松龙,VX-148,merimepodib,布喹那,沙利度胺,BCX-1777,revimid,diprolene,aclometasone二丙酸酯,氢化可的松,地塞米松,来氟米特,磺庚甲泼尼龙,强的松,氯氟米特,MNA-715(FK778),SMP-114,特立氟胺,卤倍他索,环索奈得,去氟可特,甲羟孕酮,布地缩松,双甲丙酰龙,曲安缩松,氟替卡松,莫米他松糠酸酯,醋丙甲泼尼龙,环孢菌素A,他克莫司,霉酚酸酯,ANA-245,免疫抑制性大环内酯,氨甲蝶呤,PNP-405,MDL-74428,9-(3,3-二甲基-5-膦酰戊基)鸟嘌呤,DADMe-IMMG,CP-690,550,霉酚酸酯(mycophenate),环孢菌素和咪唑立宾。
在本发明的一个实施方案中,化合物呈分离和提纯的形式。一般,该术语“分离和提纯的”意指该化合物基本上从生物材料(例如血液,组织,细胞,等等)中游离出来。在本发明的一个特定的实施方案中,该术语意指本发明的化合物或共轭物按在混合物中的重量至少约50%纯;在另一个特定的实施方案,该术语意指本发明的化合物或共轭物按在混合物中的重量至少约75%纯度;在另一个特定的实施方案中,该术语意指本发明的化合物或共轭物按在混合物中的重量至少约90%纯度;在另一个特定的实施方案中,该术语意指本发明的化合物或共轭物按在混合物中的重量至少约98%纯度;和在另一个实施方案中,该术语意指本发明的化合物或共轭物按在混合物中的重量至少约99%纯度。在另一个特定的实施方案中,本发明提供已经以合成途径制得(例如离体制得)的本发明的化合物或共轭物。
细胞内靶向
本发明化合物的膦酸酯基团可以在化合物到达所需作用位置即在细胞内之后的阶段总在活体内裂解。在细胞内的一种作用机理可以包括首先裂解,例如借助于酯酶,得到带负电荷“被锁住”的中间体。在本发明化合物中末端酯基的裂解因此获得了不稳定的中间体,它释放出带负电荷“被锁住”的中间体。
在细胞内通过后,膦酸酯或前药化合物的细胞内酶促裂解或改性会导致由“捕获”机理所引起的裂解或改性化合物的细胞内蓄积。该裂解或改性化合物然后通过在电荷、极性或其它物理性质变化上的显著变化来“锁住”在细胞中,这降低了裂解或改性化合物离开细胞的速率,相对于它们作为膦酸酯前药进入细胞中的速率而言。实现治疗效果的其它机理可以同样地起作用。能够对于本发明的膦酸酯前药化合物发生酶促激活机理的酶类包括,但不限于,酰胺酶,酯酶,微生物酶,磷脂酶,胆碱酯酶,和磷酸酶。
从以上可以明显地看出,许多不同的药物能够根据本发明来衍生化。很多的此类药物具体地在这里提到。然而,应当理解,用于本发明的衍生化的药物家族和它们的特定的成员的讨论不是穷举,而仅仅是举例说明而已。
在本发明的一个实施方案中,化合物不是抗病毒剂化合物。在另一个实施方案该化合物不是核苷化合物。在另一个实施方案中该化合物不是IMPDH抑制化合物。在另一个实施方案中该化合物不是抗代谢物化合物。在另一个实施方案该化合物不是PNP抑制剂。在另一个实施方案中该化合物不是通式500-533,535-541或543-547中任何一个的取代化合物。在另一个实施方案中该化合物不是通式1-104,107-124或128-151中任何一个的取代化合物。
立体异构体
本发明的化合物可具有手性中心,例如,手性碳或磷原子。本发明的化合物因此包括全部立体异构体的外消旋混合物,其中包括对映异构体,非对映异构体,和阻转异构体。另外,本发明的化合物包括在任何或全部不对称、手性原子上的富集或拆分旋光异构体。换句话说,在该叙述中出现的手性中心可作为手性异构体或外消旋混合物来提供。外消旋型和非对映异构型混合物两者,以及分离或合成的、基本上不含它们的对映异构体或非对映异构伙伴的单个旋光异构体,全部是在本发明范围内。该外消旋混合物可通过众所周知的技术,如用旋光活性助剂(例如酸或碱)形成的非对映体盐的分离,随后转化回到旋光活性物质,来转化成它们的单个、基本上旋光纯的异构体。大多数情况上,所需的旋光异构体利用立体选择性反应,从所需起始原料的合适的立体异构体开始,来合成的。
化合物的本发明在某些情况下也可以作为互变异构的异构体存在。虽然描述了仅仅一个离域共振结构,但是所有这些形式认为在本发明范围内。例如,烯-胺互变异构体对于嘌呤,嘧啶,咪唑,胍,脒类,和四唑体系都存在,并且全部它们的可能的互变异构形式是在本发明的范围之内。
盐和水合物
本发明的组合物任选地包括包括在这里化合物的盐,尤其含有例如
、
、
、
和
的药物学上可接受的无毒盐。这些盐类可以包括由合适的阳离子如碱和碱土金属离子或铵和季化氨基离子与酸阴离子结构部分(典型地羧酸)的结合所衍生的那些盐。如果水溶性盐类是所需的,则一价盐是优选的。
金属盐典型地通过金属氢氧化物与本发明的化合物反应来制备。以这一方式制备的金属盐的例子是含有
、
和
的盐。较低可溶性的金属盐能够通过添加合适金属化合物从更可溶性盐的溶液中沉淀得到。
另外,盐可以从某些有机和无机酸例如
、
、
、 或有机磺酸的酸加成到碱性中心(典型地为胺)或到酸性基团上来形成。最后,应当理解的是,在这里的组合物包括呈其未电离形式以及两性离子形式的本发明化合物,和它与作为水合物时的化学计量量的水的结合。
也包括在本发明中的是母体化合物与一种或多种氨基酸的盐。如上所述的氨基酸中的任何一种都是合适的,尤其作为蛋白质组分发现的天然氨基酸,虽然该氨基酸典型地是携带具有碱性或酸性基团的侧链的一种氨基酸,例如,赖氨酸,精氨酸或谷氨酸,或携带具有中性基团的侧链的氨基酸,如甘氨酸,丝氨酸,苏氨酸,丙氨酸,异亮氨酸,或亮氨酸。
免疫调节的抑制方法
本发明的另一个方面涉及抑制免疫调节剂的活性的方法,它包括用本发明的组合物处理怀疑含有免疫调节剂的样品的步骤。
本发明的组合物可用作免疫调节的抑制剂,用作该抑制剂的中间体,或具有如下所述的其它用途。该抑制剂将结合在具有对免疫调节剂独特的几何结构的免疫调节剂的表面上或空腔中的位置上。结合该免疫调节剂的组合物能够以不同程度的可逆性来结合。基本上不可逆转地结合的这些化合物是用于本发明方法中的理想备选物。一旦标记,基本上不可逆转地结合型组合物可用作免疫调节的检测的探针。因此,本发明涉及检测在怀疑含有免疫调节剂的样品中的免疫调节的方法,它包括以下步骤:用包括结合于标记物上的本发明化合物的组合物处理怀疑含有免疫调节剂的样品;和观察样品对标记物的活性的效果。合适的标记物在诊断学领域中是众所周知的,并且包括稳定的游离基团,荧光团,放射性同位素,酶,化学发光性基团和生色团。在这里的化合物是以常规的方式通过使用官能团如羟基或氨基来标记。
在本发明的范围内,怀疑含有免疫调节剂的样品包括天然或人造的物质如活生物;组织或细胞培养物;生物样品如生物材料样品(血液,血清,尿,脑脊髓液,泪液,痰液,唾液,组织样品,等);实验室试样;食品,水,或空气样品;生物制品样品如细胞提取物,尤其合成所需糖蛋白的重组细胞;等等。典型地该样品将怀疑含有免疫调节剂。样品能够包含在任何介质中,该介质包括水和有机溶剂/水混合物。样品包括活生物如人,和人造的材料如细胞培养物。
本发明的处理步骤包括将本发明的组合物添加到样品中或它包括将组合物的前体添加到样品中。添加步骤包括如上所述的任何施用方法。
如果需要,在组合物的施用之后免疫调节剂的活性能够由包括直接和间接检测免疫调节剂活性的任何方法来观察。测定免疫调节活性的定量的,定性的和半定量的方法应该全部考虑。典型地,如上所述的筛选方法中的一种是可使用的,然而,任何其它方法如活生物的生理特性的观察也是适用的。
然而,在筛选能够抑制免疫调节的化合物时,应当记住,酶活性测定的结果与细胞培养试验不相无关。因此,以细胞为基础的试验应该是主要筛选手段。
免疫调节抑制剂的筛选
可通过评价酶活性的任何常规方法对本发明的组合物进行抗免疫调节剂的抑制活性筛选。在本发明的范围内,典型地,首先对组合物在活体外免疫调节剂的抑制进行筛选,然后对显示出抑制活性的组合物活体内的活性进行筛选。具有低于约5×10-6M,典型地低于约1×10-7M和优选低于约5×10-8M的活体外Ki(抑制常数)的组合物优选在活体内使用。
有用的活体内筛选已经详细描述,在这里不在作详细说明。然而,实施例描述了合适的活体外分析。
药物制剂
本发明的化合物用常规载体和赋形剂配制,它们将按照常规实践进行选择。片剂将包含赋形剂、助流剂、填充剂、粘合剂,等等。含水制剂以无菌的形式制备,并且当预期以口服给药形式以外递送时,它通常将是等渗的。所有制剂将任选包含赋形剂,例如Handbook of Pharmaceutical Excipents (1986)中列举的。赋形剂包括抗坏血酸和其他抗氧化剂、螯合剂例如EDTA、碳水化合物例如糊精、羟基烷基纤维素、羟基烷基甲基纤维素、硬脂酸,等等。制剂的pH值范围从大约3到大约11,通常是大约7到10。
尽管活性成分有可能单独被给药,但可能优选以药物制剂的形式呈现它们。本发明兽用和人用的制剂包括至少一种如上定义的活性成分,以及一种或多种其可接受的载体和任选包含其他治疗成分。载体必须是“可接受的”,意思是与制剂的其他成分相容并且对它的接受者生理无害。
制剂包括适宜于上述给药途径的那些。制剂可常规地以合适的单位剂型呈现并可按药剂学领域的公知方法制备。技术和制剂一般见于Remington′s Pharmaceutical Sciences(Mack Publishing Co.,Easton,PA)。这些方法包括将活性成分与构成一个或多个助剂的载体结合的步骤。一般而言,制剂通过均一地和密切地使活性成分和液态载体或细碎的固态载体或这两者结合,然后,如果必要的话,将产物整形。
适合用于口服给药的本发明制剂可以分离的单位呈现,所述分离的单位如胶囊剂、扁胶囊或片剂,每一种包括预定量的活性成分;粉剂或颗粒剂;含水或无水液体中的溶液或混悬液;或水包油液体乳剂或油包水液体乳剂。活性成分也可以静脉推剂(bolus)、药糖剂(electuary)或糊剂形式给药。
可采用压制法或模塑法和任选与一种或多种助剂一起制备片剂。压制片剂可通过在适合的机器中将呈自由流动形式的活性成分,例如粉、或颗粒压缩,任选与粘合剂、润滑剂、惰性稀释剂、防腐剂、表面活性或分散剂混合进行制备。模制片剂可通过在适当的机器中将用无活性液体稀释剂湿润的粉末状活性成分的混合物塑型进行制备。为了从其中提供活性成分的慢释或控释,片剂可任选被包衣或刻痕,并任选被配制。
关于对眼睛或其它外部组织,例如口或皮肤给药,制剂优选以局部软膏剂或霜剂被应用,其包含的活性成分的量为,例如,0.075到20%w/w(包括从0.1%到20%范围内的活性成分,以0.1%w/w递增,例如0.6%w/w,0.7%w/w,等),优选为0.2到15%w/w并且最优选为0.5到10%w/w。当以软膏剂被配制时,活性成分可与石蜡族的或水可混合的软膏剂基质一起使用。可选择地,活性成分可与水包油霜剂基质一起被配制呈霜剂。
如需要,霜剂基质的水相可包括,例如,至少30%w/w多元醇,即有两个或更多个羟基的醇,例如丙二醇、丁1,3-二醇、甘露醇、山梨糖醇、丙三醇和聚乙二醇(包括PEG 400)及它的混合物。局部制剂理想地可包括增强活性成分通过皮肤或其他受影响部位的吸收或渗透的化合物。这样的皮肤渗透促进剂包括二甲基硫氧化物(sulphoxide)和相关类似物。
本发明乳剂的油相可用已知方法由公知成份构成。尽管该相可仅包含乳化剂(另外称为利泄药),但它理想的是包含至少一种乳化剂与脂肪或油的混合物或与脂肪和油二者的混合物。优选地,亲水乳化剂与用作稳定剂的亲脂乳化剂一起被包括。也优选既包括油又包括脂肪。总共,有或无稳定剂的乳化剂制成所谓的乳化蜡,乳化蜡同油和脂肪一起制成所谓的乳化软膏剂基质,其形成霜剂的油性分散相。
适用于本发明制剂的利泄药和乳剂稳定剂包括Tween_60、Span_80、十六醇十八醇混合物、苯甲醇、十四醇、单硬脂酸甘油酯和月桂基硫酸钠。
用于制剂的合适油或脂肪的选择基于获得想要的化妆品性质。霜剂应优选是非油腻的,非沾污的和可清洗的产品,具备适当的粘度以避免从管或其他容器泄漏。直链或支链,一-或二元烷基酯,例如二-异己二酸酯、异十六烷基硬脂酸酯、椰子脂肪酸的丙二醇二酯、肉豆蔻酸异丙酯、油酸癸酯、棕榈酸异丙酯、硬脂酸丁酯、2-乙基己基棕榈酸酯或被称为Crodamol CAP的支链酯的混合物可被使用,最后的三个是优选的酯。这些可以被单独应用或联合应用,取决于需要的性质。可选择地,使用高熔点类脂例如白凡士林和/或液体石蜡或其他的矿物油。
根据本发明的药物制剂包含一种或多种本发明的化合物,连同一种或多种药学上可接受的载体或赋形剂和任选其他治疗剂。含有活性成分的药物制剂可以呈适合预期给药方法的任何形式。举例说明,若用于口服应用时,可制备成片剂、糖锭、锭剂、水或油混悬液、可分散的粉剂或颗粒、乳剂、硬或软胶囊剂、糖浆剂或酏剂。预期口服应用的组合物可根据用于制造药物组合物的本领域已知的任何方法制备,并且为得到口感好的制剂,这类组合物可含有一种或多种物质,该物质例如甜味剂、调味剂、着色剂和防腐剂。含有与无毒的药学上可接受的适合片剂的制备的赋形剂混合的活性成分的片剂是可接受的。这些赋形剂可以是,例如,无活性稀释剂,例如碳酸钙或碳酸钠、乳糖、乳糖一水合物、交联羧甲基纤维素钠、聚维酮、磷酸钙或磷酸钠;粒化剂和崩解剂,例如玉米淀粉或海藻酸;粘合剂,例如纤维素、微晶纤维素、淀粉、明胶或阿拉伯胶;和润滑剂,例如硬脂酸镁、硬脂酸或滑石粉。片剂可以是无包衣的或可通过公知技术,包括微胶囊化进行包衣,以延缓在胃肠道中的崩解和吸咐,由此提供更长时间的持续释放。例如,时间延缓材料例如单硬脂酸甘油酯或二硬脂酸甘油酯可以单独被使用或同蜡一起被使用。
口服应用的制剂也可以硬明胶胶囊剂的形式呈现,其中活性成分同无活性固体稀释剂,例如磷酸钙或高岭土混合,或以软明胶胶囊剂的形式呈现,其中活性成分同水或油性介质,例如花生油、液体石蜡或橄榄油混合。
本发明的水性混悬液含有与适宜于水性混悬液制备的赋形剂混合的活性物质。这类赋形剂包括助悬剂,例如羧甲基纤维素钠、甲基纤维素、羟丙甲基纤维素、海藻酸钠、聚乙烯吡咯烷酮、西黄蓍胶和阿拉伯胶,和分散剂或湿润剂例如天然存在的磷脂(例如卵磷脂)、烯化氧同脂肪酸的缩合产物(例如,聚氧乙烯硬脂酸酯)、环氧乙烷同长链脂肪醇的缩合产物(例如,十七亚乙基氧基十六醇、环氧乙烷同从脂肪酸和己糖醇酐衍生的偏酯的缩合产物(例如,聚氧乙烯失水山梨糖醇一油酸酯)。水性混悬液还可包含一种或多种防腐剂,例如乙基或正丙基对-羟基苯甲酸酯,一种或多种着色剂,一种或多种调味剂以及一种或多种甜味剂,例如蔗糖或糖精。
油混悬液可通过将活性成分悬于植物油中进行配制,所述植物油例如花生油、橄榄油、芝麻油或椰子油、或悬于矿物油例如液体石蜡中。口服混悬液可含有增稠剂,例如蜂蜡、固体石蜡或鲸蜡醇。可添加甜味剂,如上面所述的那些,和调味剂以得到口感好的制剂。这些组合物可通过添加抗氧化剂,例如抗坏血酸来保存。
适宜于通过加水制备水性混悬液的本发明可分散粉剂和颗粒剂提供了与分散剂或湿润剂、助悬剂和一种或多种防腐剂混合的活性成分。适宜的分散剂或湿润剂和助悬剂通过上述的那些进行了举例说明。另外的赋形剂,例如甜味剂,调味剂和着色剂,也可以存在。
本发明的药物组合物也可以呈水包油型乳剂的形式。油相可以是植物油,例如橄榄油或花生油、矿物油,例如液体石蜡、或这些的混合物。适宜的乳化剂包括天然存在的胶,例如阿拉伯胶和西黄蓍胶,天然存在的磷脂,例如大豆卵磷脂、从脂肪酸和己糖醇酐衍生的酯或偏酯,例如失水山梨糖醇一油酸酯,和这些偏酯同环氧乙烷的缩合产物,例如聚氧乙烯失水山梨糖醇一油酸酯。乳剂还可包括甜味剂和调味剂。糖浆剂和酏剂可以用甜味剂,例如丙三醇、山梨糖醇或蔗糖配制。这类制剂也可包含缓和剂、防腐剂、调味剂或着色剂。
本发明的药物组合物可以呈无菌可注射制剂的形式,例如无菌可注射的水性或油性混悬液。该混悬液可根据使用如上所述的适合的分散剂或湿润剂和助悬剂的那些公知技术制备。无菌可注射的制剂也可以是无菌可注射的无毒肠胃外可接受的稀释剂或溶剂中的溶液或混悬液,所述稀释剂或溶剂例如1,3-丁-二醇溶液,或被制备成冻干粉剂。可被使用的载体和溶剂是水,林格溶液和等渗氯化钠溶液。此外,无菌的固定油类可常规地被用作溶剂或混悬介质。为此目的,可使用任何品牌的固定油,包括合成单-或二甘油酯。此外,脂肪酸,例如油酸在同样被用于制备可注射剂。
可与载体物质结合生产单一剂型的的活性成分的量,将因治疗的宿主和给药的特别模式而不同。例如,预期对人口服给药的时间-释放制剂可以包括大约1至1000mg的活性物质,该活性物质结合适宜的和方便量的载体物质,该载体物质占总组合物的大约5至大约95%(重量:重量)。可以制备药物组合物以轻易提供可测量的给药量。例如,预期静脉内输注的含水溶液可包含每毫升溶液大约3-500μg的活性成分,以可发生以大约30mL/hr的速率输注合适溶剂。
适合对眼给药的制剂包括滴眼剂,其中活性成分被溶解或混悬于适当的载体,特别是用于活性成分的水溶剂。活性成分优选以浓度0.5到20%,更有利地是0.5到10%特别是大约1.5%w/w存在于这样的制剂中。
适合于口中局部给药的制剂包括包含在香味基底,通常是蔗糖和阿拉伯胶或西黄蓍胶中的活性成分的锭剂;包含在无活性基底,例如明胶和甘油,或蔗糖和阿拉伯胶中的活性成分的软锭剂;包含在适合液态载体中的活性成分的漱口剂。
用于直肠给药的制剂可以栓剂的形式呈现,该栓剂具有合适的包含例如,可可豆脂或水杨酸酯的基质。
适合于肺内或鼻给药的制剂的颗粒大小范围例如从0.1到500微米(包括颗粒大小范围在0.1和500微米之间,增量微米例如为0.5、1,30微米、35微米,等等),它通过鼻通道快速吸入或通过口吸入而被给予以到达肺泡囊。适宜的制剂包括活性成分的水或油性溶液。适合于气雾剂或干粉剂给药的制剂可按照常规方法制备,并可同其他治疗药物一起递送,例如此前描述的化合物,如上所述该化合物用于治疗或预防病毒感染。
适合于阴道给药的制剂可以阴道栓剂、棉护垫、霜剂、凝胶剂、糊剂、泡沫剂或喷雾制剂的形式呈现,所述制剂除含活性成分之外还包含本领域公知的这类载体。
适合于胃肠外给药的制剂包括含水或无水无菌注射液,它可包含抗氧化剂,缓冲剂,抑菌剂和使制剂与计划的接受者的血液等渗的溶质;和含水或无水无菌混悬液,它包含助悬剂和增稠剂。
制剂可以在存在于单位剂量或多剂量容器,例如,密封的安瓿和小瓶,也可保存在冷冻干燥(冻干)条件下,即刻在使用前,只需要添加无菌液态载体,例如注射用水。临时的注射液和混悬液由无菌粉剂,颗粒和前述的那类片剂制备。优选的单位剂量制剂是包括日剂量或单位日次剂量,如上述,或它的适宜部分的活性成分的那些。
应该理解的是,除了上面特别提到的成分以外,本发明的制剂可包括与讨论的制剂类型有关领域中常规的其它物质,例如适合于口服给药的那些可包括调味剂。
本发明进一步提供了兽医用组合物,它包含至少一种上述活性成分及用于它的兽医用载体。
兽医用载体是适用于施用组合物的目的的物质并且可以是固体、液体或气态物质,它们在兽医领域中是其它无活性的或可接受的,并且同活性成分相容。这些兽医用组合物可被口服,肠胃外或通过任何其他希望的途径给药。
本发明化合物还可以被配制以提供活性成分的控制释放,允许更低频率给药或改善活性成分的药物动力学或毒性特征。因此,本发明还提供包含一种或多种本发明化合物的组合物,为达到持续或控制释放而被配制。
活性成分的有效量至少取决于被治疗状况的性质,毒性,不管组合物是预防使用(低剂量)或是对抗活性病毒感染,递送的方法,和药物制剂,并且将由临床医生使用常规剂量增加实验来决定。期望每天大约0.0001到大约100mg/kg体重。典型的是每天大约0.01到大约10mg/kg体重。更典型的是每天大约.01到大约5mg/kg体重。更典型的是每天大约.05到大约0.5mg/kg体重。例如,对于大约70kg体重的成人来说,每天候选剂量范围将为1mg到1000mg,优选5mg到500mg,并且可采用单或多剂量形式。
给药途径
本发明一种或多种化合物(这里被称为活性成分)采用任意对治疗情况适合的途径给药。合适的途径包括口、直肠、鼻、局部(包括颊和舌下)、阴道的和胃肠外(包括皮下、肌内、静脉内、真皮内、鞘内和硬膜外),等等。将要理解,优选的途径可根据例如接受者的情况而变化。本发明化合物的优点在于它们可口服生物利用并能口服给药。
联合治疗
本发明的活性成分也可与其它活性成分联合使用。这些联合是以需要治疗的状况,各种成分的交叉反应性和该联合物的药学性能为基础来进行选择。
也有可能的是将本发明的任何化合物与一种或多种其它活性成分相结合用于单一剂型中,以便同时或顺序地施用于患者。该联合治疗可以作为同时或顺序给药方案来施用。当顺序地施用时,该联合物可以在两次或多次施用中给药。
联合治疗可以提供“协同作用”和“协同效应”,即当活性成分一起使用时所实现的效果大于单独使用化合物时所获得的结果的总和。可以获得协同效应,当这些活性成分:(1)在联合制剂中同时共同配方设计和施用或输送时;(2)作为单独的配制剂交替或并行输送时;或(3)通过其它的方案时。对于在交替治疗中输送的情况,当化合物顺序地施用或输送,例如以单独的片剂、丸剂或胶囊剂,或通过在单独的注射器中由不同的注射来施用或输送时,可以获得协同效应。一般说来,在交替治疗期间,有效剂量的各活性成分顺序地(即连续地)施用,而在联合治疗中,有效剂量的两种或多种活性成分一起施用。本发明的化合物的代谢物
也属于本发明范围内的是在这里所述的化合物的活体内代谢产物。此类产物可以从例如所施用的化合物的氧化,还原,水解,酰胺化,酯化等产生,主要地由于酶促过程。因此,本发明包括一些由本发明的化合物与哺乳动物接触一段足以得到它的代谢产物的时间的方法所生产的化合物。此类产物典型地通过如下方法来鉴别:制备本发明的放射标记(例如,
或
)的化合物,通过胃肠外途径以可检测的剂量(例如,大于约0.5mg/kg)施用于动物如大鼠,小鼠,豚鼠,猴子或人类,允许足够的时间让新陈代谢进行(典型地约30秒至30小时),然后从尿,血液或其它生物样品中分离出它的转化产物。这些产物容易地分离出来,因为它们已被标记(其它则通过使用能够结合在代谢物中残存的表位的抗体来分离)。该代谢物结构是以常规方式,例如,由MS或NMR分析来测定的。一般说来,代谢物的分析是按照与本领域中普通技术人员公知的常规药物代谢研究相同的方式来进行的。转化产物,只要它们另外在活体内没有发现,适用于本发明化合物的治疗剂量设计中的诊断学分析,即使它们不具有它们本身的免疫调节抑制活性。
测定在代用物(surrogate)胃肠分泌中化合物的稳定性的配方和方法是已知的。当通过在37℃下培养1小时之后有小于约50mol%的受保护基团在代用物肠或胃液中去保护时,该化合物在这里被定义为在胃肠道中是稳定的。简单地,因为化合物对胃肠道是稳定的并非意谓着它们不能在活体内水解。本发明的膦酸酯前药典型地在消化系统中是稳定的,但是,在消化腔,肝脏或其它代谢器官中,或一般说来在细胞内,基本上水解成母体药物。
制备本发明的化合物的示例性方法。
本发明还涉及制造本发明组合物的方法。组合物是通过任何适用的有机合成技术来制备的。许多此类技术在本领域中是大家所熟知的。然而,许多已知的技术已经详细地在文献中说明:Compendium of Organic Synthetic Methods(John Wiley & Sons,New York),Vol.1,Ian T.Harrison and Shuyen Harrison,1971;Vol.2,Ian T.Harrisonand Shuyen Harrison,1974;Vol.3,Louis S.Hegedus and Leroy Wade,1977;Vol.4,Leroy G.Wade,jr.,1980;Vol.5,Leroy G.Wade,Jr.,1984;and Vol.6,Michael B.Smith;as well as March,J.,Advanced Organic Chemistry.Third Edition,(John Wiley & Sons,New York,1985),Comprehensive Organic Synthesis.Selectivity,Strategy & Efficiency in Modern Organic Chemistry..In 9Volumes,Barry M.Trost,Editor-in-Chief(Pergamon Press,New York,1993printing)。
制备本发明组合物的许多示例性方法在下面提供。这些方法其目的是为了举例说明这些制备的性质,不打算限制可应用方法的范围。
一般,反应条件如温度,反应时间,溶剂,后处理程序等,将是现有技术领域中对于需要进行的具体反应所常用的那些。所列举的参考材料,连同在其中引用的参考材料,含有此类条件的详细说明。典型地该温度是-100℃到200℃,溶剂是质子惰性的或质子的,和反应时间是10秒至10天。后处理典型地由淬灭任何未反应的试剂,然后在水/有机层体系之间分配(萃取)和分离含有产物的层组成。
氧化和还原反应典型地在接近室温的温度(约20℃)下进行,虽然对于金属氢化物还原来说,常常该温度减低至0℃到-100℃,溶剂对于还原来说典型地是质子惰性的和对于氧化来说可以是质子的或质子惰性的。反应时间进行调节以实现所需转化率。
缩合反应典型地在接近室温的温度下进行,虽然对于非平衡的、动力学控制的缩合反应而言,降低的温度(0℃到-100℃)也是常用的。溶剂能够是质子的(在平衡的反应中是常用的)或质子惰性的(在动力学控制的反应是常用的)。
标准合成技术如反应副产物的共沸除去和无水反应条件(例如,惰性气体环境)的使用是现有技术中常见的并且当可适用时可以使用。反应历程和实施例
这些示例性方法的一般方面描述在下面和在实施例中。下列过程的产物的每一种任选地在它用于后续过程中之前进行分离,离析,和/或提纯。
一般,反应条件如温度,反应时间,溶剂,后处理程序等,将是现有技术领域中对于需要进行的具体反应所常用的那些。所列举的参考材料,连同在其中引用的参考材料,含有此类条件的详细说明。典型地该温度是-100℃到200℃,溶剂是质子惰性的或质子的,和反应时间是10秒至10天。后处理典型地由淬灭任何未反应的试剂,然后分配在水/有机层体系之间(萃取)和分离含有产物的层组成。
氧化和还原反应典型地在接近室温的温度(约20℃)下进行,虽然对于金属氢化物还原来说,常常该温度减低至0℃到-100℃,溶剂对于还原来说典型地是质子惰性的和对于氧化来说可以是质子的或质子惰性的。反应时间进行调节以实现所需转化率。
缩合反应典型地在接近室温的温度下进行,虽然对于非平衡的、动力学控制的缩合反应而言,降低的温度(0℃到-100℃)也是常用的。溶剂能够是质子的(在平衡的反应中是常用的)或质子惰性的(在动力学控制的反应是常用的)。
标准合成技术如反应副产物的共沸除去和无水反应条件(例如,惰性气体环境)的使用是现有技术中常见的并且当可适用时可以使用。
该术语“处理的(过去式)”,“处理(现在分词)”,“处理(名词)”,等等,当与化学品合成操作关联使用时,是指接触,混合,反应,允许起反应,实施接触,和现有技术中常见的其它术语,该术语表示一种或多种化学实体以这样的方式进行处理从而将它转化成一种或多种其它化学实体。这指“用化合物2处理化合物1”在意义上与“让化合物1与化合物2反应”,“让化合物1与化合物2接触”,“化合物1与化合物2反应”,和在现有技术中常用于合理地指明化合物1用化合物2“处理”、“反应”、“允许反应”等的其它表达是相互的。例如,“处理”表明让机化学品进行反应的合理的和常见的方式。当量浓度(0.01M到10M,典型地0.1M到1M),温度(-100℃到250℃,典型地-78℃到150℃,更典型地-78℃到100℃,再更典型地0℃到100℃),反应容器(典型地玻璃,塑料,金属),溶剂,压迫,气氛(典型地,对氧和水不敏感的反应而言是空气,或对氧或水敏感的反应而言是氮气或氩气),等等,是预定的,除非另有说明。在有机合成领域中已知的类似反应的常识用于选择在给定的过程中“处理”用的条件和装置。尤其,有机合成领域中的技术人员可以根据现有技术中的常识来合理地选择预期可成功地进行所述过程的化学反应的条件和装置。
在示例性的反应历程的每一个中和在实施例(下面“示例性反应历程”)中的改进可导致生产出特定的示例性物质的各种类似物。描述有机合成的合适方法的以上列举的引用文献适用于此类改性。
在示例性反应历程的每一个中,理想的是将反应产物彼此分离和/或与起始原料实现分离。各步骤或系列步骤的所需产物利用现有技术领域中常用的技术被分离和/或提纯(以下分离)到所需均匀度。典型地该分离包括多相萃取,从溶剂或溶剂混合物中结晶,蒸馏,升华,或色谱法。色谱法能够包括许多方法,其中包括例如:反相和正常相;尺寸排阻;离子交换;高压,中等压,和低压液相色谱分离方法和装置;小规模分析方法;模拟的移动床(SMB)和制备性的薄层或厚度层色谱法,以及小规模薄层色谱分离和急骤色谱分离的技术。
另一类的分离方法包括用所选择的试剂处理混合物,从而结合于所需产物,未反应的起始原料,反应副产物等上或另外使得它们变成可分离的。此类试剂包括吸附剂或吸收剂如活性炭,分子筛,离子交换介质,等等。另外地,该试剂对于碱性物质而言能够是酸,对于酸性物质而言是碱,结合试剂如抗体,结合蛋白质,选择性螯合剂如冠醚,液体/液体离子萃取试剂(LIX),等等。
合适的分离方法的选择取决于所涉及的物质的性质。例如,在蒸馏和升华中的沸点和分子量,极性官能团在色谱法中的存在或不存在,在多相萃取中物质在酸性和碱性介质中的稳定性,等等。本领域中的技术人员很可能采用一些技术来实现所需的分离。
单个的立体异构体,例如,基本上不含它的立体异构体的对映异构体,可以通过使用例如用旋光活性拆分试剂形成非对映异构体的方法,由外消旋混合物的拆分来获得(Stereochemistry of CarbonCompounds,(1962),E.L.Eliel,McGraw Hill;Lochmuller,C.H.,(1975),J.Chromatogr.,113:(3)283-302)。本发明的手性化合物的外消旋混合物能够通过任何合适方法来分离和离析,其中包括:(1)用手性化合物形成离子型的、非对映异构的盐,和由分级结晶或其它方法实施分离,(2)用手性衍生化试剂形成非对映异构化合物,分离非对映异构体,和转化成纯立体异构体,和(3)直接在手性条件下分离足够纯或富集的立体异构体。
按照方法(1),非对映异构的盐能够通过对映异构纯的手性碱如番木鳖碱,奎宁,麻黄素,士的宁,α-甲基-β-苯基乙胺(安非他明)等与含有酸性官能团如羧酸和磺酸的不对称化合物反应来形成。非对映异构的盐可以由分级结晶或离子色谱法诱导分离。对于氨基化合物的旋光异构体的分离,手性羧酸或磺酸,如樟脑磺酸,酒石酸,扁桃酸,或乳酸的添加能够导致非对映异构盐的形成。
另外地,由方法(2),需要拆分的底物与手性化合物的一种对映异构体反应,形成非对映异构体对(Eliel,E.and Wilen,S.(1994)Stereochemistry of Organic Compounds,John Wiley & Sons,Inc.,p.322)。非对映异构体化合物能够通过不对称化合物与对映异构纯度手性衍生化试剂如_基衍生物反应,随后分离非对映异构体和水解得到游离的、对映异构体富集的呫吨来形成。测定光学纯度的方法包括制备手性酯,如在碱存在下的_基酯,例如,(-)_基氯甲酸酯,或该外消旋混合物的莫舍酯(Mosher ester),α-甲氧基-β-(三氟甲基)苯基乙酸酯(Jacob III.(1982)J.Org.Chem.47:4165),并且分析有关两种阻旋异构(atropisomeric)非对映异构体的存在的NMR谱。阻旋异构化合物的稳定的非对映异构体能够按照阻旋异构萘基-异喹啉的分离方法(Hoye,T.,WO 96/15111)由通常的反相色谱法分离和离析。利用方法(3),两种对映异构体的外消旋混合物能够通过使用手性固定相由色谱法分离(Chiral Liquid Chromatography(1989)W.J.Lough,Ed.Chapman and Hall,New York;Okamoto,(1990)J.of Chromatogr.513:375-378)。富集或提纯的对映异构体能够通过用于区别具有不对称碳原子的其它手性分子的方法来鉴别,如旋光度和圆二色性。
实施例总述部分
在这里,例如在下面的实施例中提供了本发明的化合物的许多示例性制备方法。这些方法其目的是为了举例说明这些制备的性质,不打算限制可应用方法的范围。本发明的某些化合物能够用作制备本发明的其它化合物用的中间体。例如,在下面举例说明了本发明的各种膦酸酯化合物的相互转化。膦酸酯
,
和
的互变。
以下的反应历程32-38描述一般结构
的膦酸酯的制备,其中R1基团可以相同或不同。附加到膦酸酯,或其前体的R1基团,可以使用确定的化学转化进行改变。膦酸酯的互变反应见反应历程S32说明。反应历程32中R基团代表亚结构,换言之,与取代基
连接的药物“支架”,或在本发明化合物,或在其前体中。在进行膦酸酯互变合成路线中的点,在R上的某些官能团可被保护。对于给定的膦酸酯转化所用方法取决于取代基R1以及膦酸酯所连接的底物的性质。制备和水解膦酸酯描述于有机磷化合物,G.M.Kosolapoff,L.Maeir,eds,Wiley,1976,p.9ff。
一般而言,通过使亲核体胺或醇与相应活化的膦酸酯亲电子的前体偶联来实现膦酸酯的合成。例如,在核苷5′-羟基上添加氯膦酸酯是制备核苷磷酸单酯的已知方法。活化前体可由几个已知方法制备。用于合成前药的氯膦酸酯由取代-1,3-丙二醇制备(Wissner,et al,(1992)J.Med Chem.35:1650)。氯膦酸酯通过相应的氯磷磷杂环戊烷的氧化作用制备(Anderson,et al,(1984)J.Org.Chem.49:1304),氯磷磷杂环戊烷是由取代的二醇同三氯化磷反应获得。另外,氯膦酸酯物质通过用磷酰氯处理的取代的-1,3-二醇制备(Patois,et al,(1990)J.Chem.Soc.Perkin Trans.I,1577)。氯膦酸酯类也可以由相应的环亚磷酸酯原位产生(Silverburg,et al.,(1996)Tetrahedron lett.,37:771-774),其依次可由氯磷磷杂环戊烷或氨基磷酸酯中间物制备。由焦磷酸或正磷酸制备的偶磷氟酸酯(flouridate)中间物,还可用作制备环状前药中的前体(Watanabe et al.,(1988)Tetrahedron lett.,29:5763-66)。
本发明膦酸酯前药也可通过Mitsunobu反应由游离酸制备(Mitsunobu,(1981)Synthesis,1;Campbell,(1992)J.Org.Chem.57:6331),和其他酸性偶合试剂包括,但不仅限于,碳化二亚胺(Alexander,et al,(1994)Collect.Czech.Chem.Commun.59:1853;Casara et al,(1992)Bioorg.Med.Chem.Lett.2:145;Ohashi et al,(1988)Tetrahedron Lett,29:1189),和苯并三唑基氧基三-(二甲氨基)磷鎓盐(Campagne et al(1993)Tetrahedron Lett.34:6743)。
芳基卤化物经过与亚磷酸酯衍生物的
催化反应得到含芳基膦酸酯的化合物(Balthazar,et al(1980)J.Org.Chem.45:5425)。膦酸酯还可由氯膦酸酯在有钯催化剂情况下使用芳香三氟甲磺酸酯制备(Petrakis et al(1987)J.Am.Chem.Soc.109:2831;Lu et al(1987)Synthesis726)。另一种方法,芳基膦酸酯在阴离子重排条件下由芳基磷酸酯制备(Melvin(1981)Tetrahedron Lett.22:3375;Casteel et al(1991)Synthesis,691)。N-烷氧基芳香基盐和环烷基膦酸酯的碱金属衍生物得到杂芳基-2-膦酸酯连接体的一般合成(Redmore(1970)J.Org.Chem.35:4114)。上述这些方法也可扩展到W5基团是杂环的化合物。由膦二酸和取代的丙-1,3-二醇利用偶合试剂例如1,3-二环己基碳二亚胺(DCC)在碱基(例如,吡啶)存在下也可合成膦酸酯的环-1,3-丙基前药。其他基于碳化二亚胺的偶合试剂如1,3-二异丙基(disopropyl)碳化二亚胺或水溶性试剂,1-(3-二甲氨基丙基)-3-乙基碳化二亚胺氢氯化物(EDCI),也可用于合成环膦酸酯前药。
膦酸二酯S32.1转化为相应的膦酸单酯S32.2(反应历程32,反应1)由很多方法完成。例如,R1是芳烷基例如苯甲基的酯S32.1通过与叔有机碱例如二氮杂二环辛烷(DABCO)或喹宁环反应转化为单酯化合物S32.2,见于J.Org.Chem.(1995)60:2946。反应在无活性的烃类溶剂例如甲苯或二甲苯中,大约110℃进行。R1是芳基例如苯基,或链烯基例如烯丙基的二酯S32.1转化为单酯S32.2,是通过用碱例如乙腈中的含水氢氧化钠或含水四氢呋喃中的氢氧化锂处理酯S32.1而实现的。膦酸二酯S32.1,其中R1基团中的一个是芳烷基例如苯甲基,另一个是烷基,经例如使用碳钯催化剂的氢化作用转化为单酯S32.2,其中R1是烷基。其中两个R1基团都是(链)烯基,例如烯丙基的膦酸二酯,通过用氯三(三苯基膦)铑(Wilkinson′s催化剂)在回流下乙醇水溶液中,任选在二氮杂二环辛烷存在下,例如通过使用在J.Org.Chem.(1973)38:3224描述的关于分裂烯丙基羧化物的操作的处理,转化为R1是链烯基的单酯S32.2。
膦酸二酯S32.1或膦酸单酯S32.2转化为相应的膦酸S32.3(反应历程32,反应2和3)可通过二酯或单酯同三甲基甲硅烷基溴化物反应而实现,如J.Chem.Soc.,Chem.Comm.,(1979)739中所描述。反应在惰性溶剂例如二氯甲烷,任选在甲硅烷基化试剂例如双(三甲基甲硅烷基)三氟乙酰胺存在下室温下进行。R1是芳烷基例如苯甲基的膦酸单酯S32.2,经钯催化剂氢化作用或通过在醚溶剂例如二噁烷中用氯化氢处理,转化成相应的膦酸S32.3。R1是链烯基例如烯丙基的膦酸单酯S32.2通过与Wilkinson′s催化剂在含水有机溶剂例如在15%乙腈水溶液,或在含水乙醇中反应,例如使用Helv.Chim.Acta.(1985)68:618中描述的操作,转化为膦酸S32.3。R1是苯甲基的膦酸酯S32.1的钯催化氢解见J.Org.Chem.(1959)24:434中描述。R1是苯基的膦酸酯S32.1的铂-催化氢解见J.Am.Chem.Soc.(1956)78:2336中描述。
膦酸单酯S32.2转化为新引入的R1基团是烷基、芳烷基、卤烷基例如氯乙基或芳烷基的膦酸二酯S32.1(反应历程32,反应4),是通过大量反应实现的,其中底物S32.2同羟基化合物
,在有偶合剂情况下反应。典型的是,第二膦酸酯基团不同于第一引入的膦酸酯基团,换言之,R1接着引入R2,R1和R2每一个是烷基、芳烷基、卤烷基例如氯乙基,或芳烷基(反应历程32,反应4a),由此S32.2转化为S32.1a。适宜偶合剂是用于制备羧酸酯的那些,并包括碳化二亚胺例如二环己基碳化二亚胺,在这种情况下反应优选在碱性有机溶剂例如吡啶中进行,或(苯并三唑-1-基氧基)三吡咯烷磷鎓六氟磷酸盐(PYBOP,Sigma),这种情况下反应在极性溶剂例如二甲基甲酰胺,在叔有机碱例如二异丙基乙胺存在下进行,或Aldrithiol-2(Aldrich),在这种情况下反应在碱性溶剂例如吡啶,在三芳基膦例如三苯基膦存在下进行。做为选择,通过使用Mitsunobu反应实现膦酸单酯S32.2转化为二酯S32.1,见上述(反应历程7)。在二乙基二偶氮羧化物和三芳基膦例如三苯基膦存在下,底物同羟基化合物
反应。做为选择,通过单酯同R1是链烯基或芳烷基的卤化物
反应,膦酸单酯S32.2转化为引入的R1基团是链烯基或芳烷基的膦酸二酯S32.1。烷基化反应在极性有机溶剂例如二甲基甲酰胺或乙腈,在碱例如碳酸铯存在下进行。做为选择,膦酸单酯分两步操作转化为膦酸二酯。第一步,膦酸单酯S32.2同亚硫酰(二)氯或乙二酰氯等等反应转化为氯类似物
,如Organic Phosphorus compounds,G.M.Kosolapoff,L.Maeir,eds,Wiley,1976,p.17中所述,然后由此获得产物
同羟基化合物
,在碱例如三乙胺存在条件下反应,得到膦酸二酯S32.1。
膦酸
用上述关于制备膦酸二酯
S32.1的方法,转化为膦酸单酯 (反应历程32,反应5),除了仅用1摩尔比例的组分
或 以外。二烷基膦酸酯可根据Quast et al(1974)Synthesis 490;Stowell etal (1990)Tetrahedron Lett.3261;US 5663159的方法制备。
膦酸
S32.3在偶合剂例如Aldrithiol-2(Aldrich)和三苯基膦存在下,通过同羟基化合物
的偶合反应,转化为膦酸二酯
S32.1(反应历程32,反应6)。反应在碱性溶剂例如吡啶中进行。做为选择,膦酸S32.3在约70℃使用偶合反应,使用例如,在吡啶中的二环己基碳化二亚胺,转化为R1是芳基的膦酸酯S32.1。做为选择,膦酸S32.3通过烷基化反应转化为R1是链烯基的膦酸酯S32.1,膦酸在极性有机溶剂例如乙腈溶液中,在回流温度下,在碱例如碳酸铯存在下,同链烯基溴化物
反应,得到膦酸酯S32.1。
反应历程32
反应历程32
制备膦酸酯氨基甲酸酯
膦酸酯可包括氨基甲酸酯键。氨基甲酸酯的制备见于Comprehensive Organic Functional Group Transformations,A.R.Katritzky,ed.,Pergamon,1995,卷6,p.416ff,和Organic Functional Group Preparations,由S.R.Sandler和W.Karo,Academic出版,1986,p.260ff中的描述。根据本领域已知方法,包括Ellis,US2002/0103378A1和Hajima,US6018049中的教导,通过羟基反应可形成氨基甲酰基。
反应历程33举例说明合成氨基甲酸酯键的不同方法。如反应历程33所示,在产生氨基甲酸酯的一般反应中,醇S33.1,转化成活化的衍生物S33.2,其中Lv是离去基团,例如卤素、咪唑基、苯并三唑基和类似物,正如此处描述的。活化的衍生物S33.2然后同胺S33.3反应,得到氨基甲酸酯产物S33.4。反应历程33中实施例17描述了实现一般反应的方法。实施例8-10举例说明可选择的制备氨基甲酸酯的方法。
反应历程33,实施例1举例说明使用醇S33.5的氯甲酰基衍生物制备氨基甲酸酯的方法。在此过程中,醇S33.5在0℃下在惰性溶剂中例如甲苯同光气反应,见Org.Syn.Coll.Vol.3,167,1965描述,或与等效试剂例如三氯甲氧基氯甲酸酯反应,见Org.Syn. Coll.Vol.6,715,1988描述,生成氯甲酸酯S33.6。后者化合物然后同胺组分S33.3,在有机或无机碱存在条件下反应,生成氨基甲酸酯S33.7。例如,将氯甲酰基化合物S33.6同胺S33.3在水混溶性溶剂例如四氢呋喃中,在含水氢氧化钠存在下反应,见Org.Syn.Coll. Vol.3,167,1965所描述,产生氨基甲酸酯S33.7。可做为选择的是,反应在二氯甲烷中,在有机碱例如二异丙基乙胺或二甲氨基吡啶存在下反应。
反应历程33,实施例2描述氯甲酸酯化合物S33.6同咪唑反应生成咪唑化物(imidazolide)S33.8。咪唑化物产物然后同胺S33.3反应生成氨基甲酸酯S33.7。制备咪唑化物是在0℃下,非质子溶剂中例如二氯甲烷中进行的,制备氨基甲酸酯是在室温下相似溶剂中,任选在碱例如二甲氨基吡啶存在下进行,见J.Med.Chem.,1989,32,357中的记述。
反应历程33实施例3,描述氯甲酸酯S33.6同活化的羟基化合物
反应,得到混合的碳酸酯S33.10。反应在惰性有机溶剂例如醚或二氯甲烷中,在碱存在例如二环己基胺或三乙胺存在下进行。羟基组分
从反应历程33所示的S33.19-S33.24化合物,和类似的化合物的组中选择。例如,假如组分
是羟基苯并三唑S33.19,N-羟基琥珀酰亚胺S33.20,或五氯酚,S33.21,通过氯甲酸酯同羟基化合物在醚溶剂中在有二环己基胺情况下反应,如在Can.J.Chem.,1982,60,976中描述,得到混合的碳酸酯S33.10。其中组分
是五氟酚S33.22或2-羟基吡啶S33.23的类似反应在醚溶剂中有三乙胺存在下进行,如Syn.,1986,303,和Chem.Ber.118,468,1985中所描述的。
反应历程33实施例4举例说明使用烷氧基羰基咪唑S33.8制备氨基甲酸酯。在此过程中,醇S33.5同等摩尔量的羰基二咪唑S33.11反应制备中间体S33.8。反应在非质子有机溶剂中,例如二氯甲烷或四氢呋喃中进行。酰氧基咪唑S33.8然后同等摩尔量的胺
反应生成氨基甲酸酯S33.7。反应在非质子有机溶剂中,例如二氯甲烷中进行,如Tet.Lett.,42,2001,5227中描述的,生成氨基甲酸酯S33.7。
反应历程33,实施例5说明有中间体烷氧基羰基苯并三唑S33.13制备氨基甲酸酯。在此过程中,室温下醇
同等摩尔量苯并三唑碳酰氯S33.12反应,得到烷氧基羰基产物S33.13。反应在有机溶剂例如苯或甲苯中,在叔机胺例如三乙胺存在条件下进行,如Synthesis.,1977,704.描述的。产物然后同胺
反应得到氨基甲酸酯S33.7。反应在甲苯或乙醇中,从室温到大约80℃进行,如Synthesis.,1977,704.描述的。
反应历程33,实施例6说明氨基甲酸酯的制备,其中碳酸酯
,S33.14,同醇S33.5反应得到中间体烷基氧羰基中间体S33.15。后者试剂然后同胺
反应生成氨基甲酸酯S33.7。其中试剂S33.15衍生自羟基苯并三唑S33.19的方法描述在Synthesis,1993,908中;其中试剂S33.15衍生自N-羟基琥珀酰亚胺S33.20的方法描述在Tet.Lett.,1992,2781中;其中试剂S33.15衍生自2-羟基吡啶S33.23的方法描述在Tet.Lett.,1991,4251中;其中试剂S33.15衍生自4-硝基酚S33.24的方法描述在Synthesis.1993,103中。反应在等摩尔量醇
和碳酸酯S33.14之间,在无活性有机溶剂中室温下进行。
反应历程33,实施例7说明从烷氧基羰基叠氮化物S33.16制备氨基甲酸酯。在此过程中,烷基氯甲酸酯S33.6同叠氮化物例如叠氮化纳反应,得到烷氧基羰基叠氮化物S33.16。后者化合物同等摩尔量胺
反应得到氨基甲酸酯S33.7。反应在室温下极性非质子溶剂例如二甲基亚砜中进行,例如如Synthesis.,1982,404中所述。
反应历程33,实施例8说明经醇
和胺S33.17氯甲酰衍生物之间反应制备氨基甲酸酯。在此过程中,其描述在Synthetic Organic Chemistry,R.B.Wagner,H.D.Zook,Wiley,1953,p.647中,反应物在室温下非质子溶剂例如乙腈中,在碱例如三乙胺存在条件下化合,得到氨基甲酸酯S33.7。
反应历程33,实施例9说明经醇
和异氰酸酯S33.18之间反应制备氨基甲酸酯。在此过程中,其描述在Synthetic Organic Chemistry,R.B.Wagner,H.D.Zook,Wiley,1953,p.645中,反应物在室温下非质子溶剂例如乙醚或二氯甲烷等中化合,得到氨基甲酸酯S33.7。
反应历程33,实施例10说明经醇
和胺
之间反应制备氨基甲酸酯。在此过程中,其描述在Chem.Lett.1972,373中,反应物在室温下非质子有机溶剂例如四氢呋喃中,在叔碱例如三乙胺,和硒存在下化合。一氧化碳通过溶液并且反应继续进行得到氨基甲酸酯S33.7。
反应历程33氨基甲酸酯的制备
一般反应
实施例
制备碳烷氧基-取代的膦酸酯双酰胺化物、一酰胺化物、二酯和单酯
可用很多方法将膦酸转化为酰胺化物和酯。在一组方法中,膦酸转化成分离的活化的中间体例如磷酰氯,或膦酸原位激活用于与胺或羟基化合物反应。
通过同亚硫酰二氯反应,膦酸转化为磷酰氯,例如J.Gen.Chem.USSR,1983,53,480,Zh.Obschei Khim.,1958,28,1063,或J.Org.Chem.,1994,59,6144中所述,或通过同乙二酰氯反应,如J.Am.Chem.Soc.,1994,116,3251,或J.Org.Chem.,1994,59,6144中所述,或同五氯化磷反应,如J.Org.Chem.,2001,66,329,或在J.Med.Chem.,1995,38,1372中所述,生成物磷酰氯然后同胺或羟基化合物在有碱条件下反应得到酰胺化物或酯产物。
膦酸通过与羰基二咪唑反应转化为活化的咪唑基衍生物,如J.Chem.Soc.,Chem.Comm.(1991)312,或Nucleosides & Nucleotides(2000)19:1885中所述。活化的磺酰氧衍生物通过膦酸同三氯甲磺酰氯或三异丙基苯磺酰氯反应而获得,如Tet.Lett.(1996)7857,或Bioorg.Med.Chem.Lett.(1998)8:663中描述的。活化的磺酰氧衍生物然后同胺或羟基化合物反应得到酰胺化物或酯类。
可以选择的是,膦酸和胺或羟基反应物在有二酰亚胺偶合剂存在条件下结合。通过偶合反应在有二环己基碳化二亚胺存在条件下制备膦酸酰胺化物和酯类描述,例如在J.Chem.Soc.,Chem.Comm.(1991)312或Coll.Czech.Chem.Comm.(1987)52:2792中。使用乙基二甲氨基丙基碳化二亚胺激活并偶合膦酸描述在Tet.Lett.,(2001)42:8841,或Nucleosides & Nucleotides(2000)19:1885中。
许多从膦酸制备酰胺化物和酯类的许多另外的偶合试剂已经被描述。试剂包括Aldrithiol-2,和PYBOP和BOP,如J.Org.Chem.,1995,60,5214和J.Med.Chem.(1997)40:3842中所述,均三甲苯-2-磺酰-3-硝基-1,2,4-三唑(MSNT),如J.Med.Chem.(1996)39:4958所述,二苯基磷酰叠氮化物,如J.Org.Chem.(1984)49:1158,所述,1-(2,4,6-三异丙基苯磺酰-3-硝基-1,2,4-三唑(TPSNT),如Bioorg.Med.Chem.Lett.(1998)8:1013所述,溴三(二甲氨基)磷鎓六氟磷酸酯(BroP),如Tet.Lett.,(1996)37:3997描述,2-氯-5,5-二甲基-2-氧-1,3,2-二氧杂膦烷(phosphinane),如NucleosidesNucleotides 1995,14,871所述,以及二苯基氯磷酸酯,如J.Med.Chem.,1988,31,1305描述。
膦酸经Mitsunobu反应转化为酰胺化物和酯类,其中膦酸和胺或羟基反应物在有三芳基膦和二烷基偶氮二羧化物存在条件下结合。该操作步骤描述在Org.Lett.,2001,3,643,或J.Med.Chem.,1997,40,3842中。
在合适的碱存在条件下,通过膦酸和卤代化合物之间反应也得到膦酸酯。该方法被描述在,例如,Anal Chem.,1987,59,1056,或J.Chem.Soc.Perkin Trans.,I,1993,19,2303,或J.Med.Chem.,1995,38,1372,或Tet.Lett.,2002,43,1161中。
反应历程34-37说明磷酸酯和膦酸转化为碳烷氧基-取代的膦酸双酰胺化物(反应历程34),膦酸酰胺化物(反应历程35),膦酸单酯(反应历程36)和膦酸二酯,(反应历程37)。反应历程38说明合成偕-二烷基氨基膦酸酯试剂。
反应历程34说明膦酸二酯S34.1转化为膦酸双酰胺化物S34.5的不同方法。二酯S34.1,如前述方法制备,水解成为单酯S34.2或成为膦酸S34.6。这些转化所使用的方法如上所述。单酯S34.2通过与氨基酯S34.9反应转化为一酰胺化物S34.3,其中R2基团是
或烷基;R4b基团是二价亚烷基部分,例如,
、
、
、
,和类似物,或自然界中存在的或修饰的氨基酸中的侧链基团;和基团R5b是C1-C12烷基,例如甲基、乙基、丙基,异丙基或异丁基;C6-C20芳香基,例如苯基或取代的苯基;或C6-C20芳基烷基,例如苯甲基或benzyhydryl。反应物在有偶合剂,例如碳化二亚胺,例如二环己基碳化二亚胺存在条件下,如J.Am.Chem.Soc.,(1957)79:3575中描述的,任选在激活剂,例如羟基苯并三唑存在下结合,生产酰胺化物产品S34.3。酰胺化物形成反应也在有偶合剂,例如BOP,如J.Org.Chem.(1995)60:5214中描述,Aldrithiol,PYBOP和用于制备酰胺化物和酯类的类似偶合剂存在条件下进行。可以选择的是,反应物S34.2和S34.9通过Mitsunobu反应转化为一酰胺化物S34.3。由Mitsunobu反应制备酰胺化物描述在J.Med.Chem.(1995)38:2742中。等摩尔量反应物在惰性溶剂,例如四氢呋喃中,在有三芳基膦和二烷基偶氮二羧化物存在条件下化合。如此获得的一酰胺化物酯S34.3然后转化为酰胺化物膦酸S34.4。用于水解反应的条件取决于R1基团的性质,如同前面描述的。膦酸酰胺化物S34.4然后同氨基酯S34.9反应,如上述,生成二酰胺类产物S34.5,其中氨基取代基是相同或不同的。可以选择的是,膦酸S34.6可以同两种不同的氨基酯试剂同时处理,亦即S34.9,其中R2、R4b或R5b是不同的。得到的二酰胺类产物S34.5的混合物然后可以例如通过色谱法分离。
反应历程34
此操作步骤的实施例见反应历程34,实施例1。在此过程中,二苯甲基膦酸酯S34.14同二氮杂二环辛烷(DABCO)在甲苯溶液中回流条件下反应,如J.Org.Chem.,1995,60,2946所述,得到单苯甲基膦酸酯S34.15。产物然后同等摩尔量乙基丙氨酸酯(alaninate)S34.16和二环己基碳化二亚胺在吡啶中反应,生成酰胺化物S34.17。苯甲基然后被去除,例如用钯催化剂氢解,生成可能不稳定的一元酸产物S34.18,根据J.Med.Chem.(1997)40(23):3842中记述的方法。该化合物S34.18然后在Mitsunobu反应中同乙基白酸酯S34.19、三苯基膦和二乙基偶氮二羧化物反应,如J.Med.Chem.,1995,38,2742所述,生成双酰胺化物产物S34.20。
使用上面的步骤,但使用不同氨基酯S34.9代替乙基白酸酯S34.19或乙基丙氨酸酯S34.16,获得相应的产物S34.5。
可以选择的是,膦酸S34.6通过应用上述偶合反应转化为双酰胺化物S34.5。反应在一步中进行,在该情况下,产物S34.5中存在的氮相关取代基是相同的,或在两步中进行,在该情况下,氮相关取代基可以是不同的。
该方法的实施例见反应历程34,实施例2。在此过程中,膦酸S34.6在吡啶溶液中同过量乙基苯基丙氨酸酯S34.21和二环己基碳化二亚胺反应,例如J.Chem.Soc.,Chem.Comm.,1991,1063中描述的那样,生成双酰胺化物产物S34.22。
使用上面操作步骤,但用不同氨基酯S34.9代替乙基苯丙氨酸酯,可获得相应产物S34.5。
进一步选择,膦酸S34.6转化为单或双活化的衍生物S34.7,其中Lv是离去基团,例如氯、咪唑基、三异丙基苯磺酰氧,等等。通过膦酸同亚硫酰二氯或乙二酰氯等反应实现到氯化物S34.7(Lv=
)的转化,见Organic Phosphorus Compounds,G.M.Kosolapoff,L.Maeir,eds,Wiley,1976,p.17所述。膦酸转化为单咪唑化物S34.7(Lv=咪唑基)描述在J.Med.Chem.,2002,45,1284和J.Chem.Soc.Chem.Comm.,1991,312中。可以选择的是,膦酸通过与三异丙基苯磺酰氯反应被活化,如Nucleosides and Nucleotides,2000,10,1885所述。活化产物然后同氨基酯S34.9,在有碱情况下反应生成双酰胺化物S34.5。反应在一步中进行,在这种情况下产物S34.5出现的氮相关取代基是相同的,或在两步中,经由中间体S34.11进行,在这种情况下氮取代基可以是不同的。
这些方法的实施例见反应历程34,实施例3和5。在反应历程34,实施例3中说明的步骤中,膦酸S34.6同10摩尔量的亚硫酰二氯反应,如Zh.Obschei Khim.,1958,28,1063描述的那样,生成二氯化合物S34.23。在回流温度下非质子溶剂例如乙腈中有碱例如三乙胺存在条件下,该产物同丁基丝氨酸酯S34.24反应,得到双酰胺化物产物S34.25。
使用上述操作,但用不同的氨基酯S34.9代替丁基丝氨酸酯S34.24,得到相应产物S34.5。
在反应历程34,实施例5所述操作中,膦酸S34.6如J.Chem.Soc.Chem.Comm.,1991,312所述,和羰基二咪唑反应得到咪唑化物S34.S32。产物然后在乙腈溶液中室温下,和1摩尔量乙基丙氨酸酯S34.33反应生成单取代产物S34.S34。后者化合物然后同羰基二咪唑反应得到活化的中间体S34.35,该产物然后在相同条件下和乙基N-甲基丙氨酸酯S34.33a反应得到双酰胺化物产物S34.36。
使用上述操作,但用不同的氨基酯S34.9代替乙基丙氨酸酯S34.33或乙基N-甲基丙氨酸酯S34.33a,得到相应产物S34.5。
使用上述操作,通过首先将单酯转化为其中Lv是离去基团例如卤素、咪唑基等等的活化衍生物S34.8,制备中间体一酰胺化物S34.3。产物S34.8然后和氨基酯S34.9在有碱例如吡啶条件下反应,得到中间体一酰胺化物产物S34.3。后者化合物通过除去R1基团和产物与氨基酯S34.9的偶合,如上述,转化为双酰胺化物S34.5。
此过程实施例,其中膦酸通过转化为氯衍生物S34.26而被激活,显示在反应历程34,实施例4中。在此过程中,膦酸单苯甲基酯S34.15在二氯甲烷中同亚硫酰二氯反应,如Yet.Letters.,1994,35,4097中描述的那样,得到磷酰氯S34.26。产物然后在乙腈溶液中室温下和1摩尔当量乙基3-氨基-2-甲基丙酸酯S34.27反应,得到一酰胺化物产物S34.28。在后产物在乙酸乙酯中用5%碳上钯催化剂氢化得到一元酸产物S34.29。产物经历Mitsunobu偶合步骤,和等摩尔量丁基丙氨酸酯S34.30,三苯基膦、二乙基偶氮二羧化物和三乙胺在四氢呋喃中得到双酰胺化物产物S34.31。
使用上述操作,但用不同氨基酯S34.9代替乙基3-氨基-2-甲基丙酸酯S34.27或丁基丙氨酸S34.30,得到相应产物S34.5。
活化的膦酸衍生物S34.7也经由二氨基化合物S34.10转化为双酰胺化物S34.5。活化膦酸衍生物例如磷酰氯通过同氨反应转化为氨基类似物S34.10,描述在Organic Phosphorus Compounds,G.M.KoSolapoff,L.Maeir,eds,Wiley,1976中。双氨基化合物S34.10然后在提高温度下和卤酯S34.12(Hal=卤素,也就是
、
、
、
),在极性有机溶剂例如二甲基甲酰胺,在碱例如4,4-二甲氨基吡啶(DMAP)或碳酸钾存在条件下反应,得到双酰胺化物S34.5。可以选择的是,S34.6可被两种不同氨基酯试剂同时处理,换言之S34.12中的R4b或R5b是不同的。得到的二酰胺化物产物S34.5的混合物例如可通过色谱法分离。
这个过程的实施例显示在反应历程34,实施例6中。在这种方法中,二氯膦酸酯S34.23和氨反应得到二酰胺S34.37。反应在水、含水醇或醇溶液中、回流温度下进行。得到的二氨基化合物然后和两摩尔当量的乙基2-溴-3-甲基丁酸酯S34.38,在极性有机溶剂例如N-甲基吡咯烷酮中在大约150℃,在碱例如碳酸钾存在下,任选在催化量的碘化钾存在条件下反应得到二酰胺化物产物S34.39。
使用上面操作,但用不同的卤酯S34.12代替乙基2-溴-3-甲基丁酸酯S34.38,获得相应产物S34.5。
反应历程34所示操作也适用于制备其中氨基酯部分结合不同的官能团的双酰胺化物。反应历程34,实施例7说明从酪氨酸得到的双酰胺化物的制备。在此过程中,单咪唑化物S34.32同丙基酪氨酸酯S34.40反应,如实施例5中描述的那样,得到一酰胺化物S34.41。产物同羰基二咪唑反应得到咪唑化物S34.42,并且此物质和更多摩尔当量的丙基酪氨酸酯反应生成二酰胺化物产物S34.43。
使用上面操作,但用不同氨基酯S34.9代替丙基酪氨酸酯S34.40,获得相应产物S34.5。上述操作两阶段中使用的氨基酯可相同或不同,以便制备具有相同或不同氨基取代基的双酰胺化物。
反应历程35举例说明制备膦酸酯一酰胺的方法。
在一个操作步骤中,膦酸单酯S34.1如反应历程34所述转化为活化的衍生物S34.8。此化合物然后如上所述,和氨基酯S34.9在有碱存在条件下反应生成一酰胺产物S35.1。
此操作步骤见反应历程35,实施例1。在此方法中,一苯基膦酸酯S35.7例如,亚硫酰二氯,如J.Gen.Chem.USSR.,1983,32,367中描述的那样反应得到氯产物S35.8。产物如反应历程34中描述的那样同乙基丙氨酸S3,反应生成酰胺化物S35.10。
使用上述操作,但用不同氨基酯S34.9代替乙基丙氨酸S35.9,可获得相应产物S35.1。
可以选择的是,膦酸一酯S34.1如反应历程34中描述的那样和氨基酯S34.9偶合生成酰胺化物S335.1。必要的话,R1取代基可初期分裂改变生成膦酸S35.2。该转化过程取决于R1基团,并在上面描述。膦酸和R3基团是芳基、杂环、烷基、环丙烷基、卤烷基等等的羟基化合物
反应,通过相同的偶合过程(碳化二亚胺、Aldrithiol-2、PYBOP、Mitsunobu反应等等)见反应历程34,胺和膦酸偶合的描述,转化为酯酰胺化物S35.3。
反应历程34实施例1
反应历程34实施例2
反应历程34实施例3
反应历程34实施例4
反应历程34实施例5
反应历程34实施例6
反应历程34实施例7
此方法实施例显示在反应历程35,实施例2和3中。在实施例2所示的顺序中,单苯甲基膦酸酯S35.11通过同乙基丙氨酸酯反应,使用上述方法之一,转化为一酰胺化物S35.12。然后通过在乙酸乙酯溶液中用5%碳上钯催化剂,催化氢化除去苯甲基,得到膦酸酰胺化物S35.13。产物然后在二氯甲烷溶液中室温下和等摩尔量1-(二甲氨基丙基)-3-乙基碳化二亚胺和三氟代乙醇S35.14反应,例如,如Tet.Lett.,2001,42,8841中描述的那样,生成酰胺化物酯S35.15。
在反应历程35,实施例3所示顺序中,一酰胺化物S35.13在四氢呋喃溶液中室温下,和等摩尔量二环己基碳化二亚胺和4-羟基-N-甲基哌啶S35.16偶合,生成酰胺化物酯产物S35.17。
使用上面操作,但使用不同的一元酸S35.2替换乙基丙氨酸酯产物S35.12,并且使用不同的羟基化合物
替换三氟代乙醇S35.14或4-羟基-N-甲基哌啶S35.16,获得相应产物S35.3。
可以选择的是,活化膦酸酯S34.8和氨反应得到酰胺化物S35.4。产物然后,如反应历程3中所述,同卤酯S35.5,在有碱条件下反应,生成酰胺化物产物S35.6。如果适当,R1基团的性质使用上述方法发生变化,得到产物S35.3。该方法被说明在反应历程35,实施例4中。在此顺序中,单苯基磷酰氯S35.18,如反应历程34中描述的那样,同氨反应,生成氨基产物S35.19。该物质然后在N-甲基吡咯烷酮溶液中170℃下和丁基2-溴-3-苯基丙酸酯S35.20和碳酸钾反应,生成酰胺化物产物S35.21。
使用这些操作,但使用不同的卤酯S35.5替换丁基2-溴-3-苯基丙酸酯S35.20,获得相应产物S35.6。
一酰胺化物产物S35.3也由双重激活的膦酸酯衍生物S34.7制备。在此方法中,其实施例描述在Synlett.,1998,1,73中,中间体S34.7同有限量的氨基酯S34.9反应得到单-取代产物S34.11。后者化合物然后同羟基化合物
在极性有机溶剂例如二甲基甲酰胺中,在碱例如二异丙基乙胺存在条件下,得到一酰胺化物酯S35.3。
该方法被说明在反应历程35,实施例5中。在此方法中,磷酰二氯S35.22在二氯甲烷溶液中和1摩尔当量乙基N-甲基酪氨酸酯S35.23和二甲氨基吡啶反应,产生一酰胺化物S35.24。产物然后和酚S35.25在含碳酸钾的二甲基甲酰胺中反应,得到酯酰胺化物产物S35.26。
使用这些操作,但用氨基酯34.9和/或羟基化合物
替换乙基N-甲基酪氨酸酯S35.23或酚S35.25,获得相应产物S35.3。
反应历程35
反应历程35实施例1
反应历程35实施例2
反应历程35实施例3
反应历程35实施例4
反应历程35实施例5
反应历程36说明制备其中酯基团之一结合碳烷氧基取代基的碳烷氧基-取代的膦酸二酯的方法。
一种方法中,膦酸单酯S34.1,如上述方法制备,使用上述方法之一,和其中R4b与R5b基团如反应历程34中所述的羟基酯S36.1偶合。例如,等摩尔量反应物在有碳化二亚胺例如二环己基碳化二亚胺存在条件下,如Aust.J.Chem.,1963,609中描述的那样,任选在二甲氨基吡啶存在,如Tet.,1999,55,12997中描述的那样,进行偶合。
反应在惰性溶剂室温下进行。
该方法被说明在反应历程36,实施例1中。在此方法中,单苯基膦酸酯S36.9在二氯甲烷溶液中,在二环己基碳化二亚胺存在下,和乙基3-羟基-2-甲基丙酸酯S36.10偶合,得到膦酸酯混合的二酯S36.11。
使用上述操作,但用不同的羟基酯S33.1替换乙基3-羟基-2-甲基丙酸酯S36.10,获得相应产物S33.2。
膦酸单酯S34.1转化为混合的二酯S36.2也由与羟基酯S36.1的Mitsunobu偶合反应,如Org.Lett.,Lett.,2001,643中描述的那样完成。在此方法中,反应物34.1和S36.1在极性溶剂例如四氢呋喃中,在三芳基膦和二烷基偶氮二羧化物存在条件下结合,得到混合的二酯S36.2。R1取代基通过分裂,使用如前所述的方法而发生变化,得到一元酸产物S36.3。该产物然后,例如使用上述方法,同羟基化合物
偶合,得到二酯产物S36.4。
该方法被说明在反应历程36,实施例2中。在此方法中,单烯丙基膦酸酯S36.12在四氢呋喃溶液中,在三苯基膦和二乙基偶氮二羧化物存在条件下,同乳酸乙酯S36.13偶合得到混合二酯S36.14。该产物同三(三苯基膦)氯化铑(Wilkinson催化剂)在乙腈中,如前述反应,除去烯丙基得到一元酸产物S36.15。在后化合物然后在吡啶溶液中室温下,在二环己基碳化二亚胺存在条件下,同1摩尔当量的3-羟基吡啶S36.16偶合得到混合的二酯S36.17。
使用上述方法,但用不同的羟基酯S36.1和/或不同的羟基化合物
替换乳酸乙酯S36.13或3-羟基吡啶,获得相应的产物S36.4。
混合的二酯S36.2还由单酯S34.1经由活化的单酯S36.5的居间中间性获得。在此方法中,单酯S34.1通过与例如,五氯化磷反应,如J.Org.Chem.,2001,66,329中所述,或同亚硫酰二氯或乙二酰氯(Lv=
),或同吡啶中的三异丙基苯磺酰氯反应,如Nucleosidesand Nucleotides,2000,19,1885中所述,或同羰基二咪唑反应,如J.Med.Chem.,2002,45,1284中描述的那样,转化为活化的化合物S36.5。得到的活化的单酯然后同羟基酯S36.1反应,如前所述,生成混合的二酯S36.2。
该方法被说明在反应历程36,实施例3中。在此顺序中,单苯基膦酸酯S36.9在乙腈溶液中70℃下,同十当量的亚硫酰二氯反应,得到磷酰氯S36.19。产物然后同乙基4-氨甲酰基-2-羟基丁酸酯S36.20在含三乙胺的二氯甲烷中反应,得到混合的二酯S36.21。
使用上述操作,但用不同的羟基酯S36.1替换乙基4-氨甲酰基-2-羟基丁酸酯S36.20,获得相应产物S36.2。
混合的膦酸二酯也由将
基团结合到其中已经结合羟基酯部分的中间体S36.3中的选择性途径获得。在此方法中,一元酸中间体S36.3转化为活化的衍生物S36.6,其中Lv是离去基团,例如氯、咪唑、等等,如前所述。活化的中间体然后同羟基化合物
,在碱存在条件下反应,得到混合的二酯产物S36.4。
该方法被说明在反应历程36,实施例4中。在此顺序中,膦酸酯一元酸S36.22同三氯甲磺酰氯在含可力丁的四氢呋喃中反应,如J.Med.Chem.,1995,38,4648中所述,得到三氯甲磺酰氧产物S36.23。该化合物同3-(吗啉代甲基)苯酚S36.24在含三乙胺的二氯甲烷中反应,得到混合的二酯产物S36.25。
使用以上操作,但用不同的醇
替换3-(吗啉代甲基)苯酚S36.24,获得相应产物S36.4。
膦酸酯S36.4也通过在单酯S34.1上进行的烷基化反应获得。一元酸S34.1和卤酯S36.7之间的反应在极性溶剂中,在碱例如二异丙基乙胺,如Anal.Chem.,1987,59,1056中所述,或三乙胺,如J.Med.Chem.,1995,38,1372中所述存在下,或在非极性溶剂例如苯中,在18-冠-6存在下,如Syn.Comm.,1995,25,3565中所述进行。
该方法被说明在反应历程36,实施例5中。在此过程中,一元酸S36.26同乙基2-溴-3-苯基丙酸酯酯S36.27和二异丙基乙胺在二甲基甲酰胺中80℃下反应得到混合的二酯产物S36.28。
使用以上操作,但用不同的卤酯S36.7替换乙基2-溴-3-苯基丙酸酯S36.27,获得相应产物S36.4。
反应历程36
反应历程36实施例1
反应历程36实施例2
反应历程36实施例3
反应历程36实施例4
反应历程36实施例5
反应历程37说明制备其中酯取代基二者都结合碳烷氧基的膦酸二酯的方法。
所述化合物直接或间接从膦酸S34.6制备。在一种选择中,膦酸同羟基酯S37.2,使用反应历程34-36中前面描述的反应条件偶合,例如使用二环己基碳化二亚胺或类似试剂的偶合反应,或在Mitsunobu反应条件下,得到其中酯取代基相同的二酯产物S37.3。
该方法被说明在反应历程37,实施例1中。在此过程中,膦酸S34.6同三摩尔当量的乳酸丁酯S37.5,在Aldrithiol-2和三苯基膦存在下,在吡啶中大约70℃下反应,得到二酯S37.6。
使用上面的步骤,但用不同的羟基酯S37.2替换乳酸丁酯S37.5,获得相应的产物S37.3。
可选择的是,二酯S37.3通过膦酸S34.6用卤酯S37.1烷基化获得。烷基化反应如反应历程36中关于制备酯S36.4所述的进行。
该方法被说明在反应历程37,实施例2中。在这个过程中,膦酸S34.6在大约.80下,同过量的乙基3-溴-2-甲基丙酸酯S37.7和二异丙基乙胺在二甲基甲酰胺中反应,如Anal.Chem.,1987,59,1056中所述,生成二酯S37.8。
使用上面的步骤,但用不同的卤酯S37.1替换乙基3-溴-2-甲基丙酸酯S37.7,获得相应的产物S37.3。
通过活化的膦酸衍生物S34.7同羟基酯S37.2的置换反应获得二酯S37.3。该置换反应在极性溶剂中,在合适的碱存在下进行,如反应历程36中所述。该置换反应在过量的羟酯存在下进行,得到二酯产物S37.3,其中酯取代基相同,或顺序地与有限量的不同羟基酯反应,来制备二酯S37.3,其中酯取代基不同。
该方法被说明在反应历程37,实施例3和4中。如实施例3中所示,磷酰二氯S35.22同3摩尔当量的乙基3-羟基-2-(羟甲基)丙酸酯S37.9在含碳酸钾的四氢呋喃中反应,以获得二酯产物S37.10。
使用上述操作,但用不同的羟基酯S37.2替换乙基3-羟基-2-(羟甲基)丙酸酯S37.9,获得相应的产物S37.3。
反应历程37,实施例4描述等摩尔量的磷酰二氯S35.22和乙基2-甲基-3-羟基丙酸酯S37.11之间置换反应,得到单酯产物S37.12。反应在70°于乙腈中,在二异丙基乙胺存在下进行。在相同的条件下,产物S37.12然后和1摩尔当量的乳酸乙酯S37.13反应,得到二酯产物S37.14。
使用上述操作,但用与不同的羟酯S37.2的顺序反应替换乙基2-甲基-3-羟基丙酸酯S37.11和乳酸乙酯S37.13,获得相应的产物S37.3。
反应历程37
反应历程37实施例1
反应历程37实施例2
反应历程37实施例3
反应历程37实施例4
2,2-二甲基-2-氨乙基膦酸中间体可通过反应历程5中的途径来制备。2-甲基-2-丙基亚磺酰胺和丙酮的缩合得到亚磺酰基亚胺S38.11(J.Org.Chem.1999,64,12)。添加二甲基甲膦酸酯锂到S38.11得到S38.12。S38.12的酸性甲醇分解得到S38.13。用Cbz基团保护胺,并除去甲基产生膦酸S38.14,其使用前述方法可转化为想要的S38.15(反应历程38a)。化合物S38.14的替代性合成也显示在反应历程38b中。根据文献方法(J.Org.Chem.1992,57,5813;Syn.Lett.1997,8,893),商业可获得的2-氨基-2-甲基-1-丙醇转化为氮丙啶S38.16。氮丙啶用亚膦酸酯打开生成S38.17(Tetrahedron Lett.1980,21,1623)。S38.17的再保护得到S38.14。
反应历程38a
反应历程38b
现在将通过下面的非限制性实施例来举例说明本发明。
实施例1
根据在Bioorg.Med.Chem.Lett,1995,5,1035中所报道的程序,雷帕霉素(化合物,1.1,其中雷帕霉素结构的剩余部分未显示),依维莫司的合成前体,通过使用合适的芳基铋试剂来进行以上所示的O-芳基化。3-(二甲基-叔丁基甲硅氧基)溴苯用镁在二乙醚中或用丁基锂在四氢呋喃中处理,和所形成的有机金属试剂与三氯化铋反应产生三芳基
。在用1-1.2当量的过乙酸处理后,该铋(V)试剂与雷帕霉素和乙酸铜(II)混合。让反应在室温下进行一天,或如果必要,在回流下反应,获得所需的3-(二甲基-叔丁基甲硅氧基)苯基醚,1.2。在二甲基-叔丁基甲硅烷基保护基团的除去后,O-烷基化用(溴甲基)膦酸二乙基酯在氧化银存在下实现,获得含有膦酸二乙酯的所需依维莫司类似物,1.3。银离子协助的反应已经用于媒介在结构类似于雷帕霉素的免疫抑制性大环内酯之上的O-烷基化:参见J.Med.Chem.,1998,41,1764。
实施例2
按照与实施例1中所述类似的方式,例外的是关键的三吲哚基
中间体是按照在J.Org.Chem.1998,63,6721中描述的程序从5-溴吲哚获得的,从雷帕霉素(通式,2.1,其中雷帕霉素结构的剩余部分未示出)制备依维莫司吲哚基醚的膦酸酯衍生物。
实施例3
根据在Bioorg.Med.Chem.Lett,1995,5,1035中所报道的程序,三芳基
(化合物,3.1,其中他克莫司分子的剩余部分未显示)通过使用合适的芳基铋试剂来进行以上所示的O-芳基化。3-(二甲基-叔丁基甲硅氧基)溴苯用镁在二乙醚中或用丁基锂在四氢呋喃中处理,和所形成的有机金属试剂与三氯化铋反应产生三芳基
。在用1-1.2当量的过乙酸处理后,该铋(V)试剂与他克莫司3.1和乙酸铜(II)混合。让反应在室温下进行一天,或如果必要,在回流下反应,获得所需的3-(二甲基-叔丁基甲硅氧基)苯基醚。在二甲基-叔丁基甲硅烷基保护基团用HF除去之后,O-烷基化用(溴甲基)膦酸二乙基酯在氧化银存在下实现,获得含有膦酸二乙酯的所需他克莫司类似物,3.3。银离子协助的反应已经用于媒介在结构类似于他克莫司的免疫抑制性大环内酯之上的O-烷基化(参见J.Med.Chem.,1998,41,1764)。
实施例4
按照与实施例3中所述类似的方式,例外的是关键的三吲哚基
中间体是按照在J.Org.Chem.1998,63,6721中描述的程序从5-溴吲哚获得的,从他克莫司(化合物,4.1,其中他克莫司分子的剩余部分未示出)制备他克莫司吲哚基醚4.3的膦酸酯衍生物。
实施例5
本发明的代表性化合物能够通过由Boer等人,J.Mass Spectrom.1995,30,497-504和Hoyte等人,J.Med.Chem.2002,45,5397-5405描述的程序制造;它们也可以根据下列总体路线来制备。
通式5.1和5.2的化合物,其中“link”具有对于连接基团或连接基所定义的值之中的任何一个,是本发明的代表性化合物。
实施例6
强的松龙,6A,在溶剂如氯仿中用甲醛在酸如浓盐酸存在下处理。在室温下搅拌几个小时(优选7到10小时)后,分离两层和有机层被浓缩,获得双-(亚甲基二氧基)中间体,5.3(Hirschmann,R.等人,J.Am.Chem.Soc.1964,86,1520-1527)。这一中间体用(氨基-氧基甲基)膦酸二乙基酯在溶剂如吡啶中处理,获得肟,5.4。该肟用酸的水溶液处理,除去双-(亚甲基二氧基)保护基团。例如,肟用60%甲酸水溶液处理并在90℃下加热10分钟,冷却和浓缩,使用几份乙醇以协助除去甲酸。残留物的色谱分离提纯和/或结晶得到强的松龙的膦酸酯肟类似物。
这一合成的关键前体,(氨基氧基甲基)膦酸二乙基酯,能够从(三氟甲基-磺酰基氧基甲基)膦酸二乙基酯和N-(叔丁氧基羰基)-羟胺获得。因此,N-(叔丁氧基羰基)-羟胺溶于溶剂如THF中和用氢化钠处理。当鼓泡停止时,添加(三氟甲基磺酰基氧基甲基)膦酸二乙基酯(根据Tetrahedron Lett.,1986,27,1477制得)。在用氯化铵水溶液淬灭反应和用有机溶剂如乙酸乙酯萃取产物后,由色谱分离法分离出N-BOC保护的(氨基氧基甲基)膦酸二乙基酯。该N-BOC保护基然后通过三氟乙酸的处理被除去,获得所需的(氨基氧基甲基)膦酸二乙基酯。
实施例7
根据例如由Procopiou,P.等人,J.Med.Chem.,2001,44,602-612报道的程序,在氢气氛中通过使用铑催化如三(三苯基膦)铑(I)氯化物将强的松龙6A还原成1,2-二氢强的松龙7.1。在C-2位上的甲酰化之前,在类甾醇的D环上的二羟基酮基然后使用在实施例6中描述的方法来加以保护。例如,双-(亚甲基二氧基)中间体,7.2,用新蒸镏的甲酸乙酯和氢化钠在溶剂如甲苯中处理。反应用弱碱如磷酸二氢钾的水溶液淬灭。该粗产物通过一般方法如结晶来提纯,获得2-甲酰基中间体7.3。这一2-甲酰基化合物与膦酸酯取代的苯肼缩合,在双-(亚甲基二氧基)保护基的除去后,获得了所需强的松龙的膦酸酯吡唑类似物7.4。
关键的前体,3-[(二乙基膦酰基)-甲氧基]-苯基肼,7.5,能够从(三氟甲基磺酰基氧基甲基)膦酸二乙基酯和3-硝基苯酚制备。3-硝基苯酚用碱如氢氧化钠处理,然后用(三氟甲基-磺酰基-氧基甲基)膦酸二乙基酯进行O-烷基化。该硝基用氯化锡(II)还原,和随后通过重氮化作用和利用亚硫酸钠(Chem.Ber.,1960,93,540)或氯化锡(II)(J.Med.Chem.,2001,44,4031)的还原作用被转化成芳基肼。
实施例8-13
能够用于制备通式A,B,或C的VX-148类似物的合成方法和中间化合物被描述在实施例8-13。下面化合物是通式6,7和8的化合物的代表性例子。
link包括0-8个原子;优选2-6个
实施例8
以上示出了可用于将3,5-二官能化硝基苯衍生物转化成苯胺(它能够用于制备本发明的VX-148类似物)的一般反应历程。
实施例9
3-羟基-5-硝基-苯甲酸在亚硫酰氯中简短地加热,产生酰氯。该酰氯与O,N-二甲基-羟胺在碱如三乙胺存在下缩合,产生魏因雷布(Weinreb)酰胺,后者通过与甲基锂反应而得到苯乙酰酮衍生物。苯乙酰酮衍生物用碱如碳酸钾在偶极非质子溶剂如二甲基甲酰胺中,在过量的E-1,4-二溴丁烯的存在下处理。一溴化物通过色谱分离法分离和然后用亚磷酸三乙基酯在溶剂如甲苯中进行处理(或其它Arbuzov反应条件:参加Engel,R.,“Synthesis of Carbon-phosphorus Bonds”,CRC press,1988),产生所希望的膦酸二乙酯。之后,苯乙酰酮的羰基通过使用合适的纯手性oxazaborolidine如Corey所述的化合物(J.Am.Chem.Soc.,1987,109,5551)进行对映选择性还原,所获得的醇通过使用例如Mitsunobu描述的方法被叠氮化物置换(Bull.Chem.Soc.Japan.,1971,44,3427)。该叠氮化物按照Staudinger条件(Helv.Chim.Act.,1919,2,635)被还原成胺,然后作为叔丁基碳酸酯加以保护。最后,所需的苯胺中间体通过硝基苯的锡(II)-媒介还原来产生。苯胺通过使用偶联反应被转化成通式A(也是通式6)的化合物,该偶联反应与在美国专利No.6,054,472和美国专利No.6,344,465中所述的那些类似。
实施例10
以上示出了用于将3,4-二官能化硝基苯衍生物10.1转化成苯胺的一般反应历程,后者通过使用与在美国专利No.6,054,472和美国专利No.6,344,465中描述的那些类似的偶联反应被转化成通式B(也是通式7)的化合物。
实施例11
3-取代的硝基苯11.1的处理得到苯胺11.2,它能够通过使用与在美国专利No.6,054,472和美国专利No.6,344,465中所述的那些类似的偶联反应被转化成通式C(也是通式8)的化合物。
实施例12
3-硝基苯甲醛12.1与格利雅试剂反应而引入携带受保护醇的系绳(tether)和同时产生苄基醇,如以上所示。按照与对于实施例9所述的方法相类似的方法,醇12.2被叠氮化物置换。在去保护后,释放的醇通过使用碱如叔丁醇镁在溶剂如四氢呋喃中用三氟甲磺酸二乙基膦酰基甲基酯(根据Tetrahedron Lett.,1986,27,1477制得)烷基化。叠氮化物和硝基的后续转变按照与在实施例9中所述的方法类似的方式来进行。参见Batt等人,Bioorg.Med.Chem.Lett.,1995,5,1549。
实施例13
通过使用供仲酰胺的形成的标准试剂如二环己基碳二亚胺(DCC)和羟基苯并三唑(HOBT),3-叔丁氧基羰基氨基-3-(3-硝基-苯基)-丙酸,13.1,(市场上可买到的)与2-氨基乙基膦酸二乙基酯(市场上可买到的)在溶剂如二甲基甲酰胺中偶联。硝基的后续还原按照与在实施例9中所述的方法类似的方式来进行。
实施例14
以上反应历程示出了可用于制备通式9化合物的总体路线。
实施例15
3-羟基-5-硝基-苯甲酸,15.1,在亚硫酰氯中简短地加热,产生酰氯。它然后与O,N-二甲基-羟胺在碱如三乙胺存在下缩合,产生魏因雷布(Weinreb)酰胺,后者通过与甲基锂反应而得到苯乙酰酮衍生物。它然后用碱如碳酸钾在偶极非质子溶剂如二甲基甲酰胺中,在过量的E-1,4-二溴丁烯的存在下处理。一溴化物通过色谱分离法分离和然后用亚磷酸三乙基酯在溶剂如甲苯中进行处理(或其它Arbuzov反应条件:参加Engel,R.,“Synthesis of Carbon-phosphorus Bonds”,CRC press,1988),产生所希望的膦酸二乙酯,15.2。之后,苯乙酰酮的羰基通过使用合适的纯手性oxazaborolidine如Corey所述的化合物(J.Am.Chem.Soc.,1987,109,5551)进行对映选择性还原,所获得的醇通过使用例如Mitsunobu描述的方法被叠氮化物置换(Bull.Chem.Soc.Japan.,1971,44,3427)。该叠氮化物按照Staudinger条件(Helv.Chim.Act.,1919,2,635)被还原成胺,然后作为叔丁基碳酸酯加以保护。最后,所需的苯胺中间体15.3通过硝基苯的锡(II)-媒介还原来产生。
实施例16
适合用于通式10的代表性化合物的合成中的试剂可从2-羟基-5-硝基-苯甲酸开始,通过与实施例10中所示的相类似的路线来制备。
实施例17
通式11的代表性化合物可以按照以上在实施例11-13中所说明的方法来制备。通式17.2的苯胺的制备可以按照以上在实施例11-13中所说明的方法来进行。通式17.2的苯胺通过使用与在美国专利No.6,054,472和美国专利No.6,344,465中所述的那些类似的程序被转化成通式11的化合物。
实施例18
下面是可用于制备通式15化合物的总体路线。
实施例19
化合物19.1和化合物19.2的初始Pfitzinger缩合是在单个步骤中通过使用氢氧化钾与酸性后处理来实现的,如以上所示。另外地,初始醛醇缩合可以使用二乙胺在乙醇中进行,并且该喹啉环可以在由酸如盐酸媒介的第二步骤中在溶剂如1,4-二噁烷中形成。在苄基保护基通过氢化被除去之后,苯酚能够在溶剂如四氢呋喃或二甲基甲酰胺中用碱如氢化钠处理。当鼓泡停止时,添加三氟甲磺酸二乙基膦酰基甲基酯(根据Tetrahedron Lett.,1986,27,1477制得),得到所想望的膦酸二酯。羧酸酯通过用氢氧化锂在乙醇中去保护而得到化合物19.4(它是通式12的化合物)。
实施例20
该合成与在实施例19中所述的合成类似,只是在苯酚的去质子化之后,添加过量的E-1,4-二溴丁烯。在用氯化铵水溶液淬灭反应和用有机溶剂如乙酸乙酯萃取产物之后,由色谱分离法分离出单-烷基化产物。所形成的溴化物与亚磷酸三乙基酯在溶剂如甲苯中加热,产生所需膦酸二乙酯,和该羧酸与前面一样去保护得到化合物20A(它是通式12的化合物)。
实施例21
强的松21A(美国专利No.2,897,464),和代表性膦酸酯的结构在下面示出,其中取代基R1是
,烷基,链烯基,芳基或芳烷基。该膦酸酯化合物利用可变的连接基团(表示为“link”)来引入被连接到核上的膦酸酯结构部分
。
例如,以上反应历程描述了保护-去保护序列,其中类甾醇侧链作为双-亚甲基二氧基(BMD)结构部分来保护。在这一序列中,强的松21A与仲甲醛和酸催化剂如盐酸,按照在“Protective Groups inOrganic Synthesis”中由T.W.Greene和P.G.M.Wuts,Wiley,第二版1990,第223页中所述,进行反应而得到BMD衍生物21.1。膦酸酯结构部分然后通过使用如下所述的程序被引入,生产出膦酸酯21.2。BMD结构部分然后水解,例如用50%乙酸水溶液处理,按照在“Protective Groups in Organic Synthesis”中由T.W.Greene和P.G.M.Wuts,Wiley,第二版1990,第223页中所述,获得三醇21.3(它是通式23的化合物)。
任选地,取决于所使用的反应的性质,在BMD化合物21.1中的11-酮基在膦酸酯基团的引入之前加以保护。该酮通过在甲苯溶液中在回流温度下与乙二醇和酸催化剂反应来加以保护,例如作为环状乙二醇缩酮,按照在J.Am.Chem.Soc.,1955,77,1904中所述。通过与吡啶鎓甲苯磺酸盐在丙酮水溶液中进行去保护,按照在J.Chem.Soc.,Chem.Comm.,1351,1987中所述。
另外地,该11-酮通过转化成N,N-二甲基腙来加以保护。该二甲基腙是通过该酮21.1与N,N-二甲基肼在乙醇-乙酸中反应来制备的,按照在Org.Syn.,1970,50,102中所述。该基团通过用乙酸钠和乙酸在四氢呋喃水溶液中处理来除去,按照在J.Am.Chem.Soc.,1979,101,5841中所述。
另外地,该11-酮作为二乙胺加合物来保护。在这一程序中,按照在J.Chem.Soc.,Chem.Comm.,406,1983中所述,底物21.1与四(二乙基酰胺)化钛反应,获得加合物。该酮通过与水在含水有机溶剂中反应来进行去保护。
该11-保护的BMD化合物21.4然后通过使用如下所述的程序被转化成膦酸酯21.5。去保护然后得到11-酮二醇21.3。
实施例22
以上描述了膦酸酯22.3的制备,其中膦酸酯借助于亚氨基或亚氨基氧基和可变的碳链来连接。在这一程序中,双保护的衍生物21.4与胺或羟胺22.1反应,其中R2是烷基、链烯基、环烷基或环烯基,任选地引入杂原子
、
或
,或官能团如酰胺、酯、肟、亚砜或砜等,或任选取代的芳基、杂芳基或芳烷基,任选地引入杂原子
、 或
,和X是膦酸酯基团或随后被转化成含膦酸酯的取代基的一种基团。
例如,X是二烷基膦酰基,溴,羟基,氨基,羧基等等。该反应是在等摩尔量的反应物之间在非质子传递溶剂如吡啶或二甲苯中,或在醇溶剂如乙醇中,任选在酸催化剂存在下,来进行,得到亚胺或肟。甾族3-酮的肟的制备已描述在Anal.Bioch.,1978,86,133中和在J.Mass.Spectrom.,1995,30,497中。保护基团然后被除去而获得酮二醇,22.3(它是通式16的化合物)。
实施例23
以上示出了膦酸酯P2.10的制备,其中膦酸酯通过亚氨基氧基来连接。底物23.1,其中11-酮作为二甲基腙加以保护的通式23.1的化合物,与从二烷基三氟甲基-磺酰基氧基甲基膦酸酯(TetrahedronLett.,1986,27,1477)和BOC-羟胺制备的二烷基膦酰基甲基羟胺P2.8反应,获得肟P2.9,后者通过与50%乙酸水溶液反应实现去保护,获得二醇P2.10。肟形成反应典型地在环境温度下在乙醇-乙酸溶液中在等摩尔量的反应物之间进行。
中间体二烷基膦酰基甲基羟胺P2.8(化合物,2.7,其中R2是键)能够如下制备。
其中Lv是离去基团如溴或三氟甲基磺酰基氧基的膦酸酯P2.4与BOC-羟胺P2.5(Aldrich)反应,生产醚P2.6。反应典型地在等摩尔量的反应物之间在极性溶剂如二甲基甲酰胺或四氢呋喃中,在碱如氢氧化钾或二甲基胺基吡啶存在下进行。然后进行去保护(例如通过用三氟乙酸处理),得到羟胺醚P2.7。
实施例24
按照在实施例23中所述,二烯酮23.1与从2-溴苄基溴化物制得的O-(2-溴-苄基)-羟胺P2.11反应,在去保护后,得到肟P2.12。该产物然后在钯催化剂存在下与亚磷酸二烷基酯P2.13反应,获得该膦酸酯P2.14。通过在芳基溴和二烷基亚磷酸酯之间的偶联反应制备芳基膦酸酯的方法已描述在J.Med.Chem.,1992,35,1371中。反应典型地被在惰性溶剂如甲苯中,在碱如三乙胺和催化量的四(三苯基膦)钯(0)存在下进行。
另外地,溴化合物P2.12与乙烯基膦酸二烷基酯P2.15(Aldrich)偶联,获得膦酸酯P2.16。芳基卤化物与烯烃利用Heck反应的偶联描述在例如“Advanced Organic Chemistry”,F.A.Carey和R.J.Sundberg,Plenum,2001p.503ff中和在Acc.Chem.Res.,1979,12,146中。该芳基溴和烯烃在极性溶剂中如二甲基甲酰胺或二噁烷中,在钯(0)催化剂如四(三苯基膦)钯(0)或钯(II)催化剂如乙酸钯(II)存在下,和任选地在碱如三乙胺或碳酸钾存在下,进行偶联。任选,在产物P2.16中存在的styrenoid双键例如通过与二酰亚胺反应而被还原,得到饱和类似物P2.17。烯键的还原已描述在“Comprehensive OrganicTransformations”,R.C.Larock,VCH,1989,p.6ff中。该转变利用催化氢化,例如通过使用钯/碳催化剂和氢或氢给体,或通过利用二酰亚胺或乙硼烷来进行。
通过使用以上程序,但代替苄氧基试剂P2.11使用不同的溴取代的芳基或杂芳基烷氧基羟胺,和/或不同的链烯基膦酸二烷基酯,获得了与该产物类似的产物,P2.14、P2.16和P2.17。
实施例25
以上示出了其中膦酸酯利用亚氨基来连接的通式16的膦酸酯的制备。底物23.1与4-氨基苯基膦酸二烷基酯P2.18(Epsilon)反应,在去保护后获得亚胺产物P2.19。反应典型地在烃溶剂如甲苯或二甲苯中,在回流温度下,在碱性催化剂如甲醇钠,或酸催化剂如甲苯磺酸存在下,在共沸条件下进行。
实施例26
以上示出了其中膦酸酯利用肟基和醚键来连接的通式16的代表性膦酸酯的制备。在这一程序中,该二烯酮23.1与O-(2-羟基乙基)羟胺P2.20反应(J.Chem.Soc.,Chem.Comm.,1986,903),得到肟P2.21。甾族1,4-二烯-3-酮与取代的羟胺的反应已描述在J.SteroidBioch.,1976,7,795。反应是在等摩尔量的反应物之间在极性有机溶剂如吡啶或甲醇中,任选在乙酸或乙酸钠存在下进行。该肟然后按照Mitsonobu反应与4-羟苯基膦酸二烷基酯P2.22(Epsilon),得到醚肟P2.23。利用Mitsonobu反应制备芳族醚的方法例如描述在“Comprehensive Organic Transformations”,R.C.Larock,VCH,1989,448页中,和在“Advanced Organic Chemistry”,部分B,F.A.Carey和R.J.Sundberg,Plenum,2001,153-4页中和在Org.React.,1992,42,335中。该酚和醇或硫醇组分一起在非质子传递溶剂例如四氢呋喃中,在偶氮二羧酸二烷基酯和三芳基膦存在下反应,获得醚或硫醚产物。该程序也描述在Org.React.,1992,42,335-656中。该醚产物P2.23然后被转化成酮二醇P2.24(它是通式16的化合物)。
通过使用以上程序,但代替羟胺P2.20使用不同的羟基取代的羟胺和/或不同的羟基取代的芳基膦酸酯,获得与P2.24类似的产物。
实施例27
以上示出了其中膦酸酯基团借助于芳族或杂芳族基团、杂原子和可变的碳链连接于吡唑环的1’或2’位上的通式17和18的膦酸酯的制备。在这一程序中,该BMD保护的二烯酮21.1被还原,获得1,2-二氢产物P3.1。该催化氢化反应通过三(三苯基膦)铑(I)氯化物的使用来进行,例如按照在J.Med.Chem.,2001,44,602中所述。该产物然后与甲酸乙酯和碱如氢化钠,在惰性溶剂如甲苯或二甲基甲酰胺中进行反应,按照在J.Am.Chem.Soc.,1964,86,1520中所述,获得2-甲酰基产物P3.2。这一化合物然后与烷基,芳烷基,芳基或杂芳基肼P3.3反应,其中取代基X是膦酸酯基团或可以随后转变成含膦酸酯的取代基的一种基团。例如,X是二烷基膦酰基,溴,羟基,氨基,羧基等等。反应得到异构体2’-和1’-芳基吡唑,P3.4和P3.5。该吡唑形成反应是在等摩尔量的反应物之间在酸性溶剂如乙酸中进行,按照在J.Am.Chem.Soc.,1964,86,1520中所述。该吡唑P3.4和P3.5然后经由BMD保护的中间体P3.6和P3.7转变成膦酸酯P3.8和P3.9,它们分别是通式17和18的化合物。
实施例28
以上示出了其中膦酸酯利用苯基环和酯或酰胺键来连接的膦酸酯类的制备。该酮醛P3.2与3-羧基苯基肼P3.10(Apin)反应,得到吡唑P3.11和P3.12。该2’-取代的异构体P3.11然后在二氯甲烷溶液中在环境温度中与一摩尔当量的2-羟基-2-甲基丙基膦酸二烷基酯P3.13(法国专利No.2,462,440)和二环己基碳二亚胺反应,得到酯P3.14。保护基团然后被除去,得到属于通式18化合物的二醇P3.15。
另外地,该1’-取代的吡唑P3.12与2-氨基乙基膦酸二烷基酯P3.17(Aurora)偶联,获得酰胺P3.18。从羧酸类和衍生物制备酰胺的方法例如描述在“Organic Functional Group Preparations”,S.R.Sandler和W.Karo,Academic Press,1968,第274页,和“Comprehensive Organic Transformations”,R.C.Larock,VCH,1989,p.972ff中。该羧酸与该胺在活化剂例如二环己基碳二亚胺或二异丙基碳二亚胺存在下,任选地在例如羟基苯并三唑、N-羟基-琥珀酰亚胺或N-羟基吡啶酮存在下,在非质子溶剂如吡啶、DMF或二氯甲烷中进行反应,获得酰胺。
另外地,该羧酸可以首先转化成活化的衍生物如酰氯、酸酐、混合酸酐、咪唑化物(imidazolide)等,然后与胺在有机碱例如吡啶存在下反应,获得该酰胺。羧酸转化成相应的酰氯的过程可通过用试剂例如亚硫酰氯或草酰氯在惰性有机溶剂如二氯甲烷中,任选在催化量二甲基甲酰胺存在下处理羧酸来进行的。该产物P3.18然后去保护,得到二醇P3.19(它是通式17的化合物)。
通过使用以上程序,但使用不同的氨基或羟基-取代的膦酸酯,和/或不同的羧基-取代的肼,获得与P3.15和P3.19类似的产物。官能化程序在吡唑底物P3.11和P3.12之间是可相互变化的。
实施例29
以上示出了其中膦酸酯基团利用苯基和烷氧基或烷硫基碳链来连接的通式17和18的膦酸酯的制备。在这一程序中,该酮醛P3.2与4-羟苯基肼P3.20反应(EP 437105),生产出吡唑P3.21和P3.22。该1’-取代的异构体P3.21在二甲基甲酰胺溶液中在70℃下与溴丙基膦酸二烷基酯P3.23(J.Amer.Chem.Soc.,2000,122,1554)和碳酸钾反应,得到膦酸酯P3.24。该产物然后被去保护而获得二醇P3.25
另外地,该2’-取代的吡唑P3.22在如上所述的Mitsonobu反应中与巯基乙基膦酸二烷基酯P3.26反应(zh.Obschei.Khim.,1973,43,2364),制备硫醚膦酸酯P3.27,它进行去保护而得到二醇P3.28。
通过使用以上程序,但代替羟苯基试剂P3.20使用不同的羟基取代的芳烷基、芳基或杂芳基烷氧基肼,和/或不同的二烷基溴或巯基取代的膦酸酯,获得了与化合物P3.25和P3.28类似的产物。
实施例30
以上示出了其中膦酸酯基团利用可变的碳键来连接的通式17和18的膦酸酯的制备。在这一程序中,该酮醛P3.2与肼反应,获得吡唑衍生物P4.1。甾族2-甲酰基-3-酮与肼的反应已描述在J.Am.Chem.Soc,1964,86,1520中。反应是在乙酸中在环境温度下进行的。该吡唑产物然后与溴甲基化合物P4.2反应,得到烷基化产物P4.3和P4.4。取代的吡唑的烷基化例如描述在“Heterocyclic Chemistry”,T.L.Gilchrist,Longman,1992,第309页。反应典型地在等摩尔量的底物之间在极性溶剂如二甲基甲酰胺或四氢呋喃中,在碱如二甲基氨基吡啶、六甲基二硅氮化锂(lithium hexamethyldisilazide)等存在下进行的。通过使用以上所述的程序,产物P4.3和P4.4,只是当X是二烷基膦酰基时的情况除外,被转化成膦酸酯P4.5和P4.6。去保护获得二醇P4.7和P4.8(它们分别是通式18和17的化合物)。
实施例31
如以上所说明,吡唑P4.1与一摩尔当量的三氟甲磺酰基氧基膦酸二烷基酯P4.9,如上所述,进行反应获得烷基化吡唑P4.10和P4.11。去保护得到二醇P4.12和P4.13(它们分别是通式18和17的化合物)。
实施例32
如以上示出,该吡唑P4.1按如上所述的方式与1,4-双(溴甲基)环己烷P4.14(Salor)反应,得到吡唑P4.15和P4.16。该产物P4.15进行阿尔布佐夫(Arbuzov)反应,其中溴甲基取代基通过与亚磷酸三烷基酯反应转化成二烷基膦酰基甲基取代基,在侧链的去保护之后制备出膦酸酯P4.17(它是通式18的化合物)。
该吡唑P4.16在二甲基甲酰胺中与碳酸钾和氨基甲基膦酸二烷基酯P4.18(Interchim)反应,在去保护之后得到氨基膦酸酯P4.19,它是通式17的化合物。
通过使用以上程序,但代替二溴化物P4.14使用不同的二溴化物和/或不同的氨基取代的膦酸酯,获得与P4.17和P4.19类似的产物。
实施例33
本发明的代表性化合物能够按照Westwood等人,J.Med.Chem.,1996,39,4608-4621一般描述的那样,并且根据下列总体路线来制备。
其中X1是氢,卤素,三氟甲基,(C1-C3)烷基,氰基,或(C1-C3)烷氧基的合适苯胺33.1与酰氯33.2的偶联可得到化合物33.3(它是通式19或20的代表性化合物)。
下面列出了用于上述反应中的两种合适苯胺的合成。
3-硝基苯酚用E-1,4-二溴丁烯进行烷基化和所形成的一溴化物与亚磷酸三乙基酯在溶剂如甲苯中(或其它阿尔布佐夫反应条件)反应,得到所需膦酸二乙酯33.4。(参见Engel,R.,“Synthesis ofCarbon-phosphorus Bonds”,CRC press,1988)。最后,所需的苯胺通过硝基苯的锡(II)-媒介还原来产生。
3-硝基-4-三氟甲基苯甲酸的甲酯用氯化锡(II)处理,得到相应的苯胺。3-碘苯甲酸通过重氮化和用碘化钾处理来产生。膦酸二乙基酯使用钯催化经由乙炔连接基来连接,和在苯甲酸酯的皂化之后,酰基叠氮的柯歇斯(Curtius)重排得到适合引入到本发明的代表性MNA-715类似物中的苯胺。
实施例34
通式21和22的代表性化合物能够按照Westwood等人,J.Med.Chem.,1996,39,4608-4621一般描述的那样,并且根据下列总体路线来制备。
其中X2是氢,卤素,三氟甲基,氰基,或甲基的合适苯胺34.1与酰氯34.2的偶联得到通式21和22的代表性化合物。按照在实施例33和本文其它对方描述的方法所制备的苯胺能够引入这一合成中。
实施例35
X=0-4个原子间隔基
按照在Bioorg.Med.Chem.Lett.,1999,9,1625中报道的程序,5-硝基-异苯并呋喃-1,3-二酮,35.1(市场上可买到),转化成5-氨基-2-(2,6-二氧代-哌啶-3-基)-异吲哚-1,3-二酮,35.2。这一胺中间体与二乙基膦酰基-乙醛(从烯丙基膦酸二乙基酯的臭氧分解获得)在还原剂如三乙酰氧基硼氢化钠存在下进行还原性胺化,得到所需的胺连接基类似物(J.Org.Chem.,1996,61,3849)。另外地,根据在J.Med.Chem.,1982,25,960和J.Med.Chem.,1984,27,600中描述的程序,该胺用活化二乙基膦酰基乙酸加以乙酰化,得到所需的酰胺连接基化合物。活化的二乙基膦酰基乙酸能够通过在溶剂如二甲基甲酰胺中用偶联试剂如氰基膦酸二乙基酯和碱如二异丙基乙胺在室温下处理而获得。在下面举例说明其中X是
的特定例子。
另外地,2-(1,3-二氧代-1,3-二氢-异吲哚-2-基)-戊二酸,35.4,(市场上可买到的)在溶剂如乙腈中用三乙胺,1-羟基苯并三唑,4-甲氧基苄基胺,和1,3-双环己基碳二亚胺处理。在反应完成之后,除去溶剂和残留物由色谱分离法提纯得到所需类似物35.3,根据在J.Med.Chem.,2003,46,3793中报道的程序。
实施例36
BOC-保护的(1S)-1-(9-脱氮鸟嘌呤-9-基)-1,4-双脱氧-1,4-亚氨基-D-核糖醇,化合物36.3,是通过将(1S)-1-(9-脱氮鸟嘌呤-9-基)-1,4-双脱氧-1,4-亚氨基-D-核糖醇(WO99/19338和Evans,G.B.等人,Tetrahedron,2000,56,3053,还报道在Evans,G.B.等人,J.Med.Chem.2003,46,3412中)与BOC酸酐一起搅拌来制备,按照在Greene,T.,“Protective Groups in Organic Synthesis”,Wiley-Interscience,1999中所述。化合物,36.3,然后在溶剂如二甲基甲酰胺或四氢呋喃中用碱如氢化钠处理。当鼓泡停止时,添加三氟甲磺酸二乙基膦酰基甲基酯(根据Tetrahedron Lett.,1986,27,1477制得),在使用三氟乙酸(TFA)所进行的BOC基团的去保护之后得到所需的膦酸酯二酯36.4(它是通式25的化合物)。
实施例37
使用二-叔丁基重碳酸酯在二氯甲烷中制备受保护的化合物37.1((1R)-1-(9-脱氮次黄嘌呤-9-基)-1,2,4-三脱氧-1,4-亚氨基-D-赤戊糖醇,作为该盐酸盐制得),按照在Evans,G.B.等人,Tetrahedron,2000,56,3053中所述。5’-OH的氧化和随后消除,可得到烯糖,37.3(参见Zemlicka J.等人的程序,J.Am.Chem.Soc.,1972,94,9,3213)。硒醚化(selenoetherification)得到受保护的膦酸酯,37.4(Kim,C.等人,J.Org.Chem.,1991,56,2642)。苯基硒化物的氧化消去(按照在Kim,C.等人,J.Org.Chem.,1991,56,2642所述)和随后进行立体选择的二羟基化,可得到所需的二醇37.6。最后,保护基团被除去得到化合物37.7,属于通式26的化合物。
实施例38
(1R)-1-(9-脱氮次黄嘌呤-9-基)-1,2,4-三脱氧-1,4-亚氨基-D-赤戊糖醇(按照在Evans,G.B.等人,Tetrahedron,2000,56,3053中所述的方法作为该盐酸盐制得)首先加以保护,然后用
氧化,得到羧酸38.1。脱羧消除通过使用二甲基甲酰胺二新戊乙缩醛在二甲基甲酰胺中在高温下实现(Zemlicka J.等人,J.Am.Chem.Soc.,1972,94,9,3213)。硒醚化,随后让受保护的烯糖用高氯酸银在(羟甲基)膦酸二乙基酯(Phillion,D.等人,Tetrahedron Lett.,1986,27,1477)存在下的处理得到膦酸酯38.3(Kim,C.等人,J.Org.Chem.,1991,56,2642)。硒化物的氧化消除,和随后的使用四氧化锇的二羟基化可得到二醇38.5。根据Greene,T.,“Protective Groups in OrganicSynthesis”,Wiley-Interscience,1999的程序,胺保护基团的除去可得到化合物38.6。
实施例39
可用于制备酞胺哌啶酮的类似物的前体药物的合成方法和中间化合物在下面进行描述。
link包括1个或多个原子;优选2个或多个
按照在Bioorg.Med.Chem.Lett.,1999,9,1625中报道的程序,2-甲基-4-硝基苯甲酸甲酯(可从市场上买到)转化成3-(5-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮,39.1。这一胺中间体与二乙基膦酰基-乙醛(从烯丙基膦酸二乙基酯的臭氧分解获得)在还原剂如三乙酰氧基硼氢化钠存在下进行还原性胺化,得到所需的胺连接基类似物39.2(J.Org.Chem.,1996,61,3849)。另外地,根据在J.Med.Chem.,1982,25,960和J.Med.Chem.,1984,27,600中描述的程序,该胺用活化的二乙基膦酰基乙酸加以乙酰化,得到所需的酰胺连接基化合物39.3。活化的二乙基膦酰基乙酸能够通过在溶剂如二甲基甲酰胺中用偶联试剂如氰基膦酸二乙基酯和碱如二异丙基乙胺在室温下处理而获得。
2-甲基-3-硝基苯甲酸甲酯(市场上可买到的)在溶剂如四氯化碳中用N-溴琥珀酰亚氨基在光照下处理,得到2-溴甲基-3-硝基苯甲酸甲酯,39.4。苄基溴化物在溶剂如二甲基甲酰胺中用[2-(3-氨基-2,6-二氧代-哌啶-1-基)-乙基]-膦酸二乙酯(对于这一化合物的制备参见下面的实施例40)在碱如三乙胺存在下处理。偶联的产物然后通过氢化来还原(Bioorg.Med.Chem.Lett.,1999,9,1625),获得所需的类似物。
实施例40
按照在Bioorg.Med.Chem.Lett.,1999,9,1625中报道的程序,2-甲基-4-硝基苯甲酸甲酯39.2(可从市场上买到)转化成3-(5-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮。这一胺中间体与二乙基膦酰基-乙醛(从烯丙基膦酸二乙基酯的臭氧分解获得)在还原剂如三乙酰氧基硼氢化钠存在下进行还原性胺化,得到所需的胺连接基类似物(J.Org.Chem.,1996,61,3849)。另外地,根据在J.Med.Chem.,1982,25,960和J.Med.Chem.,1984,27,600中描述的程序,该胺用活化二乙基膦酰基乙酸加以乙酰化,得到所需的酰胺连接基化合物。活化的二乙基膦酰基乙酸能够通过在溶剂如二甲基甲酰胺中用偶联试剂如氰基膦酸二乙基酯和碱如二异丙基乙胺在室温下处理而获得。
实施例40A
2-甲基-3-硝基苯甲酸甲酯39.2(市场上可买到的)在溶剂如四氯化碳中用N-溴琥珀酰亚胺在光照下处理,得到2-溴甲基-3-硝基苯甲酸甲酯,39.4。这一苄基溴化物在溶剂如二甲基甲酰胺中用[2-(3-氨基-2,6-二氧代-哌啶-1-基)-乙基]-膦酸二乙酯(对于这一化合物的制备参见下文)在碱如三乙胺存在下处理。偶联的产物然后通过氢化来还原(Bioorg.Med.Chem.Lett.,1999,9,1625),获得所需的类似物。
根据在J.Med.Chem.,2003,46,3793中报道的程序,获得[2-(3-氨基-2,6-二氧代-哌啶-1-基)-乙基]-膦酸二乙酯,40.1。因此,苄氧基羰基保护的戊二酸在溶剂如乙腈中用三乙胺,1-羟基苯并三唑,2-氨基乙基膦酸二乙酯和1,3-二环己基碳二亚胺处理。在反应结束之后,除去溶剂和由色谱分离法提纯得到环状产物,它在钯催化下接触氢而获得所需中间体。
在最终的去保护之后,对于膦酸酯结构部分能够进行进一步的处理。这些类型的转变在这里更广泛地描述。
实施例41
Diprolene,41A(美国专利No.2,897,464),和酯41.1-41.3的结构在下面示出,其中取代基R1是
,烷基,链烯基,芳基或芳烷基。化合物41.1-41.3利用可变的连接基团(在所附结构中表示为“link”)来引入被连接到核上的膦酸酯结构部分
。
实施例42
以上显示了其中类甾醇侧链作为双-亚甲基二氧基(BMD)结构部分来保护的保护-去保护序列。化合物42.1的丙酸酯基团例如通过与两个摩尔当量的氢氧化锂在二甲氧基乙烷水溶液中在环境温度下反应进行水解,得到二醇42.2。该产物然后与仲甲醛和酸催化剂如盐酸,按照在“Protective Groups in Organic Synthesis”中由T.W.Greene和P.G.M.Wuts,Wiley,第二版1990,第223页中所述,进行反应而得到BMD衍生物42.3。膦酸酯结构部分然后通过使用如下所述的程序被引入,生产出膦酸酯42.4。在BMD保护基团的水解之前,该11-羟基得到保护。保护基团进行选择,以使得它对于BMD基团的除去所需要的条件是稳定的,和使得它是可以被除去但不影响随后引入的17,21-二酯结构部分。
例如,该11-羟基通过与4-叠氮基丁酰氯在吡啶中反应而被转化成4-叠氮基丁酸酯。该11-叠氮基丁酸酯然后通过与三苯基膦反应来从二酯42.7中除去,按照在Bull.Soc.Chem.Jpn.,1986,59,1296中所述。另外地,该11-羟基通过与2-(三-甲基-甲硅烷基)乙基碳酰氯和吡啶反应被转化成2-(三甲基甲硅烷基)乙基碳酸酯来加以保护。该2-(三-甲基-甲硅烷基)碳酸酯通过与四丁铵氟化物在四氢呋喃中在环境温度下反应来从二酯42.7中除去,按照在Tet.Lett.,1981,22,969中所述。
另外地,该11-羟基通过与三氯乙酰氯在二甲基甲酰胺-吡啶中反应被转化成三氯乙酰基酯来加以保护。该三氯乙酰基酯通过与氨乙醇溶液在环境温度下反应被除去,按照在Coll.Czech.Chem.Commun.,1962,27,2567中所述。
在受保护的产物42.5中的BMD结构部分然后水解,例如用50%乙酸水溶液处理,按照在“Protective Groups in Organic Synthesis”中由T.W.Greene和P.G.M.Wuts,Wiley,第二版1990,第223页中所述,获得二醇42.6。二醇化合物然后例如通过与丙酸和二环己基碳化二亚胺在二甲基甲酰胺中在环境温度中反应,或通过与丙酰氯和三乙胺在二氯甲烷中反应,被酰化而生产出二丙酸酯42.7。然后该11-羟基按以上所述的去保护可获得二酯42.8。
另外地,20-酮基通过与四(二乙基酰胺)钛反应作为二乙胺加合物来保护,按照在Protective Groups in Organic Synthesis,T.W.Greeneand P.G.M Wuts,Wiley,第二版1990,p.219中所述。
实施例43
以上示出了膦酸酯22.3的制备,其中膦酸酯基团借助于亚氨基或亚氨基氧基和可变的碳链来连接。在这一程序中,BMD保护的衍生物42.3与胺或羟胺43.1反应,其中R2是烷基、链烯基、环烷基或环烯基,任选地引入杂原子
、
或
,或官能团如酰胺、酯、肟、亚砜或砜等,或任选取代的芳基、杂芳基或芳烷基,任选地引入杂原子
、
或
,获得亚胺或亚胺氧基产物43.2。该反应是在等摩尔量的反应物之间在非质子传递溶剂如吡啶或二甲苯中,或在醇溶剂如乙醇中,任选在酸催化剂存在下,来进行,得到亚胺或肟。甾族3-酮的肟的制备已描述在Anal.Bioch.,1978,86,133中和在J.Mass.Spectrom.,1995,30,497中。BMD保护的化合物,43.2,然后按照以上所述方法被转化成二酯43.3。
以上显示了引入膦酸酯基团的羟胺醚的制备。在这一程序中,其中Lv是离去基团如溴或三氟甲基磺酰基氧基的膦酸酯43.4与BOC-羟胺43.5(Aldrich)反应,生产醚43.6。反应是在极性溶剂如二甲基甲酰胺或四氢呋喃中,在碱如氢氧化钾或二甲基胺基吡啶存在下进行的,得到产物43.6。然后进行去保护(例如通过用三氟乙酸处理),得到羟胺醚43.7。
实施例44
以上示出了膦酸酯的制备,其中膦酸酯通过亚氨基氧基来连接。在这一程序中,底物42.3与二烷基膦酰基甲基羟胺44.1(按照以上所述从三氟甲基-磺酰基氧基甲基膦酸二烷基酯(Tetrahedron Lett.,1986,27,1477)和BOC-羟胺制得)进行反应,在去保护和侧链酰化以后,获得肟醚44.2。该肟形成反应是在环境温度下在吡啶溶液中在等摩尔量的反应物之间进行的。
使用以上程序但代替肟醚44.1而使用不同的肟醚43.7,获得相应产物43.3。
实施例45
以上示出了利用底物42.3和按照以上所述方法从2-(5-溴-2-噻吩基)乙基溴(J.Chem.Soc.,Perkin Trans.Phys.Org.Chem.,1975,821)制得的O-2-(5-溴-2-噻吩基)乙氧基羟胺45.1之间的反应,来制备引入了亚胺氧基的膦酸酯的方法。所形成的肟醚经由去保护和侧链酰化被转化成化合物45.2,它然后在钯催化剂存在下与亚磷酸二烷基酯45.3反应,获得膦酸酯45.4。通过在芳基溴和亚磷酸二烷基酯之间的偶联反应制备芳基膦酸酯的方法已描述在J.Med.Chem.,1992,35,1371中。反应在惰性溶剂如甲苯中,在碱如三乙胺和催化量的四(三苯基膦)钯(0)存在下进行。
另外地,溴取代的产物45.2,在钯催化的Heck反应中,与丙烯基膦酸二烷基酯45.5(Acros)偶联,得到不饱和膦酸酯45.6。芳基卤化物与烯烃利用Heck反应的偶联描述在例如“Advanced OrganicChemistry”,F.A.Carey和R.J.Sundberg,Plenum,2001p.503ff中和在Acc.Chem.Res.,1979,12,146中。该芳基溴和烯烃在极性溶剂中如二甲基甲酰胺或二噁烷中,在钯(0)催化剂如四(三苯基膦)钯(0)或钯(II)催化剂如乙酸钯(II)存在下,和任选地在碱如三乙胺或碳酸钾存在下,进行偶联。
任选,在产物45.6中存在的styrenoid双键例如通过与二酰亚胺反应而被还原,得到饱和类似物45.7。烯键的还原已描述在“Comprehensive Organic Transformations”,R.C.Larock,VCH,1989,p.6ff中。该转变利用催化氢化,例如通过使用钯/碳催化剂和氢或氢给体,或通过利用二酰亚胺或乙硼烷来进行。
通过使用以上程序,但代替溴噻吩基试剂45.1使用不同的溴取代的芳基或杂芳基烷氧基羟胺,和/或不同的链烯基膦酸二烷基酯,获得了与化合物45.4、45.6和45.7类似的产物。
实施例46
以上示出了膦酸酯的制备,其中膦酸酯通过亚氨基来连接。在这一程序中,底物42.3与2-氨基苯基膦酸二烷基酯46.1(Aurora)反应,在去保护和侧链酰化后获得亚胺产物46.2。反应在烃溶剂如甲苯或二甲苯中,在回流温度下,在碱性催化剂如甲醇钠或酸催化剂如甲苯磺酸存在下,在共沸条件下进行,得到产物46.2。
通过使用以上程序,但代替2-氨基-苯基膦酸酯46.1使用不同的氨基取代的芳基或杂芳基膦酸酯,获得与46.2类似的产物。
实施例47
以上示出了膦酸酯的制备的另一种方法,其中膦酸酯通过肟基来连接。在这一程序中,该二烯酮42.3与O-(羧基甲基)-羟胺47.1(Interchim)反应,在去保护和侧链酰化后,获得肟47.2。甾族1,4-二烯-3-酮与羟胺的反应已描述在J.Steroid Bioch.,1976,7,795。反应是在等摩尔量的反应物之间在极性有机溶剂如吡啶或甲醇中,任选在乙酸或乙酸钠存在下进行。该肟47.2然后与3-羟苯基膦酸二烷基酯47.3(Epsilon),按Mitsonobu反应方式进行反应,得到取代的肟47.4。利用Mitsonobu反应制备芳族醚和硫醚的方法例如描述在“Comprehensive Organic Transformations”,R.C.Larock,VCH,1989,448页中,和在“Advanced Organic Chemistry”,部分B,F.A.Carey和R.J.Sundberg,Plenum,2001,153-4页中和在Org.React.,1992,42,335中。该酚和羟基或巯基组分一起在非质子传递溶剂例如四氢呋喃中,在偶氮二羧酸二烷基酯和三芳基膦存在下反应,获得醚或硫醚产物。该程序也描述在Org.React.,1992,42,335-656中。该产物47.4然后通过去保护和酰化被转变成二酯47.5。
通过使用以上程序,但代替膦酸酯47.3使用不同的二烷基羟基-取代的芳基或杂芳基膦酸酯,获得与47.5类似的产物。
实施例48
以上示出了其中膦酸酯基团借助于芳族或杂芳族基团、杂原子和可变的碳链连接于吡唑环的1’或2’位上的膦酸酯的制备。在这一程序中,Diprolene 41A被还原,获得1,2-二氢产物48.1。该催化氢化反应通过三(三苯基膦)铑(I)氯化物的使用来进行,例如按照在J.Med.Chem.,2001,44,602中所述。该产物然后与甲酸乙酯和碱如氢化钠,在惰性溶剂如甲苯或二甲基甲酰胺中进行反应,按照在澳大利亚专利申请275950409中所述,获得2-甲酰基产物48.2。
任选地,底物41A例如按照以上在实施例42中所述的方法被保护,在按照在J.Am.Chem.Soc.,1964,86,1520中所述的甲酰化反应之前。2-甲酰基产物然后与芳基或杂芳基肼48.3反应,其中取代基X是膦酸酯基团或可以随后转变成含膦酸酯的取代基的一种基团。例如,X是二烷基膦酰基,溴,羟基,氨基,羧基等等。反应得到异构体2’-和1’-芳基吡唑,48.4和48.5。环形成反应是在等摩尔量的反应物之间在酸性溶剂如乙酸中进行,按照在J.Am.Chem.Soc.,1964,86,1520中所述。吡唑类48.4和48.5然后例如由实施例49-50中描述的程序分别转变成膦酸酯48.6和48.7。
实施例49
以上示出了膦酸酯的制备,其中膦酸酯通过苯基来连接。在这一序列中,酮醛48.2按以上所述与2-溴苯基-肼49.1(Fluka)反应,得到异构的吡唑产物49.2和49.3。产物然后,按照在这里所述的方法,与亚磷酸二烷基酯
和钯催化剂反应,分别获得膦酸酯49.4和49.5。通过使用以上程序,但代替2-溴苯肼,使用不同的溴芳基或溴杂芳基肼48.3,获得产物48.6和48.7。
实施例50
以上示出了膦酸酯类的制备,其中膦酸酯基团借助于芳族或杂芳族基团以及饱和或不饱和的烷基链来连接。在这一程序中,溴苯基取代的吡唑49.2,在Heck反应中,如上所述,与例如丁烯基膦酸二烷基酯50.1偶联,(Org.Lett.,2001,3,217)得到不饱和膦酸酯产物50.2。任选地,该产物被还原,如上所述,得到饱和的类似物50.3。以上程序对于异构的溴苯基吡唑49.3的应用可获得50.2和50.3的异构产物。通过使用以上程序,但代替膦酸酯50.1使用不同的链烯基膦酸二烷基酯和/或不同的溴芳基或杂芳基吡唑48.4或48.5,获得与50.2和50.3类似的产物。
实施例51
以上描述了膦酸酯51.5和51.6的制备,其中膦酸酯基团借助于芳基或杂芳基和烷氧基链来连接。在这一程序中,4-氨基苯硫酚51.1在二甲基甲酰胺溶液中在环境温度下与三氟甲磺酰基氧基甲基膦酸二烷基酯51.2(Tetrahedron Lett.,1986,27,1477)和碳酸钾进行反应,得到硫醚51.3。该产物然后利用在含水的盐酸乙醇溶液中的重氮化反应,随后该氯化重氮物用氯化锡(II)的还原作用,被转化成相应的肼51.4,按照在J.Med.Chem.,2001,44,4031中所述。肼然后,按以上所述,与酮醛48.2反应,形成异构的吡唑51.5和51.6。
通过使用以上程序,但代替该三氟甲磺酸酯51.2,使用不同的二烷基膦酰基烷基溴化物或三氟甲磺酸酯,和/或不同的芳族或杂芳族巯基或羟氨,获得与51.5和51.6类似的产物。
实施例52
以上示出了膦酸酯的制备,其中膦酸酯基团借助于吡啶基、杂原子和可变的碳链来连接。在这一程序中,3-氨基-5-羟基吡啶52.1通过与乙酸酐反应,被转化成双乙酰基类似物52.2。该产物然后通过重氮化和还原,如上所述,被转化成肼52.3。该肼52.3然后与酮醛48.2反应,得到异构的吡唑52.4和52.5。该2’-吡啶基产物52.4按照Mitsonobu反应的方式,如上所述,与羟乙基膦酸二烷基酯52.6(Zh.Obschei.Khim.,1973,43,2364)反应,获得醚52.7。这一程序对于异构的酚52.5的应用可获得化合物52.7的异构化产物。
另外地,该异构的酚52.5在二甲基甲酰胺溶液中在大约80℃下与一摩尔当量的溴丙炔基膦酸二烷基酯52.8(Bioorg.Med.Chem.Lett.,1994,4,273)和碳酸铯进行反应,制备膦酸酯52.9。这一程序对于异构的酚52.4的应用可获得化合物52.4的异构化产物。通过使用以上程序,但代替该甲醇52.6,或该溴化物52.8,使用不同的硫醇、醇类或溴化物,和/或不同的酚48.4或48.5,其中X是
,获得与52.7和52.9类似的相应产物。
实施例53
以上示出了其中膦酸酯基团利用可变的碳连接链来连接的膦酸酯的制备。在这一程序中,该酮醛48.2与肼反应,获得吡唑衍生物53.1。甾族2-甲酰基-3-酮与肼的反应已描述在J.Am.Chem.Soc,1964,86,1520中。反应是在乙酸中在环境温度下进行的。所形成的吡唑然后与溴甲基膦酸二烷基酯53.2(其中R2如上所定义)反应,分别生产出异构的2’和1’烷基化产物,53.3和53.4。取代的吡唑的烷基化例如描述在“Heterocyclic Chemistry”,T.L.Gilchrist,Longman,1992,第309页。
实施例54
反应历程54A
吡唑53.1,在二甲基甲酰胺溶液中在大约90℃下,与溴丙基膦酸二烷基酯,54.1(Aldrich),和碱如二甲基氨基吡啶或六甲基二硅氮化锂进行反应,得到异构的烷基化产物54.2和54.3。
如反应历程54A中所示,吡唑53.1在二甲基甲酰胺溶液中在环境温度下与一摩尔当量的1,4-二溴丁-2-炔54.4(Narchem)和碳酸钾反应,获得烷基化产物54.5和54.6。该产物然后在120℃下与亚磷酸三烷基酯在阿尔布佐夫反应中进行加热,得到膦酸酯54.7和54.8。阿尔布佐夫反应已描述在Handb.Organophosphorus Chem.,1992,115-72中。通过使用以上程序,但代替二溴化物54.4使用不同的烷基、链烯基或炔基二溴化物,获得与54.7和54.8类似的产物。
实施例55
下面给出了Aclometasone二丙酸酯,55/A(J.Med.Chem.,1980,23,430;美国专利No.4,124,707),和酯55A-55A的结构,其中该取代基R1是
,烷基,链烯基,芳基或芳烷基。化合物55A-55C利用可变的连接基团(在所附结构中表示为“link”)来引入被连接到核上的膦酸酯结构部分
。
反应历程55A
按照在反应历程55A中所述,类甾醇侧链是作为双亚甲基二氧基(BMD)结构部分来保护的。在这一序列中,丙酸酯例如通过与两个摩尔当量的氢氧化锂在二甲氧基乙烷水溶液中在环境温度下反应进行水解,得到二醇55.1。该产物然后与仲甲醛和酸催化剂如盐酸,按照在“Protective Groups in Organic Synthesis”中由T.W.Greene和P.G.M.Wuts,Wiley,第二版1990,第223页中所述,进行反应而得到BMD衍生物55.2。膦酸酯结构部分然后通过使用如下所述的程序被引入,生产出膦酸酯55.3。在BMD保护基团的水解之前,该11-羟基得到保护。保护基团进行选择,以使得它对于BMD基团的除去所需要的条件是稳定的,和使得它是可以被除去但不影响随后引入的17,21-二酯结构部分。例如,该11-羟基通过与4-叠氮基丁酰氯在吡啶中反应而被转化成4-叠氮基丁酸酯。该11-叠氮基丁酸酯然后通过与三苯基膦反应来从二酯55.6中除去,按照在Bull.Soc.Chem.Jpn.,1986,59,1296中所述。另外地,该11-羟基通过与2-(三-甲基-甲硅烷基)乙基碳酰氯和吡啶反应被转化成2-(三甲基甲硅烷基)乙基碳酸酯来加以保护。该2-(三-甲基-甲硅烷基)碳酸酯通过与四丁铵氟化物在四氢呋喃中在环境温度下反应来从二酯55.6中除去,按照在Tet.Lett.,1981,22,969中所述。
另外地,该11-羟基通过与三氯乙酰氯在二甲基甲酰胺-吡啶中反应被转化成三氯乙酰基酯来加以保护。该三氯乙酰基酯通过与氨乙醇溶液在环境温度下反应被除去,按照在Coll.Czech.Chem.Commun.,1962,27,2567中所述。在受保护的产物55.4中的BMD结构部分然后水解,例如用50%乙酸水溶液处理,按照在“Protective Groups in Organic Synthesis”中由T.W.Greene和P.G.M.Wuts,Wiley,第二版1990,第223页中所述,获得二醇55.5。二醇55.5然后例如通过与丙酸和二环己基碳化二亚胺在二甲基甲酰胺中在环境温度中反应,或通过与丙酰氯和三乙胺在二氯甲烷中反应,被酰化而生产出二丙酸酯55.6。然后该11-羟基按以上所述的方法的去保护可获得二酯55.7。
另外地,20-酮基通过与四(二乙基酰胺)钛反应作为二乙胺加合物来保护,按照在“Protective Groups in Organic Synthesis”,T.W.Greene and P.G.M Wuts,Wiley,第二版1990,p.219中所述。
实施例56
以上示出了膦酸酯22.3的制备,其中膦酸酯基团借助于亚氨基或亚氨基氧基和可变的碳链来连接。在这一程序中,BMD保护的衍生物55.2与胺或羟胺56.1反应,其中R2是烷基、链烯基、环烷基或环烯基,任选地引入杂原子
、
或
,或官能团如酰胺、酯、肟、亚砜或砜等,或任选取代的芳基、杂芳基或芳烷基,任选地引入杂原子
、
或
,获得亚胺或亚胺氧基产物56.2。该反应是在等摩尔量的反应物之间在非质子传递溶剂如吡啶或二甲苯中,或在醇溶剂如乙醇中,任选在酸催化剂存在下,来进行,得到亚胺或肟。甾族3-酮的肟的制备已描述在Anal.Bioch.,1978,86,133中和在J.Mass.Spectrom.,1995,30,497中。该BMD保护的侧链化合物,56.2,然后转化成二酯56.3。
实施例56A
也显示的是引入膦酸酯基团的羟胺醚的制备。其中Lv是离去基团如溴或三氟甲基磺酰基氧基的膦酸酯56.4与BOC-羟胺56.5(Aldrich)反应,生产醚56.6。反应是在等摩尔量的反应物之间在极性溶剂如二甲基甲酰胺或四氢呋喃中,在碱如氢氧化钾或二甲基胺基吡啶存在下进行,得到产物56.6。然后进行去保护(例如通过用三氟乙酸处理),得到羟胺醚56.7。
实施例56B
以上示出了膦酸酯的制备,其中膦酸酯通过亚氨基氧基来连接。在这一程序中,底物55.2与二烷基膦酰基甲基羟胺56.1(按照以上所述从三氟甲基-磺酰基氧基甲基膦酸二烷基酯(Tetrahedron Lett.,1986,27,1477)和BOC-羟胺制得)进行反应,在去保护和侧链酰化以后,获得肟醚56.2。该肟形成反应是在环境温度下在吡啶溶液中在等摩尔量的反应物之间进行的。
使用以上程序但代替肟醚56.1而使用不同的肟醚56.7,获得相应产物56.2。
实施例57
以上示出了利用底物55.2和按照以上所述方法从化合物55.1和2-(3-溴苯基)乙基溴分别制得的O-2-(3-溴-苯基)乙基羟胺57.1之间的反应,来制备引入了亚胺氧基的膦酸酯的方法。所形成的肟醚经由去保护和侧链酰化被转化成化合物57.2,它然后在钯催化剂存在下与亚磷酸二烷基酯57.3反应,获得膦酸酯57.4。通过在芳基溴和二烷基亚磷酸酯之间的偶联反应制备芳基膦酸酯的方法已描述在J.Med.Chem.,1992,35,1371中。反应在惰性溶剂如甲苯中,在碱如三乙胺和催化量的四(三苯基膦)钯(0)存在下进行。
另外地,溴取代的产物57.2,在钯催化的Heck反应中,与乙烯基膦酸二烷基酯57.5(Aldrich)偶联,得到不饱和膦酸酯57.6。芳基卤化物与烯烃利用Heck反应的偶联描述在例如“Advanced OrganicChemistry”,F.A.Carey和R.J.Sundberg,Plenum,2001p.503ff中和在Acc.Chem.Res.,1979,12,146中。该芳基溴和烯烃在极性溶剂中如二甲基甲酰胺或二噁烷中,在钯(0)催化剂如四(三苯基膦)钯(0)或钯(II)催化剂如乙酸钯(II)存在下,和任选地在碱如三乙胺或碳酸钾存在下,进行偶联。任选,在产物57.6中存在的styrenoid双键例如通过与二酰亚胺反应而被还原,得到饱和类似物57.7。烯键的还原已描述在“Comprehensive Organic Transformations”,R.C.Larock,VCH,1989,p.6ff中。该转变利用催化氢化,例如通过使用钯/碳催化剂和氢或氢给体,或通过利用二酰亚胺或乙硼烷来进行。
通过使用以上程序,但代替溴苯基试剂57.1使用不同的溴取代的芳基或杂芳基烷氧基羟胺,和/或不同的链烯基膦酸二烷基酯,获得了与化合物57.4、57.6和57.7类似的产物。
实施例58
以上示出了膦酸酯的制备,其中膦酸酯通过亚氨基来连接。在这一程序中,底物55.2与3-氨基苯基膦酸二烷基酯58.1(J.Med.Chem.,1984,27,654)反应,在去保护和侧链酰化后获得亚胺产物58.2。反应在烃溶剂如甲苯或二甲苯中,在回流温度下,在碱性催化剂如甲醇钠或酸催化剂如甲苯磺酸存在下,在共沸条件下进行,得到产物58.2。
通过使用以上程序,但代替3-氨基苯基膦酸酯58.1,使用不同的氨基取代的芳基或杂芳基膦酸酯,获得与58.2类似的产物。
以上示出了从二烯酮55.2开始,制备膦酸酯58.3的另一种方法,其中膦酸酯通过肟基来连接。该二烯酮与羟胺反应,在去保护和侧链酰化后,得到肟58.3。甾族1,4-二烯-3-酮与羟胺的反应已描述在J.Steroid Bioch.,1976,7,795中;反应是在等摩尔量的反应物之间在极性有机溶剂如吡啶或甲醇中,任选在乙酸或乙酸钠存在下进行。该肟然后与3-羟苯基膦酸二烷基酯58.4(Epsilon),按Mitsonobu反应方式进行反应,得到取代的肟58.5。利用Mitsonobu反应制备芳族醚和硫醚的方法例如描述在“Comprehensive Organic Transformations”,R.C.Larock,VCH,1989,448页中,和在“Advanced OrganicChemistry”,部分B,F.A.Carey和R.J.Sundberg,Plenum,2001,153-4页中和在Org.React.,1992,42,335中。该酚和羟基或巯基组分一起在非质子传递溶剂例如四氢呋喃中,在偶氮二羧酸二烷基酯和三芳基膦存在下反应,获得醚或硫醚产物。该程序也描述在Org.React.,1992,42,335-656中。
通过使用以上程序,但代替膦酸酯58.4使用不同的二烷基羟基-取代的芳基或杂芳基膦酸酯,获得与58.5类似的产物。
实施例59
以上显示了其中膦酸酯基团借助于芳族或杂芳族基团、杂原子和可变的碳链连接于吡唑环的1’或2’位上的膦酸酯的制备。在这一程序中,Aclometasone二丙酸酯59A被还原,获得1,2-二氢产物59.1。该催化氢化反应通过三(三苯基膦)铑(I)氯化物的使用来进行,例如按照在J.Med.Chem.,2001,44,602中所述。该产物然后与甲酸乙酯和碱如氢化钠,在惰性溶剂如甲苯或二甲基甲酰胺中进行反应,按照在澳大利亚专利申请275950409中所述,获得2-甲酰基产物59.2。任选地,底物59A例如按照以上在实施例55中所述的方法被保护,在按照在J.Am.Chem.Soc.,1964,86,1520中所述的甲酰化反应之前。2-甲酰基产物然后与芳基或杂芳基肼59.3反应,其中取代基X是膦酸酯基团或可以随后转变成含膦酸酯的取代基的一种基团。例如,X是二烷基膦酰基,溴,羟基,氨基,羧基等等。反应得到异构体2’-和1’-芳基吡唑,59.4和59.5。环形成反应是在等摩尔量的反应物之间在酸性溶剂如乙酸中进行,按照在J.Am.Chem.Soc.,1964,86,1520中所述。吡唑类59.4和59.5然后例如由实施例60-65中描述的程序分别转变成膦酸酯59.6和59.7。
实施例60
以上示出了膦酸酯的制备,其中膦酸酯通过苯基来连接。在这一序列中,酮醛59.2按以上所述与3-溴-苯基-肼60.1(Fluka)反应,得到异构的吡唑产物60.2和60.3。产物然后,按照以上所述的方法,与亚磷酸二烷基酯
和钯催化剂反应,分别获得膦酸酯60.4和60.5。
通过使用以上程序,但代替3-溴苯肼,使用不同的溴芳基或溴杂芳基肼59.3,获得相应产物59.6和59.7。
实施例60A
以上示出了膦酸酯类的制备,其中膦酸酯基团借助于芳族或杂芳族基团以及饱和或不饱和的烷基链来连接。在这一程序中,溴苯基取代的吡唑60.2,在Heck反应中,如上所述,与例如乙烯基膦酸二烷基酯60.6(Aldrich)偶联,得到不饱和膦酸酯产物60.7。任选地,该产物被还原,如上所述,得到饱和的类似物60.8。以上程序对于异构的溴苯基吡唑60.3的应用可获得60.7和60.8的异构产物。
通过使用以上程序,但代替膦酸酯60.6使用不同的链烯基膦酸二烷基酯和/或不同的溴芳基或杂芳基吡唑59.4或59.5(X=
),获得与60.7和60.8类似的产物。
实施例61
以上描述了膦酸酯的制备,其中膦酸酯基团借助于芳基或杂芳基和烷氧基链来连接。在这一程序中,4-氨基苯酚61.1在二甲基甲酰胺溶液中在环境温度下与三氟甲磺酰基氧基甲基膦酸二烷基酯61.2(Tetrahedron Lett.,1986,27,1477)和碳酸钾进行反应,得到醚61.3。该产物然后利用在含水的盐酸乙醇溶液中的重氮化反应,随后该氯化重氮物用氯化锡(II)的还原作用,被转化成相应的肼61.4,按照在J.Med.Chem.,2001,44,4031中所述。肼然后,按以上所述,与酮醛59.2反应,形成异构的吡唑61.5和61.6。
通过使用以上程序,但代替该三氟甲磺酸酯61.2,使用不同的二烷基膦酰基烷基溴化物或三氟甲磺酸酯,和/或不同的芳族或杂芳族羟胺,获得与61.5和61.6类似的产物。
实施例62
在这里显示了膦酸酯的制备,其中膦酸酯基团借助于吡啶基、杂原子和可变的碳链来连接。在这一程序中,3-氨基-5-羟基吡啶62.1通过与乙酸酐反应,被转化成双乙酰基类似物62.2。该产物然后通过重氮化和还原,如上所述,被转化成肼62.3。
该肼62.3然后与酮醛59.2反应,得到异构的吡唑62.4和62.5。该2,-吡啶基产物62.4按照Mitsonobu反应的方式,如上所述,与巯基乙基膦酸二烷基酯62.6(Zh.Obschei.Khim.,1973,43,2364)反应,获得硫醚62.7。这一程序对于异构的酚62.5的应用可获得化合物62.7的异构化产物。
另外地,该异构的酚62.5在二甲基甲酰胺溶液中在大约80℃下与一摩尔当量的溴丁烯基膦酸二烷基酯62.8(J.Med.Chem.,1992,35,1371)和碳酸铯进行反应,制备膦酸酯62.9。这一程序对于异构的酚62.4的应用可获得化合物62.9的异构化产物。
通过使用以上程序,但代替该硫醇62.6,或溴化物62.8,使用不同的硫醇、醇类或溴化物,和/或不同的酚59.4或59.5,其中X是
,获得与62.7和62.9类似的相应产物。
实施例63
以上示出了其中膦酸酯基团利用可变的碳连接链来连接的膦酸酯的制备。在这一程序中,该酮醛59.2与肼反应,获得吡唑衍生物63.1。甾族2-甲酰基-3-酮与肼的反应已描述在J.Am.Chem.Soc,1964,86,1520中。反应是在乙酸中在环境温度下进行的。所形成的吡唑然后与溴甲基膦酸二烷基酯63.2(其中R2如上所定义)反应,分别生产出异构的2’和1’烷基化产物,63.3和63.4。取代的吡唑的烷基化例如描述在“Heterocyclic Chemistry”,T.L.Gilchrist,Longman,1992,第309页。
实施例64
吡唑63.1,在二甲基甲酰胺溶液中在大约90℃下,与溴丙基膦酸二烷基酯,64.1(Aldrich),和碱如二甲基氨基吡啶或六甲基二硅氮化锂进行反应,得到异构的烷基化产物64.2和64.3。
实施例65
吡唑63.1,如上所述,与4-溴甲基苄基膦酸二烷基酯65.1(Tet.,1998,54,9341)进行反应,得到产物65.2和65.3。
实施例66
氢化可的松66A(美国专利No.2,602,769),和膦酸酯类的结构在下面示出,其中取代基R1是
,烷基,链烯基,芳基或芳烷基。这些化合物利用可变的连接基团(在所附的结构中表示为“link”)来引入被连接到核上的膦酸酯结构部分
。下面显示了其中类甾醇侧链作为双-亚甲基二氧基(BMD)结构部分来保护的一般的保护-去保护序列。
氢化可的松66A与仲甲醛和酸催化剂如盐酸,按照在“ProtectiveGroups in Organic Synthesis”中由T.W.Greene和P.G.M.Wuts,Wiley,第二版1990,第223页中所述,进行反应而得到BMD衍生物66.1。膦酸酯结构部分然后通过使用如下所述的程序被引入,生产出膦酸酯66.2。BMD结构部分然后水解,例如用50%乙酸水溶液处理,按照在“Protective Groups in Organic Synthesis”中由T.W.Greene和P.G.M.Wuts,Wiley,第二版1990,第223页中所述,获得三醇66.3。
实施例66A
BMD保护的衍生物66.1与胺或羟胺66.4反应,其中R2是烷基、链烯基、环烷基或环烯基,任选地引入杂原子
、
或
,或官能团如酰胺、酯、肟、亚砜或砜等,或任选取代的芳基、杂芳基或芳烷基,任选地引入杂原子
、
或
,和X是膦酸酯基团或随后被转化成含膦酸酯的取代基的一种基团。例如,X是二烷基膦酰基,溴,羟基,氨基,羧基等等。该反应是在等摩尔量的反应物之间在非质子传递溶剂如吡啶或二甲苯中,或在醇溶剂如乙醇中,任选在酸催化剂存在下,来进行,得到亚胺或肟66.5。甾族3-酮的肟的制备已描述在Anal.Bioch.,1978,86,133中和在J.Mass.Spectrom.,1995,30,497中。对于X不是二烷基膦酰基的情况,该取代基X通过使用下面所述的方法被转化成含膦酸酯的取代基;该BMD保护的侧链然后被除去而获得三醇66.6。
实施例66B
以上示出了引入膦酸酯基团的羟胺醚的制备。在这一程序中,其中Lv是离去基团如溴或三氟甲基磺酰基氧基的膦酸酯66.7与BOC-羟胺66.8(Aldrich)反应,生产醚66.9。反应是在等摩尔量的反应物之间在极性溶剂如二甲基甲酰胺或四氢呋喃中,在碱如氢氧化钾或二甲基胺基吡啶存在下进行。然后进行去保护(例如通过用三氟乙酸处理),得到羟胺醚66.10。
实施例67
底物66.1与二烷基膦酰基甲基羟胺67.1(按照以上所述从三氟甲基-磺酰基氧基甲基膦酸二烷基酯(Tetrahedron Lett.,1986,27,1477)和BOC-羟胺制得)进行反应,获得肟67.2,它在去保护后获得三醇67.3。该肟形成反应是在环境温度下在乙醇-乙酸溶液中在等摩尔量的反应物之间进行的。使用以上程序但代替羟胺醚67.1而使用不同的肟醚66.10,获得相应产物66.6。
实施例68
以上示出了其中膦酸酯基团通过苯基乙氧基来连接的化合物的制备。在这一程序中,烯酮66.1,如上所述,与如上所述从2-(3-溴苯基)乙基溴(法国专利FR 1,481,052)制得的O-(3-溴-苯基)-乙基羟胺,68.1,进行反应,在侧链的去保护后,得到肟68.2。该产物然后在钯催化剂存在下与亚磷酸二烷基酯68.3反应,获得该膦酸酯68.4。通过在芳基溴和二烷基亚磷酸酯之间的偶联反应制备芳基膦酸酯的方法已描述在J.Med.Chem.,1992,35,1371中。反应典型地被在惰性溶剂如甲苯中,在碱如三乙胺和催化量的四(三苯基膦)钯(0)存在下进行。
实施例68A
另外地,溴化合物68.2与乙烯基膦酸二烷基酯68.5(Aldrich)偶联,获得膦酸酯68.6。芳基卤化物与烯烃利用Heck反应的偶联描述在例如“Advanced Organic Chemistry”,F.A.Carey和R.J.Sundberg,Plenum,2001p.503ff中和在Acc.Chem.Res.,1979,12,146中。
该芳基溴和烯烃在极性溶剂中如二甲基甲酰胺或二噁烷中,在巴(0)催化剂如四(三苯基膦)钯(0)或钯(II)催化剂如乙酸钯(II)存在下,和任选地在碱如三乙胺或碳酸钾存在下,进行偶联。任选,在产物68.6中存在的styrenoid双键例如通过与二酰亚胺反应而被还原,得到饱和类似物68.7。烯键的还原已描述在“Comprehensive OrganicTransformations”,R.C.Larock,VCH,1989,p.6ff中。该转变利用催化氢化,例如通过使用钯/碳催化剂和氢或氢给体,或通过利用二酰亚胺或乙硼烷来进行。
通过使用以上程序,但代替溴苯基乙氧基试剂68.1使用不同的溴取代的芳基或杂芳基烷氧基羟胺,和/或不同的链烯基膦酸二烷基酯,获得了与化合物68.4、68.6和68.7类似的产物。
实施例69
该烯酮66.1与O-(2-氨基乙基)羟胺,69.1,(Pol.J.Chem.,1981,55,1163)进行反应,得到肟69.2。甾族1,4-二烯-3-酮与取代的羟胺的反应已描述在J.Steroid Bioch.,1976,7,795。反应是在等摩尔量的反应物之间在极性有机溶剂如吡啶或甲醇中,任选在乙酸或乙酸钠存在下进行。该肟然后与4-羧基苯基膦酸二烷基酯69.3(Epsilon)偶联,得到酰胺肟69.4。从羧酸类和衍生物制备酰胺的方法例如描述在“Organic Functional Group Preparations”,S.R.Sandler和W.Karo,Academic Press,1968,第274页,和“Comprehensive OrganicTransformations”,R.C.Larock,VCH,1989,p.972ff中。该羧酸与该胺在活化剂例如二环己基碳二亚胺或二异丙基碳二亚胺存在下,任选地在例如羟基苯并三唑、N-羟基-琥珀酰亚胺或N-羟基吡啶酮存在下,在非质子溶剂如吡啶、DMF或二氯甲烷中进行反应,获得酰胺。
另外地,该羧酸(例如4-羧基苯基膦酸二烷基酯69.3)可以首先转化成活化的衍生物如酰氯、酸酐、混合酸酐、咪唑化物(imidazolide)等,然后与胺在有机碱例如吡啶存在下反应,获得该酰胺。羧酸转化成相应的酰氯的过程可通过用试剂例如亚硫酰氯或草酰氯在惰性有机溶剂如二氯甲烷中,任选在催化量二甲基甲酰胺存在下处理羧酸来进行的。该酰胺产物,69.4,按照在这里所述的方法,被转化成三醇69.5。
通过使用以上程序,但代替羟胺69.1使用不同的氨基取代的羟胺和/或不同的羧基取代的膦酸酯,获得与69.5类似的产物。
实施例70
以上示出了其中膦酸酯基团借助于可变的碳链连接于吡唑环的1’或2’位上的膦酸酯的制备。在这一程序中,BMD保护的烯酮66.1与甲酸乙酯和碱如氢化钠,在惰性溶剂如甲苯或二甲基甲酰胺中进行反应,按照在J.Am.Chem.Soc.,1964,86,1520中所述,获得2-甲酰基产物70.1。这一化合物然后与烷基、芳烷基、芳基或杂芳基肼70.2进行反应,其中R2是烷基、芳烷基、芳基或杂芳基,和其中取代基X是膦酸酯基团或可以随后被转化成含膦酸酯的取代基的一种基团。例如,X是二烷基膦酰基,溴,羟基,氨基,羧基等等。反应得到异构体2’-和1’-芳基吡唑,70.3和70.4。该吡唑形成反应是在等摩尔量的反应物之间在酸性溶剂如乙酸中进行,按照在J.Am.Chem.Soc.,1964,86,1520中所述。吡唑类70.3和70.4然后,例如通过使用在这里描述的程序,经由BMD保护的中间体70.5和70.6,被转变成膦酸酯70.7和70.8。
实施例71
以上示出了其中膦酸酯结构部分利用苯基环和酰胺键来连接的膦酸酯类的制备。在这一程序中,该酮醛70.1与3-甲氧基羰基-苯基-肼,71.1(Apin)进行反应,得到吡唑类71.2和71.3。该2’-取代的异构体,71.2,然后与一摩尔当量的氢氧化锂在二甲氧基乙烷水溶液中进行反应,生产出羧酸71.4。该酸然后,如上所述,与氨基甲基膦酸二烷基酯,71.5,(Interchim)偶联,得到酰胺71.6,它在去保护后获得三醇71.7。
另外地,该1’-取代的吡唑71.3,如上所述,水解成羧酸71.8。该产物然后与3-氨基苯基膦酸二烷基酯71.9(J.Med.Chem.,1984,27,654)偶联,在去保护之后获得三醇酰胺71.10。
通过使用以上程序,但代替甲氧基羰基-苯基肼71.1,使用不同的甲氧基羰基取代的芳烷基、芳基或杂芳基烷氧基肼,和/或不同的氨基取代的膦酸二烷基酯,获得了与化合物71.7和71.10类似的产物。
实施例72
72.6X=
72.7X=
以上示出了其中膦酸酯基团利用可变的碳键来连接的膦酸酯的制备。在这一程序中,该酮醛70.1,如上所述,与4-溴苯肼72.1(J.Organomet.Chem.,1999,62,581)进行反应,生产出吡唑72.2和73.3。1’-取代的异构体72.2,按照在这里所述,在钯催化剂存在下,与丁烯基膦酸二烷基酯72.4(Org.Lett.,2001,3,217)进行反应,得到膦酸酯72.5。该产物然后被去保护而获得三醇72.6。任选,在产物72.6中存在的styrenoid双键,如上所述,被还原而得到饱和的类似物72.7。
另外地,该2’-取代的吡唑72.3,在钯催化剂存在下,与亚磷酸二烷基酯偶联,制备膦酸酯72.8,它在去保护之后得到三醇72.9。通过在芳基溴和二烷基亚磷酸酯之间的偶联反应制备芳基膦酸酯的方法已描述在J.Med.Chem.,1992,35,1371中。这一反应在惰性溶剂如甲苯中,在碱如三乙胺和催化量的四(三苯基膦)钯(0)存在下进行。
通过使用以上程序,但代替溴苯肼72.1,使用不同的溴取代的芳烷基、芳基或杂芳基烷氧基肼,和/或不同的链烯基膦酸二烷基酯,获得了与化合物72.6、72.7和72.9类似的产物。
实施例73
以上示出了其中膦酸酯基团利用可变的碳键来连接的膦酸酯的制备。在这一程序中,该酮醛70.1与肼反应,获得吡唑衍生物73.1。甾族2-甲酰基-3-酮与肼的反应已描述在J.Am.Chem.Soc,1964,86,1520中。该反应在乙醇中在回流温度下进行。该吡唑产物然后与其中R2和X如上所定义的溴甲基化合物73.2进行反应,得到烷基化产物73.3和73.4。取代的吡唑的烷基化例如描述在“HeterocyclicChemistry”,T.L.Gilchrist,Longman,1992,第309页。
反应在等摩尔量的底物之间在极性溶剂如二甲基甲酰胺或四氢呋喃中,在碱如二甲基氨基吡啶、六甲基二硅氮化锂(lithiumhexamethyldisilazide)等存在下进行的。该产物73.3和73.4通过使用这里所述的程序被转化成膦酸酯73.5和73.6,只是X是二烷基-膦酰基的情况除外。去保护之后获得三醇73.7和73.8。
实施例74
该吡唑73.1,如上所述,与一摩尔当量的4-(溴甲基)苯基膦酸二烷基酯,74.1(WO 2003/042150)进行反应,得到烷基化吡唑74.2和74.3。去保护之后得到三醇74.4和74.5。
实施例75
该吡唑73.1,如上所述,与2,5-双(溴-甲基)-噻吩,75.1(Tet.,1999,55,4709)进行反应,得到吡唑75.2和75.3。该产物进行阿尔布佐夫(Arbuzov)反应,其中溴甲基取代基通过与亚磷酸三烷基酯在120℃下反应被转化成二烷基膦酰基甲基取代基,在侧链的去保护之后制备出膦酸酯75.4和75.5。阿尔布佐夫反应已描述在Handb.Organophosphorus Chem.,1992,115-72中。在该程序中,底物在60℃到约160℃下与五倍到五十倍摩尔过量的亚磷酸三烷基酯一起加热。
通过使用以上程序,但代替二溴化物75.1使用不同的二溴化物,获得与75.4和75.5类似的产物。
实施例76
通过下面的程序来制备其中取代基R1是
,烷基,链烯基,芳基或芳烷基的地塞米松76A(美国专利No.3,007,923)类似物。化合物76.1-76.3利用可变的连接基团(在所附结构中表示为“link”)来引入被连接到核上的膦酸酯结构部分
。
反应历程M1
地塞米松76A与仲甲醛和酸催化剂如盐酸,按照在“ProtectiveGroups in Organic Synthesis”中由T.W.Greene和P.G.M.Wuts,Wiley,第二版1990,第223页中所述,进行反应而得到BMD衍生物76.1。膦酸酯结构部分然后通过使用如下所述的程序被引入,生产出膦酸酯76.2。BMD结构部分然后水解,例如用50%乙酸水溶液处理,按照在“Protective Groups in Organic Synthesis”中由T.W.Greene和P.G.M.Wuts,Wiley,第二版1990,第223页中所述,获得三醇76.3。
实施例77
以上示出了膦酸酯22.3的制备,其中膦酸酯基团借助于亚氨基或亚氨基氧基和可变的碳链来连接。在这一程序中,BMD保护的衍生物76.1与胺或羟胺77.1反应,其中R2是烷基、链烯基、环烷基或环烯基,任选地引入杂原子
、
或
,或官能团如酰胺、酯、肟、亚砜或砜等,或任选取代的芳基、杂芳基或芳烷基,任选地引入杂原子
、
或
,和X是膦酸酯基团或可以随后被转化成含膦酸酯的取代基的一种基团。例如,X是二烷基膦酰基,溴,羟基,氨基,羧基等等。该反应是在等摩尔量的反应物之间在非质子传递溶剂如吡啶或二甲苯中,或在醇溶剂如乙醇中,任选在酸催化剂存在下,来进行,得到亚胺或肟。甾族3-酮的肟的制备已描述在Anal.Bioch.,1978,86,133中和在J.Mass.Spectrom.,1995,30,497中。该BMD保护的侧链化合物77.2然后按照在实施例76的反应历程M1中所述被转化成三醇77.3。
实施例77A
以上示出了引入膦酸酯基团的羟胺醚的制备。在这一程序中,其中Lv是离去基团如溴或三氟甲基磺酰基氧基的膦酸酯77.4与BOC-羟胺77.5(Aldrich)反应,生产醚77.6。反应是在等摩尔量的反应物之间在极性溶剂如二甲基甲酰胺或四氢呋喃中,在碱如氢氧化钾或二甲基胺基吡啶存在下进行。然后进行去保护(例如通过用三氟乙酸处理),得到羟胺醚77.7。
实施例78
以上示出了膦酸酯的制备,其中膦酸酯基团通过亚氨基氧基来连接。在这一程序中,底物76.1与二烷基膦酰基甲基羟胺78.1(按照以上所述从三氟甲基-磺酰基氧基甲基膦酸二烷基酯(Tetrahedron Lett.,1986,27,1477)和BOC-羟胺制得)进行反应,获得肟78.2,它在去保护后获得三醇78.3。该肟形成反应是在环境温度下在乙醇-乙酸溶液中在等摩尔量的反应物之间进行的。
使用以上程序但代替羟胺醚78.1而使用不同的肟醚77.1,获得相应产物77.3。
实施例79
以上示出了其中膦酸酯基团通过吡啶基甲氧基来连接的化合物的制备。在这一程序中,该二烯酮76.1,如上所述,与按照以上所述方法从3-溴-5-溴-甲基-吡啶(WO95/28400)制得的O-(3-溴-5-吡啶基-甲基)-羟胺79.1进行反应,在侧链的去保护后获得肟79.2。该产物然后在钯催化剂存在下与亚磷酸二烷基酯79.3反应,获得该膦酸酯79.4。通过在芳基溴和二烷基亚磷酸酯之间的偶联反应制备芳基膦酸酯的方法已描述在J.Med.Chem.,1992,35,1371中。反应在惰性溶剂如甲苯中,在碱如三乙胺和催化量的四(三苯基膦)钯(0)存在下进行。
另外地,溴化合物79.2与乙烯基膦酸二烷基酯79.5(Aldrich)偶联,获得膦酸酯79.6。芳基卤化物与烯烃利用Heck反应的偶联描述在例如“Advanced Organic Chemistry”,F.A.Carey和R.J.Sundberg,Plenum,2001p.503ff中和在Acc.Chem.Res.,1979,12,146中。该芳基溴和烯烃在极性溶剂中如二甲基甲酰胺或二噁烷中,在钯(0)催化剂如四(三苯基膦)钯(0)或钯(II)催化剂如乙酸钯(II)存在下,和任选地在碱如三乙胺或碳酸钾存在下,进行偶联。任选,在产物79.6中存在的styrenoid双键例如通过与二酰亚胺反应而被还原,得到饱和的类似物79.7。烯键的还原已描述在“Comprehensive OrganicTransformations”,R.C.Larock,VCH,1989,p.6ff中。该转变利用催化氢化,例如通过使用钯/碳催化剂和氢或氢给体,或通过利用二酰亚胺或乙硼烷来进行。
通过使用以上程序,但代替溴吡啶基氧基试剂79.1,使用不同的溴取代的芳基或杂芳基烷氧基羟胺,和/或不同的链烯基膦酸二烷基酯,获得了与化合物79.4、79.6和79.7类似的产物。
实施例80
以上示出了膦酸酯的制备,其中膦酸酯通过亚氨基来连接。在这一程序中,底物76.1与2-氨基苯基膦酸二烷基酯80.1(Syn.,1999,1368)反应,在去保护后获得亚胺产物80.2。该反应在烃溶剂如甲苯或二甲苯中,在回流温度下,在碱性催化剂如甲醇钠,或酸催化剂如甲苯磺酸存在下,在共沸条件下进行。
通过使用以上程序,但代替2-氨基-苯基膦酸酯80.1使用不同的氨基取代的芳基或杂芳基膦酸酯,获得与80.2类似的产物。
实施例81
以上示出了其中膦酸酯基团利用肟基和酰胺键来连接的膦酸酯类的制备。在这一程序中,该二烯酮76.2与O-(2-羧基乙基)-羟胺,81.1,(J.Med.Chem.,1990,33,1423)进行反应,得到肟81.2。甾族1,4-二烯-3-酮与取代的羟胺的反应已描述在J.Steroid Bioch.,1976,7,795中;反应是在等摩尔量的反应物之间在极性有机溶剂如吡啶或甲醇中,任选在乙酸或乙酸钠存在下进行。该肟然后与甲基氨基甲基膦酸二烷基酯81.3反应,得到酰胺肟81.4。从羧酸类和衍生物制备酰胺的方法例如描述在“Organic Functional Group Preparations”,S.R.Sandler和W.Karo,Academic Press,1968,第274页,和“Comprehensive Organic Transformations”,R.C.Larock,VCH,1989,p.972ff中。该羧酸与该胺在活化剂例如二环己基碳二亚胺或二异丙基碳二亚胺存在下,任选地在例如羟基苯并三唑、N-羟基-琥珀酰亚胺或N-羟基吡啶酮存在下,在非质子溶剂如吡啶、DMF或二氯甲烷中进行反应,获得酰胺。
另外地,该羧酸可以首先转化成活化的衍生物如酰氯、酸酐、混合酸酐、咪唑化物(imidazolide)等,然后与胺在有机碱例如吡啶存在下反应,获得该酰胺。羧酸转化成相应的酰氯的过程可通过用试剂例如亚硫酰氯或草酰氯在惰性有机溶剂如二氯甲烷中,任选在催化量二甲基甲酰胺存在下处理羧酸来进行的。
该酰胺产物,81.4,按照在这里所述的方法,被转化成三醇81.5。
通过使用以上程序,但代替羟胺81.3使用不同的氨基取代的羟胺和/或不同的氨基取代的膦酸酯,获得与81.5类似的产物。
实施例82
以上示出了其中膦酸酯基团借助于芳族或杂芳族基团、杂原子和可变的碳链连接于吡唑环的1’或2’位上的膦酸酯的制备。在这一程序中,该BMD保护的二烯酮76.1被还原,获得1,2-二氢产物82.1。该催化氢化反应通过三(三苯基膦)铑(I)氯化物的使用来进行,例如按照在J.Med.Chem.,2001,44,602中所述。该产物然后与甲酸乙酯和碱如氢化钠,在惰性溶剂如甲苯或二甲基甲酰胺中进行反应,按照在J.Am.Chem.Soc.,1964,86,1520中所述,获得2-甲酰基产物82.2。这一化合物然后与烷基、芳烷基、芳基或杂芳基肼82.3进行反应,其中R2是烷基、芳烷基、芳基或杂芳基,和其中取代基X是膦酸酯基团或可以随后被转化成含膦酸酯的取代基的一种基团。例如,X是二烷基膦酰基,溴,羟基,氨基,羧基等等。反应得到异构体2’-和1’-芳基吡唑,82.4和82.5。该吡唑形成反应是在等摩尔量的反应物之间在酸性溶剂如乙酸中进行,按照在J.Am.Chem.Soc.,1964,86,1520中所述。吡唑类82.4和82.5然后,例如通过使用在这里描述的程序,经由BMD保护的中间体82.6和82.7,被转变成膦酸酯82.8和82.9。
实施例83
以上示出了其中膦酸酯利用苯基环和烷氧基或炔键来连接的膦酸酯类的制备。在这一程序中,该酮醛82.2,如上所述,与3-羟基苯基肼83.1(日本专利No.JP 03011081)进行反应,得到吡唑83.2和83.3。该2’-取代的异构体,83.2,然后在二氯甲烷溶液中在环境温度下与一摩尔当量的三氟甲基磺酰氯和二甲基氨基吡啶进行反应,得到三氟甲磺酸酯,83.4。该产物然后在甲苯溶液中与丙炔基膦酸二烷基酯83.5(Syn.,1999,2027),三乙胺和催化量的四(三苯基膦)钯(0)进行反应,得到炔产物,83.6。芳基三氟甲磺酸酯与末端乙炔的钯-催化的偶联反应已描述在WO 02/30930中。该BMD保护基然后被除去,得到三醇83.7。
另外地,该1’-取代的吡唑83.3,按照Mitsonobu反应的方式,与2-羟乙基膦酸二烷基酯83.8(Epsilon)进行反应,获得醚83.9。利用Mitsonobu反应制备芳族醚的方法例如描述在“ComprehensiveOrganic Transformations”,R.C.Larock,VCH,1989,448页中,和在“Advanced Organic Chemistry”,部分B,F.A.Carey和R.J.Sundberg,Plenum,2001,153-4页中和在Org.React.,1992,42,335中。该酚和醇组分一起在非质子传递溶剂例如四氢呋喃中,在偶氮二羧酸二烷基酯和三芳基膦存在下反应,获得醚或硫醚产物。该程序也描述在Org.React.,1992,42,335-656中。该产物,83.9,然后去保护,得到三醇83.10。
通过使用以上程序,但使用不同的炔或羟基取代的膦酸酯,获得与83.7和83.10类似的产物。官能化程序在吡唑底物83.2和83.3之间是可相互变化的。
实施例84
以上示出了膦酸酯的制备,其中膦酸酯基团借助于苄基及饱和或不饱和的碳链来连接。在这一程序中,该酮醛82.2,如上所述,与3-溴苄基肼84.1(美国专利No.4,370,339)进行反应,生产吡唑84.2和84.3。该1’-取代的异构体84.2,在钯催化剂的存在下,与乙烯基膦酸二烷基酯84.4(Aldrich)偶联,得到膦酸酯84.5。该产物然后被去保护而获得三醇84.6。任选,在产物84.6中存在的styrenoid双键,如上所述,被还原而生产出饱和的类似物84.7。
另外地,该2’-取代的吡唑84.3,在钯催化剂存在下,与亚磷酸二烷基酯偶联,制备膦酸酯84.8,它在去保护之后得到三醇84.9。通过在芳基溴和二烷基亚磷酸酯之间的偶联反应制备芳基膦酸酯的方法已描述在J.Med.Chem.,1992,35,1371中。这一反应在惰性溶剂如甲苯中,在碱如三乙胺和催化量的四(三苯基膦)钯(0)存在下进行。
通过使用以上程序,但代替溴苄基试剂84.1,使用不同的溴取代的芳烷基、芳基或杂芳基烷氧基肼,和/或不同的链烯基膦酸二烷基酯,获得了与化合物84.6、84.7和84.9类似的产物。
实施例85
以上示出了其中膦酸酯基团利用可变的碳键来连接的膦酸酯85.7和85.8的制备。在这一程序中,该酮醛82.2与肼反应,获得吡唑衍生物85.1。甾族2-甲酰基-3-酮与肼的反应已描述在J.Am.Chem.Soc,1964,86,1520中。反应是在乙酸中在环境温度下进行的。该吡唑产物然后与其中R2和X如上所定义的溴甲基化合物85.2进行反应,得到烷基化产物85.3和85.4。取代的吡唑的烷基化例如描述在“Heterocyclic Chemistry”,T.L.Gilchrist,Longman,1992,第309页。反应在等摩尔量的底物之间在极性溶剂如二甲基甲酰胺或四氢呋喃中,在碱如二甲基氨基吡啶、六甲基二硅氮化锂等存在下进行。该产物85.3和85.4,只是X是二烷基膦酰基的情况除外,通过使用这里所述的程序被转化成膦酸酯85.5和85.6,然后去保护,获得三醇85.7和85.8。
实施例86
该吡唑85.1,如上所述,与一摩尔当量的溴丙酮基膦酸二烷基酯,86.1(Tet.,1978,34,649)进行反应,得到烷基化吡唑86.2和86.3。去保护之后得到三醇86.4和86.5。
实施例87
该吡唑85.1,如上所述,与1,4-双(溴-甲基)-苯87.1反应,得到吡唑87.2和87.3。该产物进行阿尔布佐夫(Arbuzov)反应,其中溴甲基取代基通过与亚磷酸三烷基酯在120℃下反应被转化成二烷基膦酰基甲基取代基,在侧链的去保护之后制备出膦酸酯87.4和87.5。阿尔布佐夫反应已描述在Handb.Organophosphorus Chem.,1992,115-72中。在该程序中,底物在60℃到约160℃下与五倍到五十倍摩尔过量的亚磷酸三烷基酯一起加热。
通过使用以上程序,但代替二溴化物87.1使用不同的二溴化物,获得与87.4和87.5类似的产物。
实施例88
对于通式88.1和88.2的膦酸酯化合物的制备的合成方法已由Westwood等人,J.Med.Chem.,1996,39,4608-4621进行描述,根据下面列出的一般性路线。
实施例89
下面示出了具有膦酸酯基团的本发明的化合物和用于它们的合成中的中间化合物的制备。
实施例90
下面示出了具有膦酸酯基团的本发明的化合物和用于它们的合成中的中间化合物的制备。
实施例91
以上在实施例91中显示了甲基强的松龙suleptanate,91A(WO 89/00558),和膦酸酯91.1-91.3的结构,其中取代基R1是
,烷基,链烯基,芳基或芳烷基。化合物91.1-91.3利用可变的连接基团(在所附结构中表示为“link”)来引入被连接到核上的膦酸酯结构部分
。下面给出了本发明的膦酸酯化合物91.1-91.3和它们的合成所需要的中间化合物的合成方法。
甲基强的松龙91.4与仲甲醛和酸催化剂如盐酸,按照在“ProtectiveGroups in Organic Synthesis”中由T.W.Greene和P.G.M.Wuts,Wiley,第二版1990,第223页中所述,进行反应而得到BMD衍生物91.5。膦酸酯结构部分然后通过使用描述在这里的程序被引入,生产出膦酸酯91.6。BMD结构部分然后水解,例如用50%乙酸水溶液处理,按照在“Protective Groups in Organic Synthesis”中由T.W.Greene和P.G.M.Wuts,Wiley,第二版1990,第223页中所述,获得三醇91.7。按照在WO 89/00558中所述,该三醇然后被转化成21-suleptanate酯。在这一程序中,通过在碱如三乙胺存在下由suleptanic acid与新戊酰氯反应所制得的混合酸酐与21-羟基类甾醇91.7进行反应,制备21-suleptanate酯91.8。
实施例92
以上示出了膦酸酯22.3的制备,其中膦酸酯基团借助于亚氨基或亚氨基氧基和可变的碳链来连接。在这一程序中,BMD保护的衍生物91.5与胺或羟胺92.1反应,其中R2是烷基、链烯基、环烷基或环烯基,任选地引入杂原子
、
或
,或官能团如酰胺、酯、肟、亚砜或砜等,或任选取代的芳基、杂芳基或芳烷基,任选地引入杂原子
、
或
,和X是膦酸酯基团或可以随后被转化成含膦酸酯的取代基的一种基团。例如,X是二烷基膦酰基,溴,羟基,氨基,羧基等等。该反应是在等摩尔量的反应物之间在非质子传递溶剂如吡啶或二甲苯中,或在醇溶剂如乙醇中,任选在酸催化剂存在下,来进行,得到亚胺或肟。甾族3-酮的肟的制备已描述在Anal.Bioch.,1978,86,133中和在J.Mass.Spectrom.,1995,30,497中。该BMD保护的侧链化合物92.2然后转化成三醇92.3,和然后转化成suleptanate92.4,如以上在实施例91中所述。
实施例92A
以上示出了引入膦酸酯基团的羟胺醚的制备。在这一程序中,膦酸酯92.5,其中Lv是离去基团如溴或三氟甲基磺酰基氧基。该膦酸酯与BOC-羟胺92.6(Aldrich)反应,生产醚92.7。反应是在等摩尔量的反应物之间在极性溶剂如二甲基甲酰胺或四氢呋喃中,在碱如氢氧化钾或二甲基胺基吡啶存在下进行。然后进行去保护(例如通过用三氟乙酸处理),得到羟胺醚92.8。
实施例93
以上示出了膦酸酯的制备,其中膦酸酯通过亚氨基氧基来连接。在这一程序中,底物91.5与二烷基膦酰基甲基羟胺93.1(按照以上所述从三氟甲基-磺酰基氧基甲基膦酸二烷基酯(Tetrahedron Lett.,1986,27,1477)和BOC-羟胺制得)进行反应,获得肟93.4,它在去保护后获得三醇93.5,从后者制得suleptanate酯93.6。该肟形成反应是在环境温度下在乙醇-乙酸溶液中在等摩尔量的反应物之间进行的。
使用以上程序但代替羟胺醚93.1而使用不同的肟醚92.1,获得相应产物92.4。
实施例94
以上示出了其中膦酸酯基团通过苯氧基乙氧基肟基团来连接的化合物的制备。在这一程序中,二烯酮91.5,如上所述,与如上所述从3-溴苯氧基乙基溴(FR 1,481,052)和BOC保护的羟胺制得的O-(3-溴-苯氧基-乙基)羟胺94.1,进行反应,在侧链的去保护后,得到肟94.2。该产物然后在钯催化剂存在下与亚磷酸二烷基酯94.3反应,获得该膦酸酯94.4。通过在芳基溴和二烷基亚磷酸酯之间的偶联反应制备芳基膦酸酯的方法已描述在J.Med.Chem.,1992,35,1371中。反应在惰性溶剂如甲苯中,在碱如三乙胺和催化量的四(三苯基膦)钯(0)存在下进行。该21-羟基然后被转化成21-suleptanate产物94.5。
另外地,溴化合物94.2与丙烯基膦酸二烷基酯94.6(Aldrich)偶联,获得膦酸酯94.7。芳基卤化物与烯烃利用Heck反应的偶联描述在例如“Advanced Organic Chemistry”,F.A.Carey和R.J.Sundberg,Plenum,2001p.503ff中和在Acc.Chem.Res.,1979,12,146中。该芳基溴和烯烃在极性溶剂中如二甲基甲酰胺或二噁烷中,在钯(0)催化剂如四(三苯基膦)钯(0)或钯(II)催化剂如乙酸钯(II)存在下,和任选地在碱如三乙胺或碳酸钾存在下,进行偶联。任选,在产物94.7中存在的styrenoid双键例如通过与二酰亚胺反应而被还原,得到饱和的类似物94.9。烯键的还原已描述在“Comprehensive OrganicTransformations”,R.C.Larock,VCH,1989,p.6ff中。该转变利用催化氢化,例如通过使用钯/碳催化剂和氢或氢给体,或通过利用二酰亚胺或乙硼烷来进行。该产物,94.7和94.9,然后转化成suleptanate酯,94.8和94.10。
通过使用以上程序,但代替溴苯氧基乙氧基试剂94.1,使用不同的溴取代的芳基或杂芳基烷氧基羟胺,和/或不同的链烯基膦酸二烷基酯,获得了与化合物94.5、94.8和94.10类似的产物。
实施例95
以上示出了膦酸酯的制备,其中膦酸酯通过亚氨基来连接。在这一程序中,化合物91.5与4-氨基苯基膦酸二烷基酯95.1(Epsilon)反应,在去保护后获得亚胺产物95.2。该反应在烃溶剂如甲苯或二甲苯中,在回流温度下,在碱性催化剂如甲醇钠,或酸催化剂如甲苯磺酸存在下,在共沸条件下进行。该产物然后被转化成suleptanate酯,95.3。
通过使用以上程序,但代替4-氨基苯基膦酸酯95.1,使用不同的氨基取代的芳基或杂芳基膦酸酯,获得与95.3类似的产物。
实施例96
以上示出了其中膦酸酯基团利用肟基和酰胺键来连接的膦酸酯类的制备。在这一程序中,该二烯酮91.5与O-(4-氨基丁基)-羟胺,96.1(Pol.J.Chem.,1981,55,1163)进行反应,得到肟96.2。甾族1,4-二烯-3-酮与取代的羟胺的反应已描述在J.Steroid Bioch.,1976,7,795。反应是在等摩尔量的反应物之间在极性有机溶剂如吡啶或甲醇中,任选在乙酸或乙酸钠存在下进行。该肟然后与二烷基膦酰乙酸96.3(Aldrich)偶联,得到酰胺肟96.4。从羧酸类和衍生物制备酰胺的方法例如描述在“Organic Functional Group Preparations”,S.R.Sandler和W.Karo,Academic Press,1968,第274页,和“Comprehensive Organic Transformations”,R.C.Larock,VCH,1989,p.972ff中。该羧酸与该胺在活化剂例如二环己基碳二亚胺或二异丙基碳二亚胺存在下,任选地在例如羟基苯并三唑、N-羟基-琥珀酰亚胺或N-羟基吡啶酮存在下,在非质子溶剂如吡啶、DMF或二氯甲烷中进行反应,获得酰胺。
另外地,该羧酸可以首先转化成活化的衍生物如酰氯、酸酐、混合酸酐、咪唑化物等,然后与胺在有机碱例如吡啶存在下反应,获得该酰胺。羧酸转化成相应的酰氯的过程可通过用试剂例如亚硫酰氯或草酰氯在惰性有机溶剂如二氯甲烷中,任选在催化量二甲基甲酰胺存在下处理羧酸来进行的。
该酰胺产物,96.4,按照在这里所述的方法,被转化成suleptanate,96.6。
通过使用以上程序,但代替羟胺96.1,使用不同的氨基取代的羟胺和/或不同的羧基取代的膦酸酯,获得与96.6类似的产物。
实施例97
以上示出了其中膦酸酯基团借助于芳族或杂芳族基团、杂原子和可变的碳链连接于吡唑环的1’或2’位上的膦酸酯的制备。在这一程序中,该BMD保护的二烯酮91.5被还原,获得1,2-二氢产物97.1。该催化氢化反应通过三(三苯基膦)铑(I)氯化物的使用来进行,例如按照在J.Med.Chem.,2001,44,602中所述。该产物然后与甲酸乙酯和碱如氢化钠,在惰性溶剂如甲苯或二甲基甲酰胺中进行反应,按照在J.Am.Chem.Soc.,1964,86,1520中所述,获得2-甲酰基产物97.2。这一化合物然后与烷基、芳烷基、芳基或杂芳基肼97.3进行反应,其中R2是烷基、芳烷基、芳基或杂芳基,和其中取代基X是膦酸酯基团或可以随后被转化成含膦酸酯的取代基的一种基团。例如,X是二烷基膦酰基,溴,羟基,氨基,羧基等等。反应得到异构体2’-和1’-芳基吡唑,97.4和97.5。该吡唑形成反应是在等摩尔量的反应物之间在酸性溶剂如乙酸中进行,按照在J.Am.Chem.Soc.,1964,86,1520中所述。该吡唑97.4和97.5然后,例如通过在实施例98和99中描述的程序,经由BMD保护的中间体97.6和97.7,被转变成膦酸酯suleptanates,97.9和97.11。
实施例98
以上示出了其中膦酸酯利用苯基环和烷氧基或链烯基连接键来连接的膦酸酯类的制备。在这一程序中,该酮醛97.2,如上所述,与4-羟基苯基肼98.1(Epsilon)进行反应,得到吡唑98.2和98.3。该2’-取代的异构体,98.2,然后在二甲基甲酰胺溶液中在环境温度下与一摩尔当量的1,4-二溴丁-2-烯和二甲基氨基吡啶进行反应,得到溴醚,98.4。该产物然后在120℃下,在阿尔布佐夫反应中与亚磷酸三烷基酯98.5反应,得到膦酸酯产物98.6。其中烷基溴通过在60℃-150℃下与亚磷酸三烷基酯一起加热被转化成相应膦酸酯的阿尔布佐夫反应已描述在Handb.Organophosphorus Chem.,1992,115-72中。该BMD保护基然后被除去和产物被酰化,得到suleptanate酯三醇,98.8。
另外地,该1’-取代的吡唑98.3,按照Mitsonobu反应的方式,与2-羟甲基膦酸二烷基酯98.9(Aldrich)进行反应,获得醚98.10。利用Mitsonobu反应制备芳族醚的方法例如描述在“ComprehensiveOrganic Transformations”,R.C.Larock,VCH,1989,448页中,和在“Advanced Organic Chemistry”,部分B,F.A.Carey和R.J.Sundberg,Plenum,2001,153-4页中和在Org.React.,1992,42,335中。该酚和醇或硫醇组分一起在非质子传递溶剂例如四氢呋喃中,在偶氮二羧酸二烷基酯和三芳基膦存在下反应,获得醚或硫醚产物。该程序也描述在Org.React.,1992,42,335中。该产物98.10然后进行去保护而得到三醇98.11,后一种化合物被酰化,获得suleptanate,98.12。
通过使用以上程序,但使用不同的二溴化物或羟基取代的膦酸酯,获得与98.8和98.12类似的产物。官能化程序在吡唑底物98.2和98.3之间是可相互变化的。
实施例99
以上示出了膦酸酯的制备,其中膦酸酯基团借助于苯基环或苯基环及饱和或不饱和的碳链来连接。在这一程序中,该酮醛97.2,如上所述,与4-溴苯基肼99.1(J.Organomet.Chem.,1999,62,581)进行反应,生产出吡唑99.2和99.3。该1’-取代的异构体99.2,在钯催化剂的存在下,与乙烯基膦酸二烷基酯99.4(Aldrich)偶联,得到膦酸酯99.4a。该产物然后被去保护而获得三醇,99.5,它转化成suleptanate,99.6。任选,在产物99.6中存在的styrenoid双键,如上所述,被还原而生产出饱和的类似物99.8。
另外地,该2’-取代的吡唑99.3,在钯催化剂存在下,与亚磷酸二烷基酯偶联,制备膦酸酯99.9,它进行去保护,和该产物被酰化得到suleptanate酯99.11。通过在芳基溴和二烷基亚磷酸酯之间的偶联反应制备芳基膦酸酯的方法已描述在J.Med.Chem.,1992,35,1371中。这一反应在惰性溶剂如甲苯中,在碱如三乙胺和催化量的四(三苯基膦)钯(0)存在下进行。
通过使用以上程序,但代替溴苯基肼99.1,使用不同的溴取代的芳烷基、芳基或杂芳基烷氧基肼,和/或不同的链烯基膦酸二烷基酯,获得了与化合物99.6、99.8和99.11类似的产物。
实施例100
以上示出了其中膦酸酯基团利用可变的碳键来连接的膦酸酯的制备。在这一程序中,该酮醛97.2与肼反应,获得吡唑衍生物100.1。甾族2-甲酰基-3-酮与肼的反应已描述在J.Am.Chem.Soc,1964,86,1520中。反应是在乙酸中在环境温度下进行的。该吡唑产物然后与其中R2和X如上所定义的溴甲基化合物100.2进行反应,得到烷基化产物100.3和100.4。取代的吡唑的烷基化例如描述在“HeterocyclicChemistry”,T.L.Gilchrist,Longman,1992,第309页。反应在等摩尔量的底物之间在极性溶剂如二甲基甲酰胺或四氢呋喃中,在碱如二甲基氨基吡啶、六甲基二硅氮化锂等存在下进行。该产物100.3和100.4,只是X是二烷基膦酰基的情况除外,通过使用这里所述的程序被转化成膦酸酯100.5和100.6,然后去保护/酰化,获得suleptanate酯100.8和100.10。
实施例101
该吡唑100.1在四氢呋喃溶液中,如上所述,与一摩尔当量的溴丁基膦酸二烷基酯101.1(Synthesis,1994,9,909)和六甲基二硅氮化锂进行反应,得到烷基化吡唑101.2和101.3。去保护/酰化得到suleptanates,101.5和101.7。
实施例102
该吡唑100.1在四氢呋喃溶液中,如上所述,与1,2-双(溴甲基)环丙烷102.1(Tet.,1997,53,10459)进行反应,得到吡唑102.2和102.3。该产物进行阿尔布佐夫(Arbuzov)反应,其中溴甲基取代基通过与亚磷酸三烷基酯在120℃下反应被转化成二烷基膦酰基甲基取代基,在侧链的去保护和酰化之后制备出膦酸酯102.5和102.7。阿尔布佐夫反应已描述在Handb.Organophosphorus Chem.,1992,115-72中。在该程序中,底物在60℃到约160℃下与五倍到五十倍摩尔过量的亚磷酸三烷基酯一起加热。
通过使用以上程序,但代替二溴化物102.1使用不同的二溴化物,获得与102.5和102.7类似的产物。
实施例103
以上显示了氯氟美松,103A(美国专利No.3,721,687),和膦酸酯,103.1-103.3,的结构。化合物103.1-103.3利用可变的连接基团(在所附结构中表示为“link”)来引入被连接到核上的膦酸酯结构部分
。
以上示出了其中类甾醇侧链作为双-亚甲基二氧基(BMD)结构部分来保护的保护-去保护序列。在这一序列中,9α-氟-16β-甲基-11β,17α,21-三羟基孕甾-1,4-二烯-3,21-二酮,103.4(美国专利No.3,721,687),与仲甲醛和酸催化剂如盐酸进行反应,按照在“Protective Groups in Organic Synthesis”,T.W.Greene和P.G.M.Wuts,Wiley,第二版1990,223页中所述,得到BMD衍生物,103.5。膦酸酯结构部分然后通过使用如下所述的程序被引入,生产出膦酸酯103.6。BMD结构部分然后水解,例如用50%乙酸水溶液处理,按照在“Protective Groups in Organic Synthesis”中由T.W.Greene和P.G.M.Wuts,Wiley,第二版1990,第223页中所述,获得三醇103.7。按照在美国专利No.3,721,687,Chimia,1992,46,338,或J.Med.Chem.,1987,30,1581中所述,该21-羟基然后被转化成21-氯基团。在这一程序中,该21-羟基底物在大约0℃下与一摩尔当量的甲烷磺酰氯在碱性溶剂如吡啶中进行反应,获得21-甲磺酸酯,103.8。该产物然后在二甲基甲酰胺溶液中在大约70℃下与大约五摩尔当量的氯化锂反应,得到21-氯产物,103.9。
实施例104
在这里描述了膦酸酯的制备,其中膦酸酯基团借助于亚氨基或亚氨基氧基和可变的碳链来连接。在这一程序中,BMD保护的衍生物103.1与胺或羟胺104.1反应,其中R2是烷基、链烯基、环烷基或环烯基,任选地引入杂原子
、
或
,或官能团如酰胺、酯、肟、亚砜或砜等,或任选取代的芳基、杂芳基或芳烷基,任选地引入杂原子
、
或
,和X是膦酸酯基团或可以随后被转化成含膦酸酯的取代基的一种基团。例如,X是二烷基膦酰基,溴,羟基,氨基,羧基等等。该反应是在等摩尔量的反应物之间在非质子传递溶剂如吡啶或二甲苯中,或在醇溶剂如乙醇中,任选在酸催化剂存在下,来进行,得到亚胺或肟。甾族3-酮的肟的制备已描述在Anal.Bioch.,1978,86,133中和在J.Mass.Spectrom.,1995,30,497中。按照这里所述,该BMD保护的侧链化合物104.2然后转化成三醇104.3,和然后转化成21-氯产物,104.4。
实施例104A
以上示出了引入膦酸酯基团的羟胺醚的制备。在这一程序中,其中Lv是离去基团如溴或三氟甲基磺酰基氧基的膦酸酯104.5与BOC-羟胺104.6(Aldrich)反应,生产醚104.7。反应是在等摩尔量的反应物之间在极性溶剂如二甲基甲酰胺或四氢呋喃中,在碱如氢氧化钾或二甲基胺基吡啶存在下进行。然后进行去保护(例如通过用三氟乙酸处理),得到羟胺醚104.8。
实施例105
以上示出了膦酸酯的制备,其中膦酸酯基团通过亚氨基氧基来连接。在这一程序中,底物103.1与二烷基膦酰基甲基羟胺105.1(按照以上所述从三氟甲基-磺酰基氧基甲基膦酸二烷基酯(TetrahedronLett.,1986,27,1477)和BOC-羟胺制得)进行反应,获得肟105.2。然后进行去保护获得三醇105.3,从它制备21-氯化合物105.4。该肟形成反应是在环境温度下在乙醇-乙酸溶液中在等摩尔量的反应物之间进行的。使用以上程序但代替羟胺醚105.1而使用不同的肟醚104.1,获得相应产物105.4。
实施例106
在这里描述了其中膦酸酯基团通过3-吡啶基甲氧基肟基团来连接的化合物的制备。在这一程序中,该二烯酮103.1,如上所述,与按照以上所述方法从5-溴-3-溴甲基吡啶(WO95/28400)和BOC保护的羟胺制得的O-(5-溴-3-吡啶基-甲氧基)-羟胺106.1进行反应,在侧链的去保护后获得肟106.2。该产物然后在钯催化剂存在下与亚磷酸二烷基酯106.3反应,获得该膦酸酯106.4。通过在芳基溴和二烷基亚磷酸酯之间的偶联反应制备芳基膦酸酯的方法已描述在J.Med.Chem.,1992,35,1371中。反应在惰性溶剂如甲苯中,在碱如三乙胺和催化量的四(三苯基膦)钯(0)存在下进行。该21-羟基然后被转化成21-氯衍生物106.5。
另外地,该溴化合物106.2与4-乙烯基苯基膦酸二烷基酯106.6(Macromolecules,1998,31,2918)偶联,获得膦酸酯106.7。芳基卤化物与烯烃利用Heck反应的偶联描述在例如“Advanced OrganicChemistry”,F.A.Carey和R.J.Sundberg,Plenum,2001p.503ff中和在Acc.Chem.Res.,1979,12,146中。该芳基溴和烯烃在极性溶剂中如二甲基甲酰胺或二噁烷中,在钯(0)催化剂如四(三苯基膦)钯(0)或钯(II)催化剂如乙酸钯(II)存在下,和任选地在碱如三乙胺或碳酸钾存在下,进行偶联。任选,在产物106.7中存在的styrenoid双键例如通过与二酰亚胺反应而被还原,得到饱和的类似物106.9。烯键的还原已描述在“Comprehensive Organic Transformations”,R.C.Larock,VCH,1989,p.6ff中。该转变利用催化氢化,例如通过使用钯/碳催化剂和氢或氢给体,或通过利用二酰亚胺或乙硼烷来进行。该产物,106.7和106.9,然后转化成21-氯化类似物,106.8和106.10。
通过使用以上程序,但代替溴吡啶基甲氧基试剂106.1,使用不同的溴取代的芳基或杂芳基烷氧基羟胺,和/或不同的链烯基膦酸二烷基酯,获得了与化合物106.5、106.8和106.10类似的产物。
实施例107
以上示出了膦酸酯的制备,其中膦酸酯通过亚氨基来连接。在这一程序中,底物103.1与4-氨基苄基膦酸二烷基酯107.1(Fluka)反应,在去保护后获得亚胺产物107.2。该反应在烃溶剂如甲苯或二甲苯中,在回流温度下,在碱性催化剂如甲醇钠,或酸催化剂如甲苯磺酸存在下,在共沸条件下进行。该产物然后被转化成21-氯化合物,107.3。
通过使用以上程序,但代替4-氨基苄基膦酸酯107.1,使用不同的氨基取代的芳基或杂芳基膦酸酯,获得与107.3类似的产物。
实施例108
以上示出了其中膦酸酯基团利用肟基和硫醚连接键来连接的膦酸酯类的制备。在这一程序中,该二烯酮103.1与O-(2-巯基乙基)-羟胺108.1(Bioorganicheskaya Khim.,1986,12,1662)反应,得到肟108.2。甾族1,4-二烯-3-酮与取代的羟胺的反应已描述在J.SteroidBioch.,1976,7,795中;反应是在等摩尔量的反应物之间在极性有机溶剂如吡啶或甲醇中,任选在乙酸或乙酸钠存在下进行。该产物然后在Mitsonobu反应中与3-羟基-苯基膦酸二烷基酯108.3(Aurora)偶联,得到硫醚肟108.4。利用Mitsonobu反应制备芳族醚的方法例如描述在“Comprehensive Organic Transformations”,R.C.Larock,VCH,1989,448页中,和在“Advanced OrganicChemistry”,部分B,F.A.Carey和R.J.Sundberg,Plenum,2001,153-4页中和在Org.React.,1992,42,335中。该酚和醇或硫醇组分一起在非质子传递溶剂例如四氢呋喃中,在偶氮二羧酸二烷基酯和三芳基膦存在下反应,获得醚或硫醚产物。该程序也描述在Org.React.,1992,42,335-656中。该硫醚产物,108.4,然后水解和转化成21-氯产物,108.6,按照在实施例103中所述。
通过使用以上程序,但代替羟胺108.3,使用不同的羟基或巯基取代的羟胺,和/或不同的羟基芳基取代的膦酸酯,获得与108.6类似的产物。
实施例109
以上示出了其中膦酸酯基团借助于芳族或杂芳族基团、杂原子和可变的碳链连接于吡唑环的1’或2’位上的膦酸酯的制备。在这一程序中,该BMD保护的二烯酮103.5被还原,获得1,2-二氢产物109.1。该催化氢化反应通过三(三苯基膦)铑(I)氯化物的使用来进行,例如按照在J.Med.Chem.,2001,44,602中所述。该产物然后与甲酸乙酯和碱如氢化钠,在惰性溶剂如甲苯或二甲基甲酰胺中进行反应,按照在J.Am.Chem.Soc.,1964,86,1520中所述,获得2-甲酰基产物109.2。这一化合物然后与烷基、芳烷基、芳基或杂芳基肼109.3进行反应,其中R2是烷基、芳烷基、芳基或杂芳基,和其中取代基X是膦酸酯基团或可以随后被转化成含膦酸酯的取代基的一种基团。例如,X是二烷基膦酰基,溴,羟基,氨基,羧基等等。反应得到异构体2’-和1’-芳基吡唑,109.4和109.5。该吡唑形成反应是在等摩尔量的反应物之间在酸性溶剂如乙酸中进行,按照在J.Am.Chem.Soc.,1964,86,1520中所述。该吡唑109.4和109.5然后,例如通过在实施例110和111中描述的程序,经由BMD保护的中间体109.6和109.7,被转变成21-氯膦酸酯,109.9和109.11。
实施例110
以上示出了其中膦酸酯基团借助于氨基甲酸酯或氨基连接键连接于吡唑环的1’或2’位上的膦酸酯的制备。在这一程序中,该酮醛109.2,如上所述,与3-氨基-苯基-肼110.1(EP 437105)反应,得到吡唑110.2和110.3。该2’-取代的异构体110.2然后在二甲基甲酰胺溶液中在环境温度下与一摩尔当量的2-羟乙基膦酸二烷基酯,110.4(Epsilon),和羰基二咪唑进行反应,得到氨基甲酸酯110.5。氨基甲酸酯的制备方法已描述在“Comprehensive Organic Functional GroupTransformations”,A.R.Katritzky,ed.,Pergamon,1995,6卷,p 416ff中,和在“Organic Functional Group Preparations”,S.R.Sandler和W.Karo,Academic Press,1986,p.260ff中。在该程序,该胺在惰性非质子传递溶剂如二氯甲烷或四氢呋喃中,与光气或它的官能化等同物如羰基二咪唑、三光气、五氟苯基碳酸酯等反应,获得相应的活化的酰基胺。后一化合物然后与醇反应,得到氨基甲酸酯。该BMD保护基然后被除去和该产物转化成21-氯产物110.7。
另外地,该1’-取代的吡唑110.3,在还原胺化反应中,与甲酰基甲基膦酸二烷基酯110.8(Zh.Obschei.Khim.,1987,57,2793),和三乙酰氧基硼氢化钠进行反应,获得胺110.9。由还原胺化程序制备胺的方法例如已描述在“Comprehensive Organic Transformations”,R.C.Larock,VCH,p 421中,和在“Advanced Organic Chemistry”,部分B,F.A.Carey和R.J.Sundberg,Plenum,2001,p 269中。在这一程序中,该胺组分和醛或酮组分一起在还原剂如硼烷、氰基硼氢化钠、三乙酰氧基硼氢化钠或二异丁基氢化铝存在下,任选在路易斯酸如钛四异丙醇盐存在下进行反应,按照在J.Org.Chem.,1990,55,2552中所述。该产物110.9然后被去保护得到该三醇110.10,和后一种化合物被转化成21-氯化类似物,110.11。
通过使用以上程序,但使用不同的甲酰基或羟基-取代的膦酸酯,和/或不同的氨基-取代的肼,获得与110.7和110.11类似的产物。官能化程序在吡唑底物110.2和110.3之间是可相互变化的。
实施例111
以上示出了其中膦酸酯基团利用苯基环和酰胺键来连接的膦酸酯类的制备。在这一程序中,该酮醛109.2,如上所述,与3-羧基苯基肼111.1(Apin)进行反应,生产吡唑111.2和111.3。该1’-取代的异构体111.1,在二环己基碳二亚胺的存在下,与3-氨基苯基膦酸二烷基酯111.4(Aurora)偶联,得到酰胺111.5。从羧酸类和衍生物制备酰胺的方法例如描述在“Organic Functional Group Preparations”,S.R.Sandler和W.Karo,Academic Press,1968,第274页,和“Comprehensive Organic Transformations”,R.C.Larock,VCH,1989,p.972ff中。该羧酸与该胺在活化剂例如二环己基碳二亚胺或二异丙基碳二亚胺存在下,任选地在例如羟基苯并三唑、N-羟基-琥珀酰亚胺或N-羟基吡啶酮存在下,在非质子溶剂如吡啶、DMF或二氯甲烷中进行反应,获得酰胺。
另外地,该羧酸可以首先转化成活化的衍生物如酰氯、酸酐、混合酸酐、咪唑烷(imidazolide)等,然后与胺在有机碱例如吡啶存在下反应,获得该酰胺。
羧酸转化成相应的酰氯的过程可通过用试剂例如亚硫酰氯或草酰氯在惰性有机溶剂如二氯甲烷中,任选在催化量二甲基甲酰胺存在下处理羧酸来进行的。
该产物然后被去保护而获得三醇,111.6,它转化成21-氯化合物,111.7。
另外地,该2’-取代的吡唑111.3,如上所述,与甲基氨基甲基膦酸二烷基酯111.8偶联,制备酰胺膦酸酯111.9,后者进行去保护,然后该产物转化成21-氯化类似物111.11。
通过使用以上程序,但代替羧基苯基肼111.1,使用不同的羧基取代的芳烷基、芳基或杂芳基烷氧基肼,和/或不同的氨基取代的膦酸二烷基酯,获得了与化合物111.7和111.11类似的产物。
实施例112
以上示出了其中膦酸酯基团利用可变的碳键来连接的膦酸酯的制备。在这一程序中,该酮醛109.2与肼反应,获得吡唑衍生物112.1。甾族2-甲酰基-3-酮与肼的反应已描述在J.Am.Chem.Soc,1964,86,1520中。反应是在乙酸中在环境温度下进行的。该吡唑产物然后与其中R2和X如上所定义的溴甲基化合物112.2进行反应,得到烷基化产物112.3和112.4。取代的吡唑的烷基化例如描述在“Heterocyclic Chemistry”,T.L.Gilchrist,Longman,1992,第309页。反应在等摩尔量的底物之间在极性溶剂如二甲基甲酰胺或四氢呋喃中,在碱如二甲基氨基吡啶、六甲基二硅氮化锂等存在下进行。该产物112.3和112.4,只是X是二烷基膦酰基的情况除外,通过使用这里所述的程序被转化成膦酸酯112.5和112.6,然后去保护/酰化,获得21-氯化合物112.8和112.10。
实施例113
该吡唑112.1在四氢呋喃溶液中,如上所述,与一摩尔当量的溴丁烯基膦酸二烷基酯113.1(J.Med.Chem.,1992,35,1371)和六甲基二硅氮化锂进行反应,得到烷基化吡唑113.2和113.3。去保护和然后氯化,得到21-氯产物,113.5和113.7。
实施例114
该吡唑112.1在四氢呋喃溶液中,如上所述,与1,4-二溴丁-2-炔,114.1(Aldrich)进行反应,得到吡唑114.2和114.3。该产物进行阿尔布佐夫反应,其中溴甲基取代基通过与亚磷酸三烷基酯在120℃下反应被转化成二烷基膦酰基甲基取代基,在侧链的去保护和氯化之后制备出21-氯膦酸酯114.5和114.7。阿尔布佐夫反应已描述在Handb.Organophosphorus Chem.,1992,115-72中。在该程序中,底物在60℃到约160℃下与五倍到五十倍摩尔过量的亚磷酸三烷基酯一起加热。通过使用以上程序,但代替二溴化物114.1使用不同的二溴化物,获得与114.5和114.7类似的产物。
实施例115
在这里示出了具有膦酸酯基团的本发明的化合物和用于它们的合成中的中间化合物的制备。β-酮腈,115.2,是通过苯乙酸115.1在Claisen条件下与丙二腈酯缩合来产生的。与羟胺反应可得到5-氨基-1,2-噁唑,它在与氰基吗啉缩合之后得到所需的SMP-114类似物。
实施例116
该茴香醚衍生物116.1通过用路易斯酸如三溴化硼处理来脱甲基。所形成的酚用E-1,4-二溴丁烯进行烷基化,所获得的一溴化物产物与亚磷酸三乙基酯在溶剂如甲苯中一起加热(或其它Arbuzov反应条件:参加Engel,R.,“Synthesis of Carbon-phosphorus Bonds”,CRC press,1988),产生所希望的膦酸二乙酯116.2。羧酸酯的皂化得到苯乙酸,以备被引入到SMP-114类似物的合成中。
实施例117
具有膦酸酯基团的本发明化合物的制备能够按照实施例116的程序和用1,3-二溴-丙烷替代1,4-二溴丁烯来进行。
实施例118
在高香草酸乙基酯118.1中的游离酚被转化成三氟甲磺酸芳基酯,和联苯基主体是通过与苯基-硼酸的Suzuki偶联来产生的(参见Chem.Rev.,1995,95,2457)。剩余步骤类似于描述在实施例116中的那些。
实施例119
通过使用Suzuki方法(参见上面),4-溴苯基乙酸乙基酯,119.1,与4-甲氧基-苯基-硼酸偶联。剩余步骤类似于描述在实施例116中的那些。
实施例120
6α,9α-二氟-16β-甲基-11β,17α,21-三羟基孕甾-1,4-二烯-3,21-二酮,120A(美国专利No.4,619,921),与仲甲醛和酸催化剂如盐酸进行反应,按照在“Protective Groups in Organic Synthesis”,T.W.Greene和P.G.M.Wuts,Wiley,第二版1990,223页中所述,得到BMD衍生物,120.1。膦酸酯结构部分然后通过使用如下所述的程序被引入,生产出膦酸酯120.2。BMD结构部分然后水解,例如用50%乙酸水溶液处理,按照在“Protective Groups in Organic Synthesis”中由T.W.Greene和P.G.M.Wuts,Wiley,第二版1990,第223页中所述,获得三醇120.3。后一种化合物然后通过使用在Chem.Pharm.Bull.,1986,34,1613中描述的程序被转化成17,21-环状原酸酯120.4。该底物在二甲基甲酰胺中在70℃下与两摩尔当量的原丙酸三乙酯和催化量的对甲苯磺酸进行反应。该产物然后与过量的三甲基甲硅烷基氯化物在二甲基甲酰胺中在环境温度中进行反应,生产出21-氯17-丙酸酯产物,120.5。
另外地,底物120.3利用在J.Med.Chem.,1987,30:1581中描述的方法被转化成产物120.5。在这一程序中,该21-羟基通过与甲磺酰氯在吡啶中反应被转化成21-甲磺酸酯来活化;该甲磺酸酯基团然后通过与氯化锂在二甲基甲酰胺中反应被置换而得到21-氯中间体,和该17-羟基被酯化得到21-氯-17-丙酸酯衍生物,120.5。17α羟基在11β羟基的存在下的选择性酰化已描述在J.Med.Chem.,1987,30:1581中。
实施例121
BMD保护的衍生物120.1与胺或羟胺121.1反应,其中R2是烷基、链烯基、环烷基或环烯基,任选地引入杂原子
、
或
,或官能团如酰胺、酯、肟、亚砜或砜等,或任选取代的芳基、杂芳基或芳烷基,任选地引入杂原子
、
或
,和X是膦酸酯基团或随后被转化成含膦酸酯的取代基的一种基团。例如,X是二烷基膦酰基,溴,羟基,氨基,羧基等等。该反应是在等摩尔量的反应物之间在非质子传递溶剂如吡啶或二甲苯中,或在醇溶剂如乙醇中,任选在酸催化剂存在下,来进行,得到亚胺或肟。甾族3-酮的肟的制备已描述在Anal.Bioch.,1978,86,133中和在J.Mass.Spectrom.,1995,30,497中。该BMD保护的侧链化合物121.2然后转化成三醇121.3,和然后转化成21-氯17-丙酸酯产物,121.4,按照以上所述。
以上示出了引入膦酸酯基团的羟胺醚的制备。其中Lv是离去基团如溴或三氟甲基磺酰基氧基的膦酸酯121.5与BOC-羟胺121.6(Aldrich)反应,生产醚121.7。反应是在等摩尔量的反应物之间在极性溶剂如二甲基甲酰胺或四氢呋喃中,在碱如氢氧化钾或二甲基胺基吡啶存在下进行。然后进行去保护(例如通过用三氟乙酸处理),得到羟胺醚121.8。
实施例122
底物120.1与二烷基膦酰基甲基羟胺122.1(按照以上所述从三氟乙基磺酰基氧基甲基膦酸二烷基酯(Tet.Lett.,1986,27:1477)和BOC-羟胺制得)进行反应,获得肟122.2。然后进行去保护获得三醇122.3,从它制备21-氯17-丙酸酯化合物122.4。该肟形成反应是在环境温度下在乙醇-乙酸溶液中在等摩尔量的反应物之间进行的。
使用以上程序但代替羟胺醚122.1而使用不同的肟醚121.1,获得相应产物121.4。
实施例123
二烯酮121.1,如上所述,与如上所述从4-溴-2-溴甲基噻吩(WO94/20456)和BOC保护的羟胺制得的O-(4-溴-2-噻吩基甲氧基)羟胺123.1,进行反应,在侧链的去保护后,得到肟123.2。该产物然后在钯催化剂存在下与亚磷酸二烷基酯123.3反应,获得该膦酸酯123.4。通过在芳基溴和亚磷酸二烷基酯之间的偶联反应制备芳基膦酸酯的方法已描述在J.Med.Chem.,1992,35,1371中。反应在惰性溶剂如甲苯中,在碱如三乙胺和催化量的四(三苯基膦)钯(0)存在下进行。该21-羟基化合物,123.4,然后按照这里所述被转化成21-氯17-丙酸酯衍生物,123.5。
另外地,该溴化合物,123.2,与丁烯基膦酸二烷基酯,123.6,(Org.Lett.,2001,3,217)偶联,获得膦酸酯123.7。芳基卤化物与烯烃利用Heck反应的偶联描述在例如F.A.Carey和R.J.Sundberg,“Advanced Organic Chemistry”,503ff(Plenum,2001)中和在Acc.Chem.Res.,1979,12,146中。该芳基溴和烯烃在极性溶剂中如二甲基甲酰胺或二噁烷中,在钯(0)催化剂如四(三苯基膦)钯(0)或钯(II)催化剂如乙酸钯(II)存在下,和任选地在碱如三乙胺或碳酸钾存在下,进行偶联。任选,在产物123.7中存在的styrenoid双键例如通过与二酰亚胺反应而被还原,得到饱和的类似物123.9。烯键的还原已描述在R.C.Larock,“Comprehensive Organic Transformations”,6ff(VCH1989)中。该转变利用催化氢化,例如通过使用钯/碳催化剂和氢或氢给体,或通过利用二酰亚胺或乙硼烷来进行。该产物,123.7和123.9,然后转化成21-氯17-丙酸酯类似物,123.8和123.10。
通过使用以上程序,但代替溴噻吩基甲氧基试剂123.1,使用不同的溴取代的芳基或杂芳基烷氧基羟胺,和/或不同的链烯基膦酸二烷基酯,获得了与化合物123.5、123.8和123.10类似的产物。
实施例124
底物121.1与通过在4-氨基-2-溴噻吩(Tet.,1987,43,3295)和亚磷酸二烷基酯之间的钯催化偶联反应(如上所述)所制得的4-氨基-2-噻吩基膦酸二烷基酯124.1进行反应,在去保护后,得到亚胺产物124.2。该亚胺形成反应在烃溶剂如甲苯或二甲苯中,在回流温度下,在碱性催化剂如甲醇钠,或酸催化剂如甲苯磺酸存在下,在共沸条件下进行。该产物然后被转化成21-氯17-丙酸酯化合物,124.3。
通过使用以上程序,但代替4-氨基噻吩基膦酸酯124.1,使用不同的氨基取代的芳基或杂芳基膦酸酯,获得与124.3类似的产物。
实施例125
二烯酮121.1与O-(4-氨基丁基)-羟胺,125.1(Pol.J.Chem.,1981,55,1163)进行反应,得到肟125.2。甾族1,4-二烯-3-酮与取代的羟胺的反应已描述在J.Steroid Bioch.,1976,7,795中;反应是在等摩尔量的反应物之间在极性有机溶剂如吡啶或甲醇中,任选在乙酸或乙酸钠存在下进行。该产物然后与2-羟乙基膦酸二烷基酯,125.3,(Epsilon)和羰基二咪唑进行偶联,得到氨基甲酸酯肟,125.4。氨基甲酸酯的制备方法已描述在A.R.Katritzky,“Comprehensive OrganicFunctional Group Transformations”,6,416ff(Pergamon,1995)中,和在S.R.Sandler和W.Karo,“Organic Functional GroupPreparations”,260ff(Academic Press,1986)中。在该程序,该胺在惰性非质子传递溶剂如二氯甲烷或四氢呋喃中,与光气或它的官能化等同物如羰基二咪唑、三光气、五氟苯基碳酸酯等反应,获得相应的活化的酰基胺。后一化合物然后与醇反应,得到氨基甲酸酯。氨基甲酸酯125.4然后按照这里所述被转化成21-氯17-丙酸酯产物,125.6。
通过使用以上程序,但代替羟胺125.3,使用不同的氨基取代的羟胺,和/或不同的羟基取代的膦酸酯,获得与125.6类似的产物。
实施例126
该BMD保护的二烯酮121.1被还原,获得1,2-二氢产物126.1。该催化氢化反应通过三(三苯基膦)铑(I)氯化物的使用来进行,例如按照在J.Med.Chem.,2001,44,602中所述。该产物然后与甲酸乙酯和碱如氢化钠,在惰性溶剂如甲苯或二甲基甲酰胺中进行反应,按照在J.Am.Chem.Soc.,1964,86,1520中所述,获得2-甲酰基产物126.2。这一化合物然后与烷基,芳烷基,芳基或杂芳基肼126.3反应,其中取代基X是膦酸酯基团或可以随后转变成含膦酸酯的取代基的一种基团。例如,X是二烷基膦酰基,溴,羟基,氨基,羧基等等。反应得到异构体2’-和1’-芳基吡唑,126.4和126.5。该吡唑形成反应是在等摩尔量的反应物之间在酸性溶剂如乙酸中进行,按照在J.Am.Chem.Soc.,1964,86,1520中所述。该吡唑126.4和126.5然后,例如通过在实施例122和123中描述的程序,经由BMD保护的中间体126.6和126.7,被转变成21-氯17-丙酸酯膦酸酯,126.9和126.11。
实施例127
该酮醛126.2,如上所述,与3-羧基丙基肼127.1(Ind.J.Exp.Biol.,1994,32,218)进行反应,得到吡唑127.2和127.3。该2’-取代的异构体127.2然后在二甲基甲酰胺溶液中在环境温度下与一摩尔当量的4-氨基苯基膦酸二烷基酯,127.4(Epsilon),和二环己基碳二亚胺进行反应,得到酰胺127.5。从羧酸类和衍生物制备酰胺的方法例如描述在S.R.Sandler和W.Karo,“Organic Functional GroupPreparations”,274(Academic Press,1968),和R.C.Larock,“Comprehensive Organic Transformations”,972ff(VCH,1989)中。该羧酸与该胺在活化剂例如二环己基碳二亚胺或二异丙基碳二亚胺存在下,任选地在例如羟基苯并三唑、N-羟基-琥珀酰亚胺或N-羟基吡啶酮存在下,在非质子溶剂如吡啶、DMF或二氯甲烷中进行反应,获得酰胺。
另外地,该羧酸可以首先转化成活化的衍生物如酰氯、酸酐、混合酸酐、咪唑化物等,然后与胺在有机碱例如吡啶存在下反应,获得该酰胺。
羧酸转化成相应的酰氯的过程可通过用试剂例如亚硫酰氯或草酰氯在惰性有机溶剂如二氯甲烷中,任选在催化量二甲基甲酰胺存在下处理羧酸来进行的。该BMD保护基然后被除去和该产物转化成21-氯17-丙酸酯产物127.7。
该1’-取代的吡唑127.3,如上所述,与氨基甲基膦酸二烷基酯,127.8(Interchim)偶联,获得酰胺127.9。该产物127.9然后进行去保护得到三醇127.10,和后一种化合物被转化成21-氯17-丙酸酯127.11。
通过使用以上程序,但使用不同的氨基取代的膦酸酯,和/或不同的羧基取代的肼,获得与127.7和127.11类似的产物。官能化程序在吡唑底物127.2和127.3之间是可相互变化的。
实施例128
该酮醛126.2,如上所述,与烯丙基肼128.1(Zh.Org.Khim.,1967,3,983)进行反应,生产吡唑128.2和128.3。该1’-取代的异构体128.2,按照这里所述,与3-溴苯基膦酸二烷基酯128.4(Epsilon)偶联,得到膦酸酯128.5。该产物然后被去保护而获得三醇,128.6,它转化成21-氯17-丙酸酯化合物,128.7。
该2,-取代的吡唑128.3,如上所述,与5-溴-2-噻吩基膦酸二烷基酯128.8(Syn.,2003,455)偶联来制备膦酸酯128.9,它进行去保护,然后该产物被转化成21-氯17-丙酸酯类似物,128.11。
通过使用以上程序,但代替丙烯基肼128.1,使用不同的链烯基肼,和/或不同的溴取代的膦酸二烷基酯,获得与化合物128.7和128.11类似的产物。
实施例129
酮醛126.2与肼反应,获得吡唑衍生物129.1。甾族2-甲酰基-3-酮与肼的反应已描述在J.Am.Chem.Soc,1964,86,1520中。反应是在乙酸中在环境温度下进行的。该吡唑产物然后与其中R2和X如上所定义的溴甲基化合物129.2进行反应,得到烷基化产物129.3和129.4。取代的吡唑的烷基化例如描述在T.L.Gilchrist,“Heterocyclic Chemistry”,309(Longman,1992)中。反应在等摩尔量的底物之间在极性溶剂如二甲基甲酰胺或四氢呋喃中,在碱如二甲基氨基吡啶、六甲基二硅氮化锂等存在下进行。该产物129.3和129.4,只是X是二烷基膦酰基的情况除外,通过使用这里所述的程序被转化成膦酸酯129.5和129.6,然后去保护/氯化/酰化,获得21-氯17-丙酸酯化合物129.8和129.10。
实施例130
按照在实施例129中描述的程序,吡唑129.1与2-溴苄基溴化物130.1反应,得到吡唑130.2和130.3。该产物然后,如上所述,与亚磷酸二烷基酯进行偶联,在侧链去保护和改性后,按照这里所述,获得21-氯17丙酸酯130.5和130.7。
实施例131
按照在实施例129中描述的程序,吡唑129.1在四氢呋喃溶液中与4-溴甲基环己酮131.1(WO 97/37959)进行反应,得到烷基化产物131.2和131.3。该1’-取代的异构体131.2,然后在还原胺化反应中,与氨基甲基膦酸二烷基酯131.8(Interchim)和氰基硼氢钠进行反应,在去保护和侧链改性后,得到21-氯17-丙酸酯131.5。
由还原胺化程序制备胺的方法例如已描述在R.C.Larock,“Comprehensive Organic Transformations”,421(VCH,1989)中,和在F.A.Carey和R.J.Sundberg,“Advanced Organic Chemistry”,部分B,269(Plenum,2001)中。在这一程序中,该胺组分和醛或酮组分一起在还原剂如硼烷、氰基硼氢化钠、三乙酰氧基硼氢化钠或二异丁基氢化铝存在下,任选在路易斯酸如钛四异丙醇盐存在下进行反应,按照在J.Org.Chem.,1990,55,2552中所述。
该2’-取代的吡唑131.3经历相同系列的反应,得到胺膦酸酯131.7。
通过使用以上程序,但使用不同的溴甲基-取代的醛或酮,和/或不同的氨基-取代的膦酸酯,获得与131.5和131.7类似的产物。
实施例132
其中Ciclesonide,132A(美国专利No.5,482,934)的20-酮基被保护获得衍生物132.1的保护-去保护序列。该酮通过在甲苯溶液中在回流温度下与乙二醇和酸催化剂反应来加以保护,例如转化成环状乙二醇缩酮,按照在J.Am.Chem.Soc.,1955,77,1904中所述。通过与吡啶鎓甲苯磺酸盐在丙酮水溶液中进行去保护,按照在J.Chem.Soc.,Chem.Comm.,1987,1351中所述。
另外地,该20-酮通过转化成N,N-二甲基腙来加以保护。该二甲基腙是通过该酮132A与N,N-二甲基肼在乙醇-乙酸中反应来制备的,按照在Org.Syn.,1970,50,102中所述。该基团通过用乙酸钠和乙酸在四氢呋喃水溶液中处理来除去,按照在J.Am.Chem.Soc.,1979,101,5841中所述。
另外地,该20-酮作为二乙胺加合物来保护。在这一程序中,按照在J.Chem.Soc.,Chem.Comm.,1983,406中所述,底物132A与四(二乙基酰胺)钛反应,获得加合物。该酮通过与水在含水有机溶剂中反应来进行去保护。
受保护的化合物132.1然后通过使用如下所述的程序被转化成含膦酸酯的类似物132.2,然后保护基团被除去,如上所述,得到膦酸酯132.3。
实施例133
受保护的衍生物133.1与胺或羟胺133.2反应,其中R2是烷基、链烯基、环烷基或环烯基,任选地引入杂原子
、
或
,或官能团如酰胺、酯、肟、亚砜或砜等,或任选取代的芳基、杂芳基或芳烷基,任选地引入杂原子
、
或
,和X是膦酸酯基团或随后被转化成含膦酸酯的取代基的一种基团。例如,X是二烷基膦酰基,溴,羟基,氨基,羧基等等。该反应是在等摩尔量的反应物之间在非质子传递溶剂如吡啶或二甲苯中,或在醇溶剂如乙醇中,任选在酸催化剂存在下,来进行,得到亚胺或肟133.3。甾族3-酮的肟的制备已描述在Anal.Bioch.,1978,86,133中和在J.Mass.Spectrom.,1995,30,497中。保护基团然后被除去,按照在这里所述,获得20-酮膦酸酯产物133.4。
实施例133A
在这里示出了引入膦酸酯基团的羟胺醚的制备。在这一程序中,其中Lv是离去基团如溴或三氟甲基磺酰基氧基的膦酸酯133.5与BOC-羟胺133.6(Aldrich)反应,生产醚133.7。反应是在等摩尔量的反应物之间在极性溶剂如二甲基甲酰胺或四氢呋喃中,在碱如氢氧化钾或二甲基胺基吡啶存在下进行。然后进行去保护(例如通过用三氟乙酸处理),得到羟胺醚133.8。以上程序也可用于取代的羟胺的制备,后者是膦酸酯的前体。
实施例134
其中20-酮作为二甲基腙衍生物来保护的底物133.1与如上所述从三氟甲基磺酰基-氧基甲基膦酸二烷基酯(Tetrahedron Lett.,1986,27,1477)和BOC-羟胺制得的二烷基膦酰基甲基羟胺133.8进行反应,获得肟134.2。去保护,按照在实施例132中所述,获得20-酮膦酸酯134.3。该肟形成反应是在环境温度下在乙醇-乙酸溶液中在等摩尔量的反应物之间进行的。
使用以上程序但代替羟胺醚133.8而使用不同的肟醚133.2,获得相应产物133.4。
实施例135
其中20-酮作为二甲基腙来保护的二烯酮133.1,如上所述,与如上所述从4-溴苄基溴化物和BOC保护的羟胺133.6制得的O-(4-溴苄基氧基)-羟胺135.1进行反应,得到肟135.2。保护基团然后被除去,得到20-酮产物135.3。后一种产物然后在钯催化剂存在下与亚磷酸二烷基酯135.4反应,获得膦酸酯135.5。通过在芳基溴和二烷基亚磷酸酯之间的偶联反应制备芳基膦酸酯的方法已描述在J.Med.Chem.,1992,35,1371中。反应在大约100℃下在惰性溶剂如甲苯中,在碱如三乙胺和催化量的四(三苯基膦)钯(0)存在下进行。
另外地,溴化合物135.3与乙烯基膦酸二烷基酯135.6(Aldrich)偶联,获得膦酸酯135.7。芳基卤化物与烯烃利用Heck反应的偶联已描述在例如F.A.Carey和R.J.Sundberg,“Advanced OrganicChemistry”,503ff(Plenum,2001)中和在Acc.Chem.Res.,1979,12,146中。该芳基溴和烯烃在极性溶剂中如二甲基甲酰胺或二噁烷中,在钯(0)催化剂如四(三苯基膦)钯(0)或钯(II)催化剂如乙酸钯(II)存在下,和任选地在碱如三乙胺或碳酸钾存在下,进行偶联。任选,在产物135.7中存在的styrenoid双键例如通过与二酰亚胺反应而被还原,得到饱和的类似物135.8。烯键的还原已描述在R.C.Larock,“Comprehensive Organic Transformations”,6ff(VCH 1989)中。该转变利用催化氢化,例如通过使用钯/碳催化剂和氢或氢给体,或通过利用二酰亚胺或乙硼烷来进行。
通过使用以上程序,但代替溴苄基氧基试剂135.1,使用不同的溴取代的芳基或杂芳基烷氧基羟胺,和/或不同的链烯基膦酸二烷基酯,获得了与化合物135.5、135.7和135.8类似的产物。
实施例136
其中20-酮作为二甲基腙来保护的底物133.1与通过在4-氨基-2-溴呋喃(Tetrahedron Lett.,1987,43,3295)和亚磷酸二烷基酯之间的钯催化偶联反应(如上所述)所制得的4-氨基-2-呋喃基膦酸二烷基酯136.1进行反应,在去保护后,得到亚胺产物136.2。该亚胺形成反应在烃溶剂如甲苯或二甲苯中,在回流温度下,在碱性催化剂如甲醇钠,或酸催化剂如甲苯磺酸存在下,在共沸条件下进行。
通过使用以上程序,但代替4-氨基-2-呋喃基膦酸酯136.1,使用不同的氨基取代的芳基或杂芳基膦酸酯,获得与136.2类似的产物。
实施例137
其中20-酮作为二甲基腙来保护的二烯酮133.1与O-(2-羧基乙基)羟胺137.1(J.Med.Chem.,1990,33,1423)进行反应,得到肟137.2。甾族1,4-二烯-3-酮与取代的羟胺的反应已描述在J.Steroid Bioch.,1976,7,795中;反应是在等摩尔量的反应物之间在极性有机溶剂如吡啶或甲醇中,任选在乙酸或乙酸钠存在下进行。该产物137.2然后与4-氨基苯基膦酸二烷基酯137.3(Epsilon)和二环己基碳二亚胺进行偶联,在去保护之后获得酰胺肟137.4。从羧酸类和衍生物制备酰胺的方法例如描述在S.R.Sandler和W.Karo,“Organic Functional GroupPreparations”,274(Academic Press,1968),和R.C.Larock,“Comprehensive Organic Transformations”,972ff(VCH,1989)中。该羧酸与该胺在活化剂例如二环己基碳二亚胺或二异丙基碳二亚胺存在下,任选地在例如羟基苯并三唑、N-羟基-琥珀酰亚胺或N-羟基吡啶酮存在下,在非质子溶剂如吡啶、DMF或二氯甲烷中进行反应,获得酰胺。
另外地,该羧酸可以首先转化成活化的衍生物如酰氯、酸酐、混合酸酐、咪唑烷(imidazolide)等,然后与胺在有机碱例如吡啶存在下反应,获得该酰胺。
羧酸转化成相应的酰氯的过程可通过用试剂例如亚硫酰氯或草酰氯在惰性有机溶剂如二氯甲烷中,任选在催化量二甲基甲酰胺存在下处理羧酸来进行的。
通过使用以上程序,但代替羧基取代的羟胺137.1,使用不同的羧基取代的羟胺,和/或不同的氨基取代的膦酸酯,获得与137.4类似的产物。
实施例138
二烯酮132A被还原,获得1,2-二氢产物138.1。该催化氢化反应通过三(三苯基膦)铑(I)氯化物的使用来进行,例如按照在J.Med.Chem.,2001,44,602中所述。该产物然后与甲酸乙酯和碱如氢化钠,在惰性溶剂如甲苯或二甲基甲酰胺中进行反应,按照在J.Am.Chem.Soc.,1964,86,1520中所述,获得2-甲酰基产物138.2。这一化合物然后与烷基,芳烷基,芳基或杂芳基肼138.3反应,其中取代基X是膦酸酯基团或可以随后转变成含膦酸酯的取代基的一种基团。例如,X是二烷基膦酰基,溴,羟基,氨基,羧基等等。该反应得到异构的2’-和1’-芳基吡唑,138.4和138.5。该吡唑形成反应是在等摩尔量的反应物之间在酸性溶剂如乙酸中进行,按照在J.Am.Chem.Soc.,1964,86,1520中所述。吡唑类138.4和138.5然后例如由实施例139和140中描述的程序分别转变成膦酸酯138.6和138.7。
实施例139
该酮醛138.2,如上所述,与4-羟基-苯肼139.1(EP 437105)进行反应,得到吡唑139.2和139.3。该2’-取代的异构体139.2然后在二甲基甲酰胺溶液中在大约70℃下与溴丁烯基膦酸二烷基酯139.4(J.Med.Chem.,1992,35,1371)和碳酸钾进行反应,得到醚膦酸酯139.5。
该异构的吡唑139.3,按照Mitsonobu反应的方式,与巯基甲基膦酸二烷基酯139.6,(J.Med.Chem.,1985,26,1688)进行反应,得到硫醚膦酸酯139.7。利用Mitsonobu反应制备芳族醚和硫醚的方法例如已描述在R.C.Larock,“Comprehensive OrganicTransformations”,448页(VCH,1989)中,在F.A.Carey和R.J.Sundberg,“Advanced Organic Chemistry”,部分B,153-4(Plenum,2001)中,和在Org.React.,1992,42,335中。该酚和醇或硫醇组分一起在非质子传递溶剂例如四氢呋喃中,在偶氮二羧酸二烷基酯和三芳基膦存在下反应,获得醚或硫醚产物。该程序也描述在Org.React.,1992,42,335-656中。
通过使用以上程序,但使用不同的羟基取代的肼,和/或不同的溴-或巯基-取代的膦酸酯,获得与139.5和139.7类似的产物。
实施例140
该酮醛138.2,如上所述,与4-氨基苯基肼140.1(Epsilon)进行反应,生产吡唑140.2和140.3。该2’-取代的异构体140.2,如上所述,与二烷基膦酰乙酸140.4(Aldrich)和二环己基碳二亚胺偶联,得到酰胺膦酸酯140.5。
另外地,该1’-取代的吡唑140.3与3-羟丙基膦酸二烷基酯140.6(Zh.Obschei.Khim.,1973,43,2364)和羰基二咪唑进行反应,制备氨基甲酸酯膦酸酯140.7。氨基甲酸酯的制备方法已描述在“Comprehensive Organic Functional Group Transformations”,6卷,416ff(A.R.Katritzky,ed.,Pergamon,1995)中,和在S.R.Sandler和W.Karo,“Organic Functional Group Preparations”,260ff(Academic Press,1986)中。在该程序,该胺在惰性非质子传递溶剂如二氯甲烷或四氢呋喃中,与光气或它的官能化等同物如羰基二咪唑、三光气、五氟苯基碳酸酯等反应,获得相应的活化的酰基胺。后一化合物然后与醇反应,得到氨基甲酸酯。
通过使用以上程序,但代替4-氨基-苯基肼140.1,使用不同的氨基取代的肼,和/或不同的二烷基羧基或羟基-取代膦酸二烷基酯,获得了与化合物140.5和140.7类似的产物。
实施例141
酮醛138.2与肼反应,获得吡唑衍生物141.1。甾族2-甲酰基-3-酮与肼的反应已描述J.Am.Chem.Soc.,1964,86,1520中。反应是在乙酸中在环境温度下进行的。该吡唑产物然后与其中R2和X如上所定义的溴甲基化合物141.2或反应活性溴杂芳族试剂进行反应,得到烷基化产物141.3和141.4。取代的吡唑的烷基化例如描述在T.L.Gilchrist,“Heterocyclic Chemistry”,309(Longman,1992)中。反应在等摩尔量的底物之间在极性溶剂如二甲基甲酰胺或四氢呋喃中,在碱如二甲基氨基吡啶、六甲基二硅氮化锂等存在下进行。通过使用以上所述的程序,产物141.3和141.4,只是当X是二烷基膦酰基时的情况除外,被转化成膦酸酯141.5和141.6。
实施例142
该吡唑141.1,如上所述,与丙酮基膦酸二烷基酯,142.1(Tetrehedron Lett.,1978,34,649)进行反应,得到吡唑141.2和141.3。
实施例143
该吡唑141.1在四氢呋喃溶液中与2,5-双(溴甲基)噻吩143.1(Tetrahedron Lett.,1999,55,4709)和六甲基二硅氮化钾进行反应,得到烷基化产物143.2和143.3。该2’-取代的异构体143.2然后在阿尔布佐夫反应中与亚磷酸三烷基酯反应,得到膦酸酯143.4。阿尔布佐夫反应已描述在Handb.Organophosphorus Chem.,1992,115中。在其中溴取代基转化成相应膦酸酯的这一程序中,底物在约60℃到约160℃下与五倍到五十倍摩尔过量的亚磷酸三烷基酯一起加热,实施该转化。
该2’-取代的吡唑143.3在70℃下在二甲基甲酰胺溶液中与一摩尔当量的3-氨基苯基膦酸二烷基酯143.5和碳酸铯进行反应,得到胺膦酸酯143.6。
通过使用以上程序,但使用不同的二溴化物,和/或不同的氨基取代的膦酸酯,获得与143.4和143.6类似的产物。
实施例144
显示了其中去氟可特,144A(美国专利No.3,436,389)的20-酮基被保护获得衍生物144.1的保护-去保护序列。该酮通过在甲苯溶液中在回流温度下与乙二醇和酸催化剂反应来加以保护,例如转化成环状乙二醇缩酮,按照在J.Am.Chem.Soc.,1955,77,1904中所述。通过与吡啶鎓甲苯磺酸盐在丙酮水溶液中进行去保护,按照在J.Chem.Soc.,Chem.Comm.,1987,1351中所述。
另外地,该20-酮通过转化成N,N-二甲基腙来加以保护。该二甲基腙是通过该酮144A与N,N-二甲基肼在乙醇-乙酸中反应来制备的,按照在Org.Syn.,1970,50,102中所述。该基团通过用乙酸钠和乙酸在四氢呋喃水溶液中处理来除去,按照在J.Am.Chem.Soc.,1979,101,5841中所述。
另外地,该20-酮作为二乙胺加合物来保护。在这一程序中,按照在J.Chem.Soc.,Chem.Comm.,1983,406中所述,底物144A与四(二乙基胺)化锂反应,获得加合物。该酮通过与水在含水有机溶剂中反应来进行去保护。
受保护的化合物144.1然后通过使用如下所述的程序被转化成含膦酸酯的类似物144.2,然后保护基团被除去,如上所述,得到膦酸酯144.3。
实施例145
受保护的衍生物145.1与胺或羟胺145.2反应,其中R2是烷基、链烯基、环烷基或环烯基,任选地引入杂原子
、
或
,或官能团如酰胺、酯、肟、亚砜或砜等,或任选取代的芳基、杂芳基或芳烷基,任选地引入杂原子
、
或
,和X是膦酸酯基团或随后被转化成含膦酸酯的取代基的一种基团。例如,X是二烷基膦酰基,溴,羟基,氨基,羧基等等。该反应是在等摩尔量的反应物之间在非质子传递溶剂如吡啶或二甲苯中,或在醇溶剂如乙醇中,任选在酸催化剂存在下,来进行,得到亚胺或肟145.3。甾族3-酮的肟的制备已描述在Anal.Bioeh.,1978,86,133中和在J.Mass.Spectrom.,1995,30,497中。保护基团然后被除去,按照在这里所述,获得20-酮膦酸酯产物145.4。
实施例145A
在这里示出了引入膦酸酯基团的羟胺醚的制备。在这一程序中,其中Lv是离去基团如溴或三氟甲基磺酰基氧基的膦酸酯145.5与BOC-羟胺145.6(Aldrich)反应,生产醚145.7。反应是在等摩尔量的反应物之间在极性溶剂如二甲基甲酰胺或四氢呋喃中,在碱如氢氧化钾或二甲基胺基吡啶存在下进行。然后进行去保护(例如通过用三氟乙酸处理),得到羟胺醚145.8。以上程序也可用于取代的羟胺的制备,后者是膦酸酯的前体。
实施例146
其中20-酮作为二甲基腙衍生物来保护的底物145.1与如上所述从三氟甲基磺酰基-氧基甲基膦酸二烷基酯(Tetrahedron Lett.,1986,27,1477)和BOC-羟胺制得的二烷基膦酰基甲基羟胺146.1进行反应,获得肟146.2。去保护,按照在实施例144中所述,获得20-酮膦酸酯146.3。该肟形成反应是在环境温度下在乙醇-乙酸溶液中在等摩尔量的反应物之间进行的。
使用以上程序但代替羟胺醚146.1而使用不同的肟醚145.2,获得相应产物145.4。
实施例147
其中20-酮作为二甲基腙来保护的二烯酮145.1,如上所述,与如上所述从3-溴苯基乙基溴化物(法国专利FR 1481052)和BOC保护的羟胺145.6制得的O-(3-溴苯基乙氧基)-羟胺147.1进行反应,得到肟147.2。保护基团然后被除去,得到20-酮产物147.3。后一种产物然后在钯催化剂存在下与亚磷酸二烷基酯147.4反应,获得膦酸酯147.5。通过在芳基溴和二烷基亚磷酸酯之间的偶联反应制备芳基膦酸酯的方法已描述在J.Med.Chem.,1992,35,1371中。反应在大约100℃下在惰性溶剂如甲苯中,在碱如三乙胺和催化量的四(三苯基膦)钯(0)存在下进行。
另外地,溴化合物147.3与丙烯基膦酸二烷基酯147.6(Aldrich)偶联,获得膦酸酯147.7。芳基卤化物与烯烃利用Heck反应的偶联已描述在例如F.A.Carey和R.J.Sundberg,“Advanced OrganicChemistry”,503ff(Plenum,2001)中和在Acc.Chem.Res.,1979,12,146中。该芳基溴和烯烃在极性溶剂中如二甲基甲酰胺或二噁烷中,在钯(0)催化剂如四(三苯基膦)钯(0)或钯(II)催化剂如乙酸钯(II)存在下,和任选地在碱如三乙胺或碳酸钾存在下,进行偶联。任选,在产物147.7中存在的styrenoid双键例如通过与二酰亚胺反应而被还原,得到饱和的类似物147.8。烯键的还原已描述在R.C.Larock,“Comprehensive Organic Transformations”,6ff(VCH 1989)中。该转变利用催化氢化,例如通过使用钯/碳催化剂和氢或氢给体,或通过利用二酰亚胺或乙硼烷来进行。
通过使用以上程序,但代替溴苯基乙基试剂147.1,使用不同的溴取代的芳基或杂芳基烷氧基羟胺,和/或不同的链烯基膦酸二烷基酯,获得了与化合物147.5、147.7和147.8类似的产物。
实施例148
其中20-酮作为二甲基腙来保护的底物145.1与3-氨基苯基膦酸二烷基酯148.1(J.Med.Chem.,1984,27,654)进行反应,在去保护后,得到亚胺产物148.2。该亚胺形成反应在烃溶剂如甲苯或二甲苯中,在回流温度下,在碱性催化剂如甲醇钠,或酸催化剂如甲苯磺酸存在下,在共沸条件下进行。
通过使用以上程序,但代替3-氨基苯基膦酸酯148.1,使用不同的氨基取代的芳基或杂芳基膦酸酯,获得与148.2类似的产物。
实施例149
其中20-酮作为二甲基腙来保护的二烯酮145.1与O-(2-羟乙基)羟胺149.1(J.Med.Soc.Chem.Comm.,1986,903)进行反应,得到肟149.2。甾族1,4-二烯-3-酮与取代的羟胺的反应已描述在J.SteroidBioch.,1976,7,795中;反应是在等摩尔量的反应物之间在极性有机溶剂如吡啶或甲醇中,任选在乙酸或乙酸钠存在下进行。该产物149.2然后与4-氨基苯基膦酸二烷基酯149.3(Epsilon)和羰基二咪唑进行偶联,在去保护之后获得氨基甲酸酯肟149.4。氨基甲酸酯的制备方法已描述在“Comprehensive Organic Functional GroupTransformations”,6卷,416ff(A.R.Katritzky,ed.,Pergamon,1995)中,和在S.R.Sandler和W.Karo,“Organic Functional GroupPreparations”,260ff(Academic Press,1986)中。在该程序,该胺在惰性非质子传递溶剂如二氯甲烷或四氢呋喃中,与光气或它的官能化等同物如羰基二咪唑、三光气、五氟苯基碳酸酯等反应,获得相应的活化的酰基胺。后一化合物然后与醇反应,得到氨基甲酸酯。
通过使用以上程序,但代替羟基取代的羟胺149.1,使用不同的羟基取代的羟胺,和/或不同的氨基取代的膦酸酯,获得与149.4类似的产物。
实施例150
二烯酮144A被还原,获得1,2-二氢产物150.1。该催化氢化反应通过三(三苯基膦)铑(I)氯化物的使用来进行,例如按照在J.Med.Chem.,2001,44,602中所述。该产物然后与甲酸乙酯和碱如氢化钠,在惰性溶剂如甲苯或二甲基甲酰胺中进行反应,按照在J.Am.Chem.Soc.,1964,86,1520中所述,获得2-甲酰基产物150.2。这一化合物然后与烷基,芳烷基,芳基或杂芳基肼150.3反应,其中取代基X是膦酸酯基团或可以随后转变成含膦酸酯的取代基的一种基团。例如,X是二烷基膦酰基,溴,羟基,氨基,羧基等等。反应得到异构体2’-和1’-芳基吡唑,150.4和150.5。该吡唑形成反应是在等摩尔量的反应物之间在酸性溶剂如乙酸中进行,按照在J.Am.Chem.Soc.,1964,86,1520中所述。该吡唑150.4和150.5,然后例如通过这里描述的程序,被转变成膦酸酯150.6和150.7。
实施例151
该酮醛150.2,如上所述,与3-羧基苯基肼151.1(Apin)进行反应,得到吡唑151.2和151.3。该2’-取代的异构体151.2然后在二甲基甲酰胺溶液中在环境温度下与3-氨基丙基膦酸二烷基酯151.4(Acros)和二环己基碳二亚胺偶联,得到酰胺膦酸酯151.5。从羧酸类和衍生物制备酰胺的方法例如描述在S.R.Sandler和W.Karo,“OrganicFunctional Group Preparations”,274(Academic Press,1986),和R.C.Larock,“Comprehensive Organic Transformations”,972ff(VCH,1989)中。该羧酸与该胺在活化剂例如二环己基碳二亚胺或二异丙基碳二亚胺存在下,任选地在例如羟基苯并三唑、N-羟基-琥珀酰亚胺或N-羟基吡啶酮存在下,在非质子溶剂如吡啶、DMF或二氯甲烷中进行反应,获得酰胺。
另外地,该羧酸可以首先转化成活化的衍生物如酰氯、酸酐、混合酸酐、咪唑烷(imidazolide)等,然后与胺在有机碱例如吡啶存在下反应,获得该酰胺。
羧酸转化成相应的酰氯的过程可通过用试剂例如亚硫酰氯或草酰氯在惰性有机溶剂如二氯甲烷中,任选在催化量二甲基甲酰胺存在下处理羧酸来进行的。
该异构的吡唑151.3,如上所述,与2-氨基苯基膦酸二烷基酯151.6(Acros)进行反应,得到酰胺膦酸酯151.7。
通过使用以上程序,但使用不同的羧基取代的肼,和/或不同的氨基取代的膦酸酯,获得与151.5和151.7类似的产物。
实施例152
该酮醛150.2,如上所述,与1,3-双(肼基)苯152.1(Bull.Soc.Chim.Fr.,1975,1371)进行反应,生产吡唑152.2和152.3。该2’-取代的异构体152.2在四氢呋喃溶液中在环境温度下与一摩尔当量的二烷基膦酰基乙醛(Aurora)进行反应,得到腙膦酸酯152.5。
另外地,该1’-取代的吡唑152.3,如上所述,与二烷基膦酰基丁酸152.6(Epsilon)和二环己基碳化二亚胺偶联,制备膦酸酯152.7。
通过使用以上程序,但代替1,3-双(肼基)苯基肼152.1,使用不同的双肼,和/或不同的二烷基甲酰基或羧基取代的膦酸酯,获得了与化合物152.5和152.7类似的产物。
实施例153
酮醛150.2与肼反应,获得吡唑衍生物153.1。甾族2-甲酰基-3-酮与肼的反应已描述J.Am.Chem.Soc.,1964,86,1520中。反应是在乙酸中在环境温度下进行的。该吡唑产物然后与其中R2和X如上所定义的溴甲基化合物153.2或反应活性溴杂芳族试剂进行反应,得到烷基化产物153.3和153.4。取代的吡唑的烷基化例如描述在T.L.Gilchrist,“Heterocyclic Chemistry”,309(Longman,1992)中。反应在等摩尔量的底物之间在极性溶剂如二甲基甲酰胺或四氢呋喃中,在碱如二甲基氨基吡啶、六甲基二硅氮化锂(lithiumhexamethyldisilazide)等存在下进行。通过使用这里所述的程序,产物153.3和153.4,只是当X是二烷基膦酰基时的情况除外,被转化成膦酸酯153.5和153.6。
实施例154
该吡唑153.1在二甲基甲酰胺溶液中在70℃下与一摩尔当量的溴丙基膦酸二烷基酯154.1(Synthelec)和碳酸铯进行反应,得到吡唑154.2和154.3。
实施例155
该吡唑153.1在四氢呋喃溶液中与1,4-双(溴甲基)苯155.1和六甲基二硅氮化钾进行反应,得到烷基化产物155.2和155.3。该2’-取代的异构体155.2然后在阿尔布佐夫反应中与亚磷酸三烷基酯反应,得到膦酸酯155.4。阿尔布佐夫反应已描述在Handb.Organophosphorus Chem.,1992,115中。在其中溴取代基转化成相应膦酸酯的这一程序中,底物在约60℃到约160℃下与五倍到五十倍摩尔过量的亚磷酸三烷基酯一起加热,实施该转化。
该2’-取代的吡唑155.3在70℃下在二甲基甲酰胺溶液中与一摩尔当量的巯基乙基膦酸二烷基酯155.5(Zh.Obschei.Khim.,1973,43,2364)和碳酸铯进行反应,得到硫醚膦酸酯155.6。
通过使用以上程序,但使用不同的二溴化物,和/或不同的巯基取代的膦酸酯,获得与155.4和155.6类似的产物。
实施例156
6α-甲-17-羟孕酮(甲羟孕酮),156A,(美国专利No 3,043,832,3,061,616和3,377,364)加以保护而获得衍生物156.1。该酮通过在甲苯溶液中在回流温度下与乙二醇和酸催化剂反应来加以保护,例如转化成环状乙二醇缩酮,按照在J.Am.Chem.Soc.,1955,77,1904中所述。通过与吡啶鎓甲苯磺酸盐在丙酮水溶液中进行去保护,按照在J.Chem.Soc.,Chem.Comm.,1987,1351中所述。
另外地,该20-酮通过转化成N,N-二甲基腙来加以保护。该二甲基腙是通过该酮156A与N,N-二甲基肼在乙醇-乙酸中反应来制备的,按照在Org.Syn.,1970,50,102中所述。该基团通过用乙酸钠和乙酸在四氢呋喃水溶液中处理来除去,按照在J.Am.Chem.Soc.,1979,101,5841中所述。
另外地,该20-酮作为二乙胺加合物来保护。在这一程序中,按照在J.Chem.Soc.,Chem.Comm.,1983,406中所述,底物156A与四(二乙基胺)化锂反应,获得加合物。该酮通过与水在含水有机溶剂中反应来进行去保护。
受保护的化合物156.1然后通过使用如下所述的程序被转化成含膦酸酯的类似物156.2,然后保护基团被除去,如上所述,得到膦酸酯156.3。
实施例157
酮保护的衍生物156.1与羟胺或胺157.1反应,其中R2是烷基、链烯基、环烷基或环烯基,任选地引入杂原子
、
或
,或官能团如酰胺、酯、肟、亚砜或砜等,或任选取代的芳基、杂芳基或芳烷基,任选地引入杂原子
、
或
,和X是膦酸酯基团或随后被转化成含膦酸酯的取代基的一种基团。例如,X是二烷基膦酰基,溴,羟基,氨基,羧基等等。该反应是在等摩尔量的反应物之间在非质子传递溶剂如吡啶或二甲苯中,或在醇溶剂如乙醇中,任选在酸催化剂存在下,来进行,得到肟157.2。甾族3-酮的肟的制备已描述在Anal.Bioch.,1978,86,133中和在J.Mass.Spectrom.,1995,30,497中。保护基团然后被除去,按照在实施例156中所述,获得20-酮膦酸酯产物157.3。
实施例157A
在这里示出了引入膦酸酯基团的羟胺醚的制备。其中Lv是离去基团如溴或三氟甲基磺酰基氧基的膦酸酯157.4与BOC-羟胺157.5(Aldrich)反应,生产醚157.6。反应是在等摩尔量的反应物之间在极性溶剂如二甲基甲酰胺或四氢呋喃中,在碱如氢氧化钾或二甲基胺基吡啶存在下进行。然后进行去保护(例如通过用三氟乙酸处理),得到羟胺醚157.7。以上程序也可用于取代的羟胺的制备,后者是膦酸酯的前体。
实施例158
在这里示出了膦酸酯的制备,其中膦酸酯通过亚氨基氧基来连接。在这一程序中,其中20-酮作为二甲基腙衍生物来保护的底物156.1与如上所述从三氟甲基磺酰基氧基甲基膦酸二烷基酯(Tetrahedron Lett.,1986,27,1477)和BOC-羟胺制得的二烷基膦酰基甲基羟胺158.1进行反应,获得肟158.2。去保护,按照在实施例156中所述,获得20-酮膦酸酯158.3。该肟形成反应是在环境温度下在乙醇-乙酸溶液中在等摩尔量的反应物之间进行的。
使用以上程序但代替羟胺醚158.1而使用不同的肟醚157.1,获得相应产物157.3。
实施例159
其中20-酮作为二甲基腙来保护的二烯酮156.1,如上所述,与如上所述从5-溴-3-溴-甲基-吡啶(WO 95/28400)和BOC保护的羟胺157.5制得的O-(5-溴-3-吡啶基-甲氧基)-羟胺159.1进行反应,得到肟159.2。保护基团然后被除去,得到20-酮产物159.3。后一种产物然后在钯催化剂存在下与亚磷酸二烷基酯159.4反应,获得膦酸酯159.5。通过在芳基溴和二烷基亚磷酸酯之间的偶联反应制备芳基膦酸酯的方法已描述在J.Med.Chem.,1992,35,1371中。反应在大约100℃下在惰性溶剂如甲苯中,在碱如三乙胺和催化量的四(三苯基膦)钯(0)存在下进行。
另外地,溴化合物159.3与乙烯基膦酸二烷基酯159.6(Aldrich)偶联,获得膦酸酯159.7。芳基卤化物与烯烃利用Heck反应的偶联已描述在例如F.A.Carey和R.J.Sundberg,“Advanced OrganicChemistry”,503ff(Plenum,2001)中和在Acc.Chem.Res.,1979,12,146中。该芳基溴和烯烃在极性溶剂中如二甲基甲酰胺或二噁烷中,在钯(0)催化剂如四(三苯基膦)钯(0)或钯(II)催化剂如乙酸钯(II)存在下,和任选地在碱如三乙胺或碳酸钾存在下,进行偶联。任选,在产物159.7中存在的styrenoid双键例如通过与二酰亚胺反应而被还原,得到饱和的类似物159.8。烯键的还原已描述在R.C.Larock,“Comprehensive Organic Transformations”,6ff(VCH 1989)中。该转变利用催化氢化,例如通过使用钯/碳催化剂和氢或氢给体,或通过利用二酰亚胺或乙硼烷来进行。
通过使用以上程序,但代替溴吡啶基试剂159.1,使用不同的溴取代的芳基或杂芳基烷氧基羟胺,和/或不同的链烯基膦酸二烷基酯,获得了与化合物159.5、159.7和159.8类似的产物。
实施例160
其中20-酮作为二甲基腙来保护的二烯酮156.1与2-羟乙基羟胺160.1(J.Chem.Soc.Chem.Comm.,1986,903)进行反应,得到肟160.2。不饱和的甾族酮与羟胺的反应已描述在J.Steroid Bioch.,1976,7,795中;该反应是在等摩尔量的反应物之间在极性有机溶剂如吡啶或甲醇中,任选在乙酸或乙酸钠存在下进行。该产物160.2然后与4-氨基苯基膦酸二烷基酯160.3(Epsilon)和羰基二咪唑进行偶联,在去保护之后获得氨基甲酸酯肟160.4。氨基甲酸酯的制备方法已描述在“Comprehensive Organic Functional Group Transformations”,6卷,416ff(A.R.Katritzky,ed.,Pergamon,1995)中,和在S.R.Sandler和W.Karo,“Organic Functional Group Preparations”,260ff(Academic Press,1986)中。在该程序,该胺在惰性非质子传递溶剂如二氯甲烷或四氢呋喃中,与光气或它的官能化等同物如羰基二咪唑、三光气、五氟苯基碳酸酯等反应,获得相应的活化的酰基胺。后一化合物然后与醇反应,得到氨基甲酸酯。
通过使用以上程序,但代替羟基取代的羟胺160.1,使用不同的羟基取代的羟胺,和/或不同的氨基取代的膦酸酯,获得与160.4类似的产物。
实施例161
其中该20-酮作为环状乙二醇缩酮来保护的烯酮161.1与甲酸乙酯和碱如氢化钠,在惰性溶剂如甲苯或二甲基甲酰胺中进行反应,按照在J.Am.Chem.Soc.86:1520(1964)中所述,获得2-甲酰基产物161.2。这一化合物然后与烷基,芳烷基,芳基或杂芳基肼161.3反应,其中取代基X是膦酸酯基团或可以随后转变成含膦酸酯的取代基的一种基团。例如,X是二烷基膦酰基,溴,羟基,氨基,羧基等等。该反应得到,在20-酮的去保护后,异构的2’-和1’-芳基吡唑161.4和161.5。该吡唑形成反应是在等摩尔量的反应物之间在酸性溶剂如乙酸中进行,按照在J.Am.Chem.Soc.,1964,86,1520中所述。该吡唑161.4和161.5,然后例如通过这里描述的程序,被转变成膦酸酯161.6和161.7。
实施例162
该酮醛161.2,如上所述,与3-羧基苯基肼162.1(Apin)进行反应,得到吡唑162.2和162.3。该2’-取代的异构体162.2然后在二甲基甲酰胺溶液中在环境温度下与一摩尔当量的2-氨基乙基膦酸二烷基酯,162.4(Aldrich),和二环己基碳二亚胺进行反应,得到酰胺膦酸酯162.5。从羧酸类和衍生物制备酰胺的方法例如描述在S.R.Sandler和W.Karo,“Organic Functional Group Preparations”,274(AcademicPress,1968),和R.C.Larock,“Comprehensive OrganicTransformations”,972ff(VCH,1989)中。该羧酸与该胺在活化剂例如二环己基碳二亚胺或二异丙基碳二亚胺存在下,任选地在例如羟基苯并三唑、N-羟基-琥珀酰亚胺或N-羟基吡啶酮存在下,在非质子溶剂如吡啶、DMF或二氯甲烷中进行反应,获得酰胺。
另外地,该羧酸可以首先转化成活化的衍生物如酰氯、酸酐、混合酸酐、咪唑烷(imidazolide)等,然后与胺在有机碱例如吡啶存在下反应,获得该酰胺。
羧酸转化成相应的酰氯的过程可通过用试剂例如亚硫酰氯或草酰氯在惰性有机溶剂如二氯甲烷中,任选在催化量二甲基甲酰胺存在下处理羧酸来进行的。
异构的吡唑162.3,如上所述,与一摩尔当量的通过在4-氨基-2-溴噻吩(Tetrahedron Lett.,1987,43,3295)和亚磷酸二烷基酯之间的钯催化偶联反应(如上所述)所制得的4-氨基-2-噻吩基膦酸二烷基酯162.6进行反应,得到酰胺膦酸酯162.7。
通过使用以上程序,但使用不同的羧基取代的肼,和/或不同的氨基取代的膦酸酯,获得与162.5和162.7类似的产物。
实施例163
该酮醛161.2,如上所述,与3-溴苯肼163.1(fluka)进行反应,生产吡唑163.2和163.3。该2’-取代的异构体163.2,如上所述,与亚磷酸二烷基酯163.4偶联,获得膦酸酯163.5。
另外地,该1’-取代的吡唑163.3,如上所述,与乙烯基膦酸二烷基酯163.6(Aldrich)和钯催化剂进行偶联反应,制备乙烯基膦酸酯163.7。任选地,该产物被还原,如上所述,得到类似物163.8。
通过使用以上程序,但代替溴苯肼163.1,使用不同的溴取代的肼,和/或不同的链烯基膦酸二烷基酯,获得与化合物163.5、163.7和163.8类似的产物。
实施例164
该酮醛161.2与肼反应,在该20-酮的去保护后,获得吡唑衍生物164.1。甾族2-甲酰基-3-酮与肼的反应已描述J.Am.Chem.Soc.,1964,86,1520中。反应是在乙酸中在环境温度下进行的。该吡唑产物然后与其中R2和X如上所定义的溴甲基化合物164.2或反应活性溴杂芳族试剂进行反应,得到烷基化产物164.3和164.4。取代的吡唑的烷基化例如描述在T.L.Gilchrist,“Heterocyclic Chemistry”,309(Longman,1992)中。反应在等摩尔量的底物之间在极性溶剂如二甲基甲酰胺或四氢呋喃中,在碱如二甲基氨基吡啶、六甲基二硅氮化锂(lithium hexamethyldisilazide)等存在下进行。通过使用这里所述的程序,产物164.3和164.4,只是当X是二烷基膦酰基时的情况除外,被转化成膦酸酯164.5和164.6。
实施例165
该吡唑164.1在二甲基甲酰胺溶液中在70℃下与一摩尔当量的4-溴甲基膦酸二烷基酯165.1(Lancaster)和六甲基二硅氮化锂进行反应,得到吡唑165.2和165.3。
通过使用以上程序,但使用不同的溴取代的膦酸酯,获得与165.2和165.3类似的产物。
实施例166
该吡唑164.1在四氢呋喃溶液中与4-溴甲基环己酮166.1(WO97/37959)和六甲基二硅氮化锂进行反应,得到烷基化产物166.2和166.3。该2’-取代的异构体166.2然后在还原胺化反应中与氨基甲基膦酸二烷基酯166.5(Interchim)和三乙酰氧基硼氢化钠进行反应,得到胺膦酸酯166.4。由还原胺化程序制备胺的方法例如已描述在R.C.Larock,“Comprehensive Organic Transformations”,421(VCH)中,和在F.A.Carey和R.J.Sundberg,“Advanced OrganicChemistry”,部分B,269(Plenum,2001)中。在这一程序中,该胺组分和醛或酮组分一起在还原剂如硼烷、氰基硼氢钠、三乙酰氧基硼氢化钠或二异丁基氢化铝存在下,任选在路易斯酸如钛四异丙醇盐存在下进行反应,按照在J.Org.Chem.,1990,55,2552中所述。
该1’-取代的吡唑166.3通过相同的反应被转化成异构的胺膦酸酯166.6。
通过使用以上程序,但使用不同的溴取代的醛和酮,和/或不同的氨基取代的膦酸酯,获得与166.4和166.6类似的产物。
实施例167
9α-氯-16α-甲基-11β,17α,21-三羟基孕甾-1,4-二烯-3,21-二酮,167A(美国专利No.4,472,393)与仲甲醛和酸催化剂如盐酸进行反应,按照在Protective Groups in Organic Synthesis,T.W.Greene和P.G.M.Wuts,Wiley,第二版1990,p.223,得到BMD衍生物167.1。膦酸酯结构部分然后通过使用如下所述的程序被引入,生产出膦酸酯167.2。BMD结构部分然后水解,例如用50%乙酸水溶液处理,按照在“Protective Groups in Organic Synthesis”中由T.W.Greene和P.G.M.Wuts,Wiley,第二版1990,p.223页中所述,获得三醇167.3。后一种化合物然后通过使用在Chem.Pharm.Bull.,1986,34,1613中描述的程序被转化成17,21-环状原酸酯167.5。底物在二甲基甲酰胺中在70℃下与两摩尔当量的原2-糠酸三乙基酯165.4(Zh.Org.Khim.,1980,50,1348)和催化量的对甲苯磺酸进行反应。该产物然后与过量的三甲基甲硅烷基氯化物在二甲基甲酰胺中在环境温度下进行反应,生产21-氯17-(2-糠酸酯)产物,167.6。
另外地,底物167.3利用在J.Med.Chem.,1987,30,1581中描述的方法被转化成产物167.6。在这一程序中,该21-羟基通过与甲磺酰氯在吡啶中反应被转化成21-甲磺酸酯来活化;该甲磺酸酯基团然后通过与氯化锂在二甲基甲酰胺中反应被置换而得到21-氯中间体,和该17-羟基被酯化得到21-氯-17-(2-糠酸酯)衍生物167.6。17α-羟基在11β羟基的存在下的选择性酰化已描述在J.Med.Chem.,1987,30,1581中。
实施例168
BMD保护的衍生物167.1与胺或羟胺168.1反应,其中R2是烷基、链烯基、环烷基或环烯基,任选地引入杂原子
、
或
,或官能团如酰胺、酯、肟、亚砜或砜等,或任选取代的芳基、杂芳基或芳烷基,任选地引入杂原子
、
或
,和X是膦酸酯基团或随后被转化成含膦酸酯的取代基的一种基团。例如,X是二烷基膦酰基,溴,羟基,氨基,羧基等等。该反应是在等摩尔量的反应物之间在非质子传递溶剂如吡啶或二甲苯中,或在醇溶剂如乙醇中,任选在酸催化剂存在下,来进行,得到亚胺或肟。甾族3-酮的肟的制备已描述在Anal.Bioch.,1978,86,133中和在J.Mass.Spectrom.,1995,30,497中。按照这里所述,该BMD保护的侧链化合物168.2然后转化成三醇168.3,和然后转化成21-氯17-(2-糠酸酯)产物,168.4。
在这里示出了引入膦酸酯基团的羟胺醚的制备。在这一程序中,其中Lv是离去基团如溴或三氟甲基磺酰基氧基的膦酸酯168.5与BOC-羟胺168.6(Aldrich)反应,生产醚168.7。反应是在等摩尔量的反应物之间在极性溶剂如二甲基甲酰胺或四氢呋喃中,在碱如氢氧化钾或二甲基胺基吡啶存在下进行。然后进行去保护(例如通过用三氟乙酸处理),得到羟胺醚168.8。
实施例169
底物167.1与二烷基膦酰基甲基羟胺169.1(按照以上所述从三氟甲基-磺酰基氧基甲基膦酸二烷基酯(Tet.Lett.,1986,27,1477)和BOC-羟胺制得)进行反应,获得肟169.2。然后进行去保护而获得三醇169.3,通过使用实施例167中描述的程序从它制备21-氯17-(2-糠酸酯)化合物,169.4。该肟形成反应是在环境温度下在乙醇-乙酸溶液中在等摩尔量的反应物之间进行的。
使用以上程序,但代替羟胺醚169.1而使用不同的肟醚167.1,获得相应产物169.4。
实施例170
二烯酮167.1,如上所述,与按照以上所述方法从5-溴-3-溴甲基吡啶(EP511865)和BOC保护的羟胺168.6制得的O-(5-溴-3-吡啶基甲氧基)-羟胺170.1进行反应,在侧链的去保护后获得肟170.2。该产物然后在钯催化剂存在下与亚磷酸二烷基酯170.3反应,获得膦酸酯170.4。通过在芳基溴和二烷基亚磷酸酯之间的偶联反应制备芳基膦酸酯的方法已描述在J.Med.Chem.,1992,35,1371中。反应在大约100℃下在惰性溶剂如甲苯中,在碱如三乙胺和催化量的四(三苯基膦)钯(0)存在下进行。该21-羟基化合物170.4然后按照在实施例167中所述,被转化成21-氯17-(2-糠酸酯)衍生物,170.5。
另外地,溴化合物170.2与乙烯基膦酸二烷基酯170.6(Aldrich)偶联,获得膦酸酯170.7。芳基卤化物与烯烃利用Heck反应的偶联描述在例如F.A.Carey和R.J.Sundberg,“Advanced OrganicChemistry”,503ff(Plenum,2001)中和在Acc.Chem.Res.,1979,12,146中。该芳基溴和烯烃在极性溶剂中如二甲基甲酰胺或二噁烷中,在钯(0)催化剂如四(三苯基膦)钯(0)或钯(II)催化剂如乙酸钯(II)存在下,和任选地在碱如三乙胺或碳酸钾存在下,进行偶联。任选,在产物170.7中存在的styrenoid双键例如通过与二酰亚胺反应而被还原,得到饱和的类似物170.9。烯键的还原已描述在R.C.Larock,“Comprehensive Organic Transformations”6ff(VCH,1989)中。该转变利用催化氢化,例如通过使用钯/碳催化剂和氢或氢给体,或通过利用二酰亚胺或乙硼烷来进行。该产物,170.7和170.9,然后转化成21-氯17-(2-糠酸酯)类似物,170.8和170.10。
通过使用以上程序,但代替溴吡啶基甲氧基试剂170.1,使用不同的溴取代的芳基或杂芳基烷氧基羟胺,和/或不同的链烯基膦酸二烷基酯,获得了与化合物170.5、170.8和170.10类似的产物。
实施例171
在这里示出了膦酸酯的制备,其中膦酸酯通过亚氨基来连接。在这一程序中,底物167.1与4-氨基苯基膦酸二烷基酯171.1(Epsilon)反应,在去保护后获得亚胺产物171.2。该亚胺形成反应在烃溶剂如甲苯或二甲苯中,在回流温度下,在碱性催化剂如甲醇钠,或酸催化剂如甲苯磺酸存在下,在共沸条件下进行。该产物然后被转化成21-氯17-(2-糠酸酯)化合物,171.3。
通过使用以上程序,但代替4-氨基苯基膦酸酯171.1,使用不同的氨基取代的芳基或杂芳基膦酸酯,获得与171.3类似的产物。
实施例172
该二烯酮167.1与O-(2-氨基乙基)羟胺172.1(Pol.J.Chem.,1981,55,1163)进行反应,得到肟172.2。甾族1,4-二烯-3-酮与取代的羟胺的反应已描述在J.Steroid Bioch.,1976,7,795中;反应是在等摩尔量的反应物之间在极性有机溶剂如吡啶或甲醇中,任选在乙酸或乙酸钠存在下进行。该产物然后在还原胺化程序中与4-甲酰基苯基膦酸二烷基酯172.3(Epsilon)和三乙酰氧基硼氢化钠进行反应,得到胺肟172.4。由还原胺化程序制备胺的方法例如已描述在R.C.Larock,“Comprehensive Organic Transformations”,421(VCH)中,和在F.A.Carey和R.J.Sundberg,“Advanced Organic Chemistry”,部分B,269(Plenum,2001)中。在这一程序中,该胺组分和醛或酮组分一起在还原剂如硼烷、氰基硼氢化钠、三乙酰氧基硼氢化钠或二异丁基氢化铝存在下,任选在路易斯酸如钛四异丙醇盐存在下进行反应,按照在J.Org.Chem.,1990,55,2552中所述。
胺产物172.4然后按照这里所述被转化成21-氯17-(2-糠酸酯)产物,171.6。
通过使用以上程序,但代替羟胺172.3,使用不同的氨基取代的羟胺,和/或不同的甲酰基取代的膦酸酯,获得与177.6类似的产物。
实施例173
该BMD保护的二烯酮167.1被还原,获得1,2-二氢产物173.1。该催化氢化反应通过三(三苯基膦)铑(I)氯化物的使用来进行,例如按照在J.Med.Chem.,2001,44,602中所述。该产物然后与甲酸乙酯和碱如氢化钠,在惰性溶剂如甲苯或二甲基甲酰胺中进行反应,按照在J.Am.Chem.Soc.,1964,86,1520中所述,获得2-甲酰基产物173.2。这一化合物然后与烷基,芳烷基,芳基或杂芳基肼173.3反应,其中取代基X是膦酸酯基团或可以随后转变成含膦酸酯的取代基的一种基团。例如,X是二烷基膦酰基,溴,羟基,氨基,羧基等等。反应得到异构体2’-和1’-芳基吡唑,173.4和173.5。该吡唑形成反应是在等摩尔量的反应物之间在酸性溶剂如乙酸中进行,按照在J.Am.Chem.Soc.,1964,86,1520中所述。该吡唑173.4和173.5然后,例如通过在这里中描述的程序,经由BMD保护的中间体173.6和173.7,被转变成21-氯17-(2-糠酸酯)膦酸酯,173.9和173.11。
实施例174
该酮醛173.2,如上所述,与4-溴-苄基肼174.1(Ann.,1968,717,104)进行反应,得到吡唑174.2和174.3。该2’-取代的异构体174.2然后,按照在实施例170中所述,与亚磷酸二烷基酯偶联,得到膦酸酯173.4。该BMD保护基然后被除去和该产物转化成21-氯17-(2-糠酸酯)产物173.6。
异构的吡唑174.3经历相同系列的反应,获得异构产物173.9。
通过使用以上程序,但使用不同的溴取代的肼,获得与173.6和173.9类似的产物。
实施例174
该酮醛173.2,如上所述,与4-羟基-苯基肼174.1(EP 437105)进行反应,生产吡唑174.2和174.3。该1’-取代的异构体174.2在二甲基甲酰胺中在70℃下与2-溴乙基膦酸二烷基酯174.4(Aldrich)和碳酸钾进行反应,得到醚膦酸酯174.5。该产物然后被去保护而获得三醇,174.6,它转化成21-氯17-(2-糠酸酯)化合物,174.7。
另外地,该2’-取代的吡唑174.3,在Mitsonobu反应中,与2-巯基乙基膦酸二烷基酯174.8(Zh.Obschei.Khim.,1973,43,2364)偶联,制备硫醚膦酸酯174.9,它进行去保护,然后该产物被转化成21-氯17-(2-糠酸酯)类似物,174.11。利用Mitsonobu反应制备芳族醚和硫醚的方法例如已描述在R.C.Larock,“Comprehensive OrganicTransformations”,448页(VCH,1989)中,在F.A.Carey和R.J.Sundberg,“Advanced Organic Chemistry”,部分B,153-4(Plenum,2001)中,和在Org.React.,1992,42,335中。该酚和醇或硫醇组分一起在非质子传递溶剂例如四氢呋喃中,在偶氮二羧酸二烷基酯和三芳基膦存在下反应,获得醚或硫醚产物。该程序也描述在Org.React.,1992,42,335-656中。
通过使用以上程序,但代替4-羟基-苯基肼174.1,使用不同的羟基取代的肼,和/或不同的二烷基溴-或巯基-取代的膦酸二烷基酯,获得了与化合物174.7和174.11类似的产物。
实施例175
酮醛173.2与肼反应,获得吡唑衍生物175.1。甾族2-甲酰基-3-酮与肼的反应已描述在J.Am.Chem.Soc,1964,86,1520中。反应是在乙酸中在环境温度下进行的。该吡唑产物然后与其中R2和X如上所定义的溴甲基化合物175.6或反应活性溴代杂芳族试剂进行反应,得到烷基化产物175.3和175.4。取代的吡唑的烷基化例如描述在T.L.Gilchrist,“Heterocyclic Chemistry”,309(Longman,1992)中。反应在等摩尔量的底物之间在极性溶剂如二甲基甲酰胺或四氢呋喃中,在碱如二甲基氨基吡啶、六甲基二硅氮化锂等存在下进行。该产物175.3和175.4,只是当X是二烷基膦酰基的情况除外,通过使用这里所述的程序被转化成膦酸酯175.5和175.6,然后去保护/氯化/酰化,获得21-氯17-(2-糠酸酯)化合物175.8和175.10。
实施例176
该吡唑175.1与2,5-二溴嘧啶176.1(Chem.Lett.,1992,583)进行反应,得到吡唑176.2和176.3。该产物然后,如上所述,与亚磷酸二烷基酯进行偶联,在侧链去保护和改性后,按照这里所述,获得21-氯17-(2-糠酸酯),176.5和176.7。
实施例177
该吡唑175.1在四氢呋喃溶液中与1,2-双(溴甲基)环丁烷177.1(J.Org.Chem.,1981,46,3530)和六甲基二硅氮化钾进行反应,得到烷基化产物177.1和177.2。该1’-取代的异构体177.2然后在阿尔布佐夫反应中与亚磷酸三烷基酯进行反应,在去保护和侧链改性后,得到21-氯17-(2-糠酸酯),177.5。阿尔布佐夫反应已描述在Handb.Organophosphorus Chem.,1992,115中。在其中溴取代基转化成相应膦酸酯的这一程序中,底物在约60℃到约160℃下与五倍到五十倍摩尔过量的亚磷酸三烷基酯一起加热,实施该转化。
该2’-取代的吡唑177.3经历相同系列的反应,得到胺膦酸酯177.7。
通过使用以上程序,但使用不同的二溴化物,获得与177.5和177.7类似的产物。
实施例178
其中布地缩松(Budesonide)178A的20-酮基和/或21-羟基被保护获得衍生物178.1的保护-去保护序列。该酮通过在甲苯溶液中在回流温度下与乙二醇和酸催化剂反应来加以保护,例如转化成环状乙二醇缩酮,按照在J.Am.Chem.Soc.,1955,77,1904中所述。通过与吡啶鎓甲苯磺酸盐在丙酮水溶液中进行去保护,按照在J.Chem.Soc.,Chem.Comm.,1987,1351中所述。
另外地,该20-酮通过转化成N,N-二甲基腙来加以保护。该二甲基腙是通过该酮178A与N,N-二甲基肼在乙醇-乙酸中反应来制备的,按照在Org.Syn.,1970,50,102中所述。该基团通过用乙酸钠和乙酸在四氢呋喃水溶液中处理来除去,按照在J.Am.Chem.Soc.,1979,101,5841中所述。
另外地,该20-酮作为二乙胺加合物来保护。在这一程序中,按照在J.Chem.Soc.,Chem.Comm.,406,1983中所述,底物178A与四(二乙基胺)化锂反应,获得加合物。该酮通过与水在含水有机溶剂中反应来进行去保护。
该21-羟基,例如,通过与一摩尔当量的乙酰氯在二氯甲烷/吡啶中反应转化成乙酸酯来加以保护。该21-乙酰氧基团通过与一摩尔当量的氢氧化锂在含水的二甲氧基乙烷中反应而被除去。
另外地,该21-羟基通过在二甲基甲酰胺溶液中与一摩尔当量的叔丁基氯二甲基硅烷和咪唑反应转化成叔丁基二甲基甲硅烷基醚来加以保护,按照在J.Am.Chem.Soc.,1972,94,6190中所述。该甲硅烷基醚通过与四丁铵氟化物在四氢呋喃溶液中来除去,按照在J.Am.Chem.Soc.,1972,94,6190中所述。
受保护的化合物178.1然后通过使用如下所述的程序被转化成含膦酸酯的类似物178.2,然后保护基团被除去,如上所述,得到膦酸酯178.3。
实施例179
酮保护的衍生物179.1与胺或羟胺179.2反应,其中R2是烷基、链烯基、环烷基或环烯基,任选地引入杂原子
、
或
,或官能团如酰羟胺、酯、肟、亚砜或砜等,或任选取代的芳基、杂芳基或芳烷基,任选地引入杂原子
、
或
,和X是膦酸酯基团或随后被转化成含膦酸酯的取代基的一种基团。例如,X是二烷基膦酰基,溴,羟基,氨基,羧基等等。该反应是在等摩尔量的反应物之间在非质子传递溶剂如吡啶或二甲苯中,或在醇溶剂如乙醇中,任选在酸催化剂存在下,来进行,得到亚胺或肟179.3。甾族3-酮的肟的制备已描述在Anal.Bioch.,1978,86,133中和在J.Mass.Spectrom.,1995,30,497中。保护基团然后被除去,按照在这里所述,获得20-酮膦酸酯产物179.4。
实施例179A
在这里还示出了引入膦酸酯基团的羟胺醚的制备。在这一程序中,其中Lv是离去基团如溴或三氟甲基磺酰基氧基的膦酸酯179.5与BOC-羟胺179.6(Aldrich)反应,生产醚179.7。反应是在等摩尔量的反应物之间在极性溶剂如二甲基甲酰胺或四氢呋喃中,在碱如氢氧化钾或二甲基胺基吡啶存在下进行。然后进行去保护(例如通过用三氟乙酸处理),得到羟胺醚179.8。以上程序也可用于取代的羟胺的制备,后者是膦酸酯的前体。
实施例180
其中20-酮作为二甲基腙衍生物来保护的底物179.1与如上所述从三氟甲基磺酰基-氧基甲基膦酸二烷基酯(Tetrahedron Lett.,1986,27,1477)和BOC-羟胺制得的二烷基膦酰基甲基羟胺180.1进行反应,获得肟180.2。去保护,按照在实施例179中所述,获得20-酮膦酸酯180.3。该肟形成反应是在环境温度下在乙醇-乙酸溶液中在等摩尔量的反应物之间进行的。
使用以上程序但代替羟胺醚180.1而使用不同的肟醚179.2,获得相应产物179.4。
实施例181
以上示出了其中膦酸酯基团通过苄氧基肟基团来连接的化合物179.1的制备。在这一程序中,其中该20-酮作为二甲基腙来保护的二烯酮179.1,如上所述,与如上所述从2-溴苄基溴化物和BOC保护的羟胺179.6制得的O-(2-溴苄基)羟胺181.1进行反应,得到肟181.2。保护基团然后被除去,得到20-酮产物181.3。后一种产物然后在钯催化剂存在下与亚磷酸二烷基酯181.4反应,获得膦酸酯181.5。通过在芳基溴和二烷基亚磷酸酯之间的偶联反应制备芳基膦酸酯的方法已描述在J.Med.Chem.,1992,35,1371中。反应在大约100℃下在惰性溶剂如甲苯中,在碱如三乙胺和催化量的四(三苯基膦)钯(0)存在下进行。
另外地,溴化合物181.3与乙烯基膦酸二烷基酯181.6(Aldrich)偶联,获得膦酸酯181.7。芳基卤化物与烯烃利用Heck反应的偶联描述在例如“Advanced Organic Chemistry”,F.A.Carey和R.J.Sundberg,Plenum,2001,p.503ff中和在Acc.Chem.Res.,1979,12,146中。该芳基溴和烯烃在极性溶剂中如二甲基甲酰胺或二噁烷中,在钯(0)催化剂如四(三苯基膦)钯(0)或钯(II)催化剂如乙酸钯(II)存在下,和任选地在碱如三乙胺或碳酸钾存在下,进行偶联。任选,在产物181.7中存在的styrenoid双键例如通过与二酰亚胺反应而被还原,得到饱和的类似物181.8。烯键的还原已描述在“ComprehensiveOrganic Transformations”,R.C.Larock,VCH,1989,p.6ff中。该转变利用催化氢化,例如通过使用钯/碳催化剂和氢或氢给体,或通过利用二酰亚胺或乙硼烷来进行。
通过使用以上程序,但代替溴苄基试剂181.1,使用不同的溴取代的芳基或杂芳基烷氧基羟胺,和/或不同的链烯基膦酸二烷基酯,获得了与化合物181.5、181.7和181.8类似的产物。
实施例182
其中20-酮作为二甲基腙来保护的底物171.1与4-氨基苯基膦酸二烷基酯182.1(Epsilon)进行反应,在去保护后,得到亚胺产物182.2。该亚胺形成反应在烃溶剂如甲苯或二甲苯中,在回流温度下,在碱性催化剂如甲醇钠,或酸催化剂如甲苯磺酸存在下,在共沸条件下进行。
通过使用以上程序,但代替4-氨基苯基膦酸酯182.1,使用不同的氨基取代的芳基或杂芳基膦酸酯,获得与182.2类似的产物。
实施例183
在这里示出了其中膦酸酯基团利用肟基和氨基甲酸酯键来连接的膦酸酯类的制备。在这一程序中,其中该20-酮作为二甲基腙来保护的二烯酮171.1与4-氨基丁基羟胺183.1(Pol.J.Chem.,1981,55,1163)进行反应,得到肟183.2。(甾族1,4-二烯-3-酮与羟胺的反应已描述在J.Steroid Bioch.,1976,7,795。)反应是在等摩尔量的反应物之间在极性有机溶剂如吡啶或甲醇中,任选在乙酸或乙酸钠存在下进行。该产物183.2然后与2-羟乙基膦酸二烷基酯183.3(Epsilon)和羰基二咪唑(CDI)进行偶联,在去保护之后获得氨基甲酸酯肟183.4。氨基甲酸酯的制备方法已描述在“Comprehensive Organic FunctionalGroup Transformations”,A.R.Katritzky,ed.,Pergamon,1995,Vol.6,p.416ff中,和在“Organic Functional Group Preparations”,S.R.Sandler和W.Karo,Academic Press,1986,p.260ff中。在该程序,该胺在惰性非质子传递溶剂如二氯甲烷或四氢呋喃中,与光气或它的官能化等同物如羰基二咪唑、三光气、五氟苯基碳酸酯等反应,获得相应的活化的酰基胺。后一化合物然后与醇反应,得到氨基甲酸酯。
通过使用以上程序,但代替氨基取代的肼183.1,使用不同的氨基取代的肼,和/或不同的羟基取代的膦酸酯,获得与183.4类似的产物。
实施例184
其中该21-羟基按照在实施例178中所述的方式来保护的二烯酮178.3被还原,获得1,2-二氢产物184.1。该催化氢化反应通过三(三苯基膦)铑(I)氯化物的使用来进行,例如按照在J.Med.Chem.,2001,44,602中所述。该产物然后与甲酸乙酯和碱如氢化钠,在惰性溶剂如甲苯或二甲基甲酰胺中进行反应,按照在J.Am.Chem.Soc.,1964,86,1520中所述,获得2-甲酰基产物184.2。这一化合物然后与烷基,芳烷基,芳基或杂芳基肼184.3反应,其中取代基X是膦酸酯基团或可以随后转变成含膦酸酯的取代基的一种基团。例如,X是二烷基膦酰基,溴,羟基,氨基,羧基等等。该反应得到,在21-羟基的去保护后,异构的2’-和1’-芳基吡唑184.4和184.5。该吡唑形成反应是在等摩尔量的反应物之间在酸性溶剂如乙酸中进行,按照在J.Am.Chem.Soc.,1964,86,1520中所述。吡唑类184.4和184.5然后例如由实施例180和181中描述的程序分别转变成膦酸酯184.6和184.7。
实施例185
在这一程序中,化合物184.2,如上所述,与4-溴苯肼185.1(J.Organomet.Chem.,1999,62,581)进行反应,得到吡唑185.2和185.3。该2’-取代的异构体185.2然后如上所述与磷酸二烷基酯184.4进行反应,得到膦酸酯185.5。
该异构的吡唑185.3在Heck反应中,如上所述,与一摩尔当量的4-乙烯基苯基膦酸二烷基酯185.6(Macromolecules,1998,31,2918)进行反应,得到膦酸酯185.7。
通过使用以上程序,但使用不同的溴取代的肼,和/或不同的链烯基取代的膦酸酯,获得与185.5和185.7类似的产物。
实施例186
该酮醛184.2,如上所述,与4-羟基-苯基肼186.1(EP 437105)进行反应,生产吡唑186.2和186.3。该2’-取代的异构体186.2然后在二甲基甲酰胺溶液中在70℃下与一摩尔当量的溴丙基膦酸二烷基酯186.4(J.Amer.Chem.Soc.,2000,122,1554)和碳酸铯反应,得到醚膦酸酯186.5。
另外地,该1’-取代的吡唑186.3在Mitsonobu反应中与2-巯基乙基膦酸二烷基酯186.6(Zh.Obschei.Khim.,1973,43,2364)偶联,制备硫醚膦酸酯186.7。利用Mitsonobu反应制备芳族醚和硫醚的方法例如描述在“Comprehensive Organic Transformations”,R.C.Larock,VCH,1989,448页中,和在“Advanced Organic Chemistry”,部分B,F.A.Carey和R.J.Sundberg,Plenum,2001,153-4页中和在Org.React.,1992,42,335中。该酚和醇或硫醇组分一起在非质子传递溶剂例如四氢呋喃中,在偶氮二羧酸二烷基酯和三芳基膦存在下反应,获得醚或硫醚产物。该程序也描述在Org.React.,1992,42,335-656中。
通过使用以上程序,但代替羟基-苯基肼186.1,使用不同的羟基芳基肼,和/或不同的溴-或巯基-取代的膦酸二烷基酯,获得了与化合物186.5和186.7类似的产物。
实施例187
酮醛184.2与肼反应,获得吡唑衍生物187.1。甾族2-甲酰基-3-酮与肼的反应已描述J.Am.Chem.Soc.,1964,86,1520中。反应是在乙酸中在环境温度下进行的。该吡唑产物然后与其中R2和X如上所定义的溴甲基化合物187.2或反应活性溴代杂芳族试剂进行反应,得到烷基化产物187.3和187.4。取代的吡唑的烷基化例如描述在“Heterocyclic Chemistry”,T.L.Gilchrist,Longman,1992,第309页中。反应在等摩尔量的底物之间在极性溶剂如二甲基甲酰胺或四氢呋喃中,在碱如二甲基氨基吡啶、六甲基二硅氮化锂等存在下进行。通过使用这里所述的程序,产物187.3和187.4,只是当X是二烷基膦酰基时的情况除外,被转化成膦酸酯187.5和187.6。
实施例188
该吡唑187.1在二甲基甲酰胺溶液中在70℃下与一摩尔当量的4-溴甲基苯基膦酸二烷基酯188.1(Tet.,1998,54,9341)和六甲基二硅氮化锂进行反应,得到吡唑188.2和188.3。通过使用以上程序,但使用不同的溴甲基取代的膦酸酯,获得与188.2和188.3类似的产物。
实施例189
该吡唑187.1在四氢呋喃溶液中与1,3-双(溴甲基)环戊烷189.1(Bull.Soc.Chim.Fr.,1975,1295)和氢化钠进行反应,得到烷基化产物189.2和189.3。该2’-取代的异构体189.2然后在阿尔布佐夫反应中与亚磷酸三烷基酯反应,得到膦酸酯189.4。阿尔布佐夫反应已描述在Handb.Organophosphorus Chem.,1992,115中。在其中溴取代基转化成相应膦酸酯的这一程序中,底物在约60℃到约160℃下与五倍到五十倍摩尔过量的亚磷酸三烷基酯一起加热,实施该转化。
该2-取代的吡唑189.3在70℃下在二甲基甲酰胺溶液中与一摩尔当量的甲基氨基甲基膦酸二烷基酯189.5和碳酸铯进行反应,得到胺膦酸酯189.6。
通过使用以上程序,但使用不同的二卤化物,和/或不同的氨基取代的膦酸酯,获得与189.4和189.6类似的产物。
实施例190
其中双甲丙酰龙(Rimexolone)190A的20-酮基被保护获得衍生物190.1的保护-去保护序列。该酮通过在甲苯溶液中在回流温度下与乙二醇和酸催化剂反应来加以保护,例如转化成环状乙二醇缩酮,按照在J.Am.Chem.Soc.,1955,77,1904中所述。通过与吡啶鎓甲苯磺酸盐在丙酮水溶液中进行去保护,按照在J.Chem.Soc.,Chem.Comm.,1987,1351中所述。
另外地,该20-酮通过转化成N,N-二甲基腙来加以保护。该二甲基腙是通过该酮190A与N,N-二甲基肼在乙醇-乙酸中反应来制备的,按照在Org.Syn.,1970,50,102中所述。该基团通过用乙酸钠和乙酸在四氢呋喃水溶液中处理来除去,按照在J.Am.Chem.Soc.,1979,101,5841中所述。
另外地,该20-酮作为二乙胺加合物来保护。在这一程序中,按照在J.Chem.Soc.,Chem.Comm.,406,1983中所述,底物190.1与四(二乙基胺)化锂反应,获得加合物。该酮通过与水在含水有机溶剂中反应来进行去保护。
受保护的化合物190.2然后通过使用如下所述的程序被转化成含膦酸酯的类似物190.3,然后保护基团被除去,如上所述,得到膦酸酯190.3。
实施例191
酮保护的衍生物190.1与胺或羟胺191.1反应,其中R2是烷基、链烯基、环烷基或环烯基,任选地引入杂原子
、
或
,或官能团如酰羟胺、酯、肟、亚砜或砜等,或任选取代的芳基、杂芳基或芳烷基,任选地引入杂原子
、
或
,和X是膦酸酯基团或随后被转化成含膦酸酯的取代基的一种基团。例如,X是二烷基膦酰基,溴,羟基,氨基,羧基等等。该反应是在等摩尔量的反应物之间在非质子传递溶剂如吡啶或二甲苯中,或在醇溶剂如乙醇中,任选在酸催化剂存在下,来进行,得到亚胺或肟191.2。甾族3-酮的肟的制备已描述在Anal.Bioeh.,1978,86,133中和在J.Mass.Spectrom.,1995,30,497中。保护基团然后被除去,按照在实施例190中所述,获得20-酮膦酸酯产物191.3。
实施例191A
在这里还示出了引入膦酸酯基团的羟胺醚的制备。在这一程序中,其中Lv是离去基团如溴或三氟甲基磺酰基氧基的膦酸酯191.4与BOC-羟胺191.5(Aldrieh)反应,生产醚191.6。反应是在等摩尔量的反应物之间在极性溶剂如二甲基甲酰胺或四氢呋喃中,在碱如氢氧化钾或二甲基胺基吡啶存在下进行。然后进行去保护(例如通过用三氟乙酸处理),得到羟胺醚191.7。以上程序也可用于取代的羟胺的制备,后者是膦酸酯的前体。
实施例192
其中20-酮作为二甲基腙衍生物来保护的底物190.1与如上所述从三氟甲基磺酰基-氧基甲基膦酸二烷基酯(Tetrahedron Lett.,1986,27,1477)和BOC-羟胺制得的二烷基膦酰基甲基羟胺192.1进行反应,获得肟192.2。去保护,按照在实施例191中所述,获得20-酮膦酸酯192.3。该肟形成反应是在环境温度下在乙醇-乙酸溶液中在等摩尔量的反应物之间进行的。
使用以上程序但代替羟胺醚192.1而使用不同的肟醚191.1,获得相应产物191.3。
实施例193
其中该20-酮作为二甲基腙来保护的二烯酮190.1,如上所述,与如上所述从3-溴苄基溴化物和BOC保护的羟胺191.5制得的O-(3-溴苄基)羟胺193.1进行反应,得到肟193.2。保护基团然后被除去,得到20-酮产物193.3。后一种产物然后在钯催化剂存在下与亚磷酸二烷基酯193.4反应,获得膦酸酯193.5。通过在芳基溴和二烷基亚磷酸酯之间的偶联反应制备芳基膦酸酯的方法已描述在J.Med.Chem.,1992,35,1371中。反应在大约100℃下在惰性溶剂如甲苯中,在碱如三乙胺和催化量的四(三苯基膦)钯(0)存在下进行。
另外地,溴化合物193.3与丙烯基膦酸二烷基酯193.6(Aldrich)偶联,获得膦酸酯193.7。芳基卤化物与烯烃利用Heck反应的偶联描述在例如F.A.Carey和R.J.Sundberg,“Advanced OrganicChemistry”,503ff(Plenum,2001)中和在Acc.Chem.Res.,1979,12,146中。该芳基溴和烯烃在极性溶剂中如二甲基甲酰胺或二噁烷中,在钯(0)催化剂如四(三苯基膦)钯(0)或钯(II)催化剂如乙酸钯(II)存在下,和任选地在碱如三乙胺或碳酸钾存在下,进行偶联。任选,在产物193.7中存在的styrenoid双键例如通过与二酰亚胺反应而被还原,得到饱和的类似物193.8。烯键的还原已描述在R.C.Larock,“Comprehensive Organic Transformations”,6ff(VCH,1989)中。该转变利用催化氢化,例如通过使用钯/碳催化剂和氢或氢给体,或通过利用二酰亚胺或乙硼烷来进行。
通过使用以上程序,但代替溴苄基试剂193.1,使用不同的溴取代的芳基或杂芳基烷氧基羟胺,和/或不同的链烯基膦酸二烷基酯,获得了与化合物193.5、193.7和193.8类似的产物。
实施例194
其中20-酮作为二甲基腙来保护的底物190.1与通过在4-氨基-2-溴呋喃(Tet.,1987,43,3295)和亚磷酸二烷基酯之间的钯催化偶联反应(如上所述)所制得的4-氨基-2-呋喃基膦酸二烷基酯194.1进行反应,在去保护后,得到亚胺产物194.2。该亚胺形成反应在烃溶剂如甲苯或二甲苯中,在回流温度下,在碱性催化剂如甲醇钠,或酸催化剂如甲苯磺酸存在下,在共沸条件下进行。
通过使用以上程序,但代替4-氨基呋喃基膦酸酯194.1,使用不同的氨基取代的芳基或杂芳基膦酸酯,获得与194.2类似的产物。
实施例195
其中20-酮作为二甲基腙来保护的二烯酮190.1与2-羧基乙基羟胺195.1(J.Med.Chem.,1990,33,1423)进行反应,得到肟195.2。甾族1,4-二烯-3-酮与羟胺的反应已描述在J.Steroid Bioch.,1976,7,795中;反应是在等摩尔量的反应物之间在极性有机溶剂如吡啶或甲醇中,任选在乙酸或乙酸钠存在下进行。该产物195.2然后与4-氨基苯基膦酸二烷基酯195.3(Epsilon)和二环己基碳二亚胺进行偶联,在去保护之后获得酰胺肟195.4。从羧酸类和衍生物制备酰胺的方法例如描述在S.R.Sandler和W.Karo,“Organic Functional GroupPreparations”,274(Academic Press,1968),和R.C.Larock,“Comprehensive Organic Transformations”,972ff(VCH,1989)中。该羧酸与该胺在活化剂例如二环己基碳二亚胺或二异丙基碳二亚胺存在下,任选地在例如羟基苯并三唑、N-羟基-琥珀酰亚胺或N-羟基吡啶酮存在下,在非质子溶剂如吡啶、DMF或二氯甲烷中进行反应,获得酰胺。
另外地,该羧酸可以首先转化成活化的衍生物如酰氯、酸酐、混合酸酐、咪唑烷(imidazolide)等,然后与胺在有机碱例如吡啶存在下反应,获得该酰胺。
羧酸转化成相应的酰氯的过程可通过用试剂例如亚硫酰氯或草酰氯在惰性有机溶剂如二氯甲烷中,任选在催化量二甲基甲酰胺存在下处理羧酸来进行的。
通过使用以上程序,但代替羧基取代的羟胺195.1,使用不同的羧基取代的羟胺,和/或不同的氨基取代的膦酸酯,获得与195.4类似的产物。
实施例196
二烯酮190A被还原,获得1,2-二氢产物196.1。该催化氢化反应通过三(三苯基膦)铑(I)氯化物的使用来进行,例如按照在J.Med.Chem.,2001,44:602中所述。该产物然后与甲酸乙酯和碱如氢化钠,在惰性溶剂如甲苯或二甲基甲酰胺中进行反应,按照在J.Am.Chem.Soc.,1964,86,1520中所述,获得2-甲酰基产物196.2。这一化合物然后与烷基,芳烷基,芳基或杂芳基肼196.3反应,其中取代基X是膦酸酯基团或可以随后转变成含膦酸酯的取代基的一种基团。例如,X是二烷基膦酰基,溴,羟基,氨基,羧基等等。反应得到异构体2’-和1’-芳基吡唑,196.4和196.5。该吡唑形成反应是在等摩尔量的反应物之间在酸性溶剂如乙酸中进行,按照在J.Am.Chem.Soc.,1964,86,1520中所述。吡唑类196.4和196.5然后例如,由实施例192和193中描述的程序分别转变成膦酸酯196.6和196.7。任选,该还原和甲酰化反应是对于底物190.1进行的,其中该20-酮是作为环状乙二醇缩酮来保护的。
实施例197
该酮醛196.2,如上所述,与3-羟基-苯肼197.1(JP 03011081)进行反应,得到吡唑197.2和197.3。该2’-取代的异构体197.2然后在二甲基甲酰胺溶液中在70℃下与一摩尔当量的2-溴乙基膦酸二烷基酯,197.4(Aldrich),和碳酸钾进行反应,得到乙氧基膦酸酯197.5。
该异构的吡唑,197.3,在Mitsonobu反应中与一摩尔当量的3-羟丙基膦酸二烷基酯197.6(Zh.Obschei.Khim.,1974,44,1834)进行反应,得到膦酸酯197.7。利用Mitsonobu反应制备芳族醚的方法例如已描述在R.C.Larock,“Comprehensive OrganicTransformations”,448页(VCH,1989)中,在F.A.Carey和R.J.Sundberg,“Advanced Organic Chemistry”,部分B,153-4(Plenum,2001)中,和在Org.React.,1992,42,335中。该酚和醇或硫醇组分一起在非质子传递溶剂例如四氢呋喃中,在偶氮二羧酸二烷基酯和三芳基膦存在下反应,获得醚或硫醚产物。该程序也描述在Org.React.,1992,42,335-656中。
通过使用以上程序,但使用不同的羟基取代的肼,和/或不同的溴-或羟基-取代的膦酸酯,获得与195.5和197.6类似的产物。
实施例198
该酮醛196.2,如上所述,与4-氨基-苯肼198.1(Syn.Comm.,1974,4,57)进行反应,生产吡唑198.2和198.3。该2’-取代的异构体198.2然后在二甲基甲酰胺溶液中在70℃下与一摩尔当量的3-溴丙基膦酸二烷基酯198.4(J.Amer.Chem.Soc.,2000,122,1554)和碳酸铯反应,得到胺膦酸酯198.5。
另外地,该1’-取代的吡唑198.3与4-羟基甲基苯基膦酸二烷基酯198.6(美国专利No.5,569,664)和羰基二咪唑偶联,制备氨基甲酸酯膦酸酯198.7。氨基甲酸酯的制备方法已描述在“ComprehensiveOrganic Functional Group Transformations”,A.R.Katritzky,ed.,Pergamon,1995,Vol.6,p.416ff中,和在“Organic Functional GroupPreparations”,S.R.Sandler和W.Karo,Academic Press,1986,p.260ff中。在该程序,该胺在惰性非质子传递溶剂如二氯甲烷或四氢呋喃中,与光气或它的官能化等同物如羰基二咪唑、三光气、五氟苯基碳酸酯等反应,获得相应的活化的酰基胺。后一化合物然后与醇反应,得到氨基甲酸酯。
通过使用以上程序,但代替氨基苯基肼198.1,使用不同的氨基取代的肼,和/或不同的二烷基溴或羟基-取代膦酸酯,获得了与化合物198.5和198.7类似的产物。
实施例199
酮醛196.2与肼反应,获得吡唑衍生物199.1。甾族2-甲酰基-3-酮与肼的反应已描述J.Am.Chem.Soc.,1964,86,1520中。反应是在乙酸中在环境温度下进行的。该吡唑产物然后与其中R2和X如上所定义的溴甲基化合物199.2或反应活性溴代杂芳族试剂进行反应,得到烷基化产物199.3和199.4。取代的吡唑的烷基化例如描述在“Heterocyclic Chemistry”,T.L.Gilchrist,Longman,1992,第309页中。反应在等摩尔量的底物之间在极性溶剂如二甲基甲酰胺或四氢呋喃中,在碱如二甲基氨基吡啶、六甲基二硅氮化锂等存在下进行。通过使用这里所述的程序,产物199.3和199.4,只是当X是二烷基膦酰基时的情况除外,被转化成膦酸酯199.5和199.6。
实施例200
该吡唑199.1在二甲基甲酰胺溶液中在70℃下与一摩尔当量的4-溴丁烯基膦酸二烷基酯200.1(J.Med.Chem.,1992,35,1371)和六甲基二硅氮化锂进行反应,得到吡唑200.2和200.3。
通过使用以上程序,但使用不同的溴取代的膦酸酯,获得与200.2和200.3类似的产物。
实施例201
该吡唑199.1在四氢呋喃溶液中与2,5-双(溴甲基)呋喃201.1(Tet.,1999,55,4709)和六甲基二硅氮化钾进行反应,得到烷基化产物201.2和201.3。该2’-取代的异构体201.2然后在阿尔布佐夫反应中与亚磷酸三烷基酯反应,得到膦酸酯201.4。阿尔布佐夫反应已描述在Handb.Organophosphorus Chem.,1992,115中。在其中溴取代基转化成相应膦酸酯的这一程序中,底物在约60℃到约160℃下与五倍到五十倍摩尔过量的亚磷酸三烷基酯一起加热,实施该转化。
该1’-取代的吡唑201.3在环境温度下在二甲基甲酰胺溶液中与一摩尔当量的巯基甲基膦酸二烷基酯201.5(J.Med.Chem.,1985,26,1688)和碳酸铯进行反应,得到硫醚膦酸酯201.6。
通过使用以上程序,但使用不同的二卤化物,和/或不同的巯基取代的膦酸酯,获得与201.4和201.6类似的产物。
实施例202
该类型的C-21伯羟基的衍生物,202.1,容易地通过用所示的合适膦酸酯将曲安奈德202A烷基化来制备。
实施例203
在化合物202A的伯羟基质子利用一个当量的氢化钠所实现的化学选择性夺取之后,加成膦酸酯三氟甲磺酸酯得到醚203.1。
实施例204
该伯羟基由合适的保护基来掩蔽。在化合物204.1的仲羟基结构部分上用连接了离去基团的膦酸酯实施烷基化和随后进行去保护之后,获得所需的类似物204.2。
实施例205
曲安奈德,202A通过使用标准TBSCl和咪唑条件(J.Am.Chem.Soc.1972,94,6190)作为它的甲硅烷基醚来进行化学选择性保护。在暴露的仲羟基上用氢化钠和膦酸酯三氟甲磺酸酯的烷基化可得到中间体205.6。甲硅烷基醚的最终TBAF去保护获得所需的产物205.7。
实施例206
该缩醛的膦酸酯衍生物容易地从曲安奈德202A的酸性水解成二醇206.1的过程制得,根据在反应历程3.1中所示。二醇用膦酸酯醛的乙酰化作用得到所需的缩醛206.2。
实施例207
曲安奈德202A,首先在乙酸水溶液中水解。(Can.J.Chem.1983,61,634)所形成的二醇207.1与膦酸酯醛和高氯酸进行缩醛化,获得缩醛207.2(J.Med.Chem.1996,39,4888-4896)。
实施例208
C-11羟基的衍生化是通过双甲丙酰龙208A用合适膦酸酯的烷基化,得到该类型的类似物208.1来实现的。
在化合物208A中的羟基质子的氢化钠夺去之后,加成二乙基膦酸酯三氟甲磺酸酯获得醚208.2。
实施例209
在C-17上羰基的衍生物容易地从氟替卡松209A皂化成羧酸209.1来制备。羧酸的活化,随后与硫代膦酸酯或氨基膦酸酯亲核试剂反应,分别得到所需的硫酯209.2和酰胺209.3。
实施例210
氟替卡松,209A,首先用氢氧化钾在丙酮中皂化。(Synthesis,2002,921-927)所获得的羧酸209.1,通过1,1’-羰二咪唑(CDI)(J.Med.Chem.1994,37,3717-3729)的加成而活化成羧酸咪唑。用硫代膦酸酯的处理获得硫酯,210.1。可添加乙醇镁来帮助增强反应活性(Tetrahedron Lett.1981,22,3245-3246)。另外地,从209.1衍生的羰咪唑中间体能够与氨基膦酸酯反应,生产酰胺210.2。
实施例211
较少位阻的C-11羟基用合适的膦酸酯进行选择性地烷基化,得到通式211.1的类似物。
实施例212
在化合物209A中C-11羟基质子利用一个当量的氢化钠所实现的区域选择性夺去之后,加成膦酸酯三氟甲磺酸酯得到醚212.1。
实施例213
该C-11羟基由合适的保护基来掩蔽。在化合物213.1的C-17羟基结构部分上用连接了离去基团的膦酸酯实施烷基化和随后进行去保护之后,获得所需的类似物213.3。
实施例214
氟替卡松209A通过使用标准乙酸酐和DMAP条件(J.Org.Chem.1998,63,2342-2347)作为它的C-11乙酸酯来进行区域选择性保护。在暴露的C-17羟基上用氢化钠和膦酸酯三氟甲磺酸酯的烷基化可得到中间体214.2。乙酸酯的最终氨去保护获得所需的醚214.3。
实施例215
C-11羟基的衍生化是通过莫米松糠酸酯,215A,用合适膦酸酯的烷基化,得到该类型的类似物215.1来实现的。
实施例216
在化合物215A中的羟基质子的氢化钠夺去之后,加成二乙基膦酸酯三氟甲磺酸酯获得醚216.1。
实施例217
在莫米松糠酸酯(215A)中的唯一暴露的羟基的保护之后,中间体217.1被皂化得到醇217.3。在C-17羟基上用合适的膦酸酯的烷基化和后续的去保护可得到所需产物217.4。
实施例218
莫米松糠酸酯215A通过使用标准TBSCl和咪唑条件(J.Am.Chem.Soc.1972,94,6190)作为它的甲硅烷基醚来保护。呋喃甲酸酯利用氢氧化钠水溶液的皂化可以得到醇,218.1(J.Chem.Soc.PerkinTrans.1,1993,12,1359-1366)。叔羟基通过氢氧化钠和膦酸酯三氟甲磺酸酯的添加来烷基化。在中间体218.3中的甲硅烷基醚用TBAF的去保护之后,获得膦酸二乙基酯,218.4。
实施例219
在C-11羟基上的衍生化是通过用合适膦酸酯将醋丙甲基强的松龙(219A)烷基化来实现的,得到实施例219.1的类似物。
实施例220
在化合物219A中的羟基质子的氢化钠夺去之后,加成二乙基膦酸酯三氟甲磺酸酯获得醚220.1。
实施例221
在219A中的唯一暴露的羟基的保护之后,中间体221.1被皂化得到二醇221.2。在伯羟基上用合适膦酸酯的烷基化和后续的酰化可得到丙酸酯221.4。在去保护之后获得所需的产物221.5。
实施例222
醋丙甲基强的松龙(219A)通过使用标准TBSCl和咪唑条件(J.Am.Chem.Soc.1972,94,6190)作为它的甲硅烷基醚来保护。两个酯结构部分使用氢氧化钠水溶液的皂化得到二醇222.2。较少位阻的伯羟基通过氢氧化钠和膦酸酯三氟甲磺酸酯的添加来烷基化。在中间体222.3用丙酸酐在吡啶中处理之后,以前水解的C-17丙烯酸酯被置换(J.Med.Chem.,1980,23,430-437)。甲硅烷基醚的TBAF去保护得到膦酸二乙基酯,222.5。
实施例223
二醇221.2的两个羟基在区域选择性上的差异在于在伯位(primarysite)上的保护,因此允许在叔羟基上的烷基化。所形成的膦酸酯中间体223.1然后去保护而获得二醇223.3。再次,更容易接近的伯羟基被酰化生产出所需的类似物223.4。
实施例224
二醇222.2用二乙基膦酸酯三氟甲磺酸酯烷基化,所形成的中间体224.2用TBAF处理得到二醇224.3。乙酸酐和吡啶用于产生最终产物224.4(J.Mol.Biol.,1972,72,219)。
实施例225
化合物如225.1能够根据下面列出的一般路线来制备。
实施例226
PNP-405,225A根据Littler,B.J.等人,7th International Conferenceon Organic Process Research and Development,New Orleans,LA,March 16-19,2003的方法来制备。PNP-405在溶剂如二甲基甲酰胺或四氢呋喃中用碱如氢化钠处理。当鼓泡停止时,添加三氟甲磺酸二乙基膦酸甲基酯(根据Tetrahedron Lett.,1986,27,1477制得),得到所需产物,化合物226.1。
实施例227
化合物如227.1(其中X=
,Z=
),能够根据Littler,B.J.等人,7th International Conference on Organic Process Research andDevelopment,New Orleans,LA,March 16-19,2003的程序(反应历程3和4)来制备。该起始原料,2-苄氧基苯基乙酸,227.1,(由Avocado提供)能够经由混合酸酐用所示的oxazolidinone在80-85℃下酰化,用三乙胺作为碱,得到化合物227.2。用溴乙腈的低温烷基化会导致化合物227.3的形成,有良好的非对映体比率。在还原性条件下手性助剂的除去得到化合物227.4,没有外消旋作用。所获得的醇用三苯甲基基团的保护得到化合物227.5。后续的吡咯环构造以及制备六元2-氨基嘧啶酮环的环胍化反应是按照在实施例228中对于化合物228.9所述的方法来进行的,得到化合物227.6。
实施例228
化合物,228.1,(其中X=
,Z=
)能够根据以上列出的一般路线来制备。该起始原料,3-(2-苄氧基-苯基)-丙腈,228.1,可以通过根据1954年出版的美国专利No.2,789,995,酚与丙烯腈的路易斯酸媒介反应来获得。中间体,227.5,能够按照这里列出的相同合成步骤来进行,获得化合物227.1。
吡咯环构造能够在三个步骤中从3-(2-苄氧基-苯基)-丙腈228.1完成。3-羟基-丙烯腈,228.2,的形成能够通过228.1暴露于LDA和甲酸乙酯来实现。这一产物与2-氨基-丙二酸二乙酯在
和乙酸钠中的缩合会得到化合物228.3,后者在
和
的碱性介质中进行脱羧环化,得到吡咯228.4。对于化合物227.1合成的情况,在这一阶段中在苄基醇上的三苯甲基保护基被除去。随后,使用氨基氰的胍化反应得到化合物228.5,它在用氢氧化钠处理之后环化,形成2-氨基嘧啶酮环(化合物,228.6)。在氢解条件下酚保护基的除去得到游离酚,它用作前体药物基团的连接位点。各种的连接基可以用于将前体药物结构部分连接到骨架分子上。以上显示了其中二乙基膦酰基甲基三氟甲磺酸酯用作起始原料的特殊实施例。因此,化合物228.7在溶剂如四氢呋喃或二甲基甲酰胺中用碱如氢化钠或碳酸铯处理。当鼓泡停止时,添加三氟甲磺酸二乙基膦酸甲基酯(根据Tetrahedron Lett.,1986,27,1477制得),得到所需产物,化合物228.2。
实施例229
化合物如229.1(其中X=
,Y=
,Z=
)能够从4-苄氧基苯基乙酸(可以从Aldrich获得)制备。按照与以上所述序列相类似的序列,制备中间体229.5。继续进行以上所示的序列,229.5,能够转变成所需的产物229.1。
化合物如230A能够根据以上列出的一般路线来制备。
实施例231
DADMe-ImmG的制备已在Lewandowics A.等人,Biochemistry,2003,42,6057中报道。该环的叔氮不会干涉仲醇的烷基化和在这种情况下不需要加以保护,如果需要的话可以使用在Greene,T.,ProtectiveGroups in Organic Synthesis,Wiley-Interscience,1999中描述的标准保护和去保护规程。伯醇231.1与碱的反应,然后合适地活化的膦酸酯的加成,得到受保护的产物。总的去保护得到所需的膦酸酯231.2。
实施例232
化合物如232.1能够根据以上列出的一般路线来制备。
实施例233
保护的DADMe衍生物能够在溶剂如四氢呋喃或二甲基甲酰胺中用碱如氢化钠处理。当鼓泡停止时,添加二乙基膦酰基乙基三氟甲磺酸酯(根据Tetrahedron Lett.,1986,27,1477制得),得到所想望的膦酸酯。保护基团的除去能够按照在Greene,T.,Protective Groups inOrganic Synthesis,Wiley-Interscience,1999中所述进行,得到所需膦酸酯233.1。
实施例234
化合物如234.2能够根据以上列出的一般路线来制备。
CP-690,550,3-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-3-氧代-丙腈,234.1,能够按照在WO 02096909和WO03048162中所述来制备。利用2当量以上的碱在α-氰基酰胺位上的烯醇盐形成,然后三氟甲磺酸二乙基膦酸甲基酯(根据TetrahedronLett.,1986,27,1477制得)的加成,得到所需化合物234.3。溶剂如THF,DMF或其它无水溶剂可以用于这一反应。对于吡咯氮干涉所需的烷基化的情况,保护基如BOC可以在烷基化反应之前被引入。BOC基团的除去能够通过反应产物与TFA的接触来实现,按照在Greene,T.,Protective Groups in Organic Synthesis,Wiley-Interscience,1999中所述。
实施例235
化合物235.1根据WO 02096909来制备。吡咯氮使用甲苯磺酰基的保护是按照在Sakamoto T.等人,Tetrahedron Lett.1994,35,18,2919中所述来实现的。按照在以上参考文献以及Seela,F.等人,Chem.Ber.1977,110,4,1462中所述,采用
的邻位锂化和用甲醛的淬灭,可以在所需要的位点上引入取代基。所形成的伯醇,借助于使用碱和二乙基膦酰基甲基-三氟甲磺酸酯(根据TetrahedronLett.,1986,27,1477制得)在无水溶剂中的醚形成,可用于膦酸酯结构部分的连接。苄基保护基的除去可通过使用氢解条件来实现。哌啶氮然后与氰基乙酸2,5-二氧代-吡咯烷-1-基酯偶联,得到化合物235.5。甲苯磺酰基保护基的除去能够通过使用碱性条件来实现,得到所需产物235.6。
实施例236
具体地说,(1-苄基-4-甲基-哌啶-3-基)-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺,化合物,236.1,(根据在WO 02,096,909中所述方法制得)首先使用甲苯磺酰基在吡咯氮上加以保护。使用由Sakamoto,T.等人,(Tetrahedron Lett.1994,35,2919)报道的程序来进行的后续甲酰化可得到化合物236.3。该伯醇然后在溶剂如四氢呋喃或二甲基甲酰胺中用碱如氢化钠处理。当鼓泡停止时,添加三氟甲磺酸二乙基膦酸甲基酯(根据Tetrahedron Lett.,1986,27,1477制得),得到所需的产物236.4。哌啶氮的脱苄基作用,随后偶联于氰基乙酸2,5-二氧代-吡咯烷-1-基酯上,得到化合物236.5。甲苯磺酰基保护基的除去可得到所需的前体药物236.6。
实施例237
以上示出了本发明的膦酸酯化合物和用于它们的合成中的中间体化合物的合成。
实施例238
以上示出了本发明的膦酸酯化合物的制备。该5-羟基-1-β-D-呋喃核糖基-1H-咪唑-4-羧酰胺,238.1(根据美国专利No.3,888,843制得),能够在溶剂如四氢呋喃或二甲基甲酰胺中用碱如氢化钠处理。当鼓泡停止时,添加三氟甲磺酸二乙基膦酸甲基酯(根据TetrahedronLett.,1986,27,1477制得),得到所想望的膦酸二酯238.2。
实施例239
以上说明膦酸酯的制备。通过咪唑碱(JP Kokai 76 88965)在3,5-双保护的2-脱氧-D-赤-呋喃戊糖基氯化物(Hayashi,M.等人,Chem.Pharm.Bull.,1975,23,1,245;Montgomery,J.A.等人,J.Med.Chem.,1969,12,3,498;和Iwamoto,R.H.等人,J.Med.Chem.,1963,6,684)上的加成所制备的化合物239.1,5-羟基-1-(4-羟基-5-羟甲基-四氢呋喃-2-基甲基)-1H-咪唑-4-羧酸酰胺,可以在该咪唑-4-醇上加以保护。
的氧化,随后消去,得到烯糖239.2。(参见在Zemlicka J.等人,J.Am.Chem.Soc.,1972,94,9,3213中的程序。)硒醚化(selenoetherification)得到受保护的膦酸酯,239.3(Kim,C.等人,J.Org.Chem.,1991,56,2642)。苯基硒化物的氧化消除(按照在Kim,C.等人,J.Org.Chem.,1991,56,2642所述)和随后进行立体有择的二羟基化,可得到所需的二醇239.4。最后,保护基团被除去,得到化合物239.5。
实施例240
以上说明膦酸酯的制备。具体地说,化合物239.1,5-羟基-1-(4-羟基-5-羟甲基-四氢呋喃-2-基甲基)-1H-咪唑-4-羧酸酰胺,首先使用TBS基团来保护。用
的后续氧化得到羧酸240.1。脱羧消除通过使用二甲基甲酰胺二新戊乙缩醛在DMF中在高温下实现(Zemlicka J.等人,J.Am.Chem.Soc.,1972,94,9,3213)。一旦呋喃型化合物烯糖已获得,它用高氯酸银在(羟甲基)膦酸二乙基酯(Phillion,D.等人,Tetrahedron Lett.,1986,27,1477)存在下进行处理,得到膦酸酯240.3(Kim,C.等人,J.Org.Chem.,1991,56,2642)。硒化物的氧化消去,然后用四氧化锇的二羟基化,可得到二醇240.5,具有所需的立体化学。TBS基团的去保护能够通过使用TBAF来实现,得到化合物240.6。
实施例241
以上显示了属于CsA,241A(和相关的环孢子菌素)的类似物的本发明化合物的合成。
实施例242
以上示出了本发明的膦酸酯化合物和用于它们的合成中的中间体化合物的合成。烯烃易位方法已描述在J.Med.Chem.,2003,46,674中。
实施例243
在这里示出了具有膦酸酯基团的本发明的化合物和用于它们的合成中的中间化合物的制备。
实施例244
在这里示出了具有膦酸酯基团的本发明的化合物和用于它们的合成中的中间化合物的制备。
实施例245
各取代基转化成基团
,其中R1如以上所定义,或实际上如以上所定义的
的最后阶段能够在合成序列的任何适当阶段中或在最后步骤中进行。引入膦酸酯取代基的合适步骤的选择是在考虑所需要的化学程序和底物对于这些程序的稳定性之后作出。在基团
或
的引入过程中需要保护反应活性基团例如羟基或氨基。在这里显示了具有通式,245.5-245.8,的本发明的化合物的特定例子。
根据在这里描述的方法来合成本发明的化合物。显示了举例性的中间体膦酸酯,其中R1是氢,烷基,芳基,卤代烷基,链烯基,芳烷基,或芳基。这些化合物可用于由本领域中技术人员通过使用取代膦酸酯的已知合成方法来制备本发明的化合物。这些方法类似于对于酰胺合成所述的那些方法。从羧酸类和衍生物制备酰胺的方法例如描述在“Organic Functional Group Preparations”,S.R.Sandler和W.Karo,Academic Press,1968,第274页。其它一些方法在下面实施例中对于膦酸二酯类的合成进行了描述并且在一些情况下适用于磷酰胺的合成。
在这里显示了用于转化成携带氨基酸的膦酸酯结构部分的膦酸酯,245.1-245.4,或乳酸酯。环孢菌素(CsA)245.10,能够从SigmaAldrich购买,它可以合成(参见美国专利No.4,396,542)或按照在美国专利No.4,117,118中所述从生物来源获得。其它环孢子菌素衍生物能够是在性质上合成的(参见美国专利No.4,396,542)或通过与CsA(参见美国专利No.6,410,696B1)类似的方式分离得到。
以上示出了膦酸酯连接键经由氨基酸1的羟基连接于CsA上得到通式245.1化合物的过程。将CsA,245.10,溶于合适溶剂例如DMF或其它非质子溶剂中,然后在合适的有机或无机碱存在下用携带离去基团例如溴、甲磺酰基、甲苯磺酰基或三氟甲磺酰基的膦酸酯试剂245.9处理。
例如溶于DMF中的245.10用一个当量的氢化钠和一个当量的(甲苯-4-磺酰基甲基)-膦酸二苄基酯245.11(根据在J.Org.Chem.1996,61,7697中的程序制得)处理,得到CsA膦酸酯245.5。使用以上程序,但使用不同的膦酸酯试剂245.9,代替化合物245.11,获得携带不同连接基团的相应产物245.1。
实施例246
以上示出了CsA-膦酸酯共轭物的制备。氨基酸1的羟基首先用合适的保护基团,例如甲硅烷基醚、苄基醚、三苯甲基醚等来保护,按照在Greene and Wuts,“Protecting Groups in Organic Synthesis”,第三版,John Wiley and Sons,Inc中所述。受保护的产物246.1然后用氧化剂处理,其中的许多实施例已描述在“Comprehensive OrganicTransformations”,John Wiley & Sons,第二版,R.C.Larock,p1211-1215,得到醛246.2。
醛,246.2,然后用通式246.3的胺膦酸酯在还原性胺化条件下处理,获得胺246.4。利用还原性胺化程序制备胺类的方法例如描述在“Comprehensive Organic Transformations”,R.C.Larock,第二版,835页中。在这一程序中,胺组分和醛组分在还原剂例如硼烷、氰基硼氢钠或二异丁基氢化铝的存在下一起反应,得到胺产物。最后,按照在Greene and Wuts,“Protecting Groups in Organic Synthesis”,第三版,John Wiley and Sons Inc.p116-121中所述的程序,将羟基进行去保护而得到膦酸酯246.5。
实施例247
例如,245.10在吡啶和二氯甲烷中用三甲基甲硅烷基氯化物处理,按照在美国专利No.6,410,696B1中所述,得到甲硅烷基醚247.1。甲硅烷基醚,247.1,然后用臭氧处理,随后用二甲硫醚进行后处理,得到醛247.2。醛247.2用一个当量的根据J.Med.Chem.,1998,41,23,p4439制得的(2-氨基-乙基)-膦酸酯二乙酯的盐酸盐,247.3,和合适的碱,例如许尼希(hunigs)碱、三乙胺等,进行处理,直到形成亚胺为止。该中间体亚胺溶液然后用氰基硼氢化钠处理,得到胺247.4。胺247.4然后通过用TBAF在非质子传递溶剂如THF或二噁烷中处理进行去保护,得到膦酸酯247.5。使用以上程序,但使用不同的膦酸酯试剂246.3,代替膦酸酯247.3,获得携带不同连接基团的相应产物246.5。
实施例248
在这里示出了其中膦酸酯连接到在氨基酸7和8,化合物245.3和245.4,中的丙氨酸氮上的CsA膦酸酯共轭物的制备。受保护的CsA,246.1(实施例246),用具有足够的碱性以除去酰胺质子的碱例如金属氢化物、金属胺化物进行处理。该产物然后用携带离去基团例如溴、甲磺酰基、甲苯磺酰基或三氟甲磺酰基膦酸酯的膦酸酯试剂245.9进行处理,得到248.1和248.2。该烷基化产物然后通过色谱分离法分离并独立地通过使用在Greene and Wuts,“Protecting Groupsin Organic Synthesis”,第三版,John Wiley and Sons Inc.p116-121中描述的普通条件进行去保护,得到具有通式245.3和245.4的化合物。
实施例249
甲硅烷基醚247.1在甲苯中用氢化钠和15-冠-5-醚处理,随后用一个当量的溴甲基膦酸二烯丙基酯249.1(Lancaster)处理,分别得到膦酸酯249.2和249.3。膦酸酯249.2和249.3通过在非质子传递溶剂如THF或二噁烷中用TBAF处理进行去保护,得到分别具有通式249.4和249.5的化合物,其中该连接键是亚甲基基团。通过使用以上程序但使用不同的膦酸酯试剂245.9,代替膦酸酯试剂249.1,获得有不同的连接基团的具有通式245.3和245.4的相应产物。
实施例250
在这里示出了具有膦酸酯基团的本发明的化合物和用于它们的合成中的中间化合物的制备。在右边的亚结构用于表示在下列实施例中的环孢菌素A。
实施例251:环-[[(2S,3R,4R,6E)-7-(4-乙酰氧基苯基)-4-甲基-3-羟基-2-(甲基氨基)-6-庚烯酰基]-L-2-氨基丁酰基-肌氨酰基-N-甲基-L-亮氨酰基-L-缬氨酰基-N-甲基-L-亮氨酰基-L-丙氨酰基-D-丙氨酰基-N-甲基-L-亮氨酰基-N-甲基-L-亮氨酰基-N-甲基-L-缬氨酰基]
环孢菌素A(360mg,0.3mmol),4-乙酰氧基苯乙烯(730mg,4.5mmol)和(1,3-双-(2,4,6-三甲基苯基)-2-咪唑叉基)-二氯-(O-异丙氧基苯基亚甲基)钌(Hoveyda-Grubbs催化剂,20mg,0.032mmol)在二氯甲烷(1mL)中的混合物用氮气吹洗,并在回流状态下搅拌16小时。在冷却之后,反应混合物使用
由硅胶柱色谱分析法提纯,得到固体物形式的产物(395mg,99%)。
MS(m/z)1322.9[M+H]+,1344.9[M+Na]+;HPLC停留时间3.3min.(相对于环孢菌素A的4.1min.;Phenominex Synergi 4微米hydro-RP 80A 50×4.6mm;溶剂,35%水和65%乙腈;流速2mL/min.;柱温60℃)。
实施例252:环-[[(2S,3R,4R,6E)-7-(4-羟苯基)-4-甲基-3-羟基-2-(甲基氨基)-6-庚烯酰基]-L-2-氨基丁酰基-肌氨酰基-N-甲基-L-亮氨酰基-L-缬氨酰基-N-甲基-L-亮氨酰基-L-丙氨酰基-D-丙氨酰基-N-甲基-L-亮氨酰基-N-甲基-L-亮氨酰基-N-甲基-L-缬氨酰基]
环-[[(2S,3R,4R,6E)-7-(4-乙酰氧基苯基)-4-甲基-3-羟基-2-(甲基氨基)-6-庚烯酰基]-L-2-氨基丁酰基-肌氨酰基-N-甲基-L-亮氨酰基-L-缬氨酰基-N-甲基-L-亮氨酰基-L-丙氨酰基-D-丙氨酰基-N-甲基-L-亮氨酰基-N-甲基-L-亮氨酰基-N-甲基-L-缬氨酰基](385mg,0.29mmol)和三乙胺(1mL)在甲醇(10mL)中的溶液在环境温度下搅拌16小时。反应混合物真空浓缩和该残留物使用
由硅胶柱色谱分析法提纯,得到所需产物(310mg,83%)。
MS(m/z)1280.9[M+H]+,1278.8[M-H]-;HPLC停留时间1.6min.(相对于环孢菌素A的4.0min.;Phenominex Synergi 4微米hydro-RP 80A 50×4.6mm;溶剂,35%水和65%乙腈;流速2mL/min.;柱温60℃)。
实施例253:环-[[(2S,3R,4R,6E)-7-(4-(二乙氧基磷酰基-甲氧基)-苯基)-4-甲基-3-羟基-2-(甲基氨基)-6-庚烯酰基]-L-2-氨基-丁酰基-肌氨酰基-N-甲基-L-亮氨酰基-L-缬氨酰基-N-甲基-L-亮氨酰基-L-丙氨酰基-D-丙氨酰基-N-甲基-L-亮氨酰基-N-甲基-L-亮氨酰基-N-甲基-L-缬氨酰基]
向环-[[(2S,3R,4R,6E)-7-(4-羟基苯基)-4-甲基-3-羟基-2-(甲基氨基)-6-庚烯酰基]-L-2-氨基丁酰基-肌氨酰基-N-甲基-L-亮氨酰基-L-缬氨酰基-N-甲基-L-亮氨酰基-L-丙氨酰基-D-丙氨酰基-N-甲基-L-亮氨酰基-N-甲基-L-亮氨酰基-N-甲基-L-缬氨酰基](113mg,0.088mmol)和碳酸铯(33mg,0.1mmol)在DMF(1mL)中的混合物中添加三氟甲烷磺酸二乙氧基磷酰基甲基酯(60mg,0.2mmol)。混合物在室温下搅拌16小时。反应用2%氯化锂水溶液淬灭,混合物用乙酸乙酯萃取。该乙酸乙酯萃取液进行真空浓缩。该残留物由硅胶柱色谱分析法提纯得到被未反应的起始原料污染的所需产物(310mg,83%),它进一步使用Phenomenex Synergi 5μHydro RP 80A柱(50×21.2mm),用
洗脱剂,由RP HPLC提纯。含有所需产物的级分被收集并浓缩至干燥(62mg,49%)。
MS(m/z)1431.0[M+H]+,1428.7[M-H]-;31P(121.4MHz,CDCl3)δ19.5。
实施例254:环-[[(2S,3R,4R,6E)-7-(4-(二苄氧基磷酰基-甲氧基)-苯基)-4-甲基-3-羟基-2-(甲基氨基)-6-庚烯酰基]-L-2-氨基丁酰基-肌氨酰基-N-甲基-L-亮氨酰基-L-缬氨酰基-N-甲基-L-亮氨酰基-L-丙氨酰基-D-丙氨酰基-N-甲基-L-亮氨酰基-N-甲基-L-亮氨酰基-N-甲基-L-缬氨酰基]
向环-[[(2S,3R,4R,6E)-7-(4-羟基苯基)-4-甲基-3-羟基-2-(甲基氨基)-6-庚烯酰基]-L-2-氨基丁酰基-肌氨酰基-N-甲基-L-亮氨酰基-L-缬氨酰基-N-甲基-L-亮氨酰基-L-丙氨酰基-D-丙氨酰基-N-甲基-L-亮氨酰基-N-甲基-L-亮氨酰基-N-甲基-L-缬氨酰基](300mg,0.234mmol)和碳酸铯(326mg,1mmol)在DMF(2mL)中的混合物中添加三氟甲烷磺酸二苄氧基磷酰基甲基酯(60mg,0.2mmol)。混合物在室温下搅拌16小时。反应混合物经Acrodisc(具有0.45微米尼龙膜的13mm针筒式过滤器)进行过滤,然后使用Phenomenex Synergi 5μHydroRP 80A柱(50×21.2mm),用
洗脱剂,由RP HPLC提纯。含有所需产物的级分被收集并浓缩至干燥,获得白色固体(115mg,32%)。
MS(m/z)1554.9[M+H]+,1552.7[M-H]-;31P(121.4MHz,CDCl3)δ20.5。
实施例255:环-[[(2S,3R,4R,6E)-7-(4-(二羟基磷酰基-甲氧基)-苯基)-4-甲基-3-羟基-2-(甲基氨基)-6-庚烯酰基]-L-2-氨基丁酰基-肌氨酰基-N-甲基-L-亮氨酰基-L-缬氨酰基-N-甲基-L-亮氨酰基-L-丙氨酰基-D-丙氨酰基-N-甲基-L-亮氨酰基-N-甲基-L-亮氨酰基-N-甲基-L-缬氨酰基]
向环-[[(2S,3R,4R,6E)-7-(4-(二苄氧基-磷酰基-甲氧基)-苯基)-4-甲基-3-羟基-2-(甲基氨基)-6-庚烯酰基]-L-2-氨基丁酰基-肌氨酰基-N-甲基-L-亮氨酰基-L-缬氨酰基-N-甲基-L-亮氨酰基-L-丙氨酰基-D-丙氨酰基-N-甲基-L-亮氨酰基-N-甲基-L-亮氨酰基-N-甲基-L-缬氨酰基](115mg,0.074mmol)和2,6-二甲基吡啶(40μL,0.35mmol)在二氯甲烷(2mL)中的混合物中添加三甲基甲硅烷基溴化物(50μL,0.35mmol)。混合物在室温下搅拌2小时。反应用甲醇(1mL)淬灭,该混合物然后浓缩。该残留物用氟化铵溶液(0.5M,2mL)处理,搅拌1小时,浓缩,和分配在二氯甲烷和1N
之间。该二氯甲烷层进行浓缩和粗产物使用Phenomenex Synergi 5μ Hydro RP 80A柱(50×21.2mm),用0.1%TFA
-0.1% TFA
洗脱剂,由RP HPLC提纯。含有所需产物的级分被收集并浓缩至干燥,获得吸湿性固体(68mg,63%)。
MS(m/z)1374.9[M+H]+,1373.1[M-H]-;HPLC停留时间0.3min.(相对于环孢菌素A的4.0min.;Phenominex Synergi 4微米hydro-RP80A 50×4.6mm;溶剂,35%水和65%乙腈;流速2mL/min.;柱温60℃)。
实施例256:环-[[(2S,3R,4R,6E)-7-(4-(1-(S)-乙氧基-羰基-乙氧基)-苯氧基-磷酰基-甲氧基)苯基)-4-甲基-3-羟基-2-(甲基氨基)-6-庚烯酰基]-L-2-氨基丁酰基-肌氨酰基-N-甲基-L-亮氨酰基-L-缬氨酰基-N-甲基-L-亮氨酰基-L-丙氨酰基-D-丙氨酰基-N-甲基-L-亮氨酰基-N-甲基-L-亮氨酰基-N-甲基-L-缬氨酰基]
环-[[(2S,3R,4R,6E)-7-(4-(二羟基-磷酰基-甲氧基)苯基)-4-甲基-3-羟基-2-(甲基氨基)-6-庚烯酰基]-L-2-氨基丁酰基-肌氨酰基-N-甲基-L-亮氨酰基-L-缬氨酰基-N-甲基-L-亮氨酰基-L-丙氨酰基-D-丙氨酰基-N-甲基-L-亮氨酰基-N-甲基-L-亮氨酰基-N-甲基-L-缬氨酰基](34mg,0.023mmol),苯酚(22mg,0.23mmol),二环己基碳二亚胺(47mg,0.23mmol)和4-(N,N-二甲基氨基)吡啶(5.6mg,0.046mmol)在DMF(2mL)中的混合物在140℃下搅拌20分钟。在冷却之后,单苯基单膦酸产物使用Phenomenex Synergi 5μHydro RP 80A柱(50×21.2mm),用0.1%TFA
-0.1%TFA
洗脱剂,由RPHPLC提纯。MS(m/z)1450.9[M+H]+,1449.1[M-H]-;31P(121.4MHz,CDCl3)δ14.9。这一中间体与(S)-(-)-乳酸乙基酯(40mg,0.34mmol),PyBOP(80mg,0.15mmol),二异丙基乙胺(45μL,0.26mmol)和DMF(1.7mL)混合。所形成的混合物在室温下搅拌2小时。在不溶性杂质的除去之后,粗产物使用Phenomenex Synergi 5μHydro RP 80A柱(50×21.2mm),用0.1%TFA
-0.1%TFA
洗脱剂,由RP HPLC提纯。所需的级分被收集下来并分配在乙腈和饱和碳酸氢钠水溶液之间。有机层进行浓缩,获得固体形式的产物(12mg,34%)。
MS(m/z)1573.1[M+Na]+,1548.8[M-H]-;31p(121.4MHz,CDCl3)δ15.3和17.4。
实施例257:环-[[(2S,3R,4R,6E)-7-(4-(1-(S)-羟基羰基-乙氧基)-羟基-磷酰基甲氧基)苯基)-4-甲基-3-羟基-2-(甲基氨基)-6-庚烯酰基]-L-2-氨基丁酰基-肌氨酰基-N-甲基-L-亮氨酰基-L-缬氨酰基-N-甲基-L-亮氨酰基-L-丙氨酰基-D-丙氨酰基-N-甲基-L-亮氨酰基-N-甲基-L-亮氨酰基-N-甲基-L-缬氨酰基]
向环-[[(2S,3R,4R,6E)-7-(4-(1-(S)-乙氧基-羰基乙氧基)-苯氧基磷酰基甲氧基)苯基)-4-甲基-3-羟基-2-(甲基-氨基)-6-庚烯酰基]-L-2-氨基丁酰基-肌氨酰基-N-甲基-L-亮氨酰基-L-缬氨酰基-N-甲基-L-亮氨酰基-L-丙氨酰基-D-丙氨酰基-N-甲基-L-亮氨酰基-N-甲基-L-亮氨酰基-N-甲基-L-缬氨酰基](5mg,3.2μmol)在水和乙腈(0.5mL和4.5mL)的混合溶剂中的溶液添加1N
(40μL)。溶液在室温下搅拌2小时。所获得的反应混合物进行浓缩并使用Phenomenex Synergi5μHydro RP 80A柱(50×21.2mm),用0.1%TFA
-0.1%TFA
洗脱剂,由RP HPLC提纯。所需的级分浓缩至干燥,获得固体形式的产物(1.5mg,32%)。
MS(m/z)1446.9[M+H]+,1444.9[M-H]-;HPLC停留时间0.2min.(相对于环孢菌素A的4.0min.;Phenominex Synergi 4微米hydro-RP 80A 50×4.6mm;溶剂,35%水和65%乙腈;流速2mL/min.;柱温60℃)。
实施例258
在这里显示了属于BCX-1777的类似物的本发明化合物的合成。
本发明的化合物,例如258.1,能够根据这里列出的一般路线来制备。
实施例259
BOC-保护的(1S)-1-(9-脱氮鸟嘌呤-9-基)-1,4-双脱氧-1,4-亚氨基-D-核糖醇,化合物259.1,是通过将(1S)-1-(9-脱氮鸟嘌呤-9-基)-1,4-双脱氧-1,4-亚氨基-D-核糖醇(WO 9,919,338和Evans,G.B.等人,Tetrahedron,2000,56,3053,还报道在Evans,G.B.等人,J.Med.Chem.2003,46,3412中)与BOC酸酐一起搅拌来制备,按照在Greene,T.,“Protective Groups in Organic Synthesis”,Wiley-Interscience,1999中所述。化合物,259.1,然后在溶剂如二甲基甲酰胺或四氢呋喃中用碱如氢化钠处理。当鼓泡停止时,添加三氟甲磺酸二乙基膦酰基甲基酯(根据Tetrahedron Lett.,1986,27,1477制得),在使用三氟乙酸(TFA)所进行的BOC基团的去保护之后得到所需的膦酸酯二酯259.2。
实施例260
化合物如260.1和260.2能够根据这里列出的一般路线来制备。
实施例261
BOC-保护的(1S)-1-(9-脱氮鸟嘌呤-9-基)-1,4-双脱氧-1,4-亚氨基-D-核糖醇,化合物259.1,是通过将(1S)-1-(9-脱氮鸟嘌呤-9-基)-1,4-双脱氧-1,4-亚氨基-D-核糖醇(WO 9,919,338和Evans,G.B.等人,Tetrahedron,2000,56,3053,还报道在Evans,G.B.等人,J.Med.Chem.2003,46,3412中)与BOC酸酐一起搅拌来制备,按照在Greene,T.,“Protective Groups in Organic Synthesis”,Wiley-Interscience,1999中所述。伯醇使用TBS基团的后续保护能够通过在溶剂如
中使用TBSCl和咪唑来实现,按照在Greene,T.,“Protective Groups in Organic Synthesis”,Wiley-Interscience,1999中所述,从而得到化合物261.1。化合物,261.1,然后在溶剂如二甲基甲酰胺或四氢呋喃中用碱如氢化钠处理。当鼓泡停止时,添加三氟甲磺酸二乙基膦酸甲基酯(根据TetrahedronLett.,1986,27,1477制得),在使用三氟乙酸(TFA)所进行的BOC基团的去保护之后得到所需的膦酸酯二酯261.2和261.3的混合物。化合物261.2和261.3也能够经由化合物261.1的更复杂
保护的类似物,然后用三氟甲磺酸二乙基膦酸甲基酯进行烷基化而仅仅得到化合物261.2来制备。化合物261.3也能够通过在
位上附接不同的保护基团,随后是
的去保护和在2’中心上用三氟甲磺酸二乙基膦酸甲基酯进行烷基化,随后进行总的去保护来制备。
实施例262
本发明的代表性化合物能够按以上所示的方法来制备。在C-11羟基上的衍生化是通过用合适膦酸酯将醋丙甲基强的松龙(262.1)烷基化来实现的,得到通式262.2的类似物。本发明的特定化合物能够如下制备。
在化合物262.1中的羟基质子的氢化钠夺去之后,加成二乙基膦酸酯三氟甲磺酸酯获得醚262.3。
实施例263
本发明的代表性化合物能够按照以上所述方法,通过利用在当醋丙甲基强的松龙(262.1)完全水解时可得到的三个羟基之间的反应活性差异,来制备。在262.1中唯一暴露的羟基的保护之后,中间体263.1被皂化得到二醇263.2。在伯羟基上用合适膦酸酯的烷基化和后续的酰化可得到丙酸酯263.4。在去保护之后获得所需的产物263.5。
实施例264
醋丙甲基强的松龙(262.1)通过使用标准TBSCl和咪唑条件作为它的甲硅烷基醚来保护。(J.Am.Chem.Soc,1972,94,6190)。两个酯结构部分使用氢氧化钠水溶液的皂化得到二醇264.2。较少位阻的伯羟基通过氢氧化钠和膦酸酯三氟甲磺酸酯的添加来烷基化。在用丙酸酐在吡啶中处理中间体264.3后,先前水解的C-17丙烯酸酯被置换。(J.Med.Chem.,1980,23,430-437)。甲硅烷基醚的TBAF去保护得到膦酸二乙基酯264.5。
实施例265
本发明的代表性化合物能够按以上所示的方法来制备。二醇263.2的两个羟基在区域选择性上的差异在于在伯位(primary site)上的保护,因此允许在叔羟基上的烷基化。所形成的膦酸酯中间体265.2然后去保护而获得二醇265.3。再次,更容易接近的伯羟基被酰化生产出所需的类似物265.4。
实施例266
二醇,264.2(参见实施例264),作为它的甲硅烷基醚266.1在伯位上加以保护。在用二乙基膦酸酯三氟甲磺酸酯进行烷基化之后,所获得的中间体266.2用TBAF处理,得到二醇266.3。乙酸酐和吡啶用于产生最终产物266.4。(J.Mol.Biol.,1972,72,219)。
实施例267
本发明的代表性化合物能够按以上所示的方法来制备。通过烷基化反应从母体化合物合成含有磷的merimepodib类似物267.2。由描述在美国专利No.6,054,472和美国专利No.6,344,465中的程序获得Merimepodib 267.1。merimepodib 267.1的甲氧基通过使用合适的试剂如三溴化硼进行脱甲基,得到酚式
。该膦酸酯结构部分在合适的非质子传递溶剂如DMF中被引入到酚式
上,然后用携带离去基团例如溴、甲磺酰基、甲苯磺酰基或三氟甲磺酰基的膦酸酯试剂,在合适的有机或无机碱存在下进行处理。本发明的特定化合物能够如下制备。
267.1在二氯甲烷中的溶液用三溴化硼处理,获得脱甲基的化合物267.8。化合物267.8然后用碳酸铯和一个当量的(三氟甲磺酰基氧基)-甲基膦酸二乙酯267.9处理,得到merimepodib-膦酸酯267.10。使用以上程序但使用不同的膦酸酯试剂,能够获得携带不同的连接基团的相应产物267.2。
实施例268
本发明的代表性化合物能够按以上所示的方法来制备。含有咪唑的中间体268.13是由在Tetrahedron Lett.1993,34,595中的Shih的程序从醛268.12合成的。化合物268.12是通过描述在美国专利No.5,807,876,美国专利No.6,054,472和美国专利No.6,344,465中的两步骤程序来制备的。该咪唑通过使用合适试剂例如2-(三-甲基-甲硅烷基)-乙氧基甲基(SEM)氯化物来保护,和化合物268.14通过在美国专利No.6,054,472和美国专利No.6,344,465中对于197.1的合成所描述的类似程序被转化成268.15。在268.15的咪唑上的保护基团被除去之后,含有膦酸酯的结构部分被引入到咪唑中得到本发明的化合物。本发明的特定化合物能够如下制备。
化合物268.15用四丁铵氟化物在THF中在回流条件下进行处理,然后所形成的268.16通过使用氢化钠作为碱用268.9烷基化,获得两种异构体268.17和268.18,它们由色谱分离法分离。
实施例269
本发明的代表性化合物能够按以上所示的方法来制备。四取代的苯衍生物通过文献程序来获得(Ichikawa and Ichibagase YakugakuZasshi 1963,83,103;Norio,A.et al.Tetrahedron Lett.1992,33(37),5403)。在酚式
用合适的保护基例如苄基保护之后,化合物269.21由描述在美国专利No.6,054,472和美国专利No.6,344,465中的相同程序来合成。在保护基团被除去之后,含有膦酸酯的结构部分通过使用携带合适离去基团的膦酸酯试剂269.7被引入到酚式
。本发明的特定化合物能够如下制备。
例如,化合物269.22(它由Norio等人的程序(Tetrahedron Lett.1992,33(37),5403)获得)的溶液用氢化钠和一个当量的苄基溴在DMF中处理,得到269.23。化合物269.23通过一系列的步骤,如在美国专利No.6,054,472和美国专利No.6,344,465中报道的那些步骤,被转化成269.24。在由催化氢化除去269.24的苄基保护基之后,通过所获得的酚在DMF中用氢化钠和一个当量的(三氟甲磺酰基氧基)-甲基膦酸二乙酯269.9进行烷基化来连接携带膦酸酯的结构部分,得到269.25。
实施例270
本发明的代表性化合物能够按以上所示的方法来制备。化合物270.26用羰二咪唑或三光气处理,接着是化合物270.27,它具有柄(handle)来连接膦酸酯结构部分。携带额外取代基的化合物270.27是从具有氰基和硝基的三取代酚合成的,后者可从市场上买到的或由文献程序合成(Zolfigol,M.A.等人,Indian J.Chem.Sect.B 2001,40,1191;DE Jongh,R.O.等人Recl.Trav.Chim.Pays-Bas 1968,87,1327)。所形成的270.28通过使用与在美国专利No.6,054,472和美国专利No.6,344,465中所述的那些相类似的程序被转化成270.29。在270.29的苄基的去保护之后,270.6的膦酸酯结构部分连接上去。
例如,化合物270.30的溴取代基通过De Jongh,R.O.等人的程序(Recl.Trav.Chim.Pays-Bas 1968,87,1327)用氰基基团替代和该甲氧基转化成作为保护基的苄氧基,获得化合物270.31。在氰基由硼烷选择性还原成氨基甲基后,该氨基用BOC基团保护,然后该硝基使用氯化锡(II)还原,产生化合物270.32。这一取代的苯胺270.32然后用化合物270.26和羰二咪唑的反应混合物处理,按照在美国专利No.6,054,472和美国专利No.6,344,465中所述,形成脲270.33。化合物270.33转化成270.34。苄基使用催化氢化的去保护,然后在碳酸铯存在下膦酸酯结构部分使用270.9的连接,得到化合物270.35。
实施例271
以上示出了本发明的膦酸酯化合物和用于它们的合成中的中间体化合物的合成。在C-21羟基上的衍生化是通过用合适膦酸酯将地塞米松271A烷基化来实现的,得到在这里显示的类似物。
在C-21羟基上的衍生化是通过用合适膦酸酯将地塞米松271A烷基化来实现的,得到271.2型的类似物。
在化合物271A中的伯羟基质子的氢化钠夺去之后,加成二乙基膦酸酯三氟甲磺酸酯获得醚271.5。
实施例272
在这里显示了具有通式271.4的C-21膦酸酯类似物的合成这一次地塞米松271A在较少位阻的位点上实施保护得到醇271.5,它在唯一暴露的羟基上用合适膦酸酯烷基化。保护基团的除去完成了类似物271.4的构造。
实施例272
地塞米松(271A)通过使用标准TBSCl和咪唑条件作为它的甲硅烷基醚来保护。(J.Am.Chem.Soc.,1972,94,6190;然而,双保护需要比较苛刻的条件)。在用二乙基膦酸酯三氟甲磺酸酯进行烷基化后,所形成的中间体271.9用TBAF处理,得到所需的膦酸酯271.10。
实施例273
具有一般结构273A的许多化合物可以使用在文献中描述的程序来制备,或从商业来源购买。下面是与制备一般结构273A的各种化合物的现有技术有关的信息的较好来源,Townsend,Chemistry ofNucleosides and Nucleotides,Plenum Press,1994;和Vorbruggen andRuh-Pohlenz,Handbook of Nucleoside Synthesis,John Wiley & Sons,Inc.,2001。
在这些实施例中对于这里所述的本发明化合物,取代基具有下列通式273A:
其中Z取代基中的一个或多个被A0基团取代;和其中:
Z1和Z2独立地选自氢,或C1-C18酰基,和Z3是
,C1-C18酰基,
或
或Z1是氢,并且Z2和Z3一起是
碱基是
其中X和Y独立地是
或
;Z4是氢,氨基,羟基,或选自 和
中的卤素。
更具体地说,一般结构273A的制备已描述在Nagahara等人,J.Med.Chem.;33;1990;407-415中。该结构273.2已描述在Kini等人,J.Med.Chem.;34;1991;3006-3010中。以上列举的两篇专利也提供了化合物273A的合成的实施例。
这一反应序列的核心组分是从273.3到273.6的化合物转变。合适的氧化剂能够将在273.3中所示的伯醇(5′-羟基)转化成羧酸或它的相应酯。对于酯而言,附加的去保护步骤将得到羧酸273.4。各种的氧化程序已在文献中存在并且能够在这里使用。这些包括但不限于下列方法:(i)吡啶鎓重铬酸盐在
,
和二氯甲烷中生产叔丁基酯,随后使用试剂如三氟乙酸进行去保护,将该酯转化成相应的羧酸(参见Classon等人,Acta Chem.Scand.Ser.B;1985,39,501-504.Cristalli等人,J.Med.Chem.,1988,31,1179-1183);(ii)碘代苯双乙酸酯和2,2,6,6-四甲基-1-哌啶子基氧基,自由基(TEMPO)在乙腈中,生产羧酸(参见Epp等;J.Org.Chem.64;1999;293-295.Jung等;J.Org.Chem.;66;2001;2624-2635.);(iii)高碘酸钠,氯化钌(III)在氯仿中生产羧酸(参见Kim等,J Med.Chem.,37;1994;4020-4030.Homma等;J.Med.Chem.;35;1992;2881-2890);(iv)三氧化铬在乙酸中生产羧酸(参见Olsson等;J.Med.Chem.;29;1986;1683-1689.Gallo-Rodriguez等;J.Med.Chem.;37;1994;636-646);(v)高锰酸钾在氢氧化钾水溶液中生产羧酸(参见Ha等人;J.Med.Chem.;29;1986;1683-1689.Franchetti等人;J.Med.Chem.;41;1998;1708-1715.);(vi)来自S.maltophilia的核苷氧化酶,得到羧酸(参见Mahmoudian等人;Tetrahedron;54;1998;8171-8182.)
从化合物273.4开始,使用铅(IV)四乙酸盐(Lv=
)制备化合物273.5的方法已由Teng等人进行描述;J.Org.Chem.;59;1994;278-280和Schultz等人;J.Org.Chem.;48;1983;3408-3412。当铅(IV)四乙酸盐与氯化锂(参见Kochi等人;J.Am.Chem.Soc.;87;1965;2052)一起使用时,获得相应氯化物(273.5,Lv=
)铅(IV)四乙酸盐与N-氯琥珀酰亚氨基相结合,生产相同的产物(273.5,Lv=
)(参见Wang等人;Tet.Asym.;1;1990;527和Wilson等人;Tet.Asym.;1;1990;525)。另外地,该乙酸酯离去基团(Lv)也能够转化成其它离去基团,如通过三甲基甲硅烷基溴化物的处理得到273.5来转化成溴(参见Spencer等人;J.Org.Chem.;64;1999;3987-3995)。
273.5(Lv=
)与各种亲核试剂的偶联已由Teng等人;Synlett;1996;346-348和美国专利No.6,087,482;54栏64行到55栏20行进行描述。具体地说,描述了在273.5和羟基甲基膦酸二乙基酯之间在三氟甲烷磺酸三甲基甲硅烷基酯(TMS-OTf)存在下的偶联。也能够设想到,具有HO-连接基-PORP1RP2的一般结构的其它化合物也能够使用,只要在这些化合物中的官能团与偶联反应条件相适应就行。在已出版的文献中有许多的实施例描述了273.5(Lv=卤素)与各种醇类的偶联。这些反应能够用许多试剂来促进,如银(I)盐(参见Kim等人;J.Org.Chem.;56;1991;2642-2647,Toikka等人;J.Chem.Soe.PerkinsTrans.1;13;1999;1877-1884),汞(II)盐(参见Veeneman等人;Recl.Trav.Chim.Pays-Bas;106;1987;129-131),三氟化硼二乙醚合物(参见Kunz等人;Hel.Chim Acta;68;1985;283-287),氯化锡(II)(参见O’Leary等人;J.Org.Chem.;59;1994;6629-6636),醇盐(参见Shortnacy-Fowler等人;Nucleosides Nucleotides;20;2001;1583-1598),和碘(参见Kartha等人;Chem.Soc.PerkinsTrans.1;2001;770-772)。这些方法能够有选择地与用于形成具有各种离去基团(Lv)的273.5的不同方法相结合使用,生产273.6。
从273.1转变成273.2,从273.2转变成到273.3,和从273.6转变成到273.7希望让这些转变(从273.3到273.6)的核心组分出现,同时保护早已在化合物结构中存在的官能团。因此,该合成要求保护基引入到化合物中和保护基从化合物中除去的方法是在有机合成中常用的技术。应该理解,在从273.6到273.7的转变中,RP1和RP2不需要保持不变。RP1和RP2的最终形式能够选自各种可能的结构。
实施例274
化合物274.1通过使用在专利申请WO 01/90121(在115页中表)中描述的方法来制备′。在274.1中的5′-羟基是作为叔丁基二甲基甲硅烷基(TBDMS)醚来保护。该2′-和3′-羟基能够作为苄基(Bz)酯来保护,得到274.2。该5′-羟基能够去保护得到274.3。使用碘代苯双乙酸酯和2,2,6,6-四甲基-1-哌啶子基氧基,自由基(TEMPO)的氧化反应将伯醇转化成相应酸274.4。274.4使用四乙酸铅的进一步氧化能够生产274.5。由TMS-OTf进行的在274.5和羟基甲基膦酸二乙基酯(可以从Sigma-Aldrich,Cat.No.39,262-6)之间的偶联能够获得274.6。用TMS-Br处理274.6可将该磷酸二酯转化成相应的膦酸274.7。该2′-和3′-羟基的去保护得到274.8,作为同属结构A的一个例子,其中Base是7-硫杂-8-氧代-鸟嘌呤核苷,R1,R2,RP1和RP2是氢,连接基(linker)是亚甲基。
该膦酸在274.7和274.8作为一个例子来用于进一步说明的目的。其它形式的膦酸酯能够经由膦酸,或其它形式如这里所述的相应二酯,来获得。
实施例275
来氟米特(下面的结构,和它的活性代谢物)(参见美国专利No.4,284,786)是异噁唑的衍生物。本发明的代表性化合物能够按以上所示,通过使用与在J.Med.Chem.1996,39,4608中描述的那些程序类似的程序来制备。它们的结构显示如下。
对于诸如这些化合物之类的化合物的合成方法已由Westwood等人,J.Med.Chem.,1996,39,4608-4621进行描述,根据下面列出的一般路线。
实施例275A
合适的含膦酸酯的苯胺的合成显示如下。
实施例275B
实施例276
本发明的代表性化合物能够按以上所示,通过使用与在J.Med.Chem.1996,39,4608中描述的那些程序类似的程序来制备。本发明的化合物276.1用碱处理可得到化合物276.2,它是本发明的化合物。
实施例277
本发明的代表性化合物能够按以上所示的方法来制备。本发明的化合物277.1用碱处理可得到化合物277.2,它是本发明的化合物。
实施例278
实施例278A:K-105-44的合成
在氩气氛中将2-甲基-5-硝基苯酚(2.00g,13.05mmol)溶于干燥DMF(10mL)中,和冷却到0℃。顺序地添加二乙基磷酰基甲基-O-三氟甲磺酸酯(4.70gm,15.66mmol)和碳酸铯(6.38gm,19.58mmol)。反应混合物在0℃下搅拌4小时。TLC(环己烷/
,1∶1)显示反应的完成。添加去离子水(15mL),混合物用
萃取(2×50mL)。该有机层用1N
(20mL),随后用水(2×20mL)洗涤,在 上干燥和浓缩成半固体。由硅胶柱色谱分析(环己烷/
,1∶1)提纯,获得油形式的纯化合物K-105-44(3.86g,97%)。
ESI-MS m/z 304[M+H]+.
实施例278B:K-105-48的合成
在氩气氛中将化合物K-105-44(2.8g,9.24mmol)溶于15mL的无水乙醇(15mL)和6N
(2mL)中。在
(5.26g,27.72mmol)的添加之后,反应混合物在室温下搅拌一夜。TLC(
/
,9∶1)显示反应的完成。混合物浓缩成半固体和溶于乙酸乙酯(30mL)中。乙酸乙酯层用去离子水(10mL)和饱和的
(10mL)洗涤并在
上干燥。浓缩得到固体物,它无需提纯就可使用。
ESI-MS m/z 274[M+H]+。
实施例278C:K-105-49-3的合成
在氩气氛中将粗化合物K-105-48(900mg,3.38mmol)溶于15mL的干燥THF(15mL)中。在5-甲基异噁唑-4-羧酸(381mg,3.00mmol)和二异丙基碳二亚胺(511μL,3.30mmol)的添加之后,反应混合物在室温下搅拌6小时。TLC(
/
,9∶1)显示反应的完成。反应混合物进行过滤,该滤液被浓缩得到固体,它溶于乙酸乙酯(25mL)中。溶液用去离子水(2×10mL)洗涤并在
上干燥。浓缩得到固体,它由硅胶柱色谱分析(
/
,95∶5)提纯,获得纯化合物K-105-49-3,为浅黄色固体(680mg,55%)。
ESI-MS m/z 383[M+H]+。
1H NMR(300MHz,CDCl3):δ7.11(1H,s,ArH),7.06(2H,s,ArH),4.29-4.20(4H,m,
),4.14(2H,d,J=10.4Hz,
),2.76(3H,s,
),2.14(3H,s,
),1.37(6H,t,J=7.0Hz,
)。
31P NMR(121.7MHz,DMSO-d6/外部
)δppm19.7-20.0(m)
HPLC:98%纯度(Sphereclone 5μL,
:
,从10-90%
的20min线性,1.0mL/min)
实施例278D:K-105-54-1的合成
在氩气氛中将化合物K-105-54-1(250mg,0.65mmol)溶于10mL的无水乙醇(15mL)中。在
(29mg,0.72mmol)的添加之后,反应混合物在室温下搅拌一夜。TLC(
/
,9∶1)显示反应的完成。反应混合物浓缩成固体和溶于乙酸乙酯(20mL)中。溶液用去离子水(2×10mL)洗涤并在
上干燥。浓缩得到固体,它由硅胶柱色谱分析(
/
,4∶1)提纯,获得纯化合物K-105-54-1,为固体物(188mg,75%)。
ESI-MS m/z 383[M+H]+。
1H NMR(300MHz,DMSO-d6):δ7.32(1H,s,ArH),6.96(2H,s,ArH),4.31(2H,d,J=9.9Hz,
),4.18-4.08(4H,m,2x
),2.08(3H,s,
),2.00(3H,s,
),1.26(6H,t,J=7.0Hz,
)。
31P NMR(121.7MHz,DMSO-d6/外部
)δppm20.0-20.4(m)
HPLC:93%纯度(Sphereclone 5μL,
:
,从10-90%
的20min线性,1.0mL/min)
实施例279
本发明的代表性化合物能够按以上所示的方法来制备。本发明的特定化合物能够按在下面所示的方法来制备。
和
实施例280
本发明的代表性大环内酯化合物,其中该结构280.1被理解为化合物他克莫司、子囊霉素或西罗莫司,能够按照以上所示,例如通过使用芳基铋试剂如在Bioorg.Med.Chem.Lett,1995,5,1035中描述的试剂来制备。另外,银盐已经用于媒介在免疫抑制大环内酯上的烷基化,比如这些:参见J.Med.Chem.,1998,41,1764。本发明的特定化合物能够按在下面所示的方法来制备。
实施例281
本发明的代表性大环内酯化合物,其中该结构212.1被理解为化合物他克莫司、子囊霉素或西罗莫司,能够按照以上所示,例如通过使用芳基铋试剂如在Bioorg.Med.Chem.Lett,1995,5,1035中描述的试剂来制备。另外,银盐已经用于媒介在免疫抑制大环内酯上的烷基化,比如这些:参见J.Med.Chem.,1998,41,1764。本发明的特定化合物能够按在下面所示的方法来制备。
实施例282
本发明的代表性化合物能够按以上所示的方法来制备。在C-21羟基上的衍生化是通过用合适膦酸酯将强的松282.1进行烷基化,得到本发明的化合物282.2来实现的。本发明的特定化合物能够如下制备。
在化合物282.1中的伯羟基质子的氢化钠夺去之后,加成二乙基膦酸酯三氟甲磺酸酯获得醚282.4。
实施例283
本发明的代表性化合物283.3能够按以上所示的方法来制备。强的松283.1在较少位阻的伯位上实施保护得到醇283.5,它在唯一暴露的羟基上用合适膦酸酯烷基化,得到283.6。保护基团的除去完成了类似物283.3的构造。特定的化合物能够如下制备。
强的松283.1作为它的TBS醚283.7来单保护。在用二乙基膦酸酯三氟甲磺酸酯进行烷基化后,所形成的中间体283.8用TBAF处理,得到所需的膦酸酯283.9。
以上示出了本发明的膦酸酯化合物和用于它们的合成中的中间体化合物的合成。在C-21羟基上的衍生化是通过用合适膦酸酯将地塞米松1烷基化来实现的,得到在这里显示的类似物。
实施例284
本发明的代表性化合物能够按以上所示的方法来制备。在C-11羟基上的衍生化是通过用合适膦酸酯将双甲丙酰龙284.1烷基化来实现的,得到通式284.2的类似物。本发明的特定化合物能够按在下面所示的方法来制备。
在化合物284.1中的羟基质子的氢化钠夺去之后,加成二乙基膦酸酯三氟甲磺酸酯获得醚284.5。
实施例285
将二酸(100mg,0.304mmol),氨基酸(100mg,0.651mmol),苯酚(145mg,1.54mmol),和三乙胺(510μL,3.66mmol)溶于吡啶(5mL)中。混合物被加热至60℃保持5分钟。向这一反应混合物中添加由三苯基膦(560mg,2.14mmol)和Aldrithiol(2)(470mg,2.13mmol)溶于吡啶(5mL)中所获得的溶液。反应然后在60℃下加热12小时。反应混合物在
中稀释,用
、饱和
(水溶液)和盐水洗涤。有机层进行干燥(
),浓缩和用色谱分离法在硅胶上提纯(1%
/
→10%
/
),得到单酰胺化物130-1(5mg,3%)和双酰胺化物130-2(5mg,3%)。
对于130-1:1H NMR(300MHz,CD3OD)δ7.78(1H,m),7.35(2H,m),7.20(3H,m),4.18-3.95(5H,m),2.24-1.90(2H,m),1.87-1.62(4H,m),1.38-1.18(6H,m),1.02(6H,m);31P NMR(121MHz,CD3OD)δ36.3,35.3;LC-MS(方法:0.5min 95%
/5%
→5min 0%
/100%
,rt=2.18min.对于
(MH+)的MS计算值:505.2。实测值:505.2。
对于130-2:1H NMR(300MHz,CD3OD)δ7.77(1H,s),4.23-3.92(8H,m),2.04-1.50(6H,m),1.42(3H,d),1.40(3H,d),1.28(3H,t),1.22(3H,t),1.02(3H,s),1.01(3H,s);31P NMR(121MHz,CD3OD)δ33.9;LC-MS(方法:0.5min 95%
/5%
→5min 0%
/100%
,rt=1.79min.对于
(MH+)的MS计算值:528.3。
实测值:528.3。
实施例286
将二酸(25mg,0.072mmol),氨基酸(25mg,0.16mmol),苯酚(38mg,0.40mmol),和三乙胺(127μL,0.911mmol)溶于吡啶(1.25mL)中。混合物被加热至60℃保持5分钟。向这一反应混合物中添加由三苯基膦(140mg,0.534mmol)和Aldrithiol(2)(119mg,0.540mmol)溶于吡啶(1.25mL)中所获得的溶液。反应然后在60℃下加热12小时。另一批的二酸(12mg,0.035mmol)按照如上所述来处理。来自两批的反应混合物被合并,并在
中稀释,用
、饱和
(水溶液)和盐水洗涤。有机层进行干燥(
),浓缩和用色谱分离法在硅胶上提纯(1%
/
→10%
/
),得到单酰胺化物133-1(3mg,8%)和双酰胺化物133-2(8mg,20%)。
对于133-1:1H NMR(300MHz,CD3OD)δ8.38-8.08(1H,m),7.78-7.60(2H,m),7.50-7.18(8H,m),6.67-6.05(1H,m),5.60-5.30(2H,m),4.63(1H,bs),4.25-3.95(3H,m),1.37(3H,m),1.18(3H,m);31PNMR(121MHz,CD3OD)δ21.5,20.2;LC-MS(方法:0.5min 95%
/5%
→5min 0%
/100%
,rt=1.98min.对于
(MH+)的MS计算值:523.2。实测值:523.2。
对于133-2:1H NMR(300MHz,CD3OD)δ8.15(1H,dd),7.72(1H,s),7.67(1H,m),7.39(2H,m),7.28(1H,m),6.44(1H,dd),5.40(2H,s),4.23-3.90(6H,m),1.42(6H,m),1.27(3H,t),1.18(3H,t);31PNMR (121MHz,CD3OD)δ19.7;LC-MS(方法:0.5min 95%
/5%
→5min 0%
/100%
,rt=1.86min.对于
(MH+)的MS计算值:546.2。实测值:546.2。
实施例287 前体药物裂解分析
PBMC萃取物的分离:
新鲜的人PBMCs是从遭受leukophoresis的患者体内获得;细胞置于血浆中并在抽取后的26小时内进行处理。通过使用菲可帕克(Ficoll-Paque)方法来实现提纯:通过在1200Xg下离心处理5分钟来收集PBMC细胞,然后通过再悬浮在RBC溶胞缓冲剂(155mM
,0.1mM EDTA,10mM
)中来洗涤三次。将洗涤过的细胞悬浮于溶胞缓冲剂(在1mL的10mM Tris,pH7.4,150mM
,20mM
,1mM DTT和1%NP40中0.2×109个细胞)中并在冰上培养20分钟。PBMC粗提取物在1000Xg下离心处理30分钟以除去未溶解的细胞和该上清液在100,000Xg下处理1小时。该100,000Xg上清液(PBMC提取物:P0)被收集,在液氮中紧压冷冻和在-70℃下贮存。测量前体药物被PBMC提取物裂解的方案:
反应混合物在100μl的最终体积中含有25mM MesNa(pH6.5),100mM
,1mM DTT,0.1%NP-40,30μM底物,和变化量的酶。该酶催反应是在37℃下进行10-120分钟,和在3-4个的单个时点通过添加180μl的冰冷的甲醇来停止。样品在-20℃下培养30分钟,和在13,000RPM下离心处理30分钟(@4℃)。该上清液被转移到96孔板上并在真空下通过使用真空离心蒸发浓缩器来进行蒸发。将沉淀物溶于100μl的20mM
+5%
中。由HPLC(在260nm处监测)测量前体药物的消失。PBMC提取物对于所试验的前体药物的比活性被定义为:v(裂解速度)/μg蛋白质=p mol/min/μg。
结果
化合物 人PBMC提取物比活性
(pmol/min/μg)
130-1 3.48
130-2 0.65
133-1 4.9
133-2 0.38
实施例288
具有下面通式的本发明的代表性化合物能够按照在这里所述的方法来制备。
例如,麦考酚酸吗啉乙酯的三个区域能够用于膦酸酯前体药物的连接,如以上所示化合物D、E和G证实的。同样,该羧酸能够与在化合物F中一样被膦酸替换。
实施例288A
本发明的代表性化合物能够按以上所示的方法来制备。该吗啉代乙基结构部分能够作为前体药物官能团来改进生物利用率并能够被如上所示的膦酸酯前体药物柄(handle)所替换。霉酚酸例如可以从Sigma Chemical Company,St.Louis,Mo商购。羧酸288.1在游离酚存在下的活化,然后携带膦酸酯基团的醇的添加,会导致所需产物288.3(美国专利No.4,786,637)的形成。本发明的特定化合物能够如下制备。
将霉酚酸288.1溶于二氯甲烷中。添加亚硫酰氯,然后添加催化量的DMF。反应混合物在室温下搅拌3小时,在此之后挥发性组分在真空下被除去。将膦酸酯-醇溶于二氯甲烷中和在冰浴上冷冻到约4℃。将该霉酚酰氯288.2溶于二氯甲烷中和添加到冷冻的溶液中。在约4℃下搅拌90分钟后,反应混合物用水洗涤,然后用碳酸氢钠水溶液洗涤。该有机溶液进行干燥和蒸发,得到膦酸酯288.4。
实施例289
本发明的代表性化合物能够按以上所示的方法来制备。该C-4酚位置为以上所示的其它类似物提供反应活性柄(handle)。一旦289.1的羧酸被吗啉代乙基封闭,如在化合物289.2中,该酚能够在碱性条件下烷基化。可以使用碱如吡啶,碳酸钾或三乙胺。离去基团如三氟甲基磺酸酯,甲磺酸酯,溴,或碘连接于该膦酸酯前体药物亚单元上并在碱存在下与化合物289.2进行反应。化合物289.3能够直接使用,或以盐化合物289.4的形式使用。在能够制备的大量的盐中,氯化物和硫酸氢盐是本发明的一个具体实例。本发明的特定化合物能够如下制备。
类似于化合物289.2(描述在实施例288中),制备化合物289.5。吗啉代乙醇在二氯甲烷中的溶液被冷却到约4℃。将霉酚酰氯289.5溶于二氯甲烷中和添加到冷却了的溶液中。将该溶液约90分钟,得到化合物289.2。反应混合物用水洗涤,并用硫酸钠干燥。溶剂的除去得到了离析的化合物289.2。在289.2的酚位置上的烷基化是通过将该化合物悬浮于吡啶中来实现的。三氟甲磺酸酯289.6被添加到溶液中和混合物在室温下搅拌约90分钟。将反应混合物倾倒在水中,该产物用乙酸乙酯萃取。有机层的除去得到了化合物289.7。能够任选地制备289.7的盐酸盐。将化合物289.7溶于异丙醇中,将所得溶液添加到氯化氢在异丙醇中的混合物之中。过滤收集盐酸盐289.8,在真空下干燥。
实施例290
本发明的代表性化合物能够按以上所示的方法来制备。霉酚酸的羧酸能够被也可用作前体药物柄的膦酸替换。为了除去含羧酸的侧链,该酰氯290.5(在实施例289中制得)转化成酯290.1。该酚用甲硅烷基团的保护,随后二羟基化和该二醇的裂解,将产生醛290.3(Pankiewicz等人,J.Med.Chem.,2002,45,703),(Patterson等人,美国专利No.5,444,072)。与携带适当地保护的膦酸酯的内鎓盐(ylide)290.4之间的维蒂希(Wittig)反应会得到所需化合物290.5。最终的去保护得到化合物290.6。本发明的特定化合物能够如下制备。
霉酚酸酯290.8能够简单地通过将该酰氯290.7与
一起搅拌来制备。然后,霉酚酸酯的苯位置被甲硅烷基如TBS保护,得到化合物290.9。一旦该酚位置被保护,使用四氧化锇进行二羟基化,随后进行高碘酸盐(periodinate)裂解,得到醛290.10。醛290.10和过量的内鎓盐290.11在苯中在回流下加热约24小时。反应混合物进行浓缩和该残留物由柱色谱法提纯,得到烯烃290.12(Pankiewics等人,J.Med.Chem.,2002,45,703)。使用HF-吡啶的最终去保护将得到最终产物290.13。
实施例291
本发明的代表性化合物能够按以上所示的方法来制备。在以上所示的霉酚酸酯291.2的脱甲基之后,化合物的另一个连接点能够解除封闭。为此,该
需要用保护基(P)如甲硅烷基基团来掩蔽。一旦该
脱甲基和烷基化,在4位上的保护基团被除去以露出最终产物291.4。该morphonyl乙醇基团在早期安装并通过烷基化步骤来承载。不同的保护基可以最初安装和随后除去。在后一类型的合成中,最后的步骤是吗啉代乙基酯前体药物的形成。本发明的特定化合物能够按如下所述来制备。
酚291.5通过使用咪唑作为碱在
中用TBS基团加以保护,得到291.6。通过使用硫醇盐亲核试剂进行脱甲基,产生化合物291.7。各种其它方法也在文献中找到,如在Greene and Wuts的ProtectiveGroups in Organic Synthesis所述。该
采用膦酸酯的三氟甲磺酸酯的烷基化可通过使用
或TEA来很好地进行,得到291.8。最终的去保护以除去TBS基团可以得到产物291.9。
实施例292
本发明的代表性化合物能够按以上所示的方法来制备。
[4-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基氧基甲基]-膦酸二异丙基酯
7-羟基-6-(4-羟基-3-甲基-丁-2-烯基)-5-甲氧基-4-甲基-3H-异苯并呋喃-1-酮1A(50mg,0.18mmol,Pankiewicz等人,J.Med.Chem.,45,703),溴甲基膦酸二异丙基酯(93mg,0.36mmol)和叔丁醇锂(在THF中1M浓度,0.54mL)在DMF(3mL)中的混合物在70℃下加热5小时。反应用1N
淬灭。将混合物倾倒在5%氯化锂水溶液中,用乙酸乙酯萃取,和浓缩。该残留物用色谱分离法在硅胶上提纯,获得[4-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基氧基甲基]-膦酸二异丙基酯1B(25mg,32%);1H NMR(300MHz,CDCl3)δ1.25(m,12H),1.79(s,3H),2.05(s,3H),3.37(d,J=6.6Hz,2H),3.58(d,2H),3.77(s,3H),3.97(m,2H),4.68(m,2H),5.19(s,2H),5.45(t,J=6.6Hz,1H),7.83(s,1H)ppm。[4-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基氧基甲基]-膦酸和[4-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基氧基甲基]-膦酸单异丙基酯
在0℃下向[4-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基氧基甲基]-膦酸二异丙基酯1B(25mg,0.055mmol)和2,6-二甲基吡啶(0.18mL,1.65mmol)在乙腈中的溶液添加三甲基甲硅烷基溴化物(0.126mL,1.1mmol)。混合物升至室温和搅拌4小时。反应用0℃的甲醇淬灭,然后该合成混合物进行浓缩。该残留物由制备性反相HPLC提纯,在除去溶剂之后获得[4-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基氧基甲基]-膦酸1C,为油状物(17mg,83%);1H NMR(300MHz,CD3OD)δ1.81(s,3H),2.06(s,3H),3.40(d,J=6.6Hz,2H),3.50(d,2H),3.77(s,3H),3.97(s,2H),5.20(s,2H),5.47(t,J=6.6Hz,1H)和[4-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基氧基甲基]-膦酸单异丙基酯1D,为油状物(2mg,7%);1HNMR(300MHz,CD3OD)δ1.23(d,6H),1.81(s,3H),2.08(s,3H),3.40(d,J=6.6Hz,2H),3.50(d,2H),3.77(s,3H),3.90(s,2H),4.50(m,1H),5.20(s,2H),5.47(t,J=6.6Hz,1H)ppm。
实施例293
本发明的代表性化合物能够按在下面所示的方法来制备。
[5-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-3-甲基-戊-1,3-二烯基]-膦酸二甲酯
向四甲基亚甲基二膦酸酯(102mg,0.44mmol)在THF(2.5mL)中的溶液添加双(三甲基甲硅烷基)胺化钠(1.0M,0.44mL)的THF溶液。在搅拌30分钟后,将4-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯醛2A(30mg,0.11mmol,Pankiewicz等人,J.Med.Chem.,45,703)在THF(2.5mL)中的溶液添加进去,然后继续搅拌另外15分钟。反应用饱和氯化铵水溶液淬灭。混合物用乙酸乙酯萃取。在蒸发溶剂后,残留物由色谱分离法在硅胶上用乙酸乙酯(50%到100%)/己烷洗脱来提纯,获得油形式的[5-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-3-甲基-戊-1,3-二烯基]-膦酸二甲酯2B(30mg,71%);1H NMR(300MHz,CDCl3)δ1.80(s,3H),2.04(s,3H),3.45(d,J=6.6Hz,2H),3.76(s,3H),3.88(d,6H),5.20(s,3H),5.55(m,1H),5.95(m,1H),7.05(m,1H),7.65(s,1H)ppm。
[5-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-3-甲基-戊-1,3-二烯基]-膦酸
在0℃下向[5-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-3-甲基-戊-1,3-二烯基]-膦酸二甲酯2B(22mg,0.057mmol)和2,6-二甲基吡啶(0.22mL,1.71mmol)在乙腈中的溶液添加三甲基甲硅烷基溴化物(0.183mL,1.71mmol)。混合物升至室温和搅拌1小时。反应用0℃的甲醇淬灭,然后该合成混合物进行浓缩。该残留物用制备性反相HPLC提纯,在除去溶剂后获得固体形式的[5-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-3-甲基-戊-1,3-二烯基]-膦酸2C(13mg,65%);1H NMR(300MHz,CD3OD)δ1.91(s,3H),2.10(s,3H),3.55(d,J=6.6Hz,2H),3.75(s,3H),5.2(s,2H),5.6-5.8(m,2H),6.9(m,1H)ppm。
实施例294
本发明的代表性化合物能够按在下面所示的方法来制备。
6-(4-溴-3-甲基-丁-2-烯基)-7-羟基-5-甲氧基-4-甲基-3H-异苯并呋喃-1-酮
将聚合物担载的三苯基膦(3mmol/g,0.5g)在二氯甲烷(10mL)中浸泡1小时,顺序地添加7-羟基-6-(4-羟基-3-甲基-丁-2-烯基)-5-甲氧基-4-甲基-3H-异苯并呋喃-1-酮1A(100mg,0.36mmol)和四溴化碳(143mg,0.43mmol),混合物在室温下摇振1小时。添加更多的四溴化碳(143mg,0.43mmol),混合物进一步摇振1小时。将混合物过滤,滤液进行浓缩。该残留物在硅胶(0%到60%乙酸乙酯/己烷)上色谱分离,获得油形式的6-(4-溴-3-甲基-丁-2-烯基)-7-羟基-5-甲氧基-4-甲基-3H-异苯并呋喃-1-酮3B(52mg,42%);1H NMR(300MHz,CDCl3)δ1.95(s,3H),2.16(s,3H),3.44(d,J=7.2Hz,2H),3.78(s,3H),3.98(s,2H),5.21(s,2H),5.68(t,J=7.2Hz,1H),7.71(brs,1H)ppm。
[5-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-3-甲基-戊-3-烯基]-膦酸二乙酯
在-20℃下将正丁基锂(在己烷中1.6M浓度,1mL)添加到同等体积的THF中。然后将甲基膦酸二乙基酯(220mg,1.45mmol)在THF(1mL)中的溶液滴加进去,溶液搅拌30分钟。在-60℃下冷却之后,溶液经由移液管转移到含有碘化亚铜(I)(276mg,1.45mmol)的管形瓶中,所形成的混合物搅拌在-30℃下搅拌1小时。将6-(4-溴-3-甲基-丁-2-烯基)-7-羟基-5-甲氧基-4-甲基-3H-异苯并呋喃-1-酮3B(50mg,0.15mmol)在THF(1mL)中的溶液添加进去,让混合物升至0℃保持2小时,之后添加饱和氯化铵水溶液。反应混合物用2N
酸化,然后用乙酸乙酯萃取。乙酸乙酯萃取液进行浓缩和残留物在硅胶上进行色层分离(40%到100%乙酸乙酯/己烷),获得油形式的[5-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-3-甲基-戊-3-烯基]-膦酸二乙酯3C(27mg,被起始甲基膦酸二乙基酯污染);1H NMR(300MHz,CDCl3)δ1.32(m,6H),1.8-1.9(m,5H),2.18(s,3H),2.25(m,2H),3.42(d,J=7.2Hz,2H),3.78(s,3H),4.15(m,4H),5.21(s,2H),5.24(t,J=7.2Hz,1H),7.65(s,1H)ppm。
[5-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-3-甲基-戊-3-烯基]-膦酸单乙基酯
[5-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-3-甲基-戊-3-烯基]-膦酸二乙酯3C(27mg,0.066mmol),
(200mg),
(3mL)和水(1mL)的混合物在70℃下搅拌4小时。在冷却之后,反应溶液用2N
酸化,与盐水混合,和用乙酸乙酯/乙腈萃取。该有机萃取液进行浓缩和残留物用制备性反相HPLC提纯(乙腈和0.1%
水溶液),获得[5-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-3-甲基-戊-3-烯基]-膦酸单乙基酯3D(7mg,28%);1H NMR(300MHz,CD3OD)δ1.28(t,J=6.9Hz,3H),1.7-1.9(m,5H),2.20(s,3H),2.2-2.3(m,2H),3.41(d,J=6.6Hz,2H),3.80(s,3H),4.02(m,2H),5.2-5.3(m,3H)ppm。
[5-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-3-甲基-戊-3-烯基]-膦酸
向{5-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-3-甲基-戊-3-烯基}-膦酸二乙酯(20mg,0.039mmol)在DMF(0.5mL)和DCM(0.5mL)中的溶液添加TMSBr(50.5μL,0.39mmol),随后添加2,6-二甲基吡啶(45.3μL,0.39mmol)。让反应继续进行1小时,此时由LCMS判断反应已结束。反应混合物用
淬灭,和浓缩到干燥。残留物用制备性反相HPLC提纯。含有所需产物的级分进行浓缩和用10%TFA/DCM处理5分钟。在浓缩后,该残留物用制备性反相HPLC提纯,得到固体形式的7mg(50%)的[5-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-3-甲基-戊-3-烯基]-膦酸。1H NMR(300MHz,CD3OD)δ1.66-1.78(m,5H),2.10(s,3H),2.16-2.22(m,2H),3.34(d,J=7.2Hz,2H),3.72(s,3H),5.16(s,2H),5.20(t,J=7.2Hz,1H)ppm;31P(121.4MHz,CD3OD)δ31.57ppm;MS(m/z)355[M-H]-,357[M+H]+。
实施例295
本发明的代表性化合物能够按在下面所示的方法来制备。
2-(4-溴-丁-2-烯基)-6-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-4-甲基-己-4-烯酸甲基酯
向霉酚酸甲酯4A(138mg,0.41mmol)在THF(2.5mL)中的冷却了(-78℃)的溶液添加双(三甲基甲硅烷基)胺化钠(1.0M,0.98mL)的THF溶液。在搅拌30分钟后,将1,4-二溴-2-丁烯(950mg,4.1mmol)在THF(2.5mL)中的溶液添加进去并继续搅拌10分钟。所形成的混合物升至-30℃和在这一温度下贮存16小时。反应用饱和氯化铵水溶液淬灭。混合物用乙酸乙酯萃取,在蒸发溶剂后获得残留物,后者由在硅胶上的色谱分离法用乙酸乙酯(0%到40%)/己烷洗脱来提纯,获得油形式的2-(4-溴-丁-2-烯基)-6-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-4-甲基-己-4-烯酸甲基酯4B(150mg,78%);1H NMR(300MHz,CDCl3)δ1.75(s,3H),2.0-2.4(m,8H),2.62(m,1H),3.37(d,J=6.6Hz,2H),3.58(s,3H),3.76(s,3H),3.88(d,J=4.8Hz,2H),5.1-5.3(m,3H),5.67(brs,2H),7.67(s,1H)ppm。2-[4-(二乙氧基-磷酰基)-丁-2-烯基]-6-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-4-甲基-己-4-烯酸甲酯
2-(4-溴-丁-2-烯基)-6-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-4-甲基-己-4-烯酸甲酯4B(140mg,0.30mmol)和亚磷酸三乙基酯(600mg,3.6mmol)在甲苯(30mL)中的溶液在回流状态下搅拌20小时。混合物进行浓缩,在硅胶上用乙酸乙酯(60%到100%)/己烷洗脱来进行色层分离,获得油形式的2-[4-(二乙氧基-磷酰基)-丁-2-烯基]-6-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-4-甲基-己-4-烯酸甲酯4C(70mg,43%);1H NMR(300MHz,CDCl3)δ1.27(m,6H),1.79(s,3H),2.0-2.7(m,8H),3.37(d,J=6.6Hz),3.52(s,3H),3.75(s,3H),4.08(m,4H),5.20m,3H),5.45(m,2H)ppm。
2-[4-(二乙氧基-磷酰基)-丁-2-烯基]-6-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-4-甲基-己-4-烯酸
2-[4-(二乙氧基-磷酰基)-丁-2-烯基]-6-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-4-甲基-己-4-烯酸甲酯4C(33mg,0.063mmol)和氢氧化锂(44mg)在THF(6mL)和水(1mL)的溶剂混合物中的混合物在室温下搅拌6小时。将有机溶剂除去,该残留物被分配在乙酸乙酯和5%碳酸氢钠水溶液之间。水层用2N
酸化,然后用乙酸乙酯萃取。该乙酸乙酯萃取液进行浓缩,获得油形式的2-[4-(二乙氧基-磷酰基)-丁-2-烯基]-6-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-4-甲基-己-4-烯酸4D(30mg,100%);1HNMR(300MHz,CDCl3)δ1.27(m,6H),1.79(s,3H),2.0-2.7(m,8H),3.37(d,J=6.6Hz),3.75(s,3H),4.08(m,4H),5.19(s,2H),5.25(m,1H),5.44(m,1H),5.55(m,1H),5.45(m,2H)ppm。
2-[4-(乙氧基-羟基-磷酰基)-丁-2-烯基]-6-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-4-甲基-己-4-烯酸
2-[4-(二乙氧基-磷酰基)-丁-2-烯基]-6-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-4-甲基-己-4-烯酸甲酯4C(25mg,0.048mmol)和氢氧化锂(200mg)在甲醇(3mL)和水(1mL)的溶剂混合物中的混合物在70℃下搅拌2小时。有机溶剂进行蒸发和残留物用
酸化,并用乙酸乙酯/乙腈萃取。有机萃取液进行浓缩,残留物用制备性反相HPLC提纯(乙腈和0.1%
水溶液),获得油形式的2-[4-(乙氧基-羟基-磷酰基)-丁-2-烯基]-6-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-4-甲基-己-4-烯酸4E(15mg,89%);1H NMR(300MHz,CD3OD)δ1.25(t,J=6.9Hz,3H),1.81(s,3H),2.1-2.6(m,8H),3.40(d,J=6.6Hz,2H),3.77(s,3H),3.97(m,2H),5.1-5.3(m,3H),5.67(brs,2H)ppm。
2-[4-(二甲氧基-磷酰基)-丁-2-烯基]-6-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-4-甲基-己-4-烯酸甲酯
在
气氛中,2-(4-溴-丁-2-烯基)-6-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-4-甲基-己-4-烯酸甲酯(490mg,1.05mmol)在亚磷酸三甲基酯(2.5mL,21.1mmol)中的溶液在120℃下加热1小时。让反应冷却到室温。反应混合物通过在真空中除去溶剂来进行后处理,随后使用EtOAc-己烷进行色谱分离,得到460mg(88%)的油形式的产物。1H NMR(300MHz,CDCl3)δ1.77(s,3H),2.081-2.31(m,4H),2.15(s,3H),2.52(d,1H,J=22Hz),2.54(d,1H,J=22Hz),2.55-2.63(m,1H),3.36(d,2H,J=7Hz),3.57(s,3H),3.72(d,6H,J=11Hz),3.76(s,3H),5.20(s,2H),5.20-5.26(m,1H),5.36-5.56(m,2H),7.69(s,1H)ppm;31P(121.4MHz,CDCl3)δ30.1ppm;MS(m/z)497.2[M+H]+,519.2[M+Na]+。
2-[4-(二甲氧基-磷酰基)-丁-2-烯基]-6-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-4-甲基-己-4-烯酸
2-[4-(二甲氧基-磷酰基)-丁-2-烯基]-6-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-4-甲基-己-4-烯酸甲酯(460mg,0.927mmol)在1∶1∶2的
,
,THF(8mL)的溶液中的混合物与
(78mg,1.86mmol)一起在环境温度下搅拌12小时。添加第二批的
(40mg,0.952mmol)。反应混合物在室温下搅拌另外16小时,在此之后没有观察到进一步的进展。通过添加
的饱和水溶液来淬灭反应。该有机层在真空中被除去,产物用
从水层中萃取,该水层已通过添加5滴2N
来酸化。该产物进一步用色谱分离法提纯,得到所需产物。1H NMR(300MHz,CDCl3)δ1.79(s,3H),2.08-2.38(m,4H),2.15(s,3H),2.53(d,1H,J=22Hz),2.60(d,1H,J=22Hz),2.57-2.64(m,1H),3.38(d,2H,J=7Hz),3.72(d,6H,J=11Hz)3.76(s,3H),5.20(s,2H),5.27(t,1H,J=6Hz),5.36-5.63(m,2H)ppm;31P(121.4MHz,CDCl3)δ30.5ppm;MS(m/z)481.2[M-H]-。
2-[4-(2-[4-(二甲氧基-磷酰基)-丁-2-烯基]-6-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-4-甲基-己-4-烯酸
向2-[4-(二甲氧基-磷酰基)-丁-2-烯基]-6-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-4-甲基-己-4-烯酸(25mg,0.052mmol)在乙腈(2mL)中的溶液添加2,6-二甲基吡啶(60μL,0.52mmol)和TMSBr(67μL,0.52mmol)。让反应继续进行45分钟,此时由LCMS判断反应已结束。反应混合物在减压下浓缩和用
水溶液(1mL)淬灭反应。该产物用RP HPLC(使用C18柱,梯度为:
,0.1%TFA-乙腈,0.1%TFA)提纯,得到14.2mg(60%)固体形式的产物。1H NMR(300MHz,CD3OD)δ1.81(s,3H),2.081-2.31(m,4H),2.16(s,3H),2.45(d,1H,J=22Hz),2.47(d,1H,J=22Hz),2.55-2.63(m,1H),3.38(d,2H,J=7Hz),3.77(s,3H),5.25(s,2H),5.20-5.36(m,1H),5.36-5.56(m,2H)ppm;31P(121.4MHz,CD3OD)δ25.4ppm;MS(m/z)453[M-H]-。
2-[4-(二甲氧基-磷酰基)-丁-2-烯基]-6-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-4-甲基-己-4-烯酸2-三甲基硅烷基-乙酯
2-[4-(二甲氧基-磷酰基)-丁-2-烯基]-6-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-4-甲基-己-4-烯酸(160mg,0.332mmol)和三甲基甲硅烷基乙醇(160mg,1.36mmol)在THF(8.00mL)中的溶液与三苯基膦(345mg,1.33mmol)一起搅拌。在0℃下向该溶液中添加偶氮二羧酸二乙基酯(230μL,1.33mmol)。混合物升至室温和搅拌16小时。添加另外的三苯基膦(180mg,0.692mmol),三甲基甲硅烷基乙醇(160mg,1.36mmol),和偶氮二羧酸二乙基酯(115μL,0.665mmol),然后反应混合物在室温下搅拌另外1天。该反应通过在真空中除去溶剂来进行后处理,由硅胶色谱分离法提纯残留物,得到192mg(85%)的澄明油形式的产物。1H NMR(300MHz,CDCl3)δ0.03(s,9H),0.05(s,9H),0.93-0.96(m,2H),1.20-1.29(m,2H),1.78(s,3H),2.01-2.32(m,4H),2.17(s,3H),2.51(d,1H,J=22Hz),2.58(d,1H,J=22Hz),2.50-2.60(m,1H),3.37(d,2H,J=7Hz),3.72(d,6H,J=11Hz),3.76(s,3H),4.08(appt t,2H,J=8Hz),4.30(appt t,2H,J=8Hz),5.12(s,2H),5.15-5.25(m,1H),5.36-5.63(m,2H)ppm;31P(121.4MHz,CDCl3)δ29.3ppm;MS(m/z)705.3[M+Na]+。
2-[4-(羟基-甲氧基-磷酰基)-丁-2-烯基]-6-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-4-甲基-己-4-烯酸2-三甲基硅烷基-乙基酯
2-[4-(二甲氧基-磷酰基)-丁-2-烯基]-6-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-4-甲基-己-4-烯酸2-三甲基硅烷基-乙酯(184mg,0.270mmol)在叔丁胺(2.8mL,27mmol)中的混合物在60℃下加热24小时。让溶液冷却至室温和进行浓缩。该残留物使用
/
(0-30%)由硅胶柱色谱分析法提纯,得到75mg的澄明油的产物。1H NMR(300MHz,CDCl3)δ0.01(s,9H),0.04(s,9H),0.89(appt t,2H,J=9Hz),1.23(appt t,2H,J=9Hz),1.77(s,3H),2.01-2.31(m,4H),2.17(s,3H),2.36(d,1H,J=22Hz),2.38(d,1H,J=22Hz),2.52(septet,1H,J=9Hz),3.39(d,2H,J=7Hz),3.51(d,3H,J=11Hz),4.01-4.08(m,2H),4.30(dd,2H,J=8,9Hz),5.11(s,2H),5.19(brt,1H,J=6Hz),5.33-5.56(m,2H),8.49(brs,1H)ppm;31P(121.4MHz,CDCl3)δ22.1ppm;MS(m/z)667.4[M+Na]+。
2-{4-[(1-乙氧基羰基-乙氧基)-甲氧基-磷酰基]-丁-2-烯基}-6-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-4-甲基-己-4-烯酸2-三甲基硅烷基-乙酯
2-[4-(羟基-甲氧基-磷酰基)-丁-2-烯基]-6-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-4-甲基-己-4-烯酸2-三甲基硅烷基-乙酯(67mg,0.10mmol)和PyBOP(234mg,0.450mmol)在DMF(1.5mL)中的溶液与(S)-(-)-乳酸乙基酯(53mg,0.45mmol)和DIEA(174μL,1.00mmol)在环境温度下搅拌1小时,此时观察到起始原料的完全消耗。该反应通过饱和氯化钠水溶液和乙酸乙酯的添加来进行后处理。分离出有机层,用5%氯化锂水溶液洗涤。有机层在真空中干燥和残留物由硅胶色谱分离法使用
(0-20%)提纯,得到57mg(74%)澄明油形式的所需产物。1H NMR(300MHz,CDCl3)δ0.02(s,9H),0.05(s,9H),0.88-0.94(m,2H),1.20-1.30(m,2H),1.29(t,3H,J=7Hz),1.45(d,3H,J=7Hz),1.78(s,3H),2.01-2.31(m,4H),2.17(s,3H),2.50-2.58(m,1H),2.65(d,1H,J=22Hz),2.67(d,1H,J=22Hz),3.39(d,2H,J=7Hz),3.69和3.77(d,3H,J=11Hz),3.76(s,3H),4.07(appt t,2H,J=7Hz),4.20(dq,2H,J=3,7Hz),4.29(appt t,2H,J=9Hz),4.85-4.99(m,1H),5.12(s,2H),5.19(br t,1H,J=6Hz),5.33-5.61(m,2H)ppm;31P(121.4MHz,CDCl3)δ28.9,29.9ppm;MS(m/z)791.4[M+Na]+。
2-{4-[(1-乙氧基羰基-乙氧基)-甲氧基-磷酰基]-丁-2-烯基}-6-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-4-甲基-己-4-烯酸
2-{4-[(1-乙氧基羰基-乙氧基)-甲氧基-磷酰基]-丁-2-烯基}-6-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-4-甲基-己-4-烯酸2-三甲基硅烷基-乙酯(14mg,0.018mmol)在THF(1mL)中的溶液与TBAF在THF中的1M溶液(55μL,0.055mmol)一起搅拌1小时。反应混合物进行浓缩,用1N
酸化和用
萃取。有机层用盐水洗涤并干燥。产物由硅胶柱色谱分析法
(0-10%)提纯。通过将产物溶于
中并让化合物流过具有0.45μm尼龙膜的13mm Acrodisc针筒式滤器来进行进一步提纯,得到8mg(77%)的产物。1H NMR(300MHz,CDCl3)δ0.92(t,3H,J=7Hz),1.30(d,3H,J=8Hz),1.79(s,3H),2.10-2.39(m,4H),2.15(s,3H),2.53(d,1H,J=8Hz),2.65(d,1H,J=22Hz),2.68(d,1H,J=22Hz),3.38(d,2H,J=7Hz),3.70和3.74(d,3H,J=11Hz),3.76(s,3H),4.07(m,2H),4.96(dq,1H,J=7Hz),5.20(s,2H),5.27(br t,1H,J=7Hz),5.33-5.55(m,2H),7.51-7.56(m,1H),7.68-7.74(m,1H)ppm;31P(121.4MHz,CDCl3)δ29.0,30.1ppm;MS(m/z)569.2[M+H]+,591.3[M+Na]+。
2-{4-[(1-羧基-乙氧基)-羟基-磷酰基]-丁-2-烯基}-6-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-4-甲基-己-4-烯酸2-三甲基硅烷基-乙酯
2-{4-[(1-乙氧基羰基-乙氧基)-甲氧基-磷酰基]-丁-2-烯基}-6-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-4-甲基-己-4-烯酸2-三甲基硅烷基乙基酯(12mg,0.016mmol)在叔丁胺(1mL,9.6mmol)中的溶液在65℃下加热16小时。让溶液冷却到室温和浓缩,得到油形式的粗产物。1H NMR(300MHz,CDCl3)δ0.03(s,9H),0.04(s,9H),0.86-0.98(m,2H),1.22-1.33(m,2H),1.50(d,3H,J=7Hz),1.78(s,3H),2.05-2.30(m,4H),2.10(s,3H),2.48-2.63(m,3H),3.40(d,2H,J=7Hz),3.76(s,3H),4.08(appt t,2H,J=9Hz),4.25-4.33(m,2H),4.75-4.84(m,1H),5.13(s,2H),5.15-5.23(m,1H),5.33-5.55(m,2H)ppm;31P(121.4MHz,CDCl3)δ28.9ppm;MS(m/z)725.3[M-H]-。
2-{4-[(1-羧基-乙氧基)-羟基-磷酰基]-丁-2-烯基}-6-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-4-甲基-己-4-烯酸
粗2-{4-[(1-羧基-乙氧基)-羟基-磷酰基]-丁-2-烯基}-6-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-4-甲基-己-4-烯酸2-三甲基硅烷基-乙酯(AC-2101-59)和四丁铵氟化物在THF(1M,54μL,0.054mmol)中的溶液与THF(1mL)一起在环境温度下搅拌2小时,此时添加更多的四丁铵氟化物在THF中的溶液(54μL,0.054mm0l)。反应搅拌另外16小时,在此时反应已完成。反应混合物真空浓缩和该产物使用Phenomenex Synergi 5μHydro RP 80A柱(50×21.2mm),用
,0.1%
,0.1%TFA的洗脱剂,由RP HPLC提纯,得到澄明油形式的产物(8.0mg)。1H NMR(300MHz,CDCl3)δ1.51(d,3H,J=7Hz),1.79(s,3H),2.05-2.40(m,4H),2.11(s,3H),2.49-2.71(m,3H),3.38(d,2H,J=6Hz),3.76(s,3H),4.85(br s,1H),5.20(s,2H),5.21-5.30(m,1H),5.33-5.63(m,2H)ppm;31P(121.4MHz,CDCl3)δ27.7ppm;MS(m/z)525.2[M-H]-。
2-{4-[(1-乙氧基羰基-乙基胺)-甲氧基-磷酰基]-丁-2-烯基}-6-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-4-甲基-己-4-烯酸2-三甲基硅烷基-乙酯
2-[4-(羟基-甲氧基-磷酰基)-丁-2-烯基]-6-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-4-甲基-己-4-烯酸2-三甲基硅烷基-乙酯(20mg,0.030mmol),PyBOP(62.4mg,0.120mmol)在DMF(1.0mL)中的溶液与L-丙氨酸乙酯盐酸盐(18mg,0.12mmol)和DIEA(26μL,0.15mmol)一起在环境温度下搅拌1小时,此时观察到起始原料的完全消耗。该反应通过添加水来进行后处理,直到反应溶液变成浑浊为止。滴加DMF,直至混合物再次变透明为止。反应混合物经Acrodisc(具有0.45微米尼龙膜的13mm针筒式过滤器)进行过滤,然后使用Phenomenex Synergi 5μHydro RP 80A柱(50×21.2mm),用水和乙腈洗脱,由RP HPLC提纯。含有产物的级分被收集在一起,然后真空浓缩以除去乙腈。剩余的溶液用氯化钠饱和,和用
和乙腈萃取,得到7.2mg的产物。1H NMR(300MHz,CDCl3)δ0.03(s,9H),0.05(s,9H),0.923(appt t,2H,J=8Hz),1.18-1.31(m,5H),1.41(t,3H,J=7Hz),1.78(s,3H),2.03-2.36(m,4H),2.18(s,3H),2.43-2.63(m,3H),3.10-3.30(m,1H),3.40(d,2H,J=7Hz),3.62和3.65(d,3H,J=11Hz),3.76(s,3H),4.03-4.12(m,2H),4.20(dq,2H,J=2,7Hz),4.29(appt t,2H,J=8Hz),5.12(s,2H),5.18-5.28(m,1H),5.33-5.67(m,2H)ppm;31P(121.4MHz,CDCl3)δ30.4,31.2ppm;MS(m/z)790.4[M+Na]+。
2-{4-[(1-乙氧基羰基-乙基胺)-甲氧基-磷酰基]-丁-2-烯基}-6-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-4-甲基-己-4-烯酸
在室温下向2-{4-[(1-乙氧基羰基-乙基胺)-甲氧基-磷酰基]-丁-2-烯基}-6-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-4-甲基-己-4-烯酸2-三甲基硅烷基-乙酯(7.2mg,9.38mmol)在THF(1mL)中的溶液添加TBAF(40μL,在THF中1M浓度溶液)。反应混合物进一步搅拌20分钟,此时由LCMS判断起始原料完全地转化成所需产物。反应混合物在真空中干燥和再溶于DMF中。该产物通过使用Phenomenex Synergi 5μHydro RP 80A(50×21.2mm),用
的洗脱剂,由RP HPLC提纯。含有所需产物的级分被收集,进一步在已填充在4.5cm×2cm柱上的Dowex50WX8-400上提纯,以
(1∶1)洗脱该钠盐,得到3.2mg所需产物。1H NMR(300MHz,CD3OD)δ1.26(dd,3H,J=4,7Hz),1.37(t,3H,J=8Hz),1.80(s,3H),2.00-2.22(m,4H),2.10(s,3H),2.25-2.60(m,3H),3.37(d,2H,J=7Hz),3.60和3.65(d,3H,J=11Hz),3.74(s,3H),3.83-3.96(m,1H),4.18(q,2H,J=8Hz),5.15(s,2H),5.25-5.42(m,2H),5.55-5.69(m,1H)ppm;31P(121.4MHz,CD3OD)δ33.8,34.2ppm;MS(m/z)568.2[M+H]+,590.3[M+Na]+。
6-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-[4-(羟基-甲氧基-磷酰基)-丁-2-烯基]-4-甲基-己-4-烯酸
在室温下向2-[4-(羟基-甲氧基-磷酰基)-丁-2-烯基]-6-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-4-甲基-己-4-烯酸2-三甲基硅烷基乙基酯(11mg,0.016mmol)在THF(1mL)中的溶液添加TBAF(50μL,在THF中1M溶液)。溶液搅拌16小时,然后浓缩。溶液在减压下干燥和再悬浮在DMF(0.8mL)和水(0.25mL)中。溶液经Acrodisc(具有0.45微米尼龙膜的13mm针筒式过滤器)进行过滤,然后使用Phenomenex Synergi 5μHydro RP80A柱(50×21.2mm),用
,0.1%
,0.1%TFA的洗脱剂,由RP HPLC提纯。来自柱中的产物通过使用2×4.5cm柱,用
(1∶1)洗脱,进行离子交换色谱法(钠盐形式的Dowex50WX8-400),得到7.5mg油形式的所需产物。1H NMR(300MHz,CDCl3)δ1.80(s,3H),2.01-2.29(m,5H),2.11(s,3H),2.35(d,2H,J=22Hz),3.38(d,2H,J=7Hz),3.53(d,3H,J=11Hz),3.75(s,3H),5.19(s,2H),5.26(t,1H,J=6Hz),5.43-5.54(m,2H)ppm;31P(121.4MHz,CDCl3)δ23.5ppm;MS(m/z)469.2[M+H]+,491.3[M+Na]+。
6-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-4-甲基-己-4-烯酸甲基酯
向6-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-4-甲基-己-4-烯酸甲基酯(222mg,0.66mmol),三苯基膦(260mg,0.996mmol),和偶氮二羧酸二乙基酯(173mg,0.996mmol)在THF(3mL)中的0℃溶液添加2-三甲基甲硅烷基乙醇(142μL,0.996mmol)在THF(3mL)中的溶液。让所获得的黄色溶液升至室温和搅拌一夜。反应浓缩到干燥和添加乙醚和己烷。三苯基氧膦由过滤除去和该滤液进行浓缩并由硅胶色谱分离法提纯,得到248mg无色油形式的所需产物。1H NMR(300MHz,CDCl3)δ0.03(s,9H),1.18-1.30(m,2H),1.81(s,3H),2.18(s,3H),2.25-2.33(m,2H),2.37-2.45(m,2H),3.42(d,2H,J=7Hz),3.62(s,3H),3.77(s,3H),4.25-4.35(m,2H),5.13(s,2H),5.12-5.22(m,1H)ppm。
[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-乙醛
根据Smith,D.B.等人,J.Org.Chem.,1996,61,6,2236的程序,6-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-4-甲基-己-4-烯酸甲基酯(618mg,1.42mmol)在
(10mL),
(10mL)和吡啶(50μL,0.618mmol)中的溶液通过使用干冰/丙酮浴被冷却至-70℃。经由气相分散管将臭氧气流鼓泡通入反应中,直至反应变成蓝色为止(15分钟)。该臭氧管线用氮气流置换并继续鼓泡另外15分钟,在此时蓝色已消失。在-70℃下将硫脲(75.7mg,0.994mmol)作为一份添加到该溶液中,然后移走冷却浴。反应升至室温和搅拌15小时。反应由过滤除去固体硫脲S-二氧化物来进行后处理,并分配在
和水之间。除去有机层。水层再一次用
洗涤,合并各有机萃取液。该有机层用1N
水溶液,饱和
水溶液和盐水洗涤。有机萃取液在真空中干燥,残留物由硅胶色谱分离法提纯,获得357mg(75%)白色固体形式的产物。1H NMR(300MHz,CDCl3)δ-0.01(s,9H),1.05-1.15(m,2H),2.15(s,3H),3.69(s,3H),3.78(d,2H,J=1Hz),4.27-4.39(m,2H),5.11(s,2H),9.72(d,1H,J=1Hz)ppm。
4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯醛
[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-乙醛(70mg,0.21mmol)在甲苯(2mL)中的溶液在100℃下与2-(三苯基-phosphanylidene)-丙醛(72.9mg,0.23mmol)一起加热一夜。添加第二份的2-(三苯基-phosphanylidene)-丙醛(33mg,0.11mmol),反应混合物加热另外1天。在浓缩后,残留物用硅胶色谱分离法提纯,得到54mg(83%)浅黄色油形式的所需产物。1H NMR(300MHz,CDCl3)δ0.00(s,9H),1.10-1.21(m,2H),1.87(s,3H),2.16(s,3H),3.67-3.76(m,2H),3.74(s,3H),4.27-4.39(m,2H),5.11(s,2H),6.40-6.48(m,1H),9.2(s,1H)ppm。
6-(4-羟基-3-甲基-丁-2-烯基)-5-甲氧基-4-甲基-7-(2-三甲基硅烷基-乙氧基)-3H-异苯并呋喃-1-酮
将4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯醛(103mg,0.27mmol)在甲醇(5mL)中的溶液冷却到0℃。添加
(0.68mL,
∶
,9∶1)的溶液,随后添加
(0.14mL,0.28mmol的在THF中2M溶液)。移走冰浴,让反应混合物升至室温。反应混合物进一步搅拌另外40分钟,此时TLC指示起始醛的完全消耗。反应通过添加1N
水溶液(0.5mL)进行后处理,产物用
萃取。该有机层用饱和的碳酸氢钠水溶液和盐水洗涤。该有机层在减压下浓缩,该残留物由硅胶色谱分离法提纯,得到100mg(97%)澄清液体形式的产物。1H NMR(300MHz,CDCl3)δ0.00(s,9H),1.20(dd,2H,J=7,8Hz),1.81(s,3H),2.13(s,3H),3.38-3.50(m,2H),3.74(s,3H),3.95(s,2H),4.27(dd,2H,J=7,8Hz),5.08(s,2H),5.17-5.44(m,1H)ppm。
6-(2-羟基-乙基)-5-甲氧基-4-甲基-7-(2-三甲基硅烷基-乙氧基)-3H-异苯并呋喃-1-酮
向[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-乙醛(97mg,0.29mmol)在THF(5mL)中的溶液添加在THF中2 M
的等分部分(150μL,0.300mmol)。反应混合物在室温下搅拌1小时,此时由TLC观察到起始原料的完全消耗。反应混合物通过添加1N
水溶液和用
萃取来进行后处理。该有机层在真空中干燥,残留物用硅胶色谱分离法提纯,得到产物。1H NMR(300MHz,CDCl3)δ0.00(s,9H),1.20(dd,2H,J=7,9Hz),2.07(br s,1H),2.14(s,3H),2.97(t,2H,J=6Hz),3.76(t,2H,J=6Hz),3.77(s,3H),4.32(dd,2H,J=7,8Hz),5.08(s,2H)ppm。
{2-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-乙氧基甲基}-膦酸二异丙基酯
6-(2-羟基-乙基)-5-甲氧基-4-甲基-7-(2-三甲基硅烷基-乙氧基)-3H-异苯并呋喃-1-酮(79mg,0.23mmol)与溴甲基膦酸二异丙基酯(120mg,0.46mmol)的混合物在DMF(2mL)中在叔丁醇锂(22mg,0.27mmol)存在下在70℃下加热一夜。反应混合物用RP HPLC(乙腈和0.1%
水溶液)提纯,得到所需产物。1H NMR(300MHz,CDCl3)δ0.00(s,9H),1.13-1.25(m,2H),1.26(t,12H,J=6Hz),2.12(s,3H),2.98(t,2H,J=7Hz),3.60-3.73(m,4H),3.77(s,3H),4.05-4.16(m,2H),4.62-4.74(m,2H),5.07(s,2H)ppm;MS(m/z)539[M+Na]+。
实施例296
本发明的代表性化合物能够按在下面所示的方法来制备。
[2-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-乙氧基甲基]-膦酸
在室温下向{2-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-乙氧基甲基}-膦酸二异丙基酯(7.5mg,0.014mmol)在乙腈(2mL)和2,6-二甲基吡啶(25μL,0.21mmol)中的溶液添加三甲基甲硅烷基溴化物(27μL,0.21mmol)。让反应继续进行18小时,此时由LCMS指示反应已完成。反应通过添加
来淬灭,然后浓缩。该残留物由RP-HPLC使用C18柱提纯。将所收集的产物溶于10%TFA/
的溶液中以确保完全的去保护。反应混合物经冻干得到所需产物。1H NMR(300MHz,CD3OD)δ2.12(s,3H),2.98(t,2H,J=7Hz),3.66-3.76(m,4H),3.78(s,3H),5.21(s,2H)ppm;MS(m/z)331[M-H]-。
实施例297
本发明的代表性化合物能够按在下面所示的方法来制备。
6-(4-溴-3-甲基-丁-2-烯基)-7-羟基-5-甲氧基-4-甲基-3H-异苯并呋喃-1-酮
将聚合物担载的三苯基膦(3mmol/g,0.5g)在二氯甲烷(10mL)中浸泡1小时,顺序地添加7-羟基-6-(4-羟基-3-甲基-丁-2-烯基)-5-甲氧基-4-甲基-3H-异苯并呋喃-1-酮1A(100mg,0.36mmol)和四溴化碳(143mg,0.43mmol),混合物在室温下摇振1小时。添加更多的四溴化碳(143mg,0.43mmol),混合物进一步摇振1小时。将混合物过滤,滤液进行浓缩。该残留物在硅胶(0%到60%乙酸乙酯/己烷)上进行色层分离,获得油形式的6-(4-溴-3-甲基-丁-2-烯基)-7-羟基-5-甲氧基-4-甲基-3H-异苯并呋喃-1-酮(52mg,42%);1H NMR(300MHz,CDCl3)δ1.95(s,3H),2.16(s,3H),3.44(d,J=7.2,2H),3.78(s,3H),3.98(s,2H),5.21(s,2H),5.68(t,J=7.2Hz,1H),7.71(brs,1H)ppm。
[4-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基]-膦酸二甲基酯
将6-(4-溴-3-甲基-丁-2-烯基)-7-羟基-5-甲氧基-4-甲基-3H-异苯并呋喃-1-酮(33mg,0.097mmol)在亚磷酸三甲基酯(1.0mL,8.5mmol)中的溶液加热至100℃保持1小时,此时由LCMS指示完全的反应。该反应通过在减压下除去过量的试剂来进行后处理,残留物由硅胶色谱分离法使用EtOAc-己烷(20-100%)提纯,得到20mg(60%)的所需产物。1H NMR(300 MHz,CDCl3)δ1.90(s,3H),2.09(s,3H),2.48(d,2H,J=22Hz),3.38(t,2H,J=6Hz),3.64(d,6H,J=11Hz),3.72(s,3H),5.14(s,2H),5.33(q,1H,J=6Hz),7.65(br s,1H)ppm;MS(m/z)371 [M+H]+。
实施例298
本发明的代表性化合物能够按在下面所示的方法来制备。
[4-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基]-膦酸
在0℃下向[4-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基]-膦酸二甲酯(18mg,0.049mmol)在乙腈(2mL)中的溶液添加TMSBr(63μL,0.49mmol)和2,6-二甲基吡啶(85μL,0.73mmol)。反应溶液升至室温和搅拌2小时,此时由LCMS观察到反应的完成。反应冷却至0℃和通过添加
来淬灭。反应混合物在减压下浓缩,和该残留物由RP HPLC使用C18柱以H2O-乙腈(5-0%)的梯度经过20分钟提纯,得到12.2mg(73%)的产物。1HNMR(300MHz,CD3OD)δ1.95(s,3H),2.15(s,3H),2.48(d,2H,J=22Hz),3.44(t,2H,J=6Hz),3.79(s,3H),5.24(s,2H),5.38(q,1H,J=7Hz),6.87(br s,1H)ppm;MS(m/z)341[M-H]-。
实施例299
本发明的代表性化合物能够按在下面所示的方法来制备。
[4-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基氧基甲基]-膦酸单苯基酯和[4-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基氧基甲基]-膦酸二苯基酯
在0℃下慢慢地向[4-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基氧基甲基]-膦酸(49mg,0.13mmol)在DMF(0.4mL)和苯酚(62mg,0.65mmol)中的溶液添加二环己基碳二亚胺(107mg,0.52mmol)和DMAP(8mg,0.065mmol)在DMF(0.6mL)中的溶液。反应升至室温和加热到140℃保持10小时。在冷却到室温之后混合物进行过滤和用1N
水溶液萃取。水层用1N
酸化和用
萃取。该有机层在
上干燥和浓缩至干燥。该残留物由RP HPLC提纯,得到18.5mg的[4-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基氧基甲基]-膦酸单苯基酯,为浅黄色固体,和4.1mg的[4-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基氧基甲基]-膦酸二苯酯(次要产物),也为浅黄色固体。主要产物:1H NMR(300MHz,CD3OD)δ1.82(s,3H),2.16(s,3H),3.46(d,2H,J=7Hz),3.70(d,2H,J=8Hz),3.77(s,3H),3.96(s,2H),5.25(s,2H),5.52(t,1H,J=8Hz),7.10-7.21(m,3H),7.30(t,2H,J=8Hz)ppm;31P(121.4MHz,CD3OD)δ17.3ppm;MS(m/z)449.0[M+H]+,471.2[M+Na]+。次要产物:1H NMR(300MHz,CD3OD)δ1.82(s,3H),2.15(s,3H),3.47(d,2H,J=7Hz),3.77(s,3H),3.98-4.06(m,4H),5.25(s,2H),5.50-5.61(m,1H),7.10-7.25(m,6H),7.30-7.41(m,4H)ppm;31P(121.4MHz,CD3OD)δ16.3ppm;MS(m/z)525.2[M+H]+,547.2[M+Na]+。
实施例300
本发明的代表性化合物能够按在下面所示的方法来制备。
2-{[4-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基氧基甲基]-苯氧基-膦酰基氧基}-丙酸乙酯
向[4-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基氧基甲基]-膦酸单苯基酯(18.5mg,0.040mmol)和(S)-(-)-乳酸乙基酯(47μL,0.400mmol)在吡啶(0.5mL)中的溶液添加PyBOP(32mg,0.060mmol)。溶液在室温下搅拌1小时,此时添加另外部分的PyBOP(21mg,0.040mmol)。溶液搅拌另一小时,然后浓缩。该残留物由HPLC提纯,得到7.5mg澄明油形式的所需产物。1H NMR(300MHz,CD3OD)δ1.22和1.25(t,3H,J=7Hz),1.42and 1.50(d,3H,J=7Hz),1.82和1.83(s,3H),2.16(s,3H),3.47(d,2H,J=7Hz),3.78(s,3H),3.89(d,1H,J=8Hz),3.93-4.02(m,3H),4.10-4.22(m,2H),4.94-5.08(m,1H),5.25(s,2H),5.50-5.60(m,1H),7.15-7.27(m,3H),7.33-7.41(m,2H)ppm;31P(121.4MHz,CD3OD)δ18.9,20.3ppm(在磷上的非对映异构体);MS(m/z)549.2[M+H]+,571.3[M+Na]+。
实施例301
本发明的代表性化合物能够按在下面所示的方法来制备。
2-{[4-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基氧基甲基]-苯氧基-膦酰基氨基-丙酸乙酯
向[4-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基氧基甲基]-膦酸单苯基酯(20mg,0.045mmol)和L-丙氨酸乙酯盐酸盐(68.5mg,0.45mmol)在吡啶(1.0mL)中的溶液添加PyBOP(70mg,0.14mmol)。在搅拌一夜后,混合物进行浓缩和残留物由RP HPLC使用C18柱以
,0.1%TFA-乙腈,0.1%TFA的梯度来提纯,得到3.6mg无色凝胶形式的产物。1H NMR(300MHz,CD3OD)δ1.17-1.3(m,6H),1.8-1.9(m,3H),2.16(s,3H),3.17(m,1H),3.47(d,2H),3.72-3.8(m,5H),3.92-4.2(m,4H),5.25(s,2H),5.54(m,1H),7.18(m,3H),7.33(m,2H)ppm;31P(121.4MHz,CD3OD)δ24.1,25.0ppm(在磷上的非对映异构体);MS(m/z)546.2[M-H]+。
实施例302
本发明的代表性化合物能够按在下面所示的方法来制备。
[4-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基氧基甲基]-膦酸单甲基酯
向[4-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基氧基甲基]-膦酸二苯酯(53mg,0.1mmol)在甲醇(0.5mL)中的溶液添加1N
的水溶液(300μL)。在搅拌一夜后,混合物进行浓缩和残留物由RP HPLC使用C18柱以
,0.1%TFA-乙腈,0.1%TFA的梯度进行提纯,得到5mg的无色凝胶形式的产物,同时还有膦酸单苯基酯(7mg)和膦酸二甲酯(14.5mg)。1H NMR(300MHz,CD3OD)δ1.84(s,3H),2.16(s,3H),3.47(d,2H,J=7Hz),3.6(d,2H,J=12Hz),3.75(d,3H,J=11Hz),3.79(s,3H),3.94(s,2H),5.26(s,2H),5.53(t,1H,J=7Hz)ppm;31P(121.4MHz,CD3OD)δ21.5ppm;MS(m/z)385.2 [M-H]+,387.1[M+H]+。
实施例303
本发明的代表性化合物能够按在下面所示的方法来制备。
(2-{4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯基氨基}-乙基)-膦酸二乙基酯
在室温下向4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯醛(84mg,0.22mmol),(2-氨基-乙基)-膦酸二乙酯草酸盐(91mg,0.33mmol),和三乙酰氧基硼氢化钠(93mg,0.44mmol)在DMF(1.5mL)中的溶液添加乙酸(60μL,1.0mmol)。溶液搅拌2天,此时它通过添加饱和碳酸氢钠水溶液和
来淬灭。分离有机层违和在减压下浓缩。该残留物由RP HPLC使用C18柱以
,0.1%TFA-乙腈,0.1%TFA的梯度进行提纯,得到115mg(96%)油形式的产物。1H NMR(300MHz,CDCl3)δ0.04(s,9H),1.16-1.27(m,2H),1.34(t,6H,J=7Hz),1.94(s,3H),2.18(s,3H),2.20-2.31(m,2H),3.13-3.31(m,2H),3.48(d,2H,J=7Hz),3.54(s,2H),3.78(s,3H),4.14(pent,4H,J=7Hz),4.30-4.37(m,2H),5.13(s,2H),5.65(t,1H,J=7Hz),6.23(br s,2H)ppm;31P(121.4MHz,CDCl3)δ27.8ppm;MS(m/z)542.3[M+H]+,564.2[M+Na]+。
{2-[4-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基氨基]-乙基}-膦酸
(2-{4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯基氨基}-乙基)-膦酸二乙酯(30mg,0.055mmol),TMSBr(72μL,0.55mmol),和2,6-二甲基吡啶(64μL,0.55mmol)在
(1mL)和DMF(0.5mL)中的溶液在环境温度下搅拌1小时。反应混合物由RP HPLC使用C18柱,以
,0.1%TFA-乙腈,0.1%TFA的梯度提纯,得到7.8mg白色固体形式的产物。1H NMR(300MHz,CD3OD)δ1.96(s,3H),1.95-2.07(m,2H),2.16(s,3H),3.10-3.24(m,2H),3.51(d,2H,J=7Hz),3.57(s,2H),3.81(s,3H),5.25(s,2H),5.73(t,1H,J=7Hz)ppm;31P(121.4MHz,CD3OD)δ20.2 ppm;19F NMR(282.6MHz,CD3OD)δ-74.0ppm;MS(m/z)386.3[M+H]+。
实施例304
本发明的代表性化合物能够按在下面所示的方法来制备。
[2-(甲磺酰基-{4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯基}-氨基)-乙基]-膦酸二乙酯
(2-{4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯基氨基}-乙基)-膦酸二乙酯(45mg,0.092mmol)在
(0.5mL)中的溶液与甲烷磺酰氯(21μL,0.28mmol)和吡啶(45μL,0.55mmol)一起在环境温度下搅拌一夜。反应通过添加2滴水来淬灭。反应混合物进行浓缩和由RP HPLC使用C18柱以
,0.1%TFA-乙腈,0.1%TFA的梯度进行提纯,得到36 mg澄明凝胶形式的产物(63%)。1H NMR(300MHz,CDCl3)δ0.05(s,9H),1.18-1.29(m,2H),1.29(t,6H,J=7Hz),1.85(s,3H),2.00-2.13(m,2H),2.19(s,3H),2.85(s,3H),3.32-3.43(m,2H),3.47(d,2H,J=7Hz),3.69(s,2H),3.79(s,3H),4.05(pent,4H,J=7Hz),4.30-4.37(m,2H),5.13(s,2H),5.45(t,1H,J=7Hz)ppm;31P(121.4MHz,CD3Cl)δ27.5ppm;MS(m/z)642.2 [M+Na]+。
(2-{[4-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基]-甲磺酰基-氨基}-乙基)-膦酸
[2-(甲磺酰基-{4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯基}-氨基)-乙基]-膦酸二乙酯(18mg,0.029mmol)在乙腈(0.5mL)中的溶液与TMSBr(38μL,0.29mmol)和2,6-二甲基吡啶(34μL,0.29mmol)一起在室温下搅拌2小时。该反应通过添加
和1N
水溶液来进行后处理。该有机层用盐水洗涤和在真空中除去溶剂。将残留物悬浮于10%
的溶液中达10分钟,之后干燥,得到9.9mg白色固体形式的所需产物(73%)。1H NMR(300MHz,DMSO-d6)δ1.76(s,3H),1.76-1.88(m,2H),2.10(s,3H),2.87(s,3H),3.24-3.35(m,2H),3.39(d,2H,J=7Hz),3.65(s,2H),3.75(s,3H),5.22(s,2H),5.41-5.48(m,1H)ppm;31P(121.4MHz,DMSO-d6)δ21.4ppm;MS(m/z)464.1[M+H]+。
实施例305
本发明的代表性化合物能够按在下面所示的方法来制备。
[2-(乙酰基-{4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯基}-氨基)-乙基]-膦酸二乙酯
向(2-{4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯基氨基}-乙基)-膦酸二乙酯(32mg,0.059mmol)在乙酸(0.5mL)中的溶液添加乙酸酐(0.5mL)。溶液在室温下搅拌90分钟,此时通过添加2滴水来淬灭反应。溶液在真空中干燥和残留物由RP HPLC使用C18柱以
,0.1%TFA-乙腈,0.1%TFA的梯度提纯,得到28mg澄明凝胶形式的产物(81%)。这一化合物的NMR数据显示了按70∶30比率的两种旋转异构体。1H NMR(300MHz,CDCl3)δ0.05(s,9H),1.17-1.27(m,2H),1.30和1.31(t,6H,J=7Hz),1.70-1.79(m,2H),1.76(s,3H),2.00(s,3H),2.18(s,3H),3.40-3.52(m,2H),3.46(d,2H,J=7Hz),3.77(s,3H),3.79和3.93(s,3H),4.07(pent,4H,J=7Hz),4.27-4.35(m,2H),5.13(s,2H),5.22-5.30(m,1H)ppm;31P(121.4MHz,CDCl3)δ27.5和28.9ppm;MS(m/z)584.1[M+H]+,606.2[M+Na]+。
(2-{乙酰基-[4-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基]-氨基}-乙基)-膦酸
向[2-(乙酰基-{4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯基}-氨基)-乙基]-膦酸二乙酯(14mg,0.024mmol)在乙腈(0.5mL)中的溶液添加TMSBr(31μL,0.24mmol)和2,6-二甲基吡啶(28μL,0.24mmol)。溶液在室温下搅拌1小时。该反应通过添加甲醇和1N
水溶液来淬灭。产物用
萃取。合并的有机萃取液在
上干燥和真空浓缩。该产物由RP HPLC使用C18柱以
,0.1%TFA-乙腈,0.1%TFA的梯度提纯,得到5.4mg白色固体形式的产物(53%)。这一化合物的NMR数据显示有两种旋转异构体。1H NMR(300 MHz,CDCl3)δ1.67和1.73(s,3H),1.85-2.12(m,5H),2.13(s,3H),3.30-3.61(m,4H),3.75(s,3H),3.76(br s,2H),5.17(s,2H),5.31(br s,1H)ppm;31P(121.4MHz,CDCl3)δ27.5和28.8ppm;MS(m/z)428.2[M+H]+,450.2[M+Na]+。
实施例306
本发明的代表性化合物能够按在下面所示的方法来制备。
[2-(苄基-{4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯基}-氨基)-乙基]-膦酸二乙酯
(2-{4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯基胺基}-乙基)-膦酸二乙酯(30mg,0.055mmol),苯甲醛(5.6μL,0.055mmol),和三乙酰氧基硼氢化钠(23mg,0.11mmol)的溶液与乙酸(15.7μL,0.28mmol)一起在DMF(0.5mL)中在室温下搅拌一夜。反应用10%
水溶液淬灭和该产物用
萃取。该有机层进行干燥和在减压下浓缩。该产物由RP HPLC使用C18柱以
,0.1%TFA-乙腈,0.1%TFA的梯度提纯,得到15mg澄明凝胶形式的产物(43%)。1H NMR(300MHz,CDCl3)δ0.02(s,9H),1.18-1.25(m,2H),1.24(t,6H,J=7Hz),1.86(s,3H),1.88-2.02(m,2H),2.16(s,3H),2.65-2.74(m,2H),3.93(s,2H),3.46(br d,4H,J=7Hz),3.76(s,3H),4.00(pent,4H,J=7Hz),4.25-4.34(m,2H),5.11(s,2H),5.34-5.43(m,1H),7.18-7.33(m,5H)ppm;31P(121.4MHz,CDCl3)δ30.9ppm;MS(m/z)632.4[M+H]+,654.3[M+Na]+。
(2-{苄基-[4-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基]-氨基}-乙基)-膦酸
(2-{4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯基胺基}-乙基)-膦酸二乙酯(15mg,0.024mmol)在乙腈(0.5mL)中的溶液用TMSBr(31μL,0.24mmol)和2,6-二甲基吡啶(28μL,0.24mmol)处理。溶液在环境温度下搅拌1小时,然后用甲醇淬灭。溶剂在减压下被除去和该残留物由RP HPLC使用C18柱以
,0.1%TFA-乙腈,0.1%TFA的梯度提纯,得到11mg白色固体形式的产物(93%)。1H NMR(300MHz,CD3OD)δ1.89(s,3H),2.03-2.15(m,2H),2.14(s,3H),3.30-3.47(m,2H),3.50(br s,2H),3.62(br s,2H),3.79(s,3H),4.28(s,2H),5.23(s,2H),5.76(br s,1H),7.46(br s,5H)ppm;31P(121.4MHz,CDCl3)δ20.1ppm;MS(m/z)476.3[M+H]+,498.3[M+Na]+。
实施例307
本发明的代表性化合物能够按在下面所示的方法来制备。
[2-(甲酰基-{4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯基}-氨基)-乙基]-膦酸二乙酯
向(2-{4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯基氨基}-乙基)-膦酸二乙酯(74mg,0.14mmol)在甲酸(1mL)中的溶液添加甲酸酐(1mL),然后所得溶液在室温下搅拌1小时。反应混合物进行浓缩和该粗产物输送到下一步。这一化合物的NMR数据显示了按70∶30比率的两种旋转异构体。1H NMR(300MHz,CDCl3)δ0.05(s,9H),1.18-1.28(m,2H),1.28和1.30(t,6H,J=7Hz),1.74(s,3H),1.84-2.08(m,2H),2.19(s,3H),3.34-3.45(m,2H),3.47(d,2H,J=7Hz),3.72和3.87(s,2H),3.78和3.79(s,3H),4.06和4.07(pent,4H,J=7Hz),4.26-4.37(m,2H),5.13(s,2H),5.30-5.46(m,1H),8.03和8.19(s,1H)ppm;31P(121.4MHz,CDCl3)δ27.5和28.1ppm;MS(m/z)570.1[M+H]+,592.2[M+Na]+。
(2-{甲酰基-[4-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基]-氨基}-乙基)-膦酸
向粗[2-(甲酰基-{4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯基}-氨基)-乙基]-膦酸二乙酯(78mg,0.14mmol)在乙腈(1mL)中的溶液添加TMSBr(177μL,1.4mmol)和2,6-二甲基吡啶(163μL,1.4mmol)。溶液在室温下搅拌1小时,它然后通过添加甲醇和1N
水溶液来淬灭。该产物用
萃取和由RP HPLC使用C18柱以
,0.1%TFA-乙腈,0.1%TFA的梯度提纯,得到29mg白色固体形式的产物。这一化合物的NMR数据显示了按大约70∶30比率的两种旋转异构体。1H NMR(300MHz,CD3OD)δ1.62和1.64(s,3H),1.83-1.98(m,2H),2.16(s,3H),3.38-3.55(m,4H),3.78(s,3H),3.80和3.91(s,2H),5.22(s,2H),5.39-5.52(m,1H),8.03和8.18(s,1H)ppm;MS(m/z)414.2[M+H]+,436.2[M+Na]+。
实施例308
本发明的代表性化合物能够按在下面所示的方法来制备。
({4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]+2-甲基-丁-2-烯基氨基}-甲基)-膦酸二乙酯
在室温下向4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯醛(500mg,1.33mmol),(2-氨基甲基)膦酸二乙酯草酸盐(376mg,1.46mmol),三乙酰氧基硼氢化钠(563mg,2.66mmol)在DMF(10mL)中的溶液添加乙酸(380μL,6.65mmol)。溶液搅拌一夜,此时它通过添加饱和碳酸氢钠水溶液和
来淬灭。分离有机层和在减压下浓缩。该残留物用硅胶色谱分离法提纯,得到500mg(71%)油形式的产物。1HNMR(300MHz,CDCl3)δ0.00(s,9H),1.13-1.23(m,2H),1.25和1.27(t,6H,J=7Hz),1.65-1.75(m,2H),1.77(s,3H),2.13(s,3H),2.80(s,1H),3.14(s,2H),3.41(d,2H,J=7Hz),3.73(s,3H),4.08和4.09(pent,4H,J=7Hz),4.20-4.30(m,2H),5.08(s,2H),5.30(t,1H,J=7Hz)ppm;31P(121.4MHz,CDCl3)δ26.5ppm;MS(m/z)528.1[M+H]+,550.2[M+Na]+。
{[4-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基氨基]-甲基}-膦酸
向({4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯基氨基}-甲基)-膦酸二乙酯(20mg,0.038mmol)在DMF(0.5mL)中的溶液添加TMSBr(49μL,0.38mmol)和2,6-二甲基吡啶(44μL,0.38mmol)。溶液在室温下搅拌1小时,它然后通过添加甲醇来淬灭。该产物由RP HPLC使用C18柱以
,0.1%TFA-乙腈,0.1%TFA的梯度提纯,得到5.6mg白色固体形式的产物。1H NMR(300MHz,CD3OD and CDCl3)δ1.93(s,3H),2.13(s,3H),2.94(br d,2H,J=11Hz),3.42-3.53(m,2H),3.60(s,2H),3.78(s,3H),5.22(s,2H),5.71(br s,1H)ppm;31P(121.4MHz,CDCl3)δ8.5ppm;MS(m/z)372.2[M+H]+,743.2[2M+H]+。
实施例309
本发明的代表性化合物能够按在下面所示的方法来制备。
2-({2-[4-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基氨基]-乙基}-苯氧基-膦酰基氧基)-丙酸乙酯
4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯醛(188mg,0.5mmol)与2-[(2-氨基乙基)苯氧基-膦酰基氧基]-丙酸乙基酯乙酸盐(315.8mg,0.75mmol)一起在
(3mL)中的溶液在环境温度下搅拌2小时。将三乙酰氧基硼氢化钠(159mg,0.75mmol)添加到溶液中,让反应进行1小时。反应通过添加饱和
水溶液来淬灭,产物用
萃取。该有机层在减压下除去溶剂,残留物再悬浮于10%TFA/
中达1小时。反应混合物进行浓缩和产物由RP HPLC使用C18柱以
,0.1%TFA-乙腈,0.1%TFA的梯度提纯,得到198mg白色固体形式的产物。这一化合物的NMR数据显示了按照大约45∶55比率的在磷上的两种非对映异构体。1H NMR(300MHz,CD3OD)δ1.23和1.24(t,3H,J=7Hz),1.38和1.52(d,3H,J=7Hz),1.97和1.98(s,3H),2.14(s,3H),2.44-2.66(m,2H),3.31-3.48(m,2H),3.51(d,2H,J=7Hz),3.66(d,2H,J=5Hz),3.80(s,3H),4.10-4.27(m,2H),4.90-5.10(m,1H),5.20(s,2H),5.73-5.82(m,1H),7.15-7.27(m,3H),7.35-7.45(m,2H)ppm;31P(121.4MHz,CD3OD)δ22.6,24.3ppm;MS(m/z)561.9[M+H]+。
实施例310
本发明的代表性化合物能够按在下面所示的方法来制备。
2-[羟基-(2-{4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯基氨基}-乙基)-膦酰基氧基]-丙酸乙酯
4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯醛(38mg,0.1mmol)与2-[(2-氨基乙基)-苯氧基-膦酰基氧基]-丙酸乙酯乙酸(63mg,0.15mmol)一起在
(1mL)中的溶液在环境温度下搅拌2小时。将三乙酰氧基硼氢化钠(32mg,0.15mmol)添加到溶液中,让反应进行1小时。反应通过添加饱和
水溶液来淬灭,产物用
萃取。该有机层在减压下除去和残留物再悬浮在10%TFA/
中达1小时。反应混合物进行浓缩和该产物由RP HPLC使用C18柱以
,0.1%TFA-乙腈,0.1%TFA的梯度提纯,得到15mg的产物(154-2)。1H NMR(300MHz,CDCl3)δ0.04(s,9H),1.15-1.24(m,2H),1.26(t,3H,J=7Hz),1.48(d,3H,J=7Hz),1.93(s,3H),2.10-2.25(m,2H),2.18(s,3H),3.10-3.31(m,2H),3.48(d,2H,J=7Hz),3.48-3.61(m,2H),3.77(s,3H),4.04-4.21(m,2H),4.29-4.40(m,2H),4.81-4.92(m,1H),5.13(s,2H),5.64(t,1H,J=7Hz),8.70-9.11(m,3H)ppm;31P(121.4MHz,CDCl3)δ21.9ppm;MS(m/z)586.3[M+H]+,1171.4[2M+H]+。
2-(羟基-{2-[4-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基氨基]-乙基}-膦酰基氧基)-丙酸
2-[羟基-(2-{4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯基氨基}-乙基)-膦酰基氧基]-丙酸乙酯(15mg,0.026mmol)在10%
(1mL)中的溶液在环境温度下搅拌10分钟。反应通过除去溶剂来进行后处理。将残留物溶于THF(0.5mL)和水(0.4mL)中,添加1N
水溶液(0.1mL)。溶液在室温下搅拌20分钟,此时用1N
水溶液酸化。所形成的溶液由RP HPLC使用C18柱以
,0.1%TFA-乙腈,0.1%TFA的梯度提纯,得到6.8mg白色固体形式的产物。1H NMR(300MHz,CDCl3)δ1.38(d,3H,J=7Hz),1.91(s,3H),2.13(s,3H),2.12-2.28(m,2H),3.12-3.33(m,2H),3.41(d,2H,J=6Hz),3.56(br s,2H),3.75(s,3H),4.71-4.88(m,1H),5.16(s,2H),5.58-5.71(m,1H),7.88(br s,3H),8.60(br s,1H),8.78(br s,1H)ppm;31P(121.4MHz,CDCl3)δ22.0ppm;MS(m/z)458.3[M+H]+,480.3[M+Na]+。
实施例311
本发明的代表性化合物能够按在下面所示的方法来制备。
{1-氰基-5-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-3-甲基-戊-3-烯基}-膦酸二乙酯
向羟基甲基膦酸二乙基酯(241mg,1.38mmol)在THF(1mL)中的溶液添加双(三甲基甲硅烷基)胺化钠的THF溶液(1.0m,1.13mL,1.15mmol)。在搅拌30分钟后,将溶液滴加到6-(4-溴-3-甲基-丁-2-烯基)-7-羟基-5-甲氧基-4-甲基-3H-异苯并呋喃-1-酮(100mg,0.23mmol)在THF(1mL)中的溶液中。所形成的混合物在室温下搅拌1小时,之后添加饱和氯化铵水溶液。反应混合物用乙酸乙酯萃取。该有机层在硫酸钠上和浓缩至干燥。该残留物由硅胶柱色谱分析法提纯,获得110mg(90%)的所需产物。1H NMR(300MHz,CDCl3)δ0.04(s,9H),1.24(dd,J=7,8Hz,2H),1.36(t,6H),1.86(s,3H),2.17(s,3H),2.43-2.57(m,2H),3.04-3.17(m,1H),3.47(d,J=7.2Hz,2H),3.79(s,3H),4.12-4.37(m,6H),5.13(s,2H),5.44(t,J=7.2Hz,1H)ppm;31P(121.4MHz,CDCl3)δ18.18ppm;MS(m/z)560[M+Na]+。
[1-氰基-5-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-3-甲基-戊-3-烯基]-膦酸二乙酯
将{1-氰基-5-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-3-甲基-戊-3-烯基}-膦酸二乙酯(25mg,0.047mmol)溶于10%TFA/
的溶液(5mL)中并在室温下搅拌2小时。反应混合物在减压下干燥和产物用由RP-HPLC提纯,得到16mg(80%)白色固体形式的所需产物。1H NMR(300MHz,CDCl3)δ1.38(t,6H),1.86(s,3H),2.15(s,3H),2.40-2.58(m,2H),3.01-3.14(m,1H),3.45(d,J=7.2Hz,2H),3.79(s,3H),4.18-4.30(m,4H),5.21(s,2H),5.48(t,J=7.2Hz,1H)ppm;31P(121.4MHz,CDCl3)δ18.09ppm;MS(m/z)436[M-H]-,438 [M+H]+。
实施例312
本发明的代表性化合物能够按在下面所示的方法来制备。
[1-氰基-5-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-3-甲基-戊-3-烯基]-膦酸
向{1-氰基-5-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-3-甲基-戊-3-烯基}-膦酸二乙酯(35mg,0.065mmol)在乙腈(2mL)中的溶液添加TMSBr(180μL,1.38mmol)和2,6-二甲基吡啶(160μL,1.38mmol)。反应溶液在室温下搅拌1小时,之后用
淬灭。反应混合物在减压下干燥和该残留物由RP HPLC使用C18柱以
,0.1%TFA-乙腈,0.1%TFA的梯度提纯,得到15mg(60%)的所需产物。1H NMR(300MHz,CD3OD)δ1.86(s,3H),2.15(s,3H),2.38-2.57(m,2H),3.17-3.28(m,1H),3.44(d,J=7.2Hz,2H),3.80(s,3H),5.25(s,2H),5.47(t,J=7.2Hz,1H)ppm;31P(121.4MHz,CD3OD)δ15.28ppm;MS(m/z)380[M-H]-,382 [M+H]+。
实施例313
本发明的代表性化合物能够按在下面所示的方法来制备。
{1-氰基-5-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-1,3-二甲基-戊-3-烯基}-膦酸二乙酯
向{1-氰基-5-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-3-甲基-戊-3-烯基}-膦酸二乙酯(45mg,0.084mmol)在THF(0.5mL)中的溶液添加双(三甲基甲硅烷基)胺化钠(1.0m,1.13mL,1.15mmol)。在搅拌20分钟后,滴加碘代甲烷(52μL,0.84mmol),所获得的混合物在室温下搅拌2小时。反应混合物用饱和氯化铵水溶液淬灭,然后用乙酸乙酯萃取。该有机层在硫酸钠上和浓缩至干燥。该残留物由RP HPLC使用C18柱以
,0.1%TFA-乙腈,0.1%TFA的梯度提纯,获得6.6mg(23%)的所需产物。1H NMR(300MHz,CDCl3)δ0.00(s,9H),1.16(dd,J=7,8Hz,2H),1.31(t,6H),1.38(d,3H),1.92(s,3H),2.17(s,3H),2.23(m,1H),2.65(m,1H),3.30-3.42(m,2H),3.73(s,3H),4.14-4.27(m,6H),5.08(s,2H),5.28(t,J=7.2Hz,1H)ppm;31P(121.4MHz,CDCl3)δ22.26ppm;MS(m/z)574[M+Na]+。
[1-氰基-5-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-1,3-二甲基-戊-3-烯基]-膦酸
向{1-氰基-5-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-1,3-二甲基-戊-3-烯基}-膦酸二乙酯(18mg,0.04mmol)在DMF(0.5mL)和DCM(0.5mL)中的溶液添加TMSBr(51μL,0.4mmol)和2,6-二甲基吡啶(46μL,0.4mmol)。反应溶液在室温下搅拌一夜,之后用
淬灭。反应混合物在减压下干燥和该残留物由RP HPLC使用C18柱以
,0.1%TFA-乙腈,0.1%TFA的梯度提纯,得到4.5mg(33%)的所需产物。1H NMR(300MHz,CD3OD)δ1.37(d,3H),1.87(s,3H),2.13(s,3H),2.26(m,1H),2.64(m,1H),3.39(m,2H),3.75(s,3H),5.18(s,2H),5.34(m,1H)ppm;31P(121.4MHz,CD3OD)δ21.47ppm;MS(m/z)422[M-H]-,424[M+H]+。
实施例314
本发明的代表性化合物能够按在下面所示的方法来制备。
2-乙基-4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-丁-2-烯醛
[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-乙醛(1.5g,4.46mmol)在甲苯(14mL)中的溶液在100℃下与2-(三苯基-phosphanylidene)-丁醛(1.68g,5.35mmol)一起加热一夜。添加第二部分的2-(三苯基-phosphanylidene)-丁醛(495mg,1.49mmol),反应混合物加热另外一天。在浓缩后,残留物用硅胶色谱分离法提纯,得到1.3g(83%)油形式的所需产物。1H NMR(300MHz,CDCl3)δ0.01(s,9H),1.03(t,3H),1.10-1.21(m,2H),2.15(s,3H),2.15-2.44(m,2H),3.67-3.76(m,2H),3.74(s,3H),4.31-4.36(m,2H),5.10(s,2H),6.34-6.38(m,1H),9.28(s,1H)ppm。
6-(3-羟甲基-戊-2-烯基)-5-甲氧基-4-甲基-7-(2-三甲基硅烷基-乙氧基)-3H-异苯并呋喃-1-酮
将2-乙基-4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-丁-2-烯醛(1.3g,3.30mmol)在甲醇(10mL)和THF(10mL)中的溶液冷却至0℃。添加
(8.25mL,0.4M,
∶
,9∶1)的溶液,随后添加
(1.66mL,3.30mmol的在THF中2M溶液)。移走冰浴,让反应混合物升至室温。反应混合物进一步搅拌另外40分钟,此时TLC指示起始醛的完全消耗。反应通过1N
水溶液的添加来进行后处理和产物用
萃取。该有机层用饱和的碳酸氢钠水溶液和盐水洗涤。该有机层在减压下浓缩和残留物由硅胶色谱分离法得到948mg(73%)无色油形式的产物。1HNMR(300MHz,CDCl3)δ0.00(s,9H),1.07(t,3H),1.20(dd,2H,J=7,8Hz),2.13(s,3H),2.38-2.50(m,2H),3.77(s,3H),3.99(s,2H),4.27(dd,2H,J=7,8Hz),5.08(s,2H),5.34(t,J=7.2Hz,1H)ppm。
6-(3-溴甲基-戊-2-烯基)-5-甲氧基-4-甲基-7-(2-三甲基硅烷基-乙氧基)-3H-异苯并呋喃-1-酮
将聚合物担载的三苯基膦(3mmol/g,0.66g)在二氯甲烷(6mL)中浸泡1小时,顺序地添加6-(3-羟甲基-戊-2-烯基)-5-甲氧基-4-甲基-7-(2-三甲基硅烷基-乙氧基)-3H-异苯并呋喃-1-酮(260mg,0.66mmol)和四溴化碳(657mg,1.98mmol),和混合物在室温下摇振1小时。将混合物过滤,滤液进行浓缩。该残留物由硅胶色谱分离法提纯,得到233mg(77%)白色固体形式的产物。1H NMR(300MHz,CDCl3)δ0.00(s,9H),1.08(t,3H),1.20(dd,2H,J=7,8Hz),2.14(s,3H),2.35-2.43(m,2H),3.44(d,J=7.2,2H),3.73(s,3H),3.95(s,2H),4.27(dd,2H,J=7,8 Hz),5.08(s,2H),5.53(t,J=7.2Hz,1H)ppm。
[2-乙基-4-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-丁-2-烯基]-膦酸
将6-(3-溴甲基-戊-2-烯基)-5-甲氧基-4-甲基-7-(2-三甲基硅烷基-乙氧基)-3H-异苯并呋喃-1-酮(230mg,0.5mmol)在亚磷酸三甲基酯(1.5mL,12.75mmol)中的溶液加热至100℃保持4小时。反应通过在减压下除去过量的亚磷酸三甲基酯来进行后处理。将残留物溶于乙腈(1mL)中和在0℃下添加TMSBr(646μL,5.0mmol)和2,6-二甲基吡啶(580μL,5.0mmol)。反应溶液升至室温和搅拌4小时。反应冷却至0℃和添加
来淬灭。反应混合物在减压下干燥和该残留物由RP HPLC使用C18柱以
,0.1%TFA-乙腈,0.1%TFA的梯度提纯,得到77mg(58%)的产物。1H NMR(300MHz,CD3OD)δ1.08(t,3H),2.16(s,3H),2.43(m,2H),2.48(d,2H,J=22Hz),3.46(t,2H,J=6Hz),3.79(s,3H),5.25(s,2H),5.38(q,1H,J=7Hz)ppm.;31P(121.4MHz,CD3OD)δ25.65ppm.;MS(m/z)355[M-H]-,357[M+H]+。
实施例315
本发明的代表性化合物能够按在下面所示的方法来制备。
{1-氰基-3-乙基-5-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-戊-3-烯基}-膦酸二乙酯
向羟基甲基膦酸二乙基酯(233mg,1.32mmol)在THF(1mL)中的溶液添加双(三甲基甲硅烷基)胺化钠的THF溶液(1.0m,1.21mL,1.21mmol)。在搅拌30分钟后,将该溶液滴加到6-(3-溴甲基-戊-2-烯基)-5-甲氧基-4-甲基-7-(2-三甲基硅烷基-乙氧基)-3H-异苯并呋喃-1-酮(100mg,0.22mmol)在THF(1mL)中的溶液之中。所形成的混合物在室温下搅拌一夜,之后添加饱和氯化铵水溶液。反应混合物用乙酸乙酯萃取。该有机层在硫酸钠上和浓缩至干燥。该残留物用制备性反相HPLC提纯,获得51mg(42%)的所需产物。1H NMR(300MHz,CDCl3)δ0.04(s,9H),1.07(t,3H),1.24(dd,2H,J=7,8Hz),1.36(t,6H),2.12(m,1H),2.18(s,3H),2.35-2.47(m,2H),2.67(m,1H),3.00-3.14(m,1H),3.44(d,J=7.2,2H),3.79(s,3H),4.12-4.37(m,6H),5.13(s,2H),5.38(t,J=7.2Hz,1H)ppm;31P(121.4MHz,CDCl3)δ18.26ppm;MS(m/z)574 [M+Na]+。
[1-氰基-3-乙基-5-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-戊-3-烯基]-膦酸
将{1-氰基-3-乙基-5-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-戊-3-烯基}-膦酸二乙酯(19.5mg,0.035mmol)溶于10%TFA/
(2mL)的溶液中并在室温下搅拌10分钟。反应混合物在减压下干燥和由RP-HPLC提纯,得到9.5mg(61%)的所需产物。将该物质溶于DMF(0.5mL)和DCM(0.5mL)中和添加TMSBr(27μL,0.2mmol)和2,6-二甲基吡啶(23μL,0.2mmol)。反应溶液在室温下搅拌一夜,之后用
淬灭。反应混合物在减压下干燥和该残留物由RP HPLC使用C18柱以
,0.1%TFA-乙腈,0.1%TFA的梯度提纯,得到5.1mg(65%)白色固体形式的所需产物体。1H NMR(300MHz,CD3OD)δ1.10(t,3H),2.16(s,3H),2.23-2.52(m,3H),2.67(m,1H),3.05-3.20(m,1H),3.48(d,J=7.2,2H),3.81(s,3H),5.26(s,2H),5.43(t,J=7.2Hz,1H)ppm;31P(121.4MHz,CD3OD)δ14.18ppm;MS(m/z)394[M-H]-,396[M+H]+。
实施例316
本发明的代表性化合物能够按在下面所示的方法来制备。
{2-乙基-4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-丁-2-烯基氧基甲基}-膦酸二异丙基酯
向溴甲基膦酸二异丙基酯(680mg,2.62mmol)和6-(3-羟甲基-戊-2-烯基)-5-甲氧基-4-甲基-7-(2-三甲基硅烷基-乙氧基)-3H-异苯并呋喃-1-酮(688mg,1.75mmol)在DMF(3mL)中的溶液添加叔丁醇锂(在THF中1.0M;2.6ml)。反应在70℃加热2小时。在冷却至环境温度之后,添加更多的溴甲基膦酸二异丙基酯(680mg,2.62mmol)和叔丁醇锂(在THF中1.0M;2.6ml)。反应混合物在70℃下加热另外一小时,冷却,倾倒在氯化锂的溶液(5%水溶液)中和用乙酸乙酯萃取。有机萃取液进行干燥和产物用硅胶色谱分离法,用己烷-乙酸乙酯洗脱提纯,得到347mg(35%)无色油形式的产物。1H NMR(300MHz,CDCl3)δ0.04(s,9H),1.09(t,3H,J=7.5Hz),1.20-1.26(m,2H),1.31(t,12H,J=6Hz),2.18(s,3H),2.29(q,2H,J=7.5Hz),3.5(m,2H),3.59(d,2H,J=8.7Hz),3.78(s,3H),3.98(s,2H),4.28-4.35(m,2H),4.6-4.8(m,2H),5.13(s,2H),5.4(t,1H,J=7Hz)ppm;31P(121.4MHz,CDCl3)δ20.26ppm;MS(m/z)593.3[M+Na]+。
[2-乙基-4-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-丁-2-烯基氧基甲基]-膦酸
向{2-乙基-4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-丁-2-烯基氧基甲基}-膦酸二异丙基酯(347mg,0.61mmol)在乙腈(5mL)中的溶液添加2,6-二甲基吡啶(0.71mL,6.1mmol)和溴三甲基硅烷(0.786mL,6.1mmol)。混合物在室温下搅拌3小时,用甲醇(5mL)淬灭,浓缩,并且分配在乙酸乙酯和1N
(水溶液)之间。有机层进行浓缩得到无色油形式的游离膦酸(205mg,70%)。将该物质(20mg)溶于三氟乙酸(0.3ml)和二氯甲烷(2.7ml)的溶液中,和在环境温度下搅拌30分钟。在浓缩后,该残留物由RP HPLC使用C18柱以
,0.1%TFA-乙腈,0.1%TFA的梯度提纯,在冷冻干燥后,获得白色固体形式的产物(10mg)。1H NMR(300MHz,CDCl3)δ1.007(t,3H,J=7.5Hz),2.13(s,3H),2.32(q,2H,J=7.5Hz),3.41(d,2H,J=6.3Hz),3.56(d,2H,J=9Hz),3.75(s,3H),3.95(s,2H),5.16(s,2H),5.43(t,1H,J=6.3Hz)ppm;31P(121.4MHz,CDCl3)δ22.8ppm;MS(m/z)385.2[M-H]+,387.1[M+H]+。
实施例317
本发明的代表性化合物能够按在下面所示的方法来制备。
6-烯丙氧基-3-甲基-4-三氟甲磺酰基氧基-邻苯二甲酸二甲基酯
在0℃下向6-烯丙氧基-4-羟基-3-甲基-邻苯二甲酸二甲酯(8.06g,28.8mmol)[根据J.W.Patterson,Tetrahedron,1993,49,4789-4798来合成]和吡啶(11.4g,144.0mmol)在二氯甲烷(DCM)(20mL)中的溶液添加三氟甲磺酸酐(12.19g,43.2mmol)。反应在0℃下搅拌2小时,在此之后添加附加的三氟甲磺酸酐(3mL)。在0℃下继续搅拌另外一小时。将反应混合物倾倒在DCM和
(1N)的混合物中。分离各层,水层用DC萃取M。合并的有机层在硫酸钠上干燥。过滤和在真空中蒸发溶剂得到粗产物,它由硅胶色谱分离法提纯,得到8.39g油形式的产物。1H NMR(300MHz,CDCl3):δ=2.32(s,3H),3.89(s,6H),4.60(m,2H),5.33(d,J=9.3Hz,1H),5.41(d,J=18.6Hz,1H),5.95(m,1H),6.95(s,1H)ppm;19F NMR(282MHz,CDCl3):δ=-74ppm。
6-羟基-3-甲基-4-三氟甲磺酰基氧基-邻苯二甲酸二甲酯
在氮气氛中在室温下向6-烯丙氧基-3-甲基-4-三氟甲磺酰基氧基-邻苯二甲酸二甲酯(8.39g,20.3mmol)在甲苯(20mL)中的溶液添加四(三苯基膦)钯(0.47g,0.40mmol)和二乙胺(2.97g,40.86mmol)。在室温下的搅拌继续进行,直到全部的起始原料消耗为止。粗反应混合物被分配在二乙醚和
(0.1N)之间。有机层用盐水洗涤并在硫酸钠上干燥。过滤和在真空中蒸发溶剂得到粗物质,它由硅胶色谱分离法提纯,得到4.16g(55%)灰白色固体形式的所需产物。1H NMR(300MHz,CDCl3):δ=2.20(s,3H),3.93(s,3H),3.95(s,3H),7.01(s,1H)ppm;
19F NMR(282 MHz,CDCl3):δ=-74ppm。
6-羟基-3-甲基-4-乙烯基-邻苯二甲酸二甲酯
向6-羟基-3-甲基-4-三氟甲磺酰基氧基-邻苯二甲酸二甲酯(2.17g的话,5.85mmol)在N-甲基吡咯烷酮(15mL)中的溶液添加氯化锂(743mg,17.5mmol)和三苯胂(179mg,0.585mmol)。添加三丁基乙烯基锡(2.04g,6.43mmol),随后添加三(三苯甲叉基丙酮)二钯(O)-氯仿加合物(90mg添加,0.087mmol)。将反应置于氮气氛中并在60℃下加热18小时。让反应冷却至室温和倾倒在冰(20g),
(40mL),和氟化钾(1g)的混合物中。继续搅拌1小时。水层用
萃取和有机萃取液经由赛力特硅藻土过滤。合并的有机层用水洗涤并在硫酸钠上干燥。过滤和在真空中蒸发溶剂得到粗物质,它由硅胶色谱分离法提纯,得到1.27g(87%)灰白色固体形式的产物。1H NMR(300MHz,CDCl3):δ=2.16(s,3H),3.91(s,3H),3.92(s,3H),5.46(dd,J=11.1,1.2Hz,1H),5.72(dd,J=17.1,0.9Hz,1H),6.86(dd,J=17.1,11.1Hz,1H),7.14(s,1H),10.79(s,1H)ppm。
4-乙基-6-羟基-3-甲基-邻苯二甲酸二甲酯
将6-羟基-3-甲基-4-乙烯基-邻苯二甲酸二甲酯(1.27g,5.11mmol)溶于苯(10mL)和
(10mL)中。添加三(三苯基膦)三氯化铑(150mg),将反应置于氢气氛中。在室温下继续搅拌。在14小时后,在真空中除去溶剂和粗物质由硅胶色谱分离法提纯,得到1.14g(88%)灰白色固体形式的所需产物。1H NMR(300MHz,CDCl3):δ=1.19(t,J=7.8Hz,3H),2.10(s,3H),2.60(q,J=7.8Hz,2H),3.89(s,6H),6.87(s,1H),10.79(s,1H)ppm。
16-烯丙氧基-4-乙基-3-甲基-邻苯二甲酸二甲酯
将4-乙基-6-羟基-3-甲基-邻苯二甲酸二甲酯(1.01g,4.02mmol)溶于DMF(5mL)中。添加碳酸钾(3.33g,24.14mmol),随后添加烯丙基溴(2.92g,24.14mmol)。悬浮液在60℃下加热。在14小时后,反应冷却至室温和进行过滤。在真空中除去溶剂,粗物质由硅胶色谱分离法提纯,得到0.976g(83%)无色油的所需产物。1H NMR(300MHz,CDCl3):δ=1.16(t,J=7.2Hz,3H),2.20(s,3H),2.62(q,J=7.2Hz,2H),3.83(s,3H),3.84(s,3H),4.57(m,2H),5.26(dd,J=9.3,1.5Hz,1H),5.41(dd,J=13.5,1.5Hz,1H),5.98(m,1H),6.82(s,1H)ppm。
4-烯丙基-5-乙基-3-羟基-6-甲基-邻苯二甲酸二甲酯
6-烯丙氧基-4-乙基-3-甲基-邻苯二甲酸二甲酯(1.25g,4.28mmol)在210℃下在氮气氛中加热。在14小时后,反应冷却至室温。粗物质由硅胶色谱分离法提纯,得到0.971g(77%)无色油形式的所需产物。1H NMR(300MHz,CDCl3):δ=1.14(t,J=7.8Hz,3H),2.17(s,3H),2.68(q,J=7.8Hz,2H),3.49(m,2H),3.86(s,3H),3.89(s,3H),4.89-5.01(m,2H),5.93(m,1H),11.22(s,1H)ppm。
5 6-烯丙基-5-乙基-7-羟基-4-甲基-3H-异苯并呋喃-1-酮
在室温下将4-烯丙基-5-乙基-3-羟基-6-甲基-邻苯二甲酸二甲酯(0.971g,3.32mmol)溶于
(8mL)中。添加氢氧化钠(0.798g,19.95mmol)在水(10mL)中的溶液,悬浮液在55℃下加热。在16小时后,反应冷却至室温和用二乙醚洗涤。水层被酸化(1N
)和该悬浮液用
萃取。合并的有机层在硫酸钠上干燥。过滤和在真空中蒸发溶剂得到所需的双酸,为白色固体(0.846g,98%,M+=263)。
将该双酸溶于乙酸(6mL)和
(浓,1.5mL)中。反应在80℃下加热。经过7小时,每小时分几份添加Zn粉(0.635g,9.72mmol,各份)。在80℃下继续搅拌另外10小时。反应冷却至室温,和添加水。所形成的悬浮液用
萃取。合并的有机萃取物用碳酸氢钠溶液洗涤并在硫酸钠上干燥。过滤和在真空中蒸发溶剂而得到粗产物,它由硅胶色谱分离法提纯可得到0.375g(50%)白色固体形式的产物。1HNMR(300MHz,CDCl3):δ=1.14(t,J=7.5Hz,3H),2.18(s,3H),2.71(q,J=7.5Hz,2H),3.49(m,2H),4.95(d,J=17.1Hz,1H),5.02(d,J=10.2Hz,1H),5.23(s,2H),5.98(m,1H),7.66(s,1H)ppm。
5 6-烯丙基-5-乙基-4-甲基-7-(2-三甲基硅烷基-乙氧基)-3H-异苯并呋喃-1-酮
在0℃向6-烯丙基-5-乙基-7-羟基-4-甲基-3H-异苯并呋喃-1-酮(199mg,0.857mmol),PPh3(337mg,1.286mmol),和2-三甲基甲硅烷基乙醇在THF(3mL)中的溶液添加偶氮二羧酸二异丙基酯(259mg,1.286mmol)。所获得的黄色溶液升至室温和搅拌1小时。在真空中除去溶剂,将该粗物质溶于二乙醚(3mL)中。添加己烷(1.5mL)。三苯基氧膦由过滤除去,该滤液进行浓缩和由硅胶色谱分离法提纯,得到所需产物(261mg,92%),为澄明油。1H NMR(300MHz,CDCl3):δ=0.04(s,9H),1.15(t,J=7.8Hz,3H),1.25(m,2H),2.20(s,3H),2.73(q,J=7.8Hz,2H),3.54(m,2H),4.28(m,2H),4.95(d,J=17.1Hz,1H),5.02(d,J=10.2Hz,1H),5.15(s,2H),5.95(m,1H)ppm。
[6-乙基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-乙醛
根据Smith,D.B.等人,J.Org.Chem.,1996,61,6,2236的程序,使用干冰/丙酮浴将6-烯丙基-5-乙基-4-甲基-7-(2-三甲基硅烷基-乙氧基)-3H-异苯并呋喃-1-酮(261mg,0.788mmol)在
(5mL),
(5mL)和吡啶(50μL)中的溶液冷却至-78℃。经由气相分散管将臭氧气流鼓泡通入反应中,直至反应变成蓝色为止(15分钟)。该臭氧管线用氮气流置换并继续鼓泡另外15分钟,在此时蓝色已消失。在-78℃下将硫脲(59.9mg,0.788mmol)作为一份添加到该溶液中,然后移走冷却浴。反应升至室温和搅拌15小时。反应混合物进行过滤,然后分配在
和水之间。该水层再一次用
萃取,合并有机萃取液,用1N
水溶液、饱和
水溶液和盐水洗涤,并在硫酸钠上干燥。过滤和在真空中蒸发溶剂而得到粗产物,它由硅胶色谱分离法提纯可得到181g(69%)白色固体形式的产物。1H NMR(300MHz,CDCl3):δ=0.04(s,9H),1.11(t,J=7.5Hz,3H),1.19(m,2H),2.21(s,3H),2.66(q,J=7.5Hz,2H),3.90(s,2H),4.36(m,2H),5.18(s,2H),9.71(s,1H)ppm。
4-[6-乙基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯醛
[6-乙基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-乙醛(90mg,0.269mmol)和2-(三苯基-phosphorylidene)-丙醛(72.9mg,0.23mmol)在甲苯(3mL)中在100℃下加热。在15小时之后,添加第二份的2-(三苯基-phosphanylidene)-丙醛(33mg,0.11mmol),反应混合物加热另外9小时。在真空中除去甲苯,残留物由硅胶色谱分离法提纯,得到77.6mg(77%)的所需产物,为浅黄色油。1H NMR(300MHz,CDCl3):δ=0.03(s,9H),1.15(t,J=7.5Hz,3H),1.21(m,2H),1.93(s,3H),2.21(s,3H),2.71(q,J=7.5Hz,2H),3.82(d,J=6.9Hz,2H),4.34(m,2H),5.18(s,2H),6.38(m,1H),9.35(s,1H)ppm。
5-乙基-6-(4-羟基-3-甲基-丁-2-烯基)-4-甲基-7-(2-三甲基硅烷基-乙氧基)-3H-异苯并呋喃-1-酮
将4-[6-乙基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯醛(77.6mg,0.207mmol)溶于 (4mL)中。将
(51.1mg,0.207mmol)在
/水(9/1,0.66mL)中的溶液添加进去,所得溶液冷却至0℃。将硼氢化锂在THF(2M,0.105mL)中的溶液滴加进去。在15分钟后,反应用1N
(0.5mL)淬灭。在真空中除去
,粗物质被分配在DCM和水之间。水层用DCM萃取,合并的有机层用碳酸氢钠溶液洗涤并在硫酸钠上干燥。过滤和蒸发溶剂,得到粗油,它由硅胶色谱分离法提纯而得到57.2mg(73%)的所需产物。1H NMR(300MHz,CDCl3):δ=0.04(s,9H),1.15(t,J=7.8Hz,3H),1.26(m,2H),1.86(s,3H),2.19(s,3H),2.72(q,J=7.8Hz,2H),3.52(d,J=6.3Hz,2H),3.99(s,2H),4.34(m,2H),5.14(s,2H),5.32(m,1H)ppm。
6-(4-溴-3-甲基-丁-2-烯基)-5-乙基-4-甲基-7-(2-三甲基硅烷基-乙氧基)-3H-异苯并呋喃-1-酮
将5-乙基-6-(4-羟基-3-甲基-丁-2-烯基)-4-甲基-7-(2-三甲基硅烷基-乙氧基)-3H-异苯并呋喃-1-酮(57.2mg,0.152mmol)溶于DCM(3.5mL)中。将聚合物结合的三苯基膦(3mmol/g,152.1mg)添加进去,混合物在室温下机械搅拌。添加四溴化碳(151.3mg,0.456mmol),溶液在室温下搅拌。在2小时后,反应进行过滤,然后在真空中除去溶剂。粗物质由硅胶色谱分离法提纯,得到58.0mg(87%)的所需产物。1H NMR(300MHz,CDCl3):δ=0.04(s,9H),1.15(t,J=7.8Hz,3H),1.25(m,2H),1.95(s,3H),2.20(s,3H),2.70(q,J=7.8Hz,2H),3.52(d,J=6.3Hz,2H),3.94(s,2H),4.28(m,2H),5.14(s,2H),5.50(m,1H)ppm 。
{4-[6-乙基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯基}-膦酸
4-[6’-乙基-7’-甲基-3’-氧代-4’-(2”-三甲基硅烷基-乙氧基)-1’,3’-二氢-异苯并呋喃-5’-基]-2-甲基-丁-2-烯基溴化物(58mg,0.132mmol)在亚磷酸三甲基酯(0.8mL)中的溶液在110℃下加热。在2小时之后反应完成。反应冷却至室温和在真空中除去过量的亚磷酸三甲基酯。该粗物质无需进一步提纯就可用于下一步。
将阿尔布佐夫反应的粗产物溶于
(0.8mL)中。添加三甲基甲硅烷基溴化物(202.2mg,1.321mmol),反应在室温下搅拌。在15分钟后,添加二甲基吡啶(155.7mg,1.453mmol)并在室温下继续搅拌。在2小时后,添加另外的三甲基甲硅烷基溴化物(202.2mg,1.321mmol)并在室温下继续搅拌。在4小时后,反应用
(2mL)淬灭。在真空中蒸发溶剂,和粗物质由RP-HPLC提纯(洗脱剂:水/
)。含有产物的级分被合并,然后冻干,得到2.3mg(5.1%)的游离膦酸。1H NMR(300MHz,DMSO-d6):δ=1.07(t,J=7.5Hz,3H),1.84(s,3H),2.14(s,3H),2.64(q,J=7.5Hz,2H),3.34(m,4H),5.06(m,1H),5.25(s,2H)ppm;31P NMR(121MHz,DMSO-d6):δ=22.19ppm;MS=341[M++1]。
实施例318
本发明的代表性化合物能够按在下面所示的方法来制备。
[2-乙基-4-[6-乙基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-丁-2-烯醛
[6-乙基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-乙醛(90mg,0.269mmol)和2-(三苯基-phosphorylidene)-丁醛(98.4mg,0.296mmol)在甲苯(3mL)中在100℃下加热。在15小时之后,添加第二份的2-(三苯基-phosphanylidene)-丁醛(98.4mg,0.296mmol),反应混合物加热另外33小时。在浓缩后,该残留物由硅胶色谱分离法提纯,得到50.3mg(48%)浅黄色油形式的所需产物。
5-乙基-6-(3-羟甲基-戊-2-烯基)-4-甲基-7-(2-三甲基硅烷基-乙氧基)-3H-异苯并呋喃-1-酮
将2-乙基-4-[6-乙基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-丁-2-烯醛(50.3mg,0.129mmol)溶于
(3mL)中。将
(31.9mg,0.129mmol)在
/水(9/1,0.66mL)中的溶液添加进去,所得溶液冷却至0℃。将硼氢化锂在THF(2M,0.065mL)中的溶液滴加进去。在10分钟后,反应用1N
(0.5mL)淬灭。在真空中除去甲醇,粗物质被分配在DCM和水之间。水层用DCM萃取,合并的有机层用碳酸氢钠溶液洗涤并在硫酸钠上干燥。过滤和在真空中蒸发溶剂,得到粗油,它由硅胶色谱分离法提纯而得到35.4mg(70%)的所需产物。1H NMR(300MHz,CDCl3):δ=0.04(s,9H),1.10-1.19(m,6H),1.26(m,2H),2.19(s,3H),2.32(q,J=7.5Hz,2H),2.72(q,J=7.5Hz,2H),3.54(d,J=6.6Hz,2H),4.05(s,2H),4.26(m,2H),5.14(s,2H),5.27(m,1H)ppm。
6-(3-溴甲基-戊-2-烯基)-5-乙基-4-甲基-7-(2-三甲基硅烷基-乙氧基)-3H-异苯并呋喃-1-酮
将5-乙基-6-(3-羟甲基-戊-2-烯基)-4-甲基-7-(2-三甲基硅烷基-乙氧基)-3H-异苯并呋喃-1-酮(35.4mg,0.090mmol)溶于DCM(3.0mL)中。将聚合物结合的三苯基膦(3mmol/g,90.7mg)添加进去,混合物在室温下机械搅拌。添加四溴化碳(90.2mg,0.272mmol),所得溶液在室温下搅拌。在2小时后,反应进行过滤,然后在真空中除去溶剂。粗物质由硅胶色谱分离法提纯,得到32.0mg(78%)的所需产物。该粗物质无需进一步表征就可用于下一步。
[2-乙基-4-(6-乙基-4-羟基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-丁-2-烯基]-膦酸
将6-(3-溴甲基-戊-2-烯基)-5-乙基-4-甲基-7-(2-三甲基硅烷基-乙氧基)-3H-异苯并呋喃-1-酮(32mg,0.070mmol)在亚磷酸三甲基酯(0.8mL)中的溶液在110℃下加热。在2小时之后,反应完成。反应冷却至室温和在真空中除去过量的亚磷酸三甲基酯。该粗物质无需进一步提纯就可用于下一步。
将阿尔布佐夫反应的粗产物溶于
(0.8mL)中。添加三甲基甲硅烷基溴化物(108.0mg,0.706mmol),反应在室温下搅拌。在2小时后,添加第二批的三甲基甲硅烷基溴化物(108.0mg,0.706mmol)。在3小时后,反应用
(2mL)淬灭。在真空中蒸发溶剂,和粗物质由RP-HPLC提纯(洗脱剂:水/
)。含有产物的级分被合并,然后冻干,得到15.7mg(63%)的产物。1H NMR(300MHz,DMSO-d6):δ=0.98-1.09(m,6H),2.10(s,3H),2.30(m,2H),2.64(q,J=7.5Hz,2H),3.38(m,4H),5.03(m,1H),5.25(s,2H)ppm;31P NMR(121MHz,DMSO-d6):δ=22.26ppm;MS=355[M++1]。
实施例319
本发明的代表性化合物能够按在下面所示的方法来制备。
(2-{4-[6-乙基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯基氨基}-乙基)-膦酸二乙酯
将4-[6-乙基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯醛(19.7mg,0.052mmol)和氨基乙基膦酸二乙酯草酸盐(15.6mg,0.057mmol)溶于DMF(0.5mL)中。添加乙酸(15.7mg,0.263mmol),然后添加三乙酰氧基硼氢化钠(22.3mg,0.105mmol)。在4小时后,该粗反应混合物由RP-HPLC提纯(洗脱剂:水/
),在冷冻干燥之后得到27.7mg(97%)的所需产物。1HNMR(300MHz,CDCl3):δ=0.04(s,9H),1.14(t,J=7.5Hz,3H),1.26(m,2H),1.30(t,J=7.2Hz,6H),1.95(s,3H),2.19(s,3H),2.23(m,2H),2.68(q,J=7.5Hz,2H),3.18(m,2H),3.53(s,2H),4.13(m,4H),4.28(m,2H),5.15(s,2H),5.51(m,1H)ppm;31P NMR(121MHz,CDCl3):δ=27.39ppm;MS=540[M++1]。
{2-[4-(6-乙基-4-羟基-7-甲基-3-氧-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基氨基]-乙基}-膦酸:
将(2-{4-[6-乙基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯基胺基}-乙基)-膦酸二乙酯(27.7mg,0.051mmol)溶于DMF(0.5mL)和DCM(0.5mL)中。添加三甲基甲硅烷基溴化物(78.3mg,0.512mmol),反应在室温下搅拌。在20小时后,反应用
(0.3mL)淬灭。在真空中蒸发溶剂,和粗物质由RP-HPLC提纯(洗脱剂:水/
)。含有产物的级分被合并,然后冻干得到14.2mg(57%)的游离膦酸[MS:484M++1]。
将该物质溶于DCM(0.5mL)中。添加TFA(0.05mL)并在室温下继续搅拌。在20分钟后,在真空中除去溶剂和该粗物质由RP-HPLC提纯(洗脱剂:水/
*0.1%TFA)。将含有产物的级分合并,冻干得到7.6mg(52%)产物,为TFA盐。1H NMR(300MHz,DMSO-d6):δ=1.07(t,J=7.5Hz,3H),1.84(s,3H),1.90(m,2H),2.11(s,3H),2.63(q,J=7.5Hz,2H),2.99(m,2H),3.43(d,J=6.3Hz,2H),3.51(s,2H),5.26(s,2H),5.45(m,1H)ppm;31P NMR(121MHz,DMSO-d6):δ=20.02ppm;MS=384[M++1]。
(2-{2-乙基-4-[6-乙基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-丁-2-烯基氨基}-乙基)-膦酸二乙酯
将2-乙基-4-[6-乙基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-丁-2-烯醛(26.6mg,0.068mmol)和氨基乙基膦酸二乙酯草酸盐(20.4mg,0.075mmol)溶于DMF(0.8mL)中。添加乙酸(20.5mg,0.342mmol),然后添加三乙酰氧基硼氢化钠(27.6mg,0.137mmol)。在8小时后,该粗反应混合物由RP-HPLC提纯(洗脱剂:水/
),在冷冻干燥之后得到24.9mg(65%)的所需产物。1H NMR(300 MHz,CDCl3):δ=0.05(s,9H),1.10-1.24(m,8H),1.35(t,J=7.5Hz,6H),2.19(s,3H),2.23(m,2H),2.35(q,J=7.8Hz,2H),2.70(q,J=7.2Hz,2H),3.25(m,2H),3.56(m,4H),4.15(m,4H),4.29(m,2H),5.15(s,2H),5.47(m,1H)ppm;31P NMR(121MHz,CDCl3):δ=27.71ppm;MS=554[M++1]。
{2-[2-乙基-4-(6-乙基-4-羟基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-丁-2-烯基氨基]-乙基}-膦酸
将(2-{2-乙基-4-[6-乙基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-丁-2-烯基氨基}-乙基)-膦酸二乙酯(24.9mg,0.045mmol)溶于DMF(0.5mL)和DCM(0.5ml)中。添加三甲基甲硅烷基溴化物(68.7mg,0.449mmol),反应在室温下搅拌。在20小时后,反应用
(0.15mL)淬灭。在真空中蒸发溶剂,和粗物质由RP-HPLC提纯(洗脱剂:水/
)。含有产物的级分被合并,然后冻干得到8.0mg的游离膦酸[MS:498M++1]。
将该物质溶于DCM(0.5mL)中。添加TFA(0.05mL),然后在室温下继续搅拌。在20分钟后,在真空中除去溶剂和该粗物质由RP-HPLC提纯(洗脱剂:水/
*0.1%TFA)。将含有产物的级分合并,冻干得到4.4mg(54%)产物,为TFA盐。1H NMR(300MHz,DMSO-d6):δ=1.05(m,6H),1.60(m,2H),2.10(s,3H),2.67(q,J=7.5Hz,2H),2.63(q,J=6.9Hz,2H),2.93(m,2H),3.45(m,4H),5.24(s,2H),5.36(m,1H)ppm.;31P NMR(121MHz,DMSO-d6):δ=16.93ppm;MS=398[M++1]。
实施例320
本发明的代表性化合物能够按在下面所示的方法来制备。
2-({4-[6-乙基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯基}-苯氧基-膦酰基氨基)-丙酸乙酯
将4-[6’-乙基-7’-甲基-3’-氧代-4’-(2”-三甲基硅烷基-乙氧基)-1’,3’-二氢-异苯并呋喃-5’-基]-2-甲基-丁-2-烯-膦酸(44.8mg,0.101mmol),二环己基碳二亚胺(52.6mg,0.254mmol),和苯酚(95.8mg,1.018mmol)溶于吡啶(0.3mL)中和在70℃下加热4小时。反应混合物冷却至室温,在真空中除去吡啶。粗物质被分配在DCM和
(0.1N)之间。水层用DCM萃取,合并的有机层用硫酸钠干燥。过滤和在真空中蒸发溶剂得到粗物质,它无需进一步提纯就可用于下一步。
将粗物质溶于
(0.8mL)和水(0.3mL)中。分几份(0.2mL)添加氢氧化钠水溶液(2N,0.8mL)。在全部的起始原料消耗之后,在真空中除去有机溶剂,然后粗物质被分配在氯仿和
水溶液(1N)之间。水层用氯仿萃取。合并的有机层在硫酸钠上干燥。过滤和蒸发溶剂,得到粗产物,为单苯基酯和对称的酸酐的混合物。
将前一步骤的粗物质和(L)-丙氨酸乙基酯盐酸盐(78.1mg,0.509mmol)溶于DMF(0.4mL)中。添加DMAP(1.2mg,催化作用的),随后添加二异丙基乙胺(131.3mg,1.018mmol)。在室温下继续搅拌。在20分钟后,观察到酸酐的完全转化。在2小时后,添加PyBOP(101mg,0.202mmol)并在室温下继续搅拌。反应进行过滤,粗反应溶液由RP-HPLC提纯(洗脱剂:水/
)。将含有产物的级分合并,冻干得到产物(15.7mg,经过三个步骤达25%收率),为白色粉末。1H NMR(300MHz,CDCl3):δ=0.03(s,9H),1.13-1.28(m,8H),2.03(s,3H),2.19(s,3H),2.62-2.74(m,4H),3.38(m,1H),3.53(t,J=6.3Hz,2H),4.03(m,3H),4.30(m,2H),5.14(s,2H),5.31(m,1H),7.11-7.17(m,3H),7.25-7.30(m,2H)ppm;31P NMR(121MHz,CDCl3):δ=27.04,27.73ppm;MS=615[M++1]。
2-{[4-(6-乙基-4-羟基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基]-苯氧基-膦酰基氨基-丙酸乙酯
在-20℃下将2-({4-[6-乙基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯基}-苯氧基-膦酰基氨基)-丙酸乙酯(7.5mg,0.012mmol)溶于TFA/DCM(10%,0.3mL)中。反应混合物升至0℃和在这一温度下搅拌45分钟。添加吡啶(0.09mL),在真空中除去溶剂。该粗物质由RP-HPLC提纯(洗脱剂:水/
)。将含有产物的级分合并,冻干得到白色粉末(5.5mg,87%)。1H NMR(300MHz,CDCl3):δ=1.12-1.29(m,6H),2.03(s,3H),2.17(s,3H),2.65-2.74(m,4H),3.38(m,1H),3.53(t,J=6.3Hz,2H),4.03(m,3H),5.22(s,2H),5.36(m,1H),7.11-7.16(m,3H),7.24-7.30(m,2H),7.72(m,1H)ppm;31P NMR(121MHz,CDCl3):δ=27.11,27.57ppm;MS=515[M++1]。
实施例321
本发明的代表性化合物能够按在下面所示的方法来制备。
6-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-4-甲基-己-4-烯酸
将6-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-4-甲基-己-4-烯酸甲酯(1.5g,3.45mmol)和氢氧化钠(552mg)在由甲醇(20mL)和水(7mL)组成的混合物中的混合物在室温下搅拌一小时。溶液用1N
酸化。由抽滤收集沉淀物,用水洗涤得到所需产物(1.2g,83%)。1H NMR(300MHz,CDCl3)δ0.02(s,9H),1.15-1.22(m,2H),1.76(s,3H),2.13(s,3H),2.12-2.28(m,2H),2.35-2.41(m,2H),3.37(d,2H,J=7Hz),3.71(s,3H),4.22-4.28(m,2H),5.07(s,2H),5.13-5.17(m,1H)ppm;MS(m/z)419.3[M-H]-,443.2[M+Na]+。
({6-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-4-甲基-己-4-烯酰氨基}-甲基)-膦酸二乙酯
在0℃下向6-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-4-甲基-己-4-烯酸(50mg,0.12mmol)在THF(1mL)中的溶液添加氯甲酸异丁酯(17μL,0.13mmol)和三乙胺(50μL,0.36mmol)。在0℃下搅拌2小时后,添加(氨基甲基)膦酸二乙基酯草酸盐(62mg,0.26mmol),然后在室温下继续搅拌20分钟。在除去溶剂后,该残留物用制备性反相HPLC提纯,获得54.8mg(81%)的所需产物。1H NMR(300 MHz,CDCl3)δ0.03(s,9H),1.15-1.22(m,2H),1.31(t,6H),1.81(s,3H),2.18(s,3H),2.30(m,4H),3.41(d,2H,J=7Hz),3.65(dd,2H,J=6,12Hz),3.77(s,3H),3.77-4.16(m,4H),4.26-4.32(m,2H),5.12(s,2H),5.17-5.19(m,1H),5.86(bs,1H)ppm;31P(121.4MHz,CDCl3)δ23.01ppm;MS(m/z)568 [M-H]-,592[M+Na]+。
{[6-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-4-甲基-己-4-烯酰氨基]-甲基}-膦酸
向({6-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-4-甲基-己-4-烯酰氨基}-甲基)-膦酸二乙酯(40mg,0.07mmol)在乙腈(1mL)中的溶液添加TMSBr(91μL,0.7mmol),然后添加2,6-二甲基吡啶(81.5μL,0.7mmol)。让反应继续进行一夜,此时由LCMS判断反应已结束。反应混合物用
淬灭,和浓缩到干燥。该残留物用制备性反相HPLC提纯,获得2.6mg(9%)的所需产物,为白色固体。1H NMR(300MHz,CD3OD)δ1.67(s,3H),2.17(m,5H),2.30-2.46(m,2H),2.80-2.86(m,2H),3.55(m,2H),3.82(s,3H),5.26(s,3H)ppm;31P(121.4MHz,CD3OD)δ10.27ppm;MS(m/z)412[M-H]-,414[M+H]+。
实施例322
本发明的代表性化合物能够按在下面所示的方法来制备。
在0℃下向6-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-4-甲基-己-4-烯酸(50mg,0.12mmol)在THF(1mL)中的溶液添加氯甲酸异丁酯(17μL,0.13mmol)和三乙胺(50μL,0.36mmol)。在0℃下搅拌2 小时后,添加(氨基乙基)膦酸二乙基酯草酸盐(62mg,0.26mmol),然后在室温下继续搅拌1小时。在除去溶剂后,该残留物用制备性反相HPLC提纯,获得37mg(54%)白色固体形式的所需产物。1H NMR(300MHz,CDCl3)δ0.03(s,9H),1.15-1.22(m,2H),1.31(t,6H),1.81(s,3H),1.85-1.93(m,2H),2.18(s,3H),2.30(m,4H),3.41(d,2H,J=7Hz),3.48-3.54(m,2H),3.77(s,3H),3.77-4.16(m,4H),4.26-4.32(m,2H),5.12(s,2H),5.17-5.19(m,1H),6.30(bs,1H)ppm;31P(121.4MHz,CDCl3)δ29.91ppm;MS(m/z)584[M+H]+。
{2-[6-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-4-甲基-己-4-烯酰氨基]-乙基}-膦酸
向(2-{6-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-4-甲基-己-4-烯酰氨基}-乙基)-膦酸二乙酯(36.6mg,0.063mmol)在乙腈(1mL)中的溶液添加TMSBr(81μL,0.63mmol),随后添加2,6-二甲基吡啶(73μL,0.63mmol)。让反应继续进行一夜,此时由LCMS判断反应已结束。反应混合物用
淬灭,和浓缩到干燥。该残留物用制备性反相HPLC提纯,获得5.8mg(29%)的所需产物,为白色固体。1H NMR(300MHz,CD3OD)δ1.80(s,3H),2.14(m,5H),2.25(m,4H),3.35(m,2H),3.38-3.38(m,2H),3.75(s,3H),5.23(s,3H)ppm;31P(121.4MHz,CD3OD)δ26.03ppm;MS(m/z)426[M-H]-,428[M+H]+。
实施例323
本发明的代表性化合物能够按在下面所示的方法来制备。
{4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯基}-膦酸二苯酯
向[{4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯基}-膦酸(260mg,0.59mmol)在DMF(6mL)和苯酚(555mg,5.9mmol)中的溶液添加二环己基碳二亚胺(1.21g,5.9mmol)和DMAP(36mg,0.295mmol)。反应混合物被加热至140℃保持30分钟。在冷却到室温之后,混合物被分配在
/己烷(1∶1)和5%
水溶液之间。该有机层反复地用5% 水溶液洗涤,然后用
干燥。在除去溶剂后,该残留物由硅胶色谱分离法提纯得到75mg(21%)的所需产物。MS(m/z)617[M+Na]+
{4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯基}-膦酸单苯基酯
向{4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯基}-膦酸二苯酯(75mg,0.126mmol)在THF(5mL)中的溶液添加1N
(0.1mL)溶液。混合物在室温下搅拌16小时。添加
,所获得的混合物用1H
洗涤。该有机层浓缩至干燥和该残留物由RP HPLC使用C18柱以
,0.1%TFA-乙腈,0.1%TFA的梯度提纯而得到24.8mg(38%)的所需产物。MS(m/z)517[M-H]-,541[M+Na]+。
2-({4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯基}-苯氧基-膦酰基氧基)-丙酸乙酯
向{4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯基}-膦酸单苯基酯(25mg,0.048mmol)和(S)-(-)-乳酸乙基酯(34mg,0.288mmol)在吡啶(1mL)中的溶液添加PyBOP(125mg,0.24mmol)。溶液在室温下搅拌16小时和浓缩。该残留物由RP HPLC使用C18柱以
,0.1%TFA-乙腈,0.1%TFA的梯度提纯,得到24mg(83%)的所需产物。MS(m/z)641[M+Na]+。
2-{[4-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基]-苯氧基-膦酰基氧基}-丙酸乙酯
向2-({4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯基}-苯氧基-膦酰基氧基)-丙酸乙酯(24mg,0.039mmol)在DCM(1mL)中的溶液添加TFA(0.5mL),然后混合物在室温下搅拌10分钟。反应混合物在减压下干燥和该残留物由RP-HPLC提纯,得到18mg(90%)澄明油形式的所需产物。1H NMR(300MHz,CDCl3)δ1.18-1.34(m,3H),1.36-1.48(dd,3H),2.02(m,3H),2.17(s,3H),2.78-2.98(dd,2H),3.45(m,2H),3.79(s,3H),4.05-4.25(m,2H),4.97(m,1H),5.21(s,2H),5.48(t,J=7.2Hz,1H),7.05-7.18(m,5H)ppm;31P(121.4MHz,CDCl3)δ24.59,26.13ppm;MS(m/z)517 [M-H]-,519[M+H]+。
实施例324
本发明的代表性化合物能够按在下面所示的方法来制备。
2-{[4-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基]-苯氧基-膦酰基氧基}-丙酸
向2-{[4-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基]-苯氧基-膦酰基氧基}-丙酸乙酯(10mg,0.019mmol)在THF(3mL)中的溶液添加1N
(232μL),然后混合物在室温下搅拌1小时。反应混合物在减压下干燥和该残留物由RP-HPLC提纯,得到6mg(77%)澄明油形式的所需产物。1H NMR(300MHz,CD3OD)δ1.41(d,J=7Hz,3H),1.97(s,3H),2.16(s,3H),2.59(d,J=22Hz,2H),3.45(m,2H),3.79(s,3H),4.83(m,1H),5.26(s,2H),5.43(t,J=7.2Hz,1H)ppm;31P(121.4MHz,CD3OD)δ27.02ppm;MS(m/z)413[M-H]-,415[M+H]+。
实施例325
本发明的代表性化合物能够按在下面所示的方法来制备。
2-{[4-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基]-苯氧基-膦酰基氨基-丙酸乙酯
{4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯基}-膦酸单苯基酯(1g,~1.9mmol)与PyBOP(2g,4mmol)和DMAP(120mg,0.96mmol)掺混。将L-丙氨酸乙酯盐酸盐(2.9g,19mmol)和二异丙基乙胺(6.7mL,38mmol)在吡啶(5mL)中的溶液添加到该一元酸混合物中,然后反应在室温下搅拌12小时。反应混合物然后浓缩和由柱色谱分析两次提纯(1%
/
3%
/
)。在-40℃下将所获得的油溶于10%TFA/
(30mL)的剧烈搅拌溶液中。反应逐渐地升至0℃。在约3小时之后,反应完成。添加吡啶(4.5mL),反应混合物进行浓缩。产物用制备TLC(5%
/
)提纯,然后浓缩得到210mg(21%)的所需产物,为浅黄色油。1H NMR(300MHz,CDCl3)δ7.83-7.70(m,1H),7.30-7.20(m,2H),7.18-7.03(m,3H),5.60-5.35(m,1H),5.21(s,2H),4.17-3.95(m,3H),3.79(s,3H),3.60-3.40(m,3H),2.80-2.60(m,2H),2.17(m,3H),2.01(m,3H),1.30-1.10(m,6H)ppm;31P NMR(121MHz,CDCl3)δ28.0,27.5ppm;MS(m/z)516 [M-H]-。
实施例326
本发明的代表性化合物能够按在下面所示的方法来制备。
2-(二甲氧基-磷酰基)-6-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-4-甲基-己-4-烯酸甲酯
在环境温度下向三甲基膦酰基乙酸酯(63μL,0.39mmol)在THF(1mL)中的溶液添加
(0.39mmol,0.39mL)。在30分钟后,将6-(4-溴-3-甲基-丁-2-烯基)-5-甲氧基-4-甲基-7-(2-三甲基硅烷基-乙氧基)-3H-异苯并呋喃-1-酮(69mg,0.156mmol)在THF(1mL)中的溶液添加进去。反应混合物搅拌2小时,之后观察到沉淀。反应混合物通过添加饱和氯化铵水溶液和用
萃取产物来进行后处理。有机萃取液进行干燥,产物通过使用硅胶色谱分离法以0-100%EtOAc-己烷来提纯,得到40mg的所需产物,为无色油。1H NMR(300MHz,CDCl3)δ0.05(s,9H),1.20-1.26(m,2H),1.79(s,3H),2.17(s,3H),2.42-2.72(m,2H),3.19(ddd,1H,J=4,12,23Hz),3.39(d,2H,J=7Hz),3.62(s,3H),3.75(s,3H),3.77-3.84(m,6H),4.27-4.34(m,2H),5.12(s,2H),5.24(t,1H,J=7Hz)ppm;31P(121.4MHz,CDCl3)δ25.1ppm;MS(m/z)565.2[M+Na]+。
6-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-4-甲基-2-膦酰基己-4-烯酸甲酯
向2-(二甲氧基-磷酰基)-6-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-4-甲基-己-4-烯酸甲酯(30mg,0.055mmol)在乙腈(2mL)中的溶液添加三甲基甲硅烷基溴化物(0.18mL)。在10分钟后,在环境温度下将2,6-二甲基吡啶(0.16mL)添加到反应中。反应进行16小时,之后浓缩至干燥。将残留物再悬浮在DMF∶
(8∶2,1mL)的溶液中,然后由RP HPLC使用C18柱以
,0.1%TFA-乙腈,0.1%TFA的梯度提纯,得到18mg白色粉末形式的产物。1H NMR(300MHz,CD3OD)δ1.81(s,3H),2.16(s,3H),2.40-2.49(m,1H),2.63(dt,1H,J=6,17Hz),3.07(ddd,1H,J=4,12,23Hz),3.38(3,2H,J=7Hz),3.52(s,3H),3.77(s,3H),5.25(s,2H),5.28(t,1H,J=7Hz)ppm;31P(121.4MHz,CDCl3)δ19.5ppm;MS(m/z)415.2 [M+H]+,437.2[M+Na]+。
实施例327
本发明的代表性化合物能够按在下面所示的方法来制备。
2-(双-(2,2,2-三氟乙氧基)磷酰基)-6-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-4-甲基-己-4-烯酸甲酯
向[双-(2,2,2-三氟-乙氧基)-磷酰基]-乙酸甲酯(186μL,0.88mmol)在无水THF(2mL)中的溶液添加由1N
溶于THF(0.88mL,0.88mmol)中所获得的溶液。溶液在室温下搅拌30分钟,之后添加6-(4-溴-3-甲基-丁-2-烯基)-5-甲氧基-4-甲基-7-(2-三甲基硅烷基-乙氧基)-3H-异苯并呋喃-1-酮(98mg,0.22mmol)在THF(1mL)中的溶液。反应混合物搅拌一夜,之后观察到沉淀。反应混合物通过添加饱和氯化铵水溶液和用
萃取产物来进行后处理。有机萃取液进行干燥和产物由RP HPLC使用C18柱以
,0.1%TFA-乙腈,0.1%TFA的梯度提纯,得到72mg(48%)的产物,为无色油。1H NMR(300MHz,CDCl3)δ0.05(s,9H),1.22(t,3H,J=7Hz),1.81(s,3H),2.18(s,3H),2.5-2.7(m,2H),3.3(ddd,1H,J=4,12,23Hz),3.40(d,2H,J=7Hz),3.65(s,3H),3.76(s,3H),4.29-5.13(m,6H),5.13(s,2H),5.28(t,1H,J=7Hz)ppm;MS(m/z)701.2[M+Na]+。
2-(双-(2,2,2-三氟乙氧基)磷酰基)-6-[6-甲氧基-7-甲基-3-氧代-4-(2-羟基氧基)-1,3-二氢-异苯并呋喃-5-基]-4-甲基-己-4-烯酸甲酯
将[2-(双-(2,2,2-三氟乙氧基)磷酰基)-6-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-4-甲基-己-4-烯酸甲酯(70mg)溶于在二氯甲烷(5ml)中10%三氟乙酸溶液中。在10分钟后,混合物进行浓缩和产物由RP HPLC使用C18柱以
,0.1%TFA-乙腈,0.1%TFA的梯度提纯,得到45mg(75%)的产物,为无色油。1H NMR(300MHz,CDCl3)δ1.81(s,3H),2.16(s,3H),2.5-2.7(m,2H),3.3(ddd,1H),3.38(d,2H,J=7Hz),3.65(s,3H),3.77(s,3H),4.33-4.43(m,4H),5.21(s,2H),5.33(t,1H,J=7Hz)ppm;31P(121.4MHz,CDCl3)δ25.8ppm;MS(m/z)601.2[M+Na]+。
实施例328
本发明的代表性化合物能够按在下面所示的方法来制备。
6-(4-羟基-6-甲氧基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-[羟基-(2,2,2-三氟-乙氧基)-磷酰基]-4-甲基-己-4-烯酸
向[双-(2,2,2-三氟-乙氧基)-磷酰基]-乙酸甲基酯(186μL,0.88mmol)在无水THF(0.5mL)中的溶液添加1N
(水溶液;0.06mL)和N-甲基吡咯烷酮(0.2mL)的溶液。在6.5小时后,添加另一个等分部分的1N
(0.06ml),混合物搅拌一夜。在浓缩后,将残留物悬浮于DMF(<1mL)中,用几滴的TFA来中和,然后由RP HPLC使用C18柱以
,0.1%TFA-乙腈,0.1%TFA的梯度提纯,在冻干之后得到5.6mg(72%)的产物,为白色粉末。1H NMR(300MHz,CD3OD)δ1.83(s,3H),2.16(s,3H),2.43-2.51(m,1H),2.59-2.70(m,1H),3.13(ddd,1H),3.40(d,2H),3.76(s,3H),4.36-4.47(m,2H),5.25(s,2H),5.34(t,1H,J=7Hz)ppm;MS(m/z)505.2[M+Na]+。
实施例329
本发明的代表性化合物能够按在下面所示的方法来制备。亚磷酸单-{4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯基}酯
向6-(4-羟基-3-甲基-丁-2-烯基)-5-甲氧基-4-甲基-7-(2-三甲基硅烷基-乙氧基)-3H-异苯并呋喃-1-酮(75mg,0.20mmol)和DIEA(49μL,0.28mmol)在二噁烷(2mL)中的溶液添加2-氯-4H-1,3,2-苯并二氧杂phosphorin-4-酮(56.7mg,0.28mmol),根据Shadid,B.等人,Tetrahedron,1989,45,12,3889的程序。在10分钟后,添加另一部分的2-氯-4H-1,3,2-苯并二氧杂phosphorin-4-酮(40mg,0.20mmol)和DIEA(35μL,0.20mmol)。反应在室温下进行另外1小时,之后通过添加
来淬灭反应。溶液搅拌另外10分钟,然后真空浓缩到较小体积。产物与二乙醚一起研磨,从乙腈(4×10mL)中共同蒸发而得到产物。1H NMR(300MHz,CDCl3)δ0.03(s,9H),1.08-1.30(m,2H),1.84(br s,3H),2.17(s,3H),3.46(br s,2H),3.76(s,3H),4.21-4.39(m,4H),5.12(s,2H),5.43-5.60(m,1H),7.83(br s,1H);31P(121.4MHz,CDCl3)δ7.22;MS(m/z)441[M-H]-。
实施例330
本发明的代表性化合物能够按在下面所示的方法来制备。磷酸单-{4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯基}酯
亚磷酸单-{4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯基}酯(27mg,0.06mmol)在二噁烷(1mL)中的溶液与DIEA(21μL,0.12mmol)和N,O-双(三甲基甲硅烷基)乙酰胺(29μL,0.12mmol)在室温下搅拌3小时。向反应溶液中添加2,2’-二吡啶基二硫化物(16mg,0.072mmol),让混合物在室温下搅拌另外2小时。反应混合物通过添加
来稀释,该溶液搅拌另外2小时,之后进行浓缩。将残留物溶于10%TFA/
的溶液中,然后在室温下搅拌9小时。反应混合物在减压下干燥和产物用反相HPLC提纯,得到白色固体形式的所需产物。1H NMR(300MHz,CD3OD)δ1.87(s,3H),2.16(s,3H),3.47(d,2H,J=7Hz),3.79(s,3H),4.28(d,2H,J=6Hz),5.26(s,2H),5.50-5.61(m,1H);31P(121.4MHz,CD3OD)δ0.50;MS(m/z)357[M-H]-。
实施例331
下面给出了本发明的几种化合物。
实施例332
根据下面给出的方法能够制备本发明的其它代表性化合物,和它们的中间体。
在R1,R2上有变体的苯乙醛类的合成
如下所示,该母体化合物(R1=
;R2=Me)可通过由半合成法从霉酚酸获得:
在氮气氛中向霉酚酸(500g,1.56mol)在
(4L)中的溶液中滴加硫酸(10mL),然后所得悬浮液在室温下搅拌。在2小时后,反应变成均匀的,不久以后形成沉淀。反应在室温下搅拌10小时,在此之后TLC指明了完全的反应。反应在冰浴中冷却到10℃,然后使用布氏漏斗进行过滤。该滤饼用冰冷的甲醇(750mL),随后用己烷(750mL)洗涤,然后干燥得到497g(95%)固体形式的所需产物:1H NMR(300MHz,CDCl3)δ,1.81(s,3H),2.18(s,3H),2.15(s,3H),2.37-2.50(m,4H),3.38(d,2H,J=7Hz),3.62(s,3H),3.77(s,3H),5.13(s,2H),5.22(m,1H),7.17(s,1H)。
在0℃下向化合物(3.99g,11.9mmol),PPh3(4.68g,17.9mmol),和偶氮二羧酸二异丙基酯(3.46mL,17.9mmol)在THF(60mL)中的溶液添加2-三甲基甲硅烷基乙醇(2.05mL,14.3mmol)在THF(20mL)中的溶液。所获得的黄色溶液升至室温和搅拌4小时。反应通过浓缩该溶液至干燥和然后添加乙醚和己烷,来进行后处理。三苯基氧膦由过滤除去,该滤液进行浓缩并由硅胶色谱分离法提纯,得到4.8g(100%)澄明油形式的产物:1H NMR(300MHz,CDCl3)δ0.03(s,9H),1.18-1.30(m,2H),1.81(s,3H),2.18(s,3H),2.25-2.33(m,2H),2.37-2.45(m,2H),3.42(d,2H,J=7Hz),3.62(s,3H),3.77(s,3H),4.25-4.35(m,2H),5.13(s,2H),5.12-5.22(m,1H)。
使用干冰/丙酮浴将化合物(9.6g,22mmol)在
(90mL),
(90mL)和吡啶(0.7mL)中的溶液冷却至-70℃。经由气相分散管将臭氧气流鼓泡通入反应中,直至反应变成蓝色为止(1.5小时)。该臭氧管线用氮气流置换并继续鼓泡另外30分钟,在此时蓝色已消失。在-78℃下将硫脲(1.2g,15.4mmol)作为一份添加到该溶液中,然后移走冷却浴。反应升至室温和搅拌15小时。反应由过滤除去固体硫脲S-二氧化物来进行后处理,并分配在
和水之间。除去有机层。该水层再一次用
萃取,合并有机萃取液,用1N
水溶液、饱和
水溶液和盐水洗涤,并在真空中干燥。该残留物由硅胶色谱分离法提纯,获得7.3g(99%)白色固体形式的产物:1HNMR(300MHz,CDCl3)δ-0.01(s,9H),1.05-1.15(m,2H),2.15(s,3H),3.69(s,3H),3.78(d,2H,J=1Hz),4.27-4.39(m,2H),5.11(s,2H),9.72(d,1H,J=1Hz)。
R1变量
通过使用与以上所述的那些方法类似的方法将起始原料,根据J.Med.Chem.,1996,39,4181-4196合成,转化成所需的醛。
通过使用与以上所述的那些方法类似的方法将起始原料,根据J.Med.Chem.,1996,39,4181-4196合成,转化成所需的醛。
通过使用与以上所述的那些方法类似的方法将起始原料,根据J.Med.Chem.,1996,39,4181-4196合成,转化成所需的醛。
将该醛溶于有机溶剂如甲醇中,然后添加硼氢化钠。在反应结束之后,添加
水溶液,在真空中除去溶剂。由色谱分离法进一步提纯。
将所形成的醇溶于有机溶剂如二氯甲烷(DCM)中。添加吡啶和乙酸酐,并在室温下继续搅拌。在反应结束时添加另外的DCM,所得溶液用
水溶液、碳酸氢钠水溶液洗涤,然后用硫酸钠干燥。过滤和在真空中蒸发溶剂,得到该粗产物。由色谱分离法进一步提纯。
将乙酸酯溶于DCM中和添加溴,根据J.Med.Chem.,1996,39,4181-4196的程序。在反应结束时,添加另外的DCM,所得溶液用硫代硫酸钠水溶液和盐水洗涤。有机层在硫酸钠上干燥。过滤和蒸发溶剂,得到粗物质。由色谱分离法进一步提纯。
根据J.Med.Chem.,1996,39,4181-4196的程序,将前一步骤的产物,氯化锂,三苯胂,三丁基乙烯基锡,和三(二苄叉基丙酮)二钯(O)-氯仿加合物在有机溶剂如N-甲基吡咯烷酮中在大约55℃的升高温度下加热。在反应结束时,混合物冷却至室温,然后倾倒在冰,氟化钾,水和乙酸乙酯的混合物中。继续搅拌一小时。悬浮液经赛力特硅藻土过滤,用乙酸乙酯萃取。合并的有机萃取物用硫酸钠干燥。在真空中除去溶剂和该粗物质进一步用色谱分离法提纯。
将前一步骤的产物溶于有机溶剂如DCM或THF中。根据J.Org.Chem.,1984,48,4155-4156的程序,添加1,1,1-三(酰氧基)-1,1-二氢-1,2-benziodoxol-3-(1H)-酮(Dess-Martin试剂),所得溶液在室温下搅拌。在反应结束时,添加二乙醚,随后添加氢氧化钠水溶液。分离两层和有机层用氢氧化钠水溶液、水洗涤,然后用硫酸钠干燥。过滤和蒸发溶剂,得到粗产物。由色谱分离法进一步提纯。
将起始原料溶于有机溶剂如甲苯中。根据J.Org.Chem.,2003,68,452-459的程序,添加P(异丁基NCH2CH2)3N,乙酸钯(II),叔丁醇钠,和苄胺,混合物在80℃下加热。在反应结束时,混合物冷却至室温和在真空中除去溶剂。粗物质用色谱分离法提纯。通过用甲醇钠甲醇溶液简单处理来除去任何残留乙酸盐。
将苄基保护的苯胺溶于有机溶剂如DMF中。添加钯/碳,反应混合物放置在氢气氛中。在反应结束时,混合物经由赛力特硅藻土过滤。在真空中除去溶剂。由色谱分离法进一步提纯。
将所获得的伯苯胺溶于有机溶剂如THF、乙腈或DMF中,并用甲醛和三乙酰氧基硼氢化钠处理,按照在J.Org.Chem,1996,61,3849-3862中所述。反应用碳酸氢钠水溶液淬灭,产物用有机溶剂如乙酸乙酯萃取。该粗物质用二叔丁基重碳酸酯在有机溶剂如二甲基甲酰胺和氢氧化钠水溶液中处理。所形成的氨基甲酸酯用色谱分离法提纯。
将伯醇产物溶于有机溶剂如DCM或THF中。根据J.Org.Chem.,1984,48,4155-4156的程序,添加1,1,1-三(酰氧基)-1,1-二氢-1,2-benziodoxol-3-(1H)-酮(Dess-Martin试剂),所得溶液在室温下搅拌。在反应结束时,添加二乙醚,随后添加氢氧化钠水溶液。分离两层和有机层用氢氧化钠水溶液、水洗涤,然后用硫酸钠干燥。过滤和蒸发溶剂,得到粗产物。由色谱分离法进一步提纯。
根据Recl.Trav.Chem.Pay-Bas,1982,101,460的程序,将起始原料溶于有机溶剂如DCM或THF中并用甲酸和特戊酸的混合酸酐处理。在反应结束时,在真空中除去溶剂和全部的挥发分,粗产物进一步用色谱分离法提纯。
将产物溶于有机溶剂如DCM或THF中。根据J.Org.Chem.,1984,48,4155-4156的程序,添加1,1,1-三(酰氧基)-1,1-二氢-1,2-benziodoxol-3-(1H)-酮(Dess-Martin试剂),所得溶液在室温下搅拌。在反应结束时,添加二乙醚,随后添加氢氧化钠水溶液。分离两层和有机层用氢氧化钠水溶液、水洗涤,然后用硫酸钠干燥。过滤和蒸发溶剂,得到粗产物。由色谱分离法进一步提纯。
R2变量
根据J.Med.Chem.,1996,39,4181-4196的程序,将起始原料溶于有机溶剂如DMF中并与N-氯琥珀酰亚胺反应。在起始原料消耗之后,将反应混合物倾倒在水中和产物用二乙醚萃取。合并的有机层在硫酸钠上干燥。过滤和蒸发溶剂,得到粗反应产物。
将步骤1的产物溶于有机溶剂如甲醇,DCM和吡啶的混合物中。将溶液冷却至-78℃,然后将臭氧鼓泡通入到溶液中,直到蓝色存留为止。多余的臭氧用氮气流除去。反应混合物升至室温,添加硫脲。在室温下继续搅拌。反应混合物进行过滤,然后分配在DCM和水之间。该水层用DCM萃取,合并的有机层用
(1N),饱和碳酸氢钠水溶液和盐水洗涤。溶液用硫酸钠干燥。过滤和蒸发溶剂,得到粗醛。由色谱分离法进一步提纯。
将起始原料溶于有机溶剂如甲醇,DCM和吡啶的混合物中。将溶液冷却至-78℃,然后将臭氧鼓泡通入到溶液中,直到蓝色存留为止。多余的臭氧用氮气流除去。反应混合物升至室温,添加硫脲。在室温下继续搅拌。反应混合物进行过滤,然后分配在DCM和水之间。该水层用DCM萃取,合并的有机层用
(1N),饱和碳酸氢钠水溶液和盐水洗涤。溶液用硫酸钠干燥。过滤和蒸发溶剂,得到粗醛。由色谱分离法进一步提纯。
将步骤1的产物溶于有机溶剂如苯中。添加三氟甲烷磺酰氯和二氯三(三苯基膦)钌,所得溶液被脱气。根据J.Chem.Soc.,Perkin Trans.1,1994,1339-1346的程序,将反应混合物在120℃下加热。在反应结束时,混合物冷却至室温和在真空中除去溶剂。产物由色谱分离法进一步提纯。
连接到膦酸酯上的烯烃和连接体的合成
将在甲苯(50mL)中的苯乙醛(5.3g,15.8mmol)在100℃下与2-(三苯基-phosphanylidene)-丙醛(6.8g,20.5mmol)一起加热一夜。在浓缩后,残留物由硅胶色谱分离法提纯,得到4.24g(72%)浅黄色固体形式的不饱和醛。1H NMR(300MHz,CDCl3)δ0.00(s,9H),1.10-1.21(m,2H),1.87(s,3H),2.16(s,3H),3.67-3.76(m,2H),3.74(s,3H),4.27-4.39(m,2H),5.11(s,2H),6.40-6.48(m,1H),9.2(s,1H)。
根据例如在Tetrahedron,1995,51,2099中报道的程序,三甲基甲硅烷基乙基保护的醛用亚磷酸二乙基酯在溶剂如乙腈中在碱如三乙胺存在下处理,获得羟基膦酸酯。该羟基膦酸酯进行O-烷基化,然后通过用三氟乙酸或四丁铵氟化物处理除去保护基团来产生所需的甲氧基膦酸酯类似物。
另外地,该醛与(2-氨基乙基)膦酸二乙基酯混合并用还原剂如三乙酰氧基硼氢化钠处理,产生氨基膦酸酯类似物。
将4-[6-甲氧基-7-甲基-3-氧代-4-(2-三甲基硅烷基-乙氧基)-1,3-二氢-异苯并呋喃-5-基]-2-甲基-丁-2-烯醛(103mg,0.27mmol)在甲醇(5mL)中的溶液冷却到0℃。添加
(0.68mL,
∶
,9∶1)的溶液,随后添加
(0.14mL,0.28mmol的在THF中2M溶液)。移走冰浴,让反应混合物升至室温。反应混合物进一步搅拌另外40分钟,此时TLC指示起始醛的完全消耗。反应通过添加1N 水溶液(0.5mL)进行后处理,产物用
萃取。该有机层用饱和的碳酸氢钠水溶液和盐水洗涤。有机层在减压下浓缩和该残留物由硅胶色谱分离法提纯,得到100mg(97%)的产物,为澄清液。1H NMR(300MHz,CDCl3)δ0.00(s,9H),1.20(dd,2H,J=7,8Hz),1.81(s,3H),2.13(s,3H),3.38-3.50(m,2H),3.74(s,3H),3.95(s,2H),4.27(dd,2H,J=7,8Hz),5.08(s,2H),5.17-5.44(m,1H)。
将聚合物担载的三苯基膦在DCM中浸泡1小时。顺序地添加烯丙基醇和四溴化碳。当反应完成时,混合物进行过滤和该滤液进行浓缩。根据需要,该溴化物由色谱分离法提纯。
根据例如描述在WO 95/22538中的程序,该烯丙基溴在惰性有机溶剂如二甲基甲酰胺中用二乙氧基磷酰基乙酸乙基酯(由二乙氧基磷酰基乙酸乙基酯与六甲基二硅氮化钠或氢化钠反应制得)的碱金属盐处理,获得乙氧基羰基膦酸酯。根据通常用于酰胺形成和酯还原的方法,将羧酸酯基团转化成羧酰胺和羟甲基基团。例如,该羧酸酯用氢氧化锂水溶液皂化。该酸用氯甲酸乙酯活化,并用硼氢化钠还原,在保护基团的除去后,产生羟甲基膦酸酯类似物。该酸也转化成它的酰氯,然后与乙基胺反应,获得酰胺类似物。
根据例如在Synthesis,1999,282中描述的程序,该芳基乙醛与2-(二乙氧基磷酰基)-丁-3-烯酸乙酯偶联,产生2-乙烯基取代的酯。在环丙烷化条件如在Tetrahedron Lett.1998,39,8621中描述的那些条件下,2-乙烯基转化成2-环丙基基团。该酯转化成醇,它任选地还进行一些反应,如在下面描述的反应,产生各种含膦酸酯的霉酚酸类似物。
该烯丙基醇用溴甲基膦酸二异丙基酯在碱如叔丁醇锂存在下在溶剂如二甲基甲酰胺中处理。该苯酚保护基然后通过用三氟乙酸处理来除去。
根据例如在J.Org.Chem.1987,52,849中报道的程序,该苯乙醛另外转化成烯丙基膦盐。该膦盐然后用商购的3,3,3-三氟-2-氧代-丙酸乙酯和碱如氢化钠处理,产生2-三氟甲基取代的酯。该酯转化成醇,它任选地还进行一些前面描述的反应,产生具有含膦酸酯基团的各种侧链的霉酚酸类似物。
R4变量的引入
根据J.Med.Chem.,1996,39,4181-4196的程序,将烯酮(在Tetrahedron,1985,41,4881-4889中评述的合成)和二烯(Chem.Pharm.Bull.,1989,37,2948-2951)溶于有机溶剂如甲苯中,在室温下搅拌24小时和加热到回流保持另外5小时。反应混合物冷却至室温和在真空中除去溶剂。粗反应产物进一步用色谱分离法提纯。
根据J.Med.Chem.,1996,39,4181-4196的程序,将步骤1的产物溶于有机溶剂如DCM中和添加间-氯过苯甲酸。在反应结束时,将溶液倾倒在亚硫酸氢钠水溶液中。该有机层用饱和碳酸氢钠水溶液洗涤,用硫酸钠干燥。过滤和蒸发溶剂,得到粗产物。
根据J.Med.Chem.,1996,39,4181-4196的程序,将粗产物溶于有机溶剂如甲苯中并用二氯二氰基醌(DDQ)处理。在反应结束时,在真空中除去溶剂和粗物质进一步用色谱分离法提纯。
根据J.Med.Chem.,1996,39,46-55的改进程序,将产物溶于有机溶剂如DCM中和用三氯化硼在回流温度下处理。在反应结束时,溶液用
水溶液洗涤。溶液用硫酸钠干燥。溶剂的除去得到了粗反应产物。由色谱分离法进一步提纯。
将前一步骤的产物和三苯基膦溶于有机溶剂如四氢呋喃(THF)中。在0℃下滴加偶氮二羧酸二异丙基酯(DIAD)。继续搅拌。将2-三甲基甲硅烷基乙醇在THF中的溶液添加进去,继续搅拌。在反应结束时,在真空中除去溶剂。粗反应固体用有机溶剂如己烷和二乙醚的混合物来萃取。洗液被合并,在真空中除去溶剂。所需产物进一步由色谱分离法从不希望有的区域异构体中提纯和分离。
根据J.Med.Chem.,1996,39,4181-4196的程序,将起始原料溶于有机溶剂如二甲基甲酰胺(DMF)中并与N-氯琥珀酰亚胺反应。在起始原料消耗之后,将反应混合物倾倒在水中和产物用二乙醚萃取。合并的有机层在硫酸钠上干燥。过滤和蒸发溶剂,得到粗产物。由色谱分离法进一步提纯。
根据J.Am.Chem.Soc.,1966,88,5855-5866的程序,将起始原料溶于有机溶剂如苯中并与二甲亚砜(DMSO),二环己基碳二亚胺(DCC),和正磷酸进行反应。在反应结束时,悬浮液进行过滤和有机层用碳酸氢钠水溶液洗涤并用硫酸钠干燥。过滤和蒸发溶剂,得到粗物质。由色谱分离法进一步提纯。
根据在Chem.Rev.,1962,62,347-404中评述的程序,将步骤1的产物溶于有机溶剂如DCM或THF中和用拉内镍处理。当全部的起始原料消耗时,反应进行过滤,在真空中除去溶剂。由色谱分离法进一步提纯。
将起始原料溶于有机溶剂如DCM中和添加溴,根据J.Med.Chem.,1996,39,4181-4196的程序。在反应结束时,添加另外的DCM,所得溶液用硫代硫酸钠水溶液和盐水洗涤。有机层在硫酸钠上干燥。过滤和蒸发溶剂,得到粗物质。产物由硅胶上的色谱分离法进一步提纯。
根据J.Med.Chem.,1996,39,4181-4196的程序,将该起始原料,氯化锂,三苯胂,三丁基乙烯基锡,和三(二苄叉基丙酮)二钯(0)-氯仿加合物在有机溶剂如N-甲基吡咯烷酮中在大约55℃的稍高温度下加热。在反应结束时,混合物冷却至室温,然后倾倒在冰,氟化钾,水和乙酸乙酯的混合物中。继续搅拌1小时。悬浮液经赛力特硅藻土过滤,用乙酸乙酯萃取。合并的有机萃取物用硫酸钠干燥。在真空中除去溶剂和该粗物质进一步用色谱分离法提纯。
将步骤2的产物溶于有机溶剂如苯和乙酸乙酯的混合物中。根据J.Med.Chem.,1996,39,4181-4196的程序,添加三(三苯基膦)铑(I)氯化物,让反应处于氢气氛中。在真空中除去溶剂和该粗反应混合物经由硅胶过滤。由色谱分离法进一步提纯。
将起始原料溶于有机溶剂如DMF中。根据J.Med.Chem.,1996,39,4181-4196的程序,添加碳酸钾和烯丙基溴并在室温下继续搅拌。在全部的起始原料消耗之后,添加
水溶液和二乙醚,收集有机层和在真空中除去溶剂。
将粗物质溶于N,N二乙苯胺中和反应混合物在约180℃的升高温度下加热。在反应结束时,混合物冷却至室温和倾倒在
水溶液(2N)和乙酸乙基酯的混合物中。有机层用
水溶液(2N)洗涤并在硫酸钠上干燥。过滤和除去溶剂,得到粗产物。由色谱分离法进一步提纯。
将步骤2的产物溶于有机溶剂如甲醇,DCM和吡啶的混合物中。将溶液冷却至-78℃,然后将臭氧鼓泡通入到溶液中,直到蓝色存留为止。多余的臭氧用氮气流除去。反应混合物升至室温,添加硫脲。在室温下继续搅拌。反应混合物进行过滤,然后分配在DCM和水之间。该水层用DCM萃取,合并的有机层用
(1N),饱和碳酸氢钠水溶液和盐水洗涤。溶液用硫酸钠干燥。过滤和蒸发溶剂,得到粗醛。由色谱分离法进一步提纯。
根据在Chem.Rev.,1989,89,863-927中评述的程序,将该醛溶于有机溶剂如THF中并与三苯基磷鎓仲丁基溴化物和叔丁醇钾反应。在反应结束时,在真空中除去溶剂和粗物质进一步用色谱分离法提纯。
(A)连接体引入至膦酸酯上
在这里所示的酚类可以任选地用所选择的试剂加以烷基化。任选地,膦酸酯结构部分将是此类试剂的一部分。另外地,它将在后续步骤中通过各种方式引入,在以上描述了其中的三种。例如,烷基卤可以与亚磷酸三乙基酯在溶剂如甲苯中加热(或其它Arbuzov反应条件:参加Engel,R.,“Synthesis of Carbon-phosphorus Bonds”,CRC press,1988)。另外地,环氧化物可以与二烷基亚膦酸酯的阴离子反应。在另一个实例中,该膦酸酯试剂可以是亲电子试剂,例如,乙炔化物阴离子可以与三氯氧化磷缩合,中间体二氯膦酸酯用乙醇淬灭可产生所需膦酸二乙酯。
实施例333
本发明的特定化合物能够如下制备。
[4-(6-乙基-4-羟基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基氧基甲基]-膦酸
这一产物通过使用与这里,例如在实施例292和317中描述的那些方法类似的方法来制备。MS(负模式):369.3[M+-1]。
实施例333A
本发明的特定化合物能够如下制备。
2-{[4-(6-乙基-4-羟基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基氧基甲基]-苯氧基-膦酰基氨基-丙酸乙酯
通过使用与这里,例如在实施例302中描述的那些方法类似的方法,从实施例333开始制备所需产物。MS(正模式):546.3[M++1]& 568.3[M++Na]。
实施例334
本发明的特定化合物能够如下制备:
2-({2-[4-(6-乙基-4-羟基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基胺基]-乙基}-苯氧基-膦酰基氨基)-丙酸乙酯
通过采用与在这里,例如在实施例309和333中描述的那些方法类似的方法,在还原胺化步骤中使用2-[(2-氨基-乙基)-苯氧基-膦酰基氨基]-丙酸乙酯,来制备这一产物。
MS(正模式):559.4[M++1] & 581.3[M++Na]。
实施例335
本发明的特定化合物能够如下制备:
2-((1-乙氧基羰基-乙基氨基)-{2-[4-(6-乙基-4-羟基-7-甲基-3-氧代-1,3-二氢-异苯并呋喃-5-基)-2-甲基-丁-2-烯基胺基]-乙基}-膦酰基氨基)-丙酸乙酯
通过采用与在这里,例如在实施例334中描述的那些方法类似的方法,在还原胺化步骤中使用2-[(2-氨基乙基)-(1-乙氧基羰基-乙基氨基)-膦酰基氨基]-丙酸乙酯,来制备这一产物。MS(正模式):582.4[M++1] & 604.3[M++Na]。
实施例336
(2-{4-[(2,4-二氨基-蝶啶-6-基甲基)-甲基-氨基]-苯甲酰基氨基-甲基)-膦酸二乙酯
向4-[(2,4-二氨基-蝶啶-6-基甲基)-甲基-氨基]-苯甲酸半盐酸盐二水合物(67.0mg,177μmol)在DMF(3.0mL)中的溶液添加氰基膦酸二乙基酯(34.8μL,230μmol)和二异丙基乙胺(Hunig碱,DIEA,30.4μL,177μmol)。溶液在环境温度下搅拌4小时,此时添加(氨基甲基)-膦酸二乙基酯(45.4mg,177μmol)。溶液搅拌另外4小时,之后观察到起始原料的完全消耗。反应通过在真空中除去溶剂和由硅胶色谱分离法使用
(10-30%)提纯残留物来进行后处理。从这一色谱分离步骤中收集的产物具有足够的纯度,可以输送到下一反应。少量的产物(20mg)由RP HPLC在C18柱上通过使用
/乙腈(2-95%)再提纯,得到12.9mg(76%)的纯产物。1H NMR(300MHz,DMSO-d6)δ1.19(t,6H,J=7.2Hz),3.21(s,3H),3.70(m,2H),4.00(q,4H,J=7.2Hz),4.81(s,2H),6.81(d,2H,J=9Hz),7.71(d,2H,J=9Hz),8.40(br s,1H),8.61(s,1H)。31P(121.4MHz,DMSO-d6)δ23.4.MS(m/z)475.2 [M+H]+,597.2[M+Na]+。
实施例337(2-{4-[(2,4-二氨基-蝶啶-6-基甲基)-甲基-氨基]-苯甲酰基氨基-甲基)-膦酸
在环境温度下,向经历硅石柱色谱法之后的粗(2-{4-[(2,4-二氨基-蝶啶-6-基甲基)-甲基-氨基]-苯甲酰基氨基-乙基)-膦酸二乙酯(60mg,126μmol)在干燥DMF(0.90mL)中的溶液添加三甲基甲硅烷基溴化物(溴三甲基硅烷,TMSBr,130.6μL,1,010μmol)。溶液然后在70℃下加热4.0小时,在此之后将反应混合物冷却到室温。溶剂体积在真空中减少至~700μL,然后用
(100μL)稀释。该溶液由RP HPLC在C18柱上使用
/乙腈(2-95%)提纯,得到26.8mg(51%)黄色固体形式的所需化合物。1H NMR(300 MHz,DMSO-d6)δ3.18(s,3H),3.50(m,2H),4.77(s,2H),6.79(d,2H,J=9Hz),7.79(d,2H,J=9Hz),8.07(br s,1H),8.56(s,1H);MS(m/z)419.2[M+H]+。
实施例338(2-{4-[(2,4-二氨基-蝶啶-6-基甲基)-甲基-氨基]-苯甲酰基氨基-乙基)-膦酸二乙酯
向4-[(2,4-二氨基-蝶啶-6-基甲基)-甲基-氨基]-苯甲酸半盐酸盐二水合物(61.2mg,161μmol)在DMF(2.8mL)中的溶液添加氰基膦酸二乙基酯(31.8μL,210μmol)和DIEA(27.8μL,161μmol)。溶液在环境温度下搅拌4小时,此时添加(氨基乙基)膦酸二乙基酯(43.8mg,161μmol)。溶液搅拌另外3小时,之后观察到起始原料的完全消耗。反应通过在真空中除去溶剂和由硅胶色谱分离法使用 (10-30%)提纯残留物来进行后处理。从这一色谱分离步骤中收集的产物具有足够的纯度,可以输送到下一反应。少量的产物(32mg)由RPHPLC在C18柱上通过使用
/乙腈(2-95%)再提纯,得到19mg(70%)的纯产物。1H NMR(300MHz,DMSO-d6)δ1.21(t,6H,J=7Hz),1.95-2.05(m,2H),3.20(s,3H),3.13-3.22(m,2H),3.98(appt septet,4H,J=7Hz),4.79(s,2H),6.80(d,2H,J=9Hz),7.65(d,2H,J=9Hz),8.20(br s,1H),8.60(s,1H)。31P(121.4MHz,DMSO-d6)δ28.9。MS(m/z)489.2[M+H]+,511.2[M+Na]+。
实施例339(2-{4-[(2,4-二氨基-蝶啶-6-基甲基)-甲基-氨基]-苯甲酰基氨基-乙基)-膦酸
在环境温度下,向经历硅石柱色谱法之后的粗(2-{4-[(2,4-二氨基-蝶啶-6-基甲基)-甲基-氨基]-苯甲酰基氨基-乙基)-膦酸二乙酯(61mg,126μmol)在干燥DMF(1.00mL)中的溶液添加TMSBr(129.0μL,999.2μmol)。溶液然后在70℃下加热5.5小时,那之后LCMS分析表明反应已完成90%。反应混合物冷却到室温和搅拌另外12小时。该反应通过在真空中除去溶剂和将残留物溶于DMF/
(800μL,1∶1)和1N
水溶液(15μL)中来进行后处理。该产物由RP HPLC在C18柱上使用
/乙腈(2-95%)提纯,得到29mg(53%)黄色固体形式的所需化合物。1H NMR(300MHz,DMSO-d6)δ1.67-1.85(m,2H),3.19(s,3H),3.25-3.40(m,2H),4.76(s,2H),6.71(br s,2H),5.80(d,2H,J=9Hz),7.64(d,2H,J=9Hz),7.73(br s,2H),8.15(br s,1H),8.56(s,1H)。31P(121.4MHz,DMSO-d6)δ23.0.MS(m/z)431.3[M-H]-。
实施例340
(2-{4-[(2,4-二氨基-蝶啶-6-基甲基)-甲基-氨基]-苯甲酰基氨基-丙基)-膦酸二乙酯
向4-[(2,4-二氨基-蝶啶-6-基甲基)-甲基-氨基]-苯甲酸半盐酸盐二水合物(61.2mg,161μmol)在DMF(2.8mL)中的溶液添加氰基膦酸二乙基酯(31.8μL,210μmol)和DIEA(27.8μL,161μmol)。溶液在环境温度下搅拌3小时,此时添加(氨基丙基)膦酸二乙基酯(34.9mg,122.6μmol)。溶液搅拌另外2小时,之后观察到起始原料的完全消耗。反应通过在真空中除去溶剂和由硅胶色谱分离法使用 (10-30%)提纯残留物来进行后处理。从这一色谱分离步骤中收集的产物(65.5mg)具有足够的纯度,可以输送到下一反应。少量的产物(32.8mg)由RP HPLC在C18柱上通过使用
/乙腈(2-95%)再提纯,得到23.2mg(75%)的纯产物。1H NMR(300MHz,DMSO-d6)δ1.20(t,6H,J=7.2Hz),1.64-1.75(m,4H),3.22(s,3H),3.41(m,2H),3.98(apptseptet,4H,J=7.2Hz),4.85(s,2H),6.79(d,2H,J=9Hz),7.68(d,2H,J=9Hz),8.17(br s,1H),8.70(s,1H);31P(121.4MHz,DMSO-d6)δ31.9;MS(m/z)503.2[M+H]+。
实施例341(2-{4-[(2,4-二氨基-蝶啶-6-基甲基)-甲基-氨基]-苯甲酰基氨基-丙基)-膦酸
在环境温度下,向经历硅石柱色谱法之后的粗(2-{4-[(2,4-二氨基-蝶啶-6-基甲基)-甲基-氨基]-苯甲酰基氨基-丙基)-膦酸二乙酯(32.2mg,66.2μmol)在干燥DMF(0.50mL)中的溶液添加TMSBr(68.0μL,529.6μmol)。溶液然后在70℃下加热1.0小时,那之后LCMS分析表明反应已完成。反应混合物冷却到室温,然后添加水(60μL)和甲醇(60μL)。粗反应混合物由RP HPLC在C18柱上使用
/乙腈(2-95%)提纯,得到11.2mg(38%)黄色固体形式的所需化合物。1HNMR(300MHz,DMSO-d6)δ1.50(m,2H),1.61(m,2H),3.22(s,3H),3.25-3.40(m,2H),4.84(s,2H),6.80(d,2H,J=9Hz),7.69(d,2H,J=9Hz),8.20(br s,1H),8.69(s,1H)。31P(121.4MHz,DMSO-d6)δ26.3.MS(m/z)447.3 [M-H]-。
实施例342
2-[(2-{4-[(2,4-二氨基-蝶啶-6-基甲基)甲基-氨基]苯甲酰基氨基-乙基)苯氧基膦酰基氧基]丙酸乙酯[在磷上的非对映异构混合物]
向4-[(2,4-二氨基-蝶啶-6-基甲基)-甲基-氨基]-苯甲酸半盐酸盐二水合物(60.0mg,158.3μmol)在DMF(2.5mL)中的溶液添加氰基膦酸二乙基酯(31.2μL,205.7μmol)和DIEA(81.8μL,474.9μmol)。溶液在环境温度下搅拌3.5小时,之后将(S)-2-[(2-氨基乙基)苯氧基膦酰基氧基]-丙酸乙酯单乙酸盐(57.1mg,158.3μmol;在磷上的非对映异构体混合物)在DMF(200μL)中的溶液添加进去。溶液搅拌另外1.5小时,之后观察到起始原料的完全消耗。在真空中除去溶剂和该粗物质由硅胶色谱分离法使用
(10-30%)来提纯。少量的产物(24.8mg)由RP HPLC在C18柱上通过使用
/乙腈(2-95%)再提纯,得到15.8mg(65%)的纯产物。1H NMR(300MHz,DMSO-d6)δ1.17-1.27(m,3H),1.32(d,2H,J=7.5Hz),1.42(d,1H,J=7.5Hz)2.27(m,2H),3.19(s,3H),3.53(m,2H),4.08-4.14(m,2H),4.77(s,2H),4.98(m,1H),6.72(br s,1H),6.81(d,2H,J=9Hz),7.21(m,3H),7.36(m,2H),7.66(d,2H,J=9Hz),8.26(br s,1H),8.56(s,1H);31P(121.4MHz,DMSO-d6)δ26.6,27.4。MS(m/z)609.2[M+H]+。
实施例343 2-[(2-{4-[(2,4-二氨基蝶啶-6-基甲基)甲基-氨基]苯甲酰基氨基-乙基)苯氧基膦酰基氧基]-丙酸[在磷上的非对映异构混合物]
向2-[(2-{4-[(2,4-二氨基蝶啶-6-基甲基)甲基-氨基]苯甲酰基氨基}乙基)苯氧基-膦酰基氧基]丙酸乙酯(在磷上非对映异构体的混合物;40.0mg,65.7μmol)在DMF(0.4mL),乙腈(0.2mL)和水(0.2mL)中的溶液添加氢氧化钠水溶液(1N,131.4μL)。溶液在环境温度下搅拌4小时。在真空中除去溶剂,粗产物由RP HPLC在C18柱上使用
/乙腈(2-95%)提纯,得到23.7mg(71.3%)的纯产物。1H NMR(300MHz,DMSO-d6)δ1.30(d,2H,J=6.9Hz),1.79(m,2H),3.21(s,3H),3.37(m,2H),4.61(m,1H),4.81(s,2H),6.79(d,2H,J=8.7Hz),7.64(d,2H,J=9.7Hz),8.25(br s,1H),8.63(s,1H);31P(121.4MHz,DMSO-d6)δ25.1。MS(m/z)505.2[M+H]+。
实施例343A 2-[(2-{4-[(2,4-二氨基蝶啶-6-基甲基)甲基氨基]-苯甲酰基氨基}乙基)苯氧基膦酰基氧基]丙酸乙酯[在磷上非对映异构纯]
向4-[(2,4-二氨基-蝶啶-6-基甲基)-甲基-氨基]-苯甲酸半盐酸盐二水合物(101.9mg,268.9μmol)在DMF(3.3mL)中的溶液添加氰基膦酸二乙基酯(53.0μL,349.5μmol)和DIEA(138.0μL,806.7μmol)。溶液在环境温度下搅拌2.5小时,之后将(S)-2-[(2-氨基乙基)苯氧基膦酰基氧基]-丙酸乙酯单乙酸盐(在磷上非对映异构纯;268.9μmol)在DMF(500μL)中的溶液添加进去。溶液搅拌另外30分钟,之后观察到起始原料的完全消耗。在真空中除去溶剂和该粗物质由硅胶色谱分离法使用
(10-30%)来提纯。少量的产物(40.0mg)由RPHPLC在C18柱上通过使用
/乙腈(2-95%)再提纯,得到28.7mg(75.1%)的纯产物。1H NMR(300MHz,DMSO-d6)δ1.15(t,3H,J=7.2Hz),1.44(d,3H,J=6.9Hz),2.26(m,2H),3.23(s,3H),3.51(m,2H),4.09(q,2H,J=7.2Hz),4.86(s,2H),5.01(m,1H),6.81(d,2H,J=9.3Hz),7.21(m,3H),7.35(m,2H),7.68(d,2H,J=9.3Hz),8.29(br s,1H),8.71(s,1H);31P(121.4MHz,DMSO-d6)δ26.6。MS(m/z)609.2[M+H]+。
实施例344 2-[(2-{4-[(2,4-二氨基蝶啶-6-基甲基)甲基氨基]-苯甲酰基氨基-乙基}-苯氧基膦酰基氨基]丙酸乙酯(在磷上非对映异构体的混合物)
向4-[(2,4-二氨基-蝶啶-6-基甲基)-甲基-氨基]-苯甲酸半盐酸盐二水合物(39.6mg,104.0(mol)在DMF(1.2mL)中的溶液添加氰基膦酸二乙基酯(20.6μL,136.1μmol)和DIEA(36.0μL,209.4μmol)。溶液在环境温度下搅拌3小时,之后将(S)-2-[(2-氨基乙基)苯氧基膦酰基氨基]丙酸乙酯单乙酸盐(在磷上非对映异构体的混合物;104.0μmol)在DMF(200μL)中的溶液添加进去。溶液搅拌另外30分钟,之后观察到起始原料的完全消耗。等分部分(66%)的反应混合物由硅胶色谱分离法使用
(10-30%)提纯,得到27.2mg的粗产物。少量的产物(10mg)由RP HPLC在C18柱上通过使用
/乙腈(2-95%)再提纯,得到4.2mg(26%)的纯产物。1H NMR(300MHz,DMSO-d6)δ1.11(t,3H,J=6.9Hz),1.18(d,3H,J=7.2Hz),2.06-2.17(m,2H),3.20(s,3H),3.51(m,2H),3.88(m,1H),4.02(m,2H),4.79(s,2H),5.61(m,1H),6.80(d,2H,J=9Hz),6.98(br s,1H),7.18(m,3H),7.32(m,2H),7.67(d,2H,J=9Hz),8.20(br s,1H),8.59(s,1H);31P(121.4MHz,DMSO-d6)δ29.5,30.1。MS(m/z)608.2[M+H]+。
实施例345 2-{4-[(2,4-二氨基-蝶啶-6-基甲基)-甲基-氨基]-苯甲酰基氨基-6-(二乙氧基-磷酰基)-己酸
向4-[(2,4-二氨基-蝶啶-6-基甲基)-甲基-氨基]-苯甲酸半盐酸盐二水合物(63.0mg,166.2μmol)在DMF(2.8mL)中的溶液添加氰基膦酸二乙基酯(30.8μL,199.4μmol)和DIEA(85.8μL,498.6μmol)。溶液在环境温度下搅拌3.5小时,之后添加(L)-2-氨基-6-二乙基磷酸根己酸(44.3mg,166.2μmol)。溶液搅拌另外48小时。反应通过在真空中除去溶剂和由硅胶色谱分离法使用
(10-30%)提纯残留物来进行后处理。从这一色谱分离步骤中收集的产物(87mg)具有足够的纯度,可以输送到下一反应。等分部分的产物(51.0mg)由RPHPLC在C18柱上通过使用
/乙腈(2-95%)再提纯,得到24.7mg(44%)的纯产物。1H NMR(300MHz,DMSO-d6)δ1.18(t,6H,J=6.9Hz),1.42(m,4H),1.65(m,4H),3.20(s,3H),3.92(m,4H),4.29(m,1H),4.78(s,2H),6.72(br s,1H),6.81(d,2H,J=9Hz),7.73(d,2H,J=9Hz),8.14(d,1H,J=7.8Hz),8.56(s,1H);31P(121.4MHz,DMSO-d6)δ31.8;MS(m/z)574.3[M]+。
实施例346 2-{4-[(2,4-二氨基蝶啶-6-基甲基)甲基氨基]-苯甲酰基氨基-6-(磷酰基)己酸
在环境温度下,向经历硅石柱色谱法之后的粗(2-{4-[(2,4-二氨基-蝶啶-6-基甲基)-甲基-氨基]-苯甲酰基氨基})-2’(L)-(6’-(膦酸二乙酯)己酸)(20mg,34.6μmol)在干燥DMF(0.60mL)中的溶液添加TMSBr(18.0μL,139.2μmol)。溶液然后在70℃下加热18小时,在此之后将反应混合物冷却到室温。在真空中除去溶剂和溶于DMF(400μL)和水(60μL)中。该溶液由RP HPLC在C18柱上使用
/乙腈(2-95%)提纯,得到8.9mg(49%)黄色固体形式的产物。1H NMR(300 MHz,DMSO-d6)δ1.45(m,6H),1.75(m,2H),3.20(s,3H),4.25(m,1H),4.77(s,2H),6.62(br s,1H),6.80(d,2H,J=8.7Hz),7.73(d,2H,J=8.7Hz),8.14(br s,1H),8.55(s,1H);MS(m/z)519.2[M+H]+。实施例347 2-{4-[(2,4-二氨基-蝶啶-6-基甲基)-甲基-氨基]-苯甲酰基氨基-6’-(单苯基-膦酸酯)己酸
乙基-TMS酯在适宜条件下水解,得到本发明的相应酸。
中间体2-{4-[(2,4-二氨基-蝶啶-6-基甲基)-甲基-氨基]-苯甲酰基氨基-6’-(单苯基-膦酸酯)-己酸TMS乙醇酯能够如下制备。
a.(L)-2-Cbz-胺基-己酸-6-膦酸。
在环境温度下向(L)-2-氨基-6-(二乙氧基膦酰基)己酸(106mg,396.8μmol)在干燥DMF(2.00mL)中的悬浮液添加TMSBr(307.0mL,2,381.0μmol)。溶液然后在70℃下加热2小时,在此之后将反应混合物冷却到室温。在真空中除去溶剂。将粗物质溶于水(0.25mL)和
(1-N,2.50mL)中。添加氯甲酸苄基酯(79.3μL,555.5μmol)并在室温下继续搅拌。在2小时后,溶液用乙醚(2mL)洗涤和水层用
水溶液酸化到pH1。该水层用
萃取(3×5mL)。合并的有机萃取物用硫酸钠干燥。过滤和蒸发溶剂,得到粗产物,它具有足够的纯度可用于进一步的转变。1H NMR(300MHz,DMSO-d6)δ1.42-1.65(m,8H),3.90(m,1H),5.02(s,2H),7.32(s,5H),7.55(m,1H),7.94(s,1H);31P(121.4MHz,DMSO-d6)δ26.5;MS(m/z)345.6[M+H]+。
b.(L)-2--胺基-己酸2’TMS乙基酯-6-膦酸单苯基酯
向(L)-2-Cbz-氨基-己酸-6-膦酸(137.3mg,397.9μmol)在2-TMS乙醇(2.5mL)中的溶液添加乙酰氯(50μL)。在室温下继续搅拌。在22小时之后观察到完全的转化。在真空中除去溶剂。该粗物质具有足够的纯度,可用于下一步。
将粗物质的一半(198.9μmol)在室温下溶于甲苯(3.0mL)中。添加亚硫酰氯(167.2mg,1,416.0μmol),反应混合物在70℃(油浴)下加热。在4小时后,反应冷却至室温和在真空中除去溶剂。将该粗物质再溶于二氯甲烷(2.0mL)中,然后将苯酚(36.6mg,389.0μmol)和DIEA(67.0μL,389.0μmol)在二氯甲烷(1.0mL)中的溶液添加进去。在室温下继续搅拌。在4小时之后,在真空中除去溶剂。
将粗物质溶于四氢呋喃(THF)(3.0mL)中和添加氢氧化钠水溶液(1N,0.885mL)。在室温下继续搅拌。在14小时之后在真空中除去溶剂得到粗膦酸酯单苯酯(63.8mg)。将该物质溶于2-TMS乙醇(1.0mL)和添加乙酰氯(20μL)。在室温下继续搅拌。在22小时后观察到已完全转化成羧酸酯。在真空中除去溶剂。该物质具有足够的纯度,可用于下一步。
将粗物质的一半(75μmol)溶于乙醇(1.5mL)中。添加
/
(5%,20mg),让反应处于氢气氛中。在1.5小时之后添加赛力特硅藻土,该粗反应混合物由赛力特硅藻土过滤。在真空中除去溶剂,粗物质无需进一步提纯就可用于下一步。
c.2-{4-[(2,4-二氨基-蝶啶-6-基甲基)-甲基-氨基]-苯甲酰基氨基-6’-(单苯基-膦酸酯)-己酸TMS乙醇酯
向4-[(2,4-二氨基-蝶啶-6-基甲基)-甲基-氨基]-苯甲酸半盐酸盐二水合物(22.7mg,60.0μmol)在DMF(0.80mL)中的溶液添加氰基膦酸二乙基酯(12.4μL,78.0μmol)和DIEA(31.0μL,180.0μmol)。溶液在环境温度下搅拌1小时,之后将已悬浮在DMF(0.2mL)中的(L)-2-氨基-6-单苯氧基膦酸根己酸2’TMS乙基酯(70.5μmol)添加进去。溶液搅拌另外3.5小时。粗反应混合物用RP HPLC在C18柱上使用
/乙腈(5-95%)提纯,得到19.4mg(46%)的2-{4-[(2,4-二氨基-蝶啶-6-基甲基)-甲基-氨基]-苯甲酰基氨基-6’-(单苯基-膦酸酯)-己酸TMS乙醇酯。1H NMR(300MHz,DMSO-d6)δ0.0(s,9H),0.91(t,2H,J=8.1Hz),1.42-1.53(m,4H),1.67-1.76(m,4H),3.24(s,3H),4.10(t,2H,J=8.1Hz),4.29(m,1H),4.86(s,2H),6.81(d,2H,J=9Hz),7.12(m,3H),7.31(m,2H),7.74(d,2H,J=9Hz),8.14(d,1H,J=7.8Hz),8.71(s,1H);31P(121.4MHz,DMSO-d6)δ26.2;MS(m/z)695.2[M]+。
实施例347A 4-[(2,4-二氨基-蝶啶-6-基甲基)甲基氨基]-苯甲酰基氨基-6’-(单苯基单(S)乙基乳酸酯-膦酸酯)己酸
乙基-TMS酯在适宜条件下水解,得到本发明的相应酸。
中间体2-{4-[(2,4-二氨基-蝶啶-6-基甲基)-甲基-氨基]-苯甲酰基氨基-6’-(单苯基单(S)乙基乳酸酯-膦酸酯)-己酸TMS乙醇酯能够如下制备。
a.2-{4-[(2,4-二氨基-蝶啶-6-基甲基)-甲基-氨基]-苯甲酰基氨基-6’-(单苯基单(S)乙基乳酸酯-膦酸酯)-己酸TMS乙醇酯
向2-{4-[(2,4-二氨基-蝶啶-6-基甲基)-甲基-氨基]-苯甲酰基氨基-6’-(单苯基-膦酸酯)-己酸TMS乙醇酯(14.5mg,20.8μmol,实施例225)在DMF(0.70mL)中的溶液添加PyBOP(32.4mg,62.4μmol),DIEA(21.4mg,166.4μmol)和(S)乙基乳酸酯(19.6mg,166.4μmol)。反应混合物在室温下搅拌1小时。该粗反应混合物由RP HPLC在C18柱上使用
/乙腈(5-95%)提纯,得到13.5mg(81%)的纯产物,为在磷上非对映异构体的混合物(~4∶1)。1H NMR(300MHz,CDCl3)δ0.0(s,9H),1.02(t,2H,J=8.7Hz),1.23(t,3H,J=9.3Hz),1.35(d,2.4H,J=6.6Hz),1.42-1.53(m,4.6H),1.67-1.86(m,4H),3.14(s,3H),4.03-4.27(m,4H),4.71(br s,3H),4.98(m,0.8H),5.10(m,0.2H),6.57(d,2H,J=7.5Hz),7.00(m,1H),7.16(m,3H),7.30(m,2H),7.63(d,2H,J=7.5Hz),8.43(s,1H);31P(121.4MHz,DMSO-d6)δ30.5,29.2;MS(m/z)795.2[M]+。
实施例348
举例来说但没有限制意义,本发明的实例在下面以表格形式列举(表100)。这些实例具有通式“MBF”:
MBF的各实例被描述为取代的核(Sc)。Sc描述在这里的通式1-151中,其中A0是Sc连接到Lg上的共价连接点,以及描述在下面的表1.1到1.5中。对于描述在表100中的那些实例,Sc是由数字表示的核和各取代基按照字母或数字的顺序来标明。表1.1到1.5是用于形成表100的实例的核的列表。各核(Sc)从表1.1到1.5都给出了数字标号,并且这一数字标号首先出现在各实例名称中。类似地,表10.1到10.19和表20.1到20.36再次分别以字母或数字标号列出了所选择的连接基团(Lg)和前体药物(Pd1和Pd2)取代基。因此,通式MBF的化合物包括具有以这里的通式1-151为基础的Sc基团的化合物以及根据下面表100的化合物。在所有情况下,通式MBF的化合物具有列于下列各表中的基团Lg,Pd1和Pd2。
因此,表100的每一命名的实例是由标明来自表1.1-1.5中的核的数字来表述,后面跟有标明来自表10.1-10.19中的连接基团(Lg)的字母,和两个数字标明来自表20.1-20.36中的两种前体药物基团(Pd1和Pd2)。在图示的表格形式中,表100的各实例表示为具有以下句法的名称:
Sc.Lg.Pd1.Pd2
各Sc基团显示具有tilda(“~”)。tilda是Sc共价连接到Lg的点。应该理解,连接基团(Lg)的Q1和Q2不表示基团或原子,但只不过是连接标识而已。Q1是共价键连接到核(Sc)上的位点和Q2是共价键连接到通式MBF的磷原子上的位点。各前体药物基团(Pd1和Pd2)在tilda符号(“~”)处以共价键方式连接到MBF的磷原子上。表10.1-10.19和20.1-20.36的一些实例可以标识为字母和数字(表10.1-10.19)或数字和字母(表20.1-20.36)的结合。例如有BJ1和BJ2的表10条目。在任何情况下,表10.1-10.19的条目总是以字母开始和表20.1-20.36的条目总是以数字开始。当核(Sc)显示被圈在方括号(“[]”)内和共价键延伸到方括号之外时,Sc共价连接到Lg上的点可以是在SC上的任何可取代的位点上。在这里描述连结点的选择。举例来说但没有限制意义,该连结点选自在反应历程和实施例中描述的那些。
表1.1
表1.2
表1.3
表1.4
表1.5
VI.表10.1
表10.2
表10.3
表10.4
表10.5
表10.6
表10.7
表10.8
表10.9
表10.10
表10.11
表10.12
表10.13
表10.14
表10.15
表10.16
表10.17
表10.18
表10.19
VII.表20.1
表20.2
表20.3
表20.4
表20.5
表20.6
表20.7
表20.8
表20.9
表20.10
表20.11
表20.12
表20.13
表20.14
表20.15
表20.16
表20.17
表20.18
表20.19
VIII.表20.20
IX.表20.21
X.表20.22
XI.表20.23
XII.表20.24
XIII.表20.25
XIV.表20.26
XV.表20.27
XVI.表20.28
XVII.表20.29
XVIII.表20.30
XIX.表20.31
XX.表20.32
XXI.表20.33
XXII.表20.34
XXIII.表20.35
XXIV.表20.36
表20.37
表100
1.B的前体药物
1.B.228.228; | 1.B.228.229; | 1.B.228.230; | 1.B.228.231; |
1.B.228.236; | 1.B.228.237; | 1.B.228.238; | 1.B.228.239; |
1.B.228.154; | 1.B.228.157; | 1.B.228.166; | 1.B.228.169; |
1.B.228.172; | 1.B.228.175; | 1.B.228.240; | 1.B.228.244; |
1.B.229.228; | 1.B.229.229; | 1.B.229.230; | 1.B.229.231; |
1.B.229.236; | 1.B.229.237; | 1.B.229.238; | 1.B.229.239; |
1.B.229.154; | 1.B.229.157; | 1.B.229.166; | 1.B.229.169; |
1.B.229.172; | 1.B.229.175; | 1.B.229.240; | 1.B.229.244; |
1.B.230.228; | 1.B.230.229; | 1.B.230.230; | 1.B.230.231; |
1.B.230.236; | 1.B.230.237; | 1.B.230.238; | 1.B.230.239; |
1.B.230.154; | 1.B.230.157; | 1.B.230.166; | 1.B.230.169; |
1.B.230.172; | 1.B.230.175; | 1.B.230.240; | 1.B.230.244; |
1.B.231.228; | 1.B.231.229; | 1.B.231.230; | 1.B.231.231; |
1.B.231.236; | 1.B.231.237; | 1.B.231.238; | 1.B.231.239; |
1.B.231.154; | 1.B.231.157; | 1.B.231.166; | 1.B.231.169; |
1.B.231.172; | 1.B.231.175; | 1.B.231.240; | 1.B.231.244; |
1.B.236.228; | 1.B.236.229; | 1.B.236.230; | 1.B.236.231; |
1.B.236.236; | 1.B.236.237; | 1.B.236.238; | 1.B.236.239; |
1.B.236.154; | 1.B.236.157; | 1.B.236.166; | 1.B.236.169; |
1.B.236.172; | 1.B.236.175; | 1.B.236.240; | 1.B.236.244; |
1.B.237.228; | 1.B.237.229; | 1.B.237.230; | 1.B.237.231; |
1.B.237.236; | 1.B.237.237; | 1.B.237.238; | 1.B.237.239; |
1.B.237.154; | 1.B.237.157; | 1.B.237.166; | 1.B.237.169; |
1.B.237.172; | 1.B.237.175; | 1.B.237.240; | 1.B.237.244; |
1.B.238.228; | 1.B.238.229; | 1.B.238.230; | 1.B.238.231; |
1.B.238.236; | 1.B.238.237; | 1.B.238.238; | 1.B.238.239; |
1.B.238.154; | 1.B.238.157; | 1.B.238.166; | 1.B.238.169; |
1.B.238.172; | 1.B.238.175; | 1.B.238.240; | 1.B.238.244; |
1.B.239.228; | 1.B.239.229; | 1.B.239.230; | 1.B.239.231; |
1.B.239.236; | 1.B.239.237; | 1.B.239.238; | 1.B.239.239; |
1.B.239.154; | 1.B.239.157; | 1.B.239.166; | 1.B.239.169; |
1.B.239.172; | 1.B.239.175; | 1.B.239.240; | 1.B.239.244; |
1.B.154.228; | 1.B.154.229; | 1.B.154.230; | 1.B.154.231; |
1.B.154.236; | 1.B.154.237; | 1.B.154.238; | 1.B.154.239; |
1.B.154.154; | 1.B.154.157; | 1.B.154.166; | 1.B.154.169; |
1.B.154.172; | 1.B.154.175; | 1.B.154.240; | 1.B.154.244; |
1.B.157.228; | 1.B.157.229; | 1.B.157.230; | 1.B.157.231; |
1.B.157.236; | 1.B.157.237; | 1.B.157.238; | 1.B.157.239; |
1.B.157.154; | 1.B.157.157; | 1.B.157.166; | 1.B.157.169; |
1.B.157.172; | 1.B.157.175; | 1.B.157.240; | 1.B.157.244; |
1.B.166.228; | 1.B.166.229; | 1.B.166.230; | 1.B.166.231; |
1.B.166.236; | 1.B.166.237; | 1.B.166.238; | 1.B.166.239; |
1.B.166.154; | 1.B.166.157; | 1.B.166.166; | 1.B.166.169; |
1.B.166.172; | 1.B.166.175; | 1.B.166.240; | 1.B.166.244; |
1.B.169.228; | 1.B.169.229; | 1.B.169.230; | 1.B.169.231; |
1.B.169.236; | 1.B.169.237; | 1.B.169.238; | 1.B.169.239; |
1.B.169.154; | 1.B.169.157; | 1.B.169.166; | 1.B.169.169; |
1.B.169.172; | 1.B.169.175; | 1.B.169.240; | 1.B.169.244; |
1.B.172.228; | 1.B.172.229; | 1.B.172.230; | 1.B.172.231; |
1.B.172.236; | 1.B.172.237; | 1.B.172.238; | 1.B.172.239; |
1.B.172.154; | 1.B.172.157; | 1.B.172.166; | 1.B.172.169; |
1.B.172.172; | 1.B.172.175; | 1.B.172.240; | 1.B.172.244; |
1.B.175.228; | 1.B.175.229; | 1.B.175.230; | 1.B.175.231; |
1.B.175.236; | 1.B.175.237; | 1.B.175.238; | 1.B.175.239; |
1.B.175.154; | 1.B.175.157; | 1.B.175.166; | 1.B.175.169; |
1.B.175.172; | 1.B.175.175; | 1.B.175.240; | 1.B.175.244; |
1.B.240.228; | 1.B.240.229; | 1.B.240.230; | 1.B.240.231; |
1.B.240.236; | 1.B.240.237; | 1.B.240.238; | 1.B.240.239; |
1.B.240.154; | 1.B.240.157; | 1.B.240.166; | 1.B.240.169; |
1.B.240.172; | 1.B.240.175; | 1.B.240.240; | 1.B.240.244; |
1.B.244.228; | 1.B.244.229; | 1.B.244.230; | 1.B.244.231; |
1.B.244.236; | 1.B.244.237; | 1.B.244.238; | 1.B.244.239; |
1.B.244.154; | 1.B.244.157; | 1.B.244.166; | 1.B.244.169; |
1.B.244.172; | 1.B.244.175; | 1.B.244.240; | 1.B.244.244; |
1.D的前体药物
1.D.228.288; | 1.D.228.229; | 1.D.228.230; | 1.D.228.231; |
1.D.228.236; | 1.D.228.237; | 1.D.228.238; | 1.D.228.239; |
1.D.228.154; | 1.D.228.157; | 1.D.228.166; | 1.D.228.169; |
1.D.228.172; | 1.D.228.175; | 1.D.228.240; | 1.D.228.244; |
1.D.229.228; | 1.D.229.229; | 1.D.229.230; | 1.D.229.231; |
1.D.229.236; | 1.D.229.237; | 1.D.229.238; | 1.D.229.239; |
1.D.229.154; | 1.D.229.157; | 1.D.229.166; | 1.D.229.169; |
1.D.229.172; | 1.D.229.175; | 1.D.229.240; | 1.D.229.244; |
1.D.230.228; | 1.D.230.229; | 1.D.230.230; | 1.D.230.231; |
1.D.230.236; | 1.D.230.237; | 1.D.230.238; | 1.D.230.239; |
1.D.230.154; | 1.D.230.157; | 1.D.230.166; | 1.D.230.169; |
1.D.230.172; | 1.D.230.175; | 1.D.230.240; | 1.D.230.244; |
1.D.231.228; | 1.D.231.229; | 1.D.231.230; | 1.D.231.231; |
1.D.231.236; | 1.D.231.237; | 1.D.231.238; | 1.D.231.239; |
1.D.231.154; | 1.D.231.157; | 1.D.231.166; | 1.D.231.169; |
1.D.231.172; | 1.D.231.175; | 1.D.231.240; | 1.D.231.244; |
1.D.236.228; | 1.D.236.229; | 1.D.236.230; | 1.D.236.231; |
1.D.236.236; | 1.D.236.237; | 1.D.236.238; | 1.D.236.239; |
1.D.236.154; | 1.D.236.157; | 1.D.236.166; | 1.D.236.169; |
1.D.236.172; | 1.D.236.175; | 1.D.236.240; | 1.D.236.244; |
1.D.237.228; | 1.D.237.229; | 1.D.237.230; | 1.D.237.231; |
1.D.237.236; | 1.D.237.237; | 1.D.237.238; | 1.D.237.239; |
1.D.237.154; | 1.D.237.157; | 1.D.237.166; | 1.D.237.169; |
1.D.237.172; | 1.D.237.175; | 1.D.237.240; | 1.D.237.244; |
1.D.238.228; | 1.D.238.229; | 1.D.238.230; | 1.D.238.231; |
1.D.238.236; | 1.D.238.237; | 1.D.238.238; | 1.D.238.239; |
1.D.238.154; | 1.D.238.157; | 1.D.238.166; | 1.D.238.169; |
1.D.238.172; | 1.D.238.175; | 1.D.238.240; | 1.D.238.244; |
1.D.239.228; | 1.D.239.229; | 1.D.239.230; | 1.D.239.231; |
1.D.239.236; | 1.D.239.237; | 1.D.239.238; | 1.D.239.239; |
1.D.239.154; | 1.D.239.157; | 1.D.239.166; | 1.D.239.169; |
1.D.239.172; | 1.D.239.175; | 1.D.239.240; | 1.D.239.244; |
1.D.154.228; | 1.D.154.229; | 1.D.154.230; | 1.D.154.231; |
1.D.154.236; | 1.D.154.237; | 1.D.154.238; | 1.D.154.239; |
1.D.154.154; | 1.D.154.157; | 1.D.154.166; | 1.D.154.169; |
1.D.154.172; | 1.D.154.175; | 1.D.154.240; | 1.D.154.244; |
1.D.157.228; | 1.D.157.229; | 1.D.157.230; | 1.D.157.231; |
1.D.157.236; | 1.D.157.237; | 1.D.157.238; | 1.D.157.239; |
1.D.157.154; | 1.D.157.157; | 1.D.157.166; | 1.D.157.169; |
1.D.157.172; | 1.D.157.175; | 1.D.157.240; | 1.D.157.244; |
1.D.166.228; | 1.D.166.229; | 1.D.166.230; | 1.D.166.231; |
1.D.166.236; | 1.D.166.237; | 1.D.166.238; | 1.D.166.239; |
1.D.166.154; | 1.D.166.157; | 1.D.166.166; | 1.D.166.169; |
1.D.166.172; | 1.D.166.175; | 1.D.166.240; | 1.D.166.244; |
1.D.169.228; | 1.D.169.229; | 1.D.169.230; | 1.D.169.231; |
1.D.169.236; | 1.D.169.237; | 1.D.169.238; | 1.D.169.239; |
1.D.169.154; | 1.D.169.157; | 1.D.169.166; | 1.D.169.169; |
1.D.169.172; | 1.D.169.175; | 1.D.169.240; | 1.D.169.244; |
1.D.172.228; | 1.D.172.229; | 1.D.172.230; | 1.D.172.231; |
1.D.172.236; | 1.D.172.237; | 1.D.172.238; | 1.D.172.239; |
1.D.172.154; | 1.D.172.157; | 1.D.172.166; | 1.D.172.169; |
1.D.172.172; | 1.D.172.175; | 1.D.172.240; | 1.D.172.244; |
1.D.175.228; | 1.D.175.229; | 1.D.175.230; | 1.D.175.231; |
1.D.175.236; | 1.D.175.237; | 1.D.175.238; | 1.D.175.239; |
1.D.175.154; | 1.D.175.157; | 1.D.175.166; | 1.D.175.169; |
1.D.175.172; | 1.D.175.175; | 1.D.175.240; | 1.D.175.244; |
1.D.240.228; | 1.D.240.229; | 1.D.240.230; | 1.D.240.231; |
1.D.240.236; | 1.D.240.237; | 1.D.240.238; | 1.D.240.239; |
1.D.240.154; | 1.D.240.157; | 1.D.240.166; | 1.D.240.169; |
1.D.240.172; | 1.D.240.175; | 1.D.240.240; | 1.D.240.244; |
1.D.244.228; | 1.D.244.229; | 1.D.244.230; | 1.D.244.231; |
1.D.244.236; | 1.D.244.237; | 1.D.244.238; | 1.D.244.239; |
1.D.244.154; | 1.D.244.157; | 1.D.244.166; | 1.D.244.169; |
1.D.244.172; | 1.D.244.175; | 1.D.244.240; | 1.D.244.244; |
1.E的前体药物
1.E.228.228; | 1.E.228.229; | 1.E.228.230; | 1.E.228.231; |
1.E.228.236; | 1.E.228.237; | 1.E.228.238; | 1.E.228.239; |
1.E.228.154; | 1.E.228.157; | 1.E.228.166; | 1.E.228.169; |
1.E.228.172; | 1.E.228.175; | 1.E.228.240; | 1.E.228.244; |
1.E.229.228; | 1.E.229.229; | 1.E.229.230; | 1.E.229.231; |
1.E.229.236; | 1.E.229.237; | 1.E.229.238; | 1.E.229.239; |
1.E.229.154; | 1.E.229.157; | 1.E.229.166; | 1.E.229.169; |
1.E.229.172; | 1.E.229.175; | 1.E.229.240; | 1.E.229.244; |
1.E.230.228; | 1.E.230.229; | 1.E.230.230; | 1.E.230.231; |
1.E.230.236; | 1.E.230.237; | 1.E.230.238; | 1.E.230.239; |
1.E.230.154; | 1.E.230.157; | 1.E.230.166; | 1.E.230.169; |
1.E.230.172; | 1.E.230.175; | 1.E.230.240; | 1.E.230.244; |
1.E.231.228; | 1.E.231.229; | 1.E.231.230; | 1.E.231.231; |
1.E.231.236; | 1.E.231.237; | 1.E.231.238; | 1.E.231.239; |
1.E.231.154; | 1.E.231.157; | 1.E.231.166; | 1.E.231.169; |
1.E.231.172; | 1.E.231.175; | 1.E.231.240; | 1.E.231.244; |
1.E.236.228; | 1.E.236.229; | 1.E.236.230; | 1.E.236.231; |
1.E.236.236; | 1.E.236.237; | 1.E.236.238; | 1.E.236.239; |
1.E.236.154; | 1.E.236.157; | 1.E.236.166; | 1.E.236.169; |
1.E.236.172; | 1.E.236.175; | 1.E.236.240; | 1.E.236.244; |
1.E.237.228; | 1.E.237.229; | 1.E.237.230; | 1.E.237.231; |
1.E.237.236; | 1.E.237.237; | 1.E.237.238; | 1.E.237.239; |
1.E.237.154; | 1.E.237.157; | 1.E.237.166; | 1.E.237.169; |
1.E.237.172; | 1.E.237.175; | 1.E.237.240; | 1.E.237.244; |
1.E.238.228; | 1.E.238.229; | 1.E.238.230; | 1.E.238.231; |
1.E.238.236; | 1.E.238.237; | 1.E.238.238; | 1.E.238.239; |
1.E.238.154; | 1.E.238.157; | 1.E.238.166; | 1.E.238.169; |
1.E.238.172; | 1.E.238.175; | 1.E.238.240; | 1.E.238.244; |
1.E.239.228; | 1.E.239.229; | 1.E.239.230; | 1.E.239.231; |
1.E.239.236; | 1.E.239.237; | 1.E.239.238; | 1.E.239.239; |
1.E.239.154; | 1.E.239.157; | 1.E.239.166; | 1.E.239.169; |
1.E.239.172; | 1.E.239.175; | 1.E.239.240; | 1.E.239.244; |
1.E.154.228; | 1.E.154.229; | 1.E.154.230; | 1.E.154.231; |
1.E.154.236; | 1.E.154.237; | 1.E.154.238; | 1.E.154.239; |
1.E.154.154; | 1.E.154.157; | 1.E.154.166; | 1.E.154.169; |
1.E.154.172; | 1.E.154.175; | 1.E.154.240; | 1.E.154.244; |
1.E.157.228; | 1.E.157.229; | 1.E.157.230; | 1.E.157.231; |
1.E.157.236; | 1.E.157.237; | 1.E.157.238; | 1.E.157.239; |
1.E.157.154; | 1.E.157.157; | 1.E.157.166; | 1.E.157.169; |
1.E.157.172; | 1.E.157.175; | 1.E.157.240; | 1.E.157.244; |
1.E.166.228; | 1.E.166.229; | 1.E.166.230; | 1.E.166.231; |
1.E.166.236; | 1.E.166.237; | 1.E.166.238; | 1.E.166.239; |
1.E.166.154; | 1.E.166.157; | 1.E.166.166; | 1.E.166.169; |
1.E.166.172; | 1.E.166.175; | 1.E.166.240; | 1.E.166.244; |
1.E.169.228; | 1.E.169.229; | 1.E.169.230; | 1.E.169.231; |
1.E.169.236; | 1.E.169.237; | 1.E.169.238; | 1.E.169.239; |
1.E.169.154; | 1.E.169.157; | 1.E.169.166; | 1.E.169.169; |
1.E.169.172; | 1.E.169.175; | 1.E.169.240; | 1.E.169.244; |
1.E.172.228; | 1.E.172.229; | 1.E.172.230; | 1.E.172.231; |
1.E.172.236; | 1.E.172.237; | 1.E.172.238; | 1.E.172.239; |
1.E.172.154; | 1.E.172.157; | 1.E.172.166; | 1.E.172.169; |
1.E.172.172; | 1.E.172.175; | 1.E.172.240; | 1.E.172.244; |
1.E.175.228; | 1.E.175.229; | 1.E.175.230; | 1.E.175.231; |
1.E.175.236; | 1.E.175.237; | 1.E.175.238; | 1.E.175.239; |
1.E.175.154; | 1.E.175.157; | 1.E.175.166; | 1.E.175.169; |
1.E.175.172; | 1.E.175.175; | 1.E.175.240; | 1.E.175.244; |
1.E.240.228; | 1.E.240.229; | 1.E.240.230; | 1.E.240.231; |
1.E.240.236; | 1.E.240.237; | 1.E.240.238; | 1.E.240.239; |
1.E.240.154; | 1.E.240.157; | 1.E.240.166; | 1.E.240.169; |
1.E.240.172; | 1.E.240.175; | 1.E.240.240; | 1.E.240.244; |
1.E.244.228; | 1.E.244.229; | 1.E.244.230; | 1.E.244.231; |
1.E.244.236; | 1.E.244.237; | 1.E.244.238; | 1.E.244.239; |
1.E.244.154; | 1.E.244.157; | 1.E.244.166; | 1.E.244.169; |
1.E.244.172; | 1.E.244.175; | 1.E.244.240; | 1.E.244.244; |
1.G的前体药物
1.G.228.228; | 1.G.228.229; | 1.G.228.230; | 1.G.228.231; |
1.G.228.236; | 1.G.228.237; | 1.G.228.238; | 1.G.228.239; |
1.G.228.154; | 1.G.228.157; | 1.G.228.166; | 1.G.228.169; |
1.G.228.172; | 1.G.228.175; | 1.G.228.240; | 1.G.228.244; |
1.G.229.228; | 1.G.229.229; | 1.G.229.230; | 1.G.229.231; |
1.G.229.236; | 1.G.229.237; | 1.G.229.238; | 1.G.229.239; |
1.G.229.154; | 1.G.229.157; | 1.G.229.166; | 1.G.229.169; |
1.G.229.172; | 1.G.229.175; | 1.G.229.240; | 1.G.229.244; |
1.G.230.228; | 1.G.230.229; | 1.G.230.230; | 1.G.230.231; |
1.G.230.236; | 1.G.230.237; | 1.G.230.238; | 1.G.230.239; |
1.G.230.154; | 1.G.230.157; | 1.G.230.166; | 1.G.230.169; |
1.G.230.172; | 1.G.230.175; | 1.G.230.240; | 1.G.230.244; |
1.G.231.228; | 1.G.231.229; | 1.G.231.230; | 1.G.231.231; |
1.G.231.236; | 1.G.231.237; | 1.G.231.238; | 1.G.231.239; |
1.G.231.154; | 1.G.231.157; | 1.G.231.166; | 1.G.231.169; |
1.G.231.172; | 1.G.231.175; | 1.G.231.240; | 1.G.231.244; |
1.G.236.228; | 1.G.236.229; | 1.G.236.230; | 1.G.236.231; |
1.G.236.236; | 1.G.236.237; | 1.G.236.238; | 1.G.236.239; |
1.G.236.154; | 1.G.236.157; | 1.G.236.166; | 1.G.236.169; |
1.G.236.172; | 1.G.236.175; | 1.G.236.240; | 1.G.236.244; |
1.G.237.228; | 1.G.237.229; | 1.G.237.230; | 1.G.237.231; |
1.G.237.236; | 1.G.237.237; | 1.G.237.238; | 1.G.237.239; |
1.G.237.154; | 1.G.237.157; | 1.G.237.166; | 1.G.237.169; |
1.G.237.172; | 1.G.237.175; | 1.G.237.240; | 1.G.237.244; |
1.G.238.228; | 1.G.238.229; | 1.G.238.230; | 1.G.238.231; |
1.G.238.236; | 1.G.238.237; | 1.G.238.238; | 1.G.238.239; |
1.G.238.154; | 1.G.238.157; | 1.G.238.166; | 1.G.238.169; |
1.G.238.172; | 1.G.238.175; | 1.G.238.240; | 1.G.238.244; |
1.G.239.228; | 1.G.239.229; | 1.G.239.230; | 1.G.239.231; |
1.G.239.236; | 1.G.239.237; | 1.G.239.238; | 1.G.239.239; |
1.G.239.154; | 1.G.239.157; | 1.G.239.166; | 1.G.239.169; |
1.G.239.172; | 1.G.239.175; | 1.G.239.240; | 1.G.239.244; |
1.G.154.228; | 1.G.154.229; | 1.G.154.230; | 1.G.154.231; |
1.G.154.236; | 1.G.154.237; | 1.G.154.238; | 1.G.154.239; |
1.G.154.154; | 1.G.154.157; | 1.G.154.166; | 1.G.154.169; |
1.G.154.172; | 1.G.154.175; | 1.G.154.240; | 1.G.154.244; |
1.G.157.228; | 1.G.157.229; | 1.G.157.230; | 1.G.157.231; |
1.G.157.236; | 1.G.157.237; | 1.G.157.238; | 1.G.157.239; |
1.G.157.154; | 1.G.157.157; | 1.G.157.166; | 1.G.157.169; |
1.G.157.172; | 1.G.157.175; | 1.G.157.240; | 1.G.157.244; |
1.G.166.228; | 1.G.166.229; | 1.G.166.230; | 1.G.166.231; |
1.G.166.236; | 1.G.166.237; | 1.G.166.238; | 1.G.166.239; |
1.G.166.154; | 1.G.166.157; | 1.G.166.166; | 1.G.166.169; |
1.G.166.172; | 1.G.166.175; | 1.G.166.240; | 1.G.166.244; |
1.G.169.228; | 1.G.169.229; | 1.G.169.230; | 1.G.169.231; |
1.G.169.236; | 1.G.169.237; | 1.G.169.238; | 1.G.169.239; |
1.G.169.154; | 1.G.169.157; | 1.G.169.166; | 1.G.169.169; |
1.G.169.172; | 1.G.169.175; | 1.G.169.240; | 1.G.169.244; |
1.G.172.228; | 1.G.172.229; | 1.G.172.230; | 1.G.172.231; |
1.G.172.236; | 1.G.172.237; | 1.G.172.238; | 1.G.172.239; |
1.G.172.154; | 1.G.172.157; | 1.G.172.166; | 1.G.172.169; |
1.G.172.172; | 1.G.172.175; | 1.G.172.240; | 1.G.172.244; |
1.G.175.228; | 1.G.175.229; | 1.G.175.230; | 1.G.175.231; |
1.G.175.236; | 1.G.175.237; | 1.G.175.238; | 1.G.175.239; |
1.G.175.154; | 1.G.175.157; | 1.G.175.166; | 1.G.175.169; |
1.G.175.172; | 1.G.175.175; | 1.G.175.240; | 1.G.175.244; |
1.G.240.228; | 1.G.240.229; | 1.G.240.230; | 1.G.240.231; |
1.G.240.236; | 1.G.240.237; | 1.G.240.238; | 1.G.240.239; |
1.G.240.154; | 1.G.240.157; | 1.G.240.166; | 1.G.240.169; |
1.G.240.172; | 1.G.240.175; | 1.G.240.240; | 1.G.240.244; |
1.G.244.228; | 1.G.244.229; | 1.G.244.230; | 1.G.244.231; |
1.G.244.236; | 1.G.244.237; | 1.G.244.238; | 1.G.244.239; |
1.G.244.154; | 1.G.244.157; | 1.G.244.166; | 1.G.244.169; |
1.G.244.172; | 1.G.244.175; | 1.G.244.240; | 1.G.244.244; |
1.I的前体药物
1.I.228.228 | 1.I.228.229; | 1.I.228.230; | 1.I.228.231; |
1.I.228.236; | 1.I.228.237; | 1.I.228.238; | 1.I.228.239; |
1.I.228.154; | 1.I.228.157; | 1.I.228.166; | 1.I.228.169; |
1.I.228.172; | 1.I.228.175; | 1.I.228.240; | 1.I.228.244; |
1.I.229.228; | 1.I.229.229; | 1.I.229.230; | 1.I.229.231; |
1.I.229.236; | 1.I.229.237; | 1.I.229.238; | 1.I.229.239; |
1.I.229.154; | 1.I.229.157; | 1.I.229.166; | 1.I.229.169; |
1.I.229.172; | 1.I.229.175; | 1.I.229.240; | 1.I.229.244; |
1.I.230.228; | 1.I.230.229; | 1.I.230.230; | 1.I.230.231; |
1.I.230.236; | 1.I.230.237; | 1.I.230.238; | 1.I.230.239; |
1.I.230.154; | 1.I.230.157; | 1.I.230.166; | 1.I.230.169; |
1.I.230.172; | 1.I.230.175; | 1.I.230.240; | 1.I.230.244; |
1.I.231.228; | 1.I.231.229; | 1.I.231.230; | 1.I.231.231; |
1.I.231.236; | 1.I.231.237; | 1.I.231.238; | 1.I.231.239; |
1.I.231.154; | 1.I.231.157; | 1.I.231.166; | 1.I.231.169; |
1.I.231.172; | 1.I.231.175; | 1.I.231.240; | 1.I.231.244; |
1.I.236.228; | 1.I.236.229; | 1.I.236.230; | 1.I.236.231; |
1.I.236.236; | 1.I.236.237; | 1.I.236.238; | 1.I.236.239; |
1.I.236.154; | 1.I.236.157; | 1.I.236.166; | 1.I.236.169; |
1.I.236.172; | 1.I.236.175; | 1.I.236.240; | 1.I.236.244; |
1.I.237.228; | 1.I.237.229; | 1.I.237.230; | 1.I.237.231; |
1.I.237.236; | 1.I.237.237; | 1.I.237.238; | 1.I.237.239; |
1.I.237.154; | 1.I.237.157; | 1.I.237.166; | 1.I.237.169; |
1.I.237.172; | 1.I.237.175; | 1.I.237.240; | 1.I.237.244; |
1.I.238.228; | 1.I.238.229; | 1.I.238.230; | 1.I.238.231; |
1.I.238.236; | 1.I.238.237; | 1.I.238.238; | 1.I.238.239; |
1.I.238.154; | 1.I.238.157; | 1.I.238.166; | 1.I.238.169; |
1.I.238.172; | 1.I.238.175; | 1.I.238.240; | 1.I.238.244; |
1.I.239.228; | 1.I.239.229; | 1.I.239.230; | 1.I.239.231; |
1.I.239.236; | 1.I.239.237; | 1.I.239.238; | 1.I.239.239; |
1.I.239.154; | 1.I.239.157; | 1.I.239.166; | 1.I.239.169; |
1.I.239.172; | 1.I.239.175; | 1.I.239.240; | 1.I.239.244; |
1.I.154.228; | 1.I.154.229; | 1.I.154.230; | 1.I.154.231; |
1.I.154.236; | 1.I.154.237; | 1.I.154.238; | 1.I.154.239; |
1.I.154.154; | 1.I.154.157; | 1.I.154.166; | 1.I.154.169; |
1.I.154.172; | 1.I.154.175; | 1.I.154.240; | 1.I.154.244; |
1.I.157.228; | 1.I.157.229; | 1.I.157.230; | 1.I.157.231; |
1.I.157.236; | 1.I.157.237; | 1.I.157.238; | 1.I.157.239; |
1.I.157.154; | 1.I.157.157; | 1.I.157.166; | 1.I.157.169; |
1.I.157.172; | 1.I.157.175; | 1.I.157.240; | 1.I.157.244; |
1.I.166.228; | 1.I.166.229; | 1.I.166.230; | 1.I.166.231; |
1.I.166.236; | 1.I.166.237; | 1.I.166.238; | 1.I.166.239; |
1.I.166.154; | 1.I.166.157; | 1.I.166.166; | 1.I.166.169; |
1.I.166.172; | 1.I.166.175; | 1.I.166.240; | 1.I.166.244; |
1.I.169.228; | 1.I.169.229; | 1.I.169.230; | 1.I.169.231; |
1.I.169.236; | 1.I.169.237; | 1.I.169.238; | 1.I.169.239; |
1.I.169.154; | 1.I.169.157; | 1.I.169.166; | 1.I.169.169; |
1.I.169.172; | 1.I.169.175; | 1.I.169.240; | 1.I.169.244; |
1.I.172.228; | 1.I.172.229; | 1.I.172.230; | 1.I.172.231; |
1.I.172.236; | 1.I.172.237; | 1.I.172.238; | 1.I.172.239; |
1.I.172.154; | 1.I.172.157; | 1.I.172.166; | 1.I.172.169; |
1.I.172.172; | 1.I.172.175; | 1.I.172.240; | 1.I.172.244; |
1.I.175.228; | 1.I.175.229; | 1.I.175.230; | 1.I.175.231; |
1.I.175.236; | 1.I.175.237; | 1.I.175.238; | 1.I.175.239; |
1.I.175.154; | 1.I.175.157; | 1.I.175.166; | 1.I.175.169; |
1.I.175.172; | 1.I.175.175; | 1.I.175.240; | 1.I.175.244; |
1.I.240.228; | 1.I.240.229; | 1.I.240.230; | 1.I.240.231; |
1.I.240.236; | 1.I.240.237; | 1.I.240.238; | 1.I.240.239; |
1.I.240.154; | 1.I.240.157; | 1.I.240.166; | 1.I.240.169; |
1.I.240.172; | 1.I.240.175; | 1.I.240.240; | 1.I.240.244; |
1.I.244.228; | 1.I.244.229; | 1.I.244.230; | 1.I.244.231; |
1.I.244.236; | 1.I.244.237; | 1.I.244.238; | 1.I.244.239; |
1.I.244.154; | 1.I.244.157; | 1.I.244.166; | 1.I.244.169; |
1.I.244.172; | 1.I.244.175; | 1.I.244.240; | 1.I.244.244; |
1.J的前体药物
1.J.228.228; | 1.J.228.229; | 1.J.228.230; | 1.J.228.231; |
1.J.228.236; | 1.J.228.237; | 1.J.228.238; | 1.J.228.239; |
1.J.228.154; | 1.J.228.157; | 1.J.228.166; | 1.J.228.169; |
1.J.228.172; | 1.J.228.175; | 1.J.228.240; | 1.J.228.244; |
1.J.229.228; | 1.J.229.229; | 1.J.229.230; | 1.J.229.231; |
1.J.229.236; | 1.J.229.237; | 1.J.229.238; | 1.J.229.239; |
1.J.229.154; | 1.J.229.157; | 1.J.229.166; | 1.J.229.169; |
1.J.229.172; | 1.J.229.175; | 1.J.229.240; | 1.J.229.244; |
1.J.230.228; | 1.J.230.229; | 1.J.230.230; | 1.J.230.231; |
1.J.230.236; | 1.J.230.237; | 1.J.230.238; | 1.J.230.239; |
1.J.230.154; | 1.J.230.157; | 1.J.230.166; | 1.J.230.169; |
1.J.230.172; | 1.J.230.175; | 1.J.230.240; | 1.J.230.244; |
1.J.231.228; | 1.J.231.229; | 1.J.231.230; | 1.J.231.231; |
1.J.231.236; | 1.J.231.237; | 1.J.231.238; | 1.J.231.239; |
1.J.231.154; | 1.J.231.157; | 1.J.231.166; | 1.J.231.169; |
1.J.231.172; | 1.J.231.175; | 1.J.231.240; | 1.J.231.244; |
1.J.236.228; | 1.J.236.229; | 1.J.236.230; | 1.J.236.231; |
1.J.236.236; | 1.J.236.237; | 1.J.236.238; | 1.J.236.239; |
1.J.236.154; | 1.J.236.157; | 1.J.236.166; | 1.J.236.169; |
1.J.236.172; | 1.J.236.175; | 1.J.236.240; | 1.J.236.244; |
1.J.237.228; | 1.J.237.229; | 1.J.237.230; | 1.J.237.231; |
1.J.237.236; | 1.J.237.237; | 1.J.237.238; | 1.J.237.239; |
1.J.237.154; | 1.J.237.157; | 1.J.237.166; | 1.J.237.169; |
1.J.237.172; | 1.J.237.175; | 1.J.237.240; | 1.J.237.244; |
1.J.238.228; | 1.J.238.229; | 1.J.238.230; | 1.J.238.231; |
1.J.238.236; | 1.J.238.237; | 1.J.238.238; | 1.J.238.239; |
1.J.238.154; | 1.J.238.157; | 1.J.238.166; | 1.J.238.169; |
1.J.238.172; | 1.J.238.175; | 1.J.238.240; | 1.J.238.244; |
1.J.239.228; | 1.J.239.229; | 1.J.239.230; | 1.J.239.231; |
1.J.239.236; | 1.J.239.237; | 1.J.239.238; | 1.J.239.239; |
1.J.239.154; | 1.J.239.157; | 1.J.239.166; | 1.J.239.169; |
1.J.239.172; | 1.J.239.175; | 1.J.239.240; | 1.J.239.244; |
1.J.154.228; | 1.J.154.229; | 1.J.154.230; | 1.J.154.231; |
1.J.154.236; | 1.J.154.237; | 1.J.154.238; | 1.J.154.239; |
1.J.154.154; | 1.J.154.157; | 1.J.154.166; | 1.J.154.169; |
1.J.154.172; | 1.J.154.175; | 1.J.154.240; | 1.J.154.244; |
1.J.157.228; | 1.J.157.229; | 1.J.157.230; | 1.J.157.231; |
1.J.157.236; | 1.J.157.237; | 1.J.157.238; | 1.J.157.239; |
1.J.157.154; | 1.J.157.157; | 1.J.157.166; | 1.J.157.169; |
1.J.157.172; | 1.J.157.175; | 1.J.157.240; | 1.J.157.244; |
1.J.166.228; | 1.J.166.229; | 1.J.166.230; | 1.J.166.231; |
1.J.166.236; | 1.J.166.237; | 1.J.166.238; | 1.J.166.239; |
1.J.166.154; | 1.J.166.157; | 1.J.166.166; | 1.J.166.169; |
1.J.166.172; | 1.J.166.175; | 1.J.166.240; | 1.J.166.244; |
1.J.169.228; | 1.J.169.229; | 1.J.169.230; | 1.J.169.231; |
1.J.169.236; | 1.J.169.237; | 1.J.169.238; | 1.J.169.239; |
1.J.169.154; | 1.J.169.157; | 1.J.169.166; | 1.J.169.169; |
1.J.169.172; | 1.J.169.175; | 1.J.169.240; | 1.J.169.244; |
1.J.172.228; | 1.J.172.229; | 1.J.172.230; | 1.J.172.231; |
1.J.172.236; | 1.J.172.237; | 1.J.172.238; | 1.J.172.239; |
1.J.172.154; | 1.J.172.157; | 1.J.172.166; | 1.J.172.169; |
1.J.172.172; | 1.J.172.175; | 1.J.172.240; | 1.J.172.244; |
1.J.175.228; | 1.J.175.229; | 1.J.175.230; | 1.J.175.231; |
1.J.175.236; | 1.J.175.237; | 1.J.175.238; | 1.J.175.239; |
1.J.175.154; | 1.J.175.157; | 1.J.175.166; | 1.J.175.169; |
1.J.175.172; | 1.J.175.175; | 1.J.175.240; | 1.J.175.244; |
1.J.240.228; | 1.J.240.229; | 1.J.240.230; | 1.J.240.231; |
1.J.240.236; | 1.J.240.237; | 1.J.240.238; | 1.J.240.239; |
1.J.240.154; | 1.J.240.157; | 1.J.240.166; | 1.J.240.169; |
1.J.240.172; | 1.J.240.175; | 1.J.240.240; | 1.J.240.244; |
1.J.244.228; | 1.J.244.229; | 1.J.244.230; | 1.J.244.231; |
1.J.244.236; | 1.J.244.237; | 1.J.244.238; | 1.J.244.239; |
1.J.244.154; | 1.J.244.157; | 1.J.244.166; | 1.J.244.169; |
1.J.244.172; | 1.J.244.175; | 1.J.244.240; | 1.J.244.244; |
1.L的前体药物
1.L.228.228; | 1.L.228.229; | 1.L.228.230; | 1.L.228.231; |
1.L.228.236; | 1.L.228.237; | 1.L.228.238; | 1.L.228.239; |
1.L.228.154; | 1.L.228.157; | 1.L.228.166; | 1.L.228.169; |
1.L.228.172; | 1.L.228.175; | 1.L.228.240; | 1.L.228.244; |
1.L.229.228; | 1.L.229.229; | 1.L.229.230; | 1.L.229.231; |
1.L.229.236; | 1.L.229.237; | 1.L.229.238; | 1.L.229.239; |
1.L.229.154; | 1.L.229.157; | 1.L.229.166; | 1.L.229.169; |
1.L.229.172; | 1.L.229.175; | 1.L.229.240; | 1.L.229.244; |
1.L.230.228; | 1.L.230.229; | 1.L.230.230; | 1.L.230.231; |
1.L.230.236; | 1.L.230.237; | 1.L.230.238; | 1.L.230.239; |
1.L.230.154; | 1.L.230.157; | 1.L.230.166; | 1.L.230.169; |
1.L.230.172; | 1.L.230.175; | 1.L.230.240; | 1.L.230.244; |
1.L.231.228; | 1.L.231.229; | 1.L.231.230; | 1.L.231.231; |
1.L.231.236; | 1.L.231.237; | 1.L.231.238; | 1.L.231.239; |
1.L.231.154; | 1.L.231.157; | 1.L.231.166; | 1.L.231.169; |
1.L.231.172; | 1.L.231.175; | 1.L.231.240; | 1.L.231.244; |
1.L.236.228; | 1.L.236.229; | 1.L.236.230; | 1.L.236.231; |
1.L.236.236; | 1.L.236.237; | 1.L.236.238; | 1.L.236.239; |
1.L.236.154; | 1.L.236.157; | 1.L.236.166; | 1.L.236.169; |
1.L.236.172; | 1.L.236.175; | 1.L.236.240; | 1.L.236.244; |
1.L.237.228; | 1.L.237.229; | 1.L.237.230; | 1.L.237.231; |
1.L.237.236; | 1.L.237.237; | 1.L.237.238; | 1.L.237.239; |
1.L.237.154; | 1.L.237.157; | 1.L.237.166; | 1.L.237.169; |
1.L.237.172; | 1.L.237.175; | 1.L.237.240; | 1.L.237.244; |
1.L.238.228; | 1.L.238.229; | 1.L.238.230; | 1.L.238.231; |
1.L.238.236; | 1.L.238.237; | 1.L.238.238; | 1.L.238.239; |
1.L.238.154; | 1.L.238.157; | 1.L.238.166; | 1.L.238.169; |
1.L.238.172; | 1.L.238.175; | 1.L.238.240; | 1.L.238.244; |
1.L.239.228; | 1.L.239.229; | 1.L.239.230; | 1.L.239.231; |
1.L.239.236; | 1.L.239.237; | 1.L.239.238; | 1.L.239.239; |
1.L.239.154; | 1.L.239.157; | 1.L.239.166; | 1.L.239.169; |
1.L.239.172; | 1.L.239.175; | 1.L.239.240; | 1.L.239.244; |
1.L.154.228; | 1.L.154.229; | 1.L.154.230; | 1.L.154.231; |
1.L.154.236; | 1.L.154.237; | 1.L.154.238; | 1.L.154.239; |
1.L.154.154; | 1.L.154.157; | 1.L.154.166; | 1.L.154.169; |
1.L.154.172; | 1.L.154.175; | 1.L.154.240; | 1.L.154.244; |
1.L.157.228; | 1.L.157.229; | 1.L.157.230; | 1.L.157.231; |
1.L.157.236; | 1.L.157.237; | 1.L.157.238; | 1.L.157.239; |
1.L.157.154; | 1.L.157.157; | 1.L.157.166; | 1.L.157.169; |
1.L.157.172; | 1.L.157.175; | 1.L.157.240; | 1.L.157.244; |
1.L.166.228; | 1.L.166.229; | 1.L.166.230; | 1.L.166.231; |
1.L.166.236; | 1.L.166.237; | 1.L.166.238; | 1.L.166.239; |
1.L.166.154; | 1.L.166.157; | 1.L.166.166; | 1.L.166.169; |
1.L.166.172; | 1.L.166.175; | 1.L.166.240; | 1.L.166.244; |
1.L.169.228; | 1.L.169.229; | 1.L.169.230; | 1.L.169.231; |
1.L.169.236; | 1.L.169.237; | 1.L.169.238; | 1.L.169.239; |
1.L.169.154; | 1.L.169.157; | 1.L.169.166; | 1.L.169.169; |
1.L.169.172; | 1.L.169.175; | 1.L.169.240; | 1.L.169.244; |
1.L.172.228; | 1.L.172.229; | 1.L.172.230; | 1.L.172.231; |
1.L.172.236; | 1.L.172.237; | 1.L.172.238; | 1.L.172.239; |
1.L.172.154; | 1.L.172.157; | 1.L.172.166; | 1.L.172.169; |
1.L.172.172; | 1.L.172.175; | 1.L.172.240; | 1.L.172.244; |
1.L.175.228; | 1.L.175.229; | 1.L.175.230; | 1.L.175.231; |
1.L.175.236; | 1.L.175.237; | 1.L.175.238; | 1.L.175.239; |
1.L.175.154; | 1.L.175.157; | 1.L.175.166; | 1.L.175.169; |
1.L.175.172; | 1.L.175.175; | 1.L.175.240; | 1.L.175.244; |
1.L.240.228; | 1.L.240.229; | 1.L.240.230; | 1.L.240.231; |
1.L.240.236; | 1.L.240.237; | 1.L.240.238; | 1.L.240.239; |
1.L.240.154; | 1.L.240.157; | 1.L.240.166; | 1.L.240.169; |
1.L.240.172; | 1.L.240.175; | 1.L.240.240; | 1.L.240.244; |
1.L.244.228; | 1.L.244.229; | 1.L.244.230; | 1.L.244.231; |
1.L.244.236; | 1.L.244.237; | 1.L.244.238; | 1.L.244.239; |
1.L.244.154; | 1.L.244.157; | 1.L.244.166; | 1.L.244.169; |
1.L.244.172; | 1.L.244.175; | 1.L.244.240; | 1.L.244.244; |
1.O的前体药物
1.O.228.228; | 1.O.228.229; | 1.O.228.230; | 1.O.228.231; |
1.O.228.236; | 1.O.228.237; | 1.O.228.238; | 1.O.228.239; |
1.O.228.154; | 1.O.228.157; | 1.O.228.166; | 1.O.228.169; |
1.O.228.172; | 1.O.228.175; | 1.O.228.240; | 1.O.228.244; |
1.O.229.228; | 1.O.229.229; | 1.O.229.230; | 1.O.229.231; |
1.O.229.236; | 1.O.229.237; | 1.O.229.238; | 1.O.229.239; |
1.O.229.154; | 1.O.229.157; | 1.O.229.166; | 1.O.229.169; |
1.O.229.172; | 1.O.229.175; | 1.O.229.240; | 1.O.229.244; |
1.O.230.228; | 1.O.230.229; | 1.O.230.230; | 1.O.230.231; |
1.O.230.236; | 1.O.230.237; | 1.O.230.238; | 1.O.230.239; |
1.O.230.154; | 1.O.230.157; | 1.O.230.166; | 1.O.230.169; |
1.O.230.172; | 1.O.230.175; | 1.O.230.240; | 1.O.230.244; |
1.O.231.228; | 1.O.231.229; | 1.O.231.230; | 1.O.231.231; |
1.O.231.236; | 1.O.231.237; | 1.O.231.238; | 1.O.231.239; |
1.O.231.154; | 1.O.231.157; | 1.O.231.166; | 1.O.231.169; |
1.O.231.172; | 1.O.231.175; | 1.O.231.240; | 1.O.231.244; |
1.O.236.228; | 1.O.236.229; | 1.O.236.230; | 1.O.236.231; |
1.O.236.236; | 1.O.236.237; | 1.O.236.238; | 1.O.236.239; |
1.O.236.154; | 1.O.236.157; | 1.O.236.166; | 1.O.236.169; |
1.O.236.172; | 1.O.236.175; | 1.O.236.240; | 1.O.236.244; |
1.O.237.228; | 1.O.237.229; | 1.O.237.230; | 1.O.237.231; |
1.O.237.236; | 1.O.237.237; | 1.O.237.238; | 1.O.237.239; |
1.O.237.154; | 1.O.237.157; | 1.O.237.166; | 1.O.237.169; |
1.O.237.172; | 1.O.237.175; | 1.O.237.240; | 1.O.237.244; |
1.O.238.228; | 1.O.238.229; | 1.O.238.230; | 1.O.238.231; |
1.O.238.236; | 1.O.238.237; | 1.O.238.238; | 1.O.238.239; |
1.O.238.154; | 1.O.238.157; | 1.O.238.166; | 1.O.238.169; |
1.O.238.172; | 1.O.238.175; | 1.O.238.240; | 1.O.238.244; |
1.O.239.228; | 1.O.239.229; | 1.O.239.230; | 1.O.239.231; |
1.O.239.236; | 1.O.239.237; | 1.O.239.238; | 1.O.239.239; |
1.O.239.154; | 1.O.239.157; | 1.O.239.166; | 1.O.239.169; |
1.O.239.172; | 1.O.239.175; | 1.O.239.240; | 1.O.239.244; |
1.O.154.228; | 1.O.154.229; | 1.O.154.230; | 1.O.154.231; |
1.O.154.236; | 1.O.154.237; | 1.O.154.238; | 1.O.154.239; |
1.O.154.154; | 1.O.154.157; | 1.O.154.166; | 1.O.154.169; |
1.O.154.172; | 1.O.154.175; | 1.O.154.240; | 1.O.154.244; |
1.O.157.228; | 1.O.157.229; | 1.O.157.230; | 1.O.157.231; |
1.O.157.236; | 1.O.157.237; | 1.O.157.238; | 1.O.157.239; |
1.O.157.154; | 1.O.157.157; | 1.O.157.166; | 1.O.157.169; |
1.O.157.172; | 1.O.157.175; | 1.O.157.240; | 1.O.157.244; |
1.O.166.228; | 1.O.166.229; | 1.O.166.230; | 1.O.166.231; |
1.O.166.236; | 1.O.166.237; | 1.O.166.238; | 1.O.166.239; |
1.O.166.154; | 1.O.166.157; | 1.O.166.166; | 1.O.166.169; |
1.O.166.172; | 1.O.166.175; | 1.O.166.240; | 1.O.166.244; |
1.O.169.228; | 1.O.169.229; | 1.O.169.230; | 1.O.169.231; |
1.O.169.236; | 1.O.169.237; | 1.O.169.238; | 1.O.169.239; |
1.O.169.154; | 1.O.169.157; | 1.O.169.166; | 1.O.169.169; |
1.O.169.172; | 1.O.169.175; | 1.O.169.240; | 1.O.169.244; |
1.O.172.228; | 1.O.172.229; | 1.O.172.230; | 1.O.172.231; |
1.O.172.236; | 1.O.172.237; | 1.O.172.238; | 1.O.172.239; |
1.O.172.154; | 1.O.172.157; | 1.O.172.166; | 1.O.172.169; |
1.O.172.172; | 1.O.172.175; | 1.O.172.240; | 1.O.172.244; |
1.O.175.228; | 1.O.175.229; | 1.O.175.230; | 1.O.175.231; |
1.O.175.236; | 1.O.175.237; | 1.O.175.238; | 1.O.175.239; |
1.O.175.154; | 1.O.175.157; | 1.O.175.166; | 1.O.175.169; |
1.O.175.172; | 1.O.175.175; | 1.O.175.240; | 1.O.175.244; |
1.O.240.228; | 1.O.240.229; | 1.O.240.230; | 1.O.240.231; |
1.O.240.236; | 1.O.240.237; | 1.O.240.238; | 1.O.240.239; |
1.O.240.154; | 1.O.240.157; | 1.O.240.166; | 1.O.240.169; |
1.O.240.172; | 1.O.240.175; | 1.O.240.240; | 1.O.240.244; |
1.O.244.228; | 1.O.244.229; | 1.O.244.230; | 1.O.244.231; |
1.O.244.236; | 1.O.244.237; | 1.O.244.238; | 1.O.244.239; |
1.O.244.154; | 1.O.244.157; | 1.O.244.166; | 1.O.244.169; |
1.O.244.172; | 1.O.244.175; | 1.O.244.240; | 1.O.244.244; |
1.P的前体药物
1.P.228. 228; | 1.P.228.229; | 1.P.228.230; | 1.P.228.231; |
1.P.228.236; | 1.P.228.237; | 1.P.228.238; | 1.P.228.239; |
1.P.228.154; | 1.P.228.157; | 1.P.228.166; | 1.P.228.169; |
1.P.228.172; | 1.P.228.175; | 1.P.228.240; | 1.P.228.244; |
1.P.229.228; | 1.P.229.229; | 1.P.229.230; | 1.P.229.231; |
1.P.229.236; | 1.P.229.237; | 1.P.229.238; | 1.P.229.239; |
1.P.229.154; | 1.P.229.157; | 1.P.229.166; | 1.P.229.169; |
1.P.229.172; | 1.P.229.175; | 1.P.229.240; | 1.P.229.244; |
1.P.230.228; | 1.P.230.229; | 1.P.230.230; | 1.P.230.231; |
1.P.230.236; | 1.P.230.237; | 1.P.230.238; | 1.P.230.239; |
1.P.230.154; | 1.P.230.157; | 1.P.230.166; | 1.P.230.169; |
1.P.230.172; | 1.P.230.175; | 1.P.230.240; | 1.P.230.244; |
1.P.231.228; | 1.P.231.229; | 1.P.231.230; | 1.P.231.231; |
1.P.231.236; | 1.P.231.237; | 1.P.231.238; | 1.P.231.239; |
1.P.231.154; | 1.P.231.157; | 1.P.231.166; | 1.P.231.169; |
1.P.231.172; | 1.P.231.175; | 1.P.231.240; | 1.P.231.244; |
1.P.236.228; | 1.P.236.229; | 1.P.236.230; | 1.P.236.231; |
1.P.236.236; | 1.P.236.237; | 1.P.236.238; | 1.P.236.239; |
1.P.236.154; | 1.P.236.157; | 1.P.236.166; | 1.P.236.169; |
1.P.236.172; | 1.P.236.175; | 1.P.236.240; | 1.P.236.244; |
1.P.237.228; | 1.P.237.229; | 1.P.237.230; | 1.P.237.231; |
1.P.237.236; | 1.P.237.237; | 1.P.237.238; | 1.P.237.239; |
1.P.237.154; | 1.P.237.157; | 1.P.237.166; | 1.P.237.169; |
1.P.237.172; | 1.P.237.175; | 1.P.237.240; | 1.P.237.244; |
1.P.238.228; | 1.P.238.229; | 1.P.238.230; | 1.P.238.231; |
1.P.238.236; | 1.P.238.237; | 1.P.238.238; | 1.P.238.239; |
1.P.238.154; | 1.P.238.157; | 1.P.238.166; | 1.P.238.169; |
1.P.238.172; | 1.P.238.175; | 1.P.238.240; | 1.P.238.244; |
1.P.239.228; | 1.P.239.229; | 1.P.239.230; | 1.P.239.231; |
1.P.239.236; | 1.P.239.237; | 1.P.239.238; | 1.P.239.239; |
1.P.239.154; | 1.P.239.157; | 1.P.239.166; | 1.P.239.169; |
1.P.239.172; | 1.P.239.175; | 1.P.239.240; | 1.P.239.244; |
1.P.154.228; | 1.P.154.229; | 1.P.154.230; | 1.P.154.231; |
1.P.154.236; | 1.P.154.237; | 1.P.154.238; | 1.P.154.239; |
1.P.154.154; | 1.P.154.157; | 1.P.154.166; | 1.P.154.169; |
1.P.154.172; | 1.P.154.175; | 1.P.154.240; | 1.P.154.244; |
1.P.157.228; | 1.P.157.229; | 1.P.157.230; | 1.P.157.231; |
1.P.157.236; | 1.P.157.237; | 1.P.157.238; | 1.P.157.239; |
1.P.157.154; | 1.P.157.157; | 1.P.157.166; | 1.P.157.169; |
1.P.157.172; | 1.P.157.175; | 1.P.157.240; | 1.P.157.244; |
1.P.166.228; | 1.P.166.229; | 1.P.166.230; | 1.P.166.231; |
1.P.166.236; | 1.P.166.237; | 1.P.166.238; | 1.P.166.239; |
1.P.166.154; | 1.P.166.157; | 1.P.166.166; | 1.P.166.169; |
1.P.166.172; | 1.P.166.175; | 1.P.166.240; | 1.P.166.244; |
1.P.169.228; | 1.P.169.229; | 1.P.169.230; | 1.P.169.231; |
1.P.169.236; | 1.P.169.237; | 1.P.169.238; | 1.P.169.239; |
1.P.169.154; | 1.P.169.157; | 1.P.169.166; | 1.P.169.169; |
1.P.169.172; | 1.P.169.175; | 1.P.169.240; | 1.P.169.244; |
1.P.172.228; | 1.P.172.229; | 1.P.172.230; | 1.P.172.231; |
1.P.172.236; | 1.P.172.237; | 1.P.172.238; | 1.P.172.239; |
1.P.172.154; | 1.P.172.157; | 1.P.172.166; | 1.P.172.169; |
1.P.172.172; | 1.P.172.175; | 1.P.172.240; | 1.P.172.244; |
1.P.175.228; | 1.P.175.229; | 1.P.175.230; | 1.P.175.231; |
1.P.175.236; | 1.P.175.237; | 1.P.175.238; | 1.P.175.239; |
1.P.175.154; | 1.P.175.157; | 1.P.175.166; | 1.P.175.169; |
1.P.175.172; | 1.P.175.175; | 1.P.175.240; | 1.P.175.244; |
1.P.240.228; | 1.P.240.229; | 1.P.240.230; | 1.P.240.231; |
1.P.240.236; | 1.P.240.237; | 1.P.240.238; | 1.P.240.239; |
1.P.240.154; | 1.P.240.157; | 1.P.240.166; | 1.P.240.169; |
1.P.240.172; | 1.P.240.175; | 1.P.240.240; | 1.P.240.244; |
1.P.244.228; | 1.P.244.229; | 1.P.244.230; | 1.P.244.231; |
1.P.244.236; | 1.P.244.237; | 1.P.244.238; | 1.P.244.239; |
1.P.244.154; | 1.P.244.157; | 1.P.244.166; | 1.P.244.169; |
1.P.244.172; | 1.P.244.175; | 1.P.244.240; | 1.P.244.244; |
1.U的前体药物
1.U.228.228; | 1.U.228.229; | 1.U.228.230; | 1.U.228.231; |
1.U.228.236; | 1.U.228.237; | 1.U.228.238; | 1.U.228.239; |
1.U.228.154; | 1.U.228.157; | 1.U.228.166; | 1.U.228.169; |
1.U.228.172; | 1.U.228.175; | 1.U.228.240; | 1.U.228.244; |
1.U.229.228; | 1.U.229.229; | 1.U.229.230; | 1.U.229.231; |
1.U.229.236; | 1.U.229.237; | 1.U.229.238; | 1.U.229.239; |
1.U.229.154; | 1.U.229.157; | 1.U.229.166; | 1.U.229.169; |
1.U.229.172; | 1.U.229.175; | 1.U.229.240; | 1.U.229.244; |
1.U.230.228; | 1.U.230.229; | 1.U.230.230; | 1.U.230.231; |
1.U.230.236; | 1.U.230.237; | 1.U.230.238; | 1.U.230.239; |
1.U.230.154; | 1.U.230.157; | 1.U.230.166; | 1.U.230.169; |
1.U.230.172; | 1.U.230.175; | 1.U.230.240; | 1.U.230.244; |
1.U.231.228; | 1.U.231.229; | 1.U.231.230; | 1.U.231.231; |
1.U.231.236; | 1.U.231.237; | 1.U.231.238; | 1.U.231.239; |
1.U.231.154; | 1.U.231.157; | 1.U.231.166; | 1.U.231.169; |
1.U.231.172; | 1.U.231.175; | 1.U.231.240; | 1.U.231.244; |
1.U.236.228; | 1.U.236.229; | 1.U.236.230; | 1.U.236.231; |
1.U.236.236; | 1.U.236.237; | 1.U.236.238; | 1.U.236.239; |
1.U.236.154; | 1.U.236.157; | 1.U.236.166; | 1.U.236.169; |
1.U.236.172; | 1.U.236.175; | 1.U.236.240; | 1.U.236.244; |
1.U.237.228; | 1.U.237.229; | 1.U.237.230; | 1.U.237.231; |
1.U.237.236; | 1.U.237.237; | 1.U.237.238; | 1.U.237.239; |
1.U.237.154; | 1.U.237.157; | 1.U.237.166; | 1.U.237.169; |
1.U.237.172; | 1.U.237.175; | 1.U.237.240; | 1.U.237.244; |
1.U.238.228; | 1.U.238.229; | 1.U.238.230; | 1.U.238.231; |
1.U.238.236; | 1.U.238.237; | 1.U.238.238; | 1.U.238.239; |
1.U.238.154; | 1.U.238.157; | 1.U.238.166; | 1.U.238.169; |
1.U.238.172; | 1.U.238.175; | 1.U.238.240; | 1.U.238.244; |
1.U.239.228; | 1.U.239.229; | 1.U.239.230; | 1.U.239.231; |
1.U.239.236; | 1.U.239.237; | 1.U.239.238; | 1.U.239.239; |
1.U.239.154; | 1.U.239.157; | 1.U.239.166; | 1.U.239.169; |
1.U.239.172; | 1.U.239.175; | 1.U.239.240; | 1.U.239.244; |
1.U.154.228; | 1.U.154.229; | 1.U.154.230; | 1.U.154.231; |
1.U.154.236; | 1.U.154.237; | 1.U.154.238; | 1.U.154.239; |
1.U.154.154; | 1.U.154.157; | 1.U.154.166; | 1.U.154.169; |
1.U.154.172; | 1.U.154.175; | 1.U.154.240; | 1.U.154.244; |
1.U.157.228; | 1.U.157.229; | 1.U.157.230; | 1.U.157.231; |
1.U.157.236; | 1.U.157.237; | 1.U.157.238; | 1.U.157.239; |
1.U.157.154; | 1.U.157.157; | 1.U.157.166; | 1.U.157.169; |
1.U.157.172; | 1.U.157.175; | 1.U.157.240; | 1.U.157.244; |
1.U.166.228; | 1.U.166.229; | 1.U.166.230; | 1.U.166.231; |
1.U.166.236; | 1.U.166.237; | 1.U.166.238; | 1.U.166.239; |
1.U.166.154; | 1.U.166.157; | 1.U.166.166; | 1.U.166.169; |
1.U.166.172; | 1.U.166.175; | 1.U.166.240; | 1.U.166.244; |
1.U.169.228; | 1.U.169.229; | 1.U.169.230; | 1.U.169.231; |
1.U.169.236; | 1.U.169.237; | 1.U.169.238; | 1.U.169.239; |
1.U.169.154; | 1.U.169.157; | 1.U.169.166; | 1.U.169.169; |
1.U.169.172; | 1.U.169.175; | 1.U.169.240; | 1.U.169.244; |
1.U.172.228; | 1.U.172.229; | 1.U.172.230; | 1.U.172.231; |
1.U.172.236; | 1.U.172.237; | 1.U.172.238; | 1.U.172.239; |
1.U.172.154; | 1.U.172.157; | 1.U.172.166; | 1.U.172.169; |
1.U.172.172; | 1.U.172.175; | 1.U.172.240; | 1.U.172.244; |
1.U.175.228; | 1.U.175.229; | 1.U.175.230; | 1.U.175.231; |
1.U.175.236; | 1.U.175.237; | 1.U.175.238; | 1.U.175.239; |
1.U.175.154; | 1.U.175.157; | 1.U.175.166; | 1.U.175.169; |
1.U.175.172; | 1.U.175.175; | 1.U.175.240; | 1.U.175.244; |
1.U.240.228; | 1.U.240.229; | 1.U.240.230; | 1.U.240.231; |
1.U.240.236; | 1.U.240.237; | 1.U.240.238; | 1.U.240.239; |
1.U.240.154; | 1.U.240.157; | 1.U.240.166; | 1.U.240.169; |
1.U.240.172; | 1.U.240.175; | 1.U.240.240; | 1.U.240.244; |
1.U.244.228; | 1.U.244.229; | 1.U.244.230; | 1.U.244.231; |
1.U.244.236; | 1.U.244.237; | 1.U.244.238; | 1.U.244.239; |
1.U.244.154; | 1.U.244.157; | 1.U.244.166; | 1.U.244.169; |
1.U.244.172; | 1.U.244.175; | 1.U.244.240; | 1.U.244.244; |
1.W的前体药物
1.W.228.228; | 1.W.228.229; | 1.W.228.230; | 1.W.228.231; |
1.W.228.236; | 1.W.228.237; | 1.W.228.238; | 1.W.228.239; |
1.W.228.154; | 1.W.228.157; | 1.W.228.166; | 1.W.228.169; |
1.W.228.172; | 1.W.228.175; | 1.W.228.240; | 1.W.228.244; |
1.W.229.228; | 1.W.229.229; | 1.W.229.230; | 1.W.229.231; |
1.W.229.236; | 1.W.229.237; | 1.W.229.238; | 1.W.229.239; |
1.W.229.154; | 1.W.229.157; | 1.W.229.166; | 1.W.229.169; |
1.W.229.172; | 1.W.229.175; | 1.W.229.240; | 1.W.229.244; |
1.W.230.228; | 1.W.230.229; | 1.W.230.230; | 1.W.230.231; |
1.W.230.236; | 1.W.230.237; | 1.W.230.238; | 1.W.230.239; |
1.W.230.154; | 1.W.230.157; | 1.W.230.166; | 1.W.230.169; |
1.W.230.172; | 1.W.230.175; | 1.W.230.240; | 1.W.230.244; |
1.W.231.228; | 1.W.231.229; | 1.W.231.230; | 1.W.231.231; |
1.W.231.236; | 1.W.231.237; | 1.W.231.238; | 1.W.231.239; |
1.W.231.154; | 1.W.231.157; | 1.W.231.166; | 1.W.231.169; |
1.W.231.172; | 1.W.231.175; | 1.W.231.240; | 1.W.231.244; |
1.W.236.228; | 1.W.236.229; | 1.W.236.230; | 1.W.236.231; |
1.W.236.236; | 1.W.236.237; | 1.W.236.238; | 1.W.236.239; |
1.W.236.154; | 1.W.236.157; | 1.W.236.166; | 1.W.236.169; |
1.W.236.172; | 1.W.236.175; | 1.W.236.240; | 1.W.236.244; |
1.W.237.228; | 1.W.237.229; | 1.W.237.230; | 1.W.237.231; |
1.W.237.236; | 1.W.237.237; | 1.W.237.238; | 1.W.237.239; |
1.W.237.154; | 1.W.237.157; | 1.W.237.166; | 1.W.237.169; |
1.W.237.172; | 1.W.237.175; | 1.W.237.240; | 1.W.237.244; |
1.W.238.228; | 1.W.238.229; | 1.W.238.230; | 1.W.238.231; |
1.W.238.236; | 1.W.238.237; | 1.W.238.238; | 1.W.238.239; |
1.W.238.154; | 1.W.238.157; | 1.W.238.166; | 1.W.238.169; |
1.W.238.172; | 1.W.238.175; | 1.W.238.240; | 1.W.238.244; |
1.W.239.228; | 1.W.239.229; | 1.W.239.230; | 1.W.239.231; |
1.W.239.236; | 1.W.239.237; | 1.W.239.238; | 1.W.239.239; |
1.W.239.154; | 1.W.239.157; | 1.W.239.166; | 1.W.239.169; |
1.W.239.172; | 1.W.239.175; | 1.W.239.240; | 1.W.239.244; |
1.W.154.228; | 1.W.154.229; | 1.W.154.230; | 1.W.154.231; |
1.W.154.236; | 1.W.154.237; | 1.W.154.238; | 1.W.154.239; |
1.W.154.154; | 1.W.154.157; | 1.W.154.166; | 1.W.154.169; |
1.W.154.172; | 1.W.154.175; | 1.W.154.240; | 1.W.154.244; |
1.W.157.228; | 1.W.157.229; | 1.W.157.230; | 1.W.157.231; |
1.W.157.236; | 1.W.157.237; | 1.W.157.238; | 1.W.157.239; |
1.W.157.154; | 1.W.157.157; | 1.W.157.166; | 1.W.157.169; |
1.W.157.172; | 1.W.157.175; | 1.W.157.240; | 1.W.157.244; |
1.W.166.228; | 1.W.166.229; | 1.W.166.230; | 1.W.166.231; |
1.W.166.236; | 1.W.166.237; | 1.W.166.238; | 1.W.166.239; |
1.W.166.154; | 1.W.166.157; | 1.W.166.166; | 1.W.166.169; |
1.W.166.172; | 1.W.166.175; | 1.W.166.240; | 1.W.166.244; |
1.W.169.228; | 1.W.169.229; | 1.W.169.230; | 1.W.169.231; |
1.W.169.236; | 1.W.169.237; | 1.W.169.238; | 1.W.169.239; |
1.W.169.154; | 1.W.169.157; | 1.W.169.166; | 1.W.169.169; |
1.W.169.172; | 1.W.169.175; | 1.W.169.240; | 1.W.169.244; |
1.W.172.228; | 1.W.172.229; | 1.W.172.230; | 1.W.172.231; |
1.W.172.236; | 1.W.172.237; | 1.W.172.238; | 1.W.172.239; |
1.W.172.154; | 1.W.172.157; | 1.W.172.166; | 1.W.172.169; |
1.W.172.172; | 1.W.172.175; | 1.W.172.240; | 1.W.172.244; |
1.W.175.228; | 1.W.175.229; | 1.W.175.230; | 1.W.175.231; |
1.W.175.236; | 1.W.175.237; | 1.W.175.238; | 1.W.175.239; |
1.W.175.154; | 1.W.175.157; | 1.W.175.166; | 1.W.175.169; |
1.W.175.172; | 1.W.175.175; | 1.W.175.240; | 1.W.175.244; |
1.W.240.228; | 1.W.240.229; | 1.W.240.230; | 1.W.240.231; |
1.W.240.236; | 1.W.240.237; | 1.W.240.238; | 1.W.240.239; |
1.W.240.154; | 1.W.240.157; | 1.W.240.166; | 1.W.240.169; |
1.W.240.172; | 1.W.240.175; | 1.W.240.240; | 1.W.240.244; |
1.W.244.228; | 1.W.244.229; | 1.W.244.230; | 1.W.244.231; |
1.W.244.236; | 1.W.244.237; | 1.W.244.238; | 1.W.244.239; |
1.W.244.154; | 1.W.244.157; | 1.W.244.166; | 1.W.244.169; |
1.W.244.172; | 1.W.244.175; | 1.W.244.240; | 1.W.244.244; |
1.Y的前体药物
1.Y.228.228; | 1.Y.228.229; | 1.Y.228.230; | 1.Y.228.231; |
1.Y.228.236; | 1.Y.228.237; | 1.Y.228.238; | 1.Y.228.239; |
1.Y.228.154; | 1.Y.228.157; | 1.Y.228.166; | 1.Y.228.169; |
1.Y.228.172; | 1.Y.228.175; | 1.Y.228.240; | 1.Y.228.244; |
1.Y.229.228; | 1.Y.229.229; | 1.Y.229.230; | 1.Y.229.231; |
1.Y.229.236; | 1.Y.229.237; | 1.Y.229.238; | 1.Y.229.239; |
1.Y.229.154; | 1.Y.229.157; | 1.Y.229.166; | 1.Y.229.169; |
1.Y.229.172; | 1.Y.229.175; | 1.Y.229.240; | 1.Y.229.244; |
1.Y.230.228; | 1.Y.230.229; | 1.Y.230.230; | 1.Y.230.231; |
1.Y.230.236; | 1.Y.230.237; | 1.Y.230.238; | 1.Y.230.239; |
1.Y.230.154; | 1.Y.230.157; | 1.Y.230.166; | 1.Y.230.169; |
1.Y.230.172; | 1.Y.230.175; | 1.Y.230.240; | 1.Y.230.244; |
1.Y.231.228; | 1.Y.231.229; | 1.Y.231.230; | 1.Y.231.231; |
1.Y.231.236; | 1.Y.231.237; | 1.Y.231.238; | 1.Y.231.239; |
1.Y.231.154; | 1.Y.231.157; | 1.Y.231.166; | 1.Y.231.169; |
1.Y.231.172; | 1.Y.231.175; | 1.Y.231.240; | 1.Y.231.244; |
1.Y.236.228; | 1.Y.236.229; | 1.Y.236.230; | 1.Y.236.231; |
1.Y.236.236; | 1.Y.236.237; | 1.Y.236.238; | 1.Y.236.239; |
1.Y.236.154; | 1.Y.236.157; | 1.Y.236.166; | 1.Y.236.169; |
1.Y.236.172; | 1.Y.236.175; | 1.Y.236.240; | 1.Y.236.244; |
1.Y.237.228; | 1.Y.237.229; | 1.Y.237.230; | 1.Y.237.231; |
1.Y.237.236; | 1.Y.237.237; | 1.Y.237.238; | 1.Y.237.239; |
1.Y.237.154; | 1.Y.237.157; | 1.Y.237.166; | 1.Y.237.169; |
1.Y.237.172; | 1.Y.237.175; | 1.Y.237.240; | 1.Y.237.244; |
1.Y.238.228; | 1.Y.238.229; | 1.Y.238.230; | 1.Y.238.231; |
1.Y.238.236; | 1.Y.238.237; | 1.Y.238.238; | 1.Y.238.239; |
1.Y.238.154; | 1.Y.238.157; | 1.Y.238.166; | 1.Y.238.169; |
1.Y.238.172; | 1.Y.238.175; | 1.Y.238.240; | 1.Y.238.244; |
1.Y.239.228; | 1.Y.239.229; | 1.Y.239.230; | 1.Y.239.231; |
1.Y.239.236; | 1.Y.239.237; | 1.Y.239.238; | 1.Y.239.239; |
1.Y.239.154; | 1.Y.239.157; | 1.Y.239.166; | 1.Y.239.169; |
1.Y.239.172; | 1.Y.239.175; | 1.Y.239.240; | 1.Y.239.244; |
1.Y.154.228; | 1.Y.154.229; | 1.Y.154.230; | 1.Y.154.231; |
1.Y.154.236; | 1.Y.154.237; | 1.Y.154.238; | 1.Y.154.239; |
1.Y.154.154; | 1.Y.154.157; | 1.Y.154.166; | 1.Y.154.169; |
1.Y.154.172; | 1.Y.154.175; | 1.Y.154.240; | 1.Y.154.244; |
1.Y.157.228; | 1.Y.157.229; | 1.Y.157.230; | 1.Y.157.231; |
1.Y.157.236; | 1.Y.157.237; | 1.Y.157.238; | 1.Y.157.239; |
1.Y.157.154; | 1.Y.157.157; | 1.Y.157.166; | 1.Y.157.169; |
1.Y.157.172; | 1.Y.157.175; | 1.Y.157.240; | 1.Y.157.244; |
1.Y.166.228; | 1.Y.166.229; | 1.Y.166.230; | 1.Y.166.231; |
1.Y.166.236; | 1.Y.166.237; | 1.Y.166.238; | 1.Y.166.239; |
1.Y.166.154; | 1.Y.166.157; | 1.Y.166.166; | 1.Y.166.169; |
1.Y.166.172; | 1.Y.166.175; | 1.Y.166.240; | 1.Y.166.244; |
1.Y.169.228; | 1.Y.169.229; | 1.Y.169.230; | 1.Y.169.231; |
1.Y.169.236; | 1.Y.169.237; | 1.Y.169.238; | 1.Y.169.239; |
1.Y.169.154; | 1.Y.169.157; | 1.Y.169.166; | 1.Y.169.169; |
1.Y.169.172; | 1.Y.169.175; | 1.Y.169.240; | 1.Y.169.244; |
1.Y.172.228; | 1.Y.172.229; | 1.Y.172.230; | 1.Y.172.231; |
1.Y.172.236; | 1.Y.172.237; | 1.Y.172.238; | 1.Y.172.239; |
1.Y.172.154; | 1.Y.172.157; | 1.Y.172.166; | 1.Y.172.169; |
1.Y.172.172; | 1.Y.172.175; | 1.Y.172.240; | 1.Y.172.244; |
1.Y.175.228; | 1.Y.175.229; | 1.Y.175.230; | 1.Y.175.231; |
1.Y.175.236; | 1.Y.175.237; | 1.Y.175.238; | 1.Y.175.239; |
1.Y.175.154; | 1.Y.175.157; | 1.Y.175.166; | 1.Y.175.169; |
1.Y.175.172; | 1.Y.175.175; | 1.Y.175.240; | 1.Y.175.244; |
1.Y.240.228; | 1.Y.240.229; | 1.Y.240.230; | 1.Y.240.231; |
1.Y.240.236; | 1.Y.240.237; | 1.Y.240.238; | 1.Y.240.239; |
1.Y.240.154; | 1.Y.240.157; | 1.Y.240.166; | 1.Y.240.169; |
1.Y.240.172; | 1.Y.240.175; | 1.Y.240.240; | 1.Y.240.244; |
1.Y.244.228; | 1.Y.244.229; | 1.Y.244.230; | 1.Y.244.231; |
1.Y.244.236; | 1.Y.244.237; | 1.Y.244.238; | 1.Y.244.239; |
1.Y.244.154; | 1.Y.244.157; | 1.Y.244.166; | 1.Y.244.169; |
1.Y.244.172; | 1.Y.244.175; | 1.Y.244.240; | 1.Y.244.244; |
2.B的前体药物
2.B.228.228; | 2.B.228.229; | 2.B.228.230; | 2.B.228.231; |
2.B.228.236; | 2.B.228.237; | 2.B.228.238; | 2.B.228.239; |
2.B.228.154; | 2.B.228.157; | 2.B.228.166; | 2.B.228.169; |
2.B.228.172; | 2.B.228.175; | 2.B.228.240; | 2.B.228.244; |
2.B.229.228; | 2.B.229.229; | 2.B.229.230; | 2.B.229.231; |
2.B.229.236; | 2.B.229.237; | 2.B.229.238; | 2.B.229.239; |
2.B.229.154; | 2.B.229.157; | 2.B.229.166; | 2.B.229.169; |
2.B.229.172; | 2.B.229.175; | 2.B.229.240; | 2.B.229.244; |
2.B.230.228; | 2.B.230.229; | 2.B.230.230; | 2.B.230.231; |
2.B.230.236; | 2.B.230.237; | 2.B.230.238; | 2.B.230.239; |
2.B.230.154; | 2.B.230.157; | 2.B.230.166; | 2.B.230.169; |
2.B.230.172; | 2.B.230.175; | 2.B.230.240; | 2.B.230.244; |
2.B.231.228; | 2.B.231.229; | 2.B.231.230; | 2.B.231.231; |
2.B.231.236; | 2.B.231.237; | 2.B.231.238; | 2.B.231.239; |
2.B.231.154; | 2.B.231.157; | 2.B.231.166; | 2.B.231.169; |
2.B.231.172; | 2.B.231.175; | 2.B.231.240; | 2.B.231.244; |
2.B.236.228; | 2.B.236.229; | 2.B.236.230; | 2.B.236.231; |
2.B.236.236; | 2.B.236.237; | 2.B.236.238; | 2.B.236.239; |
2.B.236.154; | 2.B.236.157; | 2.B.236.166; | 2.B.236.169; |
2.B.236.172; | 2.B.236.175; | 2.B.236.240; | 2.B.236.244; |
2.B.237.228; | 2.B.237.229; | 2.B.237.230; | 2.B.237.231; |
2.B.237.236; | 2.B.237.237; | 2.B.237.238; | 2.B.237.239; |
2.B.237.154; | 2.B.237.157; | 2.B.237.166; | 2.B.237.169; |
2.B.237.172; | 2.B.237.175; | 2.B.237.240; | 2.B.237.244; |
2.B.238.228; | 2.B.238.229; | 2.B.238.230; | 2.B.238.231; |
2.B.238.236; | 2.B.238.237; | 2.B.238.238; | 2.B.238.239; |
2.B.238.154; | 2.B.238.157; | 2.B.238.166; | 2.B.238.169; |
2.B.238.172; | 2.B.238.175; | 2.B.238.240; | 2.B.238.244; |
2.B.239.228; | 2.B.239.229; | 2.B.239.230; | 2.B.239.231; |
2.B.239.236; | 2.B.239.237; | 2.B.239.238; | 2.B.239.239; |
2.B.239.154; | 2.B.239.157; | 2.B.239.166; | 2.B.239.169; |
2.B.239.172; | 2.B.239.175; | 2.B.239.240; | 2.B.239.244; |
2.B.154.228; | 2.B.154.229; | 2.B.154.230; | 2.B.154.231; |
2.B.154.236; | 2.B.154.237; | 2.B.154.238; | 2.B.154.239; |
2.B.154.154; | 2.B.154.157; | 2.B.154.166; | 2.B.154.169; |
2.B.154.172; | 2.B.154.175; | 2.B.154.240; | 2.B.154.244; |
2.B.157.228; | 2.B.157.229; | 2.B.157.230; | 2.B.157.231; |
2.B.157.236; | 2.B.157.237; | 2.B.157.238; | 2.B.157.239; |
2.B.157.154; | 2.B.157.157; | 2.B.157.166; | 2.B.157.169; |
2.B.157.172; | 2.B.157.175; | 2.B.157.240; | 2.B.157.244; |
2.B.166.228; | 2.B.166.229; | 2.B.166.230; | 2.B.166.231; |
2.B.166.236; | 2.B.166.237; | 2.B.166.238; | 2.B.166.239; |
2.B.166.154; | 2.B.166.157; | 2.B.166.166; | 2.B.166.169; |
2.B.166.172; | 2.B.166.175; | 2.B.166.240; | 2.B.166.244; |
2.B.169.228; | 2.B.169.229; | 2.B.169.230; | 2.B.169.231; |
2.B.169.236; | 2.B.169.237; | 2.B.169.238; | 2.B.169.239; |
2.B.169.154; | 2.B.169.157; | 2.B.169.166; | 2.B.169.169; |
2.B.169.172; | 2.B.169.175; | 2.B.169.240; | 2.B.169.244; |
2.B.172.228; | 2.B.172.229; | 2.B.172.230; | 2.B.172.231; |
2.B.172.236; | 2.B.172.237; | 2.B.172.238; | 2.B.172.239; |
2.B.172.154; | 2.B.172.157; | 2.B.172.166; | 2.B.172.169; |
2.B.172.172; | 2.B.172.175; | 2.B.172.240; | 2.B.172.244; |
2.B.175.228; | 2.B.175.229; | 2.B.175.230; | 2.B.175.231; |
2.B.175.236; | 2.B.175.237; | 2.B.175.238; | 2.B.175.239; |
2.B.175.154; | 2.B.175.157; | 2.B.175.166; | 2.B.175.169; |
2.B.175.172; | 2.B.175.175; | 2.B.175.240; | 2.B.175.244; |
2.B.240.228; | 2.B.240.229; | 2.B.240.230; | 2.B.240.231; |
2.B.240.236; | 2.B.240.237; | 2.B.240.238; | 2.B.240.239; |
2.B.240.154; | 2.B.240.157; | 2.B.240.166; | 2.B.240.169; |
2.B.240.172; | 2.B.240.175; | 2.B.240.240; | 2.B.240.244; |
2.B.244.228; | 2.B.244.229; | 2.B.244.230; | 2.B.244.231; |
2.B.244.236; | 2.B.244.237; | 2.B.244.238; | 2.B.244.239; |
2.B.244.154; | 2.B.244.157; | 2.B.244.166; | 2.B.244.169; |
2.B.244.172; | 2.B.244.175; | 2.B.244.240; | 2.B.244.244; |
2.D的前体药物
2.D.228.228; | 2.D.228.229; | 2.D.228.230; | 2.D.228.231; |
2.D.228.236; | 2.D.228.237; | 2.D.228.238; | 2.D.228.239; |
2.D.228.154; | 2.D.228.157; | 2.D.228.166; | 2.D.228.169; |
2.D.228.172; | 2.D.228.175; | 2.D.228.240; | 2.D.228.244; |
2.D.229.228; | 2.D.229.229; | 2.D.229.230; | 2.D.229.231; |
2.D.229.236; | 2.D.229.237; | 2.D.229.238; | 2.D.229.239; |
2.D.229.154; | 2.D.229.157; | 2.D.229.166; | 2.D.229.169; |
2.D.229.172; | 2.D.229.175; | 2.D.229.240; | 2.D.229.244; |
2.D.230.228; | 2.D.230.229; | 2.D.230.230; | 2.D.230.231; |
2.D.230.236; | 2.D.230.237; | 2.D.230.238; | 2.D.230.239; |
2.D.230.154; | 2.D.230.157; | 2.D.230.166; | 2.D.230.169; |
2.D.230.172; | 2.D.230.175; | 2.D.230.240; | 2.D.230.244; |
2.D.231.228; | 2.D.231.229; | 2.D.231.230; | 2.D.231.231; |
2.D.231.236; | 2.D.231.237; | 2.D.231.238; | 2.D.231.239; |
2.D.231.154; | 2.D.231.157; | 2.D.231.166; | 2.D.231.169; |
2.D.231.172; | 2.D.231.175; | 2.D.231.240; | 2.D.231.244; |
2.D.236.228; | 2.D.236.229; | 2.D.236.230; | 2.D.236.231; |
2.D.236.236; | 2.D.236.237; | 2.D.236.238; | 2.D.236.239; |
2.D.236.154; | 2.D.236.157; | 2.D.236.166; | 2.D.236.169; |
2.D.236.172; | 2.D.236.175; | 2.D.236.240; | 2.D.236.244; |
2.D.237.228; | 2.D.237.229; | 2.D.237.230; | 2.D.237.231; |
2.D.237.236; | 2.D.237.237; | 2.D.237.238; | 2.D.237.239; |
2.D.237.154; | 2.D.237.157; | 2.D.237.166; | 2.D.237.169; |
2.D.237.172; | 2.D.237.175; | 2.D.237.240; | 2.D.237.244; |
2.D.238.228; | 2.D.238.229; | 2.D.238.230; | 2.D.238.231; |
2.D.238.236; | 2.D.238.237; | 2.D.238.238; | 2.D.238.239; |
2.D.238.154; | 2.D.238.157; | 2.D.238.166; | 2.D.238.169; |
2.D.238.172; | 2.D.238.175; | 2.D.238.240; | 2.D.238.244; |
2.D.239.228; | 2.D.239.229; | 2.D.239.230; | 2.D.239.231; |
2.D.239.236; | 2.D.239.237; | 2.D.239.238; | 2.D.239.239; |
2.D.239.154; | 2.D.239.157; | 2.D.239.166; | 2.D.239.169; |
2.D.239.172; | 2.D.239.175; | 2.D.239.240; | 2.D.239.244; |
2.D.154.228; | 2.D.154.229; | 2.D.154.230; | 2.D.154.231; |
2.D.154.236; | 2.D.154.237; | 2.D.154.238; | 2.D.154.239; |
2.D.154.154; | 2.D.154.157; | 2.D.154.166; | 2.D.154.169; |
2.D.154.172; | 2.D.154.175; | 2.D.154.240; | 2.D.154.244; |
2.D.157.228; | 2.D.157.229; | 2.D.157.230; | 2.D.157.231; |
2.D.157.236; | 2.D.157.237; | 2.D.157.238; | 2.D.157.239; |
2.D.157.154; | 2.D.157.157; | 2.D.157.166; | 2.D.157.169; |
2.D.157.172; | 2.D.157.175; | 2.D.157.240; | 2.D.157.244; |
2.D.166.228; | 2.D.166.229; | 2.D.166.230; | 2.D.166.231; |
2.D.166.236; | 2.D.166.237; | 2.D.166.238; | 2.D.166.239; |
2.D.166.154; | 2.D.166.157; | 2.D.166.166; | 2.D.166.169; |
2.D.166.172; | 2.D.166.175; | 2.D.166.240; | 2.D.166.244; |
2.D.169.228; | 2.D.169.229; | 2.D.169.230; | 2.D.169.231; |
2.D.169.236; | 2.D.169.237; | 2.D.169.238; | 2.D.169.239; |
2.D.169.154; | 2.D.169.157; | 2.D.169.166; | 2.D.169.169; |
2.D.169.172; | 2.D.169.175; | 2.D.169.240; | 2.D.169.244; |
2.D.172.228; | 2.D.172.229; | 2.D.172.230; | 2.D.172.231; |
2.D.172.236; | 2.D.172.237; | 2.D.172.238; | 2.D.172.239; |
2.D.172.154; | 2.D.172.157; | 2.D.172.166; | 2.D.172.169; |
2.D.172.172; | 2.D.172.175; | 2.D.172.240; | 2.D.172.244; |
2.D.175.228; | 2.D.175.229; | 2.D.175.230; | 2.D.175.231; |
2.D.175.236; | 2.D.175.237; | 2.D.175.238; | 2.D.175.239; |
2.D.175.154; | 2.D.175.157; | 2.D.175.166; | 2.D.175.169; |
2.D.175.172; | 2.D.175.175; | 2.D.175.240; | 2.D.175.244; |
2.D.240.228; | 2.D.240.229; | 2.D.240.230; | 2.D.240.231; |
2.D.240.236; | 2.D.240.237; | 2.D.240.238; | 2.D.240.239; |
2.D.240.154; | 2.D.240.157; | 2.D.240.166; | 2.D.240.169; |
2.D.240.172; | 2.D.240.175; | 2.D.240.240; | 2.D.240.244; |
2.D.244.228; | 2.D.244.229; | 2.D.244.230; | 2.D.244.231; |
2.D.244.236; | 2.D.244.237; | 2.D.244.238; | 2.D.244.239; |
2.D.244.154; | 2.D.244.157; | 2.D.244.166; | 2.D.244.169; |
2.D.244.172; | 2.D.244.175; | 2.D.244.240; | 2.D.244.244; |
2.E的前体药物
2.E.228.228; | 2.E.228.229; | 2.E.228.230; | 2.E.228.231; |
2.E.228.236; | 2.E.228.237; | 2.E.228.238; | 2.E.228.239; |
2.E.228.154; | 2.E.228.157; | 2.E.228.166; | 2.E.228.169; |
2.E.228.172; | 2.E.228.175; | 2.E.228.240; | 2.E.228.244; |
2.E.229.228; | 2.E.229.229; | 2.E.229.230; | 2.E.229.231; |
2.E.229.236; | 2.E.229.237; | 2.E.229.238; | 2.E.229.239; |
2.E.229.154; | 2.E.229.157; | 2.E.229.166; | 2.E.229.169; |
2.E.229.172; | 2.E.229.175; | 2.E.229.240; | 2.E.229.244; |
2.E.230.228; | 2.E.230.229; | 2.E.230.230; | 2.E.230.231; |
2.E.230.236; | 2.E.230.237; | 2.E.230.238; | 2.E.230.239; |
2.E.230.154; | 2.E.230.157; | 2.E.230.166; | 2.E.230.169; |
2.E.230.172; | 2.E.230.175; | 2.E.230.240; | 2.E.230.244; |
2.E.231.228; | 2.E.231.229; | 2.E.231.230; | 2.E.231.231; |
2.E.231.236; | 2.E.231.237; | 2.E.231.238; | 2.E.231.239; |
2.E.231.154; | 2.E.231.157; | 2.E.231.166; | 2.E.231.169; |
2.E.231.172; | 2.E.231.175; | 2.E.231.240; | 2.E.231.244; |
2.E.236.228; | 2.E.236.229; | 2.E.236.230; | 2.E.236.231; |
2.E.236.236; | 2.E.236.237; | 2.E.236.238; | 2.E.236.239; |
2.E.236.154; | 2.E.236.157; | 2.E.236.166; | 2.E.236.169; |
2.E.236.172; | 2.E.236.175; | 2.E.236.240; | 2.E.236.244; |
2.E.237.228; | 2.E.237.229; | 2.E.237.230; | 2.E.237.231; |
2.E.237.236; | 2.E.237.237; | 2.E.237.238; | 2.E.237.239; |
2.E.237.154; | 2.E.237.157; | 2.E.237.166; | 2.E.237.169; |
2.E.237.172; | 2.E.237.175; | 2.E.237.240; | 2.E.237.244; |
2.E.238.228; | 2.E.238.229; | 2.E.238.230; | 2.E.238.231; |
2.E.238.236; | 2.E.238.237; | 2.E.238.238; | 2.E.238.239; |
2.E.238.154; | 2.E.238.157; | 2.E.238.166; | 2.E.238.169; |
2.E.238.172; | 2.E.238.175; | 2.E.238.240; | 2.E.238.244; |
2.E.239.228; | 2.E.239.229; | 2.E.239.230; | 2.E.239.231; |
2.E.239.236; | 2.E.239.237; | 2.E.239.238; | 2.E.239.239; |
2.E.239.154; | 2.E.239.157; | 2.E.239.166; | 2.E.239.169; |
2.E.239.172; | 2.E.239.175; | 2.E.239.240; | 2.E.239.244; |
2.E.154.228; | 2.E.154.229; | 2.E.154.230; | 2.E.154.231; |
2.E.154.236; | 2.E.154.237; | 2.E.154.238; | 2.E.154.239; |
2.E.154.154; | 2.E.154.157; | 2.E.154.166; | 2.E.154.169; |
2.E.154.172; | 2.E.154.175; | 2.E.154.240; | 2.E.154.244; |
2.E.157.228; | 2.E.157.229; | 2.E.157.230; | 2.E.157.231; |
2.E.157.236; | 2.E.157.237; | 2.E.157.238; | 2.E.157.239; |
2.E.157.154; | 2.E.157.157; | 2.E.157.166; | 2.E.157.169; |
2.E.157.172; | 2.E.157.175; | 2.E.157.240; | 2.E.157.244; |
2.E.166.228; | 2.E.166.229; | 2.E.166.230; | 2.E.166.231; |
2.E.166.236; | 2.E.166.237; | 2.E.166.238; | 2.E.166.239; |
2.E.166.154; | 2.E.166.157; | 2.E.166.166; | 2.E.166.169; |
2.E.166.172; | 2.E.166.175; | 2.E.166.240; | 2.E.166.244; |
2.E.169.228; | 2.E.169.229; | 2.E.169.230; | 2.E.169.231; |
2.E.169.236; | 2.E.169.237; | 2.E.169.238; | 2.E.169.239; |
2.E.169.154; | 2.E.169.157; | 2.E.169.166; | 2.E.169.169; |
2.E.169.172; | 2.E.169.175; | 2.E.169.240; | 2.E.169.244; |
2.E.172.228; | 2.E.172.229; | 2.E.172.230; | 2.E.172.231; |
2.E.172.236; | 2.E.172.237; | 2.E.172.238; | 2.E.172.239; |
2.E.172.154; | 2.E.172.157; | 2.E.172.166; | 2.E.172.169; |
2.E.172.172; | 2.E.172.175; | 2.E.172.240; | 2.E.172.244; |
2.E.175.228; | 2.E.175.229; | 2.E.175.230; | 2.E.175.231; |
2.E.175.236; | 2.E.175.237; | 2.E.175.238; | 2.E.175.239; |
2.E.175.154; | 2.E.175.157; | 2.E.175.166; | 2.E.175.169; |
2.E.175.172; | 2.E.175.175; | 2.E.175.240; | 2.E.175.244; |
2.E.240.228; | 2.E.240.229; | 2.E.240.230; | 2.E.240.231; |
2.E.240.236; | 2.E.240.237; | 2.E.240.238; | 2.E.240.239; |
2.E.240.154; | 2.E.240.157; | 2.E.240.166; | 2.E.240.169; |
2.E.240.172; | 2.E.240.175; | 2.E.240.240; | 2.E.240.244; |
2.E.244.228; | 2.E.244.229; | 2.E.244.230; | 2.E.244.231; |
2.E.244.236; | 2.E.244.237; | 2.E.244.238; | 2.E.244.239; |
2.E.244.154; | 2.E.244.157; | 2.E.244.166; | 2.E.244.169; |
2.E.244.172; | 2.E.244.175; | 2.E.244.240; | 2.E.244.244; |
2.G的前体药物
2.G.228.228; | 2.G.228.229; | 2.G.228.230; | 2.G.228.231; |
2.G.228.236; | 2.G.228.237; | 2.G.228.238; | 2.G.228.239; |
2.G.228.154; | 2.G.228.157; | 2.G.228.166; | 2.G.228.169; |
2.G.228.172; | 2.G.228.175; | 2.G.228.240; | 2.G.228.244; |
2.G.229.228; | 2.G.229.229; | 2.G.229.230; | 2.G.229.231; |
2.G.229.236; | 2.G.229.237; | 2.G.229.238; | 2.G.229.239; |
2.G.229.154; | 2.G.229.157; | 2.G.229.166; | 2.G.229.169; |
2.G.229.172; | 2.G.229.175; | 2.G.229.240; | 2.G.229.244; |
2.G.230.228; | 2.G.230.229; | 2.G.230.230; | 2.G.230.231; |
2.G.230.236; | 2.G.230.237; | 2.G.230.238; | 2.G.230.239; |
2.G.230.154; | 2.G.230.157; | 2.G.230.166; | 2.G.230.169; |
2.G.230.172; | 2.G.230.175; | 2.G.230.240; | 2.G.230.244; |
2.G.231.228; | 2.G.231.229; | 2.G.231.230; | 2.G.231.231; |
2.G.231.236; | 2.G.231.237; | 2.G.231.238; | 2.G.231.239; |
2.G.231.154; | 2.G.231.157; | 2.G.231.166; | 2.G.231.169; |
2.G.231.172; | 2.G.231.175; | 2.G.231.240; | 2.G.231.244; |
2.G.236.228; | 2.G.236.229; | 2.G.236.230; | 2.G.236.231; |
2.G.236.236; | 2.G.236.237; | 2.G.236.238; | 2.G.236.239; |
2.G.236.154; | 2.G.236.157; | 2.G.236.166; | 2.G.236.169; |
2.G.236.172; | 2.G.236.175; | 2.G.236.240; | 2.G.236.244; |
2.G.237.228; | 2.G.237.229; | 2.G.237.230; | 2.G.237.231; |
2.G.237.236; | 2.G.237.237; | 2.G.237.238; | 2.G.237.239; |
2.G.237.154; | 2.G.237.157; | 2.G.237.166; | 2.G.237.169; |
2.G.237.172; | 2.G.237.175; | 2.G.237.240; | 2.G.237.244; |
2.G.238.228; | 2.G.238.229; | 2.G.238.230; | 2.G.238.231; |
2.G.238.236; | 2.G.238.237; | 2.G.238.238; | 2.G.238.239; |
2.G.238.154; | 2.G.238.157; | 2.G.238.166; | 2.G.238.169; |
2.G.238.172; | 2.G.238.175; | 2.G.238.240; | 2.G.238.244; |
2.G.239.228; | 2.G.239.229; | 2.G.239.230; | 2.G.239.231; |
2.G.239.236; | 2.G.239.237; | 2.G.239.238; | 2.G.239.239; |
2.G.239.154; | 2.G.239.157; | 2.G.239.166; | 2.G.239.169; |
2.G.239.172; | 2.G.239.175; | 2.G.239.240; | 2.G.239.244; |
2.G.154.228; | 2.G.154.229; | 2.G.154.230; | 2.G.154.231; |
2.G.154.236; | 2.G.154.237; | 2.G.154.238; | 2.G.154.239; |
2.G.154.154; | 2.G.154.157; | 2.G.154.166; | 2.G.154.169; |
2.G.154.172; | 2.G.154.175; | 2.G.154.240; | 2.G.154.244; |
2.G.157.228; | 2.G.157.229; | 2.G.157.230; | 2.G.157.231; |
2.G.157.236; | 2.G.157.237; | 2.G.157.238; | 2.G.157.239; |
2.G.157.154; | 2.G.157.157; | 2.G.157.166; | 2.G.157.169; |
2.G.157.172; | 2.G.157.175; | 2.G.157.240; | 2.G.157.244; |
2.G.166.228; | 2.G.166.229; | 2.G.166.230; | 2.G.166.231; |
2.G.166.236; | 2.G.166.237; | 2.G.166.238; | 2.G.166.239; |
2.G.166.154; | 2.G.166.157; | 2.G.166.166; | 2.G.166.169; |
2.G.166.172; | 2.G.166.175; | 2.G.166.240; | 2.G.166.244; |
2.G.169.228; | 2.G.169.229; | 2.G.169.230; | 2.G.169.231; |
2.G.169.236; | 2.G.169.237; | 2.G.169.238; | 2.G.169.239; |
2.G.169.154; | 2.G.169.157; | 2.G.169.166; | 2.G.169.169; |
2.G.169.172; | 2.G.169.175; | 2.G.169.240; | 2.G.169.244; |
2.G.172.228; | 2.G.172.229; | 2.G.172.230; | 2.G.172.231; |
2.G.172.236; | 2.G.172.237; | 2.G.172.238; | 2.G.172.239; |
2.G.172.154; | 2.G.172.157; | 2.G.172.166; | 2.G.172.169; |
2.G.172.172; | 2.G.172.175; | 2.G.172.240; | 2.G.172.244; |
2.G.175.228; | 2.G.175.229; | 2.G.175.230; | 2.G.175.231; |
2.G.175.236; | 2.G.175.237; | 2.G.175.238; | 2.G.175.239; |
2.G.175.154; | 2.G.175.157; | 2.G.175.166; | 2.G.175.169; |
2.G.175.172; | 2.G.175.175; | 2.G.175.240; | 2.G.175.244; |
2.G.240.228; | 2.G.240.229; | 2.G.240.230; | 2.G.240.231; |
2.G.240.236; | 2.G.240.237; | 2.G.240.238; | 2.G.240.239; |
2.G.240.154; | 2.G.240.157; | 2.G.240.166; | 2.G.240.169; |
2.G.240.172; | 2.G.240.175; | 2.G.240.240; | 2.G.240.244; |
2.G.244.228; | 2.G.244.229; | 2.G.244.230; | 2.G.244.231; |
2.G.244.236; | 2.G.244.237; | 2.G.244.238; | 2.G.244.239; |
2.G.244.154; | 2.G.244.157; | 2.G.244.166; | 2.G.244.169; |
2.G.244.172; | 2.G.244.175; | 2.G.244.240; | 2.G.244.244; |
2.I的前体药物
2.I.228.228; | 2.I.228.229; | 2.I.228.230; | 2.I.228.231; |
2.I.228.236; | 2.I.228.237; | 2.I.228.238; | 2.I.228.239; |
2.I.228.154; | 2.I.228.157; | 2.I.228.166; | 2.I.228.169; |
2.I.228.172; | 2.I.228.175; | 2.I.228.240; | 2.I.228.244; |
2.I.229.228; | 2.I.229.229; | 2.I.229.230; | 2.I.229.231; |
2.I.229.236; | 2.I.229.237; | 2.I.229.238; | 2.I.229.239; |
2.I.229.154; | 2.I.229.157; | 2.I.229.166; | 2.I.229.169; |
2.I.229.172; | 2.I.229.175; | 2.I.229.240; | 2.I.229.244; |
2.I.230.228; | 2.I.230.229; | 2.I.230.230; | 2.I.230.231; |
2.I.230.236; | 2.I.230.237; | 2.I.230.238; | 2.I.230.239; |
2.I.230.154; | 2.I.230.157; | 2.I.230.166; | 2.I.230.169; |
2.I.230.172; | 2.I.230.175; | 2.I.230.240; | 2.I.230.244; |
2.I.231.228; | 2.I.231.229; | 2.I.231.230; | 2.I.231.231; |
2.I.231.236; | 2.I.231.237; | 2.I.231.238; | 2.I.231.239; |
2.I.231.154; | 2.I.231.157; | 2.I.231.166; | 2.I.231.169; |
2.I.231.172; | 2.I.231.175; | 2.I.231.240; | 2.I.231.244; |
2.I.236.228; | 2.I.236.229; | 2.I.236.230; | 2.I.236.231; |
2.I.236.236; | 2.I.236.237; | 2.I.236.238; | 2.I.236.239; |
2.I.236.154; | 2.I.236.157; | 2.I.236.166; | 2.I.236.169; |
2.I.236.172; | 2.I.236.175; | 2.I.236.240; | 2.I.236.244; |
2.I.237.228; | 2.I.237.229; | 2.I.237.230; | 2.I.237.231; |
2.I.237.236; | 2.I.237.237; | 2.I.237.238; | 2.I.237.239; |
2.I.237.154; | 2.I.237.157; | 2.I.237.166; | 2.I.237.169; |
2.I.237.172; | 2.I.237.175; | 2.I.237.240; | 2.I.237.244; |
2.I.238.228; | 2.I.238.229; | 2.I.238.230; | 2.I.238.231; |
2.I.238.236; | 2.I.238.237; | 2.I.238.238; | 2.I.238.239; |
2.I.238.154; | 2.I.238.157; | 2.I.238.166; | 2.I.238.169; |
2.I.238.172; | 2.I.238.175; | 2.I.238.240; | 2.I.238.244; |
2.I.239.228; | 2.I.239.229; | 2.I.239.230; | 2.I.239.231; |
2.I.239.236; | 2.I.239.237; | 2.I.239.238; | 2.I.239.239; |
2.I.239.154; | 2.I.239.157; | 2.I.239.166; | 2.I.239.169; |
2.I.239.172; | 2.I.239.175; | 2.I.239.240; | 2.I.239.244; |
2.I.154.228; | 2.I.154.229; | 2.I.154.230; | 2.I.154.231; |
2.I.154.236; | 2.I.154.237; | 2.I.154.238; | 2.I.154.239; |
2.I.154.154; | 2.I.154.157; | 2.I.154.166; | 2.I.154.169; |
2.I.154.172; | 2.I.154.175; | 2.I.154.240; | 2.I.154.244; |
2.I.157.228; | 2.I.157.229; | 2.I.157.230; | 2.I.157.231; |
2.I.157.236; | 2.I.157.237; | 2.I.157.238; | 2.I.157.239; |
2.I.157.154; | 2.I.157.157; | 2.I.157.166; | 2.I.157.169; |
2.I.157.172; | 2.I.157.175; | 2.I.157.240; | 2.I.157.244; |
2.I.166.228; | 2.I.166.229; | 2.I.166.230; | 2.I.166.231; |
2.I.166.236; | 2.I.166.237; | 2.I.166.238; | 2.I.166.239; |
2.I.166.154; | 2.I.166.157; | 2.I.166.166; | 2.I.166.169; |
2.I.166.172; | 2.I.166.175; | 2.I.166.240; | 2.I.166.244; |
2.I.169.228; | 2.I.169.229; | 2.I.169.230; | 2.I.169.231; |
2.I.169.236; | 2.I.169.237; | 2.I.169.238; | 2.I.169.239; |
2.I.169.154; | 2.I.169.157; | 2.I.169.166; | 2.I.169.169; |
2.I.169.172; | 2.I.169.175; | 2.I.169.240; | 2.I.169.244; |
2.I.172.228; | 2.I.172.229; | 2.I.172.230; | 2.I.172.231; |
2.I.172.236; | 2.I.172.237; | 2.I.172.238; | 2.I.172.239; |
2.I.172.154; | 2.I.172.157; | 2.I.172.166; | 2.I.172.169; |
2.I.172.172; | 2.I.172.175; | 2.I.172.240; | 2.I.172.244; |
2.I.175.228; | 2.I.175.229; | 2.I.175.230; | 2.I.175.231; |
2.I.175.236; | 2.I.175.237; | 2.I.175.238; | 2.I.175.239; |
2.I.175.154; | 2.I.175.157; | 2.I.175.166; | 2.I.175.169; |
2.I.175.172; | 2.I.175.175; | 2.I.175.240; | 2.I.175.244; |
2.I.240.228; | 2.I.240.229; | 2.I.240.230; | 2.I.240.231; |
2.I.240.236; | 2.I.240.237; | 2.I.240.238; | 2.I.240.239; |
2.I.240.154; | 2.I.240.157; | 2.I.240.166; | 2.I.240.169; |
2.I.240.172; | 2.I.240.175; | 2.I.240.240; | 2.I.240.244; |
2.I.244.228; | 2.I.244.229; | 2.I.244.230; | 2.I.244.231; |
2.I.244.236; | 2.I.244.237; | 2.I.244.238; | 2.I.244.239; |
2.I.244.154; | 2.I.244.157; | 2.I.244.166; | 2.I.244.169; |
2.I.244.172; | 2.I.244.175; | 2.I.244.240; | 2.I.244.244; |
2.J的前体药物
2.J.228.228; | 2.J.228.229; | 2.J.228.230; | 2.J.228.231; |
2.J.228.236; | 2.J.228.237; | 2.J.228.238; | 2.J.228.239; |
2.J.228.154; | 2.J.228.157; | 2.J.228.166; | 2.J.228.169; |
2.J.228.172; | 2.J.228.175; | 2.J.228.240; | 2.J.228.244; |
2.J.229.228; | 2.J.229.229; | 2.J.229.230; | 2.J.229.231; |
2.J.229.236; | 2.J.229.237; | 2.J.229.238; | 2.J.229.239; |
2.J.229.154; | 2.J.229.157; | 2.J.229.166; | 2.J.229.169; |
2.J.229.172; | 2.J.229.175; | 2.J.229.240; | 2.J.229.244; |
2.J.230.228; | 2.J.230.229; | 2.J.230.230; | 2.J.230.231; |
2.J.230.236; | 2.J.230.237; | 2.J.230.238; | 2.J.230.239; |
2.J.230.154; | 2.J.230.157; | 2.J.230.166; | 2.J.230.169; |
2.J.230.172; | 2.J.230.175; | 2.J.230.240; | 2.J.230.244; |
2.J.231.228; | 2.J.231.229; | 2.J.231.230; | 2.J.231.231; |
2.J.231.236; | 2.J.231.237; | 2.J.231.238; | 2.J.231.239; |
2.J.231.154; | 2.J.231.157; | 2.J.231.166; | 2.J.231.169; |
2.J.231.172; | 2.J.231.175; | 2.J.231.240; | 2.J.231.244; |
2.J.236.228; | 2.J.236.229; | 2.J.236.230; | 2.J.236.231; |
2.J.236.236; | 2.J.236.237; | 2.J.236.238; | 2.J.236.239; |
2.J.236.154; | 2.J.236.157; | 2.J.236.166; | 2.J.236.169; |
2.J.236.172; | 2.J.236.175; | 2.J.236.240; | 2.J.236.244; |
2.J.237.228; | 2.J.237.229; | 2.J.237.230; | 2.J.237.231; |
2.J.237.236; | 2.J.237.237; | 2.J.237.238; | 2.J.237.239; |
2.J.237.154; | 2.J.237.157; | 2.J.237.166; | 2.J.237.169; |
2.J.237.172; | 2.J.237.175; | 2.J.237.240; | 2.J.237.244; |
2.J.238.228; | 2.J.238.229; | 2.J.238.230; | 2.J.238.231; |
2.J.238.236; | 2.J.238.237; | 2.J.238.238; | 2.J.238.239; |
2.J.238.154; | 2.J.238.157; | 2.J.238.166; | 2.J.238.169; |
2.J.238.172; | 2.J.238.175; | 2.J.238.240; | 2.J.238.244; |
2.J.239.228; | 2.J.239.229; | 2.J.239.230; | 2.J.239.231; |
2.J.239.236; | 2.J.239.237; | 2.J.239.238; | 2.J.239.239; |
2.J.239.154; | 2.J.239.157; | 2.J.239.166; | 2.J.239.169; |
2.J.239.172; | 2.J.239.175; | 2.J.239.240; | 2.J.239.244; |
2.J.154.228; | 2.J.154.229; | 2.J.154.230; | 2.J.154.231; |
2.J.154.236; | 2.J.154.237; | 2.J.154.238; | 2.J.154.239; |
2.J.154.154; | 2.J.154.157; | 2.J.154.166; | 2.J.154.169; |
2.J.154.172; | 2.J.154.175; | 2.J.154.240; | 2.J.154.244; |
2.J.157.228; | 2.J.157.229; | 2.J.157.230; | 2.J.157.231; |
2.J.157.236; | 2.J.157.237; | 2.J.157.238; | 2.J.157.239; |
2.J.157.154; | 2.J.157.157; | 2.J.157.166; | 2.J.157.169; |
2.J.157.172; | 2.J.157.175; | 2.J.157.240; | 2.J.157.244; |
2.J.166.228; | 2.J.166.229; | 2.J.166.230; | 2.J.166.231; |
2.J.166.236; | 2.J.166.237; | 2.J.166.238; | 2.J.166.239; |
2.J.166.154; | 2.J.166.157; | 2.J.166.166; | 2.J.166.169; |
2.J.166.172; | 2.J.166.175; | 2.J.166.240; | 2.J.166.244; |
2.J.169.228; | 2.J.169.229; | 2.J.169.230; | 2.J.169.231; |
2.J.169.236; | 2.J.169.237; | 2.J.169.238; | 2.J.169.239; |
2.J.169.154; | 2.J.169.157; | 2.J.169.166; | 2.J.169.169; |
2.J.169.172; | 2.J.169.175; | 2.J.169.240; | 2.J.169.244; |
2.J.172.228; | 2.J.172.229; | 2.J.172.230; | 2.J.172.231; |
2.J.172.236; | 2.J.172.237; | 2.J.172.238; | 2.J.172.239; |
2.J.172.154; | 2.J.172.157; | 2.J.172.166; | 2.J.172.169; |
2.J.172.172; | 2.J.172.175; | 2.J.172.240; | 2.J.172.244; |
2.J.175.228; | 2.J.175.229; | 2.J.175.230; | 2.J.175.231; |
2.J.175.236; | 2.J.175.237; | 2.J.175.238; | 2.J.175.239; |
2.J.175.154; | 2.J.175.157; | 2.J.175.166; | 2.J.175.169; |
2.J.175.172; | 2.J.175.175; | 2.J.175.240; | 2.J.175.244; |
2.J.240.228; | 2.J.240.229; | 2.J.240.230; | 2.J.240.231; |
2.J.240.236; | 2.J.240.237; | 2.J.240.238; | 2.J.240.239; |
2.J.240.154; | 2.J.240.157; | 2.J.240.166; | 2.J.240.169; |
2.J.240.172; | 2.J.240.175; | 2.J.240.240; | 2.J.240.244; |
2.J.244.228; | 2.J.244.229; | 2.J.244.230; | 2.J.244.231; |
2.J.244.236; | 2.J.244.237; | 2.J.244.238; | 2.J.244.239; |
2.J.244.154; | 2.J.244.157; | 2.J.244.166; | 2.J.244.169; |
2.J.244.172; | 2.J.244.175; | 2.J.244.240; | 2.J.244.244; |
2.L的前体药物
2.L.228.228; | 2.L.228.229; | 2.L.228.230; | 2.L.228.231; |
2.L.228.236; | 2.L.228.237; | 2.L.228.238; | 2.L.228.239; |
2.L.228.154; | 2.L.228.157; | 2.L.228.166; | 2.L.228.169; |
2.L.228.172; | 2.L.228.175; | 2.L.228.240; | 2.L.228.244; |
2.L.229.228; | 2.L.229.229; | 2.L.229.230; | 2.L.229.231; |
2.L.229.236; | 2.L.229.237; | 2.L.229.238; | 2.L.229.239; |
2.L.229.154; | 2.L.229.157; | 2.L.229.166; | 2.L.229.169; |
2.L.229.172; | 2.L.229.175; | 2.L.229.240; | 2.L.229.244; |
2.L.230.228; | 2.L.230.229; | 2.L.230.230; | 2.L.230.231; |
2.L.230.236; | 2.L.230.237; | 2.L.230.238; | 2.L.230.239; |
2.L.230.154; | 2.L.230.157; | 2.L.230.166; | 2.L.230.169; |
2.L.230.172; | 2.L.230.175; | 2.L.230.240; | 2.L.230.244; |
2.L.231.228; | 2.L.231.229; | 2.L.231.230; | 2.L.231.231; |
2.L.231.236; | 2.L.231.237; | 2.L.231.238; | 2.L.231.239; |
2.L.231.154; | 2.L.231.157; | 2.L.231.166; | 2.L.231.169; |
2.L.231.172; | 2.L.231.175; | 2.L.231.240; | 2.L.231.244; |
2.L.236.228; | 2.L.236.229; | 2.L.236.230; | 2.L.236.231; |
2.L.236.236; | 2.L.236.237; | 2.L.236.238; | 2.L.236.239; |
2.L.236.154; | 2.L.236.157; | 2.L.236.166; | 2.L.236.169; |
2.L.236.172; | 2.L.236.175; | 2.L.236.240; | 2.L.236.244; |
2.L.237.228; | 2.L.237.229; | 2.L.237.230; | 2.L.237.231; |
2.L.237.236; | 2.L.237.237; | 2.L.237.238; | 2.L.237.239; |
2.L.237.154; | 2.L.237.157; | 2.L.237.166; | 2.L.237.169; |
2.L.237.172; | 2.L.237.175; | 2.L.237.240; | 2.L.237.244; |
2.L.238.228; | 2.L.238.229; | 2.L.238.230; | 2.L.238.231; |
2.L.238.236; | 2.L.238.237; | 2.L.238.238; | 2.L.238.239; |
2.L.238.154; | 2.L.238.157; | 2.L.238.166; | 2.L.238.169; |
2.L.238.172; | 2.L.238.175; | 2.L.238.240; | 2.L.238.244; |
2.L.239.228; | 2.L.239.229; | 2.L.239.230; | 2.L.239.231; |
2.L.239.236; | 2.L.239.237; | 2.L.239.238; | 2.L.239.239; |
2.L.239.154; | 2.L.239.157; | 2.L.239.166; | 2.L.239.169; |
2.L.239.172; | 2.L.239.175; | 2.L.239.240; | 2.L.239.244; |
2.L.154.228; | 2.L.154.229; | 2.L.154.230; | 2.L.154.231; |
2.L.154.236; | 2.L.154.237; | 2.L.154.238; | 2.L.154.239; |
2.L.154.154; | 2.L.154.157; | 2.L.154.166; | 2.L.154.169; |
2.L.154.172; | 2.L.154.175; | 2.L.154.240; | 2.L.154.244; |
2.L.157.228; | 2.L.157.229; | 2.L.157.230; | 2.L.157.231; |
2.L.157.236; | 2.L.157.237; | 2.L.157.238; | 2.L.157.239; |
2.L.157.154; | 2.L.157.157; | 2.L.157.166; | 2.L.157.169; |
2.L.157.172; | 2.L.157.175; | 2.L.157.240; | 2.L.157.244; |
2.L.166.228; | 2.L.166.229; | 2.L.166.230; | 2.L.166.231; |
2.L.166.236; | 2.L.166.237; | 2.L.166.238; | 2.L.166.239; |
2.L.166.154; | 2.L.166.157; | 2.L.166.166; | 2.L.166.169; |
2.L.166.172; | 2.L.166.175; | 2.L.166.240; | 2.L.166.244; |
2.L.169.228; | 2.L.169.229; | 2.L.169.230; | 2.L.169.231; |
2.L.169.236; | 2.L.169.237; | 2.L.169.238; | 2.L.169.239; |
2.L.169.154; | 2.L.169.157; | 2.L.169.166; | 2.L.169.169; |
2.L.169.172; | 2.L.169.175; | 2.L.169.240; | 2.L.169.244; |
2.L.172.228; | 2.L.172.229; | 2.L.172.230; | 2.L.172.231; |
2.L.172.236; | 2.L.172.237; | 2.L.172.238; | 2.L.172.239; |
2.L.172.154; | 2.L.172.157; | 2.L.172.166; | 2.L.172.169; |
2.L.172.172; | 2.L.172.175; | 2.L.172.240; | 2.L.172.244; |
2.L.175.228; | 2.L.175.229; | 2.L.175.230; | 2.L.175.231; |
2.L.175.236; | 2.L.175.237; | 2.L.175.238; | 2.L.175.239; |
2.L.175.154; | 2.L.175.157; | 2.L.175.166; | 2.L.175.169; |
2.L.175.172; | 2.L.175.175; | 2.L.175.240; | 2.L.175.244; |
2.L.240.228; | 2.L.240.229; | 2.L.240.230; | 2.L.240.231; |
2.L.240.236; | 2.L.240.237; | 2.L.240.238; | 2.L.240.239; |
2.L.240.154; | 2.L.240.157; | 2.L.240.166; | 2.L.240.169; |
2.L.240.172; | 2.L.240.175; | 2.L.240.240; | 2.L.240.244; |
2.L.244.228; | 2.L.244.229; | 2.L.244.230; | 2.L.244.231; |
2.L.244.236; | 2.L.244.237; | 2.L.244.238; | 2.L.244.239; |
2.L.244.154; | 2.L.244.157; | 2.L.244.166; | 2.L.244.169; |
2.L.244.172; | 2.L.244.175; | 2.L.244.240; | 2.L.244.244; |
2.O的前体药物
2.O.228.228; | 2.O.228.229; | 2.O.228.230; | 2.O.228.231; |
2.O.228.236; | 2.O.228.237; | 2.O.228.238; | 2.O.228.239; |
2.O.228.154; | 2.O.228.157; | 2.O.228.166; | 2.O.228.169; |
2.O.228.172; | 2.O.228.175; | 2.O.228.240; | 2.O.228.244; |
2.O.229.228; | 2.O.229.229; | 2.O.229.230; | 2.O.229.231; |
2.O.229.236; | 2.O.229.237; | 2.O.229.238; | 2.O.229.239; |
2.O.229.154; | 2.O.229.157; | 2.O.229.166; | 2.O.229.169; |
2.O.229.172; | 2.O.229.175; | 2.O.229.240; | 2.O.229.244; |
2.O.230.228; | 2.O.230.229; | 2.O.230.230; | 2.O.230.231; |
2.O.230.236; | 2.O.230.237; | 2.O.230.238; | 2.O.230.239; |
2.O.230.154; | 2.O.230.157; | 2.O.230.166; | 2.O.230.169; |
2.O.230.172; | 2.O.230.175; | 2.O.230.240; | 2.O.230.244; |
2.O.231.228; | 2.O.231.229; | 2.O.231.230; | 2.O.231.231; |
2.O.231.236; | 2.O.231.237; | 2.O.231.238; | 2.O.231.239; |
2.O.231.154; | 2.O.231.157; | 2.O.231.166; | 2.O.231.169; |
2.O.231.172; | 2.O.231.175; | 2.O.231.240; | 2.O.231.244; |
2.O.236.228; | 2.O.236.229; | 2.O.236.230; | 2.O.236.231; |
2.O.236.236; | 2.O.236.237; | 2.O.236.238; | 2.O.236.239; |
2.O.236.154; | 2.O.236.157; | 2.O.236.166; | 2.O.236.169; |
2.O.236.172; | 2.O.236.175; | 2.O.236.240; | 2.O.236.244; |
2.O.237.228; | 2.O.237.229; | 2.O.237.230; | 2.O.237.231; |
2.O.237.236; | 2.O.237.237; | 2.O.237.238; | 2.O.237.239; |
2.O.237.154; | 2.O.237.157; | 2.O.237.166; | 2.O.237.169; |
2.O.237.172; | 2.O.237.175; | 2.O.237.240; | 2.O.237.244; |
2.O.238.228; | 2.O.238.229; | 2.O.238.230; | 2.O.238.231; |
2.O.238.236; | 2.O.238.237; | 2.O.238.238; | 2.O.238.239; |
2.O.238.154; | 2.O.238.157; | 2.O.238.166; | 2.O.238.169; |
2.O.238.172; | 2.O.238.175; | 2.O.238.240; | 2.O.238.244; |
2.O.239.228; | 2.O.239.229; | 2.O.239.230; | 2.O.239.231; |
2.O.239.236; | 2.O.239.237; | 2.O.239.238; | 2.O.239.239; |
2.O.239.154; | 2.O.239.157; | 2.O.239.166; | 2.O.239.169; |
2.O.239.172; | 2.O.239.175; | 2.O.239.240; | 2.O.239.244; |
2.O.154.228; | 2.O.154.229; | 2.O.154.230; | 2.O.154.231; |
2.O.154.236; | 2.O.154.237; | 2.O.154.238; | 2.O.154.239; |
2.O.154.154; | 2.O.154.157; | 2.O.154.166; | 2.O.154.169; |
2.O.154.172; | 2.O.154.175; | 2.O.154.240; | 2.O.154.244; |
2.O.157.228; | 2.O.157.229; | 2.O.157.230; | 2.O.157.231; |
2.O.157.236; | 2.O.157.237; | 2.O.157.238; | 2.O.157.239; |
2.O.157.154; | 2.O.157.157; | 2.O.157.166; | 2.O.157.169; |
2.O.157.172; | 2.O.157.175; | 2.O.157.240; | 2.O.157.244; |
2.O.166.228; | 2.O.166.229; | 2.O.166.230; | 2.O.166.231; |
2.O.166.236; | 2.O.166.237; | 2.O.166.238; | 2.O.166.239; |
2.O.166.154; | 2.O.166.157; | 2.O.166.166; | 2.O.166.169; |
2.O.166.172; | 2.O.166.175; | 2.O.166.240; | 2.O.166.244; |
2.O.169.228; | 2.O.169.229; | 2.O.169.230; | 2.O.169.231; |
2.O.169.236; | 2.O.169.237; | 2.O.169.238; | 2.O.169.239; |
2.O.169.154; | 2.O.169.157; | 2.O.169.166; | 2.O.169.169; |
2.O.169.172; | 2.O.169.175; | 2.O.169.240; | 2.O.169.244; |
2.O.172.228; | 2.O.172.229; | 2.O.172.230; | 2.O.172.231; |
2.O.172.236; | 2.O.172.237; | 2.O.172.238; | 2.O.172.239; |
2.O.172.154; | 2.O.172.157; | 2.O.172.166; | 2.O.172.169; |
2.O.172.172; | 2.O.172.175; | 2.O.172.240; | 2.O.172.244; |
2.O.175.228; | 2.O.175.229; | 2.O.175.230; | 2.O.175.231; |
2.O.175.236; | 2.O.175.237; | 2.O.175.238; | 2.O.175.239; |
2.O.175.154; | 2.O.175.157; | 2.O.175.166; | 2.O.175.169; |
2.O.175.172; | 2.O.175.175; | 2.O.175.240; | 2.O.175.244; |
2.O.240.228; | 2.O.240.229; | 2.O.240.230; | 2.O.240.231; |
2.O.240.236; | 2.O.240.237; | 2.O.240.238; | 2.O.240.239; |
2.O.240.154; | 2.O.240.157; | 2.O.240.166; | 2.O.240.169; |
2.O.240.172; | 2.O.240.175; | 2.O.240.240; | 2.O.240.244; |
2.O.244.228; | 2.O.244.229; | 2.O.244.230; | 2.O.244.231; |
2.O.244.236; | 2.O.244.237; | 2.O.244.238; | 2.O.244.239; |
2.O.244.154; | 2.O.244.157; | 2.O.244.166; | 2.O.244.169; |
2.O.244.172; | 2.O.244.175; | 2.O.244.240; | 2.O.244.244; |
2.P的前体药物
2.P.228.228; | 2.P.228.229; | 2.P.228.230; | 2.P.228.231; |
2.P.228.236; | 2.P.228.237; | 2.P.228.238; | 2.P.228.239; |
2.P.228.154; | 2.P.228.157; | 2.P.228.166; | 2.P.228.169; |
2.P.228.172; | 2.P.228.175; | 2.P.228.240; | 2.P.228.244; |
2.P.229.228; | 2.P.229.229; | 2.P.229.230; | 2.P.229.231; |
2.P.229.236; | 2.P.229.237; | 2.P.229.238; | 2.P.229.239; |
2.P.229.154; | 2.P.229.157; | 2.P.229.166; | 2.P.229.169; |
2.P.229.172; | 2.P.229.175; | 2.P.229.240; | 2.P.229.244; |
2.P.230.228; | 2.P.230.229; | 2.P.230.230; | 2.P.230.231; |
2.P.230.236; | 2.P.230.237; | 2.P.230.238; | 2.P.230.239; |
2.P.230.154; | 2.P.230.157; | 2.P.230.166; | 2.P.230.169; |
2.P.230.172; | 2.P.230.175; | 2.P.230.240; | 2.P.230.244; |
2.P.231.228; | 2.P.231.229; | 2.P.231.230; | 2.P.231.231; |
2.P.231.236; | 2.P.231.237; | 2.P.231.238; | 2.P.231.239; |
2.P.231.154; | 2.P.231.157; | 2.P.231.166; | 2.P.231.169; |
2.P.231.172; | 2.P.231.175; | 2.P.231.240; | 2.P.231.244; |
2.P.236.228; | 2.P.236.229; | 2.P.236.230; | 2.P.236.231; |
2.P.236.236; | 2.P.236.237; | 2.P.236.238; | 2.P.236.239; |
2.P.236.154; | 2.P.236.157; | 2.P.236.166; | 2.P.236.169; |
2.P.236.172; | 2.P.236.175; | 2.P.236.240; | 2.P.236.244; |
2.P.237.228; | 2.P.237.229; | 2.P.237.230; | 2.P.237.231; |
2.P.237.236; | 2.P.237.237; | 2.P.237.238; | 2.P.237.239; |
2.P.237.154; | 2.P.237.157; | 2.P.237.166; | 2.P.237.169; |
2.P.237.172; | 2.P.237.175; | 2.P.237.240; | 2.P.237.244; |
2.P.238.228; | 2.P.238.229; | 2.P.238.230; | 2.P.238.231; |
2.P.238.236; | 2.P.238.237; | 2.P.238.238; | 2.P.238.239; |
2.P.238.154; | 2.P.238.157; | 2.P.238.166; | 2.P.238.169; |
2.P.238.172; | 2.P.238.175; | 2.P.238.240; | 2.P.238.244; |
2.P.239.228; | 2.P.239.229; | 2.P.239.230; | 2.P.239.231; |
2.P.239.236; | 2.P.239.237; | 2.P.239.238; | 2.P.239.239; |
2.P.239.154; | 2.P.239.157; | 2.P.239.166; | 2.P.239.169; |
2.P.239.172; | 2.P.239.175; | 2.P.239.240; | 2.P.239.244; |
2.P.154.228; | 2.P.154.229; | 2.P.154.230; | 2.P.154.231; |
2.P.154.236; | 2.P.154.237; | 2.P.154.238; | 2.P.154.239; |
2.P.154.154; | 2.P.154.157; | 2.P.154.166; | 2.P.154.169; |
2.P.154.172; | 2.P.154.175; | 2.P.154.240; | 2.P.154.244; |
2.P.157.228; | 2.P.157.229; | 2.P.157.230; | 2.P.157.231; |
2.P.157.236; | 2.P.157.237; | 2.P.157.238; | 2.P.157.239; |
2.P.157.154; | 2.P.157.157; | 2.P.157.166; | 2.P.157.169; |
2.P.157.172; | 2.P.157.175; | 2.P.157.240; | 2.P.157.244; |
2.P.166.228; | 2.P.166.229; | 2.P.166.230; | 2.P.166.231; |
2.P.166.236; | 2.P.166.237; | 2.P.166.238; | 2.P.166.239; |
2.P.166.154; | 2.P.166.157; | 2.P.166.166; | 2.P.166.169; |
2.P.166.172; | 2.P.166.175; | 2.P.166.240; | 2.P.166.244; |
2.P.169.228; | 2.P.169.229; | 2.P.169.230; | 2.P.169.231; |
2.P.169.236; | 2.P.169.237; | 2.P.169.238; | 2.P.169.239; |
2.P.169.154; | 2.P.169.157; | 2.P.169.166; | 2.P.169.169; |
2.P.169.172; | 2.P.169.175; | 2.P.169.240; | 2.P.169.244; |
2.P.172.228; | 2.P.172.229; | 2.P.172.230; | 2.P.172.231; |
2.P.172.236; | 2.P.172.237; | 2.P.172.238; | 2.P.172.239; |
2.P.172.154; | 2.P.172.157; | 2.P.172.166; | 2.P.172.169; |
2.P.172.172; | 2.P.172.175; | 2.P.172.240; | 2.P.172.244; |
2.P.175.228; | 2.P.175.229; | 2.P.175.230; | 2.P.175.231; |
2.P.175.236; | 2.P.175.237; | 2.P.175.238; | 2.P.175.239; |
2.P.175.154; | 2.P.175.157; | 2.P.175.166; | 2.P.175.169; |
2.P.175.172; | 2.P.175.175; | 2.P.175.240; | 2.P.175.244; |
2.P.240.228; | 2.P.240.229; | 2.P.240.230; | 2.P.240.231; |
2.P.240.236; | 2.P.240.237; | 2.P.240.238; | 2.P.240.239; |
2.P.240.154; | 2.P.240.157; | 2.P.240.166; | 2.P.240.169; |
2.P.240.172; | 2.P.240.175; | 2.P.240.240; | 2.P.240.244; |
2.P.244.228; | 2.P.244.229; | 2.P.244.230; | 2.P.244.231; |
2.P.244.236; | 2.P.244.237; | 2.P.244.238; | 2.P.244.239; |
2.P.244.154; | 2.P.244.157; | 2.P.244.166; | 2.P.244.169; |
2.P.244.172; | 2.P.244.175; | 2.P.244.240; | 2.P.244.244; |
2.U的前体药物
2.U.228.228; | 2.U.228.229; | 2.U.228.230; | 2.U.228.231; |
2.U.228.236; | 2.U.228.237; | 2.U.228.238; | 2.U.228.239; |
2.U.228.154; | 2.U.228.157; | 2.U.228.166; | 2.U.228.169; |
2.U.228.172; | 2.U.228.175; | 2.U.228.240; | 2.U.228.244; |
2.U.229.228; | 2.U.229.229; | 2.U.229.230; | 2.U.229.231; |
2.U.229.236; | 2.U.229.237; | 2.U.229.238; | 2.U.229.239; |
2.U.229.154; | 2.U.229.157; | 2.U.229.166; | 2.U.229.169; |
2.U.229.172; | 2.U.229.175; | 2.U.229.240; | 2.U.229.244; |
2.U.230.228; | 2.U.230.229; | 2.U.230.230; | 2.U.230.231; |
2.U.230.236; | 2.U.230.237; | 2.U.230.238; | 2.U.230.239; |
2.U.230.154; | 2.U.230.157; | 2.U.230.166; | 2.U.230.169; |
2.U.230.172; | 2.U.230.175; | 2.U.230.240; | 2.U.230.244; |
2.U.231.228; | 2.U.231.229; | 2.U.231.230; | 2.U.231.231; |
2.U.231.236; | 2.U.231.237; | 2.U.231.238; | 2.U.231.239; |
2.U.231.154; | 2.U.231.157; | 2.U.231.166; | 2.U.231.169; |
2.U.231.172; | 2.U.231.175; | 2.U.231.240; | 2.U.231.244; |
2.U.236.228; | 2.U.236.229; | 2.U.236.230; | 2.U.236.231; |
2.U.236.236; | 2.U.236.237; | 2.U.236.238; | 2.U.236.239; |
2.U.236.154; | 2.U.236.157; | 2.U.236.166; | 2.U.236.169; |
2.U.236.172; | 2.U.236.175; | 2.U.236.240; | 2.U.236.244; |
2.U.237.228; | 2.U.237.229; | 2.U.237.230; | 2.U.237.231; |
2.U.237.236; | 2.U.237.237; | 2.U.237.238; | 2.U.237.239; |
2.U.237.154; | 2.U.237.157; | 2.U.237.166; | 2.U.237.169; |
2.U.237.172; | 2.U.237.175; | 2.U.237.240; | 2.U.237.244; |
2.U.238.228; | 2.U.238.229; | 2.U.238.230; | 2.U.238.231; |
2.U.238.236; | 2.U.238.237; | 2.U.238.238; | 2.U.238.239; |
2.U.238.154; | 2.U.238.157; | 2.U.238.166; | 2.U.238.169; |
2.U.238.172; | 2.U.238.175; | 2.U.238.240; | 2.U.238.244; |
2.U.239.228; | 2.U.239.229; | 2.U.239.230; | 2.U.239.231; |
2.U.239.236; | 2.U.239.237; | 2.U.239.238; | 2.U.239.239; |
2.U.239.154; | 2.U.239.157; | 2.U.239.166; | 2.U.239.169; |
2.U.239.172; | 2.U.239.175; | 2.U.239.240; | 2.U.239.244; |
2.U.154.228; | 2.U.154.229; | 2.U.154.230; | 2.U.154.231; |
2.U.154.236; | 2.U.154.237; | 2.U.154.238; | 2.U.154.239; |
2.U.154.154; | 2.U.154.157; | 2.U.154.166; | 2.U.154.169; |
2.U.154.172; | 2.U.154.175; | 2.U.154.240; | 2.U.154.244; |
2.U.157.228; | 2.U.157.229; | 2.U.157.230; | 2.U.157.231; |
2.U.157.236; | 2.U.157.237; | 2.U.157.238; | 2.U.157.239; |
2.U.157.154; | 2.U.157.157; | 2.U.157.166; | 2.U.157.169; |
2.U.157.172; | 2.U.157.175; | 2.U.157.240; | 2.U.157.244; |
2.U.166.228; | 2.U.166.229; | 2.U.166.230; | 2.U.166.231; |
2.U.166.236; | 2.U.166.237; | 2.U.166.238; | 2.U.166.239; |
2.U.166.154; | 2.U.166.157; | 2.U.166.166; | 2.U.166.169; |
2.U.166.172; | 2.U.166.175; | 2.U.166.240; | 2.U.166.244; |
2.U.169.228; | 2.U.169.229; | 2.U.169.230; | 2.U.169.231; |
2.U.169.236; | 2.U.169.237; | 2.U.169.238; | 2.U.169.239; |
2.U.169.154; | 2.U.169.157; | 2.U.169.166; | 2.U.169.169; |
2.U.169.172; | 2.U.169.175; | 2.U.169.240; | 2.U.169.244; |
2.U.172.228; | 2.U.172.229; | 2.U.172.230; | 2.U.172.231; |
2.U.172.236; | 2.U.172.237; | 2.U.172.238; | 2.U.172.239; |
2.U.172.154; | 2.U.172.157; | 2.U.172.166; | 2.U.172.169; |
2.U.172.172; | 2.U.172.175; | 2.U.172.240; | 2.U.172.244; |
2.U.175.228; | 2.U.175.229; | 2.U.175.230; | 2.U.175.231; |
2.U.175.236; | 2.U.175.237; | 2.U.175.238; | 2.U.175.239; |
2.U.175.154; | 2.U.175.157; | 2.U.175.166; | 2.U.175.169; |
2.U.175.172; | 2.U.175.175; | 2.U.175.240; | 2.U.175.244; |
2.U.240.228; | 2.U.240.229; | 2.U.240.230; | 2.U.240.231; |
2.U.240.236; | 2.U.240.237; | 2.U.240.238; | 2.U.240.239; |
2.U.240.154; | 2.U.240.157; | 2.U.240.166; | 2.U.240.169; |
2.U.240.172; | 2.U.240.175; | 2.U.240.240; | 2.U.240.244; |
2.U.244.228; | 2.U.244.229; | 2.U.244.230; | 2.U.244.231; |
2.U.244.236; | 2.U.244.237; | 2.U.244.238; | 2.U.244.239; |
2.U.244.154; | 2.U.244.157; | 2.U.244.166; | 2.U.244.169; |
2.U.244.172; | 2.U.244.175; | 2.U.244.240; | 2.U.244.244; |
2.W的前体药物
2.W.228.228; | 2.W.228.229; | 2.W.228.230; | 2.W.228.231; |
2.W.228.236; | 2.W.228.237; | 2.W.228.238; | 2.W.228.239; |
2.W.228.154; | 2.W.228.157; | 2.W.228.166; | 2.W.228.169; |
2.W.228.172; | 2.W.228.175; | 2.W.228.240; | 2.W.228.244; |
2.W.229.228; | 2.W.229.229; | 2.W.229.230; | 2.W.229.231; |
2.W.229.236; | 2.W.229.237; | 2.W.229.238; | 2.W.229.239; |
2.W.229.154; | 2.W.229.157; | 2.W.229.166; | 2.W.229.169; |
2.W.229.172; | 2.W.229.175; | 2.W.229.240; | 2.W.229.244; |
2.W.230.228; | 2.W.230.229; | 2.W.230.230; | 2.W.230.231; |
2.W.230.236; | 2.W.230.237; | 2.W.230.238; | 2.W.230.239; |
2.W.230.154; | 2.W.230.157; | 2.W.230.166; | 2.W.230.169; |
2.W.230.172; | 2.W.230.175; | 2.W.230.240; | 2.W.230.244; |
2.W.231.228; | 2.W.231.229; | 2.W.231.230; | 2.W.231.231; |
2.W.231.236; | 2.W.231.237; | 2.W.231.238; | 2.W.231.239; |
2.W.231.154; | 2.W.231.157; | 2.W.231.166; | 2.W.231.169; |
2.W.231.172; | 2.W.231.175; | 2.W.231.240; | 2.W.231.244; |
2.W.236.228; | 2.W.236.229; | 2.W.236.230; | 2.W.236.231; |
2.W.236.236; | 2.W.236.237; | 2.W.236.238; | 2.W.236.239; |
2.W.236.154; | 2.W.236.157; | 2.W.236.166; | 2.W.236.169; |
2.W.236.172; | 2.W.236.175; | 2.W.236.240; | 2.W.236.244; |
2.W.237.228; | 2.W.237.229; | 2.W.237.230; | 2.W.237.231; |
2.W.237.236; | 2.W.237.237; | 2.W.237.238; | 2.W.237.239; |
2.W.237.154; | 2.W.237.157; | 2.W.237.166; | 2.W.237.169; |
2.W.237.172; | 2.W.237.175; | 2.W.237.240; | 2.W.237.244; |
2.W.238.228; | 2.W.238.229; | 2.W.238.230; | 2.W.238.231; |
2.W.238.236; | 2.W.238.237; | 2.W.238.238; | 2.W.238.239; |
2.W.238.154; | 2.W.238.157; | 2.W.238.166; | 2.W.238.169; |
2.W.238.172; | 2.W.238.175; | 2.W.238.240; | 2.W.238.244; |
2.W.239.228; | 2.W.239.229; | 2.W.239.230; | 2.W.239.231; |
2.W.239.236; | 2.W.239.237; | 2.W.239.238; | 2.W.239.239; |
2.W.239.154; | 2.W.239.157; | 2.W.239.166; | 2.W.239.169; |
2.W.239.172; | 2.W.239.175; | 2.W.239.240; | 2.W.239.244; |
2.W.154.228; | 2.W.154.229; | 2.W.154.230; | 2.W.154.231; |
2.W.154.236; | 2.W.154.237; | 2.W.154.238; | 2.W.154.239; |
2.W.154.154; | 2.W.154.157; | 2.W.154.166; | 2.W.154.169; |
2.W.154.172; | 2.W.154.175; | 2.W.154.240; | 2.W.154.244; |
2.W.157.228; | 2.W.157.229; | 2.W.157.230; | 2.W.157.231; |
2.W.157.236; | 2.W.157.237; | 2.W.157.238; | 2.W.157.239; |
2.W.157.154; | 2.W.157.157; | 2.W.157.166; | 2.W.157.169; |
2.W.157.172; | 2.W.157.175; | 2.W.157.240; | 2.W.157.244; |
2.W.166.228; | 2.W.166.229; | 2.W.166.230; | 2.W.166.231; |
2.W.166.236; | 2.W.166.237; | 2.W.166.238; | 2.W.166.239; |
2.W.166.154; | 2.W.166.157; | 2.W.166.166; | 2.W.166.169; |
2.W.166.172; | 2.W.166.175; | 2.W.166.240; | 2.W.166.244; |
2.W.169.228; | 2.W.169.229; | 2.W.169.230; | 2.W.169.231; |
2.W.169.236; | 2.W.169.237; | 2.W.169.238; | 2.W.169.239; |
2.W.169.154; | 2.W.169.157; | 2.W.169.166; | 2.W.169.169; |
2.W.169.172; | 2.W.169.175; | 2.W.169.240; | 2.W.169.244; |
2.W.172.228; | 2.W.172.229; | 2.W.172.230; | 2.W.172.231; |
2.W.172.236; | 2.W.172.237; | 2.W.172.238; | 2.W.172.239; |
2.W.172.154; | 2.W.172.157; | 2.W.172.166; | 2.W.172.169; |
2.W.172.172; | 2.W.172.175; | 2.W.172.240; | 2.W.172.244; |
2.W.175.228; | 2.W.175.229; | 2.W.175.230; | 2.W.175.231; |
2.W.175.236; | 2.W.175.237; | 2.W.175.238; | 2.W.175.239; |
2.W.175.154; | 2.W.175.157; | 2.W.175.166; | 2.W.175.169; |
2.W.175.172; | 2.W.175.175; | 2.W.175.240; | 2.W.175.244; |
2.W.240.228; | 2.W.240.229; | 2.W.240.230; | 2.W.240.231; |
2.W.240.236; | 2.W.240.237; | 2.W.240.238; | 2.W.240.239; |
2.W.240.154; | 2.W.240.157; | 2.W.240.166; | 2.W.240.169; |
2.W.240.172; | 2.W.240.175; | 2.W.240.240; | 2.W.240.244; |
2.W.244.228; | 2.W.244.229; | 2.W.244.230; | 2.W.244.231; |
2.W.244.236; | 2.W.244.237; | 2.W.244.238; | 2.W.244.239; |
2.W.244.154; | 2.W.244.157; | 2.W.244.166; | 2.W.244.169; |
2.W.244.172; | 2.W.244.175; | 2.W.244.240; | 2.W.244.244; |
2.Y的前体药物
2.Y.228.228; | 2.Y.228.229; | 2.Y.228.230; | 2.Y.228.231; |
2.Y.228.236; | 2.Y.228.237; | 2.Y.228.238; | 2.Y.228.239; |
2.Y.228.154; | 2.Y.228.157; | 2.Y.228.166; | 2.Y.228.169; |
2.Y.228.172; | 2.Y.228.175; | 2.Y.228.240; | 2.Y.228.244; |
2.Y.229.228; | 2.Y.229.229; | 2.Y.229.230; | 2.Y.229.231; |
2.Y.229.236; | 2.Y.229.237; | 2.Y.229.238; | 2.Y.229.239; |
2.Y.229.154; | 2.Y.229.157; | 2.Y.229.166; | 2.Y.229.169; |
2.Y.229.172; | 2.Y.229.175; | 2.Y.229.240; | 2.Y.229.244; |
2.Y.230.228; | 2.Y.230.229; | 2.Y.230.230; | 2.Y.230.231; |
2.Y.230.236; | 2.Y.230.237; | 2.Y.230.238; | 2.Y.230.239; |
2.Y.230.154; | 2.Y.230.157; | 2.Y.230.166; | 2.Y.230.169; |
2.Y.230.172; | 2.Y.230.175; | 2.Y.230.240; | 2.Y.230.244; |
2.Y.231.228; | 2.Y.231.229; | 2.Y.231.230; | 2.Y.231.231; |
2.Y.231.236; | 2.Y.231.237; | 2.Y.231.238; | 2.Y.231.239; |
2.Y.231.154; | 2.Y.231.157; | 2.Y.231.166; | 2.Y.231.169; |
2.Y.231.172; | 2.Y.231.175; | 2.Y.231.240; | 2.Y.231.244; |
2.Y.236.228; | 2.Y.236.229; | 2.Y.236.230; | 2.Y.236.231; |
2.Y.236.236; | 2.Y.236.237; | 2.Y.236.238; | 2.Y.236.239; |
2.Y.236.154; | 2.Y.236.157; | 2.Y.236.166; | 2.Y.236.169; |
2.Y.236.172; | 2.Y.236.175; | 2.Y.236.240; | 2.Y.236.244; |
2.Y.237.228; | 2.Y.237.229; | 2.Y.237.230; | 2.Y.237.231; |
2.Y.237.236; | 2.Y.237.237; | 2.Y.237.238; | 2.Y.237.239; |
2.Y.237.154; | 2.Y.237.157; | 2.Y.237.166; | 2.Y.237.169; |
2.Y.237.172; | 2.Y.237.175; | 2.Y.237.240; | 2.Y.237.244; |
2.Y.238.228; | 2.Y.238.229; | 2.Y.238.230; | 2.Y.238.231; |
2.Y.238.236; | 2.Y.238.237; | 2.Y.238.238; | 2.Y.238.239; |
2.Y.238.154; | 2.Y.238.157; | 2.Y.238.166; | 2.Y.238.169; |
2.Y.238.172; | 2.Y.238.175; | 2.Y.238.240; | 2.Y.238.244; |
2.Y.239.228; | 2.Y.239.229; | 2.Y.239.230; | 2.Y.239.231; |
2.Y.239.236; | 2.Y.239.237; | 2.Y.239.238; | 2.Y.239.239; |
2.Y.239.154; | 2.Y.239.157; | 2.Y.239.166; | 2.Y.239.169; |
2.Y.239.172; | 2.Y.239.175; | 2.Y.239.240; | 2.Y.239.244; |
2.Y.154.228; | 2.Y.154.229; | 2.Y.154.230; | 2.Y.154.231; |
2.Y.154.236; | 2.Y.154.237; | 2.Y.154.238; | 2.Y.154.239; |
2.Y.154.154; | 2.Y.154.157; | 2.Y.154.166; | 2.Y.154.169; |
2.Y.154.172; | 2.Y.154.175; | 2.Y.154.240; | 2.Y.154.244; |
2.Y.157.228; | 2.Y.157.229; | 2.Y.157.230; | 2.Y.157.231; |
2.Y.157.236; | 2.Y.157.237; | 2.Y.157.238; | 2.Y.157.239; |
2.Y.157.154; | 2.Y.157.157; | 2.Y.157.166; | 2.Y.157.169; |
2.Y.157.172; | 2.Y.157.175; | 2.Y.157.240; | 2.Y.157.244; |
2.Y.166.228; | 2.Y.166.229; | 2.Y.166.230; | 2.Y.166.231; |
2.Y.166.236; | 2.Y.166.237; | 2.Y.166.238; | 2.Y.166.239; |
2.Y.166.154; | 2.Y.166.157; | 2.Y.166.166; | 2.Y.166.169; |
2.Y.166.172; | 2.Y.166.175; | 2.Y.166.240; | 2.Y.166.244; |
2.Y.169.228; | 2.Y.169.229; | 2.Y.169.230; | 2.Y.169.231; |
2.Y.169.236; | 2.Y.169.237; | 2.Y.169.238; | 2.Y.169.239; |
2.Y.169.154; | 2.Y.169.157; | 2.Y.169.166; | 2.Y.169.169; |
2.Y.169.172; | 2.Y.169.175; | 2.Y.169.240; | 2.Y.169.244; |
2.Y.172.228; | 2.Y.172.229; | 2.Y.172.230; | 2.Y.172.231; |
2.Y.172.236; | 2.Y.172.237; | 2.Y.172.238; | 2.Y.172.239; |
2.Y.172.154; | 2.Y.172.157; | 2.Y.172.166; | 2.Y.172.169; |
2.Y.172.172; | 2.Y.172.175; | 2.Y.172.240; | 2.Y.172.244; |
2.Y.175.228; | 2.Y.175.229; | 2.Y.175.230; | 2.Y.175.231; |
2.Y.175.236; | 2.Y.175.237; | 2.Y.175.238; | 2.Y.175.239; |
2.Y.175.154; | 2.Y.175.157; | 2.Y.175.166; | 2.Y.175.169; |
2.Y.175.172; | 2.Y.175.175; | 2.Y.175.240; | 2.Y.175.244; |
2.Y.240.228; | 2.Y.240.229; | 2.Y.240.230; | 2.Y.240.231; |
2.Y.240.236; | 2.Y.240.237; | 2.Y.240.238; | 2.Y.240.239; |
2.Y.240.154; | 2.Y.240.157; | 2.Y.240.166; | 2.Y.240.169; |
2.Y.240.172; | 2.Y.240.175; | 2.Y.240.240; | 2.Y.240.244; |
2.Y.244.228; | 2.Y.244.229; | 2.Y.244.230; | 2.Y.244.231; |
2.Y.244.236; | 2.Y.244.237; | 2.Y.244.238; | 2.Y.244.239; |
2.Y.244.154; | 2.Y.244.157; | 2.Y.244.166; | 2.Y.244.169; |
2.Y.244.172; | 2.Y.244.175; | 2.Y.244.240; | 2.Y.244.244; |
3.B的前体药物
3.B.228.228; | 3.B.228.229; | 3.B.228.230; | 3.B.228.231; |
3.B.228.236; | 3.B.228.237; | 3.B.228.238; | 3.B.228.239; |
3.B.228.154; | 3.B.228.157; | 3.B.228.166; | 3.B.228.169; |
3.B.228.172; | 3.B.228.175; | 3.B.228.240; | 3.B.228.244; |
3.B.229.228; | 3.B.229.229; | 3.B.229.230; | 3.B.229.231; |
3.B.229.236; | 3.B.229.237; | 3.B.229.238; | 3.B.229.239; |
3.B.229.154; | 3.B.229.157; | 3.B.229.166; | 3.B.229.169; |
3.B.229.172; | 3.B.229.175; | 3.B.229.240; | 3.B.229.244; |
3.B.230.228; | 3.B.230.229; | 3.B.230.230; | 3.B.230.231; |
3.B.230.236; | 3.B.230.237; | 3.B.230.238; | 3.B.230.239; |
3.B.230.154; | 3.B.230.157; | 3.B.230.166; | 3.B.230.169; |
3.B.230.172; | 3.B.230.175; | 3.B.230.240; | 3.B.230.244; |
3.B.231.228; | 3.B.231.229; | 3.B.231.230; | 3.B.231.231; |
3.B.231.236; | 3.B.231.237; | 3.B.231.238; | 3.B.231.239; |
3.B.231.154; | 3.B.231.157; | 3.B.231.166; | 3.B.231.169; |
3.B.231.172; | 3.B.231.175; | 3.B.231.240; | 3.B.231.244; |
3.B.236.228; | 3.B.236.229; | 3.B.236.230; | 3.B.236.231; |
3.B.236.236; | 3.B.236.237; | 3.B.236.238; | 3.B.236.239; |
3.B.236.154; | 3.B.236.157; | 3.B.236.166; | 3.B.236.169; |
3.B.236.172; | 3.B.236.175; | 3.B.236.240; | 3.B.236.244; |
3.B.237.228; | 3.B.237.229; | 3.B.237.230; | 3.B.237.231; |
3.B.237.236; | 3.B.237.237; | 3.B.237.238; | 3.B.237.239; |
3.B.237.154; | 3.B.237.157; | 3.B.237.166; | 3.B.237.169; |
3.B.237.172; | 3.B.237.175; | 3.B.237.240; | 3.B.237.244; |
3.B.238.228; | 3.B.238.229; | 3.B.238.230; | 3.B.238.231; |
3.B.238.236; | 3.B.238.237; | 3.B.238.238; | 3.B.238.239; |
3.B.238.154; | 3.B.238.157; | 3.B.238.166; | 3.B.238.169; |
3.B.238.172; | 3.B.238.175; | 3.B.238.240; | 3.B.238.244; |
3.B.239.228; | 3.B.239.229; | 3.B.239.230; | 3.B.239.231; |
3.B.239.236; | 3.B.239.237; | 3.B.239.238; | 3.B.239.239; |
3.B.239.154; | 3.B.239.157; | 3.B.239.166; | 3.B.239.169; |
3.B.239.172; | 3.B.239.175; | 3.B.239.240; | 3.B.239.244; |
3.B.154.228; | 3.B.154.229; | 3.B.154.230; | 3.B.154.231; |
3.B.154.236; | 3.B.154.237; | 3.B.154.238; | 3.B.154.239; |
3.B.154.154; | 3.B.154.157; | 3.B.154.166; | 3.B.154.169; |
3.B.154.172; | 3.B.154.175; | 3.B.154.240; | 3.B.154.244; |
3.B.157.228; | 3.B.157.229; | 3.B.157.230; | 3.B.157.231; |
3.B.157.236; | 3.B.157.237; | 3.B.157.238; | 3.B.157.239; |
3.B.157.154; | 3.B.157.157; | 3.B.157.166; | 3.B.157.169; |
3.B.157.172; | 3.B.157.175; | 3.B.157.240; | 3.B.157.244; |
3.B.166.228; | 3.B.166.229; | 3.B.166.230; | 3.B.166.231; |
3.B.166.236; | 3.B.166.237; | 3.B.166.238; | 3.B.166.239; |
3.B.166.154; | 3.B.166.157; | 3.B.166.166; | 3.B.166.169; |
3.B.166.172; | 3.B.166.175; | 3.B.166.240; | 3.B.166.244; |
3.B.169.228; | 3.B.169.229; | 3.B.169.230; | 3.B.169.231; |
3.B.169.236; | 3.B.169.237; | 3.B.169.238; | 3.B.169.239; |
3.B.169.154; | 3.B.169.157; | 3.B.169.166; | 3.B.169.169; |
3.B.169.172; | 3.B.169.175; | 3.B.169.240; | 3.B.169.244; |
3.B.172.228; | 3.B.172.229; | 3.B.172.230; | 3.B.172.231; |
3.B.172.236; | 3.B.172.237; | 3.B.172.238; | 3.B.172.239; |
3.B.172.154; | 3.B.172.157; | 3.B.172.166; | 3.B.172.169; |
3.B.172.172; | 3.B.172.175; | 3.B.172.240; | 3.B.172.244; |
3.B.175.228; | 3.B.175.229; | 3.B.175.230; | 3.B.175.231; |
3.B.175.236; | 3.B.175.237; | 3.B.175.238; | 3.B.175.239; |
3.B.175.154; | 3.B.175.157; | 3.B.175.166; | 3.B.175.169; |
3.B.175.172; | 3.B.175.175; | 3.B.175.240; | 3.B.175.244; |
3.B.240.228; | 3.B.240.229; | 3.B.240.230; | 3.B.240.231; |
3.B.240.236; | 3.B.240.237; | 3.B.240.238; | 3.B.240.239; |
3.B.240.154; | 3.B.240.157; | 3.B.240.166; | 3.B.240.169; |
3.B.240.172; | 3.B.240.175; | 3.B.240.240; | 3.B.240.244; |
3.B.244.228; | 3.B.244.229; | 3.B.244.230; | 3.B.244.231; |
3.B.244.236; | 3.B.244.237; | 3.B.244.238; | 3.B.244.239; |
3.B.244.154; | 3.B.244.157; | 3.B.244.166; | 3.B.244.169; |
3.B.244.172; | 3.B.244.175; | 3.B.244.240; | 3.B.244.244; |
3.D的前体药物
3.D.228.228; | 3.D.228.229; | 3.D.228.230; | 3.D.228.231; |
3.D.228.236; | 3.D.228.237; | 3.D.228.238; | 3.D.228.239; |
3.D.228.154; | 3.D.228.157; | 3.D.228.166; | 3.D.228.169; |
3.D.228.172; | 3.D.228.175; | 3.D.228.240; | 3.D.228.244; |
3.D.229.228; | 3.D.229.229; | 3.D.229.230; | 3.D.229.231; |
3.D.229.236; | 3.D.229.237; | 3.D.229.238; | 3.D.229.239; |
3.D.229.154; | 3.D.229.157; | 3.D.229.166; | 3.D.229.169; |
3.D.229.172; | 3.D.229.175; | 3.D.229.240; | 3.D.229.244; |
3.D.230.228; | 3.D.230.229; | 3.D.230.230; | 3.D.230.231; |
3.D.230.236; | 3.D.230.237; | 3.D.230.238; | 3.D.230.239; |
3.D.230.154; | 3.D.230.157; | 3.D.230.166; | 3.D.230.169; |
3.D.230.172; | 3.D.230.175; | 3.D.230.240; | 3.D.230.244; |
3.D.231.228; | 3.D.231.229; | 3.D.231.230; | 3.D.231.231; |
3.D.231.236; | 3.D.231.237; | 3.D.231.238; | 3.D.231.239; |
3.D.231.154; | 3.D.231.157; | 3.D.231.166; | 3.D.231.169; |
3.D.231.172; | 3.D.231.175; | 3.D.231.240; | 3.D.231.244; |
3.D.236.228; | 3.D.236.229; | 3.D.236.230; | 3.D.236.231; |
3.D.236.236; | 3.D.236.237; | 3.D.236.238; | 3.D.236.239; |
3.D.236.154; | 3.D.236.157; | 3.D.236.166; | 3.D.236.169; |
3.D.236.172; | 3.D.236.175; | 3.D.236.240; | 3.D.236.244; |
3.D.237.228; | 3.D.237.229; | 3.D.237.230; | 3.D.237.231; |
3.D.237.236; | 3.D.237.237; | 3.D.237.238; | 3.D.237.239; |
3.D.237.154; | 3.D.237.157; | 3.D.237.166; | 3.D.237.169; |
3.D.237.172; | 3.D.237.175; | 3.D.237.240; | 3.D.237.244; |
3.D.238.228; | 3.D.238.229; | 3.D.238.230; | 3.D.238.231; |
3.D.238.236; | 3.D.238.237; | 3.D.238.238; | 3.D.238.239; |
3.D.238.154; | 3.D.238.157; | 3.D.238.166; | 3.D.238.169; |
3.D.238.172; | 3.D.238.175; | 3.D.238.240; | 3.D.238.244; |
3.D.239.228; | 3.D.239.229; | 3.D.239.230; | 3.D.239.231; |
3.D.239.236; | 3.D.239.237; | 3.D.239.238; | 3.D.239.239; |
3.D.239.154; | 3.D.239.157; | 3.D.239.166; | 3.D.239.169; |
3.D.239.172; | 3.D.239.175; | 3.D.239.240; | 3.D.239.244; |
3.D.154.228; | 3.D.154.229; | 3.D.154.230; | 3.D.154.231; |
3.D.154.236; | 3.D.154.237; | 3.D.154.238; | 3.D.154.239; |
3.D.154.154; | 3.D.154.157; | 3.D.154.166; | 3.D.154.169; |
3.D.154.172; | 3.D.154.175; | 3.D.154.240; | 3.D.154.244; |
3.D.157.228; | 3.D.157.229; | 3.D.157.230; | 3.D.157.231; |
3.D.157.236; | 3.D.157.237; | 3.D.157.238; | 3.D.157.239; |
3.D.157.154; | 3.D.157.157; | 3.D.157.166; | 3.D.157.169; |
3.D.157.172; | 3.D.157.175; | 3.D.157.240; | 3.D.157.244; |
3.D.166.228; | 3.D.166.229; | 3.D.166.230; | 3.D.166.231; |
3.D.166.236; | 3.D.166.237; | 3.D.166.238; | 3.D.166.239; |
3.D.166.154; | 3.D.166.157; | 3.D.166.166; | 3.D.166.169; |
3.D.166.172; | 3.D.166.175; | 3.D.166.240; | 3.D.166.244; |
3.D.169.228; | 3.D.169.229; | 3.D.169.230; | 3.D.169.231; |
3.D.169.236; | 3.D.169.237; | 3.D.169.238; | 3.D.169.239; |
3.D.169.154; | 3.D.169.157; | 3.D.169.166; | 3.D.169.169; |
3.D.169.172; | 3.D.169.175; | 3.D.169.240; | 3.D.169.244; |
3.D.172.228; | 3.D.172.229; | 3.D.172.230; | 3.D.172.231; |
3.D.172.236; | 3.D.172.237; | 3.D.172.238; | 3.D.172.239; |
3.D.172.154; | 3.D.172.157; | 3.D.172.166; | 3.D.172.169; |
3.D.172.172; | 3.D.172.175; | 3.D.172.240; | 3.D.172.244; |
3.D.175.228; | 3.D.175.229; | 3.D.175.230; | 3.D.175.231; |
3.D.175.236; | 3.D.175.237; | 3.D.175.238; | 3.D.175.239; |
3.D.175.154; | 3.D.175.157; | 3.D.175.166; | 3.D.175.169; |
3.D.175.172; | 3.D.175.175; | 3.D.175.240; | 3.D.175.244; |
3.D.240.228; | 3.D.240.229; | 3.D.240.230; | 3.D.240.231; |
3.D.240.236; | 3.D.240.237; | 3.D.240.238; | 3.D.240.239; |
3.D.240.154; | 3.D.240.157; | 3.D.240.166; | 3.D.240.169; |
3.D.240.172; | 3.D.240.175; | 3.D.240.240; | 3.D.240.244; |
3.D.244.228; | 3.D.244.229; | 3.D.244.230; | 3.D.244.231; |
3.D.244.236; | 3.D.244.237; | 3.D.244.238; | 3.D.244.239; |
3.D.244.154; | 3.D.244.157; | 3.D.244.166; | 3.D.244.169; |
3.D.244.172; | 3.D.244.175; | 3.D.244.240; | 3.D.244.244; |
3.E的前体药物
3.E.228.228; | 3.E.228.229; | 3.E.228.230; | 3.E.228.231; |
3.E.228.236; | 3.E.228.237; | 3.E.228.238; | 3.E.228.239; |
3.E.228.154; | 3.E.228.157; | 3.E.228.166; | 3.E.228.169; |
3.E.228.172; | 3.E.228.175; | 3.E.228.240; | 3.E.228.244; |
3.E.229.228; | 3.E.229.229; | 3.E.229.230; | 3.E.229.231; |
3.E.229.236; | 3.E.229.237; | 3.E.229.238; | 3.E.229.239; |
3.E.229.154; | 3.E.229.157; | 3.E.229.166; | 3.E.229.169; |
3.E.229.172; | 3.E.229.175; | 3.E.229.240; | 3.E.229.244; |
3.E.230.228; | 3.E.230.229; | 3.E.230.230; | 3.E.230.231; |
3.E.230.236; | 3.E.230.237; | 3.E.230.238; | 3.E.230.239; |
3.E.230.154; | 3.E.230.157; | 3.E.230.166; | 3.E.230.169; |
3.E.230.172; | 3.E.230.175; | 3.E.230.240; | 3.E.230.244; |
3.E.231.228; | 3.E.231.229; | 3.E.231.230; | 3.E.231.231; |
3.E.231.236; | 3.E.231.237; | 3.E.231.238; | 3.E.231.239; |
3.E.231.154; | 3.E.231.157; | 3.E.231.166; | 3.E.231.169; |
3.E.231.172; | 3.E.231.175; | 3.E.231.240; | 3.E.231.244; |
3.E.236.228; | 3.E.236.229; | 3.E.236.230; | 3.E.236.231; |
3.E.236.236; | 3.E.236.237; | 3.E.236.238; | 3.E.236.239; |
3.E.236.154; | 3.E.236.157; | 3.E.236.166; | 3.E.236.169; |
3.E.236.172; | 3.E.236.175; | 3.E.236.240; | 3.E.236.244; |
3.E.237.228; | 3.E.237.229; | 3.E.237.230; | 3.E.237.231; |
3.E.237.236; | 3.E.237.237; | 3.E.237.238; | 3.E.237.239; |
3.E.237.154; | 3.E.237.157; | 3.E.237.166; | 3.E.237.169; |
3.E.237.172; | 3.E.237.175; | 3.E.237.240; | 3.E.237.244; |
3.E.238.228; | 3.E.238.229; | 3.E.238.230; | 3.E.238.231; |
3.E.238.236; | 3.E.238.237; | 3.E.238.238; | 3.E.238.239; |
3.E.238.154; | 3.E.238.157; | 3.E.238.166; | 3.E.238.169; |
3.E.238.172; | 3.E.238.175; | 3.E.238.240; | 3.E.238.244; |
3.E.239.228; | 3.E.239.229; | 3.E.239.230; | 3.E.239.231; |
3.E.239.236; | 3.E.239.237; | 3.E.239.238; | 3.E.239.239; |
3.E.239.154; | 3.E.239.157; | 3.E.239.166; | 3.E.239.169; |
3.E.239.172; | 3.E.239.175; | 3.E.239.240; | 3.E.239.244; |
3.E.154.228; | 3.E.154.229; | 3.E.154.230; | 3.E.154.231; |
3.E.154.236; | 3.E.154.237; | 3.E.154.238; | 3.E.154.239; |
3.E.154.154; | 3.E.154.157; | 3.E.154.166; | 3.E.154.169; |
3.E.154.172; | 3.E.154.175; | 3.E.154.240; | 3.E.154.244; |
3.E.157.228; | 3.E.157.229; | 3.E.157.230; | 3.E.157.231; |
3.E.157.236; | 3.E.157.237; | 3.E.157.238; | 3.E.157.239; |
3.E.157.154; | 3.E.157.157; | 3.E.157.166; | 3.E.157.169; |
3.E.157.172; | 3.E.157.175; | 3.E.157.240; | 3.E.157.244; |
3.E.166.228; | 3.E.166.229; | 3.E.166.230; | 3.E.166.231; |
3.E.166.236; | 3.E.166.237; | 3.E.166.238; | 3.E.166.239; |
3.E.166.154; | 3.E.166.157; | 3.E.166.166; | 3.E.166.169; |
3.E.166.172; | 3.E.166.175; | 3.E.166.240; | 3.E.166.244; |
3.E.169.228; | 3.E.169.229; | 3.E.169.230; | 3.E.169.231; |
3.E.169.236; | 3.E.169.237; | 3.E.169.238; | 3.E.169.239; |
3.E.169.154; | 3.E.169.157; | 3.E.169.166; | 3.E.169.169; |
3.E.169.172; | 3.E.169.175; | 3.E.169.240; | 3.E.169.244; |
3.E.172.228; | 3.E.172.229; | 3.E.172.230; | 3.E.172.231; |
3.E.172.236; | 3.E.172.237; | 3.E.172.238; | 3.E.172.239; |
3.E.172.154; | 3.E.172.157; | 3.E.172.166; | 3.E.172.169; |
3.E.172.172; | 3.E.172.175; | 3.E.172.240; | 3.E.172.244; |
3.E.175.228; | 3.E.175.229; | 3.E.175.230; | 3.E.175.231; |
3.E.175.236; | 3.E.175.237; | 3.E.175.238; | 3.E.175.239; |
3.E.175.154; | 3.E.175.157; | 3.E.175.166; | 3.E.175.169; |
3.E.175.172; | 3.E.175.175; | 3.E.175.240; | 3.E.175.244; |
3.E.240.228; | 3.E.240.229; | 3.E.240.230; | 3.E.240.231; |
3.E.240.236; | 3.E.240.237; | 3.E.240.238; | 3.E.240.239; |
3.E.240.154; | 3.E.240.157; | 3.E.240.166; | 3.E.240.169; |
3.E.240.172; | 3.E.240.175; | 3.E.240.240; | 3.E.240.244; |
3.E.244.228; | 3.E.244.229; | 3.E.244.230; | 3.E.244.231; |
3.E.244.236; | 3.E.244.237; | 3.E.244.238; | 3.E.244.239; |
3.E.244.154; | 3.E.244.157; | 3.E.244.166; | 3.E.244.169; |
3.E.244.172; | 3.E.244.175; | 3.E.244.240; | 3.E.244.244; |
3.G的前体药物
3.G.228.228; | 3.G.228.229; | 3.G.228.230; | 3.G.228.231; |
3.G.228.236; | 3.G.228.237; | 3.G.228.238; | 3.G.228.239; |
3.G.228.154; | 3.G.228.157; | 3.G.228.166; | 3.G.228.169; |
3.G.228.172; | 3.G.228.175; | 3.G.228.240; | 3.G.228.244; |
3.G.229.228; | 3.G.229.229; | 3.G.229.230; | 3.G.229.231; |
3.G.229.236; | 3.G.229.237; | 3.G.229.238; | 3.G.229.239; |
3.G.229.154; | 3.G.229.157; | 3.G.229.166; | 3.G.229.169; |
3.G.229.172; | 3.G.229.175; | 3.G.229.240; | 3.G.229.244; |
3.G.230.228; | 3.G.230.229; | 3.G.230.230; | 3.G.230.231; |
3.G.230.236; | 3.G.230.237; | 3.G.230.238; | 3.G.230.239; |
3.G.230.154; | 3.G.230.157; | 3.G.230.166; | 3.G.230.169; |
3.G.230.172; | 3.G.230.175; | 3.G.230.240; | 3.G.230.244; |
3.G.231.228; | 3.G.231.229; | 3.G.231.230; | 3.G.231.231; |
3.G.231.236; | 3.G.231.237; | 3.G.231.238; | 3.G.231.239; |
3.G.231.154; | 3.G.231.157; | 3.G.231.166; | 3.G.231.169; |
3.G.231.172; | 3.G.231.175; | 3.G.231.240; | 3.G.231.244; |
3.G.236.228; | 3.G.236.229; | 3.G.236.230; | 3.G.236.231; |
3.G.236.236; | 3.G.236.237; | 3.G.236.238; | 3.G.236.239; |
3.G.236.154; | 3.G.236.157; | 3.G.236.166; | 3.G.236.169; |
3.G.236.172; | 3.G.236.175; | 3.G.236.240; | 3.G.236.244; |
3.G.237.228; | 3.G.237.229; | 3.G.237.230; | 3.G.237.231; |
3.G.237.236; | 3.G.237.237; | 3.G.237.238; | 3.G.237.239; |
3.G.237.154; | 3.G.237.157; | 3.G.237.166; | 3.G.237.169; |
3.G.237.172; | 3.G.237.175; | 3.G.237.240; | 3.G.237.244; |
3.G.238.228; | 3.G.238.229; | 3.G.238.230; | 3.G.238.231; |
3.G.238.236; | 3.G.238.237; | 3.G.238.238; | 3.G.238.239; |
3.G.238.154; | 3.G.238.157; | 3.G.238.166; | 3.G.238.169; |
3.G.238.172; | 3.G.238.175; | 3.G.238.240; | 3.G.238.244; |
3.G.239.228; | 3.G.239.229; | 3.G.239.230; | 3.G.239.231; |
3.G.239.236; | 3.G.239.237; | 3.G.239.238; | 3.G.239.239; |
3.G.239.154; | 3.G.239.157; | 3.G.239.166; | 3.G.239.169; |
3.G.239.172; | 3.G.239.175; | 3.G.239.240; | 3.G.239.244; |
3.G.154.228; | 3.G.154.229; | 3.G.154.230; | 3.G.154.231; |
3.G.154.236; | 3.G.154.237; | 3.G.154.238; | 3.G.154.239; |
3.G.154.154; | 3.G.154.157; | 3.G.154.166; | 3.G.154.169; |
3.G.154.172; | 3.G.154.175; | 3.G.154.240; | 3.G.154.244; |
3.G.157.228; | 3.G.157.229; | 3.G.157.230; | 3.G.157.231; |
3.G.157.236; | 3.G.157.237; | 3.G.157.238; | 3.G.157.239; |
3.G.157.154; | 3.G.157.157; | 3.G.157.166; | 3.G.157.169; |
3.G.157.172; | 3.G.157.175; | 3.G.157.240; | 3.G.157.244; |
3.G.166.228; | 3.G.166.229; | 3.G.166.230; | 3.G.166.231; |
3.G.166.236; | 3.G.166.237; | 3.G.166.238; | 3.G.166.239; |
3.G.166.154; | 3.G.166.157; | 3.G.166.166; | 3.G.166.169; |
3.G.166.172; | 3.G.166.175; | 3.G.166.240; | 3.G.166.244; |
3.G.169.228; | 3.G.169.229; | 3.G.169.230; | 3.G.169.231; |
3.G.169.236; | 3.G.169.237; | 3.G.169.238; | 3.G.169.239; |
3.G.169.154; | 3.G.169.157; | 3.G.169.166; | 3.G.169.169; |
3.G.169.172; | 3.G.169.175; | 3.G.169.240; | 3.G.169.244; |
3.G.172.228; | 3.G.172.229; | 3.G.172.230; | 3.G.172.231; |
3.G.172.236; | 3.G.172.237; | 3.G.172.238; | 3.G.172.239; |
3.G.172.154; | 3.G.172.157; | 3.G.172.166; | 3.G.172.169; |
3.G.172.172; | 3.G.172.175; | 3.G.172.240; | 3.G.172.244; |
3.G.175.228; | 3.G.175.229; | 3.G.175.230; | 3.G.175.231; |
3.G.175.236; | 3.G.175.237; | 3.G.175.238; | 3.G.175.239; |
3.G.175.154; | 3.G.175.157; | 3.G.175.166; | 3.G.175.169; |
3.G.175.172; | 3.G.175.175; | 3.G.175.240; | 3.G.175.244; |
3.G.240.228; | 3.G.240.229; | 3.G.240.230; | 3.G.240.231; |
3.G.240.236; | 3.G.240.237; | 3.G.240.238; | 3.G.240.239; |
3.G.240.154; | 3.G.240.157; | 3.G.240.166; | 3.G.240.169; |
3.G.240.172; | 3.G.240.175; | 3.G.240.240; | 3.G.240.244; |
3.G.244.228; | 3.G.244.229; | 3.G.244.230; | 3.G.244.231; |
3.G.244.236; | 3.G.244.237; | 3.G.244.238; | 3.G.244.239; |
3.G.244.154; | 3.G.244.157; | 3.G.244.166; | 3.G.244.169; |
3.G.244.172; | 3.G.244.175; | 3.G.244.240; | 3.G.244.244; |
3.I的前体药物
3.I.228.228; | 3.I.228.229; | 3.I.228.230; | 3.I.228.231; |
3.I.228.236; | 3.I.228.237; | 3.I.228.238; | 3.I.228.239; |
3.I.228.154; | 3.I.228.157; | 3.I.228.166; | 3.I.228.169; |
3.I.228.172; | 3.I.228.175; | 3.I.228.240; | 3.I.228.244; |
3.I.229.228; | 3.I.229.229; | 3.I.229.230; | 3.I.229.231; |
3.I.229.236; | 3.I.229.237; | 3.I.229.238; | 3.I.229.239; |
3.I.229.154; | 3.I.229.157; | 3.I.229.166; | 3.I.229.169; |
3.I.229.172; | 3.I.229.175; | 3.I.229.240; | 3.I.229.244; |
3.I.230.228; | 3.I.230.229; | 3.I.230.230; | 3.I.230.231; |
3.I.230.236; | 3.I.230.237; | 3.I.230.238; | 3.I.230.239; |
3.I.230.154; | 3.I.230.157; | 3.I.230.166; | 3.I.230.169; |
3.I.230.172; | 3.I.230.175; | 3.I.230.240; | 3.I.230.244; |
3.I.231.228; | 3.I.231.229; | 3.I.231.230; | 3.I.231.231; |
3.I.231.236; | 3.I.231.237; | 3.I.231.238; | 3.I.231.239; |
3.I.231.154; | 3.I.231.157; | 3.I.231.166; | 3.I.231.169; |
3.I.231.172; | 3.I.231.175; | 3.I.231.240; | 3.I.231.244; |
3.I.236.228; | 3.I.236.229; | 3.I.236.230; | 3.I.236.231; |
3.I.236.236; | 3.I.236.237; | 3.I.236.238; | 3.I.236.239; |
3.I.236.154; | 3.I.236.157; | 3.I.236.166; | 3.I.236.169; |
3.I.236.172; | 3.I.236.175; | 3.I.236.240; | 3.I.236.244; |
3.I.237.228; | 3.I.237.229; | 3.I.237.230; | 3.I.237.231; |
3.I.237.236; | 3.I.237.237; | 3.I.237.238; | 3.I.237.239; |
3.I.237.154; | 3.I.237.157; | 3.I.237.166; | 3.I.237.169; |
3.I.237.172; | 3.I.237.175; | 3.I.237.240; | 3.I.237.244; |
3.I.238.228; | 3.I.238.229; | 3.I.238.230; | 3.I.238.231; |
3.I.238.236; | 3.I.238.237; | 3.I.238.238; | 3.I.238.239; |
3.I.238.154; | 3.I.238.157; | 3.I.238.166; | 3.I.238.169; |
3.I.238.172; | 3.I.238.175; | 3.I.238.240; | 3.I.238.244; |
3.I.239.228; | 3.I.239.229; | 3.I.239.230; | 3.I.239.231; |
3.I.239.236; | 3.I.239.237; | 3.I.239.238; | 3.I.239.239; |
3.I.239.154; | 3.I.239.157; | 3.I.239.166; | 3.I.239.169; |
3.I.239.172; | 3.I.239.175; | 3.I.239.240; | 3.I.239.244; |
3.I.154.228; | 3.I.154.229; | 3.I.154.230; | 3.I.154.231; |
3.I.154.236; | 3.I.154.237; | 3.I.154.238; | 3.I.154.239; |
3.I.154.154; | 3.I.154.157; | 3.I.154.166; | 3.I.154.169; |
3.I.154.172; | 3.I.154.175; | 3.I.154.240; | 3.I.154.244; |
3.I.157.228; | 3.I.157.229; | 3.I.157.230; | 3.I.157.231; |
3.I.157.236; | 3.I.157.237; | 3.I.157.238; | 3.I.157.239; |
3.I.157.154; | 3.I.157.157; | 3.I.157.166; | 3.I.157.169; |
3.I.157.172; | 3.I.157.175; | 3.I.157.240; | 3.I.157.244; |
3.I.166.228; | 3.I.166.229; | 3.I.166.230; | 3.I.166.231; |
3.I.166.236; | 3.I.166.237; | 3.I.166.238; | 3.I.166.239; |
3.I.166.154; | 3.I.166.157; | 3.I.166.166; | 3.I.166.169; |
3.I.166.172; | 3.I.166.175; | 3.I.166.240; | 3.I.166.244; |
3.I.169.228; | 3.I.169.229; | 3.I.169.230; | 3.I.169.231; |
3.I.169.236; | 3.I.169.237; | 3.I.169.238; | 3.I.169.239; |
3.I.169.154; | 3.I.169.157; | 3.I.169.166; | 3.I.169.169; |
3.I.169.172; | 3.I.169.175; | 3.I.169.240; | 3.I.169.244; |
3.I.172.228; | 3.I.172.229; | 3.I.172.230; | 3.I.172.231; |
3.I.172.236; | 3.I.172.237; | 3.I.172.238; | 3.I.172.239; |
3.I.172.154; | 3.I.172.157; | 3.I.172.166; | 3.I.172.169; |
3.I.172.172; | 3.I.172.175; | 3.I.172.240; | 3.I.172.244; |
3.I.175.228; | 3.I.175.229; | 3.I.175.230; | 3.I.175.231; |
3.I.175.236; | 3.I.175.237; | 3.I.175.238; | 3.I.175.239; |
3.I.175.154; | 3.I.175.157; | 3.I.175.166; | 3.I.175.169; |
3.I.175.172; | 3.I.175.175; | 3.I.175.240; | 3.I.175.244; |
3.I.240.228; | 3.I.240.229; | 3.I.240.230; | 3.I.240.231; |
3.I.240.236; | 3.I.240.237; | 3.I.240.238; | 3.I.240.239; |
3.I.240.154; | 3.I.240.157; | 3.I.240.166; | 3.I.240.169; |
3.I.240.172; | 3.I.240.175; | 3.I.240.240; | 3.I.240.244; |
3.I.244.228; | 3.I.244.229; | 3.I.244.230; | 3.I.244.231; |
3.I.244.236; | 3.I.244.237; | 3.I.244.238; | 3.I.244.239; |
3.I.244.154; | 3.I.244.157; | 3.I.244.166; | 3.I.244.169; |
3.I.244.172; | 3.I.244.175; | 3.I.244.240; | 3.I.244.244; |
3.J的前体药物
3.J.228.228; | 3.J.228.229; | 3.J.228.230; | 3.J.228.231; |
3.J.228.236; | 3.J.228.237; | 3.J.228.238; | 3.J.228.239; |
3.J.228.154; | 3.J.228.157; | 3.J.228.166; | 3.J.228.169; |
3.J.228.172; | 3.J.228.175; | 3.J.228.240; | 3.J.228.244; |
3.J.229.228; | 3.J.229.229; | 3.J.229.230; | 3.J.229.231; |
3.J.229.236; | 3.J.229.237; | 3.J.229.238; | 3.J.229.239; |
3.J.229.154; | 3.J.229.157; | 3.J.229.166; | 3.J.229.169; |
3.J.229.172; | 3.J.229.175; | 3.J.229.240; | 3.J.229.244; |
3.J.230.228; | 3.J.230.229; | 3.J.230.230; | 3.J.230.231; |
3.J.230.236; | 3.J.230.237; | 3.J.230.238; | 3.J.230.239; |
3.J.230.154; | 3.J.230.157; | 3.J.230.166; | 3.J.230.169; |
3.J.230.172; | 3.J.230.175; | 3.J.230.240; | 3.J.230.244; |
3.J.231.228; | 3.J.231.229; | 3.J.231.230; | 3.J.231.231; |
3.J.231.236; | 3.J.231.237; | 3.J.231.238; | 3.J.231.239; |
3.J.231.154; | 3.J.231.157; | 3.J.231.166; | 3.J.231.169; |
3.J.231.172; | 3.J.231.175; | 3.J.231.240; | 3.J.231.244; |
3.J.236.228; | 3.J.236.229; | 3.J.236.230; | 3.J.236.231; |
3.J.236.236; | 3.J.236.237; | 3.J.236.238; | 3.J.236.239; |
3.J.236.154; | 3.J.236.157; | 3.J.236.166; | 3.J.236.169; |
3.J.236.172; | 3.J.236.175; | 3.J.236.240; | 3.J.236.244; |
3.J.237.228; | 3.J.237.229; | 3.J.237.230; | 3.J.237.231; |
3.J.237.236; | 3.J.237.237; | 3.J.237.238; | 3.J.237.239; |
3.J.237.154; | 3.J.237.157; | 3.J.237.166; | 3.J.237.169; |
3.J.237.172; | 3.J.237.175; | 3.J.237.240; | 3.J.237.244; |
3.J.238.228; | 3.J.238.229; | 3.J.238.230; | 3.J.238.231; |
3.J.238.236; | 3.J.238.237; | 3.J.238.238; | 3.J.238.239; |
3.J.238.154; | 3.J.238.157; | 3.J.238.166; | 3.J.238.169; |
3.J.238.172; | 3.J.238.175; | 3.J.238.240; | 3.J.238.244; |
3.J.239.228; | 3.J.239.229; | 3.J.239.230; | 3.J.239.231; |
3.J.239.236; | 3.J.239.237; | 3.J.239.238; | 3.J.239.239; |
3.J.239.154; | 3.J.239.157; | 3.J.239.166; | 3.J.239.169; |
3.J.239.172; | 3.J.239.175; | 3.J.239.240; | 3.J.239.244; |
3.J.154.228; | 3.J.154.229; | 3.J.154.230; | 3.J.154.231; |
3.J.154.236; | 3.J.154.237; | 3.J.154.238; | 3.J.154.239; |
3.J.154.154; | 3.J.154.157; | 3.J.154.166; | 3.J.154.169; |
3.J.154.172; | 3.J.154.175; | 3.J.154.240; | 3.J.154.244; |
3.J.157.228; | 3.J.157.229; | 3.J.157.230; | 3.J.157.231; |
3.J.157.236; | 3.J.157.237; | 3.J.157.238; | 3.J.157.239; |
3.J.157.154; | 3.J.157.157; | 3.J.157.166; | 3.J.157.169; |
3.J.157.172; | 3.J.157.175; | 3.J.157.240; | 3.J.157.244; |
3.J.166.228; | 3.J.166.229; | 3.J.166.230; | 3.J.166.231; |
3.J.166.236; | 3.J.166.237; | 3.J.166.238; | 3.J.166.239; |
3.J.166.154; | 3.J.166.157; | 3.J.166.166; | 3.J.166.169; |
3.J.166.172; | 3.J.166.175; | 3.J.166.240; | 3.J.166.244; |
3.J.169.228; | 3.J.169.229; | 3.J.169.230; | 3.J.169.231; |
3.J.169.236; | 3.J.169.237; | 3.J.169.238; | 3.J.169.239; |
3.J.169.154; | 3.J.169.157; | 3.J.169.166; | 3.J.169.169; |
3.J.169.172; | 3.J.169.175; | 3.J.169.240; | 3.J.169.244; |
3.J.172.228; | 3.J.172.229; | 3.J.172.230; | 3.J.172.231; |
3.J.172.236; | 3.J.172.237; | 3.J.172.238; | 3.J.172.239; |
3.J.172.154; | 3.J.172.157; | 3.J.172.166; | 3.J.172.169; |
3.J.172.172; | 3.J.172.175; | 3.J.172.240; | 3.J.172.244; |
3.J.175.228; | 3.J.175.229; | 3.J.175.230; | 3.J.175.231; |
3.J.175.236; | 3.J.175.237; | 3.J.175.238; | 3.J.175.239; |
3.J.175.154; | 3.J.175.157; | 3.J.175.166; | 3.J.175.169; |
3.J.175.172; | 3.J.175.175; | 3.J.175.240; | 3.J.175.244; |
3.J.240.228; | 3.J.240.229; | 3.J.240.230; | 3.J.240.231; |
3.J.240.236; | 3.J.240.237; | 3.J.240.238; | 3.J.240.239; |
3.J.240.154; | 3.J.240.157; | 3.J.240.166; | 3.J.240.169; |
3.J.240.172; | 3.J.240.175; | 3.J.240.240; | 3.J.240.244; |
3.J.244.228; | 3.J.244.229; | 3.J.244.230; | 3.J.244.231; |
3.J.244.236; | 3.J.244.237; | 3.J.244.238; | 3.J.244.239; |
3.J.244.154; | 3.J.244.157; | 3.J.244.166; | 3.J.244.169; |
3.J.244.172; | 3.J.244.175; | 3.J.244.240; | 3.J.244.244; |
3.L的前体药物
3.L.228.228; | 3.L.228.229; | 3.L.228.230; | 3.L.228.231; |
3.L.228.236; | 3.L.228.237; | 3.L.228.238; | 3.L.228.239; |
3.L.228.154; | 3.L.228.157; | 3.L.228.166; | 3.L.228.169; |
3.L.228.172; | 3.L.228.175; | 3.L.228.240; | 3.L.228.244; |
3.L.229.228; | 3.L.229.229; | 3.L.229.230; | 3.L.229.231; |
3.L.229.236; | 3.L.229.237; | 3.L.229.238; | 3.L.229.239; |
3.L.229.154; | 3.L.229.157; | 3.L.229.166; | 3.L.229.169; |
3.L.229.172; | 3.L.229.175; | 3.L.229.240; | 3.L.229.244; |
3.L.230.228; | 3.L.230.229; | 3.L.230.230; | 3.L.230.231; |
3.L.230.236; | 3.L.230.237; | 3.L.230.238; | 3.L.230.239; |
3.L.230.154; | 3.L.230.157; | 3.L.230.166; | 3.L.230.169; |
3.L.230.172; | 3.L.230.175; | 3.L.230.240; | 3.L.230.244; |
3.L.231.228; | 3.L.231.229; | 3.L.231.230; | 3.L.231.231; |
3.L.231.236; | 3.L.231.237; | 3.L.231.238; | 3.L.231.239; |
3.L.231.154; | 3.L.231.157; | 3.L.231.166; | 3.L.231.169; |
3.L.231.172; | 3.L.231.175; | 3.L.231.240; | 3.L.231.244; |
3.L.236.228; | 3.L.236.229; | 3.L.236.230; | 3.L.236.231; |
3.L.236.236; | 3.L.236.237; | 3.L.236.238; | 3.L.236.239; |
3.L.236.154; | 3.L.236.157; | 3.L.236.166; | 3.L.236.169; |
3.L.236.172; | 3.L.236.175; | 3.L.236.240; | 3.L.236.244; |
3.L.237.228; | 3.L.237.229; | 3.L.237.230; | 3.L.237.231; |
3.L.237.236; | 3.L.237.237; | 3.L.237.238; | 3.L.237.239; |
3.L.237.154; | 3.L.237.157; | 3.L.237.166; | 3.L.237.169; |
3.L.237.172; | 3.L.237.175; | 3.L.237.240; | 3.L.237.244; |
3.L.238.228; | 3.L.238.229; | 3.L.238.230; | 3.L.238.231; |
3.L.238.236; | 3.L.238.237; | 3.L.238.238; | 3.L.238.239; |
3.L.238.154; | 3.L.238.157; | 3.L.238.166; | 3.L.238.169; |
3.L.238.172; | 3.L.238.175; | 3.L.238.240; | 3.L.238.244; |
3.L.239.228; | 3.L.239.229; | 3.L.239.230; | 3.L.239.231; |
3.L.239.236; | 3.L.239.237; | 3.L.239.238; | 3.L.239.239; |
3.L.239.154; | 3.L.239.157; | 3.L.239.166; | 3.L.239.169; |
3.L.239.172; | 3.L.239.175; | 3.L.239.240; | 3.L.239.244; |
3.L.154.228; | 3.L.154.229; | 3.L.154.230; | 3.L.154.231; |
3.L.154.236; | 3.L.154.237; | 3.L.154.238; | 3.L.154.239; |
3.L.154.154; | 3.L.154.157; | 3.L.154.166; | 3.L.154.169; |
3.L.154.172; | 3.L.154.175; | 3.L.154.240; | 3.L.154.244; |
3.L.157.228; | 3.L.157.229; | 3.L.157.230; | 3.L.157.231; |
3.L.157.236; | 3.L.157.237; | 3.L.157.238; | 3.L.157.239; |
3.L.157.154; | 3.L.157.157; | 3.L.157.166; | 3.L.157.169; |
3.L.157.172; | 3.L.157.175; | 3.L.157.240; | 3.L.157.244; |
3.L.166.228; | 3.L.166.229; | 3.L.166.230; | 3.L.166.231; |
3.L.166.236; | 3.L.166.237; | 3.L.166.238; | 3.L.166.239; |
3.L.166.154; | 3.L.166.157; | 3.L.166.166; | 3.L.166.169; |
3.L.166.172; | 3.L.166.175; | 3.L.166.240; | 3.L.166.244; |
3.L.169.228; | 3.L.169.229; | 3.L.169.230; | 3.L.169.231; |
3.L.169.236; | 3.L.169.237; | 3.L.169.238; | 3.L.169.239; |
3.L.169.154; | 3.L.169.157; | 3.L.169.166; | 3.L.169.169; |
3.L.169.172; | 3.L.169.175; | 3.L.169.240; | 3.L.169.244; |
3.L.172.228; | 3.L.172.229; | 3.L.172.230; | 3.L.172.231; |
3.L.172.236; | 3.L.172.237; | 3.L.172.238; | 3.L.172.239; |
3.L.172.154; | 3.L.172.157; | 3.L.172.166; | 3.L.172.169; |
3.L.172.172; | 3.L.172.175; | 3.L.172.240; | 3.L.172.244; |
3.L.175.228; | 3.L.175.229; | 3.L.175.230; | 3.L.175.231; |
3.L.175.236; | 3.L.175.237; | 3.L.175.238; | 3.L.175.239; |
3.L.175.154; | 3.L.175.157; | 3.L.175.166; | 3.L.175.169; |
3.L.175.172; | 3.L.175.175; | 3.L.175.240; | 3.L.175.244; |
3.L.240.228; | 3.L.240.229; | 3.L.240.230; | 3.L.240.231; |
3.L.240.236; | 3.L.240.237; | 3.L.240.238; | 3.L.240.239; |
3.L.240.154; | 3.L.240.157; | 3.L.240.166; | 3.L.240.169; |
3.L.240.172; | 3.L.240.175; | 3.L.240.240; | 3.L.240.244; |
3.L.244.228; | 3.L.244.229; | 3.L.244.230; | 3.L.244.231; |
3.L.244.236; | 3.L.244.237; | 3.L.244.238; | 3.L.244.239; |
3.L.244.154; | 3.L.244.157; | 3.L.244.166; | 3.L.244.169; |
3.L.244.172; | 3.L.244.175; | 3.L.244.240; | 3.L.244.244; |
3.O的前体药物
3.O.228.228; | 3.O.228.229; | 3.O.228.230; | 3.O.228.231; |
3.O.228.236; | 3.O.228.237; | 3.O.228.238; | 3.O.228.239; |
3.O.228.154; | 3.O.228.157; | 3.O.228.166; | 3.O.228.169; |
3.O.228.172; | 3.O.228.175; | 3.O.228.240; | 3.O.228.244; |
3.O.229.228; | 3.O.229.229; | 3.O.229.230; | 3.O.229.231; |
3.O.229.236; | 3.O.229.237; | 3.O.229.238; | 3.O.229.239; |
3.O.229.154; | 3.O.229.157; | 3.O.229.166; | 3.O.229.169; |
3.O.229.172; | 3.O.229.175; | 3.O.229.240; | 3.O.229.244; |
3.O.230.228; | 3.O.230.229; | 3.O.230.230; | 3.O.230.231; |
3.O.230.236; | 3.O.230.237; | 3.O.230.238; | 3.O.230.239; |
3.O.230.154; | 3.O.230.157; | 3.O.230.166; | 3.O.230.169; |
3.O.230.172; | 3.O.230.175; | 3.O.230.240; | 3.O.230.244; |
3.O.231.228; | 3.O.231.229; | 3.O.231.230; | 3.O.231.231; |
3.O.231.236; | 3.O.231.237; | 3.O.231.238; | 3.O.231.239; |
3.O.231.154; | 3.O.231.157; | 3.O.231.166; | 3.O.231.169; |
3.O.231.172; | 3.O.231.175; | 3.O.231.240; | 3.O.231.244; |
3.O.236.228; | 3.O.236.229; | 3.O.236.230; | 3.O.236.231; |
3.O.236.236; | 3.O.236.237; | 3.O.236.238; | 3.O.236.239; |
3.O.236.154; | 3.O.236.157; | 3.O.236.166; | 3.O.236.169; |
3.O.236.172; | 3.O.236.175; | 3.O.236.240; | 3.O.236.244; |
3.O.237.228; | 3.O.237.229; | 3.O.237.230; | 3.O.237.231; |
3.O.237.236; | 3.O.237.237; | 3.O.237.238; | 3.O.237.239; |
3.O.237.154; | 3.O.237.157; | 3.O.237.166; | 3.O.237.169; |
3.O.237.172; | 3.O.237.175; | 3.O.237.240; | 3.O.237.244; |
3.O.238.228; | 3.O.238.229; | 3.O.238.230; | 3.O.238.231; |
3.O.238.236; | 3.O.238.237; | 3.O.238.238; | 3.O.238.239; |
3.O.238.154; | 3.O.238.157; | 3.O.238.166; | 3.O.238.169; |
3.O.238.172; | 3.O.238.175; | 3.O.238.240; | 3.O.238.244; |
3.O.239.228; | 3.O.239.229; | 3.O.239.230; | 3.O.239.231; |
3.O.239.236; | 3.O.239.237; | 3.O.239.238; | 3.O.239.239; |
3.O.239.154; | 3.O.239.157; | 3.O.239.166; | 3.O.239.169; |
3.O.239.172; | 3.O.239.175; | 3.O.239.240; | 3.O.239.244; |
3.O.154.228; | 3.O.154.229; | 3.O.154.230; | 3.O.154.231; |
3.O.154.236; | 3.O.154.237; | 3.O.154.238; | 3.O.154.239; |
3.O.154.154; | 3.O.154.157; | 3.O.154.166; | 3.O.154.169; |
3.O.154.172; | 3.O.154.175; | 3.O.154.240; | 3.O.154.244; |
3.O.157.228; | 3.O.157.229; | 3.O.157.230; | 3.O.157.231; |
3.O.157.236; | 3.O.157.237; | 3.O.157.238; | 3.O.157.239; |
3.O.157.154; | 3.O.157.157; | 3.O.157.166; | 3.O.157.169; |
3.O.157.172; | 3.O.157.175; | 3.O.157.240; | 3.O.157.244; |
3.O.166.228; | 3.O.166.229; | 3.O.166.230; | 3.O.166.231; |
3.O.166.236; | 3.O.166.237; | 3.O.166.238; | 3.O.166.239; |
3.O.166.154; | 3.O.166.157; | 3.O.166.166; | 3.O.166.169; |
3.O.166.172; | 3.O.166.175; | 3.O.166.240; | 3.O.166.244; |
3.O.169.228; | 3.O.169.229; | 3.O.169.230; | 3.O.169.231; |
3.O.169.236; | 3.O.169.237; | 3.O.169.238; | 3.O.169.239; |
3.O.169.154; | 3.O.169.157; | 3.O.169.166; | 3.O.169.169; |
3.O.169.172; | 3.O.169.175; | 3.O.169.240; | 3.O.169.244; |
3.O.172.228; | 3.O.172.229; | 3.O.172.230; | 3.O.172.231; |
3.O.172.236; | 3.O.172.237; | 3.O.172.238; | 3.O.172.239; |
3.O.172.154; | 3.O.172.157; | 3.O.172.166; | 3.O.172.169; |
3.O.172.172; | 3.O.172.175; | 3.O.172.240; | 3.O.172.244; |
3.O.175.228; | 3.O.175.229; | 3.O.175.230; | 3.O.175.231; |
3.O.175.236; | 3.O.175.237; | 3.O.175.238; | 3.O.175.239; |
3.O.175.154; | 3.O.175.157; | 3.O.175.166; | 3.O.175.169; |
3.O.175.172; | 3.O.175.175; | 3.O.175.240; | 3.O.175.244; |
3.O.240.228; | 3.O.240.229; | 3.O.240.230; | 3.O.240.231; |
3.O.240.236; | 3.O.240.237; | 3.O.240.238; | 3.O.240.239; |
3.O.240.154; | 3.O.240.157; | 3.O.240.166; | 3.O.240.169; |
3.O.240.172; | 3.O.240.175; | 3.O.240.240; | 3.O.240.244; |
3.O.244.228; | 3.O.244.229; | 3.O.244.230; | 3.O.244.231; |
3.O.244.236; | 3.O.244.237; | 3.O.244.238; | 3.O.244.239; |
3.O.244.154; | 3.O.244.157; | 3.O.244.166; | 3.O.244.169; |
3.O.244.172; | 3.O.244.175; | 3.O.244.240; | 3.O.244.244; |
3.P的前体药物
3.P.228.228; | 3.P.228.229; | 3.P.228.230; | 3.P.228.231; |
3.P.228.236; | 3.P.228.237; | 3.P.228.238; | 3.P.228.239; |
3.P.228.154; | 3.P.228.157; | 3.P.228.166; | 3.P.228.169; |
3.P.228.172; | 3.P.228.175; | 3.P.228.240; | 3.P.228.244; |
3.P.229.228; | 3.P.229.229; | 3.P.229.230; | 3.P.229.231; |
3.P.229.236; | 3.P.229.237; | 3.P.229.238; | 3.P.229.239; |
3.P.229.154; | 3.P.229.157; | 3.P.229.166; | 3.P.229.169; |
3.P.229.172; | 3.P.229.175; | 3.P.229.240; | 3.P.229.244; |
3.P.230.228; | 3.P.230.229; | 3.P.230.230; | 3.P.230.231; |
3.P.230.236; | 3.P.230.237; | 3.P.230.238; | 3.P.230.239; |
3.P.230.154; | 3.P.230.157; | 3.P.230.166; | 3.P.230.169; |
3.P.230.172; | 3.P.230.175; | 3.P.230.240; | 3.P.230.244; |
3.P.231.228; | 3.P.231.229; | 3.P.231.230; | 3.P.231.231; |
3.P.231.236; | 3.P.231.237; | 3.P.231.238; | 3.P.231.239; |
3.P.231.154; | 3.P.231.157; | 3.P.231.166; | 3.P.231.169; |
3.P.231.172; | 3.P.231.175; | 3.P.231.240; | 3.P.231.244; |
3.P.236.228; | 3.P.236.229; | 3.P.236.230; | 3.P.236.231; |
3.P.236.236; | 3.P.236.237; | 3.P.236.238; | 3.P.236.239; |
3.P.236.154; | 3.P.236.157; | 3.P.236.166; | 3.P.236.169; |
3.P.236.172; | 3.P.236.175; | 3.P.236.240; | 3.P.236.244; |
3.P.237.228; | 3.P.237.229; | 3.P.237.230; | 3.P.237.231; |
3.P.237.236; | 3.P.237.237; | 3.P.237.238; | 3.P.237.239; |
3.P.237.154; | 3.P.237.157; | 3.P.237.166; | 3.P.237.169; |
3.P.237.172; | 3.P.237.175; | 3.P.237.240; | 3.P.237.244; |
3.P.238.228; | 3.P.238.229; | 3.P.238.230; | 3.P.238.231; |
3.P.238.236; | 3.P.238.237; | 3.P.238.238; | 3.P.238.239; |
3.P.238.154; | 3.P.238.157; | 3.P.238.166; | 3.P.238.169; |
3.P.238.172; | 3.P.238.175; | 3.P.238.240; | 3.P.238.244; |
3.P.239.228; | 3.P.239.229; | 3.P.239.230; | 3.P.239.231; |
3.P.239.236; | 3.P.239.237; | 3.P.239.238; | 3.P.239.239; |
3.P.239.154; | 3.P.239.157; | 3.P.239.166; | 3.P.239.169; |
3.P.239.172; | 3.P.239.175; | 3.P.239.240; | 3.P.239.244; |
3.P.154.228; | 3.P.154.229; | 3.P.154.230; | 3.P.154.231; |
3.P.154.236; | 3.P.154.237; | 3.P.154.238; | 3.P.154.239; |
3.P.154.154; | 3.P.154.157; | 3.P.154.166; | 3.P.154.169; |
3.P.154.172; | 3.P.154.175; | 3.P.154.240; | 3.P.154.244; |
3.P.157.228; | 3.P.157.229; | 3.P.157.230; | 3.P.157.231; |
3.P.157.236; | 3.P.157.237; | 3.P.157.238; | 3.P.157.239; |
3.P.157.154; | 3.P.157.157; | 3.P.157.166; | 3.P.157.169; |
3.P.157.172; | 3.P.157.175; | 3.P.157.240; | 3.P.157.244; |
3.P.166.228; | 3.P.166.229; | 3.P.166.230; | 3.P.166.231; |
3.P.166.236; | 3.P.166.237; | 3.P.166.238; | 3.P.166.239; |
3.P.166.154; | 3.P.166.157; | 3.P.166.166; | 3.P.166.169; |
3.P.166.172; | 3.P.166.175; | 3.P.166.240; | 3.P.166.244; |
3.P.169.228; | 3.P.169.229; | 3.P.169.230; | 3.P.169.231; |
3.P.169.236; | 3.P.169.237; | 3.P.169.238; | 3.P.169.239; |
3.P.169.154; | 3.P.169.157; | 3.P.169.166; | 3.P.169.169; |
3.P.169.172; | 3.P.169.175; | 3.P.169.240; | 3.P.169.244; |
3.P.172.228; | 3.P.172.229; | 3.P.172.230; | 3.P.172.231; |
3.P.172.236; | 3.P.172.237; | 3.P.172.238; | 3.P.172.239; |
3.P.172.154; | 3.P.172.157; | 3.P.172.166; | 3.P.172.169; |
3.P.172.172; | 3.P.172.175; | 3.P.172.240; | 3.P.172.244; |
3.P.175.228; | 3.P.175.229; | 3.P.175.230; | 3.P.175.231; |
3.P.175.236; | 3.P.175.237; | 3.P.175.238; | 3.P.175.239; |
3.P.175.154; | 3.P.175.157; | 3.P.175.166; | 3.P.175.169; |
3.P.175.172; | 3.P.175.175; | 3.P.175.240; | 3.P.175.244; |
3.P.240.228; | 3.P.240.229; | 3.P.240.230; | 3.P.240.231; |
3.P.240.236; | 3.P.240.237; | 3.P.240.238; | 3.P.240.239; |
3.P.240.154; | 3.P.240.157; | 3.P.240.166; | 3.P.240.169; |
3.P.240.172; | 3.P.240.175; | 3.P.240.240; | 3.P.240.244; |
3.P.244.228; | 3.P.244.229; | 3.P.244.230; | 3.P.244.231; |
3.P.244.236; | 3.P.244.237; | 3.P.244.238; | 3.P.244.239; |
3.P.244.154; | 3.P.244.157; | 3.P.244.166; | 3.P.244.169; |
3.P.244.172; | 3.P.244.175; | 3.P.244.240; | 3.P.244.244; |
3.U的前体药物
3.U.228.228; | 3.U.228.229; | 3.U.228.230; | 3.U.228.231; |
3.U.228.236; | 3.U.228.237; | 3.U.228.238; | 3.U.228.239; |
3.U.228.154; | 3.U.228.157; | 3.U.228.166; | 3.U.228.169; |
3.U.228.172; | 3.U.228.175; | 3.U.228.240; | 3.U.228.244; |
3.U.229.228; | 3.U.229.229; | 3.U.229.230; | 3.U.229.231; |
3.U.229.236; | 3.U.229.237; | 3.U.229.238; | 3.U.229.239; |
3.U.229.154; | 3.U.229.157; | 3.U.229.166; | 3.U.229.169; |
3.U.229.172; | 3.U.229.175; | 3.U.229.240; | 3.U.229.244; |
3.U.230.228; | 3.U.230.229; | 3.U.230.230; | 3.U.230.231; |
3.U.230.236; | 3.U.230.237; | 3.U.230.238; | 3.U.230.239; |
3.U.230.154; | 3.U.230.157; | 3.U.230.166; | 3.U.230.169; |
3.U.230.172; | 3.U.230.175; | 3.U.230.240; | 3.U.230.244; |
3.U.231.228; | 3.U.231.229; | 3.U.231.230; | 3.U.231.231; |
3.U.231.236; | 3.U.231.237; | 3.U.231.238; | 3.U.231.239; |
3.U.231.154; | 3.U.231.157; | 3.U.231.166; | 3.U.231.169; |
3.U.231.172; | 3.U.231.175; | 3.U.231.240; | 3.U.231.244; |
3.U.236.228; | 3.U.236.229; | 3.U.236.230; | 3.U.236.231; |
3.U.236.236; | 3.U.236.237; | 3.U.236.238; | 3.U.236.239; |
3.U.236.154; | 3.U.236.157; | 3.U.236.166; | 3.U.236.169; |
3.U.236.172; | 3.U.236.175; | 3.U.236.240; | 3.U.236.244; |
3.U.237.228; | 3.U.237.229; | 3.U.237.230; | 3.U.237.231; |
3.U.237.236; | 3.U.237.237; | 3.U.237.238; | 3.U.237.239; |
3.U.237.154; | 3.U.237.157; | 3.U.237.166; | 3.U.237.169; |
3.U.237.172; | 3.U.237.175; | 3.U.237.240; | 3.U.237.244; |
3.U.238.228; | 3.U.238.229; | 3.U.238.230; | 3.U.238.231; |
3.U.238.236; | 3.U.238.237; | 3.U.238.238; | 3.U.238.239; |
3.U.238.154; | 3.U.238.157; | 3.U.238.166; | 3.U.238.169; |
3.U.238.172; | 3.U.238.175; | 3.U.238.240; | 3.U.238.244; |
3.U.239.228; | 3.U.239.229; | 3.U.239.230; | 3.U.239.231; |
3.U.239.236; | 3.U.239.237; | 3.U.239.238; | 3.U.239.239; |
3.U.239.154; | 3.U.239.157; | 3.U.239.166; | 3.U.239.169; |
3.U.239.172; | 3.U.239.175; | 3.U.239.240; | 3.U.239.244; |
3.U.154.228; | 3.U.154.229; | 3.U.154.230; | 3.U.154.231; |
3.U.154.236; | 3.U.154.237; | 3.U.154.238; | 3.U.154.239; |
3.U.154.154; | 3.U.154.157; | 3.U.154.166; | 3.U.154.169; |
3.U.154.172; | 3.U.154.175; | 3.U.154.240; | 3.U.154.244; |
3.U.157.228; | 3.U.157.229; | 3.U.157.230; | 3.U.157.231; |
3.U.157.236; | 3.U.157.237; | 3.U.157.238; | 3.U.157.239; |
3.U.157.154; | 3.U.157.157; | 3.U.157.166; | 3.U.157.169; |
3.U.157.172; | 3.U.157.175; | 3.U.157.240; | 3.U.157.244; |
3.U.166.228; | 3.U.166.229; | 3.U.166.230; | 3.U.166.231; |
3.U.166.236; | 3.U.166.237; | 3.U.166.238; | 3.U.166.239; |
3.U.166.154; | 3.U.166.157; | 3.U.166.166; | 3.U.166.169; |
3.U.166.172; | 3.U.166.175; | 3.U.166.240; | 3.U.166.244; |
3.U.169.228; | 3.U.169.229; | 3.U.169.230; | 3.U.169.231; |
3.U.169.236; | 3.U.169.237; | 3.U.169.238; | 3.U.169.239; |
3.U.169.154; | 3.U.169.157; | 3.U.169.166; | 3.U.169.169; |
3.U.169.172; | 3.U.169.175; | 3.U.169.240; | 3.U.169.244; |
3.U.172.228; | 3.U.172.229; | 3.U.172.230; | 3.U.172.231; |
3.U.172.236; | 3.U.172.237; | 3.U.172.238; | 3.U.172.239; |
3.U.172.154; | 3.U.172.157; | 3.U.172.166; | 3.U.172.169; |
3.U.172.172; | 3.U.172.175; | 3.U.172.240; | 3.U.172.244; |
3.U.175.228; | 3.U.175.229; | 3.U.175.230; | 3.U.175.231; |
3.U.175.236; | 3.U.175.237; | 3.U.175.238; | 3.U.175.239; |
3.U.175.154; | 3.U.175.157; | 3.U.175.166; | 3.U.175.169; |
3.U.175.172; | 3.U.175.175; | 3.U.175.240; | 3.U.175.244; |
3.U.240.228; | 3.U.240.229; | 3.U.240.230; | 3.U.240.231; |
3.U.240.236; | 3.U.240.237; | 3.U.240.238; | 3.U.240.239; |
3.U.240.154; | 3.U.240.157; | 3.U.240.166; | 3.U.240.169; |
3.U.240.172; | 3.U.240.175; | 3.U.240.240; | 3.U.240.244; |
3.U.244.228; | 3.U.244.229; | 3.U.244.230; | 3.U.244.231; |
3.U.244.236; | 3.U.244.237; | 3.U.244.238; | 3.U.244.239; |
3.U.244.154; | 3.U.244.157; | 3.U.244.166; | 3.U.244.169; |
3.U.244.172; | 3.U.244.175; | 3.U.244.240; | 3.U.244.244; |
3.W的前体药物
3.W.228.228; | 3.W.228.229; | 3.W.228.230; | 3.W.228.231; |
3.W.228.236; | 3.W.228.237; | 3.W.228.238; | 3.W.228.239; |
3.W.228.154; | 3.W.228.157; | 3.W.228.166; | 3.W.228.169; |
3.W.228.172; | 3.W.228.175; | 3.W.228.240; | 3.W.228.244; |
3.W.229.228; | 3.W.229.229; | 3.W.229.230; | 3.W.229.231; |
3.W.229.236; | 3.W.229.237; | 3.W.229.238; | 3.W.229.239; |
3.W.229.154; | 3.W.229.157; | 3.W.229.166; | 3.W.229.169; |
3.W.229.172; | 3.W.229.175; | 3.W.229.240; | 3.W.229.244; |
3.W.230.228; | 3.W.230.229; | 3.W.230.230; | 3.W.230.231; |
3.W.230.236; | 3.W.230.237; | 3.W.230.238; | 3.W.230.239; |
3.W.230.154; | 3.W.230.157; | 3.W.230.166; | 3.W.230.169; |
3.W.230.172; | 3.W.230.175; | 3.W.230.240; | 3.W.230.244; |
3.W.231.228; | 3.W.231.229; | 3.W.231.230; | 3.W.231.231; |
3.W.231.236; | 3.W.231.237; | 3.W.231.238; | 3.W.231.239; |
3.W.231.154; | 3.W.231.157; | 3.W.231.166; | 3.W.231.169; |
3.W.231.172; | 3.W.231.175; | 3.W.231.240; | 3.W.231.244; |
3.W.236.228; | 3.W.236.229; | 3.W.236.230; | 3.W.236.231; |
3.W.236.236; | 3.W.236.237; | 3.W.236.238; | 3.W.236.239; |
3.W.236.154; | 3.W.236.157; | 3.W.236.166; | 3.W.236.169; |
3.W.236.172; | 3.W.236.175; | 3.W.236.240; | 3.W.236.244; |
3.W.237.228; | 3.W.237.229; | 3.W.237.230; | 3.W.237.231; |
3.W.237.236; | 3.W.237.237; | 3.W.237.238; | 3.W.237.239; |
3.W.237.154; | 3.W.237.157; | 3.W.237.166; | 3.W.237.169; |
3.W.237.172; | 3.W.237.175; | 3.W.237.240; | 3.W.237.244; |
3.W.238.228; | 3.W.238.229; | 3.W.238.230; | 3.W.238.231; |
3.W.238.236; | 3.W.238.237; | 3.W.238.238; | 3.W.238.239; |
3.W.238.154; | 3.W.238.157; | 3.W.238.166; | 3.W.238.169; |
3.W.238.172; | 3.W.238.175; | 3.W.238.240; | 3.W.238.244; |
3.W.239.228; | 3.W.239.229; | 3.W.239.230; | 3.W.239.231; |
3.W.239.236; | 3.W.239.237; | 3.W.239.238; | 3.W.239.239; |
3.W.239.154; | 3.W.239.157; | 3.W.239.166; | 3.W.239.169; |
3.W.239.172; | 3.W.239.175; | 3.W.239.240; | 3.W.239.244; |
3.W.154.228; | 3.W.154.229; | 3.W.154.230; | 3.W.154.231; |
3.W.154.236; | 3.W.154.237; | 3.W.154.238; | 3.W.154.239; |
3.W.154.154; | 3.W.154.157; | 3.W.154.166; | 3.W.154.169; |
3.W.154.172; | 3.W.154.175; | 3.W.154.240; | 3.W.154.244; |
3.W.157.228; | 3.W.157.229; | 3.W.157.230; | 3.W.157.231; |
3.W.157.236; | 3.W.157.237; | 3.W.157.238; | 3.W.157.239; |
3.W.157.154; | 3.W.157.157; | 3.W.157.166; | 3.W.157.169; |
3.W.157.172; | 3.W.157.175; | 3.W.157.240; | 3.W.157.244; |
3.W.166.228; | 3.W.166.229; | 3.W.166.230; | 3.W.166.231; |
3.W.166.236; | 3.W.166.237; | 3.W.166.238; | 3.W.166.239; |
3.W.166.154; | 3.W.166.157; | 3.W.166.166; | 3.W.166.169; |
3.W.166.172; | 3.W.166.175; | 3.W.166.240; | 3.W.166.244; |
3.W.169.228; | 3.W.169.229; | 3.W.169.230; | 3.W.169.231; |
3.W.169.236; | 3.W.169.237; | 3.W.169.238; | 3.W.169.239; |
3.W.169.154; | 3.W.169.157; | 3.W.169.166; | 3.W.169.169; |
3.W.169.172; | 3.W.169.175; | 3.W.169.240; | 3.W.169.244; |
3.W.172.228; | 3.W.172.229; | 3.W.172.230; | 3.W.172.231; |
3.W.172.236; | 3.W.172.237; | 3.W.172.238; | 3.W.172.239; |
3.W.172.154; | 3.W.172.157; | 3.W.172.166; | 3.W.172.169; |
3.W.172.172; | 3.W.172.175; | 3.W.172.240; | 3.W.172.244; |
3.W.175.228; | 3.W.175.229; | 3.W.175.230; | 3.W.175.231; |
3.W.175.236; | 3.W.175.237; | 3.W.175.238; | 3.W.175.239; |
3.W.175.154; | 3.W.175.157; | 3.W.175.166; | 3.W.175.169; |
3.W.175.172; | 3.W.175.175; | 3.W.175.240; | 3.W.175.244; |
3.W.240.228; | 3.W.240.229; | 3.W.240.230; | 3.W.240.231; |
3.W.240.236; | 3.W.240.237; | 3.W.240.238; | 3.W.240.239; |
3.W.240.154; | 3.W.240.157; | 3.W.240.166; | 3.W.240.169; |
3.W.240.172; | 3.W.240.175; | 3.W.240.240; | 3.W.240.244; |
3.W.244.228; | 3.W.244.229; | 3.W.244.230; | 3.W.244.231; |
3.W.244.236; | 3.W.244.237; | 3.W.244.238; | 3.W.244.239; |
3.W.244.154; | 3.W.244.157; | 3.W.244.166; | 3.W.244.169; |
3.W.244.172; | 3.W.244.175; | 3.W.244.240; | 3.W.244.244; |
3.Y的前体药物
3.Y.228.228; | 3.Y.228.229; | 3.Y.228.230; | 3.Y.228.231; |
3.Y.228.236; | 3.Y.228.237; | 3.Y.228.238; | 3.Y.228.239; |
3.Y.228.154; | 3.Y.228.157; | 3.Y.228.166; | 3.Y.228.169; |
3.Y.228.172; | 3.Y.228.175; | 3.Y.228.240; | 3.Y.228.244; |
3.Y.229.228; | 3.Y.229.229; | 3.Y.229.230; | 3.Y.229.231; |
3.Y.229.236; | 3.Y.229.237; | 3.Y.229.238; | 3.Y.229.239; |
3.Y.229.154; | 3.Y.229.157; | 3.Y.229.166; | 3.Y.229.169; |
3.Y.229.172; | 3.Y.229.175; | 3.Y.229.240; | 3.Y.229.244; |
3.Y.230.228; | 3.Y.230.229; | 3.Y.230.230; | 3.Y.230.231; |
3.Y.230.236; | 3.Y.230.237; | 3.Y.230.238; | 3.Y.230.239; |
3.Y.230.154; | 3.Y.230.157; | 3.Y.230.166; | 3.Y.230.169; |
3.Y.230.172; | 3.Y.230.175; | 3.Y.230.240; | 3.Y.230.244; |
3.Y.231.228; | 3.Y.231.229; | 3.Y.231.230; | 3.Y.231.231; |
3.Y.231.236; | 3.Y.231.237; | 3.Y.231.238; | 3.Y.231.239; |
3.Y.231.154; | 3.Y.231.157; | 3.Y.231.166; | 3.Y.231.169; |
3.Y.231.172; | 3.Y.231.175; | 3.Y.231.240; | 3.Y.231.244; |
3.Y.236.228; | 3.Y.236.229; | 3.Y.236.230; | 3.Y.236.231; |
3.Y.236.236; | 3.Y.236.237; | 3.Y.236.238; | 3.Y.236.239; |
3.Y.236.154; | 3.Y.236.157; | 3.Y.236.166; | 3.Y.236.169; |
3.Y.236.172; | 3.Y.236.175; | 3.Y.236.240; | 3.Y.236.244; |
3.Y.237.228; | 3.Y.237.229; | 3.Y.237.230; | 3.Y.237.231; |
3.Y.237.236; | 3.Y.237.237; | 3.Y.237.238; | 3.Y.237.239; |
3.Y.237.154; | 3.Y.237.157; | 3.Y.237.166; | 3.Y.237.169; |
3.Y.237.172; | 3.Y.237.175; | 3.Y.237.240; | 3.Y.237.244; |
3.Y.238.228; | 3.Y.238.229; | 3.Y.238.230; | 3.Y.238.231; |
3.Y.238.236; | 3.Y.238.237; | 3.Y.238.238; | 3.Y.238.239; |
3.Y.238.154; | 3.Y.238.157; | 3.Y.238.166; | 3.Y.238.169; |
3.Y.238.172; | 3.Y.238.175; | 3.Y.238.240; | 3.Y.238.244; |
3.Y.239.228; | 3.Y.239.229; | 3.Y.239.230; | 3.Y.239.231; |
3.Y.239.236; | 3.Y.239.237; | 3.Y.239.238; | 3.Y.239.239; |
3.Y.239.154; | 3.Y.239.157; | 3.Y.239.166; | 3.Y.239.169; |
3.Y.239.172; | 3.Y.239.175; | 3.Y.239.240; | 3.Y.239.244; |
3.Y.154.228; | 3.Y.154.229; | 3.Y.154.230; | 3.Y.154.231; |
3.Y.154.236; | 3.Y.154.237; | 3.Y.154.238; | 3.Y.154.239; |
3.Y.154.154; | 3.Y.154.157; | 3.Y.154.166; | 3.Y.154.169; |
3.Y.154.172; | 3.Y.154.175; | 3.Y.154.240; | 3.Y.154.244; |
3.Y.157.228; | 3.Y.157.229; | 3.Y.157.230; | 3.Y.157.231; |
3.Y.157.236; | 3.Y.157.237; | 3.Y.157.238; | 3.Y.157.239; |
3.Y.157.154; | 3.Y.157.157; | 3.Y.157.166; | 3.Y.157.169; |
3.Y.157.172; | 3.Y.157.175; | 3.Y.157.240; | 3.Y.157.244; |
3.Y.166.228; | 3.Y.166.229; | 3.Y.166.230; | 3.Y.166.231; |
3.Y.166.236; | 3.Y.166.237; | 3.Y.166.238; | 3.Y.166.239; |
3.Y.166.154; | 3.Y.166.157; | 3.Y.166.166; | 3.Y.166.169; |
3.Y.166.172; | 3.Y.166.175; | 3.Y.166.240; | 3.Y.166.244; |
3.Y.169.228; | 3.Y.169.229; | 3.Y.169.230; | 3.Y.169.231; |
3.Y.169.236; | 3.Y.169.237; | 3.Y.169.238; | 3.Y.169.239; |
3.Y.169.154; | 3.Y.169.157; | 3.Y.169.166; | 3.Y.169.169; |
3.Y.169.172; | 3.Y.169.175; | 3.Y.169.240; | 3.Y.169.244; |
3.Y.172.228; | 3.Y.172.229; | 3.Y.172.230; | 3.Y.172.231; |
3.Y.172.236; | 3.Y.172.237; | 3.Y.172.238; | 3.Y.172.239; |
3.Y.172.154; | 3.Y.172.157; | 3.Y.172.166; | 3.Y.172.169; |
3.Y.172.172; | 3.Y.172.175; | 3.Y.172.240; | 3.Y.172.244; |
3.Y.175.228; | 3.Y.175.229; | 3.Y.175.230; | 3.Y.175.231; |
3.Y.175.236; | 3.Y.175.237; | 3.Y.175.238; | 3.Y.175.239; |
3.Y.175.154; | 3.Y.175.157; | 3.Y.175.166; | 3.Y.175.169; |
3.Y.175.172; | 3.Y.175.175; | 3.Y.175.240; | 3.Y.175.244; |
3.Y.240.228; | 3.Y.240.229; | 3.Y.240.230; | 3.Y.240.231; |
3.Y.240.236; | 3.Y.240.237; | 3.Y.240.238; | 3.Y.240.239; |
3.Y.240.154; | 3.Y.240.157; | 3.Y.240.166; | 3.Y.240.169; |
3.Y.240.172; | 3.Y.240.175; | 3.Y.240.240; | 3.Y.240.244; |
3.Y.244.228; | 3.Y.244.229; | 3.Y.244.230; | 3.Y.244.231; |
3.Y.244.236; | 3.Y.244.237; | 3.Y.244.238; | 3.Y.244.239; |
3.Y.244.154; | 3.Y.244.157; | 3.Y.244.166; | 3.Y.244.169; |
3.Y.244.172; | 3.Y.244.175; | 3.Y.244.240; | 3.Y.244.244; |
4.B的前体药物
4.B.228.228; | 4.B.228.229; | 4.B.228.230; | 4.B.228.231; |
4.B.228.236; | 4.B.228.237; | 4.B.228.238; | 4.B.228.239; |
4.B.228.154; | 4.B.228.157; | 4.B.228.166; | 4.B.228.169; |
4.B.228.172; | 4.B.228.175; | 4.B.228.240; | 4.B.228.244; |
4.B.229.228; | 4.B.229.229; | 4.B.229.230; | 4.B.229.231; |
4.B.229.236; | 4.B.229.237; | 4.B.229.238; | 4.B.229.239; |
4.B.229.154; | 4.B.229.157; | 4.B.229.166; | 4.B.229.169; |
4.B.229.172; | 4.B.229.175; | 4.B.229.240; | 4.B.229.244; |
4.B.230.228; | 4.B.230.229; | 4.B.230.230; | 4.B.230.231; |
4.B.230.236; | 4.B.230.237; | 4.B.230.238; | 4.B.230.239; |
4.B.230.154; | 4.B.230.157; | 4.B.230.166; | 4.B.230.169; |
4.B.230.172; | 4.B.230.175; | 4.B.230.240; | 4.B.230.244; |
4.B.231.228; | 4.B.231.229; | 4.B.231.230; | 4.B.231.231; |
4.B.231.236; | 4.B.231.237; | 4.B.231.238; | 4.B.231.239; |
4.B.231.154; | 4.B.231.157; | 4.B.231.166; | 4.B.231.169; |
4.B.231.172; | 4.B.231.175; | 4.B.231.240; | 4.B.231.244; |
4.B.236.228; | 4.B.236.229; | 4.B.236.230; | 4.B.236.231; |
4.B.236.236; | 4.B.236.237; | 4.B.236.238; | 4.B.236.239; |
4.B.236.154; | 4.B.236.157; | 4.B.236.166; | 4.B.236.169; |
4.B.236.172; | 4.B.236.175; | 4.B.236.240; | 4.B.236.244; |
4.B.237.228; | 4.B.237.229; | 4.B.237.230; | 4.B.237.231; |
4.B.237.236; | 4.B.237.237; | 4.B.237.238; | 4.B.237.239; |
4.B.237.154; | 4.B.237.157; | 4.B.237.166; | 4.B.237.169; |
4.B.237.172; | 4.B.237.175; | 4.B.237.240; | 4.B.237.244; |
4.B.238.228; | 4.B.238.229; | 4.B.238.230; | 4.B.238.231; |
4.B.238.236; | 4.B.238.237; | 4.B.238.238; | 4.B.238.239; |
4.B.238.154; | 4.B.238.157; | 4.B.238.166; | 4.B.238.169; |
4.B.238.172; | 4.B.238.175; | 4.B.238.240; | 4.B.238.244; |
4.B.239.228; | 4.B.239.229; | 4.B.239.230; | 4.B.239.231; |
4.B.239.236; | 4.B.239.237; | 4.B.239.238; | 4.B.239.239; |
4.B.239.154; | 4.B.239.157; | 4.B.239.166; | 4.B.239.169; |
4.B.239.172; | 4.B.239.175; | 4.B.239.240; | 4.B.239.244; |
4.B.154.228; | 4.B.154.229; | 4.B.154.230; | 4.B.154.231; |
4.B.154.236; | 4.B.154.237; | 4.B.154.238; | 4.B.154.239; |
4.B.154.154; | 4.B.154.157; | 4.B.154.166; | 4.B.154.169; |
4.B.154.172; | 4.B.154.175; | 4.B.154.240; | 4.B.154.244; |
4.B.157.228; | 4.B.157.229; | 4.B.157.230; | 4.B.157.231; |
4.B.157.236; | 4.B.157.237; | 4.B.157.238; | 4.B.157.239; |
4.B.157.154; | 4.B.157.157; | 4.B.157.166; | 4.B.157.169; |
4.B.157.172; | 4.B.157.175; | 4.B.157.240; | 4.B.157.244; |
4.B.166.228; | 4.B.166.229; | 4.B.166.230; | 4.B.166.231; |
4.B.166.236; | 4.B.166.237; | 4.B.166.238; | 4.B.166.239; |
4.B.166.154; | 4.B.166.157; | 4.B.166.166; | 4.B.166.169; |
4.B.166.172; | 4.B.166.175; | 4.B.166.240; | 4.B.166.244; |
4.B.169.228; | 4.B.169.229; | 4.B.169.230; | 4.B.169.231; |
4.B.169.236; | 4.B.169.237; | 4.B.169.238; | 4.B.169.239; |
4.B.169.154; | 4.B.169.157; | 4.B.169.166; | 4.B.169.169; |
4.B.169.172; | 4.B.169.175; | 4.B.169.240; | 4.B.169.244; |
4.B.172.228; | 4.B.172.229; | 4.B.172.230; | 4.B.172.231; |
4.B.172.236; | 4.B.172.237; | 4.B.172.238; | 4.B.172.239; |
4.B.172.154; | 4.B.172.157; | 4.B.172.166; | 4.B.172.169; |
4.B.172.172; | 4.B.172.175; | 4.B.172.240; | 4.B.172.244; |
4.B.175.228; | 4.B.175.229; | 4.B.175.230; | 4.B.175.231; |
4.B.175.236; | 4.B.175.237; | 4.B.175.238; | 4.B.175.239; |
4.B.175.154; | 4.B.175.157; | 4.B.175.166; | 4.B.175.169; |
4.B.175.172; | 4.B.175.175; | 4.B.175.240; | 4.B.175.244; |
4.B.240.228; | 4.B.240.229; | 4.B.240.230; | 4.B.240.231; |
4.B.240.236; | 4.B.240.237; | 4.B.240.238; | 4.B.240.239; |
4.B.240.154; | 4.B.240.157; | 4.B.240.166; | 4.B.240.169; |
4.B.240.172; | 4.B.240.175; | 4.B.240.240; | 4.B.240.244; |
4.B.244.228; | 4.B.244.229; | 4.B.244.230; | 4.B.244.231; |
4.B.244.236; | 4.B.244.237; | 4.B.244.238; | 4.B.244.239; |
4.B.244.154; | 4.B.244.157; | 4.B.244.166; | 4.B.244.169; |
4.B.244.172; | 4.B.244.175; | 4.B.244.240; | 4.B.244.244; |
4.D的前体药物
4.D.228.228; | 4.D.228.229; | 4.D.228.230; | 4.D.228.231; |
4.D.228.236; | 4.D.228.237; | 4.D.228.238; | 4.D.228.239; |
4.D.228.154; | 4.D.228.157; | 4.D.228.166; | 4.D.228.169; |
4.D.228.172; | 4.D.228.175; | 4.D.228.240; | 4.D.228.244; |
4.D.229.228; | 4.D.229.229; | 4.D.229.230; | 4.D.229.231; |
4.D.229.236; | 4.D.229.237; | 4.D.229.238; | 4.D.229.239; |
4.D.229.154; | 4.D.229.157; | 4.D.229.166; | 4.D.229.169; |
4.D.229.172; | 4.D.229.175; | 4.D.229.240; | 4.D.229.244; |
4.D.230.228; | 4.D.230.229; | 4.D.230.230; | 4.D.230.231; |
4.D.230.236; | 4.D.230.237; | 4.D.230.238; | 4.D.230.239; |
4.D.230.154; | 4.D.230.157; | 4.D.230.166; | 4.D.230.169; |
4.D.230.172; | 4.D.230.175; | 4.D.230.240; | 4.D.230.244; |
4.D.231.228; | 4.D.231.229; | 4.D.231.230; | 4.D.231.231; |
4.D.231.236; | 4.D.231.237; | 4.D.231.238; | 4.D.231.239; |
4.D.231.154; | 4.D.231.157; | 4.D.231.166; | 4.D.231.169; |
4.D.231.172; | 4.D.231.175; | 4.D.231.240; | 4.D.231.244; |
4.D.236.228; | 4.D.236.229; | 4.D.236.230; | 4.D.236.231; |
4.D.236.236; | 4.D.236.237; | 4.D.236.238; | 4.D.236.239; |
4.D.236.154; | 4.D.236.157; | 4.D.236.166; | 4.D.236.169; |
4.D.236.172; | 4.D.236.175; | 4.D.236.240; | 4.D.236.244; |
4.D.237.228; | 4.D.237.229; | 4.D.237.230; | 4.D.237.231; |
4.D.237.236; | 4.D.237.237; | 4.D.237.238; | 4.D.237.239; |
4.D.237.154; | 4.D.237.157; | 4.D.237.166; | 4.D.237.169; |
4.D.237.172; | 4.D.237.175; | 4.D.237.240; | 4.D.237.244; |
4.D.238.228; | 4.D.238.229; | 4.D.238.230; | 4.D.238.231; |
4.D.238.236; | 4.D.238.237; | 4.D.238.238; | 4.D.238.239; |
4.D.238.154; | 4.D.238.157; | 4.D.238.166; | 4.D.238.169; |
4.D.238.172; | 4.D.238.175; | 4.D.238.240; | 4.D.238.244; |
4.D.239.228; | 4.D.239.229; | 4.D.239.230; | 4.D.239.231; |
4.D.239.236; | 4.D.239.237; | 4.D.239.238; | 4.D.239.239; |
4.D.239.154; | 4.D.239.157; | 4.D.239.166; | 4.D.239.169; |
4.D.239.172; | 4.D.239.175; | 4.D.239.240; | 4.D.239.244; |
4.D.154.228; | 4.D.154.229; | 4.D.154.230; | 4.D.154.231; |
4.D.154.236; | 4.D.154.237; | 4.D.154.238; | 4.D.154.239; |
4.D.154.154; | 4.D.154.157; | 4.D.154.166; | 4.D.154.169; |
4.D.154.172; | 4.D.154.175; | 4.D.154.240; | 4.D.154.244; |
4.D.157.228; | 4.D.157.229; | 4.D.157.230; | 4.D.157.231; |
4.D.157.236; | 4.D.157.237; | 4.D.157.238; | 4.D.157.239; |
4.D.157.154; | 4.D.157.157; | 4.D.157.166; | 4.D.157.169; |
4.D.157.172; | 4.D.157.175; | 4.D.157.240; | 4.D.157.244; |
4.D.166.228; | 4.D.166.229; | 4.D.166.230; | 4.D.166.231; |
4.D.166.236; | 4.D.166.237; | 4.D.166.238; | 4.D.166.239; |
4.D.166.154; | 4.D.166.157; | 4.D.166.166; | 4.D.166.169; |
4.D.166.172; | 4.D.166.175; | 4.D.166.240; | 4.D.166.244; |
4.D.169.228; | 4.D.169.229; | 4.D.169.230; | 4.D.169.231; |
4.D.169.236; | 4.D.169.237; | 4.D.169.238; | 4.D.169.239; |
4.D.169.154; | 4.D.169.157; | 4.D.169.166; | 4.D.169.169; |
4.D.169.172; | 4.D.169.175; | 4.D.169.240; | 4.D.169.244; |
4.D.172.228; | 4.D.172.229; | 4.D.172.230; | 4.D.172.231; |
4.D.172.236; | 4.D.172.237; | 4.D.172.238; | 4.D.172.239; |
4.D.172.154; | 4.D.172.157; | 4.D.172.166; | 4.D.172.169; |
4.D.172.172; | 4.D.172.175; | 4.D.172.240; | 4.D.172.244; |
4.D.175.228; | 4.D.175.229; | 4.D.175.230; | 4.D.175.231; |
4.D.175.236; | 4.D.175.237; | 4.D.175.238; | 4.D.175.239; |
4.D.175.154; | 4.D.175.157; | 4.D.175.166; | 4.D.175.169; |
4.D.175.172; | 4.D.175.175; | 4.D.175.240; | 4.D.175.244; |
4.D.240.228; | 4.D.240.229; | 4.D.240.230; | 4.D.240.231; |
4.D.240.236; | 4.D.240.237; | 4.D.240.238; | 4.D.240.239; |
4.D.240.154; | 4.D.240.157; | 4.D.240.166; | 4.D.240.169; |
4.D.240.172; | 4.D.240.175; | 4.D.240.240; | 4.D.240.244; |
4.D.244.228; | 4.D.244.229; | 4.D.244.230; | 4.D.244.231; |
4.D.244.236; | 4.D.244.237; | 4.D.244.238; | 4.D.244.239; |
4.D.244.154; | 4.D.244.157; | 4.D.244.166; | 4.D.244.169; |
4.D.244.172; | 4.D.244.175; | 4.D.244.240; | 4.D.244.244; |
4.E的前体药物
4.E.228.228; | 4.E.228.229; | 4.E.228.230; | 4.E.228.231; |
4.E.228.236; | 4.E.228.237; | 4.E.228.238; | 4.E.228.239; |
4.E.228.154; | 4.E.228.157; | 4.E.228.166; | 4.E.228.169; |
4.E.228.172; | 4.E.228.175; | 4.E.228.240; | 4.E.228.244; |
4.E.229.228; | 4.E.229.229; | 4.E.229.230; | 4.E.229.231; |
4.E.229.236; | 4.E.229.237; | 4.E.229.238; | 4.E.229.239; |
4.E.229.154; | 4.E.229.157; | 4.E.229.166; | 4.E.229.169; |
4.E.229.172; | 4.E.229.175; | 4.E.229.240; | 4.E.229.244; |
4.E.230.228; | 4.E.230.229; | 4.E.230.230; | 4.E.230.231; |
4.E.230.236; | 4.E.230.237; | 4.E.230.238; | 4.E.230.239; |
4.E.230.154; | 4.E.230.157; | 4.E.230.166; | 4.E.230.169; |
4.E.230.172; | 4.E.230.175; | 4.E.230.240; | 4.E.230.244; |
4.E.231.228; | 4.E.231.229; | 4.E.231.230; | 4.E.231.231; |
4.E.231.236; | 4.E.231.237; | 4.E.231.238; | 4.E.231.239; |
4.E.231.154; | 4.E.231.157; | 4.E.231.166; | 4.E.231.169; |
4.E.231.172; | 4.E.231.175; | 4.E.231.240; | 4.E.231.244; |
4.E.236.228; | 4.E.236.229; | 4.E.236.230; | 4.E.236.231; |
4.E.236.236; | 4.E.236.237; | 4.E.236.238; | 4.E.236.239; |
4.E.236.154; | 4.E.236.157; | 4.E.236.166; | 4.E.236.169; |
4.E.236.172; | 4.E.236.175; | 4.E.236.240; | 4.E.236.244; |
4.E.237.228; | 4.E.237.229; | 4.E.237.230; | 4.E.237.231; |
4.E.237.236; | 4.E.237.237; | 4.E.237.238; | 4.E.237.239; |
4.E.237.154; | 4.E.237.157; | 4.E.237.166; | 4.E.237.169; |
4.E.237.172; | 4.E.237.175; | 4.E.237.240; | 4.E.237.244; |
4.E.238.228; | 4.E.238.229; | 4.E.238.230; | 4.E.238.231; |
4.E.238.236; | 4.E.238.237; | 4.E.238.238; | 4.E.238.239; |
4.E.238.154; | 4.E.238.157; | 4.E.238.166; | 4.E.238.169; |
4.E.238.172; | 4.E.238.175; | 4.E.238.240; | 4.E.238.244; |
4.E.239.228; | 4.E.239.229; | 4.E.239.230; | 4.E.239.231; |
4.E.239.236; | 4.E.239.237; | 4.E.239.238; | 4.E.239.239; |
4.E.239.154; | 4.E.239.157; | 4.E.239.166; | 4.E.239.169; |
4.E.239.172; | 4.E.239.175; | 4.E.239.240; | 4.E.239.244; |
4.E.154.228; | 4.E.154.229; | 4.E.154.230; | 4.E.154.231; |
4.E.154.236; | 4.E.154.237; | 4.E.154.238; | 4.E.154.239; |
4.E.154.154; | 4.E.154.157; | 4.E.154.166; | 4.E.154.169; |
4.E.154.172; | 4.E.154.175; | 4.E.154.240; | 4.E.154.244; |
4.E.157.228; | 4.E.157.229; | 4.E.157.230; | 4.E.157.231; |
4.E.157.236; | 4.E.157.237; | 4.E.157.238; | 4.E.157.239; |
4.E.157.154; | 4.E.157.157; | 4.E.157.166; | 4.E.157.169; |
4.E.157.172; | 4.E.157.175; | 4.E.157.240; | 4.E.157.244; |
4.E.166.228; | 4.E.166.229; | 4.E.166.230; | 4.E.166.231; |
4.E.166.236; | 4.E.166.237; | 4.E.166.238; | 4.E.166.239; |
4.E.166.154; | 4.E.166.157; | 4.E.166.166; | 4.E.166.169; |
4.E.166.172; | 4.E.166.175; | 4.E.166.240; | 4.E.166.244; |
4.E.169.228; | 4.E.169.229; | 4.E.169.230; | 4.E.169.231; |
4.E.169.236; | 4.E.169.237; | 4.E.169.238; | 4.E.169.239; |
4.E.169.154; | 4.E.169.157; | 4.E.169.166; | 4.E.169.169; |
4.E.169.172; | 4.E.169.175; | 4.E.169.240; | 4.E.169.244; |
4.E.172.228; | 4.E.172.229; | 4.E.172.230; | 4.E.172.231; |
4.E.172.236; | 4.E.172.237; | 4.E.172.238; | 4.E.172.239; |
4.E.172.154; | 4.E.172.157; | 4.E.172.166; | 4.E.172.169; |
4.E.172.172; | 4.E.172.175; | 4.E.172.240; | 4.E.172.244; |
4.E.175.228; | 4.E.175.229; | 4.E.175.230; | 4.E.175.231; |
4.E.175.236; | 4.E.175.237; | 4.E.175.238; | 4.E.175.239; |
4.E.175.154; | 4.E.175.157; | 4.E.175.166; | 4.E.175.169; |
4.E.175.172; | 4.E.175.175; | 4.E.175.240; | 4.E.175.244; |
4.E.240.228; | 4.E.240.229; | 4.E.240.230; | 4.E.240.231; |
4.E.240.236; | 4.E.240.237; | 4.E.240.238; | 4.E.240.239; |
4.E.240.154; | 4.E.240.157; | 4.E.240.166; | 4.E.240.169; |
4.E.240.172; | 4.E.240.175; | 4.E.240.240; | 4.E.240.244; |
4.E.244.228; | 4.E.244.229; | 4.E.244.230; | 4.E.244.231; |
4.E.244.236; | 4.E.244.237; | 4.E.244.238; | 4.E.244.239; |
4.E.244.154; | 4.E.244.157; | 4.E.244.166; | 4.E.244.169; |
4.E.244.172; | 4.E.244.175; | 4.E.244.240; | 4.E.244.244; |
4.G的前体药物
4.G.228.228; | 4.G.228.229; | 4.G.228.230; | 4.G.228.231; |
4.G.228.236; | 4.G.228.237; | 4.G.228.238; | 4.G.228.239; |
4.G.228.154; | 4.G.228.157; | 4.G.228.166; | 4.G.228.169; |
4.G.228.172; | 4.G.228.175; | 4.G.228.240; | 4.G.228.244; |
4.G.229.228; | 4.G.229.229; | 4.G.229.230; | 4.G.229.231; |
4.G.229.236; | 4.G.229.237; | 4.G.229.238; | 4.G.229.239; |
4.G.229.154; | 4.G.229.157; | 4.G.229.166; | 4.G.229.169; |
4.G.229.172; | 4.G.229.175; | 4.G.229.240; | 4.G.229.244; |
4.G.230.228; | 4.G.230.229; | 4.G.230.230; | 4.G.230.231; |
4.G.230.236; | 4.G.230.237; | 4.G.230.238; | 4.G.230.239; |
4.G.230.154; | 4.G.230.157; | 4.G.230.166; | 4.G.230.169; |
4.G.230.172; | 4.G.230.175; | 4.G.230.240; | 4.G.230.244; |
4.G.231.228; | 4.G.231.229; | 4.G.231.230; | 4.G.231.231; |
4.G.231.236; | 4.G.231.237; | 4.G.231.238; | 4.G.231.239; |
4.G.231.154; | 4.G.231.157; | 4.G.231.166; | 4.G.231.169; |
4.G.231.172; | 4.G.231.175; | 4.G.231.240; | 4.G.231.244; |
4.G.236.228; | 4.G.236.229; | 4.G.236.230; | 4.G.236.231; |
4.G.236.236; | 4.G.236.237; | 4.G.236.238; | 4.G.236.239; |
4.G.236.154; | 4.G.236.157; | 4.G.236.166; | 4.G.236.169; |
4.G.236.172; | 4.G.236.175; | 4.G.236.240; | 4.G.236.244; |
4.G.237.228; | 4.G.237.229; | 4.G.237.230; | 4.G.237.231; |
4.G.237.236; | 4.G.237.237; | 4.G.237.238; | 4.G.237.239; |
4.G.237.154; | 4.G.237.157; | 4.G.237.166; | 4.G.237.169; |
4.G.237.172; | 4.G.237.175; | 4.G.237.240; | 4.G.237.244; |
4.G.238.228; | 4.G.238.229; | 4.G.238.230; | 4.G.238.231; |
4.G.238.236; | 4.G.238.237; | 4.G.238.238; | 4.G.238.239; |
4.G.238.154; | 4.G.238.157; | 4.G.238.166; | 4.G.238.169; |
4.G.238.172; | 4.G.238.175; | 4.G.238.240; | 4.G.238.244; |
4.G.239.228; | 4.G.239.229; | 4.G.239.230; | 4.G.239.231; |
4.G.239.236; | 4.G.239.237; | 4.G.239.238; | 4.G.239.239; |
4.G.239.154; | 4.G.239.157; | 4.G.239.166; | 4.G.239.169; |
4.G.239.172; | 4.G.239.175; | 4.G.239.240; | 4.G.239.244; |
4.G.154.228; | 4.G.154.229; | 4.G.154.230; | 4.G.154.231; |
4.G.154.236; | 4.G.154.237; | 4.G.154.238; | 4.G.154.239; |
4.G.154.154; | 4.G.154.157; | 4.G.154.166; | 4.G.154.169; |
4.G.154.172; | 4.G.154.175; | 4.G.154.240; | 4.G.154.244; |
4.G.157.228; | 4.G.157.229; | 4.G.157.230; | 4.G.157.231; |
4.G.157.236; | 4.G.157.237; | 4.G.157.238; | 4.G.157.239; |
4.G.157.154; | 4.G.157.157; | 4.G.157.166; | 4.G.157.169; |
4.G.157.172; | 4.G.157.175; | 4.G.157.240; | 4.G.157.244; |
4.G.166.228; | 4.G.166.229; | 4.G.166.230; | 4.G.166.231; |
4.G.166.236; | 4.G.166.237; | 4.G.166.238; | 4.G.166.239; |
4.G.166.154; | 4.G.166.157; | 4.G.166.166; | 4.G.166.169; |
4.G.166.172; | 4.G.166.175; | 4.G.166.240; | 4.G.166.244; |
4.G.169.228; | 4.G.169.229; | 4.G.169.230; | 4.G.169.231; |
4.G.169.236; | 4.G.169.237; | 4.G.169.238; | 4.G.169.239; |
4.G.169.154; | 4.G.169.157; | 4.G.169.166; | 4.G.169.169; |
4.G.169.172; | 4.G.169.175; | 4.G.169.240; | 4.G.169.244; |
4.G.172.228; | 4.G.172.229; | 4.G.172.230; | 4.G.172.231; |
4.G.172.236; | 4.G.172.237; | 4.G.172.238; | 4.G.172.239; |
4.G.172.154; | 4.G.172.157; | 4.G.172.166; | 4.G.172.169; |
4.G.172.172; | 4.G.172.175; | 4.G.172.240; | 4.G.172.244; |
4.G.175.228; | 4.G.175.229; | 4.G.175.230; | 4.G.175.231; |
4.G.175.236; | 4.G.175.237; | 4.G.175.238; | 4.G.175.239; |
4.G.175.154; | 4.G.175.157; | 4.G.175.166; | 4.G.175.169; |
4.G.175.172; | 4.G.175.175; | 4.G.175.240; | 4.G.175.244; |
4.G.240.228; | 4.G.240.229; | 4.G.240.230; | 4.G.240.231; |
4.G.240.236; | 4.G.240.237; | 4.G.240.238; | 4.G.240.239; |
4.G.240.154; | 4.G.240.157; | 4.G.240.166; | 4.G.240.169; |
4.G.240.172; | 4.G.240.175; | 4.G.240.240; | 4.G.240.244; |
4.G.244.228; | 4.G.244.229; | 4.G.244.230; | 4.G.244.231; |
4.G.244.236; | 4.G.244.237; | 4.G.244.238; | 4.G.244.239; |
4.G.244.154; | 4.G.244.157; | 4.G.244.166; | 4.G.244.169; |
4.G.244.172; | 4.G.244.175; | 4.G.244.240; | 4.G.244.244; |
4.I的前体药物
4.I.228.228; | 4.I.228.229; | 4.I.228.230; | 4.I.228.231; |
4.I.228.236; | 4.I.228.237; | 4.I.228.238; | 4.I.228.239; |
4.I.228.154; | 4.I.228.157; | 4.I.228.166; | 4.I.228.169; |
4.I.228.172; | 4.I.228.175; | 4.I.228.240; | 4.I.228.244; |
4.I.229.228; | 4.I.229.229; | 4.I.229.230; | 4.I.229.231; |
4.I.229.236; | 4.I.229.237; | 4.I.229.238; | 4.I.229.239; |
4.I.229.154; | 4.I.229.157; | 4.I.229.166; | 4.I.229.169; |
4.I.229.172; | 4.I.229.175; | 4.I.229.240; | 4.I.229.244; |
4.I.230.228; | 4.I.230.229; | 4.I.230.230; | 4.I.230.231; |
4.I.230.236; | 4.I.230.237; | 4.I.230.238; | 4.I.230.239; |
4.I.230.154; | 4.I.230.157; | 4.I.230.166; | 4.I.230.169; |
4.I.230.172; | 4.I.230.175; | 4.I.230.240; | 4.I.230.244; |
4.I.231.228; | 4.I.231.229; | 4.I.231.230; | 4.I.231.231; |
4.I.231.236; | 4.I.231.237; | 4.I.231.238; | 4.I.231.239; |
4.I.231.154; | 4.I.231.157; | 4.I.231.166; | 4.I.231.169; |
4.I.231.172; | 4.I.231.175; | 4.I.231.240; | 4.I.231.244; |
4.I.236.228; | 4.I.236.229; | 4.I.236.230; | 4.I.236.231; |
4.I.236.236; | 4.I.236.237; | 4.I.236.238; | 4.I.236.239; |
4.I.236.154; | 4.I.236.157; | 4.I.236.166; | 4.I.236.169; |
4.I.236.172; | 4.I.236.175; | 4.I.236.240; | 4.I.236.244; |
4.I.237.228; | 4.I.237.229; | 4.I.237.230; | 4.I.237.231; |
4.I.237.236; | 4.I.237.237; | 4.I.237.238; | 4.I.237.239; |
4.I.237.154; | 4.I.237.157; | 4.I.237.166; | 4.I.237.169; |
4.I.237.172; | 4.I.237.175; | 4.I.237.240; | 4.I.237.244; |
4.I.238.228; | 4.I.238.229; | 4.I.238.230; | 4.I.238.231; |
4.I.238.236; | 4.I.238.237; | 4.I.238.238; | 4.I.238.239; |
4.I.238.154; | 4.I.238.157; | 4.I.238.166; | 4.I.238.169; |
4.I.238.172; | 4.I.238.175; | 4.I.238.240; | 4.I.238.244; |
4.I.239.228; | 4.I.239.229; | 4.I.239.230; | 4.I.239.231; |
4.I.239.236; | 4.I.239.237; | 4.I.239.238; | 4.I.239.239; |
4.I.239.154; | 4.I.239.157; | 4.I.239.166; | 4.I.239.169; |
4.I.239.172; | 4.I.239.175; | 4.I.239.240; | 4.I.239.244; |
4.I.154.228; | 4.I.154.229; | 4.I.154.230; | 4.I.154.231; |
4.I.154.236; | 4.I.154.237; | 4.I.154.238; | 4.I.154.239; |
4.I.154.154; | 4.I.154.157; | 4.I.154.166; | 4.I.154.169; |
4.I.154.172; | 4.I.154.175; | 4.I.154.240; | 4.I.154.244; |
4.I.157.228; | 4.I.157.229; | 4.I.157.230; | 4.I.157.231; |
4.I.157.236; | 4.I.157.237; | 4.I.157.238; | 4.I.157.239; |
4.I.157.154; | 4.I.157.157; | 4.I.157.166; | 4.I.157.169; |
4.I.157.172; | 4.I.157.175; | 4.I.157.240; | 4.I.157.244; |
4.I.166.228; | 4.I.166.229; | 4.I.166.230; | 4.I.166.231; |
4.I.166.236; | 4.I.166.237; | 4.I.166.238; | 4.I.166.239; |
4.I.166.154; | 4.I.166.157; | 4.I.166.166; | 4.I.166.169; |
4.I.166.172; | 4.I.166.175; | 4.I.166.240; | 4.I.166.244; |
4.I.169.228; | 4.I.169.229; | 4.I.169.230; | 4.I.169.231; |
4.I.169.236; | 4.I.169.237; | 4.I.169.238; | 4.I.169.239; |
4.I.169.154; | 4.I.169.157; | 4.I.169.166; | 4.I.169.169; |
4.I.169.172; | 4.I.169.175; | 4.I.169.240; | 4.I.169.244; |
4.I.172.228; | 4.I.172.229; | 4.I.172.230; | 4.I.172.231; |
4.I.172.236; | 4.I.172.237; | 4.I.172.238; | 4.I.172.239; |
4.I.172.154; | 4.I.172.157; | 4.I.172.166; | 4.I.172.169; |
4.I.172.172; | 4.I.172.175; | 4.I.172.240; | 4.I.172.244; |
4.I.175.228; | 4.I.175.229; | 4.I.175.230; | 4.I.175.231; |
4.I.175.236; | 4.I.175.237; | 4.I.175.238; | 4.I.175.239; |
4.I.175.154; | 4.I.175.157; | 4.I.175.166; | 4.I.175.169; |
4.I.175.172; | 4.I.175.175; | 4.I.175.240; | 4.I.175.244; |
4.I.240.228; | 4.I.240.229; | 4.I.240.230; | 4.I.240.231; |
4.I.240.236; | 4.I.240.237; | 4.I.240.238; | 4.I.240.239; |
4.I.240.154; | 4.I.240.157; | 4.I.240.166; | 4.I.240.169; |
4.I.240.172; | 4.I.240.175; | 4.I.240.240; | 4.I.240.244; |
4.I.244.228; | 4.I.244.229; | 4.I.244.230; | 4.I.244.231; |
4.I.244.236; | 4.I.244.237; | 4.I.244.238; | 4.I.244.239; |
4.I.244.154; | 4.I.244.157; | 4.I.244.166; | 4.I.244.169; |
4.I.244.172; | 4.I.244.175; | 4.I.244.240; | 4.I.244.244; |
4.J的前体药物
4.J.228.228; | 4.J.228.229; | 4.J.228.230; | 4.J.228.231; |
4.J.228.236; | 4.J.228.237; | 4.J.228.238; | 4.J.228.239; |
4.J.228.154; | 4.J.228.157; | 4.J.228.166; | 4.J.228.169; |
4.J.228.172; | 4.J.228.175; | 4.J.228.240; | 4.J.228.244; |
4.J.229.228; | 4.J.229.229; | 4.J.229.230; | 4.J.229.231; |
4.J.229.236; | 4.J.229.237; | 4.J.229.238; | 4.J.229.239; |
4.J.229.154; | 4.J.229.157; | 4.J.229.166; | 4.J.229.169; |
4.J.229.172; | 4.J.229.175; | 4.J.229.240; | 4.J.229.244; |
4.J.230.228; | 4.J.230.229; | 4.J.230.230; | 4.J.230.231; |
4.J.230.236; | 4.J.230.237; | 4.J.230.238; | 4.J.230.239; |
4.J.230.154; | 4.J.230.157; | 4.J.230.166; | 4.J.230.169; |
4.J.230.172; | 4.J.230.175; | 4.J.230.240; | 4.J.230.244; |
4.J.231.228; | 4.J.231.229; | 4.J.231.230; | 4.J.231.231; |
4.J.231.236; | 4.J.231.237; | 4.J.231.238; | 4.J.231.239; |
4.J.231.154; | 4.J.231.157; | 4.J.231.166; | 4.J.231.169; |
4.J.231.172; | 4.J.231.175; | 4.J.231.240; | 4.J.231.244; |
4.J.236.228; | 4.J.236.229; | 4.J.236.230; | 4.J.236.231; |
4.J.236.236; | 4.J.236.237; | 4.J.236.238; | 4.J.236.239; |
4.J.236.154; | 4.J.236.157; | 4.J.236.166; | 4.J.236.169; |
4.J.236.172; | 4.J.236.175; | 4.J.236.240; | 4.J.236.244; |
4.J.237.228; | 4.J.237.229; | 4.J.237.230; | 4.J.237.231; |
4.J.237.236; | 4.J.237.237; | 4.J.237.238; | 4.J.237.239; |
4.J.237.154; | 4.J.237.157; | 4.J.237.166; | 4.J.237.169; |
4.J.237.172; | 4.J.237.175; | 4.J.237.240; | 4.J.237.244; |
4.J.238.228; | 4.J.238.229; | 4.J.238.230; | 4.J.238.231; |
4.J.238.236; | 4.J.238.237; | 4.J.238.238; | 4.J.238.239; |
4.J.238.154; | 4.J.238.157; | 4.J.238.166; | 4.J.238.169; |
4.J.238.172; | 4.J.238.175; | 4.J.238.240; | 4.J.238.244; |
4.J.239.228; | 4.J.239.229; | 4.J.239.230; | 4.J.239.231; |
4.J.239.236; | 4.J.239.237; | 4.J.239.238; | 4.J.239.239; |
4.J.239.154; | 4.J.239.157; | 4.J.239.166; | 4.J.239.169; |
4.J.239.172; | 4.J.239.175; | 4.J.239.240; | 4.J.239.244; |
4.J.154.228; | 4.J.154.229; | 4.J.154.230; | 4.J.154.231; |
4.J.154.236; | 4.J.154.237; | 4.J.154.238; | 4.J.154.239; |
4.J.154.154; | 4.J.154.157; | 4.J.154.166; | 4.J.154.169; |
4.J.154.172; | 4.J.154.175; | 4.J.154.240; | 4.J.154.244; |
4.J.157.228; | 4.J.157.229; | 4.J.157.230; | 4.J.157.231; |
4.J.157.236; | 4.J.157.237; | 4.J.157.238; | 4.J.157.239; |
4.J.157.154; | 4.J.157.157; | 4.J.157.166; | 4.J.157.169; |
4.J.157.172; | 4.J.157.175; | 4.J.157.240; | 4.J.157.244; |
4.J.166.228; | 4.J.166.229; | 4.J.166.230; | 4.J.166.231; |
4.J.166.236; | 4.J.166.237; | 4.J.166.238; | 4.J.166.239; |
4.J.166.154; | 4.J.166.157; | 4.J.166.166; | 4.J.166.169; |
4.J.166.172; | 4.J.166.175; | 4.J.166.240; | 4.J.166.244; |
4.J.169.228; | 4.J.169.229; | 4.J.169.230; | 4.J.169.231; |
4.J.169.236; | 4.J.169.237; | 4.J.169.238; | 4.J.169.239; |
4.J.169.154; | 4.J.169.157; | 4.J.169.166; | 4.J.169.169; |
4.J.169.172; | 4.J.169.175; | 4.J.169.240; | 4.J.169.244; |
4.J.172.228; | 4.J.172.229; | 4.J.172.230; | 4.J.172.231; |
4.J.172.236; | 4.J.172.237; | 4.J.172.238; | 4.J.172.239; |
4.J.172.154; | 4.J.172.157; | 4.J.172.166; | 4.J.172.169; |
4.J.172.172; | 4.J.172.175; | 4.J.172.240; | 4.J.172.244; |
4.J.175.228; | 4.J.175.229; | 4.J.175.230; | 4.J.175.231; |
4.J.175.236; | 4.J.175.237; | 4.J.175.238; | 4.J.175.239; |
4.J.175.154; | 4.J.175.157; | 4.J.175.166; | 4.J.175.169; |
4.J.175.172; | 4.J.175.175; | 4.J.175.240; | 4.J.175.244; |
4.J.240.228; | 4.J.240.229; | 4.J.240.230; | 4.J.240.231; |
4.J.240.236; | 4.J.240.237; | 4.J.240.238; | 4.J.240.239; |
4.J.240.154; | 4.J.240.157; | 4.J.240.166; | 4.J.240.169; |
4.J.240.172; | 4.J.240.175; | 4.J.240.240; | 4.J.240.244; |
4.J.244.228; | 4.J.244.229; | 4.J.244.230; | 4.J.244.231; |
4.J.244.236; | 4.J.244.237; | 4.J.244.238; | 4.J.244.239; |
4.J.244.154; | 4.J.244.157; | 4.J.244.166; | 4.J.244.169; |
4.J.244.172; | 4.J.244.175; | 4.J.244.240; | 4.J.244.244; |
4.L的前体药物
4.L.228.228; | 4.L.228.229; | 4.L.228.230; | 4.L.228.231; |
4.L.228.236; | 4.L.228.237; | 4.L.228.238; | 4.L.228.239; |
4.L.228.154; | 4.L.228.157; | 4.L.228.166; | 4.L.228.169; |
4.L.228.172; | 4.L.228.175; | 4.L.228.240; | 4.L.228.244; |
4.L.229.228; | 4.L.229.229; | 4.L.229.230; | 4.L.229.231; |
4.L.229.236; | 4.L.229.237; | 4.L.229.238; | 4.L.229.239; |
4.L.229.154; | 4.L.229.157; | 4.L.229.166; | 4.L.229.169; |
4.L.229.172; | 4.L.229.175; | 4.L.229.240; | 4.L.229.244; |
4.L.230.228; | 4.L.230.229; | 4.L.230.230; | 4.L.230.231; |
4.L.230.236; | 4.L.230.237; | 4.L.230.238; | 4.L.230.239; |
4.L.230.154; | 4.L.230.157; | 4.L.230.166; | 4.L.230.169; |
4.L.230.172; | 4.L.230.175; | 4.L.230.240; | 4.L.230.244; |
4.L.231.228; | 4.L.231.229; | 4.L.231.230; | 4.L.231.231; |
4.L.231.236; | 4.L.231.237; | 4.L.231.238; | 4.L.231.239; |
4.L.231.154; | 4.L.231.157; | 4.L.231.166; | 4.L.231.169; |
4.L.231.172; | 4.L.231.175; | 4.L.231.240; | 4.L.231.244; |
4.L.236.228; | 4.L.236.229; | 4.L.236.230; | 4.L.236.231; |
4.L.236.236; | 4.L.236.237; | 4.L.236.238; | 4.L.236.239; |
4.L.236.154; | 4.L.236.157; | 4.L.236.166; | 4.L.236.169; |
4.L.236.172; | 4.L.236.175; | 4.L.236.240; | 4.L.236.244; |
4.L.237.228; | 4.L.237.229; | 4.L.237.230; | 4.L.237.231; |
4.L.237.236; | 4.L.237.237; | 4.L.237.238; | 4.L.237.239; |
4.L.237.154; | 4.L.237.157; | 4.L.237.166; | 4.L.237.169; |
4.L.237.172; | 4.L.237.175; | 4.L.237.240; | 4.L.237.244; |
4.L.238.228; | 4.L.238.229; | 4.L.238.230; | 4.L.238.231; |
4.L.238.236; | 4.L.238.237; | 4.L.238.238; | 4.L.238.239; |
4.L.238.154; | 4.L.238.157; | 4.L.238.166; | 4.L.238.169; |
4.L.238.172; | 4.L.238.175; | 4.L.238.240; | 4.L.238.244; |
4.L.239.228; | 4.L.239.229; | 4.L.239.230; | 4.L.239.231; |
4.L.239.236; | 4.L.239.237; | 4.L.239.238; | 4.L.239.239; |
4.L.239.154; | 4.L.239.157; | 4.L.239.166; | 4.L.239.169; |
4.L.239.172; | 4.L.239.175; | 4.L.239.240; | 4.L.239.244; |
4.L.154.228; | 4.L.154.229; | 4.L.154.230; | 4.L.154.231; |
4.L.154.236; | 4.L.154.237; | 4.L.154.238; | 4.L.154.239; |
4.L.154.154; | 4.L.154.157; | 4.L.154.166; | 4.L.154.169; |
4.L.154.172; | 4.L.154.175; | 4.L.154.240; | 4.L.154.244; |
4.L.157.228; | 4.L.157.229; | 4.L.157.230; | 4.L.157.231; |
4.L.157.236; | 4.L.157.237; | 4.L.157.238; | 4.L.157.239; |
4.L.157.154; | 4.L.157.157; | 4.L.157.166; | 4.L.157.169; |
4.L.157.172; | 4.L.157.175; | 4.L.157.240; | 4.L.157.244; |
4.L.166.228; | 4.L.166.229; | 4.L.166.230; | 4.L.166.231; |
4.L.166.236; | 4.L.166.237; | 4.L.166.238; | 4.L.166.239; |
4.L.166.154; | 4.L.166.157; | 4.L.166.166; | 4.L.166.169; |
4.L.166.172; | 4.L.166.175; | 4.L.166.240; | 4.L.166.244; |
4.L.169.228; | 4.L.169.229; | 4.L.169.230; | 4.L.169.231; |
4.L.169.236; | 4.L.169.237; | 4.L.169.238; | 4.L.169.239; |
4.L.169.154; | 4.L.169.157; | 4.L.169.166; | 4.L.169.169; |
4.L.169.172; | 4.L.169.175; | 4.L.169.240; | 4.L.169.244; |
4.L.172.228; | 4.L.172.229; | 4.L.172.230; | 4.L.172.231; |
4.L.172.236; | 4.L.172.237; | 4.L.172.238; | 4.L.172.239; |
4.L.172.154; | 4.L.172.157; | 4.L.172.166; | 4.L.172.169; |
4.L.172.172; | 4.L.172.175; | 4.L.172.240; | 4.L.172.244; |
4.L.175.228; | 4.L.175.229; | 4.L.175.230; | 4.L 175.231; |
4.L.175.236; | 4.L.175.237; | 4.L.175.238; | 4.L.175.239; |
4.L.175.154; | 4.L.175.157; | 4.L.175.166; | 4.L.175.169; |
4.L.175.172; | 4.L.175.175; | 4.L.175.240; | 4.L.175.244; |
4.L.240.228; | 4.L.240.229; | 4.L.240.230; | 4.L.240.231; |
4.L.240.236; | 4.L.240.237; | 4.L.240.238; | 4.L.240.239; |
4.L.240.154; | 4.L.240.157; | 4.L.240.166; | 4.L.240.169; |
4.L.240.172; | 4.L.240.175; | 4.L.240.240; | 4.L.240.244; |
4.L.244.228; | 4.L.244.229; | 4.L.244.230; | 4.L.244.231; |
4.L.244.236; | 4.L.244.237; | 4.L.244.238; | 4.L.244.239; |
4.L.244.154; | 4.L.244.157; | 4.L.244.166; | 4.L.244.169; |
4.L.244.172; | 4.L.244.175; | 4.L.244.240; | 4.L.244.244; |
4.O的前体药物
4.O.228.228; | 4.O.228.229; | 4.O.228.230; | 4.O.228.231; |
4.O.228.236; | 4.O.228.237; | 4.O.228.238; | 4.O.228.239; |
4.O.228.154; | 4.O.228.157; | 4.O.228.166; | 4.O.228.169; |
4.O.228.172; | 4.O.228.175; | 4.O.228.240; | 4.O.228.244; |
4.O.229.228; | 4.O.229.229; | 4.O.229.230; | 4.O.229.231; |
4.O.229.236; | 4.O.229.237; | 4.O.229.238; | 4.O.229.239; |
4.O.229.154; | 4.O.229.157; | 4.O.229.166; | 4.O.229.169; |
4.O.229.172; | 4.O.229.175; | 4.O.229.240; | 4.O.229.244; |
4.O.230.228; | 4.O.230.229; | 4.O.230.230; | 4.O.230.231; |
4.O.230.236; | 4.O.230.237; | 4.O.230.238; | 4.O.230.239; |
4.O.230.154; | 4.O.230.157; | 4.O.230.166; | 4.O.230.169; |
4.O.230.172; | 4.O.230.175; | 4.O.230.240; | 4.O.230.244; |
4.O.231.228; | 4.O.231.229; | 4.O.231.230; | 4.O.231.231; |
4.O.231.236; | 4.O.231.237; | 4.O.231.238; | 4.O.231.239; |
4.O.231.154; | 4.O.231.157; | 4.O.231.166; | 4.O.231.169; |
4.O.231.172; | 4.O.231.175; | 4.O.231.240; | 4.O.231.244; |
4.O.236.228; | 4.O.236.229; | 4.O.236.230; | 4.O.236.231; |
4.O.236.236; | 4.O.236.237; | 4.O.236.238; | 4.O.236.239; |
4.O.236.154; | 4.O.236.157; | 4.O.236.166; | 4.O.236.169; |
4.O.236.172; | 4.O.236.175; | 4.O.236.240; | 4.O.236.244; |
4.O.237.228; | 4.O.237.229; | 4.O.237.230; | 4.O.237.231; |
4.O.237.236; | 4.O.237.237; | 4.O.237.238; | 4.O.237.239; |
4.O.237.154; | 4.O.237.157; | 4.O.237.166; | 4.O.237.169; |
4.O.237.172; | 4.O.237.175; | 4.O.237.240; | 4.O.237.244; |
4.O.238.228; | 4.O.238.229; | 4.O.238.230; | 4.O.238.231; |
4.O.238.236; | 4.O.238.237; | 4.O.238.238; | 4.O.238.239; |
4.O.238.154; | 4.O.238.157; | 4.O.238.166; | 4.O.238.169; |
4.O.238.172; | 4.O.238.175; | 4.O.238.240; | 4.O.238.244; |
4.O.239.228; | 4.O.239.229; | 4.O.239.230; | 4.O.239.231; |
4.O.239.236; | 4.O.239.237; | 4.O.239.238; | 4.O.239.239; |
4.O.239.154; | 4.O.239.157; | 4.O.239.166; | 4.O.239.169; |
4.O.239.172; | 4.O.239.175; | 4.O.239.240; | 4.O.239.244; |
4.O.154.228; | 4.O.154.229; | 4.O.154.230; | 4.O.154.231; |
4.O.154.236; | 4.O.154.237; | 4.O.154.238; | 4.O.154.239; |
4.O.154.154; | 4.O.154.157; | 4.O.154.166; | 4.O.154.169; |
4.O.154.172; | 4.O.154.175; | 4.O.154.240; | 4.O.154.244; |
4.O.157.228; | 4.O.157.229; | 4.O.157.230; | 4.O.157.231; |
4.O.157.236; | 4.O.157.237; | 4.O.157.238; | 4.O.157.239; |
4.O.157.154; | 4.O.157.157; | 4.O.157.166; | 4.O.157.169; |
4.O.157.172; | 4.O.157.175; | 4.O.157.240; | 4.O.157.244; |
4.O.166.228; | 4.O.166.229; | 4.O.166.230; | 4.O.166.231; |
4.O.166.236; | 4.O.166.237; | 4.O.166.238; | 4.O.166.239; |
4.O.166.154; | 4.O.166.157; | 4.O.166.166; | 4.O.166.169; |
4.O.166.172; | 4.O.166.175; | 4.O.166.240; | 4.O.166.244; |
4.O.169.228; | 4.O.169.229; | 4.O.169.230; | 4.O.169.231; |
4.O.169.236; | 4.O.169.237; | 4.O.169.238; | 4.O.169.239; |
4.O.169.154; | 4.O.169.157; | 4.O.169.166; | 4.O.169.169; |
4.O.169.172; | 4.O.169.175; | 4.O.169.240; | 4.O.169.244; |
4.O.172.228; | 4.O.172.229; | 4.O.172.230; | 4.O.172.231; |
4.O.172.236; | 4.O.172.237; | 4.O.172.238; | 4.O.172.239; |
4.O.172.154; | 4.O.172.157; | 4.O.172.166; | 4.O.172.169; |
4.O.172.172; | 4.O.172.175; | 4.O.172.240; | 4.O.172.244; |
4.O.175.228; | 4.O.175.229; | 4.O.175.230; | 4.O.175.231; |
4.O.175.236; | 4.O.175.237; | 4.O.175.238; | 4.O.175.239; |
4.O.175.154; | 4.O.175.157; | 4.O.175.166; | 4.O.175.169; |
4.O.175.172; | 4.O.175.175; | 4.O.175.240; | 4.O.175.244; |
4.O.240.228; | 4.O.240.229; | 4.O.240.230; | 4.O.240.231; |
4.O.240.236; | 4.O.240.237; | 4.O.240.238; | 4.O.240.239; |
4.O.240.154; | 4.O.240.157; | 4.O.240.166; | 4.O.240.169; |
4.O.240.172; | 4.O.240.175; | 4.O.240.240; | 4.O.240.244; |
4.O.244.228; | 4.O.244.229; | 4.O.244.230; | 4.O.244.231; |
4.O.244.236; | 4.O.244.237; | 4.O.244.238; | 4.O.244.239; |
4.O.244.154; | 4.O.244.157; | 4.O.244.166; | 4.O.244.169; |
4.O.244.172; | 4.O.244.175; | 4.O.244.240; | 4.O.244.244; |
4.P的前体药物
4.P.228.228; | 4.P.228.229; | 4.P.228.230; | 4.P.228.231; |
4.P.228.236; | 4.P.228.237; | 4.P.228.238; | 4.P.228.239; |
4.P.228.154; | 4.P.228.157; | 4.P.228.166; | 4.P.228.169; |
4.P.228.172; | 4.P.228.175; | 4.P.228.240; | 4.P.228.244; |
4.P.229.228; | 4.P.229.229; | 4.P.229.230; | 4.P.229.231; |
4.P.229.236; | 4.P.229.237; | 4.P.229.238; | 4.P.229.239; |
4.P.229.154; | 4.P.229.157; | 4.P.229.166; | 4.P.229.169; |
4.P.229.172; | 4.P.229.175; | 4.P.229.240; | 4.P.229.244; |
4.P.230.228; | 4.P.230.229; | 4.P.230.230; | 4.P.230.231; |
4.P.230.236; | 4.P.230.237; | 4.P.230.238; | 4.P.230.239; |
4.P.230.154; | 4.P.230.157; | 4.P.230.166; | 4.P.230.169; |
4.P.230.172; | 4.P.230.175; | 4.P.230.240; | 4.P.230.244; |
4.P.231.228; | 4.P.231.229; | 4.P.231.230; | 4.P.231.231; |
4.P.231.236; | 4.P.231.237; | 4.P.231.238; | 4.P.231.239; |
4.P.231.154; | 4.P.231.157; | 4.P.231.166; | 4.P.231.169; |
4.P.231.172; | 4.P.231.175; | 4.P.231.240; | 4.P.231.244; |
4.P.236.228; | 4.P.236.229; | 4.P.236.230; | 4.P.236.231; |
4.P.236.236; | 4.P.236.237; | 4.P.236.238; | 4.P.236.239; |
4.P.236.154; | 4.P.236.157; | 4.P.236.166; | 4.P.236.169; |
4.P.236.172; | 4.P.236.175; | 4.P.236.240; | 4.P.236.244; |
4.P.237.228; | 4.P.237.229; | 4.P.237.230; | 4.P.237.231; |
4.P.237.236; | 4.P.237.237; | 4.P.237.238; | 4.P.237.239; |
4.P.237.154; | 4.P.237.157; | 4.P.237.166; | 4.P.237.169; |
4.P.237.172; | 4.P.237.175; | 4.P.237.240; | 4.P.237.244; |
4.P.238.228; | 4.P.238.229; | 4.P.238.230; | 4.P.238.231; |
4.P.238.236; | 4.P.238.237; | 4.P.238.238; | 4.P.238.239; |
4.P.238.154; | 4.P.238.157; | 4.P.238.166; | 4.P.238.169; |
4.P.238.172; | 4.P.238.175; | 4.P.238.240; | 4.P.238.244; |
4.P.239.228; | 4.P.239.229; | 4.P.239.230; | 4.P.239.231; |
4.P.239.236; | 4.P.239.237; | 4.P.239.238; | 4.P.239.239; |
4.P.239.154; | 4.P.239.157; | 4.P.239.166; | 4.P.239.169; |
4.P.239.172; | 4.P.239.175; | 4.P.239.240; | 4.P.239.244; |
4.P.154.228; | 4.P.154.229; | 4.P.154.230; | 4.P.154.231; |
4.P.154.236; | 4.P.154.237; | 4.P.154.238; | 4.P.154.239; |
4.P.154.154; | 4.P.154.157; | 4.P.154.166; | 4.P.154.169; |
4.P.154.172; | 4.P.154.175; | 4.P.154.240; | 4.P.154.244; |
4.P.157.228; | 4.P.157.229; | 4.P.157.230; | 4.P.157.231; |
4.P.157.236; | 4.P.157.237; | 4.P.157.238; | 4.P.157.239; |
4.P.157.154; | 4.P.157.157; | 4.P.157.166; | 4.P.157.169; |
4.P.157.172; | 4.P.157.175; | 4.P.157.240; | 4.P.157.244; |
4.P.166.228; | 4.P.166.229; | 4.P.166.230; | 4.P.166.231; |
4.P.166.236; | 4.P.166.237; | 4.P.166.238; | 4.P.166.239; |
4.P.166.154; | 4.P.166.157; | 4.P.166.166; | 4.P.166.169; |
4.P.166.172; | 4.P.166.175; | 4.P.166.240; | 4.P.166.244; |
4.P.169.228; | 4.P.169.229; | 4.P.169.230; | 4.P.169.231; |
4.P.169.236; | 4.P.169.237; | 4.P.169.238; | 4.P.169.239; |
4.P.169.154; | 4.P.169.157; | 4.P.169.166; | 4.P.169.169; |
4.P.169.172; | 4.P.169.175; | 4.P.169.240; | 4.P.169.244; |
4.P.172.228; | 4.P.172.229; | 4.P.172.230; | 4.P.172.231; |
4.P.172.236; | 4.P.172.237; | 4.P.172.238; | 4.P.172.239; |
4.P.172.154; | 4.P.172.157; | 4.P.172.166; | 4.P.172.169; |
4.P.172.172; | 4.P.172.175; | 4.P.172.240; | 4.P.172.244; |
4.P.175.228; | 4.P.175.229; | 4.P.175.230; | 4.P.175.231; |
4.P.175.236; | 4.P.175.237; | 4.P.175.238; | 4.P.175.239; |
4.P.175.154; | 4.P.175.157; | 4.P.175.166; | 4.P.175.169; |
4.P.175.172; | 4.P.175.175; | 4.P.175.240; | 4.P.175.244; |
4.P.240.228; | 4.P.240.229; | 4.P.240.230; | 4.P.240.231; |
4.P.240.236; | 4.P.240.237; | 4.P.240.238; | 4.P.240.239; |
4.P.240.154; | 4.P.240.157; | 4.P.240.166; | 4.P.240.169; |
4.P.240.172; | 4.P.240.175; | 4.P.240.240; | 4.P.240.244; |
4.P.244.228; | 4.P.244.229; | 4.P.244.230; | 4.P.244.231; |
4.P.244.236; | 4.P.244.237; | 4.P.244.238; | 4.P.244.239; |
4.P.244.154; | 4.P.244.157; | 4.P.244.166; | 4.P.244.169; |
4.P.244.172; | 4.P.244.175; | 4.P.244.240; | 4.P.244.244; |
4.U的前体药物
4.U.228.228; | 4.U.228.229; | 4.U.228.230; | 4.U.228.231; |
4.U.228.236; | 4.U.228.237; | 4.U.228.238; | 4.U.228.239; |
4.U.228.154; | 4.U.228.157; | 4.U.228.166; | 4.U.228.169; |
4.U.228.172; | 4.U.228.175; | 4.U.228.240; | 4.U.228.244; |
4.U.229.228; | 4.U.229.229; | 4.U.229.230; | 4.U.229.231; |
4.U.229.236; | 4.U.229.237; | 4.U.229.238; | 4.U.229.239; |
4.U.229.154; | 4.U.229.157; | 4.U.229.166; | 4.U.229.169; |
4.U.229.172; | 4.U.229.175; | 4.U.229.240; | 4.U.229.244; |
4.U.230.228; | 4.U.230.229; | 4.U.230.230; | 4.U.230.231; |
4.U.230.236; | 4.U.230.237; | 4.U.230.238; | 4.U.230.239; |
4.U.230.154; | 4.U.230.157; | 4.U.230.166; | 4.U.230.169; |
4.U.230.172; | 4.U.230.175; | 4.U.230.240; | 4.U.230.244; |
4.U.231.228; | 4.U.231.229; | 4.U.231.230; | 4.U.231.231; |
4.U.231.236; | 4.U.231.237; | 4.U.231.238; | 4.U.231.239; |
4.U.231.154; | 4.U.231.157; | 4.U.231.166; | 4.U.231.169; |
4.U.231.172; | 4.U.231.175; | 4.U.231.240; | 4.U.231.244; |
4.U.236.228; | 4.U.236.229; | 4.U.236.230; | 4.U.236.231; |
4.U.236.236; | 4.U.236.237; | 4.U.236.238; | 4.U.236.239; |
4.U.236.154; | 4.U.236.157; | 4.U.236.166; | 4.U.236.169; |
4.U.236.172; | 4.U.236.175; | 4.U.236.240; | 4.U.236.244; |
4.U.237.228; | 4.U.237.229; | 4.U.237.230; | 4.U.237.231; |
4.U.237.236; | 4.U.237.237; | 4.U.237.238; | 4.U.237.239; |
4.U.237.154; | 4.U.237.157; | 4.U.237.166; | 4.U.237.169; |
4.U.237.172; | 4.U.237.175; | 4.U.237.240; | 4.U.237.244; |
4.U.238.228; | 4.U.238.229; | 4.U.238.230; | 4.U.238.231; |
4.U.238.236; | 4.U.238.237; | 4.U.238.238; | 4.U.238.239; |
4.U.238.154; | 4.U.238.157; | 4.U.238.166; | 4.U.238.169; |
4.U.238.172; | 4.U.238.175; | 4.U.238.240; | 4.U.238.244; |
4.U.239.228; | 4.U.239.229; | 4.U.239.230; | 4.U.239.231; |
4.U.239.236; | 4.U.239.237; | 4.U.239.238; | 4.U.239.239; |
4.U.239.154; | 4.U.239.157; | 4.U.239.166; | 4.U.239.169; |
4.U.239.172; | 4.U.239.175; | 4.U.239.240; | 4.U.239.244; |
4.U.154.228; | 4.U.154.229; | 4.U.154.230; | 4.U.154.231; |
4.U.154.236; | 4.U.154.237; | 4.U.154.238; | 4.U.154.239; |
4.U.154.154; | 4.U.154.157; | 4.U.154.166; | 4.U.154.169; |
4.U.154.172; | 4.U.154.175; | 4.U.154.240; | 4.U.154.244; |
4.U.157.228; | 4.U.157.229; | 4.U.157.230; | 4.U.157.231; |
4.U.157.236; | 4.U.157.237; | 4.U.157.238; | 4.U.157.239; |
4.U.157.154; | 4.U.157.157; | 4.U.157.166; | 4.U.157.169; |
4.U.157.172; | 4.U.157.175; | 4.U.157.240; | 4.U.157.244; |
4.U.166.228; | 4.U.166.229; | 4.U.166.230; | 4.U.166.231; |
4.U.166.236; | 4.U.166.237; | 4.U.166.238; | 4.U.166.239; |
4.U.166.154; | 4.U.166.157; | 4.U.166.166; | 4.U.166.169; |
4.U.166.172; | 4.U.166.175; | 4.U.166.240; | 4.U.166.244; |
4.U.169.228; | 4.U.169.229; | 4.U.169.230; | 4.U.169.231; |
4.U.169.236; | 4.U.169.237; | 4.U.169.238; | 4.U.169.239; |
4.U.169.154; | 4.U.169.157; | 4.U.169.166; | 4.U.169.169; |
4.U.169.172; | 4.U.169.175; | 4.U.169.240; | 4.U.169.244; |
4.U.172.228; | 4.U.172.229; | 4.U.172.230; | 4.U.172.231; |
4.U.172.236; | 4.U.172.237; | 4.U.172.238; | 4.U.172.239; |
4.U.172.154; | 4.U.172.157; | 4.U.172.166; | 4.U.172.169; |
4.U.172.172; | 4.U.172.175; | 4.U.172.240; | 4.U.172.244; |
4.U.175.228; | 4.U.175.229; | 4.U.175.230; | 4.U.175.231; |
4.U.175.236; | 4.U.175.237; | 4.U.175.238; | 4.U.175.239; |
4.U.175.154; | 4.U.175.157; | 4.U.175.166; | 4.U.175.169; |
4.U.175.172; | 4.U.175.175; | 4.U.175.240; | 4.U.175.244; |
4.U.240.228; | 4.U.240.229; | 4.U.240.230; | 4.U.240.231; |
4.U.240.236; | 4.U.240.237; | 4.U.240.238; | 4.U.240.239; |
4.U.240.154; | 4.U.240.157; | 4.U.240.166; | 4.U.240.169; |
4.U.240.172; | 4.U.240.175; | 4.U.240.240; | 4.U.240.244; |
4.U.244.228; | 4.U.244.229; | 4.U.244.230; | 4.U.244.231; |
4.U.244.236; | 4.U.244.237; | 4.U.244.238; | 4.U.244.239; |
4.U.244.154; | 4.U.244.157; | 4.U.244.166; | 4.U.244.169; |
4.U.244.172; | 4.U.244.175; | 4.U.244.240; | 4.U.244.244; |
4.W的前体药物
4.W.228.228; | 4.W.228.229; | 4.W.228.230; | 4.W.228.231; |
4.W.228.236; | 4.W.228.237; | 4.W.228.238; | 4.W.228.239; |
4.W.228.154; | 4.W.228.157; | 4.W.228.166; | 4.W.228.169; |
4.W.228.172; | 4.W.228.175; | 4.W.228.240; | 4.W.228.244; |
4.W.229.228; | 4.W.229.229; | 4.W.229.230; | 4.W.229.231; |
4.W.229.236; | 4.W.229.237; | 4.W.229.238; | 4.W.229.239; |
4.W.229.154; | 4.W.229.157; | 4.W.229.166; | 4.W.229.169; |
4.W.229.172; | 4.W.229.175; | 4.W.229.240; | 4.W.229.244; |
4.W.230.228; | 4.W.230.229; | 4.W.230.230; | 4.W.230.231; |
4.W.230.236; | 4.W.230.237; | 4.W.230.238; | 4.W.230.239; |
4.W.230.154; | 4.W.230.157; | 4.W.230.166; | 4.W.230.169; |
4.W.230.172; | 4.W.230.175; | 4.W.230.240; | 4.W.230.244; |
4.W.231.228; | 4.W.231.229; | 4.W.231.230; | 4.W.231.231; |
4.W.231.236; | 4.W.231.237; | 4.W.231.238; | 4.W.231.239; |
4.W.231.154; | 4.W.231.157; | 4.W.231.166; | 4.W.231.169; |
4.W.231.172; | 4.W.231.175; | 4.W.231.240; | 4.W.231.244; |
4.W.236.228; | 4.W.236.229; | 4.W.236.230; | 4.W.236.231; |
4.W.236.236; | 4.W.236.237; | 4.W.236.238; | 4.W.236.239; |
4.W.236.154; | 4.W.236.157; | 4.W.236.166; | 4.W.236.169; |
4.W.236.172; | 4.W.236.175; | 4.W.236.240; | 4.W.236.244; |
4.W.237.228; | 4.W.237.229; | 4.W.237.230; | 4.W.237.231; |
4.W.237.236; | 4.W.237.237; | 4.W.237.238; | 4.W.237.239; |
4.W.237.154; | 4.W.237.157; | 4.W.237.166; | 4.W.237.169; |
4.W.237.172; | 4.W.237.175; | 4.W.237.240; | 4.W.237.244; |
4.W.238.228; | 4.W.238.229; | 4.W.238.230; | 4.W.238.231; |
4.W.238.236; | 4.W.238.237; | 4.W.238.238; | 4.W.238.239; |
4.W.238.154; | 4.W.238.157; | 4.W.238.166; | 4.W.238.169; |
4.W.238.172; | 4.W.238.175; | 4.W.238.240; | 4.W.238.244; |
4.W.239.228; | 4.W.239.229; | 4.W.239.230; | 4.W.239.231; |
4.W.239.236; | 4.W.239.237; | 4.W.239.238; | 4.W.239.239; |
4.W.239.154; | 4.W.239.157; | 4.W.239.166; | 4.W.239.169; |
4.W.239.172; | 4.W.239.175; | 4.W.239.240; | 4.W.239.244; |
4.W.154.228; | 4.W.154.229; | 4.W.154.230; | 4.W.154.231; |
4.W.154.236; | 4.W.154.237; | 4.W.154.238; | 4.W.154.239; |
4.W.154.154; | 4.W.154.157; | 4.W.154.166; | 4.W.154.169; |
4.W.154.172; | 4.W.154.175; | 4.W.154.240; | 4.W.154.244; |
4.W.157.228; | 4.W.157.229; | 4.W.157.230; | 4.W.157.231; |
4.W.157.236; | 4.W.157.237; | 4.W.157.238; | 4.W.157.239; |
4.W.157.154; | 4.W.157.157; | 4.W.157.166; | 4.W.157.169; |
4.W.157.172; | 4.W.157.175; | 4.W.157.240; | 4.W.157.244; |
4.W.166.228; | 4.W.166.229; | 4.W.166.230; | 4.W.166.231; |
4.W.166.236; | 4.W.166.237; | 4.W.166.238; | 4.W.166.239; |
4.W.166.154; | 4.W.166.157; | 4.W.166.166; | 4.W.166.169; |
4.W.166.172; | 4.W.166.175; | 4.W.166.240; | 4.W.166.244; |
4.W.169.228; | 4.W.169.229; | 4.W.169.230; | 4.W.169.231; |
4.W.169.236; | 4.W.169.237; | 4.W.169.238; | 4.W.169.239; |
4.W.169.154; | 4.W.169.157; | 4.W.169.166; | 4.W.169.169; |
4.W.169.172; | 4.W.169.175; | 4.W.169.240; | 4.W.169.244; |
4.W.172.228; | 4.W.172.229; | 4.W.172.230; | 4.W.172.231; |
4.W.172.236; | 4.W.172.237; | 4.W.172.238; | 4.W.172.239; |
4.W.172.154; | 4.W.172.157; | 4.W.172.166; | 4.W.172.169; |
4.W.172.172; | 4.W.172.175; | 4.W.172.240; | 4.W.172.244; |
4.W.175.228; | 4.W.175.229; | 4.W.175.230; | 4.W.175.231; |
4.W.175.236; | 4.W.175.237; | 4.W.175.238; | 4.W.175.239; |
4.W.175.154; | 4.W.175.157; | 4.W.175.166; | 4.W.175.169; |
4.W.175.172; | 4.W.175.175; | 4.W.175.240; | 4.W.175.244; |
4.W.240.228; | 4.W.240.229; | 4.W.240.230; | 4.W.240.231; |
4.W.240.236; | 4.W.240.237; | 4.W.240.238; | 4.W.240.239; |
4.W.240.154; | 4.W.240.157; | 4.W.240.166; | 4.W.240.169; |
4.W.240.172; | 4.W.240.175; | 4.W.240.240; | 4.W.240.244; |
4.W.244.228; | 4.W.244.229; | 4.W.244.230; | 4.W.244.231; |
4.W.244.236; | 4.W.244.237; | 4.W.244.238; | 4.W.244.239; |
4.W.244.154; | 4.W.244.157; | 4.W.244.166; | 4.W.244.169; |
4.W.244.172; | 4.W.244.175; | 4.W.244.240; | 4.W.244.244; |
4.Y的前体药物
4.Y.228.228; | 4.Y.228.229; | 4.Y.228.230; | 4.Y.228.231; |
4.Y.228.236; | 4.Y.228.237; | 4.Y.228.238; | 4.Y.228.239; |
4.Y.228.154; | 4.Y.228.157; | 4.Y.228.166; | 4.Y.228.169; |
4.Y.228.172; | 4.Y.228.175; | 4.Y.228.240; | 4.Y.228.244; |
4.Y.229.228; | 4.Y.229.229; | 4.Y.229.230; | 4.Y.229.231; |
4.Y.229.236; | 4.Y.229.237; | 4.Y.229.238; | 4.Y.229.239; |
4.Y.229.154; | 4.Y.229.157; | 4.Y.229.166; | 4.Y.229.169; |
4.Y.229.172; | 4.Y.229.175; | 4.Y.229.240; | 4.Y.229.244; |
4.Y.230.228; | 4.Y.230.229; | 4.Y.230.230; | 4.Y.230.231; |
4.Y.230.236; | 4.Y.230.237; | 4.Y.230.238; | 4.Y.230.239; |
4.Y.230.154; | 4.Y.230.157; | 4.Y.230.166; | 4.Y.230.169; |
4.Y.230.172; | 4.Y.230.175; | 4.Y.230.240; | 4.Y.230.244; |
4.Y.231.228; | 4.Y.231.229; | 4.Y.231.230; | 4.Y.231.231; |
4.Y.231.236; | 4.Y.231.237; | 4.Y.231.238; | 4.Y.231.239; |
4.Y.231.154; | 4.Y.231.157; | 4.Y.231.166; | 4.Y.231.169; |
4.Y.231.172; | 4.Y.231.175; | 4.Y.231.240; | 4.Y.231.244; |
4.Y.236.228; | 4.Y.236.229; | 4.Y.236.230; | 4.Y.236.231; |
4.Y.236.236; | 4.Y.236.237; | 4.Y.236.238; | 4.Y.236.239; |
4.Y.236.154; | 4.Y.236.157; | 4.Y.236.166; | 4.Y.236.169; |
4.Y.236.172; | 4.Y.236.175; | 4.Y.236.240; | 4.Y.236.244; |
4.Y.237.228; | 4.Y.237.229; | 4.Y.237.230; | 4.Y.237.231; |
4.Y.237.236; | 4.Y.237.237; | 4.Y.237.238; | 4.Y.237.239; |
4.Y.237.154; | 4.Y.237.157; | 4.Y.237.166; | 4.Y.237.169; |
4.Y.237.172; | 4.Y.237.175; | 4.Y.237.240; | 4.Y.237.244; |
4.Y.238.228; | 4.Y.238.229; | 4.Y.238.230; | 4.Y.238.231; |
4.Y.238.236; | 4.Y.238.237; | 4.Y.238.238; | 4.Y.238.239; |
4.Y.238.154; | 4.Y.238.157; | 4.Y.238.166; | 4.Y.238.169; |
4.Y.238.172; | 4.Y.238.175; | 4.Y.238.240; | 4.Y.238.244; |
4.Y.239.228; | 4.Y.239.229; | 4.Y.239.230; | 4.Y.239.231; |
4.Y.239.236; | 4.Y.239.237; | 4.Y.239.238; | 4.Y.239.239; |
4.Y.239.154; | 4.Y.239.157; | 4.Y.239.166; | 4.Y.239.169; |
4.Y.239.172; | 4.Y.239.175; | 4.Y.239.240; | 4.Y.239.244; |
4.Y.154.228; | 4.Y.154.229; | 4.Y.154.230; | 4.Y.154.231; |
4.Y.154.236; | 4.Y.154.237; | 4.Y.154.238; | 4.Y.154.239; |
4.Y.154.154; | 4.Y.154.157; | 4.Y.154.166; | 4.Y.154.169; |
4.Y.154.172; | 4.Y.154.175; | 4.Y.154.240; | 4.Y.154.244; |
4.Y.157.228; | 4.Y.157.229; | 4.Y.157.230; | 4.Y.157.231; |
4.Y.157.236; | 4.Y.157.237; | 4.Y.157.238; | 4.Y.157.239; |
4.Y.157.154; | 4.Y.157.157; | 4.Y.157.166; | 4.Y.157.169; |
4.Y.157.172; | 4.Y.157.175; | 4.Y.157.240; | 4.Y.157.244; |
4.Y.166.228; | 4.Y.166.229; | 4.Y.166.230; | 4.Y.166.231; |
4.Y.166.236; | 4.Y.166.237; | 4.Y.166.238; | 4.Y.166.239; |
4.Y.166.154; | 4.Y.166.157; | 4.Y.166.166; | 4.Y.166.169; |
4.Y.166.172; | 4.Y.166.175; | 4.Y.166.240; | 4.Y.166.244; |
4.Y.169.228; | 4.Y.169.229; | 4.Y.169.230; | 4.Y.169.231; |
4.Y.169.236; | 4.Y.169.237; | 4.Y.169.238; | 4.Y.169.239; |
4.Y.169.154; | 4.Y.169.157; | 4.Y.169.166; | 4.Y.169.169; |
4.Y.169.172; | 4.Y.169.175; | 4.Y.169.240; | 4.Y.169.244; |
4.Y.172.228; | 4.Y.172.229; | 4.Y.172.230; | 4.Y.172.231; |
4.Y.172.236; | 4.Y.172.237; | 4.Y.172.238; | 4.Y.172.239; |
4.Y.172.154; | 4.Y.172.157; | 4.Y.172.166; | 4.Y.172.169; |
4.Y.172.172; | 4.Y.172.175; | 4.Y.172.240; | 4.Y.172.244; |
4.Y.175.228; | 4.Y.175.229; | 4.Y.175.230; | 4.Y.175.231; |
4.Y.175.236; | 4.Y.175.237; | 4.Y.175.238; | 4.Y.175.239; |
4.Y.175.154; | 4.Y.175.157; | 4.Y.175.166; | 4.Y.175.169; |
4.Y.175.172; | 4.Y.175.175; | 4.Y.175.240; | 4.Y.175.244; |
4.Y.240.228; | 4.Y.240.229; | 4.Y.240.230; | 4.Y.240.231; |
4.Y.240.236; | 4.Y.240.237; | 4.Y.240.238; | 4.Y.240.239; |
4.Y.240.154; | 4.Y.240.157; | 4.Y.240.166; | 4.Y.240.169; |
4.Y.240.172; | 4.Y.240.175; | 4.Y.240.240; | 4.Y.240.244; |
4.Y.244.228; | 4.Y.244.229; | 4.Y.244.230; | 4.Y.244.231; |
4.Y.244.236; | 4.Y.244.237; | 4.Y.244.238; | 4.Y.244.239; |
4.Y.244.154; | 4.Y.244.157; | 4.Y.244.166; | 4.Y.244.169; |
4.Y.244.172; | 4.Y.244.175; | 4.Y.244.240; | 4.Y.244.244; |
5.B的前体药物
5.B.228.228; | 5.B.228.229; | 5.B.228.230; | 5.B.228.231; |
5.B.228.236; | 5.B.228.237; | 5.B.228.238; | 5.B.228.239; |
5.B.228.154; | 5.B.228.157; | 5.B.228.166; | 5.B.228.169; |
5.B.228.172; | 5.B.228.175; | 5.B.228.240; | 5.B.228.244; |
5.B.229.228; | 5.B.229.229; | 5.B.229.230; | 5.B.229.231; |
5.B.229.236; | 5.B.229.237; | 5.B.229.238; | 5.B.229.239; |
5.B.229.154; | 5.B.229.157; | 5.B.229.166; | 5.B.229.169; |
5.B.229.172; | 5.B.229.175; | 5.B.229.240; | 5.B.229.244; |
5.B.230.228; | 5.B.230.229; | 5.B.230.230; | 5.B.230.231; |
5.B.230.236; | 5.B.230.237; | 5.B.230.238; | 5.B.230.239; |
5.B.230.154; | 5.B.230.157; | 5.B.230.166; | 5.B.230.169; |
5.B.230.172; | 5.B.230.175; | 5.B.230.240; | 5.B.230.244; |
5.B.231.228; | 5.B.231.229; | 5.B.231.230; | 5.B.231.231; |
5.B.231.236; | 5.B.231.237; | 5.B.231.238; | 5.B.231.239; |
5.B.231.154; | 5.B.231.157; | 5.B.231.166; | 5.B.231.169; |
5.B.231.172; | 5.B.231.175; | 5.B.231.240; | 5.B.231.244; |
5.B.236.228; | 5.B.236.229; | 5.B.236.230; | 5.B.236.231; |
5.B.236.236; | 5.B.236.237; | 5.B.236.238; | 5.B.236.239; |
5.B.236.154; | 5.B.236.157; | 5.B.236.166; | 5.B.236.169; |
5.B.236.172; | 5.B.236.175; | 5.B.236.240; | 5.B.236.244; |
5.B.237.228; | 5.B.237.229; | 5.B.237.230; | 5.B.237.231; |
5.B.237.236; | 5.B.237.237; | 5.B.237.238; | 5.B.237.239; |
5.B.237.154; | 5.B.237.157; | 5.B.237.166; | 5.B.237.169; |
5.B.237.172; | 5.B.237.175; | 5.B.237.240; | 5.B.237.244; |
5.B.238.228; | 5.B.238.229; | 5.B.238.230; | 5.B.238.231; |
5.B.238.236; | 5.B.238.237; | 5.B.238.238; | 5.B.238.239; |
5.B.238.154; | 5.B.238.157; | 5.B.238.166; | 5.B.238.169; |
5.B.238.172; | 5.B.238.175; | 5.B.238.240; | 5.B.238.244; |
5.B.239.228; | 5.B.239.229; | 5.B.239.230; | 5.B.239.231; |
5.B.239.236; | 5.B.239.237; | 5.B.239.238; | 5.B.239.239; |
5.B.239.154; | 5.B.239.157; | 5.B.239.166; | 5.B.239.169; |
5.B.239.172; | 5.B.239.175; | 5.B.239.240; | 5.B.239.244; |
5.B.154.228; | 5.B.154.229; | 5.B.154.230; | 5.B.154.231; |
5.B.154.236; | 5.B.154.237; | 5.B.154.238; | 5.B.154.239; |
5.B.154.154; | 5.B.154.157; | 5.B.154.166; | 5.B.154.169; |
5.B.154.172; | 5.B.154.175; | 5.B.154.240; | 5.B.154.244; |
5.B.157.228; | 5.B.157.229; | 5.B.157.230; | 5.B.157.231; |
5.B.157.236; | 5.B.157.237; | 5.B.157.238; | 5.B.157.239; |
5.B.157.154; | 5.B.157.157; | 5.B.157.166; | 5.B.157.169; |
5.B.157.172; | 5.B.157.175; | 5.B.157.240; | 5.B.157.244; |
5.B.166.228; | 5.B.166.229; | 5.B.166.230; | 5.B.166.231; |
5.B.166.236; | 5.B.166.237; | 5.B.166.238; | 5.B.166.239; |
5.B.166.154; | 5.B.166.157; | 5.B.166.166; | 5.B.166.169; |
5.B.166.172; | 5.B.166.175; | 5.B.166.240; | 5.B.166.244; |
5.B.169.228; | 5.B.169.229; | 5.B.169.230; | 5.B.169.231; |
5.B.169.236; | 5.B.169.237; | 5.B.169.238; | 5.B.169.239; |
5.B.169.154; | 5.B.169.157; | 5.B.169.166; | 5.B.169.169; |
5.B.169.172; | 5.B.169.175; | 5.B.169.240; | 5.B.169.244; |
5.B.172.228; | 5.B.172.229; | 5.B.172.230; | 5.B.172.231; |
5.B.172.236; | 5.B.172.237; | 5.B.172.238; | 5.B.172.239; |
5.B.172.154; | 5.B.172.157; | 5.B.172.166; | 5.B.172.169; |
5.B.172.172; | 5.B.172.175; | 5.B.172.240; | 5.B.172.244; |
5.B.175.228; | 5.B.175.229; | 5.B.175.230; | 5.B.175.231; |
5.B.175.236; | 5.B.175.237; | 5.B.175.238; | 5.B.175.239; |
5.B.175.154; | 5.B.175.157; | 5.B.175.166; | 5.B.175.169; |
5.B.175.172; | 5.B.175.175; | 5.B.175.240; | 5.B.175.244; |
5.B.240.228; | 5.B.240.229; | 5.B.240.230; | 5.B.240.231; |
5.B.240.236; | 5.B.240.237; | 5.B.240.238; | 5.B.240.239; |
5.B.240.154; | 5.B.240.157; | 5.B.240.166; | 5.B.240.169; |
5.B.240.172; | 5.B.240.175; | 5.B.240.240; | 5.B.240.244; |
5.B.244.228; | 5.B.244.229; | 5.B.244.230; | 5.B.244.231; |
5.B.244.236; | 5.B.244.237; | 5.B.244.238; | 5.B.244.239; |
5.B.244.154; | 5.B.244.157; | 5.B.244.166; | 5.B.244.169; |
5.B.244.172; | 5.B.244.175; | 5.B.244.240; | 5.B.244.244; |
5.D的前体药物
5.D.228.228; | 5.D.228.229; | 5.D.228.230; | 5.D.228.231; |
5.D.228.236; | 5.D.228.237; | 5.D.228.238; | 5.D.228.239; |
5.D.228.154; | 5.D.228.157; | 5.D.228.166; | 5.D.228.169; |
5.D.228.172; | 5.D.228.175; | 5.D.228.240; | 5.D.228.244; |
5.D.229.228; | 5.D.229.229; | 5.D.229.230; | 5.D.229.231; |
5.D.229.236; | 5.D.229.237; | 5.D.229.238; | 5.D.229.239; |
5.D.229.154; | 5.D.229.157; | 5.D.229.166; | 5.D.229.169; |
5.D.229.172; | 5.D.229.175; | 5.D.229.240; | 5.D.229.244; |
5.D.230.228; | 5.D.230.229; | 5.D.230.230; | 5.D.230.231; |
5.D.230.236; | 5.D.230.237; | 5.D.230.238; | 5.D.230.239; |
5.D.230.154; | 5.D.230.157; | 5.D.230.166; | 5.D.230.169; |
5.D.230.172; | 5.D.230.175; | 5.D.230.240; | 5.D.230.244; |
5.D.231.228; | 5.D.231.229; | 5.D.231.230; | 5.D.231.231; |
5.D.231.236; | 5.D.231.237; | 5.D.231.238; | 5.D.231.239; |
5.D.231.154; | 5.D.231.157; | 5.D.231.166; | 5.D.231.169; |
5.D.231.172; | 5.D.231.175; | 5.D.231.240; | 5.D.231.244; |
5.D.236.228; | 5.D.236.229; | 5.D.236.230; | 5.D.236.231; |
5.D.236.236; | 5.D.236.237; | 5.D.236.238; | 5.D.236.239; |
5.D.236.154; | 5.D.236.157; | 5.D.236.166; | 5.D.236.169; |
5.D.236.172; | 5.D.236.175; | 5.D.236.240; | 5.D.236.244; |
5.D.237.228; | 5.D.237.229; | 5.D.237.230; | 5.D.237.231; |
5.D.237.236; | 5.D.237.237; | 5.D.237.238; | 5.D.237.239; |
5.D.237.154; | 5.D.237.157; | 5.D.237.166; | 5.D.237.169; |
5.D.237.172; | 5.D.237.175; | 5.D.237.240; | 5.D.237.244; |
5.D.238.228; | 5.D.238.229; | 5.D.238.230; | 5.D.238.231; |
5.D.238.236; | 5.D.238.237; | 5.D.238.238; | 5.D.238.239; |
5.D.238.154; | 5.D.238.157; | 5.D.238.166; | 5.D.238.169; |
5.D.238.172; | 5.D.238.175; | 5.D.238.240; | 5.D.238.244; |
5.D.239.228; | 5.D.239.229; | 5.D.239.230; | 5.D.239.231; |
5.D.239.236; | 5.D.239.237; | 5.D.239.238; | 5.D.239.239; |
5.D.239.154; | 5.D.239.157; | 5.D.239.166; | 5.D.239.169; |
5.D.239.172; | 5.D.239.175; | 5.D.239.240; | 5.D.239.244; |
5.D.154.228; | 5.D.154.229; | 5.D.154.230; | 5.D.154.231; |
5.D.154.236; | 5.D.154.237; | 5.D.154.238; | 5.D.154.239; |
5.D.154.154; | 5.D.154.157; | 5.D.154.166; | 5.D.154.169; |
5.D.154.172; | 5.D.154.175; | 5.D.154.240; | 5.D.154.244; |
5.D.157.228; | 5.D.157.229; | 5.D.157.230; | 5.D.157.231; |
5.D.157.236; | 5.D.157.237; | 5.D.157.238; | 5.D.157.239; |
5.D.157.154; | 5.D.157.157; | 5.D.157.166; | 5.D.157.169; |
5.D.157.172; | 5.D.157.175; | 5.D.157.240; | 5.D.157.244; |
5.D.166.228; | 5.D.166.229; | 5.D.166.230; | 5.D.166.231; |
5.D.166.236; | 5.D.166.237; | 5.D.166.238; | 5.D.166.239; |
5.D.166.154; | 5.D.166.157; | 5.D.166.166; | 5.D.166.169; |
5.D.166.172; | 5.D.166.175; | 5.D.166.240; | 5.D.166.244; |
5.D.169.228; | 5.D.169.229; | 5.D.169.230; | 5.D.169.231; |
5.D.169.236; | 5.D.169.237; | 5.D.169.238; | 5.D.169.239; |
5.D.169.154; | 5.D.169.157; | 5.D.169.166; | 5.D.169.169; |
5.D.169.172; | 5.D.169.175; | 5.D.169.240; | 5.D.169.244; |
5.D.172.228; | 5.D.172.229; | 5.D.172.230; | 5.D.172.231; |
5.D.172.236; | 5.D.172.237; | 5.D.172.238; | 5.D.172.239; |
5.D.172.154; | 5.D.172.157; | 5.D.172.166; | 5.D.172.169; |
5.D.172.172; | 5.D.172.175; | 5.D.172.240; | 5.D.172.244; |
5.D.175.228; | 5.D.175.229; | 5.D.175.230; | 5.D.175.231; |
5.D.175.236; | 5.D.175.237; | 5.D.175.238; | 5.D.175.239; |
5.D.175.154; | 5.D.175.157; | 5.D.175.166; | 5.D.175.169; |
5.D.175.172; | 5.D.175.175; | 5.D.175.240; | 5.D.175.244; |
5.D.240.228; | 5.D.240.229; | 5.D.240.230; | 5.D.240.231; |
5.D.240.236; | 5.D.240.237; | 5.D.240.238; | 5.D.240.239; |
5.D.240.154; | 5.D.240.157; | 5.D.240.166; | 5.D.240.169; |
5.D.240.172; | 5.D.240.175; | 5.D.240.240; | 5.D.240.244; |
5.D.244.228; | 5.D.244.229; | 5.D.244.230; | 5.D.244.231; |
5.D.244.236; | 5.D.244.237; | 5.D.244.238; | 5.D.244.239; |
5.D.244.154; | 5.D.244.157; | 5.D.244.166; | 5.D.244.169; |
5.D.244.172; | 5.D.244.175; | 5.D.244.240; | 5.D.244.244; |
5.E的前体药物
5.E.228.228; | 5.E.228.229; | 5.E.228.230; | 5.E.228.231; |
5.E.228.236; | 5.E.228.237; | 5.E.228.238; | 5.E.228.239; |
5.E.228.154; | 5.E.228.157; | 5.E.228.166; | 5.E.228.169; |
5.E.228.172; | 5.E.228.175; | 5.E.228.240; | 5.E.228.244; |
5.E.229.228; | 5.E.229.229; | 5.E.229.230; | 5.E.229.231; |
5.E.229.236; | 5.E.229.237; | 5.E.229.238; | 5.E.229.239; |
5.E.229.154; | 5.E.229.157; | 5.E.229.166; | 5.E.229.169; |
5.E.229.172; | 5.E.229.175; | 5.E.229.240; | 5.E.229.244; |
5.E.230.228; | 5.E.230.229; | 5.E.230.230; | 5.E.230.231; |
5.E.230.236; | 5.E.230.237; | 5.E.230.238; | 5.E.230.239; |
5.E.230.154; | 5.E.230.157; | 5.E.230.166; | 5.E.230.169; |
5.E.230.172; | 5.E.230.175; | 5.E.230.240; | 5.E.230.244; |
5.E.231.228; | 5.E.231.229; | 5.E.231.230; | 5.E.231.231; |
5.E.231.236; | 5.E.231.237; | 5.E.231.238; | 5.E.231.239; |
5.E.231.154; | 5.E.231.157; | 5.E.231.166; | 5.E.231.169; |
5.E.231.172; | 5.E.231.175; | 5.E.231.240; | 5.E.231.244; |
5.E.236.228; | 5.E.236.229; | 5.E.236.230; | 5.E.236.231; |
5.E.236.236; | 5.E.236.237; | 5.E.236.238; | 5.E.236.239; |
5.E.236.154; | 5.E.236.157; | 5.E.236.166; | 5.E.236.169; |
5.E.236.172; | 5.E.236.175; | 5.E.236.240; | 5.E.236.244; |
5.E.237.228; | 5.E.237.229; | 5.E.237.230; | 5.E.237.231; |
5.E.237.236; | 5.E.237.237; | 5.E.237.238; | 5.E.237.239; |
5.E.237.154; | 5.E.237.157; | 5.E.237.166; | 5.E.237.169; |
5.E.237.172; | 5.E.237.175; | 5.E.237.240; | 5.E.237.244; |
5.E.238.228; | 5.E.238.229; | 5.E.238.230; | 5.E.238.231; |
5.E.238.236; | 5.E.238.237; | 5.E.238.238; | 5.E.238.239; |
5.E.238.154; | 5.E.238.157; | 5.E.238.166; | 5.E.238.169; |
5.E.238.172; | 5.E.238.175; | 5.E.238.240; | 5.E.238.244; |
5.E.239.228; | 5.E.239.229; | 5.E.239.230; | 5.E.239.231; |
5.E.239.236; | 5.E.239.237; | 5.E.239.238; | 5.E.239.239; |
5.E.239.154; | 5.E.239.157; | 5.E.239.166; | 5.E.239.169; |
5.E.239.172; | 5.E.239.175; | 5.E.239.240; | 5.E.239.244; |
5.E.154.228; | 5.E.154.229; | 5.E.154.230; | 5.E.154.231; |
5.E.154.236; | 5.E.154.237; | 5.E.154.238; | 5.E.154.239; |
5.E.154.154; | 5.E.154.157; | 5.E.154.166; | 5.E.154.169; |
5.E.154.172; | 5.E.154.175; | 5.E.154.240; | 5.E.154.244; |
5.E.157.228; | 5.E.157.229; | 5.E.157.230; | 5.E.157.231; |
5.E.157.236; | 5.E.157.237; | 5.E.157.238; | 5.E.157.239; |
5.E.157.154; | 5.E.157.157; | 5.E.157.166; | 5.E.157.169; |
5.E.157.172; | 5.E.157.175; | 5.E.157.240; | 5.E.157.244; |
5.E.166.228; | 5.E.166.229; | 5.E.166.230; | 5.E.166.231; |
5.E.166.236; | 5.E.166.237; | 5.E.166.238; | 5.E.166.239; |
5.E.166.154; | 5.E.166.157; | 5.E.166.166; | 5.E.166.169; |
5.E.166.172; | 5.E.166.175; | 5.E.166.240; | 5.E.166.244; |
5.E.169.228; | 5.E.169.229; | 5.E.169.230; | 5.E.169.231; |
5.E.169.236; | 5.E.169.237; | 5.E.169.238; | 5.E.169.239; |
5.E.169.154; | 5.E.169.157; | 5.E.169.166; | 5.E.169.169; |
5.E.169.172; | 5.E.169.175; | 5.E.169.240; | 5.E.169.244; |
5.E.172.228; | 5.E.172.229; | 5.E.172.230; | 5.E.172.231; |
5.E.172.236; | 5.E.172.237; | 5.E.172.238; | 5.E.172.239; |
5.E.172.154; | 5.E.172.157; | 5.E.172.166; | 5.E.172.169; |
5.E.172.172; | 5.E.172.175; | 5.E.172.240; | 5.E.172.244; |
5.E.175.228; | 5.E.175.229; | 5.E.175.230; | 5.E.175.231; |
5.E.175.236; | 5.E.175.237; | 5.E.175.238; | 5.E.175.239; |
5.E.175.154; | 5.E.175.157; | 5.E.175.166; | 5.E.175.169; |
5.E.175.172; | 5.E.175.175; | 5.E.175.240; | 5.E.175.244; |
5.E.240.228; | 5.E.240.229; | 5.E.240.230; | 5.E.240.231; |
5.E.240.236; | 5.E.240.237; | 5.E.240.238; | 5.E.240.239; |
5.E.240.154; | 5.E.240.157; | 5.E.240.166; | 5.E.240.169; |
5.E.240.172; | 5.E.240.175; | 5.E.240.240; | 5.E.240.244; |
5.E.244.228; | 5.E.244.229; | 5.E.244.230; | 5.E.244.231; |
5.E.244.236; | 5.E.244.237; | 5.E.244.238; | 5.E.244.239; |
5.E.244.154; | 5.E.244.157; | 5.E.244.166; | 5.E.244.169; |
5.E.244.172; | 5.E.244.175; | 5.E.244.240; | 5.E.244.244; |
5.G的前体药物
5.G.228.228; | 5.G.228.229; | 5.G.228.230; | 5.G.228.231; |
5.G.228.236; | 5.G.228.237; | 5.G.228.238; | 5.G.228.239; |
5.G.228.154; | 5.G.228.157; | 5.G.228.166; | 5.G.228.169; |
5.G.228.172; | 5.G.228.175; | 5.G.228.240; | 5.G.228.244; |
5.G.229.228; | 5.G.229.229; | 5.G.229.230; | 5.G.229.231; |
5.G.229.236; | 5.G.229.237; | 5.G.229.238; | 5.G.229.239; |
5.G.229.154; | 5.G.229.157; | 5.G.229.166; | 5.G.229.169; |
5.G.229.172; | 5.G.229.175; | 5.G.229.240; | 5.G.229.244; |
5.G.230.228; | 5.G.230.229; | 5.G.230.230; | 5.G.230.231; |
5.G.230.236; | 5.G.230.237; | 5.G.230.238; | 5.G.230.239; |
5.G.230.154; | 5.G.230.157; | 5.G.230.166; | 5.G.230.169; |
5.G.230.172; | 5.G.230.175; | 5.G.230.240; | 5.G.230.244; |
5.G.231.228; | 5.G.231.229; | 5.G.231.230; | 5.G.231.231; |
5.G.231.236; | 5.G.231.237; | 5.G.231.238; | 5.G.231.239; |
5.G.231.154; | 5.G.231.157; | 5.G.231.166; | 5.G.231.169; |
5.G.231.172; | 5.G.231.175; | 5.G.231.240; | 5.G.231.244; |
5.G.236.228; | 5.G.236.229; | 5.G.236.230; | 5.G.236.231; |
5.G.236.236; | 5.G.236.237; | 5.G.236.238; | 5.G.236.239; |
5.G.236.154; | 5.G.236.157; | 5.G.236.166; | 5.G.236.169; |
5.G.236.172; | 5.G.236.175; | 5.G.236.240; | 5.G.236.244; |
5.G.237.228; | 5.G.237.229; | 5.G.237.230; | 5.G.237.231; |
5.G.237.236; | 5.G.237.237; | 5.G.237.238; | 5.G.237.239; |
5.G.237.154; | 5.G.237.157; | 5.G.237.166; | 5.G.237.169; |
5.G.237.172; | 5.G.237.175; | 5.G.237.240; | 5.G.237.244; |
5.G.238.228; | 5.G.238.229; | 5.G.238.230; | 5.G.238.231; |
5.G.238.236; | 5.G.238.237; | 5.G.238.238; | 5.G.238.239; |
5.G.238.154; | 5.G.238.157; | 5.G.238.166; | 5.G.238.169; |
5.G.238.172; | 5.G.238.175; | 5.G.238.240; | 5.G.238.244; |
5.G.239.228; | 5.G.239.229; | 5.G.239.230; | 5.G.239.231; |
5.G.239.236; | 5.G.239.237; | 5.G.239.238; | 5.G.239.239; |
5.G.239.154; | 5.G.239.157; | 5.G.239.166; | 5.G.239.169; |
5.G.239.172; | 5.G.239.175; | 5.G.239.240; | 5.G.239.244; |
5.G.154.228; | 5.G.154.229; | 5.G.154.230; | 5.G.154.231; |
5.G.154.236; | 5.G.154.237; | 5.G.154.238; | 5.G.154.239; |
5.G.154.154; | 5.G.154.157; | 5.G.154.166; | 5.G.154.169; |
5.G.154.172; | 5.G.154.175; | 5.G.154.240; | 5.G.154.244; |
5.G.157.228; | 5.G.157.229; | 5.G.157.230; | 5.G.157.231; |
5.G.157.236; | 5.G.157.237; | 5.G.157.238; | 5.G.157.239; |
5.G.157.154; | 5.G.157.157; | 5.G.157.166; | 5.G.157.169; |
5.G.157.172; | 5.G.157.175; | 5.G.157.240; | 5.G.157.244; |
5.G.166.228; | 5.G.166.229; | 5.G.166.230; | 5.G.166.231; |
5.G.166.236; | 5.G.166.237; | 5.G.166.238; | 5.G.166.239; |
5.G.166.154; | 5.G.166.157; | 5.G.166.166; | 5.G.166.169; |
5.G.166.172; | 5.G.166.175; | 5.G.166.240; | 5.G.166.244; |
5.G.169.228; | 5.G.169.229; | 5.G.169.230; | 5.G.169.231; |
5.G.169.236; | 5.G.169.237; | 5.G.169.238; | 5.G.169.239; |
5.G.169.154; | 5.G.169.157; | 5.G.169.166; | 5.G.169.169; |
5.G.169.172; | 5.G.169.175; | 5.G.169.240; | 5.G.169.244; |
5.G.172.228; | 5.G.172.229; | 5.G.172.230; | 5.G.172.231; |
5.G.172.236; | 5.G.172.237; | 5.G.172.238; | 5.G.172.239; |
5.G.172.154; | 5.G.172.157; | 5.G.172.166; | 5.G.172.169; |
5.G.172.172; | 5.G.172.175; | 5.G.172.240; | 5.G.172.244; |
5.G.175.228; | 5.G.175.229; | 5.G.175.230; | 5.G.175.231; |
5.G.175.236; | 5.G.175.237; | 5.G.175.238; | 5.G.175.239; |
5.G.175.154; | 5.G.175.157; | 5.G.175.166; | 5.G.175.169; |
5.G.175.172; | 5.G.175.175; | 5.G.175.240; | 5.G.175.244; |
5.G.240.228; | 5.G.240.229; | 5.G.240.230; | 5.G.240.231; |
5.G.240.236; | 5.G.240.237; | 5.G.240.238; | 5.G.240.239; |
5.G.240.154; | 5.G.240.157; | 5.G.240.166; | 5.G.240.169; |
5.G.240.172; | 5.G.240.175; | 5.G.240.240; | 5.G.240.244; |
5.G.244.228; | 5.G.244.229; | 5.G.244.230; | 5.G.244.231; |
5.G.244.236; | 5.G.244.237; | 5.G.244.238; | 5.G.244.239; |
5.G.244.154; | 5.G.244.157; | 5.G.244.166; | 5.G.244.169; |
5.G.244.172; | 5.G.244.175; | 5.G.244.240; | 5.G.244.244; |
5.I的前体药物
5.I.228.228; | 5.I.228.229; | 5.I.228.230; | 5.I.228.231; |
5.I.228.236; | 5.I.228.237; | 5.I.228.238; | 5.I.228.239; |
5.I.228.154; | 5.I.228.157; | 5.I.228.166; | 5.I.228.169; |
5.I.228.172; | 5.I.228.175; | 5.I.228.240; | 5.I.228.244; |
5.I.229.228; | 5.I.229.229; | 5.I.229.230; | 5.I.229.231; |
5.I.229.236; | 5.I.229.237; | 5.I.229.238; | 5.I.229.239; |
5.I.229.154; | 5.I.229.157; | 5.I.229.166; | 5.I.229.169; |
5.I.229.172; | 5.I.229.175; | 5.I.229.240; | 5.I.229.244; |
5.I.230.228; | 5.I.230.229; | 5.I.230.230; | 5.I.230.231; |
5.I.230.236; | 5.I.230.237; | 5.I.230.238; | 5.I.230.239; |
5.I.230.154; | 5.I.230.157; | 5.I.230.166; | 5.I.230.169; |
5.I.230.172; | 5.I.230.175; | 5.I.230.240; | 5.I.230.244; |
5.I.231.228; | 5.I.231.229; | 5.I.231.230; | 5.I.231.231; |
5.I.231.236; | 5.I.231.237; | 5.I.231.238; | 5.I.231.239; |
5.I.231.154; | 5.I.231.157; | 5.I.231.166; | 5.I.231.169; |
5.I.231.172; | 5.I.231.175; | 5.I.231.240; | 5.I.231.244; |
5.I.236.228; | 5.I.236.229; | 5.I.236.230; | 5.I.236.231; |
5.I.236.236; | 5.I.236.237; | 5.I.236.238; | 5.I.236.239; |
5.I.236.154; | 5.I.236.157; | 5.I.236.166; | 5.I.236.169; |
5.I.236.172; | 5.I.236.175; | 5.I.236.240; | 5.I.236.244; |
5.I.237.228; | 5.I.237.229; | 5.I.237.230; | 5.I.237.231; |
5.I.237.236; | 5.I.237.237; | 5.I.237.238; | 5.I.237.239; |
5.I.237.154; | 5.I.237.157; | 5.I.237.166; | 5.I.237.169; |
5.I.237.172; | 5.I.237.175; | 5.I.237.240; | 5.I.237.244; |
5.I.238.228; | 5.I.238.229; | 5.I.238.230; | 5.I.238.231; |
5.I.238.236; | 5.I.238.237; | 5.I.238.238; | 5.I.238.239; |
5.I.238.154; | 5.I.238.157; | 5.I.238.166; | 5.I.238.169; |
5.I.238.172; | 5.I.238.175; | 5.I.238.240; | 5.I.238.244; |
5.I.239.228; | 5.I.239.229; | 5.I.239.230; | 5.I.239.231; |
5.I.239.236; | 5.I.239.237; | 5.I.239.238; | 5.I.239.239; |
5.I.239.154; | 5.I.239.157; | 5.I.239.166; | 5.I.239.169; |
5.I.239.172; | 5.I.239.175; | 5.I.239.240; | 5.I.239.244; |
5.I.154.228; | 5.I.154.229; | 5.I.154.230; | 5.I.154.231; |
5.I.154.236; | 5.I.154.237; | 5.I.154.238; | 5.I.154.239; |
5.I.154.154; | 5.I.154.157; | 5.I.154.166; | 5.I.154.169; |
5.I.154.172; | 5.I.154.175; | 5.I.154.240; | 5.I.154.244; |
5.I.157.228; | 5.I.157.229; | 5.I.157.230; | 5.I.157.231; |
5.I.157.236; | 5.I.157.237; | 5.I.157.238; | 5.I.157.239; |
5.I.157.154; | 5.I.157.157; | 5.I.157.166; | 5.I.157.169; |
5.I.157.172; | 5.I.157.175; | 5.I.157.240; | 5.I.157.244; |
5.I.166.228; | 5.I.166.229; | 5.I.166.230; | 5.I.166.231; |
5.I.166.236; | 5.I.166.237; | 5.I.166.238; | 5.I.166.239; |
5.I.166.154; | 5.I.166.157; | 5.I.166.166; | 5.I.166.169; |
5.I.166.172; | 5.I.166.175; | 5.I.166.240; | 5.I.166.244; |
5.I.169.228; | 5.I.169.229; | 5.I.169.230; | 5.I.169.231; |
5.I.169.236; | 5.I.169.237; | 5.I.169.238; | 5.I.169.239; |
5.I.169.154; | 5.I.169.157; | 5.I.169.166; | 5.I.169.169; |
5.I.169.172; | 5.I.169.175; | 5.I.169.240; | 5.I.169.244; |
5.I.172.228; | 5.I.172.229; | 5.I.172.230; | 5.I.172.231; |
5.I.172.236; | 5.I.172.237; | 5.I.172.238; | 5.I.172.239; |
5.I.172.154; | 5.I.172.157; | 5.I.172.166; | 5.I.172.169; |
5.I.172.172; | 5.I.172.175; | 5.I.172.240; | 5.I.172.244; |
5.I.175.228; | 5.I.175.229; | 5.I.175.230; | 5.I.175.231; |
5.I.175.236; | 5.I.175.237; | 5.I.175.238; | 5.I.175.239; |
5.I.175.154; | 5.I.175.157; | 5.I.175.166; | 5.I.175.169; |
5.I.175.172; | 5.I.175.175; | 5.I.175.240; | 5.I.175.244; |
5.I.240.228; | 5.I.240.229; | 5.I.240.230; | 5.I.240.231; |
5.I.240.236; | 5.I.240.237; | 5.I.240.238; | 5.I.240.239; |
5.I.240.154; | 5.I.240.157; | 5.I.240.166; | 5.I.240.169; |
5.I.240.172; | 5.I.240.175; | 5.I.240.240; | 5.I.240.244; |
5.I.244.228; | 5.I.244.229; | 5.I.244.230; | 5.I.244.231; |
5.I.244.236; | 5.I.244.237; | 5.I.244.238; | 5.I.244.239; |
5.I.244.154; | 5.I.244.157; | 5.I.244.166; | 5.I.244.169; |
5.I.244.172; | 5.I.244.175; | 5.I.244.240; | 5.I.244.244; |
5.J的前体药物
5.J.228.228; | 5.J.228.229; | 5.J.228.230; | 5.J.228.231; |
5.J.228.236; | 5.J.228.237; | 5.J.228.238; | 5.J.228.239; |
5.J.228.154; | 5.J.228.157; | 5.J.228.166; | 5.J.228.169; |
5.J.228.172; | 5.J.228.175; | 5.J.228.240; | 5.J.228.244; |
5.J.229.228; | 5.J.229.229; | 5.J.229.230; | 5.J.229.231; |
5.J.229.236; | 5.J.229.237; | 5.J.229.238; | 5.J.229.239; |
5.J.229.154; | 5.J.229.157; | 5.J.229.166; | 5.J.229.169; |
5.J.229.172; | 5.J.229.175; | 5.J.229.240; | 5.J.229.244; |
5.J.230.228; | 5.J.230.229; | 5.J.230.230; | 5.J.230.231; |
5.J.230.236; | 5.J.230.237; | 5.J.230.238; | 5.J.230.239; |
5.J.230.154; | 5.J.230.157; | 5.J.230.166; | 5.J.230.169; |
5.J.230.172; | 5.J.230.175; | 5.J.230.240; | 5.J.230.244; |
5.J.231.228; | 5.J.231.229; | 5.J.231.230; | 5.J.231.231; |
5.J.231.236; | 5.J.231.237; | 5.J.231.238; | 5.J.231.239; |
5.J.231.154; | 5.J.231.157; | 5.J.231.166; | 5.J.231.169; |
5.J.231.172; | 5.J.231.175; | 5.J.231.240; | 5.J.231.244; |
5.J.236.228; | 5.J.236.229; | 5.J.236.230; | 5.J.236.231; |
5.J.236.236; | 5.J.236.237; | 5.J.236.238; | 5.J.236.239; |
5.J.236.154; | 5.J.236.157; | 5.J.236.166; | 5.J.236.169; |
5.J.236.172; | 5.J.236.175; | 5.J.236.240; | 5.J.236.244; |
5.J.237.228; | 5.J.237.229; | 5.J.237.230; | 5.J.237.231; |
5.J.237.236; | 5.J.237.237; | 5.J.237.238; | 5.J.237.239; |
5.J.237.154; | 5.J.237.157; | 5.J.237.166; | 5.J.237.169; |
5.J.237.172; | 5.J.237.175; | 5.J.237.240; | 5.J.237.244; |
5.J.238.228; | 5.J.238.229; | 5.J.238.230; | 5.J.238.231; |
5.J.238.236; | 5.J.238.237; | 5.J.238.238; | 5.J.238.239; |
5.J.238.154; | 5.J.238.157; | 5.J.238.166; | 5.J.238.169; |
5.J.238.172; | 5.J.238.175; | 5.J.238.240; | 5.J.238.244; |
5.J.239.228; | 5.J.239.229; | 5.J.239.230; | 5.J.239.231; |
5.J.239.236; | 5.J.239.237; | 5.J.239.238; | 5.J.239.239; |
5.J.239.154; | 5.J.239.157; | 5.J.239.166; | 5.J.239.169; |
5.J.239.172; | 5.J.239.175; | 5.J.239.240; | 5.J.239.244; |
5.J.154.228; | 5.J.154.229; | 5.J.154.230; | 5.J.154.231; |
5.J.154.236; | 5.J.154.237; | 5.J.154.238; | 5.J.154.239; |
5.J.154.154; | 5.J.154.157; | 5.J.154.166; | 5.J.154.169; |
5.J.154.172; | 5.J.154.175; | 5.J.154.240; | 5.J.154.244; |
5.J.157.228; | 5.J.157.229; | 5.J.157.230; | 5.J.157.231; |
5.J.157.236; | 5.J.157.237; | 5.J.157.238; | 5.J.157.239; |
5.J.157.154; | 5.J.157.157; | 5.J.157.166; | 5.J.157.169; |
5.J.157.172; | 5.J.157.175; | 5.J.157.240; | 5.J.157.244; |
5.J.166.228; | 5.J.166.229; | 5.J.166.230; | 5.J.166.231; |
5.J.166.236; | 5.J.166.237; | 5.J.166.238; | 5.J.166.239; |
5.J.166.154; | 5.J.166.157; | 5.J.166.166; | 5.J.166.169; |
5.J.166.172; | 5.J.166.175; | 5.J.166.240; | 5.J.166.244; |
5.J.169.228; | 5.J.169.229; | 5.J.169.230; | 5.J.169.231; |
5.J.169.236; | 5.J.169.237; | 5.J.169.238; | 5.J.169.239; |
5.J.169.154; | 5.J.169.157; | 5.J.169.166; | 5.J.169.169; |
5.J.169.172; | 5.J.169.175; | 5.J.169.240; | 5.J.169.244; |
5.J.172.228; | 5.J.172.229; | 5.J.172.230; | 5.J.172.231; |
5.J.172.236; | 5.J.172.237; | 5.J.172.238; | 5.J.172.239; |
5.J.172.154; | 5.J.172.157; | 5.J.172.166; | 5.J.172.169; |
5.J.172.172; | 5.J.172.175; | 5.J.172.240; | 5.J.172.244; |
5.J.175.228; | 5.J.175.229; | 5.J.175.230; | 5.J.175.231; |
5.J.175.236; | 5.J.175.237; | 5.J.175.238; | 5.J.175.239; |
5.J.175.154; | 5.J.175.157; | 5.J.175.166; | 5.J.175.169; |
5.J.175.172; | 5.J.175.175; | 5.J.175.240; | 5.J.175.244; |
5.J.240.228; | 5.J.240.229; | 5.J.240.230; | 5.J.240.231; |
5.J.240.236; | 5.J.240.237; | 5.J.240.238; | 5.J.240.239; |
5.J.240.154; | 5.J.240.157; | 5.J.240.166; | 5.J.240.169; |
5.J.240.172; | 5.J.240.175; | 5.J.240.240; | 5.J.240.244; |
5.J.244.228; | 5.J.244.229; | 5.J.244.230; | 5.J.244.231; |
5.J.244.236; | 5.J.244.237; | 5.J.244.238; | 5.J.244.239; |
5.J.244.154; | 5.J.244.157; | 5.J.244.166; | 5.J.244.169; |
5.J.244.172; | 5.J.244.175; | 5.J.244.240; | 5.J.244.244; |
5.L的前体药物
5.L.228.228; | 5.L.228.229; | 5.L.228.230; | 5.L.228.231; |
5.L.228.236; | 5.L.228.237; | 5.L.228.238; | 5.L.228.239; |
5.L.228.154; | 5.L.228.157; | 5.L.228.166; | 5.L.228.169; |
5.L.228.172; | 5.L.228.175; | 5.L.228.240; | 5.L.228.244; |
5.L.229.228; | 5.L.229.229; | 5.L.229.230; | 5.L.229.231; |
5.L.229.236; | 5.L.229.237; | 5.L.229.238; | 5.L.229.239; |
5.L.229.154; | 5.L.229.157; | 5.L.229.166; | 5.L.229.169; |
5.L.229.172; | 5.L.229.175; | 5.L.229.240; | 5.L.229.244; |
5.L.230.228; | 5.L.230.229; | 5.L.230.230; | 5.L.230.231; |
5.L.230.236; | 5.L.230.237; | 5.L.230.238; | 5.L.230.239; |
5.L.230.154; | 5.L.230.157; | 5.L.230.166; | 5.L.230.169; |
5.L.230.172; | 5.L.230.175; | 5.L.230.240; | 5.L.230.244; |
5.L.231.228; | 5.L.231.229; | 5.L.231.230; | 5.L.231.231; |
5.L.231.236; | 5.L.231.237; | 5.L.231.238; | 5.L.231.239; |
5.L.231.154; | 5.L.231.157; | 5.L.231.166; | 5.L.231.169; |
5.L.231.172; | 5.L.231.175; | 5.L.231.240; | 5.L.231.244; |
5.L.236.228; | 5.L.236.229; | 5.L.236.230; | 5.L.236.231; |
5.L.236.236; | 5.L.236.237; | 5.L.236.238; | 5.L.236.239; |
5.L.236.154; | 5.L.236.157; | 5.L.236.166; | 5.L.236.169; |
5.L.236.172; | 5.L.236.175; | 5.L.236.240; | 5.L.236.244; |
5.L.237.228; | 5.L.237.229; | 5.L.237.230; | 5.L.237.231; |
5.L.237.236; | 5.L.237.237; | 5.L.237.238; | 5.L.237.239; |
5.L.237.154; | 5.L.237.157; | 5.L.237.166; | 5.L.237.169; |
5.L.237.172; | 5.L.237.175; | 5.L.237.240; | 5.L.237.244; |
5.L.238.228; | 5.L.238.229; | 5.L.238.230; | 5.L.238.231; |
5.L.238.236; | 5.L.238.237; | 5.L.238.238; | 5.L.238.239; |
5.L.238.154; | 5.L.238.157; | 5.L.238.166; | 5.L.238.169; |
5.L.238.172; | 5.L.238.175; | 5.L.238.240; | 5.L.238.244; |
5.L.239.228; | 5.L.239.229; | 5.L.239.230; | 5.L.239.231; |
5.L.239.236; | 5.L.239.237; | 5.L.239.238; | 5.L.239.239; |
5.L.239.154; | 5.L.239.157; | 5.L.239.166; | 5.L.239.169; |
5.L.239.172; | 5.L.239.175; | 5.L.239.240; | 5.L.239.244; |
5.L.154.228; | 5.L.154.229; | 5.L.154.230; | 5.L.154.231; |
5.L.154.236; | 5.L.154.237; | 5.L.154.238; | 5.L.154.239; |
5.L.154.154; | 5.L.154.157; | 5.L.154.166; | 5.L.154.169; |
5.L.154.172; | 5.L.154.175; | 5.L.154.240; | 5.L.154.244; |
5.L.157.228; | 5.L.157.229; | 5.L.157.230; | 5.L.157.231; |
5.L.157.236; | 5.L.157.237; | 5.L.157.238; | 5.L.157.239; |
5.L.157.154; | 5.L.157.157; | 5.L.157.166; | 5.L.157.169; |
5.L.157.172; | 5.L.157.175; | 5.L.157.240; | 5.L.157.244; |
5.L.166.228; | 5.L.166.229; | 5.L.166.230; | 5.L.166.231; |
5.L.166.236; | 5.L.166.237; | 5.L.166.238; | 5.L.166.239; |
5.L.166.154; | 5.L.166.157; | 5.L.166.166; | 5.L.166.169; |
5.L.166.172; | 5.L.166.175; | 5.L.166.240; | 5.L.166.244; |
5.L.169.228; | 5.L.169.229; | 5.L.169.230; | 5.L.169.231; |
5.L.169.236; | 5.L.169.237; | 5.L.169.238; | 5.L.169.239; |
5.L.169.154; | 5.L.169.157; | 5.L.169.166; | 5.L.169.169; |
5.L.169.172; | 5.L.169.175; | 5.L.169.240; | 5.L.169.244; |
5.L.172.228; | 5.L.172.229; | 5.L.172.230; | 5.L.172.231; |
5.L.172.236; | 5.L.172.237; | 5.L.172.238; | 5.L.172.239; |
5.L.172.154; | 5.L.172.157; | 5.L.172.166; | 5.L.172.169; |
5.L.172.172; | 5.L.172.175; | 5.L.172.240; | 5.L.172.244; |
5.L.175.228; | 5.L.175.229; | 5.L.175.230; | 5.L.175.231; |
5.L.175.236; | 5.L.175.237; | 5.L.175.238; | 5.L.175.239; |
5.L.175.154; | 5.L.175.157; | 5.L.175.166; | 5.L.175.169; |
5.L.175.172; | 5.L.175.175; | 5.L.175.240; | 5.L.175.244; |
5.L.240.228; | 5.L.240.229; | 5.L.240.230; | 5.L.240.231; |
5.L.240.236; | 5.L.240.237; | 5.L.240.238; | 5.L.240.239; |
5.L.240.154; | 5.L.240.157; | 5.L.240.166; | 5.L.240.169; |
5.L.240.172; | 5.L.240.175; | 5.L.240.240; | 5.L.240.244; |
5.L.244.228; | 5.L.244.229; | 5.L.244.230; | 5.L.244.231; |
5.L.244.236; | 5.L.244.237; | 5.L.244.238; | 5.L.244.239; |
5.L.244.154; | 5.L.244.157; | 5.L.244.166; | 5.L.244.169; |
5.L.244.172; | 5.L.244.175; | 5.L.244.240; | 5.L.244.244; |
5.O的前体药物
5.O.228.228; | 5.O.228.229; | 5.O.228.230; | 5.O.228.231; |
5.O.228.236; | 5.O.228.237; | 5.O.228.238; | 5.O.228.239; |
5.O.228.154; | 5.O.228.157; | 5.O.228.166; | 5.O.228.169; |
5.O.228.172; | 5.O.228.175; | 5.O.228.240; | 5.O.228.244; |
5.O.229.228; | 5.O.229.229; | 5.O.229.230; | 5.O.229.231; |
5.O.229.236; | 5.O.229.237; | 5.O.229.238; | 5.O.229.239; |
5.O.229.154; | 5.O.229.157; | 5.O.229.166; | 5.O.229.169; |
5.O.229.172; | 5.O.229.175; | 5.O.229.240; | 5.O.229.244; |
5.O.230.228; | 5.O.230.229; | 5.O.230.230; | 5.O.230.231; |
5.O.230.236; | 5.O.230.237; | 5.O.230.238; | 5.O.230.239; |
5.O.230.154; | 5.O.230.157; | 5.O.230.166; | 5.O.230.169; |
5.O.230.172; | 5.O.230.175; | 5.O.230.240; | 5.O.230.244; |
5.O.231.228; | 5.O.231.229; | 5.O.231.230; | 5.O.231.231; |
5.O.231.236; | 5.O.231.237; | 5.O.231.238; | 5.O.231.239; |
5.O.231.154; | 5.O.231.157; | 5.O.231.166; | 5.O.231.169; |
5.O.231.172; | 5.O.231.175; | 5.O.231.240; | 5.O.231.244; |
5.O.236.228; | 5.O.236.229; | 5.O.236.230; | 5.O.236.231; |
5.O.236.236; | 5.O.236.237; | 5.O.236.238; | 5.O.236.239; |
5.O.236.154; | 5.O.236.157; | 5.O.236.166; | 5.O.236.169; |
5.O.236.172; | 5.O.236.175; | 5.O.236.240; | 5.O.236.244; |
5.O.237.228; | 5.O.237.229; | 5.O.237.230; | 5.O.237.231; |
5.O.237.236; | 5.O.237.237; | 5.O.237.238; | 5.O.237.239; |
5.O.237.154; | 5.O.237.157; | 5.O.237.166; | 5.O.237.169; |
5.O.237.172; | 5.O.237.175; | 5.O.237.240; | 5.O.237.244; |
5.O.238.228; | 5.O.238.229; | 5.O.238.230; | 5.O.238.231; |
5.O.238.236; | 5.O.238.237; | 5.O.238.238; | 5.O.238.239; |
5.O.238.154; | 5.O.238.157; | 5.O.238.166; | 5.O.238.169; |
5.O.238.172; | 5.O.238.175; | 5.O.238.240; | 5.O.238.244; |
5.O.239.228; | 5.O.239.229; | 5.O.239.230; | 5.O.239.231; |
5.O.239.236; | 5.O.239.237; | 5.O.239.238; | 5.O.239.239; |
5.O.239.154; | 5.O.239.157; | 5.O.239.166; | 5.O.239.169; |
5.O.239.172; | 5.O.239.175; | 5.O.239.240; | 5.O.239.244; |
5.O.154.228; | 5.O.154.229; | 5.O.154.230; | 5.O.154.231; |
5.O.154.236; | 5.O.154.237; | 5.O.154.238; | 5.O.154.239; |
5.O.154.154; | 5.O.154.157; | 5.O.154.166; | 5.O.154.169; |
5.O.154.172; | 5.O.154.175; | 5.O.154.240; | 5.O.154.244; |
5.O.157.228; | 5.O.157.229; | 5.O.157.230; | 5.O.157.231; |
5.O.157.236; | 5.O.157.237; | 5.O.157.238; | 5.O.157.239; |
5.O.157.154; | 5.O.157.157; | 5.O.157.166; | 5.O.157.169; |
5.O.157.172; | 5.O.157.175; | 5.O.157.240; | 5.O.157.244; |
5.O.166.228; | 5.O.166.229; | 5.O.166.230; | 5.O.166.231; |
5.O.166.236; | 5.O.166.237; | 5.O.166.238; | 5.O.166.239; |
5.O.166.154; | 5.O.166.157; | 5.O.166.166; | 5.O.166.169; |
5.O.166.172; | 5.O.166.175; | 5.O.166.240; | 5.O.166.244; |
5.O.169.228; | 5.O.169.229; | 5.O.169.230; | 5.O.169.231; |
5.O.169.236; | 5.O.169.237; | 5.O.169.238; | 5.O.169.239; |
5.O.169.154; | 5.O.169.157; | 5.O.169.166; | 5.O.169.169; |
5.O.169.172; | 5.O.169.175; | 5.O.169.240; | 5.O.169.244; |
5.O.172.228; | 5.O.172.229; | 5.O.172.230; | 5.O.172.231; |
5.O.172.236; | 5.O.172.237; | 5.O.172.238; | 5.O.172.239; |
5.O.172.154; | 5.O.172.157; | 5.O.172.166; | 5.O.172.169; |
5.O.172.172; | 5.O.172.175; | 5.O.172.240; | 5.O.172.244; |
5.O.175.228; | 5.O.175.229; | 5.O.175.230; | 5.O.175.231; |
5.O.175.236; | 5.O.175.237; | 5.O.175.238; | 5.O.175.239; |
5.O.175.154; | 5.O.175.157; | 5.O.175.166; | 5.O.175.169; |
5.O.175.172; | 5.O.175.175; | 5.O.175.240; | 5.O.175.244; |
5.O.240.228; | 5.O.240.229; | 5.O.240.230; | 5.O.240.231; |
5.O.240.236; | 5.O.240.237; | 5.O.240.238; | 5.O.240.239; |
5.O.240.154; | 5.O.240.157; | 5.O.240.166; | 5.O.240.169; |
5.O.240.172; | 5.O.240.175; | 5.O.240.240; | 5.O.240.244; |
5.O.244.228; | 5.O.244.229; | 5.O.244.230; | 5.O.244.231; |
5.O.244.236; | 5.O.244.237; | 5.O.244.238; | 5.O.244.239; |
5.O.244.154; | 5.O.244.157; | 5.O.244.166; | 5.O.244.169; |
5.O.244.172; | 5.O.244.175; | 5.O.244.240; | 5.O.244.244; |
5.P的前体药物
5.P.228.228; | 5.P.228.229; | 5.P.228.230; | 5.P.228.231; |
5.P.228.236; | 5.P.228.237; | 5.P.228.238; | 5.P.228.239; |
5.P.228.154; | 5.P.228.157; | 5.P.228.166; | 5.P.228.169; |
5.P.228.172; | 5.P.228.175; | 5.P.228.240; | 5.P.228.244; |
5.P.229.228; | 5.P.229.229; | 5.P.229.230; | 5.P.229.231; |
5.P.229.236; | 5.P.229.237; | 5.P.229.238; | 5.P.229.239; |
5.P.229.154; | 5.P.229.157; | 5.P.229.166; | 5.P.229.169; |
5.P.229.172; | 5.P.229.175; | 5.P.229.240; | 5.P.229.244; |
5.P.230.228; | 5.P.230.229; | 5.P.230.230; | 5.P.230.231; |
5.P.230.236; | 5.P.230.237; | 5.P.230.238; | 5.P.230.239; |
5.P.230.154; | 5.P.230.157; | 5.P.230.166; | 5.P.230.169; |
5.P.230.172; | 5.P.230.175; | 5.P.230.240; | 5.P.230.244; |
5.P.231.228; | 5.P.231.229; | 5.P.231.230; | 5.P.231.231; |
5.P.231.236; | 5.P.231.237; | 5.P.231.238; | 5.P.231.239; |
5.P.231.154; | 5.P.231.157; | 5.P.231.166; | 5.P.231.169; |
5.P.231.172; | 5.P.231.175; | 5.P.231.240; | 5.P.231.244; |
5.P.236.228; | 5.P.236.229; | 5.P.236.230; | 5.P.236.231; |
5.P.236.236; | 5.P.236.237; | 5.P.236.238; | 5.P.236.239; |
5.P.236.154; | 5.P.236.157; | 5.P.236.166; | 5.P.236.169; |
5.P.236.172; | 5.P.236.175; | 5.P.236.240; | 5.P.236.244; |
5.P.237.228; | 5.P.237.229; | 5.P.237.230; | 5.P.237.231; |
5.P.237.236; | 5.P.237.237; | 5.P.237.238; | 5.P.237.239; |
5.P.237.154; | 5.P.237.157; | 5.P.237.166; | 5.P.237.169; |
5.P.237.172; | 5.P.237.175; | 5.P.237.240; | 5.P.237.244; |
5.P.238.228; | 5.P.238.229; | 5.P.238.230; | 5.P.238.231; |
5.P.238.236; | 5.P.238.237; | 5.P.238.238; | 5.P.238.239; |
5.P.238.154; | 5.P.238.157; | 5.P.238.166; | 5.P.238.169; |
5.P.238.172; | 5.P.238.175; | 5.P.238.240; | 5.P.238.244; |
5.P.239.228; | 5.P.239.229; | 5.P.239.230; | 5.P.239.231; |
5.P.239.236; | 5.P.239.237; | 5.P.239.238; | 5.P.239.239; |
5.P.239.154; | 5.P.239.157; | 5.P.239.166; | 5.P.239.169; |
5.P.239.172; | 5.P.239.175; | 5.P.239.240; | 5.P.239.244; |
5.P.154.228; | 5.P.154.229; | 5.P.154.230; | 5.P.154.231; |
5.P.154.236; | 5.P.154.237; | 5.P.154.238; | 5.P.154.239; |
5.P.154.154; | 5.P.154.157; | 5.P.154.166; | 5.P.154.169; |
5.P.154.172; | 5.P.154.175; | 5.P.154.240; | 5.P.154.244; |
5.P.157.228; | 5.P.157.229; | 5.P.157.230; | 5.P.157.231; |
5.P.157.236; | 5.P.157.237; | 5.P.157.238; | 5.P.157.239; |
5.P.157.154; | 5.P.157.157; | 5.P.157.166; | 5.P.157.169; |
5.P.157.172; | 5.P.157.175; | 5.P.157.240; | 5.P.157.244; |
5.P.166.228; | 5.P.166.229; | 5.P.166.230; | 5.P.166.231; |
5.P.166.236; | 5.P.166.237; | 5.P.166.238; | 5.P.166.239; |
5.P.166.154; | 5.P.166.157; | 5.P.166.166; | 5.P.166.169; |
5.P.166.172; | 5.P.166.175; | 5.P.166.240; | 5.P.166.244; |
5.P.169.228; | 5.P.169.229; | 5.P.169.230; | 5.P.169.231; |
5.P.169.236; | 5.P.169.237; | 5.P.169.238; | 5.P.169.239; |
5.P.169.154; | 5.P.169.157; | 5.P.169.166; | 5.P.169.169; |
5.P.169.172; | 5.P.169.175; | 5.P.169.240; | 5.P.169.244; |
5.P.172.228; | 5.P.172.229; | 5.P.172.230; | 5.P.172.231; |
5.P.172.236; | 5.P.172.237; | 5.P.172.238; | 5.P.172.239; |
5.P.172.154; | 5.P.172.157; | 5.P.172.166; | 5.P.172.169; |
5.P.172.172; | 5.P.172.175; | 5.P.172.240; | 5.P.172.244; |
5.P.175.228; | 5.P.175.229; | 5.P.175.230; | 5.P.175.231; |
5.P.175.236; | 5.P.175.237; | 5.P.175.238; | 5.P.175.239; |
5.P.175.154; | 5.P.175.157; | 5.P.175.166; | 5.P.175.169; |
5.P.175.172; | 5.P.175.175; | 5.P.175.240; | 5.P.175.244; |
5.P.240.228; | 5.P.240.229; | 5.P.240.230; | 5.P.240.231; |
5.P.240.236; | 5.P.240.237; | 5.P.240.238; | 5.P.240.239; |
5.P.240.154; | 5.P.240.157; | 5.P.240.166; | 5.P.240.169; |
5.P.240.172; | 5.P.240.175; | 5.P.240.240; | 5.P.240.244; |
5.P.244.228; | 5.P.244.229; | 5.P.244.230; | 5.P.244.231; |
5.P.244.236; | 5.P.244.237; | 5.P.244.238; | 5.P.244.239; |
5.P.244.154; | 5.P.244.157; | 5.P.244.166; | 5.P.244.169; |
5.P.244.172; | 5.P.244.175; | 5.P.244.240; | 5.P.244.244; |
5.U的前体药物
5.U.228.228; | 5.U.228.229; | 5.U.228.230; | 5.U.228.231; |
5.U.228.236; | 5.U.228.237; | 5.U.228.238; | 5.U.228.239; |
5.U.228.154; | 5.U.228.157; | 5.U.228.166; | 5.U.228.169; |
5.U.228.172; | 5.U.228.175; | 5.U.228.240; | 5.U.228.244; |
5.U.229.228; | 5.U.229.229; | 5.U.229.230; | 5.U.229.231; |
5.U.229.236; | 5.U.229.237; | 5.U.229.238; | 5.U.229.239; |
5.U.229.154; | 5.U.229.157; | 5.U.229.166; | 5.U.229.169; |
5.U.229.172; | 5.U.229.175; | 5.U.229.240; | 5.U.229.244; |
5.U.230.228; | 5.U.230.229; | 5.U.230.230; | 5.U.230.231; |
5.U.230.236; | 5.U.230.237; | 5.U.230.238; | 5.U.230.239; |
5.U.230.154; | 5.U.230.157; | 5.U.230.166; | 5.U.230.169; |
5.U.230.172; | 5.U.230.175; | 5.U.230.240; | 5.U.230.244; |
5.U.231.228; | 5.U.231.229; | 5.U.231.230; | 5.U.231.231; |
5.U.231.236; | 5.U.231.237; | 5.U.231.238; | 5.U.231.239; |
5.U.231.154; | 5.U.231.157; | 5.U.231.166; | 5.U.231.169; |
5.U.231.172; | 5.U.231.175; | 5.U.231.240; | 5.U.231.244; |
5.U.236.228; | 5.U.236.229; | 5.U.236.230; | 5.U.236.231; |
5.U.236.236; | 5.U.236.237; | 5.U.236.238; | 5.U.236.239; |
5.U.236.154; | 5.U.236.157; | 5.U.236.166; | 5.U.236.169; |
5.U.236.172; | 5.U.236.175; | 5.U.236.240; | 5.U.236.244; |
5.U.237.228; | 5.U.237.229; | 5.U.237.230; | 5.U.237.231; |
5.U.237.236; | 5.U.237.237; | 5.U.237.238; | 5.U.237.239; |
5.U.237.154; | 5.U.237.157; | 5.U.237.166; | 5.U.237.169; |
5.U.237.172; | 5.U.237.175; | 5.U.237.240; | 5.U.237.244; |
5.U.238.228; | 5.U.238.229; | 5.U.238.230; | 5.U.238.231; |
5.U.238.236; | 5.U.238.237; | 5.U.238.238; | 5.U.238.239; |
5.U.238.154; | 5.U.238.157; | 5.U.238.166; | 5.U.238.169; |
5.U.238.172; | 5.U.238.175; | 5.U.238.240; | 5.U.238.244; |
5.U.239.228; | 5.U.239.229; | 5.U.239.230; | 5.U.239.231; |
5.U.239.236; | 5.U.239.237; | 5.U.239.238; | 5.U.239.239; |
5.U.239.154; | 5.U.239.157; | 5.U.239.166; | 5.U.239.169; |
5.U.239.172; | 5.U.239.175; | 5.U.239.240; | 5.U.239.244; |
5.U.154.228; | 5.U.154.229; | 5.U.154.230; | 5.U.154.231; |
5.U.154.236; | 5.U.154.237; | 5.U.154.238; | 5.U.154.239; |
5.U.154.154; | 5.U.154.157; | 5.U.154.166; | 5.U.154.169; |
5.U.154.172; | 5.U.154.175; | 5.U.154.240; | 5.U.154.244; |
5.U.157.228; | 5.U.157.229; | 5.U.157.230; | 5.U.157.231; |
5.U.157.236; | 5.U.157.237; | 5.U.157.238; | 5.U.157.239; |
5.U.157.154; | 5.U.157.157; | 5.U.157.166; | 5.U.157.169; |
5.U.157.172; | 5.U.157.175; | 5.U.157.240; | 5.U.157.244; |
5.U.166.228; | 5.U.166.229; | 5.U.166.230; | 5.U.166.231; |
5.U.166.236; | 5.U.166.237; | 5.U.166.238; | 5.U.166.239; |
5.U.166.154; | 5.U.166.157; | 5.U.166.166; | 5.U.166.169; |
5.U.166.172; | 5.U.166.175; | 5.U.166.240; | 5.U.166.244; |
5.U.169.228; | 5.U.169.229; | 5.U.169.230; | 5.U.169.231; |
5.U.169.236; | 5.U.169.237; | 5.U.169.238; | 5.U.169.239; |
5.U.169.154; | 5.U.169.157; | 5.U.169.166; | 5.U.169.169; |
5.U.169.172; | 5.U.169.175; | 5.U.169.240; | 5.U.169.244; |
5.U.172.228; | 5.U.172.229; | 5.U.172.230; | 5.U.172.231; |
5.U.172.236; | 5.U.172.237; | 5.U.172.238; | 5.U.172.239; |
5.U.172.154; | 5.U.172.157; | 5.U.172.166; | 5.U.172.169; |
5.U.172.172; | 5.U.172.175; | 5.U.172.240; | 5.U.172.244; |
5.U.175.228; | 5.U.175.229; | 5.U.175.230; | 5.U.175.231; |
5.U.175.236; | 5.U.175.237; | 5.U.175.238; | 5.U.175.239; |
5.U.175.154; | 5.U.175.157; | 5.U.175.166; | 5.U.175.169; |
5.U.175.172; | 5.U.175.175; | 5.U.175.240; | 5.U.175.244; |
5.U.240.228; | 5.U.240.229; | 5.U.240.230; | 5.U.240.231; |
5.U.240.236; | 5.U.240.237; | 5.U.240.238; | 5.U.240.239; |
5.U.240.154; | 5.U.240.157; | 5.U.240.166; | 5.U.240.169; |
5.U.240.172; | 5.U.240.175; | 5.U.240.240; | 5.U.240.244; |
5.U.244.228; | 5.U.244.229; | 5.U.244.230; | 5.U.244.231; |
5.U.244.236; | 5.U.244.237; | 5.U.244.238; | 5.U.244.239; |
5.U.244.154; | 5.U.244.157; | 5.U.244.166; | 5.U.244.169; |
5.U.244.172; | 5.U.244.175; | 5.U.244.240; | 5.U.244.244; |
5.W的前体药物
5.W.228.228; | 5.W.228.229; | 5.W.228.230; | 5.W.228.231; |
5.W.228.236; | 5.W.228.237; | 5.W.228.238; | 5.W.228.239; |
5.W.228.154; | 5.W.228.157; | 5.W.228.166; | 5.W.228.169; |
5.W.228.172; | 5.W.228.175; | 5.W.228.240; | 5.W.228.244; |
5.W.229.228; | 5.W.229.229; | 5.W.229.230; | 5.W.229.231; |
5.W.229.236; | 5.W.229.237; | 5.W.229.238; | 5.W.229.239; |
5.W.229.154; | 5.W.229.157; | 5.W.229.166; | 5.W.229.169; |
5.W.229.172; | 5.W.229.175; | 5.W.229.240; | 5.W.229.244; |
5.W.230.228; | 5.W.230.229; | 5.W.230.230; | 5.W.230.231; |
5.W.230.236; | 5.W.230.237; | 5.W.230.238; | 5.W.230.239; |
5.W.230.154; | 5.W.230.157; | 5.W.230.166; | 5.W.230.169; |
5.W.230.172; | 5.W.230.175; | 5.W.230.240; | 5.W.230.244; |
5.W.231.228; | 5.W.231.229; | 5.W.231.230; | 5.W.231.231; |
5.W.231.236; | 5.W.231.237; | 5.W.231.238; | 5.W.231.239; |
5.W.231.154; | 5.W.231.157; | 5.W.231.166; | 5.W.231.169; |
5.W.231.172; | 5.W.231.175; | 5.W.231.240; | 5.W.231.244; |
5.W.236.228; | 5.W.236.229; | 5.W.236.230; | 5.W.236.231; |
5.W.236.236; | 5.W.236.237; | 5.W.236.238; | 5.W.236.239; |
5.W.236.154; | 5.W.236.157; | 5.W.236.166; | 5.W.236.169; |
5.W.236.172; | 5.W.236.175; | 5.W.236.240; | 5.W.236.244; |
5.W.237.228; | 5.W.237.229; | 5.W.237.230; | 5.W.237.231; |
5.W.237.236; | 5.W.237.237; | 5.W.237.238; | 5.W.237.239; |
5.W.237.154; | 5.W.237.157; | 5.W.237.166; | 5.W.237.169; |
5.W.237.172; | 5.W.237.175; | 5.W.237.240; | 5.W.237.244; |
5.W.238.228; | 5.W.238.229; | 5.W.238.230; | 5.W.238.231; |
5.W.238.236; | 5.W.238.237; | 5.W.238.238; | 5.W.238.239; |
5.W.238.154; | 5.W.238.157; | 5.W.238.166; | 5.W.238.169; |
5.W.238.172; | 5.W.238.175; | 5.W.238.240; | 5.W.238.244; |
5.W.239.228; | 5.W.239.229; | 5.W.239.230; | 5.W.239.231; |
5.W.239.236; | 5.W.239.237; | 5.W.239.238; | 5.W.239.239; |
5.W.239.154; | 5.W.239.157; | 5.W.239.166; | 5.W.239.169; |
5.W.239.172; | 5.W.239.175; | 5.W.239.240; | 5.W.239.244; |
5.W.154.228; | 5.W.154.229; | 5.W.154.230; | 5.W.154.231; |
5.W.154.236; | 5.W.154.237; | 5.W.154.238; | 5.W.154.239; |
5.W.154.154; | 5.W.154.157; | 5.W.154.166; | 5.W.154.169; |
5.W.154.172; | 5.W.154.175; | 5.W.154.240; | 5.W.154.244; |
5.W.157.228; | 5.W.157.229; | 5.W.157.230; | 5.W.157.231; |
5.W.157.236; | 5.W.157.237; | 5.W.157.238; | 5.W.157.239; |
5.W.157.154; | 5.W.157.157; | 5.W.157.166; | 5.W.157.169; |
5.W.157.172; | 5.W.157.175; | 5.W.157.240; | 5.W.157.244; |
5.W.166.228; | 5.W.166.229; | 5.W.166.230; | 5.W.166.231; |
5.W.166.236; | 5.W.166.237; | 5.W.166.238; | 5.W.166.239; |
5.W.166.154; | 5.W.166.157; | 5.W.166.166; | 5.W.166.169; |
5.W.166.172; | 5.W.166.175; | 5.W.166.240; | 5.W.166.244; |
5.W.169.228; | 5.W.169.229; | 5.W.169.230; | 5.W.169.231; |
5.W.169.236; | 5.W.169.237; | 5.W.169.238; | 5.W.169.239; |
5.W.169.154; | 5.W.169.157; | 5.W.169.166; | 5.W.169.169; |
5.W.169.172; | 5.W.169.175; | 5.W.169.240; | 5.W.169.244; |
5.W.172.228; | 5.W.172.229; | 5.W.172.230; | 5.W.172.231; |
5.W.172.236; | 5.W.172.237; | 5.W.172.238; | 5.W.172.239; |
5.W.172.154; | 5.W.172.157; | 5.W.172.166; | 5.W.172.169; |
5.W.172.172; | 5.W.172.175; | 5.W.172.240; | 5.W.172.244; |
5.W.175.228; | 5.W.175.229; | 5.W.175.230; | 5.W.175.231; |
5.W.175.236; | 5.W.175.237; | 5.W.175.238; | 5.W.175.239; |
5.W.175.154; | 5.W.175.157; | 5.W.175.166; | 5.W.175.169; |
5.W.175.172; | 5.W.175.175; | 5.W.175.240; | 5.W.175.244; |
5.W.240.228; | 5.W.240.229; | 5.W.240.230; | 5.W.240.231; |
5.W.240.236; | 5.W.240.237; | 5.W.240.238; | 5.W.240.239; |
5.W.240.154; | 5.W.240.157; | 5.W.240.166; | 5.W.240.169; |
5.W.240.172; | 5.W.240.175; | 5.W.240.240; | 5.W.240.244; |
5.W.244.228; | 5.W.244.229; | 5.W.244.230; | 5.W.244.231; |
5.W.244.236; | 5.W.244.237; | 5.W.244.238; | 5.W.244.239; |
5.W.244.154; | 5.W.244.157; | 5.W.244.166; | 5.W.244.169; |
5.W.244.172; | 5.W.244.175; | 5.W.244.240; | 5.W.244.244; |
5.Y的前体药物
5.Y.228.228; | 5.Y.228.229; | 5.Y.228.230; | 5.Y.228.231; |
5.Y.228.236; | 5.Y.228.237; | 5.Y.228.238; | 5.Y.228.239; |
5.Y.228.154; | 5.Y.228.157; | 5.Y.228.166; | 5.Y.228.169; |
5.Y.228.172; | 5.Y.228.175; | 5.Y.228.240; | 5.Y.228.244; |
5.Y.229.228; | 5.Y.229.229; | 5.Y.229.230; | 5.Y.229.231; |
5.Y.229.236; | 5.Y.229.237; | 5.Y.229.238; | 5.Y.229.239; |
5.Y.229.154; | 5.Y.229.157; | 5.Y.229.166; | 5.Y.229.169; |
5.Y.229.172; | 5.Y.229.175; | 5.Y.229.240; | 5.Y.229.244; |
5.Y.230.228; | 5.Y.230.229; | 5.Y.230.230; | 5.Y.230.231; |
5.Y.230.236; | 5.Y.230.237; | 5.Y.230.238; | 5.Y.230.239; |
5.Y.230.154; | 5.Y.230.157; | 5.Y.230.166; | 5.Y.230.169; |
5.Y.230.172; | 5.Y.230.175; | 5.Y.230.240; | 5.Y.230.244; |
5.Y.231.228; | 5.Y.231.229; | 5.Y.231.230; | 5.Y.231.231; |
5.Y.231.236; | 5.Y.231.237; | 5.Y.231.238; | 5.Y.231.239; |
5.Y.231.154; | 5.Y.231.157; | 5.Y.231.166; | 5.Y.231.169; |
5.Y.231.172; | 5.Y.231.175; | 5.Y.231.240; | 5.Y.231.244; |
5.Y.236.228; | 5.Y.236.229; | 5.Y.236.230; | 5.Y.236.231; |
5.Y.236.236; | 5.Y.236.237; | 5.Y.236.238; | 5.Y.236.239; |
5.Y.236.154; | 5.Y.236.157; | 5.Y.236.166; | 5.Y.236.169; |
5.Y.236.172; | 5.Y.236.175; | 5.Y.236.240; | 5.Y.236.244; |
5.Y.237.228; | 5.Y.237.229; | 5.Y.237.230; | 5.Y.237.231; |
5.Y.237.236; | 5.Y.237.237; | 5.Y.237.238; | 5.Y.237.239; |
5.Y.237.154; | 5.Y.237.157; | 5.Y.237.166; | 5.Y.237.169; |
5.Y.237.172; | 5.Y.237.175; | 5.Y.237.240; | 5.Y.237.244; |
5.Y.238.228; | 5.Y.238.229; | 5.Y.238.230; | 5.Y.238.231; |
5.Y.238.236; | 5.Y.238.237; | 5.Y.238.238; | 5.Y.238.239; |
5.Y.238.154; | 5.Y.238.157; | 5.Y.238.166; | 5.Y.238.169; |
5.Y.238.172; | 5.Y.238.175; | 5.Y.238.240; | 5.Y.238.244; |
5.Y.239.228; | 5.Y.239.229; | 5.Y.239.230; | 5.Y.239.231; |
5.Y.239.236; | 5.Y.239.237; | 5.Y.239.238; | 5.Y.239.239; |
5.Y.239.154; | 5.Y.239.157; | 5.Y.239.166; | 5.Y.239.169; |
5.Y.239.172; | 5.Y.239.175; | 5.Y.239.240; | 5.Y.239.244; |
5.Y.154.228; | 5.Y.154.229; | 5.Y.154.230; | 5.Y.154.231; |
5.Y.154.236; | 5.Y.154.237; | 5.Y.154.238; | 5.Y.154.239; |
5.Y.154.154; | 5.Y.154.157; | 5.Y.154.166; | 5.Y.154.169; |
5.Y.154.172; | 5.Y.154.175; | 5.Y.154.240; | 5.Y.154.244; |
5.Y.157.228; | 5.Y.157.229; | 5.Y.157.230; | 5.Y.157.231; |
5.Y.157.236; | 5.Y.157.237; | 5.Y.157.238; | 5.Y.157.239; |
5.Y.157.154; | 5.Y.157.157; | 5.Y.157.166; | 5.Y.157.169; |
5.Y.157.172; | 5.Y.157.175; | 5.Y.157.240; | 5.Y.157.244; |
5.Y.166.228; | 5.Y.166.229; | 5.Y.166.230; | 5.Y.166.231; |
5.Y.166.236; | 5.Y.166.237; | 5.Y.166.238; | 5.Y.166.239; |
5.Y.166.154; | 5.Y.166.157; | 5.Y.166.166; | 5.Y.166.169; |
5.Y.166.172; | 5.Y.166.175; | 5.Y.166.240; | 5.Y.166.244; |
5.Y.169.228; | 5.Y.169.229; | 5.Y.169.230; | 5.Y.169.231; |
5.Y.169.236; | 5.Y.169.237; | 5.Y.169.238; | 5.Y.169.239; |
5.Y.169.154; | 5.Y.169.157; | 5.Y.169.166; | 5.Y.169.169; |
5.Y.169.172; | 5.Y.169.175; | 5.Y.169.240; | 5.Y.169.244; |
5.Y.172.228; | 5.Y.172.229; | 5.Y.172.230; | 5.Y.172.231; |
5.Y.172.236; | 5.Y.172.237; | 5.Y.172.238; | 5.Y.172.239; |
5.Y.172.154; | 5.Y.172.157; | 5.Y.172.166; | 5.Y.172.169; |
5.Y.172.172; | 5.Y.172.175; | 5.Y.172.240; | 5.Y.172.244; |
5.Y.175.228; | 5.Y.175.229; | 5.Y.175.230; | 5.Y.175.231; |
5.Y.175.236; | 5.Y.175.237; | 5.Y.175.238; | 5.Y.175.239; |
5.Y.175.154; | 5.Y.175.157; | 5.Y.175.166; | 5.Y.175.169; |
5.Y.175.172; | 5.Y.175.175; | 5.Y.175.240; | 5.Y.175.244; |
5.Y.240.228; | 5.Y.240.229; | 5.Y.240.230; | 5.Y.240.231; |
5.Y.240.236; | 5.Y.240.237; | 5.Y.240.238; | 5.Y.240.239; |
5.Y.240.154; | 5.Y.240.157; | 5.Y.240.166; | 5.Y.240.169; |
5.Y.240.172; | 5.Y.240.175; | 5.Y.240.240; | 5.Y.240.244; |
5.Y.244.228; | 5.Y.244.229; | 5.Y.244.230; | 5.Y.244.231; |
5.Y.244.236; | 5.Y.244.237; | 5.Y.244.238; | 5.Y.244.239; |
5.Y.244.154; | 5.Y.244.157; | 5.Y.244.166; | 5.Y.244.169; |
5.Y.244.172; | 5.Y.244.175; | 5.Y.244.240; | 5.Y.244.244; |
6.B的前体药物
6.B.228.228; | 6.B.228.229; | 6.B.228.230; | 6.B.228.231; |
6.B.228.236; | 6.B.228.237; | 6.B.228.238; | 6.B.228.239; |
6.B.228.154; | 6.B.228.157; | 6.B.228.166; | 6.B.228.169; |
6.B.228.172; | 6.B.228.175; | 6.B.228.240; | 6.B.228.244; |
6.B.229.228; | 6.B.229.229; | 6.B.229.230; | 6.B.229.231; |
6.B.229.236; | 6.B.229.237; | 6.B.229.238; | 6.B.229.239; |
6.B.229.154; | 6.B.229.157; | 6.B.229.166; | 6.B.229.169; |
6.B.229.172; | 6.B.229.175; | 6.B.229.240; | 6.B.229.244; |
6.B.230.228; | 6.B.230.229; | 6.B.230.230; | 6.B.230.231; |
6.B.230.236; | 6.B.230.237; | 6.B.230.238; | 6.B.230.239; |
6.B.230.154; | 6.B.230.157; | 6.B.230.166; | 6.B.230.169; |
6.B.230.172; | 6.B.230.175; | 6.B.230.240; | 6.B.230.244; |
6.B.231.228; | 6.B.231.229; | 6.B.231.230; | 6.B.231.231; |
6.B.231.236; | 6.B.231.237; | 6.B.231.238; | 6.B.231.239; |
6.B.231.154; | 6.B.231.157; | 6.B.231.166; | 6.B.231.169; |
6.B.231.172; | 6.B.231.175; | 6.B.231.240; | 6.B.231.244; |
6.B.236.228; | 6.B.236.229; | 6.B.236.230; | 6.B.236.231; |
6.B.236.236; | 6.B.236.237; | 6.B.236.238; | 6.B.236.239; |
6.B.236.154; | 6.B.236.157; | 6.B.236.166; | 6.B.236.169; |
6.B.236.172; | 6.B.236.175; | 6.B.236.240; | 6.B.236.244; |
6.B.237.228; | 6.B.237.229; | 6.B.237.230; | 6.B.237.231; |
6.B.237.236; | 6.B.237.237; | 6.B.237.238; | 6.B.237.239; |
6.B.237.154; | 6.B.237.157; | 6.B.237.166; | 6.B.237.169; |
6.B.237.172; | 6.B.237.175; | 6.B.237.240; | 6.B.237.244; |
6.B.238.228; | 6.B.238.229; | 6.B.238.230; | 6.B.238.231; |
6.B.238.236; | 6.B.238.237; | 6.B.238.238; | 6.B.238.239; |
6.B.238.154; | 6.B.238.157; | 6.B.238.166; | 6.B.238.169; |
6.B.238.172; | 6.B.238.175; | 6.B.238.240; | 6.B.238.244; |
6.B.239.228; | 6.B.239.229; | 6.B.239.230; | 6.B.239.231; |
6.B.239.236; | 6.B.239.237; | 6.B.239.238; | 6.B.239.239; |
6.B.239.154; | 6.B.239.157; | 6.B.239.166; | 6.B.239.169; |
6.B.239.172; | 6.B.239.175; | 6.B.239.240; | 6.B.239.244; |
6.B.154.228; | 6.B.154.229; | 6.B.154.230; | 6.B.154.231; |
6.B.154.236; | 6.B.154.237; | 6.B.154.238; | 6.B.154.239; |
6.B.154.154; | 6.B.154.157; | 6.B.154.166; | 6.B.154.169; |
6.B.154.172; | 6.B.154.175; | 6.B.154.240; | 6.B.154.244; |
6.B.157.228; | 6.B.157.229; | 6.B.157.230; | 6.B.157.231; |
6.B.157.236; | 6.B.157.237; | 6.B.157.238; | 6.B.157.239; |
6.B.157.154; | 6.B.157.157; | 6.B.157.166; | 6.B.157.169; |
6.B.157.172; | 6.B.157.175; | 6.B.157.240; | 6.B.157.244; |
6.B.166.228; | 6.B.166.229; | 6.B.166.230; | 6.B.166.231; |
6.B.166.236; | 6.B.166.237; | 6.B.166.238; | 6.B.166.239; |
6.B.166.154; | 6.B.166.157; | 6.B.166.166; | 6.B.166.169; |
6.B.166.172; | 6.B.166.175; | 6.B.166.240; | 6.B.166.244; |
6.B.169.228; | 6.B.169.229; | 6.B.169.230; | 6.B.169.231; |
6.B.169.236; | 6.B.169.237; | 6.B.169.238; | 6.B.169.239; |
6.B.169.154; | 6.B.169.157; | 6.B.169.166; | 6.B.169.169; |
6.B.169.172; | 6.B.169.175; | 6.B.169.240; | 6.B.169.244; |
6.B.172.228; | 6.B.172.229; | 6.B.172.230; | 6.B.172.231; |
6.B.172.236; | 6.B.172.237; | 6.B.172.238; | 6.B.172.239; |
6.B.172.154; | 6.B.172.157; | 6.B.172.166; | 6.B.172.169; |
6.B.172.172; | 6.B.172.175; | 6.B.172.240; | 6.B.172.244; |
6.B.175.228; | 6.B.175.229; | 6.B.175.230; | 6.B.175.231; |
6.B.175.236; | 6.B.175.237; | 6.B.175.238; | 6.B.175.239; |
6.B.175.154; | 6.B.175.157; | 6.B.175.166; | 6.B.175.169; |
6.B.175.172; | 6.B.175.175; | 6.B.175.240; | 6.B.175.244; |
6.B.240.228; | 6.B.240.229; | 6.B.240.230; | 6.B.240.231; |
6.B.240.236; | 6.B.240.237; | 6.B.240.238; | 6.B.240.239; |
6.B.240.154; | 6.B.240.157; | 6.B.240.166; | 6.B.240.169; |
6.B.240.172; | 6.B.240.175; | 6.B.240.240; | 6.B.240.244; |
6.B.244.228; | 6.B.244.229; | 6.B.244.230; | 6.B.244.231; |
6.B.244.236; | 6.B.244.237; | 6.B.244.238; | 6.B.244.239; |
6.B.244.154; | 6.B.244.157; | 6.B.244.166; | 6.B.244.169; |
6.B.244.172; | 6.B.244.175; | 6.B.244.240; | 6.B.244.244; |
6.D的前体药物
6.D.228.228; | 6.D.228.229; | 6.D.228.230; | 6.D.228.231; |
6.D.228.236; | 6.D.228.237; | 6.D.228.238; | 6.D.228.239; |
6.D.228.154; | 6.D.228.157; | 6.D.228.166; | 6.D.228.169; |
6.D.228.172; | 6.D.228.175; | 6.D.228.240; | 6.D.228.244; |
6.D.229.228; | 6.D.229.229; | 6.D.229.230; | 6.D.229.231; |
6.D.229.236; | 6.D.229.237; | 6.D.229.238; | 6.D.229.239; |
6.D.229.154; | 6.D.229.157; | 6.D.229.166; | 6.D.229.169; |
6.D.229.172; | 6.D.229.175; | 6.D.229.240; | 6.D.229.244; |
6.D.230.228; | 6.D.230.229; | 6.D.230.230; | 6.D.230.231; |
6.D.230.236; | 6.D.230.237; | 6.D.230.238; | 6.D.230.239; |
6.D.230.154; | 6.D.230.157; | 6.D.230.166; | 6.D.230.169; |
6.D.230.172; | 6.D.230.175; | 6.D.230.240; | 6.D.230.244; |
6.D.231.228; | 6.D.231.229; | 6.D.231.230; | 6.D.231.231; |
6.D.231.236; | 6.D.231.237; | 6.D.231.238; | 6.D.231.239; |
6.D.231.154; | 6.D.231.157; | 6.D.231.166; | 6.D.231.169; |
6.D.231.172; | 6.D.231.175; | 6.D.231.240; | 6.D.231.244; |
6.D.236.228; | 6.D.236.229; | 6.D.236.230; | 6.D.236.231; |
6.D.236.236; | 6.D.236.237; | 6.D.236.238; | 6.D.236.239; |
6.D.236.154; | 6.D.236.157; | 6.D.236.166; | 6.D.236.169; |
6.D.236.172; | 6.D.236.175; | 6.D.236.240; | 6.D.236.244; |
6.D.237.228; | 6.D.237.229; | 6.D.237.230; | 6.D.237.231; |
6.D.237.236; | 6.D.237.237; | 6.D.237.238; | 6.D.237.239; |
6.D.237.154; | 6.D.237.157; | 6.D.237.166; | 6.D.237.169; |
6.D.237.172; | 6.D.237.175; | 6.D.237.240; | 6.D.237.244; |
6.D.238.228; | 6.D.238.229; | 6.D.238.230; | 6.D.238.231; |
6.D.238.236; | 6.D.238.237; | 6.D.238.238; | 6.D.238.239; |
6.D.238.154; | 6.D.238.157; | 6.D.238.166; | 6.D.238.169; |
6.D.238.172; | 6.D.238.175; | 6.D.238.240; | 6.D.238.244; |
6.D.239.228; | 6.D.239.229; | 6.D.239.230; | 6.D.239.231; |
6.D.239.236; | 6.D.239.237; | 6.D.239.238; | 6.D.239.239; |
6.D.239.154; | 6.D.239.157; | 6.D.239.166; | 6.D.239.169; |
6.D.239.172; | 6.D.239.175; | 6.D.239.240; | 6.D.239.244; |
6.D.154.228; | 6.D.154.229; | 6.D.154.230; | 6.D.154.231; |
6.D.154.236; | 6.D.154.237; | 6.D.154.238; | 6.D.154.239; |
6.D.154.154; | 6.D.154.157; | 6.D.154.166; | 6.D.154.169; |
6.D.154.172; | 6.D.154.175; | 6.D.154.240; | 6.D.154.244; |
6.D.157.228; | 6.D.157.229; | 6.D.157.230; | 6.D.157.231; |
6.D.157.236; | 6.D.157.237; | 6.D.157.238; | 6.D.157.239; |
6.D.157.154; | 6.D.157.157; | 6.D.157.166; | 6.D.157.169; |
6.D.157.172; | 6.D.157.175; | 6.D.157.240; | 6.D.157.244; |
6.D.166.228; | 6.D.166.229; | 6.D.166.230; | 6.D.166.231; |
6.D.166.236; | 6.D.166.237; | 6.D.166.238; | 6.D.166.239; |
6.D.166.154; | 6.D.166.157; | 6.D.166.166; | 6.D.166.169; |
6.D.166.172; | 6.D.166.175; | 6.D.166.240; | 6.D.166.244; |
6.D.169.228; | 6.D.169.229; | 6.D.169.230; | 6.D.169.231; |
6.D.169.236; | 6.D.169.237; | 6.D.169.238; | 6.D.169.239; |
6.D.169.154; | 6.D.169.157; | 6.D.169.166; | 6.D.169.169; |
6.D.169.172; | 6.D.169.175; | 6.D.169.240; | 6.D.169.244; |
6.D.172.228; | 6.D.172.229; | 6.D.172.230; | 6.D.172.231; |
6.D.172.236; | 6.D.172.237; | 6.D.172.238; | 6.D.172.239; |
6.D.172.154; | 6.D.172.157; | 6.D.172.166; | 6.D.172.169; |
6.D.172.172; | 6.D.172.175; | 6.D.172.240; | 6.D.172.244; |
6.D.175.228; | 6.D.175.229; | 6.D.175.230; | 6.D.175.231; |
6.D.175.236; | 6.D.175.237; | 6.D.175.238; | 6.D.175.239; |
6.D.175.154; | 6.D.175.157; | 6.D.175.166; | 6.D.175.169; |
6.D.175.172; | 6.D.175.175; | 6.D.175.240; | 6.D.175.244; |
6.D.240.228; | 6.D.240.229; | 6.D.240.230; | 6.D.240.231; |
6.D.240.236; | 6.D.240.237; | 6.D.240.238; | 6.D.240.239; |
6.D.240.154; | 6.D.240.157; | 6.D.240.166; | 6.D.240.169; |
6.D.240.172; | 6.D.240.175; | 6.D.240.240; | 6.D.240.244; |
6.D.244.228; | 6.D.244.229; | 6.D.244.230; | 6.D.244.231; |
6.D.244.236; | 6.D.244.237; | 6.D.244.238; | 6.D.244.239; |
6.D.244.154; | 6.D.244.157; | 6.D.244.166; | 6.D.244.169; |
6.D.244.172; | 6.D.244.175; | 6.D.244.240; | 6.D.244.244; |
6.E的前体药物
6.E.228.228; | 6.E.228.229; | 6.E.228.230; | 6.E.228.231; |
6.E.228.236; | 6.E.228.237; | 6.E.228.238; | 6.E.228.239; |
6.E.228.154; | 6.E.228.157; | 6.E.228.166; | 6.E.228.169; |
6.E.228.172; | 6.E.228.175; | 6.E.228.240; | 6.E.228.244; |
6.E.229.228; | 6.E.229.229; | 6.E.229.230; | 6.E.229.231; |
6.E.229.236; | 6.E.229.237; | 6.E.229.238; | 6.E.229.239; |
6.E.229.154; | 6.E.229.157; | 6.E.229.166; | 6.E.229.169; |
6.E.229.172; | 6.E.229.175; | 6.E.229.240; | 6.E.229.244; |
6.E.230.228; | 6.E.230.229; | 6.E.230.230; | 6.E.230.231; |
6.E.230.236; | 6.E.230.237; | 6.E.230.238; | 6.E.230.239; |
6.E.230.154; | 6.E.230.157; | 6.E.230.166; | 6.E.230.169; |
6.E.230.172; | 6.E.230.175; | 6.E.230.240; | 6.E.230.244; |
6.E.231.228; | 6.E.231.229; | 6.E.231.230; | 6.E.231.231; |
6.E.231.236; | 6.E.231.237; | 6.E.231.238; | 6.E.231.239; |
6.E.231.154; | 6.E.231.157; | 6.E.231.166; | 6.E.231.169; |
6.E.231.172; | 6.E.231.175; | 6.E.231.240; | 6.E.231.244; |
6.E.236.228; | 6.E.236.229; | 6.E.236.230; | 6.E.236.231; |
6.E.236.236; | 6.E.236.237; | 6.E.236.238; | 6.E.236.239; |
6.E.236.154; | 6.E.236.157; | 6.E.236.166; | 6.E.236.169; |
6.E.236.172; | 6.E.236.175; | 6.E.236.240; | 6.E.236.244; |
6.E.237.228; | 6.E.237.229; | 6.E.237.230; | 6.E.237.231; |
6.E.237.236; | 6.E.237.237; | 6.E.237.238; | 6.E.237.239; |
6.E.237.154; | 6.E.237.157; | 6.E.237.166; | 6.E.237.169; |
6.E.237.172; | 6.E.237.175; | 6.E.237.240; | 6.E.237.244; |
6.E.238.228; | 6.E.238.229; | 6.E.238.230; | 6.E.238.231; |
6.E.238.236; | 6.E.238.237; | 6.E.238.238; | 6.E.238.239; |
6.E.238.154; | 6.E.238.157; | 6.E.238.166; | 6.E.238.169; |
6.E.238.172; | 6.E.238.175; | 6.E.238.240; | 6.E.238.244; |
6.E.239.228; | 6.E.239.229; | 6.E.239.230; | 6.E.239.231; |
6.E.239.236; | 6.E.239.237; | 6.E.239.238; | 6.E.239.239; |
6.E.239.154; | 6.E.239.157; | 6.E.239.166; | 6.E.239.169; |
6.E.239.172; | 6.E.239.175; | 6.E.239.240; | 6.E.239.244; |
6.E.154.228; | 6.E.154.229; | 6.E.154.230; | 6.E.154.231; |
6.E.154.236; | 6.E.154.237; | 6.E.154.238; | 6.E.154.239; |
6.E.154.154; | 6.E.154.157; | 6.E.154.166; | 6.E.154.169; |
6.E.154.172; | 6.E.154.175; | 6.E.154.240; | 6.E.154.244; |
6.E.157.228; | 6.E.157.229; | 6.E.157.230; | 6.E.157.231; |
6.E.157.236; | 6.E.157.237; | 6.E.157.238; | 6.E.157.239; |
6.E.157.154; | 6.E.157.157; | 6.E.157.166; | 6.E.157.169; |
6.E.157.172; | 6.E.157.175; | 6.E.157.240; | 6.E.157.244; |
6.E.166.228; | 6.E.166.229; | 6.E.166.230; | 6.E.166.231; |
6.E.166.236; | 6.E.166.237; | 6.E.166.238; | 6.E.166.239; |
6.E.166.154; | 6.E.166.157; | 6.E.166.166; | 6.E.166.169; |
6.E.166.172; | 6.E.166.175; | 6.E.166.240; | 6.E.166.244; |
6.E.169.228; | 6.E.169.229; | 6.E.169.230; | 6.E.169.231; |
6.E.169.236; | 6.E.169.237; | 6.E.169.238; | 6.E.169.239; |
6.E.169.154; | 6.E.169.157; | 6.E.169.166; | 6.E.169.169; |
6.E.169.172; | 6.E.169.175; | 6.E.169.240; | 6.E.169.244; |
6.E.172.228; | 6.E.172.229; | 6.E.172.230; | 6.E.172.231; |
6.E.172.236; | 6.E.172.237; | 6.E.172.238; | 6.E.172.239; |
6.E.172.154; | 6.E.172.157; | 6.E.172.166; | 6.E.172.169; |
6.E.172.172; | 6.E.172.175; | 6.E.172.240; | 6.E.172.244; |
6.E.175.228; | 6.E.175.229; | 6.E.175.230; | 6.E.175.231; |
6.E.175.236; | 6.E.175.237; | 6.E.175.238; | 6.E.175.239; |
6.E.175.154; | 6.E.175.157; | 6.E.175.166; | 6.E.175.169; |
6.E.175.172; | 6.E.175.175; | 6.E.175.240; | 6.E.175.244; |
6.E.240.228; | 6.E.240.229; | 6.E.240.230; | 6.E.240.231; |
6.E.240.236; | 6.E.240.237; | 6.E.240.238; | 6.E.240.239; |
6.E.240.154; | 6.E.240.157; | 6.E.240.166; | 6.E.240.169; |
6.E.240.172; | 6.E.240.175; | 6.E.240.240; | 6.E.240.244; |
6.E.244.228; | 6.E.244.229; | 6.E.244.230; | 6.E.244.231; |
6.E.244.236; | 6.E.244.237; | 6.E.244.238; | 6.E.244.239; |
6.E.244.154; | 6.E.244.157; | 6.E.244.166; | 6.E.244.169; |
6.E.244.172; | 6.E.244.175; | 6.E.244.240; | 6.E.244.244; |
6.G的前体药物
6.G.228.228; | 6.G.228.229; | 6.G.228.230; | 6.G.228.231; |
6.G.228.236; | 6.G.228.237; | 6.G.228.238; | 6.G.228.239; |
6.G.228.154; | 6.G.228.157; | 6.G.228.166; | 6.G.228.169; |
6.G.228.172; | 6.G.228.175; | 6.G.228.240; | 6.G.228.244; |
6.G.229.228; | 6.G.229.229; | 6.G.229.230; | 6.G.229.231; |
6.G.229.236; | 6.G.229.237; | 6.G.229.238; | 6.G.229.239; |
6.G.229.154; | 6.G.229.157; | 6.G.229.166; | 6.G.229.169; |
6.G.229.172; | 6.G.229.175; | 6.G.229.240; | 6.G.229.244; |
6.G.230.228; | 6.G.230.229; | 6.G.230.230; | 6.G.230.231; |
6.G.230.236; | 6.G.230.237; | 6.G.230.238; | 6.G.230.239; |
6.G.230.154; | 6.G.230.157; | 6.G.230.166; | 6.G.230.169; |
6.G.230.172; | 6.G.230.175; | 6.G.230.240; | 6.G.230.244; |
6.G.231.228; | 6.G.231.229; | 6.G.231.230; | 6.G.231.231; |
6.G.231.236; | 6.G.231.237; | 6.G.231.238; | 6.G.231.239; |
6.G.231.154; | 6.G.231.157; | 6.G.231.166; | 6.G.231.169; |
6.G.231.172; | 6.G.231.175; | 6.G.231.240; | 6.G.231.244; |
6.G.236.228; | 6.G.236.229; | 6.G.236.230; | 6.G.236.231; |
6.G.236.236; | 6.G.236.237; | 6.G.236.238; | 6.G.236.239; |
6.G.236.154; | 6.G.236.157; | 6.G.236.166; | 6.G.236.169; |
6.G.236.172; | 6.G.236.175; | 6.G.236.240; | 6.G.236.244; |
6.G.237.228; | 6.G.237.229; | 6.G.237.230; | 6.G.237.231; |
6.G.237.236; | 6.G.237.237; | 6.G.237.238; | 6.G.237.239; |
6.G.237.154; | 6.G.237.157; | 6.G.237.166; | 6.G.237.169; |
6.G.237.172; | 6.G.237.175; | 6.G.237.240; | 6.G.237.244; |
6.G.238.228; | 6.G.238.229; | 6.G.238.230; | 6.G.238.231; |
6.G.238.236; | 6.G.238.237; | 6.G.238.238; | 6.G.238.239; |
6.G.238.154; | 6.G.238.157; | 6.G.238.166; | 6.G.238.169; |
6.G.238.172; | 6.G.238.175; | 6.G.238.240; | 6.G.238.244; |
6.G.239.228; | 6.G.239.229; | 6.G.239.230; | 6.G.239.231; |
6.G.239.236; | 6.G.239.237; | 6.G.239.238; | 6.G.239.239; |
6.G.239.154; | 6.G.239.157; | 6.G.239.166; | 6.G.239.169; |
6.G.239.172; | 6.G.239.175; | 6.G.239.240; | 6.G.239.244; |
6.G.154.228; | 6.G.154.229; | 6.G.154.230; | 6.G.154.231; |
6.G.154.236; | 6.G.154.237; | 6.G.154.238; | 6.G.154.239; |
6.G.154.154; | 6.G.154.157; | 6.G.154.166; | 6.G.154.169; |
6.G.154.172; | 6.G.154.175; | 6.G.154.240; | 6.G.154.244; |
6.G.157.228; | 6.G.157.229; | 6.G.157.230; | 6.G.157.231; |
6.G.157.236; | 6.G.157.237; | 6.G.157.238; | 6.G.157.239; |
6.G.157.154; | 6.G.157.157; | 6.G.157.166; | 6.G.157.169; |
6.G.157.172; | 6.G.157.175; | 6.G.157.240; | 6.G.157.244; |
6.G.166.228; | 6.G.166.229; | 6.G.166.230; | 6.G.166.231; |
6.G.166.236; | 6.G.166.237; | 6.G.166.238; | 6.G.166.239; |
6.G.166.154; | 6.G.166.157; | 6.G.166.166; | 6.G.166.169; |
6.G.166.172; | 6.G.166.175; | 6.G.166.240; | 6.G.166.244; |
6.G.169.228; | 6.G.169.229; | 6.G.169.230; | 6.G.169.231; |
6.G.169.236; | 6.G.169.237; | 6.G.169.238; | 6.G.169.239; |
6.G.169.154; | 6.G.169.157; | 6.G.169.166; | 6.G.169.169; |
6.G.169.172; | 6.G.169.175; | 6.G.169.240; | 6.G.169.244; |
6.G.172.228; | 6.G.172.229; | 6.G.172.230; | 6.G.172.231; |
6.G.172.236; | 6.G.172.237; | 6.G.172.238; | 6.G.172.239; |
6.G.172.154; | 6.G.172.157; | 6.G.172.166; | 6.G.172.169; |
6.G.172.172; | 6.G.172.175; | 6.G.172.240; | 6.G.172.244; |
6.G.175.228; | 6.G.175.229; | 6.G.175.230; | 6.G.175.231; |
6.G.175.236; | 6.G.175.237; | 6.G.175.238; | 6.G.175.239; |
6.G.175.154; | 6.G.175.157; | 6.G.175.166; | 6.G.175.169; |
6.G.175.172; | 6.G.175.175; | 6.G.175.240; | 6.G.175.244; |
6.G.240.228; | 6.G.240.229; | 6.G.240.230; | 6.G.240.231; |
6.G.240.236; | 6.G.240.237; | 6.G.240.238; | 6.G.240.239; |
6.G.240.154; | 6.G.240.157; | 6.G.240.166; | 6.G.240.169; |
6.G.240.172; | 6.G.240.175; | 6.G.240.240; | 6.G.240.244; |
6.G.244.228; | 6.G.244.229; | 6.G.244.230; | 6.G.244.231; |
6.G.244.236; | 6.G.244.237; | 6.G.244.238; | 6.G.244.239; |
6.G.244.154; | 6.G.244.157; | 6.G.244.166; | 6.G.244.169; |
6.G.244.172; | 6.G.244.175; | 6.G.244.240; | 6.G.244.244; |
6.I的前体药物
6.I.228.228; | 6.I.228.229; | 6.I.228.230; | 6.I.228.231; |
6.I.228.236; | 6.I.228.237; | 6.I.228.238; | 6.I.228.239; |
6.I.228.154; | 6.I.228.157; | 6.I.228.166; | 6.I.228.169; |
6.I.228.172; | 6.I.228.175; | 6.I.228.240; | 6.I.228.244; |
6.I.229.228; | 6.I.229.229; | 6.I.229.230; | 6.I.229.231; |
6.I.229.236; | 6.I.229.237; | 6.I.229.238; | 6.I.229.239; |
6.I.229.154; | 6.I.229.157; | 6.I.229.166; | 6.I.229.169; |
6.I.229.172; | 6.I.229.175; | 6.I.229.240; | 6.I.229.244; |
6.I.230.228; | 6.I.230.229; | 6.I.230.230; | 6.I.230.231; |
6.I.230.236; | 6.I.230.237; | 6.I.230.238; | 6.I.230.239; |
6.I.230.154; | 6.I.230.157; | 6.I.230.166; | 6.I.230.169; |
6.I.230.172; | 6.I.230.175; | 6.I.230.240; | 6.I.230.244; |
6.I.231.228; | 6.I.231.229; | 6.I.231.230; | 6.I.231.231; |
6.I.231.236; | 6.I.231.237; | 6.I.231.238; | 6.I.231.239; |
6.I.231.154; | 6.I.231.157; | 6.I.231.166; | 6.I.231.169; |
6.I.231.172; | 6.I.231.175; | 6.I.231.240; | 6.I.231.244; |
6.I.236.228; | 6.I.236.229; | 6.I.236.230; | 6.I.236.231; |
6.I.236.236; | 6.I.236.237; | 6.I.236.238; | 6.I.236.239; |
6.I.236.154; | 6.I.236.157; | 6.I.236.166; | 6.I.236.169; |
6.I.236.172; | 6.I.236.175; | 6.I.236.240; | 6.I.236.244; |
6.I.237.228; | 6.I.237.229; | 6.I.237.230; | 6.I.237.231; |
6.I.237.236; | 6.I.237.237; | 6.I.237.238; | 6.I.237.239; |
6.I.237.154; | 6.I.237.157; | 6.I.237.166; | 6.I.237.169; |
6.I.237.172; | 6.I.237.175; | 6.I.237.240; | 6.I.237.244; |
6.I.238.228; | 6.I.238.229; | 6.I.238.230; | 6.I.238.231; |
6.I.238.236; | 6.I.238.237; | 6.I.238.238; | 6.I.238.239; |
6.I.238.154; | 6.I.238.157; | 6.I.238.166; | 6.I.238.169; |
6.I.238.172; | 6.I.238.175; | 6.I.238.240; | 6.I.238.244; |
6.I.239.228; | 6.I.239.229; | 6.I.239.230; | 6.I.239.231; |
6.I.239.236; | 6.I.239.237; | 6.I.239.238; | 6.I.239.239; |
6.I.239.154; | 6.I.239.157; | 6.I.239.166; | 6.I.239.169; |
6.I.239.172; | 6.I.239.175; | 6.I.239.240; | 6.I.239.244; |
6.I.154.228; | 6.I.154.229; | 6.I.154.230; | 6.I.154.231; |
6.I.154.236; | 6.I.154.237; | 6.I.154.238; | 6.I.154.239; |
6.I.154.154; | 6.I.154.157; | 6.I.154.166; | 6.I.154.169; |
6.I.154.172; | 6.I.154.175; | 6.I.154.240; | 6.I.154.244; |
6.I.157.228; | 6.I.157.229; | 6.I.157.230; | 6.I.157.231; |
6.I.157.236; | 6.I.157.237; | 6.I.157.238; | 6.I.157.239; |
6.I.157.154; | 6.I.157.157; | 6.I.157.166; | 6.I.157.169; |
6.I.157.172; | 6.I.157.175; | 6.I.157.240; | 6.I.157.244; |
6.I.166.228; | 6.I.166.229; | 6.I.166.230; | 6.I.166.231; |
6.I.166.236; | 6.I.166.237; | 6.I.166.238; | 6.I.166.239; |
6.I.166.154; | 6.I.166.157; | 6.I.166.166; | 6.I.166.169; |
6.I.166.172; | 6.I.166.175; | 6.I.166.240; | 6.I.166.244; |
6.I.169.228; | 6.I.169.229; | 6.I.169.230; | 6.I.169.231; |
6.I.169.236; | 6.I.169.237; | 6.I.169.238; | 6.I.169.239; |
6.I.169.154; | 6.I.169.157; | 6.I.169.166; | 6.I.169.169; |
6.I.169.172; | 6.I.169.175; | 6.I.169.240; | 6.I.169.244; |
6.I.172.228; | 6.I.172.229; | 6.I.172.230; | 6.I.172.231; |
6.I.172.236; | 6.I.172.237; | 6.I.172.238; | 6.I.172.239; |
6.I.172.154; | 6.I.172.157; | 6.I.172.166; | 6.I.172.169; |
6.I.172.172; | 6.I.172.175; | 6.I.172.240; | 6.I.172.244; |
6.I.175.228; | 6.I.175.229; | 6.I.175.230; | 6.I.175.231; |
6.I.175.236; | 6.I.175.237; | 6.I.175.238; | 6.I.175.239; |
6.I.175.154; | 6.I.175.157; | 6.I.175.166; | 6.I.175.169; |
6.I.175.172; | 6.I.175.175; | 6.I.175.240; | 6.I.175.244; |
6.I.240.228; | 6.I.240.229; | 6.I.240.230; | 6.I.240.231; |
6.I.240.236; | 6.I.240.237; | 6.I.240.238; | 6.I.240.239; |
6.I.240.154; | 6.I.240.157; | 6.I.240.166; | 6.I.240.169; |
6.I.240.172; | 6.I.240.175; | 6.I.240.240; | 6.I.240.244; |
6.I.244.228; | 6.I.244.229; | 6.I.244.230; | 6.I.244.231; |
6.I.244.236; | 6.I.244.237; | 6.I.244.238; | 6.I.244.239; |
6.I.244.154; | 6.I.244.157; | 6.I.244.166; | 6.I.244.169; |
6.I.244.172; | 6.I.244.175; | 6.I.244.240; | 6.I.244.244; |
6.J的前体药物
6.J.228.228; | 6.J.228.229; | 6.J.228.230; | 6.J.228.231; |
6.J.228.236; | 6.J.228.237; | 6.J.228.238; | 6.J.228.239; |
6.J.228.154; | 6.J.228.157; | 6.J.228.166; | 6.J.228.169; |
6.J.228.172; | 6.J.228.175; | 6.J.228.240; | 6.J.228.244; |
6.J.229.228; | 6.J.229.229; | 6.J.229.230; | 6.J.229.231; |
6.J.229.236; | 6.J.229.237; | 6.J.229.238; | 6.J.229.239; |
6.J.229.154; | 6.J.229.157; | 6.J.229.166; | 6.J.229.169; |
6.J.229.172; | 6.J.229.175; | 6.J.229.240; | 6.J.229.244; |
6.J.230.228; | 6.J.230.229; | 6.J.230.230; | 6.J.230.231; |
6.J.230.236; | 6.J.230.237; | 6.J.230.238; | 6.J.230.239; |
6.J.230.154; | 6.J.230.157; | 6.J.230.166; | 6.J.230.169; |
6.J.230.172; | 6.J.230.175; | 6.J.230.240; | 6.J.230.244; |
6.J.231.228; | 6.J.231.229; | 6.J.231.230; | 6.J.231.231; |
6.J.231.236; | 6.J.231.237; | 6.J.231.238; | 6.J.231.239; |
6.J.231.154; | 6.J.231.157; | 6.J.231.166; | 6.J.231.169; |
6.J.231.172; | 6.J.231.175; | 6.J.231.240; | 6.J.231.244; |
6.J.236.228; | 6.J.236.229; | 6.J.236.230; | 6.J.236.231; |
6.J.236.236; | 6.J.236.237; | 6.J.236.238; | 6.J.236.239; |
6.J.236.154; | 6.J.236.157; | 6.J.236.166; | 6.J.236.169; |
6.J.236.172; | 6.J.236.175; | 6.J.236.240; | 6.J.236.244; |
6.J.237.228; | 6.J.237.229; | 6.J.237.230; | 6.J.237.231; |
6.J.237.236; | 6.J.237.237; | 6.J.237.238; | 6.J.237.239; |
6.J.237.154; | 6.J.237.157; | 6.J.237.166; | 6.J.237.169; |
6.J.237.172; | 6.J.237.175; | 6.J.237.240; | 6.J.237.244; |
6.J.238.228; | 6.J.238.229; | 6.J.238.230; | 6.J.238.231; |
6.J.238.236; | 6.J.238.237; | 6.J.238.238; | 6.J.238.239; |
6.J.238.154; | 6.J.238.157; | 6.J.238.166; | 6.J.238.169; |
6.J.238.172; | 6.J.238.175; | 6.J.238.240; | 6.J.238.244; |
6.J.239.228; | 6.J.239.229; | 6.J.239.230; | 6.J.239.231; |
6.J.239.236; | 6.J.239.237; | 6.J.239.238; | 6.J.239.239; |
6.J.239.154; | 6.J.239.157; | 6.J.239.166; | 6.J.239.169; |
6.J.239.172; | 6.J.239.175; | 6.J.239.240; | 6.J.239.244; |
6.J.154.228; | 6.J.154.229; | 6.J.154.230; | 6.J.154.231; |
6.J.154.236; | 6.J.154.237; | 6.J.154.238; | 6.J.154.239; |
6.J.154.154; | 6.J.154.157; | 6.J.154.166; | 6.J.154.169; |
6.J.154.172; | 6.J.154.175; | 6.J.154.240; | 6.J.154.244; |
6.J.157.228; | 6.J.157.229; | 6.J.157.230; | 6.J.157.231; |
6.J.157.236; | 6.J.157.237; | 6.J.157.238; | 6.J.157.239; |
6.J.157.154; | 6.J.157.157; | 6.J.157.166; | 6.J.157.169; |
6.J.157.172; | 6.J.157.175; | 6.J.157.240; | 6.J.157.244; |
6.J.166.228; | 6.J.166.229; | 6.J.166.230; | 6.J.166.231; |
6.J.166.236; | 6.J.166.237; | 6.J.166.238; | 6.J.166.239; |
6.J.166.154; | 6.J.166.157; | 6.J.166.166; | 6.J.166.169; |
6.J.166.172; | 6.J.166.175; | 6.J.166.240; | 6.J.166.244; |
6.J.169.228; | 6.J.169.229; | 6.J.169.230; | 6.J.169.231; |
6.J.169.236; | 6.J.169.237; | 6.J.169.238; | 6.J.169.239; |
6.J.169.154; | 6.J.169.157; | 6.J.169.166; | 6.J.169.169; |
6.J.169.172; | 6.J.169.175; | 6.J.169.240; | 6.J.169.244; |
6.J.172.228; | 6.J.172.229; | 6.J.172.230; | 6.J.172.231; |
6.J.172.236; | 6.J.172.237; | 6.J.172.238; | 6.J.172.239; |
6.J.172.154; | 6.J.172.157; | 6.J.172.166; | 6.J.172.169; |
6.J.172.172; | 6.J.172.175; | 6.J.172.240; | 6.J.172.244; |
6.J.175.228; | 6.J.175.229; | 6.J.175.230; | 6.J.175.231; |
6.J.175.236; | 6.J.175.237; | 6.J.175.238; | 6.J.175.239; |
6.J.175.154; | 6.J.175.157; | 6.J.175.166; | 6.J.175.169; |
6.J.175.172; | 6.J.175.175; | 6.J.175.240; | 6.J.175.244; |
6.J.240.228; | 6.J.240.229; | 6.J.240.230; | 6.J.240.231; |
6.J.240.236; | 6.J.240.237; | 6.J.240.238; | 6.J.240.239; |
6.J.240.154; | 6.J.240.157; | 6.J.240.166; | 6.J.240.169; |
6.J.240.172; | 6.J.240.175; | 6.J.240.240; | 6.J.240.244; |
6.J.244.228; | 6.J.244.229; | 6.J.244.230; | 6.J.244.231; |
6.J.244.236; | 6.J.244.237; | 6.J.244.238; | 6.J.244.239; |
6.J.244.154; | 6.J.244.157; | 6.J.244.166; | 6.J.244.169; |
6.J.244.172; | 6.J.244.175; | 6.J.244.240; | 6.J.244.244; |
6.L的前体药物
6.L.228.228; | 6.L.228.229; | 6.L.228.230; | 6.L.228.231; |
6.L.228.236; | 6.L.228.237; | 6.L.228.238; | 6.L.228.239; |
6.L.228.154; | 6.L.228.157; | 6.L.228.166; | 6.L.228.169; |
6.L.228.172; | 6.L.228.175; | 6.L.228.240; | 6.L.228.244; |
6.L.229.228; | 6.L.229.229; | 6.L.229.230; | 6.L.229.231; |
6.L.229.236; | 6.L.229.237; | 6.L.229.238; | 6.L.229.239; |
6.L.229.154; | 6.L.229.157; | 6.L.229.166; | 6.L.229.169; |
6.L.229.172; | 6.L.229.175; | 6.L.229.240; | 6.L.229.244; |
6.L.230.228; | 6.L.230.229; | 6.L.230.230; | 6.L.230.231; |
6.L.230.236; | 6.L.230.237; | 6.L.230.238; | 6.L.230.239; |
6.L.230.154; | 6.L.230.157; | 6.L.230.166; | 6.L.230.169; |
6.L.230.172; | 6.L.230.175; | 6.L.230.240; | 6.L.230.244; |
6.L.231.228; | 6.L.231.229; | 6.L.231.230; | 6.L.231.231; |
6.L.231.236; | 6.L.231.237; | 6.L.231.238; | 6.L.231.239; |
6.L.231.154; | 6.L.231.157; | 6.L.231.166; | 6.L.231.169; |
6.L.231.172; | 6.L.231.175; | 6.L.231.240; | 6.L.231.244; |
6.L.236.228; | 6.L.236.229; | 6.L.236.230; | 6.L.236.231; |
6.L.236.236; | 6.L.236.237; | 6.L.236.238; | 6.L.236.239; |
6.L.236.154; | 6.L.236.157; | 6.L.236.166; | 6.L.236.169; |
6.L.236.172; | 6.L.236.175; | 6.L.236.240; | 6.L.236.244; |
6.L.237.228; | 6.L.237.229; | 6.L.237.230; | 6.L.237.231; |
6.L.237.236; | 6.L.237.237; | 6.L.237.238; | 6.L.237.239; |
6.L.237.154; | 6.L.237.157; | 6.L.237.166; | 6.L.237.169; |
6.L.237.172; | 6.L.237.175; | 6.L.237.240; | 6.L.237.244; |
6.L.238.228; | 6.L.238.229; | 6.L.238.230; | 6.L.238.231; |
6.L.238.236; | 6.L.238.237; | 6.L.238.238; | 6.L.238.239; |
6.L.238.154; | 6.L.238.157; | 6.L.238.166; | 6.L.238.169; |
6.L.238.172; | 6.L.238.175; | 6.L.238.240; | 6.L.238.244; |
6.L.239.228; | 6.L.239.229; | 6.L.239.230; | 6.L.239.231; |
6.L.239.236; | 6.L.239.237; | 6.L.239.238; | 6.L.239.239; |
6.L.239.154; | 6.L.239.157; | 6.L.239.166; | 6.L.239.169; |
6.L.239.172; | 6.L.239.175; | 6.L.239.240; | 6.L.239.244; |
6.L.154.228; | 6.L.154.229; | 6.L.154.230; | 6.L.154.231; |
6.L.154.236; | 6.L.154.237; | 6.L.154.238; | 6.L.154.239; |
6.L.154.154; | 6.L.154.157; | 6.L.154.166; | 6.L.154.169; |
6.L.154.172; | 6.L.154.175; | 6.L.154.240; | 6.L.154.244; |
6.L.157.228; | 6.L.157.229; | 6.L.157.230; | 6.L.157.231; |
6.L.157.236; | 6.L.157.237; | 6.L.157.238; | 6.L.157.239; |
6.L.157.154; | 6.L.157.157; | 6.L.157.166; | 6.L.157.169; |
6.L.157.172; | 6.L.157.175; | 6.L.157.240; | 6.L.157.244; |
6.L.166.228; | 6.L.166.229; | 6.L.166.230; | 6.L.166.231; |
6.L.166.236; | 6.L.166.237; | 6.L.166.238; | 6.L.166.239; |
6.L.166.154; | 6.L.166.157; | 6.L.166.166; | 6.L.166.169; |
6.L.166.172; | 6.L.166.175; | 6.L.166.240; | 6.L.166.244; |
6.L.169.228; | 6.L.169.229; | 6.L.169.230; | 6.L.169.231; |
6.L.169.236; | 6.L.169.237; | 6.L.169.238; | 6.L.169.239; |
6.L.169.154; | 6.L.169.157; | 6.L.169.166; | 6.L.169.169; |
6.L.169.172; | 6.L.169.175; | 6.L.169.240; | 6.L.169.244; |
6.L.172.228; | 6.L.172.229; | 6.L.172.230; | 6.L.172.231; |
6.L.172.236; | 6.L.172.237; | 6.L.172.238; | 6.L.172.239; |
6.L.172.154; | 6.L.172.157; | 6.L.172.166; | 6.L.172.169; |
6.L.172.172; | 6.L.172.175; | 6.L.172.240; | 6.L.172.244; |
6.L.175.228; | 6.L.175.229; | 6.L.175.230; | 6.L.175.231; |
6.L.175.236; | 6.L.175.237; | 6.L.175.238; | 6.L.175.239; |
6.L.175.154; | 6.L.175.157; | 6.L.175.166; | 6.L.175.169; |
6.L.175.172; | 6.L.175.175; | 6.L.175.240; | 6.L.175.244; |
6.L.240.228; | 6.L.240.229; | 6.L.240.230; | 6.L.240.231; |
6.L.240.236; | 6.L.240.237; | 6.L.240.238; | 6.L.240.239; |
6.L.240.154; | 6.L.240.157; | 6.L.240.166; | 6.L.240.169; |
6.L.240.172; | 6.L.240.175; | 6.L.240.240; | 6.L.240.244; |
6.L.244.228; | 6.L.244.229; | 6.L.244.230; | 6.L.244.231; |
6.L.244.236; | 6.L.244.237; | 6.L.244.238; | 6.L.244.239; |
6.L.244.154; | 6.L.244.157; | 6.L.244.166; | 6.L.244.169; |
6.L.244.172; | 6.L.244.175; | 6.L.244.240; | 6.L.244.244; |
6.O的前体药物
6.O.228.228; | 6.O.228.229; | 6.O.228.230; | 6.O.228.231; |
6.O.228.236; | 6.O.228.237; | 6.O.228.238; | 6.O.228.239; |
6.O.228.154; | 6.O.228.157; | 6.O.228.166; | 6.O.228.169; |
6.O.228.172; | 6.O.228.175; | 6.O.228.240; | 6.O.228.244; |
6.O.229.228; | 6.O.229.229; | 6.O.229.230; | 6.O.229.231; |
6.O.229.236; | 6.O.229.237; | 6.O.229.238; | 6.O.229.239; |
6.O.229.154; | 6.O.229.157; | 6.O.229.166; | 6.O.229.169; |
6.O.229.172; | 6.O.229.175; | 6.O.229.240; | 6.O.229.244; |
6.O.230.228; | 6.O.230.229; | 6.O.230.230; | 6.O.230.231; |
6.O.230.236; | 6.O.230.237; | 6.O.230.238; | 6.O.230.239; |
6.O.230.154; | 6.O.230.157; | 6.O.230.166; | 6.O.230.169; |
6.O.230.172; | 6.O.230.175; | 6.O.230.240; | 6.O.230.244; |
6.O.231.228; | 6.O.231.229; | 6.O.231.230; | 6.O.231.231; |
6.O.231.236; | 6.O.231.237; | 6.O.231.238; | 6.O.231.239; |
6.O.231.154; | 6.O.231.157; | 6.O.231.166; | 6.O.231.169; |
6.O.231.172; | 6.O.231.175; | 6.O.231.240; | 6.O.231.244; |
6.O.236.228; | 6.O.236.229; | 6.O.236.230; | 6.O.236.231; |
6.O.236.236; | 6.O.236.237; | 6.O.236.238; | 6.O.236.239; |
6.O.236.154; | 6.O.236.157; | 6.O.236.166; | 6.O.236.169; |
6.O.236.172; | 6.O.236.175; | 6.O.236.240; | 6.O.236.244; |
6.O.237.228; | 6.O.237.229; | 6.O.237.230; | 6.O.237.231; |
6.O.237.236; | 6.O.237.237; | 6.O.237.238; | 6.O.237.239; |
6.O.237.154; | 6.O.237.157; | 6.O.237.166; | 6.O.237.169; |
6.O.237.172; | 6.O.237.175; | 6.O.237.240; | 6.O.237.244; |
6.O.238.228; | 6.O.238.229; | 6.O.238.230; | 6.O.238.231; |
6.O.238.236; | 6.O.238.237; | 6.O.238.238; | 6.O.238.239; |
6.O.238.154; | 6.O.238.157; | 6.O.238.166; | 6.O.238.169; |
6.O.238.172; | 6.O.238.175; | 6.O.238.240; | 6.O.238.244; |
6.O.239.228; | 6.O.239.229; | 6.O.239.230; | 6.O.239.231; |
6.O.239.236; | 6.O.239.237; | 6.O.239.238; | 6.O.239.239; |
6.O.239.154; | 6.O.239.157; | 6.O.239.166; | 6.O.239.169; |
6.O.239.172; | 6.O.239.175; | 6.O.239.240; | 6.O.239.244; |
6.O.154.228; | 6.O.154.229; | 6.O.154.230; | 6.O.154.231; |
6.O.154.236; | 6.O.154.237; | 6.O.154.238; | 6.O.154.239; |
6.O.154.154; | 6.O.154.157; | 6.O.154.166; | 6.O.154.169; |
6.O.154.172; | 6.O.154.175; | 6.O.154.240; | 6.O.154.244; |
6.O.157.228; | 6.O.157.229; | 6.O.157.230; | 6.O.157.231; |
6.O.157.236; | 6.O.157.237; | 6.O.157.238; | 6.O.157.239; |
6.O.157.154; | 6.O.157.157; | 6.O.157.166; | 6.O.157.169; |
6.O.157.172; | 6.O.157.175; | 6.O.157.240; | 6.O.157.244; |
6.O.166.228; | 6.O.166.229; | 6.O.166.230; | 6.O.166.231; |
6.O.166.236; | 6.O.166.237; | 6.O.166.238; | 6.O.166.239; |
6.O.166.154; | 6.O.166.157; | 6.O.166.166; | 6.O.166.169; |
6.O.166.172; | 6.O.166.175; | 6.O.166.240; | 6.O.166.244; |
6.O.169.228; | 6.O.169.229; | 6.O.169.230; | 6.O.169.231; |
6.O.169.236; | 6.O.169.237; | 6.O.169.238; | 6.O.169.239; |
6.O.169.154; | 6.O.169.157; | 6.O.169.166; | 6.O.169.169; |
6.O.169.172; | 6.O.169.175; | 6.O.169.240; | 6.O.169.244; |
6.O.172.228; | 6.O.172.229; | 6.O.172.230; | 6.O.172.231; |
6.O.172.236; | 6.O.172.237; | 6.O.172.238; | 6.O.172.239; |
6.O.172.154; | 6.O.172.157; | 6.O.172.166; | 6.O.172.169; |
6.O.172.172; | 6.O.172.175; | 6.O.172.240; | 6.O.172.244; |
6.O.175.228; | 6.O.175.229; | 6.O.175.230; | 6.O.175.231; |
6.O.175.236; | 6.O.175.237; | 6.O.175.238; | 6.O.175.239; |
6.O.175.154; | 6.O.175.157; | 6.O.175.166; | 6.O.175.169; |
6.O.175.172; | 6.O.175.175; | 6.O.175.240; | 6.O.175.244; |
6.O.240.228; | 6.O.240.229; | 6.O.240.230; | 6.O.240.231; |
6.O.240.236; | 6.O.240.237; | 6.O.240.238; | 6.O.240.239; |
6.O.240.154; | 6.O.240.157; | 6.O.240.166; | 6.O.240.169; |
6.O.240.172; | 6.O.240.175; | 6.O.240.240; | 6.O.240.244; |
6.O.244.228; | 6.O.244.229; | 6.O.244.230; | 6.O.244.231; |
6.O.244.236; | 6.O.244.237; | 6.O.244.238; | 6.O.244.239; |
6.O.244.154; | 6.O.244.157; | 6.O.244.166; | 6.O.244.169; |
6.O.244.172; | 6.O.244.175; | 6.O.244.240; | 6.O.244.244; |
6.P的前体药物
6.P.228.228; | 6.P.228.229; | 6.P.228.230; | 6.P.228.231; |
6.P.228.236; | 6.P.228.237; | 6.P.228.238; | 6.P.228.239; |
6.P.228.154; | 6.P.228.157; | 6.P.228.166; | 6.P.228.169; |
6.P.228.172; | 6.P.228.175; | 6.P.228.240; | 6.P.228.244; |
6.P.229.228; | 6.P.229.229; | 6.P.229.230; | 6.P.229.231; |
6.P.229.236; | 6.P.229.237; | 6.P.229.238; | 6.P.229.239; |
6.P.229.154; | 6.P.229.157; | 6.P.229.166; | 6.P.229.169; |
6.P.229.172; | 6.P.229.175; | 6.P.229.240; | 6.P.229.244; |
6.P.230.228; | 6.P.230.229; | 6.P.230.230; | 6.P.230.231; |
6.P.230.236; | 6.P.230.237; | 6.P.230.238; | 6.P.230.239; |
6.P.230.154; | 6.P.230.157; | 6.P.230.166; | 6.P.230.169; |
6.P.230.172; | 6.P.230.175; | 6.P.230.240; | 6.P.230.244; |
6.P.231.228; | 6.P.231.229; | 6.P.231.230; | 6.P.231.231; |
6.P.231.236; | 6.P.231.237; | 6.P.231.238; | 6.P.231.239; |
6.P.231.154; | 6.P.231.157; | 6.P.231.166; | 6.P.231.169; |
6.P.231.172; | 6.P.231.175; | 6.P.231.240; | 6.P.231.244; |
6.P.236.228; | 6.P.236.229; | 6.P.236.230; | 6.P.236.231; |
6.P.236.236; | 6.P.236.237; | 6.P.236.238; | 6.P.236.239; |
6.P.236.154; | 6.P.236.157; | 6.P.236.166; | 6.P.236.169; |
6.P.236.172; | 6.P.236.175; | 6.P.236.240; | 6.P.236.244; |
6.P.237.228; | 6.P.237.229; | 6.P.237.230; | 6.P.237.231; |
6.P.237.236; | 6.P.237.237; | 6.P.237.238; | 6.P.237.239; |
6.P.237.154; | 6.P.237.157; | 6.P.237.166; | 6.P.237.169; |
6.P.237.172; | 6.P.237.175; | 6.P.237.240; | 6.P.237.244; |
6.P.238.228; | 6.P.238.229; | 6.P.238.230; | 6.P.238.231; |
6.P.238.236; | 6.P.238.237; | 6.P.238.238; | 6.P.238.239; |
6.P.238.154; | 6.P.238.157; | 6.P.238.166; | 6.P.238.169; |
6.P.238.172; | 6.P.238.175; | 6.P.238.240; | 6.P.238.244; |
6.P.239.228; | 6.P.239.229; | 6.P.239.230; | 6.P.239.231; |
6.P.239.236; | 6.P.239.237; | 6.P.239.238; | 6.P.239.239; |
6.P.239.154; | 6.P.239.157; | 6.P.239.166; | 6.P.239.169; |
6.P.239.172; | 6.P.239.175; | 6.P.239.240; | 6.P.239.244; |
6.P.154.228; | 6.P.154.229; | 6.P.154.230; | 6.P.154.231; |
6.P.154.236; | 6.P.154.237; | 6.P.154.238; | 6.P.154.239; |
6.P.154.154; | 6.P.154.157; | 6.P.154.166; | 6.P.154.169; |
6.P.154.172; | 6.P.154.175; | 6.P.154.240; | 6.P.154.244; |
6.P.157.228; | 6.P.157.229; | 6.P.157.230; | 6.P.157.231; |
6.P.157.236; | 6.P.157.237; | 6.P.157.238; | 6.P.157.239; |
6.P.157.154; | 6.P.157.157; | 6.P.157.166; | 6.P.157.169; |
6.P.157.172; | 6.P.157.175; | 6.P.157.240; | 6.P.157.244; |
6.P.166.228; | 6.P.166.229; | 6.P.166.230; | 6.P.166.231; |
6.P.166.236; | 6.P.166.237; | 6.P.166.238; | 6.P.166.239; |
6.P.166.154; | 6.P.166.157; | 6.P.166.166; | 6.P.166.169; |
6.P.166.172; | 6.P.166.175; | 6.P.166.240; | 6.P.166.244; |
6.P.169.228; | 6.P.169.229; | 6.P.169.230; | 6.P.169.231; |
6.P.169.236; | 6.P.169.237; | 6.P.169.238; | 6.P.169.239; |
6.P.169.154; | 6.P.169.157; | 6.P.169.166; | 6.P.169.169; |
6.P.169.172; | 6.P.169.175; | 6.P.169.240; | 6.P.169.244; |
6.P.172.228; | 6.P.172.229; | 6.P.172.230; | 6.P.172.231; |
6.P.172.236; | 6.P.172.237; | 6.P.172.238; | 6.P.172.239; |
6.P.172.154; | 6.P.172.157; | 6.P.172.166; | 6.P.172.169; |
6.P.172.172; | 6.P.172.175; | 6.P.172.240; | 6.P.172.244; |
6.P.175.228; | 6.P.175.229; | 6.P.175.230; | 6.P.175.231; |
6.P.175.236; | 6.P.175.237; | 6.P.175.238; | 6.P.175.239; |
6.P.175.154; | 6.P.175.157; | 6.P.175.166; | 6.P.175.169; |
6.P.175.172; | 6.P.175.175; | 6.P.175.240; | 6.P.175.244; |
6.P.240.228; | 6.P.240.229; | 6.P.240.230; | 6.P.240.231; |
6.P.240.236; | 6.P.240.237; | 6.P.240.238; | 6.P.240.239; |
6.P.240.154; | 6.P.240.157; | 6.P.240.166; | 6.P.240.169; |
6.P.240.172; | 6.P.240.175; | 6.P.240.240; | 6.P.240.244; |
6.P.244.228; | 6.P.244.229; | 6.P.244.230; | 6.P.244.231; |
6.P.244.236; | 6.P.244.237; | 6.P.244.238; | 6.P.244.239; |
6.P.244.154; | 6.P.244.157; | 6.P.244.166; | 6.P.244.169; |
6.P.244.172; | 6.P.244.175; | 6.P.244.240; | 6.P.244.244; |
6.U的前体药物
6.U.228.228; | 6.U.228.229; | 6.U.228.230; | 6.U.228.231; |
6.U.228.236; | 6.U.228.237; | 6.U.228.238; | 6.U.228.239; |
6.U.228.154; | 6.U.228.157; | 6.U.228.166; | 6.U.228.169; |
6.U.228.172; | 6.U.228.175; | 6.U.228.240; | 6.U.228.244; |
6.U.229.228; | 6.U.229.229; | 6.U.229.230; | 6.U.229.231; |
6.U.229.236; | 6.U.229.237; | 6.U.229.238; | 6.U.229.239; |
6.U.229.154; | 6.U.229.157; | 6.U.229.166; | 6.U.229.169; |
6.U.229.172; | 6.U.229.175; | 6.U.229.240; | 6.U.229.244; |
6.U.230.228; | 6.U.230.229; | 6.U.230.230; | 6.U.230.231; |
6.U.230.236; | 6.U.230.237; | 6.U.230.238; | 6.U.230.239; |
6.U.230.154; | 6.U.230.157; | 6.U.230.166; | 6.U.230.169; |
6.U.230.172; | 6.U.230.175; | 6.U.230.240; | 6.U.230.244; |
6.U.231.228; | 6.U.231.229; | 6.U.231.230; | 6.U.231.231; |
6.U.231.236; | 6.U.231.237; | 6.U.231.238; | 6.U.231.239; |
6.U.231.154; | 6.U.231.157; | 6.U.231.166; | 6.U.231.169; |
6.U.231.172; | 6.U.231.175; | 6.U.231.240; | 6.U.231.244; |
6.U.236.228; | 6.U.236.229; | 6.U.236.230; | 6.U.236.231; |
6.U.236.236; | 6.U.236.237; | 6.U.236.238; | 6.U.236.239; |
6.U.236.154; | 6.U.236.157; | 6.U.236.166; | 6.U.236.169; |
6.U.236.172; | 6.U.236.175; | 6.U.236.240; | 6.U.236.244; |
6.U.237.228; | 6.U.237.229; | 6.U.237.230; | 6.U.237.231; |
6.U.237.236; | 6.U.237.237; | 6.U.237.238; | 6.U.237.239; |
6.U.237.154; | 6.U.237.157; | 6.U.237.166; | 6.U.237.169; |
6.U.237.172; | 6.U.237.175; | 6.U.237.240; | 6.U.237.244; |
6.U.238.228; | 6.U.238.229; | 6.U.238.230; | 6.U.238.231; |
6.U.238.236; | 6.U.238.237; | 6.U.238.238; | 6.U.238.239; |
6.U.238.154; | 6.U.238.157; | 6.U.238.166; | 6.U.238.169; |
6.U.238.172; | 6.U.238.175; | 6.U.238.240; | 6.U.238.244; |
6.U.239.228; | 6.U.239.229; | 6.U.239.230; | 6.U.239.231; |
6.U.239.236; | 6.U.239.237; | 6.U.239.238; | 6.U.239.239; |
6.U.239.154; | 6.U.239.157; | 6.U.239.166; | 6.U.239.169; |
6.U.239.172; | 6.U.239.175; | 6.U.239.240; | 6.U.239.244; |
6.U.154.228; | 6.U.154.229; | 6.U.154.230; | 6.U.154.231; |
6.U.154.236; | 6.U.154.237; | 6.U.154.238; | 6.U.154.239; |
6.U.154.154; | 6.U.154.157; | 6.U.154.166; | 6.U.154.169; |
6.U.154.172; | 6.U.154.175; | 6.U.154.240; | 6.U.154.244; |
6.U.157.228; | 6.U.157.229; | 6.U.157.230; | 6.U.157.231; |
6.U.157.236; | 6.U.157.237; | 6.U.157.238; | 6.U.157.239; |
6.U.157.154; | 6.U.157.157; | 6.U.157.166; | 6.U.157.169; |
6.U.157.172; | 6.U.157.175; | 6.U.157.240; | 6.U.157.244; |
6.U.166.228; | 6.U.166.229; | 6.U.166.230; | 6.U.166.231; |
6.U.166.236; | 6.U.166.237; | 6.U.166.238; | 6.U.166.239; |
6.U.166.154; | 6.U.166.157; | 6.U.166.166; | 6.U.166.169; |
6.U.166.172; | 6.U.166.175; | 6.U.166.240; | 6.U.166.244; |
6.U.169.228; | 6.U.169.229; | 6.U.169.230; | 6.U.169.231; |
6.U.169.236; | 6.U.169.237; | 6.U.169.238; | 6.U.169.239; |
6.U.169.154; | 6.U.169.157; | 6.U.169.166; | 6.U.169.169; |
6.U.169.172; | 6.U.169.175; | 6.U.169.240; | 6.U.169.244; |
6.U.172.228; | 6.U.172.229; | 6.U.172.230; | 6.U.172.231; |
6.U.172.236; | 6.U.172.237; | 6.U.172.238; | 6.U.172.239; |
6.U.172.154; | 6.U.172.157; | 6.U.172.166; | 6.U.172.169; |
6.U.172.172; | 6.U.172.175; | 6.U.172.240; | 6.U.172.244; |
6.U.175.228; | 6.U.175.229; | 6.U.175.230; | 6.U.175.231; |
6.U.175.236; | 6.U.175.237; | 6.U.175.238; | 6.U.175.239; |
6.U.175.154; | 6.U.175.157; | 6.U.175.166; | 6.U.175.169; |
6.U.175.172; | 6.U.175.175; | 6.U.175.240; | 6.U.175.244; |
6.U.240.228; | 6.U.240.229; | 6.U.240.230; | 6.U.240.231; |
6.U.240.236; | 6.U.240.237; | 6.U.240.238; | 6.U.240.239; |
6.U.240.154; | 6.U.240.157; | 6.U.240.166; | 6.U.240.169; |
6.U.240.172; | 6.U.240.175; | 6.U.240.240; | 6.U.240.244; |
6.U.244.228; | 6.U.244.229; | 6.U.244.230; | 6.U.244.231; |
6.U.244.236; | 6.U.244.237; | 6.U.244.238; | 6.U.244.239; |
6.U.244.154; | 6.U.244.157; | 6.U.244.166; | 6.U.244.169; |
6.U.244.172; | 6.U.244.175; | 6.U.244.240; | 6.U.244.244; |
6.W的前体药物
6.W.228.228; | 6.W.228.229; | 6.W.228.230; | 6.W.228.231; |
6.W.228.236; | 6.W.228.237; | 6.W.228.238; | 6.W.228.239; |
6.W.228.154; | 6.W.228.157; | 6.W.228.166; | 6.W.228.169; |
6.W.228.172; | 6.W.228.175; | 6.W.228.240; | 6.W.228.244; |
6.W.229.228; | 6.W.229.229; | 6.W.229.230; | 6.W.229.231; |
6.W.229.236; | 6.W.229.237; | 6.W.229.238; | 6.W.229.239; |
6.W.229.154; | 6.W.229.157; | 6.W.229.166; | 6.W.229.169; |
6.W.229.172; | 6.W.229.175; | 6.W.229.240; | 6.W.229.244; |
6.W.230.228; | 6.W.230.229; | 6.W.230.230; | 6.W.230.231; |
6.W.230.236; | 6.W.230.237; | 6.W.230.238; | 6.W.230.239; |
6.W.230.154; | 6.W.230.157; | 6.W.230.166; | 6.W.230.169; |
6.W.230.172; | 6.W.230.175; | 6.W.230.240; | 6.W.230.244; |
6.W.231.228; | 6.W.231.229; | 6.W.231.230; | 6.W.231.231; |
6.W.231.236; | 6.W.231.237; | 6.W.231.238; | 6.W.231.239; |
6.W.231.154; | 6.W.231.157; | 6.W.231.166; | 6.W.231.169; |
6.W.231.172; | 6.W.231.175; | 6.W.231.240; | 6.W.231.244; |
6.W.236.228; | 6.W.236.229; | 6.W.236.230; | 6.W.236.231; |
6.W.236.236; | 6.W.236.237; | 6.W.236.238; | 6.W.236.239; |
6.W.236.154; | 6.W.236.157; | 6.W.236.166; | 6.W.236.169; |
6.W.236.172; | 6.W.236.175; | 6.W.236.240; | 6.W.236.244; |
6.W.237.228; | 6.W.237.229; | 6.W.237.230; | 6.W.237.231; |
6.W.237.236; | 6.W.237.237; | 6.W.237.238; | 6.W.237.239; |
6.W.237.154; | 6.W.237.157; | 6.W.237.166; | 6.W.237.169; |
6.W.237.172; | 6.W.237.175; | 6.W.237.240; | 6.W.237.244; |
6.W.238.228; | 6.W.238.229; | 6.W.238.230; | 6.W.238.231; |
6.W.238.236; | 6.W.238.237; | 6.W.238.238; | 6.W.238.239; |
6.W.238.154; | 6.W.238.157; | 6.W.238.166; | 6.W.238.169; |
6.W.238.172; | 6.W.238.175; | 6.W.238.240; | 6.W.238.244; |
6.W.239.228; | 6.W.239.229; | 6.W.239.230; | 6.W.239.231; |
6.W.239.236; | 6.W.239.237; | 6.W.239.238; | 6.W.239.239; |
6.W.239.154; | 6.W.239.157; | 6.W.239.166; | 6.W.239.169; |
6.W.239.172; | 6.W.239.175; | 6.W.239.240; | 6.W.239.244; |
6.W.154.228; | 6.W.154.229; | 6.W.154.230; | 6.W.154.231; |
6.W.154.236; | 6.W.154.237; | 6.W.154.238; | 6.W.154.239; |
6.W.154.154; | 6.W.154.157; | 6.W.154.166; | 6.W.154.169; |
6.W.154.172; | 6.W.154.175; | 6.W.154.240; | 6.W.154.244; |
6.W.157.228; | 6.W.157.229; | 6.W.157.230; | 6.W.157.231; |
6.W.157.236; | 6.W.157.237; | 6.W.157.238; | 6.W.157.239; |
6.W.157.154; | 6.W.157.157; | 6.W.157.166; | 6.W.157.169; |
6.W.157.172; | 6.W.157.175; | 6.W.157.240; | 6.W.157.244; |
6.W.166.228; | 6.W.166.229; | 6.W.166.230; | 6.W.166.231; |
6.W.166.236; | 6.W.166.237; | 6.W.166.238; | 6.W.166.239; |
6.W.166.154; | 6.W.166.157; | 6.W.166.166; | 6.W.166.169; |
6.W.166.172; | 6.W.166.175; | 6.W.166.240; | 6.W.166.244; |
6.W.169.228; | 6.W.169.229; | 6.W.169.230; | 6.W.169.231; |
6.W.169.236; | 6.W.169.237; | 6.W.169.238; | 6.W.169.239; |
6.W.169.154; | 6.W.169.157; | 6.W.169.166; | 6.W.169.169; |
6.W.169.172; | 6.W.169.175; | 6.W.169.240; | 6.W.169.244; |
6.W.172.228; | 6.W.172.229; | 6.W.172.230; | 6.W.172.231; |
6.W.172.236; | 6.W.172.237; | 6.W.172.238; | 6.W.172.239; |
6.W.172.154; | 6.W.172.157; | 6.W.172.166; | 6.W.172.169; |
6.W.172.172; | 6.W.172.175; | 6.W.172.240; | 6.W.172.244; |
6.W.175.228; | 6.W.175.229; | 6.W.175.230; | 6.W.175.231; |
6.W.175.236; | 6.W.175.237; | 6.W.175.238; | 6.W.175.239; |
6.W.175.154; | 6.W.175.157; | 6.W.175.166; | 6.W.175.169; |
6.W.175.172; | 6.W.175.175; | 6.W.175.240; | 6.W.175.244; |
6.W.240.228; | 6.W.240.229; | 6.W.240.230; | 6.W.240.231; |
6.W.240.236; | 6.W.240.237; | 6.W.240.238; | 6.W.240.239; |
6.W.240.154; | 6.W.240.157; | 6.W.240.166; | 6.W.240.169; |
6.W.240.172; | 6.W.240.175; | 6.W.240.240; | 6.W.240.244; |
6.W.244.228; | 6.W.244.229; | 6.W.244.230; | 6.W.244.231; |
6.W.244.236; | 6.W.244.237; | 6.W.244.238; | 6.W.244.239; |
6.W.244.154; | 6.W.244.157; | 6.W.244.166; | 6.W.244.169; |
6.W.244.172; | 6.W.244.175; | 6.W.244.240; | 6.W.244.244; |
6.Y的前体药物
6.Y.228.228; | 6.Y.228.229; | 6.Y.228.230; | 6.Y.228.231; |
6.Y.228.236; | 6.Y.228.237; | 6.Y.228.238; | 6.Y.228.239; |
6.Y.228.154; | 6.Y.228.157; | 6.Y.228.166; | 6.Y.228.169; |
6.Y.228.172; | 6.Y.228.175; | 6.Y.228.240; | 6.Y.228.244; |
6.Y.229.228; | 6.Y.229.229; | 6.Y.229.230; | 6.Y.229.231; |
6.Y.229.236; | 6.Y.229.237; | 6.Y.229.238; | 6.Y.229.239; |
6.Y.229.154; | 6.Y.229.157; | 6.Y.229.166; | 6.Y.229.169; |
6.Y.229.172; | 6.Y.229.175; | 6.Y.229.240; | 6.Y.229.244; |
6.Y.230.228; | 6.Y.230.229; | 6.Y.230.230; | 6.Y.230.231; |
6.Y.230.236; | 6.Y.230.237; | 6.Y.230.238; | 6.Y.230.239; |
6.Y.230.154; | 6.Y.230.157; | 6.Y.230.166; | 6.Y.230.169; |
6.Y.230.172; | 6.Y.230.175; | 6.Y.230.240; | 6.Y.230.244; |
6.Y.231.228; | 6.Y.231.229; | 6.Y.231.230; | 6.Y.231.231; |
6.Y.231.236; | 6.Y.231.237; | 6.Y.231.238; | 6.Y.231.239; |
6.Y.231.154; | 6.Y.231.157; | 6.Y.231.166; | 6.Y.231.169; |
6.Y.231.172; | 6.Y.231.175; | 6.Y.231.240; | 6.Y.231.244; |
6.Y.236.228; | 6.Y.236.229; | 6.Y.236.230; | 6.Y.236.231; |
6.Y.236.236; | 6.Y.236.237; | 6.Y.236.238; | 6.Y.236.239; |
6.Y.236.154; | 6.Y.236.157; | 6.Y.236.166; | 6.Y.236.169; |
6.Y.236.172; | 6.Y.236.175; | 6.Y.236.240; | 6.Y.236.244; |
6.Y.237.228; | 6.Y.237.229; | 6.Y.237.230; | 6.Y.237.231; |
6.Y.237.236; | 6.Y.237.237; | 6.Y.237.238; | 6.Y.237.239; |
6.Y.237.154; | 6.Y.237.157; | 6.Y.237.166; | 6.Y.237.169; |
6.Y.237.172; | 6.Y.237.175; | 6.Y.237.240; | 6.Y.237.244; |
6.Y.238.228; | 6.Y.238.229; | 6.Y.238.230; | 6.Y.238.231; |
6.Y.238.236; | 6.Y.238.237; | 6.Y.238.238; | 6.Y.238.239; |
6.Y.238.154; | 6.Y.238.157; | 6.Y.238.166; | 6.Y.238.169; |
6.Y.238.172; | 6.Y.238.175; | 6.Y.238.240; | 6.Y.238.244; |
6.Y.239.228; | 6.Y.239.229; | 6.Y.239.230; | 6.Y.239.231; |
6.Y.239.236; | 6.Y.239.237; | 6.Y.239.238; | 6.Y.239.239; |
6.Y.239.154; | 6.Y.239.157; | 6.Y.239.166; | 6.Y.239.169; |
6.Y.239.172; | 6.Y.239.175; | 6.Y.239.240; | 6.Y.239.244; |
6.Y.154.228; | 6.Y.154.229; | 6.Y.154.230; | 6.Y.154.231; |
6.Y.154.236; | 6.Y.154.237; | 6.Y.154.238; | 6.Y.154.239; |
6.Y.154.154; | 6.Y.154.157; | 6.Y.154.166; | 6.Y.154.169; |
6.Y.154.172; | 6.Y.154.175; | 6.Y.154.240; | 6.Y.154.244; |
6.Y.157.228; | 6.Y.157.229; | 6.Y.157.230; | 6.Y.157.231; |
6.Y.157.236; | 6.Y.157.237; | 6.Y.157.238; | 6.Y.157.239; |
6.Y.157.154; | 6.Y.157.157; | 6.Y.157.166; | 6.Y.157.169; |
6.Y.157.172; | 6.Y.157.175; | 6.Y.157.240; | 6.Y.157.244; |
6.Y.166.228; | 6.Y.166.229; | 6.Y.166.230; | 6.Y.166.231; |
6.Y.166.236; | 6.Y.166.237; | 6.Y.166.238; | 6.Y.166.239; |
6.Y.166.154; | 6.Y.166.157; | 6.Y.166.166; | 6.Y.166.169; |
6.Y.166.172; | 6.Y.166.175; | 6.Y.166.240; | 6.Y.166.244; |
6.Y.169.228; | 6.Y.169.229; | 6.Y.169.230; | 6.Y.169.231; |
6.Y.169.236; | 6.Y.169.237; | 6.Y.169.238; | 6.Y.169.239; |
6.Y.169.154; | 6.Y.169.157; | 6.Y.169.166; | 6.Y.169.169; |
6.Y.169.172; | 6.Y.169.175; | 6.Y.169.240; | 6.Y.169.244; |
6.Y.172.228; | 6.Y.172.229; | 6.Y.172.230; | 6.Y.172.231; |
6.Y.172.236; | 6.Y.172.237; | 6.Y.172.238; | 6.Y.172.239; |
6.Y.172.154; | 6.Y.172.157; | 6.Y.172.166; | 6.Y.172.169; |
6.Y.172.172; | 6.Y.172.175; | 6.Y.172.240; | 6.Y.172.244; |
6.Y.175.228; | 6.Y.175.229; | 6.Y.175.230; | 6.Y.175.231; |
6.Y.175.236; | 6.Y.175.237; | 6.Y.175.238; | 6.Y.175.239; |
6.Y.175.154; | 6.Y.175.157; | 6.Y.175.166; | 6.Y.175.169; |
6.Y.175.172; | 6.Y.175.175; | 6.Y.175.240; | 6.Y.175.244; |
6.Y.240.228; | 6.Y.240.229; | 6.Y.240.230; | 6.Y.240.231; |
6.Y.240.236; | 6.Y.240.237; | 6.Y.240.238; | 6.Y.240.239; |
6.Y.240.154; | 6.Y.240.157; | 6.Y.240.166; | 6.Y.240.169; |
6.Y.240.172; | 6.Y.240.175; | 6.Y.240.240; | 6.Y.240.244; |
6.Y.244.228; | 6.Y.244.229; | 6.Y.244.230; | 6.Y.244.231; |
6.Y.244.236; | 6.Y.244.237; | 6.Y.244.238; | 6.Y.244.239; |
6.Y.244.154; | 6.Y.244.157; | 6.Y.244.166; | 6.Y.244.169; |
6.Y.244.172; | 6.Y.244.175; | 6.Y.244.240; | 6.Y.244.244; |
7.AH的前体药物
7.AH.4.157; | 7.AH.4.158; | 7.AH.4.196; | 7.AH.4.223; |
7.AH.4.240; | 7.AH.4.244; | 7.AH.4.243; | 7.AH.4.247; | 7.AH.5.157; |
7.AH.5.158; | 7.AH.5.196; | 7.AH.5.223; | 7.AH.5.240; | 7.AH.5.244; |
7.AH.5.243; | 7.AH.5.247; | 7.AH.7.157; | 7.AH.7.158; | 7.AH.7.196; |
7.AH.7.223; | 7.AH.7.240; | 7.AH.7.244; | 7.AH.7.243; | 7.AH.7.247; |
7.AH.15.157; | 7.AH.15.158; | 7.AH.15.196; | 7.AH.15.223; |
7.AH.15.240; | 7.AH.15.244; | 7.AH.15.243; | 7.AH.15.247; |
7.AH.16.157; | 7.AH.16.158; | 7.AH.16.196; | 7.AH.16.223; |
7.AH.16.240; | 7.AH.16.244; | 7.AH.16.243; | 7.AH.16.247; |
7.AH.18.157; | 7.AH.18.158; | 7.AH.18.196; | 7.AH.18.223; |
7.AH.18.240; | 7.AH.18.244; | 7.AH.18.243; | 7.AH.18.247; |
7.AH.26.157; | 7.AH.26.158; | 7.AH.26.196; | 7.AH.26.223; |
7.AH.26.240; | 7.AH.26.244; | 7.AH.26.243; | 7.AH.26.247; |
7.AH.27.157; | 7.AH.27.158; | 7.AH.27.196; | 7.AH.27.223; |
7.AH.27.240; | 7.AH.27.244; | 7.AH.27.243; | 7.AH.27.247; |
7.AH.29.157; | 7.AH.29.158; | 7.AH.29.196; | 7.AH.29.223; |
7.AH.29.240; | 7.AH.29.244; | 7.AH.29.243; | 7.AH.29.247; |
7.AH.54.157; | 7.AH.54.158; | 7.AH.54.196; | 7.AH.54.223; |
7.AH.54.240; | 7.AH.54.244; | 7.AH.54.243; | 7.AH.54.247; |
7.AH.55.157; | 7.AH.55.158; | 7.AH.55.196; | 7.AH.55.223; |
7.AH.55.240; | 7.AH.55.244; | 7.AH.55.243; | 7.AH.55.247; |
7.AH.56.157; | 7.AH.56.158; | 7.AH.56.196; | 7.AH.56.223; |
7.AH.56.240; | 7.AH.56.244; | 7.AH.56.243; | 7.AH.56.247; |
7.AH.157.157; | 7.AH.157.158; | 7.AH.157.196; | 7.AH.157.223; |
7.AH.157.240; | 7.AH.157.244; | 7.AH.157.243; | 7.AH.157.247; |
7.A H.196.157; | 7.AH.196.158; | 7.AH.196.196; | 7.AH.196.223; |
7.AH.196.240; | 7.AH.196.244; | 7.AH.196.243; | 7.AH.196.247; |
7.AH.223.157; | 7.AH.223.158; | 7.AH.223.196; | 7.AH.223.223; |
7.AH.223.240; | 7.AH.223.244; | 7.AH.223.243; | 7.AH.223.247; |
7.AH.240.157; | 7.AH.240.158; | 7.AH.240.196; | 7.AH.240.223; |
7.AH.240.240; | 7.AH.240.244; | 7.AH.240.243; | 7.AH.240.247; |
7.AH.244.157; | 7.AH.244.158; | 7.AH.244.196; | 7.AH.244.223; |
7.AH.244.240; | 7.AH.244.244; | 7.AH.244.243; | 7.AH.244.247; |
7.AH.247.157; | 7.AH.247.158; | 7.AH.247.196; | 7.AH.247.223; |
7.AH.247.240; | 7.AH.247.244; | 7.AH.247.243; | 7.AH.247.247; |
7.AJ的前体药物
7.AJ.4.157; | 7.AJ.4.158; | 7.AJ.4.196; | 7.AJ.4.223; | |
7.AJ.4.240; | 7.AJ.4.244; | 7.AJ.4.243; | 7.AJ.4.247; | 7.AJ.5.157; |
7.AJ.5.158; | 7.AJ.5.196; | 7.AJ.5.223; | 7.AJ.5.240; | 7.AJ.5.244; |
7.AJ.5.243; | 7.AJ.5.247; | 7.AJ.7.157; | 7.AJ.7.158; | 7.AJ.7.196; |
7.AJ.7.223; | 7.AJ.7.240; | 7.AJ.7.244; | 7.AJ.7.243; | 7.AJ.7.247; |
7.AJ.15.157; | 7.AJ.15.158; | 7.AJ.15.196; | 7.AJ.15.223; |
7.AJ.15.240; | 7.AJ.15.244; | 7.AJ.15.243; | 7.AJ.15.247; |
7.AJ.16.157; | 7.AJ.16.158; | 7.AJ.16.196; | 7.AJ.16.223; |
7.AJ.16.240; | 7.AJ.16.244; | 7.AJ.16.243; | 7.AJ.16.247; |
7.AJ.18.157; | 7.AJ.18.158; | 7.AJ.18.196; | 7.AJ.18.223; |
7.AJ.18.240; | 7.AJ.18.244; | 7.AJ.18.243; | 7.AJ.18.247; |
7.AJ.26.157; | 7.AJ.26.158; | 7.AJ.26.196; | 7.AJ.26.223; |
7.AJ.26.240; | 7.AJ.26.244; | 7.AJ.26.243; | 7.AJ.26.247; |
7.AJ.27.157; | 7.AJ.27.158; | 7.AJ.27.196; | 7.AJ.27.223; |
7.AJ.27.240; | 7.AJ.27.244; | 7.AJ.27.243; | 7.AJ.27.247; |
7.AJ.29.157; | 7.AJ.29.158; | 7.AJ.29.196; | 7.AJ.29.223; |
7.AJ.29.240; | 7.AJ.29.244; | 7.AJ.29.243; | 7.AJ.29.247; |
7.AJ.54.157; | 7.AJ.54.158; | 7.AJ.54.196; | 7.AJ.54.223; |
7.AJ.54.240; | 7.AJ.54.244; | 7.AJ.54.243; | 7.AJ.54.247; |
7.AJ.55.157; | 7.AJ.55.158; | 7.AJ.55.196; | 7.AJ.55.223; |
7.AJ.55.240; | 7.AJ.55.244; | 7.AJ.55.243; | 7.AJ.55.247; |
7.AJ.56.157; | 7.AJ.56.158; | 7.AJ.56.196; | 7.AJ.56.223; |
7.AJ.56.240; | 7.AJ.56.244; | 7.AJ.56.243; | 7.AJ.56.247; |
7.AJ.157.157; | 7.AJ.157.158; | 7.AJ.157.196; | 7.AJ.157.223; |
7.AJ.157.240; | 7.AJ.157.244; | 7.AJ.157.243; | 7.AJ.157.247; |
7.AJ.196.157; | 7.AJ.196.158; | 7.AJ.196.196; | 7.AJ.196.223; |
7.AJ.196.240; | 7.AJ.196.244; | 7.AJ.196.243; | 7.AJ.196.247; |
7.AJ.223.157; | 7.AJ.223.158; | 7.AJ.223.196; | 7.AJ.223.223; |
7.AJ.223.240; | 7.AJ.223.244; | 7.AJ.223.243; | 7.AJ.223.247; |
7.AJ.240.157; | 7.AJ.240.158; | 7.AJ.240.196; | 7.AJ.240.223; |
7.AJ.240.240; | 7.AJ.240.244; | 7.AJ.240.243; | 7.AJ.240.247; |
7.AJ.244.157; | 7.AJ.244.158; | 7.AJ.244.196; | 7.AJ.244.223; |
7.AJ.244.240; | 7.AJ.244.244; | 7.AJ.244.243; | 7.AJ.244.247; |
7.AJ.247.157; | 7.AJ.247.158; | 7.AJ.247.196; | 7.AJ.247.223; |
7.AJ.247.240; | 7.AJ.247.244; | 7.AJ.247.243; | 7.AJ.247.247; |
7.AN的前体药物
7.AN.4.157; | 7.AN.4.158; | 7.AN.4.196; | 7.AN.4.223; | |
7.AN.4.240; | 7.AN.4.244; | 7.AN.4.243; | 7.AN.4.247; | 7.AN.5.157; |
7.AN.5.158; | 7.AN.5.196; | 7.AN.5.223; | 7.AN.5.240; | 7.AN.5.244; |
7.AN.5.243; | 7.AN.5.247; | 7.AN.7.157; | 7.AN.7.158; | 7.AN.7.196; |
7.AN.7.223; | 7.AN.7.240; | 7.AN.7.244; | 7.AN.7.243; | 7.AN.7.247; |
7.AN.15.157; | 7.AN.15.158; | 7.AN.15.196; | 7.AN.15.223; |
7.AN.15.240; | 7.AN.15.244; | 7.AN.15.243; | 7.AN.15.247; |
7.AN.16.157; | 7.AN.16.158; | 7.AN.16.196; | 7.AN.16.223; |
7.AN.16.240; | 7.AN.16.244; | 7.AN.16.243; | 7.AN.16.247; |
7.AN.18.157; | 7.AN.18.158; | 7.AN.18.196; | 7.AN.18.223; |
7.AN.18.240; | 7.AN.18.244; | 7.AN.18.243; | 7.AN.18.247; |
7.AN.26.157; | 7.AN.26.158; | 7.AN.26.196; | 7.AN.26.223; |
7.AN.26.240; | 7.AN.26.244; | 7.AN.26.243; | 7.AN.26.247; |
7.AN.27.157; | 7.AN.27.158; | 7.AN.27.196; | 7.AN.27.223; |
7.AN.27.240; | 7.AN.27.244; | 7.AN.27.243; | 7.AN.27.247; |
7.AN.29.157; | 7.AN.29.158; | 7.AN.29.196; | 7.AN.29.223; |
7.AN.29.240; | 7.AN.29.244; | 7.AN.29.243; | 7.AN.29.247; |
7.AN.54.157; | 7.AN.54.158; | 7.AN.54.196; | 7.AN.54.223; |
7.AN.54.240; | 7.AN.54.244; | 7.AN.54.243; | 7.AN.54.247; |
7.AN.55.157; | 7.AN.55.158; | 7.AN.55.196; | 7.AN.55.223; |
7.AN.55.240; | 7.AN.55.244; | 7.AN.55.243; | 7.AN.55.247; |
7.AN.56.157; | 7.AN.56.158; | 7.AN.56.196; | 7.AN.56.223; |
7.AN.56.240; | 7.AN.56.244; | 7.AN.56.243; | 7.AN.56.247; |
7.AN.157.157; | 7.AN.157.158; | 7.AN.157.196; | 7.AN.157.223; |
7.AN.157.240; | 7.AN.157.244; | 7.AN.157.243; | 7.AN.157.247; |
7.AN.196.157; | 7.AN.196.158; | 7.AN.196.196; | 7.AN.196.223; |
7.AN.196.240; | 7.AN.196.244; | 7.AN.196.243; | 7.AN.196.247; |
7.AN.223.157; | 7.AN.223.158; | 7.AN.223.196; | 7.AN.223.223; |
7.AN.223.240; | 7.AN.223.244; | 7.AN.223.243; | 7.AN.223.247; |
7.AN.240.157; | 7.AN.240.158; | 7.AN.240.196; | 7.AN.240.223; |
7.AN.240.240; | 7.AN.240.244; | 7.AN.240.243; | 7.AN.240.247; |
7.AN.244.157; | 7.AN.244.158; | 7.AN.244.196; | 7.AN.244.223; |
7.AN.244.240; | 7.AN.244.244; | 7.AN.244.243; | 7.AN.244.247; |
7.AN.247.157; | 7.AN.247.158; | 7.AN.247.196; | 7.AN.247.223; |
7.AN.247.240; | 7.AN.247.244; | 7.AN.247.243; | 7.AN.247.247; |
7.AP的前体药物
7.AP.4.157; | 7.AP.4.158; | 7.AP.4.196; | 7.AP.4.223; | |
7.AP.4.240; | 7.AP.4.244; | 7.AP.4.243; | 7.AP.4.247; | 7.AP.5.157; |
7.AP.5.158; | 7.AP.5.196; | 7.AP.5.223; | 7.AP.5.240; | 7.AP.5.244; |
7.AP.5.243; | 7.AP.5.247; | 7.AP.7.157; | 7.AP.7.158; | 7.AP.7.196; |
7.AP.7.223; | 7.AP.7.240; | 7.AP.7.244; | 7.AP.7.243; | 7.AP.7.247; |
7.AP.15.157; | 7.AP.15.158; | 7.AP.15.196; | 7.AP.15.223; |
7.AP.15.240; | 7.AP.15.244; | 7.AP.15.243; | 7.AP.15.247; |
7.AP.16.157; | 7.AP.16.158; | 7.AP.16.196; | 7.AP.16.223; |
7.AP.16.240; | 7.AP.16.244; | 7.AP.16.243; | 7.AP.16.247; |
7.AP.18.157; | 7.AP.18.158; | 7.AP.18.196; | 7.AP.18.223; |
7.AP.18.240; | 7.AP.18.244; | 7.AP.18.243; | 7.AP.18.247; |
7.AP.26.157; | 7.AP.26.158; | 7.AP.26.196; | 7.AP.26.223; |
7.AP.26.240; | 7.AP.26.244; | 7.AP.26.243; | 7.AP.26.247; |
7.AP.27.157; | 7.AP.27.158; | 7.AP.27.196; | 7.AP.27.223; |
7.AP.27.240; | 7.AP.27.244; | 7.AP.27.243; | 7.AP.27.247; |
7.AP.29.157; | 7.AP.29.158; | 7.AP.29.196; | 7.AP.29.223; |
7.AP.29.240; | 7.AP.29.244; | 7.AP.29.243; | 7.AP.29.247; |
7.AP.54.157; | 7.AP.54.158; | 7.AP.54.196; | 7.AP.54.223; |
7.AP.54.240; | 7.AP.54.244; | 7.AP.54.243; | 7.AP.54.247; |
7.AP.55.157; | 7.AP.55.158; | 7.AP.55.196; | 7.AP.55.223; |
7.AP.55.240; | 7.AP.55.244; | 7.AP.55.243; | 7.AP.55.247; |
7.AP.56.157; | 7.AP.56.158; | 7.AP.56.196; | 7.AP.56.223; |
7.AP.56.240; | 7.AP.56.244; | 7.AP.56.243; | 7.AP.56.247; |
7.AP.157.157; | 7.AP.157.158; | 7.AP.157.196; | 7.AP.157.223; |
7.AP.157.240; | 7.AP.157.244; | 7.AP.157.243; | 7.AP.157.247; |
7.AP.196.157; | 7.AP.196.158; | 7.AP.196.196; | 7.AP.196.223; |
7.AP.196.240; | 7.AP.196.244; | 7.AP.196.243; | 7.AP.196.247; |
7.AP.223.157; | 7.AP.223.158; | 7.AP.223.196; | 7.AP.223.223; |
7.AP.223.240; | 7.AP.223.244; | 7.AP.223.243; | 7.AP.223.247; |
7.AP.240.157; | 7.AP.240.158; | 7.AP.240.196; | 7.AP.240.223; |
7.AP.240.240; | 7.AP.240.244; | 7.AP.240.243; | 7.AP.240.247; |
7.AP.244.157; | 7.AP.244.158; | 7.AP.244.196; | 7.AP.244.223; |
7.AP.244.240; | 7.AP.244.244; | 7.AP.244.243; | 7.AP.244.247; |
7.AP.247.157; | 7.AP.247.158; | 7.AP.247.196; | 7.AP.247.223; |
7.AP.247.240; | 7.AP.247.244; | 7.AP.247.243; | 7.AP.247.247; |
7.AZ的前体药物
7.AZ.4.157; | 7.AZ.4.158; | 7.AZ.4.196; | 7.AZ.4.223; | |
7.AZ.4.240; | 7.AZ.4.244; | 7.AZ.4.243; | 7.AZ.4.247; | 7.AZ.5.157; |
7.AZ.5.158; | 7.AZ.5.196; | 7.AZ.5.223; | 7.AZ.5.240; | 7.AZ.5.244; |
7.AZ.5.243; | 7.AZ.5.247; | 7.AZ.7.157; | 7.AZ.7.158; | 7.AZ.7.196; |
7.AZ.7.223; | 7.AZ.7.240; | 7.AZ.7.244; | 7.AZ.7.243; | 7.AZ.7.247; |
7.AZ.15.157; | 7.AZ.15.158; | 7.AZ.15.196; | 7.AZ.15.223; |
7.AZ.15.240; | 7.AZ.15.244; | 7.AZ.15.243; | 7.AZ.15.247; |
7.AZ.16.157; | 7.AZ.16.158; | 7.AZ.16.196; | 7.AZ.16.223; |
7.AZ.16.240; | 7.AZ.16.244; | 7.AZ.16.243; | 7.AZ.16.247; |
7.AZ.18.157; | 7.AZ.18.158; | 7.AZ.18.196; | 7.AZ.18.223; |
7.AZ.18.240; | 7.AZ.18.244; | 7.AZ.18.243; | 7.AZ.18.247; |
7.AZ.26.157; | 7.AZ.26.158; | 7.AZ.26.196; | 7.AZ.26.223; |
7.AZ.26.240; | 7.AZ.26.244; | 7.AZ.26.243; | 7.AZ.26.247; |
7.AZ.27.157; | 7.AZ.27.158; | 7.AZ.27.196; | 7.AZ.27.223; |
7.AZ.27.240; | 7.AZ.27.244; | 7.AZ.27.243; | 7.AZ.27.247; |
7.AZ.29.157; | 7.AZ.29.158; | 7.AZ.29.196; | 7.AZ.29.223; |
7.AZ.29.240; | 7.AZ.29.244; | 7.AZ.29.243; | 7.AZ.29.247; |
7.AZ.54.157; | 7.AZ.54.158; | 7.AZ.54.196; | 7.AZ.54.223; |
7.AZ.54.240; | 7.AZ.54.244; | 7.AZ.54.243; | 7.AZ.54.247; |
7.AZ.55.157; | 7.AZ.55.158; | 7.AZ.55.196; | 7.AZ.55.223; |
7.AZ.55.240; | 7.AZ.55.244; | 7.AZ.55.243; | 7.AZ.55.247; |
7.AZ.56.157; | 7.AZ.56.158; | 7.AZ.56.196; | 7.AZ.56.223; |
7.AZ.56.240; | 7.AZ.56.244; | 7.AZ.56.243; | 7.AZ.56.247; |
7.AZ.157.157; | 7.AZ.157.158; | 7.AZ.157.196; | 7.AZ.157.223; |
7.AZ.157.240; | 7.AZ.157.244; | 7.AZ.157.243; | 7.AZ.157.247; |
7.AZ.196.157; | 7.AZ.196.158; | 7.AZ.196.196; | 7.AZ.196.223; |
7.AZ.196.240; | 7.AZ.196.244; | 7.AZ.196.243; | 7.AZ.196.247; |
7.AZ.223.157; | 7.AZ.223.158; | 7.AZ.223.196; | 7.AZ.223.223; |
7.AZ.223.240; | 7.AZ.223.244; | 7.AZ.223.243; | 7.AZ.223.247; |
7.AZ.240.157; | 7.AZ.240.158; | 7.AZ.240.196; | 7.AZ.240.223; |
7.AZ.240.240; | 7.AZ.240.244; | 7.AZ.240.243; | 7.AZ.240.247; |
7.AZ.244.157; | 7.AZ.244.158; | 7.AZ.244.196; | 7.AZ.244.223; |
7.AZ.244.240; | 7.AZ.244.244; | 7.AZ.244.243; | 7.AZ.244.247; |
7.AZ.247.157; | 7.AZ.247.158; | 7.AZ.247.196; | 7.AZ.247.223; |
7.AZ.247.240; | 7.AZ.247.244; | 7.AZ.247.243; | 7.AZ.247.247; |
7.BF的前体药物
7.BF.4.157; | 7.BF.4.158; | 7.BF.4.196; | 7.BF.4.223; | |
7.BF.4.240; | 7.BF.4.244; | 7.BF.4.243; | 7.BF.4.247; | 7.BF.5.157; |
7.BF.5.158; | 7.BF.5.196; | 7.BF.5.223; | 7.BF.5.240; | 7.BF.5.244; |
7.BF.5.243; | 7.BF.5.247; | 7.BF.7.157; | 7.BF.7.158; | 7.BF.7.196; |
7.BF.7.223; | 7.BF.7.240; | 7.BF.7.244; | 7.BF.7.243; | 7.BF.7.247; |
7.BF.15.157; | 7.BF.15.158; | 7.BF.15.196; | 7.BF.15.223; |
7.BF.15.240; | 7.BF.15.244; | 7.BF.15.243; | 7.BF.15.247; |
7.BF.16.157; | 7.BF.16.158; | 7.BF.16.196; | 7.BF.16.223; |
7.BF.16.240; | 7.BF.16.244; | 7.BF.16.243; | 7.BF.16.247; |
7.BF.18.157; | 7.BF.18.158; | 7.BF.18.196; | 7.BF.18.223; |
7.BF.18.240; | 7.BF.18.244; | 7.BF.18.243; | 7.BF.18.247; |
7.BF.26.157; | 7.BF.26.158; | 7.BF.26.196; | 7.BF.26.223; |
7.BF.26.240; | 7.BF.26.244; | 7.BF.26.243; | 7.BF.26.247; |
7.BF.27.157; | 7.BF.27.158; | 7.BF.27.196; | 7.BF.27.223; |
7.BF.27.240; | 7.BF.27.244; | 7.BF.27.243; | 7.BF.27.247; |
7.BF.29.157; | 7.BF.29.158; | 7.BF.29.196; | 7.BF.29.223; |
7.BF.29.240; | 7.BF.29.244; | 7.BF.29.243; | 7.BF.29.247; |
7.BF.54.157; | 7.BF.54.158; | 7.BF.54.196; | 7.BF.54.223; |
7.BF.54.240; | 7.BF.54.244; | 7.BF.54.243; | 7.BF.54.247; |
7.BF.55.157; | 7.BF.55.158; | 7.BF.55.196; | 7.BF.55.223; |
7.BF.55.240; | 7.BF.55.244; | 7.BF.55.243; | 7.BF.55.247; |
7.BF.56.157; | 7.BF.56.158; | 7.BF.56.196; | 7.BF.56.223; |
7.BF.56.240; | 7.BF.56.244; | 7.BF.56.243; | 7.BF.56.247; |
7.BF.157.157; | 7.BF.157.158; | 7.BF.157.196; | 7.BF.157.223; |
7.BF.157.240; | 7.BF.157.244; | 7.BF.157.243; | 7.BF.157.247; |
7.BF.196.157; | 7.BF.196.158; | 7.BF.196.196; | 7.BF.196.223; |
7.BF.196.240; | 7.BF.196.244; | 7.BF.196.243; | 7.BF.196.247; |
7.BF.223.157; | 7.BF.223.158; | 7.BF.223.196; | 7.BF.223.223; |
7.BF.223.240; | 7.BF.223.244; | 7.BF.223.243; | 7.BF.223.247; |
7.BF.240.157; | 7.BF.240.158; | 7.BF.240.196; | 7.BF.240.223; |
7.BF.240.240; | 7.BF.240.244; | 7.BF.240.243; | 7.BF.240.247; |
7.BF.244.157; | 7.BF.244.158; | 7.BF.244.196; | 7.BF.244.223; |
7.BF.244.240; | 7.BF.244.244; | 7.BF.244.243; | 7.BF.244.247; |
7.BF.247.157; | 7.BF.247.158; | 7.BF.247.196; | 7.BF.247.223; |
7.BF.247.240; | 7.BF.247.244; | 7.BF.247.243; | 7.BF.247.247; |
7.CI的前体药物
7.CI.4.157; | 7.CI.4.158; | 7.CI.4.196; | 7.CI.4.223; | |
7.CI.4.240; | 7.CI.4.244; | 7.CI.4.243; | 7.CI.4.247; | 7.CI.5.157; |
7.CI.5.158; | 7.CI.5.196; | 7.CI.5.223; | 7.CI.5.240; | 7.CI.5.244; |
7.C I.5.243; | 7.CI.5.247; | 7.C I.7.157; | 7.CI.7.158; | 7.CI.7.196; |
7.CI.7.223; | 7.CI.7.240; | 7.CI.7.244; | 7.CI.7.243; | 7.CI.7.247; |
7.CI.15.157; | 7.CI.15.158; | 7.CI.15.196; | 7.CI.15.223; |
7.CI.15.240; | 7.CI.15.244; | 7.CI.15.243; | 7.CI.15.247; |
7.CI.16.157; | 7.CI.16.158; | 7.CI.16.196; | 7.CI.16.223; |
7.CI.16.240; | 7.CI.16.244; | 7.CI.16.243; | 7.CI.16.247; |
7.CI.18.157; | 7.CI.18.158; | 7.CI.18.196; | 7.CI.18.223; |
7.CI.18.240; | 7.CI.18.244; | 7.CI.18.243; | 7.CI.18.247; |
7.CI.26.157; | 7.CI.26.158; | 7.CI.26.196; | 7.CI.26.223; |
7.CI.26.240; | 7.CI.26.244; | 7.CI.26.243; | 7.CI.26.247; |
7.CI.27.157; | 7.CI.27.158; | 7.CI.27.196; | 7.CI.27.223; |
7.CI.27.240; | 7.CI.27.244; | 7.CI.27.243; | 7.CI.27.247; |
7.CI.29.157; | 7.CI.29.158; | 7.CI.29.196; | 7.CI.29.223; |
7.CI.29.240; | 7.CI.29.244; | 7.CI.29.243; | 7.CI.29.247; |
7.CI.54.157; | 7.CI.54.158; | 7.CI.54.196; | 7.CI.54.223; |
7.CI.54.240; | 7.CI.54.244; | 7.CI.54.243; | 7.CI.54.247; |
7.CI.55.157; | 7.CI.55.158; | 7.CI.55.196; | 7.CI.55.223; |
7.CI.55.240; | 7.CI.55.244; | 7.CI.55.243; | 7.CI.55.247; |
7.CI.56.157; | 7.CI.56.158; | 7.CI.56.196; | 7.CI.56.223; |
7.CI.56.240; | 7.CI.56.244; | 7.CI.56.243; | 7.CI.56.247; |
7.CI.157.157; | 7.CI.157.158; | 7.CI.157.196; | 7.CI.157.223; |
7.CI.157.240; | 7.CI.157.244; | 7.CI.157.243; | 7.CI.157.247; |
7.CI.196.157; | 7.CI.196.158; | 7.CI.196.196; | 7.CI.196.223; |
7.CI.196.240; | 7.CI.196.244; | 7.CI.196.243; | 7.CI.196.247; |
7.CI.223.157; | 7.CI.223.158; | 7.CI.223.196; | 7.CI.223.223; |
7.CI.223.240; | 7.CI.223.244; | 7.CI.223.243; | 7.CI.223.247; |
7.CI.240.157; | 7.CI.240.158; | 7.CI.240.196; | 7.CI.240.223; |
7.CI.240.240; | 7.CI.240.244; | 7.CI.240.243; | 7.CI.240.247; |
7.CI.244.157; | 7.CI.244.158; | 7.CI.244.196; | 7.CI.244.223; |
7.CI.244.240; | 7.CI.244.244; | 7.CI.244.243; | 7.CI.244.247; |
7.CI.247.157; | 7.CI.247.158; | 7.CI.247.196; | 7.CI.247.223; |
7.CI.247.240; | 7.CI.247.244; | 7.CI.247.243; | 7.CI.247.247; |
7.CO的前体药物
7.CO.4.157; | 7.CO.4.158; | 7.CO.4.196; | 7.CO.4.223; | |
7.CO.4.240; | 7.CO.4.244; | 7.CO.4.243; | 7.CO.4.247; | 7.CO.5.157; |
7.CO.5.158; | 7.CO.5.196; | 7.CO.5.223; | 7.CO.5.240; | 7.CO.5.244; |
7.CO.5.243; | 7.CO.5.247; | 7.CO.7.157; | 7.CO.7.158; | 7.CO.7.196; |
7.CO.7.223; | 7.CO.7.240; | 7.CO.7.244; | 7.CO.7.243; | 7.CO.7.247; |
7.CO.15.157; | 7.CO.15.158; | 7.CO.15.196; | 7.CO.15.223; |
7.CO.15.240; | 7.CO.15.244; | 7.CO.15.243; | 7.CO.15.247; |
7.CO.16.157; | 7.CO.16.158; | 7.CO.16.196; | 7.CO.16.223; |
7.CO.16.240; | 7.CO.16.244; | 7.CO.16.243; | 7.CO.16.247; |
7.CO.18.157; | 7.CO.18.158; | 7.CO.18.196; | 7.CO.18.223; |
7.CO.18.240; | 7.CO.18.244; | 7.CO.18.243; | 7.CO.18.247; |
7.CO.26.157; | 7.CO.26.158; | 7.CO.26.196; | 7.CO.26.223; |
7.CO.26.240; | 7.CO.26.244; | 7.CO.26.243; | 7.CO.26.247; |
7.CO.27.157; | 7.CO.27.158; | 7.CO.27.196; | 7.CO.27.223; |
7.CO.27.240; | 7.CO.27.244; | 7.CO.27.243; | 7.CO.27.247; |
7.CO.29.157; | 7.CO.29.158; | 7.CO.29.196; | 7.CO.29.223; |
7.CO.29.240; | 7.CO.29.244; | 7.CO.29.243; | 7.CO.29.247; |
7.CO.54.157; | 7.CO.54.158; | 7.CO.54.196; | 7.CO.54.223; |
7.CO.54.240; | 7.CO.54.244; | 7.CO.54.243; | 7.CO.54.247; |
7.CO.55.157; | 7.CO.55.158; | 7.CO.55.196; | 7.CO.55.223; |
7.CO.55.240; | 7.CO.55.244; | 7.CO.55.243; | 7.CO.55.247; |
7.CO.56.157; | 7.CO.56.158; | 7.CO.56.196; | 7.CO.56.223; |
7.CO.56.240; | 7.CO.56.244; | 7.CO.56.243; | 7.CO.56.247; |
7.CO.157.157; | 7.CO.157.158; | 7.CO.157.196; | 7.CO.157.223; |
7.CO.157.240; | 7.CO.157.244; | 7.CO.157.243; | 7.CO.157.247; |
7.CO.196.157; | 7.CO.196.158; | 7.CO.196.196; | 7.CO.196.223; |
7.CO.196.240; | 7.CO.196.244; | 7.CO.196.243; | 7.CO.196.247; |
7.CO.223.157; | 7.CO.223.158; | 7.CO.223.196; | 7.CO.223.223; |
7.CO.223.240; | 7.CO.223.244; | 7.CO.223.243; | 7.CO.223.247; |
7.CO.240.157; | 7.CO.240.158; | 7.CO.240.196; | 7.CO.240.223; |
7.CO.240.240; | 7.CO.240.244; | 7.CO.240.243; | 7.CO.240.247; |
7.CO.244.157; | 7.CO.244.158; | 7.CO.244.196; | 7.CO.244.223; |
7.CO.244.240; | 7.CO.244.244; | 7.CO.244.243; | 7.CO.244.247; | |
7.CO.4.157; | 7.CO.4.158; | 7.CO.4.196; | 7.CO.4.223; | 7.CO.4.240; |
7.CO.4.244; | 7.CO.4.243; | 7.CO.4.247; |
8.AH的前体药物
8.AH.4.157; | 8.AH.4.158; | 8.AH.4.196; | 8.AH.4.223; | |
8.AH.4.240; | 8.AH.4.244; | 8.AH.4.243; | 8.AH.4.247; | 8.AH.5.157; |
8.AH.5.158; | 8.AH.5.196; | 8.AH.5.223; | 8.AH.5.240; | 8.AH.5.244; |
8.AH.5.243; | 8.AH.5.247; | 8.AH.7.157; | 8.AH.7.158; | 8.AH.7.196; |
8.AH.7.223; | 8.AH.7.240; | 8.AH.7.244; | 8.AH.7.243; | 8.AH.7.247; |
8.AH.15.157; | 8.AH.15.158; | 8.AH.15.196; | 8.AH.15.223; |
8.AH.15.240; | 8.AH.15.244; | 8.AH.15.243; | 8.AH.15.247; |
8.AH.16.157; | 8.AH.16.158; | 8.AH.16.196; | 8.AH.16.223; |
8.AH.16.240; | 8.AH.16.244; | 8.AH.16.243; | 8.AH.16.247; |
8.AH.18.157; | 8.AH.18.158; | 8.AH.18.196; | 8.AH.18.223; |
8.AH.18.240; | 8.AH.18.244; | 8.AH.18.243; | 8.AH.18.247; |
8.AH.26.157; | 8.AH.26.158; | 8.AH.26.196; | 8.AH.26.223; |
8.AH.26.240; | 8.AH.26.244; | 8.AH.26.243; | 8.AH.26.247; |
8.AH.27.157; | 8.AH.27.158; | 8.AH.27.196; | 8.AH.27.223; |
8.AH.27.240; | 8.AH.27.244; | 8.AH.27.243; | 8.AH.27.247; |
8.AH.29.157; | 8.AH.29.158; | 8.AH.29.196; | 8.AH.29.223; |
8.AH.29.240; | 8.AH.29.244; | 8.AH.29.243; | 8.AH.29.247; |
8.AH.54.157; | 8.AH.54.158; | 8.AH.54.196; | 8.AH.54.223; |
8.AH.54.240; | 8.AH.54.244; | 8.AH.54.243; | 8.AH.54.247; |
8.AH.55.157; | 8.AH.55.158; | 8.AH.55.196; | 8.AH.55.223; |
8.AH.55.240; | 8.AH.55.244; | 8.AH.55.243; | 8.AH.55.247; |
8.AH.56.157; | 8.AH.56.158; | 8.AH.56.196; | 8.AH.56.223; |
8.AH.56.240; | 8.AH.56.244; | 8.AH.56.243; | 8.AH.56.247; |
8.AH.157.157; | 8.AH.157.158; | 8.AH.157.196; | 8.AH.157.223; |
8.AH.157.240; | 8.AH.157.244; | 8.AH.157.243; | 8.AH.157.247; |
8.AH.196.157; | 8.AH.196.158; | 8.AH.196.196; | 8.AH.196.223; |
8.AH.196.240; | 8.AH.196.244; | 8.AH.196.243; | 8.AH.196.247; |
8.AH.223.157; | 8.AH.223.158; | 8.AH.223.196; | 8.AH.223.223; |
8.AH.223.240; | 8.AH.223.244; | 8.AH.223.243; | 8.AH.223.247; |
8.AH.240.157; | 8.AH.240.158; | 8.AH.240.196; | 8.AH.240.223; |
8.AH.240.240; | 8.AH.240.244; | 8.AH.240.243; | 8.AH.240.247; |
8.AH.244.157; | 8.AH.244.158; | 8.AH.244.196; | 8.AH.244.223; |
8.AH.244.240; | 8.AH.244.244; | 8.AH.244.243; | 8.AH.244.247; |
8.AH.247.157; | 8.AH.247.158; | 8.AH.247.196; | 8.AH.247.223; |
8.AH.247.240; | 8.AH.247.244; | 8.AH.247.243; | 8.AH.247.247; |
8.AJ的前体药物
8.AJ.4.157; | 8.AJ.4.158; | 8.AJ.4.196; | 8.AJ.4.223; | |
8.AJ.4.240; | 8.AJ.4.244; | 8.AJ.4.243; | 8.AJ.4.247; | 8.AJ.5.157; |
8.AJ.5.158; | 8.AJ.5.196; | 8.AJ.5.223; | 8.AJ.5.240; | 8.AJ.5.244; |
8.AJ.5.243; | 8.AJ.5.247; | 8.AJ.7.157; | 8.AJ.7.158; | 8.AJ.7.196; |
8.AJ.7.223; | 8.AJ.7.240; | 8.AJ.7.244; | 8.AJ.7.243; | 8.AJ.7.247; |
8.AJ.15.157; | 8.AJ.15.158; | 8.AJ.15.196; | 8.AJ.15.223; |
8.AJ.15.240; | 8.AJ.15.244; | 8.AJ.15.243; | 8.AJ.15.247; |
8.AJ.16.157; | 8.AJ.16.158; | 8.AJ.16.196; | 8.AJ.16.223; |
8.AJ.16.240; | 8.AJ.16.244; | 8.AJ.16.243; | 8.AJ.16.247; |
8.AJ.18.157; | 8.AJ.18.158; | 8.AJ.18.196; | 8.AJ.18.223; |
8.AJ.18.240; | 8.AJ.18.244; | 8.AJ.18.243; | 8.AJ.18.247; |
8.AJ.26.157; | 8.AJ.26.158; | 8.AJ.26.196; | 8.AJ.26.223; |
8.AJ.26.240; | 8.AJ.26.244; | 8.AJ.26.243; | 8.AJ.26.247; |
8.AJ.27.157; | 8.AJ.27.158; | 8.AJ.27.196; | 8.AJ.27.223; |
8.AJ.27.240; | 8.AJ.27.244; | 8.AJ.27.243; | 8.AJ.27.247; |
8.AJ.29.157; | 8.AJ.29.158; | 8.AJ.29.196; | 8.AJ.29.223; |
8.AJ.29.240; | 8.AJ.29.244; | 8.AJ.29.243; | 8.AJ.29.247; |
8.AJ.54.157; | 8.AJ.54.158; | 8.AJ.54.196; | 8.AJ.54.223; |
8.AJ.54.240; | 8.AJ.54.244; | 8.AJ.54.243; | 8.AJ.54.247; |
8.AJ.55.157; | 8.AJ.55.158; | 8.AJ.55.196; | 8.AJ.55.223; |
8.AJ.55.240; | 8.AJ.55.244; | 8.AJ.55.243; | 8.AJ.55.247; |
8.AJ.56.157; | 8.AJ.56.158; | 8.AJ.56.196; | 8.AJ.56.223; |
8.AJ.56.240; | 8.AJ.56.244; | 8.AJ.56.243; | 8.AJ.56.247; |
8.AJ.157.157; | 8.AJ.157.158; | 8.AJ.157.196; | 8.AJ.157.223; |
8.AJ.157.240; | 8.AJ.157.244; | 8.AJ.157.243; | 8.AJ.157.247; |
8.AJ.196.157; | 8.AJ.196.158; | 8.AJ.196.196; | 8.AJ.196.223; |
8.AJ.196.240; | 8.AJ.196.244; | 8.AJ.196.243; | 8.AJ.196.247; |
8.AJ.223.157; | 8.AJ.223.158; | 8.AJ.223.196; | 8.AJ.223.223; |
8.AJ.223.240; | 8.AJ.223.244; | 8.AJ.223.243; | 8.AJ.223.247; |
8.AJ.240.157; | 8.AJ.240.158; | 8.AJ.240.196; | 8.AJ.240.223; |
8.AJ.240.240; | 8.AJ.240.244; | 8.AJ.240.243; | 8.AJ.240.247; |
8.AJ.244.157; | 8.AJ.244.158; | 8.AJ.244.196; | 8.AJ.244.223; |
8.AJ.244.240; | 8.AJ.244.244; | 8.AJ.244.243; | 8.AJ.244.247; |
8.AJ.247.157; | 8.AJ.247.158; | 8.AJ.247.196; | 8.AJ.247.223; |
8.AJ.247.240; | 8.AJ.247.244; | 8.AJ.247.243; | 8.AJ.247.247; |
8.AN的前体药物
8.AN.4.157; | 8.AN.4.158; | 8.AN.4.196; | 8.AN.4.223; | |
8.AN.4.240; | 8.AN.4.244; | 8.AN.4.243; | 8.AN.4.247; | 8.AN.5.157; |
8.AN.5.158; | 8.AN.5.196; | 8.AN.5.223; | 8.AN.5.240; | 8.AN.5.244; |
8.AN.5.243; | 8.AN.5.247; | 8.AN.7.157; | 8.AN.7.158; | 8.AN.7.196; |
8.AN.7.223; | 8.AN.7.240; | 8.AN.7.244; | 8.AN.7.243; | 8.AN.7.247; |
8.AN.15.157; | 8.AN.15.158; | 8.AN.15.196; | 8.AN.15.223; |
8.AN.15.240; | 8.AN.15.244; | 8.AN.15.243; | 8.AN.15.247; |
8.AN.16.157; | 8.AN.16.158; | 8.AN.16.196; | 8.AN.16.223; |
8.AN.16.240; | 8.AN.16.244; | 8.AN.16.243; | 8.AN.16.247; |
8.AN.18.157; | 8.AN.18.158; | 8.AN.18.196; | 8.AN.18.223; |
8.AN.18.240; | 8.AN.18.244; | 8.AN.18.243; | 8.AN.18.247; |
8.AN.26.157; | 8.AN.26.158; | 8.AN.26.196; | 8.AN.26.223; |
8.AN.26.240; | 8.AN.26.244; | 8.AN.26.243; | 8.AN.26.247; |
8.AN.27.157; | 8.AN.27.158; | 8.AN.27.196; | 8.AN.27.223; |
8.AN.27.240; | 8.AN.27.244; | 8.AN.27.243; | 8.AN.27.247; |
8.AN.29.157; | 8.AN.29.158; | 8.AN.29.196; | 8.AN.29.223; |
8.AN.29.240; | 8.AN.29.244; | 8.AN.29.243; | 8.AN.29.247; |
8.AN.54.157; | 8.AN.54.158; | 8.AN.54.196; | 8.AN.54.223; |
8.AN.54.240; | 8.AN.54.244; | 8.AN.54.243; | 8.AN.54.247; |
8.AN.55.157; | 8.AN.55.158; | 8.AN.55.196; | 8.AN.55.223; |
8.AN.55.240; | 8.AN.55.244; | 8.AN.55.243; | 8.AN.55.247; |
8.AN.56.157; | 8.AN.56.158; | 8.AN.56.196; | 8.AN.56.223; |
8.AN.56.240; | 8.AN.56.244; | 8.AN.56.243; | 8.AN.56.247; |
8.AN.157.157; | 8.AN.157.158; | 8.AN.157.196; | 8.AN.157.223; |
8.AN.157.240; | 8.AN.157.244; | 8.AN.157.243; | 8.AN.157.247; |
8.AN.196.157; | 8.AN.196.158; | 8.AN.196.196; | 8.AN.196.223; |
8.AN.196.240; | 8.AN.196.244; | 8.AN.196.243; | 8.AN.196.247; |
8.AN.223.157; | 8.AN.223.158; | 8.AN.223.196; | 8.AN.223.223; |
8.AN.223.240; | 8.AN.223.244; | 8.AN.223.243; | 8.AN.223.247; |
8.AN.240.157; | 8.AN.240.158; | 8.AN.240.196; | 8.AN.240.223; |
8.AN.240.240; | 8.AN.240.244; | 8.AN.240.243; | 8.AN.240.247; |
8.AN.244.157; | 8.AN.244.158; | 8.AN.244.196; | 8.AN.244.223; |
8.AN.244.240; | 8.AN.244.244; | 8.AN.244.243; | 8.AN.244.247; |
8.AN.247.157; | 8.AN.247.158; | 8.AN.247.196; | 8.AN.247.223; |
8.AN.247.240; | 8.AN.247.244; | 8.AN.247.243; | 8.AN.247.247; |
8.AP的前体药物
8.AP.4.157; | 8.AP.4.158; | 8.AP.4.196; | 8.AP.4.223; | |
8.AP.4.240; | 8.AP.4.244; | 8.AP.4.243; | 8.AP.4.247; | 8.AP.5.157; |
8.AP.5.158; | 8.AP.5.196; | 8.AP.5.223; | 8.AP.5.240; | 8.AP.5.244; |
8.AP.5.243; | 8.AP.5.247; | 8.AP.7.157; | 8.AP.7.158; | 8.AP.7.196; |
8.AP.7.223; | 8.AP.7.240; | 8.AP.7.244; | 8.AP.7.243; | 8.AP.7.247; |
8.AP.15.157; | 8.AP.15.158; | 8.AP.15.196; | 8.AP.15.223; |
8.AP.15.240; | 8.AP.15.244; | 8.AP.15.243; | 8.AP.15.247; |
8.AP.16.157; | 8.AP.16.158; | 8.AP.16.196; | 8.AP.16.223; |
8.AP.16.240; | 8.AP.16.244; | 8.AP.16.243; | 8.AP.16.247; |
8.AP.18.157; | 8.AP.18.158; | 8.AP.18.196; | 8.AP.18.223; |
8.AP.18.240; | 8.AP.18.244; | 8.AP.18.243; | 8.AP.18.247; |
8.AP.26.157; | 8.AP.26.158; | 8.AP.26.196; | 8.AP.26.223; |
8.AP.26.240; | 8.AP.26.244; | 8.AP.26.243; | 8.AP.26.247; |
8.AP.27.157; | 8.AP.27.158; | 8.AP.27.196; | 8.AP.27.223; |
8.AP.27.240; | 8.AP.27.244; | 8.AP.27.243; | 8.AP.27.247; |
8.AP.29.157; | 8.AP.29.158; | 8.AP.29.196; | 8.AP.29.223; |
8.AP.29.240; | 8.AP.29.244; | 8.AP.29.243; | 8.AP.29.247; |
8.AP.54.157; | 8.AP.54.158; | 8.AP.54.196; | 8.AP.54.223; |
8.AP.54.240; | 8.AP.54.244; | 8.AP.54.243; | 8.AP.54.247; |
8.AP.55.157; | 8.AP.55.158; | 8.AP.55.196; | 8.AP.55.223; |
8.AP.55.240; | 8.AP.55.244; | 8.AP.55.243; | 8.AP.55.247; |
8.AP.56.157; | 8.AP.56.158; | 8.AP.56.196; | 8.AP.56.223; |
8.AP.56.240; | 8.AP.56.244; | 8.AP.56.243; | 8.AP.56.247; |
8.AP.157.157; | 8.AP.157.158; | 8.AP.157.196; | 8.AP.157.223; |
8.AP.157.240; | 8.AP.157.244; | 8.AP.157.243; | 8.AP.157.247; |
8.AP.196.157; | 8.AP.196.158; | 8.AP.196.196; | 8.AP.196.223; |
8.AP.196.240; | 8.AP.196.244; | 8.AP.196.243; | 8.AP.196.247; |
8.AP.223.157; | 8.AP.223.158; | 8.AP.223.196; | 8.AP.223.223; |
8.AP.223.240; | 8.AP.223.244; | 8.AP.223.243; | 8.AP.223.247; |
8.AP.240.157; | 8.AP.240.158; | 8.AP.240.196; | 8.AP.240.223; |
8.AP.240.240; | 8.AP.240.244; | 8.AP.240.243; | 8.AP.240.247; |
8.AP.244.157; | 8.AP.244.158; | 8.AP.244.196; | 8.AP.244.223; |
8.AP.244.240; | 8.AP.244.244; | 8.AP.244.243; | 8.AP.244.247; |
8.AP.247.157; | 8.AP.247.158; | 8.AP.247.196; | 8.AP.247.223; |
8.AP.247.240; | 8.AP.247.244; | 8.AP.247.243; | 8.AP.247.247; |
8.AZ的前体药物
8.AZ.4.157; | 8.AZ.4.158; | 8.AZ.4.196; | 8.AZ.4.223; | |
8.AZ.4.240; | 8.AZ.4.244; | 8.AZ.4.243; | 8.AZ.4.247; | 8.AZ.5.157; |
8.AZ.5.158; | 8.AZ.5.196; | 8.AZ.5.223; | 8.AZ.5.240; | 8.AZ.5.244; |
8.AZ.5.243; | 8.AZ.5.247; | 8.AZ.7.157; | 8.AZ.7.158; | 8.AZ.7.196; |
8.AZ.7.223; | 8.AZ.7.240; | 8.AZ.7.244; | 8.AZ.7.243; | 8.AZ.7.247; |
8.AZ.15.157; | 8.AZ.15.158; | 8.AZ.15.196; | 8.AZ.15.223; |
8.AZ.15.240; | 8.AZ.15.244; | 8.AZ.15.243; | 8.AZ.15.247; |
8.AZ.16.157; | 8.AZ.16.158; | 8.AZ.16.196; | 8.AZ.16.223; |
8.AZ.16.240; | 8.AZ.16.244; | 8.AZ.16.243; | 8.AZ.16.247; |
8.AZ.18.157; | 8.AZ.18.158; | 8.AZ.18.196; | 8.AZ.18.223; |
8.AZ.18.240; | 8.AZ.18.244; | 8.AZ.18.243; | 8.AZ.18.247; |
8.AZ.26.157; | 8.AZ.26.158; | 8.AZ.26.196; | 8.AZ.26.223; |
8.AZ.26.240; | 8.AZ.26.244; | 8.AZ.26.243; | 8.AZ.26.247; |
8.AZ.27.157; | 8.AZ.27.158; | 8.AZ.27.196; | 8.AZ.27.223; |
8.AZ.27.240; | 8.AZ.27.244; | 8.AZ.27.243; | 8.AZ.27.247; |
8.AZ.29.157; | 8.AZ.29.158; | 8.AZ.29.196; | 8.AZ.29.223; |
8.AZ.29.240; | 8.AZ.29.244; | 8.AZ.29.243; | 8.AZ.29.247; |
8.AZ.54.157; | 8.AZ.54.158; | 8.AZ.54.196; | 8.AZ.54.223; |
8.AZ.54.240; | 8.AZ.54.244; | 8.AZ.54.243; | 8.AZ.54.247; |
8.AZ.55.157; | 8.AZ.55.158; | 8.AZ.55.196; | 8.AZ.55.223; |
8.AZ.55.240; | 8.AZ.55.244; | 8.AZ.55.243; | 8.AZ.55.247; |
8.AZ.56.157; | 8.AZ.56.158; | 8.AZ.56.196; | 8.AZ.56.223; |
8.AZ.56.240; | 8.AZ.56.244; | 8.AZ.56.243; | 8.AZ.56.247; |
8.AZ.157.157; | 8.AZ.157.158; | 8.AZ.157.196; | 8.AZ.157.223; |
8.AZ.157.240; | 8.AZ.157.244; | 8.AZ.157.243; | 8.AZ.157.247; |
8.AZ.196.157; | 8.AZ.196.158; | 8.AZ.196.196; | 8.AZ.196.223; |
8.AZ.196.240; | 8.AZ.196.244; | 8.AZ.196.243; | 8.AZ.196.247; |
8.AZ.223.157; | 8.AZ.223.158; | 8.AZ.223.196; | 8.AZ.223.223; |
8.AZ.223.240; | 8.AZ.223.244; | 8.AZ.223.243; | 8.AZ.223.247; |
8.AZ.240.157; | 8.AZ.240.158; | 8.AZ.240.196; | 8.AZ.240.223; |
8.AZ.240.240; | 8.AZ.240.244; | 8.AZ.240.243; | 8.AZ.240.247; |
8.AZ.244.157; | 8.AZ.244.158; | 8.AZ.244.196; | 8.AZ.244.223; |
8.AZ.244.240; | 8.AZ.244.244; | 8.AZ.244.243; | 8.AZ.244.247; |
8.AZ.247.157; | 8.AZ.247.158; | 8.AZ.247.196; | 8.AZ.247.223; |
8.AZ.247.240; | 8.AZ.247.244; | 8.AZ.247.243; | 8.AZ.247.247; |
8.BF的前体药物
8.BF.4.157; | 8.BF.4.158; | 8.BF.4.196; | 8.BF.4.223; | |
8.BF.4.240; | 8.BF.4.244; | 8.BF.4.243; | 8.BF.4.247; | 8.BF.5.157; |
8.BF.5.158; | 8.BF.5.196; | 8.BF.5.223; | 8.BF.5.240; | 8.BF.5.244; |
8.BF.5.243; | 8.BF.5.247; | 8.BF.7.157; | 8.BF.7.158; | 8.BF.7.196; |
8.BF.7.223; | 8.BF.7.240; | 8.BF.7.244; | 8.BF.7.243; | 8.BF.7.247; |
8.BF.15.157; | 8.BF.15.158; | 8.BF.15.196; | 8.BF.15.223; |
8.BF.15.240; | 8.BF.15.244; | 8.BF.15.243; | 8.BF.15.247; |
8.BF.16.157; | 8.BF.16.158; | 8.BF.16.196; | 8.BF.16.223; |
8.BF.16.240; | 8.BF.16.244; | 8.BF.16.243; | 8.BF.16.247; |
8.BF.18.157; | 8.BF.18.158; | 8.BF.18.196; | 8.BF.18.223; |
8.BF.18.240; | 8.BF.18.244; | 8.BF.18.243; | 8.BF.18.247; |
8.BF.26.157; | 8.BF.26.158; | 8.BF.26.196; | 8.BF.26.223; |
8.BF.26.240; | 8.BF.26.244; | 8.BF.26.243; | 8.BF.26.247; |
8.BF.27.157; | 8.BF.27.158; | 8.BF.27.196; | 8.BF.27.223; |
8.BF.27.240; | 8.BF.27.244; | 8.BF.27.243; | 8.BF.27.247; |
8.BF.29.157; | 8.BF.29.158; | 8.BF.29.196; | 8.BF.29.223; |
8.BF.29.240; | 8.BF.29.244; | 8.BF.29.243; | 8.BF.29.247; |
8.BF.54.157; | 8.BF.54.158; | 8.BF.54.196; | 8.BF.54.223; |
8.BF.54.240; | 8.BF.54.244; | 8.BF.54.243; | 8.BF.54.247; |
8.BF.55.157; | 8.BF.55.158; | 8.BF.55.196; | 8.BF.55.223; |
8.BF.55.240; | 8.BF.55.244; | 8.BF.55.243; | 8.BF.55.247; |
8.BF.56.157; | 8.BF.56.158; | 8.BF.56.196; | 8.BF.56.223; |
8.BF.56.240; | 8.BF.56.244; | 8.BF.56.243; | 8.BF.56.247; |
8.BF.157.157; | 8.BF.157.158; | 8.BF.157.196; | 8.BF.157.223; |
8.BF.157.240; | 8.BF.157.244; | 8.BF.157.243; | 8.BF.157.247; |
8.BF.196.157; | 8.BF.196.158; | 8.BF.196.196; | 8.BF.196.223; |
8.BF.196.240; | 8.BF.196.244; | 8.BF.196.243; | 8.BF.196.247; |
8.BF.223.157; | 8.BF.223.158; | 8.BF.223.196; | 8.BF.223.223; |
8.BF.223.240; | 8.BF.223.244; | 8.BF.223.243; | 8.BF.223.247; |
8.BF.240.157; | 8.BF.240.158; | 8.BF.240.196; | 8.BF.240.223; |
8.BF.240.240; | 8.BF.240.244; | 8.BF.240.243; | 8.BF.240.247; |
8.BF.244.157; | 8.BF.244.158; | 8.BF.244.196; | 8.BF.244.223; |
8.BF.244.240; | 8.BF.244.244; | 8.BF.244.243; | 8.BF.244.247; |
8.BF.247.157; | 8.BF.247.158; | 8.BF.247.196; | 8.BF.247.223; |
8.BF.247.240; | 8.BF.247.244; | 8.BF.247.243; | 8.BF.247.247; |
8.CI的前体药物
8.CI.4.157; | 8.CI.4.158; | 8.CI.4.196; | 8.CI.4.223; | |
8.CI.4.240; | 8.CI.4.244; | 8.CI.4.243; | 8.CI.4.247; | 8.CI.5.157; |
8.CI.5.158; | 8.CI.5.196; | 8.CI.5.223; | 8.CI.5.240; | 8.CI.5.244; |
8.CI.5.243; | 8.CI.5.247; | 8.CI.7.157; | 8.CI.7.158; | 8.CI.7.196; |
8.CI.7.223; | 8.CI.7.240; | 8.CI.7.244; | 8.CI.7.243; | 8.CI.7.247; |
8.CI.15.157; | 8.CI.15.158; | 8.CI.15.196; | 8.CI.15.223; |
8.CI.15.240; | 8.CI.15.244; | 8.CI.15.243; | 8.CI.15.247; |
8.CI.16.157; | 8.CI.16.158; | 8.CI.16.196; | 8.CI.16.223; |
8.CI.16.240; | 8.CI.16.244; | 8.CI.16.243; | 8.CI.16.247; |
8.CI.18.157; | 8.CI.18.158; | 8.CI.18.196; | 8.CI.18.223; |
8.CI.18.240; | 8.CI.18.244; | 8.CI.18.243; | 8.CI.18.247; |
8.CI.26.157; | 8.CI.26.158; | 8.CI.26.196; | 8.CI.26.223; |
8.CI.26.240; | 8.CI.26.244; | 8.CI.26.243; | 8.CI.26.247; |
8.CI.27.157; | 8.CI.27.158; | 8.CI.27.196; | 8.CI.27.223; |
8.CI.27.240; | 8.CI.27.244; | 8.CI.27.243; | 8.CI.27.247; |
8.CI.29.157; | 8.CI.29.158; | 8.CI.29.196; | 8.CI.29.223; |
8.CI.29.240; | 8.CI.29.244; | 8.CI.29.243; | 8.CI.29.247; |
8.CI.54.157; | 8.CI.54.158; | 8.CI.54.196; | 8.CI.54.223; |
8.CI.54.240; | 8.CI.54.244; | 8.CI.54.243; | 8.CI.54.247; |
8.CI.55.157; | 8.CI.55.158; | 8.CI.55.196; | 8.CI.55.223; |
8.CI.55.240; | 8.CI.55.244; | 8.CI.55.243; | 8.CI.55.247; |
8.CI.56.157; | 8.CI.56.158; | 8.CI.56.196; | 8.CI.56.223; |
8.CI.56.240; | 8.CI.56.244; | 8.CI.56.243; | 8.CI.56.247; |
8.CI.157.157; | 8.CI.157.158; | 8.CI.157.196; | 8.CI.157.223; |
8.CI.157.240; | 8.CI.157.244; | 8.CI.157.243; | 8.CI.157.247; |
8.CI.196.157; | 8.CI.196.158; | 8.CI.196.196; | 8.CI.196.223; |
8.CI.196.240; | 8.CI.196.244; | 8.CI.196.243; | 8.CI.196.247; |
8.CI.223.157; | 8.CI.223.158; | 8.CI.223.196; | 8.CI.223.223; |
8.CI.223.240; | 8.CI.223.244; | 8.CI.223.243; | 8.CI.223.247; |
8.CI.240.157; | 8.CI.240.158; | 8.CI.240.196; | 8.CI.240.223; |
8.CI.240.240; | 8.CI.240.244; | 8.CI.240.243; | 8.CI.240.247; |
8.CI.244.157; | 8.CI.244.158; | 8.CI.244.196; | 8.CI.244.223; |
8.CI.244.240; | 8.CI.244.244; | 8.CI.244.243; | 8.CI.244.247; |
8.CI.247.157; | 8.CI.247.158; | 8.CI.247.196; | 8.CI.247.223; |
8.CI.247.240; | 8.CI.247.244; | 8.CI.247.243; | 8.CI.247.247; |
8.CO的前体药物
8.CO.4.157; | 8.CO.4.158; | 8.CO.4.196; | 8.CO.4.223; | |
8.CO.4.240; | 8.CO.4.244; | 8.CO.4.243; | 8.CO.4.247; | 8.CO.5.157; |
8.CO.5.158; | 8.CO.5.196; | 8.CO.5.223; | 8.CO.5.240; | 8.CO.5.244; |
8.CO.5.243; | 8.CO.5.247; | 8.CO.7.157; | 8.CO.7.158; | 8.CO.7.196; |
8.CO.7.223; | 8.CO.7.240; | 8.CO.7.244; | 8.CO.7.243; | 8.CO.7.247; |
8.CO.15.157; | 8.CO.15.158; | 8.CO.15.196; | 8.CO.15.223; |
8.CO.15.240; | 8.CO.15.244; | 8.CO.15.243; | 8.CO.15.247; |
8.CO.16.157; | 8.CO.16.158; | 8.CO.16.196; | 8.CO.16.223; |
8.CO.16.240; | 8.CO.16.244; | 8.CO.16.243; | 8.CO.16.247; |
8.CO.18.157; | 8.CO.18.158; | 8.CO.18.196; | 8.CO.18.223; |
8.CO.18.240; | 8.CO.18.244; | 8.CO.18.243; | 8.CO.18.247; |
8.CO.26.157; | 8.CO.26.158; | 8.CO.26.196; | 8.CO.26.223; |
8.CO.26.240; | 8.CO.26.244; | 8.CO.26.243; | 8.CO.26.247; |
8.CO.27.157; | 8.CO.27.158; | 8.CO.27.196; | 8.CO.27.223; |
8.CO.27.240; | 8.CO.27.244; | 8.CO.27.243; | 8.CO.27.247; |
8.CO.29.157; | 8.CO.29.158; | 8.CO.29.196; | 8.CO.29.223; |
8.CO.29.240; | 8.CO.29.244; | 8.CO.29.243; | 8.CO.29.247; |
8.CO.54.157; | 8.CO.54.158; | 8.CO.54.196; | 8.CO.54.223; |
8.CO.54.240; | 8.CO.54.244; | 8.CO.54.243; | 8.CO.54.247; |
8.CO.55.157; | 8.CO.55.158; | 8.CO.55.196; | 8.CO.55.223; |
8.CO.55.240; | 8.CO.55.244; | 8.CO.55.243; | 8.CO.55.247; |
8.CO.56.157; | 8.CO.56.158; | 8.CO.56.196; | 8.CO.56.223; |
8.CO.56.240; | 8.CO.56.244; | 8.CO.56.243; | 8.CO.56.247; |
8.CO.157.157; | 8.CO.157.158; | 8.CO.157.196; | 8.CO.157.223; |
8.CO.157.240; | 8.CO.157.244; | 8.CO.157.243; | 8.CO.157.247; |
8.CO.196.157; | 8.CO.196.158; | 8.CO.196.196; | 8.CO.196.223; |
8.CO.196.240; | 8.CO.196.244; | 8.CO.196.243; | 8.CO.196.247; |
8.CO.223.157; | 8.CO.223.158; | 8.CO.223.196; | 8.CO.223.223; |
8.CO.223.240; | 8.CO.223.244; | 8.CO.223.243; | 8.CO.223.247; |
8.CO.240.157; | 8.CO.240.158; | 8.CO.240.196; | 8.CO.240.223; |
8.CO.240.240; | 8.CO.240.244; | 8.CO.240.243; | 8.CO.240.247; |
8.CO.244.157; | 8.CO.244.158; | 8.CO.244.196; | 8.CO.244.223; |
8.CO.244.240; | 8.CO.244.244; | 8.CO.244.243; | 8.CO.244.247; |
8.CO.247.157; | 8.CO.247.158; | 8.CO.247.196; | 8.CO.247.223; |
8.CO.247.240; | 8.CO.247.244; | 8.CO.247.243; | 8.CO.247.247; |
9.AH的前体药物
9.AH.4.157; | 9.AH.4.158; | 9.AH.4.196; | 9.AH.4.223; | |
9.AH.4.240; | 9.AH.4.244; | 9.AH.4.243; | 9.AH.4.247; | 9.AH.5.157; |
9.AH.5.158; | 9.AH.5.196; | 9.AH.5.223; | 9.AH.5.240; | 9.AH.5.244; |
9.AH.5.243; | 9.AH.5.247; | 9.AH.7.157; | 9.AH.7.158; | 9.AH.7.196; |
9.AH.7.223; | 9.AH.7.240; | 9.AH.7.244; | 9.AH.7.243; | 9.AH.7.247; |
9.AH.15.157; | 9.AH.15.158; | 9.AH.15.196; | 9.AH.15.223; |
9.AH.15.240; | 9.AH.15.244; | 9.AH.15.243; | 9.AH.15.247; |
9.AH.16.157; | 9.AH.16.158; | 9.AH.16.196; | 9.AH.16.223; |
9.AH.16.240; | 9.AH.16.244; | 9.AH.16.243; | 9.AH.16.247; |
9.AH.18.157; | 9.AH.18.158; | 9.AH.18.196; | 9.AH.18.223; |
9.AH.18.240; | 9.AH.18.244; | 9.AH.18.243; | 9.AH.18.247; |
9.AH.26.157; | 9.AH.26.158; | 9.AH.26.196; | 9.AH.26.223; |
9.AH.26.240; | 9.AH.26.244; | 9.AH.26.243; | 9.AH.26.247; |
9.AH.27.157; | 9.AH.27.158; | 9.AH.27.196; | 9.AH.27.223; |
9.AH.27.240; | 9.AH.27.244; | 9.AH.27.243; | 9.AH.27.247; |
9.AH.29.157; | 9.AH.29.158; | 9.AH.29.196; | 9.AH.29.223; |
9.AH.29.240; | 9.AH.29.244; | 9.AH.29.243; | 9.AH.29.247; |
9.AH.54.157; | 9.AH.54.158; | 9.AH.54.196; | 9.AH.54.223; |
9.AH.54.240; | 9.AH.54.244; | 9.AH.54.243; | 9.AH.54.247; |
9.AH.55.157; | 9.AH.55.158; | 9.AH.55.196; | 9.AH.55.223; |
9.AH.55.240; | 9.AH.55.244; | 9.AH.55.243; | 9.AH.55.247; |
9.A H.56.157; | 9.AH.56.158; | 9.AH.56.196; | 9.AH.56.223; |
9.AH.56.240; | 9.AH.56.244; | 9.AH.56.243; | 9.AH.56.247; |
9.AH.157.157; | 9.AH.157.158; | 9.AH.157.196; | 9.AH.157.223; |
9.AH.157.240; | 9.AH.157.244; | 9.AH.157.243; | 9.AH.157.247; |
9.AH.196.157; | 9.AH.196.158; | 9.AH.196.196; | 9.AH.196.223; |
9.AH.196.240; | 9.AH.196.244; | 9.AH.196.243; | 9.AH.196.247; |
9.AH.223.157; | 9.AH.223.158; | 9.AH.223.196; | 9.AH.223.223; |
9.AH.223.240; | 9.AH.223.244; | 9.AH.223.243; | 9.AH.223.247; |
9.AH.240.157; | 9.AH.240.158; | 9.AH.240.196; | 9.AH.240.223; |
9.AH.240.240; | 9.AH.240.244; | 9.AH.240.243; | 9.AH.240.247; |
9.AH.244.157; | 9.AH.244.158; | 9.AH.244.196; | 9.AH.244.223; |
9.AH.244.240; | 9.AH.244.244; | 9.AH.244.243; | 9.AH.244.247; |
9.AH.247.157; | 9.AH.247.158; | 9.AH.247.196; | 9.AH.247.223; |
9.AH.247.240; | 9.AH.247.244; | 9.AH.247.243; | 9.AH.247.247; |
9.AJ的前体药物
9.AJ.4.157; | 9.AJ.4.158; | 9.AJ.4.196; | 9.AJ.4.223; | |
9.AJ.4.240; | 9.AJ.4.244; | 9.AJ.4.243; | 9.AJ.4.247; | 9.AJ.5.157; |
9.AJ.5.158; | 9.AJ.5.196; | 9.AJ.5.223; | 9.AJ.5.240; | 9.AJ.5.244; |
9.AJ.5.243; | 9.AJ.5.247; | 9.AJ.7.157; | 9.AJ.7.158; | 9.AJ.7.196; |
9.AJ.7.223; | 9.AJ.7.240; | 9.AJ.7.244; | 9.AJ.7.243; | 9.AJ.7.247; |
9.AJ.15.157; | 9.AJ.15.158; | 9.AJ.15.196; | 9.AJ.15.223; |
9.AJ.15.240; | 9.AJ.15.244; | 9.AJ.15.243; | 9.AJ.15.247; |
9.AJ.16.157; | 9.AJ.16.158; | 9.AJ.16.196; | 9.AJ.16.223; |
9.AJ.16.240; | 9.AJ.16.244; | 9.AJ.16.243; | 9.AJ.16.247; |
9.AJ.18.157; | 9.AJ.18.158; | 9.AJ.18.196; | 9.AJ.18.223; |
9.AJ.18.240; | 9.AJ.18.244; | 9.AJ.18.243; | 9.AJ.18.247; |
9.AJ.26.157; | 9.AJ.26.158; | 9.AJ.26.196; | 9.AJ.26.223; |
9.AJ.26.240; | 9.AJ.26.244; | 9.AJ.26.243; | 9.AJ.26.247; |
9.AJ.27.157; | 9.AJ.27.158; | 9.AJ.27.196; | 9.AJ.27.223; |
9.AJ.27.240; | 9.AJ.27.244; | 9.AJ.27.243; | 9.AJ.27.247; |
9.AJ.29.157; | 9.AJ.29.158; | 9.AJ.29.196; | 9.AJ.29.223; |
9.AJ.29.240; | 9.AJ.29.244; | 9.AJ.29.243; | 9.AJ.29.247; |
9.AJ.54.157; | 9.AJ.54.158; | 9.AJ.54.196; | 9.AJ.54.223; |
9.AJ.54.240; | 9.AJ.54.244; | 9.AJ.54.243; | 9.AJ.54.247; |
9.AJ.55.157; | 9.AJ.55.158; | 9.AJ.55.196; | 9.AJ.55.223; |
9.AJ.55.240; | 9.AJ.55.244; | 9.AJ.55.243; | 9.AJ.55.247; |
9.AJ.56.157; | 9.AJ.56.158; | 9.AJ.56.196; | 9.AJ.56.223; |
9.AJ.56.240; | 9.AJ.56.244; | 9.AJ.56.243; | 9.AJ.56.247; |
9.AJ.157.157; | 9.AJ.157.158; | 9.AJ.157.196; | 9.AJ.157.223; |
9.AJ.157.240; | 9.AJ.157.244; | 9.AJ.157.243; | 9.AJ.157.247; |
9.AJ.196.157; | 9.AJ.196.158; | 9.AJ.196.196; | 9.AJ.196.223; |
9.AJ.196.240; | 9.AJ.196.244; | 9.AJ.196.243; | 9.AJ.196.247; |
9.AJ.223.157; | 9.AJ.223.158; | 9.AJ.223.196; | 9.AJ.223.223; |
9.AJ.223.240; | 9.AJ.223.244; | 9.AJ.223.243; | 9.AJ.223.247; |
9.AJ.240.157; | 9.AJ.240.158; | 9.AJ.240.196; | 9.AJ.240.223; |
9.AJ.240.240; | 9.AJ.240.244; | 9.AJ.240.243; | 9.AJ.240.247; |
9.AJ.244.157; | 9.AJ.244.158; | 9.AJ.244.196; | 9.AJ.244.223; |
9.AJ.244.240; | 9.AJ.244.244; | 9.AJ.244.243; | 9.AJ.244.247; |
9.AJ.247.157; | 9.AJ.247.158; | 9.AJ.247.196; | 9.AJ.247.223; |
9.AJ.247.240; | 9.AJ.247.244; | 9.AJ.247.243; | 9.AJ.247.247; |
9.AN的前体药物
9.AN.4.157; | 9.AN.4.158; | 9.AN.4.196; | 9.AN.4.223; | |
9.AN.4.240; | 9.AN.4.244; | 9.AN.4.243; | 9.AN.4.247; | 9.AN.5.157; |
9.AN.5.158; | 9.AN.5.196; | 9.AN.5.223; | 9.AN.5.240; | 9.AN.5.244; |
9.AN.5.243; | 9.AN.5.247; | 9.AN.7.157; | 9.AN.7.158; | 9.AN.7.196; |
9.AN.7.223; | 9.AN.7.240; | 9.AN.7.244; | 9.AN.7.243; | 9.AN.7.247; |
9.AN.15.157; | 9.AN.15.158; | 9.AN.15.196; | 9.AN.15.223; |
9.AN.15.240; | 9.AN.15.244; | 9.AN.15.243; | 9.AN.15.247; |
9.AN.16.157; | 9.AN.16.158; | 9.AN.16.196; | 9.AN.16.223; |
9.AN.16.240; | 9.AN.16.244; | 9.AN.16.243; | 9.AN.16.247; |
9.AN.18.157; | 9.AN.18.158; | 9.AN.18.196; | 9.AN.18.223; |
9.AN.18.240; | 9.AN.18.244; | 9.AN.18.243; | 9.AN.18.247; |
9.AN.26.157; | 9.AN.26.158; | 9.AN.26.196; | 9.AN.26.223; |
9.AN.26.240; | 9.AN.26.244; | 9.AN.26.243; | 9.AN.26.247; |
9.AN.27.157; | 9.AN.27.158; | 9.AN.27.196; | 9.AN.27.223; |
9.AN.27.240; | 9.AN.27.244; | 9.AN.27.243; | 9.AN.27.247; |
9.AN.29.157; | 9.AN.29.158; | 9.AN.29.196; | 9.AN.29.223; |
9.AN.29.240; | 9.AN.29.244; | 9.AN.29.243; | 9.AN.29.247; |
9.AN.54.157; | 9.AN.54.158; | 9.AN.54.196; | 9.AN.54.223; |
9.AN.54.240; | 9.AN.54.244; | 9.AN.54.243; | 9.AN.54.247; |
9.AN.55.157; | 9.AN.55.158; | 9.AN.55.196; | 9.AN.55.223; |
9.AN.55.240; | 9.AN.55.244; | 9.AN.55.243; | 9.AN.55.247; |
9.AN.56.157; | 9.AN.56.158; | 9.AN.56.196; | 9.AN.56.223; |
9.AN.56.240; | 9.AN.56.244; | 9.AN.56.243; | 9.AN.56.247; |
9.AN.157.157; | 9.AN.157.158; | 9.AN.157.196; | 9.AN.157.223; |
9.AN.157.240; | 9.AN.157.244; | 9.AN.157.243; | 9.AN.157.247; |
9.AN.196.157; | 9.AN.196.158; | 9.AN.196.196; | 9.AN.196.223; |
9.AN.196.240; | 9.AN.196.244; | 9.AN.196.243; | 9.AN.196.247; |
9.AN.223.157; | 9.AN.223.158; | 9.AN.223.196; | 9.AN.223.223; |
9.AN.223.240; | 9.AN.223.244; | 9.AN.223.243; | 9.AN.223.247; |
9.AN.240.157; | 9.AN.240.158; | 9.AN.240.196; | 9.AN.240.223; |
9.AN.240.240; | 9.AN.240.244; | 9.AN.240.243; | 9.AN.240.247; |
9.AN.244.157; | 9.AN.244.158; | 9.AN.244.196; | 9.AN.244.223; |
9.AN.244.240; | 9.AN.244.244; | 9.AN.244.243; | 9.AN.244.247; |
9.AN.247.157; | 9.AN.247.158; | 9.AN.247.196; | 9.AN.247.223; |
9.AN.247.240; | 9.AN.247.244; | 9.AN.247.243; | 9.AN.247.247; |
9.AP的前体药
9.AP.4.157; | 9.AP.4.158; | 9.AP.4.196; | 9.AP.4.223; | |
9.AP.4.240; | 9.AP.4.244; | 9.AP.4.243; | 9.AP.4.247; | 9.AP.5.157; |
9.AP.5.158; | 9.AP.5.196; | 9.AP.5.223; | 9.AP.5.240; | 9.AP.5.244; |
9.AP.5.243; | 9.AP.5.247; | 9.AP.7.157; | 9.AP.7.158; | 9.AP.7.196; |
9.AP.7.223; | 9.AP.7.240; | 9.AP.7.244; | 9.AP.7.243; | 9.AP.7.247; |
9.AP.15.157; | 9.AP.15.158; | 9.AP.15.196; | 9.AP.15.223; |
9.AP.15.240; | 9.AP.15.244; | 9.AP.15.243; | 9.AP.15.247; |
9.AP.16.157; | 9.AP.16.158; | 9.AP.16.196; | 9.AP.16.223; |
9.AP.16.240; | 9.AP.16.244; | 9.AP.16.243; | 9.AP.16.247; |
9.AP.18.157; | 9.AP.18.158; | 9.AP.18.196; | 9.AP.18.223; |
9.AP.18.240; | 9.AP.18.244; | 9.AP.18.243; | 9.AP.18.247; |
9.AP.26.157; | 9.AP.26.158; | 9.AP.26.196; | 9.AP.26.223; |
9.AP.26.240; | 9.AP.26.244; | 9.AP.26.243; | 9.AP.26.247; |
9.AP.27.157; | 9.AP.27.158; | 9.AP.27.196; | 9.AP.27.223; |
9.AP.27.240; | 9.AP.27.244; | 9.AP.27.243; | 9.AP.27.247; |
9.AP.29.157; | 9.AP.29.158; | 9.AP.29.196; | 9.AP.29.223; |
9.AP.29.240; | 9.AP.29.244; | 9.AP.29.243; | 9.AP.29.247; |
9.AP.54.157; | 9.AP.54.158; | 9.AP.54.196; | 9.AP.54.223; |
9.AP.54.240; | 9.AP.54.244; | 9.AP.54.243; | 9.AP.54.247; |
9.AP.55.157; | 9.AP.55.158; | 9.AP.55.196; | 9.AP.55.223; |
9.AP.55.240; | 9.AP.55.244; | 9.AP.55.243; | 9.AP.55.247; |
9.AP.56.157; | 9.AP.56.158; | 9.AP.56.196; | 9.AP.56.223; |
9.AP.56.240; | 9.AP.56.244; | 9.AP.56.243; | 9.AP.56.247; |
9.AP.157.157; | 9.AP.157.158; | 9.AP.157.196; | 9.AP.157.223; |
9.AP.157.240; | 9.AP.157.244; | 9.AP.157.243; | 9.AP.157.247; |
9.AP.196.157; | 9.AP.196.158; | 9.AP.196.196; | 9.AP.196.223; |
9.AP.196.240; | 9.AP.196.244; | 9.AP.196.243; | 9.AP.196.247; |
9.AP.223.157; | 9.AP.223.158; | 9.AP.223.196; | 9.AP.223.223; |
9.AP.223.240; | 9.AP.223.244; | 9.AP.223.243; | 9.AP.223.247; |
9.AP.240.157; | 9.AP.240.158; | 9.AP.240.196; | 9.AP.240.223; |
9.AP.240.240; | 9.AP.240.244; | 9.AP.240.243; | 9.AP.240.247; |
9.AP.244.157; | 9.AP.244.158; | 9.AP.244.196; | 9.AP.244.223; |
9.AP.244.240; | 9.AP.244.244; | 9.AP.244.243; | 9.AP.244.247; |
9.AP.247.157; | 9.AP.247.158; | 9.AP.247.196; | 9.AP.247.223; |
9.AP.247.240; | 9.AP.247.244; | 9.AP.247.243; | 9.AP.247.247; |
9.AZ的前体药物
9.AZ.4.157; | 9.AZ.4.158; | 9.AZ.4.196; | 9.AZ.4.223; | |
9.AZ.4.240; | 9.AZ.4.244; | 9.AZ.4.243; | 9.AZ.4.247; | 9.AZ.5.157; |
9.AZ.5.158; | 9.AZ.5.196; | 9.AZ.5.223; | 9.AZ.5.240; | 9.AZ.5.244; |
9.AZ.5.243; | 9.AZ.5.247; | 9.AZ.7.157; | 9.AZ.7.158; | 9.AZ.7.196; |
9.AZ.7.223; | 9.AZ.7.240; | 9.AZ.7.244; | 9.AZ.7.243; | 9.AZ.7.247; |
9.AZ.15.157; | 9.AZ.15.158; | 9.AZ.15.196; | 9.AZ.15.223; |
9.AZ.15.240; | 9.AZ.15.244; | 9.AZ.15.243; | 9.AZ.15.247; |
9.AZ.16.157; | 9.AZ.16.158; | 9.AZ.16.196; | 9.AZ.16.223; |
9.AZ.16.240; | 9.AZ.16.244; | 9.AZ.16.243; | 9.AZ.16.247; |
9.AZ.18.157; | 9.AZ.18.158; | 9.AZ.18.196; | 9.AZ.18.223; |
9.AZ.18.240; | 9.AZ.18.244; | 9.AZ.18.243; | 9.AZ.18.247; |
9.AZ.26.157; | 9.AZ.26.158; | 9.AZ.26.196; | 9.AZ.26.223; |
9.AZ.26.240; | 9.AZ.26.244; | 9.AZ.26.243; | 9.AZ.26.247; |
9.AZ.27.157; | 9.AZ.27.158; | 9.AZ.27.196; | 9.AZ.27.223; |
9.AZ.27.240; | 9.AZ.27.244; | 9.AZ.27.243; | 9.AZ.27.247; |
9.AZ.29.157; | 9.AZ.29.158; | 9.AZ.29.196; | 9.AZ.29.223; |
9.AZ.29.240; | 9.AZ.29.244; | 9.AZ.29.243; | 9.AZ.29.247; |
9.AZ.54.157; | 9.AZ.54.158; | 9.AZ.54.196; | 9.AZ.54.223; |
9.AZ.54.240; | 9.AZ.54.244; | 9.AZ.54.243; | 9.AZ.54.247; |
9.AZ.55.157; | 9.AZ.55.158; | 9.AZ.55.196; | 9.AZ.55.223; |
9.AZ.55.240; | 9.AZ.55.244; | 9.AZ.55.243; | 9.AZ.55.247; |
9.AZ.56.157; | 9.AZ.56.158; | 9.AZ.56.196; | 9.AZ.56.223; |
9.AZ.56.240; | 9.AZ.56.244; | 9.AZ.56.243; | 9.AZ.56.247; |
9.AZ.157.157; | 9.AZ.157.158; | 9.AZ.157.196; | 9.AZ.157.223; |
9.AZ.157.240; | 9.AZ.157.244; | 9.AZ.157.243; | 9.AZ.157.247; |
9.AZ.196.157; | 9.AZ.196.158; | 9.AZ.196.196; | 9.AZ.196.223; |
9.AZ.196.240; | 9.AZ.196.244; | 9.AZ.196.243; | 9.AZ.196.247; |
9.AZ.223.157; | 9.AZ.223.158; | 9.AZ.223.196; | 9.AZ.223.223; |
9.AZ.223.240; | 9.AZ.223.244; | 9.AZ.223.243; | 9.AZ.223.247; |
9.AZ.240.157; | 9.AZ.240.158; | 9.AZ.240.196; | 9.AZ.240.223; |
9.AZ.240.240; | 9.AZ.240.244; | 9.AZ.240.243; | 9.AZ.240.247; |
9.AZ.244.157; | 9.AZ.244.158; | 9.AZ.244.196; | 9.AZ.244.223; |
9.AZ.244.240; | 9.AZ.244.244; | 9.AZ.244.243; | 9.AZ.244.247; |
9.AZ.247.157; | 9.AZ.247.158; | 9.AZ.247.196; | 9.AZ.247.223; |
9.AZ.247.240; | 9.AZ.247.244; | 9.AZ.247.243; | 9.AZ.247.247; |
9.BF的前体药物
9.BF.4.157; | 9.BF.4.158; | 9.BF.4.196; | 9.BF.4.223; | |
9.BF.4.240; | 9.BF.4.244; | 9.BF.4.243; | 9.BF.4.247; | 9.BF.5.157; |
9.BF.5.158; | 9.BF.5.196; | 9.BF.5.223; | 9.BF.5.240; | 9.BF.5.244; |
9.BF.5.243; | 9.BF.5.247; | 9.BF.7.157; | 9.BF.7.158; | 9.BF.7.196; |
9.BF.7.223; | 9.BF.7.240; | 9.BF.7.244; | 9.BF.7.243; | 9.BF.7.247; |
9.BF.15.157; | 9.BF.15.158; | 9.BF.15.196; | 9.BF.15.223; |
9.BF.15.240; | 9.BF.15.244; | 9.BF.15.243; | 9.BF.15.247; |
9.BF.16.157; | 9.BF.16.158; | 9.BF.16.196; | 9.BF.16.223; |
9.BF.16.240; | 9.BF.16.244; | 9.BF.16.243; | 9.BF.16.247; |
9.BF.18.157; | 9.BF.18.158; | 9.BF.18.196; | 9.BF.18.223; |
9.BF.18.240; | 9.BF.18.244; | 9.BF.18.243; | 9.BF.18.247; |
9.BF.26.157; | 9.BF.26.158; | 9.BF.26.196; | 9.BF.26.223; |
9.BF.26.240; | 9.BF.26.244; | 9.BF.26.243; | 9.BF.26.247; |
9.BF.27.157; | 9.BF.27.158; | 9.BF.27.196; | 9.BF.27.223; |
9.BF.27.240; | 9.BF.27.244; | 9.BF.27.243; | 9.BF.27.247; |
9.BF.29.157; | 9.BF.29.158; | 9.BF.29.196; | 9.BF.29.223; |
9.BF.29.240; | 9.BF.29.244; | 9.BF.29.243; | 9.BF.29.247; |
9.BF.54.157; | 9.BF.54.158; | 9.BF.54.196; | 9.BF.54.223; |
9.BF.54.240; | 9.BF.54.244; | 9.BF.54.243; | 9.BF.54.247; |
9.BF.55.157; | 9.BF.55.158; | 9.BF.55.196; | 9.BF.55.223; |
9.BF.55.240; | 9.BF.55.244; | 9.BF.55.243; | 9.BF.55.247; |
9.BF.56.157; | 9.BF.56.158; | 9.BF.56.196; | 9.BF.56.223; |
9.BF.56.240; | 9.BF.56.244; | 9.BF.56.243; | 9.BF.56.247; |
9.BF.157.157; | 9.BF.157.158; | 9.BF.157.196; | 9.BF.157.223; |
9.BF.157.240; | 9.BF.157.244; | 9.BF.157.243; | 9.BF.157.247; |
9.BF.196.157; | 9.BF.196.158; | 9.BF.196.196; | 9.BF.196.223; |
9.BF.196.240; | 9.BF.196.244; | 9.BF.196.243; | 9.BF.196.247; |
9.BF.223.157; | 9.BF.223.158; | 9.BF.223.196; | 9.BF.223.223; |
9.BF.223.240; | 9.BF.223.244; | 9.BF.223.243; | 9.BF.223.247; |
9.BF.240.157; | 9.BF.240.158; | 9.BF.240.196; | 9.BF.240.223; |
9.BF.240.240; | 9.BF.240.244; | 9.BF.240.243; | 9.BF.240.247; |
9.BF.244.157; | 9.BF.244.158; | 9.BF.244.196; | 9.BF.244.223; |
9.BF.244.240; | 9.BF.244.244; | 9.BF.244.243; | 9.BF.244.247; |
9.BF.247.157; | 9.BF.247.158; | 9.BF.247.196; | 9.BF.247.223; |
9.BF.247.240; | 9.BF.247.244; | 9.BF.247.243; | 9.BF.247.247; |
9.CI的前体药物
9.CI.4.157; | 9.CI.4.158; | 9.CI.4.196; | 9.CI.4.223; | |
9.CI.4.240; | 9.CI.4.244; | 9.CI.4.243; | 9.CI.4.247; | 9.CI.5.157; |
9.CI.5.158; | 9.CI.5.196; | 9.CI.5.223; | 9.CI.5.240; | 9.CI.5.244; |
9.CI.5.243; | 9.CI.5.247; | 9.CI.7.157; | 9.CI.7.158; | 9.CI.7.196; |
9.CI.7.223; | 9.CI.7.240; | 9.CI.7.244; | 9.CI.7.243; | 9.CI.7.247; |
9.CI.15.157; | 9.CI.15.158; | 9.CI.15.196; | 9.CI.15.223; |
9.CI.15.240; | 9.CI.15.244; | 9.CI.15.243; | 9.CI.15.247; |
9.CI.16.157; | 9.CI.16.158; | 9.CI.16.196; | 9.CI.16.223; |
9.CI.16.240; | 9.CI.16.244; | 9.CI.16.243; | 9.CI.16.247; |
9.CI.18.157; | 9.CI.18.158; | 9.CI.18.196; | 9.CI.18.223; |
9.CI.18.240; | 9.CI.18.244; | 9.CI.18.243; | 9.CI.18.247; |
9.CI.26.157; | 9.CI.26.158; | 9.CI.26.196; | 9.CI.26.223; |
9.CI.26.240; | 9.CI.26.244; | 9.CI.26.243; | 9.CI.26.247; |
9.CI.27.157; | 9.CI.27.158; | 9.CI.27.196; | 9.CI.27.223; |
9.CI.27.240; | 9.CI.27.244; | 9.CI.27.243; | 9.CI.27.247; |
9.CI.29.157; | 9.CI.29.158; | 9.CI.29.196; | 9.CI.29.223; |
9.CI.29.240; | 9.CI.29.244; | 9.CI.29.243; | 9.CI.29.247; |
9.CI.54.157; | 9.CI.54.158; | 9.CI.54.196; | 9.CI.54.223; |
9.CI.54.240; | 9.CI.54.244; | 9.CI.54.243; | 9.CI.54.247; |
9.CI.55.157; | 9.CI.55.158; | 9.CI.55.196; | 9.CI.55.223; |
9.CI.55.240; | 9.CI.55.244; | 9.CI.55.243; | 9.CI.55.247; |
9.CI.56.157; | 9.CI.56.158; | 9.CI.56.196; | 9.CI.56.223; |
9.CI.56.240; | 9.CI.56.244; | 9.CI.56.243; | 9.CI.56.247; |
9.CI.157.157; | 9.CI.157.158; | 9.CI.157.196; | 9.CI.157.223; |
9.CI.157.240; | 9.CI.157.244; | 9.CI.157.243; | 9.CI.157.247; |
9.CI.196.157; | 9.CI.196.158; | 9.CI.196.196; | 9.CI.196.223; |
9.CI.196.240; | 9.CI.196.244; | 9.CI.196.243; | 9.CI.196.247; |
9.CI.223.157; | 9.CI.223.158; | 9.CI.223.196; | 9.CI.223.223; |
9.CI.223.240; | 9.CI.223.244; | 9.CI.223.243; | 9.CI.223.247; |
9.CI.240.157; | 9.CI.240.158; | 9.CI.240.196; | 9.CI.240.223; |
9.CI.240.240; | 9.CI.240.244; | 9.CI.240.243; | 9.CI.240.247; |
9.CI.244.157; | 9.CI.244.158; | 9.CI.244.196; | 9.CI.244.223; |
9.CI.244.240; | 9.CI.244.244; | 9.CI.244.243; | 9.CI.244.247; |
9.CI.247.157; | 9.CI.247.158; | 9.CI.247.196; | 9.CI.247.223; |
9.CI.247.240; | 9.CI.247.244; | 9.CI.247.243; | 9.CI.247.247; |
9.CO的前体药物
9.CO.4.157; | 9.CO.4.158; | 9.CO.4.196; | 9.CO.4.223; | |
9.CO.4.240; | 9.CO.4.244; | 9.CO.4.243; | 9.CO.4.247; | 9.CO.5.157; |
9.CO.5.158; | 9.CO.5.196; | 9.CO.5.223; | 9.CO.5.240; | 9.CO.5.244; |
9.CO.5.243; | 9.CO.5.247; | 9.CO.7.157; | 9.CO.7.158; | 9.CO.7.196; |
9.CO.7.223; | 9.CO.7.240; | 9.CO.7.244; | 9.CO.7.243; | 9.CO.7.247; |
9.CO.15.157; | 9.CO.15.158; | 9.CO.15.196; | 9.CO.15.223; |
9.CO.15.240; | 9.CO.15.244; | 9.CO.15.243; | 9.CO.15.247; |
9.CO.16.157; | 9.CO.16.158; | 9.CO.16.196; | 9.CO.16.223; |
9.CO.16.240; | 9.CO.16.244; | 9.CO.16.243; | 9.CO.16.247; |
9.CO.18.157; | 9.CO.18.158; | 9.CO.18.196; | 9.CO.18.223; |
9.CO.18.240; | 9.CO.18.244; | 9.CO.18.243; | 9.CO.18.247; |
9.CO.26.157; | 9.CO.26.158; | 9.CO.26.196; | 9.CO.26.223; |
9.CO.26.240; | 9.CO.26.244; | 9.CO.26.243; | 9.CO.26.247; |
9.CO.27.157; | 9.CO.27.158; | 9.CO.27.196; | 9.CO.27.223; |
9.CO.27.240; | 9.CO.27.244; | 9.CO.27.243; | 9.CO.27.247; |
9.CO.29.157; | 9.CO.29.158; | 9.CO.29.196; | 9.CO.29.223; |
9.CO.29.240; | 9.CO.29.244; | 9.CO.29.243; | 9.CO.29.247; |
9.CO.54.157; | 9.CO.54.158; | 9.CO.54.196; | 9.CO.54.223; |
9.CO.54.240; | 9.CO.54.244; | 9.CO.54.243; | 9.CO.54.247; |
9.CO.55.157; | 9.CO.55.158; | 9.CO.55.196; | 9.CO.55.223; |
9.CO.55.240; | 9.CO.55.244; | 9.CO.55.243; | 9.CO.55.247; |
9.CO.56.157; | 9.CO.56.158; | 9.CO.56.196; | 9.CO.56.223; |
9.CO.56.240; | 9.CO.56.244; | 9.CO.56.243; | 9.CO.56.247; |
9.CO.157.157; | 9.CO.157.158; | 9.CO.157.196; | 9.CO.157.223; |
9.CO.157.240; | 9.CO.157.244; | 9.CO.157.243; | 9.CO.157.247; |
9.CO.196.157; | 9.CO.196.158; | 9.CO.196.196; | 9.CO.196.223; |
9.CO.196.240; | 9.CO.196.244; | 9.CO.196.243; | 9.CO.196.247; |
9.CO.223.157; | 9.CO.223.158; | 9.CO.223.196; | 9.CO.223.223; |
9.CO.223.240; | 9.CO.223.244; | 9.CO.223.243; | 9.CO.223.247; |
9.CO.240.157; | 9.CO.240.158; | 9.CO.240.196; | 9.CO.240.223; |
9.CO.240.240; | 9.CO.240.244; | 9.CO.240.243; | 9.CO.240.247; |
9.CO.244.157; | 9.CO.244.158; | 9.CO.244.196; | 9.CO.244.223; |
9.CO.244.240; | 9.CO.244.244; | 9.CO.244.243; | 9.CO.244.247; |
9.CO.247.157; | 9.CO.247.158; | 9.CO.247.196; | 9.CO.247.223; |
9.CO.247.240; | 9.CO.247.244; | 9.CO.247.243; | 9.CO.247.247; |
10.AH的前体药物
10.AH.4.157; | 10.AH.4.158; | 10.AH.4.196; | 10.AH.4.223; |
10.AH.4.240; | 10.AH.4.244; | 10.AH.4.243; | 10.AH.4.247; |
10.AH.5.157; | 10.AH.5.158; | 10.AH.5.196; | 10.AH.5.223; |
10.AH.5.240; | 10.AH.5.244; | 10.AH.5.243; | 10.AH.5.247; |
10.AH.7.157; | 10.AH.7.158; | 10.AH.7.196; | 10.AH.7.223; |
10.AH.7.240; | 10.AH.7.244; | 10.AH.7.243; | 10.AH.7.247; |
10.AH.15.157; | 10.AH.15.158; | 10.AH.15.196; | 10.AH.15.223; |
10.AH.15.240; | 10.AH.15.244; | 10.AH.15.243; | 10.AH.15.247; |
10.AH.16.157; | 10.AH.16.158; | 10.AH.16.196; | 10.AH.16.223; |
10.AH.16.240; | 10.AH.16.244; | 10.AH.16.243; | 10.AH.16.247; |
10.AH.18.157; | 10.AH.18.158; | 10.AH.18.196; | 10.AH.18.223; |
10.AH.18.240; | 10.AH.18.244; | 10.AH.18.243; | 10.AH.18.247; |
10.AH.26.157; | 10.AH.26.158; | 10.AH.26.196; | 10.AH.26.223; |
10.AH.26.240; | 10.AH.26.244; | 10.AH.26.243; | 10.AH.26.247; |
10.AH.27.157; | 10.AH.27.158; | 10.AH.27.196; | 10.AH.27.223; |
10.AH.27.240; | 10.AH.27.244; | 10.AH.27.243; | 10.AH.27.247; |
10.AH.29.157; | 10.AH.29.158; | 10.AH.29.196; | 10.AH.29.223; |
10.AH.29.240; | 10.AH.29.244; | 10.AH.29.243; | 10.AH.29.247; |
10.AH.54.157; | 10.AH.54.158; | 10.AH.54.196; | 10.AH.54.223; |
10.AH.54.240; | 10.AH.54.244; | 10.AH.54.243; | 10.AH.54.247; |
10.AH.55.157; | 10.AH.55.158; | 10.AH.55.196; | 10.AH.55.223; |
10.AH.55.240; | 10.AH.55.244; | 10.AH.55.243; | 10.AH.55.247; |
10.AH.56.157; | 10.AH.56.158; | 10.AH.56.196; | 10.AH.56.223; |
10.AH.56.240; | 10.AH.56.244; | 10.AH.56.243; | 10.AH.56.247; |
10.AH.157.157; | 10.AH.157.158; | 10.AH.157.196; | 10.AH.157.223; |
10.AH.157.240; | 10.AH.157.244; | 10.AH.157.243; | 10.AH.157.247; |
10.AH.196.157; | 10.AH.196.158; | 10.AH.196.196; | 10.AH.196.223; |
10.AH.196.240; | 10.AH.196.244; | 10.AH.196.243; | 10.AH.196.247; |
10.AH.223.157; | 10.AH.223.158; | 10.AH.223.196; | 10.AH.223.223; |
10.AH.223.240; | 10.AH.223.244; | 10.AH.223.243; | 10.AH.223.247; |
10.AH.240.157; | 10.AH.240.158; | 10.AH.240.196; | 10.AH.240.223; |
10.AH.240.240; | 10.AH.240.244; | 10.AH.240.243; | 10.AH.240.247; |
10.AH.244.157; | 10.AH.244.158; | 10.AH.244.196; | 10.AH.244.223; |
10.AH.244.240; | 10.AH.244.244; | 10.AH.244.243; | 10.AH.244.247; |
10.AH.247.157; | 10.AH.247.158; | 10.AH.247.196; | 10.AH.247.223; |
10.AH.247.240; | 10.AH.247.244; | 10.AH.247.243; | 10.AH.247.247; |
10.AJ的前体药物
10.AJ.4.157; | 10.AJ.4.158; | 10.AJ.4.196; | 10.AJ.4.223; |
10.AJ.4.240; | 10.AJ.4.244; | 10.AJ.4.243; | 10.AJ.4.247; |
10.AJ.5.157; | 10.AJ.5.158; | 10.AJ.5.196; | 10.AJ.5.223; |
10.AJ.5.240; | 10.AJ.5.244; | 10.AJ.5.243; | 10.AJ.5.247; |
10.AJ.7.157; | 10.AJ.7.158; | 10.AJ.7.196; | 10.AJ.7.223; |
10.AJ.7.240; | 10.AJ.7.244; | 10.AJ.7.243; | 10.AJ.7.247; |
10.AJ.15.157; | 10.AJ.15.158; | 10.AJ.15.196; | 10.AJ.15.223; |
10.AJ.15.240; | 10.AJ.15.244; | 10.AJ.15.243; | 10.AJ.15.247; |
10.AJ.16.157; | 10.AJ.16.158; | 10.AJ.16.196; | 10.AJ.16.223; |
10.AJ.16.240; | 10.AJ.16.244; | 10.AJ.16.243; | 10.AJ.16.247; |
10.AJ.18.157; | 10.AJ.18.158; | 10.AJ.18.196; | 10.AJ.18.223; |
10.AJ.18.240; | 10.AJ.18.244; | 10.AJ.18.243; | 10.AJ.18.247; |
10.AJ.26.157; | 10.AJ.26.158; | 10.AJ.26.196; | 10.AJ.26.223; |
10.AJ.26.240; | 10.AJ.26.244; | 10.AJ.26.243; | 10.AJ.26.247; |
10.AJ.27.157; | 10.AJ.27.158; | 10.AJ.27.196; | 10.AJ.27.223; |
10.AJ.27.240; | 10.AJ.27.244; | 10.AJ.27.243; | 10.AJ.27.247; |
10.AJ.29.157; | 10.AJ.29.158; | 10.AJ.29.196; | 10.AJ.29.223; |
10.AJ.29.240; | 10.AJ.29.244; | 10.AJ.29.243; | 10.AJ.29.247; |
10.AJ.54.157; | 10.AJ.54.158; | 10.AJ.54.196; | 10.AJ.54.223; |
10.AJ.54.240; | 10.AJ.54.244; | 10.AJ.54.243; | 10.AJ.54.247; |
10.AJ.55.157; | 10.AJ.55.158; | 10.AJ.55.196; | 10.AJ.55.223; |
10.AJ.55.240; | 10.AJ.55.244; | 10.AJ.55.243; | 10.AJ.55.247; |
10.AJ.56.157; | 10.AJ.56.158; | 10.AJ.56.196; | 10.AJ.56.223; |
10.AJ.56.240; | 10.AJ.56.244; | 10.AJ.56.243; | 10.AJ.56.247; |
10.AJ.157.157; | 10.AJ.157.158; | 10.AJ.157.196; | 10.AJ.157.223; |
10.AJ.157.240; | 10.AJ.157.244; | 10.AJ.157.243; | 10.AJ.157.247; |
10.AJ.196.157; | 10.AJ.196.158; | 10.AJ.196.196; | 10.AJ.196.223; |
10.AJ.196.240; | 10.AJ.196.244; | 10.AJ.196.243; | 10.AJ.196.247; |
10.AJ.223.157; | 10.AJ.223.158; | 10.AJ.223.196; | 10.AJ.223.223; |
10.AJ.223.240; | 10.AJ.223.244; | 10.AJ.223.243; | 10.AJ.223.247; |
10.AJ.240.157; | 10.AJ.240.158; | 10.AJ.240.196; | 10.AJ.240.223; |
10.AJ.240.240; | 10.AJ.240.244; | 10.AJ.240.243; | 10.AJ.240.247; |
10.AJ.244.157; | 10.AJ.244.158; | 10.AJ.244.196; | 10.AJ.244.223; |
10.AJ.244.240; | 10.AJ.244.244; | 10.AJ.244.243; | 10.AJ.244.247; |
10.AJ.247.157; | 10.AJ.247.158; | 10.AJ.247.196; | 10.AJ.247.223; |
10.AJ.247.240; | 10.AJ.247.244; | 10.AJ.247.243; | 10.AJ.247.247; |
10.AN的前体药物
10.AN.4.157; | 10.AN.4.158; | 10.AN.4.196; | 10.AN.4.223; |
10.AN.4.240; | 10.AN.4.244; | 10.AN.4.243; | 10.AN.4.247; |
10.AN.5.157; | 10.AN.5.158; | 10.AN.5.196; | 10.AN.5.223; |
10.AN.5.240; | 10.AN.5.244; | 10.AN.5.243; | 10.AN.5.247; |
10.AN.7.157; | 10.AN.7.158; | 10.AN.7.196; | 10.AN.7.223; |
10.AN.7.240; | 10.AN.7.244; | 10.AN.7.243; | 10.AN.7.247; |
10.AN.15.157; | 10.AN.15.158; | 10.AN.15.196; | 10.AN.15.223; |
10.AN.15.240; | 10.AN.15.244; | 10.AN.15.243; | 10.AN.15.247; |
10.AN.16.157; | 10.AN.16.158; | 10.AN.16.196; | 10.AN.16.223; |
10.AN.16.240; | 10.AN.16.244; | 10.AN.16.243; | 10.AN.16.247; |
10.AN.18.157; | 10.AN.18.158; | 10.AN.18.196; | 10.AN.18.223; |
10.AN.18.240; | 10.AN.18.244; | 10.AN.18.243; | 10.AN.18.247; |
10.AN.26.157; | 10.AN.26.158; | 10.AN.26.196; | 10.AN.26.223; |
10.AN.26.240; | 10.AN.26.244; | 10.AN.26.243; | 10.AN.26.247; |
10.AN.27.157; | 10.AN.27.158; | 10.AN.27.196; | 10.AN.27.223; |
10.AN.27.240; | 10.AN.27.244; | 10.AN.27.243; | 10.AN.27.247; |
10.AN.29.157; | 10.AN.29.158; | 10.AN.29.196; | 10.AN.29.223; |
10.AN.29.240; | 10.AN.29.244; | 10.AN.29.243; | 10.AN.29.247; |
10.AN.54.157; | 10.AN.54.158; | 10.AN.54.196; | 10.AN.54.223; |
10.AN.54.240; | 10.AN.54.244; | 10.AN.54.243; | 10.AN.54.247; |
10.AN.55.157; | 10.AN.55.158; | 10.AN.55.196; | 10.AN.55.223; |
10.AN.55.240; | 10.AN.55.244; | 10.AN.55.243; | 10.AN.55.247; |
10.AN.56.157; | 10.AN.56.158; | 10.AN.56.196; | 10.AN.56.223; |
10.AN.56.240; | 10.AN.56.244; | 10.AN.56.243; | 10.AN.56.247; |
10.AN.157.157; | 10.AN.157.158; | 10.AN.157.196; | 10.AN.157.223; |
10.AN.157.240; | 10.AN.157.244; | 10.AN.157.243; | 10.AN.157.247; |
10.AN.196.157; | 10.AN.196.158; | 10.AN.196.196; | 10.AN.196.223; |
10.AN.196.240; | 10.AN.196.244; | 10.AN.196.243; | 10.AN.196.247; |
10.AN.223.157; | 10.AN.223.158; | 10.AN.223.196; | 10.AN.223.223; |
10.AN.223.240; | 10.AN.223.244; | 10.AN.223.243; | 10.AN.223.247; |
10.AN.240.157; | 10.AN.240.158; | 10.AN.240.196; | 10.AN.240.223; |
10.AN.240.240; | 10.AN.240.244; | 10.AN.240.243; | 10.AN.240.247; |
10.AN.244.157; | 10.AN.244.158; | 10.AN.244.196; | 10.AN.244.223; |
10.AN.244.240; | 10.AN.244.244; | 10.AN.244.243; | 10.AN.244.247; |
10.AN.247.157; | 10.AN.247.158; | 10.AN.247.196; | 10.AN.247.223; |
10.AN.247.240; | 10.AN.247.244; | 10.AN.247.243; | 10.AN.247.247; |
10.AP的前体药物
10.AP.4.157; | 10.AP.4.158; | 10.AP.4.196; | 10.AP.4.223; |
10.AP.4.240; | 10.AP.4.244; | 10.AP.4.243; | 10.AP.4.247; |
10.AP.5.157; | 10.AP.5.158; | 10.AP.5.196; | 10.AP.5.223; |
10.AP.5.240; | 10.AP.5.244; | 10.AP.5.243; | 10.AP.5.247; |
10.AP.7.157; | 10.AP.7.158; | 10.AP.7.196; | 10.AP.7.223; |
10.AP.7.240; | 10.AP.7.244; | 10.AP.7.243; | 10.AP.7.247; |
10.AP.15.157; | 10.AP.15.158; | 10.AP.15.196; | 10.AP.15.223; |
10.AP.15.240; | 10.AP.15.244; | 10.AP.15.243; | 10.AP.15.247; |
10.AP.16.157; | 10.AP.16.158; | 10.AP.16.196; | 10.AP.16.223; |
10.AP.16.240; | 10.AP.16.244; | 10.AP.16.243; | 10.AP.16.247; |
10.AP.18.157; | 10.AP.18.158; | 10.AP.18.196; | 10.AP.18.223; |
10.AP.18.240; | 10.AP.18.244; | 10.AP.18.243; | 10.AP.18.247; |
10.AP.26.157; | 10.AP.26.158; | 10.AP.26.196; | 10.AP.26.223; |
10.AP.26.240; | 10.AP.26.244; | 10.AP.26.243; | 10.AP.26.247; |
10.AP.27.157; | 10.AP.27.158; | 10.AP.27.196; | 10.AP.27.223; |
10.AP.27.240; | 10.AP.27.244; | 10.AP.27.243; | 10.AP.27.247; |
10.AP.29.157; | 10.AP.29.158; | 10.AP.29.196; | 10.AP.29.223; |
10.AP.29.240; | 10.AP.29.244; | 10.AP.29.243; | 10.AP.29.247; |
10.AP.54.157; | 10.AP.54.158; | 10.AP.54.196; | 10.AP.54.223; |
10.AP.54.240; | 10.AP.54.244; | 10.AP.54.243; | 10.AP.54.247; |
10.AP.55.157; | 10.AP.55.158; | 10.AP.55.196; | 10.AP.55.223; |
10.AP.55.240; | 10.AP.55.244; | 10.AP.55.243; | 10.AP.55.247; |
10.AP.56.157; | 10.AP.56.158; | 10.AP.56.196; | 10.AP.56.223; |
10.AP.56.240; | 10.AP.56.244; | 10.AP.56.243; | 10.AP.56.247; |
10.AP.157.157; | 10.AP.157.158; | 10.AP.157.196; | 10.AP.157.223; |
10.AP.157.240; | 10.AP.157.244; | 10.AP.157.243; | 10.AP.157.247; |
10.AP.196.157; | 10.AP.196.158; | 10.AP.196.196; | 10.AP.196.223; |
10.AP.196.240; | 10.AP.196.244; | 10.AP.196.243; | 10.AP.196.247; |
10.AP.223.157; | 10.AP.223.158; | 10.AP.223.196; | 10.AP.223.223; |
10.AP.223.240; | 10.AP.223.244; | 10.AP.223.243; | 10.AP.223.247; |
10.AP.240.157; | 10.AP.240.158; | 10.AP.240.196; | 10.AP.240.223; |
10.AP.240.240; | 10.AP.240.244; | 10.AP.240.243; | 10.AP.240.247; |
10.AP.244.157; | 10.AP.244.158; | 10.AP.244.196; | 10.AP.244.223; |
10.AP.244.240; | 10.AP.244.244; | 10.AP.244.243; | 10.AP.244.247; |
10.AP.247.157; | 10.AP.247.158; | 10.AP.247.196; | 10.AP.247.223; |
10.AP.247.240; | 10.AP.247.244; | 10.AP.247.243; | 10.AP.247.247; |
10.AZ的前体药物
10.AZ.4.157; | 10.AZ.4.158; | 10.AZ.4.196; | 10.AZ.4.223; |
10.AZ.4.240; | 10.AZ.4.244; | 10.AZ.4.243; | 10.AZ.4.247; |
10.AZ.5.157; | 10.AZ.5.158; | 10.AZ.5.196; | 10.AZ.5.223; |
10.AZ.5.240; | 10.AZ.5.244; | 10.AZ.5.243; | 10.AZ.5.247; |
10.AZ.7.157; | 10.AZ.7.158; | 10.AZ.7.196; | 10.AZ.7.223; |
10.AZ.7.240; | 10.AZ.7.244; | 10.AZ.7.243; | 10.AZ.7.247; |
10.AZ.15.157; | 10.AZ.15.158; | 10.AZ.15.196; | 10.AZ.15.223; |
10.AZ.15.240; | 10.AZ.15.244; | 10.AZ.15.243; | 10.AZ.15.247; |
10.AZ.16.157; | 10.AZ.16.158; | 10.AZ.16.196; | 10.AZ.16.223; |
10.AZ.16.240; | 10.AZ.16.244; | 10.AZ.16.243; | 10.AZ.16.247; |
10.AZ.18.157; | 10.AZ.18.158; | 10.AZ.18.196; | 10.AZ.18.223; |
10.AZ.18.240; | 10.AZ.18.244; | 10.AZ.18.243; | 10.AZ.18.247; |
10.AZ.26.157; | 10.AZ.26.158; | 10.AZ.26.196; | 10.AZ.26.223; |
10.AZ.26.240; | 10.AZ.26.244; | 10.AZ.26.243; | 10.AZ.26.247; |
10.AZ.27.157; | 10.AZ.27.158; | 10.AZ.27.196; | 10.AZ.27.223; |
10.AZ.27.240; | 10.AZ.27.244; | 10.AZ.27.243; | 10.AZ.27.247; |
10.AZ.29.157; | 10.AZ.29.158; | 10.AZ.29.196; | 10.AZ.29.223; |
10.AZ.29.240; | 10.AZ.29.244; | 10.AZ.29.243; | 10.AZ.29.247; |
10.AZ.54.157; | 10.AZ.54.158; | 10.AZ.54.196; | 10.AZ.54.223; |
10.AZ.54.240; | 10.AZ.54.244; | 10.AZ.54.243; | 10.AZ.54.247; |
10.AZ.55.157; | 10.AZ.55.158; | 10.AZ.55.196; | 10.AZ.55.223; |
10.AZ.55.240; | 10.AZ.55.244; | 10.AZ.55.243; | 10.AZ.55.247; |
10.AZ.56.157; | 10.AZ.56.158; | 10.AZ.56.196; | 10.AZ.56.223; |
10.AZ.56.240; | 10.AZ.56.244; | 10.AZ.56.243; | 10.AZ.56.247; |
10.AZ.157.157; | 10.AZ.157.158; | 10.AZ.157.196; | 10.AZ.157.223; |
10.AZ.157.240; | 10.AZ.157.244; | 10.AZ.157.243; | 10.AZ.157.247; |
10.AZ.196.157; | 10.AZ.196.158; | 10.AZ.196.196; | 10.AZ.196.223; |
10.AZ.196.240; | 10.AZ.196.244; | 10.AZ.196.243; | 10.AZ.196.247; |
10.AZ.223.157; | 10.AZ.223.158; | 10.AZ.223.196; | 10.AZ.223.223; |
10.AZ.223.240; | 10.AZ.223.244; | 10.AZ.223.243; | 10.AZ.223.247; |
10.AZ.240.157; | 10.AZ.240.158; | 10.AZ.240.196; | 10.AZ.240.223; |
10.AZ.240.240; | 10.AZ.240.244; | 10.AZ.240.243; | 10.AZ.240.247; |
10.AZ.244.157; | 10.AZ.244.158; | 10.AZ.244.196; | 10.AZ.244.223; |
10.AZ.244.240; | 10.AZ.244.244; | 10.AZ.244.243; | 10.AZ.244.247; |
10.AZ.247.157; | 10.AZ.247.158; | 10.AZ.247.196; | 10.AZ.247.223; |
10.AZ.247.240; | 10.AZ.247.244; | 10.AZ.247.243; | 10.AZ.247.247; |
10.BF的前体药物
10.BF.4.157; | 10.BF.4.158; | 10.BF.4.196; | 10.BF.4.223; |
10.BF.4.240; | 10.BF.4.244; | 10.BF.4.243; | 10.BF.4.247; |
10.BF.5.157; | 10.BF.5.158; | 10.BF.5.196; | 10.BF.5.223; |
10.BF.5.240; | 10.BF.5.244; | 10.BF.5.243; | 10.BF.5.247; |
10.BF.7.157; | 10.BF.7.158; | 10.BF.7.196; | 10.BF.7.223; |
10.BF.7.240; | 10.BF.7.244; | 10.BF.7.243; | 10.BF.7.247; |
10.BF.15.157; | 10.BF.15.158; | 10.BF.15.196; | 10.BF.15.223; |
10.BF.15.240; | 10.BF.15.244; | 10.BF.15.243; | 10.BF.15.247; |
10.BF.16.157; | 10.BF.16.158; | 10.BF.16.196; | 10.BF.16.223; |
10.BF.16.240; | 10.BF.16.244; | 10.BF.16.243; | 10.BF.16.247; |
10.BF.18.157; | 10.BF.18.158; | 10.BF.18.196; | 10.BF.18.223; |
10.BF.18.240; | 10.BF.18.244; | 10.BF.18.243; | 10.BF.18.247; |
10.BF.26.157; | 10.BF.26.158; | 10.BF.26.196; | 10.BF.26.223; |
10.BF.26.240; | 10.BF.26.244; | 10.BF.26.243; | 10.BF.26.247; |
10.BF.27.157; | 10.BF.27.158; | 10.BF.27.196; | 10.BF.27.223; |
10.BF.27.240; | 10.BF.27.244; | 10.BF.27.243; | 10.BF.27.247; |
10.BF.29.157; | 10.BF.29.158; | 10.BF.29.196; | 10.BF.29.223; |
10.BF.29.240; | 10.BF.29.244; | 10.BF.29.243; | 10.BF.29.247; |
10.BF.54.157; | 10.BF.54.158; | 10.BF.54.196; | 10.BF.54.223; |
10.BF.54.240; | 10.BF.54.244; | 10.BF.54.243; | 10.BF.54.247; |
10.BF.55.157; | 10.BF.55.158; | 10.BF.55.196; | 10.BF.55.223; |
10.BF.55.240; | 10.BF.55.244; | 10.BF.55.243; | 10.BF.55.247; |
10.BF.56.157; | 10.BF.56.158; | 10.BF.56.196; | 10.BF.56.223; |
10.BF.56.240; | 10.BF.56.244; | 10.BF.56.243; | 10.BF.56.247; |
10.BF.157.157; | 10.BF.157.158; | 10.BF.157.196; | 10.BF.157.223; |
10.BF.157.240; | 10.BF.157.244; | 10.BF.157.243; | 10.BF.157.247; |
10.BF.196.157; | 10.BF.196.158; | 10.BF.196.196; | 10.BF.196.223; |
10.BF.196.240; | 10.BF.196.244; | 10.BF.196.243; | 10.BF.196.247; |
10.BF.223.157; | 10.BF.223.158; | 10.BF.223.196; | 10.BF.223.223; |
10.BF.223.240; | 10.BF.223.244; | 10.BF.223.243; | 10.BF.223.247; |
10.BF.240.157; | 10.BF.240.158; | 10.BF.240.196; | 10.BF.240.223; |
10.BF.240.240; | 10.BF.240.244; | 10.BF.240.243; | 10.BF.240.247; |
10.BF.244.157; | 10.BF.244.158; | 10.BF.244.196; | 10.BF.244.223; |
10.BF.244.240; | 10.BF.244.244; | 10.BF.244.243; | 10.BF.244.247; |
10.BF.247.157; | 10.BF.247.158; | 10.BF.247.196; | 10.BF.247.223; |
10.BF.247.240; | 10.BF.247.244; | 10.BF.247.243; | 10.BF.247.247; |
10.CI的前体药物
10.CI.4.157; | 10.CI.4.158; | 10.CI.4.196; | 10.CI.4.223; |
10.CI.4.240; | 10.CI.4.244; | 10.CI.4.243; | 10.CI.4.247; |
10.CI.5.157; | 10.CI.5.158; | 10.CI.5.196; | 10.CI.5.223; |
10.CI.5.240; | 10.CI.5.244; | 10.CI.5.243; | 10.CI.5.247; |
10.CI.7.157; | 10.CI.7.158; | 10.CI.7.196; | 10.CI.7.223; |
10.CI.7.240; | 10.CI.7.244; | 10.CI.7.243; | 10.CI.7.247; |
10.CI.15.157; | 10.CI.15.158; | 10.CI.15.196; | 10.CI.15.223; |
10.CI.15.240; | 10.CI.15.244; | 10.CI.15.243; | 10.CI.15.247; |
10.CI.16.157; | 10.CI.16.158; | 10.CI.16.196; | 10.CI.16.223; |
10.CI.16.240; | 10.CI.16.244; | 10.CI.16.243; | 10.CI.16.247; |
10.CI.18.157; | 10.CI.18.158; | 10.CI.18.196; | 10.CI.18.223; |
10.CI.18.240; | 10.CI.18.244; | 10.CI.18.243; | 10.CI.18.247; |
10.CI.26.157; | 10.CI.26.158; | 10.CI.26.196; | 10.CI.26.223; |
10.CI.26.240; | 10.CI.26.244; | 10.CI.26.243; | 10.CI.26.247; |
10.CI.27.157; | 10.CI.27.158; | 10.CI.27.196; | 10.CI.27.223; |
10.CI.27.240; | 10.CI.27.244; | 10.CI.27.243; | 10.CI.27.247; |
10.CI.29.157; | 10.CI.29.158; | 10.CI.29.196; | 10.CI.29.223; |
10.CI.29.240; | 10.CI.29.244; | 10.CI.29.243; | 10.CI.29.247; |
10.CI.54.157; | 10.CI.54.158; | 10.CI.54.196; | 10.CI.54.223; |
10.CI.54.240; | 10.CI.54.244; | 10.CI.54.243; | 10.CI.54.247; |
10.CI.55.157; | 10.CI.55.158; | 10.CI.55.196; | 10.CI.55.223; |
10.CI.55.240; | 10.CI.55.244; | 10.CI.55.243; | 10.CI.55.247; |
10.CI.56.157; | 10.CI.56.158; | 10.CI.56.196; | 10.CI.56.223; |
10.CI.56.240; | 10.CI.56.244; | 10.CI.56.243; | 10.CI.56.247; |
10.CI.157.157; | 10.CI.157.158; | 10.CI.157.196; | 10.CI.157.223; |
10.CI.157.240; | 10.CI.157.244; | 10.CI.157.243; | 10.CI.157.247; |
10.CI.196.157; | 10.CI.196.158; | 10.CI.196.196; | 10.CI.196.223; |
10.CI.196.240; | 10.CI.196.244; | 10.CI.196.243; | 10.CI.196.247; |
10.CI.223.157; | 10.CI.223.158; | 10.CI.223.196; | 10.CI.223.223; |
10.CI.223.240; | 10.CI.223.244; | 10.CI.223.243; | 10.CI.223.247; |
10.CI.240.157; | 10.CI.240.158; | 10.CI.240.196; | 10.CI.240.223; |
10.CI.240.240; | 10.CI.240.244; | 10.CI.240.243; | 10.CI.240.247; |
10.CI.244.157; | 10.CI.244.158; | 10.CI.244.196; | 10.CI.244.223; |
10.CI.244.240; | 10.CI.244.244; | 10.CI.244.243; | 10.CI.244.247; |
10.CI.247.157; | 10.CI.247.158; | 10.CI.247.196; | 10.CI.247.223; |
10.CI.247.240; | 10.CI.247.244; | 10.CI.247.243; | 10.CI.247.247; |
10.CO的前体药物
10.CO.4.157; | 10.CO.4.158; | 10.CO.4.196; | 10.CO.4.223; |
10.CO.4.240; | 10.CO.4.244; | 10.CO.4.243; | 10.CO.4.247; |
10.CO.5.157; | 10.CO.5.158; | 10.CO.5.196; | 10.CO.5.223; |
10.CO.5.240; | 10.CO.5.244; | 10.CO.5.243; | 10.CO.5.247; |
10.CO.7.157; | 10.CO.7.158; | 10.CO.7.196; | 10.CO.7.223; |
10.CO.7.240; | 10.CO.7.244; | 10.CO.7.243; | 10.CO.7.247; |
10.CO.15.157; | 10.CO.15.158; | 10.CO.15.196; | 10.CO.15.223; |
10.CO.15.240; | 10.CO.15.244; | 10.CO.15.243; | 10.CO.15.247; |
10.CO.16.157; | 10.CO.16.158; | 10.CO.16.196; | 10.CO.16.223; |
10.CO.16.240; | 10.CO.16.244; | 10.CO.16.243; | 10.CO.16.247; |
10.CO.18.157; | 10.CO.18.158; | 10.CO.18.196; | 10.CO.18.223; |
10.CO.18.240; | 10.CO.18.244; | 10.CO.18.243; | 10.CO.18.247; |
10.CO.26.157; | 10.CO.26.158; | 10.CO.26.196; | 10.CO.26.223; |
10.CO.26.240; | 10.CO.26.244; | 10.CO.26.243; | 10.CO.26.247; |
10.CO.27.157; | 10.CO.27.158; | 10.CO.27.196; | 10.CO.27.223; |
10.CO.27.240; | 10.CO.27.244; | 10.CO.27.243; | 10.CO.27.247; |
10.CO.29.157; | 10.CO.29.158; | 10.CO.29.196; | 10.CO.29.223; |
10.CO.29.240; | 10.CO.29.244; | 10.CO.29.243; | 10.CO.29.247; |
10.CO.54.157; | 10.CO.54.158; | 10.CO.54.196; | 10.CO.54.223; |
10.CO.54.240; | 10.CO.54.244; | 10.CO.54.243; | 10.CO.54.247; |
10.CO.55.157; | 10.CO.55.158; | 10.CO.55.196; | 10.CO.55.223; |
10.CO.55.240; | 10.CO.55.244; | 10.CO.55.243; | 10.CO.55.247; |
10.CO.56.157; | 10.CO.56.158; | 10.CO.56.196; | 10.CO.56.223; |
10.CO.56.240; | 10.CO.56.244; | 10.CO.56.243; | 10.CO.56.247; |
10.CO.157.157; | 10.CO.157.158; | 10.CO.157.196; | 10.CO.157.223; |
10.CO.157.240; | 10.CO.157.244; | 10.CO.157.243; | 10.CO.157.247; |
10.CO.196.157; | 10.CO.196.158; | 10.CO.196.196; | 10.CO.196.223; |
10.CO.196.240; | 10.CO.196.244; | 10.CO.196.243; | 10.CO.196.247; |
10.CO.223.157; | 10.CO.223.158; | 10.CO.223.196; | 10.CO.223.223; |
10.CO.223.240; | 10.CO.223.244; | 10.CO.223.243; | 10.CO.223.247; |
10.CO.240.157; | 10.CO.240.158; | 10.CO.240.196; | 10.CO.240.223; |
10.CO.240.240; | 10.CO.240.244; | 10.CO.240.243; | 10.CO.240.247; |
10.CO.244.157; | 10.CO.244.158; | 10.CO.244.196; | 10.CO.244.223; |
10.CO.244.240; | 10.CO.244.244; | 10.CO.244.243; | 10.CO.244.247; |
10.CO.247.157; | 10.CO.247.158; | 10.CO.247.196; | 10.CO.247.223; |
10.CO.247.240; | 10.CO.247.244; | 10.CO.247.243; | 10.CO.247.247; |
11.AH的前体药物
11.AH.4.157; | 11.AH.4.158; | 11.AH.4.196; | 11.AH.4.223; |
11.AH.4.240; | 11.AH.4.244; | 11.AH.4.243; | 11.AH.4.247; |
11.AH.5.157; | 11.AH.5.158; | 11.AH.5.196; | 11.AH.5.223; |
11.AH.5.240; | 11.AH.5.244; | 11.AH.5.243; | 11.AH.5.247; |
11.AH.7.157; | 11.AH.7.158; | 11.AH.7.196; | 11.AH.7.223; |
11.AH.7.240; | 11.AH.7.244; | 11.AH.7.243; | 11.AH.7.247; |
11.AH.15.157; | 11.AH.15.158; | 11.AH.15.196; | 11.AH.15.223; |
11.AH.15.240; | 11.AH.15.244; | 11.AH.15.243; | 11.AH.15.247; |
11.AH.16.157; | 11.AH.16.158; | 11.AH.16.196; | 11.AH.16.223; |
11.AH.16.240; | 11.AH.16.244; | 11.AH.16.243; | 11.AH.16.247; |
11.AH.18.157; | 11.AH.18.158; | 11.AH.18.196; | 11.AH.18.223; |
11.AH.18.240; | 11.AH.18.244; | 11.AH.18.243; | 11.AH.18.247; |
11.AH.26.157; | 11.AH.26.158; | 11.AH.26.196; | 11.AH.26.223; |
11.AH.26.240; | 11.AH.26.244; | 11.AH.26.243; | 11.AH.26.247; |
11.AH.27.157; | 11.AH.27.158; | 11.AH.27.196; | 11.AH.27.223; |
11.AH.27.240; | 11.AH.27.244; | 11.AH.27.243; | 11.AH.27.247; |
11.AH.29.157; | 11.AH.29.158; | 11.AH.29.196; | 11.AH.29.223; |
11.AH.29.240; | 11.AH.29.244; | 11.AH.29.243; | 11.AH.29.247; |
11.AH.54.157; | 11.AH.54.158; | 11.AH.54.196; | 11.AH.54.223; |
11.AH.54.240; | 11.AH.54.244; | 11.AH.54.243; | 11.AH.54.247; |
11.AH.55.157; | 11.AH.55.158; | 11.AH.55.196; | 11.AH.55.223; |
11.AH.55.240; | 11.AH.55.244; | 11.AH.55.243; | 11.AH.55.247; |
11.AH.56.157; | 11.AH.56.158; | 11.AH.56.196; | 11.AH.56.223; |
11.AH.56.240; | 11.AH.56.244; | 11.AH.56.243; | 11.AH.56.247; |
11.AH.157.157; | 11.AH.157.158; | 11.AH.157.196; | 11.AH.157.223; |
11.AH.157.240; | 11.AH.157.244; | 11.AH.157.243; | 11.AH.157.247; |
11.AH.196.157; | 11.AH.196.158; | 11.AH.196.196; | 11.AH.196.223; |
11.AH.196.240; | 11.AH.196.244; | 11.AH.196.243; | 11.AH.196.247; |
11.AH.223.157; | 11.AH.223.158; | 11.AH.223.196; | 11.AH.223.223; |
11.AH.223.240; | 11.AH.223.244; | 11.AH.223.243; | 11.AH.223.247; |
11.AH.240.157; | 11.AH.240.158; | 11.AH.240.196; | 11.AH.240.223; |
11.AH.240.240; | 11.AH.240.244; | 11.AH.240.243; | 11.AH.240.247; |
11.AH.244.157; | 11.AH.244.158; | 11.AH.244.196; | 11.AH.244.223; |
11.AH.244.240; | 11.AH.244.244; | 11.AH.244.243; | 11.AH.244.247; |
11.AH.247.157; | 11.AH.247.158; | 11.AH.247.196; | 11.AH.247.223; |
11.AH.247.240; | 11.AH.247.244; | 11.AH.247.243; | 11.AH.247.247; |
11.AJ的前体药物
11.AJ.4.157; | 11.AJ.4.158; | 11.AJ.4.196; | 11.AJ.4.223; |
11.AJ.4.240; | 11.AJ.4.244; | 11.AJ.4.243; | 11.AJ.4.247; |
11.AJ.5.157; | 11.AJ.5.158; | 11.AJ.5.196; | 11.AJ.5.223; |
11.AJ.5.240; | 11.AJ.5.244; | 11.AJ.5.243; | 11.AJ.5.247; |
11.AJ.7.157; | 11.AJ.7.158; | 11.AJ.7.196; | 11.AJ.7.223; |
11.AJ.7.240; | 11.AJ.7.244; | 11.AJ.7.243; | 11.AJ.7.247; |
11.AJ.15.157; | 11.AJ.15.158; | 11.AJ.15.196; | 11.AJ.15.223; |
11.AJ.15.240; | 11.AJ.15.244; | 11.AJ.15.243; | 11.AJ.15.247; |
11.AJ.16.157; | 11.AJ.16.158; | 11.AJ.16.196; | 11.AJ.16.223; |
11.AJ.16.240; | 11.AJ.16.244; | 11.AJ.16.243; | 11.AJ.16.247; |
11.AJ.18.157; | 11.AJ.18.158; | 11.AJ.18.196; | 11.AJ.18.223; |
11.AJ.18.240; | 11.AJ.18.244; | 11.AJ.18.243; | 11.AJ.18.247; |
11.AJ.26.157; | 11.AJ.26.158; | 11.AJ.26.196; | 11.AJ.26.223; |
11.AJ.26.240; | 11.AJ.26.244; | 11.AJ.26.243; | 11.AJ.26.247; |
11.AJ.27.157; | 11.AJ.27.158; | 11.AJ.27.196; | 11.AJ.27.223; |
11.AJ.27.240; | 11.AJ.27.244; | 11.AJ.27.243; | 11.AJ.27.247; |
11.AJ.29.157; | 11.AJ.29.158; | 11.AJ.29.196; | 11.AJ.29.223; |
11.AJ.29.240; | 11.AJ.29.244; | 11.AJ.29.243; | 11.AJ.29.247; |
11.AJ.54.157; | 11.AJ.54.158; | 11.AJ.54.196; | 11.AJ.54.223; |
11.AJ.54.240; | 11.AJ.54.244; | 11.AJ.54.243; | 11.AJ.54.247; |
11.AJ.55.157; | 11.AJ.55.158; | 11.AJ.55.196; | 11.AJ.55.223; |
11.AJ.55.240; | 11.AJ.55.244; | 11.AJ.55.243; | 11.AJ.55.247; |
11.AJ.56.157; | 11.AJ.56.158; | 11.AJ.56.196; | 11.AJ.56.223; |
11.AJ.56.240; | 11.AJ.56.244; | 11.AJ.56.243; | 11.AJ.56.247; |
11.AJ.157.157; | 11.AJ.157.158; | 11.AJ.157.196; | 11.AJ.157.223; |
11.AJ.157.240; | 11.AJ.157.244; | 11.AJ.157.243; | 11.AJ.157.247; |
11.AJ.196.157; | 11.AJ.196.158; | 11.AJ.196.196; | 11.AJ.196.223; |
11.AJ.196.240; | 11.AJ.196.244; | 11.AJ.196.243; | 11.AJ.196.247; |
11.AJ.223.157; | 11.AJ.223.158; | 11.AJ.223.196; | 11.AJ.223.223; |
11.AJ.223.240; | 11.AJ.223.244; | 11.AJ.223.243; | 11.AJ.223.247; |
11.AJ.240.157; | 11.AJ.240.158; | 11.AJ.240.196; | 11.AJ.240.223; |
11.AJ.240.240; | 11.AJ.240.244; | 11.AJ.240.243; | 11.AJ.240.247; |
11.AJ.244.157; | 11.AJ.244.158; | 11.AJ.244.196; | 11.AJ.244.223; |
11.AJ.244.240; | 11.AJ.244.244; | 11.AJ.244.243; | 11.AJ.244.247; |
11.AJ.247.157; | 11.AJ.247.158; | 11.AJ.247.196; | 11.AJ.247.223; |
11.AJ.247.240; | 11.AJ.247.244; | 11.AJ.247.243; | 11.AJ.247.247; |
11.AN的前体药物
11.AN.4.157; | 11.AN.4.158; | 11.AN.4.196; | 11.AN.4.223; |
11.AN.4.240; | 11.AN.4.244; | 11.AN.4.243; | 11.AN.4.247; |
11.AN.5.157; | 11.AN.5.158; | 11.AN.5.196; | 11.AN.5.223; |
11.AN.5.240; | 11.AN.5.244; | 11.AN.5.243; | 11.AN.5.247; |
11.AN.7.157; | 11.AN.7.158; | 11.AN.7.196; | 11.AN.7.223; |
11.AN.7.240; | 11.AN.7.244; | 11.AN.7.243; | 11.AN.7.247; |
11.AN.15.157; | 11.AN.15.158; | 11.AN.15.196; | 11.AN.15.223; |
11.AN.15.240; | 11.AN.15.244; | 11.AN.15.243; | 11.AN.15.247; |
11.AN.16.157; | 11.AN.16.158; | 11.AN.16.196; | 11.AN.16.223; |
11.AN.16.240; | 11.AN.16.244; | 11.AN.16.243; | 11.AN.16.247; |
11.AN.18.157; | 11.AN.18.158; | 11.AN.18.196; | 11.AN.18.223; |
11.AN.18.240; | 11.AN.18.244; | 11.AN.18.243; | 11.AN.18.247; |
11.AN.26.157; | 11.AN.26.158; | 11.AN.26.196; | 11.AN.26.223; |
11.AN.26.240; | 11.AN.26.244; | 11.AN.26.243; | 11.AN.26.247; |
11.AN.27.157; | 11.AN.27.158; | 11.AN.27.196; | 11.AN.27.223; |
11.AN.27.240; | 11.AN.27.244; | 11.AN.27.243; | 11.AN.27.247; |
11.AN.29.157; | 11.AN.29.158; | 11.AN.29.196; | 11.AN.29.223; |
11.AN.29.240; | 11.AN.29.244; | 11.AN.29.243; | 11.AN.29.247; |
11.AN.54.157; | 11.AN.54.158; | 11.AN.54.196; | 11.AN.54.223; |
11.AN.54.240; | 11.AN.54.244; | 11.AN.54.243; | 11.AN.54.247; |
11.AN.55.157; | 11.AN.55.158; | 11.AN.55.196; | 11.AN.55.223; |
11.AN.55.240; | 11.AN.55.244; | 11.AN.55.243; | 11.AN.55.247; |
11.AN.56.157; | 11.AN.56.158; | 11.AN.56.196; | 11.AN.56.223; |
11.AN.56.240; | 11.AN.56.244; | 11.AN.56.243; | 11.AN.56.247; |
11.AN.157.157; | 11.AN.157.158; | 11.AN.157.196; | 11.AN.157.223; |
11.AN.157.240; | 11.AN.157.244; | 11.AN.157.243; | 11.AN.157.247; |
11.AN.196.157; | 11.AN.196.158; | 11.AN.196.196; | 11.AN.196.223; |
11.AN.196.240; | 11.AN.196.244; | 11.AN.196.243; | 11.AN.196.247; |
11.AN.223.157; | 11.AN.223.158; | 11.AN.223.196; | 11.AN.223.223; |
11.AN.223.240; | 11.AN.223.244; | 11.AN.223.243; | 11.AN.223.247; |
11.AN.240.157; | 11.AN.240.158; | 11.AN.240.196; | 11.AN.240.223; |
11.AN.240.240; | 11.AN.240.244; | 11.AN.240.243; | 11.AN.240.247; |
11.AN.244.157; | 11.AN.244.158; | 11.AN.244.196; | 11.AN.244.223; |
11.AN.244.240; | 11.AN.244.244; | 11.AN.244.243; | 11.AN.244.247; |
11.AN.247.157; | 11.AN.247.158; | 11.AN.247.196; | 11.AN.247.223; |
11.AN.247.240; | 11.AN.247.244; | 11.AN.247.243; | 11.AN.247.247; |
11.AP的前体药物
11.AP.4.157; | 11.AP.4.158; | 11.AP.4.196; | 11.AP.4.223; |
11.AP.4.240; | 11.AP.4.244; | 11.AP.4.243; | 11.AP.4.247; |
11.AP.5.157; | 11.AP.5.158; | 11.AP.5.196; | 11.AP.5.223; |
11.AP.5.240; | 11.AP.5.244; | 11.AP.5.243; | 11.AP.5.247; |
11.AP.7.157; | 11.AP.7.158; | 11.AP.7.196; | 11.AP.7.223; |
11.AP.7.240; | 11.AP.7.244; | 11.AP.7.243; | 11.AP.7.247; |
11.AP.15.157; | 11.AP.15.158; | 11.AP.15.196; | 11.AP.15.223; |
11.AP.15.240; | 11.AP.15.244; | 11.AP.15.243; | 11.AP.15.247; |
11.AP.16.157; | 11.AP.16.158; | 11.AP.16.196; | 11.AP.16.223; |
11.AP.16.240; | 11.AP.16.244; | 11.AP.16.243; | 11.AP.16.247; |
11.AP.18.157; | 11.AP.18.158; | 11.AP.18.196; | 11.AP.18.223; |
11.AP.18.240; | 11.AP.18.244; | 11.AP.18.243; | 11.AP.18.247; |
11.AP.26.157; | 11.AP.26.158; | 11.AP.26.196; | 11.AP.26.223; |
11.AP.26.240; | 11.AP.26.244; | 11.AP.26.243; | 11.AP.26.247; |
11.AP.27.157; | 11.AP.27.158; | 11.AP.27.196; | 11.AP.27.223; |
11.AP.27.240; | 11.AP.27.244; | 11.AP.27.243; | 11.AP.27.247; |
11.AP.29.157; | 11.AP.29.158; | 11.AP.29.196; | 11.AP.29.223; |
11.AP.29.240; | 11.AP.29.244; | 11.AP.29.243; | 11.AP.29.247; |
11.AP.54.157; | 11.AP.54.158; | 11.AP.54.196; | 11.AP.54.223; |
11.AP.54.240; | 11.AP.54.244; | 11.AP.54.243; | 11.AP.54.247; |
11.AP.55.157; | 11.AP.55.158; | 11.AP.55.196; | 11.AP.55.223; |
11.AP.55.240; | 11.AP.55.244; | 11.AP.55.243; | 11.AP.55.247; |
11.AP.56.157; | 11.AP.56.158; | 11.AP.56.196; | 11.AP.56.223; |
11.AP.56.240; | 11.AP.56.244; | 11.AP.56.243; | 11.AP.56.247; |
11.AP.157.157; | 11.AP.157.158; | 11.AP.157.196; | 11.AP.157.223; |
11.AP.157.240; | 11.AP.157.244; | 11.AP.157.243; | 11.AP.157.247; |
11.AP.196.157; | 11.AP.196.158; | 11.AP.196.196; | 11.AP.196.223; |
11.AP.196.240; | 11.AP.196.244; | 11.AP.196.243; | 11.AP.196.247; |
11.AP.223.157; | 11.AP.223.158; | 11.AP.223.196; | 11.AP.223.223; |
11.AP.223.240; | 11.AP.223.244; | 11.AP.223.243; | 11.AP.223.247; |
11.AP.240.157; | 11.AP.240.158; | 11.AP.240.196; | 11.AP.240.223; |
11.AP.240.240; | 11.AP.240.244; | 11.AP.240.243; | 11.AP.240.247; |
11.AP.244.157; | 11.AP.244.158; | 11.AP.244.196; | 11.AP.244.223; |
11.AP.244.240; | 11.AP.244.244; | 11.AP.244.243; | 11.AP.244.247; |
11.AP.247.157; | 11.AP.247.158; | 11.AP.247.196; | 11.AP.247.223; |
11.AP.247.240; | 11.AP.247.244; | 11.AP.247.243; | 11.AP.247.247; |
11.AZ的前体药物
11.AZ.4.157; | 11.AZ.4.158; | 11.AZ.4.196; | 11.AZ.4.223; |
11.AZ.4.240; | 11.AZ.4.244; | 11.AZ.4.243; | 11.AZ.4.247; |
11.AZ.5.157; | 11.AZ.5.158; | 11.AZ.5.196; | 11.AZ.5.223; |
11.AZ.5.240; | 11.AZ.5.244; | 11.AZ.5.243; | 11.AZ.5.247; |
11.AZ.7.157; | 11.AZ.7.158; | 11.AZ.7.196; | 11.AZ.7.223; |
11.AZ.7.240; | 11.AZ.7.244; | 11.AZ.7.243; | 11.AZ.7.247; |
11.AZ.15.157; | 11.AZ.15.158; | 11.AZ.15.196; | 11.AZ.15.223; |
11.AZ.15.240; | 11.AZ.15.244; | 11.AZ.15.243; | 11.AZ.15.247; |
11.AZ.16.157; | 11.AZ.16.158; | 11.AZ.16.196; | 11.AZ.16.223; |
11.AZ.16.240; | 11.AZ.16.244; | 11.AZ.16.243; | 11.AZ.16.247; |
11.AZ.18.157; | 11.AZ.18.158; | 11.AZ.18.196; | 11.AZ.18.223; |
11.AZ.18.240; | 11.AZ.18.244; | 11.AZ.18.243; | 11.AZ.18.247; |
11.AZ.26.157; | 11.AZ.26.158; | 11.AZ.26.196; | 11.AZ.26.223; |
11.AZ.26.240; | 11.AZ.26.244; | 11.AZ.26.243; | 11.AZ.26.247; |
11.AZ.27.157; | 11.AZ.27.158; | 11.AZ.27.196; | 11.AZ.27.223; |
11.AZ.27.240; | 11.AZ.27.244; | 11.AZ.27.243; | 11.AZ.27.247; |
11.AZ.29.157; | 11.AZ.29.158; | 11.AZ.29.196; | 11.AZ.29.223; |
11.AZ.29.240; | 11.AZ.29.244; | 11.AZ.29.243; | 11.AZ.29.247; |
11.AZ.54.157; | 11.AZ.54.158; | 11.AZ.54.196; | 11.AZ.54.223; |
11.AZ.54.240; | 11.AZ.54.244; | 11.AZ.54.243; | 11.AZ.54.247; |
11.AZ.55.157; | 11.AZ.55.158; | 11.AZ.55.196; | 11.AZ.55.223; |
11.AZ.55.240; | 11.AZ.55.244; | 11.AZ.55.243; | 11.AZ.55.247; |
11.AZ.56.157; | 11.AZ.56.158; | 11.AZ.56.196; | 11.AZ.56.223; |
11.AZ.56.240; | 11.AZ.56.244; | 11.AZ.56.243; | 11.AZ.56.247; |
11.AZ.157.157; | 11.AZ.157.158; | 11.AZ.157.196; | 11.AZ.157.223; |
11.AZ.157.240; | 11.AZ.157.244; | 11.AZ.157.243; | 11.AZ.157.247; |
11.AZ.196.157; | 11.AZ.196.158; | 11.AZ.196.196; | 11.AZ.196.223; |
11.AZ.196.240; | 11.AZ.196.244; | 11.AZ.196.243; | 11.AZ.196.247; |
11.AZ.223.157; | 11.AZ.223.158; | 11.AZ.223.196; | 11.AZ.223.223; |
11.AZ.223.240; | 11.AZ.223.244; | 11.AZ.223.243; | 11.AZ.223.247; |
11.AZ.240.157; | 11.AZ.240.158; | 11.AZ.240.196; | 11.AZ.240.223; |
11.AZ.240.240; | 11.AZ.240.244; | 11.AZ.240.243; | 11.AZ.240.247; |
11.AZ.244.157; | 11.AZ.244.158; | 11.AZ.244.196; | 11.AZ.244.223; |
11.AZ.244.240; | 11.AZ.244.244; | 11.AZ.244.243; | 11.AZ.244.247; |
11.AZ.247.157; | 11.AZ.247.158; | 11.AZ.247.196; | 11.AZ.247.223; |
11.AZ.247.240; | 11.AZ.247.244; | 11.AZ.247.243; | 11.AZ.247.247; |
11.BF的前体药物
11.BF.4.157; | 11.BF.4.158; | 11.BF.4.196; | 11.BF.4.223; |
11.BF.4.240; | 11.BF.4.244; | 11.BF.4.243; | 11.BF.4.247; |
11.BF.5.157; | 11.BF.5.158; | 11.BF.5.196; | 11.BF.5.223; |
11.BF.5.240; | 11.BF.5.244; | 11.BF.5.243; | 11.BF.5.247; |
11.BF.7.157; | 11.BF.7.158; | 11.BF.7.196; | 11.BF.7.223; |
11.BF.7.240; | 11.BF.7.244; | 11.BF.7.243; | 11.BF.7.247; |
11.BF.15.157; | 11.BF.15.158; | 11.BF.15.196; | 11.BF.15.223; |
11.BF.15.240; | 11.BF.15.244; | 11.BF.15.243; | 11.BF.15.247; |
11.BF.16.157; | 11.BF.16.158; | 11.BF.16.196; | 11.BF.16.223; |
11.BF.16.240; | 11.BF.16.244; | 11.BF.16.243; | 11.BF.16.247; |
11.BF.18.157; | 11.BF.18.158; | 11.BF.18.196; | 11.BF.18.223; |
11.BF.18.240; | 11.BF.18.244; | 11.BF.18.243; | 11.BF.18.247; |
11.BF.26.157; | 11.BF.26.158; | 11.BF.26.196; | 11.BF.26.223; |
11.BF.26.240; | 11.BF.26.244; | 11.BF.26.243; | 11.BF.26.247; |
11.BF.27.157; | 11.BF.27.158; | 11.BF.27.196; | 11.BF.27.223; |
11.BF.27.240; | 11.BF.27.244; | 11.BF.27.243; | 11.BF.27.247; |
11.BF.29.157; | 11.BF.29.158; | 11.BF.29.196; | 11.BF.29.223; |
11.BF.29.240; | 11.BF.29.244; | 11.BF.29.243; | 11.BF.29.247; |
11.BF.54.157; | 11.BF.54.158; | 11.BF.54.196; | 11.BF.54.223; |
11.BF.54.240; | 11.BF.54.244; | 11.BF.54.243; | 11.BF.54.247; |
11.BF.55.157; | 11.BF.55.158; | 11.BF.55.196; | 11.BF.55.223; |
11.BF.55.240; | 11.BF.55.244; | 11.BF.55.243; | 11.BF.55.247; |
11.BF.56.157; | 11.BF.56.158; | 11.BF.56.196; | 11.BF.56.223; |
11.BF.56.240; | 11.BF.56.244; | 11.BF.56.243; | 11.BF.56.247; |
11.BF.157.157; | 11.BF.157.158; | 11.BF.157.196; | 11.BF.157.223; |
11.BF.157.240; | 11.BF.157.244; | 11.BF.157.243; | 11.BF.157.247; |
11.BF.196.157; | 11.BF.196.158; | 11.BF.196.196; | 11.BF.196.223; |
11.BF.196.240; | 11.BF.196.244; | 11.BF.196.243; | 11.BF.196.247; |
11.BF.223.157; | 11.BF.223.158; | 11.BF.223.196; | 11.BF.223.223; |
11.BF.223.240; | 11.BF.223.244; | 11.BF.223.243; | 11.BF.223.247; |
11.BF.240.157; | 11.BF.240.158; | 11.BF.240.196; | 11.BF.240.223; |
11.BF.240.240; | 11.BF.240.244; | 11.BF.240.243; | 11.BF.240.247; |
11.BF.244.157; | 11.BF.244.158; | 11.BF.244.196; | 11.BF.244.223; |
11.BF.244.240; | 11.BF.244.244; | 11.BF.244.243; | 11.BF.244.247; |
11.BF.247.157; | 11.BF.247.158; | 11.BF.247.196; | 11.BF.247.223; |
11.BF.247.240; | 11.BF.247.244; | 11.BF.247.243; | 11.BF.247.247; |
11.CI的前体药物
11.CI.4.157; | 11.CI.4.158; | 11.CI.4.196; | 11.CI.4.223; |
11.CI.4.240; | 11.CI.4.244; | 11.CI.4.243; | 11.CI.4.247; |
11.CI.5.157; | 11.CI.5.158; | 11.CI.5.196; | 11.CI.5.223; |
11.CI.5.240; | 11.CI.5.244; | 11.CI.5.243; | 11.CI.5.247; |
11.CI.7.157; | 11.CI.7.158; | 11.CI.7.196; | 11.CI.7.223; |
11.CI.7.240; | 11.C I.7.244; | 11.CI.7.243; | 11.CI.7.247; |
11.CI.15.157; | 11.CI.15.158; | 11.CI.15.196; | 11.CI.15.223; |
11.CI.15.240; | 11.CI.15.244; | 11.CI.15.243; | 11.CI.15.247; |
11.CI.16.157; | 11.CI.16.158; | 11.CI.16.196; | 11.CI.16.223; |
11.CI.16.240; | 11.CI.16.244; | 11.CI.16.243; | 11.CI.16.247; |
11.CI.18.157; | 11.CI.18.158; | 11.CI.18.196; | 11.CI.18.223; |
11.CI.18.240; | 11.CI.18.244; | 11.CI.18.243; | 11.CI.18.247; |
11.CI.26.157; | 11.CI.26.158; | 11.CI.26.196; | 11.CI.26.223; |
11.CI.26.240; | 11.CI.26.244; | 11.CI.26.243; | 11.CI.26.247; |
11.CI.27.157; | 11.CI.27.158; | 11.CI.27.196; | 11.CI.27.223; |
11.CI.27.240; | 11.CI.27.244; | 11.CI.27.243; | 11.CI.27.247; |
11.CI.29.157; | 11.CI.29.158; | 11.CI.29.196; | 11.CI.29.223; |
11.CI.29.240; | 11.CI.29.244; | 11.CI.29.243; | 11.CI.29.247; |
11.CI.54.157; | 11.CI.54.158; | 11.CI.54.196; | 11.CI.54.223; |
11.CI.54.240; | 11.CI.54.244; | 11.CI.54.243; | 11.CI.54.247; |
11.CI.55.157; | 11.CI.55.158; | 11.CI.55.196; | 11.CI.55.223; |
11.CI.55.240; | 11.CI.55.244; | 11.CI.55.243; | 11.CI.55.247; |
11.CI.56.157; | 11.CI.56.158; | 11.CI.56.196; | 11.CI.56.223; |
11.CI.56.240; | 11.CI.56.244; | 11.CI.56.243; | 11.CI.56.247; |
11.CI.157.157; | 11.CI.157.158; | 11.CI.157.196; | 11.CI.157.223; |
11.CI.157.240; | 11.CI.157.244; | 11.CI.157.243; | 11.CI.157.247; |
11.CI.196.157; | 11.CI.196.158; | 11.CI.196.196; | 11.CI.196.223; |
11.CI.196.240; | 11.CI.196.244; | 11.CI.196.243; | 11.CI.196.247; |
11.CI.223.157; | 11.CI.223.158; | 11.CI.223.196; | 11.CI.223.223; |
11.CI.223.240; | 11.CI.223.244; | 11.CI.223.243; | 11.CI.223.247; |
11.CI.240.157; | 11.CI.240.158; | 11.CI.240.196; | 11.CI.240.223; |
11.CI.240.240; | 11.CI.240.244; | 11.CI.240.243; | 11.CI.240.247; |
11.CI.244.157; | 11.CI.244.158; | 11.CI.244.196; | 11.CI.244.223; |
11.CI.244.240; | 11.CI.244.244; | 11.CI.244.243; | 11.CI.244.247; |
11.CI.247.157; | 11.CI.247.158; | 11.CI.247.196; | 11.CI.247.223; |
11.CI.247.240; | 11.CI.247.244; | 11.CI.247.243; | 11.CI.247.247; |
11.CO的前体药物
11.CO.4.157; | 11.CO.4.158; | 11.CO.4.196; | 11.CO.4.223; |
11.CO.4.240; | 11.CO.4.244; | 11.CO.4.243; | 11.CO.4.247; |
11.CO.5.157; | 11.CO.5.158; | 11.CO.5.196; | 11.CO.5.223; |
11.CO.5.240; | 11.CO.5.244; | 11.CO.5.243; | 11.CO.5.247; |
11.CO.7.157; | 11.CO.7.158; | 11.CO.7.196; | 11.CO.7.223; |
11.CO.7.240; | 11.CO.7.244; | 11.CO.7.243; | 11.CO.7.247; |
11.CO.15.157; | 11.CO.15.158; | 11.CO.15.196; | 11.CO.15.223; |
11.CO.15.240; | 11.CO.15.244; | 11.CO.15.243; | 11.CO.15.247; |
11.CO.16.157; | 11.CO.16.158; | 11.CO.16.196; | 11.CO.16.223; |
11.CO.16.240; | 11.CO.16.244; | 11.CO.16.243; | 11.CO.16.247; |
11.CO.18.157; | 11.CO.18.158; | 11.CO.18.196; | 11.CO.18.223; |
11.CO.18.240; | 11.CO.18.244; | 11.CO.18.243; | 11.CO.18.247; |
11.CO.26.157; | 11.CO.26.158; | 11.CO.26.196; | 11.CO.26.223; |
11.CO.26.240; | 11.CO.26.244; | 11.CO.26.243; | 11.CO.26.247; |
11.CO.27.157; | 11.CO.27.158; | 11.CO.27.196; | 11.CO.27.223; |
11.CO.27.240; | 11.CO.27.244; | 11.CO.27.243; | 11.CO.27.247; |
11.CO.29.157; | 11.CO.29.158; | 11.CO.29.196; | 11.CO.29.223; |
11.CO.29.240; | 11.CO.29.244; | 11.CO.29.243; | 11.CO.29.247; |
11.CO.54.157; | 11.CO.54.158; | 11.CO.54.196; | 11.CO.54.223; |
11.CO.54.240; | 11.CO.54.244; | 11.CO.54.243; | 11.CO.54.247; |
11.CO.55.157; | 11.CO.55.158; | 11.CO.55.196; | 11.CO.55.223; |
11.CO.55.240; | 11.CO.55.244; | 11.CO.55.243; | 11.CO.55.247; |
11.CO.56.157; | 11.CO.56.158; | 11.CO.56.196; | 11.CO.56.223; |
11.CO.56.240; | 11.CO.56.244; | 11.CO.56.243; | 11.CO.56.247; |
11.CO.157.157; | 11.CO.157.158; | 11.CO.157.196; | 11.CO.157.223; |
11.CO.157.240; | 11.CO.157.244; | 11.CO.157.243; | 11.CO.157.247; |
11.CO.196.157; | 11.CO.196.158; | 11.CO.196.196; | 11.CO.196.223; |
11.CO.196.240; | 11.CO.196.244; | 11.CO.196.243; | 11.CO.196.247; |
11.CO.223.157; | 11.CO.223.158; | 11.CO.223.196; | 11.CO.223.223; |
11.CO.223.240; | 11.CO.223.244; | 11.CO.223.243; | 11.CO.223.247; |
11.CO.240.157; | 11.CO.240.158; | 11.CO.240.196; | 11.CO.240.223; |
11.CO.240.240; | 11.CO.240.244; | 11.CO.240.243; | 11.CO.240.247; |
11.CO.244.157; | 11.CO.244.158; | 11.CO.244.196; | 11.CO.244.223; |
11.CO.244.240; | 11.CO.244.244; | 11.CO.244.243; | 11.CO.244.247; |
11.CO.247.157; | 11.CO.247.158; | 11.CO.247.196; | 11.CO.247.223; |
11.CO.247.240; | 11.CO.247.244; | 11.CO.247.243; | 11.CO.247.247; |
12.AH的前体药物
12.AH.4.157; | 12.AH.4.158; | 12.AH.4.196; | 12.AH.4.223; |
12.AH.4.240; | 12.AH.4.244; | 12.AH.4.243; | 12.AH.4.247; |
12.AH.5.157; | 12.AH.5.158; | 12.AH.5.196; | 12.AH.5.223; |
12.AH.5.240; | 12.AH.5.244; | 12.AH.5.243; | 12.AH.5.247; |
12.AH.7.157; | 12.AH.7.158; | 12.AH.7.196; | 12.AH.7.223; |
12.AH.7.240; | 12.AH.7.244; | 12.AH.7.243; | 12.AH.7.247; |
12.AH.15.157; | 12.AH.15.158; | 12.AH.15.196; | 12.AH.15.223; |
12.AH.15.240; | 12.AH.15.244; | 12.AH.15.243; | 12.AH.15.247; |
12.AH.16.157; | 12.AH.16.158; | 12.AH.16.196; | 12.AH.16.223; |
12.AH.16.240; | 12.AH.16.244; | 12.AH.16.243; | 12.AH.16.247; |
12.AH.18.157; | 12.AH.18.158; | 12.AH.18.196; | 12.AH.18.223; |
12.AH.18.240; | 12.AH.18.244; | 12.AH.18.243; | 12.AH.18.247; |
12.AH.26.157; | 12.AH.26.158; | 12.AH.26.196; | 12.AH.26.223; |
12.AH.26.240; | 12.AH.26.244; | 12.AH.26.243; | 12.AH.26.247; |
12.AH.27.157; | 12.AH.27.158; | 12.AH.27.196; | 12.AH.27.223; |
12.AH.27.240; | 12.AH.27.244; | 12.AH.27.243; | 12.AH.27.247; |
12.AH.29.157; | 12.AH.29.158; | 12.AH.29.196; | 12.AH.29.223; |
12.AH.29.240; | 12.AH.29.244; | 12.AH.29.243; | 12.AH.29.247; |
12.AH.54.157; | 12.AH.54.158; | 12.AH.54.196; | 12.AH.54.223; |
12.AH.54.240; | 12.AH.54.244; | 12.AH.54.243; | 12.AH.54.247; |
12.AH.55.157; | 12.AH.55.158; | 12.AH.55.196; | 12.AH.55.223; |
12.AH.55.240; | 12.AH.55.244; | 12.AH.55.243; | 12.AH.55.247; |
12.AH.56.157; | 12.AH.56.158; | 12.AH.56.196; | 12.AH.56.223; |
12.AH.56.240; | 12.AH.56.244; | 12.AH.56.243; | 12.AH.56.247; |
12.AH.157.157; | 12.AH.157.158; | 12.AH.157.196; | 12.AH.157.223; |
12.AH.157.240; | 12.AH.157.244; | 12.AH.157.243; | 12.AH.157.247; |
12.AH.196.157; | 12.AH.196.158; | 12.AH.196.196; | 12.AH.196.223; |
12.AH.196.240; | 12.AH.196.244; | 12.AH.196.243; | 12.AH.196.247; |
12.AH.223.157; | 12.AH.223.158; | 12.AH.223.196; | 12.AH.223.223; |
12.AH.223.240; | 12.AH.223.244; | 12.AH.223.243; | 12.AH.223.247; |
12.AH.240.157; | 12.AH.240.158; | 12.AH.240.196; | 12.AH.240.223; |
12.AH.240.240; | 12.AH.240.244; | 12.AH.240.243; | 12.AH.240.247; |
12.AH.244.157; | 12.AH.244.158; | 12.AH.244.196; | 12.AH.244.223; |
12.AH.244.240; | 12.AH.244.244; | 12.AH.244.243; | 12.AH.244.247; |
12.AH.247.157; | 12.AH.247.158; | 12.AH.247.196; | 12.AH.247.223; |
12.AH.247.240; | 12.AH.247.244; | 12.AH.247.243; | 12.AH.247.247; |
12.AJ的前体药物
12.AJ.4.157; | 12.AJ.4.158; | 12.AJ.4.196; | 12.AJ.4.223; |
12.AJ.4.240; | 12.AJ.4.244; | 12.AJ.4.243; | 12.AJ.4.247; |
12.AJ.5.157; | 12.AJ.5.158; | 12.AJ.5.196; | 12.AJ.5.223; |
12.AJ.5.240; | 12.AJ.5.244; | 12.AJ.5.243; | 12.AJ.5.247; |
12.AJ.7.157; | 12.AJ.7.158; | 12.AJ.7.196; | 12.AJ.7.223; |
12.AJ.7.240; | 12.AJ.7.244; | 12.AJ.7.243; | 12.AJ.7.247; |
12.AJ.15.157; | 12.AJ.15.158; | 12.AJ.15.196; | 12.AJ.15.223; |
12.AJ.15.240; | 12.AJ.15.244; | 12.AJ.15.243; | 12.AJ.15.247; |
12.AJ.16.157; | 12.AJ.16.158; | 12.AJ.16.196; | 12.AJ.16.223; |
12.AJ.16.240; | 12.AJ.16.244; | 12.AJ.16.243; | 12.AJ.16.247; |
12.AJ.18.157; | 12.AJ.18.158; | 12.AJ.18.196; | 12.AJ.18.223; |
12.AJ.18.240; | 12.AJ.18.244; | 12.AJ.18.243; | 12.AJ.18.247; |
12.AJ.26.157; | 12.AJ.26.158; | 12.AJ.26.196; | 12.AJ.26.223; |
12.AJ.26.240; | 12.AJ.26.244; | 12.AJ.26.243; | 12.AJ.26.247; |
12.AJ.27.157; | 12.AJ.27.158; | 12.AJ.27.196; | 12.AJ.27.223; |
12.AJ.27.240; | 12.AJ.27.244; | 12.AJ.27.243; | 12.AJ.27.247; |
12.AJ.29.157; | 12.AJ.29.158; | 12.AJ.29.196; | 12.AJ.29.223; |
12.AJ.29.240; | 12.AJ.29.244; | 12.AJ.29.243; | 12.AJ.29.247; |
12.AJ.54.157; | 12.AJ.54.158; | 12.AJ.54.196; | 12.AJ.54.223; |
12.AJ.54.240; | 12.AJ.54.244; | 12.AJ.54.243; | 12.AJ.54.247; |
12.AJ.55.157; | 12.AJ.55.158; | 12.AJ.55.196; | 12.AJ.55.223; |
12.AJ.55.240; | 12.AJ.55.244; | 12.AJ.55.243; | 12.AJ.55.247; |
12.AJ.56.157; | 12.AJ.56.158; | 12.AJ.56.196; | 12.AJ.56.223; |
12.AJ.56.240; | 12.AJ.56.244; | 12.AJ.56.243; | 12.AJ.56.247; |
12.AJ.157.157; | 12.AJ.157.158; | 12.AJ.157.196; | 12.AJ.157.223; |
12.AJ.157.240; | 12.AJ.157.244; | 12.AJ.157.243; | 12.AJ.157.247; |
12.AJ.196.157; | 12.AJ.196.158; | 12.AJ.196.196; | 12.AJ.196.223; |
12.AJ.196.240; | 12.AJ.196.244; | 12.AJ.196.243; | 12.AJ.196.247; |
12.AJ.223.157; | 12.AJ.223.158; | 12.AJ.223.196; | 12.AJ.223.223; |
12.AJ.223.240; | 12.AJ.223.244; | 12.AJ.223.243; | 12.AJ.223.247; |
12.AJ.240.157; | 12.AJ.240.158; | 12.AJ.240.196; | 12.AJ.240.223; |
12.AJ.240.240; | 12.AJ.240.244; | 12.AJ.240.243; | 12.AJ.240.247; |
12.AJ.244.157; | 12.AJ.244.158; | 12.AJ.244.196; | 12.AJ.244.223; |
12.AJ.244.240; | 12.AJ.244.244; | 12.AJ.244.243; | 12.AJ.244.247; |
12.AJ.247.157; | 12.AJ.247.158; | 12.AJ.247.196; | 12.AJ.247.223; |
12.AJ.247.240; | 12.AJ.247.244; | 12.AJ.247.243; | 12.AJ.247.247; |
12.AN的前体药物
12.AN.4.157; | 12.AN.4.158; | 12.AN.4.196; | 12.AN.4.223; |
12.AN.4.240; | 12.AN.4.244; | 12.AN.4.243; | 12.AN.4.247; |
12.AN.5.157; | 12.AN.5.158; | 12.AN.5.196; | 12.AN.5.223; |
12.AN.5.240; | 12.AN.5.244; | 12.AN.5.243; | 12.AN.5.247; |
12.AN.7.157; | 12.AN.7.158; | 12.AN.7.196; | 12.AN.7.223; |
12.AN.7.240; | 12.AN.7.244; | 12.AN.7.243; | 12.AN.7.247; |
12.AN.15.157; | 12.AN.15.158; | 12.AN.15.196; | 12.AN.15.223; |
12.AN.15.240; | 12.AN.15.244; | 12.AN.15.243; | 12.AN.15.247; |
12.AN.16.157; | 12.AN.16.158; | 12.AN.16.196; | 12.AN.16.223; |
12.AN.16.240; | 12.AN.16.244; | 12.AN.16.243; | 12.AN.16.247; |
12.AN.18.157; | 12.AN.18.158; | 12.AN.18.196; | 12.AN.18.223; |
12.AN.18.240; | 12.AN.18.244; | 12.AN.18.243; | 12.AN.18.247; |
12.AN.26.157; | 12.AN.26.158; | 12.AN.26.196; | 12.AN.26.223; |
12.AN.26.240; | 12.AN.26.244; | 12.AN.26.243; | 12.AN.26.247; |
12.AN.27.157; | 12.AN.27.158; | 12.AN.27.196; | 12.AN.27.223; |
12.AN.27.240; | 12.AN.27.244; | 12.AN.27.243; | 12.AN.27.247; |
12.AN.29.157; | 12.AN.29.158; | 12.AN.29.196; | 12.AN.29.223; |
12.AN.29.240; | 12.AN.29.244; | 12.AN.29.243; | 12.AN.29.247; |
12.AN.54.157; | 12.AN.54.158; | 12.AN.54.196; | 12.AN.54.223; |
12.AN.54.240; | 12.AN.54.244; | 12.AN.54.243; | 12.AN.54.247; |
12.AN.55.157; | 12.AN.55.158; | 12.AN.55.196; | 12.AN.55.223; |
12.AN.55.240; | 12.AN.55.244; | 12.AN.55.243; | 12.AN.55.247; |
12.AN.56.157; | 12.AN.56.158; | 12.AN.56.196; | 12.AN.56.223; |
12.AN.56.240; | 12.AN.56.244; | 12.AN.56.243; | 12.AN.56.247; |
12.AN.157.157; | 12.AN.157.158; | 12.AN.157.196; | 12.AN.157.223; |
12.AN.157.240; | 12.AN.157.244; | 12.AN.157.243; | 12.AN.157.247; |
12.AN.196.157; | 12.AN.196.158; | 12.AN.196.196; | 12.AN.196.223; |
12.AN.196.240; | 12.AN.196.244; | 12.AN.196.243; | 12.AN.196.247; |
12.AN.223.157; | 12.AN.223.158; | 12.AN.223.196; | 12.AN.223.223; |
12.AN.223.240; | 12.AN.223.244; | 12.AN.223.243; | 12.AN.223.247; |
12.AN.240.157; | 12.AN.240.158; | 12.AN.240.196; | 12.AN.240.223; |
12.AN.240.240; | 12.AN.240.244; | 12.AN.240.243; | 12.AN.240.247; |
12.AN.244.157; | 12.AN.244.158; | 12.AN.244.196; | 12.AN.244.223; |
12.AN.244.240; | 12.AN.244.244; | 12.AN.244.243; | 12.AN.244.247; |
12.AN.247.157; | 12.AN.247.158; | 12.AN.247.196; | 12.AN.247.223; |
12.AN.247.240; | 12.AN.247.244; | 12.AN.247.243; | 12.AN.247.247; |
12.AP的前体药物
12.AP.4.157; | 12.AP.4.158; | 12.AP.4.196; | 12.AP.4.223; |
12.AP.4.240; | 12.AP.4.244; | 12.AP.4.243; | 12.AP.4.247; |
12.AP.5.157; | 12.AP.5.158; | 12.AP.5.196; | 12.AP.5.223; |
12.AP.5.240; | 12.AP.5.244; | 12.AP.5.243; | 12.AP.5.247; |
12.AP.7.157; | 12.AP.7.158; | 12.AP.7.196; | 12.AP.7.223; |
12.AP.7.240; | 12.AP.7.244; | 12.AP.7.243; | 12.AP.7.247; |
12.AP.15.157; | 12.AP.15.158; | 12.AP.15.196; | 12.AP.15.223; |
12.AP.15.240; | 12.AP.15.244; | 12.AP.15.243; | 12.AP.15.247; |
12.AP.16.157; | 12.AP.16.158; | 12.AP.16.196; | 12.AP.16.223; |
12.AP.16.240; | 12.AP.16.244; | 12.AP.16.243; | 12.AP.16.247; |
12.AP.18.157; | 12.AP.18.158; | 12.AP.18.196; | 12.AP.18.223; |
12.AP.18.240; | 12.AP.18.244; | 12.AP.18.243; | 12.AP.18.247; |
12.AP.26.157; | 12.AP.26.158; | 12.AP.26.196; | 12.AP.26.223; |
12.AP.26.240; | 12.AP.26.244; | 12.AP.26.243; | 12.AP.26.247; |
12.AP.27.157; | 12.AP.27.158; | 12.AP.27.196; | 12.AP.27.223; |
12.AP.27.240; | 12.AP.27.244; | 12.AP.27.243; | 12.AP.27.247; |
12.AP.29.157; | 12.AP.29.158; | 12.AP.29.196; | 12.AP.29.223; |
12.AP.29.240; | 12.AP.29.244; | 12.AP.29.243; | 12.AP.29.247; |
12.AP.54.157; | 12.AP.54.158; | 12.AP.54.196; | 12.AP.54.223; |
12.AP.54.240; | 12.AP.54.244; | 12.AP.54.243; | 12.AP.54.247; |
12.AP.55.157; | 12.AP.55.158; | 12.AP.55.196; | 12.AP.55.223; |
12.AP.55.240; | 12.AP.55.244; | 12.AP.55.243; | 12.AP.55.247; |
12.AP.56.157; | 12.AP.56.158; | 12.AP.56.196; | 12.AP.56.223; |
12.AP.56.240; | 12.AP.56.244; | 12.AP.56.243; | 12.AP.56.247; |
12.AP.157.157; | 12.AP.157.158; | 12.AP.157.196; | 12.AP.157.223; |
12.AP.157.240; | 12.AP.157.244; | 12.AP.157.243; | 12.AP.157.247; |
12.AP.196.157; | 12.AP.196.158; | 12.AP.196.196; | 12.AP.196.223; |
12.AP.196.240; | 12.AP.196.244; | 12.AP.196.243; | 12.AP.196.247; |
12.AP.223.157; | 12.AP.223.158; | 12.AP.223.196; | 12.AP.223.223; |
12.AP.223.240; | 12.AP.223.244; | 12.AP.223.243; | 12.AP.223.247; |
12.AP.240.157; | 12.AP.240.158; | 12.AP.240.196; | 12.AP.240.223; |
12.AP.240.240; | 12.AP.240.244; | 12.AP.240.243; | 12.AP.240.247; |
12.AP.244.157; | 12.AP.244.158; | 12.AP.244.196; | 12.AP.244.223; |
12.AP.244.240; | 12.AP.244.244; | 12.AP.244.243; | 12.AP.244.247; |
12.AP.247.157; | 12.AP.247.158; | 12.AP.247.196; | 12.AP.247.223; |
12.AP.247.240; | 12.AP.247.244; | 12.AP.247.243; | 12.AP.247.247; |
12.AZ的前体药物
12.AZ.4.157; | 12.AZ.4.158; | 12.AZ.4.196; | 12.AZ.4.223; |
12.AZ.4.240; | 12.AZ.4.244; | 12.AZ.4.243; | 12.AZ.4.247; |
12.AZ.5.157; | 12.AZ.5.158; | 12.AZ.5.196; | 12.AZ.5.223; |
12.AZ.5.240; | 12.AZ.5.244; | 12.AZ.5.243; | 12.AZ.5.247; |
12.AZ.7.157; | 12.AZ.7.158; | 12.AZ.7.196; | 12.AZ.7.223; |
12.AZ.7.240; | 12.AZ.7.244; | 12.AZ.7.243; | 12.AZ.7.247; |
12.AZ.15.157; | 12.AZ.15.158; | 12.AZ.15.196; | 12.AZ.15.223; |
12.AZ.15.240; | 12.AZ.15.244; | 12.AZ.15.243; | 12.AZ.15.247; |
12.AZ.16.157; | 12.AZ.16.158; | 12.AZ.16.196; | 12.AZ.16.223; |
12.AZ.16.240; | 12.AZ.16.244; | 12.AZ.16.243; | 12.AZ.16.247; |
12.AZ.18.157; | 12.AZ.18.158; | 12.AZ.18.196; | 12.AZ.18.223; |
12.AZ.18.240; | 12.AZ.18.244; | 12.AZ.18.243; | 12.AZ.18.247; |
12.AZ.26.157; | 12.AZ.26.158; | 12.AZ.26.196; | 12.AZ.26.223; |
12.AZ.26.240; | 12.AZ.26.244; | 12.AZ.26.243; | 12.AZ.26.247; |
12.AZ.27.157; | 12.AZ.27.158; | 12.AZ.27.196; | 12.AZ.27.223; |
12.AZ.27.240; | 12.AZ.27.244; | 12.AZ.27.243; | 12.AZ.27.247; |
12.AZ.29.157; | 12.AZ.29.158; | 12.AZ.29.196; | 12.AZ.29.223; |
12.AZ.29.240; | 12.AZ.29.244; | 12.AZ.29.243; | 12.AZ.29.247; |
12.AZ.54.157; | 12.AZ.54.158; | 12.AZ.54.196; | 12.AZ.54.223; |
12.AZ.54.240; | 12.AZ.54.244; | 12.AZ.54.243; | 12.AZ.54.247; |
12.AZ.55.157; | 12.AZ.55.158; | 12.AZ.55.196; | 12.AZ.55.223; |
12.AZ.55.240; | 12.AZ.55.244; | 12.AZ.55.243; | 12.AZ.55.247; |
12.AZ.56.157; | 12.AZ.56.158; | 12.AZ.56.196; | 12.AZ.56.223; |
12.AZ.56.240; | 12.AZ.56.244; | 12.AZ.56.243; | 12.AZ.56.247; |
12.AZ.157.157; | 12.AZ.157.158; | 12.AZ.157.196; | 12.AZ.157.223; |
12.AZ.157.240; | 12.AZ.157.244; | 12.AZ.157.243; | 12.AZ.157.247; |
12.AZ.196.157; | 12.AZ.196.158; | 12.AZ.196.196; | 12.AZ.196.223; |
12.AZ.196.240; | 12.AZ.196.244; | 12.AZ.196.243; | 12.AZ.196.247; |
12.AZ.223.157; | 12.AZ.223.158; | 12.AZ.223.196; | 12.AZ.223.223; |
12.AZ.223.240; | 12.AZ.223.244; | 12.AZ.223.243; | 12.AZ.223.247; |
12.AZ.240.157; | 12.AZ.240.158; | 12.AZ.240.196; | 12.AZ.240.223; |
12.AZ.240.240; | 12.AZ.240.244; | 12.AZ.240.243; | 12.AZ.240.247; |
12.AZ.244.157; | 12.AZ.244.158; | 12.AZ.244.196; | 12.AZ.244.223; |
12.AZ.244.240; | 12.AZ.244.244; | 12.AZ.244.243; | 12.AZ.244.247; |
12.AZ.247.157; | 12.AZ.247.158; | 12.AZ.247.196; | 12.AZ.247.223; |
12.AZ.247.240; | 12.AZ.247.244; | 12.AZ.247.243; | 12.AZ.247.247; |
12.BF的前体药物
12.BF.4.157; | 12.BF.4.158; | 12.BF.4.196; | 12.BF.4.223; |
12.BF.4.240; | 12.BF.4.244; | 12.BF.4.243; | 12.BF.4.247; |
12.BF.5.157; | 12.BF.5.158; | 12.BF.5.196; | 12.BF.5.223; |
12.BF.5.240; | 12.BF.5.244; | 12.BF.5.243; | 12.BF.5.247; |
12.BF.7.157; | 12.BF.7.158; | 12.BF.7.196; | 12.BF.7.223; |
12.BF.7.240; | 12.BF.7.244; | 12.BF.7.243; | 12.BF.7.247; |
12.BF.15.157; | 12.BF.15.158; | 12.BF.15.196; | 12.BF.15.223; |
12.BF.15.240; | 12.BF.15.244; | 12.BF.15.243; | 12.BF.15.247; |
12.BF.16.157; | 12.BF.16.158; | 12.BF.16.196; | 12.BF.16.223; |
12.BF.16.240; | 12.BF.16.244; | 12.BF.16.243; | 12.BF.16.247; |
12.BF.18.157; | 12.BF.18.158; | 12.BF.18.196; | 12.BF.18.223; |
12.BF.18.240; | 12.BF.18.244; | 12.BF.18.243; | 12.BF.18.247; |
12.BF.26.157; | 12.BF.26.158; | 12.BF.26.196; | 12.BF.26.223; |
12.BF.26.240; | 12.BF.26.244; | 12.BF.26.243; | 12.BF.26.247; |
12.BF.27.157; | 12.BF.27.158; | 12.BF.27.196; | 12.BF.27.223; |
12.BF.27.240; | 12.BF.27.244; | 12.BF.27.243; | 12.BF.27.247; |
12.BF.29.157; | 12.BF.29.158; | 12.BF.29.196; | 12.BF.29.223; |
12.BF.29.240; | 12.BF.29.244; | 12.BF.29.243; | 12.BF.29.247; |
12.BF.54.157; | 12.BF.54.158; | 12.BF.54.196; | 12.BF.54.223; |
12.BF.54.240; | 12.BF.54.244; | 12.BF.54.243; | 12.BF.54.247; |
12.BF.55.157; | 12.BF.55.158; | 12.BF.55.196; | 12.BF.55.223; |
12.BF.55.240; | 12.BF.55.244; | 12.BF.55.243; | 12.BF.55.247; |
12.BF.56.157; | 12.BF.56.158; | 12.BF.56.196; | 12.BF.56.223; |
12.BF.56.240; | 12.BF.56.244; | 12.BF.56.243; | 12.BF.56.247; |
12.BF.157.157; | 12.BF.157.158; | 12.BF.157.196; | 12.BF.157.223; |
12.BF.157.240; | 12.BF.157.244; | 12.BF.157.243; | 12.BF.157.247; |
12.BF.196.157; | 12.BF.196.158; | 12.BF.196.196; | 12.BF.196.223; |
12.BF.196.240; | 12.BF.196.244; | 12.BF.196.243; | 12.BF.196.247; |
12.BF.223.157; | 12.BF.223.158; | 12.BF.223.196; | 12.BF.223.223; |
12.BF.223.240; | 12.BF.223.244; | 12.BF.223.243; | 12.BF.223.247; |
12.BF.240.157; | 12.BF.240.158; | 12.BF.240.196; | 12.BF.240.223; |
12.BF.240.240; | 12.BF.240.244; | 12.BF.240.243; | 12.BF.240.247; |
12.BF.244.157; | 12.BF.244.158; | 12.BF.244.196; | 12.BF.244.223; |
12.BF.244.240; | 12.BF.244.244; | 12.BF.244.243; | 12.BF.244.247; |
12.BF.247.157; | 12.BF.247.158; | 12.BF.247.196; | 12.BF.247.223; |
12.BF.247.240; | 12.BF.247.244; | 12.BF.247.243; | 12.BF.247.247; |
12.CI的前体药物
12.CI.4.157; | 12.CI.4.158; | 12.CI.4.196; | 12.CI.4.223; |
12.CI.4.240; | 12.CI.4.244; | 12.CI.4.243; | 12.CI.4.247; |
12.CI.5.157; | 12.CI.5.158; | 12.CI.5.196; | 12.CI.5.223; |
12.CI.5.240; | 12.CI.5.244; | 12.CI.5.243; | 12.CI.5.247; |
12.CI.7.157; | 12.CI.7.158; | 12.CI.7.196; | 12.CI.7.223; |
12.CI.7.240; | 12.CI.7.244; | 12.CI.7.243; | 12.CI.7.247; |
12.CI.15.157; | 12.CI.15.158; | 12.CI.15.196; | 12.CI.15.223; |
12.CI.15.240; | 12.CI.15.244; | 12.CI.15.243; | 12.CI.15.247; |
12.CI.16.157; | 12.CI.16.158; | 12.CI.16.196; | 12.CI.16.223; |
12.CI.16.240; | 12.CI.16.244; | 12.CI.16.243; | 12.CI.16.247; |
12.CI.18.157; | 12.CI.18.158; | 12.CI.18.196; | 12.CI.18.223; |
12.CI.18.240; | 12.CI.18.244; | 12.CI.18.243; | 12.CI.18.247; |
12.CI.26.157; | 12.CI.26.158; | 12.CI.26.196; | 12.CI.26.223; |
12.CI.26.240; | 12.CI.26.244; | 12.CI.26.243; | 12.CI.26.247; |
12.CI.27.157; | 12.CI.27.158; | 12.CI.27.196; | 12.CI.27.223; |
12.CI.27.240; | 12.CI.27.244; | 12.CI.27.243; | 12.CI.27.247; |
12.CI.29.157; | 12.CI.29.158; | 12.CI.29.196; | 12.CI.29.223; |
12.CI.29.240; | 12.CI.29.244; | 12.CI.29.243; | 12.CI.29.247; |
12.CI.54.157; | 12.CI.54.158; | 12.CI.54.196; | 12.CI.54.223; |
12.CI.54.240; | 12.CI.54.244; | 12.CI.54.243; | 12.CI.54.247; |
12.CI.55.157; | 12.CI.55.158; | 12.CI.55.196; | 12.CI.55.223; |
12.CI.55.240; | 12.CI.55.244; | 12.CI.55.243; | 12.CI.55.247; |
12.CI.56.157; | 12.CI.56.158; | 12.CI.56.196; | 12.CI.56.223; |
12.CI.56.240; | 12.CI.56.244; | 12.CI.56.243; | 12.CI.56.247; |
12.CI.157.157; | 12.CI.157.158; | 12.CI.157.196; | 12.CI.157.223; |
12.CI.157.240; | 12.CI.157.244; | 12.CI.157.243; | 12.CI.157.247; |
12.CI.196.157; | 12.CI.196.158; | 12.CI.196.196; | 12.CI.196.223; |
12.CI.196.240; | 12.CI.196.244; | 12.CI.196.243; | 12.CI.196.247; |
12.CI.223.157; | 12.CI.223.158; | 12.CI.223.196; | 12.CI.223.223; |
12.CI.223.240; | 12.CI.223.244; | 12.CI.223.243; | 12.CI.223.247; |
12.CI.240.157; | 12.CI.240.158; | 12.CI.240.196; | 12.CI.240.223; |
12.CI.240.240; | 12.CI.240.244; | 12.CI.240.243; | 12.CI.240.247; |
12.CI.244.157; | 12.CI.244.158; | 12.CI.244.196; | 12.CI.244.223; |
12.CI.244.240; | 12.CI.244.244; | 12.CI.244.243; | 12.CI.244.247; |
12.CI.247.157; | 12.CI.247.158; | 12.CI.247.196; | 12.CI.247.223; |
12.CI.247.240; | 12.CI.247.244; | 12.CI.247.243; | 12.CI.247.247; |
12.CO的前体药物
12.CO.4.157; | 12.CO.4.158; | 12.CO.4.196; | 12.CO.4.223; |
12.CO.4.240; | 12.CO.4.244; | 12.CO.4.243; | 12.CO.4.247; |
12.CO.5.157; | 12.CO.5.158; | 12.CO.5.196; | 12.CO.5.223; |
12.CO.5.240; | 12.CO.5.244; | 12.CO.5.243; | 12.CO.5.247; |
12.CO.7.157; | 12.CO.7.158; | 12.CO.7.196; | 12.CO.7.223; |
12.CO.7.240; | 12.CO.7.244; | 12.CO.7.243; | 12.CO.7.247; |
12.CO.15.157; | 12.CO.15.158; | 12.CO.15.196; | 12.CO.15.223; |
12.CO.15.240; | 12.CO.15.244; | 12.CO.15.243; | 12.CO.15.247; |
12.CO.16.157; | 12.CO.16.158; | 12.CO.16.196; | 12.CO.16.223; |
12.CO.16.240; | 12.CO.16.244; | 12.CO.16.243; | 12.CO.16.247; |
12.CO.18.157; | 12.CO.18.158; | 12.CO.18.196; | 12.CO.18.223; |
12.CO.18.240; | 12.CO.18.244; | 12.CO.18.243; | 12.CO.18.247; |
12.CO.26.157; | 12.CO.26.158; | 12.CO.26.196; | 12.CO.26.223; |
12.CO.26.240; | 12.CO.26.244; | 12.CO.26.243; | 12.CO.26.247; |
12.CO.27.157; | 12.CO.27.158; | 12.CO.27.196; | 12.CO.27.223; |
12.CO.27.240; | 12.CO.27.244; | 12.CO.27.243; | 12.CO.27.247; |
12.CO.29.157; | 12.CO.29.158; | 12.CO.29.196; | 12.CO.29.223; |
12.CO.29.240; | 12.CO.29.244; | 12.CO.29.243; | 12.CO.29.247; |
12.CO.54.157; | 12.CO.54.158; | 12.CO.54.196; | 12.CO.54.223; |
12.CO.54.240; | 12.CO.54.244; | 12.CO.54.243; | 12.CO.54.247; |
12.CO.55.157; | 12.CO.55.158; | 12.CO.55.196; | 12.CO.55.223; |
12.CO.55.240; | 12.CO.55.244; | 12.CO.55.243; | 12.CO.55.247; |
12.CO.56.157; | 12.CO.56.158; | 12.CO.56.196; | 12.CO.56.223; |
12.CO.56.240; | 12.CO.56.244; | 12.CO.56.243; | 12.CO.56.247; |
12.CO.157.157; | 12.CO.157.158; | 12.CO.157.196; | 12.CO.157.223; |
12.CO.157.240; | 12.CO.157.244; | 12.CO.157.243; | 12.CO.157.247; |
12.CO.196.157; | 12.CO.196.158; | 12.CO.196.196; | 12.CO.196.223; |
12.CO.196.240; | 12.CO.196.244; | 12.CO.196.243; | 12.CO.196.247; |
12.CO.223.157; | 12.CO.223.158; | 12.CO.223.196; | 12.CO.223.223; |
12.CO.223.240; | 12.CO.223.244; | 12.CO.223.243; | 12.CO.223.247; |
12.CO.240.157; | 12.CO.240.158; | 12.CO.240.196; | 12.CO.240.223; |
12.CO.240.240; | 12.CO.240.244; | 12.CO.240.243; | 12.CO.240.247; |
12.CO.244.157; | 12.CO.244.158; | 12.CO.244.196; | 12.CO.244.223; |
12.CO.244.240; | 12.CO.244.244; | 12.CO.244.243; | 12.CO.244.247; |
12.CO.247.157; | 12.CO.247.158; | 12.CO.247.196; | 12.CO.247.223; |
12.CO.247.240; | 12.CO.247.244; | 12.CO.247.243; | 12.CO.247.247; |
13.B的前体药物
13.B.228.228; | 13.B.228.229; | 13.B.228.230; | 13.B.228.231; |
13.B.228.236; | 13.B.228.237; | 13.B.228.238; | 13.B.228.239; |
13.B.228.154; | 13.B.228.157; | 13.B.228.166; | 13.B.228.169; |
13.B.228.172; | 13.B.228.175; | 13.B.228.240; | 13.B.228.244; |
13.B.229.228; | 13.B.229.229; | 13.B.229.230; | 13.B.229.231; |
13.B.229.236; | 13.B.229.237; | 13.B.229.238; | 13.B.229.239; |
13.B.229.154; | 13.B.229.157; | 13.B.229.166; | 13.B.229.169; |
13.B.229.172; | 13.B.229.175; | 13.B.229.240; | 13.B.229.244; |
13.B.230.228; | 13.B.230.229; | 13.B.230.230; | 13.B.230.231; |
13.B.230.236; | 13.B.230.237; | 13.B.230.238; | 13.B.230.239; |
13.B.230.154; | 13.B.230.157; | 13.B.230.166; | 13.B.230.169; |
13.B.230.172; | 13.B.230.175; | 13.B.230.240; | 13.B.230.244; |
13.B.231.228; | 13.B.231.229; | 13.B.231.230; | 13.B.231.231; |
13.B.231.236; | 13.B.231.237; | 13.B.231.238; | 13.B.231.239; |
13.B.231.154; | 13.B.231.157; | 13.B.231.166; | 13.B.231.169; |
13.B.231.172; | 13.B.231.175; | 13.B.231.240; | 13.B.231.244; |
13.B.236.228; | 13.B.236.229; | 13.B.236.230; | 13.B.236.231; |
13.B.236.236; | 13.B.236.237; | 13.B.236.238; | 13.B.236.239; |
13.B.236.154; | 13.B.236.157; | 13.B.236.166; | 13.B.236.169; |
13.B.236.172; | 13.B.236.175; | 13.B.236.240; | 13.B.236.244; |
13.B.237.228; | 13.B.237.229; | 13.B.237.230; | 13.B.237.231; |
13.B.237.236; | 13.B.237.237; | 13.B.237.238; | 13.B.237.239; |
13.B.237.154; | 13.B.237.157; | 13.B.237.166; | 13.B.237.169; |
13.B.237.172; | 13.B.237.175; | 13.B.237.240; | 13.B.237.244; |
13.B.238.228; | 13.B.238.229; | 13.B.238.230; | 13.B.238.231; |
13.B.238.236; | 13.B.238.237; | 13.B.238.238; | 13.B.238.239; |
13.B.238.154; | 13.B.238.157; | 13.B.238.166; | 13.B.238.169; |
13.B.238.172; | 13.B.238.175; | 13.B.238.240; | 13.B.238.244; |
13.B.239.228; | 13.B.239.229; | 13.B.239.230; | 13.B.239.231; |
13.B.239.236; | 13.B.239.237; | 13.B.239.238; | 13.B.239.239; |
13.B.239.154; | 13.B.239.157; | 13.B.239.166; | 13.B.239.169; |
13.B.239.172; | 13.B.239.175; | 13.B.239.240; | 13.B.239.244; |
13.B.154.228; | 13.B.154.229; | 13.B.154.230; | 13.B.154.231; |
13.B.154.236; | 13.B.154.237; | 13.B.154.238; | 13.B.154.239; |
13.B.154.154; | 13.B.154.157; | 13.B.154.166; | 13.B.154.169; |
13.B.154.172; | 13.B.154.175; | 13.B.154.240; | 13.B.154.244; |
13.B.157.228; | 13.B.157.229; | 13.B.157.230; | 13.B.157.231; |
13.B.157.236; | 13.B.157.237; | 13.B.157.238; | 13.B.157.239; |
13.B.157.154; | 13.B.157.157; | 13.B.157.166; | 13.B.157.169; |
13.B.157.172; | 13.B.157.175; | 13.B.157.240; | 13.B.157.244; |
13.B.166.228; | 13.B.166.229; | 13.B.166.230; | 13.B.166.231; |
13.B.166.236; | 13.B.166.237; | 13.B.166.238; | 13.B.166.239; |
13.B.166.154; | 13.B.166.157; | 13.B.166.166; | 13.B.166.169; |
13.B.166.172; | 13.B.166.175; | 13.B.166.240; | 13.B.166.244; |
13.B.169.228; | 13.B.169.229; | 13.B.169.230; | 13.B.169.231; |
13.B.169.236; | 13.B.169.237; | 13.B.169.238; | 13.B.169.239; |
13.B.169.154; | 13.B.169.157; | 13.B.169.166; | 13.B.169.169; |
13.B.169.172; | 13.B.169.175; | 13.B.169.240; | 13.B.169.244; |
13.B.172.228; | 13.B.172.229; | 13.B.172.230; | 13.B.172.231; |
13.B.172.236; | 13.B.172.237; | 13.B.172.238; | 13.B.172.239; |
13.B.172.154; | 13.B.172.157; | 13.B.172.166; | 13.B.172.169; |
13.B.172.172; | 13.B.172.175; | 13.B.172.240; | 13.B.172.244; |
13.B.175.228; | 13.B.175.229; | 13.B.175.230; | 13.B.175.231; |
13.B.175.236; | 13.B.175.237; | 13.B.175.238; | 13.B.175.239; |
13.B.175.154; | 13.B.175.157; | 13.B.175.166; | 13.B.175.169; |
13.B.175.172; | 13.B.175.175; | 13.B.175.240; | 13.B.175.244; |
13.B.240.228; | 13.B.240.229; | 13.B.240.230; | 13.B.240.231; |
13.B.240.236; | 13.B.240.237; | 13.B.240.238; | 13.B.240.239; |
13.B.240.154; | 13.B.240.157; | 13.B.240.166; | 13.B.240.169; |
13.B.240.172; | 13.B.240.175; | 13.B.240.240; | 13.B.240.244; |
13.B.244.228; | 13.B.244.229; | 13.B.244.230; | 13.B.244.231; |
13.B.244.236; | 13.B.244.237; | 13.B.244.238; | 13.B.244.239; |
13.B.244.154; | 13.B.244.157; | 13.B.244.166; | 13.B.244.169; |
13.B.244.172; | 13.B.244.175; | 13.B.244.240; | 13.B.244.244; |
13.D的前体药物
13.D.228.228; | 13.D.228.229; | 13.D.228.230; | 13.D.228.231; |
13.D.228.236; | 13.D.228.237; | 13.D.228.238; | 13.D.228.239; |
13.D.228.154; | 13.D.228.157; | 13.D.228.166; | 13.D.228.169; |
13.D.228.172; | 13.D.228.175; | 13.D.228.240; | 13.D.228.244; |
13.D.229.228; | 13.D.229.229; | 13.D.229.230; | 13.D.229.231; |
13.D.229.236; | 13.D.229.237; | 13.D.229.238; | 13.D.229.239; |
13.D.229.154; | 13.D.229.157; | 13.D.229.166; | 13.D.229.169; |
13.D.229.172; | 13.D.229.175; | 13.D.229.240; | 13.D.229.244; |
13.D.230.228; | 13.D.230.229; | 13.D.230.230; | 13.D.230.231; |
13.D.230.236; | 13.D.230.237; | 13.D.230.238; | 13.D.230.239; |
13.D.230.154; | 13.D.230.157; | 13.D.230.166; | 13.D.230.169; |
13.D.230.172; | 13.D.230.175; | 13.D.230.240; | 13.D.230.244; |
13.D.231.228; | 13.D.231.229; | 13.D.231.230; | 13.D.231.231; |
13.D.231.236; | 13.D.231.237; | 13.D.231.238; | 13.D.231.239; |
13.D.231.154; | 13.D.231.157; | 13.D.231.166; | 13.D.231.169; |
13.D.231.172; | 13.D.231.175; | 13.D.231.240; | 13.D.231.244; |
13.D.236.228; | 13.D.236.229; | 13.D.236.230; | 13.D.236.231; |
13.D.236.236; | 13.D.236.237; | 13.D.236.238; | 13.D.236.239; |
13.D.236.154; | 13.D.236.157; | 13.D.236.166; | 13.D.236.169; |
13.D.236.172; | 13.D.236.175; | 13.D.236.240; | 13.D.236.244; |
13.D.237.228; | 13.D.237.229; | 13.D.237.230; | 13.D.237.231; |
13.D.237.236; | 13.D.237.237; | 13.D.237.238; | 13.D.237.239; |
13.D.237.154; | 13.D.237.157; | 13.D.237.166; | 13.D.237.169; |
13.D.237.172; | 13.D.237.175; | 13.D.237.240; | 13.D.237.244; |
13.D.238.228; | 13.D.238.229; | 13.D.238.230; | 13.D.238.231; |
13.D.238.236; | 13.D.238.237; | 13.D.238.238; | 13.D.238.239; |
13.D.238.154; | 13.D.238.157; | 13.D.238.166; | 13.D.238.169; |
13.D.238.172; | 13.D.238.175; | 13.D.238.240; | 13.D.238.244; |
13.D.239.228; | 13.D.239.229; | 13.D.239.230; | 13.D.239.231; |
13.D.239.236; | 13.D.239.237; | 13.D.239.238; | 13.D.239.239; |
13.D.239.154; | 13.D.239.157; | 13.D.239.166; | 13.D.239.169; |
13.D.239.172; | 13.D.239.175; | 13.D.239.240; | 13.D.239.244; |
13.D.154.228; | 13.D.154.229; | 13.D.154.230; | 13.D.154.231; |
13.D.154.236; | 13.D.154.237; | 13.D.154.238; | 13.D.154.239; |
13.D.154.154; | 13.D.154.157; | 13.D.154.166; | 13.D.154.169; |
13.D.154.172; | 13.D.154.175; | 13.D.154.240; | 13.D.154.244; |
13.D.157.228; | 13.D.157.229; | 13.D.157.230; | 13.D.157.231; |
13.D.157.236; | 13.D.157.237; | 13.D.157.238; | 13.D.157.239; |
13.D.157.154; | 13.D.157.157; | 13.D.157.166; | 13.D.157.169; |
13.D.157.172; | 13.D.157.175; | 13.D.157.240; | 13.D.157.244; |
13.D.166.228; | 13.D.166.229; | 13.D.166.230; | 13.D.166.231; |
13.D.166.236; | 13.D.166.237; | 13.D.166.238; | 13.D.166.239; |
13.D.166.154; | 13.D.166.157; | 13.D.166.166; | 13.D.166.169; |
13.D.166.172; | 13.D.166.175; | 13.D.166.240; | 13.D.166.244; |
13.D.169.228; | 13.D.169.229; | 13.D.169.230; | 13.D.169.231; |
13.D.169.236; | 13.D.169.237; | 13.D.169.238; | 13.D.169.239; |
13.D.169.154; | 13.D.169.157; | 13.D.169.166; | 13.D.169.169; |
13.D.169.172; | 13.D.169.175; | 13.D.169.240; | 13.D.169.244; |
13.D.172.228; | 13.D.172.229; | 13.D.172.230; | 13.D.172.231; |
13.D.172.236; | 13.D.172.237; | 13.D.172.238; | 13.D.172.239; |
13.D.172.154; | 13.D.172.157; | 13.D.172.166; | 13.D.172.169; |
13.D.172.172; | 13.D.172.175; | 13.D.172.240; | 13.D.172.244; |
13.D.175.228; | 13.D.175.229; | 13.D.175.230; | 13.D.175.231; |
13.D.175.236; | 13.D.175.237; | 13.D.175.238; | 13.D.175.239; |
13.D.175.154; | 13.D.175.157; | 13.D.175.166; | 13.D.175.169; |
13.D.175.172; | 13.D.175.175; | 13.D.175.240; | 13.D.175.244; |
13.D.240.228; | 13.D.240.229; | 13.D.240.230; | 13.D.240.231; |
13.D.240.236; | 13.D.240.237; | 13.D.240.238; | 13.D.240.239; |
13.D.240.154; | 13.D.240.157; | 13.D.240.166; | 13.D.240.169; |
13.D.240.172; | 13.D.240.175; | 13.D.240.240; | 13.D.240.244; |
13.D.244.228; | 13.D.244.229; | 13.D.244.230; | 13.D.244.231; |
13.D.244.236; | 13.D.244.237; | 13.D.244.238; | 13.D.244.239; |
13.D.244.154; | 13.D.244.157; | 13.D.244.166; | 13.D.244.169; |
13.D.244.172; | 13.D.244.175; | 13.D.244.240; | 13.D.244.244; |
13.E的前体药物
13.E.228.228; | 13.E.228.229; | 13.E.228.230; | 13.E.228.231; |
13.E.228.236; | 13.E.228.237; | 13.E.228.238; | 13.E.228.239; |
13.E.228.154; | 13.E.228.157; | 13.E.228.166; | 13.E.228.169; |
13.E.228.172; | 13.E.228.175; | 13.E.228.240; | 13.E.228.244; |
13.E.229.228; | 13.E.229.229; | 13.E.229.230; | 13.E.229.231; |
13.E.229.236; | 13.E.229.237; | 13.E.229.238; | 13.E.229.239; |
13.E.229.154; | 13.E.229.157; | 13.E.229.166; | 13.E.229.169; |
13.E.229.172; | 13.E.229.175; | 13.E.229.240; | 13.E.229.244; |
13.E.230.228; | 13.E.230.229; | 13.E.230.230; | 13.E.230.231; |
13.E.230.236; | 13.E.230.237; | 13.E.230.238; | 13.E.230.239; |
13.E.230.154; | 13.E.230.157; | 13.E.230.166; | 13.E.230.169; |
13.E.230.172; | 13.E.230.175; | 13.E.230.240; | 13.E.230.244; |
13.E.231.228; | 13.E.231.229; | 13.E.231.230; | 13.E.231.231; |
13.E.231.236; | 13.E.231.237; | 13.E.231.238; | 13.E.231.239; |
13.E.231.154; | 13.E.231.157; | 13.E.231.166; | 13.E.231.169; |
13.E.231.172; | 13.E.231.175; | 13.E.231.240; | 13.E.231.244; |
13.E.236.228; | 13.E.236.229; | 13.E.236.230; | 13.E.236.231; |
13.E.236.236; | 13.E.236.237; | 13.E.236.238; | 13.E.236.239; |
13.E.236.154; | 13.E.236.157; | 13.E.236.166; | 13.E.236.169; |
13.E.236.172; | 13.E.236.175; | 13.E.236.240; | 13.E.236.244; |
13.E.237.228; | 13.E.237.229; | 13.E.237.230; | 13.E.237.231; |
13.E.237.236; | 13.E.237.237; | 13.E.237.238; | 13.E.237.239; |
13.E.237.154; | 13.E.237.157; | 13.E.237.166; | 13.E.237.169; |
13.E.237.172; | 13.E.237.175; | 13.E.237.240; | 13.E.237.244; |
13.E.238.228; | 13.E.238.229; | 13.E.238.230; | 13.E.238.231; |
13.E.238.236; | 13.E.238.237; | 13.E.238.238; | 13.E.238.239; |
13.E.238.154; | 13.E.238.157; | 13.E.238.166; | 13.E.238.169; |
13.E.238.172; | 13.E.238.175; | 13.E.238.240; | 13.E.238.244; |
13.E.239.228; | 13.E.239.229; | 13.E.239.230; | 13.E.239.231; |
13.E.239.236; | 13.E.239.237; | 13.E.239.238; | 13.E.239.239; |
13.E.239.154; | 13.E.239.157; | 13.E.239.166; | 13.E.239.169; |
13.E.239.172; | 13.E.239.175; | 13.E.239.240; | 13.E.239.244; |
13.E.154.228; | 13.E.154.229; | 13.E.154.230; | 13.E.154.231; |
13.E.154.236; | 13.E.154.237; | 13.E.154.238; | 13.E.154.239; |
13.E.154.154; | 13.E.154.157; | 13.E.154.166; | 13.E.154.169; |
13.E.154.172; | 13.E.154.175; | 13.E.154.240; | 13.E.154.244; |
13.E.157.228; | 13.E.157.229; | 13.E.157.230; | 13.E.157.231; |
13.E.157.236; | 13.E.157.237; | 13.E.157.238; | 13.E.157.239; |
13.E.157.154; | 13.E.157.157; | 13.E.157.166; | 13.E.157.169; |
13.E.157.172; | 13.E.157.175; | 13.E.157.240; | 13.E.157.244; |
13.E.166.228; | 13.E.166.229; | 13.E.166.230; | 13.E.166.231; |
13.E.166.236; | 13.E.166.237; | 13.E.166.238; | 13.E.166.239; |
13.E.166.154; | 13.E.166.157; | 13.E.166.166; | 13.E.166.169; |
13.E.166.172; | 13.E.166.175; | 13.E.166.240; | 13.E.166.244; |
13.E.169.228; | 13.E.169.229; | 13.E.169.230; | 13.E.169.231; |
13.E.169.236; | 13.E.169.237; | 13.E.169.238; | 13.E.169.239; |
13.E.169.154; | 13.E.169.157; | 13.E.169.166; | 13.E.169.169; |
13.E.169.172; | 13.E.169.175; | 13.E.169.240; | 13.E.169.244; |
13.E.172.228; | 13.E.172.229; | 13.E.172.230; | 13.E.172.231; |
13.E.172.236; | 13.E.172.237; | 13.E.172.238; | 13.E.172.239; |
13.E.172.154; | 13.E.172.157; | 13.E.172.166; | 13.E.172.169; |
13.E.172.172; | 13.E.172.175; | 13.E.172.240; | 13.E.172.244; |
13.E.175.228; | 13.E.175.229; | 13.E.175.230; | 13.E.175.231; |
13.E.175.236; | 13.E.175.237; | 13.E.175.238; | 13.E.175.239; |
13.E.175.154; | 13.E.175.157; | 13.E.175.166; | 13.E.175.169; |
13.E.175.172; | 13.E.175.175; | 13.E.175.240; | 13.E.175.244; |
13.E.240.228; | 13.E.240.229; | 13.E.240.230; | 13.E.240.231; |
13.E.240.236; | 13.E.240.237; | 13.E.240.238; | 13.E.240.239; |
13.E.240.154; | 13.E.240.157; | 13.E.240.166; | 13.E.240.169; |
13.E.240.172; | 13.E.240.175; | 13.E.240.240; | 13.E.240.244; |
13.E.244.228; | 13.E.244.229; | 13.E.244.230; | 13.E.244.231; |
13.E.244.236; | 13.E.244.237; | 13.E.244.238; | 13.E.244.239; |
13.E.244.154; | 13.E.244.157; | 13.E.244.166; | 13.E.244.169; |
13.E.244.172; | 13.E.244.175; | 13.E.244.240; | 13.E.244.244; |
13.G的前体药物
13.G.228.228; | 13.G.228.229; | 13.G.228.230; | 13.G.228.231; |
13.G.228.236; | 13.G.228.237; | 13.G.228.238; | 13.G.228.239; |
13.G.228.154; | 13.G.228.157; | 13.G.228.166; | 13.G.228.169; |
13.G.228.172; | 13.G.228.175; | 13.G.228.240; | 13.G.228.244; |
13.G.229.228; | 13.G.229.229; | 13.G.229.230; | 13.G.229.231; |
13.G.229.236; | 13.G.229.237; | 13.G.229.238; | 13.G.229.239; |
13.G.229.154; | 13.G.229.157; | 13.G.229.166; | 13.G.229.169; |
13.G.229.172; | 13.G.229.175; | 13.G.229.240; | 13.G.229.244; |
13.G.230.228; | 13.G.230.229; | 13.G.230.230; | 13.G.230.231; |
13.G.230.236; | 13.G.230.237; | 13.G.230.238; | 13.G.230.239; |
13.G.230.154; | 13.G.230.157; | 13.G.230.166; | 13.G.230.169; |
13.G.230.172; | 13.G.230.175; | 13.G.230.240; | 13.G.230.244; |
13.G.231.228; | 13.G.231.229; | 13.G.231.230; | 13.G.231.231; |
13.G.231.236; | 13.G.231.237; | 13.G.231.238; | 13.G.231.239; |
13.G.231.154; | 13.G.231.157; | 13.G.231.166; | 13.G.231.169; |
13.G.231.172; | 13.G.231.175; | 13.G.231.240; | 13.G.231.244; |
13.G.236.228; | 13.G.236.229; | 13.G.236.230; | 13.G.236.231; |
13.G.236.236; | 13.G.236.237; | 13.G.236.238; | 13.G.236.239; |
13.G.236.154; | 13.G.236.157; | 13.G.236.166; | 13.G.236.169; |
13.G.236.172; | 13.G.236.175; | 13.G.236.240; | 13.G.236.244; |
13.G.237.228; | 13.G.237.229; | 13.G.237.230; | 13.G.237.231; |
13.G.237.236; | 13.G.237.237; | 13.G.237.238; | 13.G.237.239; |
13.G.237.154; | 13.G.237.157; | 13.G.237.166; | 13.G.237.169; |
13.G.237.172; | 13.G.237.175; | 13.G.237.240; | 13.G.237.244; |
13.G.238.228; | 13.G.238.229; | 13.G.238.230; | 13.G.238.231; |
13.G.238.236; | 13.G.238.237; | 13.G.238.238; | 13.G.238.239; |
13.G.238.154; | 13.G.238.157; | 13.G.238.166; | 13.G.238.169; |
13.G.238.172; | 13.G.238.175; | 13.G.238.240; | 13.G.238.244; |
13.G.239.228; | 13.G.239.229; | 13.G.239.230; | 13.G.239.231; |
13.G.239.236; | 13.G.239.237; | 13.G.239.238; | 13.G.239.239; |
13.G.239.154; | 13.G.239.157; | 13.G.239.166; | 13.G.239.169; |
13.G.239.172; | 13.G.239.175; | 13.G.239.240; | 13.G.239.244; |
13.G.154.228; | 13.G.154.229; | 13.G.154.230; | 13.G.154.231; |
13.G.154.236; | 13.G.154.237; | 13.G.154.238; | 13.G.154.239; |
13.G.154.154; | 13.G.154.157; | 13.G.154.166; | 13.G.154.169; |
13.G.154.172; | 13.G.154.175; | 13.G.154.240; | 13.G.154.244; |
13.G.157.228; | 13.G.157.229; | 13.G.157.230; | 13.G.157.231; |
13.G.157.236; | 13.G.157.237; | 13.G.157.238; | 13.G.157.239; |
13.G.157.154; | 13.G.157.157; | 13.G.157.166; | 13.G.157.169; |
13.G.157.172; | 13.G.157.175; | 13.G.157.240; | 13.G.157.244; |
13.G.166.228; | 13.G.166.229; | 13.G.166.230; | 13.G.166.231; |
13.G.166.236; | 13.G.166.237; | 13.G.166.238; | 13.G.166.239; |
13.G.166.154; | 13.G.166.157; | 13.G.166.166; | 13.G.166.169; |
13.G.166.172; | 13.G.166.175; | 13.G.166.240; | 13.G.166.244; |
13.G.169.228; | 13.G.169.229; | 13.G.169.230; | 13.G.169.231; |
13.G.169.236; | 13.G.169.237; | 13.G.169.238; | 13.G.169.239; |
13.G.169.154; | 13.G.169.157; | 13.G.169.166; | 13.G.169.169; |
13.G.169.172; | 13.G.169.175; | 13.G.169.240; | 13.G.169.244; |
13.G.172.228; | 13.G.172.229; | 13.G.172.230; | 13.G.172.231; |
13.G.172.236; | 13.G.172.237; | 13.G.172.238; | 13.G.172.239; |
13.G.172.154; | 13.G.172.157; | 13.G.172.166; | 13.G.172.169; |
13.G.172.172; | 13.G.172.175; | 13.G.172.240; | 13.G.172.244; |
13.G.175.228; | 13.G.175.229; | 13.G.175.230; | 13.G.175.231; |
13.G.175.236; | 13.G.175.237; | 13.G.175.238; | 13.G.175.239; |
13.G.175.154; | 13.G.175.157; | 13.G.175.166; | 13.G.175.169; |
13.G.175.172; | 13.G.175.175; | 13.G.175.240; | 13.G.175.244; |
13.G.240.228; | 13.G.240.229; | 13.G.240.230; | 13.G.240.231; |
13.G.240.236; | 13.G.240.237; | 13.G.240.238; | 13.G.240.239; |
13.G.240.154; | 13.G.240.157; | 13.G.240.166; | 13.G.240.169; |
13.G.240.172; | 13.G.240.175; | 13.G.240.240; | 13.G.240.244; |
13.G.244.228; | 13.G.244.229; | 13.G.244.230; | 13.G.244.231; |
13.G.244.236; | 13.G.244.237; | 13.G.244.238; | 13.G.244.239; |
13.G.244.154; | 13.G.244.157; | 13.G.244.166; | 13.G.244.169; |
13.G.244.172; | 13.G.244.175; | 13.G.244.240; | 13.G.244.244; |
13.I的前体药物
13.I.228.228; | 13.I.228.229; | 13.I.228.230; | 13.I.228.231; |
13.I.228.236; | 13.I.228.237; | 13.I.228.238; | 13.I.228.239; |
13.I.228.154; | 13.I.228.157; | 13.I.228.166; | 13.I.228.169; |
13.I.228.172; | 13.I.228.175; | 13.I.228.240; | 13.I.228.244; |
13.I.229.228; | 13.I.229.229; | 13.I.229.230; | 13.I.229.231; |
13.I.229.236; | 13.I.229.237; | 13.I.229.238; | 13.I.229.239; |
13.I.229.154; | 13.I.229.157; | 13.I.229.166; | 13.I.229.169; |
13.I.229.172; | 13.I.229.175; | 13.I.229.240; | 13.I.229.244; |
13.I.230.228; | 13.I.230.229; | 13.I.230.230; | 13.I.230.231; |
13.I.230.236; | 13.I.230.237; | 13.I.230.238; | 13.I.230.239; |
13.I.230.154; | 13.I.230.157; | 13.I.230.166; | 13.I.230.169; |
13.I.230.172; | 13.I.230.175; | 13.I.230.240; | 13.I.230.244; |
13.I.231.228; | 13.I.231.229; | 13.I.231.230; | 13.I.231.231; |
13.I.231.236; | 13.I.231.237; | 13.I.231.238; | 13.I.231.239; |
13.I.231.154; | 13.I.231.157; | 13.I.231.166; | 13.I.231.169; |
13.I.231.172; | 13.I.231.175; | 13.I.231.240; | 13.I.231.244; |
13.I.236.228; | 13.I.236.229; | 13.I.236.230; | 13.I.236.231; |
13.I.236.236; | 13.I.236.237; | 13.I.236.238; | 13.I.236.239; |
13.I.236.154; | 13.I.236.157; | 13.I.236.166; | 13.I.236.169; |
13.I.236.172; | 13.I.236.175; | 13.I.236.240; | 13.I.236.244; |
13.I.237.228; | 13.I.237.229; | 13.I.237.230; | 13.I.237.231; |
13.I.237.236; | 13.I.237.237; | 13.I.237.238; | 13.I.237.239; |
13.I.237.154; | 13.I.237.157; | 13.I.237.166; | 13.I.237.169; |
13.I.237.172; | 13.I.237.175; | 13.I.237.240; | 13.I.237.244; |
13.I.238.228; | 13.I.238.229; | 13.I.238.230; | 13.I.238.231; |
13.I.238.236; | 13.I.238.237; | 13.I.238.238; | 13.I.238.239; |
13.I.238.154; | 13.I.238.157; | 13.I.238.166; | 13.I.238.169; |
13.I.238.172; | 13.I.238.175; | 13.I.238.240; | 13.I.238.244; |
13.I.239.228; | 13.I.239.229; | 13.I.239.230; | 13.I.239.231; |
13.I.239.236; | 13.I.239.237; | 13.I.239.238; | 13.I.239.239; |
13.I.239.154; | 13.I.239.157; | 13.I.239.166; | 13.I.239.169; |
13.I.239.172; | 13.I.239.175; | 13.I.239.240; | 13.I.239.244; |
13.I.154.228; | 13.I.154.229; | 13.I.154.230; | 13.I.154.231; |
13.I.154.236; | 13.I.154.237; | 13.I.154.238; | 13.I.154.239; |
13.I.154.154; | 13.I.154.157; | 13.I.154.166; | 13.I.154.169; |
13.I.154.172; | 13.I.154.175; | 13.I.154.240; | 13.I.154.244; |
13.I.157.228; | 13.I.157.229; | 13.I.157.230; | 13.I.157.231; |
13.I.157.236; | 13.I.157.237; | 13.I.157.238; | 13.I.157.239; |
13.I.157.154; | 13.I.157.157; | 13.I.157.166; | 13.I.157.169; |
13.I.157.172; | 13.I.157.175; | 13.I.157.240; | 13.I.157.244; |
13.I.166.228; | 13.I.166.229; | 13.I.166.230; | 13.I.166.231; |
13.I.166.236; | 13.I.166.237; | 13.I.166.238; | 13.I.166.239; |
13.I.166.154; | 13.I.166.157; | 13.I.166.166; | 13.I.166.169; |
13.I.166.172; | 13.I.166.175; | 13.I.166.240; | 13.I.166.244; |
13.I.169.228; | 13.I.169.229; | 13.I.169.230; | 13.I.169.231; |
13.I.169.236; | 13.I.169.237; | 13.I.169.238; | 13.I.169.239; |
13.I.169.154; | 13.I.169.157; | 13.I.169.166; | 13.I.169.169; |
13.I.169.172; | 13.I.169.175; | 13.I.169.240; | 13.I.169.244; |
13.I.172.228; | 13.I.172.229; | 13.I.172.230; | 13.I.172.231; |
13.I.172.236; | 13.I.172.237; | 13.I.172.238; | 13.I.172.239; |
13.I.172.154; | 13.I.172.157; | 13.I.172.166; | 13.I.172.169; |
13.I.172.172; | 13.I.172.175; | 13.I.172.240; | 13.I.172.244; |
13.I.175.228; | 13.I.175.229; | 13.I.175.230; | 13.I.175.231; |
13.I.175.236; | 13.I.175.237; | 13.I.175.238; | 13.I.175.239; |
13.I.175.154; | 13.I.175.157; | 13.I.175.166; | 13.I.175.169; |
13.I.175.172; | 13.I.175.175; | 13.I.175.240; | 13.I.175.244; |
13.I.240.228; | 13.I.240.229; | 13.I.240.230; | 13.I.240.231; |
13.I.240.236; | 13.I.240.237; | 13.I.240.238; | 13.I.240.239; |
13.I.240.154; | 13.I.240.157; | 13.I.240.166; | 13.I.240.169; |
13.I.240.172; | 13.I.240.175; | 13.I.240.240; | 13.I.240.244; |
13.I.244.228; | 13.I.244.229; | 13.I.244.230; | 13.I.244.231; |
13.I.244.236; | 13.I.244.237; | 13.I.244.238; | 13.I.244.239; |
13.I.244.154; | 13.I.244.157; | 13.I.244.166; | 13.I.244.169; |
13.I.244.172; | 13.I.244.175; | 13.I.244.240; | 13.I.244.244; |
13.J的前体药物
13.J.228.228; | 13.J.228.229; | 13.J.228.230; | 13.J.228.231; |
13.J.228.236; | 13.J.228.237; | 13.J.228.238; | 13.J.228.239; |
13.J.228.154; | 13.J.228.157; | 13.J.228.166; | 13.J.228.169; |
13.J.228.172; | 13.J.228.175; | 13.J.228.240; | 13.J.228.244; |
13.J.229.228; | 13.J.229.229; | 13.J.229.230; | 13.J.229.231; |
13.J.229.236; | 13.J.229.237; | 13.J.229.238; | 13.J.229.239; |
13.J.229.154; | 13.J.229.157; | 13.J.229.166; | 13.J.229.169; |
13.J.229.172; | 13.J.229.175; | 13.J.229.240; | 13.J.229.244; |
13.J.230.228; | 13.J.230.229; | 13.J.230.230; | 13.J.230.231; |
13.J.230.236; | 13.J.230.237; | 13.J.230.238; | 13.J.230.239; |
13.J.230.154; | 13.J.230.157; | 13.J.230.166; | 13.J.230.169; |
13.J.230.172; | 13.J.230.175; | 13.J.230.240; | 13.J.230.244; |
13.J.231.228; | 13.J.231.229; | 13.J.231.230; | 13.J.231.231; |
13.J.231.236; | 13.J.231.237; | 13.J.231.238; | 13.J.231.239; |
13.J.231.154; | 13.J.231.157; | 13.J.231.166; | 13.J.231.169; |
13.J.231.172; | 13.J.231.175; | 13.J.231.240; | 13.J.231.244; |
13.J.236.228; | 13.J.236.229; | 13.J.236.230; | 13.J.236.231; |
13.J.236.236; | 13.J.236.237; | 13.J.236.238; | 13.J.236.239; |
13.J.236.154; | 13.J.236.157; | 13.J.236.166; | 13.J.236.169; |
13.J.236.172; | 13.J.236.175; | 13.J.236.240; | 13.J.236.244; |
13.J.237.228; | 13.J.237.229; | 13.J.237.230; | 13.J.237.231; |
13.J.237.236; | 13.J.237.237; | 13.J.237.238; | 13.J.237.239; |
13.J.237.154; | 13.J.237.157; | 13.J.237.166; | 13.J.237.169; |
13.J.237.172; | 13.J.237.175; | 13.J.237.240; | 13.J.237.244; |
13.J.238.228; | 13.J.238.229; | 13.J.238.230; | 13.J.238.231; |
13.J.238.236; | 13.J.238.237; | 13.J.238.238; | 13.J.238.239; |
13.J.238.154; | 13.J.238.157; | 13.J.238.166; | 13.J.238.169; |
13.J.238.172; | 13.J.238.175; | 13.J.238.240; | 13.J.238.244; |
13.J.239.228; | 13.J.239.229; | 13.J.239.230; | 13.J.239.231; |
13.J.239.236; | 13.J.239.237; | 13.J.239.238; | 13.J.239.239; |
13.J.239.154; | 13.J.239.157; | 13.J.239.166; | 13.J.239.169; |
13.J.239.172; | 13.J.239.175; | 13.J.239.240; | 13.J.239.244; |
13.J.154.228; | 13.J.154.229; | 13.J.154.230; | 13.J.154.231; |
13.J.154.236; | 13.J.154.237; | 13.J.154.238; | 13.J.154.239; |
13.J.154.154; | 13.J.154.157; | 13.J.154.166; | 13.J.154.169; |
13.J.154.172; | 13.J.154.175; | 13.J.154.240; | 13.J.154.244; |
13.J.157.228; | 13.J.157.229; | 13.J.157.230; | 13.J.157.231; |
13.J.157.236; | 13.J.157.237; | 13.J.157.238; | 13.J.157.239; |
13.J.157.154; | 13.J.157.157; | 13.J.157.166; | 13.J.157.169; |
13.J.157.172; | 13.J.157.175; | 13.J.157.240; | 13.J.157.244; |
13.J.166.228; | 13.J.166.229; | 13.J.166.230; | 13.J.166.231; |
13.J.166.236; | 13.J.166.237; | 13.J.166.238; | 13.J.166.239; |
13.J.166.154; | 13.J.166.157; | 13.J.166.166; | 13.J.166.169; |
13.J.166.172; | 13.J.166.175; | 13.J.166.240; | 13.J.166.244; |
13.J.169.228; | 13.J.169.229; | 13.J.169.230; | 13.J.169.231; |
13.J.169.236; | 13.J.169.237; | 13.J.169.238; | 13.J.169.239; |
13.J.169.154; | 13.J.169.157; | 13.J.169.166; | 13.J.169.169; |
13.J.169.172; | 13.J.169.175; | 13.J.169.240; | 13.J.169.244; |
13.J.172.228; | 13.J.172.229; | 13.J.172.230; | 13.J.172.231; |
13.J.172.236; | 13.J.172.237; | 13.J.172.238; | 13.J.172.239; |
13.J.172.154; | 13.J.172.157; | 13.J.172.166; | 13.J.172.169; |
13.J.172.172; | 13.J.172.175; | 13.J.172.240; | 13.J.172.244; |
13.J.175.228; | 13.J.175.229; | 13.J.175.230; | 13.J.175.231; |
13.J.175.236; | 13.J.175.237; | 13.J.175.238; | 13.J.175.239; |
13.J.175.154; | 13.J.175.157; | 13.J.175.166; | 13.J.175.169; |
13.J.175.172; | 13.J.175.175; | 13.J.175.240; | 13.J.175.244; |
13.J.240.228; | 13.J.240.229; | 13.J.240.230; | 13.J.240.231; |
13.J.240.236; | 13.J.240.237; | 13.J.240.238; | 13.J.240.239; |
13.J.240.154; | 13.J.240.157; | 13.J.240.166; | 13.J.240.169; |
13.J.240.172; | 13.J.240.175; | 13.J.240.240; | 13.J.240.244; |
13.J.244.228; | 13.J.244.229; | 13.J.244.230; | 13.J.244.231; |
13.J.244.236; | 13.J.244.237; | 13.J.244.238; | 13.J.244.239; |
13.J.244.154; | 13.J.244.157; | 13.J.244.166; | 13.J.244.169; |
13.J.244.172; | 13.J.244.175; | 13.J.244.240; | 13.J.244.244; |
13.L的前体药物
13.L.228.228; | 13.L.228.229; | 13.L.228.230; | 13.L.228.231; |
13.L.228.236; | 13.L.228.237; | 13.L.228.238; | 13.L.228.239; |
13.L.228.154; | 13.L.228.157; | 13.L.228.166; | 13.L.228.169; |
13.L.228.172; | 13.L.228.175; | 13.L.228.240; | 13.L.228.244; |
13.L.229.228; | 13.L.229.229; | 13.L.229.230; | 13.L.229.231; |
13.L.229.236; | 13.L.229.237; | 13.L.229.238; | 13.L.229.239; |
13.L.229.154; | 13.L.229.157; | 13.L.229.166; | 13.L.229.169; |
13.L.229.172; | 13.L.229.175; | 13.L.229.240; | 13.L.229.244; |
13.L.230.228; | 13.L.230.229; | 13.L.230.230; | 13.L.230.231; |
13.L.230.236; | 13.L.230.237; | 13.L.230.238; | 13.L.230.239; |
13.L.230.154; | 13.L.230.157; | 13.L.230.166; | 13.L.230.169; |
13.L.230.172; | 13.L.230.175; | 13.L.230.240; | 13.L.230.244; |
13.L.231.228; | 13.L.231.229; | 13.L.231.230; | 13.L.231.231; |
13.L.231.236; | 13.L.231.237; | 13.L.231.238; | 13.L.231.239; |
13.L.231.154; | 13.L.231.157; | 13.L.231.166; | 13.L.231.169; |
13.L.231.172; | 13.L.231.175; | 13.L.231.240; | 13.L.231.244; |
13.L.236.228; | 13.L.236.229; | 13.L.236.230; | 13.L.236.231; |
13.L.236.236; | 13.L.236.237; | 13.L.236.238; | 13.L.236.239; |
13.L.236.154; | 13.L.236.157; | 13.L.236.166; | 13.L.236.169; |
13.L.236.172; | 13.L.236.175; | 13.L.236.240; | 13.L.236.244; |
13.L.237.228; | 13.L.237.229; | 13.L.237.230; | 13.L.237.231; |
13.L.237.236; | 13.L.237.237; | 13.L.237.238; | 13.L.237.239; |
13.L.237.154; | 13.L.237.157; | 13.L.237.166; | 13.L.237.169; |
13.L.237.172; | 13.L.237.175; | 13.L.237.240; | 13.L.237.244; |
13.L.238.228; | 13.L.238.229; | 13.L.238.230; | 13.L.238.231; |
13.L.238.236; | 13.L.238.237; | 13.L.238.238; | 13.L.238.239; |
13.L.238.154; | 13.L.238.157; | 13.L.238.166; | 13.L.238.169; |
13.L.238.172; | 13.L.238.175; | 13.L.238.240; | 13.L.238.244; |
13.L.239.228; | 13.L.239.229; | 13.L.239.230; | 13.L.239.231; |
13.L.239.236; | 13.L.239.237; | 13.L.239.238; | 13.L.239.239; |
13.L.239.154; | 13.L.239.157; | 13.L.239.166; | 13.L.239.169; |
13.L.239.172; | 13.L.239.175; | 13.L.239.240; | 13.L.239.244; |
13.L.154.228; | 13.L.154.229; | 13.L.154.230; | 13.L.154.231; |
13.L.154.236; | 13.L.154.237; | 13.L.154.238; | 13.L.154.239; |
13.L.154.154; | 13.L.154.157; | 13.L.154.166; | 13.L.154.169; |
13.L.154.172; | 13.L.154.175; | 13.L.154.240; | 13.L.154.244; |
13.L.157.228; | 13.L.157.229; | 13.L.157.230; | 13.L.157.231; |
13.L.157.236; | 13.L.157.237; | 13.L.157.238; | 13.L.157.239; |
13.L.157.154; | 13.L.157.157; | 13.L.157.166; | 13.L.157.169; |
13.L.157.172; | 13.L.157.175; | 13.L.157.240; | 13.L.157.244; |
13.L.166.228; | 13.L.166.229; | 13.L.166.230; | 13.L.166.231; |
13.L.166.236; | 13.L.166.237; | 13.L.166.238; | 13.L.166.239; |
13.L.166.154; | 13.L.166.157; | 13.L.166.166; | 13.L.166.169; |
13.L.166.172; | 13.L.166.175; | 13.L.166.240; | 13.L.166.244; |
13.L.169.228; | 13.L.169.229; | 13.L.169.230; | 13.L.169.231; |
13.L.169.236; | 13.L.169.237; | 13.L.169.238; | 13.L.169.239; |
13.L.169.154; | 13.L.169.157; | 13.L.169.166; | 13.L.169.169; |
13.L.169.172; | 13.L.169.175; | 13.L.169.240; | 13.L.169.244; |
13.L.172.228; | 13.L.172.229; | 13.L.172.230; | 13.L.172.231; |
13.L.172.236; | 13.L.172.237; | 13.L.172.238; | 13.L.172.239; |
13.L.172.154; | 13.L.172.157; | 13.L.172.166; | 13.L.172.169; |
13.L.172.172; | 13.L.172.175; | 13.L.172.240; | 13.L.172.244; |
13.L.175.228; | 13.L.175.229; | 13.L.175.230; | 13.L.175.231; |
13.L.175.236; | 13.L.175.237; | 13.L.175.238; | 13.L.175.239; |
13.L.175.154; | 13.L.175.157; | 13.L.175.166; | 13.L.175.169; |
13.L.175.172; | 13.L.175.175; | 13.L.175.240; | 13.L.175.244; |
13.L.240.228; | 13.L.240.229; | 13.L.240.230; | 13.L.240.231; |
13.L.240.236; | 13.L.240.237; | 13.L.240.238; | 13.L.240.239; |
13.L.240.154; | 13.L.240.157; | 13.L.240.166; | 13.L.240.169; |
13.L.240.172; | 13.L.240.175; | 13.L.240.240; | 13.L.240.244; |
13.L.244.228; | 13.L.244.229; | 13.L.244.230; | 13.L.244.231; |
13.L.244.236; | 13.L.244.237; | 13.L.244.238; | 13.L.244.239; |
13.L.244.154; | 13.L.244.157; | 13.L.244.166; | 13.L.244.169; |
13.L.244.172; | 13.L.244.175; | 13.L.244.240; | 13.L.244.244; |
13.O的前体药物
13.O.228.228; | 13.O.228.229; | 13.O.228.230; | 13.O.228.231; |
13.O.228.236; | 13.O.228.237; | 13.O.228.238; | 13.O.228.239; |
13.O.228.154; | 13.O.228.157; | 13.O.228.166; | 13.O.228.169; |
13.O.228.172; | 13.O.228.175; | 13.O.228.240; | 13.O.228.244; |
13.O.229.228; | 13.O.229.229; | 13.O.229.230; | 13.O.229.231; |
13.O.229.236; | 13.O.229.237; | 13.O.229.238; | 13.O.229.239; |
13.O.229.154; | 13.O.229.157; | 13.O.229.166; | 13.O.229.169; |
13.O.229.172; | 13.O.229.175; | 13.O.229.240; | 13.O.229.244; |
13.O.230.228; | 13.O.230.229; | 13.O.230.230; | 13.O.230.231; |
13.O.230.236; | 13.O.230.237; | 13.O.230.238; | 13.O.230.239; |
13.O.230.154; | 13.O.230.157; | 13.O.230.166; | 13.O.230.169; |
13.O.230.172; | 13.O.230.175; | 13.O.230.240; | 13.O.230.244; |
13.O.231.228; | 13.O.231.229; | 13.O.231.230; | 13.O.231.231; |
13.O.231.236; | 13.O.231.237; | 13.O.231.238; | 13.O.231.239; |
13.O.231.154; | 13.O.231.157; | 13.O.231.166; | 13.O.231.169; |
13.O.231.172; | 13.O.231.175; | 13.O.231.240; | 13.O.231.244; |
13.O.236.228; | 13.O.236.229; | 13.O.236.230; | 13.O.236.231; |
13.O.236.236; | 13.O.236.237; | 13.O.236.238; | 13.O.236.239; |
13.O.236.154; | 13.O.236.157; | 13.O.236.166; | 13.O.236.169; |
13.O.236.172; | 13.O.236.175; | 13.O.236.240; | 13.O.236.244; |
13.O.237.228; | 13.O.237.229; | 13.O.237.230; | 13.O.237.231; |
13.O.237.236; | 13.O.237.237; | 13.O.237.238; | 13.O.237.239; |
13.O.237.154; | 13.O.237.157; | 13.O.237.166; | 13.O.237.169; |
13.O.237.172; | 13.O.237.175; | 13.O.237.240; | 13.O.237.244; |
13.O.238.228; | 13.O.238.229; | 13.O.238.230; | 13.O.238.231; |
13.O.238.236; | 13.O.238.237; | 13.O.238.238; | 13.O.238.239; |
13.O.238.154; | 13.O.238.157; | 13.O.238.166; | 13.O.238.169; |
13.O.238.172; | 13.O.238.175; | 13.O.238.240; | 13.O.238.244; |
13.O.239.228; | 13.O.239.229; | 13.O.239.230; | 13.O.239.231; |
13.O.239.236; | 13.O.239.237; | 13.O.239.238; | 13.O.239.239; |
13.O.239.154; | 13.O.239.157; | 13.O.239.166; | 13.O.239.169; |
13.O.239.172; | 13.O.239.175; | 13.O.239.240; | 13.O.239.244; |
13.O.154.228; | 13.O.154.229; | 13.O.154.230; | 13.O.154.231; |
13.O.154.236; | 13.O.154.237; | 13.O.154.238; | 13.O.154.239; |
13.O.154.154; | 13.O.154.157; | 13.O.154.166; | 13.O.154.169; |
13.O.154.172; | 13.O.154.175; | 13.O.154.240; | 13.O.154.244; |
13.O.157.228; | 13.O.157.229; | 13.O.157.230; | 13.O.157.231; |
13.O.157.236; | 13.O.157.237; | 13.O.157.238; | 13.O.157.239; |
13.O.157.154; | 13.O.157.157; | 13.O.157.166; | 13.O.157.169; |
13.O.157.172; | 13.O.157.175; | 13.O.157.240; | 13.O.157.244; |
13.O.166.228; | 13.O.166.229; | 13.O.166.230; | 13.O.166.231; |
13.O.166.236; | 13.O.166.237; | 13.O.166.238; | 13.O.166.239; |
13.O.166.154; | 13.O.166.157; | 13.O.166.166; | 13.O.166.169; |
13.O.166.172; | 13.O.166.175; | 13.O.166.240; | 13.O.166.244; |
13.O.169.228; | 13.O.169.229; | 13.O.169.230; | 13.O.169.231; |
13.O.169.236; | 13.O.169.237; | 13.O.169.238; | 13.O.169.239; |
13.O.169.154; | 13.O.169.157; | 13.O.169.166; | 13.O.169.169; |
13.O.169.172; | 13.O.169.175; | 13.O.169.240; | 13.O.169.244; |
13.O.172.228; | 13.O.172.229; | 13.O.172.230; | 13.O.172.231; |
13.O.172.236; | 13.O.172.237; | 13.O.172.238; | 13.O.172.239; |
13.O.172.154; | 13.O.172.157; | 13.O.172.166; | 13.O.172.169; |
13.O.172.172; | 13.O.172.175; | 13.O.172.240; | 13.O.172.244; |
13.O.175.228; | 13.O.175.229; | 13.O.175.230; | 13.O.175.231; |
13.O.175.236; | 13.O.175.237; | 13.O.175.238; | 13.O.175.239; |
13.O.175.154; | 13.O.175.157; | 13.O.175.166; | 13.O.175.169; |
13.O.175.172; | 13.O.175.175; | 13.O.175.240; | 13.O.175.244; |
13.O.240.228; | 13.O.240.229; | 13.O.240.230; | 13.O.240.231; |
13.O.240.236; | 13.O.240.237; | 13.O.240.238; | 13.O.240.239; |
13.O.240.154; | 13.O.240.157; | 13.O.240.166; | 13.O.240.169; |
13.O.240.172; | 13.O.240.175; | 13.O.240.240; | 13.O.240.244; |
13.O.244.228; | 13.O.244.229; | 13.O.244.230; | 13.O.244.231; |
13.O.244.236; | 13.O.244.237; | 13.O.244.238; | 13.O.244.239; |
13.O.244.154; | 13.O.244.157; | 13.O.244.166; | 13.O.244.169; |
13.O.244.172; | 13.O.244.175; | 13.O.244.240; | 13.O.244.244; |
13.P的前体药物
13.P.228.228; | 13.P.228.229; | 13.P.228.230; | 13.P.228.231; |
13.P.228.236; | 13.P.228.237; | 13.P.228.238; | 13.P.228.239; |
13.P.228.154; | 13.P.228.157; | 13.P.228.166; | 13.P.228.169; |
13.P.228.172; | 13.P.228.175; | 13.P.228.240; | 13.P.228.244; |
13.P.229.228; | 13.P.229.229; | 13.P.229.230; | 13.P.229.231; |
13.P.229.236; | 13.P.229.237; | 13.P.229.238; | 13.P.229.239; |
13.P.229.154; | 13.P.229.157; | 13.P.229.166; | 13.P.229.169; |
13.P.229.172; | 13.P.229.175; | 13.P.229.240; | 13.P.229.244; |
13.P.230.228; | 13.P.230.229; | 13.P.230.230; | 13.P.230.231; |
13.P.230.236; | 13.P.230.237; | 13.P.230.238; | 13.P.230.239; |
13.P.230.154; | 13.P.230.157; | 13.P.230.166; | 13.P.230.169; |
13.P.230.172; | 13.P.230.175; | 13.P.230.240; | 13.P.230.244; |
13.P.231.228; | 13.P.231.229; | 13.P.231.230; | 13.P.231.231; |
13.P.231.236; | 13.P.231.237; | 13.P.231.238; | 13.P.231.239; |
13.P.231.154; | 13.P.231.157; | 13.P.231.166; | 13.P.231.169; |
13.P.231.172; | 13.P.231.175; | 13.P.231.240; | 13.P.231.244; |
13.P.236.228; | 13.P.236.229; | 13.P.236.230; | 13.P.236.231; |
13.P.236.236; | 13.P.236.237; | 13.P.236.238; | 13.P.236.239; |
13.P.236.154; | 13.P.236.157; | 13.P.236.166; | 13.P.236.169; |
13.P.236.172; | 13.P.236.175; | 13.P.236.240; | 13.P.236.244; |
13.P.237.228; | 13.P.237.229; | 13.P.237.230; | 13.P.237.231; |
13.P.237.236; | 13.P.237.237; | 13.P.237.238; | 13.P.237.239; |
13.P.237.154; | 13.P.237.157; | 13.P.237.166; | 13.P.237.169; |
13.P.237.172; | 13.P.237.175; | 13.P.237.240; | 13.P.237.244; |
13.P.238.228; | 13.P.238.229; | 13.P.238.230; | 13.P.238.231; |
13.P.238.236; | 13.P.238.237; | 13.P.238.238; | 13.P.238.239; |
13.P.238.154; | 13.P.238.157; | 13.P.238.166; | 13.P.238.169; |
13.P.238.172; | 13.P.238.175; | 13.P.238.240; | 13.P.238.244; |
13.P.239.228; | 13.P.239.229; | 13.P.239.230; | 13.P.239.231; |
13.P.239.236; | 13.P.239.237; | 13.P.239.238; | 13.P.239.239; |
13.P.239.154; | 13.P.239.157; | 13.P.239.166; | 13.P.239.169; |
13.P.239.172; | 13.P.239.175; | 13.P.239.240; | 13.P.239.244; |
13.P.154.228; | 13.P.154.229; | 13.P.154.230; | 13.P.154.231; |
13.P.154.236; | 13.P.154.237; | 13.P.154.238; | 13.P.154.239; |
13.P.154.154; | 13.P.154.157; | 13.P.154.166; | 13.P.154.169; |
13.P.154.172; | 13.P.154.175; | 13.P.154.240; | 13.P.154.244; |
13.P.157.228; | 13.P.157.229; | 13.P.157.230; | 13.P.157.231; |
13.P.157.236; | 13.P.157.237; | 13.P.157.238; | 13.P.157.239; |
13.P.157.154; | 13.P.157.157; | 13.P.157.166; | 13.P.157.169; |
13.P.157.172; | 13.P.157.175; | 13.P.157.240; | 13.P.157.244; |
13.P.166.228; | 13.P.166.229; | 13.P.166.230; | 13.P.166.231; |
13.P.166.236; | 13.P.166.237; | 13.P.166.238; | 13.P.166.239; |
13.P.166.154; | 13.P.166.157; | 13.P.166.166; | 13.P.166.169; |
13.P.166.172; | 13.P.166.175; | 13.P.166.240; | 13.P.166.244; |
13.P.169.228; | 13.P.169.229; | 13.P.169.230; | 13.P.169.231; |
13.P.169.236; | 13.P.169.237; | 13.P.169.238; | 13.P.169.239; |
13.P.169.154; | 13.P.169.157; | 13.P.169.166; | 13.P.169.169; |
13.P.169.172; | 13.P.169.175; | 13.P.169.240; | 13.P.169.244; |
13.P.172.228; | 13.P.172.229; | 13.P.172.230; | 13.P.172.231; |
13.P.172.236; | 13.P.172.237; | 13.P.172.238; | 13.P.172.239; |
13.P.172.154; | 13.P.172.157; | 13.P.172.166; | 13.P.172.169; |
13.P.172.172; | 13.P.172.175; | 13.P.172.240; | 13.P.172.244; |
13.P.175.228; | 13.P.175.229; | 13.P.175.230; | 13.P.175.231; |
13.P.175.236; | 13.P.175.237; | 13.P.175.238; | 13.P.175.239; |
13.P.175.154; | 13.P.175.157; | 13.P.175.166; | 13.P.175.169; |
13.P.175.172; | 13.P.175.175; | 13.P.175.240; | 13.P.175.244; |
13.P.240.228; | 13.P.240.229; | 13.P.240.230; | 13.P.240.231; |
13.P.240.236; | 13.P.240.237; | 13.P.240.238; | 13.P.240.239; |
13.P.240.154; | 13.P.240.157; | 13.P.240.166; | 13.P.240.169; |
13.P.240.172; | 13.P.240.175; | 13.P.240.240; | 13.P.240.244; |
13.P.244.228; | 13.P.244.229; | 13.P.244.230; | 13.P.244.231; |
13.P.244.236; | 13.P.244.237; | 13.P.244.238; | 13.P.244.239; |
13.P.244.154; | 13.P.244.157; | 13.P.244.166; | 13.P.244.169; |
13.P.244.172; | 13.P.244.175; | 13.P.244.240; | 13.P.244.244; |
13.U的前体药物
13.U.228.228; | 13.U.228.229; | 13.U.228.230; | 13.U.228.231; |
13.U.228.236; | 13.U.228.237; | 13.U.228.238; | 13.U.228.239; |
13.U.228.154; | 13.U.228.157; | 13.U.228.166; | 13.U.228.169; |
13.U.228.172; | 13.U.228.175; | 13.U.228.240; | 13.U.228.244; |
13.U.229.228; | 13.U.229.229; | 13.U.229.230; | 13.U.229.231; |
13.U.229.236; | 13.U.229.237; | 13.U.229.238; | 13.U.229.239; |
13.U.229.154; | 13.U.229.157; | 13.U.229.166; | 13.U.229.169; |
13.U.229.172; | 13.U.229.175; | 13.U.229.240; | 13.U.229.244; |
13.U.230.228; | 13.U.230.229; | 13.U.230.230; | 13.U.230.231; |
13.U.230.236; | 13.U.230.237; | 13.U.230.238; | 13.U.230.239; |
13.U.230.154; | 13.U.230.157; | 13.U.230.166; | 13.U.230.169; |
13.U.230.172; | 13.U.230.175; | 13.U.230.240; | 13.U.230.244; |
13.U.231.228; | 13.U.231.229; | 13.U.231.230; | 13.U.231.231; |
13.U.231.236; | 13.U.231.237; | 13.U.231.238; | 13.U.231.239; |
13.U.231.154; | 13.U.231.157; | 13.U.231.166; | 13.U.231.169; |
13.U.231.172; | 13.U.231.175; | 13.U.231.240; | 13.U.231.244; |
13.U.236.228; | 13.U.236.229; | 13.U.236.230; | 13.U.236.231; |
13.U.236.236; | 13.U.236.237; | 13.U.236.238; | 13.U.236.239; |
13.U.236.154; | 13.U.236.157; | 13.U.236.166; | 13.U.236.169; |
13.U.236.172; | 13.U.236.175; | 13.U.236.240; | 13.U.236.244; |
13.U.237.228; | 13.U.237.229; | 13.U.237.230; | 13.U.237.231; |
13.U.237.236; | 13.U.237.237; | 13.U.237.238; | 13.U.237.239; |
13.U.237.154; | 13.U.237.157; | 13.U.237.166; | 13.U.237.169; |
13.U.237.172; | 13.U.237.175; | 13.U.237.240; | 13.U.237.244; |
13.U.238.228; | 13.U.238.229; | 13.U.238.230; | 13.U.238.231; |
13.U.238.236; | 13.U.238.237; | 13.U.238.238; | 13.U.238.239; |
13.U.238.154; | 13.U.238.157; | 13.U.238.166; | 13.U.238.169; |
13.U.238.172; | 13.U.238.175; | 13.U.238.240; | 13.U.238.244; |
13.U.239.228; | 13.U.239.229; | 13.U.239.230; | 13.U.239.231; |
13.U.239.236; | 13.U.239.237; | 13.U.239.238; | 13.U.239.239; |
13.U.239.154; | 13.U.239.157; | 13.U.239.166; | 13.U.239.169; |
13.U.239.172; | 13.U.239.175; | 13.U.239.240; | 13.U.239.244; |
13.U.154.228; | 13.U.154.229; | 13.U.154.230; | 13.U.154.231; |
13.U.154.236; | 13.U.154.237; | 13.U.154.238; | 13.U.154.239; |
13.U.154.154; | 13.U.154.157; | 13.U.154.166; | 13.U.154.169; |
13.U.154.172; | 13.U.154.175; | 13.U.154.240; | 13.U.154.244; |
13.U.157.228; | 13.U.157.229; | 13.U.157.230; | 13.U.157.231; |
13.U.157.236; | 13.U.157.237; | 13.U.157.238; | 13.U.157.239; |
13.U.157.154; | 13.U.157.157; | 13.U.157.166; | 13.U.157.169; |
13.U.157.172; | 13.U.157.175; | 13.U.157.240; | 13.U.157.244; |
13.U.166.228; | 13.U.166.229; | 13.U.166.230; | 13.U.166.231; |
13.U.166.236; | 13.U.166.237; | 13.U.166.238; | 13.U.166.239; |
13.U.166.154; | 13.U.166.157; | 13.U.166.166; | 13.U.166.169; |
13.U.166.172; | 13.U.166.175; | 13.U.166.240; | 13.U.166.244; |
13.U.169.228; | 13.U.169.229; | 13.U.169.230; | 13.U.169.231; |
13.U.169.236; | 13.U.169.237; | 13.U.169.238; | 13.U.169.239; |
13.U.169.154; | 13.U.169.157; | 13.U.169.166; | 13.U.169.169; |
13.U.169.172; | 13.U.169.175; | 13.U.169.240; | 13.U.169.244; |
13.U.172.228; | 13.U.172.229; | 13.U.172.230; | 13.U.172.231; |
13.U.172.236; | 13.U.172.237; | 13.U.172.238; | 13.U.172.239; |
13.U.172.154; | 13.U.172.157; | 13.U.172.166; | 13.U.172.169; |
13.U.172.172; | 13.U.172.175; | 13.U.172.240; | 13.U.172.244; |
13.U.175.228; | 13.U.175.229; | 13.U.175.230; | 13.U.175.231; |
13.U.175.236; | 13.U.175.237; | 13.U.175.238; | 13.U.175.239; |
13.U.175.154; | 13.U.175.157; | 13.U.175.166; | 13.U.175.169; |
13.U.175.172; | 13.U.175.175; | 13.U.175.240; | 13.U.175.244; |
13.U.240.228; | 13.U.240.229; | 13.U.240.230; | 13.U.240.231; |
13.U.240.236; | 13.U.240.237; | 13.U.240.238; | 13.U.240.239; |
13.U.240.154; | 13.U.240.157; | 13.U.240.166; | 13.U.240.169; |
13.U.240.172; | 13.U.240.175; | 13.U.240.240; | 13.U.240.244; |
13.U.244.228; | 13.U.244.229; | 13.U.244.230; | 13.U.244.231; |
13.U.244.236; | 13.U.244.237; | 13.U.244.238; | 13.U.244.239; |
13.U.244.154; | 13.U.244.157; | 13.U.244.166; | 13.U.244.169; |
13.U.244.172; | 13.U.244.175; | 13.U.244.240; | 13.U.244.244; |
13.W的前体药物
13.W.228.228; | 13.W.228.229; | 13.W.228.230; | 13.W.228.231; |
13.W.228.236; | 13.W.228.237; | 13.W.228.238; | 13.W.228.239; |
13.W.228.154; | 13.W.228.157; | 13.W.228.166; | 13.W.228.169; |
13.W.228.172; | 13.W.228.175; | 13.W.228.240; | 13.W.228.244; |
13.W.229.228; | 13.W.229.229; | 13.W.229.230; | 13.W.229.231; |
13.W.229.236; | 13.W.229.237; | 13.W.229.238; | 13.W.229.239; |
13.W.229.154; | 13.W.229.157; | 13.W.229.166; | 13.W.229.169; |
13.W.229.172; | 13.W.229.175; | 13.W.229.240; | 13.W.229.244; |
13.W.230.228; | 13.W.230.229; | 13.W.230.230; | 13.W.230.231; |
13.W.230.236; | 13.W.230.237; | 13.W.230.238; | 13.W.230.239; |
13.W.230.154; | 13.W.230.157; | 13.W.230.166; | 13.W.230.169; |
13.W.230.172; | 13.W.230.175; | 13.W.230.240; | 13.W.230.244; |
13.W.231.228; | 13.W.231.229; | 13.W.231.230; | 13.W.231.231; |
13.W.231.236; | 13.W.231.237; | 13.W.231.238; | 13.W.231.239; |
13.W.231.154; | 13.W.231.157; | 13.W.231.166; | 13.W.231.169; |
13.W.231.172; | 13.W.231.175; | 13.W.231.240; | 13.W.231.244; |
13.W.236.228; | 13.W.236.229; | 13.W.236.230; | 13.W.236.231; |
13.W.236.236; | 13.W.236.237; | 13.W.236.238; | 13.W.236.239; |
13.W.236.154; | 13.W.236.157; | 13.W.236.166; | 13.W.236.169; |
13.W.236.172; | 13.W.236.175; | 13.W.236.240; | 13.W.236.244; |
13.W.237.228; | 13.W.237.229; | 13.W.237.230; | 13.W.237.231; |
13.W.237.236; | 13.W.237.237; | 13.W.237.238; | 13.W.237.239; |
13.W.237.154; | 13.W.237.157; | 13.W.237.166; | 13.W.237.169; |
13.W.237.172; | 13.W.237.175; | 13.W.237.240; | 13.W.237.244; |
13.W.238.228; | 13.W.238.229; | 13.W.238.230; | 13.W.238.231; |
13.W.238.236; | 13.W.238.237; | 13.W.238.238; | 13.W.238.239; |
13.W.238.154; | 13.W.238.157; | 13.W.238.166; | 13.W.238.169; |
13.W.238.172; | 13.W.238.175; | 13.W.238.240; | 13.W.238.244; |
13.W.239.228; | 13.W.239.229; | 13.W.239.230; | 13.W.239.231; |
13.W.239.236; | 13.W.239.237; | 13.W.239.238; | 13.W.239.239; |
13.W.239.154; | 13.W.239.157; | 13.W.239.166; | 13.W.239.169; |
13.W.239.172; | 13.W.239.175; | 13.W.239.240; | 13.W.239.244; |
13.W.154.228; | 13.W.154.229; | 13.W.154.230; | 13.W.154.231; |
13.W.154.236; | 13.W.154.237; | 13.W.154.238; | 13.W.154.239; |
13.W.154.154; | 13.W.154.157; | 13.W.154.166; | 13.W.154.169; |
13.W.154.172; | 13.W.154.175; | 13.W.154.240; | 13.W.154.244; |
13.W.157.228; | 13.W.157.229; | 13.W.157.230; | 13.W.157.231; |
13.W.157.236; | 13.W.157.237; | 13.W.157.238; | 13.W.157.239; |
13.W.157.154; | 13.W.157.157; | 13.W.157.166; | 13.W.157.169; |
13.W.157.172; | 13.W.157.175; | 13.W.157.240; | 13.W.157.244; |
13.W.166.228; | 13.W.166.229; | 13.W.166.230; | 13.W.166.231; |
13.W.166.236; | 13.W.166.237; | 13.W.166.238; | 13.W.166.239; |
13.W.166.154; | 13.W.166.157; | 13.W.166.166; | 13.W.166.169; |
13.W.166.172; | 13.W.166.175; | 13.W.166.240; | 13.W.166.244; |
13.W.169.228; | 13.W.169.229; | 13.W.169.230; | 13.W.169.231; |
13.W.169.236; | 13.W.169.237; | 13.W.169.238; | 13.W.169.239; |
13.W.169.154; | 13.W.169.157; | 13.W.169.166; | 13.W.169.169; |
13.W.169.172; | 13.W.169.175; | 13.W.169.240; | 13.W.169.244; |
13.W.172.228; | 13.W.172.229; | 13.W.172.230; | 13.W.172.231; |
13.W.172.236; | 13.W.172.237; | 13.W.172.238; | 13.W.172.239; |
13.W.172.154; | 13.W.172.157; | 13.W.172.166; | 13.W.172.169; |
13.W.172.172; | 13.W.172.175; | 13.W.172.240; | 13.W.172.244; |
13.W.175.228; | 13.W.175.229; | 13.W.175.230; | 13.W.175.231; |
13.W.175.236; | 13.W.175.237; | 13.W.175.238; | 13.W.175.239; |
13.W.175.154; | 13.W.175.157; | 13.W.175.166; | 13.W.175.169; |
13.W.175.172; | 13.W.175.175; | 13.W.175.240; | 13.W.175.244; |
13.W.240.228; | 13.W.240.229; | 13.W.240.230; | 13.W.240.231; |
13.W.240.236; | 13.W.240.237; | 13.W.240.238; | 13.W.240.239; |
13.W.240.154; | 13.W.240.157; | 13.W.240.166; | 13.W.240.169; |
13.W.240.172; | 13.W.240.175; | 13.W.240.240; | 13.W.240.244; |
13.W.244.228; | 13.W.244.229; | 13.W.244.230; | 13.W.244.231; |
13.W.244.236; | 13.W.244.237; | 13.W.244.238; | 13.W.244.239; |
13.W.244.154; | 13.W.244.157; | 13.W.244.166; | 13.W.244.169; |
13.W.244.172; | 13.W.244.175; | 13.W.244.240; | 13.W.244.244; |
13.Y的前体药物
13.Y.228.228; | 13.Y.228.229; | 13.Y.228.230; | 13.Y.228.231; |
13.Y.228.236; | 13.Y.228.237; | 13.Y.228.238; | 13.Y.228.239; |
13.Y.228.154; | 13.Y.228.157; | 13.Y.228.166; | 13.Y.228.169; |
13.Y.228.172; | 13.Y.228.175; | 13.Y.228.240; | 13.Y.228.244; |
13.Y.229.228; | 13.Y.229.229; | 13.Y.229.230; | 13.Y.229.231; |
13.Y.229.236; | 13.Y.229.237; | 13.Y.229.238; | 13.Y.229.239; |
13.Y.229.154; | 13.Y.229.157; | 13.Y.229.166; | 13.Y.229.169; |
13.Y.229.172; | 13.Y.229.175; | 13.Y.229.240; | 13.Y.229.244; |
13.Y.230.228; | 13.Y.230.229; | 13.Y.230.230; | 13.Y.230.231; |
13.Y.230.236; | 13.Y.230.237; | 13.Y.230.238; | 13.Y.230.239; |
13.Y.230.154; | 13.Y.230.157; | 13.Y.230.166; | 13.Y.230.169; |
13.Y.230.172; | 13.Y.230.175; | 13.Y.230.240; | 13.Y.230.244; |
13.Y.231.228; | 13.Y.231.229; | 13.Y.231.230; | 13.Y.231.231; |
13.Y.231.236; | 13.Y.231.237; | 13.Y.231.238; | 13.Y.231.239; |
13.Y.231.154; | 13.Y.231.157; | 13.Y.231.166; | 13.Y.231.169; |
13.Y.231.172; | 13.Y.231.175; | 13.Y.231.240; | 13.Y.231.244; |
13.Y.236.228; | 13.Y.236.229; | 13.Y.236.230; | 13.Y.236.231; |
13.Y.236.236; | 13.Y.236.237; | 13.Y.236.238; | 13.Y.236.239; |
13.Y.236.154; | 13.Y.236.157; | 13.Y.236.166; | 13.Y.236.169; |
13.Y.236.172; | 13.Y.236.175; | 13.Y.236.240; | 13.Y.236.244; |
13.Y.237.228; | 13.Y.237.229; | 13.Y.237.230; | 13.Y.237.231; |
13.Y.237.236; | 13.Y.237.237; | 13.Y.237.238; | 13.Y.237.239; |
13.Y.237.154; | 13.Y.237.157; | 13.Y.237.166; | 13.Y.237.169; |
13.Y.237.172; | 13.Y.237.175; | 13.Y.237.240; | 13.Y.237.244; |
13.Y.238.228; | 13.Y.238.229; | 13.Y.238.230; | 13.Y.238.231; |
13.Y.238.236; | 13.Y.238.237; | 13.Y.238.238; | 13.Y.238.239; |
13.Y.238.154; | 13.Y.238.157; | 13.Y.238.166; | 13.Y.238.169; |
13.Y.238.172; | 13.Y.238.175; | 13.Y.238.240; | 13.Y.238.244; |
13.Y.239.228; | 13.Y.239.229; | 13.Y.239.230; | 13.Y.239.231; |
13.Y.239.236; | 13.Y.239.237; | 13.Y.239.238; | 13.Y.239.239; |
13.Y.239.154; | 13.Y.239.157; | 13.Y.239.166; | 13.Y.239.169; |
13.Y.239.172; | 13.Y.239.175; | 13.Y.239.240; | 13.Y.239.244; |
13.Y.154.228; | 13.Y.154.229; | 13.Y.154.230; | 13.Y.154.231; |
13.Y.154.236; | 13.Y.154.237; | 13.Y.154.238; | 13.Y.154.239; |
13.Y.154.154; | 13.Y.154.157; | 13.Y.154.166; | 13.Y.154.169; |
13.Y.154.172; | 13.Y.154.175; | 13.Y.154.240; | 13.Y.154.244; |
13.Y.157.228; | 13.Y.157.229; | 13.Y.157.230; | 13.Y.157.231; |
13.Y.157.236; | 13.Y.157.237; | 13.Y.157.238; | 13.Y.157.239; |
13.Y.157.154; | 13.Y.157.157; | 13.Y.157.166; | 13.Y.157.169; |
13.Y.157.172; | 13.Y.157.175; | 13.Y.157.240; | 13.Y.157.244; |
13.Y.166.228; | 13.Y.166.229; | 13.Y.166.230; | 13.Y.166.231; |
13.Y.166.236; | 13.Y.166.237; | 13.Y.166.238; | 13.Y.166.239; |
13.Y.166.154; | 13.Y.166.157; | 13.Y.166.166; | 13.Y.166.169; |
13.Y.166.172; | 13.Y.166.175; | 13.Y.166.240; | 13.Y.166.244; |
13.Y.169.228; | 13.Y.169.229; | 13.Y.169.230; | 13.Y.169.231; |
13.Y.169.236; | 13.Y.169.237; | 13.Y.169.238; | 13.Y.169.239; |
13.Y.169.154; | 13.Y.169.157; | 13.Y.169.166; | 13.Y.169.169; |
13.Y.169.172; | 13.Y.169.175; | 13.Y.169.240; | 13.Y.169.244; |
13.Y.172.228; | 13.Y.172.229; | 13.Y.172.230; | 13.Y.172.231; |
13.Y.172.236; | 13.Y.172.237; | 13.Y.172.238; | 13.Y.172.239; |
13.Y.172.154; | 13.Y.172.157; | 13.Y.172.166; | 13.Y.172.169; |
13.Y.172.172; | 13.Y.172.175; | 13.Y.172.240; | 13.Y.172.244; |
13.Y.175.228; | 13.Y.175.229; | 13.Y.175.230; | 13.Y.175.231; |
13.Y.175.236; | 13.Y.175.237; | 13.Y.175.238; | 13.Y.175.239; |
13.Y.175.154; | 13.Y.175.157; | 13.Y.175.166; | 13.Y.175.169; |
13.Y.175.172; | 13.Y.175.175; | 13.Y.175.240; | 13.Y.175.244; |
13.Y.240.228; | 13.Y.240.229; | 13.Y.240.230; | 13.Y.240.231; |
13.Y.240.236; | 13.Y.240.237; | 13.Y.240.238; | 13.Y.240.239; |
13.Y.240.154; | 13.Y.240.157; | 13.Y.240.166; | 13.Y.240.169; |
13.Y.240.172; | 13.Y.240.175; | 13.Y.240.240; | 13.Y.240.244; |
13.Y.244.228; | 13.Y.244.229; | 13.Y.244.230; | 13.Y.244.231; |
13.Y.244.236; | 13.Y.244.237; | 13.Y.244.238; | 13.Y.244.239; |
13.Y.244.154; | 13.Y.244.157; | 13.Y.244.166; | 13.Y.244.169; |
13.Y.244.172; | 13.Y.244.175; | 13.Y.244.240; | 13.Y.244.244; |
14.AH的前体药物
14.AH.4.157; | 14.AH.4.158; | 14.AH.4.196; | 14.AH.4.223; |
14.AH.4.240; | 14.AH.4.244; | 14.AH.4.243; | 14.AH.4.247; |
14.AH.5.157; | 14.AH.5.158; | 14.AH.5.196; | 14.AH.5.223; |
14.AH.5.240; | 14.AH.5.244; | 14.AH.5.243; | 14.AH.5.247; |
14.AH.7.157; | 14.AH.7.158; | 14.AH.7.196; | 14.AH.7.223; |
14.AH.7.240; | 14.AH.7.244; | 14.AH.7.243; | 14.AH.7.247; |
14.AH.15.157; | 14.AH.15.158; | 14.AH.15.196; | 14.AH.15.223; |
14.AH.15.240; | 14.AH.15.244; | 14.AH.15.243; | 14.AH.15.247; |
14.AH.16.157; | 14.AH.16.158; | 14.AH.16.196; | 14.AH.16.223; |
14.AH.16.240; | 14.AH.16.244; | 14.AH.16.243; | 14.AH.16.247; |
14.AH.18.157; | 14.AH.18.158; | 14.AH.18.196; | 14.AH.18.223; |
14.AH.18.240; | 14.AH.18.244; | 14.AH.18.243; | 14.AH.18.247; |
14.AH.26.157; | 14.AH.26.158; | 14.AH.26.196; | 14.AH.26.223; |
14.AH.26.240; | 14.AH.26.244; | 14.AH.26.243; | 14.AH.26.247; |
14.AH.27.157; | 14.AH.27.158; | 14.AH.27.196; | 14.AH.27.223; |
14.AH.27.240; | 14.AH.27.244; | 14.AH.27.243; | 14.AH.27.247; |
14.AH.29.157; | 14.AH.29.158; | 14.AH.29.196; | 14.AH.29.223; |
14.AH.29.240; | 14.AH.29.244; | 14.AH.29.243; | 14.AH.29.247; |
14.AH.54.157; | 14.AH.54.158; | 14.AH.54.196; | 14.AH.54.223; |
14.AH.54.240; | 14.AH.54.244; | 14.AH.54.243; | 14.AH.54.247; |
14.AH.55.157; | 14.AH.55.158; | 14.AH.55.196; | 14.AH.55.223; |
14.AH.55.240; | 14.AH.55.244; | 14.AH.55.243; | 14.AH.55.247; |
14.AH.56.157; | 14.AH.56.158; | 14.AH.56.196; | 14.AH.56.223; |
14.AH.56.240; | 14.AH.56.244; | 14.AH.56.243; | 14.AH.56.247; |
14.AH.157.157; | 14.AH.157.158; | 14.AH.157.196; | 14.AH.157.223; |
14.AH.157.240; | 14.AH.157.244; | 14.AH.157.243; | 14.AH.157.247; |
14.AH.196.157; | 14.AH.196.158; | 14.AH.196.196; | 14.AH.196.223; |
14.AH.196.240; | 14.AH.196.244; | 14.AH.196.243; | 14.AH.196.247; |
14.AH.223.157; | 14.AH.223.158; | 14.AH.223.196; | 14.AH.223.223; |
14.AH.223.240; | 14.AH.223.244; | 14.AH.223.243; | 14.AH.223.247; |
14.AH.240.157; | 14.AH.240.158; | 14.AH.240.196; | 14.AH.240.223; |
14.AH.240.240; | 14.AH.240.244; | 14.AH.240.243; | 14.AH.240.247; |
14.AH.244.157; | 14.AH.244.158; | 14.AH.244.196; | 14.AH.244.223; |
14.AH.244.240; | 14.AH.244.244; | 14.AH.244.243; | 14.AH.244.247; |
14.AH.247.157; | 14.AH.247.158; | 14.AH.247.196; | 14.AH.247.223; |
14.AH.247.240; | 14.AH.247.244; | 14.AH.247.243; | 14.AH.247.247; |
14.AJ的前体药物
14.AJ.4.157; | 14.AJ.4.158; | 14.AJ.4.196; | 14.AJ.4.223; |
14.AJ.4.240; | 14.AJ.4.244; | 14.AJ.4.243; | 14.AJ.4.247; |
14.AJ.5.157; | 14.AJ.5.158; | 14.AJ.5.196; | 14.AJ.5.223; |
14.AJ.5.240; | 14.AJ.5.244; | 14.AJ.5.243; | 14.AJ.5.247; |
14.AJ.7.157; | 14.AJ.7.158; | 14.AJ.7.196; | 14.AJ.7.223; |
14.AJ.7.240; | 14.AJ.7.244; | 14.AJ.7.243; | 14.AJ.7.247; |
14.AJ.15.157; | 14.AJ.15.158; | 14.AJ.15.196; | 14.AJ.15.223; |
14.AJ.15.240; | 14.AJ.15.244; | 14.AJ.15.243; | 14.AJ.15.247; |
14.AJ.16.157; | 14.AJ.16.158; | 14.AJ.16.196; | 14.AJ.16.223; |
14.AJ.16.240; | 14.AJ.16.244; | 14.AJ.16.243; | 14.AJ.16.247; |
14.AJ.18.157; | 14.AJ.18.158; | 14.AJ.18.196; | 14.AJ.18.223; |
14.AJ.18.240; | 14.AJ.18.244; | 14.AJ.18.243; | 14.AJ.18.247; |
14.AJ.26.157; | 14.AJ.26.158; | 14.AJ.26.196; | 14.AJ.26.223; |
14.AJ.26.240; | 14.AJ.26.244; | 14.AJ.26.243; | 14.AJ.26.247; |
14.AJ.27.157; | 14.AJ.27.158; | 14.AJ.27.196; | 14.AJ.27.223; |
14.AJ.27.240; | 14.AJ.27.244; | 14.AJ.27.243; | 14.AJ.27.247; |
14.AJ.29.157; | 14.AJ.29.158; | 14.AJ.29.196; | 14.AJ.29.223; |
14.AJ.29.240; | 14.AJ.29.244; | 14.AJ.29.243; | 14.AJ.29.247; |
14.AJ.54.157; | 14.AJ.54.158; | 14.AJ.54.196; | 14.AJ.54.223; |
14.AJ.54.240; | 14.AJ.54.244; | 14.AJ.54.243; | 14.AJ.54.247; |
14.AJ.55.157; | 14.AJ.55.158; | 14.AJ.55.196; | 14.AJ.55.223; |
14.AJ.55.240; | 14.AJ.55.244; | 14.AJ.55.243; | 14.AJ.55.247; |
14.AJ.56.157; | 14.AJ.56.158; | 14.AJ.56.196; | 14.AJ.56.223; |
14.AJ.56.240; | 14.AJ.56.244; | 14.AJ.56.243; | 14.AJ.56.247; |
14.AJ.157.157; | 14.AJ.157.158; | 14.AJ.157.196; | 14.AJ.157.223; |
14.AJ.157.240; | 14.AJ.157.244; | 14.AJ.157.243; | 14.AJ.157.247; |
14.AJ.196.157; | 14.AJ.196.158; | 14.AJ.196.196; | 14.AJ.196.223; |
14.AJ.196.240; | 14.AJ.196.244; | 14.AJ.196.243; | 14.AJ.196.247; |
14.AJ.223.157; | 14.AJ.223.158; | 14.AJ.223.196; | 14.AJ.223.223; |
14.AJ.223.240; | 14.AJ.223.244; | 14.AJ.223.243; | 14.AJ.223.247; |
14.AJ.240.157; | 14.AJ.240.158; | 14.AJ.240.196; | 14.AJ.240.223; |
14.AJ.240.240; | 14.AJ.240.244; | 14.AJ.240.243; | 14.AJ.240.247; |
14.AJ.244.157; | 14.AJ.244.158; | 14.AJ.244.196; | 14.AJ.244.223; |
14.AJ.244.240; | 14.AJ.244.244; | 14.AJ.244.243; | 14.AJ.244.247; |
14.AJ.247.157; | 14.AJ.247.158; | 14.AJ.247.196; | 14.AJ.247.223; |
14.AJ.247.240; | 14.AJ.247.244; | 14.AJ.247.243; | 14.AJ.247.247; |
14.AN的前体药物
14.AN.4.157; | 14.AN.4.158; | 14.AN.4.196; | 14.AN.4.223; |
14.AN.4.240; | 14.AN.4.244; | 14.AN.4.243; | 14.AN.4.247; |
14.AN.5.157; | 14.AN.5.158; | 14.AN.5.196; | 14.AN.5.223; |
14.AN.5.240; | 14.AN.5.244; | 14.AN.5.243; | 14.AN.5.247; |
14.AN.7.157; | 14.AN.7.158; | 14.AN.7.196; | 14.AN.7.223; |
14.AN.7.240; | 14.AN.7.244; | 14.AN.7.243; | 14.AN.7.247; |
14.AN.15.157; | 14.AN.15.158; | 14.AN.15.196; | 14.AN.15.223; |
14.AN.15.240; | 14.AN.15.244; | 14.AN.15.243; | 14.AN.15.247; |
14.AN.16.157; | 14.AN.16.158; | 14.AN.16.196; | 14.AN.16.223; |
14.AN.16.240; | 14.AN.16.244; | 14.AN.16.243; | 14.AN.16.247; |
14.AN.18.157; | 14.AN.18.158; | 14.AN.18.196; | 14.AN.18.223; |
14.AN.18.240; | 14.AN.18.244; | 14.AN.18.243; | 14.AN.18.247; |
14.AN.26.157; | 14.AN.26.158; | 14.AN.26.196; | 14.AN.26.223; |
14.AN.26.240; | 14.AN.26.244; | 14.AN.26.243; | 14.AN.26.247; |
14.AN.27.157; | 14.AN.27.158; | 14.AN.27.196; | 14.AN.27.223; |
14.AN.27.240; | 14.AN.27.244; | 14.AN.27.243; | 14.AN.27.247; |
14.AN.29.157; | 14.AN.29.158; | 14.AN.29.196; | 14.AN.29.223; |
14.AN.29.240; | 14.AN.29.244; | 14.AN.29.243; | 14.AN.29.247; |
14.AN.54.157; | 14.AN.54.158; | 14.AN.54.196; | 14.AN.54.223; |
14.AN.54.240; | 14.AN.54.244; | 14.AN.54.243; | 14.AN.54.247; |
14.AN.55.157; | 14.AN.55.158; | 14.AN.55.196; | 14.AN.55.223; |
14.AN.55.240; | 14.AN.55.244; | 14.AN.55.243; | 14.AN.55.247; |
14.AN.56.157; | 14.AN.56.158; | 14.AN.56.196; | 14.AN.56.223; |
14.AN.56.240; | 14.AN.56.244; | 14.AN.56.243; | 14.AN.56.247; |
14.AN.157.157; | 14.AN.157.158; | 14.AN.157.196; | 14.AN.157.223; |
14.AN.157.240; | 14.AN.157.244; | 14.AN.157.243; | 14.AN.157.247; |
14.AN.196.157; | 14.AN.196.158; | 14.AN.196.196; | 14.AN.196.223; |
14.AN.196.240; | 14.AN.196.244; | 14.AN.196.243; | 14.AN.196.247; |
14.AN.223.157; | 14.AN.223.158; | 14.AN.223.196; | 14.AN.223.223; |
14.AN.223.240; | 14.AN.223.244; | 14.AN.223.243; | 14.AN.223.247; |
14.AN.240.157; | 14.AN.240.158; | 14.AN.240.196; | 14.AN.240.223; |
14.AN.240.240; | 14.AN.240.244; | 14.AN.240.243; | 14.AN.240.247; |
14.AN.244.157; | 14.AN.244.158; | 14.AN.244.196; | 14.AN.244.223; |
14.AN.244.240; | 14.AN.244.244; | 14.AN.244.243; | 14.AN.244.247; |
14.AN.247.157; | 14.AN.247.158; | 14.AN.247.196; | 14.AN.247.223; |
14.AN.247.240; | 14.AN.247.244; | 14.AN.247.243; | 14.AN.247.247; |
14.AP的前体药物
14.AP.4.157; | 14.AP.4.158; | 14.AP.4.196; | 14.AP.4.223; |
14.AP.4.240; | 14.AP.4.244; | 14.AP.4.243; | 14.AP.4.247; |
14.AP.5.157; | 14.AP.5.158; | 14.AP.5.196; | 14.AP.5.223; |
14.AP.5.240; | 14.AP.5.244; | 14.AP.5.243; | 14.AP.5.247; |
14.AP.7.157; | 14.AP.7.158; | 14.AP.7.196; | 14.AP.7.223; |
14.AP.7.240; | 14.AP.7.244; | 14.AP.7.243; | 14.AP.7.247; |
14.AP.15.157; | 14.AP.15.158; | 14.AP.15.196; | 14.AP.15.223; |
14.AP.15.240; | 14.AP.15.244; | 14.AP.15.243; | 14.AP.15.247; |
14.AP.16.157; | 14.AP.16.158; | 14.AP.16.196; | 14.AP.16.223; |
14.AP.16.240; | 14.AP.16.244; | 14.AP.16.243; | 14.AP.16.247; |
14.AP.18.157; | 14.AP.18.158; | 14.AP.18.196; | 14.AP.18.223; |
14.AP.18.240; | 14.AP.18.244; | 14.AP.18.243; | 14.AP.18.247; |
14.AP.26.157; | 14.AP.26.158; | 14.AP.26.196; | 14.AP.26.223; |
14.AP.26.240; | 14.AP.26.244; | 14.AP.26.243; | 14.AP.26.247; |
14.AP.27.157; | 14.AP.27.158; | 14.AP.27.196; | 14.AP.27.223; |
14.AP.27.240; | 14.AP.27.244; | 14.AP.27.243; | 14.AP.27.247; |
14.AP.29.157; | 14.AP.29.158; | 14.AP.29.196; | 14.AP.29.223; |
14.AP.29.240; | 14.AP.29.244; | 14.AP.29.243; | 14.AP.29.247; |
14.AP.54.157; | 14.AP.54.158; | 14.AP.54.196; | 14.AP.54.223; |
14.AP.54.240; | 14.AP.54.244; | 14.AP.54.243; | 14.AP.54.247; |
14.AP.55.157; | 14.AP.55.158; | 14.AP.55.196; | 14.AP.55.223; |
14.AP.55.240; | 14.AP.55.244; | 14.AP.55.243; | 14.AP.55.247; |
14.AP.56.157; | 14.AP.56.158; | 14.AP.56.196; | 14.AP.56.223; |
14.AP.56.240; | 14.AP.56.244; | 14.AP.56.243; | 14.AP.56.247; |
14.AP.157.157; | 14.AP.157.158; | 14.AP.157.196; | 14.AP.157.223; |
14.AP.157.240; | 14.AP.157.244; | 14.AP.157.243; | 14.AP.157.247; |
14.AP.196.157; | 14.AP.196.158; | 14.AP.196.196; | 14.AP.196.223; |
14.AP.196.240; | 14.AP.196.244; | 14.AP.196.243; | 14.AP.196.247; |
14.AP.223.157; | 14.AP.223.158; | 14.AP.223.196; | 14.AP.223.223; |
14.AP.223.240; | 14.AP.223.244; | 14.AP.223.243; | 14.AP.223.247; |
14.AP.240.157; | 14.AP.240.158; | 14.AP.240.196; | 14.AP.240.223; |
14.AP.240.240; | 14.AP.240.244; | 14.AP.240.243; | 14.AP.240.247; |
14.AP.244.157; | 14.AP.244.158; | 14.AP.244.196; | 14.AP.244.223; |
14.AP.244.240; | 14.AP.244.244; | 14.AP.244.243; | 14.AP.244.247; |
14.AP.247.157; | 14.AP.247.158; | 14.AP.247.196; | 14.AP.247.223; |
14.AP.247.240; | 14.AP.247.244; | 14.AP.247.243; | 14.AP.247.247; |
14.AZ的前体药物
14.AZ.4.157; | 14.AZ.4.158; | 14.AZ.4.196; | 14.AZ.4.223; |
14.AZ.4.240; | 14.AZ.4.244; | 14.AZ.4.243; | 14.AZ.4.247; |
14.AZ.5.157; | 14.AZ.5.158; | 14.AZ.5.196; | 14.AZ.5.223; |
14.AZ.5.240; | 14.AZ.5.244; | 14.AZ.5.243; | 14.AZ.5.247; |
14.AZ.7.157; | 14.AZ.7.158; | 14.AZ.7.196; | 14.AZ.7.223; |
14.AZ.7.240; | 14.AZ.7.244; | 14.AZ.7.243; | 14.AZ.7.247; |
14.AZ.15.157; | 14.AZ.15.158; | 14.AZ.15.196; | 14.AZ.15.223; |
14.AZ.15.240; | 14.AZ.15.244; | 14.AZ.15.243; | 14.AZ.15.247; |
14.AZ.16.157; | 14.AZ.16.158; | 14.AZ.16.196; | 14.AZ.16.223; |
14.AZ.16.240; | 14.AZ.16.244; | 14.AZ.16.243; | 14.AZ.16.247; |
14.AZ.18.157; | 14.AZ.18.158; | 14.AZ.18.196; | 14.AZ.18.223; |
14.AZ.18.240; | 14.AZ.18.244; | 14.AZ.18.243; | 14.AZ.18.247; |
14.AZ.26.157; | 14.AZ.26.158; | 14.AZ.26.196; | 14.AZ.26.223; |
14.AZ.26.240; | 14.AZ.26.244; | 14.AZ.26.243; | 14.AZ.26.247; |
14.AZ.27.157; | 14.AZ.27.158; | 14.AZ.27.196; | 14.AZ.27.223; |
14.AZ.27.240; | 14.AZ.27.244; | 14.AZ.27.243; | 14.AZ.27.247; |
14.AZ.29.157; | 14.AZ.29.158; | 14.AZ.29.196; | 14.AZ.29.223; |
14.AZ.29.240; | 14.AZ.29.244; | 14.AZ.29.243; | 14.AZ.29.247; |
14.AZ.54.157; | 14.AZ.54.158; | 14.AZ.54.196; | 14.AZ.54.223; |
14.AZ.54.240; | 14.AZ.54.244; | 14.AZ.54.243; | 14.AZ.54.247; |
14.AZ.55.157; | 14.AZ.55.158; | 14.AZ.55.196; | 14.AZ.55.223; |
14.AZ.55.240; | 14.AZ.55.244; | 14.AZ.55.243; | 14.AZ.55.247; |
14.AZ.56.157; | 14.AZ.56.158; | 14.AZ.56.196; | 14.AZ.56.223; |
14.AZ.56.240; | 14.AZ.56.244; | 14.AZ.56.243; | 14.AZ.56.247; |
14.AZ.157.157; | 14.AZ.157.158; | 14.AZ.157.196; | 14.AZ.157.223; |
14.AZ.157.240; | 14.AZ.157.244; | 14.AZ.157.243; | 14.AZ.157.247; |
14.AZ.196.157; | 14.AZ.196.158; | 14.AZ.196.196; | 14.AZ.196.223; |
14.AZ.196.240; | 14.AZ.196.244; | 14.AZ.196.243; | 14.AZ.196.247; |
14.AZ.223.157; | 14.AZ.223.158; | 14.AZ.223.196; | 14.AZ.223.223; |
14.AZ.223.240; | 14.AZ.223.244; | 14.AZ.223.243; | 14.AZ.223.247; |
14.AZ.240.157; | 14.AZ.240.158; | 14.AZ.240.196; | 14.AZ.240.223; |
14.AZ.240.240; | 14.AZ.240.244; | 14.AZ.240.243; | 14.AZ.240.247; |
14.AZ.244.157; | 14.AZ.244.158; | 14.AZ.244.196; | 14.AZ.244.223; |
14.AZ.244.240; | 14.AZ.244.244; | 14.AZ.244.243; | 14.AZ.244.247; |
14.AZ.247.157; | 14.AZ.247.158; | 14.AZ.247.196; | 14.AZ.247.223; |
14.AZ.247.240; | 14.AZ.247.244; | 14.AZ.247.243; | 14.AZ.247.247; |
14.BF的前体药物
14.BF.4.157; | 14.BF.4.158; | 14.BF.4.196; | 14.BF.4.223; |
14.BF.4.240; | 14.BF.4.244; | 14.BF.4.243; | 14.BF.4.247; |
14.BF.5.157; | 14.BF.5.158; | 14.BF.5.196; | 14.BF.5.223; |
14.BF.5.240; | 14.BF.5.244; | 14.BF.5.243; | 14.BF.5.247; |
14.BF.7.157; | 14.BF.7.158; | 14.BF.7.196; | 14.BF.7.223; |
14.BF.7.240; | 14.BF.7.244; | 14.BF.7.243; | 14.BF.7.247; |
14.BF.15.157; | 14.BF.15.158; | 14.BF.15.196; | 14.BF.15.223; |
14.BF.15.240; | 14.BF.15.244; | 14.BF.15.243; | 14.BF.15.247; |
14.BF.16.157; | 14.BF.16.158; | 14.BF.16.196; | 14.BF.16.223; |
14.BF.16.240; | 14.BF.16.244; | 14.BF.16.243; | 14.BF.16.247; |
14.BF.18.157; | 14.BF.18.158; | 14.BF.18.196; | 14.BF.18.223; |
14.BF.18.240; | 14.BF.18.244; | 14.BF.18.243; | 14.BF.18.247; |
14.BF.26.157; | 14.BF.26.158; | 14.BF.26.196; | 14.BF.26.223; |
14.BF.26.240; | 14.BF.26.244; | 14.BF.26.243; | 14.BF.26.247; |
14.BF.27.157; | 14.BF.27.158; | 14.BF.27.196; | 14.BF.27.223; |
14.BF.27.240; | 14.BF.27.244; | 14.BF.27.243; | 14.BF.27.247; |
14.BF.29.157; | 14.BF.29.158; | 14.BF.29.196; | 14.BF.29.223; |
14.BF.29.240; | 14.BF.29.244; | 14.BF.29.243; | 14.BF.29.247; |
14.BF.54.157; | 14.BF.54.158; | 14.BF.54.196; | 14.BF.54.223; |
14.BF.54.240; | 14.BF.54.244; | 14.BF.54.243; | 14.BF.54.247; |
14.BF.55.157; | 14.BF.55.158; | 14.BF.55.196; | 14.BF.55.223; |
14.BF.55.240; | 14.BF.55.244; | 14.BF.55.243; | 14.BF.55.247; |
14.BF.56.157; | 14.BF.56.158; | 14.BF.56.196; | 14.BF.56.223; |
14.BF.56.240; | 14.BF.56.244; | 14.BF.56.243; | 14.BF.56.247; |
14.BF.157.157; | 14.BF.157.158; | 14.BF.157.196; | 14.BF.157.223; |
14.BF.157.240; | 14.BF.157.244; | 14.BF.157.243; | 14.BF.157.247; |
14.BF.196.157; | 14.BF.196.158; | 14.BF.196.196; | 14.BF.196.223; |
14.BF.196.240; | 14.BF.196.244; | 14.BF.196.243; | 14.BF.196.247; |
14.BF.223.157; | 14.BF.223.158; | 14.BF.223.196; | 14.BF.223.223; |
14.BF.223.240; | 14.BF.223.244; | 14.BF.223.243; | 14.BF.223.247; |
14.BF.240.157; | 14.BF.240.158; | 14.BF.240.196; | 14.BF.240.223; |
14.BF.240.240; | 14.BF.240.244; | 14.BF.240.243; | 14.BF.240.247; |
14.BF.244.157; | 14.BF.244.158; | 14.BF.244.196; | 14.BF.244.223; |
14.BF.244.240; | 14.BF.244.244; | 14.BF.244.243; | 14.BF.244.247; |
14.BF.247.157; | 14.BF.247.158; | 14.BF.247.196; | 14.BF.247.223; |
14.BF.247.240; | 14.BF.247.244; | 14.BF.247.243; | 14.BF.247.247; |
14.CI的前体药物
14.CI.4.157; | 14.CI.4.158; | 14.CI.4.196; | 14.CI.4.223; |
14.CI.4.240; | 14.CI.4.244; | 14.CI.4.243; | 14.CI.4.247; |
14.CI.5.157; | 14.CI.5.158; | 14.CI.5.196; | 14.CI.5.223; |
14.CI.5.240; | 14.CI.5.244; | 14.CI.5.243; | 14.CI.5.247; |
14.CI.7.157; | 14.CI.7.158; | 14.CI.7.196; | 14.CI.7.223; |
14.CI.7.240; | 14.CI.7.244; | 14.CI.7.243; | 14.CI.7.247; |
14.CI.15.157; | 14.CI.15.158; | 14.CI.15.196; | 14.CI.15.223; |
14.CI.15.240; | 14.CI.15.244; | 14.CI.15.243; | 14.CI.15.247; |
14.CI.16.157; | 14.CI.16.158; | 14.CI.16.196; | 14.CI.16.223; |
14.CI.16.240; | 14.CI.16.244; | 14.CI.16.243; | 14.CI.16.247; |
14.CI.18.157; | 14.CI.18.158; | 14.CI.18.196; | 14.CI.18.223; |
14.CI.18.240; | 14.CI.18.244; | 14.CI.18.243; | 14.CI.18.247; |
14.CI.26.157; | 14.CI.26.158; | 14.CI.26.196; | 14.CI.26.223; |
14.CI.26.240; | 14.CI.26.244; | 14.CI.26.243; | 14.CI.26.247; |
14.CI.27.157; | 14.CI.27.158; | 14.CI.27.196; | 14.CI.27.223; |
14.CI.27.240; | 14.CI.27.244; | 14.CI.27.243; | 14.CI.27.247; |
14.CI.29.157; | 14.CI.29.158; | 14.CI.29.196; | 14.CI.29.223; |
14.CI.29.240; | 14.CI.29.244; | 14.CI.29.243; | 14.CI.29.247; |
14.CI.54.157; | 14.CI.54.158; | 14.CI.54.196; | 14.CI.54.223; |
14.CI.54.240; | 14.CI.54.244; | 14.CI.54.243; | 14.CI.54.247; |
14.CI.55.157; | 14.CI.55.158; | 14.CI.55.196; | 14.CI.55.223; |
14.CI.55.240; | 14.CI.55.244; | 14.CI.55.243; | 14.CI.55.247; |
14.CI.56.157; | 14.CI.56.158; | 14.CI.56.196; | 14.CI.56.223; |
14.CI.56.240; | 14.CI.56.244; | 14.CI.56.243; | 14.CI.56.247; |
14.CI.157.157; | 14.CI.157.158; | 14.CI.157.196; | 14.CI.157.223; |
14.CI.157.240; | 14.CI.157.244; | 14.CI.157.243; | 14.CI.157.247; |
14.CI.196.157; | 14.CI.196.158; | 14.CI.196.196; | 14.CI.196.223; |
14.CI.196.240; | 14.CI.196.244; | 14.CI.196.243; | 14.CI.196.247; |
14.CI.223.157; | 14.CI.223.158; | 14.CI.223.196; | 14.CI.223.223; |
14.CI.223.240; | 14.CI.223.244; | 14.CI.223.243; | 14.CI.223.247; |
14.CI.240.157; | 14.CI.240.158; | 14.CI.240.196; | 14.CI.240.223; |
14.CI.240.240; | 14.CI.240.244; | 14.CI.240.243; | 14.CI.240.247; |
14.CI.244.157; | 14.CI.244.158; | 14.CI.244.196; | 14.CI.244.223; |
14.CI.244.240; | 14.CI.244.244; | 14.CI.244.243; | 14.CI.244.247; |
14.CI.247.157; | 14.CI.247.158; | 14.CI.247.196; | 14.CI.247.223; |
14.CI.247.240; | 14.CI.247.244; | 14.CI.247.243; | 14.CI.247.247; |
14.CO的前体药物
14.CO.4.157; | 14.CO.4.158; | 14.CO.4.196; | 14.CO.4.223; |
14.CO.4.240; | 14.CO.4.244; | 14.CO.4.243; | 14.CO.4.247; |
14.CO.5.157; | 14.CO.5.158; | 14.CO.5.196; | 14.CO.5.223; |
14.CO.5.240; | 14.CO.5.244; | 14.CO.5.243; | 14.CO.5.247; |
14.CO.7.157; | 14.CO.7.158; | 14.CO.7.196; | 14.CO.7.223; |
14.CO.7.240; | 14.CO.7.244; | 14.CO.7.243; | 14.CO.7.247; |
14.CO.15.157; | 14.CO.15.158; | 14.CO.15.196; | 14.CO.15.223; |
14.CO.15.240; | 14.CO.15.244; | 14.CO.15.243; | 14.CO.15.247; |
14.CO.16.157; | 14.CO.16.158; | 14.CO.16.196; | 14.CO.16.223; |
14.CO.16.240; | 14.CO.16.244; | 14.CO.16.243; | 14.CO.16.247; |
14.CO.18.157; | 14.CO.18.158; | 14.CO.18.196; | 14.CO.18.223; |
14.CO.18.240; | 14.CO.18.244; | 14.CO.18.243; | 14.CO.18.247; |
14.CO.26.157; | 14.CO.26.158; | 14.CO.26.196; | 14.CO.26.223; |
14.CO.26.240; | 14.CO.26.244; | 14.CO.26.243; | 14.CO.26.247; |
14.CO.27.157; | 14.CO.27.158; | 14.CO.27.196; | 14.CO.27.223; |
14.CO.27.240; | 14.CO.27.244; | 14.CO.27.243; | 14.CO.27.247; |
14.CO.29.157; | 14.CO.29.158; | 14.CO.29.196; | 14.CO.29.223; |
14.CO.29.240; | 14.CO.29.244; | 14.CO.29.243; | 14.CO.29.247; |
14.CO.54.157; | 14.CO.54.158; | 14.CO.54.196; | 14.CO.54.223; |
14.CO.54.240; | 14.CO.54.244; | 14.CO.54.243; | 14.CO.54.247; |
14.CO.55.157; | 14.CO.55.158; | 14.CO.55.196; | 14.CO.55.223; |
14.CO.55.240; | 14.CO.55.244; | 14.CO.55.243; | 14.CO.55.247; |
14.CO.56.157; | 14.CO.56.158; | 14.CO.56.196; | 14.CO.56.223; |
14.CO.56.240; | 14.CO.56.244; | 14.CO.56.243; | 14.CO.56.247; |
14.CO.157.157; | 14.CO.157.158; | 14.CO.157.196; | 14.CO.157.223; |
14.CO.157.240; | 14.CO.157.244; | 14.CO.157.243; | 14.CO.157.247; |
14.CO.196.157; | 14.CO.196.158; | 14.CO.196.196; | 14.CO.196.223; |
14.CO.196.240; | 14.CO.196.244; | 14.CO.196.243; | 14.CO.196.247; |
14.CO.223.157; | 14.CO.223.158; | 14.CO.223.196; | 14.CO.223.223; |
14.CO.223.240; | 14.CO.223.244; | 14.CO.223.243; | 14.CO.223.247; |
14.CO.240.157; | 14.CO.240.158; | 14.CO.240.196; | 14.CO.240.223; |
14.CO.240.240; | 14.CO.240.244; | 14.CO.240.243; | 14.CO.240.247; |
14.CO.244.157; | 14.CO.244.158; | 14.CO.244.196; | 14.CO.244.223; |
14.CO.244.240; | 14.CO.244.244; | 14.CO.244.243; | 14.CO.244.247; |
14.CO.4.157; | 14.CO.4.158; | 14.CO.4.196; | 14.CO.4.223; |
14.CO.4.240; | 14.CO.4.244; | 14.CO.4.243; | 14.CO.4.247; |
以上的全部文献和专利引证在它们的引用位置被特意地引入作为参考。具体地说,以上列举的著作的所列举节段或页码被特意引入作参考。本发明已经进行了详细描述,足以让所属技术领域中的技术人员得到和使用所附权利要求的主题。很明显,对所附权利要求的方
法和组成的某些改进能够在本发明的范围和精神内进行。
在所附的权利要求中,不同变量的下角标与上角标是不同的。例如R1与R1不同。
Claims (118)
1.包含连接到一个或多个膦酸酯基团上的免疫调节化合物的共轭物;或它的药物学上可接受的盐或溶剂化物。
2.权利要求1的共轭物,或它的药物学上可接受的盐或溶剂化物,它是通式500-547中任何一个的化合物,被一个或多个基团A0取代,
其中:
A0是A1,A2或W3,条件是所述共轭物包括至少一个A1;
A1是:
A2是:
A3是:
Y1独立地是
,
,
,
,
,
,或
;
Y2独立地是键,
,
,
,
,
,
,
,或
;和当Y2联接两个亚磷原子时,Y2也可以是
;
Rx独立地是
,R1,R2,W3,保护基,或以下通式:
其中:
Ry独立地是
,W3,R2或保护基;
R1独立地是
或1到18个碳原子的烷基;
R2独立地是
,R1,R3或R4,其中各R4独立地被0到3个R3基团取代或一起连在碳原子上,两个R2基团形成3到8个碳的环和该环可以被0到3个R3基团取代;
R3是R3a,R3b,R3c或R3d,条件是当R3结合到杂原子上时,则R3是R3c或R3d;
R3a是
,
,
,
,
,
或
;
R3b是Y1;
R3c是
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,或
;
R3d是
,
或
;
R4是1到18个碳原子的烷基,2到18个碳原子的链烯基,或2到18个碳原子的炔基;
R5是R4,其中各R4被0到3个R3基团取代;
W3是W4或W5;
W4是R5,
,
,
,或
;
W5是碳环或杂环,其中W5独立地被0到3个R2基团取代;
W6是独立地被1、2或3个A3基团取代的W3;
M2是0,1或2;
M12a是1,2,3,4,5,6,7,8,9,10,11或12;
M12b是0,1,2,3,4,5,6,7,8,9,10,11或12;
M1a,M1c和M1d独立地是0或1;和
M12c是0,1,2,3,4,5,6,7,8,9,10,11或12。
3.权利要求2的共轭物,或它的药物学上可接受的盐或溶剂化物,它具有通式:
[DRUG]-(A0)nn
其中:
DRUG是通式500-547中任何一个的化合物;和
nn是1,2,或3。
4.权利要求2的共轭物,它具有通式1-151中的任何一个,其中:
一个A0是A1;各X50独立地是氢,
,
,
,
,甲基,或叔丁基;
X51是氢,卤素,三氟甲基,(C1-C3)烷基,氰基,或(C1-C3)烷氧基;
X52是氢,氟,氯,溴,甲基或三氟甲基;
X53是
,或
;
X54和X55独立地选自氢或C1-C18酰基;
X56是氢,C1-C18酰基,或
或X54是氢以及X55和X56一起是
X57是
,氨基,羟基,或选自
和
的卤素;
X58是氢,
,
,
,氰基,甲基或叔丁基;
X59是氢,
;
X60是
;
X62是甲基,氯,或三氟甲基;
X63是
,甲基,乙基,环丙基,乙烯基,或三氟甲基;
X64是
,甲基,乙基,环丙基,氯,乙烯基,烯丙基,3-甲基-1-丁烯-1-基;
X65是氢或
;和
Ar是芳基或杂芳基。
7.权利要求2-4中任何一项的共轭物,其中各A1具有以下通式:
9.权利要求2-4中任何一项的共轭物,其中各A1具有以下通式:
其中:W5a是碳环或杂环,其中W5a独立地被0或1个R2基团取代。
10.权利要求2-4中任何一项的共轭物,其中M12a是1。
11.权利要求2-4中任何一项的共轭物,其中各A1具有以下通式:
14.权利要求2-4中任何一项的共轭物,其中各A1具有以下通式:
其中:
Y2b是
或
;和
M12d是1,2,3,4,5,6,7或8。
16.权利要求2-4中任何一项的共轭物,其中各A1具有以下通式:
其中:W5a是碳环或杂环,其中W5a独立地被0或1个R2基团取代。
20.权利要求2-17中任何一项的共轭物,其中各M12b是1。
21.权利要求20的共轭物,其中M12b是0,Y2是键和W5是碳环或杂环,其中W5任选地和独立地被1,2,或3个R2基团取代。
23.权利要求22的共轭物,其中M12a是1。
24.权利要求2-17中任何一项的共轭物,其中各A2选自苯基,取代的苯基,苄基,取代的苄基,吡啶基和取代的吡啶基。
26.权利要求2-17中任何一项的共轭物,其中各A2具有以下通式:
27.权利要求26的共轭物,其中M12b是1。
30.权利要求2-27中任何一项的共轭物,其中各A3具有以下通式:
其中:
Y1a是
或
;和
Y2a是
,
或
。
31.权利要求2-27中任何一项的共轭物,其中各A3具有以下通式:
其中Y2b是
或
。
34.权利要求33的共轭物,其中M12d是1。
37.权利要求36的共轭物,其中W5是碳环。
39.权利要求38的共轭物,其中W5是苯基。
40.权利要求39的共轭物,其中M12b是1。
41.权利要求2-27中任何一项的共轭物,其中各A3具有以下通式:
其中:
Y1a是
或
;和
Y2a是
,
或
。
42.权利要求2-27中任何一项的共轭物,其中各A3具有以下通式:
其中Y2b是
或
。
43.权利要求2-27中任何一项的共轭物,其中各A3具有以下通式:
其中:
Y2b是
或
;和
M12d是1,2,3,4,5,6,7或8。
44.权利要求43的共轭物,其中R1是
。
45.权利要求44的共轭物,其中M12d是1。
47.权利要求2-27中任何一项的共轭物,其中各A3具有以下通式:
其中所述苯基碳环被0,1,2,或3个R2基团取代。
51.权利要求2-27中任何一项的共轭物,其中各A3具有以下通式:
其中:
Y1a是
或
;和
Y2a是
,
或
。
54.权利要求2-27中任何一项的共轭物,其中各A3具有以下通式:
其中:
Y2b是
或
;和
M12d是1,2,3,4,5,6,7或8。
61.权利要求2-27中任何一项的共轭物,其中各A3具有以下通式:
其中:
Y2b是
或
;和
M12d是1,2,3,4,5,6,7或8。
63.权利要求3的共轭物,其中A0具有以下通式:
其中各R独立地是烷基。
64.权利要求1,2,3或4的共轭物,它具有以下通式:
或它的药物学上可接受的盐或溶剂化物,
其中:
DRUG是免疫调节化合物;
Y1独立地是
,
,
,
,
,
,或
;
Y2独立地是键,
,
,
,
,
,
,
,或
;
Rx独立地是
,R2,W3,保护基,或以下通式:
Ry独立地是
,W3,R2或保护基;
R2独立地是
,R3或R4,其中各R4独立地被0到3个R3基团取代;
R3是R3a,R3b,R3c或R3d,条件是当R3结合到杂原子上时,则R3是R3c或R3d;
R3a是
,
,
,
,
,
或
;
R3b是Y1;
R3c是
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,或
;
R3d是
,
或
;
R4是1到18个碳原子的烷基,2到18个碳原子的链烯基,或2到18个碳原子的炔基;
R5是R4,其中各R4被0到3个R3基团取代;
W3是W4或W5;
W4是R5,
,
,
,或
;
W5是碳环或杂环,其中W5独立地被0到3个R2基团取代;
M2是1,2,或3;
M1a,M1c和M1d独立地是0或1;
M12c是0,1,2,3,4,5,6,7,8,9,10,11或12;
nn是1,2,或3;和
L是直接的键或连接基团。
68.权利要求65-67中任何一项的共轭物,其中各Ry独立地是
或1到10个碳的烷基。
72.权利要求64的共轭物,其中各Y1是
或
。
73.权利要求64的共轭物,其中各Y2是
,
或
。
74.权利要求64-73中任何一项的共轭物,其中nn是1。
75.权利要求64-73中任何一项的共轭物,其中nn是2。
76.权利要求64-73中任何一项的共轭物,其中nn是3。
77.权利要求64的共轭物,其中激酶抑制化合物是通式500-547中任何一个的化合物。
78.权利要求77的共轭物,其中各L具有约20道尔顿到约400道尔顿的分子量。
79.权利要求77的共轭物,其中各L具有约5埃到约300埃的长度。
80.权利要求77的共轭物,其中各L以约5埃到约200埃,包括该范围端值,的距离分开通式500-547之中任何一个的化合物与膦酸酯基团的亚磷原子。
81.权利要求77的共轭物,其中各L是二价的,支化或未支化的,饱和或不饱和的烃链,具有2到25个碳原子,其中所述碳原子中的一个或多个任选地被(
)替代,和其中所述链任选在碳上被一个或多个取代基取代,该取代基选自(C1-C6)烷氧基,(C3-C6)环烷基,(C1-C6)烷酰基,(C1-C6)烷酰基氧基,(C1-C6)烷氧基羰基,(C1-C6)烷硫基,叠氮基,氰基,硝基,卤素,羟基,氧代(
),羧基,芳基,芳氧基,杂芳基,和杂芳氧基。
82.权利要求77的共轭物,其中各L具有通式W-A,其中A是(C1-C24)亚烷基,(C2-C24)亚链烯基,(C2-C24)亚炔基,(C3-C8)亚环烷基,(C6-C10)芳基或它们的组合,其中各W是
,
,
,
,
,
,
,
,
,
,
,
,
,
,或直接的键;其中各R独立地是
或1到10个碳的烷基。
83.权利要求82的共轭物,其中各A是1到10碳的亚烷基。
84.权利要求77的共轭物,其中各L是从肽形成的二价基团。
85.权利要求77的共轭物,其中各L是从氨基酸形成的二价基团。
86.权利要求77的共轭物,其中各L是从聚-L-谷氨酸,聚-L-天冬氨酸,聚-L-组氨酸,聚-L-鸟氨酸,聚-L-丝氨酸,聚-L-苏氨酸,聚-L-酪氨酸,聚-L-亮氨酸,聚-L-赖氨酸-L-苯基丙氨酸,聚-L-赖氨酸或聚-L-赖氨酸-L-酪氨酸形成的二价基团。
87.权利要求77的共轭物,其中各L具有通式
,其中,n在约1和约10之间;和W是
,
,
,
,
,
,
,
,
,
,
,
,
,
,或直接的键;其中各R独立地是
或(C1-C6)烷基。
88.权利要求77的共轭物,其中各L是亚甲基,亚乙基,或亚丙基。
89.权利要求77的共轭物,其中各L在L的碳原子上连接于P。
90.如权利要求1-89中任何一项中描述的共轭物,它是分离和提纯的。
91.权利要求1-90中任何一项的共轭物,它不是抗炎化合物。
92.权利要求1-91中任何一项的共轭物,它不是抗感染剂。
93.权利要求1-92中任何一项的共轭物,它不是一种不是激酶抑制剂的化合物。
94.权利要求1-93中任何一项的共轭物,它不是有抗新陈代谢病活性的化合物。
95.权利要求1-94中任何一项的共轭物,它不是抗病毒剂。
96.权利要求1-95中任何一项的共轭物,它不是核苷。
97.权利要求1-96中任何一项的共轭物,它不是IMPDH抑制剂。
98.权利要求1-97中任何一项的共轭物,它不是抗代谢物。
99.权利要求1-98中任何一项的共轭物,它不是PNP抑制剂。
100.权利要求2-99中任何一项的共轭物,它不是通式500-533,535-541,或543-547中任何一个的取代的化合物。
101.权利要求2-100中任何一项的共轭物,它不是通式534或542的取代化合物。
102.权利要求4-101中任何一项的共轭物,它不是通式1-104,107-124,或128-151中任何一个的化合物。
103.权利要求4-102中任何一项的共轭物,它不是通式105-106,或125-127的化合物。
104.本申请描述的激酶抑制剂共轭物。
105.通式MBF的化合物。
106.权利要求105的化合物,它选自表100。
107.药物组合物,它包含药物学上可接受的赋形剂和权利要求1-89和91-104中任何一项中所述的共轭物或权利要求105或106中描述的化合物。
108.单位剂量形式,它包含权利要求1-89和91-104中任何一项中所述的共轭物或权利要求105或106中描述的化合物以及药物学上可接受的赋形剂。
109.体外或体内抑制免疫应答的方法,它包括将需要这样处理的样品与权利要求1-89和91-104中任何一项中所述的共轭物或权利要求105或106中描述的化合物接触。
110.权利要求109的方法,其中所述接触是在体内。
111.本发明还提供了调节哺乳动物中免疫应答的方法,该方法包括对所述哺乳动物施用权利要求1-89和91-104中任何一项中所述的化合物或权利要求105或106中描述的化合物。
112.权利要求111的方法,其中所述化合物用药物学上可接受的载体来配制。
113.权利要求112的方法,其中所得制剂进一步包括第二活性成分。
114.权利要求111或112的方法,其中免疫应答被抑制。
115.用于医学治疗的权利要求1-89和91-104中任何一项中所述的共轭物或权利要求105或106中描述的化合物。
116.权利要求1-89和91-104中任何一项中所述的共轭物或权利要求105或106中描述的化合物用于制备在动物体内调节免疫应答的药物的用途。
117.本申请描述的膦酸酯取代的免疫调节共轭物。
118.制备本申请中的方案和实施例中所述的共轭物的方法。
Applications Claiming Priority (70)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US46553203P | 2003-04-25 | 2003-04-25 | |
US60/465,377 | 2003-04-25 | ||
US60/465,424 | 2003-04-25 | ||
US60/465,531 | 2003-04-25 | ||
US60/465,581 | 2003-04-25 | ||
US60/465,481 | 2003-04-25 | ||
US60/465,420 | 2003-04-25 | ||
US60/465,373 | 2003-04-25 | ||
US60/465,844 | 2003-04-25 | ||
US60/465,574 | 2003-04-25 | ||
US60/465,433 | 2003-04-25 | ||
US60/465,532 | 2003-04-25 | ||
US60/465,380 | 2003-04-25 | ||
US60/493,303 | 2003-08-07 | ||
US60/493,309 | 2003-08-07 | ||
US60/493,302 | 2003-08-07 | ||
US60/493,310 | 2003-08-07 | ||
US60/495,427 | 2003-08-15 | ||
US60/495,614 | 2003-08-15 | ||
US60/495,456 | 2003-08-15 | ||
US60/495,417 | 2003-08-15 | ||
US60/495,425 | 2003-08-15 | ||
US60/495,416 | 2003-08-15 | ||
US60/495,537 | 2003-08-15 | ||
US60/495,661 | 2003-08-15 | ||
US60/495,393 | 2003-08-15 | ||
US60/495,455 | 2003-08-15 | ||
US60/495,533 | 2003-08-15 | ||
US60/495,398 | 2003-08-15 | ||
US60/495,529 | 2003-08-15 | ||
US60/514,144 | 2003-10-24 | ||
US60/514,424 | 2003-10-24 | ||
US60/513,561 | 2003-10-24 | ||
US60/514,140 | 2003-10-24 | ||
US60/514,394 | 2003-10-24 | ||
US60/514,201 | 2003-10-24 | ||
US60/513,971 | 2003-10-24 | ||
US60/514,161 | 2003-10-24 | ||
US60/514,113 | 2003-10-24 | ||
US60/514,202 | 2003-10-24 | ||
US60/514,325 | 2003-10-24 | ||
US60/513,979 | 2003-10-24 | ||
US60/513,946 | 2003-10-24 | ||
US60/513,579 | 2003-10-24 | ||
US60/513,593 | 2003-10-24 | ||
US60/513,592 | 2003-10-24 | ||
US60/513,948 | 2003-10-24 | ||
US60/514,051 | 2003-10-24 | ||
US60/514,280 | 2003-10-24 | ||
US60/514,175 | 2003-10-24 | ||
US60/513,588 | 2003-10-24 | ||
US60/514,298 | 2003-10-24 | ||
US60/514,044 | 2003-10-24 | ||
US60/513,975 | 2003-10-24 | ||
US60/513,563 | 2003-10-24 | ||
US60/514,021 | 2003-10-24 | ||
US60/514,453 | 2003-10-24 | ||
US60/514,054 | 2003-10-24 | ||
US60/513,562 | 2003-10-24 | ||
US60/513,589 | 2003-10-24 | ||
US60/514,258 | 2003-10-24 | ||
US60/514,075 | 2003-10-24 | ||
US60/532,160 | 2003-12-01 | ||
US60/514,522 | 2003-12-22 | ||
US60/531,940 | 2003-12-22 | ||
US60/531,960 | 2003-12-22 | ||
US60/532,230 | 2003-12-22 | ||
US60/531,932 | 2003-12-22 | ||
US60/532,591 | 2003-12-23 | ||
US60/536,005 | 2004-01-12 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA2008101837060A Division CN101591281A (zh) | 2003-04-25 | 2004-04-26 | 具有免疫调节活性的膦酸酯化合物 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1780630A true CN1780630A (zh) | 2006-05-31 |
Family
ID=36770600
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN 200480011231 Pending CN1780630A (zh) | 2003-04-25 | 2004-04-26 | 具有免疫调节活性的膦酸酯化合物 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN1780630A (zh) |
-
2004
- 2004-04-26 CN CN 200480011231 patent/CN1780630A/zh active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1313472C (zh) | Hiv蛋白酶抑制剂化合物的膦酸酯类似物的细胞蓄积及这类化合物 | |
CN101031306A (zh) | 作为抗hiv剂的核苷膦酸酯缀合物 | |
JP6944462B2 (ja) | チエノピリミジンジオンacc阻害剤の固体形態およびその生成のための方法 | |
JP6349360B2 (ja) | Cb2アゴニストとして有用なピリジン−2−アミド | |
TWI389908B (zh) | 抗病毒化合物類 | |
CN1921847B (zh) | 氨基醇化合物 | |
CN101410120A (zh) | 抗炎的膦酸酯化合物 | |
CN101627035A (zh) | 哌啶gpcr激动剂 | |
TW200819460A (en) | Antiviral phosphinate compounds | |
JP6599976B2 (ja) | 置換ジヒドロピリミジノン及び好中球エラスターゼ活性の阻害薬としてのそれらの使用 | |
EP3806958B1 (en) | 6-aminopyridin-3-yl pyrazoles as modulators of roryt | |
KR102420210B1 (ko) | 치환된 바이사이클릭 디하이드로피리미디논 및 호중구 엘라스타제 활성 억제제로서의 이의 용도 | |
JP2022538270A (ja) | 3-(5-メチル-1,3-チアゾール-2-イル)-n-{(1r)-1-[2-(トリフルオロメチル)ピリミジン-5-イル]エチル}ベンズアミドのアナログ | |
EP2300424B1 (fr) | Utilisation de derives d'indole comme activateurs de nurr-1, pour le traitement de la maladie de parkinson | |
TW202115077A (zh) | Malt1抑制劑及其用途 | |
KR20190100944A (ko) | 브라디키닌 b1 수용체의 길항제로서의 카르복실산 방향족 아미드 | |
WO2006090853A1 (ja) | 含窒素複素環化合物およびその医薬用途 | |
CN1906196A (zh) | 具有hiv和hcv抗病毒活性的4'-取代的卡波韦-和阿巴卡韦-衍生物以及相关化合物 | |
KR20060028632A (ko) | 항염증 포스포네이트 화합물 | |
WO2019067396A1 (en) | ZAP-70 KINASE INHIBITOR COMPOSITIONS, METHODS AND USES THEREOF | |
CN1780643A (zh) | 抗病毒的膦酸酯类似物 | |
CN1780630A (zh) | 具有免疫调节活性的膦酸酯化合物 | |
CN1819832A (zh) | 激酶抑制性膦酸酯类似物 | |
WO2013026587A1 (en) | 1,4 disubstituted pyrrolidine - 3 - yl -amine derivatives and their use for the treatment of metabolic disorders | |
CN1780631A (zh) | 抗癌膦酸酯类似物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C12 | Rejection of a patent application after its publication | ||
RJ01 | Rejection of invention patent application after publication |