CN114874131A - Kakeromycin及其衍生物的制造方法 - Google Patents
Kakeromycin及其衍生物的制造方法 Download PDFInfo
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- CN114874131A CN114874131A CN202210533159.4A CN202210533159A CN114874131A CN 114874131 A CN114874131 A CN 114874131A CN 202210533159 A CN202210533159 A CN 202210533159A CN 114874131 A CN114874131 A CN 114874131A
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B33/00—Oxidation in general
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
- C07C225/04—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated
- C07C225/06—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated and acyclic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/18—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by doubly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/74—Oxygen atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明提供通过化学合成而制造显示抗真菌活性及细胞毒性、可期待作为新型的抗真菌剂及抗癌剂的Kakeromycin及其衍生物的方法。本发明涉及的是式(1)所示化合物或其盐的制造方法,其包括:使式(2)所示的化合物或其盐进行氧化反应的工序。
Description
本申请是申请号为201680020805.X的中国专利申请(申请日:2016年2月26日,发明名称:Kakeromycin及其衍生物的制造方法)的分案申请。
技术领域
本发明涉及Kakeromycin及其衍生物的制造方法。
背景技术
近年来,老年人的增加、高度医疗的发展、晚期癌症患者的免疫缺陷等由真菌引起的感染症正不断增加。这些感染症会造成严重结果、甚至常常导致死亡。已有的抗真菌药由于种类缺乏、毒性也较高,因此期待出现与迄今为止的药物不同的新型抗真菌剂的母核。另外,抗真菌药的使用会引起耐性菌的出现增加,因而急需开发出新型的药物。另外,Candin类抗真菌剂的毒性低,但其分子量大、与血清之间的反应性成为问题。唑类抗真菌药因其毒性而存在着难以实现高浓度给药的问题。因此,强烈要求出现一种低分子、且与血清之间的反应性低、毒性低的有效化合物。
以往,从微生物代谢产物中寻求药用种子化合物主要采集的是陆地上的分离源,已被逐渐用于微生物分离。迄今为止所发现的微生物代谢产物中,发现了以青霉素、阿霉素为首的数量众多的抗生物质、抗癌剂,已逐渐被用作感染症、癌症等的治疗药。然而,经过长期持续探索的结果,从陆地区域得到的微生物代谢产物几乎全部为已知化合物,很难获得能够成为新型药物的候选的次级代谢产物。因此,天然药物创制企业的新药开发已迅速萎缩。为了打破这种现状,使用化学库(天然物及合成化合物)的筛选已在全球范围内得以进行。然而,结果却与预想相反,从化学库中并未能得到有前景的新药候选化合物。基于这些情况,获得新型的药物候选化合物已陷入了极度困难的境地。
鉴于对新药候选化合物的探索的上述现状,海洋性微生物资源得到了关注。而海洋性微生物资源迄今为止几乎未被利用,极有可能会发现新型的次级代谢产物。
最近,从采集自鹿儿岛县奄美群岛的加计吕麻岛周边的海底砂的微生物中发现的下式所示的新型化合物被命名为“Kakeromycin”。
[化学式1]
该“Kakeromycin”显示出抗真菌活性,特别是对于念珠菌症的病原体显示出较强的抗菌活性,其很有可能以与现有的抗真菌剂不同的新的作用实现抗菌,可期待在今后的进一步的研究开发。另外,该“Kakeromycin”由于会对HepG2肝脏癌细胞、PANC-1胰腺癌细胞显示细胞毒性,因此可期待作为抗癌剂对其进行开发。
发明内容
发明要解决的问题
本发明的目的在于提供通过化学合成制造Kakeromycin及其衍生物的方法。
解决问题的方法
本发明人等为了解决上述课题而进行了深入研究,结果发现了通过化学合成制造下述式(1)所示的Kakeromycin及其衍生物的方法,进而完成了本发明。
即,本发明如下所述。
[1]式(1)所示的化合物或其盐的制造方法,其包括:使式(2)所示的化合物或其盐进行氧化反应的工序。
[化学式2]
[式中,
R表示任选被取代的烃基或任选被取代的杂环基;
n表示0或1。]
[化学式3]
[式中,R及n与上述同义。]
[2]上述[1]所述的制造方法,其进一步包括:使式(3)所示的化合物或其盐进行分子内脱水缩合反应而制造式(2)所示的化合物或其盐的工序。
[化学式4]
[式中,R及n与[1]中定义相同。]
[3]上述[2]所述的制造方法,其进一步包括:使式(4)所示的化合物或其盐进行分子内加成反应而制造式(3)所示的化合物或其盐的工序。
[化学式5]
[式中,R及n与[1]中定义相同。]
[4]上述[3]所述的制造方法,其进一步包括:使式(5)所示的化合物或其盐的氨基的酰基保护基进行脱保护反应而制造式(4)所示的化合物或其盐的工序。
[化学式6]
[式中,R4表示任选被取代的烃基或任选被取代的烃氧基,R及n与[1]中定义相同。]
[5]上述[4]所述的制造方法,其进一步包括:使式(6)所示的化合物或其盐进行还原反应而制造式(5)所示的化合物或其盐的工序。
[化学式7]
[式中,R及n与[1]中定义相同,R4与[4]中定义相同。]
[6]上述[5]所述的制造方法,其进一步包括:使式(7)所示的化合物或其盐与式(8)所示的化合物或其盐进行环化加成反应而制造式(6)所示的化合物或其盐的工序。
[化学式8]
[式中,n与[1]中定义相同,R4与[4]中定义相同。]:
[化学式9]
[式中,R与[1]中定义相同。]
[7]上述[1]~[6]中任一项所述的制造方法,其进一步包括:使式(1)所示的化合物或其盐的羟基进行保护反应而制造式(1-1)所示的化合物或其盐的工序。
[化学式10]
[式中,R3表示任选被取代的烃基或任选被取代的酰基,R及n与[1]中定义相同。]
[8]上述[1]~[7]中任一项所述的制造方法,其中,R为式(A)所示的基团。
[化学式11]
[式中,R1及R2相同或不同,表示任选被取代的烃基或任选被取代的杂环基。]
[9]上述[1]~[8]中任一项所述的制造方法,其中,n为1;
[10]式(1)所示的化合物或其盐。
[化学式12]
[式中,
R表示任选被取代的烃基或任选被取代的杂环基;
n表示0或1。]
[11]上述[10]所述的化合物或其盐,其中,R为式(A)所示的基团。
[化学式13]
[式中,R1及R2相同或不同,表示任选被取代的烃基或任选被取代的杂环基。]
[12]式(2)所示的化合物或其盐。
[化学式14]
[式中,
R表示任选被取代的烃基或任选被取代的杂环基;
n表示0或1。]
[13]式(3)所示的化合物或其盐。
[化学式15]
[式中,
R表示任选被取代的烃基或任选被取代的杂环基;
n表示0或1。]
[14]式(4)所示的化合物或其盐。
[化学式16]
[式中,
R表示任选被取代的烃基或任选被取代的杂环基;
n表示0或1。]
[15]式(5)所示的化合物或其盐。
[化学式17]
[式中,
R表示任选被取代的烃基或任选被取代的杂环基;
R4表示任选被取代的烃基或任选被取代的烃氧基;
n表示0或1。]
[16]式(6)所示的化合物或其盐。
[化学式18]
[式中,
R表示任选被取代的烃基或任选被取代的杂环基;
R4表示任选被取代的烃基或任选被取代的烃氧基;
n表示0或1。]
发明的效果
根据本发明的制造方法,能够通过化学合成而制造显示抗真菌活性及细胞毒性、可期待作为新型的抗真菌剂及抗癌剂的Kakeromycin及其衍生物。
具体实施方式
以下,针对本说明书中的结构式中采用的各基团的定义进行详细说明。
R、R1及R2分别表示任选被取代的烃基或任选被取代的杂环基。
R3表示任选被取代的烃基或任选被取代的酰基。
R4表示任选被取代的烃基或任选被取代的烃氧基。
作为“任选被取代的烃基”的“烃基”及“任选被取代的烃氧基”的“烃”(烃部分),可列举例如:C1-20烷基、C2-20烯基、C2-20炔基、C3-20环烷基、C3-20环烯基、C6-20芳基、C7-20芳烷基。
作为“C1-20烷基”,可列举例如:甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、1-乙基丙基、己基、异己基、1,1-二甲基丁基、2,2-二甲基丁基、3,3-二甲基丁基、2-乙基丁基。
作为“C2-20烯基”,可列举例如:乙烯基、1-丙烯基、2-丙烯基、2-甲基-1-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、3-甲基-2-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、4-甲基-3-戊烯基、1-己烯基、3-己烯基、5-己烯基。
作为“C2-20炔基”,可列举例如:乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、3-丁炔基、1-戊炔基、2-戊炔基、3-戊炔基、4-戊炔基、1-己炔基、2-己炔基、3-己炔基、4-己炔基、5-己炔基、4-甲基-2-戊炔基。
作为“C3-20环烷基”,可列举例如:环丙基、环丁基、环戊基、环己基、环庚基、环辛基、双环[2.2.1]庚基、双环[2.2.2]辛基、双环[3.2.1]辛基、金刚烷基。
作为“C3-20环烯基”,可列举例如:环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、环辛烯基。
作为“C6-20芳基”,可列举例如:苯基、1-萘基、2-萘基、1-蒽基、2-蒽基、9-蒽基。
作为“C7-20芳烷基”,可列举例如:苄基、苯乙基、萘基甲基、苯基丙基。
作为“任选被取代的杂环基”的“杂环基”,可列举例如:作为环构成原子除了碳原子以外还分别含有选自氮原子、硫原子及氧原子中的1~4个杂原子的(i)芳香族杂环基、(ii)非芳香族杂环基及(iii)7~10元杂桥环基。
作为“芳香族杂环基”,可列举例如:作为环构成原子除了碳原子以外还含有选自氮原子、硫原子及氧原子中的1~4个杂原子的5~14元(优选为5~10元)的芳香族杂环基。
作为该“芳香族杂环基”的优选例,可列举:噻吩基、呋喃基、吡咯基、咪唑基、吡唑基、噻唑基、异噻唑基、唑基、异唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、1,2,4-二唑基、1,3,4-二唑基、1,2,4-噻二唑基、1,3,4-噻二唑基、三唑基、四唑基、三嗪基等5~6元单环式芳香族杂环基;
苯并噻吩基、苯并呋喃基、苯并咪唑基、苯并唑基、苯并异唑基、苯并噻唑基、苯并异噻唑基、苯并三唑基、咪唑并吡啶基、噻吩并吡啶基、呋喃并吡啶基、吡咯并吡啶基、吡唑并吡啶基、唑并吡啶基、噻唑并吡啶基、咪唑并吡嗪基、咪唑并嘧啶基、噻吩并嘧啶基、呋喃并嘧啶基、吡咯并嘧啶基、吡唑并嘧啶基、唑并嘧啶基、噻唑并嘧啶基、吡唑并三嗪基、萘并[2,3-b]噻吩基、吩噻基、吲哚基、异吲哚基、1H-吲唑基、嘌呤基、异喹啉基、喹啉基、酞嗪基、萘啶基、喹喔啉基、喹唑啉基、噌啉基、咔唑基、β-咔啉基、菲啶基、吖啶基、吩嗪基、吩噻嗪基、吩嗪基等8~14元稠合多环式(优选为2或3环式)芳香族杂环基。
作为“非芳香族杂环基”,可列举例如:作为环构成原子除了碳原子以外还含有选自氮原子、硫原子及氧原子中的1~4个杂原子的3~14元(优选为4~10元)非芳香族杂环基。
作为该“非芳香族杂环基”的优选例,可列举:氮杂环丙基、环氧乙烷基、硫杂丙环基、氮杂环丁基、氧杂环丁基、硫杂环丁基、四氢噻吩基、四氢呋喃基、吡咯啉基、吡咯烷基、咪唑啉基、咪唑烷基、唑啉基、唑烷基、吡唑啉基、吡唑烷基、噻唑啉基、噻唑烷基、四氢异噻唑基、四氢唑基、四氢异唑基、哌啶基、哌嗪基、四氢吡啶基、二氢吡啶基、二氢噻喃基、四氢嘧啶基、四氢哒嗪基、二氢吡喃基、四氢吡喃基、四氢噻喃基、吗啉基、硫代吗啉基、氮杂环庚基、二氮杂环庚基、氮杂基、氧杂环庚基、氮杂环辛基、二氮杂环辛基等3~8元单环式非芳香族杂环基;
二氢苯并呋喃基、二氢苯并咪唑基、二氢苯并唑基、二氢苯并噻唑基、二氢苯并异噻唑基、二氢萘并[2,3-b]噻吩基、四氢异喹啉基、四氢喹啉基、4H-喹嗪基、二氢吲哚基、异二氢吲哚基、四氢噻吩并[2,3-c]吡啶基、四氢苯并氮杂基、四氢喹喔啉基、四氢菲啶基、六氢吩噻嗪基、六氢吩嗪基、四氢酞嗪基、四氢萘啶基、四氢喹唑啉基、四氢噌啉基、四氢咔唑基、四氢-β-咔啉基、四氢吖啶基、四氢吩嗪基、四氢噻吨基、八氢异喹啉基等9~14元稠合多环式(优选为2或3环式)非芳香族杂环基。
作为“7~10元杂桥环基”的优选例,可列举:喹咛环基、7-氮杂双环[2.2.1]庚基。
作为“任选被取代的酰基”的“酰基”,可列举例如:甲酰基、羧基、C1-6烷基-羰基、C2-6烯基-羰基、C3-10环烷基-羰基、C3-10环烯基-羰基、C6-14芳基-羰基、C7-16芳烷基-羰基、芳香族杂环-羰基、非芳香族杂环-羰基、C1-6烷氧基-羰基、C6-14芳氧基-羰基、C7-16芳烷氧基-羰基、氨基甲酰基。
作为“C1-6烷基-羰基”,可列举例如:乙酰基、丙酰基、丁酰基、2-甲基丙酰基、戊酰基、3-甲基丁酰基、2-甲基丁酰基、2,2-二甲基丙酰基、己酰基、庚酰基。
作为“C2-6烯基-羰基”,可列举例如:乙烯基羰基、1-丙烯基羰基、2-丙烯基羰基、2-甲基-1-丙烯基羰基、1-丁烯基羰基、2-丁烯基羰基、3-丁烯基羰基、3-甲基-2-丁烯基羰基、1-戊烯基羰基、2-戊烯基羰基、3-戊烯基羰基、4-戊烯基羰基、4-甲基-3-戊烯基羰基、1-己烯基羰基、3-己烯基羰基、5-己烯基羰基。
作为“C3-20环烷基-羰基”,可列举例如:环丙基羰基、环丁基羰基、环戊基羰基、环己基羰基、环庚基羰基、环辛基羰基、双环[2.2.1]庚基羰基、双环[2.2.2]辛基羰基、双环[3.2.1]辛基羰基、金刚烷基羰基。
作为“C3-20环烯基-羰基”,可列举例如:环丙烯基羰基、环丁烯基羰基、环戊烯基羰基、环己烯基羰基、环庚烯基羰基、环辛烯基羰基。
作为“C6-14芳基-羰基”,可列举例如:苯甲酰基、1-萘甲酰基、2-萘甲酰基。
作为“C7-16芳烷基-羰基”,可列举例如:苯基乙酰基、苯基丙酰基。
作为“芳香族杂环-羰基”,可列举例如:烟酰基、异烟酰基、噻吩甲酰基、呋喃甲酰基。
作为“非芳香族杂环-羰基”,可列举例如:吗啉基羰基、哌啶基羰基、吡咯烷基羰基。
作为“C1-6烷氧基-羰基”,可列举例如:甲氧基羰基、乙氧基羰基、丙氧基羰基、异丙氧基羰基、丁氧基羰基、异丁氧基羰基、仲丁氧基羰基、叔丁氧基羰基、戊氧基羰基、己氧基羰基。
作为“C6-14芳氧基-羰基”,可列举例如:苯氧基羰基、1-萘氧基羰基、2-萘氧基羰基。
作为“C7-16芳烷氧基-羰基”,可列举例如:苄氧基羰基、苯乙氧基羰基。
作为“任选被取代的烃基”、“任选被取代的烃氧基”、“任选被取代的杂环基”及“任选被取代的酰基”的“取代基”,可列举如下。
(1)卤原子、
(2)硝基、
(3)氰基、
(4)氧代基、
(5)羟基、
(6)任选被取代的C1-6烷氧基、
(7)任选被取代的C6-14芳氧基、
(8)任选被取代的C7-16芳烷氧基、
(9)任选被取代的芳香族杂环-氧基、
(10)任选被取代的非芳香族杂环-氧基、
(11)任选被取代的C1-6烷基-羰氧基、
(12)任选被取代的C6-14芳基-羰氧基、
(13)任选被取代的C1-6烷氧基-羰氧基、
(14)任选被取代的单-或二-C1-6烷基-氨基甲酰基氧基、
(15)任选被取代的C6-14芳基-氨基甲酰基氧基、
(16)任选被取代的5~14元芳香族杂环-羰氧基、
(17)任选被取代的3~14元非芳香族杂环-羰氧基、
(18)任选被取代的C1-6烷基磺酰氧基、
(19)任选被取代的C6-14芳基磺酰氧基、
(20)任选被取代的C1-6烷硫基、
(21)任选被取代的5~14元芳香族杂环基、
(22)任选被取代的3~14元非芳香族杂环基、
(23)甲酰基、
(24)羧基、
(25)任选被取代的C1-6烷基-羰基、
(26)任选被取代的C6-14芳基-羰基、
(27)任选被取代的5~14元芳香族杂环-羰基、
(28)任选被取代的3~14元非芳香族杂环-羰基、
(29)任选被取代的C1-6烷氧基-羰基、
(30)任选被取代的C6-14芳氧基-羰基、
(31)任选被取代的C7-16芳烷氧基-羰基、
(32)氨基甲酰基、
(33)硫代氨基甲酰基、
(34)任选被取代的单-或二-C1-6烷基-氨基甲酰基、
(35)任选被取代的C6-14芳基-氨基甲酰基、
(36)任选被取代的5~14元芳香族杂环-氨基甲酰基、
(37)任选被取代的3~14元非芳香族杂环-氨基甲酰基、
(38)任选被取代的C1-6烷基磺酰基、
(39)任选被取代的C6-14芳基磺酰基、
(40)任选被取代的5~14元芳香族杂环-磺酰基、
(41)任选被取代的C1-6烷基亚磺酰基、
(42)任选被取代的C6-14芳基亚磺酰基、
(43)任选被取代的5~14元芳香族杂环-亚磺酰基、
(44)氨基、
(45)任选被取代的单-或二-C1-6烷基氨基、
(46)任选被取代的单-或二-C6-14芳基氨基、
(47)任选被取代的5~14元芳香族杂环-氨基、
(48)任选被取代的C7-16芳烷基氨基、
(49)甲酰基氨基、
(50)任选被取代的C1-6烷基-羰基氨基、
(51)任选被取代的(C1-6烷基)(C1-6烷基-羰基)氨基、
(52)任选被取代的C6-14芳基-羰基氨基、
(53)任选被取代的C1-6烷氧基-羰基氨基、
(54)任选被取代的C7-16芳烷氧基-羰基氨基、
(55)任选被取代的C1-6烷基磺酰基氨基、
(56)任选被取代的C6-14芳基磺酰基氨基、
(57)任选被取代的C1-6烷基、
(58)任选被取代的C2-6烯基、
(59)任选被取代的C2-6炔基、
(60)任选被取代的C3-10环烷基、
(61)任选被取代的C3-10环烯基、及
(62)任选被取代的C6-14芳基。
“任选被取代的烃基”、“任选被取代的烃氧基”、“任选被取代的杂环基”及“任选被取代的酰基”中的上述“取代基”的个数例如为1~5个、优选为1~3个。取代基数为2个以上的情况下,各取代基可以相同也可以不同。
R优选为任选被取代的C2-20烯基(例如:乙烯基),更优选为式(A)所示的基团,
[化学式19]
[式中,R1及R2相同或不同,表示任选被取代的烃基或任选被取代的杂环基。]
进一步优选为R1及R2相同或不同地为任选被取代的C1-20烷基(例如:甲基)或任选被取代的C7-20芳烷基(例如:苄基)的式(A)所示的基团,特别优选为R1及R2相同或不同地为C1-20烷基(例如:甲基)或C7-20芳烷基(例如:苄基)的式(A)所示的基团。
在本发明的別的实施方式中,R优选为任选被取代的C2-20烯基(例如:乙烯基)、任选被取代的C1-20烷基(例如:庚基)、任选被取代的C6-20芳基(例如:苯基、萘基)或任选被取代的C7-20芳烷基(例如:苯基乙基),更优选为式(A)所示的基团、任选被取代的C1-20烷基(例如:庚基)、任选被取代的C6-20芳基(例如:苯基、萘基)或任选被取代的C7-20芳烷基(例如:苯基乙基),
[化学式20]
[式中,R1及R2相同或不同,表示任选被取代的烃基或任选被取代的杂环基。]
进一步优选为R1及R2相同或不同地为任选被取代的C1-20烷基(例如:甲基)、任选被取代的C6-20芳基(例如:苯基)或任选被取代的C7-20芳烷基(例如:苄基、苯基乙基)的式(A)所示的基团、任选被取代的C1-20烷基(例如:庚基)、任选被取代的C6-20芳基(例如:苯基、萘基)或任选被取代的C7-20芳烷基(例如:苯基乙基),特别优选为R1及R2相同或不同地为任选被C1-20烷基(例如:甲基)、卤原子(例如:氯原子)取代的C6-20芳基(例如:苯基)或C7-20芳烷基(例如:苄基、苯基乙基)的式(A)所示的基团、C1-20烷基(例如:庚基)、C6-20芳基(例如:苯基、萘基)或C7-20芳烷基(例如:苯基乙基)。
R3优选为任选被取代的C1-20烷基(例如:甲基)或任选被取代的C1-6烷基-羰基(例如:乙酰基),更优选为C1-20烷基(例如:甲基)或C1-6烷基-羰基(例如:乙酰基),进一步优选为甲基或乙酰基。
R4优选为任选被取代的C1-20烷基(例如:甲基)、任选被取代的C6-20芳基(例如:苯基)、任选被取代的C1-20烷基-氧基(例如:叔丁氧基)或任选被取代的C7-20芳烷基-氧基(例如:苄氧基),更优选为C1-20烷基(例如:甲基)、C6-20芳基(例如:苯基)、C1-20烷基-氧基(例如:叔丁氧基)或C7-20芳烷基-氧基(例如:苄氧基),进一步优选为甲基、苯基、叔丁氧基或苄氧基,特别优选为叔丁氧基。
n表示0或1。n优选为1。
以下,针对本发明的制造方法进行说明。
以下,示出了本发明的制造方法的整体流程。
[化学式21]
[式中,各符号与上述同义。]
(工序1:肟8的制造)
肟(8)可通过醛(9)与由盐酸羟胺和碱制备的羟胺的脱水缩合反应而合成。作为碱,可使用相对于盐酸羟胺为通常1~5摩尔当量、优选1~1.5摩尔当量的碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、三乙胺等叔胺等,但特别优选碳酸氢钠。相对于醛(9),可使用通常1~5摩尔当量、优选1~1.5摩尔当量的盐酸羟胺。反应温度通常为0~50℃、优选为20~30℃的范围,反应时间因试剂的种类、反应温度等而异,但通常为1~48小时、优选为2~10小时。作为反应溶剂,可使用THF、水、乙腈、乙酸乙酯、二氯甲烷、或它们的混合溶剂等,但特别优选THF-水的混合溶剂。
需要说明的是,醛(9)可以以市售品获取,另外,也可以按照自身公知的方法或基于这些的方法而制造。
二氢异唑(6A、6B)可通过由肟(8)与次氯酸钠水溶液、或由肟(8)与氯胺-T制备的氧化腈、和N-酰基氨基丁烯(7A)或N-酰基氨基丙烯(7B)的(3+2)环化加成反应而合成。相对于肟8,次氯酸钠水溶液或氯胺-T通常可使用1~5摩尔当量、优选使用1~2摩尔当量。相对于N-酰基氨基丁烯(7A)或N-酰基氨基丙烯(7B),肟(8)通常可使用0.5~3摩尔当量、优选使用0.8~1.2摩尔当量。反应温度通常为0~80℃、优选为20~30℃的范围,反应时间因试剂的种类、反应温度等而异,但通常为1~48小时、优选为2~10小时。作为反应溶剂,可使用:THF、乙酸乙酯、二氯甲烷、乙醇、甲醇、乙腈或它们的混合溶剂等。
需要说明的是,N-酰基氨基丁烯(7A)或N-酰基氨基丙烯(7B)可以以市售品获取,另外,也可以按照自身公知的方法或基于这些的方法而制造。
(工序3:N-酰基氨基羟基酮5A、5B的制造)
N-酰基氨基羟基酮(5A、5B)可通过将二氢异唑(6A、6B)的N-O键还原来合成。作为还原剂,可使用六羰基钼、八羰基钴、铁、锌、镁等,其用量因试剂的种类、反应温度等而异,但相对于二氢异唑(6A、6B)通常为1~5摩尔当量、优选为1~2摩尔当量,但特别优选为六羰基钼。反应温度通常为0~100℃、优选为70~90℃的范围,反应时间因试剂的种类、反应温度等而异,但通常为1~24小时、优选为1~3小时。作为反应溶剂,可使用:乙腈、丙腈、水、THF、乙酸乙酯、二氯甲烷、二氯乙烷、或它们的混合溶剂等,但特别优选为乙腈-水的混合溶剂。
(工序4:氨基羟基酮4A、4B的制造)
氨基羟基酮(4A、4B)可通过将N-酰基氨基羟基酮(5A、5B)的氨基的酰基保护基进行脱保护而合成。作为脱保护剂,可使用相对于N-酰基氨基羟基酮(5A、5B)为通常1~50摩尔当量、优选1~10摩尔当量的三氟乙酸、盐酸、氢氧化钠、氢氧化钾等,但特别优选为三氟乙酸。反应温度通常为0~50℃、优选为20~30℃的范围,反应时间因试剂的种类、反应温度等而异,但通常为1~24小时、优选为1~3小时。作为反应溶剂,可使用:THF、乙酸乙酯、二氯甲烷、二氯乙烷、或它们的混合溶剂等,但特别优选为二氯甲烷、二氯乙烷。
(工序5:环状半胺醛3A、3B的制造)
环状半胺醛(3A、3B)可通过氨基羟基酮(4A、4B)的分子内加成反应来合成。分子内加成反应有时即使不特别使用反应剂也会得以进行,但在酸催化剂为必要的情况下,可使用相对于氨基羟基酮(4A、4B)为通常0.01~5摩尔当量、优选0.01~1摩尔当量的三氟乙酸、乙酸、对甲苯磺酸、甲磺酸等。反应温度通常为0~100℃、优选为30~50℃的范围,反应时间因试剂的种类、反应温度等而异,但通常为1~24小时、优选为1~6小时。作为反应溶剂,可使用:THF、乙酸乙酯、二氯甲烷、二氯乙烷、甲苯、或它们的混合溶剂等,但特别优选为THF、二氯乙烷。
(工序6:环状亚胺2A、2B的制造)
环状亚胺(2A、2B)可通过环状半胺醛(3A、3B)的分子内脱水缩合反应来合成。作为脱水剂,可使用三氟乙酸、乙酸、分子筛、无水硫酸钠等,其用量因试剂的种类、反应温度等而异,但相对于环状半胺醛(3A、3B)通常为0.01~100摩尔当量、优选为0.01~10摩尔当量。反应温度通常为0~100℃、优选为20~60℃的范围,反应时间因试剂的种类、反应温度等而异,但通常为1~24小时、优选为3~12小时。作为反应溶剂,可使用:THF、乙酸乙酯、二氯甲烷、二氯乙烷、甲苯、或它们的混合溶剂等,但特别优选为THF。
(工序7:双环状氧杂氮丙啶1A、1B的制造)
双环状氧杂氮丙啶(1A、1B)可通过环状亚胺(2A、2B)的氧化反应来合成。作为氧化剂,可使用相对于环状亚胺(2A、2B)为通常1~5摩尔当量、优选1~2摩尔当量的间氯过氧苯甲酸、过氧乙酸等,但特别优选为间氯过氧苯甲酸。反应温度通常为0~50℃、优选为10~30℃的范围,反应时间因试剂的种类、反应温度等而异,但通常为0.5~12小时、优选为1~2小时。作为反应溶剂,可使用:THF、乙酸乙酯、二氯甲烷、二氯乙烷、甲苯、乙醇、甲醇、乙腈或它们的混合溶剂等,但特别优选为THF、二氯甲烷。
(工序8:双环状氧杂氮丙啶衍生物1-1A、1-1B的制造)
双环状氧杂氮丙啶衍生物(1-1A、1-1B)可通过对双环状氧杂氮丙啶(1A、1B)的羟基加以保护来合成。
R3为任选被取代的烃基的情况下,对于作为保护剂而对应的卤化物、及碱,可分别使用相对于双环状氧杂氮丙啶衍生物(1-1A、1-1B)为通常1~10摩尔当量、优选1~3摩尔当量来进行保护反应。作为卤化物,特别优选为碘甲烷。作为碱,可使用碳酸钠、碳酸钾、氢化钠、正丁基锂等,但特别优选为氢化钠。反应温度通常为0~50℃、优选为20~30℃的范围,反应时间因试剂的种类、反应温度等而异,但通常为0.5~24小时、优选为1~12小时。作为反应溶剂,可使用:THF、二甲亚砜、二甲基甲酰胺、乙腈、二氯甲烷、二氯乙烷、或它们的混合溶剂等,但特别优选为二甲亚砜、乙腈。
R3为任选被取代的酰基的情况下,对于作为保护剂而对应的酰卤化合物或酸酐,可以在胺碱存在下使用相对于双环状氧杂氮丙啶衍生物(1-1A、1-1B)为通常1~10摩尔当量、优选1~3摩尔当量进行保护反应。作为酰卤化合物或酸酐,特别优选为乙酸酐。作为胺碱,可使用相对于双环状氧杂氮丙啶衍生物(1-1A、1-1B)为通常1~10摩尔当量、优选1~3摩尔当量的三乙胺、二异丙基乙基胺等叔胺、或吡啶、二甲基氨基吡啶等吡啶衍生物,但特别优选为三乙胺、二甲基氨基吡啶。反应温度通常为0~50℃、优选为20~30℃的范围,反应时间因试剂的种类、反应温度等而异,但通常为0.5~24小时、优选为1~12小时。作为反应溶剂,可使用:THF、乙酸乙酯、乙腈、二氯甲烷、二氯乙烷、或它们的混合溶剂等,但特别优选为THF、二氯甲烷。
利用本发明的制造方法得到的式(1)及(1-1)所示的Kakeromycin衍生物(Kakeromycin除外)、以及式(2)、(3)、(4)、(5)及(6)所示的其合成中间体为新型化合物。
利用本发明的制造方法得到的Kakeromycin及其衍生物(双环状氧杂氮丙啶及其衍生物)及其合成中间体也可以是盐。作为这样的盐,可列举例如:与盐酸、氢溴酸、硝酸、硫酸、磷酸等无机酸形成的盐,或与乙酸、邻苯二甲酸、富马酸、草酸、酒石酸、马来酸、柠檬酸、琥珀酸、甲磺酸、对甲苯磺酸等有机酸形成的盐。这些盐中,优选药学上可接受的盐。
利用本发明的制造方法得到的Kakeromycin及其衍生物(双环状氧杂氮丙啶及其衍生物)对广泛的真菌显示出强抗真菌活性,可期待作为新型的抗真菌剂。另外,该Kakeromycin及其衍生物对癌细胞显示出细胞毒性。因此,含有该Kakeromycin及其衍生物作为有效成分的化合物可被用作医药、农药等。
作为抗真菌药的目标真菌,可列举例如:念珠菌属(例如:Candida albicans、Candida parapsilosis、Candida tropicalis、Candida krusei、Candida glabrata、Candida quilliermondii、Candida lusitaniae等)、曲霉属(例如:Aspergillus fumigatus、Aspergillus flavus、Aspergillusniger、Aspergillus terreus等)、毛癣菌属(例如:Trichophyton rubrum、Trichophyton mentagrophytes、Trichophyton tonsurans、Microsporum canis、Microsporum gypseum、Trichophyton verrucosum等)等真菌,但并不限定于这些。另外,作为真菌病,没有特别限定,可列举深层皮肤真菌病、深部真菌病、足菌肿、或真菌血症。
对于使用抗真菌药作为农药的情况下的目标作物,没有特殊限定,可列举例如:谷类(例如,大米、大麦、小麦、黑麦、燕麦、玉米、高粱等)、豆类(大豆、小豆、蚕豆、豌豆、花生等)、果树/果实类(苹果、柑橘类、梨、葡萄、桃、梅、樱桃、核桃、杏仁、香蕉、草莓等)、蔬菜类(卷心菜、番茄、菠菜、西兰花、生菜、洋葱、葱、青椒等)、根菜类(胡萝卜、马铃薯、红薯、萝卜、莲藕、芜菁等)、加工用作物类(棉、麻、构树、黄瑞香、油菜子、糖萝卜、啤酒花、甘蔗、甜菜、橄榄、橡胶、咖啡、烟草、茶等)、瓜类(南瓜、黄瓜、西瓜、蜜瓜等)、牧草类(鸭茅、高粱、梯牧草、三叶草、苜蓿等)、结缕草类(高丽草、本草等)、香料等用作物类(薰衣草、迷迭香、百里香、荷兰芹、胡椒、姜等)、花卉类(菊花、玫瑰、兰花等)等植物。就抗真菌药而言,通过用其有效量对目标作物和/或目标作物的种子进行处理,可以用于防除该作物中与如上所述的真菌相关的病害。
该农药可以以如下所述的形态使用,通常可以和制剂领域中惯用的辅助剂共同使用。利用本发明的制造方法得到的Kakeromycin及其衍生物可利用公知的方法制剂成例如乳剂原液、可喷雾的糊剂、可喷雾或稀释的溶液、稀释乳剂、可湿性粉剂、水溶剂、粉剂、粒剂、悬浮剂、干悬浮剂、熏剂、熏蒸剂、以及基于例如聚合物物质的胶囊剂。
作为添加剂及载体,在以固形制剂为目标的情况下,可使用大豆粉、小麦粉等植物性粉末、硅藻土、磷灰石、石膏、滑石、膨润土、粘土等矿物性微粉、苯甲酸钠、尿素、芒硝等有机及无机化合物。
在以液体剂型为目标的情况下,使用植物油、矿物油、煤油、二甲苯及甲苯这样的芳香族烃、甲酰胺、二甲基甲酰胺这样的酰胺类、二甲亚砜这样的亚砜类、甲基异丁基酮及丙酮这样的酮类、三氯乙烯、水等作为溶剂。这些制剂中,为了取得均一且稳定的形态,也可以根据需要而添加表面活性剂。对于这样得到的可湿性粉剂、乳剂、水溶液、悬浮剂、干悬浮剂,可以利用水稀释至给定浓度而制成悬浮液或乳浊液而使用,对于粉剂、粒剂,可以直接以散布于土壤或植物的方法而使用。
包含利用本发明的制造方法得到的Kakeromycin及其衍生物的农药中的有效成分含量及施用量可根据剂型、作为施用对象的真菌的种类、目标作物等而在宽范围内改变。
另一方面,在使用抗真菌药作为医药的情况下,可以以口服或非口服(例如,静脉注射、肌肉注射、皮下给药、直肠给药、经皮给药)的任意给药途径对治疗对象、例如哺乳动物(例如,人、小鼠、大鼠、仓鼠、兔、猫、狗、牛、绵羊、猴等)进行给药。
将抗真菌药进行经皮给药的情况下,除了上述有效成分以外,还可以根据需要而配合油性基质、乳化剂及乳化稳定剂、溶解助剂、粉末成分、高分子成分、粘结性改良剂、被膜形成剂、pH调节剂、抗氧化剂、防腐剂、保存剂、保型剂、保湿剂、皮肤保护剂、清凉剂、香料、着色剂、螯合剂、润滑剂、血液循环促进剂、收敛剂、组织修复促进剂、止汗剂、植物萃取成分、动物萃取成分、抗炎剂、止痒剂等。这些添加物均可使用通常被用于制剂的那些。
抗真菌药可以将有效成分以外的上述成分等利用在医药制剂领域中惯用的方法制成霜剂、液剂、洗剂、乳剂、酊剂、软膏、水性凝胶剂、油性凝胶剂、喷雾式药剂、粉剂、香波、肥皂、或指甲涂布用指甲油等外用药而进行制剂化后使用。
将抗真菌药进行口服给药的情况下,可制备成胶囊剂、片剂、颗粒剂、散剂、丸剂、细粒剂、锭剂等适于口服给药的剂形。这些制剂可以使用通常被用于口服剂的赋形剂、增量剂、结合剂、湿润剂、崩解剂、表面活性剂、润滑剂、分散剂、缓冲剂、保存剂、溶解助剂、防腐剂、矫味矫臭剂、无痛剂、稳定剂等添加剂,按照常规方法进行制造。
抗癌剂的目标细胞可列举例如HepG2细胞(肝脏癌细胞)、PANC1细胞(胰腺癌细胞)等癌细胞,但并不限定于这些。另外,作为癌,没有特别限定,可列举脑肿瘤、皮肤癌、白血病、食道癌、胃癌、大肠癌、乳腺癌、前列腺癌、直肠癌、骨肉瘤等。
实施例
本发明可进一步结合一下的实施例进行详细说明,但本发明并不限定于这些实施例,另外,可以在不脱离本发明的范围的情况下加以改变。
1H及13C NMR谱利用核磁共振装置(Varian制、400MR及Mercury-300)测定、并将全部δ值以ppm表示。质谱利用HPLC-Chip/QTOF质谱分析系统(Agilent Technologies公司)测定、并显示为m/z值。
实施例1
[化学式22]
(工序1)
将醛9a-01(72mg、0.45mmol)溶解于THF(3mL),并于室温下加入盐酸羟胺(47mg、0.68mmol)、碳酸氢钠(57mg、0.68mmol)及水(2mL),室温下进行了12小时搅拌。加入硫酸钠(5g),除去反应体系内的水,使用棉花进行了过滤。利用旋转蒸发仪对所得滤液进行了浓缩。将所得粗产物利用硅胶柱色谱(溶剂:己烷及乙酸乙酯)进行精制,得到了无色液体形式的肟8a-01(75mg、0.43mmol)(收率95%)。
1H NMR(300MHz,CDCl3):δ1.85(d,3H,J=7.5Hz),3.70(s,2H),6.01(q,1H,J=7.5Hz),7.04-7.32(m,5H),7.75(s,1H)。
(工序2)
将肟8a-01(52mg、0.30mmol)及N-Boc-氨基丁烯7A-01(62mg、0.36mmol)溶解于THF(5mL),于0℃加入次氯酸钠水溶液(5%、2mL),室温下进行了12小时搅拌。加入硫酸钠(5g),除去反应体系内的水,使用棉花进行了过滤。利用旋转蒸发仪对所得滤液进行了浓缩。将所得粗产物利用硅胶柱色谱(溶剂:己烷及乙酸乙酯)进行精制,得到了无色液体形式的二氢异唑6Aa-001(120mg、0.35mmol)(收率86%)。
1H NMR(300MHz,CDCl3):δ1.41(s,9H),1.72-1.86(m,2H),1.87(d,3H,J=7.5Hz),2.75(dd,1H,J=8.1,16.2Hz),3.18(dd,1H,J=10.2,16.2Hz),3.15-3.30(m,2H),3.80(s,2H),4.55-4.68(m,1H),4.68-4.98(br,1H),5.95(q,1H,J=7.5Hz),7.05-7.28(m,5H)。
13C NMR(75MHz,CDCl3):δ14.4,28.3,32.6,35.2,37.6,39.8,79.1,79.6,125.8,128.2,128.4,131.5,131.7,139.6,156.0,158.8。
(工序3)
将二氢异唑6Aa-001(110mg、0.32mmol)及六羰基钼(170mg、0.64mmol)溶解于乙腈(3mL),加入水(0.5mL),于85℃进行了2小时搅拌。加入乙酸乙酯(5mL),于室温下进行了24小时搅拌。将所得混合物使用乙酸乙酯进行硅藻土过滤,将滤液利用旋转蒸发仪进行了浓缩。将所得粗产物利用硅胶柱色谱(溶剂:己烷及乙酸乙酯)进行精制,得到了无色液体形式的N-Boc氨基羟基酮5Aa-001(83mg、0.24mmol)(收率75%)。
1H NMR(300MHz,CDCl3):δ1.20-1.62(m,2H),1.43(s,9H),1.96(d,3H,J=7.5Hz),2.78-2.83(m,2H),3.10-3.41(m,2H),3.68(s,2H),4.16-4.28(m,1H),4.75-5.10(br,1H),6.94(q,1H,J=7.5Hz),7.08-7.24(m,5H)。
(工序4及5)
将N-Boc氨基羟基酮5Aa-001(50mg、0.14mmol)溶解于二氯乙烷(3mL),并加入三氟乙酸(0.5mL),室温下进行了1小时搅拌。将反应液利用旋转蒸发仪进行浓缩,得到了黄色液体形式的氨基羟基酮4Aa-001与环状半胺醛3Aa-001的混合物(31mg、0.13mol)(收率87%)。
1H NMR(300MHz,CDCl3):δ1.20-1.64(m,2H),1.95(d,3H,J=7.5Hz),2.76-2.96(m,4H),3.67(s,2H),4.12-4.28(m,1H),6.92(q,1H,J=7.5Hz),7.08-7.24(m,5H)。
(工序6)
将氨基羟基酮4Aa-001与环状半胺醛3Aa-001的混合物(30mg、0.12mmol)溶解于THF(3mL),加入4A-分子筛(100mg),室温下进行了12小时搅拌。将反应液以乙酸乙酯为溶剂进行硅藻土过滤之后,利用旋转蒸发仪进行浓缩,得到了黄色液体形式的环状亚胺2Aa-001(24mg、0.10mmol)(收率83%)。
(工序7)
将环状亚胺2Aa-001(9mg、0.039mmol)溶解于THF(3mL),加入间氯过氧苯甲酸(11mg),室温下进行了3小时搅拌。将反应液利用旋转蒸发仪进行了浓缩。将所得粗产物利用硅胶柱色谱(溶剂:己烷及乙酸乙酯)进行精制,得到了黄色液体形式的双环状氧杂氮丙啶1Aa-001(3mg、0.012mmol)(收率31%)。
1H NMR(400MHz,CDCl3):δ1.16-1.36(m,1H),1.69(d,3H,J=7.6Hz),1.80-1.98(m,1H),1.99(dd,1H,J=6.9,15.1Hz),2.35(ddd,1H,J=1.3,6.2,15.1Hz),3.15-3.25(m,1H),3.36-3.60(m,3H),3.75-3.84(m,1H),5.91(q,1H,J=6.9Hz),7.05-7.28(m,5H)。
MS:m/z 246([M+1],C15H19NO2)
实施例2
[化学式23]
(工序2)
1H NMR(300MHz,CDCl3):δ0.82(t,3H,J=7.5Hz),1.16-1.80(m,12H),1.39(s,9H),2.20-2.36(m,2H),2.56(dd,1H,J=8.1,16.2Hz),2.98(dd,1H,J=10.2,16.2Hz),3.10-3.24(m,2H),4.48-4.60(m,1H),4.92-5.00(br,1H)。
(工序3)
1H NMR(300MHz,CDCl3):δ0.83(t,3H,J=7.5Hz),1.16-1.76(m,10H),1.40(s,9H),2.32-2.60(m,6H),3.16-3.44(m,2H),4.00-4.26(m,1H),4.96-5.04(br,1H).
(工序4及5)
与实施例1的工序4及5同样地,使用N-Boc氨基羟基酮5A-01作为基质,得到了黄色液体形式的氨基羟基酮4A-01与环状半胺醛3A-01的混合物(收率90%)。
1H NMR(300MHz,CDCl3):δ0.83(t,3H,J=7.5Hz),1.16-1.76(m,10H),2.32-2.60(m,6H),2.64-3.02(m,2H),3.98-4.16(m,1H).
(工序6及7)
与实施例1的工序6同样地,使用氨基羟基酮4A-01与环状半胺醛3A-01的混合物作为基质,得到了环状亚胺2A-01,然后,与实施例1的工序7同样地得到了黄色液体形式的双环状氧杂氮丙啶1A-01(收率23%)。
1H NMR(300MHz,CDCl3):δ0.83(t,3H,J=7.5Hz),1.20-1.74(m,10H),1.92-2.20(m,2H),2.32-2.60(m,4H),3.78-4.12(m,2H),4.12-4.22(m,1H)。
MS:m/z 214([M+1],C12H23NO2)
实施例3
[化学式24]
(工序2)
1H NMR(300MHz,CDCl3):δ1.43(s,9H),1.62-1.80(m,2H),2.40-2.66(m,2H),2.82-3.02(m,4H),3.16-3.24(m,2H),4.50-4.62(m,1H),4.85-4.98(br,1H),7.14-7.48(m,5H)。
(工序3)
1H NMR(300MHz,CDCl3):δ1.41(s,9H),1.60-1.80(m,2H),2.46-2.62(m,2H),2.64-2.94(m,4H),3.04-3.42(m,2H),4.02-4.18(m,1H),4.98-5.04(br,1H),7.14-7.32(m,5H)。
(工序4及5)
与实施例1的工序4及5同样地,使用N-Boc氨基羟基酮5A-02作为基质,得到了黄色液体形式的氨基羟基酮4A-02与环状半胺醛3A-02的混合物(收率92%)。
1H NMR(300MHz,CDCl3):δ1.42(s,9H),1.60-1.80(m,2H),2.46-2.62(m,2H),2.62-3.20(m,6H),4.00-4.18(m,1H),7.12-7.34(m,5H)。
(工序6及7)
与实施例1的工序6同样地,使用氨基羟基酮4A-02与环状半胺醛3A-02的混合物作为基质,得到了环状亚胺2A-02,然后,与实施例1的工序7同样地得到了黄色液体形式的双环状氧杂氮丙啶1A-02(收率23%)。
1H NMR(300MHz,CDCl3):δ1.58-1.98(m,6H),2.46-2.54(m,2H),3.86-4.20(m,2H),4.14-4.24(m,1H),7.22-7.40(m,5H)。
MS:m/z 220([M+1],C13H17NO2)
实施例4
[化学式25]
(工序2)
1H NMR(300MHz,CDCl3):δ1.18-1.64(m,2H),1.43(s,9H),2.78-2.83(m,2H),3.08-3.42(m,2H),4.14-4.28(m,1H),4.75-5.10(br,1H),7.20-7.52(m,5H)。
(工序3)
1H NMR(300MHz,CDCl3):δ1.18-1.64(m,2H),1.44(s,9H),2.76-2.84(m,2H),3.08-3.42(m,2H),4.15-4.29(m,1H),4.72-5.12(br,1H),7.20-7.52(m,5H)。
(工序4及5)
与实施例1的工序4及5同样地,使用N-Boc氨基羟基酮5A-03作为基质,得到了黄色液体形式的氨基羟基酮4A-03与环状半胺醛3A-03的混合物(收率90%)。
1H NMR(300MHz,CDCl3):δ1.16-1.66(m,2H),2.74-2.84(m,2H),2.62-2.98(m,2H),4.14-4.28(m,1H),7.20-7.52(m,5H)。
(工序6及7)
与实施例1的工序6同样地,使用氨基羟基酮4A-03与环状半胺醛3A-03的混合物作为基质,得到了环状亚胺2A-03,然后,与实施例1的工序7同样地得到了黄色液体形式的双环状氧杂氮丙啶1A-03(收率25%)。
1H NMR(300MHz,CDCl3):δ1.40-1.52(m,1H),1.82-1.98(m,1H),2.30-2.48(m,1H),2.78-2.86(m,1H),3.48-3.84(m,2H),4.14-4.22(m,1H),7.25-7.50(m,5H)。
实施例5
[化学式26]
(工序2)
1H NMR(300MHz,CDCl3):δ1.45(s,9H),1.84-2.00(m,2H),3.02-3.20(m,1H),3.28-3.40(m,2H),3.50-3.62(m,1H),4.78-4.88(m,1H),4.90-5.18(br,1H),7.42-8.00(m,7H)。
(工序3)
1H NMR(300MHz,CDCl3):δ1.43(s,9H),1.62-1.84(m,2H),3.18-3.52(m,4H),4.30-4.42(m,1H),5.02-5.18(br,1H),7.42-8.02(m,6H),8.40(s,1H)。
(工序4及5)
与实施例1的工序4及5同样地,使用N-Boc氨基羟基酮5A-04作为基质,得到了黄色液体形式的氨基羟基酮4A-04与环状半胺醛3A-04的混合物(收率91%)。
1H NMR(300MHz,CDCl3):δ1.60-1.86(m,2H),2.76-3.50(m,4H),4.28-4.40(m,1H),7.40-8.02(m,6H),8.42(s,1H).
(工序6及7)
与实施例1的工序6同样地,使用氨基羟基酮4A-04与环状半胺醛3A-04的混合物作为基质,得到了环状亚胺2A-04,然后,与实施例1的工序7同样地得到了黄色液体形式的双环状氧杂氮丙啶1A-04(收率24%)。
1H NMR(300MHz,CDCl3):δ1.42-1.82(m,2H),1.96-2.26(m,2H),3.46-3.86(m,2H),4.13-4.21(m,1H),7.10-8.20(m,7H)。
MS:m/z 242([M+1],C15H15NO2)
实施例6
[化学式27]
(工序1)
与实施例1的工序1同样地,使用醛9a-02和盐酸羟胺作为基质,得到了无色固体形式的肟8a-02(收率90%)。
(工序2)
1H NMR(300MHz,CDCl3):δ1.47(s,9H),2.40-2.84(m,7H),3.12-3.40(m,3H),3.80(s,2H),4.60-4.74(m,1H),4.76-5.00(br,1H),5.92(t,1H,J=6.6Hz),7.16-7.40(m,10H)。
(工序3)
1H NMR(300MHz,CDCl3):δ1.43(s,9H),2.56-2.82(m,7H),3.02-3.44(m,3H),3.82(s,2H),4.02-4.16(m,1H),4.92-5.02(br,1H),6.81(t,1H,J=6.6Hz),7.10-7.38(m,10H).
(工序4及5)
与实施例1的工序4及5同样地,使用N-Boc氨基羟基酮5Aa-002作为基质,得到了黄色液体形式的氨基羟基酮4Aa-002与环状半胺醛3Aa-002的混合物(收率92%)。
1H NMR(300MHz,CDCl3):δ2.56-2.82(m,7H),2.94-3.40(m,3H),3.81(s,2H),43.98-4.10(m,1H),6.78(t,1H,J=6.6Hz),7.10-7.40(m,10H).
(工序6及7)
与实施例1的工序6同样地,使用氨基羟基酮4Aa-002与环状半胺醛3Aa-002的混合物作为基质,得到了环状亚胺2Aa-002,然后,与实施例1的工序7同样地得到了黄色液体形式的双环状氧杂氮丙啶1Aa-002(收率22%)。
MS:m/z 336([M+1],C22H25NO2)
实施例7
[化学式28]
(工序1)
与实施例1的工序1同样地,使用醛9a-03和盐酸羟胺作为基质,得到了无色固体形式的肟8a-03(收率85%)。
(工序2)
1H NMR(300MHz,CDCl3):δ1.42(s,9H),1.70-1.84(m,2H),1.76(d,3H,J=6.6Hz),1.92(s,3H),2.64-2.80(m,1H),3.22-3.35(m,3H),4.58-4.64(m,1H),4.80-4.98(br,1H),5.72-5.82(m,1H)。
(工序3)
1H NMR(300MHz,CDCl3):δ1.42(s,9H),1.50-1.70(m,2H),1.76(s,3H),1.84(d,3H,J=6.6Hz),2.72-2.82(m,2H),3.10-3.42(m,2H),4.12-4.20(m,1H),4.96-5.10(br,1H),6.70-6.82(m,1H)。
(工序4及5)
与实施例1的工序4及5同样地,使用N-Boc氨基羟基酮5Aa-003作为基质,得到了黄色液体形式的氨基羟基酮4Aa-003与环状半胺醛3Aa-003的混合物(收率82%)。
1H NMR(300MHz,CDCl3):δ1.48-1.72(m,2H),1.76(s,3H),1.84(d,3H,J=6.6Hz),2.72-2.82(m,2H),2.96-3.22(m,2H),4.02-4.12(m,1H),6.68-6.82(m,1H)。
(工序6及7)
与实施例1的工序6同样地,使用氨基羟基酮4Aa-003和环状半胺醛3Aa-003的混合物作为基质,得到了环状亚胺2Aa-003,然后,与实施例1的工序7同样地得到了黄色液体形式的双环状氧杂氮丙啶1Aa-003(收率18%)。
MS:m/z 170([M+1],C9H15NO2)
实施例8
[化学式29]
(工序1)
与实施例1的工序1同样地,使用醛9a-04和盐酸羟胺作为基质,得到了无色固体形式的肟8a-04(收率87%)。
(工序2)
1H NMR(300MHz,CDCl3):δ1.43(s,9H),2.44-2.80(m,2H),3.12-3.40(m,4H),3.94(s,2H),4.62-4.76(m,1H),5.10-5.18(br,1H),6.80(s,1H),7.12-7.56(m,9H)。
(工序3)
1H NMR(300MHz,CDCl3):δ1.43(s,9H),2.46-2.84(m,2H),3.14-3.42(m,4H),3.95(s,2H),4.14-4.22(m,1H),5.12-5.20(br,1H),7.10-7.60(m,10H)。
(工序4及5)
与实施例1的工序4及5同样地,使用N-Boc氨基羟基酮5Aa-004作为基质,得到了黄色液体形式的氨基羟基酮4Aa-004与环状半胺醛3Aa-004的混合物(收率80%)。
1H NMR(300MHz,CDCl3):δ2.46-2.84(m,2H),3.12-3.42(m,4H),3.94(s,2H),4.08-4.20(m,1H),6.20(s,1H),7.12-7.60(m,9H)。
(工序6及7)
与实施例1的工序6同样地,使用氨基羟基酮4Aa-004与环状半胺醛3Aa-004的混合物作为基质,得到了环状亚胺2Aa-004,然后,与实施例1的工序7同样地得到了黄色液体形式的双环状氧杂氮丙啶1Aa-004(收率15%)。
MS:m/z 342([M+1],C20H20ClNO2)
工业实用性
根据本发明,能够通过化学合成而制造显示抗真菌活性及细胞毒性、可期待作为新型的抗真菌剂及抗癌剂的Kakeromycin及其衍生物。
本申请以在日本提出申请的日本特愿2015-039363为基础,其全部内容应包含在本说明书中。
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PCT/JP2016/055891 WO2016136963A1 (ja) | 2015-02-27 | 2016-02-26 | カケロマイシンおよびその誘導体の製造方法 |
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US11509003B2 (en) | 2019-01-25 | 2022-11-22 | Toyota Jidosha Kabushiki Kaisha | Cooling structure for power storage stack and cooling system for power storage stack |
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