TW202304462A - 糖皮質素受體激動劑 - Google Patents
糖皮質素受體激動劑 Download PDFInfo
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- TW202304462A TW202304462A TW111109320A TW111109320A TW202304462A TW 202304462 A TW202304462 A TW 202304462A TW 111109320 A TW111109320 A TW 111109320A TW 111109320 A TW111109320 A TW 111109320A TW 202304462 A TW202304462 A TW 202304462A
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- Prior art keywords
- compound
- pharmaceutically acceptable
- acceptable salt
- mmol
- dioxol
- Prior art date
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- 229940124750 glucocorticoid receptor agonist Drugs 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 201
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- CYCGRDQQIOGCKX-UHFFFAOYSA-N Dehydro-luciferin Natural products OC(=O)C1=CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 CYCGRDQQIOGCKX-UHFFFAOYSA-N 0.000 description 1
- BJGNCJDXODQBOB-UHFFFAOYSA-N Fivefly Luciferin Natural products OC(=O)C1CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 BJGNCJDXODQBOB-UHFFFAOYSA-N 0.000 description 1
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- 241000124008 Mammalia Species 0.000 description 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
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- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
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- DBTNVRCCIDISMV-UHFFFAOYSA-L lithium;magnesium;propane;dichloride Chemical compound [Li+].[Mg+2].[Cl-].[Cl-].C[CH-]C DBTNVRCCIDISMV-UHFFFAOYSA-L 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/0026—Oxygen-containing hetero ring cyclic ketals
- C07J71/0031—Oxygen-containing hetero ring cyclic ketals at positions 16, 17
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
Abstract
本發明提供一種式I化合物:
其中R為H或
;
R
1為H、鹵素、C1-C3烷基、C3-C6環烷基、C1-C3烷氧基、C2-C3烯基、OCF
3、
、、或;
R
2為H、鹵素、C1-C3烷基、C1-C3烷氧基或C2-C4烯基;
R
3為NH
2或CH
2NH
2;且
X為O、OCH
2、OCH
2CH
2、OCH(CH
3)、CH
2O、SCH
2、CH
2S、CH
2、NHCH
2、CH
2NH、N(CH
3)CH
2、CH
2CH
2、C≡C或鍵,其中X連接至苯環A之鄰位或間位,或其醫藥學上可接受之鹽,其中該式I化合物或其醫藥學上可接受之鹽適用於治療自體免疫及發炎性疾病,諸如異位性皮膚炎及類風濕性關節炎。
Description
本發明提供作為糖皮質素受體激動劑且適用於治療自體免疫及發炎性疾病(諸如異位性皮膚炎、發炎性腸病、全身性紅斑狼瘡、狼瘡性腎炎及類風濕性關節炎)之化合物、製備此等化合物之方法、包含此等化合物之醫藥組合物,且亦提供使用此等化合物及組合物之方法。
異位性皮膚炎係一種慢性、瘙癢性的復發緩解型發炎性皮膚病,其頻繁發生在兒童中,且亦影響許多成人。異位性皮膚炎之當前治療包括光療法、含有皮質類固醇或鈣調神經磷酸酶抑制劑之外用乳膏或被稱為度匹魯單抗(dupilumab)之皮下可注射生物製劑。儘管在治療異位性皮膚炎方面取得進展,但仍非常需要用以治療異位性皮膚炎及其他發炎性及自體免疫疾病之新穎化合物。
WO2017/210471揭示適用於治療自體免疫或發炎性疾病之某些糖皮質素受體激動劑及其免疫結合物。WO2018/089373揭示新穎類固醇、其蛋白質結合物以及用於治療疾病、病症及病況之方法,該等方法包含投與該等類固醇及結合物。
本發明提供作為糖皮質素受體激動劑之某些新穎化合物。本發明進一步提供作為糖皮質素受體激動劑之前藥的某些新穎化合物。另外,本發明提供作為糖皮質素受體激動劑且適用於治療自體免疫及發炎性疾病之某些新穎化合物,該等自體免疫及發炎性疾病諸如異位性皮膚炎、發炎性腸病、類風濕性關節炎、全身性紅斑狼瘡及狼瘡性腎炎。
因此,在一個實施例中,本發明提供一種式I化合物:
其中R為H或
;
R
1為H、鹵素、CN、C1-C3烷基、C3-C6環烷基、C1-C3烷氧基、C2-C3烯基、OCF
3、
;
R
2為H、鹵素、C1-C3烷基、C1-C3烷氧基或C2-C3烯基;
R
3為NH
2或CH
2NH
2;且
X為O、OCH
2、OCH
2CH
2、CH
2O、SCH
2、CH
2S、CH
2、NHCH
2、CH
2NH、N(CH
3)CH
2、CH
2CH
2、C≡C或鍵,其中X連接至苯環A之鄰位或間位,或其醫藥學上可接受之鹽。
在一個實施例中,本發明提供一種式Ia化合物:
其中R為H或
;
R
1為H、鹵素、C1-C3烷基、C3-C6環烷基、C1-C3烷氧基、C2-C3烯基、OCF
3、
;
R
2為H、鹵素、C1-C3烷基、C1-C3烷氧基或C2-C4烯基;
R
3為NH
2或CH
2NH
2;且
X為O、OCH
2、OCH
2CH
2、OCH
2C≡C、OCH(CH
3)、CH
2O、SCH
2、CH
2S、CH
2、NHCH
2、CH
2NH、N(CH
3)CH
2、CH
2CH
2、C≡C或鍵,其中X連接至苯環A之鄰位或間位,或其醫藥學上可接受之鹽。
在一個實施例中,本發明提供一種式Ib化合物:
其中R為H或
;
R
1為H、鹵素、C1-C3烷基、C3-C6環烷基、C1-C3烷氧基、C2-C3烯基、OCF
3、
;
R
2為H、鹵素、C1-C3烷基、C1-C3烷氧基或C2-C4烯基;
R
3為NH
2或CH
2NH
2;且
X為O、OCH
2、OCH
2CH
2、OCH(CH
3)、CH
2O、SCH
2、CH
2S、CH
2、NHCH
2、CH
2NH、N(CH
3)CH
2、CH
2CH
2、C≡C或鍵,其中X連接至苯環A之鄰位或間位,或其醫藥學上可接受之鹽。
在一個實施例中,本發明提供一種式Ic化合物:
其中R為H或
;
R
1為H、鹵素、C1-C3烷基、C3-C6環烷基、C1-C3烷氧基、C2-C3烯基、OCF
3、
;
R
2為H、鹵素、C1-C3烷基、C1-C3烷氧基或C2-C4烯基;
R
3為NH
2或CH
2NH
2;且
X為O、OCH
2、OCH
2CH
2、OCH(CH
3)、CH
2O、SCH
2、CH
2S、CH
2、NHCH
2、CH
2NH、N(CH
3)CH
2、CH
2CH
2、C≡C或鍵,其中X連接至苯環A之鄰位或間位,或其醫藥學上可接受之鹽。
在一實施例中,R為H。
在一實施例中,R
1為CH
3。
在一實施例中,R
1為H。
在一實施例中,R
1為OCH
3。
在一實施例中,R
1為F。
在一實施例中,R
2為H。
在一實施例中,R
2為CH
3。
在一實施例中,R
2為F。
在一實施例中,R
2為OCH
3。
在一實施例中,X為O。
在一實施例中,X為OCH
2。
在一實施例中,X為SCH
2。
在一實施例中,X為CH
2。
在一實施例中,X為鍵。
在一實施例中,R為H,R
1為CH
3,R
2為F,且X為OCH
2。
在一實施例中,R為H,R
1為OCH
3,R
2為F,且X為OCH
2。
在一實施例中,X在間位連接至苯環A。
在一實施例中,X在鄰位連接至苯環A。
在一實施例中,本發明亦提供一種治療需要此類治療之患者之發炎性疾病的方法,其包含向該患者投與有效量的式I化合物或其醫藥學上可接受之鹽。在一實施例中,本發明亦提供一種治療需要此類治療之患者之異位性皮膚炎的方法,其包含向該患者投與有效量的式I化合物或其醫藥學上可接受之鹽。在一實施例中,本發明進一步提供一種治療需要此類治療之患者之發炎性腸病的方法,其包含向該患者投與有效量的式I化合物或其醫藥學上可接受之鹽。在一實施例中,本發明進一步提供一種治療需要此類治療之患者之類風濕性關節炎的方法,其包含向該患者投與有效量的式I化合物或其醫藥學上可接受之鹽。在一實施例中,本發明亦提供一種治療需要此類治療之患者之全身性紅斑狼瘡的方法,其包含向該患者投與有效量的式I化合物或其醫藥學上可接受之鹽。在一實施例中,本發明亦提供一種治療需要此類治療之患者之狼瘡性腎炎的方法,其包含向該患者投與有效量的式I化合物或其醫藥學上可接受之鹽。
在一實施例中,本發明進一步提供一種用於療法中之式I化合物或其醫藥學上可接受之鹽。在一實施例中,本發明提供一種用於治療發炎性疾病之式I化合物或其醫藥學上可接受之鹽。在一實施例中,本發明提供一種用於治療異位性皮膚炎之式I化合物或其醫藥學上可接受之鹽。在一實施例中,本發明提供一種用於治療類風濕性關節炎之式I化合物或其醫藥學上可接受之鹽。在一實施例中,本發明提供一種用於治療發炎性腸病之式I化合物或其醫藥學上可接受之鹽。在一實施例中,本發明提供一種用於治療狼瘡性腎炎之式I化合物或其醫藥學上可接受之鹽。在一實施例中,本發明提供一種用於治療全身性紅斑狼瘡之式I化合物或其醫藥學上可接受之鹽。
在一實施例中,本發明亦提供一種式I化合物或其醫藥學上可接受之鹽的用途,其用於製造供治療發炎性疾病所用之藥劑。在一實施例中,本發明提供一種式I化合物或其醫藥學上可接受之鹽的用途,其用於製造供治療異位性皮膚炎所用之藥劑。在一實施例中,本發明提供一種式I化合物或其醫藥學上可接受之鹽的用途,其用於製造供治療類風濕性關節炎所用之藥劑。在一實施例中,本發明進一步提供一種式I化合物或其醫藥學上可接受之鹽的用途,其用於製造供治療發炎性腸病所用之藥劑。在一實施例中,本發明進一步提供一種式I化合物或其醫藥學上可接受之鹽的用途,其用於製造供治療狼瘡性腎炎所用之藥劑。在一實施例中,本發明亦提供一種式I化合物或其醫藥學上可接受之鹽的用途,其用於製造供治療全身性紅斑狼瘡所用之藥劑。
在一實施例中,本發明進一步提供一種醫藥組合物,其包含式I化合物或其醫藥學上可接受之鹽以及一或多種醫藥學上可接受之載劑、稀釋劑或賦形劑。在一實施例中,本發明進一步提供一種用於製備醫藥組合物之方法,其包含摻合式I化合物或其醫藥學上可接受之鹽與一或多種醫藥學上可接受之載劑、稀釋劑或賦形劑。在一實施例中,本發明亦涵蓋用於合成式I化合物之新穎中間物及方法。
本申請案主張2021年3月23日申請之美國申請案第63/164,613號及2021年8月20日申請之美國申請案第63/260,451號的優先權益,該等申請案之內容以全文引用之方式併入。
如本文所使用,術語「治療(treating/treatment)」或「以治療(to treat)」包括限制、減緩、遏止或逆轉現有症狀或病症之進展或嚴重程度。
如本文所使用,術語「患者」係指哺乳動物,尤其人類。
如本文所使用,術語「有效量」係指當向患者投與單一或多個劑量時,在診斷或治療之患者中提供所要效果之本發明化合物或其醫藥學上可接受之鹽的量或劑量。
有效量可由熟習此項技術者藉由使用已知技術且藉由在類似情況下獲得的觀測結果來確定。在確定用於患者之有效量時,主治診斷醫師考慮多個因素,包括(但不限於):患者之物種;其體型、年齡及一般健康狀況;所涉及之特定疾病或病症;疾病或病症之累及程度或嚴重程度;個別患者之反應;所投與之特定化合物;投與模式;所投與之製劑之生物可用性特徵;所選擇之劑量方案;伴隨藥品之使用;及其他相關情形。
如本文所使用,應理解,式I涵蓋式Ia、Ib、Ic、Ib(i)、Ic(i)、Ib(ii)、Ic(ii)、Ib(iii)、Ic(iii)、II、IIa、IIb、IIc、III、IIIa、IIIb及IIIc,且本文中對式I之提及皆應理解為包括式Ia、Ib、Ic、Ib(i)、Ic(i)、Ib(ii)、Ic(ii)、Ib(iii)、Ic(iii)、II、IIa、IIb、IIc、III、IIIa、IIIb及IIIc。
如本文所使用,應理解,式II涵蓋式IIa、IIb及IIc,且本文中對式II之提及皆應理解為包括式IIa、IIb及IIc。
如本文所使用,應理解,式III涵蓋式IIIa、IIIb及IIIc,且本文中對式III之提及皆應理解為包括式IIIa、IIIb及IIIc。
如本文所使用,「鹵素」係指F、Cl、Br及I。
如本文所使用,「C1-C3烷基」係指CH
3、CH
2CH
3、CH
2CH
2CH
3及CH(CH
3)
2。
如本文所使用,「C3-C6環烷基」係指環丙基、環丁基、環戊基及環己基。
如本文所使用,「C1-C3烷氧基」係指OCH
3、OCH
2CH
3、OCH
2CH
2CH
3及OCH(CH
3)
2。
如本文所使用,「C2-C3烯基」係指HC=CH
2及C(CH
3)=CH
2。
一般熟習此項技術者應瞭解,當X如式I"中所示在鄰位連接至苯環A時,R
2為H。
另外,本發明化合物可藉由熟習此項技術者所理解之方法與抗體結合以形成抗體藥物結合物(ADC)。此類結合之一個實例將包括本發明化合物經由連接子化合物連接至抗體。熟習此項技術者已知之連接子化合物包括例如可裂解連接子及不可裂解連接子。此類ADC可將本發明化合物遞送至特定目標組織或細胞。因此,本文亦提供包含式I化合物之ADC。在一些實施例中,式I化合物經由連接子,例如可裂解連接子或不可裂解連接子與抗體結合。
本發明之化合物或結合物可調配為藉由任何途徑投與之醫藥組合物,該途徑使化合物或結合物生物可用,包括例如經口、外用或皮下投與。包括ADC在內的此類醫藥組合物可使用此項技術中已知之技術及方法製備。包括ADC在內的此類醫藥組合物可使用此項技術中已知之技術及方法製備(參見例如Remington: The Science and Practice of Pharmacy, A. Adejare編, 第23版, 2020年出版, Elsevier Science;WO 2017/062271及WO 2017/210471)。
式I之醫藥學上可接受之鹽包括在本發明之範疇內。本發明化合物(諸如式I化合物)的醫藥學上可接受之鹽可例如藉由使本發明化合物之適當游離鹼與適當的醫藥學上可接受之酸在適合溶劑(諸如二乙醚)中在此項技術中熟知的標準條件下反應而形成。參見例如Berge, S.M.等人, 「Pharmaceutical Salts」,
Journal of Pharmaceutical Sciences,
66: 1-19, (1977)。
以下製備中所描述之某些化合物可含有適合的氮保護基,在本文中稱為「Pg」。應理解,保護基可按熟習此項技術者所瞭解,視待進行之特定反應條件及特定變換而變化。保護及去保護條件已為熟習此項技術者所熟知且描述於文獻中(參見例如「
Greene's Protective Groups in Organic Synthesis」, 第四版, Peter G.M. Wuts及Theodora W. Greene, John Wiley and Sons, Inc. 2007)。
表 1 :縮寫及定義
術語 | 定義 |
ACN | 乙腈 |
aq | 水溶液 |
Å | 埃 |
BOC/Boc | 三級丁氧基羰基 |
C18 | 十八烷基矽烷 |
DCM | 二氯甲烷 |
DEA | 二乙胺 |
DIBAL-H | 氫化二異丁基鋁 |
DMEA | 二甲基乙胺 |
DMF | N,N-二甲基甲醯胺 |
DMSO | 二甲亞碸 |
dppf | 1,1'-雙(二苯基膦基)二茂鐵 |
equiv | 當量 |
ES/MS | 電噴霧質譜分析 |
EtOAc | 乙酸乙酯 |
EtOH | 乙醇 |
FA | 甲酸 |
g | 公克 |
h | 小時 |
HPLC | 高效液相層析 |
IPA | 異丙醇 |
IPAm | 異丙胺 |
L | 公升 |
LC | 液相層析 |
LCMS | 液相層析質譜分析 |
LDA | 二異丙胺鋰 |
M | 莫耳 |
mbar | 毫巴 |
MeOH | 甲醇 |
min | 分鐘 |
mL | 毫升 |
mM | 毫莫耳 |
mmol | 毫莫耳 |
mol | 莫耳 |
MS | 質譜分析 |
MTBE | 甲基三級丁基醚 |
MW | 分子量 |
m/z | 質荷比 |
nm | 奈米 |
NMR | 核磁共振 |
Pet ether | 石油醚 |
ppm | 百萬分率 |
ROE | 旋轉座標系的歐沃豪斯增強(rotating-frame Overhauser enhancement) |
RP-HPLC | 逆相HPLC |
rt | 室溫 |
satd | 飽和 |
SFC | 超臨界流體層析 |
SM | 起始物質 |
THF | 四氫呋喃 |
wt | 重量 |
本發明化合物或其鹽可容易地藉由一般熟習此項技術者已知的各種程序來製備,其中一些在以下製備方案及實例中加以說明。一般熟習此項技術者認識到,所描述途徑中之每一者之特定合成步驟可以不同方式組合或與不同流程之步驟結合以製備本發明化合物或其鹽。各步驟之產物可藉由此項技術中熟知之習知方法回收,包括萃取、蒸發、沈澱、層析、過濾、濕磨及結晶。除非另外指明,否則所有取代基如先前所定義。試劑及起始物質係一般熟習此項技術者容易獲得的。以下製備方案、實例及分析進一步說明本發明,但不應解釋為以任何方式限制本發明之範疇。
平行進行兩個反應。在-78℃下經30分鐘向4-溴-2-氟-1-甲氧基苯(250 g,1.2 mol)於THF (1500 mL)中之溶液中緩慢添加LDA (2 M,730 mL)。再過30分鐘後,在-78℃下經30分鐘緩慢添加DMF (140 mL,1.8 mol)。1小時後,合併兩個反應物,且將混合物用檸檬酸水溶液(2000 mL)稀釋且用EtOAc (1500 mL × 2)萃取。合併之有機層用飽和鹽水(1000 mL)洗滌且減壓濃縮,得到殘餘物。將殘餘物在室溫下用石油醚(1000 mL)濕磨12小時,得到標題化合物(382 g,67%產率)。ES/MS m/z 233.9 (M+H)。
平行進行三個反應。將6-溴-2-氟-3-甲氧基苯甲醛(120 g,5.3 mol)、甲基酸(47 g,7.9 mol)、Pd(dppf)Cl
2(12 g,0.02 mol)及Cs
2CO
3(340 g,1.1 mol)添加至二㗁烷(600 mL)及水(120 mL)之混合物中。在120℃下攪拌混合物。12小時後,合併三個反應物,且將混合物用飽和NH
4Cl水溶液(1000 mL)稀釋且用MTBE (1500 mL × 2)萃取。合併之有機層用飽和NaCl水溶液(1000 mL)洗滌且減壓濃縮,得到殘餘物。殘餘物藉由正相層析進行純化,用40:1之石油醚:EtOAc溶離,得到標題化合物(180 g,59%產率)。ES/MS m/z 169.3 (M+H)。
將2-氟-3-甲氧基-6-甲基苯甲醛(175 g,1.0 mol)添加至DCM (1050 mL)中。在0℃下將BBr
3(200 mL,2.1 mol)緩慢添加至溶液中。在室溫下攪拌反應物。1小時後,將混合物用飽和碳酸氫鈉水溶液(1000 mL)稀釋,直至pH=7至8,且用MTBE (1500 mL × 2)萃取。合併之有機層用飽和NaCl水溶液(1000 mL)洗滌且減壓濃縮,得到標題化合物(110 g,68%產率)。ES/MS m/z 154.9 (M+H)。
在室溫下將2-氟-3-羥基-6-甲基苯甲醛(130 g,0.84 mol)、(3-(溴甲基)苯基)胺基甲酸三級丁酯(200 g,0.70 mol)及碳酸鉀(350 g,2.5 mol)添加於乙腈(780 mL)中,且接著加熱至50℃。5小時後,將反應物用水(600 mL)稀釋且用EtOAc (800 mL × 2)萃取。合併之有機層用鹽水(800 mL)洗滌且減壓濃縮,得到殘餘物。殘餘物藉由正相層析進行純化,用50:1之石油醚:EtOAc溶離,得到粗產物。將粗產物在室溫下用MTBE (500 mL)濕磨30分鐘,得到標題化合物(103 g,32%產率)。ES/MS m/z 382.1 (M+Na)。
製備 5三乙酸(2R,3S,4S,5R,6R)-2-(乙醯氧基甲基)-6-(2-((6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-2-氟-6-甲基苯基)-7-羥基-6a,8a-二甲基-4-側氧基-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氫-8bH-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-8b-基)-2-側氧基乙氧基)四氫-2H-哌喃-3,4,5-三基酯
在室溫下將3Å分子篩(5 g)添加至(6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-2-氟-6-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮(150 mg,0.24 mmol,下方實例2)、2,3,4,6-四-O-乙醯基-α-D-半乳哌喃糖基溴化物(155 mg,0.37 mmol)及DCM (5 mL)中。1小時後,將反應物冷卻至0℃。添加氧化銀(I) (115 mg,0.49 mmol)及三氟甲磺酸三甲基矽酯(45 μL,0.24 mmol)。30分鐘後,反應物用飽和碳酸氫鈉水溶液淬滅,經矽藻土過濾,且用DCM (10 mL)及甲醇(10 mL)沖洗。將合併之有機層減壓濃縮,得到殘餘物。殘餘物藉由逆相層析純化,用1:5之10 mM碳酸氫銨水+5%甲醇:乙腈溶離,得到標題化合物(43 mg,19%產率)。ES/MS m/z 948.0 (M+1)。
向2-氟-4-甲氧基苯酚(25 g,180 mmol)於DMF (350 mL,0.5 M)中之溶液中添加咪唑(18 g,260 mmol)及三級丁基氯二苯基矽烷(55 mL,200 mmol)。在室溫下攪拌反應物18小時。用乙酸乙酯稀釋混合物。有機溶液用水及鹽水洗滌,經Na
2SO
4乾燥,過濾且濃縮,得到粗殘餘物。殘餘物藉由正相純化進行純化,用5:1之己烷:乙酸乙酯溶離,得到標題化合物(67 g,93%產率)。
1H NMR (399.8 MHz, d
6-DMSO) δ 7.67-7.65 (m, 4H), 7.51-7.44 (m, 6H), 6.82 (dd, J= 2.9, 12.7 Hz, 1H), 6.59 (t, J= 9.4 Hz, 1H), 6.47 (ddd, J= 9.0, 3.0, 1.4 Hz, 1H), 3.64 (s, 3H), 1.06 (s, 9H)。
將三級丁基(2-氟-4-甲氧基苯氧基)二苯基矽烷(56 g,150 mmol,製備6)溶解於50 mL甲苯中,且真空濃縮18小時。將乾燥固體溶解於THF (500 mL)中且冷卻至-80℃。用較大孔套管將正丁基鋰(1.7 M,100 mL,170 mmol)快速添加至冷卻溶液中。1.5小時後,將DMF (25 mL,320 mmol)添加至溶液中且移除冰浴。30分鐘後,將5N HCl水溶液(35 mL)添加至反應物中,然後添加氟化四丁銨(1 M THF溶液,185 mL,185 mmol)。2.5小時後,將有機層蒸發,用5N HCl水溶液酸化,且分溶於乙酸乙酯與水(500 mL)之間。合併之有機萃取物用水及鹽水洗滌,經MgSO
4乾燥,過濾且濃縮,得到粗殘餘物。殘餘物藉由正相純化進行純化,用1:1之己烷:乙酸乙酯溶離,得到標題化合物(22 g,88%產率)。MS m/z 170.8 (M+H)。
將2-氟-3-羥基-6-甲氧基苯甲醛(2.5 g,15 mmol)及N-[3-(溴甲基)苯基]胺基甲酸三級丁酯(5.1 g,18 mmol)溶解於乙腈(50 mL)中。將碳酸鉀(2.9 g,29 mmol)添加至漿液中,且在室溫下攪拌反應物。1小時後,使反應物升溫至40℃。3小時後,將反應物冷卻,過濾,且蒸發溶劑。粗殘餘物藉由正相純化進行純化,用7:3之己烷:EtOAc溶離,得到標題化合物(3.1 g,57%產率)。MS m/z 374.4 (M-H)。
表2中之以下化合物以基本上類似於製備8中所描述之程序的方式製備。
表2:製備9至50
製備編號 | 結構 | ES/MS (m/z) (M+H) | 起始苯酚 |
9 | 326.0 | 2-羥基苯甲醛 | |
10 | 379.0 | 2-氯-6-氟-3-羥基苯甲醛 | |
11 | 344.0 | 3-氟-5-羥基苯甲醛 | |
12 | 360.0 | 2-氯-5-羥基苯甲醛 | |
13 | 360.0 | 3-氯-5-羥基苯甲醛 | |
14 | 344.0 | 2-氟-5-羥基苯甲醛 | |
15 | 404.0 | 2-溴-5-羥基苯甲醛 | |
16 | 422.0 (M-H) | 6-溴-2-氟-3-羥基苯甲醛 | |
17 | 356.4 (M-H) | 3-羥基-2-甲氧基苯甲醛 | |
18 | 451.4 (M-H) | 5-羥基-2-碘苯甲醛 | |
19 | 359.2 | 6-氟-3-羥基-2-甲基苯甲醛 | |
20 | 356.0 (M-H) | 5-羥基-2-甲氧基苯甲醛 | |
21 | 410.6 (M-H) | 5-羥基-2-(三氟甲氧基)苯甲醛 | |
22 | 374.5 (M-H) | 6-氟-3-羥基-2-甲氧基苯甲醛 | |
23 | 363.2 | 3-羥基苯甲醛 | |
24 | 360.0 (M-H) | 2-氯-6-羥基苯甲醛 | |
25 | 372.0 (M-H) | 2-氟-3-羥基-6-甲基苯甲醛 | |
26 | 378.0 (M-H) | 6-氯-2-氟-3-羥基苯甲醛 | |
27 | 246.0 (M+H-Boc) | 2-氟-3-羥基苯甲醛 | |
28 | 340.0 (M-H) | 5-羥基-2-甲基苯甲醛 | |
29 | 344.0 (M-H) | 2-氟-6-羥基苯甲醛 | |
30 | 340.2 (M-H) | 3-羥基-2-甲基苯甲醛 | |
31 | 374.2 (M-H) | 2-氟-3-羥基-4-甲氧基苯甲醛 | |
32 | 360.0 (M-H) | 4-氯-3-羥基苯甲醛 | |
33 | 402.2 (M+Na) | 6-氯-2-氟-3-羥基苯甲醛 | |
34 | 396.2 (M+Na) | 2-氟-3-羥基-6-甲基苯甲醛 | |
35 | 382.2 (M+Na) | 2-氟-3-羥基-6-甲基苯甲醛 | |
36 | 382.2 (M+Na) | 3-羥基-5-甲基苯甲醛 | |
37 | 379.2 (M+NH 4) | 2-氯-3-羥基苯甲醛 | |
38 | 396.2 (M+Na) | 2-氟-3-羥基-6-甲基苯甲醛 | |
39 | 396.2 (M+Na) | 2,4-二氟-3-羥基苯甲醛 | |
40 | 370.4 (M-H) | 2-乙氧基-5-羥基苯甲醛 | |
41 | 356.4 (M-H) | 5-羥基-2-甲氧基苯甲醛 | |
42 | 374.4 (M-H) | 2-氟-3-羥基-6-甲氧基苯甲醛 | |
43 | 344.2 (M-H) | 2-氟-3-羥基苯甲醛 | |
44 | 340.2 (M-H) | 5-羥基-2-甲基苯甲醛 | |
45 | 362.0 (M+NH 4) | 2,6-二氟-3-羥基苯甲醛 | |
46 | 378.0 (M-H) | 2-氯-6-氟-3-羥基苯甲醛 | |
47 | 362.2 (M-H) | 2,6-二氟-3-羥基苯甲醛 | |
48 | 340.3 (M-H) | 3-羥基-2-甲基苯甲醛 | |
49 | 372.8 (M+NH 4) | 3-羥基-2,6-二甲基苯甲醛 | |
50 | 406.6 | 2-溴-3-羥基苯甲醛 |
在微波試管中,將(3-((4-溴-3-甲醯基苯氧基)甲基)苯基)胺基甲酸三級丁酯(0.73 g,1.8 mmol)、2-呋喃基酸(0.30 g,2.7 mmol)、肆(三苯基膦)鈀(0) (0.10 g,0.09 mmol)及N,N-二異丙基乙胺(1.6 mL,1.2 mmol)溶解於DMF (2 mL,26 mmol)中。將試管用N
2沖洗且加蓋。將反應物在140℃下微波處理45分鐘。將反應物冷卻,倒至冰水上,用EtOAc萃取,且用鹽水洗滌。有機層經Na
2SO
4乾燥,過濾且蒸發,得到標題化合物(0.70 g,98%產率)。MS m/z 392.2 (M-H)。
表3中之以下化合物以基本上類似於製備51中所描述之程序的方式製備。
表3:製備52至55
製備編號 | 結構 | ES/MS (m/z) (M+H) | 酸 |
52 | 392.2 | 呋喃-3-基酸 | |
53 | 408.4 (M-H) | 苯硫-2-基酸 | |
54 | 420.6 (M-H) | 苯基酸 | |
55 | 402.2 (M-H) | 苯基酸 |
在40 mL反應小瓶中,將3-溴苯甲醛(1.5 g,8.1 mmol)、(3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)苯基)胺基甲酸三級丁酯(2.1 g,6.4 mmol)及碳酸鉀(3.3 g,24 mmol)溶解於1,4二㗁烷(11 mL)及水(3 mL)中。攪拌所得均質混合物並脫氣三次。添加1,1'雙(二三級丁基膦基)二茂鐵二氯鈀(II)二氯甲烷錯合物(530 mg,0.81 mmol),且將混合物脫氣、加蓋且加熱至90℃後保持2.25小時。將反應物冷卻,經矽藻土過濾,且蒸發溶劑。粗殘餘物藉由正相層析純化,用7:3之己烷:EtOAc溶離,得到標題化合物(1.5 g,63%產率)。MS m/z 315.4 (M+18)。
表4中之以下化合物以基本上類似於製備56中所描述之程序的方式製備。
表4:製備57
製備編號 | 結構 | ES/MS (m/z) (M+H) | 酸 |
57 | 296.2 (M-H) | (4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)苯基)胺基甲酸三級丁酯 |
在小瓶中,將3-(溴甲基)苯甲醛(320 mg,1.5 mmol)、(3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)苯基)胺基甲酸三級丁酯(300 mg,0.94 mmol)及碳酸鉀(410 mg,3.0 mmol)溶解於甲苯(9 mL)及水(1 mL)中。用氬氣吹掃反應物。添加1,1'雙(二三級丁基膦基)二茂鐵二氯鈀(II)二氯甲烷錯合物(80 mg,0.10 mmol),將小瓶加蓋且加熱至100℃後保持1.5小時。將反應物冷卻,經矽藻土過濾,且蒸發溶劑。粗殘餘物藉由正相層析純化,用7:3之庚烷:EtOAc溶離,得到標題化合物(300 mg,54%產率)。MS m/z 329.4 (M+18)。
表5中之以下化合物以基本上類似於製備58中所描述之程序的方式製備。
表5:製備59至60
製備編號 | 結構 | ES/MS (m/z) (M+H) | 酸/酯 |
59 | 329.4 (M+NH 4) | (2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)苯基)胺基甲酸三級丁酯 | |
60 | 329.4 (M+NH 4) | (4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)苯基)胺基甲酸三級丁酯 |
將3-(溴甲基)苯基胺基甲酸三級丁酯(1.5 g,5.0 mmol)、2,6-二氟-3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)苯甲醛(1.5 g,5.6 mmol)及碳酸鉀(2.1 g,3.0 mmol)放入含有水(1 mL)及甲苯(9 mL)之反應小瓶中。向反應混合物中鼓泡通入N
2,添加1,1'-雙(二三級丁基膦基)二茂鐵二氯鈀(II)二氯甲烷錯合物(310 mg,0.37 mmol),且將小瓶加蓋且在100℃下加熱10分鐘。將反應物冷卻,過濾,且蒸發濾液。粗殘餘物藉由正相層析純化,用1:1之庚烷:EtOAc溶離,得到標題化合物(1.38 g,3.85 mmol,77%產率)。MS m/z 365.2 (M+NH
4)。
表6中之以下化合物以基本上類似於製備61中所描述之程序的方式製備。
表6:製備62至66
製備編號 | 結構 | ES/MS (m/z) (M+H) | 酸/酯 |
62 | 無離子 | 2-氟-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)苯甲醛 | |
63 | 381.0 (M+NH 4) | (4-氯-2-氟-3-甲醯基苯基)酸 | |
64 | 381.2 (M+NH 4) | (4-氯-2-氟-3-甲醯基苯基)酸 | |
65 | 363.2 (M+NH 4) | (4-氯-3-甲醯基苯基)酸 | |
66 | 363.2 (M+H) | (4-氯-3-甲醯基苯基)酸 |
在小瓶中,將(3-甲醯基苯基)酸(610 mg,4.1 mmol)、(4-羥苯基)胺基甲酸三級丁酯(420 mg,2.0 mmol)、乙酸銅(II) (370 mg,2.0 mmol)、三乙胺(1.4 mL,10 mmol)及4 Å分子篩(500 mg)添加於DCM (15 mL)中。將反應物在室溫下培育10小時。反應物經矽藻土過濾,且蒸發溶劑。粗殘餘物藉由正相層析純化,用7:3之己烷:EtOAc溶離,得到標題化合物(180 mg,29%產率)。MS m/z 312.2 (M-H)。
表7中之以下化合物以基本上類似於製備67中所描述之程序的方式製備。
表7:製備68
製備編號 | 結構 | ES/MS (m/z) (M+H) | 苯酚 |
68 | 312.2 (M-H) | (3-羥苯基)胺基甲酸三級丁酯 |
將5-羥基-2-甲氧基苯甲醛(1.00 g,6.57 mmol)、[4-(三級丁氧基羰基胺基)苯基]酸(3.12 g,13.2 mmol)、乙酸銅(II) (1.19 g,6.57 mmol)及4 Å分子篩(1.0 g)添加至燒瓶中。然後添加DCM (60 mL)及三乙胺(4.6 mL,33 mmol)。將反應混合物在室溫下攪拌隔夜。添加更多的[4-(三級丁氧基羰基胺基)苯基]酸(1.1 g,4.6 mmol)及乙酸銅(II) (400 mg,2.2 mmol),且將反應混合物在室溫下攪拌三天。過濾反應物且蒸發溶劑。粗殘餘物藉由正相層析純化,用庚烷:EtOAc溶離,得到標題化合物(400 mg,18%產率)。MS m/z 361.0 (M+NH
4)。
表8中之以下化合物以基本上類似於製備69中所描述之程序的方式製備。
表8:製備70
製備編號 | 結構 | ES/MS (m/z) (M+H) | 酸 |
70 | 361.0 (M+NH 4) | [3-(三級丁氧基羰基胺基)苯基]酸 |
在N
2下將3-乙炔基-2-氟苯甲醛(0.25 g,1.7 mmol)與含N-(3-碘苯基)胺基甲酸三級丁酯(0.55 g,1.7 mmol)、二氯化雙(三苯基膦)鈀(II) (0.025 g,0.036 mmol)及碘化銅(I) (0.01 g,0.05 mmol)之三乙胺(10 mL,72 mmol)混合。將反應混合物在室溫下攪拌隔夜。反應混合物用EtOAc稀釋且經由矽藻土過濾。濾液用1 M HCl水溶液、鹽水洗滌,經Na
2SO
4乾燥且過濾。蒸發溶劑,得到標題化合物(0.57 g,100%產率)。MS m/z 338.2 (M-H)。
向微波小瓶中添加含2-(2-溴-6-氟-3-甲氧基苯基)-1,3-二氧雜環戊烷(970 mg,3.5 mmol)、溶於THF中之三甲基環三硼氧烷(50質量%) (600 μL,4.3 mmol)及碳酸銫(2.3 g,7.1 mmol)之1,4-二㗁烷(12 mL,140 mmol)及水(2 mL,110 mmol)。用N
2使溶液脫氣2分鐘。添加[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II) (130 mg,0.17 mmol),且用N
2使溶液脫氣2分鐘。將小瓶加蓋且在110℃下微波處理1小時。將反應混合物用水(10 mL)稀釋且用EtOAc (10 mL)萃取。有機層經Na
2SO
4乾燥,經由濾紙過濾且旋轉蒸發,得到粗油狀物。粗油狀物藉由正相層析純化,用7:3之己烷:MTBE溶離,得到標題化合物(0.61 g,82%產率)。MS m/z 212.8 (M+H)。
表9中之以下化合物以基本上類似於製備72中所描述之程序的方式製備。
表9:製備73至78
*
1H NMR (400.14 MHz, DMSO):δ 10.40 (s, 1H), 9.39 (s, 1H), 7.55-7.50 (m, 2H), 7.26 (d, J= 8.3 Hz, 1H), 7.19 (t, J= 7.9 Hz, 1H), 7.08 (d, J= 7.9 Hz, 1H), 6.96 (d, J= 7.8 Hz, 1H), 4.22 (s, 2H), 1.46 (s, 10H)
**
1H NMR (400.21 MHz, DMSO):δ 10.45 (s, 1H), 7.97 (s, 1H), 7.78 (t, J= 7.8 Hz, 1H), 7.65-7.61 (m, 1H), 7.22-7.20 (m, 1H), 7.14-7.12 (m, 1H), 7.07-7.02 (m, 1H), 6.95-6.91 (m, 1H), 5.21 (s, 2H), 2.57 (s, 3H), 1.43 (s, 9H)
製備編號 | 結構 | ES/MS (m/z) (M+H) | 溴化物 |
73 | 無離子* | (3-((4-溴-2-氟-3-甲醯基苯甲基)硫代)苯基)胺基甲酸三級丁酯 | |
74 | 305.9 (M-Boc+H) | 6-溴-3-(((2-((三級丁氧基羰基)胺基)苯基)硫代)甲基)-2-氟苯甲酸甲酯 | |
75 | 359.0 | (3-((4-溴-2-氟-3-甲醯基苯甲基)胺基)苯基)胺基甲酸三級丁酯 | |
76 | 無離子** | (2-((4-溴-2-氟-3-甲醯基苯甲基)氧基)苯基)胺基甲酸三級丁酯 | |
77 | 315.9 | (E)-6-溴-2-氟-3-(4-硝基苯乙烯基)苯甲酸甲酯 | |
78 | 359.0 | (2-((4-溴-2-氟-3-甲醯基苯甲基)胺基)苯基)胺基甲酸三級丁酯 |
經2分鐘之時段將含三溴化硼之DCM (14 mL,14 mmol,1 mol/L)添加至冷卻至0℃的2-(6-氟-3-甲氧基-2-甲基苯基)-1,3-二氧雜環戊烷(600 mg,2.8 mmol)於DCM (14 mL,220 mmol)中之溶液中。在添加之後移除浴液。30分鐘後,用飽和NH
4Cl水溶液淬滅反應物。反應物用DCM稀釋,用2 M NaOH水溶液洗滌,且接著用5 M HCl水溶液洗滌。有機層經Na
2SO
4乾燥,經由濾紙過濾且旋轉蒸發,得到粗殘餘物。粗殘餘物藉由正相層析純化,用7:3之己烷:EtOAc溶離,得到標題化合物(130 mg,30%產率)。MS m/z 153.0 (M-H)。
向4-氟-2-甲氧基-苯酚(2.3 g,16 mmol)於DCM (35 mL)中之溶液中添加咪唑(2.8 g,41 mmol)及三級丁基氯二苯基矽烷(6 mL,23 mmol)。1.75小時後,蒸發溶劑,且將殘餘物分溶於200 mL含10% EtOAc之己烷與100 mL水之間。有機物用鹽水洗滌一次,經MgSO
4乾燥,過濾且蒸發。粗殘餘物藉由正相層析純化,用9:1之己烷:EtOAc溶離,得到標題化合物(6.7 g,全收量產率)。
1H NMR (399.8 MHz, d
6-DMSO) δ7.64 (dd, J= 1.5, 7.9 Hz, 4H), 7.48-7.43 (m, 6H), 6.82 (dd, J= 2.9, 10.5 Hz, 1H), 6.60 (dd, J= 5.9, 8.8 Hz, 1H), 6.48 (td, J= 8.5, 3.0 Hz, 1H), 3.56 (s, 3H), 1.05 (s, 9H)
將三級丁基(4-氟-2-甲氧基苯氧基)二苯基矽烷(3.2 g,8.5 mmol)溶解於四氫呋喃(30 mL)中且冷卻至-78℃。歷經3分鐘添加正丁基鋰(7 mL,11 mmol,1.6 M)。1.5小時後,在-78℃下添加DMF (2 mL)。1小時後,添加約4 mL的10% NH
4Cl水溶液,且使其經1.5小時升溫至室溫。蒸發溶劑,得到粗殘餘物,然後用1 M HCl水溶液使其呈酸性,且將其分溶於水與300 mL EtOAc之間。有機層用水、鹽水洗滌,經MgSO
4乾燥,過濾且蒸發。粗殘餘物藉由正相層析純化,用3:2之己烷:EtOAc溶離,得到標題化合物(0.79 g,55%產率)。MS m/z 171.0 (M+H)。
將(3-((4-溴-3-(1,3-二氧雜環戊-2-基)-2-氟苯氧基)甲基)苯基)胺基甲酸三級丁酯(200 mg,0.43 mmol)、環丙基酸(0.21 g,2.4 mmol)及磷酸三鉀(0.28 g,1.3 mmol)放入用N
2吹掃之25 mL小瓶中。添加甲苯(3 mL)及水(0.75 mL)。用N
2使反應混合物脫氣5分鐘,且接著一次添加全量肆(三苯基膦)鈀(0) (0.10 g,0.09 mmol)。將反應物加熱至100℃後保持隔夜。冷卻至室溫後,添加EtOAc及水;分離各相,且用EtOAc萃取水層兩次。合併之有機層經Na
2SO
4乾燥,過濾且濃縮,得到粗殘餘物。粗殘餘物藉由正相層析純化,用1:1之己烷:EtOAc溶離,得到標題化合物(170 mg,94%產率)。MS m/z 428.4 (M-H)。
將2,6-二甲基-3-硝基苯甲醛(1.9 g,10 mmol)溶解於DCM (23 mL)中,然後添加乙酸酐(1.3 mL,14 mmol)及三氟甲磺酸銅(II) (41 mg,0.11 mmol)。在室溫下攪拌溶液3.5小時。用飽和NaHCO
3水溶液淬滅反應物。分離有機層,用水、鹽水洗滌,經Na
2SO
4乾燥,過濾且濃縮,得到粗殘餘物。粗殘餘物藉由正相層析純化,用3:2之己烷:EtOAc溶離,得到標題化合物(2.4 g,81%產率)。
1H NMR (400.13 MHz, DMSO-d6):7.96 (s, 1H), 7.80 (d, J= 8.3 Hz, 1H), 7.35 (d, J= 8.4 Hz, 1H), 2.58 (s, 3H), 2.53 (s, 2H), 2.12 (s, 6H)。
將硫化之5wt%鉑/碳(1.0 g,5.2 mmol)添加至500 mL帕爾(Parr)振盪瓶中,且用N
2脫氣。將25 mL EtOAc添加至瓶中,然後將含(2,6-二甲基-3-硝基苯基)亞甲基二乙酸酯(2.7 g,9.6 mmol)之25 mL EtOAc添加至瓶中。將瓶密封,用N
2吹掃,用H
2吹掃,且在室溫下加壓至60 psi H
2後保持1.5小時。過濾反應混合物且濃縮,得到標題化合物(2.1 g,全收量產率)。MS m/z 251.8 (M+H)。
將(3-胺基-2,6-二甲基苯基)亞甲基二乙酸酯(276 mg,1.10 mmol)及碳酸鉀(435 mg,3.15 mmol)於DMF (3 mL)中之混合物在室溫下攪拌1小時。將N-[3-(溴甲基)苯基]胺基甲酸三級丁酯(300 mg,1.05 mmol)添加至漿液中,且在50℃下攪拌反應物1小時。冷卻後,將反應混合物分溶於乙酸乙酯與水之間。分離各相。將有機相轉移至圓底燒瓶中,且真空蒸發溶劑。將殘餘DMF與二甲苯蒸發(共沸),得到呈透明糊狀物之殘餘物。粗殘餘物藉由正相純化進行純化,用1:1之EtOAc:己烷溶離,得到標題化合物(363 mg,76%產率)。MS m/z 457.2 (M+H)。
將(3-甲醯基苯基)胺基甲酸三級丁酯(1.2 g,5.2 mmol)、3-胺基-2-氟-6-甲基苯甲酸甲酯(950 mg,4.8 mmol)及乙酸(0.55 mL,9.6 mmol)溶解於甲醇(5 mL)中且冷卻至0℃。將氰基硼氫化鈉(0.61 g,9.5 mmol)謹慎添加至溶液中。移除冰浴,且將反應混合物在N
2下在室溫下攪拌隔夜。藉由添加水(10 mL)來淬滅反應物。將反應混合物分溶於EtOAc與水之間。合併之有機萃取物用鹽水洗滌,經Na
2SO
4乾燥,過濾且濃縮,得到粗殘餘物。粗殘餘物藉由正相層析純化,用3:2之石油醚:EtOAc溶離,得到標題化合物(1.9 g,75%產率)。MS m/z 389.0 (M+H)。
表10中之以下化合物以基本上類似於製備86中所描述之程序的方式製備。
表10:製備87
製備編號 | 結構 | ES/MS (m/z) (M+H) | 甲醯基起始物質 |
87 | 389.0 | (2-甲醯基苯基)胺基甲酸三級丁酯 |
將N-溴丁二醯亞胺(5.8 g,31 mmol)添加至6-溴-2-氟-3-甲基苯甲酸甲酯(3.9 g,14 mmol)於四氯化碳(36 mL)中之溶液中,接著添加2,2'-偶氮雙(2-甲基丙腈) (0.24 g,1.4 mmol),且將反應混合物在85℃下攪拌隔夜。混合物用DCM稀釋,用鹽水洗滌,經Na
2SO
4乾燥且濃縮,得到粗殘餘物。將殘餘物溶解於ACN中且藉由製備型C18 HPLC (35%-60%水[0.225% FA]-ACN)純化。將溶離劑濃縮,得到6-溴-3-(二溴甲基)-2-氟苯甲酸甲酯(1.9 g,4.6 mmol)。將該物質溶解於乙醇(15 mL)中。添加硝酸銀(2.0 g,12 mmol)於水(10 mL)中之混合物,且將反應混合物在N
2下在75℃下加熱6小時。過濾反應物質且用EtOAc洗滌。濃縮濾液,得到粗殘餘物。粗殘餘物藉由正相層析純化,用8% EtOAc:石油醚溶離,得到標題化合物(1.1 g,91%產率)。
將6-溴-2-氟-3-甲醯基苯甲酸甲酯(1.0 g,3.7 mmol)、N-(3-胺基苯基)胺基甲酸三級丁酯(870 mg,4.1 mmol)及乙酸(0.43 mL,7.5 mmol)溶解於甲醇(9 mL)中且冷卻至0℃。將氰基硼氫化鈉(480 mg,7.5 mmol)謹慎添加至溶液中。移除冰浴,且將反應混合物在N
2下在室溫下攪拌隔夜。藉由添加水(30 mL)來淬滅反應物。將反應混合物分溶於EtOAc與水之間。合併之有機萃取物用鹽水洗滌,經Na
2SO
4乾燥,過濾且濃縮,得到粗殘餘物。粗殘餘物藉由正相層析純化,用7:3之石油醚:EtOAc溶離,得到標題化合物(1.7 g,89%產率)。MS m/z 454.9 (M+H)。
表11中之以下化合物以基本上類似於製備89中所描述之程序的方式製備。
表11:製備90
製備編號 | 結構 | ES/MS (m/z) (M+H) | 甲醯基起始物質 |
90 | 454.9 | 6-溴-2-氟-3-甲醯基苯甲酸甲酯 |
向3-((3-((三級丁氧基羰基)胺基)苯甲基)胺基)-2-氟-6-甲基苯甲酸甲酯(1.7 g,3.3 mmol)於甲醇(5 mL)中之溶液中添加氰基硼氫化鈉(420 mg,6.5 mmol)及乙酸(0.5 mL,9 mmol)。然後在25℃下添加含甲醛之水(730 μL,9.8 mmol,37質量%)。將混合物在N
2下在室溫下攪拌隔夜。粗混合物藉由正相層析純化,用4:1之石油醚:EtOAc溶離,得到標題化合物(1.3 g,92%產率)。MS m/z 403.0 (M+H)。
在0℃下向3-((3-((三級丁氧基羰基)胺基)苯甲基)(甲基)胺基)-2-氟-6-甲基苯甲酸甲酯(1.2 g,2.8 mmol)於DCM (10 mL)中之溶液中添加含DIBAL-H之甲苯(7 mL,7.0 mmol,1.0 mol/L)。使反應混合物升溫至室溫後保持3小時。將溶液重新冷卻至0℃,且添加飽和羅謝爾(Rochelle)鹽水溶液及DCM,接著用DCM萃取。有機層用鹽水洗滌,經Na
2SO
4乾燥,使其通過矽膠塞並濃縮,得到粗殘餘物。殘餘物藉由正相層析純化,用1:1之石油醚:EtOAc溶離,得到標題化合物(640 mg,57%產率)。MS m/z 375.0 (M+H)。
表12中之以下化合物以基本上類似於製備92中所描述之程序的方式製備。
表12:製備93至98
*
1H NMR (400.14 MHz, DMSO):δ 9.23 (s, 1H), 7.35-7.31 (m, 2H), 7.09-7.02 (m, 3H), 6.89 (d, J= 7.8 Hz, 1H), 4.92 (t, J= 5.3 Hz, 1H), 4.49-4.48 (m, 2H), 4.03 (q, J= 7.1 Hz, 1H), 2.79-2.72 (m, 4H), 2.33 (s, 3H), 1.46 (s, 9H)。
製備編號 | 結構 | ES/MS (m/z) (M+H) | 酯SM |
93 | 278.0 (M-Boc+H) | 3-(((2-((三級丁氧基羰基)胺基)苯基)硫代)甲基)-2-氟-6-甲基苯甲酸甲酯 | |
94 | 426.9 | 6-溴-3-(((3-((三級丁氧基羰基)胺基)苯基)胺基)甲基)-2-氟苯甲酸甲酯 | |
95 | 361.0 | 3-((2-((三級丁氧基羰基)胺基)苯甲基)胺基)-2-氟-6-甲基苯甲酸甲酯 | |
96 | 361.2 | 3-((3-((三級丁氧基羰基)胺基)苯甲基)胺基)-2-氟-6-甲基苯甲酸甲酯 | |
97 | 無離子* | 3-(4-((三級丁氧基羰基)胺基)苯乙基)-2-氟-6-甲基苯甲酸甲酯 | |
98 | 426.9 | 6-溴-3-(((2-((三級丁氧基羰基)胺基)苯基)胺基)甲基)-2-氟苯甲酸甲酯 |
向(3-(((2-氟-3-(羥甲基)-4-甲基苯基)(甲基)胺基)甲基)苯基)胺基甲酸三級丁酯(590 mg,1.5 mmol)於EtOAc (5 mL)中之溶液中添加2-碘氧基苯甲酸(630 mg,2.2 mmol)。將反應混合物在80℃下攪拌6小時。濾出固體且濃縮濾液,得到粗殘餘物。殘餘物藉由正相層析純化,用7:3之石油醚:EtOAc溶離,得到標題化合物(580 mg,94%產率)。MS m/z 373.0 (M+H)。
表13中之以下化合物以基本上類似於製備99中所描述之程序的方式製備。
表13:製備100至104
*
1H NMR (400.15 MHz, DMSO):δ 10.31 (d, J= 0.8 Hz, 1H), 7.90-7.86 (m, 1H), 7.78 (dd, J= 0.8, 8.4 Hz, 1H), 4.84 (d, J= 1.0 Hz, 2H)
**
1H NMR (400.15 MHz, DMSO):δ 10.42 (s, 1H), 9.23 (s, 1H), 7.44-7.40 (m, 1H), 7.36-7.33 (m, 2H), 7.09-7.05 (m, 3H), 2.92-2.81 (m, 4H), 2.50 (s, 3H), 1.47 (s, 9H)。
製備編號 | 結合 | ES/MS (m/z) (M+H) | 醇起始物質 |
100 | 無離子* | (6-溴-3-(溴甲基)-2-氟苯基)甲醇 | |
101 | 275.9 (M-Boc+H) | (2-((2-氟-3-(羥甲基)-4-甲基苯甲基)硫代)苯基)胺基甲酸三級丁酯 | |
102 | 424.9 | (3-((4-溴-2-氟-3-(羥甲基)苯甲基)胺基)苯基)胺基甲酸三級丁酯 | |
103 | 無離子** | (4-(2-氟-3-(羥甲基)-4-甲基苯乙基)苯基)胺基甲酸三級丁酯 | |
104 | 425.0 | (2-((4-溴-2-氟-3-(羥甲基)苯甲基)胺基)苯基)胺基甲酸三級丁酯 |
向2-氟-3-羥基-6-甲基苯甲醛(250 mg,1.5 mmol)及4-甲基苯磺酸4-((三級丁氧基羰基)胺基)苯乙酯(760 mg,1.9 mmol)於乙腈(10 mL)中之溶液中添加碳酸鉀(670 mg,4.9 mmol)。將懸浮液在80℃下攪拌16小時。將反應混合物減壓濃縮,得到殘餘物。殘餘物用水(40 mL)稀釋,用EtOAc (20 mL)萃取。合併之有機層用鹽水(20 mL)洗滌,經無水Na
2SO
4乾燥,過濾且減壓濃縮,得到殘餘物。殘餘物藉由正相層析純化,用17:3之石油醚:EtOAc溶離,得到標題化合物(510 mg,85%產率)。
1H NMR (400.15 MHz, CDCl
3):δ 10.47 (s, 1H), 7.24 (d, J= 8.4 Hz, 2H), 7.15 (d, J= 8.5 Hz, 2H), 6.96 (t, J= 8.4 Hz, 1H), 6.82 (d, J= 8.4 Hz, 1H), 6.37-6.35 (m, 1H), 4.12 (t, J= 7.0 Hz, 2H), 3.01 (t, J= 6.9 Hz, 2H), 2.45 (s, 3H), 1.45 (s, 8H)。
向在氮氣氛圍下且在冰浴中冷卻的6-溴-3-(溴甲基)-2-氟苯甲酸(4.9 g,11 mmol)於THF (100 mL)中之溶液中逐滴添加含硼烷-THF複合物之THF (35 mL,35 mmol,1 mol/L)。使反應混合物升溫至室溫後保持隔夜。藉由添加MeOH (100 mL)淬滅反應物且真空濃縮。將所得殘餘物分溶於EtOAc (100 mL)與1 M HCl (30 mL)之間,且用EtOAc (100 mL)萃取水層一次。合併之有機萃取物經Na
2SO
4乾燥,過濾且濃縮,得到粗殘餘物。殘餘物藉由正相層析純化,用7:3之石油醚:EtOAc溶離,得到標題化合物(2.9 g,62%產率)。
1H NMR (400.15 MHz, DMSO):δ7.50-7.42 (m, 2H), 5.38-5.23 (m, 1H), 4.70 (d, J= 0.5 Hz, 2H), 4.59 (d, J= 1.5 Hz, 2H)。
其中J為氫或Boc。
在N
2下向6-溴-3-(溴甲基)-2-氟苯甲醛(620 mg,1.9 mmol)及N-(3-氫硫基苯基)胺基甲酸三級丁酯(500 mg,2.0 mmol)於DCM (10 mL)中之混合物中添加三乙胺(530 μL,3.8 mmol)。將混合物在室溫下攪拌2小時。將反應混合物分溶於DCM (30 mL)與水(30 mL)之間。將合併之有機萃取物真空濃縮,得到粗殘餘物。殘餘物藉由正相層析純化,用3:1之石油醚:EtOAc溶離,得到標題化合物(780 mg,89%產率)。
1H NMR (400.15 MHz, DMSO):δ 10.19 (s, 1H), 9.39 (s, 1H), 7.57-7.51 (m, 2H), 7.47 (s, 1H), 7.27 (d, J= 8.6 Hz, 1H), 7.19 (t, J= 7.9 Hz, 1H), 6.96 (d, J= 7.8 Hz, 1H), 4.21 (s, 2H), 1.46 (s, 9H)。
向3-(((2-胺基苯基)硫代)甲基)-6-溴-2-氟苯甲酸甲酯(1.3 g,3.4 mmol)於三級丁醇(13 mL,140 mmol)中之溶液中添加二碳酸二三級丁酯(3.5 mL,15 mmol)。將混合物在N
2下在50℃下攪拌隔夜。將反應物真空濃縮,得到粗殘餘物。殘餘物藉由正相層析純化,用10:1之石油醚:EtOAc溶離,得到標題化合物(1.6 g,全收量產率)。MS m/z 371.8 (M-Boc+H)。
在0℃下向3-溴-2-氟-4-甲基苯甲醛(2 g,6.6 mmol)於MeOH中之溶液中添加硼氫化鈉(620 mg,16 mmol)。攪拌混合物1小時。將混合物在N
2下用1 M HCl水溶液(30 mL)緩慢淬滅,調節至pH 6。將反應混合物真空濃縮,得到粗殘餘物。殘餘物藉由正相層析純化,用1:2之石油醚:EtOAc溶離,得到標題化合物(820 mg,51%產率)。
向(3-溴-2-氟-4-甲基苯基)甲醇(650 mg,2.7 mmol)、(3-羥苯基)胺基甲酸三級丁酯(870 mg,4.0 mmol)及四丁基膦(1.1 g,5.4 mmol)於THF (10 mL,120 mmol)中之溶液中添加N,N,N′,N′-四甲基偶氮二甲醯胺(940 mg,5.4 mmol)。將反應混合物在無水N
2下在室溫下攪拌2小時。將反應混合物分溶於EtOAc (100 mL)與水(100 mL)之間。合併之有機萃取物用鹽水(200 mL)洗滌,經Na
2SO
4乾燥,過濾且真空濃縮,得到粗殘餘物。殘餘物藉由正相層析純化,用9:1之石油醚:EtOAc溶離,得到標題化合物(1.2 g,96%產率)。MS m/z 355.8 (M-tBu+H)。
在0℃下向(3-((3-溴-2-氟-4-甲基苯甲基)氧基)苯基)胺基甲酸三級丁酯(0.82 g,1.8 mmol)於THF (5 mL,62 mmol)中之溶液中添加氯化異丙基鎂氯化鋰錯合物之THF溶液(3.1 mL,4.0 mmol,1.3 mol/L)且攪拌30分鐘。在0℃下將DMF (450 μL,5.7 mmol)添加至混合物中。使混合物升溫至室溫後保持1.5小時,接著藉由添加飽和NH
4Cl水溶液(5 mL)淬滅。將反應混合物分溶於EtOAc (30 mL)與水(30 mL)之間。將合併之有機萃取物真空濃縮,得到粗產物。殘餘物藉由正相層析純化,用95:5之石油醚:EtOAc溶離,得到標題化合物(220 mg,25%產率)。MS m/z 259.9 (M-Boc+H)。
將碳酸銫(230 mg,0.71 mmol)添加至(2-羥苯基)胺基甲酸三級丁酯(100 mg,0.47 mmol)及6-溴-3-(溴甲基)-2-氟-苯甲醛(160 mg,0.51 mmol)於DMF (3 mL)中之溶液中。將反應混合物在N
2下在室溫下攪拌1小時,且接著藉由添加水來淬滅。將反應混合物分溶於EtOAc (20 mL)與水(20 mL)之間。將合併之有機萃取物真空濃縮,得到粗產物。殘餘物藉由正相層析純化,用4:1之石油醚:EtOAc溶離,得到標題化合物(210 mg,全收量產率)。
1H NMR (400.21 MHz, DMSO):δ 10.24 (s, 1H), 8.08 (s, 1H), 7.82 (t, J= 7.9 Hz, 1H), 7.69 (d, J= 8.3 Hz, 1H), 7.63 (d, J= 7.6 Hz, 1H), 7.10 (dd, J= 1.0, 8.1 Hz, 1H), 7.06-7.02 (m, 1H), 6.95-6.91 (m, 1H), 5.21 (s, 2H), 1.44 (s, 9H)。
向硫代乙酸S-(2-((三級丁氧基羰基)胺基)苯甲基)酯(670 mg,2.2 mmol)於1,4-二㗁烷(10 mL)及水(2 mL)中之溶液中添加3-溴-2-氟-6-甲基-苯甲醛(550 mg,1.8 mmol)、2-二環己基膦基-2',4',6'-三異丙基聯苯(220 mg,0.44 mmol)、碳酸鉀(610 mg,4.4 mmol)及參(二苯亞甲基丙酮)二鈀(0) (210 mg,0.22 mmol)。將混合物加熱至100℃後保持隔夜。完成後,將反應混合物減壓濃縮。殘餘物用水(20 mL)稀釋且用EtOAc (20 mL × 2)萃取。合併之有機層用鹽水(40 mL)洗滌,經Na
2SO
4乾燥且真空濃縮,得到殘餘物。殘餘物藉由正相層析純化,用95:5之石油醚:EtOAc溶離,得到標題化合物(670 mg,54%產率)。MS m/z 275.9 (M-Boc+H)。
表15中之以下化合物以基本上類似於製備114中所描述之程序的方式製備。
表15:製備115至116
製備編號 | 結構 | ES/MS (m/z) (M+H) | 硫代酸酯SM |
115 | 398.2 (M+Na) | 硫代乙酸S-(3-((三級丁氧基羰基)胺基)苯甲基)酯 | |
116 | 275.9 (M-Boc+H) | 硫代乙酸S-(3-((三級丁氧基羰基)胺基)苯甲基)酯 |
在室溫下向(2-(((2-氟-3-(羥甲基)-4-甲基苯基)胺基)甲基)苯基)胺基甲酸三級丁酯(950 mg,2.4 mmol)於THF (20 mL)中之溶液中添加二氧化錳(2.2 g,25 mmol)。將所得混合物在70℃下攪拌隔夜。向不完全反應物中添加額外的二氧化錳(2.2 g,25 mmol),且在70℃下繼續攪拌4小時。完成後,反應混合物經由矽藻土墊過濾且用MeOH:DCM (1:1)洗滌,並且減壓濃縮濾液,得到粗產物。殘餘物藉由正相層析純化,用9:1之石油醚:EtOAc溶離,得到標題化合物(220 mg,20%產率)。MS m/z 359.0 (M+H)。
表16中之以下化合物以基本上類似於製備117中所描述之程序的方式製備。
表16:製備118
製備編號 | 結構 | ES/MS (m/z) (M+H) | 醇SM |
118 | 303.0 (M-tBu+H) | (3-(((2-氟-3-(羥甲基)-4-甲基苯基)胺基)甲基)苯基)胺基甲酸三級丁酯 |
將(3-(溴甲基)苯基)胺基甲酸三級丁酯(2.0 g,6.7 mmol)及硫代乙酸鉀(1.6 g,14 mmol)溶解於DMF (9 mL,120 mmol)中,且在N
2下在室溫下攪拌2小時。反應物藉由添加飽和NH
4Cl水溶液(20 mL)淬滅且用EtOAc (3 × 30 mL)萃取。合併之有機萃取物用鹽水(20 mL)洗滌,經Na
2SO
4乾燥,過濾且真空濃縮,得到粗產物。殘餘物藉由正相層析純化,用17:3之石油醚:EtOAc溶離,得到標題化合物(1.8 g,89%產率)。MS m/z 225.9 (M-tBu+H)。
向(4-硝基苯甲基)膦酸二乙酯(1.7 g,6.1 mmol)及15-冠-5 (1.3 g,5.7 mmol)於DMF (30 mL)中之溶液中添加含氫化鈉之油(340 mg,8.5 mmol,60質量%)。在0℃下攪拌30分鐘之後,在N
2下添加6-溴-2-氟-3-甲醯基苯甲酸甲酯(1.5 g,5.7 mmol)。1.5小時後,藉由添加飽和NH
4Cl水溶液(40 mL)淬滅反應物以沈澱出黃色固體。藉由抽吸過濾收集固體,用水洗滌且真空乾燥,得到標題化合物(2.2 g,89%產率)。MS m/z 379.9, 381.9 (M+H)。
向(E)-2-氟-6-甲基-3-(4-硝基苯乙烯基)苯甲酸甲酯(710 mg,2.2 mmol)於MeOH (15 mL)中之溶液中添加鈀(650 mg,0.31 mmol)及二碳酸二三級丁酯(0.57 mL,2.5 mmol)。將混合物在H
2(15 psi)下在室溫下攪拌2小時。反應混合物經由矽藻土墊過濾,且減壓濃縮濾液,得到粗產物。殘餘物藉由正相層析純化,用3:2之石油醚:EtOAc溶離,得到標題化合物(620 mg,69%產率)。
1H NMR (400.21 MHz, DMSO):δ 9.24 (s, 1H), 7.34 (d, J= 8.3 Hz, 2H), 7.26 (t, J= 7.9 Hz, 1H), 7.05 (dd, J= 8.2, 14.8 Hz, 3H), 3.87 (s, 3H), 2.86-2.68 (m, 4H), 2.26 (s, 3H), 1.47 (s, 10H)。
在連接迪恩-斯達克(Dean-Stark)分水器的情況下,使(3-((4-溴-2-氟-3-甲醯基苯氧基)甲基)苯基)胺基甲酸三級丁酯(1.0 g,2.5 mmol)、乙二醇(0.55 mL,9.8 mmol)及對甲苯磺酸一水合物(47 mg,0.25 mmol)於甲苯(16 mL,150 mmol)中之溶液在135℃下回流1小時。將反應溶液冷卻至室溫且用水(15 mL)及EtOAc (25 mL)稀釋。分離各相,且用EtOAc萃取水相。合併之有機層經Na
2SO
4乾燥,過濾且蒸發,得到粗殘餘物。殘餘物藉由正相層析純化,用24:1之DCM:MeOH溶離,得到標題化合物(1.2 g,44%產率)。MS m/z 486.8 (M+NH
4)。
替代製備122 (3-((4-溴-3-(1,3-二氧雜環戊-2-基)-2-氟苯氧基)甲基)苯基)胺基甲酸三級丁酯
在連接迪恩-斯達克分水器的情況下,使6-溴-2-氟-3-羥基苯甲醛(1.04 g,4.75 mmol)、乙二醇(1.1 mL,20 mmol)及對甲苯磺酸一水合物(88 mg,0.46 mmol)於甲苯(32 mL)中之溶液在135℃下回流1小時。將反應溶液冷卻至室溫且用水(15 mL)洗滌。分離各相。有機層經Na
2SO
4乾燥,過濾且蒸發,得到粗殘餘物。殘餘物藉由正相層析純化,用20:1之DCM:MeOH溶離,得到4-溴-3-(1,3-二氧雜環戊-2-基)-2-氟-苯酚(1.06 g,4.03 mmol)。將此物質溶解於DMF (8.0 mL)中且添加碳酸鉀(1.40 g,10.1 mmol)。在室溫下攪拌此混合物5分鐘。然後添加3-(溴甲基)苯基胺基甲酸三級丁酯(1.21 g,4.23 mmol)且攪拌混合物75分鐘。混合物接著用水(40 mL)稀釋且用EtOAc (40 mL)萃取。分離各相。有機層經Na
2SO
4乾燥,過濾且蒸發,得到粗殘餘物。殘餘物藉由正相層析純化,用3:1之EtOAc:己烷溶離,得到(3-((4-溴-3-(1,3-二氧雜環戊-2-基)-2-氟苯氧基)甲基)苯基)胺基甲酸三級丁酯(1.72 g,3.66 mmol,77%產率)。MS m/z 485.0, 487.2 (M+NH
4)。
其中K為氫或甲基。
將(3-((4-溴-3-(1,3-二氧雜環戊-2-基)-2-氟苯氧基)甲基)苯基)胺基甲酸三級丁酯(400 mg,0.85 mmol)、乙烯基三氟硼酸鉀(0.14 g,1.0 mmol)及碳酸銫(0.84 g,2.6 mmol)放入用N
2吹掃之25 mL微波小瓶中。添加THF (9 mL)及水(1 mL,56 mmol)。藉由在次表面鼓泡通入N
25分鐘使混合物脫氣,添加乙酸鈀(II) (10 mg,0.04 mmol),且將反應物加熱至100℃後保持隔夜。將反應物冷卻至室溫後保持3天。添加EtOAc及水,分離各相,且用EtOAc萃取水層兩次。合併之有機層經Na
2SO
4乾燥,過濾且濃縮,得到粗殘餘物。殘餘物藉由正相層析純化,用3:2之己烷:EtOAc溶離,得到標題化合物(320 mg,16%產率)。MS m/z 369.6 (M-H)。
表17中之以下化合物以基本上類似於製備123中所描述之程序的方式製備。
表17:製備124
製備編號 | 結構 | ES/MS (m/z) (M+H) | 硼酸鹽SM |
124 | 428.2 (M-H) | 三氟(丙-1-烯-2-基)硼酸鉀(I) |
將硫化之5wt%鉑/碳(0.057 g,0.29 mmol)添加至70 mL帕爾振盪瓶中,且用N
2脫氣。將5 mL EtOAc添加至瓶中,然後將含(3-((3-(1,3-二氧雜環戊-2-基)-2-氟-4-(丙-1-烯-2-基)苯氧基)甲基)苯基)胺基甲酸三級丁酯(0.231 g,0.538 mmol)之6 mL EtOAc添加至瓶中。將瓶密封,用N
2吹掃,用H
2吹掃,且在室溫下加壓至60 psi H
2後保持5小時。過濾反應混合物且濃縮,得到標題化合物(255 mg,全收量產率)。MS m/z 430.4 (M-H)。
在微波小瓶中,向(3-((4-溴-3-(1,3-二氧雜環戊-2-基)-2-氟苯氧基)甲基)苯基)胺基甲酸三級丁酯(240 mg,0.50 mmol)、氰化鋅(130 mg,1.1 mmol)及含氯化鋅之THF (1.0 mL,0.50 mmol,0.500 mol/L)於DMF (2.5 mL,32 mmol)中之混合物鼓泡通入N
2。添加肆(三苯基膦)鈀(0) (31 mg,0.03 mmol)。向反應混合物中鼓泡通入N
2,加蓋,且在110℃下微波處理1小時。添加額外的氰化鋅(120 mg,1.0 mmol)及肆(三苯基膦)鈀(0) (27 mg,0.02 mmol)。向反應混合物中鼓泡通入N
2,加蓋,且在120℃下微波處理30分鐘。反應溶液用水(15 mL)洗滌。有機層經Na
2SO
4乾燥,經由濾紙過濾且旋轉蒸發,得到粗殘餘物。殘餘物藉由正相層析純化,用7:3之己烷:EtOAc溶離,得到標題化合物(90 mg,43%產率)。MS m/z 412.6 (M-H)。
更特定言之,如下方流程17A中所示,使結構1a之化合物(其中R為H)與結構2之化合物(其中Pg及G如上文所定義)在一般熟習此項技術者熟知之條件下反應,得到式Ib及式Ic之化合物。
舉例而言,將約1當量的結構1a之化合物(其中R為H)及約1當量的結構2之化合物(其中Pg及G如流程17中所定義)懸浮於適合的有機溶劑(諸如乙腈)中。將懸浮液冷卻至約-10℃至約-25℃,且接著用約5當量的適合酸(諸如過氯酸(70%水溶液)或三氟乙酸)處理。然後使反應混合物升溫至室溫且攪拌約1至8小時。可添加額外有機溶劑,諸如乙腈及二甲基甲醯胺,且將混合物再攪拌約2小時。然後使用標準條件(諸如用飽和碳酸氫鈉水溶液)淬滅反應物,且使用此項技術中熟知的標準技術來分離產物,諸如用適合之有機溶劑(諸如二氯甲烷:異丙醇)萃取,經硫酸鎂乾燥有機萃取物,過濾且真空濃縮,得到粗產物混合物。此粗混合物可經純化,且使用此項技術中熟知之技術分離式Ib及式Ic之產物,該等技術諸如層析,包括例如用適合的溶離劑(諸如MeOH/DCM)進行正相層析及用適合的溶離劑(諸如2:1之10 mM碳酸氫銨水+5%甲醇:乙腈)進行逆相層析。
實例 1(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-2-氟-6-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮
在-10℃下將過氯酸(70%水溶液,4.8 mL)添加至(8S,9S,10R,11S,13S,14S,16R,17S)-11,16,17-三羥基-17-(2-羥基乙醯基)-10,13-二甲基-7,8,9,11,12,14,15,16-八氫-6H-環戊并[a]菲-3-酮(4.4 g,12 mmol,亦稱為「16α-羥基潑尼松龍(16alpha-hydroxyprednisolone)」)及N-[3-[(2-氟-3-甲醯基-4-甲基-苯氧基)甲基]苯基]胺基甲酸三級丁酯(4.0 g,11 mmol,製備4)於乙腈(110 mL)中之懸浮液中,且使其升溫至室溫。1小時後,在室溫下將DMF (10 mL)添加至懸浮液中。18小時後,將反應物用飽和碳酸氫鈉水溶液淬滅,且用9:1之二氯甲烷:異丙醇萃取。合併有機層;經硫酸鎂乾燥;過濾且減壓濃縮,得到殘餘物。殘餘物藉由逆相層析純化,用1:1之10 mM碳酸氫銨水+5%甲醇:乙腈溶離,得到標題化合物(峰1) (1.72 g,25%產率)。ES/MS m/z 618.6 (M+H)。
1H NMR (400.13 MHz, d
6-DMSO) δ 0.93-0.87 (m, 6H), 1.40 (s, 3H), 1.71-1.60 (m, 1H), 1.89-1.76 (m, 4H), 2.18-2.12 (m, 2H), 2.29 (s, 4H), 4.23-4.17 (m, 1H), 4.32-4.30 (m, 1H), 4.50-4.43 (m, 1H), 4.81 (d, J= 3.2 Hz, 1H), 4.98-4.95 (m, 3H), 5.16-5.10 (m, 3H), 5.61 (s, 1H), 5.95 (s, 1H), 6.18-6.15 (m, 1H), 6.53-6.48 (m, 2H), 6.58 (s, 1H), 6.90-6.86 (m, 1H), 6.99 (t, J= 7.7 Hz, 1H), 7.12 (t, J= 8.5 Hz, 1H), 7.33-7.30 (m, 1H)。
實例 2(6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-2-氟-6-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮
根據實例1,殘餘物藉由逆相層析純化,用1:1之10 mM碳酸氫銨水+5%甲醇:乙腈溶離,得到標題化合物(峰2) (1.24 g,18%產率)。ES/MS m/z 618.6 (M+H)。
1H NMR (400.13 MHz, d
6-DMSO) δ
1H NMR (400.13 MHz, DMSO):0.88 (s, 3H), 1.24-1.12 (m, 2H), 1.40 (s, 3H), 1.69-1.56 (m, 1H), 1.91-1.76 (m, 4H), 2.08-2.01 (m, 2H), 2.22 (s, 3H), 2.39-2.29 (m, 1H), 3.18 (d, J= 5.2 Hz, 1H), 4.12-4.00 (m, 1H), 4.37-4.30 (m, 2H), 4.79 (d, J= 3.1 Hz, 1H), 5.00-4.93 (m, 2H), 5.10-5.06 (m, 3H), 5.31 (d, J= 6.7 Hz, 1H), 5.95 (s, 1H), 6.18 (dd, J= 1.8, 10.1 Hz, 1H), 6.34 (s, 1H), 6.53-6.48 (m, 2H), 6.58 (s, 1H), 6.87 (d, J= 8.5 Hz, 1H), 6.99 (t, J= 7.7 Hz, 1H), 7.09 (t, J= 8.5 Hz, 1H), 7.33 (d, J= 10.1 Hz, 1H)。
實例 3(6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-2-氟-6-甲基苯基)-7-羥基-6a,8a-二甲基-8b-(2-(((2R,3R,4S,5R,6R)-3,4,5-三羥基-6-(羥甲基)四氫-2H-哌喃-2-基)氧基)乙醯基)-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮
將三乙酸(2R,3S,4S,5R,6R)-2-(乙醯氧基甲基)-6-(2-((6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-2-氟-6-甲基苯基)-7-羥基-6a,8a-二甲基-4-側氧基-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氫-8bH-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-8b-基)-2-側氧基乙氧基)四氫-2H-哌喃-3,4,5-三基酯(40 mg,0.04 mmol,製備5)添加至甲醇(2 mL)及碳酸鉀(20 mg,0.20 mmol)中。1小時後,將混合物裝載至矽藻土上,且藉由逆相層析純化,用1:2之10 mM碳酸氫銨水+5%甲醇:乙腈溶離,得到標題化合物(19 mg,57%產率)。ES/MS m/z 780.4 (M+H)。
1H NMR (500.11 MHz, d
6-DMSO) δ 0.90 (s, 3H), 1.28-1.27 (m, 2H), 1.41 (s, 3H), 1.72-1.69 (m, 1H), 1.92-1.88 (m, 4H), 2.11-2.10 (m, 2H), 2.22 (s, 3H), 2.40-2.35 (m, 1H), 3.50-3.46 (m, 1H), 3.57-3.53 (m, 1H), 3.64-3.61 (m, 1H), 4.17-4.15 (m, 1H), 4.34-4.32 (m, 1H), 4.43-4.39 (m, 2H), 4.57-4.52 (m, 1H), 4.64-4.62 (m, 1H), 4.75-4.72 (m, 2H), 5.00-4.93 (m, 3H), 5.12-5.08 (m, 2H), 5.31-5.29 (m, 1H), 5.95 (d, J= 0.4 Hz, 1H), 6.20-6.17 (m, 1H), 6.34 (s, 1H), 6.54-6.49 (m, 2H), 6.59 (s, 1H), 6.88 (d, J= 8.5 Hz, 1H), 7.00 (t, J= 7.7 Hz, 1H), 7.12-7.08 (m, 1H), 7.35-7.33 (m, 1H)。
實例4 (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-2-氟-6-甲氧基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮
在-20℃下向(3-((2-氟-3-甲醯基-4-甲氧基苯氧基)甲基)苯基)胺基甲酸三級丁酯(2.6 g,6.9 mmol,製備8)及16α-羥基潑尼松龍(2.5 g,6.6 mmol)於乙腈(100 mL)中之懸浮液中逐滴添加過氯酸(70%水溶液,3.3 mL,5當量)。在-20℃下攪拌混合物7小時。將溶液轉移至分液漏斗。將溶液逐滴添加至氫氧化鈉水溶液(7.5 mL 5N NaOH水溶液於1 L水中)中。添加完成後,pH經量測為5,且用5N NaOH水溶液將pH調節至8。攪拌懸浮液10分鐘。藉由真空過濾收集固體且用水洗滌固體。固體在過濾器上乾燥隔夜。固體藉由逆相層析純化,用1:1之10 mM碳酸氫銨水+5%甲醇:乙腈溶離,得到標題化合物(峰1) (804 mg,18%產率)。MS m/z 634.2 (M+H)。
1H NMR (399.8 MHz, d
6-DMSO) δ 7.33 (d, J= 10.1 Hz, 1H), 7.17 (t, J= 9.2 Hz, 1H), 6.98 (t, J= 7.8 Hz, 1H), 6.76 (dd, J= 1.0, 9.2 Hz, 1H), 6.56 (d, J= 1.6 Hz, 1H), 6.52-6.48 (m, 2H), 6.17 (dd, J= 1.9, 10.1 Hz, 1H), 5.96 (s, 1H), 5.71 (s, 1H), 5.17 (t, J= 6.0 Hz, 1H), 5.10 (s, 2H), 4.94-4.90 (m, 3H), 4.79 (d, J= 3.1 Hz, 1H), 4.44-4.38 (m, 1H), 4.33-4.31 (m, 1H), 4.22-4.15 (m, 1H), 3.70 (s, 3H), 2.37-2.33 (m, 1H), 2.14-2.04 (m, 2H), 1.96-1.88 (m, 1H), 1.82-1.70 (m, 3H), 1.64-1.56 (m, 1H), 1.41 (s, 3H), 0.86 (s, 5H)。
實例 5(6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-2-氟-6-甲氧基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮
根據實例4,殘餘物藉由逆相層析純化,用1:1之10 mM碳酸氫銨水+5%甲醇:乙腈溶離,得到標題化合物(峰2) (1.19 g,27%產率)。MS m/z 634.2 (M+H)。
1H NMR (399.8 MHz, d
6-DMSO) δ 7.32 (d, J= 10.0 Hz, 1H), 7.17-7.12 (m, 1H), 6.99 (t, J= 7.7 Hz, 1H), 6.72 (d, J= 8.8 Hz, 1H), 6.58 (s, 1H), 6.53-6.46 (m, 3H), 6.18 (dd, J= 1.7, 10.1 Hz, 1H), 5.95 (s, 1H), 5.25 (d, J= 6.5 Hz, 1H), 5.10 (s, 2H), 5.00-4.90 (m, 3H), 4.78 (d, J= 3.1 Hz, 1H), 4.37-4.31 (m, 2H), 4.02-3.96 (m, 1H), 3.63 (s, 3H), 2.34-2.31 (m, 1H), 2.11-2.02 (m, 2H), 1.88-1.76 (m, 4H), 1.60-1.54 (m, 1H), 1.40 (s, 3H), 1.23-1.18 (m, 2H), 0.87 (s, 3H)。
實例 5 之替代製備所有固體處理步驟皆在拋棄式手套袋中進行處理,包括向燒瓶中裝入16α-羥基潑尼松龍、固體過濾步驟及固體轉移步驟。
在2 L圓底燒瓶中,在-25℃下向(3-((2-氟-3-甲醯基-4-甲氧基苯氧基)甲基)苯基)胺基甲酸三級丁酯(25 g,67 mmol,製備8)及16α-羥基潑尼松龍(25 g,65 mmol)於ACN (1000 mL)中之懸浮液中逐滴添加含過氯酸之水(31 mL,330 mmol,10.6 mol/L)。在-20℃下攪拌混合物,同時藉由LCMS監測反應。內部溫度監測顯示,在添加過氯酸時有少量放熱。藉由添加乾冰保持內部溫度低於-19℃。保持混合物低於-19℃持續2小時,且接著使其升溫至-10℃。將混合物分成兩份,且分別逐滴添加至兩個分別含有76 mL含5 M NaOH水溶液之2 L水的燒杯(燒杯1及燒杯2)中。添加時會形成固體,且測試過氯酸之完全淬滅(pH 10)。將各添加步驟產生之黏性固體轉移且合併至含有含10% MeOH之DCM的第三燒杯(燒杯3)中。攪拌混合物直至黏性固體完全溶解。剩餘溶液(燒杯1及燒杯2)隨後經由濾紙過濾以收集殘餘固體。將分離出的固體用水沖洗且轉移至燒杯3中。攪拌燒杯3直至所有固體溶解。溶液經Na
2SO
4乾燥2小時,過濾且蒸發,得到棕褐色泡沫狀物。收集固體後之濾液用三份含10% IPA之DCM萃取。合併之有機萃取物在攪拌下經Na
2SO
4乾燥隔夜,然後過濾且蒸發,得到額外粗殘餘物。將粗產物溶解於150 mL含1% MeOH之DCM中,且藉由正相層析,使用0-5% MeOH/DCM純化,得到固體。其用600 mL EtOH稀釋,且在45℃下在旋轉蒸發器上離心5分鐘。將加熱槽上調至60℃。當加熱槽達到60℃時,關掉加熱槽,且旋轉燒瓶,直至浴液達到室溫。將燒瓶自旋轉蒸發器取出,加蓋,且在室溫下靜置隔夜。
在手套袋中,藉由真空過濾收集固體。固體用EtOH沖洗,且在過濾器上乾燥5小時。將固體再溶解於含20% EtOH之DCM (1.5 L)中。添加額外DCM,獲得近澄清溶液(仍有一些混濁度)。藉由在450 mbar及45℃下旋轉蒸發以移除DCM來達成溶劑交換。一旦停止蒸餾時,即降低壓力至100 mbar,以排出EtOH至約600 mL。自旋轉蒸發器移出混合物且使其在室溫下靜置5小時。藉由真空過濾收集固體且用額外的EtOH洗滌固體兩次。將濾餅在室溫下在真空烘箱中乾燥48小時,得到標題化合物(42 g,38%產率)。MS m/z 634.6 (M+H)。
對縮醛異構體進行二維通過空間ROE NMR分析,始終得到呈
R構型的H22 (縮醛)及H16之交叉峰。替代地,呈
S構型之H22始終產生約1 ppm之較大位移。所有其他化合物基本上藉由相同方法進行分配。
表18a中之以下化合物以基本上類似於實例1至4中所描述之程序的方式製備,其利用如上文所描述之對應製備及表2至17中所製備或使用一般熟習此項技術者熟知之標準程序所製備的結構1a之對應起始物質及結構2之起始物質。最終產物之純化基本上藉由以下方法進行:
A. C18管柱,使用溶離劑含10 mM NH
4HCO
3之水+5% MeOH:ACN
B. C18管柱,使用溶離劑含0.1% FA之水:ACN
C. SFC Chiralpak AY,使用溶離劑EtOH + 0.05% DEA:CO
2D. Chiralpak IC,使用溶離劑MeOH + 0.2% IPAm
E. SFC Lux Amylose-2,使用溶離劑IPA + 0.5% DMEA:CO
2F. SFC Chiralpak AD-H,使用溶離劑IPA + 0.5% DMEA:CO
2G. Chiralpak IC,使用溶離劑EtOH + 0.1% NH
3H
2O:庚烷
H. SFC Chiralpack AD,使用溶離劑IPA + 0.1% NH
3H
2O:CO
2I. Chiralcel IH,使用溶離劑EtOH+ACN (0.1% DEA):庚烷
J. SFC Chiralpak AD,使用溶離劑EtOH + 0.5% DEA:CO
2K. Chiralpak IE,使用溶離劑EtOH + 0.1% NH
3H
2O:ACN
L. Chiralpak AD-H,使用溶離劑EtOH:ACN + 0.2% IPAm
M. Chiralpak AD-H,使用溶離劑EtOH:ACN
N. SFC Chiralpak IC,使用溶離劑EtOH + 0.05% DMEA:CO
2O. SFC Chiralcel OJ-H,使用溶離劑MeOH + 0.5% DMEA:CO
2表18a:實例6至158 (結構)
表18b:實例6至158 (化學名稱)
實例編號 | 化學名稱 |
6 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-(4-胺基苯甲基)苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
7 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-(4-胺基苯甲基)苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
8 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-(3-胺基苯甲基)苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
9 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-(3-胺基苯甲基)苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
10 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-(2-胺基苯甲基)苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
11 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-(2-胺基苯甲基)苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
12 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-(4-胺基苯氧基)苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
13 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-(4-胺基苯氧基)苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
14 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-(3-胺基苯氧基)苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
15 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-(3-胺基苯氧基)苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
16 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-2-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
17 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(5-((3-胺基苯甲基)氧基)-2-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
18 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(5-((3-胺基苯甲基)氧基)-2-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
19 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
20 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
21 | (6aR,6bS,7S,8aS,8bS,10RS,11aR,12aS,12bS)-10-(5-((3-胺基苯甲基)氧基)-2-氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
22 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(5-((3-胺基苯甲基)氧基)-2-氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
23 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-4-氯苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
24 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-4-氯苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
25 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-5-氯苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
26 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-5-氯苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
27 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(5-((3-胺基苯甲基)氧基)-2-氯苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
28 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(5-((3-胺基苯甲基)氧基)-2-氯苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
29 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-5-氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
30 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-5-氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
31 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-2-氯苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
32 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-2-氯苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
33 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3'-胺基-[1,1'-聯苯]-3-基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
34 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3'-胺基-[1,1'-聯苯]-3-基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
35 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-5-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
36 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-5-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
37 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-2-氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
38 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-2-氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
39 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4'-胺基-[1,1'-聯苯]-3-基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
40 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(4'-胺基-[1,1'-聯苯]-3-基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
41 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-2-氯-6-氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
42 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(2-((3-胺基苯甲基)氧基)苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
43 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-2-氯-6-氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
44 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(2-((3-胺基苯甲基)氧基)苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
45 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(2-((3-胺基苯甲基)氧基)-6-氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
46 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(2-((3-胺基苯甲基)氧基)-6-氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
47 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-6-氯-2-氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
48 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-6-氯-2-氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
49 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-2,6-二氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
50 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-2,6-二氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
51 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(2-((3-胺基苯甲基)氧基)-6-氯苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
52 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(2-((3-胺基苯甲基)氧基)-6-氯苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
53 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(5-(4-胺基苯甲基)-2-氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
54 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(5-(4-胺基苯甲基)-2-氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
55 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)胺基)-2-氟-6-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
56 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((2-胺基苯甲基)氧基)-2-氟-6-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
57 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((2-胺基苯甲基)氧基)-2-氟-6-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
58 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-2,4-二氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
59 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-2,4-二氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
60 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-6-氟-2-甲氧基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
61 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-6-氟-2-甲氧基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
62 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((2-(胺基甲基)苯甲基)氧基)-2-氟-6-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
63 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((2-(胺基甲基)苯甲基)氧基)-2-氟-6-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
64 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((2-胺基苯甲基)胺基)-2-氟-6-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
65 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((2-胺基苯甲基)硫代)-2-氟-6-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
66 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)硫代)-2-氟-6-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
67 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((2-胺基苯氧基)甲基)-2-氟-6-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
68 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-胺基苯氧基)甲基)-2-氟-6-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
69 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-(((3-胺基苯基)胺基)甲基)-2-氟-6-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
70 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-(((2-胺基苯基)胺基)甲基)-2-氟-6-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
71 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-(((2-胺基苯基)硫代)甲基)-2-氟-6-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
72 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-(((3-胺基苯基)硫代)甲基)-2-氟-6-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
73 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)胺基)-2-氟-6-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
74 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(5-((3-胺基苯甲基)氧基)-2-(三氟甲氧基)苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
75 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-(胺基甲基)苯甲基)氧基)-2-氟-6-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
76 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((3-(胺基甲基)苯甲基)氧基)-2-氟-6-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
77 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((2-胺基苯甲基)氧基)-2-氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
78 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((2-胺基苯甲基)氧基)-2-氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
79 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(5-((3-胺基苯甲基)氧基)-2-(三氟甲氧基)苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
80 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(5-((2-胺基苯甲基)氧基)-2-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
81 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(5-((2-胺基苯甲基)氧基)-2-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
82 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((2-胺基苯甲基)氧基)-2,6-二氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
83 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((2-胺基苯甲基)氧基)-2,6-二氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
84 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-(4-胺基苯乙氧基)-2-氟-6-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
85 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-(3-胺基苯乙氧基)-2-氟-6-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
86 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)(甲基)胺基)-2-氟-6-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
87 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-(4-胺基苯乙基)-2-氟-6-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
88 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(5-((3-胺基苯甲基)氧基)-2-甲氧基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
89 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(5-((3-胺基苯甲基)氧基)-2-甲氧基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
90 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-2-甲氧基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
91 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-2-甲氧基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
92 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(5-((3-胺基苯甲基)氧基)-2-溴苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
93 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(5-((3-胺基苯甲基)氧基)-2-溴苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
94 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((2-胺基苯甲基)氧基)-2-氯-6-氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
95 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((2-胺基苯甲基)氧基)-2-氯-6-氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
96 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-6-氟-2-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
97 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-6-氟-2-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
98 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((2-胺基苯甲基)氧基)-2-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
99 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((2-胺基苯甲基)氧基)-2-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
100 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((2-胺基苯甲基)氧基)-2-氟-6-甲氧基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
101 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((2-胺基苯甲基)氧基)-2-氟-6-甲氧基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
102 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-(((3-胺基苯基)硫代)甲基)-2-氟-6-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
103 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-(((2-胺基苯基)硫代)甲基)-2-氟-6-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
104 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-(((2-胺基苯基)胺基)甲基)-2-氟-6-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
105 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-(((3-胺基苯基)胺基)甲基)-2-氟-6-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
106 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((3-胺基苯氧基)甲基)-2-氟-6-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
107 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((2-胺基苯氧基)甲基)-2-氟-6-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
108 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)硫代)-2-氟-6-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
109 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((2-胺基苯甲基)硫代)-2-氟-6-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
110 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((2-胺基苯甲基)胺基)-2-氟-6-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
111 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-(3-胺基苯乙氧基)-2-氟-6-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
112 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)(甲基)胺基)-2-氟-6-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
113 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-(4-胺基苯乙基)-2-氟-6-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
114 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-(4-胺基苯乙氧基)-2-氟-6-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
115 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(5-(4-胺基苯氧基)-2-甲氧基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
116 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(5-(3-胺基苯氧基)-2-甲氧基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
117 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-6-溴-2-氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
118 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-6-溴-2-氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
119 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-2-溴苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
120 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(5-((2-胺基苯甲基)氧基)-2-甲氧基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
121 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(5-((2-胺基苯甲基)氧基)-2-甲氧基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
122 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-((3-胺基苯甲基)氧基)-3-氟-[1,1'-聯苯]-2-基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
123 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(4-((3-胺基苯甲基)氧基)-3-氟-[1,1'-聯苯]-2-基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
124 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(5-((3-胺基苯甲基)氧基)-2-碘苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
125 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(5-((3-胺基苯甲基)氧基)-2-碘苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
126 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(5-((3-胺基苯甲基)氧基)-2-(苯硫-2-基)苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
127 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((3-胺基苯基)乙炔基)-2-氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
128 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-胺基苯基)乙炔基)-2-氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
129 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-2,6-二甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
130 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-2,6-二甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
131 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(5-((3-胺基苯甲基)氧基)-2-(呋喃-3-基)苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
132 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(5-((3-胺基苯甲基)氧基)-2-(呋喃-3-基)苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
133 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(5-((3-胺基苯甲基)氧基)-2-乙氧基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
134 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(5-((3-胺基苯甲基)氧基)-2-乙氧基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
135 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)胺基)-2,6-二甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
136 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)胺基)-2,6-二甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
137 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-2-溴苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
138 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-2-氟-6-異丙基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
139 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-2-氟-6-異丙基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
140 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((2-胺基苯甲基)氧基)-6-氯-2-氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
141 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(5-(3-胺基苯甲基)-2-氯苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
142 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(5-(4-胺基苯甲基)-2-氯苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
143 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-(3-胺基苯甲基)-6-氯-2-氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
144 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(5-((3-胺基苯甲基)氧基)-2-(呋喃-2-基)苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
145 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(5-((3-胺基苯甲基)氧基)-2-(呋喃-2-基)苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
146 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-(4-胺基苯甲基)-6-氯-2-氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
147 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-2-氟-4-甲氧基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
148 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-2-氟-4-甲氧基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
149 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-(3-胺基苯甲基)-2,6-二氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
150 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-6-環丙基-2-氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
151 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-6-環丙基-2-氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
152 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-((3-胺基苯甲基)氧基)-[1,1'-聯苯]-2-基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
153 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(4-((3-胺基苯甲基)氧基)-[1,1'-聯苯]-2-基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
154 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)硫代)-2-氟-4-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
155 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-2-氟-6-乙烯基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
156 | (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)氧基)-2-氟-6-乙烯基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
157 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-(3-胺基苯甲基)-2,6-二氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
158 | (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((3-胺基苯甲基)硫代)-2-氟-4-甲基苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮 |
實例 1594-((3-胺基苯甲基)氧基)-3-氟-2-((6aR,6bS,7S,8aS,8bS,10S,11aR,12aS, 12bS)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-4-側氧基-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-10-基)苯甲腈
在0℃下將三氟甲磺酸(920 μL,10 mmol)逐滴添加至16α-羥基潑尼松龍(140 mg,0.36 mmol)及(3-((4-氰基-3-(1,3-二氧雜環戊-2-基)-2-氟苯氧基)甲基)苯基)胺基甲酸三級丁酯(140 mg,0.34 mmol)於ACN (5 mL,95 mmol)中之懸浮液中。反應物用飽和NaHCO
3水溶液淬滅且用含10% IPA之DCM萃取。合併之有機層經MgSO
4乾燥,過濾且濃縮,得到粗殘餘物。粗殘餘物藉由逆相純化進行純化,用1:1之含10 mM NH
4HCO
3之水+5% MeOH:ACN溶離,得到標題化合物(12 mg,6%產率)。MS m/z 630.0 (M+H)。
1H NMR (400.13 MHz, d
6-DMSO) δ 7.70-7.67 (m, 1H), 7.45-7.41 (m, 1H), 7.33 (d, J= 10.1 Hz, 1H), 7.04-7.00 (m, 1H), 6.61-6.51 (m, 3H), 6.45 (s, 1H), 6.20-6.17 (m, 1H), 5.95 (s, 1H), 5.37-5.35 (m, 1H), 5.15 (s, 4H), 4.86-4.84 (m, 1H), 4.32-4.31 (m, 2H), 4.07-4.01 (m, 1H), 2.14-2.12 (m, 2H), 1.92-1.88 (m, 4H), 1.67-1.66 (m, 1H), 1.40-1.39 (m, 3H), 1.25-1.20 (m, 2H), 0.89-0.88 (m, 3H)。
hGR 共活化劑募集分析使用來自Life Technologies之LanthaScreen TR-Fret GR共活化劑分析(A15899)來量測糖皮質素化合物之活性。以3倍10點連續稀釋將化合物聲學轉移至分析盤中,最高濃度為200 nM。將十微升GR-LBD之2×溶液添加至化合物盤中且培育10分鐘。接著將十微升經螢光素-SRC1-4及Tb標記之抗GST抗體之2×溶液添加至盤中。將盤避光培育兩小時,接著在Envision盤讀取器上讀數,其中在340 nm下激發且在520 nm (螢光素)及490 nm (鋱)下發射。在Genedata中分析520/490之發射比率。為了獲得活性百分比,將資料與DMSO之陰性對照及4 µM地塞米松(dexamethasone)之陽性對照進行比較。以下例示化合物遵循如上文基本上所描述之程序進行測試且展現如表19中所列之以下活性。
表19:hGR共活化劑募集分析中實例1、2、4及5之化合物的活體外效力
實例編號 | IC 50(nM) |
1 | 2.12 |
2 | 1.44 |
4 | 2.47 |
5 | 1.40 |
實例6至44、46至51、53至79及81至158之化合物得到小於200 nM之相對IC
50。實例45、52及80之化合物得到大於200 nM之相對IC
50。
Claims (39)
- 如請求項1之化合物,其中R 3為NH 2,或其醫藥學上可接受之鹽。
- 如請求項1或請求項2之化合物,其中R為H,或其醫藥學上可接受之鹽。
- 如請求項1至4中任一項之化合物,其中R 1為C1-C3烷基,或其醫藥學上可接受之鹽。
- 如請求項1至4中任一項之化合物,其中R 1為CH 3,或其醫藥學上可接受之鹽。
- 如請求項1至4中任一項之化合物,其中R 1為C1-C3烷氧基,或其醫藥學上可接受之鹽。
- 如請求項1至4中任一項之化合物,其中R 1為OCH 3,或其醫藥學上可接受之鹽。
- 如請求項1至4中任一項之化合物,其中R 1為F,或其醫藥學上可接受之鹽。
- 如請求項1至9中任一項之化合物,其中R 2為F,或其醫藥學上可接受之鹽。
- 如請求項1至10中任一項之化合物,其中X為OCH 2,或其醫藥學上可接受之鹽。
- 如請求項1至10中任一項之化合物,其中X為O,或其醫藥學上可接受之鹽。
- 如請求項1至10中任一項之化合物,其中X為CH 2,或其醫藥學上可接受之鹽。
- 如請求項1至10中任一項之化合物,其中X為SCH 2,或其醫藥學上可接受之鹽。
- 如請求項1至10中任一項之化合物,其中X為鍵,或其醫藥學上可接受之鹽。
- 一種治療患者之異位性皮膚炎的方法,其包含向需要此類治療之患者投與有效量的如請求項1至30中任一項之化合物或其醫藥學上可接受之鹽。
- 一種治療患者之類風濕性關節炎的方法,其包含向需要此類治療之患者投與有效量的如請求項1至30中任一項之化合物或其醫藥學上可接受之鹽。
- 如請求項1至30中任一項之化合物或其醫藥學上可接受之鹽,其用於療法中。
- 如請求項1至30中任一項之化合物或其醫藥學上可接受之鹽,其用於治療異位性皮膚炎。
- 如請求項1至30中任一項之化合物或其醫藥學上可接受之鹽,其用於治療類風濕性關節炎。
- 一種如請求項1至30中任一項之化合物或其醫藥學上可接受之鹽的用途,其用於製造供治療異位性皮膚炎之藥劑。
- 一種如請求項1至30中任一項之化合物或其醫藥學上可接受之鹽的用途,其用於製造供治療類風濕性關節炎之藥劑。
- 一種醫藥組合物,其包含如請求項1至30中任一項之化合物或其醫藥學上可接受之鹽及一或多種醫藥學上可接受之載劑、稀釋劑或賦形劑。
- 一種製備醫藥組合物之方法,其包含摻合如請求項1至30中任一項之化合物或其醫藥學上可接受之鹽與一或多種醫藥學上可接受之載劑、稀釋劑或賦形劑。
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