TW202404574A - 用於捕捉介白素-1 β之環狀肽 - Google Patents
用於捕捉介白素-1 β之環狀肽 Download PDFInfo
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- TW202404574A TW202404574A TW112121925A TW112121925A TW202404574A TW 202404574 A TW202404574 A TW 202404574A TW 112121925 A TW112121925 A TW 112121925A TW 112121925 A TW112121925 A TW 112121925A TW 202404574 A TW202404574 A TW 202404574A
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- bip4co2h
- pharmaceutically acceptable
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- 108010069514 Cyclic Peptides Proteins 0.000 title description 8
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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Abstract
本發明提供式(I)化合物或其醫藥上可接受之鹽,其中X1、X2、X3、A1、A2、R1-R7、R8a、R8b、R9a、R9b、R10及R11係如本文中所闡述,
Description
本發明係關於某些捕捉介白素-1β (IL-1β)之環狀肽、包括該等肽之醫藥組合物及使用該等化合物來治療、抑制或改善一或多種可受益於捕捉IL-1β之心血管疾病狀態(包含動脈粥樣硬化)之方法。
動脈粥樣硬化特徵在於膽固醇斑塊累積於動脈內壁上之動脈疾病。動脈粥樣硬化之進展可硬化或窄化動脈並增加斑塊破裂之風險。該等破裂將膽固醇小球及其他物質釋放至血流中,此可阻止血液流向腦、心臟或其他器官。在醫學上,該等現象稱為重大不良心臟事件(MACE)。
動脈粥樣硬化性心血管疾病(ASCVD)之發生及進展之風險因子包含高膽固醇、高血壓、高飽和脂肪性飲食、吸煙、肥胖症、糖尿病、缺乏運動及C反應蛋白(CRP,一種發炎標記物)之含量升高。
用以預防ASCVD進展之一線治療係健康飲食及運動,然而,順從性通常較差。用於ASCVD之藥理學治療主要著眼於降膽固醇劑(例如斯他汀(statin))、膽固醇吸收抑制劑及低密度脂蛋白(LDL)受體抑制劑。該等藥劑可高度有效地減小脂肪酸沈積物之積累並改良動脈健康。不改善疾病狀態之開具用於ASCVD之其他藥劑包含用以防止血小板凝集於窄動脈中之薄血劑(例如阿司匹林(aspirin))及用以減小心臟病發作之風險及嚴重程度的血壓劑。用於晚期ASCVD病例中之更積極干預之手術選擇包含血管成形術、支架置入、動脈內膜切除術(斑塊之手術去除)及旁路手術。
儘管降膽固醇劑已用作用於減緩動脈粥樣硬化之進展之重要護理標準,但臨床數據證實了在仍未治療之ASCVD進展之發炎中之另一關鍵作用。發炎生物標記物(例如CRP)與增加之心血管事件風險有關且獨立於膽固醇含量。卡那單抗(Canakinumab)抗發炎性血栓形成結果研究(CANTOS)係用於展示在不存在伴隨脂質降低下減少血管發炎可減小心血管事件之發生率之第一臨床試驗。
N Engl J Med2017;377:1119-1131。卡那單抗係經批準用於風濕病病症臨床應用之抗介白素-1 β (IL-1β)人類單株抗體。IL-1β係誘導IL-6且由此升高下游發炎性生物標記物高敏性CRP (hsCRP)之促發炎性細胞介素。因此,CANTOS提供關於靶向IL-1β之療法可以與降LDL標準護理互補且可能增益之方式減小某些患者中之MACE發生率之概念驗證。
需要除標準護理降膽固醇劑外之用於減緩動脈粥樣硬化進展並降低MACE風險之其他非手術性治療方式。另外,患有發炎性病症之患者將受益於經口投與與卡那單抗阻斷相同細胞介素IL-1β之藥劑。
本發明提供某些環狀肽,其藉由結合至IL-1β細胞介素來減少發炎並防止與IL-1受體銜接,從而抑制下游促發炎性信號傳導。該等環狀肽可為用於治療心血管疾病及發炎性病症之有價值之醫藥活性化合物。在一態樣中,本發明提供式(I)化合物:
及其醫藥上可接受之鹽。
該等化合物可捕捉IL-1β且由此影響可與心血管病症有關之下游促發炎性信號傳導路徑。因此,在另一態樣中,本發明提供治療心血管病症(例如動脈粥樣硬化、血管發炎)之方法,其包括向有需要之受試者投與治療有效量之本發明化合物。在一些實施例中,投與包括經口投與化合物。
本發明另外提供製備本發明化合物之製程及包括本發明化合物及醫藥上可接受之載劑之醫藥組合物。
電子提交之序列表之參考
本申請案含有以XML格式電子提交之序列表且其全文以引用方式併入本文中。XML檔案於2023年5月25日創建,命名為25545-WO-PCT_SL.XML,且大小為916,839個位元組。
本發明化合物
在一實施例中,本發明提供具有如上文所展示結構式(I)之化合物,其中:
R1係CH3C(O)NH-CH2CH2-O-或C1;
C1係:
(i) 5至6員單環芳基或雜芳基,其中該雜芳基含有1至2個選自由N、O及S組成之群之雜原子;或
(ii) 5至6員單-或雙環、飽和環烷基或雜環烷基,其含有1至2個選自由N、O及S組成之群之雜原子;或
(iii) 5至6員單-或雙環環烷基;
其中C1未經取代或由1至3個獨立地選自由以下組成之群之RC1取代基取代:鹵基、C1-C3烷基、C1-C3氟烷基、羧基、C1-C3烷氧基及C2-C3醯基;
R
2係H、C1-C3烷基、苄基或苯基-CH2CH2-;
R3係9至10員雙環芳基或雜芳基,其中該雜芳基含有1至2個選自由N、O及S組成之群之雜原子;
其中R3未經取代或由1至3個獨立地選自由以下組成之群之R3a取代基取代:鹵基、C1-C3烷基、C1-C3氟烷基、羥基及C1-C3烷氧基;
R4係C1-C3烷基、HO2C-(CH2)m-、H2NC(O)-(CH2)m-、(CH3)2NC(O)-(CH2)m-或四唑基-(CH2)m-;
R5係胺基、H2N(CH2)n-、H2NC(O)-(CH2)n-、CH3C(O)NH-、CH3C(O)NH(CH2)n-、C5或C5-CH2-,
C5係:
(i) 5至6員單環芳基或雜芳基,其中該雜芳基含有1至2個選自由N、O及S組成之群之雜原子;
(ii) 9至10員雙環芳基或雜芳基,其中該雙環雜芳基含有1至3個選自由N、O及S組成之群之雜原子;
(iii) 5至6員單環或9至10員雜環烷基,其中該雜環烷基係飽和或部分不飽和的,且含有1至2個選自由N、O及S組成之群之雜原子;
(iv) 5至6員單環環烷基;
(v) 2,3-二氫吲哚基;
其中C5未經取代或由1至3個獨立地選自由以下組成之群之RC5取代基取代:鹵基、胺基、羥基、C1-C3烷基、C1-C3氟烷基、C1-C3烷氧基、H2N-(CH2)k-、H2NC(O)-(CH2)k-、H2C=CH-CH2O-及苯基;
R6係H、C1-C5烷基、H2N(CH2)p-、HOCH2-、(CH3)2NCH2-、H3CO-(CH2)q-或C6-CH2-;
C6係含有1至2個選自由N、O及S組成之群之雜原子之5-或6員單環、飽和雜環烷基;且其中C6未經取代或由1至3個獨立地選自由以下組成之群之RC6取代基取代:鹵基、C1-C3烷基、C1-C3氟烷基、羥基及C1-C3烷氧基;
R7係H或C1-C3烷基;
R8a係H、C1-C5烷基、HOCH2-、H2N(CH2)r-、(CH
3)
3N
+(CH2)r-或CH3C(O)NH(CH2)r-;
R8b係H或C1-C3烷基;
R9a係H或C1-C3烷基;
R9b係H、C1-C5烷基、C9-CH2-或C9-CH2CH2-;
C9係:
(i) 5至6員單環芳基或雜芳基,其中該雜芳基含有1至2個選自由N、O及S組成之群之雜原子;或
(ii) 5至6員單環、飽和環烷基或雜環烷基,其中該雜環烷基含有1至2個選自由N、O及S組成之群之雜原子;
其中C9未經取代或由1至3個獨立地選自由以下組成之群之RC9取代基取代:鹵基、胺基、羥基、氰基、C1-C3烷基、C1-C3氟烷基、C1-C3烷氧基、H2N-(CH2)k-、H2NC(O)-(CH2)k-、H2NCH2CH2O-、CH3C(O)NH-CH2CH2O-及嗎啉基-CH2CH2O-;
R
10係H、鹵基或C1-C3烷基;
R
11係H、鹵基或C1-C3烷基;
下標k在每次出現時獨立地係1或2;
下標m為1或2;
下標n為1、2、3、或4;
下標p為1、2、3、或4;
下標q為1或2;
下標r為1、2、3、或4;
X1、X2及X3獨立地係C(H)或N;且
A1及A2獨立地選自由以下組成之群:HO2C-、H2NC(O)-、CH3C(O)N(H)-、H2NS(O)2-、CH
3S(O)2N(H)-、四唑基及5-側氧基噁二唑基;或
其醫藥上可接受之鹽。
在另一實施例中,本發明提供式(I)化合物,其中:
R5係胺基、H2N(CH2)n-、H2NC(O)-(CH2)n-、C5或C5-CH2-,
C5係:
(i) 5至6員單環芳基或雜芳基,其中該雜芳基含有1至2個選自由N、O及S組成之群之雜原子;
(ii) 9至10員雙環芳基或雜芳基,其中該雙環雜芳基含有1至3個選自由N、O及S組成之群之雜原子;
(iii) 5至6員單環或9至10員雜環烷基,其中該雜環烷基係飽和或部分不飽和的,且含有1至2個選自由N、O及S組成之群之雜原子;或
(iv) 2,3-二氫吲哚基;
其中C5未經取代或由1至3個獨立地選自由以下組成之群之RC5取代基取代:鹵基、胺基、羥基、C1-C3烷基、C1-C3氟烷基、C1-C3烷氧基、H2N-(CH2)k-、H2NC(O)-(CH2)k-、H2C=CH-CH2O-及苯基;
R6係H、C2-C5烷基、H2N(CH2)p-、HOCH2-、(CH3)2NCH2-、H3CO-(CH2)q-或C6-CH2-;
R8a係H、C1-C3烷基、HOCH2-或H2N(CH2)r-;
R9a係H;
R9b係H、C1-C3烷基、C9-CH2-或C9-CH2CH2-;
R10係H;
R11係H;
下標p為1、2或3;且
下標r為2、3或4。
在一實施例中,式(I)化合物具有結構式(IA):
(IA)。
在另一實施例中,本發明提供式(I)化合物,其中:
C1係苯基、嘧啶基或六氫吡嗪基,其中C1未經取代或由1至2個RC1取代基取代;
R3係萘基或吲哚基,其中R3未經取代或由1至2個R3a取代基取代;
C5係苯基、吡啶基、嘧啶基、萘基、吲哚基、7-氮雜吲哚基、吲唑基、2,3-二氫吲哚基、六氫吡啶基、四氫吡喃基或環己基,其中C5未經取代或由1至2個RC5取代;
C6係四氫吡喃基或嗎啉基;其中C6未經取代或由1至2個RC6取代;且
C9a係H或甲基;
C9b係苯基、吡啶基、環己基、嗎啉基或六氫吡啶基,其中C9未經取代或由1至2個RC9取代。
在另一實施例中,本發明提供式(I)化合物,其中:
X1及X2係C(H);且
R1係由羧基取代之苯基。
在另一實施例中,本發明提供式(I)化合物,其中:
X1及X2係C(H);且
R1係CH3C(O)NH-CH2CH2-O-。
在另一實施例中,本發明提供式(I)化合物,其中R2係H。
在另一實施例中,本發明提供式(I)化合物,其中R3係由一個鹵基取代之吲哚基。
在另一實施例中,本發明提供式(I)化合物,其中R3係萘基。
在另一實施例中,本發明提供式(I)化合物,其中R4係HO2C-(CH2)m-。
在另一實施例中,本發明提供式(I)化合物,其中X3係C(H)。
在另一實施例中,本發明提供式(I)化合物,其中R5係H2N(CH2)n-、吲哚、7-氮雜吲哚、萘基或吡啶基。
在另一實施例中,本發明提供式(I)化合物,其中R5係H2N(CH2)n-、吲哚、萘基或吡啶基。
在另一實施例中,本發明提供式(I)化合物,其中R6係H、HOCH2-、C2-C5烷基或H2N(CH2)p-。
在另一實施例中,本發明提供式(I)化合物,其中R6係C2-C5烷基或H2N(CH2)p-。
在另一實施例中,本發明提供式(I)化合物,其中R7係H。
在另一實施例中,本發明提供式(I)化合物,其中:
R8a係甲基或H2NCH2CH2-;且
R8b係H。
在另一實施例中,本發明提供式(I)化合物,其中R9b係
。
在另一實施例中,本發明提供式(I)化合物,其中R9b係
。
在一實施例中,本發明提供式(I)化合物,其中A1係選自由以下組成之群:HO2C-、H2NC(O)-、CH3C(O)N(H)-、H2NS(O)2-、CH
3S(O)2N(H)-、四唑基及5-側氧基噁二唑基。熟習化學技術者應認識到,該胺基酸殘基中之該等部分可由下列子結構展示:
。
在一實施例中,本發明提供式(I)化合物,其中A2係選自由以下組成之群:HO2C-、H2NC(O)-、CH3C(O)N(H)-、H2NS(O)2-、CH
3S(O)2N(H)-、四唑基及5-側氧基噁二唑基。熟習化學技術者應認識到,該胺基酸殘基中之該等部分可由下列子結構展示:
。
在另一實施例中,本發明提供式(I)化合物,其中:
R10係H;且
R11係H、F或Cl。
在另一實施例中,本發明提供式(I)化合物,其中A1及A2皆係HO2C- (亦即羧基)。
在一些實施例中,本發明提供式(I)化合物,其中:
R1係4-CH3C(O)-六氫吡嗪-1-基、CH3C(O)NH-CH2CH2-O-、5-CO
2H-嘧啶-2-基或4-CO2H-苯基;
R
2係H、乙基、苄基或苯基-CH2CH2-;
R3係萘-1-基、4-氟吲哚-3-基或4-氯吲哚-3-基;
R4係甲基、HO2C-(CH2)m-或H2NC(O)-(CH2)m-;
R5係胺基、H2N(CH2)n-、萘-1-基、吲哚-3-基、7-氮雜-吲哚-3-基、吲唑-1-基、2,3-二氫吲哚-1-基、吡啶-3-基、吡啶-4-基、六氫吡啶-4-基、3-胺基甲基苯基、4-胺基甲基苯基、3-胺基苯基、4-胺基苯基、苯基、吡啶-4-基-CH2-、嘧啶-5-基、四氫吡喃-4-基-、H2NC(O)-(CH2)2-、3-聯苯、3-CH2=CH-CH2O-苯基、CH3C(O)NH-、CH3C(O)NH(CH2)3-或環己基;
R6係H、(CH3)2CHCH2-、(CH3)3CCH2-、H2N(CH2)p-、HOCH2-、H3CCH2CH2-、嗎啉-4-基-CH2-、四氫吡喃-4-基-CH2-、(CH3)2NCH2-或H3CO-(CH2)q-。
R
7係H或甲基;
R8a係H、甲基、HOCH2-、H2N(CH2)r-、(CH
3)
3NCH2CH2-或CH3C(O)NH(CH2)4-;
R8b係H或甲基;
R9a係H或甲基;
R9b係H、甲基、H3CCH2CH2CH2-、4-HO-苯基-CH2CH2-、苯基-CH2CH2-、環己基-CH2CH2-、5-NC-吡啶-3-基-CH2CH2-、4-F3C-苯基-CH2-、3-F3C-苯基-CH2-、2-F3C-苯基-CH2-、嗎啉-4-基-CH2CH2O-苯基-CH2-、4-胺基苯基-CH2-、4,4-二氟環己基-CH2-、4-H2NCH2CH2O-苯基-CH2-、4-H2NCH2CH2O-吡啶-3-基-CH2-、六氫吡啶-4-基-CH2-或4-CH3C(O)NH-CH2CH2O-苯基-CH2-;
R10係H、氟或甲基;
R11係H、氟或氯;
A1及A2皆係HO2C-;且
X1、X2及X3係C(H)。
在某些實施例中,本發明提供式(I)化合物,其中:
R1係4-CH3C(O)-六氫吡嗪-1-基、CH3C(O)NH-CH2CH2-O-、5-CO
2H-嘧啶-2-基或4-CO2H-苯基;
R
2係H、乙基、苄基或苯基-CH2CH2-;
R3係萘-1-基、4-氟吲哚-3-基或4-氯吲哚-3-基;
R4係甲基、HO2C-(CH2)m-或H2N(O)C-(CH2)m-;
R5係胺基、H2N(CH2)n-、萘-1-基、吲哚-3-基、7-氮雜-吲哚-3-基、吲唑-1-基、2,3-二氫吲哚-1-基、吡啶-3-基、吡啶-4-基、六氫吡啶-4-基、3-胺基甲基苯基、4-胺基甲基苯基、3-胺基苯基、4-胺基苯基、苯基、吡啶-4-基-CH2-、嘧啶-5-基、四氫吡喃-4-基-、H2N(O)C-(CH2)2-、3-聯苯或3-CH2=CH-CH2O-苯基,
R6係H、(CH3)2CHCH2-、H2N(CH2)p-、HOCH2-、H3CCH2CH2-、嗎啉-4-基-CH2-、四氫吡喃-4-基-CH2-、(CH3)2NCH2-或H3CO-(CH2)q-。
R7係H或甲基;
R8a係H、甲基、HOCH2-或H2N(CH2)r-;
R8b係H或甲基;
R9a係H;
R9b係H、甲基、4-HO-苯基-CH2CH2-、苯基-CH2CH2-、5-NC-吡啶-3-基-CH2CH2-、4-F3C-苯基-CH2-、3-F3C-苯基-CH2-、2-F3C-苯基-CH2-、嗎啉-4-基-CH2CH2O-苯基-CH2-、4-胺基苯基-CH2-、4,4-二氟環己基-CH2-、4-H2NCH2CH2O-苯基-CH2-、4-H2NCH2CH2O-吡啶-3-基-CH2-、六氫吡啶-4-基-CH2-或4-CH3C(O)NH-CH2CH2O-苯基-CH2-;
R10及R11皆係H;且
A1及A2皆係HO2C-。
在一些實施例中,本發明提供式(I)化合物,其中該化合物係選自由如表1中所示SEQ ID NO:1-215組成之群。在某些實施例中,本發明提供式(I)化合物,其中該化合物係選自由如表1中所示SEQ ID NO:1-173組成之群。
在具體實施例中,本發明提供式(I)化合物,其中該化合物係選自由以下組成之群:(按出現順序分別係SEQ ID NO 78、71-72、67、65、70、69、68、66、64、77、79、209、193、215、212及210):
及
。
在一些實施例中,本發明提供式(I)化合物,其中該化合物係選自由以下組成之群:SEQ ID NO:78、71-72、67、65、70、69、68、66、64、77及79。
儘管不受限於任何具體理論,但申請者認為,本發明化合物會捕捉介白素-1β,防止經由IL-1受體之信號傳導且由此減少下游標記物IL-6及CRP。因此,該等化合物可用於治療心血管疾病之發炎性部分,例如ASCVD及射血分數保留型心臟衰竭(HFpEF)。該等化合物亦可用於治療發炎性病症,例如化膿性汗腺炎(反常性痤瘡)、發炎性腸病及骨關節炎。
定義
除非另有定義,否則本文所用之所有技術及科學術語具有與熟習本發明所屬技術者通常所理解相同之意義。
如本發明通篇所用,「本發明化合物(a compound of the disclosure、compound of the present disclosure)」及「本文所揭示之化合物」可互換使用且應理解為包含所揭示環狀肽及式(I)化合物。所提及之式(I)化合物包含屬式(I)範圍內之其他通式之化合物,包含(但不限於)式(IA)化合物。式(I)化合物可形成亦在本發明範圍內之鹽。除非另外指示,否則在本文中提及本發明化合物(或式(I)化合物)應理解為包含提及其鹽。本文所用之術語「鹽」表示利用無機及/或有機酸形成之酸性以及利用無機及/或有機鹼形成之鹼性鹽。另外,在式(I)化合物含有鹼性部分(例如(但不限於)胺基、吡咯啶或咪唑)及酸性部分(例如(但不限於)羧酸)時,兩性離子(「內鹽」)可形成且包含於本文所用之術語「鹽」內。在一實施例中,鹽係醫藥上可接受(亦即無毒、生理上可接受)之鹽。在另一實施例中,鹽並非醫藥上可接受之鹽。例如,可藉由使式(I)化合物與一定量(例如,1當量量)之酸或鹼在諸如使鹽沈澱之介質等介質中或在水性介質中反應且隨後實施凍乾來形成式(I)化合物之鹽。
「醯基」意指烷基-C(O)-基團,其中烷基係如下文所定義。連至母體基團係鍵係經由羰基之碳原子。
「烷基」以及具有前綴「alk」之其他基團(例如烷氧基及諸如此類)意指可為直鏈或具支鏈或其組合且含有所指示碳原子數之碳鏈。舉例而言,C
1-C
6烷基意指具有一個(亦即甲基)至最多6個碳原子(亦即己基)之烷基。在特定實施例中,直鏈烷基具有1-6個碳原子且具支鏈烷基具有3-7個碳原子。烷基之實例包含甲基、乙基、丙基、異丙基、丁基、第二丁基及第三丁基、戊基、己基、庚基、辛基、壬基及諸如此類。
「烷氧基」及「烷基-O-」可互換使用且係指與氧連接之烷基。
「胺基」意指H2N-基團。連至母體基團之鍵係經由氮原子。
「胺基酸」係指天然α-胺基酸及其立體異構體以及非天然胺基酸(例如β-胺基酸及經取代胺基酸)及其立體異構體。在本發明肽(化合物)給出之序列中,胺基酸殘基具有其習用含義。因此,「G」係甘胺酸,「W」係色胺酸,「A」係丙胺酸,「S」係絲胺酸,等等。應理解,「D」異構體由單字母代碼或胺基酸名稱前之「d」指定,從而例如dA係L-丙胺酸之D異構體。前文未涵蓋之胺基酸殘基具有下文實例章節之表格中所提供之定義。
本文所用之「芳基」代表單環6員或雙環10員環系統,其中至少一個環係芳香族,且所有環原子皆係碳。
「雙環系統」係指兩個接合環。環可為稠合環,亦即共有兩個毗鄰原子;或「螺環」,亦即僅共有單一原子。
「羧基」意指HO2C-基團。連至母體基團之鍵係經由羰基組分之碳原子。
「環烷基」意指飽和環狀烴基。在特定實施例中,環烷基具有3-12個碳原子,從而形成1-3個稠合碳環。環烷基之實例包含環丙基、環丁基、環戊基、環己基、環庚基、金剛烷基及諸如此類。
「氟烷基」包含經單取代以及多個氟取代之烷基,最多係經全氟取代之烷基。例如,包含氟甲基、1,1-二氟乙基、三氟甲基或1,1,1,2,2-五氟丁基。
除非另有指示,否則「鹵素」或「鹵基」包含氟(fluorine、fluoro)、氯(chlorine、chloro)、溴(bromine、bromo)及碘(iodine、iodo)。在一實施例中,鹵基係氟(-F)或氯(-Cl)。
「雜環烷基」意指包括約3至約10個環原子、較佳地約5至約10個環原子之非芳香族單環、雙環或三環系統,其中環系統中之一或多個原子係除碳外之元素(例如氮、氧或硫,單獨或組合)。在環系統中不存在毗鄰氧及/或硫原子。在一些實施例中,雜環烷基含有約5至約6個環原子。雜環基根名前之前綴氮雜、氧雜或硫雜意指,至少氮、氧或硫原子分別作為環原子存在。在一些實施例中,雜環烷基之氮或硫原子可視情況氧化成相應N-氧化物、S-氧化物或S,S-二氧化物。適宜單環雜環基環之非限制性實例包含六氫吡啶基、吡咯啶基、六氫吡嗪基、嗎啉基、硫嗎啉基、噻唑啶基、1,4-二噁烷基、四氫呋喃基、四氫吡喃基、四氫噻吩基及諸如此類。
「雜芳基」係指其中環中一或多個原子(雜原子)係不同於碳之元素之芳香族單環、雙環及三環結構。雜原子通常為O、S或N原子。雜芳香族基團之實例包含吡啶基、嘧啶基、吡咯基、噠嗪基、異噁唑基、噻唑基、噁唑基、吲哚基、苯并噁唑基、苯并噻唑基及咪唑基。
當任一變量(例如,R
C1)在本文之任一組分或式(I)或其他通式中出現一次以上時,其每次出現時之定義均獨立於其在其他每次出現時之定義。取代基及/或變量之組合僅在該等組合得到穩定化合物時才被允許。在選擇本發明化合物時,熟習此項技術者將意識到應遵照化學結構連接性及穩定性之熟知原則來選擇各種取代基(例如R
C9)。除非明確說明相反之情形,否則允許在環(例如,芳基、雜芳基環或飽和雜芳基環)中任一原子上由指定取代基取代,只要該環取代以化學方式容許且產生穩定化合物即可。「穩定」化合物係可製備並分離之化合物,且其結構及性質在足夠長時間內基本保持不變或可使其基本保持不變,以容許將該化合物用於本文所述之目的(例如,治療性或預防性投與受試者)。
術語「經取代」應視為包含經指定取代基之多個取代度。倘若揭示或主張多個取代基部分,則經取代之化合物可獨立地經一或多個所揭示或主張之取代基部分單一或複數地取代。獨立地經取代意指(兩個或更多個)取代基可相同或不同。
除非明確描述或另外闡述,否則結構式中以「浮動」鍵繪示之變量允許存在於環中變量所連接之任何可用碳原子上。當式(I)或其任一實施例中將一部分闡述為「視情況經取代」時,意味著式(I)或其實施例涵蓋在該部分上含有該所述取代基(或多個取代基)之化合物及亦涵蓋在該部分上不含該所述取代基(或多個取代基)之化合物。
本文所用之波浪線
指示與化合物其餘部分之連接點。
本文所闡述之一些化合物可作為具有不同的氫連接點連同一或多個雙鍵位移之互變異構體存在。例如,酮及其烯醇形式係酮-烯醇互變異構體。本發明化合物涵蓋個別互變異構體以及其混合物。
在本發明化合物中,各原子可展現其自然同位素豐度,或者可以人工方式使一或多種原子富含具有相同原子序數但原子質量或質量數不同於在自然界中主要發現之原子質量或質量數的具體同位素。如本文所闡述及主張之本發明意欲包含所有本發明化合物及其實施例之適宜同位素變化形式。例如,氫(H)之不同同位素形式包含氕(
1H)及氘(
2H,在本文中亦以D表示)。氕係自然界中發現之主要氫同位素。富含氘可提供某些治療優點,例如,增加活體內半衰期或減少劑量需求;或可提供可用作表徵生物試樣之標準的化合物。本發明之同位素富集化合物可無需過多實驗藉由熟習此項技術者所熟知之習用技術或藉由與闡述於本文反應圖及實例中之彼等類似製程使用適當的同位素富集試劑及/或中間體來製備。
術語「醫藥上可接受之鹽」係指自醫藥上可接受之無毒鹼或酸製備之鹽。在本發明化合物為酸性(或具有可為陰離子性之官能基)時,其相應鹽可方便地自醫藥上可接受之無毒鹼(包含無機鹼及有機鹼)製得。適宜無機陽離子之實例包含(但不限於)鹼金屬離子(例如Li+、Na+及K+)、鹼土金屬陽離子(例如Ca2+及Mg2+)及其他陽離子(例如Al3+及Zn+)。適宜有機陽離子之實例包含(但不限於)銨離子(亦即NH4+)及經取代銨離子。適宜經取代銨離子之實例係衍生自甲胺、乙胺、二乙胺、三乙胺及乙二胺之彼等。在本發明化合物為鹼性時,其相應鹽可方便地自醫藥上可接受之無毒酸(包含無機酸及有機酸)製得。該等酸加成鹽之實例包含來自氫鹵酸(例如鹽酸、氫溴酸、氫碘酸)、甲酸、乙酸、癸酸及檸檬酸形成之鹽。含有乙酸鹽、甲酸鹽、癸酸鹽、氯化物或鈉鹽之鹽常用於本發明化合物。在一些實施例中,本發明化合物之鹽可藉由熟習此項技術者所熟知之交換來形成,例如藉由陰離子交換,例如使用氯離子代替三氟乙酸根離子。
另外,本發明化合物可以非晶形形式及/或一或多種結晶形式存在,且因此式(I)化合物之所有非晶形形式及結晶形式及其混合物(包含實例)皆意欲包含在本發明範圍內。另外,一些本發明化合物可與水(亦即,水合物)或常見有機溶劑(例如(但不限於)乙酸或乙腈)形成溶劑合物。該等溶劑合物及水合物、具體而言本發明化合物之醫藥上可接受之溶劑合物及水合物連同非溶劑化及無水形式一起同樣涵蓋在本發明範圍內。
活體內轉化為在本發明範圍內之化合物之本發明化合物之任一醫藥上可接受之前藥改質亦在本發明範圍內。
本發明亦係關於製備式(I)化合物之製程,該等製程闡述於下文實例中且藉由該等製程可獲得本發明化合物。
「治療(treatment及treating)」係指可減緩、中斷、阻止、控制或停止本文所闡述疾病或病症之進展之所有過程。該等術語未必指示完全消除所有疾病或病症症狀。
本文所用之「預防(preventing或prophylaxis)」係指減小感染本文所闡述疾病或病症之可能性,或減小本文所闡述疾病或病症之嚴重程度。
術語「治療有效(effective或efficacious)量」及類似闡述(例如「有效用於治療之量」或「有效劑量」)欲指將引發研究者、獸醫、醫師或其他臨床醫師所尋求的組織、系統、動物或人類之生物學或醫學反應之本發明化合物之量。在一較佳實施例中,術語「治療有效量」意指緩解人類患者之至少一種臨床症狀之本發明化合物之量。術語「預防有效(effective或efficacious)量」及類似闡述(例如「有效用於預防之量」)欲指研究者、獸醫、醫師或其他臨床醫師所尋求的在組織、系統、動物或人類中預防或降低生物學或醫學事件發生之風險之本發明化合物之量。
本發明化合物之劑量
根據包含以下之各種因素來選擇利用本發明化合物之劑量方案:患者之類型、物種、年齡、體重、性別及醫學狀況;擬治療病狀之嚴重程度;經選擇用於投與之化合物之效能;投與途徑;及患者之腎及肝功能。熟習此項技術之臨床醫師出於確定為預防、抵製或阻止病狀之進展所需要之治療有效或預防有效的劑量量之目的會充分考慮該等因素。應理解,特定日劑量量可同時為用於(例如)治療腫瘤病狀之治療有效量及用於(例如)預防腫瘤病狀之預防有效量。
儘管個體需要有所變化,但熟習此項技術者熟知本發明化合物之有效量最佳範圍之確定。對於投與人類以治癒性或預防性治療本文所鑑別之病狀及病症而言,舉例而言,本發明化合物之典型劑量可為約0.05 mg/kg/天至約50 mg/kg/天。在一些實施例中,向患者投與約5 mg/天至約120 mg/天(例如10 mg/天、20 mg/天、30 mg/天、40 mg/天、50 mg/天、60 mg/天、70 mg/天、80 mg/天、mg/天、90 mg/天或100 mg/天)之本發明化合物。在某些實施例中,向患者投與約0.2 mg/kg至約5 mg/kg (例如0.5 mg/kg、0.75 mg/kg、1.0 mg/kg、1.25 mg/kg或1.5 mg/kg)之本發明化合物。該等劑量可以單一劑量投與或可分成多個劑量。
醫藥組合物
可將本發明化合物及其醫藥上可接受之鹽作為醫藥自身、以彼此之混合物或以醫藥組合物形式投與動物、較佳地哺乳動物且具體而言人類。術語「受試者」或「患者」包含動物、較佳地哺乳動物及尤其人類,其使用本發明活性劑用於預防或治療醫學病狀。將藥物投與受試者包含自投與及由另一個人投與患者。受試者可需要或期望現有疾病或醫學病狀之治療,或可需要或期望用以預防或降低該疾病或醫學病狀發生之風險之預防性治療。如本文中所使用,「需要」現有病狀之治療或預防性治療之受試者涵蓋由醫學專業人才確定之需要以及患者對該治療之期望。
本發明由此亦提供用作醫藥之本發明化合物及其醫藥上可接受之鹽、其用於調節細胞介素IL-1β之活性之用途及尤其其用於治療及預防下文所提及疾病或病症之用途以及其用於製備用於該等目的之藥劑之用途。在某些實施例中,本發明化合物及其醫藥上可接受之鹽會捕捉IL-1β。
另外,本發明提供醫藥組合物,其包括有效劑量之至少一種本發明化合物及/或其醫藥上可接受之鹽作為活性組分及常用的醫藥上可接受之載劑(亦即,一或多種醫藥上可接受之載劑物質及/或添加劑)。
因此,本發明提供(例如)用作包括有效劑量之本發明化合物及/或其醫藥上可接受之鹽作為活性組分及常用的醫藥上可接受之載劑之醫藥組合物之該化合物及其醫藥上可接受之鹽;及該化合物及/或其醫藥上可接受之鹽在治療或預防下文所提及疾病或病症(例如動脈粥樣硬化)之用途;以及其用於製備用於該等目的之藥劑之用途。
本發明醫藥組合物可以(例如)丸劑、錠劑、塗漆錠劑、糖包衣錠劑、顆粒、硬及軟明膠膠囊、水性、醇性或油性溶液、糖漿、乳液或懸浮液形式經口投與或(例如)以栓劑形式經直腸投與。投與亦可以注射或輸注用溶液形式以非經腸方式(例如經皮下、經肌內或經靜脈內)實施。
其他適宜投與形式係(例如)經皮或局部投與,例如以軟膏、酊劑、噴霧劑或經真皮治療系統或例如微膠囊、植入體或棒劑之形式。較佳投與形式取決於(例如)擬治療之疾病及其嚴重程度。
本發明亦提供包括式(I)化合物之醫藥組合物。式(I)化合物可與任何適宜之醫藥載劑或賦形劑組合使用。該等醫藥組合物包括治療有效量之一或多種式(I)化合物及醫藥上可接受之賦形劑及/或載劑。特定醫藥組合物將受益於投與模式。在特定態樣中,醫藥可接受之載劑可為水或緩衝溶液。
醫藥組合物中所包含之賦形劑端視(例如)藥物性質及投與模式而具有不同目的。常用賦形劑之實例包含(但不限於):鹽水、緩衝鹽水、右旋糖、注射用水、甘油、乙醇及其組合、穩定劑、增溶劑及表面活性劑、緩衝劑及防腐劑、張力劑、增積劑、潤滑劑(例如滑石粉或二氧化矽及脂肪,例如植物硬脂精、硬脂酸鎂或硬脂酸)、乳化劑、懸浮或黏度劑、惰性稀釋劑、填充劑(例如纖維素、磷酸氫鈣、植物脂肪及油、乳糖、蔗糖、葡萄糖、甘露醇、山梨醇、碳酸鈣及硬脂酸鎂)、崩解劑(例如交聯聚乙烯基吡咯啶酮、羥基乙酸澱粉鈉、交聯羧甲基纖維素鈉)、結合劑(例如澱粉、明膠、纖維素、甲基纖維素或改質纖維素(例如微晶纖維素、羥丙基纖維素)、糖(例如蔗糖及乳糖)或糖醇(例如木糖醇、山梨醇或麥芽糖醇)、聚乙烯基吡咯啶酮及聚乙二醇)、潤濕劑、抗菌劑、螯合劑、包衣(例如纖維素膜包衣、合成聚合物、蟲膠、玉米蛋白zein或其他多醣及明膠)、防腐劑(包含維他命A、維他命E、維他命C、棕櫚酸視黃基酯及硒、半胱胺酸、甲硫胺酸、檸檬酸及檸檬酸鈉以及合成防腐劑(包含對羥基苯甲酸甲酯及對羥基苯甲酸丙酯))、甜味劑、芳香劑、矯味劑、著色劑、吸收增強劑、投與助劑及其組合。
在醫藥組合物之背景中,載劑係改良及/或延長活性成分向受試者之遞送之化合物及物質。載劑可用於延長藥物之活體內活性或減緩藥物在受試者中之釋放(使用受控釋放技術)。載劑亦可降低受試者中之藥物代謝及/或減小藥物之毒性。載劑亦可用於使藥物遞送靶向受試者中之特定細胞或組織。常用載劑(親水性及疏水性載劑)包含脂肪乳液、脂質、聚乙二醇化磷脂、聚乙二醇化脂質體、經由PEG間隔體使用環狀RGD肽塗覆之聚乙二醇化脂質體、脂質體及脂質球、微球體(包含由生物可降解聚合物或白蛋白製得之彼等)、聚合物基質、生物相容性聚合物、蛋白質-DNA複合物、蛋白質偶聯物、紅血球、囊泡、奈米顆粒及用於烴釘合之側鏈。亦可使用上文所提及載劑來增加式(I)化合物之細胞膜滲透性。除用於本發明之醫藥組合物中外,載劑亦可用於其他使用(例如活體外(例如用於遞送至培養細胞)及/或活體內研究應用)之組合物中。
適於經口投與之醫藥組合物可呈現為離散單位,例如膠囊或錠劑;呈現為粉劑或粒劑;呈現為溶液、糖漿或懸浮液(於水性或非水性液體中;或呈現為可食用發泡體或發泡物;或呈現為乳液)。用於錠劑或硬質明膠膠囊之適宜賦形劑包含乳糖、玉米澱粉或其衍生物、硬脂酸或其鹽。用於軟明膠膠囊之適宜賦形劑包含(例如)植物油、蠟、脂肪、半固體或液體多元醇等。對於溶液及糖漿之製備而言,可使用之賦形劑包含(例如)水、多元醇及糖。對於懸浮液之製備而言,可使用油(例如植物油)以提供水包油型或油包水型懸浮液。可包含促進胃腸道吸收之賦形劑,例如滲透增強劑,例如癸酸鈉。在某些情況下,延遲釋放製劑可較為有利且亦可製備可以延遲或受控釋放方式遞送本發明化合物之組合物。延長胃滯留會帶來存在於胃中之酶之降解問題,且由此亦可藉由業內標準技術來製備腸溶包衣膠囊,其中用於釋放之活性物質在胃腸道中有所降低。
適於經皮投與之醫藥組合物可以意欲保持與接受者表皮長期密切接觸之離散貼片形式呈現。舉例而言,該活性成分可藉由離子透入法自貼片遞送,如在
Pharmaceutical Research, 3(6), 318 (1986)中所概述。
適於局部投與之醫藥組合物可調配成軟膏、乳霜、懸浮液、洗劑、粉劑、溶液、膏糊、凝膠、噴霧劑、氣溶膠或油狀物。活性成分在調配於軟膏中時可與石蠟或水混溶性軟膏基質一起使用。或者,活性成分可於乳膏中與水包油型乳膏基質或油包水型基質調配在一起。適於局部投與眼之醫藥組合物包含滴眼劑,其中活性成分溶解或懸浮於適宜載劑、尤其水性溶劑中。適於口腔中之局部投與之醫藥組合物包含菱形錠劑、軟錠劑及口腔洗滌劑。
適於直腸投與之醫藥組合物可呈現為栓劑或灌腸劑。
適於經鼻投與之醫藥組合物(其中載劑係固體)包含具有(例如)在20至500微米範圍內之粒徑的粗粉末,其以鼻吸入方式投與,即,藉由經鼻腔自保持靠近鼻子處之粉末容器快速吸入。用於以鼻噴霧形式或以滴鼻劑形式投與之適宜組合物(其中載劑係液體)包含活性成分之水性或油性溶液。
適於藉由吸入投與之醫藥組合物包含可藉助各種類型之計量劑量、加壓氣溶膠、霧化器或吹入器生成之精細顆粒粉塵或霧劑。
適於陰道投與之醫藥組合物可作為子宮套、棉塞、乳霜、凝膠、膏糊、發泡體或噴霧調配物呈現。
適於非經腸投與之醫藥組合物包含水性及非水性無菌注射溶液,其可含有抗氧化劑、緩衝劑、抑菌劑及可使調配物實質上與預期受體之血液等滲的溶質;及水性及非水性無菌懸浮液,其可包含懸浮劑及增稠劑。可用於可注射溶液之賦形劑包含(例如)注射用水、醇、多元醇、甘油及植物油。該等組合物可以單位劑量或多劑量容器(例如,密封安瓿及小瓶)呈現且可儲存於冷凍乾燥(凍乾)條件下,僅需在即將使用前添加無菌液體載劑(例如,注射用水或鹽水)。臨時配製注射溶液及懸浮液可由無菌粉末、顆粒及錠劑製得。醫藥組合物可含有防腐劑、增溶劑、穩定劑、潤濕劑、乳化劑、甜味劑、著色劑、氣味劑、鹽(本發明物質可自身以醫藥上可接受之鹽形式提供)、緩衝劑、包衣劑或抗氧化劑。其亦可含有除本發明化合物外之治療活性劑。
使用本發明化合物之方法
本申請案提供IL-1介導之細胞信號傳導之方法,其包括使細胞與本發明化合物或其醫藥上可接受之鹽接觸。可藉由檢測下游生物標記物IL-6及CRP (例如hsCRP)之含量降低來評價IL-1介導之細胞信號傳導之抑制。
本申請案亦提供使用本發明化合物(或其醫藥上可接受之鹽)或含有該等化合物之醫藥組合物來治療疾病病狀(包含(但不限於)涉及IL-1β之病狀)之方法。
在一些實施例中,本發明提供治療心血管疾病之方法,該方法包括向需要該治療之受試者投與治療有效量之本發明化合物(或其醫藥上可接受之鹽)或任一包括此一化合物之前述醫藥組合物。在一些實施例中,心血管疾病係血管發炎。在一些實施例中,心血管疾病係動脈粥樣硬化。在一些實施例中,心血管疾病係射血分數保留型心臟衰竭(HFpEF)。在其他實施例中,心血管疾病係射血分數降低型心臟衰竭(HFrEF)。
在一些實施例中,本發明提供治療慢性腎病之方法,該方法包括向需要該治療之受試者投與治療有效量之本發明化合物(或其醫藥上可接受之鹽)或任一包括此一化合物之前述醫藥組合物。
在一些實施例中,本發明提供治療發炎性病症之方法,該方法包括向需要該治療之受試者投與治療有效量之本發明化合物(或其醫藥上可接受之鹽)或任一包括此一化合物之前述醫藥組合物。在某些實施例中,發炎性病症係選自由以下組成之群:化膿性汗腺炎(反常性痤瘡)、發炎性腸病、關節炎及非酒精性脂肪性肝炎(NASH)。
在一些實施例中,發炎性病症係化膿性汗腺炎(反常性痤瘡)。
在某些實施例中,發炎性病症係發炎性腸病,例如克羅恩氏病(Crohn’s disease)或潰瘍性結腸炎。
在一些實施例中,發炎性病症係關節炎,例如骨關節炎、類風濕性關節炎、牛皮癬性關節炎或痛風性關節炎。
在其他實施例中,發炎性病症係非酒精性脂肪性肝炎(NASH)。
組合療法
一或多種其他藥理學活性劑可與本發明化合物組合投與。一或多種其他活性劑欲指在體內具有活性之一或多種醫藥活性劑,包含不同於式I化合物之在投與之後轉化成醫藥活性形式之前藥,且亦包含該等其他活性劑之游離酸、游離鹼及醫藥上可接受之鹽。通常,任何適宜的一或多種其他活性劑(包含(但不限於)抗高血壓劑、抗動脈粥樣硬化劑(例如脂質改質化合物)、抗糖尿病劑及/或抗肥胖劑、抗發炎劑)可與本發明化合物之任一組合在單一劑量調配物(固定劑量藥物組合)中使用,或可以容許同時或連續投與活性劑(共投與分開活性劑)之一或多種分開劑量調配物投與受試者。
可用於治療心血管病症之其他活性劑之實例包含(但不限於)血管緊張素轉化酶抑制劑(例如阿拉普利(alacepril)、貝那普利(benazepril)、卡托普利(captopril)、西羅普利(ceronapril)、西拉普利(cilazapril)、地拉普利(delapril)、依那普利(enalapril)、依那普利拉(enalaprilat)、福辛普利(fosinopril)、咪達普利(imidapril)、賴諾普利(lisinopril)、莫維普利(moveltipril)、培哚普利(perindopril)、喹那普利(quinapril)、雷米普利(ramipril)、司派普利(spirapril)、替莫普利(temocapril)或群多普利(trandolapril))、血管緊張素II受體拮抗劑(例如氯沙坦(losartan) (亦即COZAAR®)、纈沙坦(valsartan) (包含與沙庫巴曲(sacubitril)之組合)、坎地沙坦(candesartan)、奧美沙坦(olmesartan)、替美沙坦(telmesartan)及與氫氯噻嗪(hydrochlorothiazide) (例如HYZAAR®)組合使用之該等藥物中之任一者);sGC活化劑(例如利奧西哌(riociguat)及維利西哌(vericiguat))、PCSK9抑制劑(例如依伏庫單抗(evolocumab)、阿裡羅單抗(alirocumab)、MK-0616及揭示於WO2019/246349中之彼等)、中性內肽酶抑制劑(例如硫甲基氧代苯丙甘胺酸(thiorphan)及磷醯二肽(phosphoramidon))、醛固酮拮抗劑、醛固酮合酶抑制劑、腎素抑制劑、內皮素受體拮抗劑、磷酸二酯酶-5抑制劑(例如西地那非(sildenafil)、他達拉非(tadalafil)及伐地那非(vardenafil))、血管舒張劑、鈣通道阻斷劑(例如胺氯地平(amlodipine)、硝苯地平(nifedipine)、維拉帕米(verapamil)、地爾硫卓(diltiazem)、戈洛帕米(gallopamil)、尼魯地平(niludipine)、尼莫地平(nimodipins)、尼卡地平(nicardipine))、鉀通道活化劑(例如尼可地爾(nicorandil)、吡那地爾(pinacidil)、色滿卡林(cromakalim)、米諾地爾(minoxidil)、阿普卡林(aprilkalim)、氯普唑侖(loprazolam))、利尿劑(例如氫氯噻嗪)、交感神經阻滯藥、β-腎上腺素能阻斷藥(例如普萘洛爾(propranolol)、阿替洛爾(atenolol)、比索洛爾(bisoprolol)、卡維地洛(carvedilol)、美托洛爾(metoprolol)或酒石酸美托洛爾)、α腎上腺素能阻斷藥(例如多沙唑嗪(doxazocin)、哌唑嗪(prazocin)或α甲基多巴(methyldopa))、中樞α腎上腺素能激動劑、周邊血管舒張劑(例如肼屈嗪(hydralazine));降脂質劑,例如HMG-CoA還原酶抑制劑(例如以ZOCOR®及MEVACOR®與內酯前藥形式銷售且在投與之後用作抑制劑之斯伐他汀(simvastatin)及洛伐他汀(lovastatin))及二羥基開環酸性HMGCoA還原酶抑制劑(例如阿托伐他汀(atorvastatin) (尤其以LIPITOR®出售之鈣鹽)、瑞舒伐他汀(rosuvastatin) (尤其以CRESTOR®出售之鈣鹽)、普伐他汀(pravastatin) (尤其以PRAVACHOL®出售之鈉鹽)、氟伐他汀(fluvastatin) (尤其以LESCOL®出售之鈉鹽)、西立伐他汀(crivastatin)及匹伐他汀(pitavastatin))之醫藥上可接受之鹽;膽固醇吸收抑制劑,例如依折麥布(ezetimibe) (ZETIA®)及與任何其他降脂質劑(例如上述HMG-CoA還原酶抑制劑)及尤其與斯伐他汀(VYTORIN®)或與阿托伐他汀鈣組合之依折麥布;呈立即釋放或受控釋放形式及/或與HMG-CoA還原酶抑制劑一起使用之尼亞新(niacin);尼亞新受體激動劑(例如阿西莫司(acipimox)及阿昔呋喃(acifran))以及尼亞新受體部分激動劑;代謝改變劑,包含胰島素及胰島素模擬物(例如德麩胰島素(insulin degludec)、甘精胰島素(insulin glargine)、賴脯胰島素(insulin lispro));二肽基肽酶-IV (DPP-4)抑制劑(例如西他列汀(sitagliptin)、阿洛列汀(alogliptin)、奧格列汀(omarigliptin)、利拉列汀(linagliptin)、維格列汀(vildagliptin));胰島素敏化劑,包含(i) PPARy激動劑,例如格列酮(glitazone) (例如吡格列酮(pioglitazone)、米格列酮(mitoglitazone)、洛貝格列酮(lobeglitazone)、羅格列酮(rosiglitazone)及柏格列酮(balaglitazone))及其他PPAR配體(包含(1) PPARα/γ雙重激動劑,例如西格列紮(chiglitazar)、莫格列紮(muraglitazar)、阿格列紮(aleglitazar)、索格列紮(sodelglitazar)及納格列紮(naveglitazar);(2) PPARα激動劑,例如非諾貝特酸(fenofibric acid)衍生物(例如吉非羅齊(gemfibrozil)、氯貝特(clofibrate)、環丙貝特(ciprofibrate)、非諾貝特(fenofibrate)、苯紮貝特(bezafibrate));(3)選擇性PPAR γ調節劑(SPPAR γ M)、(例如揭示於WO 02/060388、WO 02/08188、WO 2004/019869、WO 2004/020409、WO 2004/020408及WO 2004/066963中之彼等);及(4) PPAR γ部分激動劑);(ii)雙胍,例如二甲雙胍(metformin)及其醫藥上可接受之鹽,尤其二甲雙胍鹽酸鹽及其延長釋放調配物(例如Glumetza™、Fortamet™及GlucophageXR™);及(iii)蛋白質酪胺酸磷酸酶-1 B (PTP-1 B)抑制劑;胰島素或胰島素類似物(例如地特胰島素(insulin detemir)、麩賴胰島素(insulin glulisine)、德麩胰島素、甘精胰島素、賴脯胰島素及每一者之可吸入調配物);瘦素與瘦素衍生物及激動劑;澱粉素及澱粉素類似物(例如普蘭林肽(pramlintide));磺醯脲及非磺醯脲胰島素促泌素(例如甲苯磺丁脲(tolbutamide)、格列苯脲(glyburide)、格列吡嗪(glipizide)、格列美脲(glimepiride)、米格列奈(mitiglinide)、美格替耐(meglitinides)、那格列奈(nateglinide)及瑞格列奈(repaglinide));α-葡醣苷酶抑制劑(例如阿卡波糖(acarbose)、伏格列波糖(voglibose)及米格列醇(miglitol));升糖素受體拮抗劑;腸促胰液素模擬物,例如GLP-1、GLP-1類似物、衍生物及模擬物;及GLP-1受體激動劑(例如度拉糖肽(dulaglutide)、索馬魯肽(semaglutide)、阿必魯肽(albiglutide)、艾塞那肽(exenatide)、利拉魯肽(liraglutide)、利西拉肽(lixisenatide)、他司魯肽(taspoglutide),包含其鼻內、經真皮及每週一次性調配物);膽汁酸鉗合劑(例如考來替蘭(colestilan)、考來米德(colestimide)、考來維侖鹽酸鹽(colesevalam hydrochloride)、考來替泊(colestipol)、消膽胺(cholestyramine)及交聯右旋糖酐之二烷基胺基烷基衍生物)、醯基CoA:膽固醇醯基轉移酶抑制劑(例如阿伐麥布(avasimibe));抗肥胖化合物;意欲用於發炎性病狀中之藥劑,例如阿司匹林、非類固醇抗發炎藥或NSAID、糖皮質激素及選擇性環氧合酶-2或COX-2抑制劑;葡萄糖激酶活化劑(GKA);1型11 β-羥基類固醇去氫酶抑制劑(例如揭示於美國專利第6,730,690號中之彼等);果糖1,6-雙磷酸酶抑制劑(例如揭示於美國專利第6,054,587號、第6,110,903號、第6,284,748號、第6,399,782號及第6,489,476號中之彼等);乙醯基CoA羧基酶-1或2 (ACC1或ACC2)之抑制劑;AMP活化蛋白激酶(AMPK)活化劑;G蛋白偶合受體:(i) GPR-109、(ii) GPR-119及(iii) GPR-40之其他激動劑;SSTR3拮抗劑(例如揭示於WO 2009/001836中之彼等);神經介素U受體激動劑(例如揭示於WO 2009/042053中之彼等,包含(但不限於)神經介素S (NMS));SCD調節劑;GPR-105拮抗劑(例如揭示於WO 2009/000087中之彼等);SGLT抑制劑(例如恩格列淨(empagliflozin)、達格列淨(dapagliflozin)、卡格列淨(canagliflozin)、埃格列淨(ertugliflozin)、瑞格列淨(remogloflozin)、托格列淨(tofogliflozin)及伊格列淨(ipragliflozin));醯基輔酶A:二醯基甘油醯基轉移酶1及2 (DGAT-1及DGAT-2)之抑制劑;脂肪酸合酶抑制劑;醯基輔酶A:單醯基甘油醯基轉移酶1及2 (MGAT-1及MGAT-2)之抑制劑;TGR5受體(亦稱為GPBAR1、BG37、GPCR19、GPR131及M-BAR)之激動劑;回腸膽汁酸轉運蛋白抑制劑;PACAP、PACAP模擬物及PACAP受體3激動劑;PPAR激動劑;蛋白質酪胺酸磷酸酶-1 B (PTP-1 B)抑制劑;IL-1β抗體(例如吉沃珠單抗(gevokizumab)及卡那單抗);以及甲磺酸溴隱亭(bromocriptine mesylate)及其快速釋放調配物;或有益於治療上文所提及病狀或病症之其他藥物,包含上述活性劑之化學可能之游離酸、游離鹼及醫藥上可接受之鹽形式。
可用於治療發炎性病症之其他活性劑之實例包含(但不限於)類固醇及非類固醇抗發炎劑、糖皮質激素及治療激素。在特定實施例中,在治療化膿性汗腺炎(反常性痤瘡)時,其他活性劑可為抗生素、可注射類固醇、治療激素、TNF抑制劑(例如英夫利昔單抗(infliximab)、阿達木單抗(adalimumab)、依那西普(etanercept)、戈利木單抗(golimumab)、賽妥珠單抗(certolizumab))、疼痛劑(例如可待因(codeine)、氫可酮(hydrocodone)、嗎啡、普瑞巴林(pregabalin)、加巴噴丁(gabapentin)、病灶內曲安西龍(triamcinolone)、皮質類固醇、萘普生(naproxen)、酮洛(ketoprofen)、雙氯芬酸(diclofenac)、布洛芬(ibuprofen)、乙醯胺酚(acetaminophen))。在其他實施例中,在治療發炎性腸病時,其他活性劑可為胺甲喋呤(methotrexate)、TNF抑制劑、口服神經鞘胺醇1-磷酸受體調節劑(例如芬戈莫德(fingolimod)、辛波莫德(siponimod)、奧紮莫德(ozanimod)、波內西莫德(ponesimod))或選擇性JAK抑制劑(例如托法替尼(tofacitinib)、巴瑞克替尼(baricitinib)、烏帕替尼(upadacitinib))。在一些實施例中,在治療骨關節炎時,其他活性劑可為疼痛劑(上文所列示之實例)。在其他實施例中,在治療痛風性關節炎時,其他活性劑可為秋水仙鹼(colcichine)、非類固醇抗發炎劑或糖皮質激素。
製備本發明化合物之方法
本文所闡述之化合物可根據下列反應圖及實例之程序使用適當材料來製備且進一步藉由下列具體實例進行例示。該等實例亦包含在細胞分析中測試該等化合物之方法。然而,實例中所闡釋之化合物不應解釋為形成視為本發明之唯一類別。
該等實例進一步闡釋用於製備本發明化合物之細節。熟習此項技術者將易於瞭解,可使用以下製備性程序之條件及製程之已知變化來製備該等化合物。舉例而言,在一些情形下,實施反應方案之步驟順序可經改變以有利於反應或避免不期望之反應產物。用於最終化合物之起始材料及中間體係購得的、自已知程序或如另外闡釋說明來製得。該等實例僅出於進一步闡釋之目的提供且並非意欲限制本發明。
在300 MHz或400 MHz儀器上於CDCl
3、DMSO-
d6或甲醇-
d4中來獲得NMR數據,其中相對於四甲基矽烷標準來報告化學位移。藉由下列縮寫報告共振信號:s =單峰,d =雙重峰,t =三重峰,q =四重峰,dd =雙(雙重峰),m =多重峰或非等效共振之重疊。偶合常數(
J)係以赫茲(Hz)報告。
在合成反應圖及實例通篇中,除非另有指示,否則縮寫及首字母縮略詞可以下列含義使用:
縮寫
縮寫 | 定義 |
1Inda | (S)-2-胺基-3-(1H-吲唑-1-基)丙酸 |
1Indolin | (S)-2-胺基-3-(二氫吲哚-1-基)丙酸 |
1Nal | 3-(1-萘基)-L-丙胺酸 |
3AzaPhe4AcPip | (S)-3-(6-(4-乙醯基六氫吡嗪-1-基)吡啶-3-基)-2-胺基丙酸 |
3AzaTyrEtNAc | (S)-3-(6-(2-乙醯胺基乙氧基)吡啶-3-基)-2-胺基丙酸 |
3Pal | 3-吡啶基丙胺酸或3-吡啶基-L-丙胺酸 |
3Pal4Ph4CO2H | (S)-4-(5-(2-胺基-2-羧乙基)吡啶-2-基)苯甲酸 |
4Pal | 4-吡啶基丙胺酸或4-吡啶基-L-丙胺酸 |
A | L-丙胺酸 |
AA | 胺基酸 |
AbuMph | (S)-2-胺基-4-嗎啉基丁酸 |
AcOH | 乙酸 |
AEF | (S)-2-胺基-3-(6-(2-胺基乙氧基)吡啶-3-基)丙酸 |
Aib | 胺基異丁酸或α-甲基丙胺酸 |
AlaPip4 | (S)-2-胺基-3-(六氫吡啶-4-基)丙酸 |
AlaTHP4 | (S)-2-胺基-3-(四氫-2H-吡喃-4-基)丙酸 |
Alloc-OSu | N-(烯丙基氧基羰基氧基)琥珀醯亞胺 |
aMeNle | (S)-2-胺基-2-甲基己酸 |
ASCVD | 動脈粥樣硬化性心血管疾病 |
Bip4CO2H | L-聯苯丙胺酸-4-甲酸或(S)-4'-(2-胺基-2-羧乙基)-[1,1'-聯苯]-4-甲酸 |
BnBr | 苄基溴 |
Boc | 第三丁氧基-羰基 |
Boc2O | 二碳酸二-第三丁基酯 |
CANTOS | 卡那單抗抗發炎性血栓形成結果研究 |
CDCl 3 | 氘化氯仿 |
Cha | (S)-2-胺基-3-環己基丙酸 |
Cha44F2 | (S)-2-胺基-3-(4,4-二氟環己基)丙酸 |
CRP | C反應蛋白 |
D | L-天門冬胺酸 |
dA | D-丙胺酸 |
Dab | L-2,4-二胺基丁酸 |
daMeDab | (R)-2,4-二胺基-2-甲基丁醛 |
Dap | L-2,3-二胺基丙酸 |
DapAc | (S)-3-乙醯胺基-2-胺基丙酸 |
DapMe2 | (S)-2-胺基-3-(二甲基胺基)丙酸 |
DCE | 二氯乙烷 |
DCM | 二氯甲烷 |
dDab | D-2,4-二胺基丁酸 |
dDabMe3 | [(R)-3-胺基-3-羧丙基]-三甲基氮鎓 |
dDap | D-2,3-二胺基丙酸 |
DIAD | 偶氮二甲酸二異丙基酯 |
DIC | N,N'-二異丙基碳化二亞胺 |
DIPEA | N,N-二異丙基乙基胺或休尼格氏鹼(Hunig’s base) |
dK | D-離胺酸 |
dL | D-白胺酸 |
dLysAc | (R)-6-乙醯胺基-2-胺基己酸 |
DMA | N,N-二甲基乙醯胺 |
DMAP | 4-二甲基胺基吡啶 |
DMF | N,N-二甲基甲醯胺 |
DMSO | 二甲基亞碸 |
dNle | D-正白胺酸 |
dNMeA | D- N-甲基-丙胺酸 |
dNva | D-正纈胺酸 |
dOrn | D-鳥胺酸 |
dS | D-絲胺酸 |
E | L-麩胺酸 |
ES | 電噴霧 |
EtOAc | 乙酸乙酯 |
F | L-苯基丙胺酸 |
F4bcpA | 3-[4-[(S)-2-胺基-2-羧乙基]苯基]雙環[1.1.1]戊烷-1-甲酸 |
F4pcCCA | (1R,4s)-4-(4-((S)-2-胺基-2-羧乙基)苯基)環己烷-1-甲酸 |
F4ptCCA | (1S,4r)-4-(4-((S)-2-胺基-2-羧乙基)苯基)環己烷-1-甲酸 |
Fmoc | 9 H-茀-9-基甲氧基羰基 |
G | 甘胺酸 |
h | 小時 |
h3Pal5CN | (S)-2-胺基-4-(5-氰基吡啶-3-基)丁酸 |
h4Pal | (S)-2-胺基-4-(吡啶-4-基)丁酸 |
HATU | 六氟磷酸1-[雙(二甲基胺基)亞甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物或六氟磷酸N-[(二甲基胺基)-1H-1,2,3-三唑并-[4,5-b]吡啶-1-基亞甲基]-N-甲基甲銨N-氧化物 |
hCha | (S)-2-胺基-4-環己基丁酸 |
hF | L-高苯基丙胺酸 |
hF2CF3 | (S)-2-胺基-4-(2-(三氟甲基)苯基)丁酸 |
hF3CF3 | (S)-2-胺基-4-(3-(三氟甲基)苯基)丁酸 |
hF4CF3 | (S)-2-胺基-4-(4-(三氟甲基)苯基)丁酸 |
HFIP | 六氟異丙醇 |
HFpEF | 射血分數保留型心臟衰竭 |
hK | L-高離胺酸 |
HPLC | 高效液相層析 |
hQ | L-高麩醯胺酸 |
hsCRP | 高敏感性C反應蛋白 |
hSOMe | (S)-2-胺基-4-甲氧基丁酸 |
hY | L-高酪胺酸 |
Im | 1 H-咪唑 |
K | L-離胺酸 |
L | L-白胺酸 |
LDL | 低密度脂蛋白 |
LysAc | (S)-6-乙醯胺基-2-胺基己酸 |
MACE | 重大不良心臟事件 |
mAF | (S)-2-胺基-3-(3-(胺基甲基)苯基)丙酸 |
mBip | (S)-2-胺基-3-(3-苯基苯基)丙酸 |
MeCN | 乙腈 |
MeOH | 甲醇 |
min | 分鐘 |
MS | 質譜 |
mTyrOAl | (S)-2-胺基-3-(3-丙-2-烯氧基苯基)丙酸 |
N | L-天門冬醯胺酸 |
NIS | N-碘琥珀醯亞胺 |
Nle | L-正白胺酸 |
NMP | N-甲基-2-吡咯啶酮 |
NMR | 核磁共振 |
Nva | L-正纈胺酸 |
NsCl | 4-硝基苯磺醯氯 |
o.n. | 過夜 |
OMpe | β-甲基戊基酯 |
Orn | L-鳥胺酸 |
OSu | O-琥珀醯亞胺 |
Oxyma | 氰基(羥基亞胺基)乙酸乙酯 |
PE | 石油醚 |
PfTrpB-0B2 | 來自激烈火球菌(Pyrococcus furiosus)之經改造色胺酸合酶 |
PfTrpB-4D11 | 來自激烈火球菌之經改造色胺酸合酶 |
PfTrpB-7E6 | 來自激烈火球菌之經改造色胺酸合酶 |
Phe3NH2 | (S)-2-胺基-3-(3-胺基苯基)丙酸 |
Phe4AcPip | (S)-2-胺基-3-(4-(4-乙醯基六氫吡嗪-1-基)苯基)丙酸 |
Phe4CH2NH2 | (S)-2-胺基-3-[4-(胺基甲基)苯基]丙酸 |
Phe4COOH | L-苯基丙胺酸-4-甲酸或(S)-4-(2-胺基-2-羧乙基)苯甲酸 |
Phe4NH2 | (S)-2-胺基-3-(4-胺基苯基)丙酸 |
Phe4Pyrim5CO2H | (S)-2-(4-(2-胺基-2-羧乙基)苯基)嘧啶-5-甲酸 |
PLP | 3-羥基-2-甲基-5-([膦醯基氧基]甲基)-4-吡啶甲醛或5-磷酸吡哆醛 |
PPH 3 | 三苯基膦 |
Prot4NH2 | (2S,4R)-4-胺基吡咯啶-2-甲酸 |
Prot4NHBn | (2S,4R)-4-(苄基胺基)吡咯啶-2-甲酸 |
Prot4NHCH2CH2Ph | (2S,4R)-4-(苯乙基胺基)吡咯啶-2-甲酸 |
Prot4NHEt | (2S,4R)-4-(乙基胺基)吡咯啶-2-甲酸 |
psi | 磅力/平方英吋 |
PyAOP | 六氟磷酸(7-氮雜苯并三唑-1-基氧基)三吡咯啶基鏻 |
PyrimAla | (S)-2-胺基-3-(嘧啶-5-基)丙酸 |
PyrimAla4AcPip | (S)-3-(2-(4-乙醯基六氫吡嗪-1-基)嘧啶-5-基)-2-胺基丙酸 |
Q | L-麩醯胺酸 |
RP | 反相 |
rpm | 轉/分鐘 |
rt | 室溫 |
S | L-絲胺酸 |
SerOMe | O-甲基-L-絲胺酸 |
sbMe1Nal | (2S,3S)-2-胺基-3-(萘-1-基)丁酸 |
sbMeW4Cl | (2S,3S)-2-胺基-3-(4-氯-1H-吲哚-3-基)丁酸 |
sbMeW4F | (2S,3S)-2-胺基-3-(4-氟-1H-吲哚-3-基)丁酸 |
SFC | 超臨界流體層析 |
SPPS | 固相肽合成 |
tBu | 第三丁基 |
t-BuOH | 第三丁醇 |
Tba | (S)-2-胺基-4,4-二甲基戊酸 |
TBAB | 四丁基溴化銨 |
TBAI | 四丁基碘化銨 |
TEA | 三乙胺 |
TFA | 三氟乙酸 |
THF | 四氫呋喃 |
TIS | 三異丙基矽烷 |
Trp6Cl | (S)-2-胺基-3-(6-氯-1H-吲哚-3-基)丙酸 |
Trp6F | (S)-2-胺基-3-(6-氟-1H-吲哚-3-基)丙酸 |
Trp7F | (S)-2-胺基-3-(7-氟-1H-吲哚-3-基)丙酸 |
Trp7az | (S)-2-胺基-3-(1H-吡咯并[2,3-b]吡啶-3-基)丙酸 |
Trp7Me | (S)-2-胺基-3-(7-甲基-1H-吲哚-3-基)丙酸 |
TyrEtMor | (S)-2-胺基-3-(4-(2-嗎啉基乙氧基)苯基)丙酸 |
TyrEtNAc | L-酪胺酸 O-乙基乙醯胺或(S)-3-(4-(2-乙醯胺基乙氧基)苯基)-2-胺基丙酸 |
UPLC | 超高效液相層析或超高壓液相層析 |
W | L-色胺酸 |
中間體合成: 合成反應圖 1 1Inda (S)-2-((((9H- 茀 -9- 基 ) 甲氧基 ) 羰基 ) 胺基 )-3-(1H- 吲唑 -1- 基 ) 丙酸步驟1:在65℃下,向經惰性氮氣氛吹掃及維持之2-L 4頸圓底燒瓶中放置DMSO (150 mL)、1H-吲唑(15 g, 127 mmol)及(S)-2-胺基-3-羥基丙酸(14.01 g, 133 mmol)及pH 8 0.2 M磷酸鉀緩衝液(600 mL, 127 mmol)。將於H
2O (2 mL)中之[(4-甲醯基-5-羥基-6-甲基吡啶-3-基)甲氧基]膦酸(PLP) (96 mg, 0.00284當量)及於0.2 M磷酸鉀緩衝液(2 mL)中之PfTrpB-0B2 (1.05 g, 10 wt%)添加至溶液中。將所得溶液在65℃下攪拌16 h。藉由HPLC-MS監測反應進展。
步驟2:在0℃下向所得溶液中添加於THF (150 mL)中之Na
2CO
3(21.55 g, 2.0當量)及Fmoc-OSu (37.68 g, 1.1當量)。然後將溶液在25℃下攪拌2 h。藉由HPLC-MS監測反應進展。使用氯化氫(6 M)將溶液調節至pH 3。使用EtOAc (3 × 500 mL)萃取溶液。合併有機層並使用H
2O (2 x 1 L)及NaCl (1 x 1 L)洗滌。藉由無水硫酸鈉乾燥有機層並在真空下濃縮。使用DCM (15V)將粗產物製成漿液且藉由過濾收集固體。HPLC-MS:(ESI, m/z):428 [M+H] +。
1H NMR:(400 MHz, DMSO-
d6, ppm):δ 13.08 (s, 1H), 8.10 (d, J = 1.0 Hz, 1H), 7.87 (dt, J = 7.7, 1.0 Hz, 2H), 7.81 – 7.71 (m, 2H), 7.71 – 7.65 (m, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7.41 (dtd, J = 6.0, 4.4, 4.3, 3.2 Hz, 2H), 7.40 – 7.33 (m, 1H), 7.36 – 7.24 (m, 1H), 7.29 – 7.20 (m, 1H), 7.16 – 7.08 (m, 1H), 4.83 – 4.65 (m, 2H), 4.61 – 4.51 (m, 1H), 4.22 – 4.06 (m, 3H)。
合成反應圖 2 1Indolin (S)-2-((((9H- 茀 -9- 基 ) 甲氧基 ) 羰基 ) 胺基 )-3-( 二氫吲哚 -1- 基 ) 丙酸步驟1:在25℃下向10 L 3頸圓底燒瓶中添加二氫吲哚(125 g, 1.05 mol, 1.00當量)、DMSO (625 mL)、pH 8 0.2 M磷酸鉀緩衝液(5625 mL)及PLP (778.32 mg, 2.94 mmol)、L-絲胺酸(115.75 g, 1.10 mol, 1.05當量)及PfTrpB-4D11 (12.50 g)。將所得溶液在65℃及氮下攪拌4 h。藉由HPLC-MS監測反應進展。
步驟2:在0℃下向上述溶液中添加Na
2CO
3(129 g, 2.00當量)、Fmoc-OSu (306 g, 1.50當量)及THF (2.5 L)。將反應混合物在25℃及氮下攪拌3 h。使用6 M HCl將溶液酸化至pH 3。藉由過濾收集母液,然後使用EtOAc (3 x 1 L)萃取。合併有機層並使用H
2O (2 x 800 mL)及NaCl (1 x 800 mL)洗滌,藉由Na
2SO
4乾燥並在真空下濃縮。藉由使用PE/EtOAc (3:1)洗脫之矽膠管柱層析純化殘餘物以提供粗產物。然後藉由使用乙腈/水 + 0.05% TFA (在30 min內50%至70%梯度)洗脫之製備型反相(C18) HPLC純化粗產物。在真空及20℃下濃縮混合物以去除MeCN,然後使用EtOAc (3 x 1 L)萃取,藉由Na
2SO
4乾燥並在真空下濃縮。將純產物在己烷(1 L)中製成漿液並保持30 min。藉由過濾收集固體。此會產生(2S)-3-(2,3-二氫吲哚-1-基)-2-[[(9H-茀-9-基甲氧基)羰基]胺基]丙酸。HPLC-MS:(ESI, m/z):429 [M+H] +。
1H NMR:(400 MHz, DMSO-
d6, ppm) δ 7.89 (d, J = 7.5 Hz, 2H), 7.74 – 7.67 (m, 2H), 7.41 (t, J = 7.5 Hz, 2H), 7.35 – 7.25 (m, 2H), 7.00 (ddd, J = 17.4, 7.5, 1.3 Hz, 2H), 6.61 – 6.48 (m, 2H), 4.35 – 4.18 (m, 4H), 3.47 – 3.28 (m, 4H), 2.87 (t, J = 8.2 Hz, 2H)。
合成反應圖 3 3AzaPhe4AcPip (S)-2-((((9H- 茀 -9- 基 ) 甲氧基 ) 羰基 ) 胺基 )-3-(6-(4- 乙醯基六氫吡嗪 -1- 基 ) 吡啶 -3- 基 ) 丙酸步驟1:在氬及室溫下,向1-(六氫吡嗪-1-基)乙烷-1-酮(21.85 g, 170 mmol)於DMF (150 mL)中之混合物中添加5-溴-2-氟吡啶(15 g, 85 mmol)。將反應液在100℃下攪拌2 h,然後使用300 mL EtOAc稀釋並使用H
2O (3 x 80 mL)、飽和NaCl水溶液(80 mL)洗滌,藉由Na
2SO
4乾燥並過濾。在減壓下濃縮濾液。藉由使用於PE中之0% - 100% EtOAc梯度洗脫之矽膠管柱層析純化殘餘物。合併含有期望產物之級分並在減壓下濃縮以提供1-(4-(5-溴吡啶-2-基)六氫吡嗪-1-基)乙烷-1-酮。C11H15BrN3O [M + H]
+之MS ESI計算值:284.03及286.03,實驗值:283.90及285.90。
步驟2:將氯化鎳(II)乙二醇二甲基醚複合物(0.696 g, 3.17 mmol)及1,10-菲咯啉(0.571 g, 3.17 mmol)於DMA (2 mL)中之混合物在50℃下加熱0.5小時。在25℃下添加1-(4-(5-溴吡啶-2-基)六氫吡嗪-1-基)乙烷-1-酮(4.5 g, 15.84 mmol)、(R)-2-((((9H-茀-9-基)甲氧基)羰基)胺基)-3-溴丙酸第三丁基酯(7.78 g, 17.42 mmol)及四丁基碘化銨(5.85 g, 15.84 mmol)於DMA (2 mL)中之混合物。然後添加鋅粉(2.071 g, 31.7 mmol)。將所得混合物在50℃下攪拌1 h。將所得混合物傾倒至水(300 mL)中並使用EtOAc (3 x 300 mL)萃取。使用水(100 mL)及鹽水(2 x 80 mL)洗滌有機層,藉由無水硫酸鈉乾燥並在減壓下濃縮。藉由管柱層析在使用DCM-MeOH (10:1)洗脫之矽膠上來純化殘餘物以提供(S)-2-((((9H-茀-9-基)甲氧基)羰基)胺基)-3-(6-(4-乙醯基六氫吡嗪-1-基)吡啶-3-基)丙酸第三丁基酯。C33H39N4O5 [M + H]
+之MS ESI計算值:571.28,實驗值:571.40。
步驟3:在氬及室溫下,向(S)-2-((((9H-茀-9-基)甲氧基)羰基)胺基)-3-(6-(4-乙醯基六氫吡嗪-1-基)吡啶-3-基)丙酸第三丁基酯(7.3 g, 12.79 mmol)於DCM (70 mL)中之混合物中添加TFA (70 mL, 909 mmol)。將反應液在室溫下攪拌1 h,然後在減壓下濃縮。將殘餘物溶於THF (20 mL)中且藉由反相Combi-Flash使用下列條件來純化所得混合物:管柱:C18矽膠管柱(330 g),20-35 μm;移動相A:5 mM TFA水溶液;移動相B:MeCN;(梯度:保持0% B 10 min,在35 min內升至42.3% B,保持42.3% B 3.2 min;在2 min內升至95% B,保持95% B 10 min);流速:60 mL/min;檢測器:UV 254 & 210 nm;RT:35.32 min。收集含產物級分並在真空下濃縮以提供(S)-2-((((9H-茀-9-基)甲氧基)羰基)胺基)-3-(6-(4-乙醯基六氫吡嗪-1-基)吡啶-3-基)丙酸。C29H31N4O5 [M + H]
+之MS ESI計算值:515.22,實驗值:515.15。
1H NMR (300 MHz,甲醇-
d4) δ 7.87 - 7.79 (m, 4H), 7.62 - 7.55 (m, 2H), 7.42 - 7.27 (m, 4H), 7.11 - 7.09 (m, 1H), 4.51 - 4.46 (m, 1H), 4.32 - 4.09 (m, 3H), 3.65 - 3.54 (m, 8H), 3.29 - 3.20 (m, 1H), 2.94 - 2.89 (m, 1H), 2.12 (s, 3H)。
合成反應圖 4 3TyrEtNAc (S)-2-((((9H- 茀 -9- 基 ) 甲氧基 ) 羰基 ) 胺基 )-3-(6-(2- 乙醯胺基乙氧基 ) 吡啶 -3- 基 ) 丙酸步驟1:在氬及室溫下,向
N-(2-羥乙基)乙醯胺(17.58 g, 170 mmol)於
t-BuOH (150 mL)中之混合物中添加5-溴-2-氟吡啶(15 g, 85 mmol),隨後添加第三丁醇鉀(19.13 g, 170 mmol)。將反應液在室溫下攪拌1 h,然後在減壓下濃縮。使用500 mL EtOAc稀釋殘餘物並使用飽和NaHCO
3水溶液(3 x 250 mL)、飽和NaCl水溶液(250 mL)洗滌,藉由Na
2SO
4乾燥並過濾。在減壓下濃縮濾液以提供粗製N-(2-((5-溴吡啶-2-基)氧基)乙基)乙醯胺。C9H12BrN2O2 [M + H]
+之MS ESI計算值:259.00及261.00,實驗值:258.90及261.90。
步驟2:將氯化鎳(II)乙二醇二甲基醚複合物(1.187 g, 5.40 mmol)及1,10-菲咯啉(0.974 g, 5.40 mmol)於DMA (70 mL)中之混合物在50℃下加熱0.5小時。在25℃下添加N-(2-((5-溴吡啶-2-基)氧基)乙基)乙醯胺(7 g, 27.0 mmol)、(R)-2-((((9H-茀-9-基)甲氧基)羰基)胺基)-3-溴丙酸第三丁基酯(13.26 g, 29.7 mmol)及四丁基碘化銨(9.98 g, 27.0 mmol)於DMA (70 mL)中之混合物。然後添加鋅粉(3.53 g, 54.0 mmol)且將所得混合物在50℃下攪拌1 h。使用300 mL EtOAc稀釋反應混合物並使用飽和NaHCO
3水溶液(3 x 80 mL)、鹽水(80 mL)洗滌,藉由Na
2SO
4乾燥並過濾。在減壓下濃縮濾液。藉由使用於MeOH中之0% - 20% DCM梯度洗脫之矽膠管柱層析純化殘餘物。合併含有期望產物之級分並在減壓下濃縮以提供(S)-2-((((9H-茀-9-基)甲氧基)羰基)胺基)-3-(6-(2-乙醯胺基乙氧基)吡啶-3-基)丙酸第三丁基酯。C31H36N3O6 [M + H]
+之MS ESI計算值:546.25,實驗值:546.40。
步驟3:在氬及室溫下,向(S)-2-((((9H-茀-9-基)甲氧基)羰基)胺基)-3-(6-(2-乙醯胺基乙氧基)吡啶-3-基)丙酸第三丁基酯(8 g, 14.66 mmol)於DCM (80 mL)中之混合物中添加TFA (80 mL, 1038 mmol)。將反應液在室溫下攪拌1 h,然後在減壓下濃縮。藉由RP急速管柱層析使用下列條件來純化殘餘物:管柱:C18矽膠管柱(330 g), 20-35 μm;移動相A:5 mM NH
4HCO
3水溶液;移動相B:MeCN;(梯度:保持0% B 5 min,在20 min內升至45% B,保持45% B 10 min;在15 min內升至95% B,保持95% B 10 min);流速:60 mL/min;檢測器:UV 254 & 210 nm;RT:35.32 min。收集含產物級分並在減壓下濃縮以得到(S)-2-((((9H-茀-9-基)甲氧基)羰基)胺基)-3-(6-(2-乙醯胺基乙氧基)吡啶-3-基)丙酸。C27H28N3O6 [M + H]
+之MS ESI計算值:490.19,實驗值:490.10。
1H NMR (400 MHz,甲醇-
d4) δ 8.02 - 8.00 (m, 1H), 7.79 - 7.77 (m, 2H), 7.67 - 7.64 (m, 1H), 7.61 - 7.57 (m, 2H), 7.40 - 7.36 (m, 2H), 7.31 - 7.27 (m, 2H), 6.82 - 6.80 (m, 1H), 4.42 - 4.39 (m, 1H), 4.33 - 4.22 (m, 4H), 4.16 - 4.13 (m, 1H), 3.53 - 3.51 (m, 2H), 3.20 - 3.15 (m, 1H), 2.93 - 2.87 (m, 1H), 1.92 (s, 3H)。
合成反應圖 5 3Pal4Ph4CO2H (S)-2-((((9H- 茀 -9- 基 ) 甲氧基 ) 羰基 ) 胺基 )-3-(6-(4-( 第三丁氧基羰基 ) 苯基 ) 吡啶 -3- 基 ) 丙酸步驟1:在室溫及氮氣氛下,向NiCl
2-glyme (0.918 g, 4.18 mmol)於DMA (100 mL)中之經攪拌溶液中添加1,10-菲咯啉(0.905 g, 4.18 mmol)。將所得溶液在50℃下攪拌1 h。在室溫下將2-氯-5-碘吡啶(5 g, 20.88 mmol)、(
R)-2-((((9
H-茀-9-基)甲氧基)羰基)胺基)-3-碘丙酸第三丁基酯(12.36 g, 25.06 mmol)、TBAI (8.01 g, 20.88 mmol)及Zn (2.73 g, 41.8 mmol)添加至上述混合物中且將所得混合物在25℃下攪拌2 h。使用H
2O (200 mL)終止反應,使用EtOAc (2 x 500 mL)萃取。使用鹽水(3 x 200 mL)洗滌合併之有機層,藉由無水Na
2SO
4乾燥並過濾。在減壓下濃縮濾液且藉由使用於PE中之0 - 30% EtOAc洗脫之矽膠管柱層析純化殘餘物以得到(
S)-2-((((9
H-茀-9-基)甲氧基)羰基)胺基)-3-(6-氯吡啶-3-基)丙酸第三丁基酯。C
27H
28ClN
2O
4[M + H]
+之MS ESI計算值:479.17,實驗值:479.20。
步驟2:在室溫下,向(
S)-2-((((9
H-茀-9-基)甲氧基)羰基)胺基)-3-(6-氯吡啶-3-基)丙酸第三丁基酯(5 g, 10.48 mmol)於DCM (5 mL)中之經攪拌溶液中添加TFA (10 mL)。將溶液在25℃下攪拌1 h。在減壓下濃縮溶劑且藉由RP-flash使用下列條件來純化殘餘物:管柱:Flash C18 (330 g);移動相A:水(0.1% TFA),移動相B:MeCN;(梯度:保持5% B 5 min,在15 min內升至30% B,保持30% B 5 min,在20 min內升至95% B,保持95% B 10 min);流速:90 mL/min;檢測器:UV 210 nm;RT = 40 min。收集含產物級分並在真空中蒸發以得到(
S)-2-((((9
H-茀-9-基)甲氧基)羰基)胺基)-3-(6-氯吡啶-3-基)丙酸。C
23H
20ClN
2O
4[M + H]
+之MS ESI計算值:423.10,實驗值:423.10。
步驟3:在25℃及氮下,向(
S)-2-((((9
H-茀-9-基)甲氧基)羰基)胺基)-3-(6-氯吡啶-3-基)丙酸(3 g, 7.09 mmol)於THF (25 mL)及水(5 mL)中之經攪拌溶液中添加(4-(第三丁氧基羰基)苯基)酸(1.890 g, 8.51 mmol)及K
3PO
4(7.53 g, 35.5 mmol)。將所得溶液在25℃下攪拌10 min。將Pd(dtbpf)Cl
2(0.694 g, 1.064 mmol)添加至溶液中且然後將混合物在60℃下攪拌16 h。將反應液冷卻至室溫並使用H
2O (200 mL)驟冷,且使用EtOAc (2 x 500 mL)萃取。使用鹽水(3 x 200 mL)洗滌合併之有機層,藉由無水Na
2SO
4乾燥,並過濾。在減壓下濃縮濾液且藉由RP-flash使用下列條件來純化殘餘物:管柱:Flash C18 (330 g);移動相A:水(0.1% TFA),移動相B:MeCN;(梯度:保持5% B 5 min,在15 min內升至60% B,保持60% B 15 min;在10 min內升至95% B,保持95% B 10 min);流速:90 mL/min;檢測器:UV 210 nm;RT = 55 min。收集含產物級分並在真空中蒸發以得到(
S)-2-((((9
H-茀-9-基)甲氧基)羰基)胺基)-3-(6-(4-(第三丁氧基羰基)苯基)吡啶-3-基)丙酸。C
34H
33N
2O
6[M + H]
+之MS ESI計算值:565.23,實驗值:565.15;
1H NMR (400 MHz,甲醇-
d4) δ 8.66 (d,
J= 1.9 Hz, 1H), 8.12 - 8.07 (m, 3H), 7.99 - 7.92 (m, 3H), 7.77 (d,
J= 7.5 Hz, 2H), 7.59 - 7.56 (m, 2H), 7.37 - 7.33 (m, 2H), 7.30 - 7.22 (m, 2H), 4.60 - 4.56 (m, 1H), 4.29 - 4.27 (m, 2H), 4.14 - 4.10 (m, 1H), 3.45 - 3.41 (m, 1H), 3.14 - 3.10 (m, 1H), 1.62 (s, 9H)。
合成反應圖 6 AbuMph (S)-2-((((9H- 茀 -9- 基 ) 甲氧基 ) 羰基 ) 胺基 )-4- 嗎啉基丁酸步驟1:在0℃及氮氣氛下,向((苄基氧基)羰基)-
L-高絲胺酸(2.5 g, 9.87 mmol)及NaHCO
3(2.488 g, 29.6 mmol)於DMF (50 mL)中之經攪拌混合物中添加苄基溴(2.026 g, 11.85 mmol)。將混合物在25℃下攪拌16 h,然後使用水(200 mL)驟冷,使用EtOAc (3 x 200 mL)萃取。使用鹽水(3 x 100 mL)洗滌合併之有機層,藉由無水Na
2SO
4乾燥。在過濾之後,在減壓下濃縮濾液且藉由使用於PE中之0 - 45% EtOAc洗脫之矽膠管柱層析純化殘餘物以提供((苄基氧基)羰基)-
L-高絲胺酸苄基酯。C
19H
21NO
5Na [M + Na]
+之MS ESI計算值:366.14,實驗值:366.15。
步驟2:在N
2氣氛下於兩頸500 mL燒瓶中,在0℃下將I
2(22.17 g, 87 mmol)添加至PPh
3(17.19 g, 65.5 mmol)及1
H-咪唑(4.46 g, 65.5 mmol)於無水CH
2Cl
2(100 mL)中之溶液中。將反應液升溫至25℃並攪拌15 min。經10分鐘添加((苄基氧基)羰基)-
L-高絲胺酸苄基酯(15 g, 43.7 mmol)於CH
2Cl
2(100 mL)中之溶液且然後在室溫下攪拌2 h。藉由飽和Na
2S
2O
3溶液(3 x 200 mL)、隨後鹽水(3 x 50 mL)洗滌混合物。使用Na
2SO
4乾燥有機層,在減壓下濃縮濾液且藉由使用於PE中之0 - 40% EtOAc洗脫之矽膠管柱層析純化殘餘物以提供(
S)-2-(((苄基氧基)羰基)胺基)-4-碘丁酸苄基酯。C
19H
21INO
4[M + H]
+之MS ESI計算值:454.04,實驗值:454.05。
1H NMR (400 MHz, CDCl
3) δ 7.45 - 7.31 (m, 10H), 5.37 - 5.35 (m, 1H), 5.19 - 5.15 (m, 2H), 5.11 (s, 2H), 4.48 - 4.41 (m, 1H), 3.15 - 3.10 (m, 2H), 2.46 - 2.44 (m, 1H), 2.25 - 2.20 (m, 1H)。
步驟3:在室溫下,向(
S)-2-(((苄基氧基)羰基)胺基)-4-碘丁酸苄基酯(13.6 g, 30.0 mmol)溶於THF (140 mL)中之經攪拌混合物中添加嗎啉(20.91 g, 240 mmol)。將所得混合物在50℃下攪拌16 h。在減壓下濃縮反應混合物且藉由使用於PE中之0 ~ 80% EtOAc洗脫之矽膠管柱層析純化殘餘物,且收集含產物級分並在減壓下濃縮以提供(
S)-2-(((苄基氧基)羰基)胺基)-4-嗎啉基丁酸苄基酯。C
23H
29N
2O
5[M + H]
+之MS ESI計算值:413.21,實驗值:413.35。
1H NMR (400 MHz, CDCl
3) δ 7.36 - 7.34 (m, 10H), 6.67 (s, 1H), 5.24 - 5.02 (m, 4H), 4.52 - 4.47 (m, 1H), 3.67 - 3.52 (m, 4H), 2.38 - 2.51 (m, 6H), 2.15 - 1.81 (m, 2H)。
步驟4:將(
S)-2-(((苄基氧基)羰基)胺基)-4-嗎啉基丁酸苄基酯(6.5 g, 15.76 mmol)溶於EtOH (65 mL)中並將所得混合物抽真空,且在環境溫度下施加氮氣氛。然後在氮氣氛下添加Pd-C (2.6 g,乾燥,20%wt)。將懸浮液在真空下脫氣並使用H
2吹掃若干次,將反應溶液在25℃及1 atm H
2下攪拌5 h。過濾懸浮液且在減壓下濃縮濾液以得到粗製(
S)-2-胺基-4-嗎啉基丁酸。C
8H
17N
2O
3[M + H]
+之MS ESI計算值:189.12,實驗值:189.25。
步驟5:在25℃下向(
S)-2-胺基-4-嗎啉基丁酸(2.97 g, 15.76 mmol)於THF (25 mL)及水(25 mL)中之溶液中添加NaHCO
3(6.63 g, 79 mmol)及Fmoc-OSu (4.85 g, 14.20 mmol)。將反應混合物在25℃下攪拌16 h。在完成後,使用1 M HCl將溶液之pH值調節至3。藉由反相急速層析使用下列條件來純化混合物:C18管柱(120 g);移動相A:水(0.05% TFA),移動相B:MeCN;(梯度:保持5% B 5 min,在30 min內升至38 % B,保持38% B 2.6 min;在2 min內升至95% B,保持95% B 5 min);流速:60 mL/min;檢測器:UV 210 nm;RT = 31 min。收集含產物級分並在減壓下濃縮以得到(
S)-2-((((9
H-茀-9-基)甲氧基)羰基)胺基)-4-嗎啉基丁酸。C
23H
27N
2O
5[M - H]
-之MS ESI計算值:411.19,實驗值:411.30。
1H NMR (300 MHz,甲醇-
d4) δ 7.81 - 7.79 (m, 2H), 7.68 - 7.65 (m, 2H), 7.42 - 7.37 (m, 2H), 7.33 - 7.29 (m, 2H), 4.48 - 4.45 (m, 2H), 4.42 - 4.23 (m, 2H), 4.01 - 3.77 (m, 4H), 3.33 - 3.30 (m, 2H), 3.29 - 3.14 (m, 4H), 2.45 - 2.05 (m, 2H)。
合成反應圖 7 Bip4CO2H (S)-2-((((9H- 茀 -9- 基 ) 甲氧基 ) 羰基 ) 胺基 )-3-(4'-( 第三丁氧基羰基 )-[1,1'- 聯苯 ]-4- 基 ) 丙酸使氬氣鼓泡通過(
S)-2-((((9
H-茀-9-基)甲氧基)羰基)胺基)-3-(4-溴苯基)丙酸(6 g, 12.87 mmol)、(4-(第三丁氧基羰基)苯基)酸(4.29 g, 19.30 mmol)及K
3PO
4(8.19 g, 38.6 mmol)於THF (40 mL)中之混合物10 min,然後添加[1,1'-雙(二-第三丁基膦基)二茂鐵]二氯鈀(II) (0.839 g, 1.287 mmol)。在將所得混合物在50℃下攪拌16 h之後,使用EtOAc (300 mL)將其稀釋並使用飽和NaHCO3水溶液(3 x 80 mL)、鹽水(2 x 40 mL)洗滌,藉由Na
2SO
4乾燥並過濾。在減壓下濃縮濾液。藉由使用於PE中之0% - 50% EtOAc梯度洗脫之矽膠管柱層析純化殘餘物。收集含產物級分並在真空中旋轉蒸發
。藉由combi-Flash使用下列條件來再純化殘餘物:管柱:管柱:C18凝膠管柱(330 g), 20-35 μm;移動相A:0.5% TFA水溶液;移動相B:MeCN;(梯度:保持0% B 10 min,在25 min內升至62.3% B,保持62.3% B 6.2 min;在2 min內升至95% B,保持95% B 10 min);流速:90 mL/min;檢測器:UV 254 & 210 nm;RT:32.32 min。收集含產物級分並在減壓下濃縮以提供(
S)-2-((((9
H-茀-9-基)甲氧基)羰基)胺基)-3-(4'-(第三丁氧基羰基)-[1,1'-聯苯]-4-基)丙酸。C
35H
34NO
6[M + 1]
+之MS ESI計算值:564.23,實驗值:564.15。
1H NMR (300 MHz,甲醇-
d4) δ 7.97 - 7.95 (m, 2H), 7.78 - 7.76 (m, 2H), 7.61 - 7.53 (m, 6H), 7.38 - 7.21 (m, 2H), 4.51 - 4.11 (m, 4H), 3.32 - 3.25 (m, 1H), 3.03 - 2.95 (m, 1H), 1.61 (s, 9H)。
合成反應圖 8 h3Pal5CN (S)-2-((((9H- 茀 -9- 基 ) 甲氧基 ) 羰基 ) 胺基 )-4-(5- 氰基吡啶 -3- 基 ) 丁酸步驟1:在室溫下,向(((9
H-茀-9-基)甲氧基)羰基)-
L-高絲胺酸(15 g, 43.9 mmol)於DCM (200 mL)中之經攪拌溶液中添加(
Z)-
N,
N'-二異丙基胺基甲亞胺酸第三丁基酯(35.2 g, 176 mmol)。將溶液在30℃下攪拌4 h。過濾出固體且在減壓下濃縮濾液。藉由使用於PE中之0 - 32% EtOAc洗脫之矽膠管柱層析純化殘餘物以提供(((9
H-茀-9-基)甲氧基)羰基)-
L-高絲胺酸第三丁基酯。C
23H
28NO
5[M + H]
+之MS ESI計算值:398.19,實驗值:398.15.1H NMR (300 MHz, CDCl
3) δ 7.81 - 7.74 (m, 2H), 7.64 - 7.56 (m, 2H), 7.45 - 7.37 (m, 2H), 7.37 - 7.28 (m, 2H), 5.61 (d,
J= 7.7 Hz, 1H), 4.54 - 4.32 (m, 3H), 4.22 (t,
J= 6.9 Hz, 1H), 3.76 - 3.52 (m, 2H), 2.25 - 2.07 (m, 1H), 1.71 - 1.55 (m, 1H), 1.48 (s, 9H)。
步驟2:在室溫及氮氣氛下,向PPh
3(12.67 g, 48.3 mmol)及1
H-咪唑(4.38 g, 64.4 mmol)於DCM (200 mL)中之經攪拌溶液中添加I
2(12.26 g, 48.3 mmol)。將混合物在室溫下攪拌10 min。將(((9
H-茀-9-基)甲氧基)羰基)-
L-高絲胺酸第三丁基酯(12.8 g, 32.2 mmol)添加至混合物中並在25℃下攪拌2 h。在減壓下濃縮溶劑且藉由使用於PE中之0 - 18% EtOAc洗脫之矽膠管柱層析純化殘餘物以提供(
S)-2-((((9
H-茀-9-基)甲氧基)羰基)胺基)-4-碘丁酸第三丁基酯。C
23H
26INO
4Na [M + Na]
+之MS ESI計算值:530.09,實驗值:530.20。
1H NMR (300 MHz, CDCl
3) δ 7.83 - 7.71 (m, 2H), 7.65 - 7.56 (m, 2H), 7.47 - 7.36 (m, 2H), 7.36 - 7.28 (m, 2H), 5.35 (d,
J= 8.3 Hz, 1H), 4.52 - 4.35 (m, 2H), 4.34 - 4.16 (m, 2H), 3.21 - 3.04 (m, 2H), 2.52 - 2.32 (m, 1H), 2.28 - 2.07 (m, 1H), 1.48 (s, 9H)。
步驟3:在室溫及氬氣氛下,向1,10-菲咯啉(1.083 g, 6.01 mmol)於DMA (300 mL)中之經攪拌溶液中添加NiCl
2-glyme (1.321 g, 6.01 mmol)。將混合物在50℃下攪拌1 h,然後冷卻至室溫。然後在室溫下將(
S)-2-((((9
H-茀-9-基)甲氧基)羰基)胺基)-4-碘丁酸第三丁基酯(15.25 g, 30.1 mmol)、5-溴菸鹼甲腈(5.5 g, 30.1 mmol)、TBAI (15.25 g, 30.1 mmol)及鋅(3.93 g, 60.1 mmol)添加至混合物中並在35℃下攪拌2.5 h。將混合物冷卻至室溫並使用水(500 mL)及EtOAc (800 mL)稀釋。過濾出固體且分離有機層。使用鹽水(3 x 150 mL)洗滌有機層,藉由無水Na
2SO
4乾燥,並過濾。在減壓下濃縮濾液且藉由使用於PE中之0 - 40% EtOAc洗脫之矽膠管柱層析純化殘餘物以提供(
S)-2-((((9
H-茀-9-基)甲氧基)羰基)胺基)-4-(5-氰基吡啶-3-基)丁酸第三丁基酯。C
29H
30N
3O
4[M + H]
+之MS ESI計算值:484.22,實驗值:484.20。
1H NMR (300 MHz, CDCl
3) δ 8.75 (s, 1H), 8.66 (s, 1H), 7.87 - 7.71 (m, 3H), 7.61 (d,
J= 7.4 Hz, 2H), 7.47 - 7.28 (m, 4H), 5.40 (d,
J= 7.8 Hz, 1H), 4.55 - 4.37 (m, 2H), 4.36 - 4.18 (m, 2H), 2.85 - 2.59 (m, 2H), 2.26 - 2.08 (m, 1H), 2.02 - 1.82 (m, 1H), 1.49 (s, 9H)。
步驟4:在室溫下,向(
S)-2-((((9
H-茀-9-基)甲氧基)羰基)胺基)-4-(5-氰基吡啶-3-基)丁酸第三丁基酯(7.5 g, 15.51 mmol)於DCM (50 mL)中之經攪拌溶液中添加TFA (100 mL)。將溶液在25℃下攪拌3 h,然後在減壓下濃縮。藉由RP-flash使用下列條件來純化殘餘物:C18管柱,330 g,在10 min內5% -5%、在40 min內5% - 55%、在10 min內55% -55%之於水中之MeCN (0.05% TFA)以得到(
S)-2-((((9
H-茀-9-基)甲氧基)羰基)胺基)-4-(5-氰基吡啶-3-基)丁酸。C
25H
22N
3O
4[M + H]
+之MS ESI計算值:428.15,實驗值:428.05。
1H NMR (400 MHz, DMSO-
d6) δ 12.78 (br, 1H), 8.87 (s, 1H), 8.75 (s, 1H), 8.18 (s, 1H), 7.92 - 7.90 (m, 2H), 7.76 - 7.73 (m, 3H), 7.44 - 7.33 (m, 4H), 4.39 - 4.20 (m, 3H), 3.94 - 3.89 (m, 1H), 2.79 - 2.67 (m, 2H), 2.09 - 1.89 (m, 2H)。
合成反應圖 9 Phe4AcPip (S)-2-((((9H- 茀 -9- 基 ) 甲氧基 ) 羰基 ) 胺基 )-3-(4-(4- 乙醯基六氫吡嗪 -1- 基 ) 苯基 ) 丙酸步驟1:在25℃及氮下,向(
S)-3-(4-溴苯基)-2-((第三丁氧基羰基)胺基)丙酸(6 g, 17.43 mmol)於甲苯(180 mL)中之經攪拌溶液中添加XPhos Pd G
2(2.057 g, 2.61 mmol)。將所得溶液在100℃下攪拌10 min。添加1-(六氫吡嗪-1-基)乙烷-1-酮(2.234 g, 17.43 mmol)及Cs
2CO
3(5.04 g, 26.1 mmol)且所得溶液在110℃下攪拌2 h。將反應液冷卻至室溫並使用H
2O (500 mL)驟冷,使用EtOAc (2 x 500 mL)萃取。使用鹽水(3 x 200 mL)洗滌合併之有機層,藉由無水Na
2SO
4乾燥並過濾。在減壓下濃縮濾液且藉由使用於PE中之0 - 60% EtOAc洗脫之矽膠管柱層析純化殘餘物以得到(
S)-3-(4-(4-乙醯基六氫吡嗪-1-基)苯基)-2-((第三丁氧基羰基)胺基)丙酸。C
20H
30N
3O
5[M + H]
+之MS ESI計算值:392.21,實驗值:392.25。
1H NMR (400 MHz,甲醇-
d4) δ 7.12 (d,
J= 8 Hz, 2H), 6.89 (d,
J= 8 Hz, 2H), 4.16 - 4.13 (m, 1H), 3.72 - 3.65 (m, 4H), 3.14 - 3.04 (m, 4H), 2.93 - 2.81 (m, 2H), 2.13 (s, 3H), 1.38 - 1.29 (m, 9H)。
步驟2:在室溫下,向(
S)-3-(4-(4-乙醯基六氫吡嗪-1-基)苯基)-2-((第三丁氧基羰基)胺基)丙酸(10 g, 25.5 mmol)於DCM (30 mL)中之經攪拌溶液中添加TFA (30 mL)。將溶液在25℃下攪拌1 h,然後在減壓下濃縮。粗製(
S)-3-(4-(4-乙醯基六氫吡嗪-1-基)苯基)-2-胺基丙酸未經任何進一步純化即直接用於下一步驟中。C
15H
22N
3O
3[M + H]
+之MS ESI計算值:292.16,實驗值:292.20。
步驟3:在25℃及氮下,向(
S)-3-(4-(4-乙醯基六氫吡嗪-1-基)苯基)-2-(羧基胺基)丙酸(7 g, 20.87 mmol)於THF (25 mL)及水(25 mL)中之經攪拌溶液中添加Fmoc-OSu (6.34 g, 18.79 mmol)。且然後添加NaHCO
3(8.77 g, 104 mmol)。將所得混合物在25℃下攪拌2 h。使用1 N HCl將pH調節至5並使用EtOAc (2 x 200 mL)萃取。使用鹽水(3 x 100 mL)洗滌合併之有機層,藉由無水Na
2SO
4乾燥並過濾。在減壓下濃縮濾液且藉由反相急速層析使用下列條件來純化殘餘物:管柱:C18矽膠(330 g);移動相A:水(0.1% TFA),移動相B:MeCN;(梯度:保持5% B 5 min,在15 min內升至55% B,保持55% B 5 min;在20 min內升至95% B,保持95% B5 min);流速:90 mL/min;檢測器:UV 210 nm;RT = 45 min。收集含產物級分並在真空中濃縮以得到(
S)-2-((((9
H-茀-9-基)甲氧基)羰基)胺基)-3-(4-(4-乙醯基六氫吡嗪-1-基)苯基)丙酸。C
30H
32N
3O
5[M + H]
+之MS ESI計算值:514.23,實驗值:514.30。
1H NMR (400 MHz,甲醇-
d4) δ 7.78 - 7.76 (m, 2H), 7.61 - 7.52 (m, 2H), 7.40 - 7.37 (m, 2H), 7.32 - 7.22 (m, 4H), 7.08 - 6.98 (m, 2H), 4.47 - 4.43 (m, 1H), 4.33 - 4.31 (m, 1H), 4.14 - 4.02 (m, 2H), 3.68 - 3.63 (m, 4H), 3.23 - 3.08 (m, 5H), 2.91 - 2.85 (m, 1H), 2.11 (s, 3H)。
合成反應圖 10 Phe4Pyrim5CO2H (S)-2-((((9H- 茀 -9- 基 ) 甲氧基 ) 羰基 ) 胺基 )-3-(4-(5-( 第三丁氧基羰基 ) 嘧啶 -2- 基 ) 苯基 ) 丙酸步驟1:在氬及室溫下,向2-氯嘧啶-5-甲酸(10 g, 63.1 mmol)於
t-BuOH (100 mL)中之混合物中添加DMAP (0.771 g, 6.31 mmol)及Boc
2O (16.52 g, 76 mmol)。將所得混合物在50℃下攪拌16 h,然後將其冷卻至室溫並在真空下濃縮。藉由使用於PE中之0 - 60% EtOAc洗脫之矽膠管柱層析純化殘餘物以得到2-氯嘧啶-5-甲酸第三丁基酯。C
9H
12ClN
2O
2[M + H]
+之MS ESI計算值:215.05,實驗值:214.95。
步驟2:在氬及室溫下,向2-氯嘧啶-5-甲酸第三丁基酯(4 g, 18.64 mmol)於1,4-二噁烷(40 mL)及水(8 mL)中之混合物中添加(
S)-3-(4-二羥硼基苯基)-2-((第三丁氧基羰基)胺基)丙酸(8.64 g, 28.0 mmol)、PdCl
2(dppf) (1.364 g, 1.864 mmol)及K
2CO
3(7.73 g, 55.9 mmol)。將所得混合物在80℃下攪拌3 h,然後使用1 N HCl將pH調節至4並使用EtOAc (2 x 300 mL)萃取。使用鹽水(3 x 50 mL)洗滌合併之有機層,藉由無水Na
2SO
4乾燥並過濾。在減壓下濃縮濾液。藉由使用於PE中之0 -100% EtOAc洗脫之矽膠管柱層析純化殘餘物以得到(
S)-2-((第三丁氧基羰基)胺基)-3-(4-(5-(第三丁氧基羰基)嘧啶-2-基)苯基)丙酸。C
23H
30N
3O
6[M + H]
+之MS ESI計算值: 444.21,實驗值:444.35。
1H NMR (400 MHz, CDCl
3) δ 9.27 (s, 2H), 8.42 (d,
J= 7.8 Hz, 2H), 7.36 (d,
J= 7.9 Hz, 2H), 4.69 - 4.68 (m, 1H), 3.29 - 3.24 (m, 2H), 1.63 (s, 9H), 1.44 (s, 9H)。
步驟3:在氬及室溫下,向(
S)-2-((第三丁氧基羰基)胺基)-3-(4-(5-(第三丁氧基羰基)嘧啶-2-基)苯基)丙酸(7 g, 15.78 mmol)於DCM (70 mL)中之混合物中添加TFA (14 mL, 182 mmol)。在室溫下攪拌1 h之後,濃縮反應液以獲得(
S)-2-胺基-3-(4-(5-(第三丁氧基羰基)嘧啶-2-基)苯基)丙酸。C
18H
22N
3O
4[M + H]
+之MS ESI計算值:344.15,實驗值:344.20。
步驟4:在氬及室溫下,向(
S)-2-胺基-3-(4-(5-(第三丁氧基羰基)嘧啶-2-基)苯基)丙酸(4 g, 11.65 mmol)於THF (40 mL)及H
2O (40 mL)中之混合物中添加NaHCO
3(4.89 g, 58.2 mmol)及Fmoc-OSu (3.54 g, 10.48 mmol)。在室溫下攪拌1 h之後,使用1 N HCl將pH調節至4且使用EtOAc (2 x 300 mL)萃取溶液。使用鹽水(150 mL)洗滌合併之有機層,藉由無水Na
2SO
4乾燥,並過濾。在減壓下濃縮濾液且藉由RP-flash使用下列條件來純化殘餘物:管柱:C18管柱(330 g);移動相A:水(0.05% TFA);移動相B:MeCN;(梯度:保持0% B 5 min,在30 min內升至73% B,保持73% B 10 min;在4 min內升至95% B,保持95% B 10 min);流速:60 mL/min;檢測器:UV 254 & 210 nm;RT:35.32 min)以得到(
S)-2-((((9
H-茀-9-基)甲氧基)羰基)胺基)-3-(4-(5-(第三丁氧基羰基)嘧啶-2-基)苯基)丙酸。C
33H
32N
3O
6[M + H]
+之MS ESI計算值:566.22,實驗值:566.35。
1H NMR (300 MHz, DMSO-
d6) δ 12.85 (s, 1H), 9.24 (s, 2H), 8.37 (d,
J= 8.0 Hz, 2H), 7.88 - 7.79 (m, 3H), 7.66 - 7.14 (m, 8H), 4.30 - 4.14 (m, 4H), 3.22 - 3.16 (m, 1H), 3.05 - 2.82 (m, 1H), 1.59 (s, 9H)。
合成反應圖 11 Prot4NHBn (2S,4R)-1-(((9H- 茀 -9- 基 ) 甲氧基 ) 羰基 )-4-( 苄基胺基 ) 吡咯啶 -2- 甲酸步驟1:在室溫下,向(2
S,4
R)-4-胺基吡咯啶-1,2-二甲酸1-(第三丁基)酯2-甲基酯(10 g, 40.9 mmol)於DCM (100 mL)中之混合物中添加TEA (14.26 mL, 102 mmol)及NsCl (10.89 g, 49.1 mmol)。將反應液在室溫下攪拌4 h。使用水(150 mL)將所得溶液驟冷並使用EtOAc (3 x 300 mL)萃取。合併有機層,使用鹽水(2 x 150 mL)洗滌,藉由無水Na
2SO
4乾燥,並過濾。在真空中濃縮濾液。藉由使用於PE中之0%至45% EtOAc梯度洗脫之矽膠層析純化殘餘物以提供(2
S,4
R)-4-((4-硝基苯基)磺醯胺基)吡咯啶-1,2-二甲酸1-(第三丁基)酯2-甲基酯。C
17H
24N
3O
8S [M + H - Boc]
+之MS ESI計算值:330.12,實驗值:330.10。
1H NMR (400 MHz, CDCl
3) δ 8.18 - 8.16 (m, 1H), 7.91 - 7.87 (m, 1H), 7.79 - 7.75 (m, 2H), 4.40 - 4.29 (m, 1H), 4.18 - 4.15 (m, 1H), 3.72 (s, 3H), 3.66 - 3.62 (m, 1H), 3.26 - 3.19 (m, 1H), 2.29 - 2.15 (m, 2H), 1.38 (s, 9H)。
步驟2:在環境溫度下,向(2
S,4
R)-4-((4-硝基苯基)磺醯胺基)吡咯啶-1,2-二甲酸1-(第三丁基)酯2-甲基酯(17 g, 39.6 mmol)於DCM (60 mL)中之混合物中添加TFA (30 mL, 389 mmol)。將反應液在環境溫度下攪拌2 h,然後在真空下濃縮以提供(2
S,4
R)-4-((4-硝基苯基)磺醯胺基)吡咯啶-2-甲酸甲酯。C
12H
16N
3O
6S [M + H ]
+之MS ESI計算值:330.07,實驗值:330.10。
步驟3:在環境溫度下,向(2
S,4
R)-4-((4-硝基苯基)磺醯胺基)吡咯啶-2-甲酸甲酯(18.5 g, 39.3 mmol)於THF (150 mL)及水(150 mL)中之溶液中添加NaHCO
3(16.52 g, 197 mmol)及Alloc-OSu (5.46 mL, 35.4 mmol)。將反應液在環境溫度下攪拌4小時,然後使用水(100 mL)稀釋並使用EtOAc (3 x 250 mL)萃取。合併有機層,使用鹽水(2 x 150 mL)洗滌,藉由無水Na
2SO
4乾燥,並過濾。在真空中濃縮濾液。藉由使用於PE中之0%至55% EtOAc梯度洗脫之矽膠層析純化殘餘物以提供(2
S,4
R)-4-((4-硝基苯基)磺醯胺基)吡咯啶-1,2-二甲酸1-烯丙基酯2-甲基酯。C
16H
20N
3O
8S [M + H]
+之MS ESI計算值:414.09,實驗值:413.95。
1H NMR (300 MHz, CDCl
3) δ 8.18 - 8.15 (m, 1H), 7.91 - 7.88 (m, 1H), 7.82 - 7.77 (m, 2H), 5.84 - 5.70 (m, 1H), 5.30 - 5.16 (m, 2H), 4.58 - 4.52 (m, 2H), 4.50 - 4.48 (m, 1H), 4.47 - 4.15 (m, 1H), 3.78 - 3.73 (m, 4H), 3.32 - 3.28 (m, 1H), 2.30 - 2.19 (m, 2H)。
步驟4:在環境溫度下,向(2
S,4
R)-4-((4-硝基苯基)磺醯胺基)吡咯啶-1,2-二甲酸1-烯丙基酯2-甲基酯(8.1 g, 19.59 mmol)於DMF (100 mL)中之溶液中添加(溴甲基)苯(4.02 g, 23.51 mmol)及K
2CO
3(8.12 g, 58.8 mmol)。將反應液在環境溫度下攪拌4 h,然後使用水(100 mL)驟冷並使用EtOAc (3 x 250 mL)萃取。合併有機層,使用鹽水(4 x 200 mL)洗滌,藉由無水Na
2SO
4乾燥,並過濾。在真空下濃縮濾液。藉由使用於PE中之0%至55% EtOAc梯度洗脫之矽膠層析純化殘餘物以提供(2
S,4
R)-4-((
N-苄基-4-硝基苯基)磺醯胺基)吡咯啶-1,2-二甲酸1-烯丙基酯2-甲基酯。C
23H
26N
3O
8S [M + H]
+之MS ESI計算值:504.14,實驗值:504.20。
1H NMR (300 MHz, CDCl
3) δ 7.88 - 7.84 (m, 1H), 7.68 - 7.67 (m, 2H), 7.66 - 7.55 (m, 1H), 7.29 - 7.23 (m, 5H), 5.85 - 5.75 (m, 1H), 5.25 - 5.18 (m, 2H), 4.19 - 4.15 (m, 6H), 3.73 - 3.25 (m, 5H), 2.23 - 2.15 (m, 2H)。
步驟5:在環境溫度下,向(2
S,4
R)-4-((
N-苄基-4-硝基苯基)磺醯胺基)吡咯啶-1,2-二甲酸1-烯丙基酯2-甲基酯(9.3 g, 18.47 mmol)於DMF (40 mL)中之溶液中添加4-甲氧基苯硫醇(3.11 g, 22.16 mmol)及K
2CO
3(7.66 g, 55.4 mmol)。將反應液在環境溫度下攪拌1小時,然後使用水(100 mL)稀釋並使用EtOAc (3 x 150 mL)萃取。合併有機層,使用鹽水(2 x 100 mL)洗滌,藉由無水Na
2SO
4乾燥,並過濾。藉由RP-flash使用下列條件來純化殘餘物:管柱:Flash C18 (330 g);移動相A:水(0.05% TFA),移動相B:MeCN;(梯度:保持5% B 5 min,升在15 min內至32% B,保持32% B 6 min;在5 min內升至95% B,保持95% B 5 min);流速:90 mL/min;檢測器:UV 210 nm;RT = 36 min。收集含產物級分並在真空中濃縮以得到(2
S,4
R)-4-(苄基胺基)吡咯啶-1,2-二甲酸1-烯丙基酯2-甲基酯。C
17H
23N
2O
4[M + H]
+之MS ESI計算值:319.16,實驗值:319.10。
1H NMR (300 MHz, CDCl
3) δ 7.39 - 7.34 (m, 5H), 5.90 - 5.85 (m, 1H), 5.32 - 5.17 (m, 2H), 4.60 - 4.36 (m, 3H), 3.96 - 3.57 (m, 8H), 2.07 - 1.99 (m, 2H)。
步驟6:在環境溫度下,向(2
S,4
R)-4-(苄基胺基)吡咯啶-1,2-二甲酸1-烯丙基酯2-甲基酯(4.5 g, 12.72 mmol)於DCM (40 mL)中之溶液中添加Boc
2O (4.16 g, 19.08 mmol)及TEA (5.32 mL, 38.2 mmol)。將反應液在環境溫度下攪拌4小時,然後使用水(30 mL)驟冷並使用EtOAc (3 x 200 mL)萃取。合併有機層,使用鹽水(2 x 100 mL)洗滌,藉由無水Na
2SO
4乾燥,並過濾。在真空下濃縮濾液。藉由使用於PE中之0%至40% EtOAc梯度洗脫之矽膠層析純化殘餘物以提供(2
S,4
R)-4-(苄基(第三丁氧基羰基)胺基)吡咯啶-1,2-二甲酸1-烯丙基酯2-甲基酯。C
22H
31N
2O
6[M + H]
+之MS ESI計算值:419.21,實驗值:419.15。
1H NMR (300 MHz, CDCl
3) δ 7.34 - 7.15 (m, 5H), 5.90 - 5.85 (m, 1H), 5.25 - 5.18 (m, 2H), 4.58 - 4.32 (m, 6H), 3.74 - 3.44 (m, 5H), 2.49 - 2.38 (m, 1H), 2.12 - 1.99 (m, 1H), 1.42 (s, 9H)。
步驟7:在0℃下,向(2
S,4
R)-4-(苄基(第三丁氧基羰基)胺基)吡咯啶-1,2-二甲酸1-烯丙基酯2-甲基酯(3 g, 5.73 mmol)於THF (15 mL)中之混合物中添加LiOH (11.47 mL, 11.47 mmol, 1 M於水中)。將反應液在環境溫度下攪拌2 h,然後使用HCl水溶液酸化至pH 3~4並使用EtOAc (3 x 150 mL)萃取。合併有機層,使用鹽水(2 x 80 mL)洗滌,藉由無水Na
2SO
4乾燥,並過濾。在真空下濃縮濾液以提供(2
S,4
R)-1-((烯丙基氧基)羰基)-4-(苄基(第三丁氧基羰基)胺基)吡咯啶-2-甲酸。C
21H
29N
2O
6[M + H]
+之MS ESI計算值:405.19,實驗值:405.30。
1H NMR (300 MHz, CDCl
3) δ 7.35 - 7.14 (m, 5H), 5.89 - 5.75 (m, 1H), 5.14 - 5.19 (m, 2H), 4.61 - 4.30 (m, 6H), 3.82 - 3.32 (m, 2H), 2.47 - 2.18 (m, 2H), 1.42 (s, 9H)。
步驟8:在環境溫度下,向(2
S,4
R)-1-((烯丙基氧基)羰基)-4-(苄基(第三丁氧基羰基)胺基)吡咯啶-2-甲酸(2.6 g, 5.46 mmol)於DCM (150 mL)中之混合物中添加AcOH (0.751 mL, 13.11 mmol)及Pd(Ph
3P)
4(0.126 g, 0.109 mmol)。且然後向反應液中添加Bu
3SnH (1.749 g, 6.01 mmol)。在將反應液在環境溫度下攪拌4 h之後,將其在減壓下濃縮以提供(2
S,4
R)-4-(苄基(第三丁氧基羰基)胺基)吡咯啶-2-甲酸。C
17H
25N
2O
4[M + H]
+之MS ESI計算值:321.17,實驗值:321.15。
步驟9:向(2
S,4
R)-4-(苄基(第三丁氧基羰基)胺基)吡咯啶-2-甲酸(3.2 g, 4.99 mmol)於THF (50 mL)及水(50 mL)中之混合物中添加NaHCO
3(2.098 g, 24.97 mmol)直至pH為8~9。且然後將Fmoc-OSu (1.516 g, 4.49 mmol)添加至反應液中。將所得混合物在環境溫度下攪拌4 h,然後使用HCl水溶液酸化至pH 3~4並使用EtOAc (3 x 200 mL)萃取。合併有機層,使用鹽水(2 x 100 mL)洗滌,藉由無水Na
2SO
4乾燥,並過濾。在真空下濃縮濾液以提供粗產物。藉由RP-flash使用下列條件來純化殘餘物:管柱:Flash C18 (330 g);移動相A:水(0.05% TFA),移動相B:MeCN;(梯度:保持5% B 5 min,在25 min內升至70% B,保持70% B 8 min;在2 min內升至95% B,保持95% B 5 min);流速:90 mL/min;檢測器:UV 210 nm;RT = 45 min。收集含產物級分並在真空中濃縮以得到(2
S,4
R)-1-(((9
H-茀-9-基)甲氧基)羰基)-4-(苄基(第三丁氧基羰基)胺基)吡咯啶-2-甲酸。C
32H
35N
2O
6[M + H]
+之MS ESI計算值:543.24,實驗值:543.20。
1H NMR (400 MHz, DMSO-
d6) δ 12.93 (s, 2H), 7.88 (d,
J= 7.6 Hz, 2H), 7.61 - 7.57 (m, 2H), 7.43 - 7.18 (m, 9H), 4.43 - 4.15 (m, 8H), 3.53 - 3.25 (m, 2H), 2.51 - 2.50 (m, 1H), 2.03 - 1.92 (m, 1H), 1.37 (s, 2H)。
合成反應圖 12 Prot4NHCH2CH2Ph (2S,4R)-1-(((9H- 茀 -9- 基 ) 甲氧基 ) 羰基 )-4-( 苯乙基胺基 ) 吡咯啶 -2- 甲酸步驟1:在環境溫度下,向(2
S,4
R)-4-((4-硝基苯基)磺醯胺基)吡咯啶-1,2-二甲酸1-烯丙基酯2-甲基酯(7.2 g, 17.42 mmol)、DIAD (5.08 ml, 26.1 mmol)及PPh
3(6.85 g, 26.1 mmol)於THF (70 mL)中之混合物中添加2-苯基乙烷-1-醇(3.19 g, 26.1 mmol)。將反應液在環境溫度下攪拌4 h,然後使用水(100 mL)驟冷並使用EtOAc (3 x 250 mL)萃取。合併有機層,使用鹽水(4 x 200 mL)洗滌,藉由無水Na
2SO
4乾燥,並過濾。在減壓下濃縮濾液。藉由使用於PE中之0%至55% EtOAc梯度洗脫之矽膠層析純化殘餘物以提供(2
S,4
R)-4-((4-硝基-
N-苯乙基苯基)磺醯胺基)吡咯啶-1,2-二甲酸1-烯丙基酯2-甲基酯。C
24H
28N
3O
8S [M + H]
+之MS ESI計算值:518.15,實驗值:518.20。
步驟2:在環境溫度下,向(2
S,4
R)-4-((4-硝基-
N-苯乙基苯基)磺醯胺基)吡咯啶-1,2-二甲酸1-烯丙基酯2-甲基酯(7.2 g, 13.91 mmol)於DMF (80 mL)中之混合物中添加4-甲氧基苯硫醇(1.950 g, 13.91 mmol)及K
2CO
3(1.923 g, 13.91 mmol)。將反應液在環境溫度下攪拌1小時,然後使用水(200 mL)稀釋並使用EtOAc (3 x 150 mL)萃取。合併有機層,使用鹽水(2 x 500 mL)洗滌,藉由無水Na
2SO
4乾燥,並過濾。在減壓下濃縮濾液且藉由RP-flash使用下列條件來純化殘餘物:管柱:Flash C18 (330 g);移動相A:水(0.05% TFA),移動相B:MeCN;(梯度:保持5% B 5 min,在15 min內升至32% B,保持32% B 6 min;在5 min內升至95% B,保持95% B 5 min);流速:90 mL/min;檢測器:UV 210 nm;RT = 36 min。收集含產物級分並在真空中濃縮以得到(2
S,4
R)-4-(苯乙基胺基)吡咯啶-1,2-二甲酸1-烯丙基酯2-甲基酯。C
18H
25N
2O
4[M + H]
+之MS ESI計算值:333.17,實驗值:333.25。
步驟3:在環境溫度下,向(2
S,4
R)-4-(苯乙基胺基)吡咯啶-1,2-二甲酸1-烯丙基酯2-甲基酯(4 g, 12.03 mmol)於DCM (40 mL)中之混合物中添加Boc
2O (3.93 g, 18.04 mmol)及TEA (3.35 mL, 24.07 mmol)。將反應液在環境溫度下攪拌4小時,然後使用水(30 mL)驟冷並使用EtOAc (3 x 200 mL)萃取。合併有機層,使用鹽水(2 x 100 mL)洗滌,藉由無水Na
2SO
4乾燥,並過濾。在減壓下濃縮濾液。藉由使用於PE中之0%至40% EtOAc梯度洗脫之矽膠層析純化殘餘物以提供(2
S,4
R)-4-((第三丁氧基羰基)(苯乙基)胺基)吡咯啶-1,2-二甲酸1-烯丙基酯2-甲基酯。C
23H
33N
2O
6[M + H]
+之MS ESI計算值:433.23,實驗值:433.25。
步驟4:在0℃下,向(2
S,4
R)-4-((第三丁氧基羰基)(苯乙基)胺基)吡咯啶-1,2-二甲酸1-烯丙基酯2-甲基酯(3.84 g, 8.88 mmol)於THF (30 mL)中之混合物中添加LiOH (17.76 mL, 17.76 mmol, 1 M於水中)。將反應液在環境溫度下攪拌2 h,然後使用HCl水溶液酸化至pH 3~4並使用EtOAc (3 x 150 mL)萃取。合併有機層,使用鹽水(2 x 80 mL)洗滌,藉由無水Na
2SO
4乾燥,並過濾。在減壓下濃縮濾液且粗產物未經任何進一步純化即直接用於下一步驟中。C
22H
31N
2O
6[M + H]
+之MS ESI計算值:419.21,實驗值:419.35。
步驟5:在環境溫度下,向(2
S,4
R)-1-((烯丙基氧基)羰基)-4-((第三丁氧基羰基)(苯乙基)胺基)吡咯啶-2-甲酸(7 g, 16.73 mmol)於DCM (150 mL)中之混合物中添加AcOH (2.411 g, 40.1 mmol)及Pd(Ph
3P)
4(3.87 g, 3.35 mmol)。且然後向反應液中添加Bu
3SnH (5.36 g, 18.40 mmol)。將反應液在環境溫度下攪拌4 h,然後在減壓下濃縮。粗產物未經任何進一步純化即直接用於下一步驟中。C
18H
27N
2O
4[M + H]
+之MS ESI計算值:335.19,實驗值:335.25。
步驟6:在室溫下,向(2
S,4
R)-4-((第三丁氧基羰基)(苯乙基)胺基)吡咯啶-2-甲酸(5.4 g, 16.15 mmol)於THF (50 mL)及水(50 mL)中之混合物中添加NaHCO
3(8.56 g, 81 mmol),且然後添加Fmoc-OSu (4.89 g, 14.54 mmol)。在將反應液在環境溫度下攪拌4 h之後,使用HCl水溶液將其酸化至pH 3~4並使用EtOAc (3 x 400 mL)萃取。合併有機層,使用鹽水(2 x 200 mL)洗滌,藉由無水Na
2SO
4乾燥並過濾。在減壓下濃縮濾液。藉由RP-flash使用下列條件來純化殘餘物:管柱:Flash C18 (330 g);移動相A:水(0.05% TFA),移動相B:MeCN;(梯度:保持5% B 5 min,在25 min內升至70% B,保持70% B 8 min;在2 min內升至95% B,保持95% B 5 min);流速:90 mL/min;檢測器:UV 210 nm;RT = 45 min。收集含產物級分並在真空中濃縮以得到(2
S,4
R)-1-(((9
H-茀-9-基)甲氧基)羰基)-4-((第三丁氧基羰基)(苯乙基)胺基)吡咯啶-2-甲酸。C
33H
37N
2O
6Na [M + Na]
+之MS ESI計算值:579.26,實驗值:579.25。
1H NMR (300 MHz,甲醇-
d4) δ 7.78 - 7.76 (m, 2H), 7.63 - 7.57 (m, 2H), 7.44 - 7.24 (m, 6H), 7.20 - 7.17 (m, 3H), 4.51 - 4.28 (m, 4H), 4.25 - 4.15 (m, 1H), 3.60 - 3.41 (m, 1H), 3.39 - 3.31 (m, 3H), 2.82 - 2.77 (m, 2H), 2.45 - 2.44 (m, 1H), 1.98 - 1.94 (m, 1H), 1.46 (s, 9H)。
合成反應圖 13 Prot4NHEt (2S,4R)-1-(((9H- 茀 -9- 基 ) 甲氧基 ) 羰基 )-4-( 乙基胺基 ) 吡咯啶 -2- 甲酸步驟1:在室溫下,向(2
S,4
R)-4-((4-硝基苯基)磺醯胺基)吡咯啶-1,2-二甲酸1-烯丙基酯2-甲基酯(9.6 g, 23.22 mmol)於DMF (100 mL)中之混合物中添加碘乙烷(4.35 g, 27.9 mmol)及K
2CO
3(9.63 g, 69.7 mmol)。將反應液在室溫下攪拌12 h,然後使用水(80 mL)驟冷並使用EtOAc (3 x 200 mL)萃取。合併有機層,使用鹽水(4 x 150 mL)洗滌,藉由無水Na
2SO
4乾燥,並過濾。在減壓下濃縮濾液。藉由使用於PE中之0%至55% EtOAc梯度洗脫之矽膠層析純化殘餘物以提供(2
S,4
R)-4-((
N-乙基-4-硝基苯基)磺醯胺基)吡咯啶-1,2-二甲酸1-烯丙基酯2-甲基酯。C
18H
24N
3O
8S [M + H]
+之MS ESI計算值:442.12,實驗值:442.05。
1H NMR (300 MHz, CDCl
3) δ 8.02 - 8.01 (m, 1H), 7.73 - 7.62 (m, 3H), 5.95 - 5.78 (m, 1H), 5.29 - 5.18 (m, 2H), 4.58 - 4.43 (m, 4H), 3.76 - 3.73 (m, 4H), 3.38 - 3.29 (m, 3H), 2.29 - 2.26 (m, 2H), 1.26 - 1.20 (m, 3H)。
步驟2:在室溫下,向(2
S,4
R)-4-((
N-乙基-4-硝基苯基)磺醯胺基)吡咯啶-1,2-二甲酸1-烯丙基酯2-甲基酯(5.5 g, 12.46 mmol)及K
2CO
3(5.17 g, 37.4 mmol)於DMF (80 mL)中之經攪拌混合物中添加4-甲氧基苯硫醇(3.49 g, 24.92 mmol)。在將混合物在室溫下攪拌1 h之後,藉由水(200 mL)將其驟冷,使用EtOAc (3 x 200 mL)萃取。使用鹽水(3 x 100 mL)洗滌合併之有機層,藉由無水Na
2SO
4乾燥。在過濾之後,在減壓下濃縮濾液且藉由使用於DCM中之0 - 3% MeOH洗脫之矽膠管柱層析純化殘餘物以提供(2
S,4
R)-4-(乙基胺基)吡咯啶-1,2-二甲酸1-烯丙基酯2-甲基酯。C
12H
21N
2O
4[M + H]
+之MS ESI計算值:257.14,實驗值:257.15。
1H NMR (300 MHz, CDCl
3) δ 6.02 - 5.76 (m, 1H), 5.40 - 5.11 (m, 2H), 4.68 - 4.38 (m, 3H), 3.91 - 3.77 (m, 1H), 3.77 - 3.67 (m, 3H), 3.61 - 3.42 (m, 1H), 3.42 - 3.21 (m, 1H), 2.68 (q,
J= 7.2 Hz, 2H), 2.28 - 2.00 (m, 2H), 1.14 (t,
J= 7.1 Hz, 3H)。
步驟3:在室溫下,向(2
S,4
R)-4-(乙基胺基)吡咯啶-1,2-二甲酸1-烯丙基酯2-甲基酯(2.9 g, 11.31 mmol)及TEA (3.15 mL, 22.63 mmol)於DCM (50 mL)中之經攪拌溶液中添加Boc
2O (3.94 mL, 16.97 mmol)。將所得溶液在25℃下攪拌16 h,然後在減壓下濃縮。藉由使用於PE中之0 - 30% EtOAc洗脫之矽膠管柱層析純化殘餘物以提供(2
S,4
R)-4-((第三丁氧基羰基)(乙基)胺基)吡咯啶-1,2-二甲酸1-烯丙基酯2-甲基酯。C
17H
29N
2O
6[M + H]
+之MS ESI計算值:357.19,實驗值:357.30。
1H NMR (400 MHz, CDCl
3) δ 6.01 - 5.79 (m, 1H), 5.37 - 5.14 (m, 2H), 4.70 - 4.40 (m, 4H), 3.85 - 3.75 (m, 1H), 3.73 (d,
J= 7.8 Hz, 3H), 3.49 - 3.36 (m, 1H), 3.28 - 3.06 (m, 2H), 2.53 - 2.38 (m, 1H), 2.22 - 2.07 (m, 1H), 1.46 (s, 9H), 1.11 (t,
J= 7.0 Hz, 3H)。
步驟4:在室溫下,向(2
S,4
R)-4-((第三丁氧基羰基)(乙基)胺基)吡咯啶-1,2-二甲酸1-烯丙基酯2-甲基酯(3.8 g, 10.66 mmol)於THF (50 mL)中之經攪拌溶液中添加LiOH (32 mL, 32.0 mmol, 1 N於水中)。在將溶液在25℃下攪拌2 h之後,3使用1 N HCl將溶液之pH調節至且然後使用EtOAc (3 x 100 mL)萃取。使用鹽水(100 mL)洗滌合併之有機層,藉由無水Na
2SO
4乾燥。在過濾之後,在減壓下濃縮濾液以得到(2
S,4
R)-1-((烯丙基氧基)羰基)-4-((第三丁氧基羰基)(乙基)胺基)吡咯啶-2-甲酸。C
16H
27N
2O
6[M + H]
+之MS ESI計算值:343.18,實驗值:343.30。
步驟5:在室溫下,向(2
S,4
R)-1-((烯丙基氧基)羰基)-4-((第三丁氧基羰基)(乙基)胺基)吡咯啶-2-甲酸(3.4 g, 9.93 mmol)、AcOH (1.431 g, 23.83 mmol)及Pd(Ph
3P)
4(2.295 g, 1.986 mmol)於DCM (150 mL)中之經攪拌溶液中逐滴添加Bu
3SnH (3.18 g, 10.92 mmol)。將所得溶液在25℃下攪拌1 h,然後在減壓下濃縮以得到(2
S,4
R)-4-((第三丁氧基羰基)(乙基)胺基)吡咯啶-2-甲酸。C
12H
23N
2O
4[M + H]
+之MS ESI計算值:259.16,實驗值:259.30。
步驟6:在室溫下,向(2
S,4
R)-4-((第三丁氧基羰基)(乙基)胺基)吡咯啶-2-甲酸(2.5 g, 9.68 mmol)及Na
2CO
3(3.08 g, 29.0 mmol)於THF (60 mL)及水(60 mL)中之經攪拌溶液中添加Fmoc-OSu (3.26 g, 9.68 mmol)。在將所得混合物在25℃下攪拌16 h之後,使用1 N HCl將pH調節至3且然後使用EtOAc (3 x 100 mL)萃取。使用鹽水(2 x 50 mL)洗滌合併之有機層,藉由無水Na
2SO
4乾燥。在過濾之後,在減壓下濃縮濾液且藉由RP-flash使用下列條件來純化殘餘物:330 g C18管柱,在5 min內5% - 5%、在40 min內5% - 65%之於水中之MeCN (0.05% TFA)以得到(2
S,4
R)-1-(((9
H-茀-9-基)甲氧基)羰基)-4-((第三丁氧基羰基)(乙基)胺基)吡咯啶-2-甲酸。C
27H
33N
2O
6[M + H]
+之MS ESI計算值:481.23,實驗值:481.10。
1H NMR (400 MHz, DMSO-
d6) δ 12.98 (br, 1H), 7.90 (d,
J= 7.6 Hz, 2H), 7.68 - 7.64 (m, 2H), 7.44 - 7.41 (m, 2H), 7.35 - 7.31 (m, 2H), 4.43 - 4.18 (m, 5H), 3.60 - 3.56 (m, 1H), 3.29 - 3.22 (m, 1H), 3.16 - 3.12 (m, 2H), 2.42 - 2.38 (m, 1H), 2.08 - 2.01 (m, 1H), 1.40 (s, 9H), 1.05 - 1.00 (m, 3H)。
合成反應圖 14 PyrimAla4AcPip (S)-2-((((9H- 茀 -9- 基 ) 甲氧基 ) 羰基 ) 胺基 )-3-(2-(4- 乙醯基六氫吡嗪 -1- 基 ) 嘧啶 -5- 基 ) 丙酸步驟1:在室溫下,向5-溴-2-氟嘧啶(7 g, 39.6 mmol)於DMF (70 ml)中之混合物中添加1-(六氫吡嗪-1-基)乙烷-1-酮(10.14 g, 79 mmol)及K
2CO
3(10.93 g, 79 mmol)。將反應混合物在100℃下攪拌2 h,然後冷卻回室溫。使用500 mL EtOAc萃取反應混合物,使用H
2O (3 x 100 mL)及鹽水(80 mL)洗滌,藉由Na
2SO
4乾燥,過濾且在減壓下濃縮濾液。藉由使用於PE中之0% - 80% EtOAc梯度洗脫之矽膠管柱層析純化殘餘物。合併含有期望產物之級分並在減壓下濃縮以提供4-(5-溴嘧啶-2-基)六氫吡嗪-1-甲醛。C
10H
14BrN
4O [M + H]
+之MS ESI計算值:285.03、287.03,實驗值:284.95、286.95。1H NMR (300 MHz, CDCl
3) δ 8.32 (s, 2H), 3.90 - 3.74 (m, 4H), 3.74 - 3.64 (m, 2H), 3.58 - 3.48 (m, 2H), 2.15 (s, 3H)。
步驟2:將氯化鎳(II)乙二醇二甲基醚複合物(0.693 g, 3.16 mmol)及1,10-菲咯啉(0.569 g, 3.16 mmol)於DMA (50 mL)中之混合物在50℃下加熱0.5小時。在25℃下添加1-(4-(5-溴嘧啶-2-基)六氫吡嗪-1-基)乙烷-1-酮(4.5 g, 15.78 mmol)、(
R)-2-((((9
H-茀-9-基)甲氧基)羰基)胺基)-3-碘丙酸第三丁基酯(11.68 g, 23.67 mmol)及TBAI (5.83 g, 15.78 mmol)於DMA (50 mL)中之溶液。然後添加Zn (2.064 g, 31.6 mmol)。在將所得混合物在30℃下攪拌24 h之後,過濾反應混合物並使用DCM洗滌。在減壓下濃縮有機相。藉由RP-flash使用下列條件來純化殘餘物:管柱:C18管柱(330 g);移動相A:水(0.05% TFA);移動相B:MeCN;(梯度:保持0% B 5 min,在30 min內升至82% B,保持82% B 6 min;在2 min內升至95% B,保持95% B 3 min);流速:60 mL/min;檢測器:UV 254 & 210 nm;RT:35 min)以得到(
S)-2-((((9
H-茀-9-基)甲氧基)羰基)胺基)-3-(2-(4-乙醯基六氫吡嗪-1-基)嘧啶-5-基)丙酸第三丁基酯。C
32H
38N
5O
5[M + H]
+之MS ESI計算值:572.28,實驗值:572.30。1H NMR (300 MHz, CDCl
3) δ 8.19 (s, 2H), 7.77 (d,
J= 7.6 Hz, 2H), 7.63 - 7.52 (m, 2H), 7.46 - 7.26 (m, 4H), 4.48 - 4.42 (m,2H), 4.35 - 4.30 (m, 1H), 4.22 - 4.17 (m, 1H), 3.89 - 3.81 (m, 4H), 3.71 - 3.68 (m, 2H), 3.56 - 3.52 (m, 2H), 3.08 - 3.02 (m, 1H), 2.92 - 2.87 (m, 1H), 2.17 (s, 3H), 1.48 (s, 9H)。
步驟3:在氬及室溫下,向(
S)-2-((((9
H-茀-9-基)甲氧基)羰基)胺基)-3-(2-(4-乙醯基六氫吡嗪-1-基)嘧啶-5-基)丙酸第三丁基酯(4.6 g, 8.05 mmol)於DCM (40 mL)中之混合物中添加TFA (80 mL, 1038 mmol)。將反應液在室溫下攪拌3 h,然後在減壓下濃縮。藉由RP-flash使用下列條件來純化殘餘物:管柱:C18凝膠管柱(330 g);移動相A:水(0.05% TFA);移動相B:MeCN;(梯度:保持0% B 5 min,在30 min內升至72% B,保持72% B 6 min;在2 min內升至95% B,保持95% B 10 min);流速:60 mL/min;檢測器:UV 254 & 210 nm;RT:35 min)以得到(
S)-2-((((9
H-茀-9-基)甲氧基)羰基)胺基)-3-(2-(4-乙醯基六氫吡嗪-1-基)嘧啶-5-基)丙酸。C
28H
30N
5O
5[M + H]
+之MS ESI計算值: 516.22,實驗值:516.35。
1H NMR (300 MHz, DMSO-
d6) δ 8.31 (s, 2H), 7.89 (d,
J= 7.5 Hz, 2H), 7.81 (d,
J= 8.6 Hz, 1H), 7.74 - 7.62 (m, 2H), 7.59 - 7.22 (m, 4H), 4.29 - 4.09 (m, 4H), 3.74 - 3.60 (m, 4H), 3.47 - 3.46 (m, 4H), 2.98 - 2.92 (m, 1H), 2.76 - 2.68 (m, 1H), 2.03 (s, 3H)。
合成反應圖 15 sbMeW4F (2S,3S)-2- 胺基 -3-(4- 氟 -1H- 吲哚 -3- 基 ) 丁酸向經惰性氮氣氛吹掃及維持之1-L 3頸圓底燒瓶中放置4-氟-1H-吲哚(10 g, 1.00當量)、L-蘇胺酸(10.6 g, 1.20當量)、DMSO (100 mL)、磷酸鉀緩衝液(0.2 M, 300 mL, pH = 7.4)。將反應混合物加熱至65℃,然後添加PfTrpB-7E6 (2.5 g, 25 wt%)及3-羥基-2-甲基-5-([膦醯基氧基]甲基)-4-吡啶甲醛(0.078 g, 0.004當量)。將所得溶液在65℃下攪拌過夜 然後將混合物冷卻至室溫並直接用於下一步驟中。
在0℃下,向上述反應混合物中添加THF (100 mL)、碳酸鈉(23.56 g, 3.0當量)及碳酸2,5-二側氧基吡咯啶-1-基酯9H-茀-9-基甲基酯(29.96 g, 1.20當量)。將所得溶液在室溫下攪拌過夜。藉由3 M HCl將pH調節至4且過濾掉固體沈澱物。使用EtOAc (3 x 500 mL)萃取所得溶液。合併有機級分,並使用鹽水(1 L)洗滌,藉由無水硫酸鈉乾燥並在真空下濃縮。將混合物施加於含有MeOH:DCM = 1:5之矽膠管柱上。HPLC-MS:(ES, m/z):[M+1]:459。
1H NMR (300 MHz, DMSO-
d6) δ 12.60 (s, 1H), 11.15 (s, 1H), 7.87 (d, J = 7.6 Hz, 2H), 7.76 – 7.49 (m, 3H), 7.47 – 7.34 (m, 2H), 7.34 – 7.16 (m, 4H), 7.03 (td, J = 7.9, 5.0 Hz, 1H), 6.73 (dd, J = 11.8, 7.7 Hz, 1H), 4.36 (t, J = 8.5 Hz, 1H), 4.31 – 4.02 (m, 3H), 3.51 (q, J = 7.4 Hz, 1H), 1.31 (d, J = 7.0 Hz, 4H), 0.78 (s, 1H)。
合成反應圖 16 sbMeW4Cl (2S,3S)-2- 胺基 -3-(4- 氯 -1H- 吲哚 -3- 基 ) 丁酸向經惰性氮氣氛吹掃及維持之1-L 3頸圓底燒瓶中放置4-氯-1H-吲哚(10g, 1.00當量)、L-蘇胺酸(14.09 g, 1.8當量)、DMSO (100 mL)、磷酸鉀緩衝液(0.2 M, 300 mL, PH = 7.4),將反應混合物加熱至65℃,然後添加PfTrpB-7E6 (7.5g, 25 wt%)及3-羥基-2-甲基-5-([膦醯基氧基]甲基)-4-吡啶甲醛(174 mg, 0.01當量)。將所得溶液在65℃下攪拌36 h。然後將混合物冷卻至室溫並直接用於下一步驟中。
在0℃下,向上述反應混合物中添加THF (100 mL)、碳酸鈉(20.9 g, 3.0當量)及碳酸2,5-二側氧基吡咯啶-1-基酯9H-茀-9-基甲基酯(31.0 g, 1.40當量)。將所得溶液在室溫下攪拌過夜。藉由3 M HCl將pH調節至4且過濾掉固體沈澱物。使用EtOAc (3 x 500 mL)萃取所得溶液。合併有機級分,並使用鹽水(1 L)洗滌,藉由無水硫酸鈉乾燥並在真空下濃縮。HPLC-MS:(ES, m/z):[M+1]:475
合成反應圖 17 sbMe1Nal (2S,3S)-2- 胺基 -3-( 萘 -1- 基 ) 丁酸步驟1:在20℃下,向(2S,3R)-2-((((9H-茀-9-基)甲氧基)羰基)胺基)-3-羥基丁酸(250 g, 1.00當量)於DMF (1.5 L)中之溶液中逐滴添加苄基溴(250 g, 2.00當量)。然後,添加碳酸銫(477 g, 2.00當量)且將溶液在20℃下攪拌3 h。將反應液傾倒至冰H
2O (3 L)中並使用EtOAc (500 mL x 3)萃取。使用3% LiCl溶液(500 mL x 2)及鹽水(500 mL)洗滌有機相,藉由硫酸鈉乾燥並在真空及40℃下濃縮。使用甲基第三丁基醚:PE = 6:1研磨粗產物。
1H NMR (400 MHz, CDCl
3):δ 7.77 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.31-7.36 (m, 10H), 5.65-5.71 m, 1H), 5.13-5.31 (m, 3H), 4.39-4.43 (m, 3H), 4.22-4.25 (m, 1H), 1.25 (d, J = 6.4 Hz, 3H)
步驟2:在惰性氮氣氛下,向3頸圓底燒瓶中添加(2S,3R)- 2-((((9H-茀-9-基)甲氧基)羰基)胺基)-3-羥基丁酸苄基酯(125 g, 1.00當量)及DCE (750 mL)。將反應液冷卻至0℃,隨後添加NIS (195 g, 3.00當量)及PPh
3(228 g, 3.00當量)。使溫度升至50℃且將反應混合物攪拌3 h。將反應液傾倒至冰H
2O (500 mL)中並使用DCM (500 mL x 2)萃取。藉由硫酸鈉乾燥有機相並在真空及40℃下濃縮。藉由矽膠管柱層析(PE/EtOAc =1/0至0/1)純化殘餘物。
1H NMR (400 MHz, CDCl
3):δ 7.78 (d,
J= 7.6 Hz, 2H), 7.68 (d,
J= 7.2 Hz, 2H), 7.33-7.43 (m, 9H), 5.27-5.68 (m,
1H), 5.21-5.23 (m, 2H), 4.39-4.52 (m, 3H), 4.25-4.38 (m, 1H), 1.91-1.95 (m, 3H)。
步驟3:向3頸圓底燒瓶中放置2-((((9H-茀-9-基)甲氧基)羰基)胺基)-3-碘丁酸1-碘萘(42.2 g, 1.20當量)、TBAI (76.7 g, 1.50當量)、Zn (19.0 g, 2.10當量)及DMA (750 mL)。在25℃下,向第二3頸圓底燒瓶中放置2-脒基吡啶.2HCl (42.2 g, 1.20當量)、NiCl
2.glyme (7.61 g, 0.25當量)及DMA (750 mL)。在氬下,將第二燒瓶之內容物添加至第一燒瓶中。然後將所得混合物在25℃下攪拌12 h。將反應液傾倒至冰H
2O (3 L)中並使用EtOAc (1 L x 2)萃取。藉由硫酸鈉乾燥有機相並在真空及40℃下濃縮。藉由反相HPLC (MeCN:H
2O)純化粗產物。HPLC-MS:[M+23]:564。
1H NMR (400 MHz, CDCl
3) δ:8.17-8.24 (m, 1H), 8.15-8.17 (m, 1H), 7.77-7.87 (m, 2H), 7.76-7.77 (m, 4H), 7.30-7.41 (m, 10H), 5.30-5.38 (m, 1H), 4.96-5.04 (m, 3H), 4.85-4.87 (m, 1H), 4.30-4.34 (m, 1H), 4.18-4.26 (m, 4H), 1.43-1.45 (m, 3H)。
步驟4:藉由SFC分離143 g (2S)-2-((((9H-茀-9-基)甲氧基)羰基)胺基)-3-(萘-1-基)丁酸苄基酯。在真空及35℃下濃縮有機相。
峰1:(2S,3R)-2-((((9H-茀-9-基)甲氧基)羰基)胺基)-3-(萘-1-基)丁酸苄基酯。
1H NMR (400 MHz, DMSO-
d6):δ 8.11-8.12 (m, 2H), 8.10-8.11 (m, 1H), 7.88-7.90 (m, 2H), 7.54-7.88 (m, 1H), 7.44-7.53 (m, 2H), 7.42-7.44 (m, 4H), 7.33-7.42 (m, 3H), 7.27-7.33 (m, 6H), 7.08-7.09 (m, 2H), 4.91-4.94 (m, 1H), 4.79- 4.82 (m, 1H), 4.58 (t,
J= 8.0 Hz), 4.17-4.25 (m, 4H), 1.39 (d,
J= 6.8 Hz, 3H)。峰2:(2S,3S)-2-((((9H-茀-9-基)甲氧基)羰基)胺基)-3-(萘-1-基)丁酸苄基酯。
1H NMR (400 MHz, DMSO-
d6):δ 7.92-8.15 (m, 1H), 7.86-7.92 (m, 1H), 7.84-7.86 (m, 1H), 7.57-7.84 (m, 2H), 7.56-7.57 (m, 1H), 7.41-7.54 (m, 4H), 7.30-7.38 (m, 4H), 7.27-7.30 (m, 7H), 5.08-5.14 (m, 2H), 4.65 (t,
J= 8.0 Hz), 4.23-4.26 (m, 1H), 4.05-4.18 (m, 3H), 1.30 (d,
J= 6.8 Hz, 3H)。
步驟5:向3頸圓底燒瓶中添加(2S,3S)-2-((((9H-茀-9-基)甲氧基)羰基)胺基)-3-(萘-1-基)丁酸苄基酯(40.0 g, 1.00當量)及THF (200 mL)。添加10%濕潤Pd/C (7.00 g)且使用H
2將反應液吹掃3次並在25℃及H
2(15 psi)下攪拌12 h。經由矽藻土墊過濾反應液並在真空及35℃下濃縮。使用PE在25℃下將粗產物研磨1 h。在過濾之後,將濾餅溶於MeCN (100 mL)中並在真空及35℃下濃縮以去除殘餘溶劑。HPLC-MS:[M+23]:474。
1H NMR (400 MHz, DMSO-
d6) δ 12.78 (s, 1H), 8.23 (d,
J= 7.6 Hz, 1H), 7.86-7.88 (m, 1H), 7.80-7.86 (m, 2H), 7.61-7.80 (m, 2H), 7.55-7.59 (m, 4H), 7.481-7.55 (m, 1H), 7.40-7.48 (m, 3H), 7.27-7.29 (m, 2H), 4.28-4.60 (m, 1H), 4.24-4.28 (m, 1H), 4.17-4.24 (m, 2H), 4.04-4.15 (m, 1H), 1.36 (d,
J= 6.8 Hz, 3H)。
合成反應圖 18 L - 酪胺酸 O - 乙基乙醯胺或 (S)-3-(4-(2- 乙醯胺基乙氧基 ) 苯基 )-2- 胺基丙酸步驟1:在室溫下,向(第三丁氧基羰基)-L-酪胺酸甲酯(10.0 g, 33.9 mmol)、(2-溴乙基)胺基甲酸苄基酯(26.2 g, 102 mmol)及TBAB (5.46 g, 16.93 mmol)於DMF (150 mL)中之經攪拌溶液中添加碳酸鉀(14.04 g, 102 mmol)。然後將混合物在50℃下攪拌24 h。將混合物冷卻至室溫,使用水(250 mL)驟冷並使用EtOAc (2 x 500 mL)萃取。使用鹽水(3 x 150 mL)洗滌合併之有機層,藉由無水硫酸鈉乾燥並過濾。在減壓下濃縮濾液,且藉由使用於PE中之0 - 30% EtOAc洗脫之矽膠管柱層析純化殘餘物。C
25H
32N
2O
7[M + Na]
+之MS ESI計算值:495.22,實驗值:495.10;
1H NMR (300 MHz, CDCl
3) δ 7.38 - 7.32 (m, 5H), 7.04 (d,
J= 8.4 Hz, 2H), 6.81 (d,
J= 8.4 Hz, 2H), 5.31 (br, 1H), 5.21 (s, 2H), 4.97 (br, 1H), 4.56 - 4.53 (m, 1H), 4.03 (t,
J= 5.0 Hz, 2H), 3.72 (s, 3H), 3.64 - 3.58 (m, 2H), 3.06 - 3.01 (m, 2H), 1.43 (s, 9H)。
步驟2:在室溫及氮氣氛下,向(
S)-3-(4-(2-(((苄基氧基)羰基)胺基)乙氧基)苯基)-2-((第三丁氧基羰基)胺基)丙酸甲酯(16.0 g, 33.9 mmol)及乙酸酐(6.39 mL, 67.7 mmol)於THF (200 mL)中之經攪拌溶液中添加Pd/C (3.60 g, 33.9 mmol,乾燥,10%wt)。使用氫將混合物脫氣3次並在20℃下攪拌4 h。將DIPEA (17.74 mL, 102 mmol)添加至混合物中並在20℃下攪拌1 h。過濾混合物,且在減壓下濃縮濾液。藉由使用於DCM中之0 - 3% MeOH洗脫之矽膠管柱層析純化殘餘物。C
19H
28N
2O
6[M + Na]
+之MS ESI計算值:403.19,實驗值:403.10;
1H NMR (300 MHz, CDCl
3) δ 7.05 (d,
J= 8.4 Hz, 2H), 6.85 - 6.80 (m, 2H), 5.99 (br, 1H), 5.32 (br, 1H), 4.99 - 4.97 (m, 1H), 4.02 (t,
J= 5.0 Hz, 2H), 3.72 (s, 3H), 3.69 - 3.63 (m, 2H), 3.10 - 2.89 (m, 2H), 2.02 (s, 3H), 1.42 (s, 9H)。
步驟3:在室溫下,向(
S)-3-(4-(2-乙醯胺基乙氧基)苯基)-2-((第三丁氧基羰基)胺基)丙酸甲酯(12.5 g, 32.9 mmol)於THF (100 mL)中之經攪拌溶液中添加氫氧化鋰(65.7 mL, 65.7 mmol, 1 N於水中)。將溶液在20℃下攪拌2 h。使用1 N HCl將溶液之pH調節至3。使用EtOAc (2 x 250 mL)萃取水層。使用鹽水(150 mL)洗滌合併之有機層,藉由無水硫酸鈉乾燥,過濾,並在減壓下濃縮。
MS ESI [M + H]
+:367.10。
步驟4:在室溫下,向(
S)-3-(4-(2-乙醯胺基乙氧基)苯基)-2-((第三丁氧基羰基)胺基)丙酸(12.5 g, 30.7 mmol)於THF (20 mL)中之經攪拌溶液中添加於二噁烷中之4 N HCl (200 mL)。將溶液在20℃下攪拌1 h。在減壓下濃縮溶劑。MS ESI [M + H]
+:267.05。
步驟5:在室溫下,向(
S)-3-(4-(2-乙醯胺基乙氧基)苯基)-2-胺基丙酸鹽酸鹽(9.50 g, 25.1 mmol)及NaHCO
3(10.54 g, 126 mmol)於THF (100 mL)及水(100 mL)中之經攪拌混合物中添加Fmoc-OSu (7.62 g, 22.59 mmol)。將混合物在20℃下攪拌1 h。使用1 N HCl將溶液之pH值調節至3。使用EtOAc (2 x 500 mL)萃取水相。使用鹽水(150 mL)洗滌合併之有機層,藉由無水碳酸氫鈉乾燥並過濾。在減壓下濃縮濾液,且自EtOAc (200 mL)使殘餘物重結晶。藉由過濾收集固體並在真空下乾燥。MS ESI [M + H]
+:489.05;
1H NMR (300 MHz,甲醇-
d4) δ 7.79 (d,
J= 7.6 Hz, 2H), 7.62-7.57 (m, 2H), 7.42-7.26 (m, 4H), 7.17-7.14 (m, 2H), 6.83 (d,
J= 8.4 Hz, 2H), 4.41-4.31 (m, 2H), 4.29-4.10 (m, 2H), 3.96 (t,
J= 4.8 Hz, 2H), 3.51 (t,
J= 5.4 Hz, 2H), 3.19-3.13 (m, 1H), 2.92-2.84 (m, 1H), 1.94 (s, 3H)。
合成反應圖 19 (S)-2-((((9H- 茀 -9- 基 ) 甲氧基 ) 羰基 ) 胺基 )-3-(4-(2- 嗎啉基乙氧基 ) 苯基 ) 丙酸步驟1:在0℃下,向(第三丁氧基羰基)-L-酪胺酸第三丁基酯(400 mg, 1.185 mmol)於DMF (4.742 ml)中之溶液中添加碳酸銫(1 g, 3.08 mmol)。將反應液攪拌15 min且添加4-甲基苯磺酸2-嗎啉基乙基酯(474 mg, 1.660 mmol),並在0℃下攪拌2.5小時。使用EtOAc稀釋反應液並使用10% LiCl水溶液洗滌。使用1 M HCl、飽和NaHCO
3水溶液及NaCl水溶液洗滌有機層,然後使用硫酸鈉乾燥,過濾,並濃縮。藉由管柱層析使用RediSep Rf Gold 24 g二氧化矽預封裝管柱在Isco上(使用於己烷中之0-100% EtOAc梯度洗脫,經30 min.過程)來純化粗製材料以得到產物。MW:450.576;MS ESI [M + H]
+:451.3。
步驟2:在環境溫度下,將(S)-2-((第三丁氧基羰基)胺基)-3-(4-(2-嗎啉基乙氧基)苯基)丙酸第三丁基酯(525 mg, 1.165 mmol)溶於DCM (3 mL)中。添加TFA (3 mL)並在環境溫度下攪拌1.5小時。在減壓下濃縮反應液並以粗製物形式繼續使用。MW:294.351,實驗值:MS ESI [M + H]
+:295.1。
步驟3:在環境溫度下,將(S)-2-胺基-3-(4-(2-嗎啉基乙氧基)苯基)丙酸(354 mg, 1.203 mmol)溶於四氫呋喃(3 mL)及水(3 mL)中。將反應液冷凍至0℃。添加碳酸鈉(382 mg, 3.61 mmol)且將溶液在0℃下攪拌5 min。添加碳酸(9H-茀-9-基)甲酯(2,5-二側氧基吡咯啶-1-基)酯(406 mg, 1.203 mmol)並攪拌2 h。在減壓下去除THF。使用1 N HCl將水溶液酸化至pH 3。使用EtOAc萃取反應液,使用水洗滌,使用硫酸鈉乾燥,過濾,並濃縮。藉由反相管柱層析使用50 g C18預封裝管柱在Isco上(使用於TFA改質水中之10-100% TFA改質性MeCN梯度洗脫,經30 min.過程)純化粗製材料以得到呈級分形式之產物。合併級分,冷凍於-78℃乾冰/丙酮浴中,並凍乾以提供產物。MW:516.94。實驗值:MS ESI [M + H]
+:517.2。
合成反應圖 20 (R)-2,4- 二胺基 -2- 甲基丁醛步驟1:在室溫下,向(
R)-2-胺基-2-甲基戊-4-烯酸(1.3 g, 10.07 mmol)及DIPEA (5.27 mL, 30.2 mmol)於二噁烷(20 mL)及水(20 mL)中之經攪拌溶液中添加Fmoc-OSu (3.73 g, 11.07 mmol)。將所得溶液在25℃下攪拌16 h。使用1 N HCl將pH調節至3且藉由反相急速管柱層析使用下列條件來純化溶液:C18管柱,330 g,在5 min內5% - 5%、在30 min內5% - 50%、在5 min內98% - 98%之於水中之MeCN (0.05% TFA)以得到(
R)-2-((((9
H-茀-9-基)甲氧基)羰基)胺基)-2-甲基戊-4-烯酸。C
21H
21NO
4Na [M + Na]
+之MS ESI計算值:374.15,實驗值:374.05。
1H NMR (400 MHz, CDCl
3)
δ7.79 (d,
J= 7.5 Hz, 2H), 7.61 (d,
J= 7.5 Hz, 2H), 7.48 - 7.29 (m, 4H), 5.71 (s, 1H), 5.48 (s, 1H), 5.20 - 5.16 (m, 2H), 4.44 - 4.40 (m, 2H), 4.25 (t,
J= 6.7 Hz, 1H), 2.82-2.71 (m, 2H)。
步驟2:在室溫下,向(
R)-2-((((9
H-茀-9-基)甲氧基)羰基)胺基)-2-甲基戊-4-烯酸(3 g, 8.54 mmol)及
N-甲基嗎啉
N-氧化物(2.2 g, 9.39 mmol, 50%於水中)於丙酮(60 mL)中之經攪拌溶液中添加OsO
4(2.170 g, 0.854 mmol, 10%於水中)。將所得溶液在25℃下攪拌4 h。將於水(20 mL)中之過碘酸鈉(2.00 g, 9.39 mmol)添加至溶液中且將所得混合物在25℃下攪拌16 h。使用水(50 mL)稀釋反應混合物並使用EtOAc (3 x 200 mL)萃取。使用鹽水(2 x 100 mL)洗滌合併之有機層,藉由無水硫酸鈉乾燥,並過濾。然後在減壓下濃縮濾液以得到(
R)-2-((((9
H-茀-9-基)甲氧基)羰基)胺基)-2-甲基-4-側氧基丁酸。C
20H
20NO
5[M + H]
+之MS ESI計算值:354.13,實驗值:354.00。
步驟3:在室溫下,向(
R)-2-((((9
H-茀-9-基)甲氧基)羰基)胺基)-2-甲基-4-側氧基丁酸(3 g, 6.79 mmol)於甲苯(120 mL)中之經攪拌溶液中添加胺基甲酸第三丁基酯(4.77 g, 40.8 mmol)及TFA (2.32 g, 20.38 mmol)。將所得溶液在25℃下攪拌2 h。在減壓下濃縮溶液以得到(
R,
Z)-2-((((9
H-茀-9-基)甲氧基)羰基)胺基)-4-((第三丁氧基羰基)亞胺基)-2-甲基丁酸。C
25H
27N
2O
6[M - H]
+之MS ESI計算值:451.19,實驗值:450.90。
步驟4:在室溫下,向(
R,
Z)-2-((((9
H-茀-9-基)甲氧基)羰基)胺基)-4-((第三丁氧基羰基)亞胺基)-2-甲基丁酸(3.1 g, 5.48 mmol)及二甲基(苯基)矽烷(1.87 g, 13.7 mmol)於甲苯(120 mL)中之經攪拌溶液中添加參(五氟苯基)硼烷(0.281 g, 0.548 mmol)。將溶液在25℃下攪拌16 h。在減壓下濃縮溶劑且藉由反相急速層析使用下列條件來純化殘餘物:330 g C18管柱,在5 min內5% - 5%、在30 min內5% - 55%、在5 min內98% - 98%之於水中之MeCN (0.05% TFA), RT = 35 min)以得到(
R)-2-((((9
H-茀-9-基)甲氧基)羰基)胺基)-4-((第三丁氧基羰基)胺基)-2-甲基丁酸。C
25H
31N
2O
6[M + H]
+之MS ESI計算值:455.21,實驗值:455.10;
1H NMR (400 MHz, DMSO-
d 6) δ 12.48 (s, 1H), 7.90 (d,
J= 7.2 Hz, 2H), 7.73 (d,
J= 7.2 Hz, 2H), 7.54 (s, 1H), 7.44 - 7.41 (m, 2H), 7.36 - 7.32 (m, 2H), 6.78 (s, 1H), 4.25 - 4.23 (m, 3H), 2.92 - 2.91 (m, 2H), 1.99 - 1.93 (m, 1H), 1.87 - 1.81 (m, 1H), 1.37 - 1.34 (m, 9H)。
合成反應圖 21 [(R)-3- 胺基 -3- 羧丙基 ]- 三甲基氮鎓步驟1:在環境溫度下,向(
R)-4-胺基-2-((第三丁氧基羰基)胺基)丁酸(7 g, 32.1 mmol)於MeOH (30 mL)中之混合物中添加CH
3I (10.03 mL, 160 mmol)及KHCO
3(16.05 g, 160 mmol)。將反應液升溫至35℃並保持12 h。然後過濾反應混合物且在減壓下濃縮濾液以提供粗產物。將殘餘物溶於乙醇中且隨後再次過濾。在減壓下濃縮濾液以提供(
R)-3-((第三丁氧基羰基)胺基)-3-羧基-
N,
N,
N-三甲基丙烷-1-碘化銨。C
12H
25IN
2O
4[M - I]
+之MS ESI計算值:261.18,實驗值:261.30。
步驟2:在環境溫度下,向(
R)-3-((第三丁氧基羰基)胺基)-3-羧基-
N,
N,
N-三甲基丙烷-1-碘化銨(15 g, 23.18 mmol)於DCM (60 mL)中之混合物中添加TFA (30 mL, 389 mmol)。將反應液在環境溫度下攪拌1 h,然後在減壓下濃縮以提供(
R)-2,2,2-三氟乙酸3-胺基-3-羧基-
N,
N,
N-三甲基丙烷-1-銨。C
9H
17F
3N
2O
4[M-CF
3COO]
+之MS ESI計算值:161.13,實驗值:161.30。
步驟3:向(
R)-2,2,2-三氟乙酸3-胺基-3-羧基-
N,
N,
N-三甲基丙烷-1-銨(11.5 g, 20.97 mmol)於THF (40 mL)及水(40 mL)中之混合物中添加NaHCO
3(8.81 g, 105 mmol)及Fmoc-OSu (6.37 g, 18.87 mmol)。將反應液在環境溫度下攪拌2 h,然後使用HCl水溶液酸化至pH 3-4並過濾以提供粗產物。藉由反相管柱層析使用下列條件來純化粗產物:330 g C18管柱;移動相A:水(0.05% TFA),移動相B:MeCN;(梯度:保持0% B 5 min,在19 min內升至33% B,保持38% B 7 min;在5 min內升至95% B,保持95% B 5 min);流速:80 mL/min。收集含產物級分並凍乾以提供(
R)-2,2,2-三氟乙酸3-((((9
H-茀-9-基)甲氧基)羰基)胺基)-3-羧基-
N,
N,
N-三甲基丙烷-1-銨。C
24H
27F
3N
2O
6[M-CF
3COO]
+之MS ESI計算值:383.20,實驗值:383.25。
1H NMR (300 MHz, DMSO-
d 6)
δ7.91 (d,
J= 7.2 Hz, 2H), 7.79 - 7.71 (m, 3H), 7.46 - 7.41 (m, 2H), 7.37 - 7.32 (m, 2H), 4.42 - 4.22 (m, 3H), 4.07 - 4.01 (m, 1H), 3.99 - 3.41 (m, 1H), 3.33 - 3.28 (m, 1H), 3.07 (s, 9H), 2.21 - 2.16 (m, 1H), 2.08 - 2.04 (m, 1H)。
19F-NMR (282 MHz, DMSO-
d 6)
δ73.931。
合成反應圖 22 3-[4-[(S)-2- 胺基 -2- 羧乙基 ] 苯基 ] 雙環 [1.1.1] 戊烷 -1- 甲酸步驟1:在0℃及氬氣氛下,向(
S)-2-((第三丁氧基羰基)胺基)-3-(4-碘苯基)丙酸(3.91 g, 10 mmol)於DMF (40 mL)中之經攪拌混合物中添加3-溴丙-1-烯(3.63 g, 30.0 mmol)及NaHCO
3(0.840 g, 10.00 mmol)。將所得混合物在40℃下攪拌16 h。將反應混合物冷卻至室溫並使用水(200 mL)驟冷,且使用EtOAc (2 x 200 mL)萃取。使用鹽水(3 x 100 mL)洗滌合併之有機層,藉由無水硫酸鈉乾燥,並過濾。在減壓下濃縮濾液且藉由矽膠管柱層析(使用於PE中之0 ~ 40% EtOAc洗脫)純化殘餘物,且收集含產物級分並在減壓下蒸發以提供(
S)-2-((第三丁氧基羰基)胺基)-3-(4-碘苯基)丙酸烯丙基酯。C
27H
25INO
4[M + H]
+之MS ESI計算值:554.08,實驗值:554.20。
步驟2:在室溫下,向3-(甲氧基羰基)雙環[1.1.1]戊烷-1-甲酸(8 g, 47.0 mmol)於DCM (100 mL)中之經攪拌溶液中添加(
Z)-
N,
N'-二異丙基胺基甲亞胺酸第三丁基酯(37.7 g, 188 mmol)。將所得溶液在40℃下攪拌2 h。然後將混合物冷卻至室溫。過濾出固體且在減壓下濃縮濾液以得到雙環[1.1.1]戊烷-1,3-二甲酸1-(第三丁基)酯3-甲基酯。
1H NMR (400 MHz, DMSO-
d 6) δ 3.61 (s, 3H), 2.17 (s, 6H), 1.39 (s, 9H)。
步驟3:在室溫下,向雙環[1.1.1]戊烷-1,3-二甲酸1-(第三丁基)酯3-甲基酯(15 g, 39.8 mmol)於THF (150 mL)中之經攪拌溶液中添加LiOH (119 mL, 119 mmol, 1 N於水中)。將所得溶液在25℃下攪拌5 h。使用1 N HCl將溶液之pH調節至3且然後使用EtOAc (3 x 100 mL)萃取。使用鹽水(2 x 50 mL)洗滌合併之有機層,藉由無水硫酸鈉乾燥,並過濾。然後在減壓下濃縮濾液以得到3-(第三丁氧基羰基)雙環[1.1.1]戊烷-1-甲酸。C
11H
15O
4[M - H]
-之MS ESI計算值:211.10,實驗值:211.10。
步驟4:在室溫下,向3-(第三丁氧基羰基)雙環[1.1.1]戊烷-1-甲酸(10 g, 28.3 mmol)、2-羥基異二氫吲哚-1,3-二酮(6.00 g, 36.7 mmol)及DMAP (0.345 g, 2.83 mmol)於DCM (100 mL)中之經攪拌溶液中添加
N,N′- 二環己基碳化二亞胺(6.42 g, 31.1 mmol)。將所得混合物在25℃下攪拌16 h。過濾出固體且在減壓下濃縮濾液。藉由使用於PE中之0 - 40% EtOAc洗脫之矽膠管柱層析純化殘餘物以提供雙環[1.1.1]戊烷-1,3-二甲酸1-(第三丁基)酯3-(1,3-二側氧基異二氫吲哚-2-基)酯。
1H NMR (400 MHz, CDCl
3) δ 7.89 (dd,
J= 5.5, 3.1 Hz, 2H), 7.79 (dd,
J= 5.5, 3.1 Hz, 2H), 2.50 (s, 6H), 1.47 (s, 9H)。
步驟5:在室溫及氮氣氛下,向NiBr
2.3H
2O (0.791 g, 2.90 mmol)於DMA (80 mL)中之經攪拌溶液中添加4,4′-二-第三丁基-2,2′-二吡啶(0.973 g, 3.63 mmol)。在將所得混合物在50℃下攪拌30 min.之後,將其冷卻至室溫。在室溫下,將雙環[1.1.1]戊烷-1,3-二甲酸1-(第三丁基)酯3-(1,3-二側氧基異二氫吲哚-2-基)酯(4.8 g, 12.09 mmol)、(
S)-2-((((9
H-茀-9-基)甲氧基)羰基)胺基)-3-(4-碘苯基)丙酸烯丙基酯(6.69 g, 12.09 mmol)、三甲基矽基氯(0.131 g, 1.209 mmol)及鋅(3.95 g, 60.4 mmol)添加至上述混合物中。將所得混合物在25℃下攪拌2 h。使用鹽水(150 mL)終止反應並使用EtOAc (3 x 100 mL)萃取。使用鹽水(3 x 100 mL)洗滌合併之有機層,藉由無水硫酸鈉乾燥,並過濾。然後在減壓下濃縮濾液且藉由使用於PE中之0 - 40% EtOAc洗脫之矽膠管柱層析純化殘餘物以提供(
S)-3-(4-(2-((((9
H-茀-9-基)甲氧基)羰基)胺基)-3-(烯丙基氧基)-3-側氧基丙基)苯基)雙環[1.1.1]戊烷-1-甲酸第三丁基酯。C
37H
40NO
6[M + H]
+之MS ESI計算值:594.28,實驗值:594.30。
步驟6:在室溫及氮氣氛下,向(
S)-3-(4-(2-((((9
H-茀-9-基)甲氧基)羰基)胺基)-3-(烯丙基氧基)-3-側氧基丙基)苯基)雙環[1.1.1]戊烷-1-甲酸第三丁基酯(2.3 g, 1.55 mmol)及苯基矽烷(0.335 g, 3.10 mmol)於THF (30 mL)中之經攪拌溶液中添加Pd(Ph
3P)
4(0.090 g, 0.077 mmol)。將所得混合物在室溫下攪拌1 h,然後在減壓下濃縮且藉由反相管柱層析使用下列條件來純化殘餘物:C18管柱,330 g,在5 min內5% - 5%、在40 min內5% - 70%於水中之MeCN (0.05% TFA)以得到(
S)-2-((((9
H-茀-9-基)甲氧基)羰基)胺基)-3-(4-(3-(第三丁氧基羰基)雙環[1.1.1]戊烷-1-基)苯基)丙酸。C
34H
34NO
6[M - H]
-之MS ESI計算值:552.25,實驗值:552.30。1H NMR (400 MHz,甲醇-
d4) δ 7.80 - 7.77 (m, 2H), 7.67 - 7.65 (m, 2H), 7.48 - 7.23 (m, 4H), 7.19 - 7.17 (m, 2H), 7.10 - 7.07 (m, 2H), 4.45 - 4.44 (m, 1H), 4.42 - 4.41 (m, 1H), 4.34 - 4.29 (m, 2H), 3.24 - 3.18 (m, 1H), 2.94 - 2.86 (m, 1H), 2.12 (s, 6H), 1.45 (s, 9H)。
合成反應圖 23 (1R,4s)-4-(4-((S)-2- 胺基 -2- 羧乙基 ) 苯基 ) 環己烷 -1- 甲酸步驟1:在室溫下,向4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)環己-3-烯-1-甲酸第三丁基酯(29.5 g, 96 mmol)於THF (30 mL)中之混合物中添加(
S)-2-((第三丁氧基羰基)胺基)-3-(4-碘苯基)丙酸甲酯(15.5 g, 38.2 mmol)及Pd(Ph
3P)
4(2.21 g, 1.91 mmol)。將反應液升溫至60℃並保持4 h。使用水(100 mL)將所得溶液驟冷並使用EtOAc (3 x 300 mL)萃取。合併有機層,使用鹽水(2 x 200 mL)洗滌,藉由無水硫酸鈉乾燥,並過濾。在減壓下濃縮濾液以提供粗產物。藉由使用於石油醚中之乙酸乙酯梯度(0%至25%)洗脫之矽膠層析純化殘餘物以提供4'-((
S)-2-((第三丁氧基羰基)胺基)-3-甲氧基-3-側氧基丙基)-2,3,4,5-四氫-[1,1'-聯苯]-4-甲酸第三丁基酯。C
26H
38NO
6Na [M + Na]
+之MS ESI計算值:482.26,實驗值:482.10。
步驟2:在室溫下,向4'-((
S)-2-((第三丁氧基羰基)胺基)-3-甲氧基-3-側氧基丙基)-2,3,4,5-四氫-[1,1'-聯苯]-4-甲酸第三丁基酯(16 g, 34.8 mmol)於甲醇(160 mL)中之混合物中添加Pd-C (10%於碳上,經約55%水潤濕,5.3 g, 4.98 mmol)。使用H
2將溶液脫氣三次並在室溫及H
2氣氛(1.5 atm)下攪拌1 h。過濾所得溶液且在減壓下濃縮濾液以提供(
S)-4-(4-(2-((第三丁氧基羰基)胺基)-3-甲氧基-3-側氧基丙基)苯基)環己烷-1-甲酸第三丁基酯。C
26H
41NO
6[M + H]
+之MS ESI計算值:462.28,實驗值:462.30。
步驟3:在室溫下,向(
S)-4-(4-(2-((第三丁氧基羰基)胺基)-3-甲氧基-3-側氧基丙基)苯基)環己烷-1-甲酸第三丁基酯(15 g, 32.5 mmol)於THF (300 mL)中之經攪拌溶液中添加LiOH (65.0 mL, 65.0 mmol)。將溶液在20℃下攪拌1 h。使用1 N HCl將溶液之pH調節至3。在減壓下濃縮反應液以得到(
S)-2-((第三丁氧基羰基)胺基)-3-(4-(4-(第三丁氧基羰基)環己基)苯基)丙酸。C
25H
38NO
6Na [M + Na]
+之MS ESI計算值:470.26,實驗值:470.30。
步驟4:使用製備型超臨界流體層析使用下列條件來分離(
S)-2-((第三丁氧基羰基)胺基)-3-(4-(4-(第三丁氧基羰基)環己基)苯基)丙酸(14 g, 31.3 mmol):管柱:CHIRAL ART Cellulose-SB, 3 x 25 cm, 5µm;移動相A:CO
2,移動相B:MeOH (0.1% 2M NH
3-MEOH);流速:80 mL/min;梯度:10% B;220 nm;峰1之滯留時間:7.45;峰2之滯留時間:8.38;從而提供第一洗脫峰(
S)-2-((第三丁氧基羰基)胺基)-3-(4-((
1s,
4R)-4-(第三丁氧基羰基)環己基)苯基)丙酸。C
25H
38NO
6Na [M + Na]
+之MS ESI計算值:470.26,實驗值:470.30。1H NMR (300 MHz, CDCl
3) δ 7.11 (d, J = 3.0 Hz, 4H), 4.27 (s, 1H), 3.18 - 3.12 (m, 1H), 2.91 (s, 1H), 2.60 (s, 1H), 2.49 (s, 1H), 2.20 (d, J = 10.9 Hz, 2H), 1.78 - 1.52 (m, 6H), 1.49 (d, J = 0.7 Hz, 9H), 1.36 (s, 9H)。
且提供第二洗脫峰(
S)-2-((第三丁氧基羰基)胺基)-3-(4-((
1r,
4S)-4-(第三丁氧基羰基)環己基)苯基)丙酸。C
25H
38NO
6Na [M + Na]
+之MS ESI計算值:470.26,實驗值:470.30。1H NMR (300 MHz, CDCl
3) δ 7.14 - 7.06 (m, 4H), 4.25 (s, 1H), 3.14 (d,
J= 12.3 Hz, 1H), 2.88 (s, 1H), 2.49 - 2.41 (m, 1H), 2.29 - 2.15 (m, 1H), 2.05 (d,
J= 12.2 Hz, 2H), 1.90 (d,
J= 12.1 Hz, 2H), 1.69 - 1.47 (m, 2H), 1.47 (s, 11H), 1.34 (s, 9H)。
步驟5:在室溫下,向(
S)-2-((第三丁氧基羰基)胺基)-3-(4-((
1s,
4R)-4-(第三丁氧基羰基)環己基)苯基)丙酸(8.3 g, 18.54 mmol)於THF (80 mL)中之溶液中逐份添加HCl (9.27 mL, 18.54 mmol)。在減壓下濃縮反應液以提供(
S)-2-胺基-3-(4-((
1s,
4R)-4-(第三丁氧基羰基)環己基)苯基)丙酸。C
20H
30NO
4[M + H]
+之MS ESI計算值:348.21,實驗值:348.25。
步驟6:向(
S)-2-胺基-3-(4-((
1s,
4R)-4-(第三丁氧基羰基)環己基)苯基)丙酸(6 g, 17.27 mmol)及NaHCO
3(7.25 g, 86 mmol)於THF (60 mL)及水(60.0 mL)中之經攪拌溶液中添加Fmoc-OSu (5.24 g, 15.54 mmol)。將混合物在室溫下攪拌1 h。使用1 N HCl將溶液之pH調節至3。使用EtOAc (2 x 200 mL)萃取水相。使用鹽水(150 mL)洗滌合併之有機層,藉由無水硫酸鈉乾燥,並過濾。在減壓下濃縮濾液,且藉由反相管柱層析純化殘餘物以得到(
S)-2-((((9
H-茀-9-基)甲氧基)羰基)胺基)-3-(4-((
1s,
4R)-4-(第三丁氧基羰基)環己基)苯基)丙酸。C
35H
41NO
6[M + H]
+之MS ESI計算值:570.28,實驗值:570.15。
1H NMR (300 MHz,甲醇-
d 4) δ 7.81 (d,
J= 7.5 Hz, 2H), 7.61 (d,
J= 7.5 Hz, 2H), 7.43 - 7.27 (m, 4H), 7.16 (d,
J= 7.8 Hz, 2H), 7.07 (d,
J= 7.9 Hz, 2H), 4.45-4.33 (m, 2H), 4.22 - 4.06 (m, 2H), 3.26 - 3.14 (m, 1H), 2.96 - 2.88 (m, 1H), 2.59 (s, 1H), 2.48 (s, 1H), 2.15 (s, 2H), 1.61 (d,
J= 5.5 Hz, 6H), 1.49 (s, 9H)。
合成反應圖 24 F4ptCCA (1S,4r)-4-(4-((S)-2- 胺基 -2- 羧乙基 ) 苯基 ) 環己烷 -1- 甲酸步驟1:在室溫下,向(
S)-2-((第三丁氧基羰基)胺基)-3-(4-((
1r,
4S)-4-(第三丁氧基羰基)環己基)苯基)丙酸(3 g, 6.70 mmol)於THF (30 mL)中之混合物中逐份添加氯化氫(30 mL, 60.0 mmol)。在減壓下濃縮反應液以提供(
S)-2-胺基-3-(4-((
1r,
4S)-4-(第三丁氧基羰基)環己基)苯基)丙酸。C
20H
31NO
4[M + H]
+之MS ESI計算值:348.21,實驗值:348.25。
步驟2:在室溫下,向
(S)-2-胺基-3-(4-((
1r,
4S)-4-(第三丁氧基羰基)環己基)苯基)丙酸(2 g, 5.76 mmol) (1.748 g, 5.18 mmol)及NaHCO
3(2.418 g, 28.8 mmol)於THF (20 mL)及水(20 mL)中之經攪拌溶液中添加Fmoc-OSu (1.748 g, 5.18 mmol)。將混合物在20℃下攪拌1 h。使用1 N HCl將溶液之pH調節至3。使用EtOAc (2 x 200 mL)萃取水相。使用鹽水(3 x 50 mL)洗滌合併之有機層,藉由無水硫酸鈉乾燥,並過濾。在減壓下濃縮濾液且藉由反相管柱層析純化殘餘物以得到(
S)-2-((((9
H-茀-9-基)甲氧基)羰基)胺基)-3-(4-((
1r,
4S)-4-(第三丁氧基羰基)環己基)苯基)丙酸。C
35H
41NO
6[M + H]
+之MS ESI計算值:570.28,實驗值:570.35。
1H NMR (300 MHz,甲醇-
d 4) δ 7.81 (d,
J= 7.6 Hz, 2H), 7.61 (d, J = 7.5 Hz, 2H), 7.43 - 7.38 (m, 2H), 7.34 - 7.27 (m, 2H), 7.17 (d,
J= 8.0 Hz, 2H), 7.08 (d,
J= 7.8 Hz, 2H), 4.47 - 4.43 (m, 1H), 4.35 - 4.30 (m, 1H), 4.21 - 4.02 (m, 2H), 3.24 - 3.18 (m, 1H), 2.94 - 2.87 (m, 1H), 2.40 (s, 1H), 2.17 (d,
J= 11.9 Hz, 1H), 1.96 (s, 3H), 1.82 - 1.55 (m, 2H), 1.47 (s, 13H)。
最終化合物之製備:A.用於合成線性肽前體之一般化程序
使用標準固相合成且使用Fmoc/
tBu化學如以下文獻中所例示來合成表1中之肽:Chan, W.C.; White, P.D. 「Fmoc Solid-Phase Synthesis:a Practical Approach」, Oxford University Press, Oxford, 2000;Steward, J.; Young, J. 「Solid Phase Peptide Synthesis」, Pierce Chemical Company, Rockford, 1984.;Benoiton, N.L. 「Chemistry of Peptide Synthesis」, CRC Press, New York, 2006;及Lloyd-Williams, P.; Albericio, F.; Giralt, E. 「Chemical Approaches to the Synthesis of Peptides and Proteins」, CRC Press, New York, 1997。
在肽鏈伸長期間,使用9
H-茀-9-基甲氧基羰基(Fmoc)保護每一胺基酸之α-胺基。為避免鏈伸長步驟期間之任何副反應,任何反應性胺基酸側鏈亦攜載酸不穩定性保護基團,從而有效遮蔽反應性基團直至使用強酸處理去除為止。在完成每一偶合步驟之後,使用六氫吡啶或4-甲基六氫吡啶去除
N-末端胺基酸之Fmoc基團且充分洗滌樹脂以備用於後續經Fmoc保護之胺基酸衍生物之偶合。
所用側鏈保護基團係:用於S、hY、Bip4CO2H、Phe4COOH、F4pcCCA、F4ptCCA、F4bcpA之第三丁基(
tBu);用於Dap、dDab、dK、dOrn、K、Prot4NH2、dDap、daMeDab之第三丁氧基-羰基(Boc);及用於D之β-甲基戊基酯(OMpe)。
經Fmoc保護之胺基酸通常係自諸如Sigma-Aldrich、Novabiochem、Chem-Impex及Combi-Block等供應商獲得。
B.用於製備環狀肽之合成程序
合成反應圖
25
固相肽合成方案 A在來自CEM公司之Liberty Blue™合成器上使用標準固相合成且使用Fmoc/
tBu化學如上文在反應圖25中所匯總來合成肽。使用
N,N'-二異丙基碳化二亞胺(DIC)與氰基(羥基亞胺基)乙酸乙酯(Oxyma)作為偶合劑以在樹脂結合性經保護肽之游離胺基末端與經Fmoc保護之胺基酸之羧酸之間形成醯胺鍵。
使用加載H-Gly之2-氯三苯甲基樹脂(200-400網目,0.79 mmol/g載量,1%交聯聚苯乙烯,Novabiochem)進行合成。所有胺基酸皆以0.2 M濃度溶於DMF
(N,N-二甲基甲醯胺)中。使用等莫耳量之Oxyma溶液(0.5 M於DMF)中及2倍莫耳過量之DIC溶液(1.0 M於DMF中)來活化胺基酸。或者,將胺基酸以0.125 M濃度溶於DMF (
N,N-二甲基甲醯胺)中。使用等莫耳量之Oxyma純溶液(0.125 M於DMF中;含有0.05 M DIEA)及2倍莫耳過量之DIC溶液(0.25 M於DMF中)來活化胺基酸。通常以25 µmol規模來實施反應。
每一合成循環包含:藉由於DMF中之20%六氫吡啶實施Fmoc-胺基酸去保護(90℃微波輔助加熱,2 min),及使用經Fmoc經保護之胺基酸/DIC/Oxyma (分別5、5及10當量;90℃微波輔助加熱,2 min或4 min)進行偶合(困難偶合可能重複兩次)。使用期望單體重複Fmoc去保護及經Fmoc保護之胺基酸偶合之循環直至形成全線性肽為止。
固相肽合成方案 B或者,在Biotage® Syro II肽合成器上使用標準固相合成且使用Fmoc/
tBu化學如上文在反應圖25中所匯總來合成肽。使用HATU與DIPEA作為偶合劑以在樹脂結合性經保護肽之游離胺基末端與經Fmoc保護之胺基酸之羧酸之間產生醯胺鍵。使用加載H-Gly之2-氯三苯甲基樹脂(200-400網目,0.79 mmol/g載量,1%交聯聚苯乙烯,Novabiochem)進行合成。所有胺基酸皆以0.2 M濃度溶於1:1 DMF:NMP中。通常以12 µmol規模來實施反應。
每一合成循環包含:(1)使用經Fmoc保護之胺基酸/HATU/DIPEA (分別4、4及8當量;室溫;15 min)進行偶合(重複兩次)。過濾混合物,且使用DMF (2 x 1 mL)洗滌肽基樹脂;(2) Fmoc去保護(重複三次):於DMF中之20% 4-甲基六氫吡啶(1 mL;室溫;3 min)。過濾混合物,且使用DMF (4 x 1 mL)洗滌肽基樹脂。使用期望單體重複Fmoc去保護及經Fmoc保護之胺基酸偶合之循環直至形成全線性肽為止。
經保護肽之選擇性裂解及大環內醯胺化為自固體載體裂解經保護線性肽,使用25%六氟異丙醇(HFIP)在室溫下於DCM中將肽基樹脂(~16 mg)處理20 min,過濾,且在減壓下去除溶劑。將所得殘餘物溶於DMF (5mL)中。添加HATU (0.44當量)及DIPEA (2.5當量)。將混合物在室溫下攪拌5 min。然後再添加0.66當量HATU。在完成大環內醯胺化(藉由UPLC-MS監測)後,在減壓下去除溶劑。
最終側鏈去保護將TFA/H
2O/TIS溶液(90/8/2, v/v/v, 1 mL)添加至粗製經保護環狀肽中。將混合物在室溫下攪拌10 min。將冷二乙醚(15 mL)添加至溶液中。藉由離心(3200 rpm, -10℃)使肽沈澱。使用二乙醚(2 x 10 mL)洗滌沈澱物並在真空下乾燥過夜以得到固體形式之粗製經去保護環狀肽。
HPLC 純化藉由製備型反相高效液相層析(RP-HPLC)在Waters X-Bridge Prep C18 OBD Prep管柱(130 Å, 5 pm,管柱大小:19 * 100 mm)上使用Waters MS-Directed AutoPurification HPLC/MS系統來實施純化。移動相:(A)於HPLC水中之0.16% TFA及(B)於HPLC乙腈中之0.16% TFA;流速:25 mL/min;UV波長λ = 215 nm;梯度:在5 min內25-50% B。或者,在Waters CSH-C18管柱(19 x 250mm, 5 uM)上使用具有1290 infinity II製備型LC系統及LC-MSD XT質譜儀之Agilent系統來實施純化。移動相:(A)於HPLC水中之0.1%甲酸及(B)於HPLC乙腈中之0.1%甲酸;流速:25 mL/min;UV波長λ = 215 nm;梯度:在2.5 min內20% B,在2.5-20 min內55% B。收集含有靶m/z離子之UV吸收級分且藉由LC/MS證實含產物級分。
藉由UPLC-MS來實施最終化合物之身份證實及純度評價,此係藉由反相Waters Acquity UPLC-MS系統來量測。管柱:Waters XSelect CSH C18管柱(130 Å, 2.5 µm,管柱大小:2.1 * 50 mm)。移動相:(A)於HPLC水中之0.05% TFA及(B)於HPLC乙腈中之0.05% TFA;注入體積:1 µL;流速:1 mL/min;UV波長λ = 215 nm;梯度:在5 min內5-100% B。凍乾含有純肽之合併級分以產生粉末形式之最終環化產物。
生物分析:
MRC5 細胞中之 IL-6 分析程序在MRC5細胞中評估IL-1β誘導性IL-6分泌之抑制。在含有0.025% BSA (Sigma A9576)、1X青黴素(penicillin)/鏈黴素(streptomycin) (Gibco 15070-063)、1X NEAA (Gibco 11140-050)、1X GlutaMax (Gibco 35050-061)及1X丙酮酸鈉(Gibco 11360-070)之接種培養基EMEM (ATCC 30-2003)中製備2X EC
80濃度之重組人類IL-1β (BioLegend 579404)。將20 µL IL-1β添加至384孔膠原塗覆板(Corning 354664)中並在環境溫度下與200 nL使用ECHO 555液體處理器分配之化合物一起預培育1小時。以3000個細胞/20 µL/孔之密度添加人類肺纖維母細胞MRC5細胞(ATCC CCL-171)。藉由在經膠原塗覆之T175燒瓶(Greiner 661950)中於含有10%胎牛血清(Gibco 16140-071)、1X青黴素/鏈黴素(Gibco 15070-063)、1X NEAA (Gibco 11140-050)、1X GlutaMax (Gibco 35050-061)及1X丙酮酸鈉(Gibco 11360-070)之生長培養基EMEM (ATCC 30-2003)中傳代三次來製備細胞並在5分鐘之0.25%胰蛋白酶-EDTA (Gibco 25200-056)消解之後收穫於接種培養基中。將最終體積為40 µL之384孔膠原塗覆板在37℃、5% CO
2下培育過夜。將5 µL條件化培養基轉移至384孔AlphaLISA板(PerkinElmer 6005350)中以根據製造商方案使用人類αLISA IL-6套組(PerkinElmer AL223F)來檢測IL-6。將20 µL受體珠粒/生物素化抗體混合物添加至384孔AlphaLISA板中並在環境溫度下培育1小時。使供體珠粒混合物避光且將25 µL添加至板中,並在環境溫度下培育30分鐘。在EnVision多模式讀板儀(Perkin Elmer模型2104)使用AlphaScreen設置(雷射激發於680 nm下並發射於570 nm下)來讀取AlphaLISA板。以Spotfire軟體(Tibco, Palo Alto, CA)使用4參數邏輯方程式來分析劑量反應曲線及IC
50值。
第1-215號實例(SEQ ID NO:1-215)之胺基酸序列、生物活性(MRC IC50)、計算單一同位素質量、分子式、計算分子量及質譜數據([M+H]+或[M+2H]/2+)提供於下表1中。
表1
SEQ ID NO. | 序列 | MRC5 IC 50(nM) | 確切質量 (Da) | 分子式 | 分子量 (g/mol) | 量測質量 (Da) | 觀察離子 |
1 | 3AzaPhe4AcPip-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-4Pal-Dap-dA-h3Pal5CN | 0.0365 | 2047.87944 | C106H117N23O21 | 2049.2 | 1025.5 | [M+2H]/2+ |
2 | 3AzaPhe4AcPip-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-K-L-dA-h3Pal5CN | 0.0217 | 2054.94679 | C107H126N22O21 | 2056.28 | 1029.0 | [M+2H]/2+ |
3 | 3AzaPhe4AcPip-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-K-L-dA-hY | 0.05985 | 2044.95121 | C107H128N20O22 | 2046.28 | 1024.1 | [M+2H]/2+ |
4 | 3AzaPhe4AcPip-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-W-Dap-dA-h3Pal5CN | 0.0438 | 2085.89509 | C109H119N23O21 | 2087.25 | 1044.5 | [M+2H]/2+ |
5 | 3AzaPhe4AcPip-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-W-Dap-dA-hY | 0.6739 | 2075.8995 | C109H121N21O22 | 2077.25 | 1039.4 | [M+2H]/2+ |
6 | 3AzaPhe4AcPip-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-K-L-dA-hY | 0.0666 | 2051.93703 | C105H126FN21O22 | 2053.25 | 1027.6 | [M+2H]/2+ |
7 | 3AzaPhe4AcPip-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-K-L-dDab-hY | 0.1353 | 2080.96358 | C106H129FN22O22 | 2082.29 | 1042.2 | [M+2H]/2+ |
8 | 3AzaPhe4AcPip-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-W-G-dDab-hY | 0.1401 | 2082.88533 | C107H119FN22O22 | 2084.22 | 1043.0 | [M+2H]/2+ |
9 | 3AzaTyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-K-L-dA-hY | 0.1182 | 2026.9054 | C103H123FN20O23 | 2028.2 | 1015.7 | [M+2H]/2+ |
10 | 3Pal4Ph4CO2H-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-3Pal4Ph4CO2H-W-Dap-dA-hY | 0.256 | 2070.83657 | C109H114N20O23 | 2072.19 | 1036.7 | [M+2H]/2+ |
11 | 3Pal4Ph4CO2H-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-W-Dap-dA-hY | 0.0908 | 2069.84132 | C110H115N19O23 | 2071.2 | 1036.7 | [M+2H]/2+ |
12 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-3Pal4Ph4CO2H-W-Dap-dA-hY | 0.0551 | 2069.84132 | C110H115N19O23 | 2071.2 | 1036.5 | [M+2H]/2+ |
13 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-1Inda-Dap-dA-hY | 0.03096 | 2069.84132 | C110H115N19O23 | 2071.2 | 1037.4 | [M+2H]/2+ |
14 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-1Indolin-Dap-dA-hY | 0.02974 | 2070.86172 | C111H118N18O23 | 2072.23 | 1037.4 | [M+2H]/2+ |
15 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-1Nal-Dab-Aib-G | 0.6535 | 1987.82461 | C107H113N17O22 | 1989.14 | 997.4 | [M+2H]/2+ |
16 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-1Nal-Dab-Aib-hY | 0.175 | 2107.88212 | C115H121N17O23 | 2109.29 | 1057.7 | [M+2H]/2+ |
17 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-1Nal-Dap-Aib-G | 0.222 | 1973.80896 | C106H111N17O22 | 1975.12 | 989.2 | [M+2H]/2+ |
18 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-1Nal-Dap-Aib-h3Pal5CN | 0.0885 | 2103.86206 | C114H117N19O22 | 2105.26 | 2104.4 | [M+H]+ |
19 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-1Nal-L-Aib-G | 0.1179 | 2000.84501 | C109H116N16O22 | 2002.18 | 1002.8 | [M+2H]/2+ |
20 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-1Nal-Orn-Aib-G | 0.4401 | 2001.84026 | C108H115N17O22 | 2003.17 | 1004.1 | [M+2H]/2+ |
21 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-4Pal-Dap-dA-h3Pal5CN | 0.0234 | 2040.82601 | C108H112N20O22 | 2042.17 | 1022.0 | [M+2H]/2+ |
22 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-4Pal-Dap-dA-hY | 0.03251 | 2030.83042 | C108H114N18O23 | 2032.17 | 1017.4 | [M+2H]/2+ |
23 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-AlaTHP4-Dap-dA-h3Pal5CN | 0.0112 | 2047.85697 | C108H117N19O23 | 2049.2 | 1025.5 | [M+2H]/2+ |
24 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-AlaTHP4-Dap-dA-hY | 0.02912 | 2037.86139 | C108H119N17O24 | 2039.2 | 1021.1 | [M+2H]/2+ |
25 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-K-L-dA-hY | 0.05424 | 2037.89777 | C109H123N17O23 | 2039.24 | 1021.0 | [M+2H]/2+ |
26 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-K-L-dS-hY | 0.06881 | 2053.89269 | C109H123N17O24 | 2055.24 | 1029.0 | [M+2H]/2+ |
27 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-PyrimAla-Dap-dA-h3Pal5CN | 0.017 | 2041.82125 | C107H111N21O22 | 2043.15 | 1022.6 | [M+2H]/2+ |
28 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-PyrimAla-Dap-dA-hY | 0.03926 | 2031.82567 | C107H113N19O23 | 2033.16 | 1017.9 | [M+2H]/2+ |
29 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-Trp7az-Dap-dA-hY | 0.0205 | 2069.84132 | C110H115N19O23 | 2071.2 | 1036.6 | [M+2H]/2+ |
30 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-W-Dap-dA-h3Pal5CN | 0.0185 | 2078.84166 | C111H114N20O22 | 2080.21 | 1040.9 | [M+2H]/2+ |
31 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-W-Dap-dA-hY | 0.02075 | 2068.84607 | C111H116N18O23 | 2070.22 | 1035.7 | [M+2H]/2+ |
32 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-W-G-dDab-hY | 0.03296 | 2068.84607 | C111H116N18O23 | 2070.22 | 2070.1 | [M+H]+ |
33 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-A-dNMeA-G-Bip4CO2H-1Nal-L-Aib-G | 0.5443 | 1979.81146 | C106H114ClN17O20 | 1981.59 | 992.9 | [M+2H]/2+ |
34 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-1Nal-Dap-Aib-h3Pal5CN | 0.0755 | 2126.81833 | C112H115ClN20O22 | 2128.69 | 1064.9 | [M+2H]/2+ |
35 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-1Nal-L-Aib-G | 0.1598 | 2023.80129 | C107H114ClN17O22 | 2025.6 | 1012.9 | [M+2H]/2+ |
36 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-1Nal-L-Aib-hY | 0.05222 | 2143.8588 | C115H122ClN17O23 | 2145.75 | 1074.6 | [M+2H]/2+ |
37 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-1Nal-Orn-Aib-G | 0.1031 | 2024.79654 | C106H113ClN18O22 | 2026.59 | 1014.2 | [M+2H]/2+ |
38 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-3Pal-S-dA-hY | 0.2167 | 2054.77071 | C106H111ClN18O24 | 2056.57 | 1029.0 | [M+2H]/2+ |
39 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-4Pal-S-dA-hY | 0.232 | 2054.77071 | C106H111ClN18O24 | 2056.57 | 1029.1 | [M+2H]/2+ |
40 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-AlaPip4-S-dA-hY | 0.5085 | 2060.81766 | C106H117ClN18O24 | 2062.62 | 1032.6 | [M+2H]/2+ |
41 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-Dap-S-dA-hY | 0.4688 | 1992.75506 | C101H109ClN18O24 | 1994.51 | 998.6 | [M+2H]/2+ |
42 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-K-L-dA-hY | 0.6266 | 2060.85405 | C107H121ClN18O23 | 2062.67 | 1032.3 | [M+2H]/2+ |
43 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-K-L-dDab-hY | 0.2437 | 2089.8806 | C108H124ClN19O23 | 2091.71 | 1047.1 | [M+2H]/2+ |
44 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-K-L-dS-hY | 0.1321 | 2076.84896 | C107H121ClN18O24 | 2078.66 | 1040.1 | [M+2H]/2+ |
45 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-K-S-dA-hY | 0.174 | 2034.80201 | C104H115ClN18O24 | 2036.59 | 1019.1 | [M+2H]/2+ |
46 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-K-S-dDab-hY | 0.1336 | 2063.82856 | C105H118ClN19O24 | 2065.63 | 1034.1 | [M+2H]/2+ |
47 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-K-S-dS-hY | 0.1235 | 2050.79693 | C104H115ClN18O25 | 2052.58 | 1027.6 | [M+2H]/2+ |
48 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-mAF-S-dA-hY | 0.04098 | 2082.80201 | C108H115ClN18O24 | 2084.63 | 1043.1 | [M+2H]/2+ |
49 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-Orn-S-dA-hY | 0.4016 | 2020.78636 | C103H113ClN18O24 | 2022.56 | 1012.6 | [M+2H]/2+ |
50 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-Phe3NH2-S-dA-hY | 0.5196 | 2068.78636 | C107H113ClN18O24 | 2070.6 | 1036.2 | [M+2H]/2+ |
51 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-Phe4CH2NH2-S-dA-hY | 0.3199 | 2082.80201 | C108H115ClN18O24 | 2084.63 | 1043.5 | [M+2H]/2+ |
52 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-Phe4NH2-S-dA-hY | 0.4537 | 2068.78636 | C107H113ClN18O24 | 2070.6 | 1036.1 | [M+2H]/2+ |
53 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-W-Dap-dA-hY | 0.04179 | 2091.80235 | C109H114ClN19O23 | 2093.64 | 1047.0 | [M+2H]/2+ |
54 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-sbMeW4Cl-D-dNMeA-G-Bip4CO2H-W-G-dDab-hY | 0.06922 | 2091.80235 | C109H114ClN19O23 | 2093.64 | 1047.0 | [M+2H]/2+ |
55 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-sbMeW4Cl-E-dNMeA-G-Bip4CO2H-W-G-dDab-hY | 0.0493 | 2105.818 | C110H116ClN19O23 | 2107.66 | 1055.7 | [M+2H]/2+ |
56 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-sbMeW4Cl-N-dNMeA-G-Bip4CO2H-W-G-dDab-hY | 0.02065 | 2090.81833 | C109H115ClN20O22 | 2092.65 | 1046.8 | [M+2H]/2+ |
57 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-sbMeW4Cl-Q-dNMeA-G-Bip4CO2H-W-G-dDab-hY | 0.08728 | 2104.83398 | C110H117ClN20O22 | 2106.68 | 1055.2 | [M+2H]/2+ |
58 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4F-A-dNMeA-G-Bip4CO2H-K-L-dA-hY | 0.2475 | 2000.89377 | C106H121FN18O21 | 2002.2 | 1002.4 | [M+2H]/2+ |
59 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-4Pal-L-dA-hY | 0.03617 | 2064.8523 | C109H117FN18O23 | 2066.2 | 1034.7 | [M+2H]/2+ |
60 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-F-L-dA-hY | 0.06889 | 2063.85705 | C110H118FN17O23 | 2065.21 | 1034.2 | [M+2H]/2+ |
61 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-h4Pal-L-dA-hY | 0.312 | 2078.86795 | C110H119FN18O23 | 2080.23 | 1041.5 | [M+2H]/2+ |
62 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-hK-L-dA-hY | 0.283 | 2058.89925 | C108H123FN18O23 | 2060.24 | 1031.5 | [M+2H]/2+ |
63 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-hQ-L-dA-hY | 0.06295 | 2058.86287 | C107H119FN18O24 | 2060.19 | 1031.2 | [M+2H]/2+ |
64 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-K-AlaTHP4-dA-h3Pal5CN | 0.0182 | 2096.88975 | C109H121FN20O23 | 2098.25 | 1050.1 | [M+2H]/2+ |
65 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-K-AlaTHP4-dA-hY | 0.0158 | 2086.89417 | C109H123FN18O24 | 2088.25 | 1045.0 | [M+2H]/2+ |
66 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-K-L-dA-h3Pal5CN | 0.02985 | 2054.87918 | C107H119FN20O22 | 2056.21 | 2056.2 | [M+H]+ |
67 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-K-L-dA-hY | 0.046 | 2044.8836 | C107H121FN18O23 | 2046.21 | 1024.7 | [M+2H]/2+ |
68 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-K-L-dDab-hY | 0.296 | 2073.91015 | C108H124FN19O23 | 2075.25 | 1038.5 | [M+2H]/2+ |
69 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-K-L-dS-hY | 0.3335 | 2060.87852 | C107H121FN18O24 | 2062.21 | 1032.4 | [M+2H]/2+ |
70 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-K-L-G-hY | 0.09734 | 2030.86795 | C106H119FN18O23 | 2032.18 | 1017.5 | [M+2H]/2+ |
71 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-K-Nva-dA-hY | 0.09256 | 2030.86795 | C106H119FN18O23 | 2032.18 | 1017.6 | [M+2H]/2+ |
72 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-K-S-dA-hY | 0.10655 | 2018.83156 | C104H115FN18O24 | 2020.13 | 1011.5 | [M+2H]/2+ |
73 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-mAF-L-dA-hY | 0.05088 | 2092.8836 | C111H121FN18O23 | 2094.25 | 1048.7 | [M+2H]/2+ |
74 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-mAF-S-dA-hY | 0.296 | 2066.83156 | C108H115FN18O24 | 2068.17 | 1034.9 | [M+2H]/2+ |
75 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-mBip-L-dA-hY | 0.1648 | 2139.88835 | C116H122FN17O23 | 2141.31 | 1071.5 | [M+2H]/2+ |
76 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-mTyrOAl-L-dA-hY | 0.1217 | 2119.88327 | C113H122FN17O24 | 2121.28 | 1061.7 | [M+2H]/2+ |
77 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-sbMeW4F-D-dNMeA-G-Bip4CO2H-W-G-dDab-hY | 0.06011 | 2075.8319 | C109H114FN19O23 | 2077.18 | 1038.5 | [M+2H]/2+ |
78 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-W-L-dA-hY | 0.07324 | 2102.86795 | C112H119FN18O23 | 2104.25 | 1052.9 | [M+2H]/2+ |
79 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-W-Nva-dA-A | 0.1893 | 1982.81044 | C104H111FN18O22 | 1984.1 | 993.2 | [M+2H]/2+ |
80 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4F-N-dNMeA-G-Bip4CO2H-K-L-dA-hY | 0.2915 | 2043.89958 | C107H122FN19O22 | 2045.23 | 1023.9 | [M+2H]/2+ |
81 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4F-N-dNMeA-G-Bip4CO2H-K-L-dDab-hY | 0.2547 | 2072.92613 | C108H125FN20O22 | 2074.27 | 1038.1 | [M+2H]/2+ |
82 | Bip4CO2H-W-Phe4COOH-G-Prot4NHBn-SbMe1Nal-D-dNMeA-G-Bip4CO2H-W-Dap-dA-hY | 0.0157 | 2158.89302 | C118H122N18O23 | 2160.34 | 1081.0 | [M+2H]/2+ |
83 | Bip4CO2H-W-Phe4COOH-G-Prot4NHCH2CH2Ph-SbMe1Nal-D-dNMeA-G-Bip4CO2H-W-Dap-dA-hY | 0.0329 | 2172.90867 | C119H124N18O23 | 2174.36 | 1088.1 | [M+2H]/2+ |
84 | Bip4CO2H-W-Phe4COOH-G-Prot4NHEt-SbMe1Nal-D-dNMeA-G-Bip4CO2H-W-Dap-dA-hY | 0.0258 | 2096.87737 | C113H120N18O23 | 2098.27 | 1049.6 | [M+2H]/2+ |
85 | Phe4AcPip-W-Phe4COOH-G-Prot4NH2-sbMeW4Cl-D-dNMeA-G-Bip4CO2H-W-G-dDab-hY | 0.05433 | 2097.86053 | C108H120ClN21O22 | 2099.69 | 1050.9 | [M+2H]/2+ |
86 | Phe4Pyrim5CO2H-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-W-Dap-dA-hY | 0.0223 | 2070.83657 | C109H114N20O23 | 2072.19 | 1037.8 | [M+2H]/2+ |
87 | Phe4Pyrim5CO2H-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-W-Dap-dA-hY | 0.1415 | 2070.83657 | C109H114N20O23 | 2072.19 | 1037.9 | [M+2H]/2+ |
88 | PyrimAla4AcPip-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-W-Dap-dA-hY | 0.0945 | 2076.89475 | C108H120N22O22 | 2078.24 | 1039.7 | [M+2H]/2+ |
89 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-A-dNMeA-G-Bip4CO2H-W-Dap-dA-hY | 0.271 | 2005.88279 | C107H119N19O21 | 2007.2 | 1004.6 | [M+2H]/2+ |
90 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-1Inda-G-dDab-h3Pal5CN | 0.0507 | 2060.86345 | C107H116N22O22 | 2062.2 | 1032.1 | [M+2H]/2+ |
91 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-1Indolin-G-dDab-h3Pal5CN | 0.0234 | 2061.88385 | C108H119N21O22 | 2063.23 | 1032.5 | [M+2H]/2+ |
92 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-1Nal-Dab-Aib-G | 0.457 | 1968.85116 | C104H116N18O22 | 1970.14 | 987.3 | [M+2H]/2+ |
93 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-1Nal-Dab-Aib-hY | 0.12 | 2088.90867 | C112H124N18O23 | 2090.29 | 1047.7 | [M+2H]/2+ |
94 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-1Nal-Dap-Aib-h3Pal5CN | 0.0639 | 2084.88861 | C111H120N20O22 | 2086.26 | 1043.4 | [M+2H]/2+ |
95 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-1Nal-L-Aib-G | 0.4222 | 1981.87156 | C106H119N17O22 | 1983.18 | 991.9 | [M+2H]/2+ |
96 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-1Nal-L-Aib-hY | 0.4637 | 2124.88535 | C112H125ClN18O23 | 2126.75 | 1063.7 | [M+2H]/2+ |
97 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-1Nal-L-dA-A | 0.2945 | 1981.87156 | C106H119N17O22 | 1983.18 | 992.8 | [M+2H]/2+ |
98 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-1Nal-Nva-dA-A | 0.494 | 1967.85591 | C105H117N17O22 | 1969.15 | 986.1 | [M+2H]/2+ |
99 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-1Nal-Orn-Aib-hY | 0.256 | 2102.92432 | C113H126N18O23 | 2104.32 | 1053.1 | [M+2H]/2+ |
100 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-4Pal-Dab-dA-hF4CF3 | 0.274 | 2077.86509 | C107H118F3N19O22 | 2079.19 | 2079.0 | [M+H]+ |
101 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-4Pal-Dab-dA-hY | 0.247 | 2025.87262 | C106H119N19O23 | 2027.19 | 2027.0 | [M+H]+ |
102 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-4Pal-G-dDab-h3Pal5CN | 0.0421 | 2021.85255 | C105H115N21O22 | 2023.16 | 1012.6 | [M+2H]/2+ |
103 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-4Pal-S-dA-hF2CF3 | 0.066 | 2064.83346 | C106H115F3N18O23 | 2066.15 | 1033.1 | [M+2H]/2+ |
104 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-4Pal-S-dA-hF3CF3 | 0.041 | 2064.83346 | C106H115F3N18O23 | 2066.15 | 1033.5 | [M+2H]/2+ |
105 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-4Pal-S-dA-hF4CF3 | 0.091 | 2064.83346 | C106H115F3N18O23 | 2066.15 | 1033.9 | [M+2H]/2+ |
106 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-AlaTHP4-G-dDab-h3Pal5CN | 0.0263 | 2028.88352 | C105H120N20O23 | 2030.2 | 1016.1 | [M+2H]/2+ |
107 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-K-G-Aib-hY | 0.05819 | 1976.87737 | C103H120N18O23 | 1978.16 | 989.7 | [M+2H]/2+ |
108 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-K-G-dA-hY | 0.102 | 1962.86172 | C102H118N18O23 | 1964.14 | 983.0 | [M+2H]/2+ |
109 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-K-G-dNMeA-hY | 0.07747 | 1976.87737 | C103H120N18O23 | 1978.16 | 989.0 | [M+2H]/2+ |
110 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-K-L-dA-hY | 0.1955 | 2018.92432 | C106H126N18O23 | 2020.24 | 2020.0 | [M+H]+ |
111 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-K-S-dA-hF4CF3 | 0.133 | 2044.86476 | C104H119F3N18O23 | 2046.16 | 2046.0 | [M+H]+ |
112 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-K-S-dA-hY | 0.06175 | 1992.87229 | C103H120N18O24 | 1994.16 | 1994.0 | [M+H]+ |
113 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-PyrimAla-G-dDab-h3Pal5CN | 0.0918 | 2022.8478 | C104H114N22O22 | 2024.15 | 1013.0 | [M+2H]/2+ |
114 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-Trp7az-G-dDab-h3Pal5CN | 0.0233 | 2060.86345 | C107H116N22O22 | 2062.2 | 1031.6 | [M+2H]/2+ |
115 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-W-Dab-dA-hF | 0.085 | 2047.89336 | C109H121N19O22 | 2049.24 | 1025.2 | [M+2H]/2+ |
116 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-W-Dab-dA-hY | 0.492 | 2063.88827 | C109H121N19O23 | 2065.24 | 2065.1 | [M+H]+ |
117 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-W-Dap-Aib-hY | 0.1595 | 2063.88827 | C109H121N19O23 | 2065.24 | 1034.5 | [M+2H]/2+ |
118 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-W-Dap-dA-A | 0.973 | 1943.83076 | C101H113N19O22 | 1945.09 | 973.7 | [M+2H]/2+ |
119 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-W-Dap-dA-hY | 0.06017 | 2049.87262 | C108H119N19O23 | 2051.21 | 1026.3 | [M+2H]/2+ |
120 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-W-Dap-dA-TyrEtMor | 0.86 | 2148.94104 | C113H128N20O24 | 2150.35 | 1076.1 | [M+2H]/2+ |
121 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-W-Dap-dNMeA-hY | 0.08498 | 2063.88827 | C109H121N19O23 | 2065.24 | 2064.7 | [M+H]+ |
122 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-W-G-dDab-h3Pal5CN | 0.0248 | 2059.8682 | C108H117N21O22 | 2061.21 | 1031.1 | [M+2H]/2+ |
123 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-W-G-dDab-hY | 0.04565 | 2049.87262 | C108H119N19O23 | 2051.21 | 1025.6 | [M+2H]/2+ |
124 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-W-L-dA-A | 0.636 | 1970.86681 | C104H118N18O22 | 1972.16 | 987.2 | [M+2H]/2+ |
125 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-W-L-dA-hY | 0.06403 | 2076.90867 | C111H124N18O23 | 2078.28 | 1039.7 | [M+2H]/2+ |
126 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-W-L-dDab-hY | 0.3705 | 2105.93522 | C112H127N19O23 | 2107.32 | 2107.0 | [M+H]+ |
127 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-D-dNMeA-G-Bip4CO2H-W-Orn-Aib-hY | 0.4325 | 2091.91957 | C111H125N19O23 | 2093.29 | 2093.1 | [M+H]+ |
128 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-W-S-dA-hY | 0.090 | 2050.85664 | C108H118N18O24 | 2052.2 | 1026.4 | [M+2H]/2+ |
129 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-sbMe1Nal-N-dNMeA-G-Bip4CO2H-W-Dap-dA-hY | 0.08279 | 2048.88861 | C108H120N20O22 | 2050.23 | 1025.1 | [M+2H]/2+ |
130 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-1Nal-Dap-Aib-h3Pal5CN | 0.114 | 2107.84488 | C109H118ClN21O22 | 2109.68 | 2109.0 | [M+H]+ |
131 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-1Nal-L-dA-hY | 0.04984 | 2110.8697 | C111H123ClN18O23 | 2112.72 | 1056.5 | [M+2H]/2+ |
132 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-sbMeW4Cl-D-dNMeA-G-Bip4CO2H-1Nal-Orn-Aib-G | 0.3701 | 2005.82308 | C103H116ClN19O22 | 2007.59 | 1003.9 | [M+2H]/2+ |
133 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-1Nal-S-dA-Phe4NH2 | 0.766 | 2069.818 | C107H116ClN19O23 | 2071.63 | 1036.9 | [M+2H]/2+ |
134 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-4Pal-Dab-dA-hY | 0.3785 | 2048.8289 | C104H117ClN20O23 | 2050.61 | 1026.3 | [M+2H]/2+ |
135 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-4Pal-L-dA-hY | 0.310 | 2061.8493 | C106H120ClN19O23 | 2063.65 | 1033.1 | [M+2H]/2+ |
136 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-4Pal-Nva-dA-Cha44F2 | 0.396 | 2059.85119 | C104H120ClF2N19O22 | 2061.63 | 1031.8 | [M+2H]/2+ |
137 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-K-L-dA-hF3CF3 | 0.09385 | 2093.87307 | C105H123ClF3N19O22 | 2095.66 | 1048.8 | [M+2H]/2+ |
138 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-K-S-dA-hY | 0.2145 | 2015.82856 | C101H118ClN19O24 | 2017.58 | 1009.6 | [M+2H]/2+ |
139 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-K-S-dDab-hY | 0.1325 | 2044.85511 | C102H121ClN20O24 | 2046.62 | 1024.2 | [M+2H]/2+ |
140 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-W-AbuMph-dA-G | 0.515 | 2036.8289 | C103H117ClN20O23 | 2038.6 | 1019.2 | [M+2H]/2+ |
141 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-W-AbuMph-dA-hY | 0.177 | 2156.88641 | C111H125ClN20O24 | 2158.75 | 1079.9 | [M+2H]/2+ |
142 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-W-Dab-dA-hF | 0.159 | 2070.84963 | C107H119ClN20O22 | 2072.66 | 1037.1 | [M+2H]/2+ |
143 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-W-Dab-dA-hY | 0.230 | 2086.84455 | C107H119ClN20O23 | 2088.66 | 1045.1 | [M+2H]/2+ |
144 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-W-Dap-dA-hF | 0.07494 | 2056.83398 | C106H117ClN20O22 | 2058.64 | 1029.7 | [M+2H]/2+ |
145 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-W-Dap-dA-hY | 0.07482 | 2072.8289 | C106H117ClN20O23 | 2074.64 | 1038.0 | [M+2H]/2+ |
146 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-W-DapMe2-dA-hY | 0.114 | 2100.8602 | C108H121ClN20O23 | 2102.69 | 1051.7 | [M+2H]/2+ |
147 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-W-hSOMe-dA-hY | 0.09264 | 2101.84421 | C108H120ClN19O24 | 2103.67 | 1052.5 | [M+2H]/2+ |
148 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-W-L-dA-hY | 0.04831 | 2099.86495 | C109H122ClN19O23 | 2101.7 | 1051.3 | [M+2H]/2+ |
149 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-sbMeW4Cl-D-dNMeA-G-Bip4CO2H-W-L-dDab-hY | 0.81 | 2128.8915 | C110H125ClN20O23 | 2130.74 | 1065.9 | [M+2H]/2+ |
150 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-W-S-dA-hF | 0.06331 | 2057.818 | C106H116ClN19O23 | 2059.62 | 1030.1 | [M+2H]/2+ |
151 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-W-S-dA-hY | 0.07588 | 2073.81291 | C106H116ClN19O24 | 2075.62 | 1038.4 | [M+2H]/2+ |
152 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-W-SerOMe-dA-hF | 0.06003 | 2071.83365 | C107H118ClN19O23 | 2073.65 | 1037.5 | [M+2H]/2+ |
153 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-W-SerOMe-dA-hY | 0.088 | 2087.82856 | C107H118ClN19O24 | 2089.65 | 1045.1 | [M+2H]/2+ |
154 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-1Nal-Dab-dA-hY | 0.196 | 2081.87885 | C109H120FN19O23 | 2083.23 | 1041.7 | [M+2H]/2+ |
155 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-1Nal-S-dA-hY | 0.2203 | 2068.84722 | C108H117FN18O24 | 2070.19 | 1036.7 | [M+2H]/2+ |
156 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-4Pal-L-dA-hY | 0.948 | 2045.87885 | C106H120FN19O23 | 2047.2 | 1024.2 | [M+2H]/2+ |
157 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-4Pal-Nva-dA-hY | 0.403 | 2031.8632 | C105H118FN19O23 | 2033.17 | 1017.8 | [M+2H]/2+ |
158 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-K-L-dA-h3Pal5CN | 0.0257 | 2035.90573 | C104H122FN21O22 | 2037.21 | 2036.4 | [M+H]+ |
159 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-K-L-dA-hY | 0.1185 | 2025.91015 | C104H124FN19O23 | 2027.21 | 1014.9 | [M+2H]/2+ |
160 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-K-L-dDab-hY | 0.5225 | 2054.9367 | C105H127FN20O23 | 2056.25 | 1029.4 | [M+2H]/2+ |
161 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-K-L-dS-hY | 0.483 | 2041.90506 | C104H124FN19O24 | 2043.21 | 1022.9 | [M+2H]/2+ |
162 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-W-AbuMph-dA-G | 0.749 | 2020.85845 | C103H117FN20O23 | 2022.15 | 1012.1 | [M+2H]/2+ |
163 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-W-Dab-dA-hF | 0.156 | 2054.87918 | C107H119FN20O22 | 2056.21 | 1029.5 | [M+2H]/2+ |
164 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-W-L-dA-AEF | 0.459 | 2112.92105 | C110H125FN20O23 | 2114.29 | 1058.0 | [M+2H]/2+ |
165 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-W-L-dA-AlaPip4 | 0.781 | 2060.92613 | C107H125FN20O22 | 2062.26 | 1031.9 | [M+2H]/2+ |
166 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-W-L-dA-hF | 0.1486 | 2067.89958 | C109H122FN19O22 | 2069.25 | 1035.7 | [M+2H]/2+ |
167 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-W-L-dA-hY | 0.1357 | 2083.8945 | C109H122FN19O23 | 2085.25 | 1044.2 | [M+2H]/2+ |
168 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-W-L-dDab-hY | 0.08471 | 2112.92105 | C110H125FN20O23 | 2114.29 | 1058.7 | [M+2H]/2+ |
169 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-W-L-dK-hY | 0.1119 | 2140.95235 | C112H129FN20O23 | 2142.34 | 1072.7 | [M+2H]/2+ |
170 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-W-L-dOrn-hY | 0.09664 | 2126.9367 | C111H127FN20O23 | 2128.31 | 1065.8 | [M+2H]/2+ |
171 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-W-L-dS-hY | 0.1453 | 2099.88941 | C109H122FN19O24 | 2101.25 | 1052.2 | [M+2H]/2+ |
172 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-W-S-dA-hY | 0.246 | 2057.84246 | C106H116FN19O24 | 2059.17 | 1031.2 | [M+2H]/2+ |
173 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-W-S-dA-TyrEtNAc | 0.9592 | 2128.87958 | C109H121FN20O25 | 2130.24 | 1066.3 | [M+2H]/2+ |
174 | 3AzaPhe4AcPip-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-Dab-L-dA-hCha | 0.015 | 2006.9719 | C105H130N20O21 | 2008.28 | 2008.99 | [M+H]+ |
175 | 3AzaPhe4AcPip-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-Dap-L-dA-hCha | 0.016 | 1992.9563 | C104H128N20O21 | 1994.25 | 1994.97 | [M+H]+ |
176 | 3AzaPhe4AcPip-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-hQ-L-dA-h3Pal5CN | 0.017 | 2068.9261 | C107H124N22O22 | 2070.26 | 2070.94 | [M+H]+ |
177 | 3AzaPhe4AcPip-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-K-L-dA-hCha | 0.013 | 2035.0032 | C107H134N20O21 | 2036.33 | 2037.01 | [M+H]+ |
178 | 3AzaPhe4AcPip-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-K-L-dL-h3Pal5CN | 0.019 | 2096.9937 | C110H132N22O21 | 2098.36 | 2099.02 | [M+H]+ |
179 | 3AzaPhe4AcPip-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-K-L-dNle-h3Pal5CN | 0.017 | 2096.9937 | C110H132N22O21 | 2098.36 | 2099.03 | [M+H]+ |
180 | 3AzaPhe4AcPip-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-K-L-dNva-h3Pal5CN | 0.021 | 2082.9781 | C109H130N22O21 | 2084.33 | 2085.01 | [M+H]+ |
181 | 3AzaPhe4AcPip-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-K-Tba-dA-h3Pal5CN | 0.015 | 2068.9624 | C108H128N22O21 | 2070.31 | 2070.98 | [M+H]+ |
182 | 3AzaPhe4AcPip-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-Orn-L-dA-hCha | 0.013 | 2020.9876 | C106H132N20O21 | 2022.30 | 2023.00 | [M+H]+ |
183 | 3AzaPhe4AcPip-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-Q-L-dA-h3Pal5CN | 0.013 | 2054.9104 | C106H122N22O22 | 2056.24 | 2056.93 | [M+H]+ |
184 | Bip4CO2H-Trp6Cl-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-K-L-dA-hY | 0.018 | 2078.8446 | C107H120ClFN18O23 | 2080.66 | 2079.70 | [M+H]+ |
185 | Bip4CO2H-Trp7F-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-K-L-dA-hY | 0.024 | 2062.8742 | C107H120F2N18O23 | 2064.20 | 1032.76 | [M+2H]/2+ |
186 | Bip4CO2H-Trp7Me-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-K-L-dA-hY | 0.038 | 2058.8993 | C108H123FN18O23 | 2060.24 | 1030.33 | [M+2H]/2+ |
187 | Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-K-L-dLysAc-hY | 0.009 | 2143.9520 | C112H130FN19O24 | 2145.34 | 2145.97 | [M+H]+ |
188 | F4bcpA-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-1Inda-G-dDab-hCha | 0.016 | 2049.9090 | C109H123N19O22 | 2051.26 | 2052.87 | [M+H]+ |
189 | F4bcpA-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-Cha-G-dDab-hCha | 0.019 | 2015.9498 | C108H129N17O22 | 2017.28 | 2017.49 | [M+H]+ |
190 | F4bcpA-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-Cha-G-dDab-hY | 0.018 | 2025.8978 | C108H123N17O23 | 2027.23 | 2028.19 | [M+H]+ |
191 | F4pcCCA-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-4Pal-G-dDab-hCha | 0.019 | 2026.9294 | C108H126N18O22 | 2028.26 | 2029.36 | [M+H]+ |
192 | F4ptCCA-Trp6F-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-4Pal-G-dDab-hCha | 0.015 | 2044.9200 | C108H125FN18O22 | 2046.25 | 2046.42 | [M+H]+ |
193 | F4ptCCA-Trp6F-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-4Pal-S-dDab-hCha | 0.012 | 2074.9306 | C109H127FN18O23 | 2076.28 | 2076.24 | [M+H]+ |
194 | F4ptCCA-Trp6F-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-4Pal-S-dDabMe3-hCha | 0.015 | 2117.9853 | C112H134FN18O23 | 2119.37 | 2119.29 | [M+H]+ |
195 | F4ptCCA-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-4Pal-G-dDab-aMeNle | 0.022 | 1986.8981 | C105H122N18O22 | 1988.20 | 1988.96 | [M+H]+ |
196 | F4ptCCA-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-4Pal-G-dDab-hCha | 0.030 | 2026.9294 | C108H126N18O22 | 2028.26 | 2029.60 | [M+H]+ |
197 | F4ptCCA-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-4Pal-G-dDab-Nle | 0.024 | 1972.8825 | C104H120N18O22 | 1974.17 | 1974.94 | [M+H]+ |
198 | Phe4AcPip-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-1Indolin-G-dDab-hY | 0.021 | 2076.9199 | C110H124N20O22 | 2078.28 | 1040.18 | [M+2H]/2+ |
199 | Phe4AcPip-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-4Pal-G-daMeDab-hCha | 0.024 | 2040.9563 | C108H128N20O21 | 2042.29 | 2043.02 | [M+H]+ |
200 | Phe4AcPip-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-4Pal-G-dDab-aMeNle | 0.034 | 1986.9093 | C104H122N20O21 | 1988.20 | 1988.97 | [M+H]+ |
201 | Phe4AcPip-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-4Pal-G-dDab-hCha | 0.030 | 2026.9406 | C107H126N20O21 | 2028.27 | 2028.77 | [M+H]+ |
202 | Phe4AcPip-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-Cha-G-dDab-hY | 0.029 | 2041.9403 | C108H127N19O22 | 2043.28 | 2044.64 | [M+H]+ |
203 | Phe4AcPip-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-Dab-L-dA-hCha | 0.012 | 2005.9767 | C106H131N19O21 | 2007.29 | 2008.04 | [M+H]+ |
204 | Phe4AcPip-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-DapAc-K-dA-h3Pal5CN | 0.009 | 2068.9261 | C107H124N22O22 | 2070.26 | 2071.00 | [M+H]+ |
205 | Phe4AcPip-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-DapAc-L-dDap-h3Pal5CN | 0.010 | 2068.9261 | C107H124N22O22 | 2070.26 | 2070.96 | [M+H]+ |
206 | Phe4AcPip-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-Dap-L-dA-hCha | 0.015 | 1991.9610 | C105H129N19O21 | 1993.26 | 1994.03 | [M+H]+ |
207 | Phe4AcPip-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-K-L-dA-hCha | 0.011 | 2034.0080 | C108H135N19O21 | 2035.34 | 2036.08 | [M+H]+ |
208 | Phe4AcPip-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-LysAc-L-dA-h3Pal5CN | 0.018 | 2095.9621 | C110H129N21O22 | 2097.33 | 2097.97 | [M+H]+ |
209 | Phe4AcPip-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-Orn-L-dA-hCha | 0.009 | 2019.9923 | C107H133N19O21 | 2021.32 | 2022.07 | [M+H]+ |
210 | TyrEtNAc-Trp6Cl-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-Trp7az-S-dDab-hCha | 0.020 | 2104.8915 | C108H125ClN20O23 | 2106.72 | 1053.44 | [M+2H]/2+ |
211 | TyrEtNAc-Trp6F-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-1Indolin-G-dDab-hY | 0.027 | 2069.8789 | C108H120FN19O23 | 2071.22 | 2071.32 | [M+H]+ |
212 | TyrEtNAc-Trp6F-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-Trp7az-S-dDab-hCha | 0.025 | 2088.9211 | C108H125FN20O23 | 2090.27 | 1045.22 | [M+2H]/2+ |
213 | TyrEtNAc-Trp6F-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-Trp7az-S-dDabMe3-hCha | 0.018 | 2131.9758 | C111H132FN20O23 | 2133.35 | 2133.32 | [M+H]+ |
214 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-Trp7az-G-dDab-hCha | 0.020 | 2040.9199 | C107H124N20O22 | 2042.25 | 1022.67 | [M+2H]/2+ |
215 | TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-Trp7az-G-dDab-hY | 0.024 | 2050.8679 | C107H118N20O23 | 2052.20 | 1026.43 | [M+2H]/2+ |
TW202404574A_112121925_SEQL.xml
Claims (28)
- 一種式(I)化合物, 或其醫藥上可接受之鹽或水合物, 其中: R1係CH3C(O)NH-CH2CH2-O-或C1; C1係: (i) 5至6員單環芳基或雜芳基,其中該雜芳基含有1至2個選自由N、O及S組成之群之雜原子;或 (ii) 5至6員單-或雙環、飽和環烷基或雜環烷基,其含有1至2個選自由N、O及S組成之群之雜原子;或 (iii) 5至6員單-或雙環環烷基; 其中C1未經取代或由1至3個獨立地選自由以下組成之群之RC1取代基取代:鹵基、C1-C3烷基、C1-C3氟烷基、羧基、C1-C3烷氧基及C2-C3醯基; R 2係H、C1-C3烷基、苄基或苯基-CH2CH2-; R3係9至10員雙環芳基或雜芳基,其中該雜芳基含有1至2個選自由N、O及S組成之群之雜原子; 其中R3未經取代或由1至3個獨立地選自由以下組成之群之R3a取代基取代:鹵基、C1-C3烷基、C1-C3氟烷基、羥基及C1-C3烷氧基; R4係C1-C3烷基、HO2C-(CH2)m-、H2NC(O)-(CH2)m-、(CH3)2NC(O)-(CH2)m-或四唑基-(CH2)m-; R5係胺基、H2N(CH2)n-、H2NC(O)-(CH2)n-、CH3C(O)NH-、CH3C(O)NH(CH2)n-、C5或C5-CH2-, C5係: (ii) 5至6員單環芳基或雜芳基,其中該雜芳基含有1至2個選自由N、O及S組成之群之雜原子; (ii) 9至10員雙環芳基或雜芳基,其中該雙環雜芳基含有1至3個選自由N、O及S組成之群之雜原子; (iii) 5至6員單環或9至10員雜環烷基,其中該雜環烷基係飽和或部分不飽和的,且含有1至2個選自由N、O及S組成之群之雜原子; (iv) 5至6員單環環烷基; (v) 2,3-二氫吲哚基; 其中C5未經取代或由1至3個獨立地選自由以下組成之群之RC5取代基取代:鹵基、胺基、羥基、C1-C3烷基、C1-C3氟烷基、C1-C3烷氧基、H2N-(CH2)k-、H2NC(O)-(CH2)k-、H2C=CH-CH2O-及苯基; R6係H、C1-C5烷基、H2N(CH2)p-、HOCH2-、(CH3)2NCH2-、H3CO-(CH2)q-或C6-CH2-; C6係含有1至2個選自由N、O及S組成之群之雜原子之5-或6員單環、飽和雜環烷基;且其中C6未經取代或由1至3個獨立地選自由以下組成之群之RC6取代基取代:鹵基、C1-C3烷基、C1-C3氟烷基、羥基及C1-C3烷氧基; R7係H或C1-C3烷基; R8a係H、C1-C5烷基、HOCH2-、H2N(CH2)r-、(CH 3) 3N +(CH2)r-或CH3C(O)NH(CH2)r-; R8b係H或C1-C3烷基; R9a係H或C1-C3烷基; R9b係H、C1-C5烷基、C9-CH2-或C9-CH2CH2-; C9係: (i) 5至6員單環芳基或雜芳基,其中該雜芳基含有1至2個選自由N、O及S組成之群之雜原子;或 (ii) 5至6員單環、飽和環烷基或雜環烷基,其中該雜環烷基含有1至2個選自由N、O及S組成之群之雜原子; 其中C9未經取代或由1至3個獨立地選自由以下組成之群之RC9取代基取代:鹵基、胺基、羥基、氰基、C1-C3烷基、C1-C3氟烷基、C1-C3烷氧基、H2N-(CH2)k-、H2NC(O)-(CH2)k-、H2NCH2CH2O-、CH3C(O)NH-CH2CH2O-及嗎啉基-CH2CH2O-; R 10係H、鹵基或C1-C3烷基; R 11係H、鹵基或C1-C3烷基; 下標k在每次出現時獨立地係1或2; 下標m為1或2; 下標n為1、2、3、或4; 下標p為1、2、3、或4; 下標q為1或2; 下標r為1、2、3、或4; X1、X2及X3獨立地係C(H)或N;且 A1及A2獨立地選自由以下組成之群:HO2C-、H2NC(O)-、CH3C(O)N(H)-、H2NS(O)2-、CH 3S(O)2N(H)-、四唑基及5-側氧基噁二唑基。
- 如請求項1之化合物或其醫藥上可接受之鹽或水合物,其中: R5係胺基、H2N(CH2)n-、H2NC(O)-(CH2)n-、C5或C5-CH2-, C5係: (i) 5至6員單環芳基或雜芳基,其中該雜芳基含有1至2個選自由N、O及S組成之群之雜原子; (ii) 9至10員雙環芳基或雜芳基,其中該雙環雜芳基含有1至3個選自由N、O及S組成之群之雜原子; (iii) 5至6員單環或9至10員雜環烷基,其中該雜環烷基係飽和或部分不飽和的,且含有1至2個選自由N、O及S組成之群之雜原子;或 (iv) 2,3-二氫吲哚基; 其中C5未經取代或由1至3個獨立地選自由以下組成之群之RC5取代基取代:鹵基、胺基、羥基、C1-C3烷基、C1-C3氟烷基、C1-C3烷氧基、H2N-(CH2)k-、H2NC(O)-(CH2)k-、H2C=CH-CH2O-及苯基; R6係H、C2-C5烷基、H2N(CH2)p-、HOCH2-、(CH3)2NCH2-、H3CO-(CH2)q-或C6-CH2-; R8a係H、C1-C3烷基、HOCH2-或H2N(CH2)r-; R9a係H; R9b係H、C1-C3烷基、C9-CH2-或C9-CH2CH2-; R10係H; R11係H; 下標p為1、2或3;且 下標r為2、3或4。
- 如請求項1之化合物或其醫藥上可接受之鹽或水合物,其中: C1係苯基、嘧啶基或六氫吡嗪基,其中C1未經取代或由1至2個RC1取代基取代; R3係萘基或吲哚基,其中R3未經取代或由1至2個R3a取代基取代; C5係苯基、吡啶基、嘧啶基、萘基、吲哚基、7-氮雜吲哚基、吲唑基、2,3-二氫吲哚基、六氫吡啶基、四氫吡喃基或環己基,其中C5未經取代或由1至2個RC5取代; C6係四氫吡喃基或嗎啉基;其中C6未經取代或由1至2個RC6取代;且 C9a係H或甲基; C9b係苯基、吡啶基、環己基、嗎啉基或六氫吡啶基,其中C9未經取代或由1至2個RC9取代。
- 如請求項1之化合物或其醫藥上可接受之鹽或水合物,其中X1及X2係C(H);且R1係經羧基取代之苯基。
- 如請求項1之化合物或其醫藥上可接受之鹽或水合物,其中X1及X2係C(H);且R1係CH 3C(O)NH-CH 2CH 2-O-。
- 如請求項1之化合物或其醫藥上可接受之鹽或水合物,其中R2係H。
- 如請求項1之化合物或其醫藥上可接受之鹽或水合物,其中R3係經一個鹵基取代之吲哚基。
- 如請求項1之化合物或其醫藥上可接受之鹽或水合物,其中R3係萘基。
- 如請求項1之化合物或其醫藥上可接受之鹽或水合物,其中R4係HO2C-(CH2)m-。
- 如請求項1之化合物或其醫藥上可接受之鹽或水合物,其中X3係C(H)。
- 如請求項1之化合物或其醫藥上可接受之鹽或水合物,其中R5係H2N(CH2)n-、吲哚、7-氮雜吲哚、萘基或吡啶基。
- 如請求項5之化合物或其醫藥上可接受之鹽或水合物,其中R5係H2N(CH2)n-、吲哚、萘基或吡啶基。
- 如請求項1之化合物或其醫藥上可接受之鹽或水合物,其中R6係H、HOCH2-、C2-C5烷基或H2N(CH2)p-。
- 如請求項13之化合物或其醫藥上可接受之鹽或水合物,其中R6係C2-C5烷基或H2N(CH2)p-。
- 如請求項1之化合物或其醫藥上可接受之鹽或水合物,其中R7係H。
- 如請求項1之化合物或其醫藥上可接受之鹽或水合物,其中: R8a係甲基或H2NCH2CH2-;且R8b係H。
- 如請求項1之化合物或其醫藥上可接受之鹽或水合物,其中R9b係 。
- 如請求項1之化合物或其醫藥上可接受之鹽或水合物,其中R9b係 。
- 如請求項1之化合物或其醫藥上可接受之鹽或水合物,其中 R10係H;且R11係H、F或Cl。
- 如請求項1之化合物或其醫藥上可接受之鹽或水合物,其中A1及A2皆係HO2C-。
- 如請求項1之化合物或其醫藥上可接受之鹽或水合物,其中: R1係4-CH3C(O)-六氫吡嗪-1-基、CH3C(O)NH-CH2CH2-O-、5-CO 2H-嘧啶-2-基或4-CO2H-苯基; R 2係H、乙基、苄基或苯基-CH2CH2-; R3係萘-1-基、4-氟吲哚-3-基或4-氯吲哚-3-基; R4係甲基、HO2C-(CH2)m-或H2NC(O)-(CH2)m-; R5係胺基、H2N(CH2)n-、萘-1-基、吲哚-3-基、7-氮雜-吲哚-3-基、吲唑-1-基、2,3-二氫吲哚-1-基、吡啶-3-基、吡啶-4-基、六氫吡啶-4-基、3-胺基甲基苯基、4-胺基甲基苯基、3-胺基苯基、4-胺基苯基、苯基、吡啶-4-基-CH2-、嘧啶-5-基、四氫吡喃-4-基-、H2NC(O)-(CH2)2-、3-聯苯、3-CH2=CH-CH2O-苯基、CH3C(O)NH-、CH3C(O)NH(CH2)3-或環己基; R6係H、(CH3)2CHCH2-、(CH3)3CCH2-、H2N(CH2)p-、HOCH2-、H3CCH2CH2-、嗎啉-4-基-CH2-、四氫吡喃-4-基-CH2-、(CH3)2NCH2-或H3CO-(CH2)q-; R7係H或甲基; R8a係H、甲基、HOCH2-、H2N(CH2)r-、(CH 3) 3NCH2CH2-或CH3C(O)NH(CH2)4-; R8b係H或甲基; R9a係H或甲基; R9b係H、甲基、H3CCH2CH2CH2-、4-HO-苯基-CH2CH2-、苯基-CH2CH2-、環己基-CH2CH2-、5-NC-吡啶-3-基-CH2CH2-、4-F3C-苯基-CH2-、3-F3C-苯基-CH2-、2-F3C-苯基-CH2-、嗎啉-4-基-CH2CH2O-苯基-CH2-、4-胺基苯基-CH2-、4,4-二氟環己基-CH2-、4-H2NCH2CH2O-苯基-CH2-、4-H2NCH2CH2O-吡啶-3-基-CH2-、六氫吡啶-4-基-CH2-或4-CH3C(O)NH-CH2CH2O-苯基-CH2-; R10係H、氟或甲基; R11係H、氟或氯; A1及A2皆係HO2C-;且 X1、X2及X3係C(H)。
- 如請求項1之化合物或其醫藥上可接受之鹽或水合物,其係選自由SEQ ID NO:1-215或其醫藥上可接受之鹽或水合物組成之群。
- 如請求項1之化合物或其醫藥上可接受之鹽或水合物,其係選自由以下組成之群:(按出現順序分別係SEQ ID NO: 78、71-72、67、65、70、69、68、66、64、77、79、209、193、215、212及210): 及 或其醫藥上可接受之鹽或水合物。
- 一種醫藥組合物,其包括如請求項1至23中任一項之化合物或其醫藥上可接受之鹽或水合物及醫藥上可接受之載劑。
- 一種如請求項1至23中任一項之化合物或其醫藥上可接受之鹽或水合物之用途,其用以製造用於治療動脈粥樣硬化之藥劑。
- 一種如請求項1至23中任一項之化合物或其醫藥上可接受之鹽或水合物之用途,其用以製造用於治療血管發炎之藥劑。
- 一種如請求項1至23中任一項之化合物或其醫藥上可接受之鹽或水合物之用途,其用以製造用於治療發炎性病症之藥劑。
- 如請求項25、26或27之用途,其中該藥劑係用於經口投與。
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US6054587A (en) | 1997-03-07 | 2000-04-25 | Metabasis Therapeutics, Inc. | Indole and azaindole inhibitors of fructose-1,6-bisphosphatase |
US6284748B1 (en) | 1997-03-07 | 2001-09-04 | Metabasis Therapeutics, Inc. | Purine inhibitors of fructose 1,6-bisphosphatase |
AU6691498A (en) | 1997-03-07 | 1998-09-22 | Metabasis Therapeutics, Inc. | Novel benzimidazole inhibitors of fructose-1,6-bisphosphatase |
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US7186746B2 (en) | 2002-08-29 | 2007-03-06 | Merck & Co., Inc. | Indoles having anti-diabetic activity |
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