TW202206409A - 用於ubr盒結構域配體之化合物以及醫藥組成物 - Google Patents
用於ubr盒結構域配體之化合物以及醫藥組成物 Download PDFInfo
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- TW202206409A TW202206409A TW110115106A TW110115106A TW202206409A TW 202206409 A TW202206409 A TW 202206409A TW 110115106 A TW110115106 A TW 110115106A TW 110115106 A TW110115106 A TW 110115106A TW 202206409 A TW202206409 A TW 202206409A
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- compound
- hydroxybenzyl
- amino
- mmol
- mixture
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- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
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- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- DUYAAUVXQSMXQP-UHFFFAOYSA-M thioacetate Chemical compound CC([S-])=O DUYAAUVXQSMXQP-UHFFFAOYSA-M 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- HFFLGKNGCAIQMO-UHFFFAOYSA-N trichloroacetaldehyde Chemical compound ClC(Cl)(Cl)C=O HFFLGKNGCAIQMO-UHFFFAOYSA-N 0.000 description 1
- 125000006168 tricyclic group Chemical group 0.000 description 1
- 229950009811 ubenimex Drugs 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Images
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Abstract
本說明書是關於作為UBR盒結構域配體的化合物。本說明書提供一種與UBR盒結構域結合的小分子化合物。此外,本說明書提供一種用於抑制UBR盒結構域基質結合的組成物,包含與UBR盒結構域結合的配體化合物、用於治療UBR相關疾病的醫藥組成物以及其用途。
Description
本說明書中所揭露的內容是關於作為UBR盒結構域配體的化合物。UBR盒結構域為通常存在於N端規則路徑的泛素蛋白連接酶E3組分n-識別蛋白(UBR)蛋白中的結構域。在此情況下,UBR盒結構域稱為基質所結合的結構域。UBR盒結構域對於與基質的N末端殘基結合以在基質中形成多泛素鏈是必需的,且已知基質藉由此過程降解。
本說明書是關於用作與UBR盒結構域結合的配體的化合物。
細胞藉由降解蛋白質調節活體內蛋白質的量及功能。在此情況下,活體內蛋白質可取決於N末端殘基序列而降解,且此類降解路徑稱為N端規則路徑。亦即,N端規則路徑為使用特定蛋白質N端作為降解信號的蛋白水解系統。N端規則路徑可包含以下蛋白水解過程。
在真核生物的情況下,N-識別蛋白識別蛋白質的N末端降解信號,且N-識別蛋白可藉由允許泛素與待降解的蛋白質結合來降解蛋白質。在此情況下,N末端降解信號可包含在N末端具有帶正電荷的殘基(類型1:例如精胺酸、離胺酸以及組胺酸)或較大疏水性殘基(類型2:苯丙胺酸、白胺酸、色胺酸、異白胺酸及酪胺酸)的彼等N末端降解信號。本發明人首次發現或選殖N-識別蛋白UBR 1、UBR2、UBR3以及UBR5,且揭露N-識別蛋白具有作為基質識別結構域的UBR盒結構域(Tasaki等人2005)。在此情況下,將由N-識別蛋白與N端規則配體的結合所產生的泛素化基質遞送至蛋白酶體且降解為短肽。在此過程中,特定N末端殘基(Nt-Arg、Nt-His、Nt-Lys、Nt-Trp、Nt-Phe、Nt-Tyr、Nt-Leu、Nt-Leu)提供在N-識別蛋白靶向N端規則基質時所需的大部分氫鍵,且因此為結合所必需的決定子(determinant)(Sriram及Kwon, 2010)。
UBR為泛素蛋白連接酶E3組分n-識別蛋白的縮寫,且UBR為識別蛋白質的N末端降解信號的N-識別蛋白。已知至少7種類型的UBR 1至UBR 7存在於哺乳動物中。此外,UBR共同具有的UBR盒結構域是大小為約70個殘基的鋅指模體,且稱為高度保守的基質結合結構域。[Kwon等人, 1998; Xie及Varshavsky, 1999; Kwak等人, 2004; Varshavsky, 1996; Varshavsky,1997; Kwon等人, 2011; 以及Zenker等人, 2014].
亦即,UBR為與N端規則路徑相關的N-識別蛋白,所述N端規則路徑為蛋白水解路徑,且UBR中的UBR盒結構域為基質結合結構域。特定而言,在UBR 1至UBR 7中,已知UBR1、UBR2、UBR3以及UBR5充當泛素蛋白接合酶E3且具有RING結構域或HECT結構域。與UBR結合的N端規則基質藉由泛素蛋白酶體路徑降解。特定而言,UBR中的UBR盒結構域識別基質的N末端胺基酸且經由RING結構域或HECT結構域將基質泛素化,由此經由蛋白酶體路徑降解基質。舉例而言,當錯誤摺疊蛋白質保留在細胞中持續延長時段時,蛋白質可能聚集以阻斷蛋白酶體或降低其他細胞功能,且因此經由泛素蛋白酶體路徑降解(Ji及Kwon, 2017)。
亦即,UBR盒結構域藉由識別N末端降解信號而在胞內蛋白水解路徑中起重要作用。因此,與UBR盒結構域結合的配體可能影響胞內蛋白水解路徑。
如上文所描述,本說明書是關於一種作為配體的化合物,所述配體與同胞內蛋白水解路徑相關的UBR盒結構域結合。
技術問題
本說明書提供一種與UBR盒結構域結合的小分子化合物。在此情況下,UBR盒結構域包含UBR 1至UBR7中的UBR盒結構域。小分子化合物可充當適合於與UBR盒結構域結合的配體。
在一個實施例中,本說明書提供一種用於抑制UBR盒結構域基質結合的組成物,包括與UBR盒結構域結合的配體化合物。
在一個特定實施例中,本說明書提供一種用於治療UBR相關疾病的醫藥組成物及其用途,且所述組成物包括與UBR盒結構域結合的配體化合物。
在一更特定實施例中,本說明書提供一種用於治療疾病的醫藥組成物,所述疾病包含由肌肉萎縮症(貝克爾(Becker)、先天性、杜興氏(Duchenne)、遠端型、埃-德二氏(Emery-Dreifuss)、面肩臂、肢帶型、肌強直性、眼咽部(ocuophargyngeal))引起的肌肉損失;由肌肉損失或降解介導的肌肉萎縮疾病,包含肌肉減少症或癌症惡病質;由過度的蛋白質降解引起的疾病,包含脂肪肉瘤、囊腫纖維化、約翰遜-布利澤德症候群(Johanson-Blizzard syndrome)、阻塞性尿路疾病(尿道阻塞序列);自體免疫性胰臟炎;或與UBR盒及UBR蛋白相關的已知疾病,包含尤塞氏症候群(Usher syndrome),及其用途,且所述組成物包括與UBR盒結構域結合的配體化合物。
技術解決方案
本說明書提供一種具有式1結構的化合物或其鹽。
[式1]
其中X1
為選擇性的經一或多個R2
取代的或未經取代的苯基、環烷基或雜環基;
各R2
獨立地選自烷基、烷氧基、胺基、胺基烷基、-NO2
、=O、-NHC2
H4
OH、-C(=NH)NH2
、-C(=O)NH2
、-C(=O)NHCH3
、-C(=O)OH、苯基或雜環烷基;
X4
為選擇性的經一或多個R3
取代的或未經取代的苯基、環烷基或雜環基;
各R3
獨立地選自烷基、烷氧基、胺基、鹵基、羥基、烷基胺基、二烷基胺基、-NO2
、-CONR'R''、-CO2
R'、-NHCOR'、苯基或雜環烷基;
各R'及R''獨立地為-H或烷基;
X2
為SO2
或CRa
Rb
;
Ra
及Rb
各自獨立地為H或CH3
;
X3
為NH或CH2
;
B1
為CH2
或NH;
A1
為CH2
或NH。
在此情況下,作為一實例,在式1中,
-X2-B1-X3由下述者所組成的族群中選出:-SO2
-NH-NH、-SO2
-NH-CH2
、-SO2
-CH2
-NH以及-CH2
-NH-NH,
X1為選擇性的經一或多個R2
取代的或未經取代的苯基、環烷基或雜環基;
各R2
獨立地選自烷基、烷氧基、胺基、胺基烷基、-NO2
、=O、-NHC2
H4
OH、-C(=NH)NH2
、-C(=O)NH2
、-C(=O)NHCH3
、-C(=O)OH、苯基或雜環烷基;
X4
為選擇性的經一或多個R3
取代的或未經取代的苯基、環烷基或雜環基;
各R3
獨立地選自烷基、烷氧基、胺基、鹵基、羥基、烷基胺基、二烷基胺基、-NO2
、-CONR'R''、-CO2
R'、-NHCOR'、苯基或雜環烷基;其中各R'及R''獨立地為-H或烷基;
A1為CH2
或NH,
I為0或1的整數。
作為一特定實例,各X1
及X4
獨立地為經取代的或未經取代的苯基、環烷基或雜環基;其中各X1
及X4
可獨立地選自經取代的或未經取代的苯基、環己基、環戊基、呋喃基、噻唑基、1H-吡唑基、吡咯啶基、哌啶基、哌嗪基、嗎啉基、吲哚啉基、1H-吲哚啉基、1H-吲唑基、異吲哚啉基、吲哚啉-2-酮基、2,3-二氫-1H-茚基以及1H-吡咯并吡啶基。
在此情況下,作為一實例,各R2
可獨立地選自甲基、乙基、胺基、胺基烷基、胺基(羥基烷基)、甲氧基、乙氧基、-C(=NH)NH2
、-C(=O)NH2
、-C(=O)NHCH3
、-C(=O)OH、苯基、吡咯啶基、哌嗪基、哌啶基及嗎啉基。
在此情況下,作為一實例,各R3
獨立地選自羥基、氟、氯、溴、胺基、甲基、乙基、異丙基、甲氧基、乙氧基、異丙氧基、烷基胺基、二烷基胺基、-NO2
、-C(=O)NH2
、-CO2
R'、-NHCOR'、-CONR'R''以及苯基;
各R'及R''獨立地為-H或烷基。
在此情況下,在式1-1、式1-2、式1-3以及式1-4中,
作為一實例,
其中X1
為選擇性的經一或多個R2
取代的或未經取代的苯基、環烷基或雜環基,其中各R2
獨立地選自烷基、烷氧基、胺基、胺基烷基、-NO2
、=O、-NHC2H4OH、-C(=NH)NH2、-C(=O)NH2、-C(=O)NHCH3、-C(=O)OH、苯基或雜環烷基;
X4
為選擇性的經一或多個R3
取代的或未經取代的苯基、環烷基或雜環基;其中各R3
獨立地選自烷基、烷氧基、胺基、鹵基、羥基、烷基胺基、二烷基胺基、-NO2
、-CONR'R''、-CO2
R'、-NHCOR'、苯基或雜環烷基;各R'及R''獨立地為-H或烷基。
作為一特定實例,各X1
及X4
獨立地為經取代的或未經取代的苯基、環烷基或雜環基;其中各X1及X4可獨立地選自經取代的或未經取代的苯基、環己基、環戊基、呋喃基、噻唑基、1H-吡唑基、吡咯啶基、哌啶基、哌嗪基、嗎啉基、吲哚啉基、1H-吲哚啉基、1H-吲唑基、異吲哚啉基、吲哚啉-2-酮基、2,3-二氫-1H-茚基以及1H-吡咯并吡啶基。
在此情況下,作為一實例,各R2
可獨立地選自甲基、乙基、胺基、胺基烷基、胺基(羥基烷基)、甲氧基、乙氧基、-C(=NH)NH2、-C(=O)NH2、-C(=O)NHCH3、-C(=O)OH、苯基、吡咯啶基、哌嗪基、哌啶基及嗎啉基。
在此情況下,作為一特定實例,本說明書提供一種化合物或其鹽,其中R2
為胺基。
在此情況下,作為一實例,各R3
獨立地選自羥基、氟、氯、溴、胺基、甲基、乙基、異丙基、甲氧基、乙氧基、異丙氧基、烷基胺基、二烷基胺基、-NO2
、-C(=O)NH2
、-CO2
R'、-NHCOR'、-CONR'R''以及苯基;
各R'及R''獨立地為-H或烷基。
在此情況下,作為一實例,
化合物可選自:
N'-(4-羥基苯甲醯基)-4-甲基苯磺醯肼;
4-胺基-N'-(4-羥基苯甲醯基)苯磺醯肼;
4-胺基-N'-(4-羥基苯甲醯基)-3-嗎啉基苯磺醯肼;N'
-(4-羥基苯甲醯基)-2-側氧基吲哚啉-5-磺醯肼;N'
-(4-羥基苯甲醯基)吲哚啉-5-磺醯肼;N'
-([1,1'-聯苯]-4-羰基)-4-胺基苯磺醯肼;N'
-([1,1'-聯苯]-3-羰基)-4-胺基苯磺醯肼;
3-胺基-N'-(4-羥基苯甲醯基)苯磺醯肼;
4-(1-胺基乙基)-N'-(4-羥基苯甲醯基)苯磺醯肼;
3,5-二胺基-N'-(4-羥基苯甲醯基)苯磺醯肼;N'
-(4-羥基苯甲醯基)-4-((2-羥基乙基)胺基)苯磺醯肼;N'
-(4-羥基苯甲醯基)-4-甲氧基苯磺醯肼;
4-((2-(4-羥基苯甲醯基)肼基)磺醯基)苯甲脒;
4-((2-(4-羥基苯甲醯基)肼基)磺醯基)苯甲醯胺;
6-胺基-N'-(4-羥基苯甲醯基)-[1,1'-聯苯]-3-磺醯肼;
4-(2-((4-胺基苯基)磺醯基)肼-1-羰基)苯甲醯胺;
4-胺基-N'-(1H-吲哚-3-羰基)苯磺醯肼;
4-胺基-N'-(4-羥基苯甲醯基)-3-(吡咯啶-1-基)苯磺醯肼;N'
-(4-羥基苯甲醯基)-4-硝基-3-(吡咯啶-1-基)苯磺醯肼;
4-胺基-N'
-(4-羥基苯甲醯基)-3-(哌啶-1-基)苯磺醯肼;N'
-(4-羥基苯甲醯基)-1H
-吡唑-4-磺醯肼;N'
-(4-羥基苯甲醯基)吲哚啉-4-磺醯肼;N'
-(4-羥基苯甲醯基)-1H
-吲哚-4-磺醯肼;
2-((4-胺基苯基)磺醯基)-N-苯肼-1-甲醯胺;
4-胺基-N'
-(1H
-吲哚-4-羰基)-3-嗎啉基苯磺醯肼;
4-胺基-N'
-(吲哚啉-4-羰基)苯磺醯肼;
4-胺基-N'
-(4-羥基苯甲醯基)-3-(哌嗪-1-基)苯磺醯肼;
4-胺基-N'
-(2,3-二氫-1H
-茚-2-羰基)苯磺醯肼;
4-胺基-N'
-(異吲哚啉-2-羰基)苯磺醯肼;N'
-(4-羥基苯甲醯基)-1H
-吲哚-2-磺醯肼;
4-胺基-N'
-(2-苯基乙醯基)苯磺醯肼;N'
-(4-羥基苯甲醯基)-1H
-吲唑-3-磺醯肼;
4-胺基-N'-(吲哚啉-6-羰基)苯磺醯肼;
4-胺基-N'
-(吲哚啉-3-羰基)苯磺醯肼;N'
-(4-羥基苯甲醯基)哌啶-4-磺醯肼;
4-胺基-N'
-(吲哚啉-6-羰基)-3-嗎啉基苯磺醯肼;
4-胺基-N'
-(哌嗪-1-羰基)苯磺醯肼;
4-胺基-3-嗎啉基-N'
-(哌嗪-1-羰基)苯磺醯肼;
N'-(4-羥基苯甲醯基)-2-甲基噻唑-4-磺醯肼;
(1S,4S)-4-胺基-N'
-(4-羥基苯甲醯基)環己烷-1-磺醯肼;
(1R,4R)-4-胺基-N'
-(4-羥基苯甲醯基)環己烷-1-磺醯肼;
4-((2-(4-羥基苯甲醯基)肼基)磺醯基)-5-甲基呋喃-2-甲酸;N'
-(4-羥基苯甲醯基)吡咯啶-3-磺醯肼;N'
-(4-羥基苯甲醯基)-1H
-吡咯并[2,3-b]吡啶-2-磺醯肼;
2-((4-胺基苯基)磺醯基)-N-(3-羥基苯基)肼-1-甲醯胺;
2-((4-胺基-3-嗎啉基苯基)磺醯基)-N-苯肼-1-甲醯胺;N'
-(4-胺基苯甲基)-4-羥基苯甲醯肼;
4-羥基-N'-(4-甲氧基苯甲基)苯甲醯肼;
N'-(4-胺基苯甲基)-2,3-二氫-1H-茚-2-碳醯肼;
4-胺基-N
-(2-(4-羥基苯基)-2-側氧基乙基)苯磺醯胺;
4-胺基-N-(2-(4-羥基苯基)-2-側氧基乙基)-3-嗎啉基苯磺醯胺;
3,5-二胺基-N-(2-(4-羥基苯基)-2-側氧基乙基)苯磺醯胺;N
-(((4-胺基苯基)磺醯基)甲基)-4-羥基苯甲醯胺;
4-羥基-N-(((4-甲氧基苯基)磺醯基))甲基)苯甲醯胺;
N-(((4-胺基苯基)磺醯基)甲基)-[1,1'-聯苯]-4-甲醯胺。
在另一態樣中,本說明書提供一種用於治療UBR相關疾病的醫藥組成物,包括化合物或其醫藥學上可接受的鹽;及一種藉由使用化合物治療UBR相關疾病的方法。
在此情況下,作為一實例,UBR相關疾病可選自由肌肉萎縮症(貝克爾、先天性、杜興氏、遠端型、埃-德二氏、面肩臂、肢帶型、肌強直性、眼咽部)引起的肌肉損失;由肌肉損失或降解介導的肌肉萎縮疾病,包含肌肉減少症或癌症惡病質;由過度的蛋白質降解引起的疾病,包含脂肪肉瘤、囊腫纖維化、約翰遜-布利澤德症候群、阻塞性尿路疾病(尿道阻塞序列);自體免疫性胰臟炎;或尤塞氏症候群。
有利效應
本文所揭露的發明提供一種相對於UBR盒結構域具有高結合強度的配體化合物。
經由UBR盒結構域配體化合物可抑制UBR盒結構域基質結合,且可提供利用此特徵的各種應用。舉例而言,UBR相關疾病(例如,肌肉減少症及類似者)可藉由UBR盒結構域配體化合物來治療。
在下文中,將參考隨附圖式經由特定例示性實施例及實例更詳細地描述本發明的內容。應注意,隨附圖式包含本發明的一些例示性實施例,但並非所有例示性實施例。由本說明書揭露的本發明內容可不同地實施,且不限於本文中所描述的特定例示性實施例。本文中揭露的發明所涉及的所屬領域中具有通常知識者將能夠設想本文所揭露的發明內容的許多修改及其他例示性實施例。因此,應理解,本文所揭露的本發明內容不限於本文所描述的特定例示性實施例,且其修改及其他例示性實施例亦在申請專利範圍的範疇內。術語的定義
下文給出本文中所使用的主要術語的定義。泛素蛋白連接酶 E3 組分 n- 識別蛋白( UBR )
如本文所使用的術語UBR指代泛素蛋白連接酶E3組分n-識別蛋白的縮寫。UBR為識別蛋白質的N末端殘基的N-識別蛋白,且已知至少7種類型的UBR 1至UBR 7存在於哺乳動物中。UBR為N-識別蛋白且與N端規則路徑相關,所述N端規則路徑為活體內蛋白水解路徑。特定而言,UBR識別蛋白質的N末端降解信號(N-降解決定子),且參與經由泛素蛋白酶體路徑降解基質蛋白的過程。UBR 盒結構域
本文所使用的術語UBR盒結構域為存在於UBR蛋白中的結構域,且為鋅指模體。UBR蛋白包含UBR 1至UBR 7蛋白。UBR盒結構域稱為基質蛋白所結合的結構域。本文所揭露的作為UBR盒結構域配體的化合物可藉由與UBR盒結構域結合來抑制UBR盒結構域基質結合。此外,本文所揭露的作為UBR盒結構域配體的化合物可影響胞內蛋白水解路徑。RING 結構域
已知本文所使用的術語RING結構域存在於UBR 1、UBR2以及UBR3蛋白中。RING結構域亦可與RING泛素化結構域互換。RING結構域為存在於蛋白質中的結構域且為鋅指模體。RING結構域為在將存在於E2中的泛素轉移至基質蛋白的過程中起重要作用的結構域,且RING結構域用於允許在一個步驟中進行將泛素轉移至基質蛋白的過程。HECT 結構域
已知本文所使用的術語HECT結構域存在於UBR 5蛋白中。HECT結構域亦可與HECT泛素化結構域互換。HECT結構域為在將存在於E2中的泛素轉移至基質蛋白的過程中起重要作用的結構域。將存在於E2中的泛素遞送至HECT結構域且隨後轉移至基質蛋白。亦即,HECT結構域用於允許在兩個步驟中進行將泛素轉移至基質蛋白的過程。鋅指模體
如本文所使用,術語鋅指模體指代其中存在一或多個鋅離子以使蛋白質結構穩定的蛋白質結構模體。本說明書的UBR盒結構域及RING結構域為鋅指模體。配體
如本文所使用,術語配體指代與蛋白質特異性結合的物質。蛋白質包含酶或受體,且當蛋白質為酶時,配體可指代與酶結合的基質或類似物,且當蛋白質為受體時,配體可指代與受體結合的激素或類似物。
本文所提供的作為UBR盒結構域配體的化合物意謂與UBR盒結構域結合的化合物。作為一實例,化合物指代與UBR蛋白中的UBR盒結構域結合的化合物。作為一特定實例,化合物指代與存在於UBR 1至UBR 7的一或多種蛋白質中的UBR盒結構域結合的化合物。然而,化合物不限於此。
本文所提供的作為UBR盒結構域配體的化合物可與UBR盒結構域的基質競爭性地起作用。亦即,化合物可抑制UBR盒結構域的基質結合。另外,化合物可藉由抑制基質的結合來抑制基質的降解。胺基烷基
如本文所使用,術語胺基烷基指代經胺基取代的烷基部分。胺基烷基包含-CH(NH2
)CH3
及-CH2
(NH2
)。環烷基及雜環烷基
如本文所使用,術語環烷基指代含有一或多個飽和環結構的碳環基,且包含雙環基團。環烷基的實例包含環丙基、環丁基、環戊基、環己基、環庚基以及環辛基。
雜環烷基指代除環烷基中的環碳原子以外亦包含一或多個選自P、N、O以及S的雜原子的環結構。雜環基
如本文所使用,術語雜環基指代具有12至14個環碳原子的不飽和、飽和或部分不飽和的單環、雙環或三環基團,且除環碳原子以外亦包含一或多個選自P、N、O及S的雜原子。雜環基包含雜環烷基。在各種例示性實施例中,雜環基經由碳或雜原子連接至另一部分,且選擇性的在碳或雜原子上經取代。雜環基的實例包含吖呾基、苯并咪唑基、苯并呋喃基、苯并呋呫基、苯并吡唑基、苯并三唑基、苯并噻吩基、苯并噁唑基、咔唑基、咔啉基(carbolinyl)、噌啉基(cinnolinyl)、呋喃基、咪唑基、吲哚啉基、異吲哚啉基、吲哚基、吲哚嗪基、吲唑基、異苯并呋喃基、異吲哚基、異喹啉基、異噻唑基、異噁唑基、萘吡啶基、噁二唑基、噁唑基、噁唑啉、異噁唑啉、氧呾基(oxetanyl)、哌喃基、吡嗪基、吡唑基、噠嗪基、吡啶并吡啶基、噠嗪基、吡啶基、嘧啶基、吡咯基、喹唑啉基、喹啉基、喹喏啉基、四氫哌喃基、四氫硫代哌喃基、四氫異喹啉基、四唑基、四唑並吡啶基、噻二唑基、噻唑基、噻吩基、三唑基、1,4-二噁烷基、六氫氮呯基(hexahydroazepinyl)、哌嗪基、哌啶基、哌啶-2-酮基、吡咯啶基、吡咯并吡啶基、嗎啉基、硫代嗎啉基、二氫苯并咪唑基、二氫苯并呋喃基、二氫苯并噻吩基、二氫苯并噁唑基、二氫呋喃基、二氫咪唑基、二氫吲哚基、二氫異噁唑基、二氫異噻唑基、二氫噁二唑基、二氫噁唑基、二氫吡嗪基、二氫吡唑基、二氫吡啶基、二氫嘧啶基、二氫吡咯基、二氫喹啉基、二氫四唑基、二氫噻二唑基、二氫噻唑基、二氫噻吩基、二氫三唑基、二氫吖呾基、亞甲基二氧苯甲醯基、四氫呋喃基、四氫噻吩基及類似基團。
除非另外定義,否則本文所用的所有技術及科學術語均具有與本發明所涉及的所屬領域中具有通常知識者通常所理解相同的含義。本文提及的所有公開案、專利以及其他參考案均以全文引用的方式併入本文中。
在下文中,將揭露本發明的具體內容。I.UBR 盒結構域 1. 概述
本文所提供的作為UBR盒結構域配體的化合物與UBR盒結構域結合。UBR盒結構域稱為N末端殘基序列或N末端降解信號所結合的結構域。結構域與蛋白質藉由N端規則路徑降解的過程相關。因此,化合物可經由N端規則途徑影響蛋白水解過程。2. N 端規則路徑
細胞經由蛋白水解調節蛋白質的量。在此情況下,已知藉由識別降解決定子(其為蛋白質的降解信號)的過程來執行蛋白質降解過程。特定而言,蛋白水解取決於蛋白質的N-末端殘基序列而調節,且存在於N末端處的蛋白水解信號統稱為N-降解決定子。N-降解決定子包含在N末端處具有帶正電荷的殘基(例如,精胺酸、離胺酸以及組胺酸)或較大疏水性殘基(苯丙胺酸、白胺酸、色胺酸、異白胺酸以及酪胺酸)的彼等N-降解決定子。如上文所描述,已基於蛋白質的半衰期藉由存在於蛋白質的N末端處的胺基酸殘基判定的關聯來使用術語N端規則。3. UBR 盒結構域
在N端規則路徑中,N-降解決定子由N-識別蛋白識別且泛素蛋白連接酶E3組分n-識別蛋白(UBR)被發現為N-識別蛋白。已知UBR藉由UBR盒結構域識別N末端殘基序列或N末端降解信號。亦即,UBR經由UBR盒結構域識別蛋白質降解信號,且經由識別蛋白質降解信號來執行蛋白質降解過程。
由UBR進行的蛋白質降解過程可包含以下內容。UBR盒結構域識別具有N末端降解信號的基質,泛素與基質結合,且泛素結合的基質可由蛋白酶體降解。亦即,具有N末端降解信號的基質可由泛素蛋白酶體系統(ubiquitin proteasome system;UPS)降解。II.UBR 盒結構域配體 1. 概述 1 ) 本說明書的化合物反映 UBR 盒結構域的結構及與 N 末端路徑基質結合的特徵
考慮到UBR盒結構域的結構及UBR盒結構域及N末端路徑基質的結合形式,設計本文所揭露的作為UBR盒結構域配體的化合物。
存在於UBR盒結構域中的各種胺基酸經由離子相互作用、氫鍵結、疏水相互作用及類似者與N末端路徑基質中的胺基酸相互作用且與N末端路徑基質中的胺基酸結合。藉由分析此等結合模式,在本文中合成且提供能夠與UBR盒結構域形成適合結合模式的小分子化合物。此外,下文提供根據式1至式55的化合物。2 ) 本說明書的化合物具有增強與 UBR 盒結構域結合的核心結構。
在本說明書中,如上文所描述分析UBR盒結構域的結合模式及N末端路徑基質的胺基酸,且推導化合物的核心結構。本文所提供的化合物可具有基於化合物的核心結構推導的以下[式1]的結構。[式1]如下:
[式1]。
在本說明書中,基於[式1]設計且提供各種化合物。在此情況下,考慮到與UBR盒結構域的結合模式推導X1
、X2
、X3
、B1
、A1
、X4
的候選物。下文給出基於[式1]的各種化合物的更詳細描述。2. 式 1 [ 式 1]
1)X2
、B1
、X3
以及A1 X2
在式1中,X2
可為在本文所揭露的化合物中誘導扭結結構的結構。扭結結構有助於平穩地維持本文所揭露的化合物X1
與UBR盒結構域的電荷-電荷相互作用或氫鍵結或疏水相互作用,且增強結合強度。因此,作為一實例,X2
可為可誘導扭結結構的各種結構中的一者。作為一特定實例,X2
可為SO2
或CRa
Rb
。在此情況下,Ra
及Rb
可各自獨立地選自H或CH2
。此外,X2
可為CH2
、CH(CH3
)或C(CH3
)2
。作為另一特定實例,X2
可為SO2
。B1
、X3
以及A1
在式1中,作為一實例,A1
可為CH2
或NH。
在式1中,作為一實例,B1
可為CH2
或NH。
在式1中,作為一實例,X3
可為CH2
或NH。
在此情況下,作為一實例,當式1中的B1
為CH2
時,X3
可不為CH2
。
式1可具有選自下文所描述的彼等結構的結構:
[式1-1] [式1-2]、、
[式1-3] [式1-4]、、
[式1-5] [式1-6]、、
[式1-7] [式1-8]、、
[式1-9] [式1-10]、、
[式1-11] [式1-12]、、
[式1-13] [式1-14]、、
[式1-15] [式1-16]、、
[式1-17] [式1-18]、、
[式1-19] [式1-20]、、
[式1-21] [式1-22]、、
[式1-23] [式1-24]、、
[式1-25] [式1-26]、、
[式1-27] [式1-28]、、
[式1-29] [式1-30]、、
[式1-31] [式1-32]、、
[式1-33] [式1-34]、、
[式1-35] [式1-36]、、
[式1-37] [式1-38]、、
[式1-39] [式1-40]、、
[式1-41] [式1-42]、、
[式1-43] [式1-44]、、
[式1-45]。
作為一特定實例,在式1中,
-X2
-B1
-X3
由下述者所組成的族群中選出:-SO2
-NH-NH、-SO2
-NH-CH2
、-SO2
-CH2
-NH以及-CH2
-NH-NH,
A1為CH2
或NH,且
I為0或1的整數。
作為對UBR1及UBR2的UBR盒及N-降解決定子的複合物執行結構分析及具有式1的核心結構的化合物的分子對接研究的結果,在式1中,X1
對應於N-降解決定子的第一殘基(N1)的側鏈,且預期X1
與負電荷包圍的區域結合。因此,作為一實例,在式1中,X1
可具有帶電荷或包含形成氫鍵的部分的環結構。作為一特定實例,X1
可為帶電荷或具有包含形成氫鍵的部分的平面結構的環結構。另外,當化合物與另一物質組合使用時,式1中的X1
可包含能夠與連接子結合的結構。
作為一實例,X1
可為選擇性的經一或多個R2
取代的或未經取代的苯基、環烷基或雜環基,作為一特定實例,X1
可選自選擇性的經一或多個R2
取代的或未經取代的苯基、環己基、環戊基、呋喃基、噻唑基、1H-吡唑基、吡咯啶基、哌啶基、哌嗪基、嗎啉基、吲哚啉基、1H-吲哚啉基、1H-吲哚基、1H-吲唑基、異吲哚啉基、吲哚啉-2-酮基、2,3-二氫-1H-茚基以及1H-吡咯并吡啶基。在此情況下,各R2
可獨立地選自烷基、烷氧基、胺基、胺基烷基、-NO2
、=O、-NHC2
H4
OH、-C(=NH)NH2
、-C(=O)NH2
、-C(=O)NHCH3
、-C(=O)OH、苯基或雜環烷基。作為一實例,各R2
可獨立地選自甲基、乙基、胺基、胺基烷基、胺基(羥基烷基)、甲氧基、乙氧基、-C(=NH)NH2
、-C(=O)NH2
、-C(=O)NHCH3
、-C(=O)OH、苯基、吡咯啶基、哌嗪基、哌啶基及嗎啉基。作為一特定實例,R2
可為胺基。
在式1中,X4
對應於N-降解決定子的第二殘基的側鏈,且可具有環或鏈結構,以便能夠在與UBR盒結合時填充結合間隙。在此情況下,作為一實例,環或鏈結構可藉由引入具有電荷或形成氫鍵的部分來增強結合強度。另外,在本說明書的化合物隨後與另一種物質組合使用時,X4
可包含能夠起與連接子結合的作用的結構。
作為一實例,X4
可為選擇性的經一或多個R3
取代的或未經取代的苯基、環烷基或雜環基,作為一特定實例,X4
可選自選擇性的經一或多個R3
取代的或未經取代的苯基、環己基、環戊基、呋喃基、噻唑基、1H-吡唑基、吡咯啶基、哌啶基、哌嗪基、嗎啉基、吲哚啉基、1H-吲哚啉基、1H-吲哚基、1H-吲唑基、異吲哚啉基、吲哚啉-2-酮基、2,3-二氫-1H-茚基以及1H-吡咯并吡啶基。在此情況下,各R3
可獨立地選自烷基、烷氧基、胺基、鹵基、羥基、烷基胺基、二烷基胺基、-NO2
、-CONR'R''、-CO2
R'、-NHCOR'、苯基或雜環烷基。作為一實例,各R3
可獨立地選自羥基、氟、氯、溴、胺基、甲基、乙基、異丙基、甲氧基、乙氧基、異丙氧基、烷基胺基、二烷基胺基、-NO2
、-C(=O)NH2
、-CO2
R'、-NHCOR'、-CONR'R''以及苯基。作為一特定實例,R3
可為羥基。在此情況下,各R'及R''可獨立地為-H或烷基。
本文所揭露的化合物可以其立體異構體或其鹽形式存在,且此類化合物的異構體或鹽的形式包含在本說明書的範疇內。III. 作為 UBR 盒結構域配體的化合物的特定實例 1. 化合物的特定實例
以下內容顯示本文所揭露的化合物的特定實例。以下特定實例為容易理解本文所揭露的化合物的例示性結構,且本文所揭露的化合物的範疇不限於以下實例。
在此情況下,在化合物中,A1為CH2
或NH,且I為0或1的整數。
X1
及X4
以與內容II. UBR盒結構域配體的2)X1
及3)X4
中所描述的內容相同的方式應用。
作為一甚至更特定實例,[式1-1]的特定例示性化合物可選自下文所描述的彼等化合物。
[表1]
式[1-1]的特定例示性化合物
化合物編號 | 化合物 |
1 | N'-(4-羥基苯甲醯基)-4-甲基苯磺醯肼 |
2 | 4-胺基-N'-(4-羥基苯甲醯基)苯磺醯肼 |
3 | 4-胺基-N'-(4-羥基苯甲醯基)-3-嗎啉基苯磺醯肼 |
4 | N' -(4-羥基苯甲醯基)-2-側氧基吲哚啉-5-磺醯肼 |
5 | N' -(4-羥基苯甲醯基)吲哚啉-5-磺醯肼 |
6 | N' -([1,1'-聯苯]-4-羰基)-4-胺基苯磺醯肼 |
7 | N' -([1,1'-聯苯]-3-羰基)-4-胺基苯磺醯肼 |
8 | 3-胺基-N'-(4-羥基苯甲醯基)苯磺醯肼 |
9 | 4-(1-胺基乙基)-N'-(4-羥基苯甲醯基)苯磺醯肼 |
10 | 3,5-二胺基-N'-(4-羥基苯甲醯基)苯磺醯肼 |
11 | N' -(4-羥基苯甲醯基)-4-((2-羥基乙基)胺基)苯磺醯肼 |
13 | N' -(4-羥基苯甲醯基)-4-甲氧基苯磺醯肼 |
14 | 4-((2-(4-羥基苯甲醯基)肼基)磺醯基)苯甲脒 |
15 | 4-((2-(4-羥基苯甲醯基)肼基)磺醯基)苯甲醯胺 |
17 | 6-胺基-N'-(4-羥基苯甲醯基)-[1,1'-聯苯]-3-磺醯肼 |
18 | 4-(2-((4-胺基苯基)磺醯基)肼-1-羰基)苯甲醯胺 |
20 | 4-胺基-N'-(1H-吲哚-3-羰基)苯磺醯肼 |
21 | 4-胺基-N'-(4-羥基苯甲醯基)-3-(吡咯啶-1-基)苯磺醯肼 |
22 | N' -(4-羥基苯甲醯基)-4-硝基-3-(吡咯啶-1-基)苯磺醯肼 |
23 | 4-胺基-N' -(4-羥基苯甲醯基)-3-(哌啶-1-基)苯磺醯肼 |
24 | N' -(4-羥基苯甲醯基)-1H -吡唑-4-磺醯肼 |
25 | N' -(4-羥基苯甲醯基)吲哚啉-4-磺醯肼 |
26 | N' -(4-羥基苯甲醯基)-1H -吲哚-4-磺醯肼 |
27 | 2-((4-胺基苯基)磺醯基)-N-苯肼-1-甲醯胺 |
28 | 4-胺基-N' -(1H -吲哚-4-羰基)-3-嗎啉基苯磺醯肼 |
29 | 4-胺基-N' -(吲哚啉-4-羰基)苯磺醯肼 |
30 | 4-胺基-N' -(4-羥基苯甲醯基)-3-(哌嗪-1-基)苯磺醯肼 |
31 | 4-胺基-N' -(2,3-二氫-1H -茚-2-羰基)苯磺醯肼 |
32 | 4-胺基-N' -(異吲哚啉-2-羰基)苯磺醯肼 |
33 | N' -(4-羥基苯甲醯基)-1H -吲哚-2-磺醯肼 |
34 | 4-胺基-N' -(2-苯基乙醯基)苯磺醯肼 |
35 | N' -(4-羥基苯甲醯基)-1H -吲唑-3-磺醯肼 |
36 | 4-胺基-N'-(吲哚啉-6-羰基)苯磺醯肼 |
37 | 4-胺基-N' -(吲哚啉-3-羰基)苯磺醯肼 |
38 | N' -(4-羥基苯甲醯基)哌啶-4-磺醯肼 |
39 | 4-胺基-N' -(吲哚啉-6-羰基)-3-嗎啉基苯磺醯肼 |
40 | 4-胺基-N' -(哌嗪-1-羰基)苯磺醯肼 |
41 | 4-胺基-3-嗎啉基-N' -(哌嗪-1-羰基)苯磺醯肼 |
42 | N' -(4-羥基苯甲醯基)-2-甲基噻唑-4-磺醯肼 |
43 | (1S,4S)-4-胺基-N' -(4-羥基苯甲醯基)環己烷-1-磺醯肼 |
44 | (1R,4R)-4-胺基-N' -(4-羥基苯甲醯基)環己烷-1-磺醯肼 |
45 | 4-((2-(4-羥基苯甲醯基)肼基)磺醯基)-5-甲基呋喃-2-甲酸 |
46 | N' -(4-羥基苯甲醯基)吡咯啶-3-磺醯肼 |
47 | N' -(4-羥基苯甲醯基)-1H -吡咯并[2,3-b]吡啶-2-磺醯肼 |
52 | 2-((4-胺基苯基)磺醯基)-N-(3-羥基苯基)肼-1-甲醯胺 |
53 | 2-((4-胺基-3-嗎啉基苯基)磺醯基)-N-苯肼-1-甲醯胺 |
在此情況下,化合物的X1
及X4
以與內容II. UBR盒結構域配體的2)X1
及3)X4
中所描述的內容相同的方式應用。
[式1-2]的特定例示性化合物可選自以下:
[表2]
式[1-2]的特定例示性化合物
化合物編號 | 化合物 |
19 | N' -(4-胺基苯甲基)-4-羥基苯甲醯肼 |
48 | 4-羥基-N'-(4-甲氧基苯甲基)苯甲醯肼 |
49 | N'-(4-胺基苯甲基)-2,3-二氫-1H-茚-2-碳醯肼 |
在此情況下,化合物的X1
及X4
以與內容II. UBR盒結構域配體的2)X1
及3)X4
中所描述的內容相同的方式應用。
[式1-3]的特定例示性化合物可選自以下:
[表3]
式[1-3]的特定例示性化合物
化合物編號 | 化合物 |
12 | 4-胺基-N -(2-(4-羥基苯基)-2-側氧基乙基)苯磺醯胺 |
50 | 4-胺基-N-(2-(4-羥基苯基)-2-側氧基乙基)-3-嗎啉基苯磺醯胺 |
51 | 3,5-二胺基-N-(2-(4-羥基苯基)-2-側氧基乙基)苯磺醯胺 |
[式1-4]的特定例示性化合物可選自以下:
[表4]
式[1-4]的特定例示性化合物
化合物編號 | 化合物 |
16 | N -(((4-胺基苯基)磺醯基)甲基)-4-羥基苯甲醯胺 |
54 | 4-羥基-N-(((4-甲基氧苯基)磺醯基)甲基)苯甲醯胺 |
55 | N-(((4-胺基苯基)磺醯基)甲基)-[1,1'-聯苯]-4-甲醯胺 |
在此情況下,可考慮其可能的異構體形式或其混合物形式作為化合物。舉例而言,可考慮所有立體異構體,包含對映異構體及非對映異構體,或其混合物(例如,外消旋混合物)。2. 化合物的鹽
作為本文所揭露的化合物,可考慮其鹽形式。在此情況下,所述鹽含有醫藥學上可接受的鹽。本文所揭露的鹽包含酸加成鹽或鹼加成鹽。形成鹽的例示性酸包含鹽酸、硫酸、磷酸、乙醇酸、乳酸、丙酮酸、檸檬酸、丁二酸、戊二酸及類似者,且形成鹽的例示性鹼包含鋰、鈉、鉀、鈣、鎂、甲胺、三甲胺及類似者。然而,酸及鹼不限於此且可容易地由所屬領域中具通常知識者選擇。IV. 化合物的用途 1.UBR 盒結構域基質結合的抑制 用於抑制 UBR 盒結構域基質結合的組成物
本文所揭露的化合物可用於製備用於抑制UBR盒結構域基質結合的組成物。作為一實例,包含本文所揭露的化合物的組成物可用於藉由與UBR盒結構域結合來抑制UBR盒結構域基質結合。作為另一實例,包含化合物的組成物可用於防止與UBR盒結構域結合且降解的基質降解的用途。作為一特定實例,包含化合物的組成物可用於防止與UBR盒結構域結合的基質由泛素蛋白酶體路徑降解的用途。
作為一特定實例,包含本文所揭露的化合物的組成物可用於抑制具有與UBR盒結構域結合的N末端殘基的基質的結合的用途。作為一特定實例,包含本文所揭露的化合物的組成物可用於抑制具有N末端殘基的基質的結合的用途,所述N末端殘基諸如精胺酸(Arg)、離胺酸(Lys)、組胺酸(His)、色胺酸(Trp)、苯丙胺酸(Phe)、酪胺酸(Tyr)、白胺酸(Leu)以及異白胺酸(Ile)。然而,所述用途不限於此,所述組成物可用於抑制所屬領域中已知為UBR盒結構域的基質的物質的結合的用途。
參看實例,可確認本文所揭露的化合物藉由與UBR結合來抑制基質的降解(參見圖1至圖19)。2. UBR 相關疾病的治療
本說明書的化合物或其鹽具有與UBR盒結構域結合的特性。亦即,本說明書的化合物為充當與UBR盒結構域結合的配體的化合物。因此,此等化合物可用於抑制藉由與體內的UBR盒結構域結合而降解的蛋白質的降解,且此類機制可用於治療UBR相關疾病。1 )醫藥組成物
本文所揭露的化合物可用於製備用於治療有需要的個體的醫藥組成物。
在此情況下,治療包含具有改善特定醫學病況的症狀或延緩疾病發展的作用。在此情況下,個體包含人類及非人類動物。在此情況下,醫藥組成物可包含為醫藥學上可接受的載體、賦形劑及/或添加劑,以及前述化合物。醫藥學上可接受的載體、賦形劑以及添加劑包含水、鹽水、乙二醇、丙三醇、動物及植物脂肪、油、澱粉及類似物,但不限於此,且包含醫藥學上可接受的所屬領域中已知的所有可接受的載體、賦形劑及/或添加劑。2 )治療方法
本說明書提供一種治療方法,包含向有需要的個體投與本文所揭露的化合物或其醫藥學上可接受的鹽。在此情況下,與未投與化合物或其鹽的個體相比,投與化合物或其醫藥學上可接受的鹽可具有緩解特定醫學病況的症狀或延緩疾病發展的作用。在此情況下,個體包含人類及非人類動物。-UBR 相關疾病
作為一實例,本說明書提供一種治療方法,包含向患有UBR相關疾病的個體投與化合物或其醫藥學上可接受的鹽。亦即,本文所揭露的化合物或其醫藥學上可接受的鹽可用於治療UBR相關疾病。作為一特定實例,化合物或其醫藥學上可接受的鹽可用於藉由抑制藉由與UBR盒結構域結合而降解的蛋白質的降解來治療待治療的特定疾病。
特定疾病包含肌肉萎縮症(貝克爾、先天性、杜興氏、遠端型、埃-德二氏、面肩臂、肢帶型、肌強直性、眼咽部)引起的肌肉損失;由肌肉損失或降解介導的肌肉萎縮疾病,包含肌肉減少症或癌症惡病質;由過度的蛋白質降解引起的疾病,包含脂肪肉瘤、囊腫纖維化、約翰遜-布利澤德症候群、阻塞性尿路疾病(尿道阻塞序列);自體免疫性胰臟炎;或與UBR盒及UBR蛋白相關的已知疾病,包含尤塞氏症候群。作為一實例,化合物或其醫藥學上可接受的鹽可用於治療由UBR介導的肌肉損失。舉例而言,伴隨著諸如癌症、敗血症以及甲狀腺高能症之疾病病況的肌肉質量的快速損失與肌肉內蛋白質的降解的增加相關,已知所述降解與泛素蛋白酶體系統的活化相關。在此情況下,已知泛素結合尤其藉由活化N端規則途徑而增加,從而引起肌肉損失的出現[ALFRED L GOLDBERG等人1998, 1999]。因此,本文所揭露的化合物或其醫藥學上可接受的鹽可用於藉由與UBR盒結構域結合而防止肌肉損失路徑的活化來治療疾病。然而,本發明不限於此,且特定疾病包含所屬領域中已知為與UBR相關的疾病的所有疾病。V. 實例 實例 1. 化合物的合成
[表5]
化合物的列表
編號 | 化合物的名稱 |
1 | N'-(4-羥基苯甲醯基)-4-甲基苯磺醯肼 |
2 | 4-胺基-N'-(4-羥基苯甲醯基)苯磺醯肼 |
3 | 4-胺基-N'-(4-羥基苯甲醯基)-3-嗎啉基苯磺醯肼 |
4 | N' -(4-羥基苯甲醯基)-2-側氧基吲哚啉-5-磺醯肼 |
5 | N' -(4-羥基苯甲醯基)吲哚啉-5-磺醯肼 |
6 | N' -([1,1'-聯苯]-4-羰基)-4-胺基苯磺醯肼 |
7 | N' -([1,1'-聯苯]-3-羰基)-4-胺基苯磺醯肼 |
8 | 3-胺基-N'-(4-羥基苯甲醯基)苯磺醯肼 |
9 | 4-(1-胺基乙基)-N'-(4-羥基苯甲醯基)苯磺醯肼 |
10 | 3,5-二胺基-N'-(4-羥基苯甲醯基)苯磺醯肼 |
11 | N' -(4-羥基苯甲醯基)-4-((2-羥基乙基)胺基)苯磺醯肼 |
12 | 4-胺基-N -(2-(4-羥基苯基)-2-側氧基乙基)苯磺醯胺 |
13 | N' -(4-羥基苯甲醯基)-4-甲氧基苯磺醯肼 |
14 | 4-((2-(4-羥基苯甲醯基)肼基)磺醯基)苯甲脒 |
15 | 4-((2-(4-羥基苯甲醯基)肼基)磺醯基)苯甲醯胺 |
16 | N -(((4-胺基苯基)磺醯基)甲基)-4-羥基苯甲醯胺 |
17 | 6-胺基-N'-(4-羥基苯甲醯基)-[1,1'-聯苯]-3-磺醯肼 |
18 | 4-(2-((4-胺基苯基)磺醯基)肼-1-羰基)苯甲醯胺 |
19 | N' -(4-胺基苯甲基)-4-羥基苯甲醯肼 |
20 | 4-胺基-N'-(1H-吲哚-3-羰基)苯磺醯肼 |
21 | 4-胺基-N'-(4-羥基苯甲醯基)-3-(吡咯啶-1-基)苯磺醯肼 |
22 | N' -(4-羥基苯甲醯基)-4-硝基-3-(吡咯啶-1-基)苯磺醯肼 |
23 | 4-胺基-N' -(4-羥基苯甲醯基)-3-(哌啶-1-基)苯磺醯肼 |
24 | N' -(4-羥基苯甲醯基)-1H -吡唑-4-磺醯肼 |
25 | N' -(4-羥基苯甲醯基)吲哚啉-4-磺醯肼 |
26 | N' -(4-羥基苯甲醯基)-1H -吲哚-4-磺醯肼 |
27 | 2-((4-胺基苯基)磺醯基)-N-苯肼-1-甲醯胺 |
28 | 4-胺基-N' -(1H -吲哚-4-羰基)-3-嗎啉基苯磺醯肼 |
29 | 4-胺基-N' -(吲哚啉-4-羰基)苯磺醯肼 |
30 | 4-胺基-N' -(4-羥基苯甲醯基)-3-(哌嗪-1-基)苯磺醯肼 |
31 | 4-胺基-N' -(2,3-二氫-1H -茚-2-羰基)苯磺醯肼 |
32 | 4-胺基-N' -(異吲哚啉-2-羰基)苯磺醯肼 |
33 | N' -(4-羥基苯甲醯基)-1H -吲哚-2-磺醯肼 |
34 | 4-胺基-N' -(2-苯基乙醯基)苯磺醯肼 |
35 | N' -(4-羥基苯甲醯基)-1H -吲唑-3-磺醯肼 |
36 | 4-胺基-N'-(吲哚啉-6-羰基)苯磺醯肼 |
37 | 4-胺基-N' -(吲哚啉-3-羰基)苯磺醯肼 |
38 | N' -(4-羥基苯甲醯基)哌啶-4-磺醯肼 |
39 | 4-胺基-N' -(吲哚啉-6-羰基)-3-嗎啉基苯磺醯肼 |
40 | 4-胺基-N' -(哌嗪-1-羰基)苯磺醯肼 |
41 | 4-胺基-3-嗎啉基-N' -(哌嗪-1-羰基)苯磺醯肼 |
42 | N' -(4-羥基苯甲醯基)-2-甲基噻唑-4-磺醯肼 |
43 | (1S,4S)-4-胺基-N' -(4-羥基苯甲醯基)環己烷-1-磺醯肼 |
44 | (1R,4R)-4-胺基-N' -(4-羥基苯甲醯基)環己烷-1-磺醯肼 |
45 | 4-((2-(4-羥基苯甲醯基)肼基)磺醯基)-5-甲基呋喃-2-甲酸 |
46 | N' -(4-羥基苯甲醯基)吡咯啶-3-磺醯肼 |
47 | N' -(4-羥基苯甲醯基)-1H -吡咯并[2,3-b]吡啶-2-磺醯肼 |
48 | 4-羥基-N'-(4-甲氧基苯甲基)苯甲醯肼 |
49 | N'-(4-胺基苯甲基)-2,3-二氫-1H-茚-2-碳醯肼 |
50 | 4-胺基-N-(2-(4-羥基苯基)-2-側氧基乙基)-3-嗎啉基苯磺醯胺 |
51 | 3,5-二胺基-N-(2-(4-羥基苯基)-2-側氧基乙基)苯磺醯胺 |
52 | 2-((4-胺基苯基)磺醯基)-N-(3-羥基苯基)肼-1-甲醯胺 |
53 | 2-((4-胺基-3-嗎啉基苯基)磺醯基)-N-苯肼-1-甲醯胺 |
54 | 4-羥基-N-(((4-甲基氧苯基)磺醯基)甲基)苯甲醯胺 |
55 | N-(((4-胺基苯基)磺醯基)甲基)-[1,1'-聯苯]-4-甲醯胺 |
1
H NMR光譜記錄在Bruker Avance III 400 MHz及Bruker Fourier 300 MHz上且使用TMS作為內標。LCMS在Agilent 1260HPLC及6120MSD(管柱:C18(50×4.6毫米,5微米)上的四極質譜儀上進行,以ES(+)或(-)電離模式操作;T = 30℃;流動速率= 1.5毫升/分鐘;所偵測波長:220奈米、254奈米。 實驗實例 1-1. 製備化合物 1 ( N' -(4- 羥基苯甲醯基 )-4- 甲基苯磺醯肼 )
步驟1)合成A2
將A1
(4-羥基苯甲酸甲酯,2.00公克,13毫莫耳,1.0當量)及單水合肼(20毫升)的混合物在100℃下攪拌16小時。在減壓下濃縮溶劑,以得到粗產物,藉由急驟管柱(DCM/MeOH=50/1至1/1)純化所述粗產物,以得到呈白色固體狀的A2
(4-羥基苯甲醯肼,2.0公克,產率60%)。1
H NMR (DMSO-d 6
, 400 MHz): δ 9.49 (s, 1H), 7.67-7.69 (m, 2H), 6.76-6.79 (m, 2H), 4.38 (br s, 2H)。
步驟2)合成化合物1
將A2
(4-羥基苯甲醯肼,0.3公克,1.97毫莫耳,1.0當量)及4-甲基苯磺醯氯(0.3公克,1.57毫莫耳,0.8當量)於吡啶(5毫升)中的混合物在80℃下攪拌16小時。隨後向混合物中添加1N HCl直至pH=3,且用EA(20毫升×3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥且濃縮,以得到粗產物(400毫克)。藉由製備型HPLC純化約130毫克的粗產物。將收集的溶離份濃縮以移除大部分CH3
CN。將殘餘溶離份冷凍乾燥,以得到呈白色固體狀的化合物 1
(N'
-(4-羥基苯甲醯基)-4-甲基苯磺醯肼,50毫克,24.8%產率)。1
HNMR (DMSO-d 6
, 400 MHz): δ 10.38 (s, 1H), 10.09 (s, 1H), 9.76 (s, 1H), 7.69 (d,J
= 8.4 Hz, 1H), 7.56 (d,J
= 8.8 Hz, 1H), 7.32 (d,J
= 8.0 Hz, 1H), 6.76 (d,J
= 8.8 Hz, 1H), 2.35 (s, 3H)。
LCMS;質量計算值:306.3;MS實驗值:306.9。實驗實例 1-2. 製備化合物 2 ( 4- 胺基 -N'
-(4- 羥基苯甲醯基 ) 苯磺醯肼 )
步驟1)合成A3
將A2
(4-羥基苯甲醯肼,0.3公克,1.97毫莫耳,1.0當量)及4-硝基苯-1-磺醯氯(0.35公克,1.57毫莫耳,0.8當量)於吡啶(5毫升)中的混合物在80℃下攪拌16小時。隨後向混合物中添加1N HCl直至pH=3,且用EA(20毫升×3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥且濃縮,以得到呈黃色固體狀的粗A3
(N'
-(4-羥基苯甲醯基)-4-硝基苯磺醯肼,370毫克)。LCMS;質量計算值:337.1;MS實驗值:337.6[MS]、359.6[MS 22]。
步驟2)合成化合物2
將A3
(N'
-(4-羥基苯甲醯基)-4-硝基苯磺醯肼,150毫克,0.45毫莫耳,1.0當量)及5% Pd/C(200毫克,50%於水中)於EtOH(10毫升)中的混合物在10℃下用H2
氣球攪拌4小時。隨後過濾混合物且濃縮濾液,以得到粗產物,藉由製備型HPLC純化所述粗產物。將收集的溶離份濃縮以移除大部分CH3
CN。將殘餘溶離份經冷凍乾燥,以得到呈白色固體狀的化合物 2
(4-胺基-N'
-(4-羥基苯甲醯基)苯磺醯肼,50毫克,產率36.6%)。1
HNMR (DMSO-d 6
, 400 MHz): δ 10.31 (s, 1H), 10.06 (s, 1H), 9.13 (s, 1H), 7.56 (d,J
= 8.8 Hz, 2H), 7.41 (d,J
= 8.8 Hz, 2H), 6.76 (d,J
= 8.08 Hz, 2H), 6.50 (d,J
= 8.8 Hz, 2H), 5.95 (s, 2H)。
LCMS;質量計算值:307.3;MS實驗值:307.9。實驗實例 1-3. 製備化合物 3 ( 4- 胺基 -N'
-(4- 羥基苯甲醯基 )-3- 嗎啉基苯磺醯肼 )
步驟1)合成A4
向A2
(4-羥基苯甲醯肼,500毫克,3.29毫莫耳,1.0當量)於吡啶(5毫升)中的混合物中逐滴添加含3-氟-4-硝基苯-1-磺醯氯(790毫克,3.29毫莫耳,1.0當量)的吡啶(3毫升)。隨後將混合物在25℃下攪拌3小時。將上述溶液倒入水(30毫升)中。用EA(30毫升×3)萃取混合物。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥且濃縮,以得到粗產物,藉由急驟管柱(DCM/MeOH=50/1至30/1)純化所述粗產物,以得到呈白色固體狀的A4
(3-氟-N'
-(4-羥基苯甲醯基)-4-硝基苯磺醯肼,500毫克,42.8%)。1
HNMR (DMSO-d 6
, 400 MHz): δ 10.55 (s, 1H), 10.49 (s, 1H), 10.14 (s, 1H), 8.32 (t,J
= 8.0 Hz, 1H), 7.98 (d,J
= 10.4 Hz, 1H), 7.85 (d,J
= 8.8 Hz, 1H), 7.60 (d,J
= 8.8 Hz, 2H), 6.78 (d,J
= 8.4 Hz, 2H)。
步驟2)合成A5
在25℃下,向A4
(3-氟-N'
-(4-羥基苯甲醯基)-4-硝基苯磺醯肼,500毫克,1.41毫莫耳,1.0當量)及嗎啉(184毫克,2.11毫莫耳,1.5當量)於DMF(10毫升)中的混合物中添加K2
CO3
(486毫克,3.52毫莫耳,2.5當量)。隨後將混合物在25℃下攪拌16小時。將上述溶液倒入水(30毫升)中。用EA(30毫升×3)萃取混合物。將合併的有機層用水(50毫升×3)及鹽水洗滌,經Na2
SO4
乾燥且濃縮,以得到粗產物,藉由急驟管柱(DCM/MeOH=50/1至30/1)純化所述粗產物,以得到呈白色固體狀的A5
(N'
-(4-羥基苯甲醯基)-3-嗎啉基-4-硝基苯磺醯肼,180毫克,30.3%)。1
HNMR (DMSO-d 6
, 400 MHz): δ 10.51 (s, 1H), 10.24 (s, 1H), 10.14 (s, 1H), 7.96 (d,J
= 8.4 Hz, 1H), 7.60-7.62 (m, 3H), 7.52 (d,J
= 8.4 Hz, 1H), 6.79 (d,J
= 8.4 Hz, 2H), 3.64 (t,J
= 4.8 Hz, 4H), 2.90-2.94 (m, 4H)。
步驟3)合成化合物3
在25℃下,向A5
(N'
-(4-羥基苯甲醯基)-3-嗎啉基-4-硝基苯磺醯肼,180毫克,0.427毫莫耳,1.0當量)於EtOH(10毫升)中的混合物中添加Pd/C(200毫克)。隨後將混合物在25℃下在H2
氣球下攪拌4小時。過濾上述溶液且將濾液濃縮並藉由製備型HPLC純化,以得到呈白色固體狀的化合物 3
(4-胺基-N'
-(4-羥基苯甲醯基)-3-嗎啉基苯磺醯肼,40毫克,23.9%)。(TLC: N/A)1
HNMR (DMSO-d 6
, 400 MHz): δ 10.35 (d,J
= 3.6 Hz, 1H), 10.06 (s, 1H), 9.20 (d,J
= 4.0 Hz, 1H), 7.58 (d,J
= 8.4 Hz, 2H), 7.23-7.28 (m, 2H), 6.76 (d,J
= 8.8 Hz, 2H), 6.66 (d,J
= 8.4 Hz, 1H), 5.63 (s, 2H), 3.69 (t,J
= 4.4 Hz, 4H), 2.62 (t,J
= 4.4 Hz, 4H)。
LCMS;質量計算值:392.4;MS實驗值:393。實驗實例 1-4. 製備化合物 4 ( N' -(4- 羥基苯甲醯基 )-2- 側氧基吲哚啉 -5- 磺醯肼 )
步驟1)合成A7
將氯磺酸(0.88公克,7.52毫莫耳,1.0當量)及A6
(吲哚啉-2-酮,1.0公克,7.52毫莫耳,1.0當量)的混合物在25℃下攪拌1.5小時,且隨後在68℃下攪拌1小時。將混合物冷卻且小心地倒入水中。藉由過濾收集所形成的沈澱物,用水洗滌且在真空下乾燥,以得到呈粉紅色固體狀的A7
(2-側氧基吲哚啉-5-磺醯氯,0.7公克,粗物質)。1
HNMR (DMSO-d 6
, 400 MHz): δ10.47 (br s, 1H), 7.44-7.46 (m, 2H), 6.75 (d,J
= 8.8 Hz, 1H), 3.47 (s, 2H)。
步驟2)合成化合物4
將A2
(4-羥基苯甲醯肼,0.20公克,1.32毫莫耳,1.0當量)及A7
(2-側氧基吲哚啉-5-磺醯氯,0.30公克,1.32毫莫耳,1.0當量)於吡啶(10毫升)中的混合物在30℃下攪拌5小時。將混合物倒入水中。藉由過濾收集所形成的沈澱物,用水洗滌且在真空下乾燥。將固體在30℃下在DCM中攪拌30分鐘。過濾混合物且乾燥濾餅,以得到呈粉色固體狀的化合物 4
(N'
-(4-羥基苯甲醯基)-2-側氧基吲哚啉-5-磺醯肼,50毫克,11%)。1
HNMR (DMSO-d 6
, 400 MHz): δ 10.79 (br s, 1H), 10.35 (br s, 1H), 10.11 (br s, 1H), 9.62 (br s, 1H), 7.63-7.66 (m, 2H), 7.57 (d,J
= 8.4 Hz, 2H), 6.88 (d,J
= 8.4 Hz, 1H), 6.77 (d,J
= 8.4 Hz, 2H), 3.51 (s, 2H)。
LCMS;質量計算值:347.3;MS實驗值:347.8。實驗實例 1-5. 製備化合物 5 ( N' -(4- 羥基苯甲醯基 ) 吲哚啉 -5- 磺醯肼 )
步驟1)合成A8
將A2
(4-羥基苯甲醯肼,293毫克,1.93毫莫耳,1.0當量)及1-乙醯基吲哚啉-5-磺醯氯(500毫克,1.93毫莫耳,1.0當量)於吡啶(10毫升)中的混合物在30℃下攪拌5小時。在完成之後,將反應混合物用H2
O(20毫升)稀釋且用EA(20毫升×3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥且濃縮,以得到呈黃色固體狀的A8
(1-乙醯基-N'
-(4-羥基苯甲醯基)吲哚啉-5-磺醯肼,500毫克,粗物質)。
步驟2)合成化合物5
將A8
(1-乙醯基-N'
-(4-羥基苯甲醯基)吲哚啉-5-磺醯肼,200毫克,0.53毫莫耳,1.0當量)及2N HCl(6毫升)於THF(10毫升)中的混合物在50℃下攪拌5小時。在完成之後,將反應混合物用H2
O(20毫升)稀釋且用EA(20毫升×3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥且濃縮。藉由製備型HPLC純化粗產物且凍乾,以得到呈白色固體狀的化合物5(N'
-(4-羥基苯甲醯基)吲哚啉-5-磺醯肼,50毫克,28.2%)。1
HNMR (DMSO-d 6
, 400 MHz): δ 10.30 (br s, 1H), 10.05 (br s, 1H), 9.14 (br s, 1H), 7.58 (d,J
= 8.4 Hz, 2H), 7.33-7.36 (m, 2H), 6.77 (d,J
= 8.4 Hz, 2H), 6.37-6.40(m, 2H), 3.51 (t,J
= 8.4 Hz, 2H), 2.90 (t,J
= 8.4 Hz, 2H)。
LCMS;質量計算值:333.3;MS實驗值:333.8。實驗實例 1-6. 製備化合物 6 ( N' -([1,1'- 聯苯 ]-4- 羰基 )-4- 胺基苯磺醯肼 )
步驟1)合成A10
在室溫下,向溴苯(400毫克,2.5毫莫耳)於二噁烷中的溶液中添加4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)苯甲酸甲酯(A9
,801毫克,3.0毫莫耳)、K3
PO4
(541毫克,7.5毫莫耳)以及Pd(dppf) Cl2
-CH2
Cl2
(208毫克,0.25毫莫耳)。將混合物在100℃下攪拌12小時。在反應完成之後,冷卻反應混合物。將反應混合物經由矽藻土過濾且隨後用乙酸乙酯萃取。將有機層經無水MgSO4
乾燥且在減壓下濃縮。藉由急驟管柱層析(Hex/EA = 3/1)純化殘餘物,以得到呈白色固體狀的A10
([1,1'-聯苯]-4-甲酸甲酯,160毫克,產率:45%)。1H NMR (DMSO-d6
, 600 MHz) δ (ppm): 8.05-8.03 (m, 2H), 7.84-7.83 (m, 2H), 7.76-7.74 (m, 2H), 7.52-7.50 (m, 2H), 7.50-7.42 (m, 1H), 3.87 (s, 3H); C14
H12
O2
[M+H]+
的LCMS計算值m/z為213.25,實驗值為213。
步驟2)合成A11
將A10
([1,1'-聯苯]-4-甲酸甲酯,160毫克,0.70毫莫耳)於單水合肼(8毫升)中的溶液在100℃下攪拌16小時。在反應完成之後,將反應混合物冷卻且隨後在減壓下濃縮,隨後藉由急驟管柱層析(DCM/MeOH = 15/1)純化,以得到呈白色固體狀的粗產物A11
([1,1'-聯苯]-4-碳醯肼,152毫克,理論產率:100%)。C13
H12
N2
O [M+H]+
的LCMS計算值m/z為213.25,實驗值為213。
步驟3)合成A12
向A11
([1,1'-聯苯]-4-碳醯肼,152毫克,0.70毫莫耳)於吡啶(5毫升)中的溶液中添加4-硝基磺醯氯(143毫克,0.60毫莫耳)。使混合物回流12小時。在反應完成之後,將所得混合物冷卻且蒸發以移除吡啶,隨後藉由急驟管柱層析(DCM/MeOH = 15/1)純化,以得到呈黃色固體狀的粗產物A12
(N'
-([1,1'-聯苯]-4-羰基)-4-硝基苯磺醯肼,60毫克,產率:21%)。C19
H15
N3
O5
S [M+H]+
的LCMS計算值m/z為398.41,實驗值為398。
步驟4)合成化合物6
向A12
(N'
-([1,1'-聯苯]-4-羰基)-4-硝基苯磺醯肼,60毫克,0.15毫莫耳)於THF:MeOH = 3:1(12毫升)中的溶液中添加Zn(99毫克,1.5毫莫耳)及NH4
Cl(81毫克,1.5毫莫耳)。將混合物在室溫下攪拌12小時。在反應完成之後,隨後添加乙酸乙酯。經由矽藻土過濾混合物。在減壓下濃縮濾液。藉由急驟管柱層析(DCM/MeOH = 15/1)純化殘餘物,以得到呈白色固體狀的化合物 6
(N'-([1,1'-聯苯]-4-羰基)-4-胺基苯磺醯肼,10毫克,產率:20%)。1H NMR (DMSO-d6, 600 MHz) δ (ppm): δ 10.64 (br s, 1H), 9.32 (br s, 1H), 7.79-7.77 (m, 2H), 7.74-7.70 (m, 4H), 7.49 (t, 2H), 7.45-7.39 (m, 3H), 6.51 (d, J = 6.0 Hz, 2H), 5.96 (s, 1H), 6.52(d, J = 5.0 Hz, 2H); C19
H17
N3
O3
S [M+H]+
的LCMS計算值m/z為368.42,實驗值為368。實驗實例 1-7. 製備化合物 7 ( N' -([1,1'- 聯苯 ]-3- 羰基 )-4- 胺基苯磺醯肼 )
步驟1)合成A14
在室溫下,向溴苯(400毫克,2.5毫莫耳)於二噁烷中的溶液中添加3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)苯甲酸甲酯(A13
,801毫克,3.0毫莫耳)、K3
PO4
(541毫克,7.5毫莫耳)以及Pd(dppf) Cl2
-CH2
Cl2
(208毫克,0.25毫莫耳)。將混合物在100℃下攪拌12小時。在反應完成之後,冷卻反應混合物。將混合物經由矽藻土過濾且隨後用乙酸乙酯萃取。將有機層經無水MgSO4
乾燥且在減壓下濃縮。藉由急驟管柱層析(Hex/EA = 3/1)純化殘餘物,以得到呈白色固體狀的A14
([1,1'-聯苯]-3-甲酸甲酯,160毫克,產率:49%)。
1H NMR (DMSO-d6, 600 MHz) δ (ppm) : 8.18 (t, J = 1.8 Hz, 1H), 7.97-7.95 (m, 2H), 7.71-7.70 (m, 2H), 7.63 (t, J = 7.7 Hz, 1H), 7.52-7.49 (m, 2H), 7.43-7.41 (m, 1H), 3.89 (s, 3H); C14
H12
O2
[M+H]+
的LCMS計算值m/z為213.25,實驗值為213。
步驟2)合成A15
將A14
([1,1'-聯苯]-3-甲酸甲酯,160毫克,7.5毫莫耳)於單水合肼(8毫升)中的溶液在100℃下攪拌16小時。在反應完成之後,將反應混合物冷卻且隨後在減壓下濃縮,隨後藉由急驟管柱層析(DCM/MeOH = 15/1)純化,以得到呈黃色固體狀的粗產物A15
([1,1'-聯苯]-3-碳醯肼,200毫克,產率:100%)。C13
H12
N2
O [M+H]+
的LCMS計算值m/z為213.25,實驗值為213。
步驟3)合成A16
向A15
([1,1'-聯苯]-3-碳醯肼,200毫克,0.90毫莫耳)於吡啶(7毫升)中的溶液中添加4-硝基磺醯氯(2.5毫升)。使混合物回流12小時。在反應完成之後,將所得混合物冷卻且蒸發以移除吡啶,隨後藉由急驟管柱層析(DCM/MeOH = 15/1)純化,以得到呈奶白固體狀的粗產物A16
(N'
-([1,1'-聯苯]-3-羰基)-4-硝基苯磺醯肼,102毫克,產率:53%)。C19
H15
N3
O5
S [M+H]+
的LCMS計算值m/z為398.41,實驗值為398。
步驟4)合成化合物 7
向A16
(N'
-([1,1'-聯苯]-3-羰基)-4-硝基苯磺醯肼,102毫克,0.25毫莫耳)於THF:MeOH = 3:1(10毫升)中的溶液中添加Zn(168毫克,2.5毫莫耳)及NH4
Cl(137毫克,2.5毫莫耳)。將混合物在室溫下攪拌12小時。在反應完成之後,隨後添加乙酸乙酯。經由矽藻土過濾混合物。在減壓下濃縮濾液。藉由急驟管柱層析(DCM/MeOH = 15/1)純化殘餘物,以得到呈白色固體狀的化合物 7
(N'
-([1,1'-聯苯]-3-羰基)-4-胺基苯磺醯肼,14毫克,產率:14%,純度:96.8%)。
1H NMR (DMSO-d6, 600 MHz) δ (ppm) : δ 10.71 (br s, 1H), 9.37 (br s, 1H), 7.97 (s, 1H), 7.83 (d, J = 6.0 Hz, 1H), 7.72 (d, J = 6.0 Hz, 2H), 7.65 (d, J = 6.0 Hz, 1H), 7.54-7.49 (m, 3H), 7.45 (d, J = 6.0 Hz, 2H), 7.42 (t, 1H), 6.52(d, J = 6.0 Hz, 2H), 5.97 (s, 2H); C19
H17
N3
O3
S [M+H]+
的ESI-MS計算值m/z為368.42,實驗值為368。實驗實例 1-8. 製備化合物 8 ( 3- 胺 基 -N'
-(4- 羥基苯甲醯基 ) 苯磺醯肼)
步驟1)合成A17
向A2
(200毫克,0.90毫莫耳)於吡啶(8毫升)中的溶液中添加3-硝基磺醯氯(168毫克,1.08毫莫耳)。使混合物回流12小時。在反應完成之後,將所得混合物冷卻且蒸發以移除吡啶,隨後藉由急驟管柱層析(DCM/MeOH = 15/1)純化,以得到呈奶白固體狀的粗產物A17
(N'
-(4-羥基苯甲醯基)-3-硝基苯磺醯肼,129毫克,產率:43%)。C13
H11
N3
O6
S [M+H]+
的LCMS計算值m/z為338.31,實驗值為338。
步驟2)合成化合物8
向A17
(N'
-(4-羥基苯甲醯基)-3-硝基苯磺醯肼,129毫克,0.38毫莫耳)於THF:MeOH = 3:1(10毫升)中的溶液中添加Zn(250毫克,3.8毫莫耳)及NH4
Cl(204毫克,3.8毫莫耳)。將混合物在室溫下攪拌12小時。在反應完成之後,隨後添加乙酸乙酯。經由矽藻土過濾混合物。在減壓下濃縮濾液。藉由急驟管柱層析(DCM/MeOH = 15/1)純化殘餘物,以得到呈白色固體狀的UTL1013
(3-胺基-N'
-(4-羥基苯甲醯基)苯磺醯肼,25毫克,產率:21%,純度:98.0%)。1H NMR (DMSO-d6, 600 MHz) δ (ppm) : δ 10.36 (br s, 1H), 10.06 (br s, 1H), 9.53 (br s, 1H), 7.59 (d, J = 12 Hz, 2H), 7.11-7.08 (t, J = 9.0 Hz, 1H), 7.02 (s, 1H) 6.90 (d, J = 6.0 Hz, 1H), 6.77 (d, J = 6.0 Hz, 1H), 6.71 (d, J = 12 Hz, 1H), 5.49 (s, 2H); C13
H13
N3
O4
S [M+H]+
的LCMS計算值m/z為308.32,實驗值為308。實驗實例 1-9. 製備化合物 9 ( 4-(1- 胺基乙基 )-N'
-(4- 羥 基苯甲醯基 ) 苯磺醯肼 )
步驟1)合成A18
將A2
(4-羥基苯甲醯肼,500毫克,3.29毫莫耳,1.0當量)及4-乙醯苯-1-磺醯氯(717毫克,3.29毫莫耳,1.0當量)於吡啶(5毫升)中的混合物在25℃下攪拌3小時。將混合物冷卻且小心地倒入水中。用EA(50毫升×2)萃取混合物。將合併的有機層用鹽水洗滌,經無水Na2
SO4
乾燥且濃縮,以得到呈褐色固體狀的A18
(4-乙醯基-N'-(4-羥基苯甲醯基)苯磺醯肼,0.5公克,粗物質)。C15
H14
N2
O5
S [M+H]+
的LCMS計算值m/z為335.3,實驗值為335。
步驟2)合成化合物9
將A18
(4-乙醯基-N'-(4-羥基苯甲醯)苯磺醯肼,200毫克,0.60毫莫耳,1.0當量)、NH4
OAc(461毫克,5.98毫莫耳,10當量)以及氰基硼氫化鈉(188毫克,2.99毫莫耳,5當量)於MeOH(5毫升)中的混合物在60℃下攪拌16小時。濃縮混合物且藉由製備型HPLC純化並凍乾,以得到呈白色固體狀的化合物 9
(4-(1-胺基乙基)-N'
-(4-羥基苯甲醯基)苯磺醯肼,55毫克,24%)。1
HNMR (DMSO-d 6
, 400 MHz): δ 10.37 (br s, 2H), 8.28 (s, 1H), 7.80 (d,J
= 8.0 Hz, 2H), 7.57 (dd,J
= 11.2, 8.8 Hz, 2H), 6.77 (d,J
= 8.4 Hz, 2H), 4.22 (q,J
= 6.8 Hz, 1H), 1.33 (d,J
= 6.4 Hz, 3H)。
LCMS;質量計算值: 335.3(C15
H17
N3
O4
S);MS實驗值:336。實驗實例 1-10. 製備化合物 10 ( 3,5- 二胺基 -N'
-(4- 羥基苯甲醯基 ) 苯磺醯肼 )
步驟1)合成A20
在0℃下向3,5-二硝基苯胺(A19
,500毫克,2.73毫莫耳,1.0當量)於濃HCl(10毫升)中的混合物中添加含NaNO2
(226毫克,3.28毫莫耳,1.2當量)的H2
O(2毫升)。將混合物在0℃下攪拌0.5小時。在0℃下向CuCl(27毫克,0.27毫莫耳,0.1當量)於H2
O(10毫升)中的混合物中添加SOCl2
(1.30公克,10.9毫莫耳,4.0當量)。隨後在0℃下逐滴添加重氮鹽溶液。將混合物在0℃下攪拌3小時且隨後倒入水中。藉由過濾收集所形成的沈澱物且在真空下乾燥,以得到呈黃色固體狀的A20
(3,5-二硝基苯磺醯氯,0.5公克,粗物質)。
步驟2)合成A21
將A20
(3,5-二硝基苯磺醯氯,175毫克,0.66毫莫耳,1.0當量)及A2
(4-羥基苯甲醯肼,100毫克,0.66毫莫耳,1.0當量)於吡啶(5毫升)中的混合物在60℃下攪拌16小時。將混合物冷卻且小心地倒入水中。用EA(50毫升×2)萃取混合物。將合併的有機層用鹽水洗滌,經無水Na2
SO4
乾燥且濃縮,以得到呈粉紅色固體狀的A21
(N'
-(4-羥基苯甲醯基)-3,5-二硝基苯磺醯肼,0.1公克,粗物質)。
步驟3)合成化合物10(3,5-二胺基-N'-(4-羥基苯甲醯基)苯磺醯肼)
將A21
(N'
-(4-羥基苯甲醯基)-3,5-二硝基苯磺醯肼,0.1公克,0.26毫莫耳,1.0當量)及10% Pd/C(0.1公克)於EtOH(5毫升)中的混合物在室溫下在H2
氣球下攪拌3小時。過濾反應混合物,且用EA(50毫升×2)洗滌濾餅。濃縮合併的濾液,以得到粗產物,將所述粗產物在MeOH(5毫升)中攪拌10分鐘。過濾混合物且將濾餅在真空中乾燥,以得到呈黃色固體狀的化合物 10
(3,5-二胺基-N'
-(4-羥基苯甲醯基)苯磺醯肼,27毫克,32%)。1
HNMR (DMSO-d 6
, 400 MHz): δ 10.20 (br s, 1H), 10.04 (br s, 1H), 9.19 (br s, 1H), 7.63 (d,J
= 8.8 Hz, 2H), 7.78 (d,J
= 8.4 Hz, 2H), 6.26 (d,J
= 1.6 Hz, 2H), 5.94 (s, 1H), 5.10 (s, 4H)。
LCMS;質量計算值: 322.3(C13
H14
N4
O4
S);MS實驗值:323 [MS+1]。實驗實例 1-11. 製備化合物 11 ( N' -(4- 羥基苯甲醯基 )-4-((2- 羥 基乙基 ) 胺基 ) 苯磺醯肼 )
將化合物 2
(4-胺基-N'
-(4-羥基苯甲醯基)苯磺醯肼,500毫克,1.63毫莫耳,1.0當量)及環氧乙烷(72毫克,1.63毫莫耳,1.0當量)於AcOH/H2
O=1:1(4毫升)中的混合物在25℃下攪拌4小時。隨後向混合物中添加NaHCO3
直至pH=8,且用EA(50毫升×3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥且濃縮,以得到粗產物,藉由製備型TLC純化所述粗產物,以得到呈白色固體狀的化合物 11
(N'
-(4-羥基苯甲醯基)-4-((2-羥基乙基)胺基)苯磺醯肼,50毫克,產率8.8%)。1
HNMR (DMSO-d 6
, 400 MHz): δ 7.56 (d,J
= 8.4 Hz, 2H), 7.46 (d,J
= 8.8 Hz, 2H), 6.73 (d,J
= 8.4 Hz, 2H), 6.56 (d,J
= 8.8 Hz, 2H), 6.45 (t,J
= 5.2 Hz, 1H), 3.53 (t,J
= 6.0 Hz, 2H), 3.12 (q,J
= 6.0 Hz, 2H)。
LCMS;質量計算值:351.3;MS實驗值:351.8 [MS+1]。實驗實例 1-12. 製備化合物 12 ( 4- 胺基 -N
-(2-(4- 羥基苯基 )-2- 側氧基乙基 ) 苯磺醯胺 )
步驟1)合成A23
在5℃下向A22
(1-(4-(苯甲氧基)苯基)乙-1-酮,4.0公克,17.7毫莫耳,1.0當量)於EtOH(40毫升)中的混合物中添加Br2
(2.83公克,17.7毫莫耳,1.0當量)。將混合物在30℃下攪拌30分鐘。將混合物倒入PE中且攪拌30分鐘。過濾混合物且乾燥濾餅,以得到呈白色固體狀的A23
(1-(4-(苯甲氧基)苯基)-2-溴乙-1-酮,2.5公克,46.3%)。
步驟2)合成A24
將A23
(1-(4-(苯甲氧基)苯基)-2-溴乙-1-酮,2.0公克,6.55毫莫耳,1.0當量)及HMTA(1.38公克,9.83毫莫耳,1.5當量)於DCM(20毫升)中的混合物在10℃下攪拌2小時。隨後過濾混合物且使濾餅溶解於EtOH(15毫升)及濃HCl(5毫升)中。將混合物在85℃下攪拌2小時。過濾混合物且乾燥濾餅,以得到呈白色固體狀的A24
(2-胺基-1-(4-(苯甲氧基)苯基)乙-1-酮鹽酸,2.0公克,粗物質)。1
HNMR (CD3
OD, 400 MHz): δ 8.03 (d,J
= 8.8 Hz, 2H), 7.47 (d,J
= 7.2 Hz, 2H), 7.34-7.42 (m, 3H), 7.17 (d,J
= 8.8 Hz, 2H), 5.23 (s, 2H), 4.55 (s, 2H)。
步驟3)合成A25
將A24
(2-胺基-1-(4-(苯甲氧基)苯基)乙-1-酮鹽酸,2.00公克,7.20毫莫耳,1.0當量)、4-硝基苯-1-磺醯氯(1.60公克,7.20毫莫耳,1.0當量)及TEA(2.19公克,21.6毫莫耳,3.0當量)於DCM(20毫升)中的混合物在20℃下攪拌1小時。將混合物倒入水中且用DCM萃取。將有機層用水及鹽水洗滌,經Na2
SO4
乾燥且濃縮,以得到粗產物,將所述粗產物在PE中攪拌30分鐘。過濾混合物且乾燥濾餅,以得到呈白色固體狀的A25
(N-(2-(4-(苯甲氧基)苯基)-2-側氧基乙基)-4-硝基苯磺醯胺,1.0公克,對於2個步驟為35.8%)。1
HNMR (CD3
Cl, 400 MHz): δ 8.36 (d,J
= 8.8 Hz, 2H), 8.10 (d,J
= 8.4 Hz, 2H), 7.84 (d,J
= 8.8 Hz, 2H), 7.37-7.43 (m, 5H), 7.03 (d,J
= 8.4 Hz, 2H), 5.86 (t,J
= 4.0 Hz, 1H), 5.16 (s, 2H), 4.49 (d,J
= 4.0 Hz, 2H)。
步驟4)合成化合物12
將A25
(N-(2-(4-(苯甲氧基)苯基)-2-側氧基乙基)-4-硝基苯磺醯胺,200毫克,0.47毫莫耳,1.0當量)及Pd/C(150毫克,50%於水中)於EtOH(10毫升)中的混合物在25℃下在H2
氣球下攪拌4小時。隨後過濾混合物且將混合物濃縮並藉由製備型HPLC純化且凍乾,以得到呈白色固體狀的化合物 12
(4-胺基-N
-(2-(4-羥基苯基)-2-側氧基乙基)苯磺醯胺,69毫克,產率48.0%)。1
HNMR (DMSO-d 6
, 400 MHz): δ 10.43 (s, 1H), 7.79 (d,J
= 8.4 Hz, 2H), 7.46 (d,J
= 8.4 Hz, 2H), 7.32 (t,J
= 5.6 Hz, 1H), 6.83 (d,J
= 8.4 Hz, 1H), 6.58 (d,J
= 8.8 Hz, 2H), 5.91 (s, 2H), 4.19 (d,J
= 5.6 Hz, 2H)。
LCMS;質量計算值:306.3;MS實驗值:307 [MS+1]。實驗實例 1-13. 製備化合物 13 ( N' -(4- 羥基苯甲醯基 )-4- 甲氧基苯磺醯肼)
向A2
(4-羥基苯甲醯肼,100毫克,0.66毫莫耳)於DMF(6毫升)中的溶液中添加三乙胺(0.11毫升,0.76毫莫耳)及4-甲氧基苯磺醯氯(124毫克,0.60毫莫耳)。使混合物在室溫下12小時。在反應完成之後,將反應混合物蒸發且用乙酸乙酯萃取。將有機層用鹽水洗滌,經無水MgSO4乾燥且在減壓下濃縮。藉由急驟管柱層析(DCM/MeOH = 5/1)純化殘餘物,以得到呈白色固體狀的化合物 13
(N'-(4-羥基苯甲醯基)-4-甲氧基苯磺醯肼,25毫克,產率:12%,純度:96.9%)。1H NMR (DMSO-d6, 600 MHz) δ (ppm): δ 10.37 (br s, 1H), 10.07 (br s, 1H), 9.64 (br s, 1H), 7.73 (d, J = 12 Hz, 2H), 7.57 (d, J = 6.0 Hz, 2H), 7.03 (d, J = 6.0 Hz, 2H), 6.76 (d, J = 6.0 Hz, 2H), 3.80 (s, 3H); C14
H14
N2
O5
S [M+H]+
的LCMS計算值m/z為323.3,實驗值為323。實驗實例 1-14. 製備化合物 14 ( 4-((2-(4- 羥基苯甲醯基 ) 肼基 ) 磺醯基 ) 苯甲脒 )
步驟1)合成A26
向A2
(4-羥基苯甲醯肼,1.00公克,6.57毫莫耳,1.0當量)於吡啶(10毫升)中的混合物中逐滴添加含4-氰基苯-1-磺醯氯(1.33公克,6.57毫莫耳,1.0當量)的吡啶(3毫升)。隨後將混合物在25℃下攪拌3小時。將上述溶液倒入水(50毫升)中。用EA(50毫升×3)萃取混合物。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥且濃縮,以得到粗產物,藉由急驟管柱(PE/EA=1/1)純化所述粗產物,以得到呈白色固體狀的A26
(4-氰基-N'
-(4-羥基苯甲醯基)苯磺醯肼;1.40公克,67.1%)。1
HNMR (DMSO-d 6
, 400 MHz): δ 10.49 (s, 1H), 10.27 (s, 1H), 10.14 (s, 1H), 8.02-8.04 (m, 2H), 7.97-7.99 (m, 2H), 7.57 (d,J
= 8.4 Hz, 2H), 7.78 (d,J
= 8.8 Hz, 2H)。
步驟2)合成化合物14
將A26
(4-氰基-N'
-(4-羥基苯甲醯基)苯磺醯肼,200毫克,0.63毫莫耳,1.0當量)於HCl/EtOH(5毫升,6莫耳/公升)中的混合物在25℃下攪拌3小時。將上述溶液濃縮且添加至MeOH中。再次濃縮混合物。將殘餘物添加至MeOH(10毫升)中且隨後添加至NH4
OAc(485毫克,6.30毫莫耳,10當量)中。將混合物在25℃下攪拌16小時。將混合物濃縮且藉由製備型HPLC純化並凍乾,以得到呈白色固體狀的化合物 14
(4-(2-(4-羥基苯甲醯基)肼基)磺醯基)苯甲脒,26毫克,10.8%)。1
HNMR (DMSO-d 6
, 400 MHz): δ 8.43 (s, 1H), 8.00 (d,J
= 8.0 Hz, 2H), 7.92 (d,J
= 8.4 Hz, 2H), 7.59 (d,J
= 8.8 Hz, 2H), 6.77 (d,J
= 8.8 Hz, 2H)。
LCMS;質量計算值:334;MS實驗值:334.8 [MS+1]。實驗實例 1-15. 製備化合物 15 ( 4-((2-(4- 羥基苯甲醯基 ) 肼基 ) 磺醯基 ) 苯甲醯胺 )
向A26
(4-氰基-N'
-(4-羥基苯甲醯基)苯磺醯肼,210毫克,0.66毫莫耳)於DMSO中的冷卻(0℃)溶液中添加過氧化氫,35% w/w水溶液(0.42毫升,4.8毫莫耳)及碳酸鉀(30毫克,0.20毫莫耳)。使反應物升溫至室溫且攪拌12小時。在反應完成之後,蒸發反應混合物且用乙酸乙酯萃取。將有機層用鹽水洗滌,經無水MgSO4
乾燥且在減壓下濃縮。藉由急驟管柱層析(DCM/MeOH = 5/1)純化殘餘物,以得到呈白色固體狀的化合物 15
(4-((2-(4-羥基苯甲醯基)肼基)磺醯基)苯甲醯胺,20毫克,產率:10%,純度:96.5%)。1H NMR (DMSO-d6, 600 MHz) δ (ppm) : δ 10.44 (br s, 1H), 10.10 (br s, 1H), 10.03 (br s, 1H), 8.15 (br s, 1H), 7.96 (d, J = 6.0 Hz, 2H), 7.87 (d, J = 10 Hz, 2H), 7.59 (br s, 1H), 7.57 (d, J = 6.0 Hz, 2H), 6.76 (d, J = 6.0 Hz, 2H); C14
H13
N3
O5
S [M+H]+
的LCMS計算值m/z為336.33,實驗值為336。實驗實例 1-16. 製備化合物 16 ( N -(((4- 胺基苯基 ) 磺醯基 ) 甲基 )-4- 羥基苯甲醯胺 )
步驟1)合成A28
向A27
(4-羥基苯甲醯胺,4.0公克,29.2毫莫耳,1.0當量)於DMF(40毫升)中的混合物中添加K2
CO3
(6.05公克,43.8毫莫耳,1.5當量)及BnBr(4.99公克,29.2毫莫耳,1.0當量)。將混合物在60℃下攪拌16小時。將混合物倒入水中且用EA萃取。將有機層用水及鹽水洗滌,隨後經Na2
SO4
乾燥且濃縮,以得到呈白色固體狀的A28
(4-(苯甲氧基)苯甲醯胺,6.0公克,90.5%)。
步驟2)合成A29
將A28
(4-(苯甲氧基)苯甲醯胺,4.0公克,17.6毫莫耳,1.0當量)、K2
CO3
(0.24公克,1.76毫莫耳,0.1當量)及HCOH(1.43公克,17.6毫莫耳,37%於水中,1.0當量)於THF/H2
O(40毫升,v/v=1/1)中的混合物在65℃下攪拌16小時。隨後濃縮混合物且過濾。乾燥濾餅,以得到呈白色固體狀的A29
(4-(苯甲氧基)-N
-(羥甲基)苯甲醯胺,4.0公克,粗物質)。
步驟3)合成A30
將A29
(4-(苯甲氧基)-N
-(羥甲基)苯甲醯胺,4.00公克,15.6毫莫耳,1.0當量)及4-硝基苯硫醇(2.41公克,15.6毫莫耳,1.0當量)於TFA(20毫升)中的混合物在20℃下攪拌1小時。將混合物濃縮且添加至水中並用NaHCO3
水溶液調節pH=8。用EA萃取混合物。將有機層用鹽水洗滌,經Na2SO4乾燥且濃縮,以得到呈白色固體狀的A30
(4-(苯甲氧基)-N
-(((4-硝基苯基)硫基)甲基)苯甲醯胺,2.0公克,對於2個步驟為32.6%)。
步驟4)合成A31
將A30
(4-(苯甲氧基))-N
-(((4-硝基苯基)硫基)甲基)苯甲醯胺500毫克,1.27毫莫耳,1.0當量)及m-CPBA(656公克,3.80毫莫耳,3.0當量)於DCM(20毫升)中的混合物在20℃下攪拌16小時。將混合物倒入Na2
O3
S2
水溶液中且萃取。將有機層用NaHCO3
水溶液及鹽水洗滌,經Na2
SO4
乾燥且濃縮,以得到呈白色固體狀的A31
(4-(苯甲氧基)-N
-(((4-硝基苯基)磺醯基)甲基)苯甲醯胺,300毫克,粗物質)。1
HNMR (DMSO-d 6
, 400 MHz): δ 9.39 (t,J
= 6.4 Hz, 1H), 8.42 (d,J
= 8.8 Hz, 2H), 8.14 (d,J
= 8.8 Hz, 2H), 7.73 (d,J
= 8.8 Hz, 2H), 7.34-7.46 (m, 5H), 7.08 (d,J
= 8.8 Hz, 2H), 5.17 (s, 2H), 5.00 (d,J
= 6.4 Hz, 2H)。
步驟5)合成化合物16
將A31
(4-(苯甲氧基)-N
-(((4-硝基苯基)磺醯基)甲基)苯甲醯胺,300毫克,0.47毫莫耳,1.0當量)及Pd/C(150毫克,50%於水中)於EtOH(10毫升)中的混合物在25℃下在H2
氣球下攪拌2小時。隨後過濾混合物且將混合物濃縮並藉由製備型HPLC純化且凍乾,以得到呈白色固體狀的化合物 16
(N-(((4-胺基苯基)磺醯基)甲基)-4-羥基苯甲醯胺,35毫克,對於2個步驟產率為9.0%)。1
HNMR (DMSO-d 6
, 400 MHz): δ 10.15 (br s, 1H), 9.06 (t,J
= 6.4 Hz, 1H), 7.65 (d,J
= 8.8 Hz, 2H), 7.40 (d,J
= 8.8 Hz, 2H), 6.79 (d,J
= 8.8 Hz, 2H), 6.58 (d,J
= 8.8 Hz, 2H), 6.12 (s, 2H), 4.65 (d,J
= 6.4 Hz, 2H)。
LCMS;質量計算值:306;MS實驗值:307 [MS+1]。實驗實例 1-17. 製備化合物 17 ( 6- 胺基 -N'
-(4- 羥基苯甲醯基 )-[1,1'- 聯苯 ]-3- 磺醯肼 )
步驟1)合成A33
將A32
(3-溴基-4-硝基苯胺,1公克,4.61毫莫耳,1.0當量)、苯基硼酸(0.56公克,4.61毫莫耳,1.0當量)、Pd(dppf)Cl2
(337毫克,0.09毫莫耳,0.1當量)以及AcOK(1.14公克,13.8毫莫耳,3.0當量)於甲苯(10毫升)中的混合物在90℃下在N2
下攪拌16小時。將混合物倒入水(30毫升)中且用EA(30毫升×2)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥且濃縮。藉由急驟管柱(PE/EA = 30/1~10/1)純化粗產物,以得到呈黃色固體狀的A33
(6-硝基-[1,1'-聯苯]-3-胺,1公克,粗物質)。
步驟2)合成A34
在0℃下向A33
(6-硝基-[1,1'-聯苯]-3-胺,500毫克,2.33毫莫耳,1.0當量)於AcOH(10毫升)及濃HCl(5毫升)中的混合物中逐滴添加含NaNO2
(193毫克,2.8毫莫耳,1.2當量)的H2
O(2毫升)。將混合物在0℃下攪拌0.5小時。在0℃下向CuCl(31.3毫克,0.23毫莫耳,0.1當量)於H2
O(10毫升)中的混合物中添加SOCl2
(1.39公克,11.6毫莫耳,5.0當量)。隨後在0℃下逐滴添加重氮鹽溶液。將混合物在0℃下攪拌3小時且隨後倒入水中。藉由過濾收集所形成的沈澱物且在真空下乾燥,以得到呈黃色固體狀的A34
(6-硝基-[1,1'-聯苯]-3-磺醯氯,400毫克,57.6%)。1
HNMR (DMSO-d 6
, 400 MHz): δ 7.98 (d,J
= 8.4 Hz, 1H), 7.78-7.80 (m, 1H), 7.64 (d,J
= 1.2 Hz, 1H), 7.44-7.50 (m, 3H), 7.32-7.34 (m, 2H)。
步驟3)合成A35
將A34
(6-硝基-[1,1'-聯苯]-3-磺醯氯,200毫克,0.67毫莫耳,1.0當量)及4-羥基苯甲醯肼(122毫克,0.81毫莫耳,1.2當量)於吡啶(5毫升)中的混合物在30℃下攪拌0.5小時。小心地將混合物倒入水中。用EA(50毫升×2)萃取混合物。將合併的有機層用鹽水洗滌,經無水Na2
SO4
乾燥且濃縮,以得到呈褐色固體狀的A35
(N'
-(4-羥基苯甲醯基)-6-硝基-[1,1'-聯苯]-3-磺醯肼,200毫克,粗物質)。
步驟4)合成化合物17
將A35
(N'
-(4-羥基苯甲醯基)-6-硝基-[1,1'-聯苯]-3-磺醯肼,200毫克,0.48毫莫耳,1.0當量)及10% Pd/C(200毫克)於EtOH(10毫升)中的混合物在30℃下在H2
氣球下攪拌3小時。過濾反應混合物且用EA(50毫升×2)洗滌濾餅。濃縮合併的濾液,以得到粗產物,藉由製備型HPLC純化且凍乾所述粗產物,以得到呈白色固體狀的化合物 17
(6-胺基-N'
-(4-羥基苯甲醯基)-[1,1'-聯苯]-3-磺醯肼,45毫克,對於2個步驟為17.5%)。1
HNMR (DMSO-d 6
, 400 MHz): δ 10.39 (s, 1H), 10.09 (s, 1H), 9.32 (s, 1H), 7.61 (d,J
= 8.8 Hz, 2H), 7.32-7.59 (m, 5H), 7.23 (d,J
= 6.4 Hz, 2H), 6.73-6.79 (m, 3H), 5.64 (s, 2H)。
LCMS;質量計算值:383;MS實驗值:384 [MS+1]。實驗實例 1-18. 製備化合物 18 ( 4-(2-((4- 胺基苯基 ) 磺醯基 ) 肼 -1- 羰基 ) 苯甲醯胺 )
步驟1)合成A37
向4-(氯羰基)苯甲酸甲酯(A36,1.5公克,7.5毫莫耳)於DCM中的冷卻(0℃)溶液中添加氨溶液(25%至30%)(1.8毫升,15毫莫耳)。使反應物升溫至室溫且攪拌4小時。在反應完成之後,蒸發反應混合物且隨後添加水。藉由過濾收集所形成的沈澱物。將濾餅用水洗滌且乾燥,以得到呈白色固體狀的A37
(4-胺基甲醯基苯甲酸甲酯,1.0公克,74%)。C9
H9
NO3
[M+H]+
的LCMS計算值m/z為152.17,實驗值為152。
步驟2)合成A38
將A37
(4-胺基甲醯基苯甲酸甲酯,1公克,6.6毫莫耳)及單水合肼(10毫升)於MeOH(10毫升)中的溶液在80℃下攪拌16小時。在減壓下濃縮溶劑,以得到粗產物,藉由急驟管柱(DCM/MeOH = 10/1)純化所述粗產物,以得到呈白色固體狀的A38
(4-(肼羰基)苯甲醯胺,600毫克,產率:60%)。1H NMR (DMSO-d6, 600 MHz) δ (ppm) : δ 9.87 (s, 1H), 8.06 (s, 1H), 7.92-7.91 (m, 2H), 7.87-7.86 (m, 2H), 7.48 (s, 1H), 4.55 (brs, 2H)。
步驟3)合成A39
向A38
(4-(肼羰基)苯甲醯胺,600毫克,3.3毫莫耳)於DMF(7毫升)的溶液中添加TEA(0.55毫升,3.9毫莫耳)及4-甲氧基苯磺醯氯(676毫克,3.0毫莫耳)。使混合物在室溫下12小時。在反應完成之後,將反應混合物蒸發且用乙酸乙酯萃取。將有機層用鹽水洗滌,經無水MgSO4
乾燥且在減壓下濃縮。藉由急驟管柱層析(DCM/MeOH = 10/1)純化殘餘物,以得到呈白色固體狀的A39
(4-(2-(4-硝基苯基)磺醯基)肼-1-羰基)苯甲醯胺,366毫克,產率:30%)。C14
H12
N4
O6
S [M+H]+
的LCMS計算值m/z為365.33,實驗值為365。
步驟4)合成化合物18
在60℃下,向A39
(4-(2-((4-硝基苯基)磺醯基)肼-1-羰基)苯甲醯胺,366毫克,1.0毫莫耳)於THF:MeOH = 3:1(10毫升)中的溶液中添加Zn(657毫克,10毫莫耳)及NH4
Cl(537毫克,10毫莫耳),持續5小時。在反應完成之後,將反應混合物冷卻且隨後添加乙酸乙酯。經由矽藻土過濾混合物。在減壓下濃縮濾液。藉由急驟管柱層析(DCM/MeOH = 15/1)純化殘餘物,以得到呈白色固體狀的化合物 18
(4-(2-(4-胺基苯基)磺醯基)肼-1-羰基)苯甲醯胺,10毫克,4.51毫莫耳,產率:3%,純度:97.0%)。1H NMR (DMSO-d6, 600 MHz) δ (ppm) : δ 10.68 (br s, 1H), 9.38 (br s, 1H), 8.06 (s, 1H), 7.90 (d, J = 6.0 Hz, 2H), 7.73 (d, J = 6.0 Hz, 2H), 7.05 (s, 1H), 7.44 (d, J = 6.0 Hz, 2H), 6.51 (d, J = 6.0 Hz, 2H), 5.97 (s, 2H); C14
H14
N4
O4
S [M+H]+
的LCMS計算值m/z為335.35,實驗值為335。實驗實例 1-19. 製備化合物 19 ( N' -(4- 胺基苯甲基 )-4- 羥基苯甲醯肼)
步驟1)合成A40
向A2
(500毫克,3.2毫莫耳)於DMF(10毫升)中的溶液中添加三乙胺(0.46毫升,3.2毫莫耳)及1-(溴甲基)-4-硝基苯(545毫克,2.5毫莫耳)。使混合物在室溫下12小時。在反應完成之後,將反應混合物蒸發且用乙酸乙酯萃取。將有機層用鹽水洗滌,經無水MgSO4
乾燥且在減壓下濃縮。藉由急驟管柱層析(DCM/MeOH = 5/1)純化殘餘物,以得到呈黃色固體狀的A40
(4-羥基-N'
-(4-硝基苯甲基)苯甲醯肼,410毫克,產率:44%)。C14
H13
N3
O4
[M+H]+
的LCMS計算值m/z為288.28,實驗值為288。
步驟2)合成化合物19
向A40
(4-羥基-N'
-(4-硝基苯甲基)苯甲醯肼,410毫克,1.4毫莫耳)於THF:MeOH = 3:1(12毫升)中的溶液中添加Zn(933毫克,14毫莫耳)及NH4
Cl(764毫克,14毫莫耳)。將混合物在室溫下攪拌12小時。在反應完成之後,隨後添加乙酸乙酯。經由矽藻土過濾混合物。在減壓下濃縮濾液。藉由急驟管柱層析(DCM/MeOH = 15/1)純化殘餘物,以得到呈白色固體狀的化合物 19
(N'
-(4-胺基苯甲基)-4-羥基苯甲醯肼,6毫克,產率:16%,純度:95.0%)。1H NMR (DMSO-d6, 600 MHz) δ (ppm): δ 10.03 (br s, 1H), 9.80 (br s, 1H), 7.67 (d, J = 6.0 Hz, 2H), 7.00 (d, J = 6.0 Hz, 2H), 6.77 (d, J = 6.0 Hz, 2H), 6.51 (d, J = 6.0 Hz, 2H), 4.97 (bs, 3H), 3.72 (bs, 2H); C14
H15
N3
O2
[M+H]+
的LCMS計算值m/z為258.29,實驗值為258。實驗實例 1-20. 合成化合物 20 ( 4- 胺基 -N'
-(1H
- 吲哚 -3- 羰基 ) 苯磺醯肼 )
步驟1)合成A42
向A41
(1H
-吲哚-3-碳醯肼,500毫克,2.85毫莫耳,1.0當量)於吡啶(5毫升)中的混合物中逐滴添加含4-硝基苯-1-磺醯氯(632毫克,2.85毫莫耳,1.0當量)的吡啶(5毫升)。隨後將混合物在10℃下攪拌2小時。將上述溶液倒入水(30毫升)中且用EA(30毫升×3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥且濃縮,以得到粗產物,藉由急驟管柱(DCM/MeOH=50/1至30/1)純化所述粗產物,以得到呈黃色固體狀的A42
(N'
-(1H
-吲哚-3-羰基)-4-硝基苯磺醯肼,0.9公克,產率87.5%)。(TLC:DCM/MeOH =20/1,Rf=0.5)
步驟2)合成化合物20
向A42
(N'
-(1H
-吲哚-3-羰基)-4-硝基苯磺醯肼,300毫克,0.83毫莫耳,1.0當量)於MeOH(10毫升)中的混合物中添加Pd/C(100毫克)。隨後將混合物在10℃下在H2
氣球下攪拌2小時。過濾上述溶液且濾液藉由製備型HPLC純化並凍乾,以得到呈黃色固體狀的化合物 20
(4-胺基-N'
-(1H
-吲哚-3-羰基)苯磺醯肼,30毫克,產率10.9%)。1
HNMR (DMSO-d 6
, 400 MHz): δ 11.62 (d,J
= 2.8 Hz, 1H), 9.98 (s, 1H), 9.11 (d,J
= 3.2 Hz, 1H), 8.00 (d,J
= 2.8 Hz, 1H), 7.90 (d,J
= 7.6 Hz, 1H), 7.40-7.46 (m, 3H), 7.05-7.16 (m, 2H), 6.51 (d,J
= 8.8 Hz, 2H), 5.89 (br s, 2H)。
LCMS;質量計算值:330;MS實驗值:331.1 [MS+1]。實驗實例 1-21. 及實例 1-22. 製備化合物 21 ( 4- 胺基 -N'-(4- 羥基苯甲醯基 )-3-( 吡咯啶 -1- 基 ) 苯磺醯肼 ) 及化合物 22 ( N' -(4- 羥基苯甲醯基 )-4- 硝基 -3-( 吡咯啶 -1- 基 ) 苯磺醯肼 )
步驟1)合成化合物22
在10℃下,向A4
(3-氟-N'
-(4-羥基苯甲醯基)-4-硝基苯磺醯肼,400毫克,1.13毫莫耳,1.0當量)及K2
CO3
(389毫克,2.81毫莫耳,2.5當量)於DMF(10毫升)中的混合物中添加吡咯啶(96毫克,1.35毫莫耳,1.2當量)。隨後將混合物在25℃下攪拌16小時。將上述溶液倒入水(30毫升)中且用EA(30毫升×3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥且濃縮,以得到粗產物,藉由急驟管柱(DCM/MeOH=50/1至30/1)純化所述粗產物,以得到呈黃色固體狀的化合物 22
(N'
-(4-羥基苯甲醯基)-4-硝基-3-(吡咯啶-1-基)苯磺醯肼,176毫克,產率38.5%)。1
HNMR (DMSO-d 6
, 400 MHz): δ 10.48 (s, 1H), 10.14 (s, 2H), 7.86 (d,J
= 8.8 Hz, 1H), 7.61 (d,J
= 8.8 Hz, 2H), 7.37 (d,J
= 1.6 Hz, 1H), 7.11-7.13 (m, 1H), 6.78 (d,J
= 8.8 Hz, 2H), 3.64 (t,J
= 6.0 Hz, 4H), 1.86 (t,J
= 6.0 Hz, 4H)。
步驟2)合成化合物21
向化合物 22
(N'
-(4-羥基苯甲醯基)-4-硝基-3-(吡咯啶-1-基)苯磺醯肼,100毫克,0.54毫莫耳,1.0當量)於MeOH(5毫升)中的混合物中添加Pd/C(30毫克)。隨後將混合物在10℃下在H2
氣球下攪拌16小時。過濾上述溶液且濃縮濾液,以得到粗產物,將所述粗產物在MeOH(5毫升)及DMSO(0.5毫升)中攪拌5分鐘。過濾混合物且將濾餅用MeOH洗滌並乾燥,以得到呈灰白色固體狀的化合物 21
(4-胺基-N'-(4-羥基苯甲醯基)-3-(吡咯啶-1-基)苯磺醯肼,30毫克,產率32.4%)。1
HNMR (DMSO-d 6
, 400 MHz): δ 10.34 (s, 1H), 10.06 (s, 1H), 9.13 (s, 1H), 7.54 (d,J
= 8.4 Hz, 2H), 7.17 (t,J
= 1.6 Hz, 2H), 6.76 (d,J
= 8.8 Hz, 2H), 6.61 (d,J
= 8.4 Hz, 1H), 5.47 (s, 2H), 2.80 (s, 4H), 1.77 (s, 4H)。
LCMS;質量計算值:330;MS實驗值:331.1 [MS+1]。實驗實例 1-23. 合成化合物 23 ( 4- 胺基 -N'
-(4- 羥基苯甲醯基 )-3-( 哌啶 -1- 基 ) 苯磺醯肼 )
步驟1)合成A43
在10℃下,向A4
(3-氟-N'
-(4-羥基苯甲醯基)-4-硝基苯磺醯肼,400毫克,1.13毫莫耳,1.0當量)及K2
CO3
(389毫克,2.81毫莫耳,2.5當量)於DMF(10毫升)中的混合物中添加哌啶(115毫克,1.35毫莫耳,1.2當量)。隨後將混合物在25℃下攪拌16小時。將上述溶液倒入水(30毫升)中且用EA(30毫升×3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥且濃縮,以得到粗產物,藉由急驟管柱(DCM/MeOH=50/1至30/1)純化所述粗產物,以得到呈黃色固體狀的A43
(N'-(4-羥基苯甲醯基)-4-硝基-3-(哌啶-1-基)苯磺醯肼,240毫克,產率50.7%)。1
HNMR (DMSO-d 6
, 400 MHz): δ 10.53 (s, 1H), 10.21 (s, 1H), 10.15 (s, 1H), 7.91 (d,J
= 8.4 Hz, 1H), 7.62 (d,J
= 8.8 Hz, 2H), 7.56 (d,J
= 1.6 Hz, 1H), 7.40-7.43 (m, 1H), 6.79 (d,J
= 8.8 Hz, 2H), 2.88 (t,J
= 5.2 Hz, 4H), 1.50-1.51 (m, 6H)。
步驟2)合成化合物23
向A43
(N'
-(4-羥基苯甲醯基)-4-硝基-3-(哌啶-1-基)苯磺醯肼,100毫克,0.24毫莫耳,1.0當量)於MeOH(5毫升)中的混合物中添加Pd/C(30毫克)。隨後將混合物在10℃下在H2
氣球下攪拌16小時。過濾上述溶液且濾液藉由製備型HPLC純化並凍乾,以得到呈黃色固體狀的化合物 23
(4-胺基-N'
-(4-羥基苯甲醯基)-3-(哌啶-1-基)苯磺醯肼,25毫克,產率26.9%)。1
HNMR (DMSO-d 6
, 400 MHz): δ10.37 (d,J
= 4.0 Hz, 1H), 10.07 (s, 1H), 9.17 (d,J
= 4.0 Hz, 1H), 7.58 (d,J
= 8.8 Hz, 2H), 7.2-7.25 (m, 2H), 6.77 (d,J
= 7.2 Hz, 2H), 6.64 (d,J
= 8.4 Hz, 1H), 5.51 (s, 2H), 2.55 (s, 4H), 1.55-1.60 (m, 4H), 1.45 (s, 2H)。
LCMS;質量計算值:390;MS實驗值:390.8 [MS+1]。實驗實例 1-24. 合成化合物 24 ( N' -(4- 羥基苯甲醯基 )-1H
- 吡唑 -4- 磺醯肼 )
步驟1)合成A44
將1H
-吡唑(1公克,14.7毫莫耳,1.0當量)於氯磺酸(5毫升)中的溶液在100℃下攪拌隔夜。將上述溶液倒入水(30毫升)中且用EA(30毫升×3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥且濃縮,以得到呈灰白色固體狀的A44
(1H
-吡唑-4-磺醯氯,340毫克,產率14%)。1
HNMR (CDCl3, 400 MHz): 8.22 (s, 2H), 7.92 (s, 1H)。
步驟2)合成化合物24
將A44
(1H
-吡唑-4-磺醯氯,100毫克,0.6毫莫耳,1.0當量)及A2
(4-羥基苯甲醯肼,109毫克,0.72毫莫耳,1.2當量)於吡啶(20毫升)中的混合物在80℃下攪拌隔夜。將上述溶液倒入水(30毫升)中且用EA(30毫升×3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥且濃縮,以得到粗產物。藉由製備型TLC純化殘餘物,以得到灰白色固體狀的化合物 24
(N'
-(4-羥基苯甲醯基)-1H
-吡唑-4-磺醯肼,60毫克)。1
HNMR (DMSO-d 6
, 400 MHz): 13.4 (s, 1H), 10.39 (s, 1H), 10.1 (s, 1H), 9.5 (s, 1H), 8.47-7.63 (m, 2H), 7.62 (d, 2H), 6.78 (d, 2H)。實驗實例 1-25 及實驗實例 1-26. 製備化合物 25 ( N' -(4- 羥基苯甲醯基 ) 吲哚啉 -4- 磺醯肼 ) 及化合物 26 ( N' -(4- 羥基苯甲醯基 )-1H
- 吲哚 -4- 磺醯肼 )
步驟1)合成A46
在0℃下向A45
(4-溴基-1H
-吲哚,1.0公克,5.10毫莫耳,1.0當量)於THF(10毫升)及Et2
O(10毫升)中的溶液中添加NaH(204毫克,5.10毫莫耳,60%於礦物油中,1.0當量)。在攪拌15分鐘之後,將混合物冷卻至-78℃,且緩慢添加t-BuLi(7.9毫升,10.2毫莫耳,1.3 M於THF中,2.0當量)。在30分鐘之後,在-78℃下緩慢添加SO2
(氣體,1公升)。隨後使混合物升溫至室溫且攪拌隔夜。在0℃下添加乙酸(307毫克,5.10毫莫耳,1.0當量)於Et2
O(15毫升)中的混合物。將混合物在0℃下攪拌30分鐘且隨後過濾。用Et2
O快速洗滌濾餅。將固體懸浮於Et2
O(15毫升)中,冷卻至0℃且小心地添加NCS(682公克,5.10毫莫耳,1.0當量)。將所得懸浮液快速攪拌30分鐘,且隨後過濾。用Et2
O洗滌濾餅。濃縮合併的濾液,以得到呈褐色固體狀的A46
(1H
-吲哚-4-磺醯氯,420毫克,粗物質)。
步驟2)合成化合物26
將A46
(1H
-吲哚-4-磺醯氯,420毫克,1.95毫莫耳,1.0當量)及4-羥基苯甲醯肼(A2
,297毫克,1.95毫莫耳,1.0當量)於吡啶(30毫升)中的混合物在25℃下攪拌30分鐘。將上述溶液倒入水(30毫升)中。藉由過濾收集所形成的固體且用水洗滌濾餅。粗產物藉由製備型HPLC純化且凍乾,以得到呈白色固體狀的化合物 26
(N'
-(4-羥基苯甲醯基)-1H
-吲哚-4-磺醯肼,200毫克,產率31.0%)。1
HNMR (DMSO-d 6
, 400 MHz): δ 11.48 (s, 1H), 10.30 (s, 1H), 10.04 (s, 1H), 9.52 (s, 1H), 7.65 (d,J
= 8.0 Hz, 1H), 7.49-7.52 (m, 4H), 7.16 (t,J
= 8.0 Hz, 1H), 6.85 (t,J
= 2.0 Hz, 1H), 6.73 (dd,J
= 6.8, 2.0 Hz, 2H。
LCMS;質量計算值:331.3;MS實驗值:331.9 [MS+1]。
步驟3)合成化合物25
在0℃下向化合物 26
(N'
-(4-羥基苯甲醯基)-1H
-吲哚-4-磺醯肼,150毫克,0.48毫莫耳,1.0當量)於TFA(5毫升)及DCM(5毫升)中的混合物中添加NaBH3
CN(89毫克,1.43毫莫耳,3.0當量)。將混合物在10℃下攪拌30分鐘。將上述溶液倒入水(30毫升)中且用DCM(30毫升×3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥且濃縮,以得到粗產物,所述粗產物藉由製備型HPLC純化且凍乾,以得到呈灰色固體狀的化合物 25
(N'
-(4-羥基苯甲醯基)吲哚啉-4-磺醯肼,30毫克,產率20.0%)。1
HNMR (DMSO-d 6
, 400 MHz): δ 10.35 (d,J
= 2.8 Hz, 1H), 10.09 (s, 1H), 9.62 (d,J
= 2.8 Hz, 1H), 7.57 (d,J
= 8.8 Hz, 2H), 6.97-6.99 (m, 1H), 6.93 (d,J
= 6.8 Hz, 1H), 6.76 (d,J
= 8.8 Hz, 2H), 6.67 (d,J
= 7.2 Hz, 1H), 3.39-3.44 (m, 2H), 3.27-3.32 (m, 2H)。
LCMS;質量計算值:333;MS實驗值:333.8 [MS+1]。實驗實例 1-27. 製備化合物 27 ( 2-((4- 胺基苯基 ) 磺醯基 )-N
- 苯肼 -1- 甲醯胺 )
步驟1)合成A47
向4-硝基苯磺醯氯(3公克,13.5毫莫耳,1.0當量)於吡啶(25毫升)中的混合物中逐滴添加含肼甲酸三級丁酯(1.8公克,13.6毫莫耳,1.0當量)的吡啶(5毫升)。隨後將混合物在10℃下攪拌2小時。將上述溶液倒入水(100毫升)中且攪拌溶液1小時。藉由過濾收集所形成的固體且乾燥,以得到呈黃色固體狀的A47
(2-((4-硝基苯基)磺醯基)肼-1-甲酸三級丁酯,3.0公克,產率69.7%)。1
HNMR (CDCl3
, 400 MHz): δ 8.35 (d,J
= 8.4 Hz, 2H), 8.13 (dd,J
= 7.2, 2.0 Hz, 2H), 6.79 (s, 1H), 6.68 (s, 1H), 1.25 (s, 9H)。
步驟2)合成A48
向A47
(2-((4-硝基苯基)磺醯基)肼-1-甲酸三級丁酯,3公克,9.45毫莫耳,1.0當量)於MeOH(30毫升)中的混合物中添加MeOH/HCl(30毫升,6莫耳/公升)。隨後將混合物在10℃下攪拌2小時。濃縮上述溶液,以得到呈黃色固體狀的A48
(4-硝基苯磺醯肼鹽酸鹽,2.0公克,產率83.4%)。1
HNMR (DMSO-d 6
, 400 MHz): δ 8.45-8.48 (m, 2H), 8.15 (d,J
= 8.8 Hz, 2H)。
步驟3)合成A49
在10℃下向A48
(4-硝基苯磺醯肼鹽酸鹽,500毫克,1.97毫莫耳,1.0當量)於THF(20毫升)中的混合物中添加DIEA(764毫克,5.91毫莫耳,3.0當量)及異氰酸基苯(235毫克,1.97毫莫耳,1.0當量)。隨後將混合物在10℃下攪拌2小時。將上述溶液倒入水(80毫升)中。過濾所形成的固體且將濾餅在EA(20毫升)中攪拌30分鐘。隨後再次過濾混合物且乾燥濾餅,以得到呈白色固體狀的A49
(2-((4-硝基苯基)磺醯基)-N
-苯肼-1-甲醯胺,340毫克,產率51.3%)。1
HNMR (DMSO-d 6
, 400 MHz): δ 10.09 (s, 1H), 8.69 (s, 1H), 8.53 (s, 1H), 8.40-8.43 (m, 2H), 8.09 (dd,J
= 7.2, 2.0 Hz, 2H), 7.34 (t,J
= 8.0 Hz, 2H), 7.21 (t,J
= 8.0 Hz, 1H), 6.94 (t,J
= 7.2 Hz, 1H)。
步驟4)合成化合物27
將A49
(2-((4-硝基苯基)磺醯基)-N
-苯肼-1-甲醯胺,340毫克,1.01毫莫耳,1.0當量)及Pd/C(200毫克)於MeOH(30毫升)中的混合物在10℃下在H2
氣球下攪拌15小時。過濾上述溶液且濃縮濾液,以得到粗產物,將所述粗產物在MeOH(5毫升)中攪拌30分鐘。過濾混合物且真空乾燥濾餅,以得到呈白色固體狀的化合物 27
(2-((4-胺基苯基)磺醯基)-N
-苯肼-1-甲醯胺,50毫克,產率16.2%)。1
HNMR (DMSO-d 6
, 400 MHz): δ 9.12 (s, 1H), 8.41 (s, 1H), 8.15 (s, 1H), 7.47 (d,J
= 8.8 Hz, 2H), 7.38 (d,J
= 8.0 Hz, 2H), 7.22 (t,J
= 8.0 Hz, 2H), 6.94 (t,J
= 7.2 Hz, 1H), 6.60 (d,J
= 8.8 Hz, 2H), 6.04 (s, 2H)。
LCMS;質量計算值:306;MS實驗值:306.9。實驗實例 1-28. 製備化合物 28 ( 4- 胺基 -N'
-(1H
- 吲哚 -4- 羰基 )-3- 嗎啉基苯磺醯肼 )
步驟1)合成A51
將A50
(1H
-吲哚-4-甲酸甲酯,1.00公克,5.71毫莫耳,1.0當量)於N2
H4
H2
O(10毫升)中的混合物在100℃下攪拌1小時。將上述溶液倒入水中且用EA(30毫升×3)萃取。將合併的有機層經Na2
SO4
乾燥且濃縮,以得到呈黃色固體狀的A51
(1H-吲哚-4-碳醯肼,500毫克,粗物質)。
步驟2)合成A52
向A51
(1H-吲哚-4-碳醯肼,100毫克,0.57毫莫耳,1.0當量)於吡啶(2毫升)中的混合物中逐滴添加含3-氟-4-硝基苯-1-磺醯氯(175毫克,0.57毫莫耳,1.0當量)的吡啶(2毫升)。隨後將混合物在10℃下攪拌3小時。將上述溶液倒入水(30毫升)中且用EA(30毫升×3)萃取。將合併的有機層用1N HCl(30毫升×2)及鹽水洗滌,經Na2
SO4
乾燥且濃縮,以得到呈黃色固體狀的A52
(3-氟-N'
-(1H
-吲哚-4-羰基)-4-硝基苯磺醯肼,200毫克,粗物質)。
步驟3)合成A53
在10℃下,向A52
(3-氟-N'
-(1H
-吲哚-4-羰基)-4-硝基苯磺醯肼,200毫克,0.52毫莫耳,1.0當量)及K2
CO3
(183毫克,1.30毫莫耳,2.5當量)於DMF(5毫升)中的混合物中添加嗎啉(54毫克,0.62毫莫耳,1.2當量)。隨後將混合物在25℃下攪拌16小時。將上述溶液倒入水(30毫升)中且用EA(30毫升×3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥且濃縮,以得到呈黃色固體狀的A53
(N'
-(1H
-吲哚-4-羰基)-3-嗎啉基-4-硝基苯磺醯肼,100毫克,粗物質)。
步驟4)合成化合物28
向A53
(N'
-(1H
-吲哚-4-羰基)-3-嗎啉基-4-硝基苯磺醯肼,100毫克,0.22毫莫耳,1.0當量)於EtOH(5毫升)中的混合物中添加Fe(61.6毫克,1.10毫莫耳,5.0當量)及飽和NH4
Cl水溶液(3毫升)。隨後將混合物在85℃下攪拌3小時。過濾上述溶液且濾液藉由製備型HPLC純化並凍乾,以得到呈白色固體狀的化合物 28
(4-胺基-N'
-(1H
-吲哚-4-羰基)-3-嗎啉基苯磺醯肼,20毫克,產率21.5%)。1
HNMR (DMSO-d 6
, 400 MHz): δ11.30 (s, 1H), 10.34 (s, 1H), 9.35 (d,J
= 4.0 Hz, 1H), 7.54 (d,J
= 8.4 Hz, 1H), 7.43 (t,J
= 2.4 Hz, 1H), 7.30-7.35 (m, 3H), 7.11 (t,J
= 7.6 Hz, 1H), 6.65-6.67 (m, 2H), 5.60 (br s, 2H), 3.64 (t,J
= 4.0 Hz, 4H), 2.60 (t,J
= 4.0 Hz, 4H).
LCMS;質量計算值:415;MS實驗值:415.9 [MS+1]。實驗實例 1-29. 製備化合物 29 ( 4- 胺基 -N'
-( 吲哚啉 -4- 羰基 ) 苯磺醯肼 )
步驟1)合成A54
向A51
(1H
-吲哚-4-碳醯肼,400毫克,2.29毫莫耳,1.0當量)於吡啶(5毫升)中的混合物中逐滴添加含4-硝基苯-1-磺醯氯(505毫克,2.29毫莫耳,1.0當量)的吡啶(5毫升)。隨後將混合物在10℃下攪拌3小時。將上述溶液倒入水(30毫升)中且用EA(30毫升×3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥且濃縮,以得到呈黃色固體狀的A54
(N'
-(1H
-吲哚-4-羰基)-4-硝基苯磺醯肼,300毫克,粗物質)。
步驟2)合成A55
在10℃下向A54
(N'
-(1H
-吲哚-4-羰基)-4-硝基苯磺醯肼,300毫克,0.83毫莫耳,1.0當量)於DCM(5毫升)中的混合物中添加TFA(1.5毫升)及NaBH3
CN(157毫克,2.49毫莫耳,3.0當量)。隨後將混合物在10℃下攪拌45分鐘。將上述溶液倒入水(30毫升)中且用飽和NaHCO3
水溶液調節pH = 7。過濾混合物且將濾餅用MTBE洗滌並真空乾燥,以得到呈黃色固體狀的A55
(N'
-(吲哚啉-4-羰基)-4-硝基苯磺醯肼,150毫克,粗物質)。
步驟3)合成化合物29
將A55
(N'
-(吲哚啉-4-羰基)-4-硝基苯磺醯肼,150毫克,0.41毫莫耳,1.0當量)及Pd/C(100毫克)於MeOH(5毫升)中的混合物在10℃下在H2
氣球下攪拌2小時。過濾以上溶液且濃縮濾液,以得到粗產物,將所述粗產物在MeOH(10毫升)中攪拌30分鐘。過濾混合物且在真空中乾燥濾餅,以得到呈白色固體狀的化合物 29
(4-胺基-N'
-(吲哚啉-4-羰基)苯磺醯肼,40毫克,產率29.1%)。1
HNMR (DMSO-d 6
, 400 MHz): δ10.28 (d,J
= 3.6 Hz, 1H), 9.28 (d,J
= 3.6 Hz, 1H), 7.46 (d,J
= 8.4 Hz, 2H), 7.03 (t,J
= 8.0 Hz, 1H), 6.83 (d,J
= 7.2 Hz, 1H), 6.75 (d,J
= 7.2 Hz, 1H), 6.53 (d,J
= 8.8 Hz, 2H), 3.42 (t,J
= 8.4 Hz, 2H), 2.96 (t,J
= 8.4 Hz, 2H)。
LCMS;質量計算值:332;MS實驗值:332.8 [MS+1]。實驗實例 1-30. 製備化合物 30 ( 4- 胺基 -N'-(4- 羥基苯甲醯基 )-3-( 哌嗪 -1- 基 ) 苯磺醯肼 )
步驟1)合成A56
在10℃下,向A4
(3-氟-N'
-(4-羥基苯甲醯基)-4-硝基苯磺醯肼,500毫克,1.41毫莫耳,1.0當量)及K2
CO3
(290毫克,2.10毫莫耳,1.5當量)於DMF(5毫升)中的混合物中添加哌嗪-1-甲酸三級丁酯(315毫克,1.69毫莫耳,1.2當量)。隨後將混合物在10℃下攪拌16小時。將上述溶液倒入水(30毫升)中且用EA(30毫升×3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥且濃縮,以得到粗產物,藉由急驟管柱(DCM/MeOH=50/1至30/1)純化所述粗產物,以得到呈黃色固體狀的A56
(4-(5-((2-(4-羥基苯甲醯基)肼基)磺醯基)-2-硝基苯基)哌嗪-1-甲酸三級丁酯,310毫克,粗物質)。
步驟2)合成A57
向A56
(4-(5-((2-(4-羥基苯甲醯基)肼基)磺醯基)-2-硝基苯基)哌嗪-1-甲酸三級丁酯,250毫克,0.48毫莫耳,1.0當量)於EtOH(3毫升)中的混合物中添加飽和NH4
Cl水溶液(3毫升)及Fe(135毫克,2.41毫莫耳,5.0當量)。隨後將混合物在85℃下攪拌1小時。過濾上述溶液且將濾液倒入水(30毫升)中並用EA(30毫升×3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥且濃縮,以得到呈黃色固體狀的A57
(4-(2-胺基-5-((2-(4-羥基苯甲醯基)肼基)磺醯基)苯基)哌嗪-1-甲酸三級丁酯,210毫克,粗物質)。
步驟3)合成化合物30
在10℃下,向A57
(4-(2-胺基-5-((2-(4-羥基苯甲醯基)肼基)磺醯基)苯基)哌嗪-1-甲酸三級丁酯,270毫克,0.55毫莫耳,1.0當量)於DCM(5毫升)中的混合物中添加TFA(0.5毫升)。隨後將混合物在10℃下攪拌3小時。濃縮上述溶液,以得到粗產物,藉由製備型HPLC純化且凍乾所述粗產物,以得到粗產物。將粗產物在MeOH(2.5毫升)及CH3
CN(2.5毫升)中攪拌5分鐘。過濾混合物且將濾餅用MeOH洗滌並乾燥,以得到呈白色固體狀的化合物 30
(4-胺基-N'
-(4-羥基苯甲醯基)-3-(哌嗪-1-基)苯磺醯肼,20毫克,產率9.30%)。1
HNMR (DMSO-d 6
, 400 MHz): δ 7.57 (d,J
= 8.0 Hz, 2H), 7.21-7.25 (m, 2H), 6.76 (d,J
= 8.0 Hz, 2H), 6.64 (d,J
= 8.4 Hz, 1H), 5.54 (s, 2H), 2.78 (s, 4H), 2.54 (s, 4H)。
LCMS;質量計算值:391;MS實驗值:392.1 [MS+1]。實驗實例 1-31. 製備化合物 31 ( 4- 胺基 -N'
-(2,3- 二氫 -1H
- 茚 -2- 羰基 ) 苯磺醯肼 )
步驟1)合成A59
向A58
(2,3-二氫-1H
-茚-2-甲酸,5.0公克,30.8毫莫耳,1.0當量)於MeOH(50毫升)中的混合物中逐滴添加H2
SO4
(5毫升)。隨後將混合物在70℃下攪拌12小時。將上述溶液倒入水(60毫升)中且用EA(60毫升×3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥且濃縮,以得到呈黃色油狀的A59
(2,3-二氫-1H
-茚-2-甲酸甲酯,5.3公克,產率97.5%)。
步驟2)合成A60
向A59
(2,3-二氫-1H
-茚-2-甲酸甲酯,3.0公克,17.1毫莫耳,1.0當量)於MeOH(30毫升)中的混合物中逐滴添加N2
H4
.H2
O(8.56公克,171毫莫耳,10當量)。隨後將混合物在80℃下攪拌12小時。濃縮上述溶液,以得到呈黃色固體狀的A60
(2,3-二氫-1H
-茚-2-碳醯肼,2.0公克,產率87.5%)。1
HNMR (DMSO-d6, 400 MHz): δ 9.13 (s, 1H), 7.18-7.20 (m, 2H), 7.11-7.13 (m, 2H), 4.25 (br s, 2H), 3.01-3.11 (m, 5H)。
步驟3)合成A61
向A60
(2,3-二氫-1H
-茚-2-碳醯肼,2公克,11.4毫莫耳,1.0當量)於吡啶(20毫升)中的混合物中逐份添加4-硝基苯-1-磺醯氯(2.52公克,11.4毫莫耳,1.0當量)。隨後將混合物在10℃下攪拌2小時。將上述溶液倒入水(100毫升)中且用EA(100毫升×3)萃取。將合併的有機層經鹽水洗滌,經Na2
SO4
乾燥且濃縮,以得到呈黃色固體狀的A61
(N'
-(2,3-二氫-1H
-茚-2-羰基)-4-硝基苯磺醯肼,1.4公克,產率34.1%)。(TLC:DCM/MeOH =10/1,Rf=0.5)
步驟4)合成化合物31
向A61
(N'
-(2,3-二氫-1H
-茚-2-羰基)-4-硝基苯磺醯肼,200毫克,0.83毫莫耳,1.0當量)於MeOH(10毫升)中的混合物中添加Pd/C(100毫克)。隨後將混合物在10℃下在H2
氣球下攪拌12小時。過濾上述溶液且將濾液藉由製備型HPLC純化並凍乾,以得到呈白色固體狀的化合物 31
(4-胺基-N'
-(2,3-二氫-1H
-茚-2-羰基)苯磺醯肼,80毫克,產率43.6%)。1
HNMR (CD3
OD, 400 MHz): δ 7.55 (dd,J
= 6.8, 2.0 Hz, 2H), 7.07-7.12 (m, 4H), 6.65 (dd,J
= 6.8, 2.0 Hz, 2H), 2.92-3.03 (m, 5H)。
LCMS;質量計算值:331;MS實驗值:331.8 [MS+1]。實驗實例 1-32. 製備化合物 32 ( 4- 胺基 -N'
-( 異吲哚啉 -2- 羰基 ) 苯磺醯肼 )
步驟1)合成A63
向A62(異吲哚啉,1.00公克,8.4毫莫耳,1.0當量)於二氯甲烷(10毫升)中的混合物中添加三乙胺(2毫升)及氯甲酸4-硝基苯酯(1.68公克,8.4毫莫耳)。將混合物在室溫下攪拌16小時。將上述溶液倒入水(30毫升)中,且用二氯甲烷(30毫升×3)萃取。將合併的有機層經Na2
SO4
乾燥且濃縮。將產物添加至四氫呋喃(10 mL)及N2
H4
H2
O(2毫升)中。將混合物在60℃下攪拌16小時。將上述溶液倒入水(50毫升)中且用乙酸乙酯(30毫升×3)萃取。將合併的有機層經硫酸鈉(Na2
SO4
)乾燥且濃縮,以得到呈黃色固體狀的A63
(異吲哚啉-2-碳醯肼,600毫克,粗物質)。(TLC:DCM/MeOH =10/1,Rf=0.6)LCMS;質量計算值:177.2;MS實驗值:178.2 [MS+1]。
步驟2)合成A64
向A63
(異吲哚啉-2-碳醯肼,600毫克,3.39毫莫耳,1.0當量)於吡啶(10毫升)中的混合物中逐滴添加含4-硝基苯-1-磺醯氯(750毫克,3.39毫莫耳,1.0當量)的吡啶(5毫升)。隨後將混合物在10℃下攪拌3小時。將上述溶液倒入水(50毫升)中且用EA(50毫升×3)萃取。將合併的有機層用1N HCl(50毫升×2)及鹽水洗滌,經Na2
SO4
乾燥且濃縮,以得到呈黃色固體狀的A64
(N'
-(異吲哚啉-2-羰基)-4-硝基苯磺醯肼,200毫克,粗物質)。(TLC:DCM/MeOH =20/1,Rf=0.5)
LCMS;質量計算值:362.3;MS實驗值:363.1 [MS+1]。步驟 3 ) 合成化合物 32 ( 4- 胺基 -N'
-( 異吲哚啉 -2- 羰基 ) 苯磺醯肼 )
向A64
(200毫克,0.55毫莫耳,1.0當量)於乙醇(10毫升)中的混合物中添加Fe(154毫克,2.75毫莫耳,5.0當量)及飽和NH4
Cl水溶液(6毫升)。隨後將混合物在85℃下攪拌3小時。過濾上述溶液且濃縮濾液,以獲得粗產物。粗產物藉由製備型HPLC純化且凍乾,以得到呈白色固體狀的化合物 32
(4-胺基-N'
-(異吲哚啉-2-羰基)苯磺醯肼,20毫克,產率11.0%)。
1HNMR (DMSO-d6, 400 MHz): δ 8.64 (s, 1H), 8.53 (s, 1H), 7.41-7.44 (m, 2H), 7.29-7.31 (m, 4H), 6.51-6.54 (m, 2H), 5.93 (s, 2H), 4.51 (s, 4H)。
LCMS;質量計算值:332;MS實驗值:333 [MS+1]。實驗實例 1-33. 製備化合物 33 ( N' -(4- 羥基苯甲醯基 )-1H
- 吲哚 -2- 磺醯肼 )
步驟1)合成A66
在-70℃下,向A65
(1H
-吲哚-1-甲酸三級丁酯,2.00公克,9.2毫莫耳,1.0當量)於四氫呋喃(20毫升)中的經攪拌溶液中逐滴添加n-BuLi(4.0毫升,2.5M於己烷中,10.0毫莫耳,1.1當量)。在1小時之後,在-70℃下緩慢添加SO2
(氣體,1公升)。隨後歷經2小時的時段使反應混合物升溫至10℃。在減壓下移除溶劑,且將殘餘物溶解於二氯甲烷(DCM,20毫升)中。添加N
-氯代二醯亞胺(NCS,1.84公克,13.8毫莫耳,1.5當量)。將混合物在室溫下攪拌10小時。用水(2×20毫升)及鹽水(2×20毫升)洗滌混合物。將有機相乾燥且濃縮。藉由管柱層析(PE/EA=30/1-5/1)純化殘餘物,以得到呈褐色油狀的A66
(2-(氯磺醯基)-1H
-吲哚-1-甲酸三級丁酯,1.0公克,產率34.4%)。
1HNMR (CDCl3, 400 MHz): δ 8.23-8.25 (m, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.69 (s, 1H), 7.56-7.60 (m, 1H), 7.35-7.39 (m, 1H), 1.75(s, 9H)。
步驟2)合成A67
在0℃下向4-羥基苯甲醯肼(481毫克,3.17毫莫耳,1.0當量)於吡啶(10毫升)中的經攪拌溶液中逐滴添加A66
(2-(氯磺醯基)-1H
-吲哚-1-甲酸三級丁酯,1.0公克,3.17毫莫耳,1.0當量)於吡啶(5毫升)中的溶液。將混合物在室溫下攪拌5小時。過濾混合物。濃縮濾液且藉由管柱層析純化,以得到呈白色固體狀的A67
(2-((2-(4-羥基苯甲醯基)肼基)磺醯基)-1H
-吲哚-1-甲酸三級丁酯,500毫克,產率36.5%)。
步驟3)合成化合物33
在0℃下向A67
(500毫克,1.16毫莫耳,1.0當量)於甲醇(MeOH,5毫升)中的經攪拌溶液中添加4N HCl(公克)/MeOH(2毫升)。將混合物在室溫下攪拌4小時。將混合物濃縮,藉由製備型HPLC純化且凍乾,以得到呈白色固體狀的化合物 33
(N'
-(4-羥基苯甲醯基)-1H
-吲哚-2-磺醯肼,50毫克,產率13%)。
1HNMR (DMSO-d6, 400 MHz): δ 11.94 (s, 1H), 10.42 (d, J = 1.6 Hz, 1H), 10.09 (s, 1H), 9.86 (d, J = 2.8 Hz, 1H), 7.61-7.64 (m, 3H), 7.45-7.47 (m, 1H), 7.24-7.28 (m, 1H), 7.07-7.11 (m, 1H), 6.99 (d, J = 1.2 Hz, 1H), 6.77 (d, J = 8.8 Hz, 2H)。
LCMS;質量計算值:341;MS實驗值:342 [MS+1]。實驗實例 1-34. 製備化合物 34 ( 4- 胺基 -N'
-(2- 苯基乙醯基 ) 苯磺醯肼 )
步驟1)合成A69
向A68
(2-苯基乙醯肼,500毫克,3.33毫莫耳,1.0當量)於吡啶(5毫升)中的混合物中逐滴添加含4-硝基苯-1-磺醯氯(738毫克,3.33毫莫耳,1.0當量)的吡啶(5毫升)。隨後將混合物在10℃下攪拌2小時。將上述溶液倒入水(30毫升)中且用乙酸乙酯(EA,30毫升×3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥且濃縮,以得到粗產物,將所述粗產物在DCM(30毫升)中攪拌30分鐘。過濾混合物且將濾餅乾燥,以得到呈黃色固體狀的A69
(4-硝基-N'
-(2-苯基乙醯基)苯磺醯肼,1公克,產率89.6%)。
1HNMR (DMSO-d6, 400 MHz): δ 10.50 (s, 1H), 10.37 (s, 1H), 8.22 (d, J = 8.8 Hz, 2H), 7.92 (d, J = 8.8 Hz, 2H), 7.21-7.29 (m, 3H), 7.10-7.12 (m, 2H), 3.30 (s, 2H)。
步驟1)合成化合物34
向A69
(200毫克,0.60毫莫耳,1.0當量)於MeOH(10毫升)中的混合物中添加Pd/C(50毫克)。隨後將混合物在10℃下在H2
氣球下攪拌2小時,過濾上述溶液且濃縮濾液。粗產物自MeOH(10毫升)結晶三次,以得到呈灰色固體狀的化合物 34
(4-胺基-N'
-(2-苯基乙醯基)苯磺醯肼,20毫克,產率10.9%)。(TLC:DCM/MeOH =10/1,Rf=0.3)
1HNMR (DMSO-d6, 400 MHz): δ 9.87 (s, 1H), 8.77 (s, 1H), 7.40 (d, J = 6.8 Hz, 2H), 7.18-7.29 (m, 3H), 7.13 (d, J = 6.8 Hz, 2H), 5.74 (s, 2H), 3.37 (s, 2H)。
LCMS;質量計算值:305;MS實驗值:306.1 [MS+1]。實驗實例 1-35. 製備化合物 35 ( N' -(4- 羥基苯甲醯基 )-1H
- 吲唑 -3- 磺醯肼 )
步驟1)合成A70
在0℃下向1H
-吲唑-3-胺(1.00公克,7.5毫莫耳,1.0當量)於乙酸(16毫升)、濃鹽酸(1.6毫升)以及甲酸(1.6毫升)中的經攪拌溶液中添加NaNO2
(0.62公克,9.0毫莫耳,1.2當量)。將混合物攪拌1小時。在0℃下緩慢添加SO2
(氣體,1公升)及CuCl2
(0.38公克,2.3毫莫耳,0.3當量)。使反應混合物升溫至10℃。在減壓下濃縮混合物。藉由管柱層析(PE/EA==30:1-1:1)純化殘餘物,以得到呈棕色固體狀的A70
(1H
-吲唑-3-磺醯氯,0.5公克,產率30.8%)。
1HNMR (DMSO-d6, 400 MHz): δ 14.13 (s, 2H), 7.94-7.92 (m, 1H), 7.46-7.38 (m, 2H), 7.14 (s, 1H)。
步驟2)合成化合物35(N'
-(4-羥基苯甲醯基)-1H
-吲唑-3-磺醯肼)
在0℃下向4-羥基苯甲醯肼(225毫克,1.48毫莫耳,0.8當量)於吡啶(5毫升)中的經攪拌溶液中逐滴添加A70
(1H
-吲唑-3-磺醯氯,0.40公克,1.85毫莫耳,1.0當量)於吡啶(5毫升)中的溶液。將混合物在室溫下攪拌5小時。濃縮混合物。殘餘物藉由製備型HPLC純化且凍乾,以得到呈白色固體狀的化合物 35
(N'
-(4-羥基苯甲醯基)-1H
-吲唑-3-磺醯肼,60毫克,產率9.77%)。
1HNMR (DMSO-d6, 400 MHz): δ 13.90 (s, 1H), 10.43 (s, 1H), 10.05-9.99 (m, 2H), 7.92 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.42 (t, J = 7.0 Hz, 1H), 7.22 (t, J = 7.0 Hz, 1H), 6.72 (d, J = 8.0 Hz, 2H)。
LCMS;質量計算值:332;MS實驗值:333 [MS+1]。實驗實例 1-36. 製備化合物 36 ( 4- 胺基 -N'
-( 吲哚啉 -6- 羰基 ) 苯磺醯肼 )
步驟1)合成A72
將A71
(1H
-吲哚-6-甲酸甲酯,500毫克,2.86毫莫耳,1.0當量)及單水合肼(10毫升)的混合物在100℃下攪拌3小時。隨後將混合物冷卻至0℃且過濾。將濾餅用冰水洗滌且真空乾燥,以得到呈白色固體狀的A72
(1H
-吲哚-6-碳醯肼,300毫克,產率60.0%)。
LCMS;質量計算值:175.18;MS實驗值:176.0 [MS+1]。
步驟2)合成A73
在0℃下向A72
(300毫克,1.71毫莫耳,1.0當量)於吡啶(5毫升)的混合物中添加4-硝基苯磺醯氯(380毫克,1.71毫莫耳,1.0當量)。隨後將混合物在10℃下攪拌3小時。將上述溶液倒入水(30毫升)中且用EA(30毫升×3)萃取。將合併的有機層用1N HCl(30毫升×2)及鹽水洗滌,經Na2
SO4
乾燥且濃縮,以得到粗產物,藉由急驟管柱(DCM/MeOH=50/1至30/1)純化所述粗產物,以得到呈黃色固體狀的A73
(N'
-(1H
-吲哚-6-羰基)-4-硝基苯磺醯肼,500毫克,產率81.0%)。
LCMS;質量計算值:360.34;MS實驗值:361.1 [MS+1]。
步驟3)合成A74
在0℃下向A73
(400毫克,1.11毫莫耳,1.0當量)於DCM(15毫升)及TFA(5毫升)中的混合物中添加NaBH3
CN(209毫克,3.33毫莫耳,3.0當量)。隨後將混合物在15℃下攪拌1小時。將上述溶液倒入水(30毫升)中且用飽和NaHCO3
水溶液調節pH=7~8。過濾上述溶液且濾餅用PE洗滌並乾燥,以得到呈黃色固體狀的A74
(N'
-(吲哚啉-6-羰基)-4-硝基苯磺醯肼,200毫克,粗物質)。
LCMS;質量計算值:362.36;MS實驗值:363.1 [MS+1]。
步驟3)合成化合物36
將A74
(200毫克,0.55毫莫耳,1.0當量)、NH4
Cl(146毫克,2.75毫莫耳,5.0當量)、Fe(154毫克,2.75毫莫耳,5.0當量)於H2
O(10毫升)及EtOH(20毫升)中的混合物在85℃下攪拌2小時。過濾混合物,且用EA(20毫升×3)萃取濾液。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥且濃縮。粗產物用甲醇再結晶,凍乾固體,以得到呈白色固體狀的化合物 36
(4-胺基-N'
-(吲哚啉-6-羰基)苯磺醯肼,60毫克,32.7%)。
1HNMR (DMSO-d6, 400 MHz): δ 10.32 (s, 1H), 9.14 (s, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 7.6 Hz, 1H), 6.87 (d, J = 7.2 Hz, 1H), 6.75 (s, 1H), 6.49 (d, J = 8.4 Hz, 2H), 5.95 (s, 2H), 5.67 (s, 1H), 3.41 (t, J = 8.2 Hz, 2H), 2.91 (t, J = 8.6 Hz, 2H)。
LCMS;質量計算值:332;MS實驗值:333 [M+1]。實驗實例 1-37. 製備化合物 37 ( 4- 胺基 -N'
-( 吲哚啉 -3- 羰基 ) 苯磺醯肼 )
步驟1)合成A76
在20℃下,向A75
(1H
-吲哚-3-甲酸甲酯,1.00公克,5.71毫莫耳,1.0當量)及三乙胺(TEA,1.16公克,11.4毫莫耳,2.0當量)於DCM(10毫升)中的混合物中逐滴添加Boc2
O(1.37公克,6.28毫莫耳,1.1當量)。隨後將混合物在20℃下攪拌12小時。將上述溶液倒入水(60毫升)中且用DCM(60毫升×3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥且濃縮,以得到呈黃色固體狀的A76
(3-甲基1H
-吲哚-1,3-二甲酸1-(三級丁酯),1.20公克,粗物質)。
步驟2)合成A77
向A76
(1.20公克,4.36毫莫耳,1.0當量)於乙酸乙酯(EA,30毫升)中的混合物中添加Pd/C(0.65公克)且脫氣。隨後將混合物在H2
(50磅每平方吋)下在60℃下攪拌12小時。過濾上述溶液且濃縮濾液,以得到粗產物。藉由矽膠(PE/EA=30:1~15:1)純化粗產物,以得到呈白色固體狀的A77
(3-甲基吲哚啉-1,3-二甲酸1-(三級丁酯),0.80公克,產率66.2%)。
步驟3)合成A78
向A77
(800毫克,2.89毫莫耳,1.0當量)於MeOH(20毫升)中的混合物中添加N2
H4
.H2
O(1.6毫升)。隨後將混合物在80℃下攪拌4小時。濃縮反應混合物,以得到呈白色固體狀的A78
(3-(肼羰基)吲哚啉-1-甲酸三級丁酯,700毫克,產率87.5%)。
步驟3)合成A79
向A78
(3-(肼羰基)吲哚啉-1-甲酸三級丁酯,300毫克,1.08毫莫耳,1.0當量)於吡啶(5毫升)中的混合物中逐份添加4-硝基苯-1-磺醯氯(0.24公克,1.08毫莫耳,1.0當量)。隨後將混合物在10℃下攪拌4小時。將上述溶液倒入水(100毫升)中且用EA(100毫升×3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥且濃縮,以得到呈黃色固體狀的A79
(3-(2-((4-硝基苯基)磺醯基)肼-1-羰基)吲哚啉-1-甲酸三級丁酯,200毫克,產率39.7%)。
步驟4)合成A80
向A79
(200毫克,0.43毫莫耳,1.0當量)於EA(10毫升)中的混合物中添加Pd/C(50毫克)。隨後將混合物在10℃下在H2氣球下攪拌12小時。過濾上述溶液且濃縮濾液,以得到呈黃色固體狀的A80
(3-(2-((4-胺基苯基)磺醯基)肼-1-羰基)吲哚啉-1-甲酸三級丁酯,200毫克,產率:100%)。
步驟5)合成化合物37(4-胺基-N'
-(吲哚啉-3-羰基)苯磺醯肼)
向A80
(200毫克,0.463毫莫耳,1.0當量)於DCM(5毫升)中的混合物中添加三氟乙酸(TFA,1毫升)。隨後將混合物在10℃下攪拌2小時。濃縮上述溶液,向殘餘物添加H2
O(5毫升)且用K2
CO3
水溶液調節pH=9-10。用EA(20毫升×3)萃取溶液。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥且濃縮,以得到粗產物。粗產物藉由製備型HPLC純化且凍乾,以得到呈灰白色固體狀的化合物 37
(4-胺基-N'
-(吲哚啉-3-羰基)苯磺醯肼,30.0毫克,產率19.6%)。1HNMR (DMSO_d6, 400 MHz): δ 7.45 (d, J = 8.4 Hz, 2H), 6.91-6.95 (m, 2H), 6.48-6.59 (m, 4H), 5.72 (s, 2H), 5.23 (s, 1H), 3.93 (br s, 1H), 3.49 (d, J = 9.2 Hz, 2H)。
LCMS;MS實驗值:333.1 [MS+1]。實驗實例 1-38. 製備化合物 38 ( N' -(4- 羥基苯甲醯基 ) 哌啶 -4- 磺醯肼 )
步驟1)合成A82
在0℃下向4-羥基苯甲醯肼(A2,268毫克,1.77毫莫耳,1.0當量)於吡啶(2毫升)中的混合物中逐滴添加A81
(4-(氯磺醯基)哌啶-1-甲酸三級丁酯,500毫克,1.77毫莫耳,1.0當量)於吡啶(1毫升)中的溶液。將混合物在室溫下攪拌5小時。過濾上述溶液。將濾液濃縮且藉由管柱層析(DCM/MeOH=100:1-10:1)純化,以得到呈黃色固體狀的A82
(4-((2-(4-羥基苯甲醯基)肼基)磺醯基)哌啶-1-甲酸三級丁酯,300毫克,產率42%)。
1HNMR (CDCl3, 400 MHz): δ 8.47 (br s, 1H), 7.70 (d, J = 8.8 Hz, 2H), 7.30 (br s, 1H), 6.87 (d, J = 8.4 Hz, 2H), 3.15-3.18 (m, 1H), 2.67-2.71 (m, 2H), 2.25 (d, J = 10.8 Hz, 2H), 1.72-1.78 (m, 2H), 1.61-1.63 (m, 2H), 1.45 (s, 9H)。
步驟2)合成化合物38(N'
-(4-羥基苯甲醯基)哌啶-4-磺醯肼)
在0℃下向A82
(300毫克,0.75毫莫耳,1.0當量)於DCM(5毫升)中的混合物中添加TFA(1.5毫升)。將混合物在室溫下攪拌4小時。將上述溶液濃縮且藉由製備型HPLC純化並凍乾,以得到呈黃色固體狀的化合物 38
(N'
-(4-羥基苯甲醯基)哌啶-4-磺醯肼,50毫克,產率22%)。
1HNMR (DMSO-d6, 400 MHz): δ 10.40 (br s, 1H), 8.34 (s, 1H), 7.75 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 3.17-3.24 (m, 3H), 2.69 (t, J = 12.0 Hz, 2H), 2.28 (d, J = 12.0 Hz, 2H), 1.64-1.74 (m, 2H)。
LCMS;質量計算值:299;MS實驗值:300 [Ms+1]。實驗實例 1-39. 製備化合物 39 ( 4- 胺基 -N'
-( 吲哚啉 -6- 羰基 )-3- 嗎啉基苯磺醯肼 )
步驟1)合成A83
在0℃下,向A72
(1H
-吲哚-6-碳醯肼,500毫克,2.86毫莫耳,1.0當量)於吡啶(5毫升)中的混合物中逐滴添加3-氟-4-硝基苯-1-磺醯氯(686毫克,2.86毫莫耳,1.0當量)於吡啶(2毫升)中的混合物。隨後將混合物在10℃下攪拌3小時。濃縮上述溶液,以得到粗產物,藉由管柱(DCM:MeOH=50:1-20:1)純化所述粗產物,以得到呈黃色固體狀的A83
(3-氟-N'
-(1H
-吲哚-6-羰基)-4-硝基苯磺醯肼,700毫克,產率:64.8%)。
LCMS;質量計算值:378.3;MS實驗值:379.1 [Ms+1]。
步驟2)合成A84
在10℃下向A83
(700毫克,1.85毫莫耳,1.0當量)及K2
CO3
(640毫克,4.64毫莫耳,2.5當量)於DMF(7毫升)中的混合物中添加嗎啉(193毫克,2.22毫莫耳,1.2當量)。隨後將混合物在25℃下攪拌16小時。將上述溶液倒入水(30毫升)中且用EA(30毫升×3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥且濃縮,以得到呈黃色固體狀的A84
(N'
-(1H
-吲哚-6-羰基)-3-嗎啉基-4-硝基苯磺醯肼,600毫克,產率:72.8%)。
LCMS;質量計算值:445.4;MS實驗值:446.1 [Ms+1]。
步驟3)合成A85
在10℃下向A84
(600毫克,1.35毫莫耳,1.0當量)於DCM(5毫升)中的混合物中添加TFA(1毫升)及NaBH3
CN(251毫克,4.04毫莫耳,3.0當量)。隨後將混合物在25℃下攪拌4小時。將上述溶液倒入水(30毫升)中且用EA(30毫升×3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥且濃縮,以得到呈黃色固體狀的A85
(N'
-(吲哚啉-6-羰基)-3-嗎啉基-4-硝基苯磺醯肼,450毫克,粗物質)。
LCMS;質量計算值:447.4;MS實驗值:448.2 [Ms+1]。
步驟4)合成化合物39(4-胺基-N'
-(吲哚啉-6-羰基)-3-嗎啉基苯磺醯肼)
向A85
(450毫克,1.01毫莫耳,1.0當量)於EtOH(5毫升)中的混合物中添加Fe(282毫克,5.05毫莫耳,5.0當量)及飽和NH4
Cl水溶液(1毫升)。隨後將混合物在85℃下攪拌3小時。濃縮上述溶液,隨後添加DMSO(5毫升)且過濾。濾液藉由製備型HPLC純化且凍乾,以得到呈灰白色固體狀的化合物 39
(4-胺基-N'
-(吲哚啉-6-羰基)-3-嗎啉基苯磺醯肼,30毫克,產率7.0%)。1HNMR (DMSO-d6, 400 MHz): δ10.36 (d, J = 4.4 Hz, 1H), 9.21 (d, J = 4.4 Hz, 1H), 7.23-7.27 (m, 2H), 7.03 (d, J = 7.6 Hz, 1H), 6.89 (d, J = 7.6 Hz, 1H), 6.67 (s, 1H), 6.65 (d, J = 8.4 Hz, 1H), 5.63 (br s, 2H), 3.69 (t, J = 4.2 Hz, 4H), 3.42 (t, J = 8.6 Hz, 2H), 2.91 (t, J = 8.6 Hz, 2H),2.63 (t, J = 4.2 Hz, 4H)。
LCMS;質量計算值:417.1;MS實驗值:418.1 [MS+1]。實驗實例 1-40. 製備化合物 40 ( 4- 胺基 -N'
-( 哌嗪 -1- 羰基 ) 苯磺醯肼 )
步驟1)合成A87
在10℃下,向A86
(4-(肼羰基)哌嗪-1-甲酸三級丁酯,1.00公克,4.09毫莫耳,1.0當量)於吡啶(10毫升)中的混合物中逐滴添加含4-硝基苯-1-磺醯氯(906毫克,4.09毫莫耳,1.0當量)的吡啶(5毫升)。隨後將混合物在10℃下攪拌3小時。將上述溶液倒入水(50毫升)中且用EA(50毫升×3)萃取。將合併的有機層用1N HCl(50毫升×2)及鹽水洗滌,經Na2
SO4
乾燥且濃縮,以得到粗產物。將粗產物用EA(5毫升)洗滌,過濾,且真空乾燥固體,以得到呈黃色固體狀的A87
(4-(2-((4-硝基苯基)磺醯基)肼-1-羰基)哌嗪-1-甲酸三級丁酯,800毫克,產率45.5%)。
1HNMR (DMSO-d6, 400 MHz): δ 9.74 (s, 1H), 9.08 (s, 1H), 8.38 (d, J = 8.0 Hz, 2H), 8.03 (d, J = 8.4 Hz, 2H), 3.17 (br s, 8H), 1.40 (s, 9H)。
步驟2)合成A88
向A87
(400毫克,0.93毫莫耳,1.0當量)於THF(10毫升)中的混合物中添加Pd/C(40毫克)。隨後將混合物在10℃下在H2
氣球下攪拌16小時。過濾上述溶液且濃縮濾液,以得到呈黃色固體狀的A88
(4-(2-((4-胺基苯基)磺醯基)肼-1-羰基)哌嗪-1-甲酸三級丁酯,350毫克,產率:94%)。
步驟3)合成化合物40(4-胺基-N'
-(哌嗪-1-羰基)苯磺醯肼)
向A88
(150毫克,0.37毫莫耳,1.0當量)於DCM(5毫升)中的混合物中添加TFA(1毫升)。隨後將混合物在25℃下攪拌3小時。濃縮上述溶液,以得到粗產物。向粗產物中添加MeOH(5毫升),添加K2
CO3
(62毫克,0.45毫莫耳)且在室溫下攪拌1小時。過濾溶液且將溶液藉由製備型HPLC純化並凍乾,以得到呈白色固體狀的化合物 40
(4-胺基-N'
-(哌嗪-1-羰基)苯磺醯肼,50毫克,產率38.7%)。
1HNMR (DMSO-d6, 400 MHz): δ 8.80 (d, J = 2.8 Hz, 1H), 8.28-8.32 (m, 3H), 7.38 (d, J = 8.8 Hz, 2H), 6.56 (d, J = 8.8 Hz, 2H), 5.98 (s, 2H), 3.22 (s, 4H), 2.69 (s, 4H)。
LCMS;質量計算值:299;MS實驗值:300 [MS+1]。實驗實例 1-41. 製備化合物 41 ( 4- 胺基 -3- 嗎啉 基 -N'
-( 哌嗪 -1- 羰基 ) 苯磺醯肼 )
步驟1)合成A89
向A86
(1.50公克,6.14毫莫耳,1.0當量)於吡啶(10毫升)中的混合物中逐滴添加含3-氟-4-硝基苯-1-磺醯氯(1.46公克,6.14毫莫耳,1.0當量)的吡啶(5毫升)。隨後將混合物在10℃下攪拌3小時。將上述溶液倒入水(30毫升)中且用EA(30毫升×3)萃取。將合併的有機層用1N HCl(30毫升×2)及鹽水洗滌,經Na2
SO4
乾燥且濃縮,以得到呈黃色固體狀的A89
(4-(2-((3-氟-4-硝基苯基)磺醯基)肼-1-羰基)哌嗪-1-甲酸三級丁酯,1.5公克,粗物質)。
步驟2)合成A90
在10℃下向A89
(1.50公克,3.35毫莫耳,1.0當量)及K2
CO3
(1.16公克,8.37毫莫耳,2.5當量)於DMF(15毫升)中的混合物中添加嗎啉(350毫克,4.02毫莫耳,1.2當量)。隨後將混合物在25℃下攪拌16小時。將上述溶液倒入水(50毫升)中且用EA(30毫升×3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥且濃縮,以得到粗產物,藉由管柱(DCM/MeOH=50/1-10/1)純化所述粗產物,以得到呈黃色固體狀的A90
(4-(2-((3-嗎啉基-4-硝基苯基)磺醯基)肼-1-羰基)哌嗪-1-甲酸三級丁酯,700毫克,產率:40.6%)。
LCMS;質量計算值:514.55;MS實驗值:516.2[MS+2]。
步驟3)合成A91
向A90
(700毫克,1.36毫莫耳,1.0當量)於THF(10毫升)中的混合物中添加Pd/C(200毫克)。隨後將混合物在H2
(50磅每平方吋)下在室溫下攪拌15分鐘。過濾上述溶液且濃縮濾液,以得到呈黃色固體狀的A91
(4-(2-((4-胺基-3-嗎啉基苯基)磺醯基)肼-1-羰基)哌嗪-1-甲酸三級丁酯,300毫克,粗物質)。
步驟4)合成化合物41(4-胺基-3-嗎啉基-N'
-(哌嗪-1-羰基)苯磺醯肼)
向A91
(200毫克,0.41毫莫耳,1.0當量)於DCM(10毫升)中的混合物中添加TFA(2毫升)。隨後將混合物在室溫下攪拌3小時。將混合物濃縮且藉由製備型HPLC純化並凍乾,以得到呈粉紅色固體狀的化合物 41
(4-胺基-3-嗎啉基-N'
-(哌嗪-1-羰基)苯磺醯肼,20.0毫克,產率12.6%)。
1HNMR (DMSO-d6, 400 MHz): δ 8.92 (d, J = 5.2 Hz, 1H), 8.69-8.75 (m, 2H), 7.23 (d, J = 5.6 Hz, 2H), 6.70 (t, J = 8.6Hz, 1H), 5.68 (s, 2H), 3.78 (s, 4H), 3.39 (s,4H), 2.98 (s, 4H), 2.76 (s, 4H).
LCMS;質量計算值:384;MS實驗值:384.9 [MS+1]。實驗實例 1-42. 製備化合物 42 ( N' -(4- 羥基苯甲醯基 )-2- 甲基噻唑 -4- 磺醯肼 )
步驟1)合成A92
2,2,2-三氯乙醛(20公克,0.13毫莫耳)、乙醯胺(7公克,0.118毫莫耳)及濃硫酸(1.2公克)的經攪拌混合物在100℃下加熱1小時。冷卻後,使反應混合物結晶。將混合物用去離子水濕磨,過濾,用大量水洗滌且自乙醇再結晶,以得到呈白色固體狀的A92
(N
-(2,2,2-三氯-1-羥基乙基)乙醯胺,15公克)。
1HNMR (DMSO_d6, 400 MHz): 8.72 (d, 1H), 7.64 (d, 1H), 5.74-5.70 (m, 1H), 1.92 (s, 3H)。
步驟2)合成A93
歷經3小時的時段,將鋅粉(5公克,78毫莫耳)逐漸添加至A92
(8公克,39毫莫耳)於冰醋酸(50毫升)中的經攪拌懸浮液中。在鋅添加期間,使反應混合物的溫度保持低於40℃。隨後將反應混合物在室溫下攪拌24小時。隨後過濾出沈澱的鋅鹽且用冰醋酸洗滌。在減壓下移除乙酸。將固體殘餘物用去離子水濕磨且再結晶,以得到呈白色固體狀的A93
(N
-(2,2-二氯乙烯基)乙醯胺,3公克)。
1HNMR (DMSO_d6, 400 MHz): 9.87 (d, 1H), 7.21 (d, 1H), 2.03 (s, 3H)。
步驟3)合成A94
將苯甲基硫醇(4公克,32毫莫耳)及三乙胺(3.29公克,32.6毫莫耳)添加至A93
(2公克,13毫莫耳)於2-丙醇(25毫升)中的經攪拌溶液中。將反應混合物在室溫下攪拌48小時。隨後在減壓下移除溶劑,且殘餘物用水濕磨,從而產生結晶固體。藉由自2-丙醇或乙醇再結晶來純化粗產物,以得到呈白色固體狀的A94
(N
-(1-(苯甲硫基)-2,2-二氯乙基)乙醯胺,2.5公克)。
1HNMR (DMSO_d6, 400 MHz): 8.72(d, 1H), 7.23-7.25 (m, 5H), 6.42 (d, 1H), 5.40 (dd, 1H), 3.87 (q, 2H), 1.93 (S, 3H)。
步驟4)合成A95
將勞森試劑(7.6公克,18.8毫莫耳)添加至A94
(5毫莫耳)於甲苯(30毫升)中的經攪拌溶液中。使反應混合物回流8小時,且隨後在減壓下移除溶劑。將殘餘物用10% NaOH水溶液濕磨,從而調整至pH 9。將粗產物過濾,乾燥且自2-丙醇再結晶。將液體產物用二氯甲烷萃取,以得到呈黃色油狀的A95
(4-(苯甲硫基)-2-甲基噻唑,粗物質,2.5公克)。
1HNMR (DMSO_d6, 400 MHz): 7.44 (s, 1H), 7.30-7.20 (m, 5H), 4.04 (s, 2H), 2.59 (S, 3H).
步驟5)合成化合物A96
在0℃下向A95
(粗物質,1公克)於乙酸(10毫升)中的溶液中添加NCS(3公克)及水(2毫升)。將反應混合物在室溫下攪拌隔夜。將反應混合物用10% NaHCO3
水溶液濕磨以調節至pH=8,用DCM(30毫升×3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥且濃縮,以得到粗產物。藉由穿過矽膠來純化殘餘物,以得到呈黃色油狀的A96
(2-甲基噻唑-4-磺醯氯,100毫克)。
1HNMR (CDCl3, 400 MHz): 8.33 (s, 1H), 2.86 (S, 3H)。
步驟6)合成化合物42(N'
-(4-羥基苯甲醯基)-2-甲基噻唑-4-磺醯肼)
將A96
(100毫克,0.5毫莫耳)及A2
(4-羥基苯甲醯肼,80毫克,0.5毫莫耳)於吡啶(20毫升)中的混合物在80℃下攪拌隔夜。將上述溶液倒入水(30毫升)中且用EA(30毫升×3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥且濃縮,以得到粗產物。藉由製備型HPLC純化殘餘物,以得到呈灰白色固體狀的化合物 42
(N'
-(4-羥基苯甲醯基)-2-甲基噻唑-4-磺醯肼,30毫克)。
1HNMR (DMSO-d6, 400 MHz): 10.53 (s, 1H), 10.27 (s, 1H), 10.13 (s, 1H), 8.02 (s, 1H), 7.63 (d, 2H), 6.80 (d, 2H), 2.70 (s, 3H)。
LCMS;質量計算值:313.3;MS實驗值:314.0 [MS+1]。實驗實例 1-43. 製備化合物 43 ( (1S,4S)-4- 胺基 -N'
-(4- 羥基苯甲醯基 ) 環己烷 -1- 磺醯肼 )
步驟1)合成A98
向A97
(((1r,4r)-4-羥基環己基)胺基甲酸三級丁酯,27公克,126毫莫耳,1.0當量)於吡啶(100毫升)中的混合物中逐份添加4-甲基苯磺醯氯(28.6公克,151毫莫耳,1.2當量),將混合物在室溫下攪拌隔夜。在真空中移除吡啶,藉由矽膠管柱層析純化殘餘物,以得到呈白色固體狀的A98
(4-甲基苯磺酸(1r,4r)-4-((三級丁氧基羰基)胺基)環己酯,40公克,86.4%)。
步驟2)合成A99
用硫代乙酸鉀(9.3公克,81.3毫莫耳,3.0當量)處理A98
(10.0公克,27.1毫莫耳,1.0當量)於DMF(100毫升)中的溶液且將反應混合物在氮氣下在60℃下攪拌4小時。將反應混合物用鹽水(200毫升)淬滅,且用EtOAc(100毫升×2)萃取。將合併的有機物乾燥且在減壓下濃縮,藉由矽膠管柱層析純化粗產物,以得到呈白色固體狀的A99
(S-((1s,4s)-4-((三級丁氧基羰基)胺基)環己基)硫乙酸酯,3.0公克,40.5%)。
步驟3)合成A100
在0℃下向A99
(2.50公克,9.16毫莫耳,1.0當量)於DCM(30毫升)及水(30毫升)中的溶液中鼓泡氯氣持續30分鐘。分離兩個層,將DCM層用硫代硫酸鈉水溶液及鹽水洗滌,經硫酸鈉乾燥,過濾且濃縮,以得到呈棕色固體狀的粗A100
(((1s,4s)-4-(氯磺醯基)環己基)胺基甲酸三級丁酯)。
步驟4)合成A101
將4-羥基苯甲醯肼(A2
,2.76公克,18.2毫莫耳,2.0當量)於吡啶(10毫升)中的溶液逐滴添加至A100
(粗物質)於DCM(5毫升)中的溶液中,將混合物在室溫下攪拌2小時。在真空中移除溶劑且藉由矽膠管柱層析純化粗產物,以得到呈白色固體狀的A101
(((1s,4s)-4-((2-(4-羥基苯甲醯基)肼基)磺醯基)環己基)胺基甲酸三級丁酯,0.2公克,對於2個步驟為5.3%)。
步驟5)合成化合物43((1s,4s)-4-胺基-N'
-(4-羥基苯甲醯基)環己烷-1-磺醯肼)
將A101
(200毫克,4.2毫莫耳,1.0當量)溶解於TFA(1毫升)及DCM(5毫升)的混合物中,攪拌2小時。在真空中濃縮混合物且溶解於MeOH中,添加NH3/MeOH至pH=9,在真空中濃縮溶劑,將殘餘物溶解於MeOH中,藉由製備型HPLC純化且冷凍乾燥,以得到呈黃色固體狀的化合物 43
((1s,4s)-4-胺基-N'
-(4-羥基苯甲醯基)環己烷-1-磺醯肼,20毫克,13.2%)。
1HNMR (CD3OD, 400 MHz): δ 7.749 (d, J=8.8Hz, 2H), 6.862 (d, J=8.4Hz, 2H), 3.286-3.331 (m, 2H), 2.315-2.350 (m, 2H), 1.995-2.153 (m, 4H), 1.855-1.918 (m, 2H)。
LCMS;MS計算值:313.11;MS實驗值:313.9([M+1]+)。實驗實例 1-44. 製備化合物 44 ( (1R
,4R
)-4- 胺基 -N'
-(4- 羥基苯甲醯基 ) 環己烷 -1- 磺醯肼 )
藉由使用((1s,4s)-4-羥基環己基)胺基甲酸三級丁酯代替A97作為起始物質,以與實驗實例 1-45
中相同的方式合成呈白色固體狀的化合物 44
(26.7%產率)。
1HNMR (CD3OD, 400 MHz): δ 7.750 (d, J=8.8Hz, 2H), 6.868 (d, J=8.4Ha, 2H), 3.042-3.174 (m, 2H), 2.567 (d, J=12.4Hz, 2H), 2.180 (d, J=12.4Hz, 2H), 1.680-1.784 (m, 2H), 1.410-1.514 (m, 2H)。
LCMS;MS計算值:313.11;MS實驗值:313.9([M+1]+)。實驗實例 1-45. 製備化合物 45 ( 4-((2-(4- 羥基苯甲醯基 ) 肼基 ) 磺醯基 )-5- 甲基呋喃 -2- 甲酸)
步驟1)合成A102
在用冰水淬滅之前將5-甲基呋喃-2-甲酸(10公克,80毫莫耳)、氯磺酸(30毫升)的經攪拌混合物在50℃下攪拌3小時。用DCM萃取水層,且將合併的有機萃取物用鹽水洗滌,經無水硫酸鈉乾燥,且在真空中濃縮,以得到呈黃色固體狀的化合物A102
(14公克)。
1HNMR (DMSO_d6, 400 MHz): 13.95 (s, 1H), 6.97 (s, 1H), 2.50 (s, 3H)。
步驟2)合成化合物45(4-((2-(4-羥基苯甲醯基)肼基)磺醯基)-5-甲基呋喃-2-甲酸)
將化合物A102
(5公克,22.3毫莫耳)及化合物A2
(3.4公克,22.3毫莫耳)於吡啶(50毫升)中的混合物在60℃下攪拌隔夜。將上述溶液倒入水(30毫升)中且用EA(30毫升×3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥且濃縮,以得到粗產物。藉由製備型HPLC純化殘餘物,以得到呈黃色固體狀的化合物 45
(4-((2-(4-羥基苯甲醯基)肼基)磺醯基)-5-甲基呋喃-2-甲酸,1.3公克)
1HNMR (DMSO-d6, 400 MHz): 13.5 (brs, 1H), 10.47 (s, 1H), 10.14 (s, 1H), 10.03 (s, 1H), 7.63 (d, 2H), 7.18 (s, 1H), 6.79 (s, 2H), 3.17 (s, 3H)。實驗實例 1-46 製備化合物 46 ( N' -(4- 羥基苯甲醯基 ) 吡咯啶 -3- 磺醯肼 )
步驟1)合成A104
在0℃下向A103
(5.00公克,26.7毫莫耳,1.0當量)及TEA(5.40公克,53.4毫莫耳,2.0當量)於DCM(50毫升)中的攪拌溶液中逐滴添加甲磺醯氯(4.59公克,40.1毫莫耳,1.5當量)。將混合物在室溫下攪拌2小時。混合物藉由H2
O(100毫升)淬滅且用DCM(100毫升×2)萃取。將合併的有機層用鹽水(100毫升)洗滌,乾燥,濃縮。藉由管柱層析(PE/EA=100:1-10:1)純化殘餘物,以得到呈黃色油狀的A104
(5.0公克,產率70.6%)。(PE/EA=10:1,Rf=0.6)
步驟2)合成A105
將A104
(5.00公克,18.9毫莫耳,1.0當量)及硫代乙酸鉀(4.30公克,37.7毫莫耳,2.0當量)於DMF(50毫升)中的混合物在70℃下攪拌16小時。將混合物用H2
O(200毫升)處理且用EA(200毫升×2)萃取。將合併的有機層用H2
O(100毫升×3)、鹽水(100毫升)洗滌,乾燥,濃縮。藉由管柱層析純化殘餘物(PE/EA=50:1-5:1),以得到呈褐色固體狀的A105
(2.0公克,產率43.4%)。
步驟3)合成A106
向A105
(2.00公克,8.16毫莫耳,1.0當量)於乙酸(AcOH 30毫升)及H2
O(30毫升)中的經攪拌溶液中添加N
-氯代二醯亞胺(5.45公克,40.8毫莫耳,5.0當量)。將混合物在室溫下攪拌16小時。將混合物濃縮且藉由管柱層析(PE/EA=50:1-1:1)純化,以得到呈黃色油狀的A106
(1.0公克,產率45.6%)。(PE/EA=3:1,Rf=0.5)
1HNMR (CDCl3, 400 MHz): δ 4.28-4.31 (m, 1H), 4.00-4.02 (m, 1H), 3.85-3.95 (m, 1H), 3.66-3.75 (m, 1H), 3.52-3.58 (m, 1H), 2.63 (br s, 1H), 2.44-2.54 (m, 1H), 1.49 (s, 9H)。
步驟4)合成A107
在0℃下向4-羥基苯甲醯肼(0.56公克,3.71毫莫耳,1.0當量)於吡錠鎓(30毫升)中的經攪拌溶液中逐滴添加A106
(1.00公克,3.71毫莫耳,1.0當量)於吡錠鎓(10毫升)中的溶液。將混合物在室溫下攪拌6小時。將混合物濃縮且藉由管柱層析(DCM/MeOH=100:1-10:1)純化,以得到呈黃色油狀的A107
(0.50公克,產率34.9%)。(DCM/MeOH=10:1,Rf=0.4)
步驟5)合成化合物46(N'
-(4-羥基苯甲醯基)吡咯啶-3-磺醯肼)
在0℃下,向A107
(500毫克,1.30毫莫耳,1.0當量)於DCM(10毫升)中的混合物中添加TFA(4毫升)。將混合物在室溫下攪拌4小時。濃縮上述溶液且藉由製備型HPLC純化並凍乾,以得到呈黃色固體狀的化合物 46
(N'
-(4-羥基苯甲醯基)吡咯啶-3-磺醯肼,30毫克,產率7.0%)。(TLC:N/A)
1HNMR (DMSO-d6, 400 MHz): δ 10.47 (br s, 2H), 8.25 (s, 1H), 7.75 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 3.67-3.72 (m, 1H), 3.19-3.21 (m, 2H), 2.89-2.91 (m, 1H), 2.83-2.85 (m, 1H), 2.07-2.10 (m, 2H)。實驗實例 1-47. 製備化合物 47 ( N' -(4- 羥基苯甲醯基 )-1H
- 吡咯并 [2,3-b] 吡啶 -2- 磺醯肼 )
步驟1)合成A109
在0℃下,向1H
-吡咯并[2,3-b]吡啶(A108
,6.00公克,50.8毫莫耳,1.0當量)於THF(60毫升)中的混合物中添加NaH(2.44公克(60%w/w),60.9毫莫耳,1.2當量)且在0℃下攪拌1小時。隨後向溶液中逐滴添加含TsCl(9.65公克,50.8毫莫耳,1.0當量)的THF(20毫升)。將溶液攪拌16小時。將上述溶液倒入水(200毫升)中且用EA(100毫升×3)萃取。將合併的有機層經Na2
SO4
乾燥且濃縮,以得到粗產物,將所述粗產物用PE(30毫升)洗滌1小時,過濾,且收集固體。在真空中乾燥固體,以得到呈白色固體狀的A109
(11.0公克,產率79.5%)。(TLC:N/A)
*LCMS;質量計算值:272.32;MS實驗值:273.1 [MS+1]。
步驟2)合成A110
在-76℃下,向A109
(2.00公克,7.35毫莫耳,1.0當量)於THF(20毫升)中的混合物中逐滴添加n-BuLi(3.24毫升,8.08毫莫耳,1.1當量)。將混合物在-76℃下攪拌1小時。隨後將混合物在-76℃至10℃下在SO2
氣球下攪拌1小時,且濃縮溶液。在20℃下將含殘餘物的DCM(30毫升)添加至NCS(1.58公克,11.7毫莫耳,1.6當量)中,隨後將混合物在20℃下攪拌1小時。將上述溶液倒入水(50毫升)中且用DCM(50毫升×3)萃取。將合併的有機層經Na2
SO4
乾燥且濃縮,以得到呈黃色固體狀的A110
(1.30公克,產率47.8%)。LCMS;質量計算值:370.82;MS實驗值:371.0 [MS+1]。
步驟3)合成A111
在10℃下,向A110
(1.30公克,3.51毫莫耳,1.0當量)於吡啶(10毫升)中的混合物中逐滴添加含4-羥基苯甲醯肼(A2
,587毫克,3.86毫莫耳,1.1當量)的吡啶(5 mL)。隨後將混合物在10℃下攪拌3小時。將上述溶液倒入水(50毫升)中且用EA(50毫升×3)萃取。將合併的有機層用1N HCl(50毫升×2)及鹽水(50毫升)洗滌,經Na2
SO4
乾燥且濃縮,以得到粗產物。將粗產物用EA(5毫升)洗滌,過濾,且真空乾燥固體,以得到呈黃色固體狀的A111
(600毫克,產率35.3%)。(TLC:N/A)
LCMS;質量計算值:486.51;MS實驗值:487.1 [MS+1]。
步驟4)合成化合物47(N'
-(4-羥基苯甲醯基)-1H
-吡咯并[2,3-b
]吡啶-2-磺醯肼)
向A111
(350毫克,0.71毫莫耳,1.0當量)於MeOH(6毫升)中的混合物中添加濃HCl(2毫升)。隨後將混合物在60℃下攪拌3小時。濃縮上述溶液,且粗產物藉由製備型HPLC純化且凍乾,以得到呈白色固體狀的化合物 47
(N'
-(4-羥基苯甲醯基)-1H
-吡咯并[2,3-b
]吡啶-2-磺醯肼,20毫克,產率8.36%)。(TLC:N/A)
1HNMR (DMSO-d6, 400 MHz): δ 12.61 (s, 1H), 10.45 (s, 1H), 10.11 (br s, 1H), 9.90 (d, J=2 Hz, 1H), 8.40-8.42 (m, 1H), 8.08-8.10 (m, 1H), 7.62 (d, J=8.8 Hz, 2H), 7.16-7.19 (m, 1H), 7.13 (s, 1H), 6.77 (d, J=8.8 Hz, 2H)。
LCMS;質量計算值:332;MS實驗值:333 [MS+1]。實驗實例 1-48. 製備化合物 48 ( 4- 羥基 -N'
-(4- 甲氧基苯甲基 ) 苯甲醯肼 )
藉由與實驗實例1-19中相同的製備方法,使用1-(溴甲基)-4-甲氧基苯代替1-(溴甲基)-4-硝基苯來獲得化合物 48
。實驗實例 1-49. 製備化合物 49 ( N' -(4- 胺基苯甲基 )-2,3- 二氫 -1H
- 茚 -2- 碳醯肼 )
藉由與實驗實例1-19中相同的製備方法,使用A60
(2,3-二氫-1H-茚-2-碳醯肼)代替A2
作為起始物質來獲得化合物 49
。實驗實例 1-50. 製備化合物 50 ( 4- 胺基 -N
-(2-(4- 羥基苯基 )-2- 側氧基乙基 )-3- 嗎啉基苯磺醯胺 )
藉由與實驗實例1-12中類似的製備方法,使用3-氟-4-硝基苯磺醯氯代替實驗實例1-12的步驟3中的4-硝基苯-1-磺醯氯來獲得化合物 50
。實驗實例 1-51. 製備化合物 51 ( 3,5- 二胺基 -N
-(2-(4- 羥基苯基 )-2- 側氧基乙基 ) 苯磺醯胺 )
藉由與實驗實例1-12中類似的製備方法,使用3,5-二硝基苯磺醯氯(A20)代替實驗實例1-12的步驟3中的4-硝基苯-1-磺醯氯來獲得化合物 51
。實驗實例 1-52. 製備化合物 52 ( 2-((4- 胺基苯基 ) 磺醯基 )-N
-(3- 羥基苯基 ) 肼 -1- 甲醯胺 )
藉由與實驗實例1-27相同的製備方法,使用3-異氰基苯酚代替實驗實例1-27的步驟3中的異氰酸基苯來獲得化合物 52 實驗實例 1-53. 製備化合物 53 ( 2-((4- 胺基 -3- 嗎啉基苯基 ) 磺醯基 )-N
- 苯肼 -1- 甲醯胺 )
藉由與實驗實例1-27中類似的製備方法,使用3-氟-4-硝基苯磺醯氯代替4-硝基苯磺醯氯作為起始物質來獲得化合物 53
。實驗實例 1-54. 製備化合物 54 ( 4- 羥基 -N
-(((4- 甲氧基苯基 ) 磺醯基 ) 甲基 ) 苯甲醯胺 )
藉由與實驗實例1-16中相同的製備方法,使用4-甲氧基苯硫酚代替4-硝基苯硫醇來獲得化合物 54
。實驗實例 1-55. 製備化合物 55 ( N -(((4- 胺基苯基 ) 磺醯基 ) 甲基 )-[1,1'- 聯苯 ]-4- 甲醯胺 )
藉由與實驗實例1-16中類似的製備方法,使用[1,1`-聯苯]-4-羧醯胺代替實驗實例1-16的中間物A28作為起始物質來獲得化合物 55
。實例 2. 結合分析實驗 實例 2-1 確認肌肉肌動蛋白是否為 Arg/N- 降解決定子路徑基質
在其中維持5%二氧化碳的培育箱中使用含有10% FBS及1%鏈黴素/青黴素的DMEM介質培養L6細胞株(其為大鼠肌原性細胞),且將細胞在培養之後等分至12孔盤中。將細胞另外培養24小時以便完全附著至盤的表面。為確認MG132是否增加UBR1結合,在單獨用MG132(10微莫耳)處理24小時之後收集細胞。為自所收集的細胞提取蛋白質,將50微升的裂解緩衝液(20 mM Tris(pH 7.4)、150 mM NaCl、1% Triton-X-100、2 mM NaF、2 mM EDTA、2 mM b-甘油磷酸鹽、5 mM原釩酸鈉、1 mM PMSF、抗纖維蛋白溶酶肽、抑肽酶)注射至各樣品中,且裂解細胞。基於所量測的總蛋白質濃度,將樣品緩衝液添加至各樣品中且使混合物在100℃下反應5分鐘。在自完全反應的樣品取出5微升且等分至丙烯醯胺凝膠的各孔中之後,執行免疫墨點法,且實驗結果示出在[圖1]中。
對於免疫墨點法,根據三個或超過三個獨立實驗示意性展示一代表性實驗。
參看圖1,已確認相較於對照,ACTA1、ACTC1以及ACTG2的含量藉由MG132增加。此外,已確認當UBR蛋白被阻斷基因表現時,ACTA1及ACTG2的含量增加。亦即,可確認肌肉肌動蛋白為Arg/N-降解決定子路徑基質。實例 2-2 藉由活體外轉錄 / 轉譯法確認 R-nsP4 降解的抑制
TnT®快速偶合轉錄/轉譯系統套組用於確認化合物的R-nsP4表現。在使用Transcend Biotin-Lysyl-tRNA、甲硫胺酸、貝他定(bestatin)、TnTquick主混合物及DHFR-Ub-R-nsP4質體製備預混物之後,將預混物與化合物(1微莫耳)混合。在使各樣品在30℃下反應40分鐘之後,向其中添加5X SDS負載染料。在使所得混合物在95℃下反應2分鐘之後,獲取5微升且等分至丙烯醯胺凝膠的各孔中,且隨後執行免疫墨點法,且實驗結果示出在[圖2]中。對於活體外轉錄/轉譯法,根據三個或超過三個獨立實驗示意性展示一代表性實驗。
參看圖2,可確認相較於對照,R-nsP4的含量藉由化合物2、化合物3、化合物7、化合物12、化合物14以及化合物16增加亦即,可確認在用根據本發明的化合物處理的情況下,R-nsP4含量藉由與UBR1結合而增加。實例 2-3 藉由轉染評估胞內 RGS4 降解的抑制
在維持5%二氧化碳的培育箱中使用含有10% FBS及1%鏈黴素/青黴素的DMEM介質培養L6細胞株(其為大鼠肌原性細胞)。為根據用選自本發明化合物的代表性化合物處理來量測UBR1結合強度,將細胞等分至6孔盤中。將細胞另外培養24小時以便完全附著至盤的表面。使Opti-MEM、脂染胺以及RGS4質體反應以進行轉染。在反應完成之後,處理細胞以使得DNA胞內表現。在單獨用化合物(5微莫耳)處理24小時之後收集細胞以確認在24小時之後化合物是否增加UBR1結合。為自所收集的細胞提取蛋白質,將50微升的裂解緩衝液(20 mM Tris(pH 7.4)、150 mM NaCl、1% Triton-X-100、2 mM NaF、2 mM EDTA、2 mM b-甘油磷酸鹽、5 mM原釩酸鈉、1 mM PMSF、抗纖維蛋白溶酶肽、抑肽酶)注射至各樣品中,且裂解細胞。基於所量測的總蛋白質濃度,將樣品緩衝液添加至各樣品中且使混合物在100℃下反應5分鐘。在自完全反應的樣品取出5微升且等分至丙烯醯胺凝膠的各孔中之後,執行免疫墨點法,且實驗結果示出在[圖3]中。對於免疫墨點法,根據三個或超過三個獨立實驗示意性展示一代表性實驗。
參看圖3,可確認相較於對照,RGS4的含量藉由化合物2及化合物3增加。亦即,可確認在用根據本發明的化合物處理的情況下,RGS4含量藉由與UBR1結合而增加。實例 2-4 藉由免疫墨點評估肌肉細胞肌動蛋白降解的抑制
為評估化合物在肌肉細胞中的肌動蛋白降解,在其中維持5%二氧化碳的培育箱中使用含有10% FBS及1%鏈黴素/青黴素的DMEM介質培養L6細胞株(其為大鼠肌原性細胞)。為根據用選自本發明化合物的代表性化合物處理來量測UBR1結合強度,將細胞等分至12孔盤中。將細胞另外培養24小時以便完全附著至盤的表面。在單獨用化合物(5微莫耳)處理24小時之後收集細胞以確認化合物是否增加UBR1結合。為自所收集的細胞提取蛋白質,將50微升的裂解緩衝液(20 mM Tris(pH 7.4)、150 mM NaCl、1% Triton-X-100、2 mM NaF、2 mM EDTA、2 mM b-甘油磷酸鹽、5 mM原釩酸鈉、1 mM PMSF、抗纖維蛋白溶酶肽、抑肽酶)注射至各樣品中,且裂解細胞。基於所量測的總蛋白質濃度,將樣品緩衝液添加至各樣品中且使混合物在100℃下反應5分鐘。在自完全反應樣品獲取5微升且等分至丙烯醯胺凝膠的各孔中之後,執行免疫墨點法,且實驗結果示出在[圖4]、[圖5]、[圖6]、[圖7]、[圖8]以及[圖9]中。對於免疫墨點法,根據三個或超過三個獨立實驗示意性展示一代表性實驗。
參看圖4及圖5,可確認相較於對照,ACTA1的含量藉由化合物1、化合物2、化合物3、化合物4、化合物5、化合物6、化合物7、化合物16、化合物35、化合物36、化合物37、化合物38、化合物39、化合物43、化合物44、化合物45、化合物46及化合物47進一步增加。亦即,可確認在使用根據本發明的化合物處理的情況下,肌肉內蛋白質ACTA1的降解藉由與UBR1結合來抑制。
參看圖6及圖7,可確認相較於對照,ACTA2的含量藉由化合物8、化合物9、化合物18、化合物19、化合物20、化合物21、化合物22、化合物23、化合物24、化合物25、化合物26、化合物27、化合物28、化合物32、化合物33以及化合物34進一步增加。亦即,可確認在使用根據本發明的化合物處理的情況下,肌肉內蛋白質ACTA2的降解藉由與UBR1結合來抑制。
參考圖8,可確認相較於對照,ACTC1的含量藉由化合物41及化合物42進一步增加。亦即,可確認在使用根據本發明的化合物處理的情況下,肌肉內蛋白質ACTC1的降解藉由與UBR1結合來抑制。
參看圖9,可確認相較於對照,ACTG2的含量藉由化合物12、化合物13、化合物14、化合物15、化合物17、化合物29、化合物30以及化合物31進一步增加。亦即,可確認在使用根據本發明的化合物處理的情況下,肌肉內蛋白質ACTG2的降解藉由與UBR1結合來抑制。實例 2-5 藉由免疫沈澱分析評估 UBR 盒結構域結合強度
為評估化合物經由UBR盒結構域與UBR1、UBR2、UBR3以及UBR5的結合強度,在其中維持5%二氧化碳的培育箱中使用含有10% FBS及1%鏈黴素/青黴素的DMEM介質培養L6細胞株(其為大鼠肌原性細胞)。為根據使用選自本發明化合物的代表性化合物處理來量測UBR1結合強度,將細胞等分至100 pi盤中。將細胞另外培養24小時以便完全附著至盤的表面。為確認化合物是否增加UBR1結合,將細胞用單獨的化合物(5毫莫耳)、蛋白酶體抑制劑MG132(10毫莫耳)或陽性對照(5毫莫耳)處理24小時,且隨後收集細胞。為自所收集的細胞提取蛋白質,將50微升的裂解緩衝液(20 mM Tris(pH 7.4)、150 mM NaCl、1% Triton-X-100、2 mM NaF、2 mM EDTA、2 mM b-甘油磷酸鹽、5 mM原釩酸鈉、1 mM PMSF、抗纖維蛋白溶酶肽、抑肽酶)注射至各樣品中,且裂解細胞。基於所量測的總蛋白濃度使各樣品與UBR1抗體反應16小時,且隨後與蛋白質A/G珠粒反應3小時。將樣品緩衝液添加至完全反應的樣品中且使所得混合物在100℃下反應5分鐘。在自完全反應的樣品取出20微升且等分至丙烯醯胺凝膠的各孔中之後,執行免疫墨點法,且實驗結果示出在[圖10]及[圖11]中。對於免疫墨點法,根據三個或超過三個獨立實驗示意性展示一代表性實驗。
參看圖10及圖11,與陽性對照類似,藉由顯示ACTA1、UBR2及ACTA1、UBR3及ACTA1、UBR5及ACTA1的結合強度在用化合物處理細胞時降低的結果可確認化合物2(其為根據本發明的化合物)實際上與UBR蛋白質的UBR盒結構域結合。而UBR1與基質ACTA1之間的結合強度在用DMSO對照組處理細胞時維持且蛋白酶體抑制劑MG132用作陰性對照。
亦即,可確認在用根據本發明的化合物處理的情況下,肌肉內蛋白質ACTG2的降解藉由與UBR1、UBR2、UBR3或UBR5結合來抑制。實例 2-6 藉由 MST 評估 UBR 盒結構域結合強度
1)製備UBR1蛋白質
將對應於人類UBR1的UBR盒的Gln97-Pro168部分(UniProt ID: Q8IWV7)選殖至經修飾的表現載體中,且隨後在大腸桿菌(E.coli)中表現。在使用親和力層析法之後,藉由蛋白酶移除標記,且隨後將Gly-His-Met添加至N末端。在執行離子層析法之後,在10 mM NaCl、20 mM Tris-HCl、2 mM β-巰基乙醇以及pH 7.5的緩衝液組成物中使用凝膠過濾層析法純化UBR1的最終UBR盒蛋白。
2)UBR1 UBR盒蛋白標記
Monolith蛋白標記套組RED-NHS第2代的染料(目錄號MO-L011)具有與一級胺(離胺酸殘基)形成共價鍵的NHS-酯基團。此染料針對配備有RED偵測器的Monolith系列裝置最佳化。根據所提供方案使用此套組來標記純化的UBR1 UBR盒蛋白。
3)使用MST量測UBR1與配體之間是否存在結合
熱泳指代粒子由於溫度梯度而移動的現象。存在於高溫區中的粒子具有比存在於低溫區中的粒子更大的動能,且與具有更大能量的周圍粒子更頻繁地碰撞。因此,粒子自高溫區移動至低溫區。
蛋白質的熱泳通常與蛋白質配體複合物的熱泳不同。此是因為配體的結合改變其大小、電荷以及溶合能。此外,即使配體結合不明顯地改變蛋白質的大小及電荷,MST亦可偵測由配體結合造成的蛋白分子的溶劑熵的變化。因此,使用MST來量測UBR1 UBR盒蛋白與配體化合物的結合,且確認所提供的配體與UBR1 UBR盒結合。(參見圖12至圖19)。
無
圖1示出使用免疫墨點法確認肌肉肌動蛋白是否為Arg/N-降解決定子路徑基質的實驗結果。
圖2示出使用活體外轉錄/轉譯法確認R-nsp4的降解是否被抑制的實驗結果,所述R-nsp4藉由允許化合物(化合物2、化合物3、化合物7、化合物12、化合物14以及化合物16)與UBR1結合而降解。
圖3示出使用免疫墨點法確認RGS4的降解是否被抑制的實驗結果,所述RGS4為胚胎腎細胞中的UBR蛋白的基質且藉由允許化合物(化合物2及化合物3)與UBR1結合而降解。
圖4示出使用免疫墨點法確認化合物(化合物1、化合物2、化合物3、化合物4、化合物5、化合物6、化合物7以及化合物16)是否抑制肌動蛋白的降解的實驗結果,所述肌動蛋白為肌肉細胞中的UBR蛋白的基質。
圖5示出使用免疫墨點法確認化合物(化合物35、化合物36、化合物37、化合物38、化合物39、化合物43、化合物44、化合物45、化合物46以及化合物47)是否抑制肌肉細胞中的肌動蛋白的降解的實驗結果。
圖6示出使用免疫墨點法確認化合物(化合物8、化合物9、化合物18、化合物19、化合物20、化合物21、化合物22、化合物23以及化合物24)是否抑制肌肉細胞中的肌動蛋白的降解的實驗結果。
圖7示出使用免疫墨點法確認化合物(化合物25、化合物26、化合物27、化合物28、化合物32、化合物33以及化合物34)是否抑制肌肉細胞中的肌動蛋白的降解的實驗結果。
圖8示出使用免疫墨點法確認化合物(化合物41及化合物42)是否抑制肌肉細胞中的肌動蛋白的降解的實驗結果。
圖9示出使用免疫墨點法確認化合物(化合物12、化合物13、化合物14、化合物15、化合物17、化合物29、化合物30以及化合物31)是否抑制肌肉細胞中的肌動蛋白的降解的實驗結果。
圖10及圖11示出使用免疫墨點法確認化合物(化合物2)在細胞中與UBR 1、UBR 2、UBR 3以及UBR 5結合的功效的實驗結果。
圖12至圖19示出確認化合物(化合物1、化合物2、化合物5、化合物8、化合物9、化合物11、化合物12以及化合物13)是否與UBR1結合的微尺度熱泳(MST)實驗結果。
Claims (20)
- 一種化合物,具有式1的結構: [式1] 或其鹽, 其中X1 為選擇性的經一或多個R2 取代的或未經取代的苯基、環烷基或雜環基; 各R2 獨立地選自烷基、烷氧基、胺基、胺基烷基、-NO2 、=O、-NHC2H4OH、-C(=NH)NH2、-C(=O)NH2、-C(=O)NHCH3、-C(=O)OH、苯基或雜環烷基; X4 為選擇性的經一或多個R3 取代的或未經取代的苯基、環烷基或雜環基; 各R3 獨立地選自烷基、烷氧基、胺基、鹵基、羥基、烷基胺基、二烷基胺基、-NO2 、-CONR'R''、-CO2 R'、-NHCOR'、苯基或雜環烷基; 各R'及R''獨立地為-H或烷基; X2 為SO2 或CRa Rb ; Ra 及Rb 各自獨立地為H或CH3 ; X3 為NH或CH2 ; B1 為CH2 或NH; A1 為CH2 或NH。
- 如請求項1所述的化合物, 其中式1的所述-X2 -B1 -X3 由下述者所組成的族群中選出:SO2 -NH-NH、-SO2 -NH-CH2 、-SO2 -CH2 -NH以及-CH2 -NH-NH。
- 如請求項1至請求項6中任一項所述的化合物, 其中所述各X1 及X4 獨立地為經取代的或未經取代的苯基、環烷基或雜環基; 其中各X1 及X4 獨立地選自經取代的或未經取代的苯基、環己基、環戊基、呋喃基、噻唑基、1H-吡唑基、吡咯啶基、哌啶基、哌嗪基、嗎啉基、吲哚啉基、1H-吲哚啉基、1H-吲唑基、異吲哚啉基、吲哚啉-2-酮基、2,3-二氫-1H-茚基以及1H-吡咯并吡啶基。
- 如請求項1至請求項6中任一項所述的化合物, 其中所述各R2 獨立地選自甲基、乙基、胺基、胺基烷基、胺基(羥基烷基)、甲氧基、乙氧基、-C(=NH)NH2、-C(=O)NH2、-C(=O)NHCH3、-C(=O)OH、苯基、吡咯啶基、哌嗪基、哌啶基及嗎啉基。
- 如請求項8所述的化合物, 其中所述R2 為胺基。
- 如請求項1至請求項6中任一項所述的化合物, 其中所述每各R3 獨立地選自羥基、氟、氯、溴、胺基、甲基、乙基、異丙基、甲氧基、乙氧基、異丙氧基、烷基胺基、二烷基胺基、-NO2、-C(=O)NH2、-CO2R'、-NHCOR'、-CONR'R''以及苯基; 各R'及R''獨立地為-H或烷基。
- 如請求項11所述的化合物, 其中所述R3 為羥基。
- 如請求項3所述的化合物, 其中所述化合物選自下述者: N'-(4-羥基苯甲醯基)-4-甲基苯磺醯肼; 4-胺基-N'-(4-羥基苯甲醯基)苯磺醯肼; 4-胺基-N'-(4-羥基苯甲醯基)-3-嗎啉基苯磺醯肼; N'-(4-羥基苯甲醯基)-2-側氧基吲哚啉-5-磺醯肼;N' -(4-羥基苯甲醯基)吲哚啉-5-磺醯肼; N'-([1,1'-聯苯]-4-羰基)-4-胺基苯磺醯肼; N'-([1,1'-聯苯]-3-羰基)-4-胺基苯磺醯肼; 3-胺基-N'-(4-羥基苯甲醯基)苯磺醯肼; 4-(1-胺基乙基)-N'-(4-羥基苯甲醯基)苯磺醯肼; 3,5-二胺基-N'-(4-羥基苯甲醯基)苯磺醯肼; N'-(4-羥基苯甲醯基)-4-((2-羥基乙基)胺基)苯磺醯肼;N' -(4-羥基苯甲醯基)-4-甲氧基苯磺醯肼; 4-((2-(4-羥基苯甲醯基)肼基)磺醯基)苯甲脒; 4-((2-(4-羥基苯甲醯基)肼基)磺醯基)苯甲醯胺; 6-胺基-N'-(4-羥基苯甲醯基)-[1,1'-聯苯]-3-磺醯肼; 4-(2-((4-胺基苯基)磺醯基)肼-1-羰基)苯甲醯胺; 4-胺基-N'-(1H-吲哚-3-羰基)苯磺醯肼; 4-胺基-N'-(4-羥基苯甲醯基)-3-(吡咯啶-1-基)苯磺醯肼;N' -(4-羥基苯甲醯基)-4-硝基-3-(吡咯啶-1-基)苯磺醯肼; 4-胺基-N' -(4-羥基苯甲醯基)-3-(哌啶-1-基)苯磺醯肼;N' -(4-羥基苯甲醯基)-1H -吡唑-4-磺醯肼;N' -(4-羥基苯甲醯基)吲哚啉-4-磺醯肼;N' -(4-羥基苯甲醯基)-1H -吲哚-4-磺醯肼; 2-((4-胺基苯基)磺醯基)-N-苯肼-1-甲醯胺; 4-胺基-N' -(1H -吲哚-4-羰基)-3-嗎啉基苯磺醯肼; 4-胺基-N' -(吲哚啉-4-羰基)苯磺醯肼; 4-胺基-N' -(4-羥基苯甲醯基)-3-(哌嗪-1-基)苯磺醯肼; 4-胺基-N' -(2,3-二氫-1H -茚-2-羰基)苯磺醯肼; 4-胺基-N' -(異吲哚啉-2-羰基)苯磺醯肼;N' -(4-羥基苯甲醯基)-1H -吲哚-2-磺醯肼; 4-胺基-N' -(2-苯基乙醯基)苯磺醯肼;N' -(4-羥基苯甲醯基)-1H -吲唑-3-磺醯肼; 4-胺基-N'-(吲哚啉-6-羰基)苯磺醯肼; 4-胺基-N' -(吲哚啉-3-羰基)苯磺醯肼;N' -(4-羥基苯甲醯基)哌啶-4-磺醯肼; 4-胺基-N' -(吲哚啉-6-羰基)-3-嗎啉基苯磺醯肼; 4-胺基-N' -(哌嗪-1-羰基)苯磺醯肼; 4-胺基-3-嗎啉基-N' -(哌嗪-1-羰基)苯磺醯肼;N' -(4-羥基苯甲醯基)-2-甲基噻唑-4-磺醯肼; (1S,4S)-4-胺基-N' -(4-羥基苯甲醯基)環己烷-1-磺醯肼; (1R,4R)-4-胺基-N' -(4-羥基苯甲醯基)環己烷-1-磺醯肼; 4-((2-(4-羥基苯甲醯基)肼基)磺醯基)-5-甲基呋喃-2-甲酸;N' -(4-羥基苯甲醯基)吡咯啶-3-磺醯肼;N' -(4-羥基苯甲醯基)-1H -吡咯并[2,3-b]吡啶-2-磺醯肼; 2-((4-胺基苯基)磺醯基)-N-(3-羥基苯基)肼-1-甲醯胺; 2-((4-胺基苯基)磺醯基)-N -苯肼-1-甲醯胺;以及 2-((4-胺基-3-嗎啉基苯基)磺醯基)-N-苯肼-1-甲醯胺。
- 如請求項14所述的化合物, 其中所述化合物選自下述者: 4-胺基-N' -(4-羥基苯甲醯基)苯磺醯肼; 2-((4-胺基苯基)磺醯基)-N -苯肼-1-甲醯胺; 4-胺基-N' -(4-羥基苯甲醯基)-3-嗎啉基苯磺醯肼;以及 4-胺基-N' -(1H -吲哚-4-羰基)-3-苯甲醯磺醯肼。
- 如請求項4所述的化合物, 其中所述化合物選自下述者:N' -(4-胺基苯甲基)-4-羥基苯甲醯肼; 4-羥基-N'-(4-甲氧基苯甲基)苯甲醯肼;以及 N'-(4-胺基苯甲基)-2,3-二氫-1H-茚-2-碳醯肼。
- 如請求項5所述的化合物, 其中所述化合物選自下述者: 4-胺基-N -(2-(4-羥基苯基)-2-側氧基乙基)苯磺醯胺; 4-胺基-N-(2-(4-羥基苯基)-2-側氧基乙基)-3-嗎啉基苯磺醯胺;以及 3,5-二胺基-N-(2-(4-羥基苯基)-2-側氧基乙基)苯磺醯胺。
- 如請求項6所述的化合物, 其中所述化合物選自下述者:N -(((4-胺基苯基)磺醯基)甲基)-4-羥基苯甲醯胺; 4-羥基-N-(((4-甲氧基苯基)磺醯基))甲基)苯甲醯胺;以及 N-(((4-胺基苯基)磺醯基)甲基)-[1,1'-聯苯]-4-甲醯胺。
- 一種用於治療UBR相關疾病的醫藥組成物, 其中所述組成物包括如請求項1至請求項6中任一項所述的化合物或其醫藥學上可接受的鹽。
- 如請求項19所述的用於治療UBR相關疾病的醫藥組成物, 其中所述UBR相關疾病包括由肌肉萎縮症(貝克爾(Becker)、先天性、杜興氏(Duchenne)、遠端型、埃-德二氏(Emery-Dreifuss)、面肩臂、肢帶型、肌強直性、眼咽部(ocuophargyngeal))引起的肌肉損失;由肌肉損失或降解介導的肌肉萎縮疾病,包含肌肉減少症或癌症惡病質;由過度的蛋白質降解引起的疾病,包含脂肪肉瘤、囊腫纖維化、約翰遜-布利澤德症候群(Johanson-Blizzard syndrome)、阻塞性尿路疾病(尿道阻塞序列);自體免疫性胰臟炎;或與UBR盒及UBR蛋白相關的已知疾病,包含尤塞氏症候群(Usher syndrome)。
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