TWI820077B - 治療涉及酸性或缺氧性患病組織之疾病之化合物、組合物及方法 - Google Patents
治療涉及酸性或缺氧性患病組織之疾病之化合物、組合物及方法 Download PDFInfo
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- TWI820077B TWI820077B TW108100452A TW108100452A TWI820077B TW I820077 B TWI820077 B TW I820077B TW 108100452 A TW108100452 A TW 108100452A TW 108100452 A TW108100452 A TW 108100452A TW I820077 B TWI820077 B TW I820077B
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本發明係關於治療具有酸性或缺氧性患病組織之疾病之化合物,及包含該等化合物之醫藥組合物,以及用於製備及使用該等化合物及組合物之方法。
Description
本發明係關於治療涉及酸性或缺氧性患病組織之疾病(包括癌症、心血管疾病(諸如中風及心肌梗塞)及長期神經退化性疾病)之治療性化合物及醫藥組合物,及關於其使用及製造之方法。
缺氧及酸中毒係許多疾病過程(包括癌症)之生理標誌。在癌症中,缺氧係造成實體腫瘤內的酸環境發展的一種機制。因此,必須從細胞移去氫離子(例如,藉由質子泵)以維持細胞內的正常pH。由於氫離子之此種輸出,因此相較於正常細胞,癌細胞具有跨細胞膜脂質雙層增加之pH梯度及細胞外環境中減低之pH。
癌症係以細胞生長之異常控制為特徵之疾病群。估計僅在美國每年癌症發病率超過160萬。雖然使用手術、放射、化療及激素以治療癌症,但其仍係美國第二主要死亡原因。估計每年約600,000美國人將死於癌症。
藉由全身投與藥劑治療人類癌症通常藉由減慢或終止為癌細胞特徵之不受控制的複製起作用。此等藥劑之一種類別為DNA修復抑制劑。然而,此減慢或終止不僅影響癌細胞之複製,而且影響非癌細胞之複製,此導致此種癌症治療之熟知的非所欲副作用。極度期望將此等藥劑選擇性地遞送至目標癌細胞且最小化或避免因全身投與引起的副作用。
PARP酵素家族(包括聚(ADP-核糖)聚合酶(PARP-1)及相關酵素PARP-2及PARP-3(統稱為「PARP」))為DNA單股斷裂之修復(尤其藉由鹼基切除修復途徑)中的重要元件。若單股斷裂未於DNA複製前修復,則可能形成雙股斷裂。雙股斷裂數越來越多的細胞變得更依賴於其他修復途徑,諸如同源重組,及(若單股斷裂繼續未被修復)該等細胞死亡。
已開發PARP之抑制劑且繼續開發為抗癌藥。因為此等抑制劑阻止DNA單股斷裂之修復,故其等在治療癌症中具有多種作用。(參見,例如,Nicola J. Curtin及Ricky A. Sharma – 「PARP Inhibitors for Cancer Treatment」,Cancer Drug Discovery and Development,第83卷,Humana Press 2015。)
PARP抑制劑可用於治療相比正常細胞更依賴於PARP之癌症形式(所謂的「PARP敏感性」癌症)。例如,具有同源重組缺陷(HRD)(諸如涉及BRCA1及BRCA2基因之缺陷)之患者有益地以PARP抑制劑呈單藥療法或以與其他藥劑組合的方式治療。由於經PARP抑制之細胞之DNA修復及存活極度地依賴於HR,故帶有BRCA相關突變之患者(其展現HRD)極適合用PARP抑制劑治療。
雖然PARP抑制劑可用於治療癌症,但該等化合物亦展現副作用。PARP副作用(其包括嚴重血液及胃腸道不良反應及潛在致命性急性骨髓性白血病)係極度不期望的。
預期其他DNA修復抑制癌症療法在全身性投與時類似地展現非所欲的副作用。此種其他DNA修復抑制癌症療法包括彼等針對蛋白激酶共濟失調毛細血管擴張症突變(ATM)、ATM-Rad3相關蛋白激酶(ATR)及核絲胺酸/蘇胺酸蛋白激酶DNA-PK之療法。若受此等機制作用之化合物可選擇性地遞送至癌細胞且因此避免對正常細胞產生非所欲效應,則癌症療法將顯著有益。
此外,PARP抑制劑於治療除癌症外之藉由PARP在除DNA修復之外的功能(諸如參與調節凋亡誘導因子(AIF)之粒腺體-至-核移位或參與調節與發炎相關之蛋白質之表現)中之可能作用之其他疾病(包括心血管及發炎疾病)中具有潛在效用。(參見,例如,Pacher及Szabo – 「Role of Poly (ADP-ribose) polymerase 1 (PARP-1) in Cardiovascular Diseases: The Therapeutic Potential of PARP Inhibitors,Cardiovasc Drug Rev. 2007;25(3):235-260)。PARP抑制劑優先遞送至此等患病組織將同樣係有益的。
本發明提供尤其一種式(I)化合物:
或其醫藥上可接受之鹽,其中成分變量係如本文中所定義。
一般而言,本發明提供(1)包含(諸如)經含雙硫鍵之連接子或將於細胞內環境中裂解之其他連接子連接在一起之治療性分子(例如,R7
)及pH-敏感性(或pH-依賴性)肽(例如,R8
)之化合物,(2)包含此等化合物及醫藥上可接受之載劑之醫藥組合物,(3)於人類及其他哺乳動物之涉及酸性及/或缺氧性細胞之疾病及病況之治療中使用此等化合物及組合物之方法,及(4)製備該等化合物及組合物之方法及可用於該等方法中之中間物。
本發明進一步提供一種醫藥組合物,其包含本發明之化合物或其醫藥上可接受之鹽及至少一種醫藥上可接受之載劑或賦形劑。
本發明亦提供一種藉由對需要此治療的人類或其他哺乳動物投與治療有效量之本發明化合物來治療涉及酸性或缺氧性患病組織之疾病或病況之方法。本發明亦提供減小與電離輻射或細胞毒性劑之投與相關之骨髓毒性之方法,其包括對人類或其他哺乳動物投與治療有效量之本發明化合物與電離輻射或細胞毒性劑之組合。
本發明亦提供本文所述化合物於製造用於療法中的藥物之用途。本發明亦提供本文所述化合物,其係用於療法中。
本發明亦提供用於合成本發明化合物之方法及可用於此等方法中之中間物。
本文中提供一種式(I)化合物:
或其醫藥上可接受之鹽,其中:
R7
為肽;
R8
係選自由如下組成之群: ;
Q係選自由如下組成之群:
R1
、R2
、R3
、R4
、R5
、R6
、R9
、R10
、R11
及R12
各獨立地選自H、C1-4
烷基、C1-4
烯基、C6-10
芳基、5-10員雜芳基、鹵基、CN、NO2
、ORa1
、SRa1
、C(O)Rb1
、C(O)NRc1
Rd1
、C(O)ORa1
、OC(O)Rb1
、OC(O)NRc1
Rd1
、NRc1
Rd1
、NRc1
C(O)Rb1
、NRc1
C(O)ORa1
及NRc1
C(O)NRc1
Rd1
,其中該C1-4
烷基、C1-4
烯基、C6-10
芳基及5-10員雜芳基各視需要經1、2或3個獨立選自鹵基、CN、NO2
、ORa1
、SRa1
、C(O)Rb1
、C(O)NRc1
Rd1
、C(O)ORa1
、OC(O)Rb1
、OC(O)NRc1
Rd1
、NRc1
Rd1
、NRc1
C(O)Rb1
、NRc1
C(O)ORa1
及NRc1
C(O)NRc1
Rd1
之取代基取代;
或R1
及R2
與其所連接的碳原子共同形成C3-7
環烷基,視需要經1、2或3個獨立選自鹵基、CN、NO2
、ORa1
、SRa1
、C(O)Rb1
、C(O)NRc1
Rd1
、C(O)ORa1
、OC(O)Rb1
、OC(O)NRc1
Rd1
、NRc1
Rd1
、NRc1
C(O)Rb1
、NRc1
C(O)ORa1
及NRc1
C(O)NRc1
Rd1
之取代基取代;
或R1
及R3
與其所連接的碳原子共同形成C3
-7
環烷基,視需要經1、2或3個獨立選自鹵基、CN、NO2
、ORa1
、SRa1
、C(O)Rb1
、C(O)NRc1
Rd1
、C(O)ORa1
、OC(O)Rb1
、OC(O)NRc1
Rd1
、NRc1
Rd1
、NRc1
C(O)Rb1
、NRc1
C(O)ORa1
及NRc1
C(O)NRc1
Rd1
之取代基取代;
或R3
及R4
與其所連接的碳原子共同形成C3
-7
環烷基,視需要經1、2或3個獨立選自鹵基、CN、NO2
、ORa1
、SRa1
、C(O)Rb1
、C(O)NRc1
Rd1
、C(O)ORa1
、OC(O)Rb1
、OC(O)NRc1
Rd1
、NRc1
Rd1
、NRc1
C(O)Rb1
、NRc1
C(O)ORa1
及NRc1
C(O)NRc1
Rd1
之取代基取代;
或R5
及R6
與其所連接的碳原子共同形成C3
-7
環烷基,視需要經1、2或3個獨立選自鹵基、CN、NO2
、ORa1
、SRa1
、C(O)Rb1
、C(O)NRc1
Rd1
、C(O)ORa1
、OC(O)Rb1
、OC(O)NRc1
Rd1
、NRc1
Rd1
、NRc1
C(O)Rb1
、NRc1
C(O)ORa1
及NRc1
C(O)NRc1
R1d1
之取代基取代
R13
為H或C1-6
烷基;
A為H或C1
-4
烷基;為C6-10
芳基或5-10員雜芳基;其中該5-10員雜芳基具有至少一個成環碳原子及獨立選自N、O及S之1、2、3或4個成環雜原子;
[N、O、S]為NH、O或S;
[N、O]為NH或O;
[C、N、O]為CRX
RY
、NH或O;
各RX
及RY
係獨立地選自H及C1-4
烷基;
[AA]X
為可藉由酵素作用裂解之肽;
S1為;
各Ra
、Rb
、Rc
及Rd
獨立地選自H、C1-4
烷基、ORa2
、CO2
Ra2
及OC(=O)Ra2
,其中該C1-4
烷基係視需要經ORa2
、CO2
Ra2
及OC(=O)Ra2
取代;
Ra1
、Rb1
、Rc1
及Rd1
各獨立地選自H、C1-6
烷基、C2-6
烯基、C2-6
炔基、C1-6
鹵烷基、OH、CN、NO2
及CO2
CH3
;其中該C1-6
烷基及C2-6
烯基各視需要經OH、CN、NO2
或CO2
CH3
取代;
Ra2
為H或C1-4
烷基;及
n為0或1。
在一些實施例中,Q的左邊連接至R8
及Q的右邊連接至R7
。
在一些實施例中,Q之二硫部分之硫原子係R7
之半胱胺酸殘基之部分。
用作R7
之適宜肽述於(例如)美國專利案第8,076,451號及第9,289,508號(該等案件以全文引用的方式併入本文中)中,然而,可使用可如此選擇性***之其他肽。其他適宜肽述於(例如) Weerakkody等人,PNAS 110 (15),5834-5839 (2013年4月9日)中,該案亦以全文引用的方式併入本文中。在不受理論約束下,據信R7
肽因應pH變化而可逆地摺疊且***穿過細胞膜。R7
肽可靶向酸性組織且因應低胞外pH而選擇性地轉移極性、細胞不滲透之分子穿過細胞膜。在一些實施例中,R7
為可選擇性地遞送R8
Q-穿過具有pH小於約6.0之酸性或缺氧性外套之細胞膜之肽。在一些實施例中,R7
為可選擇性地遞送R8
Q-穿過具有pH小於約6.5之酸性或缺氧性外套之細胞膜之肽。在一些實施例中,R7
為可選擇性地遞送R8
Q-穿過具有pH小於約5.5之酸性或缺氧性外套之細胞膜之肽 。在一些實施例中,R7
為可選擇性地遞送R8
Q-穿過具有pH介於約5.0與約6.0之間之酸性或缺氧性外套之細胞膜之肽。
在一些實施例中,R7
係經由R7
之半胱胺酸殘基連接至Q。在一些實施例中,半胱胺酸殘基之硫原子可形成含雙硫鍵之連接子的雙硫鍵的部分。
在一些實施例中,R7
為包含如下序列中之至少一者之肽:
ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO.1;Pv1),
AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG (SEQ ID NO.2;Pv2),及
ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG (SEQ ID NO.3;Pv3);
Ac-AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTKCG (SEQ ID NO.4;Pv4);及
AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTC (SEQ ID No. 5;Pv5);
其中R7
係經由R7
的半胱胺酸殘基連接至Q。
在一些實施例中,R7
為包含如下序列中之至少一者之肽:
ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO.1;Pv1),
AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG (SEQ ID NO.2;Pv2),及
ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG (SEQ ID NO.3;Pv3),
其中R7
係經由R7
的半胱胺酸殘基連接至Q。
在一些實施例中,R7
為包含序列ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO.1;Pv1)之肽。
在一些實施例中,R7
為包含序列AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG (SEQ ID NO.2;Pv2)之肽。
在一些實施例中,R7
為包含序列ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG (SEQ ID NO.3;Pv3)之肽。
在一些實施例中,R7
為包含序列Ac-AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTKCG (SEQ ID NO.4;Pv4)之肽。
在一些實施例中,R7
為包含序列AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTC (SEQ ID NO.5;Pv5)之肽。
在一些實施例中,R7
為由序列ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO.1;Pv1)組成之肽。
在一些實施例中,R7
為由序列AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG (SEQ ID NO.2;Pv2)組成之肽。
在一些實施例中,R7
為由序列ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG (SEQ ID NO.3;Pv3)組成之肽。
在一些實施例中,R7
為由序列Ac-AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTKCG (SEQ ID NO.4;Pv4)組成之肽。
在一些實施例中,R7
為由序列AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTC (SEQ ID NO.5;Pv5)組成之肽。
在一些實施例中,R7
為包含選自如表1中所顯示之SEQ ID NO:6至SEQ ID NO:311中之至少一個序列之肽。
在一些實施例中,R7
為由選自如表1中所顯示之SEQ ID NO:6至SEQ ID NO:311之序列組成之肽。
表1. 其他R7
序列
在一些實施例中,R7
為具有10至50個胺基酸之肽。在一些實施例中,R7
為具有20至40個胺基酸之肽。在一些實施例中,R7
為具有20至40個胺基酸之肽。在一些實施例中,R7
為具有10至20個胺基酸之肽。在一些實施例中,R7
為具有20至30個胺基酸之肽。在一些實施例中,R7
為具有30至40個胺基酸之肽。
用於本發明中之適宜治療性分子(例如,R8
)包括彼等當全身性投與時因其於正常組織之可能的有害作用而具有非所欲副作用之分子。實例治療性分子為DNA修復抑制化合物,諸如PARP、ATR、DNK-PK及ATM之抑制劑。此DNA修復抑制化合物可用於治療其中將期望抑制DNA修復之癌症及其他疾病。
目前已有三種PARP抑制劑(奧拉帕利(olaparib)、蘆卡帕尼(rucaparib)及尼拉帕尼(niraparib))可從市面購得及其他正在開發中,諸如AG-014699 (Agouron/Pfizer)、KU-0059436 (KuDOS/AstraZeneca)、INO-1001 (Inotek/Genentech)、NT-125 (現稱為E-7449;Eisai;3H-噠嗪并[3,4,5-de]喹唑啉-3-酮、8-[(1,3-二氫-2H-異吲哚-2-基)甲基]-1,2-二氫-)、2X-121(2X Oncology;3H-噠嗪并[3,4,5-de]喹唑啉-3-酮、8-[(1,3-二氫-2H-異吲哚-2-基)甲基]-1,2-二氫-)及ABT-888 (縮寫詞)。PARP抑制劑揭示於(例如)美國專利案第6,100,283號;第6,310,082號;第6,495,541號;第6,548,494號;第6,696,437號;第7,151,102號;第7,196,085號;第7,449,464號;第7,692,006號;第7,781,596號;第8,067,613號;第8,071,623號;及第8,697,736號中,該等專利案係以全文引用的方式併入本文中。
在一些實施例中,R1
及R2
各獨立地選自H及甲基,且R3
、R4
、R5
及R6
各為氫。
在一些實施例中,R1
及R2
各獨立地選自H及甲基。
在一些實施例中,R1
及R2
各為H。
在一些實施例中,R3
及R4
各為H。
在一些實施例中,R5
及R6
各為H。
在一些實施例中,R9
、R10
、R11
及R12
各獨立地選自H及甲基。
在一些實施例中,可裂解[AA]X
之酵素為組織蛋白酶B、基質-金屬蛋白酶(MMP)、DPPIV、醣蛋白、肽酶或凋亡蛋白酶。在一些實施例中,[AA]x為具有兩個至十二個(x為2至12)胺基酸(AA)殘基之肽。在一些實施例中,[AA]x為具有兩個至十個(x為2至10)胺基酸(AA)殘基之肽。在一些實施例中,[AA]x為具有兩個至五個(x為2至5)胺基酸(AA)殘基之肽。在一些實施例中,[AA]x為具有六個至九個(x為6至9)胺基酸(AA)殘基之肽。在一些實施例中,[AA]x為具有三個至八個(x為3至8)胺基酸(AA)殘基之肽。
可藉由蛋白質裂解之肽連接子(例如,[AA]X
)述於Yang, Y.,Acta Pharmaceutica Sinica B 2011,1(3),143-159;Choi, K.,Theranostics 2012,2,156-178;及Anderson, C.,Ind. Eng. Chem. Res. 2017,56,4761-5777中。
可藉由DPPIV裂解之肽連接子(例如,[AA]X
)述於Diez-Torrubia, A.,J. Med. Chem. 2010,53,559-572;Garcia-Aparicio, C.,J. Med. Chem.2006,49,5339-5351;Diez-Torrubia, A.,ChemMedChem 2012,7,618-628;Dahan, A.,Mol. Pharmaceutics 2014,11,4385-4394;Wickstrom, M.,Oncotarget 2017,8,66641-66655;及Simplicio, A. L.,Molecules,2008,13,519-547中。
可藉由組織蛋白酶B裂解之肽連接子(例如,[AA]X
)述於Caculitan, N.,Cancer Res. 2017,77(24),7027-7037;Zhong, Y-J,International Journal of Oncology 2013,42,373-383;及Fan, P.,Drug Metabolism and Disposition 2016,44,1253-1261中。
可藉由MMP (例如,MMP-9)裂解之肽連接子(例如,[AA]X
)述於Kalafatovic, D.,Biomaterials 98 (2016),192-202;Kim, HS,Gene Therapy 2013,20,378-385;及Yao, W.,Trends in Pharmacological Sciences 2018,39,766-781中。
在一些實施例中,[AA]X
為-Pro_Gly-;-Val_Cit-、-Gly_Pro_Leu_Gly_Leu_Ala_Gly_Asp_Asp-、-Gly_Pro_GLeu_Gly_Val_Arg_Gly或-Ser_Ser_Lys_Leu_Gly-。
在一些實施例中,S1為具有如下結構之基團:。
在一些實施例中,S1為具有如下結構之基團:。
S1基團可為可藉由葡萄糖醛酸苷酶裂解之碳水化合物。此類碳水化合物基團在相關技術中用作葡萄糖醛酸苷前藥,且述於Grinda,M. Med. Chem. Commun.2012,3,68-70;Herceg, V.,Biorganic Chemistry 2018,78,372-380;Adiyala P.,Bioorganic Chemistry 2018,76,288-293;及Kolakowski, R.,Angew. Chem. Int. Ed. 2016,55,7948-7951中。
本文亦提供式(I)化合物
及其醫藥上可接受之鹽,其中
R8
為選自由如下組成之群的成員: ;
Q為選自由如下組成之群的成員
其中R1
、R2
、R3
、R4
、R5
及R6
係獨立地選自H、視需要經取代之C1
-C4
烷基、視需要經取代之C1
-C4
烯基、視需要經取代之C1
-C4
烷氧基、視需要經一個或兩個C1
-C4
烷基取代基、鹵基、硝基或羥基取代之胺基,且其中[NH,O,S}意指連接NH、O或S部分,
及
R7
為可以pH依賴性方式選擇性地遞送R8
Q穿過具有酸性或缺氧性外套之細胞膜之肽。
在一些實施例中,R7
為選自由ADDQNPWRAYLDLLFPTDTLLLDLLWCG(SEQ ID NO.1;Pv1)、
AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG(SEQ ID NO.2;Pv2)及
ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG(SEQ ID NO.3;Pv3)組成之群的成員,
其中R7
及Q係經由半胱胺酸殘基連接。
在一些實施例中,R1
及R2
各獨立地選自H及甲基且R3
、R4
、R5
及R6
各為氫。
在一些實施例中,R7
為ADDQNPWRAYLDLLFPTDTLLLDLLWCG(SEQ ID NO.1;Pv1)。
在一些實施例中,R7
為AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG (SEQ ID NO.2;Pv2)。
在一些實施例中,R7
為ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG(SEQ ID NO.3;Pv3)。
在一些實施例中,式(I)之化合物係選自:
本發明之分子可用(例如)探針(諸如螢光團、放射性同位素及類似物)標記。在一些實施例中,探針為螢光探針,諸如LICOR。螢光探針可包括可於光激發後再發射光之任何部分(例如,螢光團)。
胺基酸以IUPAC縮寫表示,如下:丙胺酸(Ala;A)、精胺酸(Arg;R)、天冬醯胺酸(Asn;N)、天冬胺酸(Asp;D)、半胱胺酸(Cys;C)、麩醯胺酸(Gln;Q)、麩胺酸(Glu;E)、甘胺酸(Gly;G)、組胺酸(His;H)、異白胺酸(Ile;I)、白胺酸(Leu;L)、離胺酸(Lys;K)、甲硫胺酸(Met;M)、***酸(Phe;F)、脯胺酸(Pro;P)、絲胺酸(Ser;S)、蘇胺酸(Thr;T)、色胺酸(Trp;W)、酪胺酸(Tyr;Y)、纈胺酸(Val;V)。術語「Pv1」意指ADDQNPWRAYLDLLFPTDTLLLDLLWCG,其為SEQ ID No. 1之肽。術語「Pv2」意指AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG,其為SEQ ID No. 2之肽。術語「Pv3」意指ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG,其為SEQ ID No. 3之肽。術語「Pv4」意指Ac-AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTKCG,其為SEQ ID NO.4之肽。術語「Pv5」意指AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTC,其為SEQ ID NO.5之肽。在本發明之化合物中,肽R7
經半胱胺酸部分連接至雙硫鍵連接子。
術語「酸性及/或缺氧性外套」係指所述患病組織中之細胞之環境,其具有低於7.0且較佳低於6.5之pH。酸性或缺氧性外套更佳具有約5.5之pH且最佳具有約5.0之pH。式(I)化合物以pH依賴性方式***穿過具有酸性及/或缺氧性外套之細胞膜以將R8
Q***細胞中,此後雙硫鍵連接子裂解而遞送游離R8
H。由於式(I)化合物係pH-依賴性的,故其等僅於存在環繞細胞之酸性或缺氧性外套下優先地***穿過細胞膜而非穿過「正常」細胞之細胞膜(其不具有酸性或缺氧性外套)中。
如本文所使用,術語「pH-敏感性」或「pH-依賴性」係指肽R7
或肽R7
之***穿過細胞膜之模式或本發明化合物之***穿過細胞膜之模式,意指該肽具有對具有酸性或缺氧性外套之細胞膜脂質雙層比對中性pH下之膜脂質雙層更高的親和力。因此,本發明之化合物在細胞膜脂質雙層具有酸性或缺氧性外套(「患病」細胞)時優先地***穿過細胞膜以將R8
Q***細胞內部(且因此遞送如上文所述之R8
H),但在外套(細胞膜脂質雙層之環境)不為酸性或缺氧性(「正常」細胞)時不插***穿過細胞膜。據信此種優先***由於肽R7
形成螺旋配置(其促進膜***)而達成。
進一步瞭解到為清晰起見描述於不同實施例上下文中之本發明之某些特徵亦可以組合方式提供於單一實施例中(然而,該等實施例意欲如同書寫為多重相關形式般組合)。相反地,為簡短起見描述於單一實施例上下文中之本發明之各種特徵亦可單獨地或以任何適宜子組合方式提供。因此,預期描述為式(I)化合物之實施例之特徵可以任何適宜組合方式組合。
在本說明書中的不同地方,該等化合物之某些特徵係以組別或以範圍形式揭示。明確意欲該揭示包括此等組別及範圍之成員之每一個別子組合。例如,術語「C1-6
烷基」明確意欲個別地揭示(但不限於)甲基、乙基、C3
烷基、C4
烷基、C5
烷基及C6
烷基。
術語「n-員」(其中n為整數)通常描述某一部分中的成環原子數,其中成環原子數為n。例如,哌啶基為6-員雜環烷基環之實例,吡唑基為5-員雜芳基環之實例,吡啶基為6-員雜芳基環之實例及1,2,3,4-四氫-萘為10-員環烷基之實例。
在本說明書中的不同地方,可描述定義二價連接基之變數。明確希望每個連接取代基包括連接取代基之前向及後向形式。例如,-NR(CR'R'')n
-包括-NR(CR'R'')n
-及-(CR'R'')n
NR-且意欲個別地揭示該等形式中的每種形式。在該結構需要連接基的情況下,針對該基團所列出的Markush變數應理解為連接基。例如,若該結構需要連接基且該變數之Markush群組定義列出「烷基」或「芳基」,則應理解該「烷基」或「芳基」分別表示連接伸烷基或伸芳基。
術語「經取代」意指原子或原子團通常置換氫作為與另一基團連接的「取代基」。除非另有說明,否則術語「經取代」係指任何程度之取代,例如,單-、二-、三-、四-或五取代(在此取代被允許的情況下)。獨立地選擇該等取代基,且取代可係在任何化學上可達位置。應瞭解所給定原子之處的取代受價數限制。應瞭解所給定原子之處的取代導致化學穩定之分子。片語「視需要經取代」意指未經取代的或經取代的。術語「經取代」意指氫原子被移除並被取代基置換。單個二價取代基(例如,側氧基)可置換兩個氫原子。
術語「Cn-m
」指示包含端點的範圍,其中n及m為整數且指示碳數。實例包括C1-4
、C1-6
及類似物。
單獨使用或與其他術語組合使用的術語「烷基」係指可為直鏈或分支鏈之飽和烴基。術語「Cn-m
烷基」係指具有n至m個碳原子之烷基。烷基通常對應於一個C-H鍵經烷基對化合物其餘部分之連接點置換之烷烴。在一些實施例中,烷基包含1至6個碳原子、1至4個碳原子、1至3個碳原子或1至2個碳原子。烷基部分之實例包括(但不限於)化學基團,諸如甲基、乙基、正丙基、異丙基、正丁基、第三丁基、異丁基、第二丁基;高碳數同系物,諸如2-甲基-1-丁基、正戊基、3-戊基、正己基、1,2,2-三甲基丙基及類似物。
單獨使用或與其他術語組合使用的術語「烯基」係指對應於烷基之具有一或多個碳-碳雙鍵之直鏈或分支鏈烴基。烯基通常對應於一個C-H鍵經烯基對化合物其餘部分之連接點置換之烯烴。術語「Cn-m
烯基」係指具有n至m個碳之烯基。在一些實施例中,烯基部分包含2至6、2至4個或2至3個碳原子。示例性烯基包括(但不限於)乙烯基、正丙烯基、異丙烯基、正丁烯基、第二丁烯基及類似物。
單獨使用或與其他術語組合使用的術語「炔基」係指對應於烷基之具有一或多個碳-碳三鍵之直鏈或分支鏈烴基。炔基通常對應於一個C-H鍵經烷基對化合物之其餘部分的連接點置換之炔烴。術語「Cn-m
炔基」係指具有n至m個碳之炔基。實例炔基包括(但不限於)乙炔基,丙炔-1-基,丙炔-2-基及類似物。在一些實施例中,炔基部分包含2至6、2至4、或2至3個碳原子。
單獨使用或與其他術語組合使用的術語「伸烷基」係指二價烷基連接基。伸烷基通常對應於兩個C-H鍵經伸烷基對化合物之其餘部分的連接點置換之烷烴。術語「Cn-m
伸烷基」係指具有n至m個碳原子之伸烷基。伸烷基的實例包括但不限於乙-1,2-二基,乙-1,1-二基,丙-1,3-二基,丙-1,2-二基,丙-1,1-二烷基,丁-1,4-二基,丁-1,3-二基,丁-1,2-二基,2-甲基-丙-1,3-二基等。
術語「胺基」係指式-NH2
之基團。
單獨使用或與其他術語組合使用的術語「羰基」係指-C(=O)-基,其亦可寫為C(O)。
術語「氰基」或「腈」係指式-C≡N之基團,其亦可寫為-CN。
單獨使用或與其他術語組合使用的術語「鹵基」或「鹵素」係指氟基、氯基、溴基及碘基。在一些實施例中,「鹵基」係指選自F、Cl或Br之鹵原子。在一些實施例中,鹵基為F。
如本文所用,術語「鹵烷基」係指其中一個或多個氫原子已被鹵素原子置換之烷基。術語「Cn-m
鹵烷基」係指具有n至m個碳原子且形成至少一個至{2(n至m)+1}個鹵素原子(其可係相同或不同)之Cn-m
烷基。在一些實施例中,該等鹵素原子為氟原子。在一些實施例中,該鹵烷基具有1至6個或1至4個碳原子。實例鹵烷基包括CF3
、C2
F5
、CHF2
、CH2
F、CCl3
、CHCl2
、C2
Cl5
及類似物。在一些實施例中,鹵烷基為氟烷基。
單獨使用或與其他術語組合使用的術語「鹵烷氧基」係指式-O-鹵烷基之基團,其中鹵烷基係如上文所定義。術語「Cn-m
鹵烷氧基」係指鹵烷氧基,其鹵烷基具有n至m個碳。實例鹵烷氧基包括三氟甲氧基及類似物。在一些實施例中,鹵烷氧基具有1至6個、1至4個或1至3個碳原子。
術語「側氧基」係指作為二價取代基的氧原子,當與碳連接時形成羰基,或與雜原子連接形成亞碸或碸基或N-氧化物基團。在一些實施例中,雜環基可視需要經1或2個側氧基(=O)取代基取代。
關於成環N原子之術語「氧化」係指成環N-氧化物。
關於成環S原子之術語「氧化」係指成環磺醯基或成環亞磺醯基。
術語「芳族」係指具有一或多個具有芳族特徵(即,具有(4n + 2)離域π (pi)電子,其中n為整數)之多不飽和環之碳環或雜環。
單獨使用或與其他術語組合使用的術語「芳基」係指芳族烴基,其可係單環或多環(例如,具有2個稠環)。術語「Cn-m
芳基」係指具有n至m個環碳原子之芳基。芳基包括(例如)苯基、萘基及類似物。在一些實施例中,芳基具有6至約10個碳原子。在一些實施例中,芳基具有6個碳原子。在一些實施例中,芳基具有10個碳原子。在一些實施例中,芳基為苯基。
單獨使用或與其他術語組合使用的術語「雜芳基」或「雜芳族」係指具有至少一個選自硫、氧及氮之雜原子環成員之單環或多環芳族雜環。在一些實施例中,雜芳基環具有1、2、3或4個獨立選自氮、硫及氧之雜原子環成員。在一些實施例中,雜芳基部分中之任何成環N可為N-氧化物。在一些實施例中,雜芳基具有5-14個環原子,包括碳原子及1、2、3或4個獨立選自氮、硫及氧之雜原子環成員。在一些實施例中,雜芳基具有5-10個環原子,包括碳原子及1、2、3或4個獨立選自氮、硫及氧之雜原子環成員。在一些實施例中,雜芳基具有5-6個環原子及1或2個獨立選自氮、硫及氧之雜原子環成員。在一些實施例中,雜芳基為五-員或六-員雜芳基環。在其他實施例中,雜芳基是八-員、九-員或十-員稠合雙環雜芳基環。
五-員雜芳基環為具有五個環原子之雜芳基,其中一或多個(例如,1、2或3個)環原子係獨立地選自N、O及S。
六-員雜芳基環為具有六個環原子之雜芳基,其中一或多個(例如,1、2或3個)環原子係獨立地選自N,O及S。
單獨使用或與其他術語組合使用的術語「環烷基」係指非芳族烴環系統(單環、雙環或多環),括環化烷基及烯基。術語「Cn-m
環烷基」係指具有n至m個環成員碳原子之環烷基。環烷基可包括單環或多環(例如,具有2、3或4個稠環)基團及螺環。環烷基可具有3、4、5、6或7個成環碳(C3-7
)。在一些實施例中,環烷基具有3至6個環成員、3至5個環成員或3至4個環成員。在一些實施例中,環烷基係單環的。在一些實施例中,環烷基係單環或雙環的。在一些實施例中,環烷基為C3-6
單環環烷基。環烷基之成環碳原子可視需要經氧化以形成側氧基或硫離子基(sulfido)。環烷基亦包括亞環烷基。在一些實施例中,環烷基為環丙基、環丁基、環戊基或環己基。環烷基定義中亦包括具有稠合(即,具有共同鍵)至環烷基環之一或多個芳族環之部分,例如,環戊烷、環己烷及類似物之苯并或噻吩基衍生物。含有稠合芳族環之環烷基可經任何成環原子(包括稠合芳族環之成環原子)連接。環烷基之實例包括環丙基、環丁基、環戊基、環己基、環庚基、環戊烯基、環己烯基、環己二烯基及類似物。在一些實施例中,環烷基為環丙基、環丁基、環戊基或環己基。
單獨使用或與其他術語組合使用的術語「雜環烷基」係指非芳族環或環系統,其可視需要含有一個或多個伸烯基作為環結構的部分,其具有至少一個雜獨立選自氮、硫、氧及磷之原子環成員,且其具有4-10個環成員、4-7個環成員或4-6個環成員。術語「雜環烷基」包括單環4-、5-、6-及7-員雜環烷基。雜環烷基可包括單環或雙環(例如,具有兩個稠合或橋接環)或螺環環系統。在一些實施例中,雜環烷基為具有1、2或3個獨立選自氮、硫及氧之雜原子之單環基團。雜環烷基之成環碳原子及雜原子可視需要經氧化以形成側氧基或硫離子基或其他氧化鍵(例如,C(O)、S(O)、C(S)或S(O)2
、N-氧化物等)或氮原子可經四級銨化。雜環烷基可經成環碳原子或成環雜原子連接。在一些實施例中,雜環烷基含有0至3個雙鍵。在一些實施例中,雜環烷基含有0至2個雙鍵。雜環烷基定義中亦包括具有稠合(即,具有共同鍵)至雜環烷基環之一個或多個芳族環之部分,例如,哌啶、嗎啉、氮呯等之苯并或噻吩基衍生物。含有稠合芳族環之雜環烷基可經任何成環原子(包括稠合芳族環之成環原子)連接。雜環烷基之實例包括2-吡咯啶基;嗎啉基;吖丁啶基;及哌嗪基。
在某些地方,該等定義或實施例係指特定環(例如,吖丁啶環、吡啶環等)。除非另有說明,否則此等環可經連接至任何環成員上,但條件係不超過原子之價數。例如,吖丁啶環可連接在環的任何位置,而吖丁啶-3-基環係連接在3-位。
本文所述的化合物可係不對稱的(例如,具有一或多個立體中心)。除非另有說明,否則預期所有立體異構體(諸如對映異構體及非對映異構體)。含有經不對稱取代之碳原子之本發明化合物可以光學活性或外消旋形式分離。關於如何由光學惰性起始材料製備光學活性形式之方法係本技術已知的,諸如藉由解析外消旋混合物或藉由立體選擇性合成。烯烴、C=N雙鍵及類似物之許多幾何異構體亦可存在於本文所述的化合物中,且本發明中涵蓋所有此等穩定異構體。本發明化合物之順式及反式幾何異構體已經描述且可分離為異構體之混合物或分離的異構形式。
化合物之外消旋混合物之解析可藉由本技術中已知的許多方法中的任何一種方法進行。一種方法包括使用掌性解析酸進行分段再結晶,該掌性解析酸為光學活性成鹽有機酸。適用於分段再結晶方法之解析劑為(例如)光學活性酸,諸如酒石酸之D及L形式、二乙醯基酒石酸、二苯甲醯基酒石酸、扁桃酸、蘋果酸、乳酸或各種光學活性樟腦磺酸(例如β-樟腦磺酸)。適於分段結晶方法之其他解析劑包括α-甲基苄胺之立體異構純形式(例如,S及R形式或非立體異構純形式)、2-苯基甘胺醇、降麻黃鹼(norephedrine)、麻黃鹼(ephedrine)、N-甲基麻黃鹼、環己基乙胺、1,2-二胺基環己烷及類似物。
外消旋混合物之解析亦可藉由在裝有光學活性解析劑(例如,二硝基苯甲醯基苯基甘胺酸)的管柱上洗脫來進行。適宜之洗脫溶劑組合物可由熟習此項技術者確定。
在一些實施例中,本發明之化合物具有(R)-組態。在其他實施例中,該等化合物具有(S)-組態。在具有多於一個掌性中心之化合物中,除非另有說明,否則化合物中的每個掌性中心可獨立地為(R)或(S)。
本發明之化合物亦包括互變異構形式。互變異構形式係由單鍵與相鄰雙鍵交換以及質子伴隨遷移而產生的。互變異構形式包括質子性互變異構體,其為具有相同經驗式及總電荷的異構質子化態。實例質子移變互變異構體包括酮-烯醇對、醯胺-醯亞胺酸對、內醯胺-內醯亞胺對、烯胺-亞胺對及其中質子可佔雜環系統之兩個或更多個位置之環狀形式,例如,1H-及3H-咪唑、1H-、2H-及4H-1,2,4-***、1H-及2H-異吲哚及1H-及2H-吡唑。互變異構形式可藉由適宜取代處於平衡或空間鎖定成一種形式。
本發明之化合物亦可包括中間物或最終化合物中出現之原子的所有同位素。同位素包括彼等具有相同原子序數但具有不同質量數之原子。例如,氫的同位素包括氚及氘。本發明化合物之一或多個組成原子可經天然或非天然豐度的原子的同位素置換或取代。在一些實施例中,該化合物包含至少一個氘原子。例如,本發明化合物中之一或多個氫原子可經氘置換或取代。在一些實施例中,該化合物包含兩個或更多個氘原子。在一些實施例中,該化合物包含1、2、3、4、5、6、7、8、9、10、11或12個氘原子。將同位素包含於有機化合物中之合成方法係本技術已知的(Deuterium Labeling in Organic Chemistry,Alan F. Thomas (New York,N.Y.,Appleton-Century-Crofts,1971;The Renaissance of H/D Exchange,Jens Atzrodt、Volker Derdau、Thorsten Fey及Jochen Zimmermann,Angew. Chem. Int. Ed.2007,7744-7765;The Organic Chemistry of Isotopic Labelling,James R. Hanson,Royal Society of Chemistry,2011)。同位素標記化合物可用於各種研究,例如NMR光譜學、代謝實驗及/或分析。
經較重同位素(諸如氘)之取代可提供源自更佳代謝穩定性之某些治療優點(例如,活體內半衰期增加或劑量需求降低),且因此在一些情況下可能較佳。(A. Kerekes等人J. Med. Chem. 2011,54,201-210;R. Xu等人J. Label Compd. Radiopharm. 2015,58,308-312)。
如本文所用,術語「化合物」意欲包括所描繪結構之所有立體異構體、幾何異構體、互變異構體及同位素。該術語亦意指係指本發明之化合物,不論其等製法例如合成、藉由生物過程(例如,代謝或酵素轉化)或其組合。
所有化合物及其醫藥上可接受之鹽可與其他物質(諸如水及溶劑)一起發現(例如,水合物及溶劑合物),或可經分離。當處於固態時,本文所述的化合物及其鹽可以各種形式存在且可(例如)呈溶劑合物(包括水合物)之形式。該等化合物可呈任何固態形式,諸如多晶型物或溶劑合物,因此除非另有明確說明,否則本說明書中提及的化合物及其鹽應理解為包涵該化合物之任何固態形式。
在一些實施例中,大體上分離本發明之化合物或其鹽。「大體上分離」意指該化合物至少部分地或大體上與其形成或檢測的環境分離。部分分離可包括(例如)富含本發明化合物之組合物。大體分離可包括含有至少約50重量%、至少約60重量%、至少約70重量%、至少約80重量%、至少約90重量%、至少約95重量%、至少約97重量%或至少約99重量%之本發明化合物或其鹽之組合物。
本文使用術語「醫藥上可接受」係指在合理範圍的醫療判斷下適用於與人類及動物之組織接觸而無過量毒性、刺激、過敏性反應或其他問題或併發症且符合合理的效益/風險比之彼等化合物、材料、組合物及/或劑型。
如本文所用,表述「環境溫度」及「室溫」係本技術中所瞭解的,且一般係指約為於其中進行反應的室溫(例如,約20℃至約30℃)之溫度(例如,反應溫度)。
本發明亦包括本文所述化合物之醫藥上可接受之鹽。術語「醫藥上可接受之鹽」係指所揭示化合物之衍生物,其中親體化合物係藉由將現有的酸或鹼部分轉化為其鹽形式來修飾。醫藥上可接受之鹽之實例包括(但不限於)鹼性殘基(諸如胺)之無機或有機酸鹽;酸性殘基(諸如羧酸)之鹼性或有機鹽;及類似物。本發明之醫藥上可接受之鹽包括(例如)自非毒性無機或有機酸形成的親體化合物之非毒性鹽。本發明之醫藥上可接受之鹽可藉由習知化學方法自含有鹼性或酸性部分之親體化合物合成。一般而言,此等鹽可藉由使此等化合物之游離酸或鹼形式與化學計量之適宜鹼或酸於水中或於有機溶劑中或於二者之混合物中反應來製備;一般而言,以非水性介質(例如醚、乙酸乙酯、醇(例如,甲醇、乙醇、異丙醇或丁醇)或乙腈(MeCN))為較佳。適宜鹽之清單可參見Remington's Pharmaceutical Sciences,第17版,(Mack Publishing Company,Easton,1985),p. 1418,Berge等人,J. Pharm. Sci.,1977,66(1),1-19及Stahl等人,Handbook of Pharmaceutical Salts: Properties, Selection, and Use,(Wiley,2002)。在一些實施例中,本文所述的化合物包括N-氧化物形式。
如本技術中所瞭解,結構式中使用符號表示為含該符號之部分對化合物之相鄰部分的連接點的鍵。根據類似的規約,可不明確地表示側基碳原子及其所連接的氫原子。因此,符號表示甲基,符號表示乙基,符號表示環戊基,依此類推。取代基於分子或部分中之定向以如下規約表示:符號表示基團從頁面平面突出朝向讀者的鍵,而符號表示基團從頁面平面後突離開讀者的鍵,及符號表示基團具有中間定向的鍵(即,該化合物係非對映的)。
除非另有說明,否則本說明書中如本文所用之所有術語應按照技術中已知的其一般含義理解。例如,「C1-4
烷基」為含有1-4個碳之飽和脂族烴單價基團,諸如甲基、乙基、正丙基、1-甲基乙基(異丙基)、正丁基或第三丁基;「C1-4
烷氧基」為具有末端氧之C1-4
烷基,諸如甲氧基、乙氧基、丙氧基、丁氧基。所有烷基、烯基及炔基應理解為係結構上可能之分支鏈或無分支鏈、環化或非環化,除非另有說明。其他更多具體的定義如下:
單獨或與另一基團組合的術語「C1-n
-烷基」(其中n為2至6之整數)表示具有1至n個C原子之非環狀飽和分支鏈或直鏈烴基。例如,術語C1-5
-烷基包括基團H3
C-、H3
C-CH2
-、H3
C-CH2
-CH2
-、H3
C-CH(CH3
)-、H3
C-CH2
-CH2
-CH2
-、H3
C-CH2
-CH(CH3
)-、H3
C-CH(CH3
)-CH2
-、H3
C-C(CH3
)2
-、H3
C-CH2
-CH2
-CH2
-CH2
-、H3
C-CH2
-CH2
-CH(CH3
)-、H3
C-CH2
-CH(CH3
)-CH2
-、H3
C-CH(CH3
)-CH2
-CH2
-、H3
C-CH2
-C(CH3
)2
-、H3
C-C(CH3
)2
-CH2
-、H3
C-CH(CH3
)-CH(CH3
)-及H3
C-CH2
-CH(CH2
CH3
)-。
單獨或與另一基團組合的術語「C3-n
-環烷基」(其中n為4至7之整數)表示具有3至n個C原子之環狀飽和無分支鏈烴基。例如,術語C3-7
-環烷基包括環丙基、環丁基、環戊基、環己基及環庚基。
如本文所用,術語「雜原子」應理解為意指碳原子之外的原子,諸如O、N、S及P。
在一些實施例中(烷基或碳鏈),一或多個碳原子可視需要經以下雜原子置換:O、S或N。應瞭解,若N不表示為經取代的,則其為NH,及雜原子可置換分支鏈或無分支鏈碳鏈中之末端碳原子或內部碳原子。此等基團可按照上述之方式藉由基團諸如側氧基取代,以產生諸如但不限於烷氧基羰基、醯基、醯胺基及硫酮基之定義。
在一些實施例中,如本文所用,單獨或與另一基團組合的術語「芳基」表示含有6個碳原子之碳環芳族單環基團,其可進一步稠合至可為芳族、飽和或不飽和之第二5-或6-員碳環基團。芳基包括(但不限於)苯基、二氫茚基、茚基、萘基,蒽基、菲基、四氫萘基及二氫萘基。
在一些實施例中,術語「雜芳基(heteroaryl)」(有時縮寫為「雜芳基(hetaryl)」)意指芳族5至6-員單環雜芳基或芳族7至11-員雜芳基雙環,其中該等環中之至少一個環係芳族的,其中該雜芳基環含有1-4個雜原子諸如N、O及S。5至6-員單環雜芳基環之非限制性實例包括呋喃基、噁唑基、異噁唑基、噁二唑基、噻唑基、吡唑基、吡咯基、咪唑基、四唑基、***基,噻吩基、噻二唑基、吡啶基、嘧啶基、噠嗪基、吡嗪基、三嗪基及嘌呤基。7至11-員雜芳基雙環雜芳基環之非限制性實例包括苯并咪唑基、喹啉基、二氫-2H-喹啉基、四氫喹啉基、異喹啉基、喹唑啉基、吲唑基、噻吩并[2,3-d]嘧啶基、吲哚基、異吲哚基、苯并呋喃基、二氫苯并呋喃基、苯并哌喃基、苯并二氧雜環戊烯基、苯并噁唑基及苯并噻唑基。
如在Q中所用,「芳基及雜芳基」之定義係如上文所述。其等較佳為苯基或咪唑基,諸如以下部分,其與[NH,O,S]在化學上一起經歷分解以釋放R8
H,如下文所述。
在一些實施例中,術語「雜環基」意指穩定非芳族4至8員單環雜環基或穩定非芳族6至11-員稠合雙環、橋接雙環或螺環雜環基。5至11-員雜環由碳原子及一或多個(較佳一至四個)選自氮、氧及硫之雜原子組成。雜環可係飽和或部分不飽和的。非芳族4至8員單環雜環基團之非限制性實例包括四氫呋喃基、吖丁啶基、吡咯啶基、哌喃基、四氫哌喃基、二氧雜環己烷基、硫嗎啉基、1,1-二側氧基-1λ6
-硫嗎啉基、嗎琳基、哌啶基、哌嗪基及氮呯基。非芳族6至11-員稠合雙環基團之非限制性實例包括八氫吲哚基、八氫苯并呋喃基及八氫苯并噻吩基。非芳族6至11-員橋接雙環基團之非限制性實例包括2-氮雜雙環[2.2.1]庚基、3-氮雜雙環[3.1.0]己基及3-氮雜雙環[3.2.1]辛基。非芳族6至11-員螺環雜環基團之非限制性實例包括7-氮雜-螺[3,3]庚基、7-螺[3,4]辛基及7-氮雜-螺[3,4]辛基。術語「雜環基」意欲包括所有可能的異構形式。
如本說明書中所用,術語「鹵素」及對應術語「鹵基」應理解為意指溴、氯、氟或碘、或對應之溴基、氯基、氟基或碘基。定義「鹵化」、「部分或完全鹵化」、「部分或完全氟化」;「經一或多個鹵原子取代」包括例如於一或多個碳原子上之單、二或三鹵衍生物。對於烷基,非限制性實例為-CH2
CHF2
、-CF3
等。
本文所述的各烷基、環烷基、雜環、芳基或雜芳基、或其類似物應理解為視需要經部分或完全鹵化。
如本文所用,「氮」或「N」及「硫」或「S」包括氮及硫之任何氧化形式及任何鹼性氮之四級銨化形式。例如,除非另外說明,否則對於-S-C1-6
烷基基團,應理解為包括-S(O)-C1-6
烷基及-S(O)2
-C1-6
烷基,同樣地,當Ra
為苯基時且在m為0、1或2的情況下,-S-Ra
可表示為苯基-S(O)m
-。
除非明確說明,否則在本說明書及隨附之申請專利範圍中,給出的化學式或名稱應涵蓋互變異構體,及所有立體、光學及幾何異構體(例如對映異構體、非對映異構體、E/Z異構體等),及其外消旋異構體;以及不同比例之個別對映異構體之混合物,非對映異構體之混合物,或任何前述形式之混合物,其中存在該等異構體及對映異構體;以及鹽,包括其醫藥可接受的鹽,及其溶劑合物,諸如水合物,包括游離化合物之溶劑合物,或該化合物之鹽的溶劑合物。在肽R7
中,胺基酸可係全部L組態、全部D組態、或D及L組態之混合物。
本發明之化合物亦包括其同位素標記形式。除了化合物之一或多個原子已經由具有不同於通常在自然中發現之該原子之原子質量或質量數之原子質量或質量數的原子置換外,本發明化合物之同位素標記形式等同於該活性藥物。商業上容易獲得且可按照完善的程序摻入本發明化合物中的同位素之實例包括氫、碳、氮、氧、磷、氟及氯之同位素,例如,分別為2
H (氘或「D」)、3
H、13
C、14
C、15
N、18
O、17
O、31
P、32
P、35
S、18
F及36
Cl。包含一或多種上述同位素及/或其他原子之其他同位素之本發明之化合物、其前藥或其醫藥上可接受的鹽視為在本發明之範圍內。
本發明包括式(I)化合物之醫藥上可接受之衍生物。術語「醫藥上可接受的衍生物」係指任何醫藥上可接受的鹽或酯或經投與至患者時能夠(直接或間接)提供適用於本發明之化合物,或其藥理活性代謝物或藥理活性殘質的任何其他化合物。藥理活性代謝物應理解為意指能夠以酵素或化學方式代謝之任何本發明之化合物。此包括(例如)式(I)之羥基化或氧化之衍生化合物。
如本文所用,「醫藥上可接受之鹽」係指所揭示化合物之衍生物,其中親體化合物藉由製備其酸或鹼鹽來修飾。醫藥上可接受之鹽之實例包括(但不限於)鹼性殘基(諸如胺)之無機或有機酸鹽;酸性殘基(諸如羧酸)之鹼性或有機鹽;及類似物。例如,此等鹽包括乙酸鹽、抗壞血酸鹽、苯磺酸鹽(benzenesulfonate)、苯甲酸鹽、苯磺酸鹽(besylate)、碳酸氫鹽、酒石酸氫鹽、溴化物/氫溴酸鹽、乙二胺四乙酸鹽、樟腦磺酸鹽、碳酸鹽、氯化物/鹽酸鹽、檸檬酸鹽、乙二磺酸鹽、乙烷二磺酸鹽、依託酸鹽(estolate)、乙磺酸鹽、富馬酸鹽、葡庚糖酸鹽、葡萄糖酸鹽、麩胺酸鹽、乙醇酸鹽、乙醇醯基胺基苯砒酸鹽(glycollylarsnilate)、己基間苯二酚鹽、海巴明(hydrabamine)、羥基馬來酸鹽、羥基萘、碘化物、羥乙基磺酸鹽(isothionate)、乳酸鹽、乳糖醛酸鹽、蘋果酸鹽、馬來酸鹽、扁桃酸鹽、甲磺酸鹽、甲基溴化物、甲基硝酸鹽、甲基硫酸鹽、黏酸鹽、萘磺酸鹽、硝酸鹽、草酸鹽、雙羥萘酸鹽、泛酸鹽、苯基乙酸鹽、磷酸鹽/二磷酸鹽、聚半乳糖醛酸鹽、丙酸鹽、水楊酸鹽、硬脂酸鹽、次乙酸鹽(subacetate)、琥珀酸鹽、磺醯胺、硫酸鹽、單寧酸鹽(tannate)、酒石酸鹽、茶氯酸鹽(teoclate)、甲苯磺酸鹽、三乙碘化物、銨、苄星(benzathine)、氯普魯卡因(chloroprocaine)、膽鹼、二乙醇胺、乙二胺、葡甲胺及普魯卡因。其他醫藥上可接受之鹽可由金屬(例如鋁、鈣、鋰、鎂、鉀、鈉、鋅及類似)之陽離子形成。(參見,例如,Pharmaceutical Salts,Birge, S.M.等人,J. Pharm. Sci.,(1977),66
,1-19)。
本發明之醫藥上可接受之鹽可藉由習知化學方法自含有鹼性或酸性部分之親體化合物合成。一般而言,此等鹽可藉由使該等化合物之游離酸或鹼形式與足量之適宜鹼或酸於水中或於有機稀釋劑(例如醚、乙酸乙酯、乙醇、異丙醇或乙腈、或其混合物)中反應來製備。
除上述酸之外的(例如)可用於純化或分離本發明之化合物之其他酸之鹽(例如三氟乙酸鹽)亦構成本發明的一部分。
此外,在本發明範圍內的係式(I)化合物之前藥。前藥包括彼等於簡單化學轉化後被改性以產生本發明化合物之化合物。簡單化學轉化包括水解、氧化及還原。具體而言,當將前藥投與患者時,前藥可轉化為上文所揭示的化合物,藉此賦予所需的藥理學效果。藉由保留對任何此群組(包括群組內的任何子範圍或子範圍之組合)的任何個別成員進行限制或排除的權利(該權利可根據范圍或以任何類似方式主張),可出於任何原因主張本發明之不完全措施。此外,藉由保留對任何個別取代基、類似物、化合物、配體、結構或其組別或所主張組別的任何成員進行限制或排除的權利,可出於任何原因主張本發明之不完全措施。
除非另作指明,否則術語「一」、「一個」及「該」意欲包括複數個替代物,例如,至少一個。例如,揭示內容「治療劑」或「化合物」意欲分別涵蓋一種治療劑或化合物、或多於一種治療劑或化合物之混合物或組合。
雖然組合物及方法係根據「包括」各種組分或步驟描述的,但該等組合物及方法亦可「基本上由」或「由」各種組分或步驟「組成」。例如,本文所述的藥物組合物可包含如下;替代性地,可基本上由如下組成;或替代性地,可由如下組成;(i)治療有效量之化合物或其醫藥上可接受之鹽、及(ii)醫藥上可接受之稀釋劑、賦形劑或載劑。
合成
本發明之化合物(包括其鹽)可採用已知的有機合成技術來製備且可根據多種可能的合成途徑(諸如下文方案中的彼等)中之任何一種來合成。
用於製備本發明之化合物之反應可在適宜溶劑中進行,該等溶劑可由熟習有機合成技術者輕易地選擇。適宜之溶劑可於進行反應的溫度(例如,可在溶劑的冷凍溫度至溶劑沸騰溫度範圍內之溫度)下與起始原料(反應物)、中間物或產物實質上不反應。給定的反應可在一種溶劑或多於一種溶劑之混合物中進行。取決於特定反應步驟,用於特定反應步驟之適宜溶劑可由熟習此項技術者選擇。
本發明化合物之製法可涉及各種化學基團之保護及去保護。對保護及去保護之需要及適宜保護基之選擇可由熟習此項技術者輕易地確定。保護基之化學述於(例如)Kocienski,Protecting Groups,(Thieme,2007);Robertson,Protecting Group Chemistry,(Oxford University Press,2000);Smith等人,March's Advanced Organic Chemistry: Reactions,Mechanisms,及Structure,第6版(Wiley,2007);Peturssion等人,「Protecting Groups in Carbohydrate Chemistry」,J. Chem. Educ.,1997,74(11),1297;及Wuts等人,Protective Groups in Organic Synthesis,第4版,(Wiley,2006)。
反應可根據本技術中已知的任何適宜方法監測。例如,產物形成可藉由光譜法監測,諸如核磁共振光譜法(例如,1
H或13
C)、紅外光譜法、分光光度法(例如,UV-可見光)、質譜法或藉由層析,諸如高效液相層析(HPLC)或薄層層析(TLC)。
以下方案提供與本發明化合物之製備有關的一般指導。熟習此項技術者將瞭解,該等方案中所顯示的製法可使用有機化學之一般知識來修改或最佳化,以製備本發明之各種化合物。
式(I)化合物可(例如)使用如下方案中所說明的方法來製備。
如方案1中所顯示,兩側為正交離去基之中間物II可與親核R8
H化合物反應以得到中間物III。然後使中間物III與含硫醇之肽(HS-R7
)反應,該肽參與二硫鍵交換反應以得到最終化合物。適宜離去基如下所述。
方案1:碳酸酯及胺甲酸酯連接之化合物之合成
胺縮醛連接之化合物之合成示於方案2中。使親核R8
H化合物與溴乙酸衍生物反應以得到中間物IV。使該含酯中間物在鹼性條件下水解得到中間物酸V。將所得酸轉化為醯基疊氮化物中間物且然後經歷Curtius重排條件。用含羥基之中間物I捕捉對應之瞬時異氰酸酯以得到中間物VII。然後使中間物VII與含硫醇之肽(HS-R7
)反應,該肽參與二硫鍵交換反應以得到最終化合物。
方案2:胺縮醛連接之化合物之合成
胺縮醛連接之共軛物之替代合成示於方案3中。使可包含保護基(PG)之親核R8
-H與具有預裝連接之離去基2之AcO-半胺縮醛胺甲酸酯VIII反應以得到中間物IX。用除去保護基之條件處理該化合物且使所得化合物VII與R7
-SH反應以得到所需共軛物。
方案3:胺縮醛連接之共軛物之合成2
胺縮醛連接之共軛物之另一替代合成示於方案4中。使具有預裝連接之離去基2之一級胺甲酸酯X與羰基化合物及對甲苯亞磺酸鈉鹽反應以得到磺醯基胺甲酸酯XI。用具有保護基(PG)之親核R8
-H進一步處理該磺醯基胺甲酸酯XI以得到IX。如前所述處理該化合物以得到所需共軛物。
方案4:胺縮醛連接之共軛物之合成3
硫丙酸酯連接之共軛物之示例性合成示於方案5中。使具有預裝離去基1及2之丙酸酯二硫鍵XII選擇性地與親核R8
-H反應以得到XII。使該化合物進一步與R7
-SH反應以得到所需共軛物。
方案5:硫丙酸酯連接之共軛物之合成1
硫丙酸酯連接之共軛物之替代合成示於方案6中。使硫羰基酯(Thionoester) XIV與親核R8
-H反應以得到丙酸酯硫醇XV。該化合物參與二硫鍵交換反應以得到XIII。用R7
-SH處理該化合物以得到所需共軛物
方案6:硫基丙酸酯連接之共軛物之合成2
對苯甲酸連接之共軛物之合成描繪於方案7中。對胺基苯甲醇XVI經氧下選擇性地保護以得到XVII。然後將其在苯胺位置處與II反應以得到胺甲酸芳酯XVIII。除去保護基得到游離OH XIX,用活化劑處理該游離OH XIX以得到含有正交離去基之XX。使XX與R8
-H反應以得到XXI,接著與R7
-SH反應以得到所需共軛物。
方案7:對苯甲酸連接之共軛物之合成1
對苯甲酸連接之共軛物之替代合成示於方案8中。使4-巰基苯甲醇XXII在二硫鍵交換反應中反應以得到含有離去基2之4-巰基苯甲醇二硫化物XXI。處理剩餘的芐醇以得到經活化之化合物XXIV。該經活化之化合物XXIV進一步選擇性地與親核R8
-H反應且所得XXV與R7
-SH反應以得到所需共軛物。
方案8:對苯甲酸連接之共軛物之合成2
鄰苯甲酸連接之共軛物之合成示於方案9中。使2-巰基苯甲醇XXVIII如前面針對方案8所述般進行反應以得到所需共軛物。
方案9:鄰苯甲酸連接之共軛物之合成
胺基酸苯甲酸胺甲酸酯連接之共軛物之合成示於方案10中。對胺基苯甲醇/異苯甲醇XVI可經選擇性地偶聯至N-保護的胺基酸或肽XXX以得到XXXI。可除去保護基以得到XXXII,然後使其與II反應以得到安裝離去基2之胺甲酸酯XXXIII。可選擇性地使醇反應以得到存有離去基1之碳酸酯XXXIV。離去基1可於隨後經R8
-H置換以得到XXXV,其與R7
-SH反應以得到所需胺基酸苯甲酸胺甲酸酯連接之共軛物。
方案10:胺基酸苯甲酸胺甲酸酯連接之共軛物之合成
胺基酸連接之共軛物之合成示於方案11中。N-保護的胺基酸或肽XXX可經偶聯至R8
-H以得到XXXVI。可除去保護基團以得到XXXVII,其於隨後可與II反應,置換離去基團1以得到XXXVIII。然後,可用R7
-SH處理該中間物以得到共軛物。
方案11:胺基酸連接之共軛物之合成
苯甲醇連接之葡萄糖醛酸苷共軛物之合成示於方案12中。2-硝基苯酚XXXIX可與受保護的葡萄糖醛酸苷XL偶聯以得到XLI。該中間物可在羰基上選擇性地還原以得到醇XLII且然後可還原硝基以得到苯胺XLIII。該中間物可進一步與丙酸衍生物XLIV偶聯以得到含有離去基2之醯胺XLV。然後,XLV可以在醇下反應以安裝離子基2,從而得到XLVI。離去基1可經R8
-H選擇性地置換以得到XLVII。可除去葡萄糖醛酸苷上的保護基且可使XLVIII與R7
-SH反應以得到共軛物。
方案12:苯甲醇連接之葡萄糖醛酸苷共軛物之合成
可藉由在緩衝液中用過量的麩胱甘肽(GSH)處理化合物且在37℃下培養來達成最終化合物裂解以釋放R8
H。在所需時間下使用逆相HPLC分析來追蹤裂解過程。
方案13:肽共軛物之裂解
肽R7
可採用最先在Merrifield in J.A.C.S.,第85卷,pgs. 2149-2154 (1963)中描述的固相合成法來製備,然而,亦可採用其他技術已知方法。Merrifield技術係很好理解的且係用於製備肽之常用方法。用於固相肽合成之有用的技術描述在若干書籍諸如教科書「Principles of Peptide Synthesis」,Bodanszky,Springer Verlag 1984中。該合成方法涉及將受保護的胺基酸逐步加入至生長之肽鏈中,該肽鏈係經共價鍵結合至固體樹脂顆粒。藉由該程序,藉由過濾除去試劑及副產物,藉此消除純化中間物的必要性。該方法的一般概念取決於將鏈的第一胺基酸經共價鍵連接至固體聚合物,接著以逐步方式一次一個地加入隨後的受保護的胺基酸,直到所需的序列組裝好。最後,從固體樹脂擔體上除去受保護的肽並切下保護基。
胺基酸可連接至任何適宜聚合物。該聚合物必須不溶於所用的溶劑中,必須具有允許準備過濾之穩定物理形式,且必須含有第一受保護的胺基酸可經共價鍵牢固地連接的官能基。各種聚合物適用於此目的,諸如纖維素、聚乙烯醇、聚甲基丙烯酸甲酯及聚苯乙烯。
使用方法
本發明之另一個態樣係式(I)化合物於治療涉及酸性或缺氧性患病組織之疾病諸如癌症、中風、心肌梗塞或長期神經退化性疾病中之用途。在一些實施例中,該癌症係PARP敏感的。在一些實施例中,該癌症係與ATM之異常表現或活性相關。在一些實施例中,該癌症係與ATM之異常表現或活性相關。在一些實施例中,該癌症係與DNA-PK之異常表現或活性相關。在一些實施例中,該癌症為BRCA突變之乳癌。在一些實施例中,該癌症為生殖系BRCA突變之卵巢癌。
3. 在此等治療方法中,治療有效量之式(I)化合物或其醫藥上可接受之鹽可作為單一藥劑或與其他治療形式(就癌症而言,諸如電離輻射或細胞毒性劑)組合投與。在組合療法中,式(I)化合物可於其他治療方式之前、同時或之後投與,如熟習此項技術者所理解。任何一種治療方法(單一藥劑或與其他治療形式之組合)可作為涉及一段時間內多種劑量或治療之治療過程投與。本文亦提供一種降低與電離輻射或細胞毒性劑之投與相關之骨髓毒性之方法,其包括對人類或其他哺乳動物投與治療有效量之本發明之化合物或其醫藥上可接受之鹽,與電離輻射或細胞毒性劑組合使用。當電離輻射或細胞毒性劑連同R8
H一起投與而不是具有相同R8
之本發明化合物(例如,其中R8
H化合物對應於本發明之R8
-Q-R7
化合物之質子化R8
部分)時,骨髓毒性之降低可能與觀察到的骨髓毒性有關。在一些實施例中,毒性可藉由骨髓組織中之PAR基化來測定。在一些實施例中,毒性可根據總成核骨髓細胞測定。在一些實施例中,細胞毒性劑可為彼等本文所列出的任何細胞毒性劑。在一些實施例中,該細胞毒性劑為替莫唑胺(TMZ)。
可使用本發明化合物治療之癌症之實例包括(但不限於)骨癌、胰癌、皮膚癌、頭頸癌、皮膚或眼內惡性黑色素瘤、子宮癌、卵巢癌、直腸癌、肛門癌、胃癌,睾丸癌、子宮癌、輸卵管癌、子宮內膜癌、子宮內膜癌、子宮頸癌、***癌、外陰癌、霍奇金病(Hodgkin's Disease)、非霍奇金淋巴瘤、食道癌、小腸癌、內分泌系統癌、甲狀腺癌、副甲狀腺癌、腎上腺癌、軟組織肉瘤、尿道癌、陰莖癌、慢性或急性白血病(包括急性骨髓性白血病、慢性骨髓性白血病、急性淋巴母細胞性白血病、慢性淋巴母細胞性白血病)、兒童實體腫瘤、淋巴球性淋巴瘤、膀胱癌、腎癌或尿道癌、腎盂癌、中樞神經系統(CNS)腫瘤、原發性CNS淋巴瘤、腫瘤血管生成、脊髓軸腫瘤、腦幹膠質瘤、垂體腺瘤、卡波西氏(Kaposi's)肉瘤、表皮樣癌、鱗狀細胞癌、T細胞淋巴瘤、環境引起之癌症(包括彼等由石棉引起之癌症)及該等癌症之組合。
在一些實施例中,可用本發明化合物治療之癌症包括黑色素瘤(例如,轉移性惡性黑色素瘤)、腎癌(例如,透明細胞癌)、***癌(例如,激素難治性***腺癌)、乳癌、三陰性乳癌、結腸癌及肺癌(例如,非小細胞肺癌及小細胞肺癌)。另外,本發明包括可使用本發明之化合物抑制生長的難治性或複發性惡性病。
在一些實施例中,可使用本發明化合物治療之癌症包括(但不限於)實體腫瘤(例如,***癌、結腸癌、食道癌、子宮內膜癌、卵巢癌、子宮癌、腎癌、肝癌、胰癌、胃癌、乳癌、肺癌,頭頸癌、甲狀腺癌、神經膠質母細胞瘤、肉瘤、膀胱癌等)、血液性癌症(例如,淋巴瘤、白血病(諸如急性淋巴母細胞性白血病(ALL)、急性骨髓性白血病(AML)、慢性淋巴球性白血病(CLL)、慢性骨髓性白血病(CML))、DLBCL、套細胞淋巴瘤、非霍奇金淋巴瘤(包括復發性或難治性NHL及復發性濾泡)、霍奇金淋巴瘤或多發性骨髓瘤)及該等癌症之組合。
在某些實施例中,式(I)化合物或其醫藥上可接受之鹽可與化療劑、靶向癌症療法、免疫療法或放射療法組合使用。該等藥劑可與本發明之化合物組合成單一劑型,或該等藥劑可呈單獨劑型同時或依序投與。在一些實施例中,化治劑、靶向癌症療法、免疫療法或放射療法對患者的毒性較小,諸如藉由相較於當與對應之游離DNA修復抑制化合物(例如,R8
-H)(諸如如本文所述的PARP、ATR、DNK-PK或ATM之抑制劑)組合投與時,當連同式(I)化合物或其醫藥上可接受之鹽一起投與時顯示降低的骨髓毒性。
適宜之化療劑或其他抗癌劑包括(例如)烷基化劑(包括(但不限於)氮芥、伸乙亞胺衍生物、烷基磺酸鹽、亞硝基脲及三氮烯),諸如尿嘧啶氮芥、氮芥(chlormethine)、環磷醯胺(CytoxanTM
)、異環磷醯胺、美法崙(melphalan)、苯丁酸氮芥(chlorambucil)、哌泊溴烷(pipobroman)、三伸乙基三聚氰胺、三伸乙基硫基磷胺、白消安(busulfan)、卡莫司汀(carmustine)、洛莫司汀(lomustine)、鏈脲黴素、達卡巴嗪(dacarbazine)及替莫唑胺。
與本發明化合物組合使用的其他適宜試劑包括:達卡巴嗪(DTIC),視需要,連同其他化療藥物(諸如卡莫司汀(BCNU)及順鉑)一起;達特茅斯方案,其係由DTIC、BCNU、順鉑及他莫昔芬(tamoxifen)組成;順鉑、長春花鹼(vinblastine)及DTIC之組合;或替莫唑胺。根據本發明之化合物亦可與免疫治療藥物(包括細胞介素,例如干擾素α、介白素2及腫瘤壞死因子(TNF))組合。
適宜之化療劑或其他抗癌劑包括(例如)抗代謝物(包括(但不限於)葉酸拮抗劑、嘧啶類似物、嘌呤類似物及腺苷脫胺酶抑制劑),諸如甲胺蝶呤、5-氟尿嘧啶、氟尿苷、阿糖胞苷、6-巰基嘌呤、6-硫鳥嘌呤、氟達拉濱(fludarabine)磷酸鹽、噴司他汀(pentostatine)及吉西他濱(gemcitabine)。
適宜之化療劑或其他抗癌劑進一步包括(例如)某些天然產物及其衍生物(例如,長春花生物鹼(vinca alkaloids)、抗腫瘤抗生素、酵素、淋巴細胞活素及表鬼臼毒素(epipodophyllotoxin)),諸如長春花鹼、長春新鹼(vincristine)、長春地辛(vindesine)、博來黴素(bleomycin)、放線菌素(dactinomycin)、柔紅黴素(daunorubicin)、多柔比星(doxorubicin)、表柔比星(epirubicin)、伊達比星(idarubicin)、ara-C、太平洋紫杉醇(paclitaxel)(TAXOLTM
)、光輝黴素(mithramycin)、去氧助间霉素(deoxycoformycin)、絲裂黴素-C、L-天冬醯胺酸酶、干擾素(尤其係IFN-α)、依托泊苷(etoposide)及替尼泊苷(teniposide)。
可與本發明化合物組合投與的其他細胞毒性劑包括(例如)納瓦賓(navelbene)、CPT-11、阿那曲唑(anastrazole)、來曲唑(letrazole)、卡培他濱(capecitabine)、雷洛昔芬(reloxafine)、環磷醯胺、異環磷醯胺及屈洛昔芬(droloxafine)。
細胞毒性劑亦適宜,諸如(例如)表葉毒素(epidophyllotoxin);抗腫瘤酵素;拓撲異構酶抑制劑;丙卡巴肼(procarbazine);米托蒽醌(mitoxantrone);鉑配位錯合物,諸如順鉑及卡鉑(carboplatin);生物反應調節劑;生長抑制劑;抗激素治療劑;甲醯四氫葉酸(leucovorin);替加氟(tegafur);及造血生長因子。
其他抗癌劑包括抗體治療劑(諸如曲妥珠單抗(trastuzumab)(Herceptin))、共刺激分子抗體(諸如CTLA-4,4-1BB及PD-1)或細胞介素抗體(IL-10、TGF-α等)。
其他抗癌劑亦包括彼等阻斷免疫細胞遷移之抗癌劑,諸如趨化激素受體拮抗劑,包括CCR2及CCR4。
其他抗癌劑亦包括彼等增強免疫系統之抗癌劑,諸如佐劑或過繼性T細胞轉移。
可與本發明化合物組合投與的抗癌疫苗包括(例如)樹突細胞、合成肽、DNA疫苗及重組病毒。
與本發明化合物組合使用的其他適宜試劑包括化療組合,諸如用於肺癌及其他實體腫瘤中之鉑基雙聯體(doublet)(順鉑或卡鉑加上吉西他濱;順鉑或卡鉑加上多烯紫杉醇(docetaxel);順鉑或卡鉑加上太平洋紫杉醇;順鉑或卡鉑加上培美曲塞(pemetrexed))或吉西他濱加上紫杉醇結合顆粒(Abraxane®)。
本發明之化合物可有效地與抗激素劑組合用於治療乳癌及其他腫瘤。適宜實例為抗***藥劑(包括(但不限於)他莫昔芬及托瑞米芬(toremifene))、芳香酶抑制劑(包括(但不限於)來曲唑(letrozole)、阿那曲唑(anastrozole)及依西美坦(exemestane))、腎上腺皮質激素(例如潑尼松(prednisone))、孕激素(例如甲地孕酮乙酸鹽)及***受體拮抗劑(例如氟維司群(fulvestrant))。用於治療***癌及其他癌症之適宜抗激素劑亦可與本發明化合物組合。此等包括抗雄激素藥(包括(但不限於)氟他胺(flutamide)、比卡魯胺(bicalutamide)及尼魯米特(nilutamide))、黃體化激素釋放激素(LHRH)類似物(包括亮丙瑞林(leuprolide)、戈舍瑞林(goserelin)、曲普瑞林(triptorelin)及組胺瑞林(histrelin))、LHRH拮抗劑(例如,地加瑞克(degarelix))、雄激素受體阻斷劑(例如,恩雜魯胺(enzalutamide))及抑制雄激素生成之藥劑(例如阿比特龍(abiraterone))。
本發明之化合物可與針對膜受體激酶之其他藥劑組合或依次投與,特別係對於已經對靶向療法發展出原發性或獲得性抗性的患者。此等治療劑包括針對EGFR、Her2、VEGFR、c-Met、Ret、IGFR1或Flt-3之抑制劑或抗體及針對癌症相關融合蛋白激酶(例如Bcr-Abl及EML4-Alk)之抑制劑或抗體。針對EGFR之抑制劑包括吉非替尼(gefitinib)及厄洛替尼(erlotinib),及針對EGFR/Her2之抑制劑包括(但不限於)達克替尼(dacomitinib)、阿法替尼(afatinib)、腹替尼(lapitinib)及奈拉替尼(neratinib)。針對EGFR之抗體包括(但不限於)西妥昔單抗(cetuximab)、帕尼單抗(panitumumab)及奈西木單抗(necitumumab)。c-Met之抑制劑可與本發明之化合物組合使用。此等包括奧土珠單抗(onartumzumab)、地法替尼(tivantnib)及INC-280。針對Abl (或Bcr-Abl)之藥劑包括伊馬替尼(imatinib)、達沙替尼(dasatinib)、尼羅替尼(nilotinib)及普納替尼(ponatinib)及針對Alk (或EML4-ALK)之彼等藥劑包括克唑替尼(crizotinib)。
血管生成抑制劑在一些腫瘤中與本發明之化合物組合可為有效的。此等包括針對VEGF或VEGFR之抗體或VEGFR之激酶抑制劑。針對VEGF之抗體或其他治療性蛋白質包括貝伐單抗(bevacizumab)及阿柏西普(aflibercept)。VEGFR激酶之抑制劑及其他抗血管生成抑制劑包括(但不限於)舒尼替尼(sunitinib)、索拉非尼(sorafenib)、阿西替尼(axitinib)、西地尼布(cediranib)、帕唑帕尼(pazopanib)、瑞格非尼(regorafenib)、布麗凡尼(brivanib)及凡德他尼(vandetanib)。
細胞內信號傳導途徑之活化在癌症中係常見的,且靶向此等途徑之組分之藥劑已與受體靶向劑組合以增強效力並降低抗性。可與本發明化合物組合的藥劑之實例包括PI3K-AKT-mTOR途徑之抑制劑、Raf-MAPK途徑之抑制劑、JAK-STAT途徑之抑制劑、及蛋白質伴護蛋白及細胞週期進程之抑制劑。
針對PI3激酶之藥劑包括(但不限於)托拉里斯(topilaralisib)、艾代拉里斯(idelalisib)、布帕里斯(buparlisib)。mTOR之抑制劑(諸如雷帕黴素(rapamycin)、西羅莫司(sirolimus)、替西羅莫司(temsirolimus)及依維莫司(everolimus))可與本發明之化合物組合。其他適宜實例包括(但不限於)維羅非尼(vemurafenib)及達拉菲尼(dabrafenib)(Raf抑制劑)及曲美替尼(trametinib)、司美替尼(selumetinib)及GDC-0973(MEK抑制劑)。一或多種JAK(例如,魯索替尼(ruxolitinib)、巴瑞克替尼(baricitinib)、托法替尼(tofacitinib))、Hsp90(例如,坦螺旋黴素(tanespimycin))、細胞週期蛋白依賴性激酶(例如,帕布昔利布(palbociclib)),HDAC(例如,帕比司他(panobinostat)),PARP(例如,奧拉帕利(olaparib))及蛋白酶體(例如,硼替佐米(bortezomib)、卡非佐米(carfilzomib))之抑制劑亦可與本發明之化合物組合。
熟習此項技術者已知用於安全且有效地投與大多數此等化療劑之方法。另外,其投與述於標准文獻中。例如,許多化療劑之投與述於「Physicians' Desk Reference」 (PDR,例如,1996版,Medical Economics Company,Montvale,NJ)中,該案之全文以引用的方式併入本文中。
片語化合物(治療劑、活性成分、藥物等)之「治療有效量」係指欲投與需要療法或治療之個體之化合物的量,根據欲治療的病症或病況之臨床上可接受之標準,該量減輕症狀,改善病況,或減慢疾病發作病況。例如,治療有效量可為已證實在體外分析、體內動物分析或臨床試驗中具有所需治療效果的量。治療有效量可基於特定劑型、投藥方法、治療方案、欲治療的特定疾病或病況、效益/風險比等及許多其他因素改變。
該治療有效量可自臨床試驗、動物模型或體外細胞培養分析中獲得。本技術中已知適於人類使用的有效量可自藉由動物模型或體外細胞培養分析確定的有效量計算得。例如,據Reagan-Shaw等人,FASEB J. 2008:22(3) 659-61報導,「μg/ml」(基於體外培養分析之有效量)=「mg/kg體重/天」(用於小鼠之有效量)。此外,用於人類之有效量可基於小鼠代謝速率比人類代謝速率快6倍的事實,從用於小鼠之有效量來計算。
作為使用式(I)化合物作為單藥療法之治療之實例,可將治療有效劑量之式(I)化合物(其中R8
H為PARP抑制劑)投與罹患PARP依賴性癌症之患者(諸如罹患BRCA突變乳癌、生殖系BRCA突變卵巢癌或輸卵管癌之女性)或罹患原發性腹膜癌、鱗狀細胞肺癌或非小細胞肺癌之患者、或罹患中風、心肌梗塞或長期神經退化性疾病之患者。作為另一個實例,可將治療有效劑量之式(I)化合物(其中R8
H為靶向蛋白激酶共濟失調-毛細血管擴張突變(ATM)之DNA修復抑制劑、ATM-Rad3相關蛋白激酶(ATR)或核絲胺酸/蘇胺酸蛋白激酶DNA-PK)投與罹患癌症之患者,其中一或多種上述蛋白質之抑制將係治療上有用的。
作為使用式(I)化合物與細胞毒性劑組合治療的實例,可將治療有效量之式(I)化合物作為治療方案的部分投與罹患癌症的患者,亦涉及治療有效量之電離輻射或細胞毒性劑。在該治療方案之背景下,術語「治療有效」量應理解為意指在組合療法中有效。熟習癌症治療領域者將明瞭如何調整劑量以達成最佳治療結果。
類似地,熟習醫學技術者可輕易地確定用於治療非癌性疾病或病況(諸如心血管疾病)之本發明化合物之適宜劑量。
如本文所用,術語「治療」包括投與化合物或組合物,相對於未接受該化合物或組合物之個體,該化合物或組合物於一個體中降低涉及酸性或缺氧性患病組織之疾病(諸如癌症、中風、心肌梗塞或長期神經退化性疾病)之頻率,延遲其發作或減少其症狀之進展。此可包括以增進或穩定個體病況的方式逆轉、減少或阻止病況之症狀、臨床徵兆或潛在病理(例如,就癌症而言,腫瘤生長消退,或在心肌梗塞、中風或類似心血管疾病中減少或改善心肌缺血再灌流損傷)。術語「抑制」或「減少」參照方法用於癌症,相較於未治療的對照群體,抑制或減少群體中腫瘤生長(例如,減小腫瘤尺寸)。
本文提及的所有公開案(包括專利)係針對描述及揭示(例如)公開案中所述構築體及方法(其可與本文所述的揭示內容結合使用)之目的以引用的方式併入本文中。本文中論述的公開案僅係為了在本申請案的提交日之前揭示。
本文揭示幾種類型之範圍。當揭示或主張任何類型之範圍時,意圖係單獨地揭示或主張此種範圍可合理地涵蓋的每個可能的數字(包括該範圍的端點)及涵蓋於其中的任何子範圍及子範圍之組合。例如,當揭示或主張活性成分之有效量之範圍時,意圖係單獨地揭示或主張此範圍可涵蓋的每個可能的數字,與本文揭示內容一致。例如,揭示化合物之治療有效量可在約1 mg/kg至約50 mg/kg (個體體重)範圍內,意圖係敘述該治療有效量可等於約1 mg/kg、約2 mg/kg、約3 mg/kg、約4 mg/kg、約5 mg/kg、約6 mg/kg、約7 mg/kg、約8 mg/kg、約9 mg/kg、約10 mg/kg、約11 mg/kg、約12 mg/kg、約13 mg/kg、約14 mg/kg、約15 mg/kg、約16 mg/kg、約17 mg/kg、約18 mg/kg、約19 mg/kg、約20 mg/kg、約21 mg/kg、約22 mg/kg、約23 mg/kg、約24 mg/kg、約25 mg/kg、約26 mg/kg、約27 mg/kg、約28 mg/kg、約29 mg/kg、約30 mg/kg、約31 mg/kg、約32 mg/kg、約33 mg/kg、約34 mg/kg、約35 mg/kg、約36 mg/kg、約37 mg/kg、約38 mg/kg、約39 mg/kg、約40 mg/kg、約41 mg/kg、約42 mg/kg、約43 mg/kg、約44 mg/kg、約45 mg/kg、約46 mg/kg、約47 mg/kg、約48 mg/kg、約49 mg/kg或約50 mg/kg。另外,該治療有效量可在涵蓋於約1 mg/kg至約50 mg/kg中之任一子範圍內(例如,該量可在約2 mg/kg至約10 mg/kg範圍內),且該治療有效量亦包括介於約1 mg/kg與約50 mg/kg之間的範圍之任何組合(例如,該量可在約1 mg/kg至約5 mg/kg或約20 mg/kg至約35 mg/kg範圍內)。同樣地,本文所揭示的所有其他範圍應以類似於該實例之方式解釋。
調配、劑型及投藥
為製備本發明之藥物組合物,根據習知藥物複合技術將式(I)化合物或其醫藥上可接受之鹽作為活性成分與藥物載劑緊密混合,該載劑可採用多種形式,取決於投藥(例如經口或非經腸)所需的製劑形式。在製備呈口服劑型之組合物中,可使用任何常用的藥物介質,諸如(例如),在口服液體製劑(諸如(例如),懸浮液、酏劑及溶液)的情況下,水、二醇、油、醇、矯味劑、防腐劑、著色劑及類似物;或在口服固體製劑(諸如(例如)粉末、膠囊及錠劑)的情況下,載劑諸如澱粉、糖、稀釋劑、粒化劑、潤滑劑、黏合劑、崩解劑及類似物。由於其等易於投與,故錠劑及膠囊代表最有利的口服單位劑型,在該情況中明顯會使用固體藥物載劑。若需要,可藉由標準技術將錠劑用糖包覆或用腸衣包覆。對於非經腸投與,載劑通常包括無菌水,但可包括其他成分(例如)以幫助溶解或用於防腐目的。亦可製備可注射之懸浮液,在該情況中,可使用適宜液體載劑、懸浮劑及類似物。對於欲治療的特定疾病或病況,熟習藥學及醫學技術者將能夠輕易地確定本發明之藥物組合物之合適劑量。
實例
如本文所使用,所用縮寫、符號及約定均符合彼等用於當代科學文獻中者。參見,例如,Janet S. Dodd編,The ACS Style Guide:A Manual for Authors and Editors,第2版,Washington, D.C.:American Chemical Society,1997。以下定義描述本文所使用的術語及縮寫:
● 鹽水:於水中之飽和NaCl溶液
● DCM:二氯甲烷
● TFA:三氟乙酸
● DIPEA:二異丙基乙胺
● DMA:二甲基乙醯胺
● DME:二甲氧基乙烷
● DMF:二甲基甲醯胺
● DMSO:甲基亞碸
● DTT:二硫蘇糖醇
● MSD:質譜檢測器
● Et2
O:***
● EtOAc:乙酸乙酯
● EtOH:乙醇
● HATU:O-(7-氮雜苯并***-1-基)-N,N,N′,N′-四甲基脲鎓六氟磷酸鹽
● HOBt:1-羥基苯并***
● RP:逆相
● HPLC:高效液相層析
● IPA:異丙醇
● LAH:氫化鋰鋁
● N-BuLi:正丁基鋰
● LC-MS:液相層析-質譜法
● LDA:二異丙基乙基醯胺鋰
● Me:甲基
● MeOH:甲醇
● MTBE:甲基第三丁基醚
● NMP:N-甲基吡咯啶
● Ph:苯基
● PNPC:氯甲酸對硝基苯基酯
● RT或rt:室溫
● SFC:超臨界流體層析
● TBAI:碘化四丁基銨
● TBME:第三丁基甲基醚
● tBu:第三丁基
● THF:四氫呋喃
● TEA:三乙胺
● TMEDA:四甲基乙二胺
● GSH:麩胱甘肽
● GS:於硫處所鍵結的麩胱甘肽
● LiOH:氫氧化鋰
● DPPA:二苯基磷醯基疊氮化物
● Sn(Bu)2
(月桂酸酯)2
:二月桂酸二丁基錫
● PBS:磷酸鹽緩衝鹽水
● ACN:乙腈
● AcOH:乙酸
● EEDQ:N-乙氧基羰基-2-乙氧基-1,2-二氫喹啉
● DMAP:4-二甲基胺基吡啶
● EDC:1-乙基-3-(3-二甲基胺基丙基)碳化二亞胺
HPLC法
所有HPLC法使用逆相條件:H2
O/乙腈/TFA改性劑(0.05%);流速:1 mL/min;波長 = 217 nm。管柱條件述於下列:
A:Sunfire C18 150x4.6mm
B:Ace Equivalence 250x4.6 mm
C:Sunfire C18 150x30 mm
R8
H 中間物
用於所有實例中之R8
H組係購買的或如表2中所示合成。
表2:R8
H中間物
連接子
本文所使用的連接子係購買的或如表3中所示合成:
表3:市售連接子
連接子 L4 : (2R)-2- 硫基丙 -1- 醇 步驟 1 : (2R)-2- 乙醯基硫基丙酸甲酯
將硫乙酸(2.24 g,29.4 mmol)及碳酸銫(7.98 g,24.5 mmol)溶解於40 mL無水DMF中。在RT下攪拌該混合物30分鐘,接著加入(2S)-2-氯丙酸甲酯(3.00 g,24.5 mmol)。然後再攪拌該混合物3小時。加入***(150 mL)及水(150 mL)且分離層。用額外的醚洗水層且經過Na2
SO4
乾燥已合併的有機物。濃縮有機層且藉由管柱層析(SiO2
,0-10% EtOAc/己烷)純化殘餘物以得到3.50 g、88%之(2R)-2-乙醯基硫基丙酸甲酯。
步驟 2 : (2R)-2- 硫基丙 -1- 醇
在0℃下將(2R)-2-乙醯基硫基丙酸甲酯(3.50 g,21.6 mmol)於THF (30 mL)中之溶液滴加至LAH (4.10 g,108 mmol)於THF (60 mL)中之懸浮液。於加入完成後,在RT下攪拌該混合物3小時。將反應冷卻至0℃,然後藉由滴加2N HCl (~75mL)淬滅。於加入完成後,在RT下攪拌該混合物1小時。以CH2
Cl2
(5×100 mL)萃取該混合物且用Na2
SO4
乾燥。粗(2R)-2-硫基丙-1-醇(1.60 g,81%)無需進一步純化即可使用。
連接子 XXII-2 : (3- 甲基 -4- 硫基 - 苯基 ) 甲醇
步驟1:4-((3-((2-乙基己基)氧基)-3-側氧基丙基)硫基)-3-甲基苯甲酸酯
將DIPEA (0.32 mL,1.80 mmol)、氧雜蒽膦(Xanthphos)(0.005 g,0.009 mmol)加入至4-溴-3-甲基苯甲酸甲酯(0.20 g,0.88 mmol)及3-巰基丙酸2-乙基己酯(0.21 g,0.96 mmol)於1,4-二噁烷(2 mL)中之攪拌溶液。用氬氣沖洗反應混合物5分鐘。加入Pd(dba)3
(0.008 g,0.009 mmol)且在100℃下加熱該反應混合物6小時。反應完成後,用水(10 mL)淬滅該反應混合物,且萃取至乙酸乙酯(20 mL)中。用氯化鈉溶液(20 mL)洗有機層且經過Na2
SO4
乾燥以得到粗產物。藉由快速層析(SiO2
,0-5%乙酸乙酯/己烷)純化粗產物以得到呈黃色液體(0.2 g,62%產率)之4-((3-((2-乙基己基)氧基)-3-側氧基丙基)硫基)-3-甲基苯甲酸酯。MS m/z 367.1 [M+H]+
。
步驟2:4-巰基-3-甲基苯甲酸乙酯
將4-((3-((2-乙基己基)氧基)-3-側氧基丙基)硫基)-3-甲基苯甲酸甲酯(0.20 g,0.54 mmol)於THF(5 mL)中之攪拌溶液冷卻至0℃。加入乙醇鈉(35 wt.%,2 mL)且在室溫下攪拌該混合物4小時。反應完成後,用2N HCl (10 mL)酸化該反應混合物並濃縮。將所得殘餘物萃取至乙酸乙酯(20 mL)中。用水(20 mL)、飽和氯化鈉溶液(20 mL)洗有機層且經過Na2
SO4
乾燥以得到呈無色液體(80 mg,80%產率)之4-巰基-3-甲基苯甲酸乙酯。MS m/z 197.1 [M+H]+
。
步驟3:(3-甲基-4-硫基-苯基)甲醇
將LAH於THF (7.80 mL,7.80 mmol)中之1M溶液慢慢地加入至維持在0℃的4-巰基-3-甲基苯甲酸乙酯(0.60 g,3.07 mmol)於THF (20 mL)中之攪拌溶液。在室溫下攪拌反應混合物3小時。反應完成後,將該反應混合物冷卻至0℃且用水(20 mL)淬滅。於淬滅期間,使溫度維持低於20℃。完成猝滅後,用2N HCl將pH調節至2-3。將所得殘餘物萃取至乙酸乙酯(20 mL)中且用氯化鈉溶液(20 mL)洗有機層。經過Na2
SO4
乾燥有機層以得到粗產物。藉由快速層析(SiO2,0-20%乙酸乙酯/己烷)純化該粗產物以得到呈無色液體(0.45 g,90%產率)之(3-甲基-4-硫基-苯基)甲醇。MS m/z 153.0 [M-H]-
。
如下表4中所示,以類似於連接子XXII-2的方法合成XXII-3及XXII-4。
表4:另外連接子
中間物 中間物 I-1 : 2-(2- 吡啶基二硫基 ) 乙醇
將2-硫基乙醇(0.498 mL,7.10 mmol)以逐滴方式加入至2-(2-吡啶基二硫基)吡啶(4.693 g,21.3 mmol)於40 ml經脫氣(N2
)之MeOH。於N2
下攪拌該混合物2-20小時。將該混合物濃縮至乾燥且直接純化(SiO2
,0-5% EtOAc/CH2
Cl2
)以得到3個溶離份;(F1混合物SM A及產物;F2產物;F3 2-硫基吡啶/產物混合物)。非純物質經再次純化(SiO2
,0-50% EtOAc/己烷)以得到1.17 g、88%產率之2-(2-吡啶基二硫基)乙醇。MS m/z實測值188.4 [M+H]+
類似於中間物I-1製備示於表5中之以下中間物。
表5.中間物
中間物 I-3 : 2- 甲基 -2-[(5- 硝基 -2- 吡啶基 ) 二硫基 ] 丙 -1- 醇
於4℃在N2
氛圍下將SO2
Cl2
(0.382 mL,4.71 mmol)滴加至5-硝基吡啶-2-硫醇(668 mg,4.28 mmol)於無水DCM(15 mL)中之攪拌懸浮液。反應混合物從黃色懸浮液變為黃色溶液且在攪拌下讓其升至室溫2小時,於該時間後,濃縮該混合物以得到黃色固體。將固體再溶解於DCM (15 mL)中且於4℃在N2
氛圍下用2-甲基-2-硫基-丙-1-醇(454 mg,4.28 mmol)於無水DCM (10 mL)中之溶液逐滴處理。使反應混合物升至室溫且攪拌20小時。藉由LC/MS監測反應以得到所需產物質量。將50 mL H2
O加入至該混合物且用氫氧化銨溶液處理經稀釋之混合物。用50 mL EtOAc稀釋該反應混合物,分層,及分離。用MgSO4
乾燥有機相,過濾,然後濃縮以得到粗產物。純化(SiO2
,0-50% EtOAc/己烷)該粗產物以得到721 mg、65%產率之2-甲基-2-[(5-硝基-2-吡啶基)二硫基]丙-1-醇。MS m/z實測值261.7 [M+H]+
。
中間物 I-4 : (2R)-2-(2- 吡啶基二硫基 ) 丙 -1- 醇
將(2R)-2-硫基丙-1-醇(0.75 g,8.14 mmol)以逐滴方式加入至於經N2
脫氣之40 ml MeOH中之2-(2-吡啶基二硫基)吡啶(5.00 g,22.7 mmol)。於N2
下攪拌該混合物2小時。濃縮該混合物至乾燥且直接加載至SiO2
快速管柱且用0-50% EtOAc/己烷洗脫以得到1.17 g、71% (2R)-2-(2-吡啶基二硫基)丙-1-醇。MS m/z實測值202.1 [M+H]+
中間物 I-5
以類似於中間物I-4的方式自L-5製備中間物I-5。
中間物 I-6
類似於中間物I-3自連接子L-6製備中間物I-6。
中間物 XII 之合成
表6.中間物XII
中間物 XII-1 之合成: 4-(2- 吡啶基二硫基 ) 丁酸
將4-硫基丁酸(500 mg,4.16 mmol)以逐滴方式加入至於20 ml經脫氣(N2
)之MeOH中之2-(2-吡啶基二硫基)吡啶(1120 mg,5.08 mmol)。於N2
下攪拌該混合物16小時。濃縮該混合物至乾燥且藉由逆相層析(Sunfire C18,30x150 mm,5-95% CH3
CN/H2
O,0.05% TFA)純化以得到187 mg、19.6%之4-(2-吡啶基二硫基)丁酸。MS m/z實測值230.0 [M+H]+
。
中間物 XIX-1 : N-[4-( 羥基甲基 ) 苯基 ] 胺甲酸 2-(2- 吡啶基二硫基 ) 乙酯
步驟1:4-[[第三丁基(二甲基)矽基]氧基甲基]苯胺之合成
於30分鐘內將(4-胺基苯基)甲醇(5.00 g,40.6 mmol)於無水DMF(10 mL)中之溶液滴加至第三丁基-氯-二甲基-矽烷(7.34 g,48.7 mmol)及咪唑(7.90 mL,81.2 mmol)於無水DMF(40 mL)中之攪拌溶液。室溫下攪拌16小時後,將反應混合物倒入至水(400 mL)中且以CH2
Cl2
(3 × 100 mL)萃取。用水(2 × 100 mL)洗已合併的有機層且經過MgSO4乾燥。於真空中移除揮發物後,藉由管柱層析(SiO2,0-25% EtOAc/己烷)純化殘餘物,得到4-[[第三丁基(二級胺基)矽基]氧基甲基]苯胺(7.91 mg,33.3 mmol,產率:82.1%)。
步驟2:N-[4-[[第三丁基(二甲基)矽基]氧基甲基]苯基]胺甲酸2-(2-吡啶基二硫基)乙酯之合成
將4-[[第三丁基(二甲基)矽基]氧基甲基]苯胺(202 mg,0.85 mmol)、1-羥基苯并***水合物(104 mg,0.68 mmol)及200 mg經活化之4 A Mol篩加入至於2 mL DMF中之碳酸(4-硝基苯基酯) 2-(2-吡啶基二硫基)乙酯(200 mg,0.57 mmol)。攪拌該混合物18小時。濾去固體且用2 mL DMF沖洗矽藻土塞柱。濃縮濾液至乾燥且藉由管柱層析(SiO2,0-50% EtoAc/己烷)純化殘餘物以得到N-[4-[[第三丁基(二甲基)矽基]氧基甲基]苯基]胺甲酸2-(2-吡啶基二硫基)乙酯(244 mg,0.54 mmol,產率:95.4%)。
步驟3:N-[4-(羥基甲基)苯基]胺甲酸2-(2-吡啶基二硫基)乙酯
將N-[4-[[第三丁基(二甲基)矽基]氧基甲基]苯基]-胺甲酸2-(2-吡啶基二硫基)乙酯(194 mg,0.430 mmol)溶解於2 mL THF中且於N2
下冷卻至0℃。加入HF-吡啶(780 µL,8.89 mmol)且於0℃下繼續攪拌溶液1小時。加入水(3 mL),且用飽和NaHCO3
中和反應並以CH2
Cl2
(3X50 mL)萃取。濃縮有機層且藉由管柱層析(SIO2
,0-75% EtOAc/己烷)純化以得到N-[4-(羥基甲基)苯基]胺甲酸2-(2-吡啶基二硫基)乙酯(99.1 mg,0.29 mmol,產率:68.4%)。
中間物 XXIII-1 : [4-(2- 吡啶基二硫基 ) 苯基 ] 甲醇
於N2
下使1,2-二(吡啶-2-基)二硫烷(2.68 g,12.1 mmol)於AcOH:乙醇(5 mL,1:10)溶劑中之攪拌溶液脫氣。此後,歷時20分鐘滴加於AcOH/乙醇(5 mL)溶劑混合物中之4-巰基苯基)甲醇(0.74 g,5.2 mmol)且於N2
氛圍在室溫下攪拌12小時。於減壓下濃縮反應以得到粗產物,藉由管柱層析(SiO2
,60-70% EtOAc/己烷)純化該粗產物以得到呈無色液體(800 mg,61%產率)之[4-(2-吡啶基二硫基)苯基]甲醇。
中間物 XXIII-2 : [3- 甲基 -4-(2- 吡啶基二硫基 ) 苯基 ] 甲醇
用N2
沖洗溶解於乙酸/乙醇(1:10,37 mL)中之1,2-二(吡啶-2-基)二硫烷(1.10 g,4.90 mmol)之攪拌溶液5分鐘。歷時20分鐘時間將4-巰基-3-甲基苯基)甲醇(0.51 g,3.30 mmol)於乙酸/乙醇(1:10,18 mL)中之溶液滴加該溶液。於室溫下攪拌所得反應混合物16小時。反應完成後,於減壓下濃縮該混合物以得到粗產物。藉由快速層析(SiO2
,0-70 % EtOAc/己烷梯度)純化該粗產物以得到呈無色液體(0.69 g,80%產率)之[3-甲基-4-(2-吡啶基二硫基)苯基]甲醇。MS m/z實測值264.0 [M+H]+
。
中間物 XXIII-3 及 XXIII-4
類似於XXIII-2製備顯示於表7中之中間物XXIII-3及XXIII-4。
表7.中間物XXIII 自中間物 XXXII 製備 中間物 XXXIII
表8.中間物XXXIII 中間物 XXXIII-1 之合成 : N-[(1S)-1-[[(1S)-1-[[4-( 羥基甲基 ) 苯基 ] 胺甲醯基 ]-4- 脲基 - 丁基 ] 胺甲醯基 ]-2- 甲基 - 丙基 ] 胺甲酸 2-(2- 吡啶基二硫基 ) 乙酯
於N2
下將N,N-二異丙基乙胺(0.122 mL,0.659 mmol)及碳酸(4-硝基苯基酯) 2-(2-吡啶基二硫基)乙酯(92.9 mg,0.264 mmol)加入至於2 mL無水DMF中之(2S)-2-[[(2S)-2-胺基-3-甲基-丁醯基]胺基]-N-[4-(羥基甲基)苯基]-5-脲基-戊醯胺(100 mg,0.264 mmol)。於N2
下攪拌該混合物16小時。濃縮該混合物至固體。於SiO2
管柱(12 g,0-10% MeOH/CH2
Cl2
)上純化粗殘餘物以得到N-[(1S)-1-[[(1S)-1-[[4-(羥基甲基)苯基]胺甲醯基]-4-脲基-丁基]胺甲醯基]-2-甲基-丙基]胺甲酸2-(2-吡啶基二硫基)乙酯(149 mg,0.251 mmol,產率:95.4%)。MS m/z實測值593.2 [M+H]+
。
XLI-1 之合成 : (2S,3S,4S,5R,6S)-3,4,5- 三乙醯氧基 -6-(4- 甲醯基 -2- 硝基 - 苯氧基 ) 四氫哌喃 -2- 羧酸甲酯
如US 2017/0145044 A1中所述製備標題化合物。
XLII-1 之合成 : (2S,3S,4S,5R,6S)-3,4,5- 三乙醯氧基 -6-[4-( 羥基甲基 )-2- 硝基 - 苯氧基 ] 四氫哌喃 -2- 羧酸甲酯
如WO 2011/066418 A1中所述製備標題化合物。
XLIII-1 之合成 : (2S,3S,4S,5R,6S)-3,4,5- 三乙醯氧基 -6-[2- 胺基 -4-( 羥基甲基 ) 苯氧基 ] 四氫哌喃 -2- 羧酸甲酯
將(2S,3S,4S,5R)-3,4,5-三乙醯氧基-6-[4-(羥基甲基)-2-硝基-苯氧基]四氫哌喃-2-羧酸甲酯(361 mg,0.74 mmol)溶解於MeOH中且將Pd/C (50.0 mg,0.47 mmol)加入至其,接著加入NaBH4
(84.4 mg,2.23 mmol)。在RT下攪拌反應混合物15分鐘。LC-MS指示所需產物已形成。使反應混合物濾過矽藻土且然後用飽和NH4
Cl淬滅。以DCM、EtOAc萃取產物且將有機層合併。用鹽水洗其等,然後濃縮。粗產物分成兩半且藉由RP HPLC(20-95% ACN/H2
O)純化一部分以得到(2S,3S,4S,5R,6S)-3,4,5-三乙醯氧基-6-[2-胺基-4-(羥基甲基)苯氧基]四氫哌喃-2-羧酸甲酯(180 mg,0.40 mmol,53.1%產率)。MS m/z實測值456.2 [M+H]+
。
XLV-1 之合成 : (2S,3S,4S,5R,6S)-3,4,5- 三乙醯氧基 -6-[3-R10-2-R11-4-( 羥基甲基 )-6-[3-(2- 吡啶基二硫基 ) 丙醯基胺基 ] 苯氧基 ] 四氫哌喃 -2- 羧酸甲酯
將EEDQ (130 mg,0.527 mmol)加入至已溶於DCM中之3-(2-吡啶基二硫基)丙酸(56.7 mg,0.263 mmol)且於N2
下攪拌20分鐘。將(2S,3S,4S,5R)-3,4,5-三乙醯氧基-6-[2-胺基-4-(羥基甲基)苯氧基]四氫哌喃-2-羧酸甲酯(120 mg,0.263 mmol)溶解於DCM中且加入至該混合物並攪拌過夜。LC-MS指示所需產物已形成。濃縮該反應混合物且藉由逆相層析(20-95% ACN/H2O)純化以得到63 mg (2S,3S,4S,5R)-3,4,5-三乙醯氧基-6-[4-(羥基甲基)-2-[3-(2-吡啶基二硫基)丙醯基胺基]苯氧基]四氫哌喃-2-羧酸甲酯(63.0 mg,0.0965 mmol,產率:36.6%)。MS m/z實測值653.2 [M+H]+
。
中間物 II-1 :碳酸 (4- 硝基苯基酯 ) 2-(2- 吡啶基二硫基 ) 乙酯
於N2
在4℃下將N,N-二異丙基乙胺(1.02 mL,5.52mmol)及氯碳酸(4-硝基苯基酯)(834 mg,4.14 mmol)加入至於20 ml CH2
Cl2
中之2-(2-吡啶基二硫基)乙醇(517 mg,2.76 mmol)。於N2
下攪拌該混合物16小時。將該混合物溶解於40 mL EtOAc中且用20 mL飽和NH4
Cl淬滅。用2x20 mL H2O及1x20 mL飽和鹽水洗該混合物。藉由SiO2
管柱(從0-50% EtOAc/洗脫)純化粗產物以得到碳酸(4-硝基苯基酯) 2-(2-吡啶基二硫基)乙酯(482 mg,50%產率)。
中間物 II-2 、 II-3 及 II-5
類似於中間物II-1,使用適宜中間物I-2、I-3及I-5,製備中間物II-2、II-3及II-5,如下所示:
表9.另外中間物
中間物 II-4 :碳酸 (4- 硝基苯基酯 ) [(2R)-2-(2- 吡啶基二硫基 ) 丙基 ] 酯
於N2
下將吡啶(0.16 mL,1.94 mmol)及氯碳酸(4-硝基苯基酯)(0.59 g,2.91 mmol)加入至於THF中之(2R)-2-(2-吡啶基二硫基)丙-1-醇(0.39 g,1.94 mmol)。於N2
下攪拌該混合物16小時。用EtOAc稀釋該混合物且用20 mL飽和NH4
Cl淬滅。用水及鹽水洗該混合物然後濃縮有機層。藉由管柱層析(SiO2
,0-50% EtOAc/己烷)純化粗混合物以得到0.59 g、83%之碳酸(4-硝基苯基酯) [(2R)-2-(2-吡啶基二硫基)丙基]酯。MS m/z實測值367.1 [M+H]+
。
中間物 II-6 至 II-9
類似於中間物II-4來製備中間物II-6、II-7、II-8及II-9,如下表10中所示:
表10.另外中間物 中間物 XXVII-1 之合成
類似於中間物XXII來製備中間物XXVII-1。
表11.中間物XXVII
中間物 XX-1 :碳酸 (4- 硝基苯基酯 ) [4-[2-(2- 吡啶基二硫基 ) 乙氧基羰基胺基 ] 苯基 ] 甲酯
於N2
下將DIPEA (0.15 mL,0.81 mmol)及氯碳酸(4-硝基苯基酯)(122 mg,0.61 mmol)加入至於5 ml CH2
Cl2
中之N-[4-(羥基甲基)苯基]胺甲酸2-(2-吡啶基二硫基)乙酯(136 mg,0.41 mmol)。於N2
下攪拌該混合物16小時。將該混合物溶解於20 mL EtOAc中且用20 mL飽和NH4
Cl淬滅。用2x20 mL H2
O及1x20 mL飽和鹽水洗該混合物。藉由管柱層析(SiO2
,0-25% EtOAc/己烷)純化粗混合物以得到碳酸(4-硝基苯基酯) [4-[2-(2-吡啶基二硫基)乙氧基羰基胺基]苯基]甲酯(44.2 mg,0.09 mmol,產率:21.8%)。
中間物 XXIV-1 :碳酸 (4- 硝基苯基酯 ) [4-(2- 吡啶基二硫基 ) 苯基 ] 甲酯
於0℃下將氯甲酸4-硝基苯基酯(0.65 g,3.2 mmol)、吡啶(0.25 mL,3.20 mmol)、催化量之DMAP (0.005 g)加入至(4-(吡啶-2-基二硫基)苯基)甲醇(0.40 g,1.60 mmol)於CH2
Cl2
(10 mL)中之攪拌溶液。允許該混合物在室溫下攪拌2小時。用1.5 N HCl溶液淬滅該反應混合物。分離有機層且用鹽水洗,經過無水Na2
SO4
乾燥然後濃縮。藉由管柱層析(SiO2
,20-30% of EtOAc/己烷)純化粗產物以得到呈無色液體之碳酸(4-硝基苯基酯) [4-(2-吡啶基二硫基)苯基]甲酯(600 mg,91%產率);MS m/z 415.0 [M+H]+
中間物 XXIV-2 :碳酸 [3- 甲基 -4-(2- 吡啶基二硫基 ) 苯基酯 ] 甲基 (4- 硝基苯基酯 )
在0℃下將氯甲酸4-硝基苯基酯(1.05 g,5.2 mmol)、吡啶(0.43 mL,5.2 mmol)及催化量之DMAP (0.005 g)加入至已溶於CH2
Cl2
(10 mL)中的(3-甲基-4-(吡啶-2-基二硫基)苯基)甲醇(0.69 g,2.60 mmol)之攪拌溶液。允許該混合物在室溫下攪拌2小時。反應完成後,用1.5 N HCl淬滅反應混合物。分離有機層,用氯化鈉溶液(10 mL)洗,經過無水Na2
SO4
乾燥然後濃縮。藉由快速管柱層析(SiO2
,20-30% EtOAc/己烷)純化粗產物以得到碳酸[3-甲基-4-(2-吡啶基二硫基)苯基酯]甲基(4-硝基苯基酯) (700 mg,62%產率)。MS m/z 429.0 [M+H]+
。
類似於中間物XXIV-1及XXIV-2製備以下中間物,如下表12中所示:
表12.另外中間物 中間物 XXVIII
表13.中間物XXVIII
類似於中間物XXIV來製備中間物XXVIII-1。中間物 XXXIV
表14. 中間物XXXIV XXXIV-1 之合成 : 碳酸 [4-[[(2S)-2-[[(2S)-3- 甲基 -2-[2-(2- 吡啶基二硫基 )- 乙氧基羰基胺基 ] 丁醯基 ] 胺基 ]-5- 脲基 - 戊醯基 ] 胺基 ] 苯基 ] 甲酯 (4- 硝基苯基酯 )
將N-[(1S)-1-[[(1S)-1-[[4-(羥基甲基)苯基]胺甲醯基]-4-脲基-丁基]胺甲醯基]-2-甲基-丙基]胺甲酸2-(2-吡啶基二硫基)乙酯(149 mg,0.251 mmol)溶解於2 mL無水DMF中且冷卻至4℃。於其中加入碳酸雙(4-硝基苯基酯) (153 mg,0.503 mmol)及N,N-二異丙基乙胺(0.0928 mL,0.503 mmol)。允許該混合物歷時2小時升至RT。藉由LC-MS監測反應過程。濃縮該混合物且純化(25 g SiO2,0-10% MeOH/CH2Cl2)以得到碳酸 [4-[[(2S)-2-[[(2S)-3-甲基-2-[2-(2-吡啶基二硫基)乙氧基羰基胺基]丁醯基]胺基]-5-脲基-戊醯基]胺基]苯基]甲酯(4-硝基苯基酯) (139 mg,產率:73.1%)。MS m/z實測值758.2 [M+H]+
。
XLVI-1 之合成 : (2S,3S,4S,5R,6S)-3,4,5- 三乙醯氧基 -6-[2-R11-4-[(4- 硝基苯氧基 ) 羰基氧基甲基 ]-6-[3-(2- 吡啶基二硫基 ) 丙醯基胺基 ]- 苯氧基 ] 四氫哌喃 -2- 羧酸甲酯
將(2S,3S,4S,5R)-3,4,5-三乙醯氧基-6-[4-(羥基甲基)-2-[3-(2-吡啶基二硫基)丙醯基胺基]苯氧基]四氫哌喃-2-羧酸甲酯(102 mg,0.15 mmol)溶解於THF中且於其中加入吡啶(0.02 mL, 0.19 mmol),接著加入氯碳酸(4-硝基苯基酯)(63.0 mg,0.313 mmol)。於N2
下攪拌反應混合物過夜。LC-MS指示反應完全。用100 mL EtOAc稀釋該混合物且用50 mL飽和NH4
Cl淬滅。用50 mL飽和鹽水洗該混合物。用NaSO4
乾燥有機層並濃縮。藉由管柱層析(50-100% EtOAc/己烷)純化粗混合物以得到(2S,3S,4S,5R,6S)-3,4,5- 三乙醯氧基 -6-[2-R11-4-[(4- 硝基苯氧基 ) 羰基氧基甲基 ]-6-[3-(2- 吡啶基二硫基 ) 丙醯基胺基 ]- 苯氧基 ] 四氫哌喃 -2- 羧酸甲酯
(58.0 mg,0.07 mmol,45.4%)。MS m/z實測值818.2 [M+H]+
。
中間物 III-1 : [4-(4- 胺甲醯基 -1H- 苯并咪唑 -2- 基 ) 苯基 ] 甲基 2-(2- 吡啶基二硫基 ) 乙基碳酸酯
將N,N-二異丙基乙胺(0.207 mL,1.12 mmol)、DMAP(68.6 mg,0.561 mmol)及(4-硝基苯基) 2-(2-吡啶基二硫基)乙基碳酸酯(241 mg,0.684 mmol)加入在N2
下於4 mL無水DMF中之2-[4-(羥基甲基)苯基]-1~{H}-苯并咪唑-4-甲醯胺(150 mg,0.561 mmol)。攪拌該混合物16小時,及然後用50 ml EtOAc稀釋,且依次用1x20 mL飽和NH4
Cl、3x30 mL飽和NaHCO3
、3x30 mL H2
O及1x20 mL飽和鹽水洗。用MgSO4
乾燥有機相,過濾,及濃縮。純化(SiO2
,50-100% EtOAc/己烷)粗殘餘物,得到260 mg、97%產率之[4-(4-胺甲醯基-1H-苯并咪唑-2-基)苯基]甲基2-(2-吡啶基二硫基)乙基碳酸酯。
中間物 III-4 : N-[[4-(6- 氟 -3,10- 二氮雜三環 [6.4.1.04,13] 十三碳 -1,4,6,8(13)- 四烯 -2- 基 ) 苯基 ] 甲基 ]-N- 甲基 - 胺甲酸 [(2R)-2-(2- 吡啶基二硫基 ) 丙酯 ]
將(4-硝基苯基)[(2R)-2-(2-吡啶基二硫基)丙基]碳酸酯[中間物II-4] (105 mg,0.29 mmol)加入HOBt (48.0 mg,0.31 mmol)、吡啶(0.11 mL,1.31 mmol)、細磨之分子篩4 Å(250 mg)及6-氯-2-[4-(甲基胺基甲基)苯基]-3,10-二氮雜三環[6.4.1.04,13]十三碳-1,4,6,8(13)-四烯-9-酮磷酸酯(110 mg,0.26 mmol)於5 mL無水DMF中之混合物中。在室溫攪拌16小時後,濾去分子篩且在真空中移除溶劑。然後將殘餘物吸附至SiO2
上且藉由管柱層析(SiO2
,0-10% MeOH/CH2
Cl2
)純化,得到N-[[4-(6-氟-3,10-二氮雜三環[6.4.1.04,13]十三碳-1,4,6,8(13)-四烯-2-基)苯基]甲基]-N-甲基-胺甲酸[(2R)-2-(2-吡啶基二硫基)丙酯](115 mg,80%產率) MS m/z 551.1 (M+H)+
。
中間物 III-2 、 III-3 及 III-5 至 III-15
類似於中間物III-1及III-4製備以下中間物,如下表15中所示。
表15. 另外中間物 酯連接之中間物 XIII
表16.中間物XIII
XIII-1 之合成: 4-(2- 吡啶基二硫基 ) 丁酸 [4-(4- 胺甲醯基 -1H- 苯并咪唑 -2- 基 ) 苯基 ] 甲酯
將2-[4-(羥基甲基)苯基]-1H-苯并咪唑-4-甲醯胺(51.3 mg,0.192 mmol)加入至4-(2-吡啶基二硫基)丁酸TFA鹽(81.2 mg,0.236 mmol)、EDC HCl (47.8 mg,0.250 mmol)及DIEA (0.0986 mL,0.576 mmol)於2 mL DMF中之混合物。攪拌該混合物過夜且藉由LC-MS監測。濃縮該混合物且用SiO2
層析(0-10% MeOH/CH2Cl2)純化以得到4-(2- 吡啶基二硫基 ) 丁酸 [4-(4- 胺甲醯基 -1H- 苯并咪唑 -2- 基 ) 苯基 ] 甲酯
(83.1 mg,0.17 mmol,產率:90.4%) MS m/z實測值479.0 [M+H]+
。
中間物 VII-1 : N-[[(11S,12R)-7- 氟 -11-(4- 氟苯基 )-12-(2- 甲基 -1,2,4- *** -3- 基 )-4- 側氧基 -2,3,10- 三氮雜三環 [7.3.1.05,13] 十三 碳 -1,5,7,9(13)- 四烯 -10- 基 ] 甲基 ] 胺甲酸 2-(2- 吡啶基二硫基 ) 乙酯
將2-[(11S,12R)-7-氟-11-(4-氟苯基)-12-(2-甲基-1,2,4-***-3-基)-4-側氧基-2,3,10-三氮雜三環[7.3.1.05,13]十三碳-1,5,7,9(13)-四烯-10-基]乙醯基疊氮化物V-1 (170 mg,0.367 mmol)溶解於無水DMF (2 mL)中且加入2-(2-吡啶基二硫基)乙醇(137 mg,0.734 mmol)。將反應加熱至65℃維持2小時。加入催化性二月桂酸二丁基錫(40 uL)且在65℃下攪拌反應混合物過夜。濃縮該混合物且藉由管柱層析(0-10%MeOH/DCM)純化以得到3個峰。NMR指示峰2為所需產物。MALDI顯示624 (所需產物)、646 (產物+23)及380 (BMN)之3種質量。產率:80 mg中間物VII-1: N-[[(11S,12R)-7-氟-11-(4-氟苯基)-12-(2-甲基-1,2,4-***-3-基)-4-側氧基-2,3,10-三氮雜三環[7.3.1.05,13]十三碳-1,5,7,9(13)-四烯-10-基]甲基]胺甲酸2-(2-吡啶基二硫基)乙酯。
中間物 VII-2 至 VII-5
分別使用R8
H-15及中間物II-4、II-5及II-6來製備中間物VII-2、VII-3及VII-4。使用R8
H-17及中間物II-1製備中間物VII-5,如表17中所示。
表17.另外中間物
中間物 VII-6 : N-[[6- 氟 -2-[4-( 甲基胺基甲基 ) 苯基 ]-9- 側氧基 -3,10- 二氮雜三環 [6.4.1.04,13] 十三碳 -1,4,6,8(13)- 四烯 -3- 基 ] 甲基 ] 胺甲酸 2-(2- 吡啶基二硫基 ) 乙酯
步驟1:(((2-(吡啶-2-基二硫基)乙氧基)羰基)胺基)甲基乙酸酯
將多聚甲醛(0.01 g,0.47 mmol)及乙酸酐(1.78 mL)加入2-(吡啶-2-基二硫基)乙基胺甲酸酯(0.10 g,0.43 mmol)於乙酸(0.59 mL)中之攪拌溶液。在75℃下加熱該混合物3小時。反應完成後,用水(20 mL)淬滅反應且以乙酸乙酯(20 mL x 2)萃取。用水(20 mL)及鹽水溶液(20 mL)洗已合併的有機層。經過無水Na2
SO4
乾燥有機層然後濃縮。藉由管柱層析(SiO2
,40-50%乙酸乙酯/己烷)純化粗產物以得到呈黃色液體(120 mg,70%)之(((2-(吡啶-2-基二硫基)乙氧基)羰基)胺基)甲基乙酸酯。MS m/z 303.3 (M+H)+
步驟2:(4-(8-氟-1-側氧基-6-((((2-(吡啶-2基二硫基)乙氧基)羰基)胺基)甲基)-2,3,4,6-四氫-1H-氮呯酮基[5,4,3-cd]吲哚-5-基)苄基)(甲基)胺甲酸(9H-茀-9-基)甲酯
將碳酸銫(0.06 g,0.18 mmol)加入至(4-(8-氟-1-側氧基-2,3,4,6-四氫-1H-氮呯酮基[5,4,3-cd]吲哚-5-基)苄基)(甲基)胺甲酸(9H-茀-9-基)甲酯(0.05 g,0.09 mmol)於丙酮(1.0 mL)中之攪拌溶液且在室溫於N2
氛圍下攪拌5分鐘。然後加入(((2-(吡啶-2-基二硫基)乙氧基)羰基)胺基)甲基乙酸酯(0.03 g,0.09 mmol)及DMF (0.1 mL)且在室溫下再攪拌30分鐘。用水(25 mL)淬滅反應且然後以10% MeOH/CH2
Cl2
混合物(50 mL x 2)萃取。已合併的有機層經過無水硫酸鈉乾燥,然後在減壓下濃縮以得到粗產物,其藉由快速管柱層析使用60-70% EtOAc/己烷混合物純化以得到 (4-(8-氟-1-側氧基-6-((((2-(吡啶-2基二硫基)乙氧基)羰基)胺基)甲基)-2,3,4,6-四氫-1H-氮呯酮基[5,4,3-cd]吲哚-5-基)苄基)(甲基)胺甲酸(9H-茀-9-基)甲酯(12 mg,17%產率);MS m/z 788.8 (M+H)+
。
步驟3: N-[[6-氟-2-[4-(甲基胺基甲基)苯基]-9-側氧基-3,10-二氮雜三環[6.4.1.04,13]十三碳-1,4,6,8(13)-四烯-3-基]甲基]胺甲酸2-(2-吡啶基二硫基)乙酯
在N2
於室溫下攪拌 (4-(8-氟-1-側氧基-6-((((2-(吡啶-2基二硫基)乙氧基)羰基)胺基)甲基)-2,3,4,6-四氫-1H-氮呯酮基[5,4,3-cd]吲哚-5-基)苄基)(甲基)胺甲酸(9H-茀-9-基)甲酯(0.15 g,0.19 mmol)與於DMF (1.4 mL)中之20%二乙胺1小時。濃縮反應混合物至乾燥且藉由製備型HPLC[管柱:Inertsil ODS 3V (250mm X 20mm X 5mic);於H2
O中之流動相-A-0.1%氨:流動相-B-ACN]純化以得到呈無色固體(30 mg,28%產率)之N-[[6-氟-2-[4-(甲基胺基甲基)苯基]-9-側氧基-3,10-二氮雜三環[6.4.1.04,13]十三碳-1,4,6,8(13)-四烯-3-基]甲基]胺甲酸2-(2-吡啶基二硫基)乙酯。MS m/z 566.4 (M+H)+
。
中間物 VII-7 : N-[1-[6- 氟 -2-[4-( 甲基胺基甲基 ) 苯基 ]-9- 側氧基 -3,10- 二氮雜三環 [6.4.1.04,13] 十三碳 -1,4,6,8(13)- 四烯 -3- 基 ]-3- 甲基 - 丁基 ] 胺甲酸 2-(2- 吡啶基二硫基 ) 乙酯
步驟1:(3-甲基-1-(苯基硫基)丁基)胺甲酸2-(吡啶-2-基二硫基)乙酯
將對甲苯亞磺酸鈉(1.93 g,0.01 mol)、3-甲基丁醛(1.26 mL,0.01 mol)加入至2-(吡啶-2-基二硫基)乙基胺甲酸酯(2.50 g,0.01 mol)於THF:水(19 mL,1:1)中之攪拌溶液且然後加入甲酸(2.5 mL)。在室溫於N2
下攪拌該混合物16小時。濃縮反應混合物至乾燥且接著藉由快速管柱層析(SiO2
,40-70% EtOAc/己烷)純化以得到 (3-甲基-1-(苯基磺醯基)丁基)胺甲酸2-(吡啶-2-基二硫基)乙酯(1.7 g,41%產率)。MS m/z 455.1 [M+H]+
。
步驟2: (4-(8-氟-6-(3-甲基-1-(((2-(吡啶-2-基二硫基)乙氧基)羰基)胺基)丁基)-1-側氧基-2,3,4,6-四氫-1H-氮呯酮基[5,4,3-cd]吲哚-5-基)苄基)(甲基)胺甲酸(9H-茀-9-基)甲酯
歷時4小時將 (3-甲基-1-(苯基磺醯基)丁基)胺甲酸2-(吡啶-2-基二硫基)乙酯(0.80 g,1.83 mmol)逐份地加入至 (4-(8-氟-1-側氧基-2,3,4,6-四氫-1H-氮呯酮基[5,4,3-cd]吲哚-5基)苄基)(甲基)胺甲酸(9H-茀-9-基)甲酯(0.5 g,0.92 mmol)及碳酸銫(0.89 g,2.74 mmol)於CH2
Cl2
:DMF(5:1,12 mL)中之攪拌溶液。在N2
於室溫下再攪拌該混合物2小時。藉由TLC監測反應。用水(25 mL)及DCM(100 mL)稀釋反應混合物。分離有機層,用水、鹽水洗。有機相經過無水Na2
SO4
乾燥然後濃縮。藉由快速管柱層析(SiO2
,90-100% EtOAc/己烷)純化粗產物以得到 (4-(8-氟-6-(3-甲基-1-(((2-(吡啶-2-基二硫基)乙氧基)羰基)胺基)丁基)-1-側氧基-2,3,4,6-四氫-1H-氮呯酮基[5,4,3-cd]吲哚-5-基)苄基)(甲基)胺甲酸(9H-茀-9-基)甲酯(0.35 g,45%產率)。MS m/z 844.1 [M+H]+
。
步驟3: N-[1-[6-氟-2-[4-(甲基胺基甲基)苯基]-9-側氧基-3,10-二氮雜三環[6.4.1.04,13]十三碳-1,4,6,8(13)-四烯-3-基]-3-甲基-丁基]胺甲酸2-(2-吡啶基二硫基)乙酯
在室溫於N2
下將(4-(8-氟-6-(3-甲基-1-(((2-(吡啶-2-基二硫基)乙氧基)羰基)胺基)丁基)-1-側氧基-2,3,4,6-四氫-1H-氮呯酮基[5,4,3-cd]吲哚-5-基)苄基)(甲基)胺甲酸(9H-茀-9-基)甲酯(0.30 g,0.355 mmol)與於DMF(1.4 mL)中之10%哌啶攪拌20分鐘。濃縮反應混合物至乾燥且然後用***研磨以得到無色固體。藉由製備型HPLC[管柱:Inertsil ODS 3V (250mm X 20mm X 5mic),於H2
O中之流動相-A-0.1%氨:流動相-B-ACN]進一步純化所得固體以得到N-[1-[6-氟-2-[4-(甲基胺基甲基)苯基]-9-側氧基-3,10-二氮雜三環[6.4.1.04,13]十三碳-1,4,6,8(13)-四烯-3-基]-3-甲基-丁基]胺甲酸2-(2-吡啶基二硫基)乙酯(0.07 g,30%產率)。MS m/z 622.0 [M+H]+
。
中間物 XXI-1 : N-[[4-(6- 氟 -9- 側氧基 -3,10- 二氮雜三環 [6.4.1.04,13] 十三 碳 -1,4(13),5,7- 四烯 -2- 基 ) 苯基 ] 甲基 ]-N- 甲基 - 胺甲酸 [4-[2-(2- 吡啶基二硫基 ) 乙氧基羰基胺基 ] 苯基 ] 甲酯
於N2
下將DIPEA (0.03 mL,0.18 mmol)、DMAP (10.9 mg,0.09 mmol)及碳酸(4-硝基苯基酯)[4-[2-(2-吡啶基二硫基)乙氧基羰基胺基]苯基]甲酯(44.8 mg,0.09 mmol)加入至於2 mL無水DMF中之2-[4-(甲基胺基甲基)苯基]-3,10-二氮雜雙環[6.4.1.04,13]十三碳-1,4(13),5,7-四烯-9-酮;磷酸(36.0 mg,0.09 mmol)。攪拌該混合物16小時。用20 ml EtOAc稀釋該混合物,用1x20 mL飽和NH4
Cl、2x20 mL飽和NaHCO3
、3x30 mL H2
O及1x20 mL飽和鹽水洗。用MgSO4
乾燥該混合物,過濾然後濃縮。藉由管柱層析(SiO2
,0-5% MeOH/CH2
Cl2
)純化粗殘餘物以得到N-[[4-(6-氟-9-側氧基-3,10-二氮雜三環[6.4.1.04,13]十三碳-1,4(13),5,7-四烯-2-基)苯基]甲基]-N-甲基-胺甲酸[4-[2-(2-吡啶基二硫基)乙氧基羰基胺基]苯基]甲酯(44.2 mg,0.06 mmol,產率:75.4%)。
中間物 XXV-1 : N-[[4-(6- 氟 -9- 側氧基 -3,10- 二氮雜雙環 [6.4.1.04,13] 十三碳 -1,4,6,8(13)- 四烯 -2- 基 ) 苯基 ] 甲基 ]-N- 甲基 - 胺甲酸 [4-(2- 吡啶基二硫基 ) 苯基 ] 甲酯
於N2
下將TEA (1.40 mL,3.04 mmol)、HOBt (0.21 g,1.50 mmol)及碳酸4-硝基苯基酯(4-(吡啶-2-基二硫烷基)苄基酯)(1.40 g,3.40 mmol)加入至2-[4-(甲基胺基甲基)苯基]-3,10-二氮雜三環[6.4.1.04,13]十三碳-1,4(13),5,7-四烯-9-酮;磷酸(1.00 g,3.09 mmol)於THF(20 mL)中之攪拌溶液。於N2
在室溫下攪拌該混合物16小時。濃縮反應混合物且藉由快速層析(SiO2
, 0-5% MeOH/CH2
Cl2
)純化粗物質,得到呈無色固體之N-[[4-(6-氟-9-側氧基-3,10-二氮雜三環[6.4.1.04,13]十三碳-1,4,6,8(13)-四烯-2-基)苯基]甲基]-N-甲基-胺甲酸[4-(2-吡啶基二硫基)苯基]甲酯(1.13 g,59%產率)。MS m/z 599.0 (M+H)+
。
中間物 XXV-2 至 XXV-5
類似於中間物XXV-1,使用適宜R8
-H化合物及中間物XXIV-2至XXIV-5製備中間物XXV-2至XXV-5,如下表18中所示。
表18.另外中間物 自 XXVII 合成中間物 XXVIX
表19. 中間物XXVIX
類似於中間物XXV-1,自中間物XXVIII-1製備中間物XXVIX-1。
自 XXXIV 製備中間物 XXXV
表20.中間物XXXV
類似於中間物XXV-1,自中間物XXXIV-1製備中間物XXXV-1。
自 XXX 製備中間物 XXXVII
表21.中間物XXXVII XXXVII-1 之合成 : (2S)-1-(2- 胺基乙醯基 )-N-[[4-(6- 氟 -9- 側氧基 -3,10- 二氮雜三環 [6.4.1.04,13] 十三 碳 -1,4,6,8(13)- 四烯 -2- 基 ) 苯基 ] 甲基 ]-N- 甲基 - 吡咯啶 -2- 甲醯胺
步驟1. 第三丁基-N-[2-[(2S)-2-[[4-(6-氟-9-側氧基-3,10-二氮雜三環[6.4.1.04,13]十三碳-1,4,6,8(13)-四烯-2-基)苯基]甲基-甲基-胺甲醯基]吡咯啶-1-基]-2-側氧基-乙基]胺甲酸酯之合成
將1-[2-(第三丁氧基羰基胺基)乙醯基]吡咯啶-2-羧酸(0.16 g,0.59 mmol)溶解於DMF中且於其中加入1-羥基苯并***水合物(80.0%,114 mg,0.59 mmol)及EDC HCl(114 mg,0.59 mmol)。於RT下攪拌該溶液15分鐘,接著加入6-氟-2-[4-(甲基胺基甲基)苯基]-3,10-二氮雜三環[6.4.1.04,13]十三碳-1,4,6,8(13)-四烯-9-酮;磷酸(200 mg, 0.475 mmol)及N,N-二異丙基乙胺(0.44 mL,2.37 mmol)。然後將該溶液加熱至65℃過夜。LC-MS指示反應完全。用EtOAc稀釋反應混合物,用飽和NH4
Cl、水及鹽水洗。粗N-[[4-(6-氟-9-側氧基-3,10-二氮雜三環[6.4.1.04,13]十三碳-1,4,6,8(13)-四烯-2-基)苯基]甲基]-N-甲基-胺甲酸[1-[2-(第三丁氧基羰基胺基)乙醯基]吡咯啶-2-基酯](141 mg,0.24 mmol,產率:50.0%)係按原樣進行。MS m/z 478.2 (M+H減去BOC)+
。
步驟2.(2S)-1-(2-胺基乙醯基)-N-[[4-(6-氟-9-側氧基-3,10-二氮雜三環[6.4.1.04,13]十三碳-1,4,6,8(13)-四烯-2-基)苯基]甲基]-N-甲基-吡咯啶-2-甲醯胺之合成
將第三丁基-N-[2-[2-[[4-(6-氟-9-側氧基-3,10-二氮雜三環[6.4.1.04,13]十三碳-1,4,6,8(13)-四烯-2-基)苯基]甲基-甲基-胺甲醯基]吡咯啶-1-基]-2-側氧基-乙基]胺甲酸酯(141 mg,0.24 mmol)溶解於DCM中且加入於二噁烷中之1 mL HCl (4.00 M,0.12 mL,0.48 mmol)。於RT下攪拌反應混合物過夜。LC-MS指示反應完全。濃縮該反應混合物且藉由逆相層析(20-85% ACN/H2
O)純化以得到68 mg 1-(2-胺基乙醯基)-N-[[4-(6-氟-9-側氧基-3,10-二氮雜三環[6.4.1.04,13]十三碳-1,4,6,8(13)-四烯-2-基)苯基]甲基]-N-甲基-吡咯啶-2-甲醯胺(68.0 mg,0.142 mmol,產率:58.3%)。MS m/z 478.2 (M+H)+
。
中間物 XXXVIII
表22.中間物XXXVIII XXXVIII-1 之合成 : N-[2-[(2S)-2-[[4-(6- 氟 -9- 側氧基 -3,10- 二氮雜三環 [6.4.1.04,13] 十三 碳 -1,4,6,8(13)- 四烯 -2- 基 ) 苯基 ] 甲基 - 甲基 - 胺甲醯基 ] 吡咯啶 -1- 基 ]-2- 側氧基 - 乙基 ] 胺甲酸 2-(2- 吡啶基二硫基 ) 乙酯
將DMAP (17.4 mg,0.142 mmol)、碳酸(4-硝基苯基酯) 2-(2-吡啶基二硫基)乙酯(50.2 mg,0.142 mmol)及N,N-二異丙基乙胺(27.6 mg,0.214 mmol)加入至於2 mL無水DMF中之1-(2-胺基乙醯基)-N-[[4-(6-氟-9-側氧基-3,10-二氮雜三環[6.4.1.04,13]十三碳-1,4,6,8(13)-四烯-2-基)苯基]甲基]-N-甲基-吡咯啶-2-甲醯胺(68.0 mg,0.142 mmol)。攪拌該混合物16小時且接著用50 ml EtOAc稀釋,用1x20 mL飽和NH4
Cl、3x30 mL H2
O及1x20 mL飽和鹽水洗。用MgSO4
乾燥該混合物,過濾,然後濃縮。於SiO2
管柱(0-3% MeOH/DCM)上純化粗殘餘物以得到30 mg N-[2-[2-[[4-(6-氟-9-側氧基-3,10-二氮雜三環[6.4.1.04,13]十三碳-1,4,6,8(13)-四烯-2-基)苯基]甲基-甲基-胺甲醯基]吡咯啶-1-基]-2-側氧基-乙基]胺甲酸2-(2-吡啶基二硫基)乙酯(30.0 mg,0.0434 mmol,產率:30.5%)。MS m/z 691.2 (M+H)+
。
自 XLVI 製備中間物 XLVIII
表23.中間物XLVIII XLVII-1 之合成 : (2S,3S,4S,5R,6S)-3,4,5- 三乙醯氧基 -6-[3-R10-2-R11-4-[[[4-(6- 氟 -9- 側氧基 -3,10- 二氮雜三環 [6.4.1.04,13] 十三 碳 -1,4,6,8(13)- 四烯 -2- 基 ) 苯基 ] 甲基 - 甲基 - 胺甲醯基 ] 氧基甲基 ]-6-[3-(2- 吡啶基二硫基 ) 丙醯基胺基 ] 苯氧基 ] 四氫哌喃 -2- 羧酸甲酯
將(2S,3S,4S,5R)-3,4,5-三乙醯氧基-6-[4-[(4-硝基苯氧基)羰基氧基甲基]-2-[3-(2-吡啶基二硫基)丙醯基胺基]苯氧基]四氫哌喃-2-羧酸甲酯(58.0 mg,0.0709 mmol)加入至1-羥基苯并***水合物(13.0 mg,0.0851 mmol)、細磨之分子篩4 Å (100 mg)及6-氟-2-[4-(甲基胺基甲基)苯基]-3,10-二氮雜三環[6.4.1.04,13]十三碳-1,4,6,8(13)-四烯-9-酮;磷酸(35.9 mg,0.0851 mmol)於2 mL無水DMF中之混合物。在室溫下攪拌16小時後,濾去分子篩且在真空中移除溶劑。用EtOAc稀釋反應混合物,用飽和NH4
Cl、水及鹽水洗。用NaSO4
乾燥有機層並濃縮。藉由管柱層析(0-3% MeOH/DCM)純化粗殘餘物以得到具有少量未知雜質的35 mg (2S,3S,4S,5R)-3,4,5-三乙醯氧基-6-[4-[[[4-(6-氟-9-側氧基-3,10-二氮雜三環[6.4.1.04,13]十三碳-1,4,6,8(13)-四烯-2-基)苯基]甲基-甲基-胺甲醯基]氧基甲基]-2-[3-(2-吡啶基二硫基)丙醯基胺基]苯氧基]四氫哌喃-2-羧酸甲酯(43.0 mg,0.0429 mmol,產率:60.5%)。MS m/z 1002.1 (M+H)+
。
共軛化合物 實例 3
藉由鼓泡N2
脫氣含有PBS之一個8 mL小瓶及含有DMF之一個8 mL小瓶1小時。將肽變體3(「Pv3」,50.0 mg,1.31e-5 mol)置於單獨小瓶中。將經脫氣之1.0 mL PBS及DMF之3.0 mL部分加入至碳酸[4-(4-胺甲醯基-1H-苯并咪唑-2-基)苯基]甲酯2-(2-吡啶基二硫基)乙酯 (18.9 mg,3.92e-5 mol)。將CH3
CO2
H (0.05 mL 0.000873 mol)加入至該混合物。將該混合物置於N2
下且在RT下攪拌16小時。藉由RP HPLC監測混合物之進展,直至完全消耗起始肽及剩餘的吡啶二硫化物(Ace當量250x4.6 mm,50%等濃度,25分鐘運行)。藉由製備型RP HPLC (Sunfire 30x150 mm;CH3
CN/H2
O(0.1% TFA)梯度,16分鐘運行)純化粗反應混合物以得到28.6 mg、54%產率之實例3。
實例 18
藉由鼓泡N2
脫氣分別含有PBS及DMF之兩個單獨的8 mL小瓶1小時。將Pv1 (50.0 mg,0.02 mmol)置於一個單獨的小瓶中。將N-[[4-(6-氟-3,10-二氮雜三環[6.4.1.04,13]十三碳-1,4,6,8(13)-四烯-2-基)苯基]甲基]-N-甲基-胺甲酸[(2R)-2-(2-吡啶基二硫基)丙酯] [中間物III-4](16.2 mg,0.03 mmol)、1.33 mL PBS及4 mL DMF加入至該小瓶,接著加入乙酸(4.2 µL,0.08 mmol)。將該混合物置於N2
下且在RT下攪拌過夜。藉由製備型HPLC (40-72% CH3
CN/H2
O,15分鐘)純化該混合物以得到29.0 mg、0.008 mmol、53%之實例18。
類似於實例18,使用適宜中間物及肽製備以下化合物。
表24.實例化合物
類似於實例18,自適宜VII中間物及肽製備以下化合物。
表25.實例化合物 自中間物 XII 合成最終化合物
自中間物XII-1合成以下化合物。
表26.其他實例 實例 32
自中間物XXI及肽Pv2合成實例32。MS (Maldi-TOF)實測值為4582.9。使用30-50%乙腈/水、條件3、在11分鐘及8.3分鐘時洗脫純化該化合物。
自中間物 XXV 合成化合物
類似於實例18,自中間物XXV合成以下化合物。
表27.實例化合物 自中間物 XXV 合成最終化合物
類似於實例18,自中間物XXV合成以下化合物。
表28.實例化合物 自中間物 XXXV 合成最終化合物
類似於實例18,自中間物XXXV-1合成以下化合物。
表29.實例化合物 自中間物 XXXVIII 合成最終化合物
類似於實例18,自中間物XXXVIII-1合成以下化合物。
表30.實例化合物 實例 A. 化合物之裂解
將2 mL 1M Tris HCl緩衝液(pH 7.0)加入至(2S)-2-胺基-5-[[(1R)-2-(羧基甲基胺基)-2-側氧基-1-(硫基甲基)乙基]胺基]-5-側氧基-戊酸(4.90 mg,0.0159 mmol)以產生8 mM溶液。將1 mL該溶液之一個等分試樣加入至實例3 (0.400 mg,9.81x10-5
mmol)以產生100 µM溶液。在37℃下加熱該混合物,以15分鐘為間隔的時間點測定共軛物完整性。藉由2-[4-(羥基甲基)苯基]-1~{H}-苯并咪唑-4-甲醯胺之相稱外觀觀察到共軛物之穩定損失。到60分鐘的時間點完全裂解,如藉由MSD觀察到/證實。HPLC條件:ES Industries Sonoma 4.6x50 mm;5-100% CH3
CN/H2
O (0.1% TFA);5.5 min運行 共軛物RT:3.71 產物RT:2.24。
其他化合物類似地裂解以得到適宜之R8
H分子。
如以下在實例B及C中所述分析含有本發明之經裂解之化合物之粗裂解溶液來評估經裂解之R8
H的量。除了經裂解之化合物外,亦對表2中所列出的R8
起始原料中的幾種進行分析。
實例 B. 經裂解之化合物 (PARP) 之酵素分析 1
使用Trevigens HT F均質PARP抑制分析套組(#4690-096-K)進行如下分析:將經純化之PARP酵素在一式兩份經連續稀釋之PARP抑制劑(例如,根據實例A裂解之實例化合物)及1 uM NAD之存在下於室溫下在黑色圓底96孔板中培養30分鐘。將等體積的循環混合物加入至各孔且在室溫下培養反應一小時。藉由加入終止溶液終止該反應且使用螢光(544 nm激發及590 nm發射)終點於BioTek Cytation 5板式讀取器上讀取該等板。將結果繪製於GraphPad Prism中並在以下給出。
表31.經裂解之化合物之HT F均質PARP抑制分析
實例 C. 經裂解之化合物之酵素分析 2 (PARP)
使用Trevigen HT通用化學發光PARP分析套組(#4676-096-K)進行如下分析:將經純化之PARP酵素在一式兩份經連續稀釋之PARP抑制劑(例如,根據實例A裂解之實例化合物)之存在下於室溫下在含有結合組蛋白之再水合之96孔條帶孔中培養10分鐘。將等體積的含有活化DNA之1x PARP混合物加入至各孔且在室溫下培養反應一小時。用1x PBS + 0.1% Triton X-100洗該等孔兩次且用PBS洗兩次。加入50 ul/孔之經稀釋之鏈黴親和素–HRP且在室溫下培養一小時。用1x PBS + 0.1% Triton X-100洗該等孔兩次且用PBS洗兩次。移除液體,加入加入100 ul/孔1:1 PeroxyGlow A/ PeroxyGlow B且使用發光纖維終點於BioTek Cytation 5板式讀取器上測定化學發光讀數。將結果繪製於GraphPad Prism中並示以下。
表32.經裂解之化合物之HT通用化學發光PARP分析
實例 D. Elisa PAR 基化分析
用HeLa細胞接種十二--孔組織培養板且在37℃下於5% CO2
中培養以在第二天產生80%匯合細胞單層。於37℃下於所需pH下用游離藥物或共軛物之三倍稀釋系列液處理該等單層1小時。吸出該等單層且每孔接受補充蛋白酶及磷酸酶抑制劑之150 μl RIPA裂解緩衝液。在冰上培養板10分鐘且然後冷凍。解凍後,對該等裂解物補充Mg且在37℃下用DNA酶培養90分鐘。藉由在4℃下以12,000 x g離心5’澄清樣本且將經澄清之裂解物轉移至乾淨的管並使用BCA蛋白質分析進行蛋白質測定。
使用Trevigen HT PARP體內藥效動力學分析II (#4520-096-K)進行如下分析:將一式兩份的25 ul樣本裂解物裝載於預塗佈/預阻斷的ELISA條帶上且在4℃下結合經連續稀釋之純化的PAR標準品培養16小時。用PBST洗4x該等孔且在室溫下用於抗體稀釋劑中之50 ul/孔之PAR多株檢測抗體培養2小時。用PBST洗4x該等孔且在室溫下用於抗體稀釋劑中之50 ul/孔山羊抗-兔IgG-HRP共軛物培養1小時。用PBST洗4x該等孔,用100 ul/孔之1:1 PARP PeroxyGlow A及PARP PeroxyGlow B培養且使用發光纖維終點在BioTek Cytation 5中讀數。使用從標準曲線計算得的值,將結果繪製為初始發光單位或繪製為PAR (pg/ml),且示於以下。
表33.PAR基化分析結果
如前面所述在pH 7.4下處理細胞且培養16小時。
表34.PAR基化分析結果
實例 E. 生長延遲分析
將細胞接種於96孔黑色壁-透明底的板(Griener)中,將DLD-1 WT細胞以2500個細胞/孔、將DLD-1 BRCA2-/-以5000個細胞/孔接種於含有10% FBS之生長培養基中。允許細胞在室溫下黏附60分鐘,接著返回至37C、5% CO2培養箱。於24小時後,移除培養基且用含有不同藥物濃度之新製生長培養基更換。每種藥物濃度以一式三份方式加入。未經藥物處理之對照組僅含有生長培養基。將細胞返回至培養箱。於加入藥物後九十六小時,用4%多聚甲醛固定細胞20分鐘且用1 ug/mL的Hoechst染色。將該等板成像於Cytation 5自動化成像器(BioTek)上且使用CellProfiler(http://cellprofiler.org)計數細胞。計算細胞生長延遲百分比並使用GraphPad Prism繪製數據。
表35.生長延遲分析總結
上述結果證實本發明之化合物在經歷於細胞內複製彼等之條件時被裂解以釋放游離R8
H且展示生物靶標(其在該特定分析中為PARP)之抑制。基於此等結果,熟習此項技術者將容易知曉本發明之化合物可用於治療涉及酸性或缺氧性患病組織之疾病且尤其可用於治療PARP突變癌症。
實例 F. 體內腫瘤生長延遲
研究設計(R8
H-15,實例12)
雌性裸小鼠在6週齡時到達該設施且在丟棄式IVC籠養系統(Innovive)中每籠5隻飼養於Alpha-Dri床上。在5-10天的適應期後,將DLD-1 BRACA2-/-
細胞在無酚紅Matrigel中1:1稀釋且以100 µL中5x106
個細胞之密度皮下植入每隻小鼠的左側腹中。監測異種移植腫瘤生長且每週兩次實現測徑規測量。當異種移植物達到100 mm3
之最小體積時,每天一次對小鼠投與腹膜內(IP)劑量之媒劑、實施例12 (6.4、20或50 mg/kg)或口服劑量之R8
H-15 (0.3 mg/kg)共8天。於給藥後立即對所有小鼠投與口服劑量之10 mg/kg替莫唑胺(TMZ),其係於20%葡萄糖中製備。每週兩次實現測徑規測量以評估化合物對腫瘤生長的影響。在8天給藥期後再繼續監測腫瘤生長7週(洗出期)。若體重損失超過20%或若腫瘤體積增加至原始大小4x,則將小鼠安樂死。使用Kaplan-Meier分析以評估基於死亡或從研究中移除之存活率。
研究設計(R8
H-16,實例18)
雌性裸小鼠在6週齡時到達該設施且在丟棄式IVC籠養系統(Innovive)中每籠5隻飼養於Alpha-Dri床上。在5-10天的適應期後,將DLD-1 BRACA2-/-
細胞在無酚紅Matrigel中1:1稀釋且以100 µL中5x106
個細胞之密度皮下植入每隻小鼠的左側腹中。監測異種移植腫瘤生長且每週兩次實現測徑規測量。當異種移植物達到100 mm3
之最小體積時,每天一次對小鼠投與腹膜內(IP)劑量之媒劑、實施例18 (8.8、17.7或44.2 mg/kg)或R8
H-16 (1、2、5 mg/kg)共8天。於給藥5天後立即對所有小鼠投與口服劑量之10 mg/kg替莫唑胺(TMZ),其係於20%葡萄糖中製備。每週兩次實現測徑規測量以評估化合物對腫瘤生長的影響。在8天給藥期後再繼續監測腫瘤生長8天(洗出期)。若體重損失超過20%或若腫瘤體積增加至原始大小4x,則將小鼠安樂死。
用於植入之DLD-1 BRCA2-/-
細胞製劑(R8
H-15,實例12;R8
H-16,實例18)
將Matrigel在準備用於DLD-1 BRCA2-/-
細胞植入之前在4℃下於冰上解凍過夜且在所有預備步驟中保存於冰上。在準備植入之前,將細胞繼代一至三天。根據需要每2-3天更換生長培養基以維持細胞存活率。在植入當天,將細胞胰蛋白酶化,用完全培養基洗且藉由以1200 rpm離心5分鐘集結成粒。丟棄上清液且用無菌PBS洗細胞三次並藉由離心集結成粒。在最後的離心中,使用台盼藍(trypan blue)排除法確定存活率。將細胞以5x106
個細胞/50 μL之濃度再懸浮於無菌PBS中。在植入之前,將細胞與Matrigel 1:1混合,最終濃度為5x106
個細胞/100 µL。將錐形管中的Matrigel /細胞混合物保存於冰上直至用於植入。
DLD-1 BRCA2-/-
細胞植入(R8
H-15,實例12;R8
H-16,實例18)
將保存於冰上之於錐形管中之Matrigel/DLD-1 BRCA2-/-
細胞(5x106
個細胞/100 µL)吸入裝有無菌27號針的無菌1cc注射器中。將過量的Matrigel/細胞混合物排出回至錐形管中,在每個注射器中留下100 μL的注射體積。將經填充之注射器保存於冰上直至植入時間以避免Matrigel於注射器中聚合。將細胞皮下植入每隻小鼠的左側腹中且於發展出明顯異種移植物後,每週兩次實現測徑規測量。當異種移植物達到100 mm3
之最小體積時,繼續進行化合物評估。
化合物投與(R8
H-15,實例12)
如上所述在於PBS中之8% PEG400 + 2%吐溫80 (Tween 80)中製備6.4、20及50 mg/kg腹膜內劑量之實例12且每天一次投與共8天。小鼠以12 mL/kg (300 µL/25 g小鼠)之體積給藥。在0.5%甲基纖維素中製備口服劑量0.3 mg/kg之R8
H-15 (BMN673)且以10 mL/kg (250 µL/25 g小鼠)之體積每天一次投與8天以進行比較。於化合物投與後不久,對所有小鼠投與口服劑量10 mg/kg之替莫唑胺(TMZ)(於20%葡萄糖中)。
化合物投與(R8
H-16,實例18)
將實例18溶解於100%二甲基亞碸(DMSO)中以得到0.1 mg/µL原液。藉由用包含8% PEG400 + 2%吐溫80於PBS中的1950 μL媒劑分別稀釋14、29或72 µL原液,每天新製備8.83、17.66或 44.15 mg/kg之腹膜內(IP)劑量。將該等劑量渦旋以獲得均質懸浮液且以12 mg/mL (300 µL/25 g小鼠)之濃度每天一次給藥共8天。每天,將2.5 mg R8
H-16懸浮於包含8% PEG400 + 2%吐溫80於PBS中的6 mL媒劑中。該懸浮液經音波處理10分鐘以得到均質5 mg/kg腹膜內劑量,用媒劑進一步1:5及1:2.5稀釋,以分別獲得1及2 mg/kg劑量。將所有劑量渦旋且以12 mL/kg (300 µL/25 g小鼠)之濃度每天一次投與共8天。藉由將70 mg化合物懸浮於14 mL 20%葡萄糖媒劑中,每天新製備50 mg/kg口服劑量之替莫唑胺(TMZ)。最終的5 mg/mL劑量經音波處理15分鐘直至達到均質懸浮液。在投與實例18或R8
H-16後立即以10 mL/kg (250 µL/25 g小鼠)每天一次經口投與小鼠TMZ共5天。
腫瘤生長
監測腫瘤生長且在8天的給藥期內每週兩次實現測徑規測量以評估化合物對腫瘤生長速率之效力。在停止給藥後,再繼續生長測量7週。當腫瘤體積超過其原始大小4x時,從研究中移除小鼠。
統計分析
使用方差分析(ANOVA)以測試組間的顯著差異。使用Post-hoc Bonferroni多重比較檢驗分析來確定平均值之間的顯著差異。使用Graph Pad Prism 7.03軟體完成所有統計分析。當體重損失超過初始體重的20%時,使用Kaplan-Meier分析來評估基於死亡或從研究中移除之存活率。
圖1顯示BRCA-/-
小鼠中R8
H-15及實例12之腫瘤生長延遲。
圖2顯示BRCA-/-
小鼠中R8
H-15及實例12之存活率。
圖3顯示BRCA-/-
小鼠中R8
H-16及實例18之腫瘤生長延遲。
實例 G. 腫瘤 PAR 基化
研究設計(R8
H-16,實例18)
雌性裸小鼠在6週齡時到達該設施且在丟棄式IVC籠養系統(Innovive)中每籠5隻飼養於Alpha-Dri床上。將人DLD-1 BRACA2-/-
細胞在無酚紅Matrigel中1:1稀釋且以100 µL中5x106
個細胞之密度皮下植入每隻小鼠的左側腹中。每週兩次實現測徑規測量且當異種移植物達到250 mm3
之最小體積時開始治療。腹膜內(IP)劑量之實例18 (8.83、17.66或44.15 mg/kg)或R8
H-16(2或10 mg/kg)於8% PEG400 + 2%吐溫80媒劑中每天一次投與共9天。亦投與小鼠口服劑量之20%葡萄糖。第八劑量於第九劑量之前約12小時在晚上投與。於投與第九劑量後2小時收集血清及組織樣本。在腫瘤及骨髓中確定化合物對PAR基化之影響。
化合物投與(R8
H-16,實例18)
將實例18溶解於100%二甲基亞碸(DMSO)中以得到0.1 mg/µL原液。藉由用包含8% PEG400 + 2%吐溫80於PBS中的1800 µL媒劑分別稀釋13、26或66 µL原液,每天新製備8.8、17.7或44.2 mg/kg之腹膜內(IP)劑量。渦旋該等劑量以獲得均質懸浮液。藉由將5 mg R8
H-16懸浮於包含8% PEG400 + 2%吐溫80於PBS中的6 mL媒劑中,每天新製備10 mg/kg腹膜內(IP)劑量之R8
H-16。渦旋該等劑量以獲得均質懸浮液。藉由用媒劑1:5稀釋10 mg/kg劑量來製備2 mg/kg之IP劑量。腹膜內(IP)劑量之實例18或R8
H-16以12 mL/kg(300 µL/25 g小鼠)之體積每天一次投與,歷時9天。
組織收集(R8
H-16,實例18)
於收集血液後,在麻醉下藉由頸椎脫位使小鼠安樂死。移走異種移植腫瘤,稱重,且用解剖刀片切成小塊。在冷凍管中收集隨機的100 mg腫瘤樣本,在液氮中快速冷凍並儲存在-80℃下直至處理。在腫瘤均質物中進行PAR基化測量。
腫瘤均質物中之乙醯化(R8
H-16,實例18)
將冷凍的腫瘤樣本於含有蛋白酶及磷酸酶抑制劑(1 mg/mL)之RIPA緩衝液中均質化且使300 L等分試樣達到1% SDS最終濃度。在100℃下加熱樣本5分鐘,在冰上淬滅且藉由以14,000 x g離心5分鐘澄清。將腫瘤樣本在RIPA/HALT緩衝液中1:10稀釋,以用於使用Pierce Rapid Gold BCA蛋白質分析套組進行蛋白質定量。將樣本於樣本緩衝液中稀釋至200 μg/mL(10 μg/孔)且將50 L等分試樣(10 μg/孔)加載於預塗佈/預阻斷之ELISA條帶孔。在4℃下培養16小時後,用PBST (1 L PBS + 1 mL吐溫20)洗4x樣本且在室溫下用50 µL PAR檢測抗體培養2小時。用PBST洗4x樣本且在室溫下用50 µL山羊抗兔IgG-HRP共軛物培養1小時。於PBST的最後4x洗後,將100 µL PeroxyGlowTM
加入至每個樣本且使用發光纖維終點及條帶孔區板定義在BioTek Cytation 5上測定發光。
圖4顯示實例18及R8
H-16之9天腹膜內投與在鼠類DLD-1 BRCA2-/-
異種移植模型中對腫瘤PAR基化的影響。
實例 H. 骨髓選擇性
研究設計(R8
H-15,實例12)
雌性裸小鼠在6週齡時到達該設施且在丟棄式IVC籠養系統(Innovive)中每籠5隻飼養於Alpha-Dri床上。在5-10天的適應期後,將DLD-1 BRACA2-/-
腫瘤細胞在無酚紅Matrigel中1:1稀釋且以100 µL中5x106
個細胞之密度皮下植入每隻小鼠的左側腹中。監測腫瘤生長且每週兩次實現測徑規測量。當腫瘤達到100 mm3
之最小體積時,每天一次對小鼠僅投與50 mg/kg口服劑量之替莫唑胺(TMZ)或與0.3 mg/kg口服劑量之R8
H-15或10 mg/kg靜脈內劑量之實例12組合投與共2天。在第3天,在麻醉下藉由頸脫位使餵養的小鼠安樂死且移走腫瘤,稱重且在液氮中快速冷凍。移走腿骨且用PBS將骨髓擠出至50 mL錐形管中,藉由離心分離骨髓細胞。藉由骨髓細胞計數及藉由如Elisa測定的PAR基化抑制來評估骨髓毒性。藉由Elisa PAR基化分析測定化合物對腫瘤細胞存活率之有效性。
研究設計(R8
H-16,實例18)
雌性裸小鼠在6週齡時到達該設施且在丟棄式IVC籠養系統(Innovive)中每籠5隻飼養於Alpa-Dri床上。將人DLD-1 BRACA2-/-
細胞在無酚紅Matrigel中1:1稀釋且以100 µL中5x106
個細胞之密度皮下植入每隻小鼠的左側腹中。每週兩次實現測徑規測量且當異種移植物達到250 mm3
之最小體積時開始治療。腹膜內(IP)劑量之實例18 (8.83、17.66或44.15mg/kg)或R8
H-16 (2或10 mg/kg)於8% PEG400 + 2%吐溫80媒劑中每天一次投與共9天。亦投與小鼠口服劑量之20%葡萄糖。第八劑量於第九劑量之前約12小時在晚上投與。於投與第九劑量後2小時收集血清及組織樣本。在骨髓中確定化合物對PAR基化之影響。
化合物投與(R8
H-15,實例12)
將5 mg實例12溶解於50 µL 100%二甲基亞碸(DMSO)中以得到0.1 mg/µL原液。藉由用2475 μL無菌PBS稀釋25 μL原液製備最終10 mg/kg靜脈內劑量。輕輕地混合劑量以得到透明可注射之1 mg/mL給藥溶液。劑量係以10 mL/kg(200 µL/20 g小鼠)藉由尾靜脈注射每天一次投與,歷時2天。與50 g/kg口服劑量之替莫唑胺組合投與小鼠。藉由將1.5 mg化合物懸浮於5 mL 10%二甲基乙醯胺(DMAc) + 6% Solutol + 84% PBS媒劑中製備口服劑量3 mg / kg之R8
H-15。將懸浮液在媒劑中進一步1:10稀釋。最終的0.3 mg/kg劑量經音波處理15分鐘直至獲得0.3 mg/mL均質懸浮液。以10 mL/kg (200 µL/20 g小鼠)組合50 mg/kg口服劑量之替莫唑胺每天一次經口投與小鼠共2天。
化合物投與(R8
H-16,實例18)
化合物投與如實例F之化合物投與(R8
H-16,實例18)部分中所述。
骨髓收集(R8
H-15,實例12)
於收集腫瘤後,移走腿骨,且藉由用裝在含有RPMI + 2%胎牛血清(FBS)的5cc注射器上的23號針沖洗骨頭,將骨髓擠出至50 mL錐形管中。藉由溫和移液均質化骨髓且濾過100 μm尼龍篩網過濾器。藉由在4℃下以1200 rpm離心5分鐘使骨髓細胞集結成粒。用5 mL PBE (PBS + 0.2%牛血清白蛋白 + 2 mM EDTA)洗細胞且如上所述藉由離心再集結成粒。將細胞再懸浮於3 mL 1X RBC裂解緩衝液中且在室溫下培養2-5分鐘。將PBE加入至最終體積25 mL且藉由離心使細胞集結成粒。將細胞再懸於5 mL PBE中,通過40 μm尼龍篩網過濾器,且藉由離心收穫。將細胞再懸於1 mL PBE中。在準備用於PAR基化分析之前,於TC-20細胞計數器(Biorad)上使用台盼藍排除法確定細胞濃度及存活率。於細胞計數後,藉由在4℃下以1200 rpm (300 rcf)離心5分鐘使1.5 mL骨髓細胞集結成粒。收集上清液且儲存在-80℃下以可能分析藥物濃度。藉由在4℃下以1200 rpm(300 rcf)離心5分鐘使剩餘的2.5 mL細胞集結成粒。在含有蛋白酶及磷酸酶抑制劑(100 µL緩衝液/106
個細胞)之RIPA緩衝液中裂解集結成粒的細胞且儲存在-20℃下以用於測定骨髓細胞中之PAR基化,如藉由Elisa PAR基化分析所確定。
骨髓細胞中之PAR基化(R8
H-15,實例12)
於含有蛋白酶/磷酸酶抑制劑之RIPA緩衝液中裂解第3天從腿骨分離的骨髓細胞。使均質化樣本達到1% SDS最終濃度,在100℃下加熱5分鐘,在冰上淬滅且藉由在4℃下以12,000 × g離心5分鐘澄清。使用Trevigen HT PARP體內藥效動力學分析II進行PAR基化分析。簡言之,將一式兩份之10 μg樣本呈含於樣本緩衝液中的50 μL體積加載至預塗佈/預阻斷的ELISA條帶孔中且在4℃下與連續稀釋之純化PAR標準品一起培養16小時。用PBST洗4x該等孔且在室溫下用於抗體稀釋劑中之50 μL/孔之PAR多株檢測抗體培養2小時。用PBST洗4x該等孔且於室溫下用於抗體稀釋劑中之50 µL/孔之山羊抗兔IgG-HRP共軛物培養1小時。用PBST洗4x該等孔,用100 µg/孔之1:1 PARP PeroxyGlow A及PARP PeroxyGlow B培養且使用發光纖維終點在BioTek Cytation 5中讀數。使用從標準曲線計算得的值將數據繪製為PAR (pg/mL)。
骨髓收集(R8
H-16,實例18)
於收集腫瘤後,移走腿骨,且藉由用裝在含有PBS + 2%胎牛血清(FBS)的5cc注射器上的23號針沖洗骨頭,將骨髓擠出至50 mL錐形管中。藉由溫和移液均質化骨髓且濾過100 μm尼龍篩網過濾器並藉由在4℃下以1200 rpm離心5分鐘使細胞集結成粒。在室溫下用3 mL裂解緩衝液裂解紅血球2分鐘。將PBS加入至25 mL體積且如上所述藉由離心細胞再集結成粒。將細胞集結粒懸浮於5 mL PBS中且在TC-20細胞計數器(BioRad)上藉由台盼藍排除法評估細胞計數。將來自每個樣本的2.5 x 106
個細胞之子集收集至微量離心管中以用於量測PAR基化。
骨髓細胞中之PAR基化(R8
H-16,實例18)
在500 μL RIPA/HALT緩衝液中裂解骨髓細胞(2.5 x 106
個細胞/集結粒)且在冰上培養15分鐘,同時進行週期性渦旋。使細胞裂解物達到1% SDS最終濃度,在100℃下加熱5分鐘且在冰上淬滅。藉由在4℃下以14,000 x g離心5分鐘除去細胞碎片且將集結成粒的細胞以250,000個細胞/50 µL之濃度再懸浮於緩衝液中。將骨髓細胞樣本加載於預塗佈/預阻斷的ELISA條帶孔上且在4℃下培養16小時。用PBST (1 L PBS + 1 mL吐溫20)洗4x樣本且在室溫下用50 µL PAR檢測抗體培養2小時。用PBST洗4x樣本且在室溫下用50 µL山羊抗兔IgG-HRP共軛物培養1小時。於PBST的最後4x洗後,將100 µL PeroxyGlowTM
加入至每個樣本且使用發光纖維終點及條帶孔區板定義在BioTek Cytation 5上測定發光。
統計分析
使用方差分析(ANOVA)以測試組間的顯著差異。使用Post-hoc Bonferroni多重比較檢驗分析來確定平均值之間的顯著差異。使用Graph Pad Prism 7.03軟體完成所有統計分析。
圖5顯示對裸小鼠靜脈內投與實例12或經口投與R8
H-15組合經口投與替莫唑胺(TMZ)後骨髓細胞中之PAR基化。
圖6顯示對裸小鼠腹膜內投與實例18或R8
H-16後骨髓細胞中之PAR基化。
熟習此項技術者將從以上描述中明白除彼等其中所述者以外之本發明之各種改良。該等改良亦係意欲落在隨附申請專利範圍之範疇內。參考文獻(包括(但不限於)本申請案中所引述的所有專利案、專利申請案及公開案)各以全文引用的方式併入本文中。
圖1顯示BRCA-/-
小鼠中R8
H-15及實例12之腫瘤生長延遲。
圖2顯示BRCA-/-
小鼠中R8
H-15及實例12之存活期。
圖3顯示BRCA-/-
小鼠中R8
H-16及實例18之腫瘤生長延遲。
圖4顯示鼠類DLD-1 BRCA2-/-
異種移植模型中實例18及R8
H-16之9-天腹膜內投與於腫瘤PAR基化(PARylation)之效應。
圖5顯示於對裸小鼠靜脈內投與實例12或經口投與R8
H-15組合經口投與替莫唑胺(temozolomide)(TMZ)後骨髓細胞中之PAR基化。
圖6顯示於對裸小鼠腹膜內投與實例18或R8
H-16後骨髓細胞中之PAR基化。
Claims (29)
- 一種式(I)化合物R8-Q-R7 (I)或其醫藥上可接受之鹽、立體異構體或水合物,其中:R7為包含如下序列中至少一者之肽:ADDQNPWRAYLDLLFPTDTLLLDLLWCG(SEQ ID NO:1;Pv1);AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG(SEQ ID NO:2;Pv2);ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG(SEQ ID NO:3;Pv3);Ac-AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTKCG(SEQ ID NO:4;Pv4);及AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTC(SEQ ID No.5;Pv5);且其中R7係經R7之半胱胺酸殘基連接至Q;R8係選自由如下組成之群:
- 如請求項1之化合物或其醫藥上可接受之鹽、立體異構體或水合物,其中R7為包含如下序列中至少一者之肽:ADDQNPWRAYLDLLFPTDTLLLDLLWCG(SEQ ID NO:1;Pv1),AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG(SEQ ID NO:2;Pv2),及 ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG(SEQ ID NO:3;Pv3),且其中R7係經R7之半胱胺酸殘基連接至Q。
- 如請求項1之化合物或其醫藥上可接受之鹽、立體異構體或水合物,其中R7為包含如下序列之肽:ADDQNPWRAYLDLLFPTDTLLLDLLWCG(SEQ ID NO:1;Pv1)。
- 如請求項1之化合物或其醫藥上可接受之鹽、立體異構體或水合物,其中R7為包含如下序列之肽:AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG(SEQ ID NO:2;Pv2)。
- 如請求項1之化合物或其醫藥上可接受之鹽、立體異構體或水合物,其中R7為包含如下序列之肽:ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG(SEQ ID NO:3;Pv3)。
- 如請求項1之化合物或其醫藥上可接受之鹽、立體異構體或水合物,其中R7為包含如下序列之肽:Ac-AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTKCG(SEQ ID NO:4;Pv4)。
- 如請求項1之化合物或其醫藥上可接受之鹽、立體異構體或水合物,其中R7為包含如下序列之肽:AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTC(SEQ ID No.5;Pv5)。
- 如請求項1至7中任一項之化合物或其醫藥上可接受之鹽、立體異構體或水合物,其中R1及R2各獨立地選自H及甲基,且R3、R4、R5及R6各為H。
- 如請求項1至7中任一項之化合物或其醫藥上可接受之鹽、立體異構體或水合物,其中R1及R2各獨立地選自H及甲基。
- 如請求項1至7中任一項之化合物或其醫藥上可接受之鹽、立體異構體或水合物,其中R1及R2各為H。
- 如請求項1至7中任一項之化合物或其醫藥上可接受之鹽、立體異構體或水合物,其中R3及R4各為H。
- 如請求項1至7中任一項之化合物或其醫藥上可接受之鹽、立體異構體或水合物,其中R5及R6各為H。
- 如請求項1至7中任一項之化合物或其醫藥上可接受之鹽、立體異構體或水合物,其中R9、R10、R11及R12各獨立地選自H及甲基。
- 如請求項1至7中任一項之化合物或其醫藥上可接受之鹽、立體異構體或水合物,其中可裂解[AA]X之酵素為組織蛋白酶B(Cathepsin B)、MMPXX、DPPIV、醣蛋白、肽酶或凋亡蛋白酶(caspase)。
- 如請求項1至7中任一項之化合物或其醫藥上可接受之鹽、立體異構體或水合物,其中[AA]x為具有兩個至十個胺基酸殘基之肽。
- 如請求項1至7中任一項之化合物或其醫藥上可接受之鹽、立體異構體或水合物,其中[AA]X為-Pro_Gly-;-Val_Cit-、-Gly_Pro_Leu_Gly_Leu_Ala_Gly_Asp_Asp-、-Gly_Pro_GLeu_Gly_Val_Arg_Gly或-Ser_Ser_Lys_Leu_Gly-。
- 一種醫藥組合物,其包含如請求項1至18中任一項之化合物或其醫藥上可接受之鹽、立體異構體或水合物。
- 一種如請求項1至18中任一項之化合物或其醫藥上可接受之鹽、立體異構體或水合物之用途,其係用於製備治療需要此治療之患病人類或其他哺乳動物中涉及酸性或缺氧性患病組織之疾病或病症之醫藥品。
- 如請求項20之用途,其中該疾病或病症係選自癌症、中風、心肌梗塞及長期神經退化性疾病。
- 如請求項21之用途,其中該疾病或病症為癌症。
- 如請求項22之用途,其中該癌症係PARP-敏感性的。
- 如請求項22之用途,其中該癌症係與ATM之異常表現或活性相關。
- 如請求項22之用途,其中該癌症係與DNA-PK之異常表現或活性相關。
- 如請求項22之用途,其中該癌症為BRCA突變乳癌。
- 如請求項22之用途,其中該癌症為生殖系BRCA突變卵巢癌。
- 如請求項21之用途,其進一步包括對該患病人類或其他哺乳動物投與治療有效量之電離輻射或細胞毒性劑。
- 一種如請求項1至18中任一項之化合物或其醫藥上可接受之鹽、立體異構體或水合物之用途,其係用於製備降低投與電離輻射或細胞毒性劑相關之骨髓毒性之醫藥品,其中該醫藥品適合與電離輻射或細胞毒性劑組合使用。
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WO2021007435A1 (en) | 2019-07-10 | 2021-01-14 | Cybrexa 2, Inc. | Peptide conjugates of cytotoxins as therapeutics |
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CN111285936A (zh) * | 2020-03-11 | 2020-06-16 | 北京双赢科创生物科技有限公司 | 靶向肿瘤的酸性敏感纳米肽段及其应用 |
WO2022150596A1 (en) | 2021-01-08 | 2022-07-14 | Cybrexa 2, Inc. | Process for preparing a conjugate linking moiety |
WO2022155172A1 (en) | 2021-01-13 | 2022-07-21 | Cybrexa 3, Inc. | Peptide conjugates of therapeutics |
CN115137818B (zh) * | 2021-03-31 | 2023-06-27 | 华南师范大学 | 谷胱甘肽激活的光敏剂-化疗药一体化分子前药及其应用 |
CN117897175A (zh) | 2021-04-29 | 2024-04-16 | 美商斯布雷克萨二号公司 | 拓扑异构酶i抑制剂的肽缀合物的给药方案 |
CN116640229B (zh) * | 2023-04-10 | 2024-01-30 | 中国人民解放军总医院第五医学中心 | 一种低pH靶向性CAR-T细胞的构建及应用 |
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CA3088858A1 (en) | 2019-07-11 |
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US20190209580A1 (en) | 2019-07-11 |
PH12020551043A1 (en) | 2021-09-06 |
IL275754A (en) | 2020-08-31 |
MA51524A (fr) | 2020-11-11 |
KR20200121800A (ko) | 2020-10-26 |
JP2021510173A (ja) | 2021-04-15 |
ECSP20046463A (es) | 2020-12-31 |
JP2024009819A (ja) | 2024-01-23 |
EP3735297A1 (en) | 2020-11-11 |
CL2020001797A1 (es) | 2021-01-29 |
MX2020007060A (es) | 2020-11-11 |
US20210299137A1 (en) | 2021-09-30 |
BR112020013672A2 (pt) | 2020-12-01 |
US10933069B2 (en) | 2021-03-02 |
CN111989137A (zh) | 2020-11-24 |
TW201938540A (zh) | 2019-10-01 |
AU2019205325A1 (en) | 2020-08-13 |
CR20200334A (es) | 2021-03-09 |
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