TW202340183A - 化合物、血管收縮素ii第一型受體拮抗劑及醫藥組合物 - Google Patents
化合物、血管收縮素ii第一型受體拮抗劑及醫藥組合物 Download PDFInfo
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- TW202340183A TW202340183A TW111150073A TW111150073A TW202340183A TW 202340183 A TW202340183 A TW 202340183A TW 111150073 A TW111150073 A TW 111150073A TW 111150073 A TW111150073 A TW 111150073A TW 202340183 A TW202340183 A TW 202340183A
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Abstract
本發明係一種化合物或其醫藥上可容許之鹽,上述化合物係由下述式(1)所表示:
[式中,
Ar為下述式(Ar1)、或(Ar2):
(式中,
R
1及R
2分別獨立地為烷基、鹵代烷基或鹵素,
R
3分別獨立地為烷基、鹵代烷基、鹵素、烷氧基、或鹵代烷氧基,
m為0~3之整數)]。
Description
本發明係關於一種化合物、血管收縮素II第一型受體拮抗劑及醫藥組合物。
作為針對血管收縮素II之受體,有血管收縮素II第一型受體(AT1受體)及血管收縮素II第二型受體(AT2受體),報告了AT1受體相關(介導)之各種疾病。
作為AT1受體相關疾病,例如報告了:高血壓症(專利文獻1)、心臟疾病(例如,心肥大、急性心衰竭、包括鬱血性心衰竭在內之慢性心衰竭、擴張不全、心肌病、心絞痛、心肌炎、心房震顫、心律不整、心跳過速、及心肌梗塞)(非專利文獻1及2)、心肌梗塞後發展成心衰竭(非專利文獻3)、腎臟疾病(例如,腎炎、腎絲球腎炎、腎絲球硬化症、腎衰竭、血栓性微血管病、透析之併發症、及放射線照射所導致之包括腎病在內之器官損傷)(非專利文獻4及5)、介入(例如,經皮冠狀動脈成形術、支架置放、冠狀動脈內視鏡、血管內超音波、及冠狀動脈血栓溶解療法)後之血管增厚、阻塞及器官損傷(非專利文獻6)、眼病(例如,青光眼、及高眼壓症)(非專利文獻7及8)、神經退化性疾病(例如,阿茲海默症)(非專利文獻9)、中樞神經損傷(例如,腦出血及腦梗塞等損傷、以及其後遺症及併發症)(非專利文獻10)、癡呆(例如,腦血管性癡呆)(非專利文獻11)、肝臟疾病(例如,非酒精性脂肪性肝病)(非專利文獻12及13)、嗜酸細胞性食管炎(非專利文獻14)、骨病(例如,變形性膝關節炎)(非專利文獻15)、皮膚病(例如,表皮分解性水皰症)(非專利文獻16)、全身疾病(例如,馬凡氏症候群)(非專利文獻17)、以及癌症(非專利文獻18)。
先前技術文獻
專利文獻
專利文獻1:國際公開第2005/80384號公報
非專利文獻
非專利文獻1:Vascular Health and Risk Management 2008, 4, 67.
非專利文獻2:Annals of Palliative Medicine 2021, 10, 8684.
非專利文獻3:The Lancet 2002, 360, 752.
非專利文獻4:The New England Journal of Medicine 2001, 345, 861.
非專利文獻5:Blood Pressure 2019, 28, 358.
非專利文獻6:BMC Cardiovascular Disorders 2017, 17, 278.
非專利文獻7:Experimental Eye Research 2005, 80, 629.
非專利文獻8:Journal of Cardiovascular Pharmacology 2000, 36, 169.
非專利文獻9:Journal of Clinical Investigation 2007, 117, 3393.
非專利文獻10:International Journal of Molecular Sciences 2012, 13, 7739.
非專利文獻11:Hypertension Research 2009, 32, 738.
非專利文獻12:Oncotarget 2018, 9, 24155.
非專利文獻13:Physiological Reports 2016, 4, e13016.
非專利文獻14:Expert Review of Clinical Immunology 2020, 16, 421.
非專利文獻15:Journal of Orthopaedic Translation 2021, 29, 30.
非專利文獻16:Dermatologic Therapy 2020, e14279.
非專利文獻17:European Heart Journal 2020, 41, 4181.
非專利文獻18:Biochemical Pharmacology 2018, 151, 96.
[發明所欲解決之問題]
本發明之目的在於提供一種具有AT1受體拮抗作用之化合物、或者包含上述化合物之AT1受體拮抗劑或醫藥組合物。
[解決問題之技術手段]
本發明人等經過銳意研究,結果發現具有特定結構之化合物具有AT1受體拮抗作用,從而完成本發明。
本發明包括以下實施方式。
[1]
一種化合物或其醫藥上可容許之鹽,上述化合物係由下述式(1)所表示:
[化1]
[式中,
Ar為下述式(Ar1)、或(Ar2):
[化2]
(式中,
R
1及R
2分別獨立地為烷基、鹵代烷基或鹵素,
R
3分別獨立地為烷基、鹵代烷基、鹵素、烷氧基、或鹵代烷氧基,
m為0~3之整數)]。
[2]
如[1]所記載之化合物或其醫藥上可容許之鹽,其中Ar為式(Ar1)。
[3]
如[1]或[2]所記載之化合物或其醫藥上可容許之鹽,其中R
1及R
2分別獨立地為烷基。
[4]
如[1]所記載之化合物或其醫藥上可容許之鹽,其中上述化合物係選自由下述化合物所組成之群:
[化3]
。
[5]
一種血管收縮素II第一型受體拮抗劑,其包含如[1]至[4]中任一項所記載之化合物或其醫藥上可容許之鹽。
[6]
一種醫藥組合物,其包含如[1]至[4]中任一項所記載之化合物或其醫藥上可容許之鹽。
[7]
如[6]所記載之醫藥組合物,其係用於預防或治療高血壓症、心臟疾病、心肌梗塞後發展成心衰竭、腎臟疾病、介入後之血管增厚、介入後之阻塞、介入後之器官損傷、青光眼、高眼壓症、阿茲海默症、中樞神經損傷、癡呆、肝臟疾病、嗜酸細胞性食管炎、變形性膝關節炎、表皮分解性水皰症、馬凡氏症候群、或癌症。
[8]
如[6]或[7]所記載之醫藥組合物,其係注射劑、貼附劑、或滴眼劑。
[9]
一種化合物或其鹽,上述化合物係由下述式(2)所表示:
[化4]
[式中,
R
4為脫離基、硼酸、硼酸酯、或-BF
3M
1,
M
1為鹼金屬]。
[10]
一種化合物或其鹽,上述化合物係由下述式(3)所表示:
[化5]
[式中,
Ar為下述式(Ar1)、或(Ar2):
[化6]
(式中,
R
1及R
2分別獨立地為烷基、鹵代烷基或鹵素,
R
3分別獨立地為烷基、鹵代烷基、鹵素、烷氧基、或鹵代烷氧基,
m為0~3之整數),
R
5為脫離基、或-OR
5A,
R
5A為氫、或保護基,
R
6為氫、或保護基]。
[11]
一種化合物或其鹽,上述化合物係由下述式(4)所表示:
[化7]
[式中,
R
7為硼酸、硼酸酯、或-BF
3M
2,
M
2為鹼金屬,
R
8為-OR
8A,
R
8A為氫、或保護基]。
又,本發明亦包括以下實施方式。
[A1]
一種抑制血管收縮素II第一型受體之方法,其包括向有此需求之患者投予有效量之如[1]至[4]中任一項所記載之化合物或其醫藥上可容許之鹽。
[A2]
一種預防或治療疾病之方法,其包括向有此需求之患者投予有效量之如[1]至[4]中任一項所記載之化合物或其醫藥上可容許之鹽。
[A3]
如[A2]所記載之方法,其中上述疾病係高血壓症、心臟疾病、心肌梗塞後發展成心衰竭、腎臟疾病、介入後之血管增厚、介入後之阻塞、介入後之器官損傷、青光眼、高眼壓症、阿茲海默症、中樞神經損傷、癡呆、肝臟疾病、嗜酸細胞性食管炎、變形性膝關節炎、表皮分解性水皰症、馬凡氏症候群、或癌症。
[B1]
如[1]至[4]中任一項所記載之化合物或其醫藥上可容許之鹽,其係用於抑制血管收縮素II第一型受體。
[B2]
如[1]至[4]中任一項所記載之化合物或其醫藥上可容許之鹽,其係用於疾病之預防或治療。
[B3]
如[B2]所記載之化合物或其醫藥上可容許之鹽,其中上述疾病係高血壓症、心臟疾病、心肌梗塞後發展成心衰竭、腎臟疾病、介入後之血管增厚、介入後之阻塞、介入後之器官損傷、青光眼、高眼壓症、阿茲海默症、中樞神經損傷、癡呆、肝臟疾病、嗜酸細胞性食管炎、變形性膝關節炎、表皮分解性水皰症、馬凡氏症候群、或癌症。
[C1]
一種如[1]至[4]中任一項所記載之化合物或其醫藥上可容許之鹽之用途,用於抑制血管收縮素II第一型受體。
[C2]
一種如[1]至[4]中任一項所記載之化合物或其醫藥上可容許之鹽之用途,用於預防或治療疾病。
[C3]
如[C2]所記載之用途,其中上述疾病係高血壓症、心臟疾病、心肌梗塞後發展成心衰竭、腎臟疾病、介入後之血管增厚、介入後之阻塞、介入後之器官損傷、青光眼、高眼壓症、阿茲海默症、中樞神經損傷、癡呆、肝臟疾病、嗜酸細胞性食管炎、變形性膝關節炎、表皮分解性水皰症、馬凡氏症候群、或癌症。
[D1]
一種如[1]至[4]中任一項所記載之化合物或其醫藥上可容許之鹽之用途,用於製造血管收縮素II第一型受體拮抗劑。
[D2]
一種如[1]至[4]中任一項所記載之化合物或其醫藥上可容許之鹽之用途,用於製造用以預防或治療疾病之醫藥組合物。
[D3]
如[D2]所記載之用途,其中上述疾病係高血壓症、心臟疾病、心肌梗塞後發展成心衰竭、腎臟疾病、介入後之血管增厚、介入後之阻塞、介入後之器官損傷、青光眼、高眼壓症、阿茲海默症、中樞神經損傷、癡呆、肝臟疾病、嗜酸細胞性食管炎、變形性膝關節炎、表皮分解性水皰症、馬凡氏症候群、或癌症。
[發明之效果]
根據本發明,可提供一種具有AT1受體拮抗作用之化合物、或包含上述化合物之AT1受體拮抗劑或醫藥組合物。
以下,對本發明之實施方式具體地進行說明,但本發明並不限定於該等,於不脫離其主旨之範圍內能夠進行各種變化。
<化合物>
本發明之一實施方式係關於一種化合物或其醫藥上可容許之鹽,上述化合物係由下述式(1)所表示:
[化8]
[式中,
Ar為下述式(Ar1)、或(Ar2):
[化9]
(式中,
R
1及R
2分別獨立地為烷基、鹵代烷基或鹵素,
R
3分別獨立地為烷基、鹵代烷基、鹵素、烷氧基、或鹵代烷氧基,
m為0~3之整數)]。
本實施方式之化合物或其醫藥上可容許之鹽具有AT1受體拮抗作用。
於本說明書中,烷基(包括鹵代烷基中之烷基)可為直鏈狀,亦可為支鏈狀。
於本說明書中,烷氧基(包括鹵代烷氧基中之烷氧基)中所含之烷基部分可為直鏈狀,亦可為支鏈狀。
式(1)中,Ar為式(Ar1)或式(Ar2),較佳為式(Ar1)。
式(1)中,R
1為烷基、鹵代烷基或鹵素,較佳為烷基或鹵素,更佳為烷基。
R
1之烷基(包括鹵代烷基中之烷基)較佳為碳數1~6之烷基,更佳為碳數1~3之烷基,進而較佳為碳數1或2之烷基,特佳為甲基。
R
1之鹵素、及鹵代烷基中之鹵素較佳為氟、氯、溴或碘,更佳為氯。
式(1)中,R
2為烷基、鹵代烷基或鹵素,較佳為烷基或鹵素,更佳為烷基。
R
2之烷基(包括鹵代烷基中之烷基)較佳為碳數1~6之烷基,更佳為碳數1~3之烷基,進而較佳為碳數1或2之烷基,特佳為甲基。
R
2之鹵素、及鹵代烷基中之鹵素較佳為氟、氯、溴或碘,更佳為氯。
式(1)中,R
3分別獨立地為烷基、鹵代烷基、鹵素、烷氧基或鹵代烷氧基,較佳為烷基或烷氧基。
R
3之烷基(包括鹵代烷基中之烷基)較佳為碳數1~6之烷基,更佳為碳數1~3之烷基,進而較佳為碳數1或2之烷基,特佳為甲基。
R
3之鹵素、以及鹵代烷基及鹵代烷氧基中之鹵素較佳為氟、氯、溴或碘,更佳為氯。
R
3之烷氧基(包括鹵代烷氧基中之烷氧基)較佳為碳數1~6之烷氧基,更佳為碳數1~3之烷氧基,進而較佳為碳數1或2之烷氧基,特佳為甲氧基。
式(1)中,m為0~3之整數,較佳為1或2,更佳為2。
式(1)所表示之化合物並無特別限定,較佳為下述化合物。
[化10]
式(1)所表示之化合物之醫藥上可容許之鹽並無特別限定,只要為可用作醫藥之鹽即可,例如可例舉:鹽酸鹽、硫酸鹽、硝酸鹽、磷酸鹽、氫溴酸鹽等無機酸鹽;富馬酸鹽、馬來酸鹽、蘋果酸鹽、酒石酸鹽、琥珀酸鹽、檸檬酸鹽、甲磺酸鹽、對甲苯磺酸鹽、乙酸鹽、乳酸鹽、棕櫚酸鹽等有機酸鹽;鈉鹽、鉀鹽、鈣鹽、鎂鹽、鋁鹽、銨鹽等無機鹼鹽;二乙胺鹽、二乙醇胺鹽、甲葡胺鹽、N,N'-二苄基乙二胺鹽等有機鹼鹽。
式(1)所表示之化合物或其醫藥上可容許之鹽亦可形成為水合物等溶劑合物。於本說明書中,溶劑合物包含於式(1)所表示之化合物或其醫藥上可容許之鹽中。
於式(1)所表示之化合物或其醫藥上可容許之鹽存在立體異構物(例如,鏡像異構物及非鏡像異構物)之情形時,各立體異構物及其等之混合物(例如,外消旋體)包含於式(1)所表示之化合物或其醫藥上可容許之鹽中。
<血管收縮素II第一型受體拮抗劑>
本發明之一實施方式係關於一種AT1受體拮抗劑,其包含式(1)所表示之化合物或其醫藥上可容許之鹽。本實施方式之AT1受體拮抗劑較佳為以內皮素A受體(ETA受體)為對照,能夠選擇性地抑制AT1受體。藉由選擇性地抑制AT1受體,從而能夠降低因ETA受體之抑制所帶來之副作用(例如,致畸胎性)之風險。
具體而言,ETA受體抑制濃度(IC
50)/AT1受體抑制濃度(IC
50)較佳為100以上,更佳為200以上,進而較佳為500以上,特佳為1,000以上。ETA受體抑制濃度(IC
50)/AT1受體抑制濃度(IC
50)之上限並無特別限定,例如,可設為10,000、8,000、6,000、4,000等。ETA受體抑制濃度、及AT1受體抑制濃度可利用實施例中所記載之方法進行測定。
本實施方式之AT1受體拮抗劑之AT1受體抑制濃度(IC
50)較佳為1.0 nM以下,更佳為0.5 nM以下,進而較佳為0.2 nM以下,特佳為0.1 nM以下。AT1受體抑制濃度(IC
50)之下限並無特別限定,例如,可設為0.0025 nM、0.005 nM、0.01 nM、0.02 nM等。
本實施方式之AT1受體拮抗劑之ETA受體抑制濃度(IC
50)較佳為10 nM以上,更佳為20 nM以上,進而較佳為50 nM以上,特佳為100 nM以上。ETA受體抑制濃度(IC
50)之上限並無特別限定,例如,可設為1,000 nM、800 nM、600 nM、400 nM等。
藉由使用本實施方式之AT1受體拮抗劑,從而能夠治療及/或預防AT1受體相關(介導)之疾病。作為此類疾病,可例舉:下述<醫藥組合物>之欄中所記載之疾病。
本實施方式之AT1受體拮抗劑及後述之醫藥組合物之投予對象較佳為哺乳動物,更佳為人類、猴、貓、豬、馬、牛、小鼠、大鼠、豚鼠、狗及兔,進而較佳為人類。
<醫藥組合物>
本發明之一實施方式係關於一種醫藥組合物,其包含式(1)所表示之化合物或其醫藥上可容許之鹽。
作為本實施方式之醫藥組合物之視為預防對象或治療對象之疾病,例如可例舉以下疾病。
高血壓症;
心臟疾病(例如,心肥大、急性心衰竭、包括鬱血性心衰竭在內之慢性心衰竭、擴張不全、心肌病、心絞痛、心肌炎、心房震顫、心律不整、心跳過速、及心肌梗塞);
心肌梗塞後發展成心衰竭;
腎臟疾病(例如,腎炎、腎絲球腎炎、腎絲球硬化症、腎衰竭、血栓性微血管病、透析之併發症、及放射線照射所導致之包括腎病在內之器官損傷);
介入(例如,經皮冠狀動脈成形術、支架置放、冠狀動脈內視鏡、血管內超音波、及冠狀動脈血栓溶解療法)後之血管增厚、阻塞及器官損傷;
眼病(例如,青光眼、及高眼壓症);
神經退化性疾病(例如,阿茲海默症);
中樞神經損傷(例如,腦出血及腦梗塞等損傷、以及其後遺症及併發症);
癡呆(例如,腦血管性癡呆);
肝臟疾病(例如,非酒精性脂肪性肝病);
嗜酸細胞性食管炎;
骨病(例如,變形性膝關節炎);
皮膚病(例如,表皮分解性水皰症);
全身疾病(例如,馬凡氏症候群);以及
癌症。
本實施方式之醫藥組合物可經口或非經口地投予。作為經口投予用之劑型,例如可例舉:錠劑、丸劑、顆粒劑、散劑、膠囊劑、糖漿劑、乳劑、及懸浮劑。作為非經口投予用之劑型,例如可例舉:注射劑、注入劑、點滴劑、滴眼劑、貼附劑及栓劑。本實施方式之醫藥組合物較佳為注射劑,但並無特別限定。藉由採用注射劑,從而能夠良好地用於緊急度較高之疾病。作為緊急度較高之疾病,例如可例舉:伴有腦出血或心肌梗塞等器官損傷之急性高血壓症。
於使本實施方式之醫藥組合物為注射劑之情形時,注射劑除了包含式(1)所表示之化合物或其醫藥上可容許之鹽以外,亦可包含第2有效成分。作為第2有效成分,例如可例舉:除了式(1)所表示之化合物或其醫藥上可容許之鹽以外之具有AT1受體拮抗作用之化合物,具體而言,可例舉:洛沙坦、纈沙坦、坎地沙坦、替米沙坦、奧美沙坦、厄貝沙坦、阿齊沙坦等。
本實施方式之醫藥組合物亦可視需要包含賦形劑、結合劑、潤滑劑、崩解劑、甜味劑、界面活性劑、懸浮劑、乳化劑、著色劑、保存劑、芳香劑、矯味劑、穩定劑、增稠劑等。
本實施方式之醫藥組合物之投予量係根據患者之狀態或體重、化合物之種類、疾病之種類、投予路徑等而有所不同,可由醫師來確定合適之量。
<中間化合物>
本發明之一實施方式係關於一種中間化合物,其能夠用於式(1)所表示之化合物或其醫藥上可容許之鹽之合成。作為中間化合物,例如可例舉:下述式(2)~式(4)所表示之化合物或其鹽。
式(2)~式(4)所表示之化合物之鹽並無特別限定,例如可例舉:作為式(1)所表示之化合物之醫藥上可容許之鹽所示之例。
式(2)~式(4)所表示之化合物或其鹽亦可形成水合物等溶劑合物。於本說明書中,溶劑合物包含於式(2)~式(4)所表示之化合物或其鹽中。
(中間化合物1)
本發明之一實施方式係關於一種化合物或其鹽,上述化合物係由下述式(2)所表示:
[化11]
[式中,
R
4為脫離基、硼酸(-B(OH)
2)、硼酸酯、或-BF
3M
1,
M
1為鹼金屬]。
作為R
4之脫離基,例如可例舉:鹵素(例如,氟、氯、溴、或碘)、甲磺醯氧基、對甲苯磺醯氧基、或三氟甲磺醯氧基。
R
4之硼酸酯例如可表示為-B(OR
4A)
2。作為R
4A,例如可例舉:烷基(例如,碳數1~6之烷基、或碳數1~3之烷基)。
又,-B(OR
4A)
2之2個R
4A可與該等所直接地或間接地鍵結之氧及硼一起形成5員或6員雜環。雜環可具有取代基。作為雜環之取代基,例如可例舉:烷基(例如,碳數1~3之烷基)、環烷基(例如,碳數5或6之環烷基)、或芳基(例如,苯基)。作為-B(OR
4A)
2,例如可例舉具有下述結構之基:
[化12]
。
作為M
1之烷基金屬,例如可例舉:鋰、鈉、或鉀。
(中間化合物2)
本發明之一實施方式係關於一種化合物或其鹽,上述化合物係由下述式(3)所表示:
[化13]
[式中,
Ar為下述式(Ar1)、或(Ar2):
[化14]
(式中,
R
1及R
2分別獨立地為烷基、鹵代烷基或鹵素,
R
3分別獨立地為烷基、鹵代烷基、鹵素、烷氧基、或鹵代烷氧基,
m為0~3之整數),
R
5為脫離基、或-OR
5A,
R
5A為氫、或保護基,
R
6為氫、或保護基]。
式(3)中,Ar之較佳之形態同上述<化合物>之欄之記載。
作為R
5之脫離基,例如可例舉:鹵素(例如,氟、氯、溴、或碘)、甲磺醯氧基、對甲苯磺醯氧基、或三氟甲磺醯氧基。
R
5A之保護基並無特別限定,只要為羥基之保護基即可,例如可例舉:甲氧基甲基(MOM)、第三丁基二甲基矽烷基(TBS)、苄基(Bn)、苯甲醯基(Bz)、乙醯基(Ac)、三甲基矽烷基(TMS)、或三乙基矽烷基(TES)。
R
6之保護基並無特別限定,只要為胺基之保護基即可,例如可例舉:甲氧基甲基(MOM)、第三丁氧基羰基(Boc)、苄氧基羰基(Cbz)、9-茀基甲氧基羰基(Fmoc)、或烯丙氧基羰基(Alloc)。
(中間化合物3)
本發明之一實施方式係關於一種化合物或其鹽,上述化合物係由下述式(4)所表示:
[化15]
[式中,
R
7為硼酸(-B(OH)
2)、硼酸酯、或-BF
3M
2,
M
2為鹼金屬,
R
8為-OR
8A,
R
8A為氫、或保護基]。
R
7之硼酸酯例如可表示為-B(OR
7A)
2。作為R
7A,例如可例舉:烷基(例如,碳數1~6之烷基、或碳數1~3之烷基)。
又,-B(OR
7A)
2之2個R
7A可與該等所直接地或間接地鍵結之氧及硼一起形成5員或6員雜環。雜環可具有取代基。作為雜環之取代基,例如可例舉:烷基(例如,碳數1~3之烷基)、環烷基(例如,碳數5或6之環烷基)、或芳基(例如,苯基)。作為-B(OR
7A)
2,例如可例舉具有下述結構之基:
[化16]
。
作為M
2之烷基金屬,例如可例舉:鋰、鈉、或鉀。
R
8A之保護基並無特別限定,只要為羥基之保護基即可,例如可例舉:甲氧基甲基(MOM)、第三丁基二甲基矽烷基(TBS)、苄基(Bn)、苯甲醯基(Bz)、乙醯基(Ac)、三甲基矽烷基(TMS)、或三乙基矽烷基(TES)。
<化合物之製造方法>
式(1)所表示之化合物或其醫藥上可容許之鹽可適當地利用公知之方法來進行合成。作為合成方法之一例,可例舉:下述方案A。
[化17]
方案A中,Ar如上所述,L
1~L
3為脫離基等,Pro為保護基。
方案A中,使化合物(A2)與金屬氫化物(例如,氫化鈉)進行反應後,與化合物(A1)進行反應,獲得化合物(A3)(步驟A1)。藉由保護基(例如,甲氧基甲基)對化合物(A4)之胺基加以保護,獲得化合物(A5)(步驟A2)。使化合物(A3)與化合物(A5)進行反應,獲得化合物(A6)(步驟A3),使化合物(A6)去保護,獲得化合物(A7)(步驟A4)。
式(1)所表示之化合物或其醫藥上可容許之鹽之合成方法並不限定於上述方案A,可根據最終化合物之結構,由本領域技術人員適當地設定合適之合成路線及反應條件。
實施例
以下,使用實施例,對本發明更加詳細地進行說明,但本發明之技術範圍並不限定於此。
[製造例1-1]
7-溴-1,3-二氫異苯并呋喃-4-胺鹽酸鹽
[化18]
於(7-溴-1,3-二氫異苯并呋喃-4-基)胺基甲酸第三丁酯(4.90 g、15.6 mmol)、及二氯甲烷(50.0 mL)之混合物中,於0℃下緩慢添加氯化氫/1,4-二㗁烷溶液(4 mol/L、15.0 mL),於室溫下攪拌6小時。對反應混合物於減壓下進行溶劑之蒸餾去除,藉由二乙醚對殘渣進行洗淨,從而獲得標題化合物(2.90 g)。
1H NMR (400 MHz, DMSO-d
6) δ 7.29 (d, J = 8.0 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 5.05 (bs, 2H), 4.89 (bs, 2H).
[製造例1-2]
4,7-二溴-1,3-二氫異苯并呋喃
[化19]
於氬氣環境下,於7-溴-1,3-二氫異苯并呋喃-4-胺鹽酸鹽(2.90 g、11.64 mmol)、及乙腈(40.0 mL)之混合物中,於0℃下緩慢添加溴化銅(II)(3.03 g、13.5 mmol)、亞硝酸第三丁酯(1.54 g、14.9 mmol)、及乙腈(20.0 mL)之混合物,於80℃下攪拌6小時。使反應混合物為室溫,添加冰水,藉由乙酸乙酯進行萃取。藉由飽和鹽水對有機層進行洗淨,藉由硫酸鈉使其乾燥,於減壓下進行溶劑之蒸餾去除。利用矽膠管柱層析法(己烷/乙酸乙酯)對殘渣進行純化,從而獲得標題化合物(1.70 g)。
1H NMR (400 MHz, DMSO-d
6) δ 7,45 (bs, 1H), 5.09 (s, 4H).
[製造例1-3]
7-溴-1,3-二氫異苯并呋喃-4-甲醛
[化20]
於氬氣環境下,於4,7-二溴-1,3-二氫異苯并呋喃(1.70 g、6.12 mmol)、及二乙醚(20.0 mL)之混合物中,於-78℃下緩慢添加正丁基鋰(2.3 M己烷溶液、5.65 mL、7.34 mmol),於相同溫度下攪拌1小時。於反應混合物中緩慢添加N,N-二甲基甲醯胺(0.95 mL、12.2 mmol),於-78℃下攪拌30分鐘。於反應混合物中添加飽和氯化銨水溶液,藉由乙酸乙酯進行萃取。藉由飽和鹽水對有機層進行洗淨,藉由硫酸鈉使其乾燥,於減壓下進行溶劑之蒸餾去除。利用矽膠管柱層析法(己烷/乙酸乙酯)對殘渣進行純化,從而獲得標題化合物(0.80 g)。
1H NMR (400 MHz, DMSO-d
6) δ 10.03 (s, 1H), 7.87-7.79 (m, 2H), 5.37 (s, 2H), 5.01 (s, 2H).
[製造例1-4]
(7-溴-1,3-二氫異苯并呋喃-4-基)甲醇
[化21]
於7-溴-1,3-二氫異苯并呋喃-4-甲醛(800 mg、3.52 mmol)、及甲醇(10 mL)之混合物中,於0℃下添加硼氫化鈉(379 mg、10.6 mmol),對反應混合物於室溫下攪拌1小時。於反應混合物中添加冰水,藉由乙酸乙酯進行萃取。藉由飽和鹽水對有機層進行洗淨,藉由硫酸鈉使其乾燥,於減壓下進行溶劑之蒸餾去除。利用矽膠管柱層析法(己烷/乙酸乙酯)對殘渣進行純化,從而獲得標題化合物(0.75 g)。
1H NMR (400 MHz, DMSO-d
6) δ 7.44 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 5.26 (t, J = 5.6 Hz, 1H), 5.14 (s, 2H), 4.96 (s, 2H), 4.42 (d, J = 5.6 Hz, 2H).
[製造例1-5]
4-溴-7-(氯甲基)-1,3-二氫異苯并呋喃
[化22]
於(7-溴-1,3-二氫異苯并呋喃-4-基)甲醇(750 mg、3.27 mmol)、及二氯甲烷(15 mL)之混合物中,於0℃下緩慢添加亞硫醯氯(584 mg、4.91 mmol),於相同溫度下攪拌30分鐘。於反應混合物中添加少量N,N-二甲基甲醯胺,於相同溫度下攪拌2小時。於反應混合物中添加冰水,藉由二氯甲烷進行萃取。藉由飽和鹽水對有機層進行洗淨,藉由硫酸鈉使其乾燥,於減壓下進行溶劑之蒸餾去除。利用矽膠管柱層析法(己烷/乙酸乙酯)對殘渣進行純化,從而獲得標題化合物(0.63 g)。
1H NMR (400 MHz, DMSO-d
6) δ 7.50 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 5.22 (s, 2H), 5.00 (s, 2H), 4.73 (s, 2H).
[製造例1-6]
3-((7-溴-1,3-二氫異苯并呋喃-4-基)甲基)-2-丁基-1,3-二氮螺[4.4]壬-1-烯-4-酮
[化23]
於2-丁基-1,3-二氮螺[4.4]壬-1-烯-4-酮(494 mg、2.55 mmol)、及DMF(N,N-Dimethylformamide,N,N-二甲基甲醯胺)(10 mL)之混合物中,於0℃下緩慢添加50%氫化鈉(153 mg、6.36 mmol),於相同溫度下攪拌30分鐘。於反應混合物中緩慢添加4-溴-7-(氯甲基)-1,3-二氫異苯并呋喃(630 mg、2.55 mmol)、及DMF(5 mL)之混合物,於相同溫度下攪拌2小時。於反應混合物中添加冰水,藉由乙酸乙酯進行萃取。藉由飽和鹽水對有機層進行洗淨,藉由硫酸鈉使其乾燥,於減壓下進行溶劑之蒸餾去除。利用矽膠管柱層析法(己烷/乙酸乙酯)對殘渣進行純化,從而獲得標題化合物(0.90 g)。
ESI-MS: m/z 405.10 [M+1]+, 407.12 [M+3]+
[製造例1-7]
2-丁基-3-((7-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-二氫異苯并呋喃-4-基)甲基)-1,3-二氮螺[4.4]壬-1-烯-4-酮
[化24]
於氬氣環境下,於3-((7-溴-1,3-二氫異苯并呋喃-4-基)甲基)-2-丁基-1,3-二氮螺[4.4]壬-1-烯-4-酮(500 mg、1.23 mmol)、雙(頻那醇酯)二硼(471 mg、1.85 mmol)、乙酸鉀(245 mg、2.47 mmol)、及1,4-二㗁烷(10 mL)之混合物中添加二氯化[1,1'-雙(二苯基膦)二茂鐵]鈀(II)二氯甲烷加成物(50.3 mg、0.0617 mmol),對反應混合物於100℃下攪拌16小時。使反應混合物為室溫,添加水,藉由乙酸乙酯進行萃取。藉由飽和鹽水對有機層進行洗淨,藉由硫酸鈉使其乾燥,於減壓下進行溶劑之蒸餾去除。利用矽膠管柱層析法(己烷/乙酸乙酯)對殘渣進行純化,從而獲得標題化合物(0.35 g)。
ESI-MS: m/z 453.26 [M+1]+.
[製造例1-8]
2-溴-N-(4,5-二甲基異㗁唑-3-基)苯磺醯胺
[化25]
於4,5-二甲基異㗁唑-3-胺(500 mg、4.46 mmol)、及吡啶(10.0 mL)之混合物中,於0℃下緩慢添加4-二甲胺基吡啶(54.5 mg、0.446 mmol)、及2-溴苯磺醯氯(1.71 g、6.69 mmol),對反應混合物於50℃下攪拌16小時。使反應混合物為室溫,添加冰水,藉由乙酸乙酯進行萃取。藉由2 mol/L鹽酸、及飽和鹽水對有機層進行洗淨,藉由硫酸鈉使其乾燥。於減壓下進行溶劑之蒸餾去除,以粗產物獲得標題化合物(1.20 g)。所獲得之粗產物不再進行純化,用於其後之反應。
ESI-MS: m/z 330.91 [M+1]+, 332.93 [M+3]+
[製造例1-9]
2-溴-N-(4,5-二甲基異㗁唑-3-基)-N-(甲氧基甲基)苯磺醯胺
[化26]
於2-溴-N-(4,5-二甲基異㗁唑-3-基)苯磺醯胺之粗產物(1.20 g、3.62 mmol)、及DMF(20.0 mL)之混合物中,於0℃下緩慢添加50%氫化鈉(217 mg、4.53 mmol),於相同溫度下攪拌30分鐘。於反應混合物中緩慢添加氯甲基甲基醚(583 mg、7.25 mmol),於室溫下攪拌3小時。於反應混合物中添加冰水,藉由乙酸乙酯進行萃取。藉由飽和鹽水對有機層進行洗淨,藉由硫酸鈉使其乾燥,於減壓下進行溶劑之蒸餾去除。利用矽膠管柱層析法(己烷/乙酸乙酯)對殘渣進行純化,從而獲得標題化合物(0.90 g)。
1H NMR (400 MHz, CDCl
3) δ 8.02-8.00 (m, 1H), 7.76-7.74 (m, 1H), 7.40-7.38 (m, 2H), 5.24 (s, 2H), 3.54 (s, 3H), 2.30 (s, 3H), 1.99 (s, 3H).
[製造例1-10]
2-(7-((2-丁基-4-側氧基-1,3-二氮螺[4.4]壬-1-烯-3-基)甲基)-1,3-二氫異苯并呋喃-4-基)-N-(4,5-二甲基異㗁唑-3-基)-N-(甲氧基甲基)苯磺醯胺
[化27]
於氬氣環境下,於2-溴-N-(4,5-二甲基異㗁唑-3-基)-N-(甲氧基甲基)苯磺醯胺(347 mg、0.92 mmol)、2-丁基-3-((7-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-二氫異苯并呋喃-4-基)甲基)-1,3-二氮螺[4.4]壬-1-烯-4-酮(350 mg、0.77 mmol)、1,4-二㗁烷(5.0 mL)、水(0.5 mL)、及碳酸鉀(314 mg、1.54 mmol)之混合物中添加二氯化[1,1'-雙(二苯基膦)二茂鐵]鈀(II)二氯甲烷加成物(63 mg、0.07 mmol),對反應混合物於100℃下攪拌16小時。使反應混合物為室溫,添加水,藉由乙酸乙酯進行萃取。藉由飽和鹽水對有機層進行洗淨,藉由硫酸鈉使其乾燥,於減壓下進行溶劑之蒸餾去除。利用矽膠管柱層析法(己烷/乙酸乙酯)對殘渣進行純化,從而獲得標題化合物(0.25 g)。
ESI-MS: m/z 621.31 [M+1]+
[實施例1]
2-(7-((2-丁基-4-側氧基-1,3-二氮螺[4.4]壬-1-烯-3-基)甲基)-1,3-二氫異苯并呋喃-4-基)-N-(4,5-二甲基異㗁唑-3-基)苯磺醯胺
[化28]
於2-(7-((2-丁基-4-側氧基-1,3-二氮螺[4.4]壬-1-烯-3-基)甲基)-1,3-二氫異苯并呋喃-4-基)-N-(4,5-二甲基異㗁唑-3-基)-N-(甲氧基甲基)苯磺醯胺(250 mg、0.40 mmol)、及甲醇(3 mL)之混合物中,於0℃下添加6 mol/L鹽酸(1.5 mL),對反應混合物於50℃下攪拌16小時。使反應混合物為室溫,添加冰水,藉由乙酸乙酯進行萃取。藉由飽和鹽水對有機層進行洗淨,藉由硫酸鈉使其乾燥,於減壓下進行溶劑之蒸餾去除。利用矽膠管柱層析法(己烷/乙酸乙酯)對殘渣進行純化,從而獲得標題化合物(55 mg)。
ESI-MS: m/z 577.30 [M+1]+
1H NMR (400 MHz, DMSO-d
6) δ 10.51 (s, 1H),8.06 (dd, J = 7.6, 1.6 Hz, 1H), 7.67-7.60 (m, 2H), 7.26 (d, J = 7.2 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.89 (d, J = 7.6 Hz, 1H), 4.99-4.97 (m, 2H), 4.73-4.67 (m, 3H), 4.50-4.47 (m, 1H), 2.34(t, J = 7.6 Hz, 2H), 2.19 (s, 3H), 1.89-1.84 (m, 6H), 1.71-1.69 (m, 2H), 1.63 (s, 3H), 1.55-1.48 (m, 2H), 1.33-1.23 (m, 3H), 0.82 (t, J = 7.2 Hz, 3H).
[製造例1-11]
4-溴-7-(((四氫-2H-哌喃-2-基)氧基)甲基)-1,3-二氫異苯并呋喃
[化29]
於(7-溴-1,3-二氫異苯并呋喃-4-基)甲醇(3.0 g、13.1 mmol)、及二氯甲烷(30 mL)之混合物中,於0℃下緩慢添加3,4-氫-2H-哌喃(2.1 g、26.2 mmol)、及少量對甲苯磺酸,於室溫下攪拌3小時。於反應混合物中添加冰水,藉由乙酸乙酯進行萃取。藉由飽和鹽水對有機層進行洗淨,藉由硫酸鈉使其乾燥,於減壓下進行溶劑之蒸餾去除。利用矽膠管柱層析法(己烷/乙酸乙酯)對殘渣進行純化,從而獲得標題化合物(2.9 g)。
1H NMR (400 MHz, DMSO): δ 7.38 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 5.27 (d, J = 1.6 Hz, 2H), 5.11 (t, J = 4.0 Hz, 2H), 4.69 (t, J = 8.0 Hz, 2H), 4.42 (d, J = 12.4 Hz, 1H), 3.90–3.85 (m, 1H), 3.59-3.54 (m, 1H), 1.88-1.84 (m, 1H), 1.79-1.73 (m, 1H), 1.68-1.57 (m, 4H).
[製造例1-12]
4,4,5,5-四甲基-2-(7-(((四氫-2H-哌喃-2-基)氧基)甲基)-1,3-二氫異苯并呋喃-4-基)-1,3,2-二氧雜硼雜環戊烷
[化30]
於氬氣環境下,於4-溴-7-(((四氫-2H-哌喃-2-基)氧基)甲基)-1,3-二氫異苯并呋喃(1.0 g、3.19 mmol)、雙(頻那醇酯)二硼(969 mg、3.38 mmol)、乙酸鉀(937 mg、9.57 mmol)、及1,4-二㗁烷(10 mL)之混合物中添加二氯化[1,1'-雙(二苯基膦)二茂鐵]鈀(II)二氯甲烷加成物(130 mg、0.159 mmol),對反應混合物於100℃下攪拌16小時。使反應混合物為室溫,添加冰水,藉由乙酸乙酯進行萃取。藉由飽和鹽水對有機層進行洗淨,藉由硫酸鈉使其乾燥,於減壓下進行溶劑之蒸餾去除。利用矽膠管柱層析法(己烷/乙酸乙酯)對殘渣進行純化,從而獲得標題化合物(300 mg)。
1H NMR (400 MHz, DMSO): δ 7.38 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 5.07-5.02 (m, 4H), 4.64 (t, J = 8.0 Hz, 2H), 4.42 (d, J = 12.4 Hz, 1H), 3.77-3.72 (m, 1H), 3.49-3.45 (m, 1H), 1.67-1.64 (m, 2H), 1.52-1.56 (m, 4H), 1.28 (s, 12H).
[製造例1-13]
N-(4,5-二甲基異㗁唑-3-基)-N-(甲氧基甲基)-2-(7-(((四氫-2H-哌喃-2-基)氧基)甲基)-1,3-二氫異苯并呋喃-4-基)苯磺醯胺
[化31]
於氬氣環境下,於4,4,5,5-四甲基-2-(7-(((四氫-2H-哌喃-2-基)氧基)甲基)-1,3-二氫異苯并呋喃-4-基)-1,3,2-二氧雜硼雜環戊烷(600 mg、1.66 mmol)、2-溴-N-(4,5-二甲基異㗁唑-3-基)-N-(甲氧基甲基)苯磺醯胺(749 mg、1.99 mmol)、1,4-二㗁烷(7.0 mL)、水(0.5 mL)、及碳酸鉀(687 mg、4.98 mmol)之混合物中添加二氯化[1,1'-雙(二苯基膦)二茂鐵]鈀(II)二氯甲烷加成物(135 mg、0.166 mmol),對反應混合物於100℃下攪拌16小時。使反應混合物為室溫,添加冰水,藉由乙酸乙酯進行萃取。藉由飽和鹽水對有機層進行洗淨,藉由硫酸鈉使其乾燥,於減壓下進行溶劑之蒸餾去除。利用矽膠管柱層析法(己烷/乙酸乙酯)對殘渣進行純化,從而獲得標題化合物(400 mg)。
1H NMR (400 MHz, DMSO): δ 7.97 (d, J = 8.0 Hz, 1H), 7.70 (t, J = 14.8 Hz, 1H), 7.58 (t, J = 15.6 Hz, 1H), 7.37 (d, J = 7.2 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 5.15 (s, 2H), 4.84-4.78 (m, 2H), 4.75-4.67 (m, 2H), 4.51-4.47 (m, 1H), 4.31-4.23 (m, 2H), 3.80-3.76 (m, 1H), 3.50-3.47 (m, 1H), 3.19 (s, 3H), 2.31 (s, 3H), 1.81 (s, 3H), 1.68-1.65 (m, 2H), 1.51-1.48 (m, 4H).
[製造例1-14]
N-(4,5-二甲基異㗁唑-3-基)-2-(7-(羥甲基)-1,3-二氫異苯并呋喃-4-基)-N-(甲氧基甲基)苯磺醯胺
[化32]
於N-(4,5-二甲基異㗁唑-3-基)-N-(甲氧基甲基)-2-(7-(((四氫-2H-哌喃-2-基)氧基)甲基)-1,3-二氫異苯并呋喃-4-基)苯磺醯胺(500 mg、0.946 mmol)、及甲醇(8.0 mL)之混合物中,於0℃下添加對甲苯磺酸(35.2 mg、0.189 mmol),於室溫下攪拌3小時。於反應混合物中添加水,藉由二氯甲烷進行萃取。藉由飽和碳酸氫鈉溶液及飽和鹽水對有機層進行洗淨,藉由硫酸鈉使其乾燥,於減壓下進行溶劑之蒸餾去除。利用矽膠管柱層析法(己烷/乙酸乙酯)對殘渣進行純化,從而獲得標題化合物(300 mg)。
1H NMR (400 MHz, CDCl
3): δ 7.97 (d, J = 8.0 Hz, 1H), 7.70 (t, J = 14.8 Hz, 1H), 7.58 (t, J = 15.6 Hz, 1H), 7.37 (d, J = 7.2 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 5.28-5.25 (m, 1H), 5.13-5.06 (m, 2H), 4.82-4.72 (m, 2H), 4.53-4.51 (m, 2H), 4.33-4.23 (m, 2H), 3.19 (s, 3H), 2.31 (s, 3H), 1.81 (s, 3H).
[製造例1-15]
2-(7-(溴甲基)-1,3-二氫異苯并呋喃-4-基)-N-(4,5-二甲基異㗁唑-3-基)-N-(甲氧基甲基)苯磺醯胺
[化33]
於N-(4,5-二甲基異㗁唑-3-基)-2-(7-(羥甲基)-1,3-二氫異苯并呋喃-4-基)-N-(甲氧基甲基)苯磺醯胺(300 mg、0.675 mmol)、及二氯甲烷(7.0 mL)之溶液中,於0℃下添加四溴甲烷(290 mg、0.877 mmol),10分鐘後,於相同溫度下添加三苯基膦(176 mg、0.675 mmol)。使反應混合物升溫至室溫並攪拌2小時。於反應混合物中添加冰水,藉由二氯甲烷進行萃取。藉由飽和鹽水對有機層進行洗淨,藉由硫酸鈉使其乾燥,於減壓下進行溶劑之蒸餾去除。利用矽膠管柱層析法(己烷/乙酸乙酯)對殘渣進行純化,從而獲得標題化合物(250 mg)。
1H NMR (400 MHz, CDCl
3): δ 7.97 (d, J = 8.0 Hz, 1H), 7.70 (t, J = 14.8 Hz, 1H), 7.58 (t, J = 15.6 Hz, 1H), 7.41-7.39 (m, 2H), 7.16 (d, J = 7.6 Hz, 1H), 5.19-5.14 (m, 2H), 4.81-4.74 (m, 4H), 4.33-4.21 (m, 2H), 3.19 (s, 3H), 2.31 (s, 3H), 1.81 (s, 3H).
[製造例1-16]
2-(7-((2-丁基-4-側氧基-1,3-二氮螺[4.4]壬-1-烯-3-基)甲基)-1,3-二氫異苯并呋喃-4-基)-N-(4,5-二甲基異㗁唑-3-基)-N-(甲氧基甲基)苯磺醯胺
[化34]
於2-丁基-1,3-二氮螺[4.4]壬-1-烯-4-酮(108 mg、0.473 mmol)之DMF(2.0 mL)溶液中,於0℃下緩慢添加60%氫化鈉(31.5 mg、0.788 mmol),於室溫下攪拌30分鐘。於反應混合物中緩慢添加2-(7-(溴甲基)-1,3-二氫異苯并呋喃-4-基)-N-(4,5-二甲基異㗁唑-3-基)-N-(甲氧基甲基)苯磺醯胺(200 mg、0.394 mmol)、及DMF(1.0 mL)之混合物,於室溫下攪拌2小時。於反應混合物中添加冰水,藉由乙酸乙酯進行萃取。藉由飽和鹽水對有機層進行洗淨,藉由硫酸鈉使其乾燥,於減壓下進行溶劑之蒸餾去除。利用矽膠管柱層析法(己烷/乙酸乙酯)對殘渣進行純化,從而獲得標題化合物(80 mg)。
1H NMR (400 MHz, DMSO): 7.97 (d, J = 8.0 Hz, 1H), 7.70 (t, J = 14.8 Hz, 1H), 7.58 (t, J = 15.6 Hz, 1H), 7.37 (d, J = 7.2 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H), 5.02 (s, 2H), 4.80-4.69 (m, 4H), 4.30-4.21 (m, 2H), 3.18 (s, 3H), 2.30 (s, 4H), 1.85-1.80 (m, 9H), 1.70-1.68 (m, 2H), 1.53-1.49 (m, 2H), 1.31-1.23 (m, 3H), 0.84-0.81 (m, 3H).
[製造例2-1]
2-溴-N-(3-甲氧基-5-甲基吡𠯤-2-基)苯磺醯胺
[化35]
於3-甲氧基-5-甲基吡𠯤-2-胺(500 mg、3.5 mmol)、及吡啶(5.0 mL)之混合物中,於室溫下添加4-二甲胺基吡啶(128 mg、1.05 mmol)、及2-溴苯磺醯氯(1.1 g、4.3 mmol),對反應混合物於50℃下攪拌12小時。使反應混合物為室溫,添加2 mol/L鹽酸(5.0 mL),藉由乙酸乙酯進行萃取。藉由飽和鹽水對有機層進行洗淨,藉由硫酸鈉使其乾燥。於減壓下進行溶劑之蒸餾去除,以粗產物獲得標題化合物(1.20 g)。利用矽膠管柱層析法(己烷/乙酸乙酯)對所獲得之粗產物進行純化,從而獲得標題化合物(1.0 g)。
1H NMR (400 MHz, DMSO-d
6): δ 10.99 (s, 1H), 8.07 (d, J = 6.8 Hz, 1H), 7.80 (dd, J = 0.8 Hz, 1H), 7.59-7.51 (m, 3H), 3.86 (s, 3H), 2.26 (s, 3H).
[製造例2-2]
2-溴-N-(3-甲氧基-5-甲基吡𠯤-2-基)-N-((2-(三甲基矽烷基)乙氧基)甲基)苯磺醯胺
[化36]
於2-溴-N-(3-甲氧基-5-甲基吡𠯤-2-基)苯磺醯胺(500 mg、1.39 mmol)、及DMF(5.0 mL)之混合物中,於0℃下添加碳酸鉀(380 mg、2.79 mmol),於相同溫度下攪拌30分鐘。於反應混合物中於0℃下緩慢添加2-(三甲基矽烷基)乙氧基甲基氯(350 mg、2.08 mmol),於室溫下攪拌1小時。於反應混合物中添加冰水,藉由乙酸乙酯進行萃取。藉由飽和鹽水對有機層進行洗淨,藉由硫酸鈉使其乾燥,於減壓下進行溶劑之蒸餾去除。利用矽膠管柱層析法(己烷/乙酸乙酯)對殘渣進行純化,從而獲得標題化合物(500 mg)。
1H NMR (400 MHz, DMSO-d
6): δ 8.09-8.07 (m, 1H), 7.99 (s, 1H), 7.87-7.85 (m, 1H), 7.57-7.54 (m, 2H), 5.14 (s, 2H), 3.78 (s, 3H), 3.62-3.58 (m, 2H), 2.42 (s, 3H), 0.76-0.72 (m, 2H), 0.065 (s, 9H).
[製造例2-3]
2-(7-((2-丁基-4-側氧基-1,3-二氮螺[4.4]壬-1-烯-3-基)甲基)-1,3-二氫異苯并呋喃-4-基)-N-(3-甲氧基-5-甲基吡𠯤-2-基)-N-((2-(三甲基矽烷基)乙氧基)甲基)苯磺醯胺
[化37]
於氬氣環境下,於2-溴-N-(3-甲氧基-5-甲基吡𠯤-2-基)-N-((2-(三甲基矽烷基)乙氧基)甲基)苯磺醯胺(400 mg、0.78 mmol)、2-丁基-3-((7-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-二氫異苯并呋喃-4-基)甲基)-1,3-二氮螺[4.4]壬-1-烯-4-酮(445 mg、0.98 mmol)、1,4-二㗁烷(4.5 mL)、水(0.5 mL)、及碳酸鉀(340 mg、2.71 mmol)之混合物中添加二氯化[1,1'-雙(二苯基膦)二茂鐵]鈀(II)二氯甲烷加成物(67 mg、0.09 mmol),對反應混合物於100℃下攪拌12小時。使反應混合物為室溫,添加水,藉由乙酸乙酯進行萃取。藉由飽和鹽水對有機層進行洗淨,藉由硫酸鈉使其乾燥,於減壓下進行溶劑之蒸餾去除。利用矽膠管柱層析法(己烷/乙酸乙酯)對殘渣進行純化,從而獲得標題化合物(170 mg)。
1H NMR (400 MHz, DMSO-d
6): δ 8.15 (d, J = 7.6 Hz, 1H), 7.796 (s, 1H), 7.69-7.58 (m, 2H), 7.32 (d, J = 7.2 Hz, 1H), 7.11 (d, J = 8 Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H), 4.99 (s, 2H), 4.74-4.67 (m, 6H), 3.76 (s, 3H), 3.45 (t, J = 8 Hz, 2H), 2.42 (s, 3H), 2.28 (t, J = 7.2 Hz, 2H), 1.86-183 (m, 6H), 1.69 (s, 2H), 1.49-1.47 (m, 2H), 1.28-1.23 (m, 4H), 0.81 (m, 3H), 0.095 (s, 9H).
[實施例2]
2-(7-((2-丁基-4-側氧基-1,3-二氮螺[4.4]壬-1-烯-3-基)甲基)-1,3-二氫異苯并呋喃-4-基)-N-(3-甲氧基-5-甲基吡𠯤-2-基)苯磺醯胺
[化38]
於2-(7-((2-丁基-4-側氧基-1,3-二氮螺[4.4]壬-1-烯-3-基)甲基)-1,3-二氫異苯并呋喃-4-基)-N-(3-甲氧基-5-甲基吡𠯤-2-基)-N-((2-(三甲基矽烷基)乙氧基)甲基)苯磺醯胺(170 mg、0.231 mmol)、及甲醇(2 mL)之混合物中,於0℃下添加50%硫酸(2.0 mL),對反應混合物於0℃下攪拌10分鐘。於使反應混合物於減壓下濃縮而獲得之殘渣中添加冰水、飽和碳酸氫鈉溶液,使pH值呈中性後,藉由乙酸乙酯進行萃取。藉由飽和鹽水對有機層進行洗淨,藉由硫酸鈉使其乾燥,於減壓下進行溶劑之蒸餾去除。利用矽膠管柱層析法(己烷/乙酸乙酯)對殘渣進行純化,從而獲得標題化合物(38 mg)。
ESI-MS: m/z 604.67 [M+1]+
1H NMR (400 MHz, DMSO-d
6): δ 11.67 (s, 1H), 10.04 (s, 1H), 8.06 (d, J = 6.8 Hz, 1H), 7.60-7.52 (m, 3H), 7.26-6.90 (m, 2H), 6.78-6.78 (m, 1H), 4.96 (s, 1H), 4.77-4.68 (m, 2H), 4.58-4.44 (m, 2H), 3.82-3.79 (m, 3H), 2.32-2.26 (m, 5H), 1.86 (s, 6H), 1.69 (s, 2H), 1.49-1.47 (m, 2H), 1.26-1.25 (m, 2H), 0.79 (s, 3H).
[製造例3-1]
2-溴-N-(4-氯-5-甲基異㗁唑-3-基)苯磺醯胺
[化39]
於4-氯-5-甲基異㗁唑-3-胺(1.0 g、7.6 mmol)、及吡啶(5.0 mL)之混合物中,於室溫下添加4-二甲胺基吡啶(91 mg、0.75 mmol)、及2-溴苯磺醯氯(2.3 g、9.1 mmol),對反應混合物於80℃下攪拌6小時。使反應混合物為室溫,添加冰水,藉由乙酸乙酯進行萃取。藉由飽和鹽水對有機層進行洗淨,藉由硫酸鈉使其乾燥,於減壓下進行溶劑之蒸餾去除。利用矽膠管柱層析法(己烷/乙酸乙酯),對所獲得之粗產物進行純化,從而獲得標題化合物(850 mg)。
1H NMR (400 MHz, DMSO-d
6): δ 11.68 (s, 1H), 8.00 (dd, J = 2 Hz, 1H), 7.92 (dd, J = 1.6 Hz, 1H), 7.63-7.59 (m, 2H), 3.34 (s, 3H).
[製造例3-2]
2-溴-N-(4-氯-5-甲基異㗁唑-3-基)-N-(甲氧基甲基)苯磺醯胺
[化40]
於2-溴-N-(4-氯-5-甲基異㗁唑-3-基)苯磺醯胺(850 mg、2.42 mmol)、及DMF(5.0 mL)之混合物中,於0℃下緩慢添加60%氫化鈉(194 mg、4.87 mmol),於相同溫度下攪拌30分鐘。於反應混合物中緩慢添加氯甲基甲基醚(292 mg、3.63 mmol),於室溫下攪拌1小時。於反應混合物中添加冰水,藉由乙酸乙酯進行萃取。藉由飽和鹽水對有機層進行洗淨,藉由硫酸鈉使其乾燥,於減壓下進行溶劑之蒸餾去除。利用矽膠管柱層析法(己烷/乙酸乙酯)對殘渣進行純化,從而獲得標題化合物(800 mg)。
1H NMR (400 MHz, DMSO-d
6): δ 8.01 (dd, J = 2 Hz, 1H), 7.92 (dd, J = 1.6 Hz, 1H), 7.63-7.59 (m, 2H), 5.19 (s, 2H), 3.38 (s, 3H), 2.42 (s, 3H).
[製造例3-3]
2-(7-((2-丁基-4-側氧基-1,3-二氮螺[4.4]壬-1-烯-3-基)甲基)-1,3-二氫異苯并呋喃-4-基)-N-(4-氯-5-甲基異㗁唑-3-基)-N-(甲氧基甲基)苯磺醯胺
[化41]
於氬氣環境下,於2-溴-N-(4-氯-5-甲基異㗁唑-3-基)-N-(甲氧基甲基)苯磺醯胺(400 mg、1.01 mmol)、2-丁基-3-((7-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3-二氫異苯并呋喃-4-基)甲基)-1,3-二氮螺[4.4]壬-1-烯-4-酮(549 mg、1.21 mmol)、1,4-二㗁烷(4.5 mL)、水(0.5 mL)、及碳酸鉀(419 mg、3.03 mmol)之混合物中添加二氯化[1,1'-雙(二苯基膦)二茂鐵]鈀(II)二氯甲烷加成物(82.5 mg、0.10 mmol),對反應混合物於100℃下攪拌12小時。使反應混合物為室溫,添加水,藉由乙酸乙酯進行萃取。藉由飽和鹽水對有機層進行洗淨,藉由硫酸鈉使其乾燥,於減壓下進行溶劑之蒸餾去除。利用矽膠管柱層析法(己烷/乙酸乙酯)對殘渣進行純化,從而獲得標題化合物(150 mg)。
1H NMR (400 MHz, DMSO-d
6): δ 8.00 (d, J = 8 Hz, 1H), 7.74 (t, J = 7.6 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.98 (d, J = 8 Hz, 1H), 5.02 (s, 2H), 4.76-4.70 (m, 4H), 4.45-4.34 (m, 2H), 3.22 (s, 3H), 2.41 (s, 3H), 2.32-2.28 (m, 2H), 1.85-1.83 (m, 6H), 1.70-1.68 (m, 2H), 1.53-1.49 (m, 2H), 1.31-1.23 (m, 2H), 0.83 (t, J = 7.6 Hz, 3H).
[實施例3]
2-(7-((2-丁基-4-側氧基-1,3-二氮螺[4.4]壬-1-烯-3-基)甲基)-1,3-二氫異苯并呋喃-4-基)-N-(4-氯-5-甲基異㗁唑-3-基)苯磺醯胺
[化42]
於2-(7-((2-丁基-4-側氧基-1,3-二氮螺[4.4]壬-1-烯-3-基)甲基)-1,3-二氫異苯并呋喃-4-基)-N-(4-氯-5-甲基異㗁唑-3-基)-N-(甲氧基甲基)苯磺醯胺(150 mg、0.23 mmol)、及甲醇(2 mL)之混合物中,於0℃下緩慢添加50%硫酸(2.0 mL),對反應混合物於50℃下攪拌2小時。於使反應混合物於減壓下濃縮而獲得之殘渣中添加冰水、飽和碳酸氫鈉溶液,使pH值呈中性後,藉由乙酸乙酯進行萃取。藉由飽和鹽水對有機層進行洗淨,藉由硫酸鈉使其乾燥,於減壓下進行溶劑之蒸餾去除。利用矽膠管柱層析法(己烷/乙酸乙酯)對殘渣進行純化,從而獲得標題化合物(48 mg)。
ESI-MS: m/z 597.67 [M+1]+
1H NMR (400 MHz, DMSO-d
6): δ 11.17 (s, 1H), 7.97 (t, J = 3.6 Hz, 1H), 7.39(bs, 2H), 7.09 (d, J = 7.6 Hz, 1H), 7.03 (s, 1H), 6.81 (d, J = 8 Hz, 1H), 4.91 (s, 2H), 4.63 (s, 2H), 4.52 (s, 2H), 2.36-2.32 (m, 2H), 2.12 (s, 3H), 1.88-1.83 (m, 6H), 1.70-1.68 (m, 2H), 1.55-1.48 (m, 2H), 1.33-1.23 (m, 2H), 0.83 (t, J = 7.6 Hz, 3H).
[試驗例1:血管收縮素II第一型受體抑制作用]
利用以下方法,對血管收縮素II第一型受體之抑制作用進行研究。
於未添加抗生素之培養基中,對強制表現人類血管收縮素II第一型受體(寄存編號NP_000676.1)之CHO-K1-mt水母發光蛋白(aequorin)-Gα16細胞培養18小時後,藉由PBS-EDTA(5 mM EDTA)進行處理,進行離心分離後(2分鐘、405×g、室溫),懸浮於分析緩衝液(含HEPES+0.1% BSA且不含蛋白酶之DMEM/HAM's F12)中。
使1×10
6個/mL之細胞於最終濃度5 μM之腔腸素h(Molecular Probes)之存在下,於室溫下保溫4小時以上,確認基於血管收縮素II之促效劑反應,求出相當於EC80之血管收縮素II濃度。
繼而,於96孔盤中添加10000個/孔之經腔腸素h處置之細胞懸浮液50 μL、及包含受驗樣品(最終濃度0.5%之DMSO(Dimethyl sulfoxide,二甲基亞碸))之分析緩衝液50 μL,15分鐘後,以最終濃度為EC80濃度之方式添加血管收縮素II溶液100 μL,藉由FDSS6000(濱松光子學),根據發光量測定受體活性。IC50值係使用XLfit(IDBS)算出。
將IC50值為1.0 nM以下、或在1.0 nM下表現出50%以上之抑制作用之情形記為「A」,將IC50值大於100 nM、或在100 nM下表現出小於50%之抑制作用之情形記為「C」,將介於「A」與「C」之間記為「B」。將結果示於表1中。
[表1]
表1:AT1受體抑制作用 | |
實施例1 | A |
實施例2 | B |
實施例3 | B |
[試驗例2:內皮素A受體抑制作用]
利用以下方法,對內皮素A受體之抑制作用進行研究。
於未添加抗生素之培養基中,對強制表現人類內皮素A受體(寄存編號NP_001948.1)之CHO-K1-mt水母發光蛋白細胞培養18小時後,藉由PBS-EDTA(5 mM EDTA)進行處理,進行離心分離後(2分鐘、405×g、室溫),懸浮於分析緩衝液(含HEPES+0.1% BSA且不含蛋白酶之DMEM/HAM's F12)中。
對1×10
6個/mL細胞,於最終濃度5 μM之腔腸素h(Molecular Probes)之存在下,於室溫下保溫4小時,確認基於內皮素之促效劑反應,求出相當於EC80之內皮素濃度。
繼而,於96孔盤中添加10000個/孔之經腔腸素h處置之細胞懸浮液50 μL、及包含受驗樣品(最終濃度0.5%之DMSO)之分析緩衝液50 μL,15分鐘後,以最終濃度為EC80濃度之方式添加內皮素,藉由FDSS6000(濱松光子學),根據發光量測定受體活性。IC50值係使用XLfit(IDBS)算出。
將IC50值為1.0 nM以下、或於1.0 nM下表現出50%以上之抑制作用之情形記為「A」,將IC50值大於100 nM、或於100 nM下表現出小於50%之抑制作用之情形記為「C」,將介於「A」與「C」之間記為「B」。將結果示於表2中。
[表2]
表2:ETA受體抑制作用 | |
實施例1 | C |
實施例2 | B |
實施例3 | B |
[試驗例3:對血管收縮素II誘發升壓作用之抑制作用]
對8~12週齡之雄性Wistar大鼠,於鎮痛劑處置與胺甲酸乙酯麻醉下,對氣管進行用於確保氣道之導管處置、對頸動脈進行用於測定血壓之導管處置、對大腿靜脈進行用於投予血管收縮素II(ATII)之導管處置。在確認到血壓及心率穩定後,花費10分鐘向靜脈內投予溶劑(PBS)或經溶劑調整之受驗樣品(實施例1之化合物)1 mg/kg(15 mL/kg)。繼而,向靜脈內投予ATII(300 ng/kg),直至投予10分鐘後,對血壓進行監測。各群以n=3來實施,解析係將ATII投予2分鐘前作為預置值,求出預置值及血壓為最大之ATII剛投予後20秒鐘之收縮期血壓、舒張期血壓,算出與預置值之差量(Δ值)。溶劑投予群與受驗樣品投予群之Δ值之比較係使用學生t檢驗。
[表3]
表3:對血管收縮素II誘發升壓作用之抑制作用 | ||
溶劑 | 實施例1 | |
收縮期血壓 | 73±13 | 8±3* |
舒張期血壓 | 56±7 | 9±5* |
Claims (11)
- 一種化合物或其醫藥上可容許之鹽,上述化合物係由下述式(1)所表示: [化1] [式中, Ar為下述式(Ar1)、或(Ar2): [化2] (式中, R 1及R 2分別獨立地為烷基、鹵代烷基或鹵素, R 3分別獨立地為烷基、鹵代烷基、鹵素、烷氧基、或鹵代烷氧基, m為0~3之整數)]。
- 如請求項1之化合物或其醫藥上可容許之鹽,其中Ar為式(Ar1)。
- 如請求項1或2之化合物或其醫藥上可容許之鹽,其中R 1及R 2分別獨立地為烷基。
- 如請求項1之化合物或其醫藥上可容許之鹽,其中上述化合物係選自由下述化合物所組成之群: [化3] 。
- 一種血管收縮素II第一型受體拮抗劑,其包含如請求項1至4中任一項之化合物或其醫藥上可容許之鹽。
- 一種醫藥組合物,其包含如請求項1至4中任一項之化合物或其醫藥上可容許之鹽。
- 如請求項6之醫藥組合物,其係用於預防或治療高血壓症、心臟疾病、心肌梗塞後發展成心衰竭、腎臟疾病、介入後之血管增厚、介入後之阻塞、介入後之器官損傷、青光眼、高眼壓症、阿茲海默症、中樞神經損傷、癡呆、肝臟疾病、嗜酸細胞性食管炎、變形性膝關節炎、表皮分解性水皰症、馬凡氏症候群、或癌症。
- 如請求項6或7之醫藥組合物,其係注射劑、貼附劑、或滴眼劑。
- 一種化合物或其鹽,上述化合物係由下述式(2)所表示: [化4] [式中, R 4為脫離基、硼酸、硼酸酯、或-BF 3M 1, M 1為鹼金屬]。
- 一種化合物或其鹽,上述化合物係由下述式(3)所表示: [化5] [式中, Ar為下述式(Ar1)、或(Ar2): [化6] (式中, R 1及R 2分別獨立地為烷基、鹵代烷基或鹵素, R 3分別獨立地為烷基、鹵代烷基、鹵素、烷氧基、或鹵代烷氧基, m為0~3之整數), R 5為脫離基、或-OR 5A, R 5A為氫、或保護基, R 6為氫、或保護基]。
- 一種化合物或其鹽,上述化合物係由下述式(4)所表示: [化7] [式中, R 7為硼酸、硼酸酯、或-BF 3M 2, M 2為鹼金屬, R 8為-OR 8A, R 8A為氫、或保護基]。
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AR (1) | AR128112A1 (zh) |
AU (1) | AU2022428746A1 (zh) |
CA (1) | CA3231724A1 (zh) |
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JP2005080384A (ja) | 2003-08-29 | 2005-03-24 | Calsonic Kansei Corp | 電動ファン制御装置 |
US7157584B2 (en) | 2004-02-25 | 2007-01-02 | Takeda Pharmaceutical Company Limited | Benzimidazole derivative and use thereof |
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WO2023127853A1 (ja) | 2023-07-06 |
AU2022428746A2 (en) | 2024-04-04 |
CN118284605A (zh) | 2024-07-02 |
MX2024007184A (es) | 2024-06-26 |
IL312723A (en) | 2024-07-01 |
CA3231724A1 (en) | 2023-07-06 |
KR20240130685A (ko) | 2024-08-29 |
AR128112A1 (es) | 2024-03-27 |
AU2022428746A1 (en) | 2024-04-04 |
JPWO2023127853A1 (zh) | 2023-07-06 |
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