TWI674257B - 作為trpm8拮抗劑之氮雜螺衍生物 - Google Patents
作為trpm8拮抗劑之氮雜螺衍生物 Download PDFInfo
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- TWI674257B TWI674257B TW104108412A TW104108412A TWI674257B TW I674257 B TWI674257 B TW I674257B TW 104108412 A TW104108412 A TW 104108412A TW 104108412 A TW104108412 A TW 104108412A TW I674257 B TWI674257 B TW I674257B
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- Prior art keywords
- decane
- difluoro
- diazaspiro
- dione
- phenyl
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- 238000000034 method Methods 0.000 claims abstract description 132
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- 208000004296 neuralgia Diseases 0.000 claims description 32
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- 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
- A61K31/4164—1,3-Diazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- 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
- A61K31/4164—1,3-Diazoles
- A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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Abstract
本發明係關於化學式(I)的氮雜螺衍生物或其藥學上可接受的鹽或其前驅藥物、製備該等之方法、含有該等之藥學組合物、以及該等在治療由TRPM8受體介導之各種病症中之用途。
Description
本發明係有關一種作為TRPM8受體的調節劑發揮作用之氮雜螺衍生物。本發明還涉及一種製備新型氮雜螺衍生物之方法、以及該等在治療廣範圍的疾病、症候群及障礙中之用途,尤其在治療炎症、疼痛及泌尿系統疾病或障礙中之用途。
瞬時受體電位(TRP)通道為離子通道中之最大群體之一,該等被劃分為6個亞家族(TRPV、TRPM、TRPA、TRPC、TRPP及TRPML)。TRP通道係被各種物理性刺激(例如,溫度刺激、滲透壓摩爾濃度刺激、機械性刺激)和化學性刺激啟動之陽離子-選擇性通道。TRPM8係TRP通道家族的成員。受體於2002年(非專利文獻1和非專利文獻2)被成功克隆,實驗結果發現對低溫和薄荷醇敏感這一事實,藉此被命名為冷薄荷醇受體-1(CMR-1)。與使用薄荷醇和伊西林等化學藥劑之情況相同,TRPM8能夠在無毒害低溫(15-28℃)和有毒害低溫(<15℃)這兩個範圍內感測溫度變化。
TRPM8位於包含A-delta及C-纖維之初級傷感感受神經元上,並且藉由炎症-介導性第二信使訊號來進行調節(非專利文獻3和非專利文獻4)。A-delta和C-纖維上的TRPM8的定位可以是在神經元變性而誘導疼痛,時常伴隨灼熱感的疼痛之病理學病症中對異常低溫敏感性奠定基礎(非專利文獻5、非專利文獻6、非專利文獻7、非專利文獻8
及非專利文獻9)。Gauchan等人報導了在初級傳入纖維中,TRPM8的表達在小鼠的奧沙利鉑-誘導之異常性冷疼痛模型有所增加(非專利文獻10)。作為第三代鉑類化療藥物之奧沙利鉑對患者誘導嚴重的感覺器官神經中毒性,其因低溫暴露而惡化。最近,Glenmark集團報導了小分子TRPM8拮抗劑在小鼠的奧沙利鉑-誘導之異常性冷疼痛中對防傷害性添足顯出劑量依賴性抑制(非專利文獻11)。
由化學冷卻或熱性冷卻而誘導之畏寒及逆行性燒灼感與在其廣範圍的臨床疾病中顯出的障礙密切對應,因此,對開發TRPM8調節劑作為新型抗痛覺過敏劑或抗異常性疼痛劑提供較強的理論根據。周知TRPM8還在腦、成牙質細胞、肺、膀胱、胃腸道、血管、前列腺及免疫細胞中表達,藉此提供其在廣範圍的疾病中對治療調節的可能性。
國際專利申請WO 2006/040136(專利文獻1)中,對用於治療泌尿系統障礙之冷薄荷醇受體-1(CMR-1)拮抗劑亦即取代之4-苄氧基-苯基甲基醯胺衍生物進行了說明。國際專利申請WO 2006/040103(專利文獻2)中,對用於治療和/或預防呼吸系統疾病或障礙之方法和藥學組合物進行了說明。最近,Amgen Inc,的國際專利申請WO 2014/025651(專利文獻3)中,對用於治療偏頭痛和神經病變性疼痛之TRPM8抑制劑亦即色滿化合物和衍生物進行了說明。
與習知技術相比,具有TRPM8受體拮抗活性之本發明化合物在結構上完全不同。
WO 2010/037081(專利文獻4)和US005739336A(專利文獻5)公開了螺呱啶衍生物。但是,兩個文獻中公開之化合物的化學結構與本發明的化合物不同。另外,兩個專利中公開之化合物分別有關於黑皮質素受體抑制劑和選擇性5HT2c受體拮抗劑,與TRPM8受體拮抗劑完全不同。
WO 2012/174342(專利文獻6)和WO 2011/148962(專利文獻7)公開了螺[環己烷-噁唑烷酮]衍生物。但是,兩個專利中公開之化合物的化學結構與本發明的化合物不同。另外,兩個專利中公開之化合物分別有關於TRPV4拮抗劑和抗菌劑,與TRPM8受體拮抗劑完全不同。WO 2005/044978(專利文獻8)的發明公開了與活性化αIIbβ3受體拮抗劑有關之螺衍生物,係在化學結構和生物活性的形態方面與本發明不同之物質。
因此,習知技術中尚未公開具有TRPM8受體拮抗活性之本發明的氮雜螺衍生物。
(先前技術文獻)
(專利文獻)
專利文獻1:WO 2006/040136
專利文獻2:WO 2006/040103
專利文獻3:WO 2014/025651
專利文獻4:WO 2010/037081
專利文獻5:US005739336A
專利文獻6:WO 2012/174342
專利文獻7:WO 2011/148962
專利文獻8:WO 2005/044978
(非專利文獻)
非專利文獻1:McKemy, D.D., et al., Nature 416, 52-58, 2002
非專利文獻2:Peier, A.D., Cell 108, 705-715, 2002
非專利文獻3:Abe, J., et al., Neurosci Lett, 397 (1-2), 140-144, 2006
非專利文獻4:Premkumar, L.S., et al., J. Neurosci, 25 (49), 11322-11329, 2005
非專利文獻5:Kobayashi, K., et al., J Comp Neurol, 493 (4), 596-606, 2005
非專利文獻6:Roza, C, et al., Pain, 120 (1-2), 24-35, 2006
非專利文獻7:Xing, H., et al., J Neurophysiol, 95 (2), 1221-30, 2006
非專利文獻8:European Journal of Pharmacology, Volume 716, Issues 1-3, 61-76, 2013
非專利文獻9:PAIN, Volume 152, Issue 10, 2211-2223, 2011
非專利文獻10:Gauchan, P., et al., Neurosci Lett, 458, 93-95, 2009
非專利文獻11:Sachin, S. Chaudhari, et al., Bioorg. Med. Chem, 21, 6542-6553, 2013
本技術領域中,要求在疾病、症候群或病狀受TRPM8受體調節影響之哺乳動物中可使用於下述疾病、症候群或病狀之TRPM8拮抗劑,前述疾病、症候群或病狀為炎症、疼痛及泌尿系統疾病或障礙的一種以上,其包括:慢性疼痛;包括異常性冷疼痛和糖尿病性神經病變在內之神經病變性疼痛;術後疼痛;骨關節炎;類風濕關節炎疼痛;癌症疼痛;神經痛;神經病變;痛覺;牙本質過敏症;神經損傷;偏頭痛;叢發性及緊張性頭痛;缺血;大腸急躁症;雷諾症候群;神經退行性病變;纖維肌痛;中風;瘙癢;包括焦慮症和抑鬱症在內之精神疾病;包括哮喘、慢性阻塞性肺病在內之炎症性疾病;包括COPD、肺動脈高血壓在內之氣道疾病;包括其他應激相關病症在內之焦慮症;包括逼尿肌過度活動症或膀胱過度活動症、尿失禁、神經性逼尿肌過度活動症或逼尿肌反射亢進、特發性逼尿肌過度活動症
或逼尿肌不穩定、良性前列腺增生症及下尿路症狀在內之泌尿系統疾病或障礙;以及該等的組合。
TRPM8拮抗劑必須從胃腸道被良好地吸收,代謝穩定且具有適當的藥物動力學特性。該等必須為無毒性。並且。理想的備選藥物會以穩定、非吸收性、容易劑型化之物理形態存在。尤其,所期望的化合物必須強力結合至TRPM8受體並顯出作為拮抗劑之功能活性。本發明提供一種具有優異的TRPM8拮抗活性之新型化合物。
相對於本領域中公開之其他化合物,本發明的化合物可顯出更少的毒性、良好的吸收與分佈、良好的溶解度、更少的血漿蛋白結合、更少的藥物-藥物相互作用、良好的代謝穩定性、HERG通道中之減少之抑制活性和/或減少之QT延長。
本發明提供以下:
[1]下述化學式(I)的化合物或其藥學上可接受的鹽或其前驅藥物:
前述式中,A為芳基及雜芳基;B為芳基及雜芳基;L獨立地選自由化學鍵、氧、硫、-NR4-、-(CRCRD)t-、-O
(CRCRD)t-、-(CRCRD)tO-、-N(R4)(CRCRD)t-、-(CRCRD)tN(R4)-、-N(R4)(CRCRD)tO-及-O(CRCRD)tN(R4)-所構成之群組;X獨立地選自由-CH2-、氧、硫及NH所構成之群組;RA和RB獨立地選自由(1)氫、(2)鹵素、(3)(C1-C10)烷基、(4)(C3-C10)環烷基及(5)(C1-C10)鹵代烷基所構成之群組;或者,RA和RB可形成側氧基(=O);或者,RA和RB可形成可含有一個或多個獨立地選自氧、硫及氮中之雜原子之3-8員環;該環視情況經1至6個獨立地選自(1)氫、(2)鹵素、(3)羥基、(4)(C1-C10)烷基、(5)(C3-C10)環烷基、(6)(C1-C10)鹵代烷基、(7)(C1-C10)烷氧基及(8)(C1-C10)鹵代烷氧基中之取代基取代;RC和RD獨立地選自由(1)氫、(2)鹵素、(3)(C1-C10)烷基、(4)(C3-C10)環烷基及(5)(C1-C10)鹵代烷基所構成之群組;或者,RC和RD可形成可含有一個或多個獨立地選自氧、硫及氮中之雜原子之3-8員環;該環視情況經1至6個獨立地選自(1)氫、(2)鹵素、(3)羥基、(4)(C1-C10)烷基、(5)(C3-C10)環烷基、(6)(C1-C10)鹵代烷基、(7)(C1-C10)烷氧基及(8)(C1-C10)鹵代烷氧基中之取代基取代;R1獨立地選自由(1)氫、(2)鹵素、(3)胺基、(4)氰基、(5)羥基、(6)(C1-C10)烷基、(7)(C3-C10)環烷基、(8)(C1-C10)鹵代烷基、(9)(C1-C10)烷氧基及(10)(C1-C10)鹵代烷氧基所構成之群組;相同的碳或不同的碳上的兩個R1可形成可含有選自氧、硫及氮中之原子之3-8員環;該環視情況經1至6個獨立地選自(1)氫、(2)鹵素、(3)羥基、(4)(C1-C10)烷基、(5)(C3-C10)環烷基、(6)(C1-C10)鹵代烷基、(7)(C1-C10)烷氧基及(8)(C1-C10)鹵代烷氧基中之取代基取代;
R2獨立地選自由(1)氫、(2)鹵素、(3)胺基、(4)-NH(C1-C6)烷基、(5)烷基相同或不同的-N[(C1-C6)烷基]2、(6)氰基、(7)羥基、(8)硝基、(9)(C1-C6)烷硫基、(10)(C1-C10)烷基、(11)(C3-C10)環烷基、(12)(C1-C10)烷氧基、(13)(C1-C10)鹵代烷基及(14)(C1-C10)鹵代烷氧基所構成之群組;R3獨立地選自由(1)氫、(2)鹵素、(3)氰基、(4)硝基、(5)羥基、(6)(C1-C6)烷硫基、(7)(C1-C6)烷基亞磺醯基、(8)(C1-C6)烷基磺醯基、(9)-NR5R6、(10)-C(=O)NR5R6、(11)三(C1-C6)烷基矽烷基、(12)(C1-C10)烷基、(13)(C3-C10)環烷基、(14)(C1-C6)烷氧基(C0-C6)烷基、(15)(C3-C10)環烷氧基、(16)-C(=O)(C1-C6)烷基、(17)-C(=O)O(C1-C6)烷基及(18)-C(=O)OH所構成之群組;該(C1-C10)烷基、(C3-C10)環烷基、(C1-C6)烷氧基(C0-C6)烷基及(C3-C10)環烷氧基視情況經1至6個獨立地選自(1)氫、(2)鹵素、(3)羥基、(4)氰基、(5)(C3-C10)環烷基、(6)(C1-C10)鹵代烷基、(7)(C1-C10)烷氧基、(8)(C1-C10)鹵代烷氧基及(9)-NR6R5中之取代基取代;其中,R5和R6可與該等所鍵合之氮原子一同形成可含有選自氧、硫及氮中之原子之3-10員環;該環視情況經1至6個獨立地選自(1)氫、(2)鹵素、(3)羥基、(4)(C1-C10)烷基、(5)(C3-C10)環烷基、(6)(C1-C10)鹵代烷基、(7)(C1-C10)烷氧基及(8)(C1-C10)鹵代烷氧基中之取代基取代;R4、R5及R6獨立地選自由(1)氫、(2)(C1-C10)烷基、(3)(C3-C10)環烷基、(4)(C1-C10)鹵代烷基、(5)羥基(C1-C10)烷基、(6)(C1-C10)烷氧基(C1-C10)烷基、(7)H2N-(C1-C10)烷基、(8)[(C1-C10)烷基]NH-(C1-C10)烷基、(9)[(C1-C10)烷
基]2N-(C1-C10)烷基、(10)(C1-C10)烷基羰基及(11)(C1-C10)烷基磺醯基所構成之群組;p為1、2、3或4;q為1、2、3或4;當q為2或2以上時,R1相同或不同,r為1、2、3或4;當r為2或2以上時,R2相同或不同,s為1、2、3、4、5、6或7;當s為2或2以上時,R3相同或不同,t為1、2或3;當t為2或2以上時,RC和RD相同或不同。
[2]如[1]所述之化合物或其藥學上可接受的鹽或其前驅藥物,其中,A為6員芳基或5至6員雜芳基。
[3]如[1]或[2]所述之化合物或其藥學上可接受的鹽或其前驅藥物,其中,A獨立地選自由苯、吡啶、噠嗪、吡嗪、嘧啶、三嗪、噻吩、呋喃、吡咯、咪唑、吡唑、噻唑、異噻唑、噁唑、異噁唑及三唑所構成之群組。
[4]如[1]至[3]中任一項所述之化合物或其藥學上可接受的鹽或其前驅藥物,其中,該化合物選自以下:3-(2-(2,5-二甲基-1-(5-甲基異噁唑-3-基)-1H-吡咯-3-基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(2,5-二甲基-1-苯基-1H-咪唑-4-基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;6-(4-(2-(2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)苯基)-2-氰基吡啶;3-(2-(1-(3-氯苯基)-2,5-二甲基-1H-咪唑-4-基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(1-(3-氟苯基)-2,5-二甲基-1H-咪唑-4-基)-2-
側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(1,4-二甲基-5-苯基-1H-吡唑-3-基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(6-甲基吡嗪-2-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;6-(4-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)苯基)-2-氰基吡啶;8,8-二氟-3-(2-(2'-(羥基甲基)-[1,1'-聯苯基]-4-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(3-甲基吡嗪-2-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(2,5-二甲基-1-苯基-1H-咪唑-4-基)-2-側氧基乙基)-8,8-二氟-1-氧雜-3-氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(2-(羥基甲基)吡啶-3-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(4-(羥基甲基)吡啶-3-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(2,5-二甲基-1-(5-甲基異噁唑-3-基)-1H-吡咯-3-基)-2-側氧基乙基)-8,8-二氟-1-氧雜-3-氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(5-(2-(羥基甲基)苯基)-4-甲基噻吩-2-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(4-(3-(羥基甲基)吡嗪-2-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(1,4-二甲基-5-苯基-1H-吡唑-3-基)-2-側氧基乙基)-8,8-二氟-1-氧雜-3-氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(4-甲基噠嗪-3-基)苯基)-2-側氧基乙基)
-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(4-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)苯基)吡嗪-2-甲腈;3-(2-(1,4-二甲基-5-苯基-1H-吡咯-2-基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(3-(羥基甲基)吡嗪-2-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(6-(甲基(吡啶-2-基)胺基)吡啶-3-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(4-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)苯基)-2-氰基吡啶;8,8-二氟-3-(2-側氧基-2-(4-(喹啉-8-基)苯基)乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(4-(1H-吲哚-4-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-側氧基-2-(4-(喹啉-2-基)苯基)乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(異喹啉-8-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(異喹啉-1-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(呋喃并[3,2-c]吡啶-4-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(6-(甲基(吡啶-2-基)胺基)吡啶-3-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(6-(甲基(苯基)胺基)吡啶-3-基)-2-側氧基
乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(3-氟吡啶-2-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(4-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)苯基)異菸鹼甲腈;8,8-二氟-3-(2-(4-(2-甲氧基吡啶-3-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(4-甲氧基吡啶-3-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-側氧基-2-(4-(2-側氧基吲哚啉-4-基)苯基)乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(4-(1H-吡咯并[3,2-c]吡啶-4-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(4-(1H-吡咯并[2,3-b]吡啶-4-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(4-(3-氯吡啶-2-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(2-甲基-1H-苯并[d]咪唑-1-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(4-(1H-吲唑-4-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(6-(1H-吲唑-4-基)吡啶-3-基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(4-(1H-苯并[d]咪唑-1-基)苯基)-2-側氧基乙基)-8,8-
二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(5-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)-1,3-二甲基-1H-吡咯-2-基)苯甲腈;3-(2-(4-(1H-吡咯并[2,3-c]吡啶-4-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(3-氟-4-(喹啉-8-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(5-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)-1-甲基-1H-吡咯-2-基)苯甲腈;3-(5-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)-3-甲基噻吩-2-基)苯甲腈;8,8-二氟-3-(2-(4-(2-(2-羥基乙氧基)吡啶-3-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(5-(3-氟苯基)-1,4-二甲基-1H-吡咯-2-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(5-(3-氯苯基)-1,4-二甲基-1H-吡咯-2-基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(5-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)-1,3-二甲基-1H-吡咯-2-基)苯甲醯胺;8,8-二氟-3-(2-(5-(2-氟苯基)-1,4-二甲基-1H-吡咯-2-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(4-(1H-吡唑并[3,4-b]吡啶-4-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(4-(1H-吡唑并[4,3-c]吡啶-4-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(4-(1H-吲唑-1-基)苯基)-2-側氧基乙基)-8,8-二氟-
1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(5-(3-氟苯基)-1-甲基-1H-咪唑-2-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(2-甲基-3H-咪唑并[4,5-b]吡啶-3-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-側氧基-2-(4-(吡啶-2-基氧基)苯基)乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(5-(3,5-二氟苯基)-1,4-二甲基-1H-吡咯-2-基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(2'-甲基-[3,3'-聯吡啶]-6-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(4-(1H-吡唑并[3,4-d]嘧啶-4-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(6-(1H-吡咯并[2,3-c]吡啶-4-基)吡啶-3-基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(3-(2-羥基乙氧基)吡嗪-2-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-側氧基-2-(4-(酞嗪-1-基)苯基)乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(4-(3H-咪唑并[4,5-b]吡啶-3-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)-4-甲基噻唑-5-基)苯甲腈;3-(2-(1,4-二甲基-5-苯基-1H-咪唑-2-基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(5-(3-氟苯基)-1,4-二甲基-1H-咪唑-2-基)-2-
側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)-1,4-二甲基-1H-咪唑-5-基)苯甲腈;8,8-二氟-3-(2-(5-(異喹啉-8-基)-1,4-二甲基-1H-咪唑-2-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(5-(2-(羥基甲基)苯基)-1,4-二甲基-1H-咪唑-2-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(2-(羥基甲基)-1H-苯并[d]咪唑-1-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(5-(3-氟苯基)-1,4-二甲基-1H-吡咯-3-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(4-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)-1,3-二甲基-1H-吡咯-2-基)苯甲腈;3-(2-(5-(1H-苯并[d]咪唑-1-基)吡嗪-2-基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(4-(2,7-萘啶-1-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-側氧基-2-(4-(2-側氧基-2,3-二氫-1H-苯并[d]咪唑-1-基)苯基)乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(5-(2-(羥基甲基)苯基)吡嗪-2-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(5-(4-甲氧基吡啶-3-基)吡嗪-2-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(5-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)-2,4-二甲基噻吩-3-基)苯甲醯胺;3-(2-(5-(3,5-二氟苯基)-1,4-二甲基-1H-咪唑-2-基)-2-側氧
基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-側氧基-2-(4-(噠嗪-3-基氧基)苯基)乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-側氧基-2-(4-(2-側氧基-1H-咪唑并[4,5-b]吡啶-3(2H)-基)苯基)乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(5-(3,5-二氟苯基)-4-甲基噻唑-2-基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;4'-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)-2'-甲氧基-[1,1'-聯苯基]-2-甲腈;2-(4-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)苯氧基)菸鹼甲腈;3-(2-(4-((3-氯吡啶-2-基)氧基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(3-(羥基甲基)吡啶-2-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(2'-(胺基甲基)-[1,1'-聯苯基]-4-基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-側氧基-2-(6-(喹啉-8-基)吡啶-3-基)乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(5-(2-甲基吡啶-3-基)吡嗪-2-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(4-(2,7-萘啶-1-基)苯基)-2-側氧基乙基)-8,8-二氟-1-氧雜-3-氮雜螺[4.5]癸烷2,4-二酮;3-(4-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)苯基)-2-甲基-3H-咪唑并[4,5-b]吡啶-5-甲腈;8,8-二氟-3-(2-側氧基-2-(4-(2-側氧基苯并[d]噁唑-3(2H)-
基)苯基)乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(4-(2,5-二甲基-3H-咪唑并[4,5-b]吡啶-3-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(5-(2-甲基-1H-苯并[d]咪唑-1-基)吡嗪-2-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(2-甲氧基-5-甲基-3H-咪唑并[4,5-b]吡啶-3-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(5-甲基-2-(三氟甲基)-3H-咪唑并[4,5-b]吡啶-3-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(4-(2-(二氟甲基)-5-甲基-3H-咪唑并[4,5-b]吡啶-3-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(5-甲基-2-側氧基-1H-咪唑并[4,5-b]吡啶-3(2H)-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;6-(4-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)苯氧基)-2-氰基吡啶;8,8-二氟-3-(2-(4-(5-甲基-3H-咪唑并[4,5-b]吡啶-3-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(3-甲氧基吡嗪-2-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(4-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)-3-氟苯基)吡嗪-2-甲腈;8,8-二氟-3-(2-(4-(咪唑并[1,2-b]噠嗪-3-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;
8,8-二氟-3-(2-(2'-(2-羥基乙基)-[1,1'-聯苯基]-4-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;2-(4'-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)-[1,1'-聯苯基]-2-基)乙腈;3-(2-(4-(1H-咪唑并[4,5-b]吡嗪-1-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(4-甲基噠嗪-3-基)苯基)-2-側氧基乙基)-1-氧雜-3-氮雜螺[4.5]癸烷-2,4-二酮;3-(4-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)苯氧基)噠嗪-4-甲腈;8,8-二氟-3-(2-(4-(2-(羥基甲基)-5-甲基-3H-咪唑并[4,5-b]吡啶-3-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-側氧基-2-(4-(吡唑并[1,5-a]嘧啶-3-基)苯基)乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;4-(4-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)苯基)菸鹼甲腈;8,8-二氟-3-(2-(2-氟-4-(4-甲基噠嗪-3-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(2-氟-4-(3-(羥基甲基)吡嗪-2-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;及2-(4-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)苯基)菸鹼甲腈。
[5][1]至[4]中任一項所述之化合物或其藥學上可接受的鹽或其前驅藥物在製備用於治療由TRPM8受體拮抗活性介導之病症或障礙之藥物中之用途。
[6]如[5]所述之用途,其中,前述病症或障礙為炎症、疼痛及泌尿系統疾病或障礙的一種以上,其包括:慢性疼痛;包括異常性冷疼痛及糖尿病性神經病變在內之神經病變性疼痛;術後疼痛;骨關節炎;類風濕關節炎疼痛;癌症疼痛;神經痛;神經病變;痛覺過敏;牙本質過敏症;神經損傷;偏頭痛;叢發性及緊張性頭痛;缺血;大腸急躁症;雷諾症候群;神經退行性病變;纖維肌痛;中風;瘙癢;包括焦慮症和抑鬱症在內之精神疾病;包括哮喘、慢性阻塞性肺病在內之炎症性疾病;包括COPD、肺動脈高血壓在內之氣道疾病;包括其他應激相關病症在內之焦慮症;包括逼尿肌過度活動症或膀胱過度活動症、尿失禁、神經性逼尿肌過度活動症或逼尿肌反射亢進、特發性逼尿肌過度活動症或逼尿肌不穩定、良性前列腺增生症及下尿路症狀在內之泌尿系統疾病或障礙;以及該等的組合。
[7]一種用於治療包括人在內之哺乳類受治者中之由TRPM8受體拮抗活性介導之病症或障礙之方法,其包括將治療有效量的[1]至[4]中任一項所述之化合物或其藥學上可接受的鹽或其前驅藥物或其前驅藥物給藥於需要該種治療之哺乳動物。
[8]如[7]所述之方法,其中,前述病症或障礙為炎症、疼痛及泌尿系統疾病或障礙的一種以上,其包括:慢性疼痛;包括異常性冷疼痛和糖尿病性神經病變在內之神經病變性疼痛;術後疼痛;骨關節炎;類風濕關節炎疼痛;癌症疼痛;神經痛;神經病變;痛覺過敏;牙本質過敏症;神經損傷;偏頭痛;叢發性及緊張性頭痛;缺血;大腸急躁症;雷諾症候群;神經退行性病變;纖維肌痛;中風;瘙癢;包括焦慮症和抑鬱症在內之精神疾病;包括哮喘、慢性阻塞性肺病在內之炎症性疾病;包括COPD、肺動脈高血壓在內之氣道疾病;包括其他應激相關病症在內之焦慮症;包括逼尿肌過度活動症或膀胱過度活動症、尿失禁、神經性逼尿肌過度活動症或逼尿肌反射亢進、特發
性逼尿肌過度活動症或逼尿肌不穩定、良性前列腺增生症及下尿路症狀在內之泌尿系統疾病或障礙;以及該等的組合。
[9]一種藥學組合物,其包含[1]至[4]中任一項所述之化合物或其藥學上可接受的鹽或其前驅藥物、以及藥學上可接受的載劑。
[10]如[9]所述之藥學組合物,其中,該藥學組合物還包含其他藥理活性劑。
[11][1]至[4]中任一項所述之化合物或其藥學上可接受的鹽或其前驅藥物,其用於治療由TRPM8受體拮抗活性介導之病症或障礙。
[12]一種製備藥學組合物之方法,其包括將[1]至[4]中任一項所述之化合物或其藥學上可接受的鹽或其前驅藥物及藥學上可接受的載劑或賦形劑進行混合。
由TRPM8受體活性介導之病症或障礙的例子並不限定於TRPM8相關疾病。
本發明的化合物顯出TRPM8受體拮抗活性。本發明的化合物可顯出更少的毒性、良好的吸收與分佈、良好的溶解度、比其他TRPM8受體更少的蛋白結合亲和力、更少的藥物-藥物相互作用、以及良好的代謝穩定性。
本申請中所使用之術語“烷基”作為基團或基團的一部份,例如在烷氧基或羥基烷基中係指直鏈或側鏈烷基的所有異構體形態。術語“C1-C4烷基”如上述所定義,係指至少含有1個及最多含有4個碳原子之烷基。作為該種烷基的例子,包括甲基、乙基、丙基、異丙基、正丁基、異丁基、第二丁基或第三丁基。作為該種烷氧基的例子,包括甲氧基、乙氧基、丙氧基、異丙氧基、丁氧基、異丁氧基、第二丁氧基及第三丁氧基。
本申請中所使用之術語“環烷基”係指單環或雙環,包括環丙基、環丁基、環戊基、環己基、環庚基、降冰片基(norbornyl)及金剛烷基等,但並不限於此。
環丙基甲基和環戊基甲基如下:
術語“鹵素”係指氟(F)、氯(Cl)、溴(Br)或碘(I),術語“鹵代”係指鹵素:氟代(-F)、氯代(-Cl)、溴代(-Br)及碘代(-I)。
本申請中所使用之術語“鹵代烷基”係指被如上所定義之鹵原子取代之烷基,包括氟甲基、二氟甲基、三氟甲基、2-氟乙基、2,2-二氟乙基、2,2,2-三氟乙基、2,2,2-三氯乙基、3-氟丙基、4-氟丁基、氯甲基、三氯甲基、碘甲基及溴甲基等,但並不限於此。
本申請中所使用之術語“鹵代烷氧基”係指鹵代烷基-O-,包括氟甲氧基、二氟甲氧基、三氟甲氧基、2-氟乙氧基、2,2-二氟乙氧基、2,2,2-三氟乙氧基、2,2,2-三氯乙氧基、3-氟丙氧基、4-氟丁氧基、氯甲氧基、三氯甲氧基、碘甲氧基及溴甲氧基等,但並不限於此。
本申請中所使用之術語“烷氧基”係指O-烷基,其中,“烷基”如上所定義。
本申請中所使用之術語“雜環”係指包含一個或多個選自氮、氧及硫中之雜原子之飽和3-至16-員環。依據本發明的目的,雜環可以是單環、雙環或三環系,其可包括稠環系、橋環系或螺環系。該種雜環基的例子包括吖啶丁基、1,4-二氧雜環己基、吡咯烷基、呱啶基、哌嗪基、嗎啉基、四氫呋喃基、硫代嗎啉基、四氫噻吩基、2-側氧基
-吡咯烷基、2-側氧基-呱啶基、2-側氧基-咪唑烷基、2-側氧基-噁唑烷基、奎寧環基、氮雜雙環[3.2.1]辛基、2-氧雜-6-氮雜螺[3.4]辛基及該等的N-氧化物和該等的S-氧化物。
本申請中所使用之術語“芳基”係指含碳原子之不飽和及部份飽和的6-至15-員環。
該種不飽和芳基的例子包括苯基、萘基、茚滿基、茚基、1,2,3,4-四氫萘基及1,2-二氫萘基,但並不限於此。
本申請中所使用之術語“雜芳基”係指含雜原子芳香族環稠合於非芳香族環例如雜環(heterocyclyl ring)或環烷基環之5-至15-員環,6-至15-員環為較佳,或者,係指芳基環稠合於雜環等含雜原子非芳香族環之5-至15-員環,6-至15-員環為較佳。
亦即,本申請所使用之術語“雜芳基”係指以下;
1)由1至5個選自氮、磷、氧及硫中之雜原子和碳原子所構成之不飽和及部份飽和的5-至15-員環,6-至15-員環為較佳。
2)雜環或環烷基環等非芳香族環稠合於上述定義之雜芳基之不飽及部份飽和的5-至15-員環,6-至15-員環為較佳。
3)芳基環稠合於雜環之不飽及部份飽和的5-至15-員環,6-至15-員環為較佳。
該種雜芳基的例子包括苯硫基、噻唑基、異噁唑基、吡唑基、四唑基、呋喃基、吡咯基、咪唑基、噁唑基、異噻唑基、三唑基、噻二唑基、吡啶基、嘧啶基、噠嗪基、吡嗪基、三嗪基、苯并呋喃基、苯并苯硫基、苯并三唑基、吲哚基、吲唑基、苯并咪唑基、吡咯并吡啶基、吡咯并嘧啶基、吡唑并吡啶基、吡唑并嘧啶基、咪唑并吡啶基、呋喃并吡啶基、苯并異噁唑基、咪唑并吡嗪基、咪唑并噠嗪基、咪唑并嘧啶基、喹啉基、異喹啉基、喹唑啉基、酞嗪基、喹喔啉基、萘啶基、吡啶并嘧啶基及該等的N-氧化物和該等的S-氧化物,但並不
限於此。
該種雜芳基的例子還包括包含以下環之雜芳基環基。
本申請所使用之術語“C 0 ”係指直接鍵合。
化學上容許時,本發明的化合物的環上的取代基可以存在於原子上。
本申請所使用之術語“保護基”係指選自文獻Protective Groups in Organic Synthesis Forth Edition edited by T.W.Greene et al.(John Wiley & Sons,2006)所記載之典型羥基保護基或胺基保護基中之羥基保護基或胺基保護基。
本申請中所使用之術語“治療之”及“治療”係指逆轉、緩解、抑制適用上述術語之障礙或病症或前述種障礙或病症的一種以上病狀的進展,或者預防該等之治療、緩解及預防措施。
如果沒有特別提及,本申請中所使用之冠詞“a”或“an”係指其冠詞所提及之對象的單數形和複數形這兩者。
本說明書中,將符號文字記為相應的英語單詞。
例如,α、β及δ分別記為alpha、beta及delta。
“本發明的化合物”的範疇內包括化學式(I)的化合物的所有鹽、溶劑化物、水合物、錯合物、多形體、前驅藥物、放射性-標記
衍生物、立體異構體及光學異構體。
化學式(I)的化合物可形成其酸加成鹽。為了在藥物中使用,可領會化學式(I)的化合物的鹽需在藥學上可接受。合適的藥學上可接受的鹽對本領域技術人員來講是周知的,包括如文獻:J.Pharm.Sci,66,1-19,1977中所記載之由無機酸(例如鹽酸、氫溴酸、硫酸、硝酸或磷酸)及有機酸(例如琥珀酸、馬來酸、甲酸、乙酸、三氟乙酸、丙酸、富馬酸、檸檬酸、酒石酸、苯甲酸、對甲苯磺酸、甲基磺酸或萘磺酸)形成之酸加成鹽。特定的化學式(I)的化合物還可以與1當量以上的該酸形成酸加成鹽。本發明包括其範疇內所有可能的化學計量及非化學計量形態。並且,含有羧基之類的酸性官能基之特定化合物可分離為抗衡離子可選自鈉、鉀、鋰、鈣、鎂等及有機鹼之該等的無機鹼形態。
另外,化學式(I)的化合物的所謂“前驅藥物”亦包括在本發明的範疇內。因此,其本身可能幾乎或完全不具有藥理活性之化學式(I)的化合物的特定衍生物當給藥於體內或體表時,例如可藉由水解性斷裂而轉化為具有目標活性之化學式(I)的化合物。該種衍生物以“前驅藥物”提及。關於前驅藥物用途的追加資訊可在下述文獻中查看:Pro-drugs as Novel Delivery Systems,Vol.14,ACS Symposium Series(T Higuchi and W Stella)and Bioreversible Carriers in Drug Design,Pergamon Press,1987(ed.E B Roche,American Pharmaceutical Association)。
本發明的前驅藥物例如可藉由將化學式(I)的化合物中所存在之適當的官能基用本領域技術人員周知的特定部份,例如文獻:Design of Prodrugs by H.Bundgaard(Elsevier,1985)中所記載之“前-部份(pro-moieties)”置換而進行製造。本發明的前驅藥物的一部份例子包括以下:
(i)當化學式(I)的化合物中含有醇官能基(-OH)時,羥基由在體內可轉化為羥基之部份置換之化合物。其中,前述在體內可轉化為羥基之部份係指,例如藉由水解和/或酶例如酯酶在體內可變換為羥基之部份。前述部份的例子包括在體內可容易水解之酯及醚基,但並不限於此。由醯氧基烷基、1-(烷氧基胺甲醯基氧基)烷基、酞基及醯氧基烷氧基胺甲醯基(例如第三戊醯氧基甲氧基胺甲醯基)置換羥基的氫之部份為較佳。
(ii)當化學式(I)的化合物中含有胺基時,將藉由與合適的酸性鹵化物或合適的酸酐的反應而製備之胺衍生物作為前驅藥物來舉例說明。作為前驅藥物,尤為佳的胺衍生物為-NHCO(CH2)2OCH3、-NHCOCH(NH2)CH3等。
前述例子的置換基的追加例子及其他前驅藥物類型的例子可在前述引用文獻中查看。
化學式(I)的化合物、其鹽及其前驅藥物可製備為晶質或無定形形態,晶質時可任意被水化或溶劑化。本發明的範疇內還包括化學計量水合物或溶劑化物及含有可變數量的水和/或溶劑之化合物。
具有非藥學上可接受的抗衡離子或聯合溶劑的鹽及溶劑化物包括在本發明的範疇內,例如在製備化學式(I)的其他化合物及該等的藥學上可接受的鹽時用作中間體。
此外,化學式(I)的化合物可以以前驅藥物來給藥。本申請中所使用之術語,化學式(I)的化合物的“前驅藥物”係給藥於患者時終究在體內釋放化學式(I)的化合物之化合物功能性衍生物。以前驅藥物給藥化學式(I)的化合物時,本領域技術人員可實施下列中的一種以上:(a)變更化合物的體內起效時間;(b)變更化合物的體內作用持續時間;(c)變更化合物的體內輸送或分佈;(d)變更化合物的體內溶解度;及(e)克服化合物所面臨之副作用或其他難點。
使用於前驅藥物的製備之典型的功能性衍生物包括在體內以化學方式或酶的方式裂解之化合物的變體。前述變體包括磷酸鹽、醯胺、酯、硫代酯、碳酸鹽及胺基甲酸鹽的製備,這對本領域技術人員來講是周知的。
特定的化學式(I)的化合物中可存在一部份手性碳原子,在該種情況下,化學式(I)的化合物作為立體異構體而存在。本發明包括對映異構體、非對映異構體及該等的混合物如外消旋體,還擴展到如化學式(I)的化合物的立體異構體形態之類的所有光學異構體。不同的立體異構體形態可藉由習知的方法相互分離或分解,或者任意給定的異構體可藉由習知的立體選擇性或非對稱合成來獲得。
本申請所記載之特定化合物可以以多種互變異構體形態而存在,且理解為本發明包括所有該種互變異構體形態。
並且,雖然本發明還包括同位素-標記化合物,前述同位素-標記化合物與本申請所記載之化合物相同,但其1個以上的原子被具有與在自然中普遍發現之原子質量或原子序數不同的原子質量或質量序數之原子取代。可摻入於本發明的化合物中之同位素的例子包括如3H、11C、14C、18F、123I及125I之類的、氫、碳、氮、氧、磷、氟、碘及氯的同位素。含有前述同位素和/或其他原子的其他同位素之本發明的化合物包括在本發明的範疇內。本發明的同位素-標記化合物,例如摻入了例如3H和14C之類的放射性同位素之化合物對藥物和/或基質組織分佈分析有用。從製備的容易性及檢測性的觀點考慮,氚(即3H)及碳-14(即14C)的同位素尤為佳。11C及18F同位素尤其對PET(正電子發射斷層攝影)有用,125I同位素尤其對SPECT(單光子發射計算機斷層攝影)有用,該等均對腦成像法有用。並且,由重氫亦即如2H的更重的同位素進行之取代可以帶來來源於更大代謝穩定性的特定治療方面的優點,例如增加體內半衰期或減少劑量需要,因此根據情況
這可以是優選的。本發明的同位素-標記化合物一般可藉由進行下述反應式和/或實施例所公開之流程,接著代替非同位素-標記試劑而使用可立即利用之同位素-標記試劑來進行製備。
本發明的化合物對TRPM8的效能和效力可藉由在本申請所記載之人克隆受體上進行之化驗報告來測定。化學式(I)的化合物利用本申請所記載之功能測定來證實了TRPM8受體中的拮抗活性。
化學式(I)的化合物及其藥學上可接受的鹽用於治療由TRPM8受體介導之病症或障礙。尤其,化學式(I)的化合物及其藥學上可接受的鹽用於治療廣範圍的疾病、症候群及障礙,尤其用於治療炎症、疼痛及泌尿系統疾病或障礙,係炎症、疼痛及泌尿系統疾病或障礙的一種以上,其包括:慢性疼痛;包括異常性冷疼痛和糖尿病性神經病變在內之神經病變性疼痛;術後疼痛;骨關節炎;類風濕關節炎疼痛;癌症疼痛;神經痛;神經病變;痛覺過敏;牙本質過敏症;神經損傷;偏頭痛;叢發性及緊張性頭痛;缺血;大腸急躁症;雷諾症候群;神經退行性病變;纖維肌痛;中風;瘙癢;包括焦慮症和抑鬱症在內之精神疾病;包括哮喘、慢性阻塞性肺病在內之炎症性疾病;包括COPD、肺動脈高血壓在內之氣道疾病;包括其他應激相關病症在內之焦慮症;包括逼尿肌過度活動症或膀胱過度活動症、尿失禁、神經性逼尿肌過度活動症或逼尿肌反射亢進、特發性逼尿肌過度活動症或逼尿肌不穩定、良性前列腺增生症及下尿路症狀在內之泌尿系統疾病或障礙;以及該等的組合。
化學式(I)的化合物對前述的各種疾病、綜合症及障礙的活性可以在本領域技術人員周知的合適的模型中加以確認。例如,在異常性冷疼痛及靜態異常性疼痛模型之類的慢性壓迫損傷(CCI)-誘發模型中確認了化學式(I)的化合物對神經病變性疼痛之活性。
本申請中所使用之術語“治療”理解為包括確定如上定義之病狀之
預防及緩輕。
可適當地在環境溫度及大氣壓中藉由混合而製備之本發明的藥學組合物一般適用於口服、非口服或直腸給藥,其本身可以是片劑、膠囊劑、口服用液劑、粉末劑、顆粒劑、錠劑、可複溶(reconstitutable)粉末劑、注射或注入溶液或懸浮液或栓劑的形態。
一般口服給藥組合物為較佳。口服給藥用片劑及膠囊劑可以是單位劑量型,亦可以含有:結合劑(例如,預膠化玉米澱粉、聚乙烯吡咯烷酮或羥丙基甲基纖維素);填充劑(例如,乳糖、微晶纖維素或磷酸氫鈣);壓片潤滑劑(例如,硬脂酸鎂、滑石或矽石);崩解劑(例如,馬鈴薯澱粉或羧基乙酸澱粉鈉);及可接受的潤濕劑(例如,十二烷基硫酸鈉)之類的習知的賦形劑。片劑可按照標準藥學實踐中的周知方法來塗覆。
口服用液劑例如可以是水性或油性懸浮液、溶液、乳液、糖漿或酏劑形態,或者亦可以是在使用前用於由水或其他合適的媒介物進行複溶之乾燥產物形態。該種液劑可含有懸浮劑(例如,山梨醇糖漿、纖維素衍生物或食用氫化油脂)、乳化劑(例如,卵磷脂或阿拉伯膠)、非水性媒介物(可含食用油,例如杏仁油、含油酯、乙醇或分餾植物性油)、防腐劑(例如,對羥基苯甲酸甲酯或對羥基苯甲酸丙酯或山梨酸)、以及根據需要可含有習知的調味劑或著色劑、緩衝鹽以及根據情況可含有甜味劑之類的習知的添加劑。口服給藥用制劑可適當地配製為賦予活性化合物或其藥學上可接受的鹽之經控制之釋放。
為了非口服給藥,利用化學式(I)的化合物或其藥學上可接受的鹽以及無菌媒介物來製備流體單位劑量型。可以一同使用化學式(I)的化合物或其藥學上可接受的鹽以及無菌媒介物與任意添加之防腐劑來以單位劑量型例如安瓿瓶或多劑量方式提供注射用劑型。組
合物可採取油性或水性媒介物中的懸浮液、溶液或乳液之類的形態,可含有如懸浮劑、穩定劑和/或分散劑之類的劑型助劑(formulatory agent)。或者,活性成份可以是在使用前溶於合適的媒介物例如無菌無熱原水之粉末形態。根據所使用之媒介物或濃度,化合物可懸浮或溶解於媒介物中。製備溶液時,化合物可被溶解用於注射,並且過濾器在填充及密封於合適的小瓶或安瓿瓶之前滅菌。局部麻醉劑、防腐劑及緩衝劑之類的佐劑溶解於媒介物中為較佳。為了增進穩定性,組合物可以在填充於小瓶後冷凍,而水在真空中去除。化合物懸浮於媒介物而不是溶解於媒介物中且無法藉由過濾來實現滅菌,除此之外,實際上藉由相同的方法來製備非口服用懸浮液。化合物在懸浮於無菌媒介物之前可以暴露在環氧乙烷來滅菌。為了促進化合物的均勻分佈,將表面活性劑或潤濕劑包含於組合物中為較佳。
可用水性或油性基質配製乳液,一般還會含有1種以上的乳化劑、穩定劑、分散劑、懸浮劑、增稠劑或著色劑。還可以用包含1種以上的分散劑、穩定劑、可溶化劑或懸浮劑之水性或非水性基質配製滴劑。該等還可以含有防腐劑。
還可以用栓劑或保留灌腸劑例如,含有可可脂或其他甘油酯之類的習知的栓劑基質之直腸組合物配製化學式(I)的化合物或其藥學上可接受的鹽。
化學式(I)的化合物或其藥學上可接受的鹽還可以配製為埋植劑。該種長效劑型可藉由移植(例如,皮下或肌肉內)或藉由肌肉內注射來給藥。因此,例如,化學式(I)的化合物或其藥學上可接受的鹽可以用合適的高分子或疏水性物質(例如,作為可接受的油中的乳液)或離子交換樹脂來配製或者可配製為難溶性衍生物例如難溶性鹽。
為了鼻腔內給藥,化學式(I)的化合物或其藥學上可接受的鹽
可以被配製為藉由合適的計量型或單一劑量裝置給藥之溶液,或者,可以用合適的載劑配製為粉末混合物用於利用合適的遞送裝置之給藥。因此,化學式(I)的化合物或其藥學上可接受的鹽可以被配製為用於口服、口腔、非口服、局部(包括眼和鼻)、埋植或直腸給藥或者適於吸入或吹入(通過嘴或鼻)給藥之形態。化學式(I)的化合物及其藥學上可接受的鹽可以被配製為用於以軟膏、霜劑、凝膠劑、乳液、陰道栓、氣溶膠或滴劑(例如,眼、耳或鼻滴劑)形態局部給藥。軟膏及霜劑例如使用水性或油性基質,添加合適的增稠劑和/或膠凝劑來配製。用於眼部給藥之軟膏可利用無菌成份以滅菌方式製備。
尤其在治療炎症、疼痛及泌尿系統疾病或障礙時,TRPM8拮抗劑可以與其他藥理活性化合物或2種以上的其他藥理活性化合物有效地組合。例如,可以與選自下述中之1種以上的制劑組合來同時、依次或分別地給藥如上述所定義之TRPM8拮抗劑尤其是化學式(I)的化合物或其藥學上可接受的鹽或其溶劑化物:-阿片類鎮痛藥,例如嗎啡、海洛因、氫嗎啡酮、氧嗎啡酮、羥甲左嗎喃、烯丙左嗎喃、美沙酮、哌替啶、芬太奴、可卡因、可待因、雙氫可待因、羥考酮、氫可酮、丙氧酚、納美芬、納洛芬、納洛酮、納曲酮、丁丙諾菲、布托啡諾、納布啡或戊唑辛;-非甾體類抗炎藥物(NSAID),例如阿司匹林、雙氯高滅酸、二氟尼柳、依託度酸、芬布芬、非諾洛芬、氟苯沙酸、氟聯苯丙酸、布洛芬、茚甲新、苯酮苯丙酸、酮咯酸、甲氯滅酸、甲滅酸、美洛昔康、萘普酮、萘普生、尼美舒利、硝基氟比洛芬、奧沙拉嗪、噁丙嗪、苯基丁氮酮、吡羅昔康、硫氮磺胺吡啶、舒林酸、托美丁或佐美酸;-巴比妥類鎮靜劑,例如異戊巴比妥、阿普比妥、仲丁巴比妥、
布他比妥、甲苯巴比妥、美沙比妥、美索比妥、戊巴比妥、苯巴比妥、司可巴比妥、他布酮、硫戊巴比妥或戊硫代巴比妥;-具有鎮靜作用之苯二氮,例如氯氮卓、氯卓酸鹽、苯甲二氮卓、氟胺安定、蘿拉西泮、奧沙西泮、替馬西泮或三唑侖;-具有鎮靜作用之H1拮抗劑,例如苯海拉明、吡拉明、異丙嗪、氯屈米或氯環嗪;-鎮靜劑,例如格魯米特、甲丙胺酯、安眠酮或氯醛比林;-骨骼肌肉鬆弛劑,例如巴氯芬、卡立普多、氯唑沙宗、環苯紮林、美索巴莫或奧芬那君;-NMDA受體拮抗劑,例如右美沙芬((+)-3-甲氧基-N-甲基嗎啡烷)或其代謝物右啡烷((+)-3-羥基-N-甲基嗎啡烷)、克他命、美金剛、吡咯并喹啉奎寧,順-4-(膦醯基甲基)-2-呱啶羧酸、布地品、EN-3231(MorphiDex(註冊商標)、嗎啡與右美沙芬的組合劑型)、托吡酯、奈拉美生(neramexane)或包括NR2B拮抗劑在內之伯井弗帖(perzinfotel),例如艾芬地爾、曲索羅地或(-)-(R)-6-{2-[4-(3-氟苯基)-4-羥基-1-呱啶基]-1-羥基乙基}-3,4-二氫-2(1H)-喹啉酮;-alpha-腎上腺素能受體阻斷劑,例如多沙唑嗪、坦舒羅新、氯壓定、胍法新、右美托咪定、莫達非尼或4-胺基-6,7-二甲氧基-2-(5-甲烷磺醯胺基-1,2,3,4-四氫異喹啉-2-基)-5-(2-吡啶基)喹唑啉;-三環抗抑鬱劑,例如地昔帕明、丙咪嗪、阿米替林或去甲替林;-抗驚厥劑,例如卡馬西平、拉莫三嗪、托吡酯或丙戊酸鹽;-速激肽(NK)拮抗劑,具體為NK-3、NK-2或NK-1拮抗劑,例如(alpha R,9R)-7-[3,5-雙(三氟甲基)苄基]-8,9,10,11-四氫-9-甲基-5-(4-甲基苯基)-7H-[1,4]二氮芳辛[2,1-g][1,7]-二氮雜萘-6,13-二酮(TAK-637)、5-[[(2R,3S)-2-[(1R)-1-[3,5-雙(三氟甲基)苯基]乙氧基-3-(4-氟苯
基)-4-嗎啉基]甲基]-1,2-二氫-3H-1,2,4-三唑-3-酮(MK-869、阿瑞匹坦)、拉奈匹坦、達匹坦或3-[[2-甲氧基-5-(三氟甲氧基)苯基]甲基胺基]-2-苯基呱啶(2S,3S);-毒蕈鹼拮抗劑,例如奧昔布寧、托特羅定、丙哌維林、曲司氯銨、達非那新、索非那新、替米維林和異丙托銨;-COX-2選擇性抑制劑,例如塞來考昔、羅非考昔、帕瑞考昔、伐地考昔、地拉考昔、艾托考昔或羅美昔布;-煤焦油鎮痛劑,具體而為撲熱息痛;-精神抑制藥,例如氟哌利多、氯丙嗪、氟哌啶醇、奮乃靜、甲硫噠嗪、美索達嗪、三氟啦嗪、氟非那嗪、氯氮平、奧氮平、利哌酮、齊拉西酮、喹硫平、施立碟、阿立哌唑、索奈哌唑、布南色林、伊潘立酮、哌羅匹隆、雷氯必利、佐替平、聯苯蘆諾(bifeprunox)、阿莫沙平、鹽酸魯拉西酮、氨磺必利、帕潘立酮、派林多(palindore)、依利色林、奧沙奈坦、利莫那班、美蘭那坦、Miraxion(註冊商標)或沙立佐坦;-辣椒素受體激動劑(例如,樹膠脂毒素)或拮抗劑(例如,抗辣椒鹼);-瞬態受體電位陽離子通道亞型(V1、V2、V3、V4、M8、M2、A1)激動劑或拮抗劑;-beta-腎上腺素能受體阻斷劑,例如普萘洛爾;-局部麻醉劑,例如美西律;-皮質類固醇,例如地塞米松;-5-HT受體激動劑或拮抗劑,尤其是5-HT1B/1D激動劑,例如依來曲坦、舒馬普坦、那拉曲坦、佐米曲坦或利紮曲坦;-5-HT2A受體拮抗劑,例如R(+)-alpha-(2,3-二甲氧基-苯基)-1-[2-(4-氟苯基乙基)]-4-呱啶甲醇(MDL-100907);
-膽鹼能(煙鹼酸)鎮痛劑,例如伊普尼可林(TC-1734)、(E)-N-甲基-4-(3-吡啶基)-3-丁烯-1-胺(RJR-2403)、(R)-5-(2-氮雜環丁基甲氧基)-2-氯代吡啶(ABT-594)或尼古丁;-Tramadol(註冊商標);-PDEV抑制劑,例如5-[2-乙氧基-5-(4-甲基-1-哌嗪基磺醯基)苯基]-1-甲基-3-正丙基-1,6-二氫-7H-吡唑并[4,3-d]嘧啶-7-酮(昔多芬)、(6R,12aR)-2,3,6,7,12,12a-六氫-2-甲基-6-(3,4-亞甲基二氧基苯基)-吡嗪并[2',1':6,1]-吡啶并[3,4-b]吲哚-1,4-二酮(IC-351或他達拉非)、2-[2-乙氧基-5-(4-乙基-哌嗪-1-基-磺醯基)-苯基]-5-甲基-7-丙基-3H-咪唑并[5,1-f][1,2,4]三嗪-4-酮(伐地那非)、5-(5-乙醯基-2-丁氧基-3-吡啶基)-3-乙基-2-(1-乙基-3-氮雜環丁基)-2,6-二氫-7H-吡唑并[4,3-d]嘧啶-7-酮、5-(5-乙醯基-2-丙氧基-3-吡啶基)-3-乙基-2-(1-異丙基-3-氮雜環丁基)-2,6-二氫-7H-吡唑并[4,3-d]嘧啶-7-酮、5-[2-乙氧基-5-(4-乙基哌嗪-1-基磺醯基)吡啶-3-基]-3-乙基-2-[2-甲氧基乙基]-2,6-二氫-7H-吡唑并[4,3-d]嘧啶-7-酮、4-[(3-氯-4-甲氧基苄基)胺基]-2-[(2S)-2-(羥基甲基)吡咯烷-1-基]-N-(嘧啶-2-基甲基)嘧啶-5-羧醯胺、3-(1-甲基-7-側氧基-3-丙基-6,7-二氫-1H-吡唑并[4,3-d]嘧啶-5-基)-N-[2-(1-甲基吡咯烷-2-基)乙基]-4-丙氧基苯磺醯胺;-alpha-2-delta配體,例如加巴噴丁、普加巴林、3-甲基加巴噴丁、(3-(胺基甲基)雙環[3.2.0]庚-3-基)乙酸、(3S,5R)-3-(胺基甲基)-5-甲基庚酸、(3S,5R)-3-胺基-5-甲基庚酸、(3S,5R)-3-胺基-5-甲基辛酸、(2S,4S)-4-(3-氯苯氧基)脯胺酸、(2S,4S)-4-(3-氟苄基)脯胺酸、
[(1R,5R,6S)-6-(胺基甲基)雙環[3.2.0]庚-6-基]乙酸、3-((1-(胺基甲基)環己基)甲基)-4H-[1,2,4]噁二唑-5-酮、C-[1-((1H-四唑-5-基)甲基)環庚基]甲基胺、(3S,4S)-(1-(胺基甲基)-3,4-二甲基環戊基)乙酸、(3S,5R)-3-(胺基甲基)-5-甲基辛酸、(3S,5R)-3-胺基-5-甲基壬酸、(3S,5R)-3-胺基-5-甲基辛酸、(3R,4R,5R)-3-胺基-4,5-二甲基庚酸及(3R,4R,5R)-3-胺基-4,5-二甲基辛酸;-大麻素;-代謝型麩胺酸亞型1受體(mGluR1)拮抗劑;-血清素再吸收抑制劑,例如舍曲林、舍曲林代謝物去甲基舍曲林、氟西汀、諾氟西汀(氟西汀去甲基代謝物)、氟伏沙明、帕羅西汀、西酞普蘭、西酞普蘭代謝物去甲基西酞普蘭、依他普侖、d,l-氟苯丙胺、苯哌甲氧苯、伊福西汀、氰基度硫平、利托西汀、達泊西汀、奈法唑酮、西克拉明和曲拉唑酮;-去甲腎上腺素再吸收抑制劑,例如馬普替林、洛非帕明、米氮平、羥丙替林、非唑拉明、托莫西汀、米塞林、安非他酮、安非他酮代謝物羥基安非拉酮、諾米芬新和維洛沙嗪(Vivalan(註冊商標)),尤其是選擇性去甲腎上腺素再吸收抑制劑,例如瑞波西汀,具體為(S,S)-瑞波西汀;-雙血清素-去甲腎上腺素再吸收抑制劑,例如文拉法辛、文拉法辛代謝物O-去甲基文拉法辛、氯米帕明、氯米帕明代謝物去甲基氯米帕明、度洛西汀、米那普倫和丙咪嗪;-可誘導的一氧化氮合酶(iNOS)抑制劑,例如S-[2-[(1-亞胺基乙基)胺基]乙基]-L-高半胱胺酸、S-[2-[(1-亞胺基乙基)-胺基]乙基]-4,4-二側氧基-L-半胱胺酸、S-[2-[(1-亞胺基乙基)胺基]乙基]-2-甲基-L-半胱胺酸、(2S,5Z)-2-胺基-2-甲基-7-[(1-亞胺基乙基)胺基]-5-庚烯酸、
2-[[(1R,3S)-3-胺基-4-羥基-1-(5-噻唑基)-丁基]硫代]-5-氯代-3-吡啶腈;2-[[(1R,3S)-3-胺基-4-羥基-1-(5-噻唑基)丁基]硫代]-4-氯代苯基腈、(2S,4R)-2-胺基-4-[[2-氯代-5-(三氟甲基)苯基]硫代]-5-噻唑丁醇、2-[[(1R,3S)-3-胺基-4-羥基-1-(5-噻唑基)丁基]硫代]-6-(三氟甲基)-3-吡啶腈、2-[[(1R,3S)-3-胺基-4-羥基-1-(5-噻唑基)丁基]硫代]-5-氯代苯基腈、N-[4-[2-(3-氯苄基胺基)乙基]苯基]噻吩-2-甲脒(carboxamidine),或胍基乙基二硫化物;-乙醯基膽鹼酯酶抑制劑,例如多奈哌齊;-前列腺素E2亞型4(EP4)拮抗劑,例如N-[({2-[4-(2-乙基-4,6-二甲基-1H-咪唑并[4,5-c]吡啶-1-基)苯基]乙基}胺基)羰基]-4-甲基苯磺醯胺或4-[(1S)-1-({[5-氯-2-(3-氟代苯氧基)吡啶-3-基]羰基}胺基)乙基]苯甲酸;-白三烯B4拮抗劑,例如1-(3-聯苯基-4-基甲基-4-羥基-色滿-7-基)-環戊烷羧酸(CP-105696)、5-[2-(2-羧基乙基)-3-[6-(4-甲氧基苯基)-5E-己烯基]氧苯氧基]-戊酸(ONO-4057)或DPC-11870;-5-脂加氧酶抑制劑,例如棄留通、6-[(3-氟-5-[4-甲氧基-3,4,5,6-四氫-2H-吡喃-4-基])苯氧基-甲基]-1-甲基-2-喹諾酮(ZD-2138)或2,3,5-三甲基-6-(3-吡啶基甲基)-1,4-苯醌(CV-6504);-鈉通道阻斷劑,例如利多卡因;-鈣通道阻斷劑,例如齊考諾肽、唑尼沙胺、米貝拉地爾;-5-HT3拮抗劑,例如昂丹司瓊;
-化療劑,例如奧沙利鉑、5-氟脲嘧啶、瘤可維、紫杉酚;-降鈣素基因相關肽(CGRP)拮抗劑;-緩激肽(BK1和BK2)拮抗劑;-電壓門控鈉依賴性通道阻斷劑(Nav1.3、Nav1.7、Nav1.8);-電壓依賴性鈣通道阻斷劑(N-型、T-型);-P2X(離子通道型ATP受體)拮抗劑;-酸-敏感離子通道(ASIC1a、ASIC3)拮抗劑;-血管緊張素AT2拮抗劑;-趨化因子CCR2B受體拮抗劑;-組織蛋白酶(B、S、K)抑制劑;-sigma1受體激動劑或拮抗劑;及-鈣/鎂;-牛車腎氣丸;及其藥學上可接受的鹽及溶劑化物。
該種組合在療法中提供包括協同活性在內之顯著優點。
根據給藥方法,組合物可含有0.1~99重量%、含有10~60重量%為較佳的活性物質。使用於前述障礙的治療中之化合物的劑量因紊亂的嚴重程度、患者體重及其他類似因素而以通常的方式發生變更。
化學式(I)的化合物或其藥學組合物的治療有效量相對於平均(70kg)的人為1天約1次或1日1次以上,例如1天2次、3次或4次的處方時,包含約0.05mg~約3000mg,包含約1mg~約1000mg為較佳,包含約10mg~約500mg更為佳的活性成份的劑量範圍,但本發明的活性化合物的治療有效量根據欲治療之疾病、症候群、病狀及障礙,會發生變動,這對本領域技術人員來講是顯而易知的。
口服給藥時,以片劑形式提供含有約0.01、約10、約50、約100、約150、約200、約250及約500毫克的本發明的化合物作為活性
成份而含有之藥學組合物為較佳。
優選地,可以將1天的劑量1次全部給藥,或者將1天的總劑量以1日2次、3次及4次的分次劑量給藥化學式(I)的化合物。
給藥之化學式(I)的化合物的最佳劑量可容易決定,根據所使用之特定化合物、給藥方式、制劑強度及疾病、症候群、病狀或障礙的進展程度,會發生變動。並且,根據包括受治療者的年齡、體重、飲食習慣及給藥時間在內之接受治療之特定受治者相關因素,會產生為實現適當的治療水準而調節劑量之必要性。
因此,上述劑量為平均事例的例示。當然,可能會有更高或更低的劑量範疇更具有效之個別情況,該種情況亦包括在本發明的範疇內。
根據任意上述組合物及給藥方案或者需要化學式(I)的化合物之對象每當要求使用該化合物時,可根據在本技術領域內確定之組合及給藥方案來給藥化學式(I)的化合物。
作為TRPM8離子通道的拮抗劑,化學式(I)的化合物在治療及預防包括動物、哺乳動物及人在內之受治者中受TRPM8受體調節的影響之疾病、症候群、病狀及障礙的方法中是有用的。該種方法包括對需要該種治療或預防之包括動物、哺乳動物及人在內之受治者給藥治療有效量的化學式(I)的化合物、鹽或溶劑化物之步驟,並且前述方法由該種步驟構成且基本上由該種步驟構成。尤其是,化學式(I)的化合物在預防或治療疼痛或誘導該種疼痛之疾病、症候群、病症或障礙、或者肺或血管功能障礙時有用。更具體而言,化學式(I)的化合物藉由對需要預防或治療之受治者給藥治療有效量的化學式(I)的化合物,而在預防或治療炎症性疼痛、炎症性痛覺過敏、神經病變性疼痛、焦慮症、抑鬱症及包括周圍血管疾病、血管性高血壓、肺動脈高血壓、雷諾病及冠狀動脈疾病在內之因感冒而惡化
之心血管疾病時有用。
炎症性疼痛的例子包括疾病、病狀、症候群、障礙或由疼痛狀態引起之疼痛,其包括炎症性腸病、內臟痛、偏頭痛、術後疼痛、骨關節炎、類風濕關節炎、背痛、下背痛、關節痛、腹痛、胸痛、陣痛、肌肉骨骼疾病、皮膚病、牙痛、胸痛、燒傷、曬傷、蛇咬傷、毒蛇咬傷、蜘蛛咬傷、毒蟲螫傷、神經原性膀胱、間質性膀胱炎、尿路感染、鼻炎、接觸性皮膚炎/過敏症、瘙癢、濕疹、咽炎、黏膜炎、腸炎、大腸急躁症、雷諾症候群、膽囊炎、胰臟炎、乳房切除術後疼痛症候群、痛經、子宮內膜異位症、鼻竇炎頭痛、緊張性頭痛或蛛網膜炎。
炎症性疼痛的一種類型為炎症性痛覺過敏,其可進一步區分為炎症性軀體痛覺過敏或炎症性內臟痛覺過敏。炎症性軀體痛覺過藉由對熱、機械和/或化學刺激存在過敏性之炎症性痛覺過敏病狀的出現而被表徵。炎症性內臟痛覺過敏亦可以藉由存在增進的內臟應激性的炎症性痛覺過敏病狀的出現而被表徵。
炎症性痛覺過敏的例子包括疾病、症候群、病狀、障礙或疼痛狀態,其包括炎症、骨關節炎、類風濕關節炎、背痛、關節痛、腹痛、肌肉骨骼疾病、皮膚病、術後疼痛、頭痛、牙痛、燒傷、曬傷、毒蟲螫傷、神經原性膀胱、尿失禁、間質性膀胱炎、尿路感染、咳嗽、哮喘、慢性阻塞性肺病、鼻炎、接觸性皮膚炎/過敏症、瘙癢、濕疹、咽炎、腸炎、大腸急躁症、雷諾症候群、包括克羅恩式病或潰瘍性結腸炎在內之炎症性腸病。
本發明的一種實施形態涉及存在對熱、機械和/或化學刺激的過敏性之炎症性軀體痛覺過敏的治療方法,其包括對需要該種治療之哺乳動物給藥治療有效量的化學式(I)的化合物、鹽或溶劑化物之步驟。
本發明的另一實施形態涉及存在增進之內臟應激性的炎症性內臟痛覺過敏的治療方法,其包括對需要該種治療之受治者給藥治療有效量的化學式(I)的化合物、鹽或溶劑化物之步驟,且前述方法由該步驟構成和/或基本上由該步驟構成。
本發明的又一實施形態涉及存在對寒冷刺激之過敏性之異常性冷疼痛的治療方法,其包括對需要該種治療之受治者給藥治療有效量的化學式(I)的化合物、鹽或溶劑化物之步驟,且前述方法由該種步驟構成且/或基本上由該種步驟構成。
炎症性過敏症的例子包括尿失禁、良性前列腺增生症、咳嗽、哮喘、鼻炎及鼻過敏症、瘙癢、接觸性皮膚炎和/或皮膚過敏及慢性阻塞性肺病。
神經病變性疼痛的例子包括疾病、症候群、病狀、障礙或由疼痛狀態引起之疼痛,其包括癌症、神經系統紊亂、脊柱及周圍神經手術、腦腫瘤、創傷性腦損傷(TBI)、骨髓損傷、慢性疼痛症候群、纖維肌痛、慢性疲勞症候群、神經痛(三叉神經痛、舌咽神經痛、帶狀皰疹後神經痛及灼痛)、狼瘡、類肉瘤病、周圍神經病變、兩側性周圍神經病變、糖尿病性神經病變、中樞性疼痛、骨髓相關神經病變、中風、肌萎縮性側束硬化症(ALS)、帕金森氏病、多發性硬化症、坐骨神經痛、下顎關節神經痛、周圍神經炎、多發性神經炎、殘端痛、幻肢痛、骨折、口腔神經病變性疼痛、夏科氏病、複雜性局部痛症候群I和II(CRPS I/II)、神經根病、格林-巴利症候群、感應異常性股痛、灼口症候群、視神經炎、發熱後神經炎、遊走性神經炎、分節性神經炎、Gombault's神經炎、神經元炎、頸臂神經痛、顱神經痛、膝狀神經痛、舌咽神經痛、偏頭痛性神經痛、特發性神經痛、肋間神經痛、乳房神經痛、莫頓氏神經痛、鼻睫神經痛、枕骨神經痛、紅斑性肢痛病(red neuralgia)、Sluder's神經痛、蝶腭神經痛、眶上神經
痛、外陰痛或翼管神經痛。
神經病變性疼痛的一種類型為神經病變性異常性冷疼痛,可藉由對寒冷刺激的過敏性的神經病理相關異常性疼痛的出現而被表徵。神經病變性異常性冷疼痛的例子包括疾病、症候群、病狀、障礙或由疼痛狀態引起之異常性疼痛,其包括神經病變性疼痛或神經痛、脊柱及由周圍神經手術或外傷引起之疼痛、外傷性腦損傷(TBI)、三叉神經痛、帶狀皰疹後神經痛、灼痛、周圍神經病變、糖尿病性神經病變、中樞性疼痛、中風、周圍神經炎、多發性神經炎、複雜性局部痛症候群I和II(CRPS I/II)及神經根病。
焦慮症的例子包括社交焦慮症、創傷後應激障礙、恐懼症、社交恐懼症、特殊恐懼症、驚恐障礙、妄想強迫失調症、急性應激障礙、分離性焦慮障礙及廣泛性焦慮障礙。
抑鬱症的例子包括重度抑鬱症、雙極性情感障礙、季節性情緒障礙、產後抑鬱症、躁鬱症及雙極性抑鬱症。
一般合成
在整個本申請中,以下述含義使用下述略語:AcOH:乙酸
aq.:水性
BINAP:2,2'-雙(二苯基膦)-1,1'-聯萘
tBuXPhos:2-二-第三丁基膦-2',4',6'-三異丙基聯苯
CDI:羰基二咪唑
Cs2CO3:碳酸銫
DABCO:1,4-二氮雜雙環[2.2.2]辛烷
DavePhos:2-二環己基膦-2'-(N,N-二甲基胺基)聯苯
DABCO:1,4-二氮雜雙環[2.2.2]辛烷
DBU:1,8-二氮雜雙環[5.4.0]十一碳-7-烯
DCM:二氯甲烷
DEAD:偶氮二羧酸二乙酯
DIPEA:二異丙基乙胺
DMF:N,N-二甲基甲醯胺
DMA:N,N-二甲基乙醯胺
DME:1,2-二甲氧基乙烷
DMSO:二甲基亞碸
戴斯-馬丁氧化劑:1,1,1-三(乙醯氧基)-1,1-二氫-1,2-苯碘醯-3-(1H)-酮
ESI:電噴霧離子化
Et:乙基
EtOAc:醋酸乙酯
EtOH:乙醇
eq.:當量
HPLC:高效液相色譜法
INT:中間體
IPE:異丙醚
K2CO3:碳酸鉀
K3PO4:磷酸鉀
KO t-Bu:第三丁醇鉀
LC:液相色譜法
LDA:二異丙基胺基鋰
LG:離去基
tR:保留時間
Me:甲基
MeCN:乙腈
MeOH:甲醇
min:分鐘
NaHCO3:碳酸氫鈉
Na2SO4:硫酸鈉
Na2S2O3:硫代硫酸鈉
NaO t-Bu:第三丁醇鈉
MHz:兆赫茲
mp:熔點
MS:質譜分析法
NMP:N-甲基-2-吡咯烷酮
NMR:核磁共振
Oxone(註冊商標):過一硫酸氫鉀複合鹽
PG:保護基
Pd2(dba)3:三(二亞苄基茚丙酮)二鈀(0)
Pd(OAc)2:乙酸鈀(II)
PdCl2(dppf)CH2Cl2:[1,1'-雙(二苯基膦)二茂鐵]二氯化鈀(II)、二氯甲烷加合物
PdCl2(Amphos)2:雙(二-第三丁基(4-二甲基胺基苯基)膦)二氯化鈀(II)
PEPPSI(商標)-IPr:[1,3-雙(2,6-二異丙基苯基)咪唑-2-叉](3-氯吡啶)二氯化鈀(II)
Pd(PPh3)4:四(三苯基膦)鈀(0)
POCl3:三氯氧化磷(V)
quant:定量
rt:室溫
sat.:飽和
TEA:三乙胺
TFA:三氟乙酸
THF:四氟呋喃
THP:2-四氟吡喃
p-TsOH:對甲苯磺酸
XPhos:2-二環己基膦-2',4',6'-三異丙基聯苯
Xantphos:4,5-雙(二苯基膦)-9,9-二甲基氧雜蒽
術語“鹼”對所使用之鹼的性質同樣沒有特別限定,在此可同等地使用在該種類型的反應中通常使用之任意鹼。該種鹼的例子包括:鹼金屬氫氧化物,例如氫氧化鋰、氫氧化鈉、氫氧化鉀及氫氧化鋇;鹼金屬氫化物,例如氫化鋰、氫化鈉及氫化鉀;鹼金屬醇鹽,例如甲醇鈉、乙醇鈉及第三丁醇鉀;鹼金屬碳酸鹽,例如碳酸鋰、碳酸鈉、碳酸鉀及碳酸銫;鹼金屬碳酸氫鹽,例如碳酸氫鋰、碳酸氫鈉及碳酸氫鉀;胺,例如N-甲基嗎琳、三乙胺、三丙胺、三丁胺、二異丙基乙胺、N-甲基呱啶、吡啶、4-吡咯烷吡啶、皮考琳,2,6-二(第三丁基)-4-甲基吡啶、喹啉、N,N-二甲基苯胺、N,N-二乙基苯胺、1,5-二氮雜雙環[4.3.0]壬-5-烯(DBN)、1,4-二氮雜雙環[2.2.2]辛烷(DABCO)、1,8-二氮雜雙環[5.4.0]十一碳-7-烯(DBU)、盧剔啶及可力丁;胺基鹼金屬,例如胺基鋰、胺基鈉、胺基鉀、二異丙胺基鋰、二異丙胺基鉀、二異丙胺基鈉、雙(三甲基矽基)胺基鋰及雙(三甲基矽基)胺基鉀。其中,三乙胺、二異丙基乙胺、DBU、DBN、DABCO、吡啶、盧剔啶、可力丁、碳酸鈉、碳酸氫鈉、氫氧化鈉、碳酸鉀、碳酸氫鉀、氫氧化鉀、磷酸鉀、氫氧化鋇及碳酸銫為較佳。
反應一般且在惰性溶劑的存在下進行為較佳。只要不對伴隨之反應或試劑帶來壞影響、且溶劑可以將試劑溶解在至少某種程度,則所使用之溶劑性質沒有特別限定。合適的溶劑的例子包括:鹵代烴,
例如DCM、氯仿、四氯化碳及二氯乙烷;醚,例如二乙醚、二異丙醚、THF及二噁烷;芳香族烴,例如苯、甲苯及硝基苯;醯胺,例如DMF、DMA及六甲基磷醯三胺;胺,例如N-甲基嗎琳、三乙胺、三丙胺、三丁胺、二異丙基乙胺、N-甲基呱啶、吡啶、4-吡咯烷吡啶、N,N-二甲基苯胺及N,N-二乙基苯胺;醇,例如甲醇、乙醇、丙醇、異丙醇及丁醇;腈,例如乙腈及苄腈;亞碸,例如二甲基亞碸(DMSO)及環丁碸;酮,例如丙酮及二乙酮,但並不限於此。在該等溶劑中,包含DMF、DMA、DMSO、THF、二乙醚、二異丙醚、二甲氧基乙烷、乙腈、DCM、二氯乙烷及氯仿為較佳,但並不限於此。
[實施例]
用下述非限定性實施例對本發明進行說明,如沒有特別提及,所有試劑均為市售品,所有操作均在室溫至環境溫度,亦即約18-25℃的範圍內進行;使用旋轉蒸發器在減壓下並在最高約60℃的浴溫度下進行溶劑的蒸發;用薄層色譜法(TLC)監控反應,僅以說明的目的給出反應時間;用以下述技術中的至少一種來確認所有分離化合物的結構和純度:TLC(Merck矽膠60 F254預塗之TLC板或Merck NH2 F254預塗之HPTLC板)、質譜分析法或核磁共振(NMR)。藉由Intiator(註冊商標)Sixty(Biotage)實施微波反應。僅以說明的目的給出收率。藉由Yamazen的快速柱色譜和Biotage(SP1,Isolera one)執行柱色譜系統。使用Merck矽膠60(230-400 mesh ASTM)、Fuji Silysia Chromatorex(註冊商標)DM2035(胺基類,30-50微米)、Biotage二氧化矽(32-63mm,KP-Sil)、Biotage胺基鍵合之二氧化矽(45-75mm,KP-NH)、Wakogel(註冊商標)C-300HGT、Hi-Flash(註冊商標)色譜柱(YAMAZEN,矽膠,40微米,60埃)、Hi-Flash(註冊商標)色譜柱(YAMAZEN,胺基類,40微米,60埃)實施快速柱色
譜。以中間體和實施例為對象,藉由帶ZQ 2000質譜分析儀和2996 PDA檢測器之Waters 2695 Alliance HPLC實施LC-MS分析。分析條件(方法-A、方法-B、方法-C、方法-D、方法-E及方法-F)如下。
方法-A、方法-B及方法-C的執行條件:
方法-D及方法-E的執行條件:
藉由下述裝置和條件進行利用了HPLC(準備好的LC-MS)之化合物的提純。
裝置:Waters MS-trigger AutoPurification(商標)系統
色譜柱:Waters XTerra C18,19×50mm,5微米粒子
條件A:甲醇或乙腈/0.01%(v/v)氨水溶液
條件B:甲醇或乙腈/0.05%(v/v)甲酸水溶液
藉由下述裝置和條件獲得低分辨質譜資料(ESI):裝置;ZQ或ZMD質譜分析儀和UV檢測器上的Waters Alliance HPLC系統。在帶HPLC(Agilent 1100系列)和自動進樣器(AMR CTC-PAL)之三段四極質譜分析儀(AB SCIEX API4000)中決定LC/MS/MS資料。以百萬分之一(parts per million)(ppm)作為內部標準,沒有特別提及就可以對四甲基矽烷(TMS)使用氘代氯仿(99.8%D)或二甲基亞碸(99.9%D)來作為溶劑,並以270MHz(JEOL JNM-LA 270分光儀)、300MHz(JEOL JNM-LA300)或600MHz(Bruker Avance 600)決定NMR資料;所使用之習知的略語如下:s=單線、d=雙重線、t=三重線、q=四重線、m=多重線、br=廣域等。化學記號具有它們通常的含義;M(摩爾/升)、L(升)、mL(毫升)、g(克)、mg(毫克)、mol(摩爾)、mmol(毫摩爾)。
分別製備之化合物一般以ChemBioDraw(Ultra,version 12.0,CambridgeSoft)命名。
HPLC保留時間決定條件:
方法:QC1
裝置:帶TUV檢測器和ZQ質譜分析儀之Waters ACQUITY Ultra Performance LC
色譜柱:Waters ACQUITY C18,2.1×100mm,1.7微米粒子大小
色譜柱溫度:60℃
流速:0.7mL/min
運行時間:3min
UV檢測:210nm
MS檢測:ESI正/負模式
流動相:
A1:10mM乙酸銨
B1:乙腈
梯度程序:(QC_中性_總_3min)
方法:QC2
裝置:帶ZQ2000質譜分析儀和2996 PDA檢測器之Waters 2795 Alliance HPLC
色譜柱:XBridge C18,2.1×50mm,3.5微米粒子大小
色譜柱溫度:45℃
流速:1.2mL/min
運行時間:4.5min
UV檢測:210-400nm掃描
MS檢測:ESI正/負模式
流動相:
A:水
B:MeCN
C:1% HCO2H水溶液
D:1% NH3水溶液
梯度程序:
化學式(I)的所有氮雜螺衍生物可藉由以下示出之一般方法中所記載之流程,或者藉由實施例合成部份和中間體合成部份中所記載之特定方法,或者在該等方法上施加通常變更來進行製備。並且,本發明不僅包括化學式(I)的氮雜螺衍生物的該等製備方法的一種以上,而且還包括使用於其中之任意新型中間體。
在下述一般方法中,如果沒有特別提及,關於化學式(I)的氮雜螺衍生物之技術術語(descriptor)如前所定義。
反應式-1:化學式(I)的化合物基於化學式(III)的化合物之合成
{化學式4}
在該反應式-1中,通式(I)的氮雜螺化合物可在惰性溶劑中,在鹼的存在下,藉由化學式(II)的氮雜螺化合物和化學式(III)的alpha-鹵代酮化合物的N-烷基化反應進行製備。較佳的鹼例如選自:鹼或鹼土金屬氫氧化物、醇鹽、碳酸鹽、鹵化物或氫化物,例如氫氧化鈉、氫氧化鉀、甲醇鈉、乙醇鈉、第三丁醇鉀、碳酸銫、碳酸鈉、碳酸鉀、磷酸鉀、氟化鉀、氫化鈉或氫化鉀;或胺,例如TEA、三丁胺、二異丙基乙胺、2,6-盧剔啶、吡啶或4-二甲基胺基吡啶,但並不限於此。合適的惰性水性或非水性有機溶劑的例子包括以下:醚,例如THF或1,4-二噁烷;丙酮;N,N-二甲基甲醯胺;DMSO;鹵化烴,例如DCM、1,2-二氯乙烷或氯仿;及吡啶;或該等的混合物。該反應可在-80℃至200℃範圍的溫度下實施,在-10℃至150℃範圍的溫度下實施為較佳。反應時間一般是10分鐘至4天,10分鐘至24h為較佳。微波爐可以任意用於增加反應率。
反應式-2:化學式(I)的化合物基於化學式(III)的化合物之合成
{化學式5}
在反應式-2中,通式(IV)的化合物可在惰性溶劑中(例如甲醇),使用合適的還原劑(例如硼氫化鈉),從化合物(III)進行製備。接著,通式(V)的化合物可按照反應式-1的一般合成方法所記載之N-烷基化,從化合物(IV)進行製備。最後,通式(I)的化合物可在惰性溶劑中(例如二氯甲烷),使用合適的氧化劑(例如戴斯-馬丁試劑),從化合物(V)進行製備。
反應式-3:化學式(I-a)的化合物基於化學式(VI)的化合物之合成
在反應式-3中,通式(I-a)的化合物可在合適的過渡金屬催化劑的存在下及鹼的存在下或非存在下,在有機溶劑或水-有機共溶劑
混合物中,在偶聯條件下藉由化學式(VI)的鹵化物和化學式(VII)的硼酸(或硼酸酯)化合物的交叉偶聯反應進行製備。R'wB、R'係指OH、O-低級烷基或氟,w為2或3,B為硼原子。雖然作為具體的取代基記述了B(OH)2、B(O-低級烷基)2、B(低級烷基)2、三氟硼酸鉀(BF3 -)(BF3K),但當為B(O-低級烷基)2時,可以在低級烷基之間形成環(cyclic ring)。另外,通式(I-a)的化合物亦可藉由化學式(IX)的鹵化物和從化學式(VI)的鹵化物轉化之化學式(VIII)的硼酸(或硼酸酯)化合物的相同的交叉偶聯反應進行製備。化學式(VII)和(VIII)的硼酸(或硼酸酯)化合物在交叉偶聯反應中用作分離試劑(isolated reagents)或現場形成之試劑(reagents generated in in situ)。
合適的過渡金屬催化劑的例子包括:四(三苯基膦)鈀(0)、雙(三苯基膦)氯化鈀(II)、銅(0)、乙酸亞銅(I)、溴化亞銅(I)、氯化亞銅(I)、碘化亞銅(I)、氧化亞銅(I)、三氟甲磺酸銅(II)、乙酸銅(II)、溴化銅(II)、氯化銅(II)、碘化銅(II)、氧化銅(II)、三氟甲磺酸銅(II)、乙酸鈀(II)、氯化鈀(II)、雙(乙腈)二氯化鈀(II)、雙(二亞苄基茚丙酮)鈀(0)、三(二亞苄基茚丙酮)二鈀(0)及[1,1'-雙(二苯基膦)二茂鐵]二氯化鈀(II)。較佳的催化劑為四(三苯基膦)鈀(0)、雙(三苯基膦)氯化鈀(II)、乙酸鈀(II)、氯化鈀(II)、雙(乙腈)二氯化鈀(0)、雙(二亞苄基茚丙酮)鈀(0)、三(二亞苄基茚丙酮)二鈀(0)及[1,1-雙(二苯基膦)二茂鐵]二氯化鈀(II)。
用於無水溶劑和水-有機共溶劑混合物之合適的有機溶劑的例子包括:THF;1,4-二噁烷;DME;DMF;乙腈;醇,例如甲醇或乙醇;鹵化烴,例如DCM、1,2-二氯乙烷、氯仿或四氯化碳;及二乙醚。該反應可在鹼例如氫氧化鉀、氫氧化鈉、氫氧化鋰、碳酸氫鈉、碳酸鈉、碳酸鉀及磷酸鉀的存在下或非存在下實施。該反應可在合適的添加劑的存在下實施。該種添加劑的例子包括:三苯基膦、三第三丁基膦、1,1'-雙(二苯基膦)二茂鐵、三-2-呋喃基膦、三鄰甲苯基膦、2-(二氯己基膦)聯苯、三苯砷、四丁基氯化銨、四丁基氟化銨、乙酸鋰、氯化鋰、三乙胺、甲醇鉀或甲醇鈉、氫氧化鈉、碳酸銫、磷酸三鉀、碳酸鈉、碳酸氫鈉和/或碘化鈉。該反應可在0℃至200℃的溫度下進行,在20℃至150℃的溫度下實施為較佳。反應時間一般是5分鐘至96h,30分鐘至24h更為佳。在代替方案中,該反應可在鹼的存在下,在惰性溶劑中藉由微波系統來實施。該反應可在100℃至200℃範圍的溫度下實施,120℃至150℃範圍的溫度下實施為較佳。反應時間一般是10分鐘至3h,15分鐘至1h為較佳。除上述Suzuki-Miyaura交叉偶聯反應以外,還可以適用使用三烷基錫來代替R'wB取代基之Stille交叉偶聯反應、以及使用鋅-鹵素(其中,作為鹵素,引用氯、溴、碘)來代替R'wB取代基之Negishi偶聯反應。
反應式-4:化學式(III)的化合物基於化學式(X)和(XI)的化合物之合成
在反應式-4的步驟-1中,通式(III)的alpha-鹵代酮化合物可使用適當的鹵化劑,藉由化合物(X)的alpha-鹵化反應(Hal=Cl、Br、I)進行準備。合適的鹵化劑例如可以利用溴、氯、碘、磺醯氯、溴化氫、N-溴代琥珀醯亞胺(NBS)、溴化銅(II)、5,5-二溴-2,2-二甲基-4,6-二側氧基-1,3-二噁烷、苯基三甲基三溴化銨、三甲基苄基三溴化銨及三甲基苄基二氯碘酸銨。合適的有機溶劑例如可以使用乙酸、25%溴化氫-乙酸溶液、48%溴化氫溶液、二硫化碳、二乙醚、四氫呋喃、N,N-二甲基甲醯胺(DMF)、鹵代烴例如二氯甲烷、1,2-二氯乙烷、氯仿、四氯化碳。該反應週期為約5分鐘至96h,一般是約30分鐘至24h。反應溫度為約0℃至250℃,一般是約30℃至150℃。此外,在反應式-4的步驟-2中,通式(III)的alpha-鹵代酮化合物亦可以按照Tetrahedron Letters,38,3175,1997所記載之流程,從酯化合物(XI)進行製備。化學式(III)的化合物通常可在-78℃下且在碘氯甲烷和二異丙基胺基鋰(LDA)的四氫呋喃(THF)的存在條件下,藉由使酯化合物(XI)反應來進行製備。
反應式-5:化學式(XIII)的化合物基於化學式(XII)的化合物之合成
在反應式-5中,通式(XIII)的alpha-鹵代酮化合物可在惰性溶劑中(例如二氯甲烷),使用氯乙醯氯和合適的路易斯酸(例如氯化鋁),藉由吡咯化合物(XII)的Friedel-Crafts反應進行製備。
反應式-6:化學式(XV)的化合物基於化學式(XIV)的化合物之合成
在反應式-6中,通式(XV)(通式(II):RA和RB為側氧基,X為NH)的化合物可藉由引用文獻(例如,Chem.Rev.,46(3),pp 403-470,1950)所記載之方法(Bucherer-Bergs反應),從通式(XIV)的化合物進行製備。化學式(XV)的化合物通常可在70℃下,在氰化鉀(或三甲基矽氰)和碳酸銨的乙醇/水(1:1v/v)的存在條件下,藉由使化學式(XIV)的酮化合物反應20h來進行製備。
反應式-7:化學式(XVII)的化合物基於化學式(XIV)的化合物之合成
在反應式-7中,化學式(XVII)(通式(II):RA和RB為側氧基,X為O)的化合物可从通式(XVI)的氰醇化合物進行製備。在步驟-1中,化學式(XVI)的化合物可在三甲基矽氰和催化(catalytic zinc)碘化鋅(II)的存在條件下,藉由在酸性條件下的O-三甲基矽基部份的脫保護,從通式(XIV)的酮化合物進行製備。此外,化學式(XVI)的化合物可按照Synthesis,p 697(1991)所記載之流程轉化為化學式(XVII)的2,4-噁唑烷二酮衍生物。在步驟-2中,化學式(XVII)的化合物通常藉由化學式(XVI)的化合物和氯磺醯異氰酸
酯的反應及酸水解進行製備。
反應式-8:化學式(XX)的化合物基於化學式(XVIII)的化合物之合成
在反應式-8中,通式(XX)(通式(II):RA和RB為氫,X為O)的化合物可從通式(XVIII)的化合物(化學式(XVI)的中間體化合物)進行製備。在步驟-1中,通式(XIX)的化合物可藉由使用例如硼烷-二甲基硫醚錯合物等還原劑之使用還原反應進行製備。此外,在步驟-2中,通式(XIX)的化合物可藉由與1,1'-羰基二咪唑(CDI)的反應轉化為化學式(XX)的噁唑烷-2-酮衍生物。
反應式-9:化學式(XXIV)的化合物基於化學式(XIV)的化合物之合成
在反應式-9中,通式(XXIV)(通式(II):RA為烷基;RB為氫或烷基,X為O)的化合物可從通式(XIV)的化合物進行製備。在步驟-1中,通式(XXIII)的化合物可藉由使從金屬鋅和alpha-溴乙酸酯衍生物製備之激活劑(XXI)和通式(XIV)的化合物之間發生Reformatsky反應,接著使通式(XXII)的化合物鹼性水解來進行製備。此外,在步驟-3中,通式(XXIII)的化合物可藉由與二苯基磷醯疊氮化物(DPPA)的反應轉化為化學式(XXIV)的噁唑烷-2-酮衍生物。
反應式-10:化學式(XXVIII)的化合物基於化學式(XXV)和(XXVII)的化合物之合成
在反應式-10中,通式(XXVIII)的化合物可藉由化學式(XXV)的鹵化物和化學式(XXVI)的化合物的反應進行製備(步驟-1)。或者,通式(XXVIII)的化合物亦可利用鈀偶聯反應、親核取代反應和烏爾曼反應中之選定流程,藉由化學式(XXVII)的苯酚化合物和化學式(IX)的化合物的反應進行製備(步驟-2)。偶聯反應可在有機溶劑或水-有機共溶劑混合物中藉由合適的鈀催化劑、配體及鹼的組合來實施。合適的過渡金屬催化劑的例子包括:乙酸鈀(II)、三(二亞苄基茚丙酮)二鈀(0)及[1,3-雙(2,6-二異丙基苯基)咪唑-2-叉](3-氯吡啶)二氯化鈀(II)。用於無水溶劑和水-有機共溶劑混合物的合適的有機溶劑包括:THF;DME;1,4-二噁烷;DMF;乙腈;及醇,例如甲醇、乙醇及第三丁醇。合適的鹼的例子包
括:碳酸氫鈉、碳酸鈉、碳酸鉀、碳酸銫、磷酸鉀、第三丁醇鈉及第三丁醇鉀。該反應可在合適的配體劑的存在下實施。該種配體劑的例子包括:2,2'-雙(二苯基膦)-1,1'-聯萘(BINAP)、2-二環己基膦-2'-(N,N-二甲基胺基)聯苯(DavePhos)、4,5-雙(二苯基膦)-9,9-二甲基氧雜蒽(Xantphos)及2-二環己基膦-2',4',6'-三異丙基聯苯(XPhos)。親核取代反應可在鹼的存在下且在偶聯條件下,在有機溶劑或水-有機共溶劑混合物中實施。合適的有機溶劑的例子包括:N,N-二甲基甲醯胺、二甲基亞碸及N-甲基-2-吡咯烷酮。合適的鹼的例子包括碳酸鉀、碳酸銫、磷酸鉀、氫化鈉、第三丁醇鈉及第三丁醇鉀。另外,烏爾曼反應可在有機溶劑中,在使用合適的銅試劑、配體及鹼之偶聯條件下實施。合適的銅試劑例如可以使用碘化亞銅(I)、溴化亞銅(I)及氯化亞銅(I)。合適的配體及鹼例如使用:配體,例如N,N-二甲基甘胺酸、L-脯胺酸、N,N'-二甲基乙二胺及反式-N,N'-二甲基環己烷-1,2-二胺;及鹼,例如碳酸鈉、碳酸鉀及碳酸銫。合適的有機溶劑包括THF、1,4-二噁烷、N,N-二甲基甲醯胺、二甲基亞碸及N-甲基-2-吡咯烷酮。該反應可在20℃至200℃的溫度下實施,在100℃至160℃的溫度下實施更為佳。反應時間一般是5分鐘至96h,30分鐘至24h更為佳。在代替方案中,該反應可在鹼的存在下且在惰性溶劑中,藉由微波系統實施。該應可在100℃至200℃範圍的溫度下實施,在120℃至150℃範圍的溫度下實施為較佳。反應時間一般是10分鐘至3h,15分鐘至1h為較佳。
反應式-11:化學式(XXXII)的化合物基於化學式(XXV)的化合物之合成
{化學式14}
在反應式-11中,通式(XXXII)的化合物可按照反應式-10所記載之一般合成方法,利用鈀偶聯反應、親核取代反應或Ullmann反應中之選定流程,藉由使化學式(XXV)的鹵化物和化學式(XXIX)、(XXX)或(XXXI)的化合物反應來進行製備。
中間體的製備
中間體-1-1-A(INT-1-1-A):8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
在70℃下,將4,4-二氟環己烷(3.00g,22.37mmol)、氰化鉀(2.91g,44.7mmol)及碳酸銨(8.60g,89.0mmol)的乙醇/水(1:1v/v,90mL)的混合物加熱20h。冷卻至室溫之後,在真空中使有機溶劑(乙醇)蒸發,直至成為一半容積。用冷水(250mL)稀釋殘留物並攪拌60min。過濾沉澱之固體,並在40℃(內部溫度)下,使用五氧化二磷在真空泵中進行乾燥而得到標題化合物(3.75g,微灰色固體)。
1H-NMR(270MHz,DMSO-d 6):delta 10.77(br.s,1H),8.53
(s,1H),2.20-1.65(m,8H)。
按照流程(INT-1-1-A),從表1中的周知或合成之之酮衍生物製備以下乙內醯脲衍生物(INT-1-2-A)。
中間體-1-3-A(INT-1-3-A):8,8-二氟-1-氧雜-3-氮雜螺[4.5]癸烷-2,4-二酮
按照Synthesis,p 697(1991)所記載之流程,從4,4-二氟-1-羥基環己烷甲腈(495mg,3.07mmol)、氯磺醯異氰酸酯(281microL,3.23mmol)及三乙胺(450microL,3.23mmol)的無水苯(10mL)製備標題化合物,得到微黃色固體的產物(600mg,95%的收率)。
1H-NMR(270MHz,DMSO-d 6):delta 12.01(br.s,1H),2.25-1.85(m,8H)。
中間體-1-4-A(INT-1-4-A):8,8-二氟-1-氧雜-3-氮雜螺[4.5]癸烷-2-酮
在75℃下,將1-(胺基甲基)-4,4-二氟環己醇鹽酸鹽(5.15g,
25.5mmol)、CDI(12.42g,77mmol)及三乙胺(7.68mL,51.1mmol)的THF(100mL)的混合物加熱20h。在其中添加2M NaOH水溶液(6eq.),並在室溫下將混合物攪拌5h。用DCM(×3)萃取混合物,在真空中使合併之有機萃取物蒸發而得到黃色油。將粗製產物溶解於DCM(300mL),並用2M HCl水溶液(×1)、接著用飽和的NaHCO3溶液、鹽水清洗,在硫酸鈉上乾燥,過濾之後在真空中濃縮而得到粗製產物(微黃色固體)。將65-100%醋酸乙酯的己烷溶液用作洗脫劑,藉由柱色譜法(Biotage)在矽膠上(100g)提純該粗製產物而得到白色固體的標題化合物(3.34g,68%的收率)。
1H-NMR(270MHz,CDCl3):delta 5.79(br.s,1H),3.38(s,2H),2.35-1.75(m,8H)。
中間體-1-5-A(INT-1-5-A):8,8-二氟-2-氮雜螺[4.5]癸烷-1,3-二酮
<步驟-1>:中間體-1-5-1(INT-1-5-1):2-氰基-2-(4,4-二氟亞己基)乙酸乙酯
在室溫下,將4,4-二氟環己酮(1.00g,7.46mmol)、2-氰基乙酸乙酯(1.10g,9.69mmol)、分子篩4埃(1.00g)及Et3N(2.08mL,14.91mmol)的DCM(10mL)的混合物攪拌1天。過濾混合物並進行濃縮。殘餘油沒有進一步提純而使用於接下來的步驟。
MS(ESI)m/z:228.3(M-H)-。
<步驟-2>:中間體-1-5-2(INT-1-5-2):1-(氰基甲基)-4,4-二氟環己烷甲腈
在75℃下,將INT-1-5-1(7.46mmol,從4,4-二氟環己酮得到之粗製混合物)和氰化鉀(1.46g,22.38mmol)的EtOH(20mL)-H2O(4mL)的混合物攪拌1天。去除溶劑之後,用飽和的NaHCO3溶液稀釋殘餘油,並用EtOAc萃取。使合併之有機溶液在Na2SO4上乾燥,過濾之後濃縮。將0-20%醋酸乙酯的己烷溶液用作洗脫劑,藉由柱色譜法在矽膠上提純殘餘油而得到米色固體的標題化合物(1.01g,在2個步驟中為74%的收率)。
1H-NMR(300MHz,CDCl3):delta 2.75(s,2H),2.32-2.05(m,6H),2.92-2.77(m,2H)。
<步驟-3>:中間體-1-5-A(INT-1-5-A):8,8-二氟-2-氮雜螺[4.5]癸烷-1,3-二酮
在125℃下,將H2SO4(0.3mL)和AcOH(1.5mL)的INT-1-5-2(200mg,1.09mmol)的混合物攪拌1h。將混合物注入到冰水中。接著,用2M NaOH水溶液使混合物呈中性並用DCM萃取。使合併之有機溶液在Na2SO4上乾燥,過濾之後濃縮。將0-50%醋酸乙酯的己烷溶液用作洗脫劑,藉由柱色譜法在矽膠上提純殘餘油而得到米色固體的標題化合物(80mg,36%的收率)。
1H-NMR(300MHz,CDCl3):delta 8.08(br s,1H),2.63(s,2H),2.41-2.06(m,4H),1.96-1.69(m,4H).
MS(ESI)m/z:202.2(M-H)-。
中間體-1-6-A(INT-1-6-A):8,8-二氟-4-甲基-1-氧雜-3-氮雜螺[4.5]癸烷-2-酮
<步驟-1>:中間體-1-6-1(INT-1-6-1):2-(4,4-二氟-1-羥基環己基)丙酸乙酯
在100℃下,將4,4-二氟環己酮(1.00g,7.46mmol)、2-溴丙酸乙酯(1.35g,7.46mmol)、鋅粉(561mg,8.57mmol)的二噁烷(20mL)的混合物攪拌1天。使用矽藻土墊過濾混合物。去除溶劑之後,將0-30%醋酸乙酯的己烷溶液用作洗脫劑,藉由柱色譜法在矽膠上提純殘餘油而得到淺黃色油的標題化合物(1.50g,85%的收率)。
1H-NMR(270MHz,CDCl3):delta 4.19(q,J=7.3Hz,2H,),3.33(d,J=2.0Hz,1H),2.75-1.82(m,6H),1.73-1.59(m,2H),1.54-1.36(m,1H),1.28(t,J=7.3Hz,3H),1.23(d,J=7.3Hz,3H)。
<步驟-2>:中間體-1-6-2(INT-1-6-2):2-(4,4-二氟-1-羥基環己基)丙酸
{化學式24}
在60℃下,將INT-1-6-1(1.50g,6.35mmol)、2M NaOH水溶液(5mL,10mmol)的THF(10mL)的混合物攪拌5h。用2M HCl水溶液使混合物酸化,並用DCM萃取。使合併之有機溶液在Na2SO4上乾燥,過濾之後濃縮而得到粗製油的標題化合物(1.43g)。
MS(ESI)m/z:207.1(M-H)-。
<步驟-3>:中間體-1-6-A(INT-1-6-A):8,8-二氟-4-甲基-1-氧雜-3-氮雜螺[4.5]癸烷-2-酮
在100℃下,將INT-1-6-2(1.43g,粗製混合物)、疊氮磷酸二苯酯(2.27g,8.24mmol)及TEA(1.44mL,10.3mmol)的甲苯(30mL)的混合物攪拌2h。用2M NaOH水溶液使混合物淬滅,並用EtOAc萃取。用水和鹽水清洗有機層,在Na2SO4上乾燥,過濾之後在真空中濃縮。將0-70%醋酸乙酯的己烷溶液用作洗脫劑,藉由柱色譜法在矽膠上提純殘餘油而得到淺黃色固體的標題化合物(507mg,在2個步驟中為39%的收率)。
1H-NMR(270MHz,CDCl3):delta 5.61(br s,1H),3.66(q,J=6.6Hz,1H),2.38-1.95(m,6H),1.88-1.59(m,2H),1.20(d,J=6.6Hz,3H)。
MS(ESI)m/z:206.1(M+H)+。
中間體-1-7-A(INT-1-7-A):8,8-二氟-4,4-二甲基-1-氧雜-3-氮雜螺[4.5]癸烷-2-酮
<步驟-1>:中間體-1-7-1(INT-1-7-1):2-(4,4-二氟-1-羥基環己基)-2-甲基丙酸乙酯
在85℃下,將4,4-二氟環己酮(1.00g,7.46mmol)、2-溴-2-甲基丙酸乙酯(1.45g,7.46mmol)及鋅粉(561mg,8.57mmol)的二噁烷(20mL)的混合物攪拌2天。使用矽藻土墊過濾混合物。去除溶劑之後,將0-30%醋酸乙酯的己烷溶液用作洗脫劑,藉由柱色譜法在矽膠上提純殘餘油而得到淺黃色油的標題化合物(1.14g,61%的收率)。
MS(ESI)m/z:249.1(M-H)-。
<步驟-2>:中間體-1-7-2(INT-1-7-2):2-(4,4-二氟-1-羥基環己基)-2-甲基丙酸
在90℃下,將INT-1-7-1(1.14g,4.55mmol)、4M NaOH水溶液(5mL,20mmol)的THF(5mL)的混合物攪拌2天。藉由IPE去除不需要的物質之後,用2M HCl水溶液使水層酸化,並用DCM萃取。使合併之有機溶液在Na2SO4上乾燥,過濾之後在真空中濃縮而得到粗製固體的標題化合物(0.77g,76%的收率)。
MS(ESI)m/z:221.1(M-H)-。
<步驟-3>:中間體-1-7-A(INT-1-7-A):8,8-二氟-4,4-二甲基-1-氧雜-3-氮雜螺[4.5]癸烷-2-酮
在85℃下,將INT-1-7-2(770mg,3.46mmol)、疊氮磷酸二苯酯
(1.14g,4.16mmol)、TEA(0.724mL,5.20mmol)的甲苯(15mL)的混合物攪拌1天。用2M NaOH水溶液使混合物淬滅,並用EtOAc萃取。用水和鹽水清洗有機層,在Na2SO4上乾燥,過濾之後在真空中濃縮。將0-70%醋酸乙酯的己烷溶液用作洗脫劑,藉由柱色譜法在矽膠上提純殘餘油而得到淺黃色固體的標題化合物(567mg,75%的收率)。
1H-NMR(270MHz,CDCl3):delta 5.80(br s,1H),2.33-2.02(m,6H),1.80-1.60(m,2H),1.27(s,3H),1.27(s,3H).
MS(ESI)m/z:220.2(M+H)+。
中間體-1-8-A(INT-1-8-A):8,8-二氟-4-異丙基-1-氧雜-3-氮雜螺[4.5]癸烷-2-酮
<步驟-1>:中間體-1-8-1(INT-1-8-1):2-(4,4-二氟-1-羥基環己基)-3-甲基丁酸乙酯
在85℃下,將4,4-二氟環己酮(1.00g,7.46mmol)、2-溴-3-甲基丁酸乙酯(1.56g,7.46mmol)、鋅粉(56lmg,8.57mmol)的二噁烷(20mL)的混合物攪拌2天。去除溶劑之後,在真空中使濾液濃縮。將0-30%醋酸乙酯的己烷溶液用作洗脫劑,藉由柱色譜法在矽膠上提純殘餘油而得到淺黃色油的標題化合物(1.46g,74%的收率)。
<步驟-2>:中間體-1-8-2(INT-1-8-2):2-(4,4-二氟-1-羥基環己基)-3-甲基丁酸
在80℃下,將INT-1-8-1(1.25g,4.73mmol)、6M NaOH水溶液(5mL,30mmol)的EtOH(5mL)的混合物攪拌1天。藉由IPE去除不需要的物質之後,用2M HCl水溶液使水層酸化,並用DCM萃取。使合併之有機溶液在Na2SO4上乾燥,過濾之後在真空中濃縮而得到粗製固體的標題化合物(0.88g,68%的收率)。
MS(ESI)m/z:235.1(M-H)-。
<步驟-3>:中間體-1-8-A(INT-1-8-A):8,8-二氟-4-異丙基-1-氧雜-3-氮雜螺[4.5]癸烷-2-酮
在85℃下,將INT-1-8-2(880mg,3.72mmol)、疊氮磷酸二苯酯(1.23g,4.47mmol)、TEA(0.779mL,5.59mmol)的甲苯(15mL)的混合物攪拌1天。用2M NaOH水溶液使混合物淬滅,並用EtOAc萃取。用水和鹽水清洗有機層,在Na2SO4上乾燥,過濾之後在真空中濃縮。將0-70%醋酸乙酯的己烷溶液用作洗脫劑,藉由柱色譜法在矽膠上提純殘餘油而得到淺黃色固體的標題化合物(476mg,55%的收率)。
1H-NMR(270MHz,CDCl3):delta 6.37(br s,1H),3.21(d,J=7.9Hz,1H),2.35-2.18(m,1H),2.18-1.98(m,5H),1.98-1.73(m,3H),1.00(d,J=6.6Hz,3H),0.92(d,J=6.6Hz,3H)。
MS(ESI)m/z:234.2(M+H)+。
中間體-2-1-A(INT-2-1-A):5-(2,5-二甲基-1H-吡咯-1-基)-3-
甲基異噁唑
在80℃下,將3-甲基異噁唑-5-胺(1.50g,15.29mmol)、己烷-2,5-二酮(1.75g,15.29mmol)及p-TsOH單水合物(291mg,1.53mmol)的乙醇(25mL)的混合物加熱15h。去除溶劑之後,用飽和的碳酸氫鈉溶液使殘留物淬滅。用醋酸乙酯(2次)萃取水層,並用鹽水清洗合併之溶液,在硫酸鈉上乾燥,過濾之後在真空中濃縮而得到粗製產物。將5-10%醋酸乙酯的己烷溶液用作洗脫劑,藉由柱色譜法(Biotage)在矽膠(100g)上提純該粗製產物而得到暗紅色固體的標題化合物(2.13g,79%的收率)。
1H-NMR(300MHz,CDCl3):delta 5.92(s,1H),5.90(s,2H),2.37(s,3H),2.19(s,6H)。
按照中間體2-1-A的流程,從表2中的周知或合成之苯胺衍生物製備以下吡咯衍生物(INT-2-2-A及INT-2-6-A)。
中間體-3-1-A(INT-3-1-A):2,5-二甲基-1-苯基-1H-咪唑-4-羧酸乙酯
按照WO 2011/005052所記載之流程,從苯胺(3.73g,40.1mmol)和2-乙醯胺基-3-側氧基-丁酸乙酯(2.50g,13.4mmol)製備標題化合物。將己烷-EtOAc(1:3v/v)用作洗脫劑,藉由柱色譜法在矽膠上實施提純而得到微棕色固體的產物(4.06g,62%的收率)。
1H-NMR(270MHz,CDCl3):delta 7.60-7.50(m,3H),7.24-7.15(m,2H),4.41(q,J=7.3Hz,2H),2.32(s,3H),2.23(s,3H),1.42(t,J=7.3Hz,3H)。
MS(ESI)m/z:245.2(M+H)+。
按照中間體3-1-A的流程,從表3中的周知或合成之苯胺衍生物和2-乙醯胺基-3-側氧基-丁酸乙酯製備以下咪唑衍生物(INT-3-2-A至INT-3-4-A)。
中間體-3-5-A(INT-3-5-A):1,4-二甲基-5-(吡啶-3-基)-1H-吡唑-3-羧酸乙酯
在120℃下,向1,4-二甲基-5-(((三氟甲基)磺醯基)氧基)-1H-吡唑-3-羧酸乙酯(500mg,1.58mmol)、吡啶-3-基硼酸(214mg,1.74mmol)、Pd(PPh3)4(183mg,0.158mmol)及2M Na2CO3水溶液(3.2mL,6.32mmol)的DME(5mL)的混合物照射微波30min。冷卻之後,藉由矽藻土墊過濾反應混合物,並用EtOAc清洗濾餅。用水和鹽水清洗濾液和清洗液,在硫酸鈉上乾燥,過濾之後在真空中濃縮。將10-100%醋酸乙酯的己烷溶液用作洗脫劑,藉由柱色譜法
(Biotage)在矽膠(25g)上提純殘留物而得到棕色無定形固體的標題化合物(136mg,35%的收率)。
1H-NMR(270MHz,CDCl3):delta 9.07(dd,J=4.6,1.3Hz,1H),8.06(d,J=8.5Hz,2H),7.84(dd,J=9.2,4.6Hz,1H),7.59-7.55(m,1H),7.36(d,J=8.5Hz,2H),2.60(s,3H)。
MS(ESI)m/z:246.3(M+H)+。
中間體-4-1-A(INT-4-1-A):2-氯-1-(2,5-二甲基-1-(3-甲基異噁唑-5-基)-1H-吡咯-3-基)乙酮
一邊用冰冷卻一邊用注射器在5-(2,5-二甲基-1H-吡咯-1-基)-3-甲基異噁唑(2120mg,12.03mmol)(INT-2-1-A)的DCM(40mL)的攪拌溶液中添加2-氯乙醯氯(1.15mL,14.44mmol)。在相同溫度下,在其中添加一部份經粉碎之氯化鋁(3210mg,24.06mmol),並在室溫下將混合物攪拌1.5h。用冰水淬滅,並用飽和的碳酸氫鈉溶液調節為pH>8之後,藉由矽藻土墊過濾混合物,並用DCM清洗濾餅。使有機層分層,用DCM萃取水層(2次)。用鹽水清洗合併之有機溶液,在硫酸鈉上乾燥,過濾之後在真空中濃縮而得到粗製產物。將10-40%醋酸乙酯的己烷溶液用作洗脫劑,藉由柱色譜法(Biotage)在矽膠(100g)上提純該粗製產物而得到所希望的產物。最後,使產物從醋酸乙酯-己烷再結晶而得到淺棕褐色固體的標題化合物(983mg,32%的收率)。
1H-NMR(270MHz,CDCl3):delta 6.31(s,1H),6.10(s,1H),4.45(s,2H),2.46(s,3H),2.41(s,3H),2.15(s,3H)。
MS(ESI)m/z:253.17(M+H)+。
按照中間體4-1-A的流程,从表4中的周知或合成之吡咯衍生物製備以下alpha-氯乙醯基衍生物(INT-4-2-A至INT-4-12-A)。
中間體-5-1-A(INT-5-1-A):2-氯-1-(2,5-二甲基-1-苯基-1H-咪唑-4-基)乙酮
在-80℃下,在2,5-二甲基-1-苯基-1H-咪唑-4-羧酸乙酯(INT-3-1-A)(600mg,2.46mmol)和氯碘甲烷(1300mg,7.37mmol)的無水THF(20mL)的溶液中添加LDA(在THF溶液中為1.09M;6.76mL,7.34mmol),並在相同溫度下將生成之混合物攪拌1.5h。用飽和的NH4Cl溶液(20mL)使混合物淬滅,並用DCM(×3)萃取。用鹽水清洗合併之有機層,在硫酸鈉上乾燥,過濾之後在真空中濃縮而得到粗製產物。將30-40%EtOAc的己烷溶液用作洗脫劑,藉由柱色譜法在矽膠(45g)上提純該粗製產物而得到微黃色固體的標題化合物(385mg,63%的收率)。
1H-NMR(270MHz,CDCl3):delta 7.62-7.52(m,3H),7.24-7.17(m,2H),4.88(s,2H),2.35(s,3H),2.21(s,3H)。
MS(ESI)m/z:249.2(M+H)+。
按照中間體5-1-A的流程,從表5中的周知或合成之酯衍生物製備以下alpha-氯甲基酮衍生物(INT-5-2-A至INT-5-19-A)。
基於酮衍生物之鹵化
(方法-A):使用苄基三甲基二氯碘酸銨之氯化
中間體-6-1-A(INT-6-1-A:1-(5-溴-1-甲基-1H-吡咯-2-基)-2-
氯乙酮
在室溫下,在1-(5-溴-1-甲基-1H-吡咯-2-基)乙酮(480mg,2.38mmol)的THF(8mL)的攪拌溶液中添加苄基三甲基二氯碘酸銨(1.24g,3.56mmol)的一部份。在70℃下,將混合物加熱2h(黃色至暗棕色的懸浮液)。冷卻之後,用醋酸乙酯稀釋混合物,並用2M HCl水溶液、飽和的硫代硫酸鈉溶液及鹽水清洗,在硫酸鈉上乾燥,過濾之後在真空中濃縮而得到粗製產物。將10-50%EtOAc的己烷溶液用作洗脫劑,藉由柱色譜法在矽膠上提純該粗製產物而得到標題化合物(498mg,89%的收率)。
(方法-B)使用溴化銅(II)之溴化
中間體-6-3-A(INT-6-3-A):2-溴-1-(1,4-二甲基-5-苯基-1H-吡咯-2-基)乙酮
在回流下,將溴化銅(II)(1.05g,4.69mmol)和1-(1,4-二甲基-5-苯基-1H-吡咯-2-基)乙酮(500mg,2.34mmol)的醋酸乙酯(10mL)的混合物加熱4h。冷卻至室溫之後,藉由矽膠墊過濾混合物,並用醋酸乙酯清洗濾餅。使合併之有機分餾物蒸發而獲得標題化合物(41mg,6%的收率)。
(方法-C)使用溴的25%HBr-乙酸溶液之溴化
中間體-6-4-A(INT-6-4-A):2-溴-1-(5-溴-1,4-二甲基-1H-咪唑-2-基)乙酮氫溴酸鹽
在60℃下,將1-(5-溴-1,4-二甲基-1H-咪唑-2-基)乙酮(260mg,1.20mmol)和溴(201mg,1.26mmol)的25%HBr的AcOH(5mL)的混合物攪拌2h。使混合物濃縮。用IPE粉碎殘餘固體而得到標題化合物(451mg,定量收率)。
按照方法(A-C)的流程,從表6中的周知或合成之甲基酮衍生物製備以下alpha-鹵代甲基酮衍生物(INT-6-1-A至INT-6-15-A)。
中間體-6-2(INT-6-2):1-(4-甲基-5-苯基噻唑-2-基)乙酮
在空氣中秤取碳酸鉀(1.47g,10.62mmol)、乙酸鈀(2mmol%)(32mg,0.142mmol)、三環己基膦氟硼酸鹽(4mol%)(104mg,0.283mmol)及特戊酸(30mol%)(217mg,2.13mmol),並載置於備有磁力攪拌棒之螺旋蓋小瓶中。用氬氣淨化小瓶,並添加DMA(24mL)。添加1-(4-甲基噻唑-2-基)乙酮(1.00g,7.08mmol)和溴化苯(1.11g,7.08mmol)。接著,在100℃下將反應混合物大力攪拌16h。將溶液冷卻至室溫之後,用EtOAc稀釋,並用H2O清洗,在MgSO4上乾燥,過濾之後在減壓下蒸發。將10-50%醋酸乙酯的己烷溶液用作洗脫劑,藉由柱色譜法在矽膠上提純粗製產物而獲得對應產物。用醋酸乙酯-乙烷混合物清洗該對應產物而得到標題化合物(586mg,38%的收率)。
1H-NMR(270MHz,CDCl3):delta 7.48-7.40(m,5H),2.71
(s,3H),2.57(s,3H)。
中間體-6-3(INT-6-3):1-(1,4-二甲基-5-苯基-1H-吡咯-2-基)乙酮
在0-5℃下,冷卻N,N-二甲基乙醯胺(0.714mL,7.71mmol),並在其中以滴加方式慢慢添加三氯化磷醯(0.699mL,7.71mmol)。接著,在室溫下將生成之混合物攪拌20分鐘。接著,用1,2-二氯乙烷(30mL)稀釋反應混合物,並冷卻至0℃。接著,將冷卻之反應混合物以滴加方式添加到1,3-二甲基-1H-吡咯(1.20g,7.01mmol)的1,2-二氯乙烷(30mL)的溶液中之後,將反應混合物加熱回流30分鐘。將如此獲得之混合物冷卻至室溫,並用三水合乙酸鈉水溶液(在25mL水中為10g)稀釋。將混合物進一步加熱回流30分鐘,分層為兩層。用二氯甲烷(3×50mL)萃取水層。用水(1×50mL)清洗合併之有機層,在無水Na2SO4上乾燥。在減壓下,使溶劑從反應混合物中蒸發而獲得粗製產物。將0-30%醋酸乙酯的己烷溶液用作洗脫劑,藉由柱色譜法在矽膠上提純該粗製產物而獲得標題化合物(1.23g,83%的收率)。
1H-NMR(270MHz,CDCl3):delta 7.51-7.37(m,3H),7.30-7.26(m,2H),6.88(s,1H),3.75(s,3H),2.45(s,3H),2.02(s,3H)。
中間體-6-4(INT-6-4):1-(5-溴-1,4-二甲基-1H-咪唑-2-基)乙酮
{化學式41}
<步驟-1>:中間體-6-4-1(INT-6-4-1):1-(4-溴-1-甲基-1H-咪唑-2-基)乙酮
在1-(1-甲基-1H-咪唑-2-基)乙酮(3.67g,29.6mmol)的MeCN(50mL)的溶液中添加N-溴代琥珀醯亞胺(5.52g,31.0mmol)。在60℃下將混合物攪拌1天。去除溶劑之後,將0-50%醋酸乙酯的己烷溶液用作洗脫劑,藉由柱色譜法在矽膠上提純殘餘固體而得到棕色固體的標題化合物(3.83g,64%的收率)。
1H-NMR(270MHz,CDCl3):delta 7.00(s,1H),3.98(s,3H),2.63(s,3H)。
MS(ESI)m/z:205.1(M+H)+。
<步驟-2>:中間體-6-4-2(INT-6-4-2):1-(1,4-二甲基-1H-咪唑-2-基)乙酮
在80℃下,將1-(4-溴-1-甲基-1H-咪唑-2-基)乙酮(INT-6-4-1)(500mg,2.46mmol)、三甲基環三硼氧烷(1.55g,12.3mmol)、雙(二-第三丁基(4-二甲基胺基苯基)膦)二氯化鈀(II)(101mg,0.12mmol)的1,4-二噁烷(10mL)-飽和的NaHCO3溶液(10mL)的混合物攪拌1天。用水稀釋混合物,並用EtOAc萃取。使合併之有機溶液在Na2SO4上乾燥,過濾之後濃縮。將0-30%醋酸乙酯的己烷溶液
用作洗脫劑,藉由柱色譜法在矽膠上提純殘餘油而得到黃色油的標題化合物(140mg,41%的收率)。
1H-NMR(270MHz,CDCl3):delta 6.77(s,1H),3.93(s,3H),2.63(s,3H),2.26(s,3H)。
MS(ESI)m/z:139.2(M+H)+。
<步驟-3>:中間體-6-4(INT-6-4):1-(5-溴-1,4-二甲基-1H-咪唑-2-基)乙酮
在1-(1,4-二甲基-1H-咪唑-2-基)乙酮(INT-6-4-2)(220mg,1.59mmol)的MeCN(5mL)的溶液中添加N-溴代琥珀醯亞胺(312mg,1.75mmol)。在60℃下將混合物攪拌1h。在真空中去除溶劑之後,將0-25%醋酸乙酯的己烷溶液用作洗脫劑,藉由柱色譜法在矽膠上提純殘餘固體而得到淺黃色油的標題化合物(270mg,78%的收率)。
1H-NMR(270MHz,CDCl3):delta 3.96(s,3H),2.62(s,3H),2.26(s,3H)。
MS(ESI)m/z:219.1(M+H)+。
中間體-6-5(INT-6-5):1-(5-溴-4-環丙基-1-甲基-1H-咪唑-2-基)乙酮
<步驟-1>:中間體-6-5-1(INT-6-5-1):1-(4-環丙基-1-甲基-1H-咪唑-2-基)乙酮
將1-(4-溴-1-甲基-1H-咪唑-2-基)乙酮(INT-6-4-1)(500mg,2.46mmol)、環丙基硼酸(635mg,7.39mmol)、雙(二-第三丁基(4-二甲基胺基苯基)膦)二氯化鈀(II)(101mg,0.12mmol)的二噁烷(10mL)-飽和的NaHCO3溶液(10mL)的混合物回流2天。用H2O稀釋混合物,並用EtOAc(×2)萃取。使合併之有機溶液在Na2SO4上乾燥,過濾之後濃縮。將0-50%醋酸乙酯的己烷溶液用作洗脫劑,藉由柱色譜法在矽膠上提純殘餘油而得到黃色油的標題化合物(103mg,26%的收率)。
1H-NMR(600MHz,CDCl3):delta 6.70(s,1H),3.91(s,3H),2.61(s,3H),1.88-1.82(m,1H),0.91-0.86(m,2H),0.73-0.69(m,2H)。
MS(ESI)m/z:165.2(M+H)+。
<步驟-2>:中間體-6-5(INT-6-5):1-(5-溴-4-環丙基-1-甲基-1H-咪唑-2-基)乙酮
在1-(4-環丙基-1-甲基-1H-咪唑-2-基)乙酮(INT-6-5-1)(103mg,0.63mmol)的MeCN(5mL)的溶液中添加N-溴代琥珀醯亞胺(128mg,0.72mmol)。在60℃下將混合物攪拌30min。在真空中去除溶劑之後,將0-25%醋酸乙酯的己烷溶液用作洗脫劑,藉由柱色譜法在矽膠上提純殘餘固體而得到淺黃色油的標題化合物(96mg,63%的收率)。
1H-NMR(270MHz,CDCl3):delta 3.94(s,3H),2.57(s,3H),1.92-1.80(m,1H),0.95-0.88(m,4H)。
MS(ESI)m/z:243.1(M+H)+。
中間體-6-6(INT-6-6):1-(5-氯-1-甲基-1H-咪唑-2-基)乙酮
在0℃下,在5-氯-1-甲基-1H-咪唑(500mg,4.29mmol)和乙醯氯-(0.31mL,4.29mmol)的DCM(30mL)的溶液中添加DIPEA(1.50mL,8.58mmol)。在室溫下將混合物攪拌1天。用2M NaOH水溶液使混合物淬滅,並用DCM萃取。使合併之有機溶液在Na2SO4上乾燥,過濾之後濃縮。將0-30%醋酸乙酯的己烷溶液用作洗脫劑,藉由柱色譜法在矽膠上提純殘餘油而得到米色固體的標題化合物(172mg,25%的收率)。
1H-NMR(270MHz,CDCl3):delta 7.11(s,1H),3.95(s,3H),2.63(s,3H)。
MS(ESI)m/z:159.2(M+H)+。
中間體-6-15(INT-6-15):1-(4-(噠嗪-3-基氧基)苯基)乙酮
在140℃下,在微波反應器(Biotage Initiator)中將1-(4-羥基苯基)乙酮(283mg,2.08mmol)、3-氯噠嗪(238mg,2.08mmol)及碳酸鉀(574mg,4.16mmol)的DMF(5mL)的混合物照射60min。冷卻之後,藉由矽藻土墊過濾反應混合物,並用EtOAc清洗濾餅。用水和鹽水清洗濾液和清洗液,在硫酸鈉上乾燥,過濾之後在真空中濃
縮。將10-80%醋酸乙酯的DCM溶液用作洗脫劑,藉由柱色譜法(Biotage)在矽膠(25g)上提純殘留物而得到白色固體的標題化合物(58mg,13%的收率)。
1H-NMR(270MHz,DMSO-d 6):delta 9.07(dd,J=4.6,1.3Hz,1H),8.06(d,J=8.5Hz,2H),7.84(dd,J=9.2,4.6Hz,1H),7.59-7.55(m,1H),7.36(d,J=8.5Hz,2H),2.60(s,3H)。
MS(ESI)m/z:215.1(M+H)+。
按照中間體6-4-A(方法C)或中間體6-1-A(方法A)的流程,從表7中的周知或合成之甲基酮衍生物製備以下alpha-溴甲基酮衍生物(INT-6-16-A至INT-6-31-A)。
酮衍生物的合成
中間體-6-19(INT-6-19):1-(4-(2-甲基-3H-咪唑并[4,5-b]吡啶-3-基)苯基)乙酮
<步驟-1>:中間體-6-19-1(INT-6-19-1):1-(4-((2-硝基苯
基)胺基)苯基)乙酮
在100℃下,將2-氯-3-硝基吡啶(951mg,6.00mmol)、1-(4-胺基苯基)乙酮(811mg,6.00mmol)、碘化鈉(90mg,0.60mmol),外消旋-BINAP(224mg,0.36mmol)、乙酸鈀(81mg,0.36mmol)及碳酸鉀(1659mg,12.0mmol)的甲苯(30mL)的混合物加熱20h。冷卻至室溫之後,用EtOAc和水稀釋混合物,並藉由矽藻土墊過濾。用EtOAc清洗濾餅,用鹽水清洗濾液和清洗液,在硫酸鈉上乾燥,過濾之後在真空中濃縮而得到粗製產物。將3-5%醋酸乙酯的DCM溶液用作洗脫劑,藉由柱色譜法(Biotage)在矽膠(100g)上提純該粗製產物而得到微紅的黃色固體的標題化合物(1273mg,82%的收率)。
1H-NMR(270MHz,CDCl3):delta 10.36(br.s,1H),8.62-8.54(m,2H),8.05-7.96(m,2H),7.88-7.80(m,2H),7.00-6.92(m,1H),2.61(s,3H)。
MS(ESI)m/z:258.1(M+H)+。
<步驟-2>:中間體-6-19-2(INT-6-19-2):1-(4-((2-胺基苯基)胺基)苯基)乙酮
在回流下,將INT-6-19-1(2.6g,10.11mmol)、鐵(3.39g,
60.6mmol)及固體氯化銨(1.62g,30.3mmol)的EtOH/水(4/1v/v)(50mL)的混合物加熱2.5h。冷卻至室溫之後,藉由矽藻土墊過濾反應混合物,使濾液濃縮。將殘留物在EtOAc和2M NaOH水溶液之間分配。用鹽水清洗有機層,在硫酸鈉上乾燥,過濾之後在真空中濃縮而得到棕色固體的標題化合物(2.22g,97%的收率)。
1H-NMR(270MHz,DMSO-d 6):delta 8.28(s,1H),7.85(d,J=8.5Hz,2H),7.69(d,J=8.5Hz,2H),7.57(dd,J=4.6,1.3Hz,1H),6.98(dd,J=7.9,1.3Hz,1H),6.75(dd,J=7.9,4.6Hz,1H),5.20(s,2H),2.46(s,3H)。
MS(ESI)m/z:228.1(M+H)+。
<步驟-3>:中間體-6-19-3(INT-6-19-3):N-(2-((4-乙醯基苯基)胺基)苯基)乙醯胺
在室溫下,將INT-6-19-2(2.22g,9.77mmol)、乙酸酐(1.05g,10.26mmol)及三乙胺(2.97g,29.3mmol)的DCM(40mL)的混合物攪拌4h。在真空中使混合物濃縮而得到標題化合物,其沒有進一步提純而使用於接下來的步驟。
1H-NMR(270MHz,DMSO-d6):delta 9.56(s,1H),8.62(s,1H),8.08(d,J=3.3Hz,1H),7.89(d,J=9.2Hz,2H),7.76-7.71(m,3H),6.95(dd,J=7.3,4.6Hz,1H),2.50(s,3H),2.12(s,3H)。
MS(ESI)m/z:270.1(M+H)+。
<步驟-4>:中間體-6-19(INT-6-19):1-(4-(2-甲基-3H-咪唑
并[4,5-b]吡啶-3-基)苯基)乙酮
在100℃下,將INT-6-19-3(2.63g,9.77mmol)的乙酸(40mL)溶液攪拌15h。冷卻之後,在真空中使反應混合物濃縮。用EtOAc稀釋殘餘油,用飽和的NaHCO3溶液使混合物鹼化至pH>10。用鹽水清洗萃取之有機層,在硫酸鈉上乾燥,過濾之後在真空中濃縮。將10-100%醋酸乙酯的DCM溶液用作洗脫劑,藉由柱色譜法(Biotage)在矽膠(100g)上提純殘餘固體而得到淡棕色固體的標題化合物(2.32g,95%的收率)。
1H-NMR(270MHz,DMSO-d 6):delta 8.25(dd,J=5.3,1.3Hz,1H),8.18(d,J=8.5Hz,2H),8.06(dd,J=7.9,1.3Hz,1H),7.77(d,J=8.5Hz,2H),7.32(dd,J=7.9,5.3Hz,1H),2.68(s,3H),2.53(s,3H)。
MS(ESI)m/z:252.1(M+H)+。
中間體-6-18(INT-6-18):1-(4-(3H-咪唑并[4,5-b]吡啶-3-基)苯基)乙酮
在回流下,將INT-6-19-2(1.49g,6.56mmol)和三乙氧基甲烷(30mL,180mmol)加熱15h。冷卻之後,用EtOAc和水稀釋反應混合物。使有機層分層,並用EtOAc萃取水層。用鹽水清洗合併之有機溶液,在硫酸鈉上乾燥,過濾之後在真空中濃縮。將10-80%醋酸乙酯的DCM溶液用作洗脫劑,藉由柱色譜法(Biotage)在矽膠(50g)上提純殘餘油而得到淺棕色固體的標題化合物(1.32g,85%的收率)。
1H-NMR(270MHz,DMSO-d 6):delta 9.07(s,1H),8.49(dd,J=4.6,1.3Hz,1H),8.27-8.17(m,5H),7.44(dd,J=7.9,4.6Hz,1H),2.66(s,3H)。
MS(ESI)m/z:238.1(M+H)+。
中間體-6-20(INT-6-20):1-(4-(1H-咪唑并[4,5-b]吡啶-1-基)苯基)乙酮
在0℃下,在60%氫化鈉(170mg,4.34mmol)的DMF(15mL)的混合物中添加1H-咪唑并[4,5-b]吡啶(310mg,2.61mmol)。添加之後,在0℃下,在混合物中添加1-(4-氟苯基)乙酮(300mg,2.17mmol),在60℃下徹夜攪拌混合物。冷卻之後,用水使反應混合物淬滅,並用EtOAc萃取。用鹽水清洗合併之有機層,在硫酸鈉上乾燥,過濾之後在真空中濃縮。將20%MeOH的DCM用作洗脫劑,藉由柱色譜法(Biotage)在矽膠(25g)上提純殘留物而得到黃色固體的標題化合物(100mg,19%的收率)。
1H-NMR(270MHz,DMSO-d 6):delta 8.99(s,1H),8.55(d,J=4.6Hz,1H),8.22-8.19(m,3H),7.92(d,J=8.6Hz,2H),7.41(dd,J=7.9,4.6Hz),2.67(s,3H)。
MS(ESI)m/z:238.3(M+H)+。
中間體-6-21(INT-6-21):1-(6-(1H-苯并[d]咪唑-1-基)吡啶-3-基)乙酮
在180℃下,在微波反應器(Biotage Initiator)中照射1-(6-氯吡啶-3-基)乙酮(593mg,3.81mmol)、1H-苯并[d]咪唑(150mg,1.27mmol)及K2CO3(702mg,5.08mmol)的DMSO(10mL)的混合物30min。冷卻之後,用水使反應混合物淬滅,並用EtOAc萃取。用鹽水清洗合併之有機層,在硫酸鈉上乾燥,過濾之後在真空中濃縮。將10-100%醋酸乙酯的DCM溶液用作洗脫劑,藉由柱色譜法(Biotage)在矽膠(25g)上提純殘留物而得到黃色固體的標題化合物(217mg,72%的收率)。
1H-NMR(270MHz,DMSO-d 6):delta 9.19(s,1H),9.12(s,1H),8.51(dd,J=8.5,1.3Hz,1H),8.45(d,J=7.9Hz,1H),8.13(d,J=8.5Hz,1H),7.80(d,J=7.9Hz,1H),7.46-7.35(m,2H),2.68(s,3H)。
MS(ESI)m/z:238.1(M+H)+。
中間體-6-22(INT-6-22):1-(6-(2-甲基-1H-苯并[d]咪唑-1-基)吡啶-3-基)乙酮
按照INT-6-21的流程,從1-(6-氯吡啶-3-基)乙酮(200mg,1.29mmol)和2-甲基-1H-苯并[d]咪唑(57mg,0.428mmol)製備標題化合物,得到黃色固體的產物(43mg,40%的收率)。
1H-NMR(270MHz,DMSO-d 6):delta 9.25(d,J=2.0Hz,1H),8.59-8.56(m,1H),7.91(d,J=8.5Hz,1H),7.68-7.65(m,1H),7.55-7.52(m,1H),7.29-7.25(m,2H),2.72(s,3H),2.65(s,3H)。
MS(ESI)m/z:252.0(M+H)+。
中間體-6-23(INT-6-23):1-(4-(2,5-二甲基-3H-咪唑并[4,5-b]吡啶-3-基)苯基)乙酮
<步驟-1>:中間體-6-23-1(INT-6-23-1):1-(4-((6-甲基-3-硝基吡啶-2-基)胺基)苯基)乙酮
按照INT-6-19-1的流程,從2-氯-6-甲基-3-硝基吡啶(951mg,5.51mmol)、1-(4-胺基苯基)乙酮(745mg,5.51mmol)、碘化鈉(83mg,0.551mmol)、外消旋-BINAP(206mg,0.331mmol)、乙酸鈀(74mg,0.331mmol)及碳酸鉀(1659mg,12.0mmol)的甲苯(30mL)溶液製備標題化合物,得到微紅的黃色固體的產物(1290mg,86%的收率)。
1H-NMR(270MHz,CDCl3):delta 10.46(br.s,1H),8.45(d,J=7.9Hz,1H),8.05-7.95(m,2H),7.93-7.85(m,2H),6.79(d,J=7.9Hz,1H),2.61(s,3H),2.59(s,3H)。
MS(ESI)m/z:272.1(M+H)+。
<步驟-2>:中間體-6-23-2(INT-6-23-2):1-(4-((3-胺基-6-甲基吡啶-2-基)胺基)苯基)乙酮
{化學式60}
按照INT-6-19-2的流程,從INT-6-23-1(400mg,1.47mmol)、氯化銨(237mg,4.42mmol)及鐵粉(494mg,8.85mmol)的EtOH(12mL)-水(3mL)溶液製備標題化合物,得到暗黃色無定形固體的產物(369mg,定量)。
1H-NMR(270MHz,CDCl3):delta 7.90(d,J=8.6Hz,2H),7.32(d,J=8.6Hz,2H),7.01(d,J=7.9Hz,1H),6.73(d,J=7.9Hz,1H),6.65(br.s,1H),3.33(br.s,2H),2.55(s,3H),2.43(s,3H)。
MS(ESI)m/z:242.2(M+H)+。
<步驟-3>:中間體-6-23(INT-6-23):1-(4-(2,5-二甲基-3H-咪唑并[4,5-b]吡啶-3-基)苯基)乙酮
按照INT-6-19-3和INT-6-19的流程,從INT-6-23-2(350mg,1.45mmol)製備標題化合物,得到暗黃色固體的產物(179mg,在2個步驟中為47%的收率)。
1H-NMR(270MHz,CDCl3):delta 8.22-8.14(m,2H),7.93(d,J=7.9Hz,1H),7.77-7.69(m,2H),7.17(d,J=7.9Hz,1H),2.68(s,3H),2.48(s,6H)。
MS(ESI)m/z:266.2(M+H)+。
中間體-6-24(INT-6-24):3-(4-乙醯基苯基)-2-甲基-3H-咪唑并[4,5-b]吡啶-5-甲腈
{化學式61}
<步驟-1>:中間體-6-24-1(INT-6-24-1):1-(4-((6-氯-3-硝基吡啶-2-基)胺基)苯基)乙酮
在170℃下,向2,6-二氯-3-硝基吡啶(1500mg,7.77mmol)、1-(4-胺基苯基)乙酮(525mg,3.89mmol)及碳酸鉀(1343mg,9.72mmol)的1,4-二噁烷(16mL)的混合物照射微波60min。通常的處理之後,僅用DCM,藉由柱色譜法在矽膠(100g)上提純粗製產物而得到黃色固體的標題化合物(817mg,72%的收率)。
1H-NMR(270MHz,CDCl3):delta 10.45(br.s,1H),8.51(d,J=8.6Hz,1H),8.08-7.97(m,2H),7.87-7.75(m,2H),6.92(d,J=8.6Hz,1H),2.61(s,3H)。
<步驟-2>:中間體-6-24-2(INT-6-24-2):1-(4-((3-胺基-6-氯吡啶-2-基)胺基)苯基)乙酮
按照INT-6-19-2的流程,從INT-6-24-1(1640mg,5.62mmol)、氯化銨(902mg,16.87mmol)及鐵(1884mg,33.7mmol)的乙醇(60mL)-水(15mL)溶液製備標題化合物,得到綠色固體的產物(1100mg,72%的收率)。
1H-NMR(270MHz,DMSO-d 6):delta 8.45(br.s,1H),7.90(d,J=8.6Hz,2H),7.69(d,J=8.6Hz,2H),7.01(d,J=7.9Hz,1H),6.78(d,J=7.9Hz,1H),5.35(s,2H),2.50(s,3H)。
MS(ESI)m/z:262.2(M+H)+。
<步驟-3>:中間體-6-24-3(INT-6-24-3):1-(4-(5-氯-2-甲基-3H-咪唑并[4,5-b]吡啶-3-基)苯基)乙酮
按照INT-6-19-3的流程(使用乙醯氯來代替乙酸酐)和INT-6-19(在170℃下,在微波系統中照射1h),從INT-6-24-2(1100mg,4.20mmol)製備標題化合物,得到微棕褐色固體的產物(1111mg,在2個步驟中為93%)。
1H-NMR(270MHz,CDCl3):delta 8.24-8.13(m,2H),7.96(d,J=7.9Hz,1H),7.60-7.50(m,2H),7.27(d,J=7.9Hz,1H),2.69(s,3H),2.58(s,3H)。
MS(ESI)m/z:286.2(M+H)+。
<步驟-4>:中間體-6-24(INT-6-24):3-(4-乙醯基苯基)-2-甲基-3H-咪唑并[4,5-b]吡啶-5-甲腈
在140℃下,向INT-6-24-3(555mg,1.94mmol)、氰化鋅(456mg,3.88mmol)及Pd(PPh3)4(449mg,0.388mmol)的DMF(16mL)的混合物照射微波30min。通常的處理之後,將45-50%醋酸乙酯的DCM溶液用作洗脫劑,藉由柱色譜法在矽膠(100g)上提純產物而得到微黃色固體的標題化合物(820mg,76%的收率)。
1H-NMR(270MHz,DMSO-d 6):delta 8.29(d,J=7.9Hz,1H),8.22(d,J=8.6Hz,2H),7.95(d,J=7.9Hz,1H),7.80(d,J=8.6Hz,2H),2.69(s,3H),2.58(s,3H)。
MS(ESI)m/z:277.3(M+H)+。
中間體-6-25(INT-6-25):1-(4-(2-甲基-5-(三氟甲基)-3H-咪唑并[4,5-b]吡啶-3-基)苯基)乙酮
<步驟-1>:中間體-6-25-1(INT-6-25-1):1-(4-((3-硝基-6-(三氟甲基)吡啶-2-基)胺基)苯基)乙酮
按照INT-6-19-1的流程,從2-氯-3-硝基-6-(三氟甲基)吡啶(827mg,3.47mmol)、1-(4-胺基苯基)乙酮(469mg,3.47mmol)、碘化鈉(52mg,0.347mmol)、外消旋-BINAP(130mg,0.208mmol)、乙酸鈀(46.7mg,0.208mmol)及碳酸鉀(959mg,6.94mmol)的甲苯(30mL)溶液製備標題化合物,得到赭色固體的產物(1072mg,95%的收率)。
1H-NMR(270MHz,DMSO-d 6):delta 10.37(br.s,1H),8.74(d,J=8.6Hz,1H),8.08-7.98(m,2H),7.90-7.82(m,2H),7.28(dd,J=8.6,2.0Hz,1H),2.62(s,3H)。
<步驟-2>:中間體-6-25-2(INT-6-25-2):1-(4-((3-胺基-6-
(三氟甲基)吡啶-2-基)胺基)苯基)乙酮
按照INT-6-19-2的流程,從INT-6-25-1(1060mg,3.26mmol)、氯化銨(523mg,9.78mmol)及鐵(1092mg,19.55mmol)的乙醇(40mL)-水(10mL)溶液製備標題化合物,得到暗紅色固體的產物(962mg,定量)。
MS(ESI)m/z:296.2(M+H)+。
<步驟-3>:中間體-6-25-A(INT-6-25-A):1-(4-(2-甲基-5-(三氟甲基)-3H-咪唑并[4,5-b]吡啶-3-基)苯基)乙酮
按照INT-6-19-3(使用乙醯氯來代替乙酸酐)和INT-6-19(在170℃下,在微波系統中照射1h)的流程,從INT-6-25-2(~3.26mmol)製備標題化合物,得到微棕色固體的產物(699mg,在2個步驟中為67%的收率)。
1H-NMR(270MHz,CDCl3):delta 8.24-8.16(m 2H),8.13(d,J=8.6Hz,1H),7.70-7.64(m,1H),7.62-7.55(m,2H),2.70(s,3H),2.65(s,3H)。
MS(ESI)m/z:320.1(M+H)+。
中間體-6-26(INT-6-26):1-(4-((6-甲基吡嗪-2-基)氧基)苯基)乙酮
按照INT-6-15的流程,從1-(4-羥基苯基)乙酮(200mg,
1.47mmol)、2-氯-6-甲基吡嗪(264mg,2.06mmol)及碳酸鉀(406mg,2.94mmol)製備標題化合物,得到淺黃色固體的產物(190mg,57%,40%的化學純度)。
1H-NMR(270MHz,CDCl3):delta 8.39(s,1H),8.35(s,3H),8.04(d,J=8.6Hz,2H),7.32(d,J=8.6Hz,2H),2.59(s,3H),2.36(s,3H)。
MS(ESI)m/z:229.13(M+H)+。
中間體-6-27(INT-6-27):1-(3-(噠嗪-3-基氧基)苯基)乙酮
在160℃下,向1-(3-羥基苯基)乙酮(466mg,3.42mmol)、3-氯噠嗪(784mg,6.85mmol)、tBuXPhos(495mg,1.17mmol)、Pd2(dba)3(313mg,0.342mmol)及K3PO4(2180mg,10.27mmol)的1,4-二噁烷(15mL)的混合物照射微波90min。藉由矽藻土墊過濾混合物,並用EtOAc(50mL)清洗濾餅。用鹽水清洗濾液和清洗液,在Na2SO4上乾燥,過濾之後在真空中濃縮。將5-60%醋酸乙酯的DCM溶液用作洗脫劑,藉由柱色譜法在矽膠(25g)上提純殘留物而得到淺棕色固體的標題化合物(513mg,70%的收率)。
1H-NMR(270MHz,DMSO-d6):delta 9.04(d,J=4.6Hz,1H),7.89(d,J=6.6Hz,1H),7.84-7.76(m,2H),7.63(t,J=7.9Hz,1H),7.56-7.51(m,2H),2.61(s,3H)。
中間體-6-28(INT-6-28):1-(5-氯-6-(吡啶-3-基氧基)吡啶-3-基)乙酮
在室溫下,將1-(5,6-二氯吡啶-3-基)乙酮(100mg,0.526mmol)、吡啶-3-醇(60mg,0.631mmol)、碳酸銫(343mg,1.052mmol)的DMSO(0.5mL)的混合物攪拌2h。用水稀釋混合物,並用DCM萃取。在真空中去除溶劑之後,將0-100%醋酸乙酯的己烷溶液用作洗脫劑,藉由柱色譜法在矽膠上提純殘餘油而得到淺黃色固體的標題化合物(120mg,92%的收率)。
1H-NMR(270MHz,CDCl3):delta 8.58-8.54(m,3H),8.35(d,J=2.0Hz,1H),7.61-7.53(m,1H),7.41(dd,J=8.6,4.6Hz,1H),2.58(s,3H)。
MS(ESI)m/z:249.2(M+H)+。
中間體-6-29(INT-6-29):1-(3-氯-4'-甲基-[2,3'-聯吡啶]-5-基)乙酮
在120℃下,向1-(5,6-二氯吡啶-3-基)乙酮(75mg,0.395mmol)、(4-甲基吡啶-3-基)硼酸(81mg,0.592mmol)、飽和的NaHCO3溶液(0.6mL)及PdCl2(dppf).CH2Cl2(32mg,0.039mmol)的1,4-二噁烷(0.6mL)的混合物照射微波20min。用水稀釋混合物,並用DCM-MeOH萃取。使合併之有機溶液在Na2SO4上乾燥,過濾之後在真空中濃縮。將0-100%醋酸乙酯的己烷溶液用作洗脫劑,藉由柱色譜法在胺基矽膠上提純殘餘油而得到淺黃色固體的標題化合物(64mg,66%的收率)。
MS(ESI)m/z:247.2(M+H)+。
中間體-6-30(INT-6-30):1-(4-(4-甲基噠嗪-3-基)苯基)乙酮
在80℃下,將(4-乙醯基苯基)硼酸(561mg,3.42mmol)、3-氯-4-甲基噠嗪(440mg,3.42mmol)及PdCl2(dppf).CH2Cl2(279mg,0.342mol)的1,4-二噁烷(5mL)和飽和的NaHCO3溶液(5mL)的混合物攪拌3h。用水使混合物淬滅,並用EtOAc萃取。用鹽水清洗有機相,在Na2SO4上乾燥,過濾之後在真空中濃縮而得到黑色固體。將0-80%EtOAc的DCM用作洗脫劑,藉由柱色譜法在矽膠(50g)上提純粗製產物而得到淺棕色固體的標題化合物(265mg,36%的收率)。
1H-NMR(270MHz,DMSO-d 6):delta 9.12(d,J=5.3Hz,1H),8.11(d,J=8.6Hz,2H),7.78(d,J=8.6Hz,2H),7.69(d,J=5.3Hz,1H),2.66(s,3H),2.34(s,3H).
MS(ESI)m/z:213.3(M+H)+。
中間體-7-1-A(INT-7-1-A):3-(2-(4-溴苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
在氮氣氛下,在8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮(INT-1-1-A)(10.2g,49.9mmol)和無水碳酸鉀(20.59g,149.0mmol)的無水DMF(110mL)的攪拌溶液中以滴加方式經10min添加2,4'-二溴苯乙酮(13.84g,49.9mmol)。在80℃下放置2h之後,將混合物注入到粉碎的冰中,並用DCM(2×100mL)萃取。使合併之有機層在無水
Na2SO4上乾燥,過濾之後在真空中蒸發而獲得粗製產物。將10-20%EtOAc的DCMto用作洗脫劑,藉由柱色譜法在矽膠上提純該粗製產物而獲得包含微量不純化合物之產物。最後,用第三丁基甲基醚粉碎該化合物而獲得米色固體的標題化合物(17.0g,79%的收率)。
1H-NMR(270MHz,DMSO-d 6):delta 9.03(s,1H),7.98(d,J=8.6Hz,2H),7.81(d,J=8.6Hz,2H),4.97(s,2H),2.25-1.75(m,8H)。
MS(ESI)m/z:399.0(M-H)-。
按照中間體7-1-A的流程,從表8中的周知或合成之alpha-鹵代乙醯基衍生物和氮雜螺衍生物製備以下乙內醯脲衍生物(INT-7-2-A至INT-7-20-A)。
中間體-7-9(INT-7-9):1-(4-溴-3,5-二甲基噻吩-2-基)-2-氯乙酮
在室溫下,依次用2-氯-1-(3,5-二甲基噻吩-2-基)乙酮(INT-4-6-A)(700mg,3.71mmol)和溴(623mg,3.90mmol)處理三氯化鋁(1.09g,8.16mmol)的氯仿(10mL)的攪拌懸浮液,並攪拌17h之後,注入到冰水中,用DCM稀釋。使有機相分層,並用DCM萃取水相。用水和鹽水清洗合併之有機層,在硫酸鈉上乾燥之後進行濃縮。將0-30%EtOAc的己烷溶液用作洗脫劑,藉由柱色譜法在矽膠上提純粗製產物而得到標題化合物(890mg,90%的收率)。
1H-NMR(270MHz,CDCl3):delta 4.48(s,2H),2.58(s,3H),2.48(s,3H)。
中間體-7-11(INT-7-11):1-(5-溴-1,4-二甲基-1H-吡咯-2-基)-2-氯乙酮
{化學式75}
在-10℃下,將N-溴代琥珀醯亞胺(674mg,3.79mmol)分批添加到INT-5-8-A(500mg,2.91mmol)的THF(50mL)的溶液中。在相同溫度下將混合物攪拌2h。在減壓下去除溶劑之後,將殘留物溶解於DCM(100mL)中,並用水(3×50mL)和鹽水清洗有機相,在Na2SO4上乾燥,過濾之後在真空中濃縮。將10-50%EtOAc的己烷溶液用作洗脫劑,藉由柱色譜法在矽膠上提純殘留物而得到標題化合物(597mg,82%的收率)。
1H-NMR(270MHz,CDCl3):delta 6.88(s,1H),4.42(s,2H),3.95(s,3H),2.07(s,3H)。
中間體-7-12(INT-7-12):1-(5-溴-1,4-二甲基-1H-吡咯-3-基)-2-氯乙酮
在-78℃至環境溫度的溫度下,按照中間體-7-11(INT-7-11)的流程,從INT-5-9-A(193mg,1.13mmol)和N-溴代琥珀醯亞胺(200mg,1.13mmol)製備標題化合物,得到產物(229mg,81%的收率)。
1H-NMR(270MHz,CDCl3):delta 7.38(s,1H),4.36(s,2H),3.64(s,3H),2.27(s,3H)。
中間體-8-1-A(INT-8-1-A):3-(2-(6-氯吡啶-3-基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
{化學式77}
按照中間體-7-1-A的N-烷基化反應所記載之流程,從8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮(INT-1-1-A)(1.62g,5.22mmol)、2-氯-1-(6-氯吡啶-3-基)乙酮(991mg,5.22mmol)及K2CO3(2.16g,15.6mmol)的DMF(15mL)製備標題化合物。將10-80%EtOAc的DCM用作洗脫劑,藉由柱色譜法在矽膠上實施提純而得到淺黃色固體的產物(856mg,46%的收率)。
1H-NMR(270MHz,DMSO-d 6):delta 9.08(d,J=2.6Hz,1H),9.04(s,1H),8.41(dd,J=8.6,2.6Hz,1H),7.76(d,J=8.6Hz,1H),5.05(s,2H),2.25-1.65(m,8H)。
MS(ESI)m/z:358.2(M+H)+。
按照中間體8-1-A的流程,從表9中的周知或合成之alpha-鹵代乙醯基衍生物和乙內醯脲衍生物製備以下乙內醯脲衍生物(INT-8-2-A至INT-8-5-A)。
中間體-9-1-A(INT-9-1-A):3-(2-(5-溴吡嗪-2-基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
<步驟-1>:中間體-9-1-1(INT-9-1-1):2-溴-1-(5-溴吡嗪-2-基)乙醇
在0℃下,在2-溴-1-(5-溴吡嗪-2-基)乙酮氫溴酸鹽(INT-6-8-A)(粗製固體,3.35mmol)的MeOH(15mL)的溶液中添加硼氫化鈉(317mg,8.38mmol)。在室溫下將混合物攪拌1h。用水使混合物
淬滅水,並用DCM萃取。使合併之有機溶液在Na2SO4上乾燥,過濾之後濃縮而得到黃色粗製油的標題化合物(740mg,78%的收率)。
MS(ESI)m/z:282.9(M+H)+。
<步驟-2>:中間體-9-1-2(INT-9-1-2):3-(2-(5-溴吡嗪-2-基)-2-羥基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
在60℃下,將8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮(INT-1-1-A)(536mg,2.62mmol)、2-溴-1-(5-溴吡嗪-2-基)乙醇(INT-9-1-1)(740mg,2.62mmol)及Cs2CO3(1.28g,3.94mmol)的DMSO(5mL)的混合物攪拌1h。用H2O稀釋混合物,並用DCM萃取。使合併之有機溶液在Na2SO4上乾燥,過濾之後在真空中濃縮。將0-70%醋酸乙酯的己烷溶液用作洗脫劑,藉由柱色譜法(Biotage)在矽膠上提純殘餘油而得到淺黃色固體的標題化合物(490mg,46%的收率)。
1H-NMR(270MHz,DMSO-d 6):delta 8.82(s,1H),8.77(s,1H),8.71(s,1H),6.19(d,J=5.3Hz,1H),4.87(td,J=6.6,5.3Hz,1H),3.64(ABqd,J=13.8,6.6Hz,2H),2.20-1.65(m,8H)。
MS(ESI)m/z:406.8(M+H)+。
<步驟-3>:中間體-9-1-A(INT-9-1-A):3-(2-(5-溴吡嗪-2-基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
在60℃下,將INT-9-1-2(560mg,1.38mmol)、2-碘-5-甲基苯磺酸鉀(23mg,0.069mmol)、OXONE(註冊商標)(552mg,0.898mmol)的MeCN(10mL)的混合物攪拌1天。用5%Na2S2O3水溶液-飽和的NaHCO3溶液(1:1v/v)使混合物淬滅,並用DCM萃取。使合併之有機溶液在Na2SO4上乾燥,過濾之後濃縮。將0-50%醋酸乙酯的己烷溶液用作洗脫劑,藉由柱色譜法(Biotage)在矽膠上提純殘餘固體而得到米色固體的標題化合物(397mg,71%的收率)。
1H-NMR(270MHz,DMSO-d 6):delta 9.09(d,J=1.3Hz,1H),9.08(s,1H),8.96(s,1H),5.00(s,2H),2.25-1.78(m,8H)。
MS(ESI)m/z:404.9(M+H)+。
中間體-9-2-A(INT-9-2-A):3-(2-(5-溴-4-甲基噻唑-2-基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
<步驟-1>:中間體-9-2-1(INT-9-2-1):1-(5-溴-4-甲基噻唑-2-基)-2-氯乙醇
按照INT-9-1-1的流程,從INT-6-10-A(1.0g,3.93mmol)製備標題化合物,得到產物(796mg,79%的收率)。
MS(ESI)m/z:258.0(M+H)+。
<步驟-2>:中間體-9-2-2(INT-9-2-2):3-(2-(5-溴-4-甲基噻唑-2-基)-2-羥基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
按照INT-9-1-2的流程,從INT-9-2-1(796mg,3.90mmol)製備標題化合物,得到產物(968mg,59%的收率)。
1H-NMR(270MHz,DMSO-d 6):delta 8.84(br.s,1H),6.75(d,J=5.3Hz,1H),4.95(td,J=7.2,5.3Hz,1H),3.58(dd,J=7.2,1.3Hz,2H),2.24(s,3H),2.25-1.3(m,8H)。
<步驟-3>中間體-9-2-A(INT-9-2-A):3-(2-(5-溴-4-甲基噻唑-2-基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
在室溫下,在INT-9-2-2(600mg,1.41mmol)的DCM(5mL)的懸浮液中添加1,1,1-三乙醯氧基-1,1-二氫-1,2-苯碘醯-3(1H)-酮(戴斯-馬丁試劑)(1.02g,2.40mmol)。在室溫下將混合物攪拌1h。用5%Na2S2O3水溶液,接著用飽和的NaHCO3溶液使混合物淬滅。用DCM萃取生成之混合物,使合併之有機溶液在Na2SO4上乾燥,過濾之後濃縮。用醋酸乙酯(6mL)使殘餘固體再結晶而得到白色固體的標題化合物(230mg,38.5%的收率)。使母液濃縮,將20-80%EtOAc的己烷溶液用作洗脫劑,藉由柱色譜法在矽膠上提純生成之固體而第二次得到白色固體的標題化合物(279mg,46.7%的收率)。
1H-NMR(270MHz,CDCl3):delta 6.36(br.s,1H),5.02(s,2H),2.50(s,3H),2.50-2.15(m,4H),2.10-1.90(m,4H)。
按照中間體9-1-1的流程,從表10中的合成之alpha-鹵代乙醯基衍
生物製備以下醇衍生物(INT-10-1-A至INT-10-6-A)。
按照中間體9-1-2的流程,從表11中的合成之2-鹵代乙醇衍生物和INT-1-4-A製備以下醇衍生物(INT-11-1-A至INT-11-6-A)。
中間體12-1-A(INT-12-1-A):8,8-二氟-3-(2-側氧基-2-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)苯基)乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
{化學式86}
在80℃下,將3-(2-(4-溴苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮(INT-7-1-A)(2.00g,4.99mmol)、雙聯頻哪醇硼酸酯(1.46g,5.73mmol)、乙酸鉀(1.22g,12.5mmol)及PdCl2(dppf).CH2Cl2(204mg,0.249mmol)的1,4-二噁烷(20mL)的混合物攪拌3h。冷卻至室溫之後,藉由矽藻土墊過濾反應混合物,用1,4-二噁烷清洗過濾墊。在真空中使濾液和清洗濃縮而得到殘餘油,用DCM/己烷粉碎該殘餘油而得到淺黃色固體的標題化合物(2.03g,91%的收率)。
1H-NMR(270MHz,DMSO-d 6):delta 9.02(s,1H),8.04(d,J=7.9Hz,2H),7.84(d,J=7.9Hz,2H),4.97(s,2H),2.25-1.75(m,8H),1.32(s,12H)。
MS(ESI)m/z:449.2(M+H)+。
中間體-12-2-A(INT-12-2-A):8,8-二氟-3-(2-側氧基-2-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)苯基)乙基)-1-氧雜-3-氮雜螺[4.5]癸烷-2-酮
<步驟-1>:中間體-12-2-1(INT-12-2-1):3-(2-(4-溴苯基)-2-羥基乙基)-8,8-二氟-1-氧雜-3-氮雜螺[4.5]癸烷-2-酮
{化學式88}
在75℃下,將INT-1-4-A(500mg,2.62mmol)、碳酸銫(1.70g,5.23mmol)及2-(4-溴苯基)環氧乙烷(599mg,3.01mmol)的DMSO(5mL)的混合物攪拌5h。用水稀釋混合物,並用EtOAc-己烷(2:1)萃取。用鹽水清洗合併之有機溶液,在Na2SO4上乾燥,過濾之後濃縮。將0-70%梯度的EtOAc的己烷溶液用作洗脫劑,藉由柱色譜法在矽膠上實施提純而得到米色固體的標題化合物(972mg,95%的收率)。
1H-NMR(270MHz,CDCl3):delta 7.51(d,J=7.9Hz,2H),7.27(d,J=7.9Hz,2H),5.03-4.92(m,1H),3.59-3.23(m,4H),2.90(br.s,1H),2.31-1.95(m,6H),1.83-1.68(m,2H)。
MS(ESI)m/z:390.1(M+H)+。
<步驟-2>:中間體-12-2-2(INT-12-2-2):3-(2-(4-溴苯基)-2-側氧基乙基)-8,8-二氟-1-氧雜-3-氮雜螺[4.5]癸烷-2-酮
在室溫下,在INT-12-2-1(390mg,0.999mmol)的DCM(20mL)溶液中添加戴斯-馬丁氧化劑(721mg,1.699mmol)。在室溫下將混合物攪拌1h。用5%Na2S2O3水溶液,接著用飽和的NaHCO3溶液使混合物淬滅,並用EtOAc萃取。使有機層在Na2SO4上乾燥,過濾之後濃縮。將0-50%梯度的EtOAc的己烷溶液用作洗脫劑,藉由柱色譜法在矽膠上實施提純而得到米色固體的標題化合物(315mg,81%的收率)。
1H-NMR(270MHz,CDCl3):delta 7.80(d,J=8.6Hz,2H),7.64(d,J=8.6Hz,2H),4.67(s,2H),3.47(s,2H),2.38-2.00(m,6H),2.00-1.80(m,2H)。
MS(ESI)m/z:390.1(M+H)+。
<步驟-3>:中間體-12-2-A(INT-12-2-A):8,8-二氟-3-(2-側氧基-2-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)苯基)乙基)-1-氧雜-3-氮雜螺[4.5]癸烷-2-酮
在80℃下,將INT-12-2-2(200mg,0.515mmol)、雙聯頻哪醇硼酸酯(150mg,0.592mmol)、PdCl2(dppf).CH2Cl2(21mg,0.026mmol)及乙酸鉀(126mg,1.288mmol)的1,4-二噁烷(3mL)的混合物攪拌3h。反應混合物(在二噁烷中為3mL)用於接下來的Suzuki-Miyaura交叉偶聯反應。
中間體12-3-A(INT-12-3-A):3-(2-(4-(5,5-二甲基-1,3,2-二氧雜己硼烷-2-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
在80℃下,將INT-7-4-A(1.15g,3.15mmol)、PdCl2(dppf).CH2Cl2(203mg,0.252mmol)、乙酸鉀(1.24g,12.6mmol)及5,5,5',5'-四甲基-2,2'-雙(1,3,2-二氧雜己硼烷)(854mg,3.78mmol)的DMSO(10mL)的混合物攪拌1.5h。用水稀釋混合物,並用EtOAc-己烷(2:1)萃取。使合併之有機溶液在Na2SO4上乾燥,過濾之後濃縮。將0-70%梯度的EtOAc的己烷溶液用作洗脫劑,藉由柱色譜法在矽膠上實施提純而得到淺黃色固體的標題化合物(475mg,38%的收
率)。
中間體-12-4-A(INT-12-4-A):3-(2-側氧基-2-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)苯基)乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
在80℃下,將INT-7-4-A(120mg,0.329mmol)、PdCl2(dppf)CH2Cl2(21mg,0.026mmol)、乙酸鉀(97mg,0.986mmol)及雙聯頻哪醇硼酸酯(100mg,0.394mmol)的DMSO(1mL)的混合物攪拌4h。完成反應之後,反應混合物沒有進行進一步提純而用於接下來的Suzuki-Miyaura交叉偶聯反應。
中間體-12-5-A(INT-12-5-A):8,8-二氟-3-(2-(3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
在80℃下,將INT-7-6-A(50mg,0.119mmol)、雙聯頻哪醇硼酸酯(36mg,0.143mmol)、PdCl2(dppf).CH2Cl2(8mg,0.0095mmol)及乙酸鉀(35mg,0.358mmol)的1,4-二噁烷(2mL)的混合物攪拌3h。冷卻之後,反應混合物沒有進行進一步提純而用於接下來的步驟。
MS(ESI)m/z:383.2(M-H)-(硼酸衍生物)。
中間體-12-6-A(INT-12-6-A):8,8-二氟-3-(2-(2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
在80℃下,將INT-7-18-A(120mg,0.286mmol)、雙聯頻哪醇硼酸酯(84mg,0.329mmol)、PdCl2(dppf).CH2Cl2(19mg,0.023mmol)及乙酸鉀(84mg,0.859mmol)的DMF(0.9mL)的混合物攪拌1.5h。冷卻之後,反應混合物沒有進行進一步提純而用於接下來的步驟。
中間體-12-7-A(INT-12-7-A):8,8-二氟-3-(2-側氧基-2-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)苯基)乙基)-1-氧雜-3-氮雜螺[4.5]癸烷-2,4-二酮
在80℃下,將INT-7-16-A(303mg,0.753mmol)、雙聯頻哪醇硼酸酯(230mg,0.904mmol)、PdCl2(dppf).CH2Cl2(49mg,0.060mmol)及乙酸鉀(222mg,2.26mmol)的1,4-二噁烷(3mL)的混合物攪拌1.5h。冷卻之後,在真空中使反應混合物濃縮。將0-30%醋酸乙酯的己烷溶液用作洗脫劑,藉由柱色譜法在矽膠上提純殘餘油而得到黃色固體的標題化合物(332mg,98%)。
MS(ESI)m/z:448.1(M-H)-。
中間體-13-1-A(INT-13-1-A):3-(2-(4-溴苯基)-2-側氧基乙基)-1-氧雜-3-氮雜螺[4.5]癸烷-2-酮
<步驟-1>:中間體-13-1-1(INT-13-1-1):3-(2-(4-溴苯基)-2-羥基乙基)-1-氧雜-3-氮雜螺[4.5]癸烷-2-酮
在75℃下,將1-氧雜-3-氮雜螺[4.5]癸烷-2-酮(200mg,1.29mmol)、碳酸銫(840mg,2.58mmol)及2-(4-溴苯基)環氧乙烷(385mg,1.93mmol)的DMSO(2mL)的混合物攪拌3h。用水稀釋混合物,並用EtOAc-己烷萃取(2:1)。用鹽水清洗合併之有機溶液,在Na2SO4上乾燥,過濾之後濃縮。將0-80%梯度的EtOAc的己烷溶液用作洗脫劑,藉由柱色譜法在矽膠上實施提純而得到米色固體的標題化合物(441mg,97%的收率)。
1H-NMR(270MHz,CDCl3):delta 7.50(d,J=7.9Hz,2H),7.28(d,J=7.9Hz,2H),4.97(dt,J=7.9,3.3Hz,1H),3.52(dd,J=15.2,3.3Hz,1H),3.39(dd,J=15.2,7.9Hz,1H),3.19(s,2H),3.20-3.14(m,1H),1.85-1.63(m,4H),1.60-1.32(m,6H)。
MS(ESI)m/z:356.0(M+H)+。
<步驟-2>:中間體-13-1-A(INT-13-1-A):3-(2-(4-溴苯基)-2-側氧基乙基)-1-氧雜-3-氮雜螺[4.5]癸烷-2-酮
在室溫下,在INT-13-1-1(116mg,0.327mmol)的DCM(5mL)
溶液中添加戴斯-馬丁氧化劑(278mg,0.655mmol)。在室溫下將混合物攪拌3h。用5%Na2S2O3水溶液,接著用飽和的NaHCO3溶液使混合物淬滅,並用EtOAc萃取。使合併之有機層Na2SO4上乾燥,過濾之後濃縮。將0-50%梯度的EtOAc的己烷溶液用作洗脫劑,藉由柱色譜法在矽膠上實施提純而得到米色固體的標題化合物(106mg,92%的收率)。
1H-NMR(270MHz,CDCl3):delta 7.81(d,J=8.5Hz,2H),7.64(d,J=8.5Hz,2H),4.65(s,2H),3.39(s,2H),2.00-1.32(m,10H)。
MS(ESI)m/z:354.0(M+H)+。
中間體-13-2-A(INT-13-2-A):3-(2-(4-溴苯基)-2-側氧基乙基)-8,8-二氟-4-甲基-1-氧雜-3-氮雜螺[4.5]癸烷-2-酮
<步驟-1>:中間體-13-2-1(INT-13-2-1):3-(2-(4-溴苯基)-2-羥基乙基)-8,8-二氟-4-甲基-1-氧雜-3-氮雜螺[4.5]癸烷-2-酮
在75℃下,將INT-1-6-A(150mg,0.731mmol)、2-(4-溴苯基)環氧乙烷(145mg,0.731mmol)及碳酸銫(476mg,1.462mmol)的DMSO(5mL)的混合物攪拌5h。用水稀釋混合物,並用EtOAc-己烷萃取(2:1)。用鹽水清洗有機層,在Na2SO4上乾燥,過濾之後在真空中濃縮。將0-70%梯度的EtOAc的己烷溶液用作洗脫劑,藉由柱色譜
法在矽膠上實施提純而得到米色固體的標題化合物(245mg,83%的收率,非對映物的混合物)。
MS(ESI)m/z:387.9(M+H-OH)+。
<步驟-2>:中間體-13-2-A(INT-13-2-A):3-(2-(4-溴苯基)-2-側氧基乙基)-8,8-二氟-4-甲基-1-氧雜-3-氮雜螺[4.5]癸烷-2-酮
在室溫下,在INT-13-2-1(245mg,0.606mmol)的DCM(10mL)溶液中添加戴斯-馬丁氧化劑(450mg,1.061mmol)。將混合物攪拌1h。用5%Na2S2O3水溶液,接著用飽和的NaHCO3溶液使混合物淬滅,並用DCM萃取。使合併之有機層在Na2SO4上乾燥,過濾之後在真空中濃縮。將0-50%梯度的EtOAc的己烷溶液用作洗脫劑,藉由柱色譜法在矽膠上實施提純而得到米色固體的標題化合物(217mg,89%的收率)。
1H-NMR(270MHz,CDCl3):delta 7.82(d,J=8.6Hz,2H),7.65(d,J=8.6Hz,2H),4.92(d,J=18.5Hz,1H),4.33(d,J=18.5Hz,1H),3.82(q,J=6.6Hz,1H),2.40-1.98(m,6H),1.93-1.66(m,2H),1.15(d,J=6.6Hz,3H)。
MS(ESI)m/z:403.8(M+H)+。
中間體-13-3-A(INT-13-3-A):3-(2-(4-溴苯基)-2-側氧基乙基)-8,8-二氟-4,4-二甲基-1-氧雜-3-氮雜螺[4.5]癸烷-2-酮
<步驟-1>:中間體-13-3-1(INT-13-3-1):3-(2-(4-溴苯基)-2-羥基乙基)-8,8-二氟-4,4-二甲基-1-氧雜-3-氮雜螺[4.5]癸烷-2-酮
在85℃下,將INT-1-7-A(175mg,0.798mmol)、2-(4-溴苯基)環氧乙烷(159mg,0.798mmol)及碳酸銫(520mg,1.597mmol)的DMSO(2mL)的混合物攪拌1天。用水稀釋混合物,並用EtOAc-己烷(2:1)萃取。用鹽水清洗合併之有機溶液,在Na2SO4上乾燥,過濾之後在真空中濃縮而得到粗製油的標題化合物。
MS(ESI)m/z:419.8(M+H)+。
<步驟-2>:中間體-13-3-A(INT-13-3-A):3-(2-(4-溴苯基)-2-側氧基乙基)-8,8-二氟-4,4-二甲基-1-氧雜-3-氮雜螺[4.5]癸烷-2-酮
在室溫下,在INT-13-3-1(粗製)的DCM(10mL)溶液中添加戴斯-馬丁氧化劑(592mg,1.397mmol)。在室溫下將混合物攪拌1h。用5%Na2S2O3水溶液,接著用飽和的NaHCO3溶液使混合物淬滅,並用DCM萃取。使合併之有機溶液在Na2SO4上乾燥,過濾之後在真空中濃縮。將0-40%梯度的EtOAc的己烷溶液用作洗脫劑,藉由柱色譜法在矽膠上實施提純而得到淺黃色固體的標題化合物(265mg,在2個步驟中為80%的收率)。
1H-NMR(270MHz,CDCl3):delta 7.83(d,J=8.6Hz,2H),7.65(d,J=8.6Hz,2H),4.52(s,2H),2.39-2.02(m,6H),1.85-1.64(m,2H),1.17(s,6H)。
MS(ESI)m/z:417.8(M+H)+。
中間體-13-4-A(INT-13-4-A):3-(2-(4-溴苯基)-2-側氧基乙基)-8,8-二氟-4-異丙基-1-氧雜-3-氮雜螺[4.5]癸烷-2-酮
{化學式101}
<步驟-1>:中間體-13-4-1(INT-13-4-1):3-(2-(4-溴苯基)-2-羥基乙基)-8,8-二氟-4-異丙基-1-氧雜-3-氮雜螺[4.5]癸烷-2-酮
在85℃下,將INT-1-8-A(186mg,0.798mmol)、2-(4-溴苯基)環氧乙烷(159mg,0.798mmol)及碳酸銫(520mg,1.597mmol)的DMSO(2mL)的混合物攪拌1天。用水稀釋混合物,並用EtOAc-己烷(2:1)萃取。用鹽水清洗合併之有機溶液,在Na2SO4上乾燥,過濾之後在真空中濃縮而得到粗製油的標題化合物。
MS(ESI)m/z:433.8(M+H)+。
<步驟-2>:中間體-13-4-A(INT-13-4-A):3-(2-(4-溴苯基)-2-側氧基乙基)-8,8-二氟-4-異丙基-1,3-二氮雜螺[4.5]癸烷-2-酮
在室溫下,在INT-13-4-1(粗製)的DCM(10mL)溶液中添加戴斯-馬丁氧化劑(592mg,1.397mmol)。在室溫下將混合物攪拌1h。用5%Na2S2O3水溶液,接著用飽和的NaHCO3溶液使混合物淬滅,並用DCM萃取。使合併之有機溶液在Na2SO4上乾燥,過濾之後在真空中濃縮。將0-40%梯度的EtOAc的己烷溶液用作洗脫劑,藉由柱色譜法在矽膠上實施提純而得到淺黃色固體的標題化合物(268mg,在2個步驟中為78%的收率)。
1H-NMR(270MHz,CDCl3):delta 7.81(d,J=8.6Hz,2H),7.65(d,J=8.6Hz,2H),5.22(d,J=18.5Hz,1H),4.40(d,J=18.5Hz,1H),3.60(d,J=2.0Hz,1H),2.62-2.49(m,1H),
2.41-1.72(m,8H),1.04(d,J=6.6Hz,6H)。
MS(ESI)m/z:431.8(M+H)+。
中間體-14-1-A(INT-14-1-A):8,8-二氟-3-(2-(4-羥基苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
在2-溴-1-(4-((第三丁基二苯基矽基)氧基)苯基)乙酮(1295mg,2.86mmol)的DMF(30mL)的攪拌溶液中添加INT-1-1-A(612mg,3.00mmol)和碳酸鉀(987mg,7.14mmol)。在85℃下將混合物加熱3.5h。冷卻至室溫之後,用1M HCl水溶液使混合物淬滅,並用醋酸乙酯-甲苯(8:1)萃取。用水和鹽水清洗合併之有機溶液,在硫酸鈉上乾燥,過濾之後在真空中濃縮而得到粗製產物(淺黃色油)。用30-70%醋酸乙酯的己烷溶液,藉由柱色譜法在矽膠上(100g)提純該粗製產物而得到白色固體的標題化合物(789mg,82%的收率)。
1H-NMR(270MHz,DMSO-d 6):delta 10.58(br.s,1H),8.98(s,1H),7.92(d,J=8.6Hz,2H),6.89(d,J=8.6Hz,2H),4.84(s,2H),2.25-1.70(m,8H)。
MS(ESI)m/z:339.06(M+H)+。
中間體-15-1-A(INT-15-1-A):3-(2-(4-((3-胺基吡啶-2-基)胺基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
{化學式104}
<步驟-1>:中間體-15-1-1(INT-15-1-1):2-溴-1-(4-((3-硝基吡啶-2-基)胺基)苯基)乙酮
在室溫下,將1-(4-((3-硝基吡啶-2-基)胺基)苯基)乙酮(INT-6-19-1)(1.0g,3.89mmol)及溴(0.621g,3.89mmol)的25%HBr-AcOH(20mL)的混合物攪拌1.5h。藉由氮流使反應混合物濃縮。用IPE和MeOH(2/1 v/v)的混合物粉碎殘留物而得到黃色固體的標題化合物的一氫溴酸鹽(mono-hydrobromide)(1.56g,定量)。
1H-NMR(270MHz,DMSO-d 6):delta 10.1(s,1H),8.63-8.59(m,2H),8.01(d,J=8.5Hz,2H),7.90(d,J=8.5Hz,2H),7.14(dd,J=7.9,4.6Hz,1H),4.89(s,2H)。
MS(ESI)m/z:337.9(M+H)+。
<步驟-2>:中間體-15-1-2(INT-15-1-2):8,8-二氟-3-(2-(4-((3-硝基吡啶-2-基)胺基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
在120℃下,在微波照射下將INT-1-1-A(104mg,0.507mmol)、INT-15-1-1(235mg,0.563mmol)及碳酸鉀(234mg,1.69mmol)的
DMF(5mL)的混合物攪拌20min。冷卻之後,用水使反應混合物淬滅,並用EtOAc萃取。用鹽水清洗合併之有機層,在硫酸鈉上乾燥,過濾之後在真空中濃縮。將10-80%醋酸乙酯的DCM溶液用作洗脫劑,藉由柱色譜法(Biotage)在矽膠(10g)上提純殘留物而得到淺黃色固體的標題化合物(0.138g,53%的收率)。
1H-NMR(270MHz,DMSO-d 6):delta 10.2(s,1H),9.02(s,1H),8.62-8.57(m,2H),8.05(d,J=8.5Hz,2H),7.94(d,J=8.5Hz,2H),7.15(dd,J=7.9,4.6Hz,1H),4.94(s,2H),2.18-1.81(m,8H)。
MS(ESI)m/z:460.0(M+H)+。
<步驟-3>:中間體-15-1-A(INT-15-1-A):3-(2-(4-((3-胺基吡啶-2-基)胺基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
在回流下,將INT-15-1-2(138mg,0.300mmol)、鐵(101mg,1.80mmol)及固體氯化銨(48mg,0.901mmol)的EtOH/水(4/1v/v)(10mL)的混合物加熱2.5h。冷卻至室溫之後,藉由矽藻土墊過濾反應混合物,並在真空中使濾液和清洗液濃縮。將殘留物在EtOAc和2M NaOH水溶液之間分配。用鹽水清洗分層之有機層,在硫酸鈉上乾燥,過濾之後在真空中濃縮而得到棕色固體的標題化合物(75mg,58%的收率)。
1H-NMR(270MHz,DMSO-d 6):delta 8.98(s,1H),8.41(s,1H),7.92(d,J=9.2Hz,2H),7.72(d,J=9.2Hz,2H),7.59(dd,J=4.6,1.3Hz,1H),7.02-6.98(m,1H),6.78(dd,J=7.9,4.6Hz,1H),5.22(s,2H),4.84(s,2H),2.17-1.85(m,8H)。
MS(ESI)m/z:430.1(M+H)+。
中間體-15-2-A(INT-15-2-A):3-(2-(4-((3-胺基-6-甲基吡啶
-2-基)胺基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
<步驟-1>:中間體-15-2-1(INT-15-2-1):2-溴-1-(4-((6-甲基-3-硝基吡啶-2-基)胺基)苯基)乙酮氫溴酸鹽
按照INT-15-1-1的流程,從INT-6-23-1(740mg,2.73mmol)、溴(126microL,2.46mmol)的25%HBr-AcOH(20mL)製備標題化合物,得到黃色固體的產物(1232mg,定量,一溴化產物的化學純度:90%)。該物質沒有進行進一步提純而用於接下來的步驟。
1H-NMR(270MHz,DMSO-d 6):delta 10.23(br.s,1H),8.53-8.45(m,1H),8.06-7.92(m,4H),7.04-6.96(m,1H),4.90(s,2H),2.52(s,3H)。
MS(ESI)m/z:350.1(M+H)+。
<步驟-2>:中間體-15-2-2(INT-15-2-2):8,8-二氟-3-(2-(4-((6-甲基-3-硝基吡啶-2-基)胺基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
按照INT-15-1-2的流程,從INT-15-2-1(700mg,1.62mmol)、INT-1-1-A(298mg,1.46mmol)及碳酸鉀(786mg,5.68mmol)的DMF(15mL)製備標題化合物,得到黃色固體的產物(314mg,41%的收率)。
1H-NMR(270MHz,DMSO-d 6):delta 10.25(br.s,1H),9.02(br.s,1H),8.53-8.46(m,1H),8.10-7.95(m,4H),7.05-6.97(m,1H),4.94(s,2H),2.53(s,3H),2.27-1.75(m,8H)。
MS(ESI)m/z:474.0(M+H)+。
<步驟-3>:中間體-15-2-A(INT-15-2-A):3-(2-(4-((3-胺基-6-甲基吡啶-2-基)胺基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
按照INT-15-1-A(步驟-3)的流程,從INT-15-2-2(310mg,0.655mmol)、氯化銨(105mg,1.96mmol)及鐵(219mg,3.93mmol)的乙醇-水(4:1)(20mL)製備標題化合物,得到暗黃色固體的產物(281mg,97%的收率)。
1H-NMR(270MHz,DMSO-d 6):delta 8.98(br.s,1H),8.37(br.s,1H),7.92(d,J=8.6Hz,2H),7.74(d,J=8.6Hz,2H),6.93(d,J=7.9Hz,1H),6.63(d,J=7.9Hz,1H),4.98(br.s,2H),4.84(br.s,2H),2.29(s,3H),2.26-1.75(m,8H)。
MS(ESI)m/z:444.0(M+H)+。
中間體-16-1-A(INT-16-1-A):4'-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)-[1,1'-聯苯基]-2-羧酸
<步驟-1>:中間體-16-1-1(INT-16-1-1):4'-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)-[1,1'-聯苯基]-2-羧酸第三丁酯
在100℃下,將8,8-二氟-3-(2-側氧基-2-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)苯基)乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮(INT-12-1-A)(300mg,0.67mmol)、2-碘苯甲酸第三丁酯(244mg,0.80mmol)、磷酸鉀(284mg,1.34mmol)及PdCl2(dppf).CH2Cl2(109mg,0.134mmol)的DMF(8mL)的混合物攪拌2h。冷卻至室溫之後,用EtOAc稀釋反應混合物,並用水清洗。使有機層在硫酸鈉上乾燥,過濾之後在真空中濃縮。將50%醋酸乙酯的己烷溶液用作洗脫劑,藉由柱色譜法(Biotage)在矽膠(25g)上提純殘留物而得到白色固體的標題化合物(245mg,73%的收率)。
1H-NMR(270MHz,CDCl3):delta 8.00(d,J=7.9Hz,2H),7.86(d,J=7.9Hz,1H),7.53-7.46(m,4H),7.30(d,J=7.3Hz,1H),6.56(s,1H),4.97(s,2H),2.48-2.21(m,4H),2.12-1.90(m,4H),1.29(s,9H)。
MS(ESI)m/z:497.2(M-H)-。
<步驟-2>:中間體-16-1-A(INT-16-1-A):4'-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)-[1,1'-聯苯基]-2-羧酸
{化學式112}
在室溫下,將INT-16-1-1(245mg,0.491mmol)和TFA(2mL)的DCM(4mL)的混合物攪拌1h。在真空中使溶劑濃縮而得到白色固體的標題化合物(217mg,>99%的收率)。
MS(ESI)m/z:441.2(M-H)-。
中間體-16-2-A(INT-16-2-A):4-(4-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)苯基)-1H-吲哚-2-羧酸
在120℃下,在微波系統中將INT-12-1-A(150mg,0.335mmol)、4-溴-1H-吲哚-2-羧酸(80mg,0.335mmol)、飽和的NaHCO3溶液(0.6mL)及PdCl2(dppf).CH2Cl2(27mg,0.033mmol)的1,4-二噁烷(0.6mL)的混合物照射20min。用2M HCl水溶液使混合物酸化,並用DCM萃取。使有機層在Na2SO4上乾燥,過濾之後在真空中濃縮。藉由PE-AX提純殘餘油而得到棕色固體的標題化合物(100mg,62%)。
MS(ESI)m/z:480.3(M-H)-。
中間體-17-1-A(INT-17-1-A):3-(2-(4-(2-(氯甲基)-5-甲基-3H-咪唑并[4,5-b]吡啶-3-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
{化學式114}
在室溫下,藉由注射器在INT-15-2-A(70mg,0.158mmol)和三乙胺(88microL,0.631mmol)的THF(2.5mL)的攪拌溶液中添加氯乙醯氯(23mg,0.205mmol)的THF(0.5mL)溶液。在室溫下攪拌2h之後,使起始原料在TLC上消失。去除溶劑之後,將粗製產物溶解於AcOH(3mL)中,並在100℃下加熱2h。去除溶劑之後,將殘留物溶解於DCM中,並用飽和的NaHCO3溶液(pH>10)和鹽水清洗。使有機溶液在硫酸鈉上乾燥,過濾之後在真空中濃縮而得到粗製產物。將40-100%醋酸乙酯的DCM溶劑用作洗脫劑,藉由柱色譜法在矽膠(12g)上提純該粗製產物而得到微橙色無定形固體的標題化合物(53.1mg,67%的收率)。
1H-NMR(270MHz,DMSO-d 6):delta 9.05(br.s,1H),8.30(d,J=8.6Hz,2H),8.09(d,J=7.9Hz,1H),7.85(d,J=8.6Hz,2H),7.29(d,J=7.9Hz,1H),5.09(br.s,2H),4.96(br.s,2H),2.52(s,3H),2.28-1.78(m,8H)。
MS(ESI)m/z:502.2(M+H)+。
中間體-17-2-A(INT-17-2-A):(3-(4-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)苯基)-3H-咪唑并[4,5-b]吡啶-2-基)乙酸甲酯
按照INT-17-1的流程,從INT-15-1-A(50mg,0.116mmol)和乙
醯氧基乙醯氯(25.4mg,0.186mmol)製備標題化合物,得到黃色無定形固體的產物(55mg,92%的收率)。
MS(ESI)m/z:512.0(M+H)+。
中間體-17-3-A(INT-17-3-A):(3-(4-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)苯基)-5-甲基-3H-咪唑并[4,5-b]吡啶-2-基)乙酸甲酯
按照INT-17-1的流程,從INT-15-2-A(70mg,0.158mmol)和乙醯氧基乙醯氯(43.1mg,0.316mmol)製備標題化合物,得到微橙色無定形固體的產物(75.9mg,91%的收率)。
MS(ESI)m/z:526.3(M+H)+。
實施例
實施例-1-1:3-(2-(2,5-二甲基-1-(5-甲基異噁唑-3-基)-1H-吡咯-3-基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
在160℃下,在微波反應器(Biotage Initiator,商標)中將2-氯-1-(2,5-二甲基-1-(5-甲基異噁唑-3-基)-1H-吡咯-3-基)乙酮(INT-4-8-A)(200mg,0.791mmol)、8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮(INT-1-1-A)(170mg,0.831mmol)及無水K2CO3(273mg,
1.98mmol)的DMF(8mL)的混合物照射15分鐘。用10%甲苯的EtOAc和水溶液稀釋混合物。使有機層分層,並用10%甲苯的EtOAc(2次)萃取水層。用水,接著用鹽水清洗合併之有機萃取物(2次),在Na2SO4上乾燥,過濾之後在真空中濃縮而得到粗製產物。將50-65%EtOAc的己烷溶液用作洗脫劑,藉由柱色譜法在矽膠上提純該粗製產物而得到黃色無定形固體的標題化合物(257mg,77%的收率)。
1H-NMR(270MHz,DMSO-d 6):delta 8.95(s,1H),6.70(s,1H),6.65(s,1H),4.59(s,2H),2.52(s,3H),2.36(s,3H),2.12(s,3H),2.25-1.70(m,8H)。
MS(ESI)m/z:421.3(M+H)+。
按照實施例-1的流程,從中間體-4-8-A(INT-4-8-A)或表12中的周知之alpha-鹵代酮衍生物和周知或合成之氮雜螺衍生物製備以下實施例(1-2至1-15)。藉由準備好的LC-MS系統,以通常的方式實施提純。將保留時間和藉由HPLC-QC方法觀察到之MS總結於表12。
按照實施例-1的流程,從表13中的周知或合成之alpha-鹵代酮衍生物和氮雜螺衍生物製備以下實施例(2-1至2-18)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。將保留時間和藉由HPLC-QC方法觀察到之MS總結於表13。
按照實施例-1的流程,從表14中的周知或合成之alpha-鹵代酮衍生物和氮雜螺衍生物製備以下實施例(3-1至3-27)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。將保留時間和藉由HPLC-QC方法觀察到之MS總結於表14。
實施例3-28:3-(2-(1-(6-(環丙基甲氧基)吡啶-2-基)-2,5-二甲基-1H-吡咯-3-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
<步驟-1>:中間體-3-28-1(INT-3-28-1):3-(2-(1-(6-氯吡啶-2-基)-2,5-二甲基-1H-吡咯-3-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
按照實施例-1的流程,從INT-4-7-A(1.00g,3.53mmol)、1,3-二氮雜螺[4.5]癸烷-2,4-二酮(624mg,3.71mmol)及碳酸鉀(1.22g,8.83mmol)的DMF(20mL)製備標題化合物,並在160℃下,在微波照射系統中照射10min。將10-80%醋酸乙酯的DCM溶液用作洗脫劑,藉由柱色譜法(Biotage)在矽膠(100g)上提純殘留物而得到淺黃色無定形固體的化合物(1.33g,91%的收率)。
1H-NMR(270MHz,DMSO-d 6):delta 8.79(s,1H),8.15(t,J=7.2Hz,1H),7.73(d,J=6.6Hz 1H),7.62(d,J=7.2Hz,1H),6.61(s,1H),4.56(s,2H),2.29(s,3H),2.06(s,3H),1.72-1.57(m,8H)。
MS(ESI)m/z:415.2(M+H)+。
<步驟-2>:實施例3-28:3-(2-(1-(6-(環丙基甲氧基)吡啶-2-基)-2,5-二甲基-1H-吡咯-3-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
在0℃下,在60%氫化鈉(14mg,0.362mmol)的DMA(2mL)溶液中添加環丙基甲醇(10mg,0.133mmol)。完成添加之後,在0℃下,在該混合物中添加INT-3-28-1(50mg,0.121mmol),並在室溫下攪拌5h。用飽和的NH4Cl溶液(pH=5~6)使反應混合物淬滅,並用EtOAc萃取。使合併之有機層在硫酸鈉上乾燥,過濾之後在真空中濃縮。將10-80%醋酸乙酯的己烷溶液用作洗脫劑,藉由柱色譜法(Biotage)在矽膠(10g)上提純殘留物而得到淺棕色無定形標題化合物(9mg,16%的收率)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。
觀察到之MS:451.2
tR/方法:1.86min./(QC1)
實施例3-29:3-(2-(1-(6-(3-羥基呱啶-1-基)吡啶-2-基)-2,5-二甲基-1H-吡咯-3-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
{化學式120}
在INT-3-28-1(20mg,0.048mmol)的DMSO(1mL)溶液中添加呱啶-3-醇(8mg,0.096mmol)及碳酸銫(79mg,0.241mmol)。在80℃下將混合物攪拌15h。藉由矽藻土墊過濾反應混合物,並用EtOAc清洗。用水和鹽水清洗濾液和清洗液,在硫酸鈉上乾燥,過濾之後在真空中濃縮。將10-100%醋酸乙酯的己烷溶液用作洗脫劑,藉由柱色譜法(Biotage)在矽膠(10g)上提純殘留物而得到淺黃色無定形固體的標題化合物(8mg,35%的收率)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。
觀察到之MS:480.2
tR/方法:1.58min./(QC1)
按照實施例-1的流程,從表15中的周知或合成之alpha-鹵代酮衍生物和氮雜螺衍生物製備以下實施例(4-1至4-12)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。將保留時間和藉由HPLC-QC方法觀察到之MS總結於表15。
按照實施例-1的流程,從表16中的周知或合成之alpha-鹵代酮衍生物和乙內醯脲衍生物製備以下實施例(5-1至5-5)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。將保留時間和藉由HPLC-QC方法觀察到之MS總結於表16。
按照實施例-1的流程,從表17中的周知或合成之alpha-鹵代酮衍生物和乙內醯脲衍生物製備以下實施例(5-6至5-14)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。將保留時間和藉由HPLC-QC方法觀察到之MS總結於表17。
實施例-5-15:8,8-二氟-3-(2-(4-(2-(羥基甲基)-1H-苯并[d]
咪唑-1-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
<步驟-1>:中間體-5-15-1(INT-5-15-1):N-(2-((4-乙醯基苯基)胺基)苯基)-2-(苄氧基)乙醯胺
在室溫下,將1-(4-((2-胺基苯基)胺基)苯基)乙酮(170mg,0.751mmol)、2-(苄氧基)乙醯氯(170mg,0.902mmol)及三乙胺(228mg,2.25mmol)的DCM(5mL)的混合物攪拌1h。去除溶劑之後,將5-80%醋酸乙酯的DCM溶液用作洗脫劑,藉由柱色譜法(Biotage)在矽膠(25g)上提純殘留物而得到黃色無定形固體的標題化合物(0.289g,定量)。
1H-NMR(270MHz,DMSO-d 6):delta 8.71(s,1H),7.89-7.74(m,3H),7.36-7.17(m,8H),6.74-6.70(m,2H),6.27(s,1H),4.50(s,2H),4.09(s,2H),2.51(s,3H)。
MS(ESI)m/z:375.1(M+H)+。
<步驟-2>:中間體-5-15-2(INT-5-15-2):1-(4-(2-((苄氧基)甲基)-1H-苯并[d]咪唑-1-基)苯基)乙酮
在60℃下,將INT-5-15-1(289mg,0.772mmol)的乙酸(5mL)溶液加熱15h。在真空中使反應混合物濃縮而得到粗製產物。將10-100%醋酸乙酯的DCM溶液用作洗脫劑,藉由柱色譜法(Biotage)在矽膠(25g)上提純該粗製產物而得到黃色無定形固體的標題化合物(246mg,92%的收率)。
1H-NMR(270MHz,DMSO-d 6):delta 8.18(d,J=8.5Hz,2H),7.80-7.75(m,3H),7.34-7.25(m,6H),7.14-7.11(m,2H),4.72(s,2H),4.45(s,2H),2.68(s,3H),2.46(s,3H)。
MS(ESI)m/z:.357.1(M+H)+。
<步驟-3>:中間體-5-15-3(INT-5-15-3):(1-(4-(2-溴乙醯基)苯基)-1H-苯并[d]咪唑-2-基)乙酸甲酯氫溴酸鹽
在室溫下,將INT-5-15-2(246mg,0.690mmol)和溴(110mg,0.690mmol)的25%HBr-AcOH(5mL)的混合物攪拌1.5h。藉由氮流使反應混合物濃縮。用IPE和MeOH(2/1 v/v)的混合物粉碎殘留物而得到暗黃色無定形固體的標題化合物(352mg,80%的化學純度)的混合物。
MS(ESI)m/z:270.1(M+H)+。
<步驟-4>:實施例-5-15:8,8-二氟-3-(2-(4-(2-(羥基甲基)-1H-苯并[d]咪唑-1-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
在80℃下,將INT-1-1-A(154mg,0.752mmol)、INT-5-15-3
(352mg,2.26mmol)及碳酸鉀(312mg,2.26mmol)的DMF(5mL)的混合物加熱3h。冷卻之後,在反應混合物中添加水,並將混合物攪拌10min。用EtOAc萃取之後,用鹽水清洗合併之有機層,在硫酸鈉上乾燥,過濾之後在真空中濃縮。將10-80%醋酸乙酯的DCM溶液用作洗脫劑,藉由柱色譜法(Biotage)在矽膠(25g)上提純殘留物而得到淺黃色固體的標題化合物(209mg,59%的收率)。
1H-NMR(270MHz,DMSO-d 6):delta 9.06(s,1H),8.30(d,J=8.5Hz,2H),7.84(d,J=8.5Hz,2H),7.32-7.28(m,4H),5.61(t,J=5.9Hz,1H),5.07(s,2H),4.65(d,J=5.9Hz,2H),2.19-1.76(m,8H)。
MS(ESI)m/z:469.1(M+H)+。
實施例-5-16:3-(2-(4-(2-(胺基甲基)-1H-苯并[d]咪唑-1-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
<步驟-1>:中間體-5-16-1(INT-5-16-1):3-(2-(4-(2-(疊氮甲基)-1H-苯并[d]咪唑-1-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
在0℃下,在實施例-5-15(50mg,0.107mmol)的THF(2mL)
溶液中添加疊氮磷酸二苯酯(DPPA)(41mg,0.149mmol)。經過5min之後,在其中添加DBU(19mg,0.128mmol),並在0℃下將反應混合物攪拌2h。在室溫下經過5h之後,用水使反應混合物淬滅,並用EtOAc萃取。使合併之有機層在硫酸鈉上乾燥,過濾之後在真空中濃縮。將10-80%醋酸乙酯的DCM溶液用作洗脫劑,藉由柱色譜法(Biotage)在矽膠(10g)上提純殘留物而得到無色無定形固體的標題化合物(32mg,61%的收率)。
MS(ESI)m/z:493.9(M+H)+。
<步驟-2>:實施例-5-16:3-(2-(4-(2-(胺基甲基)-1H-苯并[d]咪唑-1-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
在INT-5-16-1(32mg,0.065mmol)的THF(1mL)溶液中添加三苯基膦(24mg,0.091mmol)和水(0.17mL)。在室溫下將混合物攪拌3h。接著,將此用25%氫氧化銨水溶液(0.17mL)處理,並在室溫下再攪拌1h。用水使反應混合物淬滅,並用EtOAc萃取。使合併之層在硫酸鈉上乾燥,過濾之後在真空中濃縮。將殘留物加載於用1mL的MeOH調節、用5mL的MeOH沖洗、並用5mL的1M NH3/MeOH洗脫之SCX筒(Biotage,ISOLUTE SCX-2;1g/6mL×2)中。藉由氮流去除揮發物質而得到無色無定形的標題化合物(23mg,76%的收率)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。
觀察到之MS:466.5
tR/方法:1.37min./(QC1)
按照實施例-1的流程,從表18中的周知或合成之alpha-鹵代酮衍生物和氮雜螺衍生物製備以下實施例(5-17至5-42)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。將保留時間和藉由HPLC-QC方法觀察到之MS總結於表18。
一般流程(條件-A)
在INT-12-1-A(0.067mmol)的1,4-二噁烷(1mL)溶液中添加鹵化物衍生物(0.067mmol)、飽和的NaHCO3溶液(0.5mL)及PdCl2(dppf).CH2Cl2(10%mol)。在100℃下,在表19的條件下,在油浴中將混合物攪拌3~15h,或者在微波系統(MW)(Biotage,initiator)進行照射。在反應混合物中添加水和醋酸乙酯,並藉由矽藻土墊過濾混合物。用鹽水清洗分層之有機溶液,在Na2SO4上乾燥之後,在真空中濃縮。
中性化合物的提純:使用胺矽膠之短時間過濾或藉由柱色譜法之提純
鹼性化合物的提純:將殘留物加載於用1mL的MeOH調節、用5mL的MeOH沖洗、並用5mL的1M NH3/MeOH洗脫之SCX筒(Varian Bond Elute,1g/6mL)中。藉由氮流去除揮發物質而得到粗製標題化合物。根據需要,使用SCX進行提純之前,藉由柱色譜法實施提純。
藉由準備好的LC-MS系統,以通常的方式進一步實施提純。保留時間和藉由HPLC-QC方法觀察到之MS記錄在表20。
除上述條件A以外,還將以下條件(B-F)總結於表19。
按照表19中的條件A至F,從表20中的合成之芳基硼酸衍生物(INT-12-1-A)和周知或合成之鹵化物衍生物製備以下實施例(6-1至6-53)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。將保留時間和藉由HPLC-QC方法觀察到之MS總結於表20。
實施例-6-54:8,8-二氟-3-(2-(4-(3-(2-羥基乙氧基)吡嗪-2-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
<步驟-1>:中間體-6-54-1(INT6-54-1):2-氯-3-(2-((四氫-2H-吡喃-2-基)氧基)乙氧基)吡嗪
在0℃下,在2,3-二氯吡嗪(397mg,2.67mmol)和2-((四氫-2H-吡喃-2-基)氧基)乙醇(300mg,2.05mmol)的DMSO(2mL)中添加t-BuOK(299mg,2.67mmol)。在室溫下將混合物攪拌1h。用水稀釋混合物,並用EtOAc-己烷(2:1,×2)萃取。使合併之有機層在Na2SO4上乾燥,過濾之後濃縮。將0-30%梯度的EtOAc的己烷溶液用作洗脫劑,藉由柱色譜法在矽膠上實施提純而得到淺黃色油的標題化合物(350mg,66%的收率)。
1H-NMR(270MHz,CDCl3):delta 8.01(d,J=2.7Hz,1H),7.93(d,J=2.7Hz,1H),4.75(t,J=3.0Hz,1H),4.65-4.55(m,2H),4.19-4.05(m,1H),4.00-3.80(m,2H),3.60-3.50(m,1H),1.89-1.48(m,6H)。
<步驟-2>:中間體-6-54-2(INT6-54-2):8,8-二氟-3-(2-側氧基-2-(4-(3-(2-((四氫-2H-吡喃-2-基)氧基)乙氧基)吡嗪-2-基)苯基)乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
按照Suzuki-Miyaura交叉偶聯反應所記載之條件-C,從INT12-1-A(30mg,0.067mmol)、INT6-54-1(17mg,0.067mmol)及代替PdCl2(dppf)之雙(二-第三丁基(4-二甲基胺基苯基)膦)二氯化鈀(II)(5.5mg,0.0067mmol)製備標題化合物,並在120℃下,在微波照射系統中照射20min。所獲得之粗製棕色油(36mg)沒有進行提純而用於接下來的步驟。
MS(ESI)m/z:545.2(M+H)+。
<步驟-3>:實施例-6-54:8,8-二氟-3-(2-(4-(3-(2-羥基乙氧基)吡嗪-2-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
在INT6-54-2(在實施例6-54的步驟-2中製備之粗製油)的THF(1mL)溶液中添加2M HCl水溶液(1mL),並在室溫下將混合物攪拌3h。用飽和的碳酸鈉溶液使混合物淬滅,並用DCM萃取。使合併之有機層在Na2SO4上乾燥,過濾之後濃縮。將30-100%梯度的EtOAc的己烷溶液用作洗脫劑,藉由柱色譜法在矽膠上實施提純而得到淺黃色固體的標題化合物(20mg,在2個步驟中為66%的收率)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。
1H-NMR(270MHz,CDCl3):delta 8.33(d,J=2.6Hz,1H),8.24(d,J=8.6Hz,2H),8.11(d,J=2.6Hz,1H),8.05(d,J=8.6Hz,2H),6.05(br.s,1H),4.97(s,2H),4.65-4.57(m,2H),4.08-4.00(m,2H),2.58-2.19(m,5H),2.12-1.90(m,4H)。
觀察到之MS:459.3
tR/方法:1.41min./(QC1)
實施例-6-55:3-(2-(2'-(胺基甲基)-[1,1'-聯苯基]-4-基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮氫氯化物
<步驟-1>:中間體-6-55-1(INT-6-55-1):((4'-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)-[1,1'-聯苯基]-2-
基)甲基)胺基甲酸第三丁酯
按照Suzuki-Miyaura交叉偶聯反應所記載之流程的條件-A,從INT-12-1-A(838mg,1.87mmol)、2-溴苄基胺基甲酸第三丁酯(642mg,2.24mmol),在120℃下,在20min的微波照射下製備標題化合物。藉由矽藻土墊過濾反應混合物,並用EtOAc清洗矽藻土墊。用EtOAc萃取濾液和清洗液,並用水和鹽水清洗合併之有機溶液,在硫酸鈉上乾燥,過濾之後在真空中濃縮。將10-80%醋酸乙酯的DCM溶液用作洗脫劑,藉由柱色譜法(Biotage)在矽膠(50g)上提純殘留物而得到白色固體的標題化合物(756mg,77%的收率)。
1H-NMR(270MHz,CDCl3):delta 8.04(d,J=8.5Hz,2H),7.50-7.35(m,4H),7.28-7.24(m,2H),6.94(br.s,1H),4.98(s,2H),4.68(br.s,1H),4.29(d,J=5.3Hz,2H),2.38-2.24(m,4H),2.04-1.98(m,4H),1.63(s,3H),1.43(s,9H)。
MS(ESI)m/z:526.4(M-H)-。
<步驟-2>:實施例-6-55:3-(2-(2'-(胺基甲基)-[1,1'-聯苯基]-4-基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮氫氯化物
在INT-6-55-1(756mg,1.43mmol)的1,4-二噁烷(3mL)溶液中添加4M HCl-二噁烷(10mL)。在室溫下將混合物攪拌3h。藉由過濾收集沉澱之固體而得到白色固體的標題化合物(600mg,90%的收率)。
1H-NMR(270MHz,DMSO-d 6):delta 9.05(s,1H),8.33
(s,2H),8.16(d,J=8.5Hz,2H),7.71(d,J=7.2Hz,1H),7.62-7.48(m,4H),7.37(d,J=7.2Hz,1H),5.03(s,2H),3.97(s,2H),2.19-1.81(m,8H)。
MS(ESI)m/z:428.3(M+H)-。
實施例-6-56:3-(2-(4-(2-(胺基甲基)吡啶-3-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
<步驟-1>:中間體-6-56-1(INT-6-56-1):3-(2-(4-(2-(胺基甲基)吡啶-3-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
按照Suzuki-Miyaura交叉偶聯反應所記載之流程的條件-A,從INT-12-1-A和(3-溴吡啶-2-基)甲胺製備標題化合物,得到暗紅色固體的產物(173mg,21%的收率;73%的化學純度)。
MS(ESI)m/z:429.29(M+H)+。
<步驟-2>:中間體-6-56-2(INT-6-56-2):((3-(4-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)苯基)吡啶-2-基)甲基)胺基甲酸第三丁酯
在室溫下,在粗製的INT-6-56-1(178mg,0.415mmol)和三乙胺(116microL,0.831mmol)的THF(5mL)的攪拌溶液中添加二-第三
丁基二碳酸酯(90microL,0.416mmol)。在室溫下將混合物攪拌3天。去除溶劑之後,將3-20%甲醇的DCM溶液用作洗脫劑,藉由柱色譜法在矽膠(45g)上提純,接著藉由準備好的TLC(1mm×4),用MeOH-DCM(1:20)(將10%MeOH的DCM溶液用作洗脫劑)提純粗製產物而得到標題化合物(103.6mg,黃色無定形固體)。
1H-NMR(270MHz,CDCl3):delta 8.64-8.58(m,1H),8.10-8.00(m,2H),7.62-7.55(m,1H),7.53-7.45(m,2H),7.36-7.28(m,1H),7.00(br.s,1H),6.00(br.s,1H),4.96(s,2H),4.38(d,J=3.9Hz,2H),2.50-1.90(m,8H),1.65(s,3H),1.43(s,9H)。
MS(ESI)m/z:529.41(M+H)+。
<步驟-3>:實施例-6-56:3-(2-(4-(2-(胺基甲基)吡啶-3-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
用10%HCl-甲醇(8mL)處理INT-6-56-2(98mg,0.185mmol)的MeOH(3mL)的混合物。在50℃下經過2.5h之後,在真空中使溶劑蒸發。用飽和的碳酸氫鈉溶液使殘留物鹼化至pH>8,並用DCM(×3)萃取。用鹽水清洗合併之溶液,在硫酸鈉上乾燥,過濾之後在真空中濃縮而得到淺棕色~黃色固體的標題化合物(74.3mg,94%的收率)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。
1H-NMR(270MHz,DMSO-d 6):delta 9.03(br.s,1H),8.65-8.60(m,1H),8.18-8.10(m,2H),7.75-7.40(m,3H),7.44-7.35(m,1H),5.02(s,2H),3.73(s,2H),2.30-1.75(m,8H).(未觀察到由NH引起之訊號)
觀察到之MS:427.3
tR/方法:1.23min./(QC1)
實施例-6-57的合成:N-((3-(4-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)苯基)吡啶-2-基)甲基)乙醯胺
在室溫下,在實施例-6-56(38.1mg,0.089mmol)的DCM(3mL)-THF(1mL)的攪拌懸浮液中添加三乙胺(25microL,0.179mmol)接著添加乙酸酐(10microL,0.107mmol)。在室溫下將混合物攪拌5h。去除溶劑之後,藉由柱色譜法(Biotage)在胺矽膠(10g)上,用50-100%EtOAc的己烷溶液提純殘留物而得到無色無定形固體的標題化合物(38.6mg,92%的收率)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。
1H-NMR(270MHz,DMSO-d 6):delta 9.03(s,1H),8.65-8.60(m,1H),8.24-8.20(m,1H),8.18-8.10(m,2H),7.75-7.60(m,3H),7.48-7.40(m,1H),5.03(s,2H),4.32(d,J=4.3Hz,2H),2.30-1.75(m,8H),1.80(s,3H)。
觀察到之MS:469.4
tR/方法:1.33min./(QC1)
實施例-6-58:3-(2-(4-(4-(胺基甲基)吡啶-3-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
<步驟-1>:中間體-6-58-1(INT-6-58-1):((3-(4-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)苯基)吡啶-4-基)甲基)胺基甲酸第三丁酯
按照Suzuki-Miyaura交叉偶聯反應所記載之流程的條件-A,從INT-12-1-A(60mg,0.134mmol)和((3-溴吡啶-4-基)甲基)胺基甲酸第三丁酯(46mg,0.161mmol)製備標題化合物,並在120℃下,在微波照射系統中照射20min。將10-80%醋酸乙酯的DCM溶液用作洗脫劑,藉由柱色譜法(Biotage)在矽膠(10g)上提純殘留物而得到淺黃色固體的產物(63mg,89%的收率)。
1H-NMR(270MHz,DMSO-d 6):delta 9.02(s,1H),8.59(d,J=5.3Hz,1H),8.43(s,1H),8.14(d,J=7.9Hz,2H),7.64(d,J=7.9Hz,2H),7.51(t,J=5.3Hz,1H),7.39(d,J=4.6Hz,1H),5.02(s,2H),4.11(d,J=5.3Hz,2H),2.17-1.86(m,8H),1.36(s,9H)。
MS(ESI)m/z:529.3(M-H)-。
<步驟-2>:實施例-6-58:3-(2-(4-(4-(胺基甲基)吡啶-3-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
在INT-6-58-1(63mg,0.119mmol)的DCM(1mL)溶液中添加三氟乙酸(0.5mL)。在室溫下將混合物攪拌2h。藉由氮流使反應混合物濃縮。將殘留物加載於用1mL的MeOH調節、用5mL的MeOH沖洗、並用5mL的1M NH3/MeOH洗脫之SCX筒(Biotage,ISOLUTE-
SCX-2,1g/6mL)中。藉由氮流去除揮發物質而得到淺黃色無定形固體的標題化合物(41mg,76%的收率)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。
觀察到之MS:427.4
tR/方法:1.19min./(QC1)
按照表19中的A至F的條件,從表21中的合成之芳基硼酸衍生物(INT-12-1-A)和周知或合成之鹵化物衍生物製備以下實施例(6-59至6-123)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。將保留時間和藉由HPLC-QC方法觀察到之MS總結於表21。
按照表19中的條件A至F,從表22中的合成之芳基硼酸衍生物和周知或合成之鹵化物衍生物製備以下實施例(7-1至7-28)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。將保留時間和藉由HPLC-QC方法觀察到之MS總結於表22。
按照表19中的A至F的條件,從表23中之現場製備之芳基硼酸衍生物和周知或合成之鹵化物衍生物製備以下實施例(8-1至8-9)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。將保留時間和藉由HPLC-QC方法觀察到之MS總結於表23。
按照表19中的A至F的條件,從表24-28的合成之鹵化物衍生物和
周知或合成之硼酸衍生物製備以下實施例(9-1至13-72)。(從對應的溴衍生物現場製備實施例9-22至9-27的硼酸衍生物)藉由準備好的LC-MS系統,以通常的方式進一步實施提純。將保留時間和藉由HPLC-QC方法觀察到之MS總結於表24-28。
按照表19中的A至F的條件,從表29-33中的合成之鹵化物衍生物和周知或合成之硼酸衍生物製備以下實施例(14-1至18-13)(從對應的溴衍生物現場製備實施例-14-6的硼酸衍生物)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。將保留時間和藉由HPLC-QC方法觀察到之MS總結於表29-33。
實施例19-1:3-(2-(6-(甲基(間甲苯基)胺基)吡啶-3-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
條件-A
在INT-8-3-A(30mg,0.093mmol)的DME(1mL)溶液中添加N-甲基-間甲苯胺(12mg,0.103mmol)、第三丁醇鉀(16mg,0.140mmol)及Pd-PEPPSI(商標)-IPr(1.3mg,1.86mmol)。在140℃下,在微波反應器(Biotage Initiator)中將混合物照射30min
(或者,在100-150℃下,在油浴中加熱3-15h)。用水使混合物淬滅,並藉由矽藻土墊過濾。用EtOAc清洗濾餅,並用鹽水清洗濾液和清洗液,在硫酸鈉上乾燥,過濾之後在真空中濃縮。用10-100%EtOAc的己烷溶液,藉由柱色譜法在矽膠上提純殘留物而得到標題化合物(13mg,34%的收率)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。
觀察到之MS:405.4
tR/方法:1.76min./(QC1)
除上述條件A以外,還將以下條件(B-I)總結於表34。
按照表34中的條件A至I,從表35中的合成之鹵化物衍生物和周知或合成之胺衍生物製備以下實施例(19-2至19-40)。藉由準備好的
LC-MS系統,以通常的方式進一步實施提純。將保留時間和藉由HPLC-QC方法觀察到之MS總結於表35。
實施例-19-41:3-(2-(4-(3,5-二甲基-1H-吡唑-1-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
在60℃下,將INT-12-1-A(30mg,0.067mmol)、3,5-二甲基-1H-吡唑(12.9mg,0.134mmol)及乙酸銅(II)(12.2mg,0.067mmol)
的吡啶(1mL)的混合物攪拌20h。用EtOAc稀釋混合物,並用2M HCl水溶液、水及鹽水清洗。使有機層在Na2SO4上乾燥,過濾之後在真空中濃縮。將EtOAc用作洗脫劑,藉由柱色譜法在胺基鍵合矽-膠上提純殘留物而得到粗製標題化合物。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。
觀察到之MS:417.7
tR/方法:1.56min./(QC1)
實施例-20-1:3-(2-(6-(3-氯苯氧基)吡啶-3-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
在INT-8-3-A(20mg,0.062mmol)的DMSO(1mL)溶液中添加3-氯苯酚(9.6mg,0.075mmol)和Cs2CO3(61mg,0.186mmol)。在室溫下將混合物攪拌15h。藉由矽藻土墊過濾混合物,並用EtOAc清洗濾餅。用水和鹽水清洗濾液和清洗液,在Na2SO4上乾燥,過濾之後在真空中濃縮。將10-100%EtOAc的己烷溶液用作洗脫劑,藉由柱色譜法提純殘留物而得到白色固體的標題化合物(18mg,70%的收率)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。
按照實施例-20-1的流程,從表36中的合成之鹵化物衍生物和周知或合成之苯酚、硫醇或醇衍生物製備以下實施例(20-1至20-9)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。將保留時間和藉由HPLC-QC方法觀察到之MS總結於表36。
實施例-21-1:2-(4-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)苯氧基)菸鹼甲腈
{化學式141}
在140℃下,在微波反應器(Biotage Initiator)中將INT-14-1-A(35mg,0.10mmol)、2-氯菸鹼甲腈(20mg,0.145mmol)及K2CO3(29mg,0.207mmol)的DMF(1.5mL)的混合物照射30min。藉由矽藻土墊過濾反應混合物,並用EtOAc清洗濾餅。用水和鹽水清洗濾液和清洗液,在Na2SO4上乾燥,過濾之後在真空中濃縮。將5-50%EtOAc的DCM溶液用作洗脫劑,藉由柱色譜法在矽膠上提純殘留物而得到淺黃色無定形固體的標題化合物(43mg,94%的收率)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。
觀察到之MS:439.3
tR/方法:1.53min./(QC1)
實施例-21-2:
3-(2-(4-((3-氯吡啶-2-基)氧基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
在170℃下,向INT-14-1-A(34mg,0.101mmol)、2-溴-3-氯吡啶(15mg,0.078mmol)、2-(二甲基胺基)乙酸(2.4mg,0.023mmol)、碘化亞銅(I)(4.45mg,0.023mmol)及Cs2CO3(76mg,0.234mmol)的1,4-二噁烷(1.5mL)的混合物照射微波1h。通常的操作之後(用水淬滅、用EtOAc稀釋、藉由矽藻土過濾、及用EtOAc清洗),將5-50%EtOAc的DCM溶液用作洗脫劑,藉由柱色譜法在矽膠上提純殘留物而得到標題化合物(10mg,29%的收率)。藉由
準備好的LC-MS系統,以通常的方式進一步實施提純。
觀察到之MS:448.2
tR/方法:1.68min./(QC1)
按照實施例-21-2的流程,從表37中的合成之苯酚衍生物(INT-14-1-A)和周知或合成之鹵化物衍生物製備以下實施例(21-3至21-10)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。將保留時間和藉由HPLC-QC方法觀察到之MS總結於表37。
實施例-21-11:
8,8-二氟-3-(2-(4-((4-甲基噠嗪-3-基)氧基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
在160℃下,向INT-14-1-A(30mg,0.089mmol)、3-氯-4-甲基噠嗪(13.7mg,0.106mmol,Pd2(dba)3(8.1mg,0.0089mmol)、tBuXPhos(18.8mg,0.044mmol)及K3PO4(56.5mg,0.266mmol)的1,4-二噁烷(1.5mL)的混合物照射微波45min。通常的操作之後(用水淬滅、用EtOAc稀釋、藉由矽藻土過濾、及用EtOAc清洗),將5-80%EtOAc的DCM溶液用作洗脫劑,藉由柱色譜法在矽膠上提純殘留物而得到標題化合物(10mg,26%的收率)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。
觀察到之MS:431.2
tR/方法:1.43min./(QC1)
實施例-21-12:
3-(4-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)苯氧基)噠嗪-4-甲腈
按照實施例-21-11的流程,從INT-14-1-A(30mg,0.089mmol)和3-氯噠嗪-4-甲腈(30.9mg,0.222mmol)製備標題化合物,得到棕色無定形固體的產物(31mg,79%的收率)。藉由準備好的LC-MS系
統,以通常的方式進一步實施提純。
觀察到之MS:442.2
tR/方法:1.43min./(QC1)
實施例-21-13:
8,8-二氟-3-(2-側氧基-2-(4-(噻唑-2-基氧基)苯基)乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
在140℃下,向INT-14-1-A(30mg,0.089mmol)、2-氯噻唑(26.5mg,0.222mmol)及Cs2CO3(87mg,0.266mmol)的DMF(1.5mL)的混合物照射微波0.5h。通常的操作之後(用水淬滅、用EtOAc稀釋、藉由矽藻土過濾、及用EtOAc清洗),將10-100%EtOAc的DCM溶液用作洗脫劑,藉由柱色譜法在矽膠上提純殘留物而得到黃色無定形固體的標題化合物(18mg,48%的收率)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。
觀察到之MS:422.1
tR/方法:1.56min./(QC1)
實施例-21-14:
8,8-二氟-3-(2-側氧基-2-(4-(吡啶-3-基氧基)苯基)乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
按照實施例-21-11的流程,從INT-7-1-A(60mg,0.15mmol)、吡
啶-3-醇(17.1mg,0.179mmol)、t-BuXPhos(31.8mg,0.075mmol)、Pd2(dba)3(13.7mg,0.015mmol)及磷酸鉀(95mg,0.45mmol)的1,4-二噁烷(3mL)製備標題化合物,得到微黃色固體的產物(19mg,30%的收率)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。
觀察到之MS:416.4
tR/方法:1.47min./(QC1)
按照實施例-21-11的流程,從表38中的鹵化物衍生物(INT-7-1-A、INT-7-18-A及INT-7-20-A)和周知之苯酚衍生物製備以下實施例(21-15至21-17)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。將保留時間和藉由HPLC-QC方法觀察到之MS總結於表38。
實施例-21-18:
8,8-二氟-3-(2-側氧基-2-(4-(吡啶-3-基甲氧基)苯基)乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
{化學式147}
在室溫下,在INT-14-1-A(30mg,0.089mmol)和碳酸鉀(37mg,0.266mmol)的DMF(2mL)溶液中添加3-(氯甲基)吡啶(14mg,0.089mmol)。在80℃下將混合物攪拌15h。在其中添加水,用EtOAc萃取混合物。用鹽水清洗有機層,在硫酸鈉上乾燥,過濾之後在真空中濃縮。將10-80%醋酸乙酯的DCM溶液用作洗脫劑,藉由柱色譜法在矽膠上提純殘留物而得到白色固體的標題化合物(33mg,87%的收率)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。
觀察到之MS:430.1
tR/方法:1.45min./(QC1)
實施例-21-19:
8,8-二氟-3-(2-側氧基-2-(4-(吡啶-4-基甲氧基)苯基)乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
在0℃下,在INT-14-1-A(30mg,0.089mmol)的THF(2mL)溶液中添加吡啶-4-基甲醇(10mg,0.089mmol)、DEAD(在甲苯溶液中為2.2M,0.060mL,0.133mmol)及三苯基膦(35mg,0.133mmol)。在室溫下攪拌1h之後,在真空中使反應混合物濃縮。將10-100%醋酸乙酯的DCM溶液用作洗脫劑,藉由柱色譜法在矽膠上提純殘留物而得到無色無定形固體的標題化合物(44mg,定量)。藉由
準備好的LC-MS系統,以通常的方式進一步實施提純。
觀察到之MS:430.2
tR/方法:1.44min./(QC1)
實施例-21-20:
8,8-二氟-3-(2-側氧基-2-(4-(嘧啶-2-基甲氧基)苯基)乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
按照實施例-21-17的流程,從INT-14-1-A(50mg,0.148mmol)、2-(氯甲基)嘧啶(24mg,0.148mmol)及碳酸銫(144mg,0.443mmol)的DMF(2mL)製備標題化合物,得到無色無定形固體的產物(28mg,44%的收率)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。
觀察到之MS:431.2
tR/方法:1.34min./(QC1)
按照中間體-9-2-A中的步驟-3的流程,從表39中的合成之醇衍生物(INT-11-1-A至INT-11-6-A)製備以下實施例(22-1至22-6)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。將保留時間和藉由HPLC-QC方法觀察到之MS總結於表39。
實施例-23-1:
8,8-二氟-3-(2-側氧基-2-(4-(2-側氧基-1H-咪唑并[4,5-b]吡啶-3(2H)-基)苯基)乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
在INT-15-1-A(40mg,0.093mmol)的THF(1.5mL)的攪拌溶液中添加CDI(38mg,0.233mmol)和吡啶(18mg,0.233mmol)。在65℃下將混合物攪拌4h。冷卻之後,用水使反應混合物淬滅,並用EtOAc萃取。用鹽水清洗合併之有機層,在硫酸鈉上乾燥,過濾之後
在真空中濃縮。將10-100%醋酸乙酯的DCM溶液用作洗脫劑,藉由柱色譜法(Biotage)在矽膠(10g)上提純殘留物而得到白色無定形固體的標題化合物(27mg,64%的收率)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純而得到標題化合物(6.1mg)。
觀察到之MS:454.4
tR/方法:1.34min./(QC1)
實施例-23-2:
8,8-二氟-3-(2-(4-(5-甲基-2-側氧基-1H-咪唑并[4,5-b]吡啶-3(2H)-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
按照實施例-23-1的流程,從INT-15-2-A(80mg,0.18mmol)、CDI(73.1mg,0.451mmol)及吡啶(36microL,0.451mmol)的THF(3mL)製備標題化合物,得到暗黃色固體的產物(75mg,89%的收率)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。
觀察到之MS:470.4
tR/方法:1.42min./(QC1)
實施例-24-1:
3-(2-(4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
{化學式152}
在環境溫度下,在INT-15-1-A(50.0mg,0.116mmol)和三乙胺(40microL,0.282mmol)的THF(3mL)的攪拌溶液中添加2,2-二氟乙酸酐(24,5mg,0.141mmol)。在室溫下經過5h之後,在真空中使溶劑蒸發而得到橙色油的粗製產物(~0.116mmol),將其溶解於乙酸(3mL)中。在100℃下將混合物加熱16h。去除溶劑之後,用飽和的碳酸氫鈉溶液使殘留物鹼化至pH>10,並用醋酸乙酯(×2)萃取。用鹽水清洗合併之溶液,在硫酸鈉上乾燥,過濾之後在真空中濃縮而得到粗製產物(橙色油,146.4mg)。將5-60%醋酸乙酯的DCM溶液用作洗脫劑,藉由柱色譜法在矽膠(10g)上提純該粗製產物而得到橙色固體的標題化合物(36.8mg,65%的收率)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。
觀察到之MS:490.1
tR/方法:2.05min./(QC2)
按照實施例-24-1的流程,從表40中的INT-15-1-A和INT-15-2-A製備以下實施例(24-2至24-5)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。將保留時間和藉由HPLC-QC方法觀察到之MS總結於表40。
實施例-24-6:
8,8-二氟-3-(2-側氧基-2-(4-(2-(三氟甲基)-3H-咪唑并[4,5-b]吡啶-3-基)苯基)乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
在70℃下,將INT-15-1-A(50mg,0.116mmol)的混合物溶解於三氟乙酸(1mL)中,並將反應物攪拌18h。去除溶劑之後,在其中添加三乙胺,並在70℃下將混合物攪拌2h。去除溶劑之後,將10-90%醋酸乙酯的DCM溶液用作洗脫劑,藉由柱色譜法在矽膠(10g)上提純殘餘產物而得到橙色固體的標題化合物(53mg,90%的收率;40%的化學純度)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。
觀察到之MS:508.6
tR/方法:1.58min./(QC1)
實施例-24-7:
8,8-二氟-3-(2-(4-(5-甲基-2-(三氟甲基)-3H-咪唑并[4,5-b]吡啶-3-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
在100℃下,向INT-15-2-A(50mg,0.113mmol)的三氟乙酸(1mL)的混合物(懸浮液)照射微波30min。按照實施例-24-6的流程實施反應處理,得到橙色固體的標題化合物(58mg,99%的收率)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。
觀察到之MS:522.7
tR/方法:1.67min./(QC1)
實施例-25-1:
3-(2-(4-(2-((二甲基胺基)甲基)-5-甲基-3H-咪唑并[4,5-b]吡啶-3-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
在45℃下,將INT-17-1-A(30mg,0.06mmol)、2M二甲胺的THF
溶液(90microL,0.18mmol)及碳酸鉀(41.3mg,0.299mmol)的THF(1.5mL)的混合物加熱10h。藉由矽藻土墊過濾之後,用THF清洗濾餅。在氮流中使濾液和清洗液濃縮而得到橙色油的標題化合物(35.1mg)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。
觀察到之MS:511.7
tR/方法:1.48min./(QC1)
按照實施例-25-1的流程,從表41中的INT-17-1-A和對應的胺製備以下實施例(25-2至25-6)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。將保留時間和藉由HPLC-QC方法觀察到之MS總結於表41。
實施例-26-1:
8,8-二氟-3-(2-(4-(2-甲氧基-3H-咪唑并[4,5-b]吡啶-3-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
在85℃下,將INT-15-1-A(50mg,0.116mmol)、四甲氧基甲烷(0.16mL,1.199mmol)及乙酸(15microL)的THF(1.5mL)的混合物加熱18h。去除溶劑之後,將5-70%醋酸乙酯的DCM溶液用作洗脫劑,藉由柱色譜法在矽膠(10g)上提純殘留物(棕色油)而得到微紫色固體的標題化合物(43mg,78%的收率)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。
觀察到之MS:470.2
tR/方法:2.02min./(QC2)
按照實施例-26-1的流程,從表42中的INT-15-2-A製備以下實施例(26-2至26-4)。在使用代替AcOH之p-TsOH(0.3eq.)之條件下進行實施例-26-2的實施。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。將保留時間和藉由HPLC-QC方法觀察到之MS總結於表42。
實施例-27-1:
3-(4-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)苯基)-2-甲基-3H-咪唑并[4,5-b]吡啶-5-甲腈
在120℃下,向實施例-5-29(660mg,1.33mmol)的三氯氧化磷(32mL)的混合物(懸浮液)照射微波30min。在真空中使溶劑蒸發而得到殘餘產物,用飽和的碳酸氫鈉溶液使其鹼化至pH>10,並用醋酸乙酯(×2)萃取。用水和鹽水清洗合併之溶液,在硫酸鈉上乾燥,過濾之後在真空中濃縮而得到粗製產物。僅將EtOAc用作洗脫劑,藉由柱色譜法在矽膠(100g)上提純該粗製產物而得到粗製產物(固體)。用微量的AcOEt和過量的己烷粉碎產物而得到白色固體的標題產物(324mg,51%的收率)。
MS(ESI)m/z:479.3(M+H)+。
藉由準備好的LC-MS系統,以通常的方式實施被測樣品的進一步的提純。
觀察到之MS:479.2
tR/方法:1.96min./(QC2)
實施例-28-1:
3-(2-(4-(2-(二甲基胺基)-5-甲基-3H-咪唑并[4,5-b]吡啶-3-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
在80℃下,將INT-15-2-A(50mg,0.113mmol)、(二氯甲烷)二甲基氯化銨(43mg,0.338mmol)及三乙胺(22microL,0.451mmol)的1,2-二氯乙烷(3mL)的混合物加熱2h。用甲醇使混合物淬滅,並在真空中使溶劑蒸發。將殘留物溶解於DCM(50mL)中,並用水和鹽水清洗有機溶液,在硫酸鈉上乾燥,過濾之後在真空中濃縮而得到粗製產物(暗棕色油)。將20-100%醋酸乙酯的DCM溶液用作洗脫劑,藉由柱色譜法在矽膠(10g)上提純該粗製產物而得到淺黃色薄膜的標題化合物(14.2mg,20%的收率,80%的化學純度)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。
觀察到之MS:497.8
tR/方法:1.51min./(QC1)
實施例-28-2:
N-(2-((4-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷
-3-基)乙醯基)苯基)胺基)吡啶-3-基)乙醯胺
在室溫下,藉由注射器在INT-15-1-A(50mg,0.116mmol)和三乙胺(40.6microL,0,291mmol)的THF(3mL)的攪拌混合物中添加乙醯氯(13.2mg,0.169mmol)。在室溫下經過45min之後,用水使混合物淬滅,並用醋酸乙酯萃取。用鹽水清洗合併之有機溶液,在硫酸鈉上乾燥,過濾之後在真空中濃縮而得到粗製產物。僅將醋酸乙酯用作洗脫劑,藉由柱色譜法在矽膠(10g)上提純該粗製產物而得到微棕褐色固體的標題化合物(34.4mg,62%的收率)。
1H-NMR(270MHz,DMSO-d 6):delta 9.56(s,1H),8.98(s,1H),8.71(s,1H),8.14-8.08(m,1H),7.97(d,J=8.6Hz,2H),7.82-7.72(m,3H),7.02-6.95(m,1H),4.87(s,2H),2.25-1.75(m,11H,包含delta 2.12(s,3H))。
MS(ESI)m/z:472.2(M+H)+。
藉由準備好的LC-MS系統,以通常的方式進行被測樣品的進一步的提純。
觀察到之MS:472.7
tR/方法:1.35min./(QC1)
實施例-28-3:
3-(2-(4-(2-乙醯基異吲哚啉-4-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
{化學式160}
在室溫下,在實施例-6-115(32mg,0.073mmol)的DCM(2mL)溶液中添加乙酸酐(0.021mL,0.218mmol)和TEA(0.030mL,0.218mmol)。在室溫下將混合物攪拌5h。用飽和的NaHCO3溶液使混合物淬滅,並用DCM萃取。使有機溶液在Na2SO4上乾燥,過濾之後在真空中濃縮。將50-100%梯度的EtOAc溶液用作洗脫劑,接著將0-5%MeOH的EtOAc溶液用作洗脫劑,藉由柱色譜法在矽膠上實施提純而得到淺紫色固體的標題化合物(27mg,77%的收率)。
1H-NMR(270MHz,CDCl3):delta 8.10-8.06(m,2H),7.61-7.53(m,2H),7.49-7.27(m,3H),6.67(br s,1H),5.00-4.93(m,2H),4.93-4.80(m,4H),2.50-1.90(m,11H)。
MS(ESI)m/z:482.0(M+H)+。
藉由準備好的LC-MS系統,以通常的方式進一步實施提純。
觀察到之MS:482.3
tR/方法:1.51min./(QC1)
實施例-28-4:
8,8-二氟-3-(2-(4-(2-(羥基甲基)-3H-咪唑并[4,5-b]吡啶-3-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
在室溫下,將INT-17-2-A(52mg,0.102mmol)和碳酸鉀(42mg,0.305mmol)的甲醇(3mL)的混合物攪拌16h。藉由矽藻土墊過濾之後,在真空中使濾液和清洗液濃縮。將殘留物加載於用1mL的MeOH調節、用5mL的MeOH沖洗、並用5mL的1M NH3/MeOH洗脫之SCX筒(Varian Bond Elute,1g/6mL)中。藉由氮流去除揮發物質而得到標題化合物(21mg,44%的收率)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。
觀察到之MS:470.3
tR/方法:1.27min./(QC1)
實施例-28-5:
8,8-二氟-3-(2-(4-(2-(羥基甲基)-5-甲基-3H-咪唑并[4,5-b]吡啶-3-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮
按照實施例-28-4的流程,從INT-17-3-A(75.9mg,0.144mmol)和碳酸鉀(60mg,0.433mmol)的甲醇(4mL)製備標題化合物,得到白色固體的產物(29mg,41%的收率)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。
觀察到之MS:484.6
tR/方法:1.33min./(QC1)
實施例-29-1:
4'-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)-N,N-二甲基-[1,1'-聯苯基]-2-羧醯胺
在室溫下,在INT-16-1-A(20mg,0.045mmol)、苯并三氮唑-N,N,N’,N’-四甲基脲六氟磷酸酯(HBTU)(34mg,0.090mmol)及TEA(0.025mL,0.181mmmol)的DMF(1mL)的攪拌溶液中添加10%二甲胺的THF(0.2mL)溶液。在50℃下攪拌1h之後,用EtOAc稀釋混合物(4mL),並用水(4mL×2)清洗。使有機分餾物在硫酸鈉上乾燥,過濾之後在真空中濃縮。將醋酸乙酯用作洗脫劑,藉由柱色譜法在胺基鍵合之矽-膠(1g)上提純殘留物而得到淺黃色膠的標題化合物(20mg,94%的收率)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純而得到標題化合物(12.7mg)。
觀察到之MS:470.7
tR/方法:1.49min./(QC1)
按照實施例-29-1的流程,從表43中的INT-16-1-A/INT-16-2-A和對應的胺製備以下實施例(29-2至29-7)。藉由準備好的LC-MS系統,以通常的方式進一步實施提純。將保留時間和藉由HPLC-QC方法觀察到之MS總結於表43。
薄荷醇-誘導之Ca
2+
流入穩定表達人TRPM8之HEK293細胞內之
測定
利用穩定表達人TRPM8之HEK293細胞,藉由基於細胞之Ca2+流入分析來特定化合物的活性。
使穩定表達人TRPM8之HEK293細胞在5%CO2加濕培養器和T175燒瓶中在37℃的溫度下生長至約80%匯合度。培養基組成由達爾伯克氏改良伊格爾培養基(高葡萄糖)、10%胎牛血清(FCS)、100單位/mL的青黴素、100microg/mL的鏈黴素及600microg/mL的遺傳黴素構成。進行分析24小時之前,將細胞以每孔30,000細胞的培養基中的密度接種於多聚-D-賴胺酸塗覆之384-孔板(BD FALCON),在5%CO2、37℃下生長一夜。實施分析當天,去除生長之培養基,在室溫下經1小時在細胞中加載溶解於分析用緩衝液(Hank's balanced salt solution(HBSS)、19.4mM HEPES pH7.4,2.5mM Probenecid)中之0.5microM Fluo4-AM(Molecular Probes)和0.005% Pluronic F-127。用分析用緩衝液清洗之後,將細胞與各種濃度的化合物預培養5分鐘。藉由利用Hamamatsu Photonics Functional Drug Screening System(FDSS)之細胞成像技術來監控由30microM的薄荷醇的添加而引起之細胞間鈣濃度的變化。
藉由11-點劑量反應研究來決定本發明的化合物的IC50值。使用複孔的平均作為每個資料點來描繪出曲線。最後,依據由XLfit(ID Business Solutions Ltd.)決定之最佳擬合劑量曲線來計算IC50值。
所有被測化合物在上述分析中均對TRPM8顯出小於約3microM的IC50。較佳的化合物在上述分析中對TRPM8顯出小於約500nM之IC50。更佳的化合物在上述分析中對TRPM8顯出小於約100nM的IC50。最佳的化合物在上述分析中對TRPM8顯出小於約10nM的IC50。
對TRPM8具有<500nM的IC50之化合物如下:1-1、1-2、1-3、1-4、1-5、1-6、1-13、1-14、2-1、2-2、2-3、2-4、2-5、2-6、2-7、2-
8、2-11、2-12、2-13、2-14、2-15、2-16、2-17、2-18、3-1、3-2、3-3、3-4、3-5、3-6、3-7、3-8、3-9、3-10、3-11、3-12、3-13、3-14、3-15、3-16、3-17、3-18、3-19、3-20、3-21、3-22、3-23、3-24、3-25、3-26、3-27、3-28、3-29、4-1、4-2、4-3、4-4、4-5、4-6、4-7、4-8、4-9、4-10、4-11、4-12、5-1、5-2、5-3、5-4、5-5、5-6、5-7、5-8、5-9、5-10、5-11、5-12、5-13、5-14、5-15、5-16、5-17、5-18、5-19、5-20、5-21、5-22、5-23、5-24、5-25、5-26、5-27、5-28、5-30、5-31、5-32、5-33、5-39、5-40、5-41、6-1、6-2、6-3、6-4、6-5、6-6、6-7、6-8、6-9、6-10、6-11、6-12、6-13、6-14、6-15、6-16、6-17、6-18、6-19、6-20、6-21、6-22、6-23、6-24、6-25、6-26、6-27、6-28、6-29、6-30、6-31、6-32、6-33、6-34、6-35、6-36、6-37、6-38、6-39、6-40、6-41、6-42、6-43、6-44、6-45、6-46、6-47、6-48、6-49、6-50、6-51、6-52、6-53、6-54、6-55、6-56、6-57、6-58、6-59、6-62、6-63、6-64、6-65、6-67、6-68、6-69、6-71、6-72、6-76、6-78、6-80、6-81、6-82、6-84、6-85、6-87、6-90、6-92、6-93、6-95、6-96、6-97、6-98、6-99、6-100、6-102、6-104、6-106、6-108、6-110、6-113、6-114、6-116、6-117、6-119、6-120、6-122、7-1、7-2、7-3、7-4、7-5、7-6、7-7、7-8、7-9、7-10、7-11、7-12、7-13、7-14、7-15、7-16、7-17、7-18、7-19、7-20、7-21、7-22、7-23、7-24、7-25、7-26、8-1、8-2、8-3、8-4、8-5、8-6、8-7、8-8、8-9、9-1、9-2、9-3、9-4、9-5、9-6、9-7、9-8、9-9、9-10、9-11、9-12、9-13、9-14、9-15、9-16、9-17、9-18、9-19、9-20、9-21、9-22、9-23、9-24、9-25、9-26、9-27、10-1、10-2、11-1、11-2、12-1、12-2、12-3、12-4、12-5、12-6、12-7、13-1、13-2、13-3、13-4、13-5、13-6、13-7、13-8、13-9、13-10、13-11、13-12、13-13、13-14、13-15、13-16、13-17、13-18、13-
19、13-20、13-21、13-22、13-23、13-24、13-25、13-26、13-27、13-28、13-29、13-30、13-31、13-32、13-33、13-34、13-35、13-36、13-37、13-38、13-39、13-40、13-41、13-42、13-43、13-44、13-45、13-46、13-47、13-48、13-49、13-50、13-51、13-52、13-53、13-54、13-55、13-56、13-57、13-68、13-69、13-71、13-72、14-1、14-2、14-3、14-4、14-5、14-6、14-7、14-8、14-9、14-10、14-11、14-12、14-13、14-14、14-15、14-16、14-17、14-18、14-19、14-20、14-21、15-1、15-2、15-3、15-4、15-5、15-6、15-7、15-8、15-9、15-10、15-11、15-12、16-1、16-2、16-3、16-4、16-5、16-6、16-7、16-8、16-9、16-10、16-11、16-12、16-13、16-14、16-15、16-16、16-17、16-18、16-19、16-20、16-21、16-22、16-23、16-24、16-25、16-26、16-27、16-28、16-29、16-30、16-31、16-32、16-33、16-34、16-35、16-36、17-1、17-2、17-3、17-4、17-5、17-6、17-7、17-8、17-9、17-10、17-11、17-12、17-13、17-14、17-15、18-1、18-2、18-3、18-4、18-5、18-6、18-7、18-8、18-9、18-10、18-11、18-12、18-13、19-1、19-2、19-3、19-4、19-5、19-6、19-7、19-8、19-9、19-10、19-11、19-12、19-13、19-14、19-15、19-16、19-17、19-18、19-19、19-20、19-21、19-22、19-23、19-24、19-25、19-26、19-27、19-30、19-33、19-34、19-35、19-37、19-39、20-1、20-2、20-3、20-4、20-5、20-6、20-7、20-8、20-9、21-1、21-2、21-3、21-4、21-5、21-6、21-7、21-8、21-11、21-12、21-13、21-14、21-15、21-16、21-17、22-1、22-2、22-3、22-4、22-6、23-1、23-2、24-1、24-2、24-3、24-4、24-5、24-6、24-7、25-3、25-4、26-1、26-2、26-3、26-4、27-1、28-4及28-5。
對TRPM8具有<100nM的IC50之化合物如下:1-1、1-2、1-3、2-1、2-2、2-3、2-4、2-5、2-11、2-12、2-13、2-14、2-15、3-1、3-2、
3-3、3-4、3-5、3-6、3-7、3-8、3-9、3-10、3-11、3-12、3-13、3-14、3-15、3-16、3-17、3-18、3-19、4-1、4-2、4-3、4-4、4-5、4-6、4-10、5-1、5-2、5-3、5-5、5-6、5-7、5-8、5-9、5-10、5-11、5-12、5-13、5-14、5-15、5-17、5-18、5-19、5-20、5-22、5-25、5-26、5-27、5-28、5-30、5-31、5-32、5-33、5-39、5-41、6-1、6-2、6-3、6-4、6-5、6-6、6-7、6-8、6-9、6-10、6-11、6-12、6-13、6-14、6-15、6-16、6-17、6-18、6-19、6-20、6-21、6-22、6-23、6-24、6-25、6-26、6-27、6-28、6-29、6-30、6-31、6-32、6-33、6-34、6-35、6-36、6-37、6-38、6-39、6-40、6-41、6-43、6-44、6-45、6-54、6-55、6-57、6-58、6-63、6-67、6-68、6-76、6-81、6-84、6-87、6-92、6-97、6-98、6-106、6-108、6-114、6-116、6-122、7-1、7-2、7-3、7-4、7-5、7-6、7-7、7-8、7-9、7-10、7-11、7-12、7-13、7-14、7-21、7-22、7-24、7-25、7-26、8-1、8-2、8-3、8-4、8-5、8-7、8-8、8-9、9-1、9-2、9-3、9-4、9-5、9-6、9-7、9-8、9-9、9-10、9-11、9-12、9-13、9-14、9-15、9-16、9-17、9-18、9-19、9-20、9-21、9-22、9-23、9-24、9-25、10-1、10-2、11-1、11-2、12-1、12-2、12-3、12-4、12-5、12-6、13-1、13-2、13-3、13-4、13-5、13-6、13-7、13-8、13-9、13-10、13-11、13-12、13-13、13-14、13-15、13-16、13-17、13-18、13-19、13-20、13-21、13-22、13-23、13-24、13-25、13-26、13-27、13-28、13-29、13-30、13-31、13-32、13-34、13-35、13-36、13-37、13-38、13-39、13-40、13-41、13-42、13-43、13-44、13-45、13-46、13-47、13-48、13-49、13-51、13-53、13-54、13-55、13-71、13-72、14-1、14-2、14-3、14-4、14-5、14-6、14-7、14-8、14-9、14-10、14-11、14-12、14-13、14-14、14-15、14-16、14-17、15-1、15-2、15-3、15-4、15-5、15-6、15-7、16-1、16-2、16-3、16-4、16-5、16-6、16-7、16-8、16-
9、16-10、16-11、16-12、16-13、16-14、16-15、16-16、16-17、16-18、16-19、16-20、16-21、16-22、16-23、16-24、16-25、16-27、17-1、17-2、17-3、17-4、17-5、17-6、17-7、17-8、17-9、17-10、17-11、18-1、18-2、18-3、18-4、18-5、18-6、18-9、18-10、18-11、19-1、19-2、19-3、19-4、19-5、19-6、19-7、19-8、19-9、19-10、19-11、19-12、19-13、19-14、19-16、19-17、19-18、19-20、19-21、19-22、19-23、19-24、19-25、19-26、19-30、19-33、19-37、20-1、20-6、20-7、20-8、21-1、21-2、21-5、21-8、21-12、21-13、21-14、21-17、22-1、22-3、22-4、23-1、23-2、24-1、24-5、24-6、24-7、26-1、26-2、26-3、26-4、27-1及28-5。
對TRPM8具有<10nM的IC50之化合物如下:5-7、5-9、5-10、5-14、5-27、5-28、6-1、6-2、6-3、6-4、6-5、6-6、6-7、6-8、7-1、7-22、9-1、9-2、9-3、9-10、9-11、9-12、12-1、13-34、13-35、13-36、13-37、13-38、13-71、14-5、15-6、16-4、17-6、18-2、19-14、19-30、19-33、24-5、24-7、26-1、26-3及27-1。
薄荷醇-誘導之Ca
2+
流入人惡性黑色素瘤細胞株中之測定
TRPM8在人惡性黑色素瘤細胞株G-361(Health Science Research Resources Bank,Osaka,Japan)中表達,因此將G-361細胞用於體外功能分析。
使G-361細胞在5%CO2加濕培養器和T175燒瓶中在37℃的溫度下生長至約80%匯合度。培養基組成由McCoy's 5A培養基和10% FCS構成。進行分析48小時之前,將細胞以每孔12,000細胞的培養基中的密度接種於多聚-D-賴胺酸塗覆之96-孔板(Corning),在5%CO2、37℃下生長一夜。實施分析當天,去除生長之培養基,在室溫下經1小時在細胞中加載溶解於分析用緩衝液(HBSS,19.4mM HEPES pH7.4,2.5mM Probenecid)中之5microM Fluo-4AM(Molecular Probes)和
0.005% Pluronic F-127。用分析用緩衝液清洗之後,將細胞與各種濃度的化合物預培養5分鐘。藉由利用FDSS之細胞成像技術來監控由300microM的薄荷醇的添加而引起之細胞間鈣濃度的變化。
藉由點劑量反應研究來決定本發明的化合物的IC50值。使用複孔的平均作為每個資料點來描繪出曲線。最後,依據由XLfit(ID Business Solutions Ltd.)決定之最佳擬合劑量曲線來計算IC50值。
本發明的化合物顯出良好的IC50值,其顯示適合於上述用途。
神經病變性疼痛的慢性壓迫損傷(CCI)-誘導之模型;異常性冷疼痛
從Charles River Japan,Inc.購入雄性Sprague-Dawley大鼠(實驗開始時為7週齡,n=7-10/一次治療)進行使用。按照Bennett GJ和Xie YK(Pain 1988,33:87-107)的方法形成CCI狀態。腹膜內注射戊巴比妥鈉麻醉大鼠。使左側共同坐骨神經以去掉黏附組織之狀態暴露在大腿部的中間,在其周圍利用4-0絲線(Ethicon Inc.)隔著約1mm的間隔鬆散地結紮4道。除了坐骨神經結紮以外藉由相同方式實施假手術。CCI外科手術後經過1-2週後,如Tanimoto-Mori S et al.(Behav Pharmacol.,19:85-90,2008)所記載,使用帶溫度控制器(Mode13300-0,CAL Controls Inc.)之冷卻板(LHP-1700CP,TECA)對異常性冷疼痛進行評價。使動物適應不鏽鋼板(15×33cm)上的由透明亞克力盒(10×12×12cm)構成之裝置。將冷卻板的表面維持為10℃,以0.1℃的精確度連續監控板的溫度。為了進行實驗,將大鼠載置於冷卻板上,以120秒為截止值,前後給藥化合物,測定縮足潛伏期(PWL)。將本發明的化合物或其媒介物口服給藥、皮下給藥或腹膜內給藥。如下計算抑制率。
{數學式1}
本發明的化合物在該模型中顯出較強的活性,其顯示適合於上述用途。
神經病變性疼痛的慢性壓迫損傷(CCI)-誘導之模型;靜態異常性疼痛
從Charles River Japan,Inc.購入雄性Sprague Dawley大鼠(實驗開始時為7週齡,n=7-10/一次治療)進行使用。按照Bennett GJ和Xie YK(Pain 1988,33:87-107)的方法形成CCI狀態。腹膜內注射戊巴比妥鈉麻醉大鼠。使左側共同坐骨神經以去掉黏附組織之狀態暴露在大腿部的中間,在其周圍利用4-0絲線(Ethicon Inc.)隔著約1mm的間隔鬆散地結紮4道。除了坐骨神經結紮以外藉由相同方式實施假手術。CCI外科手術後經過2-3週時,如Field MJ et al.(Pain 1999,83:303-311)所記載,藉由纖毛機械刺激針(VFH)對靜態異常性疼痛進行評價。開始實驗之前,使實驗動物適應網格底籠子中。將VFH緊貼後足足底,以逐漸增加力之方式進行實驗(0.16g、0.4g、0.6g、1g、1.4g、2g、4g、6g、8g、10g、15g及26g)。將各VFH按壓於相側足6秒鐘,或者按壓至發生收縮反應。出現一次收縮反應,則以更弱的壓力按壓VFH再次進行實驗,直至不發生收縮反應。將誘發反應所需的最低壓力記為縮足閾值(PWT)。若實驗動物在無害的1.4g VFH以下作出反應,則確定為靜態異常性疼痛。將本發明的化合物或其媒介物口服給藥、皮下給藥或腹膜內給藥。如下計算抑制率。
本發明的化合物在該模型中顯出較強的活性,其顯示適合於上述用途。
神經病變性疼痛的奧沙利鉑-誘導之模型;異常性冷疼痛及靜態異常性疼痛
從Charles River Japan,Inc.購入雄性Sprague Dawley大鼠(實驗開始時為7週齡,n=7-10/一次治療)進行使用。按照Gauchan P et al.(NeuroSci Lett,2009,458,93-95)的方法進行本研究。將奧沙利鉑(Yakult Co.,Ltd.)溶解於5%葡萄糖中。在2週期間,以1週2次的頻率以腹腔內給藥的方式注射奧沙利鉑(4mg/kg)。如Tanimoto-Mori S et al.(Behav Pharmacol.,19:85-90,2008)所記載,使用帶溫度控制器(Mode13300-0,CAL Controls Inc.)之冷卻板(LHP-1700CP,TECA)對異常性冷疼痛進行評價。使動物適應不鏽鋼板(15×33cm)上的由透明亞克力盒(10×12×12cm)構成之裝置。將冷卻板的表面維持為10℃,以0.1℃的精確度連續監控板的溫度。為了進行實驗,將大鼠載置於冷卻板上,以120秒為截止值,前後給藥化合物,測定PWL。利用VFH對靜態異常性疼痛進行評價。開始實驗之前,使實驗動物適應網格或網眼底籠子。將VFH緊貼後足足底側面,以逐漸增加力之方式進行實驗(0.16g、0.4g、0.6g、1g、1.4g、2g、4g、6g、8g、10g、15g及26g)。若出現一次收縮反應,則以更弱的壓力按壓VFH來再次進行實驗,直至不發生收縮反應。將誘發反應所需的最低壓力記為縮足閾值(PWT)。為了進行實驗,給藥化合物前後測定PWT。將本發明的化合物或其媒介物口服給藥、皮下給藥或腹膜內給藥。如下計算抑制率。
本發明的化合物在模型中顯出較強的活性,其顯示適合於上述用途。
神經病變性疼痛的奧沙利鉑-誘導之模型;冷痛覺過敏/異常性冷疼痛
從Charles River Japan,Inc購入雄性Sprague Dawley大鼠(實驗開
始時為7週齡,n=8-10/一次治療)進行使用。將奧沙利鉑(Wako Pure Chemical Industries,Ltd.)以注射用途溶解於5%葡萄糖中,製造4mg/mL溶液。在2週期間,以1週2次的頻率(第1天、第2天、第8天、第9天),以1mL/kg的容積腹膜內給藥奧沙利鉑(4mg/kg)。將治療第一天定義為第1天。藉由丙酮試驗對冷痛覺過敏/異常性冷疼痛進行評價。開始實驗之前,使實驗動物適應網格或網眼底籠子。將丙酮(50mL)塗佈於後足足底。塗佈之後,將傷害性反應如下計分:0;無反應、1;跺足和/或抬足、2;一次添足/咬足或縮足、3;反覆舔足/咬足和/或縮足。將丙酮反覆塗佈於左側及右側後足(各個足2次,總計塗佈4次),因此總分最高12分,最低0分。為了進行實驗,給藥化合物前後測定總分。將本發明的化合物或其溶劑口服給藥、皮下給藥或腹膜內給藥。
本發明的化合物在該模型中顯出較強的活性,其顯示適合於上述用途。
伊西林-誘導之大鼠濕狗樣抖動
利用雄性Sprague Dawley大鼠(6-7週齡,Charles River Japan,Inc.,n=5-8/一次治療),用於評價本發明的化合物所具有之伊西林誘導之自發的濕狗樣抖動(WDS)行為的阻斷效果。注射伊西林之前,使大鼠習慣於觀察用箱子(21.5×26.5×25.0cm)至少20分鐘。將溶解於PEG400中之伊西林(Sigma)以0.5、1.0或2.5mg/kg腹膜內給藥,注射伊西林之後,計數30min自發的WDS。在注射伊西林之前,將本發明的化合物或其媒介物口服給藥、皮下給藥或腹膜內給藥。如下計算抑制率。
{數學式3}抑制率(%);[1-(化合物WDS計數/媒介物WDS計數)]×100.
本發明的化合物在該模型中顯出較強的活性,其顯示適合於上
述用途。
豚鼠的體外排尿頻率的測定
用胺基甲酸乙酯麻醉雌性豚鼠(300-450g)。實施中線腹部切開(midline abdominal incision)手術,使尿管兩側均暴露並進行結紮,將導尿管移植於膀胱極(bladder pole)之後閉合腹部。為了給藥化合物而使頸靜脈暴露,插入導尿管。進行該手術之後,通過t型導管將膀胱的導尿管和輸液泵及壓力感測器連接。輸注生理鹽水,並記錄膀胱內壓。經過1小時平衡時間,一定的排尿週期成立時,將薄荷醇(0.2-0.6mM)添加到輸注生理鹽水中。在該時刻,將媒介物(對照組)或TRPM8拮抗劑以靜脈內注射方式大量給藥。計算對排尿間隔(因膀胱的容量而不同)及排尿壓力之治療效果,並在媒介物-治療組與化合物-治療組之間進行比較。
本發明的化合物在該模型中顯出較強的活性,其顯示適合於上述用途。
麻醉之膀胱炎患者大鼠中之膀胱活性的測定
使用雌性Sprague-Dawley大鼠(7-8週齡,Japan SLC)。將溶解於生理鹽水(Otsuka)中之環磷醯胺(Wako)以200mg/kg腹膜內給藥。第二天,給藥0.9mg/kg的胺基甲酸乙酯,麻醉大鼠。藉由中線切開手術來打開腹部,通過膀胱頂(dome)移植聚乙烯導尿管。藉由T型導管將膀胱的導尿管連接於壓力感測器及微量注射泵。在室溫下,以3mL/hour的速度將生理鹽水輸注於膀胱。在給藥被測化合物之前,經約1小時將膀胱內壓連續記錄在圖表筆式記錄儀(chart pen recorder)中。
將溶解於含有WellSolve(Celeste)之PBS中之被測化合物以1mg/kg、3mg/kg、5mg/kg或10mg/kg靜脈內給藥。
在給藥被測化合物之後,根據60分鐘的排尿間隔計算排尿頻
率,並由膀胱內壓測定資料進行分析。利用Dunnett'方法,與媒介物組作對比來評價由被測化合物介導之頻率抑制率。將小於5%的概率水平視為顯著差異。藉由平均標準誤差法,由8-12只大鼠分析資料。
所有被測化合物均對麻醉之患者大鼠中的膀胱異常活動帶來顯著影響。
人多非利特結合分析
準備人HERG轉染HEK293S細胞,在內部(in-house)使其生長。使收集之細胞懸浮於50mM 3-HCl(4℃下,pH為7.4)之後,利用設定為總功率之便攜式Polytron PT 1200粉碎機,在冰上均質化20sec。在4℃下,將該均質液以48,000×g離心分離20min。接著,使顆粒再次重懸、均質化之後,以相同的方式離心分離1次以上。使最終顆粒重懸於適當容積的50mM 3-HCl、10mM KCl、1mM MgCl2(4℃下,pH為7.4)中,均質化、等分,在-80℃下保存至進行使用為止。在利用BCA蛋白質分析試劑盒(PIERCE)及ARVOsx平板讀取器(Wallac)之蛋白質濃度測定中,使用膜等分的等份量。結合分析係在384-孔板中30microL的總容積中進行。活性係利用螢光偏振技術以PHERAstar(BMG LABTECH)進行測定。在室溫下,將10microL的測試化合物與10microL的螢光配體(6nM Cy3B-標記多非利特衍生物)及10microL的膜均質液(6微克的蛋白質)培養120分鐘。在最終濃度下以10microM E4031決定非特異性結合。
與上述記載之TRPM8功能分析中的IC50值相比,本發明的所有被測化合物在人多非利特結合中顯出更高的IC50值。
WO2014/130582的實施例2-121所記載之最接近本發明之化合物如下。
{化學式164}
前述化合物在人多非利特結合分析中顯出19microM的IC50和6.5microM的Ki值,但本發明的化合物在人多非利特結合分析中顯出更高的IC50值。因此,會減少發生不良心血管事件之風險。
代謝穩定性分析:
人肝微粒體(HLM)中的半衰期
在96-深孔板上,在37℃下培養測試化合物(1microM)和100mM磷酸鉀緩衝液(pH7.4)中的1mM MgCl2及0.78mg/mL HLM(HL101)或0.74mg/mL HLM(Gentest UltraPool 150)或0.61mg/mL HLM(Xeno Tech XTreme 200)。根據需要,將反應混合物分為兩個組,亦即非-P450及P450組。NADPH僅添加到P450組的反應混合物中。(並且還使用NADPH生成系統來代替NADPH)在0、10、30及60min時刻收集P450組樣品的等份量,其中,0分鐘時刻係顯示將NADPH添加到P450組的反應混合物時之時間。在-10及65分鐘時刻收集非-P450組樣品的等份量。用含有內標物之乙腈溶液萃取收集之等份量。使沉澱之蛋白質在離心分離器(2000rpm,15min)中旋轉。上清液中的化合物濃度係藉由LC/MS/MS系統進行測定。
半衰期值係繪製時間對比化合物/內標物的峰值面積比的自然對數來獲得。代謝速度(k)係由通過點之最佳擬合線條的傾斜計算出。其利用下述公式換算為半衰期值:{數學式4}半衰期=ln2/k
本發明的化合物顯出較佳的穩定性,其顯示適合上述用途。
WO2014/130582的實施例2-121所記載之接近化合物在HLM中具
有小於5分鐘的半衰期,固有清除率(CLint)超過215mL/min/kg。相對於此,本發明的化合物在代謝穩定性評價中HLM中的半衰期小於5分鐘,CLint為<100mL/min/kg,這會呈現良好的藥物動力學特性。
藥物-藥物相互作用分析
該方法主要包括對各化合物3microM或0.4-50microM,由探針(對CYP1A2為他克林2microM或非那西汀50microM,對CYP2B6為安非拉酮3microM,對CYP2C8為阿莫地喹2microM,對CYP2C9為雙氯高滅酸5或10microM,對CYP2C19為S-美芬妥因40microM,對CYP2D6為右美沙芬5microM或丁呋洛尔5microM,對CYP3A4為咪達唑侖2microM或2.5microM)決定代謝物質生成抑制率。
更具體而言,該分析如下進行。將包含0.1mg蛋白質/mL或0.05mg蛋白質/mL的人肝微粒體、100mM磷酸鉀緩衝液(pH7.4)、1mM MgCl2或3.3mM MgCl2及探針之170microL混合物作為基質,將化合物(60microM,10microL)預培養合適的時間(5min或30min)。添加20microL的10mM NADPH或10microL的13microM NADPH來開始進行反應。在37℃下培養分析板。在合適的時刻(例如8min或10min)將乙腈或甲醇添加到培養溶液中。
藉由LC/MS/MS系統測定上清液中的代謝產物濃度。
在測試化合物存在或不存在下,依據代謝產物的生成率(%)解釋藥物-藥物相互作用程度。
本發明的化合物顯出較佳的結果,其顯示適合於上述用途。
血漿蛋白質結合分析
利用96-孔板類型裝置,藉由平衡透析方法測定測試化合物(1microM)的血漿蛋白質結合。將HTD96a(註冊商標)、再生維生素膜(分子量截止值12,000-14,000,22mm×120mm)徹夜浸泡在蒸餾水中之後,浸泡在30%乙醇中15分鐘,最後浸泡在透析緩衝液(達爾
伯克氏磷酸鹽緩衝生理鹽水,去除CaCl2和MgCl2)中20分鐘。使用人、Sprague-Dawley大鼠及比格犬的冷凍血漿。組裝透析裝置,將150microL的化合物-加強血漿(compound-fortified plasma)添加到各孔的一側,並將150microL的透析緩衝液添加到各孔的另一側。在37℃下,以150r.p.m培養4小時之後,採樣血漿及緩衝液的等份量。用300microL的含有分析用內標化合物之乙腈或乙腈/甲醇(1:1)萃取血漿及緩衝液中的化合物。藉由LC/MS/MS系統決定化合物濃度。
依據下述式(A)或(B)計算未結合化合物的比率:{數學式5}(A)fu=1-{([血漿]eq-[緩衝液]eq)/([血漿]eq)}
上述式中,[血漿]eq及[緩衝液]eq分別是血漿及緩衝液中化合物的濃度。
上述式中,Cp是血漿樣品內化合物的峰值面積;Cis,p是血漿樣品內內標物的峰值面積;Cb是緩衝液樣品內化合物的峰值面積;Cis,b是緩衝液樣品內內標物的峰值面積;4及4/3分別是血漿及緩衝液中的稀釋率的倒數。
本發明的化合物顯出較佳的血漿蛋白質結合,其顯示適合於上述用途。
平衡水溶性研究
將各化合物的DMSO溶液(2microL,30mM)分配到96-孔玻璃底板的各孔中。將磷酸鉀緩衝溶液(50mM,198microL,pH6.5)添加到各孔中,在37℃下將混合物旋轉振蕩的同時培養24小時。在
2000g下離心分離5分鐘之後,藉由Isopore膜過濾上清液。藉由一般的梯度HPLC方法(J.Pharm.Sci.,95,2115-2122,2006)決定樣品的濃度。
本申請中所引用之包括已交付專利、專利申請及期刊論文(但未限於此)之所有公開出版物全部作為參照而分別引用於本申請中。雖然將公開之形態作為參照而在上述中對本發明進行了說明,但如果是本領域技術人員就可以認識到詳細記述之具體實驗只不過是本發明的一例。應理解為只要不脫離本發明宗旨就可以進行多種變形。因此,本發明僅受下述申請專利範圍的限制。
Claims (13)
- 一種下述化學式(I)的化合物或其藥學上可接受的鹽:上述式中,A為芳基或雜芳基;B為芳基或雜芳基;L獨立地選自由化學鍵、氧、硫、-NR4-、-(CRCRD)t-、-O(CRCRD)t-、-(CRCRD)tO-、-N(R4)(CRCRD)tO-及-O(CRCRD)tN(R4)-所構成之群組;X獨立地選自由-CH2-、氧及NH所構成之群組;RA和RB獨立地選自由(1)氫及(3)(C1-C6)烷基所構成之群組;或者,RA和RB可形成側氧基(=O);每個RC和RD為(1)氫;R1獨立地選自由(2)鹵素及(8)(C1-C6)鹵代烷基所構成之群組;不同的碳上的兩個R1可形成3-8員環烷基環;R2獨立地選自由(1)氫、(2)鹵素、(10)(C1-C6)烷基、(11)(C3-C7)環烷基及(12)(C1-C6)烷氧基所構成之群組;R3獨立地選自由(1)氫、(2)鹵素、(3)氰基、(5)羥基、(8)(C1-C6)烷基磺醯基、(9)-NR5R6、(10)-C(=O)NR5R6、(12)(C1-C6)烷基、(13)(C3-C7)環烷基、(14)(C1-C6)烷氧基(C0-C6)烷基、(15)(C3-C7)環烷氧基、(16)-C(=O)(C1-C6)烷基及(17)-C(=O)O(C1-C6)烷基所構成之群組;該(C1-C6)烷基及(C1-C6)烷氧基(C0-C6)烷基視情況經1至3個獨立地選自(2)鹵素、(3)羥基、(4)氰基、(5)(C3-C7)環烷基及(9)-NR6R5中之取代基取代;其中,R5和R6可與它們所鍵合之氮原子一同形成可含有選自氧之原子之4-6員環;且該環視情況經選自(3)羥基及(7)(C1-C6)烷氧基中之一個取代基取代;R4、R5及R6獨立地選自由(1)氫、(2)(C1-C6)烷基、(5)羥基(C1-C6)烷基、(6)(C1-C6)烷氧基(C1-C6)烷基及(10)(C1-C6)烷基羰基所構成之群組;p為1、2、3、或4;q為1、2、3、或4;當q為2或2以上時,R1相同或不同,r為1或2;當r為2或2以上時,R2相同或不同,s為1或2;當s為2或2以上時,R3相同或不同,t為1、2或3;當t為2或2以上時,RC和RD相同或不同。
- 如申請專利範圍第1項所述之化合物或其藥學上可接受的鹽,其中,A為6員芳基或5至6員雜芳基。
- 如申請專利範圍第1項所述之化合物或其藥學上可接受的鹽,其中,A獨立地選自由苯、吡啶、噠嗪、吡嗪、嘧啶、三嗪、噻吩、呋喃、吡咯、咪唑、吡唑、噻唑、異噻唑、噁唑、異噁唑及三唑所構成之群組。
- 如申請專利範圍第2項所述之化合物或其藥學上可接受的鹽,其中,A獨立地選自由苯、吡啶、噠嗪、吡嗪、嘧啶、三嗪、噻吩、呋喃、吡咯、咪唑、吡唑、噻唑、異噻唑、噁唑、異噁唑及三唑所構成之群組。
- 一種下述化學式(I)的化合物或其藥學上可接受的鹽:上述式中,A選自由苯、吡啶、噠嗪、吡嗪、嘧啶、三嗪、噻吩、呋喃、咪唑、吡唑、噻唑、異噻唑、噁唑、異噁唑及三唑所構成之群組;B為芳基或雜芳基,且當A為苯基時,B不為苯基;L獨立地選自由化學鍵、氧、硫、-NR4-、-(CRCRD)t-、-O(CRCRD)t-、-(CRCRD)tO-、-N(R4)(CRCRD)tO-及-O(CRCRD)tN(R4)-所構成之群組;X獨立地選自由-CH2-、氧及NH所構成之群組;RA和RB獨立地選自由(1)氫及(3)(C1-C6)烷基所構成之群組;或者,RA和RB可形成側氧基(=O);每個RC和RD為(1)氫;R1獨立地選自由(1)氫、(2)鹵素及(6)(C1-C6)烷基所構成之群組;或者,相同的碳或不同的碳上的兩個R1可形成3-8員環烷基環;R2獨立地選自由(1)氫、(2)鹵素、(10)(C1-C6)烷基、(11)(C3-C7)環烷基及(12)(C1-C6)烷氧基所構成之群組;R3獨立地選自由(1)氫、(2)鹵素、(3)氰基、(5)羥基、(8)(C1-C6)烷基磺醯基、(9)-NR5R6、(10)-C(=O)NR5R6、(12)(C1-C6)烷基、(13)(C3-C7)環烷基、(14)(C1-C6)烷氧基(C0-C6)烷基、(15)(C3-C7)環烷氧基、(16)-C(=O)(C1-C6)烷基及(17)-C(=O)O(C1-C6)烷基所構成之群組;該(C1-C6)烷基及(C1-C6)烷氧基(C0-C6)烷基視情況經1至3個獨立地選自(2)鹵素、(3)羥基、(4)氰基、(5)(C3-C7)環烷基及(9)-NR6R5中之取代基取代;其中,R5和R6可與它們所鍵合之氮原子一同形成可含有選自氧之原子之4-6員環;且該環視情況經選自(3)羥基及(7)(C1-C6)烷氧基中之一個取代基取代;R4、R5及R6獨立地選自由(1)氫、(2)(C1-C6)烷基、(5)羥基(C1-C6)烷基、(6)(C1-C6)烷氧基(C1-C6)烷基及(10)(C1-C6)烷基羰基所構成之群組;p為1、2、3、或4;q為1、2、3、或4;當q為2或2以上時,R1相同或不同,r為1或2;當r為2或2以上時,R2相同或不同,s為1或2;當s為2或2以上時,R3相同或不同,t為1、2或3;當t為2或2以上時,RC和RD相同或不同。
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如申請專利範圍第1至5項中任一項所述之化合物或其藥學上可接受的鹽,其中,前述化合物選自以下:3-(2-(2,5-二甲基-1-(5-甲基異噁唑-3-基)-1H-吡咯-3-基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(2,5-二甲基-1-苯基-1H-咪唑-4-基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;6-(4-(2-(2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)苯基)-2-氰基吡啶;3-(2-(1-(3-氯苯基)-2,5-二甲基-1H-咪唑-4-基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(1-(3-氟苯基)-2,5-二甲基-1H-咪唑-4-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(1,4-二甲基-5-苯基-1H-吡唑-3-基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(6-甲基吡嗪-2-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;6-(4-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)苯基)-2-氰基吡啶;8,8-二氟-3-(2-(2'-(羥基甲基)-[1,1'-聯苯基]-4-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(3-甲基吡嗪-2-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(2,5-二甲基-1-苯基-1H-咪唑-4-基)-2-側氧基乙基)-8,8-二氟-1-氧雜-3-氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(2-(羥基甲基)吡啶-3-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(4-(羥基甲基)吡啶-3-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(2,5-二甲基-1-(5-甲基異噁唑-3-基)-1H-吡咯-3-基)-2-側氧基乙基)-8,8-二氟-1-氧雜-3-氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(5-(2-(羥基甲基)苯基)-4-甲基噻吩-2-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(4-(3-(羥基甲基)吡嗪-2-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(1,4-二甲基-5-苯基-1H-吡唑-3-基)-2-側氧基乙基)-8,8-二氟-1-氧雜-3-氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(4-甲基噠嗪-3-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(4-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)苯基)吡嗪-2-甲腈;3-(2-(1,4-二甲基-5-苯基-1H-吡咯-2-基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(3-(羥基甲基)吡嗪-2-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(6-(甲基(吡啶-2-基)胺基)吡啶-3-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(4-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)苯基)-2-氰基吡啶;8,8-二氟-3-(2-側氧基-2-(4-(喹啉-8-基)苯基)乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(4-(1H-吲哚-4-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-側氧基-2-(4-(喹啉-2-基)苯基)乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(異喹啉-8-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(異喹啉-1-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(呋喃并[3,2-c]吡啶-4-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(6-(甲基(吡啶-2-基)胺基)吡啶-3-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(6-(甲基(苯基)胺基)吡啶-3-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(3-氟吡啶-2-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(4-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)苯基)異菸鹼甲腈;8,8-二氟-3-(2-(4-(2-甲氧基吡啶-3-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(4-甲氧基吡啶-3-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-側氧基-2-(4-(2-側氧基吲哚啉-4-基)苯基)乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(4-(1H-吡咯并[3,2-c]吡啶-4-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(4-(1H-吡咯并[2,3-b]吡啶-4-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(4-(3-氯吡啶-2-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(2-甲基-1H-苯并[d]咪唑-1-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(4-(1H-吲唑-4-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(6-(1H-吲唑-4-基)吡啶-3-基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(4-(1H-苯并[d]咪唑-1-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(5-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)-1,3-二甲基-1H-吡咯-2-基)苯甲腈;3-(2-(4-(1H-吡咯并[2,3-c]吡啶-4-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(3-氟-4-(喹啉-8-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(5-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)-1-甲基-1H-吡咯-2-基)苯甲腈;3-(5-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)-3-甲基噻吩-2-基)苯甲腈;8,8-二氟-3-(2-(4-(2-(2-羥基乙氧基)吡啶-3-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(5-(3-氟苯基)-1,4-二甲基-1H-吡咯-2-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(5-(3-氯苯基)-1,4-二甲基-1H-吡咯-2-基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(5-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)-1,3-二甲基-1H-吡咯-2-基)苯甲醯胺;8,8-二氟-3-(2-(5-(2-氟苯基)-1,4-二甲基-1H-吡咯-2-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(4-(1H-吡唑并[3,4-b]吡啶-4-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(4-(1H-吡唑并[4,3-c]吡啶-4-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(4-(1H-吲唑-1-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(5-(3-氟苯基)-1-甲基-1H-咪唑-2-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(2-甲基-3H-咪唑并[4,5-b]吡啶-3-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-側氧基-2-(4-(吡啶-2-基氧基)苯基)乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(5-(3,5-二氟苯基)-1,4-二甲基-1H-吡咯-2-基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(2'-甲基-[3,3'-聯吡啶]-6-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(4-(1H-吡唑并[3,4-d]嘧啶-4-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(6-(1H-吡咯并[2,3-c]吡啶-4-基)吡啶-3-基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(3-(2-羥基乙氧基)吡嗪-2-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-側氧基-2-(4-(酞嗪-1-基)苯基)乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(4-(3H-咪唑并[4,5-b]吡啶-3-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)-4-甲基噻唑-5-基)苯甲腈;3-(2-(1,4-二甲基-5-苯基-1H-咪唑-2-基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(5-(3-氟苯基)-1,4-二甲基-1H-咪唑-2-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)-1,4-二甲基-1H-咪唑-5-基)苯甲腈;8,8-二氟-3-(2-(5-(異喹啉-8-基)-1,4-二甲基-1H-咪唑-2-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(5-(2-(羥基甲基)苯基)-1,4-二甲基-1H-咪唑-2-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(2-(羥基甲基)-1H-苯并[d]咪唑-1-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(5-(3-氟苯基)-1,4-二甲基-1H-吡咯-3-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(4-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)-1,3-二甲基-1H-吡咯-2-基)苯甲腈;3-(2-(5-(1H-苯并[d]咪唑-1-基)吡嗪-2-基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(4-(2,7-萘啶-1-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-側氧基-2-(4-(2-側氧基-2,3-二氫-1H-苯并[d]咪唑-1-基)苯基)乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(5-(2-(羥基甲基)苯基)吡嗪-2-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(5-(4-甲氧基吡啶-3-基)吡嗪-2-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(5-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)-2,4-二甲基噻吩-3-基)苯甲醯胺;3-(2-(5-(3,5-二氟苯基)-1,4-二甲基-1H-咪唑-2-基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-側氧基-2-(4-(噠嗪-3-基氧基)苯基)乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-側氧基-2-(4-(2-側氧基-1H-咪唑并[4,5-b]吡啶-3(2H)-基)苯基)乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(5-(3,5-二氟苯基)-4-甲基噻唑-2-基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;4'-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)-2'-甲氧基-[1,1'-聯苯基]-2-甲腈;2-(4-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)苯氧基)菸鹼甲腈;3-(2-(4-((3-氯吡啶-2-基)氧基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(3-(羥基甲基)吡啶-2-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(2'-(胺基甲基)-[1,1'-聯苯基]-4-基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-側氧基-2-(6-(喹啉-8-基)吡啶-3-基)乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(5-(2-甲基吡啶-3-基)吡嗪-2-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(4-(2,7-萘啶-1-基)苯基)-2-側氧基乙基)-8,8-二氟-1-氧雜-3-氮雜螺[4.5]癸烷-2,4-二酮;3-(4-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)苯基)-2-甲基-3H-咪唑并[4,5-b]吡啶-5-甲腈;8,8-二氟-3-(2-側氧基-2-(4-(2-側氧基苯并[d]噁唑-3(2H)-基)苯基)乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(4-(2,5-二甲基-3H-咪唑并[4,5-b]吡啶-3-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(5-(2-甲基-1H-苯并[d]咪唑-1-基)吡嗪-2-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(2-甲氧基-5-甲基-3H-咪唑并[4,5-b]吡啶-3-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(5-甲基-2-(三氟甲基)-3H-咪唑并[4,5-b]吡啶-3-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(2-(4-(2-(二氟甲基)-5-甲基-3H-咪唑并[4,5-b]吡啶-3-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(5-甲基-2-側氧基-1H-咪唑并[4,5-b]吡啶-3(2H)-基)苯基)-2-側氧基乙基)1,3-二氮雜螺[4.5]癸烷-2,4-二酮;6-(4-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)苯氧基)-2-氰基吡啶;8,8-二氟-3-(2-(4-(5-甲基-3H-咪唑并[4,5-b]吡啶-3-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(3-甲氧基吡嗪-2-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;3-(4-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)-3-氟苯基)吡嗪-2-甲腈;8,8-二氟-3-(2-(4-(咪唑并[1,2-b]噠嗪-3-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(2'-(2-羥基乙基)-[1,1'-聯苯基]-4-基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;2-(4'-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)-[1,1'-聯苯基]-2-基)乙腈;3-(2-(4-(1H-咪唑并[4,5-b]吡嗪-1-基)苯基)-2-側氧基乙基)-8,8-二氟-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(4-(4-甲基噠嗪-3-基)苯基)-2-側氧基乙基)-1-氧雜-3-氮雜螺[4.5]癸烷-2,4-二酮;3-(4-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)苯氧基)噠嗪-4-甲腈;8,8-二氟-3-(2-(4-(2-(羥基甲基)-5-甲基-3H-咪唑并[4,5-b]吡啶-3-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-側氧基-2-(4-(吡唑并[1,5-a]嘧啶-3-基)苯基)乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;4-(4-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)苯基)菸鹼甲腈;8,8-二氟-3-(2-(2-氟-4-(4-甲基噠嗪-3-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;8,8-二氟-3-(2-(2-氟-4-(3-(羥基甲基)吡嗪-2-基)苯基)-2-側氧基乙基)-1,3-二氮雜螺[4.5]癸烷-2,4-二酮;及2-(4-(2-(8,8-二氟-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-3-基)乙醯基)苯基)菸鹼甲腈。
- 一種如申請專利範圍第1至5項中任一項所述之化合物或其藥學上可接受的鹽在製備用於治療由TRPM8受體拮抗活性介導之病症或障礙之藥物中之用途。
- 一種如申請專利範圍第6項所述之化合物或其藥學上可接受的鹽在製備用於治療由TRPM8受體拮抗活性介導之病症或障礙之藥物中之用途。
- 如申請專利範圍第7項所述之用途,其中,前述病症或障礙為炎症、疼痛及泌尿系統疾病或障礙中的一種或多種,其包括:慢性疼痛;包括異常性冷疼痛和糖尿病性神經病變在內之神經病變性疼痛;術後疼痛;骨關節炎;類風濕關節炎疼痛;癌症疼痛;神經痛;神經病變;痛覺過敏;牙本質過敏症;神經損傷;偏頭痛;叢發性及緊張性頭痛;缺血;大腸急躁症;雷諾症候群;神經退行性病變;纖維肌痛;中風;瘙癢;包括焦慮症和抑鬱症在內之精神疾病;包括哮喘、慢性阻塞性肺病在內之炎症性疾病;包括COPD、肺動脈高血壓在內之氣道疾病;包括其他應激相關病症在內之焦慮症;包括逼尿肌過度活動症或膀胱過度活動症、尿失禁、神經性逼尿肌過度活動症或逼尿肌反射亢進、特發性逼尿肌過度活動症或逼尿肌不穩定、良性前列腺增生症及下尿路症狀在內之泌尿系統疾病或障礙;以及該等的組合。
- 一種藥學組合物,其包含申請專利範圍第1至5項中任一項所述之化合物或其藥學上可接受的鹽,及藥學上可接受的載劑。
- 如申請專利範圍第10項所述之藥學組合物,進一步包含另一藥理活性劑。
- 如申請專利範圍第1至5項中任一項所述之化合物或其藥學上可接受的鹽,其用於治療由TRPM8受體拮抗活性介導之病症或障礙。
- 一種製備藥學組合物之方法,其包括將如申請專利範圍第1至5項中任一項所述之化合物或其藥學上可接受的鹽及藥學上可接受的載劑或賦形劑進行混合。
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US9446033B2 (en) | 2013-03-01 | 2016-09-20 | Clio, Inc. | Pharmaceutical composition including migratory factor for guiding pluripotent stem cells to injury |
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2015
- 2015-03-16 US US15/125,615 patent/US10093678B2/en active Active
- 2015-03-16 ES ES15760744T patent/ES2850999T3/es active Active
- 2015-03-16 TW TW104108412A patent/TWI674257B/zh active
- 2015-03-16 MX MX2016011632A patent/MX2016011632A/es unknown
- 2015-03-16 CA CA2940621A patent/CA2940621C/en active Active
- 2015-03-16 WO PCT/JP2015/001454 patent/WO2015136947A1/en active Application Filing
- 2015-03-16 RU RU2016140338A patent/RU2683309C2/ru active
- 2015-03-16 KR KR1020167027045A patent/KR102425400B1/ko active IP Right Grant
- 2015-03-16 CN CN201580013708.3A patent/CN106103416B/zh active Active
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- 2015-03-16 EP EP15760744.1A patent/EP3116858B1/en active Active
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2016
- 2016-12-16 HK HK16114375A patent/HK1226064A1/zh unknown
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2018
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ES2850999T3 (es) | 2021-09-02 |
EP3116858A4 (en) | 2017-11-22 |
WO2015136947A1 (en) | 2015-09-17 |
HK1226064A1 (zh) | 2017-09-22 |
CA2940621A1 (en) | 2015-09-17 |
KR20160132041A (ko) | 2016-11-16 |
RU2683309C2 (ru) | 2019-03-28 |
RU2016140338A (ru) | 2018-04-19 |
CN106103416A (zh) | 2016-11-09 |
JP2017507981A (ja) | 2017-03-23 |
JP6643545B2 (ja) | 2020-02-12 |
EP3116858A1 (en) | 2017-01-18 |
CN106103416B (zh) | 2021-03-02 |
KR102425400B1 (ko) | 2022-07-26 |
CA2940621C (en) | 2022-03-15 |
US20170002016A1 (en) | 2017-01-05 |
TW201623250A (zh) | 2016-07-01 |
EP3116858B1 (en) | 2020-11-11 |
RU2016140338A3 (zh) | 2018-10-24 |
US10093678B2 (en) | 2018-10-09 |
MX2016011632A (es) | 2016-12-12 |
US20180339993A1 (en) | 2018-11-29 |
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