TW202045502A - 人類免疫不全病毒複製之抑制劑 - Google Patents
人類免疫不全病毒複製之抑制劑 Download PDFInfo
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Images
Classifications
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
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Abstract
闡述以下化合物
Description
本發明係關於用於治療人類免疫不全病毒(HIV)感染之化合物、組合物及方法。更具體而言,本發明提供HIV之新穎抑制劑、含有該等化合物之醫藥組合物及使用該等化合物治療HIV感染之方法。本發明亦係關於製備下文所述化合物之方法。
後天性免疫不全症候群(AIDS)係由HIV感染之結果。HIV繼續成為重大全球公共健康問題。2015年,估計36.7百萬人與HIV一起生活(包括1.8百萬兒童) -全球HIV盛行率為0.8%。此數量之絕大多數生活在低收入及中等收入國家。同年,1.1百萬人死於AIDS相關疾病。
目前對HIV感染個體之療法由經批准之抗反轉錄病毒劑之組合組成。目前已批准接近四打藥物用於HIV感染,作為單一藥劑、固定劑量組合或單一錠劑方案;後兩種含有2-4種批准之藥劑。該等藥劑屬許多不同類別,在病毒複製週期期間靶向病毒酶或病毒蛋白之功能。因此,藥劑分類為核苷酸反轉錄酶抑制劑(NRTI)、非核苷酸反轉錄酶抑制劑(NNRTI)、蛋白酶抑制劑(PI)、整合酶鏈轉移抑制劑(INSTI)或進入抑制劑(一種係馬拉維洛(maraviroc),靶向宿主CCR5蛋白;而另一種係恩夫韋肽(enfuvirtide),係靶向病毒gp160蛋白之gp41區之肽)。此外,藥物動力學增強劑(可比司他(cobicistat)或利托那韋(ritonavir))可與需要加強免疫之抗反轉錄病毒劑(ARV)組合使用。
儘管有藥劑及藥物組合之醫療設備,但仍存在對新抗反轉錄病毒劑之醫學需要。高病毒異質性、藥物相關毒性、耐受性問題及差的依從性皆可導致治療失敗,且可導致選擇具有突變之病毒,該等突變賦予對一或多種抗反轉錄病毒劑或甚至來自整個類別之多種藥物之抗性(Beyrer, C., Pozniak A. HIV drug resistance - an emerging threat to epidemic control. N. Engl. J. Med. 2017, 377, 1605-1607;Gupta, R. K.、Gregson J.等人, HIV-1 drug resistance before initiation or re-initiation of first-line antiretroviral therapy in low-income and middle-income countries: a systematic review and meta-regression analysis. Lancet Infect. Dis. 2017, 18, 346-355;Zazzi, M.、Hu, H.、Prosperi, M. The global burden of HIV-1 drug resistance in the past 20 years. PeerJ. 2018, DOI 10.7717/peerj.4848)。因此,需要更容易服用、對發展抗性具有高度遺傳障礙且相對於目前藥劑具有改良之安全性的新藥物。在此全套選擇中,可用作較佳抗反轉錄病毒療法(ART)之一部分之新穎作用機制(MOA)仍可具有重大作用,此乃因其應有效抵抗目前藥劑有抗性之病毒。使藥物更容易長期服用或甚至終生服用之改良可包括以下之全部或一些:副作用減少、藥物-藥物相互作用減少、給藥之間之持續時間增加或與個別患者偏好匹配之替代投與途徑。改良之安全性之目標將明確地包括對將導致給藥中斷之任何毒性之高治療指數,且亦可包括減少之副作用或減少之藥物-藥物相互作用。在組合方案中使用較少之總體藥物之潛能亦將可能導致改良之順從性及安全性。針對抗病毒靶標之功效增加、尤其若在人類血漿及血清白蛋白之存在下維持,亦將導致劑量減少,且可直接且積極地影響給藥之持續時間及相對於副作用及毒性之治療指數。總之,若發現具有新作用機制且亦具有上述促進長期順從性及安全性之其他益處的抗HIV藥物,則將對HIV感染患者實現最大益處。
業內已闡述某些似乎藉由破壞HIV病毒衣殼之正常功能而起作用之潛在治療性化合物。目前沒有批准之藥物藉由此機制起作用,且因此藉由此機制起作用之化合物將為可用於治療HIV感染之選項的有用補充。似乎靶向HIV衣殼之化合物已經成為最近綜述之標的,其闡述迄今為止之大部分最重要的工作。該等綜述包括以下:「HIV-1 Capsid Inhibitors as Antiretroviral Agents」 Thenin-Houssier, Suzie;Valente, Susana T. Current HIV Research,2016
,14
, 270;「Inhibitors of the HIV-1 capsid, a target of opportunity」 Carnes, Stephanie K.;Sheehan, Jonathan H.;Aiken, Christopher,Current Opinion in HIV & AIDS 2018
,13
, 359-365;「HIV Capsid Inhibitors Beyond PF74」 McArthur, Carole,Diseases
,2019
,7
, 22;及「Insights into HIV-1 capsid inhibitors in preclinical and early clinical development as antiretroviral agents」 Cevik, Muge;Orkin, ChloeExpert Opin Inv. Drugs
,2019
,28
, 1021;相關專利申請案係:WO2012065062、WO2013006738、WO 2013006792、WO2014110296、WO2014110297、WO2014110298、WO2014134566、WO2015061518、WO2015130964、WO2015130966、WO2016040084、WO2016033243、WO2016172424、WO2016172425、WO2018035359、WO2018203235、WO2019035904、WO2019035973、WO2019161017、WO2019161280及WO2019198024。
現在業內需要的是新穎且可用於治療HIV之額外化合物。另外,該等化合物應在(例如)以下一或多個方面向醫藥用途提供優點:其作用機制、結合、抑制功效、靶標選擇性、溶解性、安全特性、生物利用度及/或給藥頻率降低。業內亦需要利用該等化合物之新調配物及治療方法。
在另一態樣中,本發明揭示包含本發明之化合物或鹽的組合物。
在另一態樣中,本發明揭示治療人類之HIV感染的方法,其包含投與本發明之化合物或鹽。
在另一態樣中,本發明揭示本發明之化合物或鹽,其用於療法中。
在另一態樣中,本發明揭示本發明之化合物或鹽,其用於治療人類之HIV感染。
在另一態樣中,本發明揭示本發明之化合物或鹽在製造藥劑中之用途,該藥劑用於治療人類之HIV感染。
本發明之鹽係醫藥上可接受的。該等鹽可為酸加成鹽或鹼加成鹽。關於適宜醫藥上可接受之鹽之綜述,參見(例如) Berge等人,J. Pharm, Sci., 66, 1-19, 1977。
代表性醫藥上可接受之酸加成鹽包括(但不限於) 4-乙醯胺基苯甲酸酯、乙酸鹽、己二酸鹽、海藻酸鹽、抗壞血酸鹽、天冬胺酸鹽、苯磺酸鹽(benzenesulfonate,besylate)、苯甲酸鹽、硫酸氫鹽、酒石酸氫鹽、丁酸鹽、依地酸鈣、樟腦酸鹽、樟腦磺酸鹽(camphorsulfonate,camsylate)、癸酸鹽(caprate,decanoate)、己酸鹽(caproate,hexanoate)、辛酸鹽(caprylate,octanoate)、肉桂酸鹽、檸檬酸鹽、環己胺磺酸鹽、二葡糖酸鹽、2,5-二羥基苯甲酸鹽、二琥珀酸鹽、十二烷基硫酸鹽(依託酸鹽)、依地酸鹽(乙二胺四乙酸鹽)、依託酸鹽(月桂基硫酸鹽)、乙烷-1,2-二磺酸鹽(乙二磺酸鹽)、乙磺酸鹽(ethanesulfonate,esylate)、甲酸鹽、富馬酸鹽、半乳糖酸鹽(黏酸鹽)、龍膽酸鹽(2,5-二羥基苯甲酸鹽)、葡庚糖酸鹽(glucoheptonate,gluceptate)、葡糖酸鹽、葡糖醛酸鹽、麩胺酸鹽、戊二酸鹽、甘油磷酸鹽、羥乙酸鹽、己基間苯二酸鹽、馬尿酸鹽、哈胺(N
,N'
-二(去氫樅基)-乙二胺)、氫溴酸鹽、鹽酸鹽、氫碘酸鹽、羥基萘甲酸鹽、異丁酸鹽、乳酸鹽、乳糖酸鹽、月桂酸鹽、蘋果酸鹽、馬來酸鹽、丙二酸鹽、扁桃酸鹽、甲磺酸鹽(methanesulfonate,mesylate)、甲基硫酸鹽、黏酸鹽、萘-1,5-二磺酸鹽(萘二磺酸鹽)、萘-2-磺酸鹽(萘磺酸鹽)、菸酸鹽、硝酸鹽、油酸鹽、棕櫚酸鹽、對胺基苯磺酸鹽、對胺基柳酸鹽、雙羥萘酸鹽(pamoate,embonate)、泛酸鹽、果膠酸鹽、過硫酸鹽、苯基乙酸鹽、苯基乙基巴比妥酸鹽、磷酸鹽、聚半乳糖醛酸鹽、丙酸鹽、對甲苯磺酸鹽(p
-toluenesulfonate,tosylate)、焦麩胺酸鹽、丙酮酸鹽、柳酸鹽、癸二酸鹽、硬脂酸鹽、次乙酸鹽、琥珀酸鹽、胺基磺酸鹽、硫酸鹽、鞣酸鹽、酒石酸鹽、茶氯酸鹽(8-氯茶鹼酸鹽)、硫氰酸鹽、三乙基碘、十一酸鹽、十一碳烯酸鹽及戊酸鹽。
代表性醫藥上可接受之鹼加成鹽包括(但不限於)鋁、2-胺基-2-(羥基甲基)-1,3-丙二醇(TRIS,胺丁三醇)、精胺酸、苯乙苄胺(N
-苄基苯乙胺)、苄星青黴素(N
,N’
-二苄基乙二胺)、雙 -
(2-羥基乙基)胺、鉍、鈣、氯普魯卡因(chloroprocaine)、膽鹼、克立咪唑(clemizole) (1-對氯苄基-2-吡咯啶-1’-基甲基苯并咪唑)、環己基胺、二苄基乙二胺、二乙胺、二乙基三胺、二甲胺、二甲基乙醇胺、多巴胺、乙醇胺、乙二胺、L-組胺酸、鐵、異喹啉、對甲基吡啶、鋰、離胺酸、鎂、葡甲胺(N
-甲基葡萄糖胺)、六氫吡嗪、六氫吡啶、鉀、普魯卡因、奎寧、喹啉、鈉、鍶、第三丁基胺及鋅。
在一個實施例中,本發明之組合物進一步包含醫藥上可接受之賦形劑。在本發明之方法中,較佳之投與途徑係經口及藉由注射以皮下或肌內遞送。因此,較佳醫藥組合物包括適於經口投與之組合物(例如錠劑)及適於注射之組合物。
據信本發明之化合物及鹽具有作為其生物靶標之HIV衣殼,且因此其作用機制係以一或多種方式修飾HIV衣殼之功能。
本發明之化合物及鹽可單獨使用或與其他治療劑組合使用。因此,本發明之組合療法包含投與至少一種本發明之化合物或鹽及投與至少一種用於治療HIV感染之另一藥劑。本發明之化合物或鹽及另一藥劑可在單一醫藥組合物中一起調配及投與或可分開調配及投與。當分開調配及投與時,投與可同時或以任一順序依序進行。適宜其他藥劑包括(例如)德羅格韋(dolutegravir)、比特拉韋(bictegravir)、拉米夫定(lamivudine)、福司它韋(fostemsavir)、卡博替韋(cabotegravir)、馬拉維洛(maraviroc)、利匹韋林(rilpivirine)、阿紮那韋(atazanavir)、泰諾福韋艾拉酚胺(tenofovir alafenamide)、伊司他韋(islatravir)、多拉維林(doravirine)及達如那韋(darunavir)。較佳藥劑包括(例如)德羅格韋、比特拉韋、伊司他韋、拉米夫定、福司它韋及卡博替韋。尤佳藥劑包括(例如)德羅格韋、比特拉韋、拉米夫定、福司它韋及卡博替韋。
實例二環 [3.1.0] 己 -3- 醇之製備
在N2
氣氛下於0-5℃下經3 h之時段向環戊-3-烯醇(130 g, 1545 mmol)於DCM (1200 mL)中之攪拌溶液中逐滴添加二乙基鋅於己烷中之溶液(1.0 M, 3091 mL, 3091 mmol)。於0℃下經1h之時段向溶液中逐滴添加二碘甲烷(249 mL, 3091 mmol)於DCM (300 mL)中之溶液。使反應混合物升溫至27℃,此時觀察到形成白色沈澱。將混合物攪拌16 h。藉由TLC (SiO2
, 20% EtOAc/pet, Rf = 0.3, UV非活性、PMA活性)監測反應進程。經由小心添加飽和NH4
Cl水溶液(1.5 L)淬滅反應混合物。經矽藻土墊過濾混合物。用DCM (2 × 1L)萃取水層。將合併之有機層經無水Na2
SO4
乾燥,過濾且然後在減壓下濃縮,得到紅色液體狀粗製二環[3.1.0]己-3-醇,180 g。1
H NMR (400 MHz, CDCl3
) δ = 4.41 - 4.35 (m, 1H), 2.18 - 2.05 (m, 2H), 1.73 (d,J
= 13.9 Hz, 2H), 1.35 - 1.25 (m, 2H), 1.21 - 1.14 (m, 1H), 0.57 - 0.43 (m, 2H)。GCMS: m/z = 98.1。
二環 [3.1.0] 己 -3- 酮之製備
在N2
氣氛下於0℃下向二環[3.1.0]己-3-醇(210 g, 2054 mmol)於DCM (5000 mL)中之攪拌溶液中逐份添加戴斯-馬丁過碘烷(Dess-Martin periodinane) (954 g, 225 mmol)。使混合物升溫至27℃且然後攪拌16 h。藉由TLC (SiO2
, 20%丙酮/Hex, Rf = 0.3, UV非活性, PMA活性)監測反應進程。經由矽藻土墊過濾反應混合物且用 NaOH (1N, 8× 1 L)洗滌濾液。將合併之水相用DCM (5 × 1 L)萃取。將合併之有機層經無水Na2
SO4
乾燥,過濾,且然後在減壓下濃縮(浴溫:20℃),從而得到褐色液體狀粗製二環[3.1.0]己-3-酮。於70℃下藉由向下蒸餾進一步純化液體,從而得到淺黃色黏稠液體狀二環[3.1.0]己-3-酮,125 g (62%)。1
H NMR (400 MHz, CDCl3
) δ = 2.61 - 2.54 (m, 2H), 2.17 - 2.12 (m, 2H), 1.54 - 1.46 (m, 2H), 0.92 - 0.86 (m, 1H), -0.01 - -0.08 (m, 1H);GCMS: M/Z = 96.1。
2-(2,2- 二氟乙醯基 ) 二環 [3.1.0] 己 -3- 酮之製備
在N2
氣氛下於-78℃下向二環[3.1.0]己-3-酮(125 g, 1274 mmol)於THF (1500 mL)中之攪拌溶液中添加LDA (2.0 M,於THF中, 0.701 L, 1402 mmol)。將溶液於-78℃下攪拌1 h。經30分鐘向溶液中緩慢添加二氟乙酸乙酯(174 g, 1402 mmol)於THF (300 mL)中之溶液,維持溫度為-78℃。使反應混合物升溫至27℃且然後攪拌1 h。藉由TLC (SiO2
, 20%丙酮/己烷, Rf = 0.3, UV活性)監測反應進程。經由添加aq. HCl (1N, 2000 mL)淬滅反應混合物。將混合物攪拌30 min且然後用EtOAc (3 × 1000 mL)萃取。將合併之有機層用鹽水(1000 mL)洗滌,經無水Na2
SO4
乾燥且過濾。在減壓下濃縮濾液,從而得到淺黃色黏稠液體狀2-(2,2-二氟乙醯基)二環[3.1.0]己-3-酮,180 g (71%)。1
H NMR (400 MHz, CDCl3
) δ = 6.18 (t,J
= 54.8 Hz, 1H), 2.70 - 2.62 (m, 1H), 2.35 (d,J
= 19.4 Hz, 1H), 2.14 (br s, 1H), 1.26 - 1.21 (m, 1H), 1.04-1.03 (m, 1H), 0.22-0.21 (m, 1H), LCMS: M/Z = 173.17。
2-(3-( 二氟甲基 )-3b,4,4a,5- 四氫 -1H- 環丙 [3,4] 環戊 [1,2-c] 吡唑 -1- 基 ) 乙酸乙酯之製備 .
在N2
氣氛下於27℃下向2-(2,2-二氟乙醯基)二環[3.1.0]己-3-酮(180 g, 910 mmol)於乙醇(2 L)中之攪拌溶液中添加2-肼基乙酸乙酯鹽酸鹽(422 g, 2729 mmol),之後添加硫酸(20 mL, 375 mmol)。將混合物攪拌30 min.且然後加熱至100℃且攪拌16 h。藉由TLC (SiO2
, 20%丙酮/己烷, Rf = 0.3, UV活性)監測反應進程。在減壓下濃縮反應混合物。將殘餘物溶解於EtOAc (2000 mL)中且用水(2 × 1 L)、鹽水(1.0 L)洗滌,經無水Na2
SO4
乾燥,過濾,且然後在減壓下濃縮。使所得殘餘物經受矽膠管柱層析(pet.:丙酮100:0à98:2),從而得到灰白色固體狀2-(3-(二氟甲基)-3b,4,4a,5-四氫-1H-環丙[3,4]環戊[1,2-c]吡唑-1-基)乙酸乙酯,110 g (46%)。1
H NMR (400 MHz, DMSO-d6
) δ = 6.86 (t,J
= 54.8 Hz, 1H), 4.93 (s, 2H), 4.14 (q,J
= 7.2 Hz, 2H), 2.88 - 2.79 (m, 1H), 2.76 - 2.68 (m, 1H), 2.14 - 2.04 (m, 2H), 1.19 (t,J
= 7.2 Hz, 3H), 1.10 - 1.03 (m, 1H), 0.14 (q,J
= 4.3 Hz, 1H)。
2-(3-( 二氟甲基 )-5- 側氧基 -3b,4,4a,5- 四氫 -1H- 環丙 [3,4] 環戊 [1,2-c] 吡唑 -1- 基 ) 乙酸乙酯之製備 .
於0℃下向2-(3-(二氟甲基)-3b,4,4a,5-四氫-1H-環丙[3,4]環戊[1,2-c]吡唑-1-基)乙酸乙酯(110 g, 422 mmol)及矽藻土(395 g)於環己烷(3.5 L)中之攪拌溶液中逐份添加吡啶鎓二鉻酸鹽(794 g, 2110 mmol)。在氮氣氛下經10 min之時段向混合物中逐滴添加第三丁基氫過氧化物(355 mL, 2130 mmol)。使反應混合物升溫至27℃且然後於該溫度下攪拌48 h。藉由TLC (SiO2
, 30%丙酮/pet, Rf = 0.4, UV活性)監測反應進程。過濾反應混合物且用EtOAc (1000 mL)萃取濾餅。將濾液用飽和aq. Na2
S2
O3
(2×500 mL)、飽和aq. FeSO4
(300 mL)及然後鹽水(500 mL)洗滌。將有機層經無水Na2
SO4
乾燥;過濾且在減壓下濃縮,以獲得粗製標題化合物(150 g)。
2-(3-( 二氟甲基 )-4,4a- 二氫螺 [ 環丙 [3,4] 環戊 [1,2-c] 吡唑 -5,2'-[1,3] 二硫戊環 ]-1(3bH)- 基 ) 乙酸乙酯之製備 .
於27℃下在氮氣氛下向2-(3-(二氟甲基)-5-側氧基-3b,4,4a,5-四氫-1H-環丙[3,4]環戊[1,2-c]吡唑-1-基)乙酸乙酯(75 g, 269 mmol)於DCM (1500 mL)中之攪拌溶液中添加乙烷-1,2-二硫醇(43.0 mL, 511 mmol),之後添加三氟化硼乙酸(72.6 mL, 511 mmol)。將溶液攪拌16 h。藉由TLC (SiO2
, 20%丙酮/Pet, Rf = 0.35, UV活性)監測反應進程。完成後,將反應混合物冷卻至0℃且經由添加aq.飽和NaHCO3
(500 mL)淬滅。用DCM (2 × 1000 mL)萃取混合物。將合併之有機物用鹽水(1000 mL)洗滌,經無水Na2
SO4
乾燥,過濾且在減壓下濃縮,以獲得褐色液體。使此物質經受矽膠管柱層析(Pet.:EtOAc 95:5à90:10),從而得到灰白色固體狀2-(3-(二氟甲基)-4,4a-二氫螺[環丙[3,4]環戊[1,2-c]吡唑-5,2'-[1,3]二硫戊環]-1(3bH)-基)乙酸乙酯,80 g (74%)。1
H-NMR (400 MHz, CDCl3
) δ = 6.61 (t,J
= 55.2 Hz, 1H), 5.00 - 4.85 (m, 2H), 4.29 - 4.19 (m, 2H), 3.55 - 3.46 (m, 4H), 2.63 - 2.53 (m, 1H), 2.49 - 2.38 (m, 1H), 1.30 - 1.24 (m, 4H), 0.65 - 0.60 (m, 1H)。LCMS M+H = 346.9。
2-(3-( 二氟甲基 )-5,5- 二氟 -3b,4,4a,5- 四氫 -1H- 環丙 [3,4] 環戊 [1,2-c] 吡唑 -1- 基 ) 乙酸乙酯之製備
於-70℃下在N2
氣氛下向1,3-二溴-5,5-二甲基咪唑啶-2,4-二酮(26.3 g, 92 mmol)於DCM (20 mL)中之攪拌溶液中添加HF-吡啶(2.460 g, 24.83 mmol)。將溶液攪拌30 min。向溶液中添加2-(3-(二氟甲基)-4,4a-二氫螺[環丙[3,4]環戊[1,2-c]吡唑-5,2'-1,3]二硫戊環]-1(3bH)-基)乙酸乙酯(10 g, 25 mmol)於DCM (20 mL)中之溶液。使反應混合物升溫至-40℃且然後於該溫度下攪拌1 h。藉由TLC (SiO2, 30% EtOAc/Pet, Rf = 0.3, UV非活性)監測反應進程。經由添加aq. sat. NaHCO3
(200 mL)淬滅反應混合物。使混合物升溫至室溫且然後用EtOAc (2 × 100 mL)萃取。將合併之有機物用鹽水(50 mL)洗滌;經無水Na2
SO4
乾燥;過濾;且在減壓下濃縮,從而得到褐色固體。使此物質經受矽膠管柱層析(Pet.:EtOAc 100:0à75-25),從而得到淺黃色固體狀2-(3-(二氟甲基)-5,5-二氟-3b,4,4a,5-四氫-1H-環丙[3,4]環戊[1,2-c]吡唑-1-基)乙酸乙酯,8.5 g (91%)。1
H NMR (400 MHz, CDCl3
) δ = 6.62 (t, J = 55.2 Hz, 1H), 4.82 (s, 2H), 4.30 - 4.18 (m, 2H), 2.51 - 2.37 (m, 2H), 1.42 - 1.35 (m, 1H), 1.31 - 1.23 (m, 3H), 1.14 - 1.08 (m, 1H)。LCMS M+H = 293.07。
2-(3-( 二氟甲基 )-5,5- 二氟 -3b,4,4a,5- 四氫 -1H- 環丙 [3,4] 環戊 [1,2-c] 吡唑 -1- 基 ) 乙酸之製備
於0℃下在N2
氣氛下向2-(3-(二氟甲基)-5,5-二氟-3b,4,4a,5-四氫-1H-環丙[3,4]環戊[1,2-c]吡唑-1-基)乙酸乙酯(15 g, 50 mmol)於THF (17 mL)及MeOH (66 mL)中之攪拌溶液中添加LiOH (1.788 g, 74.7 mmol)於水(66 mL)中之溶液。使反應混合物升溫至27℃且然後於該溫度下攪拌3 h。藉由TLC (SiO2
, 5% MeOH/DCM, Rf = 0.2, UV活性)監測反應進程。完成後,在減壓下濃縮反應混合物;用水(50 mL)稀釋;且用EtOAc (2 × 250 mL)洗滌以去除雜質。使用aq. HCl (1M)將水層調整至pH 2-3,然後用EtOAc (3 × 1000 mL)萃取。將合併之有機物經無水Na2
SO4
乾燥;過濾;且在減壓下濃縮,從而得到灰白色固體狀2-(3-(二氟甲基)-5,5-二氟-3b,4,4a,5-四氫-1H-環丙[3,4]環戊[1,2-c]吡唑-1-基)乙酸,14 g (98%)。LCMS M+H = 265.15。
分離得到 2-((3bS,4aR)-3-( 二氟甲基 )-5,5- 二氟 -3b,4,4a,5- 四氫 -1H- 環丙 [3,4] 環戊 [1,2-c] 吡唑 -1- 基 ) 乙酸及 2-((3bR,4aS)-3-( 二氟甲基 )-5,5- 二氟 -3b,4,4a,5- 四氫 -1H- 環丙 [3,4] 環戊 [1,2-c] 吡唑 -1- 基 ) 乙酸
將2-(3-(二氟甲基)-5,5-二氟-3b,4,4a,5-四氫-1H-環丙[3,4]環戊[1,2-c]吡唑-1-基)乙酸(5.5 g)溶解於異丙醇(20 mL)中。使溶液逐份經受如下SFC手性分離:儀器= Thar 80;管柱= Chiralpak IC 30×250mm, 5微米;溶劑A = 超臨界CO2
;溶劑B = 具有0.5%異丙胺(v/v)之異丙醇;溶析液組合物 = 70%A:30%B;流速 = 65 g/min;反壓 = 100巴;溫度 = 30℃;注射體積 = 2.5 mL;檢測 = 220 nm。2-((3bS,4aR)-3-(二氟甲基)-5,5-二氟-3b,4,4a,5-四氫-1H-環丙[3,4]環戊[1,2-c]吡唑-1-基)乙酸收集為自7.5 min.至14 min溶析之峰;2-((3bR,4aS)-3-(二氟甲基)-5,5-二氟-3b,4,4a,5-四氫-1H-環丙[3,4]環戊[1,2-c]吡唑-1-基)乙酸收集為自2.7 min.至5.8 min溶析之峰。對於每一鏡像異構物,在減壓下濃縮所得溶液且將所得固體溶解於EtOAc中,然後用aq.檸檬酸(1M)洗滌兩次、之後用水、之後用鹽水洗滌。將有機溶液經Na2
SO4
乾燥;過濾;然後在真空中濃縮,從而得到回收率為80-90%之分離之鏡像異構物。
3- 溴 -6- 氯 -2- 氟苯甲腈之製備
於室溫下向3-溴-6-氯-2-氟苯甲醛(210.0 g, 0.89 mol, 1.0 equiv.)於水(2.1 L)中之攪拌溶液中添加羥基胺-O-磺酸(175.15 g, 1.55 mol, 1.75 equiv.)。將反應混合物加熱至50℃並攪拌18 h。將混合物冷卻至室溫且攪拌1-1.5 h。經由過濾分離固體且然後用水洗滌。將濕固體於50℃下在真空下乾燥12-15 h,從而得到3-溴-6-氯-2-氟苯甲醛,190.0 g (91%)。
7- 溴 -4- 氯 -1- 甲基 -1H- 吲唑 -3- 胺 之製備
於25-35℃下向3-溴-6-氯-2-氟苯甲腈(360.0 g, 1.55 mol, 1.0 equiv.)於乙醇(1.08 L)中之溶液中添加硫酸甲基肼(1.11 kg, 7.73 mol, 5.0 equiv.),之後添加三乙胺(1.3 L, 9.3 mol, 6.0 equiv.)。將反應混合物加熱至110℃且維持15 h (藉由TLC監測反應)。反應完成後,將混合物冷卻至室溫。添加水(3.0 L)且將混合物於室溫下攪拌1 h。經由過濾分離固體且用水洗滌。將濕固體在真空下於50℃下乾燥12-15小時。藉由管柱層析(10% EA/己烷至40% EA/己烷)純化粗固體,從而得到淺黃色固體狀產物。產率:185.0 g (46.0 %)。
N-(7- 溴 -4- 氯 -1- 甲基 -1H- 吲唑 -3- 基 ) 甲烷磺醯胺之製備
向7-溴-4-氯-1-甲基-1H-吲唑-3-胺(1.40 g, 5.37 mmol)於DCM (30 mL)中之溶液中添加休尼格鹼(Hunig's Base) (3.75 mL, 21.5 mmol)且然後將反應物在冰浴中冷卻且添加甲磺醯氯(1.26 mL, 16.1 mmol)。將反應混合物於此溫度下攪拌1h (形成沈澱)。然後將混合物用二氯甲烷(100 mL)稀釋且用水、1 M HCl及鹽水洗滌,乾燥(Na2
SO4
),過濾且在真空中濃縮。將殘餘物吸收於EtOH (30 ml)及10 ml 20% aq. NaOH中。用熱槍加熱所得混合物直至其變為均勻溶液且於rt下攪拌30 min。將混合物用水(80 mL)稀釋且用1 N HCl (60 mL)酸化。過濾沈澱,用水洗滌且在真空下乾燥,從而得到灰白色固體狀標題產物(1.5 g)。1
H NMR (500 MHz, CDCl3
) δ 7.48 (d, J=7.9 Hz, 1H), 7.24 (br s, 1H), 6.95 (d, J=7.9 Hz, 1H), 4.38 (s, 3H), 3.42 (s, 3H)。LC/MS (M+H)+
= 337.80。
N-(7- 溴 -4- 氯 -1- 甲基 -1H- 吲唑 -3- 基 )-N-(4- 甲氧基苄基 ) 甲烷磺醯胺之製備
向N-(7-溴-4-氯-1-甲基-1H-吲唑-3-基)甲烷磺醯胺(1.3 g, 3.84 mmol)及1-(氯甲基)-4-甲氧基苯(0.625 mL, 4.61 mmol)於DMF (30 mL)中之混合物中添加碳酸銫(1.626 g, 4.99 mmol)且將混合物於80℃下加熱2 h。將混合物傾倒至水(100 mL)中且用EtOAc (50 ml, 2×)萃取。將合併之有機層用鹽水洗滌,經MgSO4
乾燥,過濾且在真空中濃縮。藉由矽膠層析(己烷中之0-35% EtOAc)純化殘餘物,從而得到白色泡沫狀標題產物(1.5 g)。1
H NMR (500 MHz, CDCl3
) δ 7.44 (d, J=7.9 Hz, 1H), 7.31 (d, J=8.5 Hz, 2H), 6.99 (d, J=7.9 Hz, 1H), 6.84 (d, J=8.5 Hz, 2H), 4.99 (br s, 1H), 4.76 (br s, 1H), 4.40 (s, 3H), 3.80 (s, 3H), 3.01 (s, 3H)。
N-(7- 胺基 -4- 氯 -1- 甲基 -1H- 吲唑 -3- 基 )-N-(4- 甲氧基苄基 ) 甲烷磺醯胺之製備
遵循以下參考文獻:Andersen, Jacob等人,Synlett2005
(14), 2209-2213。向N-(7-溴-4-氯-1-甲基-1H-吲唑-3-基)-N-(4-甲氧基苄基)甲烷磺醯胺(600.0 mg, 1.308 mmol)、碘化銅(I) (49.8 mg, 0.262 mmol)、抗壞血酸鈉(518 mg, 2.62 mmol)及(1R,2R)-N1,N2-二甲基環己烷-1,2-二胺(46.5 mg, 0.327 mmol)於NMP (10 mL)中之混合物中添加疊氮化鈉(255 mg, 3.92 mmol)於水(2.0 mL)中之溶液。然後密封混合物且在微波系統中於120℃加熱2.5 h。然後經矽藻土墊過濾混合物且用EtOAc洗該墊。將濾液傾倒至水(100 mL)中且用EtOAc (50 ml, 2×)萃取。將合併之有機層用鹽水洗,經MgSO4
乾燥,過濾並在真空中蒸發。藉由矽膠層析(5-100% EtOAc於己烷中)純化殘餘物,得到灰白色固體標題產物(400 mg)。1
H NMR (400 MHz, CDCl3
) δ 7.33 - 7.29 (m, 2H), 6.89 (d, J=7.8 Hz, 1H), 6.85 - 6.79 (m, 2H), 6.48 (d, J=7.8 Hz, 1H), 5.11 (br s, 1H), 4.81 (br s, 1H), 4.30 (s, 3H), 3.80 (br s, 2H), 3.79 (s, 3H), 2.99 (s, 3H)。LC/MS (M+H)+
= 395.00。
2- 胺基 -6-( 苄基氧基 ) 菸鹼酸之製備
將2-胺基-6-氯菸鹼酸(5 g, 29 mmol)及第三丁醇鉀(9.75 g, 87 mmol)於苄醇(97 mL)中之溶液加熱至120℃保持3 h。在冷卻至環境溫度後,將極黑的反應混合物加入水中且用醚(×3)洗。然後用0.5 M檸檬酸酸化水層。過濾黃褐色沈澱以提供產物(4.4 g, 62%),其不經進一步純化即用於下一反應。1
H NMR (500 MHz, DMSO-d6) δ 12.40 (br s, 1H), 7.94 (d, J=8.55 Hz, 1H), 7.06-7.52 (m, 5H), 6.04 (d, J=8.24 Hz, 1H), 5.33 (s, 2H)。LC/MS: m/z = 245.15 [M+1]+
。
(S)-(1-(7-( 苄基氧基 )-3-(4- 氯 -3-(N-(4- 甲氧基苄基 ) 甲基磺醯胺基 )-1- 甲基 -1H- 吲唑 -7- 基 )-4- 側氧基 -3,4- 二氫吡啶并 [2,3-d] 嘧啶 -2- 基 )-2-(3,5- 二氟苯基 ) 乙基 ) 胺基甲酸第三丁基酯之製備
將(S)-2-((第三丁氧基羰基)胺基)-3-(3,5-二氟苯基)丙酸(0.247 g, 0.819 mmol)、N-(7-胺基-4-氯-1-甲基-1H-吲唑-3-基)-N-(4-甲氧基苄基)甲烷磺醯胺(0.323 g, 0.819 mmol)及亞磷酸二苯基酯(0.634 mL, 3.28 mmol)於吡啶(3 mL)中之混合物於75℃加熱2.5 h。在冷卻至環境溫度時,在真空中濃縮反應混合物且使用矽膠急速層析(120 g RediSep管柱)使用於己烷中之0-45%乙酸乙酯純化。將所欲溶離份濃縮,產生淺黃色泡沫固體(0.34 g, 47%)。LC/MS: m/z = 886.25 [M+1]+
。
(S)-N-((6P)-7-(2-(1- 胺基 -2-(3,5- 二氟苯基 ) 乙基 )-7- 羥基 -4- 側氧基吡啶并 [2,3-d] 嘧啶 -3(4H)- 基 )-4- 氯 -1- 甲基 -1H- 吲唑 -3- 基 )-N-(4- 甲氧基苄基 ) 甲烷磺醯胺之製備
向(S)-(1-((6P)-7-(苄基氧基)-3-(4-氯-3-(N-(4-甲氧基苄基)甲基磺醯胺基)-1-甲基-1H-吲唑-7-基)-4-側氧基-3,4-二氫吡啶并[2,3-d]嘧啶-2-基)-2-(3,5-二氟苯基)乙基)胺基甲酸第三丁基酯(3 g, 3.38 mmol)於DCM (16.92 ml)中之溶液中添加二噁烷中之HCl (4.0 N, 8.46 ml, 33.8 mmol)。將混合物攪拌1 h。向混合物中添加二噁烷中之HCl (4.0 N, 8.46 ml, 33.8 mmol),然後添加甲醇,從而得到均勻溶液。攪拌1 h後,在真空中濃縮淺黃色溶液。將粗產物吸收於DCM中,用飽和NaHCO3
水溶液洗滌,經Na2
SO4
乾燥,且在真空中濃縮,從而產生黃色固體。藉由反相C18層析使用(溶劑A = 95:5水:乙腈,具有0.1% TFA,溶劑B = 5:95水:乙腈,具有0.1% TFA,梯度 = A:B 90:10à60:40)純化粗固體。收集第二(主要)溶析峰且濃縮水層以去除乙腈。將所得白色懸浮液用1 N NaOH中和且將混合物用乙酸乙酯萃取。將合併之有機物經Na2
SO4
乾燥;過濾;且然後在真空中濃縮,以提供1.25 g主要阻轉異構物。藉由SFC層析使用用EtOH:庚烷(40:60)中之0.1%異丙胺溶析的Chiralpak IC管柱進一步純化此物質,以提供手性純產物(0.96 g, 41%)。1
H NMR (500 MHz, DMSO-d6) δ 7.86 - 7.98 (m, 1 H) 7.15 - 7.37 (m, 4 H) 6.97 - 7.06 (m, 1 H) 6.70 - 6.89 (m, 4 H) 6.40 - 6.48 (m, 1 H) 4.70 - 4.88 (m, 2 H) 3.41 - 3.81 (m, 7 H) 3.20 - 3.28 (m, 1 H) 3.08 - 3.12 (m, 3 H) 2.71 - 2.79 (m, 1 H) 1.69 - 2.00 (m, 2 H)。LC/MS: m/z = 696.20 [M+1]+
。
N-((S)-1-((3P)-3-(4- 氯 -3-(N-(4- 甲氧基苄基 ) 甲基磺醯胺基 )-1- 甲基 -1H- 吲唑 -7- 基 )-7- 羥基 -4- 側氧基 -3,4- 二氫吡啶并 [2,3-d] 嘧啶 -2- 基 )-2-(3,5- 二氟苯基 ) 乙基 )-2-((3bS,4aR)-3-( 二氟甲基 )-5,5- 二氟 -3b,4,4a,5- 四氫 -1H- 環丙 [3,4] 環戊 [1,2-c] 吡唑 -1- 基 ) 乙醯胺之製備
向(S)-N-((6P)-7-(2-(1-胺基-2-(3,5-二氟苯基)乙基)-7-羥基-4-側氧基吡啶并[2,3-d]嘧啶-3(4H)-基)-4-氯-1-甲基-1H-吲唑-3-基)-N-(4-甲氧基苄基)甲烷磺醯胺(0.926 g, 1.330 mmol)於DMF (13 ml)中之攪拌溶液中添加2-((3bS,4aR)-3-(二氟甲基)-5,5-二氟-3b,4,4a,5-四氫-1H-環丙[3,4]環戊[1,2-c]吡唑-1-基)乙酸(0.351 g, 1.330 mmol)、2-(3H-[1,2,3]三唑并[4,5-b]吡啶-3-基)-1,1,3,3-四甲基異脲鎓六氟磷酸鹽(V) (0.531 g, 1.397 mmol)及DIPEA (0.581 ml, 3.33 mmol)。在用水稀釋反應混合物並用乙酸乙酯萃取之後,將反應混合物攪拌2 h。用鹽水洗滌合併之EtOAc萃取物,經Na2
SO4
乾燥並在真空中濃縮。藉由矽膠急速層析使用在己烷中之10-100%乙酸乙酯純化粗產物,以提供灰白色泡沫固體狀產物(1.1 g, 88%)。LC/MS: m/z = 942.25 [M+1]+
。
實例 1 : N-((S)-1-((3P)-3-(4- 氯 -1- 甲基 -3-( 甲基磺醯胺基 )-1H- 吲唑 -7- 基 )-7-(3,3- 二氟丁氧基 )-4- 側氧基 -3,4- 二氫吡啶并 [2,3-d] 嘧啶 -2- 基 )-2-(3,5- 二氟苯基 ) 乙基 )-2-((3bS,4aR)-3-( 二氟甲基 )-5,5- 二氟 -3b,4,4a,5- 四氫 -1H- 環丙 [3,4] 環戊 [1,2-c] 吡唑 -1- 基 ) 乙醯胺之製備
於環境溫度下向N-((S)-1-((3P)-3-(4-氯-3-(N-(4-甲氧基苄基)甲基磺醯胺基)-1-甲基-1H-吲唑-7-基)-7-羥基-4-側氧基-3,4-二氫吡啶并[2,3-d]嘧啶-2-基)-2-(3,5-二氟苯基)乙基)-2-((3bS,4aR)-3-(二氟甲基)-5,5-二氟-3b,4,4a,5-四氫-1H-環丙[3,4]環戊[1,2-c]吡唑-1-基)乙醯胺(0.035 g, 0.037 mmol)、3,3-二氟丁-1-醇(0.012 g, 0.111 mmol)及三苯基膦(0.031 g, 0.119 mmol)於THF (0.8 mL)中之混合物中逐滴添加(E)-二氮烯-1,2-二甲酸二異丙基酯(0.022 mL, 0.111 mmol)於THF (0.2 mL)中之溶液。將反應混合物攪拌18 h且然後在真空中濃縮。將殘餘物吸收於DCM (0.5 mL)及TFA (0.25 mL)中。添加三氟甲磺酸(9.89 µL, 0.111 mmol)。將所得紫色溶液攪拌1 h且然後在真空中濃縮。將殘餘物吸收於乙酸乙酯(1.5 mL)中,用飽和NaHCO3
水溶液(1 mL)洗滌,且在真空中濃縮。藉由製備型HPLC使用以下條件純化粗產物:管柱:Zorbax Eclipse Plus C18, 21.2 × 100 mm, 5 μm粒子;溶劑A = 100%水中之0.1%甲酸。溶劑B = 乙腈。流速= 40 mL/min. 起始% B = 54.5 最後% B = 74.5。梯度時間 = 7 min,然後於98% B下保持2 min。波長 = 215及254 nm。ESI + 範圍:150至1500道爾頓。將樣品以30% B裝載且得到N-((S)-1-((3P)-3-(4-氯-1-甲基-3-(甲基磺醯胺基)-1H-吲唑-7-基)-7-(3,3-二氟丁氧基)-4-側氧基-3,4-二氫吡啶并[2,3-d]嘧啶-2-基)-2-(3,5-二氟苯基)乙基)-2-((3bS,4aR)-3-(二氟甲基)-5,5-二氟-3b,4,4a,5-四氫-1H-環丙[3,4]環戊[1,2-c]吡唑-1-基)乙醯胺(0.0108 g, 0.011 mmol, 30%產率)。1
H NMR (500 MHz, 甲醇-d4
) δ ppm 8.45 - 8.54 (m, 1 H), 7.27 - 7.34 (m, 1 H), 7.17 - 7.25 (m, 1 H), 7.03 - 7.11 (m, 1 H), 6.53 - 6.82 (m, 4 H), 4.74 - 4.80 (m, 2 H), 4.53 - 4.59 (m, 3 H), 3.59 - 3.65 (m, 3 H), 3.43 - 3.49 (m, 1 H), 3.21 - 3.26 (m, 3 H), 3.08 - 3.17 (m, 1 H), 2.39 - 2.60 (m, 4 H), 1.67 - 1.80 (m, 3 H), 1.32 - 1.40 (m, 1 H), 0.96 - 1.05 (m, 1 H)。LC/MS滯留時間 = 1.39 min;m/z = 914.4 [M+H]+
。管柱:Acquity BEH C18, 2.1 × 30 mm, 1.7 μm粒子;溶劑A =0.1%甲酸於100%水中。溶劑B = 0.1%甲酸於100%乙腈中。流速 = 0.8 mL/min。起始% B = 5。最後% B = 95。梯度時間= 1.7 min,然後於95% B保持0.2 min。波長 = 215及254 nm。ESI+ 範圍:150至1500道爾頓。系統:Agilent 1290 Infinity II。
步驟1: 2,6-二氯-3-硝基苯甲醛之製備
於0-5℃下向圓底燒瓶中之硫酸溶液(H2
SO4
) (5.63 L, 4.5 V)中逐份添加低於15℃之2,6-二氯苯甲醛(1.25 kg, 7.10 mol, 1.0 equiv.)。反應物質於0-5℃下攪拌30 min。將新鮮製備之硝化混合物之溶液[於0℃下自濃H2
SO4
(0.425 L, 0.34 V)及70% HNO3
(0.85 kg, 13.49 mol, 1.30 equiv.)製備]添加至低於10℃之上述反應混合物中[注意
:反應輕微放熱(3-6℃);因此較佳在較低溫度下添加]。將反應混合物於5-10℃下攪拌2-3 h。反應完成(藉由TLC監測)後,將其於低於25℃下用冰冷水(18.75 L, 15 V)驟冷。然後使反應物質升溫至室溫且攪拌2 h。藉由過濾收集固體且然後用水(2.5 L, 2.0 V)洗滌。藉由維持真空過濾60-90 min自固體去除大體積殘餘水。最初在空氣氣氛下乾燥粗濕固體;然後於50-55℃下在熱空氣烘箱中乾燥10-12 h (直至水份含量不超過5.0 %),以得到黃色固體狀乾燥標題產物2,6-二氯-3-硝基苯甲醛(1.44 kg, 92%產率)。1
H NMR (400 MHz, CDCl3
):δ
10. 44 (s, 1H), 7.88 (d,J
= 8.4 Hz, 1H), 7.56 (d,J
= 8.8 Hz, 1H)。
步驟2: 2,6-二氯-3-硝基苯甲腈之製備
(步驟2a) 於室溫下向圓底燒瓶中之DMSO (5.9 L, 5.0 V)之溶液中添加2,6-二氯-3-硝基苯甲醛(1.17 kg, 5.31 mol, 1.0 equiv.)。於室溫下攪拌30 min後,添加羥胺鹽酸鹽(0.63 kg, 9.04 mol, 1.70 equiv.)且將反應物質於室溫下攪拌3 h。反應完成(藉由TLC監測)後,藉由添加冰冷水(18.0 L, 15.0 V)淬滅反應物質,該冰冷水之添加速率足以維持溫度低於30℃(觀察結果:在添加水時形成固體)。將反應物質於室溫下攪拌60-90 min。藉由過濾分離固體;用水(2.5 L, 2.0 V)洗滌;之後用丙酮及己烷之混合物(6.0 L, 1:1比率)洗滌。藉由維持真空過濾達60-90 min自固體去除大體積殘餘水。最初使濕固體風乾且然後最後於50-55℃下在熱空氣烘箱中乾燥10-12 h (直至水份含量不超過1.0 %),以得到灰白色固體狀乾燥靶產物2,6-二氯-3-硝基苯甲醛肟(1.22 kg, 92%產率)。粗產物(其含有10-20% 2,6-二氯-3-硝基苯甲腈)不經進一步純化即直接用於下一步驟。
(步驟2b) 於0-5℃下向粗製肟(上述製劑, 1.13 kg, 4.80 mol, 1.0 equiv.)於DCM (9.04 L, 8.0 V)中之攪拌溶液中添加三乙胺(「TEA」, 1.02 kg, 10.09 mol, 2.1 equiv.)。攪拌5 min後,於15℃下緩慢添加甲磺醯氯(0.60 kg, 5.29 mol, 1.1 equiv.) (觀察結果:在添加期間注意到放熱)。然後將反應物質於室溫下攪拌30-45 min。反應完成(藉由TLC監測反應進程;移動相:己烷中之20%乙酸乙酯)後,將反應物質用水(6.78 L, 6.0 V)稀釋;分離有機層;且用DCM (3.4 L, 3.0 V)萃取水層。將合併之有機層用鹽水(5.65 L, 5.0 V)洗滌;經Na2
SO4
乾燥;且在真空下濃縮。於室溫下將所得粗固體與己烷(4.50 L, 4.0 V)一起研磨。將濕物質於50-55℃下在熱空氣烘箱中乾燥5- 6 h,以得到黃色固體狀乾燥產物2,6-二氯-3-硝基苯甲腈(0.95 kg, 91%產率)。1
H NMR (400 MHz, CDCl3
):δ
8.07 (d,J
= 8.8 Hz, 1H), 7.63 (d,J
= 8.8 Hz, 1H)。
步驟3: 4-氯-7-硝基-1H
-吲唑-3-胺之製備
於15-20℃下向2,6-二氯-3-硝基苯甲腈(750.0 g, 3.45 mol, 1.0 equiv.)於乙醇(7.5 L, 10.0 V)中之攪拌溶液中緩慢添加水合肼(519.0 g, 10.36 mol, 3.0 equiv.),同時維持反應物質低於25℃ (觀察結果:添加輕微放熱且在添加時將開始固體形成)。將反應混合物溫度緩慢升至室溫且然後將混合物攪拌3 h (觀察結果:在此時間期間,固體之量將增加)。反應完成(藉由TLC監測)後,將混合物用水(7.5 L, 10.0 V)稀釋且於室溫下進一步攪拌1 h。經由過濾分離固體且然後用水(2.25 L, 3.0 V)洗滌。將濕固體用丙酮(1.875 L, 2.5 V)及己烷(1.875 L, 2.5 V)之1:1比率之混合物洗滌。藉由維持真空過濾達60-90 min自固體去除大體積殘餘水。最後將濕固體於50℃下在熱空氣烘箱中乾燥7-8 h (直至水份含量達到低於1.5%),以得到磚紅色固體狀乾燥產物4-氯-7-硝基-1H
-吲唑-3-胺(549.0 g, 75%產率)。1
H NMR (400 MHz, CDCl3
):δ
10.36 (bs, 1H), 8.20 (d,J
= 8.4 Hz, 1H), 7.07 (d,J
= 8.40 Hz, 1H), 4.73 (bs, 2H)。
步驟4: 4-氯-1-甲基-7-硝基-1H
-吲唑-3-胺之製備
於5-10℃下向4-氯-7-硝基-1H
-吲唑-3-胺(500 g, 0.42 mol, 1.0 equiv.)於DMF (5.0 L, 10.0 V)中之攪拌溶液中緩慢添加碳酸銫(Cs2
CO3
) (1.91 kg, 5.88 mol, 2.5 equiv.),同時維持反應物質低於10℃。攪拌5-10 min後,添加硫酸二甲基酯(326.3 g, 2.59 mol, 1.1 equiv.),同時維持反應物質低於10℃ (注意:緩慢添加對於獲得更有利之區域選擇性較佳)。然後,使反應溫度緩慢升至室溫且於相同溫度下繼續攪拌額外2 h。反應完成(藉由TLC監測)後,藉由添加冰冷水(15.0 L, 30.0 V)淬滅反應物質且然後將所得混合物於室溫下攪拌6-8 h。經由過濾分離固體且然後用水(1.5 L, 3.0 V)洗滌。將濕固體用IPA (1.5 L, 3.0 V)、之後己烷(1.0 L, 2.0 V)洗滌。藉由維持真空過濾達60-90 min自固體去除大體積殘餘水。將濕固體於50℃下在熱空氣烘箱中乾燥7-8 h (直至水份含量低於1.0%)。分離之物質4-氯-1-甲基-7-硝基-1H
-吲唑-3-胺(319.0 g, 60%產率)不經進一步純化即用於下一步驟。1
H NMR (400 MHz, CDCl3
):δ
7.97 (d,J
= 8.32 Hz, 1H), 6.97 (d,J
= 8.24 Hz, 1H), 4.63 (bs, 2H), 3.96 (s, 3H)。
步驟5:N
-(4-氯-1-甲基-7-硝基-1H
-吲唑-3-基)甲烷磺醯胺之製備
(步驟5a) 於0-5℃下向4-氯-1-甲基-7-硝基-1H
-吲唑-3-胺(625.0 g, 2.76 mol, 1.0 equiv.)於DCM (6.25 L, 10.0 V)中之溶液中添加三乙胺(TEA) (837.0 g, 8.27 mol, 3.0 equiv.);之後添加4-二甲基胺基吡啶(DMAP) (20.60 g, 0.165 mol, 0.06 equiv.)。將反應物質攪拌5-10 min.,然後緩慢添加甲磺醯氯(MsCl) (790.0 g, 6.89 mol, 2.5 equiv.),同時維持反應物質低於10℃。使反應混合物升溫至室溫且然後攪拌1.5-2.0 h。反應完成(藉由TLC監測)後,用水(6.25 L, 10.0 V)稀釋混合物且然後於室溫下攪拌15 min。分離有機層,且用DCM (6.25 L, 10.0 V)萃取水層。將合併之有機層用鹽水(1.25 L, 2.0 V)洗滌,經Na2
SO4
乾燥且濃縮,以得到粗固體。於室溫下將固體與己烷(1.25 L, 2.0 V)一起研磨,以獲得中間體N-(4-氯-1-甲基-7-硝基-1H-吲唑-3-基)-N-(甲基磺醯基)甲烷磺醯胺,其直接用於下一步驟。
(ii) 於室溫下向N-(4-氯-1-甲基-7-硝基-1H-吲唑-3-基)-N-(甲基磺醯基)甲烷磺醯胺(上文製備)於乙醇(10.5 L, 20.0 V)中之攪拌溶液中緩慢添加aq. 5% NaOH溶液(4.38 L, 7.0 V) [注意:較佳經由滴液漏斗緩慢添加]。將反應物質於相同溫度下攪拌3 h。反應完成(藉由TLC監測)[用於TLC分析之樣品製備:將約1.0 ml樣品用aq. 2.0 N HCl酸化以達到pH為2-3,將其用乙酸乙酯萃取且藉由TLC分析有機層]後,將反應物質冷卻至0-5℃且藉由添加aq. 2.0 N HCl (3.13 L, 5.0 V)將pH調整至2-3, 同時維持反應溫度低於10℃ [注意:在添加HCl時出現沈澱且隨著攪拌增加]。使反應混合物升溫至室溫且然後攪拌1.5-2.0 h。經由過濾分離獲得之固體且然後用水(1.25 L, 2.0 V)洗滌;之後用己烷(1.25 L, 2.0 V)洗滌。藉由維持真空過濾達60-90 min自固體去除大體積殘餘水。將濕物質於50℃下在熱空氣烘箱中乾燥6-7 h (直至水份含量低於1.0%),以得到黃色固體狀乾燥產物N
-(4-氯-1-甲基-7-硝基-1H
-吲唑-3-基)甲烷磺醯胺(640.0 g, 76%)。1
H NMR (400 MHz, CDCl3
):δ
8.05 (d,J
= 8.32 Hz, 1H), 7.32 (bs, 1H), 7.17 (d,J
= 8.28 Hz, 1H), 4.15 (s, 3H), 3.45 (s, 3H)。
步驟6:N
-(4-氯-1-甲基-7-硝基-1H
-吲唑-3-基)-N
-(4-甲氧基苄基)甲烷磺醯胺之製備
於室溫下向N
-(4-氯-1-甲基-7-硝基-1H
-吲唑-3-基)甲烷磺醯胺(635.0 g, 2.08 mol, 1.0 equiv.)及1-(氯甲基)-4-甲氧基苯(359.0 g, 2.30 mol, 1.1 equiv.)於DMF (6.35 L, 10.0 V)中之混合物中添加碳酸鉀(374.7 g, 2.70 mol, 1.3 equiv.)。將反應混合物加熱至80-90℃且於該溫度下維持3 h。反應完成(藉由TLC監測)後,將混合物傾倒至冰冷水(19.05 L, 30.0 V)中[注意:在劇烈攪拌下緩慢淬滅係較佳的以避免在產物沈澱時凝集]。經由過濾分離所得固體且用水(1.90 L, 3.0 V)洗滌;然後用己烷(1.27 L, 2.0 V)洗滌固體。藉由維持真空過濾達60-90 min自固體去除大體積殘餘水。將分離之固體溶解於乙酸乙酯(12.7 L, 20.0 V)中且添加木炭(63.5 g)。將混合物加熱至60-70℃且然後於該溫度下攪拌30-45 min.。經由矽藻土墊趁熱(40-50℃)過濾混合物且然後用乙酸乙酯(3.17 L, 5.0 V)萃取矽藻土墊。將合併之濾液在減壓下於低於50℃下濃縮至乾燥。於室溫下向固體中添加乙酸乙酯(0.635 L, 1.0 V)。將所得固體懸浮液攪拌30 min。經由過濾分離固體且然後用己烷(1.27 L, 2.0 V)洗滌。藉由維持真空過濾達45-60 min.自固體去除殘餘水,從而得到黃色固體狀產物N
-(4-氯-1-甲基-7-硝基-1H
-吲唑-3-基)-N
-(4-甲氧基苄基)甲烷磺醯胺(705.0 g, 80%產率)。1
H NMR (400 MHz, CDCl3
):δ
7.99 (d,J
= 8.24 Hz, 1H), 7.27 (d,J
= 8.68 Hz, 2H), 7.19 (d,J
= 8.24 Hz, 1H), 6.80 (d,J
= 8.44 Hz, 2H), 4.95-4.76 (m,
2H), 4.17 (s, 3H), 3.76 (s, 3H), 3.01 (s, 3H)。
步驟7:N
-(7-胺基-4-氯-1-甲基-1H
-吲唑-3-基)-N
-(4-甲氧基苄基)甲烷磺醯胺之製備
於室溫下向鋅粉末(540.0 g, 8.23 mol, 10.0 equiv.)於THF (3.50 L, 10.0 V)及水(7.0 L, 20.0 V)之混合物中之攪拌懸浮液中添加氯化銨(NH4
Cl) (449.0 g, 8.23 mol, 10.0 equiv.)。向混合物中添加THF (7.0 L, 20.0 V)中之N
-(4-氯-1-甲基-7-硝基-1H
-吲唑-3-基)-N
-(4-甲氧基苄基)甲烷磺醯胺(350 g, 0.823 mol, 1.0 equiv.)。將反應混合物於室溫下攪拌3-4 h。反應完成(藉由過程內TLC/HPLC監測)後,將混合物用乙酸乙酯(3.5 L, 10.0 V)及水(1.12 L, 2.5 V)稀釋。將混合物攪拌15 min。經由用乙酸乙酯(1.75 L, 5.0 V)洗滌之矽藻土墊床過濾反應物質。收集雙相濾液,且分離各相。用乙酸乙酯(3.50 L, 10.0 V)萃取水層。將合併之有機層用鹽水(3.50 L, 10 V)洗滌,經Na2
SO4
乾燥,且然後在真空中濃縮,從而得到粗固體。向粗產物中添加MTBE (3.25 L, 10 V)且將懸浮液於室溫下攪拌30 min。藉由過濾分離固體。藉由維持真空過濾達30-45 min自固體去除大體積殘餘水。將濕產物在熱空氣烘箱中(50℃)乾燥2 h,從而得到灰白色固體狀標題產物N
-(7-胺基-4-氯-1-甲基-1H
-吲唑-3-基)-N
-(4-甲氧基苄基)甲烷磺醯胺(276.0 g, 85%產率)。1
H NMR (400 MHz, CDCl3
):δ
7.29-7.26 (m,
2H), 6.86-6.79 (m, 2H), 6.42 (d,J
= 7.80 Hz, 1H), 4.99-4.70 (m, 2H), 4.25 (s, 3H), 3.77 (s, 5H), 2.98 (s, 3H)。
步驟1:苯甲酸3-側氧基丁基酯之製備
於-70℃下在氮氣氛下經1 h之時段向苯甲醯氯(0.396 L, 3405 mmol)於DCM (1 L)中之攪拌溶液中逐滴添加吡啶(470 mL)。於相同溫度下攪拌30 min後,經1 h之時段逐滴添加DCM (500 mL)中之4-羥基丁-2-酮(250.0 g, 2837 mmol)。使反應混合物升溫至26℃且然後攪拌16 h。藉由TLC (SiO2
, 30% EtOAc/Pet.Rf = 0.4)監測反應進程。完成時,將反應混合物用水(2 × 1000 mL)、1N HCl (2 × 500 mL)且然後飽和NaHCO3
溶液(2 × 500 mL)洗滌。將有機層經Na2
SO4
乾燥,過濾且在減壓下濃縮,從而得到淺黃色液體狀苯甲酸3-側氧基丁基酯(400 g, 產率 = 69%)。1
H NMR (400 MHz, 氯仿-d) δ = 8.05 - 7.94 (m, 2H), 7.60 - 7.51 (m, 1H), 7.47 - 7.36 (m, 2H), 4.65 - 4.54 (t, 2H), 2.97 - 2.84 (t, 2H), 2.28 - 2.13 (s, 3H)。HPLC純度 = 94.1%。
步驟2:苯甲酸3,3-二氟丁基酯之製備
於0℃下在氮氣氛下經1 h之時段向苯甲酸3-側氧基丁基酯(90 g, 427 mmol)於二氯甲烷(700 mL)中之攪拌溶液中逐滴添加DAST (677 mL, 5125 mmol)。使反應混合物升溫至26℃且攪拌16 hr。藉由TLC (SiO2
, 20% EtOAc/Pet.Rf = 0.6)監測反應進程。完成時,將反應混合物用DCM (500 mL)稀釋且緩慢傾倒至冷aq.飽和NaHCO3
(1 L)溶液中。分離有機層且用鹽水溶液(400 mL)洗滌,經無水Na2
SO4
乾燥,過濾且在減壓下濃縮,從而得到黃色液體狀粗製化合物(95 g)。此物質藉由使用矽膠(100-200網目)之管柱層析純化,使用於pet.中之0-5% EtOAc溶析。收集含有產物之溶離份且在減壓下濃縮,從而得到褐色液體狀苯甲酸3,3-二氟丁基酯(60 g, 產率 = 59%,).1
H NMR (400 MHz, CDCl3
) δ = 8.06 - 8.01 (m, 2H), 7.60 - 7.54 (m, 1H), 7.48 - 7.40 (m, 2H), 4.54 - 4.48 (t, 2H), 2.43 - 2.29 (m, 2H), 1.77 - 1.64 (m, 3H)。LCMS純度 = 89.74%;m/z = 215.33.
步驟3: 3,3-二氟丁-1-醇之製備
於0℃下在氮氣氛下向苯甲酸3,3-二氟丁基酯(100 g, 467 mmol)於THF (800 mL)中之攪拌溶液中添加氫氧化鋰一水合物(137 g, 3268 mmol)於水(800 mL)中之溶液。使反應混合物升溫至26℃且然後攪拌16 hr。藉由TLC (SiO2
, 20% EtOAc/Pet. Rf = 0.6, KMnO4
活性)監測反應進程。完成時,將反應混合物用二乙醚(400 mL)稀釋。分離有機層並再次用二乙醚(300 mL)萃取水層。將合併之有機物用鹽水(200 mL)洗滌,經Na2
SO4
乾燥,過濾且在減壓下濃縮(揮發性產物,浴溫 = 25℃),從而得到黑色液體狀粗製化合物。將此物質用二乙醚(100 mL)稀釋且用木炭處理。經由矽藻土墊過濾混合物。用二乙醚(200 mL)萃取矽藻土墊。在減壓下濃縮合併之濾液(揮發性產物, 浴溫 = 25℃),從而得到淺黃色液體狀3,3-二氟丁-1-醇(40 g, 產率 =71%)。1
H-NMR (400 MHz, CDCl3
) δ = 3.87 (t,J
= 6.1 Hz, 2H), 2.22 - 2.07 (m, 2H), 1.73 - 1.57 (m, 3H)。GCMS純度 = 91.3%;m/z = 110.0。
步驟1:2-胺基-6-(苄基氧基)菸鹼酸之製備
於26℃下在N2
氣氛下向2-胺基-6-氯菸鹼酸(200 g, 1159 mmol)於苄醇(1400 mL, 13464 mmol)中之攪拌溶液中添加第三丁醇鉀(390 g, 3477 mmol)。將反應混合物加熱至120℃且於該溫度下攪拌16 hr。藉由TLC(SiO2
, DCM中之10% MeOH, Rf = 0.5)監測反應進程。完成時,將反應混合物用水(3 L)稀釋且用二乙醚(2 × 1000 mL)萃取。分離有機層且使用aq.檸檬酸溶液(0.5 M)將水層酸化至pH 4。藉由過濾收集沈澱之固體且然後在減壓下乾燥,從而得到灰白色固體狀2-胺基-6-(苄基氧基)菸鹼酸(220 g, 產率 = 72%)。1
H NMR (400 MHz, DMSO-d6
) δ = 12.56 - 12.32 (m, 1H), 7.97 - 7.91 (m, 1H), 7.52 - 7.41 (m, 2H), 7.38 - 7.11 (m, 5H), 6.03 (d,J
= 8.5 Hz, 1H), 5.39 - 5.31 (m, 2H)。LCMS純度 = 93%;m/z = 245.29 (M+H)。
步驟2:2-胺基-6-(苄基氧基)菸鹼酸甲基酯之製備
於26℃下在N2
氣氛下向2-胺基-6-(苄基氧基)菸鹼酸(220 g, 901 mmol)於DMF (2.5 L)中之攪拌溶液中緩慢添加碳酸鉀(373 g, 2702 mmol)及碘甲烷(0.282 L, 4504 mmol)。將反應混合物在27℃下攪拌16 hr。藉由TLC (SiO2
, 40% EtOAc/Pet., Rf = 0.6)監測反應進程。完成時,將反應混合物用水(5 L)稀釋。藉由過濾分離沈澱之固體且然後在真空下乾燥,從而得到灰白色固體狀2-胺基-6-(苄基氧基)菸鹼酸甲基酯(220 g, 產率= 92 %)。1
H NMR (400 MHz, CDCl3
)δ
= 8.00 (d,J
= 8.4 Hz, 1H), 7.42-7.40 (m, 2H), 7.39-7.35 (m, 2H), 7.34-7.31 (m, 1H), 6.01 (d,J
= 8.4 Hz, 1H), 5.33 (s, 2H), 3.84 (s, 3H)。LCMS純度 = 97%, m/z = 259.30 (M+H)。
步驟3:2-胺基-6-羥基菸鹼酸甲基酯之製備
於26℃下在N2
氣氛下向2-胺基-6-(苄基氧基)菸鹼酸甲基酯(50 g, 190 mmol)於DCM (500 mL)中之攪拌溶液中緩慢添加TFA (800 mL)及三氟甲磺酸(25 mL, 282 mmol)。將反應混合物在26℃下攪拌16 hr。藉由TLC (SiO2
, EtOAc, Rf = 0.2)監測反應進程。完成時,在真空下去除揮發性物質,從而得到粗產物。將此物質與二乙醚(3 × 1000 mL)一起研磨且然後藉由過濾分離沈澱之固體。向固體中添加水(2 L)且然後將混合物攪拌5 h。藉由過濾收集固體且用水洗滌。在真空下乾燥固體,從而得到灰白色固體狀2-胺基-6-羥基菸鹼酸甲基酯(25 g, 產率 = 78%)。1H NMR (300 MHz, DMSO-d6
)δ
= 10.92-10.76 (m, 1H), 7.65 (d,J
= 9.5 Hz, 1H), 7.43-6.87 (m, 2H), 5.51 (d,J
= 9.5 Hz, 1H), 3.69 (s, 3H)。LCMS純度 = 99.32%;m/z = 169.32 (M+H)。藉由19
F-NMR確認產物中不存在TFA及三氟甲磺酸。產物未經額外純化即直接用於下一步驟。
步驟4:2-胺基-6-(3,3-二氟丁氧基)菸鹼酸甲基酯之製備
於0℃在N2
氣氛下向2-胺基-6-羥基菸鹼酸甲基酯(25 g, 147 mmol)於THF (375 mL)中之攪拌溶液中添加三苯基膦(77 g, 294 mmol)且然後逐滴添加DIAD (57.2 mL, 294 mmol)。將反應混合物於0℃攪拌15 min,然後於0℃向混合物中逐滴添加3,3-二氟丁-1-醇(25.3 g, 221 mmol)於THF (125 mL)中之溶液。使反應混合物達到27℃且然後攪拌5 h。藉由TLC (SiO2
, EtOAc, Rf = 0.5)監測反應進程。完成時,在減壓下濃縮反應混合物,得到粗產物。將此物質在MTBE:pet. (1:1, 1 L)中攪拌。過濾混合物且用MTBE:pet. (1:1, 4 x 200 mL)萃取濾墊。在減壓下濃縮合併之濾液,得到淺黃色膠狀固體。此物質藉由使用矽膠(100-200網目)之管柱層析純化,使用於pet.中之10-20% EtOAc溶析。收集含有產物之溶離份且在減壓下濃縮,得到淺黃色液體狀2-胺基-6-(3,3-二氟丁氧基)菸鹼酸甲基酯(20 g, 產率 = 48%)。1
H NMR (400 MHz, CDCl3
) δ = 8.05 - 7.95 (m, 1H), 6.02 (d,J
= 8.8 Hz, 1H), 4.45 (t,J
= 6.8 Hz, 2H), 3.80 (s, 3H), 2.40 - 2.22 (m, 2H), 1.68 (t,J
= 18.6 Hz, 3H)。LCMS純度 = 91.1%, m/z = 261.25 (M+H)。
步驟5: 2-胺基-6-(3,3-二氟丁氧基)菸鹼酸之製備
於26℃向2-胺基-6-(3,3-二氟丁氧基)菸鹼酸甲基酯(5.7g, 20.81 mmol)於THF (120 mL)及甲醇(30 mL)中之攪拌溶液中添加LiOH (2.491 g, 104 mmol)於水(30 mL)中之溶液。將反應混合物加熱至70℃且於該溫度攪拌16 h。藉由TLC (SiO2
, 50% EtOAc/Pet Rf = 0.2)監測反應進程。在完成時,在減壓下濃縮反應混合物。將所得殘餘物溶解於水(60 mL)中且使用1N HCl酸化至pH 4。用乙酸乙酯(3 × 100 mL)萃取混合物。將合併之有機層用鹽水(100 mL)洗,經無水Na2
SO4
乾燥,且在減壓下濃縮,得到褐色固體2-胺基-6-(3,3-二氟丁氧基)菸鹼酸(4.6 g, 產率 = 87%)。1
H NMR (400 MHz, CDCl3
) δ = 11.66 - 10.84 (m, 1H), 8.12 - 7.97 (m, 1H), 6.07 (d,J
= 8.3 Hz, 1H), 4.52 - 4.36 (m, 2H), 2.41 - 2.28 (m, 2H), 1.68 (t,J
= 18.6 Hz, 3H)。LCMS純度 = 97.68%, m/z = 247.24 (M+H)。
實例
1
:
N-((S)-1-((3P)-3-(4-
氯
-1-
甲基
-3-(
甲基磺醯胺基
)-1H-
吲唑
-7-
基
)-7-(3,3-
二氟丁氧基
)-4-
側氧基
-3,4-
二氫吡啶并
[2,3-d]
嘧啶
-2-
基
)-2-(3,5-
二氟苯基
)
乙基
)-2-((3bS,4aR)-3-(
二氟甲基
)-5,5-
二氟
-3b,4,4a,5-
四氫
-1H-
環丙
[3,4]
環戊
[1,2-c]
吡唑
-1-
基
)
乙醯胺之替代製備
步驟1: (S)-(1-(3-(4-氯-3-(N-(4-甲氧基苄基)甲基磺醯胺基)-1-甲基-1H-吲唑-7-基)-7-(3,3-二氟丁氧基)-4-側氧基-3,4-二氫吡啶并[2,3-d]嘧啶-2-基)-2-(3,5-二氟苯基)乙基)胺基甲酸第三丁基酯之製備
於-25℃下在氮氣氛下向(S)-2-((第三丁氧基羰基)胺基)-3-(3,5-二氟苯基)丙酸(50 g, 166 mmol)及2-胺基-6-(3,3-二氟丁氧基)菸鹼酸(41.3 g, 166 mmol)於乙腈(1000 mL)中之攪拌溶液中添加吡啶(47.0 mL, 581 mmol)。經15 min向所得混合物中逐滴添加2,4,6-三丙基-1,3,5,2,4,6-三氧雜三次膦酸鹽2,4,6-三氧化物(「T3P」,50% wt,於EtOAc中, 494 mL, 830 mmol)。使溶液升溫至13℃且然後攪拌5 hr。於13℃下向溶液中添加N-(7-胺基-4-氯-1-甲基-1H-吲唑-3-基)-N-(4-甲氧基苄基)甲烷磺醯胺(62.3 g, 158 mmol)。然後使反應物質緩慢升溫至27℃且然後於該溫度下攪拌48 hr。藉由TLC (SiO2
, 50% EtOAc/Pet., Rf = 0.4)監測反應進程。在完成時,在減壓下濃縮反應混合物且於0℃下逐滴添加至飽和NaHCO3
水溶液(1000 mL)中。形成白色沈澱,藉由真空過濾收集。將分離之固體用水(2 L)洗滌。維持真空過濾直至大部分殘餘水自固體去除。然後將固體溶解於DCM (2 L)中。將溶液經Na2
SO4
乾燥,過濾且然後在減壓下濃縮,從而得到粗產物。藉由用Pet中之50-65% EtOAc溶析之矽膠層析純化此物質。彙集含有期望產物之部分且在減壓下濃縮,從而得到黃色泡沫固體狀(S)-(1-(3-(4-氯-3-(N-(4-甲氧基苄基)甲基磺醯胺基)-1-甲基-1H-吲唑-7-基)-7-(3,3-二氟丁氧基)-4-側氧基-3,4-二氫吡啶并[2,3-d]嘧啶-2-基)-2-(3,5-二氟苯基)乙基)胺基甲酸第三丁基酯(50 g, 產率 = 31%)。以相同規模再重複上述程序七次,以產生總共592 g產物。將合併之產物(592 g)溶解於MeOH (1 L)中。將溶液用正己烷(6 L)稀釋。灰白色固體沈澱且然後將懸浮液攪拌20 min。藉由真空過濾收集固體,同時保存濾液。在真空下乾燥固體,從而得到灰白色固體狀(S)-(1-(3-(4-氯-3-(N-(4-甲氧基苄基)甲基磺醯胺基)-1-甲基-1H-吲唑-7-基)-7-(3,3-二氟丁氧基)-4-側氧基-3,4-二氫吡啶并[2,3-d]嘧啶-2-基)-2-(3,5-二氟苯基)乙基)胺基甲酸第三丁基酯(300 g, 產率 = 48%)。產物係同手性阻轉異構物之混合物(非鏡像異構物)。LCMS分析方法:管柱 = X Bridge BEH C18 (50mm × 4.6mm, 2.5 µm粒子);移動相A = 5mM碳酸氫銨;移動相B = 乙腈;梯度特性(時間(min) / %B) = 0/5、0.5/5、1.5/15、7/98、9/98、9.5/5、10/5;管柱溫度 = 35℃;流速 = 1.3 mL/min。LCMS結果:滯留時間 = 6.20 mins.;觀察之離子 = 888.09 (M+H);LCMS純度 = 95%。注意:將保存之濾液濃縮且在真空下乾燥,從而得到產物(120 g, 淺黃色固體),其亦與上述產物分開用於下游化學。
步驟2: (S)-N-((6P)-7-(2-(1-胺基-2-(3,5-二氟苯基)乙基)-7-(3,3-二氟丁氧基)-4-側氧基吡啶并[2,3-d]嘧啶-3(4H)-基)-4-氯-1-甲基-1H-吲唑-3-基)甲烷磺醯胺之製備
於0℃下向(S)-(1-(3-(4-氯-3-(N-(4-甲氧基苄基)甲基磺醯胺基)-1-甲基-1H-吲唑-7-基)-7-(3,3-二氟丁氧基)-4-側氧基-3,4-二氫吡啶并[2,3-d]嘧啶-2-基)-2-(3,5-二氟苯基)乙基)胺基甲酸第三丁基酯(95%純度, 300 g, 321 mmol)於DCM (3000 mL)中之攪拌溶液中添加三氟乙酸(TFA) (900 mL),之後添加三氟甲磺酸(158 mL, 1782 mmol)。使溶液升溫至27℃且然後在氮氣氛下攪拌2 hr。藉由TLC (SiO2
, 80% EtOAc/Pet.Rf = 0.3)監測反應進程。完成時,在氮氣體之輕柔流下去除揮發性物質。於0℃下將殘餘物添加至飽和NaHCO3
溶液(1000 mL)中。藉由添加固體NaHCO3
將溶液調整至pH ~8 。用EtOAc (5 × 1000 mL)萃取混合物。將合併之有機層經Na2
SO4
乾燥,過濾,且然後在減壓下濃縮,從而得到粗產物。藉由用DCM中之5-10% MeOH溶析之矽膠層析純化此物質。彙集含有期望產物之部分且在減壓下濃縮,從而得到呈同手性阻轉異構物之混合物(非鏡像異構物,藉由LCMS,主要:79%及次要:10%)形式的(S)-N-(7-(2-(1-胺基-2-(3,5-二氟苯基)乙基)-7-(3,3-二氟丁氧基)-4-側氧基吡啶并[2,3-d]嘧啶-3(4H)-基)-4-氯-1-甲基-1H-吲唑-3-基)甲烷磺醯胺(211 g, 褐色泡沫固體)。將該物質溶解於甲醇:乙腈(80:20, 1800 mL)中且然後藉由prep-SFC使用以下方法純化:管柱 = (R,R) WHELK-01 (30 × 250 mm, 5 µm粒子);溶析液 = CO2
:MeOH (60:40);流速 = 90 g/min;反壓 = 100巴;檢測 = 214 nm (UV);疊加時間 = 15.5 min;每次注射之負載 = 1.125克。收集純主峰且在減壓下濃縮 ,從而得到褐色固體狀(S)-N-((6P)-7-(2-(1-胺基-2-(3,5-二氟苯基)乙基)-7-(3,3-二氟丁氧基)-4-側氧基吡啶并[2,3-d]嘧啶-3(4H)-基)-4-氯-1-甲基-1H-吲唑-3-基)甲烷磺醯胺(151 g, 產率 = 69%)。產物係單一立體異構物。1H-NMR (400 MHz, DMSO-d6
)δ
: 8.41 (d,J
= 8.8 Hz, 1H), 7.39 (dd,J
= 22.4, 7.9 Hz, 2H), 7.05 (d,J
= 8.3 Hz, 1H), 7.03-6.98 (m, 1H), 6.72 (d,J
= 8.8 Hz, 2H), 4.66-4.63 (m, 2H), 3.67 (s, 3H), 3.54-3.50 (m, 1H), 3.28-3.23 (m, 1H), 3.21 (s, 3H), 2.88-2.82 (m, 1H), 2.56-2.52 (m, 1H), 2.47-2.44 (m, 1H), 1.73 (t,J
= 19.0 Hz, 3H);LCMS方法:管柱 = Acquity BEH C18 (50mm × 2.1mm, 1.7 µm粒子);移動相A = 水中之0.1%甲酸;移動相B = MeCN中之0.1%甲酸;梯度特性(時間(min) / %B):0/3、0.4/3、3.2/98、3.8/98、4.2/3、4.5/3;管柱溫度 = 35℃;流速:0.6 mL/min。LCMS結果:滯留時間 = 1.93 mins.;觀察之離子 = 668.05 (M+H);HPLC純度 = 98%;手性HPLC純度 = 96.9%。
步驟3: N-((S)-1-((3P)-3-(4-氯-1-甲基-3-(甲基磺醯胺基)-1H-吲唑-7-基)-7-(3,3-二氟丁氧基)-4-側氧基-3,4-二氫吡啶并[2,3-d]嘧啶-2-基)-2-(3,5-二氟苯基)乙基)-2-((3bS,4aR)-3-(二氟甲基)-5,5-二氟-3b,4,4a,5-四氫-1H-環丙[3,4]環戊[1,2-c]吡唑-1-基)乙醯胺之製備
於27℃下向(S)-N-((6P)-7-(2-(1-胺基-2-(3,5-二氟苯基)乙基)-7-(3,3-二氟丁氧基)-4-側氧基吡啶并[2,3-d]嘧啶-3(4H)-基)-4-氯-1-甲基-1H-吲唑-3-基)甲烷磺醯胺(50 g, 74.1 mmol)於DMF (500 mL)中之攪拌溶液中添加2-((3bS,4aR)-3-(二氟甲基)-5,5-二氟-3b,4,4a,5-四氫-1H-環丙[3,4]環戊[1,2-c]吡唑-1-基)乙酸(21.75 g, 82 mmol),之後添加N-(3-二甲基胺基丙基)-N′-乙基碳二亞胺鹽酸鹽(「EDC-HCl」, 18.47 g, 96 mmol)、1-羥基苯并三唑水合物(「HOBt水合物」, 13.62 g, 89 mmol)及N-甲基嗎啉(65.2 mL, 593 mmol)。將反應物質於27℃下攪拌16 hr。藉由TLC (SiO2
, 50% EtOAc/Pet., Rf = 0.5)監測反應進程。完成時,將反應物質用冰水(1 L)稀釋且經由過濾收集所得沈澱且然後在真空下乾燥,從而得到灰白色固體狀粗產物(77 g)。將此粗產物與另外兩批藉由以相同規模重複程序生成之粗產物摻和。藉由用Pet中之40-50% EtOAc溶析之矽膠層析純化總共227 g粗產物。彙集含有期望產物之部分且在減壓下濃縮,從而得到純化產物(180 g)。將此純化產物與另一批類似製備之產物(25 g)摻和。藉由反相層析使用以下方法進一步逐批(30 x 5 g)純化一部分純化產物(150 g):管柱 = RediSep 275 g, HP C18 (CV 243mL, 150 mL/min);移動相A = 水:MeCN:TFA (950:50:1);移動相B = 水:MeCN:TFA (50:950:1);梯度特性(時間(min) /% B) = 3/10、6/20、9/30、12/40、15/50、18/60、42/70 (化合物開始溶析)、52/80、57/100;流速 = 80 mL/min.;管柱溫度 = 26℃;負載 = 每次5 g。彙集含有純產物之部分且在減壓下濃縮以去除乙腈組分。藉由添加飽和NaHCO3
使水溶液呈鹼性,然後用EtOAc (3 × 500 mL)萃取。將合併之有機物經無水Na2
SO4
乾燥且然後過濾。在減壓下濃縮濾液以獲得灰白色固體狀期望產物(102 g)。將此物質溶解於EtOAc (200 mL)中且然後將溶液用正己烷(1 L)稀釋。將所得沈澱於27℃下攪拌2 h且然後經由過濾收集。在真空下乾燥固體。藉由使用研缽及研杵研磨化合物去除痕量溶劑殘餘物且然後將微細固體在50℃烘箱中維持約2 h;重複(約4-5次)此研磨及加熱過程,直至去除所有痕量溶劑(藉由NMR分析),從而得到灰白色固體狀N-((S)-1-((3P)-3-(4-氯-1-甲基-3-(甲基磺醯胺基)-1H-吲唑-7-基)-7-(3,3-二氟丁氧基)-4-側氧基-3,4-二氫吡啶并[2,3-d]嘧啶-2-基)-2-(3,5-二氟苯基)乙基)-2-((3bS,4aR)-3-(二氟甲基)-5,5-二氟-3b,4,4a,5-四氫-1H-環丙[3,4]環戊[1,2-c]吡唑-1-基)乙醯胺(88.7 g, 產率 = 87%)。1H-NMR (DMSO-d6
) δ: 9.86 (s, 1H), 9.45 (d,J
= 8.3 Hz, 1H), 8.44 (d,J
= 8.7 Hz, 1H), 7.77 (d,J
= 8.3 Hz, 1H), 7.48 (d,J
= 7.4 Hz, 1H), 7.09 (d,J
= 8.7 Hz, 2H), 7.07-6.77 (m, 1H), 6.65 (d,J
= 6.2 Hz, 2H), 4.70 (d,J
= 16.7 Hz, 1H), 4.65 (t,J
= 6.3 Hz, 2H), 4.55 (d,J
= 16.7 Hz, 1H), 4.51-4.45 (m, 1H), 3.50 (s, 3H), 3.42-3.37 (m, 1H), 3.18 (s, 3H), 3.06-3.00 (m, 1H), 2.56-2.52 (m, 2H), 2.47-2.42 (m, 2H), 1.73 (t,J
= 19.2 Hz, 3H), 1.38-1.32 (m, 1H), 0.85-0.81 (m, 1H);LCMS方法:管柱 = Acquity BEH C18 (50mm × 2.1mm, 1.7 µm粒子),移動相A = 水中之0.1%甲酸;移動相B = MeCN中之0.1%甲酸;梯度特性(時間(min) / %B) = 0/3、0.4/3、7.5/98、9.5/98、9.6/3、10/3;管柱溫度= 35℃;流速 = 0.6 mL/min。LCMS結果:滯留時間 = 5.05 mins.;觀察之離子 = 913.97 (M+H);HPLC純度 = 99.5%;手性HPLC純度 = 99.5%。
實例1之命名:
如上文製備之實例1之化合物係含有軸手性之同手性物質。軸手性可使用如IUPAC Gold Book (doi:10.1351/goldbook.A00547)中詳述之P/M命名法來闡述。然而,此時僅有有限數量之軟體工具可用,其能夠產生含有P/M命名法之化學名稱,且甚至更少的選項可用於將使用此命名法之化學名稱轉換為分子之結構表示。因此,為了清楚及便利起見,下文提供實例1之若干名稱:
如由ChemDraw Ultra 12 (不存在P/M命名法)生成之實例1之名稱係:
N-((S)-1-(3-(4-氯-1-甲基-3-(甲基磺醯胺基)-1H-吲唑-7-基)-7-(3,3-二氟丁氧基)-4-側氧基-3,4-二氫吡啶并[2,3-d]嘧啶-2-基)-2-(3,5-二氟苯基)乙基)-2-((3bS,4aR)-3-(二氟甲基)-5,5-二氟-3b,4,4a,5-四氫-1H-環丙[3,4]環戊[1,2-c]吡唑-1-基)乙醯胺
如由JChem for Excel (包括P/M命名法)生成之實例1之化學名稱係:
N-[(1S)-1-[(3P)-3-(4-氯-3-甲烷磺醯胺基-1-甲基-1H-吲唑-7-基)-7-(3,3-二氟丁氧基)-4-側氧基-3H,4H-吡啶并[2,3-d]嘧啶-2-基]-2-(3,5-二氟苯基)乙基]-2-[(2S,4R)-9-(二氟甲基)-5,5-二氟-7,8-二氮雜三環[4.3.0.02
,4
]壬-1(6),8-二烯-7-基]乙醯胺
由人工添加P/M命名法之ChemDraw Ultra 12生成的化學名稱係:
N-((S)-1-((3P)-3-(4-氯-1-甲基-3-(甲基磺醯胺基)-1H-吲唑-7-基)-7-(3,3-二氟丁氧基)-4-側氧基-3,4-二氫吡啶并[2,3-d]嘧啶-2-基)-2-(3,5-二氟苯基)乙基)-2-((3bS,4aR)-3-(二氟甲基)-5,5-二氟-3b,4,4a,5-四氫-1H-環丙[3,4]環戊[1,2-c]吡唑-1-基)乙醯胺
比較測試:
將實例1之化合物與WO2018203235 (方案1)中所述之實例60.2之化合物在若干測試中進行比較。出於該等比較之目的,選擇使用每一化合物之同手性材料,此乃因此純度程度係在人類臨床試驗中使用之最有代表性的。具體地,如方案2中所示,在實例1及實例60.2中,吲唑繞指示C-N鍵之受限旋轉產生阻轉異構物(非鏡像異構物),其可藉由層析分離且在室溫下不相互轉化。因此,使用層析,以純形式分離方案2中繪示之立體異構物。
經由LC-MS/MS量化化合物之一般程序:
將所有活體外樣品注射至Exion LC 4500 Triple QuadTM
LC-MS/MS系統上。所用分析管柱係維持於室溫下之Phenomenex C18 (C18, 4.6 mm × 50 mm, 5 µm)。移動相A由MilliQ水中之0.1% (v/v)甲酸組成。移動相B由100%甲醇組成。流速係1 mL/min。梯度如下:移動相B經0.7 min自5%線性增加至90%,於90%下維持1.4 min,且於5%下維持0.7 min。
將所有活體內樣品注射於Triple QuadTM
6500 LC-MS/MS系統上。所用分析管柱係維持於室溫下之Waters BEH (C18, 2.1 mm × 50 mm, 1.7 µm)。移動相A由H2O-1mM NH4OAc-0.025%甲酸組成。移動相B由MeOH-5mM NH4OAc組成。流速係0.6 mL/min。梯度如下:移動相B經0.7 min自2%線性增加至65%,在1.3分鐘時增加至90%且維持於90%下直至1.9分鐘。
用以量測功效及細胞毒性之程序:
自NIH AIDS Research and Reference Reagent Program獲得MT-2細胞、293T細胞及NL4-3
病毒之原病毒DNA純系。使MT-2細胞在補充有10%熱不活化胎牛血清(FBS)、100 mg/mL青黴素G及高達100單位/mL之鏈黴素的RPMI1640培養基中繁殖。使293T細胞在補充有10%熱不活化FBS、100 mg/mL青黴素G及100 mg/mL鏈黴素之DMEM培養基中繁殖。將其中nef基因之一部分經海腎螢光素酶基因取代之重組NL4-3
原病毒純系用於製備該等研究中使用之參照病毒。經由使用來自Mirus Bio LLC (Madison, WI)之Transit-293轉染試劑將重組NL4-3
原病毒純系轉染至293T細胞中來製備重組病毒。2-3天後收集上清液,且藉由量測螢光素酶活性,使用螢光素酶活性作為標記物在MT-2細胞中滴定存在之病毒之量。使用來自Promega (Madison, WI)之EnduRen活細胞受質量化螢光素酶。藉由在連續稀釋之化合物存在下,量測用重組病毒感染4-5天之MT-2細胞中之螢光素酶活性來量化化合物對重組病毒之抗病毒活性。
藉由使用指數形式之中值效應等式計算50%有效濃度(EC50
),其中(Fa) = 1/[1+ (ED50
/藥物濃度)m] (Johnson VA, Byington RT. Infectivity Assay. In Techniques in HIV Research. 編輯Aldovini A, Walker BD. 71-76. New York: Stockton Press.1990)。藉由使用指數形式之中值效應等式計算50%抑制濃度(EC50
),其中抑制百分比= 1/[1 + (EC50
/藥物濃度)m
],其中m
係反映濃度-反應曲線之斜率的參數。
除了使用未感染之細胞外,使用與如抗病毒分析中所述相同之方案測定化合物之細胞毒性及相應CC50
值。在第4天在未感染之MT2細胞中藉由使用基於XTT (2,3-雙[2-甲氧基-4-硝基-5-磺苯基]-2H-四唑鎓-5-羧基苯胺內鹽)之比色分析(Sigma-Aldrich, St Louis, Mo)評價細胞毒性。
結果:
實例1及實例60.2之功效在初始抗HIV病毒學分析之誤差內(實例1之EC50
= 19 ±6 pM,實例60.2之EC50
= 18 ±13 pM)。實例1及實例60.2量測之細胞毒性CC50
皆>10 µM。
用以量測肝微粒體中之代謝之方法:
將來自人類、大鼠、狗及猴之肝微粒體解凍,且在100 mM磷酸鉀緩衝液(pH7.4)中稀釋至1 mg/mL之最終濃度。將測試化合物及對照在1:1乙腈:水(v/v)中製備為1μM之100x最終濃度並等分成微粒體混合物。將混合物在37℃下在振盪水浴中預培育10分鐘。一式兩份實施培育。培育中包括三個對照:殺鼠靈(warfarin)、非那西汀(phenacetin)及維拉帕米(verapamil)。預培育後,用NADPH以1 mM之最終濃度起始反應。在0、5、15、30、45及60分鐘時,取出25 μL樣品且用300 μL含有內標準品(替米沙坦(Telmisartan))之乙腈淬滅。將樣品以1200 rpm渦旋5分鐘且然後以4000 rpm離心10 min。將100 μL上清液之等分試樣用水稀釋三倍且注射至Exion LC 4500 Triple Quad LC-MS/MS系統上。結果報告為剩餘母體之百分比,且由在每一時間點後剩餘之測試化合物之峰面積比計算且與零時間培育進行比較。
結果:
實例1在狗肝微粒體中之穩定性係在實例60.2中之至少七倍,且實例1在猴肝微粒體中之穩定性係在實例60.2中之至少兩倍。此數據表明實例1對狗及猴活體內之代謝應比實例60.2顯著更穩定。表 1.
肝微粒體穩定性 | 實例 1 | 實例 60.2 |
人類肝微粒體T1/2 | > 120 min. | > 120 min. |
大鼠肝微粒體T1/2 | > 120 min. | > 120 min. |
狗肝微粒體T1/2 | > 120 min. | 17 min. |
猴肝微粒體T1/2 | > 120 min. | 55 min. |
用以量測人類肝細胞中之代謝的程序:
將來自人類、猴、狗、大鼠及小鼠之冷凍保藏之懸液液中之肝細胞解凍且在預熱之威廉姆氏培養基E (William's Medium E) (pH7.4)中稀釋。將肝細胞懸浮液之等分試樣添加至在預熱之威廉姆氏培養基E (pH7.4)中製備之測試化合物工作溶液中,以在0.5 × 106
個細胞/毫升及≤ 0.25% DMSO中達到0.5 μM之最終濃度。於37℃與5%二氧化碳及振盪下培育該等樣品。以單態實施培育。在時間點0、10、30、60、120及240分鐘時,取出50 μL培育混合物之等分試樣且添加至100 μL含有內標準品之乙腈之溶液中,且然後將混合物在4℃下以3500 rpm離心15分鐘。實驗完成後,藉由LC-MS/MS分析樣品。代謝穩定性結果報告為剩餘母體測試化合物之百分比。此百分比係藉由將培育後(tx
)測試化合物之LCMS峰面積除以恰好培育之前在零時間(t0
)之測試化合物之LCMS峰面積來計算。
使用非線性回歸擬合,用以下等式計算消除速率常數(k
, min-1
):Ct
= C0
× e(-k × t)
其中:C0
係表示為峰面積比(測試化合物峰面積/內標準品峰面積)之初始濃度;Ct
係表示為面積比(測試化合物峰面積/內標準品面積)之t
時之濃度;e
係自然對數之底t
係時間(min);k
係消除速率常數(min-1
)。
使用以下等式計算半衰期(t1/2
, min):
其中:k
係消除速率常數(min-1
)。
使用以下等式計算活體外固有清除率(CLint,
mL/min/百萬細胞):
CLint
= 0.693 /t1/2
/n
其中:t1/2
係半衰期;n
係每mL之細胞數。
結果:
不可量測實例1在人類肝細胞中之半衰期,此乃因在240分鐘培育後無代謝可量測。相反,在類人肝細胞中培育實例60.2達240分鐘後,僅剩餘60%之實例60.2。因此,實例60.2在人類肝細胞中之半衰期經計算為350分鐘。實例60.2在人類肝細胞中之固有清除率為0.465 mL/min/g肝,其係實例1之藥物清除率(固有清除率小於0.2 mL/min/g肝)之至少兩倍。
用於量測活體內藥物動力學參數(PK)之程序:
在雄性CD1小鼠、Wistar Han大鼠、食蟹猴及比格犬中研究PK。兩組動物(每組N = 3)以靜脈內(IV)劑量(1 mg/kg)形式或藉由經口胃管灌食(5 mg/kg溶液及懸浮液)接受測試化合物。將藥物調配於90% PEG400、10%乙醇中用於IV投與,且調配於90% PEG400、5%乙醇中用於PO投與。對於IV在給藥後0.167、0.25、0.5、0.75、1、2、3、5、7、24、48、72及96 h時收集血樣;對於經口在給藥後0.25、0.5、0.75、1、2、3、5、7、24、48、72及96 h時收集樣品。將血樣收集至K3
EDTA管中且以1500-2000 × g離心以獲得血漿。將血漿樣品儲存於-20℃下直至藉由LC-MS/MS分析。將所有活體外樣品注射至Exion LC 4500 Triple QuadTM
LC-MS/MS系統上。所用分析管柱係維持於室溫下之Phenomenex C18 (C18, 4.6 mm × 50 mm, 5 µm)。移動相A由MilliQ水中之0.1% (v/v)甲酸組成。移動相B由100%甲醇組成。流速係1 mL/min。梯度如下:移動相B經0.7 min自5%線性增加至90%,於90%下維持1.4 min,且於5%下維持0.7 min。所有LC-MS/MS分析參數介以電子方式捕獲於原始數據文件中。
藉由血漿濃度對時間數據之非分室分析(Phoenix WinNonlin v8)獲得PK參數。直接自實驗觀察結果記錄峰濃度(Cmax
)及Cmax
之時間(Tmax
)。使用線性及對數梯形求和之組合計算自時間零至最後取樣時間之曲線下面積[AUC0-T
]及自時間零至無窮大之曲線下面積[AUCINF
]。在IV投與後,估計總血漿清除率(CLTp
)、穩態分佈體積(Vss
)、表觀消除半衰期(T-HALF)及平均滯留時間(MRT)。使用具有可量化濃度之最少三個時間點估計AUC及T-HALF。絕對口服生物利用度(F)估計為口服及IV劑量後之劑量正規化AUC值的比率。
結果:
在四種臨床前物種中量測實例1及實例60.2之IV藥物動力學(PK)參數:小鼠、大鼠、狗及猴。相對於實例60.2,實例1在所有四種物種中皆展現改良之清除率。與上文提及之肝微粒體分析之結果一致,清除率之差異對於狗及猴係最顯著的,其中清除率分別提高7倍及2.5倍。同樣,實例1在狗及猴中循環之半衰期分別比實例60.2高5倍及3倍。來自大鼠、狗及猴中溶液給藥之口服生物利用度對於實例1及實例60.2二者係大致相同的。表 2.
表 3.
在預期醫藥可進入人類臨床試驗之前,通常應在兩個臨床前物種中評價化合物之安全性:一者係齧齒類動物且一者係非齧齒類動物。該等物種通常係大鼠及狗或猴。活體內安全性研究之一個目的係達成循環中藥物之濃度比給予人類有效劑量之藥物所預期之濃度高許多倍。在安全性研究中獲得之藥物濃度與在服用有效劑量之藥物之人中預期之藥物濃度之間之倍數差異稱為「限度」。在安全性研究中達成高限度係重要的,此乃因隨著限度增加,若可能發生藥物相關不良事件,則在臨床前安全性評價期間將觀察到該藥物相關不良事件之置信度將增加。
大鼠、狗或猴中改良之PK參數意味著對於該等臨床前物種,在循環中達成高藥物濃度將需要較低劑量之化合物。因此,給予一定劑量之實例1之猴或狗將比給予相同大小劑量之實例60.2達成更高之限度。由於劑量大小之實際限制,在非齧齒動物安全性評價研究中實例1可達成之限度(以及因此置信度)高於實例60.2可達成之限度。
實例 1 PK 參數 | 單位 | 小鼠 | 大鼠 | 猴 | 狗 |
CL | mL/min/kg | 1.77 | 3.60 | 8.80 | 1.16 |
Vss | L/kg | 1.14 | 1.76 | 1.73 | 0.88 |
T1/2 | h | 7.8 | 10.2 | 4.2 | 12.4 |
生物利用度 | % | 76.7 | 57.5 | 7.92 | 34.6 |
實例 60.2 PK 參數 | 單位 | 小鼠 | 大鼠 | 猴 | 狗 |
CL | mL/min/kg | 5.20 | 5.89 | 22.2 | 8.21 |
Vss | L/kg | 2.14 | 2.86 | 1.34 | 0.96 |
T1/2 | h | 5.2 | 11.0 | 1.4 | 2.5 |
生物利用度 | % | 80.1 | 45.3 | 5.48 | 33.4 |
用於對臨床前PK參數進行異速縮放以提供對人類之劑量預測的程序:
使用Phoenix WinNonlin (v 8.0)軟體及Microsoft Excel使用ModelRisk加入用於群體建模實施人類劑量預測。自臨床前物種(小鼠、大鼠、狗及食蟹猴)縮放使用平均滯留時間(MRT)測定人類IV參數(Vc、Ka、K12、K21、Kel)。對於此計算,對相關PK研究之每一動物獨立建模。藉由去卷積(PO)或自臨床前物種中之半衰期(SC)來測定吸收(Ka) (Ka = LN(2)/t1/2)。考慮到人類可變性計算PO及SC之預測人類劑量且經計算以覆蓋人群之95%。
結果:
臨床前物種PK參數通常用於在人類臨床試驗之前預測人類PK參數。用於此預測之方法稱為「異速縮放」,且通常在文獻中討論及實踐。使用異速縮放,實例1在人類中維持藥物之有效血漿濃度所需之預測之每日一次口服劑量比實例60.2低15倍。具體地,實例1之預測人類QD PO劑量小於5 mg,而實例60.2之預測人類QD PO劑量大於30 mg。
儘管特異藥物反應(即,過敏反應)在本質上係不可預測且嚴重的且因此表示重大臨床問題,但已說明,以10 mg或更少之日劑量給予之藥物若曾經與特異藥物反應之高發病率相關亦係罕見的(Uetrecht, J. P. New Concepts in Immunology Relevant to Idiosyncratic Drug Reactions: The 「Danger Hypothesis」 and Innate Immune System. Chem. Res. Toxicol. 1999, 12(5), 387-395, DOI:10.1021/tx980249i)。
皮下活體內實驗中量測藥物動力學參數之程序:
將藥物調配於1% Kolliphor P188/1% PEG3350/3.5%甘露醇/94.5%水中且然後以20 mg/kg之劑量以皮下注射形式投與Wistar Han大鼠。在0.167、0.25、0.5、0.75、1、2、3、5、7、24、48、72、96 h時採集血樣,且然後每3天採集一次,直至122天。將血樣收集至K3
EDTA管中且以1500-2000 × g離心以獲得血漿。將血漿樣品儲存於-20℃下直至藉由LC-MS/MS分析。
結果:
在大鼠SC PK實驗中評估每一化合物對皮下(SC)投與之適合性。結果概述於圖1中。如藉由此實驗所測定,化合物在血漿中之表觀半衰期對於實例1為50天,且對於實例60.2為11.5天。實例1中之藥物濃度維持在5 ng/mL以上(研究中所有三隻動物可量測之最後濃度)達87天,且實例60.2中維持達24天。使用源自SC大鼠PK之表觀半衰期連同源自異速縮放之預測人類清除率值,計算人類之預測每月一次之皮下(Q1M SC)劑量。實例1在人類中維持藥物之有效血漿濃度所需之預測之Q1M SC劑量比實例60.2低20倍。
量測冷凍保藏之人類肝細胞中之細胞色素P450誘導的程序:
遵循FDA之指南(「In Vitro Metabolism- and Transporter- Mediated Drug-Drug Interaction Studies Guidance for Industry」),使用來自相同三個個體供體(而非彙集之供體)之肝細胞測試實例1及實例60.2誘導CYP2B6表現的潛能,且使用」倍數變化方法「評估酶mRNA含量之變化。在此測試中,mRNA含量之倍數變化小於2倍被認為係陰性發現,而變化≥ 2倍被認為係陽性發現。
在CYP誘導分析中使用來自三個供體之可誘導之冷凍保藏之人類原代肝細胞測試化合物,以確定引起CYP2B6誘導之潛能(如藉由mRNA轉錄之增加所量測)。將測試化合物(0.12至30 μM最終濃度)與天然表現所有參與調控各種CYP酶表現值之核受體的原代人類肝細胞一起培育48小時。將測試化合物及對照之新鮮溶液在分析培養基中稀釋且每24小時添加,連續兩天,最終DMSO濃度為0.1%。在培育結束時,評估細胞單層之完整性、細胞密度及存活率以評價細胞毒性效應。然後將細胞溶解於細胞裂解緩衝液中,且自每一分析樣品純化總RNA。然後將其用於反轉錄聚合酶鏈式反應(RT-PCR)以量化編碼人類CYP3A4、CYP2B6及CYP1A2基因之特定mRNA物種的量。
將測試化合物及對照之誘導潛能與已知之CYP2B6誘導物苯巴比妥(Phenobarbital) (1000μM)進行比較。此分析之結果表示為誘導倍數。誘導倍數計算為用測試化合物處理之細胞中之mRNA含量與僅用DMSO (溶劑對照)處理之細胞中之mRNA含量、即基礎mRNA含量的比率,且因此代表測試化合物之誘導潛能。誘導倍數值用於計算對照活性值之百分比,然後將其擬合至4參數邏輯式回歸模型以測定EC50
及Emax
值(若觀察到誘導)。亦平行評價細胞毒性,以避免由於細胞毒性導致之偽陽性CYP誘導結果。應避免在細胞毒性濃度下評價及解釋CYP誘導潛能。
結果:
在任何測試濃度(高達30 μM)下,利用任何化合物未觀察到細胞毒性。對於實例1,所有三個供體皆發現陰性結果(無誘導)。對於實例60.2,發現3個供體中有2個(EC50
值為1.5 μM及1.8 μM)為陽性發現(誘導)。
CYP酶表現之誘導被認為係藥物-藥物相互作用之根本原因,導致代謝受誘導之CYP同功型(isoform)控制之受害藥物的清除率增加。在CYP同功型中,CYP2B6在HIV治療中特別重要,因為依法韋侖(efavirenz,EFV,一種廣泛用於治療HIV之藥物,包括在2019年之國際衛生組織基本藥物列表中)主要由CYP2B6代謝(Ward, B. A., Gorski, J. C., Jones, D. R., Hall, S. D., Flockhard, D. A., Desta, Z. The Cytochrome P450 2B6 (CYP2B6) Is the Main Catalyst of Efavirenz Primary and Secondary Metabolism: Implication for HIV/AIDS Therapy and Utility of Efavirenz as a Substrate Marker of CYP2B6 Catalytic Activity, J. Pharmacol. Exp. Ther., 2003, 306, 287-300, DOI: 10.1124/jpet.103.049601)。
圖1係概述下述大鼠SC PK實驗之圖。
Claims (14)
- 一種醫藥組合物,其包含如請求項1或2之化合物或其醫藥上可接受之鹽。
- 如請求項3之醫藥組合物,其進一步包含醫藥上可接受之賦形劑。
- 如請求項3或4之醫藥組合物,其適於經口投與、肌內注射或皮下注射。
- 一種如請求項1或2之化合物或其醫藥上可接受之鹽的用途,其用於製造用於治療人類之HIV感染的藥劑。
- 如請求項6之用途,其中該藥劑用於經口投與。
- 如請求項6之用途,其中該藥劑用於肌內注射或皮下注射。
- 如請求項6之用途,其中該藥劑進一步包含至少一種用於治療HIV感染之其他藥劑或與該其他藥劑組合使用。
- 如請求項9之用途,其中該至少一種其他藥劑係選自由以下組成之群:德羅格韋(dolutegravir)、比特拉韋(bictegravir)、拉米夫定(lamivudine)、福司它韋(fostemsavir)、卡博替韋(cabotegravir)、馬拉維洛(maraviroc)、利匹韋林(rilpivirine)、阿紮那韋(atazanavir)、泰諾福韋艾拉酚胺(tenofovir alafenamide)、伊司他韋(islatravir)、多拉維林(doravirine)及達如那韋(darunavir)。
- 如請求項10之用途,其中該至少一種其他藥劑係選自由以下組成之群:德羅格韋、比特拉韋、伊司他韋、拉米夫定、福司它韋及卡博替韋。
- 如請求項1或2之化合物或其醫藥上可接受之鹽,其用於療法。
- 如請求項1或2之化合物或其醫藥上可接受之鹽,其用於治療人類之HIV感染。
- 如請求項1或2之化合物或其醫藥上可接受之鹽,其用於製造用於治療人類之HIV感染的藥劑。
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