TW201323425A - 抗菌性咔啉化合物 - Google Patents
抗菌性咔啉化合物 Download PDFInfo
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- TW201323425A TW201323425A TW101140784A TW101140784A TW201323425A TW 201323425 A TW201323425 A TW 201323425A TW 101140784 A TW101140784 A TW 101140784A TW 101140784 A TW101140784 A TW 101140784A TW 201323425 A TW201323425 A TW 201323425A
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- Prior art keywords
- alkyl
- compound
- optionally substituted
- cycloalkyl
- composition
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
本發明提供一種包含咔啉化合物的組成物,其係用來治療感染(諸如病毒性結膜炎)。本發明亦提供一種用於治療其它感染之方法,包括眼睛感染。更特別的是,本發明係關於一種包含咔啉化合物的組成物,其係用於眼睛感染之治療,諸如病毒性結膜炎,特別是由腺病毒造成的那些。
Description
本申請案在35 U.S.C.§119下主張2011年11月4日所提出的美國臨時專利申請案案號61,555,584之優先權,其全部內容以參考之方式併入本文。
本發明普遍關於一種對感染之治療有用的咔啉化合物;特別關於一種用以治療由微生物(諸如腺病毒)造成的感染之方法及化合物。
病毒性結膜炎代表一無可獲得的治療選擇之明顯、未滿足的醫療需求。雖然一些病毒物種可開始結膜感染,腺病毒(AdV)說明最大量的臨床情況。眼睛腺病毒感染具有高度的接觸傳染性、容易從受感染處蔓延至未感染的眼睛,及例行地會傳給家族成員。結果,在美國每年有超過3百萬個缺課日係與腺病毒感染相關。腺病毒相關的濾泡性結膜炎相當溫和及自限、持續二至四週。與濾泡性腺病毒性結膜炎相關的特定血清類型包括Ad3、Ad4及Ad7。比較上,血清類型Ad8、Ad19及Ad37係與流行性角膜結膜炎(一種牽涉角膜及結膜之高接觸傳染性及更嚴重的疾病,具有可能的長期明視度後果)相關。因此,對具有寬廣範圍的血清類型活性之有效抗腺病毒劑有實際需求。
在最近20年中,於單純疱疹病毒(HSV)、流行性感冒病毒、肝炎B病毒(HBV)及人類免疫缺陷病毒(HIV)感染之治療上已經有明顯發展。但是,如上述提到,對AdV感染並無有效治療。最近,哈維(Harvey)等人(Antiviral Res.82:1-11,2009)描述出具有抗病毒活性的四氫咔唑,GSK-983。GSK-983抑制AdV血清類型5(Ad5)、多瘤病毒SV40、人乳頭瘤病毒(HPV)及埃伯坦-巴爾(Epstein-Barr)病毒(EBV)之複製,其具有EC50值在5-20 nM範圍內。但是,GSK-983先前尚未闡明具有對抗在眼部感染中發現的AdV血清類型之活性。此外,對治療由微生物(諸如腺病毒)造成的感染有用之化合物有需求。
本發明係關於一種用以治療由微生物(諸如細菌、病毒、黴菌等等)造成的感染之方法及化合物,特別是,用以治療眼睛病毒感染(諸如由腺病毒造成的那些)。此眼睛病毒感染包括(但不限於)病毒性結膜炎(包括腺病毒性結膜炎)、濾泡性結膜炎、眼角膜炎及流行性角膜結膜炎。已未預期地發現,本發明之化合物擁有寬廣範圍對抗通常在眼睛AdV感染中發現的腺病毒(AdV)血清類型之抗病毒活性。亦已闡明與在技藝中已知的其它化合物比較,本發明之化合物在酸性pH下具有高水溶解度。
本發明的另一個具體實例考慮到一種在眼睛感染之治療上有用的眼用醫藥組成物,其包含有效量之根據
式I-III的化合物。
本發明的更另一個具體實例包括一種治療眼睛感染的方法,其包括給藥一治療有效量的眼用醫藥組成物,其中該組成物包含有效量之根據式I-III的化合物。
本發明的又另一個具體實例係一種在眼睛感染之治療上有用的眼用醫藥組成物,其包含一有效量的化合物1-110。
前述簡述廣泛地描述出本發明的某些具體實例之特徵及工藝優點。將在接著的發明詳細說明中描述出額外的特徵及工藝優點。咸信係本發明的特徵之新穎的特徵將從發明詳細說明(當與任何伴隨圖形連結著考慮時)中有較好的了解。但是,想要於本文中所提供的圖形幫助闡明本發明或輔助發展出了解本發明,而不想要定義本發明的範圍。
下列圖形形成及包括本專利說明書的部分以進一步闡明本發明的某些觀點。本發明可藉由組合著參照一幅以上的這些圖形與顯現於本文的特定具體實例之詳細說明有較好地了解。
圖1係一曲線圖,其顯示出本發明之化合物6在腺病毒性眼角膜炎的兔模型中之抗病毒活性的評估結果。
在一個具體實例中,本發明提供一種式I之化合
物:
其中:X=C或N;Yn=鍵結、CH2、C(O)、C(O)O、C(O)NR6或SO2;n=0或1;p=0、1或2;R1=H、鹵素、烷基、腈或醯胺;R2=H或烷基;R3及R4各自獨立地選自於H、烷基、環烷基、雜烷基、雜環烷基、芳基或雜芳基;或R3及R4可形成一3至6員環烷基或雜環烷基環,其選擇性經烷基或鹵素取代;R5=R7N(R8)R9、R7C(O)N(R8)R9或R7SO2R10;R6=H或烷基;R7=無或選擇性經取代的伸烷基;R8及R9各自獨立地選自於H、烷基、雜烷基、環烷基、雜環烷基、芳基或雜芳基,其各者可選擇性經取代;或R8可與R7及/或R9結合以形成一3至8員雜環,其選擇性經鹵素、烷基、氰基、NR10及/或S(O)p取代;及R10=H或烷基。
在另一個具體實例中,本發明提供一種式II之化合物:
其中:R3及R4各自獨立地選自於H、烷基、環烷基、雜烷基、雜環烷基、芳基或雜芳基;或R3及R4可形成一3至6員環烷基或雜環烷基環,其選擇性經烷基或鹵素取代;R5=R7N(R8)R9、R7C(O)N(R8)R9或R7SO2R10;R7=選擇性經取代的伸烷基;R8及R9各自獨立地選自於H、烷基、雜烷基、環烷基、雜環烷基或雜芳基,其各者可選擇性經取代;或R8可與R7及/或R9結合以形成一4至8員雜環,其選擇性經鹵素、烷基、NR10、N(O)及/或S(O)p取代;及R10=H或烷基。
在更另一個具體實例中,本發明提供一種式III之化合物:
其中:R1=Cl或Br;Yn=鍵結、CH2或C(O);R5=R7N(R8)R9、R7C(O)N(R8)R9或R7SO2R10;
R7=無或選擇性經取代的伸烷基;R8及R9各自獨立地選自於H、烷基、伸烷基、雜烷基、環烷基、雜環烷基或雜芳基,其各者可選擇性經取代;或R8可與R7及/或R9結合以形成一4至8員雜環,其選擇性經鹵素、烷基、NR10及/或S(O)p取代;及R10=H或選擇性經取代的烷基。
要了解本發明之化合物可包括一個以上的對掌性中心。本發明考慮到此化合物的全部鏡像物、非鏡像異構物及混合物。
再者,某些具體實例包括根據本發明的化合物之醫藥可接受的鹽。該醫藥可接受的鹽包括(但不限於)根據本發明之化合物之可溶或可分散的形式,其合適於治療疾病而沒有過度不想要的效應(諸如過敏性反應或毒性)。典型的醫藥可接受的鹽包括(但不限於)酸加成鹽,諸如醋酸鹽、檸檬酸鹽、苯甲酸鹽、乳酸鹽或磷酸鹽;及鹼加成鹽,諸如鋰、鈉、鉀或鋁。
如於本文中所使用,用語“芳基”指為具有總共5至14個環成員的單環、雙環或三環環系統,其中在該系統中的至少一個環係芳香族,及其中在該系統中的每個環包含3至7個環成員。用語“芳基”可與用語“芳基環”互換地使用。
如於本文中所使用,用語“雜環”、“雜環基”或“雜環的”意謂著具有3至14個環成員之選擇性經取代的非芳香族或芳香族、單環、雙環或三環環系統,其中一個以上的
環成員係雜原子,其中在該系統中的每個環包含3至7個環成員。
用語“雜芳基”指為具有3至14個環成員之選擇性經取代的單環、雙環或三環環系統,其中在該系統中的至少一個環係芳香族,在該系統中的至少一個環包含一個以上的雜原子,及其中在該系統中的每個環包含3至7個環成員。
用語“選擇性經取代”意謂著該居前的基團可經取代或未經取代。當經取代時,該“選擇性經取代的”基團之取代基可包括(不限於)一個以上各自獨立地選自於下列基團或特別標明出的基團組之取代基(單獨或組合):短鏈烷基、短鏈烯基、短鏈炔基、短鏈雜烷基、短鏈雜環烷基、短鏈鹵烷基、短鏈鹵烯基、短鏈鹵炔基、短鏈全鹵烷基、短鏈全鹵烷氧基、短鏈環烷基、芳基、芳氧基、短鏈烷氧基、短鏈鹵烷氧基、短鏈醯氧基、CO2H、短鏈烷氧基羰基、胺基羰基、短鏈烷基羰氧基、短鏈烷基羰基、短鏈烷基羰基胺基、氰基、氫、鹵素、羥基、胺基、短鏈烷基胺基、芳基胺基、硝基、短鏈烷硫基、短鏈烷基硫基、短鏈全鹵烷硫基、芳硫基、磺酸鹽、SO3H、三取代的矽基、N3、SH、吡啶基、噻吩、呋喃基、短鏈烷基胺基羰氧基、短鏈烷氧基羰基胺基、及短鏈烷基胺基羰基胺基。二個取代基可連結在一起以形成稠合的五、六或七員碳環或由零至三個雜原子組成(例如,形成亞甲基二氧基或伸乙基二氧基)的雜環。選擇性經取代的基團可未經取代(例如,-CH2CH3)、完
全取代(例如,-CF2CF3)、單取代(例如,-CH2CH2F)或以在完全取代至單取代中間的任何取代程度(例如,-CH2CF3)。關於取代,若沒有限定性條件來敘述取代基時,其包括經取代及未經取代形式二者。若取代基限定為“經取代”時,經取代的形式係特別想要。額外地,如需要時,可對特別部分定義出不同的選擇性取代基組;在這些情況中,該選擇性取代將係如所定義,經常立即接著下列措辭,“選擇性經...取代”。
重要要了解的是,該取代基當併入該指定的結構單元中時,其可係單獨或多個存在。例如,該取代基鹵素(其意謂著氟、氯、溴或碘)將指示出其欲接附的單元可經一個以上的鹵素原子(其可相同或不同)取代。
本發明之化合物可使用來治療多種微生物感染。它們對病毒感染之治療特別有用,更特別是眼睛病毒感染,諸如由腺病毒造成的那些。此眼睛病毒感染包括(但不限於)病毒性結膜炎(包括腺病毒性結膜炎)、濾泡性結膜炎、眼角膜炎及流行性角膜結膜炎。
本發明之化合物較佳以治療有效量(即,消除或減低患者的病毒載量之量)併入局部眼用調配物中用以傳遞至眼睛,然而也考慮到由熟習該項技術者已知用於眼睛及非眼睛用途的其它給藥模式(例如,口服、眼房內、局部、肌肉內等等)。進一步考慮到可將本發明之化合物配製在眼內塞入或植入裝置中。該化合物可與眼科學可接受的防腐劑、界面活性劑、黏度促進劑、滲透促進劑、緩衝劑、氯
化鈉及水結合,以形成水性、無菌的眼用懸浮液或溶液。該眼用溶液調配物可藉由將一化合物溶解在生理學可接受的等滲壓水性緩衝液中製備。再者,該眼用溶液可包括一眼科學可接受的界面活性劑以輔助溶解該化合物。再者,該眼用溶液可包括一增加黏度的試劑(諸如羥甲基纖維素、羥乙基纖維素、羥丙基甲基纖維素、甲基纖維素、聚乙烯吡咯啶酮或其類似物),以改良該調配物在結膜囊中之滯留。亦可使用膠凝劑,包括(但不限於)膠凝糖及三仙膠。為了製備無菌的眼用軟膏調配物,該活性成份可在適當媒劑(諸如礦物油、液體羊毛脂或白軟石蠟)中與防腐劑結合。該無菌的眼用凝膠調配物可根據所公告用於類似的眼用製劑之調配物,藉由將該化合物懸浮於從例如卡波剖(Carbopol)-974或其類似物之組合所製備的親水性基質來製備;可併入防腐劑及張力劑。
本發明之化合物在該組成物中的濃度將依該組成物想要的用途(例如,治療現存的感染或預防手術後感染),及所選擇的化合物之相對活性而變化。包含在本發明之組成物中的該化合物之量正常將係0.01至5百分比重量/體積(“w/v%”),但是較佳的量係0.1至1w/v%。
在某些具體實例中,本發明之組成物具有pH約3.0至約8.5。在一個具體實例中,本發明之眼用組成物具有pH 3.5-8.0,較佳為pH 4.0-7.5,及最佳為pH 4.5-6.5。
適應於局部給藥至眼睛之本發明的調配物較佳為等滲壓或稍微地低張,以對付由蒸發及/或疾病造成的任
何高滲透性眼淚。此可需要一張力劑以將該調配物的滲透壓濃度帶至或接近每公斤210-320毫滲莫耳(mOsm/公斤)的程度。本發明之調配物通常具有滲透壓濃度在範圍220-320 mOsm/公斤內,及較佳為具有滲透壓濃度在範圍235-300 mOsm/公斤內。該眼用調配物通常將配製如為無菌水溶液。
本發明之化合物亦可與其它抗感染藥或抗發炎藥組合著使用。較佳的組合包括本發明之化合物與類固醇或非類固醇抗炎性化合物,諸如地塞米松(dexamethasone)、奈帕芬胺(nepafenac)、地塞米松、氯替潑諾(loteprednol)、利美索龍(rimexolone)、潑尼松龍、氟美皮質醇及氫化可體松。
除了對人類治療有用外,於本文中所揭示的某些化合物及調配物亦可對陪伴動物、野生動物及農場動物之獸醫治療有用,包括哺乳動物、齧齒目動物及其類似動物。更佳的動物包括馬、狗及貓。
本發明之額外化合物(化合物1-110)包括顯示在表1中的結構。
本發明之化合物可使用下列反應方案1-10與在技藝中可獲得的相關知識合成:
本發明藉由下列化合物及其製備進一步闡明。
在裝備有機械攪拌器、溫度探針及迴流冷凝器的1升圓底燒瓶中加入5-氯色胺鹽酸(30克,130毫莫耳)、0.1 N硫酸(450毫升)及異戊醛(21毫升,195毫莫耳)。將該懸浮液加熱至80℃及變成粉紅色均勻溶液。在80℃下攪拌該混合物2小時,然後允許冷卻至周溫。收集固體,以MTBE清洗(2x50毫升),及在45℃之真空中乾燥過夜以提供6-氯-1-異丁基-2,3,4,9-四氫-1H-吡啶并[3,4-b]吲哚鹽酸,如為灰白色固體36.5克(94%,96.5%AUC藉由HPLC)。在凱若佩克(Chiralpak)IA管柱(EtOH w/0.1%DEA,40℃)上的6-氯-1-異丁基-2,3,4,9-四氫-1H-吡啶并[3,4-b]吲哚鹽酸(11.9克)之製備型對掌性解析物提供(S)-6-氯-1-異丁基-2,3,4,9-四氫-1H-吡啶并[3,4-b]吲哚(5.4克,99.6%ee),及(R)-6-氯-1-異丁基-2,3,4,9-四氫-1H-吡啶并[3,4-b]吲哚(5.3,99.1%ee),如為白
色固體:1H NMR(400 MHz,DMSO-d6)δ10.83(s,1H),7.35(d,J=2.0 Hz,1H),7.26(d,J=8.50 Hz,1H),6.98(dd,J=2.1,8.5 Hz,1H),3.94(dd,J=1.3,8.9 Hz,1H),3.10(td,J=4.8,12.7 Hz,1H),2.82(ddd,J=5.6,7.1,12.8 Hz,1H),2.51-2.57(m,2H),2.16(br.s,1H),1.89-2.01(m,1H),1.66(ddd,J=3.3,9.9,13.4 Hz,1H),1.43-1.55(m,1H),0.97(d,J=6.5 Hz,3H),0.92(d,J=6.7 Hz,3H);MS(+ESI)263(M+)。
在(S)-6-氯-1-異丁基-2,3,4,9-四氫-1H-吡啶并[3,4-b]吲哚(5克,16.7毫莫耳)於二氯甲烷(100毫升)中之攪拌溶液中,加入N,N-二異丙基乙基胺(7.5毫升,41.8毫莫耳)。將該料漿冷卻至0℃及以保持內部溫度低於10℃的速率加入丙烯醯基氯(1.4毫升,17.5毫莫耳)。在0-10℃下攪拌該反應30分鐘,允許加熱至周溫及攪拌過夜。以水稀釋(100毫升)所產生的橙色溶液,及以二氯甲烷(2x100毫升)萃取該水相。以鹽水(100毫升)清洗結合的有機物,乾燥(MgSO4),在塞里塑料上過濾,及在真空中濃縮。對該油狀濃縮物加入MTBE(60毫升)。攪拌所產生的懸浮液30分鐘,過濾,及以冷的MTBE清洗(20毫升)。收集固體及在50℃之真空中乾燥,以提供(S)-1-(6-氯-1-異丁基-3,4-二氫-1H-吡啶并[3,4-b]吲哚-2(9H)-基)丙-2-烯-1-酮(2.9克,67%,98.7%AUC藉由HPLC),如為灰白色固體。1H NMR(400 MHz,DMSO-d6)δ11.12(s,1H),7.41(d,J=2.0 Hz,1H),7.31(d,J=8.6 Hz,1H),7.03(dd,J=2.0,8.6 Hz,1H),6.95(dd,J=10.4,16.4
Hz,1H),6.13(dd,J=2.3,16.6 Hz,1H),5.75-5.82(m,1H),5.72(dd,J=2.3,10.4 Hz,1H),4.25(dd,J=4.9,14.3 Hz,1H),3.37-3.50(m,1H),2.56-2.76(m,2H),1.80(t,J=10.2 Hz,1H),1.55-1.70(m,2H),1.05(d,J=5.8 Hz,3H),0.91(d,J=6.1 Hz,3H);LCMS(+APCI)317(M+)。
在30毫升乙醇中的(S)-1-(6-氯-1-異丁基-3,4-二氫-1H-吡啶并[3,4-b]吲哚-2(9H)-基)丙-2-烯-1-酮(1.0克,3.2毫莫耳)之攪拌溶液中,加入N,N-二異丙基乙基胺(1.7毫升,9.6毫莫耳)接著二氟哌啶鹽酸(0.75克,4.8毫莫耳)。在迴流下加熱該反應72小時。允許該反應冷卻至周溫及以EtOAc(25毫升)及水(25毫升)稀釋。以EtOAc(25毫升)萃取水相及以鹽水(25毫升)清洗結合的有機物,乾燥(MgSO4),過濾,及在真空中濃縮。藉由管柱層析法(40克SiO2凝膠,30-60%EtOAc/己烷類)純化該粗產物殘餘物,以獲得化合物6(1.2克,87%),如為白色海綿狀物質。1H NMR(400 MHz,DMSO-d6)δ11.02-11.16(m,1H),7.41(d,J=2.1 Hz,1H),7.30(dd,J=0.3,8.5 Hz,1H),7.03(dd,J=2.1,8.5 Hz,1H),5.65-5.80(m,1H),4.03-4.19(m,1H),3.34-3.47(m,1H),2.61-2.79(m,5H),2.53(s,5H),1.85-1.99(m,4H),1.70-1.80(m,1H),1.53-1.67(m,2H),1.03(d,J=6.0 Hz,3H),0.90(d,J=6.3 Hz,3H);LCMS(+ESI)437(M+)。
如先前對化合物6所描述般結合(S)-1-(6-氯-1-異丁基-3,4-二氫-1H-吡啶并[3,4-b]吲哚-2(9H)-基)丙-2-烯-1-酮與4-(三氟甲基)哌啶鹽酸,以提供20如為白色固體。1H NMR(400 MHz,CD2Cl2)δ8.02(s,1H),7.45(d,J=2.0 Hz,1H),7.29(dd,J=0.4,8.6 Hz,1H),7.12(dd,J=2.1,8.6 Hz,1H),5.89(dd,J=4.4,10.0 Hz,1H),4.09(dd,J=4.8,14.3 Hz,1H),3.51(ddd,J=4.6,11.8,14.3 Hz,1H),3.04(t,J=10.0 Hz,2H),2.52-2.90(m,6H),2.04(t,J=11.4 Hz,2H),1.68-1.92(m,4H),1.59(s,4H),1.10(d,J=6.4 Hz,3H),1.01(d,J=6.6 Hz,3H);LCMS(+ESI)470(M+)。
如先前對化合物6所描述般結合(S)-1-(6-氯-1-異丁基-3,4-二氫-1H-吡啶并[3,4-b]吲哚-2(9H)-基)丙-2-烯-1-
酮與4-氟哌啶鹽酸,以提供28如為白色固體。1H NMR(400 MHz,CD2Cl2)δ8.02(s,1H),7.38(d,J=2.1 Hz,1H),7.23(dd,J=0.4,8.6 Hz,1H),7.06(dd,J=2.0,8.6 Hz,1H),5.84(dd,J=4.4,9.9 Hz,1H),4.51-4.72(m,1H),3.99-4.08(m,1H),3.45(ddd,J=4.6,11.7,14.3 Hz,1H),2.48-2.83(m,7H),2.37(d,J=3.6 Hz,2H),1.49-1.95(m,8H),1.05(d,J=6.4 Hz,3H),0.95(d,J=6.6 Hz,3H);LCMS(+ESI)420(M+)。
如先前對化合物6所描述般結合(S)-1-(6-氯-1-異丁基-3,4-二氫-1H-吡啶并[3,4-b]吲哚-2(9H)-基)丙-2-烯-1-酮與4-(二氟甲基)哌啶鹽酸,以提供29如為白色固體。1H NMR(600 MHz,CD2Cl2-d2)δ8.00(br.s.,1H),7.41(d,J=1.9 Hz,1H),7.25(d,J=8.7 Hz,1H),7.08(dd,J=1.98,8.6 Hz,1H),5.86(dd,J=4.4,10.1 Hz,1H),5.47-5.69(m,1H),4.06(dd,J=5.1,14.3 Hz,1H),3.47(ddd,J=4.3,12.1,14.3 Hz,1H),2.97(t,J=12.1 Hz,2H),2.45-2.84(m,6H),1.97-2.04(m,2H),1.64-1.83(m,5H),1.52-1.60(m,1H),
1.38-1.48(m,2H),1.07(d,J=6.5 Hz,3H),0.97(d,J=6.7 Hz,3H);LCMS(+APCI)452(M+)。
如先前對化合物6所描述般結合(S)-1-(6-氯-1-異丁基-3,4-二氫-1H-吡啶并[3,4-b]吲哚-2(9H)-基)丙-2-烯-1-酮與(S)-3-氟吡咯啶鹽酸,以提供35。1H NMR(400 MHz,CD3OD)δ7.26(s,1H),7.13(dd,J=0.4,8.6 Hz,1H),6.92(dd,J=2.0,8.6 Hz,1H),5.74(dd,J=4.3,10.0 Hz,1H),5.02-5.22(m,1H),4.06(dd,J=4.8,14.2 Hz,1H),3.21(ddd,J=4.5,11.7,14.2 Hz,1H),2.88(m,2H),2.58-2.76(m,7H),2.36(m,1H),2.05(m,1H),1.73(m,1H),1.71(m,1H),1.57(m,2H),1.02(d,J=6.40 Hz,3H),0.86(d,J=6.5 Hz,3H);LCMS(+ESI)406(M+)。
如先前對化合物6所描述般結合(S)-1-(6-氯-1-異丁基-3,4-二氫-1H-吡啶并[3,4-b]吲哚-2(9H)-基)丙-2-烯-1-酮與4-(2,2-二氟乙基)哌啶鹽酸,以提供73如為白色固體。1H NMR(400 MHz,DMSO-d6)δ11.08(s,1H),7.41(d,J=1.94 Hz,1H),7.30(d,J=8.53 Hz,1H),7.02(dd,J=2.07,8.53 Hz,1H),5.92-6.32(m,1H),5.65-5.80(m,1H),4.01-4.17(m,1H),3.38(br.s.,1H),2.62-2.79(m,5H),2.28-2.61(m,11H),1.74(t,J=10.26 Hz,1H),1.52-1.66(m,2H),1.03(d,J=5.96 Hz,3H),0.89(d,J=6.27 Hz,3H);LCMS(+ESI)468(M+)。
在冰水浴中,將在二氯甲烷(50毫升)中的(S)-6-氯-1-異丁基-2,3,4,9-四氫-1H-吡啶并[3,4-b]吲哚(0.5克,1.90毫莫耳)之攪拌溶液冷卻至0℃,及以N,N-二異丙基乙基胺(0.66毫升,3.80毫莫耳)處理。經由注射器逐滴加入氯乙
醯基氯(0.17毫升,2.09毫莫耳)及在0℃下攪拌該反應30分鐘。允許該反應混合物加熱至周溫及攪拌過夜。以水(50毫升)稀釋所產生的棕色溶液及以二氯甲烷(2x50毫升)萃取水相。以鹽水(50毫升)清洗結合的有機物,乾燥(MgSO4),過濾及在真空中濃縮。藉由管柱層析法(12克SiO2凝膠,0-20%EtOAc/己烷類)純化該粗產物殘餘物,以獲得2-氯-1-((S)-6-氯-1-異丁基-1,3,4,9)-四氫-β-咔啉-2-基)乙酮(0.45克,69.7%),如為灰白色固體。1H NMR(400 MHz,CDCl3)δ7.93(s,1H),7.43(s,1H),7.24(dd,1H),7.12(dd,1H),5.80(m,1H),4.21(m,2H),4.06(m,1H),3.61(m,1H),2.77-2.94(m,2H),1.63-1.86(m,5H),1.1(d,J=6.02 Hz,3H),1.01(d,J=6.34 Hz,3H);LCMS(+ESI)340(M+)。
經由注射器,對在乙腈(20毫升)中的(S)-2-氯-1-(6-氯-1-異丁基-3,4-二氫-1H-吡啶并[3,4-b]吲哚-2(9H)-基乙酮(0.45克,1.15毫莫耳)之攪拌溶液逐滴加入環丙基胺(0.30毫升,4.62毫莫耳)。允許該反應混合物加熱至周溫及攪拌過夜。以水(50毫升)稀釋所產生的溶液,及以二氯甲烷(2x50毫升)萃取水相。以鹽水(50毫升)清洗結合的有機物,乾燥(MgSO4),過濾及在真空中濃縮。藉由管柱層析法(12克SiO2凝膠,0-60%EtOAc/己烷類)純化該粗產物殘餘物,以獲得化合物91(0.16克,29%),如為白色固體。1H NMR(400 MHz,DMSO-d6)δ11.09(s,1H),7.41(d,J=2.02 Hz,1H),7.30(dd,J=0.37,8.56 Hz,1H),7.03(d,J=2.14 Hz,1H),5.67-5.73(m,1H),4.03(dd,J=4.07,14.09 Hz,1H),
3.52-3.57(m,1H),3.44-3.63(m,1H),3.44-3.57(m,1H),2.63-2.82(m,3H),2.13(tt,J=3.42,6.63 Hz,1H),1.72-1.80(m,1H),1.54-1.65(m,2H),1.05(d,J=5.99 Hz,3H),0.90(d,J=6.24 Hz,3H),0.31-0.34(m,2H),0.22-0.26(m,2H);HRLCMS m/z 360.1837(M+)。
對在10毫升乙醇中的2-氯-1-((S)-6-氯-1-異丁基-1,3,4,9)-四氫-β-咔啉-2-基)乙酮(0.25克,0.73毫莫耳)之攪拌溶液,加入N,N-二異丙基乙基胺(0.64毫升,3.68毫莫耳)接著4,4-二氟環己烷胺鹽酸(0.19克,1.1毫莫耳)及碘化鉀(0.18克,1.1毫莫耳)。在100℃下加熱該反應12小時。允許該反應冷卻至周溫及以EtOAc(25毫升)與水(25毫升)稀釋。以EtOAc(25毫升)萃取水相及以鹽水(25毫升)清洗結合的有機物,乾燥(MgSO4),過濾及在真空中濃縮。藉由管柱層析法純化該粗產物殘餘物,以獲得化合物94(0.22克,68%)如為灰白色粉末。1H NMR(400 MHz,CD3OD)δ7.34(s,1H),7.22(dd,J=0.4,8.6 Hz,1H),6.99(dd,J=2.0,8.6 Hz,1H),5.80(d,J=4.0 Hz,1H),4.03-4.08(m,1H),3.68(d,J=20.1
Hz,1H),3.55(d,J=16.3 Hz,1H),3.47(m,1H),2.63-2.82(m,3H),1.68-2.14(m,10h),1.50(m,2H),1.11(d,J=8.0 Hz,3H),0.95(d,J=8.0 Hz,3H);LCMS(+ESI)438(M+)。
如先前對化合物94所描述般結合2-氯-1-((S)-6-氯-1-異丁基-1,3,4,9)-四氫-β-咔啉-2-基)乙酮與1-3,3-二氟環丁烷胺鹽酸,以提供104。1H NMR(400 MHz,CD3OD)δ7.38(s,1H),7.25(dd,J=0.4,8.6 Hz,1H),7.04(dd,J=2.0,8.6 Hz,1H),5.84(dd,J=2.0,8.6 Hz,1H),4.04-4.09(dd,J=4.0,12.1 Hz,1H),3.6(d,J=16.3 Hz,1H),3.56(d,J=16.3 Hz,1H),3.49-3.52(m,1H),3.25-3.30(m,1H),2.72-2.84(m,4H),2.41-2.45(m,2H),1.86(t,J=8.2 Hz,1H),1.67-1.72(m,2H),1.13(d,J=8.0 Hz,3H),0.97(d,J=8.0 Hz,3H);LCMS(+ESI)410(M+)。
如先前對化合物94所描述般結合2-氯-1-((S)-6-氯-1-異丁基-1,3,4,9)-四氫-β-咔啉-2-基)乙酮與3,3,3-三氟丙烷-1-胺鹽酸,以提供108。1H NMR(400 MHz,CD3OD)δ7.25(d,J=4.1 Hz,1H),7.13(d,J=8.3 Hz,1H),6.91(dd,J=2.0,8.6 Hz,1H),5.73(dd,J=2.0,8.6 Hz,1H),4.70(bs,1H),3.93-3.98(dd,J=4.0,12.1 Hz,1H),3.62(d,J=16.2 Hz,1H),3.48(d,J=16.2 Hz,1H),3.37-3.45(m,1H),2.61-2.79(m,4H),2.25-2.36(m,2H),1.75(t,J=12.0 Hz,1H),1.55-1.60(m,2H),1.11(d,J=8.0 Hz,3H),0.95(d,J=8.0 Hz,3H);LCMS(+ESI)416(M+)。
如先前對化合物94所描述般結合2-氯-1-(6-氯-1-異丁基-3,4-二氫-1H-吡啶并[3,4-b]吲哚-2(9H)-基)乙酮與3,3-三氟吖呾鹽酸,以提供85。1H NMR(400 MHz,CD3OD)δ7.25(s,1H),7.14(d,J=8.2 Hz,1H),6.91(dd,J=2.0,
8.2 Hz,1H),5.67(dd,J=2.0,8.4 Hz,1H),3.91-3.94(dd,J=4.0,12.1 Hz,1H),3.51-3.70(m,4H),3.37-3.42(m,1H),2.60-2.74(m,2H),1.58(t,J=8.0 Hz,1H),1.52-1.54(m,2H),1.15(d,J=8.0 Hz,3H),0.92(d,J=8.0 Hz,3H);LCMS(+ESI)396(M+)。
將在20毫升二氯甲烷中的3-氟-1,3-吖呾二羧酸三級丁基酯(1.0克,4.56毫莫耳)之攪拌溶液冷卻至0℃及以1,1’-羰基二咪唑(0.88克,5.47毫莫耳)處理。允許將該反應混合物加熱至室溫及攪拌3小時。以三乙基胺(1.3毫升,9.12毫莫耳)接著6-氯-1-異丁基-2,3,4,9-四氫-1H-吡啶并[3,4-b]吲哚鹽酸(1.4克,4.56毫莫耳)處理該反應,然後加熱至50℃及攪拌過夜。以水(50毫升)稀釋所產生的溶液,及以醋酸乙酯(2x50毫升)萃取水相。以鹽水(50毫升)清洗結合的有機物,乾燥(MgSO4),過濾及在真空中濃縮,以提供1.2克(59%)的3-(6-氯-1-異丁基-2,3,4,9-四氫-1H-吡啶并[3,4-b]吲哚-2-羰基)-3-氟吖呾-1-羧酸三級丁酯,如為固體。1H NMR(400 MHz,DMSO-d6)δ11.14(s,1H),7.44(d,J=2.02 Hz,1H),7.32(d,J=8.56 Hz,1H),7.04(dd,J=2.08,8.56 Hz,1H),
5.64(br.s.,1H),4.34-4.56(m,2H),4.24(m,2H),3.69-3.78(m,1H),3.48-3.58(m,1H),2.73(d,J=4.59 Hz,2H),1.82(m,1H),1.54-1.70(m,2H),1.40(s,9H),1.04(d,J=6.17 Hz,3H),0.92(d,J=6.36 Hz,3H)。將所產生的3-(6-氯-1-異丁基-2,3,4,9-四氫-1H-吡啶并[3,4-b]吲哚-2-羰基)-3-氟吖呾-1-羧酸三級丁酯溶解在3:1的二氯甲烷與三氟醋酸之混合物(40毫升)中,及在室溫下攪拌4小時。在真空中濃縮該反應及將所產生的殘餘物分配在二氯甲烷(100毫升)與飽和碳酸氫鹽溶液(50毫升)間。以鹽水(50毫升)清洗有機層,乾燥(MgSO4),過濾及在真空中濃縮。藉由管柱層析法(12克SiO2凝膠,4%甲醇在二氯甲烷中)純化該粗產物殘餘物以獲得化合物1020.70克(66%),如為白色固體。1H NMR(400 MHz,DMSO-d6)δ 11.14(s,1H),7.42(d,J=1.90 Hz,1H),7.32(d,J=8.56 Hz,1H),7.04(dd,J=2.02,8.56 Hz,1H),5.63-5.68(m,1H),3.91-4.12(m,2H),3.65-3.84(m,3H),3.43-3.53(m,1H),2.66-2.80(m,3H),1.76-1.85(m,1H),1.56-1.69(m,2H),0.99-1.09(m,3H),0.91(s,3H);LCMS(+ESI)364(M+)。
對在無水二氯甲烷(20毫升)中的化合物102(0.20克,0.55毫莫耳)及異丁醛(0.048克,0.66毫莫耳)溶液加入二滴醋酸接著三乙醯氧基硼氫化鈉(0.18克,0.85毫莫耳)。在室溫下攪拌該反應14小時,以NaHCO3水溶液(50毫升)稀釋及以二氯甲烷(2x50毫升)萃取。以鹽水清洗結合的有機物,乾燥(MgSO4),過濾及在真空中濃縮。藉由管柱層析法
(4克SiO2凝膠,4%甲醇在二氯甲烷中)純化該粗產物殘餘物以獲得103(0.09克,39%),如為白色固體。1H NMR(400 MHz,DMSO-d6)δ11.13(s,1H),7.42(d,J=1.90 Hz,1H),7.32(d,J=8.56 Hz,1H),7.04(dd,J=2.05,8.59 Hz,1H),5.65(dd,J=3.24,10.39 Hz,1H),3.62-3.81(m,3H),3.41-3.55(m,3H),2.63-2.76(m,2H),2.25(d,J=6.91 Hz,2H),1.74-1.86(m,1H),1.45-1.71(m,3H),1.04(d,J=6.11 Hz,3H),0.92(d,J=6.36 Hz,3H),0.83(d,J=6.60 Hz,6H);LCMS(+ESI)420(M+)。
對在10毫升無水二甲基甲醯胺中的(S)-6-氯-1-異丁基-2,3,4,9-四氫-1H-吡啶并[3,4-b]吲哚(0.54克,2.05毫莫耳)與1-(三級丁氧基羰基)吖呾-3-羧酸(0.45克,2.24毫莫耳)之溶液,相繼地加入二異丙基乙基胺(1.42毫升,8.15毫莫耳)、1-羥基苯并三唑(0.28克,2.07毫莫耳)及1-乙基-3-(3-二甲基胺基丙基)碳化二醯亞胺(0.54毫升/克,3.08毫莫耳)。在室溫下攪拌該反應混合物4小時及分配在二氯甲烷(100毫升)與水(100毫升)間。以飽和NaHCO3水溶液(50毫升)
接著鹽水(50毫升)清洗有機層,乾燥(MgSO4),過濾及濃縮,以提供原油。將該油溶解在3:1的二氯甲烷與三氟醋酸(40毫升)混合物中及在室溫下攪拌4小時。在真空中濃縮該反應。將所產生的殘餘物溶解在二氯甲烷(100毫升)中及以飽和NaHCO3水溶液(50毫升)清洗。以鹽水(50毫升)清洗有機層,乾燥(MgSO4),過濾及在真空中濃縮。藉由管柱層析法(12克SiO2凝膠,4%甲醇在二氯甲烷中)純化該粗產物物質,以獲得(S)-吖呾-3-基(6-氯-1-異丁基-3,4-二氫-1H-吡啶并[3,4-b]吲哚-2(9H)-基)甲酮(0.4克,76%),如為白色海綿狀物質。LCMS(+ESI)346(M+)。
如先前對化合物103所描述般結合(S)-吖呾-3-基(6-氯-1-異丁基-3,4-二氫-1H-吡啶并[3,4-b]吲哚-2(9H)-基)甲酮與3,3,3-三氟丙醛,以提供47如為白色固體。1H NMR(400 MHz,DMSO-d6)δ11.09(s,1H),7.40(d,J=1.59 Hz,1H),7.30(d,J=8.50 Hz,1H),7.02(dd,J=1.86,8.53 Hz,1H),5.68(d,J=8.31 Hz,1H),3.79(dd,J=4.40,14.24 Hz,1H),3.46-3.65(m,3H),3.31-3.44(m,2H),3.13(t,J=6.08 Hz,2H),2.58-2.71(m,2H),2.19-2.33(m,2H),1.67-1.79(m,1H),1.52-1.64(m,2H),1.04(d,J=5.62 Hz,3H),0.90(d,J=5.81 Hz,3H);LCMS(+ESI)442(M+)。
如對化合物99所描述般結合(S)-1-(6-氯-1-異丁基-3,4-二氫-1H-吡啶并[3,4-b]吲哚-2(9H)-基)丙-2-烯-1-酮與1-環丙基吖呾-3-羧酸,以提供92。1H NMR(400 MHz,CD3OD)δ7.40(s,1H),7.28(dd,J=0.4,8.6 Hz,1H),7.07(dd,J=2.0,8.6 Hz,1H),5.84(d,J=6.0 Hz,1H),4.44-4.80(m,4H),4.15-4.41(m,1H),3.60(ddd,J=4.5,11.7,14.2 Hz,1H),3.57(ddd,J=4.5,11.7,14.2 Hz,1H),3.11(m,1H),2.75-2.78(m,2H),1.71(m,1H),1.57(m,2H),1.68(d,J=6.4 Hz,3H),1.30(d,J=6.5 Hz,3H),1.09-1.14(m,4H);LCMS(+ESI)386(M+)。
如先前對化合物47之合成所描述般結合(S)-6-氯-1-異丁基-2,3,4,9-四氫-1H-吡啶并[3,4-b]吲哚與1-(三級丁氧基羰基)哌啶-4-羧酸,以提供(S)-(6-氯-1-異丁基-3,4-二氫
-1H-吡啶并[3,4-b]吲哚-2(9H)-基)(哌啶-4-基)甲酮(1.0克,54%),如為白色固體。LCMS(+ESI)374(M+)。
在4埃分子篩(0.5克)上攪拌於5毫升MeOH中之(S)-(6-氯-1-異丁基-3,4-二氫-1H-吡啶并[3,4-b]吲哚-2(9H)-基)(哌啶-4-基)甲酮(0.90克,2.41毫莫耳)溶液,及相繼地以醋酸(2.5毫升)、(1-乙氧基環丙氧基)三甲基矽烷(2.12克,12.1毫莫耳)及氰硼氫化鈉(0.71克,11.2毫莫耳)處理。將該反應混合物加熱至50℃及攪拌18小時。以二氯甲烷(20毫升)稀釋該反應,以1 N的NaOH水溶液及鹽水清洗,乾燥(MgSO4),過濾及在真空中濃縮。藉由管柱層析法(12克SiO2凝膠,4%甲醇在CH2Cl2中)純化該粗產物殘餘物以獲得化合物93(0.15克,15%),如為白色固體。1H NMR(400 MHz,DMSO-d6)δ11.08(s,1H),7.41(d,J=1.96 Hz,1H),7.29(d,J=8.56 Hz,1H),7.27-7.31(m,1H),7.02(dd,J=2.02,8.56 Hz,1H),5.71-5.76(m,1H),4.15(dd,J=3.64,14.21 Hz,1H),3.36-3.45(m,1H),2.89-2.97(m,2H),2.65-2.74(m,3H),2.18-2.30(m,2H),1.63-1.77(m,3H),1.50-1.61(m,5H),1.00(d,J=5.93 Hz,3H),0.89(d,J=6.17 Hz,3H),0.36-0.42(m,2H),0.27(d,J=2.57 Hz,2H);LCMS(+ESI)414(M+)。
在冰水浴中,將在20毫升二氯甲烷中的(S)-6-氯-1-異丁基-2,3,4,9-四氫-1H-吡啶并[3,4-b]吲哚(0.1克,0.38毫莫耳)之攪拌溶液冷卻至0℃,及以N,N-二異丙基乙基胺(0.13毫升,0.75毫莫耳)處理,接著經由注射器逐滴加入3-環己基丙醯基氯(0.13克,0.42毫莫耳)。在0℃下攪拌該反應30分鐘。移除冷卻浴及攪拌該反應過夜。以水(50毫升)稀釋該棕色溶液及以二氯甲烷(2x50毫升)萃取水相。以鹽水(50毫升)清洗結合的有機物,乾燥(MgSO4),過濾及在真空中濃縮。藉由管柱層析法(4克SiO2凝膠,20-80%EtOAc/己烷類)純化該粗產物殘餘物,以提供化合物43(0.095克,63%)如為白色固體。1H NMR(400 MHz,CD3OD)δ7.38(d,J=1.76 Hz,1H),7.25(d,J=8.60 Hz,1H),7.03(dd,J=1.98,8.63 Hz,1H),5.83-5.88(m,1H),4.13(br.s.,1H),3.50-3.59(m,1H),2.75-2.82(m,2H),2.78(d,J=4.52 Hz,1H),2.57-2.67(m,1H),1.52-1.88(m,10H),0.92-139(m,12H);LCMS(+ESI)401(M+)。
以2-溴-1,1-二乙氧基乙烷(0.25毫升,1.7毫莫耳)處理在5毫升乙腈中的4,4-二氟哌啶鹽酸(0.53克,3.36毫莫耳)與N,N-二異丙基乙炔胺(1.2毫升,6.70毫莫耳)之攪拌溶液。在100℃下加熱該反應混合物24小時。允許該反應冷卻至周溫及以NaHCO3水溶液(100毫升)稀釋。以二氯甲烷(2x50毫升)萃取水相及乾燥(MgSO4)結合的有機層,過濾及在真空中濃縮,以提供1-(2,2-二乙氧基乙基)-4,4-二氟哌啶(0.41克,100%),如為琥珀色油。LCMS(+ESI)238(M+)。
在密封管中加入6-氯-1-異丁基-2,3,4,9-四氫-1H-吡啶并[3,4-b]吲哚鹽酸(0.20克,0.87毫莫耳)、1-(2,2-二乙氧基乙基)-4,4-二氟哌啶(0.21克,0.87毫莫耳)及1 N鹽酸水溶液(1.7毫升,1.7毫莫耳)。該混合物以N2除氣及在110℃下加熱6小時。允許所產生的棕色溶液冷卻至周溫及以NaHCO3水溶液稀釋,以二氯甲烷(2x50毫升)萃取,乾燥(MgSO4),過濾及濃縮,以提供90毫克(30%)的粗產物6-氯-1-((4,4-二氟哌啶-1-基)甲基)-2,3,4,9-四氫-1H-吡啶并[3,4-b]吲哚,藉由LCMS(+ESI)340(M+);主要雜質(+ESI)237(M+)。
如先前對化合物43所描述般結合粗產物6-氯
-1-((4,4-二氟哌啶-1-基)甲基)-2,3,4,9-四氫-1H-吡啶并[3,4-b]吲哚與3-環己基丙醯基氯,以提供78如為白色固體。1H NMR(400 MHz,CDCl3)δ8.91(s,1H),7.44(s,1H),7.27及7.12(d,J=8.0 Hz,2H),5.59(dd,J=2.0,8.1 Hz,1H),4.13(dt,J=1.2,9.1 Hz,1H),3.24-3.33(m,1H),2.90-2.99(m,2H),2.59-2.80(m,4H),2.41-2.49(m,2H),2.00-2.14(m,4H),1.55-1.79(m,8H),1.10-1.36(m,3H),及0.88-1.00(m,2H);LCMS(+ESI)478(M+)。
以4,4-二氟哌鹽酸(0.43克,2.70毫莫耳)、二異丙基乙基胺(0.70克,5.40毫莫耳)及碘化鈉(觸媒)處理在50毫升無水四氫呋喃中的(S)-2-氯-1-(6-氯-1-異丁基-3,4-二氫-1H-吡啶并[3,4-b]吲哚-2(9H)-基)乙酮(0.61克,1.80毫莫耳)之攪拌溶液,及在迴流下加熱2天。允許該反應冷卻至周溫及在真空中濃縮。以NaHCO3水溶液(50毫升)處理所產生的殘餘物及以醋酸乙酯(2x50毫升)萃取。乾燥(MgSO4)結合的有機物,過濾及濃縮。藉由管柱層析法(40克SiO2凝膠,5-60%EtOAc/己烷類)純化該粗產物物質,以提供(S)-1-(6-氯-1-異丁基-3,4-二氫-1H-吡啶并[3,4-b]吲哚-2(9H)-
基)-2-(4,4-二氟哌啶-1-基)乙酮0.57克(75%),如為暗黃色油。1H NMR(400 MHz,CDCl3)δ7.90(bs,1H),7.42(d,J=2.0 Hz,1H),7.24(d,J=8.6 Hz,1H),7.12(dd,J=8.5,2.0 Hz,1H),5.82(m,1H),4.13(m,1H),3.49(m,1H),3.34(d,2H),2.89-2.55(m,6H),1.82-1.65(m,2H),1.07(d,J=6.3 Hz,3H),0.99(d,J=6.5 Hz,3H);LCMS(+ESI)424(M+)。
在氮氣下,經由注射器將2 N在四氫呋喃中的氫化鋁鋰(4毫升,8.0毫莫耳)加入至在30毫升無水四氫呋喃中之(S)-1-(6-氯-1-異丁基-3,4-二氫-1H-吡啶并[3,4-b]吲哚-2(9H)-基)-2-(4,4-二氟哌啶-1-基)乙酮(0.57克,1.34毫莫耳)的攪拌溶液。在55℃下加熱該反應混合物2小時。移除該加熱浴,允許該反應冷卻至周溫及攪拌12小時。以2 N的NaOH水溶液(1.5毫升)逐滴中止該反應及攪拌2小時。讓該混合物過濾過塞里塑料塞。以NaHCO3水溶液(50毫升)稀釋濾出液及以醋酸乙酯(2x50毫升)萃取。Na2SO4乾燥結合的有機物,過濾及在真空中濃縮。藉由管柱層析矽膠層析法(40克SiO2凝膠,10-100%EtOAc/己烷類)純化該粗產物物質,以提供化合物1100.25克(45%),如為淡黃色油。1H NMR(600MHz,CDCl3)δ7.63(bs,1H),7.43(d,J=1.8 Hz,1H),7.21(d,J=8.5 Hz,1H),7.09(dd,J=8.4,1.9 Hz,1H),3.75(m,1H),3.20(m,1H),2.99(m,1H),2.82(m,1H),2.72(m,2H),2.67(m,6H),2.48(m,1H),1.96(m,5H),1.74(m,1H),1.43(m,1H),1.01(d,J=6.6 Hz,3H),0.99(d,J=6.6 Hz,3H);LCMS(+ESI)410(M+)。
相繼地以[(1-乙氧基環丙基)氧基]三甲基矽烷(12.6克,72.4毫莫耳)、3埃分子篩(1.0克)、醋酸(7.26克,121毫莫耳)及氰硼氫化鈉(3.42克,54.5毫莫耳)處理在100毫升1:1的MeOH/EtOH中之吖呾-3-羧酸乙基酯鹽酸(2.0克,12.1毫莫耳)的攪拌溶液。在惰性環境中,於75℃下加熱該混合物20小時。過濾及濃縮所產生的懸浮液。以飽和NaHCO3水溶液(80毫升)稀釋該粗產物殘餘物及以醋酸乙酯(2x50毫升)萃取。乾燥(MgSO4)結合的有機物,過濾及在真空中濃縮。藉由管柱層析法與ELSD偵測器(40克SiO2凝膠,0-100%EtOAc/己烷類)純化該粗產物物質,以提供1-環丙基吖呾-3-羧酸乙酯1.25克(62%),如為無色油。1H NMR(400 MHz,CDCl3)δ4.17(q,J=7.1 Hz,2H),3.70(m,2H),3.48(m,2H),3.43(p,J=7.8 Hz,1H),1.98(m,1H),1.26(t,J=7.2 Hz,3H),0.36-0.40(m,4H);LCMS(+ESI)170(M+)。
以2 N的NaOH水溶液(7.20毫升,14.4毫莫耳)處理在40毫升1:1的THF/MeOH中之1-環丙基吖呾-3-羧酸乙酯(0.81克,4.79毫莫耳)的攪拌溶液。在周溫下攪拌該反應
混合物8小時及在80℃下加熱1小時。允許該反應冷卻至周溫,以2 N的HCl水溶液(7.20毫升,14.4毫莫耳)中止反應及濃縮至乾燥。將該殘餘物混於甲醇(20毫升)中,過濾,濃縮及在78℃的真空中乾燥,以提供1-環丙基吖呾-3-羧酸如為原油0.66克(97%)。將該油使用在下一個反應中沒有進一步純化。1H NMR(400 MHz,CDCl3)δ3.39(t,J=7.8 Hz,2H),3.24(t,J=7.0 Hz,2H),3.10(m,1H),1.82(m,1H),0.31(m,2H),0.16(m,2H);LCMS(+ESI)142(M+)。
以異戊醛(10.0毫升,92.6毫莫耳)處理在250毫升0.1 N硫酸水溶液中的5-溴色胺鹽酸(17.0克,61.7毫莫耳)之攪拌懸浮液。在80℃下加熱該懸浮液3小時。允許所產生的溶液冷卻至周溫,然後在冰水浴中進一步冷卻至0℃。過濾析出的產物,以MTBE(300毫升)清洗,在高真空下乾燥過夜,以提供6-溴-1-異丁基-2,3,4,9-四氫-1H-吡啶并[3,4-b]吲哚鹽酸19.3克(92%),如為白色固體。1H NMR(600 MHz,DMSO-d6)δ11.41(s,1H),9.92(br.s.,1H),9.46(br.s.,1H),7.66(d,J=1.88 Hz,1H),7.33(d,J=8.56 Hz,1H),7.21(dd,J=1.88,8.56 Hz,1H),4.66(br.s.,1H),3.54(d,J=12.14 Hz,1H),3.27(br.s.,1H),2.86-3.01(m,2H),2.01-2.09(m,1H),1.91-1.99(m,1H),1.83(ddd,J=4.09,10.23,14.28 Hz,1H),1.03(d,J=6.31 Hz,3H),0.97(d,J=6.59 Hz,3H)。將此物質加入至500毫升的飽和NaHCO3水溶液及以醋酸乙酯(3x100毫升)萃取。乾燥(Na2SO4)醋酸乙酯層,過濾及在真空中濃縮,以提供6-溴-1-異丁基-2,3,4,9-四氫-1H-吡啶并
[3,4-b]吲哚17.0克(90%),如為白色固體。在凱若佩克IA管柱(EtOH w/0.1% DEA,30℃)上的6-溴-1-異丁基-2,3,4,9-四氫-1H-吡啶并[3,4-b]吲哚(10.0克)之製備型對掌性解析物提供(S)-6-溴-1-異丁基-2,3,4,9-四氫-1H-吡啶并[3,4-b]吲哚5.68克[>100%(高回收,由於在樣品中過量的Et2NH),>99%ee],及(R)-6-溴-1-異丁基-2,3,4,9-四氫-1H-吡啶并[3,4-b]吲哚4.52克(90.4%,>99%ee)如為白色固體。
以1-環丙基吖呾-3-羧酸(0.63克,4.49毫莫耳)、N,N-二異丙基乙基胺(0.78毫升,0.58克,4.49毫莫耳)及O-苯并三唑-N,N,N’,N’-四甲基--六氟-磷酸鹽(HBTU)(1.59克,4.19毫莫耳)處理在50毫升無水DMF中的(S)-6-溴-1-異丁基-2,3,4,9-四氫-1H-吡啶并[3,4-b]吲哚(1.03克,2.99毫莫耳)之攪拌溶液。攪拌該反應混合物3小時,以額外的HBTU(0.6克,1.8毫莫耳)處理及攪拌1小時。以飽和NaHCO3水溶液(200毫升)稀釋該反應及以醋酸乙酯(3x100毫升)萃取。以2 N的NaOH水溶液(50毫升)、鹽水(50毫升)清洗結合的有機物,乾燥(MgSO4),過濾及在真空中濃縮。藉由管柱層析法(40克SiO2凝膠,20:1:0.1二氯甲烷/甲醇/氫氧化銨)純化該粗產物殘餘物,以提供化合物990.83克(61%)如為無色固體。1H NMR(400 MHz,CDCl3)δ8.03(bs,1H),7.54(d,J=1.9 Hz,1H),7.24(dd,J=8.6,1.8 Hz,1H),7.19(d,J=8.5 Hz,1H),5.82(m,1H),3.79(m,1H),3.67(m,2H),3.42-3.52(m,4H),2.69(m,2H),1.85(m,1H),1.75-1.55(m,7H),1.06(d,J=6.2 Hz,3H),0.98(d,J=6.4 Hz,3H),0.36(m,
4H);LCMS(+ESI)431(M+)。
如先前對化合物99所描述般結合(S)-6-溴-1-異丁基-2,3,4,9-四氫-1H-吡啶并[3,4-b]吲哚與1-環丙基哌啶-4-羧酸,以提供97。1H NMR(400 MHz,CDCl3)δ8.19(bs,1H),7.55(d,J=1.8 Hz,1H),7.24(dd,J=8.6,1.8 Hz,1H),7.l7(d,J=8.5 Hz,1H),5.89(m,1H),4.11(m,1H),3.49(m,1H),3.12(m,2H),2.78(m,2H),2.59(m,1H),2.25(m,2H),1.54-1.91(m,9H),0.98(d,J=6.2 Hz,3H),0.92(d,J=6.4 Hz,3H),0.34(m,4H);LCMS(+ESI)458(M+)。
如先前對化合物91所描述般結合(S)-1-(6-溴-1-異丁基-3,4-二氫-1H-吡啶并[3,4-b]吲哚-2(9H)-基)-2-氯乙
酮與環丙烷胺鹽酸,以提供98。1H NMR(400 MHz,DMSO-d6)δ11.10(s,1H),7.55(d,J=1.59 Hz,1H),7.26(d,J=8.50 Hz,1H),7.14(dd,J=1.90,8.50 Hz,1H),5.76-5.80(m,1H),4.03(dd,J=3.61,14.49 Hz,1H),3.43-3.63(m,2H),3.31-3.40(m,2H),2.66-2.73(m,2H),2.13(tt,J=3.29,6.49 Hz,1H),1.72-1.79(m,1H),1.57-1.64(m,2H),1.04(d,J=5.81 Hz,3H),0.90(d,J=6.05 Hz,3H),0.31-0.35(m,2H),0.22-0.26(m,2H);LCMS(+ESI)404(M+)。
如先前對化合物6之合成所描述般結合(S)-6-溴-1-異丁基-2,3,4,9-四氫-1H-吡啶并[3,4-b]吲哚及丙烯醯基氯,以提供(S)-1-(6-溴-1-異丁基-3,4-二氫-1H-吡啶并[3,4-b]吲哚-2(9H)-基)丙-2-烯-1-酮。1H NMR(400 MHz,CDCl3):δ7.99(br.s.,1H),7.57(d,J=1.4 Hz,1H),7.22-7.27(m,1H),7.17-7.22(m,1H),6.73(dd,J=10.6,16.8 Hz,1H),6.35(dd,J=1.7,16.7 Hz,1H),5.94(dd,J=4.5,9.3 Hz,1H),5.78(dd,J=1.7,10.5 Hz,1H),4.19(dd,J=4.0,14.2 Hz,1H),3.54(ddd,J=5.0,11.1,14.2 Hz,1H),3.06-3.20(m,
1H),2.62-2.97(m,2H),1.70-1.95(m,1H),1.50-1.70(m,2H),0.94-1.18(m,6H);LCMS(+ESI)361(M+)。
如先前對化合物6所描述般結合(S)-1-(6-溴-1-異丁基-3,4-二氫-1H-吡啶并[3,4-b]吲哚-2(9H)-基)丙-2-烯-1-酮與(S)-3-氟吡咯啶鹽酸,以提供105。1H NMR(400 MHz,CD3OD)δ7.1(d,J=4.1 Hz,1H),7.14-7.24(m,2H),5.86(dd,J=4.3,8.5 Hz,1H),5.12-5.32(m,1H),4.18(dd,J=4.3,14.2 Hz,1H),3.56(ddd,J=4.5,11.7,14.2 Hz,1H),2.66-3.34(m,9H),2.17-2.48(m,1H),2.47(m,1H),2.17(m,1H),1.85(t,J=8.6 Hz,1H),1.66-1.70(m,2H),1.14(d,J=6.4 Hz,3H),0.97(d,J=6.5 Hz,3H);LCMS(+ESI)450(M+)。
提供下列實施例(包括所進行的實驗及所達成的結果)僅用於闡明的目的及不欲解釋為限制本發明。
以Ad5基因組複製分析(一種以細胞為基底在A549細胞(一種人類肺癌細胞株)中的Ad5基因組複製之QPCR分析)來測試本發明之化合物對抗Ad5的效力。在此複製分析中所使用的人類Ad5之血清類型亦可在腺病毒眼角膜炎的NZW兔模型中複製。
藉由QPCR來測量對腺病毒複製之抑制的EC50值(μM)。簡單來說,在2%FBS F12-K A549培養媒質中,以25,000 pfu/井接種10,000個培養的A549細胞3小時。在接種後,以式I之化合物在含有0.3% DMSO的10%FBS F12-K培養媒質中之對數單位稀釋物(~10 μM至~10 pM)來處理A549細胞額外3天。以阿拉瑪藍(Alamar Blue)(10微升/井2小時;螢光性Ex353;Em595nm)評估細胞生存能力。以125微升PBS清洗該板3次,使用細胞至SNP配套元件(Cells to SNP kit)(生命技術(Life Technologies))來製備用於QPCR分析的細胞溶成物。以RNaseP及Ad5六鄰體塔克門分析(hexon Taqman Assays)(生命技術)來測量每細胞的Ad5基因組程度。從Ad5基因組/細胞對化合物濃度的圖來估計EC50(抑制Ad5基因組複製形成50%的濃度)。
顯示在表2中的結果指示出本發明之所測試的化合物在顯型腺病毒分析中闡明明顯的抗病毒活性。
在溶斑減少試驗(plaque reduction assay)(一種AdV複製之細胞基底的分析)中測試本發明之化合物對抗AdV血清類型Ad3、Ad4、Ad5、Ad7a、Ad8、Ad19及Ad37的效力。Ad8、Ad19及Ad37血清類型最通常與流行性角膜結膜炎(EKC)相關。Ad3、Ad4及Ad7a係最通常與濾泡性結膜炎相關的血清類型,及血清類型Ad5可在腺病毒性眼角膜炎的NZW兔模型中複製。在該查理斯T.坎貝爾眼用微生物學實驗室(Charles T.Campbell Microbiology Laboratory)中,從呈現有典型的腺病毒眼睛疾病之患者回收Ad3、Ad4、Ad5、Ad7a、Ad8及Ad19。無臨床分離的Ad37可獲得,因此使用ATCC(美國型式培養收集(American Type Culture Collection),馬納薩斯(Manassas),VA)參考株Ad37。
藉由溶斑減少試驗來測量用以抑制腺病毒複製的EC50值(微克/毫升)。簡單地說,以大約100 pfu所指定的腺病毒血清類型來接種所培養的A549細胞。以包含化合物2(在100、10、1、0.1、0.01及0.001微克/毫升下)的甲基纖維素媒體覆蓋經接種的細胞,及在37℃/5% CO2下培養大約7天。以龍膽紫染色該板,及在25x解剖顯微鏡中計數溶斑。從平均溶斑計數對濃度的圖來估計1C50(一種抑制溶斑形成50%的濃度)。
總整理在表3中,本發明之所測試的化合物對抗全部7種所測試的AdV血清類型具有明顯的抗病毒活性。
化合物6在腺病毒(Ad5)眼角膜炎的兔模型中具有明顯的抗病毒功效。這些結果顯現在圖1中。麻醉紐西蘭白兔及劃破(12條#25針的交叉線畫)角膜,並以50微升3.0x107 pfu/毫升(1.5x106 pfu/眼睛)Ad5接種。在pH 4.5含有2%PEG 8000、1.0%聚山梨酸酯80及0.5%HPMC的醋酸鈉緩衝溶液中配製化合物6(1%)。對兔子進行一天局部給藥8次9天,給藥間隔至少45分鐘。鹽液及0.5%西多福韋(cidofovir)各別係負及正對照。在第0、1、3、4、5、7、9、11及14天時,在最後給藥後,培養眼睛的Ad5至少1小時。局部麻醉兔子眼睛,及將棉花頭拭子放入每眼的下穹窿中及向上滾
過角膜進入上穹窿中以從淚液膜及角膜及結膜表面回收腺病毒。將來自每眼的拭子各別放入包含1毫升長出(outgrowth)媒質的管子中,及在-70℃下冷凍。藉由溶斑形成試驗滴定在A549細胞中的培養物。資料以每日眼睛滴定量中點顯現。化合物6闡明遍及治療持續明顯的抗病毒活性。化合物6從第2-11天明顯減低病毒滴定量中點(相對於鹽液對照)。
已經詳細地描述出本發明及其具體實例。但是,本發明之範圍不想要限制至在本專利說明書中所描述的事件、化合物、工具、方法及/或步驟之任何方法、製造、組成物的特別具體實例。可對所揭示的材料製得多種改質、取代及變化而沒有離開本發明之精神及/或基本特徵。此外,一般技藝人士將從本揭示容易地察知可根據本發明的此相關具體實例使用晚後之改質、取代及/或變化,其將進行與於本文中所描述的具體實例實質上相同的功能或達成實質上相同的結果。因此,想要下列申請專利範圍在其範圍內包含對於本文中所揭示的事件、化合物、工具、方法及/或步驟之方法、製造、組成物的改質、取代及變化。
Claims (19)
- 一種用於眼睛感染之治療的眼用醫藥組成物,其包含一有效量之根據式I的化合物或其醫藥上可接受的鹽:
- 如申請專利範圍第1項之組成物,更包含選自於由下列所組成之群的化合物:眼科學可接受的防腐劑、界面活性劑、黏度促進劑、滲透促進劑、膠凝劑、疏水性基質、媒劑、緩衝劑、氯化鈉及水。
- 如申請專利範圍第1項之組成物,其中該組成物除了式I之化合物外更包含一抗感染或抗發炎劑。
- 如申請專利範圍第3項之組成物,其中該抗感染或抗發炎劑係選自於由下列所組成之群:類固醇抗發炎藥、非類固醇抗發炎藥、奈帕芬胺、地塞米松及其等之組合。
- 如申請專利範圍第1項之組成物,其中該組成物包含約0.01百分比重量/體積至約5百分比重量/體積的該化合物。
- 一種治療眼睛感染的方法,其包括將一治療有效量的醫藥組成物給藥至人類或其它哺乳動物,其中該組成物包含一根據式I的化合物或其醫藥上可接受的鹽:
- 如申請專利範圍第6項之方法,其中該給藥包括每日施加1至2滴包含約0.01百分比重量/體積至約5百分比重量/體積之根據式I的化合物之組成物1至4次。
- 如申請專利範圍第7項之方法,其中該組成物除了式I之化合物外更包含一抗感染或抗發炎治療劑。
- 如申請專利範圍第8項之方法,其中該抗感染或抗發炎劑係選自於由下列所組成之群:類固醇抗發炎藥、非類固醇抗發炎藥、奈帕芬胺、地塞米松及其等之組合。
- 如申請專利範圍第7項之方法,其中該組成物包含約0.1百分比重量/體積至約1百分比重量/體積的該化合物。
- 一種用於眼睛感染之治療的眼用醫藥組成物,其包含一有效量之根據式II的化合物或其醫藥上可接受的鹽:
- 如申請專利範圍第11項之組成物,更包含一選自於由下列所組成之群的化合物:眼科學可接受的防腐劑、界面活性劑、黏度促進劑、滲透促進劑、膠凝劑、疏水性基質、媒劑、緩衝劑、氯化鈉及水。
- 如申請專利範圍第11項之組成物,其中該組成物除了式II之化合物外更包含一抗感染或抗發炎劑,該藥劑係選自於由下列所組成之群:類固醇抗發炎藥、非類固醇抗發炎藥、奈帕芬胺、地塞米松及其等之組合。
- 如申請專利範圍第11項之組成物,其中該組成物包含約0.01百分比重量/體積至約5百分比重量/體積的該化合物。
- 一種治療眼睛感染的方法,其包括將一治療有效量之醫藥組成物給藥至人類或其它哺乳動物,其中該組成物包含根據式II的化合物或其醫藥上可接受的鹽。
- 一種用於眼睛感染之治療的眼用醫藥組成物,其包含一有效量之根據式III之化合物或其醫藥上可接受的鹽:
- 一種治療眼睛感染的方法,其包括將一治療有效量的醫藥組成物給藥至人類或其它哺乳動物,其中該組成物包含一根據式III之化合物或其醫藥上可接受的鹽。
- 一種化合物,其係選自於由化合物1-110所組成之群。
- 一種式I之化合物:
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US201161555584P | 2011-11-04 | 2011-11-04 |
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TW101140784A TW201323425A (zh) | 2011-11-04 | 2012-11-02 | 抗菌性咔啉化合物 |
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US (1) | US20130116219A1 (zh) |
AR (1) | AR088639A1 (zh) |
TW (1) | TW201323425A (zh) |
UY (1) | UY34433A (zh) |
WO (1) | WO2013067409A1 (zh) |
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US20210163479A1 (en) * | 2018-08-16 | 2021-06-03 | Recreo Pharmaceuticals Llc | 1,3,4,9-tetrahydro-2h-pyrido[3,4-b]indole derivative compounds and uses thereof |
BR112021011023A2 (pt) * | 2018-12-06 | 2021-08-31 | Lipicare Life Sciences Ltd. | Microemulsões de vitamina d e suas utilizações |
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US20050101623A1 (en) * | 2003-07-23 | 2005-05-12 | Pharmacia Corporation | Beta-carboline compounds and analogues thereof as mitogen-activated protein kinase-activated protein kinase-2 inhibitors |
SG184755A1 (en) * | 2004-03-15 | 2012-10-30 | Ptc Therapeutics Inc | Carboline derivatives useful in the inhibition of angiogenesis |
US8076353B2 (en) * | 2004-03-15 | 2011-12-13 | Ptc Therapeutics, Inc. | Inhibition of VEGF translation |
US7767689B2 (en) * | 2004-03-15 | 2010-08-03 | Ptc Therapeutics, Inc. | Carboline derivatives useful in the treatment of cancer |
RU2010138799A (ru) * | 2008-02-21 | 2012-03-27 | Иста Фармасьютикалз (Us) | Офтальмологические нестероидные противовоспалительные средства в качестве адъювантов |
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- 2012-11-02 AR ARP120104126A patent/AR088639A1/es not_active Application Discontinuation
- 2012-11-02 TW TW101140784A patent/TW201323425A/zh unknown
- 2012-11-02 WO PCT/US2012/063397 patent/WO2013067409A1/en active Application Filing
- 2012-11-05 UY UY0001034433A patent/UY34433A/es not_active Application Discontinuation
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WO2013067409A1 (en) | 2013-05-10 |
US20130116219A1 (en) | 2013-05-09 |
UY34433A (es) | 2013-05-31 |
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