TWI595838B - 甜味修飾劑 - Google Patents
甜味修飾劑 Download PDFInfo
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- TWI595838B TWI595838B TW100111669A TW100111669A TWI595838B TW I595838 B TWI595838 B TW I595838B TW 100111669 A TW100111669 A TW 100111669A TW 100111669 A TW100111669 A TW 100111669A TW I595838 B TWI595838 B TW I595838B
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- substituted
- amino
- alkyl
- group
- carboxylic acid
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Classifications
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Description
本發明係關於可用作甜味修飾劑及/或促味劑之化合。
味覺系統提供關於外界之化學組成的感受資訊。味覺傳導係化學品引發之動物感覺之最複雜形式中的一種。人們發現味覺之信號傳導存於整個動物界中,自簡單的後生動物至最複雜的脊椎動物。據信,哺乳動物具有5種基本的味覺形態:甜、苦、酸、鹹及鮮味(umami)(麩胺酸單鈉之味道,亦稱為佳味)。
肥胖、糖尿病及心血管疾病係在全球出現的健康問題,但在美國正以驚人的速度增長。糖及卡路里係可限制對健康造成不利營養作用之關鍵成份。高強度甜味劑可使糖具有不同味道品質之甜度。由於其比糖甜很多倍,故需要很少的甜味劑即可替代糖。
高強度甜味劑具有多種化學上不同之結構且因此具有不同性質,例如但不限於氣味、風味、口感及餘味。人們熟知該等性質(尤其風味及餘味)隨品嘗時間而變化,從而使得每一暫時特徵皆具有甜味劑特異性(Tunaley,A.,「Perceptual Characteristics of Sweeteners」,Progress in Sweeteners,T. H. Grenby編輯,Elsevier Applied Science,1989)。
諸如糖精及6-甲基-1,2,3-氧雜噻嗪-4(3H)-酮-2,2-二氧化物鉀鹽(乙醯胺基磺酸鉀)等甜味劑之特徵通常在於具有苦的及/或金屬餘味。有人聲稱由2,4-二羥基苯甲酸製得之產品展示減少之與甜味劑相關之不合意餘味,且在低於彼等可感知其自身味道之濃度的濃度下同樣如此。此外,人們報導高強度甜味劑(例如蔗糖素及阿斯巴甜(aspartame))具有甜度遞送問題,即,甜度延遲發作及拖延(S. G. Wiet等人,J. Food Sci.,58(3):599-602,666(1993))。
已報導細胞外結構域(例如,化學感受受體之捕蠅夾域,尤其該捕蠅夾域內之一個或多個相互作用位點)係化合物或其他實體調節該化學感受受體及/或其配體之適宜靶。已報導某些化合物具有優異的甜味增強性質且闡述於下文所列示之四個專利申請案中。
(1) 2007年6月8日申請之標題為「Modulation of Chemosensory Receptors and Ligands Associated Therewith」之美國專利第11/760,592號;(2) 2007年8月8日申請之標題為「Modulation of Chemosensory Receptors and Ligands Associated Therewith」之美國專利第11/836,074號;(3) 2008年2月8日申請之標題為「Modulation of Chemosensory Receptors and Ligands Associated Therewith」之美國專利第61/027,410號;及(4) 2008年6月3日申請之標題為「Modulation of Chemosensory Receptors and Ligands Associated Therewith」之國際申請案第PCT/US2008/065650號。出於所有目的,該等申請案之全部內容以引用方式併入本文中。
本發明提供具有合意特性之新穎及發明性甜味增強劑。
在一個實施例中,本發明提供具有結構式(I)或(I')之化合物:
或互變異構體、鹽及/或溶劑合物,其中:A係-OR1、-NR1C(O)R2、-NHOR1、-NR1R2、-NR1CO2R2、-NR1C(O)NR2R3、-NR1C(S)NR2R3或-NR1C(=NH)NR2R3;B係氫、烷基、經取代之烷基、芳基、經取代之芳基、芳基烷基、經取代之芳基烷基、醯基、經取代之醯基、雜烷基、經取代之雜烷基、雜芳基、經取代之雜芳基、雜芳基烷基、經取代之雜芳基烷基、-CN、-OR4、-S(O)aR4、-NR4R5、-C(O)NR4R5、-CO2R4、-NR4CO2R5、-NR4C(O)NR5R6、-NR4C(S)NR5R6、-NR4C(=NH)NR5R6、-SO2NR4R5、-NR4SO2R5、-NR4SO2NR5R6、-B(OR4)(OR5)、-P(O)(OR4)(OR5)或-P(O)(R4)(OR5);C係-OR7、-S(O)bR7、SO3R7、-C(O)NR7R8、-CO2R7、-NR7CO2R8、-NR7C(O)NR8R9、-NR7C(=NH)NR8R9、-SO2NR7R8、-NR7SO2R8、-NR7SO2NR8R9、-B(OR7)(OR8)、-P(O)(OR7)(OR8)、-P(O)(R7)(OR8)或雜芳基(例如,四唑);D係芳基、經取代之芳基、雜芳基、經取代之雜芳基、環烷基、經取代環烷基、雜環烷基或經取代之雜環烷基環,其中該環視情況稠合至另一芳基、經取代之芳基、雜芳基、經取代之雜芳基、環烷基、經取代環烷基、雜環烷基或經取代之雜環烷基環;a及b獨立地為0、1或2;且R1、R2、R3、R4、R5、R6、R7、R8及R9獨立地為氫、烷基、經取代之烷基、芳基、經取代之芳基、芳基烷基、經取代之芳基烷基、醯基、經取代之醯基、雜烷基、經取代之雜烷基、雜芳基、經取代之雜芳基、雜芳基烷基或經取代之雜芳基烷基;或者,R1與R2、R2與R3、R4與R5、R5與R6、R7與R8或R8與R9連同其所鍵結之原子一起形成雜環烷基或經取代之雜環烷基環。
在另一實施例中,本發明提供可攝取組合物,其包含本發明化合物及攝取上可接受之賦形劑。
在另一實施例中,本發明提供調味濃縮調配物,其包含本發明化合物及載劑。
在另一實施例中,本發明提供調節可攝取組合物甜味之方法,其包含使該可攝取組合物或其前體與本發明化合物接觸以形成經修飾之可攝取組合物。
在另一實施例中,本發明提供製備本發明化合物之方法。
在下文部分中將提供本發明之該等及其他實施例、優點及特徵。除非另外定義,否則本文所用所有科學及技術術語均具有與本發明所屬領域技術之一般技術人員通常所瞭解含義相同的含義。
「烷基」(自身或作為另一取代基之一部分)係指藉由自母體烷烴、烯烴或炔烴之單一碳原子去除一個氫原子所產生之飽和或不飽和、具支鏈、直鏈或環狀單價烴基團。術語「烷基」包括如下文所定義之「環烷基」。典型烷基包括但不限於甲基;乙基,例如乙烷基、乙烯基、乙炔基;丙基,例如丙烷-1-基、丙烷-2-基、環丙烷-1-基、丙-1-烯-1-基、丙-1-烯-2-基、丙-2-烯-1-基(烯丙基)、環丙-1-烯-1-基;環丙-2-烯-1-基、丙-1-炔-1-基、丙-2-炔-1-基等;丁基,例如丁烷-1-基、丁烷-2-基、2-甲基-丙烷-1-基、2-甲基-丙烷-2-基、環丁烷-1-基、丁-1-烯-1-基、丁-1-烯-2-基、2-甲基-丙-1-烯-1-基、丁-2-烯-1-基、丁-2-烯-2-基、丁-1,3-二烯-1-基、丁-1,3-二烯-2-基、環丁-1-烯-1-基、環丁-1-烯-3-基、環丁-1,3-二烯-1-基、丁-1-炔-1-基、丁-1-炔-3-基、丁-3-炔-1-基等;及諸如此類。術語「烷基」明確意欲包括具有任一飽和程度或飽和度之基團,即,只具有碳碳單鍵之基團、具有一個或多個碳碳雙鍵之基團、具有一個或多個碳碳三鍵之基團及具有碳碳單鍵、雙鍵及三鍵之混合物的基團。當意欲表示具體飽和度時,使用表達「烷烴基」、「烯基」及「炔基」。在一些實施例中,烷基包含1個至20個碳原子(C1-C20烷基)。在其他實施例中,烷基包含1個至10個碳原子(C1-C10烷基)。在又一些實施例中,烷基包含1個至6個碳原子(C1-C6烷基)。應注意,當烷基進一步連接至另一原子時,其變成「伸烷基」。換言之,術語「伸烷基」係指二價烷基。舉例而言,-CH2CH3係乙基,而-CH2CH2-係伸乙基。即,「伸烷基」(自身或作為另一取代基之一部分)係指自母體烷、烯或炔之單一碳原子或兩個不同碳原子去除兩個氫原子所產生之飽和或不飽和、具支鏈、直鏈或環狀二價烴基。術語「伸烷基」包括如下文所定義之「伸環烷基」。術語「伸烷基」特別欲包括具有任一飽和程度或飽和度之基團,即,只具有碳-碳單鍵之基團、具有一個或多個碳-碳雙鍵之基團、具有一個或多個碳-碳三鍵之基團及具有碳-碳單鍵、雙鍵及三鍵之混合物的基團。當意欲表示特定飽和度時,使用「伸烷基」、「伸烯基」及「伸炔基」表達。在一些實施例中,伸烷基包含1個至20個碳原子(C1-C20伸烷基)。在其他實施例中,伸烷基包含1個至10個碳原子(C1-C10伸烷基)。在又一些實施例中,伸烷基包含1個至6個碳原子(C1-C6伸烷基)。
「烷基」(自身或作為另一取代基之一部分)係指自母體烷之單一碳原子去除一個氫原子所產生之飽和具支鏈、直鏈或環狀烷基。術語「烷基」包括如下文所定義之「環烷基」。典型烷基包括(但不限於)甲烷基;乙烷基;丙烷基,例如丙-1-基、丙-2-基(異丙基)、環丙-1-基等;丁烷基,例如丁-1-基、丁-2-基(第二丁基)、2-甲基-丙-1-基(異丁基)、2-甲基-丙-2-基(第三丁基)、環丁-1-基等;及諸如此類。
「烯基」(自身或作為另一取代基之一部分)係指自母體烯之單一碳原子去除一個氫原子所產生之具有至少一個碳-碳雙鍵之不飽和具支鏈、直鏈或環狀烷基。術語「烯基」包括如下文所定義之「環烯基」。該基團可關於雙鍵呈順式或反式構形。典型烯基包括(但不限於)乙烯基;丙烯基,例如丙-1-烯-1-基、丙-1-烯-2-基、丙-2-烯-1-基(烯丙基)、丙-2-烯-2-基、環丙-1-烯-1-基;環丙-2-烯-1-基;丁烯基,例如丁-1-烯-1-基、丁-1-烯-2-基、2-甲基-丙-1-烯-1-基、丁-2-烯-1-基、丁-2-烯-1-基、丁-2-烯-2-基、丁-1,3-二烯-1-基、丁-1,3-二烯-2-基、環丁-1-烯-1-基、環丁-1-烯-3-基、環丁-1,3-二烯-1-基等;及諸如此類。
「炔基」(自身或作為另一取代基之一部分)係指藉由自母體炔烴之單一碳原子去除一個氫原子所產生之具有至少一個碳碳三鍵之不飽和具支鏈、直鏈或環狀烷基。典型炔基包括但不限於乙炔基;丙炔基,例如丙-1-炔-1-基、丙-2-炔-1-基等;丁炔基,例如丁-1-炔-1-基、丁-1-炔-3-基、丁-3-炔-1-基等;及諸如此類。
「烷氧基」(自身或作為另一取代基之一部分)係指式-O-R199基團,其中R199係如本文所定義之烷基或經取代之烷基。
「醯基」(自身或作為另一取代基之一部分)係指基團-C(O)R200,其中R200係氫、烷基、經取代之烷基、芳基、經取代之芳基、芳基烷基、經取代之芳基烷基、雜烷基、經取代之雜烷基、雜芳基烷基或經取代之雜芳基烷基,如上文所定義。代表性實例包括但不限於甲醯基、乙醯基、環己基羰基、環己基甲基羰基、苯甲醯基、苄基羰基及諸如此類。
「芳基」(自身或作為另一取代基之一部分)係指藉由自母體芳香族環系統之單一碳原子去除一個氫原子所產生之單價芳香族烴基團,如上文所定義。典型芳基包括但不限於衍生自下列之基團:醋蒽烯、苊烯、醋菲烯、蒽、甘菊環、苯、艸屈、蒄、螢蒽、茀、并六苯、己芬、伸己基、不對稱引達省(as-indacene)、對稱引達省(s-indacene)、二氫茚、茚、萘、并辛苯、辛芬、艾氏劑(octalene)、卵苯、戊-2,4-二烯、並五苯、並環戊二烯、戊芬、苝、非那烯(phenalene)、菲、苉、七曜烯、芘、皮蒽、玉紅省(rubicene)、苯并菲、聯三萘及諸如此類。I在一些實施例中,芳基包含6個至20個碳原子(C6-C20芳基)。在其他實施例中,芳基包含6個至15個碳原子(C6-C15芳基)。在又一些實施例中,芳基包含6個至15個碳原子(C6-C10芳基)。
「芳基烷基」(自身或作為另一取代基之一部分)係指其中與碳原子(通常為末端或sp3碳原子)鍵結之一個氫原子經芳基取代之非環狀烷基,如上文所定義。典型芳基烷基包括但不限於苄基、2-苯基乙烷-1-基、2-苯基乙烯-1-基、萘基甲基、2-萘基乙烷-1-基、2-萘基乙烯-1-基、萘并苄基、2-萘并苯基乙烷-1-基及諸如此類。當意欲指示特定烷基部分時,使用命名芳基烷烴基、芳基烯基及/或芳基炔基。在一些實施例中,芳基烷基係(C6-C30)芳基烷基,例如,芳基烷基之烷烴基、烯基或炔基部分係(C1-C10)烷基且芳基部分係(C6-C20)芳基。在其他實施例中,芳基烷基係(C6-C20)芳基烷基,例如,芳基烷基之烷烴基、烯基或炔基部分係(C1-C8)烷基且芳基部分係(C6-C12)芳基。在又一些實施例中,芳基烷基係(C6-C15)芳基烷基,例如,芳基烷基之烷烴基、烯基或炔基部分係(C1-C5)烷基且芳基部分系(C6-C10)芳基。
「環烷基」或「碳環基」(自身或作為另一取代基之一部分)係指飽和或不飽和環狀烷基,如上文所定義。同樣,「伸環烷基」或「伸碳環基」(自身或作為另一取代基之一部分)係指飽和或不飽和環狀伸烷基,如上文所定義。當意欲指示特定飽和度時,使用命名「環烷烴基」、「環烯基」或「環炔基」。典型環烷基包括但不限於衍生自環丙烷、環丁烷、環戊烷、環己烷及諸如此類之基團。在一些實施例中,該環烷基包含3個至10個環原子(C3-C10環烷基)。在其他實施例中,該環烷基包含3個至7個環原子(C3-C7環烷基)。環烷基可進一步經一個或多個雜原子(包括但不限於N、P、O、S及Si)取代,該等雜原子經由單價或多價鍵連接至環烷基之碳原子。
「雜烷基」、「雜烷烴基」、「雜烯基」及「雜炔基」(自身或作為其他取代基之一部分)分別指其中一個或多個碳原子(及視情況任何經結合氫原子)各自彼此獨立地經相同或不同雜原子或雜原子基團替代之烷基、烷烴基、烯基及炔基。同樣,「伸雜烷基」、「伸雜烷烴基」、「伸雜烯基」及「伸雜炔基」(自身或作為其他取代基之一部分)分別指其中一個或多個碳原子(及視情況任何經結合氫原子)各自彼此獨立地經相同或不同雜原子或雜原子基團替代之伸烷基、伸烷烴基、伸烯基及伸炔基。可替代碳原子之典型雜原子或雜原子基團包括但不限於-O-、-S-、-N-、-Si-、-NH-、-S(O)-、-S(O)2-、-S(O)NH-、-S(O)2NH-及諸如此類及其組合。雜原子或雜原子基團可位於烷基、烯基或炔基之任一內部位置。可包括於該等基團中之典型雜原子基團包括但不限於-O-、-S-、-O-O-、-S-S-、-O-S-、-NR201R202-、=N-N=、-N=N-、-N=N-NR203R204、-PR205-、-P(O)2-、-POR206-、-O-P(O)2-、-O-、-SO2-、-SnR207R208-及諸如此類,其中R201、R202、R203、R204、R205、R206、R207及R208獨立地為氫、烷基、經取代之烷基、芳基、經取代之芳基、芳基烷基、經取代之芳基烷基、環烷基、經取代環烷基、雜環烷基、經取代之雜環烷基、雜烷基、經取代之雜烷基、雜芳基、經取代之雜芳基、雜芳基烷基或經取代之雜芳基烷基。
「雜環烷基」或「雜環基」(自身或作為另一取代基之一部分)係指其中一個或多個碳原子(及視情況任何經結合氫原子)獨立地經相同或不同雜原子替代之飽和或不飽和環狀烷基。「伸雜環烷基」或「伸雜環基」(自身或作為另一取代基之一部分)係指其中一個或多個碳原子(及視情況任何經結合氫原子)獨立地經相同或不同雜原子替代之飽和或不飽和環狀伸烷基。雜環烷基可進一步經一個或多個雜原子(包括但不限於N、P、O、S及Si)取代,該等雜原子經由單價或多價鍵連接至雜環烷基之碳原子。可替代碳原子之典型雜原子包括但不限於N、P、O、S、Si等。當意欲指示特定飽和度時,使用命名「雜環烷烴基」或「雜環烯基」。典型雜環烷基包括但不限於衍生自下列之基團:環氧化物、氮丙啶、硫雜環丙烷、咪唑啶、嗎啉、哌嗪、六氫吡啶、吡唑啶、吡咯啶酮、奎寧環及諸如此類。在一些實施例中,雜環烷基包含3個至10個環原子(3-10員雜環烷基)。在其他實施例中,環烷基包含5個至7個環原子(5-7員雜環烷基)。雜環烷基可在雜原子(例如,氮原子)處經(C1-C6)烷基取代。作為具體實例,N-甲基-咪唑啶基、N-甲基-嗎啉基、N-甲基-哌嗪基、N-甲基-六氫吡啶基、N-甲基-吡唑啶基及N-甲基-吡咯啶基均包括在所定義「雜環烷基」範圍內。雜環烷基可經由環碳原子或環雜原子連接至該分子之其餘部分。
「化合物」係指本文所揭示結構式(例如(I)、(II)、(IIa)、(IIb)、(III)、(IIIa)、(IIIb)、(IIIc)及(IIId))所涵蓋之化合物,且包括在該等式內之任何特定化合物,其結構揭示於本文中。化合物可由其化學結構及/或化學名稱來識別。當化學結構與化學名稱發生衝突時,化學結構決定化合物之身份。本文所述化合物可含有一或多個對掌性中心及/或雙鍵且因此,可以立體異構體形式存在,例如雙鍵異構體(即,幾何異構體)、對映異構體或非對映異構體。因此,本文所繪示化學結構涵蓋所闡釋化合物之所有可能對映異構體及立體異構體,包括立體異構純形式(例如,幾何純、對映異構純或非對映異構純)及對映異構及立體異構混合物。可使用熟習此項技術者熟知之分離技術或對掌性合成技術將對映異構或立體異構混合物拆分成其組成對映異構體或立體異構體。該等化合物亦可以一些互變異構形式(包括烯醇形式、酮形式及其混合物)存在。因此,本文所繪示化學結構涵蓋所闡釋化合物之所有可能互變異構形式。本文所用術語「互變異構體」係指容易彼此互變以使其可以平衡狀態一起存在之異構體。一般而言,化合物可為水合物、溶劑合物或N-氧化物。某些化合物可以多種結晶或非晶形形式存在。一般而言,所有物理形式可等效用於本文所涵蓋之用途且意欲在本發明之範疇內。此外,應瞭解,當闡釋化合物之部分結構時,括弧指示該部分結構與該分子其餘部分之連接點。
「鹵基」(自身或作為另一取代基之一部分)係指基團-F、-Cl、-Br或-I。
「雜芳基」(自身或作為另一取代基之一部分)係指藉由自母體雜芳香族環系統之單一原子去除一個氫原子所產生之單價雜芳香族基團,如本文所定義。典型雜芳基包括但不限於衍生自下列之基團:吖啶、β-哢啉、烷、烯、啉、呋喃、咪唑、吲唑、吲哚、二氫吲哚、吲嗪、異苯并呋喃、異烯、異吲哚、異二氫吲哚、異喹啉、異噻唑、異噁唑、萘啶、噁二唑、噁唑、萘嵌間二氮雜苯、菲啶、啡啉、吩嗪、呔嗪、蝶啶、嘌呤、吡喃、吡嗪、吡唑、噠嗪、吡啶、嘧啶、吡咯、吡咯嗪、喹唑啉、喹啉、喹嗪、喹喏啉、四唑、噻二唑、噻唑、噻吩、三唑、呫噸及諸如此類。在一些實施例中,雜芳基包含5個至20個環原子(5-20員雜芳基)。在其他實施例中,雜芳基包含5個至10個環原子(5-10員雜芳基)。例示性雜芳基包括彼等衍生下列者:呋喃、噻吩、吡咯、苯并噻吩、苯并呋喃、苯并咪適、吲哚、吡啶、吡唑、喹啉、咪唑、噁唑、異噁唑及吡嗪。
「雜芳基烷基」(自身或作為另一取代基之一部分)係指其中與碳原子(通常為末端或sp3碳原子)鍵結之一個氫原子經雜芳基替代之非環狀烷基。當意欲指示特定烷基部分時,使用命名雜芳基烷烴基、雜芳基烯基及/或雜芳基炔基。在一些實施例中,雜芳基烷基係6-21員雜芳基烷基,例如,雜芳基烷基之烷烴基、烯基或炔基部分係(C1-C6)烷基且雜芳基部分係5-15-員雜芳基。在其他實施例中,雜芳基烷基係6-13員雜芳基烷基,例如,烷烴基、烯基或炔基部分係(C1-C3)烷基且雜芳基部分係5-10員雜芳基。
保護基團」係指在連接至分子中之反應性官能基時可遮蔽、降低或阻止該官能基之反應性的一組原子。保護基團之實例可見於Green等人,「Protective Groups in Organic Chemistry」,(Wiley,第2版,1991)及Harrison等人,「Compendium of Synthetic Organic Methods」,第1卷至第8卷(John Wiley and Sons,1971-1996)中。代表性胺基保護基團包括但不限於甲醯基、乙醯基、三氟乙醯基、苄基、苄基氧基羰基(「CBZ」)、第三丁氧基羰基(「Boc」)、三甲基甲矽烷基(「TMS」)、2-三甲基甲矽烷基-乙烷磺醯基(「SES」)、三苯甲基及經取代三苯甲基、烯丙基氧基羰基、9-茀基甲基氧基羰基(「FMOC」)、硝基-藜蘆基氧基羰基(「NVOC」)及諸如此類。代表性羥基保護基團包括(但不限於)彼等其中羥基經醯化或烷基化者,例如苄基、及三苯甲基醚以及烷基醚、四氫吡喃基醚、三烷基甲矽烷基醚及烯丙基醚。
「鹽」係指具有母體化合物之期望藥理活性的化合物鹽。該等鹽包括:(1)酸加成鹽,由諸如下列等無機酸形成:氫氯酸、氫溴酸、硫酸、硝酸、磷酸及諸如此類;或由諸如下列等有機酸形成:乙酸、丙酸、己酸、環戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、蘋果酸、馬來酸、富馬酸、酒石酸、檸檬酸、苯甲酸、3-(4-羥基苯甲醯基)苯甲酸、肉桂酸、苯乙醇酸、甲烷磺酸、乙烷磺酸、1,2-乙烷-二磺酸、2-羥基乙烷磺酸、苯磺酸、4-氯苯磺酸、2-萘磺酸、4-甲苯磺酸、樟腦磺酸、4-甲基二環[2.2.2]-辛-2-烯-1-甲酸,葡庚糖酸、3-苯基丙酸、三甲基乙酸、第三丁基醋酸、月桂基硫酸、葡萄糖酸、麩胺酸、羥基萘甲酸、水楊酸、硬脂酸、黏康酸及諸如此類;或(2)當存於母體化合物中之酸性質子經金屬離子(例如,鹼金屬離子、鹼土金屬離子或鋁離子)替代時;或與有機鹼(例如,乙醇胺、二乙醇胺、三乙醇胺、N-甲基葡糖胺及諸如此類)配位時所形成之鹽。
「溶劑合物」意指藉由溶劑化(溶劑分子與溶質之分子或離子組合)所形成之化合物、或由溶質離子或分子(即本發明化合物)與一或多種溶劑分子組成之聚集物。當水係溶劑時,相應溶劑合物係「水合物」。
「N-氧化物」(亦稱為胺氧化物或胺-N-氧化物)意指經由氧化本發明化合物之胺基而衍生自本發明化合物之化合物。N-氧化物通常含有官能基R3N+-O-(有時寫為R3N=O或R3N→O)。
「經取代」在用於修飾特定基團(group或radical)時意指該特定基團之一個或多個氫原子各自彼此獨立地經相同或不同取代基替代。可用於取代特定基團之飽和碳原子之取代基包括但不限於-Ra、鹵素、-O-、=O、-ORb、-SRb、-S-、=S、-NRcRc、=NRb、=N-ORb、三鹵代甲基、-CF3、-CN、-OCN、-SCN、-NO、-NO2、=N2、-N3、-S(O)2Rb、-S(O)2NRb、-S(O)2O-、-S(O)2ORb、-OS(O)2Rb、-OS(O)2O-、-OS(O)2ORb、-P(O)(O-)2、-P(O)(ORb)(O-)、-P(O)(ORb)(ORb)、-C(O)Rb、-C(S)Rb、-C(NRb)Rb、-C(O)O-、-C(O)ORb、-C(S)ORb、-C(O)NRcRc、-C(NRb)NRcRc、-OC(O)Rb、-OC(S)Rb、-OC(O)O-、-OC(O)ORb、-OC(S)ORb、-NRbC(O)Rb、-NRbC(S)Rb、-NRbC(O)O-、-NRbC(O)ORb、-NRbC(S)ORb、-NRbC(O)NRcRc、-NRbC(NRb)Rb及-NRbC(NRb)NRcRc,其中Ra選自由下列組成之群:烷基、環烷基、雜烷基、雜環烷基、芳基、芳基烷基、雜芳基及雜芳基烷基;各Rb獨立地為氫或Ra;且各Rc獨立地為Rb,或者,該兩個Rc可連同其所鍵結氮原子一起形成4-、5-、6-或7-員雜環烷基,該雜環烷基可視情況包括1個至4個選自由O、N及S組成之群之相同或不同其他雜原子。作為特定實例,-NRcRc意欲包括-NH2、-NH-烷基、N-吡咯啶基及N-嗎啉基。作為另一特定實例,經取代之烷基意欲包括-伸烷基-O-烷基、-伸烷基-雜芳基、-伸烷基-雜環烷基、-伸烷基-C(O)ORb、-伸烷基-C(O)NRbRb及-CH2-CH2-C(O)-CH3。一或多個取代基可連同其所鍵結之原子一起形成環,包括環烷基及雜環烷基。
同樣,可用於取代特定基團之不飽和碳原子之取代基包括但不限於-Ra、鹵素、-O-、-ORb、-SRb、-S-、-NRcRc、三鹵代甲基、-CF3、-CN、-OCN、-SCN、-NO、-NO2、-N3、-S(O)2Rb、-S(O)2O-、-S(O)2ORb、-OS(O)2Rb、-OS(O)2O-、-OS(O)2ORb、-P(O)(O-)2、-P(O)(ORb)(O-)、-P(O)(ORb)(ORb)、-C(O)Rb、-C(S)Rb、-C(NRb)Rb、-C(O)O-、-C(O)ORb、-C(S)ORb、-C(O)NRcRc、-C(NRb)NRcRc、-OC(O)Rb、-OC(S)Rb、-OC(O)O-、-OC(O)ORb、-OC(S)ORb、-NRbC(O)Rb、-NRbC(S)Rb、-NRbC(O)O-、-NRbC(O)ORb、-NRbC(S)ORb、-NRbC(O)NRcRc、-NRbC(NRb)Rb及-NRbC(NRb)NRcRc,其中Ra、Rb及Rc係如先前所定義。
可用於取代雜烷基及雜環烷基之氮原子之取代基包括但不限於-Ra、-O-、-ORb、-SRb、-S-、-NRcRc、三鹵代甲基、-CF3、-CN、-NO、-NO2、-S(O)2Rb、-S(O)2O-、-S(O)2ORb、-OS(O)2Rb、-OS(O)2O-、-OS(O)2ORb、-P(O)(O-)2、-P(O)(ORb)(O-)、-P(O)(ORb)(ORb)、-C(O)Rb、-C(S)Rb、-C(NRb)Rb、-C(O)ORb、-C(S)ORb、-C(O)NRcRc、-C(NRb)NRcRc、-OC(O)Rb、-OC(S)Rb、-OC(O)ORb、-OC(S)ORb、-NRbC(O)Rb、-NRbC(S)Rb、-NRbC(O)ORb、-NRbC(S)ORb、-NRbC(O)NRcRc、-NRbC(NRb)Rb及-NRbC(NRb)NRcRc,其中Ra、Rb及Rc係如先前所定義。
上文所列示可用於取代其他特定基團或原子之取代基應為熟習此項技術者所瞭解。
用於取代特定基團之取代基可進一步經取代,通常經一個或多個選自上文所指定各基團之相同或不同基團取代。
「媒劑」係指與化合物一起投與之稀釋劑、佐劑、賦形劑或載劑。
本文所用「可攝取組合物」包括欲用於或不用於食用且可單獨或與另一物質一起經口服用之任一物質。可攝取組合物包括「食物或飲料產品」及「非食物性產品」。「食物或飲料產品」意指欲供人或動物食用之任一食物性產品,包括固體、半固體或液體(例如,飲料)。術語「非食物性產品」或「非食性組合物」包括可出於非食用性目的或作為食物或飲料由人類或動物服用之任一產品或組合物。舉例而言,非食物性產品或非食性組合物包括補充品、營養品、功能性食品(例如,聲稱除補充營養物之基本營養功能以外具有促進健康及/或預防疾病性質的任一新鮮或經處理食物)、藥品及非處方藥物、口腔護理產品(例如潔齒劑及漱口劑)、化妝品(例如帶甜味的唇膏)及其他可含有或不含有任一甜味劑之個人護理產品。
「攝取上可接受之載劑或賦形劑」係用於製備本發明化合物之期望劑型以便以經分散/經稀釋形式投與本發明化合物,以最大化本發明化合物之生物學效果的介質及/或組合物。該介質及/或組合物可呈任一形式,例如,固體、半固體、液體、糊、凝膠、洗劑、乳霜、泡沫狀物質、懸浮液、溶液或其任一組合(例如含有固體內含物之液體),此視產品之預期用途而定。攝取上可接受之載劑包括多種常用食物成份,例如pH為中性、酸性或鹼性的水、果汁或蔬菜汁、調味液、啤酒、白酒、天然水/脂肪乳(例如牛奶或煉乳)、食物性油及起酥油、脂肪酸及其烷基酯、低分子量丙二醇寡聚物、脂肪酸甘油酯、及該等疏水性物質於水性介質中之分散液或乳液、鹽(例如氯化鈉)、小麥粉、溶劑(例如乙醇)、固體食物性稀釋劑(例如蔬菜粉)或麵粉、或其他液體媒劑;分散或懸浮助劑;表面活性劑;等滲劑;增稠劑或乳化劑、防腐劑;固體黏結劑;潤滑劑及諸如此類。
本文「增強劑」係指可調節(增加)特定受體(較佳化學感應受體,例如T1R2/T1R3受體)活化之化合物或其攝取上可接受之鹽或溶劑合物。本文該等增強劑將藉由配體來增強化學感應受體之活化。通常,「增強劑」將專一於特定配體,即,其將無法藉由特定化學感應配體或與其密切相關之配體以外的化學感應配體來增強化學感應受體之活化。大多數增強劑在其配體增強濃度下自身不會實質上活化特定受體。通常,增強劑之配體增強濃度係增強劑藉由配體來增加或增強特定受體活化的濃度含量,增強劑自身未實質上活化特定受體。在一些實施例中,某些增強劑在以高於配體增強濃度之濃度使用時,除可調節(例如增加或增強)受體活化以外,自身亦可活化特定受體。舉例而言,某些增強劑在以高於配體增強濃度之濃度使用時,亦可為甜味劑(即甜調味劑/實體)。
本文「風味(flavor)」係指個體之味覺感知,其包括甜、酸、鹹、苦及鮮味。該個體可為人類或動物。
本文「調味劑」係指可在動物或人類中誘發風味或味道之化合物或其攝取上可接受之鹽或溶劑合物。調味劑可為天然、半合成或合成。
本文「風味修飾劑(flavor modifier或flavor modifying agent)」係指可在動物或人類中調節(包括增強或加強、及/或誘發)調味劑味道之化合物或其攝取上可接受之鹽或溶劑合物。
本文「增味劑」係指增強及/或倍增調味劑味道之化合物或其攝取上可接受之鹽,或包含該調味劑之可攝取組合物。
「甜味」係指通常在動物或人類中由糖(例如蔗糖)誘發之甜味。
本文「甜調味劑」、「甜味實體」、「甜味劑」、「甜化合物」或「甜味受體活化化合物」係指在個體中引發可檢測甜味之化合物或其攝取上可接受之鹽,例如蔗糖,或在活體外活化T1R2/T1R3受體之化合物。該個體可為人類或動物。
本文「甜味修飾劑(sweet flavor modifier或sweet flavor modifying agent)」係指在動物或人類中調節(包括增強或加強)、產生或阻斷甜調味劑之甜味的化合物或其攝取上可接受之鹽或溶劑合物。甜味修飾劑包括甜味增強劑及甜調味劑二者。
本文「甜味增強劑(sweet flavor enhancer或 sweet flavor enhancing agent)」係指甜味之增強劑,其中術語增強劑係與上文所定義相同。
本文「甜味受體活化化合物」係指可活化甜味受體(例如T1R2/T1R3受體)之化合物。甜味受體活化化合物之一個實例係甜味劑,例如蔗糖。
本文「甜味受體調節化合物」係指調節(活化、阻斷或增強/降低活化)甜味受體之化合物,例如T1R2/T1R3受體。
本文「甜味受體增強化合物」係指增強或加強甜味受體活化化合物(例如,蔗糖)效果之化合物。
儘管大多數甜味受體增強化合物或甜味增強劑以其配體增強濃度使用自身不會實質上活化特定受體,一些甜味受體增強化合物或甜味增強劑在以高於其配體增強濃度之濃度使用時,除可調節(增加)受體活化以外,自身亦可活化特定受體。舉例而言,一些甜味受體增強化合物或甜味增強劑在以高於其配體增強濃度之濃度使用時亦可活化甜味受體(例如T1R2/T1R3受體),其充當受體激動劑。
本文「甜味調節量」係指足以改變(增加或降低)可攝取組合物或其前體之甜味且人類個體可充分地感知之式(I)化合物的量。在本發明之很多實施例中,將需要存在至少約0.001 ppm本發明化合物以使大多數人類個體感知包含本發明化合物之可攝取組合物之甜味調節。為經濟地提供合意之甜味調節程度,通常可使用濃度之寬範圍可為約0.001 ppm至100 ppm,或約0.1 ppm至約10 ppm之窄範圍。甜味調節量之替代範圍可為約0.01 ppm至約30 ppm、約0.05 ppm至約15 ppm、約0.1 ppm至約5 ppm、或約0.1 ppm至約3 ppm。
本文「甜味增強量」係指足以增強可攝取組合物中調味劑(例如,蔗糖)味道之化合物的量,如動物或人類所感知。甜味增強量之寬範圍可為約0.001 ppm至100 ppm,或約0.1 ppm至約10 ppm之窄範圍。甜味增強量之替代範圍可為約0.01 ppm至約30 ppm、約0.05 ppm至約15 ppm、約0.1 ppm至約5 ppm、或約0.1 ppm至約3 ppm。在一些實施例中,甜味增強量係相當於本發明甜味增強劑之配體增強濃度的量。
本文「甜味受體調節量」係指足以調節(活化、增強或阻斷)甜味受體蛋白之化合物的量。在本發明許多實施例中,甜味受體調節量為至少約1 pM、或至少約1 nM、或至少約10 nM、或至少約100 nM(即約0.1 μM)。「T1R2/T1R3受體調節或活化量」係足以調節或活化T1R2/T1R3受體之化合物的量。「甜味受體」係受甜化合物調節之味覺受體。較佳地,甜味受體係G蛋白偶合受體,且更佳地,甜味受體係T1R2/T1R3受體。
在一個實施例中,本發明提供具有結構式(I)或(I')之化合物:
或互變異構體、鹽及/或溶劑合物,其中:A係-OR1、-NR1C(O)R2、-NHOR1、-NR1R2、-NR1CO2R2、-NR1C(O)NR2R3、-NR1C(S)NR2R3或-NR1C(=NH)NR2R3;B係氫、烷基、經取代之烷基、芳基、經取代之芳基、芳基烷基、經取代之芳基烷基、醯基、經取代之醯基、雜烷基、經取代之雜烷基、雜芳基、經取代之雜芳基、雜芳基烷基、經取代之雜芳基烷基、-CN、-OR4、-S(O)aR4、-NR4R5、-C(O)NR4R5、-CO2R4、-NR4CO2R5、-NR4C(O)NR5R6、-NR4C(S)NR5R6、-NR4C(=NH)NR5R6、-SO2NR4R5、-NR4SO2R5、-NR4SO2NR5R6、-B(OR4)(OR5)、-P(O)(OR4)(OR5)或-P(O)(R4)(OR5);C係-OR7、-S(O)bR7、SO3R7、-C(O)NR7R8、-CO2R7、-NR7CO2R8、-NR7C(O)NR8R9、-NR7C(=NH)NR8R9、-SO2NR7R8、-NR7SO2R8、-NR7SO2NR8R9、-B(OR7)(OR8)、-P(O)(OR7)(OR8)、-P(O)(R7)(OR8)或雜芳基(例如,四唑);D係芳基、經取代之芳基、雜芳基、經取代之雜芳基、環烷基、經取代環烷基、雜環烷基或經取代之雜環烷基環,其中該環視情況稠合至另一芳基、經取代之芳基、雜芳基、經取代之雜芳基、環烷基、經取代環烷基、雜環烷基或經取代之雜環烷基環;a及b獨立地為0、1或2;且R1、R2、R3、R4、R5、R6、R7、R8及R9獨立地為氫、烷基、經取代之烷基、芳基、經取代之芳基、芳基烷基、經取代之芳基烷基、醯基、經取代之醯基、雜烷基、經取代之雜烷基、雜芳基、經取代之雜芳基、雜芳基烷基或經取代之雜芳基烷基;或者,R1與R2、R2與R3、R4與R5、R5與R6、R7與R8或R8與R9連同其所鍵結之原子一起形成雜環烷基或經取代之雜環烷基環。
在本發明之一個實施例中,式(I)受以下限制條件約束:(a)當D係經取代之苯基;B係氫;C係-CO2R7;R7係氫或烷基;A係-NR1R2;且R1及R2中之一者係氫時;則R1及R2中之另一者不為經取代之芳基烷基;及(b)當D係苯基或經取代之苯基;C係-CO2R7;R7係烷基;A係-NR1R2;且R1及R2二者皆為氫時;則B不為-CO2R4;其中R4係烷基。
在本發明之一個實施例中,式(I)不包括以下化合物:8-溴-4-(4-甲氧基苄基)胺基-5-甲氧基喹啉-3-甲酸乙基酯;4-(4-甲氧基苄基)胺基-5-甲氧基喹啉-3-甲酸乙基酯;4-(4-甲氧基苄基)胺基-5-甲氧基喹啉-3-甲酸;4-(4-甲氧基苄基)胺基-8-甲氧基喹啉-3-甲酸乙基酯;4-(4-甲氧基苄基)胺基-8-甲氧基喹啉-3-甲酸;4-胺基-3-乙氧基羰基-2-乙氧基羰基甲基喹啉;及4-胺基-3-乙氧基羰基-2-乙氧基羰基甲基-5-甲氧基喹啉。
在式(I)之一個實施例中,R1及R2獨立地為氫、烷基、經取代之烷基、芳基、經取代之芳基、芳基烷基、醯基、經取代之醯基、雜烷基、經取代之雜烷基、雜芳基、經取代之雜芳基、雜芳基烷基或經取代之雜芳基烷基;或者,R1與R2、R2與R3、R4與R5、R5與R6、R7與R8、或R8與R9連同其所鍵結之原子一起形成雜環烷基或經取代之雜環烷基環。
在式(I)之一個實施例中,當B係經取代之烷基時,則該烷基上之取代基不為-C(O)ORb,其中Rb係烷基。
在式(I)之一個實施例中,當B係經取代之烷基時,則該烷基上之取代基選自由下列組成之群:-Ra、鹵基、-O-、=O、-ORb、-SRb、-S-、=S、-NRcRc、=NRb、=N-ORb、三鹵代甲基、-CF3、-CN、-OCN、-SCN、-NO、-NO2、=N2、-N3、-S(O)2Rb、-S(O)2NRb、-S(O)2O-、-S(O)2ORb、-OS(O)2Rb、-OS(O)2O-、-OS(O)2ORb、-P(O)(O-)2、-P(O)(ORb)(O-)、-P(O)(ORb)(ORb)、-C(O)Rb、-C(S)Rb、-C(NRb)Rb、-C(O)O-、-C(S)ORb、-C(O)NRcRc、-C(NRb)NRcRc、-OC(O)Rb、-OC(S)Rb、-OC(O)O-、-OC(O)ORb、-OC(S)ORb、-NRbC(O)Rb、-NRbC(S)Rb、-NRbC(O)O-、-NRbC(O)ORb、-NRbC(S)ORb、-NRbC(O)NRcRc、-NRbC(NRb)Rb及-NRbC(NRb)NRcRc,其中Ra選自由烷基、環烷基、雜烷基、雜環烷基、芳基、芳基烷基、雜芳基及雜芳基烷基組成之群;各Rb獨立地為氫或Ra;且各Rc獨立地為Rb或者,該兩個Rc可連同其所鍵結之氮原子一起形成4-、5-、6-或7-員雜環烷基,其可視情況包括1個至4個選自由O、N及S組成之群之相同或不同其他雜原子。
在本發明之一個實施例中,式(I)或(I')之化合物具有式(II)或(II')之結構式:
或互變異構體、鹽及/或溶劑合物,其中:Y與W或Z形成單鍵並與W或Z中之另一者形成雙鍵;W係-C(R10)-、-S-、-N-、-N(R11)-或-O-;Y係-C(R12)-或-N-;Z係-C(R13)-、-S-、-N-、-N(R14)-或-O-;R10係氫、烷基、經取代之烷基、芳基、經取代之芳基、芳基烷基、經取代之芳基烷基、醯基、經取代之醯基、雜烷基、經取代之雜烷基、雜芳基、經取代之雜芳基、雜芳基烷基、經取代之雜芳基烷基、鹵基、-CN、-OR15、-S(O)cR15、-NR15R16、-C(O)NR15R16、-CO2R15、-SO2NR15R16、-NR15SO2R16、-P(O)(OR15)(OR16)或-P(O)(R15)(OR16);R12係氫、烷基、經取代之烷基、芳基、經取代之芳基、芳基烷基、經取代之芳基烷基、醯基、經取代之醯基、雜烷基、經取代之雜烷基、雜芳基、經取代之雜芳基、雜芳基烷基、經取代之雜芳基烷基、鹵基、-CN、-OR17、-S(O)dR17、-OC(O)R17、-NR17R18、-C(O)NR17R18、-CO2R17、-SO2NR17R18、-NR17SO2R18、-P(O)(OR17)(OR18)或-P(O)(R17)(OR18);R13係氫、烷基、經取代之烷基、芳基、經取代之芳基、芳基烷基、經取代之芳基烷基、醯基、經取代之醯基、雜烷基、經取代之雜烷基、雜芳基、經取代之雜芳基、雜芳基烷基、經取代之雜芳基烷基、鹵基、-CN、-OR19、-S(O)eR19、-OC(O)R19、-NR19R20、-C(O)NR19R20、-C(O)R19、-CO2R19、-SO2NR19R20、-NR19SO2R20、-P(O)(OR19)(OR20)或-P(O)(R19)(OR20);或者,R10與R12或R12與R13連同其所連接之原子一起形成環烷基、經取代環烷基、雜環烷基或經取代之雜環烷基環;c、d及e獨立地為0、1或2;R11及R14獨立地為氫、烷基、經取代之烷基、芳基、經取代之芳基、芳基烷基、經取代之芳基烷基、醯基、經取代之醯基、雜烷基、經取代之雜烷基、雜芳基、經取代之雜芳基、雜芳基烷基或經取代之雜芳基烷基;且R15、R16、R17、R18、R19及R20獨立地為氫、烷基、經取代之烷基、芳基、經取代之芳基、芳基烷基、經取代之芳基烷基、醯基、經取代之醯基、雜烷基、經取代之雜烷基、雜芳基、經取代之雜芳基、雜芳基烷基或經取代之雜芳基烷基;或者,R15與R16、R17與R18或R19與R20連同其所連接之原子一起形成雜環烷基或經取代之雜環烷基環;且受以下限制條件約束:(a)當W係-O-或-S-或-NR11-時,則Z係-C(R13)-或-N-;(b)當Z係-O-或-S-或-NR14-時,則W係-C(R10)-或-N-;及(c)當W係-C(R10)-或-N-時,則Z不能為-C(R13)-或-N-。
在本發明之一個實施例中,式(II)或(II')之化合物具有結構式(IIa)或(IIa'),
或互變異構體、鹽及/或溶劑合物,其中,W係-C(R10)-或-N-;Y係-C(R12)-或-N-;且Z係-S-、-N(R14)-或-O-。在本發明之一個實施例中,式(II)或(II')之化合物具有結構式(IIb)或(IIb'),
或互變異構體、鹽及/或溶劑合物,其中,W係-S-、-N(R11)-或-O-;Y係-C(R12)-或-N-;且Z係-C(R13)-或-N-。在本發明之一個實施例中,式(I)或(I')之化合物具有結構式(III)或(III'),
或其互變異構體、鹽及/或溶劑合物,其中:H係-C(R21)-或-N-;I係-C(R22)或-N-;J係-C(R23)-或-N-;K係-C(R24)-或-N-;R21係氫、烷基、經取代之烷基、鹵基、-CN、-OR25;R22係氫、烷基、經取代之烷基、鹵基、-CN、-OR27;R23係氫、烷基、經取代之烷基、芳基、經取代之芳基、芳基烷基、經取代之芳基烷基、醯基、經取代之醯基、鹵基、雜烷基、經取代之雜烷基、雜芳基、經取代之雜芳基、雜芳基烷基、經取代之雜芳基烷基、-CN、-OR29、-S(O)fR29、-OC(O)R29、-NR29R30、-C(O)NR29R30、-CO2R29、-SO2NR29R30、-NR29SO2R30、-B(OR29)(OR30)、-P(O)(OR29)(OR30)或-P(O)(R29)(OR30);R24係氫、烷基、經取代之烷基、芳基、經取代之芳基、芳基烷基、經取代之芳基烷基、醯基、經取代之醯基、鹵基、雜烷基、經取代之雜烷基、雜芳基、經取代之雜芳基、雜芳基烷基、經取代之雜芳基烷基、-CN、-OR31、-S(O)gR31、-OC(O)R31、-NR31R32、-C(O)NR31R32、-C(O)R31、-CO2R31、-SO2NR31R32、-NR31SO2R32、-B(OR31)(OR32)、-P(O)(OR31)(OR32)或-P(O)(R31)(OR32);或者,R23與R24連同其所連接之原子一起形成環烷基、經取代環烷基、雜環烷基或經取代之雜環烷基環;f及g獨立地為0、1或2;且R25、R26、R27、R28、R29、R30、R31及R32獨立地為氫、烷基、經取代之烷基、芳基、經取代之芳基、芳基烷基、經取代之芳基烷基、醯基、經取代之醯基、雜烷基、經取代之雜烷基、雜芳基、經取代之雜芳基、雜芳基烷基或經取代之雜芳基烷基;或者,R25與R26、R27與R28、R29與R30、或R31與R32連同其所連接之原子一起形成雜環烷基或經取代之雜環烷基環;限制條件係H、I、J及K中之至多兩者為-N-。
在式(III)之一個實施例中,H、I、J及K中之一者或兩者為-N-。
在式(III)之一個實施例中,H係-N-,I係-C(R22)-,J係-C(R23)-,且K係-C(R24)-。
在式(III)之一個實施例中,H係-C(R21)-,I係-N-,J係-C(R23)-,且K係-C(R24)-。
在式(III)之一個實施例中,H係-C(R21)-,I係-C(R22)-,J係-N-,且K係-C(R24)-。
在式(III)之一個實施例中,H係-C(R21)-,I係-C(R22),J係-C(R23)-,且K係-N-。
在式(III)之一個實施例中,H及I係-N-。
在式(III)之一個實施例中,H及J係-N-。
在式(III)之一個實施例中,H及K係-N-。
在式(III)之一個實施例中,I及J係-N-。
在式(III)之一個實施例中,I及K係-N-。
在式(III)之一個實施例中,J及K係-N-。
在本發明之一個實施例中,式(III)或(III')之化合物具有結構式(IIIa)或(IIIa'),
或其互變異構體、鹽及/或溶劑合物。在式(IIIa)之一個實施例中,R21、R22、R23及R24中之兩者或三者為氫。
在式(IIIa)之一個實施例中,R21係氫;R22係氫、烷基、經取代之烷基、鹵基、-CN或-OR27;R23係氫、烷基、經取代之烷基、-CN、-OR29、-S(O)fR29、-OC(O)R29、-NR29R30、-C(O)NR29R30、-C(O)R29、-CO2R29、-SO2NR29R30或-NR29SO2R30;R24係氫、烷基、經取代之烷基、-CN、-OR31、-S(O)gR31、-OC(O)R31、-NR31R32、-C(O)NR31R32、-C(O)R31、-CO2R31、-SO2NR31R32或-NR31SO2R32;或者,R23與R24連同其所連接之原子一起形成環烷基、經取代環烷基、雜環烷基或經取代之雜環烷基環;且R27、R29、R30、R31及R32獨立地為氫、烷基、經取代之烷基、芳基、經取代之芳基、芳基烷基、經取代之芳基烷基、醯基、經取代之醯基、雜烷基、經取代之雜烷基、雜芳基、經取代之雜芳基、雜芳基烷基或經取代之雜芳基烷基;或者,R25與R26、R27與R28、R29與R30或R31與R32連同其所連接之原子一起形成雜環烷基或經取代之雜環烷基環。在式(IIIa)之一個實施例中,R21及R22皆為氫。在式(IIIa)之一個實施例中,R23與R24連同其所連接之原子一起形成環烷基、經取代環烷基、雜環烷基或經取代之雜環烷基環。
在式(IIIa)之一個實施例中,R23與R24連同其所連接之原子一起形成含有一個或多個取代基之經取代之雜環烷基環,該等取代基選自由下列組成之群:-Ra、鹵基、-O-、=O、-ORb、-SRb、-S-、=S、-NRcRc、=NRb、=N-ORb、三鹵代甲基、-CF3、-CN、-OCN、-SCN、-NO、-NO2、=N2、-N3、-S(O)2Rb、-S(O)2NRb、-S(O)2O-、-S(O)2ORb、-OS(O)2Rb、-OS(O)2O-、-OS(O)2ORb、-P(O)(O-)2、-P(O)(ORb)(O-)、-P(O)(ORb)(ORb)、-C(O)Rb、-C(O)ORb、-C(S)Rb、-C(NRb)Rb、-C(O)O-、-C(S)ORb、-C(O)NRcRc、-C(NRb)NRcRc、-OC(O)Rb、-OC(S)Rb、-OC(O)O-、-OC(O)ORb、-OC(S)ORb、-NRbC(O)Rb、-NRbC(S)Rb、-NRbC(O)O-、-NRbC(O)ORb、-NRbC(S)ORb、-NRbC(O)NRcRc、-NRbC(NRb)Rb及-NRbC(NRb)NRcRc,其中Ra選自由烷基、環烷基、雜烷基、雜環烷基、芳基、芳基烷基、雜芳基及雜芳基烷基組成之群;各Rb獨立地為氫或Ra;且各Rc獨立地為Rb,或者,該兩個Rc可連同其所鍵結氮原子一起形成4-、5-、6-或7-員雜環烷基,該雜環烷基可視情況包括1個至4個選自由O、N及S組成之群之相同或不同其他雜原子;或者,該雜環烷基環上取代基中之兩者連同其所鍵結之原子一起形成環烷基、經取代環烷基、雜環烷基或經取代之雜環烷基環。在式(IIIa)之一個實施例中,R21、R22、R23及R24皆為氫。
在式(IIIa)之一個實施例中,A係-OR1、-NR1C(O)R2、-NHOR1、-NR1R2、-NOR1、-NR1CO2R2、-NR1C(O)NR2R3、-NR1CSNR2R3或-NR1C(=NH)NR2R3。在式(IIIa)之一個實施例中,C係-S(O)bR7、SO3R7、-C(O)NR7R8、-CO2R7、-NR7CO2R8、-NR7C(O)NR8R9、-NR7C(S)NR8R9、-NR7C(=NH)NR8R9、-SO2NR7R8、-NR7SO2R8、-NR7SO2NR8R9、-B(OR7)(OR8)、-P(O)(OR7)(OR8)或-P(O)(R7)(OR8)。
在式(IIIa)之一個實施例中,B係氫、烷基、經取代之烷基、芳基、經取代之芳基、芳基烷基、經取代之芳基烷基、醯基、經取代之醯基、雜烷基、經取代之雜烷基、雜芳基、經取代之雜芳基、雜芳基烷基或經取代之雜芳基烷基。
在式(IIIa)之一個實施例中,R21、R22、R23及R24中之三者為氫;A係-OR1、-NR1C(O)R2、-NHOR1、-NR1R2、-NR1CO2R2、-NR1C(O)NR2R3、-NR1C(S)NR2R3或-NR1C(=NH)NR2R3;C係-S(O)bR7、-SO3R7、-C(O)NR7R8、-CO2R7、-NR7CO2R8、-NR7C(O)NR8R9、-NR7C(S)NR8R9、-NR7C(=NH)NR8R9、-SO2NR7R8、-NR7SO2R8、-NR7SO2NR8R9、-B(OR7)(OR8)、-P(O)(OR7)(OR8)或-P(O)(R7)(OR8)或四唑;B係氫、烷基、經取代之烷基、芳基、經取代之芳基、芳基烷基、經取代之芳基烷基、醯基、經取代之醯基、雜烷基、經取代之雜烷基、雜芳基、經取代之雜芳基、雜芳基烷基或經取代之雜芳基烷基。
在本發明之一個實施例中,式(IIIa)或(IIIa')之化合物具有結構式(IIIb)或(IIIb'),
或其互變異構體、鹽及/或溶劑合物;其中L1係伸烷基或經取代之伸烷基;L2係-NR34-、-O-、-S-、-NR34-C(O)-、-C(O)-NR34-、-O-C(O)-、-C(O)-O-、-NR34-C(O)-O-、-O-C(O)-NR34-、-NR34-C(O)-NR35-、-O-C(O)-O-、-伸雜環基-C(O)-或-(經取代之伸雜環基)-C(O)-;R33係烷基、經取代之烷基、碳環基、經取代之碳環基;芳基、經取代之芳基、芳基烷基、經取代之芳基烷基、雜環基、經取代之雜環基、雜烷基、經取代之雜烷基、雜芳基、經取代之雜芳基、雜芳基烷基或經取代之雜芳基烷基;且R34及R35獨立地為氫、烷基、經取代之烷基、碳環基、經取代之碳環基;芳基、經取代之芳基、芳基烷基、經取代之芳基烷基、雜環基、經取代之雜環基、雜烷基、經取代之雜烷基、雜芳基、經取代之雜芳基、雜芳基烷基或經取代之雜芳基烷基。
在本發明之一個實施例中,式(IIIb)或(IIIb')之化合物具有結構式(IIIc)、(IIIc')、(IIId)或(IIId'),
或其互變異構體、鹽及/或溶劑合物;其中R33係烷基、經取代之烷基、碳環基、經取代之碳環基;芳基、經取代之芳基、芳基烷基、經取代之芳基烷基、雜環基、經取代之雜環基、雜烷基、經取代之雜烷基、雜芳基、經取代之雜芳基、雜芳基烷基或經取代之雜芳基烷基。在式(IIIc)或(IIId)之一個實施例中,R33係烷基、經取代之烷基、碳環基、經取代之碳環基;雜環基、經取代之雜環基、雜烷基或經取代之雜烷基。在式(IIIb)、(IIIc)或(IIId)之一個實施例中,A係-OR1、-NR1C(O)R2、-NHOR1、-NR1R2、-NR1CO2R2、-NR1C(O)NR2R3、-NR1CSNR2R3或-NR1C(=NH)NR2R3。在式(IIIb)、(IIIc)或(IIId)之一個實施例中,C係-S(O)bR7、SO3R7、-C(O)NR7R8、-CO2R7、-NR7CO2R8、-NR7C(O)NR8R9、-NR7C(S)NR8R9、-NR7C(=NH)NR8R9、-SO2NR7R8、-NR7SO2R8、-NR7SO2NR8R9、-B(OR7)(OR8)、-P(O)(OR7)(OR8)或-P(O)(R7)(OR8)。
在式(IIIb)、(IIIc)或(IIId)之一個實施例中,B係氫、烷基、經取代之烷基、芳基、經取代之芳基、芳基烷基、經取代之芳基烷基、醯基、經取代之醯基、雜烷基、經取代之雜烷基、雜芳基、經取代之雜芳基、雜芳基烷基或經取代之雜芳基烷基。
在式(IIIb)之一個實施例中,A係-OR1、-NHOR1或-NR1R2;B係氫、烷基、經取代之烷基、芳基或經取代之芳基;C係-SO3R7、-C(O)NR7R8、-CO2R7、-SO2NR7R8、-B(OR7)(OR8)、-P(O)(OR7)(OR8)或-P(O)(R7)(OR8);L1係伸烷基或經取代之伸烷基;L2係-NR34-、-O-、-NR34-C(O)-、-C(O)-NR34-、-O-C(O)-、-C(O)-O-、-伸雜環基-C(O)-或-(經取代之伸雜環基)-C(O)-;R33係烷基、經取代之烷基、碳環基、經取代之碳環基;芳基、經取代之芳基、芳基烷基、經取代之芳基烷基、雜環基、經取代之雜環基、雜烷基、經取代之雜烷基、雜芳基、經取代之雜芳基、雜芳基烷基或經取代之雜芳基烷基;且R34及R35獨立地為氫、烷基或經取代之烷基。
在式(IIIc)或(IIId)之一個實施例中,A係-OR1、-NHOR1或-NR1R2;B係氫、烷基、經取代之烷基、芳基或經取代之芳基;C係-SO3R7、-C(O)NR7R8、-CO2R7、-SO2NR7R8、-B(OR7)(OR8)、-P(O)(OR7)(OR8)或-P(O)(R7)(OR8);R33係烷基、經取代之烷基、碳環基、經取代之碳環基;雜環基、經取代之雜環基、雜烷基或經取代之雜烷基。在本發明之一些特定實施例中,化合物選自由下列組成之群:
在另一實施例中,本發明提供製備式(IV)化合物之方法:
其中B係氫、烷基、經取代之烷基、芳基、經取代之芳基、芳基烷基、經取代之芳基烷基、醯基、經取代之醯基、雜烷基、經取代之雜烷基、雜芳基、經取代之雜芳基、雜芳基烷基或經取代之雜芳基烷基;R1、R2及R7獨立地為氫、烷基、經取代之烷基、芳基、經取代之芳基、芳基烷基、經取代之芳基烷基、雜烷基、經取代之雜烷基、雜芳基、經取代之雜芳基、雜芳基烷基或經取代之雜芳基烷基;或者,R1與R2連同其所鍵結之原子一起形成雜環烷基或經取代之雜環烷基環;R21係氫、烷基、經取代之烷基、鹵基、-CN、-OR25;R22係氫、烷基、經取代之烷基、鹵基、-CN、-OR27;R23係氫、烷基、經取代之烷基、芳基、經取代之芳基、芳基烷基、經取代之芳基烷基、醯基、經取代之醯基、鹵基、雜烷基、經取代之雜烷基、雜芳基、經取代之雜芳基、雜芳基烷基、經取代之雜芳基烷基、-OR29、-S(O)fR29、-OC(O)R29、-NR29R30、-C(O)NR29R30、-CO2R29、-SO2NR29R30、-NR29SO2R30、-B(OR29)(OR30)、-P(O)(OR29)(OR30)或-P(O)(R29)(OR30);R24係氫、烷基、經取代之烷基、芳基、經取代之芳基、芳基烷基、經取代之芳基烷基、醯基、經取代之醯基、鹵基、雜烷基、經取代之雜烷基、雜芳基、經取代之雜芳基、雜芳基烷基、經取代之雜芳基烷基、-OR31、-S(O)gR31、-OC(O)R31、-NR31R32、-C(O)NR31R32、-C(O)R31、-CO2R31、-SO2NR31R32、-NR31SO2R32、-B(OR31)(OR32)、-P(O)(OR31)(OR32)或-P(O)(R31)(OR32);或者,R23與R24連同其所連接之原子一起形成環烷基、經取代環烷基、雜環烷基或經取代之雜環烷基環;f及g獨立地為0、1或2;且R25、R26、R27、R28、R29、R30、R31及R32獨立地為氫、烷基、經取代之烷基、芳基、經取代之芳基、芳基烷基、經取代之芳基烷基、醯基、經取代之醯基、雜烷基、經取代之雜烷基、雜芳基、經取代之雜芳基、雜芳基烷基或經取代之雜芳基烷基;或者,R25與R26、R27與R28、R29與R30或R31與R32連同其所連接之原子一起形成雜環烷基或經取代之雜環烷基環。
該方法包含使式(IVa)化合物:
與式(IVb)化合物:
在路易士酸(Lewis)存在下在無水且非極性溶劑中反應;其中R7b係烷基、經取代之烷基、芳基、經取代之芳基、芳基烷基、經取代之芳基烷基、雜烷基、經取代之雜烷基、雜芳基、經取代之雜芳基、雜芳基烷基或經取代之雜芳基烷基;且R21、R22、R23及R24與式(IV)中所定義相同。在式(IV)中之R7係氫時,則可藉由水解R7係烷基或經取代之烷基之相應化合物來獲得該化合物,而該相應化合物又可自式(IVa)化合物與(IVb)化合物之反應來製備。此一水解條件可為鹼性、酸性或熟習此項技術者已知之任一條件。
「路易士酸」意指為電子對受體且因此能夠藉由共用由路易士鹼提供之電子對而與路易士鹼反應形成路易士加合物之化合物。一個闡釋性實例係三甲基硼(路易士酸)與氨(路易士鹼)反應得到加合物Me3BNH3。適用於式(IVa)化合物與(IVb)化合物反應之路易士酸可為熟習此項技術者已知之任一路易士酸。在一個特定實施例中,路易士酸係金屬鹵化物,例如,氯化錫、三鹵化硼或氯化鋁。用於實施化學反應之溶劑可大體上分為兩類:極性及非極性。通常,溶劑之介電常數提供溶劑極性之粗略量度。通常認為介電常數小於15之溶劑係非極性的。非極性溶劑之實例包括但不限於戊烷、環戊烷、己烷、環己烷、苯、甲苯、1,4-二噁烷、氯仿、乙醚及其組合。
在該方法之一個實施例中,式(IVa)化合物與式(IVb)化合物之反應至少部分地係在約60℃或更高之溫度下實施。舉例而言,該反應可部分地在室溫下實施且部分地在約60℃或更高之溫度下實施。在一個實施例中,約60℃或更高之溫度係約70℃或更高之溫度;在另一實施例中,約60℃或更高之溫度係約80℃或更高之溫度;在另一實施例中,約60℃或更高之溫度係約90℃或更高之溫度;在另一實施例中,約60℃或更高之溫度係約100℃或更高之溫度;在另一實施例中,約60℃或更高之溫度係低於約130℃之溫度。在式(IV)之一個實施例中,R1、R2及R7係氫。在式(IV)之一個實施例中,B係烷基或經取代之烷基。在式(IV)之一個實施例中,R24係-OR31,且R31係烷基、經取代之烷基、碳環基、經取代之碳環基;芳基、經取代之芳基、芳基烷基、經取代之芳基烷基、雜環基、經取代之雜環基、雜烷基、經取代之雜烷基、雜芳基、經取代之雜芳基、雜芳基烷基或經取代之雜芳基烷基。
在本發明之一個實施例中,式(IV)化合物由式(IVc)代表:
其中B係烷基或經取代之烷基;且R31係烷基、經取代之烷基、碳環基及經取代之碳環基。
組合物
本發明化合物可用於本發明之一或多個方法(例如,調節或增強甜味)。一般而言,本發明化合物(單獨或組合)可提供於組合物(例如,可攝取組合物)中。式(I)化合物及其各亞類、及其鹽及/或溶劑合物較佳應在食用性上可接受,例如,自賦予未經修飾之食性組合物以改良及/或愉快之甜味角度而言,人們認為適用於食物或飲品中,且在其用作食性組合物之調味劑之典型濃度下對動物或人類不會有顯著毒性或引起不愉快或不合意之藥理學或毒物學影響。
證實香料化合物在食用性上可接受之典型方法係由香料及提取物製造者協會專家小組(Expert Panel of the Flavor and Extract Manufacturers Association)對該化合物進行測試及/或評價並宣佈為「一般認為安全」(「GRAS」)。對香料化合物之FEMA/GRAS評價過程複雜,但為食品製備領域之一般技術人員所熟知,如Smith等人在標題為「GRAS Flavoring Substances 21」(Food Technology,57(5),第46頁至第59頁,2003年5月)之文章中所論述,該文章之全部內容以引用方式併入本文中。在一個實施例中,本發明化合物可以其配體增強濃度(例如,在每百萬數份數量級上之極低濃度)與一或多種已知甜味劑(天然或人造)組合使用,以減少製備具有期望甜度之可攝取組合物所需已知甜味劑之濃度。
可用於該等甜味劑組合之常用已知或人造甜味劑包括但不限於常見糖類甜味劑,例如,蔗糖、果糖、葡萄糖;及包含天然糖之甜味劑組合物,例如玉米糖漿(包括高果糖玉米糖漿)或其他來源於天然水果及蔬菜來源之糖漿或甜味劑濃縮物;半合成「糖醇」甜味劑,例如赤蘚醇、異麥芽酮糖醇、乳糖醇、甘露糖醇、山梨糖醇、木糖醇、麥芽糊精及諸如此類;及人造甜味劑,例如阿斯巴甜(aspartame)、糖精、安賽蜜(acesulfame-K)、環己胺磺酸鹽、蔗糖素及阿力甜(alitame)。甜味劑亦包括環拉酸(cyclamic acid)、羅漢果糖苷、塔格糖(tagatose)、麥芽糖、半乳糖、甘露糖、蔗糖、果糖、乳糖、紐甜(neotame)及其他阿斯巴甜衍生物、葡萄糖、D-色胺酸、甘胺酸、麥芽糖醇、乳糖醇、異麥芽酮糖醇、氫化葡萄糖漿(HGS)、氫化澱粉水解物(HSH)、甜菊苷、甜菊糖苷A及其他基於甜菊(sweet Stevia)之糖苷、卡瑞拉(carrelame)及其他基於胍之甜味劑等。術語「甜味劑」亦包括如本文所揭示甜味劑之組合。
在一個實施例中,將本發明化合物添加至非食性組合物或非食物性產品中,例如補充劑、營養品、功能性食品(例如,除補充營養物之基本營養功能以外聲稱具有促進健康及/或預防疾病性質之任一新鮮或經加工食物)、藥品及非處方藥物、口腔護理產品(例如潔齒劑及漱口劑)、化妝品(例如帶甜味的唇膏)及其他使用蔗糖、蔗糖素及/或其他甜味劑之個人護理產品。
一般而言,非處方(OTC)產品及口腔衛生產品通常係指可無需處方及/或無需訪問醫學專業人員所出售之用於家庭及/或個人用途之產品。OTC產品之實例包括但不限於維生素及膳食補充劑;局部止痛劑及/或麻醉劑;止咳藥、感冒藥及過敏藥;抗組胺藥及/或過敏藥;及其組合。維生素及膳食補充劑包括但不限於維生素、膳食補充劑、滋補品/瓶裝營養飲品、兒童專用維生素、膳食補充劑、任何其他營養產品或營養相關產品或可提供營養之產品、及其組合。局部止痛劑及/或麻醉劑包括用於緩解表皮或深處酸痛及疼痛(例如肌肉疼痛)之任何局部乳霜/軟膏/凝膠;出牙凝膠;含有止痛成份之貼劑;及其組合。止咳藥、感冒藥及過敏藥包括但不限於解充血藥、止咳藥、咽部製劑、藥物糖果、抗組胺藥及兒童專用止咳藥、感冒藥及過敏藥;及組合產品。抗組胺藥及/或過敏藥包括但不限於用於花粉症、鼻過敏症、昆蟲咬傷及叮咬之任何全身性治療劑。口腔衛生產品之實例包括但不限於口腔清潔條、牙膏、牙刷、漱口劑/牙科漱口劑、假牙護理液、口氣清新劑、家用型牙齒增白劑及牙線。
在另一實施例中,將本發明化合物添加至食物或飲料產品或調配物中。食物及飲料產品或調配物之實例包括但不限於食性產品之甜味包衣、糖霜或冰衣或以下類別中所包括之任一實體:湯料類、乾燥加工食物類、飲料類、即食餐(ready meal)類、罐裝或保藏食物類、冷凍(Frozen)加工食物類、冷卻(Chilled)加工食物類、點心食物類、烘焙食物類、糖果類、乳製品類、冰淇淋類、正餐替代品類、意大利麵(Pasta)及麵條類、及調料、敷料、佐料類、嬰兒食物類、及/或塗醬(Spreads)類。
一般而言,湯料類係指罐裝/保藏、脫水、速溶、冷卻、UHT及冷凍湯料。出於該定義之目的,湯意指自肉、禽肉、魚、蔬菜、穀類、水果及其他成份製得之食物,在可包括某些或所有該等成份之可見碎片的液體中烹調。其可為澄清的(例如肉湯)或為濃稠的(例如雜燴湯)、滑爽的、濃湯或黏厚的、現成的、半濃縮或濃縮湯且可作為一餐的第一道菜或主菜或作為兩餐間之點心趁熱或放涼食用(像喝飲料一般吮吸)。湯料可用作製備其他正餐組份之成份且可涵蓋肉湯(肉煮的清湯)至調料(基於奶油或奶酪之湯料)。「脫水及烹飪食物類」通常意指:(i)諸如下列等烹調輔助產品:佐料、粒料、漿料、濃縮液體產物(包括濃縮肉清湯、肉清湯及呈擠壓立方體、錠劑或粉末或顆粒形式之肉清湯樣產品),其可作為最終產品或作為產品、調料及什錦烹飪物(recipe mixes)之成份(與技術無關)單獨出售;(ii)諸如下列等餐用溶液產品:脫水及冷凍乾燥湯料,包括脫水什錦湯料、脫水速溶湯料、現成的湯料、現成菜肴、餐點及單獨提供主菜(entree)(包括意大利麵、馬鈴薯及稻米菜肴)之脫水或環境配製物;及(iii)諸如下列等餐點潤飾產品:調味品、醃泡汁、色拉敷料、色拉澆頭、澆汁、麵包屑、麵漿混料(batter mixes)、可長期保存的塗醬、燒烤調料、液體什錦烹調物、濃縮物、調料或什錦調料,包括用於色拉之什錦烹調物,作為最終產品或作為產品之成份出售,與脫水、液體抑或冷凍無關。
飲料類通常意指飲料、飲料混合料及濃縮物,包括但不限於含碳及不含碳之飲料、含酒精及不含酒精之飲料、即飲飲料、用於製備飲料之液體濃縮調配物(例如小蘇打)、及乾粉狀飲料前體混合料。飲料類亦包括含酒精飲品、軟飲品、運動飲品、等滲飲料及熱飲品。含酒精飲品包括但不限於啤酒、蘋果酒/梨酒、FAB、葡萄酒及烈性酒。軟飲品包括但不限於碳酸飲品,例如可樂及非可樂碳酸飲品;果汁,例如汁液、花蜜、果汁飲品及水果味飲品;瓶裝水,其包括汽水、泉水及純淨水/飲用水;功能性飲品,其可係含二氧化碳飲料或不起泡飲料且包括運動、能量或酏劑飲品(elixir drink);濃縮物,例如即飲量度之液體及粉末濃縮物。飲品(熱或冷)包括但不限於咖啡或冰咖啡,例如鮮咖啡、速溶咖啡及組合咖啡;茶或冰茶,例如黑茶、綠茶、白茶、烏龍茶及調味茶;及其他飲品,包括與牛奶或水混合且基於香料、麥芽或植物的粉末、顆粒、塊體或錠劑。
點心食物類通常係指可為非正式正餐之任一食物,其包括但不限於甜味及風味點心及點心棒(snack bar)。點心食物之實例包括但不限於水果點心、炸馬鈴薯豆條/薯片、擠出點心(extruded snacks)、墨西哥玉米餅(tortilla)/玉米片、爆米花、椒鹽脆餅乾、堅果及其他甜點及風味點心。點心棒之實例包括但不限於格蘭諾拉麥片(granola)/精力棒(muesli bars)、早餐棒、能量棒、水果棒及其他點心棒。烘焙食物類通常係指製備方法涉及暴露於熱或過量日光之任一食物性產品。烘焙食物之實例包括但不限於麵包、小麵包、曲奇、松餅、穀類食物、酥皮糕點、糕點、華夫餅(waffle)、墨西哥玉米餅、餅乾、餡餅、百吉餅(bagel)、塔類、乳蛋餅、蛋糕、任何烘焙食物及其任一組合。冰淇淋類通常係指含有奶油及糖及調味料之冷凍甜點。
冰淇淋之實例包括但不限於:現製冰淇淋(impulse ice cream);外賣冰淇淋;冷凍酸乳酪及手工冰淇淋;基於大豆、燕麥、豆類(例如、紅豆及綠豆)及大米之冰淇淋。糖果類通常係指有甜味的食物性產品。糖果之實例包括但不限於冰糖、膠糖、巧克力糖果、甜食、香口膠、及諸如此類及任一組合產品。正餐替代品類通常係指欲用於替代正餐之任一食物,尤其用於具有健康或體能問題的人。正餐替代品之實例包括但不限於減肥產品及康復期用產品(convalescence product)。
即食餐類通常係指無需大量準備工作或加工即可充當餐點之任一食物。即食餐包括製造者在製作時附加多種烹調「技巧」,因而十分快捷、完備且便於食用之產品。即食餐之實例包括但不限於罐裝/保藏、冷凍、乾燥、冷卻即食餐;什錦主餐(dinner mixes);冷凍比薩餅;冷卻比薩餅;及製好的色拉。
意大利麵及麵條類包括任何意大利麵及/或麵條包括但不限於罐裝、乾製及冷卻/鮮咖啡意大利麵;及陽春麵、方便麵、冷卻麵條、冷凍麵條及點心麵。
罐裝/保藏食物類包括但不限於罐裝/保藏肉及肉製品、魚/海鮮、蔬菜、番茄、豆類、水果、即食餐、湯料、意大利麵及其他罐裝/保藏食物。
冷凍加工食物類包括但不限於冷凍加工之紅色肉類、經加工之禽肉、經加工之魚/海鮮、經加工之蔬菜、肉替代品、經加工之馬鈴薯、焙烤產品、甜點、即食餐、比薩餅、湯料、麵條及其他冷凍食物。乾燥加工食物類包括但不限於大米、什錦甜點(dessert mixes)、幹製即食餐、脫水湯料、速溶湯料、乾製意大利麵、陽春麵及方便麵。
冷卻加工食物類包括但不限於冷卻加工肉、經加工之魚/海鮮產品、午餐便當(lunch kit)、鮮切水果、即食餐、比薩餅、製好的色拉、湯料、鮮意大利麵及麵條。調料、敷料及佐料類,包括但不限於蕃茄醬及番茄泥、肉清湯/濃縮固體湯料、香草及香料、麩胺酸單鈉(MSG)、桌上調料、基於大豆之調料、意大利麵調料、濕/烹調調料、乾調料/混合粉、調味醬、蛋黃醬、芥菜、色拉敷料、酸醬油、澆汁、醃製產品、及其他調料、敷料及佐料。嬰兒食物類包括(但不限於)基於牛奶或大豆之配方;及製好的、乾製及其他嬰兒食物。
塗醬類包括(但不限於)果醬及蜜餞、蜂蜜、巧克力塗醬、基於堅果之塗醬及基於酵母之塗醬。乳製品類通常係指自哺乳動物的奶製備之食物性產品。乳製品之實例包括但不限於飲用奶產品、奶酪、酸乳酪及酸奶飲品、及其他乳製品。食性組合物(尤其食物及飲料產品或調配物)之其他實例提供如下。例示性食性組合物包括下列中的一種或多種:糖果、巧克力糖果、錠劑、白巧克力(countline)、袋裝巧克力棒(selfline)/軟棒(softline)、盒裝品種、標準盒裝品種、扭結包裝小型物、季節性巧克力、玩具型巧克力、焦糖牛奶醬夾心餅乾(alfajores)、其他巧克力糖果、薄荷糖、標準薄荷糖、粉狀薄荷糖、硬糖、香錠、香口膠、果膠及咀嚼物、太妃糖、焦糖及牛軋糖、藥物糖果、棒棒糖、甘草、其他甜食、香口膠、口香糖、含糖香口膠、無糖香口膠、功能香口膠、泡泡糖、麵包、包裝/工業生產麵包、非包裝/手工生產麵包、糕點、蛋糕、包裝/工業生產蛋糕、非包裝/手工蛋糕、曲奇、塗有巧克力之餅乾、夾心餅乾、注心餅乾、開胃餅乾及脆餅、麵包替代品、早餐穀類食物、即食穀類製品、家庭早餐穀類製品、薄片餅乾、穆茲利(muesli)、其他即食穀類製品、兒童用早餐谷類製品、熱穀物製品(hot cereal)、冰淇淋、現製冰淇淋、單份乳製冰淇淋、單份水製冰淇淋、合裝包乳製冰淇淋、合裝包水製冰淇淋、外賣冰淇淋、外賣乳製冰淇淋、冰淇淋甜點、散裝冰淇淋(bulk ice cream)、外賣水製冰淇淋、冷凍酸乳、手工生產冰淇淋、乳製品、牛奶、新鮮/經加熱滅菌之牛奶、新鮮/經加熱滅菌之全脂牛奶、新鮮/經加熱滅菌之半脫脂牛奶、保存期較長/經超熱處理之牛奶、保存期較長/經超熱處理之全脂牛奶、保存期較長/經超熱處理之半脫脂牛奶、保存期較長/經超熱處理之脫脂牛奶、山羊奶、煉乳/脫水牛奶、原味煉乳/脫水牛奶、增味、功能性及其他煉乳、增味牛奶飲品、僅含乳製品之增味牛奶飲品、具有果汁之增味牛奶飲品、豆奶、酸味牛奶飲品、發酵乳製飲品、咖啡奶精(coffee whitener)、奶粉、增味奶粉飲品、奶油、奶酪、經加工奶酪、可塗開之經加工奶酪、不可塗開之經加工奶酪、未經加工奶酪、可塗開之未經加工奶酪、硬質奶酪、包裝硬質奶酪、未經包裝硬質奶酪、酸乳酪、原味/天然酸乳酪、增味酸乳酪、水果味酸乳酪、益生酸乳酪、優酪乳(drinking yoghurt)、一般飲用酸乳酪、益生飲用酸乳酪、冷卻及儲存穩定的甜點、乳製甜點、豆製甜點、冷卻點心、清爽乾酪及酸奶酪、原味清爽乾酪及酸奶酪、增味清爽乾酪及酸奶酪、開胃清爽乾酪及酸奶酪、甜味及開胃點心、水果點心、炸馬鈴薯條/薯片、擠出點心、墨西哥玉米餅/玉米片、爆米花、椒鹽卷餅、堅果、其他甜味及開胃點心、點心棒、格蘭諾拉麥片棒、早餐棒、能量棒、水果棒、其他點心棒、代餐產品、瘦身產品、康復期用飲品(convalescence drinks)、即食餐、罐裝即食餐、冷凍即食餐、乾燥即食餐、冷卻即食餐、什錦主餐、冷凍比薩餅、冷卻比薩餅、湯、罐裝湯、脫水湯料、速溶湯料、冷卻湯料、經超熱處理之湯料、冷凍湯料、意大利麵、罐裝意大利麵、乾燥意大利麵、冷卻/新鮮意大利麵、麵條、原味麵條、方便麵、杯狀/碗狀方便麵、袋裝方便麵、冷卻麵條、點心麵、罐裝食物、罐裝肉及肉製產品、罐裝魚/海產品、罐裝蔬菜、罐裝番茄、罐裝豆類、罐裝水果、罐裝即食餐、罐裝湯、罐裝意大利麵、其他罐裝食物、冷凍食物、冷凍加工紅肉、冷凍加工禽肉、冷凍加工魚/海產品、冷凍加工蔬菜、冷凍肉替代品、冷凍馬鈴薯、經烘箱焙烤之馬鈴薯片、其他經烘箱焙烤之馬鈴薯產品、未經烘箱焙烤之冷凍馬鈴薯、冷凍焙烤產品、冷凍甜點、冷凍即食餐、冷凍比薩餅、冷凍湯、冷凍麵條、其他冷凍食物、乾燥食物、什錦甜點、乾燥即食餐、脫水湯、速溶湯料、乾燥意大利麵、原味麵條、方便麵、杯裝/碗裝方便麵、袋裝方便麵、冷卻食物、冷卻經加工肉、冷卻魚/海產品產品、冷卻加工魚、冷卻魚(chilled coated fish)、冷卻燻製魚、冷卻午餐便當、冷卻即食餐、冷卻比薩餅、冷卻湯、冷卻/新鮮意大利麵、冷卻麵條、油脂、橄欖油、植物油及籽油、豬油(cooking fats)、黃油、人造黃油、可塗開油脂、功能性可塗開油脂、醬、敷料及調味品、番茄醬及番茄泥、肉清湯/濃縮固體湯料、濃縮固體湯料、肉質顆粒、液體原汁及溶化奶油(fonds)、草藥及香料、發酵醬、豆製醬、意大利麵醬、濕醬、幹調料/混合粉、調味醬、蛋黃醬、一般蛋黃醬、芥末、色拉敷料、一般色拉敷料、低脂色拉敷料、酸醬油、澆汁、醃製產品、其他醬、敷料及調味品、嬰兒食物、配方奶粉、標準配方奶粉、後續配方奶粉、幼兒配方奶粉、低過敏原配方奶粉、配製嬰兒食物、乾燥嬰兒食物、其他嬰兒食物、塗醬、果醬及蜜餞、蜂蜜、巧克力塗醬、堅果塗醬及發酵粉塗醬。實例性食性組合物亦包括糖果、焙烤產品、冰淇淋、乳製品、甜味及風味點心、點心棒、正餐替代品產品、即食餐、湯料、意大利麵、麵條、罐裝食物、冷凍食物、乾製食物、冷卻食物、油類及脂肪、嬰兒食物、或塗醬或其混合物。實例性食性組合物亦包括早餐穀類食物、甜飲料或用於製備飲料之固體或液體濃縮組合物,理想地,應能降低先前已知糖甜味劑或人造甜味劑之濃度。通常,將向可攝取組合物中添加至少甜味受體調節量、甜味受體配體調節量、甜味調節量、甜調味劑量或甜味增強量的一或多種本發明化合物,視情況在已知甜味劑存在下,例如,以使與未由本發明化合物製備之可攝取組合物相比,甜味經修飾之可攝取組合物具有增加之甜味,如由人類或動物大體上判定,或在調配物測試之情況下,由至少8名人類測味者之評定小組中之大多數人經由業內習知程序判定。
當然,調節或改善可攝取組合物之風味所需甜調味劑之濃度應視多種變量而定,包括可攝取組合物之特定類型及其各種其他成份,尤其所存在其他已知甜調味劑及其濃度、天然遺傳變異性及個人偏好及品嘗該等組合物之各人的健康狀況、及特定化合物對該等化學感受化合物之味覺的主觀效應。
本發明化合物之一個應用係用於調節(引發、增強或抑制)其他天然或合成甜味促味劑、及由其製成之可攝取組合物之甜味或其他味覺性質。在一個實施例中,本發明化合物係以其配體增強濃度使用或提供。舉例而言,通常可能需要本發明化合物或實體具有寬且低的濃度範圍(即,約0.001 ppm至100 ppm)或更窄之替代範圍,約0.1 ppm至約10 ppm、約0.01 ppm至約30 ppm、約0.05 ppm至約10 ppm、約0.01 ppm至約5 ppm、或約0.02 ppm至約2 ppm、或約0.01ppm至約1 ppm。在一個實施例中,本發明提供增甜組合物。該增甜組合物以有效甜化之量(例如,甜味增強量與甜味劑之第一量之組合)包含本發明化合物,其中該甜化強於不含該化合物之第一量甜味劑之甜化。在一個實施例中,本發明提供包含本發明增甜組合物之可攝取組合物。在某些實施例中,本發明可攝取組合物係呈以下形式:食物或飲料產品、醫藥組合物、營養產品、飲食補充劑、非處方藥物或口腔護理產品。在一個實施例中,本發明提供甜味劑替代組合物,其以有效甜化之量(例如,在不存在除本發明化合物以外的甜味劑(例如,蔗糖)時以高於其配體增強濃度之濃度)包含一或多種本發明化合物。
根據本發明之另一態樣,本發明化合物係提供於(例如)適於後續加工以產生即用(即,現成的)產品之調味濃縮調配物中。「調味濃縮調配物」意指應與一或多種稀釋介質以重建變成即用組合物之調配物。術語「即用組合物」在本文中可與「可攝取組合物」互換使用,其表示欲用於或不用於食用且可單獨或與另一物質一起經口服用之任一物質。在一個實施例中,即用組合物包括人類或動物可直接食用之組合物。調味濃縮調配物通常以與一或多種稀釋介質(例如,任一可食用或可攝取成份或產品)混合或經其稀釋之方式使用以賦予或修飾稀釋介質一或多種風味。此一使用過程通常稱為重建。重建可在家庭環境或工業環境中進行。例如,消費者可在廚房中將冷凍果汁濃縮物與水或其他水性介質重建以獲得即用果汁飲料。在另一實例中,製造商可以大工業規模將軟飲品糖漿濃縮物與水或其他水性介質重建以製造即用軟飲品。由於調味濃縮調配物中調味劑或風味修飾劑之濃度高於即用組合物,故調味濃縮調配物通常不適於不經重建即直接食用。使用及製造調味濃縮調配物具有諸多益處。舉例而言,由於調味濃縮調配物可在使用時藉由添加適宜溶劑、固體或液體進行重建,故一個益處係運輸重量及體積減小。
在一個實施例中,調味濃縮調配物包含i)本發明化合物作為風味修飾成份;ii)載劑;及iii)視情況至少一種佐劑、術語「風味修飾成份」表示在調配物中本發明化合物充當調味劑或風味修飾劑(例如增味劑)。術語「載劑」表示通常無活性的附屬物質,例如溶劑、黏合劑或其他惰性介質,其與本發明化合物及一或多種可選佐劑組合使用以形成調配物。舉例而言,水或澱粉可為調味濃縮調配物之載劑。在一些實施例中,載劑與用於重建調味濃縮調配物之稀釋介質相同;且在其他實施例中,載劑與該稀釋介質不同。本文所用術語「載劑」包括但不限於攝取上可接受之載劑。
術語「佐劑」表示可補充、穩定、維持或增強活性成份(例如本發明化合物)預期功能或效果的添加劑。在一個實施例中,至少一種佐劑包含一或多種調味劑。該調味劑可為任一熟習此項技術者或消費者已知之風味,例如巧克力、咖啡、茶、摩卡咖啡(mocha)、法國香草(French vanilla)、花生醬、印度奶茶(chai)、或其組合之風味。在另一實施例中,至少一種佐劑包含一或多種甜味劑。該一或多種甜味劑可為本申請案中所述之任一甜味劑。在另一實施例中,至少一種佐劑包含一或多種選自由下列組成之群之成份:乳化劑、穩定劑、抗微生物防腐劑、抗氧化劑、維生素、礦物質、脂肪、澱粉、蛋白濃縮物及分離物、鹽及其組合。乳化劑、穩定劑、抗微生物防腐劑、抗氧化劑、維生素、礦物質、脂肪、澱粉、蛋白濃縮物及分離物、及鹽之實例闡述於U.S. 6,468,576中,出於所有目的,該專利之全部內容以引用方式併入本文中。
在一個實施例中,本發明調味濃縮調配物可呈選自由下列組成之群之形式:液體(包括溶液及懸浮液)、固體、泡沫狀物質、糊、凝膠、乳霜、及其組合(例如含有一定量固體內含物之液體)。在一個實施例中,調味濃縮調配物係呈液體(包括水基及非水基)形式。本發明調味濃縮調配物可含碳或不含碳。
調味濃縮調配物可進一步包含凝固點降低劑、成核劑或二者作為至少一種佐劑。凝固點降低劑係可降低其中添加有化合物或試劑之液體或溶劑之凝固點的攝取上可接受之化合物或試劑。即,含有凝固點降低劑之液體或溶液比不含凝固點降低劑之液體或溶劑具有更低之凝固點。除降低最初凝固點以外,凝固點降低劑亦可降低調味濃縮調配物之水活性。凝固點降低劑之實例包括但不限於碳水化合物、油類、乙醇、多元醇(例如,甘油)及其組合。成核劑表示能促進成核之攝取上可接受之化合物或試劑。在調味濃縮調配物中存在成核劑可改良冷凍雪泥之口感且有助於在冷凍溫度下藉由增加合意之冰結晶中心之數量來維持雪泥之物理性質及性能。成核劑之實例包括但不限於矽酸鈣、碳酸鈣、二氧化鈦及其組合。
在一個實施例中,調味濃縮調配物經調配在預期貨架期期間具有低水活性。水活性係調配物中水之蒸汽壓與同一溫度下純水之蒸汽壓之比率。在一個實施例中,調味濃縮調配物具有小於約0.85之水活性。在另一實施例中,調味濃縮調配物具有小於約0.80之水活性。在另一實施例中,調味濃縮調配物具有小於約0.75之水活性。
在一個實施例中,調味濃縮調配物中本發明化合物之濃度為即用組合物中該化合物之濃度的至少2倍。在一個實施例中,調味濃縮調配物中本發明化合物之濃度為即用組合物中該化合物之濃度的至少5倍。在一個實施例中,調味濃縮調配物中本發明化合物之濃度為即用組合物中該化合物之濃度的至少10倍。在一個實施例中,調味濃縮調配物中本發明化合物之濃度為即用組合物中該化合物之濃度的至少15倍。在一個實施例中,調味濃縮調配物中本發明化合物之濃度為即用組合物中該化合物之濃度的至少20倍。在一個實施例中,調味濃縮調配物中本發明化合物之濃度為即用組合物中該化合物之濃度的至少30倍。在一個實施例中,調味濃縮調配物中本發明化合物之濃度為即用組合物中該化合物之濃度的至少40倍。在一個實施例中,調味濃縮調配物中本發明化合物之濃度為即用組合物中該化合物之濃度的至少50倍。在一個實施例中,調味濃縮調配物中本發明化合物之濃度為即用組合物中該化合物之濃度的至少60倍。在一個實施例中,調味濃縮調配物中本發明化合物之濃度為即用組合物中該化合物之濃度的至多100倍。
製備
用於製備本發明化合物之起始材料(即各種結構子類及種類的本發明式(I)化合物之合成前體化合物)通常為已知化合物或可藉由文獻中所述之已知方法來合成,或購自熟習此項技術者熟知之各種來源,例如,Sigma-Aldrich公司(St. Louis,Missouri USA)及其下屬公司Fluka and Riedel-de Haen,at其各個其他全球辦事處、及其他熟知化學供應商,例如Fisher Scientific、TCI America(Philadelphia,PA)、ChemDiv(San Diego,CA)、Chembridge(San Diego,CA)、Asinex(Moscow,Russia)、SPECS/BIOSPECS(the Netherlands)、Maybridge(Cornwall,England)、Acros、TimTec(Russia)、Comgenex(South San Francisco,CA)及ASDI Biosciences(Newark,DE)。
應認識到,有機化學領域之熟練技術人員可在未經進一步指導之情況下容易地實施許多起始材料之合成及後續處理,即,熟習此項技術者可熟練實施許多期望處理。該等包括將羰基化合物還原成其相應醇、氧化、醯基化、芳香族取代(親電取代或親核取代二者)、醚化、酯化、皂化、硝化、氫化、還原胺化及諸如此類。該等處理論述於標準教材中,例如March's Advanced Organic Chemistry(第3版,1985,Wiley-Interscience,New York);Feiser and Feiser's Reagents for Organic Synthesis;及oMethoden der Organischen Chemie(Houben-Weyl)之各個卷及版本;及諸如此類。用於製備起始材料之很多常見方法包含不同經取代之雜環、雜芳基及芳基環(Ar、hAr1及/或hAr2之前體)可見於Methoden der Organischen Chemie(Houben-Weyl)中,其各個卷及版本可自Georg Thieme Verlag,Stuttgart購得。上文所引用論文之全部揭示內容之全部內容以引用方式併入本文中關於合成有機化合物及其前體之方法之教示內容。
熟練技術人員亦將容易地瞭解,某些反應較佳在分子中官能基受遮蔽或受保護時實施,由此避免任何不合意之副反應及/或增加反應產率。熟練技術人員通常利用保護基團來達成該等增加之產率或避免不期望之反應。該等反應可見於文獻中且亦在熟練技術人員範疇內。多種該等處理之實例可見於(例如)T. Greene及P. Wuts,Protecting Groups in Organic Synthesis,第3版,John Wiley & Sons(1999)中。用於製備本發明化合物之一些實例性合成方法闡釋於下文反應圖1至4中。
反應圖1:自經取代之苯胺(I)製備經取代之4-胺基喹啉-3-甲酸酯衍生物(VI)
如反應圖1中所示,經取代4-胺基喹啉-3-甲酸酯衍生物(VI)可藉由以下方式來製備:使相應苯胺I與2-(烷氧基亞甲基)丙二酸酯II反應,隨後在高溫下使中間體III環化以提供羥基中間體IV,羥基中間體IV可經POCl3或SO2Cl2處理以提供相應氯化物衍生物V,氯化物衍生物V可進一步經氨或胺處理,得到期望胺基-喹啉VI。(Kamal,A.等人Bioorg. Med. Chem. 2005,13,2021-2029;Fryer,R. I.等人J. Med. Chem. 1993,36,1669-1673;Bi,Y.等人Bioorg. Med. Chem. Lett. 2004,14,1577-1580;Li,S. Y.等人Bioorg. Med. Chem. 2006,14,7370-376.;Koga,H.等人J. Med. Chem. 1980,23,1358-1363)。反應圖2:自經取代2-胺基苯甲酸衍生物(VIII)製備經取代4-胺基喹啉-3-甲酸酯衍生物(VI)
經取代4-胺基喹啉-3-甲酸酯衍生物(VI)亦可藉由以下方式來製備:使相應2-胺基苯甲酸VIII與光氣或等效物反應以提供衣托酸酐IX,衣托酸酐IX可進一步與X反應,得到衍生物IV(Mai,A.等人J. Med. Chem. 2006,49,6897-6907;Beutner,G. L.等人J. Org. Chem. 2007,72,7058-7061;及其中所引用之參考文獻),可如反應圖1中所述將衍生物IV轉化為VI。反應圖3:自經取代2-胺基苄腈衍生物(XI)製備經取代4-胺基喹啉-3-甲酸酯衍生物(VI)
另一選擇為,經取代4-胺基喹啉-3-甲酸酯衍生物(VI)可藉由以下方式來製備:使相應胺基苄腈XI與X反應以提供胺基衍生物XII(Sestili,I.等人Eur. J. Med. Chem. 2004,39,1047-1057;Doucet-Personeni,C.等人J. Med. Chem. 2001,44,3203-3215;Veronese,A. C.等人Tetrahedron 1995,51,12277-12284;及其中所引用之參考文獻),可進一步對胺基衍生物XII實施烷基化,得到經取代胺基喹啉VI,如反應圖3中所示。胺基喹啉XII亦可藉由以下方式來製備:經由2-胺基苄腈XI與各種α,β-不飽和甲酸酯衍生物XIII、XIV或XV之邁克爾加成(Michael addition)來提供加合物XVI(MacNab,H.等人Synthesis 2009,2171-2174;Vicario,J. L. Synthesis 2007,2065-2092;及其中所引用之參考文獻),可進一步對加合物XVI實施環化,得到胺基喹啉XII(Han,G. F.等人Synth. Commun. 2009,39,2492-2505;Tabarrini,O.等人Bioorg. Med. Chem. 2001,9,2921-2928;Shutske,G. M.等人J. Med. Chem. 1989,32,1805-1813;及其中所引用之參考文獻)。反應圖4:經取代4-胺基喹啉-3-甲酸(XVII、XX)及醯胺(XVIII及XXI)之製備
如反應圖4中所示,使4-胺基喹啉-3-甲酸酯衍生物VI或XII在NaOH存在下水解以提供4-胺基喹啉-3-甲酸XVII(Zhao,Y. L.等人Eur. J. Med. Chem. 2005,40,792-797.),可使4-胺基喹啉-3-甲酸XVII進一步與胺XXII在標準條件下偶合,得到4-胺基喹啉-3-甲醯胺衍生物XVIII。當R3及/或R4=H時,4-胺基喹啉-3-甲酸酯VI或XII可藉由與酸XXIII偶合來進一步官能化,得到4-甲醯胺基喹啉-3-甲酸酯XIX。
化合物XIX可進一步水解成酸XX,酸XX可進一步與胺XXII偶合以提供醯胺衍生物XXI。 實例 現在已概括地闡述本發明,參照下列實例可更容易地理解本發明,該等實例僅出於說明目的且非意欲對本發明加以限制。應理解可在不背離本發明之精神及範圍之情況下對本文所揭示例示性實施例進行各種修改及改變。實例1:4-胺基-6-甲氧基喹啉-3-甲酸
在室溫下向4-胺基-6-甲氧基喹啉-3-甲酸乙基酯(實例1a,1.23 g,5.0 mmol)於EtOH(20.0 mL)中之經攪拌溶液中添加NaOH水溶液(2.0 N,5.0 mL)。然後將反應混合物回流3小時。然後過濾所得溶液並用水洗滌。將濾液冷卻至0℃並用1 N HCl小心地中和至pH 7。在減壓下去除大部分EtOH,並藉由過濾收集沉澱,用冷水洗滌,並在真空下乾燥,得到呈灰白色固體形式之標題化合物(1.01 g,93%)。1H NMR(400 MHz,DMSO-d6)δ3.89(s,3H),7.40(dd,J=2.8,9.4 Hz,1H),7.73(d,J=9.4 Hz,1H),7.77(d,J=2.8 Hz,1H),8.77(s,1H)。MS 219(MH+)。
實例1a:4-胺基-6-甲氧基喹啉-3-甲酸乙基酯在110℃下在壓力反應器中將4-氯-6-甲氧基喹啉-3-甲酸乙基酯(實例1b,796 mg,3.0 mmol)及氨(25%水溶液,10mL)於異丙醇(40 mL)中之混合物攪拌過夜。然後在減壓下去除大部分溶劑,並用水稀釋反應混合物。藉由過濾收集沉澱,用冷水洗滌,並在真空下乾燥,得到呈灰白色固體形式之標題化合物(680 mg,92%)。1H NMR(400 MHz,DMSO-d6)δ1.33(t,J=7.0 Hz,3H),3.88(s,3H),4.32(q,J=7.0 Hz,2H),7.36(dd,J=2.8,8.8 Hz,1H),7.72(d,J=8.8 Hz,1H),7.74(d,J=2.8 Hz,1H),8.23(bs,2H),8.77(s,1H)。MS 247(MH+)。
實例1b:4-氯-6-甲氧基喹啉-3-甲酸乙基酯在氮下將4-羥基-6-甲氧基喹啉-3-甲酸乙基酯(實例1c,1.24 g,5.0 mmol)於POCl3中之溶液回流3小時,將溶液冷卻至室溫並在減壓下蒸發。用冰小心地淬滅殘餘物,並用2.0 N NaOH中和至pH 7。藉由過濾收集沉澱,用冷水洗滌,並在真空下乾燥,得到呈淺黃色固體形式之標題化合物(1.29 g,97%)。1H NMR(400 MHz,DMSO-d6)δ1.36(t,J=7.0 Hz,3H),3.96(s,3H),4.41(q,J=7.0 Hz,2H),7.57(d,J=2.8 Hz,1H),7.61(dd,J=2.8,8.8 Hz,1H),8.05(d,J=8.8 Hz,1H),8.97(s,1H)。MS 266,268(MH+)。
實例1c:4-羥基-6-甲氧基喹啉-3-甲酸乙基酯在120℃及氮下將4-甲氧基苯胺(12.3 g,100 mmol)及2-(乙氧基亞甲基)丙二酸二乙基酯(21.6 g,100 mmol)之混合物攪拌4小時。將溶液冷卻至室溫並添加Ph2O(100 mL)。在260℃及氮下將反應混合物回流8小時。將溶液冷卻至室溫並用己烷稀釋。藉由過濾收集所得沉澱,用存於己烷中之25%乙酸乙酯洗滌,並在真空下乾燥,得到呈淺黃色固體形式之4-羥基-6-甲氧基喹啉-3-甲酸乙基酯(4.21 g,17%)。1H NMR(400 MHz,DMSO-d6)δ1.26(t,J=7.0 Hz,3H),3.83(s,3H),4.19(q,J=7.0 Hz,2H),7.32(dd,J=3.2,9.6 Hz,1H),7.55(d,J=3.2 Hz,1H),7.56(d,J=9.6 Hz,1H),8.47(s,1H),12.27(s,1H)。MS 248(MH+)。
實例2:4-胺基-5-(2,2-二甲基-3-側氧基-3-(丙基胺基)丙氧基)-2-甲基-喹啉-3-甲酸
如實例1自4-胺基-5-(2,2-二甲基-3-側氧基-3-(丙基胺基)-丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例2a)進行製備,得到灰白色固體(41%)。1H NMR(400 MHz,DMSO-d6)δ0.73(t,J=7.6 Hz,3H),1.25(s,6H),1.33-1.42(m,2H),2.76(s,3H),3.00-3.05(m,2H),4.16(s,2H),7.01(d,J=8.0 Hz,1H),7.29(d,J=8.0 Hz,1H),7.67(t,J=8.0 Hz,1H),7.89(t,J=5.8 Hz,1H),8.85(bs,1H),12.28(bs,1H),12.78(bs,1H)。MS 360(MH+)。
實例2a:4-胺基-5-(2,2-二甲基-3-側氧基-3-(丙基胺基)丙氧基)-2-甲基喹啉-3-甲酸乙基酯在室溫及氮下經由注射向3-(3-胺基-2-氰基苯氧基)-2,2-二甲基-N-丙基丙-醯胺(Tachdjian,C.等人PCT Int. Appl. 2008,WO 2008154221,1.38 g,5.0 mmol)及乙醯乙酸乙酯(0.66 g,5.0 mmol)於無水甲苯(150 mL)中之溶液中逐滴添加SnCl4(2.61 g,10.0 mmol)。在在室溫下放置1小時後,再將反應混合物回流5小時。將溶液冷卻至室溫並在減壓下去除溶劑。用EtOAc稀釋殘餘物,並在室溫下添加NaOH水溶液(2N)至pH>8。過濾溶液並分離出有機層。用EtOAc(5X)萃取水層。用鹽水洗滌合併之有機層,並經Na2SO4乾燥。在溶劑蒸發後,藉由在矽膠上實施層析(存於EtOAc中之0.5% MeOH)來純化殘餘物,得到呈灰白色固體形式之標題化合物(1.63 g,84%)。1H NMR(400 MHz,DMSO-d6)δ0.73(t,J=7.6 Hz,3H),1.25(s,6H),1.32(t,J=7.4 Hz,3H),1.35-1.42(m,2H),2.54(s,3H),3.00-3.05(m,2H),4.12(s,2H),4.31(q,J=7.4 Hz,2H),6.87(d,J=8.0 Hz,1H),7.23(d,J=8.0 Hz,1H),7.50(t,J=8.0 Hz,1H),7.80(t,J=5.6 Hz,1H),8.08(s,2H)。MS 388(MH+)。
實例3:4-胺基-6-甲氧基-2-甲基喹啉-3-甲酸
如實例1自4-胺基-6-甲氧基-2-甲基喹啉-3-甲酸乙基酯(實例3a)進行製備,得到白色固體(87%)。1H NMR(400 MHz,DMSO-d6)δ2.83(s,3H),3.90(s,3H),7.57(dd,J=2.4,8.2 Hz,1H),8.09(d,J=8.2 Hz,1H),8.10(d,J=2.4 Hz,1H),9.39(s,1H),9.67(s,1H)。MS 233(MH+)。實例3a:4-胺基-6-甲氧基-2-甲基喹啉-3-甲酸乙基酯如實例2a自2-胺基-5-甲氧基苄腈(Campbell,J. B.等人Synth. Commun. 1989,19,2255-2263.)及乙醯乙酸乙酯進行製備,得到灰白色固體(92%)。1H NMR(400 MHz,DMSO-d6)δ1.33(t,J=6.8 Hz,3H),2.57(s,3H),3.86(s,3H),4.33(q,J=6.8 Hz,2H),7.28(dd,J=2.8,9.2 Hz,1H),7.59(d,J=9.2 Hz,1H),7.60(bs,2H),7.63(d,J=2.8 Hz,1H)。MS 261(MH+)。
實例4:4-胺基-2-苯基喹啉-3-甲酸
如實例1自4-胺基-2-苯基喹啉-3-甲酸乙基酯(實例4a)進行製備,得到灰白色固體(33%)。1H NMR(400 MHz,DMSO-d6)δ7.39-7.52(m,7H),7.79(m,3H),8.33(d,J=8.0 Hz,1H),12.63(bs,1H)。MS 265(MH+)。實例4a:4-胺基-2-苯基喹啉-3-甲酸乙基酯如實例2a自2-胺基苄腈及3-側氧基-3-苯基丙酸乙基酯進行製備,得到黃色固體(45%)。1H NMR(400 MHz,DMSO-d6)δ0.72(t,J=8.0 Hz,3H),3.92(q,J=8.0 Hz,2H),7.44(m,5H),7.50(m,1H),7.61(bs,2H),7.73(m,1H),7.83(d,J=8.0 Hz,1H),8.37(d,J=8.0 Hz,1H)。MS 293(MH+)。實例5:4-胺基-2-乙基喹啉-3-甲酸
如實例2自4-胺基-2-乙基喹啉-3-甲酸甲基酯(實例5a)進行製備,得到白色固體(26%)。1H NMR(400 MHz,DMSO-d6+1滴D2O)δ1.24(t,J=8.0 Hz,3H),3.28(q,J=8.0 Hz,2H),7.56(t,J=8.0 Hz,1H),7.78(d,J=8.0 Hz,1H),7.83(t,J=8.0 Hz,1H),8.36(d,J=8.0 Hz,1H)。MS 217(MH+)。實例5a:4-胺基-2-苯基喹啉-3-甲酸乙基酯如實例2a自2-胺基苄腈及3-側氧基戊酸甲基酯進行製備,得到固體(27%)。1H NMR(400 MHz,DMSO-d6)δ1.18(t,J=8.0 Hz,3H),2.88(q,J=8.0 Hz,2H),3.86(s,3H),7.40(m,1H),7.44(bs,2H),7.64(m,1H),7.68(m,1H),8.26(d,J=8.0 Hz,1H)。MS 231(MH+)。實例6:4-胺基-2-甲基喹啉-3-甲酸
如實例1自4-胺基-2-甲基喹啉-3-甲酸乙基酯(實例6a)進行製備,得到灰白色固體(41%)。1H NMR(400 MHz,DMSO-d6)δ1.05(t,J=8.0 Hz,3H),2.84(s,3H),7.56(bs,1H),7.76(m,1H),7.82(bs,1H),8.39(d,J=8.0 Hz,1H),8.99(bs,1H),12.00(bs,1H),12.98(bs,1H)。MS 203(MH+)。實例6a:4-胺基-2-甲基喹啉-3-甲酸乙基酯如實例2a自2-胺基苄腈及3-側氧基丁酸乙基酯進行製備,得到黃色固體(32%)。1H NMR(400 MHz,DMSO-d6)δ1.33(t,J=8.0 Hz,3H),2.61(s,3H),4.34(q,J=8.0 Hz,2H),7.41(m,1H),7.66(m,2H),7.74(bs,2H),8.27(d,J=8.0 Hz,1H)。MS 231(MH+)。實例7:4-胺基-5-(2,2-二甲基-3-側氧基-3-(丙基胺基)丙氧基)-2-乙基-喹啉-3-甲酸
如實例1自4-胺基-5-(2,2-二甲基-3-側氧基-3-(丙基胺基)丙氧基)-2-乙基喹啉-3-甲酸甲基酯(實例7a)進行製備,得到固體(75%)。1H NMR(400 MHz,DMSO-d6)δ0.75(t,J=8.0 Hz,3H),1.03(t,J=8.0 Hz,3H),1.27(s,6H),1.39(m,2H),3.04(q,J=4.0 Hz,2H),3.45(q,J=4.0 Hz,2H),4.17(s,2H),7.04(d,J=8.0 Hz,1H),7.32(d,J=8.0 Hz,1H),7.69(t,J=8.0 Hz,1H),7.90(t,J=4.0 Hz,1H),8.89(bs,1H),12.75(bs,1H)。MS 374(MH+)。實例7a:4-胺基-5-(2,2-二甲基-3-側氧基-3-(丙基胺基)丙氧基)-2-乙基喹啉-3-甲酸甲基酯如實例2a自3-(3-胺基-2-氰基苯氧基)-2,2-二甲基-N-丙基丙-醯胺(Tachdjian,C.等人PCT Int. Appl. 2008,WO 2008154221)及3-側氧基戊酸甲基酯進行製備,得到黃色固體(17%)。1H NMR(400 MHz,DMSO-d6)δ0.75(t,J=8.0 Hz,3H),1.17(t,J=8.0 Hz,3H),1.26(s,6H),1.40(m,2H),2.84(q,J=8.0 Hz,2H),3.04(q,J=8.0 Hz,2H),3.85(s,3H),4.13(s,2H),6.88(d,J=8.0 Hz,1H),7.27(dd,J=8.0 Hz,1H),7.51(t,J=8.0 Hz,1H),7.81(m,3H)。MS 388(MH+)。實例8:4-胺基-6-苯氧基喹啉-3-甲酸
如實例1自4-胺基-6-苯氧基喹啉-3-甲酸乙基酯(實例8a)進行製備,得到灰白色固體(50%)。1H NMR(400 MHz,DMSO-d6)δ7.07(d,J=8.0 Hz,2H),7.16(t,J=8.0 Hz,1H),7.42(m,2H),7.49(dd,J=8.0 Hz,1H),7.87(d,J=8.0 Hz,1H),8.13(d,J=4.0 Hz,1H),8.86(s,1H)。MS 281(MH+)。實例8a:4-胺基-6-苯氧基喹啉-3-甲酸乙基酯如實例1a自4-氯-6-苯氧基喹啉-3-甲酸乙基酯(實例8b)及氨進行製備,得到灰白色固體(82%)。1H NMR(400 MHz,DMSO-d6)δ1.35(t,J=8.0 Hz,3H),4.35(q,J=8.0 Hz,2H),7.05(d,J=8.0 Hz,2H),7.15(t,J=8.0 Hz,1H),7.40(m,d,2H),7.46(dd,J=8.0 Hz,1H),7.87(d,J=8.0 Hz,1H),8.13(d,J=4.0 Hz,1H),8.27(bs,2H),8.87(s,1H)。MS 309(MH+)。實例8b:4-氯-6-苯氧基喹啉-3-甲酸乙基酯如實例1b自4-羥基-6-苯氧基喹啉-3-甲酸乙基酯(實例8c)及POCl3進行製備,得到棕褐色固體(96%)。1H NMR(400 MHz,DMSO-d6)δ1.36(t,J=8.0 Hz,3H),4.40(q,J=8.0 Hz,2H),7.23(d,J=8.0 Hz,2H),7.29(t,J=8.0 Hz,1H),7.50(t,J=8.0 Hz,2H),7.63(d,J=4.0 Hz,1H),7.76(dd,J=8.0 Hz,1H),8.21(d,J=8.0 Hz,1H),9.06(s,1H)。MS 328,330(MH+)。實例8c:4-羥基-6-苯氧基喹啉-3-甲酸乙基酯如實例1c自4-苯氧基苯胺及2-(乙氧基亞甲基)丙二酸二乙基酯進行製備,得到白色固體(41%)。1H NMR(400 MHz,DMSO-d6)δ1.24(t,J=8.0 Hz,3H),4.18(q,J=8.0 Hz,2H),7.07(d,J=8.0 Hz,2H),7.20(t,J=8.0 Hz,1H),7.43(t,J=8.0 Hz,2H),7.47(m,2H),7.69(d,J=12.0 Hz,1H),12.39(bs,1H)。MS 310(MH+)。
實例9:4-胺基-7-氟喹啉-3-甲酸
如實例1自乙基4-胺基-7-氟喹啉-3-甲酸酯(實例9a)進行製備,得到灰白色固體(66%)。1H NMR CD3OD,400 MHz)δ.7.49(m,2H),8.50(dd,J=10.0,5.2 Hz,1H),8.94(s,1H)。MS 207(MH+)。實例9a:4-胺基-7-氟喹啉-3-甲酸乙基酯如實例1a自4-氯-7-氟喹啉-3-甲酸乙基酯(實例9b)及氨進行製備,得到灰白色固體(99%)。MS 235(MH+)。實例9b:4-氯-7-氟喹啉-3-甲酸乙基酯如實例1b自7-氟-4-羥基喹啉-3-甲酸乙基酯(實例9c)及POCl3進行製備,得到灰白色固體(96%)。MS 254,256(MH+)。
實例9c:7-氟-4-羥基喹啉-3-甲酸乙基酯如實例1c自3-氟苯胺及2-(乙氧基亞甲基)丙二酸二乙基酯進行製備,得到褐色固體(51%)。MS 236(MH+)。實例10:4-胺基-6-異丙氧基喹啉-3-甲酸
如實例1自4-胺基-6-異丙氧基喹啉-3-甲酸乙基酯(實例10a)進行製備,得到灰白色固體(94%)。1H NMR(400 MHz,DMSO-d6)δ1.30(s,3H),1.32(s,3H),4.82(m,1H),7.37(d,J=9.2 Hz,1H),7.72(d,J=9.2 Hz,1H),7.78(s,1H),8.75(s,1H)。MS 247(MH+)。實例10a:4-胺基-6-異丙氧基喹啉-3-甲酸乙基酯如實例1a自4-氯-6-異丙氧基喹啉-3-甲酸乙基酯(實例10b)及氨進行製備,得到灰白色固體(75%)。MS 275(MH+)。實例10b:4-氯-6-異丙氧基喹啉-3-甲酸酯如實例1b自4-羥基-6-異丙氧基喹啉-3-甲酸乙基酯(實例10c)及POCl3進行製備,得到淺黃色固體(93%)。MS 294,296(MH+)。實例10c:4-羥基-6-異丙氧基喹啉-3-甲酸乙基酯如實例1c自4-異丙氧基苯胺及2-(乙氧基亞甲基)丙二酸二乙基酯進行製備,得到黃色固體(20%)。MS 276(MH+)。實例11:4-胺基-6-甲氧基-2-甲基-1,5-萘啶-3-甲酸
如實例1自4-胺基-6-甲氧基-2-甲基-1,5-萘啶-3-甲酸乙基酯(實例11a)進行製備,得到灰白色固體(56%)。1H NMR(400 MHz,DMSO-d6)δ2.68(s,3H),4.02(s,3H),7.21(d,J=8.8 Hz,1H),7.99(d,J=9.2 Hz,1H)。MS 234(MH+)。
實例11a:4-胺基-6-甲氧基-2-甲基-1,5-萘啶-3-甲酸乙基酯如實例2a自3-胺基-6-甲氧基-2-氰基吡啶(實例11b)及3-側氧基丁酸乙基酯進行製備,得到灰白色固體(45%)。MS 262(MH+)。
實例11b:3-胺基-6-甲氧基-2-氰基吡啶在0℃下向6-甲氧基-3-硝基-2-氰基吡啶(Piersanti,G.等人Org. Biomolecular Chem. 2007,5,2567-2571.)(2.0 g,11.1 mmol)於二甘醇二甲醚(52 mL)中之溶液中逐滴添加SnCl2(6.35 g,33.5 mmol)於濃HCl溶液(26 mL)中之溶液。在0℃下將溶液攪拌1小時,然後用濃NaOH溶液中和反應混合物,並用EtOAc(2X)萃取。用鹽水洗滌合併之有機層,並經Na2SO4乾燥。在溶劑蒸發後,藉由在矽膠上實施層析(存於己烷中之50% EtOAc)來純化殘餘物,得到呈褐色固體形式之3-胺基-6-甲氧基-2-氰基吡啶(966 mg,58%)。1H NMR(400 MHz,CDCl3)δ3.81(s,3H),4.10(bs,2H),6.81(d,J=8.0 Hz,1H),7.08(d,J=8.0 Hz,1H)。MS 150(MH+)。
實例12:4-胺基-2,5-二甲基喹啉-3-甲酸
將4-(4-甲氧基苄基胺基)-2,5-二甲基喹啉-3-甲酸乙基酯(實例12a,0.563 g,1.54 mmol)溶於TFA(8 mL)中並在室溫下將所得溶液攪拌15分鐘,然後在真空下去除TFA,得到粗製4-胺基-2,5-二甲基喹啉-3-甲酸乙基酯產物,將其溶於EtOH(4 mL)中。向該溶液中添加NaOH(4.0 N,3.86 mL)並在100℃下將反應混合物攪拌1小時。添加水(25 mL),並自不溶材料傾析除去溶劑,然後用AcOH酸化至pH 5.5。藉由過濾收集沉澱,得到呈白色固體形式之標題化合物(300 mg,90%)。1H NMR(400 MHz,DMSO-d6)δ2.78(s,3H),2.88(s,3H),7.30(d,J=7.2 Hz,1H),7.58(d,J=8.0 Hz,1H),7.65(m,1H),7.8-8.0(br,1H),12.2-12.9(br,2H)。MS 217(MH+)。
實例12a:4-(4-甲氧基苄基胺基)-2,5-二甲基喹啉-3-甲酸乙基酯在115℃及氮下將4-氯-2,5-二甲基喹啉-3-甲酸乙基酯(實例12b,0.518 g,1.96 mmol)及(4-甲氧基苯基)甲胺(1.15 mL,8.86 mmol)於甲苯(10 mL)及DMF(5 mL)中之溶液攪拌12小時。在真空下去除溶劑,並藉由在矽膠上實施層析(存於己烷中之0%至50% EtOAc)來純化殘餘物,得到油狀標題化合物(563 mg,79%)。1H NMR(400 MHz,DMSO-d6)δ1.24(t,J=7.6 Hz,3H),2.45(s,3H),2.78(s,3H),3.73(s,3H),4.2-4.3(m,4H),6.27(t,J=6.0 Hz,1H),6.88(d,J=8.4 Hz,2H),7.19(m,3H),7.48(m,1H),7.58(d,J=8.4 Hz,1H)。MS 365(MH+)。
實例12b:4-氯-2,5-二甲基喹啉-3-甲酸乙基酯在氮下將5-甲基-1H-苯并[d][1,3]噁嗪-2,4-二酮(實例12c)(1.36 g,7.68 mmol)、3-側氧基丁酸乙基酯(1.46 mL,11.5 mmol)及NaOH(0.046 g,1.15 mmol)於無水二噁烷(10 mL)中之溶液回流15小時。然後在真空下去除溶劑,並將殘餘物重新溶於DMF(15 mL)中。向該溶液中添加POCl3(1.41 mL,15.4 mmol),並在室溫下將反應混合物攪拌45分鐘。用冰水(150 mL)小心地淬滅反應,並用DCM(2×75 mL)萃取。用鹽水洗滌合併之有機層,並經Na2SO4乾燥。在溶劑蒸發後,藉由層析在矽膠上利用存於己烷中之50% EtOAc洗脫來純化殘餘物,得到紅色油狀標題化合物(520 mg,26%)。1H NMR(400 MHz,DMSO-d6)δ1.36(t,J=7.6 Hz,3H),2.58(s,3H),2.97(s,3H),4.46(q,J=7.6Hz,2H),7.51(d,J=7.2 Hz,1H),7.71(m,1H),7.87(d,J=7.6 Hz,1H)。MS 264,266(MH+)。實例12c:5-甲基-1H-苯并[d][1,3]噁嗪-2,4-二酮在氮下將氯甲酸三氯甲基酯(2.04 mL,16.9 mmol)添加至存於無水二噁烷(32 mL)中之2-胺基-6-甲基苯甲酸(2.13 g,14.1 mmol)中,然後回流30分鐘。添加乙醚(100 mL),並藉由過濾收集所沉澱固體,得到5-甲基-1H-苯并[d][1,3]噁嗪-2,4-二酮(1.4 g,56%),其未經進一步純化即使用。
實例13:4-胺基-6-乙氧基喹啉-3-甲酸
如實例1自4-胺基-6-乙氧基喹啉-3-甲酸乙基酯(實例13a)進行製備,得到灰白色固體(76%)。1H NMR(400 MHz,DMSO-d6)δ1.39(t,J=7.2 Hz,3H),4.18(q,J=7.2 Hz,2H),7.50-7.53(m,1H),7.86(d,J=8.8 Hz,1H),7.95(d,J=2.0 Hz,1H),8.86(s,1H),9.26(bs,1H),9.86(bs,1H)。MS 233(MH+)。
實例13a:4-胺基-6-乙氧基喹啉-3-甲酸乙基酯如實例1a自4-氯-6-乙氧基喹啉-3-甲酸乙基酯(實例13b)及氨進行製備,得到灰白色固體(77%)。1H NMR(400 MHz,DMSO-d6)δ1.31-1.40(m,6H),4.15(q,J=7.2 Hz,2H),4.31(q,J=6.8 Hz,2H),7.34(q,J=6.4 Hz,1H),7.69-7.74(m,2H),8.21(bs,2H),8.77(s,1H)。MS 261(MH+)。實例13b:4-氯-6-乙氧基喹啉-3-甲酸乙基酯如實例1b自6-乙氧基-4-羥基喹啉-3-甲酸乙基酯(實例13c)及POCl3進行製備,得到淺黃色固體(100%)。1H NMR(400 MHz,DMSO-d6)δ1.34-1.42(m,6H),4.21(q,J=7.2 Hz,2H),4.40(q,J=7.2 Hz,2H),7.52(d,J=2.8 Hz,1H),7.56-7.59(m,1H),8.02(d,J=8.8 Hz,1H),8.94(s,1H)。MS 280,282(MH+)。
實例13c:6-乙氧基-4-羥基喹啉-3-甲酸乙基酯如實例1c自4-乙氧基苯胺及2-(乙氧基亞甲基)丙二酸二乙基酯進行製備,得到白色固體(26%)。1H NMR(400 MHz,DMSO-d6)δ1.24-1.37(m,6H),4.09(q,J=6.8 Hz,2H),4.19(q,J=7.2 Hz,2H),7.29-7.32(m,1H),7.52-7.56(m,2H),8.47(s,1H),12.27(s,1H)。MS 262(MH+)。
實例14:4-胺基-6-丙氧基喹啉-3-甲酸
如實例1自4-胺基-6-丙氧基喹啉-3-甲酸乙基酯(實例14a)進行製備,得到白色固體(56%)。1H NMR(400 MHz,DMSO-d6)δ1.01(t,J=7.6 Hz,3H),1.77-1.82(m,2H),4.06(t,J=6.8 Hz,2H),7.43(d,J=2.0 Hz,1H),7.71-7.78(m,2H),8.77(s,1H)。MS 247(MH+)。實例14a:4-胺基-6-丙氧基喹啉-3-甲酸酯如實例1a自4-氯-6-丙氧基喹啉-3-甲酸乙基酯(實例14b)及氨進行製備,得到白色固體。MS 275(MH+)。實例14b:4-氯-6-丙氧基喹啉-3-甲酸乙基酯如實例1b自4-羥基-6-丙氧基喹啉-3-甲酸乙基酯(實例14c)及POCl3進行製備,得到淺黃色固體。MS 294,296(MH+)。實例14c:4-羥基-6-丙氧基喹啉-3-甲酸乙基酯如實例1c自4-丙氧基苯胺及2-(乙氧基亞甲基)丙二酸二乙基酯進行製備,得到白色固體(65%)。1H NMR(400 MHz,DMSO-d6)δ0.98(t,J=7.2 Hz,3H),1.25(t,J=7.2 Hz,3H),1.72-1.77(m,2H),3.98(t,J=6.0 Hz,2H),4.16-4.21(m,2H),6.97-6.99(m,1H),7.53-7.56(m,2H),8.47(d,J=5.2 Hz,1H),12.27(s,1H)。MS 276(MH+)。
實例15:4-胺基-5-甲氧基-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-甲氧基-2-甲基喹啉-3-甲酸乙基酯(實例15a)進行製備,得到灰白色固體。1H NMR(400 MHz,DMSO-d6)δ2.49(s,3H),4.05(s,3H),7.19(d,J=7.6 Hz,1H),7.61(d,J=8.0 Hz,1H),7.85(t,J=8.0 Hz,1H),9.49(s,1H),9.85(s,1H)。MS 233(MH+)。實例15a:4-胺基-5-甲氧基-2-甲基喹啉-3-甲酸乙基酯如實例2a自2-胺基-6-甲氧基苄腈及3-側氧基丁酸乙基酯進行製備,得到淺黃色固體。1H NMR(400 MHz,DMSO-d6)δ1.32(t,J=7.2 Hz,3H),2.55(s,3H),3.96(s,3H),4.30(q,J=7.2 Hz,2H),6.88(d,J=8.4 Hz,1H),7.22(d,J=7.6 Hz,1H),7.52(t,J=8.0 Hz,1H),8.15(s,2H。MS 261(MH+)。實例16:4-胺基-2-甲基-5-(新戊基氧基)喹啉-3-甲酸
如實例1自4-胺基-2-甲基-5-(新戊基氧基)喹啉-3-甲酸乙基酯(實例16a)進行製備,得到白色固體。1H NMR(400MHz,DMSO-d6)δ1.06(s,9H),2.76(s,3H),3.93(s,2H),7.05(d,J=8.4 Hz,1H),7.31(d,J=8.0 Hz,1H),7.66(t,J=8.0 Hz,1H)。MS 289(MH+)。實例16a:4-胺基-2-甲基-5-(新戊基氧基)喹啉-3-甲酸乙基酯如實例2a自2-胺基-6-(新戊基氧基)苄腈(Tachdjian,C.等人PCT Int. Appl. 2008,WO 2008154221)及3-側氧基丁酸乙基酯進行製備,得到白色固體(64%)。1H NMR(400 MHz,DMSO-d6)δ1.06(s,9H),1.32(t,J=6.8 Hz,3H),2.54(s,3H),3.86(s,2H),4.31(q,J=6.8 Hz,2H),6.88-6.91(m,1H),7.22-7.25(m,1H),7.50(t,J=8.0 Hz,1H),8.06(s,2H)。MS 317(MH+)。
實例17:4-胺基-2-(羧甲基)喹啉-3-甲酸
如實例1自4-胺基-2-(2-乙氧基-2-側氧基乙基)喹啉-3-甲酸乙基酯(實例17a)進行製備,得到白色固體(26%)。1H NMR(400 MHz,DMSO-d6)δ3.76(s,2H),7.36(t,J=8.0 Hz,1H),7.58(t,J=8.0 Hz,1H),7.64(d,J=12.0 Hz,1H),7.87(bs,2H),8.17(d,J=8.0 Hz,1H)。MS 188(MH+-CH2CO2H)。實例17a:4-胺基-2-(2-乙氧基-2-側氧基乙基)喹啉-3-甲酸乙基酯
如實例2a自2-胺基苄腈及3-側氧基戊二酸二乙基酯進行製備,得到淺黃色固體(25%)。1H NMR(400 MHz,DMSO-d6)δ1.19(t,J=8.0 Hz,3H),1.30(t,J=8.0 Hz,3H),4.08(m,4H),4.28(q,J=8.0 Hz,2H),7.50(m,1H),7.73(m,2H),8.10(bs,2H),8.53(d,J=8.0 Hz,1H)。MS 303(MH+)。實例18:4-胺基-5-(環戊基甲氧基)-2-甲基喹啉-3-甲酸
在室溫下向4-胺基-5-(環戊基甲氧基)-2-甲基喹啉-3-甲酸乙基酯(實例18a,16.8 g,51.2 mmol)於EtOH(100 mL)中之溶液中添加NaOH(2 N,64 mL)。將反應混合物回流4 h。在將其冷卻至室溫後,過濾反應溶液以去除任一可能之固體殘餘物。在0℃下用2N HCl小心地將濾液中和至pH 7,藉由過濾收集所得沉澱,用水洗滌,重新溶於EtOH(500 mL)及水(30 mL)中,並在70℃下用活性炭(650 mg)處理0.5 h。藉由過濾去除炭,並濃縮濾液並在4℃下儲存過夜。藉由過濾收集所得沉澱,用冷的存於H2O中之25% EtOH洗滌,並在真空及60℃下乾燥過夜,得到呈灰白色固體形式之標題化合物(7.5 g,49%)。1H NMR(400 MHz,DMSO-d6)δ1.31-1.37(m,2H),1.53-1.64(m,4H),1.79-1.85(m,2H),2.47-2.50(m,1H),2.75(s,3H),4.11(d,J=8.8 Hz,2H),7.03(d,J=8.0 Hz,1H),7.26(d,J=8.4 Hz,1H),7.66(t,J=8.0 Hz,1H),8.77(brs,1H),12.26(brs,1H),12.75(brs,1H)。1H NMR(400 MHz,CD3OD)δ1.39-1.49(m,2H),1.63-1.77(m,4H),1.91-1.98(m,2H),2.51-2.61(m,1H),2.78(s,3H),4.16(d,J=8.0 Hz,2H),7.08(d,J=8.0 Hz,1H),7.23(d,J=8.0 Hz,1H),7.72(t,J=8.0 Hz,1H)。MS 301(MH+)。實例18a:4-胺基-5-(環戊基甲氧基)-2-甲基喹啉-3-甲酸乙基酯在室溫及氮下經25分鐘時間向2-胺基-6-(環戊基甲氧基)苄腈(Tachdjian,C.等人PCT Int. Appl.2008,WO 2008154221)(21.63 g,100.0 mmo1)及乙醯乙酸乙酯(12.6 mL,100.0 mmol)於無水甲苯(300 mL)中之溶液中添加SnCl4(23.1 mL,200.0 mmol)。然後在氮下將經攪拌反應混合物回流5h。在將其冷卻至室溫後,在減壓下濃縮反應溶液以去除大部分溶劑。將殘餘物重新溶於EtOAc(3.5 L)中並在0℃下用NaOH水溶液(6.0 N,約130 mL)小心地中和至pH 8。在室溫下將所得混合物攪拌過夜。濾除沉澱,並分離出有機層並用鹽水(400 mL)洗滌,經Na2SO4乾燥並在減壓下濃縮。藉由管柱層析在矽膠上利用存於己烷中之30% EtOAc洗脫來純化殘餘物,得到呈淺黃色固體形式之標題化合物(24.6 g,75%)。1H NMR(400 MHz,DMSO-d6)δ1.30-1.36(m,5H),1.53-1.65(m,4H),1.81-1.86(m,2H),2.42-2.45(m,1H),2.54(s,3H),4.05(d,J=7.2 Hz,2H),4.31(q,J=7.2 Hz,2H),6.89(d,J=7.6 Hz,1H),7.21-7.23(m,1H),7.50(t,J=8.0 Hz,1H),8.08(s,2H)。MS 329(MH+)。
實例19:4-胺基-5-(環戊基氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(環戊基氧基)-2-甲基喹啉-3-甲酸乙基酯(實例19a)進行製備,得到灰白色固體(83%)。1H NMR(400 MHz,DMSO-d6)δ1.56-1.60(m,2H),1.67-1.70(m,2H),1.83-1.87(m,2H),1.92-1.96(m,2H),2.67(s,3H),5.05-5.07(m,1H),6.93(d,J=8.4 Hz,1H),7.18(d,J=8.4 Hz,1H),7.57(t,J=8.4 Hz,1H)。MS 287(MH+)。實例19a:4-胺基-5-(環戊基氧基)-2-甲基喹啉-3-甲酸乙基酯如實例2a自2-胺基-6-(環戊基氧基)苄腈(Tachdjian,C.等人PCT Int. Appl. 2008,WO 2008154221)及3-側氧基丁酸乙基酯進行製備,得到黃色固體(40%)。MS 315(MH+)。實例20:4-胺基-2,3-丁烯-6-甲基噻吩并[2,3-b]吡啶-5-甲酸
如實例1自4-胺基-2,3-丁烯-6-甲基噻吩并[2,3-b]吡啶-5-甲酸乙基酯(實例20a)進行製備,得到固體。1H NMR(400 MHz,DMSO-d6)δ1.78-1.79(m,4H),2.53(s,3H),2.71-2.72(m,2H),2.94-2.96(m,2H),6.86(s,2H)。MS 263(MH+)。實例20a:4-胺基-2,3-丁烯-6-甲基噻吩并[2,3-b]吡啶-5-甲酸乙基酯如實例2a自2-胺基-4,5,6,7-四氫苯并[b]噻吩-3-甲腈(Tachdjian,C.等人PCT Int. Appl. 2008,WO 2008154221)及3-側氧基丁酸乙基酯進行製備,得到黃色固體。MS 291(MH+)。實例21:4-胺基-5-(3,3-二甲基丁基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(3,3-二甲基丁基)-2-甲基喹啉-3-甲酸乙基酯(實例21a)進行製備,得到白色固體(88%)。1H NMR(400 MHz,DMSO-d6)δ0.93(s,9H),1.40(t,J=8.8 Hz,2H),2.75(s,3H),3.17(t,J=8.4 Hz,2H),7.35(d,J=7.2 Hz,1H),7.57(d,J=8.4 Hz,1H),7.66(t,J=8.0 Hz,1H),12.78(s,1H)。MS 287(MH+)。實例21a:4-胺基-5-(3,3-二甲基丁基)-2-甲基喹啉-3-甲酸乙基酯如實例2a自2-胺基-6-(3,3-二甲基丁基)苄腈(實例21b)及3-側氧基丁酸乙基酯進行製備,得到白色固體(95%)。1H NMR(400 MHz,DMSO-d6)δ0.93(s,9H),1.32(t,J=7.2 Hz,3H),1.42-1.46(m,1H),2.55(s,3H),3.11-3.15(m,2H),4.33(q,J=7.2 Hz,2H),7.12(s,2H),7.19-7.21(m,1H),7.46-7.52(m,2H)。MS 315(MH+)。實例21b:2-胺基-6-(3,3-二甲基丁基)苄腈
在H2氣氛(利用氣球)及室溫下將2-胺基-6-(3,3-二甲基丁-1-炔基)苄腈(實例21c,690 mg,3.48 mmol)及10% Pd/C(100 mg)於EtOAc/EtOH(1:1,20 mL)中之懸浮液攪拌過夜。藉由過濾去除Pd/C,濃縮濾液,並藉由層析在矽膠上利用存於己烷中之20% EtOAc洗脫來純化,得到呈淡黃色固體形式之標題化合物(620 mg,88%)。1H NMR(400 MHz,DMSO-d6)δ0.92(s,9H),1.36-1.40(m,2H),2.52-2.56(m,2H),5.88(s,2H),6.45(d,J=7.6 Hz,1H),6.57(d,J=7.6 Hz,1H),7.15(t,J=8.0 Hz,1H)。MS 203(MH+)。實例21c:2-胺基-6-(3,3-二甲基丁-1-炔基)苄腈在室溫及氮下向2-胺基-6-溴苄腈(1.97 g,10.0 mmol)、3,3-二甲基丁-1-炔(2.46 g,30 mmol)、K2CO3(2.76 g,20.0 mmol)及CuI(191 mg,0.1 mmol)於DME/H2O(4:1,50 mL)中之溶液中添加Pd(PPh3)4(1.16 g,0.1 mmol)。在氮氣下將反應混合物回流過夜。在將其冷卻至室溫後,用鹽水淬滅反應,用EtOAc萃取。用鹽水洗滌有機層,經Na2SO4乾燥並濃縮。藉由層析在矽膠上利用存於己烷中之20% EtOAc來純化殘餘物,得到淺褐色油狀標題化合物(1.84 g,93%)。1H NMR(400 MHz,DMSO-d6)δ1.27(s,9H),6.10(s,2H),6.59(d,J=7.2 Hz,1H),6.71(d,J=8.0 Hz,1H),7.18-7.22(m,1H)。MS 199(MH+)。
實例22:4-胺基-5-(2-乙基丁氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(2-乙基丁氧基)-2-甲基喹啉-3-甲酸乙基酯(實例22a)進行製備,得到白色固體(45%)。M.p.:145-151℃。1H NMR(400 MHz,DMSO-d6)δ0.90(t,J=8 Hz,6H),1.48-1.41,(m,4H),1.84-1.78(m,1H),2.73(s,3H),4.11(d,J=8 Hz,2H),6.99(d,J=8 Hz,1H),7.32(d,J=8 Hz,1H),7.59(t,J=8 Hz,1H),8.40(brs,1H),11.09(brs,1H),13.91(brs,1H)。MS 303(MH+)。實例22a:4-胺基-5-(2-乙基丁氧基)-2-甲基喹啉-3-甲酸乙基酯如實例2a自2-胺基-6-(2-乙基丁氧基)苄腈(實例22b)及3-側氧基丁酸乙基酯進行製備,得到白色固體(89%)。1H NMR(400 MHz,DMSO-d6)δ0.90(t,J=8 Hz,6H),1.32(t,J=8 Hz,3H),1.48-1.41(m,4H),1.79-1.73(m,1H),2.54(s,3H),4.08(d,J=4 Hz,2H),4.31(q,J=8 Hz,2H),6.92(dd,J=2,8 Hz,1H),7.23(dd,J=2,8 Hz,1H),7.50(t,J=8 Hz,1H),8.04(brs,1H)。MS 331(MH+)。
實例22b:2-胺基-6-(2-乙基丁氧基)苄腈在0℃及氮下向2-乙基丁-1-醇(1.02 g,10.0 mmol)於無水THF(60 mL)中之溶液中以小份小心地添加NaH(60%存於礦物油中,480 mg,12.0 mmol)。在0℃及氮下將反應混合物攪拌2小時。向該溶液中添加2-胺基-6-氟苄腈(1.36 g,10.0 mmol),並在0℃至室溫下將反應溶液攪拌2小時,並然後在65℃及氮下過夜。將反應冷卻至室溫,然後用鹽水淬滅,並用EtOAc(3X)萃取。用鹽水洗滌合併之有機層,經Na2SO4乾燥。過濾並在減壓下蒸發。藉由在矽膠上實施層析(洗脫液:存於己烷中之20% EtOAc)來純化殘餘物,得到無色油狀標題化合物(1.29 g,59%)。1H NMR(400 MHz,CDCl3)δ0.93(t,J=8 Hz,6H),1.55-1.43(m,4H),1.73-1.65(m,1H),3.90(d,J=4 Hz,2H),4.10(brs,2H),6.25(d,J=8 Hz,1H),6.34(d,J=8 Hz,1H),7.20(t,J=8 Hz,1H)。
實例23:4-胺基-5-(庚-4-基氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(庚-4-基氧基)-2-甲基喹啉-3-甲酸乙基酯(實例23a)進行製備,得到白色固體(59%)。1H NMR(400 MHz,DMSO-d6)δ0.87(t,J=7.2 Hz,6H),1.49-1.25(m,4H),1.84-1.60(m 4H),2.74(s,3H),4.74-4.71(m,1H),7.07(d,J=8.4 Hz,1H),7.24(d,J=8.0 Hz,1H),7.64(t,J=8.4 Hz,1H),8.82(brs,1H)。MS 317(MH+)。實例23a:4-胺基-5-(庚-4-基氧基)-2-甲基喹啉-3-甲酸乙基酯如實例2a自2-胺基-6-(庚-4-基氧基)苄腈(實例23b)及3-側氧基丁酸乙基酯進行製備,得到淺黃色固體(65%)。1H NMR(400 MHz,DMSO-d6)δ0.87(t,J=7.2 Hz,6H),1.31(t,J=7.2 Hz,3H),1.47-1.33(m,4H),1.77-1.59(m,4H),2.54(s,3H),4.30(q,J=7.2 Hz,2H),4.67-4.64(m,1H),6.92(d,J=7.6 Hz,1H),7.19(dd,J=0.8,8.4 Hz,1H),7.49(t,J=8.0Hz,1H),8.13(brs,2H)。MS 345(MH+)。實例23b:2-胺基-6-(庚-4-基氧基)苄腈如實例22b自庚-4-醇及2-胺基-6-氟苄腈進行製備,得到白色固體(24%)。1H NMR(400 MHz,CDCl3)δ0.92(t,J=7.2 Hz,6H),1.55-1.31(m,8H),3.88(s,br,1H),4.33-4.27(m,1H),6.26(d,J=8.0 Hz,1H),6.35(d,J=8.0 Hz,1H),7.20(t,J=8.0 Hz,1H)。
實例24:4-胺基-5-(2-(異菸鹼醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(2-(異菸鹼醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例24a)進行製備,得到白色固體(67%)。M.p.:195-198℃。1H NMR(400 MHz,DMSO-d6)δ1.51(s,6H),2.75(s,3H),4.48(s,2H),7.07(d,J=8 Hz,1H),7.31(d,J=8 Hz,1H),7.67(t,J=8 Hz,1H),7.70(dd,J=1,8 Hz,2H),8.50(s,1H),8.67(dd,J=1,8 Hz,2H),8.76(brs,1H),12.19(brs,1H),12.85(brs,1H)。MS 395(MH+)。
實 例24a:4-胺基-5-(2-(異菸鹼醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯在室溫及氮下向4-胺基-5-(2-胺基-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例24b,1.0 g,3.15 mmol)於無水DMF(20 mL)中之溶液中添加異菸鹼酸(504 mg,4.10 mmol),隨後添加EDCI(783 mg,4.10 mmol)、HOBt(554 mg,4.10 mmol)及三乙胺(414 mg,4.10 mmol)。在室溫下將其攪拌12小時,在減壓下濃縮反應混合物。用水稀釋殘餘物,並用EtOAc(3X)萃取。用2 N NaOH將水層鹼化至pH 8並用EtOAc(3X)萃取。用鹽水洗滌合併之有機層,經MgSO4乾燥,過濾,濃縮,並藉由層析在矽膠上利用存於二氯甲烷中之10% MeOH洗脫來純化,得到呈黃色固體形式之標題化合物(1.1 g,83%)。1H NMR(400 MHz,DMSO-d6)δ1.29(t,J=4 Hz,3H),1.51(s,6H),2.94(s,3H),4.28(q,J=4 Hz,2H),4.42(s,2H),6.93(dd,J=1,8 Hz,1H),7.24(dd,J=1,8 Hz,2H),7.52(t,J=8 Hz,1H),7.69(dd,J=2,4 Hz,2H),8.14(s,2H),8.37(s,1H),8.67(dd,J=2,4 Hz,2H)。MS 423(MH+)。
實例24b:4-胺基-5-(2-胺基-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例2a自1-(3-胺基-2-氰基苯氧基)-2-甲基丙-2-基胺基甲酸苄基酯(實例24c)及3-側氧基丁酸乙基酯進行製備,得到黃褐色固體(91%)。1H NMR(400 MHz,DMSO-d6)δ1.15(s,6H),1.31(t,J=4 Hz,3H),2.54(s,3H),3.87(s,2H),4.31(q,J=4 Hz,2H),6.85(d,J=4 Hz,1H),7.21(d,J=4 Hz,1H),7.49(t,J=8 Hz,1H),8.38(brs,2H)。MS 318(MH+)。實例24c:1-(3-胺基-2-氰基苯氧基)-2-甲基丙-2-基胺基甲酸苄基酯
在室溫下向2-胺基-6-(2-胺基-2-甲基丙氧基)苄腈(實例24d,30.5 g,148.6 mmol)於THF/H2O(1:1,400 mL)中之溶液中添加NaHCO3(24.7 g,294 mmol),隨後添加(2,5-二側氧基吡咯啶-1-基)碳酸苄基酯(44.0 g,176 mmol)。在室溫下將反應攪拌4 h,然後分離出有機層並用EtOAc(2X)萃取水層。用鹽水洗滌合併之有機層並經MgSO4乾燥。過濾後,蒸發掉溶劑並藉由在矽膠上實施層析來純化(洗脫液:存於己烷中之0-60% EtOAc)粗製油,得到黃色油狀標題化合物(44.8 g,89%)。1H NMR(400 MHz,DMSO-d6)δ1.30(s,6H),4.02(s,2H),4.96(s,2H),5.98(s,2H),6.14(d,J=8.0 Hz,1H),6.32(dd,J=0.8,8.4 Hz,1H),7.12(t,J=8.4 Hz,1H),7.38-7.21(m,6H)。MS 340(MH+)。
實例24d:2-胺基-6-(2-胺基-2-甲基丙氧基)苄腈在0℃及氮下向2-胺基-2-甲基丙-1-醇(14.4 g,161 mmol)於無水THF(150 mL)中之溶液中以小份添加NaH(6.8 g,161 mmol,60%存於礦物油中)。在0℃下將混合物攪拌30分鐘且然後在室溫下再攪拌30分鐘。再次將溶液冷卻至0℃,並向該溶液中逐滴添加2-胺基-6-氟苄腈(20.0 g,147 mmol)於無水THF(50 mL)中之溶液。然後在氮下將反應混合物回流過夜。將反應混合物冷卻至室溫並用NH4Cl水溶液小心地淬滅並用乙酸乙酯(3X)萃取。用鹽水洗滌合併之有機層,經MgSO4乾燥,過濾並濃縮。藉由層析在矽膠上利用存於DCM中之10% MeOH洗脫來純化粗製混合物,得到呈黃色固體形式之標題化合物(23.4 g 71%)。1H NMR(400 MHz,DMSO-d6)δ1.08(s,6H),3.15(s,2H),3.64(s,2H),5.98(s,2H),6.13(d,J=8.0 Hz,1H),6.31(d,J=8.4 Hz,1H),7.15(t,J=8.4 Hz,1H)。MS 236(MH+)。實例25:4-胺基-5-(2-(3-羥基苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(2-(3-羥基苯甲醯胺基)-2-甲基-丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例25a)進行製備,得到白色固體(65%)。M.p.:195-198℃。1H NMR(400 MHz,DMSO-d6)δ1.48(s,6H),2.75(s,3H),4.47(s,2H),6.87(dt,J=8,4 Hz,1H),7.22-7.16(m,3H),7.06(d,J=8 Hz,1H),7.27(d,J=8 Hz,1H),7.67(t,J=8 Hz,1H),8.08(s,1H),8.84(brs,1H),9.69(s,1H),12.12(brs,1H),12.78(brs,1H)。MS 410(MH+)。實例25a:4-胺基-5-(2-(3-羥基苯甲醯胺基)-2-甲基丙氧基)-2-甲基-喹啉-3-甲酸乙基酯如實例24a自4-胺基-5-(2-胺基-2-甲基丙氧基)-2-甲基-喹啉-3-甲酸酯(實例24b)及3-羥基苯甲酸進行製備,得到黃褐色固體(64%)。1H NMR(400 MHz,DMSO-d6)δ1.30(t,J=4 Hz,3H),1.48(s,6H),2.55(s,3H),4.30(q,J=4 Hz,2H),4.41(s,2H),6.85-6.88(m,1H),6.92(d,J=8 Hz,1H),7.25-7.15(m,4H),7.52(t,J=8 Hz,1H),7.98(s,1H),8.19(s,2H),9.59(s,1H)。MS 438(MH+)。實例26:(S)-4-胺基-5-(2-(環己烷甲醯胺基)丙氧基)-2-甲基喹啉-3-甲酸
如實例1自(S)-4-胺基-5-(2-(環己烷甲醯胺基)-丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例26a)進行製備,得到白色固體(53%)。1H NMR(400 MHz,DMSO-d6)δ1.25-1.10(m,5H),1.34-1.31(m,2H),1.69-1.62(m,5H),2.11-2.05(m,1H),2.69(s,3H),3.93(t,J=9.2 Hz,1H),4.13(dd,J=4,9.6 Hz,1H),4.14-4.11(m,1H),6.86(d,J=8.0 Hz,1H),7.28(d,J=8.4 Hz,1H),7.49(t,J=8.0 Hz,1H),7.95(d,J=8.4 Hz,1H)。MS 386(MH+)。實例26a:(S)-4-胺基-5-(2-(環己烷甲醯胺基)丙氧基)-2-甲基-喹啉-3-甲酸乙基酯如實例24a自(S)-4-胺基-5-(2-胺基丙氧基)-2-甲基-喹啉-3-甲酸乙基酯(實例26b)及環己烷甲酸進行製備,得到褐色固體(28%)。MS 414(MH+)。實例26b:(S)-4-胺基-5-(2-胺基丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例2a自(S)-(1-(3-胺基-2-氰基苯氧基)丙-2-基)-胺基甲酸苄基酯(實例26c)及3-側氧基丁酸乙基酯進行製備,得到褐色固體。MS 304(MH+)。
實例26c:(S)-(1-(3-胺基-2-氰基苯氧基)丙-2-基)胺基甲酸苄基酯如實例24c自(S)-2-胺基-6-(2-胺基丙氧基)苄腈(實例26d)進行製備,得到褐色固體(86%)。1H NMR(400 MHz,DMSO-d6)δ1.12(d,J=6.4 Hz,3H),3.81(d,J=8.4 Hz,1H),3.95-3.92(m,1H),4.99(s,2H),5.36(s,2H),5.96(s,2H),6.20(d,J=8.0 Hz,1H),6.31(d,J=8.4 Hz,1H),7.13(t,J=8.4 Hz,1H),7.44-7.38(m,5H)。MS 326(MH+)。實例26d:(S)-2-胺基-6-(2-胺基丙氧基)苄腈如實例24d自(S)-2-胺基丙-1-醇及2-胺基-6-氟-苄腈進行製備,得到褐色固體(73%)。1H NMR(400 MHz,DMSO-d6)δ1.01(d,J=6.5 Hz,3H),3.08(m,1H),3.71(d,J=6.1 Hz,2H),5.95(s,2H),6.15(d,J=8.3 Hz,1H),6.2(d,J=8.3 Hz,1H),7.13(t,J=8.3 Hz,1H)。MS 192(MH+)。實例27:(S)-4-胺基-5-(2-(異菸鹼醯胺基)丙氧基)-2-甲基喹啉-3-甲酸
如實例1自(S)-4-胺基-5-(2-(異菸鹼醯胺基)丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例27a)進行製備,得到灰白色固體(42%)。1H NMR(400 MHz,DMSO-d6)δ1.31(d,J=6.8 Hz,3H),2.66(s,3H),4.14(t,J=9.2 Hz,1H),4.28(dd,J=3.6,9.6 Hz,1H),4.70-4.55(m,1H),6.92(d,J=8.0 Hz,1H),7.26(d,J=8.4 Hz,1H),7.51(t,J=8.4 Hz,1H),7.75(dd,J=1.2,6.0 Hz,2H),8.71(dd,J=1.2,6.0 Hz,2H),8.95(d,J=8.0 Hz,1H)。MS 409(MH+)。實例27a:(S)-4-胺基-5-(2-(異菸鹼醯胺基)丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自(S)-4-胺基-5-(2-胺基丙氧基)-2-甲基-喹啉-3-甲酸乙基酯(實例26b)及異菸鹼酸進行製備,得到褐色固體(36%)。MS 409(MH+)。
實例28:(S)-4-胺基-5-(2-(3-羥基苯甲醯胺基)丙氧基)-2-甲基喹啉-3-甲酸
如實例1自(S)-4-胺基-5-(2-(3-羥基苯甲醯胺基)丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例28a)進行製備,得到白色固體(58%)。1H NMR(400 MHz,DMSO-d6)δ1.28(d,J=7.2 Hz,3H),2.65(s,3H),4.11(t,J=8.8 Hz,1H),4.22(dd,J=4.0,10 Hz,1H),4.65-4.55(m,1H),6.88(d,J=8.0,2H),7.25-7.13(m,4H),7.48(t,J=8.0 Hz,1H),8.49(d,J=8.0,1H),9.93(brs,1H)。MS 396(MH+)。
實例28a:(S)-4-胺基-5-(2-(3-羥基苯甲醯胺基)丙氧基)-2-甲基-喹啉-3-甲酸乙基酯如實例24a自(S)-乙基4-胺基-5-(2-胺基丙氧基)-2-甲基-喹啉-3-甲酸酯(實例26b)及3-羥基苯甲酸進行製備,得到褐色固體(41%)。MS 424(MH+)。實例29:4-胺基-5-(3-(環戊基胺基)-2,2-二甲基-3-側氧基丙氧基)-2-甲基-喹啉-3-甲酸
如實例1自4-胺基-5-(3-(環戊基胺基)-2,2-二甲基-3-側氧基丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例29a)進行製備,得到白色粉末(74%)。1H NMR(400 MHz,DMSO-d6)δ1.27(s,6H),1.36-1.46(m,4H),1.57-1.59(m,2H),1.72-1.78(m,2H),2.78(s,3H),4.04(m,1H),4.19(s,2H),7.02(d,J=8.0 Hz,1H),7.33(d,J=8.0 Hz,1H),7.64-7.71(m,2H),8.83(brs,1H),12.25(brs,1H),12.93(brs,1H)。MS 386(MH+)。
實例29a:4-胺基-5-(3-(環戊基胺基)-2,2-二甲基-3-側氧基丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例2a自3-(3-胺基-2-氰基苯氧基)-N-環戊基-2,2-二甲基丙醯胺(實例29b)及3-側氧基丁酸乙基酯進行製備,得到淡黃色固體(62%)。1H NMR(400 MHz,DMSO-d6)δ1.26(s,6H),1.34(t,J=8.0 Hz,3H),1.40-1.46(m,4H),1.57-1.59(m,2H),1.74-1.77(m,2H),2.57(s,3H),4.09(q,J=4.0 Hz,1H),4.15(s,2H),4.33(q,J=8.0 Hz,2H),6.89(d,J=4.0 Hz,1H),7.26(dd,J=8.0 Hz,1H),7.53(d,J=8.0 Hz,1H),7.56(s,1H),8.09(brs,2H)。MS 414(MH+)。
實例29b:3-(3-胺基-2-氰基苯氧基)-N-環戊基-2,2-二甲基丙醯胺如實例22b自N-環戊基-3-羥基-2,2-二甲基丙醯胺(實例29c)及2-胺基-6-氟苄腈進行製備,得到白色固體(45%)。1H NMR(400 MHz,DMSO-d6)δ1.19(s,6H),1.40-1.49(m,4H),1.61-1.63(m,2H),1.74-1.79(m,2H),3.95(s,2H),4.03(m,1H),5.98(s,2H),6.19(d,J=8.0 Hz,1H),6.33(d,J=8.0 Hz,1H),7.17(t,J=8.0 Hz,1H),7.23(d,J=8.0 Hz,1H)。MS 302(MH+)。
實例29c:N-環戊基-3-羥基-2,2-二甲基丙醯胺如實例24a自羥基新戊酸及環戊基胺進行製備,橙色油狀(32%)。1H NMR(400 MHz,DMSO-d6)δ1.00(s,6H),1.32-1.40(m,2H),1.43-1.49(m,2H),1.57-1.65(m,2H),1.73-1.81(m,2H),3.34(d,J=4.0 Hz,2H),3.98(m,1H),4.87(t,J=4.0 Hz,1H),7.22(d,J=4.0 Hz,1H)。MS 186(MH+)。實例30:4-胺基-5-(環丁基甲氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(環丁基甲氧基)-2-甲基喹啉-3-甲酸乙基酯(實例30a)進行製備,得到白色粉末(51%)。1H NMR(400 MHz,DMSO-d6)δ1.84-1.99(m,4H),2.10-2.15(m,2H),2.77(s,3H),2.92(m,1H),4.23(d,J=8.0 Hz,2H),7.05(d,J=8.0 Hz,1H),7.29(d,J=8.0 Hz,1H),7.68(t,J=8.0 Hz,1H),8.71(brs,1H),12.23(brs,1H),12.81(brs,1H)。MS 287(MH+)。實例30a:乙基4-胺基-5-(環丁基甲氧基)-2-甲基喹啉-3-甲酸酯如實例2a自2-胺基-6-(環丁基甲氧基)苄腈(Tachdjian,C.等人PCT Int. Appl. 2008,WO 2008154221)及3-側氧基丁酸乙基酯進行製備,得到橙色固體(26%)。1H NMR(400 MHz,DMSO-d6)δ1.32(t,J=8.0 Hz,3H),1.83-1.90(m,4H),2.10-2.13(m,2H),2.59(s,3H),2.86(m,1H),4.16(d,J=4.0 Hz,2H),4.32(q,J=8.0 Hz,2H),6.90(d,J=8.0 Hz,1H),7.23(d,J=8.0 Hz,1H),7.51(t,J=8.0 Hz,1H),8.05(brs,2H)。MS 315(MH+)。
實例31:4-胺基-5-(2-(環戊烷甲醯胺基)-2-甲基丙氧基)-2-甲基-喹啉-3-甲酸
如實例1自4-胺基-5-(2-(環戊烷甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例31a)進行製備,得到灰白色固體(68%)。1H NMR(400 MHz,DMSO-d6)δ1.36(s,6H),1.43-1.51(m,6H),1.65-1.69(m,2H),2.58(m,1H),2.78(m,3H),4.37(s,2H),7.04(m,1H),7.29(d,J=8.0 Hz,1H),7.68(m,1H),7.80(s,1H),8.84(brs,1H),12.42(brs,1H),12.73(brs,1H)。MS 386(MH+)。
實例31a:4-胺基-5-(2-(環戊烷甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自4-胺基-5-(2-胺基-2-甲基丙氧基)-2-甲基-喹啉-3-甲酸乙基酯(實例24b)及環戊烷甲酸進行製備,得到黃色固體(33%)。1H NMR(400 MHz,DMSO-d6)δ1.34(t,J=4.0 Hz,3H),1.37(s,6H),1.42-1.53(m,6H),1.64-1.69(m,2H),2.58(m,1H),2.62(s,3H),4.32(s,2H),4.35(m,2H),6.96(m,1H),7.28(d,J=8.0 Hz,1H),7.58(m,1H),7.66(s,1H),8.41(d,2H)。MS 414(MH+)。實例32:4-胺基-5-(環庚基氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(環庚基氧基)-2-甲基喹啉-3-甲酸乙基酯(實例32a)進行製備,得到淺黃色固體(34%)。1H NMR(400 MHz,DMSO-d6)δ1.49-1.65(m,8H),1.83-1.89(m,2H),2.04-2.09(m,2H),2.74(s,3H),4.85(m,1H),7.03(d,J=8.0 Hz,1H),7.23(d,J=8.0 Hz,1H),7.65(t,J=8.0 Hz,1H),8.82(brs,1H),12.24(brs,1H),12.64(brs,1H)。MS 315(MH+)。實例32a:4-胺基-5-(環庚基氧基)-2-甲基喹啉-3-甲酸乙基酯如實例2a自2-胺基-6-(環庚基氧基)苄腈(實例32b)及3-側氧基丁酸乙基酯進行製備,得到淡黃色固體(72%)。1H NMR(400 MHz,DMSO-d6)δ1.32(t,J=8.0 Hz,3H),1.49-1.65(m,8H),1.78-1.87(m,2H),2.04-2.10(m,2H),2.53(s,3H). 4.31(q,J=8.0 Hz,2H),4.79(m,1H),6.89(d,J=8.0 Hz,1H),7.20(d,J=8.0 Hz,1H),7.49(t,J=8.0 Hz,1H),8.14(brs,2H)。MS 343(MH+)。實例32b:2-胺基-6-(環庚基氧基)苄腈如實例22b自環庚醇及2-胺基-6-氟苄腈進行製備,黃色油狀(11%)。1H NMR(400 MHz,DMSO-d6)δ1.42-1.71(m,10H),1.88-1.93(m,2H),4.56(m,1H),5.95(s,2H),6.20(d,J=8.0 Hz,1H),6.30(d,J=8.0 Hz,1H),7.15(t,J=8.0 Hz,1H)。MS 231(MH+)。
實例33:4-胺基-2-甲基-5-(3-苯氧基丙氧基)喹啉-3-甲酸
如實例1自4-胺基-2-甲基-5-(3-苯氧基丙氧基)喹啉-3-甲酸乙基酯(實例33a)進行製備,得到黃色固體(90%)。1H NMR(400 MHz,DMSO-d6)δ2.35(m,2H),2.77(s,3H),4.19(t,J=4.0 Hz,2H),4.42(t,J=4.0 Hz,2H),6.91-6.96(m,3H),7.09(d,J=8.0 Hz,1H),7.26-7.30(m,3H),7.70(t,J=8.0 Hz,1H),8.96(brs,1H),12.24(brs,1H),12.75(brs,1H)。MS 353(MH+)。實例33a:4-胺基-2-甲基-5-(3-苯氧基丙氧基)喹啉-3-甲酸乙基酯
如實例2a自2-胺基-6-(3-苯氧基丙氧基)苄腈(實例33b)及3-側氧基丁酸乙基酯進行製備,得到黃色固體(47%)。1H NMR(400 MHz,DMSO-d6)δ1.33(t,J=8.0 Hz,3H),2.34(m,2H),2.57(s,3H),4.19(t,J=4.0 Hz,2H),4.33(q,J=8.0 Hz,2H),4.37(t,J=4.0 Hz,2H),6.91-6.97(m,4H),7.24-7.29(m,3H),7.53(t,J=8.0 Hz,1H),8.17(s,2H)。MS 381(MH+)。
實 例33b:2-胺基-6-(3-苯氧基丙氧基)苄腈如實例22b自3-苯氧基-1-丙醇及2-胺基-6-氟苄腈進行製備,黃色油狀(93%)。1H NMR(400 MHz,DMSO-d6)δ2.14(m,2H),4.10-4.16(m,4H),5.98(s,2H),6.23(d,J=8.0 Hz,1H),6.33(d,J=8.0 Hz,1H),6.89-6.94(m,5H),7.16(t,J=8.0 Hz,1H)。實例34:4-胺基-5-((1-(3-羥基苯甲醯基)六氫吡啶-4-基)甲氧基)-2-甲基-喹啉-3-甲酸
如實例1自4-胺基-5-((1-(3-羥基苯甲醯基)六氫吡啶-4-基)甲氧基)-2-甲基喹啉-3-甲酸乙基酯(實例34a)進行製備,得到橙色粉末(23%)。1H NMR(400 MHz,DMSO-d6)δ1.24(brs,2H),1.79-1.88(m,2H),2.29(m,1H),2.77(s,3H),3.07(brs,2H),3.65(brs,1H),4.17(d,J=8.0 Hz,2H),4.50(brs,1H),6.74-6.83(m,3H),7.07(d,J=8.0 Hz,1H),7.23(t,J=8.0 Hz,1H),7.29(d,J=8.0 Hz,1H),7.69(t,J=8.0 Hz,1H),8.74(brs,1H),9.75(s,1H),12.25(brs,1H),12.71(brs,1H)。MS 436(MH+)。實例34a:4-胺基-5-((1-(3-羥基苯甲醯基)六氫吡啶-4-基)甲氧基)-2-甲基喹啉-3-甲酸乙基酯如實例2a自2-胺基-6-((1-(3-羥基苯甲醯基)六氫吡啶-4-基)甲氧基)苄腈(實例34b)及3-側氧基丁酸乙基酯進行製備,得到黃色固體(49%)。1H NMR(400 MHz,DMSO-d6)δ1.24(m,2H),1.31(t,J=4.0 Hz,3H),1.77-1.89(m,2H),2.22(brs,1H),2.55(s,3H),2.79(brs,1H),3.04(brs,1H),3.64(brs,1H),4.10(m,2H),4.32(q,J=8.0 Hz,2H),4.49(brs,1H),6.71-6.82(m,3H),6.93(d,J=8.0 Hz,1H),7.19-7.25(m,2H),7.52(t,J=8.0 Hz,1H),8.06(brs,2H),9.64(s,1H)。MS 464(MH+)。
實例34b:2-胺基-6-((1-(3-羥基苯甲醯基)六氫吡啶-4-基)甲氧基)苄腈如實例24a自2-胺基-6-(六氫吡啶-4-基甲氧基)苄腈(實例34c)及3-羥基苯甲酸進行製備,得到橙色玻璃(66%)。1H NMR(400 MHz,DMSO-d6)δ1.29(m,2H),1.66-1.92(m,2H),2.06(m,1H),2.80(brs,1H),3.05(brs,1H),3.62(brs,1H),3.91(d,J=8.0 Hz,2H),4.49(brs,1H),5.99(s,2H),6.22(d,J=8.0 Hz,1H),6.34(d,J=8.0 Hz,1H),6.72-6.83(m,3H),7.15-7.24(m,2H),9.65(s,1H)。MS 352(MH+)。實例34c:2-胺基-6-(六氫吡啶-4-基甲氧基)苄腈在0℃下向4-((3-胺基-2-氰基苯氧基)甲基)六氫吡啶-1-甲酸第三丁基酯(實例34d,1.33 g,4.0 mmol)於EtOAc(20 mL)中之溶液中逐滴添加HCl水溶液(12 N,6.6 mL)。在室溫下將反應混合物攪拌過夜。在減壓下去除溶劑,得到呈褐色固體形式之標題化合物(100%),其足夠純且未經進一步純化直接用於下一步驟。MS 232(MH+)。
實例34d:4-((3-胺基-2-氰基苯氧基)甲基)六氫吡啶-1-甲酸2第三丁基酯如實例22b自N-Boc-4-六氫吡啶甲醇及2-胺基-6-氟-苄腈進行製備,得到灰白色固體(37%)。1H NMR(400 MHz,DMSO-d6)δ1.15-1.21(m,2H),1.40(s,9H),1.74(m,2H),1.99(brs,1H),2.74(brs,2H),3.87(d,J=4.0 Hz,2H),3.96(m,2H),5.99(s,2H),6.21(d,J=8.0 Hz,1H),6.33(d,J=8.0 Hz,1H),7.17(t,J=8.0 Hz,1H)。MS 232(MH+-Boc)。實例35:4-胺基-5-((1-丁醯基六氫吡啶-4-基)甲氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-((1-丁醯基六氫吡啶-4-基)甲氧基)-2-甲基喹啉-3-甲酸乙基酯(實例35a)進行製備,得到白色固體(61%)。1H NMR(400 MHz,DMSO-d6)δ0.87(t,J=8.0 Hz,3H),1.05-1.22(m,2H),1.50(m,2H),1.80(m,2H),2.24-2.31(m,3H),2.65(s,3H),3.02(2H),3.88-3.92(m,1H),4.11(m,2H),4.44(m,1H),7.05(m,1H),7.26(d,J=8.0 Hz,1H),7.69(m,1H),8.76(brs,1H),12.33(brs,1H),12.65(brs,1H)。MS 386(MH+)。實例35a:4-胺基-5-((1-丁醯基六氫吡啶-4-基)甲氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自4-胺基-2-甲基-5-(六氫吡啶-4-基甲氧基)-喹啉-3-甲酸乙基酯(實例35b)及丁酸進行製備,黃色油狀(50%)。MS 414(MH+)。
實例35b:4-胺基-2-甲基-5-(六氫吡啶-4-基甲氧基)喹啉-3-甲酸乙基酯如實例2a自4-((3-胺基-2-氰基苯氧基)甲基)六氫吡啶-1-甲酸苄基酯(實例35c)及3-側氧基丁酸乙基酯進行製備,得到橙色固體(25%)。1H NMR(400 MHz,DMSO-d6)δ1.29-1.37(m,5H),1.77-1.80(m,2H),2.07(brs,1H),2.53(s,3H),2.55-2.65(m,3H),3.06-3.09(m,2H),4.06(d,J=8.0 Hz,2H),4.32(q,J=8.0 Hz,2H),6.92(d,J=8.0 Hz,1H),7.24(d,J=8.0 Hz,1H),7.51(t,J=8.0 Hz,1H),8.08(s,2H)。MS 344(MH+)。
實例35c:4-((3-胺基-2-氰基苯氧基)甲基)六氫吡啶-1-甲酸酯如實例22b自1-N-Cbz-4-(羥基甲基)六氫吡啶及2-胺基-6-氟-苄腈進行製備,黃色油狀(18%)。1H NMR(400 MHz,D MSO-d6)δ1.20-1.25(m,2H),1.75-1.78(m,2H),1.96(brs,1H),3.88(d,J=8.0 Hz,2H),3.99-4.04(m,4H),5.07(s,2H),5.99(s,2H),6.21(d,J=8.0 Hz,1H),6.34(d,J=8.0 Hz,1H),7.17(t,J=8.0 Hz,1H),7.29-7.40(m,5H)。MS 366(MH+)。
實例36:4-胺基-5-(環己基氧基)-2-甲基喹啉-3-甲酸
在室溫下向4-胺基-5-(環己基氧基)-2-甲基喹啉-3-甲酸乙基酯(實例36a,110 g,0.335 mol)於EtOH(450 mL)中之溶液中添加NaOH(33.5 g,0.837 mol)水溶液(200 mL)。然後將反應混合物回流過夜。將反應溶液冷卻至0℃並小心地用4N HCl中和至pH 7。在減壓下濃縮所得溶液以去除大部分EtOH。藉由過濾收集沉澱,並在65℃下重新溶於EtOH(4 L)中並用活性炭(5 g)處理0.5 h。藉由經矽藻土過濾來去除炭,並濃縮濾液。藉由過濾收集沉澱,用冷水洗滌,並在60℃及真空下乾燥過夜,得到呈白色固體形式之標題化合物(100 g,99%)。M.p.:220.0-221.5℃。1H NMR(400 MHz,DMSO-d6)δ1.28-1.72(m,8H),2.00-2.04(m,2H),2.75(s,3H),4.69-4.71(m,1H),7.10-7.12(d,J=8.0 Hz,1H),7.24-7.26(d,J=8.0 Hz,1H),7.65(t,J=8.0 Hz,1H),12.80(brs,1H)。MS 301(MH+)。C17H20N2O3元素分析計算值(實驗值):C,67.98%(67.74%);H,6.71%(7.01%);N,9.33%(9.40%)。
實例36a:4-胺基-5-(環己基氧基)-2-甲基喹啉-3-甲酸乙基酯在室溫及氮下在坐於油浴中之3 L圓底燒瓶中將3-側氧基丁酸乙基酯(29.9 g,0.230 mol)於無水甲苯(200 mL)中之溶液添加至2-胺基-6-(環己基氧基)苄腈(實例36b,49.8 g,0.230 mol)於無水甲苯(1000 mL)中之溶液中。經約1 h時間緩慢添加SnCl4(53.9 mL,0.461 mol)。然後將油浴溫度升高至110℃並在該溫度下將反應混合物攪拌2.5 h。然後仍在氮下將其冷卻至5℃,並自燒瓶底部之不混溶黏稠油傾析除去甲苯。在真空及60℃下進一步濃縮黏稠油,重新溶於沸騰乙酸乙酯(1 L)中,並轉移至4升錐形燒瓶中。用更多的EtOAc(1.5 L)稀釋溶液,冷卻至-15℃,並用NaOH(3 N,500 mL)中和。分離出有機層,並將水性乳液用乙酸乙酯萃取一次。自水層濾除不溶錫鹽,然後將鹽及水性濾液二者用乙酸乙酯洗滌一次以上。合併之有機層經MgSO4乾燥,濃縮,並使用存於己烷中之0%至60%乙酸乙酯使其通過二氧化矽管柱。藉由自EtOAc重結晶來純化產物,得到呈灰白色固體形式之標題化合物(64.3 g,85%)。1H NMR(400 MHz,DMSO-d6)δ1.28-1.34(m,1H),1.32(t,3H),1.37-1.45(m,2H),1.51-1.63(m,3H),1.67-1.71(m,2H),1.99-2.03(m,2H),2.54(s,3H),4.28-4.33(q,J=6.8 Hz,2H),4.64(m,1H),6.95-6.97(d,J=7.6 Hz,1H),7.19-7.21(d,J=8.4 Hz,1H),7.65(t,J=8.4 Hz,1H),8.15(brs,2H)。MS 329(MH+)。
實例36b:2-胺基-6-(環己基氧基)苄腈在0℃及氮下向環己醇(19.1 g,0.191 mol)於無水THF(500 mL)中之溶液中以小份添加NaH(7.6 g,40%存於礦物油中,0.191 mol)。在室溫下將混合物攪拌1 h並在室溫下逐滴添加2-胺基-6-氟苄腈(20.0 g,0.15 mol)於無水THF(150 mL)中之溶液。將反應混合物加熱至回流,過夜,然後冷卻至室溫並在減壓下去除大部分THF。向濃縮反應混合物中添加冰水(100 mL),隨後添加EtOAc(500 mL)。分離出有機層並依次用水及鹽水洗滌,經Na2SO4乾燥,過濾並在減壓下蒸發。藉由層析在矽膠上利用存於己烷中之25-30%EtOAc來純化殘餘物,得到2-胺基-6-(環己基氧基)苄腈,淡黃色油狀(17.9 g,56%)。1H NMR(400 MHz,CDCl3)δ1.32-1.43(m,3H),1.51-1.55(m,1H),1.62-1.69(m,2H),1.79-1.95(m,4H),4.31-4.36(m,3H),6.23-6.27(m,2H),7.18(d,J=8.0 Hz,1H)。MS 329(MH+)。
實例36b:2-胺基-6-(環己基氧基)苄腈 替代方法a): 在室溫及氮下向2-(環己基氧基)-6-硝基苄腈(實例36c,50.0 g,0.20 mol)於THF/AcOH(以體積計1:1,500 mL)中之溶液中一次性添加鐵粉(34.0 g,0.61 mol)。在氮下將反應混合物回流40 min並冷卻至室溫並添加EtOAc(2 L)。濾除所形成沉澱並用EtOAc洗滌。分離出有機層並依次用水(2×300 mL)、NaOH水溶液(1.0 N,2×300 mL)、飽和Na2CO3溶液(300 mL)、鹽水(300 mL)洗滌,經Na2SO4乾燥,過濾並在減壓下蒸發。藉由層析在矽膠上利用存於己烷中之25% EtOAc洗脫來純化殘餘物,得到淺黃色油狀2-胺基-6-(環己基氧基)苄腈(45.0 g,94%),其在室溫下存儲過夜後固化。
替代方法b): 首先用氮吹掃3-L 3頸圓底燒瓶。然後在氮下添加10% Pd/C(2.81 g),隨後依次添加2-(環己基氧基)-6-硝基苄腈(實例36c,43.2 g,0.175 mol)、無水甲醇(389 mL)及乙酸(80.4 mL)。連接上回流冷凝器、含有甲酸銨(49.8 g,0.790 mol)於無水甲醇(498 mL)中之溶液之滴液漏斗、溫度計、氮入口及氮出口。在室溫下添加甲酸銨溶液(75 mL),然後將反應物緩慢加熱至最大42℃。仔細監測混合物直至觀察到反應開始為止(出現放氣且放熱約10℃)。在反應開始前通常花費40分鐘。然後以維持40℃至48℃之內部反應溫度之速率添加剩餘甲酸銨溶液。在完成添加後,在45℃下將反應混合物再攪拌10分鐘,然後冷卻至室溫。使用特氟隆(Teflon)過濾器濾出Pd/C,並蒸發掉溶劑。向殘餘物中添加冰水(1 L),然後傾析出水並丟棄。將殘餘物溶於乙醚中,用水洗滌,然後用飽和碳酸氫鈉溶液洗滌,然後用硫酸鎂乾燥並濃縮。然後在矽膠上使用等梯度DCM來純化產物,得到黃色油狀產物(31.5 g,83%)。
實例36c:2-(環己基氧基)-6-硝基苄腈在-40℃及氮下向環己醇(46.8克,0.467 mol)於無水THF(1 L)中之溶液中添加氫化鈉(20.3克,0.508 mol)。使反應混合物緩慢升溫至室溫並再攪拌1小時。然後將其冷卻至-55℃並添加2,6-二硝基苄腈(78.4 g,0.406 mol)。在室溫下將反應攪拌過夜,然後冷卻至-20℃,並添加檸檬酸(23.4克,0.122 mol)。然後將混合物倒入含有檸檬酸(7.8 g,0.041 mol)之冰水(5 L)中,攪拌15分鐘,並藉由過濾收集所沉澱產物。使粗產物自異丙醇(750 mL,加熱至沸騰,然後冷卻至0℃)重結晶,過濾,用異丙醇(300 mL)洗滌,然後進行空氣乾燥,得到84.4 g黃色固體。將固體溶於二氯甲烷(169 mL)中並藉助氧化鋁塞過濾,得到呈淺黃色固體形式之標題化合物(83.2 g,83.2%)。1H NMR(400 MHz,DMSO-d6)δ1.4(m,4H),1.6(m,2H),1.7(m,2H),1.9(m,2H),4.75(m,1H),7.79(dd,J=2.0,8.0 Hz,1H),7.84-7.91(m,2H)。
實例37:4-胺基-5-(2-(環己烷甲醯胺基)-2-甲基丙氧基)-2-甲基-喹啉-3-甲酸
如實例1自4-胺基-5-(2-(環己烷甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例37a)進行製備,得到白色粉末(78%)。1H NMR(400 MHz,DMSO-d6)δ1.11-1.22(m,5H),1.33(s,6H),1.56-1.62(m,5H),2.14(m,1H),2.78(s,3H),4.34(s,2H),7.01(d,J=8.4 Hz,1H),7.30(d,J=8.4 Hz,1H),7.66(t,J=8.4 Hz,1H),7.74(s,1H)。MS 400(MH+)。
實例37a:4-胺基-5-(2-(環己烷甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例2a自N-(1-(3-胺基-2-氰基苯氧基)-2-甲基丙-2-基)環己烷甲醯胺(實例37b)及3-側氧基丁酸乙基酯進行製備,得到淡黃色固體(55%)。MS 428(MH+)。實例37b:N-(1-(3-胺基-2-氰基苯氧基)-2-甲基丙-2-基)環己烷-甲醯胺如實例22b自N-(1-羥基-2-甲基丙-2-基)環己烷-甲醯胺(實例37c)及2-胺基-6-氟苄腈進行製備,得到灰白色固體(29%)。MS 316(MH+)。實例37c:N-(1-羥基-2-甲基丙-2-基)環己烷甲醯胺如實例24a自環己烷甲酸及2-胺基-2-甲基丙-1-醇進行製備,無色油狀(15%)。MS 200(MH+)。
實例38:4-胺基-5-(2-(3-(2-羥基乙氧基)-5-甲氧基苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸
向4-胺基-5-(2-(3-(2-(苄基氧基)乙氧基)-5-甲氧基苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸(實例38a,237 mg,0.5 mmol)於EtOH/EtOAc(1:1,20 mL)中之溶液中添加10%Pd/C(潤濕,50 mg)。然後在氫氣氛及室溫下將懸浮液攪拌過夜。濾除Pd/C,並濃縮濾液。藉由HPLC(洗脫液:存於H2O中之10-100% MeOH)來純化殘餘物,得到呈灰白色固體形式之標題化合物(152 mg,63%)。1H NMR(400 MHz,DMSO-d6)δ1.49(s,6H),2.75(s,3H),3.68(t,J=5.2 Hz,2H),3.73(s,3H),3.99(t,J=5.2 Hz,1H),4.47(s,2H),6.57(s,1H),6.88(s,1H),6.96(s,1H),7.06(d,J=7.6 Hz,1H),7.28(d,J=8 Hz,1H),7.67(t,J=8 Hz,1H),8.14(s,1H)。MS 484(MH+)。
實例38a:4-胺基-5-(2-(3-(2-(苄基氧基)乙氧基)-5-甲氧基苯甲醯胺基)-2-甲基-丙氧基)-2-甲基喹啉-3-甲酸如實例1自4-胺基-5-(2-(3-(2-羥基乙氧基)-5-甲氧基-苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例38b)進行製備,得到白色粉末(95%)。MS 574(MH+)。實例38b:4-胺基-5-(2-(3-(2-羥基乙氧基)-5-甲氧基-苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自4-胺基-5-(2-胺基-2-甲基丙氧基)-2-甲基喹啉-3-甲酸酯(實例24b)及3-(2-(苄基氧基)乙氧基)-5-甲氧基苯甲酸(實例39c)進行製備,得到淺褐色固體(90%)。MS 602(MH+)。
實例38c:3-(2-(苄基氧基)乙氧基)-5-甲氧基苯甲酸如實例1自3-(2-(苄基氧基)乙氧基)-5-甲氧基苯甲酸甲基酯(實例38d)進行製備,得到白色固體(64%)。1H NMR(400 MHz,DMSO-d6)δ3.83(s,3H),3.84(t,J=4.8 Hz,2H),4.18(t,J=4.8 Hz,2H),4.65(s,2H),6.74(s,1H),7.25-7.37(m,7H)。
實例38d:3-(2-(苄基氧基)乙氧基)-5-甲氧基苯甲酸甲基酯在室溫下向3-羥基-5-甲氧基苯甲酸甲基酯(Chakraporty,T. K.及Reddy,G. V. J. Org. Chem,57,1992,5462.)(3.3 g,18.1 mmol)於無水DMF(30 mL)中之溶液中添加K2CO3(6.3 g,45.3 mmol)。在室溫下將反應攪拌10分鐘,然後添加((2-溴乙氧基)甲基)苯(3.4 mL,21.7 mmol),並在160℃下將混合物攪拌2小時。將反應冷卻至室溫並用EtOAc稀釋,用水及鹽水洗滌,並經MgSO4乾燥,過濾並濃縮,得到粗產物(90%),其未經進一步純化即用於下一步驟。實例39:4-胺基-5-((2-異丁醯胺基環己基)氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-((2-異丁醯胺基環己基)氧基)-2-甲基喹啉-3-甲酸乙基酯(實例39a)進行製備,得到白色粉末(90%)。1H NMR(400 MHz,DMSO-d6)δ0.83(d,J=6.4 Hz,3H),0.93(d,J=6.4 Hz,3H),1.42(m,3H),1.65(m,4H),1.96(m,1H),2.40(m,1H),2.76(s,3H),4.13(m,1H),4.99(m,1H),7.07(d,J=8.4 Hz,1H),7.25(d,J=8.4 Hz,1H),7.63(t,J=8 hz,1H),7.93(d,J=7.6 Hz,1H)。MS 386(MH+)。實例39a:4-胺基-5-((2-異丁醯胺基環己基)氧基)-2-甲基喹啉-3-甲酸乙基酯如實例2a自N-(2-(3-胺基-2-氰基苯氧基)環己基)異丁醯胺(實例39b)及3-側氧基丁酸乙基酯進行製備,得到黃色固體(63%)。MS 414(MH+)。實例39b:N-(2-(3-胺基-2-氰基苯氧基)環己基)異丁醯胺如實例22b自N-(2-羥基環己基)異丁醯胺(實例39c)及2-胺基-6-氟苄腈進行製備,得到褐色固體(70%)。MS 302(MH+)。
實例39c:N-(2-羥基環己基)異丁醯胺如實例24a自異丁酸及2-胺基環己醇進行製備,無色油狀(53%)。MS 186(MH+)。實例40:4-胺基-5-((4-異丁醯胺基環己基)氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-((4-異丁醯胺基環己基)氧基)-2-甲基喹啉-3-甲酸乙基酯(實例40a)進行製備,得到白色粉末(87%)。1H NMR(400 MHz,DMSO-d6)δ0.97(d,J=7.2 Hz,6H),1.34-1.37(m,2H),1.65-1.68(m,2H),1.81-1.84(m,2H),2.13-2.16(m,2H),2.33(m,1H),2.75(s,3H),3.58(m,1H),4.84(m,1H),7.15(d,J=8.4 Hz,1H),7.23(d,J=8 Hz,1H),7.65(d,J=7.6 Hz,2H)。MS 386(MH+)。實例40a:4-胺基-5-((4-異丁醯胺基環己基)氧基)-2-甲基喹啉-3-甲酸乙基酯如實例2a自N-(4-(3-胺基-2-氰基苯氧基)環己基)異丁醯胺(實例40b)及3-側氧基丁酸乙基酯進行製備,得到黃色固體(57%)。MS 414(MH+)。實例40b:N-(4-(3-胺基-2-氰基苯氧基)環己基)異丁醯胺如實例22b自N-(4-羥基環己基)異丁醯胺(實例40c)及2-胺基-6-氟苄腈進行製備,得到灰白色固體(99%)。MS 302(MH+)。實例40c:N-(4-羥基環己基)異丁醯胺如實例24a自異丁酸及4-胺基環己醇進行製備,無色油狀(44%)。MS 186(MH+)。實例41:4-胺基-5-異丁氧基-2-甲基喹啉-3-甲酸
向4-胺基-5-異丁氧基-2-甲基喹啉-3-甲酸乙基酯(實例41a,18.0 g,59.53 mmol)於EtOH(150 mL)中之溶液中添加NaOH水溶液(3 N,50 mL)並將反應混合物回流過夜。然後將其冷卻至室溫並過濾溶液以去除任一可能之固體殘餘物。在0℃下將濾液用6N HCl小心地中和至pH 7。藉由過濾收集所得沉澱,用水洗滌,重新溶於EtOH(700 mL)及水(20 mL)中,並在70℃下用活性炭(650 mg)處理0.5 h。藉由過濾去除炭,並濃縮濾液並在4℃下儲存過夜。藉由過濾收集所得沉澱,用冷H2O洗滌,並在真空及60℃下乾燥過夜,得到呈白色固體形式之標題化合物(4.24 g,26%)。M.p.:203.7℃。1H NMR(400 MHz,DMSO-d6)δ1.01-1.02(m,6H),2.19-2.24(m,1H),2.77(s,3H),4.05(d,J=6.4 Hz,2H),7.08(d,J=8.0 Hz,1H),7.33(d,J=8.0 Hz,1H),7.71(t,J=8.0 Hz,1H),8.9(brs,1H),11.45(brs,1H),13.2(brs,1H)。MS 275(MH+)。C15H18N2O3‧0.75H2O元素分析計算值(實驗值):C,62.59%(62.23%);H,6.83%(7.25%);N,9.76%(9.73%)。
實 例41a:4-胺基-5-異丁氧基-2-甲基喹啉-3-甲酸乙基酯在室溫及氮下經15分鐘向2-胺基-6-異丁氧基苄腈(實例41b,16.4 g,86.32 mmol)及乙醯乙酸乙酯(10.9 mL,86.32 mmol)於無水甲苯(200 mL)中之溶液中添加SnCl4(19.9 mL,172.63 mmol)。然後在氮下將經攪拌反應混合物回流3.5 h。在將其冷卻至室溫後,在減壓下濃縮反應溶液以去除大部分溶劑。將殘餘物重新溶於EtOAc(3 L)中並在0℃下用NaOH水溶液(6.0 N,約110 mL)小心地中和至pH 8。在室溫下將所得混合物攪拌過夜。濾除沉澱,並分離出有機層並用鹽水(400 mL)洗滌,經Na2SO4乾燥並在減壓下濃縮。藉由管柱層析在矽膠上利用存於己烷中之50% EtOAc洗脫來純化殘餘物,得到呈白色固體形式之標題化合物(18.0 g,69%)。MS 303(MH+)。
實例41b:2-胺基-6-異丁氧基苄腈向2-異丁氧基-6-硝基苄腈(實例41c,34.3 g,0.156 mol)於AcOH/THF(以體積計1:1,250 mL)中之溶液中一次性添加鐵粉(17.36 g,0.311 mol)。將經攪拌懸浮液加熱至回流,保持30分鐘。在將其冷卻至室溫後,用EtOAc(1 L)稀釋反應溶液。藉由過濾去除固體,並依次用水(300 mL×2)、1N NaOH(300 mL)、飽和Na2CO3水溶液(300 mL)、鹽水(300 mL)洗滌濾液,並經Na2SO4乾燥。在溶劑蒸發後,藉由層析在矽膠上利用存於己烷中之20% EtOAc來純化殘餘物,得到黃色油狀標題化合物(16.4 g,83%)。1H NMR(400 MHz,DMSO-d6)δ0.96(d,J=6.8 Hz,6H),1.96-2.02(m,1H),3.75(d,J=6.4 Hz,2H),5.96(s,2H),6.17(d,J=8.4 Hz,1H),6.30(d,J=8.4 Hz,1H),7.15(t,J=8.8 Hz,1H)。MS 191(MH+)。
實例41b替代程序:2-胺基-6-異丁氧基苄腈在氮下將氫化鈉(存於油中之60%懸浮液,25.0 g,0.625 mol)懸浮於無水THF(1000 mL)中並加熱至40℃至45℃之內部溫度。然後緩慢並逐份添加2-甲基丙-1-醇(61.2 mL,0.661 mol)。在40℃至45℃下將混合物加熱1小時,然後冷卻至35℃。添加2-胺基-6-氟苄腈(50.0 g,0.367 mol)並回流21小時。將混合物冷卻至室溫,然後添加冰(250 g)、冰水(750 mL)及己烷(1000 mL)。濾出不溶固體並分離出有機層。將水層用乙醚(250 mL)與己烷(250 mL)之混合物萃取一次以上。將合併之有機層用檸檬酸(53 g)於水(500 mL)中之溶液洗滌兩次,然後用80%鹽水(300 mL)洗滌,然後用硫酸鎂乾燥,過濾並在減壓下濃縮。將殘餘物溶於甲醇(500 mL)中,並在分液漏斗中分離除去其自氫化鈉懸浮液攜帶的不混溶油。在真空下蒸發掉溶劑,並用己烷(250 mL)洗滌殘餘物,其後獲得黏稠油狀產物2-胺基-6-異丁氧基苄腈(46克,產率:66%)。1H NMR(400 MHz,DMSO-d6)δ7.16(t,J=8.0 Hz,1H),6.33(d,J=8.0 Hz,1H),6.17(d,J=8.0 Hz,1H),5.97(s,2H),3.75(d,J=7.2 Hz,2H),2.00(m,1H),0.97(d,J=6.8 Hz,6H) ppm。MS 191(MH+)。
實例41c:2-異丁氧基-6-硝基苄腈在0℃及N2下向2-甲基丙-1-醇(9.6 mL,0.104 mol)於無水THF(200 mL)中之溶液中以小份添加NaH(60%存於礦物油中,4.565 g,0.114 mol)。在室溫下將其攪拌30 min後,將反應混合物冷卻至-70℃並逐份添加2,6-二硝基苄腈(20.0 g,0.104 mol)。在完成添加後,在-70℃至室溫下將反應混合物攪拌過夜,然後倒入冰水(600 mL)中。藉由過濾收集所得沉澱並用水、己烷沖洗,並進行空氣乾燥,得到呈淺黃色固體形式之2-異丁氧基-6-硝基苄腈(34.3 g,100%)。1H NMR(400 MHz,DMSO-d6)δ1.0(d,J=6.8 Hz,6H),2.04-2.11(m,1H),4.02(d,J=6.8 Hz,2H),7.69-7.71(m,1H),7.84-7.90(m,2H)。MS 221(MH+)。實例42:4-胺基-5-異丙氧基-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-異丙氧基-2-甲基喹啉-3-甲酸乙基酯(實例42a)進行製備,得到白色固體(71%)。1H NMR(400 MHz,DMSO-d6)δ1.4(d,J=6.4 Hz,6H),2.73(s,3H),4.87-4.93(m,1H),7.01(d,J=8.0 Hz,1H),7.27(d,J=8.0 Hz,1H),7.60(t,J=8.4 Hz,1H)。MS 261(MH+)。實例42a:4-胺基-5-異丙氧基-2-甲基喹啉-3-甲酸乙基酯如實例2a自2-胺基-6-異丙氧基苄腈(Tachdjian,C.等人PCT Int. Appl. 2008,WO 2008154221)及3-側氧基丁酸乙基酯進行製備,得到灰白色固體(32%)。1H NMR(400 MHz,DMSO-d6)δ1.32(t,J=7.6 Hz,3H),1.38(d,J=6.0 Hz,6H),2.54(s,3H),4.3(q,J=7.2 Hz,2H),4.83-4.89(m,1H),6.93(d,J=8.0 Hz,1H),7.20(d,J=8.0 Hz,1H),7.50(t,J=8.4 Hz,1H),8.14(s,2H)。MS289(MH+)。實例43:4-胺基-5-((1-(羥基甲基)環己基)甲氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-((1-(羥基甲基)環己基)-甲氧基)-2-甲基喹啉-3-甲酸乙基酯(實例43a)進行製備,得到灰白色固體(49%)。1H NMR(400 MHz,DMSO-d6)δ1.37-1.48(m,10H),2.75(s,3H),3.50(s,2H),4.03(s,2H),5.08(brs,1H),7.06(d,J=8.4 Hz,1H),7.25(d,J=8.8 Hz,1H),7.66(t,J=8.4 Hz,1H),9.39(brs,1H),12.17(brs,1H),12.74(brs,1H)。MS 345(MH+)。
實例43a:4-胺基-5-((1-(羥基甲基)環己基)甲氧基)-2-甲基-喹啉-3-甲酸乙基酯如實例2a自乙酸(1-((3-胺基-2-氰基苯氧基)甲基)環己基)-甲基酯(Tachdjian,C.等人PCT Int. Appl. 2008,WO 2008154221)及3-側氧基丁酸乙基酯進行製備,得到灰白色固體(60%)。MS 373(MH+)。實例44:4-胺基-5-(2-(3,5-二羥基苯甲醯胺基)-2-甲基丙氧基)-2-甲基-喹啉-3-甲酸
如實例1自4-胺基-5-(2-(3,5-二羥基苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例44a)進行製備,得到白色固體(73%)。1H NMR(400 MHz,DMSO-d6)δ1.46(s,6H),2.75(s,3H),4.44(s,2H),6.3-6.31(m,1H),6.61(s,2H),7.04(d,J=8.0 Hz,1H),7.27(d,J=8.4 Hz,1H),7.66(t,J=8.0 Hz,1H),7.98(s,1H),8.79(brs,1H),9.48(s,2H)。MS 426(MH+)。實例44a:4-胺基-5-(2-(3,5-二羥基苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自4-胺基-5-(2-胺基-2-甲基丙氧基)-2-甲基喹啉-3-甲酸酯(實例24b)及3,5-二羥基苯甲酸進行製備,得到黃褐色固體(15%)。MS 454(MH+)。實例45:4-胺基-5-((4-(異丙基胺基甲醯基)環己基)氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-((4-(異丙基胺基甲醯基)環己基)-氧基)-2-甲基喹啉-3-甲酸乙基酯(實例45a)進行製備,得到白色粉末(71%)。1H NMR(400 MHz,DMSO-d6)δ1.01(d,J=6.4 Hz,6H),1.59-1.68(m,6H),2.06-2.09(m,2H),2.2-2.22(m,1H),2.76(s,3H),3.77-3.83(m,1H),4.96(s,1H),7.06(d,J=8.0 Hz,1H),7.26(d,J=8.4 Hz,1H),7.58(d,J=8.0 Hz,1H),7.65(t,J=8.4 Hz,1H),8.79(brs,1H),12.84(brs,2H)。MS 386(MH+)。實例45a:4-胺基-5-((4-(異丙基胺基甲醯基)環己基)氧基)-2-甲基-喹啉-3-甲酸乙基酯如實例2a自4-(3-胺基-2-氰基苯氧基)-N-異丙基環己烷-甲醯胺(實例45b)及3-側氧基丁酸乙基酯進行製備,得到黃色固體(56%)。MS 414(MH+)。
實例45b:4-(3-胺基-2-氰基苯氧基)-N-異丙基環己烷甲醯胺如實例22b自4-羥基-N-異丙基環己烷甲醯胺(實例45c)及2-胺基-6-氟苄腈進行製備,得到灰白色固體(17%)。1H NMR(400 MHz,DMSO-d6)δ1.01(d,J=6.4 Hz,6H),1.47-1.57(m,4H),1.67-1.77(m,2H),1.89-1.93(m,2H),2.08-2.15(m,1H),3.75-3.84(m,1H),4.57(brs,1H),5.93(s,2H),6.19(d,J=8.0 Hz,1H),6.28(d,J=8.0 Hz,1H),7.13(t,J=8.0 Hz,1H),7.48(d,J=8.0 Hz,1H)。MS 302(MH+)。實例45c:4-羥基-N-異丙基環己烷甲醯胺如實例24a自4-羥基環己烷甲酸及丙-2-胺進行製備,無色油狀(68%)。MS 186(MH+)。
實例46:4-胺基-5-(3-((3-甲氧基苄基)胺基)-2,2-二甲基-3-側氧基丙氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(3-((3-甲氧基苄基)胺基)-2,2-二甲基-3-側氧基丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例46a)進行製備,得到白色粉末(58%)。M.p.:172至174℃。1H NMR(400 MHz,DMSO-d6)δ1.31(s,6H),2.76(s,3H),3.53(s,3H),4.21(s,2H),4.27(d,J=5.6 Hz,2H),6.64(dd,J=8.0,2.4 Hz,1H),6.69(m,1H),6.72(d,J=8.0 Hz,1H),6.98-7.10(m,2H),7.28(d,J=8.0 Hz,1H),7.66(t,J=8.0 Hz,1H),8.47(t,J=5.6 Hz,1H),8.77(brs,1H),12.26(brs,1H),12.79(brs,1H)。MS 438(MH+)。實例46a:4-胺基-5-(3-((3-甲氧基苄基)胺基)-2,2-二甲基-3-側氧基丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例2a自3-(3-胺基-2-氰基苯氧基)-N-(3-甲氧基苄基)-2,2-二甲基丙醯胺(實例46b)及3-側氧基丁酸乙基酯進行製備,得到黃色固體(42%)。MS 466(MH+)。
實例46b:3-(3-胺基-2-氰基苯氧基)-N-(3-甲氧基苄基)-2,2-二甲基丙-醯胺如實例22b自3-羥基-N-(3-甲氧基苄基)-2,2-二甲基-丙醯胺(實例46c)及2-胺基-6-氟苄腈進行製備,得到白色固體(41%)。MS 354(MH+)。實例46c:3-羥基-N-(3-甲氧基苄基)-2,2-二甲基丙醯胺如實例24a自3-羥基-2,2-二甲基丙酸及(3-甲氧基苯基)甲胺進行製備,橙色油狀(41%)。MS 238(MH+)。實例47:4-胺基-5-(3-(環己基胺基)-2,2-二甲基-3-側氧基丙氧基)-2-甲基-喹啉-3-甲酸
如實例1自4-胺基-5-(3-(環己基胺基)-2,2-二甲基-3-側氧基丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例47a)進行製備,得到灰白色固體(13%)。MS 400(MH+)。實例47a:4-胺基-5-(3-(環己基胺基)-2,2-二甲基-3-側氧基丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自3-((4-胺基-3-(乙氧基羰基)-2-甲基喹啉-5-基)氧基)-2,2-二甲基丙酸(實例47b)及環己胺進行製備,得到黃褐色固體(46%)。MS 428(MH+)。實例47b:3-((4-胺基-3-(乙氧基羰基)-2-甲基喹啉-5-基)氧基)-2,2-二甲基-丙酸如實例2a自3-(3-胺基-2-氰基苯氧基)-2,2-二甲基-丙酸苄基酯(實例47c)及3-側氧基丁酸乙基酯進行製備,得到褐色固體(80%)。MS 192(MH+)。
實例47c:3-(3-胺基-2-氰基苯氧基)-2,2-二甲基丙酸酯在室溫下向3-(2-氰基-3-硝基苯氧基)-2,2-二甲基丙酸苄基酯(實例47d,200 mg,0.56 mmol)於AcOH(5 mL)中之溶液中添加鐵粉(158 mg,2.82 mmol)。然後在90℃下將反應混合物攪拌1 h。將反應混合物冷卻至室溫,然後用AcOEt稀釋。濾除沉澱並依次用1 N NaOH及鹽水洗滌濾液,然後經Na2SO4乾燥,過濾並蒸發。藉由在矽膠上實施層析(洗脫液:存於己烷中之40% EtOAc)來純化殘餘物,得到無色油狀標題化合物(187 mg,100%)。MS 325(MH+)。
實例47d:3-(2-氰基-3-硝基苯氧基)-2,2-二甲基丙酸苄基酯在0℃及氮下向3-羥基-2,2-二甲基丙酸苄基酯(Yang,D.等人J. Am. Chem. Soc. 2002,124,9966. 6.68 g,32.1 mmol)於無水THF(200 mL)中之溶液中以小份小心地添加NaH(60%存於礦物油中,3.5 g,87.5 mmol)。在0℃及氮下將反應混合物攪拌2小時。向該溶液中添加2,6-二硝基苄腈(6.19 g,32.1 mmol),並在0℃至室溫及氮下將反應溶液攪拌過夜。用鹽水淬滅反應混合物並用EtOAc(3X)萃取。用鹽水洗滌合併之有機層,經Na2SO4乾燥。在溶劑蒸發後,藉由層析在矽膠上洗脫(洗脫液:20% EtOAc存於己烷中)來純化殘餘物,得到呈褐色固體形式之標題化合物(10.0 g,87%)。MS 355(MH+)。
實例48:4-胺基-5-(3-(環庚基胺基)-2,2-二甲基-3-側氧基丙氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(3-(環庚基胺基)-2,2-二甲基-3-側氧基丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例48a)進行製備,得到灰白色固體(12%)。MS 414(MH+)。實例48a:4-胺基-5-(3-(環庚基胺基)-2,2-二甲基-3-側氧基丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自3-((4-胺基-3-(乙氧基羰基)-2-甲基喹啉-5-基)氧基)-2,2-二甲基丙酸(實例47b)及環庚胺進行製備,得到褐色固體(43%)。MS 456(MH+)。實例49:4-胺基-5-(3-(環辛基胺基)-2,2-二甲基-3-側氧基丙氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(3-(環辛基胺基)-2,2-二甲基-3-側氧基丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例49a)進行製備,得到灰白色固體(11%)。MS 428(MH+)。實例49a:4-胺基-5-(3-(環辛基胺基)-2,2-二甲基-3-側氧基丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自3-((4-胺基-3-(乙氧基羰基)-2-甲基喹啉-5-基)氧基)-2,2-二甲基丙酸(實例47b)及環辛胺進行製備,得到褐色固體(46%)。MS 456(MH+)。實例50:4-胺基-5-(3-((3-羥基-2,2-二甲基丙基)胺基)-2,2-二甲基-3-側氧基丙氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(3-((3-羥基-2,2-二甲基丙基)-胺基)-2,2-二甲基-3-側氧基丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例50a)進行製備,得到灰白色固體(87%)。1H NMR(400 MHz,DMSO-d6)δ0.71(s,6H),1.28(s,6H),2.74(s,3H),2.97(d,J=6.0 Hz,2H),3.0(s,2H),4.57(brs,1H),6.99(d,J=8.4 Hz,1H),7.27(d,J=8.0 Hz,1H),7.65(t,J=8.4 Hz,1H),7.77(t,J=6.4 Hz,1H),8.78(brs,1H),12.04(brs,1H),12.82(brs,1H)。MS 404(MH+)。實例50a:4-胺基-5-(3-((3-羥基-2,2-二甲基丙基)胺基)-2,2-二甲基-3-側氧基丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自3-((4-胺基-3-(乙氧基羰基)-2-甲基喹啉-5-基)氧基)-2,2-二甲基丙酸(實例47b)及3-胺基-2,2-二甲基丙-1-醇進行製備,得到褐色固體(40%)。MS 432(MH+)。實例51:4-胺基-5-(3- -4-基胺基)-2,2-二甲基-3-側氧基丙氧基)-2-甲基-喹啉-3-甲酸
如實例1自4-胺基-5-(3--4-基胺基)-2,2-二甲基-3-側氧基丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例51a)進行製備,得到灰白色固體(80%)。1H NMR(400 MHz,DMSO-d6)δ1.31(d,J=4.0 Hz,6H),1.80-2.00(m,2H),2.76(s,3H),4.05-4.19(m,2H),4.24(s,2H),5.10(q,J=6.8 Hz,1H),6.51(t,J=7.6 Hz,1H),6.89(d,J=8.4 Hz,1H),6.94(d,J=8.0 Hz,1H),7.01(dd,J=15.0,8.4 Hz,2H),7.30(d,J=8.8 Hz,1H),7.66(t,J=8.4 Hz,1H),8.26(d,J=8.8 Hz,1H),8.77(brs,1H),12.31(brs,1H),12.86(brs,1H)。MS 450(MH+)。實例51a:4-胺基-5-(3--4-基胺基)-2,2-二甲基-3-側氧基丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自3-((4-胺基-3-(乙氧基羰基)-2-甲基喹啉-5-基)氧基)-2,2-二甲基丙酸(實例47b)及-4-胺(Lu,Y.等人PCT Int. Appl. 2008,WO 2008043019)進行製備,得到褐色固體(37%)。MS 478(MH+)。實例52:4-胺基-5-(3-((5-甲氧基-1,2,3,4-四氫萘-1-基)胺基)-2,2-二甲基-3-側氧基丙氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(3-((5-甲氧基-1,2,3,4-四氫-萘-1-基)胺基)-2,2-二甲基-3-側氧基丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例52a)進行製備,得到灰白色固體(69%)。1H NMR(400 MHz,DMSO-d6)δ1.30(d,J=4.0 Hz,6H),1.52-1.87(m,4H),2.75(s,3H),4.22(s,2H),4.95-5.05(m,1H),6.59(d,J=7.2 Hz,1H),6.67-6.75(m,2H),6.97(d,J=8.4 Hz,1H),7.28(d,J=8.0 Hz,2H),7.64(t,J=8.4 Hz,1H),8.13(d,J=8.8 Hz,1H),8.74(brs,1H),12.22(brs,1H),12.80(brs,1H)。MS 478(MH+)。
實例52a:4-胺基-5-(3-((5-甲氧基-1,2,3,4-四氫萘-1-基)胺基)-2,2-二甲基-3-側氧基丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自3-((4-胺基-3-(乙氧基羰基)-2-甲基喹啉-5-基)氧基)-2,2-二甲基丙酸(實例47b)及5-甲氧基-1,2,3,4-四氫萘-1-胺進行製備,得到褐色固體(40%)。MS 506(MH+)。
實例53:4-胺基-5-(2-(4-甲氧基苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(2-(4-甲氧基苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例53a)進行製備,得到白色固體。MS 424(MH+)。實例53a:4-胺基-5-(2-(4-甲氧基苯甲醯胺基)-2-甲基丙氧基)-2-甲基-喹啉-3-甲酸乙基酯如實例24a自4-胺基-5-(2-胺基-2-甲基丙氧基)-2-甲基喹啉-3-甲酸酯(實例24b)及4-甲氧基苯甲酸進行製備,得到褐色固體。MS 452(MH+)。實例54:4-胺基-5-(2-(2-羥基苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(2-(2-羥基苯甲醯胺基)-2-甲基-丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例54a)進行製備,得到灰白色固體。MS 410(MH+)。實例54a:4-胺基-5-(2-(2-羥基苯甲醯胺基)-2-甲基丙氧基)-2-甲基-喹啉-3-甲酸乙基酯如實例24a自4-胺基-5-(2-胺基-2-甲基丙氧基)-2-甲基喹啉-3-甲酸酯(實例24b)及2-羥基苯甲酸進行製備,得到褐色固體。MS 438(MH+)。實例55:4-胺基-5-(2-(3-甲氧基苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(2-(3-甲氧基苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例55a)進行製備,得到白色固體。MS 424(MH+)。實例55a:4-胺基-5-(2-(3-甲氧基苯甲醯胺基)-2-甲基丙氧基)-2-甲基-喹啉-3-甲酸乙基酯如實例24a自4-胺基-5-(2-胺基-2-甲基丙氧基)-2-甲基喹啉-3-甲酸酯(實例24b)及3-甲氧基苯甲酸進行製備,得到褐色固體。MS 452(MH+)。實例56:4-胺基-5-(2-苯甲醯胺基-2-甲基丙氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(2-苯甲醯胺基-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例56a)進行製備,得到白色固體。MS 394(MH+)。實例56a:4-胺基-5-(2-苯甲醯胺基-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自4-胺基-5-(2-胺基-2-甲基丙氧基)-2-甲基喹啉-3-甲酸酯(實例24b)及苯甲酸進行製備,得到褐色固體。MS 422(MH+)。實例57:4-胺基-5-(2-(4-羥基苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(2-(4-羥基苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例57a)進行製備,得到灰白色固體。MS 410(MH+)。實例57a:4-胺基-5-(2-(4-羥基苯甲醯胺基)-2-甲基丙氧基)-2-甲基-喹啉-3-甲酸乙基酯如實例24a自4-胺基-5-(2-胺基-2-甲基丙氧基)-2-甲基喹啉-3-甲酸酯(實例24b)及4-羥基苯甲酸進行製備,得到褐色固體。MS 438(MH+)。
實例58:4-胺基-5-(2-(2-氟苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(2-(2-氟苯甲醯胺基)-2-甲基-丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例58a)進行製備,得到灰白色固體。MS 412(MH+)。實例58a:4-胺基-5-(2-(2-氟苯甲醯胺基)-2-甲基丙氧基)-2-甲基-喹啉-3-甲酸乙基酯如實例24a自4-胺基-5-(2-胺基-2-甲基丙氧基)-2-甲基喹啉-3-甲酸酯(實例24b)及2-氟苯甲酸進行製備,得到褐色固體。MS 440(MH+)。實例59:4-胺基-5-(2-(3-氟苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(2-(3-氟苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例59a)進行製備,得到灰白色固體。MS 412(MH+)。實例59a:4-胺基-5-(2-(3-氟苯甲醯胺基)-2-甲基丙氧基)-2-甲基-喹啉-3-甲酸乙基酯如實例24a自4-胺基-5-(2-胺基-2-甲基丙氧基)-2-甲基喹啉-3-甲酸酯(實例24b)及3-氟苯甲酸進行製備,得到褐色固體。MS 440(MH+)。實例60:4-胺基-5-(2-(3-羥基-4-甲氧基苯甲醯胺基)-2-甲基丙氧基)-2-甲基-喹啉-3-甲酸
如實例1自4-胺基-5-(2-(3-羥基-4-甲氧基苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例60a)進行製備,得到灰白色固體。MS 440(MH+)。實例60a:4-胺基-5-(2-(3-羥基-4-甲氧基苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自4-胺基-5-(2-胺基-2-甲基丙氧基)-2-甲基喹啉-3-甲酸酯(實例24b)及3-羥基-4-甲氧基苯甲酸進行製備,得到褐色固體。MS 468(MH+)。實例61:4-胺基-5-(2-(3-胺基甲醯基苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(2-(3-胺基甲醯基苯甲醯胺基)-2-甲基-丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例61a)進行製備,得到灰白色固體。MS 437(MH+)。實例61a:4-胺基-5-(2-(3-胺基甲醯基苯甲醯胺基)-2-甲基丙氧基)-2-甲基-喹啉-3-甲酸乙基酯如實例24a自4-胺基-5-(2-胺基-2-甲基丙氧基)-2-甲基喹啉-3-甲酸酯(實例24b)及3-胺基甲醯基苯甲酸進行製備,得到褐色固體。MS 465(MH+)。實例62:4-胺基-5-(2-(2,3-二氫苯并[b][1,4]二氧雜環戊烯-6-甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸(4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylpro-poxy)-2-methylquinoline-3-carboxylic acid)
如實例1自4-胺基-5-(2-(2,3-二氫苯并[b][1,4]二氧雜環戊烯-6-甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例62a)進行製備,得到淺黃色固體(18%)。1H NMR(400 MHz,DMSO-d6)δ1.49(s,6H),2.76(s,3H),4.25(m,4H),4.48(s,2H),6.87(d,J=8.8 Hz,1H),7.06(d,J=7.6 Hz,1H),7.39-7.26(m,3H),7.67(t,J=7.2 Hz,1H),7.99(s,1H),8.83(brs,1H),12.31(brs,1H),12.71(brs,1H)。MS 452(MH+)。
實例62a:4-胺基-5-(2-(2,3-二氫苯并[b][1,4]二氧雜環戊烯-6-甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自4-胺基-5-(2-胺基-2-甲基丙氧基)-2-甲基喹啉-3-甲酸酯(實例24b)及2,3-二氫苯并[b][1,4]二氧雜環戊烯-6-甲酸進行製備,得到褐色固體(60%)。MS 480(MH+)。實例63:4-胺基-5-(2-(2-乙基丁醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(2-(2-乙基丁醯胺基)-2-甲基-丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例63a)進行製備,得到灰白色固體。MS 388(MH+)。實例63a:4-胺基-5-(2-(2-乙基丁醯胺基)-2-甲基丙氧基)-2-甲基-喹啉-3-甲酸乙基酯如實例24a自4-胺基-5-(2-胺基-2-甲基丙氧基)-2-甲基喹啉-3-甲酸酯(實例24b)及2-乙基丁酸進行製備,得到褐色固體。MS 416(MH+)。實例64:4-胺基-5-(2-(3-甲氧基丙醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(2-(3-甲氧基丙醯胺基)-2-甲基-丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例64a)進行製備,得到灰白色固體。MS 376(MH+)。實例64a:4-胺基-5-(2-(3-甲氧基丙醯胺基)-2-甲基丙氧基)-2-甲基-喹啉-3-甲酸乙基酯如實例24a自4-胺基-5-(2-胺基-2-甲基丙氧基)-2-甲基喹啉-3-甲酸酯(實例24b)及3-甲氧基丙酸進行製備,得到褐色固體。MS 404(MH+)。
實例65:4-胺基-5-(2-丁醯胺基-2-甲基丙氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(2-丁醯胺基-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例65a)進行製備,得到灰白色固體。MS 360(MH+)。實例65a:4-胺基-5-(2-丁醯胺基-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自4-胺基-5-(2-胺基-2-甲基丙氧基)-2-甲基喹啉-3-甲酸酯(實例24b)及丁酸進行製備,得到褐色固體。MS 388(MH+)。實例66:4-胺基-2-甲基-5-(2-甲基-2-(四氫呋喃-3-甲醯胺基)丙氧基)-喹啉-3-甲酸
如實例1自4-胺基-2-甲基-5-(2-甲基-2-(四氫呋喃-3-甲醯胺基)丙氧基)喹啉-3-甲酸乙基酯(實例66a)進行製備,得到灰白色固體。MS 388(MH+)。
實例66a:4-胺基-2-甲基-5-(2-甲基-2-(四氫呋喃-3-甲醯胺基)-丙氧基)喹啉-3-甲酸乙基酯如實例24a自4-胺基-5-(2-胺基-2-甲基丙氧基)-2-甲基喹啉-3-甲酸酯(實例24b)及四氫呋喃-3-甲酸進行製備,得到褐色固體。MS 416(MH+)。實例67:4-胺基-5-(2-(4-(羥基甲基)苯甲醯胺基)-2-甲基丙氧基)-2-甲基-喹啉-3-甲酸
如實例1自4-胺基-5-(2-(4-(羥基甲基)苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例67a)進行製備,得到灰白色固體。MS 424(MH+)。實例67a:4-胺基-5-(2-(4-(羥基甲基)苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自4-胺基-5-(2-胺基-2-甲基丙氧基)-2-甲基喹啉-3-甲酸酯(實例24b)及4-(羥基甲基)苯甲酸進行製備,得到褐色固體。MS 452(MH+)。實例68:4-胺基-5-(2-(2-甲氧基乙醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(2-(2-甲氧基乙醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例68a)進行製備,得到灰白色固體。MS 362(MH+)。實例68a:4-胺基-5-(2-(2-甲氧基乙醯胺基)-2-甲基丙氧基)-2-甲基-喹啉-3-甲酸乙基酯如實例24a自4-胺基-5-(2-胺基-2-甲基丙氧基)-2-甲基喹啉-3-甲酸酯(實例24b)及2-甲氧基乙酸進行製備,得到褐色固體。MS 390(MH+)。實例69:5-(2-乙醯胺基-2-甲基丙氧基)-4-胺基-2-甲基喹啉-3-甲酸
如實例1自5-(2-乙醯胺基-2-甲基丙氧基)-4-胺基-2-甲基喹啉-3-甲酸乙基酯(實例69a)進行製備,得到灰白色固體。MS 332(MH+)。實例69a:5-(2-乙醯胺基-2-甲基丙氧基)-4-胺基-2-甲基喹啉-3-甲酸乙基酯如實例24a自4-胺基-5-(2-胺基-2-甲基丙氧基)-2-甲基喹啉-3-甲酸酯(實例24b)及乙酸進行製備,得到褐色固體。MS 390(MH+)。實例70:4-胺基-5-(2-(2,3-二氫苯并[b][1,4]二氧雜環戊烯-5-甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(2-(2,3-二氫苯并[b][1,4]二氧雜環戊烯-5-甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例70a)進行製備,得到灰白色固體。MS 452(MH+)。實例70a:4-胺基-5-(2-(2,3-二氫苯并[b][1,4]二氧雜環戊烯-5-甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自4-胺基-5-(2-胺基-2-甲基丙氧基)-2-甲基喹啉-3-甲酸酯(實例24b)及2,3-二氫苯并[b][1,4]二氧雜環戊烯-5-甲酸進行製備,得到褐色固體。MS 480(MH+)。實例71:4-胺基-5-(2-(3,5-二甲氧基苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(2-(3,5-二甲氧基苯甲醯胺基)-2-甲基-丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例71a)進行製備,得到灰白色固體。MS 454(MH+)。實例71a:4-胺基-5-(2-(3,5-二甲氧基苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自4-胺基-5-(2-胺基-2-甲基丙氧基)-2-甲基喹啉-3-甲酸酯(實例24b)及3,5-二甲氧基苯甲酸進行製備,得到褐色固體。MS 482(MH+)。實例72:4-胺基-5-(2-(3,4-二甲氧基苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(2-(3,4-二甲氧基苯甲醯胺基)-2-甲基-丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例72a)進行製備,得到灰白色固體。MS 454(MH+)。實例72a:4-胺基-5-(2-(3,4-二甲氧基苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自4-胺基-5-(2-胺基-2-甲基丙氧基)-2-甲基喹啉-3-甲酸酯(實例24b)及3,4-二甲氧基苯甲酸進行製備,得到褐色固體。MS 482(MH+)。實例73:4-胺基-5-(2-(2-(4-甲氧基苯基)乙醯胺基)-2-甲基丙氧基)-2-甲基-喹啉-3-甲酸
如實例1自4-胺基-5-(2-(2-(4-甲氧基苯基)乙醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例73a)進行製備,得到灰白色固體。MS 438(MH+)。實例73a:4-胺基-5-(2-(2-(4-甲氧基苯基)乙醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自4-胺基-5-(2-胺基-2-甲基丙氧基)-2-甲基喹啉-3-甲酸酯(實例24b)及2-(3,4-二甲氧基苯基)乙酸進行製備,得到褐色固體。MS 466(MH+)。實例74:4-胺基-5-(2-(4-氟-3-羥基苯甲醯胺基)-2-甲基丙氧 基)-2-甲基-喹啉-3-甲酸
如實例1自4-胺基-5-(2-(4-氟-3-羥基苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例74a)進行製備,得到灰白色固體。MS 428(MH+)。實例74a:4-胺基-5-(2-(4-氟-3-羥基苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自4-胺基-5-(2-胺基-2-甲基丙氧基)-2-甲基喹啉-3-甲酸酯(實例24b)及4-氟-3-羥基苯甲酸進行製備,得到褐色固體。MS 456(MH+)。實例75:4-胺基-5-(2-(3-羥基-5-甲氧基苯甲醯胺基)-2-甲基丙氧基)-2-甲基-喹啉-3-甲酸
如實例1自4-胺基-5-(2-(3-羥基-5-甲氧基苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例75a)進行製備,得到灰白色固體。MS 440(MH+)。實例75a:4-胺基-5-(2-(3-羥基-5-甲氧基苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自4-胺基-5-(2-胺基-2-甲基丙氧基)-2-甲基喹啉-3-甲酸酯(實例24b)及3-羥基-5-甲氧基苯甲酸進行製備,得到褐色固體。MS 468(MH+)。實例76:4-胺基-5-(2-(4-(2-羥基乙氧基)-3-甲氧基苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(2-(4-(2-羥基乙氧基)-3-甲氧基-苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例76a)進行製備,得到灰白色固體。MS 484(MH+)。實例76a:4-胺基-5-(2-(4-(2-羥基乙氧基)-3-甲氧基苯甲醯胺基)-2-甲基-丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自4-胺基-5-(2-胺基-2-甲基丙氧基)-2-甲基喹啉-3-甲酸酯(實例24b)及4-(2-羥基乙氧基)-3-甲氧基苯甲酸(Uto,Y.等人Bioorg. Med. Chem. Lett. 2009,19,4151.)進行製備,得到褐色固體。MS 512(MH+)。實例77:4-胺基-5-(2-(3-(2-羥基乙氧基)-4-甲氧基苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(2-(3-(2-羥基乙氧基)-4-甲氧基-苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例77a)進行製備,得到灰白色固體。MS 484(MH+)。實例77a:4-胺基-5-(2-(3-(2-羥基乙氧基)-4-甲氧基苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自4-胺基-5-(2-胺基-2-甲基丙氧基)-2-甲基喹啉-3-甲酸酯(實例24b)及3-(2-羥基乙氧基)-4-甲氧基苯甲酸進行製備,得到褐色固體。MS 512(MH+)。實例78:4-胺基-5-(2-(3-(3-羥基丙氧基)-4-甲氧基苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(2-(3-(3-羥基丙氧基)-4-甲氧基-苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例78a)進行製備,得到灰白色固體。MS 498(MH+)。實例78a:4-胺基-5-(2-(3-(3-羥基丙氧基)-4-甲氧基苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自4-胺基-5-(2-胺基-2-甲基丙氧基)-2-甲基喹啉-3-甲酸酯(實例24b)及3-(3-羥基丙氧基)-4-甲氧基苯甲酸進行製備,得到褐色固體。MS 526(MH+)。實例79:4-胺基-5-(2-(4-(3-羥基丙氧基)-3-甲氧基苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(2-(4-(3-羥基丙氧基)-3-甲氧基-苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例79a)進行製備,得到灰白色固體。MS 498(MH+)。實例79a:4-胺基-5-(2-(4-(3-羥基丙氧基)-3-甲氧基苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自4-胺基-5-(2-胺基-2-甲基丙氧基)-2-甲基喹啉-3-甲酸酯(實例24b)及4-(3-羥基丙氧基)-3-甲氧基苯甲酸(Baraldi,P.G.等人J. Med. Chem. 1999,42,5131.)進行製備,得到褐色固體。MS 526(MH+)。實例80:(S)-4-胺基-5-(2-(2,3-二氫苯并[b][1,4]二氧雜環戊烯-6-甲醯胺基)丙氧基)-2-甲基喹啉-3-甲酸
如實例1自(S)-4-胺基-5-(2-(2,3-二氫苯并[b][1,4]二氧雜環戊烯-6-甲醯胺基)丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例80a)進行製備,得到灰白色固體。MS 438(MH+)。實例80a:(S)-4-胺基-5-(2-(2,3-二氫苯并[b][1,4]二氧雜環戊烯-6-甲醯胺基)-丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自(S)-4-胺基-5-(2-胺基丙氧基)-2-甲基-喹啉-3-甲酸乙基酯(實例26b)及2,3-二氫苯并[b][1,4]二氧雜環戊烯-6-甲酸進行製備,得到褐色固體。MS 466(MH+)。實例81:(S)-4-胺基-5-(2-(2,3-二氫苯并[b][1,4]二氧雜環戊烯-5-甲醯胺基)丙氧基)-2-甲基喹啉-3-甲酸
如實例1自(S)-4-胺基-5-(2-(2,3-二氫苯并[b][1,4]二氧雜環戊烯-5-甲醯胺基)丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例81a)進行製備,得到灰白色固體。MS 438(MH+)。實例81a:(S)-4-胺基-5-(2-(2,3-二氫苯并[b][1,4]二氧雜環戊烯-5-甲醯胺基)-丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自(S)-4-胺基-5-(2-胺基丙氧基)-2-甲基-喹啉-3-甲酸乙基酯(實例26b)及2,3-二氫苯并[b][1,4]二氧雜環戊烯-5-甲酸進行製備,得到褐色固體。MS 466(MH+)。實例82:(S)-4-胺基-5-(2-(4-(2-羥基乙氧基)-3-甲氧基苯甲醯胺基)丙氧基)-2-甲基喹啉-3-甲酸
如實例1自(S)-4-胺基-5-(2-(4-(2-羥基乙氧基)-3-甲氧基苯甲醯胺基)丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例82a)進行製備,得到灰白色固體。MS 470(MH+)。實例82a:(S)-4-胺基-5-(2-(4-(2-羥基乙氧基)-3-甲氧基苯甲醯胺基)丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自(S)-4-胺基-5-(2-胺基丙氧基)-2-甲基-喹啉-3-甲酸乙基酯(實例26b)及4-(2-羥基乙氧基)-3-甲氧基苯甲酸(Uto,Y.等人Bioorg. Med. Chem. Lett. 2009,19,4151.)進行製備,得到褐色固體。MS 498(MH+)。實例83:(S)-4-胺基-5-(2-(3-(2-羥基乙氧基)-4-甲氧基苯甲醯胺基)丙氧基)-2-甲基喹啉-3-甲酸
如實例1自(S)-4-胺基-5-(2-(3-(2-羥基乙氧基)-4-甲氧基苯甲醯胺基)丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例83a)進行製備,得到灰白色固體。MS 470(MH+)。實例83a:(S)-4-胺基-5-(2-(3-(2-羥基乙氧基)-4-甲氧基苯甲醯胺基)丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自(S)-4-胺基-5-(2-胺基丙氧基)-2-甲基-喹啉-3-甲酸乙基酯(實例26b)及3-(2-羥基乙氧基)-4-甲氧基苯甲酸進行製備,得到褐色固體。MS 498(MH+)。實例84:(S)-4-胺基-5-(2-(3-(3-羥基丙氧基)-4-甲氧基苯甲醯胺基)丙氧基)-2-甲基喹啉-3-甲酸
如實例1自(S)-4-胺基-5-(2-(3-(3-羥基丙氧基)-4-甲氧基苯甲醯胺基)丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例84a)進行製備,得到灰白色固體。MS 484(MH+)。實例84a:(S)-4-胺基-5-(2-(3-(3-羥基丙氧基)-4-甲氧基苯甲醯胺基)丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自(S)-4-胺基-5-(2-胺基丙氧基)-2-甲基-喹啉-3-甲酸乙基酯(實例26b)及3-(3-羥基丙氧基)-4-甲氧基苯甲酸進行製備,得到褐色固體。MS 512(MH+)。
實例85:(S)-4-胺基-5-(2-(4-(3-羥基丙氧基)-3-甲氧基苯甲醯胺基)丙氧基)-2-甲基喹啉-3-甲酸
如實例1自(S)-4-胺基-5-(2-(4-(3-羥基丙氧基)-3-甲氧基苯甲醯胺基)丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例85a)進行製備,得到灰白色固體。MS 484(MH+)。實例85a:(S)-4-胺基-5-(2-(4-(3-羥基丙氧基)-3-甲氧基苯甲醯胺基)丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自(S)-4-胺基-5-(2-胺基丙氧基)-2-甲基-喹啉-3-甲酸乙基酯(實例26b)及4-(3-羥基丙氧基)-3-甲氧基苯甲酸(Baraldi,P. G.等人J. Med. Chem. 1999,42,5131.)進行製備,得到褐色固體。MS 512(MH+)。實例86:(R)-4-胺基-5-(2-(環己烷甲醯胺基)丙氧基)-2-甲基喹啉-3-甲酸(SID 47687595)
如實例1自(R)-4-胺基-5-(2-(環己烷甲醯胺基)-丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例86a)進行製備,得到白色固體(43%)。1H NMR(400 MHz,DMSO-d6)δ1.25-1.10(m,5H),1.34-1.31(m,2H),1.69-1.62(m,5H),2.11-2.05(m,1H),2.69(s,3H),3.93(t,J=9.2 Hz,1H),4.13(dd,J=4,9.6 Hz,1H),4.14-4.11(m,1H),6.86(d,J=8.0 Hz,1H),7.28(d,J=8.4 Hz,1H),7.49(t,J=8.0 Hz,1H),7.95(d,J=8.4 Hz,1H)。MS 386(MH+)。
實例86a:(R)-4-胺基-5-(2-(環己烷甲醯胺基)丙氧基)-2-甲基-喹啉-3-甲酸乙基酯如實例24a自(R)-4-胺基-5-(2-胺基丙氧基)-2-甲基-喹啉-3-甲酸乙基酯(實例86b)及環己烷甲酸進行製備,得到褐色固體(31%)。MS 414(MH+)。實例86b:(R)-4-胺基-5-(2-胺基丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例2a自(R)-(1-(3-胺基-2-氰基苯氧基)丙-2-基)-胺基甲酸苄基酯(實例86c)及3-側氧基丁酸乙基酯進行製備,得到褐色固體。MS 304(MH+)。實例86c:(R)-苄基(1-(3-胺基-2-氰基苯氧基)丙-2-基)胺基甲酸酯如實例24c自(R)-2-胺基-6-(2-胺基丙氧基)苄腈(實例86d)進行製備,得到褐色固體(79%)。1H NMR(400 MHz,DMSO-d6)δ1.12(d,J=6.4 Hz,3H),3.81(d,J=8.4 Hz,1H),3.95-3.92(m,1H),4.99(s,2H),5.36(s,2H),5.96(s,2H),6.20(d,J=8.0 Hz,1H),6.31(d,J=8.4 Hz,1H),7.13(t,J=8.4 Hz,1H),7.44-7.38(m,5H)。MS 326(MH+)。實例86d:(R)-2-胺基-6-(2-胺基丙氧基)苄腈如實例24d自(R)-2-胺基丙-1-醇及2-胺基-6-氟-苄腈進行製備,得到褐色固體(81%)。1H NMR(400 MHz,DMSO-d6)δ1.01(d,J=6.5 Hz,3H),3.08(m,1H),3.71(d,J=6.1 Hz,2H),5.95(s,2H),6.15(d,J=8.3 Hz,1H),6.2(d,J=8.3 Hz,1H),7.13(t,J=8.3 Hz,1H)。MS 192(MH+)。
實例87:(R)-4-胺基-5-(2-(異菸鹼醯胺基)丙氧基)-2-甲基喹啉-3-甲酸
如實例1自(R)-4-胺基-5-(2-(異菸鹼醯胺基)丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例87a)進行製備,得到灰白色固體(32%)。1H NMR(400 MHz,DMSO-d6)δ1.31(d,J=6.8 Hz,3H),2.66(s,3H),4.14(t,J=9.2 Hz,1H),4.28(dd,J=3.6,9.6 Hz,1H),4.70-4.55(m,1H),6.92(d,J=8.0 Hz,1H),7.26(d,J=8.4 Hz,1H),7.51(t,J=8.4 Hz,1H),7.75(dd,J=1.2,6.0 Hz,2H),8.71(dd,J=1.2,6.0 Hz,2H),8.95(d,J=8.0 Hz,1H)。MS 409(MH+)。實例87a:(R)-4-胺基-5-(2-(異菸鹼醯胺基)丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自(R)-4-胺基-5-(2-胺基丙氧基)-2-甲基-喹啉-3-甲酸乙基酯(實例86b)及異菸鹼酸進行製備,得到褐色固體(41%)。MS 409(MH+)。實例88:(R)-4-胺基-5-(2-(3-羥基苯甲醯胺基)丙氧基)-2-甲基喹啉-3-甲酸
如實例1自(R)-4-胺基-5-(2-(3-羥基苯甲醯胺基)丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例88a)進行製備,得到白色固體(51%)。1H NMR(400 MHz,DMSO-d6)δ1.28(d,J=7.2 Hz,3H),2.65(s,3H),4.11(t,J=8.8 Hz,1H),4.22(dd,J=4.0,10 Hz,1H),4.65-4.55(m,1H),6.88(d,J=8.0,2H),7.25-7.13(m,4H),7.48(t,J=8.0 Hz,1H),8.49(d,J=8.0,1H),9.93(brs,1H)。MS 396(MH+)。實例88a:(R)-4-胺基-5-(2-(3-羥基苯甲醯胺基)丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自(R)-4-胺基-5-(2-胺基丙氧基)-2-甲基-喹啉-3-甲酸乙基酯(實例86b)及3-羥基苯甲酸進行製備,得到褐色固體(36%)。MS 424(MH+)。實例89:(S)-4-胺基-5-((1-(環己烷羰基)吡咯啶-2-基)甲氧基)-2-甲基-喹啉-3-甲酸(SID 47039333)
如實例1自(S)-4-胺基-5-((1-(環己烷羰基)吡咯啶-2-基)甲氧基)-2-甲基喹啉-3-甲酸乙基酯(實例89a)進行製備,得到灰白色固體(31%)。1H NMR(400 MHz,DMSO-d6)δ1.34-1.11(m,5H),1.72-1.51(m,5H),2.08-1.79(m,5H),2.44-2.35(m 1H),2.52(s,3H),3.55-3.45(m,2H),4.02(dd,J=6.8,9.2 Hz,1H),4.17(dd,J=4.8,10.0 Hz,1H),4.45-4.38(m,1H),6.75(d,J=7.2 Hz),7.11(d,J=7.6 Hz,1H),7.27(t,J=8.0 Hz,1H)。MS 412(MH+)。實例89a:(S)-4-胺基-5-((1-(環己烷羰基)吡咯啶-2-基)甲氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自(S)-4-胺基-2-甲基-5-(吡咯啶-2-基甲氧基)-喹啉-3-甲酸乙基酯(實例89b)及環己烷甲酸進行製備,得到褐色固體(46%)。MS 440(MH+)。實例89b:(S)-4-胺基-2-甲基-5-(吡咯啶-2-基甲氧基)喹啉-3-甲酸乙基酯如實例2a自(S)-2-((3-胺基-2-氰基苯氧基)甲基)吡咯啶-1-甲酸苄基酯(實例89c)及3-側氧基丁酸乙基酯進行製備,得到褐色固體。MS 330(MH+)。實例89c:(S)-2-((3-胺基-2-氰基苯氧基)甲基)吡咯啶-1-甲酸苄基酯如實例24c自(S)-2-胺基-6-(吡咯啶-2-基甲氧基)苄腈(實例89d)進行製備,得到褐色固體(79%)。MS 351(MH+)。實例89d:(S)-2-胺基-6-(吡咯啶-2-基甲氧基)苄腈如實例24d自(S)-吡咯啶-2-基甲醇及2-胺基-6-氟-苄腈進行製備,得到褐色固體(51%)。MS 218(MH+)。實例90:(S)-4-胺基-5-((1-異丁醯基吡咯啶-2-基)甲氧基)-2-甲基喹啉-3-甲酸
如實例1自(S)-4-胺基-5-((1-異丁醯基吡咯啶-2-基)-甲氧基)-2-甲基喹啉-3-甲酸乙基酯(實例90a)進行製備,得到灰白色固體(39%)。1H NMR(400 MHz,DMSO-d6)δ0.99(dd,J=2.0,6.8 Hz,6H),2.05-1.83(m,4H),2.65(s,3H),3.53(t,J=7.2 Hz,2H),4.08(dd,J=6.8,10.0 Hz,1H),4.20(dd,J=6.0,10.0 Hz,1H),4.54(m,1H),6.99(d,J=8.0 Hz,1H),7.21(d,J=8.4 Hz,1H),7.50(t,J=8.0 Hz,1H)。MS 344(MH+)。實例90a:(S)-4-胺基-5-((1-異丁醯基吡咯啶-2-基)-甲氧基)-2-甲基-喹啉-3-甲酸乙基酯如實例24a自(S)-4-胺基-2-甲基-5-(吡咯啶-2-基甲氧基)-喹啉-3-甲酸乙基酯(實例89b)及異丁酸進行製備,得到褐色固體(46%)。MS 400(MH+)。實例91:(S)-5-((1-乙醯基吡咯啶-2-基)甲氧基)-4-胺基-2-甲基喹啉-3-甲酸
如實例1自(S)-5-((1-乙醯基吡咯啶-2-基)甲氧基)-4-胺基-2-甲基喹啉-3-甲酸乙基酯(實例91a)進行製備,得到灰白色固體(23%)。1H NMR(400 MHz,DMSO-d6)δ1.98(s,3H),2.03-1.82(m,4H),2.71(s,3H),3.48(t,J=6.0 Hz,2H),4.05(dd,J=6.4,10.0 Hz,1H),4.22(dd,J=6.8,10.0 Hz,1H),4.54-4.46(m,1H),6.99(d,J=8.0 Hz,1H),7.34(d,J=8.0 Hz,1H),7.54(t,J=10.0 Hz,1H)。MS 344(MH+)。實例91a:(S)-5-((1-乙醯基吡咯啶-2-基)甲氧基)-4-胺基-2-甲基喹啉-3-甲酸乙基酯如實例24a自(S)-4-胺基-2-甲基-5-(吡咯啶-2-基甲氧基)-喹啉-3-甲酸乙基酯(實例89b)及乙酸酐進行製備,得到褐色固體(31%)。MS 372(MH+)。
實例92:(R)-4-胺基-5-((1-(環己烷羰基)吡咯啶-2-基)甲氧基)-2-甲基-喹啉-3-甲酸
如實例1自(R)-4-胺基-5-((1-(環己烷羰基)吡咯啶-2-基)甲氧基)-2-甲基喹啉-3-甲酸乙基酯(實例92a)進行製備,得到灰白色固體(37%)。1H NMR(400 MHz,DMSO-d6)δ1.34-1.11(m,5H),1.72-1.51(m,5H),2.08-1.79(m,5H),2.44-2.35(m 1H),2.52(s,3H),3.55-3.45(m,2H),4.02(dd,J=6.8,9.2 Hz,1H),4.17(dd,J=4.8,10.0 Hz,1H),4.45-4.38(m,1H),6.75(d,J=7.2 Hz),7.11(d,J=7.6 Hz,1H),7.27(t,J=8.0 Hz,1H)。MS 412(MH+)。實例92a:(R)-4-胺基-5-((1-(環己烷羰基)吡咯啶-2-基)甲氧基)-2-甲基喹啉-3-甲酸乙基酯
如例24a中實自(R)-4-胺基-2-甲基-5-(吡咯啶-2-基甲氧基)-喹啉-3-甲酸乙基酯(實例92b)及環己烷甲酸進行製備,得到褐色固體(39%)。MS 440(MH+)。實例92b:(R)-4-胺基-2-甲基-5-(吡咯啶-2-基甲氧基)喹啉-3-甲酸乙基酯如實例2a自(R)-2-((3-胺基-2-氰基苯氧基)甲基)吡咯啶-1-甲酸苄基酯(實例92c)及3-側氧基丁酸乙基酯進行製備,得到褐色固體。MS 330(MH+)。實例92c:(R)-2-((3-胺基-2-氰基苯氧基)甲基)吡咯啶-1-甲酸苄基酯如實例24c自(R)-2-胺基-6-(吡咯啶-2-基甲氧基)苄腈(實例92d)進行製備,得到褐色固體(71%)。MS 351(MH+)。實例92d:(R)-2-胺基-6-(吡咯啶-2-基甲氧基)苄腈如實例24d自(R)-吡咯啶-2-基甲醇及2-胺基-6-氟-苄腈進行製備,得到褐色固體(57%)。MS 218(MH+)。實例93:(R)-4-胺基-5-((1-異丁醯基吡咯啶-2-基)甲氧基)-2-甲基喹啉-3-甲酸
如實例1自(R)-4-胺基-5-((1-異丁醯基吡咯啶-2-基)-甲氧基)-2-甲基喹啉-3-甲酸乙基酯(實例93a)進行製備,得到灰白色固體(44%)。1H NMR(400 MHz,DMSO-d6)δ0.99(dd,J=2.0,6.8 Hz,6H),2.05-1.83(m,4H),2.65(s,3H),3.53(t,J=7.2 Hz,2H),4.08(dd,J=6.8,10.0 Hz,1H),4.20(dd,J=6.0,10.0 Hz,1H),4.54(m,1H),6.99(d,J=8.0 Hz,1H),7.21(d,J=8.4 Hz,1H),7.50(t,J=8.0 Hz,1H)。MS 344(MH+)。實例93a:(R)-4-胺基-5-((1-異丁醯基吡咯啶-2-基)-甲氧基)-2-甲基-喹啉-3-甲酸乙基酯如實例24a自(R)-4-胺基-2-甲基-5-(吡咯啶-2-基甲氧基)喹啉-3-甲酸乙基酯(實例92b)及異丁酸進行製備,得到褐色固體(39%)。MS 400(MH+)。實例94:(R)-5-((1-乙醯基吡咯啶-2-基)甲氧基)-4-胺基-2-甲基喹啉-3-甲酸
如實例1自(R)-5-((1-乙醯基吡咯啶-2-基)甲氧基)-4-胺基-2-甲基喹啉-3-甲酸乙基酯(實例94a)進行製備,得到灰白色固體(19%)。1H NMR(400 MHz,DMSO-d6)61.98(s,3H),2.03-1.82(m,4H),2.71(s,3H),3.48(t,J=6.0 Hz,2H),4.05(dd,J=6.4,10.0 Hz,1H),4.22(dd,J=6.8,10.0 Hz,1H),4.54-4.46(m,1H),6.99(d,J=8.0 Hz,1H),7.34(d,J=8.0 Hz,1H),7.54(t,J=10.0 Hz,1H)。MS 344(MH+)。實例94a:(R)-5-((1-乙醯基吡咯啶-2-基)甲氧基)-4-胺基-2-甲基喹啉-3-甲酸乙基酯如實例24a自(R)-4-胺基-2-甲基-5-(吡咯啶-2-基甲氧基)喹啉-3-甲酸乙基酯(實例92b)及乙酸酐進行製備,得到褐色固體(28%)。MS 372(MH+)。
實例95:(S)-4-胺基-5-(2-(2-羥基苯甲醯胺基)-3-甲基丁氧基)-2-甲基喹啉-3-甲酸
如實例1自(S)-4-胺基-5-(2-(2-羥基苯甲醯胺基)-3-甲基-丁氧基)-2-甲基喹啉-3-甲酸乙基酯(實例95a)進行製備,得到白色固體(82%)。MS 424(MH+)。實例95a:(S)-4-胺基-5-(2-(2-羥基苯甲醯胺基)-3-甲基丁氧基)-2-甲基-喹啉-3-甲酸乙基酯如實例24a自(S)-4-胺基-5-(2-胺基-3-甲基丁氧基)-2-甲基喹啉-3-甲酸乙基酯(實例95b)及2-羥基苯甲酸進行製備,得到褐色固體(56%)。MS 452(MH+)。實例95b:(S)-4-胺基-5-(2-胺基-3-甲基丁氧基)-2-甲基喹啉-3-甲酸乙基酯如實例2a自(S)-1-(3-胺基-2-氰基苯氧基)-3-甲基丁-2-基胺基甲酸苄基酯(實例95c)及3-側氧基丁酸乙基酯進行製備,得到褐色固體(79%)。MS 332(MH+)。實例95c:(S)-1-(3-胺基-2-氰基苯氧基)-3-甲基丁-2-基胺基甲酸苄基酯如實例24c自(S)-2-胺基-6-(2-胺基-3-甲基丁氧基)苄腈(實例95d)進行製備,得到褐色固體(82%)。MS 354(MH+)。實例95d:(S)-2-胺基-6-(2-胺基-3-甲基丁氧基)苄腈如實例24d自(S)-2-胺基-3-甲基丁-1-醇及2-胺基-6-氟-苄腈進行製備,得到褐色固體(71%)。MS 220(MH+)。實例96:(S)-4-胺基-5-(2-(3-羥基苯甲醯胺基)-3-甲基丁氧基)-2-甲基喹啉-3-甲酸
如實例1自(S)-乙基4-胺基-5-(2-(3-羥基苯甲醯胺基)-3-甲基-丁氧基)-2-甲基喹啉-3-甲酸酯(實例96a)進行製備,得到白色固體(83%)。MS 424(MH+)。實例96a:(S)-4-胺基-5-(2-(3-羥基苯甲醯胺基)-3-甲基丁氧基)-2-甲基-喹啉-3-甲酸乙基酯如實例24a自(S)-4-胺基-5-(2-胺基-3-甲基丁氧基)-2-甲基喹啉-3-甲酸乙基酯(實例95b)及3-羥基苯甲酸進行製備,得到褐色固體(35%)。MS 452(MH+)。實例97:(S)-4-胺基-5-(2-(2-羥基苯甲醯胺基)丁氧基)-2-甲基喹啉-3-甲酸
如實例1自(S)-4-胺基-5-(2-(2-羥基苯甲醯胺基)丁氧基)-2-甲基喹啉-3-甲酸乙基酯(實例97a)進行製備,得到灰白色固體(78%)。MS 410(MH+)。實例97a:(S)-4-胺基-5-(2-(2-羥基苯甲醯胺基)丁氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自(S)-4-胺基-5-(2-胺基丁氧基)-2-甲基喹啉-3-甲酸乙基酯(實例97b)及2-羥基苯甲酸進行製備,得到褐色固體(46%)。MS 438(MH+)。實例97b:(S)-4-胺基-5-(2-胺基丁氧基)-2-甲基喹啉-3-甲酸乙基酯如實例2a自(S)-1-(3-胺基-2-氰基苯氧基)丁-2-基胺基甲酸苄基酯(實例97c)及3-側氧基丁酸乙基酯進行製備,得到褐色固體(75%)。MS 318(MH+)。實例97c:(S)-1-(3-胺基-2-氰基苯氧基)丁-2-基胺基甲酸苄基酯如實例24c自(S)-2-胺基-6-(2-胺基丁氧基)苄腈(實例97d)進行製備,得到褐色固體(87%)。MS 340(MH+)。實例97d:(S)-2-胺基-6-(2-胺基丁氧基)苄腈如實例24d自(S)-2-胺基丁-1-醇及2-胺基-6-氟-苄腈進行製備,得到褐色固體(73%)。MS 206(MH+)。實例98:(S)-4-胺基-5-(2-(4-(2-羥基乙氧基)-3-甲氧基苯甲醯胺基)丁氧基)-2-甲基喹啉-3-甲酸
如實例1自(S)-4-胺基-5-(2-(4-(2-羥基乙氧基)-3-甲氧基-苯甲醯胺基)丁氧基)-2-甲基喹啉-3-甲酸乙基酯(實例98a)進行製備,得到灰白色固體(83%)。MS 484(MH+)。實例98a:(S)-4-胺基-5-(2-(4-(2-羥基乙氧基)-3-甲氧基苯甲醯胺基)-丁氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自(S)-4-胺基-5-(2-胺基丁氧基)-2-甲基喹啉-3-甲酸乙基酯(實例97b)及4-(2-羥基乙氧基)-3-甲氧基苯甲酸(Uto,Y.等人Bioorg. Med. Chem. Lett. 2009,19,4151.)進行製備,得到褐色固體(38%)。MS 512(MH+)。實例99:(S)-4-胺基-5-(2-(2,3-二氫苯并[b][1,4]二氧雜環戊烯-5-甲醯胺基)丁氧基)-2-甲基喹啉-3-甲酸
如實例1自(S)-4-胺基-5-(2-(2,3-二氫苯并[b][1,4]二氧雜環戊烯-5-甲醯胺基)丁氧基)-2-甲基喹啉-3-甲酸乙基酯(實例99a)進行製備,得到灰白色固體(78%)。MS 452(MH+)。實例99a:(S)-4-胺基-5-(2-(2,3-二氫苯并[b][1,4]二氧雜環戊烯-5-甲醯胺基)-丁氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自(S)-4-胺基-5-(2-胺基丁氧基)-2-甲基喹啉-3-甲酸乙基酯(實例97b)及2,3-二氫苯并[b][1,4]二氧雜環戊烯-5-甲酸進行製備,得到褐色固體(40%)。MS 480(MH+)。實例100:(S)-4-胺基-5-(2-(4-(3-羥基丙氧基)-3-甲氧基苯甲醯胺基)丁氧基)-2-甲基喹啉-3-甲酸
如實例1自(S)-4-胺基-5-(2-(4-(3-羥基丙氧基)-3-甲氧基苯甲醯胺基)丁氧基)-2-甲基喹啉-3-甲酸乙基酯(實例100a)進行製備,得到灰白色固體(79%)。MS 498(MH+)。實例100a:(S)-4-胺基-5-(2-(4-(3-羥基丙氧基)-3-甲氧基苯甲醯胺基)-丁氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自(S)-4-胺基-5-(2-胺基丁氧基)-2-甲基喹啉-3-甲酸乙基酯(實例97b)及4-(3-羥基丙氧基)-3-甲氧基苯甲酸(Baraldi,P.G.等人J. Med. Chem. 1999,42,5131.)進行製備,得到褐色固體(41%)。MS 526(MH+)。實例101:(S)-4-胺基-5-(2-(3,5-二羥基苯甲醯胺基)丁氧基)-2-甲基喹啉-3-甲酸
如實例1自(S)-4-胺基-5-(2-(3,5-二羥基苯甲醯胺基)丁氧基)-2-甲基喹啉-3-甲酸乙基酯(實例101a)進行製備,得到灰白色固體(69%)。MS 426(MH+)。實例101a:(S)-4-胺基-5-(2-(3,5-二羥基苯甲醯胺基)丁氧基)-2-甲基-喹啉-3-甲酸乙基酯如實例24a自(S)-4-胺基-5-(2-胺基丁氧基)-2-甲基喹啉-3-甲酸乙基酯(實例97b)及3,5-二羥基苯甲酸進行製備,得到褐色固體(37%)。MS 454(MH+)。實例102:(S)-4-胺基-5-(2-(2,3-二氫苯并[b][1,4]二氧雜環戊烯-6-甲醯胺基)丁氧基)-2-甲基喹啉-3-甲酸
如實例1自(S)-4-胺基-5-(2-(2,3-二氫苯并[b][1,4]二氧雜環戊烯-6-甲醯胺基)丁氧基)-2-甲基喹啉-3-甲酸乙基酯(實例102a)進行製備,得到灰白色固體(71%)。MS 452(MH+)。實例102a:(S)-4-胺基-5-(2-(2,3-二氫苯并[b][1,4]二氧雜環戊烯-6-甲醯胺基)丁氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自(S)-4-胺基-5-(2-胺基丁氧基)-2-甲基喹啉-3-甲酸乙基酯(實例97b)及2,3-二氫苯并[b][1,4]二氧雜環戊烯-6-甲酸進行製備,得到褐色固體(46%)。MS 480(MH+)。實例103:(S)-4-胺基-5-(2-(3-羥基苯甲醯胺基)丁氧基)-2-甲基喹啉-3-甲酸
如實例1自(S)-4-胺基-5-(2-(3-羥基苯甲醯胺基)丁氧基)-2-甲基喹啉-3-甲酸乙基酯(實例103a)進行製備,得到灰白色固體(72%)。MS 410(MH+)。
實例103a:(S)-4-胺基-5-(2-(3-羥基苯甲醯胺基)丁氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自(S)-4-胺基-5-(2-胺基丁氧基)-2-甲基喹啉-3-甲酸乙基酯(實例97b)及3-羥基苯甲酸進行製備,得到褐色固體(49%)。MS 438(MH+)。實例104:(S)-4-胺基-5-(2-(4-(3-羥基丙氧基)-3-甲氧基苯甲醯胺基)-3-甲基-丁氧基)-2-甲基喹啉-3-甲酸
如實例1自(S)-4-胺基-5-(2-(4-(3-羥基丙氧基)-3-甲氧基苯甲醯胺基)-3-甲基丁氧基)-2-甲基喹啉-3-甲酸乙基酯(實例104a)進行製備,得到灰白色固體(69%)。MS 512(MH+)。實例104a:(S)-4-胺基-5-(2-(4-(3-羥基丙氧基)-3-甲氧基苯甲醯胺基)-3-甲基丁氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自(S)-4-胺基-5-(2-胺基-3-甲基丁氧基)-2-甲基喹啉-3-甲酸乙基酯(實例95b)及4-(3-羥基丙氧基)-3-甲氧基苯甲酸(Baraldi,P. G.等人J. Med. Chem. 1999,42,5131.)進行製備,得到褐色固體(29%)。MS 540(MH+)。實例105:(S)-4-胺基-5-(2-(3,5-二羥基苯甲醯胺基)-3-甲基丁氧基)-2-甲基-喹啉-3-甲酸
如實例1自(S)-4-胺基-5-(2-(3,5-二羥基苯甲醯胺基)-3-甲基丁氧基)-2-甲基喹啉-3-甲酸乙基酯(實例105a)進行製備,得到白色固體(72%)。MS 440(MH+)。實例105a:(S)-4-胺基-5-(2-(3,5-二羥基苯甲醯胺基)-3-甲基丁氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自(S)-4-胺基-5-(2-胺基-3-甲基丁氧基)-2-甲基喹啉-3-甲酸乙基酯(實例95b)及3,5-d羥基苯甲酸進行製備,得到褐色固體(29%)。MS 468(MH+)。實例106:(S)-4-胺基-5-(2-(2,3-二氫苯并[b][1,4]二氧雜環戊烯-5-甲醯胺基)-3-甲基丁氧基)-2-甲基喹啉-3-甲酸
如實例1自(S)-4-胺基-5-(2-(2,3-二氫苯并[b][1,4]二氧雜環戊烯-5-甲醯胺基)-3-甲基丁氧基)-2-甲基喹啉-3-甲酸乙基酯(實例106a)進行製備,得到白色固體(81%)。MS 466(MH+)。實例106a:(S)-4-胺基-5-(2-(2,3-二氫苯并[b][1,4]二氧雜環戊烯-5-甲醯胺基)-3-甲基丁氧基)-2-甲基喹啉-3-甲酸乙基酯
如實例24a自(S)-4-胺基-5-(2-胺基-3-甲基丁氧基)-2-甲基喹啉-3-甲酸乙基酯(實例95b)及2,3-二氫苯并[b][1,4]二氧雜環戊烯-5-甲酸進行製備,得到褐色固體(36%)。MS 494(MH+)。實例107:(S)-4-胺基-5-(2-(2,3-二氫苯并[b][1,4]二氧雜環戊烯-6-甲醯胺基)-3-甲基丁氧基)-2-甲基喹啉-3-甲酸
如實例1自(S)-4-胺基-5-(2-(2,3-二氫苯并[b][1,4]二氧雜環戊烯-6-甲醯胺基)-3-甲基丁氧基)-2-甲基喹啉-3-甲酸乙基酯(實例107a)進行製備,得到灰白色固體(76%)。MS 466(MH+)。實例107a:(S)-4-胺基-5-(2-(2,3-二氫苯并[b][1,4]二氧雜環戊烯-6-甲醯胺基)-3-甲基丁氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自(S)-4-胺基-5-(2-胺基-3-甲基丁氧基)-2-甲基喹啉-3-甲酸乙基酯(實例95b)及2,3-二氫苯并[b][1,4]二氧雜環戊烯-6-甲酸進行製備,得到褐色固體(29%)。MS 494(MH+)。實例108:4-胺基-5-((4-(異菸鹼醯胺基)環己基)甲氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-((4-(異菸鹼醯胺基)環己基)-甲氧基)-2-甲基喹啉-3-甲酸乙基酯(實例108a)進行製備,得到灰白色固體(43%)。1H NMR(400 MHz,DMSO-d6)δ1.52-2.01(m,8H),2.13(m,1H),2.74(s,3H),3.99(m,1H),4.18(d,J=6.8 Hz,2H),7.05(d,J=8.0 Hz,1H),7.26(d,J=8.0 Hz,1H),7.66(t,J=8.4 Hz,1H),7.71(d,J=6.0 Hz,2H),8.40(d,J=6.8 Hz,1H),8.71(d,J=6.0 Hz,2H),12.70(brs,1H)。MS 435(MH+)。實例108a:乙基4-胺基-5-((4-(異菸鹼醯胺基)環己基)-甲氧基)-2-甲基-喹啉-3-甲酸酯如實例2a自N-(4-((3-胺基-2-氰基苯氧基)甲基)環己基)-異菸鹼醯胺(實例108b)及3-側氧基丁酸乙基酯進行製備,得到黃色固體(25%)。MS 463(MH+)。實例108b:N-(4-((3-胺基-2-氰基苯氧基)甲基)環己基)異菸鹼醯胺如實例22b自N-(4-(羥基甲基)環己基)異菸鹼醯胺(實例108c)及2-胺基-6-氟苄腈進行製備,無色油狀(6%)。MS351(MH+)。實例108c:N-(4-(羥基甲基)環己基)異菸鹼醯胺如實例24a自(4-胺基環己基)甲醇及異菸鹼酸進行製備,黃色油狀(100%)。MS 235(MH+)。實例109:4-胺基-5-((2-甲氧基環己基)氧基)-2-甲基喹啉-3- 甲酸
如實例1自4-胺基-5-((2-甲氧基環己基)氧基)-2-甲基喹啉-3-甲酸乙基酯(實例109a)進行製備,得到白色固體(79%)。1H NMR(400 MHz,DMSO-d6)δ1.20-1.68(m,6H),2.16(m,2H),2.78(s,3H),3.34(s,3H),3.58(m,1H),4.50(m,1H),7.17(d,J=8.4 Hz,1H),7.29(d,J=8.4 Hz,1H),7.67(t,J=8.8 Hz,1H),8.92(brs,1H),12.14(brs,1H),12.86(brs,1H)。MS 331(MH+)。實例109a:4-胺基-5-((2-甲氧基環己基)氧基)-2-甲基喹啉-3-甲酸乙基酯如實例2a自2-胺基-6-(2-甲氧基環己基氧基)苄腈(實例109b)及3-側氧基丁酸乙基酯進行製備,淺黃色油狀(16%)。MS 359(MH+)。實例109b:2-胺基-6-(2-甲氧基環己基氧基)苄腈如實例22b自2-甲氧基環己醇及2-胺基-6-氟-苄腈進行製備,黃色油狀(34%)。MS 247(MH+)。實例110:4-胺基-5-((1-(3-羥基苯甲醯基)六氫吡啶-3-基)甲氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-((1-(3-羥基苯甲醯基)六氫吡啶-3-基)甲氧基)-2-甲基喹啉-3-甲酸乙基酯(實例110a)進行製備,得到白色固體(35%)。MS 436(MH+)。實例110a:4-胺基-5-((1-(3-羥基苯甲醯基)六氫吡啶-3-基)甲氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自4-胺基-2-甲基-5-(六氫吡啶-3-基甲氧基)-喹啉-3-甲酸乙基酯(實例110b)及3-羥基苯甲酸進行製備,得到白色固體(34%)。MS 464(MH+)。實例110b:4-胺基-2-甲基-5-(六氫吡啶-3-基甲氧基)喹啉-3-甲酸乙基酯如實例2a自3-((3-胺基-2-氰基苯氧基)甲基)六氫吡啶-1-甲酸苄基酯(實例110c)及3-側氧基丁酸乙基酯進行製備,黃色油狀(21%)。MS 344(MH+)。實例110c:苄基3-((3-胺基-2-氰基苯氧基)甲基)六氫吡啶-1-甲酸酯如實例24c自2-胺基-6-(六氫吡啶-3-基甲氧基)苄腈(實例110d)進行製備,得到黃色固體(70%)。實例110d:2-胺基-6-(六氫吡啶-3-基甲氧基)苄腈如實例24d自3-六氫吡啶甲醇及2-胺基-6-氟-苄腈進行製備,得到淺黃色固體(27%)。MS 232(MH+)。實例111:4-胺基-5-((1-(3-羥基苯甲醯基)六氫吡啶-2-基)甲氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-((1-(3-羥基苯甲醯基)六氫吡啶-2-基)甲氧基)-2-甲基喹啉-3-甲酸乙基酯(實例111a)進行製備,得到灰白色固體(35%)。1H NMR(400 MHz,DMSO-d6)δ1.25-1.89(m,6H),2.74(s,3H),3.44(m,2H),4.27(m,1H),4.75(m,2H),5.29(m,1H),6.64-6.73(m,2H),6.78(d,J=7.2 Hz,1H),7.18(m,2H),7.26(d,J=8.4 Hz,1H),7.68(m,1H),8.87(brs,1H),9.73(brs,1H),11.96(brs,1H),12.70(brs,1H)。MS 436(MH+)。實例111a:乙基4-胺基-5-((1-(3-羥基苯甲醯基)六氫吡啶-2-基)甲氧基)-2-甲基喹啉-3-甲酸酯如實例24a自4-胺基-2-甲基-5-(六氫吡啶-2-基甲氧基)-喹啉-3-甲酸乙基酯(實例111b)及3-羥基苯甲酸進行製備,得到白色固體(28%)。MS 464(MH+)。
實例111b:4-胺基-2-甲基-5-(六氫吡啶-2-基甲氧基)喹啉-3-甲酸乙基酯如實例2a自2-((3-胺基-2-氰基苯氧基)甲基)六氫吡啶-1-甲酸苄基酯(實例111c)及3-側氧基丁酸乙基酯進行製備,無色油狀(13%)。MS 344(MH+)。實例111c:2-((3-胺基-2-氰基苯氧基)甲基)六氫吡啶-1-甲酸苄基酯如實例24c自2-胺基-6-(六氫吡啶-2-基甲氧基)苄腈(實例111d)進行製備,得到黃色固體(100%)。MS 366(MH+)。實例111d:2-胺基-6-(六氫吡啶-2-基甲氧基)苄腈如實例24d自2-六氫吡啶甲醇及2-胺基-6-氟-苄腈進行製備,得到淺黃色固體(64%)。MS 232(MH+)。實例112:4-胺基-5-環丙基-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-環丙基-2-甲基喹啉-3-甲酸乙基酯(實例112a)進行製備,得到白色固體(85%)。1H NMR(400 MHz,MeOH-d4)δ1.03(m,2H),1.31(m,2H),2.53(m,1H),2.81(s,3H),7.50(m,1H),7.58(m,1H),7.73(m,1H)。MS 243(MH+)。實例112a:4-胺基-5-環丙基-2-甲基喹啉-3-甲酸乙基酯如實例2a自2-胺基-6-環丙基苄腈(Tachdjian,C.等人PCT Int. Appl. 2008,WO 2008154221)及3-側氧基丁酸乙基酯進行製備,得到淺黃色固體(80%)。MS 271(MH+)。實例113:4-胺基-2-(羧甲基)-5-(2-環己基乙基)喹啉-3-甲酸
如實例1自4-胺基-5-(2-環己基乙基)-2-(2-乙氧基-2-側氧基乙基)喹啉-3-甲酸乙基酯(實例113a)進行製備,得到橙色固體(69%)。1H NMR(400 MHz,DMSO-d6)δ0.89-0.92(m,2H),1.14-1.29(m,4H),1.44-1.49(m,2H),1.56-1.66(m,4H),1.73-1.76(m,1H),3.15(t,J=8.0 Hz,2H),3.70(s,2H),7.09-7.11(m,1H),7.38-7.42(m,1H),7.46-7.51(m,2H)。MS 338(MH+-H2O)。實例113a:4-胺基-5-(2-環己基乙基)-2-(2-乙氧基-2-側氧基乙基)喹啉-3-甲酸乙基酯如實例2a自2-胺基-6-(2-環己基乙基)苄腈(實例113b)及3-側氧基戊二酸二乙基酯進行製備,得到橙色固體(33%)。1H NMR(400 MHz,DMSO-d6)δ0.87-0.96(m,2H),1.14-1.22(m,7H),1.27-1.32(m,4H),1.47-1.52(m,2H),1.61-1.68(m,4H),1.74-1.77(m,2H),3.21-3.25(m,2H),4.03(s,2H),4.09(q,J=8.0 Hz,2H),4.27(q,J=8.0 Hz,2H),7.27(t,J=4.0 Hz,1H),7.57(d,J=8.0 Hz,2H),7.63(brs,2H)。MS 413(MH+)。
實例113b:2-胺基-6-(2-環己基乙基)苄腈如實例21b自2-胺基-6-(環己基乙炔基)苄腈(實例113c)進行製備,得到橙色固體(36%)。1H NMR(400 MHz,DMSO-d6)δ0.90-0.95(m,2H),1.16-1.24(m,4H),1.41-1.46(m,2H),1.60-1.75(m,5H),2.58-2.62(m,2H),5.90(s,2H),6.48(d,J=8.0 Hz,1H),6.61(d,J=8.0 Hz,1H),7.18(t,J=4.0 Hz,1H)。MS 229(MH+)。實例113c:2-胺基-6-(環己基乙炔基)苄腈如實例21c自乙炔基環己烷及2-胺基-6-溴苄腈進行製備,褐色油狀(100%)。1H NMR(400 MHz,DMSO-d6)δ1.24-1.77(m,10H),2.70(m,1H),6.13(s,2H),6.64(d,J=8.0 Hz,1H),6.74(d,J=8.0 Hz,1H),7.22(t,J=8.0 Hz,1H)。MS 225(MH+)。實例114:4-胺基-5-(3-甲氧基苯基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(3-甲氧基苯基)-2-甲基喹啉-3-甲酸乙基酯(實例114a)進行製備,得到灰白色固體(38%)。MS 309(MH+)。實例114a:4-胺基-5-(3-甲氧基苯基)-2-甲基喹啉-3-甲酸乙基酯如實例2a自3-胺基-3'-甲氧基-[1,1'-聯苯]-2-甲腈(實例114b)及3-側氧基丁酸乙基酯進行製備,得到淺黃色固體(55%)。MS 337(MH+)。實例114b:3-胺基-3'-甲氧基-[1,1'-聯苯]-2-甲腈向2-胺基-6-溴苄腈(195 mg,1.0 mmol)及(3-甲氧基苯基)硼酸(300 mg,2 mmol)於二噁烷(2 mL)中之經攪拌溶液中添加碳酸鉀水溶液(2.0 mmol,0.7 mL)。藉由鼓入N2使反應溶液脫氣2分鐘。將四三苯基膦鈀(5% mol)添加至反應混合物中並將反應容器放入微波反應器中並在165℃下輻照20分鐘。藉由過濾去除沉澱並濃縮濾液。藉由HPLC(乙腈/水;梯度為10%至90%,25分鐘)來純化殘餘物,得到呈灰白色固體形式之標題化合物(180 mg,80%)。MS 225(MH+)。
實例115:4-胺基-5-(環己基甲氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(環己基甲氧基)-2-甲基喹啉-3-甲酸乙基酯進行製備(實例115a),得到白色固體(84%)。1H NMR(400 MHz,DMSO-d6)δ1.03-1.29(m,5H),1.63-1.82(m,5H),1.94(m,1H),2.75(s,3H),4.06(d,J=6.4 Hz,2H),7.03(d,J=8.0 Hz,1H),7.26(d,J=8.4 Hz,1H),7.66(t,J=8.4 Hz,1H)。MS 315(MH+)。實例115a:4-胺基-5-(環己基甲氧基)-2-甲基喹啉-3-甲酸乙基酯如實例2a自2-胺基-6-(環己基甲氧基)苄腈(實例115b)及3-側氧基丁酸乙基酯進行製備,得到淺黃色固體(47%)。1H NMR(400 MHz,MeOD)δ1.12-1.37(m,6H),1.42(t,J=4.0 Hz,3H),1.73-2.01(m,5H),2.68(s,3H),4.06(d,J=4.0 Hz,2H),4.42(q,J=8.0 Hz,2H),6.96(d,J=8.0 Hz,1H),7.32(d,J=8.0 Hz,1H),7.58(t,J=8.0 Hz,1H)。MS 343(MH+)。實例115b:2-胺基-6-(環己基甲氧基)苄腈如實例22b自環己基甲醇及2-胺基-6-氟苄腈進行製備,無色油狀(50%)。1H NMR(400 MHz,CDCl3)δ1.07-1.09(m,2H),1.28-1.32(m,3H),1.75-1.90(m,6H),3.79(d,J=6.4 Hz,2H),4.37(s,2H),6.20(d,J=8.4 Hz,1H),6.28(d,J=8.4 Hz,1H),7.19(t,J=8.4 Hz,1H)。MS 231(MH+)。
實例116:4-胺基-5-(環己基甲氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-2-甲基-5-苯氧基喹啉-3-甲酸乙基酯(實例116a)進行製備,得到灰白色固體(47%)。1H NMR(400 MHz,DMSO-d6)δ2.77(s,3H),6.60(d,J=4.0 Hz,1H),7.23(d,J=8.0 Hz,2H),7.30(t,J=8.0 Hz,1H),7.40(dd,J=8.0 Hz,1H),7.49(t,J=8.0 Hz,2H),7.60(t,J=8.0 Hz,1H),8.81(brs,1H),12.20(brs,1H),12.81(brs,1H)。MS 295(MH+)。實例116a:4-胺基-2-甲基-5-苯氧基喹啉-3-甲酸乙基酯如實例2a自2-胺基-6-苯氧基苄腈及3-側氧基丁酸乙基酯進行製備,黃色油狀(72%)。1H NMR(400 MHz,DMSO-d6)δ1.32(t,J=8.0 Hz,3H),2.59(s,3H),4.33(q,J=8.0 Hz,2H),6.61(dd,J=8.0 Hz,1H),7.16(d,J=4.0 Hz,2H),7.25(t,J=8.0 Hz,1H),7.39-7.52(m,4H),7.93(brs,2H)。MS 323(MH+)。實例117:4-胺基-5-(3-((4-甲氧基苄基)胺基)-2,2-二甲基-3-側氧基丙氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(3-((4-甲氧基苄基)胺基)-2,2-二甲基-3-側氧基丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例117a)進行製備,得到灰白色固體(38%)。MS 438(MH+)。實例117a:4-胺基-5-(3-((4-甲氧基苄基)胺基)-2,2-二甲基-3-側氧基丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自3-((4-胺基-3-(乙氧基羰基)-2-甲基喹啉-5-基)氧基)-2,2-二甲基丙酸(實例47b)及(4-甲氧基苯基)甲胺進行製備,得到黃色固體(100%)。MS 466(MH+)。實例118:4-胺基-2-甲基-5-((四氫-2H-吡喃-4-基)氧基)喹啉-3-甲酸
如實例1自4-胺基-2-甲基-5-((四氫-2H-吡喃-4-基)氧基)喹啉-3-甲酸乙基酯(實例118a)進行製備,得到灰白色固體(80%)。1H NMR(400 MHz,DMSO-d6)δ1.81(m,2H),2.06(m,2H),2.75(s,3H),3.87(m,2H),4.91(m,1H),7.15(d,J=8.0 Hz,1H),7.26(d,J=8.0 Hz,1H),7.65(t,J=8.0 Hz,1H)。MS 303(MH+)。實例118a:4-胺基-2-甲基-5-((四氫-2H-吡喃-4-基)氧基)喹啉-3-甲酸乙基酯如實例2a自2-胺基-6-((四氫-2H-吡喃-4-基)氧基)苄腈(實例118b)及3-側氧基丁酸乙基酯進行製備,得到淺黃色固體(51%)。MS 331(MH+)。實例118b:2-胺基-6-((四氫-2H-吡喃-4-基)氧基)苄腈如實例22b自四氫-2H-吡喃-4-醇及2-胺基-6-氟苄腈進行製備,無色油狀(48%)。1H NMR(400 MHz,CDCl3)δ1.87(m,2H),2.00(m,2H),3.63(m,2H),4.00(m,2H),4.42(s,2H),4.58(m,1H),6.23(d,J=8.4 Hz,1H),6.30(d,J=8.4 Hz,1H),7.20(t,J=8.4 Hz,1H)。MS 219(MH+)。實例119:4-胺基-5-(2,2-二甲基-3-側氧基-3-((吡啶-4-基甲基)胺基)丙氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(2,2-二甲基-3-側氧基-3-((吡啶-4-基甲基)胺基)丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例119a)進行製備,得到灰白色固體(44%)。MS 409(MH+)。實例119a:4-胺基-5-(2,2-二甲基-3-側氧基-3-((吡啶-4-基甲基)胺基)丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例24a自3-((4-胺基-3-(乙氧基羰基)-2-甲基喹啉-5-基)氧基)-2,2-二甲基丙酸(實例47b)及吡啶-4-基甲胺進行製備,得到褐色固體(43%)。MS 437(MH+)。實例120:4-胺基-5-(3-羥基-2,2-二甲基丙氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(3-羥基-2,2-二甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯(實例120a)進行製備,得到灰白色固體(33%)。1H NMR(400 MHz,DMSO-d6)δ0.98(s,6H),2.75(s,3H),3.37(s,2H),3.97(s,2H),5.12(brs,1H),7.01(d,J=8.4 Hz,1H),7.25(d,J=7.6 Hz,1H),7.66(t,J=8.0 Hz,1H),9.27(brs,1H),12.23(brs,1H),12.73(brs,1H)。MS 305(MH+)。實例120a:4-胺基-5-(3-羥基-2,2-二甲基丙氧基)-2-甲基喹啉-3-甲酸乙基酯如實例2a自乙酸3-(3-胺基-2-氰基苯氧基)-2,2-二甲基丙基酯(Tachdjian,C.等人PCT Int. Appl. 2008,WO 2008154221)及3-側氧基丁酸乙基酯進行製備,得到淺黃色固體(26%)。MS 333(MH+)。實例121:4-胺基-5-((1-異丁醯基六氫吡啶-4-基)甲氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-((1-異丁醯基六氫吡啶-4-基)甲氧基)-2-甲基喹啉-3-甲酸乙基酯(實例121a)進行製備,得到白色固體(38%)。1H NMR(400 MHz,DMSO-d6)δ0.99(m,6H),1.13-1.23(m,2H),1.78-1.89(m,2H),2.26(brs,1H),2.51(m,1H),2.78(brs,3H),2.88(m,1H),3.06(t,J=12.0 Hz,1H),4.02(d,J=12.0 Hz,1H),4.41(m,2H),4.44(d,J=12.0 Hz,1H),7.07(brs,1H),7.28(d,J=8.0 Hz,1H),7.70(brs,1H),8.76(brs,1H),12.37(brs,1H),12.67(brs,1H)。MS 386(MH+)。實例121a:4-胺基-5-((1-異丁醯基六氫吡啶-4-基)甲氧基)-2-甲基喹啉-3-甲酸乙基酯如實例2a自2-胺基-6-((1-(4-甲氧基苄基)六氫吡啶-4-基)甲氧基)苄腈(實例121b)及3-側氧基丁酸乙基酯進行製備,黃色油狀(36%)。1H NMR(400 MHz,DMSO-d6)δ0.97(m,6H),1.32(t,J=8.0 Hz,3H),1.79-1.88(m,3H),2.15-2.18(m,2H),2.55(s,3H),2.86(m,1H),3.04(m,1H),4.00(m,2H),4.07(d,J=4.0 Hz,2H),4.32(q,J=8.0 Hz,2H),4.46(m,1H),6.91(d,J=8.0 Hz,1H),7.24(d,J=8.0 Hz,1H),7.51(t,J=8.0 Hz,1H),8.07(brs,2H)。MS 414(MH+)。實例121b:2-胺基-6-((1-(4-甲氧基苄基)六氫吡啶-4-基)甲氧基)苄腈如實例22b自1-(4-(羥基甲基)六氫吡啶-1-基)-2-甲基丙-1-酮(實例121c)及2-胺基-6-氟苄腈進行製備,得到淺黃色固體(21%)。1H NMR(400 MHz,DMSO-d6)δ0.99(m,6H),1.13-1.24(m,2H),1.74-1.81(m,2H),1.99(m,1H),2.55(m,1H),2.84(m,1H),3.01(m,1H),3.88(m,2H),4.02(m,1H),4.46(m,1H),5.99(s,2H),6.22(d,J=8.0 Hz,1H),6.34(d,J=8.0 Hz,1H),7.17(t,J=8.0 Hz,1H)。MS 302(MH+)。
實例121c:1-(4-(羥基甲基)六氫吡啶-1-基)-2-甲基丙-1-酮如實例24a自異丁酸及六氫吡啶-4-基甲醇進行製備,無色油狀(36%)。MS 186(MH+)。實例122:4-胺基-5-(((1R,2S,5R)-2-異丙基-5-甲基環己基)氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-(((1R,2S,5R)-2-異丙基-5-甲基-環己基)氧基)-2-甲基喹啉-3-甲酸乙基酯(實例122a)進行製備,得到白色固體(64%)。1H NMR(400 MHz,DMSO-d6)δ0.70(d,J=6.8 Hz,3H),0.89(t,J=7.6 Hz,6H),0.9-1.0(m,2H),1.04(m,2H),1.50-1.82(m,5H),1.95-2.05(m,1H),2.05-2.20(m,1H),2.72(s,3H),4.52(t-d,J=10.4,4.4 Hz,1H),7.13(d,J=8.0 Hz,1H),7.21(d,J=8.0 Hz,1H),7.61(t,J=8.0 Hz,1H),8.68(brs,1H),11.72(brs,1H),12.73(brs,1H)。MS 357(MH+)。實例122a:4-胺基-5-(((1R,2S,5R)-2-異丙基-5-甲基環己基)氧基)-2-甲基喹啉-3-甲酸乙基酯如實例2a自2-胺基-6-(((1R,2S,5R)-2-異丙基-5-甲基環-己基)氧基)苄腈(實例122b)及3-側氧基丁酸乙基酯進行製備,得到淺黃色固體(43%)。MS 385(MH+)。實例122b:2-胺基-6-(((1R,2S,5R)-2-異丙基-5-甲基環己基)氧基)苄腈如實例22b自(1R,2S,5R)-2-異丙基-5-甲基環己醇及2-胺基-6-氟苄腈進行製備,得到白色固體(51%)。MS 273(MH+)。實例123:4-胺基-5-(2-(3-(2-羥基乙氧基)-5-甲氧基苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸鹽酸鹽
向4-胺基-5-(2-(3-(2-羥基乙氧基)-5-甲氧基苯甲醯胺基)-2-甲基丙氧基)-2-甲基喹啉-3-甲酸(實例38,263 mg,0.544 mmol)於EtOH(2 mL)中之經攪拌懸浮液中添加存於EtOH中之HCl(1.25 N,479 μL,1.1當量)。在室溫下攪拌混合物直至其變成澄清溶液為止(0.5 h)。在減壓下濃縮溶液,得到呈白色固體形式之標題化合物,其藉由自EtOH/H2O重結晶來進一步純化並在真空下乾燥過夜(248 mg,87%)。1H NMR(400 MHz,DMSO-d6)δ1.51(s,6H),2.80(s,3H),3.68(t,J=5.2 Hz,2H),3.74(s,3H),3.97(t,J=5.2 Hz,1H),4.53(s,2H),6.59(s,1H),6.92(s,1H),6.94(s,1H),7.27(d,J=8.0 Hz,1H),7.57(d,J=8.4 Hz,1H),7.86(t,J=8.4 Hz,1H),8.03(s,1H),9.40(s,1H),9.98(s,1H)。484(MH+-HCl)。實例124:4-胺基-5-(環戊基甲氧基)-2-甲基喹啉-3-甲酸鹽酸鹽
如實例123自4-胺基-5-(環戊基甲氧基)-2-甲基喹啉-3-甲酸(實例18)進行製備,得到白色固體(100%)。1H NMR(400 MHz,DMSO-d6)δ1.29-1.37(m,2H),1.51-1.66(m,4H),1.82-1.90(m,2H),2.43-2.51(m,1H),2.81(s,3H),4.18(d,J=7.2 Hz,2H),7.24(d,J=8.4 Hz,1H),7.60(d,J=8.4 Hz,1H),7.84(t,J=8.4 Hz,1H),9.25(brs,1H),9.86(brs,1H)。MS 301(MH+-HCl)。實例125:4-胺基-5-((1-(4-甲氧基苄基)六氫吡啶-4-基)甲氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-((1-(4-甲氧基苄基)六氫吡啶-4-基)甲氧基)-2-甲基喹啉-3-甲酸乙基酯(實例125a)進行製備,得到白色固體(23%)。1H NMR(400 MHz,DMSO-d6)δ1.67(brs,2H),2.09(m,2H),2.31(brs,1H),2.92(brs,2H),3.48(brs,2H),3.82(s,3H),4.15(brs,2H),4.25(d,J=8.0 Hz,2H),7.02(d,J=8.0 Hz,2H),7.14(d,J=8.0 Hz,1H),7.30(d,J=8.0 Hz,1H),7.42(d,J=8.0 Hz,2H),7.76(t,J=8.0 Hz,1H)。MS 436(MH+)。實例125a:4-胺基-5-((1-(4-甲氧基苄基)六氫吡啶-4-基)甲氧基)-2-甲基喹啉-3-甲酸乙基酯如實例2a自2-胺基-6-((1-(4-甲氧基苄基)六氫吡啶-4-基)甲氧基)苄腈(實例125b)及3-側氧基丁酸乙基酯進行製備,得到灰白色固體(30%)。1H NMR(400 MHz,DMSO-d6)δ1.29-1.33(m,5H),1.74(m,2H),1.92(m,3H),2.54(s,3H),2.83(m,2H),3.38(s,2H),3.71(s,3H),4.04(d,J=8.0 Hz,2H),4.31(q,J=8.0 Hz,2H),6.86(d,J=8.0 Hz,2H),6.90(d,J=8.0 Hz,1H),7.19(d,J=8.0 Hz,2H),7.23(d,J=8.0 Hz,1H),7.50(t,J=8.0 Hz,1H),8.04(brs,2H)。MS 464(MH+)。
實例125b:2-胺基-6-((1-(4-甲氧基苄基)六氫吡啶-4-基)甲氧基)苄腈如實例22b自(1-(4-甲氧基苄基)六氫吡啶-4-基)甲醇(實例125c)及2-胺基-6-氟苄腈進行製備,得到橙色固體(19%)。MS 352(MH+)。實例125c:(1-(4-甲氧基苄基)六氫吡啶-4-基)甲醇向4-六氫吡啶甲醇(2.28 g,19.78 mmol)及4-甲氧基苯甲醛(2.30 mL,19.77 mmol)於THF/DCE(以體積計1:1,100 mL)中之溶液中以小份添加乙酸(1 mL),隨後添加NaBH(OAc)3(16.76 g,79.08 mmol)。在N2及室溫下將反應混合物攪拌過夜。用DCM稀釋反應並用2 N NaOH溶液鹼化至pH=10。分離出有機層,經Na2SO4乾燥,過濾並在減壓下濃縮。藉由在矽膠上實施層析(洗脫液:存於己烷中之60% EtOAc)來純化殘餘物,得到呈淺黃色油狀形式之標題化合物(2.13 g,46%)。1H NMR(400 MHz,DMSO-d6)δ1.04-1.13(m,2H),1.28-1.32(m,1H),1.58-1.61(m,2H),1.79-1.86(m,2H),2.75-2.77(m,2H),3.22(t,J=8.0 Hz,2H),3.34(s,2H),3.72(s,3H),4.38(t,J=4.0 Hz,1H),6.85(d,J=8.0 Hz,2H),7.16(d,J=8.0 Hz,2H)。MS 236(MH+)。實例126:4-胺基-5-((4-(異丙基胺基甲醯基)環己基)甲氧基)-2-甲基喹啉-3-甲酸
如實例1自4-胺基-5-((4-(異丙基胺基甲醯基)環己基)-甲氧基)-2-甲基喹啉-3-甲酸乙基酯(實例126a)進行製備,得到黃色固體(76%)。1H NMR(400 MHz,DMSO-d6)δ1.00(d,J=6.8 Hz,6H),1.15-2.32(m,10H),2.75(s,3H),3.82(o,J=7.6 Hz,1H),4.16(d,J=6.8 Hz,2H),7.07(br d,J=7.2 Hz,1H),7.25(d,J=8.0 Hz,1H),7.49(d,J=7.6 Hz,1H),7.67(br t,1H),8.77(s,1H),12.23(s,1H),12.66(s,1H)。MS 400(MH+)。
實例126a:4-胺基-5-((4-(異丙基胺基甲醯基)環己基)甲氧基)-2-甲基喹啉-3-甲酸乙基酯如實例2a自4-((3-胺基-2-氰基苯氧基)甲基)-N-異丙基-環己烷甲醯胺(實例126b)及3-側氧基丁酸乙基酯進行製備,得到淺黃色固體(37%)。1H NMR(400 MHz,DMSO-d6)δ1.01(d,J=6.4 Hz,6H),1.32(t,J=7.2 Hz,3H),1.38-1.81(m,8H),1.88(m,1H),2.25(m,1H),2.55(s,3H),3.82(bro,J=7.6 Hz,1H),4.10(d,J=6.4 Hz,2H),4.31(q,J=7.6 Hz,2H),6.93(d,J=7.6 Hz,1H),7.22(d,J=8.8 Hz,1H),7.50(m,2H),8.09(s,2H)。MS 428(MH+)。實例126b:4-((3-胺基-2-氰基苯氧基)甲基)-N-異丙基環己烷甲醯胺如實例21b自4-((2-氰基-3-硝基苯氧基)甲基)-N-異丙基環-己烷甲醯胺(實例126c)進行製備,得到黃色固體(81%)。1H NMR(400 MHz,DMSO-d6)δ0.99(d,J=5.6 Hz,6H),1.22-1.99(m,9H),2.17(m,1H),3.80(m,1H),3.88(d,J=7.2 Hz,2H),5.94(brs,2H),6.18(t,J=8.0 Hz,1H),6.23(d,J=8.0 Hz,1H),6.31(d,J=8.8 Hz,1H),7.44(s,1H)。MS 316(H+)。
實例126c:4-((2-氰基-3-硝基苯氧基)甲基-N-異丙基環己烷甲醯胺在0℃及N2下向4-(羥基甲基)-N-異丙基環己烷甲醯胺(實例126d,480 mg,2.41 mmol)於無水THF(10 mL)中之溶液中以小份添加NaH(60%存於礦物油中,116 mg,4.82 mmol)。在0℃及N2下將反應混合物攪拌2 h。向該溶液中添加2,6-二硝基苄腈(465 mg,2.41 mmol),並在0℃至室溫下將反應混合物再攪拌2 h,且然後在60℃及N2下攪拌過夜並冷卻至室溫。使用鹽水淬滅反應,並用EtOAc(3X)萃取。用鹽水洗滌合併之有機層,經Na2SO4乾燥,過濾,並在減壓下蒸發。藉由在矽膠上實施層析(洗脫液:存於己烷中之50% EtOAc)來純化殘餘物,得到呈黃色固體形式之標題化合物(594 mg,71%)。1H NMR(400 MHz,DMSO-d6)δ1.00(d,J=7.6 Hz,6H),1.22-2.08(m,9H),2.19(m,1H),3.79(m,1H),4.15(d,J=7.6 Hz,2H),7.45(brs,1H),7.78(d,J=7.2 Hz,1H),7.88(m,2H)。MS 346(H+)。實例126d:4-(羥基甲基)-N-異丙基環己烷甲醯胺如實例24a自4-(羥基甲基)環己烷甲酸及丙-2-胺進行製備,無色油狀(57%)。1H NMR(400 MHz,DMSO-d6)δ1.00(d,J=7.6 Hz,6H),1.22-2.08(m,9H),2.12(m,1H),3.28(t,J=7.6 Hz,2H),3.79(m,1H),4.34(s,1H),7.43(s,1H)。MS 200(MH+)。實例127:4-胺基-5-(環己基氧基)-2-甲基喹啉-3-甲酸鹽酸鹽
向4-胺基-5-(環己基氧基)-2-甲基喹啉-3-甲酸(實例36,1.0 g,3.33 mmol)於乙醇(10 mL)中之懸浮液中添加HCl於乙醇(2.93 mL,3.66 mmol)中之1.25 M溶液。將該澄清溶液攪拌30分鐘並蒸發至乾燥以提供呈白色固體形式之4-胺基-5-(環己基氧基)-2-甲基喹啉-3-甲酸鹽酸鹽(1.12 g,100%)。1H NMR(400 MHz,DMSO-d6)δ1.30(m,1H),1.39-1.47(m,2H),1.53-1.72(m,5H),2.01-2.05(m,2H),2.82(s,3H),4.78-4.82(m,1H),7.29-7.31(d,J=8.0 Hz,1H),7.61-7.63(d,J=8.0 Hz,1H),7.82(t,J=8.4 Hz,1H),9.30(bs,1H),9.93(bs,1H)。MS 301(MH+-HCl)。實例128:4-胺基-5-(環己基氧基)-2-甲基喹啉-3-甲酸鈉
向4-胺基-5-(環己基氧基)-2-甲基喹啉-3-甲酸(實例36,1.0 g,3.33 mmol)於乙醇(20 mL)中之溶液中添加NaHCO3(294 mg,3.50 mmol)於水(15 mL)中之溶液。將混合物攪拌並升溫至60℃直至溶液變透明,然後蒸發至乾燥以提供呈白色固體形式之4-胺基-5-(環己基氧基)-2-甲基喹啉-3-甲酸鈉(1.07 g,100%)。1H NMR(400 MHz,DMSO-d6)δ1.25-1.45(m,3H),1.50-1.70(m,5H),1.53-1.72(m,5H),1.98-2.00(m,2H),2.64(s,3H),4.59-4.63(m,1H),6.87-6.89(d,J=7.6 Hz,1H),7.20-7.22(d,J=8.0 Hz,1H),7.42(t,J=8.0 Hz,1H)。MS 301(MH++H-Na)。實例129:(±)-4-胺基-5-((2-(5-(異丙基胺基甲醯基)-2-甲氧基苯氧基)環己基)-氧基)-2-甲基喹啉-3-甲酸
如實例1自(±)-4-胺基-5-((2-(5-(異丙基胺基甲醯基)-2-甲氧基苯氧基)環己基)氧基)-2-甲基喹啉-3-甲酸乙基酯(實例129a)進行製備,得到白色固體(34%)。1H NMR(400 MHz,DMSO-d6)δ1.15(d,J=8.0 Hz,6H),1.35-1.51(m,3H),1.63-1.73(m,3H),2.09(d,J=12.0 Hz,1H),2.24(d,J=12.0Hz,1H),2.72(s,3H),3.56(s,3H),3.99-4.07(m,1H),4.71-4.78(m,2H),6.85(d,J=8.0 Hz,1H),7.24(d,J=12.0 Hz,2H),7.42(dd,J=8.0 Hz,1H),7.46(d,J=8.0 Hz,1H),7.66(t,J=8.0 Hz,1H),8.03(d,J=8.0 Hz,1H),8.64(brs,1H),12.00(brs,1H),12.61(brs,1H)。MS 508(MH+)。實例129a:(±)-4-胺基-5-((2-(5-(異丙基胺基甲醯基)-2-甲氧基苯氧基)-環己基)氧基)-2-甲基喹啉-3-甲酸乙基酯如實例2a自(±)-3-((2-(3-胺基-2-氰基苯氧基)環己基)氧基)-N-異丙基-4-甲氧基苯甲醯胺(實例129b)及3-側氧基丁酸乙基酯進行製備,得到黃色固體(78%)。MS 536(MH+)。實例129b:(±)-3-((2-(3-胺基-2-氰基苯氧基)環己基)氧基)-N-異丙基-4-甲氧基苯甲醯胺如實例21b自(±)-3-((2-(2-氰基-3-硝基苯氧基)環己基)氧基)-N-異丙基-4-甲氧基苯甲醯胺(實例129c)進行製備,褐色油狀(29%)。1H NMR(400 MHz,DMSO-d6)δ1.13-1.19(m,6H),1.42-1.66(m,6H),2.02-2.07(m,2H),3.74(s,3H),4.08(m,1H),4.47(m,1H),4.57(m,1H),5.93(brs,2H),6.32(d,J=8.0 Hz,1H),6.38(d,J=8.0 Hz,1H),7.00(d,J=8.0 Hz,1H),7.17(t,J=8.0 Hz,1H),7.48-7.50(m,2H),7.98(d,J=8.0 Hz,1H)。MS 424(MH+)。實例129c:(±)-3-((2-(2-氰基-3-硝基苯氧基)環己基)氧基)-N-異丙基-4-甲氧基苯甲醯胺如實例126c自(±)-3-((2-羥基環己基)氧基)-N-異丙基-4-甲氧基苯甲醯胺(實例129d)及2,6-二硝基苄腈進行製備,得到褐色固體(100%)。MS 454(MH+)。
實例129d:(±)-3-((2-羥基環己基)氧基)-N-異丙基-4-甲氧基苯甲醯胺如實例24a自(±)-3-((2-羥基環己基)氧基)-4-甲氧基苯甲酸(實例129e)及丙-2-胺進行製備,得到白色固體(80%)。1H NMR(400 MHz,DMSO-d6)δ1.14(d,J=8.0 Hz,6H),1.25-1.30(m,4H),1.61(m,2H),1.85(m,2H),3.56(m,1H),3.79(s,3H),4.03-4.12(m,2H),4.81(d,J=4.0 Hz,1H),6.98(d,J=8.0 Hz,1H),7.45-7.49(m,2H),8.01(d,J=8.0 Hz,1H)。MS 308(MH+)。
實例129e:(±)-3-((2-羥基環己基)氧基)-4-甲氧基苯甲酸如實例1自(±)-3-((2-羥基環己基)氧基)-4-甲氧基-苯甲酸乙基酯(實例129f)進行製備,得到白色固體(100%)。1H NMR(400 MHz,DMSO-d6)δ1.23-1.25(m,4H),1.59(brs,2H),1.88(m,2H),3.53(m,1H),3.72(s,3H),3.92(m,1H),4.73(d,J=4.0 Hz,1H),6.82(d,J=8.0 Hz,1H),7.39(dd,J=4.0 Hz,1H),7.48(d,J=4.0 Hz,1H)。實例129f:(±)-3-((2-羥基環己基)氧基)-4-甲氧基-苯甲酸乙基酯在室溫下向3-羥基-4-甲氧基苯甲酸甲基酯(210 mg,1.15 mmol)及環己烷氧化物(466 μL,4.61 mmol)於乙醇(11 mL)中之溶液中添加K2CO3(637 mg,4.61 mmol)。然後將反應混合物回流過夜,然後冷卻至室溫,並在減壓下蒸發直至剩餘少量乙醇為止。用DCM稀釋溶液並依次用1N HCl及鹽水洗滌,經Na2SO4乾燥,過濾並在減壓下蒸發。藉由在矽膠上實施層析(洗脫液:0-20% EtOAc/己烷)來純化殘餘物,得到無色油狀(±)-3-((2-羥基環己基)氧基)-4-甲氧基-苯甲酸乙基酯(307 mg,91%)。1H NMR(400 MHz,DMSO-d6)δ1.16-1.34(m,7H),1.61(m,2H),1.84-1.94(m,2H),3.55(m,1H),3.83(s,3H),4.03(m,1H),4.28(q,J=8.0 Hz,2H),4.85(d,J=4.0 Hz,1H),7.05(d,J=12.0 Hz,1H),7.55-7.58(m,2H)。
實例130:4-胺基-5-(環己基氧基)-2-(羥基甲基)喹啉-3-甲酸
如實例1自9-胺基-8-(環己基氧基)呋喃并[3,4-b]喹啉-1(3H)-酮(實例130a)進行製備,得到棕褐色粉末(44%)。1H NMR(400 MHz,DMSO-d6)δ1.27-1.46(m,2H),1.53-1.71(m,6H),2.00-2.04(m,2H),4.70(m,1H),4.87(s,2H),7.10(d,J=8.0 Hz,1H),7.58(d,J=8.0 Hz,1H),7.64(t,J=8.0 Hz,1H),8.74(brs,1H),11.90(brs,1H)。MS 317(MH+)。實例130a:9-胺基-8-(環己基氧基)呋喃并[3,4-b]喹啉-1(3H)-酮如實例2a自2-胺基-6-(環己基氧基)苄腈(實例36b)及4-氯-3-側氧基丁酸乙基酯進行製備,得到橙色固體(29%)。1H NMR(400 MHz,DMSO-d6)δ1.30-1.72(m,8H),2.04-2.08(m,2H),4.70(m,1H),5.26(s,2H),7.09(d,J=8.0 Hz,1H),7.36(d,J=8.0 Hz,1H),7.64(m,2H),8.14(brs,1H)。MS 299(MH+)。實例131:1-胺基-3-甲基-6b,7,8,9,10,10a-六氫苯并呋喃并[2,3-f]喹啉-2-甲酸
如實例1自1-胺基-3-甲基-6b,7,8,9,10,10a-六氫-苯并呋喃并[2,3-f]喹啉-2-甲酸乙基酯(實例131a)進行製備,得到灰白色固體(28%)。1H NMR(400 MHz,DMSO-d6)δ1.35-1.48(m,4H),1.87-1.97(m,4H),2.76(s,3H),3.38(m1H),5.03(m1H),7.20(d,J=8 Hz,1H),7.61(d,J=8 Hz,1H)。MS 299(MH+)。實例131a:1-胺基-3-甲基-6b,7,8,9,10,10a-六氫苯并呋喃并[2,3-f]喹啉-2-甲酸乙基酯如實例2a自2-胺基-6-(環己-2-烯-1-基氧基)苄腈(實例131b)及3-側氧基丁酸乙基酯進行製備,得到淺黃色固體(11%)。MS 327(MH+)。實例131b:2-胺基-6-(環己-2-烯-1-基氧基)苄腈如實例22b自環己-2-烯醇及2-胺基-6-氟苄腈進行製備,無色油狀(78%)。1H NMR(400 MHz,CDCl3)δ1.64(m,1H),1.96(m,4H),2.15(m,1H),4.39(s,2H),4.82(m,1H),5.87(m,1H),5.98(m,1H),6.30(d,2H),7.20(t,1H)。MS 215(MH+)。
實例132:4-胺基-3-羧基-5-(環己基氧基)-2-甲基喹啉1-氧化物
如實例1自4-(N-乙醯基乙醯胺基)-5-(環己基氧基)-3-(乙氧基-羰基)-2-甲基喹啉1-氧化物(實例132a)進行製備,得到白色固體(38%)。1H NMR(400 MHz,DMSO-d6)δ1.31-1.68(m,8H),1.98-2.04(m,2H),2.69(s,3H),4.71(m,1H),7.20(d,J=8.0 Hz,1H),7.67(t,J=8.0 Hz,1H),7.87(d,J=8.0 Hz,1H),8.75(brs,2H)。MS 317(MH+)。實例132a:4-(N-乙醯基乙醯胺基)-5-(環己基氧基)-3-(乙氧基羰基)-2-甲基-喹啉1-氧化物向4-(N-乙醯基乙醯胺基)-5-(環己基氧基)-2-甲基喹啉-3-甲酸乙基酯(實例132b,100 mg,0.24 mmol)於DCE(5 mL)中之溶液中添加mCPBA(163 mg,0.73 mmol)。在N2及室溫下將反應混合物攪拌過夜。在減壓下去除溶劑,並藉由層析在矽膠上利用0-100% EtOAc/己烷梯度洗脫來純化殘餘物,得到橙色油狀標題化合物(100 mg,97%)。MS 429(MH+)。
實例132b:4-(N-乙醯基乙醯胺基)-5-(環己基氧基)-2-甲基喹啉-3-甲酸乙基酯在0℃下向4-胺基-5-(環己基氧基)-2-甲基喹啉-3-甲酸乙基酯(實例36a,700 mg,2.13 mmol)及Et3N(891 μL,6.39 mmol)於DCM(20 mL)中之溶液中添加乙醯氯(455 μL,6.39 mmol),並在0℃至室溫下將反應混合物攪拌過夜。用DCM稀釋反應並依次用10%檸檬酸、飽和NaHCO3、H2O及鹽水洗滌,經Na2SO4乾燥,過濾並在減壓下蒸發。藉由層析在矽膠上利用0-40% EtOAc/己烷梯度洗脫來純化殘餘物,得到黃色油狀標題化合物(100 mg,11%)。MS 413(MH+)。實例133:4-胺基-5-((2,3-二羥基環己基)氧基)-2-甲基喹啉-3-甲酸
如實例1自二乙酸3-((4-胺基-3-(乙氧基羰基)-2-甲基喹啉-5-基)氧基)環己烷-1,2-二基酯(實例133a)進行製備,得到白色固體(74%)。1H NMR(400 MHz,DMSO-d6)δ1.42-1.50(m,3H),1.66-1.70(m,2H),2.12-2.15(m,1H),2.74(s,3H),3.71-3.73(m,1H),3.90(s,1H),4.60-4.62(m,1H),4.71(brs,1H),5.18(brs,1H),7.06(d,J=8 Hz,1H),7.24(d,J=8 Hz,1H),7.60(t,J=8.4 Hz,1H)。MS 333(MH+)。實例133a:二乙酸3-((4-胺基-3-(乙氧基羰基)-2-甲基喹啉-5-基)氧基)環己烷-1,2-二基酯如實例2a自二乙酸3-(3-胺基-2-氰基苯氧基)環己烷-1,2-二基酯(實例133b)及3-側氧基丁酸乙基酯進行製備,得到淺黃色固體(32%)。MS 445(MH+)。
實例133b:二乙酸3-(3-胺基-2-氰基苯氧基)環己烷-1,2-二基酯如實例21b自二乙酸3-(2-氰基-3-硝基苯氧基)環己烷-1,2-二基酯(實例133c)進行製備,得到白色固體(84%)。MS 333(MH+)。實例133c:二乙酸3-(2-氰基-3-硝基苯氧基)環己烷-1,2-二基酯如實例132b自2-((2,3-二羥基環己基)氧基)-6-硝基苄腈(實例133d)及乙醯氯進行製備,得到白色固體(19%)。MS 363(MH+)。
實例133d:2-((2,3-二羥基環己基)氧基)-6-硝基苄腈在室溫下向2-(環己-2-烯-1-基氧基)-6-硝基苄腈(實例133e,5.3 g,21.7 mmol)於THF/H2O(以體積計1:1,110 mL)於中之溶液中添加OsO4(110.3 mg,0.434 mmol)。在將其攪拌30分鐘後,經1 h時間以小份添加NaClO3(2.71 g,26.04 mmol),並在室溫下將反應混合物攪拌48 h。用亞硫酸氫鈉水溶液小心地淬滅反應,並用EtOAc(3X)萃取。用鹽水洗滌合併之有機層,經MgSO4乾燥、過濾並濃縮。藉由層析在矽膠上利用於己烷中之80-100% EtOAc洗脫來實施來純化殘餘物,得到呈褐色固體形式之標題化合物(3.88 g,64%)。MS 279(MH+)。
實例133e:2-(環己-2-烯-1-基氧基)-6-硝基苄腈如實例126c自環己-2-烯醇及2,6-二硝基苄腈進行製備,得到褐色固體(90%)。MS 245(MH+)。
生物學測試
實驗1:增甜劑之篩選
將hT1R2/R3-HEK293 Ga15細胞以約32,000個細胞/孔之密度接種於透明底384孔板(Fisher)中並生長過夜。在實驗當天,使用Multidrop將hT1R2/R3-HEK293 Ga15與鈣指示劑Fluo3AM(4 mM)(Invitrogen,Carlsbad,CA)負載於D-PBS(Invitrogen,Carlsbad,CA)中。在室溫下將細胞培育1小時並使用EMBLA細胞清洗器(Molecular Devices,Sunnyvale,CA)用D-PBS洗去多餘染料,每孔剩餘體積為25 ml。甜味劑及測試化合物係以4X最終濃度製備並1:1混合於384孔Greiner板中(使甜味劑及測試化合物濃度降至2X最終濃度)。在室溫下靜置30分鐘後,將負載Fluo3AM之細胞板及甜味劑/化合物板混合物負載於螢光成像板讀數器(FLIPR)(Molecular Devices,Sunnyvale,CA)中。使用480 nm激發及535 nm發射來實施成像且首先經7秒時間獲得基線螢光。然後,藉由每孔添加25 ml剌激物在線刺激細胞。經2分鐘時間每隔1秒獲得後續圖像。然後藉由計算δF/f值(在刺激後所獲得之最大螢光計數-在刺激前所獲得之最小螢光計數/在刺激前所獲得之最小螢光計數)將各孔之原始螢光計數中歸一化(使用定製數據輸入軟體)。使用非線性回歸算法(GraphPad PRISM,San Diego,CA)來測定EC50,其中希爾斜率(Hill slope)、下漸近線及上漸近線有所變化。藉由測定甜味劑EC50值左移之量值(或EC50比率)來定量測試化合物之增強性質,該比率為無增強劑時所量測之EC50值除以存在增強劑時所量測之EC50值。本發明化合物已經測試且對蔗糖展示甜味增強活性,如下文表A、表B及C中所示。特定而言,在約50 μM下用於蔗糖增強之測試化合物之EC50比率均大於約2。下文表A、表B及C中所列示化合物係上文所述實例。舉例而言,表A中化合物Q係實例7。
本發明化合物已經測試且對蔗糖素展示甜味增強活性,如下文表D中所示。特定而言,在約10 μM下用於蔗糖素增強之測試化合物之EC50比例均大於約2。
實驗2:利用人類評定者實施比例測試之甜味及甜味增強量測
將含有實驗化合物之測試樣品與甜味劑(蔗糖素、蔗糖、果糖及其他甜味劑)濃度之所感知甜度強度之劑量-反應曲線進行比較以測定等效甜度強度。
一組8個或更多個評定者品嘗包括不同濃度甜味劑之溶液以及含有及不含甜味劑之實驗化合物。然後評定者在結構化水平線刻度(標記為0至15)上評定所有樣品之甜度強度等級,其中0等於無甜度且15等於等效於15%蔗糖樣品之甜度。取各評定者之甜度強度分數之平均值。然後使用平均分數及/或甜味劑劑量-反應曲線之曲線方程來測定含有實驗化合物之樣品之等效甜度濃度。
受試者先前已熟習關鍵屬性味道且經培訓可使用0個至15個點線刻度。在測試前,禁止受試者進食或飲用(水除外)達至少1小時。受試者食用餅乾並用水漱口數次以清理口腔。
提供多種濃度(例如,對於蔗糖素而言100 ppm、200 ppm、300 ppm、400 ppm及500 ppm,或對於蔗糖或果糖而言介於0%與12%之間)的甜味劑溶液以產生劑量-反應曲線。含有實驗化合物之樣品均係單獨及在100 ppm蔗糖素溶液或6%蔗糖或果糖溶液中製備。所有樣品均係在低鈉緩衝液(pH 7.1)中。為幫助分散,可在0.1%乙醇中製作溶液。
在室溫下將該等溶液以20 ml體積分配於1盎司樣品杯中並提供給受試者。所有樣品均係以隨機平衡順序發放以減少反應偏差。此外,可使用兩個測試期來檢查評定小組精確性。
受試者單獨品嘗各樣品並在品嘗下一樣品之前在線刻度上評定甜度強度等級。所有樣品均吐出。受試者可重新品嘗樣品,但僅可使用所給定樣品體積。在各樣品之間受試者必須用水漱口。端視所品嘗樣品,可能需要在各樣品之間食用無鹽餅乾。
取受試者對各樣品之分數平均值並計算標準誤差。以圖表方式繪製劑量-反應曲線,且此可用於確保評定小組準確評定等級;即,蔗糖素之濃度增加應對應於甜度之平均分數增加。可使用雙因子ANOVA(因子為樣品及評定者)及多個比較測試(例如Tukey's真實顯著性差異測試)來測定樣品及/或評定者間之差異。可使用三因子ANOVA(第三因子為測試期)來確定各測試期之評級之間是否存在任何差異。
使用化合物J之人類味覺測試之結果見於下文。化合物J係上文所述實例中之一者。表1指示J存於6%蔗糖中之45 μM化合物之甜度等效於約9-10%蔗糖。
表1.平均甜度,n=28(14名評定者,重複2次)。Tukey's值=0.986(α=0.05)。
使用化合物C之人類味覺測試之結果見於下文中。化合物C係上文所述實例中之一者。表1_1指示存於6%蔗糖中之25 μM化合物C之甜度等效於約9-10%蔗糖。表1_1.平均甜度,n=24(12名評定者,重複2次)。Tukey's值=0.912(α=0.05)。
使用化合物O1之人類味覺測試之結果見於下文中。化合物O1係上文所述實例中之一者。表1_2指示存於6%蔗糖中之25 μM化合物O1之甜度等效於約10%蔗糖。表1_2.平均甜度,n=26(13名評定者,重複2次)。Tukey's值 =0.733(α=0.05)。
使用化合物W之人類味覺測試之結果見於下文中。化合物W係上文所述實例中之一者。表13指示存於6%蔗糖中之25 μM化合物W之甜度等效於約10%蔗糖。表1_3.平均甜度,n=28(14名評定者,重複2次)。Tukey's值=0.619(α=0.05)。
使用化合物I3之人類味覺測試之結果見於下文中。化合物I3係上文所述實例中之一者。表14指示存於6%蔗糖中之21 μM化合物I3之甜度等效於約10%蔗糖。表1_4.平均甜度,n=28(14名評定者,重複2次)。Tukey's值=0.785(α=0.05)。
使用化合物C1之人類味覺測試之結果見於下文中。化合物C1係上文所述實例中之一者。表1_5指示存於6%蔗糖中之13 μM化合物C1之甜度等效於約10%蔗糖且存於6%蔗糖中之33 μM化合物C1之甜度等效於約12%蔗糖。表1_6指示存於50 ppm蔗糖素中之33 μM化合物C1之甜度等效於介於約100 ppm蔗糖素與200 ppm蔗糖素之間。表1_5.平均甜度,n=26(13名評定者,重複2次)。Tukey's值=1.311(α=0.05)。
使用化合物B4之人類味覺測試之結果見於下文中。化合物B4係上文所述實例中之一者。表1_7指示存於6%蔗糖中之36.5 μM化合物B4之甜度等效於約10-12%蔗糖。表18指示B4存於50 ppm蔗糖素中之36.5 μM化合物之甜度等效於約100 ppm。表1_7.平均甜度,n=27(14名評定者,重複1次;及13評定者,重複1次)。Tukey's值=1.138(α=0.05)。
向評定者成對發放含有實驗化合物之測試樣品並要求其測定其中為甜味劑之樣品。一組評定者(10-16名或更多名)參與各測試。在測試前,禁止受試者進食或飲用(水除外)達至少1小時。受試者用水漱口數次以清理口腔。
所有樣品均係使用乙醇製備以確保化合物在溶液中分散。此包括不含化合物之樣品;所有溶液均用0.1%乙醇補足。
亦用低鈉緩衝液(pH 7.1)替代水來製備樣品。緩衝液含有存於40 L DIUF水中之0.952 g KCl、5.444 g Na2HPO4及0.952 g KH2PO4。樣品體積通常為20 ml。
在一個成對比較測試中,向評定者發放兩個不同樣品並要求其識別為甜味劑之樣品。在成對比較測試中樣品係以隨機平衡順序發放。在各味覺測試之間評定者延時最多1分鐘以清除口腔中任何味道。
使用二項式概率表來測定在α=0.05時各測試所發生正確數量反應之概率
使用化合物J之人類味覺測試之結果見於下文。表2指示評定者感到6%蔗糖+45 μM化合物J之甜度與10%蔗糖溶液無顯著差異(p>0.05)。表3指示45 μM化合物J單獨使用時幾乎沒有或沒有甜度。表2.評定者選作甜味劑之樣品,n=42(14名評定者,重複3次)。
使用化合物A之人類味覺測試之結果見於下文中。表21指示評定者感到6%蔗糖+25 μM化合物A之甜度與10%蔗糖溶液無顯著差異(p>0.05)。表3_1指示25 μM化合物A單獨使用時幾乎沒有或沒有甜度。
使用化合物Cl之人類味覺測試之結果見於下文中。表2_2指示評定者感到6%蔗糖+33 μM化合物Cl之甜度與12%蔗糖溶液無顯著差異(p>0.05)。表3_2指示33 μM化合物Cl單獨使用時幾乎沒有或沒有甜度。表2_2.評定者選作甜味劑之樣品,n=30(15名評定者,重複2次)。
使用化合物13之人類味覺測試之結果見於下文中。表2_3指示評定者感到6%蔗糖+25 μM化合物I3之甜度與12%蔗糖溶液無顯著差異(p>0.05)。表3_3指示25 μM化合物I3單獨使用時幾乎沒有或沒有甜度。表2_3.評定者選作甜味劑之樣品,n=42(14名評定者,重複3次)。
使用化合物B4之人類味覺測試之結果見於下文中。表2_4指示評定者感到6%蔗糖+36.5 μM化合物B4之甜度與10%蔗糖溶液無顯著差異(p>0.05)。表3_4指示36.5 μM化合物B4單獨使用時幾乎沒有或沒有甜度。表2_4.評定者選作甜味劑之樣品,n=26(13名評定者,重複2次)。
所有出版物及專利申請案均以引用方式併入本文中,其程度如同將每一個別出版物或專利申請案特定地及個別地所指以引用方式併入本文中。
應瞭解,所給出上述詳細說明僅出於清晰理解之目的且並非具有限制性,熟習此項技術者顯然可對其作出修改。不承認本文所提供之任何信息係先前技術或與目前所主張之發明相關,或所特定地或含蓄地引用之任一出版物係先前技術。
本文闡述本發明之實施例,其包括發明者已知之用於實施本發明的最佳模式。熟習此項技術者在閱讀上述說明後可瞭解彼等較佳實施例之各種變化形式。發明者期望熟習此項技術者適當使用該等變化形式,且發明者期望本發明可以不同於本文具體闡述之方式實施。因此,本發明包括適用法律所允許的本文隨附申請專利範圍中所陳述標的物的所有修改及等效形式。此外,除非本文另有說明或上下文明顯矛盾,否則在其所有可能之變化形式中,上述元素的任何組合都涵蓋於本發明中。
Claims (35)
- 一種化合物,其具有結構式(IIIb)或(IIIb'),
- 一種化合物,其具有結構式(IIIc)或(IIIc'),
- 如請求項2之化合物,其中R33係烷基、經取代之烷基、碳環基、經取代之碳環基;雜環基、經取代之雜環基、雜烷基或經取代之雜烷基。
- 如請求項1之化合物,其中B係氫或烷基。
- 如請求項1之化合物,其中B係氫或烷基;L1係伸烷基或經取代之伸烷基;L2係-NR34-、-O-、-NR34-C(O)-、-C(O)-NR34-、-O-C(O)-、-C(O)-O-、-伸雜環基-C(O)-或-(經取代之伸雜環基)-C(O)-;及R34及R35獨立地為氫、烷基或經取代之烷基。
- 如請求項2之化合物,其中R33係烷基、經取代之烷基、碳環基、經取代之碳環基;雜環基、經取代之雜環基、雜烷基或經取代之雜烷基。
- 一種可攝取組合物,其包含如請求項1或2之化合物;及攝取上可接受之賦形劑。
- 如請求項7之可攝取組合物,其進一步包含一或多種甜味劑。
- 如請求項8之可攝取組合物,其中該甜味劑選自由下列組成之群:蔗糖、果糖、葡萄糖、半乳糖、甘露糖、乳糖、塔格糖(tagatose)、麥芽糖、玉米糖漿(包括高果糖玉米糖漿)、D-色胺酸、甘胺酸、赤蘚糖醇、異麥芽酮糖醇(isomalt)、乳糖醇、甘露糖醇、山梨糖醇、木糖醇、麥芽糊精、麥芽糖醇、異麥芽酮糖醇、氫化葡萄糖漿(HGS)、氫化澱粉水解物(HSH)、甜菊苷(stevio-side)、甜菊糖苷(rebaudioside)A、其他基於甜菊(sweet Stevia)之糖苷、卡瑞拉(carrelame)、其他基於胍之甜味劑、糖精、安賽蜜(acesulfame-K)、環己胺磺酸鹽(cyclamate)、蔗糖素、阿力甜(alitame)、羅漢果糖苷(mogroside)、紐甜(neotame)、阿斯巴甜(aspartame)、其他阿斯巴甜衍生物、及其組合。
- 如請求項7之可攝取組合物,其與不含如請求項1或2之化合物之可攝取組合物相比具有增加之甜味,如由至少8名人類測味者之評定小組中之大多數人所判定。
- 如請求項7之可攝取組合物,其係呈以下形式:食物或飲料產品、醫藥組合物、營養產品、飲食補充劑、非處方藥物(over-the-counter medication)或口腔護理產品。
- 如請求項11之可攝取組合物,其中該食物或飲料產品係供人類或動物食用。
- 如請求項7之可攝取組合物,其中該食物或飲料產品選 自由下列組成之群:湯料類;乾燥加工食物類;飲料類;即食餐(ready meal)類;罐裝或保藏食物類;冷凍(frozen)加工食物類;冷卻(chilled)加工食物類;點心食物類;烘焙食物類;糖果類;乳製品類;冰淇淋類;正餐替代品類;意大利麵(Pasta)及麵條類;調料(Sauces)、敷料(Dressings)、佐料(Condiments)類;嬰兒食物類;塗醬(Spreads)類;甜味包衣(coatings)、糖霜(frostings)或冰衣(glazes);及其組合。
- 一種增強可攝取組合物甜味之方法,其包含使該可攝取組合物與如請求項1或2之化合物接觸以形成經修飾之可攝取組合物。
- 一種增甜組合物,其包含有效提供甜化量之如請求項1或2之化合物與第一量之甜味劑組合,其中該甜化強於不含該化合物之該第一量之甜味劑所提供之甜化。
- 一種可攝取組合物,其包含如請求項15之增甜組合物。
- 如請求項16之可攝取組合物,其係呈以下形式:食物或飲料產品、醫藥組合物、營養產品、飲食補充劑、非處方藥物或口腔護理產品。
- 一種調味濃縮調配物,其包含i)如請求項1或2之化合物作為風味(flavor)修飾成份;ii)載劑;及iii)視情況至少一種佐劑。
- 如請求項18之調味濃縮調配物,其中該至少一種佐劑包含一或多種調味劑。
- 如請求項18或19之調味濃縮調配物,其中該至少一種佐劑包含一或多種甜味劑。
- 如請求項20之調味濃縮調配物,其中該至少一種佐劑包含一或多種選自由下列組成之群之成份:乳化劑、穩定劑、抗微生物防腐劑、抗氧化劑、維生素、礦物質、脂肪、澱粉、蛋白濃縮物及分離物、鹽、凝固點(freezing point)降低劑、成核劑及其組合。
- 如請求項21之調味濃縮調配物,其係呈選自由下列組成之群之形式:液體、固體、半固體、泡沫狀物質、糊、凝膠、乳霜、洗劑及其組合。
- 如請求項22之調味濃縮調配物,其中如請求項1或2之化合物之濃度為可直接食用之組合物中濃度的至少2倍。
- 一種製備式(IV)化合物之方法:
- 如請求項24之方法,其中該路易士酸係金屬鹵化物。
- 如請求項24或25之方法,其中該式(IVa)化合物與該式(IVb)化合物之反應係至少部分地在約60℃或更高之溫度實施。
- 如請求項26之方法,其中R1、R2及R7係氫。
- 如請求項27之方法,其中B係烷基。
- 如請求項28之方法,其中R24係-OR31,且R31係烷基、經取代之烷基、碳環基、經取代之碳環基;芳基、經取代之芳基、芳基烷基、經取代之芳基烷基、雜環基、經取代之雜環基、雜烷基、經取代之雜烷基、雜芳基、經取代之雜芳基、雜芳基烷基或經取代之雜芳基烷基。
- 如請求項29之方法,其中該式(IV)化合物由式(IVc)表示:
- 如請求項1之化合物,其選自由以下組成之群:
- 如請求項1之化合物,其選自由以下組成之群:
- 如請求項2之化合物,其選自由以下組成之群:
- 一種化合物,其選自由以下組成之群:
- 一種化合物,其選自由以下組成之群:
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