TW201713222A - 甜味改質劑 - Google Patents
甜味改質劑 Download PDFInfo
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- TW201713222A TW201713222A TW105124343A TW105124343A TW201713222A TW 201713222 A TW201713222 A TW 201713222A TW 105124343 A TW105124343 A TW 105124343A TW 105124343 A TW105124343 A TW 105124343A TW 201713222 A TW201713222 A TW 201713222A
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Abstract
本發明包括具有結構式(I)之化合物或其鹽或溶劑合物。此等化合物適用作甜味改質劑。本發明亦包括包含本發明化合物之組合物及調節組合物之甜味的方法。
Description
本申請案主張2013年3月13日申請之美國臨時申請案第61/779,502號及2012年8月6日申請之美國臨時申請案第61/679,912號的優先權權益,每一申請案之內容出於所有目的以全文引用之方式併入本文中。
本發明係關於適用於改質與化學感覺或化學感覺相關之感覺或反應相關聯的受體及其配位體的化合物。
味覺系統提供關於外部世界之化學組成的感覺資訊。味覺轉導為動物體內由化學物質引起之感覺的最複雜精密之一。整個動物界中,自簡單後生動物至最複雜之脊椎動物,皆可見味覺之信號傳導。咸信哺乳動物具有五種基本味覺模態:甜味、苦味、酸味、鹹味及鮮味(umami)(麩胺酸單鈉之味道,亦稱作原有味道)。
肥胖症、糖尿病及心血管疾病為在全世界呈上升趨勢之健康問題,而在美國以驚人之速率不斷增加。糖及熱量為可加以限制以對健康產生正向營養作用之關鍵組分。高強度甜味劑可以各種呈味品質提供糖之甜味。由於甜味劑之甜味為糖的許多倍,所以需要少得多的甜味劑來替換糖。
高強度甜味劑具有廣泛之化學相異結構且因此具有不同特性,諸如(但不限於)氣味、風味、口感及餘味。熟知此等特性(尤其
風味及餘味)會隨品嘗之時間推移而變化,使得各時間變化型態(temporal profile)具甜味劑特異性(Tunaley,A.,「Perceptual Characteristics of Sweeteners」,Progress in Sweeteners,T.H.Grenby編,Elsevier Applied Science,1989)。
諸如糖精及6-甲基-1,2,3-噁噻嗪-4(3H)-酮-2,2-二氧化物鉀鹽(艾司沙芬鉀(acesulfame potassium))之甜味劑的特徵通常為具有苦味及/或金屬餘味。據稱用2,4-二羥基苯甲酸製備之產品可使與甜味劑相關之不合需要之餘味減少,且在濃度低於其自身之味道可被感知的濃度時的確如此。並且,據報導,諸如蔗糖素(sucralose)及阿斯巴甜糖(aspartame)之高強度甜味劑具有甜味傳遞問題,亦即甜味之起始延遲及逗留(S.G.Wiet等人,J.Food Sci.,58(3):599-602,666(1993))。
已報導化學感覺受體之細胞外域(例如捕蠅草域(Venus flytrap domain)),尤其捕蠅草域內之一或多個相互作用位點為化合物或其他實體調節化學感覺受體及/或其配位體之適合目標。已報導某些化合物為T1R家族之化學感覺受體及/或其配位體之改質劑且描述於下列四個專利申請案中。
(1)2007年6月8日申請之名稱為「Modulation of Chemosensory Receptors and Ligands Associated Therewith」之美國專利申請案第11/760,592號;(2)2011年4月19日頒予之名稱為「Modulation of Chemosensory Receptors and Ligands Associated Therewith」之美國專利第7,928,111號;以及(3)2008年6月3日申請之名稱為「Modulation of Chemosensory Receptors and Ligands Associated Therewith」之國際申請案第PCT/US2008/065650號。此等申請案之內容出於所有目的以全文引用之方式併入本文中。
在此項技術中需要研發適用於改質與化學感覺或化學感覺相關之感覺或反應相關聯的受體及/或其配位體的新穎且具創新性
之化合物。
在一實施例中,本發明提供具有結構式(I)之化合物:
或其鹽或溶劑合物;其中A為視情況經取代之四至八員氮雜環;X為共價鍵或-NR1-;R1為氫或C1至C6烴基;以及Y為烴基、經取代之烴基、雜烴基、經取代之雜烴基、碳環基、經取代之碳環基、雜環基、經取代之雜環基、芳基、經取代之芳基、雜芳基、經取代之雜芳基、芳基烴基、經取代之芳基烴基、雜芳基烴基,或經取代之雜芳基烴基。
在另一實施例中,本發明提供一種可攝取組合物,其包含本發明化合物;及視情況選用之攝食上可接受之賦形劑。
在另一實施例中,本發明提供一種增加可攝食組合物之甜味的方法,其包括使其可攝食組合物與本發明化合物接觸,以形成經改質之可攝食組合物。在該方法中,本發明化合物可為化學感覺受體改質劑、化學感覺受體配位體改質劑或兩者,亦即部分化學感覺受體改質劑及部分化學感覺受體配位體改質劑。舉例而言,本發明化合物可為甜味受體促效劑或甜味調節劑,或部分甜味受體促效劑及部分甜味調節劑。
在另一實施例中,本發明提供一種甜味調節組合物,其包含有效提供甜化作用之量的本發明化合物與第一量之甜味劑的組
合,其中該甜化作用大於在不存在該化合物情況下由該第一量之甜味劑所提供之甜化作用。
在另一實施例中,本發明提供一種調味濃縮物調配物,其包含i)作為風味改質成分之本發明化合物;ii)載劑;以及iii)視情況選用之至少一種佐劑。
在另一實施例中,本發明提供一種治療與化學感覺受體相關之病狀、疾病或病症的方法,其包含向需要該治療之受試者投與治療有效量之本發明化合物,或其鹽、溶劑合物及/或前藥。
本發明之此等及其他實施例、優勢及特徵提供於以下部分中。除非另外定義,否則本文所用的所有技術及科學術語具有與本發明所屬技術的一般技術者通常所瞭解的含義相同的含義。
定義
單獨或作為另一取代基之一部分之「烴基」係指藉由自母體烷烴、烯烴或炔烴之單個碳原子移除一個氫原子所產生的飽和或不飽和分支鏈、直鏈或環狀單價烴基。術語「烴基」包括如下文所定義之「環烴基」。典型烴基包括但不限於甲基;乙基,諸如乙烷基、乙烯基、乙炔基;丙基,諸如丙-1-基、丙-2-基、環丙-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,諸如丁-1-基、丁-2-基、2-甲基-丙-1-基、2-甲基-丙-2-基、環丁-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;及其類似基團。術語「烴基」尤其意欲包括具有任何飽和程度或飽和度之基團,亦即僅具有碳-碳單鍵之基團、具有一或多個碳-碳雙鍵之基團、具有一或多個碳-碳參鍵之基團以及具有碳-碳單鍵、碳-碳雙鍵及碳-碳參鍵之混合物的基團。在意指特定飽和度的情況下,使用表述「烷基」、「烯基」及「炔基」。在一些實施例中,烴基包含1至20個碳原子(C1-C20烴基)。在其他實施例中,烴基包含1至12個碳原子(C1-C12烴基)。在其他實施例中,烴基包含1至6個碳原子(C1-C6烴基)。應注意,當烴基進一步連接至另一原子時,其變成「伸烴基」。換言之,術語「伸烴基」係指二價烴基。舉例而言,-CH2CH3為乙基,而-CH2CH2-為伸乙基。亦即,單獨或作為另一取代基之一部分之「伸烴基」係指藉由自母體烷烴、烯烴或炔烴之單個碳原子或兩個不同碳原子移除兩個氫原子所產生的飽和或不飽和分支鏈、直鏈或環狀二價烴基。術語「伸烴基」包括如下文所定義之「伸環烴基」。術語「伸烴基」尤其意欲包括具有任何飽和程度或飽和度之基團,亦即僅具有碳-碳單鍵之基團、具有一或多個碳-碳雙鍵之基團、具有一或多個碳-碳參鍵之基團以及具有碳-碳單鍵、碳-碳雙鍵及碳-碳參鍵之混合物的基團。在意指特定飽和度的情況下,使用表述「伸烷基」、「伸烯基」及「伸炔基」。在一些實施例中,伸烴基包含1至20個碳原子(C1-C20伸烴基)。在其他實施例中,伸烴基包含1至12個碳原子(C1-C12伸烴基)。在其他實施例中,伸烴基包含1至6個碳原子(C1-C6伸烴基)。
單獨或作為另一取代基之一部分之「烷基」係指藉由自母體烷烴之單個碳原子移除一個氫原子所產生的飽和分支鏈、直鏈或環狀烴基。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,諸如丙-1-基、丙-2-基(異丙基)、環丙-1-基等;丁烷基,諸如丁-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;及其類似基團。
單獨或作為另一取代基之一部分之「烯基」係指藉由自母體烯烴之單個碳原子移除一個氫原子所產生的具有至少一個碳-碳雙鍵之不飽和分支鏈、直鏈或環狀烴基。術語「烯基」包括如下文所定義之「環烯基」。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,諸如丙-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,諸如丁-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;及其類似基團。
單獨或作為另一取代基之一部分之「炔基」係指藉由自母體炔烴之單個碳原子移除一個氫原子所產生的具有至少一個碳-碳參鍵之不飽和分支鏈、直鏈或環狀烴基。典型炔基包括但不限於乙炔基;丙炔基,諸如丙-1-炔-1-基、丙-2-炔-1-基等;丁炔基,諸如丁-1-炔-1-基、丁-1-炔-3-基、丁-3-炔-1-基等;及其類似基團。
單獨或作為另一取代基之一部分之「烴氧基」係指式-O-R199之基團,其中R199為如本文所定義之烴基或經取代之烴基。
單獨或作為另一取代基之一部分之「醯基」係指基團-C(O)R200,其中R200為氫、如本文所定義之烴基、經取代之烴基、芳基、經取代之芳基、芳基烴基、經取代之芳基烴基、雜烴基、經取代之雜烴基、雜芳基烴基或經取代之雜芳基烴基。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、苯甲基羰基及其類似基團。
單獨或作為另一取代基之一部分之「芳基」係指藉由自
如本文所定義之母體芳族環系統之單個碳原子移除一個氫原子所產生的單價芳族烴基。典型芳基包括但不限於衍生自以下之基團:乙烯合蒽、苊、乙烯合菲、蒽、薁、苯、屈、蔻、茀蒽、茀、稠六苯、聯六苯、并環己三烯(hexalene)、as-二環戊二烯并苯、s-二環戊二烯并苯、茚滿、茚、萘、稠八苯、聯八苯、并環辛四烯(octalene)、莪、戊-2,4-二烯、稠五苯、并環戊二烯、聯五苯、苝、丙烯合萘、菲、苉、七曜烯、芘、苒、茹、聯伸三苯、聯伸三萘及其類似物。在一些實施例中,芳基包含6至20個碳原子(C6-C20芳基),亦即,6至20員芳環。在其他實施例中,芳基包含6至15個碳原子(C6-C15芳基),亦即,6至15員芳環。在其他實施例中,芳基包含6至15個碳原子(C6-C10芳基),亦即,6至10員芳環。
單獨或作為另一取代基之一部分之「芳基烴基(arylalkyl/aralkyl)」係指鍵結至碳原子(通常為末端或sp 3碳原子)之一個氫原子經如本文所定義之芳基置換的非環狀烴基。亦即,芳基烴基由連接至伸烴基之芳基組成,該伸烴基進一步連接至分子的其他部分。芳基烴基中之伸烴基可為具有1至12個碳原子、或1至6個碳原子、或1至3個碳原子的伸烴基。典型芳基烴基包括但不限於苯甲基、2-苯基乙-1-基、2-苯基乙烯-1-基、萘甲基、2-萘基乙-1-基、2-萘基乙烯-1-基、萘并苯甲基、2-萘并苯基乙-1-基及其類似基團。在意指特定烴基部分的情況下,使用命名芳基烷基、芳基烯基及/或芳基炔基。在一些實施例中,芳基烴基為(C6-C30)芳基烴基,例如,芳基烴基之烷基、烯基或炔基部分為(C1-C10)烴基且芳基部分為(C6-C20)芳基。在其他實施例中,芳基烴基為(C6-C20)芳基烴基,例如,芳基烴基之烷基、烯基或炔基部分為(C1-C8)烴基且芳基部分為(C6-C12)芳基。在其他實施例中,芳基烴基為(C6-C15)芳基烴基,例如,芳基烴基之烷基、烯基或炔基部分為(C1-C5)烴基且芳基部分為(C6-C10)芳
基。
單獨或作為另一取代基之一部分之「環烴基」或「碳環基」係指如本文所定義之飽和或不飽和環狀烴基。類似地,單獨或作為另一取代基之一部分之「伸環烴基」或「伸碳環基」係指如本文所定義之飽和或不飽和環狀伸烴基。在意指特定飽和度的情況下,使用命名「環烷基」、「環烯基」或「環炔基」。典型環烴基包括但不限於衍生自環丙烷、環丁烷、環戊烷、環己烷及其類似物之基團。在一些實施例中,環烴基包含3至10個環原子(C3-C10環烴基)。在其他實施例中,環烴基包含3至7個環原子(C3-C7環烴基)。環烴基可進一步經一或多個包括但不限於N、P、O、S及Si之雜原子取代,該一或多個雜原子經由單價或多價鍵連接至環烴基之碳原子上。
單獨或作為其他取代基之一部分之「雜烴基」、「雜烷基」、「雜烯基」及「雜炔基」分別指一或多個碳原子(及視情況任何相關氫原子)各自彼此獨立地經相同或不同雜原子或雜原子團置換的烴基、烷基、烯基及炔基。類似地,單獨或作為其他取代基之一部分之「伸雜烴基」、「伸雜烷基」、「伸雜烯基」及「伸雜炔基」分別指一或多個碳原子(及視情況任何相關氫原子)各自彼此獨立地經相同或不同雜原子或雜原子團置換的伸烴基、伸烷基、伸烯基及伸炔基。可置換碳原子之典型雜原子或雜原子團包括但不限於-O-、-S-、-N-、-Si-、-NH-、-S(O)-、-S(O)2-、-S(O)NH-、-S(O)2NH-及其類似基團以及其組合。雜原子或雜原子團可置放於烴基、烯基或炔基之任何內部位置上。此等基團中可包括之典型雜原子團包括但不限於-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-、-SO-、-SO2-、-SnR207R208-及其類似基團,其中R201、R202、R203、R204、R205、R206、R207及R208獨立地為氫、烴基、經取代之烴基、芳基、經取代之芳基、芳基烴基、
經取代之芳基烴基、環烴基、經取代之環烴基、雜環烴基、經取代之雜環烴基、雜烴基、經取代之雜烴基、雜芳基、經取代之雜芳基、雜芳基烴基或經取代之雜芳基烴基。
單獨或作為另一取代基之一部分之「環雜烴基」或「雜環基」係指一或多個碳原子(及視情況任何相關氫原子)獨立地經相同或不同雜原子置換的飽和或不飽和環狀烴基。類似地,單獨或作為另一取代基之一部分之「伸環雜烴基」或「伸雜環基」係指一或多個碳原子(及視情況任何相關氫原子)獨立地經相同或不同雜原子置換的飽和或不飽和環狀伸烴基。環雜烴基可進一步經一或多個包括但不限於N、P、O、S及Si之雜原子取代,該一或多個雜原子經由單價或多價鍵連接至環雜烴基之碳原子上。置換碳原子之典型雜原子包括但不限於N、P、O、S、Si等。在意指特定飽和度的情況下,使用命名「環雜烷基」或「環雜烯基」。典型環雜烴基包括但不限於衍生自以下之基團:環氧化物、氮丙啶、硫雜環丙烷、咪唑啶、嗎啉、哌嗪、哌啶、吡唑啶、吡咯啶酮、啶及其類似物。在一些實施例中,環雜烴基包含3至10個環原子(3員至10員環雜烴基)。在其他實施例中,環烴基包含5至7個環原子(5員至7員環雜烴基)。環雜烴基可在雜原子(例如氮原子)上經(C1-C6)烴基取代。作為特定實例,N-甲基-咪唑啶基、N-甲基-嗎啉基、N-甲基-哌嗪基、N-甲基-哌啶基、N-甲基-吡唑啶基及N-甲基-吡咯啶基包括於「環雜烴基」之定義內。環雜烴基可經由環碳原子或環雜原子連接至分子之其餘部分。
在一實施例中,雜環基包括「氮雜環基」,其表示在環中具有一或多個氮原子之雜環。氮雜環基亦可含有另外的其他雜原子,諸如氧及硫。氮雜環基可為具有一或多個氮原子之四、五、六、七或八員環,諸如吖丁啶、咪唑啶、嗎啉、哌嗪、哌啶、吡唑啶、吡咯啶酮、二氮雜環庚烷、氮雜環庚烷、二氮雜環辛烷及氮雜環辛烷。
「化合物」係指由本文揭示之結構式(諸如(I)、(Ia)、(Ib)、(Ic)、(Id)及(Ie))所涵蓋之化合物且包括此等式中結構揭示於本文中之任何特定化合物。化合物可由其化學結構及/或化學名稱來鑒別。當化學結構與化學名稱相抵觸時,化學結構決定化合物之身份。本文所述之化合物可含有一或多個對掌性中心及/或雙鍵且因此,可以立體異構物(諸如雙鍵異構物(亦即幾何異構物))、鏡像異構物或非鏡像異構物形式存在。因此,本文所描繪之化學結構涵蓋所說明之化合物的所有可能之鏡像異構物及立體異構物,包括立體異構純形式(例如幾何純、鏡像異構純或非鏡像異構純)以及鏡像異構物及立體異構物混合物。鏡像異構物及立體異構物混合物可使用為熟練技術人員所熟知之分離技術或對掌性合成技術解析成其組分鏡像異構物或立體異構物。化合物亦可以若干互變異構形式存在,包括烯醇形式、酮形式及其混合物。因此,本文所描繪之化學結構涵蓋所說明之化合物的所有可能之互變異構形式。如本文所用之術語「互變異構物」係指相互非常容易變成彼此從而可在平衡狀態下共同存在的異構物。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,所有實體形式皆等效地用於本文所涵蓋之用途且意欲處於本發明之範疇內。此外,應瞭解,當說明化合物之部分結構時,括號指示部分結構與分子其餘部分之連接點。
單獨或作為另一取代基之一部分之「鹵基」係指基團-F、-Cl、-Br或-I。
單獨或作為另一取代基之一部分之「雜芳基」係指藉由自如本文所定義之母體雜芳族環系統之單個原子移除一個氫原子所產生的單價雜芳族基團。典型雜芳基包括但不限於衍生自以下之基團:吖啶、β-味啉、烷、烯、啉、呋喃、咪唑、吲唑、吲哚、吲哚啉、吲哚嗪、異苯并呋喃、異烯、異吲哚、異吲哚啉、異喹啉、異
噻唑、異噁唑、啶、噁二唑、噁唑、呸啶、啡啶、啡啉、啡嗪、酞嗪、蝶啶、嘌呤、哌喃、吡嗪、吡唑、噠嗪、吡啶、嘧啶、吡咯、吡、喹唑啉、喹啉、喹嗪、喹喏啉、四唑、噻二唑、噻唑、噻吩、三唑、二苯并哌喃及其類似物。在一些實施例中,雜芳基包含5至20個環原子(5員至20員雜芳基)。在其他實施例中,雜芳基包含5至10個環原子(5員至10員雜芳基)。示範性雜芳基包括衍生自以下之基團:呋喃、噻吩、吡咯、苯并噻吩、苯并呋喃、苯并咪唑、吲哚、吡啶、吡唑、喹啉、咪唑、噁唑、異噁唑及吡嗪。
單獨或作為另一取代基之一部分之「雜芳基烴基」係指鍵結至碳原子(通常為末端或sp 3 碳原子)之一個氫原子經雜芳基置換的非環狀烴基。亦即,雜芳基烴基由連接至伸烴基之雜芳基組成,該伸烴基進一步連接至分子的其他部分。雜芳基烴基中之伸烴基可為具有1至12個碳原子、或1至6個碳原子、或1至3個碳原子之伸烴基。在意指特定烴基部分的情況下,使用命名雜芳基烷基、雜芳基烯基及/或雜芳基炔基。在一些實施例中,雜芳基烴基為6員至21員雜芳基烴基,例如,雜芳基烴基之伸烷基、伸烯基或伸炔基部分為(C1-C6)伸烴基且雜芳基部分為5員至15員雜芳基。在其他實施例中,雜芳基烴基為6員至13員雜芳基烴基,例如,伸烷基、伸烯基或伸炔基部分為(C1-C3)伸烴基且雜芳基部分為5員至10員雜芳基。
「保護基」係指當連接至分子中之反應性官能基時可掩蔽、降低或防止官能基之反應性的原子團。保護基之實例可見於Green等人,「Protective Groups in Organic Chemistry」,(Wiley,第2版,1991)及Harrison等人,「Compendium of Synthetic Organic Methods」,第1-8卷(John Wiley and Sons,1971-1996)中。代表性胺基保護基包括但不限於甲醯基、乙醯基、三氟乙醯基、苯甲基、苯甲氧羰基(「CBZ」)、第三丁氧羰基(「Boc」)、三甲基矽烷基
(「TMS」)、2-三甲基矽烷基-乙烷磺醯基(「SES」)、三苯甲基及經取代之三苯甲基、烯丙氧羰基、9-茀基甲氧羰基(「FMOC」)、硝基-藜蘆基氧羰基(「NVOC」)及其類似基團。代表性羥基保護基包括但不限於將羥基醯化或烴基化之基團,諸如苯甲基及三苯甲基醚以及烴基醚、四氫哌喃基醚、三烴基矽烷基醚及烯丙基醚。
「鹽」係指具有母體化合物之所需藥理學活性的化合物之鹽。此類鹽包括:(1)酸加成鹽,其由無機酸形成,諸如鹽酸、氫溴酸、硫酸、硝酸、磷酸及其類似無機酸;或由有機酸形成,諸如乙酸、丙酸、己酸、環戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、丁二酸、蘋果酸、順丁烯二酸、反丁烯二酸、酒石酸、檸檬酸、苯甲酸、3-(4-羥基苯甲醯基)苯甲酸、肉桂酸、扁桃酸、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-甲基雙環[2.2.2]-辛-2-烯-1-甲酸、葡庚糖酸、3-苯基丙酸、三甲基乙酸、第三丁基乙酸、月桂基硫酸、葡糖酸、麩胺酸、羥萘甲酸、水楊酸、硬脂酸、黏康酸及其類似有機酸;或(2)當母體化合物中存在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)置換;或與有機鹼(諸如乙醇胺、二乙醇胺、三乙醇胺、N-甲基葡糖胺及其類似有機鹼)形成配位鍵時所形成的鹽。
「溶劑合物」意謂由溶劑化(溶劑分子與溶質之分子或離子組合)形成之化合物,或由溶質離子或分子(亦即本發明化合物)與一或多個溶劑分子組成之聚集體。當水為溶劑時,相應溶劑合物為「水合物」。
「N-氧化物」(亦稱為胺氧化物或胺-N-氧化物)意謂經由氧化本發明化合物之胺基而衍生自本發明化合物的化合物。N-氧化物通常含有官能基R3N+-O-(有時寫成R3N=O或R3N→O)。
「經取代」在用於修飾指定基團或基時意謂指定基團或基之一或多個氫原子各自彼此獨立地經相同或不同取代基置換。術語「視情況經取代」意謂經取代或未經取代。例如,視情況經取代之氮雜環意謂氮雜環可經取代或未經取代。適於取代指定基團或基中之飽和碳原子的取代基包括但不限於-Ra、鹵基、-O-、=O、-ORb、-SRb、-S-、=S、-NRcRc、=NRb、=N-ORb、三鹵基甲基、-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選自由以下組成之群:烴基、環烴基、雜烴基、環雜烴基、芳基、芳基烴基、雜芳基及雜芳基烴基;各Rb獨立地為氫或Ra;且各Rc獨立地為Rb,或者兩個Rc可連同其所鍵結之氮原子一起形成4員、5員、6員或7員環雜烴基,該環雜烴基可視情況包括1至4個選自由O、N及S組成之群的相同或不同額外雜原子。作為特定實例,-NRcRc意欲包括-NH2、-NH-烴基、N-吡咯啶基及N-嗎啉基。作為另一特定實例,經取代之烴基意欲包括-伸烴基-O-烴基、-伸烴基-雜芳基、-伸烴基-雜環烴基、-伸烴基-C(O)ORb、-伸烴基-C(O)NRbRb及-CH2-CH2-C(O)-CH3。一或多個取代基連同其所鍵結之原子一起可形成包括環烴基及環雜烴基之環。
同樣,適於取代指定基團或基中之不飽和碳原子的取代基包括但不限於-Ra、鹵基、-O-、-ORb、-SRb、-S-、-NRcRc、三鹵基甲基、-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)CRb、-NRbC(S)ORb、-NRbC(O)NRcRc、-NRbO(NRb)Rb及-NRbC(NRb)NRcRc,其中Ra、Rb及Rc係如先前所定義。
適於取代雜烴基及環雜烴基中之氮原子的取代基包括但不限於-Ra、-O-、-ORb、-SRb、-S-、-NRcRc、三鹵基甲基、-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。
上述清單中適用於取代其他指定基團或原子之取代基對於熟習此項技術者而言顯而易見。
上文提及之以化學式表示之取代基亦可很容易由熟悉此項技術者所知的該等取代基之化學名稱加以認定。例如,彼等取代基包括烴基、雜烴基、鹵基、羥基、烷氧基、胺基、烴基胺基、氰基、硝基、鹵烴基、羧酸、醯胺、酯、醯基、硫基、烴基硫基、磺醯胺等。
用於取代指定基團之取代基通常可進一步經一或多個選自上述各種基團之相同或不同基團取代。
「治療(treating)」或「治療(treatment)」任何病狀、疾
病或病症係指改善該病狀、疾病或病症(亦即阻止或減少該病狀、疾病或病症或其至少一種臨床症狀之發展)。在其他實施例中,「治療(treating)」或「治療(treatment)」係指改善至少一種不可由患者辨別之身體參數。在其他實施例中,「治療(treating)」或「治療(treatment)」係指在身體方面(例如穩定可辨別症狀)、生理學方面(例如穩定身體參數)或兩個方面抑制病狀、疾病或病症。在其他實施例中,「治療(treating)」或「治療(treatment)」係指延遲病狀、疾病或病症之發作。
「治療有效量」意謂本發明化合物在投與患者以治療病狀、疾病或病症時足以針對該病狀、疾病或病症實現該治療作用的量。「治療有效量」將視化合物、欲治療之患者的病狀、疾病或病症及其嚴重度以及年齡、體重等而變化。在一實施例中,治療有效量不同於味覺調節量,諸如甜味受體調節量、甜味受體配位體調節量、甜味調節量或甜味調味劑量。
「媒劑」係指與化合物一起投與之稀釋劑、佐劑、賦形劑或載劑。
如本文所用之「可攝食組合物」包括無論是否預期用於食用均可單獨或連同另一物質一起經口服用之任何物質。可攝食組合物包括「食品或飲料產品」及「非食用產品」兩者。「食品或飲料產品」意謂預期由人類或動物食用之任何可食用產品,包括固體、半固體或液體(例如飲料)。術語「非食用產品」或「非食用組合物」包括可由人類或動物出於除食用或作為食品或飲料以外之目的而服用之任何產品或組合物。舉例而言,非食用產品或非食用組合物包括補充劑、營養藥物、功能型食品(例如宣稱除提供營養素之基本營養功能以外亦具有促進健康及/或預防疾病之特性的任何新鮮或加工食品)、醫藥及非處方藥物、口腔護理產品(諸如牙粉及嗽口水)、化妝品(諸如
甜化唇膏)及其他可能含有或可能不含任何甜味劑之個人護理產品。
「攝食上可接受之載劑或賦形劑」為用於製備本發明化合物之所需分散劑型以投與呈分散/稀釋形式之本發明化合物,從而使本發明化合物之生物有效性達到最大的介質及/或組合物。視產品之預期用途而定,介質及/或組合物可呈任何形式,例如固體、半固體、液體、糊狀物、凝膠、洗液、乳油、泡沫狀物質、懸浮液、溶液或其任何組合(諸如含有固體內含物之液體)。攝食上可接受之載劑包括多種常見食品成分,諸如pH值呈中性、酸性或鹼性之水、果汁或蔬菜汁、醋、醃泡汁、啤酒、葡萄酒、天然水/脂肪乳液(諸如牛乳或煉乳)、可食用油及起酥油、脂肪酸及其烴酯、丙二醇之低分子量寡聚物、脂肪酸之甘油酯、及該等疏水性物質於水性介質中之分散液或乳液、鹽(諸如氯化鈉)、小麥粉、溶劑(諸如乙醇)、固體可食用稀釋劑(諸如蔬菜粉或麵粉),或其他液體媒劑;分散或懸浮佐劑;表面活性劑;等張劑;增稠劑或乳化劑、防腐劑;固體黏合劑;潤滑劑,及其類似物。
根據本發明,化學感覺受體可為與化學感覺或化學感覺配位體觸發之信號轉導有關的任何受體,例如經由表現於味蕾或身體內臟器官(諸如胃腸道等)中之味覺受體或味覺相關受體發生之信號轉導。在一實施例中,化學感覺受體為屬7次跨膜受體超家族或G蛋白偶聯受體(GPCR)的受體。在另一實施例中,化學感覺受體為經由一或多種G蛋白進行信號轉導之受體。在另一實施例中,化學感覺受體為屬GPCR之C家族或C類之受體。在另一實施例中,化學感覺受體為屬T1R家族之受體。在另一實施例中,化學感覺受體為受體T1R1、T1R2、T1R3或其等效物或變異體或其組合。在另一實施例中,化學感覺受體為T1R2與T1R3之雜二聚體,或其等效物或變異體。
「調節劑」在本文中指調節(增強)特定受體(較佳為化學
感覺受體,例如T1R2/T1R3受體)之活化的化合物,或其攝食上可接受之鹽或溶劑合物。在本文中,該等調節劑將增強化學感覺受體由其配位體所引起之活化。通常,「調節劑」對特定配位體具特異性,亦即其不會增強由除特定化學感覺配位體或與該特定化學感覺配位體密切相關之配位體以外的化學感覺配位體所引起之化學感覺受體的活化。一些調節劑在其配位體增強濃度下本身不會引起特定受體活化。亦即,此等調節劑之配位體增強濃度為增加或增強由配位體引起之特定受體活化而該等調節劑本身不實質上活化特定受體情況下該等調節劑濃度。在一些實施例中,某些調節劑在以高於配位體增強濃度的濃度使用時除調節(例如增加或增強)受體之活化以外本身亦可活化特定受體。舉例而言,某些調節劑在以高於配位體增強濃度之濃度使用時亦可為甜味劑(亦即甜味調味劑/實體)。在其他實施例中,某些調節劑在同一濃度下除調節(例如增加或增強)受體之活化以外同時本身亦可活化特定受體。換言之,某些調節劑同時亦為甜味劑(亦即甜味調味劑/實體)。
「風味」在本文中指受試者對味道之感知,其包括甜味、酸味、鹹味、苦味及鮮味。受試者可為人類或動物。
「調味劑」在本文中指在動物或人類體內誘導風味或味覺之化合物或其攝食上可接受之鹽或溶劑合物。調味劑可為天然、半合成或合成調味劑。
「風味改質劑(flavor modifier/flavor modifying agent)」在本文中指改質(包括增效及/或誘導)動物或人類對調味劑之味覺的化合物或其攝食上可接受之鹽或溶劑合物。
「風味調節劑」在本文中指調節(增效)及/或倍增調味劑或包含調味劑之可攝食組合物之味道的化合物或其攝食上可接受之鹽。
「甜味」係指動物或人類體內通常由糖(諸如果糖)所誘導之甜味味覺。
「甜味調味劑」、「甜味實體」、「甜味劑」或「甜味化合物」在本文中指在受試者體內引起可偵測甜味之化合物或其攝食上可接受之鹽,例如果糖或在活體外活化T1R2/T1R3受體之化合物。受試者可為人類或動物。
「甜味改質劑(sweet flavor modifier/sweet flavor modifying agent)」在本文中指改質(包括增效、誘導或阻斷)動物或人類對甜味調味劑之甜味味覺之化合物或其攝食上可接受之鹽或溶劑合物。甜味改質劑包括甜味調節劑及甜味調味劑。
「甜味調節劑(sweet flavor modulator/sweet flavor modulating agent)」在本文中指甜味之調節劑,其中術語調節劑與上文所定義相同。
「甜味受體活化化合物」或「甜味受體促效劑」在本文中指活化甜味受體(諸如T1R2/T1R3受體)之化合物。甜味受體活化化合物之一實例為甜味劑,諸如果糖。
「甜味受體調節化合物」在本文中指調節諸如T1R2/T1R3受體之甜味受體(活化、阻斷甜味受體或增強/減少甜味受體活化)之化合物。例如,甜味受體調節化合物可增效甜味受體活化化合物(例如果糖)之效用。
本發明之甜味受體調節化合物在其有用之配位體增強濃度下本身可或可不引起特定受體之活化。一些甜味受體調節化合物或甜味調節劑除調節(增加)受體之活化以外本身亦可活化特定受體。舉例而言,一些甜味受體調節化合物或甜味調節劑亦可活化甜味受體,諸如T1R2/T1R3受體,從而充當受體促效劑。
「甜味調節量」在本文中指式(I)化合物足以充分地調節
可攝食組合物或其前驅體之甜味而可由人類受試者所感知的量。在本發明之許多實施例中,需要存在至少約0.001ppm之本發明化合物以使大部分人類受試者感知到對包含本發明化合物之可攝食組合物之甜味的調節。通常用於以較低成本提供所需甜味調節度的較寬濃度範圍可為約0.001ppm至100ppm,或為約0.1ppm至約10ppm之較窄範圍。甜味調節量之替代範圍可為約0.01ppm至約30ppm、約0.05ppm至約15ppm、約0.1ppm至約5ppm,或約0.1ppm至約3ppm。在一些實施例中,甜味調節量為對應於本發明之甜味調節劑之配位體增強濃度的量。
「甜味受體調節量」在本文中指化合物足以調節(活化、增強或阻斷)甜味受體蛋白之量。在本發明之許多實施例中,甜味受體調節量為至少約10nM,或至少約100nM(亦即約0.1μM),或至少約1μM,或至少約10μM。「T1R2/T1R3受體調節或活化量」為化合物足以調節或活化T1R2/T1R3受體之量。「甜味受體」為可由甜味化合物調節之味覺受體。較佳地,甜味受體為G蛋白偶聯受體,且更佳地,甜味受體為T1R2/T1R3受體。
化合物
在一實施例中,本發明提供具有結構式(I)之化合物:
或其鹽或溶劑合物;其中A為視情況經取代之四、五、六、七或八員氮雜環;X為共價鍵或-NR1-;R1為氫或C1至C6烴基;以及
Y為烴基、經取代之烴基、雜烴基、經取代之雜烴基、碳環基、經取代之碳環基、雜環基、經取代之雜環基、芳基、經取代之芳基、雜芳基、經取代之雜芳基、芳基烴基、經取代之芳基烴基、雜芳基烴基,或經取代之雜芳基烴基。
在本發明之一實施例中,式(I)不包括以下化合物:
,,,以及
在式(I)之一實施例中,X為NH。
在式(I)之一實施例中,X為共價鍵。
在式(I)之一實施例中,A為視情況經取代之五、六或七員氮雜環。在式(I)之一實施例中,A為視情況經取代之六員氮雜環。在式(I)之一實施例中,A為視情況經取代之哌啶。
在式(I)之一實施例中,化合物可由結構式(Ia)表示:
其中,m為1、2、3、4、5或6;n為0、1、2或3;其限制條件為m+n大於1且小於7;q為0、1、2、3、4、5或6;其限制條件為q小於m+n;
X為共價鍵或-NR1-;R1為氫或C1至C6烴基;Y為烴基、經取代之烴基、雜烴基、經取代之雜烴基、碳環基、經取代之碳環基、雜環基、經取代之雜環基、芳基、經取代之芳基、雜芳基、經取代之雜芳基、芳基烴基、經取代之芳基烴基、雜芳基烴基,或經取代之雜基芳烴基;以及各R2獨立地選自由烴基、雜烴基、鹵基、羥基、烷氧基、胺基、烴基胺基、氰基、硝基、鹵烴基、羧酸、醯胺、酯、醯基、硫基、烴基硫基及磺醯胺組成之群。
在式(Ia)之一實施例中,X為NH。
在式(Ia)之一實施例中,X為共價鍵。
在式(Ia)之一實施例中,m為1、2、3或4;且n為0、1或2。
在式(Ia)之一實施例中,q為1、2或3。
在式(Ia)之一實施例中,q為0。
在式(Ia)之一實施例中,m為4,且n為0;或m為3且n為1;或m與n皆為2。
在式(Ia)之一實施例中,化合物可由結構式(Ib)表示:
其中,Y為烴基、經取代之烴基、雜烴基、經取代之雜烴基、碳環基、經取代之碳環基、雜環基、經取代之雜環基、芳基、經取代之芳基、雜芳基、經取代之雜芳基、芳基烴基、經取代之芳基烴基、雜芳基烴
基,或經取代之雜芳基烴基。
在式(Ia)之一實施例中,化合物可由結構式(Ic)表示:
其中,Y為烴基、經取代之烴基、雜烴基、經取代之雜烴基、碳環基、經取代之碳環基、雜環基、經取代之雜環基、芳基、經取代之芳基、雜芳基、經取代之雜芳基、芳基烴基、經取代之芳基烴基、雜芳基烴基,或經取代之雜芳基烴基。
在式(Ia)之一實施例中,化合物可由結構式(Id)表示:
其中,Y為烴基、經取代之烴基、雜烴基、經取代之雜烴基、碳環基、經取代之碳環基、雜環基、經取代之雜環基、芳基、經取代之芳基、雜芳基、經取代之雜芳基、芳基烴基、經取代之芳基烴基、雜芳基烴基,或經取代之雜芳基烴基。
在式(Ia)之一實施例中,化合物可由結構式(Ie)表示:
在式(Ib)、(Ic)、(Id)或(Ie)之一實施例中,Y為C1至C12烴基、經取代之C1至C12烴基,C1至C12雜烴基,或經取代之C1至C12雜烴基。
在式(Ib)、(Ic)、(Id)或(Ie)之一實施例中,Y為三至十員碳環基、經取代之三至十員碳環基,三至十員雜環基,或經取代之三至十員雜環基。
在式(Ib)、(Ic)、(Id)或(Ie)之一實施例中,Y為六至十五員芳基、經取代之六至十五員芳基,五至十員雜芳基,或經取代之五至十員雜芳基。
在式(Ib)、(Ic)、(Id)或(Ie)之一實施例中,Y為-(C1至C3伸烴基)-芳基或-(C1至C3伸烴基)-經取代之芳基。
在式(Ib)、(Ic)、(Id)或(Ie)之一實施例中,Y為-(C1至C3伸烴基)-雜芳基或-(C1至C3伸烴基)-經取代之雜芳基。
在式(Ic)或(Ie)之一實施例中,Y為C1至C12烴基、經取代之C1至C12烴基、五或六員雜芳基、經取代之五或六員雜芳基、-(C1至C3伸烴基)-(五或六員雜芳基),或-(C1至C3伸烴基)-(經取代之五或六員雜芳基)。在此等先前實施例中任一項中,雜芳基為吡咯、吡啶、嘧啶、噠嗪或吡嗪,其各自視情況經取代。在前述實施例中任一項中,雜芳基為視情況經取代之吡啶。
在式(Ib)或(Id)之一實施例中,Y為C1至C12烴基、經取代之C1至C12烴基,C1至C12雜烴基,或經取代之C1至C12雜烴基。在前述實施例中任一項中,視情況經取代之C1至C12烴基或C1至C12
雜烴基可為直鏈或支鏈。
在式(Ib)或(Id)之一實施例中,Y為三、四、五、六或七員環烴基,或經取代之三、四、五、六或七員環烴基,五、六或七員雜環基,或經取代之五、六或七員雜環基。在此等先前實施例中任一項中,雜烴基為環丙基、環丁基、環戊基、環己基或環庚基,其各自視情況經取代。在此等先前實施例中任一項中,雜環基為四氫呋喃或四氫哌喃,其各自視情況經取代。
在式(Ib)或(Id)之一實施例中,Y為苯基或經取代之苯基。
在式(Ib)或(Id)之一實施例中,Y為視情況經取代之五或六員單環雜芳基,或視情況經取代之十至十二員雙環雜芳基。在此等先前實施例中任一項中,雜芳基選自由吡咯、吡啶、嘧啶、噠嗪、吡嗪、吡啶N-氧化物、喹啉、咪唑并吡啶及吡唑并吡啶組成之群,其各自視情況經取代。
在式(Ib)或(Id)之一實施例中,Y為-CH2-苯基或-C(CH3)2-經取代之苯基。
在式(Ib)或(Id)之一實施例中,Y為-CH2-雜芳基或-C(CH3)2-經取代之雜芳基。在此等先前實施例中任一項中,雜芳基為吡咯、吡啶、嘧啶、噠嗪或吡嗪,其各自視情況經取代。在此等前述實施例中任一項中,雜芳基為視情況經取代之吡啶。
在式(I)之某些特定實施例中,化合物選自由以下組成之群:
,以及
組合物
本發明化合物可用於本發明之例如調節與化學感覺或化學感覺相關性感覺或反應有關之受體及其配位體之一或多種方法中。根據本發明,調節化學感覺受體及/或其配位體之方法包括調節化學感覺受體之活性、結構、功能、表現及/或修飾,以及調節、治療與化學感覺受體有關之病狀(例如生理性或病理性病狀)或針對該病狀採取預防措施。一般而言,與化學感覺受體有關之生理性或病理性病狀包括與化學感覺受體及/或其配位體有關之病狀、疾病或病症,例如胃腸病症、代謝障礙、功能性胃腸病症等。在一實施例中,該方法包括增加或增效甜味。在另一實施例中,該方法包括調節表現於除味蕾以外之身體部位(諸如內臟器官)上之甜味受體及/或其配位體。一般而言,本發明之化合物可以組合物(諸如可攝食組合物)形式個別地或組合提供。在一實施例中,本發明化合物可藉由在甜味劑組合物中將一或多種本發明化合物與一或多種甜味劑組合來賦予甜味劑組合物以更類似於糖之時間變化型態及/或風味變化型態(flavor profile)。在另一
實施例中,本發明化合物可藉由使其組合物與一或多種本發明化合物接觸以形成經調節組合物來增加或增效該組合物之甜味。在另一實施例中,本發明化合物可處於調節表現於除味蕾以外之身體部位上之甜味受體及/或其配位體的組合物中。
式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)及其各種亞屬及種之化合物及其鹽及/或溶劑合物較佳應為食用上可接受的,例如,認為就給予未經改質之可食用組合物以改良及/或合意之甜味的觀點而言適於以食品或飲料形式食用,且在其作為調味劑用於可食用組合物的典型濃度下對動物或人類不具顯著毒性或不會引起不合意或不合需要之藥理學或毒理學作用。
一種證明調味料化合物在食用上可接受之方法為化合物由美國香料及萃取物製造者協會(Flavor and Extract Manufacturers Association,FEMA)專家組測試及/或評估且宣佈其「公認為安全的(Generally Recognized As Safe)」(「GRAS」)。FEMA/GRAS對調味料化合物之評估方法為複雜的,但為食品製備技術之一般技術者所熟知,如由Smith等人在名稱為「GRAS Flavoring Substances 21」,Food Technology,57(5),第46-59頁,2003年5月之文章中所論述,該文章之整個內容以引用方式併入本文中。除FEMA專家組之外,亦可由製造商形成一個獨立且具資質之相關科學學科專家組來針對GRAS資格評估特定化合物之安全性。此方法被稱為「GRAS資格自決(self determination of GRAS status)」。另一證明調味料化合物在食用上可接受之方法為獲得WHO/FAO聯合食品添加劑專家委員會(Joint Expert Committee on Food Additives)或JECFA之有利審查結果。亦存在其他評估方法,諸如管理機構之獨立審查,此等評估方法一般為食品製備技術之一般技術者所已知。
在一實施例中,本發明化合物可以其配位體增強濃度
(例如約幾個百萬分率的極低濃度)與一或多種已知之天然或人工甜味劑組合使用,以降低製備具有所需甜度之可攝食組合物所需的已知甜味劑之濃度。
在本發明之一實施例中,本發明化合物可在廣泛範圍之pH值(例如較低pH值至中性pH值)下增效(亦即增強或倍增)甜味劑之甜味。較低及中性pH值包括但不限於約2.1至約8.5;約2.3至約8.0;約2.5至約7.5;及約2.6至約7.3之pH值。在一實施例中,本發明化合物可在約2.8至約7.1之pH範圍內,增效(亦即增強或倍增)甜味劑之甜味。在某些實施例中,本發明化合物可在味覺測試中,於約50μM、40μM、30μM、20μM或10μM之化合物濃度下,在低至中性pH值下,增效固定濃度之甜味劑的所感知甜味。在某些實施例中,本發明化合物在較低pH值下之增效因數實質上類似於該等化合物在中性pH值下之增效因數。該種在廣泛範圍之pH值下一致之甜味增效特性使得本發明化合物成為可廣泛用於多種食品及飲料中之良好候選者。
用於該等甜味劑組合中之常用已知或人工甜味劑包括但不限於常見醣類甜味劑,例如蔗糖、果糖、葡萄糖;及包含天然糖之甜味劑組合物,諸如玉米糖漿(包括高果糖玉米糖漿)或其他自天然水果及蔬菜來源獲得之糖漿或甜味劑濃縮物;半合成「糖醇」甜味劑,諸如赤藻糖醇、異麥芽酮糖醇、乳糖醇、甘露糖醇、山梨糖醇、木糖醇、麥芽糊精及其類似物;及人工甜味劑,諸如阿斯巴甜糖、糖精、艾司沙芬鉀(acesulfame-K)、賽克拉美、蔗糖素及阿力甜(alitame)。甜味劑亦包括環己胺基磺酸、羅漢果甜苷(mogroside)、塔格糖、麥芽糖、半乳糖、甘露糖、蔗糖、果糖、乳糖、紐甜(neotame)及其他阿斯巴甜糖衍生物、葡萄糖、D-色胺酸、甘胺酸、麥芽糖醇、乳糖醇、異麥芽酮糖醇、氫化葡萄糖糖漿(HGS)、氫化澱粉水解物(HSH)、甜菊苷、萊鮑迪苷A(rebaudioside A)及其他基於甜菊(sweet Stevia)之醣
苷、N-[[(3,5-二氯苯基)胺基][(二苯基甲基)胺基]亞甲基]甘胺酸(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之甜味劑的組合。
在一實施例中,將本發明化合物添加至非食用組合物或非食用產品,諸如補充劑、營養藥物、功能型食品(例如宣稱除提供營養素之基本營養功能以外亦具有促進健康及/或預防疾病之特性的任何新鮮或加工食品)、醫藥產品、非處方(OTC)產品、口腔護理產品、化妝品(諸如甜化唇膏)及其他個人護理產品。
一般而言,非處方(OTC)產品及口腔護理產品一般指可在未開立處方的情況下及/或在未拜訪醫學專業人員的情況下出售之供家庭及/或個人使用之產品。OTC產品之實例包括但不限於維生素及膳食補充劑;局部鎮痛劑及/或麻醉劑;咳嗽、感冒及過敏藥物;抗組織胺劑及/或過敏藥物;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/瓶裝營養飲料、兒童專用維生素、膳食補充劑、任何其他營養產品或任何其他與營養有關或提供營養之產品,及其組合。局部鎮痛劑及/或麻醉劑包括任何用於減輕表面或深層痛覺及疼痛(例如肌肉疼痛)之任何局部乳油劑/軟膏/凝膠劑;出牙凝膠;含鎮痛成分之貼片;及其組合。咳嗽、感冒及過敏藥物包括但不限於去充血劑、咳嗽藥物、咽部製劑、藥製糖食、抗組織胺劑及兒童專用咳嗽、感冒及過敏藥物;及組合產品。抗組織胺劑及/或過敏藥物包括但不限於任何用於枯草熱、鼻過敏、昆蟲咬傷及螫傷之全身性治療。口腔護理產品之實例包括但不限於口腔清潔條、牙膏、牙刷、嗽口水/牙科沖洗液、假牙護理劑、口腔清新劑、家用牙齒增白劑、牙粉及牙線。
在另一實施例中,將本發明化合物添加至食品或飲料產品或調配物中。食品及飲料產品或調配物之實例包括但不限於用於可
食用產品之糖衣、糖霜或糖釉或以下類別中所包括之任何實體:湯類、乾燥加工食品類、飲料類、即食膳食類、罐裝或保藏食品類、冷凍加工食品類、冷藏加工食品類、點心食品類、烘烤製品類、糖食類、乳製品類、冰淇淋類、膳食替代品類、意大利麵及麵條類,以及調味醬、醬汁、調味品類、嬰兒食品類及/或塗抹食品類。
一般而言,湯類係指罐裝/保藏、脫水、速溶、冷藏、UHT及速凍湯。出於此定義之目的,湯意謂藉由在液體中烹調肉、家禽、魚、蔬菜、穀物、水果及其他成分所製成之食品,其可包括一些或所有此等成分之明顯碎片。其可為澄清(呈肉湯形式)或稠厚(呈雜燴湯形式)、細滑、濃稠或滿是大塊食物、即可食用、半濃縮或濃縮的且可以熱或冷湯形式,作為進餐之第一道菜或作為主菜或作為兩餐之間的點心(如飲料一般啜飲)食用。湯可用作製備其他膳食組分之成分且範圍可包括肉湯(清燉肉湯)至調味醬(基於奶油或乾酪之湯)。
脫水及烹飪用食品類通常意謂:(i)烹調輔助產品,諸如:粉末、顆粒、糊狀物、濃縮液體產品,包括呈壓製立方體、片狀物或粉末或粒化形式之濃縮肉汁、肉汁及肉汁類產品,其分別以最終產品形式或以產品、調味醬及配方混合物內之成分形式出售(與技術無關);(ii)膳食溶液產品,諸如:脫水及冷凍乾燥湯,包括脫水湯混合物、脫水速溶湯、脫水即可烹調湯、現成菜肴、膳食及單份主菜(包括意大利麵、馬鈴薯及米飯主食)之脫水或環境製備物;及(iii)膳食點綴產品,諸如:調味品、醃泡汁、沙拉醬汁、沙拉澆汁(salad topping)、蘸料、拌粉、麵糊混料(batter mix)、存放穩定性塗抹食品、燒烤用調味醬、液體配方混合物、濃縮物、調味醬或調味醬混合物,包括沙拉之配方混合物,以最終產品形式或以產品內之成分形式出售(脫水、液體或冷凍)。
飲料類通常意謂飲料、飲料混合物及濃縮物,包括但不
限於碳酸飲料及非碳酸飲料、酒精性及非酒精性飲料、即可飲用之飲料、用於製備飲料之液體濃縮物調配物,諸如蘇打及乾粉狀飲料前驅混合物。飲料類亦包括酒精飲料、清涼飲料、運動型飲料、等張飲料及熱飲。酒精飲料包括但不限於啤酒、蘋果酒/梨酒、FAB、葡萄酒及烈酒。清涼飲料包括但不限於碳酸飲料,諸如可樂及非可樂碳酸飲料;水果汁,諸如果汁、花蜜、果汁飲料及水果味飲料;瓶裝水,包括汽水、礦泉水及純化/飲用水;功能型飲料,其可充有二氧化碳或不含氣體且包括運動、能量或藥酒飲料;濃縮物,諸如即可飲用定量之液體及粉末濃縮物。熱飲料或冷飲料包括但不限於咖啡或冰咖啡,諸如新鮮、速溶及組合咖啡;茶或冰茶,諸如紅茶、綠茶、白茶、烏龍茶及調味茶;及其他飲料,包括與牛乳或水混合之基於風味、麥芽或植物之粉末、顆粒、塊狀物或片狀物。
點心食品類一般指可為非正式便餐之任何食品,包括但不限於甜味且美味之點心以及點心棒。點心食品之實例包括但不限於水果點心、薄片食品/鬆脆食品、壓模點心、玉米粉圓餅/玉米片、爆米花、椒鹽卷餅、堅果及其他甜味及美味點心。點心棒之實例包括但不限於燕麥花卷(granola)/牛奶什錦早餐(muesli)棒、早餐棒、能量棒、水果棒及其他點心棒。
烘烤製品類一般指製備方法涉及暴露於熱或過度日光之任何可食用產品。烘烤製品之實例包括但不限於麵包、小圓麵包、小甜餅、鬆餅、穀類食品、土司糕點(toaster pastry)、糕點、華夫餅乾、玉米粉圓餅、餅乾、餡餅、百吉餅、果餡餅、乳蛋餅、蛋糕、任何烘烤食品及其任何組合。
冰淇淋類一般指含有奶油及糖以及調味劑之冷凍甜食。冰淇淋之實例包括但不限於:衝動購買型冰淇淋(impulse ice cream);家庭裝冰淇淋;冷凍酸乳酪及手工冰淇淋;基於大豆、燕
麥、豆類(例如赤豆及綠豆)以及稻米之冰淇淋。
糖食類一般指味道為甜味之可食用產品。糖食之實例包括但不限於硬糖、果凍、巧克力糖食、糖類糖食、口香糖及其類似物以及任何組合產品。
膳食替代品類一般指尤其用於有健康或健身問題之人的任何意欲替代正常進餐之食品。膳食替代品之實例包括但不限於瘦身產品及保健產品。
即食膳食類一般指可在不深入製備或加工的情況下用作膳食之任何食品。即食膳食包括已由製造商使用配方「技能」進行加工,以使之具有高度即食性、完備性及便利性的產品。即食膳食之實例包括但不限於罐裝/保藏、冷凍、乾燥、冷藏之即食膳食;正餐混合物;冷凍披薩;冷藏披薩;及精製沙拉。
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、乾燥及冷藏/新鮮意大利麵;及素麵、速食麵、冷藏麵、冷凍麵及點心麵。
罐裝/保藏食品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、即食膳食、湯、意大利面,及其他罐裝/保藏食品。
冷凍加工食品類包括但不限於冷凍加工紅肉、加工家禽、加工魚/海鮮、加工蔬菜、肉類替代品、加工馬鈴薯、烘烤產品、甜食、即食膳食、披薩、湯、麵條及其他冷凍食品。
乾燥加工食品類包括但不限於稻米、甜食混合物、乾燥即食膳食、脫水湯、速溶湯、乾燥意大利麵、素麵及速食麵。
冷藏加工食品類包括但不限於冷藏加工肉、加工魚/海鮮產品、午餐套組、鮮切水果、即食膳食、披薩、精製沙拉、湯、新鮮意大利麵及麵條。
調味醬、醬汁及調味品類包括但不限於番茄醬及蕃茄糊、肉汁/濃縮固體湯料(stock cube)、藥草及香辛料、麩胺酸單鈉(MSG)、餐桌調味醬、基於大豆之調味醬、意大利麵調味醬、濕潤/烹調調味醬、乾調味醬/粉末混合物、調味番茄醬、蛋黃醬、芥末、沙拉醬汁、調味醋醬、蘸料、鹽漬產品及其他調味醬、醬汁及調味品。
嬰兒食品類包括但不限於基於牛乳或大豆之配方食品;及精製、乾燥及其他嬰兒食品。
塗抹食品類包括但不限於果醬及醬、蜂蜜、巧克力塗抹食品、基於堅果之塗抹食品及基於酵母之塗抹食品。
乳製品類一般指由哺乳動物乳汁製成之可食用產品。乳製品之實例包括但不限於飲用乳製品、乾酪、酸乳酪及酸乳飲料及其他乳製品。
可食用組合物,尤其食品及飲料產品或調配物之其他實例提供如下。示範性可食用組合物包括一或多種糖食、巧克力糖食、片狀物、countline、裝袋selfline/softline、盒裝什錦、標準盒裝什錦、扭結包裝之微型食玩、季節性巧克力、帶玩具之巧克力、美洲夾心餅(alfajore)、其他巧克力糖食、薄荷糖、標準薄荷糖、強力薄荷糖、硬糖果、軟果糖、口香糖、果子凍及咀嚼食品、太妃糖、焦糖及牛軋糖、藥製糖食、棒棒糖、甘草、其他糖類糖食、口香糖、橡皮糖、加糖口香糖、無糖口香糖、功能型口香糖、泡泡糖、麵包、封裝/工業化生產麵包、散裝/手工麵包、糕點、蛋糕、封裝/工業化生產之蛋糕、散裝/手工蛋糕、小甜餅、塗有巧克力之餅乾、夾心餅乾、注心餅乾、美味餅乾及薄脆餅乾、麵包替代品、早餐穀類食品、即食穀類食品、家庭裝早餐穀類食品、薄片狀食品、牛奶什錦早餐、其他穀類食品、兒童早餐穀類食品、熱穀類食品、冰淇淋、衝動購買型冰淇淋、單份乳製冰淇淋、單份水冰淇淋、多包裝乳製冰淇淋、多包裝水
冰淇淋、家庭裝冰淇淋、家庭裝乳製冰淇淋、冰淇淋甜食、散裝冰淇淋、家庭裝水冰淇淋、冷凍酸乳酪、手工冰淇淋、乳製品、牛乳、新鮮/殺菌乳、全脂新鮮/殺菌乳、半脫脂新鮮/殺菌乳、保存期較長/超高溫殺菌乳、全脂保存期較長/超高溫殺菌乳、半脫脂保存期較長/超高溫殺菌乳、脫脂保存期較長/超高溫殺菌乳、山羊乳、煉乳/蒸發乳、原味煉乳/蒸發乳、調味、功能型及其他煉乳、調味乳飲料、純乳製調味乳飲料、含果汁之調味乳飲料、豆乳、酸乳飲料、發酵乳製飲料、咖啡奶精、乳粉、調味乳粉飲料、奶油、乾酪、加工乾酪、可塗抹加工乾酪、不可塗抹加工乾酪、未加工乾酪、可塗抹未加工乾酪、硬質乾酪、封裝硬質乾酪、散裝硬質乾酪、酸乳酪、原味/天然酸乳酪、調味酸乳酪、加水果調味酸乳酪、益生菌酸乳酪、飲用酸乳酪、普通飲用酸乳酪、益生菌飲用酸乳酪、冷藏及存放穩定性甜食、基於乳製品之甜食、基於大豆之甜食、冷藏點心、清爽乾酪及凝乳、原味清爽乾酪及凝乳、調味清爽乾酪及凝乳、美味清爽乾酪及凝乳、甜味及美味點心、水果點心、薄片食品/鬆脆食品、壓模點心、玉米粉圓餅/玉米片、爆米花、椒鹽卷餅、堅果、其他甜味及美味點心、點心棒、燕麥花卷棒、早餐棒、能量棒、水果棒、其他點心棒、膳食替代產品、瘦身產品、保健飲料、即食膳食、罐裝即食膳食、冷凍即食膳食、乾燥即食膳食、冷藏即食膳食、正餐混合物、冷凍披薩、冷藏披薩、湯、罐裝湯、脫水湯、速溶湯、冷藏湯、熱湯、冷凍湯、意大利麵、罐裝意大利麵、乾燥意大利麵、冷藏/新鮮意大利麵、麵條、素麵、速食麵、杯裝/碗裝速食麵、袋裝速食麵、冷藏麵條、點心麵條、罐裝食品、罐裝肉及肉製品、罐裝魚/海鮮、罐裝蔬菜、罐裝番茄、罐裝豆類、罐裝水果、罐裝即食膳食、罐裝湯、罐裝意大利麵、其他罐裝食品、冷凍食品、冷凍加工紅肉、冷凍加工家禽、冷凍加工魚/海鮮、冷凍加工蔬菜、冷凍肉類替代品、冷凍馬鈴薯、烘箱
烘烤馬鈴薯片、其他烘箱烘烤馬鈴薯產品、非烘箱烘烤冷凍馬鈴薯、冷凍烘烤產品、冷凍甜食、冷凍即食膳食、冷凍披薩、冷凍湯、冷凍麵條、其他冷凍食品、乾燥食品、甜食混合物、乾燥即食膳食、脫水湯、速溶湯、乾燥意大利麵、素麵、速食麵、杯裝/碗裝速食麵、袋裝速食麵、冷藏食品、冷藏加工肉類、冷藏魚/海鮮產品、冷藏加工魚、冷藏裹料魚(chilled coated fish)、冷藏燻魚、冷藏午餐套組、冷藏即食膳食、冷藏披薩、冷藏湯、冷藏/新鮮意大利麵、冷藏麵條、油及脂肪、橄欖油、植物油及種子油、烹調用脂肪、黃油、人造奶油、可塗抹油及脂肪、功能型可塗抹油及脂肪、調味醬、醬汁及調味品、番茄醬及蕃茄糊、肉汁/濃縮固體湯料、濃縮固體湯料、肉鹵顆粒、液體高湯及高湯湯頭、藥草及香辛料、發酵調味醬、基於大豆之調味醬、意大利麵調味醬、濕調味醬、乾調味醬/粉末混合物、調味番茄醬、蛋黃醬、普通蛋黃醬、芥末、沙拉醬汁、普通沙拉醬汁、低脂沙拉醬汁、調味醋醬、蘸料、鹽漬產品、其他調味醬、醬汁及調味品、嬰兒食品、配方乳品、標準配方乳品、第二階段配方乳品(follow-on milk formula)、幼童配方乳品、低過敏原配方乳品、精製嬰兒食品、乾燥嬰兒食品、其他嬰兒食品、塗抹食品、果醬及醬、蜂蜜、巧克力塗抹食品、基於堅果之塗抹食品及基於酵母之塗抹食品。示範性可食用組合物亦包括糖食、烘烤產品、冰淇淋、乳製品、甜味及美味點心、點心棒、膳食替代產品、即食膳食、湯、意大利麵、麵條、罐裝食品、冷凍食品、乾燥食品、冷藏食品、油及脂肪、嬰兒食品或塗抹食品或其混合物。示範性可食用組合物亦包括早餐穀類食品、甜味飲料或用於製備飲料之固體或液體濃縮物組合物,理想的是能夠使得先前已知之醣類甜味劑或人工甜味劑之濃度降低。
通常將至少甜味受體調節量、甜味受體配位體調節量、甜味調節量、甜味調味劑量或治療有效量之一或多種本發明化合物視
情況在已知甜味劑存在下添加至可攝食組合物中,例如以使甜味經改質之可攝食組合物的甜味相較於在不存在本發明化合物下所製備之可攝食組合物有所增加,如通常由人類或動物所判定,或在調配物測試的狀況下,如經由該領域中通常已知之程序由含至少八名人類味覺測試者之小組中大多數測試者所判定。
調節或改良可攝食組合物之風味所需的甜味調味劑之濃度當然將視多種變數而定,包括可攝食組合物之特定類型及其各種其他成分,尤其其他已知甜味調味劑之存在及其濃度、品嘗該等組合物之各個人類之天然遺傳變異性及個別偏好以及健康狀況,及特定化合物對該等化學感覺化合物之味道之主觀效應。
本發明化合物之一種應用為用於調節(誘導、增效或抑制)其他天然或合成甜味促味劑及由其製成之可攝食組合物之甜味或其他味覺特性。在一實施例中,本發明化合物以其配位體增強濃度使用或提供。舉例而言,通常需要處於較寬且亦較低濃度範圍內之本發明化合物或實體,亦即約0.001ppm至100ppm,或為約0.1ppm至約10ppm、約0.01ppm至約30ppm、約0.05ppm至約10ppm、約0.01ppm至約5ppm或約0.02ppm至約2ppm,或約0.01ppm至約1ppm之較窄替代範圍。
在一實施例中,本發明提供一種甜味調節組合物。該甜味調節組合物包含有效提供甜化作用之量(例如甜味調節量)的本發明化合物與第一量之甜味劑的組合,其中該甜化作用大於在不存在該化合物下由第一量之甜味劑所提供之甜化作用。
在一實施例中,本發明提供一種可攝食組合物,其包含本發明之甜味調節組合物。在某些實施例中,本發明可攝食組合物呈食品或飲料產品、醫藥組合物、營養產品、膳食補充劑、非處方藥物或口腔護理產品的形式。
在一實施例中,本發明提供一種甜味劑替代組合物,該組合物包含一或多種本發明化合物,該一或多種本發明化合物之量為在不存在除本發明化合物以外之甜味劑(例如蔗糖)下例如在濃度高於其配位體增強濃度下有效提供甜化作用之量。
根據本發明之另一態樣,本發明化合物以例如適於後續加工以生產即食型(亦即,即可食用)產品之調味濃縮物調配物形式提供。「調味濃縮物調配物」意謂應用一或多種稀釋介質復原而變成即食型組合物之調配物。術語「即食型組合物」在本文中與「可攝食組合物」可互換使用,其表示無論是否預期用於食用均可單獨或連同另一物質一起經口服用之任何物質。在一實施例中,即食型組合物包括可由人類或動物直接食用之組合物。調味濃縮物調配物通常藉由與一或多種稀釋介質混合或由一或多種稀釋介質稀釋(例如任何可食用或可攝食成分或產品)而用以賦予稀釋介質以一或多種風味或改質稀釋介質之一或多種風味。該種使用方法常稱為復原。復原可在家庭配置或工業配置下進行。舉例而言,冷凍果汁濃縮物可由消費者在廚房中用水或其他水性介質復原,得到即食型果汁飲料。在另一實例中,清涼飲料糖漿濃縮物可由製造廠用水或其他水性介質以較大工業規模復原以生產即食型清涼飲料。由於調味濃縮物調配物中調味劑或風味改質劑之濃度高於即食型組合物中調味劑或風味改質劑之濃度,所以調味濃縮物調配物通常不適合在未復原的情況下直接食用。使用及製備調味濃縮物調配物存在許多益處。舉例而言,一種益處在於降低運輸之重量及體積,因為調味濃縮物調配物可在使用時藉由添加適合溶劑、固體或液體來復原。
在一實施例中,調味濃縮物調配物包含i)作為風味改質成分之本發明化合物;ii)載劑;及iii)視情況選用之至少一種佐劑。術語「作為風味改質成分」表示本發明化合物在調配物中充當調味劑
或風味改質劑(諸如風味調節劑)。術語「載劑」表示與本發明化合物及一或多種視情況選用之佐劑組合用以形成調配物的通常不具活性之輔助物質,諸如溶劑、黏合劑或其他惰性介質。舉例而言,水或澱粉可為用於調味濃縮物調配物之載劑。在一些實施例中,載劑與用於復原調味濃縮物調配物之稀釋介質相同;且在其他實施例中,載劑不同於稀釋介質。如本文所用之術語「載劑」包括但不限於攝食上可接受之載劑。
術語「佐劑」表示補充、穩定化、維持或增強活性成分(諸如本發明化合物)之預期功能或有效性的添加劑。在一實施例中,至少一種佐劑包含一或多種調味劑。調味劑可具有熟習此項技術者或消費者所已知之任何風味,諸如巧克力、咖啡、茶、摩卡咖啡(mocha)、法國香草、花生醬、印度茶(chai)之風味或其組合。在另一實施例中,至少一種佐劑包含一或多種甜味劑。一或多種甜味劑可為本申請案中所述之任何甜味劑。在另一實施例中,至少一種佐劑包含選自由以下組成之群的一或多種成分: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、蛋白質濃縮物及分離物、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、蛋白質濃縮物及分離物以及鹽之實例描述於U.S.6,468,576中,該案之內容出於所有目的以全文引用之方式併入本文中。
在一實施例中,本發明調味濃縮物調配物可呈選自由以下組成之群的形式:液體,包括溶液及懸浮液;固體;泡沫狀物質;糊狀物;凝膠;乳油;及其組合,諸如含有一定量固體內含物之液體。在一實施例中,調味濃縮物調配物呈液體形式,包括水基及非水基液體。本發明調味濃縮物調配物可充有二氧化碳或未充二氧化碳。
調味濃縮物調配物可進一步包含冰點抗凍劑、成核劑或
兩者作為至少一種佐劑。冰點抗凍劑為一種攝食上可接受之化合物或試劑,其可使得添加有該化合物或試劑之液體或溶劑的凝固點下降。亦即,含有冰點抗凍劑之液體或溶液的凝固點低於不含冰點抗凍劑之液體或溶劑。除使得起始凝固點下降之外,冰點抗凍劑亦可降低調味濃縮物調配物之水活性。冰點抗凍劑之實例包括但不限於碳水化合物、油、乙醇、多元醇(例如甘油)及其組合。成核劑表示能夠促成晶核生成之攝食上可接受之化合物或試劑。在調味濃縮物調配物中存在成核劑可藉由增加所需冰結晶中心之數目來改良冷凍冰沙之冷凍冰沙口感且有助於維持冰沙在凝固溫度下之物理特性及效能。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。
在一實施例中,調味濃縮物調配物調配成具有較低水活性,以延長存放期。水活性為在同一溫度下調配物中水之蒸氣壓與純水之蒸氣壓的比值。在一實施例中,調味濃縮物調配物之水活性小於約0.85。在另一實施例中,調味濃縮物調配物之水活性小於約0.80。在另一實施例中,調味濃縮物調配物之水活性小於約0.75。
在一實施例中,調味濃縮物調配物中本發明化合物之濃度為即食型組合物中該化合物之濃度的至少2倍。在一實施例中,調味濃縮物調配物中本發明化合物之濃度為即食型組合物中該化合物之濃度的至少5倍。在一實施例中,調味濃縮物調配物中本發明化合物之濃度為即食型組合物中該化合物之濃度的至少10倍。在一實施例中,調味濃縮物調配物中本發明化合物之濃度為即食型組合物中該化合物之濃度的至少15倍。在一實施例中,調味濃縮物調配物中本發明化合物之濃度為即食型組合物中該化合物之濃度的至少20倍。在一實施例中,調味濃縮物調配物中本發明化合物之濃度為即食型組合物中該化合物之濃度的至少30倍。在一實施例中,調味濃縮物調配物中本發明化合物之濃度為即食型組合物中該化合物之濃度的至少40倍。在
一實施例中,調味濃縮物調配物中本發明化合物之濃度為即食型組合物中該化合物之濃度的至少50倍。在一實施例中,調味濃縮物調配物中本發明化合物之濃度為即食型組合物中該化合物之濃度的至少60倍。在一實施例中,調味濃縮物調配物中本發明化合物之濃度高達即食型組合物中該化合物之濃度的100倍。
治療效用
在本發明之一態樣中,本發明化合物可用於治療目的。亦即,本發明化合物可用於調節化學感覺受體及/或其配位體以達成治療作用之方法中。舉例而言,本發明方法包括調節表現於除味蕾以外之身體部位上之化學感覺受體及/或其配位體。
在一實施例中,例如調節化學感覺受體及/或其配位體之本發明方法包括調節與激素、肽、酶產生有關之表現T1R之細胞的表現、分泌及/或功能度。在一實例中,本發明方法包括調節葡萄糖含量,例如,化學感覺受體(諸如T1R2)之抑制劑可用於降低受試者之葡萄糖含量(例如葡萄糖吸收)。在另一實例中,本發明方法包括調節腸促胰島素之含量,例如,化學感覺受體(諸如T1R2)之促效劑可用於增加升糖素樣肽1(GLP-1)且因而增加胰島素產生。在另一實例中,本發明方法包括調節由表現T1R之細胞或產生胃腸道激素之細胞產生之激素或肽的表現、分泌及/或活性度,例如5HT受體之配位體(例如血清素)、腸促胰島素(例如GLP-1及葡萄糖依賴性促胰島素多肽(GIP))、胃泌素、分泌素、胃蛋白酶、膽囊收縮素、澱粉酶、胃促生長素、瘦素、生長抑素等。在另一實例中,本發明方法包括調節與由表現T1R之細胞分泌之激素、肽及/或酶有關的路徑。
在另一實施例中,例如調節化學感覺受體及/或其配位體之本發明方法包括調節表現T1R(例如T1R1、T1R2或T1R3)之細胞的活性,例如肝臟細胞(例如肝細胞、內皮細胞、柯弗氏細胞(Kupffer
cell)、星形細胞、膽管上皮細胞等)、心臟細胞(例如內皮細胞、心肌細胞及平滑肌細胞等)、胰臟細胞(例如α細胞、β細胞、δ細胞、神經分泌PP細胞、D1細胞等)、乳頭中之細胞(例如導管上皮細胞等)、胃細胞(例如黏液細胞、胃壁細胞、主細胞、G細胞、P/D1細胞)、腸細胞(例如腸內分泌細胞、刷細胞等)、唾液腺細胞(例如漿液黏液細胞、黏液細胞、肌上皮細胞、閏管細胞、紋狀管細胞等)、L細胞(例如表現GLP-1等)、腸嗜鉻細胞(例如表現血清素)、腸嗜鉻細胞樣細胞、G細胞(例如表現胃泌素)、D細胞(δ細胞,例如表現生長抑素)、I細胞(例如表現膽囊收縮素(CCK))、K細胞(例如表現抑胃多肽)、P/D1細胞(例如表現胃促生長素)、主細胞(例如表現胃蛋白酶)及S細胞(例如表現分泌素)。在一實例中,本發明方法包括增加表現T1R之細胞中T1R之表現量。在另一實例中,本發明方法包括增加表現T1R之細胞的分泌量。
在另一實施例中,例如調節化學感覺受體及/或其配位體之本發明方法包括調節、治療與胃腸系統有關之病狀及/或針對該病狀採取預防措施,在無任何限制下包括與食道運動性有關之病狀(例如環咽部弛緩不能、協識脫離性塞喉覺、弛緩不能、彌漫性食管痙攣及相關運動障礙、累及食管之硬皮病等)、發炎性病症(例如胃食管逆流及食管炎、感染性食管炎等)、消化性潰瘍、十二指腸潰瘍、胃潰瘍、胃泌素瘤、應激性潰瘍及糜爛、藥物相關性潰瘍及糜爛、胃炎、食道癌、胃腫瘤、吸收障礙(例如特定營養素,諸如碳水化合物、蛋白質、胺基酸、脂肪、膽固醇及脂溶性維生素、水及鈉、鈣、鐵、水溶性維生素等的吸收)、吸收障礙病症、黏膜功能缺陷(例如發炎性或浸潤性病症、生物化學或遺傳異常、內分泌及代謝障礙、蛋白丟失性腸病等)、消化道自體免疫性疾病(例如乳糜瀉、克羅恩氏病(Crohn's disease)、潰瘍性結腸炎等)、大腸急躁症、發炎性腸病、發
炎性腸病併發症、發炎性腸病之腸外表現、腸運動障礙、腸血管病症、肛腸病(例如痔瘡、肛門炎症等)、結腸直腸癌、小腸腫瘤、肛門癌、肝代謝紊亂、高膽紅素血症、肝炎、酒精性肝病及肝硬化、膽汁性肝硬化、肝臟贅生物、侵襲肝臟之浸潤性及代謝疾病(例如脂肪肝、雷依氏症候群(reye's syndrome)、糖尿病性肝醣病、肝醣貯積病、威爾遜氏病(Wilson's disease)、血色素沈著病)、膽囊及膽管疾病、胰臟病症(例如胰臟炎、胰臟外分泌功能不全、胰臟癌等)、胃腸道及胰臟之內分泌腫瘤等。
在另一實施例中,例如調節化學感覺受體及/或其配位體之本發明方法包括調節、治療與代謝障礙有關之病狀及/或對該病狀採取預防措施,例如食欲、體重、食物或液體攝食或受試者對食物或液體攝食的反應,或飽食狀態或受試者對飽食狀態之感知、營養攝食及調節(例如蛋白質-能量營養不良症、與蛋白質-能量營養不良症有關之生理障礙等)、肥胖症、繼發性肥胖症(例如甲狀腺功能低下、庫欣氏病(Cushing's disease)、胰島素瘤、下丘腦病症等)、進食障礙(例如神經性厭食症、貪食症等)、維生素缺乏及過量、胰島素代謝、糖尿病(第I型及第II型)及其併發症(例如循環異常、視網膜病變、糖尿病性腎病變、糖尿病性神經病變、糖尿病性足潰瘍等)、葡萄糖代謝、脂肪代謝、低血糖、高血糖、高脂蛋白血症等。
在另一實施例中,例如調節化學感覺受體及/或其配位體之本發明方法包括調節、治療與功能性胃腸病症有關之病狀及/或對該病狀採取預防措施,例如,在不存在任何特定病理性病狀(諸如消化性潰瘍及癌症)下,受試者患有腹部消化不良,例如腹脹感、噁心、嘔吐、腹痛、厭食、胃酸逆流或腸運動異常(便秘、腹瀉及其類似症狀),視情況基於胃腸道中,尤其胃中內容物的滯留。在一實例中,功能性胃腸病症包括不存在任何胃腸道器質性疾病,但存在影響
受試者(例如人類)之生活品質之一或多種複現性胃腸症狀的病狀。
示範性功能性胃腸病症在無任何限制下包括功能性消化不良、胃食管逆流病狀、糖尿病性胃輕癱、逆流性食管炎、手術後胃腸功能失調及其類似病狀、噁心、嘔吐、感覺有病、胃灼熱、腹脹感、胃積滯、打嗝、胸悶、胸痛、胃部不適、厭食、吞咽困難、胃酸逆流、腹痛、便秘、腹瀉、氣促、窒息感、動力或活力水準低下、咽部堵塞、異物感、易疲勞、頸僵硬、肌強直、口腔乾燥(口乾、口渴等)、呼吸促迫、胃腸道燒灼感、四胺冷感、注意力難以集中、急躁、睡眠障礙、頭痛、全身不適、心悸、盜汗、焦慮、眩暈、頭暈、潮熱、過度出汗、抑鬱症等。
在另一實施例中,例如調節化學感覺受體及/或其配位體之本發明方法包括增加或促進受試者之消化、吸收、血液營養素含量及/或胃腸道運動性,例如促進胃排空(例如胃內容物之清除)、減少早期餐後時段的腹脹、改善厭食等。一般而言,該促進可直接達成或經由增加調節性實體(例如激素等)之分泌來達成。
在另一實施例中,例如調節化學感覺受體及/或其配位體之本發明方法包括增強受試者之一或多種胃腸功能,例如以改善受試者之生活品質或健康狀態。
在一實施例中,本發明提供一種醫藥組合物,其含有治療有效量之一或多種本發明化合物,或其鹽、溶劑合物及/或前藥,視情況連同適量之醫藥學上可接受之媒劑。在另一實施例中,該醫藥組合物包含治療有效量之一或多種本發明化合物,或其鹽、溶劑合物及/或前藥;及適量之醫藥學上可接受之媒劑,以提供用於向患者適當投藥的形式。
在一實施例中,在投與患者時,本發明化合物及視情況選用之醫藥學上可接受之媒劑為無菌的。在一實施例中,當靜脈內投
與本發明化合物時,水為較佳之媒劑。生理食鹽水溶液及右旋糖水溶液及甘油溶液亦可用作液體媒劑,尤其用於可注射溶液。適合醫藥媒劑亦包括賦形劑,諸如澱粉、葡萄糖、乳糖、蔗糖、明膠、麥芽、稻米、麵粉、白堊、矽膠、硬脂酸鈉、單硬脂酸甘油酯、滑石、氯化鈉、脫脂乳粉、甘油、丙烯、二醇、水、乙醇及其類似物。必要時,本發明醫藥組合物亦可含有少量濕潤劑或乳化劑,或pH值緩衝劑。另外,可使用佐劑、穩定劑、增稠劑、潤滑劑及著色劑。
包含本發明化合物之醫藥組合物可藉助於習知混合、溶解、粒化、製備糖衣藥丸、水磨、乳化、囊封、覆埋或凍乾方法來製造。醫藥組合物可以習知方式,使用有助於將本發明化合物加工成可在醫藥學上使用之製劑的一或多種生理學上可接受之載劑、稀釋劑、賦形劑或佐劑來調配。適當調配物視所選投藥途徑而定。
本發明醫藥組合物可採用溶液、懸浮液、乳液、錠劑、藥丸、丸粒、膠囊、含有液體之膠囊、散劑、持續釋放調配物、栓劑、乳液、氣霧劑、噴霧劑、懸浮液或任何其他適合使用之形式的形式。在一些實施例中,醫藥學上可接受之媒劑為膠囊(參見例如Grosswald等人之美國專利第5,698,155號)。適合醫藥媒劑之其他實例在此項技術中已有描述(參見Remington:The Science and Practice of Pharmacy,Philadelphia College of Pharmacy and Science,第20版,2000)。
對於局部投藥,本發明化合物可調配成溶液、凝膠劑、軟膏、乳油劑、懸浮液等,如此項技術中所熟知。
全身性調配物包括設計用於藉由注射(例如皮下、靜脈內、肌肉內、鞘內或腹膜內注射)投與之調配物,以及設計用於經皮、經黏膜、經口或肺部投與之調配物。全身性調配物可與另一改善氣管黏液之黏膜纖毛清除率或降低黏液黏度的活性劑組合製備。此等
活性劑包括但不限於鈉通道阻斷劑、抗生素、N-乙醯半胱胺酸、高半胱胺酸及磷脂。
在一些實施例中,本發明化合物係根據常規程序調配成適於靜脈內投與人類的醫藥組合物。通常,用於靜脈內投與之本發明化合物為處於無菌等張水性緩衝液中之溶液。對於注射,本發明化合物可於水溶液中,較佳於生理學上相容之緩衝液(諸如漢克斯氏溶液(Hanks' solution)、林格氏溶液(Ringer's solution)或生理食鹽水緩衝液)中調配。溶液可含有調配劑,諸如懸浮劑、穩定劑及/或分散劑。必要時,醫藥組合物亦可包括增溶劑。
用於靜脈內投與之醫藥組合物可視情況包括局部麻醉劑(諸如利多卡因(lignocaine))以減輕注射部位處的疼痛。一般而言,各成分分別或以混合在一起之單位劑型(例如以凍乾粉末或無水濃縮物形式)於指示活性劑之量的密封容器(諸如安瓿或藥囊)中供應。當藉由輸注投與本發明化合物時,其可例如用容納無菌醫藥級水或生理食鹽水的輸注瓶來分配。當藉由注射投與本發明化合物時,可提供容納無菌注射用水或生理食鹽水之安瓿,以便可在投藥之前混合各成分。
對於經黏膜投藥,在調配物中使用適用於欲滲透之障壁的滲透劑。該等滲透劑在此項技術中一般為已知的。
用於經口傳遞之醫藥組合物可呈例如錠劑、口含錠、水性或油性懸浮液、顆粒、散劑、乳液、膠囊、糖漿或酏劑的形式。經口投與之醫藥組合物可含有一或多種視情況選用之試劑,例如甜味劑,諸如果糖、阿斯巴甜糖或糖精;調味劑,諸如胡椒薄荷、冬青油或櫻桃著色劑,及防腐劑,以提供醫藥學上可口之製劑。
此外,在呈錠劑或藥丸形式的情況下,醫藥組合物可經包覆以延遲於胃腸道中之崩解及吸收,從而在延長時段內提供持續作用。包圍滲透活性驅動化合物之選擇性滲透膜亦適用於經口投與之本
發明化合物。在此等後者的平台中,由驅動化合物吸收包圍膠囊之環境中的流體,該膠囊膨脹以經由孔隙排出藥劑或藥劑組合物。此等傳遞平台可提供與即刻釋放調配物之尖峰狀曲線相反的基本上零級傳遞曲線。亦可使用時間延遲物質,諸如單硬脂酸甘油酯或硬脂酸甘油酯。口服組合物可包括標準媒劑,諸如甘露糖醇、乳糖、澱粉、硬脂酸鎂、糖精鈉、纖維素、碳酸鎂等。該等媒劑較佳為醫藥級。
對於口服液體製劑,諸如懸浮液、酏劑及溶液,適合載劑、賦形劑或稀釋劑包括水、生理食鹽水、伸烴二醇(例如丙二醇)、聚伸烴二醇(例如聚乙二醇)、油、醇、pH 4與pH 6之間的微酸性緩衝液(例如約5.0mM至約50.0mM之間的乙酸鹽、檸檬酸鹽、抗壞血酸鹽)等。另外,可添加調味劑、防腐劑、著色劑、膽鹽、醯基肉鹼及其類似物。
對於經頰投藥,醫藥組合物可採用以習知方式調配之錠劑、口含錠等的形式。
適用於霧化器及液體噴霧裝置及EHD氣霧劑裝置的液體藥物調配物通常包括本發明化合物以及醫藥學上可接受之媒劑。較佳地,醫藥學上可接受之媒劑為液體,諸如醇、水、聚乙二醇或全氟化碳。視情況,可添加另一物質以改變本發明化合物之溶液或懸浮液之氣霧劑特性。較佳地,此物質為液體,諸如醇、二醇、聚二醇或脂肪酸。調配適用於氣霧劑裝置中之液體藥物溶液或懸浮液的其他方法為熟習此項技術者所已知(參見例如Biesalski之美國專利第5,112,598號;Biesalski之美國專利第5,556,611號)。
本發明化合物亦可調配成例如含有習知栓劑基質(諸如可可脂或其他甘油酯)的直腸或陰道醫藥組合物,諸如栓劑或保留灌腸劑。
除先前所述之調配物外,本發明化合物亦可調配成儲積
式製劑。該等長效調配物可藉由植入(例如皮下或肌肉內)或藉由肌肉內注射來投與。因而,舉例而言,本發明化合物可用適合之聚合或疏水性物質(例如調配成於可接受之油中之乳液形式)或離子交換樹脂調配,或調配成微溶衍生物,例如微溶鹽。
本發明化合物及/或其醫藥組合物一般以有效達成預期目的之量使用。為用於治療或預防疾病或病症,投與或施用治療有效量之本發明化合物及/或其醫藥組合物。
本發明化合物有效治療本文所揭示之特定病症或病狀的量將視病症或病狀之性質而定且可由此項技術中已知之標準臨床技術來確定。另外,可視情況使用活體外或活體內分析來協助鑒別最佳劑量範圍。相對於其他因素,所投與本發明化合物之量當然將取決於所治療之受試者、受試者之體重、病痛之嚴重度、投藥方式以及處方醫師之判定。
舉例而言,可藉由單次投藥,藉由多次施用或控制釋放以醫藥組合物形式傳遞劑量。在一些實施例中,藉由經口持續釋放投藥來傳遞本發明化合物。給藥可間歇地重複進行,可單獨提供或與其他藥物組合提供且可持續,只要為有效治療疾病病況或病症所需。
適用於經口投藥之劑量範圍視效能而定,但一般在每公斤體重約0.001mg至約200mg本發明化合物之間。劑量範圍可容易地藉由一般技術者所已知之方法來確定。
適用於靜脈內(i.v.)投藥之劑量範圍為每公斤體重約0.01mg至約100mg。適用於鼻內投藥之劑量範圍一般為每公斤體重約0.01mg至每公斤體重約1mg。栓劑一般含有每公斤體重約0.01毫克至約50毫克之本發明化合物且包含約0.5重量%至約10重量%範圍內的活性成分。用於皮內、肌肉內、腹膜內、皮下、硬膜外、舌下或腦內投藥之推薦劑量處於每公斤體重約0.001mg至約200mg之範圍內。有效劑量
可自由活體外或動物模型測試系統獲得的劑量反應曲線外推而來。該等動物模型及系統在此項技術中為熟知的。
在一實施例中,本文所述之治療有效劑量之本發明化合物將在不引起實質性毒性的情況下提供治療益處。本發明化合物之毒性可使用標準醫藥程序來測定且可容易地由熟練技術人員確定。毒性作用與治療作用之間的劑量比率為治療指數。本發明化合物較佳展現出特別高的治療疾病及病症的治療指數。本文所述之本發明化合物之劑量較佳處於幾乎不存在或不存在毒性之循環濃度範圍內(包括有效劑量)。
在本發明之某些實施例中,本發明化合物及/或其醫藥組合物可與至少一種其他藥劑一起用於組合療法中。本發明化合物及/或其醫藥組合物與其他藥劑可起累加作用,或更佳可起協同作用。在一些實施例中,本發明化合物及/或其醫藥組合物與投與另一藥劑同時投與,該另一藥劑可與本發明化合物為同一醫藥組合物之一部分或可為不同醫藥組合物。在其他實施例中,在投與另一藥劑之前或之後投與本發明之醫藥組合物。
製備
用於製備本發明化合物之起始物質(亦即本發明式(I)化合物之合成前驅體之化合物之各種結構子類及種類)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,或可自一般技術者所熟知之各種來源購得,諸如Sigma-Aldrich Corporation(St.Louis,Missouri USA)及其在其各個其他遍及全世界之辦事處的子公司Fluka及Riedel-de Haen,及其他熟知之化學製品供應商,諸如Fisher Scientific、TCI America(Philadelphia,PA)、ChemDiv(San Diego,CA)、Chembridge(San Diego,CA)、Asinex(Moscow,Russia)、SPECS/BIOSPECS(Netherlands)、Maybridge(Cornwall,England)、
Acros、TimTec(Russia)、Comgenex(South San Francisco,CA)及ASDI Biosciences(Newark,DE)。
應瞭解,有機化學技術之熟練技術人員可在無其他指導的情況下容易地進行許多起始物質之合成及後續操作,亦即,進行許多所需之操作完全處於熟練技術人員之範疇及業務範圍內。此等操作包括將羰基化合物還原成其相應醇、氧化、醯化、芳族取代(親電子及親核取代)、醚化、酯化、皂化、硝化、氫化、還原胺化及其類似操作。此等操作論述於標準著作中,諸如March's Advanced Organic Chemistry(第3版,1985,Wiley-Interscience,New York)、Feiser and Feiser's Reagents for Organic Synthesis,及各個卷冊及版本oϊMethoden der Organischen Chemie(Houben-Weyl)及其類似著作中。多種用於製備包含經不同取代之雜環、雜芳環及芳環之起始物質(Ar、hAr1及/或hAr2之前驅體)的一般方法可見於Methoden der Organischen Chemie(Houben-Weyl)中,該著作之各個卷冊及版本可獲自Georg Thieme Verlag,Stuttgart。上述論文對於其關於用於合成有機化合物及其前驅體之方法之教示的全部揭示內容以全文引用的方式併入本文中。
熟練技術人員亦應容易地瞭解,某些反應最好在分子中的其他官能基受到遮蔽或保護時進行,因而避免任何不合需要之副反應及/或增加反應產率。熟練技術人員常利用保護基來達成該等增加之產率或避免不合需要之反應。此等反應可見於文獻中且亦完全處於熟練技術人員之範疇內。此等操作中許多操作之實例可見於例如T.Greene及P.Wuts,Protecting Groups in Organic Synthesis,第3版,John Wiley & Sons(1999)中。
可用於製備本發明化合物或其中間物之一些示範性合成方法可於2010年2月4日公開的名稱為「Processes and Intermediates for
Making Sweet Taste Enhancers」之WO 2010/014666中查到。
實例
現已大體描述本發明,藉由參考以下實例應更容易地理解本發明,該等實例以說明方式提供且不欲具有限制性。應瞭解,可在不背離本發明之精神及範疇的情況下對本文所揭示之示範性實施例作出各種修改及變化。
實例1:(S)-1-(3-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)丁-1-酮
在室溫下,向(S)-2-胺磺醯基胺基-6-((1-丁醯基哌啶-3-基)甲氧基)苯甲腈(實例1a,9.5g,24.97mmol)於EtOH(65mL)中之攪拌溶液添加NaOH水溶液(2.0N,37mL,74.91mmol)。將反應混合物回流4小時,接著冷卻至0℃且用2N HCl小心地中和。藉由過濾收集沈澱物、將其自EtOH/H2O再結晶,且真空乾燥以得到呈白色固體之標題化合物(6g),產率63%。1H NMR(400MHz,DMSO-d 6 ,)δ 0.82-0.86(m,3H),1.30-1.51(m,4H),1.65(m,1H),1.82(m,1H),2.01-2.21(m,2H),2.22-2.27(m,2H),2.71-3.12(m,2H),3.63-3.86(m,1H),4.03(m,2H),4.12(m,1H),6.60(m,1H),6.75(t,J=8.0Hz,1H),7.43-7.45(m,1H),7.77(d,J=20Hz,1H),8.36(m,1H),10.91(s,1H)。MS 381(MH+)。元素分析計算值:C,53.67%;H,6.36%;N,14.73%。實驗值:C,53.64%;H,6.63%;N,14.73%。
實例1a:(S)-2-胺磺醯基胺基-6-((1-丁醯基哌啶-3-基)甲氧基)苯甲腈
在室溫且在氮氣下,向(S)-2-胺基-6-((1-丁醯基哌啶-3-基)甲氧基)苯甲腈(實例1b,9.2g,30.53mmol)於DMA(60mL)中之溶液添加胺磺醯氯(實例1f,10.54g,91.58mmol)。在室溫且在氮氣下將反應混合物攪拌隔夜,接著減壓濃縮,以EtOAc稀釋,相繼以NaHCO3、水及鹽水洗滌,經Na2SO4乾燥、過濾,且減壓移除溶劑以得到無色凝膠狀之標題化合物(9.5g),產率82%。MS 381(MH+)。
實例1b:(S)-2-胺基-6-((1-丁醯基哌啶-3-基)甲氧基)苯甲腈
在室溫下,向(S)-2-((1-丁醯基哌啶-3-基)甲氧基)-6-硝基苯甲腈(實例1c,9.92g,32.92mmol)於乙酸(60mL)及THF(60mL)中之溶液添加鐵粉(5.5g,98.76mmol)。將反應混合物加熱至70℃且攪拌1小時,接著冷卻至室溫,以EtOAc稀釋,經由矽藻土過濾。將濾液減壓濃縮且接著再溶解於EtOAc中,以NaHCO3、水及鹽水洗滌,經MgSO4乾燥、過濾且蒸發。自DCM/EtOAc再結晶殘餘物,得到灰白色固體狀之標題化合物(9.92g,兩步之產率:93%)。MS 302(MH+)。
實例1c:(S)-2-((1-丁醯基哌啶-3-基)甲氧基)-6-硝基苯甲腈
向(S)-2-硝基-6-(哌啶-3-基甲氧基)苯甲腈鹽酸鹽(實例
1d,9.8g,32.92mmol)於CH2Cl2(550mL)及DMF(50mL)中之懸浮液添加三乙胺(9.2mL,65.84mmol)。於室溫下攪拌5分鐘之後,添加丁酸(3.33mL,36.21mmol)、EDCI(6.94g,36.21mmol)及HOBt(4.89g,36.21mmol)於DCM(50mL)中之溶液,且接著將反應混合物在室溫下攪拌隔夜。將所得混合物以CH2Cl2稀釋,以0.5N HCl、水、NaHCO3及鹽水洗滌,經MgSO4乾燥、過濾且蒸發,得到淡褐色凝膠狀之粗產物,將該粗產物原樣用於下一步驟中。MS 332(MH+)。
實例1d:(S)-2-硝基-6-(哌啶-3-基甲氧基)苯甲腈鹽酸鹽
向(S)-3-((2-氰基-3-硝基苯氧基)甲基)哌啶-1-甲酸第三丁酯(實例1e,41.74g)於二噁烷(115mL)中的在冰浴中冷卻至0℃之溶液添加4N HCl於二噁烷(70mL,280mmol)中之溶液。將反應混合物在室溫下攪拌隔夜,接著減壓蒸發。向殘餘物中添加Et2O(700mL)且將懸浮液回流1小時。藉由過濾收集固體且高真空乾燥,得到淺桃紅色固體狀之(S)-2-硝基-6-(哌啶-3-基甲氧基)苯甲腈鹽酸鹽(24.64g,兩步之產率:89%)。1H NMR(400MHz,DMSO-d6)δ 1.47-1.30(m,1H).1.77-1.62(m,1H),1.84(t,J=12.4Hz,2H),2.32(d,J=9.4Hz,1H),2.87-2.68(m,2H),3.27-3.16(m,2H),4.15(dd,J=9.7,7.2Hz,1H),4.25(dd,J=9.7,5.4Hz,1H),7.72(dd,J=7.6,1.9Hz,1H),7.96-7.86(m,2H),9.20-8.89(m,2H)。MS 262(MH+)。
實例1e:(S)-3-((2-氰基-3-硝基苯氧基)甲基)哌啶-1-甲酸第三丁酯
向配備加料漏斗及溫度計之2L三頸圓底燒瓶中添加無水THF(700mL)及NaH(60wt%,3.90g,97.5mmol)。將懸浮液在異丙醇/乾冰浴中冷卻直至內部溫度為約-20℃。經由加料漏斗逐滴添加溶於無水THF(300mL)中之(S)-3-(羥甲基)哌啶-1-甲酸第三丁酯(20.0g,92.9mmol),同時保持內部溫度在-20℃至-15℃之間。一旦完成添加,將反應在0℃至10℃之間的溫度下攪拌45分鐘。接著將反應冷卻至-70℃,且經由加料漏斗逐滴添加2,6-二硝基苯甲腈(19.9g,103mmol)於無水DMF(200mL)中之溶液。使反應逐步升溫至室溫隔夜,且減壓移除THF。將剩餘溶液在冰浴中冷卻且以冷卻的飽和NH4Cl溶液(200mL)處理。將所得混合物以EtOAc稀釋且相繼以水及鹽水洗滌。將有機層經由Na2SO4乾燥、過濾且減壓蒸發,得到橘色固體狀之粗品(S)-3-((2-氰基-3-硝基苯氧基)甲基)哌啶-1-甲酸第三丁酯(41.74g)。MS 262(MH+-Boc)。此物質無需純化用於下一步驟中。
實例1f:胺磺醯氯
在0℃下,向氯磺醯異氰酸鹽(65.2g,461mmol)於二氯甲烷(100mL)中之溶液添加乙酸(17.4mL,461mmol)於二氯甲烷(100mL)中之溶液。將混合物在0℃下攪拌1小時,加熱至室溫且繼續攪拌18小時。接著將混合物冷卻至-78℃,攪拌2小時,且傾析掉大部分溶劑。將所得固體真空乾燥,得到白色固體狀之胺磺醯氯(48g,90%)。
實例2:(S)-1-(3-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)-2-環丙基乙酮
向(S)-4-胺基-5(哌啶-3-基甲氧基)-1H-苯并[c][1,2,6]噻二
嗪2,2-二氧化物鹽酸鹽(實例2a,694mg,2.0mmol)於H2O/ACN(5mL,1:1)中之溶液添加三乙胺(228uL,2.0mmol)。於室溫下攪拌5分鐘後,向混合物中添加2-環丙基乙酸(200mg,2.0mmol)、HOBt(272mg,2.0mmol)及EDCI-HCl(382mg,2.0mmol)於H2O/ACN(5mL,1:1)中之溶液。添加另一當量之三乙胺(228uL,2.0mmol),且在室溫下將反應混合物攪拌隔夜。藉由真空過濾收集析出溶液之產物。接著將化合物經由製備RP HPLC(水中10至90%之EtOH)純化,接著以10mL水稀釋,且添加200mg NaHCO3。將溶液在90℃下加熱20分鐘直至所有化合物溶解,接著將其冷卻至0℃且以1N HCl溶液中和。產物沈澱出且藉由過濾收集且乾燥得到標題化合物(410mg,52.3%)。1H NMR(DMSO-d6,400MHz,80℃):0.12(br s,2H),0.44(m,2H),0.96(br s,1H),1.42(m,2H),1.70(m,1H),1.88(m,1H),1.98(br s,1H),2.09(m,1H),2.26(br s,2H),2.91(m,2H),3.67(br s,0.5H),3.85(br s,0.5H),4.09(m,3H),6.65(d,J=8.4Hz,1H),6.71(d,J=8.4Hz,1H),7.46(t,J=8.4Hz,1H),7.75(br s,1H),8.16(br s,1H),10.79(s,1H)。M+H=393。
實例2a:(S)-4-胺基-5-(哌啶-3-基甲氧基)-1H-苯并[c][1,2,6]噻二嗪2,2-二氧化物鹽酸鹽
將(S)-3-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-甲酸第三丁酯(實例2b,7.0g,17.1mmol)於濃HCl:MeOH(1:1,170mL)中之溶液在室溫下攪拌4小時。將沈澱物藉由真空過濾收集且乾燥得到白色固體狀之所需產物(3.75g,63.2%)。1H NMR(DMSO-d6,400MHz):δ 1.29(m,1H),1.65(m,1H),
1.82(m,2H),2.37(m,1H),2.75(m,2H),3.20(d,J=8.0Hz,1H),3.27(d,J=11.2Hz,1H),4.10(d,J=6.0Hz,3H),6.27(d,J=8.4Hz,1H),6.75(d,J=8.4Hz,1H),7.45(t,J=8.4Hz,1H),7.68(s,1H),8.35(br s,1H),8.74(m,1H),9.05(m,1H),10.98(s,1H)。MS 311(MH+)。
實例2b:(S)-3-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-甲酸第三丁酯
向(S)-3-((3-胺基-2-氰基苯氧基)甲基)哌啶-1-甲酸第三丁酯(實例2c,11.0g,33.2mmol)於DMA(100mL)中之溶液添加吡啶(13.4mL,166mmol)及少量胺磺醯氯(7.64g,66.4mmol)。在室溫下,將混合物在氮氣下攪拌1小時直至根據LCMS反應完成。添加飽和NaHCO3直至混合物為中性,且以EtOAc(3X)萃取溶液。將合併有機物經由Na2SO4乾燥且濃縮。將殘餘物以EtOH(100mL)稀釋且添加NaOH(66.4mL,132.8mmol,2M溶液),接著將溶液加熱至80℃歷時3小時。接著使反應混合物冷卻至室溫。將溶液進一步冷卻至0℃且以2N HCl中和。添加水且所需產物析出。接著將產物過濾出且乾燥,得到標題化合物(7.0g,51.4%)。(M+H)-Boc=311。
實例2c:(S)-3-((3-胺基-2-氰基苯氧基)甲基)哌啶-1-甲酸第三丁酯
向(S)-3-((2-氰基-3-硝基苯氧基)甲基)哌啶-1-甲酸第三丁酯(實例1e,13g,36mmol)於EtOAc(200mL)中之溶液添加Pd/C(3.82g,3.6mmol 10%溶液),且將混合物在室溫下且在H2下攪拌6
小時直至反應完成。將混合物過濾且濃縮。將殘餘物藉由矽膠層析法(EtOAc/己烷)純化以產生標題化合物(11g,92.3%)。(M+H)-Boc=232。
實例3:(S)-(3-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)(吡啶-4-基)甲酮
如實例2,自(S)-5-(哌啶-3-基甲氧基)-1H-苯并[c][1,2,6]噻二嗪-4-胺基-2,2-二氧化物鹽酸鹽(實例2a)及異菸鹼酸製備(55%產率)。M.p.:>250℃。1H NMR(400MHz,DMSO-d 6 )δ 1.41-1.89(m,4H),2.22(m,1H),2.92-3.09(m,2H),3.36-3.55(m,1H),3.91-3.99(m,1H),4.12-4.31(m,2H),6.57-6.80(m,2H),7.28-7.46(m,3H),7.51,7.81(s,1H),8.16,8.40(s,1H),8.61-8.65(m,2H),10.95(s,1H)。MS 416(MH+)。
實例4:(S)-1-(3-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)丙-1-酮
如實例2,自(S)-5-(哌啶-3-基甲氧基)-1H-苯并[c][1,2,6]噻二嗪-4-胺基-2,2-二氧化物鹽酸鹽(實例2a)及戊酸製備(74.6%產率)。1H NMR(DMSO-d6,400MHz,80℃):0.85(t,3H,J=7.0Hz),1.28(sext,2H,J=7.0Hz),1.40(m,2H),1.47(pent,2H,J=7.3Hz),1.68(m,1H),1.87(m,1H),2.06(m,1H),2.27(t,2H,J=7.3Hz),2.93(m,2H),3.93(m,1H),4.08(m,3H),6.64(d,1H,J=8.0Hz),6.74(d,1H,J
=8.3Hz),7.43(t,1H,J=8.3Hz),7.78(br s,1H),7.99(br s,1H),10.69(s,1H)。M+H=395。
實例5:(S)-1-(3-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)-3-甲基丁-1-酮
在室溫下,向(S)-2-胺磺醯基胺基-6-((1-(3-甲基丁醯基)哌啶-3-基)甲氧基)苯甲腈(實例5a,19.5g,49.4mmol)於EtOH(130mL)中之攪拌溶液添加2N NaOH溶液(84mL)。接著將反應混合物在65℃加熱大約18小時直至經LC/MS證實起始物質耗盡。將混合物濃縮以移除乙醇,以水(500mL)稀釋且以乙酸乙酯(50mL×2)洗滌。將乙醇(100mL)添加至水相且將混合物以1M HCl水溶液酸化直至pH=3。藉由真空過濾收集所形成的沈澱物,得到白色固體,將其進一步懸浮在乙醇(300mL)中且將溶液加熱至回流歷時1小時,然後冷卻至0℃。收集沈澱物且真空乾燥,得到灰白色固體狀之標題化合物(17.7g,82%產率)。將此物質與按照相同程序合成之若干其他批料合併。將該等合併批料(73.6g,186.57mmol)於水(1500mL)中之懸浮液以NaHCO3(39.18g,466.43mmol,2.5當量)於水(500mL)中之溶液處理,且加熱至98℃歷時12小時,直至完成溶解。接著過濾熱溶液以移除未溶解的細顆粒,且將濾液冷卻至室溫且以0.3M HCl逐滴處理直至中性pH,接著以2M HCl處理直至pH 3,且將溶液進一步攪拌30分鐘。將所形成的沈澱物藉由真空過濾收集、以水洗滌,且真空乾燥,得到灰白色粉末狀之標題化合物(72.44g)。1H NMR(400MHz,DMSO-d 6 ,80℃)δ 0.89(d,6H,J=4.0Hz),1.37-1.47(m,2H),1.67-1.72(m,1H),1.86-1.91(m,1H),1.94-2.19(m,4H),2.96(br.s,2H),3.55-4.14(m,
4H),6.66(d,1H,J=4.0Hz),6.75(d,1H,J=8.0Hz),7.45(t,1H,J=8.0Hz),7.78(br.s,1H)8.00(br.s,1H),10.69(s,1H)。MS 395(MH+)。Mp 237-238。
實例5a:(S)-2-胺磺醯基胺基-6-((1-(3-甲基丁醯基)哌啶-3-基)甲氧基)苯甲腈
向(S)-2-胺基-6-((1-甲基丁醯基)哌啶-3-基)甲氧基)苯甲腈(實例5b,54.55g,172.95mmol)於DMA(110mL)中的在冰浴中冷卻至0℃的攪拌溶液分兩份添加胺磺醯氯(55g,476mmol)(一份20g,一份35g)。在N2下,將反應混合物在0℃下攪拌30分鐘,接著在室溫下攪拌4小時。將反應混合物緩緩倒入快速攪拌的冷水(2L)中,得到乳狀溶液。將另外的800mL水分若干份添加以沈澱所需產物(此時,乳狀溶液已變澄清)。藉由傾析出水收集沈澱物且將其懸浮於乙酸乙酯(500mL)中,接著快速攪拌直至其形成細微的白色固體。藉由真空過濾收集固體物質且將其真空乾燥,得到白色固體狀之(S)-2-胺磺醯基胺基-6-((1-(3-甲基丁醯基)哌啶-3-基)甲氧基)苯甲腈(59.25g,150.2mmol),產率為87%。MS 395(MH+)
實例5b:(S)-2-胺基-6-((1-(3-甲基丁醯基)哌啶-3-基)甲氧基)苯甲腈
向(S)-2-((1-(3-甲基丁醯基)哌啶-3-基)甲氧基)-6-硝基苯甲腈(實例5c,43.26g,約18.0mmol)於冰醋酸(35mL)中的在冰浴中
冷卻至0℃之溶液添加鐵粉(2.02g,36.1mmol)。將溶液在N2球壓下且在0℃下攪拌10分鐘,接著在室溫下攪拌隔夜,且經由矽藻土床過濾,用EtOAc充分沖洗。接著將EtOAc溶液相繼以2N Na2CO3、水及鹽水洗滌,經由Na2SO4乾燥、過濾且濃縮,得到橙色油狀之粗產物。藉由矽膠層析法,使用0-60% EtOAc/己烷梯度純化殘餘物,接著自EOAc/己烷再結晶,得到淡黃色固體狀之標題化合物(27.01g,85.63mmol,兩步之產率:71%)。1H NMR(400MHz,DMSO-d6,20℃)δ 0.79-0.92(3xd,J=6.4Hz,.6H),1.19-1.46(m,2H),1.51-2.01(m,4H),2.03-2.25(m,2H),2.57(dd,J=10.4,12.8Hz,0.3H),2.75-2.88(m,0.6H),2.92-3.10(m,1H),3.65-4.08(m,3.6H),4.27-4.40(dm,0.3H),5.98 & 6.00(s & s,2H),6.18(偽t,J=8.4 & 9.2Hz,1H),6.32(偽d,J=8.4Hz,1H),7.11-7.21(m,1H)。MS 316(MH+)。
或者,(S)-2-胺基-6-((1-(3-甲基丁醯基)哌啶-3-基)甲氧基)苯甲腈(實例5b)可如下製備:
在0℃下,將(S)-1-(3-(羥甲基)哌啶-1-基)-3-甲基丁-1-酮(實例5d)(42g,210.75mmol,1.2當量(eq.))於無水THF(300mL)中之溶液逐滴添加至NaH(60%於礦物油中,8.43g,273.97mmol,1.63eq.)無水THF(600mL)中之懸浮液。使混合物升溫至約25℃且攪拌1小時,同時保持溫度在25℃以下。逐滴添加2-胺基-6-氟苯甲腈(22.95g,168.6mmol,1eq.)於THF(300mL)中之溶液。緩慢加熱反應至回流且攪拌隔夜。將混合物冷卻至室溫,濃縮為約400mL的殘餘物質。添加飽和氯化銨(200mL)。在劇烈攪拌15分鐘後,添加EtOAc(800mL)且再繼續攪拌30分鐘。將有機相隨後以水、鹽水洗滌且經Na2SO4乾燥。真空移除溶劑且對剩餘物進行矽膠層析(Hex/EtOAc),得到所需產物(44.6g,141.40mmol,83.87%)。1H NMR(400MHz,DMSO-d6,20℃)δ 0.79-0.92(3xd,J=6.4Hz/each,6H),1.19-1.46(m,2H),1.51-
2.01(m,4H),2.03-2.25(m,2H),2.57(dd,J=10.4,12.8Hz,0.3H),2.75-2.88(m,0.6H),2.92-3.10(m,1H),3.65-4.08(m,3.6H),4.27-4.40(dm,0.3H),5.98 & 6.00(s & s,2H),6.18(偽t,J=8.4 & 9.2Hz,1H),6.32(偽d,J=8.4Hz,1H),7.11-7.21(m,1H)。MS 316(MH+)
實例5c:(S)-2-((1-(3-甲基丁醯基)哌啶-3-基)甲氧基)-6-硝基苯甲腈
向(S)-2-硝基-6-(哌啶-3-基甲氧基)苯甲腈鹽酸鹽(實例1d,35.84g,120.41mmol)於DCM(600mL)中的在冰浴中冷卻至0℃之懸浮液添加三乙胺(42mL,300.94mmol),接著逐滴添加異戊醯氯(2.77mL,132.35mmol)。在0℃下,將反應混合物在N2下攪拌30分鐘,接著在室溫下攪拌隔夜。將溶液以DCM稀釋,且相繼以10%檸檬酸、飽和NaHCO3溶液、水、鹽水洗滌,經Na2SO4乾燥、過濾且濃縮,得到金棕色油狀之粗品(S)-2-((1-(3-甲基丁醯基)哌啶-3-基)甲氧基)-6-硝基苯甲腈(43.26g)。MS 346(MH+)。此物質無需純化用於下一步驟中。
實例5d:(S)-1-(3-(羥甲基)哌啶-1-基)-3-甲基丁-1-酮
在0℃下,將水(25mL)中之(S)-哌啶-3-基甲醇鹽酸鹽(10g,65.95mmol)用NaOH(13.2g,330mmol,5eq.)於水(25mL)中之溶液逐滴處理。將混合物攪拌15分鐘,且在劇烈攪拌的同時,逐滴添加異戊醯氯(15.90g,131.9mmol,2eq.)於無水THF(25mL)中之溶液。在30分鐘後,在0℃下,將反應緩慢加熱至室溫且攪拌隔夜。在劇烈
攪拌的同時,向反應混合物中添加Et2O(500mL)。分離有機層且將其用鹽水洗滌,經Na2SO4乾燥且濃縮,得到殘餘物,其藉由矽膠層析法(Hex/EtOAc 0-100)純化,得到無色油狀之所需化合物(16.27g,82.62mmol,94%)。1H NMR(400MHz,DMSO-d6,20℃)δ 0.88(偽d,J=6.4Hz,6H),1.06-1.75(m,5H),1.88-2.05(m,1H),2.07-2.23(m,2H),2.30(dd,J=10.8,12.8Hz,0.5H),2.64(ddd,J=3.2,10.8,13.2Hz,0.5H),2.78(dd,J=10.4,13.2Hz,0.5H),2.93(ddd,J=2.4,11.6,13.6Hz,0.5H),3.14-3.35(m,2H),3.70-3.85(m,1H),4.08-4.18(dm,0.5H),4.31-4.40(dm,0.5H),4.49(t,J=5.2Hz,0.5H),4.58(t,J=5.2Hz,0.5H)。MS 200(MH+)。
或者,(S)-1-(3-羥甲基)哌啶-1-基)-3-甲基丁-1-酮(實例5d)可如下製備:
將(S)-1-(3-甲基丁醯基)哌啶-3-甲酸乙酯(實例5e,37.4g,154.97mmol)於無水THF(200mL)中之溶液冷卻至0℃,且用LiCl(17g,401.04mmol)處理。在攪拌5分鐘後,在相同溫度下添加NaBH4(15g,396.50mmol)。將反應進一步冷卻至-20℃,且逐滴添加無水乙醇(400mL)。使反應保持在冷卻浴中,允許將其緩慢升溫至室溫且攪拌隔夜。添加乙醇(100mL)且用飽和檸檬酸水溶液(600mL)逐份處理反應,且再繼續攪拌30分鐘。真空移除易揮發物質,得到稠的無色物質。將水(100mL)及DCM(800mL)添加至殘餘物中且將混合物劇烈攪拌15分鐘。分離各相,且用DCM(2×800ML)進一步萃取水相。將合併的有機萃取相以鹽水洗滌且經Na2SO4乾燥。真空移除溶劑,得到無色殘餘物,其藉由矽膠層析法(3次溶離:Hex/EtOAc 0-100)純化,得到乾淨產物(29.65g,148.79mmol,96%)。
實例5e:(S)-1-(3-甲基丁醯基)哌啶-3-甲酸乙酯
將無水DCM(500mL)中之(S)-哌啶-3-甲酸乙酯(25g,159.02mmol)冷卻至0℃且用Et3N處理。在0℃下逐滴添加異戊醯氯(23.27mL,190.08mmol,1.2eq.)於無水DCM(200mL)中之溶液。使所得反應混合物保持在冷卻浴中,且允許緩慢加熱至室溫。在6小時後,將反應物相繼以HCl水溶液(2M)、飽和NaHCO3、鹽水洗滌,經Na2SO4乾燥、過濾,且真空濃縮,且使用EtOAc作溶劑在短矽膠柱上藉由過濾純化。真空移除溶劑,得到淺黃色油狀之所需產物(37.4g,154.97mmol,97.5%),其無需進一步純化即食於下一步驟中。1H NMR(400MHz,DMSO-d6,20℃)δ 0.88(偽d,J=6.4Hz,6H),1.13-1.23(m,3H),1.26-1.45(m,1H),1.47-1.75(m,2H),1.82-2.03(m,2H),2.10-2.28(m,2H),2.28-2.39(m,0.5H),2.45-2.56(m,0.5H),2.84(dd,J=10.0,12.8Hz,0.5H),2.97-3.11(m,1H),3.38(dd,J=8.8,13.6Hz,0.5H),3.63-3.83(m,1.5H),4.00-4.14(m,2H),4.26-4.36(dm,0.5H)。MS 242(MH)。
實例6:(S)-(3-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)(環己基)甲酮
如實例2,自環己烷羧酸及(S)-4-胺基-5-(哌啶-3-基甲氧基)-1H-苯并[c][1,2,6]噻二嗪2,2-二氧化物鹽酸鹽(實例2a)製備,產率為25%。1H NMR(DMSO-d6,400MHz,80℃):1.07-1.50(m,7H),1.51-1.77(m,5H),1.88(m,2H),2.08(m,2H),2.95(br m,2H),3.88(br m,2H),4.09(m,2H),6.65(d,1H,8.4Hz),6.76(d,1H,8.0Hz),7.45(t,
1H,8.4Hz),7.75(br s,1H),8.14(br s,1H),10.78(s,1H)。M+H=421。
實例7:(S)-1-(3-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)-2,2-二甲基丙-1-酮
將三甲基乙酸(71mg,0.692mmol)、1H-苯并[d][1,2,3]三氮唑-1-醇(117mg,0.865mmol)及1-(3-二甲基胺丙基)-3-乙基碳二亞胺鹽酸鹽(166mg,10.8mmol)置於20mL微波燒瓶中且以無水CAN(12mL)稀釋,接著添加(S)-4-胺基-5-(哌啶-3-基甲氧基)-1H-苯并[c][1,2,6]噻二嗪2,2-二氧化物鹽酸鹽(實例2a,200mg,0.577mmol)及TEA(320uL,2.30mmol)於DMF(2mL)中之溶液。在攪拌的同時,將混合物在130℃下的微波中加熱1小時,接著使其冷卻至室溫,轉移至250mL圓底燒瓶中且經由旋轉蒸發濃縮。將殘餘物以製備RP HPLC(在水中之10至90% ACN)純化。收集純溶離份且將其乾燥,然後以水(6mL)稀釋且添加NaHCO3(100mg),接著將溶液加熱至90℃歷時15分鐘,直至化合物全部溶解。接著將溶液冷卻至0℃且以1N HCl中和。收集沈澱物且將其乾燥,得到標題化合物(110mg,48%)。1H NMR(DMSO-d6,400MHz,80℃):1.15(s,9H),1.35(m,2H),1.68(br s,1H),1.85(br s,1H),2.05(br s,1H),2.83(br s,2H),2.16(br s,2H),4.06(d,J=8Hz,2H),4.12(d,J=12Hz,1H),4.20(d,J=16Hz,1H),6.60(d,J=8Hz,1H),6.76(d,J=8Hz,1H),7.44(t,J=8Hz,1H),7.78(s,1H),8.37(s,1H),10.93(s,1H)。M+H=395。
實例8:(S)-(3-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)(環戊基)甲酮
向(S)-3-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶鎓鹽酸鹽(實例2a,528mg,1.52mmol)於H2O:THF(20mL,2:1)中之溶液添加NaHCO3(640mg,7.60mmol)。在完成NaHCO3溶解之後,逐滴添加氯化環戊烷羰基(945uL,7.60mmol)。將反應在室溫下攪拌隔夜。藉由真空過濾收集沈澱物且將其以製備HPLC(溶於水中之10-90%乙腈)純化。將純溶離份合併、濃縮,接著溶解於NaHCO3溶液(250mg,於10mL水中)中。在溶解完成後,將混合物在冰浴中冷卻且以1N HCl中和。藉由真空過濾收集所得白色固體,得到白色固體狀之所需產物(322mg,52%),1H NMR(DMSO-d6,400MHz,80℃):1.43(m,2H),1.51-1.80(m,10H),1.90(m,1H),2.09(m,1H),2.96(m,2H),4.01(br m,2H),4.12(d,J=6.4Hz,2H),6.67(d,J=7.8Hz,1H),6.77(d,J=8.3Hz,1H),7.46(t,J=8.3Hz,1H),7.92(br s,2H),10.70(br s,1H)。MS=407(MH+)。
實例9:(S)-(3-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)(環丁基)甲酮
如實例8,自(S)-4-胺基-5-(哌啶-3-基甲氧基)-1H-苯并[c][1,2,6]噻二嗪2,2-二氧化物鹽酸鹽(實例2a)及環丁烷羧酸製備(產率:43.4%)。1H NMR(DMSO-d6,400MHz,60℃):1.35(m,2H),1.62-1.80(m,2H),1.82-1.98(m,2H),2.00-2.23(m,5H),2.76(br s,0.5H),2.88(br s,1H),3.07(br s,0.5H),3.30(m,1H),3.54(br s,0.5H),
3.70(br s,3H),4.09(d,J=6.8Hz,2H),4.14(m,1H),6.73(d,J=8.0Hz,1H),6.77(d,J=7.6Hz,1H),7.46(t,J=8.0Hz,1H),7.74(br s,1H),8.20(br s,1H),10.79(s,1H)。M+H=393。
實例10:(S)-1-(3-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)-2-(吡啶-4-基)乙酮
如實例2,自(S)-4-胺基-5-(哌啶-3-基甲氧基)-1H-苯并[c][1,2,6]噻二嗪2,2-二氧化物鹽酸鹽(實例2a)及2-(吡啶-4-基)乙酸製備(產率:34.9%)。1H NMR(400MHz,DMSO-d 6 ,80℃)δ:1.35(m,2H),1.68(br s,1H),1.79(br s,1H),1.89(br s,1H),2.09(br s,2H),3.55-3.91(m,3H),4.01(br s,3H),6.57(d,J=8.0Hz,1H),6.65(d,J=8.4Hz,1H),7.11(d,J=8.0Hz,2H),7.36(t,J=8.4Hz,1H),7.74(br s,2H),8.55(d,2H,8.4Hz),10.54(br s,1H)。MS 430(MH+)。
實例11:(S)-(3-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)(噠嗪-4-基)甲酮
如實例2,自(S)-4-胺基-5-(哌啶-3-基甲氧基)-1H-苯并[c][1,2,6]噻二嗪2,2-二氧化物鹽酸鹽(實例2a)及噠嗪-4-甲酸製備(產率:40.8%)。1H NMR(400MHz,DMSO-d 6 ,80℃)δ:1.41(m,2H),1.68(br s,1H),1.87(br s,1H),1.98(br s,1H),2.16(br s,2H),3.65-4.00(br s,1H),4.08(br s,3H),6.65(d,J=8.0Hz,1H),6.73(d,J=8.4
Hz,1H),7.43(t,J=8.4Hz,1H),7.86(br s,2H),8.12(d,J=8.0Hz,1H),9.49(d,J=8.0Hz,1H,),9.82(s,1H),10.69(br s,1H)。MS 417(MH+)。
實例12:(S)-(3-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)(2-(甲基胺基)吡啶-4-基)甲酮
如實例2,自(S)-4-胺基-5-(哌啶-3-基甲氧基)-1H-苯并[c][1,2,6]噻二嗪2,2-二氧化物鹽酸鹽(實例2a)及2-(甲基胺基)異菸鹼酸製備。(產率:44%)。1H NMR(400MHz,DMSO-d 6 ,60℃)δ 1.45(br m,2H),1.68(br m,1H),1.91(br m,1H),2.15(br m,1H),2.77(d,J=7.6Hz,3H),3.02(br m,1H),1.97(br m,1H),2.13(br m,2H),2.80(br m,2H),3.19(br m,1H),3.30-4.09(br m,4H),6.34(br m,1H),6.38(br m,1H),6.64(d,J=8.4Hz,1H),6.74(m,1H),7.42(t,J=8.4Hz,1H),7.73(br s,2H),8.01(m,1H),10.70(br s,1H)。MS 445(MH+)。
實例13:(S)-(3-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)(2-甲基吡啶-4-基)甲酮
如實例2,自(S)-4-胺基-5-(哌啶-3-基甲氧基)-1H-苯并[c][1,2,6]噻二嗪2,2-二氧化物鹽酸鹽(實例2a)及2-甲基異菸鹼酸製備(產率:15%)。1H NMR(400MHz,DMSO-d 6 ,60℃)δ 1.48(br m,2H),1.70(br m,1H),1.90(br m,1H),2.16(br m,1H),3.02(br m,2H),3.30-4.09(br m,4H),6.57(d,J=6.4Hz,1H),6.62(m,1H),7.10(m,
1H),7.16(s,1H),7.35(t,J=8.4Hz,1H),7.53s,1H),8.48(d,J=4.8Hz,1H),10.56(s,1H)。MS 430(MH+)。
實例14:(S)-(3-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)(2-(二甲基胺基)吡啶-4-基)甲酮
如實例2,自(S)-4-胺基-5-(哌啶-3-基甲氧基)-1H-苯并[c][1,2,6]噻二嗪2,2-二氧化物鹽酸鹽(實例2a)及2-(二甲基胺基)異菸鹼酸製備(8%)。1H NMR(400MHz,DMSO-d 6 ,60℃)δ 1.45(br m,2H),1.68(br m,1H),1.90(br m,1H),2.16(br m,2H),3.00(s,6H),3.30-4.09(br m,4H),6.44(d,J=5.6Hz,1H),6.47(s,1H),6.61(d,J=8.4Hz,1H),6.69(d,J=6.8Hz,1H),7.39(t,J=8.0Hz,1H),7.67(br s,2H),10.67(br s,1H)。MS 459(MH+)
實例15:(R)-1-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)-3-甲基丁-1-酮
向(R)-4-胺基-5-(哌啶-2-基甲氧基)-1H-苯并[c][1,2,6]噻二嗪2,2-二氧化物鹽酸鹽(實例15a,500mg,1.44mmol)於DMF(12mL)中之溶液添加三乙胺(399uL,2.88mmol)、3-甲基丁酸(159uL,1.44mmol)、EDCI-HCl(276mg,1.44mmol)及HOBt(220mg,1.44mmol)。在室溫下,將反應混合物在氮氣下攪拌18小時,接著過濾且藉由HPLC(於水中之10-90%乙腈)純化。將純溶離份合併、濃縮且自
乙醇及水結晶,得到白色固體狀之標題化合物(73mg,產率13%)。1H NMR(400MHz,DMSO-d 6 ,80℃)δ 0.89(d,J=6.8Hz,6H),1.37(m,1H),1.51-1.70(m,4H),1.78(d,J=12.8Hz,1H),2.01(m,1H),2.13-2.27(m,2H),3.02(br s,1H),3.89(br s,1H),4.18(br s,1H),4.48(t,J=9.2Hz,1H),5.02(br s,1H),6.63(d,J=8,0Hz,1H),6.83(d,J=8.8Hz,1H),7.42(t,J=8.4Hz,1H),7.82(br s,2H),10.63(s,1H)。MS 395(MH+)。
實例15a:(R)-2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶鎓鹽酸鹽
向(R)-2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-甲酸第三丁酯(實例15b,10.7g,26.1mmol)於乙醇(175mL)中之溶液添加溶於乙醇(104mL,2.5M,261mmol)中之HCl。在60℃下,將反應在氮氣下攪拌4小時。藉由過濾收集化合物,其為灰白色固體(7.70g,三步之產率:85%)。1H NMR(400MHz,DMSO-d 6 )δ 1.03-1.90(br m,6H),2.89(br t,J=2.8Hz,1H),3.27(br m,1H),3.61(br m,1H),4.27-4.40(br m,2H),6.67(d,J=7.6Hz,1H),6.80(d,J=8.8Hz,1H),7.46(t,J=8.0Hz,1H),7.79(br s,1H),8.35(br s,1H),9.26(br s,2H),10.97(br s,1H)。MS 311(MH+)。
實例15b:(R)-2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-甲酸第三丁酯
向(R)-2-((2-氰基-3-(胺磺醯基胺基)苯氧基)甲基)哌啶-1-甲酸第三丁酯(實例15c,10.7g,26.1mmol)於乙醇(130mL)中之溶液添加NaOH水溶液(2N,130mL,26.1mmol)。在氮氣下,使溶液回流18小時。在冷卻至室溫後,將溶液冷卻至0℃且以1N HCl中和。將混合物部分濃縮且藉由過濾收集產物,得到(R)-2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-甲酸第三丁酯,其立即食於下一步驟中。MS 311(MH+-boc)。
實例15c:(R)-2-((2-氰基-3-(胺磺醯基胺基)苯氧基)甲基)哌啶-1-甲酸第三丁酯
向(R)-2-((3-胺基-2-氰基苯氧基)甲基)哌啶-1-甲酸第三丁酯(實例15d,8.65g,26.1mmol)於二甲基乙醯胺(48mL)中之溶液添加吡啶(8.44mL,104mmol)及胺磺醯氯(6.03g,52.2mmol)。將反應混合物在室溫下攪拌1小時,以飽和NaHCO3水溶液中和且用乙酸乙酯萃取。萃取物經無水Na2SO4乾燥、過濾且濃縮,得到透明油狀之標題化合物,其立即食於下一步驟中。MS 311(MH+-boc)。
實例15d:(R)-2-((3-胺基-2-氰基苯氧基)甲基)哌啶-1-甲酸第三丁酯
向(R)-2-((2-氰基-3-硝基苯氧基)甲基)哌啶-1-甲酸第三丁酯(實例15e,10.8g,29.85mmol)於乙酸乙酯(86mL)中之溶液添加
10% Pd/C(1.08g,3mmol)。藉由添加添加H2,且將混合物在室溫下攪拌48小時。在反應完成時,經由矽藻土襯墊過濾混合物,在真空中移除溶劑。自乙酸乙酯/己烷再結晶殘餘物,得到灰白色固體狀之(R)-2-((3-胺基-2-氰基苯氧基)甲基)哌啶-1-甲酸第三丁酯(8.65g,88%)。MS 323(MH+-boc)。
實例15e:(R)-2-((2-氰基-3-硝基苯氧基)甲基)哌啶-1-甲酸第三丁酯
向(R)-2-(羥甲基)哌啶-1-甲酸第三丁酯(實例15f,7.10g,33.0mmol)及2,6-二硝基苯甲腈(6.37g,33.0mmol)於THF(142mL)中的冷卻至-78℃之溶液添加NaH(60%分散在油中,1.45g,36.3mmol)。使反應升溫至室溫且繼續攪拌18小時。在反應完成時,冷卻至0℃,且用水急冷。以乙酸乙酯萃取混合物,且將有機萃取物合併且經無水Na2SO4乾燥、過濾且濃縮。自乙酸乙酯/己烷再結晶殘餘物,得到黃色固體狀之(R)-2-((2-氰基-3-硝基苯氧基)甲基)哌啶-1-甲酸第三丁酯(10.8g,91%)。MS 282(MH+-boc)。
實例15f:(R)-2-(羥甲基)哌啶-1-甲酸第三丁酯
將(R)-1-(第三丁基羰基)哌啶-2-甲酸(實例15g,18.5g,80.7mmol)於無水THF(44.4mL)中之溶液冷卻至0℃。在15分鐘內逐滴添加BH3 .Me2S(44.4mL,88.8mmol)。在完成添加後,使混合物升溫至室溫,且繼續攪拌18小時。將混合物用水急冷且以乙酸乙酯萃取。將有機萃取物經無水Na2SO4乾燥、過濾且濃縮。使所得殘餘物矽
膠急驟層析(於己烷中之35%乙酸乙酯),得到白色固體狀之(R)-2-(羥甲基)哌啶-1-甲酸第三丁酯(14.2g,82%)。MS 116(MH+-boc)
實例15g:(R)-1-(第三丁氧基羰基)哌啶-2-甲酸
向(R)-哌啶-2-甲酸(12.5g,96.8mmol)於水(88mL)及1,4-二噁烷(133mL)中之懸浮液添加二碳酸二第三丁酯(23.2g,106mmol)及三乙胺(13.5mL,96.8mmol)。在室溫下將溶液攪拌20小時。將混合物真空濃縮,以乙酸乙酯(200mL)稀釋,且以5% HCl水溶液洗滌。分離有機相且使其經無水Na2SO4乾燥、過濾且濃縮,得到白色固體狀之化合物(18.5g,83%)。MS 130(MH+-boc)。
實例16:(R)-1-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)丁-1-酮
在室溫下且在氮氣下,向(R)-2-胺基-6-((1-丁醯基哌啶-2-基)甲氧基)苯甲腈(實例16a,1.0g,3.32mmol)於DMA(15.0mL)中之溶液添加胺磺醯氯(2.68g,23.21mmol)。接著在室溫下,將反應混合物在氮氣下攪拌2小時,且將溶液以EtOAc稀釋,以水、鹽水洗滌且經Na2SO4乾燥。減壓移除溶劑,且將殘餘物藉由Biotage SP-1(40s柱)以EtOAc/己烷(10%-70%)溶離來純化。將中間物溶於EtOH(25.0mL)中且在室溫下添加NaOH水溶液(2.0N,5.0mL)。接著,將反應混合物回流隔夜,然後冷卻至0℃且用1N HCl小心地中和。藉由過濾收集沈澱物且以20%水/EtOH再結晶,得到白色固體狀之標題化
合物(730mg,產率58%)。1H NMR(400MHz,DMSO-d 6 ,室溫)δ 0.86(t,J=7.6Hz,3H),1.35-1.76(m,8H),2.28-2.32(m,2H),3.14(t,J=13.6Hz,1H),3.74(d,J=14Hz,1H),4.07-4.11(m,1H),4.25-4.38(m,異構物),4.50(t,J=10Hz,1H),5.16(t,J=4.4Hz,1H),6.59(d,J=8.0Hz,1H),6.84(d,J=8.0Hz,1H),7.44(t,J=8.0Hz,1H),7.68(s,異構物),7.77(s,1H),8.23(s,1H),8.36(s,異構物),10.89(s,1H)。1H NMR(400MHz,DMSO-d 6 ,80℃)δ 0.88(t,J=7.6Hz,3H),1.35-1.40(m,8H),1.49-1.67(m,2H),1.77(d,J=11.6Hz,1H),2.27-2.32(m,2H),3.85-3.90(m,1H),4.18-4.20(m,1H),4.07-4.11(m,1H),4.46(t,J=10Hz,1H),5.00-5.03(m,1H),6.63(d,J=8.4Hz,1H),6.82(t,J=7.6Hz,1H),7.42(t,J=8.0Hz,1H),7.81(s,1H),10.64(s,1H),381(MH+)。
實例16a:(R)-2-胺基-6-((1-丁醯基哌啶-2-基)甲氧基)苯甲腈
向(R)-2-((1-丁醯基哌啶-2-基)甲氧基)-6-硝基苯甲腈(實例16b,1.5g,4.53mmol)於乙醇(40mL)中之溶液添加10% Pd/C(300mg)。在室溫下將反應混合物以氫氣球裝填隔夜,接著經由矽藻土過濾且減壓濃縮。將殘餘物藉由Biotage SP-1(40s柱)以EtOAc/己烷(10%-70%)溶離來純化,得到油狀所需產物(1.1g,81%)。1H NMR(400MHz,DMSO-d 6 )δ 0.86(t,J=7.2Hz,3H),1.46-1.65(m,7H),1.77-1.85(m,1H),2.24-2.30(m,1H),2.38-2.42(m,1H),2.56-2.63(m,0.5H),3.1-3.16(m,0.5H),3.71-3.74(m,0.3H),3.92-3.98(m,1H),y 2H),7.15-7.19(m,1H)。MS 302(MH+)。
實例16b:(R)-2-((1-丁醯基哌啶-2-基)甲氧基)-6-硝基苯甲腈
在室溫下,向(R)-2-((2-氰基-3-硝基苯氧基)甲基)哌啶-1-鎓2,2,2-三氟乙酸鹽(實例16c,2.26g,6.03mmol)於無水DCM(50mL)中之溶液添加三乙胺(4.2mL,30.1mmol)。將反應混合物冷卻至0℃且添加丁醯氯(0.95mL,9.05mmol),接著將溶液在室溫下攪拌隔夜。接著減壓移除溶劑且以EtOAc(150mL)稀釋殘餘物,將有機層相繼以水、鹽水洗滌,且經Na2SO4乾燥、過濾且蒸發。將殘餘物藉由Biotage SP-1(40s柱)以EtOAc/己烷(10%-70%)溶離來純化,得到所需產物(1.5g,75%)。MS 332(MH+)。
實例16c:(R)-2-((2-氰基-3-硝基苯氧基)甲基)哌啶-1-鎓2,2,2-三氟乙酸鹽
在室溫下,向(R)2-((2-氰基-3-硝基苯氧基)甲基)哌啶-1-甲酸第三丁酯(實例15e,2.18g,6.03mmol)於無水DCM(65mL)中之溶液添加三氟乙酸(7.91mL)。在室溫下將反應混合物攪拌歷時1小時。減壓移除溶劑且真空乾燥殘餘物,得到標題化合物,其無需進一步純化即可用於下一步反應中。MS 262(MH+)。
實例17:(R)-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)(環己基)甲酮
如實例15,自(R)-4-胺基-5-(哌啶-2-基甲氧基)-1H-苯并[c][1,2,6]噻二嗪2,2-二氧化物鹽酸鹽(實例15a)及環己烷羧酸製備(產率:23%)。1H NMR(400MHz,DMSO-d 6 ,80℃)δ 1.80-1.20(m,17H),2.55-2.52(m,1H),4.00-3.90(m,1H),4.20-4.16(m,1H),4.51-4.20(m,1H),5.04-5.00(m,1H),6.63(d,1H,J=8.4Hz,1H),6.83(d,J=8.4Hz,1H),7.42(t,J=8.4Hz,1H),7.80(br.s,2H),10.5(br.s,1H)。MS 421(MH+)。
實例18:(R)-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)(環丁基)甲酮
如實例15,自(R)-4-胺基-5-(哌啶-2-基甲氧基)-1H-苯并[c][1,2,6]噻二嗪2,2-二氧化物鹽酸鹽(實例15a)及環丁烷羧酸製備(產率:25%)。1H NMR(400MHz,DMSO-d 6 ,80℃)δ 1.67-1.35(m,6H),1.94-1.85(m,2H),2.16-2.10(m,3H),2.33-2.24(m,2H),3.40-3.30(m,1H),3.68-3.60(m,1H),4.21-4.20(m,1H),4.50-4.20(m,1H),5.11-5.00(m,1H),6.65(d,J=8.4Hz,1H),6.85(d,J=8.4Hz,1H),7.44(t,J=8.4Hz,1H),7.81(br s,2H),10.6(br s,1H),MS 393(MH+)。
實例19:(R)-1-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)-2-(4-甲氧基苯基)乙酮
如實例8,自(R)-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶鎓鹽酸鹽(實例15a)及2-(4-甲氧基苯基)乙醯氯製備,產率為14%。1H NMR(DMSO-d6,400MHz,80℃):1.15-1.29(m,1H),1.44-1.65(m,4H),1.70-1.78(m,1H),3.01(m,1H),3.66(s,2H),3.70(s,3H),3.90(br s,1H),4.19(br s,1H),4.43(t,J=12Hz,1H),5.03(br s,1H),5.64(d,J=8Hz,1H),6.80(t,J=8Hz,3H),7.13(d,J=8Hz,2H),7.41(t,J=8Hz,1H),7.81(br s,2H),10.63(s,1H)。M+H=459。
實例20:(R)-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)(2,4-二羥基苯基)甲酮
如實例15,自(R)-4-胺基-5-(哌啶-2-基甲氧基)-1H-苯并[c][1,2,6]噻二嗪2,2-二氧化物鹽酸鹽(實例15a)及2,4-二羥基苯甲酸製備(產率:10%),呈白色固體狀。1H NMR(400MHz,DMSO-d 6 ,80℃)δ 1.81-1.51(m,6H),3.71-3.70(m,1H),4.30-4.26(m,2H),4.60-4.52(m,1H),5.02-5.00(m,1H),6.23(dd,J=2.4,8.4Hz,1H),6.30(d,J=2.4Hz,1H),6.65(d,J=8.4Hz,1H),6.80(d,J=8.4Hz,1H),6.91(d,J=8.4Hz,1H),7.42(t,J=8.0Hz,1H),7.90(br s,2H),9.24(br s,1H),9.40(br s,1H),10.6(br s,1H)。MS 447(MH+)。
實例21:(R)-1-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)-3-(哌啶-3-基)丙-1-酮
如實例15,自3-(哌啶-3-基)丙酸及(R)-4-胺基-5-(哌啶-2-基甲氧基)-1H-苯并[c][1,2,6]噻二嗪2,2-二氧化物鹽酸鹽(實例15a)製備,產率為27.1%。1H NMR(DMSO-d6,400MHz,60℃):1.20-1.40(m,1H),1.45-1.67(m,4H),1.74(m,1H),2.68(m,2H),2.86(m,2H),3.17(s,1H),3.76(br s,1H),4.17(br s,1H),4.45(t,J=9.6Hz,1H),5.13(br s,1H),6.63(d,J=8.0Hz,1H),6.82(d,J=8.0Hz,1H),7.24(m,1H),7.43(t,J=8.0Hz,1H),7.64(m,1H),7.74(br s,1H),8.07(br s,1H),8.36(m,1H),8.46(s,1H),10.74(s,1H)。(444 MH+)。
實例22:(R)-1-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)-3-(吡啶-4-基)丙-1-酮
如實例15,自(R)-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶鎓鹽酸鹽(實例15a)製備,產率為23%。1H NMR(DMSO-d6,400MHz,80℃):1.34(m,1H),1.59(m,4H),1.76(m,1H),2.67(br t,J=7.3Hz,2H),2.86(t,J=7.3Hz,2H),3.01(m,1H),3.87(br s,1H),4.20(m,1H),4.46(t,J=10.0Hz,1H),5.02(br s,1H),6.64(dd,J=8.2,0.8Hz,1H),6.82(dd,J=8.2,0.8Hz,
1H),7.22(d,J=5.1Hz,2H),7.43(t,J=8.3Hz,1H),7.76(br s,1H),7.91(br s,1H),8.40(m,2H),10.65(s,1H)。MS 444(MH+)。
實例23:(R)-1-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)-2-(哌啶-3-基)乙酮
如實例15,自2-(哌啶-3-基)乙酸及(R)-4-胺基-5-(哌啶-2-基甲氧基)-1H-苯并[c][1,2,6]噻二嗪2,2-二氧化物鹽酸鹽(實例15a)製備,產率為40%。1H NMR(400MHz,DMSO-d 6 ,80℃)δ 1.31(br m,1H),1.60(br m,3H),1.77(br m,2H),3.04(br m,1H),3.77(s,2H),3.95(br s,1H),4.23(br s,1H),4.49(m,1H),5.02(br s,1H),6.64(d,J=8.4Hz,1H),6.83(d,J=8.8Hz,1H),7.26(m,1H),7.43(t,J=8.4Hz,1H),7.60(d,J=8.0Hz,1H),7.82(br s,1H),8.39(m,1H),8.43(m,1H),10.66(s,1H)。MS 430(MH+)。
實例24:(R)-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)(環戊基)甲酮
如實例15,自(R)-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶鎓鹽酸鹽(實例15a)及環戊基羧酸製備,產率為25%。1H NMR(DMSO-d6,400MHz,80℃):1.40(m,1H),1.53(m,2H),1.63(m,8H),1.77(m,4H),3.00(m,1H),3.97(br m,
1H),4.20(m,1H),4.50(t,J=8.0Hz,1H),5.06(br s,1H),6.67(d,J=8.0Hz,1H),6.84(d,J=8.0Hz,1H),7.43(t,J=8.0Hz,1H),7.80(br s,2H),10.6(br s,1H)。MS=407(MH+)。
實例25:(R)-1-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)-2-(吡啶-4-基)乙酮
如實例15,自(R)-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶鎓鹽酸鹽(實例15a)及2-(吡啶-4-基)乙酸製備,產率為27%。1H NMR(DMSO-d6,400MHz,80℃):1.21-1.37(m,1H),1.48-1.70(m,4H),1.71-1.82(m,1H),3.01(m,1H),3.78(br s,3H),4.22(br s,1H),4.43(t,J=8Hz,1H),5.05(br s,1H),6.64(d,J=8Hz,1H),6.82(d,J=8Hz,1H),7.21(d,J=8Hz,2H),7.42(t,J=8Hz,1H),7.82(br s,2H),8.43(d,J=8Hz,2H),10.67(s,1H)。M+H=430。
實例26:2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)-N-乙基哌啶-1-甲醯胺
向2-((2-氰基-3-(胺磺醯基胺基)苯氧基)甲基)-N-乙基哌啶-1-甲醯胺(實例26a,0.6g,1.57mmol)於EtOH(10mL)中之溶液添加2M NaOH(1.57mL,1.57mmol),且將反應混合物在100℃下加熱2小時。接著將溶液蒸發至乾燥。以水(7.0mL)稀釋殘餘物,且在0℃下
添加10% AcOH(3.5mL,3.5mmol),得到白色沈澱物,將其過濾且用冷水洗滌,且藉由Biotage純化系統(120g矽膠循環柱,DCM:THF=4:1作為溶離劑)進一步純化,得到標題化合物(0.318g,53%)。MS 382(MH+)。
實例26a:((2-氰基-3-(胺磺醯基胺基)苯氧基)甲基)-N-乙基哌啶-1-甲醯胺
向2-((3-胺基-2-氰基苯氧基)甲基)-N-乙基哌啶-1-甲醯胺(實例26b,0.407g,1.35mmol)於DMA(5mL)中之溶液添加胺磺醯氯(0.234mg,2.02mmol),且將反應混合物在室溫下劇烈攪拌2小時,接著以H2O/EtOAc萃取。將合併的有機相用鹽水洗滌,經MgSO4乾燥、過濾且蒸發。藉由Biotage純化系統(120g矽膠循環柱,DCM:THF=4:1作為溶離劑)純化殘餘物,得到所需產物(0.606g,90%)。MS 382(MH+)。
實例26b:2-((3-胺基-2-氰基苯氧基)甲基)-N-乙基哌啶-1-甲醯胺
向2-((2-氰基-3-硝基苯氧基)甲基)-N-乙基哌啶-1-甲醯胺(實例26c,0.458g,1.46mmol)於EtOH(20mL)中之溶液添加環己烯(0.74mL,7.3mmol)及催化劑量的10% Pd/C(0.146mg)。將反應混合物在100℃加熱40分鐘,接著經由矽藻土過濾,以EtOH(100mL)洗滌且蒸發,得到2-((3-胺基-2-氰基苯氧基)甲基)-N-乙基哌啶-1-甲醯胺
(0.407g,92%),其無需進一步純化即食於下一步驟中。MS 303(MH+)。
實例26c:2-((2-氰基-3-硝基苯氧基)甲基)-N-乙基哌啶-1-甲醯胺
向2-硝基-6-(哌啶-2-基甲氧基)苯甲腈鹽酸鹽(實例26d,0.5g,1.68mmol)於THF中之溶液添加三乙胺(0.514mL,3.7mmol)及異氰酸乙酯(0.2mL,2.52mmol),且在室溫下,將反應混合物在氮氣下攪拌3小時。以水稀釋溶液且以EtOAc萃取,將合併的有機相以鹽水洗滌,經MgSO4乾燥,過濾且蒸發,得到2-((2-氰基-3-硝基苯氧基)甲基)-N-乙基哌啶-1-甲醯胺(0.485g,87%),其無需進一步純化即食於下一步驟中。MS 333(MH+)。
實例26d:2-硝基-6-(哌啶-2-基甲氧基)苯甲腈鹽酸鹽
向2-((2-氰基-3-硝基苯氧基)甲基)哌啶-1-甲酸第三丁酯(實例26e,1.02g,2.83mmol)於EtOH(20mL)中之溶液添加溶於EtOH(11.3mL,14.13mmol)中之1.25N HCl,且在80℃下,將反應混合物在氮氣下攪拌1小時。在冷卻至室溫後,將反應混合物在真空中濃縮。以己烷:DCM(1:4)洗滌油性殘餘物,且真空濃縮溶劑,得到2-硝基-6-(哌啶-2-基甲氧基)苯甲腈鹽酸鹽(0.982g,116%)。MS 262(MH+)。
實例26e:2-((2-氰基-3-硝基苯氧基)甲基)哌啶-1-甲酸第三丁酯
在-20℃下,向2-(羥甲基)哌啶-1-甲酸第三丁酯(0.86g,4mmol)於無水THF(30mL)中之溶液添加NaH(0.32g,8mmol),且在-20℃下將混合物攪拌10分鐘,且接著在室溫下再攪拌20分鐘。接著將反應混合物冷卻至-20℃,且在15分鐘期間內逐滴添加溶於無水THF(10mL)及DMF(1mL)中之2,6-二硝基苯甲腈(0.772g,4mmol)。在室溫下,將溶液在氮氣下攪拌18小時,以水稀釋且以EtOAc萃取,將合併的有機相以鹽水洗滌,經MgSO4乾燥、過濾且蒸發。藉由Biotagc純化系統(120g矽膠循環柱,己烷:EtOAc=3:2作為溶離劑)純化殘餘物,得到2-((2-氰基-3-硝基苯氧基)甲基)哌啶-1-甲酸第三丁酯(1.02g,70.6%)。MS 262[M+H-Boc]+。
實例27:(R)-(-2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)-N-(吡啶-4-基甲基)哌啶-1-甲醯胺
如實例26,自(R)-2-((2-氰基-3-(胺磺醯基胺基)苯氧基)甲基)-N-(吡啶-4-基甲基)哌啶-1-甲醯胺(實例27a)製備。產率為28%,呈灰白色固體狀。1H NMR(400MHz,DMSO-d 6 )δ:1.35(m,1H),1.59(m,4H),1.77(m,1H),3.86(m,1H),4.03(dd,J=7.6,5.2Hz,1H),4.16(t,J=7.6Hz,1H),4.24(dd,J=13.2,4.4Hz,1H),4.34(dd,1H,J=10.4,4.4Hz),4.71(m,1H),6.05(d,J=6.0Hz,1H),6.19(dd,J=6.8,0.8Hz,1H),6.93(t,J=8.0Hz,1H),7.16(t,J=4.4Hz,1H),7.24(m,
2H),8.47(m,2H)。MS 445(MH+)。
實例27a:(R)-2-((2-氰基-3-(胺磺醯基胺基)苯氧基)甲基)-N-(吡啶-4-基甲基)哌啶-1-甲醯胺
如實例26a,自(R)-2-((3-胺基-2-氰基苯氧基)甲基)-N-(吡啶-4-基甲基)哌啶-1-甲醯胺(實例27b)製備。產率為48%,呈白色固體狀。MS 445(MH+)。
實例27b:(R)-2-((3-胺基-2-氰基苯氧基)甲基)-N-(吡啶-4-基甲基)哌啶-1-甲醯胺
向(R)-2-((2-氰基-3-硝基苯氧基)甲基)-N-(吡啶-4-基甲基)哌啶-1-甲醯胺(實例27c,365mg,0.98mmol)於THF/乙酸(20mL,1:1)中之溶液添加鐵粉(164mg,2.94mmol)。在氮氣下,將反應加熱至回流歷經15分鐘,且在回流下攪拌30分鐘。在完成後,將反應冷卻至室溫、濃縮、且以乙酸乙酯稀釋,且相繼以飽和NaHCO3溶液洗滌、經Na2SO4乾燥、過濾、濃縮且經急驟層析(溶於二氯甲烷中之0-10%甲醇),得到所需產物(141mg,40%)。MS=366(MH+)。
實例27c:(R)-2-((2-氰基-3-硝基苯氧基)甲基)-N-(吡啶-4-基甲基)哌啶-1-甲醯胺
向(R)-2-((2-氰基-3-硝基苯氧基)甲基)哌啶鎓2,2,2-三氟乙酸鹽(實例16c,1.12g,2.99mmol)於二氯甲烷(5mL)中之溶液添加三乙胺(420uL,3.01mmol)。向混合物中添加4-硝基苯基吡啶-4-基甲基胺甲酸酯(實例27d,980mg,3.59mmol)於二氯甲烷(5mL)中之懸浮液,接著添加三乙胺(420uL,3.01mmol)。於室溫下攪拌23小時後,添加另外部分的4-硝基苯基吡啶-4-基甲基胺甲酸酯(980mg,3.59mmol)及三乙胺(420uL,3.01mmol),且將所得反應混合物攪拌1小時,此時將其倒入水中,且相繼以飽和NaHCO3水溶液、水及鹽水洗滌,經MgSO4乾燥、過濾、濃縮,且藉由急驟層析(用己烷中之0-100%乙酸乙酯,接著用二氯甲烷中之0-10%甲醇)純化,得到(R)-2-((2-氰基-3-硝基苯氧基)甲基)-N-(吡啶-4-基甲基)哌啶-1-甲醯胺(365mg,32%)。MS=396(MH+)。
實例27d:4-硝基苯基吡啶-4-基甲基胺甲酸酯
在室溫下,將吡啶-4-基甲胺(505uL,5mmol)及對硝基苯基氯甲酸酯(1.0g,5mmol)於二氯甲烷(20mL)中之溶液攪拌5小時。在完成後,藉由真空過濾收集產物,以二氯甲烷洗滌,且藉由製備HPLC(於水中之10-90%乙腈)純化,得到白色固體狀之4-硝基苯基吡啶-4-基甲基胺甲酸酯。MS=274(MH+)。
實例28:(R)-2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-
基)氧基)甲基)-N-(吡啶-4-基)哌啶-1-甲醯胺
向(S)-4-胺基-5-(哌啶-3-基甲氧基)-1H-苯并[c][1,2,6]噻二嗪2,2-二氧化物鹽酸鹽(實例15a,346mg,1.0mmol)及4-硝基苯基吡啶-4-基胺甲酸酯(實例28a,518mg,2.0mmol)於DMF(10mL)中之溶液添加碳酸鉀(414mg,3.0mmol),且將反應混合物在室溫下攪拌2小時。經由製備RP HPLC(於水中之10至90%乙腈)純化化合物,得到所需產物(120mg,28%)。1H NMR(DMSO-d6,400MHz):1.47(m,1H),1.65(m,4H),1.80(m,1H),3.12(t,1H,J=12.0Hz),4.03(m,1H),4.17(m,1H),4.61(t,1H,J=10.4Hz),4.93(br s,1H),6.61(d,1H,J=8.4),6.89(d,1H,J=8.4),7.48(m,3H),7.99(br s,1H),8.30(d,2H,J=5.6Hz),8.35(br s,1H),8.92(s,1H),10.94(s,1H)。M+H=431。
實例28a:4-硝基苯基吡啶-4-基胺甲酸酯
如實例27d,自哌啶-4-胺及對硝基苯基氯甲酸酯製備,得到灰白色固體狀之化合物。MS=260(MH+)。
實例29:(S)-3-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)-N-(吡啶-4-基甲基)哌啶-1-甲醯胺
將4-硝基苯基(吡啶-4-基甲基)胺甲酸酯(實例27d,27.3
mg,100umol)、(S)-3-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶鎓鹽酸鹽(實例2a,34.6mg,0.10mmol)及K2CO3於DMF(1mL)中之溶液在室溫下攪拌隔夜。將所得混合物過濾且藉由製備HPLC(於水中之10-90%乙腈)純化,得到白色固體狀之標題化合物。MS=445(MH+)。
實例30:(S)-3-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)-N-(吡啶-4-基)哌啶-1-甲醯胺
如實例29,自4-硝基苯基吡啶-4-基胺-甲酸酯(實例28a)及(S)-3-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶鎓鹽酸鹽(實例2a)製備。MS=431(MH+)。
實例31:(S)-1-(3-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)-2-(嘧啶-2-基)乙酮
如實例2,自(S)-5-(哌啶-3-基甲氧基)-1H-苯并[c][1,2,6]噻二嗪-4-胺基-2,2-二氧化物鹽酸鹽(實例2a)及2-(嘧啶-2-基)乙酸製備(實例31a)(產率10%)。1H NMR(400MHz,DMSO-d 6 )δ 1.31-1.47(m,2H),1.57-1.76(m,1H),1.85(m,1H),2.00(d,1H,J=7.9Hz),2.03-2.25(m,1H),3.00(m,1H),3.69-4.22(m,6H),6.56(m,1H),6.65(m,1H),7.32(t,1H,J=4.9Hz),7.39(t,1H,J=4.9Hz),7.53-7.84(m,2H),8.70(d,1H,J=4.9Hz),8.76(d,1H,J=4.9Hz),10.98(br s,
1H)。MS 431(MH+)。
實例31a:2-(嘧啶-2-基)乙酸
在室溫及氮氣下,向2-(嘧啶-2-基)乙酸乙酯(實例31b,410mg,2.47mmol)於乙醇(5mL)中之溶液添加2N NaOH(2mL)。在室溫下,將反應混合物在氮氣下攪拌72小時,然後減壓濃縮。將殘餘物用乙醇研磨且減壓濃縮,得到標題化合物,其無需進一步純化即食於下一步驟中。MS 139(MH+)。
實例31b:2-(嘧啶-2-基)乙酸乙酯
在-78℃下,向二乙基丙二酸酯(6.65mL,43.65mmol)於DMF(30mL)中之溶液添加NaH(1.76g,52.38mmol,60%分散於礦物油中)。將反應在-78℃下攪拌10分鐘,升溫至室溫,且添加溶於DMF(3mL)中之2-氯嘧啶(1.0g,8.73mmol)。將反應混合物加熱至80℃歷時72小時,然後加熱至120℃歷時18小時,且在完成後,冷卻至室溫。添加1N HCl以急冷溶液,以飽和NaHCO3水溶液中和且以EtOAc(3×)萃取。將合併的有機物經Na2SO4乾燥、過濾、濃縮且藉由矽膠急驟層析法(於己烷中之0-100% EtOAc)純化,得到橘黃色油狀之標題化合物(1.34g,92%)。MS 167(MH+)。
實例32:(R)-1-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)-2-(嘧啶-2-基)乙酮
如實例15,自(R)-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶鎓鹽酸鹽(實例15a)及2-(嘧啶-2-基)乙酸(實例31a)製備(產率36%)。1H NMR(400MHz,DMSO-d 6 )δ 1.25(m,1H),1.47-1.67(m,4H),1.76(m,1H),3.16(t,1H,J=12.6Hz),2.77-4.20(m,3H),4.27-4.72(m,2H),5.13(m,1H),6.57(d,1H,J=8.2Hz),6.78(br d,1H,J=7.6Hz),7.35(t,1H,J=5.0Hz),7.40(br t,1H,J=8.2Hz),7.71(br s,1H),7.91(br s,1H),8.71(m,2H),10.90(br s,1H)。MS 431(MH+)。
實例33:(R)-1-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)-2-(嘧啶-4-基)乙酮
如實例15,自(R)-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶鎓鹽酸鹽(實例15a)及2-(嘧啶-4-基)乙酸(實例33a)製備(產率44%)。1H NMR(400MHz,DMSO-d 6 )δ 1.35(m,1H),1.54-1.68(m,4H),1.79(m,1H),3.21(t,1H,J=12.3Hz),3.84(m,1H),3.98(m,2H),4.16(dd,1H,J=10.0,4.6Hz),4.29-4.75(m,1H),5.16(m,1H),6.60(d,1H,J=8.6Hz),6.81(br d,1H,J=7.9
Hz),7.43(d,1H,J=11.0Hz),7.45(d,1H,J=8.3Hz),7.72(br s,1H),8.07(br s,1H),8.70(d,1H,J=5.0Hz),9.08(m,1H),10.91(br s,1H)。MS 431(MH+)。
實例33a:2-(嘧啶-4-基)乙酸
在室溫下且於氮氣下,向2-(嘧啶-4-基)乙酸乙酯(實例33b,450mg,2.71mmol)於乙醇(5mL)中之溶液添加2N NaOH(2mL)。在室溫下,將反應混合物在氮氣下攪拌24小時,接著減壓濃縮且懸浮於乙醇中。藉由真空移除固體,且減壓濃縮濾液,以乙醇研磨,再濃縮,且無需進一步純化即食於下一步驟中。MS 139(MH+)。
實例33b:2-(嘧啶-4-基)乙酸乙酯
在-70℃下,向含有LiHMDS(32mL,31.89mmol,1.0M於THF中)之燒瓶中緩慢加入4-甲基嘧啶(1.0g,10.63mmol)。於-70℃下攪拌5分鐘後,添加碳酸二乙酯(1.93mL,15.95mmol),使反應緩慢升溫至室溫且攪拌4天。藉由添加1N HCl以急冷反應混合物,以飽和NaHCO3水溶液中和且以EtOAc(3×)萃取。將合併的有機物經Na2SO4乾燥、過濾、減壓濃縮且藉由矽膠急驟層析法(於己烷中之0-100% EtOAc)純化,得到黃色油狀之標題化合物(1.38g,78%)。MS 167(MH+)。
實例34:(R)-1-(3-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)-3-甲基丁-1-酮
如實例5,自(R)-2-胺磺醯基胺基-6-((1-(3-甲基丁醯基)哌啶-3-基)甲氧基)苯甲腈(實例34a)製備(產率54%)。1H NMR(400MHz,DMSO-d 6 ,80℃)δ 0.89(d,6H,J=4.0Hz),1.41(m,2H),1.69(m,1H),1.88(m,1H),1.98(m,1H),2.07(m,1H),2.17(m,2H),2.96(br.s,2H),3.55-4.14(m,4H),6.66(d,1H,J=8.2Hz),6.75(d,1H,J=8.2Hz),7.44(t,1H,J=8.2Hz),7.75(br.s,1H)8.00(br.s,1H),10.69(s,1H)。MS 395(MH+)。
實例34a:(R)-2-胺磺醯基胺基-6-((1-(3-甲基丁醯基)哌啶-3-基)甲氧基)苯甲腈
如實例5a,自(R)-2-胺基-6-((1-(3-甲基丁醯基)哌啶-3-基)甲氧基)苯甲腈(實例34b)製備。MS 395(MH+)。
實例34b:(R)-2-胺基-6-((1-(3-甲基丁醯基)哌啶-3-基)甲氧基)苯甲腈
在0℃下,向(R)-1-(3-(羥甲基)哌啶-1-基)-3-甲基丁-1-酮(實例34c)(145mg,0.73mmol)於THF(15mL)中之溶液添加NaH(44mg,1.09mmol,60%分散於礦物油中)。將反應升溫至室溫且攪拌15分鐘,此時添加2-胺基-6-氟苯甲腈(109mg,0.80mmol)。將混合物在80℃下加熱隔夜,以水急冷,且減壓濃縮以移除THF且以EtOAc(3×)萃取。將合併的萃取物經Na2SO4乾燥、過濾、減壓濃縮,且藉由矽膠急驟層析法(EtOAc/己烷)純化。藉由掌性HPLC(正相,乙醇/異
丙醇/甲醇/己烷)進一步純化殘餘物,得到白色固體狀之標題化合物(96mg,41%)。MS 316(MH+)。
實例34c:(R)-1-(3-(羥甲基)哌啶-1-基)-3-甲基丁-1-酮
在0℃下,向(R)-1-(3-甲基丁醯基)哌啶-3-甲酸(實例34d)(2.52g,11.84mmol)於THF(20mL)中之溶液逐滴添加BH3Me2S(1.2mL,13.0mmol)歷時15分鐘。將反應升溫至室溫且攪拌隔夜,冷卻至0℃,以水急冷,且減壓濃縮以移除THF且以EtOAc萃取。將合併的萃取物以飽和NaHCO3水溶液洗滌,經Na2SO4乾燥、過濾、減壓濃縮,且藉由矽膠急驟層析法(EtOAc/己烷)純化,得到標題化合物(184mg,6%)。MS 200(MH+)。
實例34d:(R)-1-(3-甲基丁醯基)哌啶-3-甲酸
向(R)-哌啶-3-甲酸(2.0g,15.48mmol)於水(40mL)及THF(20mL)中之溶液添加NaHCO3(3.30g,38.70mmol)及3-甲基丁醯氯(2.8mL,23.2mmol)。將反應攪拌隔夜,減壓濃縮,以水(50mL)稀釋且以EtOAc(1×)萃取。以1N HCl酸化含水層且以EtOAc(3×)萃取,且將合併的萃取物經Na2SO4乾燥、過濾且減壓濃縮,得到標題化合物(2.53g,76%)。MS 214(MH+)。
實例35:(R)-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)(吡啶-4-基)甲酮
如實例15,自(R)-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶鎓鹽酸鹽(實例15a)及異菸鹼酸製備(產率26%)。1H NMR(400MHz,DMSO-d 6 ,80℃)δ 1.48(m,1H),1.58-1.87(m,5H),3.19(br t,1H,J=12.4Hz),3.19(br s,1H),4.30(m,1H),4.64(t,1H,J=8.8Hz),4.99(br s,1H),6.64(d,1H,J=8.8Hz),6.80(br s,1H),7.28(dd,2H,J=6.4Hz),7.40(t,1H,J=8.0Hz),7.86(br s,2H),8.60(dd,2H,J=5.2Hz),10.66(br s,1H)。MS 416(MH+)。
實例36:(R)-1-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)-2-(吡啶-4-基)乙酮
如實例15,自(R)-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶鎓鹽酸鹽(實例15a)及2-(吡啶-4-基)乙酸製備(產率26%)。1H NMR(400MHz,DMSO-d 6 ,80℃)δ 1.20-1.33(m,1H),1.49-1.65(m,4H),1.72-1.79(m,1H),3.01(m,1H),3.90(br s,3H),4.22(br s,1H),4.45(t,1H,J=8.0Hz),5.06(br s,1H),6.64(d,1H,J=8.0Hz),6.82(d,1H,J=8.0Hz),7.19(ddd,1H,J=8.0,4.8,0.8Hz),7.27(d,1H,J=8.0Hz),7.42(t,1H,J=8.0Hz),7.67(dt,1H,J=8.0,2.0Hz),7.80(br s,2H),8.43(dq,1H,J=8.0Hz,0.8Hz),10.65
(s,1H)。MS 430(MH+)。
實例37:(R)-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)(2-羥基-6-甲基吡啶-4-基)甲酮
如實例15,自(R)-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶鎓鹽酸鹽(實例15a)及2-羥基-6-甲基異菸鹼酸製備。1H NMR(400MHz,DMSO-d 6 )δ 1.42(m,1H),1.54-1.72(m,5H),1.80(m,1H),2.16(s,3H),3.21(m,1H),3.44(m,1H),4.19(dd,1H,J=10.3,4.2Hz),4.37(m,1H),4.61(t,1H,J=10.0Hz),5.14(m,1H),5.88(s,1H),6.02(s,1H),6.61(d,1H,J=8.4Hz),6.86(d,1H,J=8.4Hz),7.44(t,1H,J=8.4Hz),7.75(br s,1H),8.34(br s,1H),10.92(s,1H)。MS 446(MH+)。
實例38:(R)-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)(2,6-二甲基喹啉-4-基)甲酮
如實例15,自(R)-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶鎓鹽酸鹽(實例15a)及2,6-二甲基喹啉-4-甲酸製備。1H NMR(400MHz,DMSO-d 6 )δ 1.12-1.53(m,2H),1.58-1.84(m,4H),1.98(s,3H),2.64(s,3H),3.02(m,1H),3.19(m,
1H),4.18(dd,1H,J=9.9,3.1Hz),4.95(t,1H,J=10.2Hz),5.45(m,1H),6.66(m,1H),7.01(d,1H,J=8.2Hz),7.27(s,1H),7.38(s,1H),7.46-7.61(m,2H),7.81(d,1H,J=8.6Hz),7.98(br s,1H),8.26(br s,1H),10.94(s,1H)。MS 494(MH+)。
實例39:(R)-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)(2-(甲基胺基)吡啶-4-基)甲酮
如實例15,自(R)-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶鎓鹽酸鹽(實例15a)及2-(甲基胺基)異菸鹼酸製備。1H NMR(400MHz,DMSO-d 6 )δ 1.41(m,1H),1.52-1.74(m,4H),1.83(m,1H),2.74(d,3H,J=4.6Hz,),3.19(m,1H),3.40(m,1H),4.19(dd,1H,J=9.9,3.6Hz,),4.65(t,1H,J=10.1Hz,),5.20(m,1H),6.30(s,1H),6.61(m,2H),6.88(d,1H,J=8.5Hz),7.46(t,1H,J=8.6Hz,),7.83(br s,1H),8.01(d,1H,J=5.4Hz,),8.30(br s,1H),10.93(s,1H)。MS 445(MH+)。
實例40:(R)-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)(2-羥基吡啶-4-基)甲酮
如實例15,自(R)-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶鎓鹽酸鹽(實例15a)及2-羥基異
菸鹼酸製備。1H NMR(400MHz,DMSO-d 6 )δ 1.41(m,1H),1.52-1.74(m,4H),1.81(m,1H),3.22(m,1H),3.43(m,1H),4.19(dd,1H,J=10.1,3.8Hz),4.62(t,1H,J=10.5Hz),5.16(m,1H),6.06(d,1H,J=7.0Hz),6.23(s,1H),6.61(d,1H,J=8.0Hz,),6.87(d,1H,J=8.7Hz),7.45(m,2H),7.75(br s,1H),8.36(br s,1H),10.92(s,1H),11.73(br s,1H)。MS 432(MH+)。
實例41:(R)-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)(3-羥基吡啶-4-基)甲酮
如實例15,自(R)-2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶鎓鹽酸鹽(實例15a)及3-羥基異菸鹼酸製備。1H NMR(400MHz,DMSO-d 6 )δ 1.45(m,1H),1.52-1.74(m,4H),1.84(m,1H),3.19(m,2H),4.18(dd,1H,J=10.2,4.0Hz),4.64(t,1H,J=10.0Hz),5.25(m,1H),6.61(d,1H,J=8.2Hz),6.87(d,1H,J=8.2Hz),7.08(d,1H,J=5.5Hz),7.46(t,1H,J=8.2Hz),7.84(br s,1H),8.07(d,1H,J=5.5Hz),8.19(s,1H),8.29(br s,1H),10.28(s,1H),10.9(br s,1H)。MS 432(MH+)。
實例42:(R)-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)(6-甲基喹啉-4-基)甲酮
如實例15,自(R)-2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶鎓鹽酸鹽(實例15a)及6-甲基喹啉-4-甲酸製備。1H NMR(400MHz,DMSO-d 6 )δ 1.34-1.53(m,2H),1.59-1.86(m,4H),2.01(s,3H),3.01(m,1H),3.20(m,1H),4.19(dd,1H,J=10.1,3.2Hz),4.95(t,1H,J=10.6Hz),5.46(m,1H),6.67(d,1H,J=8.1Hz),7.01(d,1H,J=8.3Hz,),7.34(s,1H),7.48-7.56(m,2H),7.60-7.68(m,1H),7.92(d,1H,J=8.7Hz),7.99(br s,1H),8.27(br s,1H),8.87(d,1H,J=4.4Hz),10.94(s,1H)。MS 480(MH+)。
實例43:(R)-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)(2-甲基吡啶-3-基)甲酮
如實例15,自(R)-2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶鎓鹽酸鹽(實例15a)及2-甲基菸鹼酸製備。1H NMR(400MHz,DMSO-d 6 )δ 1.35(m,1H),1.48-1.81(m,4H),1.86(m,1H),2.24(s,3H),3.12(m,1H),3.24(m,1H),4.16(m,1H),4.77(t,1H,J=9.8Hz),5.32(m,1H),6.62(d,1H,J=8.0Hz),6.90(d,1H,J=8.3Hz),7.27(m,1H),7.47(t,1H,J=8.3Hz),7.66(m,1H),7.93(br s,1H),8.31(br s,1H),8.47(dd,1H,J=5.1,1.7Hz),
10.92(s,1H)。MS 430(MH+)。
實例44:(R)-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)(噠嗪-4-基)甲酮
如實例15,自(R)-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶鎓鹽酸鹽(實例15a)及噠嗪-4-甲酸製備。1H NMR(400MHz,DMSO-d 6 )δ 1.46-1.89(m,6H),2.24(s,3H),3.28(m,2H),4.26(m,1H),4.64(t,1H,J=10.1Hz),5.29(m,1H),6.62(d,1H,J=8.2Hz),6.87(d,1H,J=8.2Hz),7.46(t,1H,J=8.2Hz),7.69(dd,1H,J=5.0,1.8Hz),7.77(br s,1H),8.37(br s,1H),9.26(m,1H),9.35(d,1H,J=5.0Hz),10.94(s,1H)。MS 417(MH+)。
實例45:(R)-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)(異喹啉-1-基)甲酮
如實例15,自(R)-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶鎓鹽酸鹽(實例15a)及異喹啉-1-甲酸製備。1H NMR(400MHz,DMSO-d 6 )δ 1.33(m,1H),1.47(m,1H),1.56-1.74(m,2H),1.81(m,1H),1.93(m,1H),3.00(m,1H),3.21(m,1H),4.26(dd,1H,J=10.1,3.7Hz),4.82(t,1H,J=10.1Hz,),5.45
(m,1H),6.66(d,1H,J=8.0Hz,),6.95(d,1H,J=8.5Hz),7.50(t,1H,J=8.5Hz,),7.61(m,1H),7.74-7.90(m,3H),7.97(br s,1H),8.02(d,1H,J=8.0Hz),8.28(br s,1H),8.49(d,1H,J=5.8Hz,),10.94(s,1H)。MS 466(MH+)。
實例46:(R)-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)(2-甲基吡啶-4-基)甲酮
如實例15,自(R)-2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶鎓鹽酸鹽(實例15a)及2-甲基異菸鹼酸製備。1H NMR(400MHz,CD3OD)δ 1.51-2.00(m,6H),2.57(s,3H),3.27(m,1H),3.45(m,1H),4.28(m,1H),4.73(t,1H,J=10.5Hz),5.42(m,1H),6.66(d,1H,J=8.1Hz),6.87(d,1H,J=8.1Hz,),7.22(m,1H),7.26(s,1H),7.48(t,1H,J=8.6Hz),8.50(d,1H,J=4.8Hz)。MS 430(MH+)。
實例47:(S)-1-(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)-3-甲基丁-1-酮
如實例5,自(S)-2-胺磺醯基胺基-6-((1-(3-甲基丁醯基)哌啶-2-基)甲氧基)苯甲腈(實例47a)製備(產率41%)。1H NMR(400MHz,DMSO-d 6 )δ 0.86(d,3H,J=6.9Hz),0.88(d,3H,J=6.9Hz),
1.35(m,1H),1.46-1.68(m,4H),1.75(m,1H),1.99(sept,1H,J=6.9Hz),2.22(d,2H,J=6.8Hz),3.15(m,1H),3.78(m,1H),4.08(dd,1H,J=10.1,4.1Hz),4.53(t,1H,J=9.9Hz),5.17(m,1H),6.59(d,1H,J=8.2Hz),6.84(d,1H,J=8.2Hz),7.44(t,1H,J=8.7Hz),7.81(br.s,1H)8.22(br.s,1H),10.88(s,1H)。MS 395(MH+)。
實例47a:(S)-2-胺磺醯基胺基-6-((1-(3-甲基丁醯基)哌啶-2-基)甲氧基)苯甲腈
如實例5a,自(S)-2-胺基-6-((1-(3-甲基丁醯基)哌啶-2-基)甲氧基)苯甲腈(實例47b)製備(產率100%)。MS 395(MH+)。
實例47b:(S)-2-胺基-6-((1-(3-甲基丁醯基)哌啶-2-基)甲氧基)苯甲腈
如實例2c,自(S)-2-((1-(3-甲基丁醯基)哌啶-2-基)甲氧基)-6-硝基苯甲腈(實例47c)製備(產率96%)。MS 316(MH+)。
實例47c:(S)-2-((1-(3-甲基丁醯基)哌啶-2-基)甲氧基)-6-硝基苯甲腈
如實例34d,自(S)-2-硝基-6-(哌啶-2-基甲氧基)苯甲腈鹽
酸鹽(實例47d)及異戊醯氯製備(產率40%)。MS 346(MH+)。
實例47d:(S)-2-硝基-6-(哌啶-2-基甲氧基)苯甲腈鹽酸鹽
如實例1d,自(S)-2-((2-氰基-3-硝基苯氧基)甲基)哌啶-1-甲酸第三丁酯(實例47e)製備。MS 262(MH+-HCl)。
實例47e:(S)-2-((2-氰基-3-硝基苯氧基)甲基)哌啶-1-甲酸第三丁酯
如實例1e,自(S)-2-(羥甲基)哌啶-1-甲酸第三丁酯(實例47f)及2,6-二硝基苯甲腈製備(產率91%)。MS 262(MH+-boc)。
實例47f:(S)-2-(羥甲基)哌啶-1-甲酸第三丁酯
如實例15f,自(S)-1-(第三丁氧羰基)哌啶-2-甲酸製備。MS 116(MH+-boc)。
實例48:(S)-4-胺基-5-((1-(3-甲基丁醯基)哌啶-3-基)甲氧基)苯并[c][1,2,6]噻二嗪-1-鈉2,2-二氧化物
向(S)-1-(3-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)-3-甲基丁-1-酮(2.0g,5.07mmol)(實例
5)於水(25mL)中之懸浮液添加NaHCO3(425mg,5.07mmol)。將反應加熱至回流直至發生固體物質之完全溶解,然後減壓濃縮。將所得殘餘物溶於水中且凍乾,得到米色固體狀之標題化合物(2.1g,100%)。1H NMR(400MHz,DMSO-d 6 )δ 0.78-0.96(m,6H),1.21-1.50(m,2H),1.55-1.75(m,1H),1.78-2.07(m,3H),2.10-2.25(m,2H),2.60-2.78(m,1H),2.88-3.15(m,2H),3.65-3.97(m,3H),4.00-4.41(m,1H),5.97(t,1H,J=8.0Hz),6.21(d,1H,J=8.8Hz),6.57(br.s,2H),6.95(d,1H,J=8.0,3.2Hz)。MS 395(MH+-Na)。
實例49:1-(3-(羥甲基)哌啶-1-基)-3-甲基丁-1-酮
如實例5,自2-胺磺醯基胺基-6-((1-(3-甲基丁醯基)哌啶-3-基)甲氧基)苯甲腈(實例49a)製備(產率89%)。1H NMR(400MHz,DMSO-d 6 ,80℃)δ 0.88(d,6H,J=6.3Hz),1.40(t,2H,J=9.2,9.2Hz),1.63-1.73(m,1H),1.80-1.90(m,1H),1.90-2.20(m,4H),2.88-2.98(m,2H),3.58-4.25(m,4H),6.64(dd,1H,J=8.2,1.1Hz),6.74(d,1H,J=8.4Hz),7.43(t,1H,J=8.2,8.2Hz),7.79(br s,1H),7.95(br s,1H),10.68(s,1H)。MS 395(MH+)。
實例49a:2-胺磺醯基胺基-6-((1-(3-甲基丁醯基)哌啶-3-基)甲氧基)苯甲腈
如實例5a,自2-胺基-6-((1-(3-甲基丁醯基)哌啶-3-基)甲
氧基)苯甲腈(實例49b)製備(產率98%)。MS 395(MH+)
實例49b:2-胺基-6-((1-(3-甲基丁醯基)哌啶-3-基)甲氧基)苯甲腈
如實例34b,自1-(3-(羥甲基)哌啶-1-基)-3-甲基丁-1-酮(實例49c)製備。MS 316(MH+)。
實例49c:1-(3-(羥甲基)哌啶-1-基)-3-甲基丁-1-酮
在0℃下,向哌啶-3-基甲醇(10g,86.83mmol)於水(25mL)中之溶液逐滴添加NaOH(13.89g,347.31mmol)於水(25mL)中之溶液。將混合物攪拌15分鐘,之後,在劇烈攪拌下,逐滴添加溶於THF(25mL)中之3-甲基丁醯氯(20.94g,173.66mmol)。將反應緩慢升溫至室溫,且在完成後,以Et2O(500mL)稀釋,其在劇烈攪拌下添加。在15分鐘後,分離相,且以Et2O(2×)萃取水相。將合併的有機萃取物以鹽水洗滌,經Na2SO4乾燥、減壓濃縮且藉由矽膠急驟層析法(於己烷中之0-100% EtOAc)純化,得到無色油狀之標題化合物(16.27g,94%)。MS 200(MH+)。
實例50:(S)-5-(4-(3-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)-2-甲基-4-側氧基丁-2-基)-2-甲氧基苯基乙烷磺酸酯
如實例2,自(S)-4-胺基-5-(哌啶-3-基甲氧基)-1H-苯并
[c][1,2,6]噻二嗪2,2-二氧化物鹽酸鹽(實例2a)及3-(4-甲氧基-3-((甲基磺醯基)氧基)苯基)-3-甲基丁酸製備(實例50a)(產率23%)。1H NMR(400MHz,DMSO-d 6 )δ 1.17-1.26(m,1H),130-1.34(m,7H),1.46-1.57(m,1H),1.74-1.76(m,1H),1.90(brs,1H),2.56-2.93(m,4H),3.28-3.29(m,3H),3.49-3.61(m,1H),3.68(s,1.5H),3.77(s,1.5H),3.89-4.03(m,3H),6.58-6.63(m,1H),6.69-6.75(m,1H),6.98-7.05(m,1H),7.13-7.28(m,2H),7.44-7.46(m,1H),7.72-7.74(m,1H),8.33-8.38(m,1H),10.95(s,1H)。MS 595(MH+)。
實例50a:3-(4-甲氧基-3-((甲基磺醯基)氧基)苯基)-3-甲基丁酸
在0℃下,向2-甲氧基苯基甲烷磺酸酯(實例50b)(82g,406.4mmol)與3-甲基丁-2-烯酸(20.3g,203.2mmol)之混合物添加濃硫酸(11mL,96%,206.3mmol)。將反應混合物在0℃下攪拌15分鐘,接著加熱至70℃且在氮氣下攪拌隔夜。在完成後,將反應冷卻至室溫,以冰水(500mL)急冷且以乙醚(1×)萃取。分離相,且將有機層以2N NaOH(1×)洗滌。在0℃下,用12N HCl將合併的含水層酸化至pH 1,且以乙醚(1×)萃取。將有機層以鹽水洗滌,經Na2SO4乾燥、過濾且減壓蒸發,得到紅褐色油狀之標題化合物(14.4g,含有<20%的3-甲基丁-2-烯酸)1H NMR(400MHz,DMSO-d 6 )δ 1.33(s,6H),2.53(s,2H),3.31(s,3H),3.79(s,3H),7.08-7.31(m,3H),11.87(s,1H)。
實例50b:2-甲氧基苯基甲烷磺酸酯
在0℃且在氮氣下,向2-甲氧基苯酚(50g,402.8mmol)及三乙胺(84.2mL,604.2mmol)於無水二氯甲烷(300mL)中之溶液添
加甲烷磺醯氯(37.6mL,483.3mmol)。在0℃下,將反應混合物攪拌2小時,以冰水(250mL)急冷,且轉移至分液漏斗。將有機相以NaOH(8g)於冰水(200mL)中之溶液、鹽水洗滌,經Na2SO4乾燥、過濾且減壓濃縮,得到無色液體狀之標題化合物(81.44g,100%)。1H NMR(400MHz,DMSO-d 6 )δ 3.32(s,3H),3.83(s,3H),6.96-7.0(m,1H),7.18-7.2(m,1H),7.27-7.33(m,2H)。
實例51:(S)-1-(3-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)-3-(3-羥基-4-甲氧基苯基)-3-甲基丁-1-酮
向(S)-5-(4-(3-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)-2-甲基-4-側氧基丁-2-基)-2-甲氧基苯基甲烷磺酸酯(200mg,0.34mmol)(實例50)於EtOH(20mL)中之溶液添加2N NaOH水溶液(0.34mL)。將反應混合物在85℃下攪拌3小時、冷卻至0℃且以2N HCl中和。將溶液減壓濃縮且以製備HPLC(於水中之10-90%乙腈)濃縮,得到標題化合物(78mg,45%)。1H NMR(400MHz,DMSO-d 6 )δ 1.17-1.32(m,8H),1.43-1.64(m,2H),1.74-1.8(m,1H),2.52-2.67(m,2H),2.77-2.83(m,0.5H),3.51-3.54(m,0.5H),3.65-3.68(m,4H),3.73-3.84(m,2H),4.1-4.18(m,1H),5.9-5.94(m,1H),6.15-6.19(m,1H),6.5(brs,1H),6.66-6.78(m,3H),6.89-6.95(m,1H),8.71(s,1H)。MS 517(MH+)。
實例52:(S)-(2-(1H-咪唑-1-基)吡啶-4-基)(3-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)-甲酮
如實例2,自(S)-5-(哌啶-3-基甲氧基)-1H-苯并[c][1,2,6]噻二嗪-4-胺基-2,2-二氧化物鹽酸鹽(實例2a)及2-(1H-咪唑-1-基)異菸鹼酸製備(實例52a)(產率42%)。1H NMR(400MHz,DMSO-d 6 ,80℃)δ 1.42-1.60(m,2H),1.71(m,1H),1.93(m,1H),2.22(m,1H),3.11(m,1H),3.34-3.75(m,1H),3.92-4.42(m,2H),6.63(m,1H),6.74(br s,1H),7.11(s,1H),7.29(m,1H),7.42(m,1H),7.52-8.28(br s,2H),7.76(m,1H),7.93(m,1H),8.52(m,2H),10.71(br s,1H)。MS 482(MH+)。
實例52a:2-(1H-咪唑-1-基)異菸鹼酸
向2-溴異菸鹼酸(1.87g,9.26mmol)、1H-咪唑(573mg,8.42mmol)及Cs2CO3(6.03g,18.5mmol)於DMSO(18.6mL)中之溶液添加CuI(176mg,0.926mmol)。將混合物加熱至125℃,攪拌18小時,冷卻至室溫、過濾且藉由製備HPLC(於水中之10-90%乙腈)純化,得到淺粉紅色固體狀之標題化合物(1.72g,98%)。MS 190(MH+)。
實例53:(R)-(2-(1H-咪唑-1-基)吡啶-4-基)(2-(((4-胺基-2,2-二氧化-1H-苯并[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶-1-基)甲酮
如實例15,自(R)-(2-(((4-胺基-2,2-二氧化-1H-苯并
[c][1,2,6]噻二嗪-5-基)氧基)甲基)哌啶鎓鹽酸鹽(實例15a)及2-(1H-咪唑-1-基)異菸鹼酸(實例52a)製備(產率22%)。1H NMR(400MHz,DMSO-d 6 )δ 1.47-1.91(m,6H),3.02(m,1H),3.35(m,1H),4.28(dd 1H,J=10.4,4.4Hz),4.65(t,1H,J=10.4Hz),5.24(m,1H),6.63(d,1H,J=8.2Hz),6.90(d,1H,J=8.5Hz),7.31(d,1H,J=5.2Hz),7.48(d,1H,J=8.2Hz),7.77(s,1H),7.84(br s,1H),8.00(s,1H),8.44(br s,1H),8.52-8.59(m,2H),10.95(br s,1H)。MS 482(MH+)。
以下表A中之化合物係遵循上述程序合成。
生物學測試
本發明化合物已獲測試且顯示甜味增效活性。具體而言,本發明化合物已證明能活化T1R2/T1R3受體且增強T1R2/T1R3受體之活化以及對甜味劑(諸如果糖)之甜味增效活性。下文實驗1及實驗2中所述的用於人類味覺測試之化合物Q1、J2、K2、L2、B1及F3選自貫穿本文檔描述的化合物,包括表A中列出之實例及化合物。
實驗1:利用人類官能檢查員進行的成對比較測試來對甜味及甜味增效作用進行量測
將含有實驗化合物之測試樣本成對提供給官能檢查員且讓其判定哪種樣本更甜。平均而言,本發明化合物顯示在寬的pH值範圍內的甜味增效作用,且此試驗提供在pH約2.8或7.1下測試的樣本之結果。10至16名或16名以上的官能檢查員為一組參與每一測試。受試者在測試前至少1小時克制不進食或喝飲品(水除外)。受試者用水漱口數次以清潔口腔。
在化合物存在或不存在之情形下,以蔗糖或HFCS作甜味劑進行味覺測試。製備化合物於含碳酸氫鈉之水中的0.2%儲液,且接著將此儲液以最終樣本稀釋以達成化合物的最終目標濃度。針對在pH 2.8下評估的樣本,使用檸檬酸將溶液pH降低至大約為pH 2.8。亦在不含蔗糖或HFCS的低磷酸鈉緩衝液(pH 7.1;「LSB」)中製備味覺樣本,以評估單獨化合物之味覺。低磷酸鈉緩衝液由0.3mM KCl、
0.5mM Na2HPO4及0.175mM KH2PO4組成。樣本體積一般為20ml。
在一成對比較測試中,向官能檢查員提供兩種不同的樣本,且讓其鑒別哪種樣本較甜。成對比較測試中之樣本係以隨機化、互相平衡的次序提供。官能檢查員在味覺測試之間可延遲至多1分鐘以清潔口腔除去任何味道。
使用二項式概率表以判定在α=0.05下每一測試出現的正確響應數量之概率。
以化合物Q1進行人類味覺測試之結果見以下。表1-a表明,官能檢查員認為在pH 7.1下,6%蔗糖+21μM化合物Q1相較於12%蔗糖溶液在甜度上並無顯著不同。表1-b表明,官能檢查員認為在pH 2.8下,6%蔗糖+7.8μM化合物Q1相較於12%蔗糖溶液在甜度上並無顯著不同。表2-a表明,官能檢查員認為在pH 7.1下,6%高果糖玉米糖漿+26.3μM化合物Q1相較於9%高果糖玉米糖漿溶液在甜度上並無顯著不同。表2-b表明,官能檢查員認為在pH 2.8下,6%高果糖玉米糖漿+7.8μM化合物Q1相較於8%高果糖玉米糖漿溶液在甜度上並無顯著不同。表3表明,26.3μM單獨化合物Q1與1%蔗糖溶液一樣甜。
表1-b. 官能檢查員選擇的較甜樣本,n=42(14名官能檢查員×3次重複)。pH 2.8
以化合物J2進行人類味覺測試之結果見以下。表4-a表明,官能檢查員認為在pH 7.1下,6%蔗糖+12.7μM化合物J2相較於12%蔗糖溶液在甜度上並無顯著不同。表4-b表明,官能檢查員認為
在pH 2.8下,6%蔗糖+12.7μM化合物J2相較於12%蔗糖溶液在甜度上並無顯著不同。表5-a表明,官能檢查員認為在pH 7.1下,6%高果糖玉米糖漿+20.4μM化合物J2相較於9%高果糖玉米糖漿溶液在甜度上並無顯著不同。表5-b表明,官能檢查員認為在pH 2.8下,6%高果糖玉米糖漿+12.7μM化合物J2相較於9%高果糖玉米糖漿溶液在甜度上並無顯著不同。表6表明,20.4μM單獨的化合物J2與1%蔗糖溶液一樣甜。
以化合物K2進行人類味覺測試之結果見以下。表7-a表明,官能檢查員認為在pH 7.1下,6%蔗糖+12.7μM化合物K2相較於12%蔗糖溶液在甜度上並無顯著不同。表7-b表明,官能檢查員認為在pH 2.8下,6%蔗糖+12.7μM化合物K2相較於12%蔗糖溶液在甜度上並無顯著不同。表8-a表明,官能檢查員認為在pH 7.1下,6%高果糖玉米糖漿+12.7μM化合物K2相較於9%高果糖玉米糖漿溶液在甜度上並無顯著不同。表8-b表明,官能檢查員認為在pH 2.8下,6%高果糖玉米糖漿+12.7μM化合物K2相較於8%高果糖玉米糖漿溶液在甜度上並無顯著不同。表9表明,12.7μM單獨的化合物K2與1%蔗糖溶液一樣甜。
以化合物L2進行人類味覺測試之結果見以下。表10表
明,官能檢查員認為在pH 7.1下,6%蔗糖+12.7μM化合物L2相較於12%蔗糖溶液在甜度上並無顯著不同。表11表明,官能檢查員認為在pH 2.8下,6%高果糖玉米糖漿+12.7μM化合物L2相較於9%高果糖玉米糖漿溶液在甜度上並無顯著不同。表12表明,12.7μM單獨的化合物L2與1%蔗糖溶液一樣甜。
以化合物B1進行人類味覺測試之結果見以下。表13表明,官能檢查員認為在pH 7.1下,6%蔗糖+11.9μM化合物B1相較於12%蔗糖溶液在甜度上並無顯著不同。表14表明,官能檢查員認為在
pH 2.8下,6%高果糖玉米糖漿+11.9μM化合物B1相較於9%高果糖玉米糖漿溶液在甜度上並無顯著不同。表12表明,11.9μM單獨的化合物B1與1%蔗糖溶液一樣甜。
以化合物F3進行人類味覺測試之結果見以下。表16表明,官能檢查員認為在pH 7.1下,6%蔗糖+9.2μM化合物F3相較於10%蔗糖溶液在甜度上並無顯著不同。表17表明,官能檢查員認為在pH 2.8下,6%高果糖玉米糖漿+9.2μM化合物F3相較於9%高果糖玉米糖漿溶液在甜度上並無顯著不同。表18表明,9.2μM單獨的化合物
F3與1%蔗糖溶液一樣甜。
實驗2:利用人類官能檢查員在產品原型中對甜味及甜味增效作用進行量測
實驗2-1:化合物K2在冰咖啡中之蔗糖增效作用:
所有樣本均製成冰咖啡調配物的形式,其由沖煮咖啡、2%乳、蔗糖及水組成。使用以0.2%碳酸氫鈉及水製成的0.2%化合物儲液製備樣本。將測試樣本成對提供給官能檢查員且讓其判定哪種樣本更甜。
在一成對比較測試中,向官能檢查員提供兩種不同的樣本,且讓其鑒別哪種樣本較甜。成對比較測試中之樣本係以隨機化、互相平衡的次序提供。官能檢查員在味覺測試之間可延遲至多1分鐘以清潔口腔除去任何味道。
使用二項式概率表以判定在α=0.05下每一測試出現的正確響應數量之概率。
表19表明,官能檢查員認為4%蔗糖冰咖啡+7.6μM化合物K2相較於8%蔗糖冰咖啡溶液在甜度上並無顯著不同。
本文中之所有公開案及專利申請案以引用之方式併入本文中,其程度如同特定及個別地指示各個別公開案或專利申請案以引用之方式併入本文中一般。
上述實施方式僅出於清楚瞭解的目的提供且不應自其瞭解到不必要的限制,因為修改對於熟習此項技術者而言為顯而易見的。並不承認本文提供之任何資訊為先前技術或與目前所主張之發明有關,或明確或含蓄地引用之任何公開案為先前技術。
本發明之實施例描述於本文中,包括為本發明者所知之進行本發明的最佳方式。彼等較佳實施例之變體對於一般技術者而言在閱讀了上述描述之後將變得顯而易見。本發明者期望熟練技術人員在適當時使用該等變體,且本發明者意欲以除如本文明確描述之方式以外之其他方式來實施本發明。因此,本發明包括如由適用法律所允
許的隨附申請專利範圍中所述之標的物的所有修改及等效物。此外,除非本文另外指示或上下文另外明顯相抵觸,否則本發明涵蓋其所有可能變體中上述要素之任何組合。
Claims (50)
- 一種具有結構式(I)之化合物:
- 如請求項1中任一項之化合物,其中X為NH。
- 如請求項1中任一項之化合物,其中X為共價鍵。
- 如請求項1至3中任一項之化合物,其中A為視情況經取代之五至七員氮雜環。
- 如請求項1至4中任一項之化合物,其中A為視情況經取代之哌啶。
- 如請求項1之化合物,其由結構式(Ia)表示:
- 如請求項6中任一項之化合物,其中X為NH。
- 如請求項6中任一項之化合物,其中X為共價鍵。
- 如請求項6至8中任一項之化合物,其中m為1、2、3或4;且n為 0、1或2。
- 如請求項6至9中任一項之化合物,其中q為1、2或3。
- 如請求項6至9中任一項之化合物,其中q為0。
- 如請求項9或11之化合物,其中m為4,且n為0;或m為3且n為1;或m與n皆為2。
- 如請求項6或12之化合物,其由結構式(Ib)表示:
- 如請求項6或12之化合物,其由結構式(Ic)表示:
- 如請求項6或12之化合物,其由結構式(Id)表示:
- 如請求項6或12之化合物,其由結構式(Ie)表示:
- 如請求項13至16中任一項之化合物,其中Y為C1至C12烴基、經取代之C1至C12烴基,C1至C12雜烴基,或經取代之C1至C12雜烴基。
- 如請求項13至16中任一項之化合物,其中Y為三至十員碳環基、經取代之三至十員碳環基,三至十員雜環基,或經取代之三至十員雜環基。
- 如請求項13至16中任一項之化合物,其中Y為十五員芳基、經取 代之六至十五員芳基,五至十員雜芳基,或經取代之五至十員雜芳基。
- 如請求項13至16中任一項之化合物,其中Y為-(C1至C3伸烴基)-芳基或-(C1至C3伸烴基)-經取代之芳基。
- 如請求項13至16中任一項之化合物,其中Y為-(C1至C3伸烴基)-雜芳基或-(C1至C3伸烴基)-經取代之雜芳基。
- 如請求項14或16之化合物,其中Y為C1至C12烴基、經取代之C1至C12烴基、五或六員雜芳基、經取代之五或六員雜芳基、-(C1至C3伸烴基)-(五或六員雜芳基),或-(C1至C3伸烴基)-(經取代之五或六員雜芳基)。
- 如請求項22之化合物,其中該雜芳基為吡咯、吡啶、嘧啶、噠嗪或吡嗪,其各自視情況經取代。
- 如請求項13或15之化合物,其中Y為C1至C12烴基、經取代之C1至C12烴基,C1至C12雜烴基,或經取代之C1至C12雜烴基。
- 如請求項13或15之化合物,其中Y為三至七員環烴基、經取代之三至七員環烴基,五至七員雜環基,或經取代之五至七員雜環基。
- 如請求項25之化合物,其中該環烴基為環丙基、環丁基、環戊基、環己基、或環庚基,其各自視情況經取代;且該雜環基為四氫呋喃或四氫哌喃,其各自視情況經取代。
- 如請求項13或15之化合物,其中Y為苯基或經取代之苯基。
- 如請求項13或15之化合物,其中Y為視情況經取代之五或六員單環雜芳基,或視情況經取代之十至十二員雙環雜芳基。
- 如請求項28之化合物,其中該雜芳基選自由吡咯、吡啶、嘧啶、噠嗪、吡嗪、吡啶N-氧化物、喹啉、咪唑并吡啶及吡唑并吡啶組成之群,其各自視情況經取代。
- 如請求項13或15之化合物,其中Y為-CH2-苯基或-C(CH3)2-經取代之苯基。
- 如請求項13或15之化合物,其中Y為-CH2-雜芳基或-C(CH3)2-經取代之雜芳基。
- 如請求項31之化合物,其中該雜芳基為吡咯、吡啶、嘧啶、噠嗪或吡嗪,其各自視情況經取代。
- 如請求項1之化合物,其選自由以下組成之群:
- 一種可攝食組合物,其包含如請求項1至33中任一項之化合物;以及視情況選用攝食上可接受之賦形劑。
- 如請求項34之可攝食組合物,其進一步包含一或多種甜味劑。
- 如請求項35之可攝食組合物,其中該甜味劑選自由以下組成之群:蔗糖、果糖、葡萄糖、半乳糖、甘露糖、乳糖、塔格糖、麥芽糖、玉米糖漿(包括高果糖玉米糖漿)、D-色胺酸、甘胺酸、赤藻糖醇、異麥芽酮糖醇、乳糖醇、甘露糖醇、山梨糖醇、木糖醇、麥芽糊精、麥芽糖醇、異麥芽酮糖醇、氫化葡萄糖糖漿(HGS)、氫化澱粉水解物(HSH)、甜菊苷、萊鮑迪苷A(rebaudioside A)、其他基於甜菊(sweet Stevia)之醣苷、N-[[(3,5-二氯苯基)胺基][(二苯基甲基)胺基]亞甲基]甘胺酸(carrelame)及其他基於胍之甜味劑、糖精、艾司沙芬鉀(acesulfame-K)、賽克拉美、蔗糖素、阿力甜(alitame)、羅漢果甜苷(mogroside)、紐甜(neotame)、阿斯巴甜糖、其他阿斯巴甜糖衍生物,及其組合物。
- 如請求項34之可攝食組合物,其相較於不含請求項1至33中任一項之化合物的可攝食組合物具有增加的甜味味覺。
- 如請求項34之可攝食組合物,其為食品或飲料產品、醫藥組合物、營養產品、膳食補充劑、非處方藥物或口腔護理產品。
- 如請求項38之可攝食組合物,其中該食品或飲料產品係供人類或動物消耗。
- 如請求項38之可攝食組合物,其中該食品或飲料產品選自由以下組成之群:湯類、乾燥加工食品類、飲料類、即食膳食類、罐裝或保藏食品類、冷凍加工食品類、冷藏加工食品類、點心食品類、烘烤製品類、糖食類、乳製品類、冰淇淋類、膳食替代品類、意大利麵及麵條類、調味醬、醬汁、調味品類、嬰兒食品類,塗抹食品類;糖衣、糖霜或糖釉;及其組合。
- 一種增加組合物之甜味味覺之方法,其包括使該組合物與如請求項1至33中任一項之化合物接觸,以形成經改質之組合物。
- 一種甜味調節組合物,其包含有效提供甜化作用之量的如請求項1至33中任一項之化合物與第一量之甜味劑的組合,其中該甜化作用大於在不存在該化合物情況下由該第一量之甜味劑所提供之該甜化作用。
- 一種可攝食組合物,其包含如請求項42之甜味調節組合物的。
- 如請求項43之可攝食組合物,其呈食品或飲料產品、醫藥組合物、營養產品、膳食補充劑、非處方藥物或口腔護理產品的形式。
- 一種調味濃縮物調配物,其包含i)作為風味改質成分之如請求項1至33中任一項之化合物;ii)載劑;以及iii)視情況選用之至少一種佐劑。
- 如請求項45之調味濃縮物調配物,其中該至少一種佐劑包含一或多種調味劑。
- 如請求項45或46之調味濃縮物調配物,其中該至少一種佐劑包含一或多種甜味劑。
- 如請求項45至47中任一項之調味濃縮物調配物,其中該至少一種佐劑包含選自由以下物質組成之群的一或多種成份: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、蛋白質濃縮物及分離物、鹽、冰點抗凍劑、成核劑,及其組合。
- 如請求項45至48中任一項之調味濃縮物調配物,其係呈選自由液體、固體、半固體、泡沫狀物質、糊狀物、凝膠、乳油、洗液,及其組合組成之群的形式。
- 如請求項45至49中任一項之調味濃縮物調配物,其中如請求項1至33中任一項之化合物的濃度為於即食型組合物中之濃度的至少2倍。
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Families Citing this family (93)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SI1945632T1 (sl) * | 2005-11-08 | 2014-03-31 | Vertex Pharmaceuticals Incorporated | Heterocikliäśni modulatorji za prenaĺ alce z atp-vezavno kaseto |
US9603848B2 (en) | 2007-06-08 | 2017-03-28 | Senomyx, Inc. | Modulation of chemosensory receptors and ligands associated therewith |
WO2010014666A2 (en) | 2008-07-31 | 2010-02-04 | Senomyx, Inc. | Processes and intermediates for making sweet taste enhancers |
WO2012021837A2 (en) | 2010-08-12 | 2012-02-16 | Senomyx, Inc. | Method of improving stability of sweet enhancer and composition containing stabilized sweet enhancer |
PE20191204A1 (es) | 2012-08-06 | 2019-09-10 | Firmenich Incorporated | Modificador del sabor dulce |
JO3155B1 (ar) | 2013-02-19 | 2017-09-20 | Senomyx Inc | معدِّل نكهة حلوة |
US20140272068A1 (en) * | 2013-03-14 | 2014-09-18 | Indra Prakash | Beverages containing rare sugars |
JP6479050B2 (ja) * | 2014-05-09 | 2019-03-06 | フイルメニツヒ ソシエテ アノニムFirmenich Sa | 甘味調節剤及びフレーバーの可溶化 |
ES2903031T3 (es) | 2014-09-11 | 2022-03-30 | Pepsico Inc | Potenciador de dulzor |
MY190296A (en) | 2015-10-29 | 2022-04-12 | Firmenich Incorporated | High intensity sweeteners |
EP3439488B1 (en) | 2016-04-06 | 2020-12-02 | The Coca-Cola Company | Sweetness and taste improvement of steviol glycoside or mogroside sweeteners |
US10494397B2 (en) | 2016-07-15 | 2019-12-03 | Pepsico, Inc. | Rebaudioside analogs |
US10966447B2 (en) | 2016-07-19 | 2021-04-06 | Pepsico, Inc. | Glucosyringic acid analogs as sweetness profile modifiers |
US10085472B2 (en) | 2016-08-29 | 2018-10-02 | Pepsico, Inc. | Compositions comprising rebaudioside J |
PL3317260T3 (pl) | 2016-09-21 | 2020-05-18 | Celanese International Corporation | Kompozycje acesulfamu potasu oraz sposoby jego wytwarzania |
WO2018057389A1 (en) | 2016-09-21 | 2018-03-29 | Celanese International Corporation | Acesulfame potassium compositions and processes for producing same |
SI3319948T1 (sl) | 2016-09-21 | 2021-11-30 | Celanese International Corporation | Sestavki kalijevega acesulfama in postopek za izdelavo le-teh |
SI3319949T1 (sl) | 2016-09-21 | 2020-11-30 | Celanese International Corporation, | Sestavki kalijevega acesulfama in postopki za njihovo izdelavo |
MX2019012940A (es) | 2017-05-03 | 2019-12-16 | Firmenich Incorporated | Metodos para producir edulcorantes de alta intensidad. |
JP2020536537A (ja) | 2017-10-06 | 2020-12-17 | カーギル インコーポレイテッド | 易溶解性ステビオールグリコシド組成物 |
US11019837B2 (en) | 2017-11-08 | 2021-06-01 | Pepsico, Inc. | Mouthfeel modulation in reduced and sugar-free beverages using a blend of pectin and xanthan gum |
US10806165B2 (en) | 2018-04-24 | 2020-10-20 | Stokely-Van Camp, Inc. | Ready-to-drink plant protein beverage product and methods for making same |
US11700869B2 (en) | 2018-06-27 | 2023-07-18 | Pepsico, Inc. | Mouthfeel enhancing composition |
WO2020033420A1 (en) | 2018-08-07 | 2020-02-13 | Firmenich Incorporated | 5-substituted 4-amino-1h-benzo[c][1,2,6]thiadiazine 2,2-dioxides and formulations and uses thereof |
EP3860369B1 (en) | 2019-03-28 | 2024-05-08 | Firmenich SA | Flavor system |
WO2020200916A1 (en) | 2019-04-04 | 2020-10-08 | Firmenich Sa | Mogroside compounds and uses thereof |
EP3952667A1 (en) | 2019-04-06 | 2022-02-16 | Cargill, Incorporated | Sensory modifiers |
WO2020260628A1 (en) | 2019-06-28 | 2020-12-30 | Firmenich Sa | Fat blends, emulsions thereof, and related uses |
US20220273012A1 (en) | 2019-09-05 | 2022-09-01 | Firmenich Sa | Flavanone derivatives and their use as sweetness enhancers |
EP4054575A1 (en) * | 2019-11-06 | 2022-09-14 | DSM IP Assets B.V. | Novel method |
US20220273011A1 (en) | 2019-11-11 | 2022-09-01 | Firmenich Sa | Gingerol compounds and their use as flavor modifiers |
US20230028760A1 (en) | 2019-12-13 | 2023-01-26 | Firmenich Incorporated | Taste modifying compositions and uses thereof |
US20220361547A1 (en) | 2019-12-13 | 2022-11-17 | Firmenich Incorporated | Taste modifying compositions and uses thereof |
JP2023507887A (ja) | 2019-12-18 | 2023-02-28 | フィルメニッヒ インコーポレイテッド | 味覚修飾組成物およびその使用 |
WO2021126569A1 (en) | 2019-12-18 | 2021-06-24 | Firmenich Incorporated | Taste modifying compositions and uses thereof |
US20230061835A1 (en) | 2020-03-05 | 2023-03-02 | Firmenich Sa | 11-oxo cucurbitanes and their use as flavor modifiers |
WO2021198199A1 (en) | 2020-03-31 | 2021-10-07 | Firmenich Sa | Flavor composition |
EP4055006A1 (en) | 2020-04-17 | 2022-09-14 | Firmenich SA | Amino acid derivatives and their use as flavor modifiers |
EP4096714A1 (en) | 2020-05-22 | 2022-12-07 | Firmenich SA | Compositions for reducing salty taste and uses thereof |
JP2023527492A (ja) | 2020-06-03 | 2023-06-29 | フイルメニツヒ ソシエテ アノニム | 雑味を減らす組成物およびその使用 |
WO2021259945A1 (en) | 2020-06-24 | 2021-12-30 | Firmenich Sa | Sweetening compositions and uses thereof |
EP4110475A1 (en) | 2020-07-14 | 2023-01-04 | Firmenich SA | Reduction of undesirable taste notes in oral care products |
US20230276835A1 (en) | 2020-07-24 | 2023-09-07 | Firmenich Incorporated | Savory taste enhancement via transmembrane region binding |
JP2023541748A (ja) | 2020-09-22 | 2023-10-04 | フイルメニツヒ ソシエテ アノニム | サリチル酸メチル不含のウィンターグリーンフレーバー組成物 |
CN114901081B (zh) | 2020-10-13 | 2023-03-24 | 弗门尼舍有限公司 | 丙二酰基甜菊醇糖苷及其可食用用途 |
JP2023545892A (ja) | 2020-10-27 | 2023-11-01 | フイルメニツヒ ソシエテ アノニム | 共役ジイン、及びフレーバー改質剤としてのその使用 |
JP2023550963A (ja) | 2020-11-24 | 2023-12-06 | フィルメニッヒ インコーポレイテッド | コク味の増強及び関連するスクリーニング方法 |
EP4175490A1 (en) | 2020-11-29 | 2023-05-10 | Firmenich SA | Compositions that reduce peroxide off taste and uses thereof |
WO2022136288A1 (en) | 2020-12-23 | 2022-06-30 | Firmenich Sa | Uses of fat blends and emulsions thereof |
WO2022150445A1 (en) | 2021-01-07 | 2022-07-14 | Conagen Inc. | Compounds and methods for enhancing sweetness of sweeteners |
JP2024503845A (ja) | 2021-01-13 | 2024-01-29 | フィルメニッヒ インコーポレイテッド | 清涼効果を増強する組成物 |
JP2024503099A (ja) | 2021-01-15 | 2024-01-24 | フィルメニッヒ インコーポレイテッド | モグロシドを含む甘味料組成物およびその使用 |
EP4258895A1 (en) | 2021-01-15 | 2023-10-18 | Firmenich Incorporated | Sweetener compostions comprising siamenoside i and uses thereof |
US20240074479A1 (en) | 2021-02-10 | 2024-03-07 | Firmenich Sa | Fiber blends, sweetened fiber blends, and their comestible use |
CN115315195A (zh) | 2021-03-09 | 2022-11-08 | 弗门尼舍有限公司 | 羟基取代和甲氧基取代的类黄酮及其用途 |
WO2022189155A1 (en) | 2021-03-09 | 2022-09-15 | Firmenich Sa | Hydroxy- and methoxy-substituted flavones and their use |
WO2022214275A1 (en) | 2021-04-06 | 2022-10-13 | Firmenich Sa | Use of gingerdiol compounds to enhance flavor |
BR112023022012A2 (pt) | 2021-04-26 | 2023-12-26 | Firmenich Incorporated | Compostos de amida e seu uso como modificadores de sabor |
JP2024517692A (ja) | 2021-04-26 | 2024-04-23 | フィルメニッヒ インコーポレイテッド | アミド化合物および風味修飾剤としてのその使用 |
EP4307919A2 (en) | 2021-05-11 | 2024-01-24 | Firmenich SA | Process of making gingerol compounds and their use as flavor modifiers |
WO2022248405A1 (en) | 2021-05-24 | 2022-12-01 | Firmenich Sa | Flavored fiber blends and their comestible use |
WO2022251628A1 (en) | 2021-05-28 | 2022-12-01 | Firmenich Incorporated | Compositions that enhance the cooling effect |
WO2022253681A1 (en) | 2021-06-02 | 2022-12-08 | Firmenich Sa | Deacetylation process, compositions, and uses thereof |
WO2022268875A1 (en) | 2021-06-23 | 2022-12-29 | Firmenich Sa | Flavor-modifying compositions containing lactase |
WO2023278394A1 (en) | 2021-06-28 | 2023-01-05 | Firmenich Incorporated | Polycationic salts of phenolic compounds and uses thereof |
EP4333645A1 (en) | 2021-06-29 | 2024-03-13 | Firmenich Incorporated | Mogroside compounds and their comestible use |
EP4362704A1 (en) | 2021-06-29 | 2024-05-08 | Firmenich SA | Licorice compounds and their use as flavor modifiers |
CN118043443A (zh) | 2021-09-27 | 2024-05-14 | 弗门尼舍公司 | 香草基醚用于修饰蒸馏酒的风味的用途 |
WO2023046914A1 (en) | 2021-09-27 | 2023-03-30 | Firmenich Sa | Flavor compositions containing iron compounds and their use |
WO2023072604A1 (en) | 2021-11-01 | 2023-05-04 | Firmenich Sa | Composition comprising a nutrient and a taste modulator |
WO2023091315A2 (en) | 2021-11-16 | 2023-05-25 | Firmenich Incorporated | Amide compounds and their use as flavor modifiers |
WO2023107904A1 (en) | 2021-12-07 | 2023-06-15 | Firmenich Incorporated | Reduction of bitter taste of plant proteins and related assays and screening methods |
WO2023118002A1 (en) | 2021-12-20 | 2023-06-29 | Firmenich Sa | Encapsulated metal compounds and comestible uses thereof |
WO2023117643A1 (en) | 2021-12-23 | 2023-06-29 | Firmenich Sa | Antimicrobial composition having encapsulated colorant |
WO2023165764A1 (en) | 2022-03-04 | 2023-09-07 | Firmenich Sa | Purification process for polymethoxylated flavonoids and compositions obtained therefrom |
WO2023172415A1 (en) | 2022-03-07 | 2023-09-14 | Firmenich Incorporated | Sweetener compositions |
WO2023169995A1 (en) | 2022-03-10 | 2023-09-14 | Firmenich Sa | Sweetener compositions |
WO2023172372A1 (en) | 2022-03-11 | 2023-09-14 | Firmenich Incorporated | Amide compounds and their use as flavor modifiers |
WO2023172394A1 (en) | 2022-03-11 | 2023-09-14 | Firmenich Incorporated | Flavanone compounds and their use as flavor modifiers |
WO2023180063A1 (en) | 2022-03-25 | 2023-09-28 | Firmenich Sa | Fatty acid amides and their use as flavor modifiers |
WO2023186792A1 (en) | 2022-03-28 | 2023-10-05 | Firmenich Sa | Non-animal protein compositions and uses thereof |
WO2023196128A1 (en) | 2022-04-06 | 2023-10-12 | Firmenich Incorporated | Taste modifying compositions and uses thereof |
WO2023198436A2 (en) | 2022-04-11 | 2023-10-19 | Firmenich Sa | Sweetener compositions |
WO2023224814A1 (en) | 2022-05-16 | 2023-11-23 | Firmenich Incorporated | Saturated fatty acids and their use to modify taste |
WO2023224812A1 (en) | 2022-05-16 | 2023-11-23 | Firmenich Incorporated | Unsaturated fatty acids and their use to modify taste |
WO2023232968A1 (en) | 2022-06-03 | 2023-12-07 | Firmenich Sa | Fat reduction in non-animal protein compositions |
WO2023242177A1 (en) | 2022-06-14 | 2023-12-21 | Firmenich Sa | Polyelectrolyte complexes of proteins and uses thereof |
WO2023247332A1 (en) | 2022-06-24 | 2023-12-28 | Firmenich Sa | Taste modifying compositions and uses thereof |
WO2024011086A1 (en) | 2022-07-07 | 2024-01-11 | Firmenich Incorporated | Compositions that enhance the cooling effect |
WO2024041974A1 (en) | 2022-08-22 | 2024-02-29 | Firmenich Sa | Gel compositions and their use in seafood analogue products |
WO2024091457A1 (en) | 2022-10-26 | 2024-05-02 | Firmenich Incorporated | Taste modifying compositions and uses thereof |
WO2024089025A1 (en) | 2022-10-26 | 2024-05-02 | Firmenich Sa | Extrusion methods and flavored products formed thereby |
WO2024094523A1 (en) | 2022-11-01 | 2024-05-10 | Firmenich Sa | Low-calorie composition for flavor modification |
Family Cites Families (100)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB951651A (en) | 1960-02-17 | 1964-03-11 | Shell Res Ltd | Substituted benzonitriles, their preparation and compositions containing them |
US3278532A (en) | 1964-07-06 | 1966-10-11 | Sandoz Ag | Dioxybenzothiadiazines |
US3843804A (en) | 1971-03-10 | 1974-10-22 | Int Flavors & Fragrances Inc | Novel flavoring compositions and processes |
US3857972A (en) | 1971-03-10 | 1974-12-31 | Int Flavors & Fragrances Inc | Flavoring with an oxocyclic pyrimidine |
LU64388A1 (zh) | 1971-12-02 | 1973-07-16 | ||
FI54312C (fi) | 1972-05-09 | 1978-11-10 | Sumitomo Chemical Co | Foerfarande foer framstaellning av tieno-(2,3-d)pyrimidinderivat med avsoendring av urinsyra i urin utoekande |
US3845770A (en) | 1972-06-05 | 1974-11-05 | Alza Corp | Osmatic dispensing device for releasing beneficial agent |
US3960860A (en) | 1973-01-08 | 1976-06-01 | International Flavors & Fragrances Inc. | 2-Methyl-5,7-dihydrothieno-[3,4d]-pyrimidine |
US3966965A (en) | 1973-03-23 | 1976-06-29 | American Home Products Corporation | Oxamic acid derivatives for the prevention of immediate type hypersensitivity reactions |
US4036837A (en) | 1973-03-23 | 1977-07-19 | American Home Products Corporation | 2 Alkoxyoxamoyl-pyrazines |
US3916899A (en) | 1973-04-25 | 1975-11-04 | Alza Corp | Osmotic dispensing device with maximum and minimum sizes for the passageway |
GB1570494A (en) | 1975-11-28 | 1980-07-02 | Ici Ltd | Thienopyrimidine derivatives and their use as pesticides |
US4137325A (en) | 1977-03-17 | 1979-01-30 | American Home Products Corporation | Antisecretory oxamic acid esters |
US4196207A (en) | 1977-05-23 | 1980-04-01 | Ici Australia Limited | Process for controlling eradicating or preventing infestations of animals by Ixodid ticks |
ES472163A1 (es) | 1978-07-28 | 1979-03-16 | Consejo Superior Investigacion | Ÿun nuevo procedimiento para la obtencion de 5,5-dioxido de 7-amino-2h-4h-vic-triazolo (4,5-c) (1,2,6) tiadiazinaÿ |
IE51802B1 (en) | 1979-12-03 | 1987-04-01 | Fujisawa Pharmaceutical Co | Quinazoline derivatives,processes for their preparation and pharmaceutical compositions containing them |
JPS5951290A (ja) | 1982-09-14 | 1984-03-24 | Dai Ichi Seiyaku Co Ltd | ベンゾチエノイミダゾピリミジンジオン化合物 |
ES8507558A1 (es) | 1984-03-30 | 1985-09-01 | Consejo Superior Investigacion | Procedimiento para la preparacion de aminociclotiadiazinas |
GB8504253D0 (en) | 1985-02-19 | 1985-03-20 | Ici Plc | Electrostatic spraying apparatus |
US4672116A (en) | 1985-12-20 | 1987-06-09 | Ortho Pharmaceutical Corporation | Substituted 5,6-dialkoxyquinazoline derivatives |
JPS6387959A (ja) | 1986-10-01 | 1988-04-19 | Sanyo Kokusaku Pulp Co Ltd | ステビア甘味料の呈味性改善法 |
US4960870A (en) | 1987-02-11 | 1990-10-02 | Ciba-Geigy Corporation | Heavy metal complex azo dyes containing a benzothiophene-1,1-dioxide, 2,1-benzothiazine-2,2-dioxide, 1,4-benzothiazine-1,1-dioxide or thienopyridine-1,1-dioxide coupling component |
KR970002877B1 (ko) | 1987-07-17 | 1997-03-12 | 더 누트라스웨트 캄파니 | 고성능 감미제 |
US5380541A (en) | 1987-08-07 | 1995-01-10 | Tate & Lyle Public Limited Company | Sucralose compositions |
DE3815221C2 (de) | 1988-05-04 | 1995-06-29 | Gradinger F Hermes Pharma | Verwendung einer Retinol- und/oder Retinsäureester enthaltenden pharmazeutischen Zubereitung zur Inhalation zur Einwirkung auf die Schleimhäute des Tracheo-Bronchialtraktes einschließlich der Lungenalveolen |
JPH02238856A (ja) | 1989-03-14 | 1990-09-21 | Mitajiri Kagaku Kogyo Kk | ミラクリンを有効成分とする矯味・調味料及びこれを含有する飲食品 |
US5192785A (en) | 1989-09-03 | 1993-03-09 | A. H. Robins Company, Incorporated | Sulfamates as antiglaucoma agents |
US5504095A (en) | 1990-09-19 | 1996-04-02 | Pfizer Inc. | Aminobenzosultam derivatives as lipoxygenase inhibitors |
US5698155A (en) | 1991-05-31 | 1997-12-16 | Gs Technologies, Inc. | Method for the manufacture of pharmaceutical cellulose capsules |
IL102764A0 (en) | 1991-08-16 | 1993-01-31 | Merck & Co Inc | Quinazoline derivatives,and pharmaceutical compositions containing them |
PT100905A (pt) | 1991-09-30 | 1994-02-28 | Eisai Co Ltd | Compostos heterociclicos azotados biciclicos contendo aneis de benzeno, ciclo-hexano ou piridina e de pirimidina, piridina ou imidazol substituidos e composicoes farmaceuticas que os contem |
GB9127188D0 (en) | 1991-12-21 | 1992-02-19 | Smithkline Beecham Plc | Novel compounds |
KR970010069B1 (ko) | 1992-08-24 | 1997-06-20 | 주식회사 럭키 | 신규 세팔로스포린계 항생제 및 이의 제조방법 |
WO1996028206A1 (en) | 1995-03-14 | 1996-09-19 | Siemens Aktiengesellschaft | Ultrasonic atomizer device with removable precision dosating unit |
PT814861E (pt) | 1995-03-14 | 2002-09-30 | Siemens Ag | Pulverizador ultra-sonico com uma unidade de dosagem de precisao amovivel |
US6046206A (en) | 1995-06-07 | 2000-04-04 | Cell Pathways, Inc. | Method of treating a patient having a precancerous lesions with amide quinazoline derivatives |
DE19632423A1 (de) | 1996-08-12 | 1998-02-19 | Merck Patent Gmbh | Thienopyrimidine |
WO1998027831A2 (de) | 1996-12-20 | 1998-07-02 | Nutrinova Nutrition Specialties & Food Ingredients Gmbh | Verfahren zur verstärkung der süsskraft und zur geschmacksverbesserung einer mischung hochintensiver süssstoffe |
KR100220953B1 (ko) | 1996-12-31 | 1999-10-01 | 김영환 | 아미드 또는 이미드를 도입한 ArF 감광막 수지 |
GB9711650D0 (en) | 1997-06-05 | 1997-07-30 | Pfizer Ltd | Compounds useful in therapy |
US5954047A (en) | 1997-10-17 | 1999-09-21 | Systemic Pulmonary Development, Ltd. | Methods and apparatus for delivering aerosolized medication |
US5990117A (en) | 1998-04-15 | 1999-11-23 | Cell Pathways, Inc. | Method for inhibiting neoplastic cells and related conditions by exposure to quinazoline derivatives |
MXPA00011773A (es) | 1998-05-28 | 2002-06-04 | Parker Hughes Inst | Quinazolinas para tratar tumores en el cerebro. |
US6169118B1 (en) | 1998-11-12 | 2001-01-02 | Block Drug Company, Inc. | Flavor blend for masking unpleasant taste of zinc compounds |
JP2003500397A (ja) | 1999-05-19 | 2003-01-07 | スミスクライン ビーチャム パブリック リミテッド カンパニー | Mrs阻害剤としての2−nh−ピリドンおよびピリミドン |
GB9915995D0 (en) | 1999-07-09 | 1999-09-08 | Ahmed S | Non-steroidal sulphamate compounds for use as oestrone sulphatase inhibitors |
JP3523166B2 (ja) | 1999-09-02 | 2004-04-26 | 高砂香料工業株式会社 | 食品香料劣化防止剤、食品香料劣化防止方法およびその食品香料劣化防止剤を含有する食品 |
TW201006846A (en) | 2000-03-07 | 2010-02-16 | Senomyx Inc | T1R taste receptor and genes encidung same |
AU5125801A (en) | 2000-04-07 | 2001-10-23 | Senomyx Inc | T2r taste receptors and genes encoding same |
US6468576B1 (en) | 2000-06-23 | 2002-10-22 | Nestec S.A. | Frozen slush liquid concentrate and method of making same |
TW201022287A (en) | 2001-01-03 | 2010-06-16 | Senomyx Inc | T1R taste receptors and genes encoding same |
US6852862B2 (en) | 2001-03-02 | 2005-02-08 | Sumika Fine Chemicals Co., Ltd. | Process for producing quinoline-3-carboxylic acid compound |
US7368285B2 (en) | 2001-03-07 | 2008-05-06 | Senomyx, Inc. | Heteromeric umami T1R1/T1R3 taste receptors and isolated cells that express same |
EP2293067B1 (en) | 2001-06-26 | 2016-04-20 | Senomyx, Inc. | T1R hetero-oligomeric taste receptors and cell lines that express said receptors and use thereof for identification of taste compounds |
CA2452716C (en) | 2001-07-03 | 2012-06-26 | The Regents Of The University Of California | Mammalian sweet and amino acid heterodimeric taste receptors |
US20060134693A1 (en) | 2001-07-06 | 2006-06-22 | Guy Servant | Olfactory cyclic nucleotide-gated channel cell-based assays to identify T1R and T2R taste modulators |
CN100442996C (zh) | 2001-07-19 | 2008-12-17 | 三荣源有限公司 | 味道改良组合物及其应用 |
WO2003022214A2 (en) | 2001-09-06 | 2003-03-20 | Millennium Pharmaceuticals, Inc. | Piperazine and homopiperazine compounds |
US7348433B2 (en) | 2001-12-14 | 2008-03-25 | Merck Frosst Canada & Co. | Quinolinones as prostaglandin receptor ligands |
WO2003055866A1 (en) | 2001-12-21 | 2003-07-10 | Bayer Pharmaceuticals Corporation | Quinazoline and quinoline derivative compounds as inhibitors of prolylpeptidase, inducers of apoptosis and cancer treatment agents |
GB0206033D0 (en) | 2002-03-14 | 2002-04-24 | Pfizer Ltd | Compounds useful in therapy |
AU2003261354A1 (en) | 2002-08-02 | 2004-02-23 | The Regents Of The University Of California | New uses for inhibitors of inosine monophosphate dehydrogenase |
GB0230015D0 (en) | 2002-12-23 | 2003-01-29 | Novartis Ag | Organic compounds |
DE10324548A1 (de) | 2003-05-28 | 2004-12-16 | Nutrinova Nutrition Specialties & Food Ingredients Gmbh | Diätisches Lebensmittel bei einer gewichtskontrollierenden bzw. gewichtsreduzierenden Ernährung |
NZ545747A (en) | 2003-08-06 | 2010-06-25 | Senomyx Inc | T1R hetero-oligomeric taste receptors, cell lines that express said receptors, and taste compounds |
WO2005016889A1 (en) | 2003-08-08 | 2005-02-24 | Virginia Commonwealth University | Compounds having antiestrogenic and tissue selective estrogenic properties |
CA2558683A1 (en) | 2004-03-05 | 2005-09-22 | Sunil Srivastava | High-intensity sweetener-polyol compositions |
WO2005116069A2 (en) | 2004-04-14 | 2005-12-08 | Monell Chemical Senses Center | Taste receptors of the t1r family from domestic dog |
CA2569763C (en) | 2004-06-08 | 2013-03-12 | Decode Chemistry, Inc. | 2,4-diaminoquinazolines for spinal muscular atrophy |
US20060045953A1 (en) | 2004-08-06 | 2006-03-02 | Catherine Tachdjian | Aromatic amides and ureas and their uses as sweet and/or umami flavor modifiers, tastants and taste enhancers |
KR101205568B1 (ko) | 2004-10-15 | 2012-11-27 | 아지노모토 가부시키가이샤 | 감미료 조성물 |
US20080261823A1 (en) | 2004-12-10 | 2008-10-23 | Yitzhak Tor | Fluorescent Nucleoside Analogs That Mimic Naturally Occurring Nucleosides |
JP2008524134A (ja) | 2004-12-17 | 2008-07-10 | エフ.ホフマン−ラ ロシュ アーゲー | Gaba−bアロステリックエンハンサーとしてのチエノ−ピリジン誘導体 |
CA2597134C (en) | 2005-02-04 | 2015-05-26 | Senomyx, Inc. | Compounds comprising linked heteroaryl moieties and their use as novel umami flavor modifiers, tastants and taste enhancers for comestible compositions |
TW200638882A (en) | 2005-02-04 | 2006-11-16 | Senomyx Inc | Molecules comprising linked organic moieties as flavor modifiers for comestible compositions |
US8796441B2 (en) | 2005-04-13 | 2014-08-05 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Human sweet and umami taste receptor variants |
US20080176830A1 (en) | 2005-04-14 | 2008-07-24 | Adams Nicholas D | Compounds, Compositions, and Methods |
RU2007143161A (ru) | 2005-05-25 | 2009-07-10 | Вайет (Us) | Способы синтеза замещенных 3-цианохинов и их продуктов |
AR055329A1 (es) | 2005-06-15 | 2007-08-15 | Senomyx Inc | Amidas bis-aromaticas y sus usos como modificadores de sabor dulce, saborizantes, y realzadores de sabor |
JP2007007591A (ja) | 2005-07-01 | 2007-01-18 | Mikuni Corp | 電解水及びその製造方法 |
CN101277939A (zh) | 2005-09-09 | 2008-10-01 | 布里斯托尔-迈尔斯斯奎布公司 | 无环ikur抑制剂 |
EP1937718B1 (en) | 2005-10-20 | 2017-12-06 | Senomyx, Inc. | Chimeric human sweet-umami and umami-sweet taste receptors |
US8506956B2 (en) | 2005-10-31 | 2013-08-13 | Kaneka Corporation | Method for stabilizing reduced coenzyme Q10 |
AU2006328194A1 (en) | 2005-12-22 | 2007-06-28 | Astrazeneca Ab | Quinazoline derivatives, process for their preparation and their use as anti-cancer agents |
US20090286863A1 (en) | 2006-07-05 | 2009-11-19 | David Bruge | Sulfamatobenzothiophene derivatives |
AU2007288220A1 (en) | 2006-08-22 | 2008-02-28 | Redpoint Bio Corporation | Heterocyclic compounds as sweetener enhancers |
US9603848B2 (en) | 2007-06-08 | 2017-03-28 | Senomyx, Inc. | Modulation of chemosensory receptors and ligands associated therewith |
US8633186B2 (en) | 2007-06-08 | 2014-01-21 | Senomyx Inc. | Modulation of chemosensory receptors and ligands associated therewith |
US7928111B2 (en) | 2007-06-08 | 2011-04-19 | Senomyx, Inc. | Compounds including substituted thienopyrimidinone derivatives as ligands for modulating chemosensory receptors |
CN102170797B (zh) | 2008-07-31 | 2014-02-19 | 西诺米克斯公司 | 包含甜味增强剂的组合物和它们的制备方法 |
WO2010014666A2 (en) | 2008-07-31 | 2010-02-04 | Senomyx, Inc. | Processes and intermediates for making sweet taste enhancers |
JP5988506B2 (ja) | 2010-04-02 | 2016-09-07 | セノミックス インコーポレイテッド | 甘味修飾物質 |
WO2012001547A1 (en) | 2010-06-29 | 2012-01-05 | Firmenich Sa | Active ingredient delivery system |
WO2012021837A2 (en) * | 2010-08-12 | 2012-02-16 | Senomyx, Inc. | Method of improving stability of sweet enhancer and composition containing stabilized sweet enhancer |
US8785481B2 (en) * | 2010-09-29 | 2014-07-22 | Merck Sharp & Dohme Corp. | Ether benzotriazole derivatives |
WO2012054526A2 (en) * | 2010-10-19 | 2012-04-26 | Elcelyx Therapeutics, Inc. | Chemosensory receptor ligand-based therapies |
EP2695899A1 (de) | 2012-08-06 | 2014-02-12 | Basf Se | Polyharnstoff-Elastomere mit erhöhter Chemikalienbeständigkeit |
PE20191204A1 (es) | 2012-08-06 | 2019-09-10 | Firmenich Incorporated | Modificador del sabor dulce |
JO3155B1 (ar) | 2013-02-19 | 2017-09-20 | Senomyx Inc | معدِّل نكهة حلوة |
CN105143421A (zh) | 2013-03-13 | 2015-12-09 | 帝斯曼营养产品股份公司 | 从尿素/油复合物回收尿素和油 |
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