TWI827847B - 環狀緩激肽b2受體拮抗劑、包含其的醫藥組合物、組合製劑和藥劑及其用途 - Google Patents
環狀緩激肽b2受體拮抗劑、包含其的醫藥組合物、組合製劑和藥劑及其用途 Download PDFInfo
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- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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Abstract
本發明係關於一種根據通式(I)之化合物,其充當緩激肽(BK)B2受體拮抗劑;一種醫藥組合物,其含有一或多種本發明之化合物;一種組合製劑,其含有至少一種本發明之化合物及至少一種另外的活性醫藥成分;及前述一或多種化合物之用途,包括作為藥劑之用途。
Description
本發明係關於一種根據通式(I)之化合物,其充當緩激肽(bradykinin;BK)B2受體拮抗劑;一種醫藥組合物,其含有一或多種本發明之化合物;一種組合製劑,其含有至少一種本發明之化合物及至少一種另外的活性醫藥成分;及前述一或多種化合物之用途,包括作為藥劑之用途。
BK係一種肽激素,其藉由活化內皮細胞而參與發炎性過程,導致血管舒張、血管通透性增加、一氧化氮產生及花生四烯酸動員。BK亦刺激感覺神經末梢,引起燒灼觸物感痛。因此,發炎之經典參數(例如,發紅、發熱、腫脹及疼痛)全部皆可由BK形成引起。BK為激肽釋放素-激肽系統之短暫組分。循環BK之濃度在正常生理條件下維持在低水平且可在病理情況下藉由稱為激肽原之循環醣蛋白前驅物之酶降解而快速增加。兩種最有效的激肽原代謝酶為胰蛋白酶樣絲胺酸蛋白酶血漿激肽釋放素及組織激肽釋放素。這些酶之前驅物通常存在於所有組織中且準備好藉由生理或病理生理過程而活化。(Sainz,I.M.等人,Thromb.Haemost.2007,98,77-83)。BK B2受體在組成上表現於大多數細胞及組織類型中且當它產生於血漿或組織中時介導BK之大多數已知的作用。(Regoli,D.等人,Pharmacol.Rev.1980,32,1-46)。大量體內研究顯示,阻斷BK B2受體之劑在諸如氣喘、過敏性鼻炎、胰臟炎、骨關節炎、外傷性腦損傷、阿茲海默氏病及血管性水腫之病理病狀中提供治療益處。
先前技術中描述了BK B2受體之數種肽及非肽拮抗劑。例如WO 2014/159637、WO 2010/031589、WO 2008/116620、WO 2006/40004、WO 03/103671、WO 03/87090、WO 00/23439、WO 00/50418、WO 99/64039、WO 97/41104、WO 97/28153、WO 97/07115、WO 96/13485、EP 0 795 547、EP 0 796 848、EP 0 867 432及EP 1 213 289中揭示了具有作為BK B2受體拮抗劑之活性的喹啉衍生物。然而,這些化合物顯示出許多不足,妨礙了它們作為藥物之實用性,包括代謝穩定性低、生物有效性低、麩胱甘肽加合物之形成及生物活化(毒性),如WO 2014/159637中所揭示。
鑒於先前技術化合物之缺陷及與BK之病理生理水平有關之嚴重病狀(急性及慢性),仍需要一種新穎的BK B2受體拮抗劑。
本發明係鑒於先前技術及上文所述之需要完成,且因此本發明之目標係提供新穎的根據通式(I)之BK B2受體拮抗劑,較佳地具有一或多種改良的性質之BK B2受體拮抗劑,例如改良的藥物動力學及/或生理化學性質,包括生物有效性、溶解度、代謝穩定性及LADME(釋放、吸收、分佈、代謝及排出)性質。本發明之其他目標係提供一種醫藥組合物,其包含至少一種如本文所述之BK B2受體拮抗劑;一種組合製劑,其含有至少一種本發明之化合物及至少一種另外的活性醫藥成分;及本發明之化合物之用途,包括作為藥劑之用途。
這些目標藉由隨附申請專利範圍之標的物解決,如在參考以下描述及定義時將變得顯而易見。
本發明係關於:
其中,A表示以下基團:
A1係N或CH;A2係N或C-RA2;A3係N或C-RA3;A4係NH、O或S;A5係N-RA5;RA1表示氫原子或甲基;RA2及RA3各自彼此獨立地表示氫原子、鹵素原子、OH、CN、NH2;(C1-C3)烷基,其可經一或多個相同或不同的選自鹵素原子、OH、=O及NH2之基團取代;(C1-C3)烷氧基,其可經一或多個相同或不同的選自鹵素原子、OH、=O及NH2之基團取代;(C2-C5)烷氧基烷基,其可經一或多個相同或不同的選自鹵素原子、OH、=O及NH2之基團取代;C(O)NRA6RA7;或NRA6RA7;RA5、RA6及RA7各自彼此獨立地表示氫原子或(C1-C3)烷基,其可經一或多個相同或不同的選自鹵素原子、OH、=O及NH2之基團取代;R1表示(C1-C3)烷基或(C2-C5)烷氧基烷基,前述烷基或烷氧基烷基可經一或多個相同或不同的選自氘原子、鹵素原子、OH、=O及NH2之基團取代;
R2表示氫原子或氘原子;B表示具有至少一個側氧基取代基及n個取代基R之5或6員含氮雜環烷基,其中,n表示數字0、1、2、3、4或5;且各R獨立地在各情況下表示鹵素原子、OH、NRC1RC2、=O、G、OG或(C3-C5)環烷基;RC1及RC2各自彼此獨立地表示氫原子或(C1-C3)烷基;G表示(C1-C6)烷基,其中之1至5個H原子可獨立地在各情況下經鹵素原子、=O、ORG1或NRG2RG3置換,及/或其中之一個CH2基團或兩個不相鄰的CH2基團可經O、C(O)、OC(O)、C(O)O、C(O)NH、NHC(O)、NH、S、SO及/或SO2置換;以及RG1、RG2及RG3各自彼此獨立地表示氫原子、(C1-C3)烷基、(C1-C3)鹵烷基、(C1-C3)羥烷基、(C1-C3)雜烷基或(C3-C5)環烷基。
化合物在本文中通常使用以下呈現之標準命名法或定義進行描述。對於具有不對稱中心之化合物,應理解,除非另外指定,否則涵蓋所有光學異構物及其混合物。具有二或更多個不對稱元素之化合物亦可呈非鏡像異構物之混合物而存在。此外,除非另外指定,否則具有碳-碳雙鍵之化合物可以Z及E形式存在,化合物之所有異構形式均包括在本發明中。當化合物以各種互變異構形式存在時,所列舉之化合物不限於任一種特定互變異構物,而是旨在涵蓋所有互變異構形式。顯而易見的是,本發明之化合物可但不必呈水合物、溶劑合物或非溶劑合物複合物而存在。此外,各種晶形及多形體均在本發明之範疇內,如本發明之化合物之前藥。所列舉之化合物進一步旨在涵蓋一或多個原子經同位素(亦即,原子數相同但質量數不同的原子)置換的化合物。藉助於一般實例且不加以限制,氫之同位素包括氚及氘,且碳之同位素包括11C、13C及14C。
具有一或多個立體異構源中心之根據本文所提供之式之化合物
具有至少50%之鏡像異構物過量。例如,此類化合物可具有至少60%、70%、80%、85%、90%、95%或98%之鏡像異構物過量。化合物之一些實施例具有至少99%之鏡像異構物過量。顯而易見的是,可藉由不對稱合成、自光學純的前驅物合成或藉由拆分外消旋物來獲得單一鏡像異構物(光學活性形式)。外消旋物之拆分可例如藉由習知方法諸如在拆分劑之存在下的結晶或使用例如掌性高效液相層析法(high performance liquid chromatography;HPLC)管柱的層析術來完成。
根據本發明之化合物在本文中使用包括諸如以下之變數的通式來描述:A、A1-A5、B、B1-B7、R、R1-R2、RA1-RA7、RB1-RB7、RB11-RB19、RC1-RC2及RG1-RG3。除非另外指定,否則此一式內之各變數係與任一其他變數獨立地定義,且在式中出現多於一次的任一變數在每次出現時均經獨立定義。因此,例如,若基團顯示經0至2個R*取代,則基團可未經取代或經1或2個基團R*取代,其中R*在每次出現時獨立地選自R*之對應定義。同樣,僅當取代基及/或變數之組合產生穩定的化合物亦即可經分離、表徵及測試生物活性的化合物時,此類組合是允許的。
如本文所用,用詞定義長度範圍之限制例如「1至5」意謂1至5之任一整數,亦即1、2、3、4及5。換言之,明確提及之兩個整數所定義之任一範圍意謂包含且揭示定義前述限制之任一整數及包含在前述範圍中之任一整數。例如,術語「C1-C3」係指1至3(亦即,1、2或3)個碳原子;且術語「C1-C6」係指1至6(亦即,1、2、3、4、5或6)個碳原子。另外,如本文所用之前綴「(Cx-y)」意謂前綴之直接關聯中所指示之鏈、環或呈整體之鏈及環結構之組合可由最少x個且最大y個碳原子(亦即,x<y)組成,其中x及y表示定義鏈之長度(碳原子數)及/或環之大小(環碳原子數)之限制的整數。
本文所揭示之化合物之「藥理學上可接受之鹽」係通常在此項技術中被認為適用於與人類或動物組織接觸而無過度毒性或致癌性,且較佳無刺激、過敏反應或其他問題或併發症。此類醫藥鹽包括鹼性殘基諸如胺之無機鹽
及有機酸鹽以及酸性殘基諸如羧酸之鹼金屬或有機鹽。
合適之醫藥鹽包括但不限於以下酸之鹽,諸如鹽酸、磷酸、氫溴酸、蘋果酸、乙醇酸、反丁烯二酸、硫酸、胺磺酸、磺胺酸、甲酸、甲苯磺酸、甲磺酸、苯磺酸、乙二磺酸、2-羥乙基磺酸、硝酸、苯甲酸、2-乙醯氧基苯甲酸、檸檬酸、酒石酸、乳酸、硬脂酸、柳酸、麩胺酸、抗壞血酸、撲酸、琥珀酸、反丁烯二酸、順丁烯二酸、丙酸、羥基順丁烯二酸、氫碘酸、苯乙酸、烷酸諸如乙酸、HOOC-(CH2)n-COOH(其中n係0至4之任一整數(亦即,0、1、2、3或4)及其類似者。類似地,醫藥學上可接受之陽離子包括但不限於鈉、鉀、鈣、鋁、鋰及銨。熟習此項技術者將認識到本文所提供之化合物之另外的藥理學上可接受之鹽。通常,可藉由任一習知化學方法由含有鹼性或酸性部分之親體化合物合成藥理學上可接受之酸或鹼鹽。簡言之,可藉由將這些化合物之游離酸或鹼形式於水中、或於有機溶劑中、或於兩者之混合物中與化學計量之量之適當鹼或酸反應來製備此類鹽。通常,較佳使用非水性媒介物,諸如醚、乙酸乙酯、乙醇、異丙醇或乙腈。
如本文所用,「取代基」係指共價鍵結至感興趣之分子內之原子的分子部分。例如,環上之取代基可為諸如鹵素原子、烷基、鹵烷基、羥基、氰基或胺基之部分或者共價鍵結至作為環成員之原子較佳碳或氮原子之任一其他取代基。
如本文所用,術語「經取代之」意謂指定原子或基團(例如,烷基、烷氧基、烷氧基烷基、環烷基、雜環烷基、雜芳基)上之任何一或多個氫原子經所指示之取代基之選擇置換,限制條件係不超過所指定之原子之正常價或可能的取代位點之基團數,且取代產生穩定的化合物,亦即可經分離、表徵及測試生物活性的化合物。當取代基係側氧基(亦即,=O)時,則原子上之2個氫經置換。作為芳族碳原子之取代基的側氧基導致-CH-向-C(=O)-的轉化且可導致芳香性損失。例如,經側氧基取代之吡啶基係吡啶酮。指示經單、二、三
或四取代指示具有一個(單)、兩個(三)或四個(四)取代基之基團,限制條件係取代不超過可能的取代位點之數目且產生穩定的化合物。例如,經單取代之咪唑基可為咪唑啶-2-酮基,且經二取代之異噁唑基可為(3,5-二甲基)異噁唑基。
如本文所用,「包含」、「包括」、「含有」、「特徵在於」及其語法等效物係不排除額外未描述之元素或方法步驟之包括性或開放性術語。然而,「包含」等亦分別解釋為包括更具限制性術語「基本上由...組成」及「由...組成」。
如本文所用,「由...組成」排除在申請專利範圍中未指定之任何元素、步驟或成分。
當在本文中使用商標名時,旨在獨立地包括商標名產品調配物、學名藥及商標名產品之活性醫藥成分。
通常,除非另外定義,否則本文所用之技術及科學術語具有與一般熟習本發明所屬之技術者通常所理解的相同含義且與一般教科書及詞典一致。
表述烷基(alkyl或alkyl group)指示含有1至20個碳原子、較佳1至12個碳原子、更佳1至6個碳原子或前綴中所指示之碳原子數的飽和直鏈或支鏈烴基。若烷基經取代,則取代可彼此獨立地藉由分子之個別碳原子之單、二或三取代來進行,例如,1、2、3、4、5、6或7個氫原子可獨立地在各情況下經所指示之取代基之選擇置換。若烷基形成例如鹵烷基、羥烷基、烷胺基、烷氧基或烷氧基烷基之基團之一部分時,前述亦適用。烷基之實例包括甲基、乙基、丙基、異丙基、正丁基、異丁基、二級丁基、三級丁基、正戊基、異戊基、正己基、2,2-二甲基丁基或正辛基,且經取代之烷基或烷基形成基團之一部分的基團之實例包括:鹵烷基,例如三氟甲基或二氟甲基;羥烷基,例如羥甲基或2-羥乙基;及甲氧基甲基。術語「(C1-6)烷基」包括例如H3C-、H3C-CH2-、
H3C-CH2-CH2-、H3C-CH(CH3)-、H3C-CH2-CH2-CH2-、H3C-CH2-CH(CH3)-、H3C-CH(CH3)-CH2、H3C-C(CH3)2-、H3C-CH2-CH2-CH2-CH2-、H3C-CH2-CH2-CH(CH3)-、H3C-CH2-CH(CH3)-CH2-、H3C-CH(CH3)-CH2-CH2-、H3C-CH2-C(CH3)2-、H3C-C(CH3)2-CH2-、H3C-CH(CH3)-CH(CH3)-、H3C-CH2-CH(CH2CH3)-、-CH2CH2CH2CH2CH2CH3、-CH(CH3)CH2CH2CH2CH3、(H3CH2C)CH(CH2CH2CH3)-、-C(CH3)2(CH2CH2CH3)、-CH(CH3)CH(CH3)CH2CH3及-CH(CH3)CH2CH(CH3)2。
表述烷氧基(alkoxy或alkoxy group)係指單鍵結至氧的烷基,亦即-O-烷基。術語「(C1-C6)烷氧基」包括例如甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、二級丁氧基、異丁氧基、三級丁氧基、正戊氧基、三級戊氧基-或正己氧基,且據此(C1-C3)烷氧基包括甲氧基、乙氧基、正丙氧基或異丙氧基。
表述烷氧基烷基(alkoxyalkyl或alkoxyalkyl group)係指單鍵結至一或多個烷氧基之烷基,例如-烷基-O-烷基或-烷基-O-烷基-O-烷基。術語「(C2-C5)烷氧基烷基」包括例如甲氧基甲基、甲氧基乙基、甲氧基正丙基、甲氧基異丙基、甲氧基正丁基、甲氧基二級丁基、甲氧基異丁基、甲氧基三級丁基、甲氧基乙氧基甲基、甲氧基乙氧基乙基、乙氧基甲氧基甲基、乙氧基甲氧基乙基及1-乙氧基乙基。
表述鹵烷基(haloalkyl或haloalkyl group)係指一、二、三或更多個氫原子彼此獨立地經鹵素原子置換的烷基。術語「(C1-C3)鹵烷基」包括例如氟甲基、二氟甲基、三氟甲基、氯甲基、二氯甲基、溴甲基、二溴甲基、碘甲基、(1-或2-)鹵乙基(例如(1-或2-)氟乙基或(1-或2-)氯乙基)、(2-或3-)鹵丙基(例如(2-或3-)氟丙基或(2-或3-)氯丙基)。
表述羥烷基(hydroxyalkyl或hydroxyalkyl group)係指一、二、三或更多個氫原子彼此獨立地經羥基(OH)置換的烷基。術語「(C1-C4)羥烷基」包
括例如羥甲基、羥乙基、羥丙基及羥丁基。
如本文所用,表述雜烷基(heteroalkyl或heteroalkyl group)係指一或多個較佳1、2、3或4個碳原子彼此獨立地經氧、氮、硒、矽或硫原子;較佳經氧、硫或氮原子;C(O);OC(O);C(O)O;C(O)NH;NHC(O);NH;SO;SO2;或經CH=CH基團置換的如上文所定義之直鏈或支鏈烷基,其中前述雜烷基可經取代。例如,「(C1-C4)雜烷基」含有1至4個(例如,1、2、3或4個)碳原子及1、2、3或4個(較佳1、2或3個)選自氧、氮及硫(尤其,氧及氮)之雜原子。雜烷基之實例包括烷胺基、二烷胺基、烷胺基烷基、二烷胺基烷基、醯基、醯基烷基、烷氧基羰基、醯氧基、醯氧基烷基、羧基烷基醯胺、烷氧基羰氧基、烷基胺甲醯基、烷基醯胺基、烷基胺甲醯基烷基、烷基醯胺基烷基、烷基胺甲醯基氧基烷基、烷基脲基烷基、烷氧基、烷氧基烷基或烷硫基。表述烷硫基(alkylthio或alkylthio group)係指一或多個不相鄰的CH2基團經硫置換的烷基,其中烷硫基之烷基部分可經取代。雜烷基之特定實例包括醯基、甲氧基、三氟甲氧基、乙氧基、正丙基氧基、異丙基氧基、三級丁基氧基、甲氧基甲基、乙氧基甲基、甲氧基乙基、甲胺基、乙胺基、二甲胺基、二乙胺基、異丙基乙胺基、甲胺基甲基、乙胺基甲基、二異丙胺基乙基、二甲胺基甲基、二甲胺基乙基、乙醯基、丙醯基、丁醯氧基、乙醯氧基、甲氧基羰基、乙氧基羰基、異丁醯基胺基-甲基、N-乙基-N-甲基胺甲醯基、N-甲基胺甲醯基、氰基、腈、異腈、硫氰酸根、異氰酸根、異硫氰酸根及烷基腈。
表述環烷基(cycloalkyl或cycloalkyl group)係指含有一或多個環(較佳1或2個)且含有3至14個環碳原子、較佳3至10個(更佳3、4、5、6或7個)環碳原子之飽和碳環基團;環烷基可經取代且可呈取代基經由環系之每一合適位置經鍵結。環烷基之實例包括單環烴環、雙環烴環及螺烴環。在雙環環烷基中,兩個環連接在一起,以使得它們具有至少兩個共同的碳原子。在螺烴環中,2或3個環藉由一個共同的碳原子(螺原子)連接在一起。若環烷基經取代,則
取代可彼此獨立地藉由分子之個別環碳原子之單或二取代而發生,且呈整體之環烷基可攜帶所指示之取代基之選擇之1、2、3或4個取代基,亦即環碳原子之1、2、3或4個氫原子可獨立地在各情況下藉由選自所指示之取代基之清單之取代基置換,從而產生經單、二、三或四取代之環烷基。環烷基之實例包括環丙基、環丁基、環戊基、環己基、環庚基、雙環[2.2.0]己基、雙環[3.2.0]庚基、雙環[3.2.1]辛基、雙環[2.2.2]辛基、雙環[4.3.0]壬基(八氫茚基)、雙環[4.4.0]癸基(十氫萘基)、雙環[2.2.1]庚基(降莰基)、雙環[4.1.0]庚基(降蒈基)、雙環[3.1.1]庚基(蒎基)、螺[2.5]辛基及螺[3.3]庚基。若環烷基係部分不飽和的,則基團含有一、二或更多個雙鍵,諸如環烯基,包括環丙烯基、環丁烯基、環戊烯基、環己烯基、環庚烯基、環丁二烯基、環戊二烯基、環己二烯基、雙環[2.2.1]庚二烯基及螺[4,5]癸烯基。
表述雜環烷基(heterocycloalkyl或heterocycloalkyl group)係指一或多個(較佳1、2或3個)環碳原子彼此獨立地經氧、氮或硫原子(較佳氧或氮)或經NO、SO或SO2置換之如上文所定義之飽和或部分不飽和環烷基;雜環烷基可經取代且可呈取代基經由環系之每一合適的位置鍵結;至少一個碳原子必須存在於兩個氧原子之間及兩個硫原子之間或氧原子與硫原子之間;且呈整體之環必須具有化學穩定性。雜環烷基較佳具有1或2個含有3至10個(更佳3、4、5、6或7個,且最佳5、6或7個)環原子之環。雜環烷基之實例包括氮丙啶基、環氧乙烷基、環硫乙烷基、氧氮丙啶基、二環氧乙烷基、吖呾基、氧呾基、硫呾基、二吖呾基、二氧呾基、二硫呾基、吡咯啶基、四氫呋喃基、硫戊環基(thiolanyl)、唑基、噻唑基、異噻唑基、咪唑啶基、吡唑啶基、噁唑啶基、異噁唑啶基、噻唑啶基(thiazolidinyl)、異噻唑啶基、二氧戊環基(dioxolanyl)、二硫戊環基、哌嗪基、嗎啉基、硫嗎啉基、三噁烷基(trioxanyl)、氮雜環庚烷基(azepanyl)、氧雜環庚烷基(oxepanyl)、硫雜環庚烷基(thiepanyl)、高哌嗪基(homopiperazinyl)、伏洛托品基(urotropinyl)、噁唑啶酮基、二氫吡唑基、二氫吡咯基、二氫哌嗪基、二
氫吡啶基、二氫嘧啶基、二氫呋喃基、二氫哌喃基,且經取代之雜環烷基之實例包括內醯胺、內酯及環狀胺甲酸酯、環狀胺甲醯胺以及環狀醯亞胺環系。
如本文所用之表述鹵素或鹵素原子意謂氟、氯、溴或碘。
如本文所用之表述雜原子較佳指示氧、氮或硫原子,更佳氮或氧原子。
本發明較佳係關於以下中之一或多者:
[5]根據[1]至[4]中任一項之化合物或鹽,其中R1表示(C1-C2)烷基或(C2-C4)烷氧基烷基,前述烷基或烷氧基烷基可經一或多個相同或不同的選自鹵素原子及OH之基團取代;
[6]根據[1]至[5]中任一項之化合物或鹽,其中R1表示甲基、乙基、甲氧基甲基、甲氧基乙基或乙氧基甲基,它們可經一或多個相同或不同的選自鹵素原子及OH之基團取代;
[7]根據[1]至[6]中任一項之化合物或鹽,其中R1表示CH3、C2H5、CH2OH、CH2F、CHF2、CF3、CH2CH2OH、CH2CH2F、CH2CF3、CH2OCH3、CH2OCHF2或CH2OCF3;
[8]根據[1]至[7]中任一項之化合物或鹽,其中R1表示CH3、C2H5或CH2OH;
[9]根據[1]至[8]中任一項之化合物或鹽,其中n表示數字0、1、2、3或4;且較佳數字0、1、2或3;
[10]根據[1]至[9]中任一項之化合物或鹽,其中R2表示氫原子;
[11]根據[1]至[9]中任一項之化合物或鹽,其中R2表示氘原子;
其中B1係N-RB1、O或CRB2RB3;B2係CRB4RB5;以及B3係CRB6RB7;RB1表示氫原子、G或(C3-C5)環烷基;
RB2及RB3各自彼此獨立地表示氫原子、鹵素原子、OH、G、OG或NRC1RC2;RB4及RB5各自彼此獨立地表示氫原子、鹵素原子、OH、G或OG;或者RB4及RB5一起形成=O;RB6及RB7各自彼此獨立地表示氫原子、鹵素原子或G;以及G、RC1及RC2係如[1]中所定義;
[13]根據[12]之化合物或鹽,其中最大1、2或3個選自RB1至RB7之環取代基與氫原子不同;
[14]根據[12]或[13]之化合物或鹽,其中B1至B3係如以下(i)至(iii)中任一者所定義:(i)B1係N-RB1;B2係C=O或CH2;且B3係CH2或CH(CH3);(ii)B1係O;B2係CRB4RB5;且B3係CH2或CH(CH3);或者(iii)B1係CRB2RB3;B2係CRB4RB5;且B3係CH2;以及RB1、RB2、RB3、RB4及RB5係如[12]中所定義;
[15]根據[12]至[14]中任一項之化合物或鹽,其中RB2、RB3、RB4、RB5、RB6及RB7中之各者且彼此獨立地表示氫原子、鹵素原子、OH、(C1-C3)烷基、(C1-C3)鹵烷基、(C1-C3)羥烷基、O(C1-C3)烷基或O(C1-C3)鹵烷基;
[16]根據[12]至[15]中任一項之化合物或鹽,其中RB1表示氫原子、(C1-C3)烷基、(C1-C3)鹵烷基、(C1-C3)羥烷基、(C3-C5)環烷基、((C1-C3)烷基)-NRC1RC2或((C1-C3)烷基)-C(O)-NRC1RC2,且RC1及RC2中之各者係如[1]中所定義;
其中B4係C=O或CRB11RB12;B5係N-RB13、O或CRB14RB15;B6係C=O或CRB16RB17;B7係CRB18RB19;RB11、RB12、RB14、RB15、RB16、RB17、RB18及RB19各自彼此獨立地表示氫原子、鹵素原子、G、OH、OG、(C3-C5)環烷基或O(C3-C5)環烷基;RB13表示氫原子、G或(C3-C5)環烷基;以及G係如[1]中所定義;
[19]根據[18]之化合物或鹽,其中最大1、2、3或4個(較佳1、2或3個)選
自RB11至RB19之環取代基與氫原子不同;
[20]根據[18]或[19]之化合物或鹽,其中RB11、RB12、RB14、RB15、RB16、RB17、RB18及RB19中之各者且彼此獨立地表示氫原子、鹵素原子、G1、OH、OG1、(C3-C5)環烷基或O(C3-C5)環烷基;G1表示(C1-C4)烷基,其中之1至3個H原子可獨立地在各情況下經鹵素原子、=O、ORG1或NRG2RG3置換,及/或其中之一個CH2基團或兩個不相鄰的CH2基團可經O、C(O)、OC(O)、C(O)O、C(O)NH、NHC(O)、NH、S、SO及/或SO2置換;以及RG1、RG2及RG3中之各者係如[1]中所定義;
[21]根據[18]至[20]中任一項之化合物或鹽,其中RB11、RB12、RB14、RB15、RB16、RB17、RB18及RB19中之各者且彼此獨立地表示氫原子、鹵素原子、OH、(C1-C3)烷基、(C1-C3)鹵烷基、(C1-C3)羥烷基、O(C1-C3)烷基或O(C1-C3)鹵烷基;
[22]根據[18]至[21]中任一項之化合物或鹽,其中RB13表示氫原子、(C1-C3)烷基、(C1-C3)鹵烷基、(C1-C3)羥烷基或(C3-C5)環烷基;較佳氫原子、(C1-C3)烷基或(C1-C3)鹵烷基;且更佳氫原子或(C1-C3)烷基;
[23]根據[18]至[22]中任一項之化合物或鹽,其中B4至B6係如以下(i)至(v)中任一者所定義:(i)B4係C=O;B5係N-RB13;且B6係CRB16RB17;(ii)B4係CRB11RB12;B5係N-RB13;且B6係C=O;(iii)B4係CRB11RB12;B5係O;且B6係CRB16RB17;(iv)B4係CRB11RB12,B5係N-RB13;且B6係CRB16RB17;或者(v)B4係CRB11RB12,B5係CRB14RB15;且B6係CRB16RB17;B7表示CH2或CH(CH3);RB11、RB12、RB14、RB15、RB16、RB17、RB18及RB19係如[18]、[20]或[21]中任一項所定義;以及
RB13係如[18]或[22]中所定義;
包括根據通式(I)之化合物或其鹽之較佳實施例(亦即,[2]至[25])之合適組合的化合物係特別較佳的;例如,包括如本文所揭示之[1]、[3]、[6]及[9]之組合的化合物或其鹽。換言之,本發明明確涵蓋如上文所指示之[1]至[24]之產生穩定化合物的所有可能組合。
根據本文所提供之[1]至[25]中任一項之化合物對人類BK B2受體表現出高活性,例如,在下文所提及之檢定中,針對BK誘導之BK B2受體活性之抑制常數IC50(半數最大抑制性濃度)係1微莫耳(μM)或更小,例如251奈莫耳(nM)至1μM;較佳IC50係250nM或更小,例如51nM至250nM;更佳IC50係50nM
或更小;甚至更佳IC50係約10nM或更小、或1nM或更小。根據[1]至[25]中任一項之化合物可對人類BK B2受體且亦對除人類以外的其他物種(例如,大鼠、小鼠、沙鼠、天竺鼠、兔、狗、貓、豬或石蟹獼猴)之BK B2受體表現出高活性。
根據本發明之化合物之活性且更特定言之生物活性可使用熟悉此項技術者抑制的適當檢定例如體外或體內檢定來評定。例如,本發明之化合物對B2受體活性之抑制作用(表述為IC50值)可經由細胞內鈣動員(calcium mobilization)檢定來確定,諸如實例14中所提供之檢定,因此其係標準體外B2受體介導之檢定之實施例。根據[1]至[25]中任一項之特別較佳化合物或鹽在標準體外BK B2受體檢定中表現出50nM或更小之IC50;例如,實例14中所提供之檢定。
通式(I)之化合物、其藥理學上可接受之鹽、溶劑合物或水合物之治療用途;以及同樣含有前述之調配物或醫藥組合物之治療用途均在本發明之範疇內。本發明亦關於通式(I)之化合物作為藥劑之製備或製造中之活性成分的用途。
根據本發明之醫藥組合物包含至少一種式(I)化合物或其藥理學上可接受之鹽(較佳如[1]至[25]中任一項之化合物或其鹽)及視情況至少一種(亦即,一或多種)載劑物質、賦形劑及/或佐劑。具體而言,本發明之醫藥組合物可包含一或多種根據本發明之化合物(例如,如[1]至[25]中任一項之化合物)及視情況至少一種載劑物質、賦形劑及/或佐劑。
醫藥組合物可另外包含例如以下中之一或多者:水、緩衝液(例如,中性緩衝鹽水或磷酸鹽緩衝鹽水)、乙醇、礦物油、植物油、二甲亞碸、碳水化合物(例如,葡萄糖、甘露糖、蔗糖或右旋糖)、甘露醇、蛋白、佐劑、多肽或胺基酸(諸如,甘胺酸)、抗氧化劑、螯合劑(諸如,EDTA或麩胱甘肽)及/或防腐劑。
此外,一或多種其他活性成分可(但不必)包括在本文所提供之醫藥組合物中。例如,一或多種本發明之化合物可有利地含於含有至少一種另
外活性醫藥成分的組合製劑中。另外或補充性活性劑或活性醫藥成分較佳係在一或多種對BK B2受體調節有反應的病狀之預防或治療中具有實用性的活性劑或活性醫藥成分,前述病狀包括選自包含以下之群組之病狀:皮膚病症;眼部疾病;耳部疾病;嘴部、喉部及呼吸疾病;胃腸疾病;肝部、膽囊及胰臟疾病;尿路及腎臟疾病;男性生殖器官及女性生殖器官之疾病;激素系統疾病;代謝疾病;心血管疾病;血液病;淋巴疾病;中樞神經系統之病症;腦部病症;肌肉骨骼系統疾病;過敏症;疼痛;傳染病;發炎性病症;損傷;免疫學病症;癌症;遺傳性疾病;及水腫。例如,至少一種本發明之化合物或醫藥學上可接受之鹽可有利地含於包括以下之組合製劑中:抗生素、抗真菌或抗病毒劑;抗組織胺;非類固醇消炎藥;疾病調節抗風濕藥物;細胞生長抑制藥物;具有平滑肌活性調節活性之藥物;抗體;或呈另外或補充性活性劑或活性醫藥成分之前述各者之混合物。
本發明之醫藥組合物或組合製劑可經調配以供任何適當的投與方式,包括例如局部(例如,經皮或眼部)、經口、經頰、經鼻、經陰道、經直腸或腸胃外投與。如本文所用之術語腸胃外包括皮下、皮內、血管內(例如,靜脈內)、肌肉內、經脊椎、顱內、鞘內、眼內、眼周、眶內、滑膜內及腹膜內注射以及任何類似注射或輸注技術。在某些實施例中,以合適於經口之形式的組合物係較佳的。此類形式包括例如錠劑、喉錠、口含錠、水性或油性懸液劑、可分散粉劑或顆粒劑、乳劑、硬質或軟質膠囊或者糖漿或酏劑。在其他實施例中,本文所提供之組合物可調配為凍乾物。針對某些病狀(例如,在諸如燒傷或癢病之治療中),較佳可為用於局部投與之調配物。簡言之,醫藥組合物以及組合製劑可例如調配為氣溶膠、霜劑、凝膠、丸劑、膠囊、糖漿、溶液、經皮貼片劑或醫藥遞送裝置。
為了預防及/或治療由BK或其類似物介導之疾病,根據本發明之生物活性化合物之劑量可在很寬的範圍內變化且可根據個別需要進行調整。根
據本發明之活性化合物通常以治療有效量投與。較佳劑量範圍係每天每公斤體重約0.1mg至約140mg(每天每患者約0.5mg至約7g)。日劑量可呈單一劑量或以複數個劑量之形式投與。可與載劑材料組合以產生單一劑型之活性成分之量將視所治療宿主及特定投與模式而變化。劑量單位形式通常將含有約1mg至約500mg之間的活性成分。
然而,應理解,任一具體患者之特定劑量水平將取決於多種因素,包括所採用之特定化合物之活性、年齡、體重、一般健康狀況、性別、膳食、投與時間、投與途徑及排泄速率、藥物組合(亦即,用於治療患者之其他藥物)及經歷治療之具體疾病之嚴重程度。
本文所提供之通式(I)化合物亦可在多種應用(體外及體內)中用作BK B2受體之拮抗劑。根據本發明之BK B2受體拮抗劑可用於抑制BK B2受體配體(例如,BK)在體外或體內與BK B2受體結合。此用途包括例如抑制BK在體外或體內與BK B2受體結合之方法,其中前述方法包含在各條件下且以足以可偵測地抑制BK或任一其他物質與BK B2受體結合之量使BK B2受體與至少一種根據本發明(例如,根據[1]至[25]中任一項)之化合物或鹽接觸。本文所提供之BK B2受體拮抗劑較佳經口或局部向患者(例如,人類)投與,且存在於患者之至少一種體液或組織內同時調節BK B2受體活性。
根據[1]至[25]中任一項之BK B2受體拮抗劑,根據本發明之醫藥組合物或組合製劑可用作藥劑。具體而言,根據本發明之BK B2受體拮抗劑、醫藥組合物或組合製劑可用於治療及/或預防及/或防治對BK B2受體調節有反應的病狀或疾病。對BK B2受體調節有反應的病狀或疾病可為:皮膚病症;眼部疾病、耳部疾病;嘴部、喉部及呼吸疾病;胃腸疾病;肝部、膽囊及胰臟疾病;尿路及腎臟疾病;男性生殖器官及女性生殖器官之疾病;激素系統疾病;代謝疾病;心血管疾病;血液病;淋巴疾病;中樞神經系統之病症;腦部病症;肌肉骨骼系統疾病;過敏症;疼痛;傳染病;發炎性病症;損傷;免疫學病症;癌症;
遺傳性疾病;水腫;或毛細血管滲漏症候群。在下文中進一步指定了上文指示之對BK B2受體調節有反應的疾病及病狀。
皮膚病症:在本發明中,術語「皮膚病症」涵蓋但不限於以下病症,諸如:皮膚老化;皮膚發疹,包括壓瘡,褥瘡,受刺激、敏感性及觸物感痛性皮膚,紅斑,皮疹,皮膚水腫,乾癬,濕疹,苔蘚;細菌、病毒、真菌及寄生蟲誘導之皮膚感染,包括癤、膿腫、蜂窩組織炎、丹毒、毛囊炎及膿皰病、蝨、疥瘡及單純皰疹;痤瘡;疹病;皮膚炎,包括異位性皮膚炎、過敏性接觸性皮膚炎(Scholzen,T.E.,Luger,T.A.,Exp Dermatol.2004;13增刊4:22-6)、神經皮膚炎;輻射損害;曬傷;搔癢症;搔癢;蕁麻疹(EP0622361;Frigas,E.,Park,M.,Immunol.Allergy Clin.North Am.2006,26,739-51;Luquin,E.,Kaplan,A.P.,Ferrer,M.,Clin.Exp.Allergy 2005,35,456-60;Kaplan,A.P.,Greaves,M.W.,J.Am.Acad.Dermatol.2005,53,373-88;quiz 389-92);乾癬;黴菌病;組織潰瘍;水皰性表皮鬆解症;創傷,包括創傷癒合異常、燒傷(Nwariaku,F.E.,Sikes,P.J.,Lightfoot,E.,Mileski,W.J.,Baxter,C.,Burns 1996,22,324-7;Neely,A.N.,Imwalle,A.R.,Holder,I.A.,Burns 1996,22,520-3)、凍瘡;皮膚發炎;及由毒液引起之水腫;禿髮;毛髮鱗屑;雞眼;疣;及瘭疽。
眼部疾病:在本發明內,術語「眼部疾病」涵蓋但不限於:發炎性病症,諸如鞏膜炎、結膜炎、結膜水腫、虹膜炎、虹膜睫狀體炎、眼色素層炎、脈絡膜視網膜炎;以及諸如視網膜脈絡膜循環病症之病症;細菌眼部感染;非特異性結膜炎及眼部刺激;早產兒視網膜病變;增殖性玻璃體視網膜病變;黃斑變性(包括年齡相關之黃斑變性且包括濕性及乾性形式);角膜疾病,包括角膜移植物排斥、角膜損傷、角膜結疤、角膜潰瘍、角膜霧化、圓錐角膜;青光眼(較佳隅角開放性青光眼);近視;高眼壓症;眼血管損害;血管生成;眼部纖維化(例如,前囊下纖維化、後囊下混濁、後囊混濁、雷射手術後角膜霧化、青光眼手術後結膜下結疤);增殖性玻璃體視網膜病變(PVR);細菌眼部
感染,包括麥粒腫及睫毛脫落。
耳部疾病:在本發明內,術語「耳部疾病」涵蓋但不限於以下病症,諸如梅尼爾氏病、中耳發炎、外聽道發炎及急性聽力喪失。
嘴部、喉部及呼吸疾病:在本發明內,術語「嘴部、喉部及呼吸疾病」涵蓋但不限於以下病症,諸如:口腔黏膜及牙齦之發炎,包括口瘡及口炎;牙周炎;會厭炎;咽炎;喉氣管炎;扁桃腺炎;普通感冒;咽峽炎;鼻炎,包括季節性過敏性鼻炎或常年性過敏性鼻炎;鼻漏;任何類型、病因或發病機制的竇炎或是選自由化膿性或非化膿性竇炎、急性及慢性竇炎以及篩、額、上頜或蝶竇炎組成之群組之成員的竇炎;咳痰;任何類型或成因的塵肺症,包括例如礬土肺、煤肺、石棉肺、石末肺、鐵肺、矽肺、煙塵肺及特別是棉塵肺;支氣管炎;咳嗽;氣管炎;充血;肺炎;嗜伊紅性肺浸潤;慢性嗜伊紅性肺炎;特發性肺纖維化及其他纖維化肺部疾病;與例如放射、胺甲喋呤、化學療法、胺碘酮或硝基呋喃妥因相關之治療相關纖維化肺部疾病;類肉瘤;急性呼吸窘迫症候群(acute respiratory distress syndrome;ARDS);支氣管收縮;任何類型(Akbary,A.M.,Wirth,K.J.,Scholkens,B.A.,Immunopharmacology 1996,33,238-42;WO 00/75107 A2)、病因或發病機制的氣喘或者是選自異位性氣喘、非異位性氣喘、過敏性及非過敏性氣喘、由環境因素引起之外源性氣喘、由病理生理紊亂引起之內生性氣喘、支氣管氣喘、IgE介導之氣喘、自發性氣喘及未知或不明顯原因之自發性氣喘、真性氣喘、氣腫性氣喘、運動誘導之氣喘、職業性氣喘、由細菌、真菌、原蟲或病毒感染引起之感染性氣喘、初期氣喘、嬰兒氣喘症候群(wheezy infant syndrome)之群組之成員的氣喘;支氣管高反應性;慢性阻塞性肺病(chronic obstructive pulmonary disease;COPD),特徵在於不可逆進行性氣道阻塞之COPD;急性呼吸窘迫症候群(ARDS);及其他藥物療法之後氣道高反應性之惡化;呼吸困難;高氧肺泡損傷;肺氣腫;肋膜炎;結核病;高海拔暴露,亦即急性高山病及較佳高空肺水腫(high altitude pulmonary edema;
HAPE);抗性咳嗽;支氣管低反應性。
胃腸疾病:在本發明內,術語「胃腸疾病」涵蓋但不限於以下病症,包括:食道炎;胃炎;胃激躁(irritable stomach);胃及十二指腸潰瘍;腸阻塞;結腸激躁;發炎性腸病,包括克羅恩氏病及潰瘍性結腸炎;腸炎;高血壓性胃病及結腸病;結腸炎;腹膜炎;闌尾炎;直腸炎;由門脈高壓引起之胃腸道出血;側枝循環或充血;胃切除後傾食症候群;消化不適;腹瀉;痔瘡;蟲病;腹絞痛;及胃腸系統之部分絞痛。
肝部、膽囊及胰臟疾病(Cugno,M.,Salerno,F.,Nussberger,J.,Bottasso,B.,Lorenzano,E.,Agostoni,A.,Clin.Sci.(Lond)2001,101,651-7;WO 01/56995 A1;EP0797997 B1;Wirth,K.J.,Bickel,M.,Hropot,M.,Gunzler,V.,Heitsch,H.,Ruppert,D.,Scholkens,B.A.,Eur.J.Pharmacol.1997,337,45-53):在本發明內,術語「肝部及膽囊疾病」涵蓋但不限於以下病症,諸如:肝炎、肝硬化、肝纖維化(例如,歸因於病毒(HBV/HCV)感染、毒素(酒精)、脂肪肝、膽汁鬱積、缺氧)、門脈高壓、肝腎症候群、肝原性水腫、膽管炎、膽囊炎、急性及慢性胰臟炎及膽道絞痛。
尿路及腎臟疾病:在本發明內,術語「尿路及腎臟疾病」涵蓋但不限於:尿路感染,諸如急性及慢性膀胱炎、間質性膀胱炎(Campbell,D.J.,Clin.Exp.Pharmacol.Physiol.2001,28,1060-5;Meini,S.,Patacchini,R.,Giuliani,S.,Lazzeri,M.,Turini,D.,Maggi,C.A.,Lecci,A.,Eur.J.Pharmacol.2000,388,177-82;Zuraw,B.L.,Sugimoto,S.,Parsons,C.L.,Hugli,T.,Lotz,M.,Koziol,J.,J.Urol.1994,152,874-8;Rosamilia,A.,Clements,J.A.,Dwyer,P.L.,Kende,M.,Campbell,D.J.,J.Urol.1999,162,129-34);膀胱激躁;膀胱過動症(WO 2007003411 A2);失禁,包括但不限於應力性失禁、急迫性失禁及反射性失禁;良性攝護腺肥大(Srinivasan,D.,Kosaka,A.H.,Daniels,D.V.,Ford,A.P.,Bhattacharya,A.,Eur J Pharmacol.2004,504(3):155-67);慢性腎病;尿道炎;發
炎性腎病,包括腎絲球腎炎、腎絲球腎病、間質性腎炎、腎盂腎炎;多尿症;蛋白尿;利尿鈉;利尿鈣(calciuresis);水平衡失調;電解質平衡失調;酸鹼平衡失調;及腎絞痛;腎纖維化;慢性腎同種異體移植物功能障礙;顯影劑誘導之腎病變。
男性生殖器官及女性生殖器官之疾病:在本發明內,術語「男性生殖器官及女性生殖器官之疾病」涵蓋但不限於精子活力改變、男性不育症、睪丸炎、攝護腺炎、攝護腺肥大、乳腺炎、發炎性骨盆疾病、陰道感染及疼痛、子宮附件炎、陰道炎、軟下疳、梅毒、淋病及卵巢過度刺激症候群(Ujioka,T.,Matsuura,K.,Tanaka,N.,Okamura,H.,Hum Reprod.1998年11月;13(11):3009-15.)。
激素系統疾病:在本發明內,術語「激素系統疾病」涵蓋但不限於月經失調及疼痛、更年期紊亂、嘔吐、早產子宮收縮、早產陣痛、子宮內膜異位、子宮內膜炎、肌瘤、子癇前症。
代謝疾病:在本發明內,術語「代謝疾病」涵蓋但不限於以下病症,諸如:糖尿病,包括非胰島素依賴性糖尿病;糖尿病視網膜病變;糖尿病黃斑部水腫(Speicher,M.A.,Danis,R.P.,Criswell,M.,Pratt,L.,Expert Opin.Emerg.Drugs 2003,8,239-50;Gao,B.B.,Clermont,A.,Rook,S.,Fonda,S.J.,Srinivasan,V.J.,Wojtkovvski,M.,Fujimoto,J.G.,Avery,R.L.,Arrigg,P.G.,Bursell,S.E.,Aiello,L.P.,Feener,E.P.,Nat.Med.2007,13,181-8;Tranos,P.G.,Wickremasinghe,S.S.,Stangos,N.T.,Topouzis,F.,Tsinopoulos,I.,Pavesio,C.E.,Surv.Ophthalmol 2004,49,470-90);糖尿病腎病變及糖尿病神經病變;胰島素抗性及糖尿病潰瘍;蛋白代謝及嘌呤代謝疾病,諸如痛風及脂肪代謝病症;低血糖。
心血管疾病:在本發明內,術語「心血管疾病」涵蓋但不限於以下病症,包括:血管通透性、血管舒張、末梢性循環病症;動脈循環病症,包括主動脈瘤、腹主動脈瘤、腦主動脈瘤;與白血病有關之高血壓及低血壓;經
皮穿腔冠狀動脈血管成形術之後的再狹窄;動脈粥樣硬化,包括動脈粥樣硬化斑塊破裂(Fernando,A.N.,Fernando,L.P.,Fukuda,Y.,Kaplan,A.P.,Am J Physiol Heart Circ Physiol.2005年7月;289(1):H251-7);血管瘤;血管纖維瘤;靜脈病症,諸如血栓、靜脈曲張、靜脈炎、血栓靜脈炎、靜脈栓塞;心臟病;鬱血性心臟衰竭;冠狀動脈心臟病;類癌症候群;心絞痛;心臟節律異常;發炎性心臟病,包括心內膜炎、心包炎及束縮性心包炎;心肌炎;心肌梗塞;心肌梗塞後症候群;左心室擴大;缺血再灌注後損傷;休克及虛脫,包括敗血性、過敏性、創傷後及低血容積休克;羊水栓塞(Robillard,J.,Gauvin,F.,Molinaro,G.,Leduc,L.,Adam,A.,Rivard,G.E,Am J Obstet Gynecol.2005年10月;193(4):1508-12.);全身性發炎反應症候群(systemic inflammatory response syndrome;SIRS),包括在手術期間由心肺分流引起之SIRS;敗血症;及在心肺分流手術期間的內部及外部併發症,包括但不限於肝素之硫酸魚精蛋白反轉之後不良的血流動力學作用(Pretorius,M.,Scholl,F.G.,McFarlane,J.A.,Murphey,L.J.,Brown,N.J.,.Clin Pharmacol Ther.2005年11月;78(5):477-85)。
血液病:在本發明內,術語「血液病」涵蓋但不限於以下病症,諸如凝血、瀰漫性血管內凝固症、出血、出血性素質、高膽固醇血症及高脂血症、血容積過少性休克、陣發性夜間血紅素尿症。
淋巴疾病:在本發明內,如本文所用之術語「淋巴疾病」涵蓋但不限於脾腫大、淋巴管炎、淋巴腺炎及腺樣增生。
中樞神經系統之病症:在本發明內,術語「中樞神經系統之病症」涵蓋但不限於以下病症,諸如:中樞神經系統之發炎性疾病,包括腦炎、腦膜炎、腦脊髓炎、腦膜腦炎;水腦;肌萎縮性脊髓側索硬化症;脊髓創傷;脊髓水腫;神經系統之髓鞘脫失病;多發性硬化症;急性及慢性神經退化性病症,包括老化、阿茲海默氏病及帕金森氏病;神經炎及周邊神經病變;抑鬱;厭食症;焦慮及精神分裂症;睡眠障礙。
腦部病症:在本發明內,術語「腦部病症」涵蓋但不限於以下病症,包括:聰明藥或認知增強、類澱粉腦血管病變、中風、頭部及腦部創傷、外傷性腦損傷(Marmarou,A.,Guy,M.,Murphey,L.,Roy,F.,Layani,L.,Combal,J.P.,Marquer,C.,American Brain Injury Consortium J Neurotrauma 2005年12月;22(12):1444-55)、腦腫瘤、大腦熱損害、大腦缺血、大腦出血、創傷後及缺血後大腦水腫、一般腦水腫、急性高山病及較佳高山腦水腫(HACE)、細胞毒性腦水腫、血管性腦水腫、手術後腦水腫、與代謝疾病有關之腦水腫、血腦障壁或血腦腫瘤障壁之滲透性增加。
肌肉骨骼系統疾病:在本發明內,術語「肌肉骨骼系統疾病」涵蓋但不限於以下病症,諸如:發炎性肌肉骨骼病症;關節病;非炎性骨關節病;骨關節炎;關節創傷之後或半月板或膝蓋骨損傷或韌帶撕裂之後相對長時間固定關節之後的軟骨稀鬆;任何類型、病因或發病機制之風濕性關節炎,包括急性關節炎、急性痛風性關節炎、慢性發炎性關節炎、退化性關節炎、傳染性關節炎、萊姆關節炎、增生性關節炎、脊椎關節炎、敗血性關節炎、牛皮癬性關節炎、慢性多發性關節炎;風濕病;修格連氏症候群;腰痛;脊椎炎;椎關節炎;關節黏連性脊椎炎;骨髓炎;扭傷;腱鞘炎;發炎誘導之骨吸收;骨折或其類似者;骨質疏鬆症;肌肉骨骼疼痛及硬化;椎間盤症候群。
過敏症:在本發明內,術語「過敏症」涵蓋但不限於以下病症,諸如:一般過敏性反應;食物過敏;過敏性休克;過敏性接觸性過敏症;過敏性皮膚反應;過敏性氣喘;春季型結膜炎;及季節性或常年性過敏性鼻炎(Summers,C.W.,Pumphrey,R.S.,Woods,C.N.,McDowell,G.,Pemberton,P.W.,Arkwright,P.D.J Allergy Clin Immunol.2008,121(3),632-638)。
疼痛:在本發明內,術語「疼痛」涵蓋但不限於:中樞及周邊介導之疼痛;血管性疼痛;內臟性疼痛;發炎性介導之疼痛;神經痛性疼痛;轉移疼痛;傷害感受性疼痛;反射性疼痛;身心疼痛,諸如由急性損傷引起之急
性疼痛;骨、肌肉、組織、軟組織、器官之創傷或手術;蟲咬之後的疼痛;中風後疼痛症候群;手術後疼痛;與疼痛有關之進行性疾病,諸如由神經病性疼痛病狀引起之慢性疼痛(包括但不限於複雜性局部疼痛症候群(WO00/75107 A2;Yamaguchi-Sase,S.,Hayashi,I.,Okamoto,H.,Nara,Y.,Matsuzaki,S.,Hoka,S.,Majima,M.,Inflamm.Res.2003,52,164-9;Petersen,M.,Eckert,A.S.,Segond von Banchet,G.,Heppelmann,B.,Klusch,A.,Kniffki,K.D.,Neuroscience 1998,83,949-59;Birklein,F.,Schmelz,M.,Schifter,S.,Weber,M.,Neurology 2001,57,2179-84;Weber,M.,Birklein,F.,Neundorfer,B.,Schmelz,M.Pain 2001,91,251-7)、灼熱痛、morbus sudeck、反射性交感神經失養症);糖尿病周邊神經病變;皰疹後神經痛;三叉神經痛;癌症相關疼痛;與類風濕性關節炎、骨關節炎(Bond,A.P.,Lemon,M.,Dieppe,P.A.,Bhoola,K.D.,Immunopharmacology 1997,36,209-16;Cassim,B.,Naidoo,S.,Ramsaroop,R.,Bhoola,K.D.,Immunopharmacology 1997,36,121-5;Calixto,J.B.,Cabrini,D.A.,Ferreira,J.,Campos,M.M.Pain 2000,87,1-5;Kaneyama,K.,Segami,N.,Sato,J.,Fujimura,K.,Nagao,T.,Yoshimura,H.,J.Oral.Maxillofac.Surg.2007,65,242-7)、腱鞘炎、痛風、月經及咽峽炎有關之疼痛;纖維肌痛;眼部疼痛;背部疼痛;頭痛;叢發性頭痛;偏頭痛(Ebersberger,A.,Ringkamp,M.,Reeh,P.W.,Handwerker,H.O.,J Neurophysiol.1997年6月;77(6):3122-33);可能與急性發炎或慢性發炎有關之發炎性疼痛。發炎性疼痛包括但不限於:神經病性疼痛、缺血性疼痛;由關節炎誘導之疼痛;由急性或慢性發炎誘導之肌肉疼痛;由急性或慢性發炎誘導之神經痛;痛覺過敏。同樣,化學療法誘導之周邊神經病變、痛覺過敏、鴉片類誘導之痛覺過敏及發熱。另外,本發明之化合物可用作在全身麻醉及監測麻醉期間使用之鎮痛劑。
傳染病:在本發明內,術語「傳染病」涵蓋但不限於以下疾病,包括由細菌、病毒、真菌、寄生蟲、原生動物、普里昂蛋白或分枝桿菌感染介
導之疾病。較佳地,本發明可用於治療由鏈球菌屬(Streptococcus)、埃希氏菌屬(Escherichia)、沙門氏菌屬(Salmonella)、葡萄球菌屬(Staphylococcus)、克雷伯氏菌屬(Klebsiella)、莫拉菌屬(Moracella)、嗜血桿菌屬(Haemophilus)及耶氏桿菌屬(Yersinia)引起之細菌感染。意欲在本發明之範疇內之細菌感染之實例包括但不限於以下疾病,諸如鼠疫、敗血症、流行性斑疹傷寒、食物中毒、破傷風、猩紅、百日咳、白喉。意欲在本發明之範疇內之病毒感染之實例包括但不限於以下疾病,諸如水痘及帶狀皰疹、AIDS、流行性感冒、天花及兒童疾病諸如麻疹、風疹、腮腺炎、急性脊髓前灰白質炎。本發明可用於治療由曼森血吸蟲、屋塵蟎及三日瘧原蟲引起之原生動物及寄生蟲感染。意欲在本發明之範疇內之普恩蛋白感染之實例包括但不限於以下疾病,諸如牛海綿狀腦病(bovine spongiform encephalopathy;BSE)、庫賈氏病及庫魯病、登革熱、出血熱。
發炎性病症:在本發明內,術語「發炎性病症」涵蓋但不限於以下病症,諸如急性期反應;局部及全身發炎;及由其他任何類型、病因或發病機制之疾病引起及由在本發明中指定之發炎性疾病引起之發炎。
損傷:在本發明內,術語「損傷」涵蓋但不限於多發性創傷;頭部創傷;肺損傷;外部、內部及手術創傷。
免疫學病症:在本發明內,術語「免疫學病症」涵蓋但不限於以下病症,諸如:感覺過敏、自體免疫病症、移植中之移植物排斥、移植體毒性、肉芽腫性發炎/組織重塑、重症肌無力、免疫抑制、免疫複合體病、抗體之過度產生及產生不足、脈管炎、移植物功能延遲、狼瘡。
癌症:在本發明內,術語「癌症」涵蓋但不限於以下病症,諸如:實體腫瘤癌症,包括乳癌、肺癌(非小細胞肺癌及小細胞肺癌)、攝護腺癌、口腔及咽(唇部、舌頭、嘴巴、咽)癌、食道癌、胃癌、小腸癌、大腸癌、結腸癌、直腸癌、膽囊及膽道癌、胰臟癌、喉癌、肺癌、骨癌、骨肉瘤、結締組織癌、皮膚癌(包括卡波西氏症候群、黑色素瘤及皮膚轉移)、表皮樣癌、基
底細胞癌、子宮頸癌、子宮體內膜癌、卵巢癌、睪丸癌、膀胱癌、輸尿管及尿道癌、腎癌、眼癌、腦及中樞神經系統癌、腦假瘤、肉瘤、肉狀瘤、甲狀腺及其他內分泌腺癌(包括但不限於類癌瘤)、霍奇金氏病、非霍奇金氏淋巴瘤、多發性骨髓瘤、造血惡性腫瘤(包括白血病及淋巴瘤包括淋巴球性淋巴瘤、顆粒球性淋巴瘤及單核球性淋巴瘤)、腫瘤侵入、轉移、腹水、腫瘤生長及血管生成。
遺傳性疾病:在本發明內,術語「遺傳性疾病」涵蓋但不限於以下病症,諸如:遺傳性血管性水腫(Davis,A.E.等人.,3rd Transfus.Apher.Sci.2003,29,195-203;Zuraw,B.L.,Immunol.Allergy Clin.North Am.2006,26,691-708;Bas,M.等人,.Allergy 2006,61,1490-2)及血管神經病性水腫、軟骨鈣化症、亨汀頓氏舞蹈病、膠稠性黏液病。
水腫:在本發明內,術語「水腫」涵蓋但不限於:一般水腫及由發炎引起之水腫;因子XII缺乏誘導之水腫;其他藥物例如藥物誘導之血管性水腫,包括但不限於血管收縮素轉化酶抑制劑誘導之血管性水腫(Mathelier-Fusade,P.,Clin.Rev.Allergy lmmunol.2006,30,19-23;Finley,C.J.等人,Am.J.Emerg.Med.1992,10,550-2;Bielory,L.等人,Allergy Proc.1992,13,85-7);感染;燒傷;損傷;創傷;凍瘡;手術;扭曲;骨折;暴露於高空(例如,高空肺水腫(HAPE)及高空腦水腫(high altitude cerebral edema;HACE));遺傳性、自體免疫及其他疾病及病症,具體而言但不限於本發明中所指定之那些病症;壓力誘導之腸水腫(稱為腫脹)。
毛細血管滲漏症候群:在本發明內,術語「毛細血管滲漏症候群」涵蓋但不限於敗血症(Marx,G.,Eur J Anaesihesiol.2003 20(6):429-42;Traber,D.L.,Crit Care Med.2000,28(3):882-3)、燒傷(Jonkam,C.C.,Enkhbaatar,P.,Nakano,Y.,Boehm,T.,Wang,J.,Nussberger,J.Esechie,A.,Traber,L.D.,Herndon,D.,Traber,D.L.,Shock.2007年12月;28(6):704-9)、過敏、藥物/毒素誘導之病狀、
器官移植及IL-2細胞介素療法中之全身性毛細血管滲漏症候群。
根據本發明之化合物亦可用作診斷劑或用於製造診斷劑。此一診斷劑尤其可用於診斷本文所揭示之可出於治療及/或預防目的由本發明之化合物處理之疾病及病狀。根據本發明之化合物亦可用於在如本文在下文中所揭示之特定方法及診斷。
方法及診斷:本發明之化合物可藉由同位素、螢光或發光標誌物、抗體或抗體片段、任何其他親和標記(如奈米抗體、適配體、肽等)、酶或酶底物進行標記。本發明之這些經標記之化合物可用於在體內、離體、體外及原位(例如,經由自動放射攝影術在組織切片中)且作為正電子發射斷層攝影術(positron emission tomography;PET)成像、單光子發射電腦斷層攝影術(single photon emission computerized tomography;SPECT)及其類似者表徵活體受試者中之彼等受體或其他材料的放射示蹤劑來映射緩激肽受體之定位。
本發明亦關於用於在體外及體內改變緩激肽受體之訊號轉導活性的方法。例如,本發明之化合物及其經標記之衍生物可用作確定潛在藥品結合至BK B2受體之能力中之標準及試劑。
本發明亦提供用於定位或偵測組織較佳組織切片中之BK B2受體之方法,前述方法涉及將含有BK B2受體之組織樣品與經可偵測標記之根據本發明之化合物在允許化合物與BK B2受體結合之條件下接觸以及偵測經結合之化合物。此類方法及它們各自條件係熟習此項技術者已知的且包括例如實例14中所揭示之結合檢定。
本發明進一步提供一種用於治療患有對如上文所提及之BK B2受體調節有反應的病狀或疾病之患者的方法。用於治療需要此類治療的受試者之方法包含投與根據本發明(例如,根據[1]至[25]中任一項)之化合物、其醫藥學上可接受之鹽、如本文所揭示之醫藥組合物或如本文所揭示之組合製劑。如本文所用,術語「治療」涵蓋疾病修飾治療及症狀性治療,其各自可係預防性(亦
即,在症狀發作之前,為了預防、延遲症狀或降低症狀之嚴重程度)或治療性(亦即,在症狀發作之後,為了降低症狀之嚴重程度及/或減少症狀之持續時間)。若BK B2受體活性之調節導致病狀或其症狀之減輕,則前述病狀「對BK B2受體調節有反應」。患者可包括但不限於靈長類動物(尤其是人類)、經馴養之同伴動物(諸如狗、貓、馬)及牲畜(諸如牛、豬、綿羊),劑量如本文所述。
當與目前最佳技術中已知的BK B2受體拮抗劑相比時,根據本發明之通式(I)化合物具有改良之性質,尤其是,一或多種改良之藥物動力學及/或生理化學性質,包括例如生物有效性、代謝穩定性、改良之活性/敏感度、低毒性及低藥物間相互作用。因此,本文所揭示之化合物(或其醫藥學上可接受之鹽)、醫藥組合物或組合製劑可用作藥劑。例如,本文所揭示之化合物(或其醫藥學上可接受之鹽)、醫藥組合物或組合製劑可用於治療及/或預防對BK B2受體調節有反應的病狀,包括例如上文所列出之病狀。
現藉由以下實例進一步說明本發明,自以下實例可得到本發明之進一步特徵、實施例及優點。然而,本發明不應解釋為限於實例,而是涵蓋申請專利範圍中所定義之主題。
[實例]
以下合成實例中所用之縮寫係如下:ACN係乙腈;Boc係三級丁基氧基羰基;DCM係二氯甲烷;DIPEA係乙基-二異丙基-胺;DMF係二甲基甲醯胺;EA係乙酸乙酯;HATU係(1-[雙(二甲胺基)亞甲基]-1H-1,2,3-三唑[4,5-b]吡啶3-氧六氟磷酸
鹽;HPLC係高效液相層析法;R f 係滯留因子;NMP係N-甲基吡咯啶酮;RT係室溫;TBAF係四丁基氟化銨;THF係四氫呋喃;TLC係薄層層析法;sat係飽和。
以下實例中提供式(I)化合物之製備之特定實施例。除非另外指定,否則所有起始材料及試劑均屬於標準商業級別,且在無進一步純化之情況下即使用,或可藉由常規方法容易地由此類材料製備。熟習有機合成之技術者將認識到,可改變起始材料及反應條件,包括產生本發明所涵蓋之化合物之額外步驟。
實例1:化合物編號1之製備
(S)-2-(3-(1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-2,5-二側氧基咪唑啶-1-基)乙醯胺。
步驟A. 3-胺基-5-氟-2-甲基苯甲酸甲酯之合成
將5-氟-2-甲基-3-硝基苯甲酸甲酯[Gillmore,A.T.等人,Org.Process Res.Dev.
2012,16,1897-1904](4.69g;22mmol)溶解於MeOH(100mL)中並添加在活性炭上之鈀-10% Pd(200mg)。將溶液用氮氣沖洗並真空化三次,之後用氫氣沖洗。將反應混合物在1atm氫氣下劇烈攪拌。在入TLC所指示之反應完成之後(21h),將溶液經由矽膠過濾。以甲醇(5×20mL)洗滌濾餅。將濾液在減壓下濃縮,且將殘餘物藉由在矽膠上之快速層析法(以EA/庚烷溶離)進行純化以得到標題化合物。MS(m/z):184.0[M+H+]。
步驟B. 3-氯-5-氟-2-甲基苯甲酸甲酯之合成
在0℃下,將NaNO2(1.68g,24.4mmol)添加至3-胺基-5-氟-2-甲基苯甲酸甲酯(4.00g,18.8mmol)於半濃縮HCl水溶液(400mL)中之溶液。在0℃下攪拌5min之後,將CuCl(3.72g,37.5mmol)添加至反應混合物。在0℃下攪拌2h之後,以DCM(2×100mL)萃取反應混合物。將合併之有機層以濃NaHCO3水溶液(1×)洗滌,經由Na2SO4乾燥,過濾且在真空中濃縮。將殘餘物藉由在矽膠上之快速層析法(以DCM/庚烷溶離)進行純化以得到標題化合物。
步驟C. 2-(溴甲基)-3-氯-5-氟苯甲酸甲酯之合成
將過氧化苯甲醯(26mg,0.11mmol)及N-溴琥珀醯亞胺(210mg,1.18mmol)添加至經攪拌之3-氯-5-氟-2-甲基苯甲酸甲酯(200mg,0.99mmol)於苯(7.0mL)中之溶液。在回流下攪拌1.5h之後,以EA(20mL)稀釋反應混合物,且以10% Na2S2O3水溶液(1×5mL)洗滌。將有機層經由Na2SO4乾燥,過濾且在真空中濃縮以得到標題化合物。
步驟D. 3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯甲酸甲酯之合成
將Cs2CO3(617mg,3.20mmol)添加至經攪拌之2-(溴甲基)-3-氯-5-氟苯甲酸酯(300mg,1.07mmol)及4-甲氧基苯酚(172mg,1.39mmol)於ACN(7.0mL)中之溶液。在RT下攪拌隔夜之後,將反應混合物過濾且在真空中濃縮。將殘餘物藉由在矽膠上之快速層析法(以EA/庚烷溶離)進行純化以得到標題化合物。MS(m/z):342.1[M+NH4 +]。
步驟E. 3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯甲酸之合成
在0℃下將LiOH(2.37g,57mmol)於水(50mL)中之溶液添加至經攪拌之3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯甲酸甲酯(9.16g,28mmol)於二噁烷(100mL)中之溶液。在RT下攪拌2h之後,在真空中濃縮反應混合物,且藉由添加濃HCl水溶液將pH值調整至1至2。以DCM(3×100mL)萃取混合物,將合併之有機層經由Na2SO4乾燥,過濾且在真空中濃縮以得到標題化合物。
步驟F. 1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙酮之合成
在0℃下,將甲基鋰(1.6M,30.2mL)於乙醚中之溶液逐滴添加至3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯甲酸(5.00g,16mmol)於無水乙醚(110mL)中之溶液。在0℃下攪拌30min之後,藉由在0℃下添加飽和NH4Cl水溶液(15mL)來將反應淬滅。以水(15mL)稀釋混合物,將有機層分離且以乙醚(3×50mL)萃取水層。將合併之有機層經由Na2SO4乾燥,過濾且在真空中濃縮。將殘餘物藉由在矽膠上之快速層析法(以EA/庚烷溶離)進行純化以得到標題化合物。
步驟G. (R)-N-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-2-甲基丙-2-亞磺醯胺之合成
在氬氣氣氛下,將乙氧化鈦(IV)(2.53mL,12.1mmol)逐滴添加至1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙酮(1.24g,4.02mmol)及(R)-(+)-2-甲基-2-丙亞磺醯胺(535.5mg,4.42mmol)於無水THF(10mL)中之溶液。在回流下加熱混合物,直至轉化完成(TLC)。隨後,將混合物冷卻至0℃且逐滴添加L-Selectride(1M溶液,12.05mL,12.05mmol)。在此溫度下攪拌混合物,直至轉化完成(TLC)。隨後,添加甲醇(約10mL),直至氣體溢出停止。將溶液傾倒至飽和NaCl水溶液(30mL)中。然後,將混合物經由矽藻土墊過濾且小心地以DCM淋洗。以飽和NaCl水溶液洗滌濾液。以DCM萃取水層。將合併之有機層經由Na2SO4乾燥,過濾且蒸發至乾。將剩餘殘餘物藉由在矽膠上之快速層析法(以EA/庚烷溶離)進行純化以得到標題化合物。MS(m/z):458.2[M+HCO2 -]。
步驟H. (S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺之合成
在室溫下攪拌(R)-N-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-2-甲基丙-2-亞磺醯胺(2.19g,5.29mmol)於3M甲醇HCl(3.53mL,10.6mmol)中之溶液,直至轉化完成(TLC)。將溶液在真空中濃縮。將剩餘殘餘物溶解於DCM(5mL)中且以飽和NaHCO3水溶液(6mL)及水(6mL)洗滌。將有機層經由Na2SO4乾燥,過濾且在真空中濃縮以得到標題化合物。MS(m/z):354.4[M+HCO2 -]。
步驟I. (S)-2-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)乙酸乙酯之合成
將(S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺(160mg,516.5μmol)、50%於甲苯中之乙醛酸乙酯溶液(112.6μl,568.2μmol)及硼烷-吡啶-複合物(78.3μl,775μmol)溶解於丙-2-醇(5mL)中。添加0.5M HCl水溶液(約10μl),且在RT下攪拌反應混合物隔夜。在TLC指示反應完成之後,將溶液傾倒在SCX-匣(Phenomenex,Strata SCX,0.6mmol/g)上且以甲醇淋洗。隨後,將樹脂以8M甲醇氨溶液(3×)溶離以在蒸發溶劑之後得到粗產物。將殘餘物藉由在矽膠上之快速層析法(以EA/庚烷溶離)進行純化以得到標題化合物。MS(m/z):396.1[M+H+]。
步驟J. (S)-2-(1-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-3-(2-乙氧基-2-側氧基乙基)脲基)乙酸乙酯之合成
將(S)-2-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)乙酸乙酯(53.50mg,135.4μmol)溶解於吡啶(62.5μL)及DCM(2.5mL)中,且添加2-異氰氧基乙酸乙酯(33.4μL,149μmol)。在RT下攪拌反應混合物,直至TLC指示反應完成。隨後,以水淬滅反應且以DCM(3×)萃取。將合併之有機層經由Na2SO4乾燥,過濾且在減壓下蒸發至乾以得到標題化合物。MS(m/z):547.3[M+Na]。
步驟K. (S)-2-(3-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-2,5-二側氧基咪唑啶-1-基)乙醯胺之合成
將(S)-2-(1-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-3-(2-乙氧基-2-側氧基乙基)脲基)乙酸乙酯(70.97mg,135.2μmol)溶解於醇(1mL)及8M甲醇氨溶液(1mL)中並在RT下攪拌隔夜。以水淬滅反應且以DCM(3×)萃取。將合併之有機層經由Na2SO4乾燥,過濾且在減壓下蒸發至乾以得到標題化合物。MS(m/z):450.4[M+H+]。
步驟L. (S)-2-(3-(1-(3-氯-5-氟-2-(羥甲基)苯基)乙基)-2,5-二側氧基咪唑啶-1-基)乙醯胺之合成
在0℃下,將硝酸鈰(IV)銨(185mg,337μmol)於H2O(350μl)中之溶液添加至經攪拌之(S)-2-(3-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-2,5-二側氧基咪唑啶-1-基)乙醯胺(60.7mg,135μmol)於ACN(1.4mL)中之溶液。在0℃下攪拌10min之後,藉由添加鹽水(1.7mL)及H2O(0.7mL)來將反應淬滅。以EA(3×5mL)萃取混合物,將合併之有機層經由Na2SO4乾燥,過濾且在真空中濃縮。將殘餘物藉由在矽膠上之快速層析法(以EA/庚烷溶離)進行純化以得到標題化合物。MS(m/z):366.1[M+Na]。
步驟M. (S)-2-(3-(1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)-2,5-二側氧基咪唑啶-1-基)乙醯胺之合成
在RT下,將SOCl2(20.21mg,12.32μl)及水(1μL)添加至經攪拌之(S)-2-(3-(1-(3-氯-5-氟-2-(羥甲基)苯基)乙基)-2,5-二側氧基咪唑啶-1-基)乙醯胺(29mg,85μmol)於DCM(1mL)中之溶液。在反應完成(TLC)之後,在真空中移除溶劑以得到標題化合物。MS(m/z):384.4[M+Na]。
步驟N. (S)-2-(3-(1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-2,5-二側氧基咪唑啶-1-基)乙醯胺之合成
將Cs2CO3(73.4mg,225μmol)添加至經攪拌之(S)-2-(3-(1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)-2,5-二側氧基咪唑啶-1-基)乙醯胺(27.2mg,75μmol)及4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-醇(18.27mg,75μmol)於ACN(1mL)中之溶液。在RT下
攪拌隔夜之後,將反應混合物過濾且在真空中濃縮。藉由HPLC純化殘餘物得到標題化合物。MS(m/z):569.1[M+H+]。
步驟O. 4-(4-氟-1H-吡唑-1-基)-8-甲氧基-2-甲基喹啉之合成
將K2CO3(4.99g,36.1mmol)添加至經攪拌之4-氯-8-甲氧基-2-甲基喹啉(5.00g,24.0mmol)及4-氟-1H-吡唑(3.85g,28.8mmol)於無水NMP(12mL)中之混合物。在140℃下攪拌48h之後,將反應混合物冷卻至RT並過濾。將殘餘物以DMF(13mL)淋洗。隨後,將水(90mL)添加至合併之濾液。將沉澱物濾出並藉由在矽膠上之快速層析法(以DCM/甲醇溶離)進行純化以得到標題化合物。MS(m/z):258.0[M+H+]。
步驟P. 4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-醇之合成
將4-(4-氟-1H-吡唑-1-基)-8-甲氧基-2-甲基喹啉(5.51g,21.4mmol)於無水甲苯(37.8mL)中之溶液升溫至80℃且逐滴添加至經劇烈攪拌之AlCl3(8.58g,64.3mmol)於無水甲苯(32.4mL)中之混合物。在80℃下攪拌8h之後,將反應混合物冷卻至0℃且藉由添加水(106mL)及濃NH3水溶液(27mL)來淬滅。在RT下攪拌隔夜之後,將混合物離心。以EA(3×200mL)萃取上清液且將合併之有機層經由Na2SO4乾燥,過濾且在真空中濃縮。將殘餘物藉由在矽膠上之快速層析法(以DCM/甲醇溶離)進行純化以得到標題化合物。MS(m/z):244.3[M+H+]。
實例2:化合物編號2之製備
1-((S)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-3-乙基-5-甲基咪唑啶-2,4-二酮之非鏡像異構物B。
步驟A. 2-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)丙酸甲酯之非鏡像異構物A及B之合成
將(S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺(220mg,710μmol)、丙酮酸甲酯(72.0μL,79.8mg,781μmol)及硼烷-吡啶-複合物(107.6μl,1.06mmol)溶解於丙-2-醇(5mL)中。添加約10μL 0.5M HCl水溶液且在RT下將反應混合物攪拌隔夜。在反應完成(TLC)之後,將溶液傾倒在SCX-匣(Phenomenex,Strata SCX,0.6mmol/g)上且以甲醇溶離。隨後將樹脂以約8M甲醇氨溶液洗滌以在蒸發溶劑之後得到粗產物。將剩餘殘餘物藉由在矽膠上之快速層析法(以EA/庚烷溶離)進行純化以得到異構純的標題化合物。
非鏡像異構物A:MS(m/z):396.1[M+H+],R f (TLC,EA/庚烷1:1)=0.55。
非鏡像異構物B:MS(m/z):418.3[M+Na],R f (TLC,EA/庚烷1:1)=0.51。
步驟B. 2-(1-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-3-乙基脲基)丙酸甲酯之非鏡像異構物B之合成
將2-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)丙酸甲酯之非鏡像異構物B(37.15mg,94.0μmol)溶解於吡啶(62.5μL)及DCM(2.5mL)之混合物中且根據(S)-2-(1-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-3-(2-乙氧基-2-側氧基乙基)脲基)乙酸乙酯之合成與異氰酸乙酯(205.0μl,2.35mmol)反應以得到標題化合物。MS(m/z):387.0[M+H+]。
步驟C. 1-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-3-乙基-5-甲基咪唑啶-2,4-二酮之非鏡像異構物B之合成
將2-(1-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-3-乙基脲基)丙酸甲酯之非鏡像異構物B(42.3mg,90.6μmol)溶解於甲醇(1mL)中且根據(S)-2-(3-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-2,5-二側氧基咪唑啶
-1-基)乙醯胺之合成與約8M甲醇氨溶液(1mL)反應以得到標題化合物。MS(m/z):435.0[M+H+]。
步驟D. 1-((S)-1-(3-氯-5-氟-2-(羥甲基)苯基)乙基)-3-乙基-5-甲基咪唑啶-2,4-二酮之非鏡像異構物B之合成
將1-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-3-乙基-5-甲基咪唑啶-2,4-二酮之非鏡像異構物B(38mg,88μmol)根據(S)-2-(3-(1-(3-氯-5-氟-2-(羥甲基)苯基)乙基)-2,5-二側氧基咪唑啶-1-基)乙醯胺之合成與硝酸鈰(IV)銨(120mg,219μmol)反應以得到標題化合物。MS(m/z):329.0[M+H+]。
步驟E. 1-((S)-1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)-3-乙基-5-甲基咪唑啶-2,4-二酮之非鏡像異構物B之合成
將1-((S)-1-(3-氯-5-氟-2-(羥甲基)苯基)乙基)-3-乙基-5-甲基咪唑啶-2,4-二酮之非鏡像異構物B(29.2mg,85μmol)根據(S)-2-(3-(1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)-2,5-二側氧基咪唑啶-1-基)乙醯胺之合成與SOCl2(12.32μL,20.21mg,170μmol)反應以得到標題化合物。MS(m/z):347.0[M+H+]。
步驟F. 1-((S)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-3-乙基-5-甲基咪唑啶-2,4-二酮之非鏡像異構物B之合成
將1-((S)-1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)-3-乙基-5-甲基咪唑啶-2,4-二酮之非鏡像異構物B(10mg,29μmol)根據(S)-2-(3-(1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-2,5-二側氧基咪唑啶-1-基)乙醯胺之合成與4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-醇(7.0mg,29μmol)反應以得到標題化合物。MS(m/z):554.0[M+H+]。
實例3:化合物編號3之製備
(S)-1-(1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)咪唑啶-2-酮。
步驟A. (S)-2-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)乙基胺甲酸三級丁酯之合成
將(S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺(100mg,323μmol)、N-Boc-2-胺基乙醛(113.1μl,355μmol)及硼烷-吡啶-複合物(48.9μl,484μmol)溶解於2-丙醇(4mL)中。添加約10μL 0.5M HCl溶液且在RT下將反應混合物攪拌隔夜。在反應完成(TLC)之後,添加飽和NaHCO3水溶液且以DCM(3×)萃取水相。將合併之有機層經由Na2SO4乾燥且在過濾之後在減壓下蒸發至乾。將粗產物藉由在矽膠上之快速層析法(以EA/庚烷溶離)進行純化以得到標題化合物。MS(m/z):453.7[M+H+]。
步驟B. (S)-2-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)乙基胺甲酸三級丁酯之合成
將(S)-2-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)乙基胺甲酸三級丁酯(45mg,99μmol)及三乙胺(13.8μl,99μmol)溶解於DCM(2mL)中。將溶液冷卻至0℃。在氬氣之氣氛下,添加溶解於DCM(1mL)中之三光氣(11.8mg,40μmol)。在RT下攪拌反應混合物直至轉化完成;隨後以飽和NH4Cl水溶液淬滅並以DCM(3×)萃取。將合併之有機層經由Na2SO4乾燥且在過濾之後在減壓下蒸發至乾。將粗產物藉由在矽膠上之快速層析法(以EA/庚烷溶離)進行純化以得到標題化合物。MS(m/z):479.2[M+H+]。
步驟C. (S)-3-(1-(3-氯-5-氟-2-(羥甲基)苯基)乙基)-2-側氧基咪唑啶-1-甲酸三級丁酯之合成
將(S)-2-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)乙基胺甲酸三級丁酯(27.0mg,56μmol)根據(S)-2-(3-(1-(3-氯-5-氟-2-(羥甲基)苯基)乙基)-2,5-二側氧基咪唑啶-1-基)乙醯胺之合成與硝酸鈰(IV)銨(77.3mg,141μmol)反應以得到標題化合物。MS(m/z):395.5[M+Na+]。
步驟D. (S)-1-(1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)咪唑啶-2-酮之合成
將((S)-3-(1-(3-氯-5-氟-2-(羥甲基)苯基)乙基)-2-側氧基咪唑啶-1-甲酸三級丁酯(11.1mg,30μmol)根據(S)-2-(3-(1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)-2,5-二側氧基咪唑啶-1-基)乙醯胺之合成與SOCl2(4.32μL,7.09mg,60μmol)反應以得到標題化合物。
步驟E. (S)-1-(1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)咪唑啶-2-酮之合成
將(S)-1-(1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)咪唑啶-2-酮(9.2mg,32μmol)根據(S)-2-(3-(1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-2,5-二側氧基咪唑啶-1-基)乙醯胺之合成與4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-醇(7.7mg,32μmol)反應以得到標題化合物。MS(m/z):498.5[M+H+]。
實例4:化合物編號4之製備
(S)-1-((S)-1-(3-氯-5-氟-2-((2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉-8-基氧基)甲基)苯基)乙基)-3-羥基吡咯啶-2-酮。
步驟A. 8-甲氧基-2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉之合成
將4-氯-8-甲氧基-2-甲基喹啉(5.00g,24.15mmol)、1-甲基-1,2,4-三唑(42.74mL,48.30mmol)、K2CO3(6.67g,48.30mmol)、Pd(OAc)2(0.54g,2.41mmol)、三環己基膦四氟硼酸鹽(1.87g,5.07mmol)及三甲基乙酸(2.47g,24.15mmol)懸浮於無水二甲苯(20mL)中。將燒瓶真空化,隨後以氮氣通風。將除氣程序重複兩次。將混合物加熱至140℃達18h。在轉化完成之後,將混合物蒸發且藉由在矽膠上之快速層析法(以DCM/甲醇溶離)以得到標題化合物。MS(m/z):255.4[M+H+]。
步驟B. 2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉-8-醇之合成
將8-甲氧基-2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉(3.14g,12.35mmol)於無水甲苯(25mL)中之溶液升溫至80℃且逐滴添加至經劇烈攪拌之AlCl3(4.94g,37.06mmol)於無水甲苯(25mL)中之混合物。在80℃下攪拌8h之後,將反應混合物冷卻至0℃且藉由添加水(68mL)及隨後添加濃NH3水溶液直至pH 10(約1.7mL)來淬滅。將混合物離心。以EA萃取上清液且將合併之有機層經由Na2SO4乾燥,過濾且在真空中濃縮。將殘餘物藉由在矽膠上之快速層析法(以DCM/甲醇溶離)進行純化以得到標題化合物。MS(m/z):239.2[M-H+]。
步驟C. (S)-2-(三級丁基二甲基矽基氧基)-4-側氧基丁酸甲酯之合成
將(S)-2-(三級丁基二甲基矽基氧基)-4-羥基丁酸甲酯[Dauben,W.G.等人,Tetrahedron Letters 1995,36,2385-2388](195.3mg,787.0μmol)溶解於無水二氯甲烷(5mL)中,隨後添加戴斯-馬丁高碘烷(400.8mg,944.6μmol),且在RT下攪拌反應混合物隔夜。以DCM及飽和硫代硫酸鈉水溶液(5mL)及飽和NaHCO3水溶液(5mL)稀釋混合物。將所得混合物劇烈攪拌1h。分離有機層且以DCM(2×)萃取
水層。將合併之有機層以水洗滌若干次,然後經由Na2SO4乾燥。過濾之後,在減壓下蒸發溶劑且將剩餘殘餘物藉由在矽膠上之快速層析法(以EA/庚烷溶離)進行純化以得到標題化合物。
步驟D. (S)-2-(三級丁基二甲基矽基氧基)-4-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)丁酸甲酯之合成
將(S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺(50mg,161μmol)根據(S)-2-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)乙酸乙酯之合成與(S)-2-(三級丁基二甲基矽基氧基)-4-側氧基丁酸甲酯(43.7mg,178μmol)及硼烷-吡啶-複合物(24.5μl,242.1μmol)反應以得到標題化合物。MS(m/z):540.4[M+H+]。
步驟E. (S)-2-(三級丁基二甲基矽基氧基)-4-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)丁酸之合成
在0℃下將LiOH(10.7mg,254.5μmol)於水(0.5mL)中之溶液添加至經攪拌之(S)-2-(三級丁基二甲基矽基氧基)-4-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)丁酸甲酯(55.0mg,101.8μmol)於THF(1mL)中之溶液。在RT下攪拌5h之後,在真空中濃縮反應混合物,且藉由添加濃HCl水溶液將pH值調整至1至2。以EA(3×10mL)萃取混合物,將合併之有機層經由Na2SO4乾燥,過濾且在真空中濃縮以得到標題化合物。MS(m/z):526.3[M+H+]。
步驟F. (S)-3-(三級丁基二甲基矽基氧基)-1-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)吡咯啶-2-酮之合成
將(S)-2-(三級丁基二甲基矽基氧基)-4-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)丁酸(50.0mg,95.0μmol)溶解於無水DMF(5mL)中。添加HATU(72.3,190.0μmol)及DIPEA(32.54μl,190.0μmol)且在室溫下攪拌反應混合物隔夜。藉由添加飽和NH4Cl水溶液來將反應淬滅且以DCM萃取水層數次。將合併之有機層以飽和NH4Cl水溶液、鹽水洗滌且經由Na2SO4乾燥。過濾之後,
在減壓下將濾液蒸發至乾且將剩餘殘餘物藉由快速層析法(溶離液:庚烷/EA)來純化。MS(m/z):530.2[M+Na+]。
步驟G. (S)-1-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-3-羥基吡咯啶-2-酮之合成
將(S)-3-(三級丁基二甲基矽基氧基)-1-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)吡咯啶-2-酮(48.3mg,95.0μmol)溶解於5ml THF中且將溶液冷卻至0℃。逐滴添加四丁基氟化銨溶液(1M於THF中,104.5μl,104.5μmol)。反應完成之後,以EA稀釋反應混合物。以鹽水萃取,經由Na2SO4乾燥且過濾之後,在減壓下將濾液蒸發至乾且將剩餘殘餘物藉由快速層析法(溶離液:庚烷/EA)來純化。MS(m/z):416.2[M+Na+]。
步驟H. (S)-1-((S)-1-(3-氯-5-氟-2-(羥甲基)苯基)乙基)-3-羥基吡咯啶-2-酮之合成
將(S)-1-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-3-羥基吡咯啶-2-酮(36.0mg,91.4μmol)根據(S)-2-(3-(1-(3-氯-5-氟-2-(羥甲基)苯基)乙基)-2,5-二側氧基咪唑啶-1-基)乙醯胺之合成與硝酸鈰(IV)銨(125.3mg,228.5μmol)反應以得到標題化合物。MS(m/z):332.2[M+HCO2 -]。
步驟I. (S)-1-((S)-1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)-3-羥基吡咯啶-2-酮之合成
將(S)-1-((S)-1-(3-氯-5-氟-2-(羥甲基)苯基)乙基)-3-羥基吡咯啶-2-酮(13.0mg,45.0μmol)根據(S)-2-(3-(1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)-2,5-二側氧基咪唑啶-1-基)乙醯胺之合成與SOCl2(16.4μL,26.9mg,226.0μmol)反應以得到標題化合物。MS(m/z):328.3[M+Na+]。
步驟J. (S)-1-((S)-1-(3-氯-5-氟-2-((2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉-8-基氧基)甲基)苯基)乙基)-3-羥基吡咯啶-2-酮之合成
將Cs2CO3(44.0mg,135.0μmol)添加至經攪拌之(S)-1-((S)-1-(3-氯-2-(氯甲
基)-5-氟苯基)乙基)-3-羥基吡咯啶-2-酮(13.8mg,45.0μmol)及2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉-8-醇(10.8mg,45.0μmol)於ACN(1.0mL)中之溶液。在RT下攪拌隔夜之後,將反應混合物過濾且在真空中濃縮。藉由逆相HPLC純化殘餘物得到標題化合物。MS(m/z):507.9[M+H+]。
實例5:化合物編號5之製備
(R)-1-((S)-1-(3-氯-5-氟-2-((2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉-8-基氧基)甲基)苯基)乙基)-3-氟吡咯啶-2-酮。
合成。將(S)-1-((S)-1-(3-氯-5-氟-2-((2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉-8-基氧基)甲基)苯基)乙基)-3-羥基吡咯啶-2-酮(8.75mg,17.2μmol)溶解於1ml甲苯中且將溶液冷卻至0℃。逐滴添加DBU(3.8μL,25.7μmol)及九氟-1-丁磺醯氟(4.5μL,25.5μmol)。在0℃下再繼續攪拌30min,之後移除冷卻浴。反應完成之後,將混合物傾倒至冰/水上,且以乙酸乙酯萃取水相數次。將合併之有機層以鹽水洗滌且經由Na2SO4乾燥。過濾之後,在真空下移除溶劑且將剩餘殘餘物藉由快速層析法(溶離液:二氯甲烷/甲醇)來純化以得到標題化合物。MS(m/z):512.0[M+H+]。
實例6:化合物編號6之製備
(S)-1-((S)-1-(3-氯-5-氟-2-((2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉-8-基氧基)甲基)苯基)乙基)-4-(二氟甲氧基)吡咯啶-2-酮。
步驟A. (S)-3-(三級丁基二甲基矽基氧基)-4-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)丁酸甲酯之合成
將(S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺(160.0mg,516.5μmol)根據((S)-2-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)乙酸乙酯之合成與(S)-3-(三級丁基二甲基矽基氧基)-4-側氧基丁酸甲酯[Si,Chang-Mei.等人,Org.Chem.Front.2015,2,1485-1499](140.0mg,568.2μmol)反應以得到標題化合物。MS(m/z):540.4[M+H+]。
步驟B. (S)-3-(三級丁基二甲基矽基氧基)-4-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)丁酸之合成
將(S)-3-(三級丁基二甲基矽基氧基)-4-((S)-1-(3-氯-5-氟-2-((4-甲氧基-苯氧基)甲基)苯基)乙胺基)丁酸甲酯(195.0mg,361.0μmol)根據((S)-2-(三級丁基二甲基矽基氧基)-4-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)丁酸之合成與氫氧化鋰單一水合物(37.88mg,902.54μmol)反應以得到標題化合物。MS(m/z):526.3[M+H+]。
步驟C. (S)-4-(三級丁基二甲基矽基氧基)-1-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)吡咯啶-2-酮之合成
將(S)-3-(三級丁基二甲基矽基氧基)-4-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)丁酸(182.0mg,345.9μmol)根據(S)-3-(三級丁基二甲基矽基氧基)-1-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)吡咯啶-2-酮之合成與HATU(263.0mg,691.87μmol)及DIPEA(89.4mg,118μL,691.87μmol)反應以得到標題化合物。MS(m/z):508.6[M+H+]。
步驟D. (S)-1-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-4-羥基吡咯啶-2-酮之合成
將(S)-4-(三級丁基二甲基矽基氧基)-1-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)吡咯啶-2-酮(80.0mg,157.5μmol)根據(S)-1-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-3-羥基吡咯啶-2-酮之合成與TBAF(1M於THF中之溶液,173μl,173μmol)反應以得到標題化合物。MS(m/z):416.2[M+Na+]。
步驟E. (S)-1-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-4-(二氟甲氧基)吡咯啶-2-酮
將(S)-1-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-4-羥基吡咯啶-2-酮(34.5mg,87.6mmol)溶解於ACN(5mL)中且添加CuI(3.34mg,17.52μmol)。將混合物除氣數次且加熱至50℃。在氬氣氣氛下,將2-(氟磺醯基)二氟-乙酸(78.0mg,45.27mL,438.0μmol)在1h內添加至混合物。在50℃下繼續攪拌隔夜。對於處理,將混合物冷卻至室溫且添加NaHCO3水溶液。以EA萃取水層數次。將合併之有機層經由Na2SO4乾燥且在過濾之後在真空中蒸發。將剩餘殘餘物藉由快速層析法(溶離液:庚烷/EA)來純化以得到標題化合物。MS(m/z):466.3[M+Na+]。
步驟F (S)-1-((S)-1-(3-氯-5-氟-2-(羥甲基)苯基)乙基)-4-(二氟甲氧基)吡咯啶-2-酮之合成
將(S)-1-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-4-(二氟甲氧基)吡咯啶-2-酮(12mg,27.0μmol)根據(S)-2-(3-(1-(3-氯-5-氟-2-(羥甲基)苯基)乙基)-2,5-二側氧基咪唑啶-1-基)乙醯胺之合成與硝酸鈰(IV)銨(37.0mg,67.6μmol)反應以得到標題化合物。MS(m/z):360.4[M+Na+]。
步驟G. (S)-1-((S)-1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)-4-(二氟甲氧基)吡咯啶-2-酮之合成
將(S)-1-((S)-1-(3-氯-5-氟-2-(羥甲基)苯基)乙基)-4-(二氟甲氧基)吡咯啶-2-酮(8.3mg,25μmol)根據(S)-2-(3-(1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)-2,5-二側氧基
咪唑啶-1-基)乙醯胺之合成與SOCl2(8.91μL,14.62mg,123μmol)反應以得到標題化合物。MS(m/z):477.1[M+Na+]。
步驟H (S)-1-((S)-1-(3-氯-5-氟-2-((2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉-8-基氧基)甲基)苯基)乙基)-4-(二氟甲氧基)吡咯啶-2-酮之合成
將(S)-1-((S)-1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)-4-(二氟甲氧基)吡咯啶-2-酮(20.0mg,65μmol)根據(S)-2-(3-(1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-2,5-二側氧基咪唑啶-1-基)乙醯胺之合成與2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉-8-醇(15.7mg,65μmol)反應以得到標題化合物。MS(m/z):560.0[M+H+]。
實例7:化合物編號7之製備
(R)-1-((S)-1-(3-氯-5-氟-2-((2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉-8-基氧基)甲基)苯基)乙基)-3-羥基哌啶-2-酮。
步驟A. (R)-2-(三級丁基二甲基矽基氧基)-5-羥基戊酸三級丁酯之合成
將(R)-1-三級丁基5-甲基2-(三級丁基二甲基矽基氧基)戊二酸酯[Kulkarni,S.S.等人,Organic Letters 2014,16,4336-4339](3.42g,10.3mmol)溶解於甲苯(100mL)中且將溶液冷卻至-78℃。將二丁基氫化鋁(25%於甲苯中,約1.5M,10.29mL,15.44mmol)滴加至溶液。添加之後,移除冷卻浴且繼續攪拌隔夜。小心地添加水,並再繼續攪拌一小時。將甲苯層分離並經由Na2SO4乾燥。過濾且在真空中蒸發之後,將剩餘殘餘物藉由快速層析法(溶離液:庚烷/EA)來純化以得到標題化合物。
步驟B. (R)-2-(三級丁基二甲基矽基氧基)-5-側氧基戊酸三級丁酯之合成
將(R)-2-(三級丁基二甲基矽基氧基)-5-羥基戊酸三級丁酯(435.10mg,1.43mmol)根據(S)-2-(三級丁基二甲基矽基氧基)-4-側氧基丁酸甲酯之合成與戴斯-馬丁高碘烷(237mg,1.71mmol)反應以得到標題化合物。
步驟C. (R)-2-(三級丁基二甲基矽基氧基)-5-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)戊酸三級丁酯之合成
將(S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺(248.8mg,803.2μmol)根據((S)-2-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)乙酸乙酯之合成與(R)-2-(三級丁基二甲基矽基氧基)-5-側氧基戊酸三級丁酯(267.25mg,883.5μmol)反應以得到標題化合物。MS(m/z):596.5[M+H+]。
步驟D. (R)-5-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)-2-羥基戊酸之合成
將(R)-2-(三級丁基二甲基矽基氧基)-5-((S)-1-(3-氯-5-氟-2-((4-甲氧基-苯氧基)甲基)苯基)乙胺基)戊酸三級丁酯(400.0mg,671.0μmol)溶解於HCl於二噁烷中之溶液(3N,15mL)且攪拌隔夜。蒸發溶劑得到標題化合物。MS(m/z):426.4[M+H+]。
步驟E. (R)-1-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-3-羥基哌啶-2-酮之合成
將(R)-5-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)-2-羥基戊酸(321.1mg,754.0μmol)根據(S)-3-(三級丁基二甲基矽基氧基)-1-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)吡咯啶-2-酮之合成與HATU(573.36mg,1.5mmol)及DIPEA(292.3mg,387.2μL,2.26mmol)反應以得到標題化合物。MS(m/z):430.6[M+Na+]。
步驟F (R)-1-((S)-1-(3-氯-5-氟-2-(羥甲基)苯基)乙基)-3-羥基哌啶
-2-酮之合成
將(R)-1-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-3-羥基哌啶-2-酮(135.2mg,331.5μmol)根據(S)-2-(3-(1-(3-氯-5-氟-2-(羥甲基)苯基)乙基)-2,5-二側氧基咪唑啶-1-基)乙醯胺之合成與硝酸鈰(IV)銨(454.3mg,828.7μmol)反應以得到標題化合物。MS(m/z):324.4[M+Na+]。
步驟G. (R)-1-((S)-1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)-3-羥基哌啶-2-酮之合成
將(R)-1-((S)-1-(3-氯-5-氟-2-(羥甲基)苯基)乙基)-3-羥基哌啶-2-酮(53.3mg,176.6μmol)根據(S)-2-(3-(1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)-2,5-二側氧基咪唑啶-1-基)乙醯胺之合成與SOCl2(25.63μL,42.03mg,353.3μmol)反應以得到標題化合物。
步驟H. (R)-1-((S)-1-(3-氯-5-氟-2-((2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉-8-基氧基)甲基)苯基)乙基)-3-羥基哌啶-2-酮之合成
將(R)-1-((S)-1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)-3-羥基哌啶-2-酮(28.3mg,88.32μmol)根據((S)-2-(3-(1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-2,5-二側氧基咪唑啶-1-基)乙醯胺之合成與在ACN(2mL)中之2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉-8-醇(21.22mg,88.32μmol)反應以得到標題化合物。MS(m/z):524.2[M+H+]。
實例8:化合物編號8之製備
(S)-1-((S)-1-(3-氯-5-氟-2-((2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉-8-基氧基)甲基)苯基)乙基)-5-羥基哌啶-2-酮。
步驟A. (R)-2-(三級丁基二甲基矽基氧基)-5-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)戊酸三級丁酯之合成
將(S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺(80.0mg,258.3μmol)根據((S)-2-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)乙酸乙酯之合成與(S)-4-(三級丁基二甲基矽基氧基)-5-側氧基戊酸甲酯[Petasis,N.A.等人,Organic Letters 2013,15,1424-1427](73.98mg,284.1μmol)反應以得到標題化合物。MS(m/z):554.5[M+H+]。
步驟B. (S)-4-(三級丁基二甲基矽基氧基)-5-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)戊酸之合成
將(R)-2-(三級丁基二甲基矽基氧基)-5-((S)-1-(3-氯-5-氟-2-((4-甲氧基-苯氧基)甲基)苯基)乙胺基)戊酸三級丁酯(82.7mg,149μmol)根據(S)-2-(三級丁基二甲基矽基氧基)-4-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)丁酸之合成與氫氧化鋰單一水合物(15.66mg,373.1μmol)反應以得到標題化合物。MS(m/z):540.4[M+H+]。
步驟C. (S)-5-(三級丁基二甲基矽基氧基)-1-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)哌啶-2-酮之合成
將(S)-4-(三級丁基二甲基矽基氧基)-5-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)戊酸(72.7mg,134.6μmol)根據(S)-3-(三級丁基二甲基矽基氧基)-1-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)吡咯啶-2-酮之合成與HATU(102.3mg,269.2μmol)及DIPEA(34.8mg,46.1μL,269.2μmol)反應以得到標題化合物。MS(m/z):522.4[M+H+]。
步驟D (S)-5-(三級丁基二甲基矽基氧基)-1-((S)-1-(3-氯-5-氟-2-(羥甲基)苯基)乙基)哌啶-2-酮之合成
將(S)-5-(三級丁基二甲基矽基氧基)-1-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)哌啶-2-酮(49.1mg,94.0μmol)根據(S)-2-(3-(1-(3-氯-5-氟-2-(羥甲
基)苯基)乙基)-2,5-二側氧基咪唑啶-1-基)乙醯胺之合成與硝酸鈰(IV)銨(128.9mg,235.1μmol)反應以得到標題化合物。MS(m/z):438.4[M+Na+]。
步驟E. (S)-1-((S)-1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)-5-羥基哌啶-2-酮之合成
將((S)-5-(三級丁基二甲基矽基氧基)-1-((S)-1-(3-氯-5-氟-2-(羥甲基)苯基)乙基)哌啶-2-酮(21.6mg,52.0μmol)根據(S)-2-(3-(1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)-2,5-二側氧基咪唑啶-1-基)乙醯胺之合成與SOCl2(18.83μL,30.9mg,259.6μmol)反應以得到標題化合物。MS(m/z):320.5[M+H+]。
步驟F (S)-1-((S)-1-(3-氯-5-氟-2-((2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉-8-基氧基)甲基)苯基)乙基)-5-羥基哌啶-2-酮之合成
將(S)-1-((S)-1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)-5-羥基哌啶-2-酮(8.3mg,26.0μmol)根據(S)-2-(3-(1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-2,5-二側氧基咪唑啶-1-基)乙醯胺之合成與2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉-8-醇(6.24mg,26.0μmol)反應以得到標題化合物。MS(m/z):524.2[M+H+]。
實例9:化合物編號9之製備
(S)-1-(1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-4-甲基哌嗪-2-酮。
步驟A. (S)-N 1-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)乙-1,2-二胺之合成
將(S)-2-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)乙基胺甲酸三級丁酯(1.17g,2.58mmol)溶解於甲醇(5mL)及HCl(3M於甲醇中,5mL)之混合物中。將溶液攪拌2h,然後在減壓下蒸發至乾。添加於甲醇中之氨且將溶液在減壓下再蒸發至乾。將剩餘殘餘物藉由快速層析法(溶離液:DCM/MeOH/氨水)來純化以得到標題化合物。MS(m/z):375.4[M+Na+]。
步驟B (S)-2-(2-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)乙胺基)乙酸乙酯之合成
將(S)-N 1-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)乙-1,2-二胺(500mg,1.41mmol)根據(S)-2-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)乙酸乙酯之合成與50%於甲苯中之乙醛酸乙酯溶液(309.0μL,1.56mmol)及硼烷-吡啶-複合物(214.7μl,2.12mmol)反應以得到標題化合物。MS(m/z):439.6[M+H+]。
步驟C. (S)-2-(三級丁氧基羰基(2-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)乙基)胺基)乙酸乙酯之合成
將((S)-2-(2-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)乙胺基)乙酸乙酯(82.7mg,149.2μmol)溶解於二噁烷(5mL)中且添加溶解於水(2.5mL)中之碳酸鈉溶液(79.1mg,746.4μmol)。將懸浮液冷卻至0℃且分數份添加碳酸二(三級丁)酯(142.5mg,653.1μmol)。然後,移除冷卻浴且將混合物在室溫下攪拌2小時。在真空中移除二噁烷且以DCM(3×)萃取水相。將合併之有機層經由Na2SO4乾燥且在過濾之後在減壓下蒸發。將剩餘殘餘物藉由快速層析法(溶離液:庚烷/EA)來純化以得到標題化合物。MS(m/z):561.7[M+Na+]。
步驟D. (S)-2-(三級丁氧基羰基(2-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)乙基)胺基)乙酸之合成
將(S)-2-(三級丁氧基羰基(2-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)乙基)胺基)乙酸乙酯(258.0mg,478.6μmol)根據(S)-2-(三級丁基二甲基矽基氧基)-4-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)丁酸之合成與
氫氧化鋰單一水合物(50.22mg,1.2mmol)反應以得到標題化合物。511.3[M+H+]。
步驟E. (S)-4-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-3-側氧基哌嗪-1-甲酸三級丁酯之合成
將((S)-2-(三級丁氧基羰基(2-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)乙基)胺基)乙酸(243.0mg,475.5μmol)根據(S)-3-(三級丁基二甲基矽基氧基)-1-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)吡咯啶-2-酮之合成與HATU(361.6mg,951.1μmol)及DIPEA(122.9mg,162.8μL,951.1μmol)反應以得到標題化合物。MS(m/z):515.5[M+Na+]。
步驟F (S)-4-(1-(3-氯-5-氟-2-(羥甲基)苯基)乙基)-3-側氧基哌嗪-1-甲酸三級丁酯之合成
將(S)-4-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-3-側氧基哌嗪-1-甲酸三級丁酯(202.0mg,409.7μmol)根據(S)-2-(3-(1-(3-氯-5-氟-2-(羥甲基)苯基)乙基)-2,5-二側氧基咪唑啶-1-基)乙醯胺之合成與硝酸鈰(IV)銨(561.6mg,1.0mmol)反應以得到標題化合物。MS(m/z):409.3[M+Na+]。
步驟G. (S)-1-(1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)哌嗪-2-酮之合成
將(S)-4-(1-(3-氯-5-氟-2-(羥甲基)苯基)乙基)-3-側氧基哌嗪-1-甲酸三級丁酯(64.0mg,165.0μmol)根據(S)-2-(3-(1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)-2,5-二側氧基咪唑啶-1-基)乙醯胺之合成與SOCl2(60.0μL,98.4mg,827.0μmol)反應以得到標題化合物。MS(m/z):427.6[M+Na+]。
步驟H. (S)-1-(1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)哌嗪-2-酮之合成
將(S)-1-(1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)哌嗪-2-酮(50.3mg,165.0μmol)根據(S)-2-(3-(1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-2,5-二側氧基咪唑啶-1-基)乙醯胺之合成與4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-醇(40.1mg,165μmol)反應以得到標題化合物。MS(m/z):512.0
[M+H+]。
步驟I. (S)-1-(1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-4-甲基哌嗪-2-酮之合成
將(S)-1-(1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)哌嗪-2-酮(15mg,29.3μmol)根據(S)-2-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)乙酸乙酯之合成與甲醛水溶液(37%,150.5μL,3.96mmol)及硼烷-吡啶-複合物(5.9μl,58.6μmol)反應以得到標題化合物。MS(m/z):526.2[M+H+]。
實例10:化合物編號10之製備
(S)-1-(1-(3-氯-5-氟-2-((2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉-8-基氧基)甲基)苯基)乙基)-3,3,4-三甲基哌嗪-2-酮。
步驟A. (S)-2-(三級丁氧基羰基(1-(3-氯-5-氟-2-((4-甲氧基-苯氧基)甲基)苯基)乙基)胺基)乙酸乙酯之合成
將(S)-2-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)乙酸乙酯(726.0mg,1.8mmol)根據(S)-2-(三級丁氧基羰基(2-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)乙基)胺基)乙酸乙酯之合成與二碳酸二(三級丁)酯(2.0g,9.17mmol)反應以得到標題化合物。MS(m/z):518.3[M+Na+]。
步驟B. (S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基(2-羥乙基)胺甲酸三級丁酯之合成
將(S)-2-(三級丁氧基羰基(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)胺基)乙酸乙酯(787.0mg,1.59mmol)根據(R)-2-(三級丁基二甲基矽基氧基)-5-羥
基戊酸三級丁酯之合成與25%於甲苯中之二丁基氫化鋁(1.5M,1.59mL,2.38mmol)反應以得到標題化合物。MS(m/z):476.5[M+Na+]。
步驟C. (S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基(2-側氧基乙基)胺甲酸三級丁酯之合成
將(S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基(2-羥基-乙基)胺甲酸三級丁酯(467.3mg,1.03mmol)根據(S)-2-(三級丁基二甲基矽基氧基)-4-側氧基丁酸甲酯之合成與戴斯-馬丁高碘烷(170.7mg,1.23mmol)反應以得到標題化合物。
步驟D. (S)-2-(2-(三級丁氧基羰基(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)胺基)乙胺基)-2-甲基丙酸甲酯之合成
將(S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基(2-側氧基乙基)胺甲酸三級丁酯(148.3mg,328.7μmol)根據(S)-2-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)乙酸乙酯之合成與鹽酸2-胺基-2-甲基丙酸甲酯(55.5mg,361.6μmol)及硼烷-吡啶複合物(49.8μL,493.1μmol)反應以得到標題化合物。MS(m/z):551.2[M-H+]。
步驟E. (S)-2-(2-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)乙胺基)-2-甲基丙酸甲酯之合成
將(S)-2-(2-(三級丁氧基羰基(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)胺基)乙胺基)-2-甲基丙酸甲酯(205.8mg,372.1μmol)溶解於二氯甲烷(3mL)及三氟乙酸(0.75mL)中且將所得混合物攪拌1h。然後將溶液冷卻至0℃並小心地添加飽和碳酸鈉水溶液直至氣體逸出停止,且將pH至調整至9。以DCM稀釋混合物且以DCM(3×)萃取水層。將合併之有機層經由Na2SO4乾燥且過濾之後在真空中蒸發以得到標題化合物。
步驟F. (S)-2-(2-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)乙胺基)-2-甲基丙酸之合成
將(S)-2-(2-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)乙胺基)-2-
甲基丙酸甲酯(149.2mg,329.4μmol)根據(S)-2-(三級丁基二甲基矽基氧基)-4-((S)-1-(3-氯-5-氟-2-((4-甲氧基-苯氧基)甲基)苯基)乙胺基)丁酸之合成與氫氧化鋰單一水合物(34.5mg,823.5μmol)反應以得到標題化合物。MS(m/z):453.4[M+H+]。
步驟G. (S)-1-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-3,3-二甲基哌嗪-2-酮之合成
將(S)-2-(2-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)乙胺基)-2-甲基丙酸(129.3mg,294.6μmol)根據(S)-3-(三級丁基二甲基矽基氧基)-1-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)吡咯啶-2-酮之合成與HATU(224.0mg,589.1μmol)及DIPEA(76.1mg,100.8μL,589.1μmol)反應以得到標題化合物。MS(m/z):443.5[M+Na+]。
步驟H. (S)-1-(1-(3-氯-5-氟-2-(羥甲基)苯基)乙基)-3,3-二甲基哌嗪-2-酮之合成
將(S)-1-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-3,3-二甲基哌嗪-2-酮(97.3mg,231.1μmol)根據(S)-2-(3-(1-(3-氯-5-氟-2-(羥甲基)苯基)乙基)-2,5-二側氧基咪唑啶-1-基)乙醯胺之合成與硝酸鈰(IV)銨(316.8mg,577.9μmol)反應以得到標題化合物。MS(m/z):337.3[M+Na+]。
步驟I. (S)-1-(1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)-3,3-二甲基哌嗪-2-酮之合成
將(S)-1-(1-(3-氯-5-氟-2-(羥甲基)苯基)乙基)-3,3-二甲基哌嗪-2-酮(31.8mg,101.0μmol)根據(S)-2-(3-(1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)-2,5-二側氧基咪唑啶-1-基)乙醯胺之合成與SOCl2(22.0μL,36.0mg,303.0μmol)反應以得到標題化合物。
步驟J. (S)-1-(1-(3-氯-5-氟-2-((2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉-8-基氧基)甲基)苯基)乙基)-3,3-二甲基哌嗪-2-酮之合成
將(S)-1-(1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)-3,3-二甲基哌嗪-2-酮(16.8mg,50.5μmol)根據(S)-2-(3-(1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-2,5-二側氧基咪唑啶-1-基)乙醯胺之合成與2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉-8-醇(12.13mg,50.5μmol)反應以得到標題化合物。
MS(m/z):537.4[M+H+]。
步驟K. (S)-1-(1-(3-氯-5-氟-2-((2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉-8-基氧基)甲基)苯基)乙基)-3,3,4-三甲基哌嗪-2-酮
將(S)-1-(1-(3-氯-5-氟-2-((2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉-8-基氧基)甲基)苯基)乙基)-3,3-二甲基哌嗪-2-酮(3.7mg,6.9μmol)根據(S)-2-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)乙酸乙酯之合成與甲醛水溶液(37%,35.4μL,931.0μmol)及硼烷-吡啶-複合物(1.4μl,13.8μmol)反應以得到標題化合物。MS(m/z):551.1[M+H+]。
實例11:化合物編號11之製備
(R)-1-((S)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-4,5-二甲基哌嗪-2,3-二酮。
步驟A. 2-(((R)-2-(三級丁氧基羰基(甲基)胺基)丙基)((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)胺基)乙酸乙酯之合成
將(S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基(2-側氧基乙基)胺甲酸三級丁酯(74.0mg,130.5μmol)根據(S)-2-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)乙酸乙酯之合成與(R)-甲基(1-側氧基丙-2-基)胺甲酸三級丁酯
(55.5mg,361.6μmol)及硼烷-吡啶複合物(49.8μL,493.1μmmol)反應以得到標題化合物。MS(m/z):589.6[M+Na+]。
步驟B. 2-(((R)-2-(三級丁氧基羰基(甲基)胺基)丙基)((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)胺基)乙酸之合成
將2-(((R)-2-(三級丁氧基羰基(甲基)胺基)丙基)((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)胺基)乙酸乙酯(74.0mg,130.5μmol)根據(S)-2-(三級丁基二甲基矽基氧基)-4-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)丁酸與氫氧化鋰單一水合物(13.7mg,326.2μmol)反應以得到標題化合物。MS(m/z):537.4[M-H+]。
步驟C. 2-(((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)((R)-2-(甲胺基)丙基)胺基)乙酸之合成
將2-(((R)-2-(三級丁氧基羰基(甲基)胺基)丙基)((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)胺基)乙酸(70.3mg,130.53μmol)根據(S)-2-(2-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)乙胺基)-2-甲基丙酸甲酯之合成於二氯甲烷(1mL)及三氟乙酸(0.25mL)中處理以得到標題化合物。MS(m/z):439.6[M+H+]。
步驟D. (R)-4-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-1,6-二甲基哌嗪-2-酮之合成
將2-(((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)((R)-2-(甲胺基)丙基)胺基)乙酸(57.2mg,130.3μmol)根據(S)-3-(三級丁基二甲基矽基氧基)-1-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)吡咯啶-2-酮之合成與HATU(99.1mg,260.6μmol)及DIPEA(33.7mg,44.6μL,260.6μmol)反應以得到標題化合物。MS(m/z):421.6[M+H+]。
步驟E. (R)-1-((S)-1-(3-氯-5-氟-2-(羥甲基)苯基)乙基)-4,5-二甲基哌嗪-2,3-二酮之合成
將(R)-4-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-1,6-二甲基哌嗪-2-酮(46.5mg,110.5μmol)根據(S)-2-(3-(1-(3-氯-5-氟-2-(羥甲基)苯基)乙基)-2,5-二側氧基咪唑啶-1-基)乙醯胺之合成與硝酸鈰(IV)銨(151.4mg,276.2μmol)反應以得到標題化合物。MS(m/z):329.5[M+H+]。
步驟F. (R)-1-((S)-1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)-4,5-二甲基哌嗪-2,3-二酮之合成
將(R)-1-((S)-1-(3-氯-5-氟-2-(羥甲基)苯基)乙基)-4,5-二甲基哌嗪-2,3-二酮(17.0mg,52.0μmol)根據(S)-2-(3-(1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)-2,5-二側氧基咪唑啶-1-基)乙醯胺之合成與SOCl2(18.8μL,30.8mg,259.0μmol)反應以得到標題化合物。MS(m/z):347.3[M+H+]。
步驟G. (R)-1-((S)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-4,5-二甲基哌嗪-2,3-二酮之合成
將(R)-1-((S)-1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)-4,5-二甲基哌嗪-2,3-二酮(17.7mg,51.0μmol)根據(S)-2-(3-(1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-2,5-二側氧基咪唑啶-1-基)乙醯胺之合成與4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-醇(12.4mg,51.0μmol)反應以得到標題化合物。MS(m/z):554.1[M+H+]。
實例12:化合物編號12之製備
(S)-1-((S)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-3,4-二甲基哌嗪-2,5-二酮。
步驟A. (S)-2-(三級丁氧基羰基(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)
甲基)苯基)乙基)胺基)乙酸之合成
將(S)-2-(三級丁氧基羰基(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)胺基)乙酸乙酯(74.0mg,130.5μmol)根據(S)-2-(三級丁基二甲基矽基氧基)-4-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)丁酸之合成與氫氧化鋰單一水合物(13.7mg,326.2μmol)反應以得到標題化合物。MS(m/z):468.4[M+H+]。
步驟B. (S)-2-(2-(三級丁氧基羰基((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)胺基)-N-甲基乙醯胺基)丙酸甲酯
將(S)-2-(三級丁氧基羰基(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)胺基)乙酸(133.0,284.2μmol)及鹽酸(2S)-2-(甲胺基)丙酸甲酯(50.2mg,326.9μmol)溶解於DMF(5mL)中且將溶液冷卻至0℃。隨後添加PyBOP(192.7mg,369.5μmol)及DIPEA(84.1μL,483.2μmol)。在RT下攪拌隔夜之後,將反應混合物在真空中濃縮。將剩餘殘餘物藉由快速層析法(溶離液:庚烷/EA)來純化以得到標題化合物。MS(m/z):589.6[M+Na+]。
步驟C. (S)-2-(2-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)-N-甲基乙醯胺基)丙酸甲酯之合成
將(S)-2-(2-(三級丁氧基羰基((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)胺基)-N-甲基乙醯胺基)丙酸甲酯(135mg,238.0μmol)根據(S)-2-(2-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)乙胺基)-2-甲基丙酸甲酯之合成於DCM(1mL)中與三氟乙酸(0.25mL)反應以得到標題化合物。MS(m/z):467.5[M+H+]。
步驟D. (S)-2-(2-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)-N-甲基乙醯胺基)丙酸之合成
將(S)-2-(2-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)-N-甲基乙醯胺基)丙酸甲酯(109.0mg,233.4μmol)根據(S)-2-(三級丁基二甲基矽基氧
基)-4-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)丁酸之合成與氫氧化鋰單一水合物(24.5mg,583.6.2μmol)反應以得到標題化合物。MS(m/z):451.0[M-H+]。
步驟E. (S)-1-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-3,4-二甲基哌嗪-2,5-二酮之合成
將(S)-2-(2-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺基)-N-甲基乙醯胺基)丙酸(105.8mg,233.6μmol)根據(S)-3-(三級丁基二甲基矽基氧基)-1-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)吡咯啶-2-酮之合成與HATU(177.7mg,467.3μmol)及DIPEA(60.4mg,80.0μL,467.3μmol)反應以得到標題化合物。MS(m/z):435.1[M+H+]。
步驟F. (S)-1-((S)-1-(3-氯-5-氟-2-(羥甲基)苯基)乙基)-3,4-二甲基哌嗪-2,5-二酮之合成
將(S)-1-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-3,4-二甲基哌嗪-2,5-二酮(103.0mg,236.8μmol)根據(S)-2-(3-(1-(3-氯-5-氟-2-(羥甲基)苯基)乙基)-2,5-二側氧基咪唑啶-1-基)乙醯胺之合成與硝酸鈰(IV)銨(324.6mg,592.1μmol)反應以得到標題化合物。MS(m/z):351.4[M+Na+]。
步驟G. (S)-1-((S)-1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)-3,4-二甲基哌嗪-2,5-二酮之合成
將(S)-1-((S)-1-(3-氯-5-氟-2-(羥甲基)苯基)乙基)-3,4-二甲基哌嗪-2,5-二酮(50.0mg,152.0μmol)根據(S)-2-(3-(1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)-2,5-二側氧基咪唑啶-1-基)乙醯胺之合成與SOCl2(55.2μL,90.5mg,760.4μmol)反應以得到標題化合物。MS(m/z):347.4[M+H+]。
步驟H. (S)-1-((S)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-3,4-二甲基哌嗪-2,5-二酮之合成
將(S)-1-((S)-1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)-3,4-二甲基哌嗪-2,5-二酮
(30.0mg,86.4μmol)根據(S)-2-(3-(1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-2,5-二側氧基咪唑啶-1-基)乙醯胺之合成與4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-醇(21.0mg,86.4μmol)反應以得到標題化合物。MS(m/z):554.2[M+H+]。
實例13:化合物編號13至107
以下表1中所示之化合物編號13至107號係本發明之根據通式(I)之化合物之另外代表性實例。這些化合物已使用上文所述之方法,連同本文所引用之參考文獻中所揭示或合成有機化學技術中已知之合成方法一起,以及如熟習此項技術者所理解之對其進行之變化經合成。本文中關於實例1至12中所述之合成途徑所引用之各參考文獻特此以引用之方式併入本說明書中。無論如何,熟習有機合成技術者將認識到產生化合物之起始材料及反應條件包括變化。
實例14:測試化合物對人類B2R之拮抗活性
以下基於細胞之人類緩激肽B2受體鈣動員(hB2R-CaM)檢定用於確定選自
實例化合物編號1至107之化合物對人類緩激肽B2受體(hB2R)之拮抗活性。檢定在本文中定義為標準體外B2受體活性檢定,其可用於確定根據本發明之化合物(例如,實例1至13中所示之化合物)之IC50值。
根據提供商之說明書,以hB2R-CaM檢定,使用B2緩激肽受體穩定細胞株HTS041C(Eurofins,St.Charles MO)及FLIPR鈣6檢定套組(Molecular Devices,Wokingham,UK)研究根據本發明之化合物之拮抗活性。CaM檢定量測係以Flexstation 3系統(Molecular Devices)進行,前述系統允許向細胞精確添加化合物(B2R拮抗劑)及緩激肽(B2R促效劑)並隨後連續記錄時間依賴性CaM檢定訊號。
[細胞結構、平板接種及饑餓]
將HTS041C細胞在37℃、5% CO2氣氛下於細胞培養器中培養於補充有10%熱滅活FBS(PAN Biotech)、10mM HEPES、青黴素/鏈黴素(200U/mL,200μg/mL)、1×非必需胺基酸(Lonza)及250μg/mL G418(Invivogen)之高葡萄糖DMEM細胞培養基(Lonza)中。在CaM檢定實驗前一天,將細胞在透明底黑色96孔板(ThermoFisher #165305)上接種於200μL具有減少之FBS(5%)且不具有G418之DMEM細胞培養基中。藉由將每孔70.000個細胞培養(37℃,5% CO2)24h至28h來進行細胞饑餓。緊接在鈣染料裝載之前,小心地吸出培養基且以調整至pH 7,4的含有Ca2+、Mg2+及20mM HEPES之漢克氏平衡鹽溶液(HBSS,Gibco)(HBSS+)洗滌細胞。
[細胞之鈣染料裝載]
對於鈣染料裝載,將一份FLIPR 6檢定等分試樣溶解於20mL HBSS+中。將150μL染料裝載溶液添加至細胞平板且在37℃及5% CO2下培養120min。在染料裝載之後,緊接著將細胞平板轉移至經預熱(37℃)之Flexstation 3系統以供CaM檢定。
[細胞內鈣動員檢定(CaM檢定)]
將在非結合平板(Costar)中之新製備化合物(B2受體拮抗劑)稀釋系列(8pt,n=2)及緩激肽(B2受體促效劑)溶液轉移至Flexstation系統(源板),之後立即開始實驗。以用8pt濃度反應曲線之n>3初步實驗(n=8)中所確定之EC80濃度添加緩激肽。藉由Flexstation 3系統執行CaM檢定,以在底讀Flex方法中記錄鈣敏感性染料螢光開始,ex/em=485nm/525nm,截止(em)=515nm。20s之後,將50μL 4倍濃縮之化合物稀釋液添加至細胞,得到在細胞平板中0.1%的最終DMSO(Sigma)濃度。在添加之後監測CaM訊號達80s以用於偵測潛在的促效活性。在緩激肽刺激之前,在Flexstation系統內將化合物及媒介物處理之細胞在37℃下培養25min。隨後添加50μL 5倍濃縮之緩激肽溶液(HBSS+,0.1% DMSO)以觸發CaM訊號(讀出:最大-最小值),在緩激肽刺激之後量測這些訊號達80s。
藉由使用XLFIT(IDBS)軟體對8pt(n=2)化合物濃度反應曲線進行4參數邏輯模型曲線擬合來進行IC50確定。
量測結果:
實例化合物編號4、5、11、12、15、26、27、30、34、37、40、41、44、45、46、48、49、50、53、55、60、61、63、67、68、72、73、76、81、82、86、87、88、91、92、93、94、97、98及104顯示對人類緩激肽B2受體(hB2R)等於或低於10nM之IC50值。
實例化合物編號1、2、3、6、7、8、9、10、13、14、16、17、18、19、20、21、22、23、24、25、29、32、33、35、36、38、39、42、43、47、51、54、56、57、58、59、62、64、65、66、69、70、71、74、75、77、78、83、84、89、90、95、96、99、100、101、102、103、105、106及107顯示對人類緩激肽B2受體(hB2R)在11與100nM之間之IC50值。
實例化合物編號28、31、52、79、80及85顯示對人類緩激肽B2受體(hB2R)在101nM與500nM之間之IC50值。
在基於細胞之測試系統中,所有測試化合物均未顯示任何毒性作
用。
本說明書及/或申請專利範圍中所揭示之本發明之特徵既可單獨又可以其任何組合之形式係以各種形式認識本發明的材料。
Claims (15)
- 一種通式(I)之化合物或其鹽,
- 如請求項1所記載之化合物或其鹽,其中,R1表示(C1-C2)烷基或(C2-C4)烷氧基烷基,前述烷基或烷氧基烷基可經一或多個相同或不同的選自鹵素原子及OH之基團取代。
- 如請求項3所記載之化合物或其鹽,其中,B1至B3係如以下(i)至(iii)中任一者所定義:(i)B1係N-RB1;B2係C=O或CH2;且B3係CH2或CH(CH3);(ii)B1係O;B2係CRB4RB5;且B3係CH2或CH(CH3);或者(iii)B1係CRB2RB3;B2係CRB4RB5;且B3係CH2;以及RB1、RB2、RB3、RB4及RB5係如請求項3中所定義。
- 如請求項6所記載之化合物或其鹽,其中,B4至B6係如以下(i)至(v)中任一者所定義:(i)B4係C=O;B5係N-RB13;且B6係CRB16RB17;(ii)B4係CRB11RB12;B5係N-RB13;且B6係C=O;(iii)B4係CRB11RB12;B5係O;且B6係CRB16RB17;(iv)B4係CRB11RB12,B5係N-RB13;且B6係CRB16RB17;或者(v)B4係CRB11RB12,B5係CRB14RB15;且B6係CRB16RB17;B7表示CH2或CH(CH3);以及RB11、RB12、RB13、RB14、RB15、RB16及RB17係如請求項6中所定義。
- 一種醫藥組合物,其包含一或多種如請求項1至9中任一項所記載之化合物或其鹽;及視情況至少一種載劑物質、賦形劑及/或佐劑。
- 如請求項10所記載之醫藥組合物,其中,前述醫藥組合物經調配為氣溶膠、霜劑、凝膠、丸劑、膠囊、糖漿、溶液、經皮貼片劑或醫藥遞送裝置。
- 一種組合製劑,其含有至少一種如請求項1至9中任一項所記載之化合物或其鹽;及至少一種另外的活性醫藥成分。
- 一種藥劑,其含有至少一種如請求項1至9中任一項所記載之化合物或其鹽、如請求項10或11所記載之醫藥組合物或如請求項12所記載之組合製劑。
- 一種如請求項1至9中任一項所記載之化合物或其鹽、如請求項10或11所記載之醫藥組合物或如請求項12所記載之組合製劑用於製備治療對緩激肽B2受體調節有反應的病狀之藥物的用途。
- 如請求項14所記載之用途,其中,前述病狀為:皮膚病症;眼部疾病;耳部疾病;嘴部、喉部及呼吸疾病;胃腸疾病;肝部、膽囊及胰臟疾病;尿路及腎臟疾病;男性生殖器官及女性生殖器官之疾病;激素系統疾病;代謝疾病;心血管疾病;血液病;淋巴疾病;中樞神經系統之病症;腦部病症;肌肉骨骼系統疾病;過敏症;疼痛;傳染病;發炎性病症;損傷;免疫學病症; 癌症;遺傳性疾病;或水腫。
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- 2020-05-21 UY UY0001038706A patent/UY38706A/es unknown
- 2020-05-21 AR ARP200101443A patent/AR118982A1/es unknown
- 2020-05-22 TW TW109117162A patent/TWI827847B/zh active
- 2020-05-25 MX MX2021014288A patent/MX2021014288A/es unknown
- 2020-05-25 AU AU2020280924A patent/AU2020280924B2/en active Active
- 2020-05-25 EP EP20732502.8A patent/EP3983402B1/en active Active
- 2020-05-25 CA CA3139229A patent/CA3139229A1/en active Pending
- 2020-05-25 JP JP2021569938A patent/JP7462683B2/ja active Active
- 2020-05-25 ES ES20732502T patent/ES2962971T3/es active Active
- 2020-05-25 WO PCT/EP2020/064375 patent/WO2020234479A1/en unknown
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- 2020-05-25 PL PL20732502.8T patent/PL3983402T3/pl unknown
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UY38706A (es) | 2020-12-31 |
PL3983402T4 (pl) | 2024-04-02 |
US20220135542A1 (en) | 2022-05-05 |
JP7462683B2 (ja) | 2024-04-05 |
JP2022534389A (ja) | 2022-07-29 |
PL3983402T3 (pl) | 2024-04-02 |
CN113906018B (zh) | 2024-04-12 |
ES2962971T3 (es) | 2024-03-22 |
WO2020234479A1 (en) | 2020-11-26 |
AU2020280924B2 (en) | 2023-07-27 |
EP3983402A1 (en) | 2022-04-20 |
EP3983402B1 (en) | 2023-08-16 |
AU2020280924A1 (en) | 2021-11-25 |
CN113906018A (zh) | 2022-01-07 |
CA3139229A1 (en) | 2020-11-26 |
AR118982A1 (es) | 2021-11-17 |
EP3983402C0 (en) | 2023-08-16 |
MX2021014288A (es) | 2022-01-06 |
TW202110429A (zh) | 2021-03-16 |
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