TWI603958B - 腦啡肽酶抑制劑 - Google Patents
腦啡肽酶抑制劑 Download PDFInfo
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- TWI603958B TWI603958B TW102128546A TW102128546A TWI603958B TW I603958 B TWI603958 B TW I603958B TW 102128546 A TW102128546 A TW 102128546A TW 102128546 A TW102128546 A TW 102128546A TW I603958 B TWI603958 B TW I603958B
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Classifications
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- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Description
本發明係關於經活體內代謝為具有作為腦啡肽酶抑制劑之活性的化合物的新穎化合物。本發明亦係關於包含此等化合物之醫藥組合物、用於製備此等化合物之方法及中間物、及使用此等化合物治療疾病(諸如高血壓、心臟衰竭、肺高血壓及腎病)的方法。
Fleury等人於2012年2月16日申請的共同讓渡之美國專利公開案第2012/0213806號描述具有作為腦啡肽酶抑制劑之活性的新穎化合物,該公開案之揭示內容以引用之方式併入本文中。詳言之,描述以下種類之化合物:
視變數而定,此種類內之化合物可視為呈活性形式或視為前藥,該前藥經活體內代謝以產生該化合物之活性形式。
然而儘管存在此等化合物,但仍需要此種類內的具有不同代謝及裂解特性之化合物及前藥。舉例而言,仍需要經口吸收改善之活性化合物及/或前藥化合物,且需要可進行快速裂解以形成活性化合物
之前藥化合物。本發明係針對該需要。
本發明之一個態樣係關於式I化合物,
其中:
(i)X為或;且
(a)Ra及Rb為H;R2為H;且R7係選自-CH2CF2CH3、-CH2CF2CF3、-(CH2)5CH3、-(CH2)6CH3及
或R2為-C1-6烷基或-C(O)-C1-6烷基,且R7為H;或(b)Ra係選自-CH3、-OCH3及Cl,且Rb為H;或Ra係選自H、-CH3、Cl及F,且Rb為Cl;或Ra為H,且Rb係選自-CH3及-CN;R2係選自H、-C1-6烷基、-(CH2)2-3ORe及-(CH2)2-3NReRe;R7係選自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-環己基、-CH2CH(NH2)C(O)OCH3、-C2-4伸烷基-N(CH3)2、-C0-6伸烷基嗎啉基及
(c)Ra為H,且Rb為F;或Ra為F,且Rb為H;R2係選自H、-C1-6烷基、-(CH2)2-3ORe及-(CH2)2-3NReRe;且R7係選自-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-環己基、-CH2CH(NH2)C(O)OCH3、-C2-4伸烷基-N(CH3)2、-C0-6伸烷基嗎啉基及
(ii)X為;且
(a)Ra為Cl,且Rb為H;或Ra為H,且Rb係選自Cl、F、-CH3及CN;或Ra為F且Rb為Cl;R2係選自H、-C1-6烷基、-(CH2)2-3ORe及-(CH2)2-3NReRe;R4係選自-OH、-OCH3、-OCH2CH3及-C1-4烷基;且R7係選自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-環己基、-CH2CH(NH2)C(O)OCH3、-C2-4伸烷基-N(CH3)2、-C0-6伸烷基嗎啉基及
(b)Ra為F,且Rb為H;R2為H;R4為-OH;且R7係選自-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-環己基、-CH2CH(NH2)C(O)OCH3、-C2-4伸烷基-N(CH3)2、-C0-6伸烷基嗎啉基及
(iii)X為或;且
(a)Ra為Cl,且Rb為H;或Ra為H,且Rb係選自Cl、F、-CH3及-CN;或Ra為F,且Rb為Cl;R2係選自H、-C1-6烷基、-(CH2)2-3ORe及-(CH2)2-3NReRe;且R7係選自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-環己基、-CH2CH(NH2)C(O)OCH3、-C2-4伸烷基-N(CH3)2、-C0-6伸烷基嗎啉基及
(b)Ra為F,且Rb為H;R2為H;且R7係選自-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-環己基、-CH2CH(NH2)C(O)OCH3、-C2-4伸烷基-N(CH3)2、-C0-6伸烷基嗎啉基及
(iv)X為
(a)Ra及Rb為H;R2係選自-C1-6烷基、-(CH2)2-3ORe及-(CH2)2-3NReRe;R3係選自-OH、-OCH3、-OCH2CH3及-C1-4烷基;且R7為H;或(b)Ra係選自Cl及F,且Rb為H;或Ra為H,且Rb係選自Cl、F、-
CH3及-CN;或Ra為F,且Rb為Cl;R2係選自H、-C1-6烷基、-(CH2)2-3ORe及-(CH2)2-3NReRe;R3係選自-OH、-OCH3、-OCH2CH3及-C1-4烷基;且R7係選自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-環己基、-CH2CH(NH2)C(O)OCH3、-C2-4伸烷基-N(CH3)2、-C0-6伸烷基嗎啉基及
(v)X為或
Ra係選自Cl及F,且Rb為H;或Ra為H,且Rb係選自Cl、F、-CH3及-CN;或Ra為F,且Rb為Cl;R2係選自H、-C1-6烷基、-(CH2)2-3ORe及-(CH2)2-3NReRe;R3係選自-OH、-OCH3、-OCH2CH3及-C1-4烷基;R4係選自H、-C1-6烷基及苯基;且R7係選自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-環己基、-CH2CH(NH2)C(O)OCH3、-C2-4伸烷基-N(CH3)2、-C0-6伸烷基嗎啉基及
(vi)X為或
Ra係選自Cl及F,且R為H;或Ra為H,且Rb係選自Cl、F、-CH3及-CN;或Ra為F,且Rb為Cl;R2係選自H、-C1-6烷基、-(CH2)2-3ORe及-(CH2)2-3NReRe;R4係選自H、-C1-6烷基及苯基;且R7係選自H、-
C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-環己基、-CH2CH(NH2)C(O)OCH3、-C2-4伸烷基-N(CH3)2、-C0-6伸烷基嗎啉基及
(vii)X為
Ra係選自Cl及F,且Rb為H;或Ra為H,且Rb係選自Cl、F、-CH3及-CN;或Ra為F,且Rb為Cl;R2係選自H、-C1-6烷基、-(CH2)2-3ORe及-(CH2)2-3NReRe;且R7係選自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-環己基、-CH2CH(NH2)C(O)OCH3、-C2-4伸烷基-N(CH3)2、-C0-6伸烷基嗎啉基及
(viii)X為
Ra係選自Cl及F,且Rb為H;或Ra為H,且Rb係選自Cl、F、-CH3及-CN;或Ra為F,且Rb為Cl;R2係選自H、-C1-6烷基、-(CH2)2-3ORe及-(CH2)2-3NReRe;且R7係選自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-環己基、-CH2CH(NH2)C(O)OCH3、-C2-4伸烷基-N(CH3)2、-C0-6伸烷基嗎啉
基及
其中各Rc獨立地為H或-C1-3烷基;各Rd獨立地為H、-CH3、-CH(CH3)2、苯基或苯甲基;且各Re獨立地為H或-CH3;或其醫藥學上可接受之鹽。
本發明提供經活體內代謝為發現具有腦啡肽酶(NEP酶)抑制活性之化合物的化合物。相應地,預期本發明化合物適用作且宜用作治療劑,該等治療劑用於治療罹患可藉由抑制NEP酶或藉由增加其肽受質之含量來治療的疾病或病症的患者。因此,本發明之一個態樣係關於一種治療高血壓、心臟衰竭或腎病之方法,該方法包含向患者投與治療有效量的本發明化合物。
本發明之另一個態樣係關於包含醫藥學上可接受之載劑及本發明化合物的醫藥組合物。
本發明之又一個態樣係關於適用於製備本發明化合物的方法及中間物。本發明之另一個態樣係關於一種製備式I化合物的醫藥學上可接受之鹽的方法,該方法包含使呈游離酸或鹼形式之式I化合物與醫藥學上可接受之鹼或酸接觸。在其他態樣中,本發明係關於藉由本文中所述之任何方法製備的產物,以及在該等方法中所使用之新穎中間物。
本發明之又另一個態樣係關於式I化合物或其醫藥學上可接受之鹽用於製造藥劑,尤其用於製造適用於治療高血壓、心臟衰竭或腎病之藥劑的用途。本發明之另一個態樣係關於本發明化合物用於抑制哺乳動物中之NEP酶的用途。本發明之再另一個態樣係關於本發明化合物作為研究工具的用途。本文中揭示本發明之其他態樣及實施例。
當描述本發明化合物、組合物、方法及製程時,除非另外指明,否則下列術語具有下列含義。另外,除非所使用之上下文另外明確指示,否則如本文中所用,單數形式「一(a/an)」及「該」包括相應複數形式。術語「包含」、「包括」及「具有」意欲為包含性的,且意謂可能存在除所列要素之外的其他要素。除非另外指明,否則本文中所用的表示成分數量、特性(諸如分子量、反應條件等)之所有數量均應理解為在所有情況下均由術語「約」修飾。相應地,本文中所闡述之數值為可視本發明所設法獲得之所需特性而變化的近似值。最低限度,且不試圖將等效物原則之應用限制為申請專利範圍之範疇,各數值應至少根據所報告之有效數位且藉由應用普通捨入技術來解釋。
術語「烷基」意謂可為直鏈或分支鏈之單價飽和烴基。除非另外定義,否則該等烷基通常含有1至10個碳原子,且包括例如-C1-6烷基,意謂具有1至6個碳原子之烷基,其中碳原子呈任何可接受之組態。舉例而言,代表性烷基包括甲基、乙基、正丙基、異丙基、正丁基、第二丁基、異丁基、第三丁基、正戊基、正己基及其類似基團。
如本文中所用,短語「式」或「具有式」或「具有結構」並不意欲為限制性的,且以與通常使用術語「包含」之方式相同的方式使用。舉例而言,若描繪一種結構,則應瞭解除非另外說明,否則包涵所有立體異構體及互變異構體形式。
術語「醫藥學上可接受」係指當在本發明中使用時,不為生物學上不可接受或在其他方面不可接受的物質。舉例而言,術語「醫藥學上可接受之載劑」係指可併入組合物中且向患者投與,而不引起不可接受之生物效應或以不可接受之方式與組合物之其他組分相互作用
的物質。該等醫藥學上可接受之物質通常滿足毒理學及製造測試之所需標準,且包括由美國食品與藥物管理局(U.S.Food and Drug administration)鑑別為適合之非活性成分的彼等物質。
術語「醫藥學上可接受之鹽」意謂自鹼或酸製備的在向患者(諸如哺乳動物)投與時可接受之鹽,例如對於指定劑量方案而言具有可接受之哺乳動物安全性的鹽。然而,應瞭解由本發明所涵蓋之鹽不必為醫藥學上可接受之鹽,諸如不意欲用於向患者投與的中間化合物之鹽。醫藥學上可接受之鹽可衍生自醫藥學上可接受之無機或有機鹼,且衍生自醫藥學上可接受之無機或有機酸。另外,當式I化合物含有鹼性部分(諸如胺、吡啶或咪唑)及酸性部分(諸如甲酸或四唑)時,可形成兩性離子,且包括在如本文中所用之術語「鹽」內。衍生自醫藥學上可接受之無機鹼的鹽包括銨鹽、鈣鹽、銅鹽、正鐵鹽、亞鐵鹽、鋰鹽、鎂鹽、六價錳鹽、二價錳鹽、鉀鹽、鈉鹽及鋅鹽、及其類似物。衍生自醫藥學上可接受之有機鹼的鹽包括一級、二級及三級胺之鹽:該等胺包括經取代之胺、環狀胺、天然產生之胺及其類似物,諸如精胺酸、甜菜鹼(betaine)、咖啡因、膽鹼、N,N'-二苯甲基乙二胺、二乙胺、2-二乙胺基乙醇、2-二甲胺基乙醇、乙醇胺、乙二胺、N-乙基嗎啉、N-乙基哌啶、還原葡糖胺(glucamine)、葡糖胺(glucosamine)、組胺酸、海卓胺(hydrabamine)、異丙胺、離胺酸、甲基還原葡糖胺、嗎啉、哌嗪、哌啶、聚胺樹脂、普魯卡因(procaine)、嘌呤、可可豆鹼(theobromine)、三乙胺、三甲胺、三丙胺、緩血酸胺(tromethamine)及其類似物。衍生自醫藥學上可接受之無機酸的鹽包括以下之鹽:硼酸、碳酸、氫鹵酸(氫溴酸、氫氯酸(鹽酸)、氫氟酸或氫碘酸)、硝酸、磷酸、胺磺酸及硫酸。衍生自醫藥學上可接受之有機酸的鹽包括以下之鹽:脂族羥基酸(例如檸檬酸、葡萄糖酸、乙醇酸、乳酸、乳糖酸、蘋果酸及酒石酸)、脂族單羧酸(例
如乙酸、丁酸、甲酸、丙酸及三氟乙酸)、胺基酸(例如天冬胺酸及麩胺酸)、芳族羧酸(例如苯甲酸、對氯苯甲酸、二苯基乙酸、龍膽酸、馬尿酸及三苯基乙酸)、芳族羥基酸(例如鄰羥基苯甲酸、對羥基苯甲酸、1-羥基萘-2-甲酸及3-羥基萘-2-甲酸)、抗壞血酸、二羧酸(例如反丁烯二酸、順丁烯二酸、乙二酸及丁二酸)、葡萄糖醛酸(glucoronic acid)、扁桃酸、黏液酸、菸鹼酸、乳清酸、雙羥萘酸(pamoic acid)、泛酸、磺酸(例如苯磺酸、樟腦磺酸、乙二磺酸(edisylic acid)、乙磺酸、羥乙基磺酸、甲磺酸、萘磺酸、萘-1,5-二磺酸、萘-2,6-二磺酸及對甲苯磺酸)、辛那酸(xinafoic acid)、及其類似物。
如本文中所用,術語「前藥」意欲意謂在體內於生理條件下(例如藉由正常代謝過程)轉化為其活性形式的非活性(或活性明顯較小)之藥物前驅物。該等化合物可能不必具有對NEP之藥理學活性,但可經口或非經腸投與且其後在體內代謝,以形成對NEP具有藥理學活性之化合物。
術語「治療有效量」意謂在向有需要之患者投與時足以實現治療之量,亦即為獲得所需治療效果所需之藥物量。舉例而言,用於治療高血壓之治療有效量為例如減輕、抑制、消除或預防高血壓之症狀或治療高血壓之潛在原因所需的化合物量。在一個實施例中,治療有效量為降低血壓所需之藥物量或維持正常血壓所需之藥物量。另一方面,術語「有效量」意謂足以獲得所需結果(可能不必為治療結果)之量。舉例而言,當研究包含NEP酶之系統時,「有效量」可為抑制該酶所需之量。
如本文中所用之術語「治療(treating/treatment)」意謂治療患者(諸如哺乳動物,尤其人類)中之疾病或醫學病狀(諸如高血壓),其包括下列一或多者:(a)預防疾病或醫學病狀出現,亦即預防疾病或醫學病狀復發或預防性治療易患該疾病或醫學病狀之患者;(b)改善疾
病或醫學病狀,亦即消除患者中之疾病或醫學病狀或使該疾病或醫學病狀消退;(c)抑制疾病或醫學病狀,亦即減緩或阻止患者中疾病或醫學病狀之發展;或(d)減輕患者中之疾病或醫學病狀的症狀。舉例而言,術語「治療高血壓」將包括預防高血壓出現、改善高血壓、抑制高血壓及減輕高血壓之症狀(例如降低血壓)。術語「患者」意欲包括需要治療或疾病預防,或目前正為了疾病預防或治療特定疾病或醫學病狀而進行治療的彼等哺乳動物(諸如人類),以及其中對結晶化合物進行評估或用於分析之測試個體(例如動物模型)。
本文中所用之所有其他術語均意欲具有一般熟習其相關技術者所理解之其普通含義。
本發明化合物含有一或多個對掌性中心,且因此,此等化合物可以其各種立體異構形式製備並使用。在一些實施例中,為使本發明化合物的治療活性(例如治療高血壓)最佳化,可能需要碳原子具有特定(R,R)、(S,S)、(S,R)或(R,S)組態或具有該組態之立體異構形式增濃。在其他實施例中,本發明化合物以外消旋混合物形式存在。相應地,除非另外指明,否則本發明亦係關於外消旋混合物、純立體異構體(例如對映異構體及非對映異構體)、立體異構體增濃之混合物及其類似物。當在本文中描繪無任何立體化學之化學結構時,應瞭解該結構包涵所有可能之立體異構體。類似地,當在本文中展示或命名特定立體異構體時,熟習此項技術者應理解,除非另外指明,否則本發明之組合物中可能存在少量之其他立體異構體,其限制條件為組合物整體之效用不因該等其他異構體之存在而消除。個別立體異構體可藉由此項技術中熟知之大量方法來獲得,包括使用適合之對掌性固定相或載體的對掌性層析;或藉由將該等立體異構體化學轉化為非對映異構體,藉由習知手段(諸如層析或再結晶)分離該等非對映異構體,隨後再生初始立體異構體來獲得。
另外除非另外說明,否則在適用情況下,本發明化合物的所有順-反或E/Z異構體(幾何異構體)、互變異構形式及拓撲異構形式均包括在本發明之範疇內。舉例而言,儘管化學式描繪如下:
但應瞭解該化合物亦可以互變異構形式存在,諸如:
且本發明涵蓋兩種形式。
本發明化合物以及用於其合成之彼等化合物亦可包括經同位素標記之化合物,亦即其中一或多個原子中原子質量不同於在自然界中主要所見之原子質量的原子增濃。可併入式I化合物中之同位素的實例例如包括(但不限於)2H、3H、13C、14C、15N、18O、17O、35S、36Cl及18F。尤其受關注的為氚或碳-14增濃之式I化合物,其可用於例如組織分佈研究;氘增濃(尤其在代謝位點處氘增濃)的本發明化合物,其產生例如具有較大代謝穩定性之化合物;及正電子發射同位素(諸如11C、18F、15O及13N)增濃之式I化合物,其可用於例如正電子發射斷層攝影(Positron Emission Topography,PET)研究中。
本文中用於命名本發明化合物的命名法在本文之實例中進行說明。此命名法已使用可商購之AutoNom軟體(MDL,San Leandro,
California)得到。
美國專利公開案第2012/0213806號特定揭示(2S,4R)-5-聯苯-4-基-2-羥甲基-2-甲基-4-[(3H-[1,2,3]三唑-4-羰基)胺基]-戊酸,其由式I'表示(其中Ra及Rb為H):
諸如此類之化合物可以互變異構體形式存在,例如(2S,4R)-5-聯苯-4-基-2-羥甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)胺基]-戊酸。在一個實施例中,此化合物稱為活性形式且作為前藥投與,其經活體內代謝以形成式I'化合物。美國專利公開案第2012/0213806號亦揭示式I'化合物之某些前藥,諸如乙酯、丙酯、異丙酯、丁酯、異丁酯、3-甲基丁酯、戊酯、美度米(medoxomil)酯、2-嗎啉-4-基乙酯、2-嗎啉-4-基-2-側氧基乙酯、2-甲氧基乙酯、2-(2-甲氧基乙氧基)乙酯、2-甲磺醯基乙酯、2-二甲胺基乙酯、2-哌啶-1-基乙酯、茚滿-5-基酯、氧雜環丁烷-3-基酯、二甲基胺甲醯基甲酯、甲氧基羰基甲酯、乙醯氧基甲酯、丁醯氧基甲酯、苯甲氧基羰基甲酯、2-(2-側氧基吡咯啶-1-基)乙酯、乙氧基羰基氧基甲酯、苯甲酯、(S)-2-胺基-3-甲基-丁醯氧基甲酯、(S)-2-甲氧基羰基胺基-3-甲基-丁醯氧基甲酯、(R)-1-環己基氧基羰基氧基乙酯、(S)-1-環己基氧基羰基氧基乙酯;及5-甲基-2-側氧基-[1,3]二氧雜環戊烯-4-基甲酯前藥。
本發明之一個態樣係關於式I'化合物之其他前藥及變化形式。此等化合物為其中X為以下之式I化合物:
此等化合物由式IIa或IIb表示:
在式IIa及IIb化合物之一個實施例中,Ra及Rb為H;R2為H;且R7係選自-CH2CF2CH3、-CH2CF2CF3、-(CH2)5CH3、-(CH2)6CH3及
或R2為-C1-6烷基或-C(O)-C1-6烷基,且R7為H。在一個特定實施例中,R2為H,且R7係選自-CH2CF2CH3、-CH2CF2CF3、-(CH2)5CH3、-(CH2)6CH3及
R2係選自-CH3、-CH2CH3、-C(O)CH3、-C(O)CH(CH3)2及-C(O)CH2CH(CH3)2;且R7為H。
在式IIa及IIb化合物之另一個實施例中,Ra係選自-CH3、-OCH3及Cl,且Rb為H;或Ra係選自H、-CH3、Cl及F,且Rb為Cl;或Ra為H,且Rb係選自-CH3及-CN;R2係選自H、-C1-6烷基、-(CH2)2-3ORe及-(CH2)2-3NReRe;且R7係選自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-
CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-環己基、-CH2CH(NH2)C(O)OCH3、-C2-4伸烷基-N(CH3)2、-C0-6伸烷基嗎啉基及
其中各Rc獨立地為H或-C1-3烷基;各Rd獨立地為H、-CH3、-CH(CH3)2、苯基或苯甲基;且各Re獨立地為H或-CH3。在一個特定實施例中,Ra係選自-CH3、-OCH3及Cl,且Rb為H;或Ra係選自H、-CH3、Cl及F,且Rb為Cl;或Ra為H,且Rb係選自-CH3及-CN;R2係選自H、-C1-6烷基(例如-CH3、-CH2CH3或-CH(CH3))及其中Re為H之-(CH2)2-3ORe(例如-(CH2)2OH及-(CH2)3OH)或其中Re為-CH3之(CH2)2-3ORe(例如-(CH2)2OCH3);且R7為H。
美國專利公開案第2012/0213806號亦揭示其中Ra為H且Rb為F之式I'化合物,即(2S,4R)-5-(3'-氟聯苯-4-基)-2-羥甲基-2-甲基-4-[(3H-[1,2,3]三唑-4-羰基)胺基]戊酸,及其中Ra為F且Rb為H之式I'化合物,即(2S,4R)-5-(2'-氟聯苯-4-基)-2-羥甲基-2-甲基-4-[(3H-[1,2,3]三唑-4-羰基)胺基]戊酸。因此,本發明之另一個態樣係關於該等化合物之前藥。因此,在式IIa及IIb化合物之另一個實施例中,Ra為H,且Rb為F;或Ra為F,且Rb為H;R2係選自H、-C1-6烷基、-(CH2)2-3ORe及-(CH2)2-3NReRe;且R7係選自-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-環己基、-CH2CH(NH2)C(O)OCH3、-C2-4伸烷基-N(CH3)2、-C0-6伸烷基嗎啉基及
其中各Rc獨立地為H或-C1-3烷基;各Rd獨立地為H、-CH3、-CH(CH3)2、苯基或苯甲基;且各Re獨立地為H或-CH3。
本發明之另一個態樣係關於其中X為以下之式I化合物:
此等化合物由式III表示:
在式III化合物之一個實施例中,Ra為Cl,且Rb為H;或Ra為H,且Rb係選自Cl、F、-CH3及-CN;或Ra為F,且Rb為Cl;R2係選自H、-C1-6烷基、-(CH2)2-3ORe及-(CH2)2-3NReRe;R4係選自-OH、-OCH3、OCH2CH3及-C1-4烷基;且R7係選自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-環己基、-CH2CH(NH2)C(O)OCH3、-C2-4伸烷基-N(CH3)2、-C0-6伸烷基嗎啉基及
其中各Rc獨立地為H或-C1-3烷基;各Rd獨立地為H、-CH3、-CH(CH3)2、苯基或苯甲基;且各Re獨立地為H或-CH3。在一個特定實施例中,Ra為F,Rb為Cl,R2為H,R4為-OCH3或-OCH2CH3,且R7為
H。
美國專利公開案第2012/0213806號揭示其中Ra為F,Rb為H,R2為H且R7為H之式III化合物,即(2S,4R)-5-(2'-氟聯苯-4-基)-2-羥甲基-4-[(1-羥基-1H-[1,2,3]三唑-4-羰基)胺基]-2-甲基戊酸。因此,本發明之另一個態樣係關於此化合物之前藥。因此,在式III化合物之另一個實施例中,Ra為F,且Rb為H;R2為H;R4為-OH;且R7係選自-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRdNH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-環己基、-CH2CH(NH2)C(O)OCH3、-C2-4伸烷基-N(CH3)2、-C0-6伸烷基嗎啉基及
其中各Rc獨立地為H或-C1-3烷基;且各Rd獨立地為H、-CH3、-CH(CH3)2、苯基或苯甲基。
本發明之另一個態樣係關於其中X為以下之式I化合物:
此等化合物由式IVa或IVb表示:
在式IVa及IVb化合物之一個實施例中,Ra為Cl,且Rb為H;或Ra為H,且Rb係選自Cl、F、-CH3及-CN;或Ra為F,且Rb為Cl;R2係選
自H、-C1-6烷基、-(CH2)2-3ORe及-(CH2)2-3NReRe;且R7係選自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-環己基、-CH2CH(NH2)C(O)OCH3、-C2-4伸烷基-N(CH3)2、-C0-6伸烷基嗎啉基及
其中各Rc獨立地為H或-C1-3烷基;各Rd獨立地為H、-CH3、-CH(CH3)2、苯基或苯甲基;且各Re獨立地為H或-CH3。在一個特定實施例中,Ra為F,Rb為Cl,R2為H,且R7為H。
美國專利公開案第2012/0213806號揭示其中Ra為F,Rb為H,R2為H且R7為H之式IVa化合物,即(2S,4R)-5-(2'-氟聯苯-4-基)-2-羥甲基-2-甲基-4-[(2-側氧基-2,3-二氫噁唑-4-羰基)胺基]戊酸,及其中Ra為F,Rb為H,R2為H且R7為H之式IVb化合物,即(2S,4R)-5-(2'-氟聯苯-4-基)-2-羥甲基-2-甲基-4-[(2-側氧基-2,3-二氫噁唑-5-羰基)胺基]戊酸。因此,本發明之另一個態樣係關於此等化合物之前藥。因此,在式IVa及IVb化合物之另一個實施例中,Ra為F,且Rb為H;R2為H;且R7係選自-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-環己基、-CH2CH(NH2)C(O)OCH3、-C2-4伸烷基-N(CH3)2、-C0-6伸烷基嗎啉基及
其中各Rc獨立地為H或-C1-3烷基;且各Rd獨立地為H、-CH3、-CH(CH3)2、苯基或苯甲基。
美國專利公開案第2012/0213806號特定揭示(2S,4R)-5-聯苯-4-基-4-[(3-羥基異噁唑-5-羰基)胺基]-2-羥甲基-2-甲基戊酸,其由式V'(其中Ra及Rb為H且R3為-OH)表示:
美國專利公開案第2012/0213806號亦揭示式V'化合物之某些前藥,諸如其乙酯。本發明之一個態樣係關於式V'化合物之其他前藥及變化形式。此等化合物為其中X為以下之式I化合物:
此等化合物由式V表示:
在式V化合物之一個實施例中,Ra及Rb為H;R2係選自C1-6烷基、-(CH2)2-3ORe及-(CH2)2-3NReRe;R3係選自-OH、-OCH3、OCH2CH3及-C1-4烷基;且R7為H;其中各Re獨立地為H或-CH3。在式V化合物之一個特定實施例中,Ra及Rb為H,R2為-CH3,R3為-OH或-OCH3,且R7為H。
在式V化合物之另一個實施例中,Ra係選自Cl及F,且Rb為H;或Ra為H,且Rb係選自Cl、F、-CH3及-CN;或Ra為F,且Rb為Cl;R2係
選自H、-C1-6烷基、-(CH2)2-3ORe及-(CH2)2-3NReRe;R3係選自-OH、-OCH3、-OCH2CH3及-C1-4烷基;且R7係選自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-環己基、-CH2CH(NH2)C(O)OCH3、-C2-4伸烷基-N(CH3)2、-C0-6伸烷基嗎啉基及
其中各Rc獨立地為H或-C1-3烷基;各Rd獨立地為H、-CH3、-CH(CH3)2、苯基或苯甲基;且各Re獨立地為H或-CH3。在式V化合物之一個特定實施例中,Ra為H,Rb為Cl,R2為H、-CH3、-CH2CH3或-(CH2)2OH,R3為-OH或-OCH3,且R7為H;或Ra為F,Rb為Cl,R2為H或-C1-6烷基(例如-CH3或-CH2CH3),R3為-OH、-OCH3或-C1-4烷基(例如-CH2CH3、-(CH2)2CH3或-CH2CH(CH3)2),且R7為H。
本發明之另一個態樣係關於其中X為以下之式I化合物:
此等化合物由式VIa或VIb表示:
在式VI化合物之一個實施例中,Ra係選自Cl及F,且Rb為H;或
Ra為H,且Rb係選自Cl、F、-CH3及-CN;或Ra為F,且Rb為Cl;R2係選自H、-C1-6烷基、-(CH2)2-3ORe及-(CH2)2-3NReRe;R3係選自-OH、-OCH3、-OCH2CH3及-C1-4烷基;R4係選自H、-C1-6烷基及苯基;且R7係選自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-環己基、-CH2CH(NH2)C(O)OCH3、-C2-4伸烷基-N(CH3)2、-C0-6伸烷基嗎啉基及
其中各Rc獨立地為H或-C1-3烷基;各Rd獨立地為H、-CH3、-CH(CH3)2、苯基或苯甲基;且各Re獨立地為H或-CH3。在式VIa及VIb化合物之一個特定實施例中,Ra為H或F;Rb為Cl;R2為H或-C1-6烷基(例如-CH3);R3為-OCH3、-OCH2CH3或-C1-4烷基(例如-CH(CH3)2或-CH2CH(CH3)2);R4(若存在)為H;且R7為H。
本發明之另一個態樣係關於其中X為以下之式I化合物:
此等化合物由式VIIa或VIIb表示:
在式VII化合物之一個實施例中,Ra係選自Cl及F,且Rb為H;或
Ra為H,且Rb係選自Cl、F、-CH3及-CN;或Ra為F,且Rb為Cl;R2係選自H、-C1-6烷基、-(CH2)2-3ORe及-(CH2)2-3NReRe;R4係選自H、-C1-6烷基及苯基;且R7係選自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-環己基、-CH2CH(NH2)C(O)OCH3、-C2-4伸烷基-N(CH3)2、-C0-6伸烷基嗎啉基及
其中各Rc獨立地為H或-C1-3烷基;各Rd獨立地為H、-CH3、-CH(CH3)2、苯基或苯甲基;且各Re獨立地為H或-CH3。在式VIIa及VIIb化合物之一個特定實施例中,Ra為F,Rb為Cl,R2為H或-C1-6烷基(例如-CH3或-CH2CH3),R4(若存在)為H,且R7為H。
本發明之另一個態樣係關於其中X為以下之式I化合物:
此等化合物由式VIII表示:
在式VIII化合物之一個實施例中,Ra係選自Cl及F,且Rb為H;或Ra為H,且Rb係選自Cl、F、-CH3及-CN;或Ra為F,且Rb為Cl;R2係選自H、-C1-6烷基、-(CH2)2-3ORe及-(CH2)2-3NReRe;且R7係選自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-
CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-環己基、-CH2CH(NH2)C(O)OCH3、-C2-4伸烷基-N(CH3)2、-C0-6伸烷基嗎啉基及
其中各Rc獨立地為H或-C1-3烷基;各Rd獨立地為H、-CH3、-CH(CH3)2、苯基或苯甲基;且各Re獨立地為H或-CH3。
本發明之另一個態樣係關於其中X為以下之式I化合物:
此等化合物由式IX表示:
在式IX化合物之一個實施例中,Ra係選自Cl及F,且Rb為H;或Ra為H,且Rb係選自Cl、F、-CH3及-CN;或Ra為F,且Rb為Cl;R2係選自H、-C1-6烷基、-(CH2)2-3ORe及-(CH2)2-3NReRe;且R7係選自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-環己基、-CH2CH(NH2)C(O)OCH3、-C2-4伸烷基-N(CH3)2、-C0-6伸烷基嗎啉基及
其中各Rc獨立地為H或-C1-3烷基;各Rd獨立地為H、-CH3、-CH(CH3)2、苯基或苯甲基;且各Re獨立地為H或-CH3。
本發明化合物可使用下列一般方法、在實例中所闡述之程序自易於獲得之起始物質來製備,或藉由使用一般技術者已知之其他方法、試劑及起始物質來製備。儘管下列程序可說明本發明之特定實施例,但應瞭解本發明之其他實施例可使用相同或類似之方法,或藉由使用一般技術者已知之其他方法、試劑及起始物質來類似地製備。亦應理解,當指定典型或較佳製程條件(例如反應溫度、時間、反應物之莫耳比、溶劑、壓力等)時,除非另外說明,否則亦可使用其他製程條件。在一些情況下,在室溫下進行反應,且不進行實際溫度量測。應瞭解室溫可用來意謂在通常與實驗室環境中之環境溫度相關的範圍內的溫度,且通常在約18℃至約30℃之範圍內。在其他情況下,在室溫下進行反應,且實際量測並記錄溫度。雖然最佳反應條件通常視所用之各種反應參數(諸如特定反應物、溶劑及數量)而變化,但一般技術者可使用常規最佳化程序容易地確定適合之反應條件。
另外,如對熟習此項技術者而言顯而易知,可能必需或需要習知保護基來防止某些官能基發生非所需反應。適合於特定官能基之保護基以及適合於對該等官能基進行保護及脫去保護基的條件及試劑的選擇為此項技術中所熟知。若需要,可使用除本文所述之程序中所說明的彼等保護基之外的保護基。舉例而言,大量保護基及其引入及移除描述於T.W.Greene及G.M.Wuts,Protecting Groups in Organic Synthesis,第四版,Wiley,New York,2006,及其中所引用之參考文獻中。
羧基保護基適合於防止羧基處之非所需反應,且實例包括(但不限於)甲基、乙基、第三丁基、苯甲基(Bn)、對甲氧基苯甲基(PMB)、
9-茀基甲基(Fm)、三甲基矽烷基(TMS)、第三丁基二甲基矽烷基(TBDMS)、二苯甲基(diphenylmethyl/benzhydryl,DPM)及其類似基團。胺基保護基適合於防止胺基處之非所需反應,且實例包括(但不限於)第三丁氧基羰基(BOC)、三苯甲基(Tr)、苯甲氧基羰基(Cbz)、9-茀基甲氧基羰基(Fmoc)、甲醯基、三甲基矽烷基(TMS)、第三丁基二甲基矽烷基(TBDMS)及其類似基團。羥基保護基適合於防止羥基處之非所需反應,且實例包括(但不限於)C1-6烷基;矽烷基,包括三C1-6烷基矽烷基,諸如三甲基矽烷基(TMS)、三乙基矽烷基(TES)及第三丁基二甲基矽烷基(TBDMS);酯基(醯基),包括C1-6烷醯基,諸如甲醯基、乙醯基及特戊醯基,及芳族醯基,諸如苯甲醯基;芳基甲基,諸如苯甲基(Bn)、對甲氧基苯甲基(PMB)、9-茀基甲基(Fm)及二苯甲基(DPM);及其類似基團。
標準脫去保護基技術及試劑用於移除保護基,且可視所用之基團而變化。舉例而言,當羧基保護基為甲基時,通常使用氫氧化鈉或氫氧化鋰;當羧基保護基為乙基或第三丁基時,通常使用酸,諸如TFA或HCl(例如4.0M HCl之1,4-二噁烷溶液);而當羧基保護基為苯甲基時,可使用H2/Pd/C。BOC胺基保護基可使用酸性試劑,諸如TFA之DCM溶液或HCl之1,4-二噁烷溶液來移除,而Cbz胺基保護基可藉由採用催化氫化條件,諸如H2(1標準大氣壓)及於醇溶劑中之10% Pd/C(「H2/Pd/C」)來移除。當羥基保護基為苯甲基時,通常使用H2/Pd/C;而當羥基保護基為醯基時,通常使用NaOH。
離去基為可在取代反應(諸如親核取代反應)中由另一個官能基或原子取代的官能基或原子。舉例而言,代表性離去基包括氯基、溴基及碘基;磺酸酯基,諸如甲磺酸酯基、甲苯磺酸酯基、溴苯磺酸酯基、硝基苯磺酸酯基及其類似基團;及醯氧基,諸如乙醯氧基、三氟乙醯氧基及其類似基團。
用於此等流程的適合之鹼包括(舉例而言但不加以限制)碳酸鉀、碳酸鈣、碳酸鈉、三乙胺(Et3N)、吡啶、1,8-二氮雜雙環-[5.4.0]十一-7-烯(DBU)、N,N-二異丙基乙胺(DIPEA)、4-甲基嗎啉、氫氧化鈉、氫氧化鉀、第三丁醇鉀及金屬氫化物。
用於此等流程的適合之惰性稀釋劑或溶劑(舉例而言但不加以限制)包括四氫呋喃(THF)、乙腈(MeCN)、N,N-二甲基甲醯胺(DMF)、N,N-二甲基乙醯胺(DMA)、二甲亞碸(DMSO)、甲苯、二氯甲烷(DCM)、氯仿(CHCl3)、四氯化碳(CCl4)、1,4-二噁烷、甲醇、乙醇、水、乙醚、丙酮及其類似物。
適合之羧酸/胺偶合試劑包括六氟磷酸苯并三唑-1-基氧基參(二甲胺基)鏻(BOP)、六氟磷酸苯并三唑-1-基氧基三吡咯啶基鏻(PyBOP)、六氟磷酸N,N,N',N'-四甲基-O-(7-氮雜苯并三唑-1-基)(HATU)、1,3-二環己基碳化二亞胺(DCC)、N-(3-二甲胺基丙基)-N'-乙基碳化二亞胺(EDC)、羰基二咪唑(CDI)、1-羥基苯并三唑(HOBt)及其類似物。偶合反應在鹼(諸如DIPEA)存在下於惰性稀釋劑中進行,且在習知醯胺鍵形成條件下進行。
所有反應通常均在約-78℃至100℃之範圍內的溫度下(例如在室溫下)進行。反應可藉由使用薄層層析(TLC)、高效液相層析(HPLC)及/或LCMS監測直至完成。反應可在數分鐘內完成,或可耗時數小時,通常1-2小時至長達48小時。在完成後,所得混合物或反應產物可經進一步處理以獲得所需產物。舉例而言,所得混合物或反應產物可經歷一或多種下列程序:濃縮或分配(例如在EtOAc與水之間,或在5% THF之EtOAc溶液與1M磷酸之間);萃取(例如用EtOAc、CHCl3、DCM、氯仿);洗滌(例如用飽和NaCl水溶液、飽和NaHCO3水溶液、Na2CO3(5%)、CHCl3或1M NaOH);乾燥(例如經MgSO4、經Na2SO4或在真空中);過濾;結晶(例如自EtOAc及己烷);濃縮(例如在真空
中);及/或純化(例如矽膠層析、急驟層析、製備型HPLC、逆相HPLC或結晶)。
舉例而言,式I化合物以及其鹽可如流程I-IV中所示來製備。
流程I為酯基轉移反應。一般而言,此反應涉及使酯與熱、所需醇(HO-R7)及適合之酸催化劑(例如鹽酸)反應。HO-R7醇為可商購的,或可藉由此項技術中已知或本文所述之技術來製備。例示性HO-R7包括HO-CH2CF2CH3、HO-CH2CF2CF3及
流程II為親核取代反應,其中L為適合之離去基。一般而言,此反應在適合之鹼(諸如三乙胺)存在下於適合之惰性稀釋劑或溶劑(諸如丙酮)中進行。L-R7化合物為可商購的,或可藉由此項技術中已知或本文所述之技術來製備。
流程III
流程III為親核取代反應,其中L為適合之離去基。一般而言,此反應在適合之鹼(諸如N,N-二異丙基乙胺)存在下於適合之惰性稀釋劑或溶劑中(諸如二氯甲烷)進行。L-R2化合物為可商購的,或可藉由此項技術中已知或本文所述之技術來製備。例示性L-R2化合物包括Cl-C(O)-CH3、Cl-C(O)-CH(CH3)2及Cl-C(O)-CH2CH(CH3)2。
流程IV為偶合反應,其中P為H或適合之胺基保護基。當P為胺基保護基時,該製程進一步包含在偶合步驟之前或當場對化合物脫去保護基。例示性偶合試劑包括HATU及含EDC之HOBt。一般而言,此反應在鹼(諸如DIPEA或4-甲基嗎啉)及惰性稀釋劑或溶劑(諸如DMF或DMA)存在下進行。羧酸起始物質一般為可商購的,或可使用此項技術中已知之程序來製備。
舉例而言,式II-式X化合物以及其鹽可如流程V中所示製備。
於惰性稀釋劑中,在適合之鹼(諸如碳酸鉀或碳酸鈉)存在下將(R)-3-(4-溴苯基)-2-第三丁氧基羰基胺基丙酸及所需鹵代苯基酸與鈀催化劑組合。例示性鹵代苯基酸為2-氟苯基酸、3-氟苯基酸、2-氯苯基酸、3-氯苯基酸及2-氟-5-氯苯基酸。例示性鈀催化劑包括1,1-雙(二苯基膦基)二茂鐵氯化鈀、二氯雙(三苯基膦)鈀(II)、雙(三第三丁基膦)鈀(0)及肆(三苯膦)鈀(0)。
隨後藉由包含若干步驟之製程將化合物1轉變為化合物5(其中P為H或適合之胺基保護基),該製程於實例部分中詳細描述。
最後,如上文流程IV中所描述,將化合物5與所需X基團偶合。
關於用於製備本發明之代表性化合物或其中間物的特定反應條件及其他程序的其他細節描述於以下所闡述之實例中。
式I'化合物具有作為腦啡肽酶抑制劑之活性,且預期其具有作為腦啡肽酶抑制劑之治療效用。預期此化合物之前藥一旦經活體內代謝
即具有相同效用。因此,當論述本發明化合物的活性時,應瞭解此等前藥一旦經代謝即具有預期之活性。
例示性分析(舉例而言但不加以限制)包括量測NEP抑制之分析。適用之二級分析包括量測ACE抑制及胺基肽酶P(APP)抑制之分析(例如在Sulpizio等人(2005)JPET 315:1306-1313中所描述)。用於評定ACE及NEP在麻醉之大鼠中之活體內抑制效能的藥力學分析描述於Seymour等人(1985)Hypertension 7(增刊I):I-35-I-42及Wigle等人(1992)Can.J.Physiol.Pharmacol.70:1525-1528)中,其中ACE抑制以對血管收縮素I(angiotensin I)加壓響應之抑制的百分比來量測,而NEP抑制以泌尿系統環狀鳥苷3',5'-單磷酸(cGMP)的排出增加來量測。
亦可使用許多活體內分析。有意識的自發性高血壓大鼠(SHR)模型為腎素(renin)依賴性高血壓模型。參見例如Intengan等人(1999)Circulation 100(22):2267-2275及Badyal等人(2003)Indian Journal of Pharmacology 35:349-362。有意識的乙酸去氧皮質固酮-鹽(DOCA-鹽)大鼠模型為適用於量測NEP活性之體積依賴性高血壓模型。參見例如Trapani等人(1989)J.Cardiovasc.Pharmacol.14:419-424、Intengan等人(1999)Hypertension 34(4):907-913及Badyal等人(2003)同前)。DOCA-鹽模型尤其適用於評估測試化合物降低血壓之能力,以及量測測試化合物預防或延遲血壓上升之能力。達爾鹽敏感性(Dahl salt-sensive,DSS)高血壓大鼠模型為對膳食鹽(NaCl)敏感之高血壓模型,且描述於例如Rapp(1982)Hypertension 4:753-763中。描述於例如Kato等人(2008)J.Cardiovasc.Pharmacol.51(1):18-23中的肺動脈高血壓之大鼠野百合鹼模型為用於治療肺動脈高血壓之臨床功效的可靠預測因子。心臟衰竭動物模型包括心臟衰竭之DSS大鼠模型及主動脈-下腔靜脈瘺管模型(AV分流),後者描述於例如Norling等人(1996)
J.Amer.Soc.Nephrol.7:1038-1044中。其他動物模型(諸如熱板、閃尾(tail-flick)及福馬林測試)以及神經病變性疼痛之脊神經結紮(SNL)模型可用於量測化合物之止痛特性。參見例如Malmberg等人(1999)Current Protocols in Neuroscience 8.9.1-8.9.15。化合物之其他特性及效用可使用熟習此項技術者所熟知之各種活體外及活體內分析進行論證。
預期本發明化合物適用於治療及/或預防對NEP抑制有響應之醫學病狀。因此預期罹患可藉由抑制NEP酶或藉由增加其肽受質之含量而治療之疾病或病症的患者可藉由投與治療有效量的本發明化合物來治療。舉例而言,預期該化合物藉由抑制NEP來增強由NEP代謝之內源性肽的生物效應,該等內源性肽諸如利尿鈉肽(natriuretic peptide)、鈴蟾素(bombesin)、緩激肽(bradykinin)、降鈣素(calcitonin)、內皮素(endothelin)、腦啡肽(enkephalin)、神經調壓素(neurotensin)、P物質及血管活性腸肽(vasoactive intestinal peptide)。因此,預期該等化合物對例如腎系統、中樞神經系統、生殖系統及胃腸系統具有其他生理作用。
預期本發明化合物可藉由增強血管活性肽(如利尿鈉肽及緩激肽)之效應而適用於治療及/或預防醫學病狀(諸如心血管疾病)。參見例如Roques等人(1993)Pharmacol.Rev.45:87-146及Dempsey等人(2009)Amer.J.of Pathology 174(3):782-796。尤其受關注之心血管疾病包括高血壓及心臟衰竭。高血壓(舉例而言但不加以限制)包括:原發性高血壓,亦稱為本態性高血壓或特發性高血壓;繼發性高血壓;伴隨有腎病之高血壓;伴隨有或不伴隨有腎病之重度高血壓;肺高血壓,包括肺動脈高血壓;及頑固性高血壓。心臟衰竭(舉例而言但不加以限制)包括:充血性心臟衰竭;急性心臟衰竭;慢性心臟衰竭,例如伴
隨有左心室射血分數降低之心臟衰竭(亦稱為收縮性心臟衰竭)或伴隨有左心室射血分數保持之心臟衰竭(亦稱為舒張性心臟衰竭);及伴隨有或不伴隨有腎病的急性及慢性代償失調心臟衰竭。因此,本發明之一個實施例係關於一種用於治療高血壓,尤其原發性高血壓或肺動脈高血壓之方法,其包含向患者投與治療有效量的本發明化合物。
對治療原發性高血壓,治療有效量通常為足以降低患者之血壓的量。此包括輕度至中度高血壓及重度高血壓。當用於治療高血壓時,化合物可與其他治療劑組合投與,該等其他治療劑諸如醛固酮(aldosterone)拮抗劑、血管收縮素轉化酶抑制劑及雙重作用血管收縮素轉化酶/腦啡肽酶抑制劑、血管收縮素轉化酶2(ACE2)活化劑及刺激劑、血管收縮素-II疫苗、抗糖尿病藥劑、抗脂質藥劑、抗血栓藥劑、AT1受體拮抗劑及雙重作用AT1受體拮抗劑/腦啡肽酶抑制劑、β1-腎上腺素激導性受體(adrenergic receptor)拮抗劑、雙重作用β-腎上腺素激導性受體拮抗劑/α1-受體拮抗劑、鈣離子通道阻斷劑、利尿劑、內皮素受體拮抗劑、內皮素轉化酶抑制劑、腦啡肽酶抑制劑、利尿鈉肽及其類似物、利尿鈉肽清除受體拮抗劑、氧化氮供體、非類固醇消炎劑、磷酸二酯酶抑制劑(特定言之PDE-V抑制劑)、前列腺素(prostaglandin)受體促效劑、腎素抑制劑、可溶性鳥苷酸環化酶(guanylate cyclase)刺激劑及活化劑及其組合。在本發明之一個特定實施例中,本發明化合物與AT1受體拮抗劑、利尿劑、鈣離子通道阻斷劑或其組合組合,且用於治療原發性高血壓。在本發明之另一個特定實施例中,本發明化合物與AT1受體拮抗劑組合,且用於治療伴隨有腎病之高血壓。
對治療肺動脈高血壓,治療有效量通常為足以降低肺血管阻力之量。療法之其他目的為改善患者之運動能力。舉例而言,在一種臨床配置中,治療有效量可為改善患者舒適步行6分鐘之時間段(涵蓋約
20-40公尺之距離)的能力的量。當用於治療肺動脈高血壓時,化合物可與其他治療劑組合投與,該等其他治療劑諸如α-腎上腺素激導性拮抗劑、β1-腎上腺素激導性受體拮抗劑、β2-腎上腺素激導性受體促效劑、血管收縮素轉化酶抑制劑、抗凝劑(anticoagulant)、鈣離子通道阻斷劑、利尿劑、內皮素受體拮抗劑、PDE-V抑制劑、前列腺素類似物、選擇性血清素(serotonin)再吸收抑制劑及其組合。在本發明之一個特定實施例中,本發明化合物與PDE-V抑制劑或選擇性血清素再吸收抑制劑組合,且用於治療肺動脈高血壓。
本發明之另一個實施例係關於一種用於治療心臟衰竭,詳言之充血性心臟衰竭(包括收縮性及舒張性充血性心臟衰竭)的方法,其包含向患者投與治療有效量的本發明化合物。治療有效量通常為足以降低血壓及/或改善腎功能之量。在一種臨床配置中,治療有效量可為足以改善心臟血液動力學,例如降低楔壓(wedge pressure)、右心房壓、填充壓及血管阻力之量。在一個實施例中,化合物以靜脈內劑型投與。當用於治療心臟衰竭時,化合物可與其他治療劑組合投與,該等其他治療劑諸如腺苷受體拮抗劑、晚期糖基化終產物裂解劑、醛固酮拮抗劑、AT1受體拮抗劑、β1-腎上腺素激導性受體拮抗劑、雙重作用β-腎上腺素激導性受體拮抗劑/α1-受體拮抗劑、凝乳酶(chymase)抑制劑、地高辛(digoxin)、利尿劑、內皮素轉化酶(ECE)抑制劑、內皮素受體拮抗劑、利尿鈉肽及其類似物、利尿鈉肽清除受體拮抗劑、氧化氮供體、前列腺素類似物、PDE-V抑制劑、可溶性鳥苷酸環化酶活化劑及刺激劑、及血管加壓素(vasopressin)受體拮抗劑。在本發明之一個特定實施例中,本發明化合物與醛固酮拮抗劑、β1-腎上腺素激導性受體拮抗劑、AT1受體拮抗劑或利尿劑組合,且用於治療充血性心臟衰竭。
預期本發明化合物作為NEP抑制劑可抑制內源性腦啡肽之降解,且因此該等化合物亦可適用於治療腹瀉,包括感染性及分泌性/水性腹瀉。參見例如Baumer等人(1992)Gut 33:753-758;Farthing(2006)Digestive Diseases 24:47-58及Marçais-Collado(1987)Eur.J.Pharmacol.144(2):125-132。當用於治療腹瀉時,本發明化合物可與一或多種其他止瀉療法組合。
預期本發明化合物藉由增強血管活性肽(如利尿鈉肽及緩激肽)之效應來增強腎功能(參見Chen等人(1999)Circulation 100:2443-2448;Lipkin等人(1997)Kidney Int.52:792-801及Dussaule等人(1993)Clin.Sci.84:31-39),且適用於治療及/或預防腎病。尤其受關注之腎病包括糖尿病性腎病、慢性腎病、蛋白尿,且尤其包括急性腎臟損傷或急性腎衰竭(參見Sharkovska等人(2011)Clin.Lab.57:507-515及Newaz等人(2010)Renal Failure 32:384-390)。當用於治療腎病時,化合物可與其他治療劑組合投與,該等其他治療劑諸如血管收縮素轉化酶抑制劑、AT1受體拮抗劑及利尿劑。
亦預期本發明化合物藉由增強利尿鈉肽之效應而適用於預防性療法,此係由於該等利尿鈉肽之抗肥厚性及抗纖維化性效應(參見Potter等人(2009)Handbook of Experimental Pharmacology 191:341-366),該等預防性療法例如用於預防心肌梗塞之後心機能不全之發展、預防血管成形術之後動脈再狹窄、預防血管手術之後血管壁變厚、預防動脈粥樣硬化及預防糖尿病性血管病。
預期本發明化合物藉由增強利尿鈉肽之效應而適用於治療青光眼。參見例如Diestelhorst等人(1989)International Ophthalmology
12:99-101。當用於治療青光眼時,本發明化合物可與一或多種其他抗青光眼藥劑組合。
預期本發明化合物作為NEP抑制劑可抑制內源性腦啡肽之降解,且因此該等化合物亦可適用作止痛劑。參見例如Roques等人(1980)Nature 288:286-288及Thanawala等人(2008)Current Drug Targets 9:887-894。當用於治療疼痛時,本發明化合物可與一或多種其他抗傷痛感受性藥物組合,該等抗傷痛感受性藥物諸如胺基肽酶N或二肽基肽酶III抑制劑、非類固醇消炎劑、單胺再吸收抑制劑、肌肉鬆弛劑、NMDA受體拮抗劑、類鴉片受體促效劑、5-HT1D血清素受體促效劑及三環抗抑鬱劑。
亦預期本發明化合物由於其NEP抑制特性而適用作止咳劑,並且適用於治療伴隨有肝硬化之肝門性高血壓(參見Sansoe等人(2005)J.Hepatol.43:791-798)、癌症(參見Vesely(2005)J.Investigative Med.53:360-365)、抑鬱症(參見Noble等人(2007)Exp.Opin.Ther.Targets 11:145-159)、月經異常、早產、子癇前症、子宮內膜異位症、生殖障礙(例如男性及女性不孕症、多囊性卵巢症候群、著床失敗(implantation failure))及男性及女性性功能障礙,包括男性勃起困難及女性性興奮障礙。更特定言之,預期本發明化合物適用於治療女性性功能障礙(參見Pryde等人(2006)J.Med.Chem.49:4409-4424),女性性功能障礙常常被定義為女性患者難以或無法在性行為中得到滿足。此涵蓋各種不同女性性功能障礙,包括(舉例而言但不加以限制)減退性性欲障礙(hypoactive sexual desire disorder)、性興奮障礙、性高潮障礙及性疼痛障礙。當用於治療該等病症,尤其女性性功能障礙時,本發明化合物可與一或多種下列第二藥劑組合:PDE-V抑制劑、
多巴胺促效劑、雌激素受體促效劑及/或拮抗劑、雄激素及雌激素。亦預期本發明化合物由於其NEP抑制特性而具有消炎特性,且預期其尤其在與士他汀(statin)組合使用時具有如此效用。
近期研究表明,NEP在胰島素缺乏性糖尿病及膳食誘導性肥胖症中起調控神經功能之作用。Coppey等人(2011)Neuropharmacology 60:259-266。因此,亦預期本發明化合物由於其NEP抑制特性而適用於針對由糖尿病或膳食誘導性肥胖症造成之神經損傷提供保護。
本發明化合物每劑投與量或每天投與總量可預先確定,或其可基於個別患者,藉由考慮大量因素而確定,該等因素包括患者之病狀的性質及嚴重性;所治療之病狀;患者之年齡、重量及一般健康狀況;患者對活性劑之耐受性;投藥途徑;藥理學考慮因素,諸如所投與之化合物及任何第二藥劑的活性、功效、藥代動力學及毒理學概況;及其類似因素。治療罹患疾病或醫學病狀(諸如高血壓)之患者可以預先確定之劑量或由治療醫師確定之劑量開始,且持續預防、改善、抑制或緩解疾病或醫學病狀之症狀所必需的時間段。經歷該治療之患者通常將受常規監測,以確定療法之有效性。舉例而言,在治療高血壓時,血壓量測值可用於確定治療之有效性。本文所述之其他疾病及病狀的類似指標為人所熟知,且容易由治療醫師獲得。醫師進行連續監測將保證在任何既定時間投與最佳量的本發明化合物,以及促進確定治療之持續時間。此在亦投與第二藥劑時特別有價值,因為第二藥劑之選擇、劑量及療法之持續時間亦可能需要調節。以此方式,可在治療過程中調節治療方案及給藥時程,以投與展現所需有效性的最低量之活性劑,且此外,投藥僅持續成功治療疾病或醫學病狀所必需的時間長度即可。
因為本發明化合物經活體內代謝為具有作為腦啡肽酶抑制劑之
活性的化合物,所以其亦適用作調查或研究具有NEP酶之生物系統或樣品的研究工具,例如研究其中NEP酶或其肽受質起作用之疾病。相應地,本發明之一個態樣係關於一種使用本發明化合物作為研究工具的方法,其包含使用本發明化合物進行生物分析。具有NEP酶的任何適合之生物系統或樣品均可用於該等研究中,該等研究可在活體外或活體內進行。適合於該等研究之代表性生物系統或樣品包括(但不限於)細胞、細胞提取物、質膜(plasma membrane)、組織樣品、分離之器官、哺乳動物(諸如小鼠、大鼠、天竺鼠、兔、狗、豬、人類等)及其類似物,其中哺乳動物尤其受關注。在本發明之一個特定實施例中,哺乳動物中之NEP酶活性藉由投與NEP抑制量的本發明化合物而得以抑制。亦可藉由使用該等化合物進行生物分析來將此等化合物用作研究工具。
當用作研究工具時,通常使包含NEP酶之生物系統或樣品與NEP酶抑制量的本發明化合物接觸。在將生物系統或樣品暴露於化合物之後,使用習知程序及設備,諸如藉由在結合分析中量測受體結合或在功能性分析中量測配位體介導之變化來測定抑制NEP酶之效應。暴露包涵使細胞或組織與化合物接觸,例如藉由腹膜內(i.p.)、口服(p.o)、靜脈內(i.v.)、皮下(s.c.)或吸入投藥等向哺乳動物投與結晶化合物。此測定步驟可涉及量測響應(定量分析)或可涉及進行觀測(定性分析)。量測響應涉及例如,使用習知程序及設備(諸如酶活性分析)來測定化合物對生物系統或樣品之影響,及在功能性分析中量測酶受質或產物介導之變化。分析結果可用於確定達成所需結果所必需的化合物之活性程度以及量,亦即NEP酶抑制量。該確定步驟通常涉及測定抑制NEP酶之效應。
另外,本發明化合物可用作用於評估其他化合物之研究工具,且因此亦適用於篩檢分析以發現例如具有NEP抑制活性之新穎化合
物。因此,本發明之另一個態樣係關於一種在生物分析中評估測試化合物的方法,其包含:(a)用測試化合物進行生物分析以提供第一分析值;(b)用本發明化合物進行生物分析以提供第二分析值;其中步驟(a)在步驟(b)之前、之後或與步驟(b)同時進行;及(c)比較來自步驟(a)之第一分析值與來自步驟(b)之第二分析值。例示性生物分析包括NEP酶抑制分析。以此方式,本發明化合物在分析中用作標準樣品,以比較用測試化合物與用本發明化合物所獲得的結果,由此鑑別具有大致相等或優越活性的彼等測試化合物(若存在)。舉例而言,將一種測試化合物或一組測試化合物的pKi數據與本發明化合物的pKi數據相比,以鑑別具有所需特性之彼等測試化合物,例如pKi值大致等於或優於本發明化合物的測試化合物(若存在)。本發明之此態樣包括產生比較數據(使用適當分析)與分析測試數據作為獨立實施例來鑑別所關注之測試化合物。
本發明之再另一個態樣係關於一種研究包含NEP酶之生物系統或樣品的方法,該方法包含(a)使生物系統或樣品與本發明化合物接觸;及(b)測定由該化合物對該生物系統或樣品所產生的效應。
本發明化合物通常以醫藥組合物或調配物形式向患者投與。該等醫藥組合物可藉由任何可接受之投藥途徑向患者投與,包括(但不限於)經口、經直腸、經陰道、經鼻、吸入、局部(包括經皮)、經眼及非經腸之投藥模式。此外,本發明化合物可例如經口以每天多次劑量(例如每日兩次、三次或四次),以單次日劑量或以單次週劑量投與。應瞭解,適合於特定投藥模式的本發明化合物的任何形式(亦即游離鹼、游離酸、醫藥學上可接受之鹽、溶劑合物等)均可用於本文中所論述之醫藥組合物中。
相應地,在一個實施例中,本發明係關於一種包含醫藥學上可
接受之載劑及本發明化合物的醫藥組合物。若需要,則組合物可含有其他治療劑及/或調配劑。當論述組合物時,「本發明化合物」在本文中亦可稱為「活性劑」,以將其與調配物之其他組分(諸如載劑)進行區分。因此,應瞭解術語「活性劑」包括式I化合物以及該化合物的醫藥學上可接受之鹽、溶劑合物及前藥。
本發明之醫藥組合物通常含有治療有效量的本發明化合物。然而,熟習此項技術者應認識到醫藥組合物可含有大於治療有效量(諸如在大批組合物中)或小於治療有效量(亦即經設計用於多次投藥以達成治療有效量的個別單元劑量)。組合物通常將含有約0.01wt%-95wt%之活性劑,包括約0.01wt%-30wt%,諸如約0.01wt%-10wt%,其中實際量視調配物本身、投藥途徑、給藥頻率等而定。在一個實施例中,適合於口服劑型之組合物例如可含有約5wt%-70wt%或約10wt%-60wt%之活性劑。
任何習知載劑或賦形劑可用於本發明之醫藥組合物中。特定載劑或賦形劑,或載劑或賦形劑之組合的選擇取決於用於治療特定患者或特定類型之醫學病狀或疾病病況的投藥模式。就此而言,製備適合特定投藥模式之組合物完全處於熟習醫藥技術者之範疇內。另外,該等組合物中所用之載劑或賦形劑為可商購的。進一步舉例而言,習知調配技術描述於Remington:The Science and Practice of Pharmacy,第20版,Lippincott Williams & White,Baltimore,Maryland(2000)及H.C.Ansel等人,Pharmaceutical Dosage Forms and Drug Delivery Systems,第7版,Lippincott Williams & White,Baltimore,Maryland(1999)中。
可充當醫藥學上可接受之載劑的物質的代表性實例包括(但不限於)下列各物:糖,諸如乳糖、葡萄糖及蔗糖;澱粉,諸如玉米澱粉及馬鈴薯澱粉;纖維素,諸如微晶纖維素及其衍生物,諸如羧甲基纖維素鈉、乙基纖維素及乙酸纖維素;粉末狀黃蓍膠;麥芽;明膠;滑
石;賦形劑,諸如可可脂及栓劑蠟;油,諸如花生油、棉籽油、紅花油、芝麻油、橄欖油、玉米油及大豆油;二醇,諸如丙二醇;多元醇,諸如甘油、山梨糖醇、甘露糖醇及聚乙二醇;酯,諸如油酸乙酯及月桂酸乙酯;瓊脂;緩衝劑,諸如氫氧化鎂及氫氧化鋁;海藻酸;無熱原質水;等張生理鹽水;林格氏溶液(Ringer's solution);乙醇;磷酸鹽緩衝溶液;壓縮推進劑氣體,諸如氯氟碳化物及氫氟碳化物;及在醫藥組合物中採用之其他無毒相容物質。
通常藉由將活性劑與醫藥學上可接受之載劑及一或多種視情況選用之成分充分且緊密地混合或摻合來製備醫藥組合物。所得均勻摻合之混合物可隨後使用習知程序及設備來成形或裝入錠劑、膠囊、丸劑、罐、藥筒、分配器及其類似物中。
在一個實施例中,醫藥組合物適合於經口投藥。適合用於經口投藥之組合物可呈以下形式:膠囊、錠劑、丸劑、口含錠、扁囊劑、糖衣藥丸、散劑、顆粒劑;在水性或非水性液體中之溶液或懸浮液;水包油或油包水液體乳液;酏劑或糖漿;及其類似物;各自含有預定量之活性劑。
當意欲以固體劑型(膠囊、錠劑、丸劑及其類似物)用於經口投藥時,組合物通常包含活性劑及一或多種醫藥學上可接受之載劑,諸如檸檬酸鈉或磷酸二鈣。固體劑型亦可包含:填充劑或增量劑,諸如澱粉、微晶纖維素、乳糖、蔗糖、葡萄糖、甘露糖醇及/或矽酸;黏合劑,諸如羧甲基纖維素、海藻酸鹽、明膠、聚乙烯基吡咯啶酮、蔗糖及/或阿拉伯膠;保濕劑,諸如甘油;崩解劑,諸如瓊脂-瓊脂、碳酸鈣、馬鈴薯或木薯澱粉、海藻酸、某些矽酸鹽及/或碳酸鈉;溶解延遲劑,諸如石蠟;吸收促進劑,諸如第四銨化合物;濕潤劑,諸如鯨蠟醇及/或甘油單硬脂酸酯;吸附劑,諸如高嶺土及/或膨潤土;潤滑劑,諸如滑石、硬脂酸鈣、硬脂酸鎂、固體聚乙二醇、月桂基硫酸鈉
及/或其混合物;著色劑;及緩衝劑。
釋放劑、濕潤劑、包衣劑、甜味劑、調味劑及芳香劑、防腐劑及抗氧化劑亦可存在於醫藥組合物中。用於錠劑、膠囊、丸劑及其類似物之例示性包衣劑包括用於腸溶衣之彼等包衣劑,諸如鄰苯二甲酸乙酸纖維素、聚鄰苯二甲酸乙酸乙烯酯、鄰苯二甲酸羥丙基甲基纖維素、甲基丙烯酸-甲基丙烯酸酯共聚物、偏苯三酸乙酸纖維素、羧甲基乙基纖維素、丁二酸乙酸羥丙基甲基纖維素及其類似物。醫藥學上可接受之抗氧化劑的實例包括:水溶性抗氧化劑,諸如抗壞血酸、半胱胺酸鹽酸鹽、硫酸氫鈉、偏亞硫酸鈉、亞硫酸鈉及其類似物;油溶性抗氧化劑,諸如棕櫚酸抗壞血酸酯、丁基化羥基大茴香醚、丁基化羥基甲苯、卵磷脂、沒食子酸丙酯、α-生育酚及其類似物;及金屬螯合劑,諸如檸檬酸、乙二胺四乙酸、山梨糖醇、酒石酸、磷酸及其類似物。
組合物亦可使用例如不同比例之羥丙基甲基纖維素或其他聚合物基質、脂質體及/或微球體來調配,以提供活性劑之緩慢或控制釋放。另外,本發明之醫藥組合物可含有乳濁劑,且可經調配以使得其僅在或優先在胃腸道之某一部分釋放活性劑,視情況以延遲之方式釋放。可使用之包埋組合物的實例包括聚合物質及蠟。活性劑亦可呈微囊封形式,視情況與一或多種上述賦形劑一起。
適合用於經口投藥之液體劑型(舉例而言)包括醫藥學上可接受之乳液、微乳液、溶液、懸浮液、糖漿及酏劑。液體劑型通常包含活性劑及惰性稀釋劑(諸如水)或其他溶劑、增溶劑及乳化劑,諸如乙醇、異丙醇、碳酸乙鹽、乙酸乙酯、苯甲醇、苯甲酸苯甲酯、丙二醇、1,3-丁二醇、油(例如棉籽油、花生油、玉米油、胚芽油、橄欖油、蓖麻油及芝麻油)、甘油、四氫呋喃基醇、聚乙二醇、及脫水山梨糖醇之脂肪酸酯、及其混合物。懸浮液可含有懸浮劑,諸如乙氧基化異硬
脂醇、聚氧乙烯山梨糖醇及脫水山梨糖醇酯、微晶纖維素、偏氫氧化鋁、膨潤土、瓊脂-瓊脂及黃蓍膠、及其混合物。
當意欲用於經口投藥時,本發明之醫藥組合物可以單位劑型包裝。術語「單位劑型」係指適合於向患者給藥之物理性的離散單元,亦即各單元單獨含有或與一或多個其他單元組合含有經計算可產生所需治療效果的預定量之活性劑。舉例而言,該等單位劑型可為膠囊、錠劑、丸劑及其類似劑型。
在另一個實施例中,本發明之組合物適合於吸入投與,且通常呈氣霧劑或散劑形式。一般使用熟知之傳遞裝置(諸如噴霧器、乾粉或定劑量吸入器)投與該等組合物。噴霧器裝置產生高速氣流,以使組合物以薄霧形式噴出而攜載入患者之呼吸道中。一種例示性噴霧器調配物包含活性劑溶解於載劑中以形成溶液,或活性劑經微米尺寸化且與載劑組合以形成含有可吸入尺寸之微米尺寸化粒子的懸浮液。乾粉吸入器投與呈自由流動粉末形式之活性劑,該活性劑在吸氣期間分散在患者之氣流中。一種例示性乾粉調配物包含與賦形劑(諸如乳糖、澱粉、甘露糖醇、右旋糖、聚乳酸、聚丙交酯-共-乙交酯及其組合)乾式摻合之活性劑。定劑量吸入器使用壓縮推進劑氣體排出量定量的活性劑。一種例示性定劑量調配物包含活性劑於液化推進劑(諸如氯氟碳化物或氫氟烷烴)中之溶液或懸浮液。該等調配物視情況選用之組分包括共溶劑,諸如乙醇或戊烷;及界面活性劑,諸如脫水山梨糖醇三油酸酯、油酸、卵磷脂、甘油及月桂基硫酸鈉。該等組合物通常藉由向含有活性劑、乙醇(若存在)及界面活性劑(若存在)的適合容器中添加經冷卻或經加壓之氫氟烷烴來製備。為製備懸浮液,將活性劑微米尺寸化,隨後與推進劑組合。或者,懸浮液調配物可藉由噴霧乾燥活性劑之微米尺寸化粒子上之界面活性劑塗層來製備。隨後將調配物裝入氣霧劑罐中,該氣霧劑罐形成吸入器之一部分。
本發明化合物亦可非經腸(例如藉由皮下、靜脈內、肌肉內或腹膜內注射)投與。對該等投藥,活性劑以無菌溶液、懸浮液或乳液形式提供。用於製備該等調配物之例示性溶劑包括水、生理鹽水、低分子量醇(諸如丙二醇)、聚乙二醇、油、明膠、脂肪酸酯(諸如油酸乙酯)及其類似物。非經腸調配物亦可含有一或多種抗氧化劑、增溶劑、穩定劑、防腐劑、濕潤劑、乳化劑及分散劑。界面活性劑、其他穩定劑或pH調節劑(酸、鹼或緩衝劑)及抗氧化劑尤其適用於為調配物提供穩定性,例如使酯鍵及醯胺鍵的水解或可存在於化合物中之硫醇的二聚化最小或得以避免。可藉由使用無菌可注射介質、滅菌劑、過濾、照射或加熱來使此等調配物無菌。在一個特定實施例中,非經腸調配物包含環糊精水溶液作為醫藥學上可接受之載劑。適合之環糊精包括含有在1,4位置處由如在澱粉酶、β-環糊精或環庚直鏈澱粉中之鍵連接的六個或六個以上α-D-葡萄哌喃糖單元的環狀分子。例示性環糊精包括環糊精衍生物,諸如羥丙基環糊精及磺酸基丁醚環糊精,諸如羥丙基-β-環糊精及磺酸基丁醚β-環糊精。用於該等調配物之例示性緩衝劑包括基於羧酸之緩衝劑,諸如檸檬酸鹽、乳酸鹽及順丁烯二酸鹽緩衝溶液。
本發明化合物亦可使用已知經皮傳遞系統及賦形劑來經皮投與。舉例而言,化合物可與滲透增強劑(諸如丙二醇、聚乙二醇單月桂酸酯、氮雜環烷-2-酮及其類似物)混合,且併入貼片或類似傳遞系統中。若需要則可在該等經皮組合物中使用其他賦形劑,包括膠凝劑、乳化劑及緩衝劑。
本發明化合物可適用於單獨治療疾病,或可與一或多種其他治療劑組合以獲得所需治療作用。因此,在一個實施例中,本發明之醫藥組合物含有與本發明化合物共同投與的其他藥物。舉例而言,組合
物可進一步包含一或多種藥物(亦稱為「第二藥劑」)。該等治療劑為此項技術中所熟知的,且包括腺苷受體拮抗劑、α-腎上腺素激導性受體拮抗劑、β1-腎上腺素激導性受體拮抗劑、β2-腎上腺素激導性受體促效劑、雙重作用β-腎上腺素激導性受體拮抗劑/α1-受體拮抗劑、晚期糖基化終產物裂解劑、醛固酮拮抗劑、醛固酮合成酶抑制劑、胺基肽酶N抑制劑、雄激素、血管收縮素轉化酶抑制劑及雙重作用血管收縮素轉化酶/腦啡肽酶抑制劑、血管收縮素轉化酶2活化劑及刺激劑、血管收縮素-II疫苗、抗凝劑、抗糖尿病藥劑、止瀉劑、抗青光眼藥劑、抗脂質藥劑、抗傷痛感受性藥劑、抗血栓藥劑、AT1受體拮抗劑及雙重作用AT1受體拮抗劑/腦啡肽酶抑制劑及多功能血管收縮素受體阻斷劑、緩激肽受體拮抗劑、鈣離子通道阻斷劑、凝乳酶抑制劑、地高辛、利尿劑、多巴胺促效劑、內皮素轉化酶抑制劑、內皮素受體拮抗劑、HMG-CoA還原酶抑制劑、雌激素、雌激素受體促效劑及/或拮抗劑、單胺再吸收抑制劑、肌肉鬆弛劑、利尿鈉肽及其類似物、利尿鈉肽清除受體拮抗劑、腦啡肽酶抑制劑、氧化氮供體、非類固醇消炎劑、N-甲基d-天冬胺酸受體拮抗劑、類鴉片受體促效劑、磷酸二酯酶抑制劑、前列腺素類似物、前列腺素受體促效劑、腎素抑制劑、選擇性血清素再吸收抑制劑、鈉離子通道阻斷劑、可溶性鳥苷酸環化酶刺激劑及活化劑、三環抗抑鬱劑、血管加壓素受體拮抗劑、及其組合。此等藥劑之特定實例詳述於本文中。
相應地,在本發明之又另一個態樣中,醫藥組合物包含本發明化合物、第二活性劑及醫藥學上可接受之載劑。第三、第四活性劑等亦可包括在組合物中。在組合療法中,本發明化合物的投與量以及第二藥劑之量可小於單藥療法中通常投與之量。
本發明化合物可與第二活性劑以物理方式混合以形成含有兩種藥劑之組合物;或各藥劑存在於獨立且不同之組合物中,該等組合物
係同時或在不同時間投與給患者。舉例而言,可使用習知程序及設備將本發明化合物與第二活性劑組合,以形成包含本發明化合物及第二活性劑的活性劑組合。另外,該等活性劑可與醫藥學上可接受之載劑組合,以形成包含本發明化合物、第二活性劑及醫藥學上可接受之載劑的醫藥組合物。在此實施例中,通常係將組合物之組分加以混合或摻合以產生物理性的混合物。隨後使用本文所述之任何途徑以治療有效量投與該物理性的混合物。
或者,該等活性劑在投與給患者之前是保持獨立且不同的。在此實施例中,藥劑在投藥之前不以物理方式混合在一起,而是以獨立組合物形式同時或在不同時間投與。該等組合物可分別包裝或可一起包裝在套組中。當在不同時間投與時,第二藥劑通常是在投與本發明化合物之後24小時以內投與,即在自與投與本發明化合物同時至給藥後約24小時之範圍內的任何時間。此亦稱為依序投藥。因此,本發明化合物與另一活性劑可使用兩個錠劑以同時方式或依序方式經口投與,各活性劑對應於一個錠劑,其中依序係意謂在投與本發明化合物後立即投與,或在某一預定時間後(例如一小時後或三小時後)投與。亦預期第二藥劑可在投與本發明化合物之後超過24小時投與。或者,可藉由不同投藥途徑投與組合,亦即一種藥劑經口投與而另一種藥劑藉由吸入投與。
在一個實施例中,套組係包含第一劑型及至少一種其他劑型,該第一劑型包含本發明化合物,該至少一種其他劑型包含本文中所闡述之一或多種第二藥劑,其量均足以進行本發明之方法。第一劑型及第二(或第三等)劑型一起包含用於治療或預防患者之疾病或醫學病狀的治療有效量之活性劑。
當包括第二藥劑時,其以治療有效量存在,以使得其在與本發明化合物共同投與時,通常以可產生治療學上有益之效應之量投與。
第二藥劑可呈醫藥學上可接受之鹽、溶劑合物、光學純立體異構體等形式。第二藥劑亦可呈前藥形式,例如具有已經酯化之羧酸基團的化合物。因此,本文中所列之第二藥劑意欲包括所有該等形式,且為可商購的或可使用習知程序及試劑製備。
在一個實施例中,本發明化合物與腺苷受體拮抗劑組合投與,該腺苷受體拮抗劑之代表性實例包括(但不限於)那昔茶鹼(naxifylline)、羅咯茶鹼(rolofylline)、SLV-320、茶鹼(theophylline)及托納普茶鹼(tonapofylline)。
在一個實施例中,本發明化合物與α-腎上腺素激導性受體拮抗劑組合投與,該α-腎上腺素受體拮抗劑之代表性實例包括(但不限於)多沙唑嗪(doxazosin)、哌唑嗪(prazosin)、他蘇洛辛(tamsulosin)及特拉唑嗪(terazosin)。
本發明化合物亦可與β1-腎上腺素激導性受體拮抗劑(「β1-阻斷劑」)組合投與。代表性β1-阻斷劑包括(但不限於)醋丁洛爾(acebutolol)、阿普洛爾(alprenolol)、胺磺洛爾(amosulalol)、阿羅洛爾(arotinolol)、阿替洛爾(atenolol)、苯呋洛爾(befunolol)、倍他洛爾(betaxolol)、貝凡洛爾(bevantolol)、比索洛爾(bisoprolol)、波吲洛爾(bopindolol)、布新洛爾(bucindolol)、布庫洛爾(bucumolol)、布非洛爾(bufetolol)、丁呋洛爾(bufuralol)、布尼洛爾(bunitrolol)、布拉洛爾(bupranolol)、巴布里丁(bubridine)、丁非洛爾(butofilolol)、卡拉洛爾(carazolol)、卡替洛爾(carteolol)、卡維地洛(carvedilol)、塞利洛爾(celiprolol)、塞他洛爾(cetamolol)、氯拉洛爾(cloranolol)、地來洛爾(dilevalol)、依泮洛爾(epanolol)、艾司洛爾(esmolol)、茚諾洛爾(indenolol)、拉貝洛爾(labetolol)、左布諾洛爾(levobunolol)、甲吲洛爾(mepindolol)、美替洛爾(metipranolol)、美托洛爾(metoprolol)(諸如丁二酸美托洛爾及酒石酸美托洛爾)、莫普洛爾(moprolol)、納多洛爾
(nadolol)、萘肟洛爾(nadoxolol)、奈必洛爾(nebivalol)、尼普地洛(nipradilol)、氧烯洛爾(oxprenolol)、噴布洛爾(penbutolol)、培布洛爾(perbutolol)、品多洛爾(pindolol)、普拉洛爾(practolol)、丙萘洛爾(pronethalol)、普萘洛爾(propranolol)、索他洛爾(sotalol)、薩非洛爾(sufinalol)、塔尼多(talindol)、特他洛爾(tertatolol)、替利洛爾(tilisolol)、噻嗎洛爾(timolol)、托利洛爾(toliprolol)、希苯洛爾(xibenolol)及其組合。在一個特定實施例中,β1-拮抗劑係選自阿替洛爾、比索洛爾、美托洛爾、普萘洛爾、索他洛爾及其組合。β1-阻斷劑通常將以足以提供每劑約2-900mg之量投與。
在一個實施例中,本發明化合物與β2-腎上腺素激導性受體促效劑組合投與,該β2-腎上腺素受體促效劑之代表性實例包括(但不限於)阿布叔醇(albuterol)、比托特羅(bitolterol)、非諾特羅(fenoterol)、福莫特羅(formoterol)、茚達特羅(indacaterol)、異他林(isoetharine)、左旋阿布叔醇(levalbuterol)、間羥異丙腎上腺素(metaproterenol)、吡布特羅(pirbuterol)、沙丁胺醇(salbutamol)、沙甲胺醇(salmefamol)、沙美特羅(salmeterol)、特布他林(terbutaline)、維拉特羅(vilanterol)及其類似物。β2-腎上腺素激導性受體促效劑通常以足以提供每劑約0.05-500μg之量投與。
在一個實施例中,本發明化合物與晚期糖基化終產物(AGE)裂解劑組合,該晚期糖基化終產物裂解劑之實例(舉例而言但不加以限制)包括阿拉格布(alagebrium)(或ALT-711)及TRC4149。
在另一個實施例中,本發明化合物與醛固酮拮抗劑組合投與,該醛固酮拮抗劑之代表性實例包括(但不限於)依普利酮(eplerenone)、螺內酯(spironolactone)及其組合。醛固酮拮抗劑通常將以足以提供每天約5-300mg之量投與。
在一個實施例中,本發明化合物與胺基肽酶N或二肽基肽酶III抑
制劑組合投與,該胺基肽酶N或二肽基肽酶III抑制劑之實例(舉例而言但不加以限制)包括苯丁抑制素(bestatin)及PC18(2-胺基-4-甲磺醯基丁硫醇、甲硫胺酸硫醇)。
本發明化合物亦可與血管收縮素轉化酶(ACE)抑制劑組合投與。代表性ACE抑制劑包括(但不限於)阿庫普利(accupril)、阿拉普利(alacepril)、貝那普利(benazepril)、貝那普利拉(benazeprilat)、卡托普利(captopril)、施瑞普利(ceranapril)、西拉普利(cilazapril)、地拉普利(delapril)、依那普利(enalapril)、依那普利拉(enalaprilat)、福辛普利(fosinopril)、福辛普利拉(fosinoprilat)、咪達普利(imidapril)、賴諾普利(lisinopril)、莫西普利(moexipril)、蒙諾普利(monopril)、莫維普利(moveltipril)、噴托普利(pentopril)、培哚普利(perindopril)、喹那普利(quinapril)、喹那普利拉(quinaprilat)、雷米普利(ramipril)、雷米普利拉(ramiprilat)、乙酸色拉新(saralasin acetate)、螺普利(spirapril)、替莫普利(temocapril)、群多普利(trandolapril)、佐芬普利(zofenopril)及其組合。
在一特定實施例中,ACE抑制劑係選自:貝那普利、卡托普利、依那普利、賴諾普利、雷米普利及其組合。ACE抑制劑通常將以足以提供每天約1-150mg之量投與。在另一個實施例中,本發明化合物與雙重作用血管收縮素轉化酶/腦啡肽酶(ACE/NEP)抑制劑組合投與,該ACE/NEP抑制劑之實例包括(但不限於):AVE-0848((4S,7S,12bR)-7-[3-甲基-2(S)-硫基丁醯胺基]-6-側氧基-1,2,3,4,6,7,8,12b-八氫吡啶并[2,1-a][2]-苯并氮呯-4-甲酸);AVE-7688(艾爾帕曲(ilepatril))及其母體化合物;BMS-182657(2-[2-側氧基-3(S)-[3-苯基-2(S)-硫基丙醯胺基]-2,3,4,5-四氫-1H-1-苯并氮呯-1-基]乙酸);CGS-35601(N-[1-[4-甲基-2(S)-硫基戊醯胺基]環戊基-羰基]-L-色胺酸);法西多曲(fasidotril);法西多利拉(fasidotrilate);依那普利拉;ER-32935
((3R,6S,9aR)-6-[3(S)-甲基-2(S)-硫基戊醯胺基]-5-側氧基全氫噻唑并[3,2-a]氮呯-3-甲酸);格帕曲拉(gempatrilat);MDL-101264((4S,7S,12bR)-7-[2(S)-(2-嗎啉基乙醯基硫基)-3-苯基丙醯胺基]-6-側氧基-1,2,3,4,6,7,8,12b-八氫吡啶并[2,l-a][2]苯并氮呯-4-甲酸);MDL-101287([4S-[4α,7α(R*),12bβ]]-7-[2-(羧甲基)-3-苯基丙醯胺基]-6-側氧基-1,2,3,4,6,7,8,12b-八氫吡啶并[2,1-a][2]苯并氮呯-4-甲酸);奧馬曲拉(omapatrilat);RB-105(N-[2(S)-(巰基甲基)-3(R)-苯基丁基]-L-丙胺酸);山帕曲拉(sampatrilat);SA-898((2R,4R)-N-[2-(2-羥基苯基)-3-(3-巰基丙醯基)噻唑啶-4-基羰基]-L-苯丙胺酸);Sch-50690(N-[1(S)-羧基-2-[N2-(甲磺醯基)-L-離胺醯基胺基]乙基]-L-纈胺醯基-L-酪胺酸);及其組合。在一個特定實施例中,ACE/NEP抑制劑係選自:AVE-7688、依那普利拉、法西多曲、法西多利拉、奧馬曲拉、山帕曲拉及其組合。
在一個實施例中,本發明化合物與血管收縮素轉化酶2(ACE2)活化劑或刺激劑組合投與。
在一個實施例中,本發明化合物與血管收縮素-II疫苗組合投與,該血管收縮素-II疫苗之實例包括(但不限於)ATR12181及CYT006-AngQb。
在一個實施例中,本發明化合物與抗凝劑組合投與,該抗凝劑之代表性實例包括(但不限於):香豆素(coumarin),諸如華法林(warfarin);肝素(heparin);及直接凝血酶抑制劑,諸如阿加曲班(argatroban)、比伐盧定(bivalirudin)、達比加群(dabigatran)及來匹盧定(lepirudin)。
在又另一個實施例中,本發明化合物與抗糖尿病藥劑組合投與。代表性抗糖尿藥劑包括可注射藥物以及口服有效藥物及其組合。可注射藥物之實例包括(但不限於)胰島素及胰島素衍生物。口服有效
藥物之實例包括(但不限於);雙胍(biguanide),諸如二甲雙胍(metformin);升糖素(glucagon)拮抗劑;α-葡糖苷酶(α-glucosidase)抑制劑,諸如醣祿(acarbose)及米格列醇(miglitol);二肽基肽酶IV抑制劑(DPP-IV抑制劑),諸如阿格列汀(alogliptin)、地那列汀(denagliptin)、利拉利汀(linagliptin)、沙格列汀(saxagliptin)、西他列汀(sitagliptin)及維格列汀(vildagliptin);美格替耐(meglitinide);諸如瑞格列奈(repaglinide);噁二唑啶二酮、磺醯脲,諸如氯磺丙脲(chlorpropamide)、格列美脲(glimepiride)、格列吡嗪(glipizide)、格列本脲(glyburide)及妥拉磺脲(tolazamide);噻唑啶二酮,諸如吡格列酮(pioglitazone)及羅格列酮(rosiglitazone);及其組合。
在另一個實施例中,本發明化合物與止瀉治療組合投與。代表性治療選項包括(但不限於)經口復水溶液(ORS)、洛哌丁胺(loperamide)、苯乙哌啶(diphenoxylate)及次水楊酸鉍。
在又另一個實施例中,本發明化合物與抗青光眼藥劑組合投與。代表性抗青光眼藥劑包括(但不限於):α-腎上腺素激導性促效劑,諸如溴莫尼定(brimonidine);β1-腎上腺素激導性受體拮抗劑;局部β1-阻斷劑,諸如倍他洛爾、左布諾洛爾及噻嗎洛爾;碳酸酐酶抑制劑,諸如乙醯唑胺(acetazolamide)、布林佐胺(brinzolamide)或多佐胺(dorzolamide);膽鹼激導性促效劑,諸如西維美林(cevimeline)及DMXB-假木賊鹼(DMXB-anabaseine);腎上腺素化合物;縮瞳劑(miotic),諸如匹魯卡品(pilocarpine);及前列腺素類似物。
在又另一個實施例中,本發明化合物與抗脂質藥劑組合投與。代表性抗脂質藥劑包括(但不限於)膽固醇酯轉移蛋白質抑制劑(CETP),諸如安塞曲匹(anacetrapib)、達塞曲匹(dalcetrapib)及托塞曲匹(torcetrapib);士他汀,諸如阿托伐他汀(atorvastatin)、氟伐他汀(fluvastatin)、洛伐他汀(lovastatin)、普伐他汀(pravastatin)、羅素他汀
(rosuvastatin)及辛伐他汀(simvastatin);及其組合。
在一個實施例中,本發明化合物與抗血栓藥劑組合投與。代表性抗血栓藥劑包括(但不限於)阿司匹林(aspirin);抗血小板藥劑,諸如氯吡格雷(clopidogrel)、普拉格雷(prasugrel)及噻氯匹定(ticlopidine);肝素及其組合。
在一個實施例中,本發明化合物與AT1受體拮抗劑(亦稱為血管收縮素II 1型受體阻斷劑(ARB))組合。代表性ARB包括(但不限於)阿比沙坦(abitesartan)、阿齊沙坦(azilsartan)(例如阿齊沙坦美度米(azilsartan medoxomil))、本洛沙坦(benzyllosartan)、坎地沙坦(candesartan)、坎地沙坦西來替昔(candesartan cilexetil)、依利沙坦(elisartan)、恩布沙坦(embusartan)、伊洛他索沙坦(enoltasosartan)、依普羅沙坦(eprosartan)、EXP3174、范沙坦(fonsartan)、福拉沙坦(forasartan)、格洛沙坦(glycyllosartan)、依貝沙坦(irbesartan)、伊索特林(isoteoline)、洛沙坦(losartan)、美度米(medoxomil)、米法沙坦(milfasartan)、奧美沙坦(olmesartan)(例如奧美沙坦美度米(olmesartan medoxomil))、奧普米沙坦(opomisartan)、普拉沙坦(pratosartan)、利匹沙坦(ripisartan)、沙普立沙坦(saprisartan)、色拉新(saralasin)、薩美新(sarmesin)、TAK-591、他索沙坦(tasosartan)、替米沙坦(telmisartan)、維沙坦(valsartan)、佐拉沙坦(zolasartan)及其組合。在一個特定實施例中,ARB係選自阿齊沙坦美度米、坎地沙坦西來替昔、依普羅沙坦、依貝沙坦、洛沙坦、奧美沙坦美度米、沙普立沙坦、他索沙坦、替米沙坦、維沙坦及其組合。例示性鹽及/或前藥包括坎地沙坦西來替昔、依普羅沙坦甲磺酸鹽、洛沙坦鉀鹽及奧美沙坦美度米。ARB通常將以足以提供每劑約4-600mg之量投與,其中例示性每日劑量在每天20-320mg之範圍內。
本發明化合物亦可與雙重作用藥劑組合投與,該雙重作用藥劑
諸如AT1受體拮抗劑/腦啡肽酶抑制劑(ARB/NEP抑制劑),該雙重作用藥劑之實例包括(但不限於)在均由Allegretti等人於2008年4月23日申請之美國專利公開案第2008/0269305號及第2009/0023228號中所描述的化合物,諸如化合物4'-{2-乙氧基-4-乙基-5-[((S)-2-巰基-4-甲基戊醯胺基)-甲基]咪唑-1-基甲基}-3'-氟聯苯基-2-甲酸。
本發明化合物亦可與如Kurtz及Klein(2009)Hypertension Research 32:826-834中所描述之多功能血管收縮素受體阻斷劑組合投與。
在一個實施例中,本發明化合物與緩激肽受體拮抗劑組合投與,該緩激肽受體拮抗劑例如艾替班特(icatibant)(HOE-140)。預期此組合療法可提供預防血管性水腫(angioedema)或緩激肽含量升高之其他非所需後果的優點。
在一個實施例中,本發明化合物與鈣離子通道阻斷劑組合投與。代表性鈣離子通道阻斷劑包括(但不限於)胺氯地平(amlodipine)、阿尼帕米(anipamil)、阿拉尼平(aranipine)、巴尼地平(barnidipine)、苄環烷(bencyclane)、貝尼地平(benidipine)、苄普地爾(bepridil)、克侖硫卓(clentiazem)、西尼地平(cilnidipine)、桂利嗪(cinnarizine)、地爾硫卓(diltiazem)、依福地平(efonidipine)、依高地平(elgodipine)、依他苯酮(etafenone)、非洛地平(felodipine)、芬地林(fendiline)、氟桂利嗪(flunarizine)、加洛帕米(gallopamil)、伊拉地平(isradipine)、拉西地平(lacidipine)、樂卡地平(lercanidipine)、利多氟嗪(lidoflazine)、洛美利嗪(lomerizine)、馬尼地平(manidipine)、米貝地爾(mibefradil)、尼卡地平(nicardipine)、硝苯地平(nifedipine)、尼古地平(niguldipine)、尼魯地平(niludipine)、尼伐地平(nilvadipine)、尼莫地平(nimodipine)、尼索地平(nisoldipine)、尼群地平(nitrendipine)、尼伐地平(nivaldipine)、哌克昔林(perhexiline)、普尼拉明(prenylamine)、
里奧斯汀(ryosidine)、司莫地爾(semotiadil)、特羅地林(terodiline)、替阿帕米(tiapamil)、維拉帕米(verapamil)及其組合。在一個特定實施例中,鈣離子通道阻斷劑係選自胺氯地平、苄普地爾、地爾硫卓、非洛地平、伊拉地平、拉西地平、尼卡地平、硝苯地平、尼古地平、尼魯地平、尼莫地平、尼索地平、里奧斯汀、維拉帕米及其組合。鈣離子通道阻斷劑通常將以足以提供每劑約2-500mg之量投與。
在一個實施例中,本發明化合物與凝乳酶抑制劑組合投與,該凝乳酶抑制劑諸如TPC-806及2-(5-甲醯胺基-6-側氧基-2-苯基-1,6-二氫嘧啶-1-基)-N-[{3,4-二側氧基-1-苯基-7-(2-吡啶氧基)}-2-庚基]乙醯胺(NK3201)。
在一個實施例中,本發明化合物與利尿劑組合投與。代表性利尿劑包括(但不限於):碳酸酐酶抑制劑,諸如乙醯唑胺(acetazolamide)及雙氯非那胺(dichlorphenamide);環利尿劑(loop diuretics),其包括磺醯胺衍生物(諸如乙醯唑胺、安布賽特(ambuside)、阿佐塞米(azosemide)、布美他尼(bumetanide)、布他唑胺(butazolamide)、氯米非那胺(chloraminophenamide)、氯非那胺(clofenamide)、氯帕胺(clopamide)、氯索隆(clorexolone)、二磺法胺(disulfamide)、依索唑胺(ethoxolamide)、呋塞米(furosemide)、美夫西特(mefruside)、醋甲唑胺(methazolamide)、吡咯他尼(piretanide)、托拉塞米(torsemide)、曲帕胺(tripamide)及希帕胺(xipamide))以及非磺醯胺利尿劑(諸如依他尼酸(ethacrynic acid))及其他苯氧基乙酸化合物(諸如替尼酸(tienilic acid)、茚達立酮(indacrinone)及喹卡酯(quincarbate));滲透性利尿劑,諸如甘露糖醇;留鉀利尿劑(potassium-sparing diuretics),其包括醛固酮拮抗劑(諸如螺內酯(spironolactone))及Na+通道抑制劑(諸如胺氯吡脒(amiloride)及胺苯喋啶(triamterene));噻嗪及類似噻嗪的利尿劑,諸如阿爾噻嗪
(althiazide)、苄氟噻嗪(bendroflumethiazide)、苄氫氯噻嗪(benzylhydrochlorothiazide)、苄噻嗪(benzthiazide)、布噻嗪(buthiazide)、氯噻酮(chlorthalidone)、氯噻嗪(chlorothiazide)、環戊噻嗪(cyclopenthiazide)、環噻嗪(cyclothiazide)、依匹噻嗪(epithiazide)、乙噻嗪(ethiazide)、芬喹唑(fenquizone)、氟甲噻嗪(flumethiazide)、氫氯噻嗪(hydrochlorothiazide)、氫氟噻嗪(hydroflumethiazide)、吲達帕胺(indapamide)、甲氯噻嗪(methylclothiazide)、美替克侖(meticrane)、美托拉宗(metolazone)、對氟噻嗪(paraflutizide)、多噻嗪(polythiazide)、喹乙唑酮(quinethazone)、四氯噻嗪(teclothiazide)及三氯噻嗪(trichloromethiazide);及其組合。在一個特定實施例中,利尿劑係選自胺氯吡脒、布美他尼、氯噻嗪、氯噻酮、雙氯非那胺、依他尼酸、呋塞米、氫氯噻嗪、氫氟噻嗪、吲達帕胺、甲氯噻嗪、美托拉宗、托拉塞米、胺苯喋啶及其組合。利尿劑以足以提供每天約5-50mg(更通常每天6-25mg)之量投與,其中常用劑量為每天6.25mg、12.5mg或25mg。
本發明化合物亦可與內皮素轉化酶(ECE)抑制劑組合投與,該ECE抑制劑之實例包括(但不限於)膦醯二肽(phosphoramidon)、CGS 26303及其組合。
在一個特定實施例中,本發明化合物與內皮素受體拮抗劑組合投與。代表性內皮素受體拮抗劑包括(但不限於):影響內皮素A受體之選擇性內皮素受體拮抗劑,諸如阿伏生坦(avosentan)、安立生坦(ambrisentan)、阿曲生坦(atrasentan)、BQ-123、克拉生坦(clazosentan)、達盧生坦(darusentan)、西他塞坦(sitaxentan)及齊泊替坦(zibotentan);及影響內皮素A與B受體之雙重內皮素受體拮抗劑,諸如波生坦(bosentan)、馬西替坦(macitentan)、替唑生坦
(tezosentan)。
在又另一個實施例中,本發明化合物與一或多種HMG-CoA還原酶抑制劑(亦稱為士他汀)組合投與。代表性士他汀包括(但不限於)阿托伐他汀、氟伐他汀、洛伐他汀、匹伐他汀(pitavastatin)、普伐他汀、羅素他汀及辛伐他汀。
在一個實施例中,本發明化合物與單胺再吸收抑制劑組合投與,該單胺再吸收抑制劑之實例(舉例而言但不加以限制)包括去甲腎上腺素再吸收抑制劑,諸如阿托莫西汀(atomoxetine)、丁胺苯丙酮(buproprion)及丁胺苯丙酮代謝物羥基丁胺苯丙酮、麥普替林(maprotiline)、瑞波西汀(reboxetine)及維洛沙嗪(viloxazine);選擇性血清素再吸收抑制劑(SSRI),諸如西它普蘭(citalopram)及西它普蘭代謝物去甲西它普蘭(desmethylcitalopram)、達泊西汀(dapoxetine)、依地普蘭(escitalopram)(例如乙二酸依地普蘭)、氟西汀(fluoxetine)及氟西汀去甲基代謝物去甲氟西汀(norfluoxetine)、氟伏沙明(fluvoxamine)(例如順丁烯二酸氟伏沙明)、帕羅西汀(paroxetine)、舍曲林(sertraline)及舍曲林代謝物去甲舍曲林(demethylsertraline);雙重血清素-去甲腎上腺素再吸收抑制劑(SNRI),諸如比西發定(bicifadine)、度洛西汀(duloxetine)、米那普侖(milnacipran)、奈法唑酮(nefazodone)及文拉法辛(venlafaxine);及其組合。
在另一個實施例中,本發明化合物與肌肉鬆弛劑組合投與,該肌肉鬆弛劑之實例包括(但不限於)肌安寧(carisoprodol)、氯唑沙宗(chlorzoxazone)、環苯紮平(cyclobenzaprine)、二氟尼柳(diflunisal)、美他沙酮(metaxalone)、美索巴莫(methocarbamol)及其組合。
在一個實施例中,本發明化合物與利尿鈉肽或類似物組合投與,該利尿鈉肽或類似物之實例包括(但不限於):卡培立肽(carperitide)、CD-NP(Nile Therapeutics)、CU-NP、奈西立肽
(nesiritide)、PL-3994(Palatin Technologies,Inc.)、烏拉立肽(ularitide)、森德立肽(cenderitide)及在Ogawa等人(2004)J.Biol.Chem.279:28625-31中所描述之化合物。此等化合物亦稱為利尿鈉肽受體-A(NPR-A)促效劑。在另一個實施例中,本發明化合物與利尿鈉肽清除受體(NPR-C)拮抗劑組合投與,該NPR-C拮抗劑諸如SC-46542、cANF(4-23)及AP-811(Veale(2000)Bioorg Med Chem Lett 10:1949-52)。舉例而言,當與NEP抑制劑、塞奧芬(thiorphan)組合時,AP-811展示協同作用(Wegner(1995)Clin.Exper.Hypert.17:861-876)。
在另一個實施例中,本發明化合物與腦啡肽酶(NEP)抑制劑組合投與。代表性NEP抑制劑包括(但不限於):AHU-377;坎沙曲(candoxatril);坎沙曲拉(candoxatrilat);右卡多曲(dexecadotril)((+)-N-[2(R)-(乙醯基硫基甲基)-3-苯基丙醯基]甘胺酸苯甲酯);CGS-24128(3-[3-(聯苯-4-基)-2-(膦醯基甲基胺基)丙醯胺基]丙酸);CGS-24592((S)-3-[3-(聯苯-4-基)-2-(膦醯基甲基胺基)丙醯胺基]丙酸);CGS-25155(N-[9(R)-(乙醯基硫基甲基)-10-側氧基-1-氮雜環癸-2(S)-基羰基]-4(R)-羥基-L-脯胺酸苯甲酯);描述於Hepworth等人(Pfizer Inc.)之WO 2006/027680中的3-(1-胺甲醯基環己基)丙酸衍生物;JMV-390-1(2(R)-苯甲基-3-(N-羥基胺甲醯基)丙醯基-L-異白胺醯基-L-白胺酸);依卡曲爾(ecadotril);膦醯二肽;反向塞奧芬(retrothiorphan);RU-42827(2-(巰基甲基)-N-(4-吡啶基)苯丙醯胺);RU-44004(N-(4-嗎啉基)-3-苯基-2-(磺醯基甲基)丙醯胺);SCH-32615((S)-N-[N-(1-羧基-2-苯乙基)-L-苯丙胺醯基]-β-丙胺酸)及其前藥SCH-34826((S)-N-[N-[1-[[(2,2-二甲基-1,3-二氧雜環戊烷-4-基)甲氧基]羰基]-2-苯乙基]-L-苯丙胺醯基]-β-丙胺酸);薩洛芬(sialorphin);SCH-42495(N-[2(S)-(乙醯基硫基甲基)-3-(2-甲基苯基)丙醯基]-L-甲硫胺酸乙酯);司皮諾芬(spinorphin);SQ-28132(N-[2-(巰基甲基)-1-側氧基-3-苯丙基]白胺
酸);SQ-28603(N-[2-(巰基甲基)-1-側氧基-3-苯丙基]-β-丙胺酸);SQ-29072(7-[[2-(巰基甲基)-1-側氧基-3-苯丙基]胺基]庚酸);塞奧芬及其前藥消旋卡多曲(racecadotril);UK-69578(順-4-[[[1-[2-羧基-3-(2-甲氧基乙氧基)丙基]環戊基]羰基]胺基]環己甲酸);UK-447,841(2-{1-[3-(4-氯苯基)丙基胺甲醯基]-環戊基甲基}-4-甲氧基丁酸);UK-505,749((R)-2-甲基-3-{1-[3-(2-甲基苯并噻唑-6-基)丙基胺甲醯基]環戊基}丙酸);5-聯苯-4-基-4-(3-羧基丙醯胺基)-2-甲基戊酸及5-聯苯-4-基-4-(3-羧基丙醯胺基)-2-甲基戊酸乙酯(WO 2007/056546);描述於Khder等人(Novartis AG)之WO 2007/106708中的達魯曲(daglutril)[(3S,2'R)-3-{1-[2'-(乙氧基羰基)-4'-苯基丁基]-環戊-1-羰基胺基}-2,3,4,5-四氫-2-側氧基-1H-1-苯并氮呯-1-乙酸];及其組合。在一個特定實施例中,NEP抑制劑係選自AHU-377、坎沙曲、坎沙曲拉、CGS-24128、膦醯二肽、SCH-32615、SCH-34826、SQ-28603、塞奧芬及其組合。在一個特定實施例中,NEP抑制劑為諸如達魯曲或CGS-26303([N-[2-(聯苯-4-基)-1(S)-(1H-四唑-5-基)乙基]胺基]甲基膦酸)之化合物,其具有作為內皮素轉化酶(ECE)抑制劑及NEP抑制劑之活性。亦可使用其他雙重作用ECE/NEP化合物。NEP抑制劑將以足以提供每天約20-800mg之量投與,其中典型每日劑量在每天50-700mg,更通常每天100-600mg或100-300mg之範圍內。
在一個實施例中,本發明化合物與氧化氮供體組合投與,該氧化氮供體之實例包括(但不限於)尼可地爾(nicorandil);有機硝酸酯,諸如異戊四醇四硝酸酯;及斯德酮亞胺(sydnonimine),諸如林西多明(linsidomine)及嗎多明(molsidomine)。
在又另一個實施例中,本發明化合物與非類固醇消炎劑(NSAID)組合投與。代表性NSAID包括(但不限於):阿西美辛(acemetacin)、乙醯水楊酸(acetyl salicylic acid)、阿氯芬酸(alclofenac)、阿明洛芬
(alminoprofen)、胺芬酸(amfenac)、胺普立糖(amiprilose)、阿洛普令(aloxiprin)、阿尼羅酸(anirolac)、阿帕宗(apazone)、阿紮丙宗(azapropazone)、貝諾酯(benorilate)、苯噁洛芬(benoxaprofen)、苯哌隆(bezpiperylon)、溴哌莫(broperamole)、布氯酸(bucloxic acid)、卡洛芬(carprofen)、環氯茚酸(clidanac)、雙氯芬酸(diclofenac)、二氟尼柳(diflunisal)、地弗他酮(diftalone)、依諾利康(enolicam)、依託度酸(etodolac)、依託昔布(etoricoxib)、芬布芬(fenbufen)、芬氯酸(fenclofenac)、芬克洛酸(fenclozic acid)、非諾洛芬(fenoprofen)、芬替酸(fentiazac)、非普拉宗(feprazone)、氟芬那酸(flufenamic acid)、氟苯柳(flufenisal)、氟洛芬(fluprofen)、氟比洛芬(flurbiprofen)、呋羅芬酸(furofenac)、異丁芬酸(ibufenac)、布洛芬(ibuprofen)、吲哚美辛(indomethacin)、吲哚洛芬(indoprofen)、伊索克酸(isoxepac)、伊索昔康(isoxicam)、酮洛芬(ketoprofen)、酮洛酸(ketorolac)、洛非咪唑(lofemizole)、氯諾昔康(lornoxicam)、甲氯芬那酸鹽(meclofenamate)、甲氯芬那酸(meclofenamic acid)、甲芬那酸(mefenamic acid)、美洛昔康(meloxicam)、美沙拉嗪(mesalamine)、咪洛芬(miroprofen)、莫非布宗(mofebutazone)、萘丁美酮(nabumetone)、萘普生(naproxen)、尼氟酸(niflumic acid)、奧沙普嗪(oxaprozin)、噁平酸(oxpinac)、羥布宗(oxyphenbutazone)、苯基丁氮酮(phenylbutazone)、吡羅昔康(piroxicam)、吡洛芬(pirprofen)、普拉洛芬(pranoprofen)、雙水楊酸酯(salsalate)、舒多昔康(sudoxicam)、柳氮磺胺吡啶(sulfasalazine)、舒林酸(sulindac)、舒洛芬(suprofen)、替諾昔康(tenoxicam)、硫平酸(tiopinac)、噻洛芬酸(tiaprofenic acid)、硫噁洛芬(tioxaprofen)、托芬那酸(tolfenamic acid)、托美丁(tolmetin)、三氟米酯(triflumidate)、齊多美辛(zidometacin)、佐美酸(zomepirac)及其組合。在一個特定實施例中,NSAID係選自依託度酸、氟比洛
芬、布洛芬、吲哚美辛、酮洛芬、酮咯酸、美洛昔康、萘普生、奧沙普嗪、吡羅昔康及其組合。
在一個實施例中,本發明化合物與N-甲基d-天冬胺酸(NMDA)受體拮抗劑組合投與,該NMDA受體拮抗劑之實例(舉例而言但不加以限制)包括金剛烷胺(amantadine)、右甲嗎喃(dextromethorphan)、右丙氧芬(dextropropoxyphene)、氯胺酮(ketamine)、凱托米酮(ketobemidone)、美金剛(memantine)、美沙酮(methadone)等。
在再另一個實施例中,本發明化合物與類鴉片受體促效劑(亦稱為類鴉片止痛劑)組合投與。代表性類鴉片受體促效劑包括(但不限於):丁丙諾啡(buprenorphine)、布托啡諾(butorphanol)、可待因(codeine)、二氫可待因(dihydrocodeine)、芬太尼(fentanyl)、氫可酮(hydrocodone)、氫嗎啡酮(hydromorphone)、左洛啡烷(levallorphan)、左啡諾(levorphanol)、哌替啶(meperidine)、美沙酮(methadone)、嗎啡(morphine)、納布啡(nalbuphine)、納美芬(nalmefene)、納洛芬(nalorphine)、納洛酮(naloxone)、納曲酮(naltrexone)、納洛芬(nalorphine)、氧可酮(oxycodone)、氧嗎啡酮(oxymorphone)、戊唑星(pentazocine)、丙氧芬(propoxyphene)、曲馬多(tramadol)及其組合。在某些實施例中,類鴉片受體促效劑係選自可待因、二氫可待因、氫可酮、氫嗎啡酮、嗎啡、氧可酮、氧嗎啡酮、曲馬多及其組合。
在一個特定實施例中,本發明化合物與磷酸二酯酶(PDE)抑制劑(尤其PDE-V抑制劑)組合投與。代表性PDE-V抑制劑包括(但不限於)阿伐那非(avanafil)、羅地那非(lodenafil)、米羅那非(mirodenafil)、西地那非(sildenafil)(Revatio®)、他達拉非(tadalafil)(Adcirca®)、伐地那非(vardenafil)(Levitra®)及優地那非(udenafil)。
在另一個實施例中,本發明化合物與前列腺素類似物(亦稱為前列腺素(prostanoid)或前列環素(prostacyclin)類似物)組合投與。代表性
前列腺素類似物包括(但不限於)貝前列素鈉(beraprost sodium)、比馬前列素(bimatoprost)、依前列醇(epoprostenol)、伊洛前列素(iloprost)、拉坦前列素(latanoprost)、他氟前列素(tafluprost)、曲伏前列素(travoprost)及曲前列環素(treprostinil),其中比馬前列素、拉坦前列素及他氟前列素尤其受關注。
在又另一個實施例中,本發明化合物與前列腺素受體促效劑組合投與,該前列腺素受體促效劑之實例包括(但不限於)比馬前列素、拉坦前列素、曲伏前列素等。
本發明化合物亦可與腎素抑制劑組合投與,該腎素抑制劑之實例包括(但不限於)阿利吉侖(aliskiren)、依那吉侖(enalkiren)、瑞米吉侖(remikiren)及其組合。
在另一個實施例中,本發明化合物與選擇性血清素再吸收抑制劑(SSRI)組合投與。代表性SSRI包括(但不限於):西它普蘭及西它普蘭代謝物去甲西它普蘭、達泊西汀、依地普蘭(例如乙二酸依地普蘭)、氟西汀及氟西汀去甲基代謝物去甲氟西汀、氟伏沙明(例如順丁烯二酸氟伏沙明)、帕羅西汀、舍曲林及舍曲林代謝物去甲舍曲林及其組合。
在一個實施例中,本發明化合物與5-HT1D血清素受體促效劑組合投與,該5-HT1D血清素受體促效劑之實例(舉例而言但不加以限制)包括曲普坦(triptan),諸如阿莫曲普坦(almotriptan)、阿維曲普坦(avitriptan)、依來曲普坦(eletriptan)、夫羅曲普坦(frovatriptan)、那拉曲普坦(naratriptan)、利紮曲普坦(rizatriptan)、舒馬曲普坦(sumatriptan)及佐米曲普坦(zolmitriptan)。
在一個實施例中,本發明化合物與鈉離子通道阻斷劑組合投與,該鈉離子通道阻斷劑之實例(舉例而言但不加以限制)包括卡馬西平(carbamazepine)、磷苯妥英(fosphenytoin)、拉莫三嗪
(lamotrignine)、利多卡因(lidocaine)、美西律(mexiletine)、奧卡西平(oxcarbazepine)、苯妥英(phenytoin)及其組合。
在一個實施例中,本發明化合物與可溶性鳥苷酸環化酶刺激劑或活化劑組合投與,該可溶性鳥苷酸環化酶刺激劑或活化劑之實例包括(但不限於)阿他西哌(ataciguat)、里奧西哌(riociguat)及其組合。
在一個實施例中,本發明化合物與三環抗抑鬱劑(TCA)組合投與,該TCA之實例(舉例而言但不加以限制)包括阿米替林(amitriptyline)、氧阿米替林(amitriptylinoxide)、布替林(butriptyline)、氯米帕明(clomipramine)、地美替林(demexiptiline)、地昔帕明(desipramine)、二苯西平(dibenzepin)、二甲他林(dimetacrine)、度硫平(dosulepin)、多塞平(doxepin)、丙咪嗪(imipramine)、氧米帕明(imipraminoxide)、洛夫帕明(lofepramine)、美利曲辛(melitracen)、美他帕明(metapramine)、硝沙西平(nitroxazepine)、去甲替林(nortriptyline)、諾昔替林(noxiptiline)、哌泊非嗪(pipofezine)、丙吡西平(propizepine)、普羅替林(protriptyline)、奎紐帕明(quinupramine)及其組合。
在一個實施例中,本發明化合物與血管加壓素受體拮抗劑組合投與,該血管加壓素受體拮抗劑之實例(舉例而言但不加以限制)包括考尼伐坦(conivaptan)及托伐普坦(tolvaptan)。
組合之第二治療劑亦可有助於使用本發明化合物的其他組合療法。舉例而言,本發明化合物可與利尿劑及ARB、或鈣離子通道阻斷劑及ARB、或利尿劑及ACE抑制劑、或鈣離子通道阻斷劑及士他汀組合。特定實例包括ACE抑制劑依那普利(呈順丁烯二酸鹽形式)與利尿劑氫氯噻嗪之組合,其以商標Vaseretic®出售;或鈣離子通道阻斷劑胺氯地平(呈苯磺酸鹽形式)與ARB奧美沙坦(呈美度米前藥形式)之組合;或鈣離子通道阻斷劑與士他汀之組合,所有亦可與本發明化合物
一起使用。其他治療劑(諸如α2-腎上腺素激導性受體促效劑及血管加壓素受體拮抗劑)亦可有助於組合療法。例示性α2-腎上腺素激導性受體促效劑包括可樂定(clonidine)、右美托咪啶(dexmedetomidine)及胍法新(guanfacine)。
下列調配物說明本發明之代表性醫藥組合物。
將本發明化合物(50g)、440g噴霧乾燥之乳糖及10g硬脂酸鎂充分摻合。隨後將所得組合物裝入硬明膠膠囊中(每粒膠囊500mg組合物)。或者,將本發明化合物(20mg)與澱粉(89mg)、微晶纖維素(89mg)及硬脂酸鎂(2mg)充分摻合。隨後使混合物通過45號目美國篩,且裝入硬明膠膠囊中(每粒膠囊200mg組合物)。
或者,將本發明化合物(30g)、第二藥劑(20g)、440g噴霧乾燥之乳糖及10g硬脂酸鎂充分摻合,且如上文所描述進行加工。
將本發明化合物(100mg)與聚氧乙烯脫水山梨糖醇單油酸酯(50mg)及澱粉(250mg)充分摻合。隨後將混合物裝入明膠膠囊中(每粒膠囊400mg組合物)。或者,將本發明化合物(70mg)及第二藥劑(30mg)與聚氧乙烯脫水山梨糖醇單油酸酯(50mg)及澱粉(250mg)充分摻合,且將所得混合物裝入明膠膠囊中(每粒膠囊400mg組合物)。
或者,將本發明化合物(40mg)與微晶纖維素(Avicel PH 103;259.2mg)及硬脂酸鎂(0.8mg)充分摻合。隨後將混合物裝入明膠膠囊(1號尺寸,白色,不透明)中(每粒膠囊300mg組合物)。
使本發明化合物(10mg)、澱粉(45mg)及微晶纖維素(35mg)通過20號目美國篩,且充分混合。由此產生之顆粒在50℃-60℃下乾燥,且通過16號目美國篩。將聚乙烯吡咯啶酮溶液(4mg於無菌水中之
10%溶液)與羧甲基澱粉鈉(4.5mg)、硬脂酸鎂(0.5mg)及滑石(1mg)混合,隨後使此混合物通過16號目美國篩。隨後向該等顆粒中添加羧甲基澱粉鈉、硬脂酸鎂及滑石。在混合之後,在製錠機上壓縮混合物以得到重量為100mg之錠劑。
或者,將本發明化合物(250mg)與微晶纖維素(400mg)、煙霧狀二氧化矽(10mg)及硬脂酸(5mg)充分摻合。隨後壓縮混合物以形成錠劑(每錠665mg組合物)。
或者,將本發明化合物(400mg)與玉米澱粉(50mg)、交聯羧甲纖維素鈉(25mg)、乳糖(120mg)及硬脂酸鎂(5mg)充分摻合。隨後壓縮混合物以形成單刻痕錠劑(每錠600mg組合物)。
或者,用明膠水溶液(20mg)將本發明化合物(100mg)與玉米澱粉(100mg)充分摻合。乾燥混合物,且研磨為細粉。隨後將微晶纖維素(50mg)及硬脂酸鎂(5mg)與明膠調配物混合,造粒,且壓縮所得混合物以形成錠劑(每錠100mg本發明化合物)。
混合下列成分以形成每10mL懸浮液含有100mg本發明化合物的懸浮液:
適合之液體調配物為含有基於羧酸之緩衝劑(諸如檸檬酸鹽、乳
酸鹽及順丁烯二酸鹽緩衝溶液)的調配物。舉例而言,將本發明化合物(其可與DMSO預混)與100mM檸檬酸銨緩衝劑摻合且將pH值調節至pH 5,或與100mM檸檬酸溶液摻合且將pH值調節至pH 2。該等溶液亦可包括增溶性賦形劑(諸如環糊精),舉例而言,溶液可包括10wt%羥丙基-β-環糊精。
其他適合之調配物包括含有或不含有環糊精之5% NaHCO3溶液。
將本發明化合物(0.2g)與0.4M乙酸鈉緩衝溶液(2.0mL)摻合。視需要使用0.5N鹽酸水溶液或0.5N氫氧化鈉水溶液將所得溶液之pH值調節至pH 4,隨後添加足夠之注射用水以提供20mL之總體積。隨後經由無菌過濾器(0.22微米)過濾混合物,以提供適合於注射投藥之無菌溶液。
將本發明化合物(0.2mg)微米尺寸化,隨後與乳糖(25mg)摻合。隨後將此摻合之混合物裝入明膠吸入筒中。舉例而言,使用乾粉吸入器來投與該藥筒之內容物。
或者,將微米尺寸化的本發明化合物(10g)分散在藉由將卵磷脂(0.2g)溶解於去礦物質水(200mL)中所製備之溶液中。噴霧乾燥所得懸浮液,隨後經微米尺寸化以形成包含平均直徑小於約1.5μm之粒子的微米尺寸化組合物。隨後將微米尺寸化之組合物裝入含有加壓之1,1,1,2-四氟乙烷的定劑量吸入器筒中,當用該吸入器投與時,該1,1,1,2-四氟乙烷之量足以提供每劑約10μg至約500μg本發明化合物。
或者,將本發明化合物(25mg)溶解於檸檬酸鹽緩衝(pH 5)之等張生理鹽水(125mL)中。攪拌混合物且進行超音波處理直至化合物溶
解。檢查溶液之pH值,且若需要則藉由緩慢添加1N NaOH水溶液來將pH值調節至pH 5。使用每劑提供約10μg至約500μg本發明化合物的噴霧器裝置來投與該溶液。
提供下列製備及實例以說明本發明之特定實施例。然而除非特定指明,否則此等特定實施例不意欲以任何方式限制本發明之範疇。
除非另外指明,否則下列縮寫具有下列含義,且本文中所使用但未定義之任何其他縮寫具有其一般接受之標準含義:
除非另外指示,否則所有物質(諸如試劑、起始物質及溶劑)均自商業供應商(諸如Sigma-Aldrich、Fluka Riedel-de Haën及其類似供應商)購得,且不經進一步純化即使用。
除非另外指示,否則反應在氮氣氛圍下進行。藉由薄層層析(TLC)、分析型高效液相層析(anal.HPLC)及質譜來監測反應之進程,監測之細節在特定實例中給出。用於分析型HPLC之溶劑如下:溶劑A為98% H2O/2% MeCN/1.0mL/L TFA;溶劑B為90% MeCN/10% H2O/1.0mL/L TFA。
如例如在各製備中具體所述來處理反應,通常藉由萃取及其他純化方法(諸如溫度依賴性及溶劑依賴性結晶以及沈澱)來純化反應混合物。另外,藉由製備型HPLC,通常使用Microsorb C18及Microsorb BDS管柱填充物及習知溶離劑來常規地純化反應混合物。通常藉由液相層析質譜(LCMS)來量測反應之進程。藉由核奧氏效應光譜分析(Nuclear Overhauser effect spectroscopy,NOE)來進行異構體之表徵。藉由質譜及1H-NMR光譜分析來常規地進行反應產物之表徵。對於NMR量測,將樣品溶解於氘化溶劑(CD3OD、CDCl3或DMSO-d 6)中,且在標準觀測條件下用Varian Gemini 2000儀器(400MHz)獲得1H-NMR光譜。通常用Applied Biosystems(Foster City,CA)型號API 150 EX儀器或Agilent(Palo Alto,CA)型號1200 LC/MSD儀器使用電噴霧電離法(ESMS)來進行化合物之質譜鑑別。
將1H-1,2,3-三唑-4-甲酸(20.0g,177mmol)與DMF(200mL,2.6mol)及吡啶(100mL,1.2mol)組合,且將所得混合物冷卻至0℃。逐份添加三苯甲基氯(54g,190mmol),且在室溫下攪拌混合物24小時。過濾所得漿料,且用水(2×200mL)洗滌濾餅且風乾,得到灰白色固體(60g)。於室溫下在THF(800mL)中將固體製成漿料且持續4小時,隨後過濾。隨後藉由旋轉蒸發濃縮濾液,得到濃稠油狀物。添加EtOAc(500mL),且將體積減少至約200mL。過濾所得濃稠漿料且乾燥,得到標題化合物(35.5g)。
在DMAP(3.2g,26.4mmol)中組合(R)-3-聯苯-4-基-2-第三丁氧基羰基胺基-丙酸(5.0g,15mmol)及2,2-二甲基-1,3-二噁烷-4,6-二酮(2.3g,16.1mmol)。添加另外之DMAP(2.0g,16.1mmol)及DCM(50mL),且攪拌所得混合物且冷卻至5℃(氮氣吹掃)持續30分鐘。逐份添加EDCI(HCl;(3.1g,16.1mmol)),同時在攪拌下保持內部溫度在0℃以下。隨後將混合物冷卻至-5℃,在該溫度下攪拌3小時,隨後留在-20℃下持續隔夜。隨後用0.4M KHSO4水溶液(80mL)及飽和NaCl水溶液(20mL)洗滌混合物,隨後經MgSO4乾燥隔夜。濾出固體,隨後將濾液蒸發至乾燥,得到粗化合物1(3.2g)。
於-5℃下在氮氣下將AcOH(8.6mL)添加至粗化合物1(6.4g,14mmol,1.0當量)於無水MeCN(90mL)中之溶液中。在-5℃下攪拌混合物30分鐘,隨後經2小時以小份添加硼氫化鈉(1.3g,34.5mmol,2.5當量)。在於-5℃下再攪拌1小時之後,添加飽和NaCl水溶液及1.7M NaCl水溶液(30mL)。分離各層,且用飽和NaCl水溶液(2×30mL)及水(2×30mL)洗滌有機層,經MgSO4乾燥,過濾且蒸發。藉由層析(5:1庚烷:EtOAc)來進一步純化所得粗產物,得到呈淡黃色固體狀之化合物2(1.1g,純度98.4%)。
在攪拌下於氮氣下將化合物2(5.0g,11mmol,1.0當量)及K2CO3(1.8g,13.2mmol,1.2當量)溶解於DMF(33.9mL)中,且冷卻至0℃。添加碘代甲烷(892μL,1.3當量),且在0℃下攪拌所得混合物1小時。使混合物升溫至室溫(23℃)且保持隔夜。添加飽和NaCl水溶液(35mL)及EtOAc(35mL),且攪拌所得混合物2分鐘。分離各層,且蒸發有機層。用EtOAc(20mL)濕磨殘餘物。濾出固體,且在真空下乾燥。濃縮濾液且再次用EtOAc濕磨,得到化合物3(3.9g),[(R)-2-聯苯-4-基-1-(2,2,5-三甲基-4,6-二側氧基-[1,3]二噁烷-5-基甲基)乙基]胺基甲酸第三丁酯。
將化合物3(400.0g,855.5mmol)與CPME(2L)組合以形成漿料。在0℃下冷卻漿料,且添加3.0M HCl之CPME溶液(2.0L)。在室溫下攪拌所得混合物24小時,得到自由流動之漿料。過濾且乾燥,得到呈非對映異構體之93:7混合物形式的化合物4(總共206g)。於室溫下在MeTHF(1L)中再製成漿料,繼而添加CPME(1L;漿料在室溫下隔夜),得到化合物5(170g,非對映異構體過量(de)及純度為98%)。
將化合物5(25.0g,80.8mmol)與THF(500mL)及NMM(25mL,230mmol)組合。在0℃下冷卻所得混合物(夾套溫度設定在-5℃),且藉助加料漏斗逐滴添加氯甲酸異丁酯(21.0mL,162mmol),同時維持內部溫度在5℃以下。在0℃下攪拌混合物20分鐘。逐滴添加溶解於水(40mL)中之硼氫化鈉(12.2g,323mmol),且在0℃下攪拌混合物20分鐘(>98%轉化)。用1M HCl水溶液(300mL)淬滅反應,且在室溫下攪拌混合物1小時。蒸餾出大部分溶劑,留下白色漿料。攪拌漿料60分鐘,隨後過濾(小粒子,緩慢過濾),得到呈白色固體狀之化合物6(23g,純度>98%)。
組合化合物6(300g,1.0mol)及DCM(3.8L),且在0℃下冷卻所得混合物。添加二氫哌喃(185mL,2.0mol)及對甲苯磺酸(52.5g,305mmol),且在室溫下攪拌混合物2小時。添加飽和NaHCO3水溶液(10:90,NaHCO3:水,3L),且分離各相。經Na2SO4乾燥有機層,繼而移除溶劑至約500mL。向粗產物中添加二異丙醚(2L)及晶種。在室溫下攪拌所得漿料隔夜。過濾且乾燥,得到結晶化合物7(320g,純度>98%)。
將化合物7(320.0g,843.2mmol)溶解於THF(2.5L)中,得到澄清溶液,用氮氣吹掃。在0℃下冷卻溶液,且經30分鐘逐滴添加1.0M NaHMDS之THF溶液(920mL,920mmol)。在0℃下攪拌混合物15分鐘,隨後經1小時逐滴添加溶解於THF(500mL)中之二碳酸二第三丁酯(202g,926mmol),同時維持內部溫度在5℃以下。使混合物升溫至室溫(>99%轉化為化合物8)。將混合物冷卻至<5℃,繼而添加1.0M LiOH水溶液(2.5L,2.5mol)。移除冷卻浴,且在27℃下攪拌混合物隔夜(剩餘約4%起始物質)。在35℃下加熱混合物4小時(>98%轉化),隨後冷卻至15℃。用EtOAc(3L)及飽和NH4Cl水溶液(0.37:0.63,NH4Cl:水,3L)稀釋混合物。分離各相,且用飽和NH4Cl水溶液(3L)及飽和NaCl水溶液(3L)洗滌有機層。經Na2SO4(1kg)乾燥有機層,繼而移除溶劑,得到呈玻璃狀黏性固體狀之粗標題化合物(463g)。
將(2S,4R)-5-聯苯-4-基-4-第三丁氧基羰基胺基-2-甲基-2-(四氫哌喃-2-基氧基甲基)戊酸(10.0g,20.1mmol)與DMF(50mL,600mmol)組合,且攪拌。添加K2CO3(3.3g,24mmol),且將所得混合物冷卻至0℃。添加溴甲苯(3.0mL,25mmol),且在0℃至室溫下攪拌混合物,隨後隔夜。添加1.0M HCl水溶液(250mL,250mmol)及EtOAc(300mL,3.0mol)。分離各相,且用飽和NaCl水溶液(200mL)洗滌有機層,且經Na2SO4乾燥,繼而移除溶劑。添加DCM(50mL)及3.0M HCl之CPME溶液(100mL,300mmol),且在室溫下攪拌所得混合物隔夜。藉由旋轉蒸發將體積減少一半,得到自由流動之漿料,過濾該漿料。用CPME(20mL)洗滌燒瓶及濾餅,且乾燥。將殘餘物溶解於DCM(50mL,800mmol)中,且在0℃至10℃下冷卻所得懸浮液。添加二氫哌喃(3.7mL,40.2mmol)及對甲苯磺酸(692mg,4.0mmol),且在0℃下攪拌所得混合物2小時,隨後在較冷溫度下攪拌隔夜。藉由旋轉蒸發將體積減少至約20mL。添加MTBE(約30mL),繼而添加晶種,在攪拌15分鐘之後得到稀漿料。將體積減少一半,且添加另外MTBE(20mL),同時在室溫下攪拌,得到濃稠漿料。添加另外MTBE(至100mL體積),且攪拌混合物1小時。過濾且乾燥,得到呈鹽酸鹽形式之化合物1(8.9g)。
將1-三苯甲基-1H-1,2,3-三唑-4-甲酸(9.2g,26mmol)溶解於THF(200mL,2.0mol)中。添加DIPEA(9.0mL,52mmol),且將所得混合物冷卻至0℃。逐份添加HCTU(11g,26mmol),且在0℃下攪拌混合物15分鐘。添加化合物1(鹽酸鹽;9.0g,17mmol),且自0℃至室溫攪拌所得混合物。監測反應,且在90分鐘之後用水(200mL)淬滅。添加EtOAc(200mL)。用飽和NaCl水溶液(200mL)洗滌有機層,經Na2SO4乾燥,且移除溶劑。將殘餘物(15g)溶解於DCM(100mL)中,濾出固體,且純化澄清溶液(300g SiG管柱;用10%-30% EtOAc/己烷溶離),得到化合物2(7.5g)。
將化合物2(0.20g,0.24mmol)與EtOAc(3mL,30mmol)組合。添加NaHCO3(50mg,0.6mmol),且用氮氣吹掃所得澄清溶液。添加10% Pd/C(0.05:0.45,鈀:碳黑,50mg,0.05mmol),且用氫氣吹掃所得混合物,隨後在室溫下氫化隔夜。濾出固體,且藉由旋轉蒸發移除溶劑,得到標題化合物。
將(2S,4R)-5-聯苯-4-基-2-甲基-2-(四氫哌喃-2-基氧基甲基)-4-[(1-三苯甲基-1H-1,2,3-三唑-4-羰基)胺基]戊酸苯甲酯(7.5g,9.1mmol)與EtOAc(80mL,800mmol)組合。用氮氣吹掃所得澄清溶液,且添加10% Pd/C(0.05:0.45,鈀:碳黑,1.0g,0.94mmol)。用氫氣吹掃所得混合物,隨後在室溫下氫化隔夜。用氮氣吹掃混合物,濾出固體,且藉由旋轉蒸發移除溶劑,得到標題化合物(7g)。
在-5℃下向(R)-2-胺基-3-(4-溴苯基)丙酸(50g,0.2mol)於MeCN(700mL)中之溶液中添加NaOH(16.4g,0.4mol)於水(700mL)中之溶液。在攪拌10分鐘之後,添加(BOC)2O(44.7g,0.2mol)於MeCN(100mL)中之溶液。將混合物升溫至室溫,且攪拌隔夜。在蒸發MeCN之後,用DCM(800mL)稀釋殘餘物,且在-5℃下用1M HCl酸化至pH 2。用DCM(3×200mL)萃取水層。用飽和NaCl水溶液(500mL)洗滌經合併之有機層,經無水Na2SO4乾燥且濃縮,得到呈白色固體狀之標題化合物(64.2g)。LC-MS:[M+Na]:366,[2M+Na]:709。
在室溫下在氮氣下向(R)-3-(4-溴苯基)-2-第三丁氧基羰基胺基丙酸(64.2g,187mmol)於1,4-二噁烷(500mL)中之溶液中添加3-氟苯基酸(31.3g,224mmol)及Pd(dppf)2Cl2(13.7g,19mmol)。在攪拌10分鐘之後,添加K2CO3(51.7g,374mmol)於水(250mL)中之溶液。加熱混合物至100℃,且攪拌隔夜。在蒸發溶劑之後,添加水(200mL)。用1M HCl將水層酸化至pH 2,且用EtOAc(3×200mL)萃取。用飽和NaCl水溶液(400mL)洗滌經合併之有機層,經無水Na2SO4乾燥且濃縮,得到粗產物,藉由管柱層析(己烷:EtOAc=4:1)來進一步純化該粗產物,得到呈淡黃色油狀之化合物1(45g)。LC-MS:[M+Na]:382,[2M+Na]:741。
於-5℃下在氮氣下經1小時向化合物1(45g,125mmol)、麥氏酸(Meldrum's acid)(23.5g,163mmol)及DMAP(26.0g,213mmol)於無水DCM(500mL)中之溶液中添加DCC(33.3g,163mmol)於無水DCM(200mL)中之溶液。在-5℃下攪拌混合物8小時,隨後冷藏隔夜,在此期間微小之二環已基脲晶體發生沈澱。在過濾之後,用5% KHSO4(4×200mL)及飽和NaCl水溶液(1×200mL)洗滌混合物,隨後在冷藏下經無水MgSO4乾燥隔夜。蒸發溶液,得到呈淡黃色油狀之粗化合物2(57.7g)。LC-MS:[M+Na]:508,[2M+Na]:993。
於-5℃下在氮氣下向化合物2(57.7g,119mmol)於無水DCM(1L)中之溶液中添加AcOH(78.4g,1.3mol)。在-5℃下攪拌混合物0.5小時,隨後經1小時以小份添加NaBH4(11.3g,0.3mol)。在-5℃下另外攪拌1小時之後,添加飽和NACl水溶液(300mL)。用飽和NaCl水溶液(2×300mL)及水(2×300mL)洗滌有機層,經無水MgSO4乾燥,過濾且濃縮,得到粗產物,藉由層析(己烷:EtOAc=6:1)來進一步純化該粗產物,得到呈淡黃色油狀之化合物3(28g)。LC-MS:[M+Na]:494,[2M+Na]:965。
於0℃下在氮氣下向化合物3(28g,60mmol)於無水DMF(250mL)中之溶液中添加K2CO3(9.9g,72mmol)及碘代甲烷(25.6g,180mmol)。在0℃下攪拌1小時之後,將混合物升溫至室溫,且攪拌隔夜。用水(3L)稀釋混合物,且用EtOAc(3×300mL)萃取。用飽和NaCl水溶液(500mL)洗滌經合併之有機層,經無水Na2SO4乾燥且濃縮,得到粗產物,藉由層析(己烷:EtOAc=5:1)來進一步純化該粗產物,得到呈淡黃色固體狀之標題化合物(11.7g)。LC-MS:[M+Na]=508,[2M+Na]=993。1H NMR(300MHz,CD3OD):δ7.52-7.49(m,2H),7.41-7.39(m,2H),7.32-7.27(m,3H),7.07-7.01(m,1H),6.21-6.18(d,1H),3.79(m,1H),2.78-2.61(m,2H),2.35-2.20(m,2H),1.76(s,6H),1.59(s,3H),2.21(s,1H),1.28(s,9H)。
在氮氣下吹掃蒸餾水(181mL)1小時,隨後藉助於導管引入含有0.1M二碘化釤之THF溶液(800mL)的容器中。在維持氮氣氛圍之同時,藉助於導管添加以類似方式脫氣的[(R)-1-(3'-氟聯苯-4-基甲基)-2-(2,2,5-三甲基-4,6-二側氧基-[1,3]二噁烷-5-基)乙基]胺基甲酸第三丁酯(4.9g,10.0mmol,1.0當量)及THF(20mL)之溶液。攪拌所得混合物15分鐘,隨後暴露於空氣中。蒸發溶劑。且添加EtOAc(200mL)、飽和NaCl水溶液(50mL)及10%檸檬酸(20mL)。攪拌混合物5分鐘,隨後萃取兩層。經Na2SO4乾燥有機層,且在真空下濃縮。藉由層析(330g金管柱,1:1乙醚:EtOAc(含0.5% AcOH))來純化粗產物,得到標題化合物1(1.5g)。將一部分化合物1溶解於4M HCl之二噁烷溶液(6mL)及MeCN(10mL)中。在真空下蒸發溶劑,得到標題化合物2。
在0℃下向(R)-2-胺基-3-(4-溴苯基)丙酸(100g,410μmol)於MeCN(600mL)中之混合物中逐滴添加NaOH(32.8g,820μmol)於水(800mL)中之溶液。攪拌所得溶液30分鐘。添加(BOC)2O(93.8g,430μmol)於MeCN(200mL)中之溶液,且將所得混合物升溫至室溫且攪拌隔夜。蒸發MeCN,且用DCM(1L)稀釋殘餘物,且在-5℃下用2M HCl酸化至pH=2。萃取水層,且用飽和NaCl水溶液(500mL)洗滌經
合併之有機層,經Na2SO4乾燥且濃縮,得到呈黃色固體狀之粗化合物1(141g,100%)。LC-MS:366[M+Na]+。
將化合物1(20g,58.1mmol)與2,2-二甲基-1,3-二噁烷-4,6-二酮(9.2g,63.9mmol)、DMAP(10.7g,87.2mmol)及無水DCM(400mL)組合,且冷卻至0℃。在攪拌30分鐘之後,於0℃下在氮氣下逐滴添加DCC(13.2g,63.9mmol)於DCM(50mL)中之溶液。在添加之後,移除冰浴,且在室溫下攪拌混合物隔夜。在-20℃下冷卻溶液1小時,隨後濾出固體。用5% KHSO4溶液(4×100mL)及飽和NaCl水溶液(200mL)洗滌濾液。經無水Na2SO4乾燥有機層且蒸發,得到呈灰色固體狀之粗化合物2(27.5g)。LC-MS:492[M+Na]+。
於-5℃下在氮氣下向化合物2(27.5g,58.1mmol)於無水DCM(400mL)中之溶液中添加AcOH(38.4g,639.1mmol)。在-5℃下攪拌混合物30分鐘。經30分鐘逐份添加NaBH4(5.5g,145.2mmol),且在室溫下攪拌所得溶液3小時。添加飽和NaCl水溶液(300mL)以淬滅反應。用飽和NaCl水溶液(2×200mL)洗滌有機層,經無水Na2SO4乾燥且濃縮,得到粗化合物3(22.6g)。LC-MS:478[M+Na]+。
在0℃下向化合物3(22.6g,49.6mmol)及K2CO3(8.3g,59.5mmol)於無水DMF(160mL)中之溶液中逐滴添加碘代甲烷(14g,99.2mmol)。在添加之後,在室溫下攪拌溶液隔夜。蒸發混合物,且將殘餘物溶解於EtOAc(500mL)中,且用飽和NaCl水溶液(2×200mL)洗滌。經無水Na2SO4乾燥有機溶液且濃縮,得到粗產物,用乙醚(100mL)濕磨該粗產物,隨後過濾,得到呈白色固體狀之標題化合物(14.5
g)。LC-MS:492[M+Na]+。
將[(R)-1-(4-溴苯甲基)-2-(2,2,5-三甲基-4,6-二側氧基-[1,3]二噁烷-5-基)乙基]胺基甲酸第三丁酯(8g,17mmol)、3-氯苯基酸(3g,18.7mmol)、Pd(dppf)2Cl2(400mg,550μmol)及氟化鉀(2g,34mmol)於水(80mL)及二噁烷(80mL)中之混合物於60℃下在氬氣下攪拌3小時。濃縮混合物,分散於水(150mL)中,用EtOAc(2×100mL)萃取,經無水Na2SO4乾燥且蒸發,得到粗產物,藉由管柱層析(PE:EtOAc=10:1)來純化該粗產物,得到呈白色固體狀之化合物1(7g)。LC-MS:524[M+Na]+。
用氬氣沖洗釤粉末(50g,330μmol)(20分鐘)。添加無水THF(1.5L),且用氬氣使所得懸浮液鼓泡(15分鐘)。添加碘(70g,270mmol),且再次用氬氣沖洗混合物(10分鐘)。用鋁箔覆蓋混合物,且在65℃下加熱隔夜,隨後使其冷卻至室溫。密封化合物1(7g,13.9mmol)於THF(200mL)及水(100mL)之溶液且用氬氣沖洗(10分鐘),冷卻至-70℃,用氬氣沖洗(10分鐘),冷卻至-70℃,且用氬氣沖洗(30分鐘)。隨後藉助於導管向經冷卻之溶液中添加釤粉末溶液(1.5L),且在室溫下攪拌2小時。蒸發溶液,將殘餘物溶解於EtOAc(200mL)中,用酒石酸溶液(10%,150mL)洗滌,經無水Na2SO4乾燥,濃縮且藉由管柱層析(PE:EtOAc=0至30%,添加有0.05% AcOH)來純化,得到呈白色固體狀之標題化合物(3g)。LC-MS:470[M+Na]+。1H NMR
(300MHz,CD3OD):δ 7.28~7.56(m,8H),3.94(s,1H),3.56~3.66(m,2H),2.69~2.82(m,2H),1.70~1.90(m,2H),1.17~1.31(m,12H)。
將[(R)-1-(4-溴苯甲基)-2-(2,2,5-三甲基-4,6-二側氧基-[1,3]二噁烷-5-基)乙基]胺基甲酸第三丁酯(4.8g,30.6mmol)、2-氯苯基酸、Pd(dppf)2Cl2(1.0g,1.3mmol)及氟化鉀(2.9g,51mmol)於水(50mL)及二噁烷(250mL)中之混合物於60℃下在氬氣下攪拌3小時。濃縮混合物,溶解於水(150mL)中,用EtOAc(2×200mL)萃取,經無水Na2SO4乾燥且蒸發,得到粗產物,藉由管柱層析(PE:EtOAc=3:1)來純化該粗產物,得到呈白色固體狀之化合物1(10g)。LC-MS:402[M-Boc]+。1H NMR(300MHz,CDCl3):δ 7.47(m,1H),7.38(d,J=8.0Hz,2H),7.31(m,3H),7.23(dd,J=9.9,5.7Hz,2H),4.18(d,J=10.2Hz,1H),4.01(s,1H),2.87(dd,J=13.8,5.7Hz,1H),2.71(dd,J=13.7,6.6Hz,1H),2.30(m,2H),1.75(s,6H),1.65(s,3H),1.33(d,J=11.7Hz,9H)。
用氬氣沖洗釤粉末(50g,330μmol)(20分鐘)。添加無水THF(1.5L),且用氬氣使所得懸浮液鼓泡(15分鐘)。添加碘(70g,270mmol),且再次用氬氣沖洗混合物(10分鐘)。用鋁箔覆蓋混合物,且在65℃下加熱隔夜,隨後使其冷卻至室溫。密封化合物1(7g,13.9mmol)於THF(200mL)及水(100mL)中之溶液且用氬氣沖洗(10分鐘),冷卻至-70℃,用氬氣沖洗(10分鐘),冷卻至-70℃,且用氬氣沖
洗(30分鐘)。隨後藉助於導管向經冷卻之溶液中添加釤粉末溶液(1.5L),且在室溫下攪拌2小時。蒸發溶液,將殘餘物溶解於EtOAc(200mL)中,用酒石酸溶液(10%,150mL)洗滌,經無水Na2SO4乾燥,濃縮且藉由管柱層析(PE:EtOAc=0至30%,添加有0.05% AcOH)來純化,得到呈灰白色固體狀之標題化合物(2.8g)。LC-MS:348[M-Boc]+。1H NMR(300MHz,CD3OD):δ 7.46(m,1H),7.28(m,7H),3.97(s,1H),3.63(m,2H),2.82(m,1H),2.69(m,1H),1.89(m,1H),1.74(m,1H),1.33(m,7H),1.22(m,5H)。
將[(R)-1-(4-溴苯甲基)-2-(2,2,5-三甲基-4,6-二側氧基-[1,3]二噁烷-5-基)乙基]胺基甲酸第三丁酯(12g,25.6mmol)、2-氟苯基酸(4.3g,30.7mmol)、Pd(dppf)2Cl2(950mg,1.3mmol)及氟化鉀(3.0g,51.2mmol)於水(50mL)及二噁烷(100mL)中之混合物於60℃下在氬氣下攪拌2小時。濃縮混合物,用水(100mL)稀釋,用EtOAc(3×100mL)萃取,經無水Na2SO4乾燥且蒸發,得到粗產物,藉由管柱層析(PE:EtOAc=3:1)來純化該粗產物,得到化合物1(10g)。LC-MS:386.1[M-Boc]+。1H NMR(300MHz,CDCl3):δ 7.43(m,3H),7.21(m,6H),4.15(d,J=10.6Hz,1H),3.99(s,1H),2.83(m,,1H),2.70(dd,J=13.8,6.8Hz,1H),2.26(m,2H),1.74(s,6H),1.63(s,3H),1.27(m,9H)。
用氬氣沖洗釤粉末(50g,330μmol)(20分鐘)。添加無水THF(1.5
L),且用氬氣使所得懸浮液鼓泡(15分鐘)。添加碘(70g,270mmol),且再次用氬氣沖洗混合物(10分鐘)。用鋁箔覆蓋混合物,且在65℃下加熱隔夜,隨後使其冷卻至室溫。密封化合物1(7g,14.4mmol)於THF(200mL)及水(100mL)之溶液且用氬氣沖洗(10分鐘),冷卻至-70℃,用氬氣沖洗(10分鐘),冷卻至-70℃,且用氬氣沖洗(30分鐘)。隨後藉助於針筒向經冷卻之溶液添加釤粉末溶液(1.5L),且在室溫下攪拌2小時。蒸發溶液,將殘餘物溶解於EtOAc(200mL)中,用酒石酸溶液(10%,150mL)洗滌,經無水Na2SO4乾燥,濃縮且藉由管柱層析(PE:EtOAc=0至30%,添加有0.05% AcOH)來純化,得到呈灰白色固體狀之標題化合物(2.6g)。LC-MS:332.0[M-Boc]+。1H-NMR(CD3OD,300Hz):δ 7.29(m,8H),3.96(s,1H),3.62(m,2H),2.81(m,1H),2.68(m,1H),1.89(m,1H),1.73(m,1H),1.31(m,7H),1.23(m,5H)。
在DMF(0.2mL)中將(2S,4R)-4-第三丁氧基羰基胺基-5-(2'-氟聯苯-4-基)-2-羥甲基-2-甲基戊酸(114mg,265μmol)與DIPEA(3當量)組合,得到標題化合物。
向烘箱乾燥之燒瓶中添加釤粉末(32g,210mmol),且密封該燒瓶且用氬氣沖洗20分鐘。添加無水THF(800mL),且用氬氣使所得懸浮液鼓泡15分鐘。添加碘(44.8g,176mmol),且再次用氬氣沖洗燒瓶10分鐘。覆蓋燒瓶且在65℃下加熱,隨後使其冷卻至室溫。所得SmI2溶液直接用於下一步驟。
密封[(R)-1-(4-溴苯甲基)-2-(2,2,5-三甲基-4,6-二側氧基-[1,3]二噁烷-5-基)乙基]胺基甲酸第三丁酯(4g,8.5mmol)於THF(200mL)及水(100mL)中之溶液且用氬氣沖洗10分鐘,隨後冷卻至70℃,且用氬氣再沖洗10分鐘,隨後再次冷卻至-70℃,且用氬氣再沖洗30分鐘。隨後添加SmI2溶液(800mL),且在室溫下攪拌所得溶液2小時。蒸發溶液,用EtOAc(200mL)稀釋,用酒石酸溶液(10%,150mL)洗滌,乾燥,濃縮,且藉由管柱層析(PE:EA=0至30%,添加有0.05%乙酸)來純化,得到呈灰白色固體狀之標題化合物(1.7g)。LC-MS:[M-Boc]+:316。1H NMR(300MHz,CD3OD):δ 7.36(m,2H),7.12(m,2H),3.97(s,1H),3.60(m,2H),2.6~2.7(m,2H),1.69~1.81(m,2H),1.15~1.37(m,12H)。
將(2S,4R)-5-(4-溴苯基)-4-第三丁氧基羰基胺基)-2-羥甲基)-2-甲基戊酸(1.0g,2.4mmol)與MeCN(20mL)組合。添加4N HCl之二噁烷溶液(1.8mL,7.2mmol)。攪拌所得混合物30分鐘,隨後在減壓下濃縮。
在DMF(2mL)中組合1H-[1,2,3]三唑-4-甲酸(272mg,2.4mmol)及HATU(959mg,2.5mmol),且攪拌10分鐘。添加DIPEA(1.3mL,7.2mmol)及含化合物1之DMF(2mL),且攪拌所得混合物30分鐘,隨後濃縮。藉由逆相層析(20%-100% MeCN/水)來純化殘餘物,得到標題化合物(287mg)。
將(2S,4R)-5-(4-溴苯基)-4-((第三丁氧基羰基)胺基)-2-(羥甲基)-2-甲基戊酸(1.3mg,3.1mmol)與5-氯-2-氟苯基酸(708mg,4.1mmol)、碳酸鈉(993mg,9.4mmol)、水(0.2mL)及二噁烷(1.5mL)組合。密封反應容器,藉由真空來移除空氣,且用氮氣吹掃容器。快速添加肆(三苯膦)鈀(0)(541mg,468μmol),且藉由真空來移除空氣。在90℃下加熱混合物持續45分鐘。用1N HCl/水將混合物酸化至pH約4,隨後用EtOAc萃取。移除溶劑,且將殘餘物溶解於AcOH中,且藉由逆相層析來純化,得到化合物1。
將化合物1(1.0g,2.1mmol)溶解於EtOH(4mL)及4N HCl之二噁烷溶液(4mL)中,且在60℃下攪拌3小時。蒸發溶劑,得到粗化合物2,該化合物直接用於進行下一步驟。
將化合物2(800mg,2.0mmol)溶解於DCM及(BOC)2O(472μl,2.0mmol)中,繼而添加Et3N(566μL,4.1mmol)及DMAP(1片)。攪拌所得混合物3小時。移除溶劑,且用DCM濕磨粗產物且過濾,得到化合物3(800g),該化合物不經進一步純化即使用。
藉由使(2S,4R)-4-胺基-5-(5'-氯-2'-氟聯苯-4-基)-2-羥甲基-2-甲基戊酸乙酯脫去保護基來製備標題化合物。
在氮氣下吹掃蒸餾水(140mL)30分鐘,隨後導入含有0.1M二碘化釤之THF溶液(800mL)之容器中,注意不允許任何空氣接觸溶液。在維持氮氣氛圍的同時,藉助於導管添加[(R)-2-聯苯-4-基-1-(2,2,5-三甲基-4,6-二側氧基-1,3-二噁烷(dioxinan)-5-基甲基)乙基]胺基甲酸第三丁酯(3.7g,8.0mmol,1.0當量)及THF(100mL)之脫氣溶液。攪拌所得混合物15分鐘,隨後暴露於空氣中。添加飽和NaCl水溶液(12mL)、10%檸檬酸(6mL)及EtOAc(30mL)。攪拌混合物5分鐘,隨後萃取兩層。經Na2SO4乾燥有機層,且在真空下濃縮。藉由層析(330g金管柱,50% EtOAc(含0.5% AcOH)/乙醚梯度)來純化粗產物,得到經BOC保護之酸(P2=BOC)(1.4g)。將經BOC保護之酸溶解於MeCN(10mL)中,繼而添加4N HCl之二噁烷溶液(10mL)。蒸發溶劑,且使產物與甲苯(2×)共沸,得到酸。(P2已移除)(1.0g)。
將(2S,4R)-5-聯苯-4-基-4-第三丁氧基羰基胺基-2-羥甲基-2-甲基戊酸乙酯(100mg,226μmol)及硫酸氫四丁基銨(15mg,45μmol)與DCM(1mL)及NaOH(159μL,1.6mmol)組合。添加硫酸二甲酯(114mg,906μmol),且密封反應容器且劇烈攪拌隔夜。隨後在減壓下濃縮混合物,且將殘餘物溶解於AcOH中,且藉由逆相層析(30%-100%
MeCN/水)來純化,得到化合物1(30mg)。
將化合物1(30mg,66μmol)與MeCN(1mL)及4N HCl之二噁烷溶液(0.3mL)組合,且攪拌10分鐘,隨後在減壓下濃縮,得到標題化合物(23mg)。
將(2S,4R)-4-第三丁氧基羰基胺基-5-(3'-氯聯苯-4-基)-2-羥甲基-2-甲基戊酸(860mg,1.9mmol)溶解於EtOH(4mL)及4N HCl之二噁烷溶液(4mL)中,且在60℃下攪拌3小時。蒸發溶劑,且粗化合物1用於下一步驟。
將化合物1(722mg,1.9mmol)溶解於DCM及(BOC)2O(446μL,1.9mmol)中。添加Et3N(535μL,3.8mmol)及DMAP(1片),且攪拌所得混合物3小時。蒸發溶劑且純化殘餘物(正相層析0%-60% EtOAc/己烷),得到標題化合物(800mg)。
將(2S,4R)-4-第三丁氧基羰基胺基-5-(3'-氯聯苯-4-基)-2-羥甲基-2-甲基戊酸乙酯(100mg,226μmol)及硫酸氫四丁基銨(15mg,45μmol)與DCM(1mL)及NaOH(159μL,1.6mmol)組合。添加硫酸二甲酯(114mg,906μmol),且密封反應容器且劇烈攪拌隔夜。隨後在減壓下濃縮混合物,且將殘餘物溶解於AcOH中,且藉由逆相層析(30%-100% MeCN/水)來純化,得到化合物1(32mg)。
將化合物1(32mg,66μmol)與MeCN(1mL)及4N HCl之二噁烷溶液(0.3mL)組合,且攪拌10分鐘,隨後在減壓下濃縮,得到標題化合物(26mg)。
將(2S,4R)-4-第三丁氧基羰基胺基-5-(5'-氯-2'-氟聯苯-4-基)-2-羥
甲基-2-甲基-戊酸乙酯(415mg,840μmol)及硫酸氫四丁基銨(57mg,168μmol)與DCM(1mL)及NaOH(588μL,5.9mmol)組合。添加硫酸二甲酯(424mg,3.4mmol),且密封反應容器且劇烈攪拌隔夜。用DCM及水萃取混合物,純化(正相層析;0-60 EtOAc:己烷),且在減壓下濃縮,得到化合物1(220mg)。
將化合物1(88mg,173μmol)與MeCN(1mL)及4N HCl之二噁烷溶液(0.3mL)組合,且攪拌10分鐘,隨後在減壓下濃縮,得到標題化合物(34mg)。
將(2S,4R)-4-第三丁氧基羰基胺基-5-(5'-氯-2'-氟聯苯-4-基)-2-羥甲基-2-甲基-戊酸乙酯(415mg,840μmol)及硫酸氫四丁基銨(57mg,168μmol)與DCM(1mL)及NaOH(588μL,5.9mmol)組合。添加硫酸二乙酯(518mg,3.4mmol),且密封反應容器且劇烈攪拌隔夜。用DCM及水萃取混合物,純化(正相層析;0-60 EtOAc:己烷),且在減壓下濃縮,得到化合物1(110mg)。
將化合物1(90mg,173μmol)與MeCN(1mL)及4N HCl之二噁烷溶液(0.3mL)組合,且攪拌10分鐘,隨後在減壓下濃縮,得到標題化合物(35.2mg)。
應瞭解實例1之化合物可以互變異構體形式存在,且兩種形式均由此實例所涵蓋。舉例而言,實例1A中描繪(2S,4R)-5-聯苯-4-基-2-羥甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)-胺基]戊酸5-第三丁基-2-側氧基-[1,3]二氧雜環戊烯-4-基甲酯,但應瞭解此化合物可以互變異構體形式存在,例如以(2S,4R)-5-聯苯-4-基-2-羥甲基-2-甲基-4-[(3H-[1,2,3]三唑-4-羰基)-胺基]-戊酸5-第三丁基-2-側氧基-[1,3]二氧雜環戊烯-4-基甲酯形式。實例1B-1J中之化合物同樣如此。
在DCM(5mL)中將(2S,4R)-5-聯苯-4-基-2-甲基-2-(四氫哌喃-2-基氧基甲基)-4-[(1-三苯甲基-1H-1,2,3-三唑-4-羰基)胺基]戊酸(57mg,77μmol)與HOBt(31mg,230μmol)及EDC(41μL,230μmol)組合,且攪拌15分鐘。添加DMF(0.7mL,10mmol),且攪拌所得混合物15
分鐘。添加4-第三丁基-5-羥甲基-1,3-二氧雜環戊烯-2-酮(40mg,230μmol)及4-甲基嗎啉(34μL,0.31mmol),且在室溫下攪拌混合物隔夜。添加水,且用EtOAc(20mL)萃取混合物,乾燥有機層,且蒸發溶劑。監測反應,隨後淬滅(含MeCN之1N HCl水溶液)。添加1.2M HCl之MeOH溶液(10-20體積),且攪拌混合物2小時,隨後藉由製備型HPLC來純化,得到呈TFA鹽形式之標題化合物(1.6mg)。MS m/z[M+H]+ C30H34N4O7計算值,563.24;實驗值563。
在DCM(5mL)中將(2S,4R)-5-聯苯-4-基-2-甲基-2-(四氫哌喃-2-基氧基甲基)-4-[(1-三苯甲基-1H-1,2,3-三唑-4-羰基)胺基]戊酸(57mg,77μmol)與HOBt(31mg,230μmol)及EDC(41μL,230μmol)組合,且攪拌15分鐘。添加DMF(0.7mL,10mmol),且攪拌所得混合物15分鐘。添加2,2,3,3,3-五氟-1-丙醇(23.2μL,230μmol)及4-甲基嗎啉(34μL,0.31mmol),且在室溫下攪拌混合物隔夜。添加水,且用EtOAc(20mL)萃取混合物,乾燥有機層,且蒸發溶劑。監測反應,隨後淬滅(含MeCN之1N HCl水溶液)。添加1.2M HCl之MeOH溶液(10-20體積),且攪拌混合物2小時,隨後藉由製備型HPLC來純化,得到呈TFA鹽形式之標題化合物(1.2mg)。MS m/z[M+H]+ C25H25F5N4O4計算值,541.18;實驗值541。
在DCM(5mL)中將(2S,4R)-5-聯苯-4-基-2-甲基-2-(四氫哌喃-2-基氧基甲基)-4-[(1-三苯甲基-1H-1,2,3-三唑-4-羰基)胺基]戊酸(57mg,77μmol)與HOBt(31mg,230μmol)及EDC(41μL,230μmol)組合,且攪拌15分鐘。添加DMF(0.7mL,10mmol),且攪拌所得混合物15分鐘。添加2,2-二氟丙醇(22.3mg,230μmol)及4-甲基嗎啉(34μL,0.31mmol),且在室溫下攪拌混合物隔夜。添加水,且用EtOAc(20mL)萃取混合物,乾燥有機層,且蒸發溶劑。監測反應,隨後淬滅(含MeCN之1N HCl水溶液)。添加1.2M HCl之MeOH溶液(10-20體積),且攪拌混合物2小時,隨後藉由製備型HPLC來純化,得到呈TFA鹽形式之標題化合物(1.4mg)。MS m/z[M+H]+ C25H28F2N4O4計算值,487.21;實驗值487。
在MeCN(0.7mL,10mmol)中將(2S,4R)-5-聯苯-4-基-2-甲基-2-(四氫哌喃-2-基氧基甲基)-4-[(1H-1,2,3-三唑-4-羰基)胺基]戊酸(126
mg,255μmol)與4M HCl之二噁烷溶液(191μL,765μmol)組合。隨後在減壓下濃縮混合物,且藉由逆相層析純化殘餘物。添加DCM(1mL,20mmol)及乙醯氯(24mg,306μmol),繼而添加DIPEA(133μL,765μmol)。攪拌所得混合物10分鐘。蒸發溶劑,且將殘餘物溶解於AcOH中,且藉由製備型HPLC來純化,得到標題化合物(5mg)。MS m/z[M+H]+ C24H26N4O5計算值,451.19;實驗值451。
在MeCN(0.7mL,10mmol)中將(2S,4R)-5-聯苯-4-基-2-甲基-2-(四氫哌喃-2-基氧基甲基)-4-[(1H-1,2,3-三唑-4-羰基)胺基]戊酸(126mg,255μmol)與4M HCl之二噁烷溶液(191μL,765μmol)組合。隨後在減壓下濃縮混合物,且藉由逆相層析純化殘餘物。添加DCM(1mL,20mmol)及異丁醯氯(32.6mg,306μmol),繼而添加DIPEA(133μL,765μmol)。攪拌所得混合物10分鐘。蒸發溶劑,且將殘餘物溶解於AcOH中,且藉由製備型HPLC來純化,得到標題化合物(5mg)。MS m/z[M+H]+ C26H30N4O5計算值,479.22;實驗值479。
在MeCN(0.7mL,10mmol)中將(2S,4R)-5-聯苯-4-基-2-甲基-2-(四氫哌喃-2-基氧基甲基)-4-[(1H-1,2,3-三唑-4-羰基)胺基]戊酸(126mg,255μmol)與4M HCl之二噁烷溶液(191μL,765μmol)組合。隨後在減壓下濃縮混合物,且藉由逆相層析純化殘餘物。添加DCM(1mL,20mmol)及異戊醯氯(39.9mg,306μmol),繼而添加DIPEA(133μL,765μmol)。攪拌所得混合物10分鐘。蒸發溶劑,且將殘餘物溶解於AcOH中,且藉由製備型HPLC來純化,得到標題化合物(3mg)。MS m/z[M+H]+ C27H32N4O5計算值,493.24;實驗值493。
將(2S,4R)-5-聯苯-4-基-2-甲基-2-(四氫哌喃-2-基氧基甲基)-4-[(1H-1,2,3-三唑-4-羰基)胺基]戊酸(100mg,0.2mmol)與1-己醇(0.3mL,2mmol)及4M HCl之1,4-二噁烷溶液(0.3mL,1mmol)組合。在60℃下攪拌混合物2小時。在減壓下濃縮混合物,且藉由逆相層析純化殘餘物,得到呈TFA鹽形式之標題化合物(51mg)。MS m/z[M+H]+
C28H36N4O4計算值,493.27;實驗值493。
將(2S,4R)-5-聯苯-4-基-2-甲基-2-(四氫哌喃-2-基氧基甲基)-4-[(1H-1,2,3-三唑-4-羰基)胺基]戊酸(100mg,0.2mmol)與1-庚醇(0.3mL,2mmol)及4M HCl之1,4-二噁烷溶液(0.3mL,1mmol)組合。在60℃下攪拌混合物2小時。在減壓下濃縮混合物,且藉由逆相層析純化殘餘物,得到呈TFA鹽形式之標題化合物(60mg)。MS m/z[M+H]+ C29H38N4O4計算值,507.29;實驗值507。
如本文所述使1H-[1,2,3]三唑-4-甲酸與(2S,4R)-4-胺基-5-聯苯-4-基-2-乙氧基甲基-2-甲基戊酸反應,得到呈TFA鹽形式之標題化合物(0.8mg)。MS m/z[M+H]+ C24H28N4O4計算值,437.21;實驗值437.2。
在DMF(0.5mL)中組合3H-[1,2,3]三唑-4-甲酸(3.5mg,31μmol)及HATU(12mg,31μmol),且攪拌5分鐘。添加(2S,4R)-4-胺基-5-聯苯-4-基-2-甲氧基甲基-2-甲基戊酸乙酯(11mg,31μmol)及DIPEA(16μL,93μmol)於DMF(0.5mL)中之溶液,且攪拌所得混合物20分鐘,隨後在減壓下濃縮。
將殘餘物與THF(0.6mL)及NaOH(124μL,124μmol)組合,且在60℃下攪拌2小時,隨後在減壓下濃縮。將殘餘物溶解於AcOH中,且藉由製備型HPLC來純化化合物,得到呈TFA鹽形式之標題化合物(1mg)。MS m/z[M+H]+ C23H26N4O4計算值,423.20;實驗值423.2。
應瞭解實例2之化合物可以互變異構體形式存在,且兩種形式均由此實例所涵蓋。舉例而言,實例2A中描繪(2S,4R)-2-羥甲基-5-(2'-甲氧基聯苯-4-基)-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)胺基]戊酸,但應瞭解此化合物可以互變異構體形式存在,例如以(2S,4R)-2-羥甲基-5-(2'-甲氧基聯苯-4-基)-2-甲基-4-[(3H-[1,2,3]三唑-4-羰基)胺基]戊酸形式。實例2B-2R中之化合物亦如此。
將(2S,4R)-5-(4-溴苯基)-2-羥甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)胺基]戊酸(38mg,92μmol)與2-甲氧苯基酸(28.1mg,185μmol)、碳酸鈉(29.4mg,277μmol)、水(0.2mL)及二噁烷(1.5mL)組合。密封反應容器,藉由真空來移除空氣,且用氮氣吹掃容器。快速添加肆(三苯膦)鈀(0)(21.4mg,18μmol),且藉由真空來移除空氣。在90℃下加熱混合物持續45分鐘。將混合物酸化至pH約3且過濾,且濃縮溶劑合物。將殘餘物溶解於AcOH(0.7mL)中,且藉由製備型HPLC來純化,得到呈TFA鹽形式之標題化合物(12.5mg)。MS m/z[M+H]+ C23H26N4O5計算值,439.19;實驗值439.2。
將(2S,4R)-5-(4-溴苯基)-2-羥甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)胺基]戊酸(38mg,92μmol)與2-氯苯基酸(28.9mg,185μmol)、碳酸鈉(29.4mg,277μmol)、水(0.2mL)及二噁烷(1.5mL)組合。密封反應容器,藉由真空來移除空氣,且用氮氣吹掃容器。快速添加肆(三苯膦)鈀(0)(21.4mg,18μmol),且藉由真空來移除空氣。在90℃
下加熱混合物持續45分鐘。將混合物酸化至pH約3且過濾,且濃縮溶劑合物。將殘餘物溶解於AcOH(0.7mL)中,且藉由製備型HPLC來純化,得到呈TFA鹽形式之標題化合物(18.2mg)。MS m/z[M+H]+ C22H23ClN4O4計算值,443.14;實驗值443.2。
將(2S,4R)-5-(4-溴苯基)-2-羥甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)胺基]戊酸(38mg,92μmol)與2-甲基苯基酸(25.1mg,185μmol)、碳酸鈉(29.4mg,277μmol)、水(0.2mL)及二噁烷(1.5mL)組合。密封反應容器,藉由真空來移除空氣,且用氮氣吹掃容器。快速添加肆(三苯膦)鈀(0)(21.4mg,18μmol),且藉由真空來移除空氣。在90℃下加熱混合物持續45分鐘。將混合物酸化至pH約3且過濾,且濃縮溶劑合物。將殘餘物溶解於AcOH(0.7mL)中,且藉由製備型HPLC來純化,得到呈TFA鹽形式之標題化合物(13.3mg)。MS m/z[M+H]+ C23H26N4O4計算值,423.20;實驗值423.2。
將(2S,4R)-5-(4-溴苯基)-2-羥甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)胺基]戊酸(38mg,92μmol)與3-氯苯基酸(28.9mg,185μmol)、碳酸鈉(29.4mg,277μmol)、水(0.2mL)及二噁烷(1.5mL)組合。密封反應容器,藉由真空來移除空氣,且用氮氣吹掃容器。快速添加肆(三苯膦)鈀(0)(21.4mg,18μmol),且藉由真空來移除空氣。在90℃下加熱混合物持續45分鐘。將混合物酸化至pH約3且過濾,且濃縮溶劑合物。將殘餘物溶解於AcOH(0.7mL)中,且藉由製備型HPLC來純化,得到呈TFA鹽形式之標題化合物(8.1mg)。MS m/z[M+H]+ C22H23ClN4O4計算值,443.14;實驗值443.2。
將(2S,4R)-5-(4-溴苯基)-2-羥甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)胺基]戊酸(38mg,92μmol)與5-氯-2-氟苯基酸(32.2mg,185μmol)、碳酸鈉(29.4mg,277μmol)、水(0.2mL)及二噁烷(1.5mL)組合。密封反應容器,藉由真空來移除空氣,且用氮氣吹掃容器。快速添加肆(三苯膦)鈀(0)(21.4mg,18μmol),且藉由真空來移除空氣。
在90℃下加熱混合物持續45分鐘。將混合物酸化至pH約3且過濾,且濃縮溶劑合物。將殘餘物溶解於AcOH(0.7mL)中,且藉由製備型HPLC來純化,得到呈TFA鹽形式之標題化合物(2mg)。MS m/z[M+H]+ C22H22ClFN4O4計算值,461.13;實驗值461.2。
將(2S,4R)-5-(4-溴苯基)-2-羥甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)胺基]戊酸(38mg,92μmol)與2,5-二氯苯基酸(35.3mg,185μmol)、碳酸鈉(29.4mg,277μmol)、水(0.2mL)及二噁烷(1.5mL)組合。密封反應容器,藉由真空來移除空氣,且用氮氣吹掃容器。快速添加肆(三苯膦)鈀(0)(21.4mg,18μmol),且藉由真空來移除空氣。在90℃下加熱混合物持續45分鐘。將混合物酸化至pH約3且過濾,且濃縮溶劑合物。將殘餘物溶解於AcOH(0.7mL)中,且藉由製備型HPLC來純化,得到呈TFA鹽形式之標題化合物(4.6mg)。MS m/z[M+H]+ C22H22Cl2N4O4計算值,477.10;實驗值478.2。
將(2S,4R)-5-(4-溴苯基)-2-羥甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)胺基]戊酸(38mg,92μmol)與5-氯-2-甲基苯基酸(31.4mg,185μmol)、碳酸鈉(29.4mg,277μmol)、水(0.2mL)及二噁烷(1.5mL)組合。密封反應容器,藉由真空來移除空氣,且用氮氣吹掃容器。快速添加肆(三苯膦)鈀(0)(21.4mg,18μmol),且藉由真空來移除空氣。在90℃下加熱混合物持續45分鐘。將混合物酸化至pH約3且過濾,且濃縮溶劑合物。將殘餘物溶解於AcOH(0.7mL)中,且藉由製備型HPLC來純化,得到呈TFA鹽形式之標題化合物(12.1mg)。MS m/z[M+H]+ C23H25ClN4O4計算值,457.16;實驗值457.2。
將(2S,4R)-5-(4-溴苯基)-4-第三丁氧基羰基胺基-2-羥甲基-2-甲基戊酸(40mg,96μmol)與3-氰基苯基酸(14mg,96μmol)、碳酸鈉(10.2mg,96μmol)、水(0.5mL)及二噁烷(2mL)組合。密封反應容器,藉由真空來移除空氣,且用氮氣吹掃容器。快速添加肆(三苯膦)鈀(0)(11mg,9.6μmol),藉由真空來移除空氣,且用氮氣吹掃容器。在90℃下加熱混合物持續45分鐘。過濾混合物,且濃縮溶劑合物。將殘餘物溶解於AcOH中,且藉由逆相層析來純化,得到化合物1(30mg)。
將化合物1(30mg,68μmol)與MeCN(1mL)及4M HCl之1,4-二噁烷溶液(103μL,410μmol)組合,且攪拌10分鐘。隨後在減壓下濃縮混合物,得到化合物2(27mg)。
在DMF(0.5mL)中將3H-[1,2,3]三唑-4-甲酸(9.1mg,80μmol)與HATU(30mg,80μmol)組合,且攪拌5分鐘。添加化合物2(27mg,80μmol),繼而添加DIPEA(42μL,240μmol),且攪拌所得混合物30分鐘。蒸發溶劑,且將殘餘物溶解於AcOH中,且藉由逆相層析來純化,得到呈TFA鹽形式之標題化合物(3mg)。MS m/z[M+H]+ C23H23N5O4計算值,434.18;實驗值434。
將(2S,4R)-5-(4-溴苯基)-2-羥甲基-2-甲基-4-[(1H-[1,2,3]三唑-4-羰基)胺基]戊酸(38mg,92μmol)與3-甲基苯基酸(25.1mg,185μmol)、碳酸鈉(29.4mg,277μmol)、水(0.2mL)及二噁烷(1.5mL)組合。密封反應容器,藉由真空來移除空氣,且用氮氣吹掃容器。快速添加肆(三苯膦)鈀(0)(21.4mg,18μmol),且藉由真空來移除空氣。在90℃下加熱混合物持續45分鐘。將混合物酸化至pH約3且過濾,且
濃縮溶劑合物。將殘餘物溶解於AcOH(0.7mL)中,且藉由製備型HPLC來純化,得到呈TFA鹽形式之標題化合物(10mg)。
在DMF(0.5mL)中組合3H-[1,2,3]三唑-4-甲酸(3.5mg,31μmol)及HATU(12mg,31μmol),且攪拌5分鐘。添加(2S,4R)-4-胺基-5-(3'-氯聯苯-4-基)-2-甲氧基甲基-2-甲基戊酸乙酯(12mg,31μmol)及DIPEA(16μL,93μmol)於DMF(0.5mL)中之溶液,且攪拌所得混合物20分鐘,隨後在減壓下濃縮。
將殘餘物與THF(0.6mL)及NaOH(124μL,124μmol)組合,且在60℃下攪拌2小時,隨後在減壓下濃縮。將殘餘物溶解於AcOH中,且藉由逆相層析來純化,得到呈TFA鹽形式之標題化合物(4.0mg)。MS m/z[M+H]+ C23H25ClN4O4計算值,457.16;實驗值457.2。
向瓶中添加(2S,4R)-4-第三丁氧基羰基胺基-5-(3'-氯聯苯-4-基)-2-羥甲基-2-甲基戊酸乙酯(400mg,840μmol)、硫酸氫四丁基銨(57mg,168μmol)、DCM(1mL)及NaOH(588μL,5.9mmol),繼而添加
硫酸二乙酯(518mg,3.4mmol)。將反應容器加蓋,且劇烈攪拌隔夜。用DCM及水萃取混合物,純化(正相層析0%-60% EtOAc:己烷),隨後在減壓下濃縮,得到化合物1(180mg)。
將含化合物1(87mg,173μmol)之MeCN(1mL)與4N HCl之二噁烷溶液(0.3mL)中組合。攪拌混合物10分鐘,隨後在減壓下濃縮,得到化合物2。
在DMF(0.5mL)中將化合物2(33.7mg,83μmol)與HATU(38.0mg,100μmol)、3H-[1,2,3]三唑-4-甲酸(12.3mg,108μmol)組合。添加DIPEA(43.7μL,250μmol),且攪拌混合物2小時。添加EtOAc,繼而添加飽和NH4Cl水溶液。攪拌混合物10分鐘,隨後在減壓下濃縮,得到化合物3。
將化合物3(40.7mg,82μmol)與THF(0.6mL)及NaOH(326μL,326μmol)及幾滴MeOH組合。在60℃下攪拌所得混合物2小時,
隨後在減壓下濃縮。將殘餘物溶解於AcOH中,且藉由逆相層析來純化,得到呈TFA鹽形式之標題化合物(12mg)。MS m/z[M+H]+ C24H27ClN4O4計算值,471.17;實驗值471.2。
向瓶中添加(2S,4R)-4-第三丁氧基羰基胺基-5-(3'-氯聯苯-4-基)-2-羥甲基-2-甲基戊酸乙酯(400mg,840μmol)、硫酸氫四丁基銨(57mg,168μmol)、DCM(1mL)及NaOH(588μL,5.9mmol),繼而添加[1,3,2]二氧硫雜環戊烷2,2-二氧化物(417mg,3.4mmol)。將反應容器加蓋,且劇烈攪拌隔夜。用DCM及水萃取混合物,純化(正相層析0%-60% EtOAc:己烷),隨後在減壓下濃縮,得到化合物1(90mg)。
將含化合物1(90mg,173μmol)之MeCN(1mL)與4N HCl之二噁烷溶液(0.3mL)組合。攪拌混合物10分鐘,隨後在減壓下濃縮,得到化合物2。
在DMF(0.5mL)中將化合物2(35mg,83μmol)與HATU(38mg,100μmol)、1H-[1,2,3]三唑-4-甲酸(12.3mg,108μmol)組合。添加DIPEA(43.7μL,250μmol),且攪拌混合物2小時。添加EtOAc,繼而添加飽和NH4Cl水溶液。攪拌混合物10分鐘,隨後在減壓下濃縮,得到化合物3。
將化合物3(42mg,82μmol)與THF(0.6mL)及NaOH(326μL,326μmol)及幾滴MeOH組合。在60℃下攪拌所得混合物2小時,隨後在減壓下濃縮。將殘餘物溶解於AcOH中,且藉由逆相層析來純化,得到呈TFA鹽形式之標題化合物(11mg)。MS m/z[M+H]+ C24H27ClN4O5計算值,487.17;實驗值487.2。
向瓶中添加(2S,4R)-4-第三丁氧基羰基胺基-5-(3'-氯聯苯-4-基)-2-羥甲基-2-甲基戊酸乙酯(67mg,140μmol)、硫酸氫四丁基銨(9.5mg,28μmol)、DCM(1mL)及NaOH(98μL,982μmol),繼而添加1,3-丙二醇環狀硫酸酯(78mg,561μmol)。攪拌混合物隔夜,隨後用DCM萃取,且純化(正相層析0-100% EtOAc:己烷),得到化合物1(7
mg)。
將含化合物1(26.3mg,49μmol)之MeCN(0.3mL)與4N HCl之二噁烷溶液(0.3mL)組合。攪拌混合物10分鐘,隨後在減壓下濃縮,得到化合物2。
將化合物2(18mg,47μmol)溶解於DMF(0.3mL)及1H-1,2,3-三唑-4-甲酸(5.3mg,47μmol)中。添加HATU(18mg,47μmol),繼而添加DIPEA(25μL,141μmol)。攪拌混合物30分鐘,隨後在減壓下濃縮,得到化合物3,該化合物不經進一步純化即使用。
將化合物3(23mg,47μmol)溶解於THF中,且添加NaOH(188μL,188μmol),且在60℃下攪拌混合物隔夜。將殘餘物溶解於AcOH中,且藉由製備型HPLC來純化,得到呈TFA鹽形式之標題化合物(1.2mg)。MS m/z[M+H]+ C25H29ClN4O5計算值,501.18;實驗值502.2。
向瓶中添加(2S,4R)-4-第三丁氧基羰基胺基-5-(5'-氯-2'-氟聯苯-4-基)-2-羥甲基-2-甲基戊酸乙酯(82mg,166μmol)、硫酸氫四丁基銨(11mg,33μmol)、DCM(1mL)及NaOH(116μL,1.2mmol),繼而添加硫酸二甲酯(84mg,664mmol)。將反應容器加蓋,且劇烈攪拌隔夜。用DCM萃取混合物,且在減壓下濃縮。將殘餘物溶解於AcOH中,且藉由逆相層析(30%-100% MeCN/水)來純化,得到化合物1(30mg)。
將含化合物1(84mg,166μmol)之MeCN(1mL)與4N HCl之二噁烷溶液(0.3mL)組合。攪拌混合物10分鐘,隨後在減壓下濃縮,得到化合物2。
將3H-[1,2,3]三唑-4-甲酸(21mg,183μmol)與HATU(69mg,183μmol)(在DMF(0.5mL)中)、化合物2(68mg,166μmol)及DIPEA(87μL,498μmol)組合。攪拌所得混合物20分鐘,隨後在減壓下濃縮。純化(正相層析0%-80% EtOAc:己烷)殘餘物,得到化合物3。
將化合物3(65mg,129μmol)與THF(0.6mL)及NaOH(516μL,516μmol)組合。在60℃下攪拌所得混合物2小時。添加少量NaOH及MeOH,且攪拌混合物隔夜。用濃HCl將混合物酸化至pH約4,隨後在減壓下濃縮。將殘餘物溶解於AcOH中,且藉由製備型HPLC來純化,得到呈TFA鹽形式之標題化合物(35mg)。MS m/z[M+H]+ C23H24ClFN4O4計算值,475.15;實驗值475.2。
向瓶中添加(2S,4R)-4-第三丁氧基羰基胺基-5-(5'-氯-2'-氟聯苯-4-基)-2-羥甲基-2-甲基戊酸乙酯(415mg,840μmol)、硫酸氫四丁基銨(57mg,168μmol)、DCM(1mL)及NaOH(588μL,5.9mmol),繼而添加硫酸二乙酯(518mg,3.4mmol)。將反應容器加蓋,且劇烈攪拌隔夜。用DCM及水萃取混合物,純化(正相層析0%-60% EtOAc:己烷),隨後在減壓下濃縮,得到化合物1(110mg)。
將含化合物1(90mg,173μmol)之MeCN(1mL)與4N HCl之二噁烷溶液(0.3mL)組合。攪拌混合物10分鐘,隨後在減壓下濃縮,得到化合物2。
在DMF(0.5mL)中將化合物2(35.2mg,83μmol)與HATU(38.0mg,100μmol)、3H-[1,2,3]三唑-4-甲酸(12.3mg,108μmol)組合。添加DIPEA(43.7μL,250μmol),且攪拌混合物2小時。添加EtOAc,繼而添加飽和NH4Cl水溶液。攪拌混合物10分鐘,隨後在減壓下濃縮,得到化合物3。
將化合物3(42.2mg,82μmol)與THF(0.6mL)及NaOH(326μL,326μmol)及幾滴MeOH組合。在60℃下攪拌所得混合物2小時,隨後在減壓下濃縮。將殘餘物溶解於AcOH中,且藉由逆相層析來純化,得到呈TFA鹽形式之標題化合物(23mg)。MS m/z[M+H]+ C24H26ClFN4O4計算值,489.16;實驗值489.2。
按照前述實例中所述之程序,且代入適當之起始物質及試劑,亦可製備下列化合物。
在DMF(0.2mL)中將1,2,3-三唑-4-甲酸(27.3mg,241μmol)與EDC(42.7μL,241μmol)、4-甲基嗎啉(1當量)及HOBt(32.6mg,241μmol)組合。在室溫下攪拌所得混合物5分鐘。添加(2S,4R)-4-胺基-5-(3'-氟聯苯-4-基)-2-羥甲基-2-甲基戊酸(80mg,240μmol)及4-甲基嗎啉(53.1μL,483μmol)於DMF(0.3mL)中之溶液,且攪拌所得混合物15分鐘。用ACOH淬滅反應,且藉由製備型HPLC來純化產物,且經凍乾,得到呈TFA鹽形式之標題化合物(30mg)。MS m/z[M+H]+ C22H23FN4O4計算值,427.17;實驗值427.2。
在DMF(0.2mL)中將1,2,3-三唑-4-甲酸(30mg,260μmol)與DIPEA(92.4μL,531μmol)及HATU(101mg,265μmol)組合。在室溫下攪拌所得混合物5分鐘。添加(2S,4R)-4-第三丁氧基羰基胺基-5-(2'-氟聯苯-4-基)-2-羥甲基-2-甲基戊酸(114mg,265μmol)及DIPEA(3當量)於DMF(0.2mL)中之溶液,且攪拌所得混合物15分鐘。用ACOH淬滅反應,且藉由製備型HPLC來純化產物,且經凍乾,得到呈TFA鹽形式之標題化合物(16mg)。MS m/z[M+H]+ C22H23FN4O4計算值,427.17;實驗值427.2。
在DMF(0.2mL)中將1-羥基-1H-1,2,3-三唑-4-甲酸(15mg,116μmol)與DIPEA(40.5μL,232μmol)及HATU(44.2mg,116μmol)組合。在室溫下攪拌所得混合物5分鐘。添加(2S,4R)-4-胺基-5-(2'-氟聯苯-4-基)-2-羥甲基-2-甲基戊酸(38.5mg,166μmol)及DIPEA(3當量)於DMF(0.2mL)中之溶液,且攪拌所得混合物15分鐘。用ACOH淬滅反應,且藉由製備型HPLC來純化產物,且經凍乾,得到標題化合物(8mg)。MS m/z[M+H]+ C22H23FN4O5計算值,443.17;實驗值443.2。
在DMF(1mL)中組合1-甲氧基-1H-[1,2,3]三唑-4-甲酸(4.3mg,30μmol)及HATU(11.4mg,30μmol),且在室溫下攪拌15分鐘。添加(2S,4R)-4-胺基-5-(5'-氯-2'-氟聯苯-4-基)-2-羥甲基-2-甲基戊酸(10mg,27μmol)及DIPEA(14μL,82μmol),且在室溫下攪拌所得混合物15分鐘。在真空中移除溶劑,且藉由製備型HPLC純化殘餘物,得到標題化合物(1.1mg)。MS m/z[M+H]+ C23H24ClFN4O5計算值,491.14;實驗值491.2。
在DMF(1mL)中組合1-乙氧基-1H-[1,2,3]三唑-4-甲酸(4.7mg,30μmol)及HATU(11.4mg,30μmol),且在室溫下攪拌15分鐘。添加(2S,4R)-4-胺基-5-(5'-氯-2'-氟聯苯-4-基)-2-羥甲基-2-甲基戊酸(10mg,27μmol)及DIPEA(14μL,82μmol),且在室溫下攪拌所得混合物15分鐘。在真空中移除溶劑,且藉由製備型HPLC純化殘餘物,得到標題化合物(2mg)。MS m/z[M+H]+ C24H26ClFN4O5計算值,505.16;實驗值505.1。
組合THF(1mL,10mmol)、2-側氧基-2,3-二氫噁唑-4-甲酸乙酯(12mg,76.4μmol)及1M NaOH水溶液(229μL,229μmol),且攪拌直至完成。用1N HCl將混合物酸化至pH約5,在真空中蒸發溶劑,且將產物在甲苯中共沸,且在真空中乾燥。向其中添加DIPEA(26.6
μL,153μmol)及HATU(29.0mg,76.4μmol)於DMF(0.2mL)中之溶液,且在室溫下攪拌所得混合物5分鐘。添加(2S,4R)-4-胺基-5-(2'-氟聯苯-4-基)-2-羥甲基-2-甲基戊酸(25.3mg,76.4μmol),且攪拌所得混合物15分鐘。用EtOAc及飽和NH4Cl淬滅反應。萃取產物且乾燥。添加AcOH,且藉由製備型HPLC來純化產物,得到標題化合物(2.5mg)。MS m/z[M+H]+ C23H23FN2O6計算值,443.15;實驗值443.2。
組合THF(1mL,10mmol)、2-側氧基-2,3-二氫噁唑-5-甲酸乙酯(12mg,76.4μmol)及1M NaOH水溶液(229μL,229μmol),且攪拌直至完成。用1N HCl將混合物酸化至pH約5,在真空中蒸發溶劑,且將產物在甲苯中共沸,且在真空中乾燥。向其中添加DIPEA(26.6μL,153μmol)及HATU(29.0mg,76.4μmol)於DMF(0.2mL)中之溶液,且在室溫下攪拌所得混合物5分鐘。添加(2S,4R)-4-胺基-5-(2'-氟聯苯-4-基)-2-羥甲基-2-甲基戊酸(25.3mg,76.4μmol),且攪拌所得混合物15分鐘。用EtOAc及飽和NH4Cl淬滅反應。萃取產物且乾燥。添加AcOH,且藉由製備型HPLC來純化產物,得到標題化合物(5mg)。MS m/z[M+H]+ C23H23FN2O6計算值,443.15;實驗值443.2。
在DMF(0.2mL)中組合2-側氧基-2,3-二氫噁唑-4-甲酸(7mg,55μmol)及HATU(20.8mg,55μmol),且使其在室溫下靜置10分鐘。添加含(2S,4R)-4-胺基-5-(5'-氯-2'-氟聯苯-4-基)-2-羥甲基-2-甲基戊酸(20mg,55μmol)之DMF及DIPEA(28.6μL,164μmol),且在室溫下攪拌所得混合物20分鐘。在減壓下濃縮混合物,且將殘餘物溶解於AcOH中,藉由製備型HPLC來純化,得到標題化合物(0.6mg)。MS m/z[M+H]+ C23H22ClFN2O6計算值,477.12;實驗值477.2。
在DMF(0.3mL)中組合2-側氧基-2,3-二氫噁唑-5-甲酸(7.1mg,55μmol)及HATU(21mg,55μmol),且在室溫下攪拌5分鐘。添加含(2S,4R)-4-胺基-5-(5'-氯-2'-氟聯苯-4-基)-2-羥甲基-2-甲基戊酸(20mg,55μmol)之DMF(0.5mL)及DIPEA(29μL,164μmol),且在室溫下攪拌所得混合物10分鐘。在減壓下濃縮混合物,且將殘餘物溶解於AcOH中,藉由製備型HPLC來純化,得到標題化合物(3mg)。MS m/z[M+H]+ C23H22ClFN2O6計算值,477.12;實驗值477。
將3-甲氧基異噁唑-5-甲酸(9mg,32μmol)與HATU(12mg,32μmol)及DMF(0.2mL)組合,且攪拌所得混合物5分鐘。添加DIPEA(17μL,96μmol)及預先溶解於DMF中之(2S,4R)-4-胺基-5-(3'-氯聯苯-4-基)-2-羥甲基-2-甲基戊酸(79mg,38μmol),且攪拌所得混合物15分鐘,隨後濃縮。將殘餘物溶解於AcOH中,且藉由製備型HPLC來純化,得到標題化合物(2.2mg)。MS m/z[M+H]+ C24H25ClN2O6計算值,473.14;實驗值473.2。
在DMF(0.5mL)中將3-甲氧基異噁唑-5-甲酸(4.4mg,31μmol)及HATU(12mg,31μmol)組合,且攪拌5分鐘。添加(2S,4R)-4-胺基-5-(3'-氯聯苯-4-基)-2-甲氧基甲基-2-甲基戊酸乙酯(12mg,31μmol)及DIPEA(16μL,93μmol)於DMF(0.5mL)中之溶液,且攪拌所得混合物20分鐘,隨後在減壓下濃縮。
將殘餘物與THF(0.6mL)及NaOH(124μL,124μmol)組合,且在60℃下攪拌2小時,隨後在減壓下濃縮。將殘餘物溶解於AcOH中,且藉由製備型HPLC來純化化合物,得到標題化合物(1mg)。MS m/z[M+H]+ C25H27ClN2O6計算值,487.16;實驗值487.2。
如本文所述使3-甲氧基異噁唑-5-甲酸與(2S,4R)-4-胺基-5-(3'-氯聯苯-4-基)-2-乙氧基甲基-2-甲基戊酸反應,得到標題化合物(2mg)。MS m/z[M+H]+ C26H29ClN2O6計算值,501.17;實驗值501.2。
在DMF(0.2mL)中組合3-羥基-異噁唑-5-甲酸(10.6mg,82μmol)、EDC(14.5μL,82μmol)及HOBt(11.1mg,82μmol),且攪拌5分鐘。添加(2S,4R)-4-胺基-5-聯苯-4-基-2-羥甲基-2-甲基戊酸(26mg,82μmol),且攪拌所得混合物18小時。用AcOH淬滅反應,且藉由製備型HPLC來純化產物,隨後凍乾,得到呈TFA鹽形式之標題化合物(7mg)。MS m/z[M+H]+ C23H24N2O6計算值,425.16;實驗值
425.4。
如本文所述使3-羥基-異噁唑-5-甲酸與(2S,4R)-4-胺基-5-聯苯-4-基-2-甲氧基甲基-2-甲基戊酸乙酯反應,得到標題化合物(2.4mg)。MS m/z[M+H]+ C24H26N2O6計算值,439.18;實驗值439.2。
在DMF(0.5mL)中將3-甲氧基異噁唑-5-甲酸(4.4mg,31μmol)及HATU(12mg,31μmol)組合,且攪拌5分鐘。添加(2S,4R)-4-胺基-5-聯苯-4-基-2-甲氧基甲基-2-甲基戊酸乙酯(11mg,31μmol)及DIPEA(16μL,93μmol)於DMF(0.5mL)中之溶液,且攪拌所得混合物20分鐘,隨後在減壓下濃縮。
將殘餘物與THF(0.6mL)及NaOH(124μL,124μmol)組合,且在60℃下攪拌2小時,隨後在減壓下濃縮。將殘餘物溶解於AcOH中,且藉由製備型HPLC來純化化合物,得到標題化合物(1mg)。MS m/z
[M+H]+ C25H28N2O6計算值,453.19;實驗值453。
在DMF(0.2mL)中組合3-甲氧基異噁唑-5-甲酸(8mg,55μmol)及HATU(20.8mg,55μmol),且使其在室溫下靜置10分鐘。添加含(2S,4R)-4-胺基-5-(5'-氯-2'-氟聯苯-4-基)-2-羥甲基-2-甲基戊酸(20mg,55μmol)之DMF及DIPEA(28.6μL,164μmol),且在室溫下攪拌所得混合物20分鐘。在減壓下濃縮混合物,且將殘餘物溶解於AcOH中,藉由製備型HPLC來純化,得到標題化合物(5.4mg)。MS m/z[M+H]+ C24H24ClFN2O6計算值,491.13;實驗值491.2。
在DMF(0.2mL)中組合3-乙基異噁唑-5-甲酸(8mg,55μmol)及HATU(20.8mg,55μmol),且使其在室溫下靜置10分鐘。添加含(2S,4R)-4-胺基-5-(5'-氯-2'-氟聯苯-4-基)-2-羥甲基-2-甲基戊酸(20mg,55μmol)之DMF及DIPEA(28.6μL,164μmol),且在室溫下攪拌所得混合物20分鐘。在減壓下濃縮混合物,且將殘餘物溶解於AcOH
中,藉由製備型HPLC來純化,得到標題化合物(3.6mg)。MS m/z[M+H]+ C25H26ClFN2O5計算值,489.15;實驗值490.2。
在DMF(0.2mL)中組合3-異丁基異噁唑-5-甲酸(9mg,55μmol)及HATU(20.8mg,55μmol),且使其在室溫下靜置10分鐘。添加含(2S,4R)-4-胺基-5-(5'-氯-2'-氟聯苯-4-基)-2-羥甲基-2-甲基戊酸(20mg,55μmol)之DMF及DIPEA(28.6μL,164μmol),且在室溫下攪拌所得混合物20分鐘。在減壓下濃縮混合物,且將殘餘物溶解於AcOH中,藉由製備型HPLC來純化,得到標題化合物(0.3mg)。MS m/z[M+H]+ C27H30ClFN2O5計算值,517.18;實驗值517.2。
在DMF(0.2mL)中組合3-丙基異噁唑-5-甲酸(9mg,55μmol)及HATU(20.8mg,55μmol),且使其在室溫下靜置10分鐘。添加含(2S,4R)-4-胺基-5-(5'-氯-2'-氟聯苯-4-基)-2-羥甲基-2-甲基戊酸(20mg,55μmol)之DMF及DIPEA(28.6μL,164μmol),且在室溫下攪拌
所得混合物20分鐘。在減壓下濃縮混合物,且將殘餘物溶解於AcOH中,藉由製備型HPLC來純化,得到標題化合物(0.5mg)。MS m/z[M+H]+ C26H28ClFN2O5計算值,503.17;實驗值504.2。
在DMF(0.5mL)中將3-羥基-異噁唑-5-甲酸(4μg,0.03μmol)及HATU(11μg,0.03μmol)與(2S,4R)-4-胺基-5-(5'-氯-2'-氟聯苯-4-基)-2-甲氧基甲基-2-甲基戊酸乙酯(10μg,0.03μmol)組合,且攪拌5分鐘。添加DIPEA(0.01μL,0.07μmol),且攪拌所得混合物20分鐘,且蒸發,得到粗化合物1,該化合物直接用於下一步驟。
將含化合物1(10mg)之THF(1mL)與1N NaOH(0.3mL)組合,且在60℃下攪拌所得混合物3小時。添加AcOH,且純化(逆相)產物,得到標題化合物(1mg)。MS m/z[M+H]+ C24H24ClFN2O6計算值,491.13;實驗值491。
將(2S,4R)-4-第三丁氧基羰基胺基-5-(3'-氯聯苯-4-基)-2-羥甲基-2-甲基戊酸乙酯(415mg,840μmol)及硫酸氫四丁基銨(57mg,168μmol)與DCM(1mL)及NaOH(588μL,5.9mmol)組合。添加[1,3,2]二氧硫雜環戊烷2,2-二氧化物(424mg,3.4mmol),且密封反應容器且劇烈攪拌隔夜。用DCM及水萃取混合物,隨後純化(正相層析0%-60% EtOAc/己烷),得到化合物1(90mg)。
將化合物1(90mg,173μmol)與MeCN(1mL)及4N HCl之二噁烷溶液(0.3mL)組合,且攪拌10分鐘,隨後在減壓下濃縮,得到化合物(2)。
組合化合物2(35mg,83μmol)、HATU(38.0mg,100μmol)、3-羥基-異噁唑-5-甲酸(12.3mg,108μmol)及DMF(0.5mL),繼而組合DIPEA(43.7μL,250μmol)。攪拌所得混合物2小時。添加EtOAc,隨後添加飽和NH4Cl水溶液。隨後在減壓下濃縮混合物。將
殘餘物與THF(0.6mL)及NaOH(326μL,326μmol)連同幾滴MeOH組合,且在60℃下攪拌2小時。隨後在減壓下濃縮混合物。將殘餘物溶解於AcOH中,且藉由製備型HPLC來純化,得到標題化合物(8mg)。MS m/z[M+H]+ C25H27ClN2O7計算值,503.15;實驗值503。
將(2S,4R)-4-第三丁氧基羰基胺基-5-(3'-氯聯苯-4-基)-2-羥甲基-2-甲基戊酸乙酯(415mg,840μmol)及硫酸氫四丁基銨(57mg,168μmol)與DCM(1mL)及NaOH(588μL,5.9mmol)組合。添加硫酸二乙酯(518mg,3.4mmol),且密封反應容器且劇烈攪拌隔夜。用DCM及水萃取混合物,隨後純化(正相層析0%-60% EtOAc/己烷),得到化合物1(180mg)。
將化合物1(87mg,73μmol)與MeCN(1mL)及4N HCl之二噁烷溶液(0.3mL)組合,且攪拌10分鐘,隨後在減壓下濃縮,得到化合物(2)。
組合化合物2(33.7mg,83μmol)、HATU(38.0mg,100μmol)、3-羥基-異噁唑-5-甲酸(12.3mg,108μmol)及DMF(0.5mL),繼而組合DIPEA(43.7μL,250μmol)。攪拌所得混合物2小時。添加EtOAc,隨後添加飽和NH4Cl水溶液。隨後在減壓下濃縮混合物。將殘餘物與THF(0.6mL)及NaOH(326μL,326μmol)連同幾滴MeOH組合,且在60℃下攪拌2小時。隨後在減壓下濃縮混合物。將殘餘物溶解於AcOH中,且藉由製備型HPLC來純化,得到標題化合物(8mg)。MS m/z[M+H]+ C25H27ClN2O6計算值,487.16;實驗值486.9。
將(2S,4R)-4-第三丁氧基羰基胺基-5-(5'-氯-2'-氟聯苯-4-基)-2-乙氧基甲基-2-甲基戊酸苯甲酯(720mg,1.2mmol)與MeCN(6mL)組合,繼而添加4N HCl之二噁烷溶液(5mL)。攪拌混合物10分鐘,隨後在減壓下濃縮,得到化合物1。
將3-羥基異噁唑-5-甲酸(53.3mg,413μmol)與HATU(157mg,413μmol)及DMF(0.5mL)組合,且攪拌所得混合物20分鐘。添加N-乙基-N-異丙基丙-2-胺(1當量),且攪拌所得混合物1分鐘。隨後添加預先溶解於DMF(2mL)中之化合物1(100mg,207μmol)及DIPEA(108μl,620μmol),且攪拌所得混合物隔夜,隨後在減壓下濃縮。隨後藉由正相層析來純化(40% EtOAc/己烷)該物質,得到化合物2(90mg)。
將化合物2(90mg,151μmol)與溶解於EtOAc(1mL)及AcOH(1mL)中之鈀/碳(16.1mg,30μmol)組合。將所得溶液在真空中脫氣,且用氫氣吹掃。攪拌溶液2小時。移除氫氣,且用氮氣吹掃溶液。過濾溶液,自濾液移除過量溶劑,且藉由逆相層析來純化殘餘物,得到標題化合物(60mg)。MS m/z[M+H]+ C25H26ClFN2O6計算值,505.15;實驗值505。
按照前述實例中所述之程序,且代入適當之起始物質及試劑來製備標題化合物(2.5mg)。MS m/z[M+H]+ C27H30ClFN2O5計算值,517.18;實驗值518.2。
按照前述實例中所述之程序,且代入適當之起始物質及試劑,亦可製備下列化合物。
在DMF(0.2mL)中將5-乙氧基-1H-吡唑-3-甲酸(10mg,32μmol)與HATU(12mg,32μmol)組合,且攪拌所得混合物5分鐘。添加DIPEA(17μL,96μmol)及預先溶解於DMF中之(2S,4R)-4-胺基-5-(3'-氯聯苯-4-基)-2-羥甲基-2-甲基戊酸(79mg,38μmol),且攪拌所得混合物15分鐘,隨後濃縮。將殘餘物溶解於AcOH中,且藉由製備型HPLC來純化,得到呈TFA鹽形式之標題化合物(1mg)。MS m/z[M+H]+ C25H28ClN3O5計算值,486.17;實驗值486.2。
在DMF(0.3mL)中將5-乙氧基-1H-吡唑-3-甲酸(8.5mg,55μmol)與HATU(21mg,55μmol)組合,且攪拌所得混合物5分鐘。添加DIPEA(29μL,164μmol)及預先溶解於DMF(0.5mL)中之(2S,4R)-4-胺基-5-(5'-氯-2'-氟聯苯-4-基)-2-羥甲基-2-甲基戊酸(20mg,55μmol),且攪拌所得混合物10分鐘,隨後濃縮。將殘餘物溶解於AcOH中,且藉由製備型HPLC來純化,得到呈TFA鹽形式之標題化合物(2mg)。MS m/z[M+H]+ C25H27ClFN3O5計算值,504.16;實驗值503.9。
在DMF(0.2mL)中組合5-異丙基-2H-吡唑-3-甲酸(8mg,55μmol)及HATU(20.8mg,55μmol),且使其在室溫下靜置10分鐘。添加含(2S,4R)-4-胺基-5-(5'-氯-2'-氟聯苯-4-基)-2-羥甲基-2-甲基戊酸(20mg,55μmol)之DMF及DIPEA(28.6μL,164μmol),且在室溫下攪拌所得混合物20分鐘。在減壓下濃縮混合物,且將殘餘物溶解於AcOH中,藉由製備型HPLC來純化,得到呈TFA鹽形式之標題化合物(2mg)。MS m/z[M+H]+ C26H29ClFN3O4計算值,502.18;實驗值503.2。
將含(2S,4R)-5-(5'-氯-2'-氟聯苯-4-基)-4-[(5-乙氧基-2H-吡唑-3-羰基)胺基]-2-甲氧基甲基-2-甲基戊酸乙酯(11mg)之THF(1mL)與1N NaOH(0.3mL)組合,且在60℃下攪拌所得混合物3小時。添加AcOH,且純化(逆相)產物,得到呈TFA鹽形式之標題化合物(4mg)。MS m/z[M+H]+ C26H29ClFN3O5計算值,518.18;實驗值518。
將(2S,4R)-4-胺基-5-(5'-氯-2'-氟聯苯-4-基)-2-羥甲基-2-甲基戊酸乙酯(30mg,76μmol)、HATU(29.0mg,0.076mmol)及DIPEA(39.9μl,0.228mmol)與含1H-[1,2,4]三唑-3-甲酸(8.61mg,0.076mmol)之DMF(0.5mL)組合。攪拌所得混合物2小時,隨後在減壓下濃縮。將殘餘物與THF(1mL)及NaOH(456μL,456μmol)組合,且在40℃下攪拌2天。用AcOH淬滅反應,且藉由製備型HPLC來純化物質,得到呈TFA鹽形式之標題化合物(16.4mg)。MS m/z[M+H]+ C24H25ClFN3O5
計算值,490.15;實驗值490.2。
組合5-異丁基-2H-吡唑-3-甲酸(10.1mg,60μmol)及HATU(22.9mg,60μmol),隨後在室溫下於DMF(1mL)攪拌15分鐘。將(2S,4R)-4-胺基-5-(5'-氯-2'-氟聯苯-4-基)-2-羥甲基-2-甲基戊酸(20mg,55μmol)及Et3N(38μL,273μmol)預混合在一起,隨後添加至反應溶液中。在室溫下攪拌所得混合物1小時。在真空中移除溶劑,且藉由製備型HPLC純化殘餘物,得到呈TFA鹽形式之標題化合物(13.3mg)。MS m/z[M+H]+ C27H31ClFN3O4計算值,516.20;實驗值516.2。
在DMF(0.2mL)中組合5-乙醯基-2H-吡唑-3-甲酸(8mg,55μmol)及HATU(20.8mg,55μmol),且使其在室溫下靜置10分鐘。添加含(2S,4R)-4-胺基-5-(5'-氯-2'-氟聯苯-4-基)-2-羥甲基-2-甲基戊酸(20
mg,55μmol)之DMF及DIPEA(28.6μL,164μmol),且在室溫下攪拌所得混合物20分鐘。在減壓下濃縮混合物,且將殘餘物溶解於AcOH中,藉由製備型HPLC來純化,得到呈TFA鹽形式之標題化合物(2.1mg)。MS m/z[M+H]+ C25H25ClFN3O5計算值,502.15;實驗值503.2。
向瓶中添加(2S,4R)-4-第三丁氧基羰基胺基-5-(5'-氯-2'-氟聯苯-4-基)-2-羥甲基-2-甲基戊酸乙酯(415mg,840μmol)、硫酸氫四丁基銨(57mg,168μmol)、DCM(1mL)及NaOH(588μL,5.9mmol),繼而添加硫酸二乙酯(518mg,3.4mmol)。將反應容器加蓋,且劇烈攪拌隔夜。用DCM及水萃取混合物,純化(正相層析0%-60% EtOAe:己烷),隨後在減壓下濃縮,得到化合物1(220mg)。
將含化合物1(88mg,173μmol)之McCN(1mL)與4N HCl之二噁烷溶液(0.3mL)組合。攪拌混合物10分鐘,隨後在減壓下濃縮,得到化合物2。
將含化合物2(10μg,0.03μmol)之DMF(0.5mL)與HATU(11μg,0.03μmol)及5-乙醯基-2H-吡唑-3-甲酸(4μg,0.03μmol)組合,且攪拌所得混合物5分鐘。添加DIPEA(0.01μl,0.07μmol),且攪拌混合物20分鐘。蒸發溶劑,得到化合物3,該化合物不經進一步純化即使用。
將化合物3(11mg,20μmol)與THF(1mL)及1N NaOH(0.3mL)組合。在60℃下攪拌所得混合物3小時。添加AcOH,且藉由逆相HPLC來純化產物,得到呈TFA鹽形式之標題化合物(2mg)。MS m/z[M+H]+ C26H27ClFN3O5計算值,516.16;實驗值516。
按照前述實例中所述之程序,且代入適當之起始物質及試劑來製備呈TFA鹽形式之標題化合物(3.1mg)。MS m/z[M+H]+ C27H29ClFN3O5計算值,530.18;實驗值531.2。
使用如下所述之活體外分析測定化合物對人類及大鼠腦啡肽酶(EC 3.4.24.11;NEP)及人類血管收縮素轉化酶(ACE)之抑制活性。
自成年史泊格多利(Sprague Dawley)大鼠之腎製備大鼠NEP。在冷磷酸鹽緩衝生理鹽水(PBS)中洗滌整個腎,且以每一公克腎臟5mL緩衝劑之比率在冰冷溶解緩衝液(1% Triton X-114,150mM NaCl,50mM參(羥甲基)胺基甲烷(Tris)pH 7.5;Bordier(1981)J.Biol.Chem.256:1604-1607)中培養。使用polytron手持式組織研磨器在冰上使樣品均勻化。在3℃下於旋桶式轉筒(swinging bucket rotor)中以1000×g將勻漿離心5分鐘。離心塊再懸浮於20mL冰冷溶解緩衝液中,且在冰上培育30分鐘。隨後使樣品(15-20mL)於25mL冰冷緩衝液(6% w/v蔗糖,50mM pH 7.5 Tris,150mM NaCl,0.06%,Triton X-114)上分層,加熱至37℃且持續3-5分鐘,且在室溫下於旋桶式轉筒中以1000×g離心3分鐘。吸出上兩層,留下含有增濃之膜部分的黏稠油狀沈澱。添加甘油至50%之濃度,且將樣品儲存在-20℃下。使用BCA
偵測系統,以牛血清白蛋白(BSA)作為標準物定量蛋白質濃度。
重組人類NEP及重組人類ACE為市售獲得的(R&D Systems,Minneapolis,MN,目錄號分別為1182-ZN及929-ZN)。NEP及ACE分析中分別使用螢光肽受質Mca-D-Arg-Arg-Leu-Dap-(Dnp)-OH(Medeiros等人(1997)Braz.J.Med.Biol.Res.30:1157-62;Anaspec,San Jose,CA)及Abz-Phe-Arg-Lys(Dnp)-Pro-OH(Araujo等人(2000)Biochemistry 39:8519-8525;Bachem,Torrance,CA)。
在384孔白色不透明培養盤中,於37℃下,使用在分析緩衝液(NEP:50mM HEPES,pH 7.5,100mM NaCl,0.01%聚乙二醇脫水山梨糖醇單月桂酸酯(吐溫-20),10μM ZnSO4;ACE:50mM HEPES,pH 7.5,100mM NaCl,0.01% Tween-20,1μM ZnSO4)中濃度為10μM之螢光肽受質進行分析。各別酶以使1μM受質在37℃下20分鐘之後發生定量蛋白分解之濃度使用。
在10μM至20pM之濃度範圍內分析測試化合物。將測試化合物添加至酶中,且在37℃下培育30分鐘,隨後藉由添加受質開始反應。在37℃下培育20分鐘之後,藉由添加冰乙酸至3.6%(v/v)之最終濃度來終止反應。
在螢光計上用分別設定為320nm及405nm之激發及發射波長讀取培養盤。藉由使用以下方程式(GraphPad Software,Inc.,San Diego,CA)對數據進行非線性回歸來獲得抑制常數:v=v 0/[1+(I/K')]
其中v為反應速率,v 0為不受抑制之反應速率,I為抑制劑濃度,且K'為表觀抑制常數。
在此分析中測試其中Ra及Rb為H之式I'化合物,且發現其對人類NEP之pKi值9.0。發現下列化合物對人類NEP之pKi值如下:
其餘化合物未測試(n.d.),此係因為預期其在此活體外分析中不具有活性;然而,基於其活性形式之活性,預期相應前藥具有活體內NEP活性。
在此分析中測試其中Ra為H且Rb為F之式I'化合物(實例3A)及其中Ra為F且Rb為H之式I'化合物(實例3B),且發現其對人類NEP之pKi值9.0。基於此等活性形式之活性,預期相應前藥化合物具有活體內NEP活性。
在此分析中測試Ra為F、Rb為H、R2為H且R7為H之式II化合物(實例4A),且發現其對人類NEP之pKi值9.0。基於此活性形式之活性,預期相應前藥化合物具有活體內NEP活性。亦發現下列化合物對人類NEP具有如下pKi值:
在此分析中測試其中Ra為F、Rb為H、R2為H且R7為H之式IIIa化合物(實例5A)及其中Ra為F、Rb為H、R2為H且R7為H之式IIIb化合物(實例5B),且發現其對人類NEP之pKi值9.0。基於此等活性形式之活性,預期相應前藥化合物具有活體內NEP活性。另外,亦發現下列化合物對人類NEP具有如下pKi值:
在此分析中測試其中Ra為H、Rb為Cl、R2為H、R3為-OCH3且R7為H之式V化合物(實例6A)及式V'化合物(其中Ra及Rb為H且R3為-OH;實例6D),且發現其對人類NEP之pKi值9.0。基於此等活性形式之活性,預期相應前藥化合物具有活體內NEP活性。另外,亦發現下列化合物對人類NEP具有如下pKi值:
其餘化合物在此活體外分析中未加以測試,或不展示活性(n.d.),此係因為預期其不具有活性;然而,基於活性形式之活性,預期此等相應前藥具有活體內NEP活性。
在此分析中測試式VI化合物,且發現其對人類NEP具有如下pKi值:
基於此等活性形式之活性,預期相應前藥化合物具有活體內NEP活性。
在此分析中測試式VII化合物,且發現其對人類NEP具有如下pKi值:
基於此活性形式之活性,預期相應前藥化合物具有活體內NEP活性。
雖然本發明已參考其特定態樣或實施例加以描述,但一般熟習此項技術者應瞭解,在不偏離本發明之真實精神及範疇的情況下,可作出各種變化或可代入等效物。另外,在由適用之專利狀況及規定允許之程度上,本文中所引用之所有公開案、專利及專利申請案以全文引用之方式併入本文中,該引用之程度如同將各文件個別地以引用之方式併入本文中一般。
Claims (34)
- 一種式I化合物,
- 如請求項1之化合物,其具有式IIa或IIb:
- 如請求項2之化合物,其中Ra及Rb為H;且R2為H;且R7係選自-CH2CF2CH3、-CH2CF2CF3、-(CH2)5CH3、-(CH2)6CH3及
- 如請求項3之化合物,其中R2為H,且R7係選自-CH2CF2CH3、-CH2CF2CF3、-(CH2)5CH3、-(CH2)6CH3及
- 如請求項2之化合物,其中Ra係選自-CH3、-OCH3及Cl,且Rb為H;或Ra係選自H、-CH3、Cl及F,且Rb為Cl;或Ra為H,且Rb係選自-CH3及-CN;R2係選自H、-C1-6烷基、-(CH2)2-3ORe及-(CH2)2-3NReRe;且R7係選自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-環己基、-CH2CH(NH2)C(O)OCH3、-C2-4伸烷基-N(CH3)2、-C0-6伸烷基嗎啉基及
- 如請求項5之化合物,其中Ra係選自-CH3、-OCH3及Cl,且Rb為H;或Ra係選自H、-CH3、Cl及F,且Rb為Cl;或Ra為H,且Rb係選自-CH3及-CN;R2係選自H、-C1-6烷基及其中Re為H或-CH3之-(CH2)2-3ORe;且R7為H。
- 如請求項2之化合物,其中Ra為H,且Rb為F;或Ra為F,且Rb為H;R2係選自H、-C1-6烷基、-(CH2)2-3ORe及-(CH2)2-3NReRe;且R7係選自-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-環己基、-CH2CH(NH2)C(O)OCH3、-C2-4伸烷基-N(CH3)2、-C0-6伸烷基嗎啉基及
- 如請求項1之化合物,其具有式III:
- 如請求項8之化合物,其中Ra為Cl,且Rb為H;或Ra為H,且Rb係選自Cl、F、-CH3及-CN;或Ra為F,且Rb為Cl;R2係選自H、-C1-6烷基、-(CH2)2-3ORe及-(CH2)2-3NReRe;R4係選自-OH、-OCH3、OCH2CH3及-C1-4烷基;且R7係選自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-環己基、-CH2CH(NH2)C(O)OCH3、-C2-4伸烷基-N(CH3)2、-C0-6伸烷基嗎啉基及
- 如請求項9之化合物,其中Ra為F,Rb為Cl,R2為H,R4為-OCH3或-OCH2CH3,且R7為H。
- 如請求項8之化合物,其中Ra為F,且Rb為H;R2為H;R4為-OH;且R7係選自-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRdNH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-環己基、-CH2CH(NH2)C(O)OCH3、-C2-4伸烷基-N(CH3)2、-C0-6伸烷基嗎啉基及
- 如請求項1之化合物,其具有式IVa或IVb:
- 如請求項12之化合物,其中Ra為Cl,且Rb為H;或Ra為H,且Rb係選自Cl、F、-CH3及-CN;或Ra為F,且Rb為Cl;R2係選自H、-C1-6烷基、-(CH2)2-3ORe及-(CH2)2-3NReRe;且R7係選自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-環己基、-CH2CH(NH2)C(O)OCH3、-C2-4伸烷基-N(CH3)2、-C0-6伸烷基嗎啉基及
- 如請求項13之化合物,其中Ra為F,Rb為Cl,R2為H,且R7為H。
- 如請求項12之化合物,其中Ra為F,且Rb為H;R2為H;且R7係選自-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-環己基、-CH2CH(NH2)C(O)OCH3、-C2-4伸烷基-N(CH3)2、-C0-6伸烷基嗎啉基及
- 如請求項1之化合物,其具有式V:
- 如請求項16之化合物,其中Ra及Rb為H;R2係選自-C1-6烷基、-(CH2)2-3ORe及-(CH2)2-3NReRe;R3係選自-OH、-OCH3、-OCH2CH3及-C1-4烷基;且R7為H。
- 如請求項17之化合物,其中Ra及Rb為H,R2為-CH3,R3為-OH或-OCH3,且R7為H。
- 如請求項16之化合物,其中Ra係選自Cl及F,且Rb為H;或Ra為H,且Rb係選自Cl、F、-CH3及-CN;或Ra為F,且Rb為Cl;R2係選自H、-C1-6烷基、-(CH2)2-3ORe及-(CH2)2-3NReRe;R3係選自- OH、-OCH3、-OCH2CH3及-C1-4烷基;且R7係選自H、-C1-6烷基、-[(CH2)2O]1-3CH3、-CHRcOC(O)-C1-4烷基、-CH2OC(O)CHRd-NH2、-CH2OC(O)CHRd-NHC(O)O-C1-6烷基、-CHRcOC(O)O-C2-4烷基、-CHRcOC(O)O-環己基、-CH2CH(NH2)C(O)OCH3、-C2-4伸烷基-N(CH3)2、-C0-6伸烷基嗎啉基及
- 如請求項19之化合物,其中Ra為H,Rb為Cl,R2為H、-CH3、-CH2CH3或-(CH2)2OH,R3為-OH或-OCH3,且R7為H;或Ra為F,Rb為Cl,R2為H或-C1-6烷基,R3為-OH、-OCH3或-C1-4烷基,且R7為H。
- 如請求項1之化合物,其具有式VIa或VIb:
- 如請求項21之化合物,其中Ra為H或F;Rb為Cl;R2為H或-C1-6烷基;R3為-OCH3、-OCH2CH3或-C1-4烷基;R4若存在則為H;且R7為H。
- 如請求項1之化合物,其具有式VIIa或VIIb:
- 如請求項23之化合物,其中Ra為F,Rb為Cl,R2為H或-C1-6烷基,R4若存在則為H,且R7為H。
- 如請求項1之化合物,其具有式VIII:
- 如請求項1之化合物,其具有式IX:
- 如請求項1之化合物,其係(2S,4R)-5-(5'-氯-2'-氟聯苯-4-基)-2-乙氧基甲基-4-[(3-羥基異噁唑-5-羰基)胺基]-2-甲基戊酸。
- 一種下式化合物,
- 一種醫藥組合物,其包含醫藥學上可接受之載劑及如請求項1至28中任一項之化合物。
- 如請求項29之醫藥組合物,其進一步包含選自以下之治療劑:腺苷受體拮抗劑、α-腎上腺素激導性受體拮抗劑、β1-腎上腺素激導性受體拮抗劑、β2-腎上腺素激導性受體促效劑、雙重作用β-腎上腺素激導性受體拮抗劑/α1-受體拮抗劑、晚期糖基化終產物裂解劑、醛固酮(aldosterone)拮抗劑、醛固酮合成酶抑制劑、胺基肽酶N抑制劑、雄激素、血管收縮素轉化酶抑制劑及雙重作用血管收縮素轉化酶/腦啡肽酶抑制劑、血管收縮素轉化酶2活化劑及刺激劑、血管收縮素-II疫苗、抗凝劑、抗糖尿病藥劑、止瀉劑、抗青光眼藥劑、抗脂質藥劑、抗傷痛感受性藥劑、抗血栓藥劑、AT1受體拮抗劑及雙重作用AT1受體拮抗劑/腦啡肽酶抑制劑及多功能血管收縮素受體阻斷劑、緩激肽(bradykinin)受體拮抗劑、鈣離子通道阻斷劑、凝乳酶(chymase)抑制劑、地高辛(digoxin)、利尿劑、多巴胺促效劑、內皮素(endothelin)轉化酶抑制劑、內皮素受體拮抗劑、HMG-CoA還原酶抑制劑、雌激素、雌激素受體促效劑及/或拮抗劑、單胺再吸收抑制劑、肌肉鬆弛劑、利尿鈉肽受體-A(NPR-A)促效劑、利尿鈉肽清除受體拮抗劑、腦啡肽酶抑制劑、氧化氮供體、非類固醇消炎劑、N-甲基d-天冬胺酸受體拮抗劑、類鴉片受體促效劑、磷酸二酯酶抑制 劑、貝前列素鈉(beraprost sodium)、比馬前列素(bimatoprost)、依前列醇(epoprostenol)、伊洛前列素(iloprost)、拉坦前列素(latanoprost)、他氟前列素(tafluprost)、曲伏前列素(travoprost)及曲前列環素(treprostinil)、前列腺素受體促效劑、腎素(renin)抑制劑、選擇性血清素(serotonin)再吸收抑制劑、鈉離子通道阻斷劑、可溶性鳥苷酸環化酶(guanylate cyclase)刺激劑及活化劑、三環抗抑鬱劑、血管加壓素(vasopressin)受體拮抗劑、及其組合。
- 如請求項30之醫藥組合物,其中該治療劑為AT1受體拮抗劑。
- 如請求項1至28中任一項之化合物,其用於療法中。
- 如請求項32之化合物,其用於治療高血壓、心臟衰竭或腎病。
- 一種如請求項1至28中任一項之化合物的用途,其用於製造用於治療高血壓、心臟衰竭或腎病之藥劑。
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