TWI835821B - 唑并嘧啶化合物之固體型式 - Google Patents
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- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000017613 viral reproduction Effects 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 229940111503 welchol Drugs 0.000 description 1
- 229940053867 xeloda Drugs 0.000 description 1
- 229960000523 zalcitabine Drugs 0.000 description 1
- ARAIBEBZBOPLMB-UFGQHTETSA-N zanamivir Chemical compound CC(=O)N[C@@H]1[C@@H](N=C(N)N)C=C(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO ARAIBEBZBOPLMB-UFGQHTETSA-N 0.000 description 1
- 229960001028 zanamivir Drugs 0.000 description 1
- 229950007802 zidometacin Drugs 0.000 description 1
- 229960002555 zidovudine Drugs 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 229950009268 zinostatin Drugs 0.000 description 1
- 229940072168 zocor Drugs 0.000 description 1
- 229960003414 zomepirac Drugs 0.000 description 1
- ZXVNMYWKKDOREA-UHFFFAOYSA-N zomepirac Chemical compound C1=C(CC(O)=O)N(C)C(C(=O)C=2C=CC(Cl)=CC=2)=C1C ZXVNMYWKKDOREA-UHFFFAOYSA-N 0.000 description 1
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Abstract
本發明提供3-[2-胺基-6-(1-{[6-(2-羥基丙-2-基)吡啶-2-基]甲基}-1H-1,2,3-三唑-4-基)嘧啶-4-基]-2-甲基苯甲腈之固體形式、溶劑合物及水合物,以及製備及使用其之方法。
Description
腺苷係包含腺嘌呤及核糖分子(呋喃核糖)之複合物之嘌呤核苷化合物。腺苷天然存在於哺乳動物中且在若干生物化學過程(包括能量轉移(作為腺苷三磷酸及腺苷單磷酸)及信號轉導(作為環狀腺苷單磷酸))中起重要作用。腺苷亦用於與血管舒張(包括心臟血管舒張)相關之過程中,且起神經調節劑之作用(例如,認為其參與促進睡眠)。除其參與該等生物化學過程以外,腺苷亦用作治療性抗心律不整劑以治療(例如)室上性心動過速。如本文所進一步論述,腫瘤藉由抑制免疫功能且促進耐受性來逃避宿主反應,且已顯示腺苷在介導免疫系統之腫瘤逃避方面起重要作用。已確立經由在多種免疫細胞子集及內皮細胞上表現之A2A
Rs及A2B
Rs之腺苷信號傳導在發炎反應期間保護組織方面具有重要作用。因此,在某些條件下,腺苷保護腫瘤免受免疫破壞(例如,參見Fishman, P等人(2009) Handb Exp Pharmacol 193:399-441)。
腺苷受體係一類以腺苷作為內源性配體之嘌呤能G蛋白偶合受體。人類中四種類型之腺苷受體稱為A1
、A2A
、A2B
及A3
。已提出A1
之調節用於管控且治療(例如)神經病症、氣喘以及心臟及腎衰竭;已提出A2A
拮抗劑用於管控且治療(例如)帕金森氏病(Parkinson’s disease);已提出A2B
之調節用於管控且治療(例如)慢性肺病(包括氣喘);且已提出A3
之調節用於管控且治療(例如)氣喘及慢性阻塞性肺病、青光眼、癌症及中風。
在歷史上,腺苷受體之調節劑一直係非選擇性的。此在某些適應症中係可接受的,例如其中作用於心臟組織中之所有四種腺苷受體之內源性激動劑腺苷以非經腸方式投與用以治療嚴重之心動過速。然而,使用亞型選擇性腺苷受體激動劑及拮抗劑可達成期望結果,同時使不良效應最小化或消除。
已報導如(例如)美國專利申請案第15/875,106號及PCT申請案第PCT/US18/14352號中所闡述之化合物3-[2-胺基-6-(1-{[6-(2-羥基丙-2-基)吡啶-2-基]甲基}-1H-1,2,3-三唑-4-基)嘧啶-4-基]-2-甲基苯甲腈(在本文中指定為化合物I)係亞型選擇性腺苷受體拮抗劑。化合物I係A2A
R及A2B
R之強效拮抗劑,其對兩種受體之功效均小於10 nM。業內需要可用於醫藥組合物中之化合物I之穩定固體形式。
本發明係關於調節腺苷A2A
受體(A2A
R)及/或腺苷A2B
受體(A2B
R)之化合物之固體形式,及包含該等化合物之組合物(例如醫藥組合物)。下文詳細闡述此等化合物(包括其合成方法)及組合物。
在一些實施例中,本發明提供具有下式之化合物之固體形式:(化合物I)
或其水合物或溶劑合物。
在一些實施例中,本發明提供化合物I之固體形式I或其溶劑合物或水合物,其特徵在於X射線粉末繞射(XRPD)圖案包含一或多個在6.9、8.0、8.2、12.5、12.7、14.8、15.0、15.7、16.8、18.1、18.8、19.2、20.6、21.1、21.8、24.9、27.1或27.7度2θ (± 0.1度2θ)處之峰,其中該XRPD係使用CuKα 1
輻射獲得。
本發明進一步提供製備化合物I之固體形式I之方法,其係藉由在適於製備形式I之條件下形成化合物I及包含C3
-C5
酮、二氯甲烷或甲苯之溶劑之混合物來實施。
另外,提供包含本文所闡述之固體形式之醫藥組合物。
本文進一步提供治療至少部分地由腺苷A2A
受體(A2A
R)或腺苷A2B
受體(A2B
R)介導之疾病、病症或病狀之方法,其包含向有需要之個體投與治療有效量之化合物I之固體形式。在一些實施例中,該疾病、病症或病狀係癌症,其可利用單獨之化合物I之固體形式或與其他治療劑(例如免疫檢查點抑制劑)之組合來治療。
相關申請案之交叉參考
不適用關於在聯邦政府發起之研究及研發下作出之發明權利之聲明
不適用對光碟上提交之 「 序列表 」 、表或電腦程式列表附錄之參考
不適用
在進一步闡述本發明之前,應理解,本發明並不限於本文所闡述之具體實施例,且亦應理解本文所使用之術語係僅出於闡述具體實施例之目的,且並不意欲具有限制性。
倘若提供值之範圍,則應理解,該範圍之上限與下限間之每一居間值及該所述範圍中之任何其他所述值或居間值均涵蓋在本發明內,除非上下文另有明確指示,否則該每一居間值精確至下限單位之十分之一。該等較小範圍之上限及下限可獨立地包括在較小範圍內且亦涵蓋於本發明內,但受所述範圍中之任何明確排除之限值的約束。倘若所述範圍包括限值中之一者或二者,則本發明中亦包括排除彼等所包括限值中之任一者或二者的範圍。除非另有定義,否則本文所使用之全部技術及科學術語均具有與熟習本發明所屬技術者通常所理解相同之含義。
除非上下文另外明確指示,否則如本文所使用,單數形式「一(a、an)」及「該」包括複數個指示物。應進一步注意,申請專利範圍可設計為不包括任何可選要素。因此,此陳述意欲用作前置基礎以結合申請專利範圍要素之列舉使用諸如「僅僅」、「僅」及諸如此類等排他性術語或使用「負面」限制。
本文所論述之公開案僅僅因其揭示內容先於本申請案之申請日期而提供。此外,所提供公開案之日期可能與實際公開案日期不同,此可能需要獨立地確認。概述
化合物3-[2-胺基-6-(1-{[6-(2-羥基丙-2-基)吡啶-2-基]甲基}-1H-1,2,3-三唑-4-基)嘧啶-4-基]-2-甲基苯甲腈(化合物I)係腺苷A2A
受體(A2A
R)及/或腺苷A2B
受體(A2B
R)之選擇性及強效拮抗劑:(化合物I)
本發明源自化合物I之固體形式之令人驚訝之發現、歸因於如本文所闡述形式之優點及用於製備該等固體形式之製程。結晶材料通常在物理及化學上更穩定。結晶材料之優良穩定性可使得其更適於用於最終劑型中,此乃因產品之儲放壽命與穩定性直接相關。活性醫藥成分(API)處理中之結晶步驟亦意味著藉由將雜質排斥至處理溶劑中而使原料藥純度升格之機會。定義
除非另外指示,否則以下術語意欲具有下文所闡述之含義。其他術語係在整個本說明書之其他地方進行定義。
「水合物」係指藉由將化合物I與水組合而形成之複合物。該術語包括化學計量以及非化學計量之水合物。
「溶劑合物」係指藉由將化合物I與溶劑組合而形成之複合物。
「去溶劑化」係指自作為如本文所闡述之溶劑合物之化合物I形式部分地或完全地去除溶劑分子。產生去溶劑化形式之去溶劑化技術包括(但不限於)使化合物I形式(溶劑合物)暴露於真空、使溶劑合物經受升高溫度、使溶劑合物暴露於氣體(例如空氣或氮)流或其任一組合。因此,去溶劑化之化合物I形式可係無水的(即,完全不含溶劑分子);或部分地溶劑化,其中溶劑分子係以化學計量或非化學計量量存在。
「醇」係指具有羥基之溶劑。代表性醇可具有任何適宜碳原子數,例如C1
-C6
,及任何適宜羥基數,例如1-3個。例示性醇包括(但不限於)甲醇、乙醇、正丙醇、正丙醇等。
「實質上不含化合物I之其他結晶形式」係指化合物I之結晶形式含有少於10%之化合物I之其他結晶形式。舉例而言,實質上不含可係指化合物I之結晶形式含有少於9%、8%、7%、6%、5%、4%、3%、2%或1%之化合物I之其他結晶形式。較佳地,實質上不含係指化合物I之結晶形式含有少於5%之化合物I之其他結晶形式。較佳地,實質上不含係指化合物I之結晶形式含有少於1%之化合物I之其他結晶形式。
術語「醫藥上可接受之鹽」意欲包括端視見於本文所闡述化合物上之具體取代基,利用相對無毒之酸或鹼所製備之活性化合物之鹽。當本發明之化合物含有相對酸性之官能基時,可藉由使此等化合物之中性形式與充足量之純淨的或在適宜惰性溶劑中之期望鹼接觸來獲得鹼加成鹽。衍生自醫藥上可接受之無機鹼之鹽之實例包括鋁鹽、銨鹽、鈣鹽、銅鹽、鐵鹽、亞鐵鹽、鋰鹽、鎂鹽、錳鹽、二價錳鹽、鉀鹽、鈉鹽、鋅鹽及諸如此類。衍生自醫藥上可接受之有機鹼之鹽包括以下之鹽:一級、二級及三級胺,包括經取代胺、環狀胺、天然胺及諸如此類,例如精胺酸、甜菜鹼、咖啡因、膽鹼、N,N’-二苄基乙二胺、二乙胺、2-二乙胺基乙醇、2-二甲基胺基乙醇、乙醇胺、乙二胺、N-乙基嗎啉、N-乙基六氫吡啶、還原葡糖胺、葡萄糖胺、組胺酸、哈胺(hydrabamine)、異丙胺、離胺酸、甲基還原葡糖胺、嗎啉、六氫吡嗪、六氫吡啶、聚胺樹脂、普魯卡因(procaine)、嘌呤、可可鹼、三乙胺、三甲胺、三丙胺、胺丁三醇及諸如此類。當本發明之化合物含有相對鹼性官能基時,可藉由使此等化合物之中性形式與充足量之純淨的或在適宜惰性溶劑中之期望酸接觸來獲得酸加成鹽。醫藥上可接受之酸加成鹽之實例包括衍生自無機酸(如鹽酸、氫溴酸、硝酸、碳酸、一氫碳酸、磷酸、一氫磷酸、二氫磷酸、硫酸、一氫硫酸、氫碘酸或磷酸及諸如此類)之彼等,以及衍生自相對無毒之有機酸(如乙酸、丙酸、異丁酸、丙二酸、苯甲酸、琥珀酸、辛二酸、富馬酸、扁桃酸、鄰苯二甲酸、苯磺酸、對甲苯基磺酸、檸檬酸、酒石酸、甲烷磺酸及諸如此類)之鹽。亦包括胺基酸之鹽(例如精胺酸鹽及諸如此類)及有機酸(如葡萄糖醛酸或半乳糖醛酸及諸如此類)之鹽(例如,參見Berge, S.M.等人,「Pharmaceutical Salts」,Journal of Pharmaceutical Science
,1977
,66
, 1-19)。本發明之某些特定化合物含有容許化合物轉化成鹼或酸加成鹽之鹼性及酸性官能基。
該等化合物之中性形式可藉由使鹽與鹼或酸接觸並以習用方式分離出母體化合物來再生。化合物之母體形式在某些物理性質(例如在極性溶劑中之溶解性)方面不同於各種鹽形式,然而出於本發明之目的,該等鹽在其他方面卻與化合物之母體形式等效。
本發明之某些化合物可以非溶劑化形式以及溶劑化形式(包括水合形式)存在。一般而言,溶劑化形式與非溶劑化形式等效且意欲涵蓋於本發明之範圍內。本發明之某些化合物可以多種結晶或非晶形形式存在。一般而言,所有物理形式對於本發明所涵蓋之用途而言均係等效的,且意欲在本發明之範圍內。
本發明之化合物亦可在構成此等化合物之一或多個原子處含有非天然比例之原子同位素。同位素之非天然比例可定義為在自然界中所發現之量至由100%所討論原子組成之量的範圍內。舉例而言,化合物可納入放射性同位素(例如氚(3
H)、碘-125 (125
I)或碳-14 (14
C))或非放射性同位素(例如氘(2
H)或碳-13 (13
C))。此等同位素變化形式可為本申請案內別處所闡述之彼等提供額外效用。舉例而言,本發明化合物之同位素變體可具有額外效用,包括(但不限於)作為診斷及/或成像試劑或作為細胞毒性/放射毒性治療劑。另外,本發明化合物之同位素變體可具有改變之藥物動力學及藥效學特徵,其可在治療期間有助於安全性、耐受性或效能增強。本發明化合物之所有同位素變化形式(無論具有放射性與否)均意欲涵蓋在本發明之範圍內。
術語「患者」或「個體」可互換使用以指人類或非人類動物(例如,哺乳動物)。
術語「投與(administration、administer)」及諸如此類在其應用於(例如)個體、細胞、組織、器官或生物體液時係指(例如) A2A
R/A2B
R之抑制劑、包含其之醫藥組合物或診斷劑與該個體、細胞、組織、器官或生物體液之接觸。在細胞之情況下,投與包括試劑與細胞接觸(例如,活體外或離體)以及試劑與體液接觸,其中體液係與細胞接觸。
術語「治療(treat、treating、treatment)」及諸如此類係指在疾病、病症或病狀或其症狀已診斷出、觀察到及諸如此類之後起始之行動方案(例如投與A2A
R/A2B
R之抑制劑或包含其之醫藥組合物),以便暫時或永久地消除、減少、阻抑、減輕或改善困擾個體之疾病、病症或病狀之至少一個潛在原因或與困擾個體之疾病、病症、病狀相關之至少一種症狀。因此,治療包括抑制活性疾病(例如,停止疾病、病症或病狀或與其相關之臨床症狀之發展或進一步發展)。
如本文所使用之術語「需要治療」係指由醫師或其他照護者作出之個體需要或將受益於該治療之判斷。此判斷係基於醫師或照護者之專業領域中之多種因素而作出。
術語「預防(prevent、preventing、prevention)」及諸如此類係指通常在易患特定疾病、病症或病狀之個體之情況下,以某一方式(例如,在疾病、病症、病狀或其症狀發作之前)起始之行動方案(例如投與A2A
R/A2B
R抑制劑或包含其之醫藥組合物),以便暫時或永久地預防、阻抑、抑制或減少個體發生疾病、病症、病狀或諸如此類之風險(如藉由(例如)臨床症狀之不存在所確定)或延遲其發作。在某些情況下,該等術語亦係指減緩疾病、病症或病狀之進展或將其進展抑制至有害或在其他方面不期望之狀態。
如本文所使用之術語「需要預防」係指由醫師或其他照護者作出之個體需要或將受益於預防性照護之判斷。此判斷係基於醫師或照護者之專業領域中之多種因素而作出。
片語「治療有效量」係指將藥劑單獨或作為醫藥組合物之一部分且以單一劑量或作為一系列劑量之一部分、以能夠在投與個體時對疾病、病症或病狀之任何症狀、態樣或特徵具有任何可檢測到之正面效應之量投與個體。治療有效量可藉由量測相關生理效應來確定,且其可結合投藥方案及個體病狀之診斷分析及諸如此類來調整。舉例而言,A2A
R/A2B
R抑制劑(或例如其代謝物)在投與後特定時間之血清含量之量測值可指示是否已使用治療有效量。
術語「抑制劑」及「拮抗劑」或「活化劑」及「激動劑」分別係指抑制分子或活化分子,例如用於使(例如)配體、受體、輔因子、基因、細胞、組織或器官活化。抑制劑係減少、阻斷、阻止、延遲(例如)基因、蛋白質、配體、受體或細胞之活化、使其不活化、不敏感或下調之分子。活化劑係增加、活化、促進、增強(例如)基因、蛋白質、配體、受體或細胞之活化、使其敏感或上調之分子。抑制劑亦可定義為使組成型活性降低、阻斷或不活化之分子。「激動劑」係與靶標相互作用以引起或促進靶標活化增加之分子。「拮抗劑」係與激動劑之作用相反之分子。拮抗劑阻止、降低、抑制或中和激動劑之活性,且拮抗劑亦可阻止、抑制或降低靶標(例如靶受體)之組成型活性,即使在不存在經鑑別之激動劑之情形下亦如此。
術語「調節(modulate、modulation)」及諸如此類係指分子(例如,活化劑或抑制劑)直接或間接地增加或降低A2A
R/A2B
R之功能或活性之能力。調節劑可單獨起作用,或其可使用輔因子,例如蛋白質、金屬離子或小分子。調節劑之實例包括小分子化合物及其他生物有機分子。多種小分子化合物文庫(例如組合文庫)可商業購得且可用作鑑別調節劑之起點。熟習此項技術者能夠開發出一或多種分析(例如基於生物化學或細胞之分析),其中可篩選此等化合物文庫以鑑別一或多種具有期望性質之化合物;此後,熟練的藥物化學研究員能夠藉由(例如)合成及評估類似物及其衍生物使此一或多種化合物最佳化。合成及/或分子建模研究亦可用於鑑別活化劑。
分子之「活性」可描述或係指分子與配體或與受體之結合;催化活性;刺激基因表現或細胞信號傳導、分化或成熟之能力;抗原活性;調節其他分子之活性;及諸如此類。術語「增殖活性」涵蓋促進(例如)正常細胞分裂以及癌症、腫瘤、發育不良、細胞轉型、轉移及血管生成、為其所必需或與其明確相關之活性。化合物 I 之固體形式
本發明提供化合物3-[2-胺基-6-(1-{[6-(2-羥基丙-2-基)吡啶-2-基]甲基}-1H-1,2,3-三唑-4-基)嘧啶-4-基]-2-甲基苯甲腈(化合物I)之固體形式,包括結晶及非晶形形式以及溶劑合物及水合物形式。在一些實施例中,本發明提供具有以下結構之化合物I之固體形式(例如結晶形式):
及其溶劑合物或水合物。
化合物I可採取多種固體形式,包括(但不限於)形式I、形式II及形式III。化合物I可形成兩種或更多種結晶形式之混合物,或形成實質上不含其他結晶形式之單一結晶形式。形式 I
在一些實施例中,化合物I之固體形式I之特徵可在於具有在6.9、8.0、8.2、12.5、12.7、14.8、15.0、15.7、16.8、18.1、18.8、19.2、20.6、21.1、21.8、24.9、27.1或27.7度2θ (± 0.1度2θ)處之峰之X射線粉末繞射(XRPD)圖案,其中該XRPD係使用CuKα 1
輻射獲得,或特徵可在於具有在約193℃下之吸熱之差示掃描量熱法(DSC)圖,或上文所提及之XRPD及DSC兩者。
化合物I之形式I之特徵可在於具有一或多個(例如,兩個、三個、四個、五個或更多個)在6.9、8.0、8.2、12.5、12.7、14.8、15.0、15.7、16.8、18.1、18.8、19.2、20.6、21.1、21.8、24.9、27.1或27.7度2θ (± 0.1度2θ)處之峰之X射線粉末繞射(XRPD)圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式I之特徵可在於具有兩個或更多個在6.9、8.0、8.2、12.5、12.7、14.8、15.0、15.7、16.8、18.1、18.8、19.2、20.6、21.1、21.8、24.9、27.1或27.7度2θ (± 0.1度2θ)處之峰之X射線粉末繞射圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式I之特徵可在於具有三個或更多個在6.9、8.0、8.2、12.5、12.7、14.8、15.0、15.7、16.8、18.1、18.8、19.2、20.6、21.1、21.8、24.9、27.1或27.7度2θ (± 0.1度2θ)處之峰之X射線粉末繞射圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式I之特徵可在於具有四個或更多個在6.9、8.0、8.2、12.5、12.7、14.8、15.0、15.7、16.8、18.1、18.8、19.2、20.6、21.1、21.8、24.9、27.1或27.7度2θ (± 0.1度2θ)處之峰之X射線粉末繞射圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式I之特徵可在於具有五個或更多個在6.9、8.0、8.2、12.5、12.7、14.8、15.0、15.7、16.8、18.1、18.8、19.2、20.6、21.1、21.8、24.9、27.1或27.7度2θ (± 0.1度2θ)處之峰之X射線粉末繞射圖案,其中該XRPD係使用CuKα 1
輻射獲得。
在一些實施例中,化合物I之固體形式I之特徵可在於具有六個或更多個在6.9、8.0、8.2、12.5、12.7、14.8、15.0、15.7、16.8、18.1、18.8、19.2、20.6、21.1、21.8、24.9、27.1或27.7度2θ (± 0.1度2θ)處之峰之X射線粉末繞射圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式I之特徵可在於具有七個或更多個在6.9、8.0、8.2、12.5、12.7、14.8、15.0、15.7、16.8、18.1、18.8、19.2、20.6、21.1、21.8、24.9、27.1或27.7度2θ (± 0.1度2θ)處之峰之X射線粉末繞射圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式I之特徵可在於具有八個或更多個在6.9、8.0、8.2、12.5、12.7、14.8、15.0、15.7、16.8、18.1、18.8、19.2、20.6、21.1、21.8、24.9、27.1或27.7度2θ (± 0.1度2θ)處之峰之X射線粉末繞射圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式I之特徵可在於具有九個或更多個在6.9、8.0、8.2、12.5、12.7、14.8、15.0、15.7、16.8、18.1、18.8、19.2、20.6、21.1、21.8、24.9、27.1或27.7度2θ (± 0.1度2θ)處之峰之X射線粉末繞射圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式I之特徵可在於具有十個或更多個在6.9、8.0、8.2、12.5、12.7、14.8、15.0、15.7、16.8、18.1、18.8、19.2、20.6、21.1、21.8、24.9、27.1或27.7度2θ (± 0.1度2θ)處之峰之X射線粉末繞射圖案,其中該XRPD係使用CuKα 1
輻射獲得。
在一些實施例中,化合物I之固體形式I之特徵可在於具有在6.9、8.2及15.7度2θ (± 0.1度2θ)處之峰之XRPD圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式I之特徵可在於進一步包含一或多個在14.8、15.0、18.8或21.1度2θ (± 0.1度2θ)處之峰之X射線粉末繞射(XRPD)圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式I之特徵可在於進一步包含兩個或更多個在14.8、15.0、18.8或21.1度2θ (± 0.1度2θ)處之峰之X射線粉末繞射(XRPD)圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式I之特徵可在於進一步包含三個或更多個在14.8、15.0、18.8或21.1度2θ (± 0.1度2θ)處之峰之X射線粉末繞射(XRPD)圖案,其中該XRPD係使用CuKα 1
輻射獲得。
在一些實施例中,化合物I之固體形式I之特徵可在於具有在6.9、8.2、15.7及18.8度2θ (± 0.1度2θ)處之峰之X射線粉末繞射(XRPD)圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式I之特徵可在於具有在6.9、8.2、12.5、14.8、15.7及18.8度2θ (± 0.1度2θ)處之峰之X射線粉末繞射(XRPD)圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式I之特徵可在於具有在6.9、8.2、12.5、14.8、15.7、18.8及21.1度2θ (± 0.1度2θ)處之峰之X射線粉末繞射(XRPD)圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式I之特徵可在於具有在6.9、8.2、12.5、14.8、15.7、18.8、20.6及21.1度2θ (± 0.1度2θ)處之峰之X射線粉末繞射(XRPD)圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式I之特徵可在於具有在6.9、8.2、12.5、14.8、15.7、18.8、20.6、21.1及27.7度2θ (± 0.1度2θ)處之峰之X射線粉末繞射(XRPD)圖案,其中該XRPD係使用CuKα 1
輻射獲得。
在一些實施例中,化合物I之固體形式I之特徵可在於具有在6.9、8.0、8.2、12.5、12.7、14.8、15.0、15.7、16.8、18.1、18.8、19.2、20.6、21.1、21.8、24.9、27.1及27.7度2θ (± 0.1度2θ)處之峰之XRPD圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式I之特徵可在於根據下表1中之峰之XRPD圖案:
表1. 化合物I之形式I樣品之XRPD峰列表
在一些實施例中,化合物I之固體形式I之特徵可在於實質上與圖1一致之XRPD圖案。在一些實施例中,化合物I之固體形式I可實質上不含化合物I之其他固體形式。在一些實施例中,化合物I之固體形式I可實質上不含形式II及形式III。
化合物I之形式I之特徵可在於具有在約193℃下之吸熱之差示掃描量熱法(DSC)圖。在一些實施例中,化合物I之固體形式I之特徵可在於實質上與圖2一致之DSC圖案。
化合物I之形式I之特徵可在於下表2中所示單晶X射線繞射資料之一或多個特徵。
表2:化合物I之形式I之單晶X射線繞射資料 形式 II
化合物I之形式II之特徵可在於具有一或多個(例如,兩個、三個、四個、五個或更多個)在7.1、7.8、8.2、8.7、12.4、13.9、14.9、15.3、15.6、17.5、18.3、19.3、19.8、20.2、21.4、22.2、25.0、25.6、26.4或27.1度2θ (± 0.1度2θ)處之峰之X射線粉末繞射(XRPD)圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式II之特徵可在於具有兩個或更多個在7.1、7.8、8.2、8.7、12.4、13.9、14.9、15.3、15.6、17.5、18.3、19.3、19.8、20.2、21.4、22.2、25.0、25.6、26.4或27.1度2θ (± 0.1度2θ)處之峰之X射線粉末繞射圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式II之特徵可在於具有三個或更多個在7.1、7.8、8.2、8.7、12.4、13.9、14.9、15.3、15.6、17.5、18.3、19.3、19.8、20.2、21.4、22.2、25.0、25.6、26.4或27.1度2θ (± 0.1度2θ)處之峰之X射線粉末繞射圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式II之特徵可在於具有四個或更多個在7.1、7.8、8.2、8.7、12.4、13.9、14.9、15.3、15.6、17.5、18.3、19.3、19.8、20.2、21.4、22.2、25.0、25.6、26.4或27.1度2θ (± 0.1度2θ)處之峰之X射線粉末繞射圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式II之特徵可在於具有五個或更多個在7.1、7.8、8.2、8.7、12.4、13.9、14.9、15.3、15.6、17.5、18.3、19.3、19.8、20.2、21.4、22.2、25.0、25.6、26.4或27.1度2θ (± 0.1度2θ)處之峰之X射線粉末繞射圖案,其中該XRPD係使用CuKα 1
輻射獲得。
在一些實施例中,化合物I之固體形式II之特徵可在於具有六個或更多個在7.1、7.8、8.2、8.7、12.4、13.9、14.9、15.3、15.6、17.5、18.3、19.3、19.8、20.2、21.4、22.2、25.0、25.6、26.4或27.1度2θ (± 0.1度2θ)處之峰之X射線粉末繞射圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式II之特徵可在於具有七個或更多個在7.1、7.8、8.2、8.7、12.4、13.9、14.9、15.3、15.6、17.5、18.3、19.3、19.8、20.2、21.4、22.2、25.0、25.6、26.4或27.1度2θ (± 0.1度2θ)處之峰之X射線粉末繞射圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式II之特徵可在於具有八個或更多個在7.1、7.8、8.2、8.7、12.4、13.9、14.9、15.3、15.6、17.5、18.3、19.3、19.8、20.2、21.4、22.2、25.0、25.6、26.4或27.1度2θ (± 0.1度2θ)處之峰之X射線粉末繞射圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式II之特徵可在於具有九個或更多個在7.1、7.8、8.2、8.7、12.4、13.9、14.9、15.3、15.6、17.5、18.3、19.3、19.8、20.2、21.4、22.2、25.0、25.6、26.4或27.1度2θ (± 0.1度2θ)處之峰之X射線粉末繞射圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式II之特徵可在於具有十個或更多個在7.1、7.8、8.2、8.7、12.4、13.9、14.9、15.3、15.6、17.5、18.3、19.3、19.8、20.2、21.4、22.2、25.0、25.6、26.4或27.1度2θ (± 0.1度2θ)處之峰之X射線粉末繞射圖案,其中該XRPD係使用CuKα 1
輻射獲得。
在一些實施例中,化合物I之固體形式II之特徵可在於具有在7.1、7.8及18.3度2θ (± 0.1度2θ)處之峰之XRPD圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式II之特徵可在於進一步包含一或多個在8.7、13.9、14.9、15.6或22.2度2θ (± 0.1度2θ)處之峰之X射線粉末繞射(XRPD)圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式II之特徵可在於進一步包含兩個或更多個在8.7、13.9、14.9、15.6或22.2度2θ (± 0.1度2θ)處之峰之X射線粉末繞射(XRPD)圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式II之特徵可在於進一步包含三個或更多個在8.7、13.9、14.9、15.6或22.2度2θ (± 0.1度2θ)處之峰之X射線粉末繞射(XRPD)圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式II之特徵可在於進一步包含四個或更多個在8.7、13.9、14.9、15.6或22.2度2θ (± 0.1度2θ)處之峰之X射線粉末繞射(XRPD)圖案,其中該XRPD係使用CuKα 1
輻射獲得。
在一些實施例中,化合物I之固體形式II之特徵可在於具有在7.1、7.8、14.9及18.3度2θ (± 0.1度2θ)處之峰之XRPD圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式II之特徵可在於具有在7.1、7.8、8.7、14.9及18.3度2θ (± 0.1度2θ)處之峰之XRPD圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式II之特徵可在於具有在7.1、7.8、13.9、14.9及18.3度2θ (± 0.1度2θ)處之峰之XRPD圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式II之特徵可在於具有在7.1、7.8、13.9、14.9、15.6及18.3度2θ (± 0.1度2θ)處之峰之XRPD圖案,其中該XRPD係使用CuKα 1
輻射獲得。
在一些實施例中,化合物I之固體形式II之特徵可在於具有在7.1、7.8、8.2、8.7、12.4、13.9、14.9、15.3、15.6、17.5、18.3、19.3、19.8、20.2、21.4、22.2、25.0、25.6、26.4或27.1度2θ (± 0.1度2θ)處之峰之X射線粉末繞射圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式II之特徵可在於根據下表3之峰列表:
表3. 化合物I之形式II樣品之XRPD峰列表
在一些實施例中,化合物I之固體形式II之特徵可在於實質上與圖5一致之XRPD圖案。在一些實施例中,化合物I之固體形式II可實質上不含化合物I之其他固體形式。在一些實施例中,化合物I之固體形式II可實質上不含形式I及形式III。
化合物I之形式II之特徵可在於具有在約190℃下之吸熱之差示掃描量熱法(DSC)圖。在一些實施例中,化合物I之固體形式I之特徵可在於實質上與圖6一致之DSC圖案。
在一些實施例中,化合物I之固體形式II之特徵可在於實質上與圖5一致之XRPD圖案及具有在約190℃下之吸熱之DSC圖。形式 III
化合物I之形式III之特徵可在於具有一或多個(例如,兩個、三個、四個、五個或更多個)在10.8、12.2、12.6、13.7、15.2、15.3、16.5、17.2、17.8、18.1、18.4、19.3、19.5、20.7、21.3、23.1、23.9、24.7、25.3或28.4度2θ (± 0.1度2θ)處之峰之X射線粉末繞射(XRPD)圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式III之特徵可在於具有兩個或更多個在10.8、12.2、12.6、13.7、15.2、15.3、16.5、17.2、17.8、18.1、18.4、19.3、19.5、20.7、21.3、23.1、23.9、24.7、25.3或28.4度2θ (± 0.1度2θ)處之峰之X射線粉末繞射圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式III之特徵可在於具有三個或更多個在10.8、12.2、12.6、13.7、15.2、15.3、16.5、17.2、17.8、18.1、18.4、19.3、19.5、20.7、21.3、23.1、23.9、24.7、25.3或28.4度2θ (± 0.1度2θ)處之峰之X射線粉末繞射圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式III之特徵可在於具有四個或更多個在10.8、12.2、12.6、13.7、15.2、15.3、16.5、17.2、17.8、18.1、18.4、19.3、19.5、20.7、21.3、23.1、23.9、24.7、25.3或28.4度2θ (± 0.1度2θ)處之峰之X射線粉末繞射圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式III之特徵可在於具有五個或更多個在10.8、12.2、12.6、13.7、15.2、15.3、16.5、17.2、17.8、18.1、18.4、19.3、19.5、20.7、21.3、23.1、23.9、24.7、25.3或28.4度2θ (± 0.1度2θ)處之峰之X射線粉末繞射圖案,其中該XRPD係使用CuKα 1
輻射獲得。
在一些實施例中,化合物I之固體形式III之特徵可在於具有六個或更多個在10.8、12.2、12.6、13.7、15.2、15.3、16.5、17.2、17.8、18.1、18.4、19.3、19.5、20.7、21.3、23.1、23.9、24.7、25.3或28.4度2θ (± 0.1度2θ)處之峰之X射線粉末繞射圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式III之特徵可在於具有七個或更多個在10.8、12.2、12.6、13.7、15.2、15.3、16.5、17.2、17.8、18.1、18.4、19.3、19.5、20.7、21.3、23.1、23.9、24.7、25.3或28.4度2θ (± 0.1度2θ)處之峰之X射線粉末繞射圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式III之特徵可在於具有八個或更多個在10.8、12.2、12.6、13.7、15.2、15.3、16.5、17.2、17.8、18.1、18.4、19.3、19.5、20.7、21.3、23.1、23.9、24.7、25.3或28.4度2θ (± 0.1度2θ)處之峰之X射線粉末繞射圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式III之特徵可在於具有九個或更多個在10.8、12.2、12.6、13.7、15.2、15.3、16.5、17.2、17.8、18.1、18.4、19.3、19.5、20.7、21.3、23.1、23.9、24.7、25.3或28.4度2θ (± 0.1度2θ)處之峰之X射線粉末繞射圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式III之特徵可在於具有十個或更多個在10.8、12.2、12.6、13.7、15.2、15.3、16.5、17.2、17.8、18.1、18.4、19.3、19.5、20.7、21.3、23.1、23.9、24.7、25.3或28.4度2θ (± 0.1度2θ)處之峰之X射線粉末繞射圖案,其中該XRPD係使用CuKα 1
輻射獲得。
在一些實施例中,化合物I之固體形式III之特徵可在於具有在12.2、20.7及21.3度2θ (± 0.1度2θ)處之峰之XRPD圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式III之特徵可在於進一步包含一或多個在10.8、12.6、17.2或19.3度2θ (± 0.1度2θ)處之峰之X射線粉末繞射(XRPD)圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式III之特徵可在於進一步包含兩個或更多個在10.8、12.6、17.2或19.3度2θ (± 0.1度2θ)處之峰之X射線粉末繞射(XRPD)圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式III之特徵可在於進一步包含三個或更多個在10.8、12.6、17.2或19.3度2θ (± 0.1度2θ)處之峰之X射線粉末繞射(XRPD)圖案,其中該XRPD係使用CuKα 1
輻射獲得。
在一些實施例中,化合物I之固體形式III之特徵可在於具有在12.2、12.6、20.7及21.3度2θ (± 0.1度2θ)處之峰之XRPD圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式III之特徵可在於具有在12.2、17.2、20.7及21.3度2θ (± 0.1度2θ)處之峰之XRPD圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式III之特徵可在於具有在12.2、12.6、17.2、20.7及21.3度2θ (± 0.1度2θ)處之峰之XRPD圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式III之特徵可在於具有在10.8、12.2、12.6、17.2、20.7及21.3度2θ (± 0.1度2θ)處之峰之XRPD圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式III之特徵可在於具有在10.8、12.2、12.6、17.2、19.3、20.7及21.3度2θ (± 0.1度2θ)處之峰之XRPD圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式III之特徵可在於具有在10.8、12.2、12.6、17.2、19.3、20.7、21.3及23.9度2θ (± 0.1度2θ)處之峰之XRPD圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式III之特徵可在於具有在10.8、12.2、12.6、17.2、19.3、20.7、21.3、23.9及24.7度2θ (± 0.1度2θ)處之峰之XRPD圖案,其中該XRPD係使用CuKα 1
輻射獲得。
在一些實施例中,化合物I之固體形式III之特徵可在於具有在10.8、12.2、12.6、13.7、15.2、15.3、16.5、17.2、17.8、18.1、18.4、19.3、19.5、20.7、21.3、23.1、23.9、24.7、25.3及28.4度2θ (± 0.1度2θ)處之峰之X射線粉末繞射圖案,其中該XRPD係使用CuKα 1
輻射獲得。在一些實施例中,化合物I之固體形式III之特徵可在於根據下表4之峰列表:
表4. 化合物I之形式III樣品之XRPD峰列表
在一些實施例中,化合物I之固體形式III之特徵可在於實質上與選自圖7中所示彼等中之一者一致之XRPD圖案。在一些實施例中,化合物I之固體形式III可實質上不含化合物I之其他固體形式。在一些實施例中,化合物I之固體形式III可實質上不含形式I及形式II。
化合物I之形式III之特徵可在於具有一或多個在約178℃及約193℃下之吸熱之差示掃描量熱法(DSC)圖。在一些實施例中,化合物I之固體形式III之特徵可在於具有在約178℃下之吸熱之DSC圖案。在一些實施例中,化合物I之固體形式III之特徵可在於實質上與圖8一致之DSC圖案。
在一些實施例中,化合物I之固體形式III之特徵可在於實質上與圖7一致之XRPD圖案及具有一或多個在約178℃及約193℃下之吸熱之DSC圖。製備方法
本文所提供之化合物I之固體形式可藉由如下文及實例中所闡述之方法來製備。起始材料之適合性
一般而言,起始化合物I材料之形態學對於成功回收化合物I之固體形式而言不係重要的,但可影響初始溶出之動力學。舉例而言,可使用經由凍乾獲得之非晶形材料來獲得期望固體形式。或者,可使用化合物I之一種固體形式來獲得化合物I之另一固體形式,例如可使用較不穩定之固體形式來獲得更穩定之形式。單一溶劑及二元溶劑混合物
溶劑可係適於形成溶液之任一溶劑。通常,溶劑可係極性溶劑,其在一些實施例中係質子溶劑。其他適宜溶劑包括非極性溶劑。經由使用單一溶劑或二元溶劑混合物,可使用多種溶劑來產生化合物I之期望固體形式。在單一溶劑之情形下,藉由在能夠形成合理濃縮溶液之溶劑中加熱使起始化合物I材料溶解,之後冷卻以起始期望結晶形式之形成。適宜單一溶劑包括(但不限於)醚,例如1,4-二噁烷、二乙醚及甲基第三丁基醚;烷酸酯,例如乙酸乙酯、乙酸丙酯、乙酸異丙酯及乙酸丁酯;乙二醇及聚乙二醇,例如PEG400;酮,例如C3
-C5
酮,例如、甲基乙基酮及丙酮;醇,例如C1
-C3
醇,例如甲醇、異丙醇及乙醇;芳香族化合物,例如苯及甲苯;鹵化溶劑,例如二氯甲烷、氯仿及四氯化碳;二甲亞碸(DMSO);及二甲基甲醯胺(DMF)。
緩慢蒸發材料於適當溶劑中之飽和溶液對於獲得結晶材料亦係有效的。適宜溶劑包括(但不限於)醚,例如1,4-二噁烷、二乙醚及甲基第三丁基醚;烷酸酯,例如乙酸乙酯、乙酸丙酯、乙酸異丙酯及乙酸丁酯;酮,例如C3
-C5
酮,例如甲基乙基酮及丙酮;及醇,例如C1
-C3
醇,例如甲醇、異丙醇及乙醇。
在二元溶劑混合物之情形下,首先將材料溶解於如上文所概述之能夠形成合理濃縮溶液之溶劑中,且在溶液仍較熱時,添加極性較小之溶劑(即,反溶劑),在此溶劑中材料不易溶解以起始期望材料之結晶。在選定實例中,將材料在加熱下溶解於丙酮中,且添加水以起始期望結晶形式之形成。適宜反溶劑包括(但不限於)烷烴,例如C5
-C7
烷烴,例如正戊烷及正庚烷;醚,例如1,4-二噁烷、二乙醚及甲基第三丁基醚;烷酸酯,例如乙酸異丁酯;甲基乙基酮;及水。溶劑 / 反溶劑比率
在二元溶劑混合物之情形下,溶劑對沈澱性溶劑(即,添加以形成化合物I之過飽和溶液之反溶劑)之比率並不會極大地影響化合物I之固體形式之形成,條件係添加足夠之反溶劑以起始產物之結晶。溶劑對反溶劑比率可影響結晶形式相對於化合物I之起始量之回收百分比。溶劑 / 化合物比率
化合物I相對於溶劑之比率或濃度可端視於所使用之溶劑或溶劑混合物而變化。典型濃度可在200 mg/mL至10 mg/mL範圍內,其中較高端之限制因素為材料之溶解性或一旦發生結晶材料之回收簡便性。舉例而言,可將大約70 mg化合物I溶解於1 mL丙酮中,隨後添加水以得到結晶形式。溫度
製備化合物I之結晶形式之方法可在任何適宜反應條件下來實施。舉例而言,製備化合物I之結晶形式之方法可在任何適宜溫度下來實施,例如(但不限於)低於室溫、在室溫下或高於室溫。一般而言,本文所闡述製備方法中所使用之溫度可在約20℃至溶劑之回流溫度範圍內。典型溫度係在約50℃至約80℃範圍內。一旦獲得溶液,且若需要,則添加沈澱性溶劑(即,反溶劑),將混合物冷卻至室溫。冷卻速率可影響化合物I之經分離固體形式中晶體之大小、形狀及品質。結晶速率
若干種因素顯著地影響結晶速率。該等因素包括(但不限於):反溶劑添加速率、混合物冷卻速率及成核位置(例如灰塵、晶種或玻璃表面上之缺陷)之存在。該等參數之變化可影響化合物I之經分離固體形式中晶體之大小、形狀及品質。
製備化合物I之結晶形式之方法可實施任何適宜時間。舉例而言,時間可持續數分鐘、數小時或數天。在一些實施例中,時間可為若干小時,例如過夜。製備化合物I之結晶形式之方法亦可在任何適宜壓力下來實施。舉例而言,壓力可低於大氣壓、在約大氣壓下或高於大氣壓。化合物 I 之固體形式之分離
可使用自上清液分離期望固體形式(例如結晶形式)之若干方法,包括過濾、傾析及溶劑蒸發。一般而言,藉由以下來獲得結晶形式:藉由真空過濾收集任何所形成之固體,之後進行空氣乾燥且隨後暴露於高真空以去除任何殘餘溶劑。形式 I
在一些實施例中,本發明提供製備本發明之化合物I之形式I之方法,其包括在適於製備形式I之條件下形成本發明之化合物I與溶劑之混合物。任何適宜溶劑均可用於製備化合物I形式I之方法中。在一些實施例中,溶劑可為以下各項中之至少一者:甲苯、乙醇、異丙醇、甲基乙基酮(即,2-丁酮)、丙酮、乙腈、乙酸異丁酯、乙酸乙酯、DMSO或二氯甲烷。在一些實施例中,溶劑可為以下各項中之至少一者:丙酮、乙醇、異丙醇或二氯甲烷。在一些實施例中,溶劑可包括丙酮、乙醇或異丙醇中之一者。在一些實施例中,溶劑可為丙酮、乙醇或異丙醇中之至少一者與水之組合。在一些實施例中,溶劑可為丙酮及水。
在一些實施例中,本發明提供製備化合物I之結晶形式I之方法,其係藉由在適於製備形式I之條件下形成化合物I與溶劑(包括C3
-C5
酮、二氯甲烷或甲苯)之混合物來實施。C3
-C5
酮可係丙酮、甲基乙基酮或3-戊酮。在一些實施例中,溶劑包括丙酮及甲基乙基酮中之一者。
可使用任何適宜比率之丙酮及水。舉例而言,若將材料溶解於丙酮中且添加水作為反溶劑,則丙酮對水比率可自約9:1至約1:9 (體積:體積)變化,例如自約3:1至約1:5或自約1:1至約1:6變化。在一些實施例中,丙酮對水比率(體積:體積)為約9:1、8:1、7:1、6:1、5:1、4:1、3:1、2:1、1:1、1:2、1:3、1:4、1:5、1:6、1:7、1:8或約1:9。在一些實施例中,丙酮對水比率(體積:體積)為約1:3或約1:4。形式 II
本發明亦提供用於製備化合物I形式II之方法。在一些實施例中,本發明提供製備化合物I之形式II之方法,其係藉由在適於製備形式II之條件下形成化合物I與乙腈之混合物來實施。在一些實施例中,製備化合物I之形式II之方法包含形成化合物I、乙腈及水之混合物。
可使用任何適宜比率之乙腈及水。舉例而言,若將化合物I溶解於乙腈中且添加水作為反溶劑,則丙酮對水比率可自約9:1至約1:9 (體積:體積)變化,例如自約3:1至約1:5或自約1:1至約1:6變化。在一些實施例中,乙腈對水比率(體積:體積)為約9:1、8:1、7:1、6:1、5:1、4:1、3:1、2:1、1:1、1:2、1:3、1:4、1:5、1:6、1:7、1:8或約1:9。在一些實施例中,乙腈對水比率(體積:體積)為約1:3或約1:4。形式 III
在一些實施例中,本發明提供製備本發明之化合物I之形式III之方法,其包括在適於製備形式III之條件下形成本發明之化合物I與溶劑之混合物。任何適宜溶劑均可用於製備化合物I形式III之方法中。在一些實施例中,製備化合物I之形式III之方法包含在溶劑中加熱化合物I,然後使混合物冷卻以提供形式III。在一些實施例中,溶劑可為以下各項中之至少一者:水、甲醇、乙醇、異丙醇、甲基乙基酮(即,2-丁酮)、丙酮、乙腈、乙酸異丁酯、乙酸乙酯或甲基第三丁基醚。在一些實施例中,溶劑可為以下各項中之至少一者:水、甲醇、異丙醇或乙腈。在一些實施例中,溶劑可包括水、甲醇、異丙醇或乙腈中之一者。治療及預防用途
本發明涵蓋本文所闡述之化合物I之固體形式之用途,其用於治療或預防眾多疾病、病症及/或病狀及/或其症狀。儘管下文詳細闡述具體用途,但應理解,本發明並不限於此。此外,儘管下文闡述特定疾病、病症及病狀之一般類別,但一些疾病、病症及病狀可為一種以上類別之成員且其他者可不為任何所揭示類別之成員。
在一些實施例中,本文所闡述之疾病、病症及/或病狀係至少部分地由腺苷A2A
受體(A2A
R)介導。在一些實施例中,本文所闡述之疾病、病症及/或病狀係至少部分地由腺苷A2B
受體(A2B
R)介導。在一些實施例中,本文所闡述之疾病、病症及/或病狀係至少部分地由A2A
R及A2B
R二者介導。
在一些實施例中,本文所闡述之化合物I之固體形式係以有效逆轉或終止A2A
R介導之免疫抑制之進展之量投與。
腫瘤學相關病症
。根據本發明,化合物I之固體形式可用於治療或預防增殖性病狀或病症,包括癌症,例如子宮癌、子宮頸癌、乳癌、前列腺癌、睪丸癌、胃腸道癌(例如,食管癌、口咽癌、胃癌、小腸癌或大腸癌、結腸癌或直腸癌)、腎癌、腎細胞癌、膀胱癌、骨癌、骨髓癌、皮膚癌、頭頸癌、肝癌、膽囊癌、心臟癌、肺癌、胰臟癌、唾液腺癌、腎上腺癌、甲狀腺癌、腦癌(例如,神經膠質瘤)、神經節癌、中樞神經系統(CNS)及周圍神經系統(PNS)之癌症以及造血系統及免疫系統(例如,脾或胸腺)之癌症。本發明亦提供治療或預防其他癌症相關疾病、病症或病狀之方法,包括(例如)免疫原性腫瘤、非免疫原性腫瘤、休眠腫瘤、病毒誘導之癌症(例如,上皮細胞癌、內皮細胞癌、鱗狀細胞癌及乳頭瘤病毒)、腺癌、淋巴瘤、癌、黑色素瘤、白血病、骨髓瘤、肉瘤、畸形癌、化學誘導之癌症、轉移及血管生成。本發明涵蓋例如藉由調節調節性T細胞及/或CD8+ T細胞之活性來降低對腫瘤細胞或癌細胞抗原之耐受性(例如,參見Ramirez-Montagut等人(2003)Oncogene
22:3180-87;及Sawaya等人(2003)New Engl. J. Med
. 349:1501-09)。在具體實施例中,腫瘤或癌症係結腸癌、卵巢癌、乳癌、黑色素瘤、肺癌、神經膠母細胞瘤或白血病。術語癌症相關疾病、病症及病狀之使用意欲廣泛地指與癌症直接或間接相關之病狀,且包括(例如)血管生成及癌前病狀(例如發育不良)。
在某些實施例中,癌症可為轉移性的或處於變為轉移性之風險下,或可在瀰漫組織中發生,包括血液或骨髓之癌症(例如,白血病)。在一些其他實施例中,可使用本發明之化合物來克服T細胞耐受。
在一些實施例中,本發明提供利用化合物I之固體形式及至少一種其他治療或診斷劑來治療增殖性病狀、癌症、腫瘤或癌前病狀之方法,該等其他治療或診斷劑之實例闡述於本文別處中。
免疫相關及發炎相關病症。
如本文所使用,諸如「免疫疾病」、「免疫病狀」、「免疫病症」、「發炎性疾病」、「發炎性病狀」、「發炎性病症」及諸如此類等術語意欲廣泛地涵蓋具有發炎組分之任何免疫相關之病狀(例如,自體免疫疾病)或病症,其可藉由本文所闡述之化合物I之固體形式來治療,從而使得獲得一些治療益處。此等病狀通常與其他疾病、病症及病狀密不可分。舉例而言,「免疫病狀」可係指增殖性病狀,例如癌症、腫瘤及血管生成;包括感染(急性及慢性)、腫瘤及抵抗藉由免疫系統根除之癌症。
本發明之化合物I之固體形式可用於增加或增強免疫反應;改良免疫,包括增加疫苗效能;及增加發炎。與免疫缺失性疾病、免疫抑制性醫學治療、急性及/或慢性感染及衰老相關之免疫缺失可使用本文所揭示之化合物來治療。化合物I之固體形式亦可用於刺激患有醫源性誘導之免疫抑制之患者(包括已經歷骨髓移植、化學療法或放射療法之彼等)之免疫系統。
在本揭示內容之具體實施例中,化合物I之固體形式藉由提供佐劑活性來用於增加或增強對抗原之免疫反應。在具體實施例中,將至少一種抗原或疫苗與至少一種本發明之化合物I之固體形式組合投與個體以延長對抗原或疫苗之免疫反應。亦提供治療性組合物,其包括至少一種抗原劑或疫苗組分與至少一種本發明之化合物I之固體形式之組合,該至少一種抗原劑或疫苗組分包括(但不限於)病毒、細菌及真菌或其部分、蛋白質、肽、腫瘤特異性抗原及核酸疫苗。
可利用本發明之化合物及組合物治療或預防之免疫相關及發炎相關疾病、病症及病狀之非限制性清單包括關節炎(例如,類風濕性關節炎)、腎衰竭、狼瘡、氣喘、牛皮癬、結腸炎、胰臟炎、過敏、纖維化、手術併發症(例如,其中發炎性細胞介素防止癒合)、貧血及纖維肌痛。可與慢性發炎相關之其他疾病及病症包括阿茲海默氏病(Alzheimer's disease)、鬱血性心臟衰竭、中風、主動脈瓣狹窄、動脈硬化、骨質疏鬆症、帕金森氏疾病、感染、發炎性腸病(例如,克隆氏病(Crohn's disease)及潰瘍性結腸炎)、過敏性接觸性皮膚炎及其他濕疹、全身性硬化、移植及多發性硬化。
在其他免疫相關病症中,預計抑制A2A
R/A2B
R功能亦可在免疫耐受性及預防子宮內胎兒排斥中起作用。
在一些實施例中,本文所闡述之A2A
R/A2B
R抑制劑化合物I之固體形式可與免疫抑制劑組合以減少免疫效應細胞之數量。
下文更詳細地闡述A2A
R/A2B
R抑制劑針對其可特別有效(歸因於(例如)目前療法之限制)之上文所提及疾病、病症及病狀中之一些。
類風濕性關節炎(RA)通常以關節之膜襯裡(滑膜)之慢性發炎為特徵,其影響約1%之美國人口(約2.1百萬人)。對細胞介素(包括TNF-a及IL-1)在發炎過程中之作用之進一步理解已使得能夠開發並引入一類新的疾病緩解性抗風濕藥物(DMARD)。藥劑(其中一些與針對RA之治療模式重疊)包括ENBREL (依那西普(etanercept))、REMICADE (英利昔單抗(infliximab))、HUMIRA (阿達木單抗(adalimumab))及KINERET (阿那白滯素(anakinra))。儘管該等藥劑中之一些減輕症狀、抑制結構損害之進展且改良特定患者群體之身體功能,但業內仍需要具有改良之效能、互補作用機制及更少(fewer/less)嚴重不良效應之替代藥劑。
牛皮癬係一種常見之免疫介導之慢性皮膚病之集群,其影響超過4.5百萬之美國人,其中1.5百萬被視為患有該疾病之中度至重度形式。此外,超過10%之患有牛皮癬之患者發生牛皮癬性關節炎,其損害關節周圍之骨及結締組織。對牛皮癬之潛在生理學之改進理解引入(例如)靶向負責疾病發炎性質之T淋巴球及細胞介素之活性之藥劑。此等藥劑包括TNF-α抑制劑(亦用於類風濕性關節炎(RA)之治療中),包括ENBREL (依那西普)、REMICADE (英利昔單抗)及HUMIRA (阿達木單抗))以及T細胞抑制劑(例如AMEVIVE (阿法西普(alefacept))及RAPTIVA (依法利珠單抗(efalizumab)))。儘管在某些患者群體中,該等藥劑中之若干種在一定程度上有效,但沒有一種顯示有效地治療所有患者。
微生物相關病症
。本發明涵蓋本文所闡述之A2A
R/A2B
R抑制劑化合物I之固體形式之用途,其用於治療及/或預防可受益於利用A2A
R/A2B
R抑制劑進行治療之任何病毒、細菌、真菌、寄生蟲或其他感染性疾病、病症或病狀。
所涵蓋之病毒疾病、病症及病狀之實例包括(但不限於) B型肝炎病毒(HBV)、C型肝炎病毒(HCV)、人類乳頭瘤病毒(HPV)、HIV、AIDS (包括其表現,例如惡病質、失智症及腹瀉)、單純疱疹病毒(HSV)、艾司坦-巴爾病毒(Epstein-Barr virus,EBV)、水痘帶狀疱疹病毒、柯薩奇病毒(coxsackie virus)及巨細胞病毒(CMV)。
此等疾病及病症之其他實例包括葡萄球菌及鏈球菌感染(分別例如金黃色葡萄球菌(Staphylococcus aureus)及血鏈球菌(streptococcus sanguinis))、利什曼原蟲屬(leishmania)、弓蟲屬(toxoplasma)、毛滴蟲屬(trichomonas)、梨形鞭毛蟲屬(giardia)、白色念珠菌(candida albicans)、炭疽桿菌(bacillus anthracis)及綠膿桿菌(pseudomonas aeruginosa)。在一些實施例中,疾病或病症包括分枝桿菌屬(Mycobacterium)感染(例如,麻風分枝桿菌(Mycobacterium leprae)或結核分枝桿菌(Mycobacterium tuberculosis))或由單核球增多性李氏菌(Listeria monocytogenes)或剛地弓形蟲(Toxplasma gondii)引起之感染。本發明之化合物I之固體形式可用於治療敗血症、降低或抑制細菌生長及減少或抑制發炎性細胞介素。
其他實施例涵蓋寄生蟲感染之治療,包括(但不限於)黑熱病利什曼原蟲(Leishmania donovani)、熱帶利什曼原蟲(Leishmania tropica)、碩大利什曼原蟲(Leishmania major)、埃塞俄比亞利什曼原蟲(Leishmania aethiopica)、墨西哥利什曼原蟲(Leishmania mexicana)、惡性瘧原蟲(Plasmodium falciparum)、間日瘧原蟲(Plasmodium vivax)、卵形瘧原蟲(Plasmodium ovale)或瘧疾瘧原蟲(Plasmodium malariae)。通常,預防性地投與抗寄生蟲療法(例如,在個體前往具有高頻率寄生蟲感染之地區之前)。
CNS 相關病症及神經病症
。對於患有與中樞神經系統具有一些關聯之神經病學、神經精神病學、神經退化或其他疾病、病症及病狀(包括與認知功能及運動功能受損相關之病症)之患者,化合物I之固體形式對A2A
R/A2B
R之抑制亦可係重要治療策略。實例包括帕金森氏病、錐體外症候群(EPS)、肌張力障礙、靜坐不能、遲發性運動障礙、不寧腿症候群(RLS)、癲癇、睡眠中週期性肢體抽動(PLMS)、注意力缺失症、抑鬱症、焦慮、失智症、阿茲海默氏病、亨廷頓氏病(Huntington's disease)、多發性硬化、腦缺血、出血性中風、蛛網膜下出血及創傷性腦損傷。
患有多發性硬化(MS)(一種在腦及脊髓之髓磷脂中包含多個發炎及結瘢區域之嚴重衰弱性自體免疫疾病)之個體可尤其受益於本文所闡述之化合物I之固體形式,此乃因目前治療僅緩和症狀或延遲失能之進展。
類似地,化合物I之固體形式可尤其有利於患有神經退化性病症之個體,該等神經退化性病症係例如阿茲海默氏病(AD),即一種嚴重損害患者之思考、記憶及語言過程之腦病症;及帕金森氏疾病(PD),即一種特徵在於(例如)運動異常、僵硬及顫抖之CNS之進行性病症。該等病症係進行性及衰弱性的,且無治癒性藥劑可用。
其他病症
。本發明之實施例涵蓋向個體投與本文所闡述之化合物I之固體形式以用於治療或預防可受益於至少一定程度之A2A
R/A2B
R抑制之任何其他病症。此等疾病、病症及病狀包括(例如)心血管病症(例如,心臟缺血)、胃腸病症(例如,克隆氏病)、代謝病症(例如,糖尿病)、肝病症(例如,肝纖維化、NASH及NAFLD)、肺病症(例如,COPD及氣喘)、眼科病症(例如,糖尿病性視網膜病變)及腎病症(例如,腎衰竭)。醫藥組合物
本發明之化合物I之固體形式可呈適於投與個體之組合物之形式。一般而言,此等組合物係包含化合物I之一或多種固體形式及一或多種醫藥上可接受或生理上可接受之稀釋劑、載劑或賦形劑之「醫藥組合物」。在某些實施例中,化合物I之固體形式係以在治療上可接受之量存在。醫藥組合物可用於本發明之方法中;因此,舉例而言,醫藥組合物可離體或活體內投與個體以實踐本文所闡述之治療及預防性方法及用途。
本發明之醫藥組合物可經調配以與預期投與方法或途徑相容;例示性投與途徑闡述於本文中。此外,醫藥組合物可與如本文所闡述之其他治療活性劑或化合物組合使用以治療或預防如由本發明所涵蓋之疾病、病症及病狀。
含有活性成分(例如,A2A
R/A2B
R功能之抑制劑化合物I之固體形式)之醫藥組合物可呈適於經口使用之形式,例如錠劑、膠囊、糖錠劑、菱形錠劑、水性或油性懸浮液、可分散粉末或顆粒、乳液、硬質或軟質膠囊或糖漿、溶液、微珠粒或酏劑。意欲用於經口使用之醫藥組合物可根據業內已知用於製造醫藥組合物之任一方法來製備,且此等組合物可含有一或多種試劑(例如甜味劑、矯味劑、著色劑及防腐劑),以提供醫藥上美觀且可口之製劑。錠劑、膠囊及諸如此類含有活性成分與適於製造錠劑之醫藥上可接受之無毒賦形劑之混合物。該等賦形劑可係(例如)稀釋劑,例如碳酸鈣、碳酸鈉、乳糖、磷酸鈣或磷酸鈉;造粒劑及崩解劑,例如玉米澱粉或海藻酸;黏合劑,例如澱粉、明膠或阿拉伯樹膠(acacia);及潤滑劑,例如硬脂酸鎂、硬脂酸或滑石。
適於經口投與之錠劑、膠囊及諸如此類可未經包覆或藉由已知技術來包覆以延遲在胃腸道中之崩解及吸收且藉此提供持續作用。舉例而言,可採用諸如單硬脂酸甘油酯或二硬脂酸甘油酯等延時材料。其亦可藉由業內已知之技術來塗覆以形成滲透性治療錠劑以用於受控釋放。其他藥劑包括生物可降解或生物相容性粒子或聚合物質,例如聚酯、多胺酸、水凝膠、聚乙烯吡咯啶酮、聚酸酐、聚乙醇酸、乙烯-乙酸乙烯酯、甲基纖維素、羧甲基纖維素、硫酸魚精蛋白或乳酸交酯/乙交酯共聚物、聚乳酸/乙交酯共聚物或乙烯乙酸乙烯酯共聚物,以控制所投與組合物之遞送。舉例而言,可將口服藥劑裝入藉由凝聚技術或藉由界面聚合製備之微膠囊(分別藉由使用羥甲基纖維素或明膠微膠囊或聚(甲基丙烯酸甲酯)微膠囊)中,或裝入膠體藥物遞送系統中。膠體分散系統包括巨分子複合物、奈米膠囊、微球體、微珠粒及基於脂質之系統,包括水包油乳液、膠束、混合膠束及脂質體。用於製備上文所提及調配物之方法對於熟習此項技術者將顯而易見。
用於經口使用之調配物亦可呈現為硬質明膠膠囊,其中將活性成分與惰性固體稀釋劑(例如,碳酸鈣、磷酸鈣、高嶺土(kaolin)或微晶纖維素)混合;或可呈現為軟質明膠膠囊,其中將活性成分與水或油介質(例如,花生油、液體石蠟或橄欖油)混合。
水性懸浮液含有活性材料與適於製造該等水性懸浮液之賦形劑之混合物。此等賦形劑可為懸浮劑,例如羧甲基纖維素鈉、甲基纖維素、羥丙基甲基纖維素、海藻酸鈉、聚乙烯吡咯啶酮、黃蓍膠及阿拉伯樹膠;分散劑或潤濕劑,例如天然磷脂(例如,卵磷脂)或環氧烷與脂肪酸之縮合產物(例如,聚氧乙烯硬脂酸酯)或環氧乙烷與長鏈脂肪族醇之縮合產物(例如,十七乙烯氧基鯨蠟醇)或環氧乙烷與衍生自脂肪酸及己糖醇之偏酯之縮合產物(例如,聚氧乙烯山梨醇單油酸酯)或環氧乙烷與衍生自脂肪酸及己糖醇酐之偏酯之縮合產物(例如,聚氧乙烯去水山梨醇單油酸酯)。水性懸浮液亦可含有一或多種防腐劑。
可藉由將活性成分懸浮於植物油(例如,花生油、橄欖油、芝麻油或椰子油)中或懸浮於礦物油(例如液體石蠟)中來調配油性懸浮液。該等油性懸浮液可含有增稠劑,例如蜂蠟、硬石蠟或鯨蠟醇。可添加甜味劑(例如,上文所闡述之彼等)及矯味劑以提供可口之口服製劑。
適於藉由添加水來製備水性懸浮液之可分散粉末及顆粒提供活性成份與分散劑或潤濕劑、懸浮劑及一或多種防腐劑之混合物。本文中例示適宜分散劑或潤濕劑及懸浮劑。
本發明之醫藥組合物亦可呈水包油乳液之形式。油相可為植物油(例如,橄欖油或花生油)或礦物油(例如,液體石蠟)或該等之混合物。適宜乳化劑可係天然樹膠,例如阿拉伯樹膠或黃蓍膠;天然磷脂,例如大豆卵磷脂及衍生自脂肪酸之酯或偏酯;己糖醇酐,例如去水山梨醇單油酸酯;及偏酯與環氧乙烷之縮合產物,例如聚氧乙烯去水山梨醇單油酸酯。
醫藥組合物通常包含治療有效量之本發明所涵蓋之化合物I之固體形式及一或多種醫藥上及生理上可接受之調配劑。醫藥上可接受或生理上可接受之適宜稀釋劑、載劑或賦形劑包括(但不限於)抗氧化劑(例如,抗壞血酸及硫酸氫鈉)、防腐劑(例如,苄醇、對羥苯甲酸甲酯、對羥基苯甲酸乙酯或對羥基苯甲酸正丙基酯)、乳化劑、懸浮劑、分散劑、溶劑、填充劑、增積劑、清潔劑、緩衝劑、媒劑、稀釋劑及/或佐劑。舉例而言,適宜媒劑可係生理鹽水溶液或檸檬酸鹽緩衝鹽水,其可能補充有用於非經腸投與之醫藥組合物中常見之其他材料。中性緩衝鹽水或與血清白蛋白混合之鹽水係其他例示性媒劑。熟習此項技術者將容易地認識到可用於本文所涵蓋醫藥組合物及劑型中之多種緩衝劑。典型緩衝劑包括(但不限於)醫藥上可接受之弱酸、弱鹼或其混合物。作為實例,緩衝組分可係水溶性材料,例如磷酸、酒石酸、乳酸、琥珀酸、檸檬酸、乙酸、抗壞血酸、天冬胺酸、麩胺酸及其鹽。可接受之緩衝劑包括(例如) Tris緩衝劑、N-(2-羥基乙基)六氫吡嗪-N'-(2-乙磺酸) (HEPES)、2-(N-嗎啉基)乙磺酸(MES)、2-(N-嗎啉基)乙磺酸鈉鹽(MES)、3-(N-嗎啉基)丙烷磺酸(MOPS)及N-參[羥基甲基]甲基-3-胺基丙烷磺酸(TAPS)。
在已調配醫藥組合物後,可將其作為溶液、懸浮液、凝膠、乳液、固體或去水或凍乾粉末儲存於無菌小瓶中。可將此等調配物以以下形式儲存:即用型形式、需要在使用前重構之凍乾形式、需要在使用前稀釋之液體形式或其他可接受之形式。在一些實施例中,將醫藥組合物提供於單次使用之容器(例如,單次使用之小瓶、安瓿、注射器或自動注射器(類似於例如EpiPen®))中,而在其他實施例中提供多次使用之容器(例如,多次使用之小瓶)。
調配物亦可包括載劑以保護組合物抵抗自身體快速降解或消除,例如受控釋放調配物,包括脂質體、水凝膠、前藥及微囊封化遞送系統。舉例而言,可單獨採用諸如單硬脂酸甘油酯或硬脂酸甘油酯等延時材料或與蠟組合採用。可使用任何藥物遞送設備來遞送A2A
R/A2B
R抑制劑化合物I之固體形式,包括植入物(例如,可植入幫浦)及導管系統、緩慢注射幫浦及裝置,所有該等設備均為熟習此項技術者所熟知。
積存注射劑通常以皮下方式或肌內方式來投與,其亦可用於在界定時間段內釋放本文所揭示之A2A
R/A2B
R抑制劑。積存注射劑通常係基於固體或基於油的,且通常包含本文所闡述調配物組分中之至少一者。熟習此項技術者熟悉積存注射劑之可能調配物及用途。
醫藥組合物可呈無菌可注射水性或油性懸浮液之形式。此懸浮液可根據已知技術使用本文所提及之彼等適宜分散劑或潤濕劑及懸浮劑來調配。無菌可注射製劑亦可係於無毒非經腸可接受之稀釋劑或溶劑中之無菌可注射溶液或懸浮液,例如作為於1,3-丁二醇中之溶液。可採用之可接受之稀釋劑、溶劑及分散介質包括水、林格氏溶液(Ringer's solution)、等滲氯化鈉溶液、Cremophor EL™ (BASF, Parsippany, NJ)或磷酸鹽緩衝鹽水(PBS)、乙醇、多元醇(例如,甘油、丙二醇及液體聚乙二醇)及其適宜混合物。另外,照慣例採用無菌不揮發性油作為溶劑或懸浮介質。出於此目的,可採用任一溫和不揮發性油,包括合成甘油單酯或甘油二酯。另外,諸如油酸等脂肪酸可用於可注射劑之製備中。可藉由納入延遲吸收之試劑(例如,單硬脂酸鋁或明膠)來達成特定可注射調配物之延長吸收。
本發明涵蓋投與呈用於直腸投與之栓劑形式之化合物I之固體形式。該等栓劑可藉由將藥物與適宜無刺激性賦形劑混合來製備,該賦形劑在常溫下為固體但在直腸溫度下為液體且因此將在直腸中熔融以釋放藥物。此等材料包括(但不限於)可可脂及聚乙二醇。
本發明所涵蓋之化合物I之固體形式可呈目前已知或未來開發之任何其他適宜醫藥組合物(例如,用於經鼻或吸入使用之噴霧劑)之形式。投與途徑
本發明涵蓋以任何適當方式投與化合物I之固體形式及其組合物。適宜投與途徑包括經口、非經腸(例如肌內、靜脈內、皮下(例如注射或植入)、腹膜內、腦池內、關節內、腹膜內、大腦內(實質內)及腦室內)、經鼻、經陰道、舌下、眼內、經直腸、經局部(例如經皮)、經頰及吸入。積存注射劑通常以皮下方式或肌內方式來投與,其亦可用於在界定時間段內釋放本文所揭示之化合物I之固體形式。
本發明之具體實施例涵蓋經口投與。組合療法
本發明涵蓋化合物I之固體形式與一或多種活性治療劑(例如化學治療劑)或其他預防或治療模式(例如輻射)之組合之用途。在此組合療法中,各種活性劑通常具有不同的互補作用機制。此組合療法可因容許一或多種藥劑之劑量降低、藉此降低或消除與一或多種藥劑相關之不良效應而尤其有利。此外,此組合療法可對潛在疾病、病症或病狀具有協同治療或預防效應。
如本文所使用,「組合」意欲包括可分開投與之療法(例如,分開調配以用於分開投與(例如,如可以套組提供)),及可在單一調配物(即,「共調配物」)中一起投與之療法。
在某些實施例中,化合物I之固體形式係依序投與或施加,例如其中一種藥劑係在一或多種其他藥劑之前投與。在其他實施例中,化合物I之固體形式係同時投與,例如其中兩種或更多種藥劑係在相同時間或大約相同時間投與;該兩種或更多種藥劑可以兩種或更多種分開調配物存在或組合成單一調配物(即,共調配物)。出於本發明之目的,無論該兩種或更多種藥劑係依序投與抑或同時投與,其均視為組合投與。
在該等情況下,本發明之化合物I之固體形式可以任何適當方式與至少一種其他(活性)藥劑組合使用。在一個實施例中,利用至少一種活性劑及至少一種本發明之化合物I之固體形式之治療在一定時間段內維持。在另一實施例中,降低或中斷利用至少一種活性劑之治療(例如當個體穩定時),同時以恆定投藥方案維持利用本發明之化合物I之固體形式之治療。在另一實施例中,降低或中斷利用至少一種活性劑之治療(例如當個體穩定時),同時降低利用本發明之化合物I之固體形式之治療(例如,減低劑量、減少投藥頻率或縮短治療方案)。在另一實施例中,降低或中斷利用至少一種活性劑之治療(例如當個體穩定時),且增加利用本發明之化合物I之固體形式之治療(例如,增高劑量、增多投藥頻率或延長治療方案)。在另一實施例中,維持利用至少一種活性劑之治療且降低或中斷利用本發明之化合物I之固體形式之治療(例如,減低劑量、減少投藥頻率或縮短治療方案)。在另一實施例中,降低或中斷利用至少一種活性劑之治療及利用本發明之固體形式之治療(例如,減低劑量、減少投藥頻率或縮短治療方案)。
腫瘤學相關病症
。本發明提供用於治療及/或預防增殖性病狀、癌症、腫瘤或癌前疾病、病症或病狀之方法,其係利用化合物I之固體形式及至少一種其他治療或診斷劑來實施。在一些實施例中,該其他治療或診斷劑係輻射、免疫調節劑或化學治療劑或診斷劑。可用於本發明中之適宜免疫調節劑包括CD4OL、B7及B7RP1;針對刺激性受體之活化單株抗體(mAb),例如,抗CD40、抗CD38、抗ICOS及4-IBB配體;樹突細胞抗原負載(活體外或活體內);抗癌疫苗,例如樹突細胞癌症疫苗;細胞介素/趨化介素,例如ILL IL2、IL12、IL18、ELC/CCL19、SLC/CCL21、MCP-1、IL-4、IL-18、TNF、IL-15、MDC、IFNa/b、M-CSF、IL-3、GM-CSF、IL-13及抗IL-10;細菌脂多醣(LPS);及免疫刺激性寡核苷酸。
在某些實施例中,本發明提供腫瘤生長之腫瘤抑制之方法,其包含投與本文所闡述之化合物I之固體形式與信號轉導抑制劑(STI)之組合以達成對腫瘤生長之加性或協同抑制。如本文所使用,術語「信號轉導抑制劑」係指選擇性地抑制信號傳導路徑中之一或多個步驟之藥劑。本發明之信號轉導抑制劑(STI)包括:(i) bcr/abl激酶抑制劑(例如,GLEEVEC);(ii)表皮生長因子(EGF)受體抑制劑,包括激酶抑制劑及抗體;(iii) her-2/neu受體抑制劑(例如,HERCEPTIN);(iv) Akt家族激酶或Akt路徑之抑制劑(例如,雷帕黴素(rapamycin));(v) 細胞週期激酶抑制劑(例如,夫拉平度(flavopiridol));及(vi) 磷脂醯基肌醇激酶抑制劑。參與免疫調節之藥劑亦可與本文所闡述之A2A
R/A2B
R抑制劑組合使用,以用於抑制癌症患者之腫瘤生長。
化學治療劑之實例包括(但不限於)烷基化劑,例如噻替派(thiotepa)及環磷醯胺;磺酸烷基酯,例如白消安(busulfan)、英丙舒凡(improsulfan)及哌泊舒凡(piposulfan);氮丙啶,例如苯并多巴(benzodopa)、卡波醌(carboquone)、美妥多巴(meturedopa)及脲多巴(uredopa);次乙亞胺及甲基三聚氰胺,包括六甲蜜胺、三乙烯三聚氰胺、三乙烯磷醯胺、三乙烯硫磷醯胺及三羥甲基三聚氰胺;氮芥,例如苯丁酸氮芥、萘氮芥、氯磷醯胺、雌氮芥、異環磷醯胺、甲基二(氯乙基)胺、甲基二(氯乙基)胺氧化物鹽酸鹽、美法侖(melphalan)、新氮芥(novembichin)、膽甾醇對苯乙酸氮芥、潑尼莫司汀(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥;硝基脲,例如卡莫司汀(carmustine)、氯脲菌素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)、雷莫司汀(ranimustine);抗生素,例如阿克拉黴素(aclacinomysin)、放線菌素、安麯黴素(anthramycin)、偶氮絲胺酸、博來黴素(bleomycin)、放線菌素C、卡奇黴素(calicheamicin)、卡拉黴素(carabicin)、洋紅黴素(caminomycin)、嗜癌黴素(carzinophilin)、色黴素(chromomycin)、放線菌素D、道諾黴素(daunorubicin)、地托比星(detorubicin)、6-重氮基-5-側氧基-L-正白胺酸、多柔比星(doxorubicin)、泛艾黴素(epirubicin)、依索比星(esorubicin)、伊達比星(idarubicin)、麻西羅黴素(marcellomycin)、絲裂黴素、黴酚酸(mycophenolic acid)、諾拉黴素(nogalamycin)、橄欖黴素(olivomycin)、培洛黴素(peplomycin)、泊非黴素(potfiromycin)、嘌呤黴素(puromycin)、三鐵阿黴素(quelamycin)、羅多比星(rodorubicin)、鏈黑黴素(streptonigrin)、鏈脲黴素(streptozocin)、殺結核菌素(tubercidin)、烏苯美司(ubenimex)、淨司他汀(zinostatin)、佐柔比星(zorubicin);抗代謝物,例如胺甲喋呤及5-氟尿嘧啶(5-FU);葉酸類似物,例如二甲葉酸(denopterin)、胺甲喋呤、蝶羅呤(pteropterin)、三甲曲沙(trimetrexate);嘌呤類似物,例如氟達拉濱(fludarabine)、6-巰嘌呤、硫咪嘌呤(thiamiprine)、硫鳥嘌呤;嘧啶類似物,例如安西他濱(ancitabine)、阿紮胞苷(azacitidine)、6-阿紮尿苷、卡莫氟(carmofur)、阿糖胞苷、二去氧尿苷、去氧氟尿苷、依諾他濱(enocitabine)、氟尿苷、5-FU;雄激素,例如卡普睪酮(calusterone)、丙酸屈他雄酮(dromostanolone propionate)、環硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睪內酯(testolactone);抗腎上腺藥,例如胺魯米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);葉酸補充劑,例如亞葉酸;醋葡醛內酯;醛磷醯胺醣苷;胺基乙醯丙酸;安吖啶(amsacrine);倍曲布西(bestrabucil);比生群(bisantrene);依達曲沙(edatraxate);地磷醯胺(defofamine);秋水仙胺(demecolcine);地吖醌(diaziquone);依氟鳥胺酸(elformithine);依利醋銨(elliptinium acetate);依託格魯(etoglucid);硝酸鎵;羥基脲;香菇多醣(lentinan);氯尼達明(lonidamine);米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌達醇(mopidamol);二胺硝吖啶(nitracrine);噴司他汀(pentostatin);蛋胺氮芥(phenamet);吡柔比星(pirarubicin);鬼臼酸(podophyllinic acid);2-乙基醯肼;丙卡巴肼(procarbazine);雷佐生(razoxane);西左非蘭(sizofiran);鍺螺胺(spirogermanium);替奴佐酸(tenuazonic acid);三亞胺醌(triaziquone);2,2',2''-三氯三乙胺;烏拉坦(urethan);長春地辛(vindesine);達卡巴嗪(dacarbazine);甘露莫司汀(mannomustine);二溴甘露醇(mitobronitol);二溴衛矛醇(mitolactol);哌泊溴烷(pipobroman);加賽特辛(gacytosine);阿拉伯糖苷(Ara-C);環磷醯胺;噻替派;類紫杉醇(taxoid),例如太平洋紫杉醇(paclitaxel)及多西紫杉醇(doxetaxel);氮芥苯丁酸;吉西他濱(gemcitabine);6-硫鳥嘌呤;巰嘌呤;胺甲喋呤;鉑及鉑配位錯合物,例如順鉑(cisplatin)、卡鉑(carboplatin)及奧沙利鉑(oxaliplatin);長春鹼(vinblastine);依託泊苷(etoposide)(VP-16);異環磷醯胺;絲裂黴素C;米托蒽醌;長春新鹼(vincristine);長春瑞濱(vinorelbine);溫諾平(navelbine);能滅瘤(novantrone);替尼泊苷(teniposide);道諾黴素;胺喋呤(aminopterin);截瘤達(xeloda);伊班膦酸鹽(ibandronate);CPT11;拓撲異構酶抑制劑;二氟甲基鳥胺酸(DMFO);視黃酸;埃斯培拉黴素(esperamicin);卡培他濱(capecitabine);蒽環;及以上任一者之醫藥上可接受之鹽、酸或衍生物。
化學治療劑亦包括用於調控或抑制對腫瘤之激素作用之抗激素劑,例如抗雌激素,包括(例如)他莫昔芬(tamoxifen)、雷洛昔芬(raloxifene)、芳香酶抑制4(5)-咪唑、4-羥基他莫昔芬、曲沃昔芬(trioxifene)、可莫昔芬(keoxifene)、奧那司酮(onapristone)及托瑞米芬(toremifene);及抗雄激素,例如氟他胺(flutamide)、尼魯米特(nilutamide)、比卡魯胺(bicalutamide)、柳培林(leuprolide)及戈舍瑞林(goserelin);及以上任一者之醫藥上可接受之鹽、酸或衍生物。在某些實施例中,組合療法包含包括一或多種化學治療劑之化學療法方案。在某些實施例中,組合療法包含投與激素或相關激素劑。
可與化合物I之固體形式組合使用之其他治療模式包括放射療法、針對腫瘤抗原之單株抗體、單株抗體與毒素之複合物、T細胞佐劑、骨髓移植或抗原呈遞細胞(例如樹突細胞療法)。
免疫檢查點抑制劑
。本發明涵蓋本文所闡述之A2A
R/A2B
R功能之抑制劑化合物I之固體形式與免疫檢查點抑制劑之組合之用途。
所有癌症所特有之大量遺傳及後生改變提供多組抗原,免疫系統可使用該等抗原來區分腫瘤細胞與其正常對應體。在T細胞之情形下,經由T細胞受體(TCR)識別之抗原起始的反應之最終幅度(例如細胞介素產生或增殖之程度)及品質(例如所產生免疫反應之類型,例如細胞介素產生之型式)係由共刺激性與抑制性信號(免疫檢查點)之間的平衡來調控。在正常生理條件下,免疫檢查點對於預防自體免疫性(即,維持自身耐受性)以及對於在免疫系統對病原體感染有反應時保護組織免受損害至關重要。腫瘤可使免疫檢查點蛋白質之表現失調而作為重要之免疫抗性機制。
T細胞一直係在治療上操縱內源性抗腫瘤免疫性之主要努力焦點,此乃因:i) 其選擇性識別源自所有細胞區室中之蛋白質之肽的能力;ii) 其直接識別且殺死抗原表現細胞的能力(藉由CD8+效應T細胞;亦稱為細胞毒性T淋巴球(CTL));及iii) 其藉由CD4+輔助T細胞協調各種免疫反應的能力,該等CD4+輔助T細胞整合適應性及先天性效應機制。
在臨床環境中,阻斷免疫檢查點使得抗原特異性T細胞反應放大,其已顯示係人類癌症治療中有希望之方法。
T細胞介導之免疫包括多個依序步驟,其各自藉由抵消刺激性及抑制性信號而受調控以使反應最佳化。雖然免疫反應中幾乎所有之抑制性信號最終均調節細胞內信號傳導路徑,但許多係經由膜受體起始的,該等膜受體之配體係膜結合的或可溶性的(細胞介素)。雖然相對於正常組織,調控T細胞活化之共刺激性及抑制性受體及配體通常不會在癌症中過表現,但在組織中調控T細胞效應功能之抑制性配體及受體通常在腫瘤細胞上或在與腫瘤微環境相關之未轉型細胞上過表現。可溶性及膜結合受體-配體免疫檢查點之功能可使用激動劑抗體(對於共刺激性路徑)或拮抗劑抗體(對於抑制性路徑)來調節。因此,與目前經批准用於癌症療法之大多數抗體相比,阻斷免疫檢查點之抗體不直接靶向腫瘤細胞,而是靶向淋巴球受體或其配體以增強內源性抗腫瘤活性。[參見Pardoll,(2012年4月) Nature Rev. Cancer 12:252-64]。
為阻斷候選者之免疫檢查點(配體及受體)之實例(其中一些在各種類型之腫瘤細胞中選擇性地上調)包括PD1 (程式性細胞死亡蛋白1);PDL1 (PD1配體);BTLA (B及T淋巴球減弱子);CTLA4 (細胞毒性T淋巴球相關抗原4);TIM3 (T細胞膜蛋白3);LAG3 (淋巴球活化基因3);TIGIT (具有Ig及ITIM結構域之T細胞免疫受體);及殺手抑制性受體,其可基於其結構特徵而分成兩個類別:i) 殺手細胞免疫球蛋白樣受體(KIR)及ii) C型凝集素受體(II型跨膜受體家族之成員)。其他定義較不充分之免疫檢查點已闡述於文獻中,包括受體(例如,2B4 (亦稱為CD244)受體)及配體(例如,某些B7家族抑制性配體,例如B7-H3 (亦稱為CD276)及B7-H4 (亦稱為B7-S1、B7x及VCTN1))二者。[參見Pardoll,(2012年4月) Nature Rev. Cancer 12:252-64]。
本發明涵蓋本文所闡述之A2A
R/A2B
R功能之抑制劑化合物I之固體形式與上文所提及之免疫檢查點受體及配體以及尚未闡述之免疫檢查點受體及配體之抑制劑之組合之用途。免疫檢查點之某些調節劑目前可獲得,而其他者處於後期開發中。為進行說明,當完全人類化CTLA4單株抗體伊匹單抗(ipilimumab) (YERVOY;Bristol-Myers Squibb)在2011年批准用於治療黑色素瘤時,其成為美國首個獲得監管批准之免疫檢查點抑制劑。包含CTLA4及抗體之融合蛋白(CTLA4-Ig;阿巴西普(abatcept)(ORENCIA;Bristol-Myers Squibb))已用於治療類風濕性關節炎,且其他融合蛋白已顯示在對艾伯斯坦-巴爾病毒(Epstein Barr Virus)敏感之腎移植患者中係有效的。PD1抗體處於研發中(例如,尼沃魯單抗(nivolumab)(Bristol-Myers Squibb)及蘭布魯珠單抗(lambrolizumab)(Merck)),且抗PDL1抗體亦處於評估中(例如MPDL3280A (Roche))。尼沃魯單抗已在患有黑色素瘤、肺及腎癌之患者中顯示前景。
在本發明之一態樣中,將所主張之化合物I之固體形式與免疫腫瘤學藥劑組合,該免疫腫瘤學藥劑係(i) 刺激性(包括共刺激性)受體之激動劑或(ii) T細胞上抑制性(包括共抑制性)信號之拮抗劑,二者均使得抗原特異性T細胞反應放大。某些刺激性及抑制性分子係免疫球蛋白超家族(IgSF)之成員。結合至共刺激性或共抑制性受體之膜結合配體之一個重要家族係B7家族,其包括B7-1、B7-2、B7-H1 (PD-L1)、B7-DC (PD-L2)、B7-H2 (ICOS-L)、B7-H3、B7-H4、B7-H5 (VISTA)及B7-H6。結合至共刺激性或共抑制性受體之膜結合配體之另一家族係結合至同源TNF受體家族成員之TNF分子家族,其包括CD40及CD4OL、OX-40、OX-40L、CD70、CD27L、CD30、CD3OL、4-1BBL、CD137 (4-1BB)、TRAIL/Apo2-L、TRAILR1/DR4、TRAILR2/DR5、TRAILR3、TRAILR4、OPG、RANK、RANKL、TWEAKR/Fn14、TWEAK、BAFFR、EDAR、XEDAR、TACI、APRIL、BCMA、LT13R、LIGHT、DcR3、HVEM、VEGI/TL1A、TRAMP/DR3、EDAR、EDA1、XEDAR、EDA2、TNFR1、淋巴毒素a/TNF13、TNFR2、TNFa、LT13R、淋巴毒素a 1132、FAS、FASL、RELT、DR6、TROY、NGFR。
在另一態樣中,免疫腫瘤學藥劑係抑制T細胞活化之細胞介素(例如,IL-6、IL-10、TGF-B、VEGF及其他免疫抑制性細胞介素)或刺激T細胞活化之細胞介素,其用於刺激免疫反應。
在一態樣中,T細胞反應可由所揭示之A2A
R/A2B
R抑制劑與以下各項中之一或多者之組合來刺激:(i) 抑制T細胞活化之蛋白質之拮抗劑(例如免疫檢查點抑制劑),例如CTLA-4、PD-1、PD-L1、PD-L2、LAG-3、TIM-3、半乳糖凝集素 9、CEACAM-1、BTLA、CD69、半乳糖凝集素-1、TIGIT、CD113、GPR56、VISTA、2B4、CD48、GARP、PD1H、LAIR1、TIM-1及TIM-4,及/或(ii) 刺激T細胞活化之蛋白質之激動劑,例如B7-1、B7-2、CD28、4-1BB (CD137)、4-1BBL、ICOS、ICOS-L、OX40、OX4OL、GITR、GITRL、CD70、CD27、CD40、DR3及CD2。可與本發明之A2A
R/A2B
R抑制劑組合用於治療癌症之其他藥劑包括NK細胞上抑制性受體之拮抗劑或NK細胞上活化性受體之激動劑。舉例而言,本文化合物可與KIR之拮抗劑(例如利利單抗(lirilumab))組合。
用於組合療法之其他藥劑包括抑制或消耗巨噬細胞或單核球之藥劑,包括(但不限於) CSF-1R拮抗劑,例如CSF-1R拮抗劑抗體,包括RG7155 (W011/70024、W011/107553、W011/131407、W013/87699、W013/119716、W013/132044)或FPA-008 (W011/140249;W013169264;W014/036357)。
在另一態樣中,所揭示之A2A
R/A2B
R抑制劑可與以下各項中之一或多者一起使用:連接正性共刺激性受體之激動劑、經由抑制性受體減弱信號傳導之阻斷劑、拮抗劑及一或多種全身性增加抗腫瘤T細胞之頻率之藥劑、克服腫瘤微環境內之不同免疫抑制路徑(例如,阻斷抑制性受體接合(例如,PD-L1/PD-1相互作用)、消耗或抑制Treg (例如,使用抗CD25單株抗體(例如,達克珠單抗(daclizumab))或藉由離體抗CD25珠粒消耗)或逆轉/預防T細胞無因變性或耗盡)之藥劑,及觸發腫瘤部位先天性免疫活化及/或發炎之藥劑。
在一態樣中,免疫腫瘤學藥劑係CTLA-4拮抗劑,例如拮抗性CTLA-4抗體。適宜CTLA-4抗體包括(例如) YERVOY (伊匹單抗)或曲美目單抗(tremelimumab)。
在一態樣中,免疫腫瘤學藥劑係PD-1拮抗劑,例如拮抗性PD-1抗體。適宜PD-1抗體包括(例如) OPDIVO (尼沃魯單抗)、KEYTRUDA (派姆單抗(pembrolizumab))或MEDI-0680 (AMP-514;W02012/145493)。免疫腫瘤學藥劑亦可包括匹利珠單抗(pidilizumab)(CT-011),但其對PD-1結合之特異性已受到質疑。靶向PD-1受體之另一方法係由融合至IgG1之Fc部分之PD-L2 (B7-DC)之細胞外結構域構成的重組蛋白,稱為AMP-224。
在另一態樣中,免疫腫瘤學藥劑係PD-Ll拮抗劑,例如拮抗性PD-Ll抗體。適宜PD-Ll抗體包括(例如) MPDL3280A (RG7446;W02010/077634)、德瓦魯單抗(durvalumab)(MEDI4736)、BMS-936559 (W02007/005874)及MSB0010718C (W02013/79174)。
在另一態樣中,免疫腫瘤學藥劑係LAG-3拮抗劑,例如拮抗性LAG-3抗體。適宜LAG3抗體包括(例如) BMS-986016 (W010/19570、W014/08218)或IMP-731或IMP-321 (W008/132601、W009/44273)。
在另一態樣中,免疫腫瘤學藥劑係CD137 (4-1BB)激動劑,例如激動性CD137抗體。適宜CD137抗體包括(例如)烏瑞魯單抗(urelumab)或PF-05082566 (W012/32433)。
在另一態樣中,免疫腫瘤學藥劑係GITR激動劑,例如激動性GITR抗體。適宜GITR抗體包括(例如) BMS-986153、BMS-986156、TRX-518 (W006/105021、W009/009116)及MK-4166 (W011/028683)。
在另一態樣中,免疫腫瘤學藥劑係OX40激動劑,例如激動性OX40抗體。適宜OX40抗體包括(例如) MEDI-6383或MEDI-6469。
在另一態樣中,免疫腫瘤學藥劑係OX40L拮抗劑,例如拮抗性OX40L抗體。適宜OX40L拮抗劑包括(例如) RG-7888 (W006/029879)。
在另一態樣中,免疫腫瘤學藥劑係CD40拮抗劑,例如拮抗性CD40抗體。在另一實施例中,免疫腫瘤學藥劑係CD40拮抗劑,例如拮抗性CD40抗體。適宜CD40抗體包括(例如)魯卡木單抗(lucatumumab)或達西珠單抗(dacetuzumab)。
在另一態樣中,免疫腫瘤學藥劑係CD27激動劑,例如激動性CD27抗體。適宜CD27抗體包括(例如)瓦利單抗(varlilumab)。
在另一態樣中,免疫腫瘤學藥劑係MGA271 (至B7H3) (W011/109400)。
本發明涵蓋上文中任一者之醫藥上可接受之鹽、酸或衍生物。
代謝及心血管疾病
。本發明提供用於治療及/或預防某些心血管相關及/或代謝相關疾病、病症及病狀以及與其相關之病症之方法,其係利用A2A
R/A2B
R抑制劑化合物I之固體形式及至少一種其他治療或診斷劑來實施。
可用於用以治療高膽固醇血症(以及動脈粥樣硬化)之組合療法中之治療劑之實例包括他汀類藥物(例如CRESTOR、LESCOL、LIPITOR、MEVACOR、PRAVACOL及ZOCOR),其抑制膽固醇之酶促合成;膽汁酸樹脂(例如COLESTID、LO-CHOLEST、PREVALITE、QUESTRAN及WELCHOL),其螯合膽固醇且阻止其吸收;依折麥布(ezetimibe)(ZETIA),其阻斷膽固醇吸收;纖維酸(例如TRICOR),其減少甘油三酯且可適度地增加HDL;菸鹼酸(例如NIACOR),其適度地降低LDL膽固醇及甘油三酯;及/或上文所提及者之組合(例如VYTORIN (依折麥布加斯伐他汀(simvastatin))。可為用於與本文所闡述之A2A
R/A2B
R抑制劑組合使用之候選者之替代膽固醇治療包括各種補充劑及草藥(例如,大蒜、多廿烷醇及印度沒藥(guggul))。
本發明涵蓋上文中任一者之醫藥上可接受之鹽、酸或衍生物。
免疫相關及發炎相關病症
。本發明提供用於治療及/或預防免疫相關疾病、病症及病狀以及具有發炎組分之疾病、病症及病狀之方法,其係利用A2A
R/A2B
R抑制劑化合物I之固體形式及至少一種其他治療或診斷劑來實施。
可用於組合療法中之治療劑之實例包括(但不限於)以下各項:非類固醇消炎藥(NSAID),例如阿斯匹林(aspirin)、布洛芬(ibuprofen)及其他丙酸衍生物(阿明洛芬(alminoprofen)、苯噁洛芬(benoxaprofen)、布氯酸(bucloxic acid)、卡洛芬(carprofen)、芬布芬(fenbufen)、非諾洛芬(fenoprofen)、氟洛芬(fluprofen)、氟比洛芬(flurbiprofen)、吲哚洛芬(indoprofen)、酮洛芬(ketoprofen)、咪洛芬(miroprofen)、萘普生(naproxen)、奧沙普秦(oxaprozin)、吡洛芬(pirprofen)、普拉洛芬(pranoprofen)、舒洛芬(suprofen)、噻洛芬酸(tiaprofenic acid)及硫噁洛芬(tioxaprofen))、乙酸衍生物(吲哚美辛(indomethacin)、阿西美辛(acemetacin)、阿氯芬酸(alclofenac)、環氯茚酸(clidanac)、雙氯芬酸(diclofenac)、芬氯酸(fenclofenac)、芬克洛酸(fenclozic acid)、芬替酸(fentiazac)、弗洛芬酸(fuirofenac)、異丁芬酸(ibufenac)、伊索克酸(isoxepac)、奧西平酸(oxpinac)、舒林酸(sulindac)、硫平酸(tiopinac)、妥美汀(tolmetin)、齊多美辛(zidometacin)及佐美酸(zomepirac))、芬那酸(fenamic acid)衍生物(氟芬那酸(flufenamic acid)、甲氯芬那酸(meclofenamic acid)、甲芬那酸(mefenamic acid)、尼氟滅酸(niflumic acid)及托芬那酸(tolfenamic acid))、聯苯羧酸衍生物(二氟尼柳(diflunisal)及氟苯沙酸(flufenisal))、昔康類(oxicam)(伊索昔康(isoxicam)、吡羅昔康(piroxicam)、舒多昔康(sudoxicam)及替諾昔康(tenoxican))、柳酸鹽類(乙醯基柳酸、磺胺塞拉金(sulfasalazine))及吡唑啉酮類(阿紮丙宗(apazone)、苯匹泊隆(bezpiperylon)、非普拉宗(feprazone)、莫非布宗(mofebutazone)、羥布宗(oxyphenbutazone)、苯丁吡唑酮(phenylbutazone))。其他組合包括環加氧酶-2 (COX-2)抑制劑。
用於組合之其他活性劑包括類固醇,例如普賴蘇濃(prednisolone)、普賴松(prednisone)、甲基普賴蘇濃、倍他米松(betamethasone)、地塞米松(dexamethasone)或氫化可體松(hydrocortisone)。此一組合可尤其有利,此乃因藉由逐漸減少所需要之類固醇劑量可降低或甚至消除類固醇之一或多種不良效應。
可組合用於治療(例如)類風濕性關節炎之活性劑之其他實例包括細胞介素抑制性消炎藥(CSAID);針對其他人類細胞介素或生長因子(例如,TNF、LT、IL-10、IL-2、IL-6、IL-7、IL-8、IL-15、IL-16、IL-18、EMAP-II、GM-CSF、FGF或PDGF)之抗體或其拮抗劑。
活性劑之特定組合可在自體免疫及後續發炎級聯中之不同點處進行干擾,且包括TNF拮抗劑,例如嵌合、人類化或人類TNF抗體、REMICADE、抗TNF抗體片段(例如CDP870)及可溶性p55或p75 TNF受體、其衍生物、p75TNFRIgG (ENBREL.)或p55TNFR1gG (LENERCEPT)、可溶性IL-13受體(sIL-13)以及TNFa-轉化酶(TACE)抑制劑;類似地,IL-1抑制劑(例如介白素-1-轉化酶抑制劑)可係有效的。其他組合包括介白素11、抗P7s及p-選擇素醣蛋白配體(PSGL)。可與本文所闡述之A2A
R/A2B
R抑制劑組合使用之藥劑之其他實例包括干擾素-131a (AVONEX);干擾素-13lb (BETASERON);克帕松(copaxone);高壓氧;靜脈內免疫球蛋白;克拉屈濱(cladribine);及針對其他人類細胞介素或生長因子之抗體或其拮抗劑(例如針對CD40配體及CD80之抗體)。
微生物疾病
。本發明提供用於治療及/或預防病毒、細菌、真菌及寄生蟲疾病、病症及病狀以及與其相關之病症之方法,其係利用A2A
R/A2B
R抑制劑化合物I之固體形式及至少一種其他治療或診斷劑(例如一或多種其他抗病毒劑及/或一或多種與病毒療法不相關之藥劑)來實施。
此組合療法包括靶向各個病毒生命週期階段且具有不同作用機制之抗病毒劑,包括(但不限於)以下各項:病毒脫殼之抑制劑(例如金剛烷胺(amantadine)及金剛乙胺(rimantidine));反轉錄酶抑制劑(例如阿昔洛韋(acyclovir)、齊多夫定(zidovudine)及拉米夫定(lamivudine));靶向整合酶之藥劑;阻斷反轉錄因子附接至病毒DNA之藥劑;影響轉譯之藥劑(例如反義分子) (例如福米韋生(fomivirsen));調節轉譯/核酶功能之藥劑;蛋白酶抑制劑;病毒組裝調節劑(例如利福平(rifampicin));抗反轉錄病毒,例如核苷類似物反轉錄酶抑制劑(例如疊氮基胸苷(AZT)、ddl、ddC、3TC、d4T);非核苷反轉錄酶抑制劑(例如依法韋侖(efavirenz)、奈韋拉平(nevirapine));核苷酸類似物反轉錄酶抑制劑;及預防病毒顆粒釋放之藥劑(例如紮那米韋(zanamivir)及奧司他韋(oseltamivir))。某些病毒感染(例如HIV)之治療及/或預防通常需要一組抗病毒劑(「混合液」)。
預期與化合物I之固體形式組合使用之其他抗病毒劑包括(但不限於)以下各項:阿巴卡韋(abacavir)、阿德福韋(adefovir)、金剛烷胺、安普那韋(amprenavir)、聚肌胞(ampligen)、阿比多爾(arbidol)、阿紮那韋(atazanavir)、立普妥(atripla)、波普瑞韋爾特(boceprevirertet)、西多福韋(cidofovir)、雙汰芝(combivir)、達如那韋(darunavir)、地拉韋定(delavirdine)、去羥肌苷(didanosine)、二十二醇、依度尿苷(edoxudine)、恩曲他濱(emtricitabine)、恩夫韋肽(enfuvirtide)、恩替卡韋(entecavir)、泛昔洛韋(famciclovir)、呋山那韋(fosamprenavir)、膦甲酸鹽(foscarnet)、膦乙酸鹽(fosfonet)、更昔洛韋(ganciclovir)、伊巴他濱(ibacitabine)、依諾韋(imunovir)、碘苷(idoxuridine)、咪喹莫特(imiquimod)、茚地那韋(indinavir)、肌苷、各種干擾素(例如聚乙二醇干擾素α-2a)、洛匹那韋(lopinavir)、洛韋胺(loviride)、馬拉維洛(maraviroc)、嗎啉胍(moroxydine)、美替沙腙(methisazone)、奈芬那韋(nelfinavir)、奈克沙韋(nexavir)、噴昔洛韋(penciclovir)、帕拉米韋(peramivir)、普來可那立(pleconaril)、鬼臼毒素(podophyllotoxin)、雷特格韋(raltegravir)、利巴韋林(ribavirin)、利托那韋(ritonavir)、普拉米定(pyramidine)、沙奎那韋(saquinavir)、司他夫定(stavudine)、特拉匹韋(telaprevir)、泰諾福韋(tenofovir)、替拉那韋(tipranavir)、曲氟尿苷(trifluridine)、三協唯(trizivir)、曲金剛胺(tromantadine)、特魯瓦達(truvada)、伐昔洛韋(valaciclovir,)、纈更昔洛韋(valganciclovir)、維立韋羅(vicriviroc)、阿糖腺苷(vidarabine)、維拉米定(viramidine)及紮昔他濱(zalcitabine)。
本發明涵蓋本文所闡述之化合物I功能之固體形式與抗寄生蟲劑之組合之用途。此等藥劑包括(但不限於)噻苯咪唑(thiabendazole)、雙羥萘酸噻嘧啶(pyrantel pamoate)、甲苯達唑(mebendazole)、吡喹酮(praziquantel)、氯硝柳胺(niclosamide)、硫氯酚(bithionol)、奧沙尼喹(oxamniquine)、美曲磷脂(metrifonate)、伊維菌素(ivermectin)、阿苯達唑(albendazole)、依氟鳥胺酸(eflornithine)、美拉胂醇(melarsoprol)、噴他脒(pentamidine)、苄硝唑(benznidazole)、硝呋莫司(nifurtimox)及硝基咪唑。熟習此項技術者知曉可用於治療寄生蟲病症之其他藥劑。
本發明之實施例涵蓋本文所闡述之化合物I之固體形式與可用於治療或預防細菌病症之藥劑之組合的用途。抗細菌劑可以各種方式來分類,該等方式包括基於作用機制、基於化學結構及基於活性譜。抗細菌劑之實例包括靶向細菌細胞壁(例如頭孢菌素(cephalosporin)及青黴素(penicillin))或細胞膜(例如多黏菌素(polymyxin))或干擾必需細菌酶(例如磺醯胺、雷福黴素(rifamycin)及喹啉)之彼等。靶向蛋白質合成之大多數抗細菌劑(例如四環素(tetracycline)及巨環內酯)係抑菌性的,而諸如胺基醣苷等藥劑則係殺菌性的。對抗細菌劑進行分類之另一方式係基於其靶標特異性;「窄譜」藥劑靶向特定類型之細菌(例如革蘭氏陽性(Gram-positive)細菌,例如鏈球菌屬(Streptococcus)),而「寬譜」藥劑則具有抵抗較寬細菌範圍之活性。熟習此項技術者知曉適用於特定細菌感染中之抗細菌劑之類型。
本發明之實施例涵蓋本文所闡述之A2A
R/A2B
R抑制劑與可用於治療或預防真菌病症之藥劑之組合的用途。抗真菌劑包括多烯(例如兩性黴素(amphotericin)、製黴素(nystatin)及匹馬黴素(pimaricin));唑類(例如氟康唑(fluconazole)、伊曲康唑(itraconazole)及酮康唑(ketoconazole));烯丙胺(例如萘替芬(naftifine)及特比萘芬(terbinafine))及嗎啉(例如阿莫羅芬(amorolfine));及抗代謝物(例如5-氟胞嘧啶)。
本發明涵蓋上文所述藥劑(及該等藥劑類別之成員)之醫藥上可接受之鹽、酸或衍生物。投藥
本發明之A2A
R/A2B
R抑制劑化合物I之固體形式可以取決於(例如)以下各項之量投與個體:投與目標(例如期望之消退程度);調配物所投與個體之年齡、體重、性別以及健康及身體狀況;投與途徑;及疾病、病症、病狀或其症狀之性質。投藥方案亦可慮及與所投與藥劑相關之任何不良效應之存在、性質及程度。有效劑量量及劑量方案可容易地自(例如)安全性及劑量遞增試驗、活體內研究(例如動物模型)及熟習此項技術者已知之其他方法來確定。
一般而言,投藥參數要求劑量量小於可對個體不可逆地有毒之量(最大耐受劑量(MTD))且不小於對個體產生可量測之效應所需要之量。考慮到投與途徑及其他因素,此等量係藉由(例如)與ADME相關之藥物動力學及藥效學參數來確定。
有效劑量(ED)係藥劑在一部分服用其之個體中產生治療反應或期望效應之劑量或量。藥劑之「中值有效劑量」或ED50係藥劑在投與其之群體之50%中產生治療反應或期望效應之劑量或量。儘管ED50通常用作合理預計藥劑效應之量度,但考慮到所有相關之因素,其不一定係臨床醫師可能認為適當之劑量。因此,在一些情形中,有效量大於所計算之ED50,在其他情形中,有效量小於所計算之ED50,且在其他情形中,有效量與所計算之ED50相同。
另外,本發明之化合物I之固體形式之有效劑量可係在以一或多個劑量投與個體時相對於健康個體產生期望結果之量。舉例而言,對於經歷特定病症之個體,有效劑量可係將該病症之診斷參數、量測、標記物及諸如此類改良至少約5%、至少約10%、至少約20%、至少約25%、至少約30%、至少約40%、至少約50%、至少約60%、至少約70%、至少約80%、至少約90%或大於90%之劑量,其中100%定義為正常個體所展現之診斷參數、量測、標記物及諸如此類。
在某些實施例中,本發明所涵蓋之化合物I之固體形式可以約0.01 mg/kg個體體重/天至約50 mg/kg個體體重/天或約1 mg/kg個體體重/天至約25 mg/kg個體體重/天之劑量量每天一或多次投與(例如經口)以獲得期望治療效應。
對於口服藥劑之投與,組合物可以含有1.0毫克至1000毫克活性成分、具體而言1.0毫克、3.0毫克、5.0毫克、10.0毫克、15.0毫克、20.0毫克、25.0毫克、50.0毫克、75.0毫克、100.0毫克、150.0毫克、200.0毫克、250.0毫克、300.0毫克、400.0毫克、500.0毫克、600.0毫克、750.0毫克、800.0毫克、900.0毫克及1000.0毫克活性成分之錠劑、膠囊及諸如此類之形式提供。
在某些實施例中,期望之化合物I之固體形式之劑量係含於「單位劑型」中。片語「單位劑型」係指物理離散單元,每一單元含有足以產生期望效應之預定量之單獨或與一或多種其他藥劑組合之固體形式。應瞭解,單位劑型之參數將取決於具體藥劑及欲達成之效應。套組
本發明亦涵蓋包含本文所闡述之化合物I之固體形式及其醫藥組合物之套組。該等套組通常呈如下文所闡述容納各種組分之物理結構之形式,且可用於(例如)實踐上文所闡述之方法。
套組可包括本文所揭示之化合物I之固體形式中之一或多者(提供於(例如)無菌容器中),其可呈適於投與個體之醫藥組合物之形式。本文所闡述之化合物I之固體形式可以即用型之形式(例如錠劑或膠囊)或以需要(例如)在投與之前進行重構或稀釋之形式(例如粉末)提供。當本文所闡述之化合物I之固體形式係呈需要由使用者進行重構或稀釋之形式時,套組亦可包括稀釋劑(例如無菌水)、緩衝液、醫藥上可接受之賦形劑及諸如此類,其可與本文所闡述之固體形式一起包裝或分開包裝。當涵蓋組合療法時,套組可單獨地含有若干種藥劑或該等藥劑可已在套組中合併。套組之每一組分可封閉在個別容器內,且所有各種容器均可在單一包裝內。本發明之套組可針對適當地維持其中所容納組分所必需之條件(例如冷凍或凍結)來設計。
套組可含有標籤或包裝插頁,該標籤或包裝插頁包括其中組分之鑑別資訊及其使用說明書(例如投藥參數、活性成分之臨床藥理學,包括作用機制、藥物動力學及藥效學、不良效應、禁忌等)。標籤或插頁可包括製造商資訊,例如批號及到期日。標籤或包裝插頁可(例如)整合至容納組分之物理結構中、分開含於物理結構內或黏貼至套組之組件(例如安剖、管或小瓶)。
標籤或插頁可另外包括電腦可讀媒體,例如磁碟(例如硬碟、卡片、記憶體磁碟)、光碟(例如CD-ROM/RAM或DVD-ROM/RAM、DVD、MP3、磁帶)或電儲存媒體(例如RAM及ROM)或該等之混合物(例如磁/光儲存媒體、FLASH媒體或記憶體型卡片),或併入至其中。在一些實施例中,套組中並不存在實際說明書,但提供自遠程來源(例如經由網際網路)獲得說明書之方式。實驗
提出以下實例以為熟習此項技術者提供如何製備及使用本發明之完整揭示內容及說明,且該等實例並不意欲限制本發明者視為其發明之範圍,且其並不意欲代表已實施下文實驗或其係可實施之所有實驗。應理解,以現在時書寫之例示性說明不一定實施,而是可實施該等說明以產生其中所闡述性質之資料及諸如此類。已努力確保關於所使用數值(例如量、溫度等)之準確性,但應計及一些實驗誤差及偏差。
除非另外指示,否則份數係重量份數,分子量係重量平均分子量,溫度係以攝氏度(℃)表示,且壓力係大氣壓或接近大氣壓。使用標準縮寫,包括以下:wt =野生型;bp =鹼基對;kb =千鹼基;nt =核苷酸;aa =胺基酸;s或sec =秒;min =分鐘;h或hr =小時;ng =奈克;μg =微克;mg =毫克;g =克;kg =公斤;dl或dL =分升;μl或μL =微升;ml或mL =毫升;l或L =公升;μM =微莫耳;mM =毫莫耳;M =莫耳;kDa =千道爾頓;i.m. =肌內;i.p. =腹膜內;SC或SQ =皮下;QD =每天;BID =每天兩次;QW =每週;QM =每月;HPLC =高效液相層析;BW =體重;U =單位;ns =統計學上不顯著;PBS =磷酸鹽緩衝鹽水;IHC =免疫組織化學;DMEM =達爾伯克氏伊格爾改良培養基(Dulbeco's Modification of Eagle's Medium);EDTA =乙二胺四乙酸。材料及方法
在指示之情形下使用以下一般材料及方法,或其可用於下文實例中:
文獻提供大量可用作評估本文所闡述化合物之基礎之分析及其他實驗技術。 X 射線粉末繞射 (XRPD)
XRPD分析係在PANalytical X’pert pro上在3° 2θ與35° 2θ之間掃描樣品來進行。將材料輕輕研磨以釋放任何聚集物並裝載至具有Kapton或Mylar聚合物膜之多孔板上以支撐樣品。然後將該多孔板放置至繞射儀中且使用40 kV / 40 mA發電機設置使用Cu K輻射(α1 λ = 1.54060 Å;α2 = 1.54443 Å;β = 1.39225 Å;α1 : α2比率= 0.5)以透射模式(步長0.0130° 2θ)運行進行分析。 偏振光顯微術 (PLM)
使用配備有Motic相機及影像捕獲軟體(Motic Images Plus 2.0)之Olympus BX50偏振顯微鏡確定結晶性(雙折射)之存在。所有影像均係使用20×物鏡記錄。 差示掃描量熱法 (DSC)
將大約5 mg材料稱重至鋁DSC盤中,且利用帶孔鋁蓋進行非氣密性密封。然後將樣品盤裝載至經冷卻且保持在20℃之Seiko DSC6200 (配備有冷卻器)中。在獲得穩定熱流反應後,以10℃/min之掃描速率將樣品及參考物加熱至230℃,且監測所產生之熱流反應。使用氮作為吹掃氣體,流速為50 cm3
/min。 熱重分析 (TGA)
將大約5 mg材料稱重至開放鋁盤中,且裝載至同時熱重/差熱分析儀(TG/DTA)中,並保持在室溫下。然後將樣品以10℃/min之速率自20℃加熱至300℃,在此期間記錄樣品重量之變化以及任何差熱事件(DTA)。使用氮作為吹掃氣體,流速為300 cm3
/min。 動態蒸氣吸附 (DVS)
將大約10 mg樣品放置至網型蒸氣吸附天平盤中,且裝載至DVS-1、DVS Intrinsic或DVS Advantage動態蒸氣吸附天平(Surface Measurement Systems)中。使樣品以10%增量經受自40%至90%相對濕度(RH)之斜升曲線,在每一步驟下維持樣品直至在25℃下達成穩定重量為止(dm/dt 0.004%,最小步長30 min,最大步長500 min)。在吸附循環完成後,使用相同程序將樣品乾燥至0% RH,且然後第二次吸附循環回至40% RH。實施兩次循環。繪製吸附/解吸附循環期間之重量變化,容許確定樣品之吸濕性質。然後對保留之任何固體進行XRPD分析。 重量分析蒸氣吸附 (GVS)
將大約10-20 mg樣品放置至網型蒸氣吸附天平盤中,且裝載至IGASorp水分吸附分析儀天平(Hiden Analytical)中。使樣品以10%增量經受自40%至90%相對濕度(RH)之斜升曲線,在每一步驟下維持樣品直至在25℃下達成穩定重量為止(98%步驟完成,最小步長30 min,最大步長60 min)。在吸附循環完成後,使用相同程序將樣品乾燥至0% RH,且最後回至40% RH之起始點。實施兩次循環。繪製吸附/解吸附循環期間之重量變化,容許確定樣品之吸濕性質。 高效液相層析 - 紫外檢測 (HPLC-UV )
Instrument: Agilient 1100
管柱:Zorbax Eclipse Plus C18 150 mm × 3.0 mm,3.5 µm粒徑
管柱溫度:35℃
自動進樣器溫度:環境
UV波長:228 nm
注射體積:3 µL
流速:1 mL/min
移動相A:水(於95:5水:ACN中之0.1%甲酸)
移動相B:ACN (0.1%甲酸)
梯度程式: 實例
熟習此項技術者將認識到可利用多種方法來製備申請專利範圍中所表示之分子。已使用業內已知之多種方法來製備本發明之化合物,其中之一些例示於實例中。實例 1 : 3-[2- 胺基 -6-(1-{[6-(2- 羥基丙 -2- 基 ) 吡啶 -2- 基 ] 甲基 }-1H-1,2,3- 三唑 -4- 基 ) 嘧啶 -4- 基 ]-2- 甲基苯甲腈 ( 化合物 I) 之合成
步驟 1
:於配備有磁力攪拌棒之250 mL圓底燒瓶中相繼裝填酸酯(3.89 g, 16 mmol)及2-胺基-4,6-二氯嘧啶(3.67 g, 22,4 mmol)。添加無水乙醇(100 mL),之後添加KHCO3
(4.81 g, 48 mmol)於去離子水(19 mL)中之溶液。將所得懸浮液用氮脫氣5分鐘。然後添加PdCl2
(PPh3
)2
(112 mg, 1 mol%),且將混合物在氮氣氛下加熱至78℃持續3小時。將乙醇在減壓下蒸發且添加去離子水 (150 mL)。過濾懸浮液,且將固體用額外水(100 mL)洗滌。然後將固體溶解於丙酮(220 mL)中且收集於500 mL圓底燒瓶中。添加二氧化矽與矽藻土之混合物(1:1, 150 g),且將溶劑在減壓下去除。藉由急速層析在矽膠(二氯甲烷/乙酸乙酯梯度0%至15%)上純化所得粗製材料。獲得呈白色固體之期望產物(1.91 g, 49%)。LCMS:方法A,滯留時間= 2.93 min,C12
H9
ClN4
之ESI MS [M+H]+
,計算值245.7,實測值245.2
步驟 2
:於圓底燒瓶中將5.1 g (20.8 mmol)氯-嘧啶懸浮於42 mL脫氣THF中。向此懸浮液添加8.68 mL (62.4 mmol) Et3
N及5.95 mL (25.0 mmol) TIPS-乙炔。將反應混合物攪拌5 min,之後添加219 mg (0.312 mmol) PdCl2
(PPh3
)2
及119 mg (0.624 mmol) CuI。將反應混合物在N2
下在50℃下攪拌5 h。在將反應冷卻至室溫後,將溶劑去除且將粗製材料重新懸浮於100 mL EtOAc中,自其過濾出不溶性固體。將濾液用(1:1) NH4
Cl/NH4
OH (2 × 100 mL)及10% Na2
S2
O4
(1 × 100 mL)洗滌。使用Na2
SO4
乾燥有機層,濃縮且不經進一步純化即用於下一步驟。
步驟 3
:於圓底燒瓶中,將來自先前步驟之粗製TIPS產物溶解於42 mL無水THF中且冷卻至0℃。向此添加25 mL (25.0 mmol) TBAF (1.0 M於THF中)。將反應在0℃下攪拌15 min。添加飽和NH4
Cl (100 mL)以使反應淬滅。利用EtOAc (2 × 100 mL)自水層萃取有機物。將合併之有機層用(1:1) NH4
Cl/NH4
OH (2 × 100 mL)及10% Na2
S2
O4
(1 × 100 mL)洗滌。使用Na2
SO4
乾燥有機層,濃縮且藉由與40% CH2
Cl2
/己烷一起研磨獲得呈淺棕色固體之純淨產物5
。產率:3.71 g (76%,2步)。
步驟 4
:在0℃下在N2
下經30分鐘時程向甲基溴化鎂溶液(3 M於Et2
O中,40 mL, 120 mmol, 4.0 equiv)添加2-(羥基甲基)吡啶-2-甲酸甲基酯(5.0 g, 29.9 mmol)於THF (70 mL, 0.4 M)中之溶液。使所得混合物升溫至室溫且攪拌3 h。利用NH4
Cl水溶液(55 mL)使反應混合物淬滅且添加EtOAc (50 mL)。分離有機相,且用EtOAc (3 × 40 mL)萃取水相。將合併之有機萃取物用飽和亞硫酸氫鈉水溶液(7 × 20 mL)洗滌,然後乾燥(Na2
SO4
),過濾並在真空中濃縮,得到呈淺黃色液體之標題化合物(3.45 g,69%產率;96%純度,如藉由LCMS所判斷)。LCMS:方法A,滯留時間= 0.722 min及1.06 min,C9
H13
NO2
之ESI MS [M+H]+
,計算值167.09,實測值167.2
步驟 5
:在0℃下在N2
下向2-羥基甲基-6-(1-羥基-1-甲基乙基)吡啶(5 g, 29.9 mmol, 1.0 equiv)於PhMe (33 mL, 0.9 M)中之溶液添加疊氮磷酸二苯酯(7.73 mL, 35.9 mmol, 1.2 equiv.),之後添加1,8-二氮雜二環[5.4.0]十一-7-烯(5.37 mL, 35.9 mmol, 1.2 equiv.)。使所得混合物升溫至室溫並攪拌14 h。完成後,用乙酸乙酯稀釋且用水洗滌,將有機層乾燥(Na2
SO4
),過濾並濃縮。將殘餘物溶解於1 N HCl水溶液(2 eq, 60 mmol)中並用MTBE/己烷(3:7, 100 mL)萃取,用水(50 mL)洗滌有機層且將合併之水層用2 N NaOH水溶液中和並用乙酸乙酯(3×75 mL)萃取,將有機層乾燥(Na2
SO4
),經由棉塞過濾並將濾液濃縮,得到呈淺黃色液體之純淨化合物(3.75 g, 75%)。LCMS:方法A,滯留時間= 2.67 min,C9
H12
N4
O之ESI MS [M+H]+
,計算值193.1,實測值193.2
步驟 6
:將疊氮化物(3.34 g, 17.4 mmol)、炔烴(3.71 g, 15.8 mmol)、硫酸銅(II) (39 mg;0.158 mmol)及抗壞血酸鈉(156 mg, 0.790 mmol)於2:1t
-BuOH/H2
O (158 mL)中之混合物在60℃下加熱13 h。將溶劑在真空中去除,將殘餘物乾燥裝載至矽膠上,且藉由矽膠層析(於己烷中之0-100% EtOAc)進行純化,得到呈灰白色固體之期望產物(6.08 g, 90%)。1
H NMR (400 MHz, DMSO-d 6
) δ 8.69 (s, 1H), 7.90 (d,J
= 7.8 Hz, 1H), 7.80 (t,J
= 7.8 Hz, 1H), 7.76 (d,J
= 7.8 Hz, 1H), 7.61 (d,J
= 8.0 Hz, 1H), 7.51 (t,J
= 7.8 Hz, 1H), 7.28 (s, 1H), 7.10 (d,J
= 7.6 Hz, 2H), 6.90 (s, 2H), 5.81 (s, 2H), 5.23 (s, 1H), 2.55 (s, 3H), 1.38 (s, 6H)。C23
H23
N8
O之ESI MS [M+H]+
,計算值427.2,實測值427.3。實例 2 : 3-[2- 胺基 -6-(1-{[6-(2- 羥基丙 -2- 基 ) 吡啶 -2- 基 ] 甲基 }-1H-1,2,3- 三唑 -4- 基 ) 嘧啶 -4- 基 ]-2- 甲基苯甲腈之結晶固體形式之製備
藉由加熱至回流將來自實例1步驟6之產物(7.53 g)溶解於丙酮(109 mL)中,此時以10 mL/min之速率添加水(218 mL)以起始結晶。將混合物冷卻且藉由過濾收集固體,用1:2丙酮/水(109 mL)洗滌且在真空下乾燥,得到呈白色固體之化合物I之形式I (7.08 g; 94%)。實例 3 : 3-[2- 胺基 -6-(1-{[6-(2- 羥基丙 -2- 基 ) 吡啶 -2- 基 ] 甲基 }-1H-1,2,3- 三唑 -4- 基 ) 嘧啶 -4- 基 ]-2- 甲基苯甲腈之固體形式之篩選
藉由將化合物I溶解於1,4-二噁烷中且隨後凍乾來產生非晶形化合物I。藉由XRPD缺少指示性峰來確認非晶形固體形式。向非晶形化合物I添加溶劑以獲得12 × 40 mg樣品,以製備用於熱循環之漿液。材料易溶於該12種溶劑中之許多者中,且因此若干個樣品作為飽和溶液進行熱循環。
表5:非晶形化合物I之定性溶出資料
然後將漿液/溶液熱循環(在攪動下)約72 h至室溫持續4 h,然後40℃持續4 h。將溫度循環後剩餘之任何固體材料過濾,且藉由XRPD及PLM分析所分離之材料。在材料量容許之情形下,亦對任何結晶材料收集TG/DTA。將剩餘之12種飽和溶液(過濾後或若不存在固體材料)均勻地分成3份,且進行以下各項:
- 在約2℃下速冷-小瓶置於冰箱中過夜。
- 反溶劑添加-添加1 mL反溶劑(tBME)且使樣品靜置過夜。倘若沒有固體分離出,則將溶劑蒸發且將材料再溶解於其原始溶劑中,之後添加1 mL tBME或庚烷作為反溶劑。使樣品靜置過夜。
- 蒸發-將蓋自小瓶移除以容許進行溶劑蒸發。
藉由XRPD、PLM分析在此階段分離出之任何固體,且若結晶,則收集TG/DTA (在材料量容許之情形下)。
熱循環後,以下溶劑產生無固體材料之透明溶液:1,4-二噁烷、2-乙氧基乙醇及THF。
化合物I之形式I係自25%丙酮:75%水;二氯甲烷;及甲苯產生。形式I之例示性XRPD示於圖1中,其中峰列表如表1中所示。
具有根據圖5之XRPD及根據圖6之DSC圖案之化合物I之形式II係自25%乙腈:75%水產生。圖5中形式II之XRPD之峰列表示於表3中。
化合物I之形式III係自異丙醇、乙腈、甲醇及水樣品產生。形式III具有根據圖7中所示彼等之XRPD及根據圖8之DSC圖案。圖7中形式III之XRPD之峰列表示於表4中。實例 4 :化合物 I 之其他例示性結晶條件
使用單一溶劑加熱、二元溶劑混合物加熱及緩慢蒸發之方法,鑑別出產生材料之結晶形式之多種條件。結晶度最初係經由材料之熔融範圍來確定,其中與非晶形材料相比,結晶化合物展現相對尖銳且更高之熔融範圍。經由凍乾獲得之非晶形材料展現<100℃之熔融範圍。所選條件之匯總示於表6及7中。
表6:經由加熱/冷卻或緩慢蒸發經由使用單一溶劑進行結晶
熔點以℃表示。*第二次熔融在約193℃-194℃下發生
表7:經由使用二元溶劑混合物進行結晶
熔點以℃表示。*第二次熔融在約193℃-194℃下發生
對自不同溶劑組合獲得之材料之熔點量測表明可獲得材料之至少兩種結晶形式。所觀察到之熔點最高之形式(形式I)大約在193℃-195℃下熔融,且通常係自二元混合物獲得。亦觀察到在179℃-181℃下熔融之另一形式(形式III),其通常係經由使用含有醇溶劑之二元混合物或使用單一溶劑來獲得。通常,觀察到在179℃-181℃下之部分熔融,之後固體之剩餘部分在193℃-195℃下熔融。另外,在某些樣品中,觀察到在179℃-181℃下之完全熔融,之後再凝固且在193℃-195℃下第二次熔融。所選批次之NMR分析顯示僅存在痕量之溶劑。
經由XRPD及DSC分析確認形態學之差異。XRPD分析顯示各別結晶形式之兩種不同圖案。DSC資料亦與所觀察到之熔點一致。
與在178℃下發生相變之形式III相比,形式I (熔點193℃-195℃)係更熱穩定之多晶型物,其基於DSC資料指示在194℃下發生相變。該兩種形式之競爭性1:1漿液實驗提供對穩定性之額外支持,此乃因形式III在多種溶劑中轉化成形式I。實例 5 :化合物 I 之形式 I 之單晶 X 射線繞射
在配備有Mo Kα
輻射(λ= 0.71073 Å)之Bruker Kappa APEX-II CCD繞射儀上進行單晶X射線繞射研究。利用Paratone油將0.253 × 0.227 × 0.206 mm無色塊體件安裝在Cryoloop上。使用ϕ及ϖ掃描在100(2) K下於氮氣流中收集資料。晶體至檢測器距離為40 mm,且使用2.0°之掃描寬度,曝光時間為每圖框4秒。直至25.00° (θ
)時,資料收集100%完成。收集到總計33406個反射,其覆蓋指標-17 ≤ h ≤ 18,-25 ≤ k ≤ 25,-7 ≤ l ≤ 9。發現4373個反射係對稱獨立的,其中Rint
為0.0474。指標化及單位晶胞精修指示原始之單斜晶格。發現空間群為P
21
/c。使用Bruker SAINT軟體程式整合資料且使用SADABS軟體程式進行縮放。藉由直接方法(SHELXT)之解決方案產生與所提出結構一致之完整定相模型。化合物I形式I之單晶X射線繞射資料示於表2中。
所有非氫原子藉由全矩陣最小二乘法(SHELXL-2014)各向異性地進行精修。使用騎式模型(riding model)放置所有碳鍵結之氫原子。使用SHELXL-2014中之適當HFIX命令,該等氫原子之位置均相對於其母原子受到約束。所有其他氫原子(H鍵結)均位於差異圖中。使用DFIX命令限制其相對位置並對其熱進行自由精修。實例 6 :化合物 I 之形式 I 之穩定性及吸濕性
使含有一定量化合物I之形式I之小瓶在75%相對濕度(RH)下經受40℃之溫度達一週。藉由HPLC及XRPD之分析指示,結晶材料係穩定的,未觀察到分解或形態學變化。另外,使含有一定量結晶材料之小瓶於封閉小瓶中經受80℃之溫度達一週。藉由HPLC及XRPD之分析指示,結晶材料係穩定的,未觀察到分解或形態學變化。
藉由動態蒸氣吸附(DVS)分析一定量之化合物I形式I。使樣品以10%增量經受自40%至90% RH之斜升曲線,在每一步驟下維持樣品直至在25℃下達成穩定重量為止。在吸附循環完成後,使用相同程序將樣品乾燥至0% RH,且然後第二次吸附循環回至40% RH。實施兩次循環。繪製吸附/解吸附循環期間之重量變化,容許確定樣品之吸濕性質。然後對所得固體進行XRPD分析,其中未觀察到形態學變化。DVS顯示在0-90%相對濕度範圍內水之可逆吸收,其中在90%相對濕度下最大值為1.1%水,如圖4中所示。此值指示材料略微吸濕,但低於4.22%之理論一水合物值。在循環材料時未觀察到滯後。
本發明之具體實施例闡述於本文中,包括本發明者已知用於實施本發明之最佳模式。在閱讀前述描述後,所揭示實施例之變化形式可對熟習此項技術者變得顯而易見,且預期彼等熟習此項技術者可在適當時採用此等變化形式。因此,預期本發明可以與本文所明確闡述不同之方式實踐,且本發明包括如適用法律所容許之隨附申請專利範圍中所列舉標的物之所有修改及等效內容。此外,除非本文另外指示或上下文另外明顯矛盾,否則在其所有可能之變化形式中,上述要素之任一組合均涵蓋於本發明內。
本說明書中所引用之所有公開案、專利申請案、登錄號及其他參考文獻均係以引用的方式併入本文中,如同每一個別公開案或專利申請案明確且個別地指示以引用的方式併入一般。
圖1顯示化合物I形式I之X射線粉末繞射(XRPD)圖案。
圖2顯示化合物I形式I之差示掃描量熱法(DSC)圖,其顯示在約193℃下吸熱。
圖3顯示化合物I形式I之熱重分析(TGA)。
圖4顯示化合物I形式I之動態蒸氣吸附(DVS)等溫線圖。
圖5顯示化合物I形式II之X射線粉末繞射(XRPD)圖案。
圖6顯示化合物I形式II之差示掃描量熱法(DSC)圖。
圖7顯示化合物I形式III之X射線粉末繞射(XRPD)圖案。
圖8顯示化合物I形式III之差示掃描量熱法(DSC)圖。
Claims (18)
- 如請求項1之固體形式,其進一步包含一或多個在14.8、15.0或21.1度2θ(±0.1度2θ)處之峰,其中該XRPD係使用CuKα1輻射獲得。
- 如請求項1或2之固體形式,其特徵在於具有在6.9、8.0、8.2、12.5、12.7、14.8、15.0、15.7、16.8、18.1、18.8、19.2、20.6、21.1、21.8、24.9、27.1及27.7度2θ(±0.1度2θ)處之峰的X射線粉末繞射(XRPD)圖案,其中該XRPD係使用CuKα1輻射獲得。
- 如請求項1或2之固體形式,其特徵在於與圖1實質上一致的X射線粉末繞射(XRPD)圖案。
- 如請求項1或2之固體形式,其特徵在於藉由單晶X射線繞射所測定具有以下尺寸:a=15.1880(7)Å;b=20.9125(11)Å;c=7.5242(4)Å;α=90°;β=90.7720(10)°;及γ=90°的單位晶胞。
- 如請求項1或2之固體形式,其特徵在於具有在約193℃下之吸熱的差示掃描量熱法(DSC)圖案。
- 如請求項1或2之固體形式,其特徵在於與圖2實質上一致的差示掃描量熱法(DSC)圖案。
- 一種醫藥組合物,其包含如請求項1至7中任一項之固體形式及醫藥上可接受之賦形劑。
- 一種如請求項1至7中任一項之固體形式或如請求項8之醫藥組合物之用途,其係用於製備治療至少部分地由腺苷A2A受體(A2AR)或腺苷A2B受體(A2BR)介導,或由A2AR及A2BR受體二者介導之疾病、病症或病狀的醫藥品,該治療包含向有需要之個體投與治療有效量的該固體形式或該醫藥組合物。
- 如請求項9之用途,其中該疾病、病症或病狀係癌症,或免疫相關疾病、病症或病狀。
- 如請求項10之用途,其中該癌症係前列腺癌、結腸癌、直腸癌、胰臟癌、子宮頸癌、胃癌(stomach cancer)、子宮內膜癌、腦癌、肝癌、膀胱癌、卵巢癌、睪丸癌、頭癌、頸癌、皮膚癌、間皮內襯癌、白血球癌、食管癌、乳癌、肌肉癌、結締組織癌、肺癌、腎上腺癌、甲狀腺癌、腎癌或骨癌。
- 如請求項10之用途,其中該癌症係神經膠母細胞瘤、間皮瘤、腎細胞癌、胃癌(gastric carcinoma)、肉瘤、絨毛膜癌、皮膚基底細胞癌或睪丸精原細胞瘤。
- 如請求項10之用途,其中該癌症係非小細胞肺癌。
- 如請求項10之用途,其中該癌症係前列腺癌。
- 如請求項10之用途,其中該癌症係結腸癌或直腸癌。
- 如請求項10之用途,其中該癌症係胰臟癌。
- 如請求項10至16中任一項之用途,其中該治療進一步包含向有需要之個體投與至少一種其他治療劑。
- 如請求項17之用途,其中該至少一種其他治療劑係免疫檢查點抑制劑,其中該免疫檢查點抑制劑阻斷PD-1、PD-L1、TIGIT或CTLA-4中之至少一者之活性。
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US4474599A (en) | 1982-07-14 | 1984-10-02 | The Dow Chemical Company | 1-(Pyridyl)-1H-1,2,3-triazole derivatives, and use as herbicidal agents |
JP4286146B2 (ja) * | 2001-12-18 | 2009-06-24 | メルク エンド カムパニー インコーポレーテッド | メタボトロピックグルタミン酸受容体−5のヘテロアリール置換ピラゾール系調節剤 |
WO2010077582A1 (en) | 2008-12-16 | 2010-07-08 | Merck Sharp & Dohme Corp. | Triazole derivatives for treatment of alzheimer's disease |
WO2014048065A1 (en) * | 2012-09-28 | 2014-04-03 | Merck Sharp & Dohme Corp. | Triazolyl derivatives as syk inhibitors |
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CA3090922A1 (en) | 2018-02-16 | 2019-08-22 | Arcus Biosciences, Inc. | Dosing with an azolopyrimidine compound |
CA3133078A1 (en) | 2019-03-12 | 2020-09-17 | Arcus Biosciences, Inc. | Treatment of oncogene-driven cancers |
AU2020256098A1 (en) | 2019-03-29 | 2021-10-28 | Arcus Biosciences, Inc. | Treatment of cancer utilizing an identified adenosine fingerprint |
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PH12021550084A1 (en) | 2021-11-08 |
SG11202100267TA (en) | 2021-02-25 |
AU2019306582B2 (en) | 2023-03-16 |
AU2019306582A1 (en) | 2021-03-11 |
CA3106366A1 (en) | 2020-01-23 |
JP2021531273A (ja) | 2021-11-18 |
JP2024083556A (ja) | 2024-06-21 |
TW202011964A (zh) | 2020-04-01 |
EP3823614A1 (en) | 2021-05-26 |
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