TWI822248B - Jak1抑制劑之持續釋放劑型 - Google Patents
Jak1抑制劑之持續釋放劑型 Download PDFInfo
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- TWI822248B TWI822248B TW111130598A TW111130598A TWI822248B TW I822248 B TWI822248 B TW I822248B TW 111130598 A TW111130598 A TW 111130598A TW 111130598 A TW111130598 A TW 111130598A TW I822248 B TWI822248 B TW I822248B
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- sustained release
- acetonitrile
- piperidin
- fluoro
- pyrrolo
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Abstract
本發明係關於包含{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之持續釋放劑型以及與其相關之劑量及方法。
Description
本申請案係關於包含{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之持續釋放劑型以及與其相關之劑量及方法。
蛋白激酶(PK)調控多種生物學過程,尤其包括細胞生長、存活、分化、器官形成、形態發生、新血管形成、組織修復及再生。蛋白激酶亦在以人類為宿主之疾病(包括癌症)中起特殊作用。細胞介素(低分子量多肽或糖蛋白)調控宿主對敗血症之炎性反應所涉及之許多路徑。細胞介素影響細胞分化、增殖及活化,且可調節促炎反應及抗炎反應二者以允許宿主適當地對病原體作出反應。眾多種細胞介素之信號傳導涉及Janus激酶家族(JAK)之蛋白酪胺酸激酶以及信號轉導子與轉錄活化子(STAT)。存在四種已知的哺乳動物JAK:JAK1 (Janus激酶-1)、JAK2、JAK3 (亦稱為白血球Janus激酶;JAKL;及L-JAK)及TYK2 (蛋白-酪胺酸激酶2)。
細胞介素刺激之免疫及炎性反應促成疾病之發病機制:諸如重症聯合免疫缺陷(SCID)之病理起因於免疫系統受到抑制,而活動過度或不適當的免疫/炎性反應促成自體免疫疾病(例如,氣喘、全身性紅斑狼瘡、甲狀腺炎、心肌炎)以及諸如硬皮症及骨關節炎等疾病之病理(Ortmann, R. A., T. Cheng等人(2000)
Arthritis Res2(1): 16-32)。
JAK之表現缺陷與許多疾病狀態相關。例如,Jak1-/-小鼠出生時矮小,無法看護且死於圍產期(Rodig, S. J.、M. A. Meraz等人(1998)
Cell93(3): 373-83)。Jak2-/-小鼠胚胎是貧血的且因缺乏決定性紅血球生成而在交配後第12.5天左右死亡。
認為JAK/STAT路徑且具體而言全部四種JAK在氣喘反應、慢性阻塞性肺病、枝氣管炎及其他相關下呼吸道炎性疾病之發病機制中起作用。經由JAK進行信號傳導之多種細胞介素與上呼吸道炎性疾病/病況有關聯,諸如影響鼻及鼻竇之彼等(例如,鼻炎及鼻竇炎),不論是否為典型過敏反應。JAK/STAT路徑亦牽涉眼睛炎性疾病/病況及慢性過敏反應。
在癌症中可能因細胞介素刺激(例如IL-6或GM-CSF)或因JAK信號傳導之內源性抑制因子諸如SOCS (細胞介素信號傳導之抑制因子)或PIAS (活化STAT之蛋白抑制物)減少而發生JAK/STAT之活化(Boudny, V.及Kovarik, J., Neoplasm. 49:349-355, 2002)。STAT信號傳導以及JAK下游其他路徑(例如,Akt)之活化與許多癌症類型之不良預後有關(Bowman, T.等人,Oncogene 19:2474-2488, 2000)。經由JAK/STAT傳導信號之循環細胞介素之水準升高在惡病質及/或慢性疲勞中起病因作用。因此,由於超出潛在抗腫瘤活性的原因,JAK抑制可有益於癌症患者。
JAK2酪胺酸激酶可有益於患有骨髓增殖性病症(例如,真性紅血球增多症(PV)、自發性血小板增多症(ET)、髓樣化生伴骨髓纖維變性(MMM))之患者(Levin等人,Cancer Cell,第7卷,2005: 387-397)。抑制JAK2V617F激酶可減少造血細胞之增殖,表明在患有PV、ET及MMM之患者中JAK2為藥理抑制之潛在目標。
抑制JAK可有益於患有皮膚免疫病症(諸如牛皮癬)及皮膚敏化之患者。認為牛皮癬之持續除各種趨化介素及生長因子以外還取決於多種炎性細胞介素(JCI, 113:1664-1675),該等炎性細胞介素中許多經由JAK進行信號傳導(Adv Pharmacol. 2000;47:113-74)。
由於抑制JAK之化合物在靶向免疫及炎性路徑之擴大或抑制(諸如用於器官移植之免疫抑制劑)以及自體免疫疾病、涉及活動過度炎性反應之疾病(例如,濕疹)、過敏、癌症(例如,***癌、白血病、多發性骨髓瘤)及由其他治療劑引起之某些免疫反應(例如,皮疹或接觸性皮炎或腹瀉)之治療中之有用性,故需要用於投予JAK激酶之改良之調配物。本文所描述之劑型以及上述劑量及方法針對此需要及其他目的。
JAK抑制劑描述於2011年3月9日申請之美國序號13/043,986 (US 2011/0224190)中,該專利以全文引用方式併入本文中,該等JAK抑制劑包括{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈,其在下文中繪示為式I。
I
本申請案尤其提供持續釋放劑型,其包含以游離鹼計約25 mg至約600 mg (例如,25 mg、100 mg、200 mg、300 mg或600 mg)之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽。
本發明進一步提供一或多種持續釋放劑型,其各自包含{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽;其中該一或多種持續釋放劑型一起向患者提供每日一次口服劑量為以游離鹼計約400 mg至約600 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽。
本發明亦提供一種劑量,其包括一或多種持續釋放劑型,該一或多種持續釋放劑型各自包含{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽;其中該劑量向患者提供每日一次口服劑量為以游離鹼計約400 mg至約600 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽。
本申請案進一步提供如本文所描述之一或多種持續釋放劑型,其一起向患者提供每日一次口服劑量為以游離鹼計約600 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽。
本申請案亦提供一種劑量,其包含如本文所描述之一或多種持續釋放劑型,該一或多種持續釋放劑型一起向患者提供每日一次口服劑量為以游離鹼計約600 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽。
本申請案進一步提供治療有需要之患者之自體免疫疾病、癌症、骨髓增殖性病症、炎性疾病、骨質再吸收疾病或器官移植排斥的方法,其包括向該患者經口投予如本文所描述之一或多種持續釋放劑型。
本申請案亦提供治療有需要之患者之自體免疫疾病、癌症、骨髓增殖性病症、炎性疾病、骨質再吸收疾病或器官移植排斥的方法,其包括向該患者經口投予每日一次劑量為以游離鹼計約400 mg至約600 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽,其中該劑量包括一或多種持續釋放劑型,其各自包含{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽。
本申請案進一步提供治療有需要之患者之自體免疫疾病、癌症、骨髓增殖性病症、炎性疾病、骨質再吸收疾病或器官移植排斥的方法,其包括向該患者經口投予如本文所描述之一或多種持續釋放劑型。
本申請案亦提供治療有需要之患者之自體免疫疾病、癌症、骨髓增殖性病症、炎性疾病、骨質再吸收疾病或器官移植排斥的方法,其中該方法包括按以游離鹼計約600 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之每日一次劑量向該患者經口投予該一或多種持續釋放劑型。
本申請案主張2013年8月7日申請之美國臨時申請案第61/863,325號及2013年12月6日申請之美國臨時申請案第61/913,066號之優先權,該等申請案各自以全文引用方式併入本文中。
本申請案提供持包含{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之續釋放劑型。在一些實施例中,本申請案提供一種持續釋放劑型,其包含以游離鹼計約25 mg至約600 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽。
在一些實施例中,該持續釋放劑型包含以游離鹼計約300 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽。
在一些實施例中,該持續釋放劑型包含以游離鹼計約200 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽。
在一些實施例中,該持續釋放劑型包含以游離鹼計約100 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽。
在一些實施例中,該持續釋放劑型包含以游離鹼計約300 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈己二酸鹽。
在一些實施例中,該持續釋放劑型包含以游離鹼計約200 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈己二酸鹽。
在一些實施例中,該持續釋放劑型包含以游離鹼計約100 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈己二酸鹽。
在包含約100 mg之持續釋放劑型之一些實施例中,向空腹個體經口投予三個該劑型以提供約100 nM至約1000 nM之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之平均峰值血漿濃度(Cmax)。如在此背景下所使用,經口投予意指向個體投予單次劑量(在此情形下3 × 100 mg)並隨時間自血漿濃度量測值計算PK參數。在此背景下,PK參數(在此情形下,Cmax)用於表徵單一持續釋放劑型(即,申請專利範圍係針對單一劑型,而非三個劑型)。
在包含約100 mg之持續釋放劑型之一些實施例中,向空腹個體經口投予三個該劑型以提供約400 nM至約700 nM之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之平均峰值血漿濃度(Cmax)。
在包含約100 mg之持續釋放劑型之一些實施例中,向空腹個體經口投予三個該劑型以提供約0.5小時至約3小時之達到{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之峰值血漿濃度(Tmax)之平均時間。
在包含約100 mg之持續釋放劑型之一些實施例中,向空腹個體經口投予三個該劑型以提供至少0.5小時之達到{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之峰值血漿濃度(Tmax)之平均時間。
在包含約100 mg之持續釋放劑型之一些實施例中,向空腹個體經口投予三個該劑型以提供約5至約50之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之平均峰值血漿濃度(Cmax)與平均12-小時血漿濃度(C12h)之比率。
在包含約100 mg之持續釋放劑型之一些實施例中,向空腹個體經口投予三個該劑型以提供約9至約40之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之平均峰值血漿濃度(Cmax)與平均12-小時血漿濃度(C12h)之比率。
在包含約100 mg之持續釋放劑型之一些實施例中,向空腹個體經口投予三個該劑型以提供約15至約30之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之平均峰值血漿濃度(Cmax)與平均12-小時血漿濃度(C12h)之比率。
在包含約100 mg之持續釋放劑型之一些實施例中,向空腹個體經口投予三個該劑型以提供約5小時至約15小時之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之平均半衰期(t1/2)。
在包含約100 mg之持續釋放劑型之一些實施例中,向空腹個體經口投予三個該劑型以提供約7小時至約12小時之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之平均半衰期(t1/2)。
在包含約100 mg之持續釋放劑型之一些實施例中,向空腹個體經口投予三個該劑型以提供約1小時至約20小時之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之平均半衰期(t1/2)。
在包含約100 mg之持續釋放劑型之一些實施例中,向空腹個體經口投予三個該劑型以提供約1000 nM*h至約4000 nM*h之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之平均生體可用率(AUC0-∞)。
在包含約100 mg之持續釋放劑型之一些實施例中,向空腹個體經口投予三個該劑型以提供約1500 nM*h至約3100 nM*h之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之平均生體可用率(AUC0-∞)。
在包含約100 mg之持續釋放劑型之一些實施例中,向高脂肪餐後之個體經口投予三個該劑型以提供約200 nM至約2000 nM之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之平均峰值血漿濃度(Cmax)。
在包含約100 mg之持續釋放劑型之一些實施例中,向高脂肪餐後之個體經口投予三個該劑型以提供約500 nM至約1500 nM之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之平均峰值血漿濃度(Cmax)。
在包含約100 mg之持續釋放劑型之一些實施例中,向高脂肪餐後之個體經口投予三個該劑型以提供約1小時至約9小時之達到{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之峰值血漿濃度(Tmax)之平均時間。
在包含約100 mg之持續釋放劑型之一些實施例中,向高脂肪餐後之個體經口投予三個該劑型以提供至少1.5小時之達到{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之峰值血漿濃度(Tmax)之平均時間。
在包含約100 mg之持續釋放劑型之一些實施例中,向高脂肪餐後之個體經口投予三個該劑型以提供約10至約70之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之平均峰值血漿濃度(Cmax)與平均12-小時血漿濃度(C12h)之比率。
在包含約100 mg之持續釋放劑型之一些實施例中,向高脂肪餐後之個體經口投予三個該劑型以提供約15至約50之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之平均峰值血漿濃度(Cmax)與平均12-小時血漿濃度(C12h)之比率。
在包含約100 mg之持續釋放劑型之一些實施例中,向高脂肪餐後之個體經口投予三個該劑型以提供約25至約45之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之平均峰值血漿濃度(Cmax)與平均12-小時血漿濃度(C12h)之比率。
在包含約100 mg之持續釋放劑型之一些實施例中,向高脂肪餐後之個體經口投予三個該劑型以提供約1小時至約7小時之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之平均半衰期(t1/2)。
在包含約100 mg之持續釋放劑型之一些實施例中,向高脂肪餐後之個體經口投予三個該劑型以提供約2小時至約5小時之{1-{2-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之平均半衰期(t1/2)。
在包含約100 mg之持續釋放劑型之一些實施例中,向高脂肪餐後之個體經口投予三個該劑型以提供約2000 nM*h至約5000 nM*h之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之平均生體可用率(AUC0-∞)。
在包含約100 mg之持續釋放劑型之一些實施例中,向高脂肪餐後之個體經口投予三個該劑型以提供約3000 nM*h至約4000 nM*h之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之平均生體可用率(AUC0-∞)。
在一些實施例中,持續釋放劑型相對於立即釋放劑型之Cmax幾何平均比率百分比為約15%至約30%,其中一或多種立即釋放劑型及一或多種持續釋放劑型係作為單次劑量獨立地經口投予給空腹個體,其中投予相同大小劑量之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或醫藥學上可接受之鹽。
在一些實施例中,持續釋放劑型相對於立即釋放劑型之Cmax幾何平均比率百分比為約15%至約30%,其中一或多種立即釋放劑型及一或多種持續釋放劑型係作為單次劑量獨立地經口投予給空腹個體,其中投予相同大小劑量之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或醫藥學上可接受之鹽。
在一些實施例中,持續釋放劑型相對於立即釋放劑型之AUC0-∞幾何平均比率百分比為約40%至約55%,其中一或多種立即釋放劑型及一或多種持續釋放劑型係作為單次劑量獨立地經口投予給空腹個體,其中投予相同大小劑量之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或醫藥學上可接受之鹽。
在一些實施例中,向高脂肪餐後之個體經口投予之持續釋放劑型相對於向空腹個體經口投予之持續釋放劑型之Cmax幾何平均比率百分比為約150%至約250%。
在一些實施例中,向高脂肪餐後之個體經口投予之持續釋放劑型相對於向空腹個體經口投予之持續釋放劑型之AUC0-∞幾何平均比率百分比為約125%至約170%。
在一些實施例中,本發明之持續釋放劑型可包括持續釋放基質形成劑。持續釋放基質形成劑之實例包括纖維素醚諸如羥丙甲基纖維素(HPMC、羥丙甲纖維素) (其係高黏度聚合物)、以及甲基纖維素。羥丙甲基纖維素之實例包括Methocel™ K15M、Methocel™ K4M、Methocel™ K100LV、Methocel™ E3、Methocel™ E5、Methocel™ E6、Methocel™ E15、Methocel™ E50、Methocel™ E10M、Methocel™ E4M及Methocel™ E10M。在一些實施例中,該持續釋放劑型包含一或多種羥丙甲纖維素。在一些實施例中,該持續釋放劑型包含第一羥丙甲纖維素及第二羥丙甲纖維素,該第一羥丙甲纖維素之特徵在於在2%於水中之濃度下具有約80 cP至約120 cP之表觀黏度,該第二羥丙甲纖維素之特徵在於在2%於水中之濃度下具有約3000 cP至約5600 cP之表觀黏度。在一些實施例中,該持續釋放劑型包含約8重量%至約20重量%之一或多種羥丙甲纖維素。在一些實施例中,該持續釋放劑型包含約10重量%至約15重量%之一或多種羥丙甲纖維素。
在一些實施例中,本發明之持續釋放劑型可進一步包括一或多種填充劑、助流劑、崩解劑、黏合劑或潤滑劑作為非活性成分。在一些實施例中,填充劑包含微晶纖維素、乳糖單水合物或二者。在一些實施例中,該持續釋放劑型包含約16重量%至約22重量%之微晶纖維素。在一些實施例中,該持續釋放劑型包含約45重量%至約55重量%之乳糖單水合物。
在一些實施例中,潤滑劑可以0至約5重量%之量存於本發明之劑型中。潤滑劑之非限制性實例包括硬脂酸鎂、硬脂酸(硬脂)、氫化油、聚乙二醇、硬脂醯富馬酸鈉及二十二酸甘油酯。在一些實施例中,調配物包括硬脂酸鎂、硬脂酸或二者。在一些實施例中,該持續釋放劑型包含約0.3重量%至約0.7重量%之硬脂酸鎂。
在一些實施例中,在該等劑型中可存在助流劑。在一些實施例中,助流劑可以0至約5重量%之量存於本發明之劑型中。助流劑之非限制性實例包括滑石、膠態二氧化矽及玉米澱粉。在一些實施例中,助流劑係膠態二氧化矽。
在一些實施例中,薄膜包衣劑可以0至約5重量%之量存在。薄膜包衣劑之非限制性說明性實例包括在數種市售完全包衣系統中獲得之含二氧化鈦、滑石及視情況著色劑之基於羥丙甲纖維素或聚乙烯醇鹼之包衣。
在一些實施例中,該持續釋放劑型包含預糊化澱粉。
在一些實施例中,該持續釋放劑型係錠劑。
在一些實施例中,該持續釋放劑型係藉由包括濕法造粒之製程製備。
在一些實施例中,該持續釋放劑型包含一或多種獨立地選自羥丙甲纖維素及微晶纖維素之賦形劑。
在一些實施例中,該持續釋放劑型包含一或多種獨立地選自羥丙甲纖維素、微晶纖維素、硬脂酸鎂、乳糖及乳糖單水合物之賦形劑。
在一些實施例中,該持續釋放劑型包含一或多種獨立地選自羥丙甲纖維素、微晶纖維素、硬脂酸鎂、乳糖、乳糖單水合物及預糊化澱粉之賦形劑。
本發明進一步提供一或多種持續釋放劑型,其各自包含{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽;其中該一或多種持續釋放劑型一起向患者提供每日一次口服劑量為以游離鹼計約400 mg至約600 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽。
本發明亦提供一種劑量,其包括一或多種持續釋放劑型,該一或多種持續釋放劑型各自包含{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽;其中該劑量向患者提供每日一次口服劑量為以游離鹼計約400 mg至約600 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽。
本申請案進一步提供如本文所描述之一或多種持續釋放劑型,其一起向患者提供每日一次口服劑量為以游離鹼計約600 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽。
本申請案進一步提供如本文所描述之一或多種持續釋放劑型,其一起向患者提供每日一次口服劑量為以游離鹼計約500 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽。
本申請案進一步提供如本文所描述之一或多種持續釋放劑型,其一起向患者提供每日一次口服劑量為以游離鹼計約400 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽。
在一些實施例中,所提供之該一或多種持續釋放劑型係六個以游離鹼計約100 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之劑型。在一些實施例中,所提供之該一或多種持續釋放劑型係三個以游離鹼計約200 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之劑型。在一些實施例中,所提供之該一或多種持續釋放劑型係兩個以游離鹼計約300 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之劑型。在一些實施例中,所提供之該一或多種持續釋放劑型係一個以游離鹼計約600 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之劑型。
本申請案亦提供一種劑量,其包含如本文所描述之一或多種持續釋放劑型,該一或多種持續釋放劑型向患者提供每日一次口服劑量為以游離鹼計約600 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽。
本申請案亦提供一種劑量,其包含如本文所描述之一或多種持續釋放劑型,該一或多種持續釋放劑型向患者提供每日一次口服劑量為以游離鹼計約500 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽。
本申請案亦提供一種劑量,其包含如本文所描述之一或多種持續釋放劑型,該一或多種持續釋放劑型向患者提供每日一次口服劑量為以游離鹼計約400 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽。
在一些實施例中,該劑量包括六個以游離鹼計約100 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之劑型。在一些實施例中,該劑量包括三個以游離鹼計約200 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之劑型。在一些實施例中,該劑量包括兩個以游離鹼計約300 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之劑型。在一些實施例中,該劑量包括一個以游離鹼計約600 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之劑型。
本申請案進一步提供一種套組,該套組包括如本文所描述之一或多種持續釋放劑型,該一或多種持續釋放劑型一起向患者提供每日一次口服劑量為以游離鹼計約400 mg至約600 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽。在一些實施例中,該套組進一步包括按以游離鹼計約400 mg至約600 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之每日一次劑量投予該一或多種持續釋放劑型之說明書。
本申請案進一步提供一種套組,其包括如本文所描述之一或多種持續釋放劑型,該一或多種持續釋放劑型一起向患者提供每日一次口服劑量為以游離鹼計約600 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽。在一些實施例中,該套組進一步包括按以游離鹼計約600 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之每日一次劑量投予該一或多種持續釋放劑型之說明書。
本申請案進一步提供一種套組,其包括如本文所描述之一或多種持續釋放劑型,該一或多種持續釋放劑型一起向患者提供每日一次口服劑量為以游離鹼計約500 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽。在一些實施例中,該套組進一步包括按以游離鹼計約600 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之每日一次劑量投予該一或多種持續釋放劑型之說明書。
本申請案進一步提供一種套組,其包括如本文所描述之一或多種持續釋放劑型,該一或多種持續釋放劑型一起向患者提供每日一次口服劑量為以游離鹼計約400 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽。在一些實施例中,該套組進一步包括按以游離鹼計約600 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之每日一次劑量投予該一或多種持續釋放劑型之說明書。
在一些實施例中,該套組包括六個以游離鹼計約100 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之劑型。在一些實施例中,該套組包括三個以游離鹼計約200 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之劑型。在一些實施例中,該套組包括兩個以游離鹼計約300 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之劑型。在一些實施例中,該套組包括一個以游離鹼計約600 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之劑型。
如本文所用,「持續釋放」係如業內通常理解而使用且係指經設計以在經口投予之後使活性成分緩慢釋放至患者中的調配物。
如本文所用,「劑量」係指經口投予給個體或患者之式I化合物之總量。該劑量可呈單一劑型或複數個劑型(例如,600 mg劑量可為一個600 mg劑型、兩個300 mg劑型、三個200 mg劑型、六個100 mg劑型等)。因此,一劑量可指患者幾乎同時服用的複數個藥丸。
如本文所用,「空腹個體」意指在投予該劑量之前已空腹至少10小時的個體。
如本文所用,除非另外指明,否則「平均」在冠於藥物動力學值(例如平均Cmax)前面時表示取自患者群體之藥物動力學值之算術平均值。
如本文所用,「Cmax」意指所觀察到之最大血漿濃度。
如本文所用,「C12h」係指自投予起12小時量測之血漿濃度。
如本文所用,「Tmax」係指觀察到最大血漿濃度的時間。
如本文所用,「T1/2」係指觀察到血漿濃度為最大值一半的時間。
如本文所用,「AUC」係指血漿濃度-時間曲線下面積,其係總生體可用率之量度。
如本文所用,「AUC0-∞」係指外推至無窮大之血漿濃度-時間曲線下面積。
如本文所用,「AUC0-t」係指自時間0至具有可定量血漿濃度之最後時間點(通常約12-36小時)的血漿濃度-時間曲線下面積。
如本文所用,「AUC0-τ」係指自時間0至下一劑量時間的血漿濃度-時間曲線下面積。
如本文所用,「Cl/F」係指口服清除率。
本發明亦包括本文所描述之化合物之醫藥學上可接受之鹽。如本文所用,「醫藥學上可接受之鹽」係指所揭示化合物之衍生物,其中藉由將現有酸或鹼部分轉化成其鹽形式來修飾母體化合物。醫藥學上可接受之鹽之實例包括但不限於諸如胺之鹼性殘基之無機酸鹽或有機酸鹽;諸如羧酸之酸性殘基之鹼金屬鹽或有機鹽;及諸如此類。本發明之醫藥學上可接受之鹽包括母體化合物之例如由無毒無機或有機酸形成之無毒鹽。本發明醫藥學上可接受之鹽可藉由慣用化學方法自含有鹼性或酸性部分之母體化合物合成。一般而言,該等鹽可藉由使此等化合物之游離酸或鹼形式與化學計量之量的適當鹼或酸在水中或在有機溶劑中或在該兩者之混合物中反應來製備;通常,非水介質如***、乙酸乙酯、醇(例如甲醇、乙醇、異丙醇或丁醇)或乙腈(ACN)較佳。適合鹽之清單參見Remington's Pharmaceutical Sciences,第17版,Mack Publishing Company, Easton, Pa., 1985,第1418頁及Journal of Pharmaceutical Science, 66, 2 (1977),該等參考文章各自以全文引用方式併入本文中。在一些實施例中,本文所描述之化合物包括N-氧化物形式。
方法
本申請案進一步提供治療有需要的患者之自體免疫疾病、癌症、骨髓增殖性病症、炎性疾病、骨質再吸收疾病或器官移植排斥之方法,其包括向該患者經口投予一或多種如本文所描述之持續釋放劑型。
本申請案亦提供治療有需要之患者之自體免疫疾病、癌症、骨髓增殖性病症、炎性疾病、骨質再吸收疾病或器官移植排斥的方法,其包括向該患者經口投予每日一次劑量為以游離鹼計約400 mg至約600 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽,其中該劑量包括一或多種持續釋放劑型,其各自包含{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽。
本申請案進一步提供治療有需要之患者之自體免疫疾病、癌症、骨髓增殖性病症、炎性疾病、骨質再吸收疾病或器官移植排斥之方法,其包括向該患者經口投予如本文所描述之一或多種持續釋放劑量。
本申請案亦提供治療有需要之患者之自體免疫疾病、癌症、骨髓增殖性病症、炎性疾病、骨質再吸收疾病或器官移植排斥的方法,其中該方法包括按以游離鹼計約600 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之每日一次劑量向該患者經口投予該一或多種持續釋放劑型。
本申請案亦提供治療有需要之患者之自體免疫疾病、癌症、骨髓增殖性病症、炎性疾病、骨質再吸收疾病或器官移植排斥的方法,其中該方法包括按以游離鹼計約500 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之每日一次劑量向該患者經口投予該一或多種持續釋放劑型。
本申請案亦提供治療有需要之患者之自體免疫疾病、癌症、骨髓增殖性病症、炎性疾病、骨質再吸收疾病或器官移植排斥的方法,其中該方法包括按以游離鹼計約400 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之每日一次劑量向該患者經口投予該一或多種持續釋放劑型。
在前三個段落中之方法之一些實施例中,所提供之該一或多種持續釋放劑型係六個以游離鹼計約100 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之劑型。在前三個段落中之方法之一些實施例中,所提供之該一或多種持續釋放劑型係三個以游離鹼計約200 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之劑型。在前三個段落中之方法之一些實施例中,所提供之該一或多種持續釋放劑型係兩個以游離鹼計約300 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之劑型。在前三個段落中之方法之一些實施例中,所提供之該一或多種持續釋放劑型係一個以游離鹼計約600 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之劑型。
在一些實施例中,向空腹個體經口投予一或多種持續釋放劑型以提供約0.5小時至約3小時之達到{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之峰值血漿濃度(Tmax)之平均時間。
在一些實施例中,向空腹個體經口投予一或多種持續釋放劑型以提供至少0.5小時之達到{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之峰值血漿濃度(Tmax)之平均時間。
在一些實施例中,向空腹個體經口投予一或多種持續釋放劑型以提供約5至約50之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之平均峰值血漿濃度(Cmax)與平均12-小時血漿濃度(C12h)之比率。
在一些實施例中,向空腹個體經口投予一或多種持續釋放劑型以提供約9至約40之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之平均峰值血漿濃度(Cmax)與平均12-小時血漿濃度(C12h)之比率。
在一些實施例中,向空腹個體經口投予一或多種持續釋放劑型以提供約15至約30之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之平均峰值血漿濃度(Cmax)與平均12-小時血漿濃度(C12h)之比率。
在一些實施例中,向空腹個體經口投予一或多種持續釋放劑型以提供約1小時至約20小時之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之平均半衰期(t1/2)。
在一些實施例中,向高脂肪餐後之個體經口投予一或多種持續釋放劑型以提供約1小時至約9小時之達到{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之峰值血漿濃度(Tmax)之平均時間。
在一些實施例中,向高脂肪餐後之個體經口投予一或多種持續釋放劑型以提供至少1.5小時之達到{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之峰值血漿濃度(Tmax)之平均時間。
在一些實施例中,向高脂肪餐後之個體經口投予一或多種持續釋放劑型以提供約10至約70之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之平均峰值血漿濃度(Cmax)與平均12-小時血漿濃度(C12h)之比率。
在一些實施例中,向高脂肪餐後之個體經口投予一或多種持續釋放劑型以提供約15至約50之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之平均峰值血漿濃度(Cmax)與平均12-小時血漿濃度(C12h)之比率。
在一些實施例中,向高脂肪餐後之個體經口投予一或多種持續釋放劑型以提供約25至約45之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之平均峰值血漿濃度(Cmax)與平均12-小時血漿濃度(C12h)之比率。
在一些實施例中,向高脂肪餐後之個體經口投予一或多種持續釋放劑型以提供約1小時至約7小時之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之平均半衰期(t1/2)。
在一些實施例中,向高脂肪餐後之個體經口投予一或多種持續釋放劑型以提供約2小時至約5小時之{1-{1-{2-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之平均半衰期(t1/2)。
在一些實施例中,該一或多種持續釋放劑型各自為錠劑。在一些實施例中,該一或多種持續釋放劑型係藉由包括濕法造粒之製程製備。
在一些實施例中,該一或多種持續釋放劑型各自包含一或多種羥丙甲纖維素。在一些實施例中,該一或多種持續釋放劑型各自包含一或多種獨立地選自羥丙甲纖維素及微晶纖維素之賦形劑。在一些實施例中,該一或多種持續釋放劑型各自包含一或多種獨立地選自羥丙甲纖維素、微晶纖維素、硬脂酸鎂、乳糖及乳糖單水合物之賦形劑。在一些實施例中,該一或多種持續釋放劑型各自包含第一羥丙甲纖維素及第二羥丙甲纖維素,該第一羥丙甲纖維素之特徵在於在2%於水中之濃度下具有約80 cP至約120 cP之表觀黏度,該第二羥丙甲纖維素之特徵在於在2%於水中之濃度下具有約3000 cP至約5600 cP之表觀黏度。
在一些實施例中,該一或多種持續釋放劑型各自包含約10重量%至約15重量%之一或多種羥丙甲纖維素。在一些實施例中,該一或多種持續釋放劑型各自包含約16重量%至約22重量%之微晶纖維素。在一些實施例中,該一或多種持續釋放劑型各自包含約45重量%至約55重量%之乳糖單水合物。在一些實施例中,該一或多種持續釋放劑型各自包含約0.3重量%至約0.7重量%之硬脂酸鎂。
在一些實施例中,本申請案提供治療患者之骨髓纖維變性之方法,其包括向該患者經口投予每日一次劑量為以游離鹼計約400 mg至約600 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽,其中該劑量包括一或多種持續釋放劑型,其各自包含{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽;其中該方法使得該患者之總症狀評分(TSS)與基線相比有所降低。在一些實施例中,本申請案提供治療患者之骨髓纖維變性之方法,其包括按以游離鹼計約600 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之每日一次劑量向該患者經口投予該一或多種持續釋放劑型;其中該方法使得該患者之總症狀評分(TSS)與基線相比有所降低。
在一些實施例中,本申請案提供治療患者之骨髓纖維變性之方法,其包括按以游離鹼計約500 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之每日一次劑量向該患者經口投予該一或多種持續釋放劑型;其中該方法使得該患者之總症狀評分(TSS)與基線相比有所降低。
在一些實施例中,本申請案提供治療患者之骨髓纖維變性之方法,其包括按以游離鹼計約400 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之每日一次劑量向該患者經口投予該一或多種持續釋放劑型;其中該方法使得該患者之總症狀評分(TSS)與基線相比有所降低。
在前三個段落中之方法之一些實施例中,所提供之該一或多種持續釋放劑型係六個以游離鹼計約100 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之劑型。在前三個段落中之方法之一些實施例中,所提供之該一或多種持續釋放劑型係三個以游離鹼計約200 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之劑型。在前三個段落中之方法之一些實施例中,所提供之該一或多種持續釋放劑型係兩個以游離鹼計約300 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之劑型。在前三個段落中之方法之一些實施例中,所提供之該一或多種持續釋放劑型係一個以游離鹼計約600 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之劑型。
在一些實施例中,「總症狀評分(TSS)」係指相較於基線(基線係治療前患者之基線TSS)之源自改良之骨髓纖維變性症狀評估表(MFSAF) (例如,v3.0)電子日記之TSS。在一些實施例中,骨髓纖維變性係原發性骨髓纖維變性(PMF)、真性紅血球增多症後MF或自發性血小板增多症後MF。
本申請案亦提供治療有需要之患者之自體免疫疾病、癌症、骨髓增殖性病症、炎性疾病、骨質再吸收疾病或器官移植排斥的方法,其包括向該患者經口投予每日一次劑量為以游離鹼計約400 mg至約600 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽,其中該劑量包括一或多種持續釋放劑型,其各自包含{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽;其中該方法使得貧血減輕。
本申請案亦提供治療有需要之患者之自體免疫疾病、癌症、骨髓增殖性病症、炎性疾病、骨質再吸收疾病或器官移植排斥的方法,其中該方法包括按以游離鹼計約600 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之每日一次劑量向該患者經口投予該一或多種持續釋放劑型;其中該方法使得貧血減輕。
本申請案亦提供治療有需要之患者之自體免疫疾病、癌症、骨髓增殖性病症、炎性疾病、骨質再吸收疾病或器官移植排斥的方法,其中該方法包括按以游離鹼計約500 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之每日一次劑量向該患者經口投予該一或多種持續釋放劑型;其中該方法使得貧血減輕。
本申請案亦提供治療有需要之患者之自體免疫疾病、癌症、骨髓增殖性病症、炎性疾病、骨質再吸收疾病或器官移植排斥的方法,其中該方法包括按以游離鹼計約400 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之每日一次劑量向該患者經口投予該一或多種持續釋放劑型;其中該方法使得貧血減輕。在一些實施例中,所提供之該一或多種持續釋放劑型係六個以游離鹼計約100 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之劑型。在一些實施例中,所提供之該一或多種持續釋放劑型係三個以游離鹼計約200 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之劑型。在一些實施例中,所提供之該一或多種持續釋放劑型係兩個以游離鹼計約300 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之劑型。在一些實施例中,所提供之該一或多種持續釋放劑型係一個以游離鹼計約600 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之劑型。
貧血減輕係相對於經歷每日兩次劑量為以游離鹼計200 mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽之患者而言,其中該劑量包括一或多種持續釋放劑型,其各自包含{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽。
式I化合物為JAK抑制劑。JAK1選擇性抑制劑係相較於其他Janus激酶優先抑制JAK1活性之化合物。JAK1在多種細胞介素及生長因子信號傳導路徑中起關鍵作用,其失調時會產生或促成疾病狀態。例如,在類風濕性關節炎(已顯示具有有害效應之疾病)中IL-6水準升高(Fonesca, J.E.等人,Autoimmunity Reviews, 8:538-42, 2009)。因IL-6至少部分地經由JAK1進行信號傳導,故預計經由JAK1抑制直接或間接拮抗IL-6可提供臨床益處(Guschin, D., N.等人,Embo J 14:1421, 1995;Smolen, J. S.等人,Lancet 371:987, 2008)。此外,在一些癌症中,JAK1發生突變,從而導致不希望的構成性腫瘤細胞之生長及存活(Mullighan CG, Proc Natl Acad Sci U S A.106:9414-8, 2009;Flex E.等人,J Exp Med. 205:751-8, 2008)。在其他自體免疫疾病及癌症中,活化JAK1之炎性細胞介素之全身水準升高亦可促成疾病及/或相關症狀。因此,患有該等疾病之患者可受益於JAK1抑制。JAK1之選擇性抑制劑可為有效的,同時避免對其他JAK激酶不必要的及潛在不希望的抑制作用。
JAK1之選擇性抑制劑(相對於其他JAK激酶而言)相較於較小選擇性抑制劑可具有多個治療優點。至於對JAK2之選擇性,多種重要的細胞介素及生長因子經由JAK2進行信號傳導,包括例如紅血球生成素(Epo)及血小板生成素(Tpo) (Parganas E等人,Cell. 93:385-95, 1998)。Epo係紅血球產生之關鍵生長因子;因此Epo依賴性信號傳導缺乏會導致紅血球數量降低及貧血(Kaushansky K, NEJM 354:2034-45, 2006)。Tpo (JAK2-依賴性生長因子之另一實例)在控制巨核細胞(產生血小板之細胞)之增殖及成熟中起關鍵作用(Kaushansky K, NEJM 354:2034-45, 2006)。因此,Tpo信號傳導減少將減少巨核細胞數量(巨核細胞減少症)並降低循環血小板計數(血小板減少症)。此會導致不希望及/或不可控之出血。對其他JAK (諸如JAK3及Tyk2)之抑制減少亦可係希望的,因為已證實缺少此等激酶之功能形式之人類患有多種疾病,諸如嚴重合併性免疫缺失病或高免疫球蛋白E症候群(Minegishi, Y等人,Immunity 25:745-55, 2006;Macchi P等人,Nature. 377:65-8, 1995)。因此,就減少免疫抑制、貧血及血小板減少症相關副作用而言,對其他JAK具有之低親和力之JAK1抑制劑相較於較小選擇性抑制劑將具有明顯的優點。
本發明之另一態樣係關於治療個體(例如,患者) JAK相關疾病或病症之方法,其藉由向需要該治療的該個體投予本發明之持續釋放劑型來達成。JAK相關疾病可包括與JAK之表現或活性(包括過表現及/或異常活性水準)直接或間接相關之任何疾病、病症或病況。JAK相關疾病亦可包括可藉由調節JAK活性來預防、改善或治癒之任何疾病、病症或病況。
JAK相關疾病之實例包括免疫系統相關疾病,包括例如器官移植排斥(例如,同種異體移植排斥及移植物抗宿主病)。
JAK相關疾病之其他實例包括自體免疫疾病,諸如多發性硬化、類風濕性關節炎、幼年型關節炎、牛皮癬性關節炎、第I型糖尿病、狼瘡、牛皮癬、炎性腸病、潰瘍性結腸炎、克羅恩氏病(Crohn’s disease)、重症肌無力、免疫球蛋白腎病、心肌炎、自體免疫性甲狀腺病症、慢性阻塞性肺病(COPD)及諸如此類。在一些實施例中,自體免疫疾病係自體免疫性大皰性皮膚病症,諸如尋常型天皰瘡(PV)或大皰性類天皰瘡(BP)。
JAK相關疾病之其他實例包括過敏病況,諸如氣喘、食物過敏、濕疹性皮炎、接觸性皮炎、異位性皮炎(異位性濕疹)及鼻炎。JAK相關疾病之其他實例包括病毒性疾病,諸如艾司坦氏-巴爾氏病毒(Epstein Barr Virus, EBV)、B型肝炎、C型肝炎、HIV、HTLV 1、水痘帶狀皰狀病毒(VZV)及人類乳突病毒(HPV)。
JAK相關疾病之其他實例包括與軟骨更新相關之疾病,例如,痛風性關節炎、敗血性或感染性關節炎、反應性關節炎、反射***感神經失養症、痛性失養症、蒂策症候群(Tietze syndrome)、肋骨關節症(costal athropathy)、地方性變形性骨關節炎、Mseleni病、Handigodu病、肌纖維痛導致之退化、全身性紅斑狼瘡、硬皮症或僵直性脊椎炎。
JAK相關疾病之其他實例包括先天性軟骨畸形,包括遺傳性軟骨溶解、軟骨發育不全及假性軟骨發育不全(例如,小耳症、無耳症(enotia)及幹骺端軟骨發育不全)。
JAK相關疾病或病況之其他實例包括皮膚病症,諸如牛皮癬(例如,尋常型牛皮癬)、異位性皮炎、皮疹、皮膚刺激、皮膚敏化(例如,接觸性皮炎或過敏性接觸性皮炎)。例如,某些物質(包括一些藥品)在局部施用時會引起皮膚敏化。在一些實施例中,將至少一種本發明之JAK抑制劑與引起不希望的敏化之藥劑一起共同投予或相繼投予可有助於治療該不希望的敏化或皮炎。在一些實施例中,藉由局部投予至少一種本發明之JAK抑制劑來治療皮膚病症。
在其他實施例中,JAK相關疾病係癌症,包括以實體瘤為特徵之彼等(例如,***癌、腎癌、肝癌、胰腺癌、胃癌、乳癌、肺癌、頭部及頸部癌症、甲狀腺癌、神經膠質母細胞瘤、卡波西氏肉瘤(Kaposi’s sarcoma)、斯特曼氏病(Castleman’s disease)、子宮平滑肌肉瘤、黑色素瘤等)、血液癌症(例如,淋巴瘤、白血病諸如急性淋巴母細胞性白血病(ALL)、急性骨髓性白血病(AML)或多發性骨髓瘤)及皮膚癌諸如皮膚T-細胞淋巴瘤(CTCL)及皮膚B-細胞淋巴瘤。CTCL之實例包括西紮利氏症候群(Sezary syndrome)及蕈樣真菌病。
在一些實施例中,本文所描述之劑型或其與其他JAK抑制劑(諸如美國序號11/637,545中所報導之彼等,該專利以全文引用方式併入本文中)之組合可用於治療發炎相關癌症。在一些實施例中,癌症與炎性腸病相關。在一些實施例中,炎性腸病係潰瘍性結腸炎。在一些實施例中,炎性腸病係克羅恩氏病。在一些實施例中,發炎相關癌症係結腸炎相關癌症。在一些實施例中,發炎相關癌症係結腸癌或結腸直腸癌。在一些實施例中,癌症係胃癌、胃腸道類癌瘤、胃腸道間質瘤(GIST)、腺癌、小腸癌或直腸癌。
JAK相關疾病可進一步包括以下列之表現為特徵之彼等:JAK2突變體諸如在假激酶域中具有至少一個突變之彼等(例如,JAK2V617F);在假激酶域外部具有至少一個突變之JAK2突變體;JAK1突變體;JAK3突變體;紅血球生成素受體(EPOR)突變體;或以CRLF2之表現失調為特徵之彼等。
JAK相關疾病可進一步包括骨髓增殖性病症(MPD),諸如真性紅血球增多症(PV)、自發性血小板增多症(ET)、骨髓纖維變性伴髓樣化生(MMM)、原發性骨髓纖維變性(PMF)、慢性骨髓性白血病(CML)、慢性骨髓單核球性白血病(CMML)、嗜伊紅性白血球增多症候群(HES)、全身性肥大細胞病(SMCD)及諸如此類。在一些實施例中,骨髓增殖性病症係骨髓纖維變性(例如,原發性骨髓纖維變性(PMF)或真性紅血球增多症/自發性血小板增多症後骨髓纖維變性(Post-PV/ET MF))。在一些實施例中,骨髓增殖性病症係自發性血小板增多症後骨髓纖維變性(Post-ET)。在一些實施例中,骨髓增殖性病症係真性紅血球增多症後骨髓纖維變性(Post-PV MF)。
在一些實施例中,本文所描述之劑型可用於治療肺動脈高血壓。
本發明進一步提供藉由投予本發明之劑型來治療其他藥品之皮膚病副作用之方法。例如,許多藥劑產生不希望的過敏反應,該等過敏反應可顯現為痤瘡樣疹或相關皮炎。具有該等不希望副作用之藥劑之實例包括抗癌藥物,諸如吉非替尼(gefitinib)、西妥昔單抗(cetuximab)、厄洛替尼(erlotinib)及諸如此類。本發明之劑型可與具有不希望皮膚病副作用之藥劑組合(例如,同時或相繼)進行全身投予。
其他JAK相關疾病包括發炎及炎性疾病。炎性疾病之實例包括類肉瘤病、眼睛炎性疾病(例如,虹膜炎、眼色素層炎、鞏膜炎、結膜炎或相關疾病)、呼吸道炎性疾病(例如,上呼吸道(包括鼻及鼻竇)炎性疾病,諸如鼻炎或鼻竇炎;或下呼吸道炎性疾病,包括枝氣管炎、慢性阻塞性肺病及諸如此類)、炎性肌病(諸如心肌炎)及其他炎性疾病。在一些實施例中,眼睛發炎疾病係瞼炎。
本文所描述之劑型可進一步用於治療缺血再灌注損傷或與炎性缺血事件相關之疾病或病況(諸如中風或心跳停止)。本文所描述之劑型可進一步用於治療內毒素驅動之疾病狀態(例如,繞道手術後的併發症或促成慢性心衰竭之慢性內毒素狀態)。本文所描述之劑型可進一步用於治療厭食症、惡病質或疲勞,諸如癌症導致或與癌症相關者。本文所描述之劑型可進一步用於治療再狹窄、硬化性皮炎或纖維變性。本文所描述之劑型可進一步用於治療與缺氧或星形膠質細胞增生相關之病況,諸如例如糖尿病視網膜病變、癌症或神經退化。參見,例如,Dudley, A.C.等人,Biochem. J. 2005, 390 (第2部分):427-36及Sriram, K.等人,J. Biol. Chem. 2004, 279(19):19936-47,2004年3月2日電子版,該兩篇文章之全文均以引用方式併入本文中。本文所描述之JAK抑制劑可用於治療阿爾茲海默氏病(Alzheimer’s disease)。
本文所描述之劑型可進一步用於治療其他炎性疾病,諸如全身性炎性反應症候群(SIRS)及敗血性休克。
本文所描述之劑型可進一步用於治療痛風及因(例如)良性***肥大或良性***增生所致之***尺寸增大。
其他JAK相關疾病包括骨質再吸收疾病,諸如骨質疏鬆症、骨關節炎。骨質再吸收亦可能與其他情況諸如激素失衡及/或激素療法、自體免疫疾病(例如骨類肉瘤病)或癌症(例如骨髓瘤)相關。因式I化合物而減少之骨質再吸收可為約10%、約20%、約30%、約40%、約50%、約60%、約70%、約80%或約90%。
在一些實施例中,本文所描述之劑型可進一步用於治療乾眼病症。如本文所用,「乾眼病症」意欲涵蓋乾眼研討會(Dry Eye Workshop, DEWS)之近期官方報告中所匯總之疾病狀態,該報告將乾眼定義為「一種淚液及眼表的多因素疾病,可產生不適、視覺障礙及淚膜不穩定性之症狀並對眼表具有潛在損害。其伴有淚膜滲透性增加及眼表發炎。」Lemp, 「The Definition and Classification of Dry Eye Disease: Report of the Definition and Classification Subcommittee of the International Dry Eye Workshop」, The Ocular Surface, 5(2), 75-92,2007年4月,其以全文引用方式併入本文中。在一些實施例中,乾眼病症係選自水性淚液不足型乾眼(ADDE)或蒸發型乾眼病症或其適當組合。在一些實施例中,乾眼病症係休格連症候群乾眼(Sjogren syndrome dry eye, SSDE)。在一些實施例中,乾眼病症係非休格連症候群乾眼(NSSDE)。
在又一態樣中,本發明提供如下方法:治療結膜炎、眼色素層炎(包括慢性眼色素層炎)、脈絡膜炎、視網膜炎、睫狀體炎、鞏膜炎、上鞏膜炎或虹膜炎;治療與角膜移植、LASIK (雷射輔助原位角膜磨鑲術)、屈光性角膜切除術或LASEK (雷射輔助上皮下角膜磨鑲術)相關之發炎或疼痛;抑制與角膜移植、LASIK、屈光性角膜切除術或LASEK相關之視覺敏銳度損失;或抑制有需要之患者之移植排斥,該方法包括向該患者投予本發明之劑型。
另外,本發明之劑型或其與其他JAK抑制劑(諸如美國序號11/637,545中所報導之彼等,該專利以全文引用方式併入本文中)之組合可用於治療與病毒性感染(諸如流行性感冒及SARS)相關之呼吸功能障礙或衰竭。
在一些實施例中,本發明提供如任一本文實施例中所描述之劑型用於治療任一本文所描述之疾病或病症之方法。在一些實施例中,本發明提供如任一本文實施例中所描述之劑型用於製備藥劑之用途,該藥劑用於治療任一本文所描述之疾病或病症之方法。
在一些實施例中,本發明提供如本文所描述之劑型或其醫藥學上可接受之鹽用於調節JAK1之方法。在一些實施例中,本發明亦提供如本文所描述之劑型或其醫藥學上可接受之鹽用於製備藥劑之用途,該藥劑用於調節JAK1之方法。
如本文所用,術語「個體」係人類。在一些實施例中,人類係成人受試者。
如本文所用,術語「治療(treating或treatment)」係指以下中之一或多者:(1) 抑制疾病;例如,抑制經歷或展示疾病、病況或病症之病理或症狀之個體之疾病、病況或病症(即,阻止病理及/或症狀之進一步發展);及(2)改善該疾病;例如,改善經歷或展示疾病、病況或病症之病理或症狀之個體之疾病、病況或病症(即,逆轉病理及/或症狀),諸如減小疾病之嚴重程度。
組合療法
可將一或多種其他藥劑(諸如例如化學治療劑、抗炎劑、類固醇、免疫抑制劑以及Bcr-Abl、Flt-3、RAF及FAK激酶抑制劑(諸如例如WO 2006/056399中所描述之彼等,該專利以全文引用方式併入本文中))或其他藥劑與本文所描述之劑型組合使用,用於治療JAK相關疾病、病症或病況。該一或多種其他藥劑可同時或相繼投予患者。
化學治療劑之實例包括蛋白體抑制劑(例如,硼替佐米(bortezomib))、沙利度胺(thalidomide)、來那度胺(revlimid)及DNA破壞劑(諸如美法侖(melphalan)、多柔比星(doxorubicin)、環磷醯胺(cyclophosphamide)、長春新鹼(vincristine)、依託泊苷(etoposide)、卡莫司汀(carmustine)及諸如此類)。
類固醇之實例包括皮質類固醇,諸如***(dexamethasone)或普賴松(prednisone)。
Bcr-Abl抑制劑之實例包括美國專利第5,521,184號、WO 04/005281及美國序號60/578,491中所揭示之各屬及各種之化合物及其醫藥學上可接受之鹽,所有專利以全文引用方式併入本文中。
適合之Flt-3抑制劑之實例包括如WO 03/037347、WO 03/099771及WO 04/046120中所揭示之化合物及其醫藥學上可接受之鹽,所有專利以全文引用方式併入本文中。
適合之RAF抑制劑之實例包括如WO 00/09495及WO 05/028444中所揭示之化合物及其醫藥學上可接受之鹽,該兩個專利之全文均以引用方式併入本文中。
適合之FAK抑制劑之實例包括如WO 04/080980、WO 04/056786、WO 03/024967、WO 01/064655、WO 00/053595及WO 01/014402中所揭示之化合物及其醫藥學上可接受之鹽,所有專利以全文引用方式併入本文中。
在一些實施例中,可將一或多種本發明之劑型與一或多種其他激酶抑制劑(包括伊馬替尼(imatinib))組合使用,尤其用於治療耐受伊馬替尼或其他激酶抑制劑之患者。
在一些實施例中,可將一或多種本發明之劑型與化學治療劑組合用於治療癌症(諸如多發性骨髓瘤),且與對單獨化學治療劑之反應相比可改良治療反應,而不會加劇其毒性效應。用於治療多發性骨髓瘤之其他藥劑之實例(例如)可包括不限於美法侖、美法侖加普賴松[MP]、多柔比星、***及萬珂(Velcade) (硼替佐米)。用於治療多發性骨髓瘤之另外其他藥劑包括Bcr-Abl、Flt-3、RAF及FAK激酶抑制劑。相加或協同效應係將本發明之劑型與其他藥劑組合之所需結果。此外,耐受諸如***等藥劑之多發性骨髓瘤細胞經本發明之劑型治療後可以逆轉。該等藥劑可與本發明化合物組合成單一或連續劑型,或該等藥劑可作為單獨劑型同時或相繼投予。
在一些實施例中,將皮質類固醇(諸如***)與本發明之劑型組合投予患者,其中與連續地相反地,間歇地投予***。
在一些其他實施例中,可在骨髓移植或幹細胞移植之前、期間及/或之後向患者投予一或多種本發明之JAK抑制劑與其他治療劑之組合。
在一些實施例中,其他治療劑係丙酮化氟新諾龍(fluocinolone acetonide) (Retisert®)或利美索龍(rimexolone) (AL-2178, Vexol, Alcon)。
在一些實施例中,其他治療劑係環孢素(cyclosporine) (Restasis®)。
在一些實施例中,其他治療劑係皮質類固醇。在一些實施例中,皮質類固醇係曲安西龍(triamcinolone)、***、氟新諾龍(fluocinolone)、可的松(cortisone)、潑尼松龍(prednisolone)或氟米龍(flumetholone)。
在一些實施例中,其他治療劑係選自Dehydrex™ (Holles Labs)、西瓦米德(Civamide) (Opko)、透明質酸鈉(Vismed, Lantibio/TRB Chemedia)、環孢素(ST-603, Sirion Therapeutics)、ARG101(T) (睪固酮,Argentis)、AGR1012(P) (Argentis)、依卡倍特鈉(ecabet sodium) (Senju-Ista)、吉法酯(gefarnate) (Santen)、15-(s)-羥基二十碳四烯酸(15(S)-HETE)、西維美林(cevilemine)、去氧羥四環素(doxycycline) (ALTY-0501, Alacrity)、米諾環素(minocycline)、iDestrin™ (NP50301, Nascent Pharmaceuticals)、環孢素A (Nova22007, Novagali)、羥四環素(oxytetracycline) (耐久黴素(Duramycin),MOLI1901, Lantibio)、CF101 (2S,3S,4R,5R)-3,4-二羥基-5-[6-[(3-碘苯基)甲胺基]嘌呤-9-基]-N-甲基-氧雜環戊烷-2-胺甲醯基,Can-Fite Biopharma)、伏環孢素(voclosporin) (LX212或LX214,Lux Biosciences)、ARG103 (Agentis)、RX-10045 (合成利索文(resolvin)類似物,Resolvyx)、DYN15 (Dyanmis Therapeutics)、利格列酮(rivoglitazone) (DE011, Daiichi Sanko)、TB4 (RegeneRx)、OPH-01 (Ophtalmis Monaco)、PCS101 (Pericor Science)、REV1-31 (Evolutec)、Lacritin (Senju)、瑞巴匹特(rebamipide) (Otsuka-Novartis)、OT-551 (Othera)、PAI-2 (賓夕法尼亞大學及天普大學(University of Pennsylvania and Temple University))、毛果芸香鹼(pilocarpine)、他克莫司(tacrolimus)、吡美莫司(pimecrolimus) (AMS981, Novartis)、依碳酸氯替潑諾(loteprednol etabonate)、利妥昔單抗(rituximab)、地誇磷索四鈉(diquafosol tetrasodium) (INS365, Inspire)、KLS-0611 (Kissei Pharmaceuticals)、去氫表雄酮(dehydroepiandrosterone)、阿那白滯素(anakinra)、依法珠單抗(efalizumab)、黴酚酸鈉、依那西普(etanercept) (Embrel®)、羥氯奎(hydroxychloroquine)、NGX267 (TorreyPines Therapeutics)、阿克特瑪(actemra)、吉西他濱(gemcitabine)、奧沙利鉑(oxaliplatin)、L-天門冬醯胺酶或沙利度胺。
在一些實施例中,其他治療劑係抗血管生成劑、膽鹼激導性促效劑、TRP-1受體調節劑、鈣通道阻斷劑、黏蛋白促泌素、MUC1刺激劑、鈣調神經磷酸酶抑制劑、皮質類固醇、P2Y2受體促效劑、毒蕈鹼受體促效劑、mTOR抑制劑、另一JAK抑制劑、Bcr-Abl激酶抑制劑、Flt-3激酶抑制劑、RAF激酶抑制劑及FAK激酶抑制劑,諸如例如WO 2006/056399中所述之彼等,該專利以全文引用方式併入本文中。在一些實施例中,其他治療劑係四環素衍生物(例如,米諾環素(minocycline)或多西環素(doxycline))。在一些實施例中,其他治療劑結合於FKBP12。
在一些實施例中,其他治療劑係烷化劑或DNA交聯劑;抗代謝劑/去甲基劑(例如,5-氟脲嘧啶(5-flurouracil)、卡培他濱(capecitabine)或阿紮胞苷(azacitidine));抗激素療劑(例如,激素受體拮抗劑、SERM或芳香酶抑制劑);有絲***抑制劑(例如長春新鹼或紫杉醇(paclitaxel));拓撲異構酶(I或II)抑制劑(例如米托蒽醌(mitoxantrone)及伊立替康(irinotecan));細胞凋亡誘導劑(例如ABT-737);核酸療劑(例如反義或RNAi);細胞核受體配體(例如,促效劑及/或拮抗劑:全反式視黃酸或貝瑟羅汀(bexarotene));後生靶向劑,諸如組蛋白去乙醯基酶抑制劑(例如伏立諾他(vorinostat))、低甲基化劑(例如地西他濱(decitabine));蛋白質穩定性調節劑,諸如Hsp90抑制劑、泛素及/或泛素樣接合或解接合分子;或EGFR抑制劑(厄洛替尼)。
在一些實施例中,其他治療劑係緩和性滴眼劑(亦稱為「人工淚液」),其包括但不限於含有聚乙烯醇、羥丙甲基纖維素、甘油、聚乙二醇(例如PEG400)或羧甲基纖維素之組合物。人工淚液可藉由補償降低之潤濕及潤滑淚膜之能力而幫助治療乾眼。在一些實施例中,其他治療劑係黏液分解藥物,諸如N-乙醯基-半胱胺酸,其可與黏蛋白相互作用,且因此降低淚膜黏度。
在一些實施例中,其他治療劑包括抗生素、抗病毒劑、抗真菌劑、麻醉劑、抗炎劑(包括類固醇及非類固醇抗炎劑)及抗過敏劑。適合藥劑之實例包括胺基糖苷類,諸如阿米卡星(amikacin)、健他黴素(gentamycin)、妥布黴素(tobramycin)、鏈黴素、奈替黴素(netilmycin)及康微素(kanamycin);氟喹諾酮類(fluoroquinolones),諸如環丙沙星(ciprofloxacin)、諾氟沙星(norfloxacin)、氧氟沙星(ofloxacin)、曲伐沙星(trovafloxacin)、洛美沙星(lomefloxacin)、左氧氟沙星(levofloxacin)及依諾沙星(enoxacin);萘啶;磺醯胺類;多黏菌素(polymyxin);氯黴素(chloramphenicol);新黴素(neomycin);巴龍黴素(paramomycin);甲磺酸黏菌素(colistimethate);桿菌肽(bacitracin);萬古黴素(vancomycin);四環素類;利福平(rifampin)及其衍生物(「利福平類」);環絲胺酸;β-內醯胺;頭孢菌素類;兩性黴素類(amphotericins);氟康唑(fluconazole);氟胞嘧啶(flucytosine);納他黴素(natamycin);咪康唑(miconazole);酮康唑(ketoconazole);皮質類固醇類;雙氯芬酸(diclofenac);氟比洛芬(flurbiprofen);克妥洛(ketorolac);舒洛芬(suprofen);克熱寧(cromolyn);洛度沙胺(lodoxamide);左卡巴斯汀(levocabastin);萘唑啉(naphazoline);安他唑啉(antazoline);非尼拉敏(pheniramine);或氮雜內酯抗生素(azalide antibiotic)。
實例 1. 持續釋放調配物之製備
利用下文表中所示量之賦形劑來製備持續釋放錠劑。方案A係用於SR1錠劑,方案B係用於SR2錠劑,方案C係用於SR3錠劑及25 mg SR錠劑,且方案D係用於SR4錠劑。
方案 A :步驟1. 對式I化合物之己二酸鹽、微晶纖維素、羥丙甲纖維素(Methocel K100 LV及Methocel K4M)及乳糖單水合物進行個別地篩分。
步驟2. 將來自步驟1之經篩分物質轉移至適合之摻合機中並混合。
步驟3. 將來自步驟2之摻合物轉移至適合之造粒機中並混合。
步驟4. 添加純化水,同時混合。
步驟5. 將來自步驟4之顆粒轉移至適合之乾燥機中並乾燥直至LOD小於3%。
步驟6. 篩分來自步驟5之顆粒。
步驟7. 將經篩分之硬脂酸鎂與步驟6中之顆粒在適合之摻合機中混合。
步驟8. 在適合之旋轉式壓錠機上壓製步驟7中之最終摻合物。
方案 B :步驟1. 對式I化合物之己二酸鹽、微晶纖維素、羥丙甲纖維素及預糊化澱粉進行個別地篩分。
步驟2. 將來自步驟1之經篩分物質轉移至適合之摻合機中並混合。
步驟3. 將來自步驟2之摻合物轉移至適合之造粒機中並混合。
步驟4. 添加純化水,同時混合。
步驟5. 將來自步驟4之顆粒轉移至適合之乾燥機中並乾燥直至LOD小於3%。
步驟6. 篩分來自步驟5之顆粒。
步驟7. 對polyox、二丁基羥基甲苯及膠態二氧化矽進行個別地篩分。
步驟8. 將來自步驟6之顆粒及來自步驟7之物質轉移至適合之摻合機中並混合。
步驟9. 將經篩分之硬脂酸鎂添加至步驟8中之物質中並繼續摻和。
步驟10. 在適合之旋轉式壓錠機上壓製步驟9中之最終摻合物。
方案 C :步驟1. 經由適合之篩網對乳糖單水合物、式I化合物之己二酸鹽、微晶纖維素及羥丙甲纖維素進行個別地篩分。
步驟2. 將來自步驟1之經篩分物質轉移至適合之摻合機中並混合。
步驟3. 將來自步驟2之摻合物轉移至適合之造粒機中並混合。
步驟4. 添加純化水,同時混合。
步驟5. 經由適合之篩網來篩分濕顆粒。
步驟6. 將來自步驟5之顆粒轉移至適合之乾燥機中並乾燥直至LOD小於3%。
步驟7. 研磨來自步驟6之顆粒。
步驟8. 將經篩分之硬脂酸鎂與步驟7中之顆粒在適合之摻合機中混合。
步驟9. 在適合之旋轉式壓錠機上壓製步驟8中之最終摻合物。
方案 D :步驟1. 經由適合之篩網對預糊化澱粉、式I化合物之己二酸鹽、羥丙甲纖維素及所需微晶纖維素之一部分進行個別地篩分。
步驟2. 將來自步驟1之經篩分物質轉移至適合之摻合機中並混合。
步驟3. 將來自步驟2之摻合物轉移至適合之造粒機中並混合。
步驟4. 添加純化水,同時混合。
步驟5. 經由適合之篩網來篩分濕顆粒。
步驟6. 將來自步驟5之顆粒轉移至適合之乾燥機中並乾燥直至LOD小於3%。
步驟7. 研磨來自步驟6之顆粒。
步驟8. 篩分微晶纖維素之其餘部分及一半碳酸氫鈉。
步驟9. 將來自步驟7之經研磨顆粒及來自步驟8之經篩分物質轉移至適合之摻合機中並混合。
步驟10. 篩分碳酸氫鈉之其餘部分並與步驟9中之摻合物混合。
步驟11. 篩分硬脂酸鎂並與步驟10中之摻合物混合。
步驟12. 在適合之旋轉式壓錠機上壓製步驟11中之最終摻合物。
SR1 : 100 mg 持續釋放錠劑之組成
a 己二酸鹽對游離鹼之換算因子為0.7911
b 在造粒之後添加
c 在加工期間去除
SR2 : 100 mg 持續釋放錠劑之組成
a 己二酸鹽對游離鹼之換算因子為0.7911
b 在造粒之後添加
c 在加工期間去除
SR3 (100 mg) : 100 mg 持續釋放錠劑之組成
a 己二酸鹽對游離鹼之換算因子為0.7911
b 在造粒之後添加
c 在加工期間去除
SR4 : 100 mg 持續釋放錠劑之組成
a 己二酸鹽對游離鹼之換算因子為0.7911
b 在造粒之後添加
c 在加工期間去除
d 部分在造粒之前添加且部分在造粒之後添加
25 mg SR : 25 mg 持續釋放錠劑之組成
a 己二酸鹽對游離鹼之換算因子為0.7911
b 在造粒之後添加
c 在加工期間去除
實例 2. 式 I 化合物之 IR 調配物之製備
組分 | 功能 | 重量(mg/ 錠劑 ) | 組成( 重量%) |
式I化合物之己二酸鹽a | 活性劑 | 126.42 a | 21.1 |
微晶纖維素 | 填充劑 | 60.0 | 10.0 |
羥丙甲纖維素 (Methocel K100LV) | 釋放控制劑 | 60.0 | 10.0 |
羥丙甲纖維素 (Methocel K4M) | 釋放控制劑 | 60.0 | 10.0 |
乳糖單水合物 | 填充劑 | 290.58 | 48.4 |
硬脂酸鎂 b | 潤滑劑 | 3.0 | 0.5 |
純化水c | 造粒液 | 適量 | -- |
總計 | 600.0 | 100 |
組分 | 功能 | 重量(mg/錠劑) | 組成(重量%) |
式I化合物之己二酸鹽a | 活性劑 | 126.4 a | 21.1 |
微晶纖維素 | 填充劑 | 180.0 | 30.0 |
羥丙甲纖維素 (Methocel K100LV) | 黏合劑 | 6.0 | 1.0 |
聚環氧乙烷(Polyox WRS 1105) b | 釋放控制劑 | 180.0 | 30.0 |
預糊化澱粉 | 填充劑 | 101.6 | 16.9 |
膠態二氧化矽 b | 助流劑 | 3.0 | 0.5 |
二丁基羥基甲苯 b | 抗氧化劑 | 0.012 | 0.002 |
硬脂酸鎂 b | 潤滑劑 | 3.0 | 0.5 |
純化水c | 造粒液 | 適量 | -- |
總計 | 600.0 | 100.0 |
組分 | 功能 | 重量(mg/錠劑) | 組成(重量%) |
式I化合物之己二酸鹽a | 活性劑 | 126.4 a | 21.1 |
微晶纖維素 | 填充劑 | 108.0 | 18.0 |
羥丙甲纖維素 (Methocel K100LV) | 釋放控制劑 | 42.0 | 7.0 |
羥丙甲纖維素 (Methocel K4M) | 釋放控制劑 | 30.0 | 5.0 |
乳糖單水合物 | 填充劑 | 290.6 | 48.4 |
硬脂酸鎂 b | 潤滑劑 | 3.0 | 0.5 |
純化水c | 造粒液 | 適量 | -- |
總計 | 600.0 | 100.0 |
賦形劑 | 功能 | 重量(mg/錠劑) | 組成 (重量%) |
式I化合物之己二酸鹽a | 活性劑 | 126.4 a | 21.1 |
微晶纖維素 d | 填充劑 | 104.6 | 17.4 |
羥丙甲纖維素 (Methocel K100LV) | 釋放控制劑 | 210.0 | 35.0 |
預糊化澱粉 | 填充劑 | 60.0 | 10.0 |
碳酸氫鈉 b | 胃漂浮助劑 | 96.0 | 16.0 |
硬脂酸鎂 b | 潤滑劑 | 3.0 | 0.5 |
純化水c | 造粒液 | 適量 | -- |
總計 | 600.0 | 100.0 |
組分 | 功能 | 重量(mg/錠劑) | 組成 (重量%) |
式I化合物之己二酸鹽a | 活性劑 | 31.6 a | 12.6 |
微晶纖維素 | 填充劑 | 105.0 | 42.0 |
羥丙甲纖維素(Methocel K100LV) | 釋放控制劑 | 25.0 | 10.0 |
羥丙甲纖維素(Methocel K4M) | 釋放控制劑 | 25.0 | 10.0 |
乳糖單水合物 | 填充劑 | 62.15 | 24.9 |
硬脂酸鎂 b | 潤滑劑 | 1.25 | 0.5 |
純化水c | 造粒液 | 適量 | -- |
總計 | 250 | 100.0 |
根據下文方案E以下文表中所示組成將用於實例3中之研究之IR調配物製備為50 mg膠囊。
方案 E :步驟1. 將所需量之式I化合物之己二酸鹽與近似相等量之矽化微晶纖維素(SMCC)預先混合。
步驟2. 使步驟1中之混合物通過適合之篩網(例如40目)。
步驟3. 經由用於步驟2中之同一篩網來篩分其餘SMCC。
步驟4. 將來自步驟3之經篩分SMCC與來自步驟2之混合物在適合之摻合機(例如Turbula摻合機)中摻合大約5分鐘。
步驟5. 將該摻合物填充至膠囊中至所需填充重量。
*式I化合物之己二酸鹽以0.7911為鹽換算因子
實例 3. 持續釋放劑型之相對生體可用率研究
成分 | 重量組成 (%) | 每單位量 (mg) |
式I化合物之己二酸鹽 | 35.11 | 63.20* |
矽化微晶纖維素,NF (Prosolv SMCC HD 90) | 64.89 | 116.80 |
總計 | 100.00% | 180.00 |
2號膠囊,硬明膠,白色不透明 | NA | 每個皆為1 |
招募總計72名健康成人受試者於6個組中(每組12名受試者)並按照隨機化排程在每個組內隨機安排治療順序。所有治療均以單次劑量投予式I化合物。在各治療期之間有7天的清除期。
分別在第1組、第2組、第3組及第4組中評價SR1、SR2、SR3及SR4調配物(用於研究之SR1、SR2、SR3、SR4及25 mg SR錠劑參見實例1)。該等受試者按照3向交叉設計接受IR及SR治療:
治療A:在至少10小時之隔夜空腹後經口投予300 mg (6 × 50 mg膠囊)式I化合物之IR調配物。
治療B:在至少10小時之隔夜空腹後經口投予300 mg (3 × 100 mg錠劑)式I化合物之SR調配物。
治療C:在高脂肪餐後經口投予300 mg (3 × 100 mg錠劑)式I化合物之SR調配物。
第5組中之受試者以2向交叉設計接受以下治療:
治療A:在至少10小時之隔夜空腹後經口投予300 mg (3 ×式I化合物之100 mg錠劑) SR3。
治療B:在中等脂肪餐後經口投予300 mg (3 ×式I化合物之100 mg錠劑) SR3。
第6組中之受試者以3向交叉設計接受以下治療:
治療A:在至少10小時之隔夜空腹後經口投予50 mg (2 ×式I化合物之25 mg錠劑(來自實例1之25 mg SR錠劑))。
治療B:在高脂肪餐後經口投予50 mg (2 ×式I化合物之25 mg錠劑(來自實例1之25 mg SR錠劑))。
治療C:在至少10小時之隔夜空腹後經口投予100 mg (1 × 100 mg錠劑) SR3。
在給藥後0小時、0.25小時、0.5小時、1小時、1.5小時、2小時、3小時、4小時、6小時、8小時、12小時、16小時、24小時、36小時及48小時使用紫色蓋(K2EDTA) Vacutainer®管來採集血液樣本用於測定式I化合物之血漿濃度。
藉由經GLP認證之LC/MS/MS法以5.0 nM至5000 nM之線性範圍來分析血漿樣本。表1匯總在分析來自此研究之血漿樣本期間分析品質控制樣本之準確度及精確度(CV%)。
表 1 : 血漿分析品質控制樣本之準確度及精確度
----------低QC-------- | --------中等QC------- | ----------高QC--------- | |||||||
分析物 (單位) | Theo | 準確度 | CV% | Theo | 準確度 | CV% | Theo | 準確度 | CV% |
式I 化合物 | 15.0 | 99.0% | 4.6% | 250 | 101% | 4.2% | 4000 | 99.5% | 2.2% |
CV% =變異係數百分比;QC =品質控制;Theo =理論或標稱濃度。
對於PK分析,使用實際樣本採集時間。對於任何缺少實際採集時間之樣本,使用預定時間,前提為沒有對此等樣本之採集記錄方案違反(protocol deviation)。
使用Phoenix WinNonlin版本6.0 (Pharsight Corporation, Mountain View, CA),使用標準非房室PK方法來分析該式化合物之血漿濃度資料。由此,自所觀察到之血漿濃度資料直接獲取C
max及T
max。使用終末處置期中之濃度資料之對數線性回歸來估算終末期處置速率常數(λ
z),並按ln(2)/λ
z估算t
½。使用線性梯形法則(對於增加濃度)及對數梯形法則(對於降低濃度)來估算AUC
0-t,並按AUC
0-t+ C
t/λ
z計算總AUC
0- ∞。按劑量/AUC
0- ∞估算口服劑量清除率(CL/F),並按劑量/[AUC
0- ∞*λ
z]估算終末期分佈體積(V
z/F)。
使用交叉ANOVA (固定因素=治療、順序及時程,隨機影響=受試者(順序))來比較空腹與進食給藥治療之間以及SR與IR給藥治療之間的對數轉換Cmax及AUC值(在劑量標準化之後,其中劑量係不同的)。確定各治療之間之經調整Cmax及AUC之幾何平均比率(參考物= IR或SR之空腹投予)及相應90%置信區間(CI)。另外,使用來自第1組至第4組中完成治療A、B及C之所有受試者之資料藉由分位元數圖來探究所觀察到之高脂肪餐對AUC0-∞之食物影響與SR調配物之相對生體可用率(參照IR膠囊)之相關性。使用Phoenix WinNonlin版本6.0進行統計學分析。
圖1顯示第1組至第4組中之受試者在治療A (在空腹狀態下投予300 mg IR)、治療B (在空腹狀態下投予300 mg SR)及治療C (在高脂肪餐情況下投予300 mg SR)後之式I化合物之血漿濃度(平均值± SE)。圖2比較了高脂肪餐及中等脂肪餐對單次劑量300 mg (3 × 100 mg)投予式I化合物SR3錠劑後之平均PK曲線之影響。圖3顯示第6組中之受試者在治療A (在空腹狀態下投予2 × 25 mg SR錠劑)、治療B (在高脂肪餐情況下2 × 25 mg SR錠劑)及治療C (在空腹狀態下投予1 × 100 mg SR3)後之式I化合物之血漿濃度(平均值± SE)。
表2A、2B、3A及3B匯總關於100 mg濃度SR1-SR4錠劑之第1組至第4組中之受試者之平均PK參數、相對生體可用率(參考物= IR膠囊)及食物影響(高脂肪餐)。表4A及4B匯總關於100 mg濃度SR3錠劑之第5組中之受試者之平均PK參數及食物影響(中等脂肪餐)。表5A及5B匯總關於25 mg SR錠劑之第6組中之受試者之平均PK參數、劑量標準化相對生體可用率(參考物= 100 mg SR3錠劑)及食物影響(高脂肪餐)。
表 2A
表 2B
表 3A
組/ 治療 | n | C max (μM) | T max (h) | C max/C 12h | t ½ (h) |
第1 組 | |||||
300 mg IR (空腹) | 12 | 2.29 ± 0.50 2.24 | 1.0 (0.50-2.0) | 197 ± 147 159 | 2.0 ± 0.27 2.0 |
300 mg SR1 (空腹) | 12 | 0.341 ± 0.13 0.317 | 1.3 (0.50-3.0) | 13.2 ± 7.8 11.6 | 9.2 ± 4.5 8.3 |
300 mg SR1 (高脂肪餐) | 12 | 0.610 ± 0.14 0.595 | 4.0 (2.0-8.0) | 18.0 ± 6.4 16.8 | 3.2 ± 1.4 3.0 |
第2 組 | |||||
300 mg IR (空腹) | 12 | 2.05 ± 0.67 1.92 | 1.0 (0.50-3.0) | 130 ± 72.9 112 | 2.1 ± 0.34 2.1 |
300 mg SR2 (空腹) | 12 | 0.191 ± 0.10 0.172 | 2.5 (1.0-4.0) | 11.4 ± 9.9 8.60 | 11 ± 8.4 9.23 |
300 mg SR2 (高脂肪餐) | 12 | 0.470 ± 0.16 0.443 | 6.0 (1.5-6.0) | 11.0 ± 4.0 10.4 | 3.5 ± 2.6 3.0 |
第3 組 | |||||
300 mg IR (空腹) | 11 | 2.35 ± 0.41 2.31 | 1.0 (0.50-2.0) | 136 ± 70.8 120 | 2.2 ± 0.53 2.2 |
300 mg SR3 (空腹) | 11 | 0.553 ± 0.24 0.502 | 1.5 (0.50-3.0) | 22.9 ± 13.4 19.3 | 9.8 ± 8.5 7.2 |
300 mg SR3(高脂肪餐) | 12 | 1.05 ± 0.47 0.968 | 4.0 (1.5-8.0) | 34.9 ± 15.8 30.8 | 3.3 ± 1.2 3.1 |
第4 組 | |||||
300 mg IR (空腹) | 12 | 2.94 ± 0.98 2.78 | 1.0 (0.25-1.5) | 170 ± 58.6 162 | 2.1 ± 0.58 2.1 |
300 mg SR4 (空腹) | 12 | 0.321 ± 0.27 0.249 | 2.0 (1.5-8.1) | 10.3 ± 6.0 8.92 | 7.3 ± 5.3 6.0 |
300 mg SR4(高脂肪餐) | 12 | 0.549 ± 0.28 0.481 | 4.0 (2.0-16) | 12.8 ± 14.8 6.06 | 4.9 ± 2.6 4.4 |
組/ 治療 | AUC 0-t (μM*h) | AUC 0- ∞ (μM*h) | CL/F (L/h) |
第1 組 | |||
300 mg IR (空腹) | 4.43 ± 1.00 4.33 | 4.45 ± 1.00 4.35 | 127 ± 27.1 124 |
300 mg SR1(空腹) | 1.55 ± 0.54 1.47 | 1.65 ± 0.54 1.57 | 359 ± 106 345 |
300 mg SR1 (高脂肪餐) | 2.88 ± 0.65 2.82 | 2.91 ± 0.65 2.85 | 194 ± 39.9 190 |
第2 組 | |||
300 mg IR (空腹) | 4.45 ± 1.36 4.24 | 4.47 ± 1.36 4.27 | 134 ± 50.1 127 |
300 mg SR2 (空腹) | ± 037 0.95 | 1.17 ± 0.43 1.11 | 510 ± 148 488 |
300 mg SR2 (高脂肪餐) | 2.48 ± 0.70 2.38 | 2.52 ± 0.72 2.42 | 235 ± 83.5 224 |
第3 組 | |||
300 mg IR (空腹) | 5.00 ± 1.33 4.83 | 5.03 ± 1.34 4.87 | 115 ± 32.4 111 |
300 mg SR3 (空腹) | 2.28 ± 0.71 2.17 | 2.39 ± 0.70 2.29 | 248 ± 82.8 236 |
300 mg SR3(高脂肪餐) | 3.55 ± 1.13 3.40 | 3.59 ± 1.13 3.44 | 165 ± 50.2 158 |
第4 組 | |||
300 mg IR (空腹) | 5.23 ± 2.16 4.88 | 5.25 ± 2.15 4.90 | 117 ± 39.8 111 |
300 mg SR4(空腹) | 1.61 ± 1.23 1.31 | 1.70 ± 1.25 1.40 | 456 ± 259 387 |
300 mg SR4 (高脂肪餐) | 3.00 ± 1.17 2.78 | 3.13 ± 1.20 2.92 | 200 ± 80.0 186 |
組/ 治療 | C max (μM) | T max (h) | C max/C 12h | t 1/2 (h) | |
SR1空腹相對於IR | 14.2% (11.4%-17.5%) | ||||
SR1進食相對於空腹 | 188% (152%-232%) | ||||
SR2空腹相對於IR | 8.9% (6.7%-11.9%) | ||||
SR2進食相對於空腹 | 258% (193%-344%) | ||||
SR3空腹相對於IR | 22.3% (17.4%-28.6%) | ||||
SR3進食相對於空腹 | 191% (150%-244%) | ||||
SR4空腹相對於IR | 9.0% (6.8%-11.9%) | ||||
SR4進食相對於空腹 | 193% (146%-256%) |
除了T
max係以中值(90%置信區間)報告以外,PK參數值均係平均值± SD及幾何平均值。
表 3B
組/ 治療 | AUC 0-t (μM*h) | AUC 0- ∞ (μM*h) | CL/F (L/h) |
相對生體可用率幾何平均值及90% 置信區間 | |||
SR1空腹相對於IR | 34.1% (31.3%-37.0%) | 36.1% (33.3%-39.2%) | |
SR1進食相對於空腹 | 191% (176%-208%) | 181% (167%-196%) | |
SR2空腹相對於IR | 22.4% (18.3%-27.4%) | 26.0% (21.6%-31.3%) | |
SR2進食相對於空腹 | 250% (204%-306%) | 218% (181%-262%) | |
SR3空腹相對於IR | 45.4% (39.6%-52.0%) | 47.5% (41.9%-53.9%) | |
SR3進食相對於空腹 | 151% (132%-173%) | 145% (128%-164%) | |
SR4空腹相對於IR | 26.9% (21.6%-33.4%) | 28.5% (23.2%-35.1%) | |
SR4進食相對於空腹 | 213% (171%-264%) | 215% (172%-268%) |
除了T
max係以中值(90%置信區間)報告以外,PK參數值均係平均值± SD及幾何平均值。
表 4A
組 / 治療 | n | C max (μM) | T max (h) | C max/C 12h | t ½ (h) |
第 5 組 | |||||
300 mg SR3 (空腹) | 12 | 0.619 ± 0.41 0.523 | 1.75 (0.50-4.0) | 22.8 ± 16.7 17.8 | 7.7 ± 5.2 6.2 |
300 mg SR3 (中等脂肪餐) | 12 | 0.875 ± 0.47 0.764 | 2.5 (1.5-6.0) | 40.6 ± 22.7 31.2 | 3.6 ± 2.0 3.3 |
相對生體可用率幾何平均值及 90% 置信區間 | |||||
SR3進食相對於空腹 | 146% (105%-202%) |
除了T
max係以中值(90%置信區間)報告以外,藥物動力學參數值均係平均值± SD及幾何平均值。
表 4B
組 / 治療 | AUC 0-t (μM*h) | AUC 0- ∞ (μM*h) | CL/F (L/h) | |||||
第 5 組 | ||||||||
300 mg SR3 (空腹) | 2.46 ± 1.13 2.23 | 2.58 ± 1.12 2.36 | 251 ± 105 230 | |||||
300 mg SR3(中等脂肪餐) | 2.98 ± 1.34 2.72 | 3.02 ± 1.35 2.76 | 215 ± 94.2 196 | |||||
相對生體可用率幾何平均值及 90% 置信區間 | ||||||||
SR3進食相對於空腹 | 122% (102%-146%) | 117% (99.9%-137%) |
除了T
max係以中值(90%置信區間)報告以外,藥物動力學參數值均係平均值± SD及幾何平均值。
表 5A
組/ 治療 | n | C max (nM) | T max (h) | C max/C 12h | t ½ (h) | |||
第6 組 | ||||||||
2 × 25 mg SR3 (空腹) | 12 | 55.1 ± 30.3 48.0 | 1.3 (0.50-4.0) | NR | 4.0 ± 2.6 3.4 | |||
2 × 25 mg SR3 (高脂肪餐) | 12 | 80.3 ± 27.3 76.7 | 3.0 (1.5-6.0) | NR | 2.2 ± 0.4 2.2 | |||
1 × 100 mg SR3 (空腹) | 11 | 174 ± 69.5 161 | 1.8 (0.50-4.0) | NR | ± 1.3 2.7 | |||
相對生體可用率幾何平均值及90% 置信區間 | ||||||||
2 × 25 mg SR3進食相對於空腹 | 160% (129%-199%) | |||||||
2 × 25 mg SR3相對於1 × 100 mg SR3(空腹) | 58.7% i)(46.9%-73.5%) | |||||||
NC =因在各治療之間受試者中之大量不匹配Tlast而未計算;NR =因大量C12h值係BQL而未報告。
除了Tmax係以中值(90%置信區間)報告以外,PK參數值均係平均值± SD及幾何平均值。
i)統計學比較經劑量標準化。
表 5B
組/ 治療 | AUC 0-t (nM*h) | AUC 0- ∞ (nM*h) | CL/F (L/h) | |||||||
第6 組 | ||||||||||
2 × 25 mg SR3 (空腹) | 205 ± 103 183 | 243 ± 99.9 226 | 429 ± 167 400 | |||||||
2 × 25 mg SR3 (高脂肪餐) | 333 ± 104 319 | 376 ± 94.6 366 | 253 ±57.7 247 | |||||||
1 × 100 mg SR3 (空腹) | 671 ± 230 639 | 704 ± 230 673 | 280 ±81.5 268 | |||||||
相對生體可用率幾何平均值及90% 置信區間 | ||||||||||
2 × 25 mg SR3進食 相對於空腹 | 174% (150%-202%) | 158% (138%-182%) | ||||||||
2 × 25 mg SR3相對於1 × 100 mg SR3(空腹) | NC | 66.1% (57.5%-75.9%) | ||||||||
NC =因在各治療之間受試者中之大量不匹配T
last而未計算;NR =因大量C
12h值係BQL而未報告。
除了Tmax係以中值(90%置信區間)報告以外,PK參數值均係平均值± SD及幾何平均值。
i) 統計學比較經劑量標準化。
在第1組至第4組中之受試者中,在空腹單次劑量投予300 mg IR膠囊後之平均PK曲線相似(圖1)。與IR調配物相比,在空腹單次劑量投予SR1-SR4調配物(3 × 100 mg錠劑)後,所觀察到之血漿中值T
max值得以適當地延長(延長0.3至1.5小時)且平均C
max值顯著降低(幾何平均C
max比率之90% CI之上限< 30%),從而表明對SR錠劑中式I化合物之吸收速率降低。在終末期中對SR1-SR4所觀察到之表觀平均處置t
½(在7.3小時至11小時範圍內)與IR膠囊(約2小時)相比顯著更長,從而表明式I化合物之全身消除很可能受其吸收速率限制,該吸收在終末處置期中係持續的。因更低之C
max及更長之處置t
½所致,SR錠劑之C
max/C
12h比率與IR膠囊相比顯著更低(針對相同研究受試者而言)。SR1、SR2、SR3及SR4錠劑之幾何平均C
max/C
12h比率分別為11.6倍、8.6倍、19.3倍及8.9倍,相比之下,在空腹狀態下投予之IR膠囊為112倍至162倍。
對於在空腹狀態下投予,4種SR錠劑與在相同受試者中給藥之IR膠囊相比均顯示降低之相對生體可用率。SR1、SR2、SR3及SR4之C
max幾何平均比率百分比(90% CI)分別為14.2% (11.4%-17.5%)、8.9% (6.7%-11.9%)、22.3% (17.4%-28.6%)及9.0% (6.8%-11.9%)。SR1、SR2、SR3及SR4之AUC
0-∞幾何平均比率百分比(90% CI)分別為36.1% (33.3%-39.2%)、26.0% (21.6%-31.3%)、47.5% (41.9%-53.9%)及28.5% (23.2%-35.1%)。在所測試SR調配物中,SR3及SR1分別顯示最佳及次佳相對生體可用率。
在空腹狀態下給藥時,胃滯留型調配物SR4之受試者間變異(如以血漿暴露量之變異係數百分比(CV%)衡量)顯著更高,但在設計為腸釋放之3種常規SR錠劑中,受試者間變異係相當的。對於100 mg SR1錠劑,C
max及AUC
0-∞之受試者間CV%分別為39%及33%。對於100 mg SR2錠劑,C
max及AUC
0-∞之受試者間CV%分別為50%及37%。對於100 mg SR3錠劑,C
max及AUC
0-∞之受試者間CV%分別為43%及29%。對於100 mg SR4錠劑,C
max及AUC
0-∞之受試者間CV%分別為83%及73%。彙集第1組至第5組中在空腹狀態下投予300 mg IR之所有受試者(n = 59),C
max及AUC
0-∞之受試者間CV%分別為49%及39%,與針對SR1、SR2及SR3所觀察到之CV%值相當。
以300 mg (3 × 100 mg)劑量水準進行研究之所有SR調配物均觀察到正面食物影響。在高脂肪餐後投予時,C
max及AUC
0-∞值之幾何平均值對於SR1分別增加88%及81%;對於SR2分別增加158%及118%;對於SR3分別增加91%及45%;且對於SR4分別增加93%及115%。與高脂肪餐相比,中等脂肪餐之食物影響為中等,如藉由第5組中SR3之資料所顯示。對於SR3,當其係在標準化中等脂肪餐後投予時,Cmax及AUC0-∞值分別增加46%及17%。對於SR1、SR2及SR3 (此等為經設計用於腸內釋放之SR調配物),與食物一起投予不會顯著改變式I化合物血漿暴露量之受試者間CV%。對於SR4 (其為胃滯留型SR調配物),在伴隨之高脂肪餐情況下血漿暴露量之受試者間CV%表現為顯著降低。
此研究亦以100 mg SR3錠劑為參照探究了25 mg SR錠劑之劑量標準化相對生體可用率。對於第6組中之受試者,相對於在空腹狀態下投予之1 × 100 mg SR3,2 × 25 mg SR3治療之劑量標準化Cmax及AUC0-∞之幾何平均比率百分比分別為59%及66%。然而,由於式I化合物之超線性劑量-暴露關係,25 mg SR錠劑之相對生體可用率可能被低估。對於2 × 25 mg SR劑量,高脂肪餐使式I化合物之Cmax及AUC0-∞分別增加60%及58%。
對於所評價之該四種SR調配物,所觀察到之表觀處置t½均係相當的,且自空腹單次劑量投予得到之Cmax/C12h比率(其係用作自每日兩次投予得到之P/T比率之代替物)在SR1、SR2及SR4之間係相似的(約10倍)且對於SR3則適度地更高(約20倍)。總之,全部4種SR調配物均較IR膠囊顯示顯著更平坦之PK曲線,從而滿足持續釋放之重要目標。經口投予藥品之生體可用率可定義為藥物被吸收進入全身循環之速率及程度。藉由限制藥物自藥品之釋放速率來降低藥物吸收速率係持續釋放調配物之設計要求。因此,對於SR調配物,式I化合物之吸收程度(如以血漿AUC0-∞衡量)用作評估相對生體可用率之主要終點。因此,平均相對生體可用率在SR2 (26%)與SR4 (29%)之間係相似的,其略微低於SR1之平均相對生體可用率(36%)。觀察到SR3之相對生體可用率最佳(48%)。該等結果與在進行此研究之前獲得之活體外溶解曲線相一致。
對於SR調配物,在食物影響與相對生體可用率之間存在明顯相反的相關性。一般而言,與高脂肪餐一起給藥時,對SR2 (118%)及SR4 (115%)之食物影響(以AUC0-∞增加衡量)係最大的,其低於對SR1之食物影響(81%)。觀察到SR3之食物影響最小(45%)。將來自所有受試者之資料彙集在一起時,此相關性亦係明顯的。使用所彙集之個體資料之分位元數圖(分為5個區間,每個區間9名受試者)表明,不考慮調配物,相對生體可用率小於35%之受試者之食物影響更顯著(AUC增加> 2倍)。不考慮調配物,相對生體可用率大於40%之受試者之食物影響係中等的(AUC增加為約50%或更少)。SR3提供48%之平均相對生體可用率且可能與中等食物影響相關。實際上,當SR3錠劑(3 × 100 mg)與中等脂肪餐(其係較典型日常飲食)一起給藥時,所觀察到之幾何平均值AUC
0-∞增加僅為17%,表明投予此調配物可不考慮中等脂肪餐或低脂肪餐。從避免顯著食物影響之角度來看,SR3優於其他調配物。
實例 4. 在活性類風濕性關節炎 (RA) 患者中之 2a 期臨床結果
進行該研究之最初部分(28天)以選擇向前進行之劑量,用以指導對該研究之第二部分(3個月)之劑量選擇。該研究之第2部分係隨機化、雙盲、安慰劑對照(發起人知情)的且治療達84天。擬隨機化之六十名受試者使用與部分1中相同之群體: 單一組,五個平行治療組,各12名受試者: 100 mg SR3錠劑BID;300 mg (3 × 100 mg SR3錠劑)QD;200 mg (2 × 100 mg SR3錠劑)BID;600 mg (6 × 100 mg SR3錠劑)QD;及安慰劑。將中期資料呈遞給2013年ACR (美國風濕病學會(American College of Rheumatology)) (完成84天之受試者n = 40)。3個月時之ACR評分亦顯示於表6中。與經批準用於治療RA之其他JAK抑制劑相比,600 mg QD之ACR評分係史無前例的。例如,檸檬酸托法替尼(tofacitinib citrate)之經批準產品(5 mg BID)顯示遠遠更低之3個月時之ACR評分:59% (ACR20)、31% (ACR50)及15% (ACR70) (XELJANZ® (檸檬酸托法替尼錠劑)標籤之表5)。
表 6
安慰劑 | 100 mg BID | 300 mg QD | 200 mg BID | 600 mg QD | |
ACR20 | 38 | 50 | 44 | 50 | 100 |
ACR50 | 25 | 38 | 44 | 38 | 71 |
ACR70 | 13 | 25 | 22 | 13 | 57 |
亦研究了各給藥方案之血紅素自基線之百分比變化(圖4)。如圖4中可見,200 mg BID劑量與其他劑量相比顯示遠離基線之下降,其傾向於接近安慰劑水準。例如,600 mg QD劑量未顯示與BID劑量所顯示相同之下降趨勢。然而,如表6中可見,與BID劑量相比,每日一次給藥(600 mg QD)並未削弱功效。此表明每日一次給藥(諸如600 mg QD)可達成最大功效,而未誘導諸如貧血之副作用。如圖4及表6中所顯示,600 mg QD劑量具有強效功效且血紅素水準有輕微變化。
認為此功效/副作用概況可能因該QD劑量達成最大JAK1信號傳導(與功效有關)且具有低至谷底之JAK2抑制(因JAK2信號傳導與造血有關)。此假設係由不同劑量之該式化合物之PK得到之JAK1 (IL-6)及JAK2 (TPO)抑制資料支持(表7)。具體而言,600 mg QD劑量顯示與200 mg BID及400 mg BID劑量相似之平均IL-6抑制(61%相對於64%及69%),但與200 mg BID及400 mg BID劑量相比顯示更低之谷底TPO抑制(4%相對於13%及16%)。600 mg QD劑量之谷底IL-6抑制亦低於200 mg BID及400 mg BID劑量之谷底IL-6抑制,此表明來自QD劑量之影響可能降低。
表 7
實例 5. 在斑塊狀牛皮癬患者中之臨床結果
劑量方案 | 平均IL-6抑制 | 谷底IL-6抑制 | 平均TPO抑制 | 谷底TPO抑制 |
100 mg QD | 30% | 7% | 7% | < 1% |
200 mg QD | 39% | 11% | 11% | < 1% |
300 mg QD | 47% | 16% | 18% | 1% |
600 mg QD | 61% | 31% | 36% | 4% |
100 mg BID | 44% | 22% | 11% | 2% |
200 mg BID | 64% | 52% | 24% | 13% |
400 mg BID | 69% | 56% | 33% | 16% |
在大約48名受試者中進行雙盲(發起人知情)、隨機化、安慰劑對照之研究,對該等受試者治療28天。資格要求包括: 在篩選時患活動性斑塊狀牛皮癬至少6個月;斑塊狀牛皮癬之體表面積(BSA)≥ 5%;牛皮癬面積及嚴重程度指數(PASI)評分≥ 5;靜態醫師全球評估(sPGA)評分≥ 3;對局部療法具有不適反應;允許快速提高劑量之創新設計配以保守安全性評估。自100 mg QD至200 mg QD提高至200 mg BID至600 mg QD之四個交錯的劑量組(每組為12名受試者) (9名接受活性物且3名接受PBO)。在第4區集受試者(3名接受活性物且1名接受PBO之區集)完成28天投予而無3級或更高之AE後,下一組之12名受試者開始用下一最高劑量治療;在對此組中之前4名受試者治療28天時,對第1組補充隨機化之60名患有中度至重度牛皮癬之受試者。存在五個治療組:安慰劑、100 mg QD、200 mg QD、200 mg BID及600 mg QD。使用自最低劑量增加至最高之順序招募方法,各自皆在前四名受試者以前一劑量完成28天投予之後。28天之結果顯示於表8中(PASI 50係牛皮癬面積及嚴重程度指數)。與用於牛皮癬治療之處於研發中之其他JAK抑制劑相比,600 mg QD劑量之此等PASI 50評分(81.8%)係史無前例的。例如,5 mg托法替尼(亦稱為達沙替尼(tasocitinib))在12週時顯示更低之PASI 50評分(65.3%) (於2010年10月7日公佈於http://press.pfizer.com)。在美國,出於安全性原因,5 mg托法替尼劑量係RA之經批準劑量水準。
表 8
實例 6. 在骨髓纖維變性患者中之開放標籤 II 期研究
安慰劑 | 100 mg BID | 200 mg QD | 200 mg BID | 600 mg QD | |
平均%變化sPGA | -12.5% | -22.2% | -29.4% | -35.2% | -42.4% |
% sPGA (清除或最小) | 0 | 11.1% | 22.2% | 33.3% | 45.5% |
% PASI 50 | 8.3% | 22.2% | 66.7% | 44.4% | 81.8% |
在此研究中,所招募之患者年齡≥ 18歲,經診斷為原發性骨髓纖維變性(PMF)或真性紅血球增多症後MF或自發性血小板增多症後MF (JAK2V617F陽性或陰性突變狀態),血小板計數≥ 50 × 109個/L,血紅素水準≥ 8.0 g/dL (容許為達成此等水準而進行輸血),按照DIPSS準則為中危-1或更高,且脾臟可觸及或先前接受過脾切除術。對三個不同的劑量組進行了評估: (1) 100 mg SR3錠劑BID) (2) 200 mg (2 × 100 mg SR3錠劑)BID;及(3) 600 mg (6 × 100 mg SR3錠劑)QD。圖5(a)-(b)顯示關於與基線相比、在第12週按照改良之骨髓纖維變性症狀評估表(MFSAF) v3.0電子日記、各自劑量組中總症狀評分(TSS)減少≥ 50%之受試者之比例的中期結果(改良之MFSAF v3.0包含19個問題,在0分(無)至10分(可想像的最壞症狀))之範圍內評估MF-相關症狀。圖5(a)繪示了劑量組(100 mg BID、200 mg BID及600 mg QD)在第12週TSS減少≥ 50%之患者之百分比(在第12週就診前中斷之患者視為無反應者)。圖5(b)繪示了劑量組(100 mg BID、200 mg BID及600 mg QD)在第12週TSS自基線之百分比變化(僅包括具有基線及第12週資料之患者)。圖6(a)繪示了劑量組(100 mg BID、200 mg BID及600 mg QD)隨時間之平均血紅素水準(g/dL) (所有患者之研究中期結果)。圖6(b)繪示了48週時劑量組(100 mg BID、200 mg BID及600 mg QD)隨時間之平均血紅素水準(g/dL)。圖6(c)繪示了與給予安慰劑或羅克斯替尼之個體(羅克斯替尼係按照Jakafi®之標籤給藥)相比48週時劑量組隨時間之平均血紅素水準(g/dL) (作為三個劑量組之平均值)。資料顯示600 mg QD劑量之血紅素水準增加。最後,下文表9顯示各劑量組之中期血液學實驗室結果(新的及惡化的)。
表 9
實例 A :活體外 JAK 激酶分析
事件n/N% | 100 mg BID | 200 mg BID | 600 mg QD |
暴露天數, 中值(範圍) | 102.5 (23.0, 376.0) | 169.0 (22.0, 339.0) | 16.0 (1.0, 196.0) |
貧血,3級 | 3/9 (33.3) | 12/42 (28.6) | 2/29 (6.9) |
血小板減少症 3級 4級 | 4/9 (44.4) 0/9 (0) | 12/44 (27.3) 2/45 (4.4) | 1/29 (3.4) 0/29 (0) |
根據以下描述於Park等人,
Analytical Biochemistry 1999,
269, 94-104中之活體外分析來測試本文式I化合物對JAK靶標之抑制活性。使用桿狀病毒在昆蟲細胞中表現具有N-端His標籤之人類JAK1 (a.a. 837-1142)及JAK2 (a.a. 828-1132)之催化域並純化。藉由量測生物素化肽之磷酸化來分析JAK1及JAK2之催化活性。藉由均相時間解析螢光(HTRF)來偵測磷酸化肽。在40 µL於具有100 mM NaCl、5 mM DTT及0.1 mg/mL (0.01%) BSA之50 mM Tris (pH 7.8)緩衝液中含有酶、ATP及500 nM肽之反應液中量測化合物對每種激酶之IC
50。對於1 mM IC
50量測值,反應中之ATP濃度為1 mM。在室溫下進行反應1小時且然後用含20 µL 45 mM EDTA、300 nM SA-APC、6 nM Eu-Py20之分析緩衝液(Perkin Elmer, Boston, MA)來終止反應。與銪標記之抗體結合40分鐘並在融合板讀取器(Fusion plate reader) (Perkin Elmer, Boston, MA)上量測HTRF信號。式I化合物及己二酸鹽在JAK1下之IC
50≤ 5 nM (以1 mM ATP量測)且JAK2/JAK1比率> 10 (以1 mM ATP量測)。
實例 B : 細胞分析
可將視細胞介素且因此JAK/STAT信號轉導而生長之癌細胞系以6000個細胞/孔(96孔板格式)塗鋪於RPMI 1640、10% FBS及1 nG/mL適當細胞介素中。可將化合物添加至DMSO/培養基(最終濃度為0.2% DMSO)中之細胞中並在37℃、5% CO
2下培育72小時。依次使用CellTiter -Glo發光細胞活力分析(Promega)及TopCount (Perkin Elmer, Boston, MA)進行定量來評估化合物對細胞活力之影響。使用具有相同分析讀數之非JAK驅動之細胞系併行地量測化合物之潛在脫靶效應。所有實驗通常均以一式兩份進行。
亦可使用上文細胞系來偵測化合物對JAK激酶或潛在下游受質(諸如STAT蛋白、Akt、Shp2或Erk)之磷酸化之影響。此等實驗可在細胞介素挨餓隔夜後進行,接著與化合物一起進行簡單預培育(2小時或更短時間),且進行大約1小時或更短時間之細胞介素刺激。然後自細胞萃取蛋白並藉由熟習此項技術者所熟悉之技術加以分析,包括西方墨點法(Western blotting)或ELISA,其使用可區分磷酸化蛋白與全蛋白之抗體。此等實驗可利用正常細胞或癌細胞來研究化合物對腫瘤細胞存活生物學或對炎性疾病之介質之活性。例如,關於後者,可使用諸如IL-6、IL-12、IL-23或IFN之細胞介素來刺激JAK活化,使得STAT蛋白之磷酸化並可能產生轉錄譜(藉由陣列或qPCR技術評估)或產生及/或分泌蛋白質,諸如IL-17。可使用熟習此項技術者常用之技術來量測化合物抑制此等細胞介素介導作用之能力。
亦可在經設計以評價化合物對抗突變JAK (例如,於骨髓性增殖性病症中發現之JAK2V617F突變)之效力及活性之細胞模型中測試本文化合物。此等實驗通常利用血液譜系之細胞介素依賴性細胞(例如BaF/3),其中野生型或突變JAK激酶異位表現(James, C.等人,
Nature434:1144-1148;Staerk, J.等人,JBC 280:41893-41899)。終點包括化合物對細胞存活、增殖及磷酸化JAK、STAT、Akt或Erk蛋白之影響。
可評價本文某些化合物抑制T-細胞增殖之活性。該分析可視為又一種細胞介素(即JAK)驅動之增殖分析且亦為免疫抑制或免疫活化抑制之一種簡便分析。以下為可如何進行該等實驗之簡短概述。使用Ficoll Hypaque分離法自人類全血樣本製備周邊血單核細胞(PBMC)且可藉由淘析自PBMC獲得T-細胞(級分2000)。可在37℃下將剛分離之人類T-細胞以2 × 10
6個細胞/ml之密度保持在培養基(補充有10%胎牛血清、100 U/ml青黴素、100 µg/ml鏈黴素之RPMI 1640)中至多2天。在IL-2刺激之細胞增殖分析中,首先用最終濃度為10 µg/mL之植物血球凝集素(PHA)處理T-細胞72 h。以PBS洗滌一次後,以6000個細胞/孔塗鋪於96孔板中,並用含不同濃度化合物之存有100 U/mL人類IL-2 (ProSpec-Tany TechnoGene;Rehovot, Israel)之培養基處理。將板在37℃下培育72 h並使用CellTiter-Glo發光試劑、按照製造商所建議之方案(Promega;Madison, WI)評估增殖指數。
實例 C :活體內抗腫瘤功效
可在免疫受損小鼠中在人類腫瘤異體移植模型中評價本文化合物。例如,可使用INA-6漿細胞瘤細胞系之致瘤變體對SCID小鼠進行皮下接種(Burger, R.等人,Hematol J. 2:42-53, 2001)。然後可將具有腫瘤之動物隨機分成藥物治療組或媒介物治療組,並可藉由常見途徑(包括口服、腹膜內或使用植入式幫浦之連續輸注)中之任一種來投予不同劑量之化合物。使用測徑規追蹤隨時間之腫瘤生長。此外,可在治療開始後的任何時間收穫腫瘤樣本用於如上文所描述之分析(實例B)來評價化合物對JAK活性及下游信號傳導路徑之影響。另外,可使用由其他已知激酶(例如Bcr-Abl)驅動之異體移植腫瘤模型(諸如K562腫瘤模型)來評估化合物之選擇性。
實例 D :鼠 皮膚接觸遲發型過敏反應測試
亦可在T-細胞驅動之鼠遲發過敏測試模型中測試本文化合物(抑制JAK靶標)之功效。鼠皮膚接觸遲發型過敏(DTH)反應被視為臨床接觸性皮炎及其他T-淋巴細胞介導之皮膚免疫病症(諸如牛皮癬)之有效模型(
Immunol Today. 1998年1月;19(1):37-44)。鼠DTH與牛皮癬共有多個特性,包括免疫浸潤、伴隨炎性細胞介素增加及角質細胞過度增殖。此外,在臨床中有效治療牛皮癬之許多種類之藥劑亦為小鼠DTH反應之有效抑制劑(Agents Actions. 1993年1月;38(1-2):116-21)。
在第0天及第1天,向Balb/c小鼠之經剃毛腹部局部施用抗原2,4-二硝基-氟苯(DNFB)對其致敏。在第5天,使用工程師用測微尺來量測耳朵厚度。記錄此量測值並用作基線。然後藉由以0.2%之濃度局部施用總計20 μL DNFB (10 μL施於內耳廓且10 μL施於外耳廓)對動物雙耳進行攻毒。攻毒後24至72小時,再次量測耳朵。在整個致敏及攻毒階段中(第-1天至第7天)或在攻毒階段之前及整個攻毒階段中(通常在第4天至第7天的下午)給予測試化合物治療。全身或局部實施測試化合物(以不同濃度)之治療(向耳朵局部施用治療劑)。測試化合物之功效由與未治療之情況相比耳朵腫脹之減輕指示。達成減輕20%或更多之化合物被視為有效的。在一些實驗中,對小鼠進行攻毒而未致敏(陰性對照)。
可藉由免疫組織化學分析來證實測試化合物之抑制效果(抑制JAK-STAT路徑之活化)。JAK-STAT路徑之活化導致功能轉錄因子之形成及易位。此外,免疫細胞之流入及角質細胞之增殖增加亦將提供在耳朵中之獨特表現概況變化,可對該表現概況變化進行研究及定量。使用與磷酸化STAT3 (純系58E12,Cell Signaling Technologies)特異性相互作用之抗體對經福馬林固定且經石蠟包埋之耳朵切片(在DTH模型中在攻毒階段之後收穫)進行免疫組織化學分析。用測試化合物、媒介物或***(一種臨床上有效的牛皮癬治療劑)治療小鼠耳朵或在用於比較之DTH模型中不進行任何治療。測試化合物及***可定性地及定量地產生相似之轉錄變化,且測試化合物及***均可減少浸潤細胞之數量。測試化合物之全身及局部投予均可產生抑制效果,即,減少浸潤細胞之數量及抑制轉錄變化。
實例 E : 活體內抗炎活性
可在經設計以複製單一或複雜發炎反應之齧齒動物或非齧齒動物模型中評價本文化合物。例如,關節炎之齧齒動物模型可用於評價預防性或治療性給藥之化合物之治療潛力。此等模型包括但不限於小鼠或大鼠膠原蛋白誘導之關節炎、大鼠佐劑誘導之關節炎及膠原蛋白抗體誘導之關節炎。自體免疫疾病(包括但不限於多發性硬化、第I型糖尿病、葡萄膜視網膜炎、甲狀腺炎、重症肌無力、免疫球蛋白腎病、心肌炎、氣道敏化(氣喘)、狼瘡或結腸炎)亦可用於評價本文化合物之治療潛力。此等模型係在研究團體中為公認的且為熟習此項技術者所熟悉(Current Protocols in Immunology,第3卷,Coligan, J.E.等人,Wiley Press.;
Methods in Molecular Biology:第225卷,Inflammation Protocols.,Winyard, P.G.及Willoughby, D.A.,Humana Press, 2003)。
實例 F : 用於治療乾眼、眼色素層炎及結膜炎之動物模型
可在一或多種熟習此項技術者已知之乾眼之臨床前模型中評價各藥劑,該等模型包括但不限於兔刀豆球蛋白A (ConA)淚腺模型、莨菪鹼小鼠模型(皮下或經皮)、肉毒桿菌小鼠淚腺模型或導致眼部腺體功能障礙之多種自發性齧齒動物自體免疫模型中之任一種(例如NOD-SCID、MRL/lpr或NZB/NZW) (Barabino等人,Experimental Eye Research 2004, 79, 613-621及Schrader等人,Developmental Opthalmology, Karger 2008, 41, 298-312,其各自以全文引用方式併入本文中)。此等模型中之終點可包括眼部腺體及眼睛(角膜等)之組織病理學,且可能包括量測淚液產生量之經典Schirmer測試或其改良版本(Barabino等人)。可藉由經由多個投予途徑(例如全身或局部)給藥來評估活性,此可在可量測之疾病存在之前或之後開始。
可在熟習此項技術者已知之一或多種眼色素層炎臨床前模型中評價各藥劑。此等包括但不限於實驗性自體免疫眼色素層炎(EAU)及內毒素誘導之眼色素層炎(EIU)之模型。EAU實驗可在兔、大鼠或小鼠中進行且可包括被動或主動免疫。例如,可使用多種視網膜抗原中之任一種使動物對相關免疫原致敏,此後可用相同抗原對動物眼部進行攻毒。EIU模型係更急性的且涉及以亞致死劑量局部或全身投予脂多糖。EIU及EAU模型二者之終點可包括眼底檢查、組織病理學等。此等模型由Smith等人綜述(Immunology and Cell Biology 1998, 76, 497-512,其以全文引用方式併入本文中)。藉由經由多個投予途徑(例如全身或局部)給藥來評估活性,此可在可量測之疾病存在之前或之後開始。上文所列示之一些模型亦可開發鞏膜炎/上鞏膜炎、脈絡膜炎、睫狀體炎或虹膜炎,且因此可用於研究化合物對於治療性治療此等疾病之潛在活性。
亦可在熟習此項技術者已知之一或多種結膜炎臨床前模型中評價藥劑。此等模型包括但不限於使用豚鼠、大鼠或小鼠之齧齒動物模型。豚鼠模型包括使用以抗原(諸如卵白蛋白或豬草)進行主動或被動免疫及/或免疫攻毒方案之彼等(在Groneberg, D.A.等人,Allergy 2003, 58, 1101-1113中有所綜述,其以全文引用方式併入本文中)。大鼠及小鼠模型大體上為與豚鼠類似之設計(亦由Groneberg綜述)。可藉由經由多個投予途徑(例如全身或局部)給藥來評估活性,此可在可量測之疾病存在之前或之後開始。該等研究之終點可包括例如眼部組織(諸如結膜)之組織學、免疫學、生物化學或分子分析。
實例 G :骨之活體內保護
可在熟習此項技術者已知之骨量減少、骨質疏鬆症或骨質再吸收之各種臨床前模型中評價化合物。例如,切除卵巢之齧齒動物可用於評價化合物影響骨重塑及/或骨密度之標誌及標記之能力(W.S.S. Jee及W. Yao,J Musculoskel. Nueron. Interact., 2001, 1(3), 193-207,其以全文引用方式併入本文中)。或者,可在療劑(例如糖皮質素)誘導之骨量減少模型中評價對照或經化合物治療之齧齒動物之骨密度及骨結構(Yao等人,Arthritis and Rheumatism, 2008, 58(6), 3485-3497;及同一刊物58(11), 1674-1686,該二者均以全文引用方式併入本文中)。另外,在上文(實例E)所述及之關節炎之齧齒動物模型中,化合物對骨質再吸收及密度之影響可能係可評估的。所有此等模型之終點可變化,但通常包括骨重塑之組織學及放射評估以及免疫組織學及適當生物化學標記。
圖1A-C繪示了接受單次劑量為300 mg IR膠囊(1A:第1-4組,空腹)、SR1、SR2、SR3及SR4錠劑(2B:第1-4組,空腹;及2C:第1-4組,進食高脂肪餐)之健康受試者體內式I化合物之血漿濃度(平均值± SE)。
圖2A-B繪示了單次劑量為300 mg SR3之PK曲線(平均值± SE) (2A:第3組,SR3,空腹相對於高脂肪餐;及2B:第5組,SR3,空腹相對於中等脂肪餐)。
圖3繪示了25 mg與100 mg SR3錠劑間之PK曲線(平均值± SE)之比較(治療A相對於C)及高脂肪餐對25 mg SR3錠劑之食物影響(治療B相對於A)。
圖4繪示了關於持續釋放錠劑相對於安慰劑之數種給藥方案之血紅素自基線之百分比變化。
圖5(a)繪示了劑量組(100 mg BID、200 mg BID及600 mg QD)在第12週總症狀評分(TSS)減少≥ 50%之患者之百分比。
圖5(b)繪示了劑量組(100 mg BID、200 mg BID及600 mg QD)在第12週總症狀評分(TSS)自基線之百分比變化。
圖6(a)繪示了劑量組(100 mg BID、200 mg BID及600 mg QD)隨時間之平均血紅素水準。
圖6(b)繪示了48週時劑量組(100 mg BID、200 mg BID及600 mg QD)隨時間之平均血紅素水準(g/dL)。
圖6(c)繪示了與給予安慰劑或羅克斯替尼(ruxolitinib)之個體相比48週時劑量組隨時間之平均血紅素水準(g/dL) (作為三個劑量組之平均值)。
Claims (25)
- 一種持續釋放組合物的用途,其係製備用於治療選自有需要之患者之自體免疫疾病、癌症、骨髓增殖性病症、炎性疾病、骨質再吸收疾病或器官移植排斥的藥劑,該持續釋放組合物包含:(i){1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈({1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile)或其醫藥學上可接受之鹽;(ii)第一羥丙甲纖維素(hypromellose),其為Methocel K100LV;(iii)第二羥丙甲纖維素,其為Methocel K4M,其中該組合物包含8重量%至20重量%之該第一及第二羥丙甲纖維素;(iv)16重量%至22重量%之微晶纖維素;及(v)45重量%至55重量%之乳糖單水合物。
- 如請求項1之用途,其中該組合物包含10重量%至15重量%之該第一及第二羥丙甲纖維素。
- 如請求項1之用途,其中該組合物包含16重量%至22重量%之微晶纖維素。
- 如請求項1至3中任一項之用途,其中該組合物包含45重量%至55重量%之乳糖單水合物。
- 如請求項1至3中任一項之用途,其中該組合物包含0.3重量%至0.7重量%之硬脂酸鎂。
- 一種持續釋放組合物的用途,其係製備用於治療選自有需要之患者之自體免疫疾病、癌症、骨髓增殖性病症、炎性疾病、骨質再吸收疾病或器官移植排斥的藥劑,該持續釋放組合物包含:(i)以游離鹼計約100mg之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈或其醫藥學上可接受之鹽;(ii)第一種羥丙甲纖維素,其為Methocel K100LV;(iii)第二種羥丙甲纖維素,其為Methocel K4M,其中該組合物包含10重量%至15重量%之該第一及第二羥丙甲纖維素;(iv)16重量%至22重量%之微晶纖維素;及(v)45重量%至55重量%之乳糖單水合物。
- 如請求項1至3及6中任一項之用途,其中向空腹個體經口投予一或多種該持續釋放組合物以提供{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜 環丁烷-3-基}乙腈之平均峰值血漿濃度(Cmax)對平均12-小時血漿濃度(C12h)之比率為9至40。
- 如請求項1至3及6中任一項之用途,其中向空腹個體經口投予一或多種該持續釋放組合物以提供{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之平均峰值血漿濃度(Cmax)對平均12-小時血漿濃度(C12h)之比率為15至30。
- 如請求項1至3及6中任一項之用途,其中向高脂肪餐後之個體經口投予一或多種該持續釋放組合物以提供{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之平均峰值血漿濃度(Cmax)對平均12-小時血漿濃度(C12h)之比率為10至70。
- 如請求項1至3及6中任一項之用途,其中向高脂肪餐後之個體經口投予一或多種該持續釋放組合物以提供{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之平均峰值血漿濃度(Cmax)對平均12-小時血漿濃度(C12h)之比率為15至50。
- 如請求項1至3及6中任一項之用途,其中向高脂肪餐後之個體經口投予一或多種該持續釋放組合物以提供{1-{1-[3-氟-2-(三氟甲基)異 菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之平均峰值血漿濃度(Cmax)對平均12-小時血漿濃度(C12h)之比率為25至45。
- 如請求項1至3及6中任一項之用途,其中向高脂肪餐後之個體經口投予一或多種該持續釋放組合物以提供2小時至5小時之{1-{2-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之平均半衰期(t1/2)。
- 如請求項12之用途,其中向空腹個體經口投予一或多種該持續釋放組合物以提供4.9小時±2.6小時之{1-{2-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之平均半衰期(t1/2)。
- 如請求項1至3及6中任一項之用途,其中向空腹個體經口投予一或多種該持續釋放組合物以提供0.191μM±0.10μM之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之平均峰值血漿濃度(Cmax)。
- 如請求項1至3及6中任一項之用途,其中向空腹個體經口投予一或多種該持續釋放組合物以提供0.5小時至3小時之{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之峰值血漿濃度(Tmax)。
- 如請求項12之用途,其中向空腹個體經口投予一或多種該持續釋放組合物以提供1小時至20小時之{1-{2-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之平均半衰期(t1/2)。
- 如請求項1至3及6中任一項之用途,其中向高脂肪餐後之個體經口投予一或多種該持續釋放組合物以提供1小時至7小時之{1-{2-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之平均半衰期(t1/2)。
- 如請求項1至3及6中任一項之用途,其中該持續釋放組合物為持續釋放錠劑。
- 如請求項1至3及6中任一項之用途,其中該鹽為{1-{1-[3-氟-2-(三氟甲基)異菸鹼醯基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮雜環丁烷-3-基}乙腈之己二酸鹽。
- 如請求項1至3及6中任一項之用途,其中該自體免疫疾病係皮膚病症、多發性硬化、類風濕性關節炎、牛皮癬性關節炎、幼年型關節炎、第I型糖尿病、狼瘡、炎性腸病、克羅恩氏病(Crohn’s disease)、重症肌無力、免疫球蛋白腎病、心肌炎、自體免疫性甲狀腺病症、異位性皮炎、牛皮癬、皮膚敏化、皮膚刺激、皮疹、接觸性皮炎或過敏 性接觸性敏化。
- 如請求項20之用途,其中該自體免疫疾病為類風濕性關節炎。
- 如請求項20之用途,其中該自體免疫疾病為牛皮癬。
- 如請求項1至3及6中任一項之用途,其中該癌症係***癌、腎癌、肝癌、乳癌、肺癌、甲狀腺癌、卡波西氏肉瘤(Kaposi’s sarcoma)、斯特曼氏病(Castleman’s disease)、胰腺癌、淋巴瘤、白血病、多發性骨髓瘤、真性紅血球增多症(PV)、自發性血小板增多症(ET)、髓樣化生伴骨髓纖維變性(MMM)、原發性骨髓纖維變性(PMF)、慢性骨髓性白血病(CML)、慢性骨髓單核球性白血病(CMML)、嗜伊紅性白血球增多症候群(HES)、特發性骨髓纖維變性(IMF)或全身性肥大細胞病(SMCD)。
- 如請求項1至3及6中任一項之用途,其中該骨髓增殖性病症係原發性骨髓纖維變性(PMF)。
- 如請求項1至3及6中任一項之用途,其中該骨質再吸收疾病係骨質疏鬆症、骨關節炎、與激素失衡相關之骨質再吸收、與激素療法相關之骨質再吸收、與自體免疫疾病相關之骨質再吸收或與癌症相關之骨質再吸收。
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Families Citing this family (43)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2700433T3 (es) | 2005-12-13 | 2019-02-15 | Incyte Holdings Corp | Derivados de pirrolo[2,3-d]pirimidina como inhibidores de quinasas Janus |
HUE029236T2 (en) | 2007-06-13 | 2017-02-28 | Incyte Holdings Corp | (R) -3- (4- (7H-Pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl) -3-cyclopentylpropanenitrile Crystalline salts of Janus kinase inhibitor |
WO2010135621A1 (en) | 2009-05-22 | 2010-11-25 | Incyte Corporation | 3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-1h-pyrazol-1-yl]octane- or heptane-nitrile as jak inhibitors |
WO2010135650A1 (en) | 2009-05-22 | 2010-11-25 | Incyte Corporation | N-(HETERO)ARYL-PYRROLIDINE DERIVATIVES OF PYRAZOL-4-YL-PYRROLO[2,3-d]PYRIMIDINES AND PYRROL-3-YL-PYRROLO[2,3-d]PYRIMIDINES AS JANUS KINASE INHIBITORS |
ES2662588T3 (es) | 2010-03-10 | 2018-04-09 | Incyte Holdings Corporation | Derivados de piperidin-4-IL azetidina como inhibidores de JAK1 |
CN103002875B (zh) | 2010-05-21 | 2016-05-04 | 因塞特控股公司 | Jak抑制剂的局部用制剂 |
AU2011329734B2 (en) | 2010-11-19 | 2015-05-28 | Incyte Holdings Corporation | Cyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as JAK inhibitors |
MY165963A (en) | 2011-06-20 | 2018-05-18 | Incyte Holdings Corp | Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as jak inhibitors |
UA111854C2 (uk) | 2011-09-07 | 2016-06-24 | Інсайт Холдінгс Корпорейшн | Способи і проміжні сполуки для отримання інгібіторів jak |
WO2014071031A1 (en) | 2012-11-01 | 2014-05-08 | Incyte Corporation | Tricyclic fused thiophene derivatives as jak inhibitors |
EA201590930A1 (ru) | 2012-11-15 | 2015-08-31 | Инсайт Корпорейшн | Лекарственные формы руксолитиниба с замедленным высвобождением |
WO2014110574A1 (en) | 2013-01-14 | 2014-07-17 | Incyte Corporation | Bicyclic aromatic carboxamide compounds useful as pim kinase inhibitors |
EA035929B1 (ru) | 2013-01-15 | 2020-09-02 | Инсайт Холдингс Корпорейшн | ТИАЗОЛКАРБОКСАМИДЫ И ПИРИДИНКАРБОКСАМИДЫ, ИСПОЛЬЗУЕМЫЕ В КАЧЕСТВЕ ИНГИБИТОРОВ Pim-КИНАЗЫ |
CN105189509B (zh) | 2013-03-06 | 2017-12-19 | 因赛特公司 | 用于制备jak抑制剂的方法及中间体 |
HUE063817T2 (hu) | 2013-05-17 | 2024-01-28 | Incyte Holdings Corp | Bipirazol-származékok mint JAK inhibitorok |
SI3030227T1 (sl) | 2013-08-07 | 2020-08-31 | Incyte Corporation | Dozirne oblike s podaljšanim sproščanjem za inhibitor JAK1 |
SG11201601259YA (en) | 2013-08-23 | 2016-03-30 | Incyte Corp | Furo- and thieno-pyridine carboxamide compounds useful as pim kinase inhibitors |
EA201692011A1 (ru) | 2014-04-08 | 2017-01-30 | Инсайт Корпорейшн | Лечение b-клеточных злокачественных новообразований с применением комбинации ингибиторов jak и pi3k |
KR20170007331A (ko) | 2014-04-30 | 2017-01-18 | 인사이트 코포레이션 | Jak1 억제제의 제조 방법 및 이에 대한 신규한 형태 |
WO2015184305A1 (en) | 2014-05-30 | 2015-12-03 | Incyte Corporation | TREATMENT OF CHRONIC NEUTROPHILIC LEUKEMIA (CNL) AND ATYPICAL CHRONIC MYELOID LEUKEMIA (aCML) BY INHIBITORS OF JAK1 |
WO2016010897A1 (en) | 2014-07-14 | 2016-01-21 | Incyte Corporation | Bicyclic heteroaromatic carboxamide compounds useful as pim kinase inhibitors |
US9580418B2 (en) | 2014-07-14 | 2017-02-28 | Incyte Corporation | Bicyclic aromatic carboxamide compounds useful as Pim kinase inhibitors |
AR101476A1 (es) | 2014-08-07 | 2016-12-21 | Acerta Pharma Bv | Métodos para tratar cánceres, enfermedades inmunes y autoinmunes, y enfermedades inflamatorias en base a la tasa de ocupación de la tirosin quinasa de bruton (btk) y a la tasa de resíntesis de la tirosin quinasa de bruton (btk) |
US9540347B2 (en) | 2015-05-29 | 2017-01-10 | Incyte Corporation | Pyridineamine compounds useful as Pim kinase inhibitors |
TWI734699B (zh) | 2015-09-09 | 2021-08-01 | 美商英塞特公司 | Pim激酶抑制劑之鹽 |
TW201718546A (zh) | 2015-10-02 | 2017-06-01 | 英塞特公司 | 適用作pim激酶抑制劑之雜環化合物 |
KR101836822B1 (ko) * | 2016-10-17 | 2018-03-09 | 주식회사 엔지켐생명과학 | 모노아세틸디아실글리세롤 화합물을 함유하는 건선의 예방 또는 치료용 조성물 |
TW201924683A (zh) | 2017-12-08 | 2019-07-01 | 美商英塞特公司 | 用於治療骨髓增生性贅瘤的低劑量組合療法 |
MX2020007973A (es) | 2018-01-30 | 2020-12-07 | Incyte Corp | Procesos para preparar (1-(3-fluoro-2-(trifluorometil)isonicotinil )piperidin-4-ona). |
BR122023022189A2 (pt) | 2018-02-16 | 2024-02-20 | Incyte Corporation | Usos de inibidores da via de jak1 para o tratamento de distúrbios relacionados a citocinas |
CN113768934A (zh) | 2018-03-30 | 2021-12-10 | 因赛特公司 | 使用jak抑制剂治疗化脓性汗腺炎 |
WO2019191679A1 (en) | 2018-03-30 | 2019-10-03 | Incyte Corporation | Biomarkers for inflammatory skin disease |
AU2019252259A1 (en) | 2018-04-13 | 2020-12-03 | Incyte Corporation | Biomarkers for graft-versus-host disease |
EP3873433A1 (en) | 2018-10-31 | 2021-09-08 | Incyte Corporation | Combination therapy for treatment of hematological diseases |
MA54544A (fr) | 2018-12-19 | 2021-10-27 | Incyte Corp | Inhibiteurs de la voie jak1 pour le traitement d'une maladie gastro-intestinale |
KR20210137087A (ko) * | 2019-03-05 | 2021-11-17 | 인사이트 코포레이션 | 만성 폐 동종이식 기능장애의 치료를 위한 jak1 경로 억제제 |
KR20220079550A (ko) | 2019-09-05 | 2022-06-13 | 인사이트 코포레이션 | 아토피성 피부염의 가려움증 감소를 위한 룩솔리티닙 제형 |
IL298118A (en) | 2020-06-02 | 2023-01-01 | Incyte Corp | Processes for making jak1 inhibitor |
US11833155B2 (en) | 2020-06-03 | 2023-12-05 | Incyte Corporation | Combination therapy for treatment of myeloproliferative neoplasms |
CA3192055A1 (en) | 2020-08-18 | 2022-02-24 | Incyte Corporation | Process and intermediates for preparing a jak1 inhibitor |
CA3192099A1 (en) | 2020-08-18 | 2022-02-24 | Incyte Corporation | Process and intermediates for preparing a jak inhibitor |
CA3204374A1 (en) | 2020-12-08 | 2022-06-16 | Incyte Corporation | Jak1 pathway inhibitors for the treatment of vitiligo |
JP2024503021A (ja) | 2021-01-11 | 2024-01-24 | インサイト・コーポレイション | Jak経路阻害剤及びrock阻害剤を含む併用療法 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011112662A1 (en) * | 2010-03-10 | 2011-09-15 | Incyte Corporation | Piperidin-4-yl azetidine derivatives as jak1 inhibitors |
Family Cites Families (305)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2985589A (en) | 1957-05-22 | 1961-05-23 | Universal Oil Prod Co | Continuous sorption process employing fixed bed of sorbent and moving inlets and outlets |
US3632836A (en) | 1968-10-25 | 1972-01-04 | Dow Chemical Co | Solid curable polyepoxides modified with hydrolyzed liquid polyepoxides |
US3832460A (en) | 1971-03-19 | 1974-08-27 | C Kosti | Anesthetic-vasoconstrictor-antihistamine composition for the treatment of hypertrophied oral tissue |
US4140755A (en) | 1976-02-13 | 1979-02-20 | Hoffmann-La Roche Inc. | Sustained release tablet formulations |
DE3036390A1 (de) | 1980-09-26 | 1982-05-13 | Troponwerke GmbH & Co KG, 5000 Köln | Neue pyrrolo-pyrimidine, verfahren zu ihrer herstellung und ihre verwendung bei der herstellung von biologischen wirkstoffen |
DE3220113A1 (de) | 1982-05-28 | 1983-12-01 | Basf Ag, 6700 Ludwigshafen | Difluormethoxiphenylthiophosphorsaeureester |
US4402832A (en) | 1982-08-12 | 1983-09-06 | Uop Inc. | High efficiency continuous separation process |
US4404335A (en) | 1982-08-16 | 1983-09-13 | The Dow Chemical Company | Hydrolyzing epoxy resins in absence of solvent and in presence of oxalic acid and a phosphonium compound |
US4548990A (en) | 1983-08-15 | 1985-10-22 | Ciba-Geigy Corporation | Crosslinked, porous polymers for controlled drug delivery |
US4498991A (en) | 1984-06-18 | 1985-02-12 | Uop Inc. | Serial flow continuous separation process |
NL8403224A (nl) | 1984-10-24 | 1986-05-16 | Oce Andeno Bv | Dioxafosforinanen, de bereiding ervan en de toepassing voor het splitsen van optisch actieve verbindingen. |
CA1306260C (en) | 1985-10-18 | 1992-08-11 | Shionogi & Co., Ltd. | Condensed imidazopyridine derivatives |
WO1991005784A1 (fr) | 1989-10-11 | 1991-05-02 | Teijin Limited | Derive de pyrimidine bicyclique, procede de production et preparation pharmaceutique le contenant en tant qu'ingredient actif |
US5403593A (en) | 1991-03-04 | 1995-04-04 | Sandoz Ltd. | Melt granulated compositions for preparing sustained release dosage forms |
IT1258781B (it) | 1992-01-16 | 1996-02-29 | Zambon Spa | Composizione farmaceutica oftalmica contenente n-acetilcisteina e polivinilalcol |
US5521184A (en) | 1992-04-03 | 1996-05-28 | Ciba-Geigy Corporation | Pyrimidine derivatives and processes for the preparation thereof |
FR2695126B1 (fr) | 1992-08-27 | 1994-11-10 | Sanofi Elf | Dérivés d'acide thiényl ou pyrrolyl carboxyliques, leur préparation et médicaments les contenant. |
AU671491B2 (en) | 1992-12-18 | 1996-08-29 | F. Hoffmann-La Roche Ag | N-oxycarbonyl substituted 5'-deoxy-5-fluorcytidines |
JPH0710876A (ja) | 1993-06-24 | 1995-01-13 | Teijin Ltd | 4位に環状アミノ基を有するピロロ[2,3―d]ピリミジン |
USH1439H (en) | 1993-10-18 | 1995-05-02 | The Dow Chemical Company | Method to increase the level of α-glycol in liquid epoxy resin |
EP0727217A3 (en) | 1995-02-10 | 1997-01-15 | Suntory Ltd | Pharmaceutical and cosmetic compositions containing God-type ellagitannin as an active ingredient |
IL117580A0 (en) | 1995-03-29 | 1996-07-23 | Merck & Co Inc | Inhibitors of farnesyl-protein transferase and pharmaceutical compositions containing them |
US5856326A (en) | 1995-03-29 | 1999-01-05 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
KR19990028709A (ko) | 1995-07-05 | 1999-04-15 | 미리암 디. 메코너헤이 | 살진균 피리미디논 |
BR9609617B1 (pt) | 1995-07-06 | 2010-07-27 | derivados de 7h-pirrol[2,3-d]pirimidina, e composição farmacêutica. | |
US5630943A (en) | 1995-11-30 | 1997-05-20 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Discontinuous countercurrent chromatographic process and apparatus |
GB9604361D0 (en) | 1996-02-29 | 1996-05-01 | Pharmacia Spa | 4-Substituted pyrrolopyrimidine compounds as tyrosine kinase inhibitors |
WO1997036587A1 (en) | 1996-04-03 | 1997-10-09 | Merck & Co., Inc. | A method of treating cancer |
CA2251955A1 (en) | 1996-04-18 | 1997-10-23 | Nancy E. Kohl | A method of treating cancer |
US5795909A (en) | 1996-05-22 | 1998-08-18 | Neuromedica, Inc. | DHA-pharmaceutical agent conjugates of taxanes |
EP0934270A1 (en) | 1996-05-30 | 1999-08-11 | Merck & Co., Inc. | A method of treating cancer |
US6624138B1 (en) | 2001-09-27 | 2003-09-23 | Gp Medical | Drug-loaded biological material chemically treated with genipin |
WO1998044797A1 (en) | 1997-04-07 | 1998-10-15 | Merck & Co., Inc. | A method of treating cancer |
US6063284A (en) | 1997-05-15 | 2000-05-16 | Em Industries, Inc. | Single column closed-loop recycling with periodic intra-profile injection |
US6060038A (en) | 1997-05-15 | 2000-05-09 | Merck & Co., Inc. | Radiolabeled farnesyl-protein transferase inhibitors |
US5919779A (en) | 1997-08-11 | 1999-07-06 | Boehringer Ingelheim Pharmaceuticals, Inc. | 5,6-Heteroaryl-dipyrido(2,3-B:3', 2'-F) azepines and their use in the prevention or treatment of HIV infection |
US7153845B2 (en) | 1998-08-25 | 2006-12-26 | Columbia Laboratories, Inc. | Bioadhesive progressive hydration tablets |
US6075056A (en) | 1997-10-03 | 2000-06-13 | Penederm, Inc. | Antifungal/steroid topical compositions |
US6025366A (en) | 1998-04-02 | 2000-02-15 | Merck & Co., Inc. | Antagonists of gonadotropin releasing hormone |
US6232320B1 (en) | 1998-06-04 | 2001-05-15 | Abbott Laboratories | Cell adhesion-inhibiting antiinflammatory compounds |
WO1999062908A2 (en) | 1998-06-04 | 1999-12-09 | Abbott Laboratories | Cell adhesion-inhibiting antinflammatory compounds |
RS50087B (sr) | 1998-06-19 | 2009-01-22 | Pfizer Products Inc., | Pirolo (2,3-d) pirimidin jedinjenja |
PA8474101A1 (es) | 1998-06-19 | 2000-09-29 | Pfizer Prod Inc | Compuestos de pirrolo [2,3-d] pirimidina |
ES2342240T3 (es) | 1998-08-11 | 2010-07-02 | Novartis Ag | Derivados de isoquinolina con actividad que inhibe la angiogenia. |
JP2000119271A (ja) | 1998-08-12 | 2000-04-25 | Hokuriku Seiyaku Co Ltd | 1h―イミダゾピリジン誘導体 |
EA004032B1 (ru) | 1998-09-10 | 2003-12-25 | Нюкомед Данмарк А/С | Фармацевтические композиции лекарственных веществ с быстрым высвобождением |
US6375839B1 (en) | 1998-10-29 | 2002-04-23 | Institut Francais Du Petrole | Process and device for separation with variable-length chromatographic zones |
FR2785196B1 (fr) | 1998-10-29 | 2000-12-15 | Inst Francais Du Petrole | Procede et dispositif de separation avec des zones chromatographiques a longueur variable |
US6413419B1 (en) | 1998-10-29 | 2002-07-02 | Institut Francais Du Petrole | Process and device for separation with variable-length chromatographic |
US6133031A (en) | 1999-08-19 | 2000-10-17 | Isis Pharmaceuticals Inc. | Antisense inhibition of focal adhesion kinase expression |
WO2000051614A1 (en) | 1999-03-03 | 2000-09-08 | Merck & Co., Inc. | Inhibitors of prenyl-protein transferases |
GB9905075D0 (en) | 1999-03-06 | 1999-04-28 | Zeneca Ltd | Chemical compounds |
US6217895B1 (en) | 1999-03-22 | 2001-04-17 | Control Delivery Systems | Method for treating and/or preventing retinal diseases with sustained release corticosteroids |
US6239113B1 (en) | 1999-03-31 | 2001-05-29 | Insite Vision, Incorporated | Topical treatment or prevention of ocular infections |
AU3565999A (en) | 1999-04-16 | 2000-11-02 | Coelacanth Chemical Corporation | Synthesis of azetidine derivatives |
US6921763B2 (en) | 1999-09-17 | 2005-07-26 | Abbott Laboratories | Pyrazolopyrimidines as therapeutic agents |
DE60013464T2 (de) | 1999-10-13 | 2005-09-15 | Banyu Pharmaceutical Co., Ltd. | Substituierte imidazolin-derivate |
US7235258B1 (en) | 1999-10-19 | 2007-06-26 | Nps Pharmaceuticals, Inc. | Sustained-release formulations for treating CNS-mediated disorders |
PT1382339E (pt) | 1999-12-10 | 2008-02-06 | Pfizer Prod Inc | Composições que contêm derivados de pirrolo[2,3-d]- pirimidina |
MXPA02006338A (es) | 1999-12-24 | 2002-12-13 | Aventis Pharma Ltd | Azaindoles. |
GB0004890D0 (en) | 2000-03-01 | 2000-04-19 | Astrazeneca Uk Ltd | Chemical compounds |
US7235551B2 (en) | 2000-03-02 | 2007-06-26 | Smithkline Beecham Corporation | 1,5-disubstituted-3,4-dihydro-1h-pyrimido[4,5-d]pyrimidin-2-one compounds and their use in treating csbp/p38 kinase mediated diseases |
DE60100866T2 (de) | 2000-04-07 | 2004-07-29 | Laboratoire Medidom S.A. | Cyklosporin, Hyaluronsäure und Polysorbate enthaltenes Augenarzneimittel |
WO2001081345A1 (fr) | 2000-04-20 | 2001-11-01 | Mitsubishi Pharma Corporation | Composes d'amides aromatiques |
ES2788383T3 (es) | 2000-04-25 | 2020-10-21 | Icos Corp | Inhibidores de delta fosfatidilo-inositol 3-quinasa humana |
IL153115A0 (en) | 2000-06-16 | 2003-06-24 | Curis Inc | Angiogenesis-modulating compositions and uses |
US7498304B2 (en) | 2000-06-16 | 2009-03-03 | Curis, Inc. | Angiogenesis-modulating compositions and uses |
US6335342B1 (en) | 2000-06-19 | 2002-01-01 | Pharmacia & Upjohn S.P.A. | Azaindole derivatives, process for their preparation, and their use as antitumor agents |
EP1295607B9 (en) | 2000-06-23 | 2011-10-05 | Mitsubishi Tanabe Pharma Corporation | Antitumor effect potentiators |
OA12292A (en) | 2000-06-26 | 2003-11-11 | Pfizer Prod Inc | PyrroloÄ2,3-dÜpyrimidine compounds as immunosuppressive agents. |
SI1294358T1 (en) | 2000-06-28 | 2004-12-31 | Smithkline Beecham Plc | Wet milling process |
AU2001278790A1 (en) | 2000-08-22 | 2002-03-04 | Hokuriku Seiyaku Co. Ltd | 1h-imidazopyridine derivatives |
CA2430539C (en) | 2000-12-05 | 2010-07-13 | Vertex Pharmaceuticals Incorporated | Inhibitors of c-jun n-terminal kinases (jnk) and other protein kinases |
GB0100622D0 (en) | 2001-01-10 | 2001-02-21 | Vernalis Res Ltd | Chemical compounds V111 |
JP2004520347A (ja) | 2001-01-15 | 2004-07-08 | グラクソ グループ リミテッド | Ldl−受容体発現のインデューサーとしてのアリールピペリジンおよびピペラジン誘導体 |
CA2436487A1 (en) | 2001-01-30 | 2002-08-08 | Cytopia Pty Ltd. | Methods of inhibiting kinases |
JP4316893B2 (ja) | 2001-05-16 | 2009-08-19 | バーテックス ファーマシューティカルズ インコーポレイテッド | Srcおよび他のプロテインキナーゼのインヒビター |
US7301023B2 (en) | 2001-05-31 | 2007-11-27 | Pfizer Inc. | Chiral salt resolution |
GB0115109D0 (en) | 2001-06-21 | 2001-08-15 | Aventis Pharma Ltd | Chemical compounds |
GB0115393D0 (en) | 2001-06-23 | 2001-08-15 | Aventis Pharma Ltd | Chemical compounds |
AU2002355732B2 (en) | 2001-08-01 | 2006-11-09 | Merck Sharp & Dohme Corp. | Benzimidazo[4,5-f]isoquinolinone derivatives |
HUP0401982A3 (en) | 2001-09-19 | 2012-09-28 | Aventis Pharma Sa | Indolizine derivates, process for their preparation and pharmaceutical compositions containing the compounds |
US6429231B1 (en) | 2001-09-24 | 2002-08-06 | Bradley Pharmaceuticals, Inc. | Compositions containing antimicrobials and urea for the treatment of dermatological disorders and methods for their use |
PT1441737E (pt) | 2001-10-30 | 2006-12-29 | Dana Farber Cancer Inst Inc | Derivados de estrutura como inibidores da actividade do receptor de tirosina cinase flt3 |
JP2003155285A (ja) | 2001-11-19 | 2003-05-27 | Toray Ind Inc | 環状含窒素誘導体 |
KR20040058340A (ko) | 2001-11-30 | 2004-07-03 | 데이진 가부시키가이샤 | 5-(3-시아노페닐)-3-포르밀벤조산 화합물의 제조 방법 |
GT200200234A (es) | 2001-12-06 | 2003-06-27 | Compuestos cristalinos novedosos | |
US6995144B2 (en) | 2002-03-14 | 2006-02-07 | Eisai Co., Ltd. | Nitrogen containing heterocyclic compounds and medicines containing the same |
EA007156B1 (ru) | 2002-04-15 | 2006-08-25 | Адамс Лэборетриз, Инк. | Замедленно высвобождающие лекарственные композиции гвайфенезина |
TW200403058A (en) | 2002-04-19 | 2004-03-01 | Bristol Myers Squibb Co | Heterocyclo inhibitors of potassium channel function |
EP1506189A1 (en) | 2002-04-26 | 2005-02-16 | Vertex Pharmaceuticals Incorporated | Pyrrole derivatives as inhibitors of erk2 and uses thereof |
JP2005530745A (ja) | 2002-05-02 | 2005-10-13 | メルク エンド カムパニー インコーポレーテッド | チロシンキナーゼ阻害剤 |
MXPA04011004A (es) | 2002-05-07 | 2005-01-25 | Control Delivery Sys Inc | Procesos para formar un dispositivo de administracion de farmaco. |
DE60317198T2 (de) | 2002-05-23 | 2008-12-04 | Cytopia Research Pty. Ltd., Richmond | Proteinkinaseinhibitoren |
TW200406374A (en) | 2002-05-29 | 2004-05-01 | Novartis Ag | Diaryl urea derivatives useful for the treatment of protein kinase dependent diseases |
CA2490340A1 (en) | 2002-06-26 | 2004-01-08 | Idemitsu Kosan Co., Ltd. | Hydrogenated copolymer, production process for the same and hot melt adhesive composition using the same |
GB0215676D0 (en) | 2002-07-05 | 2002-08-14 | Novartis Ag | Organic compounds |
GB0215844D0 (en) | 2002-07-09 | 2002-08-14 | Novartis Ag | Organic compounds |
WO2004007472A1 (ja) | 2002-07-10 | 2004-01-22 | Ono Pharmaceutical Co., Ltd. | Ccr4アンタゴニストおよびその医薬用途 |
KR20050057175A (ko) | 2002-09-20 | 2005-06-16 | 알콘, 인코퍼레이티드 | 안구건조증 치료용 사이토카인 합성 저해제의 용도 |
US20040204404A1 (en) | 2002-09-30 | 2004-10-14 | Robert Zelle | Human N-type calcium channel blockers |
JP4688498B2 (ja) | 2002-11-04 | 2011-05-25 | バーテックス ファーマシューティカルズ インコーポレイテッド | Jakインヒビターとしてのヘテロアリール−ピリミジン誘導体 |
US8034831B2 (en) | 2002-11-06 | 2011-10-11 | Celgene Corporation | Methods for the treatment and management of myeloproliferative diseases using 4-(amino)-2-(2,6-Dioxo(3-piperidyl)-isoindoline-1,3-dione in combination with other therapies |
CL2003002353A1 (es) | 2002-11-15 | 2005-02-04 | Vertex Pharma | Compuestos derivados de diaminotriazoles, inhibidores d ela proteina quinasa; composicion farmaceutica; procedimiento de preparacion; y su uso del compuesto en el tratamiento de enfermedades de desordenes alergicos, proliferacion, autoinmunes, condic |
US20040099204A1 (en) | 2002-11-25 | 2004-05-27 | Nestor John J. | Sheet, page, line, position marker |
KR20050086784A (ko) | 2002-11-26 | 2005-08-30 | 화이자 프로덕츠 인크. | 이식 거부반응의 치료 방법 |
UA80767C2 (en) | 2002-12-20 | 2007-10-25 | Pfizer Prod Inc | Pyrimidine derivatives for the treatment of abnormal cell growth |
TWI335819B (en) | 2002-12-24 | 2011-01-11 | Alcon Inc | Use of oculosurface selective glucocorticoid in the treatment of dry eye |
US7135493B2 (en) | 2003-01-13 | 2006-11-14 | Astellas Pharma Inc. | HDAC inhibitor |
US7444183B2 (en) | 2003-02-03 | 2008-10-28 | Enteromedics, Inc. | Intraluminal electrode apparatus and method |
CA2515132C (en) | 2003-02-07 | 2012-01-03 | Vertex Pharmaceuticals Incorporated | Heteroaryl substituted pyrroles useful as inhibitors of protein kinases |
GB0305929D0 (en) | 2003-03-14 | 2003-04-23 | Novartis Ag | Organic compounds |
EP1615906A1 (en) | 2003-04-03 | 2006-01-18 | Vertex Pharmaceuticals Incorporated | Compositions useful as inhibitors of protein kinases |
SE0301372D0 (sv) | 2003-05-09 | 2003-05-09 | Astrazeneca Ab | Novel compounds |
SE0301373D0 (sv) | 2003-05-09 | 2003-05-09 | Astrazeneca Ab | Novel compounds |
FR2857454B1 (fr) | 2003-07-08 | 2006-08-11 | Aventis Pasteur | Dosage des acides techoiques des bacteries gram+ |
US20050043346A1 (en) | 2003-08-08 | 2005-02-24 | Pharmacia Italia S.P.A. | Pyridylpyrrole derivatives active as kinase inhibitors |
AU2004268621C1 (en) | 2003-08-29 | 2011-08-18 | Exelixis, Inc. | c-Kit modulators and methods of use |
EP1678147B1 (en) | 2003-09-15 | 2012-08-08 | Lead Discovery Center GmbH | Pharmaceutically active 4,6-disubstituted aminopyrimidine derivatives as modulators of protein kinases |
PE20050952A1 (es) | 2003-09-24 | 2005-12-19 | Novartis Ag | Derivados de isoquinolina como inhibidores de b-raf |
KR101154175B1 (ko) | 2003-10-24 | 2012-06-14 | 산텐 세이야꾸 가부시키가이샤 | 각결막 장해 치료제 |
US7387793B2 (en) | 2003-11-14 | 2008-06-17 | Eurand, Inc. | Modified release dosage forms of skeletal muscle relaxants |
MY141220A (en) | 2003-11-17 | 2010-03-31 | Astrazeneca Ab | Pyrazole derivatives as inhibitors of receptor tyrosine kinases |
JP2007512316A (ja) | 2003-11-25 | 2007-05-17 | ファイザー・プロダクツ・インク | アテローム性動脈硬化症の治療方法 |
BRPI0417803A (pt) | 2003-12-17 | 2007-04-10 | Pfizer Prod Inc | método de tratamento de rejeição de transplantes |
CN1918138B (zh) | 2003-12-19 | 2011-05-04 | 先灵公司 | 作为cxc-和cc-趋化因子受体配体的噻二唑化合物 |
PL1696920T3 (pl) | 2003-12-19 | 2015-03-31 | Plexxikon Inc | Związki i sposoby opracowywania modulatorów Ret |
US8247576B2 (en) | 2003-12-23 | 2012-08-21 | Astex Therapeutics Limited | Pyrazole derivatives as protein kinase modulators |
US20050239806A1 (en) | 2004-01-13 | 2005-10-27 | Ambit Biosciences Corporation | Pyrrolopyrimidine derivatives and analogs and their use in the treatment and prevention of diseases |
WO2005089502A2 (en) | 2004-03-18 | 2005-09-29 | The Brigham And Women's Hospital, Inc. | Methods for the treatment of synucleinopathies |
MXPA06011327A (es) | 2004-03-30 | 2006-12-15 | Vertex Pharma | Azaindoles utiles como inhibidores de jak y otras proteinas cinasas. |
CA2563699C (en) | 2004-04-23 | 2014-03-25 | Exelixis, Inc. | Kinase modulators and method of use |
US7558717B2 (en) | 2004-04-28 | 2009-07-07 | Vertex Pharmaceuticals Incorporated | Crystal structure of human JAK3 kinase domain complex and binding pockets thereof |
US20060106020A1 (en) | 2004-04-28 | 2006-05-18 | Rodgers James D | Tetracyclic inhibitors of Janus kinases |
EP1755680A1 (en) | 2004-05-03 | 2007-02-28 | Novartis AG | Combinations comprising a s1p receptor agonist and a jak3 kinase inhibitor |
MXPA06013250A (es) | 2004-05-14 | 2007-02-28 | Abbott Lab | Inhibidores de quinasa como agentes terapeuticos. |
PE20060426A1 (es) | 2004-06-02 | 2006-06-28 | Schering Corp | DERIVADOS DE ACIDO TARTARICO COMO INHIBIDORES DE MMPs, ADAMs, TACE Y TNF-alfa |
US7745437B2 (en) | 2004-06-10 | 2010-06-29 | Irm Llc | Compounds and compositions as protein kinase inhibitors |
EP1760071A4 (en) | 2004-06-23 | 2008-03-05 | Ono Pharmaceutical Co | COMPOUND WITH S1P RECEPTOR BINDING ABILITY AND USE THEREOF |
CA2572058A1 (en) | 2004-06-30 | 2006-01-12 | Vertex Pharmaceuticals Incorporated | Azaindoles useful as inhibitors of protein kinases |
US7138423B2 (en) | 2004-07-20 | 2006-11-21 | Bristol-Myers Squibb Company | Arylpyrrolidine derivatives as NK-1 /SSRI antagonists |
FR2873691B1 (fr) | 2004-07-29 | 2006-10-06 | Sanofi Synthelabo | Derives d'amino-piperidine, leur preparation et leur application en therapeutique |
WO2006013114A1 (en) | 2004-08-06 | 2006-02-09 | Develogen Aktiengesellschaft | Use of a timp-2 secreted protein product for preventing and treating pancreatic diseases and/or obesity and/or metabolic syndrome |
WO2006022459A1 (en) | 2004-08-23 | 2006-03-02 | Mogam Biotechnology Institute | Primer and probe for detection of sars coronavirus, kit comprising the primer and/or the probe, and detection method thereof |
US20070054916A1 (en) | 2004-10-01 | 2007-03-08 | Amgen Inc. | Aryl nitrogen-containing bicyclic compounds and methods of use |
CN101039946B (zh) | 2004-10-13 | 2010-12-08 | 霍夫曼-拉罗奇有限公司 | 用作用于cdk2和血管生成的抑制剂及用于治疗乳腺、结肠、肺和***癌的二取代吡唑并苯并二氮杂*类 |
UY29177A1 (es) | 2004-10-25 | 2006-05-31 | Astex Therapeutics Ltd | Derivados sustituidos de purina, purinona y deazapurina, composiciones que los contienen métodos para su preparación y sus usos |
MY179032A (en) | 2004-10-25 | 2020-10-26 | Cancer Research Tech Ltd | Ortho-condensed pyridine and pyrimidine derivatives (e.g.purines) as protein kinase inhibitors |
AU2005304784B2 (en) | 2004-11-04 | 2011-03-24 | Vertex Pharmaceuticals Incorporated | Pyrazolo[1,5-a]pyrimidines useful as inhibitors of protein kinases |
CA2586605A1 (en) | 2004-11-24 | 2006-06-01 | Novartis Ag | Combinations of jak inhibitors and at least one of bcr-abl, flt-3, fak or raf kinase inhibitors |
US7517870B2 (en) | 2004-12-03 | 2009-04-14 | Fondazione Telethon | Use of compounds that interfere with the hedgehog signaling pathway for the manufacture of a medicament for preventing, inhibiting, and/or reversing ocular diseases related with ocular neovascularization |
US20060128803A1 (en) | 2004-12-14 | 2006-06-15 | Alcon, Inc. | Method of treating dry eye disorders using 13(S)-HODE and its analogs |
WO2006067445A2 (en) | 2004-12-22 | 2006-06-29 | Astrazeneca Ab | Csf-1r kinase inhibitors |
AR054416A1 (es) | 2004-12-22 | 2007-06-27 | Incyte Corp | Pirrolo [2,3-b]piridin-4-il-aminas y pirrolo [2,3-b]pirimidin-4-il-aminas como inhibidores de las quinasas janus. composiciones farmaceuticas. |
JP2008528477A (ja) | 2005-01-20 | 2008-07-31 | ファイザー・リミテッド | 化合物 |
WO2006096270A1 (en) | 2005-02-03 | 2006-09-14 | Vertex Pharmaceuticals Incorporated | Pyrrolopyrimidines useful as inhibitors of protein kinase |
US7683171B2 (en) | 2005-02-04 | 2010-03-23 | Bristol-Myers Squibb Company | 1H-imidazo[4,5-d]thieno[3,2-b]pyridine based tricyclic compounds and pharmaceutical compositions comprising same |
WO2006101783A2 (en) | 2005-03-15 | 2006-09-28 | Irm Llc | Compounds and compositions as protein kinase inhibitors |
BRPI0610514A2 (pt) | 2005-04-05 | 2016-11-16 | Pharmacopeia Inc | composto, composição farmacêutica, e, método de tratamento de um distúrbio |
GB0510139D0 (en) | 2005-05-18 | 2005-06-22 | Addex Pharmaceuticals Sa | Novel compounds B1 |
RU2435769C2 (ru) | 2005-05-20 | 2011-12-10 | Вертекс Фармасьютикалз Инкорпорейтед | Пирролопиридины, полезные в качестве ингибиторов протеинкиназы |
GB0510390D0 (en) | 2005-05-20 | 2005-06-29 | Novartis Ag | Organic compounds |
NZ563454A (en) | 2005-06-08 | 2011-03-31 | Rigel Pharmaceuticals Inc | 2,4-diaminopyrimidine derivatives for inhibition of the JAK pathway |
WO2006136823A1 (en) | 2005-06-21 | 2006-12-28 | Astex Therapeutics Limited | Heterocyclic containing amines as kinase b inhibitors |
DK1893612T3 (da) | 2005-06-22 | 2011-11-21 | Plexxikon Inc | Pyrrol [2,3-B]pyridin-derivater som proteinkinasehæmmere |
CN102127078A (zh) | 2005-07-14 | 2011-07-20 | 安斯泰来制药株式会社 | Janus激酶3的杂环类抑制剂 |
FR2889662B1 (fr) | 2005-08-11 | 2011-01-14 | Galderma Res & Dev | Emulsion de type huile-dans-eau pour application topique en dermatologie |
US20070049591A1 (en) | 2005-08-25 | 2007-03-01 | Kalypsys, Inc. | Inhibitors of MAPK/Erk Kinase |
US20070149506A1 (en) | 2005-09-22 | 2007-06-28 | Arvanitis Argyrios G | Azepine inhibitors of Janus kinases |
RU2008117151A (ru) | 2005-09-30 | 2009-11-10 | Вертекс Фармасьютикалз Инкорпорейтед (Us) | Деазапурины, пригодные в качестве ингибиторов янус-киназ |
US20070128633A1 (en) | 2005-10-11 | 2007-06-07 | Chembridge Research Laboratories, Inc. | Cell-free protein expression systems and methods of use thereof |
AU2006300182B2 (en) | 2005-10-14 | 2012-01-19 | Sumitomo Chemical Company, Limited | Hydrazide compound and pesticidal use of the same |
US20080287475A1 (en) | 2005-10-28 | 2008-11-20 | Astrazeneca Ab | 4-(3-Aminopyrazole) Pyrimidine Derivatives for Use as Tyrosine Kinase Inhibitors in the Treatment of Cancer |
MY167260A (en) | 2005-11-01 | 2018-08-14 | Targegen Inc | Bi-aryl meta-pyrimidine inhibitors of kinases |
WO2007062459A1 (en) | 2005-11-29 | 2007-06-07 | Cytopia Research Pty Ltd | Selective kinase inhibitors based on pyridine scaffold |
ES2700433T3 (es) | 2005-12-13 | 2019-02-15 | Incyte Holdings Corp | Derivados de pirrolo[2,3-d]pirimidina como inhibidores de quinasas Janus |
US20130137681A1 (en) | 2005-12-13 | 2013-05-30 | Incyte Corporation | HETEROARYL SUBSTITUTED PYRROLO[2,3-b]PYRIDINES AND PYRROLO[2,3-b]PYRIMIDINES AS JANUS KINASE INHIBITORS |
WO2007076423A2 (en) | 2005-12-22 | 2007-07-05 | Smithkline Beecham Corporation | INHIBITORS OF Akt ACTIVITY |
BRPI0620341A2 (pt) | 2005-12-23 | 2011-11-08 | Smithkline Beecham Corparation | azaindóis inibidores de cinases aurora |
JP4643455B2 (ja) | 2006-01-12 | 2011-03-02 | 株式会社ユニバーサルエンターテインメント | 遊技システム |
EP2559694A3 (en) | 2006-01-17 | 2013-04-03 | Vertex Pharmaceuticals, Inc. | Azaindoles useful as inhibitors of Janus kinases |
CA2635899A1 (en) | 2006-01-19 | 2007-07-26 | Osi Pharmaceuticals, Inc. | Fused heterobicyclic kinase inhibitors |
JP2009525350A (ja) | 2006-02-01 | 2009-07-09 | スミスクライン ビーチャム コーポレーション | Rafキナーゼ阻害薬として有用なピロロ[2,3,b]ピリジン誘導体 |
US7745477B2 (en) | 2006-02-07 | 2010-06-29 | Hoffman-La Roche Inc. | Heteroaryl and benzyl amide compounds |
US20070202172A1 (en) | 2006-02-24 | 2007-08-30 | Tomer Gold | Metoprolol succinate E.R. tablets and methods for their preparation |
US8003642B2 (en) | 2006-03-10 | 2011-08-23 | Ono Pharmaceutical Co., Ltd. | Nitrogenated heterocyclic derivative, and pharmaceutical agent comprising the derivative as active ingredient |
MX2008012738A (es) | 2006-04-03 | 2009-02-06 | Astellas Pharma Inc | Heterocompuesto. |
EP2001884A1 (en) | 2006-04-05 | 2008-12-17 | Vertex Pharmaceuticals, Inc. | Deazapurines useful as inhibitors of janus kinases |
JP2009533416A (ja) | 2006-04-12 | 2009-09-17 | ファイザー・リミテッド | ケモカインccr5受容体の調節剤としてのピロリジン誘導体 |
WO2007129195A2 (en) | 2006-05-04 | 2007-11-15 | Pfizer Products Inc. | 4-pyrimidine-5-amino-pyrazole compounds |
EP2040704A2 (en) | 2006-05-18 | 2009-04-01 | Bayer Healthcare Ag | Pharmaceutical compositions comprising implitapide and methods of using same |
US7691811B2 (en) | 2006-05-25 | 2010-04-06 | Bodor Nicholas S | Transporter-enhanced corticosteroid activity and methods and compositions for treating dry eye |
JO3235B1 (ar) | 2006-05-26 | 2018-03-08 | Astex Therapeutics Ltd | مركبات بيررولوبيريميدين و استعمالاتها |
NZ573174A (en) | 2006-06-01 | 2012-01-12 | Msd Consumer Care Inc | Sustained release pharmaceutical dosage form containing phenylephrine |
JP2009544625A (ja) | 2006-07-20 | 2009-12-17 | メーメット・カーラマン | Rhoキナーゼのベンゾチオフェン阻害剤 |
WO2008013622A2 (en) | 2006-07-27 | 2008-01-31 | E. I. Du Pont De Nemours And Company | Fungicidal azocyclic amides |
WO2008016123A1 (fr) | 2006-08-03 | 2008-02-07 | Takeda Pharmaceutical Company Limited | INHIBITEUR DE LA GSK-3β |
ATE517868T1 (de) | 2006-08-16 | 2011-08-15 | Boehringer Ingelheim Int | Pyrazinverbindungen, ihre verwendung und herstellungsverfahren |
PE20080769A1 (es) | 2006-09-08 | 2008-08-14 | Novartis Ag | Derivados de biaril-sulfonamida |
WO2008035376A2 (en) | 2006-09-19 | 2008-03-27 | Council Of Scientific & Industrial Research | A novel bio-erodible insert for ophthalmic applications and a process for the preparation thereof |
TW200831104A (en) | 2006-10-04 | 2008-08-01 | Pharmacopeia Inc | 6-substituted 2-(benzimidazolyl)purine and purinone derivatives for immunosuppression |
AR063141A1 (es) | 2006-10-04 | 2008-12-30 | Pharmacopeia Inc | Derivados de 2- ( benzimidazolil ) purina 8- sustituida para inmunosupresion |
US20120225057A1 (en) * | 2006-10-11 | 2012-09-06 | Deciphera Pharmaceuticals, Llc | Methods and compositions for the treatment of myeloproliferative diseases and other proliferative diseases |
EP2086979B1 (en) | 2006-11-06 | 2015-06-03 | Tolero Pharmaceuticals, Inc. | Imidazo[1,2-b]pyridazine and pyrazolo[1,5-a]pyrimidine derivatives and their use as protein kinase inhibitors |
US20080119496A1 (en) | 2006-11-16 | 2008-05-22 | Pharmacopeia Drug Discovery, Inc. | 7-Substituted Purine Derivatives for Immunosuppression |
WO2008064157A1 (en) | 2006-11-22 | 2008-05-29 | Incyte Corporation | Imidazotriazines and imidazopyrimidines as kinase inhibitors |
WO2008067119A2 (en) | 2006-11-27 | 2008-06-05 | Smithkline Beecham Corporation | Novel compounds |
AU2007334436A1 (en) | 2006-12-15 | 2008-06-26 | Abbott Laboratories | Novel oxadiazole compounds |
MX2009006543A (es) | 2006-12-20 | 2009-06-26 | Amgen Inc | Compuestos heterociclicos y su uso en el tratamiento de la inflamacion, angiogenesis y cancer. |
CA2672438A1 (en) | 2006-12-20 | 2008-07-03 | Amgen Inc. | Substituted heterocycles and methods of use |
ES2415863T3 (es) | 2006-12-22 | 2013-07-29 | Incyte Corporation | Heterociclos sustituidos como inhibidores de Janus Quinasas |
WO2008077712A1 (en) | 2006-12-22 | 2008-07-03 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Gel useful for the delivery of ophthalmic drugs |
WO2008082839A2 (en) | 2006-12-29 | 2008-07-10 | Abbott Laboratories | Pim kinase inhibitors as cancer chemotherapeutics |
KR20080062876A (ko) | 2006-12-29 | 2008-07-03 | 주식회사 대웅제약 | 신규한 항진균성 트리아졸 유도체 |
WO2008082840A1 (en) | 2006-12-29 | 2008-07-10 | Abbott Laboratories | Pim kinase inhibitors as cancer chemotherapeutics |
MX2009009304A (es) | 2007-03-01 | 2009-11-18 | Novartis Ag | Inhibidores de cinasa pim y metodos para su uso. |
US8138181B2 (en) | 2007-04-03 | 2012-03-20 | Array Biopharma Inc. | Imidazo[1,2-a]pyridine compounds as receptor tyrosine kinase inhibitors |
US8188178B2 (en) | 2007-05-07 | 2012-05-29 | 3M Innovative Properties Company | Cold shrinkable article including an epichlorohydrin composition |
GB0709031D0 (en) | 2007-05-10 | 2007-06-20 | Sareum Ltd | Pharmaceutical compounds |
JP5603770B2 (ja) | 2007-05-31 | 2014-10-08 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Ccr2受容体拮抗薬およびその使用 |
GB0710528D0 (en) | 2007-06-01 | 2007-07-11 | Glaxo Group Ltd | Novel compounds |
HUE029236T2 (en) | 2007-06-13 | 2017-02-28 | Incyte Holdings Corp | (R) -3- (4- (7H-Pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl) -3-cyclopentylpropanenitrile Crystalline salts of Janus kinase inhibitor |
CL2008001709A1 (es) | 2007-06-13 | 2008-11-03 | Incyte Corp | Compuestos derivados de pirrolo [2,3-b]pirimidina, moduladores de quinasas jak; composicion farmaceutica; y uso en el tratamiento de enfermedades tales como cancer, psoriasis, artritis reumatoide, entre otras. |
KR101258316B1 (ko) | 2007-07-11 | 2013-04-30 | 화이자 인코포레이티드 | 안구 건조증 치료용 약학 조성물 및 방법 |
EA201000113A1 (ru) | 2007-08-01 | 2010-08-30 | Пфайзер Инк. | Пиразольные соединения |
WO2009049028A1 (en) | 2007-10-09 | 2009-04-16 | Targegen Inc. | Pyrrolopyrimidine compounds and their use as janus kinase modulators |
CA2743756A1 (en) | 2007-11-15 | 2009-05-22 | Musc Foundation For Research Development | Inhibitors of pim protein kinases, compositions, and methods for treating cancer |
UA104849C2 (uk) | 2007-11-16 | 2014-03-25 | Інсайт Корпорейшн | 4-піразоліл-n-арилпіримідин-2-аміни і 4-піразоліл-n-гетероарилпіримідин-2-аміни як інгібітори кіназ janus |
GB0723815D0 (en) | 2007-12-05 | 2008-01-16 | Glaxo Group Ltd | Compounds |
EP2231689B1 (en) | 2008-01-18 | 2016-07-20 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Novel cytostatic 7-deazapurine nucleosides |
NZ587165A (en) | 2008-02-04 | 2012-03-30 | Mercury Therapeutics Inc | Ampk modulators |
PE20091577A1 (es) | 2008-03-03 | 2009-11-05 | Novartis Ag | Inhibidores de cinasa pim y metodos para su uso |
DK2288610T3 (en) | 2008-03-11 | 2016-11-28 | Incyte Holdings Corp | Azetidinesulfonic AND CYCLOBUTANDERIVATER AS JAK INHIBITORS |
CA2718936A1 (en) | 2008-03-21 | 2009-09-24 | Novartis Ag | Novel heterocyclic compounds and uses therof |
AU2009260389A1 (en) | 2008-06-18 | 2009-12-23 | Merck Sharp & Dohme Corp. | Inhibitors of Janus kinases |
CN105147608B (zh) | 2008-06-26 | 2019-12-10 | 安特里奥公司 | 真皮递送 |
TWI461423B (zh) | 2008-07-02 | 2014-11-21 | Astrazeneca Ab | 用於治療Pim激酶相關病狀及疾病之噻唑啶二酮化合物 |
FR2933409B1 (fr) | 2008-07-03 | 2010-08-27 | Centre Nat Rech Scient | NOUVEAUX PYRROLO °2,3-a! CARBAZOLES ET LEUR UTILISATION COMME INHIBITEURS DES KINASES PIM |
TWI496779B (zh) | 2008-08-19 | 2015-08-21 | Array Biopharma Inc | 作為pim激酶抑制劑之***吡啶化合物 |
US8557809B2 (en) | 2008-08-19 | 2013-10-15 | Array Biopharma Inc. | Triazolopyridine compounds as PIM kinase inhibitors |
ME01269B (me) | 2008-08-20 | 2013-06-20 | Zoetis Services Llc | Jedinjenja pirolo (2,3-d) pirimidina |
JP5584215B2 (ja) | 2008-09-02 | 2014-09-03 | ノバルティス アーゲー | ヘテロ環pimキナーゼ阻害剤 |
EP2342190A1 (en) | 2008-09-02 | 2011-07-13 | Novartis AG | Bicyclic kinase inhibitors |
PT2344474E (pt) | 2008-09-02 | 2015-12-28 | Novartis Ag | Derivados de picolinamida como inibidores de cinase |
CL2009001884A1 (es) * | 2008-10-02 | 2010-05-14 | Incyte Holdings Corp | Uso de 3-ciclopentil-3-[4-(7h-pirrolo[2,3-d]pirimidin-4-il)-1h-pirazol-1-il)propanonitrilo, inhibidor de janus quinasa, y uso de una composición que lo comprende para el tratamiento del ojo seco. |
WO2010043052A1 (en) | 2008-10-17 | 2010-04-22 | Merck Frosst Canada Ltd. | Azetidine derivatives as inhibitors of stearoyl-coenzyme a delta-9 desaturase |
JOP20190230A1 (ar) | 2009-01-15 | 2017-06-16 | Incyte Corp | طرق لاصلاح مثبطات انزيم jak و المركبات الوسيطة المتعلقة به |
EP2210890A1 (en) | 2009-01-19 | 2010-07-28 | Almirall, S.A. | Oxadiazole derivatives as S1P1 receptor agonists |
US8263601B2 (en) | 2009-02-27 | 2012-09-11 | Concert Pharmaceuticals, Inc. | Deuterium substituted xanthine derivatives |
WO2010135650A1 (en) | 2009-05-22 | 2010-11-25 | Incyte Corporation | N-(HETERO)ARYL-PYRROLIDINE DERIVATIVES OF PYRAZOL-4-YL-PYRROLO[2,3-d]PYRIMIDINES AND PYRROL-3-YL-PYRROLO[2,3-d]PYRIMIDINES AS JANUS KINASE INHIBITORS |
WO2010135621A1 (en) | 2009-05-22 | 2010-11-25 | Incyte Corporation | 3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-1h-pyrazol-1-yl]octane- or heptane-nitrile as jak inhibitors |
UA110324C2 (en) * | 2009-07-02 | 2015-12-25 | Genentech Inc | Jak inhibitory compounds based on pyrazolo pyrimidine |
WO2011003418A1 (en) | 2009-07-08 | 2011-01-13 | Leo Pharma A/S | Heterocyclic compounds as jak receptor and protein tyrosine kinase inhibitors |
WO2011025685A1 (en) | 2009-08-24 | 2011-03-03 | Merck Sharp & Dohme Corp. | Jak inhibition blocks rna interference associated toxicities |
TW201111385A (en) | 2009-08-27 | 2011-04-01 | Biocryst Pharm Inc | Heterocyclic compounds as janus kinase inhibitors |
TW201113285A (en) | 2009-09-01 | 2011-04-16 | Incyte Corp | Heterocyclic derivatives of pyrazol-4-yl-pyrrolo[2,3-d]pyrimidines as janus kinase inhibitors |
SG178986A1 (en) | 2009-09-08 | 2012-04-27 | Hoffmann La Roche | 4-substituted pyridin-3-yl-carboxamide compounds and methods of use |
EP2305660A1 (en) | 2009-09-25 | 2011-04-06 | Almirall, S.A. | New thiadiazole derivatives |
EP2486041B1 (en) | 2009-10-09 | 2013-08-14 | Incyte Corporation | Hydroxyl, keto, and glucuronide derivatives of 3-(4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentylpropanenitrile |
TW201125867A (en) * | 2009-10-20 | 2011-08-01 | Cellzome Ltd | Heterocyclyl pyrazolopyrimidine analogues as JAK inhibitors |
US8671402B2 (en) * | 2009-11-09 | 2014-03-11 | Bank Of America Corporation | Network-enhanced control of software updates received via removable computer-readable medium |
EP2332917B1 (en) | 2009-11-11 | 2012-08-01 | Sygnis Bioscience GmbH & Co. KG | Compounds for PIM kinase inhibition and for treating malignancy |
EP2504030A4 (en) | 2009-11-24 | 2013-06-26 | Alderbio Holdings Llc | IL-6 ANTAGONISTS FOR INCREASING ALBUMIN AND / OR REDUCING CRP |
EP2506852A4 (en) | 2009-12-04 | 2013-06-19 | Univ Texas | INTERFERONTHERAPIES IN COMBINATION WITH BLOCKING OF STAT3 ACTIVATION |
CA2782720A1 (en) * | 2009-12-18 | 2011-06-23 | Pfizer Inc. | Pyrrolo[2,3-d]pyrimidine compounds |
CA2781578A1 (en) | 2010-01-12 | 2011-07-21 | F. Hoffmann-La Roche Ag | Tricyclic heterocyclic compounds, compositions and methods of use thereof |
SA111320200B1 (ar) * | 2010-02-17 | 2014-02-16 | ديبيوفارم اس ايه | مركبات ثنائية الحلقة واستخداماتها كمثبطات c-src/jak مزدوجة |
CA2790070C (en) * | 2010-02-18 | 2018-03-06 | Incyte Corporation | Cyclobutane and methylcyclobutane derivatives as janus kinase inhibitors |
NZ603446A (en) | 2010-04-14 | 2014-05-30 | Array Biopharma Inc | 5, 7-substituted-imidazo [1, 2-c] pyrimidines as inhibitors of jak kinases |
EP2390252A1 (en) | 2010-05-19 | 2011-11-30 | Almirall, S.A. | New pyrazole derivatives |
CN103002875B (zh) | 2010-05-21 | 2016-05-04 | 因塞特控股公司 | Jak抑制剂的局部用制剂 |
WO2011156698A2 (en) | 2010-06-11 | 2011-12-15 | Abbott Laboratories | NOVEL PYRAZOLO[3,4-d]PYRIMIDINE COMPOUNDS |
US9351943B2 (en) | 2010-07-01 | 2016-05-31 | Matthew T. McLeay | Anti-fibroblastic fluorochemical emulsion therapies |
US20130252917A1 (en) | 2010-09-30 | 2013-09-26 | Portola Pharmaceuticals, Inc. | Combination therapy of 4-(3-(2h-1,2,3-triazo-2-yl)phenylamino)-2-((1r,2s)-2-aminocyclohexylamino)pyrimidine-5-carboxamide and fludarabine |
WO2012068440A1 (en) | 2010-11-19 | 2012-05-24 | Incyte Corporation | Heterocyclic-substituted pyrrolopyridines and pyrrolopyrimidines as jak inhibitors |
AU2011329734B2 (en) | 2010-11-19 | 2015-05-28 | Incyte Holdings Corporation | Cyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as JAK inhibitors |
MX2013006261A (es) | 2010-12-03 | 2013-10-01 | Ym Biosciences Australia Pty | Tratamiento de condiciones mediadas por jak2. |
EA026317B1 (ru) | 2011-02-18 | 2017-03-31 | Новартис Фарма Аг | КОМБИНИРОВАННОЕ ЛЕЧЕНИЕ С ПРИМЕНЕНИЕМ ИНГИБИТОРОВ mTOR/JAK |
CN102247368B (zh) | 2011-05-19 | 2013-05-29 | 安徽永生堂药业有限责任公司 | 一种复方阿伐斯汀缓释片及其制备方法 |
CN102218042A (zh) | 2011-05-26 | 2011-10-19 | 青岛黄海制药有限责任公司 | 富马酸喹硫平组合物的缓释片剂及其制备方法 |
MY165963A (en) | 2011-06-20 | 2018-05-18 | Incyte Holdings Corp | Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as jak inhibitors |
WO2013007768A1 (en) | 2011-07-13 | 2013-01-17 | F. Hoffmann-La Roche Ag | Tricyclic heterocyclic compounds, compositions and methods of use thereof as jak inhibitors |
WO2013007765A1 (en) | 2011-07-13 | 2013-01-17 | F. Hoffmann-La Roche Ag | Fused tricyclic compounds for use as inhibitors of janus kinases |
CA2844507A1 (en) | 2011-08-10 | 2013-02-14 | Novartis Pharma Ag | Jak pi3k/mtor combination therapy |
TW201313721A (zh) | 2011-08-18 | 2013-04-01 | Incyte Corp | 作為jak抑制劑之環己基氮雜環丁烷衍生物 |
UA111854C2 (uk) | 2011-09-07 | 2016-06-24 | Інсайт Холдінгс Корпорейшн | Способи і проміжні сполуки для отримання інгібіторів jak |
US9193733B2 (en) | 2012-05-18 | 2015-11-24 | Incyte Holdings Corporation | Piperidinylcyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as JAK inhibitors |
US10155987B2 (en) | 2012-06-12 | 2018-12-18 | Dana-Farber Cancer Institute, Inc. | Methods of predicting resistance to JAK inhibitor therapy |
WO2013188783A1 (en) | 2012-06-15 | 2013-12-19 | Concert Pharmaceuticals, Inc. | Deuterated derivatives of ruxolitinib |
WO2014016396A1 (en) | 2012-07-27 | 2014-01-30 | Ratiopharm Gmbh | Oral dosage forms for modified release comprising ruxolitinib |
CN102772384A (zh) | 2012-08-07 | 2012-11-14 | 四川百利药业有限责任公司 | 一种盐酸米诺环素缓释片及其制备方法 |
JP2015526520A (ja) * | 2012-08-31 | 2015-09-10 | プリンシピア バイオファーマ インコーポレイテッド | Itk阻害剤としてのベンズイミダゾール誘導体 |
WO2014071031A1 (en) | 2012-11-01 | 2014-05-08 | Incyte Corporation | Tricyclic fused thiophene derivatives as jak inhibitors |
EA201590930A1 (ru) * | 2012-11-15 | 2015-08-31 | Инсайт Корпорейшн | Лекарственные формы руксолитиниба с замедленным высвобождением |
CN105189509B (zh) | 2013-03-06 | 2017-12-19 | 因赛特公司 | 用于制备jak抑制剂的方法及中间体 |
HUE063817T2 (hu) | 2013-05-17 | 2024-01-28 | Incyte Holdings Corp | Bipirazol-származékok mint JAK inhibitorok |
SI3030227T1 (sl) | 2013-08-07 | 2020-08-31 | Incyte Corporation | Dozirne oblike s podaljšanim sproščanjem za inhibitor JAK1 |
CN105555313A (zh) * | 2013-08-20 | 2016-05-04 | 因赛特公司 | 在c-反应蛋白水平较高的实体肿瘤患者中的存活益处 |
EP3110409B1 (en) | 2014-02-28 | 2018-08-15 | Incyte Corporation | Jak1 inhibitors for the treatment of myelodysplastic syndromes |
EA201692011A1 (ru) | 2014-04-08 | 2017-01-30 | Инсайт Корпорейшн | Лечение b-клеточных злокачественных новообразований с применением комбинации ингибиторов jak и pi3k |
KR20170007331A (ko) | 2014-04-30 | 2017-01-18 | 인사이트 코포레이션 | Jak1 억제제의 제조 방법 및 이에 대한 신규한 형태 |
WO2015184087A2 (en) | 2014-05-28 | 2015-12-03 | Institute For Myeloma & Bone Cancer Research | Anti-cancer effects of jak2 inhibitors in combination with thalidomide derivatives and glucocorticoids |
WO2015184305A1 (en) | 2014-05-30 | 2015-12-03 | Incyte Corporation | TREATMENT OF CHRONIC NEUTROPHILIC LEUKEMIA (CNL) AND ATYPICAL CHRONIC MYELOID LEUKEMIA (aCML) BY INHIBITORS OF JAK1 |
US10766900B2 (en) | 2017-12-29 | 2020-09-08 | Formosa Laboratories, Inc. | Baricitinib intermediate, method for forming Baricitinib intermediate, and method for preparing Baricitinib or pharmaceutically acceptable salt thereof |
EP3921318A1 (en) | 2019-02-06 | 2021-12-15 | Concert Pharmaceuticals Inc. | Process for preparing enantiomerically enriched jak inhibitors |
-
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011112662A1 (en) * | 2010-03-10 | 2011-09-15 | Incyte Corporation | Piperidin-4-yl azetidine derivatives as jak1 inhibitors |
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