TWI828800B - Arg1及/或arg2之抑制劑 - Google Patents
Arg1及/或arg2之抑制劑 Download PDFInfo
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- TWI828800B TWI828800B TW108141665A TW108141665A TWI828800B TW I828800 B TWI828800 B TW I828800B TW 108141665 A TW108141665 A TW 108141665A TW 108141665 A TW108141665 A TW 108141665A TW I828800 B TWI828800 B TW I828800B
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- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
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Abstract
本發明描述係為ARG1及ARG2中至少一者之抑制劑的化合物及含有該等化合物之組合物以及合成該等化合物之方法。本發明亦描述此等化合物及組合物用於治療包括至少部分由ARG1及ARG2介導之癌症及免疫相關病症的一系列不同疾病、病症及病狀的用途。
Description
精胺酸酶在肝尿素循環中起基本作用,從而將L-精胺酸代謝為L-鳥胺酸及尿素。另外,精胺酸酶經展示對發炎觸發之免疫功能障礙、腫瘤免疫逃逸、免疫抑止及感染性疾病之免疫病理學負責或參與其中[Bronte V, Zanovello P (2005b). Regulation of immune responses by L-arginine metabolism.Nat Rev Immunol 5
: 641-654]。
在人類中,存在兩種精胺酸酶同功酶,精胺酸酶I (ARG-1)及精胺酸酶II (ARG-2)。其催化相同的生物化學反應但在細胞表現、調節及亞細胞定位方面有所不同[Jenkinson等人(1996). Comparative properties of arginases.Comp Biochem Physiol B Biochem Mol Biol 114
: 107-132]。ARG-1自腫瘤微環境消耗精胺酸,從而導致T細胞功能受損,諸如停止細胞介素之增殖及分泌。[Rodriguez等人(2002). Regulation of T cell receptor CD3zeta chain expression by L-arginine. J Biol Chem 277: 21123-21129; Munder, Arginase in the Immune System, British Journal of Pharmacology (2009)158
638-651]。已在患有各種癌症(包括胃癌、結腸癌、乳癌及肺癌)之患者中發現高含量之精胺酸酶[Suer等人(1999). Arginase and ornithine, as markers in human non-small cell lung carcinoma. Cancer Biochem Biophys 17:125-31; Singh等人(2000). Arginase activity in human breast cancer cell lines: N(omega)-hydroxy-L- arginine selectively inhibits cell proliferation and induces apoptosis in MDA-MB-468 cells. Cancer Res 60:3305-12]。
因此,在此項技術中需要精胺酸酶抑制劑。本發明解決此需求且亦提供相關優勢。
本發明係關於抑制精胺酸酶之化合物及包含該等化合物之組合物(例如,醫藥組合物)。下文詳細描述此等化合物(包括其合成方法)及組合物。
本發明亦係關於此等化合物及組合物用於治療及/或預防全部或部分由精胺酸酶介導之一系列不同疾病、病症及病狀的用途。本文其他處詳細描述此等疾病、病症及病狀。除非另外指示,否則當在本文中描述本發明化合物之用途時,應理解此等化合物可呈組合物(例如,醫藥組合物)形式。
如下文所論述,儘管認為本發明之化合物藉由抑制精胺酸酶來影響其活性,但不需要對化合物之基礎作用機制之精確理解來實踐本發明。
精胺酸酶為以兩種同功異構物形式存在於哺乳動物中之酶:ARG-1經發現於胞溶質中且主要在肝臟中表現,而ARG-2發現於粒線體中且在腎臟、小腸、大腦、單核球及巨噬細胞中表現。精胺酸酶催化胺基酸L-精胺酸轉化為鳥胺酸及尿素,其為下游代謝路徑之重要前驅體,從而允許組織再生、細胞增殖及抗炎性反應。L-精胺酸亦可由氧化氮合成酶(nitric oxide synthase;NOS)代謝,從而產生氧化氮(在巨噬細胞之細胞毒性機制中重要的高反應性化合物)。咸信ARG-1較佳在骨髓衍生之抑制細胞(myeloid-derived suppressor cell;MDSC)浸潤性腫瘤中表現,從而引起來自腫瘤微環境之精胺酸之消耗。此消耗進一步引起TCR ζ鏈(TCR之主要信號轉導元件)之表現缺失,從而造成增殖受損及細胞介素產生減少。因此,本發明之某些實施例提供化合物及藉由增加腫瘤微環境中精胺酸含量從而允許活化人體之細胞毒性T細胞來治療癌症的方法。參見Timosenko, Modulation of cancer-specific immune responses by amino acid degrading enzymes. Immunotherapy (2017) 9(1), 83-97。
在一個特定態樣中,本發明提供具有式(I)之化合物:
或其醫藥學上可接受之鹽、水合物或溶劑合物,其中,
X為N或CR4a
;
各R1
獨立地為H或C1-8
烷基;
R2
為H或CH3
;
各R3
獨立地為H或C1-8
烷基;或兩個R3
基團接合在一起以形成未經取代或經1至4個Ra
取代之5員或6員環;
各R4a
、R4b
、R4c
及R4d
獨立地選自由以下組成之群:H、鹵素、CN、C1-8
烷基、C1-8
烷氧基、C1-8
羥烷基、C1-8
鹵烷基、C1-8
鹵烷氧基、-X1
-Y、-X1
-SO2
R5a
及-X1
-NR5b
R5c
;
各R5a
、R5b
及R5c
獨立地選自由以下組成之群:H、C1-8
烷基、C1-8鹵烷基、C1-8
烷基C(O)-、C3-7環烷基、3員至7員雜環烷基、芳基、雜芳基及胺基酸,或R5b及R5c接合在一起以形成4員至6員環;且其中該4員至6員環、該C3-7環烷基或該3員至7員雜環烷基、該芳基及該雜芳基中之每一者未經取代或經1至4個Rb取代;各X1為鍵、-O-、C1-6伸烷基或-O-C1-6伸烷基,其中該等伸烷基部分未經取代或經1至4個Rc及0或1個側氧基取代;各Ra、Rb及Rc獨立地為鹵素、CN、OH、NH2、CO2H、C1-4烷基、C1-4鹵烷基、C3-6環烷基及苯基,或兩個Rc經組合以形成未經取代或經1至3個Rd取代之C3-6環烷基;各Y獨立地為苯基、5員或6員雜芳基、3員至7員雜環烷基或C3-6環烷基,其中之每一者未經取代或經1至3個Rd取代;及各Rd獨立地為鹵素、C1-4烷基、胺基、胺基C1-4烷基、C1-4鹵烷基、OH及C1-4羥烷基。
在一些實施例中,本發明涵蓋用於治療或預防個體(例如,人類)之癌症的方法,其包含向個體投與治療有效量的本文中所描述之至少一種精胺酸酶抑制劑。在一些實施例中,本發明包括藉由以有效逆轉、停止或減緩精胺酸酶介導之免疫抑止進展的量向個體投與本文中所描述之化合物中之至少一者來治療或預防個體之癌症的方法。在一些實施例中,精胺酸酶介導之免疫抑止由骨髓衍生之抑制細胞(MDSC)來介導。
可使用本文中所描述之化合物及組合物治療的癌症之實例包括(但不限於):前列腺癌、結腸直腸癌、胰臟癌、子宮頸癌、胃癌、子宮內膜癌、腦癌、肝癌、膀胱癌、卵巢癌、睪丸癌、頭部癌、頸部癌、皮膚癌(包括黑色素瘤及基底癌瘤)、間皮內膜癌、白血球癌(包括淋巴瘤及白血病)、食道癌、乳癌、肌肉癌、結締組織癌、肺癌(包括小細胞肺癌及非小細胞肺癌)、腎上腺癌、甲狀腺癌、腎癌或骨癌;神經膠母細胞瘤、間皮瘤、腎細胞癌、胃癌、肉瘤、絨膜癌、皮膚基底細胞癌瘤及睪丸精原細胞瘤。在本發明之一些實施例中,癌症為黑色素瘤、結腸癌、胰臟癌、乳癌、前列腺癌、肺癌、白血病、腦腫瘤、淋巴瘤、肉瘤、卵巢癌、頭頸癌、子宮頸癌或卡波西氏肉瘤(Kaposi's sarcoma)。下文進一步論述作為用本發明之化合物及組合物治療之候選物的癌症。
本發明涵蓋藉由投與治療有效量的精胺酸酶抑制劑治療接受骨髓移植或周邊血液幹細胞移植之個體的方法。
在某些實施例中,本發明涵蓋用於治療或預防個體(例如,人類)之感染性病症(例如,病毒感染)的方法,其包含向個體投與治療有效量的至少一種精胺酸酶抑制劑(例如,本發明之新穎抑制劑)。在一些實施例中,感染性病症為病毒感染(例如,慢性病毒感染)、細菌感染、真菌感染或寄生蟲感染。在某些實施例中,病毒感染為人類免疫缺乏病毒或細胞巨大病毒。
在又其他實施例中,本發明涵蓋用於治療或預防個體(例如,人類)之免疫相關疾病、病症或病狀的方法,其包含向個體投與治療有效量的本文中所描述之至少一種精胺酸酶抑制劑。下文描述免疫相關疾病、病症及病狀之實例。
可全部或部分藉由調節精胺酸酶活性來治療或預防的其他疾病、病症及病狀為本發明之精胺酸酶抑制劑化合物之候選適應症。
本發明進一步涵蓋本文中所描述之精胺酸酶抑制劑與一或多種額外藥劑組合的用途。一或多種額外藥劑可經由不同作用機制起作用。在一些實施例中,此等藥劑包含放射(例如,局部放射療法或全身放射療法)及/或非藥理學性質之其他治療模態。在利用組合療法時,本文中所描述之化合物及一種額外藥劑可呈單一組合物或多種組合物之形式,且可同時、依序或經由一些其他療程投與治療模態。藉助於實例,本發明涵蓋其中放射階段之後為化學治療階段的治療療程。組合療法可具有附加或協同效果。下文描述組合療法之其他益處。
在特定實施例中,本發明涵蓋本文中所描述之精胺酸酶抑制劑與免疫檢查點抑制劑組合的用途。引起抗原特異性T細胞反應之擴增的免疫檢查點之阻斷已展示為人類癌症治療法中之有前景的方法。作為阻斷之候選物的免疫檢查點(配體及受體)之實例(其中之一些在各種類型之腫瘤細胞中選擇性上調)包括:計劃性細胞死亡蛋白1 (programmed cell death protein 1;PD1);PD1配體(PD1 ligand;PDL1);B及T淋巴球衰減子(B and T lymphocyte attenuator;BTLA);細胞毒性T淋巴球相關抗原4 (cytotoxic T-lymphocyte associated antigen 4;CTLA4);T細胞膜蛋白3 (T-cell membrane protein 3;TIM3);淋巴球活化基因3 (lymphocyte activation gene 3;LAG3);具有Ig及ITIM域之T細胞免疫受體(T cell immunoreceptor with Ig and ITIM doamin;TIGIT);以及殺手抑制受體。本文其他處詳細論述免疫檢查點抑制劑及與其之組合療法。
在其他實施例中,本發明提供用於治療個體之癌症的方法,其包含向個體投與治療有效量的至少一種精胺酸酶抑制劑及至少一種化學治療劑,此等藥劑包括(但不限於):烷基化劑(例如,氮芥,諸如氯芥苯丁酸、環磷醯胺、異環磷醯胺(isofamide)、二氯甲基二乙胺(mechlorethamine)、美法侖(melphalan)及尿嘧啶氮芥;氮丙啶,諸如噻替派(thiotepa);甲烷磺酸酯,諸如白消安(busulfan);核苷類似物(例如,吉西他濱(gemcitabine));亞硝基脲,諸如卡莫司汀(carmustine)、洛莫司汀(lomustine)及鏈脲菌素(streptozocin);拓樸異構酶1抑制劑(例如,伊立替康(irinotecan));鉑複合物,諸如順鉑(cisplatin)、卡鉑(carboplatin)及奧沙利鉑(oxaliplatin);生物還原性烷基化劑,諸如絲裂黴素(mitomycin)、丙卡巴肼(procarbazine)、達卡巴嗪(dacarbazine)及六甲蜜胺(altretamine));基於蒽環黴素之治療劑(例如,小紅莓(doxorubicin)、道諾黴素(daunorubicin)、表柔比星(epirubicin)及艾達黴素(idarubicin));DNA鏈斷裂劑(例如,博萊黴素(bleomycin));拓樸異構酶II抑制劑(例如,安吖啶(amsacrine)、放線菌素d (dactinomycin)、道諾黴素、艾達黴素、米托蒽醌(mitoxantrone)、小紅莓、依託泊苷(etoposide)及替尼泊苷(teniposide));DNA小溝結合劑(例如,利卡邁汀(plicamydin));抗代謝物(例如,葉酸拮抗劑,諸如甲胺喋呤(methotrexate)及曲美沙特(trimetrexate);嘧啶拮抗劑,諸如氟尿嘧啶(fluorouracil)、氟去氧尿苷(fluorodeoxyuridine)、CB3717、阿紮胞苷(azacitidine)、阿糖胞苷(cytarabine)及氟尿苷(floxuridine);嘌呤拮抗劑,諸如巰基嘌呤(mercaptopurine)、6-硫代鳥嘌呤、氟達拉濱(fludarabine)、噴司他汀(pentostatin);利血生(asparginase);及核糖核苷酸還原酶抑制劑,諸如羥基脲);微管蛋白相互作用劑(例如,長春新鹼(vincristine)、雌莫司汀(estramustine)、長春鹼(vinblastine)、多烯紫杉醇(docetaxol)、埃坡黴素(epothilone)衍生物及太平洋紫杉醇(paclitaxel));激素劑(例如,雌激素;結合雌激素;乙炔雌二醇;己烯雌酚;氯喘尼森(chlortrianisen);依德斯爾(idenestrol);孕激素,諸如己酸羥孕酮、甲羥孕酮及甲地孕酮;及雄激素,諸如睪固酮、丙酸睪固酮、氟甲睾酮及甲睾酮);腎上腺皮質類固醇(例如,潑尼松(prednisone)、地塞米松(dexamethasone)、甲基潑尼龍(methylprednisolone)及潑尼松龍(prednisolone));黃體化激素釋放劑或促性腺激素釋放激素拮抗劑(例如,乙酸亮甲瑞林(leuprolide acetate)及乙酸戈舍瑞林(goserelin acetate));以及抗激素抗原(例如,他莫昔芬(tamoxifen)、抗雄激素劑,諸如氟他胺(flutamide);及抗腎上腺劑,諸如米托坦(mitotane)及胺魯米特(aminoglutethimide))。本發明亦涵蓋精胺酸酶抑制劑與此項技術中已知的其他藥劑(例如,三氧化二砷)及將來研發之其他化學治療劑組合的用途。
在涉及治療癌症之方法的一些實施例中,投與治療有效量的至少一種化學治療劑以及本文中所描述之精胺酸酶抑制劑使得癌症存活率大於藉由單獨投與任一者所觀測到之癌症存活率。在涉及治療癌症之方法的其他實施例中,投與治療有效量的至少一種化學治療劑以及本文中所描述之精胺酸酶抑制劑使得腫瘤大小之減小或腫瘤生長之減緩比藉由單獨投與一種藥劑所觀測到的腫瘤大小或腫瘤生長之減小更大。
在其他實施例中,本發明涵蓋用於治療或預防個體之癌症的方法,其包含向個體投與治療有效量的本文中所描述之至少一種精胺酸酶抑制劑及至少一種信號轉導抑制劑(signal transduction inhibitor;STI)。在一特定實施例中,至少一種STI選自由以下組成之群:bcr/abl激酶抑制劑、表皮生長因子(epidermal growth factor;EGF)受體抑制劑、her-2/neu受體抑制劑及法呢基轉移酶抑制劑(farnesyl transferase inhibitor;FTI)。本文其他處闡述其他候選STI藥劑。
本發明亦涵蓋強化個體之腫瘤細胞之排斥反應的方法,其包含投與精胺酸酶抑制劑連同至少一種化學治療劑及/或放射療法,其中腫瘤細胞之所得排斥反應大於單獨投與精胺酸酶抑制劑、化學治療劑或放射療法所獲得的排斥反應。
在其他實施例中,本發明提供用於治療個體之癌症的方法,其包含向個體投與治療有效量的至少一種精胺酸酶抑制劑及除至少一種除精胺酸酶抑制劑以外的免疫調節劑。在特定實施例中,至少一種免疫調節劑選自由以下組成之群:CD4OL、B7、B7RP1、抗CD40、抗CD38、抗ICOS、4-IBB配體、樹突狀細胞癌症疫苗、IL2、IL12、ELC/CCL19、SLC/CCL21、MCP-1、IL-4、IL-18、TNF、IL-15、MDC、IFN-a/IFN-13、M-CSF、IL-3、GM-CSF、IL-13、抗IL-10、吲哚胺2,3-二加氧酶1 (IDO1)抑制劑及腺苷2受體拮抗劑。本文其他處闡述其他候選免疫調節劑。
本發明涵蓋包含用於治療或預防個體(例如,人類)之感染性病症(例如,病毒感染)之方法的實施例,該等方法包含向個體投與治療有效量的本文中所描述之至少一種精胺酸酶抑制劑及治療有效量的抗感染劑。
在本發明之一些實施例中,額外治療劑為細胞介素,包括例如顆粒球-巨噬細胞群落刺激因子(granulocyte-macrophage colony stimulating factor;GM-CSF)或flt3-配體。本發明亦涵蓋用於治療或預防病毒感染(例如,慢性病毒感染)之方法,該病毒感染包括(但不限於) C型肝炎病毒(hepatitis C virus;HCV)、人類乳頭狀瘤病毒(human papilloma virus;HPV)、細胞巨大病毒(CMV)、埃-巴二氏病毒(Epstein-Barr virus;EBV)、水痘帶狀疱疹病毒、科沙奇病毒(coxsackie virus)及人類免疫缺乏病毒(human immunodeficiency virus;HIV)。下文進一步論述本文中所描述之化合物用以(單獨或呈組合療法之組分形式)治療感染之用途。
在額外實施例中,經由結合疫苗與治療有效量的本發明之精胺酸酶抑制劑之投與的共投與來實現感染性病症之治療。在一些實施例中,疫苗為抗病毒疫苗,包括(例如)抗HIV疫苗。在其他實施例中,疫苗有效針對結核病或瘧疾。在又其他實施例中,疫苗為腫瘤疫苗(例如,有效針對黑色素瘤之疫苗);腫瘤疫苗可包含基因修飾之腫瘤細胞或基因修飾之細胞株,包括經轉染以表現顆粒球-巨噬細胞刺激因子(GM-CSF)的基因修飾之腫瘤細胞或基因修飾之細胞株。在特定實施例中,疫苗包括一或多種免疫原性肽及/或樹突狀細胞。
在一些實施例中,本發明涵蓋使用本文中所描述之化合物以及一或多種抗菌劑的方法。
在涉及藉由投與精胺酸酶抑制劑及至少一種額外治療劑治療感染的某些實施例中,在投與精胺酸酶抑制劑及額外治療劑兩者之後所觀測到的感染症狀相比於在單獨投與任一者之後所觀測到的相同感染症狀有所改良。在一些實施例中,所觀測到的感染症狀可為病毒負荷之減少、CD4+
T細胞計數之增加、機會性感染之減少、存活時間之增加、慢性感染之根除,或其組合。
相關申請案之交叉參考
本申請案為根據35 U.S.C. § 119(e)主張2018年11月16日申請之美國臨時申請案第62/768,284號之權益的申請案,該申請案以全文引用之方式併入本文中。
在進一步描述本發明之前,應理解本發明不限於本文中所闡述之特定實施例,且亦應理解本文中所使用的術語僅出於描述特定實施例之目的,且不意欲為限制性的。
當提供值範圍時,應理解除非上下文另外明確指出,否則在彼範圍之上限與下限之間的各中間值至下限之單位之十分之一)及在彼所陳述範圍內之任何其他所陳述值或中間值均涵蓋於本發明內。此等較小範圍之上限及下限可獨立地包括於較小範圍內且亦涵蓋於本發明內,在所陳述範圍內受到任何特定排他性限制。當所陳述範圍包括限度中之一者或兩者時,排除彼等所包括之限度中之任一者或兩者之範圍亦包括於本發明中。除非另外限定,否則本文所使用之所有技術及科學術語具有與本發明所屬領域之一般熟習此項技術者通常所理解相同之含義。
除非上下文另外明確指定,否則如本文中所使用,單數形式「一(a/an)」及「該」包括複數個指示物。應進一步注意,申請專利範圍可經起草以排除任何視情況選用之要素。因此,此陳述意欲與對所主張要素之敍述結合充當使用諸如「僅僅(solely)」、「僅(only)」及其類似術語之此排他性術語或使用「負性(negative)」限制之前提基礎。
本文所論述之公開案僅僅提供在本申請案之申請日之前的揭示內容。另外,所提供之公開案之日期可與可能需要獨立確認之實際公開案日期不同。綜述
舉例而言,本文提供用於抑制精胺酸酶之化合物及組合物以及包含其之醫藥組合物。舉例而言,本文亦提供治療或預防藉由抑制精胺酸酶介導之疾病、病症或病狀或其症狀的方法。定義
除非另外指示,否則以下術語意欲具有下文所闡述之含義。其他術語在整個說明書中在其他處加以定義。
除非另外陳述,否則術語「烷基」自身或作為另一取代基之部分意謂具有所指定之碳原子數目的直鏈或分支鏈烴基(亦即,C1-8
意謂一至八個碳)。烷基可包括任何數目個碳,諸如C1-2
、C1-3
、C1-4
、C1-5
、C1-6
、C1-7
、C1-8
、C1-9
、C1-10
、C2-3
、C2-4
、C2-5
、C2-6
、C3-4
、C3-5
、C3-6
、C4-5
、C4-6
及C5-6
。烷基之實例包括甲基、乙基、正丙基、異丙基、正丁基、第三丁基、異丁基、第二丁基、正戊基、正己基、正庚基、正辛基及類似者。
術語「伸烷基」係指具有所指定之碳原子數且鍵聯至少兩個其他基團的直鏈或分支鏈飽和脂族基,亦即二價烴基。連接至伸烷基之兩個部分可連接至伸烷基之相同原子或不同原子。舉例而言,直鏈伸烷基可為-(CH2
)n
-之二價基團,其中n為1、2、3、4、5或6。代表性伸烷基包括(但不限於)亞甲基、伸乙基、伸丙基、伸異丙基、伸丁基、伸異丁基、伸第二丁基、伸戊基及伸己基。本申請案中常被稱作X1
基團之伸烷基可經取代或未經取代。當包含X1
之基團視情況經取代時,應理解視情況選用之取代基可在該部分(moiety)之伸烷基部分上。
如本文所使用,本文所描繪之任何化學結構中與單鍵、雙鍵或參鍵相交之波浪線「」表示單鍵、雙鍵或參鍵與分子之其餘部分之連接點。另外,延伸至環(例如,苯環)之中心之鍵意謂指示在可用環頂點中之任一者處之連接。熟習此項技術者應理解展示為連接至環之多個取代基將佔據提供穩定化合物且另外空間相容之環頂點。對於二價組分,表示意謂包括任一定向(正向或反向)。舉例而言,基團「-C(O)NH-」意謂包括在任一定向上之鍵:-C(O)NH-或-NHC(O)-,且類似地「-O-CH2
CH2
-」意謂包括-O-CH2
CH2
-及-CH2
CH2
-O-兩者。
除非另外陳述,否則術語「鹵基」或「鹵素」本身或作為另一取代基之部分意謂氟、氯、溴或碘原子。另外,諸如「鹵烷基」之術語意謂包括單鹵烷基及多鹵烷基。舉例而言,術語「C1-4
鹵烷基」意謂包括三氟甲基、2,2,2-三氟乙基、4-氯丁基、3-溴丙基及類似者。
除非另外陳述,否則術語「芳基」意謂多元不飽和,典型地為芳族之烴基,其可為單環或稠合在一起或共價連接之多個環(至多三個環)。芳基之非限制性實例包括苯基、萘基及聯苯。
在一些實施例中,上述術語(例如,「烷基」及「芳基」)將視情況經取代。下文提供各類基團之所選取代基。
烷基(包括常被稱作伸烷基、烯基及炔基之彼等基團)的視情況選用之取代基可為選自以下之各種基團:鹵素、-OR'、-NR'R"、-SR'、-SiR'R"R"'、-OC(O)R'、-C(O)R'、-CO2
R'、-CONR'R"、-OC(O)NR'R"、-NR"C(O)R'、-NR'-C(O)NR"R"'、-NR"C(O)2
R'、-NH-C(NH2
)=NH、-NR'C(NH2
)=NH、-NH-C(NH2
)=NR'、-S(O)R'、-S(O)2
R'、-S(O)2
NR'R"、-NR'S(O)2
R"、氰基(-CN)、-NO2
、芳基、芳氧基、側氧基、環烷基及雜環烷基,其數目在零至(2 m'+1)之範圍內,其中m'為此等基團中之碳原子之總數。R'、R''及R"'各自獨立地指氫、未經取代之C1-8
烷基、未經取代之芳基、經1至3個鹵素取代之芳基、C1-8
烷氧基或C1-8
硫代烷氧基或未經取代之芳基-C1-4
烷基。當R'及R''連接至相同氮原子時,其可與氮原子組合以形成3員、4員、5員、6員或7員環。舉例而言,-NR'R"意謂包括1-吡咯啶基及4-嗎啉基。
類似地,芳基的視情況選用之取代基不同且通常選自以下各者:-鹵素、-OR'、-OC(O)R'、-NR'R"、-SR'、-R'、-CN、-NO2
、-CO2
R'、-CONR'R"、-C(O)R'、-OC(O)NR'R"、-NR"C(O)R'、-NR"C(O)2
R'、-NR'-C(O)NR"R"'、-NH-C(NH2
)=NH、-NR'C(NH2
)=NH、-NH-C(NH2
)=NR'、-S(O)R'、-S(O)2
R'、-S(O)2
NR'R"、-NR'S(O)2
R"、-N3
、全氟(C1
-C4
)烷氧基及全氟(C1
-C4
)烷基,其數目在零至芳族環系統上之開放價數之總數範圍內;且其中R'、R"及R"'獨立地選自氫、C1-8
烷基、C1-8
鹵烷基、C3-6
環烷基、C2-8
烯基及C2-8
炔基。其他適合取代基包括藉由1至6個碳原子之伸烷基繫鏈連接至環原子的上述芳基取代基中之每一者。
芳基環之相鄰原子上的取代基中之兩者可視情況經式-T-C(O)-(CH2
)q
-U-之取代基置換,其中T及U獨立地為-NH-、-O-、-CH2
-或單鍵,且q為0至2之整數。替代地,芳基或雜芳基環之相鄰原子上的取代基中之兩者可視情況經式-A-(CRf
Rg
)r
-B-之取代基置換,其中A及B獨立地為-CH2
-、-O-、-NH-、-S-、-S(O)-、-S(O)2
-、-S(O)2
NR'-或單鍵,r為1至3之整數,且Rf
及Rg
各自獨立地為H或鹵素。由此形成的新環之單鍵中之一者可視情況經雙鍵置換。替代地,芳基或雜芳基環之相鄰原子上的取代基中之兩者可視情況經式-(CH2
)s
-X-(CH2
)t
-的取代基置換,其中s及t獨立地為0至3之整數,且X為-O-、-NR'-、-S-、-S(O)-、-S(O)2
-或-S(O)2
NR'-。-NR'-及-S(O)2
NR'-中之取代基R'選自氫或未經取代之C1-6
烷基。
如本文中所使用,術語「雜原子」意謂包括氧(O)、氮(N)、硫(S)及矽(Si)。
術語「醫藥學上可接受之鹽」意謂包括視本文中所描述之化合物上所發現的特定取代基而定,利用相對無毒性酸或鹼製備的活性化合物之鹽。當本發明之化合物含有相對酸性官能基時,可藉由使中性形式之此等化合物與足夠量之所需鹼在無溶劑下或在適合惰性溶劑中接觸來獲得鹼加成鹽。衍生自醫藥學上可接受之無機鹼的鹽之實例包括鋁鹽、銨鹽、鈣鹽、銅鹽、鐵鹽、亞鐵鹽、鋰鹽、鎂鹽、錳鹽、亞錳鹽、鉀鹽、鈉鹽、鋅鹽及其類似鹽。衍生自醫藥學上可接受之有機鹼的鹽包括一級、二級及三級胺之鹽,包括經取代之胺、環狀胺、天然存在之胺及其類似物,諸如精胺酸、甜菜鹼、咖啡因、膽鹼、N,N'-二苯甲基乙二胺、二乙胺、2-二乙胺基乙醇、2-二甲胺基乙醇、乙醇胺、乙二胺、N-乙基嗎啉、N-乙基哌啶、還原葡糖胺、葡糖胺、組胺酸、海卓胺、異丙胺、離胺酸、甲基還原葡糖胺、嗎啉、哌嗪、哌啶、多元胺樹脂、普魯卡因(procaine)、嘌呤、可可豆鹼、三乙胺、三甲胺、三丙胺、緩血酸胺及類似者。當本發明之化合物含有相對鹼性官能基時,可藉由使中性形式之此等化合物與足夠量之所需酸在無溶劑下或在適合惰性溶劑中接觸來獲得酸加成鹽。醫藥學上可接受之酸加成鹽之實例包括:衍生自無機酸之彼等酸加成鹽,該等無機酸如鹽酸、氫溴酸、硝酸、碳酸、一氫碳酸、磷酸、一氫磷酸、二氫磷酸、硫酸、一氫硫酸、氫碘酸或亞磷酸及類似者;以及衍生自相對無毒性有機酸之鹽,該等有機酸如乙酸、丙酸、異丁酸、丙二酸、苯甲酸、丁二酸、辛二酸、反丁烯二酸、杏仁酸、鄰苯二甲酸、苯磺酸、對甲苯基磺酸、檸檬酸、酒石酸、甲磺酸及類似者。亦包括諸如精胺酸及類似者的胺基酸之鹽及如葡糖醛酸或半乳糖醛酸及類似者的有機酸之鹽(參見例如,Berge, S.M.等人, 「Pharmaceutical Salts」,Journal of Pharmaceutical Science
,1977
,66
, 1-19)。本發明之某些特定化合物含有允許化合物轉化成鹼加成鹽或酸加成鹽之鹼性及酸性官能基兩者。
可藉由使鹽與鹼或酸接觸且以習知方式分離親本化合物來再生中性形式之化合物。化合物之親本形式與各種鹽形式的不同之處在於某些物理特性,諸如極性溶劑中之溶解性,但出於本發明之目的,在其他方面,鹽等效於化合物之親本形式。除鹽形式以外,本發明提供呈前藥形式之化合物。本文中所描述之化合物的前藥為容易在生理條件下經歷化學變化以提供本發明化合物的彼等化合物。另外,前藥可藉由化學方法或生物化學方法在離體環境中轉化為本發明化合物。舉例而言,前藥可在與適合酶或化學試劑一起置放於經皮貼片儲集層中時緩慢地轉化為本發明化合物。本文其他處更詳細地描述前藥。
除鹽形式以外,本發明提供呈前藥形式之化合物。本文中所描述之化合物的前藥為容易在生理條件下經歷化學變化以提供本發明化合物的彼等化合物。另外,前藥可藉由化學方法或生物化學方法在離體環境中轉化為本發明化合物。舉例而言,前藥可在與適合酶或化學試劑一起置放於經皮貼片儲集層中時緩慢地轉化為本發明化合物。
本發明之某些化合物可以非溶合形式以及溶劑化形式(包括水合形式)存在。一般而言,溶劑化形式等效於未溶劑化形式,且意欲涵蓋於本發明之範疇內。本發明之某些化合物可以多種結晶形式或非晶形式存在。一般來說,所有物理形式均等同地用於本發明所涵蓋之用途且意欲在本發明之範疇內。
本發明之某些化合物具有不對稱碳原子(光學中心)或雙鍵;外消旋體、非對映異構體、幾何異構體、區位異構體及個別異構體(例如,個別對映異構體)皆意欲涵蓋於本發明之範疇內。當展示立體化學描述時,其意謂指存在異構體中之一者且實質上不含其他異構體之化合物。「實質上不含」另一異構體指示兩種異構體之至少80/20比率,更佳90/10或95/5或更高比率。在一些實施例中,異構體中之一者將以至少99%之量存在。
本發明化合物亦可在構成此等化合物之原子中之一或多者處含有非天然比例之原子同位素。非天然比例之同位素可定義為在自然界中所發現之量至由100%所討論的原子組成之量的範圍內。舉例而言,化合物可併入放射性同位素,諸如氚(3
H)、碘-125 (125
I)或碳-14 (14
C);或非放射性同位素,諸如氘(2
H)或碳-13 (13
C)。此等同位素變體可為在本申請案內其他處描述之彼等者提供額外效用。舉例而言,本發明之化合物的同位素變體可發現額外效用,包括(但不限於)作為診斷及/或成像試劑或作為細胞毒性/放射性毒性治療劑。另外,本發明之化合物的同位素變體可具有改變的藥物動力學及藥效學特徵,其可有助於治療期間增強安全性、耐受性或功效。本發明化合物之所有同位素變體無論是否具放射性均意欲涵蓋於本發明之範疇內。
術語「患者」或「個體」可互換地使用以指人類或非人類動物(例如,哺乳動物)。
術語「投與(administration)」、「投與(administer)」及類似者在其施加至例如個體、細胞、組織、器官或生物流體時係指使例如精胺酸酶之抑制劑、包含其之醫藥組合物或個體、細胞、組織、器官或生物流體之診斷劑或與其接觸。在細胞之情況下,投與包括使試劑與細胞接觸(例如,活體外或離體接觸)以及使試劑與流體接觸,其中該流體與細胞接觸。
術語「治療(treat/treating/treatment)」及類似者係指在已診斷、觀測疾病、病症或病狀或其症狀及其類似者之後引發的作用過程(諸如投與精胺酸酶之抑制劑或包含其之醫藥組合物),從而暫時或持久性地消除、減少、抑止、減輕或改善折磨個體之疾病、病症或病狀之根本原因中之至少一者或與折磨個體之疾病、病症、病狀相關之症狀中之至少一者。因此,治療包括抑制(例如,遏制疾病、病症或病狀或與其相關之臨床症狀之發展或進一步發展)活動性疾病(active disease)。
如本文中所使用之術語「需要治療」係指由醫師或其他照護者作出的個體需要或將受益於治療之判斷。基於在醫師或照護者之專門知識範圍內的多種因素作出此判斷。
術語「預防(prevent/preventing/prevention)」及類似者係指通常在個體易患有特定疾病、病症或病狀之情形中,以一定方式(例如,在疾病、病症、病狀或其症狀發作之前)引發之作用過程(諸如投與精胺酸酶抑制劑或包含其之醫藥組合物),從而暫時或持久性地預防、抑止、抑制或降低個體患上疾病、病症、病狀或類似者之風險(如由例如臨床症狀之缺失所判定)或延緩其發作之風險。在某些實例中,術語亦係指減緩疾病、病症或病狀之進展或抑制其進展成有害或其他非所需狀態。
如本文中所使用之術語「需要預防」係指由醫師或其他照護者作出的個體需要或將受益於預防性照護之判斷。基於在醫師或照護者之專門知識範圍內的多種因素作出此判斷。
片語「治療有效量」係指向個體投與單獨或作為醫藥組合物之一部分且呈單一劑量或作為一系列劑量之一部分的藥劑,其呈在向個體投與時能夠對疾病、病症或病狀之任何症狀、態樣或特徵具有任何可偵測、積極效果的量。治療有效量可藉由量測相關生理效果來確定,且其可結合個體病狀之給藥方案及診斷分析以及類似者來進行調整。藉助於實例,投與後的特定時間處的精胺酸酶抑制劑之血清含量(或例如其代謝物)之量測可指示是否使用治療有效量。
片語「呈實現改變之足夠量」意謂在投與特定療法之前(例如基線含量)及之後在所量測之指示物含量之間存在可偵測差異。指示物包括任何客觀參數(例如,血清濃度)或主觀參數(例如,個體之健康感覺)。
術語「小分子」係指具有小於約10 kDa、小於約2 kDa或小於約1 kDa之分子量的化合物。小分子包括(但不限於)無機分子、有機分子、含有無機組分之有機分子、包含放射性原子之分子及合成分子。治療學上,與大分子相比,小分子可更易滲透過細胞,對降解不太敏感,且不大可能引發免疫反應。
術語「配體」係指例如可充當受體之促效劑或拮抗劑之肽、多肽、膜相關或膜結合分子,或其複合物。配體涵蓋天然及合成配體,例如細胞介素、細胞介素變體、類似物、突變蛋白及衍生自抗體之結合組合物,以及小分子。術語亦涵蓋既不為促效劑亦不為拮抗劑,但可結合至受體而不顯著影響其生物特性(例如,信號傳導或黏著力)的藥劑。此外,術語包括已藉由例如化學或重組方法改變為膜結合配體之可溶型式的膜結合配體。配體或受體可完全為細胞內的,亦即其可駐留於胞溶質、細胞核或一些其他細胞內區室中。配體與受體之複合物稱為「配體-受體複合物」。
術語「抑制劑」及「拮抗劑」或「活化子」及「促效劑」分別係指例如用於活化例如配體、受體、輔因子、基因、細胞、組織或器官的抑制或活化分子。抑制劑為減少、阻斷、預防、延遲活化、不活化、脫敏或下調例如基因、蛋白、配體、受體或細胞的分子。活化子為增加、活化、促進、增強活化、敏化或上調例如基因、蛋白質、配體、受體或細胞的分子。抑制劑亦可定義為降低、阻斷或不活化組成性活性的分子。「促效劑」為與目標相互作用以引起或促進目標活化增加的分子。「拮抗劑」為對抗促效劑之作用的分子。拮抗劑防止、降低、抑制或抵消促效劑之活性,且拮抗劑亦可防止、抑制或降低目標(例如,目標受體)之組成性活性,甚至當不存在經鑑別促效劑時亦如此。
術語「調節(modulate/modulation)」及類似者係指分子(例如,活化子或抑制劑)直接地或間接地提高或降低精胺酸酶之功能或活性的能力。調節劑可單獨起作用,或其可使用輔因子,例如蛋白質、金屬離子或小分子。調節劑之實例包括小分子化合物及其他生物有機分子。小分子化合物之眾多庫(例如,組合庫)為可商購的且可充當鑑別調節劑之起點。熟習此項技術者能夠研發一或多種分析(例如,生物化學或基於細胞之分析),其中此等化合物庫可經篩選以便鑑別一或多種具有所需特性之化合物;之後,熟練的醫藥藥劑師能夠藉由例如合成及評估其類似物及衍生物來最佳化此一或多種化合物。合成及/或分子建模研究亦可用於鑑別活化子。
分子之「活性」可描述或指分子與配體或受體之結合;催化活性;刺激基因表現或細胞信號傳導、分化或成熟之能力;抗原活性;其他分子活性之調節;及類似者。術語「增殖活性」涵蓋促進例如以下各者、為以下各者所必需或與以下各者特定相關之活性:正常細胞分裂,以及癌症、腫瘤、發育不良、細胞轉型、癌轉移及血管生成。
如本文所使用,「相當的」、「相當的活性」、「與…相當的活性」、「相當的效果」、「與…相當的效果」及類似者為可定量及/或定性方面而言之相對術語。術語之含義經常視其使用之情形而定。藉助於實例,活化受體之兩種藥劑可根據定性觀點視為具有相當的效果,但若如在技術接受之分析(例如,劑量反應分析)或技術接受之動物模型中所測定,一種藥劑僅能夠達成另一種藥劑活性之20%,則兩種藥劑可根據定量觀點視為缺乏相當的效果。當將一種結果與另一種結果(例如,一種結果與參考標準)比較時,「相當的」經常(儘管未必總是)意謂一種結果與參考標準偏差小於35%、小於30%、小於25%、小於20%、小於15%、小於10%、小於7%、小於5%、小於4%、小於3%、小於2%或小於1%。在特定實施例中,若一種結果與參考標準偏差小於15%、小於10%或小於5%,則其與參考標準相當。藉助於實例(而非限制),活性或效果可以係指功效、穩定性、溶解性或免疫原性。
「實質上純」指示組分佔組合物之總含量之大於約50%,且通常佔總多肽含量之大於約60%。更典型地,「實質上純」係指其中總組合物之至少75%、至少85%、至少90%或更多為相關組分之組合物。在一些情況下,多肽將佔組合物之總含量之大於約90%或大於約95%。
當指配體/受體、抗體/抗原或其他結合對時,術語「特異性結合」或「選擇性結合」指示確定蛋白質及其他生物製劑之非均質群體中蛋白質之存在的結合反應。因此,在特指條件下,指定配體結合至特定受體且不以大量結合至樣品中所存在之其他蛋白質。所涵蓋方法之抗體或衍生自抗體之抗原結合位點的結合組合物以比任何其他抗體或自其衍生之結合組合物的親和力大至少兩倍、大至少十倍、大至少20倍或大至少100倍的親和力結合至其抗原或其變體或突變蛋白。在一特定實施例中,抗體將具有如藉由例如史卡查分析(Scatchard analysis) (Munsen等人, 1980 Analyt. Biochem. 107:220-239)所測定的大於約109
公升/莫耳之親和力。
例如細胞、組織、器官或生物體之術語「反應」涵蓋生物化學或生理行為(例如,濃度、密度、黏著力或生物代謝區內之遷移、基因表現率或分化狀態)之變化,其中該變化與活化、刺激或治療或與內部機制(諸如基因程式化)相關。在某些情況下,術語「活化」、「刺激」及類似者係指如藉由內部機制以及藉由外部或環境因素調節之細胞活化;而術語「抑制」、「下調」及類似者係指相反效果。
本文中可互換使用之術語「多肽」、「肽」及「蛋白質」係指任何長度之胺基酸之聚合形式,其可包括基因編碼及非基因編碼之胺基酸、經化學或生物化學修飾或衍生之胺基酸及具有經修飾之多肽主鏈之多肽。術語包括:融合蛋白,包括(但不限於)具有異源胺基酸序列之融合蛋白、具有異源及同源前導序列之融合蛋白,其具有或不具有N端甲硫胺酸殘基;免疫標記蛋白;及類似者。
如本文中所使用,術語「變體」及「同源物」可互換使用以指分別與參考胺基酸或核酸序列類似的胺基酸或DNA序列。術語涵蓋天然存在之變體及非天然存在之變體。天然存在之變體包括同源物(物種之間分別在胺基酸或核苷酸序列方面不同之多肽及核酸)及對偶基因變體(物種內個體之間分別在胺基酸或核苷酸序列方面不同之多肽及核酸)。因此,變體及同源物涵蓋天然存在之DNA序列及藉此編碼之蛋白質及其同功異構物以及蛋白質或基因之剪接變體。術語亦涵蓋在一或多個鹼基方面與天然存在之DNA序列不同但歸因於基因密碼簡併仍轉譯成對應於天然存在之蛋白質的胺基酸序列之核酸序列。非天然存在之變體及同源物包括分別包含胺基酸或核苷酸序列中之變化的多肽及核酸,其中序列中之變化為人工引入的(例如,突變蛋白);例如,變化在實驗室中藉由人工干預(「人工(hand of man)」)產生。因此,非天然存在之變體及同源物亦可指與天然存在之序列不同在於一或多種保守性取代及/或標籤及/或結合物的彼等者。
如本文中所使用之術語「突變蛋白」廣泛地指突變重組蛋白。此等蛋白質通常攜帶單個或多個胺基酸取代且經常衍生自經受定點或隨機突變誘發的選殖基因或完全合成基因。
術語「DNA」、「核酸」、「核酸分子」、「多核苷酸」及類似者可在本文中互換使用以指任何長度之核苷酸之聚合形式(去氧核糖核苷酸或核糖核苷酸或類似者)。多核苷酸之非限制性實例包括線形及環狀核酸、信使RNA (mRNA)、互補DNA (cDNA)、重組多核苷酸、載體、探針、引子及類似者。精胺酸酶及其抑制
如上文所闡述,不需要對化合物的根本作用機制(本發明化合物藉由該機制影響其活性)之精確理解來實踐本發明,但咸信化合物(或其子集)抑制精胺酸酶。儘管本發明化合物通常在本文中被稱作精胺酸酶抑制劑,但應理解,術語「精胺酸酶抑制劑」涵蓋經由抑制精胺酸酶而單獨起作用但亦經由額外機制起作用的化合物。鑑別具有所需特徵之精胺酸酶抑制劑
本發明部分涉及用至少一種具有治療相關性之特性或特徵來鑑別精胺酸酶抑制劑。候選抑制劑可藉由使用例如技術接受之分析或模型來鑑別,其實例描述於本文中。
在鑑別之後,可藉由使用提供關於抑制劑特徵之資料(例如,藥物動力學參數、測定溶解性或穩定性之方式)的技術來進一步評估候選抑制劑。候選抑制劑與參考標準(其可為目前抑制劑之「最佳等級」)之比較為此等候選物之潛在活力之指示。本發明之化合物
本文提供具有式(I)之化合物
或其醫藥學上可接受之鹽、水合物或溶劑合物,其中,
X為N或CR4a
;
各R1
獨立地為H或C1-8
烷基;
R2
為H或CH3
;
各R3
獨立地為H或C1-8
烷基;或兩個R3
基團接合在一起以形成未經取代或經1至4個Ra
取代之5員或6員環;
各R4a
、R4b
、R4c
及R4d
獨立地選自由以下組成之群:H、鹵素、CN、C1-8
烷基、C1-8
烷氧基、C1-8
羥烷基、C1-8
鹵烷基、C1-8
鹵烷氧基、-X1
-Y、-X1-SO2R5a及-X1-NR5bR5c;各R5a、R5b及R5c獨立地選自由以下組成之群:H、C1-8烷基、C1-8鹵烷基、C1-8烷基C(O)-、C3-7環烷基、3員至7員雜環烷基、芳基、雜芳基及胺基酸,或R5b及R5c接合在一起以形成4員至6員環;且其中該4員至6員環、該C3-7環烷基或該3員至7員雜環烷基、該芳基及該雜芳基中之每一者未經取代或經1至4個Rb取代;各X1為鍵、-O-、C1-6伸烷基或-O-C1-6伸烷基,其中該等伸烷基部分未經取代或經1至4個Rc及0或1個側氧基取代;各Ra、Rb及Rc獨立地為鹵素、CN、OH、NH2、CO2H、C1-4烷基、C1-4鹵烷基、C3-6環烷基及苯基,或兩個Rc經組合以形成未經取代或經1至3個Rd取代之C3-6環烷基;各Y獨立地為苯基、5員或6員雜芳基、3員至7員雜環烷基或C3-6環烷基,其中之每一者未經取代或經1至3個Rd取代;及各Rd獨立地為鹵素、C1-4烷基、胺基、胺基C1-4烷基、C1-4鹵烷基、OH及C1-4羥烷基。
在一些實施例中,式(I)化合物或其醫藥學上可接受之鹽、水合物或溶劑合物為彼等化合物,其中:X為N或CR4a;各R1獨立地為H或C1-8烷基;R2為H或CH3;各R3獨立地為H或C1-8烷基;或兩個R3基團接合在一起以形成未經取代或經1至4個Ra取代之5員或6員環;各R4a、R4b、R4c及R4d獨立地選自由以下組成之群:H、鹵素、CN、
C1-8烷基、C1-8烷氧基、C1-8羥烷基、C1-8鹵烷基、-X1-Y、-X1-SO2R5a及-X1-NR5bR5c;各R5a、R5b及R5c獨立地選自由以下組成之群:H、C1-8烷基、C1-8鹵烷基、C1-8烷基C(O)-、C3-7環烷基、3員至7員雜環烷基、芳基、雜芳基及胺基酸,或R5b及R5c接合在一起以形成4員至6員環;且其中該4員至6員環、該C3-7環烷基或該3員至7員雜環烷基、該芳基及該雜芳基中之每一者未經取代或經1至4個Rb取代;各X1為鍵或未經取代或經1至4個Rc取代之C1-6伸烷基;各Ra、Rb及Rc獨立地為鹵素、CN、OH、NH2、C1-4烷基、C1-4鹵烷基、C3-6環烷基及苯基,或兩個Rc經組合以形成C3-6環烷基;各Y獨立地為苯基或5員或6員雜芳基,其中之每一者未經取代或經1至3個Rd取代;及各Rd獨立地為鹵素、C1-4烷基、胺基、胺基C1-4烷基、C1-4鹵烷基、OH及C1-4羥烷基。
在式(I)之一些實施例中,X為CR4a。在式(I)之其他實施例中,X為N。
在式(I)之一些所選實施例及上文所論述之實施例中之任一者中,各R4a、R4b、R4c及R4d獨立地選自由以下組成之群:H、F、Cl、CN、C1-4烷基、C1-4烷氧基、C1-4羥烷基、C1-4鹵烷基、-X1-Y、-X1-SO2R5a及-X1-NR5bR5c。在其他實施例中,各R4a、R4b、R4c及R4d獨立地選自由以下組成之群:H、F、Cl、CN、C1-4烷基、C1-4烷氧基、C1-4羥烷基、C1-4鹵烷基及-X1-NR5bR5c。在又其他實施例中,各R4a、R4b、R4c及R4d獨立地選自由以下組成之群:H、F、Cl、CN、C1-4烷基、C1-4烷氧基、C1-4
羥烷基、C1-4
鹵烷基及-X1
-NR5b
R5c
,且R4a
、R4b
及R4c
中之至少一者為-X1
-NR5b
R5c
。在又其他實施例中,R4c
為-X1
-NR5b
R5c
。
在式(I)之一些所選實施例及上文所論述之實施例中之任一者中,R5a
、R5b
及R5c
中之每一者獨立地選自由以下組成之群:H、C1-4
烷基、C1-4
鹵烷基、C1-4
烷基C(O)-、C3-6
環烷基、3員至6員雜環烷基、苯基、吡啶基及胺基酸,或將R5b
及R5c
接合在一起以形成4員至6員環;且其中4員至6員環、C3-6
環烷基或3員至6員雜環烷基、苯基及吡啶基中之每一者未經取代或經1至4個Rb
取代。
在式(I)之一些所選實施例及上文所論述之實施例中之任一者中,X1
為鍵。在式(I)之其他所選實施例及上文所論述之實施例中之任一者中,X1
為未經取代或經1或2個Rc
取代之亞甲基或伸乙基。在式(I)之又其他所選實施例中,X1
為亞甲基、伸乙基、。
在式(I)之一些所選實施例及上文所論述之實施例中之任一者中,-NR5b
R5c
選自由以下組成之群:-NH2
、-NHCH3
、-N(CH3
)2
、-NHCH2
CF3
、-NHCH(CH3
)2
、-NHC(O)CH3
、。
在式(I)之一些所選實施例及上文所論述之實施例中之任一者中,Y (若存在)選自由以下組成之群:苯基、吡啶基、嘧啶基、吡唑基、咪唑基、1,2,3-三唑基及1,2,4-三唑基,其中之每一者未經取代或經1至3個Rd
取代。
在實施例之一個所選群組中,提供具有下式之式(I)化合物:
其中各R1
、R2
、各R3
、R4b
、R4c
、R4d
及X具有參考式(I)或上文所提供之實施例中之任一者提供的含義。
在實施例之另一所選群組中,提供具有下式之式(I)化合物:
其中各R1
、R2
、各R3
、R4a
、R4b
、R4c
及R4d
具有參考式(I)或上文所提供之實施例中之任一者提供的含義。
在實施例之另一所選群組中,提供具有下式之式(I)化合物:
其中各R1
、R2
、各R3
、R4a
、R4b
及R4c
具有參考式(I)或上文所提供之實施例中之任一者提供的含義。
在實施例之另一所選群組中,提供具有下式之式(I)化合物:
其中R1
、R2
、各R3
、R4a
、R4b
及R4c
具有參考式(I)或上文所提供之實施例中之任一者提供的含義。
在又其他所選實施例中,提供具有下式之式(I)化合物:
其中R1
、R2
、R4a
、R4b
及R4c
具有參考式(I)或上文所提供之實施例中之任一者提供的含義。
在一些所選實施例中,提供具有下式之式(I)化合物:
其中R1
、R4a
、R4b
及R4c
具有參考式(I)或上文所提供之實施例中之任一者提供的含義。
在又其他所選實施例中,提供具有下式之式(I)化合物:
其中R1
、各Rc
、R4b
及R4c
具有參考式(I)或上文所提供之實施例中之任一者提供的含義。
在又其他所選實施例中,提供具有下式之式(I)化合物:
其中R1
、各Rc
、R4a
及R4b
具有參考式(I)或上文所提供之實施例中之任一者提供的含義。
在一些所選實施例中,式(I)化合物具有下式:
其中R1
、各Rc
及R4b
具有參考式(I)或上文所提供之實施例中之任一者提供的含義。
在式(Ii)之其他所選實施例中,R4b
選自由以下組成之群:H、CH3
、CN、CF3
、F及Cl。
在一些所選實施例中,式(I)化合物具有下式:
其中下標n為1、2或3,且R1
及R4b
具有參考式(I)或上文所提供之實施例中之任一者提供的含義。
在一些所選實施例中,式(I)化合物具有下式:
其中R1
及R4b
具有參考式(I)或上文所提供之實施例中之任一者提供的含義。
在一些所選實施例中,式(I)化合物具有選自由以下組成之群的式:。
在一些所選實施例中,提供表1之化合物中之任一者。
在一些所選實施例中,提供氘化形式之式(I)化合物。氘可在氫可能存在時在任何位置處獨立地取代氫。合成方法
一般而言,可藉由如下方實例中所描述之習知方法來製備本文中所提供之化合物。藥物遞送及 / 或半衰期延長之前藥及其他手段
在本發明之一些態樣中,本文中所描述之化合物以前藥形式投與。
為實現治療活性之延長,藥物分子可經工程改造以利用載劑進行遞送。此等載劑以非共價方式使用,其中藥物部分以物理化學方式調配成溶劑-載劑混合物,或以載劑試劑與藥物部分之官能基中之一者永久共價連接之方式使用(通常參見WO 20150202317)。
若干種非共價方法為有利的。藉助於實例(而非限制),在某些實施例中,採用包含囊封至聚合載劑中之非共價藥物的長效調配物(depot formulation)。在此等調配物中,藥物分子與載劑材料混合且經處理以使得藥物分子分佈在主體載劑內部。實例包括微粒聚合物-藥物聚集物(例如,Degradex® Microspheres (Phosphorex, Inc.)),其以可注射懸浮液形式投與;調配為凝膠形式之聚合物-藥物分子聚集物(例如,Lupron Depot® (AbbVie Inc.)),其以單一快速注射劑之形式投與;以及脂質調配物(例如,DepoCyt® (Pacira Pharmaceuticals)),其中載劑可為能夠使藥物溶解之聚合或非聚合實體。在此等調配物中,藥物分子之釋放可在載劑膨脹或以物理方式劣化時發生。在其他個例中,化學降解允許藥物擴散至生物學環境中;此等化學降解過程可為自水解的或酶催化的。除了其他限制,非共價藥物囊封需要防止藥物之不可控釋放,且生物降解後藥物釋放機制之依賴性可造成患者間可變性。
在特定實施例中,藥物分子(包括小分子及大分子兩者)經由永久共價鍵與載劑結合。在水性液體中展現低溶解性之某些小分子治療劑可藉由與親水性聚合物結合而溶解,該等親水性聚合物之實例描述於本文其他處。關於大分子蛋白質,可藉由例如用軟脂醯基部分進行永久共價修飾及藉由用自身具有經延長的半衰期之另一種蛋白質(例如,Albuferon®)進行永久共價修飾來實現半衰期延長。一般而言,藥物分子在載劑與藥物共價結合時展現降低的生物活性。
在某些實例中,可藉由針對藥物與聚合載劑之化學結合使用前藥方法來成功解決與包含非共價聚合物混合物之藥物分子或永久共價連接相關的限制。在此情形中,與藥物部分自身相比無活性或活性較小之治療劑可預見地轉化成活性分子實體。前藥相比於所釋放藥物之生物活性降低在需要減緩藥物釋放或受控藥物釋放之情況下為有利的。在此等個例中,藥物之釋放隨時間推移而發生,由此減少反覆及頻繁投與藥物之必要性。當藥物部分自身在胃腸道中未經吸收或達不到最佳吸收時,前藥方法亦可為有利的;在此等個例中,前藥促進藥物部分之吸收且接著在某一稍後時間(例如,經由首過代謝)裂解。生物活性藥物分子通常藉由載劑部分與藥物分子之羥基、胺基或羧基之間形成的臨時鍵來連接至聚合載劑部分。
上文所描述之方法與若干限制有關。前藥活化可藉由載劑與藥物分子之間的臨時鍵之酶促或非酶促裂解或兩者之順序組合(例如,酶促步驟之後進行非酶促修飾)來發生。在不含酶之活體外環境(例如,緩衝水溶液)中,諸如酯或醯胺之臨時鍵可經歷水解,但對應水解速率可能使得其超出治療有用範圍。對比而言,在活體內環境中,通常存在酯酶或醯胺酶,且酯酶及醯胺酶可造成水解動力學之顯著催化加速兩倍至高達若干數量級(參見例如,Greenwald等人(1999) J Med Chem 42(18):3857-67)。
如本文中所描述,前藥可分類為i)生物前驅體及ii)載劑連接之前藥。生物前驅體不含有載劑基團,且藉由官能基之代謝產生而活化。對比而言,在載劑連接之前藥中,活性物質經由生物活性實體之官能基處之臨時鍵與載劑部分結合。較佳官能基為羥基或胺基。連接化學反應及水解條件均視所採用官能基之類型而定。載劑可為生物性惰性的(例如,PEG)或可具有靶向特性(例如,抗體)。載劑連接之前藥之載劑部分之裂解產生相關生物活性實體,且生物活性實體之經去保護官能基之性質通常促進其生物活性。
專利及科學文獻描述了其中臨時鍵為不穩定酯鍵的許多大分子前藥。在此等情況下,生物活性實體之官能基為羥基或羧酸(參見例如,Cheng等人(2003) Bioconjugate Chem 14:1007-17)。另外,對於生物大分子及某些小分子藥物而言有利的係將載劑連接至生物活性實體之胺基(例如,蛋白質之N端胺基或離胺酸胺基)。在製備前藥期間,由於胺基相比於羥基或酚基之親核性更高,因此可更化學選擇性地定位胺基。此與含有多種不同反應性官能基之蛋白質及肽尤其相關,其中非選擇性結合反應使得需要大量地特徵化或純化之非所需產物混合物,由此降低反應產率及活性部分之治療功效。
一般而言,相比於酯鍵,醯胺鍵對水解更穩定,且醯胺鍵之裂解速率對於載劑連接之前藥之療效而言可能太慢。因此,可能有利的係添加結構性化學組分以便實現對前藥醯胺鍵之可裂解性之控制。既非由載劑實體亦非由藥物提供的此等額外控制裂解之化學組分通常被稱作「連接子」。前藥連接子可對臨時鍵之水解速率具有主要影響,且連接子之化學性質變化常常產生特定特性。用於靶向釋放之特異性酶對含胺生物活性部分之前藥活化需要連接子之結構呈現經對應內源酶識別為基質的結構性基元。在此等情況下,臨時鍵之裂解在藉由酶催化之單步法(one-step process)中發生。舉例而言,阿糖胞苷之酶促釋放由在各種腫瘤塊中濃度相對較高的蛋白酶纖維蛋白溶酶實現。
患者間可變性為主導型酶促裂解之主要缺點。個體之間的酶含量可顯著不同,從而產生利用酶促裂解的前藥活化之生物學差異。酶含量亦可視投與位點而變化(例如,對於皮下注射,身體之某些區域相比於其他區域得到較可預測的治療效果)。另外,難以確定酶依賴性載劑連接之前藥的藥物動力學特性之活體內-活體外相關性。
採用與藥物部分中之胺基之臨時鍵的其他載劑前藥係基於級聯機制。利用由掩蔽基團(masking group)與活化基團之結構性組合構成的連接子化合物來實現級聯裂解。掩蔽基團藉助於諸如酯或胺基甲酸酯之第一臨時鍵連接至活化基團。活化基團經由第二臨時鍵(例如,胺基甲酸酯)連接至藥物分子之胺基。第二臨時鍵之水解穩定性或敏感性視掩蔽基團之存在或缺失而定。在掩蔽基團之存在下,第二臨時鍵高度穩定且不大可能釋放具有治療有效動力學之藥物分子,然而在無掩蔽基團之缺失下,此鍵變得高度不穩定,從而快速裂解且釋放物部分。
第一臨時鍵之裂解為級聯機制中之速率限制步驟。第一步驟可誘導活化基團之分子重排(例如,如Greenwald等人(1999) J Med Chem 42:3657-67中所描述之1,6-消除),且重排使得第二臨時鍵更加不穩定,使得誘導其裂解。理想地,第一臨時鍵之裂解速率與給定治療情境中藥物分子之所需釋放速率相同。另外,需要第二臨時鍵之裂解在其不穩定性由第一臨時鍵之裂解誘導之後實質上為瞬時的。
另一實施例包含基於三甲基鎖內酯化的含聚合胺基前藥(參見例如,Greenwald等人(2000) J Med Chem 43(3):457-87)。在此前藥系統中,經取代之鄰羥苯基-二甲基丙酸藉由作為第一臨時鍵之酯基、碳酸酯基或胺基甲酸酯基連接至PEG,且藉助於作為第二臨時鍵之醯胺鍵連接至藥物分子之胺基。藥物釋放中之速率確定步驟為第一鍵之酶促裂解,之後為藉由內酯化之快速醯胺裂解,從而釋放芳族內酯副產物。Greenwald等人所描述的前藥系統之主要缺點為在裂解臨時鍵之後釋放高度反應性且潛在有毒的芳族小分子副產物,如醌甲基化物或芳族內酯。潛在有毒的實體與藥物以1:1化學計量釋放,且可假定具有高活體內濃度。
在基於1,6-消除的包含芳族活化基團之級聯前藥之某些實施例中,掩蔽基團在結構上與載劑分離。此可藉由採用聚合載劑與活化基團之間的穩定鍵來實現,其中該穩定鍵不參與級聯裂解機制。若載劑不充當掩蔽基團且活化基團藉助於穩定鍵偶合於載劑,則可避免潛在有毒副產物(諸如活化基團)之釋放。活化基團與聚合物之穩定連接亦抑止具有不確定藥理學之藥物-連接子中間物之釋放。
先前段落中所描述之方法之第一實例包含基於杏仁酸活化基團之聚合前藥系統(參見例如,Shabat等人(2004) Chem Eur J 10:2626-34)。在此方法中,掩蔽基團藉由胺基甲酸酯鍵連接至活化基團。活化基團經由醯胺鍵永久結合至聚丙烯醯胺聚合物。在藉由催化抗體酶促活化掩蔽基團之後,掩蔽基團藉由環化裂解且釋放藥物;活化基團在藥物釋放之後仍連接至聚丙烯醯胺聚合物。類似前藥系統係基於杏仁酸活化基團及酶促可裂解的酯連接之掩蔽基團(參見例如,Lee等人(2004) Angew Chem 116:1707-10)。
在使用前述連接子時,1,6-消除步驟仍產生高度反應性芳族中間物。即使芳族部分保持永久連接至聚合載劑,但仍可產生潛在有毒副產物之副反應或免疫原性效果。因此,有利的係使用非酶依賴性且在裂解期間不會產生反應性芳族中間物的脂族前藥連接子來產生用於形成含胺活性劑之聚合前藥的連接子技術。一個此實例使用PEG5000-順丁烯二酸酐以供可逆的修飾組織型纖維蛋白溶酶原活化子及尿激酶中之胺基(參見例如(1987) Garman等人, FEBS Lett 223(2):361-65)。功能性酶在pH 7.4緩衝液下培育之後藉由順丁烯醯胺酸鍵裂解而自PEG-uPA結合物之再生遵循半衰期大致為6小時之一級動力學。順丁烯醯胺酸鍵之缺點為結合物在較低pH值下缺乏穩定性。
另一方法包含基於N,N-雙-(2-羥基乙基)甘胺醯胺(二甘胺酸)連接子的PEG級聯前藥系統(參見例如,(2004) J Med Chem 47:726-34)。在此系統中,兩個PEG載劑分子經由臨時鍵連接至偶合於藥物分子之胺基的二甘胺酸分子。前藥活化中之第一步驟涉及連接兩個PEG載劑分子與二甘胺酸活化基團之羥基的第一臨時鍵之酶促裂解。PEG與二甘胺酸之間的不同鍵產生不同的前藥活化動力學。前藥活化中之第二步驟涉及將二甘胺酸活化基團連接至藥物分子之胺基的第二臨時鍵之裂解。此系統之缺點為此第二臨時二甘胺酸醯胺鍵之水解速率較慢,從而使得釋放經二甘胺酸修飾之前藥中間物,其相比於原生親本藥物分子可展示不同的藥物動力學、免疫原性、毒性及藥力學特性。
在特定實施例中,將二肽用於靶向或經靶向轉運之前藥研發,因為其為酶或生物轉運系統之基質。未充分限定二肽前藥形成之非酶促途徑,亦即,其經歷分子內環化以形成對應的二酮哌嗪(diketopiperazine;DKP)且釋放活性藥物之能力。
在一些實施例中,二肽經由酯鍵連接至藥物部分,如針對藥物撲熱息痛(paracetamol)之二肽酯所描述(Gomes等人(2005) Bio & Med Chem Lett)。在此情況下,環化反應由酯碳原子上肽之N端胺之親核攻擊組成,從而形成四面體中間物,之後一個質子自胺轉移至脫離基氧陰離子,同時形成肽鍵,以得到環狀DKP產物及游離藥物。此方法在活體外適用於含羥基藥物,但已發現其在活體內與酯鍵之酶促水解競爭,此係因為對應二肽酯以比在緩衝液中更快的速率釋放撲熱息痛(Gomes等人, Molecules 12 (2007) 2484-2506)。可藉由將至少一種非天然胺基酸併入二肽基元中來解決基於二肽之前藥對肽酶之敏感性。然而,能夠裂解酯鍵之內源酶不限於肽酶,且此前藥裂解之酶依賴性仍產生不可預測的活體內效能。
在一些實施例中,將酶依賴性有意地工程改造至DKP前藥中,諸如其中二肽酯前藥在二肽之胺基端處甲醯化,且使用酶促去甲醯基化來起始二酮哌嗪形成及酯-二肽鍵之後續裂解,隨後釋放藥物分子(參見例如,USP 7,163,923)。藉助於其他實例,八肽藉由酯鍵連接至長春鹼之4-羥基且在N端六肽之特異性酶促移除之後藉由DKP形成而經歷酯鍵裂解(參見Brady等人(2002) J Med Chem 45:4706-15)。
DKP形成反應之範疇亦已擴展至醯胺前藥。藉助於實例,USP 5,952,294描述針對阿糖胞苷之二肽基醯胺前藥,使用二酮哌嗪形成進行前藥活化。在此情況下,臨時鍵形成於二肽之羰基與阿糖胞苷之芳族胺基之間。然而,由於不存在載劑或其他半衰期延長部分或官能基,因此此等結合物不大可能達成緩慢釋放效果。
亦已描述能夠經由二肽擴展之二酮哌嗪形成而釋放肽的包含生物活性肽(諸如GLP-1)之二肽前藥(參見例如,WO 2009/099763)。生物活性肽部分可包括其胺基酸側鏈殘基中之一者上的額外PEG鏈,以達成生物活性肽之擴展循環。然而,此方法與若干顯著缺點相關。首先,PEG鏈必須連接至肽而不損害其生物活性,此對於許多基於肽之生物活性劑而言可能難以達成。其次,由於聚乙二醇化肽自身具有生物活性,因此二肽前部分對肽之生物活性具有效應且可不利地影響其受體結合特性。
可與本發明之化合物一起使用的特定例示性技術包括ProLynx (San Francisco, CA)及Ascendis Pharma (Palo Alto, CA)研發的彼等技術。ProLynx技術平台利用新穎連接子之集合,該等連接子經預程式化以不同速率裂解,以允許小分子及肽自循環的半固體大分子結合物之受控、可預測及持續釋放。技術允許在數週至數月內維持治療劑之所需穩態血清含量。
Ascendis技術平台合併前藥及持續釋放技術之益處以增強小分子及肽之特性。當在循環中時,專用前藥以由生理pH及溫度條件調節之預定速率釋放未經修飾之活性親本治療劑。因為治療劑係以其未經修飾形式釋放,因此其保留其原始作用機制。增強抑制劑特徵之修飾
經常有利且有時必不可少的為改良本文所揭示之治療模態的更多物理特性及/或其投與之方式中之一者。物理特性之改良包括例如增加水溶性、生物可用性、血清半衰期及/或治療半衰期及/或調節生物活性之方法。
此項技術中已知之修飾包括聚乙二醇化、Fc融合及白蛋白融合。儘管通常與大分子藥劑(例如,多肽)相關,此等修飾最近用特定小分子評估。藉助於實例,Chiang, M.等人(J. Am. Chem. Soc
., 2014, 136(9):3370-73)描述結合至免疫球蛋白Fc域的腺苷2a受體之小分子促效劑。小分子-Fc結合物保留有效Fc受體及腺苷2a受體相互作用且與未結合之小分子相比展示優良特性。亦已描述PEG分子與小分子治療劑之共價連接(Li, W.等人, Progress in Polymer Science, 2013 38:421-44)。
其他已知修飾包括改良藥物動力學、藥效學及毒性概況的氘化。由於氘之原子質量較大,因此碳-氘鍵之裂解需要比碳-氫鍵更多的能量。因為此等較強鍵更難斷裂,因此藥物代謝之速率相比於非氘化形式更慢,此允許更不頻繁地給藥且可進一步減小毒性。(Charles Schmidt,Nature Biotechnology
, 2017, 35(6): 493-494; Harbeson, S. and Tung, R.,Medchem News
, 2014(2): 8-22)。治療性及預防性用途
本發明涵蓋本文中所描述之精胺酸酶抑制劑之用途,其用於治療或預防廣泛範圍之疾病、病症及/或病狀及/或其症狀。雖然下文詳細描述特定用途,但應理解本發明不限於此。此外,儘管下文闡述一般類別之特定疾病、病症及病狀,但疾病、病症及病狀中之一些可為超過一個類別之成員,且其他可不為所揭示類別中之任一者之成員。
在一些實施例中,本文中所描述之疾病、病症及/或病狀至少部分由精胺酸酶介導。
在一些實施例中,本文中所描述之精胺酸酶抑制劑以可有效逆轉、停止或減緩精胺酸酶介導之免疫抑止之活性的量投與。
腫瘤學相關病症
.根據本發明,精胺酸酶抑制劑可用於治療或預防增殖病狀或病症,包括癌症,例如子宮癌、子宮頸癌、乳房癌、前列腺癌、睪丸癌、胃腸道癌(例如,食道癌、口咽癌、胃癌、小腸癌或大腸癌、結腸癌或直腸癌)、腎癌、腎細胞癌、膀胱癌、骨癌、骨髓癌、皮膚癌、頭頸癌、肝癌、膽囊癌、心臟癌、肺癌、胰臟癌、唾液腺癌、腎上腺癌、甲狀腺癌、腦癌(例如,神經膠質瘤)、神經節癌、中樞神經系統(CNS)癌症及周邊神經系統(PNS)癌症,以及造血系統癌症及免疫系統癌症(例如,脾臟癌或胸腺癌)。本發明亦提供治療或預防其他癌症相關疾病、病症或病狀之方法,該等疾病、病症或病狀包括例如免疫原性腫瘤、非免疫原性腫瘤、休眠腫瘤、病毒誘導之癌症(例如,上皮細胞癌、內皮細胞癌、鱗狀細胞癌及乳頭狀瘤病毒)、腺癌、淋巴瘤、癌瘤、黑色素瘤、白血病、骨髓瘤、肉瘤、畸胎癌、化學誘導之癌症、癌轉移及血管生成。本發明涵蓋抑制精胺酸酶以便逆轉使T細胞饑餓且防止其活化及增殖的精胺酸之消耗(Rodriguez等人(2004), Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses.Cancer Res.
64(16), 5839-5849)。在特定實施例中,腫瘤或癌症為結腸癌、卵巢癌、乳癌、黑色素瘤、肺癌、神經膠母細胞瘤或白血病。術語癌症相關疾病、病症及病狀之使用意謂廣泛係指與癌症直接或間接相關之病狀,且包括例如血管生成及癌變前病狀,諸如發育不良。
在某些實施例中,癌症可為轉移性的或處於變成轉移性之風險下,或可出現在彌漫性組織中,包括血液或骨髓之癌症(例如,白血病)。在一些其他實施例中,本發明之化合物可用於克服T細胞耐受性。
在一些實施例中,本發明提供用精胺酸酶抑制劑及至少一種額外治療劑或診斷劑治療增殖病狀、癌症、腫瘤或癌變前病狀之方法,該等方法之實例闡述於本文其他處。
免疫及發炎相關病症 .
如本文中所使用,諸如「免疫疾病」、「免疫病狀」、「免疫病症」、「發炎疾病」、「發炎病狀」、「發炎病症」之術語及類似者意謂廣泛地涵蓋具有可由本文中所描述之精胺酸酶抑制劑治療以使得獲得一些治療益處之發炎組分的任何免疫相關病狀(例如,自體免疫疾病)或病症。此等病狀經常無可避免地與其他疾病、病症及病狀糾纏在一起。藉助於實例,「免疫病狀」可指增殖病狀,諸如癌症、腫瘤及血管生成;包括抵抗被免疫系統根除的感染(急性及慢性)、腫瘤及癌症。
本發明之精胺酸酶抑制劑可用於增加或增強免疫反應;用於改良免疫接種,包括增加疫苗功效;以及用於增加炎症。與免疫缺陷疾病、免疫抑止醫學治療、急性及/或慢性感染及衰老相關的免疫缺陷可使用本文中所揭示之化合物來治療。精胺酸酶抑制劑亦可用於刺激患有醫源誘導之免疫抑止的患者之免疫系統,該等患者包括經歷骨髓移植、化療或放射療法之彼等患者。
在本揭示內容之特定實施例中,精胺酸酶抑制劑用於藉由提供佐劑活性來增加或增強對抗原之免疫反應。在特定實施例中,將至少一種抗原或疫苗與至少一種本發明之精胺酸酶抑制劑組合投與至個體,以延長對抗原或疫苗之免疫反應。亦提供包括至少一種抗原藥劑或疫苗組分(包括(但不限於)病毒、細菌及真菌或其部分、蛋白質、肽、腫瘤特異性抗原及核酸疫苗)以及至少一種本發明之精胺酸酶抑制劑的治療組合物。
可用本發明之化合物及組合物治療或預防的免疫及發炎相關疾病、病症及病狀之非限制性清單包括關節炎(例如,類風濕性關節炎)、腎衰竭、狼瘡、哮喘、牛皮癬、結腸炎、胰臟炎、過敏、纖維化、手術併發症(例如,其中發炎細胞介素防止癒合)、貧血及肌肉纖維疼痛。可能與慢性發炎相關之其他疾病及病症包括阿茲海默氏病(Alzheimer's disease)、充血性心臟衰竭、中風、主動脈瓣狹窄、動脈硬化症、骨質疏鬆、帕金森氏病(Parkinson's disease)、感染、發炎性腸病(例如,克羅恩氏病(Crohn's disease)及潰瘍性結腸炎)、過敏性接觸性皮炎及其他濕疹、全身性硬化症、移植及多發性硬化症。
在其他免疫相關病症中,預期抑制精胺酸酶功能亦可在免疫耐受性及預防子宮內胎兒排斥反應中起作用。
在一些實施例中,本文中所描述之精胺酸酶抑制劑可與免疫抑制劑組合以減少免疫效應細胞之數目。
下文更詳細地描述對於其精胺酸酶抑制劑可能尤其有效(由於例如當前治療劑之限制)的前述疾病、病症及病狀中之一些。
通常由關節之膜內膜(滑膜)中之慢性發炎表徵的類風濕性關節炎(Rheumatoid Arthritis;RA)影響近似1%之美國人口(約210萬人)。對包括TNF-α及IL-1之細胞介素在發炎過程中之作用的進一步理解使得能夠研發及引入新類別之疾病改善型抗風濕藥物(disease-modifying antirheumatic drug;DMARD)。藥劑(其中之一些與RA之治療模態重疊)包括恩博(ENBREL) (依那西普(etanercept))、雷米卡德(REMICADE) (英利昔單抗(infliximab))、修美樂(HUMIRA) (阿達木單抗(adalimumab))及肯瑞特(KINERET) (阿那白滯素(anakinra))。儘管在特定患者群體中此等藥劑中之一些減輕症狀、抑制結構損害之進展且改良物理功能,但仍需要具有改良功效、互補作用機制及較少/不太嚴重不良效應的替代藥劑。
牛皮癬(常見免疫介導之慢性皮膚病之群集)影響大於450萬美國人,其中150萬視為患有中度至重度形式之疾病。此外,超過10%患有牛皮癬之患者罹患損害骨骼及關節周圍之結締組織的牛皮癬性關節炎。對牛皮癬之根本生理學之改進理解使得引入例如靶向引起疾病之發炎性質之T淋巴球及細胞介素活性的藥劑。此等藥劑包括TNF-α抑制劑(亦用於治療類風濕性關節炎(RA)),包括恩博(ENBREL) (依那西普)、雷米卡德(REMICADE) (英利昔單抗)及修美樂(HUMIRA) (阿達木單抗);及T細胞抑制劑,諸如阿米里(AMEVIVE) (阿法賽特(alefacept))及瑞體膚(RAPTIVA) (艾法珠單抗(efalizumab))。儘管此等藥劑中之若干者在一些程度上在某些患者群體中有效,但無一者展示有效治療所有患者。
微生物相關病症
.本發明涵蓋本文中所描述之精胺酸酶抑制劑之用途,其用於治療及/或預防任何病毒、細菌、真菌、寄生蟲或其他感染性疾病、病症或病狀,其中用精胺酸酶抑制劑治療可為有益的。
所涵蓋之病毒性疾病、病症及病狀之實例包括(但不限於) B型肝炎病毒(hepatitis B virus;HBV)、C型肝炎病毒(HCV)、人類乳頭狀瘤病毒(HPV)、HIV、AIDS (包括其表現,諸如惡病體質、癡呆及腹瀉)、單純疱疹病毒(herpes simplex virus;HSV)、埃-巴二氏病毒(EBV)、水痘帶狀皰狀病毒、科沙奇病毒及細胞巨大病毒(CMV)。
此等疾病及病症之其他實例包括葡萄球菌及鏈球菌感染(例如,分別為金黃色葡萄球菌及血鏈球菌)、利什曼原蟲(leishmania)、弓蟲(toxoplasma)、毛滴蟲(trichomonas)、梨形鞭毛蟲(giardia)、白色念珠菌(candida albicans)、炭疽芽孢桿菌(bacillus anthracis)及綠膿桿菌(pseudomonas aeruginosa)。在一些實施例中,疾病或病症包括分枝桿菌感染(Mycobacterium infection)(例如,麻風分枝桿菌或結核分枝桿菌)或由單核球增多性李氏菌(Listeria monocytogenes)或剛地弓蟲(Toxplasma gondii)所引起之感染。本發明化合物可用於治療敗血症,減少或抑制細菌生長,且減少或抑制發炎性細胞介素。
其他實施例涵蓋治療寄生蟲感染,包括(但不限於)杜氏利什曼原蟲(Leishmania donovani)、熱帶利什曼原蟲(Leishmania tropica)、碩大利什曼原蟲(Leishmania major)、埃塞俄比亞利什曼原蟲(Leishmania aethiopica)、墨西哥利什曼原蟲(Leishmania mexicana)、惡性瘧原蟲(Plasmodium falciparum)、間日瘧原蟲(Plasmodium vivax)、卵形瘧原蟲(Plasmodium ovale)或三日瘧原蟲(Plasmodium malariae)。通常,預防性地投與抗寄生蟲療法(例如,在個體行進至具有高頻率寄生蟲感染之區域之前)。
其他病症
.本發明之實施例涵蓋將本文中所描述之精胺酸酶抑制劑投與至個體以供治療或預防可受益於精胺酸酶抑制之至少一些含量的任何其他病症。此等疾病、病症及病狀包括例如心血管病症(例如,心臟缺血)、腸胃道病症(例如,克羅恩氏病)、代謝病症(例如,糖尿病)、肝病(例如,肝纖維化、NASH及NAFLD)、肺病(例如,COPD及哮喘)、眼科學病症(例如,糖尿病性視網膜病變)及腎病(例如,腎衰竭)。醫藥組合物
本發明之精胺酸酶抑制劑可呈適用於投與至個體之組合物形式。一般而言,此等組合物為包含精胺酸酶抑制劑及一或多種醫藥學上可接受或生理學上可接受之稀釋劑、載劑或賦形劑的「醫藥組合物」。在某些實施例中,精胺酸酶抑制劑以治療學上可接受之量存在。醫藥組合物可用於本發明之方法中;因此,例如,醫藥組合物可離體或活體內投與至個體以便實踐本文中所描述之治療及預防方法及用途。
本發明之醫藥組合物可經調配以與既定方法或投與途徑相容;例示性投與途徑闡述於本文中。此外,醫藥組合物可與其他治療活性劑或如本文中所描述之化合物組合使用以便治療或預防如由本發明涵蓋之疾病、病症及病狀。
含有活性成分(例如精胺酸酶功能之抑制劑)之醫藥組合物可呈適用於經口使用之形式,例如呈錠劑、膠囊、糖衣錠、口含錠、水性或油性懸浮液、可分散散劑或顆粒、乳液、硬或軟膠囊或糖漿、溶液、微珠或酏劑形式。意欲用於經口使用之醫藥組合物可根據此項技術中已知用於製造醫藥組合物之任何方法來製備,且此等組合物可含有一或多種諸如甜味劑、調味劑、著色劑及防腐劑之試劑,以便提供醫藥學上精緻且適口的製劑。錠劑、膠囊及類似者含有與適用於製造錠劑之無毒醫藥學上可接受之賦形劑摻合的活性成分。此等賦形劑可為例如稀釋劑,諸如碳酸鈣、碳酸鈉、乳糖、磷酸鈣或磷酸鈉;粒化劑及崩解劑,例如玉米澱粉或褐藻酸;黏合劑,例如澱粉、明膠或阿拉伯膠;以及潤滑劑,例如硬脂酸鎂、硬脂酸或滑石。
適用於經口投與之錠劑、膠囊及類似者可未經包覆或由已知技術包覆以延遲在胃腸道中之崩解及吸收且由此提供持續作用。舉例而言,可採用時間延遲材料,諸如單硬脂酸甘油酯或二硬脂酸甘油酯。其亦可藉由此項技術中已知之技術包覆以形成用於控制釋放之滲透治療錠劑。額外藥劑包括生物可降解或生物相容粒子或聚合物質,諸如聚酯、多元胺酸、水凝膠、聚乙烯吡咯啶酮、聚酸酐、聚乙醇酸、乙烯-乙酸乙烯酯、甲基纖維素、羧甲基纖維素、魚精蛋白硫酸鹽或丙交酯/乙交酯共聚物、聚乳酸交酯/乙交酯共聚物或乙烯乙酸乙烯酯共聚物以便控制所投與之組合物之遞送。舉例而言,經口藥劑可截留在藉由凝聚技術或藉由界面聚合,藉由分別使用羥甲基纖維素或明膠微膠囊或聚(甲基丙烯酸甲酯)微膠囊製備之微膠囊中或在膠體藥物遞送系統中。膠體分散系統包括大分子複合物、奈米膠囊、微球、微珠及包括水包油乳化液、微胞、混合微胞及脂質體的基於脂質之系統。製備上文所提及之調配物之方法將為熟習此項技術者顯而易見。
用於經口使用之調配物亦可以硬明膠膠囊形式呈現,其中活性成分與惰性固體稀釋劑(例如,碳酸鈣、磷酸鈣、高嶺土或微晶纖維素)混合;或以軟明膠膠囊形式呈現,其中活性成分與水或油狀介質(例如,花生油、液體石蠟或橄欖油)混合。
水性懸浮液含有與適用於製造活性材料之賦形劑摻合的活性材料。此等賦形劑可為懸浮劑,例如羧甲基纖維素鈉、甲基纖維素、羥基-丙基甲基纖維素、海藻酸鈉、聚乙烯-吡咯啶酮、黃蓍膠及阿拉伯膠;分散劑或濕潤劑,例如天然存在之磷脂(例如,卵磷脂)或環氧烷與脂肪酸之縮合產物(例如,聚氧-乙烯硬脂酸酯)或環氧乙烷與長鏈脂族醇之縮合產物(例如,十七伸乙基氧基十六醇)或環氧乙烷與衍生自脂肪酸及己糖醇之偏酯的縮合產物(例如,聚氧乙烯山梨糖醇單油酸酯)或環氧乙烷與衍生自脂肪酸及己糖醇酐之偏酯的縮合產物(例如,聚乙烯脫水山梨糖醇單油酸酯)。水性懸浮液亦可含有一或多種防腐劑。
油性懸浮液可藉由將活性成分懸浮於植物油(例如,花生油、橄欖油、芝麻油或椰子油)或礦物油(諸如液體石蠟)中來調配。油性懸浮液可含有增稠劑,例如蜂蠟、硬石蠟或鯨蠟醇。可添加甜味劑(諸如上文所闡述之彼等甜味劑)及調味劑,以提供可口的經口製劑。
適用於藉由添加水來製備水性懸浮液之可分散散劑及顆粒提供與分散劑或濕潤劑、懸浮劑及一或多種防腐劑之摻合的活性成分。適合分散劑或濕潤劑及懸浮劑例示於本文中。
本發明之醫藥組合物亦可呈水包油乳液形式。油相可為植物油,例如橄欖油或花生油;或礦物油,例如液體石蠟;或此等之混合物。適合乳化劑可為天然存在之膠,例如阿拉伯膠或黃蓍膠;天然存在之磷脂,例如大豆、卵磷脂及衍生自脂肪酸之酯或偏酯;己糖醇酐,例如脫水山梨糖醇單油酸酯;以及偏酯與環氧乙烷之縮合產物,例如聚氧乙烯脫水山梨糖醇單油酸酯。
醫藥組合物通常包含治療有效量的本發明所涵蓋之精胺酸酶抑制劑及一或多種醫藥學上及生理學上可接受之調配藥劑。適合醫藥學上可接受或生理學上可接受之稀釋劑、載劑或賦形劑包括(但不限於)抗氧化劑(例如,抗壞血酸及硫酸氫鈉)、防腐劑(例如,苯甲醇、對羥基苯甲酸甲酯、對羥基苯甲酸乙酯或對羥基苯甲酸正丙酯)、乳化劑、懸浮劑、分散劑、溶劑、填充劑、膨化劑、清潔劑、緩衝液、媒劑、稀釋劑及/或佐劑。舉例而言,適合媒劑可為生理鹽水溶液或檸檬酸鹽緩衝鹽水,其可能補充有用於非經腸投與之醫藥組合物中常見的其他材料。中性緩衝鹽水或與血清白蛋白混合之鹽水為另外的例示性媒劑。熟習此項技術者將容易識別可用於本文所涵蓋之醫藥組合物及劑型中之各種緩衝液。典型緩衝液包括(但不限於)醫藥學上可接受之弱酸、弱鹼或其混合物。作為實例,緩衝液組分可為水溶性物質,諸如磷酸、酒石酸、乳酸、丁二酸、檸檬酸、乙酸、抗壞血酸、天冬胺酸、麩胺酸及其鹽。可接受之緩衝劑包括例如Tris緩衝液、N-(2-羥乙基)哌嗪-N'-(2-乙磺酸) (HEPES)、2-(N-(N-嗎啉基))乙磺酸(MES)、2-(N-(N-嗎啉基))乙磺酸鈉鹽(MES)、3-(N-(N-嗎啉基))丙磺酸(MOPS)及N-參[羥甲基]甲基-3-胺基丙磺酸(TAPS)。
在已調配醫藥組合物之後,可將其以溶液、懸浮液、凝膠、乳液、固體或脫水或凍乾粉末形式儲存於無菌小瓶中。此等調配物可以即用形式、需要在使用之前復水之凍乾形式、需要在使用之前稀釋之液體形式或其他可接受之形式儲存。在一些實施例中,在單次使用之容器(例如,單次使用之小瓶、安瓿、針筒或自動注射器(類似於例如EpiPen®))中提供醫藥組合物,然而在其他實施例中提供多次使用之容器(例如,多次使用之小瓶)。
調配物亦可包括保護組合物免於快速降解或自身體排出(諸如控制釋放調配物)之載劑,包括脂質體、水凝膠、前藥及微囊封遞送系統。舉例而言,可採用時間延遲材料,諸如僅單硬脂酸甘油酯或硬脂酸甘油酯或其與蠟之組。任何藥物遞送設備可用於遞送精胺酸酶抑制劑,包括植入物(例如,可植入泵)及導管系統、緩慢注射泵及裝置,其所有均為熟習此項技術者所熟知。
通常皮下或肌肉內投與的儲槽式注射劑亦可用於在經限定時間段內釋放本文中所揭示之精胺酸酶抑制劑。儲槽式注射劑通常基於固體或油且一般包含本文中所闡述之調配物組分中之至少一者。一般熟習此項技術者熟悉儲槽式注射劑之可能的調配物及用途。
醫藥組合物可呈無菌可注射水性或油性懸浮液形式。此懸浮液可根據已知技術使用本文中所提及之彼等適合分散劑或濕潤劑及懸浮劑來調配。無菌可注射製劑亦可為無毒非經腸可接受之稀釋劑或溶劑中之無菌可注射溶液或懸浮液,例如呈於1,3-丁二醇中之溶液形式。可採用的可接受之稀釋劑、溶劑及分散介質包括水、林格氏溶液(Ringer's solution)、等張性氯化鈉溶液、Cremophor EL™ (BASF,Parsippany,NJ)或磷酸鹽緩衝鹽水(phosphate buffered saline;PBS)、乙醇、多元醇(例如,甘油、丙二醇及液態聚乙二醇)及其適合混合物。另外,無菌不揮發性油習知地用作溶劑或懸浮介質。出於此目的,可採用任何溫和的不揮發性油,包括合成單甘油酯或二甘油酯。此外,諸如油酸之脂肪酸可用於製備可注射劑。可藉由包括延遲吸收之藥劑(例如,單硬脂酸鋁或明膠)來實現特定可注射調配物之延長吸收。
本發明涵蓋投與呈用於經直腸投與之栓劑形式的精胺酸酶抑制劑。可藉由將藥物與適合無刺激性賦形劑混合來製備栓劑,該賦形劑在常溫下為固體但在直腸溫度下為液體且因此將在直腸中熔融以釋放藥物。此等材料包括(但不限於)可可脂及聚乙二醇。
本發明所涵蓋之精胺酸酶抑制劑可呈目前已知或將來所研發的任何其他適合醫藥組合物之形式(例如,針對經鼻或吸入使用之噴霧劑)。投與途徑
本發明涵蓋以任何適當方式投與精胺酸酶抑制劑及其組合物。適合投與途徑包括經口、非經腸(例如,肌肉內、靜脈內、皮下(例如,注射或植入)、腹膜內、腦池內、關節內、腹膜內、腦內(腦實質內)及腦室內)、經鼻、陰道、舌下、眼內、經直腸、局部(例如,經皮)、頰內及吸入。通常皮下或肌肉內投與的儲槽式注射劑亦可用於在經限定時間段內釋放本文中所揭示之精胺酸酶抑制劑。
本發明之特定實施例涵蓋經口投與。組合療法
本發明涵蓋僅精胺酸酶抑制劑之用途或與一或多種活性治療劑組合之用途。額外活性治療劑可為小化學分子;大分子,諸如蛋白質、抗體、肽體、肽、DNA、RNA或此等大分子之片段;或細胞或基因療法。在此組合療法中,各種活性劑經常具有不同、互補的作用機制。此組合療法可藉由允許藥劑中之一或多者之劑量減少,由此減少或消除與藥劑中之一或多者相關之不良效應而尤其有利。此外,此組合療法可對根本疾病、病症或病狀具有協同治療性或預防性效果。
如本文中所使用,「組合」意謂包括可單獨投與之療法,例如單獨調配以供單獨投與(例如,當可在套組中提供時);及可以單一調配物(亦即,「共調配物」)形式一起投與之療法。
在某些實施例中,依序投與或施加精胺酸酶抑制劑,例如其中在一或多種其他藥劑之前投與一種藥劑。在其他實施例中,同時投與精胺酸酶抑制劑,例如其中在相同時間或約相同時間處投與兩種或多於兩種藥劑;兩種或多於兩種藥劑可以兩種或多於兩種單獨調配物形式存在或合併成單一調配物(亦即,共調配物)。不論是否依序或同時投與兩種或多於兩種藥劑,出於本發明之目的認為其應以組合形式投與。
本發明之精胺酸酶抑制劑可在該等情況下以適當之任何方式與至少一種其他(活性)藥劑組合使用。在一個實施例中,在一段時間內維持用至少一種活性劑及至少一種本發明之精胺酸酶抑制劑進行之治療。在另一實施例中,減少或中斷用至少一種活性劑進行之治療(例如,在個體穩定時),而在恆定給藥方案下維持用本發明之精胺酸酶抑制劑進行之治療。在另一實施例中,減少或中斷用至少一種活性劑進行之治療(例如,在個體穩定時),同時減少用本發明之精胺酸酶抑制劑進行之治療(例如,較低劑量、不太頻繁給藥或較短治療方案)。在又一實施例中,減少或中斷用至少一種活性劑進行之治療(例如,在個體穩定時),且增加用本發明之精胺酸酶抑制劑進行之治療(例如,較高劑量、較頻繁給藥或較長治療方案)。在又一實施例中,維持用至少一種活性劑進行之治療且減少或中斷用本發明之精胺酸酶抑制劑進行之治療(例如,較低劑量、不太頻繁給藥或較短治療方案)。在又一實施例中,減少或中斷用至少一種活性劑進行之治療及用本發明之精胺酸酶抑制劑進行之治療(例如,較低劑量、不太頻繁給藥或較短治療方案)。
腫瘤學相關病症
.本發明提供用精胺酸酶抑制劑及至少一種額外治療劑或診斷劑來治療及/或預防增殖病狀、癌症、腫瘤或癌變前疾病、病症或病狀的方法。在一些實施例中,額外治療劑或診斷劑為放射、免疫調節劑或化學治療劑或診斷劑。可用於本發明中之適合免疫調節劑包括CD4OL、B7及B7RP1;用以刺激受體之活化單株抗體(mAb),諸如抗CD40、抗CD38、抗ICOS及4-IBB配體;樹突狀細胞抗原負載(活體外或活體內);抗癌疫苗,諸如樹突狀細胞癌症疫苗;細胞介素/趨化因子,諸如IL2、IL12、IL18、ELC/CCL19、SLC/CCL21、MCP-1、IL-4、IL-18、TNF、IL-15、MDC、IFNa/b、M-CSF、IL-3、GM-CSF、IL-13及抗IL-10;細菌脂多醣(LPS);吲哚胺2,3-二加氧酶1 (IDO1)抑制劑及免疫刺激寡核苷酸。
在某些實施例中,本發明提供針對腫瘤生長之腫瘤抑制的方法,其包含投與本文中所描述之精胺酸酶抑制劑以及信號轉導抑制劑(STI),以實現腫瘤生長之附加或協同抑制。如本文中所使用,術語「信號轉導抑制劑」係指選擇性抑制信號傳導路徑中之一或多個步驟的藥劑。本發明之信號轉導抑制劑(STI)包括:(i) bcr/abl激酶抑制劑(例如,GLEEVEC);(ii)表皮生長因子(EGF)受體抑制劑,包括激酶抑制劑及抗體;(iii) her-2/neu受體抑制劑(例如,HERCEPTIN);(iv) Akt家族激酶或Akt路徑之抑制劑(例如,雷帕黴素(rapamycin));(v)細胞循環激酶抑制劑(例如,夫拉平度(flavopiridol));以及(vi)磷脂醯基肌醇激酶抑制劑。免疫調節中所涉及之藥劑亦可與本文中所描述之精胺酸酶抑制劑組合使用以供抑制癌症患者之腫瘤生長。
化學治療劑之實例包括(但不限於):烷基化劑,諸如噻替派及環磷醯胺;磺酸烷基酯,諸如白消安、英丙舒凡(improsulfan)及哌泊舒凡(piposulfan);氮丙啶,諸如苯唑多巴(benzodopa)、卡波醌(carboquone)、米特多巴(meturedopa)及尤利多巴(uredopa);伸乙亞胺及甲基三聚氰胺,包括六甲蜜胺、三伸乙基三聚氰胺、三伸乙基磷醯胺、三伸乙基硫代磷醯胺及三羥甲基三聚氰胺;氮芥,諸如氮芥苯丁酸、萘氮芥、氯磷醯胺、雌莫司汀、異環磷醯胺、二氯甲基二乙胺、二氯甲基二乙胺氧化物鹽酸鹽、美法侖、新氮芥(novembichin)、苯芥膽甾醇、潑尼氮芥(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥;亞硝基脲,諸如卡莫司汀、氯脲菌素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀、尼莫司汀(nimustine)、雷莫司汀(ranimustine);抗生素,諸如阿克拉黴素、放射菌素、安麯黴素(authramycin)、偶氮絲胺酸、博萊黴素、放線菌素C (cactinomycin)、卡奇黴素(calicheamicin)、卡柔比星(carabicin)、洋紅黴素(caminomycin)、嗜癌菌素(carzinophilin)、色黴素(chromomycins)、放線菌素D (dactinomycin)、道諾黴素(daunorubicin)、地托比星(detorubicin)、6-重氮-5-側氧基-L-正白胺酸、小紅莓、表柔比星(epirubicin)、依索比星(esorubicin)、艾達黴素(idarubicin)、麻西羅黴素(marcellomycin)、絲裂黴素(mitomycins)、黴酚酸(mycophenolic acid)、諾加黴素(nogalamycin)、橄欖黴素(olivomycins)、培洛黴素(peplomycin)、潑非黴素(potfiromycin)、嘌呤黴素、奎那黴素(quelamycin)、羅多比星(rodorubicin)、鏈黑菌素(streptonigrin)、鏈脲菌素(streptozocin)、殺結核菌素(tubercidin)、烏苯美司(ubenimex)、淨司他丁(zinostatin)、左柔比星(zorubicin);抗代謝物,諸如甲胺喋呤及5-氟尿嘧啶(5-FU);葉酸類似物,諸如迪諾特寧(denopterin)、甲胺喋呤、蝶羅呤(pteropterin)、曲美沙特;嘌呤類似物,諸如氟達拉濱、6-巰基嘌呤、硫咪嘌呤(thiamiprine)、硫鳥嘌呤(thioguanine);嘧啶類似物,諸如安西他濱(ancitabine)、阿紮胞苷、6-氮雜尿苷、卡莫氟(carmofur)、阿糖胞苷、二去氧尿苷(dideoxyuridine)、去氧氟尿苷(doxifluridine)、依諾他濱(enocitabine)、氟尿苷(floxuridine)、5-FU;雄激素,諸如卡普睾酮(calusterone)、丙酸屈他雄酮(dromostanolone propionate)、環硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睾內酯(testolactone);抗腎上腺,諸如胺魯米特、米托坦、曲洛司坦(trilostane);葉酸補充劑,諸如亞葉酸(frolinic acid);醋葡醛內酯(aceglatone);醛磷醯胺糖苷(aldophosphamide glycoside);胺基乙醯丙酸;安吖啶;倍思塔布(bestrabucil);比生群(bisantrene);艾達曲克(edatraxate);得弗伐胺(defofamine);秋水仙胺(demecolcine);地吖醌(diaziquone);艾福米辛(elformithine);依利醋銨(elliptinium acetate);依託格魯(etoglucid);硝酸鎵;羥基脲;香菇多糖(lentinan);氯尼達明(lonidamine);丙脒腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌達醇(mopidamol);二胺硝吖啶(nitracrine);噴司他汀;凡那明(phenamet);吡柔比星(pirarubicin);鬼臼酸(podophyllinic acid);2-乙基醯肼;丙卡巴肼;雷佐生(razoxane);西佐喃(sizofiran);鍺螺胺(spirogermanium);細交鏈孢菌酮酸(tenuazonic acid);三亞胺醌(triaziquone);2,2',2''-三氯三乙胺;烏拉坦(urethan);長春地辛(vindesine);達卡巴嗪;甘露莫司汀(mannomustine);二溴甘露醇(mitobronitol);二溴衛矛醇(mitolactol);哌泊溴烷(pipobroman);加西托星(gacytosine);阿拉伯糖苷(Ara-C);環磷醯胺;噻替派;紫杉烷類,例如太平洋紫杉醇及多西他賽(doxetaxel);氯芥苯丁酸;吉西他濱;6-硫鳥嘌呤;巰基嘌呤;甲胺喋呤;鉑及鉑配位複合物,諸如順鉑、卡鉑及奧沙利鉑;長春鹼;依託泊苷(VP-16);異環磷醯胺;絲裂黴素C;米托蒽醌;長春新鹼;長春瑞賓(vinorelbine);溫諾平(navelbine);諾安托(novantrone);替尼泊苷;道諾黴素;胺基喋呤;希羅達(xeloda);伊班膦酸鹽(ibandronate);CPT11;拓樸異構酶抑制劑;二氟甲基鳥胺酸(DMFO);視黃酸;埃斯波黴素(esperamicins);卡培他濱(capecitabine);蒽環黴素;以及以上中之任一者的醫藥學上可接受之鹽、酸或衍生物。
化學治療劑亦包括用以調節或抑制激素對腫瘤之作用的抗激素劑,諸如抗雌激素,包含例如他莫昔芬、雷諾昔芬(raloxifene)、芳香酶抑制4(5)-咪唑、4-羥基他莫昔芬、曲沃昔芬(trioxifene)、那洛昔芬(keoxifene)、奧那司酮(onapristone)及托瑞米芬(toremifene);及抗雄激素,諸如氟他胺、尼魯胺(nilutamide)、比卡魯胺(bicalutamide)、亮丙瑞林(leuprolide)及戈舍瑞林(goserelin);以及以上中之任一者的醫藥學上可接受之鹽、酸或衍生物。在某些實施例中,組合療法包含化療療程,該化療療程包括一或多種化學治療劑。在某些實施例中,組合療法包含投與激素或相關激素劑。
可與精胺酸酶抑制劑組合使用之額外治療模態包括放射療法、針對腫瘤抗原之單株抗體、單株抗體及毒素之複合物、T細胞佐劑、骨髓移植物或抗原呈遞細胞(例如,樹突狀細胞療法),包括用於刺激此等抗原呈遞細胞的TLR促效劑。
在某些實施例中,本發明涵蓋本文中所描述之化合物與授受細胞療法之組合的用途,該授受細胞療法為一種向癌症患者投與具有抗腫瘤活性之免疫細胞的新穎且有前景的個性化免疫療法形式。正使用經工程改造以表現例如嵌合抗原受體(chimeric antigen receptor;CAR)或T細胞受體(chimeric antigen receptor;TCR)之腫瘤浸潤性淋巴細胞(tumor-infiltrating lymphocyte;TIL)及T細胞來探索授受細胞療法。授受細胞療法通常涉及自個體採集T細胞,對其進行基因修飾以靶向特異性抗原或增強其抗腫瘤效果,從而將其擴增至充足數目,以及將經基因修飾之T細胞輸注至癌症患者中。T細胞可採集自隨後將向其重新輸注經擴充細胞之患者(例如,自體)或可採集自捐獻患者(例如,同種異體)。
在某些實施例中,本發明涵蓋本文中所描述之化合物與基於RNA干擾之療法組合以使基因表現沈默的用途。RNAi開始將較長雙鏈RNA裂解成小干涉RNA (siRNA)。siRNA中之一條鏈併入至稱為RNA誘導沈默複合物(RNA-induced silencing complex;RISC)之核糖核蛋白複合物中,其接著用於鑑別與所併入siRNA鏈至少部分互補的mRNA分子。RISC可結合於mRNA或裂解mRNA,其兩者均抑制轉譯。
在某些實施例中,本發明涵蓋本文中所描述之化合物與調節腺苷含量之藥劑組合的用途。此等治療劑可對催化ATP轉化為腺苷之胞外核苷酸起作用,包括將ATP水解為ADP且將ADP水解為AMP之胞外核苷三磷酸二磷酸水解酶1 (ENTPD1,亦稱為CD39或分化簇(Cluster of Differentiation) 39)及將AMP轉化為腺苷之胞外5'-核苷酸酶(NT5E或5NT,亦稱為CD73或分化簇73)。CD39及CD73之酶促活性在校準遞送至各種細胞(例如,免疫細胞)之嘌呤型信號的持續時間、量值及化學性質方面發揮關鍵作用。此等酶促活性之更改可改變若干病理生理學事件(包括癌症、自體免疫疾病、感染、動脈粥樣硬化症及缺血-再灌注損傷)之過程或指定其結果,從而表明此等胞外酶表示用於管理各種病症之新穎治療目標。
替代地,此等治療劑可為腺苷2受體(A2
R)拮抗劑。腺苷可結合於四種不同G蛋白偶合之受體且活化該等G蛋白偶合之受體:A1
R、A2a
R、A2b
R及A3
R。將腺苷結合於在T細胞上表現之A2a
R受體、自然殺手細胞及諸如樹突狀細胞之骨髓細胞使得增加胞內環狀AMP含量且損害此等細胞之成熟及/或活化。此製程顯著損害免疫系統抵抗癌細胞之活化。另外,A2A
R涉及選擇性地增強抗炎性細胞介素,從而促進PD-1及CTLA-4之上調,促進LAG-3及Foxp3+調節性T細胞之產生且介導對調節性T細胞之抑制。本文中進一步論述PD-1、CTLA-4及其他免疫檢查點。將本文中所描述之組合中之A2R拮抗劑組合可鑒於其不同作用機制而提供至少一種附加效果。
在某些實施例中,本發明涵蓋本文中所描述之化合物與磷脂醯肌醇3-激酶(PI3K)之抑制劑,特定言之PI3Kγ同功異構物組合的用途。PI3Kγ抑制劑可經由調節骨髓細胞,諸如藉由抑制抑止性骨髓細胞,潤濕免疫抑止性腫瘤浸潤性巨噬細胞或藉由刺激巨噬細胞及樹突狀細胞來刺激抗癌免疫反應,以產生有助於有效T細胞反應之細胞介素,從而產生減少的癌症發展及擴散。
在某些實施例中,本發明涵蓋本文中所描述之化合物與低氧誘導因子(HIF)抑制劑組合的用途。HIF轉錄因子對用於感測且對低氧含量作出反應之信號傳導路徑為不可或缺的。實體腫瘤之微環境已知為缺氧的且需要誘導與腫瘤細胞之代謝、生長、增殖及血管生成相關的基因以存活及轉移。特定而言,HIF-2α同功異構物與癌症、發炎及免疫調節病狀有關。
免疫檢查點抑制劑
.本發明涵蓋本文中所描述之精胺酸酶功能之抑制劑與免疫檢查點抑制劑組合的用途。
作為所有癌症之特徵之極大數目之基因及表觀基因變異提供免疫系統可用於區分腫瘤細胞與其正常對應物之不同組的抗原。在T細胞之情況下,利用共刺激信號與抑制信號(免疫檢查點)之間的平衡來調節經由T細胞受體(TCR)之抗原識別引發的反應之最終幅度(例如,細胞介素產生或增殖之含量)及品質(例如,所產生之免疫反應之類型,諸如細胞介素產生之模式)。在正常生理條件下,免疫檢查點對於自體免疫之預防(亦即,自身耐受性之維持)以及亦對於在免疫系統對病原性感染作出反應時使組織免受損傷而言為至關重要的。免疫檢查點蛋白之表現可藉由腫瘤失調作為重要免疫耐受機制。
T細胞由於以下而為治療學上操控內源抗腫瘤免疫性之努力之工作焦點:i)其選擇性識別所有細胞區室中自蛋白質衍生之肽的能力;ii)其直接識別且殺死抗原表現細胞(利用CD8+效應T細胞;亦稱為細胞毒性T淋巴球(CTL))的能力;以及iii)其藉由整合適應性及先天性效應機制之CD4+輔助T細胞來協調不同免疫反應的能力。
在臨床配置中,引起抗原特異性T細胞反應之擴增的免疫檢查點之阻斷經展示為人類癌症療法中之有前景的方法。
T細胞介導之免疫性包括多個依序步驟,其中之每一者藉由均衡刺激及抑制信號來調節,以便使反應最佳化。雖然免疫反應中幾乎所有抑制信號最終調節細胞內信號傳導路徑,但許多經由膜受體起始,其配體為膜結合或可溶的(細胞介素)。雖然調節T細胞活化之共刺激及抑制受體及配體相對於正常組織經常不在癌症中過度表現,但在組織中調節T細胞效應功能之抑制配體及受體通常在腫瘤細胞上或在與腫瘤微環境相關之未經轉型細胞上過度表現。可溶及膜結合受體-配體免疫檢查點之功能可使用促效劑抗體(對於共刺激路徑)或拮抗劑抗體(對於抑制路徑)來調節。因此,與目前批准用於癌症療法之大多數抗體相反,阻斷免疫檢查點之抗體並不直接靶向腫瘤細胞,而靶向淋巴球受體或其配體以便增強內源抗腫瘤活性。[參見Pardoll, (April 2012) Nature Rev. Cancer 12:252-64]。
作為阻斷之候選物的免疫檢查點(配體及受體)之實例(其中之一些在各種類型之腫瘤細胞中選擇性上調)包括PD1 (計劃性細胞死亡蛋白1);PDL1 (PD1配體);BTLA (B及T淋巴球衰減子);CTLA4 (細胞毒性T淋巴球相關抗原4);TIM3 (T細胞膜蛋白3);LAG3 (淋巴球活化基因3);TIGIT (具有Ig及ITIM域之T細胞免疫受體);及殺手抑制受體,其可基於其結構特徵劃分成兩種類別:i)殺手細胞免疫球蛋白樣受體(KIR)及ii) C型凝集素受體(II型跨膜受體家族之成員)。其他不太明確定義之免疫檢查點已描述於文獻中,包括受體(例如2B4 (亦稱為CD244)受體)及配體(例如,某些B7家族抑制配體,諸如B7-H3 (亦稱為CD276)及B7-H4 (亦稱為B7-S1、B7x及VCTN1))兩者。[參見Pardoll, (April 2012) Nature Rev. Cancer 12:252-64]。
本發明涵蓋本文中所描述之精胺酸酶功能之抑制劑與前述免疫檢查點受體及配體之抑制劑以及將描述之免疫檢查點受體及配體組合的用途。免疫檢查點之某些調節劑目前可獲得,而其他處於後階段發展中。為了說明,當完全人類化CTLA4單株抗體伊匹單抗(ipilimumab) (YERVOY;Bristol-Myers Squibb)在2011年批准用於治療黑色素瘤時,其成為接受美國管理批准之第一種免疫檢查點抑制劑。包含CTLA4及抗體(CTLA4-Ig;abatcept (ORENCIA;Bristol-Myers Squibb))之融合蛋白用於治療類風濕性關節炎,且其他融合蛋白已展示為在對埃-巴二氏病毒敏感之腎移植患者中有效。PD1抗體處於研發中(例如,納武單抗(nivolumab) (Bristol-Myers Squibb)及蘭利珠單抗(Merck)),且亦評估抗PDL1抗體(例如,MPDL3280A (Roche))。納武單抗已在患有黑色素瘤、肺癌及腎癌之患者中展示出前景。
在本發明之一個態樣中,所主張之精胺酸酶抑制劑與免疫腫瘤學藥劑組合,該免疫腫瘤學藥劑為(i)刺激(包括共刺激)受體之促效劑或(ii) T細胞上之抑制(包括共抑制)信號之拮抗劑,其兩者均使得擴增抗原特異性T細胞反應。某些刺激及抑制分子為免疫球蛋白超家族(IgSF)之成員。結合於共刺激或共抑制受體的膜結合配體之一個重要家族為B7家族,其包括B7-1、B7-2、B7-H1 (PD-L1)、B7-DC (PD-L2)、B7-H2 (ICOS-L)、B7-H3、B7-H4、B7-H5 (VISTA)及B7-H6。結合於共刺激或共抑制受體的膜結合配體之另一家族為結合於同源TNF受體家族成員的分子之TNF家族,其包括CD40及CD4OL、OX-40、OX-40L、CD70、CD27L、CD30、CD3OL、4-1BBL、CD137 (4-1BB)、TRAIL/Apo2-L、TRAILR1/DR4、TRAILR2/DR5、TRAILR3、TRAILR4、OPG、RANK、RANKL、TWEAKR/Fn14、TWEAK、BAFFR、EDAR、XEDAR、TACI、APRIL、BCMA、LT13R、LIGHT、DcR3、HVEM、VEGI/TL1A、TRAMP/DR3、EDAR、EDA1、XEDAR、EDA2、TNFR1、淋巴毒素a/TNF13、TNFR2、TNFa、LT13R、淋巴毒素a 1132、FAS、FASL、RELT、DR6、TROY、NGFR。
在另一態樣中,免疫腫瘤學藥劑為抑制T細胞活化之細胞介素(例如,IL-6、IL-10、TGF-B、VEGF及其他免疫抑制細胞介素)或刺激T細胞活化之細胞介素,以供刺激免疫反應。
在一個態樣中,T細胞反應可由所揭示精胺酸酶抑制劑與以下中之一或多者之組合來刺激:(i)抑制T細胞活化的蛋白質之拮抗劑(例如,免疫檢查點抑制劑),諸如CTLA-4、PD-1、PD-L1、PD-L2、LAG-3、TIM-3、半乳糖凝集素9、CEACAM-1、BTLA、CD69、半乳糖凝集素-1、TIGIT、CD113、GPR56、VISTA、2B4、CD48、GARP、PD1H、LAIR1、TIM-1及TIM-4;及/或(ii)刺激T細胞活化的蛋白質之促效劑,諸如B7-1、B7-2、CD28、4-1BB (CD137)、4-1BBL、ICOS、ICOS-L、OX40、OX4OL、GITR、GITRL、CD70、CD27、CD40、DR3及CD2。可與本發明之精胺酸酶抑制劑組合以用於治療癌症的其他藥劑包括NK細胞上之抑制受體之拮抗劑或NK細胞上之活化受體之促效劑。舉例而言,本文中之化合物可與KIR之拮抗劑,諸如利瑞路單抗(lirilumab)組合。
用於組合療法之又其他藥劑包括抑制或消耗巨噬細胞或單核球之藥劑,包括(但不限於):CSF-1R拮抗劑,諸如CSF-1R拮抗劑抗體,包括RG7155 (W011/70024、W011/107553、W011/131407、W013/87699、W013/119716、W013/132044)或FPA-008 (W011/140249;W013169264;W014/036357)。
在另一態樣中,所揭示精胺酸酶抑制劑可與以下中之一或多者一起使用:接合陽性共刺激受體之促效劑;經由抑制受體衰減信號傳導之阻斷劑;拮抗劑;及全身性增加抗腫瘤T細胞之頻率的一或多種藥劑;克服腫瘤微環境內不同免疫抑止路徑(例如,阻斷抑制性受體接合(例如,PD-L1/PD-1相互作用)、消耗或抑制Treg (例如,使用抗CD25單株抗體(例如,達利珠單抗(daclizumab))或藉由離體抗CD25珠粒消耗)或逆轉/防止T細胞失能或耗竭)的藥劑;以及觸發腫瘤位點處之先天性免疫活化及/或發炎的藥劑。
在一個態樣中,免疫腫瘤學藥劑為CTLA-4拮抗劑,諸如拮抗CTLA-4抗體。適合CTLA-4抗體包括例如易沃伊(YERVOY) (伊匹單抗)或曲美單抗(tremelimumab)。
在另一態樣中,免疫腫瘤學藥劑為PD-1拮抗劑,諸如拮抗PD-1抗體。適合PD-1抗體包括例如歐狄沃(OPDIVO) (納武單抗)、克珠達(KEYTRUDA) (派姆單抗(pembrolizumab))或MEDI-0680 (AMP-514;W02012/145493)。免疫腫瘤學藥劑亦可包括皮立珠單抗(pidilizumab) (CT-011),儘管已質疑其對於PD-1結合之特異性。靶向PD-1受體之另一方法為由PD-L2 (B7-DC)之胞外域與IgG1之Fc部分融合而組成之重組蛋白,稱作AMP-224。
在另一態樣中,免疫腫瘤學藥劑為PD-L1拮抗劑,諸如拮抗PD-L1抗體。適合PD-L1抗體包括例如MPDL3280A (RG7446;W02010/077634)、德瓦魯單抗(durvalumab) (MEDI4736)、BMS-936559 (W02007/005874)及MSB0010718C (W02013/79174)。
在另一態樣中,免疫腫瘤學藥劑為LAG-3拮抗劑,諸如拮抗LAG-3抗體。適合LAG3抗體包括例如BMS-986016 (W010/19570、W014/08218)或IMP-731或IMP-321 (W008/132601、W009/44273)。
在另一態樣中,免疫腫瘤學藥劑為CD137 (4-1BB)促效劑,諸如促效CD137抗體。適合CD137抗體包括例如優瑞路單抗(urelumab)及PF-05082566 (W012/32433)。
在另一態樣中,免疫腫瘤學藥劑為GITR促效劑,諸如促效GITR抗體。適合GITR抗體包括例如BMS-986153、BMS-986156、TRX-518 (W006/105021、W009/009116)及MK-4166 (W011/028683)。
在另一態樣中,免疫腫瘤學藥劑為OX40促效劑,諸如促效OX40抗體。適合OX40抗體包括例如MEDI-6383或MEDI-6469。
在另一態樣中,免疫腫瘤學藥劑為OX4OL拮抗劑,諸如拮抗OX40抗體。適合OX4OL拮抗劑包括例如RG-7888 (W006/029879)。
在另一態樣中,免疫腫瘤學藥劑為CD40促效劑,諸如促效CD40抗體。在又一實施例中,免疫腫瘤學藥劑為CD40拮抗劑,諸如拮抗CD40抗體。適合CD40抗體包括例如魯卡木單抗(lucatumumab)或達西珠單抗(dacetuzumab)。
在另一態樣中,免疫腫瘤學藥劑為CD27促效劑,諸如促效CD27抗體。適合CD27抗體包括例如瓦里木單抗(varlilumab)。
在另一態樣中,免疫腫瘤學藥劑為MGA271 (針對B7H3) (W011/109400)。
本發明涵蓋上文中之任一者的醫藥學上可接受之鹽、酸或衍生物。
代謝及心血管疾病
.本發明提供用精胺酸酶抑制劑及至少一種額外治療劑或診斷劑治療及/或預防某些心臟血管相關及/或代謝相關疾病、病症及病狀以及與其相關之病症的方法。
適用於治療高膽固醇血症(以及動脈粥樣硬化症)之組合療法的治療劑之實例包括士他汀(statins) (例如,克里斯特(CRESTOR)、來適可(LESCOL)、立普妥(LIPITOR)、默伏卡(MEVACOR)、普拉固(PRAVACOL)及素果(ZOCOR)),其抑制膽固醇之酶促合成;膽汁酸樹脂(例如,考來替泊(COLESTID)、洛膽甾(LO-CHOLEST)、普雷威力特(PREVALITE)、降膽敏(QUESTRAN)及考來維侖(WELCHOL)),其螯合膽固醇且防止其吸收;依澤替米貝(ezetimibe) (艾澤庭(ZETIA)),其阻斷膽固醇吸收;纖維酸(例如,特瑞科爾(TRICOR)),其減少三酸甘油酯且可適當地增加HDL;菸酸(例如,尼阿克(NIACOR)),其適當地降低LDL膽固醇及三酸甘油酯;及/或前述之組合(例如,維多靈(VYTORIN) (依澤替米貝與辛伐他汀(simvastatin))。可為用於與本文中所描述之精胺酸酶抑制劑組合使用之候選物的替代膽固醇治療劑包括各種補充劑及草本植物(例如,大蒜、甘蔗原素(policosanol)及印度香膠樹(guggul))。
本發明涵蓋上文中之任一者的醫藥學上可接受之鹽、酸或衍生物。
免疫及發炎相關病症
.本發明提供用精胺酸酶抑制劑及至少一種額外治療劑或診斷劑治療及/或預防免疫相關疾病、病症及病狀以及具有發炎組分之疾病、病症及病狀的方法。
適用於組合療法的治療劑之實例包括(但不限於)以下:非類固醇消炎藥(NSAID),諸如阿司匹林(aspirin)、布洛芬(ibuprofen)及其他丙酸衍生物(阿明洛芬(alminoprofen)、苯惡洛芬(benoxaprofen)、布氯酸(bucloxic acid)、卡洛芬(carprofen)、芬布芬(fenbufen)、非諾洛芬(fenoprofen)、氟洛芬(fluprofen)、氟比洛芬(flurbiprofen)、吲哚洛芬(indoprofen)、酮基布洛芬(ketoprofen)、咪洛芬(miroprofen)、萘普生(naproxen)、奧沙普嗪(oxaprozin)、吡洛芬(pirprofen)、普拉洛芬(pranoprofen)、舒洛芬(suprofen)、噻洛芬酸(tiaprofenic acid)及硫惡洛芬(tioxaprofen))、乙酸衍生物(吲哚美辛(indomethacin)、阿西美辛(acemetacin)、阿氯芬酸(alclofenac)、環氯茚酸(clidanac)、雙氯芬酸(diclofenac)、芬氯酸(fenclofenac)、芬克洛酸(fenclozic acid)、芬替酸(fentiazac)、弗洛芬克(fuirofenac)、異丁芬酸(ibufenac)、伊索克酸(isoxepac)、噁平酸(oxpinac)、舒林酸(sulindac)、硫平酸(tiopinac)、托美丁(tolmetin)、齊多美辛(zidometacin)及佐美酸(zomepirac))、芬那酸(fenamic acid)衍生物(氟芬那酸(flufenamic acid)、甲氯芬那酸(meclofenamic acid)、甲芬那酸(mefenamic acid)、氟尼酸(niflumic acid)及托芬那酸(tolfenamic acid))、聯苯羧酸衍生物(二氟尼柳(diflunisal)及氟苯柳(flufenisal))、昔康(oxicam) (伊索昔康(isoxicam)、吡羅昔康(piroxicam)、舒多昔康(sudoxicam)及替諾昔康(tenoxican))、水楊酸鹽(乙醯基水楊酸、柳氮磺胺吡啶(sulfasalazine))及二氫吡唑酮(阿帕宗(apazone)、苯哌隆(bezpiperylon)、非普拉宗(feprazone)、莫非布宗(mofebutazone)、羥布宗(oxyphenbutazone)、苯基丁氮酮)。其他組合包括環加氧酶-2 (COX-2)抑制劑。
用於組合之其他活性劑包括類固醇,諸如潑尼松龍、潑尼松、甲基潑尼龍、倍他米松(betamethasone)、地塞米松或氫皮質酮(hydrocortisone)。此組合可尤其有利,因為可藉由使所需要之類固醇劑量逐漸減少來減少或甚至消除類固醇之一或多種不良效果。
可以組合形式用於治療例如類風濕性關節炎的活性劑之額外實例包括細胞介素抑止消炎藥(cytokine suppressive anti-inflammatory drug;CSAID);針對其他人類細胞介素或生長因子之抗體或其他人類細胞介素或生長因子之拮抗劑,該等人類細胞介素或生長因子例如TNF、LT、IL-10、IL-2、IL-6、IL-7、IL-8、IL-15、IL-16、IL-18、EMAP-II、GM-CSF、FGF或PDGF。
活性劑之特定組合可在自體免疫及後續發炎級聯反應中之不同點處干擾,且包括TNF拮抗劑,諸如嵌合、人類化或人類TNF抗體、雷米卡德(REMICADE)、抗TNF抗體片段(例如,CDP870),及可溶p55或p75 TNF受體、其衍生物、p75TNFRIgG (恩博(ENBREL.))或p55TNFR1gG (來那西普(LENERCEPT))、可溶IL-13受體(sIL-13)以及TNFa轉化酶(TACE)抑制劑;類似地,IL-1抑制劑(例如,介白素-1轉化酶抑制劑)可為有效的。其他組合包括介白素11、抗P7s及p-選擇素糖蛋白配體(p-selectin glycoprotein ligand;PSGL)。適用於與本文中所描述之精胺酸酶抑制劑組合的藥劑之其他實例包括干擾素-131a (阿溫耐克斯(AVONEX));干擾素-13lb (倍泰龍(BETASERON));克帕松(copaxone);高壓氧;靜脈內免疫球蛋白;克拉屈濱(clabribine);以及針對其他人類細胞介素或生長因子之抗體或其他人類細胞介素或生長因子之拮抗劑(例如,針對CD40配體及CD80之抗體)。
微生物疾病
.本發明提供用精胺酸酶抑制劑及至少一種額外治療劑或診斷劑(例如,一或多種其他抗病毒劑及/或不與病毒療法相關之一或多種藥劑)治療及/或預防病毒、細菌、真菌及寄生蟲疾病、病症及病狀以及與其相關之病症的方法。
此等組合療法包括靶向各種病毒生命-循環階段且具有不同作用機制之抗病毒劑,包括(但不限於)以下:病毒脫殼之抑制劑(例如,金剛胺(amantadine)及金剛乙胺(rimantidine));逆轉錄酶抑制劑(例如,阿昔洛韋(acyclovir)、齊多夫定(zidovudine)及拉米夫定(lamivudine));靶向整合酶之藥劑;阻斷轉錄因子與病毒DNA之連接的藥劑;影響轉譯之藥劑(例如,反義分子) (例如,福米韋生(fomivirsen));調節轉譯/核糖核酸酶功能之藥劑;蛋白酶抑制劑;病毒裝配調節劑(例如,利福平(rifampicin));抗逆轉錄病毒劑,諸如核苷類似物逆轉錄酶抑制劑(例如,疊氮胸苷(AZT)、ddl、ddC、3TC、d4T);非核苷逆轉錄酶抑制劑(例如,依法韋侖(efavirenz)、奈韋拉平(nevirapine));核苷酸類似物逆轉錄酶抑制劑;以及防止病毒粒子釋放之藥劑(例如,紮那米韋(zanamivir)及奧司他韋(oseltamivir))。某些病毒感染(例如,HIV)之治療及/或預防經常需要一組抗病毒劑(「混合物」)。
預期用於與精胺酸酶抑制劑組合使用的其他抗病毒劑包括(但不限於)以下:阿巴卡韋(abacavir)、阿丹弗(adefovir)、金剛胺、安普那韋(amprenavir)、安普利近(ampligen)、阿比朵爾(arbidol)、阿紮那韋(atazanavir)、立普妥(atripla)、波普瑞韋爾特(boceprevirertet)、西多福韋(cidofovir)、卡貝滋(combivir)、地瑞那韋(darunavir)、地拉韋啶(delavirdine)、地達諾新(didanosine)、二十二烷醇(docosanol)、依度尿苷(edoxudine)、恩曲他濱(emtricitabine)、恩夫韋地(enfuvirtide)、因提弗(entecavir)、泛昔洛韋(famciclovir)、夫沙那韋(fosamprenavir)、膦甲酸(foscarnet)、膦乙醇(fosfonet)、http://en.wikipedia.org/wiki/Fusion_inhibitor更昔洛韋(ganciclovir)、伊巴他濱(ibacitabine)、異丙肌苷(imunovir)、碘苷(idoxuridine)、咪喹莫特(imiquimod)、茚地那韋(indinavir)、肌苷(inosine)、各種干擾素(例如,聚乙二醇化干擾素α-2a)、洛匹那韋(lopinavir)、洛韋胺(loviride)、馬拉維若(maraviroc)、嗎啉脒胍(moroxydine)、美替沙腙(methisazone)、奈非那韋(nelfinavir)、多吉美(nexavir)、噴昔洛韋(penciclovir)、帕拉米韋(peramivir)、普可那利(pleconaril)、鬼臼毒素(podophyllotoxin)、雷特格韋(raltegravir)、病毒唑(ribavirin)、利托那韋(ritonavir)、普拉咪定(pyramidine)、沙奎那韋(saquinavir)、司他夫定(stavudine)、特拉匹韋(telaprevir)、田諾弗(tenofovir)、替拉那韋(tipranavir)、曲氟尿苷(trifluridine)、曲利志韋(trizivir)、曲金剛胺(tromantadine)、特魯瓦達(truvada)、伐昔洛韋(valaciclovir)、纈更昔洛韋(valganciclovir)、維克利諾(vicriviroc)、阿糖腺苷(vidarabine)、偉拉咪定(viramidine)及紮西他濱(zalcitabine)。
本發明涵蓋本文中所描述之精胺酸酶功能之抑制劑與抗寄生蟲藥劑組合的用途。此等藥劑包括(但不限於)噻苯達唑(thiabendazole)、雙羥萘酸噻嘧啶(pyrantel pamoate)、甲苯達唑(mebendazole)、吡喹酮(praziquantel)、氯硝柳胺(niclosamide)、雙硫酸醇(bithionol)、奧沙尼喹(oxamniquine)、美曲磷酯(metrifonate)、伊維菌素(ivermectin)、阿苯達唑(albendazole)、依氟鳥胺酸(eflornithine)、美拉胂醇(melarsoprol)、噴他脒(pentamidine)、苄硝唑(benznidazole)、硝呋莫司(nifurtimox)及硝基咪唑(nitroimidazole)。熟習此項技術者瞭解可用於治療寄生蟲病症之其他藥劑。
本發明之實施例涵蓋本文中所描述之精胺酸酶抑制劑與適用於治療或預防細菌病症之藥劑組合的用途。抗細菌劑可以各種方式分類,包括基於作用機制、基於化學結構及基於活性譜。抗細菌劑之實例包括靶向細菌細胞壁(例如,頭胞菌素及青黴素)或細胞膜(例如,多黏菌素)或干擾必需細菌酶(例如,磺醯胺、利福黴素及喹啉)之彼等抗細菌劑。靶向蛋白質合成之大多數抗細菌劑(例如,四環素及巨環內酯)為抑菌的,然而諸如胺基醣苷之藥劑為殺菌的。分類抗細菌劑之另一方式係基於其靶向特異性;「窄譜(narrow-spectrum)」藥劑靶向特定類型之細菌(例如,革蘭氏陽性細菌,諸如鏈球菌),而「廣譜(broad-spectrum)」藥劑具有針對較寬範圍之細菌的活性。熟習此項技術者瞭解適合於在特定細菌感染中使用的抗細菌劑之類型。
本發明之實施例涵蓋本文中所描述之精胺酸酶抑制劑與適用於治療或預防真菌病症之藥劑組合的用途。抗真菌劑包括多烯(例如,兩性黴素(amphotericin)、耐絲菌素(nystatin)及鏈黴菌素(pimaricin));唑類(例如,氟康唑(fluconazole)、伊曲康唑(itraconazole)及酮康唑(ketoconazole));烯丙胺(例如,萘替芬(naftifine)及特比萘芬(terbinafine))及嗎啉(例如,阿莫羅芬(amorolfine));以及抗代謝物(例如,5-氟胞嘧啶)。
本發明涵蓋上文所闡述之藥劑(及藥劑之類別之成員)的醫藥學上可接受之鹽、酸或衍生物。給藥
本發明之精胺酸酶抑制劑可以視例如以下而定之量投與至個體:投與之目的(例如,所需之解析度);向其投與調配物的個體之年齡、重量、性別以及健康及生理條件;投與途徑;以及疾病、病症、病狀或其症狀之性質。給藥方案亦可考慮與投與之藥劑相關的任何不良效果之存在、性質及程度。有效劑量及給藥方案可容易地由例如安全性及劑量遞增試驗、活體內研究(例如,動物模型)及熟習此項技術者已知之其他方法來確定。
一般而言,給藥參數規定劑量小於可對個體不可逆地有毒的量(最大耐受劑量(maximum tolerated dose;MTD))且不小於產生對個體之可量測效果所需的量。此等量由例如與ADME相關之藥物動力學及藥效學參數,考慮投與途徑及其他因素來確定。
有效劑量(effective dose;ED)為在服用藥劑之一部分個體中產生治療反應或所需效果的藥劑之劑量或量。藥劑之「中值有效劑量」或ED50為在投與藥劑之50%群體中產生治療反應或所要效果的藥劑之劑量或量。儘管ED50常用作藥劑效果之合理預期之量度,但其不必需為臨床醫師可考慮所有相關因素認為合適的劑量。因此,在一些情境下有效量大於所計算ED50,在其他情境下有效量小於所計算ED50,且在又其他情境下有效量與所計算ED50相同。
另外,本發明之精胺酸酶抑制劑之有效劑量可為在以一或多次劑量投與至個體時相對於健康個體產生所需結果的量。舉例而言,針對經歷特定病症之個體,有效劑量可為將彼病症之診斷參數、量度、標記及類似者改良至少約5%、至少約10%、至少約20%、至少約25%、至少約30%、至少約40%、至少約50%、至少約60%、至少約70%、至少約80%、至少約90%或大於90%的劑量,其中100%定義為由正常個體展現之診斷參數、量度、標記及類似者。
在某些實施例中,本發明所涵蓋之精胺酸酶抑制劑可以每天約0.01 mg/kg至約50 mg/kg或約1 mg/kg至約25 mg/kg個體體重之劑量含量一天一次或多次投與(例如,經口),以獲得所需治療效果。
對於經口藥劑之投與,組合物可以含有1.0至1000毫克活性成分,尤其1.0、3.0、5.0、10.0、15.0、20.0、25.0、50.0、75.0、100.0、150.0、200.0、250.0、300.0、400.0、500.0、600.0、750.0、800.0、900.0及1000.0毫克活性成分的錠劑、膠囊及類似者之形式提供。
在某些實施例中,所需精胺酸酶抑制劑之劑量含於「單位劑型」中。片語「單位劑型」係指物理離散單位,各單位含有足以產生所需效果的預定量的單獨精胺酸酶抑制劑或與一或多種額外藥劑之組合。應瞭解,單位劑型之參數將視特定藥劑及待實現之效果而定。套組
本發明亦涵蓋包含本文中所描述之化合物及其醫藥組合物的套組。套組通常呈如下文所描述之容納各種組分之實體結構形式,且可用於例如實踐上文所描述之方法。
套組可包括本文中所揭示之化合物中之一或多者(提供於例如無菌容器中),該等化合物可呈適用於投與至個體的醫藥組合物形式。本文中所描述之化合物可以隨時可用之形式(例如,錠劑或膠囊)或以例如需要在投與之前復水或稀釋之形式(例如,散劑)提供。當本文中所描述之化合物呈需要由使用者復水或稀釋之形式時,套組亦可包括與本文中所描述之化合物一起或單獨封裝之稀釋劑(例如,無菌水)、緩衝液、醫藥學上可接受之賦形劑以及類似者。在涵蓋組合療法時,套組可單獨地含有若干種藥劑或其可已經在套組中組合。套組之各組分可密封於個別容器內,且所有各種容器可在單一封裝內。本發明之套組可經設計以用於必需適當地維持其中所容納之組分的條件(例如,製冷或凍結)。
套組可含有標籤或封裝插頁,包括組分之鑑別資訊及其使用之說明書(例如,給藥參數;活性成分之臨床藥理學,包括作用機制、藥物動力學及藥效學、不良效果、禁忌等)。標籤或插頁可包括製造商資訊,諸如批次編號及有效期。標籤或封裝插頁可例如整合至容納組分之實體結構中,單獨地含於實體結構內,或黏附至套組之組件(例如,安瓿、導管或小瓶)上。
標籤或插頁可另外包括電腦可讀媒體,諸如磁碟(例如,硬碟、卡、記憶體磁碟);光碟,諸如CD-ROM/RAM或DVD-ROM/RAM、DVD、MP3、磁帶;或電儲存媒體,諸如RAM及ROM,或此等之混合,諸如磁/光學儲存媒體、FLASH媒體或記憶型卡;或併入至其中。在一些實施例中,實際說明不存在於套組中,但提供自遠端源(例如,經由網際網路)獲得說明之方式。實驗
提出以下實例以便向一般熟習此項技術者提供如何進行及使用本發明之完整揭示內容及描述,且不意欲限制本發明者視為其發明之內容之範疇,其亦不意欲表示執行以下實驗或其為所有可執行之實驗。應理解,不一定執行以現在時書寫之例示性描述,而可執行描述以產生其中描述之性質的資料及類似者。已作出努力以確保關於所使用之數量(例如,量、溫度等)的準確性,但應考慮一些實驗誤差及偏差。
除非另外指示,否則份數為重量份,分子量為重量平均分子量,溫度以攝氏度(℃)為單位,且壓力為大氣壓或接近大氣壓。使用包括以下之標準縮寫:wt=野生型;bp=鹼基對;kb=千鹼基;nt=核苷酸;aa=胺基酸;s或sec=秒;min=分鐘;h或hr=小時;ng=奈克;µg=微克;mg=毫克;g=公克;kg=公斤;dl或dL=分升;µl或µL=微升;ml或mL=毫升;l或L=公升;µM=微莫耳;mM=毫莫耳;M=莫耳;kDa=千道爾頓;i.m.=肌肉內(ly);i.p.=腹膜內(ly);SC或SQ=皮下(ly);QD=每天;BID=每天兩次;QW=每週;QM=每月;HPLC=高效液相層析;BW=體重;U=單位;ns=統計學上不顯著;PBS=磷酸鹽緩衝鹽水;IHC=免疫組織化學;DMEM=伊格爾氏培養基(Eagle's Medium)之達爾伯克氏修飾(Dulbeco's Modification of Eagle's Medium);EDTA=乙二胺四乙酸。材料及方法
以下一般材料及方法在指示時使用或可用於以下實例中:
分子生物學中之標準方法描述於科學文獻中(參見例如,Sambrook及Russell (2001) Molecular Cloning,第3版, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.;及Ausubel等人(2001) Current Protocols in Molecular Biology, 第1至4卷, John Wiley and Sons, Inc. New York, N.Y., 其描述細菌細胞及DNA突變誘發中的選殖(第1卷)、哺乳動物細胞及酵母菌中之選殖(第2卷)、糖結合物及蛋白質表現(第3卷)以及生物資訊(第4卷))。
科學文獻描述用於蛋白質純化之方法,包括免疫沈澱、層析、電泳、離心及結晶,以及化學分析、化學修飾、轉譯後修飾、融合蛋白之產生及蛋白質之糖基化(參見例如,Coligan等人, (2000) Current Protocols in Protein Science, 第1至2卷, John Wiley and Sons, Inc., NY)。
用於測定例如抗原片段、前導序列、蛋白質摺疊、功能域、糖基化位點及序列比對之軟體套件及資料庫為可獲得的(參見例如,GCG Wisconsin Package (Accelrys, Inc., San Diego, CA);及DeCypherTM (TimeLogic Corp., Crystal Bay, NV))。
文獻充滿分析及可充當本文中所描述之化合物之評估之基礎的其他實驗技術。藉助於實例,基於質譜分析之配體結合分析(參見例如,Massink, A.等人, Purinergic Signaling (2015) 11:581. https://doi.org/10.1007/s11302-015-9477-0;Dionisotti S.等人, J Pharmacol Exp Ther. (1996)298:726-732)可用於確定本發明化合物之各種特性。
亦可採用功能性分析來分析本發明化合物。實例 通用方法 :
熟習此項技術者應認識到,多種方法可用以製備申請專利範圍中表示之分子。
上文所描述之各種方法已用於製備本發明化合物,其中一些例示於實例中。可藉由使用適當的氘化中間物來合成以下實例之氘化形式。實例 1 : 外消旋 -(1R,2S)-1- 胺基 -4-( 胺甲基 )-2-[3-( 二羥基硼烷基 ) 丙基 ]-2,3- 二氫 -1H- 茚 -1- 甲酸
步驟 1 :
向-78℃下之4-氰基茚酮(14.6 g,93.3 mmol)於無水THF (310 mL)中之懸浮液中逐滴添加LiHMDS (1 M於THF中,93.3 mL)。將溶液在-78℃下攪拌30 min。此時,緩慢添加烯丙基碘(17 mL,186 mmol,2當量)。隨後在逐漸升溫至室溫隔夜之前將反應物在-78℃下攪拌3 h。反應物藉由添加飽和NH4
Cl溶液(70 mL)及H2
O (100 mL)淬滅,隨後萃取至EtOAc (×2)中。經合併之有機層用鹽水洗滌,經Na2
SO4
乾燥且在真空中濃縮以得到藉由管柱層析(矽膠,己烷→10% EtOAc/己烷)純化之粗殘餘物,以獲得呈黃色油狀物之產物(5.75 g,31%)。C13
H12
NO之ESI MS [M+H]+
,計算值198.1,實驗值198.2。
步驟 2 :
將來自步驟 1
之產物(5.75 g,29 mmol)溶解於50%乙醇水溶液(44 mL)及(NH4
)2
CO3
(20 g,115 mmol,4當量)中,隨後添加KCN (3.79 g,58 mmol,2當量)。將反應混合物在壓力管中加熱至80℃持續36 h。在冷卻至室溫之後,緩慢添加4 N HCl直至達至pH 3為止。此時,將粗反應混合物在真空中濃縮且添加EtOAc (400 mL)。分離有機層且用EtOAc (300 mL)再萃取水層。經合併之有機層經Na2
SO4
乾燥且在真空中濃縮以得到藉由管柱層析(矽膠,己烷→70% EtOAc/己烷)純化之粗殘餘物,以獲得呈黃色油狀物之所需產物(5.0 g,1.5:1 dr,64%)。C15
H14
N3
O2
之ESI MS [M+H]+
,計算值268.1,實驗值268.0。
步驟 3 :
向來自步驟 2
之產物(4.5 g,1.5:1 dr,16.8 mmol)於THF (125 mL)中之溶液中添加Et3
N (2.5 mL,18.1 mmol,1.1 當量)及Boc2
O (18.3 g,83.9 mmol,5當量),隨後添加催化劑DMAP (0.41 g,3.4 mmol,20%莫耳)。將反應混合物在室溫下攪拌16 h。此時,將反應混合物在真空中濃縮以得到藉由管柱層析(矽膠,己烷→25% EtOAc/己烷)純化之粗殘餘物,以獲得呈無色油狀物之所需非對映異構體(2.6 g,33%)。C20
H21
N3
O4
之ESI MS [M-Boc+H]-
,計算值367.1,實驗值367.2。
步驟 4 :
將來自步驟 3
之產物(2.6 g,5.55 mmol)溶解於DME (50 mL)及1 N NaOH (50 mL)中。將反應物在室溫下攪拌1.5 h,此時將反應物在真空中縮減(以移除DME)且所得溶液用CH2
Cl2
(15 mL)洗滌。水層隨後使用10 N HCl中和至pH 7且不經進一步純化即用於下一步驟中。C14
H15
N2
O2
之ESI MS [M+H]+
,計算值243.1,實驗值243.0。
步驟 5 :
向來自步驟 4
之粗反應混合物中添加NaHCO3
直至pH 10,隨後添加THF (25 mL)及Boc2
O (12.1 g,55.5 mmol)。將所得混合物加熱至60℃持續16 h。使反應混合物冷卻至室溫,在真空中縮減(以移除THF)且隨後用CH2
Cl2
(15 mL)洗滌。使層分離且在萃取至EtOAc (×3)中之前將水層酸化至pH 3。經合併之有機層用鹽水洗滌,經Na2
SO4
乾燥且在真空中濃縮以得到不經進一步純化即用於下一步驟中之粗殘餘物。C19
H21
N2
O4
之ESI MS [M-H]-
,計算值341.2,實驗值341.0。
步驟 6 :
向來自步驟 5
之粗產物於MeCN (6 mL)中之溶液中添加Cs2
CO3
(1.53 g,11.1 mmol)及BnBr (0.79 mL,6.66 mmol)。將反應物加熱至50℃持續1 h,此時將溶劑在真空中濃縮以得到藉由管柱層析(矽膠,己烷→10% EtOAc/己烷)純化之粗殘餘物,以獲得呈無色油狀物之所需產物(0.7 g,歷經2個步驟,30%)。C21
H21
N2
O2
之ESI MS [M-Boc+H2
]+
,計算值333.2,實驗值333.2。
步驟 7 :
在氮氣氛圍下,將[Ir(cod)Cl]2
(43.5 mg,0.065 mmol,4%莫耳)及1,2-雙(二苯膦基)乙烷(51.8 mg,0.13 mmol,8%莫耳)於經脫氣CH2
Cl2
(3.2 mL)中之溶液在室溫下攪拌30 min。此時,使反應物冷卻至0℃且添加來自步驟
6之產物(700 mg,1.62 mmol)於經脫氣CH2
Cl2
(2.0 mL)中之溶液,隨後逐滴添加頻哪醇硼烷(0.35 mL,2.4 mmol,1.5當量)且使反應物立即升溫至室溫並攪拌額外1.5 h。此時,藉由逐滴添加冷H2
O (1 mL),隨後進一步添加H2
O (10 mL)及EtOAc (20 mL)來淬滅反應物。有機層經分離,用鹽水洗滌,經Na2
SO4
乾燥且在真空中濃縮以得到藉由管柱層析(矽膠,己烷→40% EtOAc/己烷)純化之粗殘餘物,以獲得呈無色油狀物之所需產物(725 mg,81%)。C27
H34
BN2
O4
之ESI MS [M-Boc+H2
]+
,計算值461.3,實驗值461.2。
步驟 8 :
在帕爾震盪器(Parr shaker)容器中,向來自步驟 7
之產物(210 mg,0.38 mmol)於MeOH (3 mL)中之溶液中添加雷尼鎳(Raney Ni) (研磨漿於H2
O中,0.16 mL)。將容器抽空,用H2
(×3)再填充且在帕爾震盪器(H2
壓力:50 psi)上靜置24 h。此時,反應物小心地經濕式矽藻土過濾且用CHCl3
/EtOAc混合物充分洗滌濾餅。溶劑在真空中濃縮以得到藉由管柱層析(矽膠,CH2
Cl2
→15% MeOH/CH2
Cl2
,1%體積NH4
OH添加劑)純化之粗殘餘物,以獲得呈白色泡沫狀之所需產物(30 mg,17%)。C26
H36
BN2
O6
之ESI MS [M+H]+
,計算值483.1,實驗值483.2。
步驟 9 :
在裝有隔墊之40 mL閃爍瓶中,將來自步驟 8
之產物(30 mg,0.062 mmol)溶解於MeOH (3 mL)中且將反應物置放於惰性氮氣氛圍下。添加Pd/C (10% wt,16 mg)且在引入H2
(1 atm)之前將小瓶抽空並用氮氣(×3)再填充。將反應物在室溫下攪拌1 h。此時,藉由穿過用MeOH充分洗滌之0.45 µm針筒過濾器來過濾反應混合物。將溶劑在真空中濃縮以得到呈白色泡沫狀之所需產物(24.3 mg,定量)。產物不經進一步純化即按原樣用於下一步驟中。C19
H30
BN2
O6
之ESI MS [M+H]+
,計算值393.2,實驗值393.2。
步驟 10 :
將來自步驟 9
之產物(24.3 mg,0.062 mmol)懸浮於含4 N HCl之二噁烷(2 mL)中且將反應混合物在室溫下攪拌1 h。將溶劑在真空中移除以得到呈白色固體狀之標題化合物(22.4 mg,定量)。1
H NMR (400 MHz, D2
O) δ 7.56 - 7.10 (m, 3H), 4.20 (s, 2H), 3.41 - 3.33 (m, 1H), 2.84 - 2.74 (m, 1H), 2.66 - 2.52 (m, 1H), 1.81 - 1.72 (m, 1H), 1.67 - 1.58 (m, 1H), 1.57 - 1.36 (m, 2H), 0.95 - 0.76 (m, 2H)。C14
H22
BN2
O4
之ESI MS [M+H]+
,計算值293.2,實驗值293.8。實例 2 : 外消旋 -(1R
)-6-( 胺甲基 )-2-[3-( 二羥基硼烷基 ) 丙基 ]-1-( 甲胺基 )-2,3- 二氫 -1H
- 茚 -1- 甲酸
以與實例 1
類似之方式合成標題化合物。1
H NMR (400 MHz, D2
O) δ 7.68-7.65 (m, 2H), 7.43 (d,J
= 7.8 Hz, 1H), 3.29 (dd,J
= 16.8, 8.1 Hz, 1H), 2.81 (dd,J
= 16.7, 10.0 Hz, 1H), 2.69 - 2.56 (m, 1H), 1.69 - 1.57 (m, 1H), 1.54 - 1.41 (m, 1H), 1.34 (qd,J
= 12.9, 7.7 Hz, 2H), 0.70 (ddt,J
= 20.2, 15.4, 7.4 Hz, 2H)。C14
H17
BN2
O4
之ESI MS [M+H]+
,計算值289.1,實驗值289.0。實例 3 : 外消旋 -(1R
,2S
)-1- 胺基 -6-( 胺甲基 )-2-[3-( 二羥基硼烷基 ) 丙基 ]-2,3- 二氫 -1H
- 茚 -1- 甲酸
以與實例 1
類似之方式合成標題化合物。1
H NMR (400 MHz, D2
O) δ 7.42 - 7.40 (m, 2H), 7.36 (t,J
= 1.1 Hz, 1H), 4.16 (s, 2H), 3.31 (dd,J
= 16.0, 8.2 Hz, 1H), 2.79 (dd,J
= 16.0, 9.8 Hz, 1H), 2.65 - 2.52 (m, 1H), 1.79 - 1.67 (m, 1H), 1.60 (qt,J
= 12.0, 6.8 Hz, 1H), 1.54 - 1.37 (m, 2H), 0.91 - 0.75 (m, 2H)。C14
H21
BN2
O4
之ESI MS [M+H]+
,計算值293.2,實驗值293.2。實例 4 : 外消旋 -(1R,2S)-1- 胺基 -5-( 胺甲基 )-2-[3-( 二羥基硼烷基 ) 丙基 ]-2,3- 二氫 -1H- 茚 -1- 甲酸
以與實例 1
類似之方式合成標題化合物。1
H NMR (400 MHz, D2
O) δ 7.29 - 7.23 (m, 2H), 7.22 - 7.12 (m, 1H), 4.03 (s, 2H), 3.17 (dd,J
= 16.0, 8.2 Hz, 1H), 2.68 (dd,J
= 16.0, 9.9 Hz, 1H), 2.58 - 2.35 (m, 1H), 1.69 - 1.53 (m, 1H), 1.53 - 1.40 (m, 1H), 1.39 - 1.21 (m, 2H), 0.71 - 0.65 (m, 2H)。C14
H22
BN2
O4
之ESI MS [M+H]+
,計算值293.1,實驗值293.2。實例 5 : 外消旋 -(1R
,2S
)-1- 胺基 -2-[3-( 二羥基硼烷基 ) 丙基 ]-6- 甲氧基 -2,3- 二氫 -1H
- 茚 -1- 甲酸
以與實例 1
類似之方式合成標題化合物。1
H NMR (400 MHz, D2
O) δ 7.29 - 7.25 (m, 1H), 6.99 - 6.93 (m, 2H), 3.80 (d,J
= 0.4 Hz, 3H), 3.21 (dd,J
= 15.3, 8.1 Hz, 1H), 2.70 (dd,J
= 15.2, 9.7 Hz, 1H), 2.59 - 2.49 (m, 1H), 1.72 (ddd,J
= 10.2, 8.0, 4.8 Hz, 1H), 1.64 - 1.50 (m, 1H), 1.50 - 1.35 (m, 2H), 0.83 (tq,J
= 15.1, 8.7, 7.5 Hz, 2H)。C14
H20
BNO5
之ESI MS [M-(OH)2
]+
,計算值259.1,實驗值259.1。實例 6 : 外消旋 -(1R
,2S
)-1- 胺基 -6- 氯 -2-[3-( 二羥基硼烷基 ) 丙基 ]-2,3- 二氫 -1H
- 茚 -1- 甲酸
以與實例 1
類似之方式合成標題化合物。1
H NMR (400 MHz, D2
O) δ 6.93 - 6.91 (m, 1H), 6.90 (d,J
= 2.0 Hz, 1H), 6.84 (dd,J
= 8.0, 0.8 Hz, 1H), 2.80 (dd,J
= 14.9, 7.0 Hz, 1H), 2.33 - 2.16 (m, 2H), 1.29 - 1.16 (m, 1H), 1.13 - 1.00 (m, 1H), 1.00 - 0.84 (m, 2H), 0.40 - 0.20 (m, 2H)。C13
H17
BClNO4
之ESI MS [M+H]+
,計算值298.1,實驗值298.0。實例 7 : (1R
,2S
)-1- 胺基 -2-[3-( 二羥基硼烷基 ) 丙基 ]-2,3- 二氫 -1H
- 茚 -1- 甲酸
以與實例 1
類似之方式合成標題化合物。1
H NMR (400 MHz, D2
O) δ 7.39 - 7.25 (m, 4H), 3.27 (dd,J
= 15.8, 8.3 Hz, 1H), 2.77 (dd,J
= 15.8, 9.7 Hz, 1H), 2.58 - 2.46 (m, 1H), 1.78 - 1.66 (m, 1H), 1.66 - 1.53 (m, 1H), 1.53 - 1.37 (m, 2H), 0.91 - 0.72 (m, 2H)。C13
H18
BNO4
之ESI MS [M+H]+
,計算值264.1,實驗值264.1。實例 8 : 外消旋 -(1R,2S)-4-( 胺甲基 )-2-[3-( 二羥基硼烷基 ) 丙基 ]-1-( 甲胺基 )-2,3- 二氫 -1H- 茚 -1- 甲酸
步驟 1 :
0℃下之苯甲酯(170 mg,0.39 mmol)於無水THF (1.7 mL)中之懸浮液中逐滴添加NaHMDS (1 M於THF中,0.43 mL,1.1當量)。將溶液在0℃下攪拌15 min。此時,緩慢添加碘甲烷(50 µL,0.79 mmol,2當量)。將反應物逐漸升溫至室溫隔夜。藉由添加飽和NH4
Cl溶液(10 mL),隨後萃取至EtOAc (2×20 mL)中來淬滅反應物。經合併之有機層用鹽水洗滌,經Na2
SO4
乾燥且在真空中濃縮以得到藉由管柱層析(矽膠,己烷→10% EtOAc/己烷)純化之粗殘餘物,以獲得呈無色油狀物之所需產物(130 mg,69%)。C22
H23
N2
O2
之ESI MS [M-Boc+H]+
,計算值347.2,實驗值347.2。
步驟 2 :
在氮氣氛圍下,將[Ir(cod)Cl]2
(7.4 mg,0.011 mmol,4%莫耳)及1,2-雙(二苯膦基)乙烷(8.7 mg,0.022 mmol,8%莫耳)於經脫氣CH2
Cl2
(0.8 mL)中之溶液在室溫下攪拌30 min。此時,使反應物冷卻至0℃且添加來自步驟 1
之產物(130 mg,0.27 mmol)於經脫氣CH2
Cl2
(0.7 mL)中之溶液,隨後逐滴添加頻哪醇硼烷(80 µL,0.55 mmol,2當量)且使反應物立即升溫至室溫並攪拌額外1.5 h。此時,藉由逐滴添加冷H2
O (1 mL),隨後進一步添加H2
O (10 mL)及EtOAc (20 mL)來淬滅反應物。有機層經分離,用鹽水洗滌,經Na2
SO4
乾燥且在真空中濃縮以得到藉由管柱層析(矽膠,己烷→35% EtOAc/己烷)純化之粗殘餘物,以獲得呈無色油狀物之所需產物(70 mg,46%)。C28
H36
BN2
O4
之ESI MS [M-Boc+H2
]+
,計算值475.3,實驗值475.3。
步驟 3 :
在裝有隔墊之40 mL閃爍瓶中,將來自步驟 2
之產物(70 mg,0.013 mmol)溶解於MeOH (3 mL)中且將反應物置放於惰性氮氣氛圍下。添加Pd/C (10% wt,13 mg)且在引入H2
(1 atm)之前將小瓶抽空並用氮氣(×3)再填充。將反應物在室溫下攪拌16 h。此時,藉由穿過用MeOH充分洗滌之0.45 µm針筒過濾器來過濾反應混合物。將溶劑在真空中濃縮以得到呈白色泡沫狀之所需產物(61 mg,定量)。產物不經進一步純化即按原樣用於下一步驟中。C21
H34
BN2
O4
之ESI MS [M-Boc+H]+
,計算值389.3,實驗值389.2。
步驟 4 :
將來自步驟 3
之產物(61 mg,0.013 mmol)懸浮於含4 N HCl之二噁烷(1.5 mL)及4 N HCl水溶液中。將反應混合物在室溫下攪拌2.5 h。將溶劑在真空中移除至藉由RP-HPLC (乙腈及水之0至10%梯度)純化之粗殘餘物,以得到呈白色固體狀之所需產物(22 mg,46%)。1
H NMR (400 MHz, D2
O) δ 7.53 - 7.22 (m, 3H),4.20 (s, 2H), 3.49 - 3.40 (m, 1H), 2.97 - 2.67 (m, 2H), 2.51 (s, 3H), 1.75 - 1.55 (m, 2H), 1.56 - 1.37 (m, 2H), 0.90 - 0.74 (m, 2H)。C15
H22
BN2
O4
之ESI MS [M-H]-
,計算值305.2,實驗值305.0。實例 9 : 外消旋 -(1R,2S)-5-( 胺甲基 )-2-[3-( 二羥基硼烷基 ) 丙基 ]-1-( 甲胺基 )-2,3- 二氫 -1H- 茚 -1- 甲酸
以與實例 8
類似之方式合成標題化合物。1
H NMR (400 MHz, D2
O) δ 7.27 (s, 1H), 7.21 (s, 2H), 4.03 (s, 2H), 3.27 - 3.17 (m, 1H), 2.67 (dd,J
= 15.8, 8.3 Hz, 1H), 2.62 - 2.53 (m, 1H), 2.36 (s, 3H), 1.58 - 1.39 (m, 2H), 1.38 - 1.23 (m, 2H), 0.77 - 0.58 (m, 2H)。C15
H24
BN2
O4
之ESI MS [M+H]+
,計算值307.2,實驗值307.2。實例 10 : 外消旋 -(1R
)-6-( 胺甲基 )-2-[3-( 二羥基硼烷基 ) 丙基 ]-1-( 甲胺基 )-2,3- 二氫 -1H
- 茚 -1- 甲酸
以與實例 8
類似之方式合成標題化合物。1
H NMR (400 MHz, D2
O) δ 7.44 (d,J
= 1.1 Hz, 2H), 7.33 (s, 1H), 4.17 (s, 2H), 3.37 (dd,J
= 16.2, 8.1 Hz, 1H), 2.81 (dd,J
= 16.1, 8.0 Hz, 1H), 2.75 - 2.66 (m, 1H), 2.51 (s, 3H), 1.70 - 1.52 (m, 2H), 1.53 - 1.35 (m, 2H), 0.82 (tt,J
= 15.8, 8.0 Hz, 2H)。C15
H24
BN2
O4
之ESI MS [M+H]+
,計算值307.2,實驗值307.2。實例 11 : 外消旋 -(1R,2S)-2-[3-( 二羥基硼烷基 ) 丙基 ]-1-( 甲胺基 )-4-[( 甲胺基 ) 甲基 ]-2,3- 二氫 -1H- 茚 -1- 甲酸
以與實例 8
類似之方式合成標題化合物。1
H NMR (400 MHz, CD3
OD) δ 7.70 - 7.15 (m, 3H), 3.48 - 3.29 (m, 1H), 3.22 - 3.04 (m, 1H), 3.04 - 2.36 (m, 2H), 2.80 - 2.47 (m, 7H), 2.04 - 1.42 (m, 4H), 1.05 - 0.77 (m, 2H)。C16
H24
BN2
O4
之ESI MS [M-H]-
,計算值319.1,實驗值319.2。實例 12 : 外消旋 -(1R,2S)-5-( 胺甲基 )-2-[3-( 二羥基硼烷基 ) 丙基 ]-6- 甲氧基 -1-( 甲胺基 )-2,3- 二氫 -1H- 茚 -1- 甲酸
以與實例 8
類似之方式合成標題化合物。1
H NMR (400 MHz, D2
O) δ 7.14 (s, 1H), 6.81 (s, 1H), 4.09 - 3.89 (m, 2H), 3.70 (s, 3H), 3.25 - 3.00 (m, 1H), 2.68 - 2.41 (m, 2H), 2.35 (s, 3H), 1.49 - 1.36 (m, 2H), 1.38 - 1.17 (m, 2H), 0.81 - 0.53 (m, 2H)。C16
H26
BN2
O5
之ESI MS [M+H]+
,計算值337.2,實驗值337.2。實例 13 : 外消旋 -(1R,2S)-5-( 胺甲基 )-6- 氯 -2-[3-( 二羥基硼烷基 ) 丙基 ]-1-( 甲胺基 )-2,3- 二氫 -1H- 茚 -1- 甲酸
以與實例 8
類似之方式合成標題化合物。1
H NMR (400 MHz, D2
O) δ 7.47 (s, 1H), 7.45 (s, 1H), 4.48 - 4.15 (m, 2H), 3.42 - 3.23 (m, 1H), 2.87 - 2.68 (m, 2H), 2.52 (s, 3H), 1.74 - 1.33 (m, 4H), 0.90 - 0.67 (m, 2H)。C15
H23
BClN2
O4
之ESI MS [M+H]+
,計算值341.1,實驗值341.0。實例 14 : 外消旋 - ( 1R
,2S
)-1- 胺基 -6-(2- 胺乙基 )-2-[3-( 二羥基硼烷基 ) 丙基 ]-2,3- 二氫 -1H
- 茚 -1- 甲酸:
步驟 1 :
將含有苯甲酯(365 mg,0.75 mmol,1.0當量)、三氟硼酸鉀鹽(207 mg,0.8 mmol,1.1當量)、Pd(dppf)Cl2
×CH2
Cl2
(31 mg,0.04 mmol,5%莫耳)及Cs2
CO3
(735 mg,2.3 mmol,3.0當量)之火焰乾燥瓶用N2
吹掃且用經脫氣甲苯(3.5 mL)及H2
O (1.2 mL)稀釋。所得混合物經N2
脫氣5 min且將所得反應混合物在90℃下加熱20 h。在冷卻至室溫之後,添加EtOAc (10 mL)及飽和NH4
Cl水溶液(2 mL)。有機層用鹽水(2 mL)洗滌,經Na2
SO4
乾燥且濃縮。殘餘物藉由管柱層析(矽膠,0→40% EtOAc/己烷)純化,以獲得呈白色泡沫狀之標題化合物(263 mg,64%)。
以與實例 8
之類似方式進行步驟 2 、 3 及 4
。1
H NMR (400 MHz, D2
O) δ 7.34 (d,J
= 7.9 Hz, 1H), 7.27 (dd,J
= 7.8, 1.7 Hz, 1H), 7.22 (d,J
= 1.5 Hz, 1H), 3.32 - 3.19 (m, 3H), 2.97 (td,J
= 7.0, 3.8 Hz, 2H), 2.80 - 2.70 (m, 1H), 2.60 - 2.50 (m, 1H), 1.78 - 1.65 (m, 1H), 1.65 - 1.52 (m, 1H), 1.52 - 1.36 (m, 2H), 0.89 - 0.74 (m, 2H)。C15
H23
BN2
O4
之ESI MS [M-OH]+
,計算值289.2,實驗值289.2。實例 15 : 外消旋 -(1R,2S)-1- 胺基 -5-(2- 胺乙基 )-2-[3-( 二羥基硼烷基 ) 丙基 ]-2,3- 二氫 -1H- 茚 -1- 甲酸
以與實例 14
類似之方式合成標題化合物。1
H NMR (400 MHz, D2
O) δ 7.44 - 7.05 (m, 3H), 3.32 - 3.13 (m, 3H), 2.99 (t,J
= 7.2 Hz, 2H), 2.85 - 2.72 (m, 1H), 2.68 - 2.52 (m, 1H), 1.80 - 1.66 (m, 1H), 1.70 - 1.53 (m, 1H), 1.50 - 1.36 (m, 2H), 0.97 - 0.64 (m, 2H)。C15
H22
BN2
O3
之ESI MS [M-H2
O+H]+
,計算值289.2,實驗值289.2。實例 16 : 外消旋 -(1R
,2S
)-1- 胺基 -6-(2- 胺乙基 )-5- 氯 -2-[3-( 二羥基硼烷基 ) 丙基 ]-2,3- 二氫 -1H
- 茚 -1- 甲酸:
以與實例 14
類似之方式合成標題化合物。1
H NMR (400 MHz, D2
O) δ 7.47 (s, 1H), 7.30 (s, 1H), 3.34 - 3.14 (m, 4H), 3.10 - 3.00 (m, 1H), 2.85 - 2.74 (m, 1H), 2.61 (q,J
= 10.7, 9.4 Hz, 1H), 1.80 - 1.66 (m, 1H), 1.65 - 1.51 (m, 1H), 1.51 - 1.38 (m, 2H), 0.90 - 0.74 (m, 2H)。C15
H22
BClN2
O4
之ESI MS [M-(OH)]+
,計算值323.1,實驗值323.0。實例 17 : (1R,2S)-6-( 胺甲基 )-5- 氯 -2-[3-( 二羥基硼烷基 ) 丙基 ]-1-( 甲胺基 )-2,3- 二氫 -1H- 茚 -1- 甲酸
步驟 1
:將(R)-(+)-2-甲基-2-丙烷亞磺醯胺(32.0 g,264.9 mmol,3當量)懸浮於無水甲苯(300 mL)中且加熱達至90℃,接著一次性添加Ti(OEt)4
(18.3 mL,88.3 mmol,1當量)。逐份添加固體6-溴-5-氯-1-茚酮(21.5 g,88.3 mmol,1當量) (在1 h內)。在將加成反應混合物在90℃下攪拌1.5 h之後,接著使其冷卻至室溫。添加Na2
SO4
×10 H2
O (28.4 g,88.3 mmol,1當量)及矽藻土(20 g)且將混合物劇烈攪拌30 min。將暗綠色懸浮液經由矽藻土過濾且固體用EtOAc (3×100 mL)洗滌。蒸發經合併之有機物且粗材料藉由管柱層析(矽膠,己烷→6:4之己烷:EtOAc)純化,以得到綠色固體(25.9 g,85%)。
步驟 2
:將Pd2
(dba)3
(662 mg,0.722 mmol,2.5%莫耳)溶解於無水、經脫氣THF (100 mL)中且一次性添加三丁基膦(0.723 mL,2.9 mmol,10%莫耳)。將混合物在室溫下攪拌10 min且接著冷卻至4℃。添加碳酸烯丙酯甲酯(6.7 mL,57.8 mmol,2當量),隨後添加TEA (8.0 mL,57.8 mmol,2當量)。最後,添加來自步驟 1
之固體亞胺(10 g,28.9 mmol)且將反應混合物在約1℃下攪拌6 h,接著用飽和NH4
Cl水溶液(50 mL)淬滅。有機層經分離,經MgSO4
乾燥,過濾且蒸發。殘餘物用少量EtOAc洗滌,以得到呈淺色固體狀之產物(5 g,45%)。
步驟 3
:在1 L圓底燒瓶中,將無水THF (240 mL)冷卻至-78℃。接著添加含二乙基鋁氰化物1 M溶液之甲苯(155 mL,155 mmol,1.5當量)且在-78℃下攪拌5 min。接著逐滴添加無水異丙醇(10.5 mL,103 mmol,1.0當量);接著將混合物立即自冷卻浴移除且使其在室溫下攪拌1 h。在單獨的2 L圓底燒瓶中,將來自步驟 2
之產物(40 g,103 mmol)溶解於無水THF (560 mL)中。使此混合物冷卻至-78℃且歷經1 h逐滴添加氰化鋁混合物。在完成添加後,將混合物自冷卻浴移除且在室溫下攪拌隔夜。使混合物再一次冷卻至-78℃且使用飽和NaHCO3
(300 mL)淬滅。將此升溫至室溫且使其攪拌1 h。混合物經砂過濾且用EtOAc (2 L)洗滌。接著混合物用鹽水洗滌,且有機物經MgSO4
乾燥,過濾且濃縮。殘餘物藉由管柱層析(矽膠,己烷→1:1之己烷:EtOAc)純化,以得到所需產物(33.2 g,77%)。
步驟 4 :
向-78℃下之來自步驟 3
之腈(15 g,36 mmol,1.0當量)於MeOH (360 mL)中之溶液中逐滴添加30% (w/w) H2
O2(aq)
(9.3 mL,90 mmol,2.5當量)。此之後添加K2
CO3
(12.5 g,90 mmol,2.5當量)。使混合物升溫至0℃且攪拌12 h並藉由TLC監測。在反應完成之後,將混合物倒入冰冷水(1 L)中且攪拌1 h。將所得沈澱物藉由過濾收集且用水(3×200 mL)洗滌,以獲得呈白色固體狀之粗醯胺(12 g),該粗醯胺不經純化即用於下一步驟中。
步驟 5 :
使來自步驟 4
之醯胺(11 g,25 mmol)於MeOH (50 mL)中之溶液冷卻至0℃且逐滴添加含3 M HCl之MeOH (50 mL) (在10 min內)。移除冷卻浴且將反應混合物在室溫下攪拌1 h。在真空中移除溶劑且使殘餘物與甲苯(2 × 100 mL)共沸以得到呈淺褐色固體狀之醯胺。將粗材料置放於厚壁壓力容器中,用2 M KOH (253 mL)稀釋且在150℃下加熱60 h。將反應混合物冷卻且過濾以移除KOH。使濾液冷卻至0℃且使用濃HCl (約20mL)將pH小心地調節至7。所得溶液直接用於下一步驟中。
步驟 6 :
在室溫下,向來自步驟 5
之pH=7的水溶液中添加THF (253mL),隨後添加固體NaHCO3
(16 g,190.5 mmol)及(Boc)2
O (30 g,138 mmol)。將所得混合物在70℃下攪拌20 h。在冷卻至室溫之後,添加EtOAc (300 mL)及飽和NH4
Cl水溶液(150 mL)。有機層用鹽水(100 mL)洗滌,經Na2
SO4
乾燥,過濾且蒸發,以得到不經進一步純化即用於下一步驟中之粗產物。
步驟 7 :
向來自步驟 6
之粗材料於MeCN (51mL)中之溶液中添加Cs2
CO3
(18.2 g,55.8 mmol,2.2當量)及溴甲苯(6.0 mL,50.7 mmol,2.0當量)。使所得混合物加熱至70℃持續12 h。在冷卻至室溫之後,添加EtOAc (400 mL)及飽和NH4
Cl水溶液(150 mL)。有機層用鹽水(100 mL)洗滌,經Na2
SO4
乾燥,過濾且蒸發。殘餘物藉由管柱層析(矽膠,己烷→8:2之己烷:EtOAc)純化,以得到苯甲酯(5 g,歷經4個步驟,38%)。
步驟 8 :
將來自步驟
7之苯甲酯(5.0 g,9.6 mmol,1.0當量)於THF (96 mL)中之溶液冷卻至0℃且逐滴添加含1 M KHMDS之MTBE (25 mL,25 mmol,2.6當量)。將反應混合物在0℃下攪拌20 min,接著逐滴添加MeI (3 mL,48 mmol,5.0當量)。在額外15 min之後,使反應混合物升溫至室溫且攪拌3 h,接著用EtOAc (200 mL)及飽和NH4
Cl水溶液(50 mL)淬滅。有機層用鹽水(20 mL)洗滌,經Na2
SO4
乾燥,過濾且蒸發。殘餘物藉由管柱層析(矽膠,己烷→9:1之己烷:EtOAc)純化,以獲得呈白色泡沫狀之標題化合物(3.0 g,59%)。C26
H29
BrClNO4
之ESI MS [M+H]+
,計算值534.1,實驗值534.0。
步驟 9 :
使來自步驟 8
之產物(0.50 g,0.93 mmol,1.0當量)在溶解於無水THF (19 mL)中之前與甲苯共沸三次。使溶液冷卻至-78℃且逐滴添加正丁基鋰於己烷(0.41 mL,1.0 mmol,1.1當量)中之2.5 M溶液。在攪拌30 min之後,快速添加DMF (1.0 mL)且將所得反應混合物在-78℃下攪拌額外30 min。乾冰-丙酮浴用冰浴置換且在0℃下繼續攪拌額外20 min。將反應混合物用飽和NH4
Cl水溶液(100 mL)淬滅且水相用EtOAc (3×50 mL)萃取。經合併之有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾且藉由旋轉蒸發濃縮。粗產物藉由管柱層析(矽膠,己烷→7:3之己烷:EtOAc)純化,以得到呈無色油狀物之所需產物(0.33 g,72%)。
步驟 10 :
使來自步驟 9
之產物(0.53 g,1.1 mmol,1.0當量)在溶解於無水MeCN (11 mL)中之前與甲苯共沸三次。在氮氣氛圍下,依序添加胺基甲酸第三丁酯(0.51 g,4.4 mmol,4.0當量)、三乙基矽烷(0.70 mL,4.4 mmol,4.0當量)及三氟乙酸(0.16 mL,2.2 mmol,2.0當量)且將其加熱至65℃。在12 h之後,混合物用飽和NaHCO3
水溶液(100 mL)處理。水層用EtOAc (3×50 mL)萃取。經合併之有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾且濃縮。粗產物藉由管柱層析(矽膠,己烷→35% EtOAc/己烷)純化,以得到呈白色固體狀之所需產物(0.41 g,64%)。
步驟 11
:將來自步驟 10
之產物(0.41 g,0.70 mmol,1.0當量)溶解於二氯甲烷(7 mL)中且將攪拌溶液抽空並用氮氣再填充三次。向此溶液中添加雙(1,5-環辛二烯)二氯化二銥(I) (24 mg,0.035 mmol,5%莫耳),隨後添加1,2-雙(二苯膦基)乙烷(28 mg,0.070 mmol,10%莫耳),在此之後將所得混合物抽空並用氮氣再填充三次。在室溫下攪拌30 min之後,使反應混合物冷卻至0℃且歷經1.5 h用注射泵逐滴添加頻哪醇硼烷(0.30 mL,1.0 mmol,1.4當量)於二氯甲烷(2 mL)中之溶液。在添加之後,移除冰浴且將反應物在室溫下攪拌額外一小時。反應混合物用飽和NH4
Cl水溶液(50 mL)淬滅且水相用二氯甲烷(3×20 mL)萃取。經合併之有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾且濃縮。粗產物藉由管柱層析(矽膠,己烷→35% EtOAc/己烷)純化,以獲得呈白色固體狀之所需產物(0.43 g,86%)。
步驟 12 :
向來自步驟 11
之產物(0.43 g,0.60 mmol,1.0當量)中添加6 N HCl (5 mL)且將混合物加熱至120℃。在15 h後,使反應混合物冷卻至室溫且濃縮。粗產物用水溶解且濃縮。重複此製程以移除任何殘留鹽酸。將粗產物溶解於水(5 mL)中且裝載至在使用前已用MeOH (3×100 mL)及水(3×100 mL)沖洗之DOWEX®
550-OH樹脂(7 g)上。將混合物攪拌25 min,且樹脂藉由過濾收集並用水(3×20 mL)、甲醇(3×20 mL)、二氯甲烷(3×20 mL)及水(3×20 mL)依序洗滌。樹脂用2 N HCl (5 mL)處理,攪拌15 min且過濾。在重複此製程之後,將經合併之水性濾液冷凍且凍乾,以獲得呈白色固體狀之最終產物(156 mg,66%)。1
H NMR (400 MHz, D2
O) δ 7.54 (s, 1H), 7.39 (s, 1H), 4.30 (m, 2H), 3.36 (dd,J
= 15.8, 8.1 Hz, 1H), 2.81 (dd,J
= 17.7, 8.0 Hz, 1H), 2.76 - 2.67 (m, 1H), 2.50 (s, 3H), 1.67 - 1.36 (m, 4H), 0.87 - 0.72 (m, 2H)。C15
H21
BClN2
O3
之ESI MS [M-H2
O+H]+
,計算值323.1,實驗值323.0。實例 18 : 外消旋 -(1R
,2S
)-5- 氯 -2-[3-( 二羥基硼烷基 ) 丙基 ]-1-( 甲胺基 )-6-[( 甲胺基 ) 甲基 ]-2,3- 二氫 -1H- 茚 -1- 甲酸
步驟 1 :
使來自實例 17
,步驟 10
之中間物(0.14 g,0.23 mmol,1.0當量)在溶解於無水THF (2.3 mL)中之前與甲苯共沸三次。使攪拌溶液冷卻至0℃且逐滴添加KHMDS於MTBE (0.60 mL,0.57 mmol,2.5當量)中之1.0 M溶液。在攪拌20 min之後,逐滴添加碘甲烷(70 µL,1.2 mmol,5.0當量)且將所得反應混合物在0℃下攪拌額外20 min。移除冰浴且在室溫下繼續攪拌額外30 min。用飽和NH4
Cl水溶液(20 mL)淬滅反應混合物且用EtOAc (3×20 mL)萃取水相。經合併之有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾且濃縮。粗產物藉由管柱層析(矽膠,0→20% EtOAc/己烷)純化,以獲得呈白色固體狀之所需產物(0.15 g,>100%),該產物不經純化即用於下一步驟中。
步驟 2 :
如實例 17 , 步驟 11
。獲得呈白色固體狀之所需產物(0.13 g,歷經2個步驟,75%)。
步驟 3 :
以與實例 17 , 步驟 12
類似之方式合成標題化合物。1
H NMR (400 MHz, D2
O) δ 7.56 (s, 1H), 7.42 (s, 1H), 4.36 (m, 2H), 3.37 (dd,J
= 16.5, 8.2 Hz, 1H), 2.82 (dd,J
= 16.3, 8.1 Hz, 1H), 2.73 (s, 3H), 2.54 - 2.49 (m, 1H) 2.51 (s, 3H), 1.67 - 1.53 (m, 2H), 1.50 - 1.38 (m, 2H), 0.87 - 0.73 (m, 2H)。C16
H23
BClN2
O3
之ESI MS [M-H2
O+H]+
,計算值337.2,實驗值337.0。實例 19 : (1R
,2S
)-6-( 胺甲基 )-2-[3-( 二羥基硼烷基 ) 丙基 ]-5- 氟 -1-( 甲胺基 )-2,3- 二氫 -1H
- 茚 -1- 甲酸
步驟 1
:將6-溴-5-氟-1-茚酮中間物(324 mg,0.625 mmol;以與來自實例 17
,步驟 7
之中間物類似之方式製備)於無水DMF (3.1 mL)中之溶液用N2
脫氣15 min,接著添加Zn(CN)2
(73 mg,0.625 mmol)及Pd(PPh3
)4
(36 mg,0.031 mmol,5%莫耳)。小瓶用具有PTFE襯裡之隔墊封蓋密封且在80℃下持續3 h。添加額外量之Pd(PPh3
)4
(36 mg,0.031 mmol,5%莫耳)及Zn(CN)2
(73 mg,0.625mmol)且將反應物在80℃下攪拌2 h。使反應物冷卻至室溫且用H2
O (10 mL)及MTBE (10 mL)稀釋。有機層用H2
O (2×5 mL)洗滌,接著經合併之水層用MTBE (3×10 mL)萃取。經合併之有機層用鹽水洗滌,經MgSO4
乾燥,濃縮。殘餘物藉由管柱層析(矽膠,己烷→20% EtOAc/己烷)純化,以獲得呈黃色油狀物之所需產物(195 mg,67%)。
進行與實例 8
類似之步驟 2 、 3 及 4
。1
H NMR (400 MHz, D2
O) δ 7.36 (d,J
= 6.7 Hz, 1H), 7.22 (d,J
= 9.9 Hz, 1H), 4.25 (d,J
= 13.8 Hz, 1H), 4.18 (d,J
= 13.8 Hz, 1H), 3.37 (dd,J
= 16.3, 7.9 Hz, 1H), 2.89 - 2.67 (m, 2H), 2.51 (s, 3H), 1.69 - 1.50 (m, 2H), 1.50 - 1.31 (m, 2H), 0.90 - 0.67 (m, 2H)。C15
H22
BFN2
O4
之ESI MS [M+H]+
,計算值325.2,實驗值325.2。實例 20 : (1R
,2S
)-6-[(1R
)-1- 胺乙基 ]-2-[3-( 二羥基硼烷基 ) 丙基 ]-5- 氟 -1-( 甲胺基 )-2,3- 二氫 -1H
- 茚 -1- 甲酸
步驟 1 :
在N2
下,使6-溴-5-氟-1-茚酮中間物(500 mg,0.964 mmol;以與來自實例 17
,步驟 7
之中間物類似之方式製備)於無水THF (9.6 mL)中之溶液冷卻至-78℃且逐滴添加n-
BuLi於己烷(1.2 mL,1.2 mmol,1.2當量)中之2.5 M溶液。在完成添加之後,將反應物在-78℃下攪拌30 min,接著逐滴添加含[N(E
),S(S
)]-N
-亞乙基-2-甲基-2-丙烷亞磺醯胺(336 mg,1.93 mmol,2當量)之無水THF (1.2 mL)。-78℃浴用0℃浴置換且將所得混合物攪拌45 min。反應物用飽和NH4
Cl水溶液(100 mL)淬滅且倒入EtOAc (150 mL)中。層經分離,且水層用EtOAc (2×100 mL)萃取。經合併之有機物用鹽水(100 mL)洗滌,經MgSO4
乾燥且過濾。濃縮混合物且藉由管柱層析(矽膠,0→70% EtOAc/己烷)純化,以獲得呈無色泡沫狀之所需產物(240 mg;42%)。
進行與實例 8
類似之步驟 2
。
進行與實例 17
類似之步驟 3
。1
H NMR (400 MHz, D2
O) δ 7.38 (d,J
= 6.6 Hz, 1H), 7.19 (d,J
= 10.4 Hz, 1H), 3.35 (dd,J
= 16.5, 8.2 Hz, 1H), 2.79 (dd,J
= 16.5, 7.9 Hz, 1H), 2.72 - 2.63 (m, 1H), 2.47 (s, 3H), 1.62 (d,J
= 7.0 Hz, 3H), 1.63 - 1.51 (m, 2H), 0.88 - 0.72 (m, 2H)。注意:
苯甲基質子共振由殘餘H2
O (大約4.77 ppm)遮蔽。在甲醇-d4 (δ 4.65 (q,J
=7.0 Hz,1H))中觀測到此共振。C16
H25
BFN2
O4
之ESI MS [M+H]+
,計算值339.2,實驗值339.2。實例 21 : (1R
,2S
)-6-[(1S
)-1- 胺乙基 ]-2-[3-( 二羥基硼烷基 ) 丙基 ]-5- 氟 -1-( 甲胺基 )-2,3- 二氫 -1H
- 茚 -1- 甲酸
以與實例 20
類似之方式,使用[N(E
),S(R
)]-N
-亞乙基-2-甲基-2-丙烷亞磺醯胺來合成標題化合物。1
H NMR (400 MHz, D2
O) δ 7.39 (d,J
= 6.7 Hz, 1H), 7.20 (d,J
= 10.4 Hz, 1H), 3.36 (dd,J
= 16.5, 8.2 Hz, 1H), 2.80 (dd,J
= 16.2, 8.1 Hz, 1H), 2.75 - 2.65 (m, 1H), 2.48 (s, 3H), 1.64 (d,J
= 6.9 Hz, 3H), 1.62 - 1.51 (m, 2H), 1.52 - 1.35 (m, 2H), 0.87 - 0.72 (m, 2H)。注意:
苯甲基質子共振由殘餘H2
O (大約4.77 ppm)遮蔽。在甲醇-d4 (δ 4.65 (q,J=7.0 Hz,1H))中觀測到此共振。C16
H23
BFN2
O3
之ESI MS [M-OH]+
,計算值321.2,實驗值321.2。實例 22 : (1R
,2S
)-6-{[(1R
,2R
)-2- 胺基環戊基 ] 氧基 -2-[3-( 二羥基硼烷基 ) 丙基 ]-5- 氟 -1-( 甲胺基 )-2,3- 二氫 -1H
- 茚 -1- 甲酸
步驟 1
:將6-溴-5-氟-1-茚酮中間物(3.0 g,6.8 mmol)、KOAc (2.0 g,20.4 mmol,3當量)及B2
Pin2
(2.6 g,10.2 mmol,1.5當量)於無水二噁烷(136 mL)中之混合物用氮氣充氣10 min且接著添加Pd(dppf)Cl2
(498 mg,0.68 mmol,10%莫耳)。繼續充氣5 min且接著將混合物在100℃下攪拌隔夜。使混合物冷卻至室溫,用EtOAc稀釋且經由矽藻土墊過濾。濾液在真空中濃縮且使用管柱層析(矽膠,己烷→20% EtOAc/己烷)純化,以得到所需產物(1.8 g,49%)。
步驟 2 :
將來自步驟 1
之中間物(1.6 g,3.3 mmol)及NMO (0.43 g,3.6 mmol,1.1當量)於二噁烷(14 mL)中之溶液在80℃下攪拌3 h。使混合物在真空中濃縮且使用管柱層析(矽膠,己烷→40% EtOAc/己烷)純化,以得到所需產物(0.78 g,62%)。
步驟 3 :
將來自步驟 2
之中間物(800 mg,2.1 mmol)、受Boc保護之胺基醇(750 mg,3.2 mmol,1.5當量)及PPh3
(840 mg,3.2 mmol,1.5當量)於無水THF (21 mL)中之混合物冷卻至0℃。逐滴添加DIAD (646 mg,3.2 mmol,1.5當量)且將反應混合物在室溫下攪拌隔夜。在用H2
O淬滅之後,混合物用CH2
Cl2
萃取且經合併之有機層經MgSO4
乾燥,過濾且蒸發。殘餘物使用管柱層析(矽膠,己烷→40% EtOAc/己烷)純化,以得到所需產物(1.0 g,83%產率)。
步驟4:如實例17,步驟11。獲得呈白色固體狀之所需產物(900 mg,73%)。
步驟 5 :
如實例 17
,步驟 12
。1
H NMR (400 MHz, D2
O) δ 7.05 (d,J
= 11.0 Hz, 1H), 6.94 (d,J
= 7.6 Hz, 1H), 4.60 - 4.53 (m, 1H), 3.67 (q,J
= 7.7 Hz, 1H), 3.23 - 3.09 (m, 1H), 2.67 - 2.53 (m, 2H), 2.38 (s, 3H), 2.19 - 2.06 (m, 1H), 2.06 - 1.94 (m, 1H), 1.77 - 1.20 (m, 8H), 0.76 - 0.55 (m, 2H)。C19
H28
BFN2
O5
之ESI-MS [M+H]+
,計算值394.2,實驗值394.3。實例 23 : (1R
,2S
)-6-[1- 胺基環丙基 ]-2-[3-( 二羥基硼烷基 ) 丙基 ]-5- 氟 -1-( 甲胺基 )-2,3- 二氫 -1H
- 茚 -1- 甲酸
步驟 1 :
向6-溴-5-氟-1-茚酮中間物(1.8 g,4.07 mmol)於無水環戊基甲醚(13.5 mL)中之經脫氣溶液中添加XPhos-Pd-G2 (160 mg,0.20 mmol)。逐滴添加環丙烷甲腈(0.36 mL,4.88 mmol)且將攪拌混合物抽空並用氮氣再填充三次。在室溫下攪拌反應混合物10 min之後,歷經15 min逐滴添加四甲基哌啶基氯化鋅氯化鋰(TMPZnCl·LiCl) (1.0 M於THF中,4.88 mL,4.88 mmol),同時將溫度維持低於30℃。在室溫下攪拌反應混合物30 min之後,將其加熱至80℃持續1 h。使反應混合物冷卻至室溫且用甲醇處理,經由矽藻土墊過濾並在真空中濃縮。殘餘物使用管柱層析(矽膠,己烷→30% EtOAc/己烷)純化,以得到所需產物(1.26 g,72%產率)。
步驟 2 :
向0℃下之來自步驟 1
之腈(0.59 g,1.38 mmol)於MeOH (14 mL)中之溶液中逐滴添加30% (w/w) H2
O2(aq)
(0.47 mL,4.14 mmol),隨後添加K2
CO3
(0.38 g,2.76 mmol)。使混合物升溫至室溫且由TLC監測。在反應完成之後,將混合物倒入水中且用二氯甲烷萃取。經合併之有機物用硫代硫酸鈉之水溶液、接著鹽水洗滌,經Na2
SO4
乾燥且過濾。將混合物濃縮且使用管柱層析(矽膠,CH2
Cl2
→10% MeOH/CH2
Cl2
)純化,以得到所需產物(0.52 g,85%產率)。
步驟 3 :
向來自步驟 2
之醯胺(0.2 g,0.45 mmol)於乙腈(13.5 mL)及第三丁醇(1.1 mL)中之溶液中一次性添加[雙(三氟乙醯氧基)碘]苯(PIFA) (0.22 g,0.50 mmol)。將反應混合物加熱至50℃持續2 h。在冷卻至室溫之後,添加EtOAc及飽和NaHCO3(aq)
。有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾且蒸發。殘餘物使用管柱層析(矽膠,己烷→30% EtOAc/己烷)純化,以得到所需產物(140 mg,62%產率)。
步驟 4 :
如實例 17
,步驟 11
。獲得呈白色固體狀之所需產物(145 mg,83%產率)。
步驟 5 :
如實例 17
,步驟 12
。獲得呈白色固體狀之所需產物(74 mg,84%)。1
H NMR (400 MHz, D2
O) δ 7.44 (d, J = 6.6 Hz, 1H), 7.22 (d,J
= 10.2 Hz, 1H), 3.37 (dd,J
= 16.3, 7.8 Hz, 1H), 2.90 - 2.70 (m, 2H), 2.50 (s, 3H), 1.67 - 1.53 (m, 2H), 1.53 - 1.36 (m, 4H), 1.31 - 1.19 (m, 2H), 0.88 - 0.71 (m, 2H)。C17
H24
BFN2
O3
之ESI-MS [M-H2
O+H]+
,計算值333.2,實驗值333.0。實例 24 : (1R
,2S
)-2-
[3-( 二羥基硼烷基 ) 丙基 ]-5- 氟 -1-( 甲胺基 )-6-[(2R
)- 吡咯啶 -2- 基 ]-2,3- 二氫 -1H
- 茚 -1- 甲酸
步驟 1 :
向-78℃下之6-溴-5-氟-1-茚酮中間物(1.02 g,2.31 mmol)於THF (33 mL)中之溶液中逐滴添加n
-BuLi (2.5 M於己烷中,0.88 mL,0.95當量)。將反應混合物在-78℃下攪拌30 min。此時,歷經15 min之時間段將(S 2 S
)-N
-[(1E
)-4-氯亞丁基]-2-甲基丙烷-2-亞磺醯胺(0.97 g,4.62 mmol,2.0當量)於THF (10.6 mL)中之溶液緩慢添加至上文反應混合物。將反應混合物在-78℃下攪拌額外1 h。隨後使反應物升溫至0℃且用飽和NH4
Cl溶液(10 mL)及H2
O (10 mL)淬滅,隨後萃取至EtOAc (×2)中。經合併之有機層用鹽水洗滌,經Na2
SO4
乾燥且在真空中濃縮以得到藉由管柱層析(矽膠,己烷→80% EtOAc/己烷)純化之粗殘餘物,以獲得呈黃色油狀物之產物(297 mg,22%)。C28
H43
ClFN2
O5
S之ESI MS [M+H]+
,計算值573.2,實驗值573.2。
步驟 2 :
將來自步驟 1
之產物(297 mg,0.519 mmol)溶解於THF (2.2 mL)中。將反應混合物在逐滴添加LiHMDS (1 M於THF中,0.78 mL,1.5當量)之前冷卻至0℃。使反應混合物立即升溫至室溫且攪拌額外1 h。此時,反應物用飽和NH4
Cl溶液(10 mL)及H2
O (10 mL)淬滅,隨後萃取至EtOAc (×2)中。經合併之有機層用鹽水洗滌,經Na2
SO4
乾燥且在真空中濃縮以得到藉由管柱層析(矽膠,己烷→80% EtOAc/己烷)純化之粗殘餘物,以獲得呈無色油狀物之產物(278 mg,定量)。C28
H42
FN2
O5
S之ESI MS [M+H]+
,計算值537.3,實驗值537.1。
步驟 3 :
如實例 17
,步驟 11
。獲得呈無色油狀物之所需產物(240 mg,70%)。C34
H54
BFN2
O7
之ESI MS [M+H]+
,計算值687.2,實驗值687.4。
步驟 4 :
將來自步驟 3
之產物(240 mg,0.36 mmol)懸浮於6 N HCl中且將反應混合物加熱至120℃持續16 h。使反應混合物冷卻至室溫,在真空中移除溶劑以得到藉由RP-HPLC (CH3
CN/H2
O)純化之粗殘餘物,以提供呈白色固體狀之(1R
,2S
)-2-[3-(二羥基硼烷基)丙基]-5-氟-1-(甲胺基)-6-[(2R
)-吡咯啶-2-基]-2,3-二氫-1H
-茚-1-甲酸(92 mg,76%)。1
H NMR (400 MHz, D2
O) δ 7.31 (d,J
= 6.7 Hz, 1H), 7.17 - 7.13 (m, 1H), 3.42 - 3.21 (m, 3H), 2.79 - 2.62 (m, 2H), 2.43 (s, 3H), 2.41 - 2.29 (m, 1H), 2.22 - 2.10 (m, 3H), 2.08 - 2.00 (m, 1H), 1.58 - 1.45 (m, 2H), 1.40 - 1.29 (m, 2H), 0.82 - 0.60 (m, 2H)。19
F NMR (376 MHz, D2
O) δ -113.7。C18
H27
BFN2
O4
之ESI MS [M+H]+
,計算值365.2,實驗值365.2。分析方法
LC:Agilent 1100系列;質譜儀:Agilent G6120BA,單四極
LC-MS方法:LCMS管柱Waters XSelect® HSS C18 3.5 μm (2.1×75 mm),35℃,0.9 mL/min流速,0至100% B之梯度2.5 min與在100% B下洗滌0.5 min;A=0.1%之甲酸/5%乙腈/94.9%水;B=0.1%之甲酸/5%水/94.9%乙腈
急驟管柱:ISCO Rf+
反相HPLC:ISCO-EZ;管柱:Kinetex 5 μm EVO C18 100 A;250×21.2 mm (Phenomenex)藉由精胺酸酶偶合之酶分析 , 使用重組人類 ARG1 及 ARG2 來 量測化合物效能
在50 mM二甘胺酸pH 8.5、100 µM MnCl2
、20%甘油及1 mM DTT中分別以14.4 µM及7.56 µM之最終原料濃度製備經純化重組人類ARG1及ARG2。將2.5 nM之ARG1或ARG2在37℃下在384孔微量培養盤(Corning™ #3640)中與呈40 µl之總體積的10 mM磷酸鈉pH 7.4、0.1 mM MnCl2
及2.5% DMSO中的不同濃度之化合物一起培育1 h。精胺酸酶酶促反應藉由在37℃下將於10 mM磷酸鈉pH 7.4及0.1 mM MnCl2
中預培育的10 µl之4 mM L-精胺酸添加至酶及化合物混合物中來引發,從而得到最終反應條件:2 nM之ARG1或ARG2及0.8 mM之L-精胺酸與不同濃度之化合物於10 mM磷酸鈉pH 7.4、0.1 mM MnCl2
及2% DMSO中。在37℃下進行2 h培育後,藉由在透明384孔微量培養盤(Greiner #781801)中將10 µl之反應物轉移至10 µl之偵測混合物(204 µM胺基-2-二羥硼基-6-己酸、0.25 µl精胺酸酶混合物、0.25 µl精胺酸酶顯影劑(Arginase Developer)、0.25 µl精胺酸酶轉化酶於精胺酸酶分析緩衝液中,來自精胺酸酶活性比色分析套組,BioVision Inc. #K755-100)中來停止精胺酸酶酶促反應。將培養盤立即放入培養盤讀取器(Synergy™ Neo2多模式微量培養盤讀數器)中以在37℃下在570 nm處監測吸收。12~20 min處之吸收值用於計算化合物效能。DMSO空白(MIN抑制=100%活性)之值用作陰性對照。藉由將8 µl之酶及DMSO混合物添加至10 µl之偵測混合物中,隨後添加2 µl之L-精胺酸(MAX抑制=0%活性)來建立陽性對照。為計算活性%,使用方程式1。Abs570nm
為給定化合物濃度下之值:
藉由GraphPad Prism,使用方程式2 (其中N為希爾係數(Hill coefficient))來計算造成50%之酶活性損失(IC 50
)的化合物之濃度:
執行計數篩檢以鑑別測試化合物對偶合酶之任何抑制。將10 µl之含0.26 mM脲與不同濃度之化合物之10 mM磷酸鈉pH 7.4、0.1 mM MnCl2
及2% DMSO添加至10 µl之偵測混合物而非精胺酸酶酶促反應混合物中。如上文所描述,在570 nm處監測吸收。無基質空白(不含脲;MAX抑制=0%活性)及DMSO空白(MIN抑制=100%活性)之值分別用作陽性及陰性對照。針對不抑制任何偶合酶之化合物,預期平坦劑量反應曲線。計數篩檢中之不活動性用於確認結果精確反映ARG1及ARG2之IC50
值。
製備且評估具有如下表1中所展示之結構及活性的額外化合物。製備方法使用與上文實例類似之合成方法論。表 1 :
特定實例(效能:hARG1:+意謂>1 μM,++意謂100 nM至1 μM,+++意謂<100 nM)
本發明之特定實施例描述於本文中,包括本發明者已知之進行本發明的最佳模式。在閱讀前文後,所揭示實施例之描述、變化形式可對在此項技術中工作之個體變得顯而易見,且吾人預期彼等熟習此項技術者可按需要採用此等變化形式。因此,意欲本發明不同於如本文中所特定描述來實踐,且本發明包括如由適用法律准許之在隨附申請專利範圍中敍述之主題之所有修改及等效物。此外,除非本文另外指示或另外與上下文明顯矛盾,否則本發明涵蓋上文所描述之要素在其所有可能變化形式中之任何組合。
本說明書中所引用之所有公開案、專利申請案、寄存編號及其他參考文獻皆以引用之方式併入本文中,如同各個別公開案或專利申請案特定地且個別地指示為以引用之方式併入一般。
Claims (28)
- 一種具有式(I)之化合物或其醫藥學上可接受之鹽或水合物,
- 如請求項1之化合物或其醫藥學上可接受之鹽或水合物,其中:X為N或CR4a;各R1獨立地為H或C1-8烷基;R2為H或CH3;各R3獨立地為H或C1-8烷基;或兩個R3基團接合在一起以形成未經取代或經1至4個Ra取代之5員或6員環;各R4a、R4b、R4c及R4d獨立地選自由以下組成之群:H、鹵素、CN、C1-8烷基、C1-8烷氧基、C1-8羥烷基、C1-8鹵烷基、-X1-Y、-X1-SO2R5a及-X1-NR5bR5c;各R5a、R5b及R5c獨立地選自由以下組成之群:H、C1-8烷基、C1-8鹵烷基、C1-8烷基C(O)-、C3-7環烷基、3員至7員雜環烷基、芳基、雜芳基及胺基酸,或R5b及R5c接合在一起以形成4員至6員環;且其中該4員至6員環、該C3-7環烷基或該3員至7員雜環烷基、該芳基及該雜芳基中之每一者未經取代或經1至4個Rb取代;各X1為鍵或未經取代或經1至4個Rc取代之C1-6伸烷基;各Ra、Rb及Rc獨立地為鹵素、CN、OH、NH2、C1-4烷基、C1-4鹵烷 基、C3-6環烷基及苯基,或兩個Rc經組合以形成C3-6環烷基;各Y獨立地為苯基或5員或6員雜芳基,其中之每一者未經取代或經1至3個Rd取代;及各Rd獨立地為鹵素、C1-4烷基、胺基、胺基C1-4烷基、C1-4鹵烷基、OH及C1-4羥烷基。
- 如請求項7之化合物或其醫藥學上可接受之鹽或水合物,其中R4b選自由以下組成之群:H、CH3、CN、CF3、F及Cl。
- 一種醫藥組合物,其包含如請求項1至12中任一項之化合物或其醫藥學上可接受之鹽或水合物,及醫藥學上可接受之賦形劑。
- 一種如請求項1至12中任一項之化合物或其醫藥學上可接受之鹽或水合物的用途,其用於製造用於藉由抑制ARG1、ARG2或ARG1及ARG2兩 者而治療至少部分由ARG1、ARG2或ARG1及ARG2兩者介導之疾病、病症或病狀的藥物。
- 如請求項14之用途,其中該藥物以有效逆轉、停止或減緩精胺酸酶介導之免疫抑止進展的量投與。
- 如請求項14之用途,其中該疾病、病症或病狀為癌症或免疫相關疾病、病症或病狀。
- 如請求項16之用途,其中該癌症為前列腺癌、結腸癌、直腸癌、胰臟癌、子宮頸癌、胃癌、子宮內膜癌、腦癌、肝癌、膀胱癌、卵巢癌、睪丸癌、頭部癌、頸部癌、皮膚癌、間皮內膜癌、白血球癌、食道癌、乳癌、肌肉癌、結締組織癌、肺癌、腎上腺癌、甲狀腺癌、腎癌、骨癌、結腸直腸癌、頭頸癌、神經膠母細胞瘤、間皮瘤、腎細胞癌、胃癌、肉瘤、絨膜癌、皮膚基底細胞癌瘤或睾丸精原細胞瘤。
- 如請求項17之用途,其中該癌症選自由以下組成之群:黑色素瘤、結腸直腸癌、胰臟癌、乳癌、前列腺癌、肺癌、白血病、腦腫瘤、淋巴瘤、卵巢癌、卡波西氏肉瘤、腎細胞癌、頭頸癌及食道癌。
- 如請求項16之用途,其中該免疫相關疾病、病症或病狀選自由以下組成之群:類風濕性關節炎、腎衰竭、狼瘡、哮喘、牛皮癬、結腸炎、胰臟炎、過敏、纖維化、貧血、肌肉纖維疼痛、阿茲海默氏病(Alzheimer's disease)、充血性心臟衰竭、中風、主動脈瓣狹窄、動脈硬化症、骨質疏鬆、帕金森氏病(Parkinson's disease)、感染、克羅恩氏病(Crohn's disease)、潰瘍性結腸炎、過敏性接觸性皮炎及其他濕疹、全身性硬化症及多發性硬化症。
- 一種組合,其包含如請求項1至12中任一項之化合物或其醫藥學上可接受之鹽或水合物,及至少一種額外治療劑。
- 如請求項20之組合,其中該至少一種額外治療劑為獨立地選自由化學治療劑、免疫及/或發炎調節劑、放射、免疫檢查點抑制劑及調節個體中腺苷含量的治療劑所組成之群。
- 如請求項21之組合,其中該至少一種額外治療劑藉由抑制CD73或藉由抑制A2aR及/或A2bR來調節個體中腺苷含量。
- 如請求項21之組合,其中該免疫檢查點抑制劑阻斷PD1、PDL1、BTLA、LAG3、B7家族成員、TIM3、TIGIT或CTLA4中至少一者之活性。
- 如請求項23之組合,其中該免疫檢查點抑制劑阻斷PD1或PDL1之活性,且選自由以下組成之群:納武單抗(nivolumab)、派姆單抗(pembrolizumab)、蘭利珠單抗(lambrolizumab)、阿維魯單抗 (avelumab)、阿特珠單抗(atezolizumab)及德瓦魯單抗(durvalumab)。
- 如請求項24之組合,其進一步包含阻斷TIGIT之活性的額外治療劑。
- 如請求項20之組合,其中該至少一種額外治療劑為免疫檢查點抑制劑,且該組合進一步包含藉由抑制CD73或藉由抑制A2aR及/或A2bR來調節個體中腺苷含量的治療劑。
- 一種如請求項1至12中任一項之化合物或其醫藥學上可接受之鹽或水合物的用途,其用於製造用於治療個體中癌症的藥物,其中該藥物進一步包含至少一種額外治療劑或該藥物用於與至少一種額外治療劑投與。
- 如請求項27之用途,其中該化合物或其醫藥學上可接受之鹽或水合物及該至少一種額外治療劑以組合方式投與或依序投與。
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JP2023528036A (ja) | 2020-06-02 | 2023-07-03 | アーカス バイオサイエンシズ インコーポレイティド | Tigitに対する抗体 |
US11649261B2 (en) | 2020-06-17 | 2023-05-16 | Arcus Biosciences, Inc. | Crystalline forms of a CD73 inhibitor and uses thereof |
TW202228720A (zh) | 2020-12-22 | 2022-08-01 | 波蘭商昂科艾倫迪治療法股份公司 | 精胺酸酶抑制劑及其使用方法 |
TW202313602A (zh) | 2021-05-21 | 2023-04-01 | 美商阿克思生物科學有限公司 | Axl化合物 |
CN117337288A (zh) | 2021-05-21 | 2024-01-02 | 艾库斯生物科学有限公司 | Axl抑制剂化合物 |
US20230159466A1 (en) | 2021-10-29 | 2023-05-25 | Arcus Biosciences, Inc. | Inhibitors of hif-2alpha and methods of use thereof |
WO2023215719A1 (en) | 2022-05-02 | 2023-11-09 | Arcus Biosciences, Inc. | Anti-tigit antibodies and uses of the same |
US20240124490A1 (en) | 2022-07-15 | 2024-04-18 | Arcus Biosciences, Inc. | Inhibitors of hpk1 and methods of use thereof |
WO2024020034A1 (en) | 2022-07-20 | 2024-01-25 | Arcus Biosciences, Inc. | Cbl-b inhibitors and methods of use thereof |
WO2024059142A1 (en) | 2022-09-14 | 2024-03-21 | Arcus Biosciences, Inc. | Dispersions of etrumadenant |
WO2024081385A1 (en) | 2022-10-14 | 2024-04-18 | Arcus Biosciences, Inc. | Hpk1 inhibitors and methods of use thereof |
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WO2020102646A2 (en) | 2020-05-22 |
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