TWI793365B - 作為jak抑制劑之5至7員雜環醯胺 - Google Patents
作為jak抑制劑之5至7員雜環醯胺 Download PDFInfo
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- TWI793365B TWI793365B TW108131710A TW108131710A TWI793365B TW I793365 B TWI793365 B TW I793365B TW 108131710 A TW108131710 A TW 108131710A TW 108131710 A TW108131710 A TW 108131710A TW I793365 B TWI793365 B TW I793365B
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P11/00—Drugs for disorders of the respiratory system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
本發明提供適用作JAK激酶抑制劑之式(I)化合物:
Description
本發明係關於用作JAK激酶抑制劑之化合物。本發明亦係關於包含此等化合物之醫藥組合物及使用此等化合物治療呼吸道疾病之方法。
哮喘為氣管之慢性疾病,其無預防或治癒方法。該疾病之特徵為氣管發炎、纖維化、高反應性及重構,其皆促成氣流限制。全世界估計有3億人罹患哮喘,且據估計,截至2025年,患有哮喘的人數將增長超過1億。在美國,約6%至8%之人口罹患哮喘,使其成為該國最常見之慢性疾病中的一種。雖然大多數患者可用吸入皮質類固醇實現對哮喘症狀之控制,該等吸入皮質類固醇可與白三烯修飾劑及/或長效β促效劑組合,但仍有一部分患有重度哮喘之患者之疾病不受習知療法控制。重度持續性哮喘被定義為對吸入皮質類固醇之較高劑量保持不受控制的疾病。雖然估計重度氣喘患者佔所有哮喘患者之約5%,其罹病率及死亡率高危且對氣喘患者中健保資源利用之不相稱份額負責。仍需要新穎治療劑來治療此等患者。
細胞介素為細胞間信號傳導分子,其包括趨化因子、干擾素、介白素、淋巴介質及腫瘤壞死因子。細胞介素對於正常細胞生長及免疫性調節至關重要且亦驅動免疫介導之疾病且有助於惡性細胞生長。多種細胞介素之經提高水準涉及哮喘發炎之病理學。舉例而言,已展示靶向介白素(IL)-5及13的基於抗體之治療劑以為重度哮喘患者子組提供臨床益處。在涉及哮喘發炎之細胞介素中,多種視經由轉錄因子之信號轉導與轉錄活化因子(Signal Transducer and Activator of Transcription;STAT)家族傳導信號之酪胺酸激酶(JAK)之傑納斯(Janus)家族而定,經由信號傳導路徑起作用。涉及經由JAK-STAT路徑傳導信號的哮喘發炎之細胞介素包括:IL-2、IL-3、IL-4、IL-5、IL-6、IL-9、IL-11、IL-13、IL-23、IL-31、IL-27、胸腺基質淋巴生成素(thymic stromal lymphopoietin;TSLP)、干擾素-γ (IFNγ)及粒細胞-巨噬細胞群落刺激因子(granulocyte-macrophage colony-stimulating factor;GM-CSF)。
JAK家族包含四個成員:JAK1、JAK2、JAK3及酪胺酸激酶2 (TYK2)。細胞介素結合至JAK依賴性細胞介素受體誘導受體二聚,其使得JAK激酶上之酪胺酸殘基磷酸化,從而影響JAK活化。磷酸化JAK轉而結合且使各種STAT蛋白質磷酸化,該等STAT蛋白質在單元細胞核中二聚、內化且直接調節基因轉錄,在其他作用中,導致與發炎疾病相關的下游作用。JAK通常與細胞介素受體成對締合作為均二聚體或雜二聚體。特定細胞介素與特定JAK配對相關。JAK家族之四個成員中之每一者涉及與哮喘發炎相關的細胞介素中之至少一者之信號傳導。因此,相對於JAK家族之所有成員,具有泛活性之化學抑制劑可調節有助於重度哮喘之寬範圍促炎性路徑。
然而,此等抑制劑之較寬抗炎性作用可抑制正常免疫細胞功能,潛在地引起感染風險提高。用JAK抑制劑托法替尼(tofacitinib)觀測到感染風險提高之證據,該抑制劑經口給藥以用於治療類風濕性關節炎。在哮喘中,發炎定位於呼吸道。除哮喘以外,氣管發炎為其他呼吸疾病所特有的。慢性阻塞性肺病(Chronic obstructive pulmonary disease;COPD)、囊腫性纖維化(cystic fibrosis;CF)、肺炎、間質肺病(包括特發性肺纖維化)、急性肺損傷、急性呼吸窘迫症候群、支氣管炎、氣腫及類肉瘤病亦為呼吸道疾病,其中咸信病理生理學與JAK信號傳導細胞介素有關。藉由吸入向肺部局部投與JAK抑制劑提供藉由將有效抗細胞介素藥劑直接遞送至作用位點而治療上有效的可能性,限制全身性暴露且因此限制不利的全身性免疫抑制之可能性。仍需要適用於向肺部局部投與以便治療呼吸疾病之有效JAK抑制劑。
JAK信號傳導細胞介素亦在T細胞活化中起主要作用,T細胞為對許多免疫過程重要的免疫細胞亞類。病理性T細胞活化對於多種呼吸道疾病之病因至關重要。自體反應性T細胞在阻塞性細支氣管炎伴機化性肺炎(亦稱為COS)中起作用。類似於COS,肺移植排斥反應之病因與移植供體肺之受體T細胞的異常T細胞活化有關。肺移植排斥反應可早期以原發性移植物功能障礙(Primary Graft Dysfunction;PGD)、機化性肺炎(organizing pneumonia;OP)、急性排斥反應(acute rejection;AR)或淋巴球性細支氣管炎(lymphocytic bronchiolitis;LB)形式發生,或其可在肺移植後數年以慢性肺同種異體移植物功能障礙(Chronic Lung Allograft Dysfunction;CLAD)形式發生。CLAD先前已知為阻塞性細支氣管炎(bronchiolitis obliterans;BO),但現在被認為可具有不同病理學表現之症候群,包括BO、限制性CLAD (rCLAD或RAS)及嗜中性球性同種異體移植物功能障礙。慢性肺同種異體移植物功能障礙(CLAD)為長期管理肺移植受體中之主要挑戰,因為其造成移植肺逐漸失去功能(Gauthier等人, Curr.Transplant. Rep.
,2016
, 3(3), 185-191)。CLAD對治療之反應不佳,且因此,仍需要能夠預防或治療此病況之有效化合物。諸如IFNγ及IL-5之若干JAK依賴性細胞介素在CLAD及肺移植排斥反應中上調(Berastegui等人,Clin. Transplant. 2017
, 31, e12898)。此外,在JAK依賴性IFN信號傳導下游之CXCR3趨化因子(諸如CXCL9及CXCL10)的高肺含量與肺移植患者之惡化結果有關(Shino等人,PLOS One
,2017
, 12 (7), e0180281)。全身性JAK抑制經展示在腎臟移植排斥反應中有效(Vicenti等人,American Journal of Transplantation
,2012
, 12, 2446-56)。因此,JAK抑制劑有可能有效治療或預防肺移植排斥反應及CLAD。如描述為肺移植排斥反應之基礎的類似T細胞活化事件亦視為造血幹細胞移植後可能發生的肺移植物抗宿主病(graft-versus-host disease;GVHD)之主要驅動因素。類似於CLAD,肺GVHD為一種慢性進行性病況,其結果極其不佳且目前尚無經批准之治療。95位接受全身性JAK抑制劑盧佐替尼(ruxolitinib)作為補救治療的患有類固醇難治性急性或慢性GVHD的患者之回溯性多中心調查研究證實,大多數患者(包括患有肺GVHD之此等患者)對盧佐替尼完全或部分反應(Zeiser等人,Leukemia
,2015
, 29, 10, 2062-68)。由於全身性JAK抑制與嚴重不良事件及小治療指數相關,仍需要吸入肺部定向之非全身性JAK抑制劑以預防及/或治療肺移植排斥反應或肺GVHD。
在一個態樣中,本發明提供具有作為JAK激酶抑制劑之活性的新穎化合物。
因此,本發明提供一種式(I)化合物:
其中:
A為含有兩個氮原子之6至7員單環雜環,其中A經由氮原子連接至(I)中之羰基,A經1至3個R2
基團取代且視情況兩個R2
基團與A一起形成-(CH2
)-橋接環;或
A為吡咯啶基,其中該吡咯啶基經由氮原子連接至(I)中之羰基且其中該吡咯啶基經NR3
R4
取代;
R1
為C1-3
烷基;
各R2
獨立地為視情況經-OH取代之C1-3
烷基;
R3
為C1-3
烷基;
且R4
為C1-3
烷基;
或其醫藥學上可接受之鹽。
本發明亦提供一種包含本發明之化合物及醫藥學上可接受之載劑的醫藥組合物。
本發明亦提供一種治療哺乳動物之呼吸道疾病(尤其哮喘或CLAD)的方法,該方法包含向哺乳動物投與治療有效量之化合物或本發明之醫藥組合物。
本發明亦提供一種如本文中所描述的本發明化合物,其用於醫學療法中;以及本發明之化合物之用途,其用於製造用於治療哺乳動物之呼吸道疾病的調配物或藥物。
相關申請案之交叉參考
本申請案主張2018年9月4日申請的美國臨時申請案第62/726,583號之權益,其揭示內容以全文引用之方式併入本文中。
在一個實施例中,本發明提供具有作為JAK激酶抑制劑之活性的新穎化合物。因此,本發明提供一種式(I)化合物:
其中:
A為含有兩個氮原子之6至7員單環雜環,其中A經由氮原子連接至(I)中之羰基,A經1至3個R2
基團取代且視情況兩個R2
基團與A一起形成-(CH2
)-橋接環;或
A為吡咯啶基,其中該吡咯啶基經由氮原子連接至(I)中之羰基且其中該吡咯啶基經NR3
R4
取代;
R1
為C1-3
烷基;
各R2
獨立地為視情況經-OH取代之C1-3
烷基;
R3
為C1-3
烷基;
且R4
為C1-3
烷基;
或其醫藥學上可接受之鹽。
在一些實施例中,R1
選自由以下組成之群:甲基、丙基及異丙基。
在一些實施例中,A選自由以下組成之群:哌嗪基、2,5-二氮雜雙環[2.2.1]庚基及1,4-二氮雜環庚基,其中之每一者經1或2個R2
基團取代,其中各R2
獨立地為視情況經-OH取代之C1-3
烷基,或A為經NR3
R4
取代之吡咯啶基,其中R3
為C1-3
烷基且R4
為C1-3
烷基。
在一些實施例中,R1
選自由甲基及丙基組成之群。
在另一實施例中,本揭示內容提供一種式(III)化合物:
其中:
R1
為C1-3
烷基;
A2
選自由以下組成之群:,
其中各R2
獨立地為視情況經-OH取代之C1-3
烷基,R3
為C1-3
烷基且R4
為C1-3
烷基;
或其醫藥學上可接受之鹽。
在一些實施例中,R1
選自由以下組成之群:甲基、異丙基及丙基。
在另一實施例中,本揭示內容提供一種式(IV)化合物:
其中:
R1
為C1-3
烷基;
A3
選自由以下組成之群:,
其中各R2
獨立地為視情況經-OH取代之C1-3
烷基,R3
為C1-3
烷基且R4
為C1-3
烷基;
或其醫藥學上可接受之鹽。
在一些實施例中,R1
選自由以下組成之群:甲基、異丙基及丙基。
此外,四氫咪唑并哌啶部分之咪唑并部分以互變異構形式存在,如下文針對本揭示內容之化合物之片段所說明。
根據IUPAC公約,此等圖示產生咪唑部分之原子之不同編號:(1H
-吲唑-3-基)-4,5,6,7-四氫-1H
-咪唑并[4,5-c]吡啶(結構A)對比於(1H
-吲唑-3-基)-4,5,6,7-四氫-3H
-咪唑并[4,5-c]吡啶(結構B)。應理解,雖然結構以特定形式展示或命名,但本發明亦包括其互變異構體。
本揭示內容之化合物可含有一或多個對掌性中心,且因此,此等化合物(及其中間物)可以外消旋混合物、純立體異構體(亦即,對映異構體或非對映異構體)、富含立體異構體之混合物及其類似者之形式存在。除非另外指示,否則本文中所展示或所命名之在對掌性中心不具有確定立體化學之對掌性化合物意欲包括在未確定的立體中心之任何或所有可能的立體異構體變化形式。除非另外指示,否則特定立體異構體之描述或命名意謂所指示立體中心具有經指定的立體化學,同時應理解為亦可存在少量的其他立體異構體,其限制條件為所描繪或所命名之化合物的效用不因另一立體異構體之存在而消除。
本揭示內容之化合物亦可含有若干鹼基(例如,胺基),且因此,此等化合物可以游離鹼之形式或以各種鹽形式存在,諸如單質子化鹽形式、二質子化鹽形式、三質子化鹽形式或其混合物。除非另外指示,否則所有此等形成均包括在本發明之範疇內。
本發明亦包括經同位素標記的式(I)、(I')、(II)、(II')、(III)、(III')、(IV)及(IV')之化合物,亦即一或多個原子經原子數相同但原子質量不同於在自然界中占絕大多數之原子質量的原子置換或富集的式(I)、(I')、(II)、(II')、(III)、(III')、(IV)及(IV')之化合物。可併入至式(I)、(I')、(II)、(II')、(III)、(III')、(IV)及(IV')之化合物中的同位素的實例包括(但不限於)2
H、3
H、11
C、13
C、14
C、13
N、15
N、15
O、17
O及18
O。備受關注的為富含氚或碳14的式(I)、(I')、(II)、(II')、(III)、(III')、(IV)及(IV')之化合物,該等化合物可用於例如組織分佈研究中。亦備受關注的為尤其在代謝位點處富含氘的式(I)、(I')、(II)、(II')、(III)、(III')、(IV)及(IV')之化合物,該等化合物預期具有較高代謝穩定性。此外,備受關注的為富含諸如11
C、15
O及13
N之正電子發射同位素的式(I)、(I')、(II)、(II')、(III)、(III')、(IV)及(IV')之化合物,該等化合物可用於例如正電子發射斷層攝影法(Positron Emission Tomography;PET)研究中。
定義
除非另外指示,否則當描述本發明(包括其各種態樣及實施例)時,以下術語具有以下含義。
術語「烷基」意謂可為直鏈或分支鏈或其組合的單價飽和烴基。除非另外定義,否則此等烷基通常含有1至10個碳原子。代表性烷基包括例如甲基(Me)、乙基(Et)、正丙基(n-Pr)或(nPr)、異丙基(i-Pr)或(iPr)、正丁基(n-Bu)或(nBu)、第二丁基、異丁基、第三丁基(t-Bu)或(tBu)、正戊基、正己基、2,2-二甲基丙基、2-甲基丁基、3-甲基丁基、2-乙基丁基、2,2-二甲基戊基、2-丙基戊基及其類似基團。
當特定數目的碳原子意欲用於特定術語時,碳原子數目在術語前展示。舉例而言,術語「C1-3
烷基」意謂具有1至3個碳原子之烷基,其中碳原子呈任何化學上可接受之組態,包括直鏈或分支鏈組態。
術語「環烷基」意謂可為單環或多環之單價飽和碳環基。除非另外定義,否則此等環烷基通常含有3至10個碳原子。代表性環烷基包括例如環丙基(cPr)、環丁基(cBu)、環戊基、環己基、環庚基、環辛基、金剛烷基及其類似基團。
術語「環丙基(cpropyl)」意謂環丙基(cyclopropyl)。
術語「雜環基(heterocyclyl)」、「雜環(heterocycle)」、「雜環的(heterocyclic)」或「雜環(heterocyclic ring)」意謂總共具有3至10個環原子的單價飽和或部分不飽和環狀非芳族基團,其中環含有2至9個碳環原子及1至4個選自氮、氧及硫之環雜原子。雜環基可為單環或多環(亦即,稠合或橋連)的。代表性雜環基包括例如吡咯啶基、哌啶基、哌嗪基、咪唑啶基、嗎啉基、硫嗎啉基、吲哚啉-3-基、2-咪唑啉基、四氫哌喃基、1,2,3,4-四氫異喹啉-2-基、奎寧環基、7-氮雜降莰烷基、降托烷基(nortropanyl)及其類似基團,其中連接點在任何可用之碳或氮環原子處。在上下文使得雜環基之連接點顯而易見的情況下,此等基團可替代地稱為非價物種,亦即吡咯啶、哌啶、哌嗪、咪唑、四氫哌喃等。
術語「鹵基」意謂氟基、氯基、溴基或碘基。
術語「治療有效量」意謂當向有需要治療之患者投與時足以實現治療的量。
術語「治療(treating/treatment)」意謂預防、改善或抑止正治療患者(特定言之為人類)之醫學病況、疾病或病症(例如,呼吸道疾病);或緩解醫學病況、疾病或病症之症狀。
術語「醫藥學上可接受之鹽」意謂向患者或哺乳動物(諸如人類)投與可接受之鹽(例如,對於既定劑量方案具有可接受哺乳動物安全性的鹽)。代表性醫藥學上可接受之鹽包括以下之鹽:乙酸、抗壞血酸、苯磺酸、苯甲酸、樟腦磺酸、檸檬酸、乙磺酸、乙二磺酸、反丁烯二酸、龍膽酸、葡萄糖酸、葡糖醛酸、麩胺酸、馬尿酸、氫溴酸、氫氯酸、羥乙基磺酸、乳酸、乳糖酸、順丁烯二酸、蘋果酸、杏仁酸、甲磺酸、黏液酸、萘磺酸、萘-1,5-二磺酸、萘-2,6-二磺酸、菸鹼酸、硝酸、乳清酸、雙羥萘酸、泛酸、磷酸、丁二酸、硫酸、酒石酸、對甲苯磺酸及羥萘甲酸以及其類似酸。
術語「其鹽」意謂當酸之氫經陽離子(諸如金屬陽離子或有機陽離子及其類似陽離子)置換時所形成之化合物。舉例而言,陽離子可為式(I)、(I')、(II)、(II')、(III)、(III')、(IV)或(IV')之化合物之質子化形式,亦即其中一或多個胺基由酸質子化的形式。通常,該鹽為醫藥學上可接受之鹽,但此對於不意欲向患者投與之中間化合物的鹽而言係不需要的。
通用合成程序
本發明之化合物及其中間物可根據以下通用方法及程序使用可商購或常規製備之起始材料及試劑來製備。除非另外指示,否則以下流程中所使用之取代基及變數(例如,A、R1
、R2
、R3
等)具有與本文中其他地方所定義相同的含義。此外,除非另外指示,否則具有酸性或鹼性原子或官能基之化合物可用作鹽或可作為鹽產生(在一些情況下,在特定反應中使用鹽將需要在進行反應之前使用常規程序將鹽轉化為非鹽形式,例如游離鹼)。
雖然可在以下程序中展示或描述本發明之特定實施例,但熟習此項技術者將認識到本發明之其他實施例或態樣亦可使用此等程序或藉由使用熟習此項技術者已知之其他方法、試劑及起始材料來製備。特定而言,應瞭解,本發明之化合物可藉由多種製程途徑製備,其中反應物以不同次序組合以提供不同中間物烯途徑,以製備最終產物。
使化合物K-18
與酮或醛在還原劑之存在下反應,以得到式K-19
化合物。接著使化合物K-19
與胺A在典型醯胺鍵形成條件下反應,以得到化合物(I)。通常,使羧酸與約1當量與約4當量之間的胺A在過量鹼之存在下接觸。醯胺鍵形成反應可利用偶合劑,諸如N,N,N',N'
-四甲基-O-(7-氮雜苯并三唑-1-基)脲鎓六氟磷酸鹽(HATU)或此項技術中已知的其他醯胺偶合劑。可添加肼以分解非所要副產物。反應通常在室溫下進行約5分鐘與約24小時之間或直至反應基本上完成為止。
醫藥組合物
本發明之化合物及其醫藥學上可接受之鹽通常以醫藥組合物或調配物之形式使用。此等醫藥組合物可有利地藉由吸入向患者投與。另外,可藉由任何可接受之投與途徑投與醫藥組合物,包括(但不限於)經口、經直腸、經鼻、局部(包括經皮)及非經腸投與模式。
因此,在其組合物態樣中之一者中,本發明係關於一種醫藥組合物,其包含醫藥學上可接受之載劑或賦形劑及式(I)、(I')、(II)、(II')、(III)、(III')、(IV)或(IV')之化合物,其中如上文所定義,「式(I)、(I')、(II)、(II')、(III)、(III')、(IV)或(IV')之化合物」意謂式(I)、(I')、(II)、(II')、(III)、(III')、(IV)或(IV')之化合物或其醫藥學上可接受之鹽。視情況,必要時此等醫藥組合物可含有其他治療劑及/或調配劑。當論述組合物及其用途時,「本發明之化合物」在本文中亦可稱為「活性劑」。如本文中所使用,術語「本發明之化合物」意欲包括式(I)所涵蓋之所有化合物以及以式(I)形式體現之物種及其醫藥學上可接受之鹽。
本發明之醫藥組合物通常含有治療有效量的本發明之化合物。然而,熟習此項技術者將認識到,醫藥組合物可含有超過治療有效量(亦即,主體組合物)或小於治療有效量(亦即,經設計以用於多次投與以獲得治療有效量的個別單位劑量)。
通常,此等醫藥組合物將含有約0.01至約95重量%之活性劑;包括例如約0.05至約30重量%;及約0.1重量%至約10重量%之活性劑。
任何習知載劑或賦形劑可用於本發明之醫藥組合物中。選擇特定載劑或賦形劑,或載劑或賦形劑之組合將視用於治療特定患者或特定類型之醫學病況或疾病狀態的投藥模式而定。就此而言,針對特定投藥模式製備適合醫藥組合物很好地在熟習醫藥技術者之範疇內。此外,本發明之醫藥組合物中所使用之載劑或賦形劑係可為商購的。藉助於進一步說明,習知調配技術描述於Remington: The Science and Practice of Pharmacy, 第20版, Lippincott Williams & White, Baltimore, Maryland (2000);及H.C. Ansel等人, Pharmaceutical Dosage Forms and Drug Delivery Systems, 第7版, Lippincott Williams & White, Baltimore, Maryland (1999)中。
可充當醫藥學上可接受之載劑的材料之代表性實例包括(但不限於)以下:糖,諸如乳糖、葡萄糖及蔗糖;澱粉,諸如玉米澱粉及馬鈴薯澱粉;纖維素,諸如微晶纖維素及其衍生物,諸如羧甲基纖維素鈉、乙基纖維素及乙酸纖維素;粉末狀黃蓍;麥芽;明膠;滑石;賦形劑,諸如可可脂及栓劑蠟;油,諸如花生油、棉籽油、紅花油、芝麻油、橄欖油、玉米油及大豆油;二醇,諸如丙二醇;多元醇,諸如丙三醇、山梨糖醇、甘露糖醇及聚乙二醇;酯,諸如油酸乙酯及月桂酸乙酯;瓊脂;緩衝劑,諸如氫氧化鎂及氫氧化鋁;褐藻酸;無熱原質水;等滲鹽水;林格氏溶液(Ringer's solution);乙醇;磷酸鹽緩衝溶液;及醫藥組合物中採用之其他無毒性相容物質。
通常藉由將活性劑與醫藥學上可接受之載劑及一或多種視情況選用之成分充分且緊密地混合或摻合來製備醫藥組合物。接著可使用習知程序及設備使所得均勻摻合之混合物成形為錠劑、膠囊、丸劑及其類似物或裝載至其中。
在一個態樣中,醫藥組合物適用於吸入投與。用於吸入投與之醫藥組合物通常呈氣霧劑或散劑形式。此等組合物一般使用吸入器遞送裝置投與,諸如乾燥散劑吸入器(dry powder inhaler;DPI)、定量吸入器(metered-dose inhaler;MDI)、噴霧器吸入器或類似遞送裝置。
在一特定實施例中,醫藥組合物藉由吸入,使用乾燥散劑吸入器投與。此等乾燥散劑吸入器通常以在吸氣期間分散於患者之氣流中的自由流動散劑形式來投與醫藥組合物。為獲得自由流動散劑組合物,治療劑通常用諸如乳糖、澱粉、甘露糖醇、右旋糖、聚乳酸(PLA)、聚乳酸交酯-共-乙交酯(PLGA)或其組合的適合賦形劑來調配。通常,使治療劑微粉化且與適合載劑組合以形成適用於吸入之組合物。
用於乾燥散劑吸入器之代表性醫藥組合物包含呈微粉化形式之乳糖及本發明之化合物。此等乾燥散劑組合物可例如藉由將乾燥研磨乳糖與治療劑組合,且接著乾摻合組分來製得。接著,通常將組合物裝載至乾燥散劑分配器中或與乾燥散劑遞送裝置一起使用之吸入套筒或膠囊中。
適用於藉由吸入投與治療劑之乾燥散劑吸入器遞送裝置描述於此項技術中且此等裝置之實例為可商購的。舉例而言,代表性乾燥散劑吸入器遞送裝置或產物包括:Aeolizer (Novartis);Airmax (IVAX);ClickHaler (Innovata Biomed);Diskhaler (GlaxoSmithKline);Diskus/Accuhaler (GlaxoSmithKline);Ellipta (GlaxoSmithKline);Easyhaler (Orion Pharma);Eclipse (Aventis);FlowCaps (Hovione);Handihaler (Boehringer Ingelheim);Pulvinal (Chiesi);Rotahaler (GlaxoSmithKline);SkyeHaler/Certihaler (SkyePharma);Twisthaler (Schering-Plough);Turbuhaler (AstraZeneca);Ultrahaler (Aventis);及其類似者。
在另一特定實施例中,醫藥組合物藉由吸入,使用定量吸入器投與。此等定量吸入器通常使用壓縮推進劑氣體排出量測量之治療劑。因此,使用定量吸入器投與之醫藥組合物通常包含治療劑於液化推進劑中之溶液或懸浮液。可採用任何適合的液化推進劑,包括氫氟烷烴(HFA),諸如1,1,1,2-四氟乙烷(HFA 134a)及1,1,1,2,3,3,3-七氟-正丙烷(HFA 227);及氯氟碳化物,諸如CCl3
F。在一特定實施例中,推進劑為氫氟烷烴。在一些實施例中,氫氟烷烴調配物含有共溶劑,諸如乙醇或戊烷;及/或界面活性劑,諸如脫水山梨糖醇三油酸酯、油酸、卵磷脂及丙三醇。
用於定量吸入器之代表性醫藥組合物包含約0.01重量%至約5重量%的本發明之化合物;約0重量%至約20重量%的乙醇;及約0重量%至約5重量%的界面活性劑;其中剩餘部分為HFA推進劑。通常藉由向含有治療劑、乙醇(若存在)及界面活性劑(若存在)之適合容器中添加經冷卻或經加壓之氫氟烷烴來製備此等組合物。為製備懸浮液,將治療劑微米尺寸化,且接著與推進劑組合。接著將組合物裝載至氣霧劑罐中,其通常形成定量吸入器裝置之部分。
適用於藉由吸入投與治療劑之定量吸入器裝置描述於此項技術中且此等裝置之實例為可商購的。舉例而言,代表性定量吸入器裝置或產物包括:AeroBid吸入器系統(Forest Pharmaceuticals);Atrovent吸入氣霧劑(Boehringer Ingelheim);Flovent (GlaxoSmithKline);Maxair吸入器(3M);Proventil吸入器(Schering);Serevent吸入氣霧劑(GlaxoSmithKline);及其類似者。
在另一特定態樣中,醫藥組合物藉由吸入,使用噴霧器吸入器投與。此等噴霧器裝置通常產生使醫藥組合物以噴霧為進入患者之呼吸道中之霧狀物的高速空氣流。因此,當調配以用於噴霧器吸入器時,可將治療劑溶解於適合載劑中以形成溶液。替代地,治療劑可經微米尺寸化或奈米研磨且與適合載劑組合以形成懸浮液。
用於噴霧器吸入器之代表性醫藥組合物包含溶液或懸浮液,其包含約0.05 μg/mL至約20 mg/mL的本發明之化合物及與霧化調配物相容之賦形劑。在一個實施例中,溶液具有約3至約8之pH。
適用於藉由吸入投與治療劑之噴霧器裝置描述於此項技術中且此等裝置之實例為可商購的。舉例而言,代表性噴霧器裝置或產物包括:Respimat Softmist吸入器(Boehringer Ingelheim);AERx肺部遞送系統(Aradigm Corp.);PARI LC Plus可再用噴霧器(Pari GmbH);及其類似者。
在又一態樣中,本發明之醫藥組合物可替代地以意欲用於經口投與之劑量形式來製備。用於經口投藥之適合醫藥組合物可呈膠囊、錠劑、丸劑、口含錠、扁囊劑、糖衣藥丸、散劑、顆粒形式;或呈於水性或非水性液體中之溶液或懸浮液形式;或呈水包油或油包水液體乳液形式;或呈酏劑或糖漿形式;及其類似者;各自含有預定量的本發明之化合物作為活性成分。
當以固體劑量形式意欲用於經口投與時,本發明之醫藥組合物將通常包含活性劑及一或多種醫藥學上可接受之載劑,諸如檸檬酸鈉或磷酸二鈣。視情況或替代地,此等固體劑型亦可包含:填充劑或增量劑、黏合劑、保濕劑、溶液阻滯劑、吸收加速劑、濕潤劑、吸附劑、潤滑劑、著色劑及緩衝劑。釋放劑、濕潤劑、包衣劑、甜味劑、調味劑及芳香劑、防腐劑及抗氧化劑亦可存在於本發明之醫藥組合物中。
替代調配物亦可包括控制釋放調配物、用於經口投與之液體劑量形式、經皮貼片及非經腸調配物。製備此等替代調配物之習知賦形劑及方法描述於例如前述Remington參考文獻中。
以下非限制性實例說明本發明之代表性醫藥組合物。
乾燥散劑組合物
將微米尺寸化式(I)化合物(1 g)與經研磨之乳糖(25 g)摻合。接著,將此摻合混合物以每劑量足以提供約0.1 mg至約4 mg之間的式I化合物的量裝載至可剝離泡殼封裝之單獨泡殼中。使用乾燥散劑吸入器投與泡殼之內含物。
乾燥散劑組合物
將微米尺寸化式(I)化合物(1 g)與經研磨之乳糖(20 g)摻合,以形成化合物與經研磨之乳糖之重量比為1:20的主體組合物。將摻合組合物封裝於每劑量能夠遞送約0.1 mg至約4 mg之間的式I化合物之乾燥散劑吸入裝置中。
定量吸入器組合物
將微米尺寸化式(I)化合物(10 g)分散於藉由使卵磷脂(0.2 g)溶解於去礦物質水(200 mL)中所製備的溶液中。噴霧乾燥所得懸浮液,且接著經微米尺寸化以形成包含平均直徑小於約1.5 μm之粒子的微米尺寸化組合物。接著,將微米尺寸化組合物裝載至以當藉由定量吸入器投與時每劑量足以提供約0.1 mg至約4 mg式I化合物的量含有加壓1,1,1,2-四氟乙烷之定量吸入器套筒中。
噴霧器組合物
將式(I)化合物(25 mg)溶解於含有1.5-2.5當量鹽酸之溶液中,隨後添加氫氧化鈉以將pH調節至3.5至5.5及3重量%之甘油。充分攪拌溶液直至所有組分溶解為止。使用每劑量提供約0.1 mg至約4 mg式(I)化合物之噴霧器裝置投與溶液。
效用
本發明之JAK抑制劑已經設計用於治療呼吸道之發炎性及纖維化疾病。特定而言,化合物經設計以使得能夠將有效抗細胞介素試劑直接遞送至肺中之呼吸疾病作用位點,同時限制全身性暴露。
本發明之化合物經展示為以下酶之JAK家族之有效抑制劑:JAK1、JAK2、JAK3及TYK2。此外,化合物經證實有效抑制促炎性及促纖維化細胞介素。已認識到,JAK抑制劑之較寬抗炎性作用可抑制正常免疫細胞功能,潛在地導致感染風險提高。本化合物因此最佳化以限制自肺至血漿中之吸收,因此使免疫抑制風險降至最低。
如以下實驗部分中所描述,典型化合物之吸收及分佈已在臨床前分析中描繪。化合物1
至6
在小鼠中進行測試且在給藥後5小時展示肺組織中之高濃度及至血漿中之低吸收。本發明之化合物經展示以抑制小鼠肺組織中之促炎性細胞介素IL-13之作用。特定而言,化合物經證實抑制STAT6在肺組織中之IL-13誘導之磷酸化,此提供活體內局部肺JAK目標參與之證據。當在投與測試化合物之後4小時投與促炎性細胞介素IL-13時觀測到此作用,從而提供肺中之顯著滯留之其他證據。
所測試化合物經證實以在肺組織中之細胞水準及顯著滯留方面展現兩個有效抑制活性。本發明者廣泛調查測定,雖然有可能鑑別在細胞水準下有效之化合物或展示肺中之顯著滯留之化合物,但發現同時展現兩個所需特徵之化合物更加困難。
JAK抑制劑之抗炎性活性已穩固地在哮喘之臨床前模型中證實(Malaviya等人,Int. Immunopharmacol., 2010
,10
, 829,-836;Matsunaga等人,Biochem. and Biophys. Res. Commun.
,2011
,404
, 261-267;Kudlacz等人,Eur. J. Pharmacol
,2008
,582
, 154-161)。涉及經由JAK-STAT路徑傳導信號的哮喘發炎之細胞介素包括:IL-2、IL-3、IL-4、IL-5、IL-6、IL-9、IL-11、IL-13、IL-23、IL-31、IL-27、胸腺基質淋巴生成素(TSLP)、干擾素-γ (IFNγ)及粒細胞-巨噬細胞群落刺激因子(GM-CSF)。因此,本發明之化合物預期適用於治療發炎性呼吸道病症,特定言之哮喘。肺之發炎及纖維化的特徵在於除了哮喘之外之其他呼吸道疾病,諸如慢性阻塞性肺病(COPD)、囊腫性纖維化(CF)、肺炎、間質性肺病(包括特發性肺纖維化)、急性肺損傷、急性呼吸窘迫症候群、支氣管炎、氣腫、阻塞性細支氣管炎及類肉瘤病。因此,本發明化合物亦預期適用於治療慢性阻塞性肺病、囊腫性纖維化、肺炎、間質性肺病(包括特發性肺纖維化)、急性肺損傷、急性呼吸窘迫症候群、支氣管炎、氣腫、阻塞性細支氣管炎及類肉瘤病。
當與對應氟基類似物(化合物C-1
、C-2
、C-3
、C-4
、C-5
及C-6
)進行比較時,化合物1
至6
經展示具有類似之JAK活性。然而,其具有引起硫酸化代謝顯著減少之優點,如分析5中所證實。此為重要的,因為硫酸化代謝發生在肺部,其可能引起活性親本化合物之暴露的快速減少。
本揭示內容之化合物經證實抑制與發炎相關之細胞介素。因此,本揭示內容之化合物可能適用於治療某些特定呼吸道疾病,如下文詳述。
嗜酸性球性氣管發炎為統稱為嗜酸性球性肺病的疾病之典型特徵(Cottin等人,Clin. Chest. Med.
,2016
, 37(3), 535-56)。嗜酸性球性疾病與IL-4、IL-13及IL-5信號傳導相關。嗜酸性球性肺病包括感染(特定而言蠕蟲感染)、藥物誘導之肺炎(例如藉由諸如抗生素、苯妥英(phenytoin)或l-色胺酸之治療藥物誘導)、真菌誘導之肺炎(例如,過敏性支氣管肺麯黴病)、過敏性肺炎及伴隨多血管炎之嗜酸性球性肉芽腫(先前已知為徹奇-斯全司症候群(Churg-Strauss syndrome))。未知病因之嗜酸性球性肺病包括特發性急性嗜酸性球性肺炎、特發性慢性嗜酸性球性肺炎、嗜伊紅白血球增多症候群及呂弗勒症候群(Löffler syndrome)。
IL-6基因中之多形現象與升高的IL-6水準及增加的發生肺動脈高血壓(PAH)之風險有關(Fang等人,J. Am. Soc. Hypertens.
,2017
, 11(3), 171-177)。確證IL-6於PAH中之作用,IL-6受體鏈gp130之抑制改善了PAH大鼠模型中之疾病(Huang等人,Can. J. Cardiol.
,2016
, 32(11), 1356.e1-1356.e10)。
諸如IFNγ、IL-12及IL-6之細胞介素已涉及一定範圍之非過敏性肺病(諸如類肉瘤病)及肺淋巴管平滑肌增生症(El-Hashemite等人,Am. J. Respir. Cell. Mol. Biol.
,2005
, 33, 227-230,及El-Hashemite等人,Cancer Res.
,2004
, 64, 3436-3443)。本發明之化合物亦經展示以抑制IFNγ信號傳導。
支氣管擴張症及浸潤性肺病為與慢性嗜中性球性發炎有關之疾病。
病理性T細胞活化對於多種呼吸道疾病之病因至關重要。自體反應性T細胞在阻塞性細支氣管炎伴機化性肺炎(亦稱為COS)中起作用。類似於COS,肺移植排斥反應之病因與移植供體肺之受體T細胞的異常T細胞活化有關。肺移植排斥反應可早期以原發性移植物功能障礙(PGD)、機化性肺炎(OP)、急性排斥反應(AR)或淋巴球性細支氣管炎(LB)形式發生,或其可在肺移植後數年以慢性肺同種異體移植物功能障礙(CLAD)形式發生。CLAD先前已知為阻塞性細支氣管炎(BO),但現在被認為可具有不同病理學表現之症候群,包括BO、限制性CLAD (rCLAD或RAS)及嗜中性球性同種異體移植物功能障礙。慢性肺同種異體移植物功能障礙(CLAD)為長期管理肺移植受體中之主要挑戰,因為其造成移植肺逐漸失去功能(Gauthier等人, Curr Transplant Rep.,2016
, 3(3), 185-191)。CLAD對治療之反應不佳,且因此,仍需要能夠預防或治療此病況之有效化合物。諸如IFNγ及IL-5之若干JAK依賴性細胞介素在CLAD及肺移植排斥反應中上調(Berastegui等人,Clin. Transplant. 2017
, 31, e12898)。此外,在JAK依賴性IFN信號傳導下游之CXCR3趨化因子(諸如CXCL9及CXCL10)的高肺含量與肺移植患者之惡化結果有關(Shino等人,PLOS One
,2017
, 12 (7), e0180281)。全身性JAK抑制經展示在腎臟移植排斥反應中有效(Vicenti等人,American Journal of Transplantation
,2012
, 12, 2446-56)。因此,JAK抑制劑有可能有效治療或預防肺移植排斥反應及CLAD。如描述為肺移植排斥反應之基礎的類似T細胞活化事件亦視為造血幹細胞移植後可能發生的肺移植物抗宿主病(GVHD)之主要驅動因素。類似於CLAD,肺GVHD為一種慢性進行性病況,其結果極其不佳且目前尚無經批准之治療。95位接受全身性JAK抑制劑盧佐替尼作為補救治療的患有類固醇難治性急性或慢性GVHD的患者之回溯性多中心調查研究證實,大多數患者(包括患有肺GVHD之此等患者)對盧佐替尼完全或部分反應(Zeiser等人,Leukemia
,2015
, 29, 10, 2062-68)。由於全身性JAK抑制與嚴重不良事件及小治療指數相關,仍需要吸入肺部定向之非全身性JAK抑制劑以預防及/或治療肺移植排斥反應或肺GVHD。本揭示內容之化合物具有滿足此需求所需之特徵。近年來,免疫檢查點抑制劑誘導之肺炎(另一種T細胞介導之肺病)隨著免疫檢查點抑制劑之使用增加而出現。在用此等T細胞刺激劑治療之癌症患者中,可能產生致死性肺炎。
因此,在一個態樣中,本發明提供一種治療哺乳動物(例如,人類)之呼吸道疾病的方法,該方法包含向哺乳動物投與治療有效量的本揭示內容之化合物或其醫藥學上可接受之鹽或醫藥組合物,該醫藥組合物包含醫藥學上可接受之載劑及本發明之化合物或其醫藥學上可接受之鹽。
在一個態樣中,呼吸道疾病為囊腫性纖維化、肺炎、慢性阻塞性肺病(COPD)、囊腫性纖維化(CF)、肺炎、間質性肺病(包括特發性肺纖維化)、急性肺損傷、急性呼吸窘迫症候群、支氣管炎、氣腫、阻塞性細支氣管炎或類肉瘤病。在另一態樣中,呼吸道疾病為哮喘或慢性阻塞性肺病。
在一個態樣中,呼吸道疾病為肺部感染、嗜酸性球性疾病、蠕蟲感染、肺動脈高血壓、類肉瘤病、肺淋巴管平滑肌增生症、支氣管擴張症、浸潤性肺病、藥物誘導之肺炎、真菌誘導之肺炎、過敏性支氣管肺麯黴病、過敏性肺炎、伴隨多血管炎之嗜酸性球性肉芽腫、特發性急性嗜酸性球性肺炎、特發性慢性嗜酸性球性肺炎、嗜伊紅白血球增多症候群、呂弗勒症候群、阻塞性細支氣管炎伴有機化肺炎、急性及慢性肺移植排斥反應(包括PGD、OP、LB、AR及CLAD、BO、限制性CLAD及嗜中性球性同種異體移植物功能障礙)、肺移植物抗宿主病、阻塞性細支氣管炎伴機化性肺炎或免疫檢查點抑制劑誘導之肺炎。
本發明進一步提供一種治療哺乳動物之哮喘的方法,該方法包含向哺乳動物投與治療有效量的本揭示內容之化合物或其醫藥學上可接受之鹽或醫藥組合物,該醫藥組合物包含醫藥學上可接受之載劑及本揭示內容之化合物或其醫藥學上可接受之鹽。
當用於治療哮喘時,本揭示內容之化合物將通常以單次日劑量或以每天多次劑量形式投與,但可使用其他投與形式。每劑量投與的活性劑之量或每天投與的總量將通常由醫師根據相關情況來確定,該等相關情況包括待治療之病況、所選投藥途徑、投與之實際化合物及其相對活性、個別患者之年齡、體重及反應、患者症狀之嚴重程度及其類似者。
本發明進一步提供一種治療哺乳動物之呼吸道疾病(包括(但不限於)本文中所描述之疾病)的方法,該方法包含向哺乳動物投與治療有效量的本發明之化合物或其醫藥學上可接受之鹽或醫藥組合物,該醫藥組合物包含醫藥學上可接受之載劑及本發明之化合物或其醫藥學上可接受之鹽。
當用於治療呼吸道疾病(包括(但不限於)本文中所描述之疾病)時,本揭示內容之化合物將通常以單次日劑量或以每天多次劑量形式投與,但可使用其他投與形式。每劑量投與的活性劑之量或每天投與的總量將通常由醫師根據相關情況來確定,該等相關情況包括待治療之病況、所選投藥途徑、投與之實際化合物及其相對活性、個別患者之年齡、體重及反應、患者症狀之嚴重程度及其類似者。
作為JAK抑制劑,本揭示內容之化合物亦可適用於多種其他疾病。本揭示內容之化合物可適用於多種胃腸發炎病症,包括(但不限於)發炎性腸病、潰瘍性結腸炎(直腸乙狀結腸炎、全結腸炎、潰瘍性直腸炎及左側結腸炎)、克羅恩氏病(Crohn's disease)、膠原性結腸炎、淋巴球性結腸炎、白塞氏病(Behcet's disease)、乳糜瀉、免疫檢查點抑制劑誘導之結腸炎、回腸炎、嗜酸性球性食道炎、移植物抗宿主疾病相關之結腸炎及感染性結腸炎。潰瘍性結腸炎(Reimund等人,J. Clin. Immunology, 1996
,16
, 144-150)、克羅恩氏病(Woywodt等人,Eur. J. Gastroenterology Hepatology
,1999
,11
, 267-276)、膠原性結腸炎(Kumawat等人,Mol. Immunology
,2013
,55
, 355-364)、淋巴球性結腸炎(Kumawat等人,2013
)、嗜酸性球性食道炎(Weinbrand-Goichberg等人,Immunol. Res.
,2013
,56
, 249-260)、移植物抗宿主疾病相關之結腸炎(Coghill等人,Blood
,2001
,117
, 3268-3276)、感染性結腸炎(Stallmach等人,Int. J. Colorectal Dis.
,2004
,19
, 308-315)、白塞氏病(Zhou等人,Autoimmun. Rev.
,2012
,11
, 699-704)、乳糜瀉(de Nitto等人,World J. Gastroenterol.
,2009
,15
, 4609-4614)、免疫檢查點抑制劑誘導之結腸炎(例如,CTLA-4抑制劑誘導之結腸炎;(Yano等人,J. Translation. Med.
,2014
,12
, 191)、PD-1或PD-L1抑制劑誘導之結腸炎)及回腸炎(Yamamoto等人,Dig. Liver Dis.
,2008
,40
, 253-259)之特徵為某些促炎性細胞介素水準之升高。因為許多促炎性細胞介素經由JAK活化進行信號傳導,因此本申請案中所描述之化合物可能能夠減輕發炎且提供症狀緩解。特定言之,本揭示內容之化合物可適用於誘導且維持潰瘍性結腸炎之緩解,且用於治療克羅恩氏病、免疫檢查點抑制劑誘導之結腸炎及移植物抗宿主疾病中之胃腸不良效應。因此,在一個態樣中,本揭示內容提供一種治療哺乳動物(例如,人類)之胃腸發炎性疾病的方法,該方法包含向哺乳動物投與本揭示內容之化合物或其醫藥學上可接受之鹽或醫藥組合物,該醫藥組合物包含醫藥學上可接受之載劑及本揭示內容之化合物或其醫藥學上可接受之鹽。
異位性皮膚炎及其他發炎性皮膚病與依賴於JAK-STAT路徑的促炎性細胞介素之升高有關。因此,本揭示內容之化合物或其醫藥學上可接受之鹽可能有益於許多皮膚發炎或瘙癢病況,其包括(但不限於)異位性皮膚炎、斑禿、白癜風、牛皮癬、皮肌炎、皮膚T細胞淋巴瘤(Netchiporouk等人,Cell Cycle
,2014
;13
, 3331-3335)及亞型(塞紮萊症候群(Sezary syndrome)、蕈樣黴菌病、佩吉特樣網狀細胞增多症(pagetoid reticulosis)、肉芽腫性鬆弛皮膚、淋巴瘤樣丘疹病、慢性苔蘚樣糠疹、急性痘瘡樣苔癬樣糠疹、CD30+皮膚T細胞淋巴瘤、繼發性皮膚CD30+大細胞淋巴瘤、非蕈樣黴菌病CD30-皮膚大T細胞淋巴瘤、多形性T細胞淋巴瘤、倫納特淋巴瘤(Lennert lymphoma)、皮下T細胞淋巴瘤、血管中心性淋巴瘤、母細胞性NK細胞淋巴瘤)、結節性癢疹、扁平苔蘚、原發性局部皮膚澱粉樣變性、大皰性類天疱瘡、移植物抗宿主病之皮膚表現、類天疱瘡、盤狀狼瘡、環狀肉芽腫、慢性單純性苔癬、外陰/陰囊/肛周瘙癢症、硬化性苔癬、帶狀疱疹後神經痛癢、扁平苔蘚及脫髮性毛囊炎。特定言之,異位性皮膚炎(Bao等人,JAK-STAT
,2013
,2
, e24137)、斑禿(Xing等人,Nat. Med. 2014
,20
, 1043-1049)、白斑病(Craiglow等人,JAMA Dermatol
.2015
,151
, 1110-1112)、結節性癢疹(Sonkoly等人,J. Allergy Clin. Immunol. 2006
,117
, 411-417)、扁平苔癬(Welz-Kubiak等人,J. Immunol. Res
.2015
, ID:854747)、原發性局部皮膚澱粉樣變性(Tanaka等人,Br. J. Dermatol
.2009
,161
, 1217-1224)、大皰性類天疱瘡(Feliciani等人,Int. J. Immunopathol. Pharmacol
.1999
,12
, 55-61)及移植物抗宿主疾病之皮膚表現(Okiyama等人,J. Invest. Dermatol. 2014
,134
, 992-1000)的特徵為經由JAK活化傳導信號的某些細胞介素之升高。因此,本揭示內容之化合物或其醫藥學上可接受之鹽可能能夠減輕由此等細胞介素驅動的相關皮膚炎或瘙癢症。特定言之,本揭示內容之化合物或其醫藥學上可接受之鹽可預期適用於治療異位性皮膚炎及其他發炎性皮膚病。因此,在一個態樣中,本揭示內容提供一種治療哺乳動物(例如,人類)之發炎性皮膚病的方法,該方法包含向哺乳動物的皮膚施加包含本揭示內容之化合物或其醫藥學上可接受之鹽及醫藥載劑的醫藥組合物。在一個態樣中,發炎性皮膚病為異位性皮膚炎。
許多眼部疾病經展示與依賴於JAK-STAT路徑的促炎性細胞介素之升高有關。因此,本揭示內容之化合物或其醫藥學上可接受之鹽可適用於治療許多眼部疾病,包括(但不限於)葡萄膜炎、糖尿病性視網膜病變、糖尿病性黃斑水腫、乾眼病、年齡相關之黃斑變性以及異位性角膜結膜炎。特定言之,葡萄膜炎(Horai及Caspi,J. Interferon Cytokine Res.
,2011
,31
, 733-744)、糖尿病性視網膜病變(Abcouwer,J. Clin. Cell. Immunol.
,2013
, 增刊1
, 1-12)、糖尿病性黃斑水腫(Sohn等人,American Journal of Opthamology
,2011
,152
, 686-694)、乾眼病(Stevenson等人,Arch. Ophthalmol.
,2012
,130
, 90-100)及年齡相關之黃斑變性(Knickelbein等人,Int. Ophthalmol. Clin.
,2015
,55(3)
, 63-78)之特徵為經由JAK-STAT路徑傳導信號的某些促炎性細胞介素之升高。因此,本揭示內容之化合物或其醫藥學上可接受之鹽可能能夠減輕相關眼部發炎且逆轉疾病進展或提供症狀緩解。因此,在一個態樣中,本揭示內容提供一種治療哺乳動物之眼部疾病的方法,該方法包含向哺乳動物之眼部投與包含本揭示內容之化合物或其醫藥學上可接受之鹽及醫藥載劑的醫藥組合物。在一個態樣中,眼部疾病為葡萄膜炎、糖尿病性視網膜病變、糖尿病性黃斑水腫、乾眼病、年齡相關之黃斑變性或異位性角膜結膜炎。在一個態樣中,該方法包含藉由玻璃體內注射投與本揭示內容之化合物或其醫藥學上可接受之鹽。本揭示內容之化合物或其醫藥學上可接受之鹽亦可與一或多種適用於眼部疾病之化合物組合使用。
本揭示內容之化合物或其醫藥學上可接受之鹽亦可適用於治療其他疾病,諸如其他發炎疾病、自體免疫疾病或癌症。本揭示內容之化合物或其醫藥學上可接受之鹽可用於治療以下中之一或多者:關節炎、類風濕性關節炎、青少年類風濕性關節炎、移植排斥反應、乾眼症、牛皮癬性關節炎、糖尿病、胰島素依賴性糖尿病、運動神經元疾病、骨髓發育不良症候群、疼痛、肌肉減少症、惡病質、敗血性休克、全身性紅斑性狼瘡症、白血病、慢性淋巴球性白血病,慢性骨髓細胞性白血病、急性淋巴細胞性白血病、急性骨髓性白血病、僵直性脊椎炎、骨髓纖維化、B細胞淋巴瘤、肝細胞癌、霍奇金氏病(Hodgkins disease)、乳癌、多發性骨髓瘤、黑素瘤、非霍奇金氏淋巴瘤、非小細胞肺癌、卵巢透明細胞癌瘤、卵巢腫瘤、胰臟腫瘤、真性紅細胞增多症、休格連症候群(Sjoegrens syndrome)、軟組織肉瘤、肉瘤、脾腫大、T細胞淋巴瘤以及重型地中海貧血。
組合療法
本揭示內容之化合物或其醫藥學上可接受之鹽可與藉由相同機制或不同機制起作用來治療疾病的一或多種試劑組合使用。不同試劑可在獨立組合物或相同組合物中依序或同時投與。用於組合療法之適用類別的試劑包括(但不限於):β 2腎上腺素受體促效劑、蕈毒鹼受體拮抗劑、糖皮質激素促效劑、G蛋白偶合受體-44拮抗劑、白三烯D4拮抗劑、蕈毒鹼M3受體拮抗劑、組織胺H1受體拮抗劑、免疫球蛋白E拮抗劑、PDE 4抑制劑、IL-4拮抗劑、蕈毒鹼M1受體拮抗劑、組織胺受體拮抗劑、IL-13拮抗劑、IL-5拮抗劑、5-脂肪加氧酶抑制劑、β腎上腺素受體促效劑、CCR3趨化因子拮抗劑、CFTR刺激劑、免疫球蛋白調節劑、介白素33配位體抑制劑、PDE 3抑制劑、磷酸肌醇-3激酶δ抑制劑、凝血脂素A2拮抗劑、彈性蛋白酶抑制劑、Kit酪胺酸激酶抑制劑、白三烯E4拮抗劑、白三烯拮抗劑、PGD2拮抗劑、TNF α配位體抑制劑、TNF黏結劑、補體級聯抑制劑、伊紅趨素配位體抑制劑、麩胱甘肽還原酶抑制劑、組織胺H4受體拮抗劑、IL-6拮抗劑、IL2基因刺激劑、免疫球蛋白γ Fc受體IIB調節劑、干擾素γ配位體、介白素13配位體抑制劑、介白素17配位體抑制劑、L-選擇蛋白拮抗劑、白血球彈性蛋白酶抑制劑、白三烯C4拮抗劑、白三烯C4合成酶抑制劑、膜銅胺氧化酶抑制劑、金屬蛋白酶-12抑制劑、金屬蛋白酶-9抑制劑、蟎過敏原調節劑、蕈毒鹼受體調節劑、菸鹼酸乙醯膽鹼受體促效劑、核因子κ B抑制劑、p-選擇蛋白拮抗劑、PDE 5抑制劑、PDGF受體拮抗劑、磷酸肌醇-3激酶γ抑制劑、TLR-7促效劑、TNF拮抗劑、Abl酪胺酸激酶抑制劑、乙醯膽鹼受體拮抗劑、酸性哺乳動物殼質酶抑制劑、ACTH受體促效劑、肌動蛋白聚合調節劑、腺苷A1受體拮抗劑、腺苷酸環化酶刺激劑、腎上腺素受體拮抗劑、促腎上腺皮質激素配位體、醇去氫酶5抑制劑、α 1抗胰蛋白酶刺激劑、α 1蛋白酶抑制劑、雄激素受體調節劑、血管收縮素轉化酶2刺激劑、ANP促效劑、Bcr蛋白抑制劑、β 1腎上腺素受體拮抗劑、β 2腎上腺素受體拮抗劑、β 2腎上腺素受體調節劑、β澱粉樣調節劑、BMP10基因抑制劑、BMP15基因抑制劑、鈣通道抑制劑、組織蛋白酶G抑制劑、CCL26基因抑制劑、CCR3趨化因子調節劑、CCR4趨化因子拮抗劑、細胞黏附分子抑制劑、伴侶蛋白刺激劑、殼質酶抑制劑、膠原蛋白I拮抗劑、補體C3抑制劑、CSF-1拮抗劑、CXCR2趨化因子拮抗劑、細胞介素受體共用β鏈調節劑、細胞毒性T淋巴球蛋白-4刺激劑、去氧核糖核酸酶I刺激劑、去氧核糖核酸酶刺激劑、二肽基肽酶I抑制劑、DNA旋轉酶抑制劑、DP前列腺素受體調節劑、E-選擇蛋白拮抗劑、EGFR家族酪胺酸激酶受體抑制劑、彈性蛋白調節劑、內皮素ET-A拮抗劑、內皮素ET-B拮抗劑、環氧化物水解酶抑制劑、FGF3受體拮抗劑、Fyn酪胺酸激酶抑制劑、GATA 3轉錄因子抑制劑、葡糖神經醯胺酶調節劑、麩胺酸受體調節劑、GM-CSF配位體抑制劑、鳥苷酸環化酶刺激劑、H+ K+ ATP酶抑制劑、血紅素調節劑、肝素促效劑、組蛋白去乙醯酶抑制劑、組蛋白去乙醯酶-2刺激劑、HMG CoA還原酶抑制劑、I-κ B激酶β抑制劑、ICAM1基因抑制劑、IL-17拮抗劑、IL-17受體調節劑、IL-23拮抗劑、IL-4受體調節劑、免疫球蛋白G調節劑、免疫球蛋白G1促效劑、免疫球蛋白G1調節劑、免疫球蛋白ε Fc受體IA拮抗劑、免疫球蛋白γ Fc受體IIB拮抗劑、免疫球蛋白κ調節劑、胰島素敏化劑、干擾素β配位體、介白素1樣受體拮抗劑、介白素18配位體抑制劑、介白素受體17A拮抗劑、介白素-1 β配位體抑制劑、介白素-5配位體抑制劑、介白素-6配位體抑制劑、KCNA電壓閘控鉀通道-3抑制劑、Kit配位體抑制劑、層黏連蛋白-5促效劑、白三烯CysLT1受體拮抗劑、白三烯CysLT2受體拮抗劑、LOXL2基因抑制劑、Lyn酪胺酸激酶抑制劑、MARCKS蛋白抑制劑、MDR相關蛋白4抑制劑、金屬蛋白酶-2調節劑、金屬蛋白酶-9調節劑、鹽皮質素受體拮抗劑、蕈毒鹼M2受體拮抗劑、蕈毒鹼M4受體拮抗劑、蕈毒鹼M5受體拮抗劑、利尿鈉肽受體A促效劑、自然殺傷細胞受體調節劑、菸鹼酸ACh受體α 7次單元刺激劑、NK細胞受體調節劑、核因子κ B調節劑、類鴉片生長因子受體促效劑、P-醣蛋白抑制劑、P2X3嘌呤受體拮抗劑、p38 MAP激酶抑制劑、肽酶1調節劑、磷脂酶A2抑制劑、磷脂酶C抑制劑、纖維蛋白溶酶原活化劑抑制劑1抑制劑、血小板激活因子受體拮抗劑、PPAR γ促效劑、前列腺環素促效劑、蛋白酪胺酸激酶抑制劑、SH2結構域肌醇磷酸酶1刺激劑、信號轉導抑制劑、鈉通道抑制劑、STAT-3調節劑、幹細胞抗原-1抑制劑、超氧化歧化酶調節劑、T細胞表面醣蛋白CD28抑制劑、T細胞表面醣蛋白CD8抑制劑、TGF β促效劑、TGF β拮抗劑、凝血脂素合成酶抑制劑、胸腺基質淋巴蛋白配位體抑制劑、胸腺素促效劑、胸腺素β 4配位體、TLR-8促效劑、TLR-9促效劑、TLR9基因刺激劑、拓樸異構酶IV抑制劑、肌鈣蛋白I快速骨骼肌刺激劑、肌鈣蛋白T快速骨骼肌刺激劑、I型IL-1受體拮抗劑、II型TNF受體調節劑、離子通道調節劑、子宮球蛋白刺激劑及VIP促效劑。
可與本JAK抑制劑化合物組合使用的特定試劑包括(但不限於):醋酸羅斯普特(rosiptor acetate)、蕪地溴銨(umeclidinium bromide)、塞庫金單抗(secukinumab)、醋酸米特法林(metenkefalin acetate)、醋酸特瑞得卡(tridecactide acetate)、丙酸氟替卡松(fluticasone propionate)、α-環糊精穩定之蘿蔔硫素、特澤派單抗(tezepelumab)、糠酸莫米松(mometasone furoate)、BI-1467335、度匹魯單抗(dupilumab)、阿地銨(aclidinium)、福莫特羅(formoterol)、AZD-1419、HI-1640V、瑞威潘塞(rivipansel)、CMP-001、甘露醇、ANB-020、奧馬珠單抗(omalizumab)、曲加力單抗(tregalizumab)、米提紮西(Mitizax)、苯納珠單抗(benralizumab)、戈利木單抗(golimumab)、羅氟司特(roflumilast)、伊馬替尼(imatinib)、REGN-3500、馬賽替尼(masitinib)、阿普司特(apremilast)、RPL-554、阿克姆(Actimmune)、阿達木單抗(adalimumab)、盧帕他定(rupatadine)、帕羅格列(parogrelil)、MK-1029、二丙酸倍氯米松(beclometasone dipropionate)、富馬酸福莫特羅(formoterol fumarate)、莫格利珠單抗(mogamulizumab)、塞曲司特(seratrodast)、UCB-4144、奈米昔布(nemiralisib)、CK-2127107、非維蘭特(fevipiprant)、達尼利辛(danirixin)、波生坦(bosentan)、阿巴西普(abatacept)、EC-18、杜維昔布(duvelisib)、多西普林斯頓(dociparstat)、環丙沙星(ciprofloxacin)、沙丁胺醇(salbutamol) HFA 、厄多司坦(erdosteine)、PrEP-001、奈多羅米(nedocromil)、CDX-0158、沙丁胺醇、恩博沙(enobosarm)、R-TPR-022、朗齊魯單抗(lenzilumab)、糠酸氟替卡松(fluticasone furoate)、三氟甲磺酸威蘭特羅(vilanterol trifenatate)、沙美特羅(salmeterol)、PT-007、PRS-060、雷米特梅爾-L (remestemcel-L)、瓜胺酸、RPC-4046、氧化氮、DS-102、吉瑞利單抗(gerilimzumab)、阿克泰(Actair)、蕪地銨(umeclidinium)、威蘭特羅(vilanterol)、AG-NPP709、凱明斯(Gamunex)、英利昔單抗(infliximab)、阿美匹恩(Ampion)、阿庫馬皮莫德(acumapimod)、康納單抗(canakinumab)、INS-1007、CYP-001、思魯庫單抗(sirukumab)、美泊利單抗(mepolizumab)、匹伐他汀(pitavastatin)、索利黴素(solithromycin)、依那西普(etanercept)、依伐卡托(ivacaftor)、阿那白滯素(anakinra)、MPC-300-IV、格隆溴銨(glycopyrronium bromide)、阿地溴銨(aclidinium bromide)、FP-025、里森基單抗(risankizumab)、格隆銨(glycopyrronium)、阿迪迫賽(Adipocell)、YPL-001、噻托溴銨(tiotropium bromide)、馬來酸茚達特羅(indacaterol maleate)、安德西單抗(andecaliximab)、奧達特羅(olodaterol)、埃索美拉唑(esomeprazole)、塵蟎疫苗、艾蒿花粉過敏原疫苗、萬莫龍(vamorolone)、格法皮克斯(gefapixant)、瑞芬那新(revefenacin)、吉非替尼(gefitinib)、瑞膠因(ReJoin)、泰魯斯特(tipelukast)、貝多拉明(bedoradrine)、SCM-CGH、SHP-652、RNS-60、布羅達單抗(brodalumab)、BIO-11006、異丙托溴銨(ipratropium bromide)、塔羅金單抗(tralokinumab)、PUR-1800、VX-561、VX-371、奧洛他定(olopatadine)、妥布特羅(tulobuterol)、曲安奈德(triamcinolone acetonide)、瑞利珠單抗(reslizumab)、羥萘甲酸沙美特羅(salmeterol xinafoate)、利蓋利珠單抗(ligelizumab)、RUTI、柏替木單抗(bertilimumab)、SENS-111、二丙酸倍氯米松、CHF-5992、LT-4001、茚達特羅(indacaterol)、菲索芬那定(fexofenadine)、阿奇黴素(azithromycin)、AZD-7594、CHF-6001、貝特芬特羅(batefenterol)、OATD-01、CJM-112、羅格列酮(rosiglitazone)、塞提普蘭特(setipiprant)、吸入干擾素β、AZD-8871、普卡那肽(plecanatide)、氟替卡松、二十碳五烯酸單甘油酸酯(eicosapentaenoic acid monoglyceride)、雷布瑞奇單抗(lebrikizumab)、RG-6149、QBKPN、莫米松(Mometasone)、AZD-9898、丙酮酸鈉、齊留通(zileuton)、CG-201、咪達那新(imidafenacin)、CNTO-6785、CLBS-03、RGN-137、丙卡特羅(procaterol)、CCI-15106、POL-6014、倍氯米松(beclomethasone)、MV-130、GC-1112、艾瑞戈瓦克庫(Allergovac depot)、MEDI-3506、QBW-251、ZPL-389、烏地那非(udenafil)、GSK-3772847、左旋西替利嗪(levocetirizine)、AXP-1275、ADC-3680、替馬蘭特(timapiprant)、阿貝特羅(abediterol)、硫酸沙丁胺醇(salbutamol sulfate)、塔得克尼α (tadekinig alfa)、ACT-774312、去氧核糖酶α、伊洛前列素(iloprost)、阿利卡弗森(alicaforsen)、環索奈德(ciclesonide)、金剛砂胺(emeramide)、阿福莫特羅(arformoterol)、SB-010、奧紮格雷(Ozagrel)、BTT-1023、德克單抗(Dectrekumab)、左旋沙丁胺醇(levalbuterol)、普魯司特(pranlukast)、玻尿酸、GSK-2292767、NOV-14、蘆西納坦(Lucinactant)、潑尼松龍(prednisolone)、依巴司汀(ebastine)、地塞米松培酯(dexamethasone cipecilate)、GSK-2586881、BI-443651、GSK-2256294、VR-179、VR-096、hdm-ASIT+、布地奈德(budesonide)、GSK-2245035、VTX-1463、依美斯汀(Emedastine)、右旋普拉克索(dexpramipexole)、N-6022、地塞米松磷酸鈉(dexamethasone sodium phosphate)、PIN-201104、OPK-0018、TEV-48107、司特(suplatast)、BI-1060469、吉米魯司特(Gemilukast)、干擾素γ、達拉紮提德(dalazatide)、比拉斯汀(bilastine)、RP-3128、苯環喹溴銨(bencycloquidium bromide)、PBF-680、CRTH2拮抗劑、噻托溴銨單水合物(tiotropium bromide monohydrate)、馬魯司特(masilukast)、RG-7990、多索茶鹼(Doxofylline)、TEV-46017、ASM-024、TA-270、氟尼縮松(Flunisolide)、色甘酸鈉、Epsi-gam、ZPL-521、阿肽地爾(aviptadil)、TRN-157、紮魯司特(Zafirlukast)、斯迪姆噴索(Stempeucel)、哌羅來斯鈉(pemirolast sodium)、納多洛爾(nadolol)、丙酸氟替卡松+羥萘甲酸沙美特羅、RV-1729、二氧化碳+全氟辛基溴化物、APL-1、德克單抗+VAK-694 、離胺酸乙醯基水楊酸鹽(lysine acetylsalicylate)、TR-4、人類同種異體脂肪衍生之間葉細胞祖細胞療法、MEDI-9314、PL-3994、HMP-301、TD-5471、NKTT-120、哌羅來斯(pemirolast)、二丙酸倍氯米松、川丁特羅(trantinterol)、α魯米諾單鈉(monosodium alpha luminol)、IMD-1041、AM-211、TBS-5、ARRY-502、重組麥迪司麥斯 (recombinant midismase)、ASM-8、地夫可特(deflazacort)、班布特羅(bambuterol)、RBx-10017609、異丙托銨(ipratropium) +非諾特羅(fenoterol)、氟替卡松+福莫特羅、依匹斯汀(epinastine)、WIN-901X、VALERGEN-DS、OligoG-COPD-5/20、奧克斯都保(oxis Turbuhaler)、DSP-3025、咪唑司汀(mizolastine)、布地奈德+沙美特羅、LH-011、AXP-E、組織胺人類免疫球蛋白、YHD-001、茶鹼(theophylline)、胺溴素(ambroxol) +厄多司坦、雷馬曲班(ramatroban)、孟魯司特(montelukast)、AG-1321001、異丙托銨+沙丁胺醇、曲尼司特(tranilast)、磺庚甲潑尼松龍(methylprednisolone suleptanate)、考福辛達羅帕特(colforsin daropate)及瑞吡司特(repirinast)。
本文亦提供一種醫藥組合物,其包含本揭示內容之化合物或其醫藥學上可接受之鹽及一或多種其他治療劑。治療劑可選自上文所規定之試劑類別及上文所描述之特定試劑的清單。在一些實施例中,醫藥組合物適用於遞送至肺。在一些實施例中,醫藥組合物適用於吸入或噴霧投與。在一些實施例中,醫藥組合物為乾燥散劑或液體組合物。
另外,在一方法態樣中,本揭示內容提供一種治療哺乳動物之疾病或病症的方法,其包含向哺乳動物投與本揭示內容之化合物或其醫藥學上可接受之鹽及一或多種其他治療劑。
當用於組合療法中時,試劑可調配成單一醫藥組合物,或試劑可提供於單獨組合物中,其同時或在不同時間藉由相同或不同投與途徑投與。此等組合物可分開地封裝或可作為套組封裝在一起。套組中兩種或更多種治療劑可藉由相同投藥途徑或藉由不同投藥途徑投與。
實例
提供以下合成及生物實例以說明本發明,且不以任何方式解釋為限制本發明之範疇。除非另外指示,否則在以下實例中,以下縮寫具有以下含義。未在下文中定義之縮寫具有其一般可接受之含義。
ACN = 乙腈
DCM = 二氯甲烷
DIPEA =N,N
-二異丙基乙胺
DMF =N,N
-二甲基甲醯胺
EtOAc = 乙酸乙酯
h = 小時
HATU =N,N,N',N'
-四甲基-O-(7-氮雜苯并三唑-1-基)脲鎓六氟磷酸鹽
IPA = 異丙醇
IPAc = 乙酸異丙酯
MeOH = 甲醇
min = 分鐘
Pd(PPh3
)4
= 肆(三苯基膦)鈀(0)
RT = 室溫
TFA = 三氟乙酸
THF = 四氫呋喃
雙(頻哪醇根基)二硼= 4,4,5,5,4',4',5',5'-八甲基-[2,2']二[[1,3,2]二氧雜硼雜環戊烷]
試劑及溶劑購自商業供應商(Aldrich、Fluka、Sigma等)且不經進一步純化即使用。藉由薄層層析(thin layer chromatography;TLC)、分析型高效液相層析(analytical high performance liquid chromatography;anal. HPLC)及質譜分析來監測反應混合物之進展。如在各反應中具體描述來處理反應混合物;通常藉由萃取及其他純化方法(諸如溫度依賴性及溶劑依賴性結晶及沈澱)來純化反應混合物。此外,藉由管柱層析或藉由製備型HPLC,通常使用C18或BDS管柱填充物及習知溶離劑來常規純化反應混合物。下文描述典型的製備型HPLC條件。
藉由質譜及1
H-NMR光譜常規地進行反應產物之表徵。對於NMR分析,將樣品溶解於氘化溶劑(諸如CD3
OD、CDCl3
或d 6
-DMSO)中,且在標準觀測條件下用Varian Gemini 2000儀器(400 MHz)獲得1
H-NMR光譜。藉由電噴霧電離法(electrospray ionization method;ESMS)用耦接至自動純化系統之Applied Biosystems (Foster City, CA)型號API 150 EX儀器或Waters (Milford, MA) 3100儀器來進行化合物之質譜鑑別。
製備型 HPLC 條件
管柱: C18, 5 μm. 21.2 × 150 mm或C18, 5 μm 21 × 250或
C14, 5 μm 21× 150 mm
管柱溫度: 室溫
流速: 20.0 mL/min
流動相: A=水+0.05% TFA
B=ACN+0.05% TFA,
注射體積: (100-1500 µL)
偵測器波長:214 nm
將粗化合物以約50 mg/mL溶解於1:1水:乙酸中。使用2.1×50 mm C18管柱進行4分鐘分析規模測試操作,隨後使用100 μL注射液用基於分析規模測試操作之B滯留%進行15或20分鐘製備型規模操作。確切梯度依賴於樣品。用21×250 mm C18管柱及/或21×150 mm C14管柱檢查具有緊密操作雜質之樣品以進行最佳分離。藉由質譜分析來鑑別含有所需產物之溶離份。
(a) 1-(苯甲氧基)-3-乙苯(I-2)
在室溫下向3-乙酚(I-1)
(25.0 g,204.0 mmol)於ACN (250 mL,10體積)中之攪拌溶液中添加碳酸鉀(42.0 g,306 mmol)。將所得反應塊狀物在室溫下攪拌15分鐘,隨後以逐滴方式添加溴甲苯(24.0 mL,204 mmol)。將所得反應混合物在室溫下攪拌6小時。在完成反應(TLC監測)之後,將所得反應塊狀物倒入水(1.0 L)中,隨後用EtOAc (2×2 L)萃取化合物。經合併之有機物用冷水、鹽水溶液洗滌且經硫酸鈉乾燥,過濾且在減壓下蒸發。接著將粗產物藉由矽膠(100-200M)管柱層析,藉由使用溶離劑2% EtOAc/己烷來純化,以得到作為淡黃色油性化合物之所需產物(I-2)
(35.0 g,81%)。1
H NMR (400 MHz, 氯仿-d) δ 7.46-7.44 (m, 2H), 7.39 (t, J = 7.6 Hz, 2H), 7.34-7.31 (m, 1H), 7.21 (t, J = 7.6 Hz), 6.86-6.80 (m, 3H), 5.07 (s, 2H), 2.64 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H)。
(b) 4-(苯甲氧基)-1-溴-2-乙苯(I-3)
歷經15分鐘之時間段向1-(苯甲氧基)-3-乙苯(I-2)
(35.0 g,164 mmol)於ACN (525 mL,15體積)中之冰冷攪拌溶液中逐份添加N-溴代丁二醯亞胺(32.0 g,181 mmol)。將所得反應混合物在室溫下攪拌下一1小時。在完成反應(TLC監測)之後,將所得反應塊狀物倒入冰冷之水(1.50 L)中,接著用EtOAc (2×1 L)萃取化合物。經合併之有機物用水洗滌且經硫酸鈉乾燥,過濾並在減壓下蒸發,以獲得粗產物。將正己烷(250 mL)添加至粗材料,產生研磨漿,隨後經由燒結漏斗過濾。將母液在減壓下蒸發,以獲得作為淡黃色油性化合物之所需產物I-3
(42.0 g,87%)。1
H NMR (400 MHz, 氯仿-d) δ 7.52-7.29 (m, 7H), 6.88 (s, 1H), 6.68 (d, J = 6.0 Hz, 1H), 5.04 (s, 2H), 2.69 (q, J = 7.6 Hz, 2H), 1.20 (t, J = 7.5 Hz, 3H)。
(c) 2-(4-(苯甲氧基)-2-乙基苯基)-4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷(I-4)
將4-(苯甲氧基)-1-溴-2-乙苯(I-3)
(42.0 g,144 mmol)、雙(頻哪醇根基)二硼(44.0 g,173 mmol)及乙酸鉀(28 g,288 mmol)於二噁烷(440 mL)中之攪拌溶液藉由吹掃N2 (g)持續15 min來脫氣,隨後添加PdCl2
(dppf).DCM錯合物(11.0 g,15 mmol)。使所得反應混合物加熱至80℃持續下一16 h。在完成反應(TLC監測)之後,使反應塊狀物經由矽藻土床過濾且將母液在減壓下蒸發,以獲得粗產物。粗殘餘物藉由矽膠(100-200 M)管柱層析,藉由使用溶離劑1% EtOAc/己烷純化,以得到作為淡黃色油性化合物之所需產物(I-4)
(32.0 g,66%)。1
H NMR (400 MHz, 氯仿-d) δ 7.74 (d, J = 8.4 Hz, 1H), 7.45-7.36 (m, 5H), 6.84-6.78 (m, 2H), 5.08 (s, 2H), 2.91 (q, J = 7.6 Hz), 1.33 (s, 12H), 1.19 (t, J = 7.6 Hz, 3H)。
(d) (4-(苯甲氧基)-2-乙基苯基)三氟-λ4
-甲硼烷,鉀鹽(I-5)
向化合物2-(4-(苯甲氧基)-2-乙基苯基)-4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷(I-4)
(20 g,59.0 mmol)於丙酮:甲醇(200 mL,1:1比率,10體積)中之攪拌溶液中添加3 M氟化氫鉀溶液(23.0 g,295 mmol,溶解於98.0 mL水中)。將所得反應混合物在室溫下攪拌16小時。在完成反應(TLC監測)之後,將所得反應塊狀物在減壓下蒸發。將因此獲得之固體溶解於水(100 mL)中且在室溫下攪拌30 min。將所得反應塊狀物經由燒結漏斗過濾,用正己烷洗滌且在減壓下乾燥,以得到呈白色固體狀之所需產物(I-5)
(14.0 g,74%)。1
H NMR (400 MHz, 氯仿-d) δ 7.43 (d, J = 7.2 Hz, 2H), 7.37 (t, J = 7.5 Hz, 2H), 7.30 (t, J = 7.1 Hz, 1H), 7.22 (d, J = 8.0 Hz), 6.58 (s, 1H), 6.53 (d, J = 7.9 Hz, 1H), 5.00 (s, 2H), 2.65 (q, J = 7.5 Hz, 2H), 1.07 (t, J = 7.4 Hz, 3H)。
(a) (S
)-4,5,6,7-四氫-3H-咪唑并[4,5-c]吡啶-6-甲酸,鹽酸鹽(I-7)
向L-組胺酸(I-6)
(5.0 kg,32.14 mol)於水(40 L,8體積)中之冰冷攪拌懸浮液中添加濃鹽酸(3.93 L,33.75 mol),隨後以逐滴方式添加甲醛(5.50 L,67.5 mol,37%水溶液)。將所得溶液在相同溫度下攪拌30分鐘且接著在80℃下加熱8小時。藉由LCMS監測反應進展。在減壓下移除水以獲得粗產物,且將所得粗物質在甲苯(20 L)中攪拌2小時。將有機物在減壓下移除以移除過量水且將化合物共沸乾燥。接著將所得材料放入乙醚(20 L)中且攪拌2小時。接著過濾固體材料且經空氣乾燥,以獲得呈灰白色固體狀之所需產物(I-7)
(6.50 Kg,85%)。1
H NMR (400 MHz, D2O) δ 8.69 (s, 1H), 4.56 (d, J = 15.4 Hz, 1H), 4.42 (d, J = 15.5 Hz, 1H), 4.20 (dd, J = 5.5, 5.2 Hz, 1H), 3.42 (dd, J = 5.0, 17.0 Hz, 1H), 3.11 (dd, J = 10.2, 16.8 Hz, 1H)。
(b) (S
)-3,5-雙(第三丁氧基羰基)-4,5,6,7-四氫-3H-咪唑并[4,5-c]吡啶-6-甲酸(I-8)
向(S
)-4,5,6,7-四氫-3H-咪唑并[4,5-c]吡啶-6-甲酸二-鹽酸鹽(I-7)
(6.10 Kg,25.40 mol)於1,4-二噁烷(48 L,8體積)及水(48 L,8體積)中之冰冷攪拌溶液中逐滴添加三乙胺(12.36 L,89 mol),隨後歷經30 min之時間段添加二碳酸二第三丁酯(18.07 L,78.74 mol,溶解於5 L之1,4-二噁烷中)。將所得反應混合物在室溫下攪拌下一16小時。在完成反應(TLC & LCMS監測)之後,將微黃色反應混合物用水(10 L)稀釋且連續用乙醚(2×10 L)及EtOAc (2×7.50 L)洗滌。丟棄有機相。水層經冷卻且用6 N HCl溶液使其達至pH約3;用EtOAc (3×10 L)萃取水相。經合併之有機物用鹽水溶液洗滌,經硫酸鈉乾燥,且在減壓下濃縮。油性殘餘物自30% EtOAc:己烷結晶,以獲得呈灰白色固體狀之所需產物(I-8)
(5.1 Kg,55%)。(m/z):C17
H25
N3
O6
之[M+H]+計算值368.18,實驗值368.21。
(c) (S
)-6,7-二氫-3H-咪唑并[4,5-c]吡啶-3,5,6(4H)-三甲酸6-苯甲酯3,5-二-第三丁酯(I-9)
向(S
)-3,5-雙(第三丁氧基羰基)-4,5,6,7-四氫-3H-咪唑并[4,5-c]吡啶-6-甲酸(I-8)
(5.1 Kg,13.88 mol)於DCM (51 L,10體積)中之冰冷溶液中依序添加飽和碳酸氫鈉水溶液(41.0 L,8體積)、四-丁基碘化銨(5.13 Kg,13.88 mol)及溴甲苯(2.47 L,20.82 mol)。將所得反應混合物在室溫下攪拌下一16小時。在完成反應(TLC & LCMS監測)之後,分離二相溶液。用DCM (3×10 L)萃取水層。經合併之有機物用鹽水溶液洗滌,經硫酸鈉乾燥,過濾且在減壓下濃縮以獲得粗產物,該粗產物藉由經由矽膠(100-200 M)管柱層析,藉由使用溶離劑40% EtOAc/己烷純化,以得到呈黏稠油狀之所需產物(I-9)
(4.50 Kg,72%)。(m/z):C24
H31
N3
O6
之[M+H]+計算值458.22,實驗值458.60。
(d) (S
)-3,4,6,7-四氫-5H-咪唑并[4,5-c]吡啶-5,6-二甲酸6-苯甲酯5-(第三丁酯)(I-10)
向(S
)-6,7-二氫-3H-咪唑并[4,5-c]吡啶-3,5,6(4H)-三甲酸6-苯甲酯3,5-二-第三丁酯(I-9)
(4.50 Kg,9.84 mol)於IPA (45 L,10體積)中之冰冷溶液中逐滴添加氫氧化銨(36 L,8體積)。將所得反應混合物進一步在室溫下攪拌下一16小時。在完成反應(TLC & LCMS監測)之後,將所得混合物用水(25 L)稀釋,接著用EtOAc (3×20 L)萃取。經合併之有機物用鹽水溶液洗滌,經硫酸鈉乾燥,過濾且在減壓下濃縮以得到粗產物,該粗產物藉由經由矽膠(100-200 M)管柱層析,藉由使用溶離劑2% MeOH/DCM純化,以獲得呈厚的黏稠油狀之所需產物(I-10)
(2.70 Kg,77%)。(m/z):C19
H23
N3
O4
之[M+H]+計算值358.17,實驗值358.33。
(e) (S
)-3-苯甲基-3,4,6,7-四氫-5H-咪唑并[4,5-c]吡啶-5,6-二甲酸6-苯甲酯5-(第三丁酯)(I-11)
向(S
)-3,4,6,7-四氫-5H-咪唑并[4,5-c]吡啶-5,6-二甲酸6-苯甲酯5-(第三丁酯)(I-10)
(2.70 kg,7.55 mol)於DCM (32.4 L,12體積)中之冰冷溶液中添加1 N氫氧化鈉水溶液(24.3 L,9體積),隨後依序添加四丁基碘化銨(2.80 Kg,7.55 mol)及溴甲苯(0.99 L,8.31 mol)。將所得反應混合物在室溫下攪拌下一2小時。在完成反應(TLC & LCMS監測)之後,分離二相溶液。用DCM (3×10 L)萃取水層。經合併之有機物用鹽水溶液洗滌,經硫酸鈉乾燥,過濾且在減壓下濃縮以得到粗產物,該粗產物藉由矽膠(100-200 M)管柱層析,藉由使用溶離劑40% EtOAc/己烷純化,以獲得呈黏稠油狀之所需產物(I-11)
(1.70 Kg,63%)。(m/z):C26
H29
N3
O4
之[M+H]+計算值448.22,實驗值448.20。
製備
3
:
(S
)-3-
苯甲基
-2-(6-(4-(
苯甲氧基
)-2-
乙基苯基
)-1H-
吲唑
-3-
基
)-3,4,6,7-
四氫
-5H-
咪唑并
[4,5-c]
吡啶
-5,6-
二甲酸
6-
苯甲酯
5-(
第三丁酯
) (I-16)
(a) 4-溴-2-氟苯甲醯基氯化物(I-13)
向4-溴-2-氟苯甲酸(I-12)
(1.25 Kg,5.71 mol)於DCM (12.5 L,15體積)中之冰冷攪拌溶液中以逐滴方式添加乙二醯氯(0.98 L,11.42 mol)。將所得反應混合物在相同溫度下攪拌10 min。接著將DMF (150 mL)以逐滴方式添加至反應混合物。使所得反應塊狀物升溫至室溫且攪拌2小時。在完成反應(藉由TLC監測)之後,在氮氣氛圍下在減壓下移除過量乙二醯氯,以獲得粗產物(I-13)
(1.08 Kg,80%),其不經進一步純化即用於下一步驟中。
(b) (S
)-3-苯甲基-2-(4-溴-2-氟苯甲醯基)-3,4,6,7-四氫-5H-咪唑并[4,5-c]吡啶-5,6-二甲酸6-苯甲酯5-(第三丁酯)(I-14)
在室溫下向(S
)-3-苯甲基-3,4,6,7-四氫-5H-咪唑并[4,5-c]吡啶-5,6-二甲酸6-苯甲酯5-(第三丁酯)(I-11)
(1.70 Kg,3.80 mol)於ACN (13.6 L,8體積)中之攪拌溶液中添加三乙胺(2.11 L,15.2 mol),隨後添加4-溴-2-氟苯甲醯氯(I-13)
(1.08 Kg,4.56 mol於3.4 L ACN中,2體積)。在完成添加之後,所得反應混合物顏色自淡黃色變為棕色。將所得反應混合物在相同溫度下攪拌30 min,且藉由TLC監測反應進展。將所得反應混合物用冰冷之水(10 L)淬滅,接著用EtOAc (3×5 L)萃取且將經合併之有機物用鹽水溶液洗滌。有機物經硫酸鈉乾燥,過濾且在減壓下濃縮以得到粗產物,該粗產物藉由矽膠(100-200 M)管柱層析,藉由使用溶離劑20% EtOAc/己烷純化,以獲得所需產物(I-14)
(1.74 Kg,71%)。(m/z):C33
H31
BrFN3
O5
之[M+H]+計算值648.14,實驗值648.20。
(c) (S
)-3-苯甲基-2-(6-溴-1H-吲唑-3-基)-3,4,6,7-四氫-5H-咪唑并[4,5-c]吡啶-5,6-二甲酸6-苯甲酯5-(第三丁酯)(I-15)
在室溫下,向(S
)-3-苯甲基-2-(4-溴-2-氟苯甲醯基)-3,4,6,7-四氫-5H-咪唑并[4,5-c]吡啶-5,6-二甲酸6-苯甲酯5-(第三丁酯)(I-14)
(1.74 Kg,2.68 mol)於THF (26.0 L,15體積)中之攪拌溶液中添加水合肼(0.705 L,13.4 mol)。將所得反應混合物在60℃下加熱3小時。在完成反應(TLC監測)之後,將所得反應塊狀物倒入冰冷之水(10 L)中,接著用EtOAc (3×10 L)萃取化合物。經合併之有機物用鹽水洗滌且經硫酸鈉乾燥,過濾,並且在減壓下蒸發以得到粗產物,該粗產物藉由矽膠(100-200 M)管柱層析,藉由使用溶離劑20% EtOAc/己烷純化,以獲得呈灰白色固體狀之所需產物(I-15)
(1.12 Kg,65%)。(m/z):C33
H32
BrN5
O4
之[M+H]+計算值642.16,實驗值642.21。
(d) (S
)-3-苯甲基-2-(6-(4-(苯甲氧基)-2-乙基苯基)-1H-吲唑-3-基)-3,4,6,7-四氫-5H-咪唑并[4,5-c]吡啶-5,6-二甲酸6-苯甲酯5-(第三丁酯)(I-16)
將雙(頻哪醇根基)二硼(250 g,984 mmol)與丙-2-醇(1.882 L,2.46E+04 mmol)一起裝入至預先使用氟化學物質蝕刻之5 L 3頸單壁燒瓶且攪拌混合物直至充分溶解為止。溶解為吸熱的(-4℃)。在預先使用氟化學物質蝕刻之4 L錐形瓶中,將氟化鉀氫氟酸鹽(538 g,6891 mmol)溶解於水(2.306 L,1.28E+05 mmol)中以形成3 M溶液。溶解為吸熱的(-12℃)。接著過濾溶液以自氟化鉀氫氟酸鹽移除少量不溶材料。 一旦充分溶解兩種溶液,則歷經15分鐘將錐形瓶之內含物逐份裝入至單壁燒瓶中。觀測到適度發熱(+10℃)。在添加期間,溶液變為厚而半透明的半不透光灰色研磨漿,且延長攪拌以保持內含物良好混合。將混合物攪拌1.5 h,且接著經由粗糙的玻璃燒結漏斗(4 L,預先蝕刻)過濾。需要30-45分鐘來完成過濾。丟棄透明的二相濾過物。將白色固體在過濾器上乾燥10分鐘(觀測到餅狀物之裂解)。將固體轉移回至乾淨的5 L 3頸單壁燒瓶中且用水(1.33 L,7.38E+04 mmol)再製成漿液。將研磨漿攪拌2 h,此後其形成透明的均勻水凝膠。將溶液攪拌另外1 h,隨即使用4 L粗糙玻璃漏斗(預先蝕刻)濾除固體/凝膠。將固體在過濾器上乾燥30分鐘。將固體轉移回至乾淨的5 L 3頸單壁燒瓶且用丙酮(1.084 L,1.48E+04 mmol)再製成漿液。將白色/灰色研磨漿攪拌1 h且接著在4 L粗糙玻璃漏斗(預先蝕刻)上過濾。需要20分鐘來完成過濾,且接著在漏斗上乾燥另外1 h。在此時間過程中,偶爾攪動固體以確保均勻乾燥。淡白色粉末在乾燥之後保留於過濾器上。將固體隨著緩慢氮氣滲出在真空下在55℃下乾燥20 h,以獲得疏鬆白色固體(收集到200.3 g)。
向(S
)-3-苯甲基-2-(6-溴-1H-吲唑-3-基)-3,4,6,7-四氫-5H-咪唑并[4,5-c]吡啶-5,6-二甲酸6-苯甲酯5-(第三丁酯)(I-15)
(10.0 g,16.0 mmol)於2-甲基四氫呋喃(100 mL,10體積)中之攪拌溶液中添加(4-(苯甲氧基)-2-乙基苯基)三氟-λ4
-甲硼烷,鉀鹽(I-5)
(8.0 g,20 mmol)及上文所獲得的疏鬆白色固體(0.20 g)。使所得反應混合物經氮氣脫氣30分鐘。向此溶液中添加所製備之碳酸銫水溶液(20.0 g,62.0 mmol於60 mL水中,6體積)。將所得反應混合物進一步脫氣15分鐘,隨後添加雙(二-第三丁基(4-二甲胺基苯基)膦)二氯化鈀(II) (0.66 g,0.93 mmol),且將反應混合物在真空下排空並藉由氮氣沖洗。將所得反應混合物在110℃下加熱20小時。在完成反應(TLC & LCMS監測)之後,使所得反應混合物冷卻至室溫且經由矽藻土床過濾,接著用EtOAc (3×0.5 L)進一步洗滌。經合併之有機物用1 N氫氧化鈉溶液(3×0.5 L)洗滌。接著經合併之有機物用鹽水洗滌且經硫酸鈉乾燥,過濾,且在減壓下蒸發以得到粗產物,該粗產物藉由矽膠(100-200 M)管柱層析,藉由使用溶離劑20% EtOAc/己烷純化,以獲得呈淡黃色固體狀之所需產物(I-16)
(作為N-苯甲基區位異構體之混合物) (8.0 g,66%)。(m/z):C48
H47
N5
O5
之[M+H]+計算值774.36,實驗值774.59。
製備
4
:
(S
)-2-(6-(2-
乙基
-4-
羥苯基
)-1H-
吲唑
-3-
基
)-4,5,6,7-
四氫
-3H-
咪唑并
[4,5-c]
吡啶
-6-
甲酸
,
鹽酸鹽
(I-18)
(a) (S
)-3-苯甲基-2-(6-(4-(苯甲氧基)-2-乙基苯基)-1H-吲唑-3-基)-4,5,6,7-四氫-3H-咪唑并[4,5-c]吡啶-6-甲酸苯甲酯,鹽酸鹽(I-17)
將(S
)-3-苯甲基-2-(6-(4-(苯甲氧基)-2-乙基苯基)-1H-吲唑-3-基)-3,4,6,7-四氫-5H-咪唑并[4,5-c]吡啶-5,6-二甲酸6-苯甲酯5-(第三丁酯)(I-16)
(1.0 g,1.292 mmol)溶解於二噁烷(8 mL)及水(1.5 mL)中,接著添加氯化氫溶液(4 M於二噁烷中) (7 mL,28.0 mmol)且將反應混合物在室溫下攪拌3小時(藉由LCMS監測反應進展)。接著冷凍且凍乾反應混合物,且將粗產物(I-17)
直接用於下一反應中(假定定量產率)。(m/z):C43
H39
N5
O3
之[M+H]+計算值674.31,實驗值674.3。
(b) (S
)-2-(6-(2-乙基-4-羥苯基)-1H-吲唑-3-基)-4,5,6,7-四氫-3H-咪唑并[4,5-c]吡啶-6-甲酸,鹽酸鹽(I-18)
將(S
)-3-苯甲基-2-(6-(4-(苯甲氧基)-2-乙基苯基)-1H-吲唑-3-基)-4,5,6,7-四氫-3H-咪唑并[4,5-c]吡啶-6-甲酸苯甲酯,鹽酸鹽(I-17)
(0.918 g,1.292 mmol)在50℃下溶解於2-丙醇(15 mL)、氯化氫溶液(5 M於水中) (0.258 mL,1.292 mmol)及水(0.25 mL)中,接著添加鈀(10% wt.於碳上),50%水(0.138 g,0.065 mmol)。接著用氮氣吹掃反應燒瓶,連接氫氣氣囊且將反應混合物在50℃下攪拌4天,其中在需要時補給氫氣氣囊(藉由LCMS監測反應進展)。接著藉由過濾移除所有固體且濃縮所得溶液。將殘餘物溶解於1:1 ACN/水中,冷凍且凍乾。所得粉末(I-18)
不經進一步純化即使用(假定定量產率)。(m/z):C22
H21
N5
O3
之[M+H]+計算值404.17,實驗值404.2。
製備 5 : (S
)-2-(6-(2- 乙基 -4- 羥苯基 )-1H- 吲唑 -3- 基 )-5- 異丙基 -4,5,6,7- 四氫 -3H- 咪唑并 [4,5-c] 吡啶 -6- 甲酸 (I-19)
將(S
)-2-(6-(2-乙基-4-羥苯基)-1H-吲唑-3-基)-4,5,6,7-四氫-3H-咪唑并[4,5-c]吡啶-6-甲酸,HCl(I-18)
(0.25 g,0.568 mmol)懸浮於DMF (2.5 mL)及丙酮(2.5 mL)中,接著添加乙酸(0.098 mL,1.705 mmol)及氰基硼氫化鈉(0.179 g,2.84 mmol)且將反應混合物在室溫下攪拌24小時(藉由LCMS監測反應進展)。濃縮反應混合物,接著將粗產物藉由逆相層析(5-70% ACN/水梯度,50 g C18aq管柱)純化,以得到標題化合物之TFA鹽(149 mg,47%產率)。(m/z):C25
H27
N5
O3
之[M+H]+計算值446.21,實驗值446.3。
製備 6 : (S
)-2-(6-(2- 乙基 -4- 羥苯基 )-1H- 吲唑 -3- 基 )-5- 丙基 -4,5,6,7- 四氫 -3H- 咪唑并 [4,5-c] 吡啶 -6- 甲酸 (I-20)
將(S
)-2-(6-(2-乙基-4-羥苯基)-1H-吲唑-3-基)-4,5,6,7-四氫-3H-咪唑并[4,5-c]吡啶-6-甲酸,HCl(I-18)
(0.160 g,0.364 mmol)及丙醛(0.039 mL,0.546 mmol)溶解於甲醇(3.0 mL)中,接著添加氰基硼氫化鈉(0.069 g,1.091 mmol)且將反應混合物在室溫下攪拌24小時(藉由LCMS監測反應進展)。濃縮反應混合物且將粗產物藉由逆相層析(5-70% ACN/水梯度,50 g C18管柱)純化,以得到標題化合物之TFA鹽(78 mg,38%產率)。(m/z):C25
H27
N5
O3
之[M+H]+計算值446.21,實驗值446.3。
製備 7 : (S
)-2-(6-(2- 乙基 -4- 羥苯基 )-1H- 吲唑 -3- 基 )-5- 甲基 -4,5,6,7- 四氫 -3H- 咪唑并 [4,5-c] 吡啶 -6- 甲酸 (I-21)
將(S
)-2-(6-(2-乙基-4-羥苯基)-1H-吲唑-3-基)-4,5,6,7-四氫-3H-咪唑并[4,5-c]吡啶-6-甲酸,HCl(I-18)
(0.160 g,0.364 mmol)及甲醛溶液(37 wt%於水中) (0.032 mL,0.436 mmol)溶解於甲醇(3.0 mL)中,接著添加氰基硼氫化鈉(0.069 g,1.091 mmol)且將反應混合物在室溫下攪拌4小時(藉由LCMS監測反應進展)。添加硼氫化鈉(14 mg,0.364 mmol)以淬滅任何過量甲醛,接著濃縮反應混合物。將粗產物藉由逆相層析(5-70% ACN/水梯度,50 g C18管柱)純化,以得到標題化合物之TFA鹽(110 mg,57%產率)。(m/z):C23
H23
N5
O3
之[M+H]+計算值418.18,實驗值418.2。
(a) (R
)-4-(2-羥乙基)-2-甲基哌嗪-1-甲酸第三丁酯(I-23)
將(R
)-1-boc-2-甲基-哌嗪(0.2 g,0.999 mmol)、DIPEA (0.698 mL,3.99 mmol)及2-溴乙醇(0.085 mL,1.198 mmol)溶解於DMF (5 mL)中且將反應混合物在60℃下攪拌16小時(藉由LCMS監測反應進展)。濃縮反應混合物,接著將10 mL乙醚添加至殘餘物。音波處理溶液直至殘餘物凝膠消失且固體形成為止。接著將醚溶液自固體傾倒出來。接著將固體直接用於下一反應中(假定定量產率)。(m/z):C12
H24
N2
O3
之[M+H]+計算值245.18,實驗值245.4。
(b) (R
)-2-(3-甲基哌嗪-1-基)乙-1-醇,二鹽酸鹽(I-24)
將(R
)-4-(2-羥乙基)-2-甲基哌嗪-1-甲酸第三丁酯(0.244 g,0.999 mmol)溶解於二噁烷(3.0 mL)及水(0.5 mL)中,接著添加氯化氫溶液(4 M於二噁烷中) (2.0 mL,65.8 mmol)且將反應混合物在室溫下攪拌3小時(藉由LCMS監測反應進展)。冷凍且凍乾反應混合物,且所得產物不經純化即使用(假定定量產率)。(m/z):C7
H16
N2
O之[M+H]+計算值145.13,實驗值145.4。
實例 1 : (S
)-(2-(6-(2- 乙基 -4- 羥苯基 )-1H- 吲唑 -3- 基 )-5- 丙基 -4,5,6,7- 四氫 -3H- 咪唑并 [4,5-c] 吡啶 -6- 基 )(4-(2- 羥乙基 ) 哌嗪 -1- 基 ) 甲酮
將(S
)-2-(6-(2-乙基-4-羥苯基)-1H-吲唑-3-基)-5-丙基-4,5,6,7-四氫-3H-咪唑并[4,5-c]吡啶-6-甲酸,TFA(I-20)
(40 mg,0.071 mmol)、正-(2-羥乙基)哌嗪(0.018 mL,0.143 mmol)及DIPEA (0.025 mL,0.143 mmol)溶解於DMF (1.5 mL)中,接著添加HATU (40.8 mg,0.107 mmol)且將反應混合物在室溫下攪拌3小時(藉由LCMS監測反應進展)。添加肼(0.011 mL,0.357 mmol)以裂解非所要副產物,接著將溶液在室溫下攪拌10分鐘。接著濃縮反應混合物且將粗產物藉由製備型HPLC (5-70% ACN/水梯度,C18管柱)純化,以得到標題化合物之TFA鹽(31 mg,56%產率)。 (m/z):C31
H39
N7
O3
之[M+H]+計算值558.31,實驗值558.3。1
H NMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H), 12.27 (d, J = 48.92 Hz, 1H), 9.40 (s, 1H), 8.28 (t, J = 8.10 Hz, 1H), 7.30 (s, 1H), 7.04 (m, 2H), 6.71 (d, J = 2.46 Hz, 1H), 6.64 (dd, J = 2.50, 8.23 Hz, 1H), 4.44 (t, J = 5.31 Hz, 1H), 4.11 (q, J = 5.26, 2H), 3.96 (m, 1H), 3.86-3.52 (m, 6H), 3.49 (q, J = 6.01 Hz, 2H), 2.95 (m, 2H), 2.48 (q, J = 7.48 Hz, 2H), 2.42-2.21 (m, 4H), 2.37 (t, J = 6.20 Hz, 2H), 1.42 (m, 2H), 1.00 (t, J = 7.52 Hz, 3H), 0.81 (m, 3H)。
實例 2 : ((S
)-2-(6-(2- 乙基 -4- 羥苯基 )-1H- 吲唑 -3- 基 )-5- 丙基 -4,5,6,7- 四氫 -3H- 咪唑并 [4,5-c] 吡啶 -6- 基 )((1S,4S)-5- 甲基 -2,5- 二氮雜雙環 [2.2.1] 庚 -2- 基 ) 甲酮
將(S
)-2-(6-(2-乙基-4-羥苯基)-1H-吲唑-3-基)-5-丙基-4,5,6,7-四氫-3H-咪唑并[4,5-c]吡啶-6-甲酸,TFA(I-20)
(40 mg,0.071 mmol)、(1S,4S)-5-甲基-2,5-二氮雜雙環[2.2.1]庚烷二氫溴酸鹽(29.4 mg,0.107 mmol)及DIPEA (0.062 mL,0.357 mmol)溶解於DMF (1.5 mL)中,接著添加HATU (40.8 mg,0.107 mmol)且將反應混合物在室溫下攪拌3小時(藉由LCMS監測反應進展)。添加肼(0.011 mL,0.357 mmol)以裂解非所要副產物,接著將溶液在室溫下攪拌10分鐘。接著濃縮反應混合物且將粗產物藉由製備型HPLC (5-70% ACN/水梯度,C18管柱)純化,以得到標題化合物之TFA鹽(32 mg,59%產率)。(m/z):C31
H37
N7
O2
之[M+H]+計算值540.30,實驗值540.3。
實例
3
:
((S
)-2,4-
二甲基哌嗪
-1-
基
)((S
)-2-(6-(2-
乙基
-4-
羥苯基
)-1H-
吲唑
-3-
基
)-5-
甲基
-4,5,6,7-
四氫
-3H-
咪唑并
[4,5-c]
吡啶
-6-
基
)
甲酮
(a) (S
)-4-((S
)-2-(6-(2-乙基-4-羥苯基)-1H-吲唑-3-基)-5-甲基-4,5,6,7-四氫-3H-咪唑并[4,5-c]吡啶-6-羰基)-3-甲基哌嗪-1-甲酸第三丁酯(I-25)
將(S
)-2-(6-(2-乙基-4-羥苯基)-1H-吲唑-3-基)-5-甲基-4,5,6,7-四氫-3H-咪唑并[4,5-c]吡啶-6-甲酸,TFA(I-21)
(55 mg,0.103 mmol)、(S
)-4-正-boc-2-甲基哌嗪(41.5 mg,0.207 mmol)及DIPEA (0.036 mL,0.207 mmol)溶解於DMF (1.5 mL)中,接著添加HATU (59.0 mg,0.155 mmol)且將反應混合物在室溫下攪拌16小時(藉由LCMS監測反應進展)。添加肼(0.016 mL,0.517 mmol)以裂解非所要副產物,接著將反應混合物在室溫下攪拌10分鐘。接著濃縮反應混合物且將粗產物藉由逆相層析(5-70% ACN/水梯度,50 g C18管柱)純化,以得到標題化合物之TFA鹽(54 mg,72%產率)。(m/z):C33
H41
N7
O4
之[M+H]+計算值600.33,實驗值600.3。
(b) ((S
)-2-(6-(2-乙基-4-羥苯基)-1H-吲唑-3-基)-5-甲基-4,5,6,7-四氫-3H-咪唑并[4,5-c]吡啶-6-基)((S
)-2-甲基哌嗪-1-基)甲酮(I-26)
將(S
)-4-((S
)-2-(6-(2-乙基-4-羥苯基)-1H-吲唑-3-基)-5-甲基-4,5,6,7-四氫-3H-咪唑并[4,5-c]吡啶-6-羰基)-3-甲基哌嗪-1-甲酸第三丁酯,TFA(I-25)
(0.126 g,0.177 mmol)溶解於二噁烷(1.5 mL)及水(0.3 mL)中,接著添加氯化氫溶液(4 M於二噁烷中) (1.5 mL,6.00 mmol)且將反應混合物在室溫下攪拌2小時(藉由LCMS監測反應進展)。冷凍且凍乾反應混合物,且將所得粉末直接用於下一反應中(假定定量產率)。(m/z):C28
H33
N7
O2
之[M+H]+計算值500.27,實驗值500.3。
(c) ((S
)-2,4-二甲基哌嗪-1-基)((S
)-2-(6-(2-乙基-4-羥苯基)-1H-吲唑-3-基)-5-甲基-4,5,6,7-四氫-3H-咪唑并[4,5-c]吡啶-6-基)甲酮
將((S
)-2-(6-(2-乙基-4-羥苯基)-1H-吲唑-3-基)-5-甲基-4,5,6,7-四氫-3H-咪唑并[4,5-c]吡啶-6-基)((S
)-2-甲基哌嗪-1-基)甲酮,二鹽酸鹽(0.101 g,0.176 mmol)及甲醛溶液(37 wt%於水中) (0.016 mL,0.212 mmol)溶解於甲醇(3.0 mL)中,接著添加氰基硼氫化鈉(0.055 g,0.882 mmol)且將反應混合物在室溫下攪拌16小時(藉由LCMS監測反應進展)。添加硼氫化鈉(7 mg,0.176 mmol)以淬滅任何剩餘甲醛。濃縮反應混合物,接著將粗產物藉由製備型HPLC (5-60% ACN/水梯度,C18管柱)純化,以得到標題化合物之TFA鹽(28 mg,21%產率)。(m/z):C29
H35
N7
O2
之[M+H]+計算值514.29,實驗值514.3。
實例 4 : (S
)-(2-(6-(2- 乙基 -4- 羥苯基 )-1H- 吲唑 -3- 基 )-5- 異丙基 -4,5,6,7- 四氫 -3H- 咪唑并 [4,5-c] 吡啶 -6- 基 )(4- 甲基 -1,4- 二氮雜環庚烷 -1- 基 ) 甲酮
將(S
)-2-(6-(2-乙基-4-羥苯基)-1H-吲唑-3-基)-5-異丙基-4,5,6,7-四氫-3H-咪唑并[4,5-c]吡啶-6-甲酸,TFA(I-19)
(50 mg,0.089 mmol)、1-甲基高哌嗪(0.022 mL,0.179 mmol)及DIPEA (0.031 mL,0.179 mmol)溶解於DMF (1.5 mL)中,接著添加HATU (51.0 mg,0.134 mmol)且將反應混合物在室溫下攪拌3小時(藉由LCMS監測反應進展)。添加肼(0.014 mL,0.447 mmol)以裂解非所要副產物,且將溶液在室溫下攪拌10分鐘。接著濃縮反應混合物且將粗產物藉由製備型HPLC (2-70% ACN/水梯度,C18管柱)純化,以得到標題化合物之TFA鹽(29 mg,42%產率)。(m/z):C31
H39
N7
O2
之[M+H]+計算值542.32,實驗值542.3。1
H NMR (400 MHz, DMSO-d6) δ 13.08 (s, 1H), 12.21 (d, J = 29.9 Hz, 1H), 9.40 (s, 1H), 8.27 (d, J = 8.33 Hz, 1H), 7.30 (s, 1H), 7.04 (t, J = 8.05, 2H), 6.71 (d, J = 2.53 Hz, 1H), 6.64 (dd, J = 2.54, 8.23 Hz, 1H), 4.11 (m, 3H), 3.91-3.52 (m, 6H), 2.97 (m, 1H), 2.91-2.53 (m, 4H), 2.49 (q, J = 7.46, 2H), 2.23 (d, J = 13.9 Hz, 3H), 1.76 (m, 2H), 1.0 (m, 9H)。
實例 5 : ((S
)-2-(6-(2- 乙基 -4- 羥苯基 )-1H- 吲唑 -3- 基 )-5- 甲基 -4,5,6,7- 四氫 -3H- 咪唑并 [4,5-c] 吡啶 -6- 基 )((R
)-4-(2- 羥乙基 )-2- 甲基哌嗪 -1- 基 ) 甲酮
將(S
)-2-(6-(2-乙基-4-羥苯基)-1H-吲唑-3-基)-5-甲基-4,5,6,7-四氫-3H-咪唑并[4,5-c]吡啶-6-甲酸,TFA(I-21)
(55 mg,0.103 mmol)、(R
)-2-(3-甲基哌嗪-1-基)乙-1-醇,二鹽酸鹽(I-24)
(33.7 mg,0.155 mmol)及DIPEA (0.090 mL,0.517 mmol)溶解於DMF (1.5 mL)中,接著添加HATU (59.0 mg,0.155 mmol)且將反應混合物在室溫下攪拌16小時(藉由LCMS監測反應進展)。添加肼(0.016 mL,0.517 mmol)以裂解非所要副產物,接著將反應混合物在室溫下攪拌10分鐘。接著濃縮反應混合物,且將粗產物藉由製備型HPLC (5-70% ACN/水梯度,C18管柱)純化,以得到標題化合物之TFA鹽(22 mg,28%產率)。(m/z):C30
H37
N7
O3
之[M+H]+計算值544.30,實驗值544.3。
實例 6 : ((S
)-3-( 二甲胺基 ) 吡咯啶 -1- 基 )((S
)-2-(6-(2- 乙基 -4- 羥苯基 )-1H- 吲唑 -3- 基 )-5- 異丙基 -4,5,6,7- 四氫 -3H- 咪唑并 [4,5-c] 吡啶 -6- 基 ) 甲酮
將(S
)-2-(6-(2-乙基-4-羥苯基)-1H-吲唑-3-基)-5-異丙基-4,5,6,7-四氫-3H-咪唑并[4,5-c]吡啶-6-甲酸,TFA(I-19)
(50 mg,0.089 mmol)、(S
)-(-)-3-(二甲胺基)吡咯啶(0.023 mL,0.179 mmol)及DIPEA (0.031 mL,0.179 mmol)溶解於DMF (1.5 mL)中,接著添加HATU (51.0 mg,0.134 mmol)且將反應混合物在室溫下攪拌3小時(藉由LCMS監測反應進展)。添加肼(0.014 mL,0.447 mmol)以裂解非所要副產物,且將溶液在室溫下攪拌10分鐘。接著濃縮反應混合物且將粗產物藉由製備型HPLC (5-70% ACN/水梯度,C18管柱)純化,以得到標題化合物之TFA鹽(37 mg,53%產率)。(m/z):C31
H39
N7
O2
之[M+H]+計算值542.32,實驗值542.3。
(a) 1-(苯甲氧基)-4-溴-5-乙基-2-氟苯
向4-溴-5-乙基-2-氟苯酚(20 g,910.32 mmol)於ACN (250 mL)中之溶液中添加K2
CO3
(31.55 g,228.3 mmol),隨後逐滴添加溴甲苯(13.10 mL,109.58 mmol)。將所得反應混合物在80℃下攪拌2 h。水層用EtOAc萃取(三次),經合併且用鹽水洗滌。有機層經Na2
SO4
乾燥且在減壓下蒸發,以獲得呈淺黃色油性液體狀之標題中間物(25 g,89%產率)。1
H NMR (400 MHz, 氯仿-d
) δ 7.48 - 7.30 (m, 5H), 7.27 (d,J
= 10.5 Hz, 1H), 6.87 (d,J
= 8.7 Hz, 1H), 5.12 (s, 2H), 2.66 (q,J
= 7.5 Hz, 2H), 1.16 (t,J
= 7.5 Hz, 3H)。
(b) 2-(4-(苯甲氧基)-2-乙基-5-氟苯基)-4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷
向先前步驟之產物(12.5 g,40.45 mmol)於二噁烷(100 mL)中之溶液中添加雙(頻哪醇根基)二硼(15.40 g,60.67 mmol)及KOAc (11.9 g,121.35 mmol)。將反應混合物用氮氣吹掃15 min,隨後添加與二氯甲烷錯合之[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(II) (1.65 g,2.023 mmol)。攪拌所得反應混合物且在110℃下加熱3 h,經由矽藻土過濾且用EtOAc洗滌殘餘物。濾過物用過量EtOAc (200 mL)稀釋且用水(100 mL),隨後鹽水(100 mL)洗滌,經硫酸鈉乾燥且在真空中濃縮以得到粗產物,該粗產物藉由(100-200)矽膠管柱層析純化,經3-5% EtOAc:己烷溶離,以獲得呈灰白色固體狀之所需產物(9.50 g,66 %產率)。1
H NMR (400 MHz, 氯仿-d
) δ 7.54 - 7.27 (m, 6H), 6.81 (d,J
= 7.9 Hz, 1H), 5.16 (s, 2H), 2.84 (q,J
= 7.5 Hz, 2H), 1.32 (s, 12H), 1.14 (t,J
= 7.5 Hz, 3H)。
(a) 6-(4-(苯甲氧基)-2-乙基-5-氟苯基)-1-(四氫-2H-哌喃-2-基)-1H
-吲唑
向6-溴-1-(四氫-2H
-哌喃-2-基)-1H
-吲唑(50 g,178.57 mmol)及2-(4-(苯甲氧基)-2-乙基-5-氟苯基)-4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷(76.3 g,214.29 mmol)於DMF:H2
O (480:120 mL)中之溶液中添加K3
PO4
(94.64 g,446.86 mmol)。將反應混合物經氮氣脫氣15 min,接著添加Pd(PPh3
)2
Cl2
催化劑(6.26 g,8.93 mmol)且將混合物再次經氮氣脫氣5 min,經攪拌且在100至110℃下加熱5 h。經由矽藻土過濾反應混合物且用EtOAc洗滌殘餘物。濾過物用EtOAc稀釋,用冷水及鹽水洗滌,經硫酸鈉乾燥且在真空中濃縮以得到粗產物,該粗產物藉由急驟管柱層析純化,以獲得呈白色固體狀之標題中間物(65 g,86%產率)。(m/z
):C27
H27
FN2
O2
之[M+H]+
計算值431.21,實驗值431.46。1
H NMR (400 MHz, 氯仿-d
) δ 8.06 - 7.98 (m, 2H), 7.70 (d,J
= 8.2 Hz, 1H), 7.51 - 7.32 (m, 5H), 7.08 (dd,J
= 809.6, 8.3 Hz, 1H), 7.03 (d,J
= 11.9 Hz, 1H), 6.95 (d,J
= 8.5 Hz, 1H), 5.76 - 5.64 (m, 1H), 5.20 (s, 2H), 4.04 (d,J
= 10.1 Hz, 1H), 3.72 (t,J
= 9.7 Hz, 1H), 2.52 (q,J
= 7.5 Hz, 2H), 2.22 - 2.02 (m, 3H), 1.80 - 1.71 (m, 3H), 1.06 (t,J
= 7.5 Hz, 3H)。
(b) 6-(4-(苯甲氧基)-2-乙基-5-氟苯基)-1H
-吲唑
向先前步驟之產物(65 g,151.16 mmol)於甲醇(700 mL)中之溶液中添加濃HCl (120 mL)且使所得溶液在60-65℃下加熱3 h,冷卻至室溫,且在真空中濃縮。將殘餘物溶解於EtOAc中且用NaHCO3
飽和水溶液及水洗滌。有機層經無水Na2
SO4
乾燥且在真空中濃縮,以獲得呈白色固體狀之標題中間物(52 g,99% (粗物質))。1
H NMR (400 MHz, 氯仿-d
) δ 8.13 (s, 1H), 7.77 (d,J
= 8.3 Hz, 1H), 7.59 - 7.30 (m, 6H), 7.10 (d,J
= 8.3 Hz, 1H), 7.01 (d,J
= 11.8 Hz, 1H), 6.96 (d,J
= 8.4 Hz, 1H), 5.21 (s, 2H), 2.53 (q,J
= 7.5 Hz, 2H), 1.05 (t,J
= 7.5 Hz, 3H)。
(c) 6-(4-(苯甲氧基)-2-乙基-5-氟苯基)-3-碘-1H
-吲唑
向6-(4-(苯甲氧基)-2-乙基-5-氟苯基)-1H
-吲唑(56 g,161.18 mmol)於DMF (400 mL)中之溶液中添加KOH (36.2 g,647.39 mmol)且將混合物攪拌5 min。在0℃下緩慢添加碘(82.2 g,323.69 mmol)於DMF (100 mL)中之溶液且在室溫下攪拌30 min,用水(3×150 mL)稀釋且用EtOAc (3×200 mL)萃取。有機層用偏亞硫酸氫鈉飽和水溶液(3×200 mL)及水(400 mL)洗滌,經無水Na2
SO4
乾燥且在減壓下濃縮以得到粗產物,該粗產物藉由急驟管柱層析純化,以獲得呈淺褐色半固體狀之標題中間物(64 g,84%產率)。1
H NMR (400 MHz, 氯仿-d
) δ 10.49 (s, 1H), 7.57 - 7.32 (m, 7H), 7.16 (d,J
= 8.3 Hz, 1H), 7.04 - 6.91 (m, 2H), 5.20 (s, 2H), 2.51 (q,J
= 7.4 Hz, 2H), 1.04 (t,J
= 7.5 Hz, 3H)。
(d) 6-(4-(苯甲氧基)-2-乙基-5-氟苯基)-3-碘-1-(四氫-2H
-哌喃-2-基)-1H
-吲唑
向先前步驟之產物(60 g,127.12 mmol)於DCM (700 mL)中之冰冷溶液中添加對甲苯磺酸(4.84 g,25.423 mmol),隨後逐滴添加3,4-二氫-2H
-哌喃(17.43 mL,190.68 mmol)。將反應混合物在室溫下攪拌隔夜,用DCM稀釋且用NaHCO3
飽和水溶液及鹽水洗滌。有機層經無水Na2
SO4
乾燥且在減壓下濃縮以得到粗產物,該粗產物藉由急驟層析(矽膠)純化,以獲得呈灰白色固體之標題中間物(64 g,91%產率)。(m/z
):C27
H26
FIN2
O2
之[M+H]+
計算值557.10,實驗值557.30。1
H NMR (400 MHz, 氯仿-d
) δ 7.56 - 7.31 (m, 7H), 7.14 (d,J
= 8.3 Hz, 1H), 7.01 (d,J
= 11.8 Hz, 1H), 6.95 (d,J
= 8.5 Hz, 1H), 5.68 (d,J
= 9.3 Hz, 1H), 5.20 (s, 2H), 4.08 - 3.99 (m, 1H), 3.77 - 3.64 (m, 1H), 2.50 (q,J
= 7.2 Hz, 2H), 2.23 - 1.97 (m, 3H), 1.81 - 1.68 (m, 3H), 1.06 (t,J
= 7.4 Hz, 3H)。
(e) 6-(4-(苯甲氧基)-2-乙基-5-氟苯基)-1-(四氫-2H
-哌喃-2-基)-3-(三甲基錫烷基)-1H
-吲唑
向6-(4-(苯甲氧基)-2-乙基-5-氟苯基)-3-碘-1-(四氫-2H
-哌喃-2-基)-1H
-吲唑(20 g,35.97 mmol)於甲苯(150 mL)中之溶液中添加六甲基二錫(9.2 mL,43.17 mmol)。反應混合物經氮氣脫氣20 min,隨後添加肆(三苯基膦)鈀(0)(2.0 g,1.80 mmol)且接著在100℃下攪拌2 h,冷卻至室溫,經由矽藻土過濾且用EtOAc洗滌殘餘物。濃縮濾過物且藉由管柱層析(經中性氧化鋁)純化,用2-5% EtOAc:己烷溶離,以獲得標題化合物(17.50 g,82%產率)。(m/z
):C30
H35
FN2
O2
Sn之[M+H]+
計算值595.17、593.17;實驗值595.49、593.55。1
H NMR (400 MHz, 氯仿-d
) δ 7.68 (d,J
= 8.0 Hz, 1H), 7.57 - 7.29 (m, 6H), 7.13 - 7.00 (m, 2H), 6.96 (d,J
= 8.4 Hz, 1H), 5.81 - 5.68 (m, 1H), 5.21 (s, 2H), 4.13 - 4.00 (m, 1H), 3.81 - 3.66 (m, 1H), 2.54 (q,J
= 7.3 Hz, 2H), 2.23 - 2.00 (m, 2H), 1.87 - 1.59 (m, 4H), 1.08 (t,J
= 7.5 Hz, 3H), 0.47 (s, 9H)。
製備
11
:
(S
)-2-
碘
-3-((2-
三甲基矽烷基
)
乙氧基
)
甲基
)-3,4,6,7-
四氫
-5H
-
咪唑并
[4,5-c]
吡啶
-5,6-
二甲酸
5-(
第三丁酯
)6-
甲酯
(a) (S
)-4,5,6,7-四氫-3H
-咪唑并[4,5-c]吡啶-6-甲酸
在0℃下向L-組胺酸(50 g,322.24 mmol)於水(420 mL)中之攪拌懸浮液中逐滴添加濃HCl (29 mL),隨後在0℃下一次性添加甲醛(55 mL,676.72 mmol)。將所得反應混合物攪拌30 min,且接著在75℃下加熱6 h並濃縮。將所得粗物質與乙醚攪拌2 h,過濾且用IPA:THF (100:300 mL)洗滌,以得到呈灰白色固體狀之標題中間物之HCl鹽(75 g,99%產率(粗物質))。(m/z
):C7
H9
N3
O2
之[M+H]+
計算值168.07,實驗值168.17。
(b) (S
)-4,5,6,7-四氫-3H
-咪唑并[4,5-c]吡啶-6-甲酸甲酯
在0℃下,向先前步驟之產物(75.0 g,312.5 mmol)於甲醇(1500 mL)中之攪拌溶液中逐滴添加SOCl2
(45.6 mL,625 mmol)且在室溫下攪拌16 h,接著加熱直至回流(70℃)持續1 h。藉由蒸餾移除溶劑且粗產物用甲醇,隨後乙醚研磨,以得到呈灰白色固體狀之標題中間物之粗HCl鹽(80 g粗物質)。1
H NMR (400 MHz, DMSO-d 6
) δ 9.05 (s, 1H), 4.71 (dd,J
= 9.4, 5.2 Hz, 1H), 4.36 (d,J
= 15.5 Hz, 1H), 4.30 (d,J
= 15.6 Hz, 1H), 3.82 (s, 3H), 3.44 - 3.21 (m, 2H)。
(c) (S
)-3,4,6,7-四氫-5H
-咪唑并[4,5-c]吡啶-5,6-二甲酸5-(第三丁酯)6-甲酯
在0℃下,向先前步驟之產物(80.0 g,314.96 mmol)於甲醇(1000 mL)中之攪拌溶液中添加DIPEA (282 mL,1574 mmol),隨後二碳酸二第三丁酯(172 mL,787.48 mmol)。將反應混合物在室溫下攪拌16 h且接著添加液體NH3
(150 mL,25%於水中),且將反應混合物在室溫下再次攪拌16 h,藉由蒸餾移除甲醇並用DCM (3×200 mL)萃取殘餘物。經合併之有機萃取物經無水Na2
SO4
乾燥,濃縮且藉由急驟層析(100-200目矽膠)純化,用5% MeOH:DCM溶離,以獲得標題中間物(41 g, 46%產率)。(m/z
):C13
H19
N3
O4
之[M+H]+
計算值282.14,實驗值282.21。1
H NMR (400 MHz, DMSO-d 6
) δ 11.85 (s, 1H), 7.50 (s, 1H), 5.18 (dd,J
= 49.3, 5.1 Hz, 1H), 4.51 (t,J
= 14.2 Hz, 1H), 4.09 (dd,J
= 43.9, 16.1 Hz, 1H), 3.59 (s, 3H), 3.08 (d,J
= 15.5 Hz, 1H), 2.94 (d,J
= 15.1 Hz, 1H), 1.45 (s, 9H)。
(d) (S
)-2-碘-3,4,6,7-四氫-5H
-咪唑并[4,5-c]吡啶-5,6-二甲酸5-(第三丁酯)6-甲酯
在0℃下,向先前步驟之產物(41.0 g,145.9 mmol)於THF (500 mL)中之溶液中添加N
-碘代丁二醯亞胺(66.0 g,291.8 mmol)且將所得溶液在室溫下攪拌4 h,用水稀釋並用乙酸乙酯萃取。有機部分用10%硫代硫酸鈉溶液(3×200 mL)洗滌。經合併之有機層經無水硫酸鈉乾燥,且經濃縮,以得到標題化合物60 g (粗物質),其不經進一步純化即用於下一步驟中。(m/z
):C13
H18
IN3
O4
之[M+H]+
計算值408.03,實驗值408.31。1
H NMR (400 MHz, DMSO-d 6
) δ 12.48 (s, 1H), 5.34 - 4.97 (m, 1H), 4.67 - 4.35 (m, 1H), 4.12 - 3.95 (m, 1H), 3.60 (s, 3H), 3.14 - 2.82 (m, 2H), 1.44 (s, 9H)。
(e) (S
)-2-碘-3-((2-三甲基矽烷基)乙氧基)甲基)-3,4,6,7-四氫-5H
-咪唑并[4,5-c]吡啶-5,6-二甲酸5-(第三丁酯)6-甲酯
在0℃下,向(S
)-2-碘-3,4,6,7-四氫-5H
-咪唑并[4,5-c]吡啶-5,6-二甲酸5-(第三丁酯)6-甲酯(40 g,0.098 mol)於DMF (150 mL)中之攪拌溶液中添加DIPEA (35.1 mL,0.19 mol)。 將反應混合物攪拌10 min,接著在0℃下逐滴添加2-(三甲基矽烷基)-乙氧基甲基氯(19.1 mL,0.10 mol)。將所得反應混合物在室溫下攪拌3 h。在4 h之後,添加冷凍水且反應混合物用EtOAc (2×200 mL)萃取。有機層經無水硫酸鈉乾燥,濃縮且藉由急驟管柱層析純化,用20-35% EtOAc:己烷溶離,以獲得呈淺黃色黏稠液態狀之標題產物(27 g)。(m/z
):C19
H32
IN3
O5
Si之[M+H]+
計算值538.12,實驗值538.42。1
H NMR (400 MHz, DMSO-d 6
) δ 5.33 - 5.04 (m, 3H), 4.79 - 4.56 (m, 1H), 4.54 - 4.14 (m, 1H), 3.60 (s, 3H), 3.47 (t,J
= 7.8 Hz, 2H), 3.31 - 3.16 (m, 1H), 2.97 (t,J
= 18.9 Hz, 1H), 1.44 (s, 9H), 0.92 - 0.74 (m, 2H), -0.03 (s, 9H)。
製備
12
:
(6S
)-5-(
第三丁氧基羰基
)-2-(6-(2-
乙基
-5-
氟
-4-
羥苯基
)-1-(
四氫
-2H
-
哌喃
-2-
基
)-1H
-
吲唑
-3-
基
)-3-((2-(
三甲基矽烷基
)
乙氧基
)
甲基
)-4,5,6,7-
四氫
-3H
-
咪唑并
[4,5-c]
吡啶
-6-
甲酸
(a) (6S
)-2-(6-(4-(苯甲氧基)-2-乙基-5-氟苯基)-1-(四氫-2H
-哌喃-2-基)-1H
-吲唑-3-基)-3-((2-(三甲基矽烷基)乙氧基)甲基)-3,4,6,7-四氫-5H
-咪唑并[4,5-c]吡啶-5,6-二甲酸5-(第三丁酯)6-甲酯
向(S
)-2-碘-3-((2-三甲基矽烷基)乙氧基)甲基)-3,4,6,7-四氫-5H
-咪唑并[4,5-c]吡啶-5,6-二甲酸5-(第三丁酯)6-甲酯(17.0 g,31.65 mmol)於甲苯(500 mL)中之攪拌溶液中添加6-(4-(苯甲氧基)-2-乙基-5-氟苯基)-1-(四氫-2H
-哌喃-2-基)-3-(三甲基錫烷基)-1H
-吲唑(20 g,34.82 mmol)。將反應混合物用氬氣吹掃15 min,添加Pd(PPh3
)4
(3.6 g,3.16 mmol)及碘化銅(1.20 g, 6.33 mmol)且將反應混合物在120℃下攪拌16 h。反應混合物經由矽藻土過濾,在減壓下濃縮濾過物且藉由矽膠管柱層析(Redisep 80 g管柱,用DCM溶離10 min且接著15-20% EtOAc/己烷溶離)純化,以獲得呈黃色固體狀之標題中間物(15.10 g,58%產率)。(m/z
):C46
H58
FN5
O7
Si之[M+H]+
計算值840.41,實驗值840.54。1
H NMR (400 MHz, 氯仿-d
) δ 8.43 (s, 1H), 7.54 - 7.33 (m, 6H), 7.20 (s, 1H), 7.05 (d,J
= 11.4 Hz, 1H), 6.95 (d,J
= 8.5 Hz, 1H), 6.09 - 5.69 (m, 3H), 5.59 - 5.36 (m, 1H), 5.20 (s, 2H), 4.97 - 4.80 (m, 1H), 4.12 - 3.90 (m, 1H), 3.68 (s, 3H), 3.57 - 3.47 (m, 2H), 3.40 (d, 1H), 3.21 - 3.05 (m, 1H), 2.74 - 2.34 (m, 4H), 2.25 - 2.07 (m, 2H), 1.94 - 1.65 (m, 4H), 1.54 (s, 9H), 1.12 - 0.99 (m, 3H), 0.91 - 0.75 (m, 2H), -0.12 (s, 9H)。
(b) (6S
)-2-(6-(4-(苯甲氧基)-2-乙基-5-氟苯基)-1-(四氫-2H
-哌喃-2-基)-1H
-吲唑-3-基)-3-((2-(三甲基矽烷基)乙氧基)甲基)-3,4,6,7-四氫-5H
-咪唑并[4,5-c]吡啶-5,6-二甲酸6-苯甲酯5-(第三丁酯)
向圓底燒瓶中添加含先前步驟之產物(15.0 g,17.85 mmol)之甲苯(400 mL)、苯甲醇(46.3 mL)及Ti(OEt)4
(7.15 mL,35.70 mmol)且使反應混合物劇烈回流(140℃) 48 h,用水稀釋且用DCM萃取。過濾懸浮液,濾過物經Na2
SO4
乾燥,在減壓下濃縮且藉由矽膠管柱層析(Redisep 80 g管柱,0-5% EtOAc/己烷)純化20 min以移除過量苯甲醇,接著用10-15% EtOAc/己烷溶離,以得到標題中間物。1
H NMR與結構一致。(m/z
):C52
H62
FN5
O7
Si之[M+H]+
計算值916.44,實驗值916.86。
(c) (6S
)-5-(第三丁氧基羰基)-2-(6-(2-乙基-5-氟-4-羥苯基)-1-(四氫-2H
-哌喃-2-基)-1H
-吲唑-3-基)-3-((2-(三甲基矽烷基)乙氧基)甲基)-4,5,6,7-四氫-3H
-咪唑并[4,5-c]吡啶-6-甲酸
向先前步驟之產物(21.0 g,22.92 mmol)於1:1 IPA:THF (400 mL)中之攪拌溶液中添加Pd(OH)2
(5.0 g)。將反應混合物在氫氣氣囊下在室溫下攪拌16 h,經由矽藻土過濾,在減壓下濃縮且藉由矽膠管柱層析(Redisep 80 g管柱,用25-40% EtOAc/己烷溶離)純化,以得到呈灰白色固體狀之標題化合物(6.1 g,8.29 mmol)。(m/z
):C38
H50
FN5
O7
Si之[M+H]+
計算值736.35,實驗值736.5。1
H NMR與結構一致。(m/z
):C38
H50
FN5
O7
Si之[M+H]+
計算值736.35,實驗值736.5。1
H NMR (400 MHz, DMSO-d 6
) δ 12.94 (s, 1H), 9.86 (s, 1H), 8.34 (t,J
= 7.6 Hz, 1H), 7.66 (s, 1H), 7.20 (d,J
= 8.7 Hz, 1H), 7.03 (d,J
= 11.8 Hz, 1H), 6.93 (d,J
= 9.1 Hz, 1H), 6.11 - 5.77 (m, 3H), 5.33 - 5.06 (m, 1H), 4.87 - 4.56 (m, 1H), 4.52 - 4.14 (m, 1H), 3.97 - 3.69 (m, 2H), 3.53 - 3.40 (m, 2H), 3.23 - 3.11 (m, 1H), 3.11 - 2.93 (m, 1H), 2.47 - 2.44 (m, 2H), 2.13 - 1.96 (m, 2H), 1.68 (d,J
= 70.9 Hz, 4H), 1.48 (s, 9H), 1.02 (t,J
= 7.5 Hz, 3H), 0.86 - 0.68 (m, 2H), -0.17 (s, 9H)。
製備 13 : (S
)-2-(6-(2- 乙基 -5- 氟 -4- 羥苯基 )-1H
- 吲唑 -3- 基 )-4,5,6,7- 四氫 -3H
- 咪唑并 [4,5-c] 吡啶 -6- 甲酸
在0℃下,向(6S
)-5-(第三丁氧基羰基)-2-(6-(2-乙基-5-氟-4-羥苯基)-1-(四氫-2H
-哌喃-2-基)-1H
-吲唑-3-基)-3-((2-(三甲基矽烷基)乙氧基)-甲基)-4,5,6,7-四氫-3H
-咪唑并[4,5-c]吡啶-6-甲酸(5.7 g,7.75 mmol)於5:1二噁烷:水(60 mL)中之攪拌溶液中逐滴添加濃HCl (20 mL)。使反應混合物升溫且在90℃下攪拌16 h並在真空下蒸餾以得到粗殘餘物,該粗殘餘物依序用經冷凍乙醚及乙腈研磨,以得到呈淡棕色固體狀之標題化合物之HCl鹽(3.6 g,95%產率)。(m/z
):C22
H20
FN5
O3
之[M+H]+
計算值422.16,實驗值422.24。1
H NMR (400 MHz, D2
O/DMSO-d 6
) δ 8.22 (d,J
= 8.4 Hz, 1H), 7.49 (s, 1H), 7.19 (d,J
= 8.1 Hz, 1 H), 6.99 (d,J
= 11.9 Hz, 1 H), 6.91 (d,J
= 9.0 Hz, 1H), 4.56 - 4.51 (m, 1H), 4.36 (d,J
= 15.5 Hz, 1H), 4.30 (d,J
= 15.5 Hz, 1H), 3.35 - 3.25 (m, 1H), 3.15 - 3.05 (m, 1H), 2.4 - 2.55 (m, 2H), 0.97 (t,J
= 7.5 Hz, 3H)。
製備 14 : (S
)-2-(6-(2- 乙基 -5- 氟 -4- 羥苯基 )-1H
- 吲唑 -3- 基 )-5- 丙基 -4,5,6,7- 四氫 -3H
- 咪唑并 [4,5-c] 吡啶 -6- 甲酸
向(S
)-2-(6-(2-乙基-5-氟-4-羥苯基)-1H-吲唑-3-基)-4,5,6,7-四氫-3H-咪唑并[4,5-c]吡啶-6-甲酸,HCl (400 mg,0.874 mmol)及丙醛(0.095 mL,1.310 mmol)於DMF (7 mL)中之溶液中添加氰基硼氫化鈉(165 mg,2.62 mmol)且將反應混合物在室溫下攪拌隔夜。添加硼氫化鈉(33 mg,0.874 mmol),溶液經濃縮且藉由製備型HPLC純化,以得到標題化合物之TFA鹽(179 mg,37%產率)(m/z
):C25
H26
FN5
O3
之[M+H]+
計算值464.20,實驗值464.5。
製備 15 : (S
)-2-(6-(2- 乙基 -5- 氟 -4- 羥苯基 )-1H
- 吲唑 -3- 基 )-5- 異丙基 -4,5,6,7- 四氫 -3H
- 咪唑并 [4,5-c] 吡啶 -6- 甲酸
向(S
)-2-(6-(2-乙基-5-氟-4-羥苯基)-1H-吲唑-3-基)-4,5,6,7-四氫-3H
-咪唑并[4,5-c]吡啶-6-甲酸,HCl (400 mg,0.874 mmol)、丙酮(0.192 mL,2.62 mmol)及乙酸(0.150 mL,2.62 mmol)於DMF (7 mL)中之溶液中添加氰基硼氫化鈉(274 mg,4.37 mmol)且將反應混合物在室溫下攪拌隔夜。添加硼氫化鈉(33 mg,0.874 mmol),溶液經濃縮且藉由製備型HPLC純化,以得到標題化合物之TFA鹽(115 mg,23%產率)。(m/z
):C25
H26
FN5
O3
之[M+H]+
計算值464.20,實驗值464.5。
製備 16 : (S
)-2-(6-(2- 乙基 -5- 氟 -4- 羥苯基 )-1H
- 吲唑 -3- 基 )-5- 甲基 -4,5,6,7- 四氫 -3H
- 咪唑并 [4,5-c] 吡啶 -6- 甲酸
向(S
)-2-(6-(2-乙基-5-氟-4-羥苯基)-1H-吲唑-3-基)-4,5,6,7-四氫-3H
-咪唑并[4,5-c]吡啶-6-甲酸,HCl (8'
) (300 mg,0.655 mmol)及在水中37重量%之甲醛(0.059 mL,0.786 mmol) DMF (5 mL)中之溶液中添加氰基硼氫化鈉(165 mg,2.62 mmol)且將反應混合物在室溫下攪拌隔夜。添加硼氫化鈉(25 mg,0.655 mmol),溶液經濃縮且藉由急驟層析(100 g管柱,5-75% ACN/水)純化,以得到標題化合物之TFA鹽(85 mg,24%產率)。(m/z
):C23
H22
FN5
O3
之[M+H]+
計算值436.17,實驗值436.45。
實例 7 : (S
)-(2-(6-(2- 乙基 -5- 氟 -4- 羥苯基 )-1H
- 吲唑 -3- 基 )-5- 丙基 -4,5,6,7- 四氫 -3H
- 咪唑并 [4,5-c] 吡啶 -6- 基 )(4-(2- 羥乙基 ) 哌嗪 -1- 基 ) 甲酮 C-1
向(S
)-2-(6-(2-乙基-5-氟-4-羥苯基)-1H
-吲唑-3-基)-5-丙基-4,5,6,7-四氫-3H
-咪唑并[4,5-c]吡啶-6-甲酸,TFA (30 mg,0.052 mmol)、2-(哌嗪-1-基)乙醇,2HCl (0.19 mL,0.156 mmol)及DIPEA (0.027 mL,0.156 mmol)於DMF (1.5 mL)中之溶液中添加HATU (29.6 mg,0.078 mmol)且將反應混合物在室溫下攪拌隔夜。添加肼(5當量),反應混合物經濃縮且藉由製備型HPLC純化,以得到標題化合物之TFA鹽(15.4 mg,37%產率)。(m/z
):C31
H38
FN7
O3
之[M+H]+
計算值576.30,實驗值576.2。
實例 8 : ((S
)-2-(6-(2- 乙基 -5- 氟 -4- 羥苯基 )-1H
- 吲唑 -3- 基 )-5- 丙基 -4,5,6,7- 四氫 -3H
- 咪唑并 [4,5-c] 吡啶 -6- 基 )((1S
,4S
)-5- 甲基 -2,5- 二氮雜雙環 -[2.2.1] 庚 -2- 基 ) 甲酮 C-2
向(S
)-2-(6-(2-乙基-5-氟-4-羥苯基)-1H
-吲唑-3-基)-5-丙基-4,5,6,7-四氫-3H
-咪唑并[4,5-c]吡啶-6-甲酸,TFA (30 mg,0.052 mmol)、(1S
,4S
)-5-甲基-2,5-二氮雜雙環[2.2.1]庚烷二氫溴酸鹽(42.7 mg,0.156 mmol)及DIPEA (0.064 mL,0.364 mmol)於DMF (1.5 mL)中之溶液中添加HATU (29.6 mg,0.078 mmol)且將反應混合物在室溫下攪拌隔夜。添加肼(5當量),反應混合物經濃縮且藉由製備型HPLC純化,以得到標題化合物之TFA鹽(27 mg,66%產率)。(m/z
):C31
H36
FN7
O2
之[M+H]+
計算值558.29,實驗值558.3。1
H NMR (400 MHz, 甲醇-d 4
) δ 8.17 (dt, 1H), 7.59 - 7.50 (m, 1H), 7.32 (dd, 1H), 6.95 (d, 1H), 6.90 (d, 1H), 5.03 - 4.91 (m, 2H), 4.56 - 4.34 (m, 2H), 4.30 - 3.88 (m, 4H), 3.76 - 3.55 (m, 1H), 3.28 - 3.10 (m, 1H), 3.10 - 2.96 (m, 4H), 2.81 - 2.62 (m, 2H), 2.53 (q, 2H), 2.47 - 2.33 (m, 1H), 2.31 - 2.14 (m, 1H), 1.79 - 1.57 (m, 2H), 1.07 (t, 3H), 0.97 (td, 3H)。
實例
9
:
((S
)-2,4-
二甲基哌嗪
-1-
基
)((S
)-2-(6-(2-
乙基
-5-
氟
-4-
羥苯基
)-1H-
吲唑
-3-
基
)-5-
甲基
-4,5,6,7-
四氫
-3H-
咪唑并
[4,5-c]
吡啶
-6-
基
)
甲酮
C-3
(a) (S
)-4-((S
)-2-(6-(2-乙基-5-氟-4-羥苯基)-1H-吲唑-3-基)-5-甲基-4,5,6,7-四氫-3H-咪唑并[4,5-c]吡啶-6-羰基)-3-甲基哌嗪-1-甲酸第三丁酯
將(S
)-2-(6-(2-乙基-5-氟-4-羥苯基)-1H-吲唑-3-基)-5-甲基-4,5,6,7-四氫-3H-咪唑并[4,5-c]吡啶-6-甲酸(0.120 g,0.276 mmol)、(S
)-4-正-boc-2-甲基哌嗪(0.110 g,0.551 mmol)及DIPEA (0.096 mL,0.551 mmol)溶解於DMF (3.0 mL)中,接著添加HATU (0.157 g,0.413 mmol)且將反應混合物在室溫下攪拌16小時(藉由LCMS監測反應進展)。添加肼(0.043 mL,1.378 mmol)以裂解非所要副產物,接著將反應混合物在室溫下攪拌10分鐘。接著濃縮反應混合物且將粗產物藉由逆相層析(5-70% ACN/水梯度,50 g C18管柱)純化,以得到標題化合物之TFA鹽(126 mg,62%產率)。 (m/z):C33
H40
FN7
O4
之[M+H]+計算值618.32,實驗值618.3。
(b) ((S
)-2-(6-(2-乙基-5-氟-4-羥苯基)-1H-吲唑-3-基)-5-甲基-4,5,6,7-四氫-3H-咪唑并[4,5-c]吡啶-6-基)((S
)-2-甲基哌嗪-1-基)甲酮
將(S)-4-((S
)-2-(6-(2-乙基-5-氟-4-羥苯基)-1H-吲唑-3-基)-5-甲基-4,5,6,7-四氫-3H-咪唑并[4,5-c]吡啶-6-羰基)-3-甲基哌嗪-1-甲酸第三丁酯,TFA (0.126 g,0.172 mmol)溶解於二噁烷(1.5 mL)及水(0.3 mL)中,接著添加鹽酸(4 M於二噁烷中) (1.5 mL,49.4 mmol)且將反應混合物在室溫下攪拌1小時(藉由LCMS監測反應進展)。冷凍且凍乾反應混合物,且將所得粉末直接用於下一反應中(假定定量產率)。(m/z):C28
H32
FN7
O2
之[M+H]+計算值518.26,實驗值518.3。
(c) ((S
)-2,4-二甲基哌嗪-1-基)((S
)-2-(6-(2-乙基-5-氟-4-羥苯基)-1H-吲唑-3-基)-5-甲基-4,5,6,7-四氫-3H-咪唑并[4,5-c]吡啶-6-基)甲酮
將((S
)-2-(6-(2-乙基-5-氟-4-羥苯基)-1H-吲唑-3-基)-5-甲基-4,5,6,7-四氫-3H-咪唑并[4,5-c]吡啶-6-基)((S
)-2-甲基哌嗪-1-基)甲酮,二鹽酸鹽(0.102 g,0.173 mmol)及甲醛溶液(37 wt%於水中) (0.015 mL,0.207 mmol)溶解於甲醇(3.0 mL)中,接著添加氰基硼氫化鈉(0.054 g,0.864 mmol)且將反應混合物在室溫下攪拌20小時(藉由LCMS監測反應進展)。添加硼氫化鈉(7 mg,0.173 mmol)以淬滅任何剩餘的甲醛。濃縮反應混合物,接著將粗產物藉由製備型HPLC (5-60% ACN/水梯度,C18管柱)純化,以得到呈TFA鹽形式之標題化合物(59 mg,45%產率)。(m/z):C29
H34
FN7
O2
之[M+H]+計算值532.28,實驗值532.3。
實例 10 : (S
)-(2-(6-(2- 乙基 -5- 氟 -4- 羥苯基 )-1H
- 吲唑 -3- 基 )-5- 異丙基 -4,5,6,7- 四氫 -3H
- 咪唑并 [4,5-c] 吡啶 -6- 基 )(4- 甲基 -1,4- 二氮雜環庚 -1- 基 ) 甲酮 C-4
向(S
)-2-(6-(2-乙基-5-氟-4-羥苯基)-1H
-吲唑-3-基)-5異丙基-4,5,6,7-四氫-3H
-咪唑并[4,5-c]吡啶-6-甲酸,TFA (30 mg,0.052 mmol)、1-甲基高哌嗪(0.019 mL,0.156 mmol)及DIPEA (0.036 mL,0.208 mmol)於DMF (1 mL)中之溶液中添加HATU (29.6 mg,0.078 mmol)且將反應混合物在室溫下攪拌3 h。添加肼(5當量),將反應混合物在室溫下攪拌10 min,濃縮且藉由製備型HPLC純化,以得到標題化合物之TFA鹽(26.9 mg,66%產率)。(m/z
):C31
H38
FN7
O2
之[M+H]+
計算值560.31,實驗值560.2。
實例 11 : ((S
)-2-(6-(2- 乙基 -5- 氟 -4- 羥苯基 )-1H
- 吲唑 -3- 基 )-5- 甲基 -4,5,6,7- 四氫 -3H
- 咪唑并 [4,5-c] 吡啶 -6- 基 )((R
)-4-(2- 羥乙基 )-2- 甲基 - 哌嗪 -1- 基 ) 甲酮 C-5
向(S
)-2-(6-(2-乙基-5-氟-4-羥苯基)-1H
-吲唑-3-基)-5-甲基-4,5,6,7-四氫-3H
-咪唑并[4,5-c]吡啶-6-甲酸,TFA (30 mg,0.052 mmol)、(R
)-2-(3-甲基哌嗪-1-基)乙醇,2 HCl (35.6 mg,0.164 mmol)及DIPEA (0.057 mL,0.328 mmol)於DMF (1 mL)中之溶液中添加HATU (31.1 mg,0.082 mmol)且將反應混合物在室溫下攪拌隔夜。添加肼(8.57 µL,0.273 mmol),反應混合物經濃縮且藉由製備型HPLC純化,以得到標題化合物之TFA鹽(15.6 mg,36%產率)。(m/z
):C30
H36
FN7
O3
之[M+H]+
計算值562.29,實驗值562.2。
實例 12 : ((S
)-3-( 二甲胺基 ) 吡咯啶 -1- 基 )((S
)-5- 乙基 -2-(6-(2- 乙基 -5- 氟 -4- 羥苯基 )-1H
- 吲唑 -3- 基 )-4,5,6,7- 四氫 -3H
- 咪唑并 [4,5-c] 吡啶 -6- 基 ) 甲酮 C-6
向(S
)-2-(6-(2-乙基-5-氟-4-羥苯基)-1H
-吲唑-3-基)-5-異丙基-4,5,6,7-四氫-3H
-咪唑并[4,5-c]吡啶-6-甲酸,TFA (179 mg,0.310 mmol)、(S
)-N,N
-二甲基吡咯啶-3-胺(0.079 mL,0.620 mmol)及DIPEA (0.162 mL,0.930 mmol)於DMF (4 mL)中之溶液中添加HATU (177 mg,0.465 mmol)且將反應混合物在室溫下攪拌隔夜。添加肼(5當量),反應混合物經濃縮且藉由製備型HPLC純化,以得到標題化合物之TFA鹽(107 mg,44%產率)。 (m/z
):C31
H38
FN7
O2
之[M+H]+
計算值560.31,實驗值560.2。1
H NMR (400 MHz, 甲醇-d 4
) δ 8.21 (d, 1H), 7.50 (s, 1H), 7.26 (d, 1H), 6.94 (d, 1H), 6.90 (d, 1H), 4.83 - 4.66 (m, 1H), 4.48 - 4.25 (m, 2H), 4.23 - 4.12 (m, 1H), 4.12 - 3.93 (m, 2H), 3.93 - 3.63 (m, 3H), 3.62 - 3.48 (m, 1H), 3.26 - 3.09 (m, 1H), 2.98 (d, 6H), 2.67 - 2.57 (m, 1H), 2.53 (q, 2H), 2.44 - 2.12 (m, 1H), 1.41 (t, 3H), 1.31 (d, 3H), 1.05 (t, 3H)。
實例 13 : (S
)-(3-( 二甲胺基 ) 氮雜環丁 -1- 基 )(2-(6-(2- 乙基 -5- 氟 -4- 羥苯基 )-1H
- 吲唑 -3- 基 )-5- 異丙基 -4,5,6,7- 四氫 -3H
- 咪唑并 [4,5-c] 吡啶 -6- 基 ) 甲酮 D-1
向(S
)-2-(6-(2-乙基-5-氟-4-羥苯基)-1H-吲唑-3-基)-5-異丙基-4,5,6,7-四氫-3H
-咪唑并[4,5-c]吡啶-6-甲酸,TFA (179 mg,0.310 mmol)、N,N
-二甲基氮雜環丁-3-胺,2 HCl (107 mg,0.465 mmol)及DIPEA (0.162 mL,0.930 mmol)於DMF (4 mL)中之溶液中添加HATU (177 mg,0.465 mmol)且將反應混合物在室溫下攪拌隔夜。添加肼(5當量),濃縮反應混合物且藉由製備型HPLC純化,以得到標題化合物之TFA鹽(63 mg,26%產率)。(m/z
):C30
H36
FN7
O2
之[M+H]+
計算值546.29,實驗值546.7。1
H NMR (400 MHz, DMSO-d 6
) δ 9.90 (s, 1H), 8.29 (dd, 1H), 7.34 (s, 1H), 7.07 (d, 1H), 7.01 (d, 1H), 6.89 (d, 1H), 4.35 - 4.18 (m, 1H), 4.11 - 3.94 (m, 1H), 3.94 - 3.73 (m, 3H), 3.70 - 3.57 (m, 2H), 3.06 - 2.94 (m, 2H), 2.87 - 2.66 (m, 2H), 2.48 - 2.40 (m, 2H), 2.13 - 2.00 (m, 6H), 1.07 (t, 3H), 1.03 - 0.93 (m, 6H)。
生物分析
已在以下生物分析中之一或多者中表徵本發明之化合物。
分析 1 : 生物化學 JAK 激酶分析
將四種LanthaScreen JAK生物化學分析之組(JAK1、2、3及Tyk2)載於常見激酶反應緩衝液(50 mM HEPES,pH 7.5,0.01% Brij-35,10 mM MgCl2
及1 mM EGTA)中。自Life Technologies獲取重組型GST標記之JAK酶及GFP標記之STAT1肽受質。
在環境溫度下在白色384孔微量盤(Corning)中,使連續稀釋之化合物與四種JAK酶中之每一者及受質一起預培育1 h。隨後以具有1% DMSO之10 μL總體積添加ATP以起始激酶反應。JAK1、2、3及Tyk2之最終酶濃度分別為4.2 nM、0.1 nM、1 nM及0.25 nM;所使用之對應Km ATP濃度為25 μM、3 μM、1.6 μM及10 μM;而對於所有四種分析,受質濃度為200 nM。在添加EDTA (10 mM最終濃度)及Tb抗pSTAT1 (pTyr701)抗體(Life Technologies,2 nM最終濃度)於TR-FRET稀釋緩衝液(Life Technologies)中之10 μl製劑之前,使激酶反應在環境溫度下進行1小時。在EnVision讀取器(Perkin Elmer)上讀取之前,使盤在環境溫度下培育1 h。記錄且利用發射比信號(520 nm/495 nm),以基於DMSO及背景對照計算抑制百分比值。
對於劑量反應分析,對比化合物濃度來繪製抑制百分比資料,且用Prism軟體(GraphPad Software)根據4參數穩固擬合模型測定IC50
值。結果表示為pIC50
(IC50
之負對數),且接著使用Cheng-Prusoff方程式轉換成pKi
(解離常數Ki之負對數)。
在四種JAK分析之每一者中具有低Ki
值或高pKi
值的測試化合物展示對JAK活性之較大抑制。
分析 2 : Tall-1 T 細胞 中 IL-2 刺激之 pSTAT5 之 抑制
使用AlphaLisa在Tall-1人類T細胞株(DSMZ)中量測測試化合物抑制介白素-2 (IL-2)刺激之STAT5磷酸化的效能。因為IL-2經由JAK1/3傳導信號,因此此分析提供JAK1/3細胞效能之量測。
經由AlphaLISA SureFire Ultra pSTAT5 (Tyr694/699)套組(PerkinElmer)量測磷酸化STAT5。
將來自Tall-1細胞株之人類T細胞在37℃、5% CO2
含濕氣培育箱中在補充有15%熱滅活胎牛血清(FBS,Life Technologies)、2 mM Glutamax (Life Technologies)、25 mM HEPES (Life Technologies)及1× Pen/Strep (Life Technologies)之RPMI (Life Technologies)中培養。將化合物連續稀釋於DMSO中且以聲學方式分配至空的孔中。分配(4微升/孔)分析培養基(補充有10% FBS (ATCC)之不含酚紅之DMEM (Life Technologies))且使盤在900 rpm下振盪10分鐘。細胞以45,000個細胞/孔接種於分析培養基(4微升/孔)中且在37℃,5% CO2
下培育1小時,隨後添加含IL-2 (R&D Systems;最終濃度300 ng/mL)之預溫熱分析培養基(4 μL)持續30分鐘。在細胞介素刺激之後,細胞用6 μl含有1× PhosStop及Complete錠劑(Roche)之3× AlphaLisa Lysis Buffer (PerkinElmer)溶解。將溶解物在室溫(RT)下,在900 rpm下振盪10分鐘。經由pSTAT5 AlphaLisa套組(PerkinElmer)量測磷酸化STAT5。在過濾綠光之<100 lux光下,將新製備之受體珠粒混合物分配於溶解物(5 μL)上。使盤在900 rpm下振盪2分鐘,簡單地快速離心且在暗處在室溫下培育2小時。在過濾綠光之<100 lux光下,分配供體珠粒(5 μL)。使盤在900 rpm下振盪2分鐘,簡單地快速離心且在暗處在室溫下培育隔夜。在過濾綠光之<100 lux光下,使用EnVision盤讀取器(PerkinElmer)在689 nm激發及570 nm發射下量測發光。
為測定測試化合物回應於IL-2之抑制效能,在人類T細胞株中量測結合於pSTAT5之珠粒之平均發射強度。根據分析信號強度對比於化合物濃度之抑制曲線來測定IC50
值。資料表示為pIC50
(負十進制對數IC50
)值(平均值±標準差)。
活體外分析結果
表
1
實例編號 | JAK1 pKi | JAK2 pKi | JAK3 pKi | Tyk2 pKi | Tall-1 pIC50 |
1 | 10.2 | 10.3 | 9.8 | 9.0 | 8.8 |
C-1 | 10.2 | 10.5 | 9.7 | 9.1 | 8.7 |
2 | 10.3 | 10.2 | 9.8 | 8.9 | 8.4 |
C-2 | 10.3 | 10.8 | 9.9 | 9.5 | 8.6 |
3 | 10.2 | 10.4 | 10.2 | 9.3 | 8.8 |
C-3 | 10.2 | 10.5 | 9.7 | 9.3 | 8.7 |
4 | 10.1 | 10.4 | 10.1 | 9.0 | 8.6 |
C-4 | 10.0 | 10.6 | 9.8 | 9.3 | 8.7 |
5 | 10.3 | 10.5 | 10.1 | 9.2 | 8.8 |
C-5 | 10.1 | 10.7 | 9.9 | 9.5 | 8.6 |
6 | 10.2 | 10.4 | 10.0 | 9.0 | 8.7 |
C-6 | 10.2 | 10.7 | 9.8 | 9.3 | 8.6 |
分析 3 : 肺組織中 IL-13 誘導之 pSTAT6 誘導之鼠類 ( 小鼠 ) 模型
IL-13為哮喘之病理生理學潛在的重要細胞介素(Kudlacz等人Eur. J. Pharmacol
,2008
,582
,154-161)。IL-13與細胞表面受體結合,使激酶之傑納斯家族(JAK)之成員活化,其接著使STAT6磷酸化且隨後進一步活化轉錄路徑。在所描述模型中,將IL-13之劑量局部遞送至小鼠肺部中以誘導STAT6之磷酸化(pSTAT6),其接著量測為終點。
在分析中使用來自Harlan之成年Balb/c小鼠。在研究當天,用異氟醚輕度麻醉動物且經由經口抽吸投與媒劑或測試化合物(1 mg/mL,50 µL總體積,經若干次呼吸)。在給藥後,將動物側臥放置且在返回其飼養籠之前監測自麻醉之完整恢復。四小時後,再次簡單地麻醉動物且在監測自麻醉恢復及返回至其飼養籠之前,經由經口抽吸用媒劑或IL-13 (0.03 µg總遞送劑量,50 µL總體積)進行刺激。在投與媒劑或IL-13後一個小時,針對肺組織勻漿中之兩種pSTAT6偵測使用Perkin Elmer AlphaLISA®SureFire
®Ultra™ HV
p-STAT6 (Tyr641)分析套組且針對肺及血漿二者中之總藥物濃度分析收集全血及肺。使血液樣品在4℃下在約12,000 rpm下離心(Eppendorf離心機,5804R)持續4分鐘,以收集血漿。肺用杜氏磷酸鹽緩衝鹽水(Dulbecco's Phosphate-Buffered Saline;DPBS)沖洗,經填塞乾燥,急驟冷凍,稱重且以1:3之稀釋液於含0.1%甲酸之HPLC水中均質化。藉由LC-MS分析,對照在測試矩陣中構建成標準曲線之分析型標準品來測定測試化合物之血漿及肺水準。將肺與血漿比率測定為在5小時時肺濃度(以ng/g為單位)與血漿濃度(以ng/mL為單位)的比率。
藉由相比於經媒劑處理、IL-13刺激之對照動物,在5小時時存在於經處理動物之肺中的pSTAT6水準降低來證明模型中之活性。經媒劑處理、IL-13刺激之對照動物與經媒劑處理、媒劑刺激之對照動物之間的差異分別指示任何給定實驗中之0%及100%抑制作用。分析中所測試之化合物展現在如下文所記錄之IL-13刺激之後在5小時時STAT6磷酸化之抑制。表 2 : 所觀測之 pSTAT6 抑制及血漿 / 肺暴露
化合物 | 在 5小時時肺濃度 (ng/g) | 在 5小時時血漿濃度 (ng/mL) | 在 5 小時時肺與血漿比率 | 在 5 小時 時 pSTAT6 抑制 |
1 | 13000±5720 | 10.3±3.9 | 1262 | 67 |
2 | 23450±12528 | 17.5±25 | 1340 | 72 |
3 | 6330±1131 | 15.4±7 | 411 | 76 |
4 | 17350±6625 | 22.0±23 | 788 | 67 |
5 | 5445±1862 | 13.0±3.7 | 418 | 73 |
6 | 11600±4682 | 11.3±5.7 | 1026 | 37 |
小鼠肺中所測試化合物中之顯著濃度之觀測結果確認,IL-13誘導之pSTAT6誘導之所觀測抑制為測試化合物活性之結果。5小時時肺與血漿比率展示,化合物1至6在小鼠中展現肺中之暴露顯著比血漿中之暴露更多。
分析
4
:
人類周邊血液單核細胞中
TSLP
誘發之
TARC
釋放之抑制
胸腺基質淋巴生成素(TSLP)及胸腺及活化調節之趨化因子(TARC)在哮喘氣管中過度表現,且與疾病嚴重程度相關。在肺中,可藉由支氣管上皮細胞回應於過敏原及病毒感染來釋放TSLP。經由IL-7Rα/TSLPR雜二聚體之TSLP信號發現於廣泛範圍之組織及細胞類型中,包括上皮細胞、內皮細胞、嗜中性球、巨噬細胞及肥大細胞。TSLP與其受體之結合誘導了構形變化,其活化JAK1及JAK2以磷酸化多種轉錄因子,包括STAT3及STAT5。在免疫細胞中,此觸發細胞內事件之級聯,該等事件引起細胞增殖、抗細胞凋亡、樹突狀細胞遷移及Th2細胞介素及趨化因子之產生。在周邊血液單核細胞(peripheral blood mononuclear cell;PBMC)中,TSLP藉由活化骨髓樹突狀細胞以吸引且刺激T細胞(由化學引誘劑TARC介導之方法)而具有促炎性作用。
在此分析中,展示TSLP刺激誘導了自PBMC釋放TARC,且此反應在用化合物治療時以劑量依賴性方式衰減。針對TARC釋放之抑制量測測試化合物之效能。
將來自3至5個供體之PBMC等分試樣(預先自全血分離且在-80℃下冷凍成等分試樣)在37℃下解凍且逐滴添加至含40 mL預溫熱、無菌過濾、完整RPMI培養基之50 mL Falcon試管中。使細胞成球粒且以2.24×106
個細胞/毫升再懸浮於完全培養基中。細胞以85 μL (190,000個細胞)/孔接種於經組織培養物處理之96孔平底微量盤中。使細胞在37℃與5% CO2
下靜置1小時。
化合物作為DMSO中的10 mM儲備溶液接收。進行3.7倍連續稀釋,以產生於DMSO中的在300×最終分析測試濃度下的9種濃度之測試化合物。在完全培養基中進行150倍中間物稀釋,以產生在2×最終分析測試濃度(0.2% DMSO)下之化合物。在1小時靜置時間段之後,將95 μL之2×化合物添加至PBMC之各孔,最終分析濃度範圍為33.33 μM至0.95 μM。將95 μL的含0.2% DMSO之完全培養基添加至未經處理之對照孔。細胞在刺激之前在37℃與5% CO2
下用化合物預處理1小時。
將重組人類TSLP蛋白以10 μg/mL在具有0.1% BSA之無菌DPBS中復原且在-20℃下以等分試樣形式儲存。在使用之前立即將等分試樣解凍且在完全培養基中以20×最終分析濃度製備。將10 μL之20× TSLP添加至PBMC之各孔,最終分析濃度為10 ng/mL。將10 μL之完全培養基添加至未經刺激之對照孔。在37℃與5% CO2
下,在化合物存在下刺激細胞48小時。
在刺激後,使用人類CCL17/TARC Quantikine ELISA Kit (R&D Systems #DDN00)根據製造商之說明書,採集細胞培養上清液且藉由酶聯結免疫吸附分析(ELISA)偵測TARC水準。
對於劑量反應分析,相對於各供體之反應百分比值繪製對數[測試化合物(M)],且使用非線性回歸分析利用GraphPad Prism軟體,使用具有變數斜率之4參數S形劑量-反應演算法來測定IC50
值。資料表示為由個別供體之pIC50
值計算的平均pIC50
(負十進制對數IC50
)值且四捨五入至一個小數位。利用原始化合物及其消氟修飾之類似物的抑制之效能值概括於表3中。表 3 : 測試化合物抑制人類周邊血液單核細胞中 TSLP 誘發之 TARC 釋放的效能值
化合物 | pIC50± 標準差 |
1 | 7.1 ± 0.1 |
C-1 | 7.0 ± 0.3 |
2 | 6.8 ± 0.2 |
C-2 | 6.6 ± 0.2 |
3 | 7.3 ± 0.2 |
C-3 | 7.0 ± 0.1 |
4 | 6.8 ± 0.1 |
C-4 | 7.0 ± 0.4 |
5 | 7.5 ± 0.6 |
C-5 | 7.3 ± 0.1 |
6 | 6.8 ± 0.2 |
C-6 | 6.8 ± 0.2 |
分析 5 : 肺 S9 代謝
在人類肺S9片段(1 μM化合物;1 mg/mL S9蛋白)中評估化合物1至6及C-1至C-6之活體外代謝穩定性。針對親本化合物,藉由高解析度LC-MS/MS來分析時間0、15、30及60分鐘之樣品。來自人類之肺S9片段(批次1410245)購自XenoTech LLC (Lenexa, KS)。NADPH (Sigma Aldrich, N1630)及3-磷酸腺苷5-磷醯硫酸(PAPS) (Sigma Aldrich, A1651)購自Sigma Aldrich (St. Louis, MO)。乙腈及水獲自VWR (Radnor, PA)且具有HPLC級別或更佳級別。雷諾昔酚(Raloxifene)及甲酸購自Sigma Aldrich (St. Louis, MO)。在96孔聚丙烯盤中,在處於37℃下在水浴中執行肺S9培育。肺S9溶液由緩衝至pH 7.4 (BD Biosciences, Woburn, MA)的補充有1 mM NADPH (Sigma-Aldrich, St. Louis, MO)、3 mM氯化鎂(Sigma Aldrich, M1028)之100 mM磷酸鉀組成且在100 µM PAPS (Sigma-Aldrich, St. Louis, MO)輔因子存在下,具有1mg/mL之最終培育蛋白質濃度。將雷諾昔酚(n=1)及化合物(n=1)之10 mM DMSO儲備液稀釋於緩衝液中且外加至培育中,以得到1 µM受質濃度(0.001% DMSO v/v)。培育體積由400 µL組成且在0、15、30及60分鐘時藉由移除70 µL等分試樣並稀釋至140 µL乙腈(0%甲酸)中來獲取時間點。使所有樣品在5℃下在2250 g下離心10分鐘。自離心樣品獲取上清液(50 µL)且稀釋至含有內部標準物之100 µL HPLC水中。樣品在Dionex Ultimate 3000自動取樣器上操作且結合Atlantis T3管柱3 µM-2.1×50 mm (Waters Inc., 186003717)使用Thermo Q-Exactive High Resolution質譜儀(Thermo, Waltham, MA)以全掃描模式進行分析。流動相A由水+0.2%甲酸組成且流動相B由乙腈+0.2%甲酸組成。使用Gubbs GMSU軟體(Gubbs Inc., Alpharetta,GA)實行峰整合。對於各樣品,藉由將分析物峰面積除以內部標準物峰面積來計算峰面積比率。對於各培育,將各t0中之分析物之峰面積比率設定為100%,且將來自60分鐘樣品之峰面積比率相對於對應t0轉換成剩餘百分比。藉由觀測基於歷史內部資料,對應於各親本化合物之O-硫酸鹽代謝物的親本離子通道中的早期溶離峰來定性地進行硫酸鹽代謝物形成之測定。分析之結果概括於表4中(n=2次重複)。表 4 : 人類肺 S9 片段中之代謝穩定性
化合物 | 清除率(µL/min/mg) | 在60 min 時 化合物剩餘(%) | 硫酸鹽出現 |
1 | 4.2 | 78 | 是 |
C-1 | 20.8 | 29 | 是 |
2 | 3.5 | 81 | 是 |
C-2 | 61.0 | 3 | 是 |
3 | 2.6 | 86 | 是 |
C-3 | 33.2 | 14 | 是 |
4 | 2.1 | 88 | 是 |
C-4 | 53.4 | 4 | 是 |
5 | 3.7 | 80 | 是 |
C-5 | 42.2 | 8 | 是 |
6 | 3.4 | 82 | 是 |
C-6 | 51.4 | 5 | 是 |
當與其對應氟基類似物(化合物C-1
至C-6
)進行比較時,化合物1
至6
引起肺S9片段中之硫酸化代謝顯著減少。
分析 6 : 小鼠中血漿及肺中之藥物動力學
以下文方式測定測試化合物之血漿及肺濃度及其比率。在分析中使用來自Charles River Laboratories之BALB/c小鼠。在含20%丙二醇中之pH 4檸檬酸鹽緩衝液中以0.2 mg/mL之濃度單獨地調配測試化合物,且藉由經口抽吸將50 µL之給藥溶液引入至小鼠之氣管中。在給藥後之多個時間點(通常為0.167、2、6、24小時),經由心臟穿刺移除血液樣品,且自小鼠切除完整肺。使血液樣品在4℃下在約12,000 rpm下離心(Eppendorf離心機,5804R)持續4分鐘,以收集血漿。肺經填塞乾燥、稱重且以1:3之稀釋液於無菌水中均勻化。藉由LC-MS分析,對照在測試矩陣中構建成標準曲線之分析型標準品來測定測試化合物之血漿及肺濃度。將肺與血漿比率測定為肺AUC (以µg hr/g為單位)與血漿AUC (以µg hr/mL為單位)之比率,其中將AUC習知地定義為在測試化合物濃度對比於時間的曲線下面積。表 5 :單次經口抽吸投與測試化合物之後的血漿及肺組織暴露
化合物 | 血漿AUC(0-24) (µg hr/mL) | 肺組織 AUC(0-24) (µg hr/g) | 肺組織:血漿AUC比率 |
1 | 0.581 | 64.6 | 111 |
5 | 0.599 | 29.9 | 49.9 |
分析 7 : IL-5 介導之嗜酸性球存活率分析
在自人類全血(AllCells)分離之人類嗜酸性球中量測測試化合物對IL-5介導之嗜酸性球存活率的效能。因為IL-5經由JAK傳導信號,因此此分析提供JAK細胞效能之量測。
自健康供體之新鮮人類全血(AllCells)分離人類嗜酸性球。將血液與4.5%聚葡萄糖(Sigma-Aldrich)混合於0.9%氯化鈉溶液(Sigma-Aldrich)中。留下紅血球以沈降35分鐘。移除富含白血球之上部層且在Ficoll-Paque (GE Healthcare)上分層並在600 g下離心30分鐘。在用水溶解粒細胞層之前移除血漿及單核細胞層,以移除任何污染的紅血球。使用人類嗜酸性球分離套組(Miltenyi Biotec)進一步純化嗜酸性球。將一部分經純化嗜酸性球與抗CD16 FITC (Miltenyi Biotec)在暗處在4℃下一起培育10分鐘。使用LSRII流式細胞儀(BD Biosciences)分析純度。
將細胞在37℃,5% CO2
含濕氣培育箱中在補充有10%熱滅活胎牛血清(FBS,Life Technologies)、2 mM Glutamax (Life Technologies)、25 mM HEPES (Life Technologies)及1× Pen/Strep (Life Technologies)的RPMI 1640 (Life Technologies)中培養。將細胞以10,000個細胞/孔接種於培養基(50 µL)中。使盤在300 g下離心5分鐘且移除上清液。將化合物連續稀釋於DMSO中且接著在培養基中稀釋另外500倍,達至2×最終分析濃度。將測試化合物(50微升/孔)添加至細胞,且在37℃,5% CO2
下培育1小時,隨後添加含IL-5 (R&D Systems;最終濃度1 ng/mL及10 pg/mL)之預溫熱分析培養基(50 μL)持續72小時。
在細胞介素刺激之後,將細胞在300 g下離心5 min,且用冷DPBS (Life Technologies)洗滌兩次。為獲得存活力及細胞凋亡,將細胞與碘化丙錠(Thermo Fisher Scientific)及APC磷脂結合蛋白V (BD Biosciences)一起培育且使用LSRII流式細胞儀(BD Biosciences)進行分析。由分析細胞存活力%對比於化合物濃度的存活力曲線來測定IC50
值。資料表示為pIC50
(負十進制對數IC50
)值。
分析 8 : 人類 3D 氣管培養物中 IFNγ 及 IL-27 誘導之趨化因子 CXCL9 及 CXCL10 之 抑制
可自Mattek (AIR-100)獲取EpiAirway組織培養物。培養物來源於哮喘供體。在細胞培養插入物中,人類來源之氣管/支氣管上皮細胞在多孔膜載體上生長及分化,使得細胞下方的溫熱培養基與上述氣態測試氛圍具有氣液界面。在37℃,5% CO2
含濕氣培育箱中,在維持培養基(Mattek,AIR-100-MM)中培養組織。可測試四個供體。在第0天,用呈10 µM、1 µM及/或0.1 µM之測試化合物處理組織培養物。將化合物在二甲亞碸(DMSO,Sigma)中稀釋至0.1%之最終濃度。0.1% DMSO可用作媒劑對照。將測試化合物與培養物在37℃,5% CO2
下培育1小時,隨後添加最終濃度為100 ng/mL的含有IFNγ (R&D Systems)或IL-27 (R&D Systems)之預溫熱培養基。將組織培養物維持8天。將培養基每2天用含有化合物及IFNγ或IL-27之新鮮培養基置換。在第8天,收集組織培養物及上清液以用於分析。針對CXCL10 (IP-10)及CXCL9 (MIG),使用流式螢光偵測術分析(EMD Millipore)分析上清液樣品。資料表示為抑制%+/-標準差(±STDV)。與經媒劑處理之細胞相比,利用化合物對IFNγ或IL-27誘導之CXCL10或CXCL9分泌的抑制效能來測定抑制百分比。資料為來自3或4個供體之平均值。
分析 9 : 細胞 JAK 效能分析 : 抑制人類 PBMC 中 IL-2/ 抗 CD3 刺激之 IFNγ
可在自人類全血(Stanford Blood Center)分離之人類周邊血液單核細胞(PBMC)中量測測試化合物抑制介白素-2 (IL-2)/抗CD3刺激之干擾素γ (IFNγ)的效能。因為IL-2經由JAK傳導信號,因此此分析提供JAK細胞效能之量測。
(1) 使用菲科爾(ficoll)梯度自健康供體之人類全血分離人類周邊血液單核細胞(PBMC)。將細胞在37℃,5% CO2
含濕氣培育箱中在補充有10%熱滅活胎牛血清(FBS,Life Technologies)、2 mM Glutamax (Life Technologies)、25 mM HEPES (Life Technologies)及1× Pen/Strep (Life Technologies)的RPMI (Life Technologies)中培養。將細胞以200,000個細胞/孔接種於培養基(50 µL)中且培養1小時。將化合物連續稀釋於DMSO中且接著在培養基中稀釋另外500倍(達至2×最終分析濃度)。將測試化合物(100微升/孔)添加至細胞,且在37℃,5% CO2
下培育1 h,隨後添加含IL-2 (R&D Systems;最終濃度100 ng/mL)及抗CD3 (BD Biosciences;最終濃度1 μg/mL)之預溫熱分析培養基(50 μL)持續24 h。
(2) 在細胞介素刺激之後,使細胞在500 g下離心5 min且移除上清液並在-80℃下冷凍。為測定測試化合物回應於IL-2/抗CD3之抑制效能,經由ELISA (R&D Systems)量測上清液IFNγ濃度。根據IFNγ濃度對比於化合物濃度的抑制曲線之分析來測定IC50
值。資料表示為pIC50
(負十進制對數IC50
)值。
分析 10 : 細胞 JAK 效能分析 : CD4+ T 細胞 中 IL-2 刺激之 pSTAT5 之 抑制
使用流式細胞量測術,在自人類全血(Stanford Blood Center)分離之人類周邊血液單核細胞(PBMC)中的CD4陽性(CD4+) T細胞中量測測試化合物抑制介白素-2 (IL-2)/抗CD3刺激之STAT5磷酸化的效能。因為IL-2經由JAK傳導信號,因此此分析提供JAK細胞效能之量測。
使用藻紅素(PE)結合之抗CD4抗體(純系RPA-T4,BD Biosciences)鑑別CD4+ T細胞,而Alexa Fluor 647結合之抗pSTAT5抗體(pY694,純系47,BD Biosciences)用於偵測STAT5磷酸化。
(1) 遵循分析9段落(1)之方案,不同之處在於用抗CD3進行細胞介素刺激持續30 min而非24 h。
(2) 在細胞介素刺激之後,將細胞用預溫熱之固定溶液(200 µL;BD Biosciences)在37℃,5% CO2
下固定10 min,用DPBS緩衝液(1 mL,Life Technologies)洗滌兩次,且在4℃下再懸浮於冰冷的Perm Buffer III (1000 µL,BD Biosciences)中持續30 min。細胞用含2% FBS之DPBS (FACS緩衝液)洗滌兩次,且接著在室溫下在暗處再懸浮於含有抗CD4 PE (1:50倍稀釋)及抗CD3 Alexa Fluor 647 (1:5倍稀釋)之FACS緩衝液(100 μL)中持續60 min。培育之後,在使用LSRII流式細胞儀(BD Biosciences)分析之前將細胞用FACS緩衝液洗滌兩次。為測定測試化合物回應於IL-2/抗CD3之抑制效能,在CD4+ T細胞中量測pSTAT5之中位螢光強度(median fluorescent intensity;MFI)。根據MFI對比於化合物濃度的抑制曲線之分析來測定IC50
值。資料表示為pIC50
(負十進制對數IC50
)值。
分析 11 : 細胞 JAK 效能分析 : CD3+ T 細胞中 IL-4 刺激之 pSTAT6 之 抑制
使用流式細胞量測術,在自人類全血(Stanford Blood Center)分離之人類周邊血液單核細胞(PBMC)中的CD3陽性(CD3+) T細胞中量測測試化合物抑制介白素-4 (IL-4)刺激之STAT6磷酸化的效能。因為IL-4經由JAK傳導信號,因此此分析提供JAK細胞效能之量測。
使用藻紅素(PE)結合之抗CD3抗體(純系UCHT1,BD Biosciences)鑑別CD3+ T細胞,而Alexa Fluor 647結合之抗pSTAT6抗體(pY641,純系18/P,BD Biosciences)用於偵測STAT6磷酸化。
如分析9及10中自健康供體之人類全血分離人類周邊血液單核細胞(PBMC)。將細胞以250,000個細胞/孔接種於培養基(200 µL)中,培養1 h且接著再懸浮於含有各種濃度之測試化合物的分析培養基(50 µL) (補充有0.1%牛血清白蛋白(Sigma)、2 mM Glutamax、25 mM HEPES及1× Penstrep之RPMI)中。將化合物連續稀釋於DMSO中且接著在分析培養基中稀釋另外500倍(達至2×最終分析濃度)。將測試化合物(50 μL)與細胞在37℃,5% CO2
下培育1 h,隨後在預溫熱之分析培養基中添加IL-4 (50 μL) (R&D Systems;最終濃度20 ng/mL)持續30 min。在細胞介素刺激之後,將細胞用預溫熱之固定溶液(100 μL) (BD Biosciences)在37℃,5% CO2
下固定10 min,用DPBS緩衝液(1 mL) (含2% FBS之DPBS)洗滌兩次,且在4℃下再懸浮於冰冷的Perm Buffer III (1000 µL) (BD Biosciences)中持續30 min。細胞用FACS緩衝液洗滌兩次,且接著在室溫下在暗處再懸浮於含有抗CD3 PE (1:50稀釋)及抗pSTAT6 Alexa Fluor 647 (1:5稀釋)之FACS緩衝液(100 μL)中持續60 min。 培育之後,在使用LSRII流式細胞儀(BD Biosciences)分析之前將細胞用FACS緩衝液洗滌兩次。
為測定測試化合物回應於IL-4之抑制效能,在CD3+ T細胞中量測pSTAT6之中位螢光強度(MFI)。根據MFI對比於化合物濃度的抑制曲線之分析來測定IC50
值。資料表示為pIC50
(負十進制對數IC50
)。
分析 12 : 細胞 JAK 效能分析 : CD3+ T 細胞中 IL-6 刺激之 pSTAT3 之 抑制
使用類似於分析11之方案來測定測試化合物抑制介白素-6 (IL-6)刺激之STAT3磷酸化的效能。Alexa Fluor 647結合之抗pSTAT3抗體(pY705,純系4/P,BD Biosciences)用於偵測STAT3磷酸化。
分析 13 : 肺之交鏈孢屬赤星病菌 (Alternaria alternata
) 誘導之嗜酸性球性發炎的小鼠模型
氣管嗜酸性球增多症為人類哮喘之標誌。交鏈孢屬赤星病菌為可加重人類哮喘且誘導小鼠之肺中之嗜酸性球性發炎的真菌氣源性過敏原(Havaux等人Clin Exp Immunol
.2005
年2月;139(2):179-88)。在小鼠中,已證實,交鏈孢屬間接地活化肺中之組織固有2型先天性淋巴細胞,其作出反應(例如,IL-2及IL-7)且釋放JAK依賴性細胞介素(例如,IL-5及IL-13)且調和嗜酸性球性發炎(Bartemes等人J Immunol
.2012
年2月1日;188(3):1503-13)。
在研究中使用來自Taconic之七至九週齡雄性C57小鼠。在研究當天,用異氟醚輕度麻醉動物且經由口咽抽吸投與媒劑或測試化合物(0.03-1.0 mg/mL,50 μL總體積,經若干次呼吸)。在給藥後,將動物側臥放置且在返回其飼養籠之前監測自麻醉之完整恢復。一個小時後,再次簡單麻醉動物且在監測自麻醉恢復及返回至其飼養籠之前,經由口咽抽吸用媒劑或交鏈孢屬萃取物(200 μg總遞送萃取物,50 μL總體積)進行刺激。在交鏈孢屬投與後四十八小時,收集支氣管肺泡灌洗液(bronchoalveolar lavage fluid;BALF)且在BALF中使用Advia 120 Hematology系統(Siemens)計數嗜酸性球。與經媒劑處理、交鏈孢屬刺激之對照動物相比,在四十八小時時存在於經處理動物之BALF中的嗜酸性球水準降低證明該模型中之活性。資料表示為經媒劑處理、交鏈孢屬刺激之BALF嗜酸性球反應之抑制百分比。為計算抑制百分比,將各條件之BALF嗜酸性球的數目轉換成平均經媒劑處理、交鏈孢屬刺激之BALF嗜酸性球之百分比且減去一百百分比。
分析 14 : 細胞 JAK 效能分析 : 抑制 IFNγ 誘導之 pSTAT1
使用流式細胞量測術,在自人類全血(Stanford Blood Center)衍生之CD14陽性(CD14+)單核球中量測測試化合物抑制干擾素γ (IFNγ)刺激之STAT1磷酸化的效能。因為IFNγ經由JAK傳導信號,因此此分析提供JAK細胞效能之量測。
使用異硫氰酸螢光素(fluorescein isothiocyanate;FITC)結合之抗CD14抗體(純系RM052,Beckman Coulter)鑑別單核球,且Alexa Fluor 647結合之抗pSTAT1抗體(pY701,純系4a,BD Biosciences)用於偵測STAT1磷酸化。
使用菲科爾梯度自健康供體之人類全血分離人類周邊血液單核細胞(PBMC)。將細胞在37℃,5% CO2
含濕氣培育箱中在補充有10%胎牛血清(FBS,Life Technologies)、2 mM Glutamax (Life Technologies)、25 mM HEPES (Life Technologies)及1× Pen/Strep (Life Technologies)的RPMI (Life Technologies)中培養。將細胞以250,000個細胞/孔接種於培養基(200 µL)中,培養2 h且再懸浮於含有各種濃度之測試化合物的分析培養基(50 μL) (補充有0.1%牛血清白蛋白(Sigma)、2 mM Glutamax、25 mM HEPES及1× Penstrep之RPMI)中。將化合物連續稀釋於DMSO中且接著在培養基中稀釋另外1000倍,以使得最終DMSO濃度達0.1%。將測試化合物稀釋液與細胞在37℃,5% CO2
下培育1 h,隨後以0.6 ng/mL之最終濃度添加含預溫熱的IFNγ (R&D Systems)之培養基(50 µL)持續30 min。在細胞介素刺激之後,將細胞用預溫熱的固定溶液(100 µL) (BD Biosciences)在37℃,5% CO2
下固定10 min,用FACS緩衝液(1 mL) (含1% BSA之PBS)洗滌兩次,再懸浮於1:10抗CD14 FITC:FACS緩衝液(100 µL)中,且在4℃下培育15 min。將細胞洗滌一次,且接著在4℃下再懸浮於冰冷的Perm Buffer III (BD Biosciences) (100 µL)中持續30 min。細胞用FACS緩衝液洗滌兩次,且接著在室溫下在暗處再懸浮於1:10抗pSTAT1 Alexa Fluor 647:FACS緩衝液(100 µL)中持續30 min,用FACS緩衝液洗滌兩次,且使用MACSQuant流式細胞儀(Miltenyi)分析。
為測定測試化合物之抑制效能,在CD14+單核球中量測pSTAT1之中位螢光強度(MFI)。根據MFI對比於化合物濃度的抑制曲線之分析來測定IC50
值。資料表示為pIC50
(負十進制對數IC50
)值。化合物1
在此分析中展現7.5之pIC50
值。化合物4
在此分析中展現7.3之pIC50
值。
分析 15 : 細胞 JAK 效能分析 : GM-CSF 誘導之 pSTAT5 之 抑制
使用流式細胞量測術,在自人類全血(Stanford Blood Center)衍生之CD14陽性(CD14+)單核球中量測測試化合物抑制粒細胞-巨噬細胞群落刺激因子(GM-CSF)刺激之STAT5磷酸化的效能。因為GM-CSF經由JAK傳導信號,因此此分析提供JAK細胞效能之量測。
使用異硫氰酸螢光素(FITC)結合之抗CD14抗體(純系RM052,Beckman Coulter)鑑別單核球,且Alexa Fluor 647結合之抗pSTAT5抗體(pY694,BD Biosciences)用於偵測STAT5磷酸化。
使用菲科爾梯度自健康供體之人類全血分離人類周邊血液單核細胞(PBMC)。將細胞在37℃,5% CO2
含濕氣培育箱中在補充有10%胎牛血清(FBS,Life Technologies)、2 mM Glutamax (Life Technologies)、25 mM HEPES (Life Technologies)及1× Pen/Strep (Life Technologies)的RPMI (Life Technologies)中培養。將細胞以250,000個細胞/孔接種於培養基(200 µL)中,培養2 h且再懸浮於含有各種濃度之測試化合物的分析培養基(50 µL) (補充有0.1%牛血清白蛋白(Sigma)、2 mM Glutamax、25 mM HEPES及1× Penstrep之RPMI)中。將化合物連續稀釋於DMSO中且接著在培養基中稀釋另外1000倍,以使得最終DMSO濃度達0.1%。將測試化合物稀釋液與細胞在37℃,5% CO2
下培育1 h,隨後以0.3 ng/mL之最終濃度添加含預溫熱的GM-CSF (R&D Systems)之培養基(50 µL)持續15 min。在細胞介素刺激之後,將細胞用預溫熱的固定溶液(100 µL) (BD Biosciences)在37℃,5% CO2
下固定10 min,用FACS緩衝液(1 mL) (含1% BSA之PBS)洗滌兩次,再懸浮於1:10抗CD14 FITC:FACS緩衝液(100 µL)中,且在4℃下培育15 min。將細胞洗滌一次,且接著在4℃下再懸浮於冰冷的Perm Buffer III (BD Biosciences) (100 µL)中持續30 min。細胞用FACS緩衝液洗滌兩次,且接著在室溫下在暗處再懸浮於1:10抗pSTAT1 Alexa Fluor 647:FACS緩衝液(100 µL)中持續30 min,用FACS緩衝液洗滌兩次,且使用MACSQuant流式細胞儀(Miltenyi)分析。
為測定測試化合物之抑制效能,在CD14+單核球中量測pSTAT5之中位螢光強度(MFI)。根據MFI對比於化合物濃度的抑制曲線之分析來測定IC50
值。資料表示為pIC50
(負十進制對數IC50
)值。化合物1
在此分析中展現6.7之pIC50
值。化合物4
在此分析中展現6.7之pIC50
值。
分析 16 : 細胞 JAK 效能分析 : IL-12 誘導之 pSTAT4 之 抑制
使用流式細胞量測術,在自人類全血(Stanford Blood Center)衍生之CD3陽性(CD3+) T細胞中量測測試化合物抑制介白素-12 (IL-12)刺激之STAT4磷酸化的效能。因為IL-12經由JAK傳導信號,因此此分析提供JAK細胞效能之量測。
使用藻紅素(PE)結合之抗CD3抗體(純系UCHT1,BD Biosciences)鑑別CD3+ T細胞,且Alexa Fluor 647結合之抗pSTAT4抗體(純系38/p-Stat4,BD Biosciences)用於偵測STAT4磷酸化。
使用菲科爾梯度自健康供體之人類全血分離人類周邊血液單核細胞(PBMC)。將細胞在37℃,5% CO2
含濕氣培育箱中在補充有10%胎牛血清(FBS,Life Technologies)、2 mM Glutamax (Life Technologies)、25 mM HEPES (Life Technologies)、1× Pen/Strep (Life Technologies)、盤結合之經純化抗CD3抗體(5 µg/ml,純系UCHT1,BD Biosciences)及可溶的抗CD28抗體(1 µg/ml,純系CD28.2,BD Biosciences)的RPMI (Life Technologies)中培養3天。細胞經採集,用培養基洗滌且接著再懸浮於含有介白素-2 (IL-2,10 ng/ml,R&D Systems)之培養基中。將細胞在37℃,5% CO2
含濕氣培育箱中培養3天。細胞經採集,用RPMI洗滌且以250,000個細胞/孔接種於培養基(200 μL)中,培養2 h並再懸浮於含有各種濃度之測試化合物的分析培養基(50 µL) (補充有0.1%牛血清白蛋白(Sigma)、2 mM Glutamax、25 mM HEPES及1× Penstrep之RPMI)中。將化合物連續稀釋於DMSO中且接著在培養基中稀釋另外1000倍,以使得最終DMSO濃度達0.1%。將測試化合物稀釋液與細胞在37℃,5% CO2
下一起培育1 h,隨後以10 ng/mL之最終濃度添加含預溫熱的IL-12 (R&D Systems)之培養基(50 µL)持續30 min。在細胞介素刺激之後,將細胞用預溫熱的固定溶液(100 µL) (BD Biosciences)在37℃,5% CO2
下固定10 min,用FACS緩衝液(1 mL) (含1% BSA之PBS)洗滌兩次,且在4℃下再懸浮於冰冷的Perm Buffer III (1000 μL) (BD Biosciences)中持續30 min。細胞用FACS緩衝液洗滌兩次,且接著在室溫下在暗處再懸浮於含有抗CD3 PE (1:50倍稀釋)及抗pSTAT4 Alexa Fluor 647 (1:10倍稀釋)的FACS緩衝液(100 μL)中持續45 min。在培育之後,在使用MACSQuant流式細胞儀(Miltenyi)分析之前將細胞用FACS緩衝液洗滌兩次。為測定測試化合物之抑制效能,在CD3+ T細胞中量測pSTAT4之中位螢光強度(MFI)。根據MFI對比於化合物濃度的抑制曲線之分析來測定IC50
值。資料表示為pIC50
(負十進制對數IC50
)值。化合物1
在此分析中展現6.2之pIC50
值。化合物4
在此分析中展現6.0之pIC50
值。
晶體結構
以2.28 Å之解析度獲得與人類JAK1結合的化合物D-1
之共晶體結構。觀測到配位體結合於ATP結合位點中。基於供體與受體原子之間的3.5 Å或更小之距離鑑別出七個特異性氫鍵相互作用。尤其應注意,在D-1
之化合物之環外醯胺之羰基與JAK1之Arg879之側鏈之間鑑別出氫鍵相互作用。可針對本發明之化合物預期類似相互作用。在早期建模研究中,已提出此相互作用作為提供對JAK1優於其他酪胺酸激酶之選擇性的方式,因為另外密切相關之激酶(例如,TRKA、VEGFR、ABL1)在同等位置處不具有精胺酸殘基。晶體結構中氫鍵相互作用之觀測結果及經改良激酶組選擇性與不具有環外醯胺之系列相比驗證了此設計假設。
雖然本發明已參考其特定態樣或實施例進行描述,但一般熟習此項技術者應瞭解,可進行各種變化或可取代等效物,而不偏離本發明之真實精神及範疇。此外,在由適用之專利狀況及法規允許之程度上,本文中所引用之所有公開案、專利及專利申請案以全文引用之方式併入本文中,該引用之程度如同將各文件單獨地以引用之方式併入本文中一般。
Claims (32)
- 如請求項2之化合物或其醫藥學上可接受之鹽,其中R1選自由以下組成之群:甲基、丙基及異丙基。
- 如請求項2之化合物或其醫藥學上可接受之鹽,其中A選自由以下組成之群:哌嗪基、2,5-二氮雜雙環[2.2.1]庚基及1,4-二氮雜環庚基,其中之每一者經1或2個R2基團取代,其中各R2獨立地為視情況經-OH取代的C1-3烷基,或A為經NR3R4取代之吡咯啶基,其中R3為C1-3烷基且R4為C1-3烷基。
- 一種醫藥組合物,其包含如請求項1至11中任一項之化合物或其醫藥學上可接受之鹽,及醫藥學上可接受之載劑。
- 如請求項1至11中任一項之化合物或其醫藥學上可接受之鹽,其用於治療哺乳動物中之呼吸道疾病。
- 如請求項13之化合物或其醫藥學上可接受之鹽,其中該呼吸道疾病選自由以下組成之群:哮喘、慢性阻塞性肺病、囊腫性纖維化、肺炎、特發性肺纖維化、急性肺損傷、急性呼吸窘迫症候群、支氣管炎、氣腫、阻塞性細支氣管炎、類肉瘤病、嗜酸性球性疾病、蠕蟲感染、肺動脈高血壓、肺淋巴管平滑肌增生症、支氣管擴張症、浸潤性肺病、藥物誘導之肺炎、真菌誘導之肺炎、過敏性支氣管肺麯黴病、過敏性肺炎、伴隨多血管炎之嗜酸性球性肉芽腫、特發性急性嗜酸性球性肺炎、特發性慢性嗜酸性球性肺炎、嗜伊紅白血球增多症候群、呂弗勒症候群(Löffler syndrome)、阻塞性細支氣管炎伴有機化肺炎、肺移植物抗宿主病及免疫檢查點抑制劑誘導之肺炎。
- 如請求項14之化合物或其醫藥學上可接受之鹽,其中該呼吸道疾病為急性肺損傷。
- 如請求項14之化合物或其醫藥學上可接受之鹽,其中該呼吸道疾病為急性呼吸窘迫症候群。
- 如請求項13之化合物或其醫藥學上可接受之鹽,其中該呼吸道疾病為哮喘或慢性阻塞性肺病。
- 如請求項1至11中任一項之化合物或其醫藥學上可接受之鹽,其用於治療哺乳動物中之肺移植排斥反應。
- 如請求項18之化合物或其醫藥學上可接受之鹽,其中該肺移植排斥反應選自由以下組成之群:原發性移植物功能障礙、機化性肺炎、急性排斥反應、淋巴球性細支氣管炎及慢性肺同種異體移植物功能障礙。
- 如請求項18之化合物或其醫藥學上可接受之鹽,其中該肺移植排斥反應為急性肺移植排斥反應。
- 如請求項18之化合物或其醫藥學上可接受之鹽,其中該肺移植排斥反應為慢性肺同種異體移植物功能障礙。
- 如請求項18之化合物或其醫藥學上可接受之鹽,其中該肺移植排斥反應選自由以下組成之群:阻塞性細支氣管炎、限制性慢性肺同種異體移植物功能障礙及嗜中性球性同種異體移植物功能障礙。
- 一種如請求項1至11中任一項之化合物或其醫藥學上可接受之鹽之用途,其用於製造用於治療哺乳動物之呼吸道疾病的藥物。
- 如請求項23之用途,其中該呼吸道疾病選自由以下組成之群:哮喘、慢性阻塞性肺病、囊腫性纖維化、肺炎、特發性肺纖維化、急性肺損傷、急性呼吸窘迫症候群、支氣管炎、氣腫、阻塞性細支氣管炎、類肉瘤病、嗜酸性球性疾病、蠕蟲感染、肺動脈高血壓、肺淋巴管平滑肌增生症、支氣管擴張症、浸潤性肺病、藥物誘導之肺炎、真菌誘導之肺炎、過敏性支氣管肺麯黴病、過敏性肺炎、伴隨多血管炎之嗜酸性球性肉芽腫、特發性急性嗜酸性球性肺炎、特發性慢性嗜酸性球性肺炎、嗜伊紅白血球增多症候群、呂弗勒氏症候群、阻塞性細支氣管炎伴有機化肺炎、肺移植物抗宿主病及免疫檢查點抑制劑誘導之肺炎。
- 如請求項24之用途,其中該呼吸道疾病為急性肺損傷。
- 如請求項24之用途,其中該呼吸道疾病為急性呼吸窘迫症候群。
- 如請求項23之用途,其中該呼吸道疾病為哮喘或慢性阻塞性肺病。
- 一種如請求項1至11中任一項之化合物或其醫藥學上可接受之鹽之用途,其用於製造用於治療哺乳動物之肺移植排斥反應的藥物。
- 如請求項28之用途,其中該肺移植排斥反應選自由以下組成之群:原發性移植物功能障礙、機化性肺炎、急性排斥反應、淋巴球性細支氣管炎及慢性肺同種異體移植物功能障礙。
- 如請求項28之用途,其中該肺移植排斥反應為急性肺移植排斥反應。
- 如請求項28之用途,其中該肺移植排斥反應為慢性肺同種異體移植物功能障礙。
- 如請求項28之用途,其中該肺移植排斥反應選自由以下組成之群:阻塞性細支氣管炎、限制性慢性肺同種異體移植物功能障礙及嗜中性球性同種異體移植物功能障礙。
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JP7383696B2 (ja) | 2023-11-20 |
TW202024075A (zh) | 2020-07-01 |
AR116114A1 (es) | 2021-03-31 |
EP3837010B1 (en) | 2023-07-05 |
US20210024517A1 (en) | 2021-01-28 |
EA202190686A1 (ru) | 2021-07-23 |
ES2955717T3 (es) | 2023-12-05 |
UA127328C2 (uk) | 2023-07-19 |
BR112021004063A2 (pt) | 2021-05-25 |
EP3837010A1 (en) | 2021-06-23 |
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