TW202309015A - 作為trpa1抑制劑之尿嘧啶衍生物 - Google Patents
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/08—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing alicyclic rings
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- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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Abstract
本揭示內容提供某些尿嘧啶衍生物,其係瞬態受體電位錨蛋白1 (TRPA1)抑制劑且因此可用於治療可藉由抑制TRPA1治療之疾病。亦提供含有其之醫藥組合物及製備該等化合物之方法。
Description
本揭示內容提供某些尿嘧啶衍生物,其係瞬態受體電位錨蛋白1 (TRPA1)抑制劑且因此可用於治療可藉由抑制TRPA1治療之疾病。亦提供含有其之醫藥組合物及製備該等化合物之方法。
瞬態受體電位通道(TRP通道)係主要位於許多哺乳動物細胞類型之質膜上之一組電壓閘控離子通道。存在大約30種結構相關之TRP通道,其分為以下群組:TRPA、TRPC、TRPM、TRPML、TRPN、TRPP及TRPV。瞬態受體電位陽離子通道亞家族A成員1 (TRPA1) (亦稱為瞬態受體電位錨蛋白1)係TRPA基因亞家族之唯一成員。在結構上,TRPA通道之特徵在於多個N-末端錨蛋白重複(在人類TRPA1之N-末端中約14個),此產生錨蛋白名稱之「A」 (Montell, 2005)。
TRPA1高度表現於服務於皮膚及肺二者之背根及結節神經節中之感覺神經元之質膜中、以及小腸、結腸、胰臟、骨骼肌、心臟、腦、膀胱及淋巴球中(https://www.proteinatlas.org/)以及人類肺纖維母細胞中。
TRPA1係最著名的環境刺激物之感測器,引起諸如疼痛、寒冷及瘙癢等體感覺樣式。TRPA1係由許多反應性、親電刺激物(例如,異硫氰酸烯丙酯、活性含氧物)以及非反應性化合物(例如冰素(icilin))激活,其涉及與氣喘、慢性肺阻塞性疾病(COPD)、特發性肺纖維化(IPF)或病毒後咳嗽相關之咳嗽或慢性特發性咳嗽以及敏感患者之咳嗽。(Song及Chang, 2015;Grace及Belvisi, 2011)。TRPA1抑制劑可用於治療IPF,其中基於顯示咳嗽引起TGF-β升高之研究,由於咳嗽與肺損傷之間之聯繫,咳嗽在IPF中非常普遍(Xie等人,2009;Froese等人,2016;Tschumperlin等人,2003;Yamamoto等人,2002;Ahamed等人,2008)。SARS-Cov-2感染導致之急性肺損傷至少部分地經由活性含氧物(ROS)介導。ROS係TRPA1之直接活化劑。此外,經由食用辛辣食物使TRPA1去敏被認為調節Nrf2路徑並減少氧化壓力(Bousquet等人,2020, Bousquet等人,2021)。因此,TRPA1抑制劑在治療新冠病毒(Covid-19)/SARS-Cov-2引起之肺損傷方面具有潛力。TRPA1拮抗劑抑制由咳嗽觸發因素(例如香煙煙霧提取物(CSE)氧化應激、發炎介質釋放及抗氧化基因表現下調)觸發之鈣信號傳導(Lin等人,2015;Wang等人,2019)。TRPA1拮抗劑在異位性皮膚炎(Oh等人,2013;Wilson等人,2013)、接觸性皮膚炎(Liu等人,2013)、牛皮癬相關之瘙癢(Wilson等人,2013)及IL-31依賴性瘙癢(Cevikbas等人,2014)之研究中係有效的。人類TRPA1功能獲得與家族性陣發性疼痛症候群相關聯(Kremeyer等人,2010)。TRPA1拮抗劑在偏頭痛相關之觸摸痛之行為模型中係有效的(Edelmayer等人,2012)。與TRPA1在支配健康牙齒之三叉神經節中之表現相比,TRPA1在支配受損牙齒之三叉神經節中之表現選擇性地增加(Haas等人,2011)。已知幾種麻醉劑係TRPA1激動劑,包括異氟醚(Matta等人,2008),此為TRPA1抑制劑緩解術後疼痛提供理論基礎。TRPA1剔除之小鼠及利用TRPA1拮抗劑治療之野生型小鼠顯示抗焦慮及抗抑鬱樣表型(de Moura等人,2014)。基於顯示AMPK與TRPA1之間反向調節之機制聯繫之研究,TRPA1抑制劑預期在治療糖尿病神經病變中具有益處(Hiyama等人,2018;Koivisto及Pertovaara, 2013;Wang等人,2018)。TRPA1剔除小鼠與野生型小鼠相比展現較小之心肌梗塞大小(Conklin等人,2019)。TRPA1剔除及藥理學介入抑制小鼠中TNBS引發之結腸炎(Engel等人,2011)。在小鼠腦缺血模型中,TRPA1剔除及TRPA1拮抗劑減少髓鞘損傷(Hamilton等人,2016)。在痛風之尿酸單鈉小鼠模型中,尿酸鹽晶體及關節發炎在TRPA1剔除小鼠中減少(Moilanen等人,2015)。大鼠中之TRPA1缺失在急性痛風發作之大鼠模型中改善關節發炎及痛覺過敏(Trevisan等人,2014)。TRPA1之激活引發在骨關節炎軟骨細胞中引發發炎反應(Nummenmaa等人,2016)。TRPA1抑制及基因缺失減少骨關節炎小鼠軟骨細胞及鼠類軟骨中之發炎介質(Nummenmaa等人,2016)。最後,TRPA1剔除小鼠在MIA誘發之膝腫脹模型中展現骨關節炎肢體之負重改良(Horvath等人,2016)。TRPA1差異表現於膀胱出口阻塞之大鼠的膀胱上皮(Du等人,2007)及患者的膀胱上皮(Du等人,2008)中。TRPA1受體調節減弱脊髓損傷之大鼠模型中之膀胱過度活動(Andrade等人,2011)且鞘內投與TRPA1拮抗劑減弱患有反射過度排尿之大鼠中環磷醯胺引發之膀胱炎(Chen等人,2016)。
因此期望提供強效TRPA1抑制劑。
各種結構類型之TRPA1抑制劑綜述於S. Skerratt, Progress in Medicinal Chemistry, 2017, 第56卷, 81-115及D. Preti、G. Saponaro、A. Szallasi, Pharm. Pat. Anal. (2015) 4 (2), 75-94及H. Chen, Transient receptor potential ankyrin 1 (TRPA1) antagonists: a patent review (2015-2019), Expert Opin Ther Pat., 2020中。
本發明揭示新穎尿嘧啶衍生物,其係瞬態受體電位錨蛋白1 (TRPA1)之抑制劑,具有適當藥理學及藥物動力學性質,使其能夠作為藥劑用於治療可藉由抑制TRPA1治療之病況及/或疾病。
本發明化合物可提供若干優點,例如增強之功效、高代謝及/或化學穩定性、高選擇性、安全性及耐受性、增強之溶解性、增強之滲透性、期望之血漿蛋白結合、增強之生物利用度、適宜藥物動力學曲線及形成穩定鹽之可能性。
本發明之化合物本發明提供尿嘧啶衍生物,其係TRPA1之令人驚訝的強效抑制劑(分析A),其特徵進一步在於
- 在人類肝微粒體中經改良之穩定性(分析B)
- 在人類肝細胞中經改良之穩定性(分析C)。
本發明化合物在結構上不同於WO2017/060488中之實例
53、
72、
73、
86及
90以及L. Schenkel等人,J. Med. Chem. 2016, 59, 2794-2809中之實例
31,此乃因其含有經取代尿嘧啶核心以及毗鄰第二脂肪族醇之取代基。該等結構差異意外地導致以下之有利組合:(i) TRPA1之抑制,(ii) 在人類肝微粒體中之穩定性,及(iii) 在人類肝細胞中之穩定性。
在人類肝微粒體中之穩定性係指在選擇及/或設計具有有利藥物動力學性質之藥物作為第一篩選步驟之情景中化合物對生物轉化之敏感性。許多藥物之主要代謝部位係肝臟。人類肝微粒體含有細胞色素P450 (CYP),且因此代表用於研究活體外I期藥物代謝之模型系統。在人類肝微粒體中之增強穩定性與若干優點相關聯,包括增加之生物利用度及足夠半衰期,此可使能夠降低及減少患者之頻繁投藥。因此,在人類肝微粒體中之增強穩定性係欲用於藥物之化合物的有利特徵。因此,除能夠抑制TRPA1以外,本發明化合物預期具有有利之活體內清除率且因此在人類中之期望作用持續時間。
在人類肝細胞中之穩定性係指在選擇及/或設計具有有利藥物動力學性質之藥物之情景中化合物對生物轉化之敏感性。許多藥物之主要代謝部位係肝臟。人類肝細胞含有細胞色素P450 (CYP)及其他藥物代謝酶,且因此代表用於研究活體外藥物代謝之模型系統。(重要的是,與肝微粒體分析相比,肝細胞分析亦涵蓋II期生物轉化以及肝特異性運輸蛋白介導之過程,且因此代表用於藥物代謝研究之更完整系統)。在人類肝細胞中之增強穩定性與若干優點相關聯,包括增加之生物利用度及足夠半衰期,此可使能夠降低及減少患者之頻繁投藥。因此,在人類肝細胞中之增強穩定性係欲用於藥物之化合物的有利特徵。
本發明之另一實施例係關於式(I)化合物,其中A選自由以下組成之群:苯基、噻吩基、苯并呋喃基及苯并噻吩基,且其中A未經取代或經由F、Cl、I及CH
3組成之基團R
1之一或兩個成員取代。
本發明之另一實施例係關於式(I)化合物,其中A選自由以下組成之群:苯基、苯并呋喃基及苯并噻吩基,且其中A未經取代或經由鹵素及C
1-4-烷基組成之基團R
1之一或兩個成員取代。
本發明之另一實施例係關於式(I)化合物,其中A選自由以下組成之群:苯基、苯并呋喃基及苯并噻吩基,且其中A未經取代或經由F、Cl、I及CH
3組成之基團R
1之一或兩個成員取代。
所用術語及定義本文中未明確定義之術語應給予熟習此項技術者根據揭示內容及上下文會給予之含義。然而,除非指定相反含義,否則如說明書中所用之以下術語具有所指示含義且遵守以下慣例。
在下文所定義之基團(group)、基團(radical)或部分中,碳原子數通常在基團之前指明,例如C
1-6烷基意指具有1至6個碳原子之烷基。通常在諸如HO、H
2N、(O)S、(O)
2S、NC (氰基)、HOOC、F
3C或諸如此類之基團中,熟習此項技術者可自基團本身之自由價看出至分子之基團附著點。對於包含兩個或以上子基團之組合基團,最後命名之子基團係基團附接點,例如取代基「芳基-C
1-3-烷基-」意指鍵結至C
1-3-烷基-基團之芳基,該C
1-3-烷基-基團鍵結至核心或該取代基所附接之基團。
在本發明化合物係以化學名稱形式描述或描述為化學式之情形中,在出現任何不一致時,以化學式為準。可在子式中使用星號來指示如所定義連接至核心分子之鍵。
取代基之原子編號始於距離核心或取代基所附接之基團最近之原子。
舉例而言,術語「3-羧基丙基-基團」代表以下取代基:
其中羧基附接至丙基之第三個碳原子。術語「1-甲基丙基-」、「2,2-二甲基丙基-」或「環丙基甲基-」基團代表以下基團:
可在子式中使用星號來指示如所定義連接至核心分子之鍵。
單獨或與另一基團組合之術語「C
1-n-烷基」(其中n係選自2、3、4或5之整數)表示具有1至n個C原子之非環狀、飽和、具支鏈或直鏈烴基團。舉例而言,術語C
1-5-烷基包括基團H
3C-、H
3C-CH
2-、H
3C-CH
2-CH
2-、H
3C-CH(CH
3)-、H
3C-CH
2-CH
2-CH
2-、H
3C-CH
2-CH(CH
3)-、H
3C-CH(CH
3)-CH
2-、H
3C-C(CH
3)
2-、H
3C-CH
2-CH
2-CH
2-CH
2-、H
3C-CH
2-CH
2-CH(CH
3)-、H
3C-CH
2-CH(CH
3)-CH
2-、H
3C-CH(CH
3)-CH
2-CH
2-、H
3C-CH
2-C(CH
3)
2-、H
3C-C(CH
3)
2-CH
2-、H
3C-CH(CH
3)-CH(CH
3)-及H
3C-CH
2-CH(CH
2CH
3)-。
添加至「烷基」、「伸烷基」或「環烷基」(飽和或不飽和)之術語「氟」係指其中一或多個氫原子經氟原子取代之烷基或環烷基。實例包括(但不限於):H
2FC-、HF
2C-及F
3C-。
如本文所用,術語「經取代」意指所指定原子上之任一或多個氫經來自所指示基團之選擇置換,前提係不超過所指示原子之正常化合價,且該取代產生穩定化合物。
除非明確指示,否則在整個說明書及隨附申請專利範圍中,給定化學式或名稱應涵蓋互變異構物及所有立體、光學及幾何異構物(例如鏡像異構物、非鏡像異構物、E/Z異構物等)及其外消旋物,以及不同比例之單獨鏡像異構物之混合物、非鏡像異構物之混合物或前述任一形式之混合物(倘若存在該等異構物及鏡像異構物),以及其鹽(包括醫藥上可接受之鹽)及其溶劑合物,例如水合物,包括游離化合物之溶劑合物或該化合物之鹽之溶劑合物。
一般而言,實質上純之立體異構物可根據熟習此項技術者已知之合成原理獲得,例如藉由分離相應混合物、藉由使用立體化學純之起始材料及/或藉由立體選擇性合成。業內已知如何製備光學活性形式,例如藉由拆分外消旋形式或藉由例如自光學活性起始材料開始來合成及/或藉由使用手性試劑。
本發明之鏡像異構純化合物或中間體可經由不對稱合成來製備,例如藉由製備及隨後分離可藉由已知方法(例如藉由層析分離或結晶)分離之適當非鏡像異構化合物或中間體及/或藉由手性試劑,例如手性起始材料、手性觸媒或手性助劑。
此外,熟習此項技術者已知如何自相應外消旋混合物製備鏡像異構純化合物,例如藉由相應外消旋混合物在手性固定相上之層析分離;或藉由外消旋混合物使用適當拆分劑之拆分,例如藉助外消旋化合物與光學活性酸或鹼之非鏡像異構鹽形成、鹽之隨後拆分及自鹽釋放期望化合物;或藉由利用光學活性手性輔助試劑衍生相應外消旋化合物、隨後非鏡像異構物分離及去除手性輔助基團;或藉由外消旋物之動力學拆分(例如藉由酶拆分);藉由在適宜條件下自鏡像晶體之聚集體進行鏡像選擇性結晶;或藉由在光學活性手性助劑之存在下自適宜溶劑(部分)結晶。
本文採用片語「醫藥上可接受」以指在合理的醫學判斷範圍內適於使用而沒有過度毒性、刺激、過敏反應或其他問題或併發症並與合理的益處/風險比相稱之彼等化合物、材料、組合物及/或劑型。
如本文所用,「醫藥上可接受之鹽」係指所揭示化合物之衍生物,其中母體化合物與酸或鹼形成鹽或錯合物。
與含有鹼性部分之母體化合物形成醫藥上可接受之鹽之酸的實例包括無機酸或有機酸,例如苯磺酸、苯甲酸、檸檬酸、乙磺酸、富馬酸、龍膽酸、氫溴酸、鹽酸、馬來酸、蘋果酸、丙二酸、苦杏仁酸、甲磺酸、4-甲基-苯磺酸、磷酸、柳酸、琥珀酸、硫酸及酒石酸。
與含有酸性部分之母體化合物形成醫藥上可接受之鹽之陽離子及鹼之實例包括Na
+、K
+、Ca
2+、Mg
2+、NH
4 +、L-精胺酸、2,2’-亞胺基雙乙醇、L-離胺酸、N-甲基-D-葡萄糖胺或參(羥基甲基)-胺基甲烷。本發明之醫藥上可接受之鹽可藉由習用化學方法自含有鹼性或酸性部分之母體化合物合成。通常,該等鹽可藉由使該等化合物之游離酸或鹼形式與足量之適當鹼或酸於水或有機稀釋劑(例如乙醚、乙酸乙酯、乙醇、異丙醇或乙腈(或其混合物))中進行反應來製得。
除上述之彼等以外可例如用於純化或分離本發明化合物之其他酸之鹽(例如三氟乙酸鹽)亦構成本發明之一部分。
生物學分析 TRPA1 活性之評估 分析 A : TRPA1 分析本發明化合物之活性可使用以下活體外TRPA1細胞分析來證實:
方法:
使用過表現人類TRPA1離子通道之人類HEK293細胞系(Perkin Elmer, 產品號AX-004-PCL)作為化合物效能及功效之測試系統。化合物活性係藉由在FLIPRtetra系統(Molecular Devices)中量測化合物對AITC (異硫氰酸烯丙酯)促效作用誘導之細胞內鈣濃度之效應來確定。
細胞培養:
細胞係在冷凍小瓶中以冷凍細胞獲得並在-150℃下儲存直至使用。
使細胞在培養基(具有10% FCS及0.4 mg/ML建那黴素(Geneticin)之MEM/EBSS培養基)中生長。重要的是密度不超過90%鋪滿。為進行傳代培養,藉由Versene將細胞自燒瓶分離。在分析前一天,將細胞分離,用培養基(具有10% FCS之MEM/EBSS培養基)洗滌兩次,並將20000個細胞以20 µl/孔接種於來自Corning之聚D-離胺酸生物塗佈之384孔板(黑色,透明底,Cat. 356697)。在用於分析之前,將板在37℃/5% CO2下培育24小時。
化合物製備
將測試化合物以10 mM之濃度溶解於100% DMSO中,且在第一步驟中於DMSO中稀釋至5 mM之濃度,隨後在100% DMSO中進行連續稀釋步驟。稀釋因子及稀釋步驟之數量可根據需要而變。通常以1:5稀釋度製備8個不同濃度,使用HBSS/HEPES緩衝液(來自Gibco之1xHEPES, Cat.14065,來自SIGMA之20 mM HEPES, Cat. 83264,來自Invitrogen之0.1% BSA Cat.11926, pH 7.4)實施物質之其他中間稀釋度(1:20)。
FLIPR分析:
在分析日,細胞用分析緩衝液洗滌3次,洗滌後20 µL緩衝液留在孔中。將於HBSS/HEPES中之10 µL Ca6套組(Cat.R8191 MolecularDevices)加載緩衝液添加至細胞中,並將板在37℃/5% CO2下加蓋培育120分鐘。將來自中間稀釋板之於HBSS/HEPES緩衝液/5% DMSO中之10 μL化合物或對照小心地添加至孔中。在FLIPRtetra裝置上讀取發光(指示鈣流入或釋放)達10分鐘,以監測化合物誘導之效應(例如促效作用)。最後,將溶於HBSS/HEPES緩衝液/0.05% DMSO中之10 µL激動劑AITC 50 µM (最終濃度為10 µM)添加至孔,隨後在FLIPRtetra裝置上額外讀取10分鐘。使用AITC添加後之信號曲線下面積(AUC)用於IC50 / %抑制計算。
數據評估及計算:
每一分析微量滴定板均含有具有媒劑(1% DMSO)對照代替化合物之孔作為用於AITC誘導發光之對照(100 %CTL;高對照)以及具有媒劑對照而無AITC之孔作為用於非特異性發光變化之對照(0 %CTL;低對照)。
數據分析係藉由計算個別孔之信號曲線下面積來實施。基於此值,使用MegaLab軟體(內部開發)計算針對每一物質濃度量測之%值(AUC(試樣) - AUC(低))*100/(AUC(高) - AUC(低))。IC50值係使用MegaLab軟體自%對照值計算。計算:[y=(a-d)/(1+(x/c)^b)+d], a = 低值, d = 高值;x = 濃度M;c=IC50 M;b = 希爾(hill)斜率;y = % ctrl
表1:分析A中所獲得本發明化合物之生物數據
表2:分析A中所獲得先前技術化合物(WO2017/060488中之實例
53 、 72 、 73 、 86 、 90)之生物數據.
表3:分析A中所獲得先前技術化合物(L. Schenkel等人,J. Med. Chem. 2016, 59, 2794-2809中之實例
31)之生物數據.
實例 | hTRPA1 IC 50 [nM] |
1 | 38 |
2 | 6 |
3 | 8 |
4 | 15 |
5 | 33 |
6 | 57 |
7 | 84 |
WO2017/060488中之實例 | hTRPA1 IC 50 [nM] |
53 | 36 |
72 | 14 |
73 | 28 |
86 | 67 |
90 | 41 |
Med. Chem. 2016, 59, 2794-2809中之實例 | hTRPA1 IC 50 [nM] |
31 | 52 |
評估微粒體清除率 分析 B : 微粒體清除率 :測試化合物之代謝降解係在37℃下利用彙集之肝微粒體進行分析。每時間點之100 µl最終培育體積含有在RT下pH 7.6之TRIS緩衝液(0.1 M)、氯化鎂(5 mM)、微粒體蛋白質(1 mg/ml)及最終濃度為1 µM之測試化合物。
在37℃下之短預培育時期後,反應藉由添加經還原形式之β-菸鹼醯胺腺嘌呤二核苷酸磷酸(NADPH, 1 mM)起始,並在不同時間點(0、5、15、30、60 min)後藉由將等份試樣轉移至溶劑中來終止。另外,在沒有NADPH之培育中監測NADPH非依賴性降解,在最後一個時間點終止。NADPH獨立培育後之[%]剩餘測試化合物係由參數c(對照) (代謝穩定性)反映。將驟冷之培育物藉由離心(10000 g, 5 min)製成丸粒。
藉由LC-MS/MS分析上清液等份試樣之母體化合物之量。半衰期(t1/2 INVITRO)係藉由濃度-時間曲線之半對數曲線圖之斜率確定。
固有清除率(CL_INTRINSIC)係藉由考慮培育中蛋白質之量來計算:
CL_INTRINSIC [µl/min/mg蛋白質] = (Ln 2 / (半衰期[min] * 蛋白質含量[mg/ml])) * 1000
CL_INTRINSIC_INVIVO [ml/min/kg] = (CL_INTRINSIC [µL/min/mg蛋白質] x MPPGL [mg蛋白質/g 肝] x肝因子[g/kg體重]) / 1000
Qh [%] = (CL [ml/min/kg] /肝血流量[ml/min/kg])
肝細胞性,人類:120x10e6個細胞/ g肝
肝因子,人類:25.7 g / kg體重
血流量,人類:21 ml/(min x kg)
表4:分析B中所獲得本發明化合物之生物數據
表5:分析B中所獲得先前技術化合物(WO2017/060488中之實例
53 、 72 、 73 、 86 、 90)之生物數據.
表6:分析B中所獲得先前技術化合物(L. Schenkel等人,J. Med. Chem. 2016, 59, 2794-2809中之實例
31)之生物數據.
實例 | 人類LM [%Qh] |
1 | <23 |
2 | <23 |
3 | 43 |
4 | <23 |
5 | <23 |
6 | 24 |
7 | <23 |
WO2017/060488中之實例 | 人類LM [%Qh] |
53 | <23 |
72 | 30 |
73 | 38 |
86 | <23 |
90 | 39 |
Med. Chem. 2016, 59, 2794-2809中之實例 | 人類LM [%Qh] |
31 | <23 |
評估肝細胞清除率 分析 C :肝細胞清除率在肝細胞懸浮液中分析測試化合物之代謝降解。將肝細胞(冷凍保存)在含有5%物種血清之達爾伯克改良伊格爾培養基(Dulbecco´s modified eagle medium) (補充有3.5 µg升糖素/500mL、2.5 mg胰島素/500mL及3.75 mg氫化可體松/500mL)中培育。
在培育器(37℃, 10% CO2)中30 min預培育之後,將5 µl測試化合物溶液(80 µM;自2mM於DMSO中之原液利用培養基1:25稀釋)添加至395 µl肝細胞懸浮液(端視物種,細胞密度在0.25-5百萬個細胞/mL之範圍內,通常1百萬個細胞/mL;測試化合物之最終濃度為1 µM,最終DMSO濃度為0.05%)。
將細胞培育六小時(培育器、定軌振盪器)並在0、0.5、1、2、4及6小時時採集試樣(25µl)。將試樣轉移至乙腈中並藉由離心(5 min)製成丸粒。將上清液轉移至新的96深孔板,在氮下蒸發並重新懸浮。
藉由HPLC-MS/MS分析母體化合物之減少。
CLint係如下計算:CL_INTRINSIC = 劑量 / AUC = (C0/CD) / (AUD + clast/k) × 1000/60。C0:培育中之初始濃度[µM],CD:活細胞之細胞密度[10e6個細胞/mL],AUD:數據下面積[µM x h],clast:最後一個數據點之濃度[µM],k:母體減少之回歸線斜率[h-1]。
所計算之活體外肝固有清除率可放大至固有活體內肝清除率並藉由使用肝臟模型(充分攪拌模型)用於預測肝活體內血液清除率(CL)。
CL_INTRINSIC_INVIVO [ml/min/kg] = (CL_INTRINSIC [µL/min/10e6個細胞] x 肝細胞性[10e6個細胞/g 肝] x肝因子[g/kg體重]) / 1000
CL [ml/min/kg] = CL_INTRINSIC_INVIVO [ml/min/kg] x肝血流量[ml/min/kg] / (CL_INTRINSIC_INVIVO [ml/min/kg] +肝血流量[ml/min/kg])
Qh [%] = (CL [ml/min/kg] /肝血流量[ml/min/kg])
肝細胞性,人類:120x10e6個細胞/ g肝
肝因子,人類:25.7 g / kg體重
血流量,人類:21 ml/(min x kg)
表7:分析C中所獲得本發明化合物之生物數據
表8:分析C中所獲得先前技術化合物(WO2017/060488中之實例
53 、 72 、 73 、 86 、 90)之生物數據.
表9:分析C中所獲得先前技術化合物(L. Schenkel等人,J. Med. Chem. 2016, 59, 2794-2809中之實例
31)之生物數據.
實例 | 人類肝細胞[%Qh] |
1 | 15 |
2 | 24 |
3 | 17 |
4 | 21 |
5 | 15 |
6 | 17 |
7 | 8 |
WO2017/060488中之實例 | 人類肝細胞[%Qh] |
53 | 25 |
72 | 50 |
73 | 36 |
86 | 12 |
90 | 61 |
Med. Chem. 2016, 59, 2794-2809中之實例 | 人類肝細胞[%Qh] |
31 | 73 |
評估滲透性將Caco-2細胞(1 - 2 × 10
5個細胞/1 cm
2面積)接種於過濾器插入物(Costar transwell聚碳酸酯或PET過濾器, 0.4 μm孔徑)並培養(DMEM) 10至25天。
將化合物溶解於適當溶劑(如DMSO, 1 - 20 mM原液)中。原液用HTP-4緩衝液(128.13 mM NaCl、5.36 mM KCl、1 mM MgSO
4、1.8 mM CaCl
2、4.17 mM NaHCO
3、1.19 mM Na
2HPO
4x 7H
2O、0.41 mM NaH
2PO
4xH
2O、15 mM HEPES、20 mM葡萄糖、0.25% BSA, pH 7.2)稀釋,以製備輸送溶液(0.1 - 300 μM化合物,最終DMSO <= 0.5 %)。輸送溶液(TL)分別施加至頂端或底側供給側用於量測A-B或B-A滲透性(3個過濾器重複)。試樣係在實驗開始及結束時自供給處收集且亦自接收側以不同時間間隔收集長達2小時,用於藉由HPLC-MS/MS或閃爍計數進行濃度量測。所採樣之接收體積由新鮮接收溶液取代。
評估血漿蛋白結合使用此平衡透析(ED)技術測定測試化合物與血漿蛋白之活體外分數結合之近似值。使用Dianorm鐵氟龍(Teflon)透析細胞(micro 0.2)。每一單元由供體及受體腔室組成,該等腔室由具有5 kDa分子量截止值之超薄半滲透膜隔開。每一測試化合物之原液係在DMSO中以1 mM製備並稀釋至1.0 μM之最終濃度。隨後之透析溶液係於來自雄性及雌性供體之彙集人類或大鼠血漿(具有NaEDTA)中製備。將200 μL透析緩衝液(100 mM磷酸鉀, pH 7.4)之等份試樣分配於緩衝液腔室中。將200 μL測試化合物透析溶液之等份試樣分配於血漿腔室中。培育在旋轉下在37℃下實施2小時。
在透析時期結束時,將透析液轉移至反應管中。緩衝液餾分之管中含有0.2 mL ACN/水(80/20)。將25 μL血漿透析液之等份試樣轉移至深孔板中並與25 μL ACN/水(80/20)、25 μL緩衝液、25 μL校正溶液及25 μL內標準品溶液混合。藉由添加200 μL ACN實施蛋白質沈澱。將50 μL緩衝液透析液之等份試樣轉移至深孔板中並與25 μL空白血漿、25 μL內標準品溶液及200 μL ACN混合。試樣在HPLC-MS/MS系統上進行量測並利用Analyst軟體進行評估。結合百分比係利用以下方程式計算:結合% = (血漿濃度-緩衝液濃度/血漿濃度) × 100。
評估溶解性飽和溶液係在孔板(格式取決於機器人)中藉由將適當體積之所選水性介質(通常在0.25 - 1.5 ml範圍內)添加至每一孔來製備,每一孔中含有已知數量之固體原料藥(通常在0.5 - 5.0 mg範圍內)。將孔振盪或攪拌預定時間段(通常在2 - 24 h之範圍內)且然後使用適當過濾膜(通常具有0.45 µm孔徑之PTFE過濾器)過濾。藉由丟棄最初幾滴濾液來避免過濾器吸收。所溶解原料藥之量係藉由UV光譜測定。此外,使用玻璃電極pH計量測飽和水溶液之pH。
評估藥物動力學特徵將測試化合物經靜脈內或經口投與給各別測試物種。在施加測試化合物後之幾個時間點採集血液試樣,抗凝並離心。
對血漿試樣中分析物(即,所投與化合物及/或代謝物)之濃度進行定量。PK參數係使用非房室法計算。AUC及Cmax正規化至1 μmol/kg之劑量。
活體外評估在人類肝細胞中之代謝使用懸浮液中之原代人類肝細胞研究測試化合物之代謝途徑。自冷凍保存恢復後,將人類肝細胞在含有5%人類血清且補充有3.5 µg升糖素/500ml、2.5 mg胰島素/500 ml及3.75 mg氫化可體松/500 ml之達爾伯克改良伊格爾培養基中培育。
在細胞培養培育器(37℃, 10% CO
2)中30 min預培育之後,將測試化合物溶液摻加於肝細胞懸浮液中以獲得1.0*10
6至4.0*10
6個細胞/ml之最終細胞密度(取決於利用原代人類肝細胞觀察之化合物的代謝轉換速率)、10 µM之最終測試化合物濃度及0.05%之最終DMSO濃度。
將細胞在細胞培養培育器中在水平振盪器上培育六小時,並在0、0.5、1、2、4或6小時後自培育取試樣,此取決於代謝轉換速率。試樣用乙腈驟冷並藉由離心製成丸粒。將上清液轉移至96深孔板,在氮下蒸發並重新懸浮,然後藉由液相層析-高解析度質譜進行生物分析以鑑別推定代謝物。
結構係基於傳立葉變換(Fourier-Transform)-MS
n數據臨時指派。代謝物報告為人類肝細胞培育中母體之百分比,其中臨限值≥ 4%。
治療方法本發明係關於通式1之化合物,其可用於預防及/或治療與TRPA1活性相關或藉由TRPA1活性調節之疾病及/或病況,包括(但不限於)治療及/或預防纖維變性疾病、發炎及免疫調節病症、呼吸道或胃腸疾病或病苦、眼科疾病、關節之發炎性疾病及鼻咽、眼睛及皮膚之發炎性疾病及疼痛及神經病症。該等病症、疾病及病苦包括咳嗽、特發性肺纖維化、其他肺間質性疾病及其他纖維變性、氣喘或過敏性疾病、嗜酸性球疾病、慢性阻塞性肺病、以及發炎及免疫調節病症(例如類風濕性關節炎及動脈粥樣硬化)、以及疼痛及神經病症(例如急性疼痛、手術疼痛、慢性疼痛及抑鬱症)及膀胱病症。
通式1之化合物可用於預防及/或治療以下各項:
(1) 咳嗽,例如慢性特發性咳嗽或慢性難治性咳嗽、與氣喘、COPD、肺癌、病毒感染後及特發性肺纖維化及其他肺間質性疾病相關之咳嗽。
(2) 肺纖維變性疾病,例如肺炎或與膠原變性相關之間質性肺炎,例如紅斑狼瘡、全身性硬皮症、類風濕性關節炎、多發性肌炎及皮肌炎、特發性間質性肺炎,例如特發性肺纖維化(IPF)、非特異性間質性肺炎、呼吸性細支氣管炎伴間質性肺病、脫屑性間質性肺炎、隱源性機化性肺炎、急性間質性肺炎及淋巴球性間質性肺炎、淋巴管平滑肌瘤病、肺泡蛋白質沉著症、蘭格罕細胞組織球增生症(Langerhan’s cell histiocytosis)、胸膜實質彈性纖維增生、已知病因之間質性肺病,例如由於職業暴露導致之間質性肺炎,例如石棉肺、矽肺病、礦工肺(煤塵)、農夫肺(乾草及黴菌)、鴿友肺(鳥類)或其他職業性空中浮游觸發因素(例如金屬粉塵或分枝桿菌),或由治療(例如輻射、胺甲喋呤(methotrexate)、胺碘達隆(amiodarone)、呋喃妥因(nitrofurantoin)或化學治療劑)導致之間質性肺炎,或肉芽腫疾病,例如肉芽腫性多發性血管炎、查-施二氏症候群(Churg-Strauss syndrome)、類肉瘤病、過敏性肺炎或由不同病因造成之間質性肺炎(例如誤吸、吸入有毒氣體、蒸氣,支氣管炎或肺炎或由心臟衰竭、X-射線、輻射、化學療法、M. boeck症或類肉瘤病、肉芽腫病、囊性纖維化或膠稠性黏液病、α-1-抗胰蛋白酶缺乏引起之間質性肺炎)、由新冠病毒/ SARS-Cov-2感染導致之急性肺損傷或繼發於新冠病毒 / SARS-Cov-2感染之肺纖維化。
(3) 其他纖維變性疾病,例如肝橋接纖維化、肝硬化、非酒精性脂肪性肝炎(NASH)、心房纖維化、心肌內膜纖維化、陳舊性心肌梗塞、膠質瘢痕、動脈僵硬、關節纖維化、Dupuytren氏攣縮、瘢瘤、硬皮症/全身性硬化、縱膈纖維化、骨髓纖維化、Peyronie氏病、腎原性全身性纖維化、腹膜後纖維化、黏連性滑膜囊炎。
(4) 發炎、自體免疫或過敏性疾病及病況,例如過敏性或非過敏性鼻炎或竇炎、慢性竇炎或鼻炎、鼻息肉、慢性鼻竇炎、急性鼻竇炎、氣喘、小兒氣喘、過敏性支氣管炎、肺泡炎、氣道高反應性、過敏性結膜炎、支氣管擴張症、成人呼吸窘迫症候群、支氣管及肺水腫、支氣管炎或肺炎、嗜酸性球性蜂窩組織炎(例如Well氏症候群)、嗜酸性球性肺炎(例如呂佛勒氏症候群(Loeffler's syndrome)、慢性嗜酸性球性肺炎)、嗜酸性球性筋膜炎(例如,Shulman氏症候群)、遲發型過敏、非過敏性氣喘;運動誘發之支氣管收縮;慢性阻塞性肺病(COPD)、急性支氣管炎、慢性支氣管炎、咳嗽、肺氣腫;全身性過敏反應或過敏性反應、藥物過敏(例如對青黴素、頭孢菌素)、由於攝入受污染色胺酸所致之嗜酸性球增多-肌痛症候群、昆蟲刺傷過敏;自體免疫疾病,例如類風濕性關節炎、格雷氏病(Graves' disease)、薛格連氏症候群(Sjogren's syndrome)、牛皮癬關節炎、多發性硬化、全身性紅斑狼瘡、重症肌無力、免疫性血小板減少症(成人ITP、新生兒血小板減少症、兒童ITP)、免疫學溶血性貧血(自體免疫及藥物誘發)、Evans氏症候群(血小板及紅血球免疫性血球減少症)、新生兒Rh病、古巴士德氏症候群(Goodpasture's syndrome)(抗GBM病)、乳糜瀉、自體免疫性心肌病、幼發型糖尿病;腎小球性腎炎、自體免疫性甲狀腺炎、貝賽特氏病(Behcet's disease);移植物排斥(例如在移植中),包括同種異體移植物排斥或移植物抗宿主疾病;發炎性腸病,例如克隆氏病(Crohn's disease)及潰瘍性結腸炎;脊椎關節疾病;硬皮症;牛皮癬(包括T細胞介導之牛皮癬)及發炎性皮膚病,例如皮膚炎、濕疹、異位性皮膚炎、過敏性接觸性皮膚炎、蕁麻疹;血管炎(例如,壞死性、皮膚及過敏性血管炎);結節性紅斑;嗜酸性球性肌炎、嗜酸性球性筋膜炎、癌症伴皮膚或器官之白血球浸潤;眼科疾病,例如年齡相關性黃斑退化、糖尿病視網膜病變及糖尿病黃斑水腫、角膜炎、嗜酸性球性角膜炎、角膜結膜炎、春季角膜結膜炎、結瘢、眼前段結瘢、眼瞼炎、瞼結膜炎、大皰性病症、疤痕性類天皰瘡、結膜黑色素瘤、乳頭狀結膜炎、乾眼症、上鞏膜炎、青光眼、神經膠瘤病、環狀肉芽腫、格雷氏眼病(Graves' ophthalmopathy)、眼內黑色素瘤、瞼裂斑、增殖性玻璃體視網膜病變、翼狀胬肉、鞏膜炎、眼色素層炎、急性痛風發作、痛風或骨關節炎。
(5) 疼痛,例如慢性特發性疼痛症候群、神經病性疼痛、感覺遲鈍、觸摸痛、偏頭痛、牙齒痛及術後疼痛。
(6) 抑鬱症、焦慮、糖尿病性神經病變及膀胱病症,例如膀胱出口阻塞、膀胱過度活動症、膀胱炎;心肌再灌注損傷或腦缺血損傷。
因此,本發明係關於作為藥劑之通式1化合物。
此外,本發明係關於通式1之化合物用於治療及/或預防與TRPA1活性相關或由TRPA1活性調節之疾病及/或病況之用途。
此外,本發明係關於通式1之化合物用於治療及/或預防纖維變性疾病、發炎及免疫調節病症、呼吸道或胃腸疾病或病苦、眼科疾病、關節之發炎性疾病及鼻咽、眼睛及皮膚之發炎性疾病、疼痛及神經病症之用途。該等病症、疾病及病苦包括咳嗽、特發性肺纖維化、其他肺間質性疾病及其他纖維變性、氣喘或過敏性疾病、嗜酸性球疾病、慢性阻塞性肺病、以及發炎及免疫調節病症(例如類風濕性關節炎及動脈粥樣硬化)、以及疼痛及神經病症(例如急性疼痛、手術疼痛、慢性疼痛及抑鬱症)及膀胱病症。
此外,本發明係關於通式1之化合物用於治療及/或預防以下各項之用途:
(1) 咳嗽,例如慢性特發性咳嗽或慢性難治性咳嗽、與氣喘、COPD、肺癌、病毒後感染及特發性肺纖維化及其他肺間質性疾病相關之咳嗽。
(2) 肺纖維變性疾病,例如肺炎或與膠原變性相關之間質性肺炎,例如紅斑狼瘡、全身性硬皮症、類風濕性關節炎、多發性肌炎及皮肌炎、特發性間質性肺炎,例如特發性肺纖維化(IPF)、非特異性間質性肺炎、呼吸性細支氣管炎伴間質性肺病、脫屑性間質性肺炎、隱源性機化性肺炎、急性間質性肺炎及淋巴球性間質性肺炎、淋巴管平滑肌瘤病、肺泡蛋白質沉著症、蘭格罕細胞組織球增生症、胸膜實質彈性纖維增生、已知病因之間質性肺病,例如由於職業暴露導致之間質性肺炎,例如石棉肺、矽肺病、礦工肺(煤塵)、農夫肺(乾草及黴菌)、鴿友肺(鳥類)或其他職業性空中浮游觸發因素(例如金屬粉塵或分枝桿菌),或由治療(例如輻射、胺甲喋呤、胺碘達隆、呋喃妥因或化學治療劑)導致之間質性肺炎,或肉芽腫疾病,例如肉芽腫性多發性血管炎、查-施二氏症候群、類肉瘤病、過敏性肺炎或由不同病因造成之間質性肺炎(例如誤吸、吸入有毒氣體、蒸氣,支氣管炎或肺炎或由心臟衰竭、X-射線、輻射、化學療法、M. boeck症或類肉瘤病、肉芽腫病、囊性纖維化或膠稠性黏液病、α-1-抗胰蛋白酶缺乏引起之間質性肺炎)、由新冠病毒/ SARS-Cov-2感染導致之急性肺損傷或繼發於新冠病毒 / SARS-Cov-2感染之肺纖維化。
(3) 其他纖維變性疾病,例如肝橋接纖維化、肝硬化、非酒精性脂肪性肝炎(NASH)、心房纖維化、心肌內膜纖維化、陳舊性心肌梗塞、膠質瘢痕、動脈僵硬、關節纖維化、Dupuytren氏攣縮、瘢瘤、硬皮症/全身性硬化、縱膈纖維化、骨髓纖維化、Peyronie氏病、腎原性全身性纖維化、腹膜後纖維化、黏連性滑膜囊炎。
(4) 發炎、自體免疫或過敏性疾病及病況,例如過敏性或非過敏性鼻炎或竇炎、慢性竇炎或鼻炎、鼻息肉、慢性鼻竇炎、急性鼻竇炎、氣喘、小兒氣喘、過敏性支氣管炎、肺泡炎、氣道高反應性、過敏性結膜炎、支氣管擴張症、成人呼吸窘迫症候群、支氣管及肺水腫、支氣管炎或肺炎、嗜酸性球性蜂窩組織炎(例如Well氏症候群)、嗜酸性球性肺炎(例如呂佛勒氏症候群、慢性嗜酸性球性肺炎)、嗜酸性球性筋膜炎(例如,Shulman氏症候群)、遲發型過敏、非過敏性氣喘;運動誘發之支氣管收縮;慢性阻塞性肺病(COPD)、急性支氣管炎、慢性支氣管炎、咳嗽、肺氣腫;全身性過敏反應或過敏性反應、藥物過敏(例如對青黴素、頭孢菌素)、由於攝入受污染色胺酸所致之嗜酸性球增多-肌痛症候群、昆蟲刺傷過敏;自體免疫疾病,例如類風濕性關節炎、格雷氏病、薛格連氏症候群、牛皮癬關節炎、多發性硬化、全身性紅斑狼瘡、重症肌無力、免疫性血小板減少症(成人ITP、新生兒血小板減少症、兒童ITP)、免疫學溶血性貧血(自體免疫及藥物誘發)、Evans氏症候群(血小板及紅血球免疫性血球減少症)、新生兒Rh病、古巴士德氏症候群(抗GBM病)、乳糜瀉、自體免疫性心肌病、幼發型糖尿病;腎小球性腎炎、自體免疫性甲狀腺炎、貝賽特氏病;移植物排斥(例如在移植中),包括同種異體移植物排斥或移植物抗宿主疾病;發炎性腸病,例如克隆氏病及潰瘍性結腸炎;脊椎關節疾病;硬皮症;牛皮癬(包括T細胞介導之牛皮癬)及發炎性皮膚病,例如皮膚炎、濕疹、異位性皮膚炎、過敏性接觸性皮膚炎、蕁麻疹;血管炎(例如,壞死性、皮膚及過敏性血管炎);結節性紅斑;嗜酸性球性肌炎、嗜酸性球性筋膜炎、癌症伴皮膚或器官之白血球浸潤;眼科疾病,例如年齡相關性黃斑退化、糖尿病視網膜病變及糖尿病黃斑水腫、角膜炎、嗜酸性球性角膜炎、角膜結膜炎、春季角膜結膜炎、結瘢、眼前段結瘢、眼瞼炎、瞼結膜炎、大皰性病症、疤痕性類天皰瘡、結膜黑色素瘤、乳頭狀結膜炎、乾眼症、上鞏膜炎、青光眼、神經膠瘤病、環狀肉芽腫、格雷氏眼病、眼內黑色素瘤、瞼裂斑、增殖性玻璃體視網膜病變、翼狀胬肉、鞏膜炎、眼色素層炎、急性痛風發作、痛風或骨關節炎。
(5) 疼痛,例如慢性特發性疼痛症候群、神經病性疼痛、感覺遲鈍、觸摸痛、偏頭痛、牙齒痛及術後疼痛。
(6) 抑鬱症、焦慮、糖尿病性神經病變及膀胱病症,例如膀胱出口阻塞、膀胱過度活動症、膀胱炎;心肌再灌注損傷或腦缺血損傷。
在其他態樣中,本發明係關於通式1之化合物,其用於治療及/或預防以上提及之疾病及病況。
在其他態樣中,本發明係關於通式1之化合物用於製備藥劑之用途,該藥劑用於治療及/或預防以上提及之疾病及病況。
在本發明之其他態樣中,本發明係關於用於治療或預防以上提及之疾病及病況之方法,該方法包含將有效量之通式1化合物投與給人類。
組合療法本發明化合物可進一步與一或多種、較佳一種其他治療劑組合。根據一個實施例,額外治療劑選自以下之群:可用於治療上文所述疾病或病況,特定地與纖維變性疾病、發炎及免疫調節病症、呼吸道或胃腸疾病或病苦、關節之發炎性疾病或鼻咽、眼睛及皮膚之發炎性疾病或病況(例如咳嗽、特發性肺纖維化、其他肺間質性疾病、氣喘或過敏性疾病、嗜酸性球疾病、慢性阻塞性肺病、異位性皮膚炎)以及自體免疫性病變(例如類風濕性關節炎及動脈粥樣硬化)相關之疾病或病況的治療劑或可用於治療眼科疾病、疼痛及抑鬱症之治療劑。
適於該等組合之其他治療劑特定包括彼等(例如)加強一或多種活性物質關於所提及適應症中之一者之治療效應者及/或允許減少一或多種活性物質之劑量者。
因此,本發明化合物可與一或多種選自由以下組成之群之其他治療劑組合:抗纖維化劑、止咳劑、消炎劑、抗異位性皮膚炎藥劑、止痛藥、抗發厥劑、抗焦慮劑、鎮靜劑、骨骼肌鬆弛劑或抗抑鬱劑。
抗纖維化劑係例如尼達尼布(nintedanib)、吡非尼酮(pirfenidone)、磷酸二酯酶-IV (PDE4)抑制劑(例如羅氟司特(roflumilast))、自分泌運動因子抑制劑(autotaxin inhibitor)(例如GLPG-1690或BBT-877);結締組織生長因子(CTGF)阻斷抗體,例如潘瑞魯單抗(Pamrevlumab);B細胞活化因子受體(BAFF-R)阻斷抗體,例如拉那魯單抗(Lanalumab);α-V/β-6阻斷抑制劑,例如BG-00011/STX-100、重組正五聚蛋白-2 (recombinant pentraxin-2, PTX-2),例如PRM-151;c-Jun N-末端激酶(JNK)抑制劑,例如CC-90001;半乳糖凝集素-3抑制劑,例如TD-139;G蛋白偶聯受體84 (GPR84)抑制劑,例如GLPG-1205;G蛋白偶聯受體84/ G蛋白偶聯受體40雙重抑制劑,例如PBI-4050;Rho相關含捲曲螺旋蛋白激酶2 (ROCK2)抑制劑,例如KD-025;熱休克蛋白47 (HSP47)小干擾RNA,例如BMS-986263/ND-L02-s0201;Wnt路徑抑制劑,例如SM-04646;LD4 / PDE3/4抑制劑,例如Tipelukast;組胺醯基tRNA合成酶(HARS)之重組免疫調節結構域,例如ATYR-1923;前列腺素合酶抑制劑,例如ZL-2102 / SAR-191801;15-羥基-二十碳五烯酸(15-HEPE,例如DS-102);離胺醯氧化酶樣蛋白2 (LOXL2)抑制劑,例如PAT-1251、PXS-5382/PXS-5338;磷酸肌醇3-激酶(PI3K)/ 哺乳動物雷帕黴素靶蛋白(mTOR)雙重抑制劑,例如HEC-68498;鈣蛋白酶抑制劑,例如BLD-2660;促分裂原活化蛋白激酶激酶激酶(MAP3K19)抑制劑,例如MG-S-2525;殼質酶抑制劑,例如OATD-01;促分裂原活化蛋白激酶活化蛋白激酶2 (MAPKAPK2)抑制劑,例如MMI-0100;轉變生長因子β 1 (TGF-beta1)小干擾RNA,例如TRK250/BNC-1021;或溶血磷脂酸受體拮抗劑,例如BMS-986278。
止咳劑係例如嘌呤受體3 (P2X3)受體拮抗劑,例如吉法匹生(gefapixant)、S-600918、BAY-1817080或BLU-5937;神經激肽1 (NK-1)受體拮抗劑,例如奧維匹坦、阿瑞匹坦;菸鹼型乙醯膽鹼受體α 7亞單位刺激物,例如ATA-101/布拉他尼林(bradanicline);可待因(codeine)、加巴噴丁(gabapentin)、普瑞巴林(pregablin)或阿奇黴素(azithromycin)。
消炎劑係例如皮質類固醇,例如普賴蘇濃(prednisolone)或地塞米松(dexamethasone);環氧化酶-2 (COX2)抑制劑,例如塞來昔布(celecoxib)、羅非昔布(rofecoxib)、帕瑞昔布(parecoxib)、伐地昔布(valdecoxib)、德拉昔布(deracoxib)、依託昔布(etoricoxib)或羅美昔布(lumiracoxib);前列腺素E2拮抗劑;白三烯B4拮抗劑;白三烯D4拮抗劑,例如孟魯司特(montelukast);5-脂肪加氧酶抑制劑;或其他非類固醇消炎劑(NSAID),例如阿斯匹林(aspirin)、雙氯芬酸(diclofenac)、二氟尼柳(diflunisal)、依託度酸(etodolac)、布洛芬(ibuprofen)或吲哚美辛(indomethacin)。
抗異位性皮膚炎劑係例如環孢素(cyclosporin)、胺甲喋呤(methotrexate)、嗎替麥考酚酯(mycophenolate mofetil)、硫唑嘌呤(azathioprine)、磷酸二酯酶抑制劑(例如阿普斯特(apremilast)、克立硼羅(crisaborole))、Janus相關激酶(JAK)抑制劑(例如托法替尼(tofacitinib))、針對IL-4/IL-13之中和抗體(例如度普利尤單抗(dupilumab))、針對IL-13之中和抗體(例如來瑞珠單抗(lebrikizumab)、曲羅蘆單抗(tralokinumab))及針對IL-31之中和抗體(奈莫利珠單抗(nemolizumab))。
止痛藥係例如類鴉片型,例如嗎啡(morphine)、氧化嗎啡(oxymorphine)、左啡諾(levorphanol)、羥考酮(oxycodone)、丙氧芬(propoxyphene)、納美芬(nalmefene)、芬太尼(fentanyl)、氫可酮(hydrocodone)、氫嗎啡酮(hydromorphone)、美利皮定(meripidine)、美沙酮(methadone)、納洛芬(nalorphine)、那若松(naloxone)、那曲酮(naltrexone)、丁基原啡因(buprenorphine)、布托啡諾(butorphanol)、納布啡(nalbuphine)、戊唑辛(pentazocine);或非類鴉片型,例如乙醯胺酚(acetaminophen)。
抗抑鬱劑係例如三環抗抑鬱劑,例如阿米替林(amitriptyline)、氯米帕明(clomipramine)、地昔帕明(desipramine)、多慮平(doxepin)、地昔帕明、伊米帕明(imipramine)、去甲替林(nortriptyline);選擇性血清素再攝取抑制劑抗抑鬱劑(SSRI),例如氟西汀(fluoxetine)、帕羅西汀(paroxetine)、舍曲林(sertraline)、西酞普蘭(citalopram)、依地普侖(escitalopram);去甲腎上腺素再攝取抑制劑抗抑鬱劑(SNRI),例如麥普替林(maprotiline)、洛非帕明(lofepramine)、米氮平(mirtazapine)、羥丙替林(oxaprotiline)、非唑拉明(fezolamine)、托莫西汀(tomoxetine)、米安舍林(mianserin)、安非他酮(buproprion)、羥基安非他酮(hydroxybuproprion)、諾米芬辛(nomifensine)、維洛沙嗪(vil㗁𠯤);雙重血清素-去甲腎上腺素再攝取抑制劑抗抑鬱劑(SNRI),例如度洛西汀(duloxetine)、萬拉法辛(venlafaxine)、地萬拉法辛(desvenlafaxine)、左米那普侖(levomilnacipran);非典型抗抑鬱藥,例如曲唑酮(trazodone)、米氮平、沃替西汀(vortioxetine)、維拉佐酮(vilazodone)、安非他酮;或單胺氧化酶抑制劑抗抑鬱劑(MAOI),例如強內心百樂明(tranylcypromine)、苯乙肼(phenelzine)或異唑肼(isocarboxazid)。
抗焦慮劑係例如苯并二氮呯,例如阿普唑侖(alprazolam)、溴西泮(bromazepam)、氯二氮平(chlordiazepoxide)、可那氮平(clonazepam)、氯拉卓酸(clorazepate)、二氮平(diazepam)、氟西泮(flurazepam)、氯羥去甲安定(lorazepam)、去甲羥基安定(oxazepam)、替馬西泮(temazepam)、三唑侖(triazolam)或托非索泮(tofisopam);或其為非苯并二氮呯類安眠藥,例如右旋佐匹克隆(eszopiclone)、紮來普隆(zaleplon)、唑吡坦(zolpidem)或佐匹克隆(zopiclone);或其為胺基甲酸酯,例如甲丙胺酯(meprobamate)、肌安寧(carisoprodol)、泰巴氨酯(tybamate)或勞氨酯(lorbamate);或其為抗組織胺,例如羥嗪(hydroxyzine)、氯苯那敏(chlorpheniramine)或苯海拉明(diphenhydramine)。
鎮靜劑係例如巴比妥酸鹽鎮靜劑,例如異戊巴比妥(amobarbital)、阿普比妥(aprobarbital)、仲丁巴比妥(butabarbital)、布他比妥(butabital)、甲苯巴比妥(mephobarbital)、美沙比妥(metharbital)、美索比妥(methohexital)、戊巴比妥(pentobarbital)、司可巴比妥(secobarbital)、他布比妥(talbutal)、硫阿米妥(thiamylal)或硫噴妥(thiopental);或其為非巴比妥酸鹽類鎮靜劑,例如格魯米特(glutethimide)、甲丙胺酯(meprobamate)、甲喹酮(methaqualone)或氯醛比林(dichloralphenazone)。
骨骼肌鬆弛劑係例如巴氯芬(baclofen)、甲丙胺酯、肌安寧、環苯紮林(cyclobenzaprine)、美他沙酮(metaxalone)、美索巴莫(methocarbamol)、替紮尼定(tizanidine)、氯唑沙宗(chlorzoxazone)或鄰甲苯海拉明(orphenadrine)。
其他適宜組合配對物係乙醯膽鹼酯酶抑制劑,例如多奈派齊(donepezil);5-HT-3拮抗劑,例如昂丹司瓊(ondansetron);代謝型麩胺酸受體拮抗劑;抗心律不整劑,例如墨西律定(mexiletine)或苯妥英(phenytoin);或NMDA受體拮抗劑。
進一步適宜組合配對物係失禁藥物,例如抗膽鹼劑,例如羥布托尼(oxybutynin)、托特羅定(tolterodine)、達非那新(darifenacin)、非索羅定(fesoterodine)、索利那新(solifenacin)或曲司銨(trospium);或其為膀胱肌肉鬆弛劑,例如米拉貝隆(mirabegron);或其為α阻斷劑,例如坦洛新(tamsulosin)、阿夫唑嗪(alfuzosin)、西洛多辛(silodosin)、多沙唑嗪(doxazosin)或特拉唑嗪(terazosin)。
上文所提及組合配對物之劑量通常係正常推薦最低劑量之1/5至最高正常推薦劑量之1/1。
因此,在另一態樣中,本發明係關於本發明化合物與上文及下文所述一或多種其他治療劑組合之用途,其用於治療可受TRPA1影響或由TRPA1介導之疾病或病況,特別地如上文及下文所述之疾病或病況。
在其他態樣中,本發明係關於用於治療患者之可受TRPA1抑制影響之疾病或病況之方法,其包括向需要該治療之患者投與治療有效量之式(I)化合物或其醫藥上可接受之鹽與治療有效量之一或多種其他治療劑之組合之步驟。
在其他態樣中,本發明係關於式(I)化合物或其醫藥上可接受之鹽與一或多種其他治療劑之組合之用途,其用於治療有需要之患者之可受TRPA1抑制影響之疾病或病況。
在另一態樣中,本發明係關於用於治療患者之由TRPA1活性介導之疾病或病況之方法,其包括向需要該治療之患者、較佳人類投與治療有效量之本發明化合物與治療有效量之上文及下文中所述一或多種其他治療劑之步驟。
本發明化合物與其他治療劑組合之使用可同時或在交錯時間進行。
本發明化合物及一或多種其他治療劑二者可一起存在於一種調配物(例如錠劑或膠囊)中或分開存在於兩種相同或不同調配物(例如所謂的部分套組(kit-of-parts)形式)中。
因此,在另一態樣中,本發明係關於醫藥組合物,其包含本發明之化合物及上文及下文所述之一或多種其他治療劑以及視情況一或多種惰性載劑及/或稀釋劑。
在再另一態樣中,本發明係關於本發明化合物在咳嗽量測裝置中之用途。
根據以下更詳細之實例可瞭解本發明之其他特徵及優點,該等實例以實例方式說明本發明之原理。
製備本發明之化合物及其中間體可使用熟習此項技術者已知且闡述於有機合成文獻中之合成方法來獲得。較佳地,化合物係以類似於下文更全面解釋,特定地如實驗部分中所述之製備方法來獲得。在一些情形中,可改變實施反應步驟之順序。亦可使用熟習此項技術者已知但本文未詳細闡述之反應方法之變化形式。
熟習此項技術者在研究下文方案後將瞭解製備本發明化合物之一般製程。起始材料或中間體中之任何官能基可使用習用保護基團進行保護。該等保護基團可在反應順序內之適宜階段使用熟習此項技術者熟知之方法再次裂解。
本發明之化合物係藉由下文所述合成方法來製備,其中通式之取代基具有上文所給含義。該等方法意欲作為本發明之說明,而非限制其標的物及該等實例所主張化合物之範圍。在未闡述起始化合物之製備之情形中,其係市面可獲得或可以與本文中所述已知化合物或方法類似之方式製備。文獻中所闡述之物質係根據公開之合成方法製備。縮寫係定義於實例部分中。
方案2:
在方案2中,尿嘧啶衍生物(C), CAS: 154942-22-0可自甲脲及基2‐(乙氧基亞甲基)丙二酸1,3-二乙酯在純淨條件下在升高溫度下合成。一級醯胺(A)可自酯(C)藉由在密封容器中在升高溫度下與氨在溶劑(例如,水或醇)中一起攪拌來合成。
方案3:
在方案3中,將自羧酸酯(D)合成之α-氰基酮(E)以對映選擇性方式藉由使用適當催化系統還原以提供醇(F),該催化系統使用過渡金屬錯合物(例如Ru或Ir)與手性配體(例如[(1S,2S)-(-)-2-胺基-1,2-二苯基乙基](4-甲苯磺醯基)醯胺基)之組合及氫源(例如甲酸三乙胺錯合物)。將羥基胺添加至該等醇(F)以提供二羥基丙脒(G)。氯亞甲基-噁二唑(B)之閉環可藉由將反應混合物與氯乙醯氯一起在鹼(例如DIPEA)之存在下攪拌來達成。
實例 製備本發明化合物及其中間體可使用熟習此項技術者已知且有機合成文獻中闡述之合成方法(例如使用「Comprehensive Organic Transformations」, 第2版, Richard C. Larock, John Wiley & Sons, 2010及「March’s Advanced Organic Chemistry」, 第7版, Michael B. Smith, John Wiley & Sons, 2013中所述之方法)獲得。較佳地,化合物係類似於下文更全面地解釋、特別地如實驗部分中所述之製備方法獲得。在一些情形中,可改變實施反應方案所採用之順序。亦可使用熟習此項技術者已知但本文未詳細闡述之該等反應之變化形式。熟習此項技術者在研究下文方案後將瞭解用於製備本發明化合物之一般方法。起始化合物可自市場購得或可藉由文獻或本文中闡述之方法來製備,或可以類似或相似的方式來製備。在實施反應之前,可使用習用保護基團來保護起始化合物中之任何相應官能基。該等保護基團可在反應序列內之適宜階段使用熟習此項技術者熟知且文獻(例如「Protecting Groups」, 第3版, Philip J. Kocienski, Thieme, 2005及「Protective Groups in Organic Synthesis」, 第4版, Peter G. M. Wuts, Theodora W. Greene, John Wiley & Sons, 2006)中所闡述之方法再次裂解。術語「環境溫度」及「室溫」可互換使用且指定約20℃之溫度,例如介於19℃與24℃之間。
縮寫:
ACN | 乙腈 |
Aq. | 水性 |
℃ | 攝氏度 |
CyH/CH | 環己烷 |
conc. | 濃縮 |
DCM | 二氯甲烷 |
DCE | 1,2-二氯乙烷 |
DIPEA | N,N-二異丙基乙胺 |
DMA | N,N-二甲基乙醯胺 |
DMF | N,N-二甲基甲醯胺 |
DMSO | 二甲基亞碸 |
ESI-MS | 電噴霧離子化質譜 |
EtOAc | 乙酸乙酯 |
EtOH | 乙醇 |
ex | 實例 |
eq | 當量 |
FA | 甲酸 |
h | 小時 |
HATU | 1-[雙(二甲基胺基)亞甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧離子基六氟磷酸鹽 |
HCl | 鹽酸 |
HPLC | 高效液相層析 |
K 2CO 3 | 碳酸鉀 |
L | 公升 |
M | 莫耳 |
MeOH | 甲醇 |
MgSO 4 | 硫酸鎂 |
min | 分鐘 |
mL | 毫升 |
MTBE | 第三丁基甲基醚 |
NH 3 | 氨 |
NMP | N-甲基-2-吡咯啶酮 |
PE | 石油醚 |
RT | 室溫(約20℃) |
sat. | 飽和 |
TBTU | 苯并三唑四甲基脲鎓四氟硼酸鹽 |
TEA | 三乙胺 |
TFA | 三氟乙酸 |
THF | 四氫呋喃 |
中間體之製備 中間體 I 中間體 I.1 ( 一般途徑 )(3S)-3-(4-氯苯基)-3-羥基丙腈
在惰性氣氛下將10.0 g (55.7 mmol) 4-氯苯甲醯基乙腈添加至100 mL ACN。添加142 mg (0.23 mmol)氯([(1S,2S)-2-胺基-1,2-二苯基乙基](4-甲苯磺醯基)醯胺基)(均三甲苯基)釕(II) (CAS 174813-81-1),隨後逐滴添加8.30 mL (19.8 mmol)甲酸三乙胺錯合物(5:2)。在RT下攪拌3 h後,在真空中去除溶劑。向剩餘粗製混合物中添加水且此混合物利用EtOAc萃取兩次。將有機層合併,經MgSO
4乾燥,過濾,並在真空中去除溶劑,以提供中間體I.1。
C
9H
8ClNO (M = 181.6 g/mol)
ESI-MS: 226 [M+HCOO]
-R
t(HPLC): 0.81 min (方法B)
以下化合物係使用類似於針對中間體I.1所述彼等之程序使用適當起始材料製備。如熟習此項技術者所瞭解,該等類似實例可涉及一般反應條件中之變化。
Int. | 起始材料 | 結構 | ESI-MS | HPLC滯留時間 [min] (方法),或 1H NMR (300 MHz, DMSO- d 6) δ ppm |
I.2 | 184 [M+Na] + | 0.76 (B) | ||
1.3 | 256 [M+H-H 2O] + | 0.84 (B) | ||
1.4 | IV.1 | 266 [M+HCOO] - | 3.03 (D) | |
1.5 | -- | δ 7.98 – 7.91 (m, 1 H), 7.82 – 7.77 (m, 1 H), 7.37 – 7.31 (m, 3 H), 6.56 (d, J= 5.0 Hz, 1 H), 5.28 – 5.20 (m, 1 H), 3.14 – 2.94 (m, 2 H) | ||
1.6 | IV.2 | 266 [M+HCOO] - | 3.12 (D) | |
1.7 | IV.3 | -- | δ 7.63 – 7.56 (m, 1 H), 7.46 (dd, J= 8.9, 2.7 Hz, 1 H), 7.14 (td, J= 9.2, 2.7 Hz, 1 H), 6.88 (s, 1 H), 6.41 (d, J= 5.5 Hz, 1 H), 5.10 – 5.01 (m, 1 H), 3.16 – 2.98 (m, 2 H) |
中間體 II 中間體 II.1 ( 一般途徑 )(3S)-3-(4-氯苯基)-N,3-二羥基丙脒
向於100 mL MeOH中之9.82 g (54.1 mmol) (3S)-3-(4-氯苯基)-3-羥基丙腈(中間體I.1)添加8.00 mL (136 mmol)羥基胺(50%於水中)並將混合物在75℃下攪拌1.5 h。冷卻至RT後,在真空中去除所有揮發物以獲得粗製產物,其不經進一步純化即使用。
C
9H
11ClN
2O
2(M = 214.6 g/mol)
ESI-MS: 215 [M+H]
+R
t(HPLC): 0.60 min (方法B)
以下化合物係使用類似於針對中間體II.1所述彼等之程序使用適當起始材料製備。如熟習此項技術者所瞭解,該等類似實例可涉及一般反應條件中之變化。
Int. | 起始材料 | 結構 | ESI-MS | HPLC滯留時間 [min] (方法) |
II.2 | I.2 | 195 [M+H]+ | 0.57 (B) | |
II.3 | 1.3 | 307 [M+H]+ | 0.71 (B) | |
II.4 | 1.4 | 255 [M+H]+ | 2.07 (D) | |
II.5 | 1.5 | 237 [M+H]+ | 1.93 (D) | |
II.6 | 1.6 | 255 [M+H]+ | 2.18 (D) | |
II.7 | 1.7 | 239 [M+H]+ | 1.90 (D) |
中間體 III 中間體 III.1 ( 一般途徑 )(1S)-2-[5-(氯甲基)-1,2,4-噁二唑-3-基]-1-(4-氯苯基)乙-1-醇
向於55 mL NMP中之11.2 g (52.4 mmol)中間體II.1中添加10.0 mL (57.8 mmol) DIPEA。將混合物冷卻至0℃,然後緩慢添加溶於5 mL NMP中之4.60 mL (57.7 mmol)氯乙醯氯並將混合物於0℃下攪拌45 min.。然後將混合物加熱至高達95℃並繼續攪拌4 h。冷卻至RT後,添加200 mL水並將所得混合物利用EtOAc萃取三次。將有機層合併,經MgSO
4乾燥,過濾並在真空中去除溶劑。殘餘物藉由管柱層析(矽膠;PE/EtOAc, 7/3)純化。
C
11H
10Cl
2N
2O
2(M = 273.1 g/mol)
ESI-MS: 271 [M-H]
-R
t(HPLC): 0.93 min (方法B)
以下化合物係使用類似於針對中間體III.1所述彼等之程序使用適當起始材料製備。如熟習此項技術者所瞭解,該等類似實例可涉及一般反應條件中之變化。
Int. | 起始材料 | 結構 | ESI-MS | HPLC滯留時間 [min] (方法) |
III.2 | II.2 | 251 [M-H] - | 0.92 (C) | |
III.3 | II.3 | 387 [M+Na] + | 1.01 (B) | |
III.4 | II.4 | 311 [M-H] - | 6.02 (E) | |
III.5 | II.5 | 295 [M+H]+ | 5.88 (E) | |
III.6 | II.6 | 311 [M-H] - | 6.12 (E) | |
III.7 | II.7 | 295 [M-H] - | 5.67 (E) |
中間體 IV 中間體 IV.1 ( 一般途徑 ) 3 ‐ (6 ‐氟‐ 1 ‐苯并噻吩‐ 2 ‐基 ) ‐ 3 ‐側氧基丙腈 在惰性氣氛下在RT下向於9.0 mL無水甲苯及0.78 mL無水ACN中之0.63g (3.00 mmol) 6-氟-1-苯并噻吩-2-甲酸甲酯中添加0.36 g (9.00 mmol)之NaH (60%於油中)。將混合物加熱至回流並攪拌16 h,冷卻至室溫,傾倒於冰/水(30mL)上,用2M HCl處理以達到pH = 1。添加EtOAc (20 mL)且相分離。將水相再次用EtOAc (20 mL)萃取,合併之有機相用鹽水(20 mL)洗滌,且在減壓下去除溶劑。藉由矽膠管柱層析使用EtOAc/己烷之梯度(30%至40%)純化粗產物。
C
11H
6FNOS (M = 219.23 g/mol)
ESI-MS: 218 [M-H]
-R
t(HPLC): 3.31 min (D)
以下化合物係使用類似於針對中間體IV.1所述彼等之程序使用適當起始材料製備。如熟習此項技術者所瞭解,該等類似實例可涉及一般反應條件中之變化。
Int. | 起始材料 | 結構 | ESI-MS | HPLC滯留時間 [min] (方法) |
IV.2 | 218 [M-H] - | 3.33 (D) | ||
IV.3 | 202 [M-H] - | 3.08 (D) |
中間體 V3‐甲基‐2,4‐二側氧基‐1,2,3,4‐四氫嘧啶‐5‐甲酸乙酯
將500 mg (6.75 mmol)甲脲及1.36 g (6.75 mmol) 2‐(甲氧基亞甲基)丙二酸1,3‐二乙酯在純淨條件下在120℃下攪拌2 h,在RT下攪拌17 h,在100℃下攪拌66 h,在150℃下攪拌17 h並在120℃下攪拌17 h。隨後,將混合物用EtOAc稀釋並回流。將混合物緩慢冷卻至RT並將沈澱之中間體濾出。
C
8H
10N
2O
4(M = 198.2 g/mol)
ESI-MS: 199 [M+H]
+R
t(HPLC): 0.24 min (方法A)
中間體 VI3‐甲基‐2,4‐二側氧基‐1,2,3,4‐四氫嘧啶‐5‐甲醯胺
將於33%氨水(120 mL)中之10.0 g (50.46 mmol) 3‐甲基‐2,4‐二側氧基‐1,2,3,4‐四氫嘧啶‐5-甲酸乙酯(CAS: 154942-22-0, 中間體V)在密封容器中在100℃下攪拌10 h。將反應混合物冷卻至RT並在減壓下濃縮。將殘餘物與ACN一起研磨,濾出並在50℃下乾燥,以提供中間體VI。
C
6H
7N
3O
3(M = 169.1 g/mol)
ESI-MS: 170 [M+H]
+R
t(HPLC): 0.48 min (方法B)
最終化合物之製備 實例 1 ( 一般程序 )
1‐({3‐[(2S)‐2‐(4‐氯苯基)‐2‐羥乙基]‐1,2,4‐噁二唑‐5‐基}甲基)‐3‐甲基‐2,4‐二側氧基‐1,2,3,4‐四氫嘧啶‐5‐甲醯胺
將19 mg (0.11 mmol)中間體VI、30 mg (0.11 mmol)中間體III.1及30 mg (0.22 mmol) K
2CO
3於1.0 mL DMF中之混合物在RT下攪拌1 h。將反應混合物過濾且濾液藉由反相HPLC (ACN/H
2O梯度, 0.1% TFA)純化,獲得期望產物。
C
17H
16ClN
5O
5(M = 405.79 g/mol)
ESI-MS: 406 [M+H]
+R
t(HPLC): 0.44 min (方法A)
1H NMR (400 MHz,
DMSO-d 6) δ ppm: 2.92 - 3.07 (m, 2 H), 3.23 (s, 3 H), 4.96 (dd,
J=7.9, 5.8 Hz, 1 H), 5.48 (d,
J=1.9 Hz, 2 H), 7.31 - 7.40 (m, 4 H), 7.65 (d,
J=3.3 Hz, 1 H), 8.19 (d,
J=3.3 Hz, 1 H), 8.80 (s, 1 H)。
以下化合物係使用類似於針對實例1一般程序所述彼等之程序使用適當起始材料製備。如熟習此項技術者所瞭解,該等類似實例可涉及一般反應條件中之變化。
以上表中所述化合物之分析數據:
Ex. | 起始材料 | 結構 | 反應條件 |
2 | VI + III.5 | 1.05 eq III.5, 2eq K 2CO 3, DMF, RT, 2 h | |
3 | VI + III.4 | 1.05 eq III.4, 2eq K 2CO 3, DMF, RT, 2 h | |
4 | VI + III.6 | 1.05 eq III.6, 2eq K 2CO 3, DMF, RT, 2 h | |
5 | VI + III.7 | 1.05 eq III.7, 2eq K 2CO 3, DMF, RT, 3 h | |
6 | VI + III.3 | 1.0 eq III.3, 2eq K 2CO 3, DMF, RT, 18 h | |
7 | VI + III.2 | 1.0 eq III.2, 2eq K 2CO 3, DMF, RT, 18 h |
Ex. | ESI-MS | HPLC滯留時間[min] (方法) | 1H NMR (400 MHz, DMSO- d 6) δ ppm |
2 | 428 [M+H]+ | 0.47 (A) | 3.14 - 3.20 (m, 2 H), 3.23 (s, 3 H), 5.31 (t, J=6.7 Hz, 1 H), 5.50 (d, J=1.7 Hz, 2 H), 7.25 (s, 1 H), 7.32 (quind, J=7.4, 1.4 Hz, 2 H), 7.66 (br d, J=3.4 Hz, 1 H), 7.74 (dd, J=7.0, 1.6 Hz, 1 H), 7.85 - 7.94 (m, 1 H), 8.19 (br d, J=3.4 Hz, 1 H), 8.81 (s, 1 H) |
3 | 446 [M+H]+ | 0.48 (A) | 3.15 - 3.19 (m, 2 H), 3.23 (s, 3 H), 5.25 – 5.33 (m, 1 H), 5.50 (d, J=1.9 Hz, 2 H), 6.16 (d, J=5.2 Hz, 1 H), 7.20 (td, J=9.1, 2.4 Hz, 1 H), 7.25 (s, 1 H), 7.66 (d, J=3.3 Hz, 1 H), 7.76 (dd, J=8.7, 5.3 Hz, 1 H), 7.82 (dd, J=9.4, 2.4 Hz, 1 H), 8.18 (d, J=3.3 Hz, 1 H), 8.80 (s, 1 H) |
4 | 446 [M+H]+ | 0.49 (A) | 3.15 - 3.29 (m, 5 H), 5.11 (dt, J=7.8, 5.7 Hz, 1 H), 5.48 (s, 2 H), 6.00 (d, J=5.7 Hz, 1 H), 6.77 (s, 1 H), 7.29 (dd, J=8.7, 2.3 Hz, 1 H), 7.57 (d, J=8.7 Hz, 1 H), 7.64 - 7.67 (m, 2 H), 8.18 (d, J=3.4 Hz, 1 H), 8.78 (s, 1 H) |
5 | 430 [M+H]+ | 0.44 (A) | 3.13 - 3.31 (m, 5 H), 5.10 (dd, J=7.9, 5.6 Hz, 1 H), 5.48 (s, 2 H), 6.77 (s, 1 H), 7.09 (td, J=9.2, 2.7 Hz, 1 H), 7.38 (dd, J=8.9, 2.7 Hz, 1 H), 7.55 (dd, J=9.0, 4.2 Hz, 1 H), 7.65 (br d, J=3.2 Hz, 1 H), 8.18 (br d, J=3.3 Hz, 1 H), 8.78 (s, 1 H) |
6 | 498 [M+H]+ | 0.49 (A) | 2.95 - 3.01 (m, 2 H), 3.23 (s, 3 H), 4.86 - 4.95 (m, 1 H), 5.48 (d, J=1.9 Hz, 2 H), 7.13 - 7.20 (m, 2 H), , 7.59 - 7.70 (m, 3 H), 8.19 (d, J=3.4 Hz, 1 H), 8.80 (s, 1 H) |
7 | 386 [M+H]+ | 0.44 (A) | 2.26 (s, 3 H), 2.89 - 3.05 (m, 2 H), 3.23 (s, 3 H), 4.91 (dd, J=8.2, 5.5 Hz, 1 H), 5.48 (d, J=1.3 Hz, 2 H), 7.07 – 7.12 (m, 2 H), 7.18 – 7.24 (m, 2 H), 7.65 (br d, J=3.2 Hz, 1 H), 8.19 (br d, J=3.3 Hz, 1 H), 8.80 (s, 1 H) |
分析型 HPLC 方法 方法 A
分析型管柱:XBridge BEH C18_2.1 x 30 mm, 1.7 μm;管柱溫度:60℃
時間(min) | 水之體積% (incl. 0.1% TFA) | ACN之體積% | 流量[mL/min] |
0.00 | 99 | 1 | 1.6 |
0.02 | 99 | 1 | 1.6 |
1.00 | 0 | 100 | 1.6 |
1.10 | 0 | 100 | 1.6 |
方法 B
分析型管柱:Stable Bond (Agilent) 1.8 µm;3.0 x 30 mm;管柱溫度:60℃
時間(min) | 水之體積% (incl. 0.1% TFA) | ACN之體積% | 流量[mL/min] |
0.00 | 97 | 3 | 2.2 |
0.20 | 97 | 3 | 2.2 |
1.20 | 0 | 100 | 2.2 |
1.25 | 0 | 100 | 3.0 |
1.40 | 0 | 100 | 3.0 |
方法 C
分析型管柱:Sunfire (Waters) 2.5 µm;3.0 x 30 mm;管柱溫度:60℃
時間(min) | 水之體積% (incl. 0.1% TFA) | ACN之體積% | 流量[mL/min] |
0.00 | 97 | 3 | 2.2 |
0.20 | 97 | 3 | 2.2 |
1.20 | 0 | 100 | 2.2 |
1.25 | 0 | 100 | 3.0 |
1.40 | 0 | 100 | 3.0 |
方法 D
分析型管柱:AQUITY UPLC C18_2.1 x 50 mm_1.8 µm. 100Å;管柱溫度:25℃
梯度/溶劑 時間[min] | 水之體積% (incl. 0.1% FA) | ACN之體積% (incl. 0.1% FA) | 流量[ml/min] |
0.01 | 95 | 5 | 0.5 |
4.00 | 5 | 95 | 0.5 |
5.00 | 5 | 95 | 0.5 |
5.20 | 95 | 5 | 0.5 |
6.00 | 95 | 5 | 0.5 |
方法 E
分析型管柱:AQUITY UPLC C18_2.1 x 50 mm_1.8 µm. 100Å;管柱溫度:25℃
梯度/溶劑 時間[min] | 水之體積% (incl. 0.1% FA) | ACN之體積% (incl. 0.1% FA) | 流量[ml/min] |
0.00 | 95 | 5 | 0.5 |
10.00 | 5 | 95 | 0.5 |
10.50 | 5 | 95 | 0.5 |
11.00 | 95 | 5 | 0.5 |
12.00 | 95 | 5 | 0.5 |
Claims (9)
- 如請求項1之式(I)化合物,其中R 1係選自F、Cl、I及CH 3。
- 一種如請求項1至4中任一項之化合物之鹽,特定地醫藥上可接受之鹽。
- 一種醫藥組合物,其包含至少一種如請求項1至4中任一項之式I化合物或其醫藥上可接受之鹽及一或多種醫藥上可接受之賦形劑。
- 一種如請求項1至4中任一項之式(I)化合物或其醫藥上可接受之鹽之用途,其用於製造藥劑。
- 如請求項7之用途,其中該藥劑用於治療或預防發炎性氣道疾病或纖維變性疾病或咳嗽。
- 如請求項7至8中任一項之用途,其中該藥劑用於治療或預防特發性肺疾病(IPF)或咳嗽。
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