TW202229292A - 作為trpa1抑制劑之四唑衍生物 - Google Patents
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
-
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/14—Antitussive agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pulmonology (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本發明提供某些四唑衍生物,其為瞬態受體電位錨蛋白1 (TRPA1)之抑制劑,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
本發明提供某些四唑衍生物,其為瞬態受體電位錨蛋白1 (TRPA1)之抑制劑,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)係一組主要位於眾多哺乳動物細胞類型之質膜上的電壓閘控離子通道。存在約30個結構相關之TRP通道,分成以下各組: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,為TRPA基因亞家族之唯一成員。在結構上,TRPA通道之特徵為多個N末端錨蛋白重複序列(約14個在人類TRPA1之N末端),由此產生錨蛋白名稱中之「A」(Montell, 2005)。
TRPA1在皮膚及肺之背根神經節及結狀神經節中之感覺神經元之質膜中以及小腸、結腸、胰臟、骨胳肌、心臟、腦、膀胱及淋巴細胞(https://www.proteinatlas.org/)以及人類肺纖維母細胞中大量表現。
TRPA1係已知的最佳環境刺激物感測器,產生軀體感覺模態,諸如疼痛、發冷及搔癢。TRPA1藉由多種反應性親電子刺激物(例如異硫氰酸烯丙酯、活性含氧物)以及非反應性化合物(例如伊西林(icilin))活化,涉及與哮喘、慢性肺阻塞性疾病(COPD)、特發性肺纖維化(IPF)或病毒感染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)。基於展示咳嗽誘導之TGF-β升高的研究,TRPA1抑制劑可用於治療IPF,其中由於咳嗽與肺損傷之間的關係,咳嗽非常普遍(Xie等人, 2009;Froese等人, 2016;Tschumperlin等人, 2003;Yamamoto等人, 2002;Ahamed等人, 2008)。TRPA1拮抗劑抑制由諸如香菸煙霧提取物(cigarette smoke extract,CSE)氧化壓力、發炎性介體釋放及抗氧化劑基因表現下調之類咳嗽觸發因素觸發的鈣信號傳導(Lin等人, 2015;Wang等人, 2019)。TRPA1拮抗劑在有關異位性皮膚炎(Oh等人, 2013;Wilson等人, 2013)、接觸性皮膚炎(Liu等人, 2013)、牛皮癬相關之搔癢(Wilson等人, 2013)及IL-31依賴性搔癢(Cevikbas等人, 2014)之研究中係有效的。人類TRPA1功能獲得已與家族性間歇性疼痛症候群相關(Kremeyer等人, 2010)。TRPA1拮抗劑在偏頭痛相關異常疼痛之行為模型中係有效的(Edelmayer等人, 2012)。當與神經支配健康牙齒之三叉神經節中的TRPA1表現相比時,TRPA1在神經支配損傷牙齒之三叉神經節中選擇性增加(Haas等人, 2011)。已知若干麻醉劑為TRPA1促效劑,包括異氟醚(isoflurane)(Matta等人, 2008),為TRPA1抑制劑緩解手術後疼痛提供理論基礎。用TRPA1拮抗劑治療之TRPA1基因剔除小鼠及野生型小鼠顯示出抗焦慮及抗抑鬱樣表型(de Moura等人, 2014)。基於顯示AMPK及TRPA1之間反向調節之機制聯繫的研究,預期TRPA1抑制劑在治療糖尿病性神經病變中具有益處(Hiyama等人, 2018;Koivisto及Pertovaara, 2013;Wang等人, 2018)。與野生型小鼠相比,TRPA1基因剔除小鼠展現較小的心肌梗塞尺寸(Conklin等人, 2019)。TRPA1基因剔除及藥理干預抑制小鼠的TNBS誘發之結腸炎(Engel等人, 2011)。在小鼠腦缺血模型中,TRPA1基因剔除及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,TRPA1基因剔除小鼠之尿酸鹽晶體及關節發炎減少(Moilanen等人, 2015)。在大鼠急性痛風發作模型中,大鼠中之TRPA1缺失改善關節發炎及痛覺過敏(Trevisan等人, 2014)。TRPA1活化會在骨關節炎軟骨細胞中引起發炎反應(Nummenmaa等人, 2016)。TRPA1抑制及基因缺失減少小鼠骨關節炎軟骨細胞及鼠類軟骨中之發炎介體(Nummenmaa等人, 2016)。最後,TRPA1基因剔除小鼠在MIA誘發膝部腫脹模型中展現患骨關節炎肢體上負重之改善(Horvath等人, 2016)。TRPA1在大鼠膀胱上皮(Du等人, 2007)及患有膀胱出口阻塞之患者(Du等人, 2008)中有差異性表現。TRPA1受體調節使大鼠脊髓損傷模型中之膀胱過度活動減弱(Andrade等人, 2011),且鞘內投與TRPA1拮抗劑減輕排尿反射亢進之大鼠的環磷醯胺誘發之膀胱炎(Chen等人, 2016)。
因此,需要提供強效的TRPA1抑制劑。
各種結構類別之TRPA1抑制劑評述於S. Skerratt, Progress in Medicinal Chemistry, 2017, 第56卷, 81-115;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。
本發明揭示新穎四唑衍生物,其為瞬態受體電位錨蛋白1 (TRPA1)之抑制劑,具有適當的藥理學及藥物動力學特性,使得其能夠用作治療可藉由抑制TRPA1治療之病狀及/或疾病之藥劑。
本發明之化合物可提供若干優點,諸如增強之效力、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、希望的血漿蛋白質結合、增強之生物可用性、適合的藥物動力學型態及形成穩定鹽之可能性。
本發明之化合物本發明提供新穎四唑衍生物,其出人意料地作為TRPA1之強效抑制劑(分析A),且其他特徵在於:
- 人類肝臟微粒體中改良之穩定性(分析B)
- 人類肝細胞中改良之穩定性(分析C)
本發明之化合物在結構上與WO2017/060488中之實例
28及
29的不同在於:其呋喃并[2,3-d]嗒𠯤醯基核心以及鄰近於二級脂族醇之取代基。另外,本發明之化合物在結構上與L. Schenkel等人, J. Med. Chem. 2016, 59, 2794−2809中之實例
31的不同在於,本發明之化合物具有四唑基環。此等結構差異意外地引起以下之有利組合:(i) TRPA1之抑制、(ii)在人類肝臟微粒體中之穩定性及(iii)在人類肝細胞中之穩定性。
因此,本發明之化合物在以下參數之組合方面優於先前技術中揭示之化合物:
- 作為TRPA1抑制劑之效力
- 在人類肝臟微粒體中之穩定性
- 在人類肝細胞中之穩定性。
在人類肝臟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特性之藥物作為第一篩選步驟之情形中化合物對生物轉化的敏感性。許多藥物之主要代謝部位係肝臟。人類肝臟微粒體含有細胞色素P450 (CYP),且因此表示用於在活體外研究I期藥物代謝之模型系統。在人類肝臟微粒體中之穩定性增強與包括生物可用性增加及適當半衰期在內之若干優點相關,由此可使患者能夠較少且不太頻繁的給藥。因此,在人類肝臟微粒體中之穩定性增強係打算用於藥物之化合物的有利特徵。因此,除能夠抑制TRPA1以外,預期本發明之化合物在人體中還具有有利的活體內清除率且因此具有所需之作用持續時間。
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特性之藥物之情形中化合物對生物轉化的敏感性。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,且因此表示用於在活體外研究藥物代謝之模型系統。(重要地是,與肝臟微粒體分析相比,肝細胞分析亦涵蓋II期生物轉化以及肝臟特異性轉運體介導之過程,且因此表示用於藥物代謝研究之更完整系統。)在人類肝細胞中之穩定性增強與包括生物可用性增加及適當半衰期在內之若干優點相關,由此能夠使患者較少且不太頻繁的給藥。因此,在人類肝細胞中之穩定性增強係打算用於藥物之化合物的有利特徵。
本發明提供根據式(I)之新穎化合物
其中
A係選自由以下組成之群:苯基、噻吩基、苯并噻吩基及苯并呋喃基,其未經取代或經群組R
3之一個或兩個成員取代,該群組由以下組成:-CN、鹵素、C
1-4烷基、O-C
1-4烷基、C
1-4氟烷基、O-C
1-4氟烷基、C
3-4環烷基、O-C
3-4環烷基、C
3-4環氟烷基及O-C
3-4環氟烷基;
R
1為H、H
3C或H
2N(O)C;
且
R
2為H
3C或H
2N(O)C;
其限制條件為:
當R
1為H
2N(O)C時,R
2為H
3C;
當R
2為H
2N(O)C時,R
1為H或H
3C。
本發明之另一實施例係關於一種式(I)化合物,其中R
3係選自由以下組成之群:Br、Cl、F及H
3C,且取代基A、R
1及R
2如前述實施例中之任一者中所定義。
本發明之另一實施例係關於一種式(I)化合物,其中
R
1為H
3C且R
2為H
2N(O)C;
且取代基A及R
3係如前述實施例中之任一者中所定義。
本發明之另一實施例係關於一種式(I)化合物,其中
R
1為H
2N(O)C且R
2為H
3C;
且取代基A及R
3係如前述實施例中之任一者中所定義。
所用術語及定義本文未具體定義之術語應具有熟習此項技術者根據揭示內容及上下文而提供的該等術語之含義。然而,除非有相反說明,否則如本說明書中所使用,以下術語具有所指定之含義且將遵守以下慣例。
在下文所定義之基團(group)、基團(radical)或部分中,碳原子數目通常在該基團之前指定,例如C
1-6烷基意謂具有1至6個碳原子之烷基(alkyl group/alkyl radical)。一般而言,在基團如HO、H
2N、(O)S、(O)
2S、NC (氰基)、HOOC、F
3C或類似基團中,熟習此項技術者可看到自基團自身之自由價至分子之基團連接點。對於包含兩個或多於兩個子基團之組合基團,最後命名之子基團為基團連接點,例如取代基「芳基-C
1-3烷基」意謂與C
1-3烷基-結合之芳基,該C
1-3烷基-與核心或與該取代基所連接之基團結合。
倘若以化學名稱及化學式形式描繪本發明之化合物,在有任何分歧之情況下,將以化學式為凖。可在子化學式中使用星號來指示連接至如所定義之核心分子之鍵。
取代基各原子之編號始於最接近核心或最接近取代基所連接之基團的原子。
可在子化學式中使用星號來指示連接至如所定義之核心分子之鍵。
單獨或與另一基團組合之術語「C
1-n烷基」表示具有1至n個C原子之非環狀、飽和、分支鏈或直鏈烴基,其中n為選自2、3、4或5之整數。舉例而言,術語C
1-5烷基涵蓋基團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)-。
術語「氟」添加至「烷基」、「伸烷基」或「環烷基」(飽和或不飽和)中意謂一或多個氫原子經氟原子置換之此類烷基或環烷基。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」意謂指定原子上之任一個或多個氫經來自指定群組之選擇置換,其限制條件為不超過指定原子之正常價態,且取代產生穩定化合物。
除非特別指示,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其互變異構物及所有立體異構物、光學異構物及幾何異構物(例如鏡像異構物、非鏡像異構物、E/Z異構物等)及外消旋物,以及呈不同比例之各別鏡像異構物之混合物、非鏡像異構物之混合物或存在此類異構物及鏡像異構物之前述形式中之任一者的混合物,以及鹽,包括其醫藥學上可接受之鹽,及其溶劑合物,諸如水合物,包括游離化合物之溶劑合物或化合物之鹽的溶劑合物。
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起始物質及/或藉由立體選擇性合成來獲得。此項技術中已知如何製備光學活性形式,諸如藉由解析外消旋形式,或藉由例如自光學活性起始物質起始來合成,及/或藉由使用對掌性試劑。
本發明之鏡像異構性純化合物或中間物可經由不對稱合成來製備,例如藉由製備且隨後分離適當非鏡像異構化合物或中間物,其可藉由已知方法(例如藉由層析分離或結晶)分離;及/或藉由使用對掌性試劑,諸如對掌性起始物質、對掌性催化劑或對掌性助劑。
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性純化合物,諸如藉由在對掌性固定相上層析分離相應外消旋混合物;或藉由使用適當解析劑解析外消旋混合物,例如藉助於外消旋化合物與光學活性酸或鹼形成非鏡像異構鹽,隨後解析該等鹽且自該鹽釋放所需化合物;或藉由用光學活性對掌性輔助試劑使相應外消旋化合物衍生化,隨後分離非鏡像異構物並移除對掌性輔助基團;或藉由對外消旋體進行動力學解析(例如藉由酶解析);藉由在適合條件下自鏡像晶體之聚結物進行鏡像選擇性結晶;或藉由在光學活性對掌性助劑存在下自適合溶劑(分步)結晶。
片語「醫藥學上可接受」在本文中用於指在合理醫學判斷之範圍內,適於使用而無過度毒性、刺激、過敏性反應或其他問題或併發症且與合理的效益/風險比相稱之化合物、材料、組合物及/或劑型。
如本文所用,「醫藥學上可接受之鹽」係指所揭示化合物之衍生物,其中母化合物與酸或鹼形成鹽或錯合物。與含有鹼性部分之母化合物形成醫藥學上可接受之鹽的酸之實例包括無機酸或有機酸,諸如苯磺酸、苯甲酸、檸檬酸、乙烷磺酸、反丁烯二酸、龍膽酸、氫溴酸、氫氯酸、順丁烯二酸、蘋果酸、丙二酸、杏仁酸、甲烷磺酸、4-甲基-苯磺酸、磷酸、水楊酸、丁二酸、硫酸及酒石酸。
與含有酸性部分之母化合物形成醫藥學上可接受之鹽的陽離子及鹼之實例包括Na
+、K
+、Ca
2+、Mg
2+、NH
4 +、L-精胺酸、2,2'-亞胺雙乙醇、L-離胺酸、N-甲基-D-葡糖胺或參(羥基甲基)-胺基甲烷。本發明之醫藥學上可接受之鹽可藉由習知化學方法自含有鹼性或酸性部分之母化合物合成。一般而言,此類鹽可藉由使此等化合物之游離酸或游離鹼形式與足量適當鹼或酸於水或於有機稀釋劑如乙醚、乙酸乙酯、乙醇、異丙醇或乙腈或其混合物中反應來製備。
可用於例如純化或分離本發明之化合物的除上文所提及之酸外的其他酸之鹽(例如三氟乙酸鹽)亦構成本發明之一部分。
生物分析
TRPA1
活性之評估
分析 A : TRPA1 分析可使用以下活體外TRPA1細胞分析來證實本發明之化合物之活性:
方法:
使用過度表現人類TRPA1離子通道之人類HEK293細胞株(Perkin Elmer,產品編號AX-004-PCL)作為化合物功效及效力之測試系統。藉由在FLIPRtetra系統(Molecular Devices)中量測化合物對由異硫氰酸烯丙酯(Allylisothiocyanat,AITC)促效作用誘導之細胞內鈣濃度的影響來測定化合物活性。
細胞培養:
細胞係在冷凍小瓶中以冷凍細胞形式獲得且在-150℃儲存待用。
使細胞在培養基(具有10% FCS及0.4 mg/ML遺傳黴素(Geneticin)之MEM/EBSS培養基)中生長。重要的是,密度不超過90%匯合。對於繼代培養,利用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,且將20000個細胞以每孔20 µl接種至來自Corning之聚D-離胺酸生物塗佈之384孔盤(黑色,透明底部,目錄號356697)中。將各盤在37℃/5% CO2下培育24小時,隨後用於分析中。
化合物製備
將測試化合物以10 mM之濃度溶解於100% DMSO中,且在第一步驟中在DMSO中稀釋至5 mM之濃度,之後在100% DMSO中進行連續稀釋步驟。稀釋因子及稀釋步驟之數目可根據需要而變化。通常按1:5稀釋度製備8種不同濃度,使用HBSS/HEPES緩衝液(來自Gibco之1×HEPES,目錄號14065;來自SIGMA之20mM HEPES,目錄號83264;來自Invitrogen的pH 7.4之0.1% BSA,目錄號11926)對物質進行進一步中間稀釋(1:20)。
FLIPR分析:
在分析日,用分析緩衝液洗滌細胞3次,在洗滌之後,有20 µL緩衝液殘留在孔中。將10 µL於HBSS/HEPES中之Ca6套組(目錄號R8191 MolecularDevices)上樣緩衝液添加至細胞中且將該等盤在蓋存在下在37℃/5% CO2下培育120分鐘。將10 µL來自中間稀釋盤的於HBSS/HEPES緩衝液/5% DMSO中之化合物或對照物小心地添加至孔中。在FLIPRtetra裝置上讀取發光(指示鈣流入或釋放),持續10分鐘,以監測化合物誘導之作用(例如促效作用)。最後,將10 µL溶解於HBSS/HEPES緩衝液/0.05% DMSO (最終濃度為10 µM)中之50 µM促效劑AITC添加至孔中,隨後在FLIPRtetra裝置上再讀取10分鐘。使用在添加AITC之後的信號曲線下面積(AUC)計算IC50/抑制%。
資料評估及計算:
每個分析微量滴定盤含有具有媒劑(1% DMSO)對照而非化合物之孔作為AITC誘導之發光的對照(100% CTL;高對照),且含有具有媒劑對照且無AITC之孔作為發光之非特異性變化的對照(0% CTL;低對照)。
藉由計算個別孔之信號曲線下面積來進行資料分析。基於此值,使用MegaLab軟體(內部研發)計算用於量測各物質濃度之%值(AUC(樣品)-AUC(低))×100/(AUC(高)-AUC(低))。使用MegaLab軟體自對照值%計算IC50值。計算:[y=(a-d)/(1+(x/c)^b)+d],a=低值,d=高值;x=濃度M;c=IC50 M;b=峰;y=對照%
表1:分析A中獲得的本發明之化合物的生物資料
表2:在分析A中獲得的先前技術化合物(WO2017/060488中之實例
28及
29)之生物資料。
表3:在分析A中獲得的先前技術化合物(L. Schenkel等人, J. Med. Chem. 2016, 59, 2794−2809中之實例
31)之生物資料。
實例 | hTRPA1 IC 50[nM] |
1 | 24 |
2 | 10 |
3 | 10 |
4 | 10 |
5 | 11 |
6 | 13 |
7 | 20 |
8 | 21 |
9 | 23 |
10 | 23 |
11 | 26 |
12 | 29 |
13 | 49 |
14 | 12 |
15 | 18 |
WO2017/060488中之實例 | hTRPA1 IC 50[nM] |
28 | 366 |
29 | 1120 |
Med. Chem. 2016, 59, 2794−2809中之實例 | hTRPA1 IC 50[nM] |
31 | 52 |
微粒體清除率之評估
分析
B
:
微粒體清除率
:
在37℃下使用彙集之肝臟微粒體來分析測試化合物之代謝降解。每個時間點100 µl之最終培育體積在室溫下含有TRIS緩衝液pH 7.6 (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℃下預培育較短時段之後,藉由添加呈還原形式之β-菸醯胺腺嘌呤二核苷酸磷酸(NADPH,1 mM)起始且藉由在不同時間點(0、5、15、30、60分鐘)之後將等分試樣轉移至溶劑中終止反應。另外,監測在不含NADPH之培育物中的NADPH非依賴性降解,在最後時間點終止。在NADPH非依賴性培育之後的殘留測試化合物[%]係由參數c (對照)反映(代謝穩定性)。藉由離心(10000 g,5分鐘)使經淬滅之培育物沈澱。
藉由LC-MS/MS分析上清液之等分試樣中的母化合物之量。藉由濃度-時間曲線之半對數標繪圖的斜率來測定半衰期(t1/2活體外)。
藉由考慮培育物中蛋白質之量來計算固有清除率(CL_INTRINSIC):
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]×MPPGL [mg蛋白質/g肝臟]×肝臟因子[g/kg體重])/1000
Qh [%]=CL [ml/min/kg]/肝血流量[ml/min/kg])
人類肝細胞數:120×10e6個細胞/g肝臟
人類肝臟因子:25.7 g/kg體重
人類血流量:21 ml/(min×kg)
表4:分析B中獲得的本發明之化合物的生物資料
表5:分析B中獲得的先前技術化合物(WO2017/060488中之實例
28及
29)之生物資料。
表6:分析B中獲得的先前技術化合物(L. Schenkel等人, J. Med. Chem. 2016, 59, 2794-2809中之實例
31)之生物資料。
1 | <23 |
2 | <23 |
3 | <23 |
4 | <23 |
5 | <23 |
6 | <23 |
7 | <23 |
8 | <23 |
9 | <23 |
10 | <23 |
11 | <23 |
12 | <23 |
13 | 26 |
14 | 42 |
15 | <23 |
1 | <23 |
WO2017/060488中之實例 | 人類LM [%Qh] |
28 | 62 |
29 | <23 |
Med. Chem. 2016, 59, 2794-2809中之實例 | 人類LM [%Qh] |
31 | <23 |
肝細胞清除率之評估
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(經冷凍保存)在含有5%物種血清的Dulbecco改良型eagle培養基(補充有3.5 µg升糖素/500 mL、2.5 mg胰島素/500 mL及3.75mg/500 mL氫皮質酮)中培育。
在培育箱(37℃,10% CO2)中預培育30分鐘後,將5 µl測試化合物溶液(80 µM;自2 mM於DMSO儲備溶液中之溶液用培養基按1:25稀釋)添加至395 µl肝細胞懸浮液(取決於物種,細胞密度在0.25至5百萬個細胞/毫升範圍內,通常為1百萬個細胞/毫升;測試化合物之最終濃度為1 µM,最終DMSO濃度為0.05%)中。
將細胞培育六小時(培育箱,迴轉式震盪器)且在0、0.5、1、2、4及6小時獲取樣品(25 µl)。將樣品轉移至乙腈中,且藉由離心(5分鐘)使其沈澱。將上清液轉移至新的96深孔盤中,在氮氣下蒸發且再懸浮。
藉由HPLC-MS/MS分析母化合物之減少。
CLint係如下計算:CL_INTRINSIC=劑量/AUC= (C0/CD)/(AUD+clast/k)×1000/60。C0:培育物中之初始濃度[µM],CD:活細胞之細胞密度[10e6個細胞/毫升],AUD:資料下之面積[µM×h],clast:最後資料點之濃度[µM],k:母體下降之回歸線的斜率[h-1]。
所計算之活體外肝固有清除率可按比例擴大而得到活體內固有肝清除率,且使用該肝清除率,藉由使用肝臟模型(良好攪拌模型)來預測活體內肝血液清除率(CL)。
CL_INTRINSIC_INVIVO [ml/min/kg]=(CL_INTRINSIC [µL/min/10e6個細胞]×肝細胞數[10e6個細胞/g肝臟]×肝臟因子[g/kg體重])/1000
CL [ml/min/kg]=CL_INTRINSIC_INVIVO [ml/min/kg]×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])
人類肝細胞數:120×10e6個細胞/g肝臟
人類肝臟因子:25.7 g/kg體重
人類血流量:21 ml/(min×kg)
表7:分析C中獲得的本發明之化合物的生物資料
表8:分析C中獲得的先前技術化合物(WO2017/060488中之實例
28及
29)之生物資料。
表9:分析C中獲得的先前技術化合物(L. Schenkel等人, J. Med. Chem. 2016, 59, 2794-2809中之實例
31)之生物資料。
實例 | 人類肝細胞[%Qh] |
1 | 4 |
2 | 23 |
3 | 5 |
4 | 30 |
5 | 23 |
6 | 24 |
7 | 15 |
8 | 14 |
9 | 16 |
10 | <4 |
11 | 8 |
12 | 16 |
13 | 22 |
14 | 42 |
15 | 21 |
WO2017/060488中之實例 | 人類肝細胞[%Qh] |
28 | 49 |
29 | 22 |
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)接種於過濾器插入件(Costar transwell聚碳酸酯或PET過濾器,0.4 μm孔徑)上並培養(DMEM)達10至25天。
將化合物溶解於適當溶劑(如DMSO,1-20 mM儲備溶液)中。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
4×7H
2O、0.41 mM NaH
2PO
4×H
2O、15 mM HEPES、20 mM葡萄糖、0.25% BSA,pH 7.2)稀釋儲備溶液以製備轉運溶液(0.1-300 μM化合物,最終DMSO<=0.5%)。將轉運溶液(TL)施加至頂部或底外側供體側以分別量測A-B或B-A滲透性(重複過濾3次)。在實驗開始及最後自供體收集樣品,且亦在至多2小時內的各個時間間隔自接收器側收集樣品,藉由HPLC-MS/MS或閃爍計數進行濃度量測。用新鮮接收器溶液更換取樣後之接收器體積。
評估血漿蛋白質結合此平衡透析(ED)技術係用於測定測試化合物與血漿蛋白質之近似活體外部分結合。使用Dianorm鐵氟龍透析槽(0.2微米)。每個槽由經具有5 kDa分子量截止值之超薄半透膜隔開的供體及受體室組成。在DMSO中製備1 mM的各測試化合物之儲備溶液且將其稀釋至1.0 μM之最終濃度。後續透析溶液係以自雄性及雌性供體彙集之人類或大鼠血漿(具有NaEDTA)製備。將200 μL透析緩衝液(100 mM磷酸鉀,pH 7.4)之等分試樣分配至緩衝液室中。將200 μL測試化合物透析溶液之等分試樣分配至血漿室中。在37℃下,在旋轉下培育2小時。
在透析期結束時,將透析液轉移至反應管中。用於緩衝液部分之管含有0.2 mL ACN/水(80/20)。將25 μL血漿透析液之等分試樣轉移至深孔盤中且與25 μl ACN/水(80/20)、25 μL緩衝液、25 μL校準溶液及25 μL內標溶液混合。藉由添加200 μL ACN進行蛋白質沈澱。將50 μL緩衝液透析液之等分試樣轉移至深孔盤中且與25 μL空白血漿、25 μL內標溶液及200 μL ACN混合。在HPLC-MS/MS系統上量測樣品且藉助於Analyst軟體加以評估。藉由下式計算結合百分比:結合%=(血漿濃度-緩衝液濃度/血漿30濃度)×100。
評估溶解性在孔盤(格式取決於機器人)中,藉由將適當體積之所選水性培養基(通常在0.25-1.5 ml範圍內)添加至含有已知量之固體原料藥(通常在0.5至5.0 mg範圍內)之各孔中來製備飽和溶液。將孔震盪或攪拌預定時間段(通常在2-24小時範圍內)且隨後使用適當的濾膜(通常為具有0.45 µm孔徑之PTFE過濾器)過濾。藉由丟棄前幾滴濾液來避免過濾器吸收。藉由UV光譜分析來確定經溶解之原料藥之量。另外,使用玻璃電極pH計量測飽和水溶液之pH值。
評估藥物動力學特徵將測試化合物經靜脈內或經口投與各別測試物種。在施用測試化合物後若干時間點採集血液樣品,進行抗凝且離心。
對血漿樣品中之分析物,即所投與之化合物及/或代謝物之濃度進行定量。使用非室體模型方法計算PK參數。將AUC及Cmax針對1 μmol/kg劑量標準化。
評估活體外在人類肝細胞中之代謝使用呈懸浮液形式之初代人類肝細胞來研究測試化合物之代謝路徑。在自冷凍保存恢復之後,將人類肝細胞在含有5%人類血清並補充有3.5 µg升糖素/500 ml、2.5 mg胰島素/500 ml及3.75 mg/500 ml氫皮質酮之Dulbecco改良型eagle培養基中培育。
在細胞培養培育箱(37℃,10% CO
2)中預培育30分鐘之後,將測試化合物溶液摻入肝細胞懸浮液中以獲得1.0×10
6至4.0×10
6個細胞/毫升之最終細胞密度(取決於利用初代人類肝細胞觀察到的化合物之代謝轉換速率)、10 µM之最終測試化合物濃度及0.05%之最終DMSO濃度。
將細胞在水平震盪器上之細胞培養培育箱中培育六小時,且根據代謝轉換速率,在0、0.5、1、2、4或6小時之後自培育物取出樣品。將樣品用乙腈淬滅且藉由離心使其沈澱。將上清液轉移至96孔深孔盤中,在氮氣下蒸發且使其再懸浮,隨後藉由液相層析-高解析度質譜進行生物分析以鑑別推定的代謝物。
基於Fourier-Transform-MS
n資料臨時地指定結構。代謝物係以人類肝細胞培育物中母體之百分比報導,且臨限值為≥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活性相關或由TRPA1活性調節之疾病及/或病狀,包括但不限於治療及/或預防纖維變性疾病、發炎性及免疫調節病症、呼吸道或胃腸道疾病或不適、眼科疾病、關節之發炎性疾病以及鼻咽、眼睛及皮膚之發炎性疾病、以及疼痛及神經病症。該等病症、疾病及不適包括咳嗽、特發性肺纖維化、其他肺間質性疾病及其他纖維變性、哮喘或過敏性疾病、嗜伊紅血球性疾病、慢性阻塞性肺病,以及發炎性及免疫調節病症,諸如類風濕性關節炎及動脈粥樣硬化,以及疼痛及神經病症,諸如急性疼痛、手術疼痛、慢性疼痛以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:
(1)咳嗽,諸如慢性特發性咳嗽或慢性難治性咳嗽、與哮喘、COPD、肺癌、病毒感染後及特發性肺纖維化以及其他肺間質性疾病相關之咳嗽。
(2)肺纖維變性疾病,諸如與膠原變性,例如紅斑狼瘡、全身性硬皮病、類風濕性關節炎、多發性肌炎及皮肌炎相關之肺炎或間質性肺炎;特發性間質性肺炎,諸如肺部肺纖維化(IPF)、非特異性間質性肺炎、呼吸性細支氣管炎相關性間質性肺病、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細胞性間質性肺炎;淋巴管平滑肌瘤病;肺泡蛋白沈積症;朗格漢氏細胞(Langerhan's cell)組織細胞增生症;肋膜肺實質彈性纖維增生;已知病因之間質性肺病,諸如由職業暴露引起之間質性肺炎,諸如石棉沈著病、矽肺病、礦工肺(煤塵)、農夫肺(乾草及黴菌)、飼鴿者肺(鳥類)或其他職業性空氣傳播之觸發因素諸如金屬粉塵或分枝桿菌,或由諸如放射、甲胺喋呤(methotrexate)、胺碘酮(amiodarone)、呋喃妥因(nitrofurantoin)或化學治療劑之類治療引起之間質性肺炎;或肉芽腫性疾病,諸如肉芽腫性多血管炎、查格-施特勞斯氏症候群(Churg-Strauss syndrome)、類肉瘤病、過敏性肺炎或由不同來源(例如抽吸、吸入有毒氣體、蒸氣、支氣管炎或肺炎)引起之間質性肺炎;或由心臟衰竭、X射線、放射、化學療法、M. boeck或類肉瘤病、肉芽腫病、囊性纖維化或黏液黏稠病或α-1抗胰蛋白酶缺乏症引起之間質性肺炎。
(3)其他纖維變性疾病,諸如肝橋纖維化、肝硬化、非酒精性脂肪變性肝炎(NASH)、心房纖維化、心內膜心肌纖維化、陳舊性心肌梗塞、膠質瘢痕、動脈硬化、關節纖維化、迪皮特朗氏攣縮(Dupuytren's contracture)、瘢痕瘤、硬皮病/全身性硬化症、縱隔纖維化、骨髓纖維化、佩洛尼氏病(Peyronie's disease)、腎源性全身性纖維化、腹膜後纖維化、黏黏性關節囊炎。
(4)發炎性、自體免疫性或過敏性疾病及病狀,諸如過敏性或非過敏性鼻炎或鼻竇炎、慢性鼻竇炎或鼻炎、鼻息肉、慢性鼻-鼻竇炎、急性鼻-鼻竇炎、哮喘、小兒哮喘、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、 成人呼吸窘迫症候群、支氣管及肺水腫、支氣管炎或肺炎、嗜伊紅血球性蜂窩組織炎(例如威爾氏症候群(Well's syndrome))、嗜伊紅血球性肺炎(例如勒夫勒氏症候群(Loeffler's syndrome)、慢性嗜伊紅血球性肺炎)、嗜伊紅血球性筋膜炎(例如舒爾曼氏症候群(Shulman's syndrome))、遲發型過敏、非過敏性哮喘;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;全身性重度過敏或過敏性反應、藥物過敏(例如對青黴素、頭孢菌素過敏)、由攝入受污染之色胺酸引起之嗜伊紅血球增多-肌痛症候群、昆蟲蜇傷過敏;自體免疫性疾病,諸如類風濕性關節炎、格雷夫氏病(Graves' disease)、休格連氏症候群(Sjogren's syndrome)、牛皮癬性關節炎、多發性硬化症、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、小兒ITP)、免疫性溶血性貧血(自體免疫性及藥物誘發)、伊凡氏症候群(Evans syndrome) (血小板及紅血球免疫性血細胞減少症)、新生兒Rh病、古巴斯德氏症候群(Goodpasture's syndrome) (抗GBM疾病)、乳糜瀉、自體免疫性心肌病、青少年發病型糖尿病;絲球體腎炎、自體免疫性甲狀腺炎、白塞氏病(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,諸如克羅恩氏病(Crohn's disease)及潰瘍性結腸炎;脊椎關節病;硬皮病;牛皮癬(包括T細胞介導型牛皮癬)及發炎性皮膚病,諸如皮膚炎、濕疹、異位性皮膚炎、過敏性接觸性皮膚炎、風疹;血管炎(例如壞死性、皮膚性及過敏性血管炎);結節性紅斑;嗜伊紅血球性肌炎、嗜伊紅血球性筋膜炎、伴隨皮膚或器官之白血球浸潤之癌症;眼科疾病,諸如年齡相關之黃斑變性、糖尿病性視網膜病變及糖尿病性黃斑水腫、角膜炎、嗜伊紅血球性角膜炎、角膜結膜炎、春季角膜結膜炎、瘢痕形成、前段瘢痕形成、瞼緣炎、瞼結膜炎、大皰性疾病、瘢痕性類天疱瘡、結膜黑素瘤、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、格雷夫氏眼病(Graves' ophthalmopathy)、眼內黑素瘤、瞼裂斑、增生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,諸如慢性特發性疼痛症候群、神經性病變疼痛、感覺遲鈍、觸摸痛、偏頭痛、牙痛及術後疼痛。
(6)抑鬱症、焦慮症、糖尿病性神經病及膀胱病症,諸如膀胱出口阻塞、膀胱過動症、膀胱炎;心肌再灌注損傷或腦缺血損傷。
因此,本發明係關於一種通式1之化合物,其用作藥劑。
此外,本發明係關於通式1之化合物的用途,其用於治療及/或預防與TRPA1活性相關或由TRPA1活性調節之疾病及/或病狀。
此外,本發明係關於通式1之化合物之用途,其用於治療及/或預防纖維變性疾病、發炎性及免疫調節病症、呼吸道或胃腸道疾病或不適、眼科疾病、關節之發炎性疾病以及鼻咽、眼睛及皮膚之發炎性疾病、疼痛及神經病症。該等病症、疾病及不適包括咳嗽、特發性肺纖維化、其他肺間質性疾病及其他纖維變性、哮喘或過敏性疾病、嗜伊紅血球性疾病、慢性阻塞性肺病,以及發炎性及免疫調節病症,諸如類風濕性關節炎及動脈粥樣硬化,以及疼痛及神經病症,諸如急性疼痛、手術疼痛、慢性疼痛以及抑鬱症及膀胱病症。
此外,本發明係關於通式1之化合物的用途,其用於治療及/或預防:
(1)咳嗽,諸如慢性特發性咳嗽或慢性難治性咳嗽、與哮喘、COPD、肺癌、病毒感染後及特發性肺纖維化以及其他肺間質性疾病相關之咳嗽。
(2)肺纖維變性疾病,諸如與膠原變性,例如紅斑狼瘡、全身性硬皮病、類風濕性關節炎、多發性肌炎及皮肌炎相關之肺炎或間質性肺炎;特發性間質性肺炎,諸如肺部肺纖維化(IPF)、非特異性間質性肺炎、呼吸性細支氣管炎相關性間質性肺病、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細胞性間質性肺炎;淋巴管平滑肌瘤病;肺泡蛋白沈積症;朗格漢氏細胞組織細胞增生症;肋膜肺實質彈性纖維增生;已知病因之間質性肺病,諸如由職業暴露引起之間質性肺炎,諸如石棉沈著病、矽肺病、礦工肺(煤塵)、農夫肺(乾草及黴菌)、飼鴿者肺(鳥類)或其他職業性空氣傳播之觸發因素諸如金屬粉塵或分枝桿菌,或由諸如放射、甲胺喋呤、胺碘酮、呋喃妥因或化學治療劑之類治療引起之間質性肺炎;或肉芽腫性疾病,諸如肉芽腫性多血管炎、查格-施特勞斯氏症候群(Churg-Strauss syndrome)、類肉瘤病、過敏性肺炎或由不同來源(例如抽吸、吸入有毒氣體、蒸氣、支氣管炎或肺炎)引起之間質性肺炎;或由心臟衰竭、X射線、放射、化學療法、M. boeck或類肉瘤病、肉芽腫病、囊性纖維化或黏液黏稠病或α-1抗胰蛋白酶缺乏症引起之間質性肺炎。
(3)其他纖維變性疾病,諸如肝橋纖維化、肝硬化、非酒精性脂肪變性肝炎(NASH)、心房纖維化、心內膜心肌纖維化、陳舊性心肌梗塞、膠質瘢痕、動脈硬化、關節纖維化、迪皮特朗氏攣縮、瘢痕瘤、硬皮病/全身性硬化症、縱隔纖維化、骨髓纖維化、佩洛尼氏病、腎源性全身性纖維化、腹膜後纖維化、黏黏性關節囊炎。
(4)發炎性、自體免疫性或過敏性疾病及病狀,諸如過敏性或非過敏性鼻炎或鼻竇炎、慢性鼻竇炎或鼻炎、鼻息肉、慢性鼻-鼻竇炎、急性鼻-鼻竇炎、哮喘、小兒哮喘、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、 成人呼吸窘迫症候群、支氣管及肺水腫、支氣管炎或肺炎、嗜伊紅血球性蜂窩組織炎(例如威爾氏症候群)、嗜伊紅血球性肺炎(例如勒夫勒氏症候群、慢性嗜伊紅血球性肺炎)、嗜伊紅血球性筋膜炎(例如舒爾曼氏症候群)、遲發型過敏、非過敏性哮喘;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;全身性重度過敏或過敏性反應、藥物過敏(例如對青黴素、頭孢菌素過敏)、由攝入受污染之色胺酸引起之嗜伊紅血球增多-肌痛症候群、昆蟲蜇傷過敏;自體免疫性疾病,諸如類風濕性關節炎、格雷夫氏病、休格連氏症候群、牛皮癬性關節炎、多發性硬化症、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、小兒ITP)、免疫性溶血性貧血(自體免疫性及藥物誘發)、伊凡氏症候群(血小板及紅血球免疫性血細胞減少症)、新生兒Rh病、古巴斯德氏症候群(抗GBM疾病)、乳糜瀉、自體免疫性心肌病、青少年發病型糖尿病;絲球體腎炎、自體免疫性甲狀腺炎、白塞氏病;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,諸如克羅恩氏病及潰瘍性結腸炎;脊椎關節病;硬皮病;牛皮癬(包括T細胞介導型牛皮癬)及發炎性皮膚病,諸如皮膚炎、濕疹、異位性皮膚炎、過敏性接觸性皮膚炎、風疹;血管炎(例如壞死性、皮膚性及過敏性血管炎);結節性紅斑;嗜伊紅血球性肌炎、嗜伊紅血球性筋膜炎、伴隨皮膚或器官之白血球浸潤之癌症;眼科疾病,諸如年齡相關之黃斑變性、糖尿病性視網膜病變及糖尿病性黃斑水腫、角膜炎、嗜伊紅血球性角膜炎、角膜結膜炎、春季角膜結膜炎、瘢痕形成、前段瘢痕形成、瞼緣炎、瞼結膜炎、大皰性疾病、瘢痕性類天疱瘡、結膜黑素瘤、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、格雷夫氏眼病、眼內黑素瘤、瞼裂斑、增生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,諸如慢性特發性疼痛症候群、神經性病變疼痛、感覺遲鈍、觸摸痛、偏頭痛、牙痛及術後疼痛。
(6)抑鬱症、焦慮症、糖尿病性神經病及膀胱病症,諸如膀胱出口阻塞、膀胱過動症、膀胱炎;心肌再灌注損傷或腦缺血損傷。
在另一態樣中,本發明係關於一種通式1之化合物,其用於治療及/或預防上文所提及之疾病及病狀。
在另一態樣中,本發明係關於通式1之化合物的用途,其用於製備供治療及/或預防上文所提及之疾病及病狀用的藥劑。
在本發明之另一態樣中,本發明係關於用於治療或預防上文所提及之疾病及病狀的方法,該方法包含向人類投與有效量的通式1之化合物。
組合療法本發明化合物可進一步與一或多種、較佳一種額外治療劑組合。根據一個實施例,該額外治療劑係選自以下之群:可用於治療上文所描述之疾病或病狀,特定言之與纖維變性疾病、發炎性及免疫調節病症、呼吸道或胃腸道疾病或不適、關節或鼻咽、眼睛及皮膚之發炎性疾病或病狀,諸如咳嗽、特發性肺纖維化、其他肺間質性疾病、哮喘或過敏性疾病、嗜伊紅血球性疾病、慢性阻塞性肺病、異位性皮膚炎以及自體免疫性病變(諸如類風濕性關節炎及動脈粥樣硬化)相關之疾病或病狀的治療劑;或可用於治療眼科疾病、疼痛及抑鬱症之治療劑。
適用於此類組合之額外治療劑特定地包括例如加強一或多種活性物質對所提及之適應症中之一者的治療作用及/或使一或多種活性物質之劑量減少的治療劑。
因此,本發明之化合物可與一或多種選自由以下組成之群的額外治療劑組合:抗纖維變性劑、止咳劑、抗炎劑、抗異位性皮膚炎劑、鎮痛劑、抗驚厥劑、抗焦慮劑、鎮靜劑、骨骼肌鬆弛劑或抗抑鬱劑。
抗纖維變性劑為例如尼達尼布(nintedanib);吡非尼酮(pirfenidone);磷酸二酯酶-IV (PDE4)抑制劑,諸如羅氟司特(roflumilast);自分泌運動因子抑制劑,諸如GLPG-1690或BBT-877;結締組織生長因子(CTGF)阻斷抗體,諸如潘瑞魯單抗(Pamrevlumab);B細胞活化因子受體(BAFF-R)阻斷抗體,諸如拉那魯單抗(Lanalumab);α-V/β-6阻斷抑制劑,諸如BG-00011/STX-100;重組穿透素-2 (PTX-2),諸如PRM-151;c-Jun N末端激酶(JNK)抑制劑,諸如CC-90001;半乳糖凝集素-3抑制劑,諸如TD-139;G-蛋白偶聯受體84 (GPR84)抑制劑,諸如GLPG-1205;G蛋白偶聯受體84/G蛋白偶聯受體40雙重抑制劑,諸如PBI-4050;Rho相關含捲曲螺旋蛋白激酶2 (ROCK2)抑制劑,諸如KD-025;熱休克蛋白47 (HSP47)小干擾RNA,諸如BMS-986263/ND-L02-s0201;Wnt路徑抑制劑,諸如SM-04646;LD4/PDE3/4抑制劑,諸如泰必魯斯特(Tipelukast);組胺醯tRNA合成酶(HARS)之重組免疫調節域,諸如ATYR-1923;前列腺素合酶抑制劑,諸如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,諸如PAT-1251、PXS-5382/PXS-5338;磷酸肌醇3-激酶(PI3K)/哺乳動物雷帕黴素目標蛋白(mTOR)雙重抑制劑,諸如HEC-68498;鈣蛋白酶(calpain)抑制劑,諸如BLD-2660;促分裂原活化蛋白激酶激酶激酶(MAP3K19)抑制劑,諸如MG-S-2525;殼質酶抑制劑,諸如OATD-01;促分裂原活化蛋白激酶活化蛋白激酶2 (MAPKAPK2)抑制劑,諸如MMI-0100;轉型生長因子β1 (TGF-β1)小干擾RNA,諸如TRK250/BNC-1021;或溶血磷脂酸受體拮抗劑,諸如BMS-986278。
止咳劑為例如嘌呤受體3 (P2X3)受體拮抗劑,諸如吉法匹生(gefapixant)、S-600918、BAY-1817080或BLU-5937;神經激肽1 (NK-1)受體拮抗劑,諸如奧維匹坦(Orvepitant)、阿瑞匹坦(Aprepitant);菸鹼型乙醯膽鹼受體α7次單元刺激劑,諸如ATA-101/布拉丹尼克(bradanicline);可待因(codeine)、加巴噴丁(gabapentin)、普瑞巴林(pregablin)或阿奇黴素(azithromycin)。
抗炎劑為例如皮質類固醇,諸如普賴蘇穠(prednisolone)或地塞米松(dexamethasone);環加氧酶2 (COX2)抑制劑,諸如塞內昔布(celecoxib)、羅非昔布(rofecoxib)、帕瑞昔布(parecoxib)、伐地昔布(valdecoxib)、德拉昔布(deracoxib)、依他昔布(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,諸如孟魯司特(monteleukast);5-脂肪加氧酶抑制劑;或其他非類固醇抗炎劑(NSAIDs),諸如阿司匹林(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)。
抗異位性皮膚炎劑為例如環孢素、甲胺喋呤、黴酚酸嗎啉乙酯(mycophenolate mofetil)、硫唑嘌呤、磷酸二酯酶抑制劑(例如阿普斯特(apremilast)、克里硼羅(crisaborole))、詹納斯(Janus)相關激酶(Janus Associated Kinase,JAK)抑制劑(例如托法替尼(tofacitinib))、針對IL-4/IL-13之中和抗體(例如度匹魯單抗(dupilamab))、針對IL-13之中和抗體(例如來瑞組單抗(lebrikizumab)、曲羅蘆單抗(tralokinumab))及針對IL-31之中和抗體(尼立珠單抗(nemolizumab))。
鎮痛劑為例如類鴉片型,諸如嗎啡鹼、氧化嗎啡鹼(oxymorphine)、樂沃帕諾(levopanol)、羥考酮(oxycodon)、丙氧芬(propoxyphene)、納美芬(nalmefene)、芬太尼(fentanyl)、氫可酮(hydrocondon)、氫嗎啡酮(hydromorphone)、美利皮定(meripidine)、美沙酮(methadone)、納洛芬(nalorphine)、納洛酮(naloxone)、納曲酮(naltrexone)、丁基原啡因(buprenorphine)、布托啡諾(butorphanol)、納布啡(nalbuphine)、戊唑星(pentazocine);或非類鴉片型,諸如苯乙胺(acetophenamine)。
抗抑鬱劑為例如三環類抗抑鬱劑,諸如阿米替林(amitriptyline)、氯米帕明(clomipramine)、地斯帕明(despramine)、多慮平(doxepin)、地昔帕明(desipramine)、丙咪嗪(imipramine)、去甲替林(nortriptyline);選擇性血清素再吸收抑制劑類抗抑鬱劑(SSRI),諸如氟西汀(fluoxetine)、帕羅西汀(paroxetine)、舍曲林(sertraline)、西酞普蘭(citalopram)、依地普蘭(escitalopram);去甲腎上腺素再吸收抑制劑類抗抑鬱劑(SNRI),諸如麥普替林(maprotiline)、洛夫帕明(lofepramine)、米氮平(mirtazapine)、羥丙替林(oxaprotiline)、非左拉明(fezolamine)、托莫西汀(tomoxetine)、米安色林(mianserin)、丁胺苯丙酮(buproprion)、羥基安非他酮(hydroxybuproprion)、諾米芬辛(nomifensine)、維洛沙嗪(viloxazine);血清素-去甲腎上腺素雙重再吸收抑制劑類抗抑鬱劑(SNRI),諸如度洛西汀(duloxetine)、文拉法辛(venlafaxine)、去甲文拉法辛(desvenlafaxine)、左旋米那普侖(levomilnacipran);非典型抗抑鬱劑,諸如曲唑酮(trazodone)、米氮平(mirtazapine)、沃替西汀(vortioxetine)、維拉唑酮(vilazodone)、安非他酮;或單胺氧化酶抑制劑類抗抑鬱劑(MAOI),諸如反苯環丙胺(tranylcypromine)、苯乙肼(phenelzine)或異卡波肼(isocarboxazid)。
抗焦慮劑為例如苯并二氮呯類,諸如阿普唑侖(alprazolam)、溴西泮(bromazepam)、氯氮卓(chlordiazepoxide)、氯硝西泮(clonazepam)、氯拉西泮(clorazepate)、地西泮(diazepam)、弗拉西泮(flurazepam)、勞拉西泮(lorazepam)、奧沙西泮(oxazepam)、替馬西泮(temazepam)、三唑侖(triazolam)或托非索泮(tofisopam);或其為非苯二氮卓類催眠藥,諸如右佐匹克隆(eszopiclone)、紮來普隆(zaleplon)、唑吡坦(zolpidem)或佐匹克隆(zopiclone);或其為胺基甲酸酯類,例如美普巴(meprobamate)、卡利索普杜(carisoprodol)、泰巴胺酯(tybamate)或勞胺酯(lorbamate);或其為抗組胺藥,諸如羥嗪(hydroxyzine)、氯芬尼拉明(chlorpheniramine)或苯海拉明(diphenhydramine)。
鎮靜劑為例如巴比妥酸鹽類鎮靜劑,諸如阿莫巴比妥(amobarbital)、阿普巴比妥(aprobarbital)、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)、塞麥妥(theamylal)或硫噴妥(thiopental);或其為非巴比妥酸鹽類鎮靜劑,諸如格魯米特(glutethimide)、美普巴、甲喹酮(methaqualone)或二氯苯甲酮(dichloalphenazone)。
骨骼肌鬆弛劑為例如貝可芬(baclofen)、美普巴、卡利索普杜、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)或奧芬那君(orphenadrine)。
其他適合之組合搭配物為以下之抑制劑:乙醯膽鹼酯酶抑制劑,諸如多奈哌齊(donepezil);5-HT-3拮抗劑,諸如昂丹司瓊(ondansetron);代謝型麩胺酸受體拮抗劑;抗心律不整藥,諸如美西律(mexiletine)或苯妥英(phenytoin);或NMDA受體拮抗劑。
其他適合之組合搭配物為失禁藥物,例如抗膽鹼激導性劑,諸如奧昔布寧(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,諸如米拉貝隆(mirabegron);或其為α阻斷劑,諸如坦索羅辛(tamsulosin)、阿夫唑嗪(alfuzosin)、西洛多辛(silodosin)、多沙唑嗪(doxazosin)或特拉唑嗪(terazosin)。
上述組合搭配物之劑量通常係通常建議之最低劑量之1/5至通常建議之劑量之1/1。
因此,在另一態樣中,本發明係關於根據本發明之化合物與一或多種上下文中所述之額外治療劑之組合的用途,其用於治療可能受TRPA1影響或由TRPA1介導的疾病或病狀,特定言之如上下文中所述之疾病或病狀。
在另一態樣中,本發明係關於一種用於治療患者的可受TRPA1抑制影響之疾病或病狀的方法,其包括以下步驟:向需要此類治療之患者投與治療有效量的式(I)化合物或其醫藥學上可接受之鹽以及治療有效量的一或多種額外治療劑。
在另一態樣中,本發明係關於式(I)化合物或其醫藥學上可接受之鹽與一或多種額外治療劑之組合的用途,其用於治療有需要之患者的可受TRPA1抑制影響的疾病或病狀。
在又一態樣中,本發明係關於一種用於治療患者的由TRPA1活性介導之疾病或病狀的方法,其包括以下步驟:向需要此類治療之患者(較佳人類)投與治療有效量的本發明之化合物以及治療有效量的一或多種上下文中所述之額外治療劑。
與該額外治療劑組合之根據本發明之化合物的使用可同時進行或在錯開的時間進行。
根據本發明之化合物及一或多種額外治療劑可二者共同存在於一種調配物,例如錠劑或膠囊中,或分別存在於兩種相同或不同的調配物中,例如呈所謂的分裝部分之套組形式。
因此,在另一態樣中,本發明係關於一種醫藥組合物,其包含根據本發明之化合物及一或多種上下文中所述之額外治療劑,視情況連同一或多種惰性載劑及/或稀釋劑。
在又一態樣中,本發明係關於根據本發明之化合物在咳嗽量測裝置中之用途。
本發明之其他特徵及優點將自以下更詳細之實例而變得顯而易知,該等實例以舉例方式說明本發明之原理。
製備根據本發明之化合物及其中間物可使用熟習此項技術者已知且描述於有機合成文獻中之合成方法來獲得。較佳地,該等化合物係以與下文更完整解釋且特定言之如實驗部分中所描述之製備方法類似的方式獲得。在一些情況下,進行反應步驟之次序可變化。亦可使用熟習此項技術者已知但在此處未詳細描述之反應方法的變型。
熟習此項技術者研究以下流程將對用於製備根據本發明之化合物的一般方法變得顯而易知。可使用習知保護基來保護起始物質或中間物中之任何官能基。此等保護基可再在反應順序內之適合階段使用熟習此項技術者熟悉之方法裂解。
根據本發明之化合物係藉由下文所述之合成方法製備,其中各通式之取代基具有上文所給出之含義。此等方法意欲作為本發明之說明,而不限制其主題及此等實例所主張之化合物的範圍。當未描述起始化合物之製備時,其係可商購的或可按與本文中所述之已知化合物或方法類似地製備。文獻中所述之物質係根據公開之合成方法製備。縮寫如實例部分中所定義。
流程1:
在流程1中,氯甲基四唑在鹼(例如K
2CO
3)存在下用在羰基α位攜帶離去基「LG」(例如Cl或Br)之適當乙酮衍生物進行
N-烷基化,得到兩種區位異構物之混合物。非所需區位異構物(未繪示)可藉由使用適當梯度進行之層析移除。所得酮(A)可藉由使用適當催化系統,使用過渡金屬錯合物(例如Ru或Ir)與對掌性配位體(例如[(1S,2S)-2-胺基-1,2-二苯基乙基](4-甲苯磺醯基)醯胺基)及氫源(諸如甲酸三乙胺錯合物)之組合以鏡像選擇性方式還原以得到醇(B)。最終化合物(F)可藉由以下方式合成:在鹼(諸如K
2CO
3)存在下,用中間物(B)使6-甲基-4-側氧基-3H,4H-呋喃并[2,3-d]嘧啶-5-甲酸(C)烷基化,且隨後在鹼存在下,用偶合試劑(諸如HATU)及氨源(諸如碳酸銨)使羧酸(D)醯胺化。替代地,最終化合物(F)可經由用偶合試劑(諸如CDI)及氨使(C)醯胺化且隨後用中間物(B)使醯胺(E)烷基化來合成。
流程2:
在流程2中,描述最終化合物(K)之合成。1-(4,6-二氯嘧啶-5-基)乙-1-酮在鹼(諸如三級丁醇鉀)存在下用乙醇酸乙酯進行親核芳族取代得到中間物(G),其隨後可用乙醇鈉及鹼(諸如三級丁醇鉀)處理以得到中間物(H)。用例如碘化鈉及氯化三甲基矽烷在乙腈中脫除(H)之嘧啶酮之保護基,得到酯(I),其可在路易斯酸(Lewis acid) (諸如氯化鈣)存在下與氨反應,得到醯胺(J)。最後,醯胺(J)在鹼(諸如碳酸鉀)存在下用中間物(B)烷基化,得到最終化合物(K)。
實例
製備
根據本發明之化合物及其中間物可使用熟習此項技術者已知且描述於有機合成文獻中的合成方法,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中描述的方法獲得。較佳地,該等化合物係以與下文更完整解釋且特定言之如實驗部分中所描述之製備方法類似的方式獲得。在一些情況下,進行反應流程所採用之順序可變化。亦可使用熟習此項技術者已知但在本文中未詳細描述之此等反應之變型。熟習此項技術者研究以下流程將對用於製備根據本發明之化合物的一般方法變得顯而易知。起始化合物係可商購的或可藉由文獻或本文中所述之方法製備,或可以類似或相似方式製備。在進行反應之前,起始化合物中之任何相應官能基均可使用習知保護基保護。此等保護基可再在反應順序內之適合階段使用熟習此項技術者熟悉且文獻中,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中所述之方法裂解。術語「環境溫度」及「室溫」可互換使用且表示約20℃,例如介於19至24℃之間的溫度。
縮寫:
ACN | 乙腈 |
Aq. | 水溶液 |
℃ | 攝氏度 |
CDI | 羰基二咪唑 |
CyH/CH | 環己烷 |
conc. | 濃縮的 |
DCM | 二氯甲烷 |
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 | 二甲亞碸 |
ESI-MS | 電噴霧電離質譜分析 |
EtOAc | 乙酸乙酯 |
EtOH | 乙醇 |
ex | 實例 |
eq | 當量 |
FA | 甲酸 |
h | 小時 |
HATU | 1-[雙(二甲胺基)亞甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧六氟磷酸鹽 |
HCl | 鹽酸 |
HPLC | 高效液相層析 |
Int. | 中間物 |
K 2CO 3 | 碳酸鉀 |
K(OtBu) | 三級丁醇鉀 |
L | 公升 |
LiOH*H 2O | 單水合氫氧化鋰 |
M | 莫耳濃度 |
MeOH | 甲醇 |
MgSO 4 | 硫酸鎂 |
min | 分鐘 |
mL | 毫升 |
MTBE | 三級丁基甲基醚 |
NaOEt | 乙醇鈉 |
NH 3 | 氨 |
PMB | 對甲氧基苯甲基 |
Prep. | 製備型 |
RP | 反相 |
RT | 室溫(約20℃) |
sat. | 飽和的 |
TBTU | 四氟硼酸苯并三唑基四甲 |
TEA | 三乙胺 |
TFA | 三氟乙酸 |
TFAA | 三氟乙酸酐 |
THF | 四氫呋喃 |
TMS-Cl | 氯化三甲基矽烷 |
中間物之製備
中間物
I
在室溫下,在攪拌下,向於15 mL DMA中之1.00 g (8.44 mmol) 5-(氯甲基)-2H-1,2,3,4-四唑及2.17 g (9.28 mmol) 4-氯苯甲醯甲基溴中添加1.63 g (11.8 mmol) K
2CO
3。在室溫下攪拌反應混合物30分鐘且隨後過濾。將濾液用水及飽和NaCl水溶液稀釋且用EtOAc萃取三次。將合併之有機相用水洗滌,經Na
2SO
4乾燥,經活性炭過濾,且在減壓下移除溶劑。藉由管柱層析(矽膠;CH/EtOAc,80/20至50/50梯度)純化殘餘物以得到產物。
C
10H
8Cl
2N
4O (M = 271.1 g/mol)
ESI-MS: 271 [M+H]
+R
t(HPLC): 1.01分鐘(方法B)
以下化合物係使用與針對中間物I.1所述程序類似之程序,使用適當起始物質製備。熟習此項技術者應瞭解,此等類似實例可涉及一般反應條件之變化。
中間物 | 起始物質 | 結構 | ESI-MS | 1H NMR (300 MHz, DMSO- d 6) δ ppm或HPLC滯留時間[分鐘] (方法) | 反應條件(與一般程序之偏差) |
I.2 | IV.1 | 295 [M+H] + | 0.56 (A) | ACN,10分鐘 | |
I.3 | 293 [M+H] + | 1.12 (B) | 起始物質1:1 | ||
I.4 | 311 [M+H] + | 1.23 (B) | 2當量鹼 | ||
I.5 | 315/317 [M+H] + | 1.00 (H) | 攪拌1小時; | ||
I.6 | 311 [M+H] + | 1.08 (H) | 起始物質1:1 | ||
I.7 | 277 [M+H] + | 1.26 (B) | 2當量鹼,起始物質1:1 攪拌15分鐘 | ||
I.8 | 277 [M+H] + | 1.01 (H) | |||
I.9 | 251 [M+H] + | 0.95 (H) | |||
I.10 | IV.2 | 295 [M+H] + | 1.02 (B) | 起始物質1:1 |
中間物
II
中間物
II.1 (
一般程序
)
(1R)-2-[5-(氯甲基)-2H-1,2,3,4-四唑-2-基]-1-(4-氯苯基)乙-1-醇
在惰性氛圍下,將1.30 g (4.80 mmol) 1-(4-氯苯基)-2-[5-(氯甲基)-2H-1,2,3,4-四唑-2-基]乙-1-酮(中間物I.1)溶解於20 mL ACN中。添加12 mg (0.02 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)釕(II) (CAS 174813-81-1),接著逐滴添加0.72 mL (1.73 mmol)甲酸三乙胺錯合物(5:2)。在室溫下攪拌3小時之後,在減壓下移除溶劑。向剩餘粗混合物中添加水且用EtOAc萃取此混合物。將有機層合併,經Na
2SO
4乾燥,過濾,用活性炭處理,過濾且在減壓下移除溶劑,得到中間物II.1。
C
10H
10Cl
2N
4O (M = 273.1 g/mol)
ESI-MS: 273 [M+H]
+R
t(HPLC): 0.96分鐘(方法B)
以下化合物係使用與針對中間物II.1所述程序類似之程序,使用適當起始物質製備。熟習此項技術者應瞭解,此等類似實例可涉及一般反應條件之變化。
中間物 | 起始物質 | 結構 | ESI-MS | HPLC滯留時間[分鐘] (方法) |
II.2 | I.2 | 297 [M+H] + | 0.52 (A) | |
II.3 | I.3 | 295 [M+H] + | 1.10 (B) | |
II.4 | I.4 | 313 [M+H] + | 1.17 (B) | |
II.5 | I.5 | 317/319 [M+H] + | 1.14 (B) | |
II.6 | I.6 | 313 [M+H] + | 1.03 (B) | |
II.7 | I.7 | 279 [M+H] + | 1.14 (B) | |
II.8 | I.8 | 279 [M+H] + | 0.97 (H) | |
II.9 | I.9 | 253 [M+H] + | 0.48 (A) | |
II.10 | I.10 | 297 [M+H] + | 0.97 (B) |
中間物 III中間物III.1
1-(7-氟-1-苯并呋喃-2-基)乙-1-酮
將6.00 g (42.8 mmol) 3-氟-2-羥基苯甲醛於60 mL丙酮中之經攪拌溶液冷卻至0℃且隨後用9.47 g (68.5 mmol)碳酸鉀處理。在0℃下攪拌10分鐘之後,逐滴添加5.12 mL (64.2 mmol)氯丙酮且在90℃下攪拌反應混合物1小時。將反應混合物冷卻至室溫且在減壓下濃縮。將粗殘餘物用EtOAc/水萃取且將有機相在減壓下濃縮以得到中間物III.1。
C
10H
7FO
2(M = 178.2 g/mol)
ESI-MS: 179 [M+H]
+R
t(HPLC): 0.50分鐘(方法A)
以下化合物係以類似於中間物III.1之方式製備。熟習此項技術者應瞭解,此類似實例可涉及一般反應條件之變化。
中間物 | 起始物質 | 結構 | ESI-MS | HPLC滯留時間 [分鐘] (方法) | 反應條件(與一般程序之偏差) |
III.2 | 179 [M+H] + | 0.95 (B) | 1.1當量氯丙酮;1.7當量鹼;在70℃下3小時 |
中間物 IV中間物IV.1
2-溴基-1-(7-氟-1-苯并呋喃-2-基)乙-1-酮
在室溫下,在攪拌下,向於66 mL THF中之5.47 g (30.7 mmol) 1-(7-氟-1-苯并呋喃-2-基)乙-1-酮(中間物III.1)中逐滴添加14.81 g (30.7 mmol)三溴化四丁基銨於3.3 mL MeOH及32 mL THF中之溶液。在室溫下攪拌反應混合物2小時,在減壓下濃縮且用EtOAc/水萃取殘餘物。在減壓下濃縮有機層且將粗物質藉由管柱層析(矽膠;己烷/EtOAc,梯度)純化。
C
10H
6BrFO
2(M = 257.1 g/mol)
ESI-MS: 257 / 259 [M+H]
+R
t(HPLC): 0.58分鐘(方法A)
以下化合物係以類似於中間物IV.1之方式製備。熟習此項技術者應瞭解,此類似實例可涉及一般反應條件之變化。
中間物 | 起始物質 | 結構 | ESI-MS | HPLC滯留時間 [分鐘] (方法) |
IV.2 | III.2 | 257/259 [M+H] + | 1.03 (B) |
在室溫下,將2.90 g (14.94 mmol) 6-甲基-4-側氧基-3H,4H-呋喃并[2,3-d]嘧啶-5-甲酸(CAS:852399-94-1,European Journal of Medicinal Chemistry, 2018, 第144卷, 第330-348頁)及2.66 g (16.43 mmol) CDI在60 mL THF中攪拌18小時。隨後,添加90 mL於THF中之NH
3(0.5 mol/L)且在室溫下持續攪拌3小時。將反應混合物減壓濃縮,倒入NaHCO
3水溶液(100 mL水+40 mL飽和NaHCO
3水溶液)中,且濾出所得沈澱物且乾燥,得到中間物V。
C
8H
7N
3O
3(M = 193.2 g/mol)
ESI-MS: 194 [M+H]
+R
t(HPLC): 0.61分鐘(方法B)
在0℃下,向111 µL (1.15 mmol)乙醇酸乙酯於5.0 mL THF中之經攪拌溶液中緩慢添加三級丁醇鉀溶液(1.26 mL,1.0 mol/L)。在0℃下攪拌35分鐘之後,添加200 mg (1.05 mmol) 1-(4,6-二氯嘧啶-5-基)乙-1-酮,且在0℃下繼續攪拌2小時且在室溫下攪拌3小時。減壓濃縮反應混合物且藉由管柱層析(矽膠;己烷/EtOAc,梯度)純化。
C
10H
11ClN
2O
4(M = 258.66 g/mol)
ESI-MS: 259 [M+H]
+R
t(HPLC): 1.05分鐘(方法B)
在-12℃下,向2.23 g (8.62 mmol)中間物VI於THF中之經攪拌溶液中緩慢添加乙醇鈉於乙醇中之溶液(2.95 mL,21%)。在0℃下攪拌反應混合物90分鐘,添加三級丁醇鉀於THF中之溶液(4.31 mL,1.0 mol/L)且在室溫下繼續攪拌隔夜。再添加THF中之三級丁醇鉀(1.0 mL,1.0 mol/L)且在室溫下繼續攪拌3小時。將反應混合物用乙酸進行酸化且在減壓下濃縮。用水/EtOAc萃取反應混合物,將有機萃取物經MgSO
4乾燥,過濾且在減壓下濃縮。經由反相HPLC (ACN/H
2O梯度,0.1% TFA)純化,得到中間物VII。
C
12H
14N
2O
4(M = 250.25 g/mol)
ESI-MS: 251 [M+H]
+R
t(HPLC): 0.63分鐘(方法A)
向50 mg (0.20 mmol)中間物VII於2 mL ACN中之經攪拌溶液中添加90 mg (0.60 mmol)碘化鈉且在室溫下攪拌混合物3分鐘。隨後,添加76 µL (0.60 mmol)氯化三甲基矽烷,且密封反應容器且在室溫下繼續攪拌2小時。將反應物用10 mL水淬滅且在室溫下攪拌5分鐘。濾出沈澱物,用水洗滌且在50℃下減壓乾燥,得到中間物VIII。
C
10H
10N
2O
4(M = 222.20 g/mol)
ESI-MS: 223 [M+H]
+R
t(HPLC): 0.78分鐘(方法B)
在密封容器中,將800 mg (3.60 mmol)中間物VIII及400 mg (3.60 mmol) CaCl
2於128 mL氨/MeOH (7 mol/L)中之混合物在50℃下攪拌36小時。在減壓下濃縮反應混合物,在50 mL水中攪拌且濾出所得沈澱物,用水洗滌且在60℃下減壓乾燥,得到中間物IX。
C
8H
7N
3O
3(M = 193.16 g/mol)
ESI-MS: 194 [M+H]
+R
t(HPLC): 0.50分鐘(方法H)
將120 mg (0.47 mmol) 6-甲基-4-側氧基-3H,4H-呋喃并[2,3-d]嘧啶-5-甲酸(CAS:852399-94-1)、92 mg (0.47 mmol) (1R)-2-[5-(氯甲基)-2H-1,2,3,4-四唑-2-基]-1-(4-甲基苯基)乙-1-醇(中間物II.9)及98 mg (0.71 mmol) K
2CO
3於2 mL DMA中之混合物在室溫下攪拌隔夜。隨後,添加98 mg (0.71 mmol) K
2CO
3且將混合物在60℃下攪拌2小時,且在80℃下攪拌5小時。將反應混合物冷卻至室溫且藉由反相HPLC (ACN/H
2O梯度,0.1% TFA)純化,得到所需產物。
C
19H
18N
6O
5(M = 410.38 g/mol)
ESI-MS: 411 [M+H]
+R
t(HPLC): 0.90分鐘(方法H)
以下化合物係使用與針對中間物X.1所述程序類似之程序,使用適當起始物質製備。熟習此項技術者應瞭解,此等類似實例可涉及一般反應條件之變化。
中間物 | 起始物質 | 結構 | ESI-MS | HPLC滯留時間 [分鐘] (方法) |
X.2 | + II.6 | 471 [M+H] + | 0.97 (H) | |
X.3 | + II.10 | 455 [M+H] + | 0.92 (H) |
最終化合物之製備
實例
1 (
一般程序
A)
3-({2-[(2R)-2-羥基-2-(4-甲基苯基)乙基]-2H-1,2,3,4-四唑-5-基}甲基)-6-甲基-4-側氧基-3H,4H-呋喃并[2,3-d]嘧啶-5-甲醯胺
在室溫下,將1.50 g (7.77 mmol) 6-甲基-4-側氧基-3H,4H-呋喃并[2,3-d]嘧啶-5-甲醯胺(中間物V)、3.22 g (23.30 mmol) K
2CO
3及1.96 g (7.77 mmol) (1R)-2-[5-(氯甲基)-2H-1,2,3,4-四唑-2-基]-1-(4-甲基苯基)乙-1-醇(中間物II.9)於25 mL DMA中之混合物攪拌隔夜。將反應混合物倒於冰水上且用EtOAc萃取三次。將合併之有機層用MgSO
4攪拌,過濾,在減壓下濃縮,且藉由反相HPLC (ACN/H
2O梯度,0.3% TFA)純化,得到所需產物。
C
19H
19N
7O
4(M = 409.4 g/mol)
ESI-MS: 410 [M+H]
+R
t(HPLC): 0.73分鐘(方法B)
1H NMR (400 MHz,
DMSO-d 6) δ ppm: 2.25 (s, 3 H), 2.72 (s, 3 H), 4.74 (d,
J=6.6 Hz, 2 H), 5.02 - 5.08 (m, 1 H), 5.58 (s, 2 H), 5.74 (s, 1 H), 7.10 (d,
J=8.0 Hz, 2 H), 7.21 (d,
J=8.0 Hz, 2 H), 7.55 (br d,
J=1.3 Hz, 1 H), 8.74 (s, 1 H), 9.16 - 9.22 (m, 1 H)
以下化合物係使用與針對實例1一般程序A所述程序類似之程序,使用適當起始物質製備。熟習此項技術者應瞭解,此等類似實例可涉及一般反應條件之變化。
實例 | 起始物質 | 結構 | 反應條件 |
2 | IX+ II.3 | DMF,1.0當量II.3,3.3當量鹼,室溫,50℃,5小時 | |
3 | IX + II.8 | DMF,1.0當量II.8,3.3當量鹼,50℃,5小時 | |
4 | V + II.4 | DMF,1.0當量II.4,3.0當量鹼,室溫,隔夜 | |
5 | V + II.3 | DMF,1.0當量II.3,3.0當量鹼,室溫,隔夜 | |
6 | IX + II.6 | DMF,1.0當量II.6,3.3當量鹼,50℃,5小時 | |
7 | V + II.8 | DMF,1.0當量II.8,1.5當量鹼,室溫,隔夜 | |
8 | IX + II.9 | DMF,1.0當量II.9,2.0當量鹼,50℃,3小時 | |
9 | V + II.1 | DMF,1.1當量II.1,1.5當量鹼,室溫,隔夜 | |
10 | IX + II.1 | DMF,1.0當量II.1,3.3當量鹼,50℃,3小時 | |
11 | V + II.7 | DMA,1.0當量II.7,3.0當量鹼,室溫,隔夜 | |
12 | V + II.5 | DMF,1.0當量II.5,3.0當量鹼,室溫,隔夜 | |
13 | V + II.2 | DMF,1.0當量II.2,3.0當量鹼,室溫,隔夜 |
化合物之分析資料描述於上表中:
實例 | ESI-MS | HPLC滯留時間[分鐘] (方法) | 1H NMR (400 MHz, DMSO- d 6) δ ppm |
2 | 452 [M+H] + | 0.58 (D) | 2.53 (s, 3 H), 4.88 - 5.02 (m, 2 H), 5.43 - 5.50 (m, 1 H), 5.52 (s, 2 H), 6.43 (d, J=5.2 Hz, 1 H), 7.28 - 7.35 (m, 3 H), 7.58 (br s, 1 H), 7.72 - 7.76 (m, 1 H), 7.87 - 7.95 (m, 2 H), 8.72 (s, 1 H) |
3 | 436 [M+H] + | 0.56 (D) | 2.53 (s, 3 H), 4.77 - 4.92 (m, 2 H), 5.26 - 5.32 (m, 1 H), 5.51 (s, 2 H), 6.39 (d, J=5.2 Hz, 1 H), 6.87 (dd, J=3.8, 0.8 Hz, 1 H), 6.94 (d, J=3.8 Hz, 1 H), 7.57 (br s, 1 H), 7.90 (br s, 1 H), 8.72 (s, 1 H) |
4 | 470 [M+H] + | 0.63 (D) | 2.72 (s, 3 H), 4.85 - 5.03 (m, 2 H), 5.39 - 5.48 (m, 1 H), 5.59 (s, 2 H), 6.45 (br d, J=3.9 Hz, 1 H), 7.21 (td, J=9.1, 2.4 Hz, 1 H), 7.28 (s, 1 H), 7.55 (br s, 1 H), 7.75 (dd, J=8.7, 5.3 Hz, 1 H), 7.81 (dd, J=9.3, 2.3 Hz, 1 H), 8.74 (s, 1 H), 9.13 - 9.23 (m, 1 H) |
5 | 452 [M+H] + | 0.61 (D) | 2.72 (s, 3 H), 4.87 - 5.04 (m, 2 H), 5.46 (dd, J=7.9, 4.75 Hz, 1 H), 5.59 (s, 2 H), 6.43 (s, 1 H), 7.29 (s, 1 H), 7.30 - 7.37 (m, 2 H), 7.55 (d, J=1.7 Hz, 1 H), 7.69 - 7.76 (m, 1 H), 7.86 - 7.93 (m, 1 H), 8.75 (s, 1 H), 9.19 (d, J=1.7 Hz, 1 H) |
6 | 470 [M+H] + | 0.61 (D) | 2.52 (s, 3 H), 4.96 - 5.08 (m, 2 H), 5.25 - 5.30 (m, 1 H), 5.50 (s, 2 H), 6.30 (br s, 1 H), 6.83 (s, 1 H), 7.30 (dd, J=8.8, 2.2 Hz, 1 H), 7.56 - 7.60 (m, 2 H), 7.66 (d, J=2.2 Hz, 1 H), 7.89 (br s, 1 H), 8.69 (s, 1 H) |
7 | 436 [M+H] + | 1.12 (B) | 2.71 (s, 3 H), 4.78 - 4.92 (m, 2 H), 5.24 - 5.32 (m, 1 H), 5.59 (s, 2 H), 6.39 (d, J=5.2 Hz, 1 H), 6.82 - 6.84 (m, 1 H), 6.92 (d, J=3.8 Hz, 1 H), 7.52 - 7.57 (m, 1 H), 8.75 (s, 1 H), 9.15 - 9.21 (m, 1 H) |
8 | 410 [M+H] + | 0.58 (E) | 2.26 (s, 3 H), 2.53 (s, 3 H), 4.74 (d, J=6.6 Hz, 2 H), 5.01 - 5.09 (m, 1 H), 5.51 (s, 2 H), 5.74 (d, J=4.8 Hz, 1 H), 7.11 (d, J=7.9 Hz, 2 H), 7.24 (d, J=7.9 Hz, 2 H), 7.58 (br s, 1 H), 7.90 (br s, 1 H), 8.72 (s, 1 H) |
9 | 430 [M+H] + | 0.84 (C) | 2.72 (s, 3 H), 4.73 - 4.84 (m, 2 H), 5.08 - 5.13 (m, 1 H), 5.57 (s, 2 H), 5.92 (s, 1 H), 7.31 - 7.38 (m, 4 H), 7.55 (br d, J=1.4 Hz, 1 H), 8.74 (s, 1 H), 9.17 - 9.22 (m, 1 H) |
10 | 430 [M+H] + | 0.97 (H) | 2.54 (s, 3 H), 4.73 - 4.84 (m, 2 H), 5.08 - 5.15 (m, 1 H), 5.50 (s, 2 H), 5.91 (d, J=4.9 Hz, 1 H), 7.33 - 7.40 (m, 4 H), 7.57 (br s, 1 H), 7.90 (br s, 1 H), 8.71 (s, 1 H) |
11 | 436 [M+H] + | 0.57 (D) | 2.72 (s, 3 H), 4.97 - 5.08 (m, 2 H), 5.26 (dt, J=7.6, 5.3 Hz, 1 H), 5.57 (s, 2 H), 6.23 (d, J=5.6 Hz, 1 H), 6.79 - 6.81 (m, 1 H), 7.19 - 7.23 (m, 1 H), 7.25 - 7.30 (m, 1 H), 7.51 - 7.58 (m, 3 H), 8.72 (s, 1 H), 9.17 (d, J=1.8 Hz, 1 H) |
12 | 474 / 476 [M+H] + | 0.66 (E) | 2.72 (s, 3 H), 4.69 - 4.86 (m, 2 H), 5.09 (dt, J=7.4, 5.1 Hz, 1 H), 5.57 (s, 2 H), 5.91 (d, J=4.8 Hz, 1 H), 7.27 - 7.32 (m, 2 H), 7.45 - 7.50 (m, 2 H), 7.54 (d, J=1.5 Hz, 1 H), 8.74 (s, 1 H), 9.19 (d, J=1.4 Hz, 1 H) |
13 | 454 [M+H] + | 0.45 (A) | 2.72 (s, 3 H), 4.98 - 5.11 (m, 2 H), 5.30 (dt, J=7.3, 5.4 Hz, 1 H), 5.57 (s, 2 H), 6.33 (d, J=5.7 Hz, 1 H), 6.89 (d, J=2.7 Hz, 1 H), 7.13 - 7.25 (m, 2 H), 7.33 - 7.42 (m, 1 H), 7.53 (d, J=1.5 Hz, 1 H), 8.70 (s, 1 H), 9.16 (d, J=1.7 Hz, 1 H) |
最終化合物之製備
實例
1 (
一般程序
B)
3-({2-[(2R)-2-羥基-2-(4-甲基苯基)乙基]-2H-1,2,3,4-四唑-5-基}甲基)-6-甲基-4-側氧基-3H,4H-呋喃并[2,3-d]嘧啶-5-甲醯胺
向於2.0 mL DMF中之35 mg (0.09 mmol) 3-({2-[(2R)-2-羥基-2-(4-甲基苯基)乙基]-2H-1,2,3,4-四唑-5-基}甲基)-6-甲基-4-側氧基-3H,4H-呋喃并[2,3-d]嘧啶-5-甲酸(中間物X.1)中添加32 mg (0.09 mmol) HATU及73 µL (0.43 mmol) DIPEA,同時在室溫下攪拌。在5分鐘之後,添加82 mg (0.85 mmol)碳酸銨且在室溫下攪拌混合物隔夜。藉由反相HPLC (ACN/H
2O梯度,0.1% NH
3)純化混合物,得到所需產物。
以下化合物係使用與針對實例1一般程序B所述程序類似之程序,使用適當起始物質製備。熟習此項技術者應瞭解,此等類似實例可涉及一般反應條件之變化。
實例 | 起始物質 | 結構 | 反應條件 |
14 | X.2 | DMF,1.0當量HATU,5.0當量DIPEA,10當量碳酸銨,室溫,隔夜 | |
15 | X.3 | DMF,1.0當量HATU,5.0當量DIPEA,10當量碳酸銨,室溫,隔夜 |
化合物之分析資料描述於上表中:
實例 | ESI-MS | HPLC滯留時間[分鐘] (方法) | 1H NMR (400 MHz, DMSO- d 6) δ ppm |
14 | 470 [M+H] + | 0.90 (H) | 2.72 (s, 3 H), 4.96 - 5.09 (m, 2 H), 5.27 (dd, J=7.4, 4.9 Hz, 1 H), 5.57 (s, 2 H), 6.80 (s, 1 H), 7.30 (dd, J=8.8, 2.2 Hz, 1 H), 7.54 (br d, J=1.3 Hz, 1 H), 7.55 - 7.59 (m, 1 H), 7.63 - 7.65 (m, 1 H), 8.71 (s, 1 H), 9.15 - 9.19 (m, 1 H) |
15 | 454 [M+H] + | 0.85 (C) | 2.72 (s, 3 H), 4.96 - 5.09 (m, 2 H), 5.22 - 5.29 (m, 1 H), 5.57 (s, 2 H), 6.27 (d, J=5.7 Hz, 1 H), 6.79 (s, 1 H), 7.10 (td, J=9.2, 2.7 Hz, 1 H), 7.36 (dd, J=8.9, 2.7 Hz, 1 H), 7.51 - 7.58 (m, 2 H), 8.70 (s, 1 H), 9.16 (d, J=1.7 Hz, 1 H) |
分析型
HPLC
方法
方法
A
方法
B
方法
C
方法
D
方法
E
方法
F
方法
G
方法
H
方法
I
方法
J
方法
K
時間(分鐘) | 體積%水 (包括0.1% TFA) | 體積% ACN | 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 |
分析管柱:XBridge BEH (Waters) C18_2.1×30 mm_1.7 μm;管柱溫度:60℃ |
時間(分鐘) | 體積%水 (包括0.1% TFA) | 體積% ACN | 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 |
分析管柱:Stable Bond (Agilent) C18_3.0×30 mm_1.8 µm;管柱溫度:60℃ |
時間(分鐘) | 體積%水 (包括0.1% NH 3) | 體積% ACN | 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 |
分析管柱:Xbridge (Waters) C18_3.0×30 mm_2.5 µm;管柱溫度:60℃ |
時間(分鐘) | 體積%水 (包括0.1% NH 4OH) | 體積% ACN | 流量[mL/min] |
0.00 | 95 | 5 | 1.5 |
1.30 | 0 | 100 | 1.5 |
1.50 | 0 | 100 | 1.5 |
1.60 | 95 | 5 | 1.5 |
分析管柱:XBridge C18_3.0×30 mm_2.5 µm (Waters);管柱溫度:60℃ |
時間(分鐘) | 體積%水 (包括0.1% TFA) | 體積% ACN 0.08%TFA | 流量[mL/min] |
0.00 | 95 | 5 | 1.5 |
1.30 | 0 | 100 | 1.5 |
1.50 | 0 | 100 | 1.5 |
1.60 | 95 | 5 | 1.5 |
分析管柱:Sunfire (Waters);C18_3.0×30 mm_2.5 µm,管柱溫度:60℃ |
時間(分鐘) | 體積%水 (包括0.1% TFA) | 體積% ACN | 流量[mL/min] |
0.00 | 95 | 5 | 1.3 |
0.02 | 95 | 5 | 1.3 |
1.00 | 0 | 100 | 1.3 |
1.30 | 0 | 100 | 1.3 |
分析管柱:XBridge BEH (Waters) C18_2.1×30 mm_2.5 μm;管柱溫度:60℃ |
時間(分鐘) | 體積%水 (包括0.1% TFA) | 體積% ACN | 流量[mL/min] |
0.00 | 99 | 1 | 1.6 |
0.02 | 99 | 1 | 1.6 |
1.0 | 0 | 100 | 1.6 |
1.1 | 0 | 100 | 1.6 |
分析管柱:Zorbax StableBond C18 (Agilent) 1.8 µm;2.1×30 mm;管柱溫度:60℃ |
時間(分鐘) | 體積%水 (包括0.1% TFA) | 體積% ACN | 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 |
分析管柱:Sunfire (Waters) 2.5 µm;3.0×30 mm;管柱溫度:60℃ |
時間(分鐘) | 體積%水 (包括0.1% TFA) | 體積% ACN | 流量[mL/min] |
0.00 | 95 | 5 | 1.5 |
1.30 | 0 | 100 | 1.5 |
1.50 | 0 | 100 | 1.5 |
分析管柱:Sunfire C18 (Waters) 2.5 µm;3.0×30 mm;管柱溫度:60℃ |
時間(分鐘) | 體積%水 (包括0.1% FA) | 體積% ACN (包括0.1% FA) | 流量[mL/min] |
0.00 | 60 | 40 | 0.5 |
6.00 | 40 | 60 | 0.5 |
6.8 | 40 | 60 | 0.5 |
7.00 | 10 | 90 | 0.5 |
8.10 | 10 | 90 | 0.5 |
8.50 | 60 | 40 | 0.5 |
10 | 60 | 40 | 0.5 |
分析管柱:Acquity UPLC BEH;C8_2.1×150 mm_1.7µm;管柱溫度:55℃ |
時間(分鐘) | 體積%水 (包括0.1% NH 3) | 體積% ACN | 流量[mL/min] |
0.00 | 95 | 5 | 1.3 |
0.02 | 95 | 5 | 1.3 |
1.00 | 0 | 100 | 1.3 |
1.30 | 0 | 100 | 1.3 |
分析管柱:XBridge BEH Phenyl (Waters) 2.1×30 mm_1.7 μm;管柱溫度:60℃ |
Claims (13)
- 如請求項1或2中任一項之式(I)化合物,其中R 3係選自由以下組成之群:Br、Cl、F及H 3C。
- 如請求項1、2及4中任一項之式(I)化合物,其中R 1為H 3C且R 2為H 2N(O)C。
- 如請求項1、2及4中任一項之式(I)化合物,其中R 1為H 2N(O)C且R 2為H 3C。
- 一種如請求項1至8中任一項之化合物之鹽,尤其是醫藥學上可接受之鹽。
- 一種醫藥組合物,其包含至少一種如請求項1至8中任一項之式I化合物或其醫藥學上可接受之鹽及一或多種醫藥學上可接受之賦形劑。
- 一種如請求項1至8中任一項之式(I)化合物或其醫藥學上可接受之鹽的用途,其用於製造藥劑。
- 一種如請求項1至8中任一項之化合物或其醫藥學上可接受之鹽的用途,其用於製造供治療或預防發炎性氣道疾病或纖維變性疾病或咳嗽用之藥劑。
- 一種如請求項1至8中任一項之化合物或其醫藥學上可接受之鹽的用途,其用於製造供治療或預防特發性肺病(IPF)或咳嗽用之藥劑。
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