TWI516265B - 作為通道抑制劑之化合物及醫藥組合物及其用途 - Google Patents
作為通道抑制劑之化合物及醫藥組合物及其用途 Download PDFInfo
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- TWI516265B TWI516265B TW101111540A TW101111540A TWI516265B TW I516265 B TWI516265 B TW I516265B TW 101111540 A TW101111540 A TW 101111540A TW 101111540 A TW101111540 A TW 101111540A TW I516265 B TWI516265 B TW I516265B
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- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical compound C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Epidemiology (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本發明係關於噻吩并嘧啶化合物，其為鉀通道抑制劑。亦提供包含該等化合物之醫藥組合物及其在治療心律不整中之用途。
離子通道為跨越細胞膜脂質雙層之蛋白質且提供特定離子(諸如Na+、K+、Ca2+及Cl-)可通過之水性路徑(Herbert,1998)。鉀通道為離子通道之最大且最多樣之子群且其在調節膜電位及控制細胞興奮性方面起著重要作用(Armstrong及Hille,1998)。鉀通道已基於其胺基酸序列及其生物物理學性質而歸類於基因家族中(關於命名，參見Gutman等人，2003)。
調節鉀通道之化合物在包括心血管、神經元、聽覺、腎臟、代謝及細胞增殖在內之數種疾病領域中具有多種治療應用(Shieh等人，2000；Ford等人，2002)。更特定言之，鉀通道(諸如Kv4.3、Kir2.1、hERG、KCNQ1/minK及Kv1.5)與心肌細胞中動作電位之再極化相有關。此等鉀通道亞型已與包括長QT症候群、肥大、心室纖維性顫動及心房纖維性顫動之心血管疾病及病症有關，所有該等疾病及病症均會引起心衰竭及死亡(Marban,2002)。
人類延遲整流電壓門控鉀通道亞單元Kv1.5僅表現於心房肌細胞中且咸信由於以下數種不同原因而為處理心房纖維性顫動提供治療機會(參見Brendel及Peukert,2002之綜
述)：(i)有證據表明Kv1.5因類似生物物理學及藥理學性質而構成人類中之心臟超速延遲整流(Kv(ur))生理電流之基礎(Wang等人，1993；及Fedida等人，1993)。此已由Kv1.5之反義寡核苷酸證明，該等反義寡核苷酸已顯示降低人類心房肌細胞中之Kv(ur)幅度(Feng等人，1997)。(ii)電生理記錄已展示Kv(ur)選擇性表現於心房肌細胞中，且因此經由干擾心室再極化來避免誘發潛在致命的心室調律不整(Amos等人，1996；Li等人，1996；及Nattel,2002)。(iii)與正常健康人類心房肌細胞相比，在心房纖維性顫動型人類心房肌細胞中抑制Kv(ur)使動作電位持續時間延長(Courtemanche等人，1999)。(iv)與傳統III類抗心律不整藥相比，藉由選擇性抑制Kv1.5來延長動作電位持續時間可藉由延長心房不應期而不改變心室不應性來提供更安全的藥理學介入，以用於防止心房再傳入心律不整(諸如心房纖維性顫動及心房撲動)(Nattel等人，1999；Knobloch等人，2002；及Wirth等人，2003)。III類抗心律不整藥已被廣泛報導為治療心律不整之較佳方法(Colatsky等人，1990)。
已報導傳統及新穎之III類抗心律不整鉀通道阻斷劑具有藉由直接調節Kv1.5或Kv(ur)來起作用之機制。已知的III類抗心律不整藥胺巴利特(ambasilide)(Feng等人，1997)、奎尼丁(quinidine)(Wang等人，1995)、氯非銨(clofilium)(Malayev等人，1995)及柏托沙米(bertosamil)(Godreau等人，2002)均已被報導為人類心房肌細胞中Kv(ur)之鉀通道
阻斷劑。在活體內犬模型中新穎苯并哌喃衍生物NIP-142阻斷Kv1.5通道，延長心房不應期且終止心房纖維性顫動及心房撲動(Matsuda等人，2001)，且S9947抑制穩定表現於爪蟾(Xenopus)卵母細胞及中國倉鼠卵巢(CHO)細胞中之Kv1.5以及天然大鼠及人類心肌細胞中之Kv(ur)(Bachmann等人，2001)。另外，已針對心律不整之治療描述了其他靶向Kv1.5或Kv(ur)之新穎鉀通道調節劑，此等調節劑包括聯苯(Peukert等人，2003)、噻吩羧酸醯胺(WO0248131)、二芳基衍生物(WO0244137、WO0246162)、碳醯胺衍生物(WO0100573、WO0125189)、鄰胺基苯甲醯胺(WO2002100825、WO02088073、WO02087568)、二氫嘧啶(WO0140231)、環烷基衍生物(WO03063797)、茚滿衍生物(WO0146155、WO9804521)、萘滿苯并環庚烷衍生物(WO9937607)、噻唑啉酮及間噻唑酮衍生物(WO9962891)、苯甲醯胺衍生物(WO0025774)、異喹啉衍生物(WO0224655)、噠嗪酮衍生物(WO9818475、WO9818476)、色滿衍生物(WO9804542)、苯并哌喃衍生物(WO0121610、WO03000675、WO0121609、WO0125224、WO02064581)、苯并噁嗪衍生物(WO0012492)及自海洋物質中純化而得之新穎化合物A1998(Xu及Xu,2000)。一般電壓門控鉀通道抑制劑已經報導，其亦可調節Kv1.5(US05753676、US05821251、EP0743936B)。
已報導噻吩并嘧啶適用作抗發炎劑、抗真菌劑、抗骨質疏鬆劑及抗微生物劑，且尤其適用作心血管藥劑(經由調
節酶之磷酸二酯酶群或經由調節鈉/質子交換系統來起作用)。
4位經視情況經取代之苯甲胺或苯乙胺部分取代且5位經甲基取代之噻吩并[2,3-d]-嘧啶可用作抗發炎劑或抗骨質疏鬆劑(Katada等人，1999)。該等化合物顯示調節數種細胞類型(包括白血球，其源自於骨髓中之造血前驅細胞)之活性。白血球活性增加會引起各種發炎疾病；因此對白血球有細胞毒性之化合物可用作抗發炎藥。認為該等化合物藉由與白血球表面上之整合素結合且阻止下游細胞信號傳導事件來抑制細胞活性。4位經雜芳基硫醇、芳基硫醇、芳基甲基硫醇、雜芳基胺、苯甲胺、羥基及氯基取代之噻吩并[2,3-d]嘧啶亦可為有用的抗發炎劑(Stewart等人，2001)。此系列化合物顯示抑制血管內皮管腔表面上之細胞黏著分子之誘導表現，由此防止白血球在發炎位點處黏著。
以下各物均已顯示具有抗微生物活性：4位具有經取代之肼且5位具有苯基之噻吩并[2,3-d]嘧啶(Hozien等人，1996)；四氫苯并[b]噻吩并[2,3-d]嘧啶(Ismail等人，1995)；2位具有氫、氯、肼、雜環基、胺基、甲基、乙基或苯基、4位具有烷基胺基、烷基芳基胺基、胺基、二烷基胺基或肼基取代基、5位具有氫或甲基、6位具有氫、甲基乙醯胺或苯基、或5,6位具有四亞甲基之噻吩并[2,3-d]嘧啶(GB7549025)；及2位具有甲基或苯基且4位具有烷基胺基或芳基胺基之5-苯基噻吩并[2,3-d]嘧啶及5,6-四亞甲基
噻吩并[2,3-d]嘧啶之引生系列(Konno等人，1989)。4位具有2-側氧基-3-吡咯啶基亞甲基-肼基部分之四氫苯并噻吩并[2,3-d]嘧啶顯示對絨葉(velvet leaf)有一定殺草活性(Ram等人，1981)。亦已報導4-氯四氫苯并噻吩并[2,3-d]嘧啶為殺草劑，4位具有硫醇、肼、2-氟苯胺基、3-氟苯胺基或4-二乙基苯胺基取代基之四氫苯并噻吩并-[2,3-d]嘧啶為糞鏈球菌(Streptococcus fecales)之殺細菌劑，且4位具有2,4-二氯苯甲基胺基或2-氟苯胺基取代基之四氫苯并噻吩并[2,3-d]嘧啶為腐黴菌(Pythium)之殺真菌劑(Ram,1979)。2位具有氫、羥基、硫醇、鹵素或氰基、4位具有烷基胺基、芳基烷基胺基或羥基烷基胺基、5位及/或6位具有氫、烷基或鹵素、或5,6位具有伸烷基之噻吩并[2,3-d]嘧啶已被報導為控壁虱劑(AU 521790)。
另外，四氫苯并[b]噻吩并[2,3-d]嘧啶顯示出抗腫瘤活性(Shehata等人，1996)及阿司匹靈(aspirin)鎮痛活性一半之鎮痛活性(Moneer等人，1994)，一系列具有4-烷基胺基或芳基胺基、5-H或5-甲基、6-甲基或5,6-四亞甲基之噻吩并[2,3-d]嘧啶顯示具有作為抗細胞分裂素之可能性(Jordis等人，1986)，一系列2位經芳基胺或雜環胺取代且4位經芳基胺取代之5,6-二甲基-噻吩并[2,3-d]嘧啶及5,6-四亞甲基噻吩并[2,3-d]嘧啶顯示血小板聚集抑制性質(DD 226893)，4位經胺基、丁胺、苯胺、環己胺、苯甲胺、苯乙胺及2-羥乙胺取代之哌喃并[3,4-b]噻吩并[5,4-d]嘧啶及硫代哌喃并[3,4-b]噻吩并[5,4-d]嘧啶已報導顯示出抗抽搐
活性(Noravyan等人，1977)，且4-[(苯并-2,1,3-噻二唑基-4)胺基]-5,6,7,8-四氫苯并噻吩并-(2,3-d)-嘧啶已報導在幼蟲肺泡包蟲病中具有驅蠕蟲活性(RU 2116309)。
4位具有經取代之胺基、5位及6位具有氫、烷基或鹵基取代基且2位具有烷基鏈之噻吩并[2,3-d]嘧啶被主張為磷酸二酯酶V之抑制劑且適用於治療心血管疾病及性功能障礙(DE10104802)。
另外，發現4位具有哌嗪基取代基之5-烷基噻吩并[2,3-d]嘧啶為鈉/質子交換劑之抑制劑且適用於治療各種心血管病症，包括心絞痛及心律不整(WO 01/27107)。
發現攜有5-噻吩基取代基及2-甲基取代基之4-[(苯基)胺基]-噻吩并[2,3-d]嘧啶具有殺軟體動物活性(Hosni等人，Acta Poloniae Pharmaceutics,1999,56(1),49-56)。
近來，噻吩并嘧啶亦已被報導為強力VEGFR抑制劑(Munchhof,2004)。
數個公開案揭示經指示作用於鉀通道之化合物。因此，US6531495揭示2'-胺基甲基聯苯-2-甲醯胺，WO2002/100825揭示鄰胺基苯甲醯胺為抗心律不整藥且WO2002/036556揭示醯基胺基烷基苯磺醯胺為心血管藥劑。
適用作鉀通道抑制劑、特定言之適用於抑制鉀通道Kv1.5或Kv(ur)之噻吩并嘧啶化合物報導於WO 2004/111057中。
本發明之第一態樣提供式(Ia)化合物：
或其醫藥學上可接受之酯或鹽。
在一個實施例中，化合物具有式(Ib)：
在另一實施例中，化合物具有式(Ic)：
在另一實施例中，式(Ia)化合物包含式(Ib)化合物及式(Ic)化合物之混合物。在另一實施例中，式(Ia)化合物包含式(Ib)化合物及式(Ic)化合物之外消旋混合物。在另一替代
性實施例中，式(Ia)化合物包含對映異構體過量之式(Ib)化合物或對映異構體過量之式(Ic)化合物。
本發明之第二態樣提供一種醫藥組合物，其包含至少一種以上化合物及視情況選用之一或多種醫藥學上可接受之賦形劑。
本發明之化合物及組合物為鉀通道抑制劑，其尤其適用於抑制鉀通道Kv1.5或Kv(ur)以用於治療心房中心律不整，諸如心房纖維性顫動。本發明不限於治療心律不整，該等化合物亦適用於治療需要抑制鉀通道之疾病(例如Shieh等人，2000；Ford等人，2002)。
因此，本發明之第三態樣提供一種鉀通道抑制之方法，其包含向個體投與有效量之至少一種本發明之化合物或組合物。本發明之此態樣另外提供本發明之化合物或組合物以供鉀通道抑制之用。此外，本發明之此態樣另外提供本發明之化合物用於製造供鉀通道抑制之用之藥物的用途。如本文所用，「鉀通道抑制之方法」及「鉀通道抑制之用途」包括治療或預防會對鉀通道功能抑制起反應之病症的方法及用途。該病症可為心律不整。
本發明之化合物與先前技術之化合物相比具有有利性質，尤其在效能及/或選擇性方面。
「外消旋混合物」含有近似等量之式(Ib)化合物及式(Ic)化合物。換言之，包含式(Ib)化合物及式(Ic)化合物之「外
消旋混合物」之化合物或組合物含有該等化合物約1：1或50：50之混合物。
包含「對映異構體過量」之式(Ib)化合物或式(Ic)化合物的化合物或組合物包含多於另一對映異構體的該對映異構體(亦稱為非外消旋(scalemic)混合物)。
對映異構體過量為一種化合物相較於另一化合物過量，以佔整體之百分比表示。舉例而言，式(Ib)化合物與式(Ic)化合物之98：2混合物具有96%對映異構體過量之式(Ib)化合物。因此，本發明之化合物及組合物可包含至少5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%或至多100%(亦即對映異構純，達至純度之偵測極限)對映異構體過量之式(Ib)化合物。或者，本發明之化合物及組合物可包含至少5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%或至多100%對映異構體過量之式(Ic)化合物。
如本文所用，根據由國際純化學與應用化學聯合會(International Union of Pure and Applied Chemistry，IUPAC)採用之Cahn-Ingold-Prelog系統，術語「R」或「S」異構體係指兩種可能的對映異構體。因此，式(Ib)化合物為「S-異構體」且式(Ic)化合物為「R-異構體」。
術語「醫藥學上可接受之酯」包括本發明化合物，其中醇基團之氫原子可能經置換以形成酯(例如氫原子可經-C(O)C1-6烷基置換)。
術語「醫藥學上可接受之鹽」包括由醫藥學上可接受之無毒性之酸或鹼(包括無機或有機酸及鹼)製備的鹽。
本發明化合物之醫藥學上可接受之酸加成鹽包括(但不限於)無機酸(諸如氫鹵酸(例如氫氯酸、氫溴酸及氫碘酸)、硫酸、硝酸及磷酸)之酸加成鹽。此外，本發明化合物之醫藥學上可接受之酸加成鹽包括(但不限於)有機酸(諸如脂族、芳族、羧酸及磺酸類有機酸)之酸加成鹽，該等有機酸之實例包括：脂族單羧酸，諸如甲酸、乙酸、丙酸或丁酸；脂族羥基酸，諸如乳酸、檸檬酸、酒石酸或蘋果酸；二羧酸，諸如順丁烯二酸或丁二酸；芳族羧酸，諸如苯甲酸、對氯苯甲酸、苯乙酸、二苯基乙酸或三苯基乙酸；芳族羥基酸，諸如鄰羥苯甲酸、對羥苯甲酸、1-羥基萘-2-甲酸或3-羥基萘-2-甲酸；及磺酸，諸如甲磺酸、乙磺酸或苯磺酸。本發明化合物之其他醫藥學上可接受之酸加成鹽包括(但不限於)乙醇酸、葡糖醛酸、糠酸、麩胺酸、鄰胺基苯甲酸、水楊酸、杏仁酸、恩波酸(embonic acid)(雙羥萘酸(pamoic acid))、泛酸、硬脂酸、對胺基苯磺酸、海藻酸(algenic acid)及半乳糖醛酸之酸加成鹽。
本發明化合物之醫藥學上可接受之鹼性鹽包括(但不限於)金屬鹽，諸如鹼金屬或鹼土金屬鹽(例如鈉鹽、鉀鹽、
鎂鹽或鈣鹽)及鋅鹽或鋁鹽。此外，本發明化合物之醫藥學上可接受之鹼性鹽包括(但不限於)與氨或醫藥學上可接受之有機胺或雜環鹼(諸如乙醇胺(例如二乙醇胺)、苯甲胺、N-甲基-葡糖胺、胺基酸(例如離胺酸)或吡啶)形成之鹽。
可使用以下流程1中所述之途徑以外消旋物、非外消旋混合物或對掌性純對映異構體之形式製備式(I)化合物：
此包括使用類似於WO2004/111057中所揭示之合成途徑之「線性途徑」自式(II)化合物及胺基乙醇製備式(I)化合
物。通常使用偶合試劑(諸如1-乙基-3-(3-二甲基胺基丙基)-碳化二亞胺(EDC)或六氟磷酸2-(7-氮雜-1H-苯并三唑-1-基)-1,1,3,3-四甲(HATU)，利用熟習此項技術者熟知之標準方法(諸如在諸如四氫呋喃、乙腈或二甲基甲醯胺之溶劑中在環境溫度至回流溫度範圍內之溫度下反應)來進行此反應。或者，可藉由在鹼(諸如N,N-二異丙基乙胺)及溶劑(諸如N-甲基吡咯啶酮)存在下在習知加熱或微波輻射下用式(IX)化合物置換2-氯取代基而自式(III)化合物製備式(I)化合物。
可藉由在鹼(諸如N,N-二異丙基乙胺)及溶劑(諸如N-甲基吡咯啶酮)存在下在習知加熱或微波輻射下用市售哌啶甲酸置換2-氯取代基而自式(III)化合物製備式(II)化合物。
藉由視情況在溶劑及鹼存在下及視情況在高溫下或在微波輻射下與2-胺基甲基吡啶發生親核取代反應而易於自式
(IV)化合物合成式(III)化合物。溶劑(若存在時)較佳為醇，較佳為乙醇，且鹼為受阻氮鹼，諸如三乙胺。反應在環境溫度下進行。
可藉由使式(V)化合物與氯化試劑(諸如苯基膦醯二氯或氧氯化磷)反應來合成式(IV)化合物。
可藉由使式(VI)化合物與鹼金屬氰酸鹽(較佳氰酸鉀)反應來合成式(V)化合物。
可利用在鹼性條件下且在適當溶劑(諸如乙醇)中使式(VII)化合物與粉末硫反應之「吉瓦爾德反應(Gewald reaction)」來製備式(VI)化合物。鹼較佳為二異丙基乙胺(許尼希鹼(Hünig's base))，且溶劑可為醇，較佳為乙醇，
且反應在25℃與65℃之間進行。
可利用克腦文蓋爾縮合反應(Knoevenagel condensation reaction)藉由在酸及乙酸銨存在下在適當溶劑(諸如甲苯)中加熱式(VIII)化合物與氰基乙酸乙酯(NCCH2CO2Et)且視情況共沸移除水來製備式(VII)化合物。酸較佳為乙酸。此得到呈一對(E及Z)幾何異構體形式之亞烷基氰基酯。
可藉由在溶劑(諸如二氯甲烷)中用強酸水解胺基甲酸第三丁酯(BOC)保護基而自式(X)化合物製備式(IX)化合物。酸通常為三氟乙酸。
可自式(XI)化合物及胺基乙醇製備式(X)化合物。通常使用偶合試劑(諸如1-乙基-3-(3-二甲基胺基丙基)-碳化二亞
胺(EDC)或六氟磷酸2-(7-氮雜-1H-苯并三唑-1-基)-1,1,3,3-四甲(HATU)，利用熟習此項技術者熟知之標準方法(諸如在諸如四氫呋喃、乙腈或二甲基甲醯胺之溶劑中在環境溫度至回流溫度範圍內之溫度下反應)來進行此反應。
如本文所述，本發明之化合物適用於治療各種病況。因此，本發明之第二態樣提供一種醫藥組合物或調配物，其包含至少一種本發明之化合物及視情況選用之一或多種醫藥學上可接受之賦形劑。
典型醫藥學上可接受之賦形劑包括：‧稀釋劑，例如乳糖、右旋糖、蔗糖、甘露糖醇、山梨糖醇、纖維素及/或甘胺酸；‧潤滑劑，例如二氧化矽、滑石、硬脂酸、其鎂鹽或鈣鹽及/或聚乙二醇；‧黏合劑，例如矽酸鎂鋁、澱粉糊、明膠、黃蓍膠、甲基纖維素、羧甲基纖維素鈉及/或聚乙烯吡咯啶酮；‧崩解劑，例如澱粉、瓊脂、海藻酸或其鈉鹽或泡騰混合物；及/或‧吸收劑、著色劑及/或甜味劑。
本發明之組合物可呈現為每劑量含有預定量之各活性成分之單位劑量形式。該種單位可適於提供5毫克/日至100
毫克/日、較佳為5毫克/日至15毫克/日、10毫克/日至30毫克/日、25毫克/日至50毫克/日、40毫克/日至80毫克/日或60毫克/日至100毫克/日之化合物。對於本發明化合物，提供在100毫克/日至1000毫克/日範圍內、較佳為100毫克/日至400毫克/日、300毫克/日至600毫克/日、或500毫克/日至1000毫克/日之劑量。該等劑量可以單次劑量或多個個別劑量之形式提供。最終劑量將視所治療之病況、投藥途徑及患者之年齡、體重及病情而定且將由醫生判斷。
本發明之組合物可適於利用任何適當途徑(例如利用經口(包括經頰或舌下)、經直腸、經鼻、局部(包括經頰、舌下或經皮)、經陰道或非經腸(包括皮下、肌肉內、靜脈內或皮內)途徑)投與。該等調配物可利用藥劑學技術中已知之任何方法(例如，藉由使活性成分與載劑或賦形劑締合)來製備。
適於經口投與之醫藥調配物可以個別單位形式呈現，諸如膠囊或錠劑；散劑或顆粒；水性或非水性液體中之溶液或懸浮液；可食用發泡體或發泡劑；或水包油型液體乳液或油包水型乳液。
適於經皮投藥之醫藥調配物可以意欲與接受者表皮保持緊密接觸較長時段之個別貼片形式呈現。舉例而言，活性成分可藉由如通常描述於Pharmaceutical Research,3(6),318(1986)中之離子導入療法(iontophoresis)自貼片傳遞。
適於局部投藥之醫藥調配物可經調配為軟膏劑、乳膏、懸浮液、洗劑、散劑、溶液、糊劑、凝膠、噴霧劑、氣霧
劑或油劑。
對於眼睛或其他外部組織(例如口腔及皮膚)之施用，調配物較佳以局部軟膏劑或乳膏劑之形式施用。當經調配為軟膏劑時，活性成分可與石蠟或水混溶性軟膏基質一起使用。或者，可用水包油型乳膏基質或油包水型基質將活性成分調配為乳膏。
適於局部投與眼睛之醫藥調配物包括滴眼劑，其中將活性成分溶解或懸浮於合適載劑(尤其水性溶劑)中。
適於局部投與口腔中之醫藥調配物包括口含錠、片劑及漱口劑。
適於經直腸投與之醫藥調配物可呈栓劑或灌腸劑之形式。
適於經鼻投與之醫藥調配物(其中載劑為固體)包括粒徑在例如20微米至500微米範圍內之粗粉末，其以用鼻吸入之方式投與，亦即藉由自貼近鼻固持之粉末容器經由鼻孔快速吸入來投與。用於以鼻噴霧劑或滴鼻劑形式投與之其中載劑為液體之適當調配物包括活性成分之水溶液或油溶液。
適於藉由吸入投與之醫藥調配物包括精細顆粒粉塵或噴霧，其可藉助於各類定劑量加壓氣霧器、噴霧器或吹入器產生。
適於陰道投與之醫藥調配物可呈子宮托、棉塞、乳膏、凝膠、糊劑、發泡劑或噴霧調配物形式。
適於非經腸投與之醫藥調配物包括可含有抗氧化劑、緩
衝劑、抑細菌劑及使得調配物與預定接受者之血液呈等滲之溶質的水性及非水性無菌注射溶液；及可包括懸浮劑及增稠劑之水性及非水性無菌懸浮液。調配物可含在單位劑量或多劑量容器(例如密封安瓿及小瓶)，且可儲存於冷凍乾燥(凍乾)條件下，僅需要在使用之前即刻添加無菌液體載劑(例如注射用水)。臨用前調製之注射溶液及懸浮液可自無菌散劑、顆粒及錠劑製備。
較佳單位劑量調配物為含有如上文所述活性成分之日劑量或子劑量或其合適分劑量的調配物。
應瞭解，除以上特定提及之成分以外，考慮到所討論調配物之類型，調配物亦可包括此項技術中習知之其他藥劑，例如適於經口投與之調配物可包括調味劑。
以下方案描述以下製備：
1.使用「彙集途徑」製備外消旋物(實例1至實例6)
2.使用「彙集途徑」製備對映異構體(實例1至實例5及實例7至實例12)
3.使用「線性途徑」製備對映異構體(實例1至實例5及實例13至實例16)
藉由仔細選擇試劑及使用適當實驗條件及順序(特定言之關於形成對掌性中心之步驟及後續反應)來獲得所需對映異構純化合物。經確定在合成過程中「線性途徑」較不傾向於外消旋化，此係因為最終醯胺形成鍵合可在較低溫
度下進行，「彙集途徑」與之相反，其提供較高產量，但具有可偵測之外消旋化。
對於「線性途徑」，藉由使用1-(S)-樟腦磺酸作為解析劑典型解析廉價市售的外消旋哌啶甲酸來獲得哌啶甲酸之純對映異構體，在形成樣品之BOC衍生物之後進行對映異構體過量分析測定。
利用對掌性HPLC測定對映異構體純度。
在Varian 400 MHz Mercury Plus光譜儀上記錄質磁共振(1H NMR)光譜。除非另有說明，否則所有光譜均在dmso-d6中測定，且化學位移以距內標四甲基矽烷(TMS)在低磁場的(δ)單位報導，且質子間偶合常數以赫茲(Hz)為單位報導，分裂模式指定如下：s，單峰；d，二重峰；t，三重峰；q，四重峰；m，多重峰；br，寬峰；dd，雙二重峰；dt，雙三重峰；bs，寬單峰；dq，雙重四峰。
在Perkin Elmer Spectrum One儀器上測定IR光譜。
在Agilent 6310離子阱儀器上測定質譜。
在Waters 2695系統上使用ZORBAX SB C-18(4.6×50 mm)管柱進行HPLC分析(方法(a))；移動相：A：0.05% TFA(AQ)，B：0.05% TFA(MeCN)；T%B：0/20，5/90，8/90，8.1/20；流動速率1.0 mL/min；對掌性管柱：Chiralpak IC(4.6×250 mm)5u，移動相：A：己烷，B：EtOH(70：30)；流動速率：在40分鐘內以0.8 ml/min操作。
在EX-Melt儀器(型號：MPA120)上測定熔點。
或者，用Waters 616流體處理系統、Waters 996光電二極體陣列偵測器進行HPLC分析(方法(b))。
對掌性管柱：Daicel Chiralpak AD-H(Chiral technologies)在244 nm下報導對掌性純度；移動相80%己烷：20% EtOH；流動速率0.8ml/min；溫度40℃。在Agilent 1100系列儀器(型號：G1946C)上測定質譜。
使用本文所概述之資訊，可合成以下化合物，其僅以舉例之方式給出。熟習此項技術者可容易地使用常規實驗(諸如本文中所說明及詳細描述於Ford等人，2002中之程序及技術)評價本發明化合物之藥理學概況。
在回流下將經攪拌的苯乙酮(VIII)(180 g，1.5 mol)、氰基乙酸乙酯(170 g，1.3 mol)、乙酸銨(23.1 g)、乙酸(72 g)與甲苯(300 ml)之混合物加熱18小時，同時藉由共沸蒸餾自反應中移除水。使混合物冷卻至環境溫度，添加甲苯(100 ml)，隨後用水(3×100 ml)洗滌混合物。將合併之水性洗液與甲苯(50 ml)一起振盪，隨後合併之甲苯溶液經硫酸鎂乾燥，過濾且在真空中移除溶劑。在減壓下蒸餾殘餘油狀物，得到呈油狀之2-氰基-3-苯基-丁-2-烯酸乙酯(309
g)，其無需進一步純化即可使用。
在環境溫度下將2-氰基-3-苯基-丁-2-烯酸乙酯(513.25 g，2.3 mol)添加至經劇烈攪拌之粉末硫(76 g，2.3 mol)於乙醇(500 ml)中之懸浮液中。在20分鐘內逐份添加二乙胺(200 ml)，在此期間，反應之溫度上升至62℃。使混合物冷卻至36℃，隨後將其加熱至50℃且在該溫度下連續攪拌1小時。此後，停止攪拌，藉由傾析自熱溶液移除未反應之硫，隨後使其冷卻至環境溫度。所得固體藉由過濾進行收集，用少量冷乙醇洗滌且在真空中乾燥，得到呈橙色固體狀之2-胺基-4-苯基噻吩-3-甲酸乙酯(195 g)，其無需進一步純化即可使用。
將2-胺基-4-苯基-噻吩-3-甲酸乙酯(2.0 g，8.1 mmol)及
氰酸鉀(Aldrich，2.0 g，24.3 mmol)添加至冰乙酸(VWR，20 ml)中，且在環境溫度下攪拌18小時。用水(50 ml)稀釋反應物，且將所得沈澱過濾，用水洗滌且乾燥至濕濾餅。使固體懸浮於水(100 ml)中且藉由添加濃氫氧化鈉鹼化至pH 12至pH 14。在攪拌下在100℃下將所得懸浮液加熱2小時，隨後冷卻至環境溫度且藉由添加冰乙酸來酸化。所得固體藉由過濾進行收集，用水洗滌且在真空中在40℃下乾燥，得到呈白色固體狀之5-苯基-1H-噻吩并[2,3-d]嘧啶-2,4-二酮。產量=(1.1 g，56%)。
在150℃下將經攪拌的5-苯基-1H-噻吩并[2,3-d]嘧啶-2,4-二酮(1.07 g，4.39 mmol)及苯基膦醯二氯(Aldrich，10 ml，過量)之混合物加熱7小時，隨後使其在環境溫度下靜置18小時。將所得深色溶液傾入冰水中且用DCM(3×150 ml)萃取。合併之萃取物以飽和碳酸氫鈉溶液(150 ml)洗滌且乾燥(MgSO4)。在真空中移除溶劑，且用40℃至60℃石油醚濕磨油性殘餘物，得到呈淺黃色固體狀之2,4-二氯-5-苯基-噻吩并[2,3-d]嘧啶。產量=(0.82 g，66%)。
將2,4-二氯-5-苯基-噻吩并[2,3-d]嘧啶(1.77 g，6.3 mmol)、2-胺基甲基吡啶(Aldrich，782 μl，7.6 mmol)與三乙胺(VWR，1.06 ml，7.63 mmol)之混合物在乙醇(30 ml)中回流3小時。一旦冷卻，即將反應傾入水(300 ml)中且攪拌1小時。將所得沈澱過濾，用水(2×30 ml)洗滌且在真空下在40℃下乾燥，得到呈淺黃色固體狀之(2-氯-5-苯基-噻吩并[2,3-d]嘧啶-4-基)-吡啶-2-基甲基-胺。產量=(1.55 g，70%)。
在Biotage微波管中將(2-氯-5-苯基-噻吩并[2,3-d]嘧啶-4-基)-吡啶-2-基甲基-胺(44 mg，0.124 mmol)、哌啶-3-甲酸(2-羥乙基)醯胺(Fluorochem，32 mg，0.188 mmol，1.5當量)及N,N-二異丙基乙胺(Aldrich，0.188 mmol)溶解於N-甲基吡咯啶酮(1.5 ml)中，且加熱至200℃，且在此溫度下維持30分鐘。一旦冷卻，即在真空中移除溶劑。用DCM(2×10 ml)濕磨殘餘物，且萃取物經合併，濃縮且藉由製備型TLC(溶離劑為10% MeOH/DCM)純化，得到呈黃色油狀之產物，其靜置時緩慢凝固成蠟狀固體。蠟狀固體可藉由在乙醚中攪拌1至2小時(0.5 g於10 ml)而轉變成自由流動的粉末。產量=18.3 mg(30%)。
在冰浴中將(S)-哌啶-1,3-二甲酸1-第三丁酯(500 mg，2.2 mmol)、HATU(833 mg，2.2 mmol)及二異丙基乙胺(761 μL，4.4 mmol)在無水DCM(10 ml)中攪拌5分鐘，隨後在室溫下攪拌5分鐘。添加乙醇胺(198 μL，3.28 mmol)且在室溫下將反應物攪拌3小時。反應物用DCM(40 ml)稀釋，經水(50 ml)洗滌，分離DCM層且乾燥(MgSO4)且濃縮。殘餘物在二氧化矽(20 g isolute)上過柱。溶離：
MeOH/DCM 0%-5% 5CV，MeOH/DCM 5%-5% 10CV，MeOH/DCM 5%-10% 5CV。TLC用KMnO4顯現。由此得到呈澄清油狀之產物(327 mg)。
類似地製備：
將以上反應之產物在1：1 TFA/DCM中攪拌2小時，隨後真空濃縮成油狀物。將此溶解於MeOH(5 ml)中且裝載至5 g SCX柱體上。用MeOH(10 ml)洗滌柱體，隨後用2 M NH3/MeOH(10 ml)溶離產物。濃縮溶離份，得到白色固體。產量=260 mg。
類似地製備：
如以上實例6中使(S)-哌啶-3-甲酸(2-羥基-乙基)-醯胺與(2-氯-5-苯基-噻吩并[2,3-d]嘧啶-4-基)-吡啶-2-基甲基-胺反應，得到呈黃色泡沫狀之(S)-1-{5-苯基-4-[(吡啶-2-基甲基)-胺基]-噻吩并[2,3-d]嘧啶-2-基}-哌啶-3-甲酸(2-羥基-乙基)-醯胺(188 mg)。
類似地製備：
在55℃至58℃下，向(S)-樟腦磺酸(18 kg，77 mol)於丙酮(127 kg)中之溶液中迅速饋入(R,S)-哌啶甲酸(10 kg，77
mol)於水(20 kg)中之溶液。使混合物維持在55℃至58℃下，直至所有固體均溶解。將溶液緩慢冷卻至20℃至25℃以使鹽沈澱析出，隨後攪拌隔夜且分離。為進一步提高非對映異構體純度，在55℃至58℃下將所得鹽自丙酮(16 kg)及水(4 kg)中再結晶。再使熱溶液冷卻至20℃至25℃，攪拌隔夜且分離，得到經純化之(S)-哌啶甲酸-(S)-樟腦磺酸鹽(14 kg)。
將(S)-哌啶-1,3-二甲酸1-第三丁酯(20 kg，87.2 mol)在乙酸(189 kg)中調成漿，且冷卻至15℃。饋入過量之氯化氫氣體(9.6 kg)且攪拌約4小時以完成脫除保護基。分離漿液，且用乙酸(2×31.5 kg)沖洗濾餅。隨後將濾餅真空乾燥，得到產物(14.4 kg)。
將(2-氯-5-苯基-噻吩并[2,3-d]嘧啶-4-基)-吡啶-2-基甲基-胺(5.9 kg，16.7 mol)及(S)-哌啶甲酸鹽酸鹽(4.15 kg，25.1 mol)溶解於丁腈(13.9 kg)中。添加過量之二異丙基乙胺(8.6 kg，66.9 mol)且將混合物加熱至110℃後持續24小時至48小時以完成反應。在偶合完成之情況下(少於2%之3-哌啶甲酸剩餘)，使反應物冷卻至室溫且饋入水(29 kg)。用25%氫氧化鈉水溶液(4.5 L)將混合物pH值調節至約10，且使各層分離。用乙酸乙酯(15.9 L)將產物水層萃取兩次，隨後向水層中添加二氯甲烷(23.5 kg)且用濃鹽酸(6.3 kg)將pH值調節至約2.5。分離各層，且用二氯甲烷(2×15.7 kg)再萃取水層。合併二氯甲烷層，且用水(18 kg)洗滌，隨後經硫酸鈉(5.9 kg)乾燥，且保持產物溶液以供在下一步驟中處理(實例16)。
將(S)-1-{5-苯基-4-[(吡啶-2-基甲基)-胺基]-噻吩并[2,3-d]嘧啶-2-基}-哌啶-3-甲酸溶液(7.4 kg，16.63 mol)(來自實
例15)冷卻至0℃，且添加二異丙胺(4.51 kg，35 mol)及乙醇胺(2.03 kg，33.3 mol)。使反應溫度維持在10℃以下，逐份饋入苯并三唑四甲-BF4(TBTU)(5.9 kg，18.3 mol)，隨後在約5℃下攪拌，直至偶合完成。隨後過濾反應溶液以移除TBTU鹽且用水(22.2 L)洗滌，隨後用檸檬酸/氫氧化鈉緩衝水溶液(pH值約為5)(2.88 kg，15 mol)進行兩次洗滌，且最終用鹽水溶液(4 L)洗滌。隨後，向混合物中饋入丁腈(17.4 L)，且部分汽提以使非對映異構體產物沈澱析出。過濾漿液以移除非對映異構體，且將濾液進一步汽提至約1/2體積。向混合物中饋入庚烷(30.4 L)以使產物沈澱析出，且使漿液冷卻至室溫。漿液經過濾，以庚烷(10.1 L)沖洗，且真空乾燥以獲得產物(4.1 kg)。
可根據與實例13至實例16類似之途徑製備(R)-1-{5-苯基-4-[(吡啶-2-基甲基)-胺基]-噻吩并[2,3-d]嘧啶-2-基}-哌啶-3-甲酸(2-羥基-乙基)-醯胺(Ic)。
下表中顯示由以上實例提供之化合物之分析資料。
在電生理學實驗中，使用表現相關通道之重組細胞在全細胞膜片鉗實驗中量測本發明化合物抑制Kv1.5鉀通道之能力。
外部浴溶液(bathing solution)含有(以mM為單位)：150 NaCl、10 KCl、3 MgCl2、1 CaCl2、10 HEPES，pH 7.4。在膜片吸管(Patch pipette)中裝滿組合物之電極溶液(以mM為單位)：160 KCl、0.5 MgCl2、10 HEPES、1 EGTA，用KOH調至pH 7.2。
將化合物溶解於DMSO(100%)中且按所需濃度(最終DMSO濃度=0.1%)在外部浴液中新鮮配製。所有實驗均在
室溫下進行。
在全細胞膜片鉗研究中，將細胞(經hKv1.5穩定轉染之CHO)接種在玻璃蓋片上，隨後進行記錄。依可以選拔分離之細胞用於膜片鉗實驗之密度將細胞接種在無菌30 mm皮氏(Petri)培養皿中。將培養皿儲存於在37℃下之加濕供氣(5% CO2)之培育箱中，直至使用時為止。
在膜片電極與細胞之間形成千兆歐姆阻抗封接(gigaohm seal)之後，使用由Pulse軟體(Ver8.5x/8.6x,HEKA，德國)控制之HEKA EPC 9/10放大器進行膜電流之全細胞膜片鉗記錄。將接種細胞之蓋片放置於固定在倒置顯微鏡平台上之記錄格中。在實驗期間，用經由緊靠細胞放置之導管傳遞之浴溶液連續澆注相關細胞，以便控制胞外液環境。僅取電流大於500 pA之細胞用於實驗。在實驗期間，總串聯電阻不超過10 MΩ且至少補償70%。在Pulse中使用P/n方法，在線上進行漏減。
如下進行電生理學電壓步進方案及數據分析。在5 kHz下收集數據，且用2.5 kHz之-3 dB帶寬過濾。使細胞保持在-80 mV電壓下。藉由使電壓步進去極化至0 mV(900 ms)、隨後首先再極化至-40 mV(100 ms)、隨後返回至-80 mV來引生電流。在整個實驗中，反覆地每5秒施加命令波形(command waveform)。在75%至95%之去極化步進至0 mV期間，使用Pulsefit軟體(v8.x,HEKA，德國)分析平均電流。在浴液中施加電壓方案，以獲得穩定電流基線，隨後經由導管澆注測試物質；流體交換耗時約15秒。在此期間
使測試物質平衡，反覆施加電壓方案且加以記錄。相對於對照之前藥值，計算在測試物質存在下之電流抑制百分比。
在以下分析中篩選本發明化合物及比較化合物：
1. Nav1.5；使用經異源hNav1.5 cDNA穩定轉染之表現hNav1.5電流之CHO細胞在Sophion QPatch上篩選。
2. Kv4.3；使用經異源Kv4.3 cDNA穩定轉染之表現hKv4.3電流之CHO細胞利用手動全細胞膜片鉗篩選。
3. hERG；使用經異源hERG cDNA穩定轉染之表現hERG電流之HEK293細胞利用手動全細胞膜片鉗篩選。
4. Kir3.1/3.4；使用經異源rKir3.1及rKir3.4 cDNA穩定轉
染之表現rKir3.1/3.4電流之HEK293細胞利用手動全細胞膜片鉗篩選。
5. KCNQ1；使用經異源hKCNQ1/hmink cDNA穩定轉染之表現hKCNQ1/hmink電流之CHO細胞利用手動全細胞膜片鉗篩選。
6. Kir2.1；使用經異源hKir2.1 cDNA穩定轉染之表現hKir2.1電流之HEK293細胞利用手動全細胞膜片鉗篩選。
7. Cav1.2；使用經異源hCav1.2 cDNA穩定轉染之表現hCav1.2電流之GH3細胞或HEK293細胞篩選。
Kv1.5與以上離子通道相比之選擇性比率顯示如下：
自經歷一系列心臟外科程序之患者獲得人類心耳(右心耳或左心耳)之樣本。在由地方研究倫理批准委員會(Local Research Ethical Approval Committee)批准後自Papworth Hospital NHS Trust,Cambs.UK.之同意患者獲得組織。使用如由Wang等人(1993)及Dobrev等人(2005)描述之改良方案進行肌細胞之機械-酶促分離。使分離之肌細胞懸浮於改良之『卡夫-布呂厄(Krafte-brühe)』(KB)溶液中直至使用。
將肌細胞置於固定於倒置顯微鏡平台上之具有玻璃蓋片
基底之小體積的記錄室中。在實驗期間，用經由緊靠細胞放置之導管傳遞之浴溶液連續澆注相關細胞以便可實現控制胞外液環境。
在膜片電極與肌細胞之間形成千兆歐姆阻抗封接之後，使用HEKA EPC-9/10放大器進行膜電流之全細胞膜片鉗記錄。自硼矽玻璃拉出玻璃膜片吸管。僅選用桿狀條紋形肌細胞。使用Pulse軟體補償電容及串聯電阻。使用Pulse軟體產生電壓鉗命令，且在PC之硬碟上記錄數據。不進行漏減且丟棄顯著滲漏之細胞。在室溫下進行實驗。為使來自其他離子電流之污染最小化，實驗溶液含有10 mM氯化四乙基銨(IK)、100 nM阿托品(atropine)(IK,ACh)、200 μM CdCl2(ICa,L及ICl,Ca)、0.5 mM BaCl2(IK1及IKACh)。阻斷劑以預期不會影響IKur之濃度使用。藉由使用基於氯化膽鹼之浴液來抑制鈉電流(INa)。每10秒施加去極化電壓步進以誘生由瞬時分量及持續分量組成之外向鉀電流。將對300 μM 4-AP敏感之持續電流定義為超快速延遲整流電流IKur。
縮寫
HGNC HUGO基因命名委員會
Kv(ur) 心臟超速延遲整流
CHO 中國倉鼠卵巢細胞
IP3 三磷酸肌醇
CRAC Ca2+釋放活化Ca2+電流
DMEM 達爾伯克氏改良伊格爾培養基(Dulbecco's Modified Eagle media)
DMSO 二甲亞碸
FCS 胎牛血清
EBSS 厄爾平衡鹽溶液(Earls Balanced Salt Solution)
WCPC 全細胞膜片鉗
HEK293 人胚腎293細胞
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Claims (14)
- 一種式(Ia)化合物：
- 如請求項1之化合物，其中該化合物具有式(Ib)：
- 如請求項1之化合物，其中該化合物具有式(Ic)：
- 如請求項1之化合物，其中該式(Ia)化合物包含如請求項2所定義之該式(Ib)化合物及如請求項3所定義之該式(Ic) 化合物之混合物。
- 如請求項4之化合物，其中該式(Ia)化合物包含該式(Ib)化合物及該式(Ic)化合物之外消旋混合物。
- 如請求項4之化合物，其中該式(Ia)化合物包含對映異構體過量之該式(Ib)化合物。
- 如請求項4之化合物，其中該式(Ia)化合物包含對映異構體過量之該式(Ic)化合物。
- 如請求項1至7中任一項之化合物，其用於抑制鉀通道。
- 如請求項8之化合物，其中該化合物用於治療或預防心律不整。
- 一種醫藥組合物，其包含至少一種如請求項1至9中任一項之化合物及視情況選用之一或多種醫藥學上可接受之賦形劑。
- 如請求項10之組合物，其用於抑制鉀通道。
- 如請求項11之組合物，其用於治療或預防心律不整。
- 一種如請求項1至9中任一項之化合物之用途，其用於製造用於抑制鉀通道之藥物。
- 如請求項13之用途，其中該藥物用於治療或預防心律不整。
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| US12391705B2 (en) | 2018-12-19 | 2025-08-19 | Shy Therapeutics, Llc | Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease |
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