CN115023416A - 用于治疗α1-抗胰蛋白酶缺乏症的4-((2-氧代吡啶-1(2H)-基)甲基)苯甲酰胺 - Google Patents
用于治疗α1-抗胰蛋白酶缺乏症的4-((2-氧代吡啶-1(2H)-基)甲基)苯甲酰胺 Download PDFInfo
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- CN115023416A CN115023416A CN202080094498.6A CN202080094498A CN115023416A CN 115023416 A CN115023416 A CN 115023416A CN 202080094498 A CN202080094498 A CN 202080094498A CN 115023416 A CN115023416 A CN 115023416A
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- oxopyridin
- a1at
- benzamide
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- 239000012089 stop solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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- GSIBTIUXYYFCPU-UHFFFAOYSA-N tert-butyl 4-(bromomethyl)benzoate Chemical compound CC(C)(C)OC(=O)C1=CC=C(CBr)C=C1 GSIBTIUXYYFCPU-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- 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
Abstract
本发明涉及五种式(1)的苯甲酰胺化合物,以及包含该化合物的药物组合物。所述化合物可以是α1‑抗胰蛋白酶(A1AT)的诱导剂,并且可用于治疗疾病或障碍,例如α1‑抗胰蛋白酶缺乏症(A1AD或AATD)。
Description
本发明涉及某些苯甲酰胺及其医疗用途。
α1-抗胰蛋白酶(A1AT)是由肝脏产生并分泌到血液中的丝氨酸蛋白酶抑制剂超家族的成员。它抑制多种丝氨酸蛋白酶,尤其是嗜中性粒细胞弹性蛋白酶。当血液的A1AT水平较低时,嗜中性粒细胞弹性蛋白酶的过度活性会使肺组织降解,导致呼吸***并发症,例如慢性阻塞性肺疾病(COPD)。
血液中A1AT的参考范围是0.9-2.3g/L。低于此水平是α1-抗胰蛋白酶缺乏症(A1AD或AATD)典型的,α1-抗胰蛋白酶缺乏症是由编码A1AT的SERPINA1基因中的突变引起的遗传疾病。Z突变是AATD最常见的原因,是A1AT(UniProtKB-P01009(A1AT_HUMAN))的第366位(对应于成熟蛋白(Z A1AT)的第342位)处的谷氨酸被赖氨酸替换。Z突变影响A1AT的折叠,导致只有一小部分获得天然/活性状态。剩余部分作为错误折叠的蛋白质被清除,或作为稳定的聚合物在肝脏中积累。由于错误折叠,Z突变的纯合子携带者(ZZ)的血浆A1AT水平为正常的10-15%,使携带者易感于COPD。Z A1AT聚合物在肝细胞中的积累使携带者易感于肝硬化、肝癌及其它肝脏疾病。
目前对AATD肺部表现的治疗包括使用由献血者血浆制备的A1AT浓缩物进行强化治疗。美国FDA已批准使用四种A1AT产品:普罗莱斯丁(Prolastin)、杰特贝林(Zemaira)、Glassia和Aralast。通过每周一次的静脉内输注给药。强化治疗已被证明减缓COPD的进展。AATD的肝脏表现(如肝硬化和肝癌)用类固醇和肝移植治疗。对于肝脏表现的改善治疗的研究方法包括抑制Z A1AT聚合和通过激活自噬提高聚合物的清除。对于肺部和肝脏表现的改善治疗的研究方法旨在改善Z A1AT折叠和分泌。
Elliott等人(Protein Science,2000,9,1274–1281)描述了A1AT的X射线晶体结构,并确定了五个空腔,它们是合理药物设计的潜在目标,以开发影响Z A1AT聚合的药剂。
Parfrey等人(J.Biol.Chem.,2003,278,35,33060–33066)进一步定义了单个空腔,它是合理药物设计的潜在目标,以开发影响Z A1AT聚合的药剂。
Knaupp等人(J.Mol.Biol.,2010,396,375–383)表明双-ANS(4,4'-联苯胺-1,1'-联萘-5,5'-二磺酸盐)能够以1:1的化学计量和700nM的Kd与Z A1AT结合,但不能与野生型A1AT(M)结合。
Chang等人(J.Cell.Mol.Med.,2009,13,8B,2304-2316)报道了一系列抑制Z A1AT聚合的肽,包括Ac-TTAI-NH2。
Burrows等人(Proc.Nat.Acad.Sci.,2000,97,4,1796–1801)表明一系列非选择***分子(包括4-苯基丁酸、甘油和三甲胺氧化物)能够增加细胞上清液和小鼠模型中的ZA1AT水平。
Bouchecareilh等人(Journal of Biological Chemistry,2012,287,45,38265-38278)描述了使用组蛋白脱乙酰酶抑制剂(特别是SAHA(辛二酰苯胺异羟肟酸))来增加细胞的M和Z A1AT的分泌。
Berthelier等人(PLOS ONE,May 11,2015)已经证明S-(4-硝基苄基)-6-硫鸟苷能够在体外阻止Z A1AT聚合。
Mallya等人(J.Med.Chem.,2007,50,22,5357–5363)描述了能够在体外阻断ZA1AT的聚合的一系列酚类,例如N-(4-羟基-3,5-二甲基苯基)-2,5-二甲基噻吩-3-磺酰胺。
Huntington(第13届蛋白酶、抑制剂和生物控制国际研讨会,2012年9月23日和第7届丝氨酸蛋白酶抑制剂生物学、结构和功能国际研讨会,2014年4月1日)讨论了来自Z A1AT的X射线晶体结构的空腔,它是合理药物设计的潜在目标,以开发影响Z A1AT聚合的药剂。
US8,436,013B2公开了多种能够在微摩尔范围内增加细胞Z A1AT分泌的结构。
WO03/068230A1公开了取代的吡啶酮作为p38 MAP激酶的调节剂。
WO2005/018557A2公开了取代的吡啶酮用于治疗由或未调节的p38 MAP激酶和/或TNF活性引起的疾病和病症。
WO2019/243841A1公开了氧代二氢吲哚-4-甲酰胺(oxoindoline-4-carboxamide)化合物作为α-1-抗胰蛋白酶的调节剂,并用于治疗与α-1-抗胰蛋白酶相关的疾病。
WO2020/081257A1公开了吡咯并-吲唑基-丙酸化合物作为α-1-抗胰蛋白酶的调节剂。
US2020/0361939A1进一步公开了吡咯并-吲唑基-丙酸化合物作为α-1-抗胰蛋白酶的调节剂。
根据本发明的一方面,提供了式(1)的氧代吡啶基化合物
其中:
·R1、R2、R3和R4独立地为氢或任选取代的C1-C6烷基基团,
·R1和R2可以稠合形成杂环,并且
·R3和R4可以稠合形成碳环
并且式(1)的化合物是
·N,N-二甲基-4-((2-氧代吡啶-1(2H)-基)甲基)苯甲酰胺或
·N-乙基-N-甲基-4-((2-氧代吡啶-1(2H)-基)甲基)苯甲酰胺或
·N-异丙基-N-甲基-4-((2-氧代吡啶-1(2H)-基)甲基)苯甲酰胺或
·N-苄基-N-甲基-4-((2-氧代吡啶-1(2H)-基)甲基)苯甲酰胺或
·N-甲基-4-((2-氧代吡啶-1(2H)-基)甲基)-N-(2,2,2-三氟乙基)苯甲酰胺。
我们已经发现本发明的化合物令人惊讶地显示出在提高正确折叠的Z A1AT水平并因此具有提高的活性Z A1AT水平的方面非常有效,同时对野生型(M)A1AT或A1AT的Siiyama变体的分泌没有影响。
本发明的化合物可以是药学上可接受的盐形式或结晶形式。
术语“药学上可接受的盐”是指本发明化合物的药学上可接受的单有机或无机盐。这可以包括无机酸的加成盐,例如盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、磷酸盐、二磷酸盐和硝酸盐,或者有机酸的加成盐,例如乙酸盐、马来酸盐、延胡索酸盐、酒石酸盐、琥珀酸盐、柠檬酸盐、乳酸盐、甲磺酸盐、对甲苯磺酸盐、棕榈酸盐(palmoate)和硬脂酸盐。示例性盐还包括草酸盐、氯化物、溴化物、碘化物、硫酸氢盐、酸式磷酸盐、异烟酸盐、水杨酸盐、酸式柠檬酸盐、油酸盐、单宁酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、龙胆酸盐(gentisinate)、葡萄糖酸盐、葡萄糖醛酸盐、糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、乙磺酸盐和苯磺酸盐。对于其它药学上可接受的盐的示例,可参考Gould(1986,Int J Pharm 33:201-217)。
根据本发明的另一方面,提供了一种药物组合物,包含如本文所述的本发明化合物和药学上或治疗学上可接受的辅料或载体。
术语“药学上或治疗学上可接受的辅料或载体”是指不干扰活性成分的有效性或生物活性且对施用它的宿主(可以是人或动物)无毒的固体或液体填充剂、稀释剂或封装物质。取决于特定的施用途径,可以使用多种药学上可接受的载体,例如本领域熟知的那些。非限制性实例包括糖、淀粉、纤维素及其衍生物、麦芽、明胶、滑石、硫酸钙、植物油、合成油、多元醇、海藻酸、磷酸盐缓冲溶液、乳化剂、等渗盐水和无热原水。
根据本发明考虑了所有合适的施用方式。例如,药物的施用可以经由口腔、皮下、直接静脉内、缓慢静脉内输注、连续静脉内输注、静脉内或硬膜外患者自控镇痛(PCA和PCEA)、肌肉内、鞘内、硬膜外、脑池内(intracistemal)、腹膜内、透皮、局部、经粘膜、经颊、舌下、经黏膜、吸入、鼻内、心房内(intra-atricular)、鼻内、直肠或眼部途径。药物可以配制成离散的剂量单位并且可以通过药学领域中熟知的任何方法配制。
考虑了所有合适的药物剂型。药物的施用可以例如以口服溶液剂和混悬剂、片剂、胶囊剂、锭剂、泡腾片剂、透粘膜膜剂、栓剂、经颊产品、口腔粘液保持产品、外用乳膏剂、软膏剂、凝胶剂、膜剂和贴剂、透皮贴剂、滥用威慑和抗滥用制剂、用于肠胃外使用的无菌溶液剂、混悬剂和贮库等,以立即释放、持续释放、延迟释放、控制释放、延长释放等形式施用。
本发明的另一方面是如本文所定义的本发明化合物在制备用于治疗疾病或障碍的药物中的用途。
本发明的另一方面是用于作为Z A1AT分泌的诱导剂使用的本发明的化合物。
进一步提供了用于在治疗疾病或障碍中使用的如本文所定义的本发明化合物。
本发明还包括治疗疾病或障碍的方法,包括向有此需要的患者施用如本文所定义的本发明的化合物或药物组合物的步骤。
本发明还包括本发明化合物作为Z A1AT分泌的诱导剂的用途。该用途可以用于治疗疾病或障碍。另外或可选地,该用途可以是体外的,例如在体外测定中。
适合根据本发明相关方面治疗的疾病或障碍是以低血浆A1AT水平为特征的疾病或障碍,例如AATD。
本说明书中数字范围的使用旨在明确地在本发明的范围内包括该范围内的所有单个整数以及给定范围的最宽范围内的上限和下限数字的所有组合。
如本文所用,术语“包含/包括”应理解为表示包含/包括和由……组成二者。因此,当本发明涉及“包含作为活性成分的化合物”的药物组合物时,该术语旨在涵盖其中可以存在其它活性成分的组合物以及仅由所定义的一种活性成分组成的组合物。
除非另有定义,否则此处使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的相同含义。类似地,此处提及的所有出版物、专利申请、所有专利和所有其它参考文献均以引用的方式整体并入(在法律允许的情况下)。
现在将描述本发明的特定非限制性实施例。
实验
实施例1:N,N-二甲基-4-((2-氧代吡啶-1(2H)-基)甲基)苯甲酰胺
使用以下顺序合成程序制备N,N-二甲基-4-((2-氧代吡啶-1(2H)-基)甲基)苯甲酰胺。
步骤a:4-((2-氧代吡啶-1(2H)-基)甲基)苯甲酸叔丁酯的合成
在室温,将吡啶-2(1H)-酮(5g,53mmol)和碳酸铯(50.85g,156mmol)在二甲基甲酰胺(50ml)中搅拌10分钟。添加4-(溴甲基)苯甲酸叔丁酯(14.11g,52mmol)并将反应搅拌3小时。将反应用水稀释,并通过过滤收集所得黄色沉淀。将粗产物通过硅胶柱色谱用乙酸乙酯/己烷(30%:50%)洗脱进行纯化,得到4-((2-氧代吡啶-1(2H)-基)甲基)苯甲酸叔丁酯。
m/z:285.16(计算值285.14)
步骤b:4-((2-氧代吡啶-1(2H)-基)甲基)苯甲酸的合成
将4-((2-氧代吡啶-1(2H)-基)甲基)苯甲酸叔丁酯(10g,35mmol)溶解在二氯甲烷(50ml)中并缓慢添加三氟乙酸(70ml)。将反应在室温搅拌3小时。减压浓缩反应,并将所得油状物与***(300ml)在室温下搅拌20分钟。通过过滤收集所得固体,用***(2×30ml)洗涤并真空干燥以得到4-((2-氧代吡啶-1(2H)-基)甲基)苯甲酸。
m/z:229.09(计算值229.07)
步骤c:N,N-二甲基-4-((2-氧代吡啶-1(2H)-基)甲基)苯甲酰胺的合成
在0℃,将4-((2-氧代吡啶-1(2H)-基)甲基)苯甲酸(64mg,0.27mmoll)和N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐(86mg,0.54mmol)在四氢呋喃(1ml)中氮气下搅拌10分钟。然后使反应升温至室温。添加三乙胺(0.11ml,81mmol)和二甲胺(四氢呋喃中的2M溶液,69mmol)并将反应搅拌2小时。减压浓缩反应并将残余物在二氧化硅柱上用二氯甲烷中的4%甲醇洗脱。将含产物的级分浓缩,得到N,N-二甲基-4-((2-氧代吡啶-1(2H)-基)甲基)苯甲酰胺。
m/z:255.96(计算值256.12)
1H NMR(400MHz,d6 DMSO)δ7.81(1H,dd),7.43(1H,m),7.36(2H,d),7.29(2H,d),6.41(1H,d),6.25(1H,t),5.11(2H,s),2.95-2.87(6H,br)。
实施例2:N-乙基-N-甲基-4-((2-氧代吡啶-1(2H)-基)甲基)苯甲酰胺
在步骤c中使用乙基甲胺代替二甲胺类似地制备N-乙基-N-甲基-4-((2-氧代吡啶-1(2H)-基)甲基)苯甲酰胺。
m/z:270.01(计算值270.14)
1H NMR(400MHz,d6 DMSO)δ7.81(1H,dd),7.44(1H,m),7.41(2H,d),7.29(2H,d),6.41(1H,d),6.25(1H,t),5.11(2H,s),3.42-3.16(2H,br),2.91-2.83(3H,br),1.10-1.03(3H,br)。
实施例3:N-异丙基-N-甲基-4-((2-氧代吡啶-1(2H)-基)甲基)苯甲酰胺
在步骤c中使用异丙基甲胺代替二甲胺类似地制备N-异丙基-N-甲基-4-((2-氧代吡啶-1(2H)-基)甲基)苯甲酰胺。
m/z:284.0(计算值284.15)
1H NMR(400MHz,d6 DMSO)δ7.81(1H,dd),7.43(1H,m),7.30(2H,d),6.42(1H,d),6.25(1H,t),4.67and 3.76(1H,br),2.78-2.68(3H,br),1.07(6H,br)。
实施例4:N-苄基-N-甲基-4-((2-氧代吡啶-1(2H)-基)甲基)苯甲酰胺
在步骤c中使用N-甲基苄胺代替二甲胺类似地制备N-苄基-N-甲基-4-((2-氧代吡啶-1(2H)-基)甲基)苯甲酰胺。
m/z:332.18(计算值332.15)
1H NMR(400MHz,d6 DMSO)δ7.80(1H,br),7.42-7.29(9H,br),7.16(1H,br),6.41(1H,br),6.24(1H,br),5.12(2H,br s),2.85-2.79(3H,br)。
实施例5:N-甲基-4-((2-氧代吡啶-1(2H)-基)甲基)-N-(2,2,2-三氟乙基)苯甲酰胺
在步骤c中使用2,2,2-三氟-N-甲基乙-1-胺代替二甲胺类似地制备N-甲基-4-((2-氧代吡啶-1(2H)-基)甲基)-N-(2,2,2-三氟乙基)苯甲酰胺。
m/z:324.07(计算值324.11)
1H NMR(400MHz,d6 DMSO)δ7.81(1H,dd),7.46-7.32(5H,m),6.42(1H,d),6.25(1H,t),5.13(2H,s),4.40.4.00(2H,br),3.00(3H,br s)。
实施例6:本发明化合物在使用HEK-Z细胞的A1AT细胞分泌测定中的活性
方法
将HEK-Z细胞(稳定转染有人Z A1AT基因的人胚肾细胞系)铺在96孔板(3.0×105个细胞/ml,200μl培养基/孔)中,在包含5%CO2的潮湿环境中于37℃过夜。孵育后,将细胞用200μl无血清培养基洗涤三次,并更换培养基以使用包含溶媒、10μM辛二酰苯胺异羟肟酸(SAHA)或本发明化合物(浓度为10、33、100和333nM)的无血清培养基一式四份地以200μl的终体积在37℃培养箱中处理48小时。在孵育步骤结束时,从孔中取出上清液,在4℃以1000×g离心10分钟,并通过ELISA(人丝氨酸蛋白酶抑制剂A1/α1-抗胰蛋白酶双重ELISA,R&DSystems,DY1268)按照制造商的说明测定人A1AT水平。
简而言之,将96孔板在室温用人A1AT捕获抗体包被过夜(由储液1:180稀释,100μl终体积/孔)。然后去除捕获抗体并用300μl洗涤缓冲液(PBS中的0.05%Tween 20)洗涤孔三次,然后在每个孔中将200μl试剂稀释液(PBS中的25%Tween 20)在室温孵育1小时。然后将稀释的样品、标准品(125、250、500、1000、2000、4000和8000pg/ml A1AT)或空白一式两份地添加到每个孔中,用封板器覆盖板并在室温放置2小时。在样品孵育步骤结束时,去除样品并如前所述洗涤所有孔,并将100μl检测抗体(由储液1:180稀释)添加到每个孔中,并在室温再孵育2小时。与检测抗体孵育后,去除上清液并如前所述洗涤孔,然后将100μl链霉亲和素-HRP溶液(由储液1:200稀释)添加到每个孔中,在黑暗中保持20分钟。之后,添加50μl终止溶液(2M H2SO4),并使用酶标仪在450nm处读取每个孔的光密度(OD),并从每个孔中减去570nm的空白。使用GraphPad Prism 7构建4参数逻辑曲线,通过从标准曲线插值并乘以适当稀释系数来确定每个样品中的A1AT浓度。
结果
表1中的数据显示了实施例1-5的化合物在33nM时增加了从HEK-Z细胞的Z A1AT分泌。
表1
实施例 | 在300nM相对于溶媒的平均A1AT%增加 |
1 | 125 |
2 | 147 |
3 | 134 |
4 | 142 |
5 | 129 |
Claims (11)
2.根据权利要求1所述的化合物,为药学上可接受的盐形式或结晶形式。
3.一种药物组合物,包含根据权利要求1或2中任一项所述的化合物和药学上或治疗学上可接受的辅料或载体。
4.根据权利要求1或2中任一项所述的化合物在制备用于治疗疾病或障碍的药物中的用途。
5.根据权利要求1或2中任一项所述的化合物,用于在治疗疾病或障碍中使用。
6.根据权利要求1或2中任一项所述的化合物,用于作为Z A1AT分泌的诱导剂使用。
7.一种治疗疾病或障碍的方法,包括向有此需要的患者施用根据权利要求1或2中任一项所述的化合物或根据权利要求3所述的药物组合物的步骤。
8.根据权利要求1或2中任一项所述的化合物在治疗疾病或障碍中的用途。
9.根据权利要求8所述的用途,作为Z A1AT分泌的诱导剂。
10.根据权利要求8或权利要求9中任一项所述的用途,其中所述用途是体外的。
11.根据权利要求4所述的用途、根据权利要求5使用的所述化合物、根据权利要求7所述的治疗方法、或根据权利要求8-10中任一项所述的用途,其中所述疾病或障碍为AATD。
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