WO2023019499A1 - 弹性蛋白酶抑制剂及在疾病治疗中的应用 - Google Patents

弹性蛋白酶抑制剂及在疾病治疗中的应用 Download PDF

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WO2023019499A1
WO2023019499A1 PCT/CN2021/113436 CN2021113436W WO2023019499A1 WO 2023019499 A1 WO2023019499 A1 WO 2023019499A1 CN 2021113436 W CN2021113436 W CN 2021113436W WO 2023019499 A1 WO2023019499 A1 WO 2023019499A1
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compound
formula
elastase
present
disease treatment
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PCT/CN2021/113436
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French (fr)
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李文华
田松川
徐欢
李成业
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上海汇伦生物科技有限公司
上海汇伦江苏药业有限公司
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Priority to PCT/CN2021/113436 priority Critical patent/WO2023019499A1/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring

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  • the invention relates to the field of medicine, in particular to a compound having inhibitory activity on elastase, a composition, and an application in disease treatment.
  • the diseases are diseases caused by the action of elastase, including systemic inflammatory response syndrome (SIRS) with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS).
  • SIRS systemic inflammatory response syndrome
  • ALI acute lung injury
  • ARDS acute respiratory distress syndrome
  • NE Human neutrophil elastase plays an important role in various inflammatory reactions in the body, tissue damage remodeling (such as pneumonia), adult respiratory distress syndrome, pulmonary fibrosis, acute (chronic) lung injury, pulmonary edema , Atherosclerosis, scleroderma and other pathological processes play an important role, and has the function of promoting the invasion of viruses and bacteria and the metastasis of cancer cells. Research on the mechanism of inflammation has shown that the imbalance of this enzyme and its endogenous inhibitors in vivo can lead to the degradation of tissue matrix and the exacerbation of inflammation.
  • Sivelestat sodium chemical name: N- ⁇ 2-[4-(2,2-dimethylpropionyloxy)benzenesulfonylamino]benzoyl ⁇ aminoacetic acid, structural formula as follows, its structural formula and preparation For the method, refer to the patent EP0347168B, which was developed by Ono Pharmaceutical Company (Ono), the world's first NE-specific inhibitor that was first launched in Japan in 2002. The indication is to improve acute Lung injury (ALI). It is also the first new anti-inflammatory enzyme inhibitor officially approved by the State Drug Administration for the improvement of systemic inflammatory response syndrome (SIRS) with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Selectively inhibits neutrophil elastase (NE).
  • SIRS systemic inflammatory response syndrome
  • ALI acute lung injury
  • ARDS acute respiratory distress syndrome
  • NE neutrophil elastase
  • neutrophil elastase inhibitor neutrophil elastase inhibitor
  • NEI neutrophil elastase inhibitor
  • SIRS systemic inflammatory response syndrome
  • ALI acute lung injury
  • ARDS acute respiratory distress syndrome
  • the first object of the present invention is to provide a compound of formula (I):
  • R 1 and R 2 are independently selected from hydrogen, C 1-6 alkyl, -AR 4 ;
  • R 3 is optionally selected from tert-butylcarbonyl, benzyloxycarbonyl;
  • A is phenyl
  • R 4 is -SO 2 NH 2 , -CONH 2 .
  • R 1 and R 2 are independently selected from hydrogen, methyl, ethyl, propyl, -AR 4 ;
  • R1 and R2 are independently selected from methyl, ethyl, propyl;
  • R 1 is hydrogen
  • R 2 is optionally selected from methyl, ethyl, propyl, -AR 4 ;
  • R is selected from tert-butylcarbonyl
  • R 4 is -CONH 2 .
  • formula (I) is the following compound:
  • the present invention provides a kind of preparation method of formula (I) compound, and its preparation method is as follows:
  • the compound of formula (I-a) reacts with amine or amine salt in an inert organic solvent (such as dichloromethane) in the presence of an organic or inorganic base (such as triethylamine) to form an amide bond to synthesize the compound of formula (I).
  • an inert organic solvent such as dichloromethane
  • an organic or inorganic base such as triethylamine
  • the second object of the present invention is to provide a pharmaceutical composition, which contains the compound of formula (I) and a pharmaceutically acceptable carrier.
  • the carrier is a pharmaceutically acceptable auxiliary material, such as an inert diluent, proppant, lubricant, disintegrant, stabilizer, isotonic buffer, suspending agent, sweetener, flavoring agent, flavoring agent , preservatives, aqueous solvents, non-aqueous solvents, suspending media, emulsifiers, dispersants, solubilizers, etc. in one or more.
  • composition can be administered by inhalation in the form of solutions, suspensions, inhalants, etc.; orally in the form of tablets, capsules, granules, etc.; or rectally or transdermally in the form of suppositories; or in the form of Administered in the form of injection.
  • Solid compositions of the present invention for oral administration include compressed tablets, capsules, dispersible powders and granules.
  • one or more active compounds are mixed with at least one inert diluent such as lactose, mannitol, dextrose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone or partial Magnesium silicate mix.
  • the composition may also contain other substances besides inert diluents, such as lubricants such as magnesium stearate, disintegrants such as calcium cellulose glycolate, stabilizers such as lactose and solubilizers such as glutamic acid and asparagine .
  • Tablets or pills can, if desired, be made into tablets or pills with a gastric or enteric film coating, such as sugar-coated gelatin coating, hydroxypropyl cellulose coating or hydroxypropyl methylcellulose, ortho
  • a gastric or enteric film coating such as sugar-coated gelatin coating, hydroxypropyl cellulose coating or hydroxypropyl methylcellulose, ortho
  • Oral compositions may also include capsules of absorbable material such as gelatin.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, and syrups, which contain inert diluents commonly used in the art, such as distilled water or ethanol. Besides inert diluents, such compositions can also include adjuvants, such as wetting and suspending agents, and sweetening, flavoring, perfuming and preservative agents.
  • compositions for oral administration include spray compositions which contain one or more active compounds which may be prepared by known methods. Besides inert diluents, such compositions can also contain stabilizers such as sodium bisulfite and isotonic buffers such as sodium chloride, sodium citrate or citric acid.
  • stabilizers such as sodium bisulfite and isotonic buffers such as sodium chloride, sodium citrate or citric acid.
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions.
  • aqueous solvents or suspension media are distilled water for injection and physiological saline solution.
  • non-aqueous solvents or suspension media are propylene glycol, polyethylene glycol, vegetable oil (eg olive oil), alcohol (eg ethanol), Tween 80.
  • adjuvants such as preservatives, wetting agents, emulsifiers, dispersants and stabilizers (eg lactose) and solubilizers (eg glutamic acid and asparagine).
  • They can be sterilized, for example, by filtration through bacteria-retaining filters, by incorporating a disinfectant in the composition, or by irradiation. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile injectable medium immediately before use.
  • the third object of the present invention is that the compound or pharmaceutical composition of the present invention can be used as a medicine for treating or preventing diseases caused by the action of elastase, and the diseases include but are not limited to: systemic inflammatory response syndrome (SIRS) ) with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS).
  • SIRS systemic inflammatory response syndrome
  • ALI acute lung injury
  • ARDS acute respiratory distress syndrome
  • alkyl refers to saturated alkanes with 1 to 6 carbon atoms, such as straight-chain alkanes or branched-chain alkanes; specific alkyl groups include but are not limited to methyl, ethyl, n-propyl, iso Propyl, n-butyl, etc.
  • the alkyl groups described in the present invention may be unsubstituted, or may optionally be substituted with one or more substituents.
  • -AR 4 is an ortho-substituted, meta-substituted or para-substituted phenyl group.
  • Example 8 Referring to the preparation method of the above-mentioned Example 1 or Example 2, react 4-(chlorosulfonyl)phenyl pivalate with the corresponding amine or amine salt to prepare the following examples 3-7, 9-10 compound.
  • Compound Example 8 was synthesized according to the method of patent EP0347168B. Its structural formula is as follows:
  • Neutrophil elastase has relatively high specificity to the substrate Suc-Ala-Pro-Ala-pNA (succinyl-alanyl-proly-alanyl-pnitroanilide), and the released pnitroanilide is quantitatively detected by spectrophotometry Aniline.
  • the reaction mixture was composed of 1 mM Suc-Ala-Pro-Ala-pNA (dissolved in N-methylpyrrolidone to a concentration of 100 mM, and then 1/100 of the solution was added to the reaction mixture), 0.1 M tris-hydrochloric acid (pH 8.0) Buffer solution, 0.2M aqueous sodium chloride solution, various concentrations of the compound sample solution of the present invention and elastase solution constitute a mixture solution with a final volume of 1.0 ml, and incubate at 37° C. for 30 minutes.

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Abstract

本发明属于药物领域，公开了一种弹性蛋白酶抑制剂及在疾病治疗中的应用。具体地，公开了式(I)化合物、包含式(I)化合物的药物组合物及其在疾病治疗中的应用。本发明的式(I)化合物对弹性蛋白酶具有抑制作用，其可用于治疗或预防由弹性蛋白酶的作用而引起的疾病，其中包括全身性炎症反应综合征(SIRS)伴急性肺损伤(ALI)/急性呼吸窘迫综合征(ARDS)。

Description

弹性蛋白酶抑制剂及在疾病治疗中的应用 技术领域
本发明涉及药物领域，具体地本发明涉及一种对弹性蛋白酶具有抑制活性的化合物、组合物、在疾病治疗中的应用。所述疾病为由于弹性蛋白酶的作用而引起的疾病，包括全身性炎症反应综合征(SIRS)伴急性肺损伤(ALI)/急性呼吸窘迫综合征(ARDS)。
背景技术
人中性粒细胞弹性蛋白酶(human neutrophil elastase，NE)在机体各种炎症反应、组织损伤重构(如肺炎)、成人呼吸窘迫综合征、肺纤维化、急(慢)性肺损伤、肺水肿、动脉糊样硬化、硬皮病等病理过程中起重要作用，并且具有促进病毒、细菌的侵入及癌细胞转移的功能。炎症机制研究显示，体内该酶及其内源性抑制剂的平衡失调可导致组织基质降解和炎症的恶化。目前，国外用NE抑制剂来治疗这一类炎症疾病的研究非常广泛，并已成功开发出第一个以抑制NE为治疗途径的上市药物西维来司钠(sivelestat sodium hydrate)，从而促进了NE抑制剂的研究与开发。
西维来司他钠，化学名称：N-{2-[4-(2,2-二甲基丙酰氧基)苯磺酰氨基]苯甲酰基}氨基乙酸，结构式如下，其结构式及制备方法参见专利EP0347168B，是由日本小野医药公司(Ono)研制开发，2002年首次在日本上市的全球首个NE特异性抑制剂，适应症为改善伴有全身性炎症反应综合征(SIRS)的急性肺损伤(ALI)。也是目前第一个国家药品监督管理局官方批准用于改善全身性炎症反应综合征(SIRS)伴急性肺损伤(ALI)/急性呼吸窘迫综合征(ARDS)的新型抗炎酶抑制剂，其可选择性抑制中性粒细胞弹性蛋白酶(NE)。
Figure PCTCN2021113436-appb-000001
利用中性粒细胞弹性蛋白酶抑制剂(neutrophil elastase inhibitor，NEI)治疗上述疾病，尤其是治疗伴有全身性炎症反应综合征(SIRS)伴急性肺损伤(ALI)/急性呼吸窘迫综合征(ARDS)是目前研究的热门课题。因此，开发高效、低毒的中性粒细胞弹性蛋白酶抑制剂具有重要的商业价值与现实意义。
发明内容
本发明第一个目的是提供一种式(I)的化合物：
Figure PCTCN2021113436-appb-000002
其中，
R 1和R 2独立选自氢、C 1-6烷基、-A-R 4；
R 3任选自叔丁基羰基、苄氧羰基；
A为苯基；
R 4为-SO 2NH 2、-CONH 2。
作为本发明优选实施方案，式(I)化合物中：R 1和R 2独立选自氢、甲基、乙基、丙基、-A-R 4；
更优选的R1和R2独立选自甲基、乙基、丙基；
更优选的R 1为氢，R 2任选自甲基、乙基、丙基、-A-R 4；
更优选的R 3选自叔丁基羰基；
更优选的R 4为-CONH 2。
作为本发明优选实施方案，式(I)为如下化合物：
Figure PCTCN2021113436-appb-000003
Figure PCTCN2021113436-appb-000004
本发明提供一种式(I)化合物的制备方法，其制备方法如下所示：
Figure PCTCN2021113436-appb-000005
式(I-a)化合物与胺或胺的盐在惰性有机溶剂(例如二氯甲烷)中，在有机或无机碱(例如三乙胺)存在下进行反应形成酰胺键合成式(I)化合物。
本发明第二个目的是提供一种药物组合物，所述组合物含有式(I)化合物和药学上可接受的载体。所述载体为药学上可接受的辅料，例如可以是惰性稀释剂、支撑剂、润滑剂、崩解剂、稳定剂、等渗缓冲剂、助悬剂、甜味剂、调味剂、加香剂、防腐剂、水性溶剂、非水溶剂、悬浮介质、乳化剂、分散剂、增溶剂等中的一种或多种。所述组合物可以溶液、悬浮液、吸入剂等形式吸入给药；或以片剂、胶囊剂、颗粒剂等形式口服给药；或以栓剂的形式直肠给药或经皮给药；或以注射液形式给药。
用于口服的本发明的固体组合物包括压制的片剂、胶囊、可分散的粉剂和颗粒剂。在这样的固体组合物中，将一种或多种活性化合物与至少一种惰性稀释剂如乳糖、甘露醇、葡萄糖、羟丙基纤维素、微晶纤维素、淀粉、聚乙烯基吡咯烷酮或偏硅酸镁混合。该组合物还可以包含除惰性稀释剂以外的其他物质，例如润滑剂例如硬脂酸镁、崩解剂例如纤维素乙醇酸钙、稳定剂例如乳糖和增溶剂例如谷氨酸和天冬酰胺酸。如果需要，可以将片剂或丸剂制成胃膜包衣或肠溶性膜包衣的片剂或丸剂，例如糖衣明胶包衣、羟丙基纤维素包衣或羟丙基甲基纤维素、邻苯二甲酸酯包衣的片剂或丸剂，可以使用两层或更多层。口服组合物还可包括可吸收物质如明胶的胶囊。
用于口服的液体组合物包括药学上可接受的乳剂、溶液剂、混悬剂、糖浆剂、其含有本领域常用的惰性稀释剂、例如蒸馏水或乙醇。除了惰性稀释剂，此类组合物还可包含佐剂、例如润湿剂和助悬剂、以及甜味剂、调味剂、加香剂和防腐剂。
其他用于口服的组合物包括可以通过已知方法制备的喷雾组合物、其包含一种或多种活 性化合物。除惰性稀释剂外、此类组合物还可包含稳定剂例如亚硫酸氢钠和等渗缓冲剂例如氯化钠、柠檬酸钠或柠檬酸。
用于肠胃外给药的注射剂包括无菌水性或非水性溶液、悬浮液或乳剂。水性溶剂或悬浮介质的实例是注射用蒸馏水和生理盐水溶液。非水溶剂或悬浮介质的实例是丙二醇、聚乙二醇、植物油(例如橄榄油)、醇(例如乙醇)、吐温80。这些组合物还可以包括佐剂、例如防腐剂、润湿剂、乳化剂、分散剂和稳定剂(例如乳糖)和增溶剂(例如谷氨酸和天冬酰胺酸)。它们可以例如通过细菌保留过滤器过滤，通过在组合物中掺入消毒剂或通过辐射进行消毒。它们也可以以无菌固体组合物的形式制造，可以在使用前立即溶于无菌水或某些其他无菌注射介质中。
本发明的第三个目的是本发明化合物或药物组合物可作为治疗或预防由于弹性蛋白酶的作用而引起的疾病药物中的用途，所述疾病包括但不限于：全身性炎症反应综合征(SIRS)伴急性肺损伤(ALI)/急性呼吸窘迫综合征(ARDS)。
术语解释
本发明中，“烷基”、是指具有1至6个碳原子的饱和烷烃，如直链烷烃或支链烷烃；具体的烷基包括但不限于甲基、乙基、正丙基、异丙基、正丁基等。本发明所述的烷基可以是未取代的，或任选可被一个或多个取代基取代。
取代基-A-R 4中，-A-R 4为邻位取代、间位取代或者对位取代的苯基。
具体实施方式
本发明实施例用于理解本发明，本发明的范围并不限制于以下实施例。除非特别说明，本发明实施例所使用的化合物、试剂等均购自合格供应商。
实施例1
4-(N,N-二甲基氨磺酰基)苯基新戊酸酯：
Figure PCTCN2021113436-appb-000006
在100ml三口瓶中加入2.2g二甲胺盐酸盐和10ml二氯甲烷，搅拌，降温至5℃，加入5.5g三乙胺，T＝5℃，滴加4-(氯磺酰基)苯基新戊酸酯和DCM的混合溶液(5g 4-(氯磺酰基)苯基新戊酸酯和10ml二氯甲烷)，取样LCMS监测反应，加入20ml水，搅拌后分液，有机相压浓缩至干得4.9g 4-(N,N-二甲基氨磺酰基)苯基新戊酸酯。HPLC纯度99.6％。
1H NMR(400MHz,CDCl 3)δ1.34(s,9H),2.68(s,6H),7.22-7.26(t,2H),7.76-7.78(d,2H).
实施例2
4-(N-(2-氨基甲酰基苯基)氨磺酰基)苯基新戊酸酯：
Figure PCTCN2021113436-appb-000007
在100ml三口瓶中加入2g 2-氨基苯甲酰胺和20ml二氯甲烷，室温下搅拌，加入4.88g 4-(氯磺酰基)苯基新戊酸酯，室温下滴加1.78g三乙胺，取样LCMS监测反应，加入20ml水，搅拌后有固体析出，过滤，滤饼用10ml水打浆0.5h，过滤，滤饼用20ml水淋洗，干燥后得2.7g4-(N-(2-氨基甲酰基苯基)氨磺酰基)苯基新戊酸酯。HPLC纯度99.4％。
1H NMR(400MHz,DMSO-d6)δ1.27(s,9H),7.07-7.15(m,1H),7.26-7.35(m,2H),7.49(dtd,2H),7.75-7.86(m,3H),7.88(s,1H),8.35(s,1H),12.29(s,1H)；
参照上述实施例1或实施例2的制备方法，将4-(氯磺酰基)苯基新戊酸酯与相应的胺或胺的盐进行反应，制备得到以下实施例3-7、9-10化合物。参照专利EP0347168B的方法合成实施例8化合物。其结构式如下：
Figure PCTCN2021113436-appb-000008
Figure PCTCN2021113436-appb-000009
活性测试
本发明化合物对人中性粒细胞弹性蛋白酶抑制活性的测试
测试方法：中性粒细胞弹性蛋白酶对底物Suc-Ala-Pro-Ala-pNA(succinyl-alanyl-proly-alanyl-pnitroanilide)具有相对高的特异性，采用分光光度法定量检测反应释放的对硝基苯胺。
反应混合物由1mM Suc-Ala-Pro-Ala-pNA(溶于N-甲基吡咯烷酮至100mM的浓度，然后将1/100量的溶液加入反应混合物中)、0.1M的tris-盐酸(pH 8.0)缓冲溶液、0.2M氯化钠水溶液、各种浓度的本发明化合物样品溶液和弹性蛋白酶溶液组成终体积为1.0ml的混合物溶液，在37℃下孵育30分钟。然后向反应混合物溶液中加入100μl的50％乙酸终止反应，然后使用Spectramax分光光度计读取405nM处的吸光度测量值，测定反应释放的对硝基苯胺。对照组中不加入本发明化合物。抑制率按如下公式计算，并根据不同浓度化合物的抑制率拟合半数抑制浓度IC 50值。
Figure PCTCN2021113436-appb-000010
表1化合物对弹性蛋白酶的抑制活性
Figure PCTCN2021113436-appb-000011
Figure PCTCN2021113436-appb-000012
实验结果表明，本发明的化合物对弹性蛋白酶具有抑制作用。

Claims (10)

  1. 式(I)的化合物：
    Figure PCTCN2021113436-appb-100001
    其中，
    R 1和R 2独立选自氢、C 1- 6烷基、-A-R 4；
    R 3任选自叔丁基羰基、苄氧羰基；
    A为苯基；
    R 4为-SO 2NH 2、-CONH 2。
  2. 如权利要求1所述的式(I)化合物：其中，R 1和R 2独立选自氢、甲基、乙基、丙基、-A-R 4。
  3. 如权利要求1或2所述的式(I)化合物：其中，R 1和R 2独立选自甲基、乙基、丙基。
  4. 如权利要求3所述的式(I)化合物：其中，R 3选自叔丁基羰基。
  5. 如权利要求1或2所述的式(I)化合物：其中，R 1为氢，R 2任选自甲基、乙基、丙基、-A-R 4。
  6. 如权利要求5所述的式(I)化合物：其中，R 3选自叔丁基羰基。
  7. 如权利要求6所述的式(I)化合物：其中，R 4为-CONH 2。
  8. 如权利要求1-2中任一项所述的式(I)化合物，其为以下化合物：
    Figure PCTCN2021113436-appb-100002
    Figure PCTCN2021113436-appb-100003
  9. 一种药物组合物，其包含如权利要求1所述的式(I)化合物和药学上可接受的载体。
  10. 如权利要求9所述的药物组合物在治疗或预防由于弹性蛋白酶的作用而引起的疾病的药物中的用途。
PCT/CN2021/113436 2021-08-19 2021-08-19 弹性蛋白酶抑制剂及在疾病治疗中的应用 WO2023019499A1 (zh)

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EP0347168A1 (en) * 1988-06-13 1989-12-20 Ono Pharmaceutical Co., Ltd. Derivatives of p-substituted phenyl ester of pivalic acid
EP0757037A2 (en) * 1995-07-28 1997-02-05 Ono Pharmaceutical Co., Ltd. Sulfonylamino acid derivatives as metalloproteinase inhibitors
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EP0347168A1 (en) * 1988-06-13 1989-12-20 Ono Pharmaceutical Co., Ltd. Derivatives of p-substituted phenyl ester of pivalic acid
EP0757037A2 (en) * 1995-07-28 1997-02-05 Ono Pharmaceutical Co., Ltd. Sulfonylamino acid derivatives as metalloproteinase inhibitors
JP2001048860A (ja) * 1999-08-03 2001-02-20 Konica Corp ヒドラジン誘導体の製造方法及び芳香族スルホン酸マグネシウム塩

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TSONG-LONG HWANG ET AL.: "Synthesis and pharmacological characterization of 2-aminobenzaldehyde oxime analogs as dual inhibitors of neutrophil elastase and proteinase 3.", BIOORGANIC & MEDICINAL CHEMISTRY., vol. 23, no. 5, 16 January 2015 (2015-01-16), XP029199003, DOI: 10.1016/j.bmc.2014.12.056 *

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