CN115259994B - Dpi-有机酸复盐及其制备方法和应用 - Google Patents

Dpi-有机酸复盐及其制备方法和应用 Download PDF

Info

Publication number
CN115259994B
CN115259994B CN202210846446.0A CN202210846446A CN115259994B CN 115259994 B CN115259994 B CN 115259994B CN 202210846446 A CN202210846446 A CN 202210846446A CN 115259994 B CN115259994 B CN 115259994B
Authority
CN
China
Prior art keywords
dpi
acid
compound
organic acid
double salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN202210846446.0A
Other languages
English (en)
Other versions
CN115259994A (zh
Inventor
娄红祥
王雪
宗岩
孙斌
董婷
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shandong University
Original Assignee
Shandong University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shandong University filed Critical Shandong University
Priority to CN202210846446.0A priority Critical patent/CN115259994B/zh
Publication of CN115259994A publication Critical patent/CN115259994A/zh
Application granted granted Critical
Publication of CN115259994B publication Critical patent/CN115259994B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C25/00Compounds containing at least one halogen atom bound to a six-membered aromatic ring
    • C07C25/18Polycyclic aromatic halogenated hydrocarbons
    • C07C25/22Polycyclic aromatic halogenated hydrocarbons with condensed rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00General protective or antinoxious agents
    • A61P39/06Free radical scavengers or antioxidants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02Dicarboxylic acids
    • C07C55/06Oxalic acid
    • C07C55/07Salts thereof
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02Dicarboxylic acids
    • C07C55/10Succinic acid
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13Dicarboxylic acids
    • C07C57/15Fumaric acid
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/185Saturated compounds having only one carboxyl group and containing keto groups
    • C07C59/195Acetoacetic acid
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235Saturated compounds containing more than one carboxyl group
    • C07C59/245Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/255Tartaric acid
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235Saturated compounds containing more than one carboxyl group
    • C07C59/245Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/265Citric acid
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40Unsaturated compounds
    • C07C59/42Unsaturated compounds containing hydroxy or O-metal groups
    • C07C59/52Unsaturated compounds containing hydroxy or O-metal groups a hydroxy or O-metal group being bound to a carbon atom of a six-membered aromatic ring
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C62/00Compounds having carboxyl groups bound to carbon atoms of rings other than six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C62/30Unsaturated compounds
    • C07C62/32Unsaturated compounds containing hydroxy or O-metal groups
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C63/00Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
    • C07C63/04Monocyclic monocarboxylic acids
    • C07C63/06Benzoic acid
    • C07C63/08Salts thereof
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/732Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/84Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/84Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
    • C07C69/88Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with esterified carboxyl groups
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic 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
    • C07D213/02Heterocyclic 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
    • C07D213/04Heterocyclic 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
    • C07D213/60Heterocyclic 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
    • C07D213/78Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79Acids; Esters
    • C07D213/80Acids; Esters in position 3
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic 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
    • C07D213/02Heterocyclic 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
    • C07D213/04Heterocyclic 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
    • C07D213/60Heterocyclic 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
    • C07D213/78Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79Acids; Esters
    • C07D213/803Processes of preparation
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D339/00Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/02Five-membered rings
    • C07D339/04Five-membered rings having the hetero atoms in positions 1 and 2, e.g. lipoic acid
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J63/00Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008Expansion of ring D by one atom, e.g. D homo steroids
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J9/00Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C07J9/005Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Biochemistry (AREA)
  • Cardiology (AREA)
  • Toxicology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pulmonology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明涉及DPI‑有机酸复盐及其制备方法和应用。常规的DPI类化合物是一种静电复合物,由DPI与简单负离子组成,例如氯离子、三氟乙磺酸根离子、硫酸根离子。本发明提供了一种由DPI类化合物与有机酸形成的新型静电复合物和合成方法及其应用,由DPI类化合物与各种有机酸复合而成,DPI类化合物与有机酸的摩尔比为1:1‑2。所形成的新型复盐进一步丰富了DPI类化合物的多样性,并且同时具有DPI和有机酸部分的生物活性,具有潜在的开发应用价值。

Description

DPI-有机酸复盐及其制备方法和应用
技术领域
本发明属于医药技术领域,具体涉及DPI-有机酸复盐及其制备方法和应用。
背景技术
公开该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解,而不必然被视为承认或以任何形式暗示该信息构成已经成为本领域一般技术人员所公知的现有技术。
常规的二亚苯基碘鎓DPI类化合物是一种由氯离子、三氟乙磺酸根离子、硫酸根离子等简单负离子组成静电复合物,是一种NADPH氧化酶(NOX)抑制剂,能够选择性抑制胞内活性氧,广泛应用于抑制氧化应激和缓解ROS升高引起的相关疾病,例如血管疾病、神经退行性疾病、肿瘤以及肝肺损伤引起的炎症反应等。尽管目前已经发现DPI在上述一些模型中表现出改善或治疗效果,但其在胞内的其它作用机制仍有待进一步研究。
有机酸类化合物是分子结构中含有羧基(-COOH)的一类化合物,在植物的叶、根、特别是果实中广泛分布。研究证明,许多天然来源的有机酸具有丰富多样的生物活性,例如绿原酸为许多中草药的主要活性成分,具有抗菌、利胆、升高白血球等作用。从甘草根中得到的甘草次酸可药食两用,既是天然的甜味剂,又具有显著的抗炎抗过敏活性。据文献报道,其抗炎症、抗过敏反应可能与抑制毛细血管通透性、抗组胺或降低细胞对刺激的反应性有关。除了上述提及到的天然有机酸外,还存在许多具有功能的天然有机酸衍生物,例如解热镇痛的乙酰水杨酸,保护肝脏的奥贝胆酸,抗氧化剂的硫辛酸等。
文献研究证明,许多天然有机酸具有缓解肺部纤维化的功能,而DPI作为一种离子型化合物,也被报道能够选择性聚集在肺部组织中,具有靶向治疗肺部疾病的潜力。基于上述两类化合物功效的重叠性,旨在拓宽治疗范围和增强治疗效果,本发明设计了将DPI类化合物与有机酸结合成静电复合物形式的复盐来治疗肺部疾病并提供了制备方法。
发明内容
本发明的目的是提供一种DPI类化合物与有机酸形成的结构新颖的复盐及其制备方法,该复盐结合了DPI类化合物、有机酸的功效,在治疗肺部疾病上有着显著的效果。
为实现上述技术目的,本发明采用如下技术方案:
本发明的第一方面,提供了一种DPI-有机酸复盐,其包括具有如下Formula I结构通式:
其中,RCOO-为有机酸的酸根,所述有机酸包括但不限于烟酸,甘草次酸,丙酮酸,奥贝胆酸,乙酰水杨酸,水杨酸,硫辛酸,富马酸,苹果酸,枸橼酸,草酸,琥珀酸,苯甲酸,咖啡酸,莽草酸,绿原酸,熊果酸,桦木酸,夫西地酸等,熊去氧胆酸;
R1和R2选自氢、卤素、烷基、硝基、氨基、羟基、乙酰基、氰基、酯基、羧基、醛基、三卤甲基等中的一种或多种;
R1的取代位置可以是C-2,C-3,C-4,C-5中的一个或多个位点;
R2的取代位置可以是C-2’,C-3’,C-4’,C-5’中的一个或多个位点;
m,n=0,1,2,3,4。
进一步的,所述烷基选自甲基,乙基以及异丙基。
进一步的,卤素为氟、氯、溴、碘中的一种或多种。
卤代甲基是指被卤素取代的甲基,可以是一取代、二取代或三取代,包括三氟甲基、溴甲基等
本发明的第二方面,提供了一种DPI-有机酸复盐的制备方法,包括如下步骤:
(a)化合物1和化合物2经Sonogoshira偶联反应得到化合物3;所述Sonogoshira偶联反应在反应溶剂中,碱性条件下,经催化剂作用进行;
(b)化合物3经环化反应得到化合物4;环化反应为在有机溶剂中由环化剂在酸性条件下进行;
(c)化合物4经离子交换后得到DPI碱式盐即化合物5;离子交换反应为经离子交换树脂在水溶液中进行;
(d)化合物5与有机酸经酸碱中和反应得到复盐类化合物I;将化合物5与有机酸溶解于有机溶剂中,静置至晶体析出,干燥即得DPI-有机酸复盐;
其中,反应过程如下所示:
进一步的,步骤(a)中,所用反应溶剂为1:1体积的四氢呋喃(THF)和水;所述碱性条件由碳酸钾提供,所用催化剂为双三苯基磷二氯化钯(PdCl2(PPh3)2)。
进一步的,步骤(a)中,所述化合物1为1,2-二碘苯或取代的1,2-二碘苯;用量为2eq,化合物2为苯硼酸或者取代的苯硼酸;用量为1eq;所用催化剂的量为催化量;提供碱性条件所用的碳酸钾为4eq;反应溶剂的体积为20mL;反应温度为70℃。
进一步的,步骤(b)中,所述的有机溶剂为二氯甲烷(DCM);所用环化剂为间氯过氧苯甲酸(m-CPBA);所用酸为三氟乙酸(TFA)。
进一步的,步骤(b)中,所用有机溶剂的体积为40mL,所用环化剂的用量为1.5eq;所用酸的用量为3eq;反应温度为室温。
进一步的,步骤(c)中,所述水溶液为去离子水;所述离子交换树脂树脂为氢氧型强碱性阴离子交换树脂。
进一步的,步骤(d)中,化合物5与有机酸溶解于有机溶剂中必要时进行超声溶解。
进一步的,步骤(d)中,化合物5与有机酸的摩尔比为1:1-2:1。
进一步的,步骤(d)中,其中,RCOO-为有机酸的酸根,所述有机酸包括烟酸,甘草次酸,丙酮酸,奥贝胆酸,乙酰水杨酸,水杨酸,硫辛酸,富马酸,苹果酸,枸橼酸,草酸,琥珀酸,苯甲酸,咖啡酸,莽草酸,绿原酸,熊果酸,桦木酸,夫西地酸,熊去氧胆酸中的一种或多种;所述有机溶剂为二甲基亚砜、甲醇、乙醇、乙腈、乙酸乙酯、四氢呋喃或二氯甲烷中的一种。
本发明的第二方面,提供上述DPI-有机酸复盐在制备治疗肺损伤药物中的应用。
本发明的第三方面,提供一种药物组合物,包括所述DPI-有机酸复盐以及药学上可接受的赋形剂;优选的,所述药物组合物的剂型为片剂,胶囊剂,喷雾剂或注射剂。
该DPI-有机酸复盐具有DPI和有机酸的双重治疗功效,可以起到协同治疗的作用。DPI类化合物与有机酸形成的复盐的治疗作用,包括DPI的生物活性,主要在于选择性抑制细胞内活性氧,广泛应用于抑制氧化应激和缓解ROS升高引起的相关疾病,包括但不限于血管疾病、神经退行性疾病、肿瘤以及肝肺损伤引起的炎症反应等。其次,DPI能够选择性聚集在肺部组织,具有靶向治疗肺部疾病的潜力,可应用于治疗相关肺部疾病,包括但不限于肺纤维化、高原肺病和急性窘迫呼吸综合征等。该DPI类化合物与有机酸形成的复盐的治疗作用,包括酸根所属的有机酸丰富多样的生物活性,包括但不限于具有抗肺部纤维化作用的甘草次酸、硫辛酸、奥贝胆酸、烟酸、丙酮酸等,具有抗氧化抗炎活性的绿原酸、甘草次酸、酒石酸、枸橼酸、丙酮酸、熊果酸、桦木酸、乙酰水杨酸、水杨酸等。除此之外,熊果酸、甘草次酸还具有一定的抗菌作用,枸橼酸和苹果酸能防止心血管动脉硬化并减少血液粘稠度。
本发明的有益效果为:
本发明的要点在于提供了一种DPI类化合物与有机酸经酸碱中和反应制备的复盐,制备方法及其应用,具有新颖的复合结构。其原理为:DPI类化合物是一类由DPI与简单负离子形成的静电复合物,例如氯离子、三氟乙磺酸根离子、硫酸根离子,将其制备成氢氧根型的碱式盐后,可和有机酸的羧基进行酸碱中和反应生成水和相应的复盐。
该种DPI类化合物与有机酸形成的复盐与现存普通DPI类化合物相比,具有新颖的复合结构,并且可以同时发挥DPI与有机酸的治疗作用,在医药卫生领域具有潜在的应用价值。
附图说明
构成本发明的一部分的说明书附图用来提供对本发明的进一步理解,本发明的示意性实施例及其说明用于解释本发明,并不构成对本发明的不当限定。
图1是实施例一中DPI-OH、烟酸与DPI-烟酸复盐(化合物I-1)核磁谱图对比(DMSO-d6,400MHz)。
图2是DPI-烟酸复盐的X-ray单晶衍射晶体结构。
图3是DPI-烟酸复盐的X-ray单晶衍射晶体空间排列。
图4是DPI-甘草次酸复盐的X-ray单晶衍射晶体结构。
图5是DPI-丙酮酸复盐的X-ray单晶衍射晶体结构。
图6是DPI-水杨酸复盐的X-ray单晶衍射晶体结构。
图7是低压低氧和脂多糖双因素实验的生存曲线图。
具体实施方式
应该指出,以下详细说明都是示例性的,旨在对本发明提供进一步的说明。除非另有指明,本发明使用的所有技术和科学术语具有与本发明所属技术领域的普通技术人员通常理解的相同含义。
除非另行定义,文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。本申请所使用的试剂或原料均可通过常规途径购买获得,如无特殊说明,本申请所使用的试剂或原料均按照本领域常规方式使用或者按照产品说明书使用。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本申请方法中。文中所述的较佳实施方法与材料仅作示范之用。
所有实施例中,1H NMR及13C NMR由AvanceⅢ-400或AvanceⅢ-600型核磁共振仪记录,化学位移以δ(ppm)表示;质谱由MS质谱-LCQ-DECA离子阱质谱仪(ESI/LR)与MS质谱-Q-TOF四极杆飞行时间质谱仪(ESI-HR)记录。
实施例一化合物I-1
其中,RCOO-如本发明内容定义的有机酸的酸根。
(a)氩气保护下,取2.4g(2eq)化合物1和0.46g(1eq)化合物2溶于20mL体积比为1:1的四氢呋喃水溶液中,加入1.5g(4eq)的碳酸钾和催化量的双三苯基磷二氯化钯,加热至70℃搅拌,TLC监测反应至反应完全,经硅胶柱层析纯化得到棕色液体化合物3(1.5g)。
(b)取1.2g(1eq)化合物3(2-碘联苯)溶于40mL无水二氯甲烷中,加入1.1g(1.5eq)间氯过氧苯甲酸,滴加1.2mL(3eq)三氟乙酸,室温搅拌至反应完全,减压蒸干溶剂,向瓶中加入8mL无水乙醚,形成混悬液,室温搅拌20min。过滤,无水乙醚洗涤滤饼两次,真空干燥得到白色固体化合物4(1.5g)。
(c)取1.2g化合物4,加入纯净水,超声分散成混悬液,经氢氧型强碱性阴离子交换树脂经离子交换24h,纯净水淋洗。重复交换两次,合并溶液减压蒸干,得到白色固体化合物5(900mg)。
(d)精密称取95.7mg(1eq)化合物5与相对应得1eq化合物6(有机酸),摩尔比为1:1或1:2,溶于有机溶剂中,反复超声静置,直至晶体析出,干燥即得DPI-有机酸复盐I-1。
以不同有机酸为化合物6,按照类似前述的步骤制备以下实施例,具体有机酸即化合物6参考表1,使用的溶剂可采用表1中所列出的任意一种:
表1
以含有不同的取代基的二碘苯为化合物1,含有不同取代基的苯硼酸为化合物2,按照类似前述步骤得到含有不同取代基的DPI衍生物,再与上述有机酸制备相应DPI衍生物与有机酸复盐,具体DPI衍生物5参考表2:
表2
以DPI-烟酸复盐(化合物I-1)为例详细说明,在DPI-烟酸复盐的核磁谱图(图1)中,烟酸羧基上的氢信号明显缺失;DPI-OH芳香区的氢质子的化学位移有明显变化。上述信息说明DPI与烟酸形成了复盐的形式,并通过其X-ray单晶衍射晶体结构(图2)及X-ray单晶衍射晶体空间排列(图3)证明了其复盐形式。除此之外,我们也采用X-ray单晶衍射实验举例证明了其他实例中的复盐结构(图4-5)。
为了验证本发明所述的DPI-有机酸复盐对低压低氧环境及脂多糖(LPS)造成的肺损伤的保护作用,进行了如下动物试验:
低压低氧实验:取体重为18-20g/只的雄性C57小鼠24只,随机分为3组,每组8只,分别为低压低氧模型组(模拟海拔7000m),低压低氧实验组(DPI-甘草次酸复盐组)和常压常氧对照组。将模型组小鼠和低压低氧实验组置于高原环境模拟舱内,缓慢匀速减压至海拔7000m高度,24h自然昼夜交替,小鼠自由进食水,第0h,8h,16h给药,给药后立即放回模拟舱。给药方式为腹腔注射给药DPI-甘草次酸复盐,给药剂量为2mg/kg,模型组和对照组均腹腔注射等体积生理盐水。24h低压低氧实验结束后观察小鼠状态,并测量呼末CO2分压值。
表3.低压低氧实验组、对照组和常压常氧空白组的小鼠呼末CO2分压值
实验结束后,常压常氧对照组小鼠精神状态良好,毛泽光亮,活动敏捷,呼吸平稳,正常进食和饮水。低压低氧模型组小鼠精神萎靡,鼠毛光泽暗淡,死亡1只。与模型组小鼠相比,DPI-甘草次酸复盐给药组的小鼠反应程度较轻,精神状态尚佳,正常进食和饮水。上述结果及统计数据表明:模型组相对于对照组有显著性差异(***p<0.001),说明低压低氧对于肺部损伤效果非常明显,而DPI-甘草次酸复盐给药组的呼末CO2分压值相对于模型组也有显著性差异(***p<0.001),说明DPI-有机酸复盐对低压低氧造成的肺损伤有显著的保护作用。
低压低氧和脂多糖双因素实验:取体重为18-20g/只的雄性C57小鼠15只,随机分为3组,每组5只,分别为模型组、DPI-有机酸复盐给药组和正常对照组。模型组和给药组分别经气管滴注脂多糖(5mg/kg)构建脂多糖诱导的小鼠急性肺损伤模型,对照组给予等体积生理盐水。造模后,DPI-有机酸复盐组腹腔注射DPI-甘草次酸复盐(2mg/kg,1次/天),其余两组均腹腔注射同体积生理盐水。给药后立即将DPI-有机酸复盐组和模型组放置于高原环境模拟舱(7000m)中5h,使得小鼠受到低压低氧和LPS双重压力。连续给药3天后观察小鼠状况,观察至第5天。
实验结果表明(如图7所示),从给药第二天开始,模型组小鼠开始出现死亡,第四天死亡率为100%,而DPI-有机酸复盐组小鼠直至实验结束仍然存活,且精神状态尚好,正常进食和饮水。说明DPI-有机酸复盐对低压低氧和LPS双重压力所引起的急性肺损伤有显著的保护作用。
最后应该说明的是,以上所述仅为本发明的优选实施例而已,并不用于限制本发明,尽管参照前述实施例对本发明进行了详细的说明,对于本领域的技术人员来说,其依然可以对前述实施例所记载的技术方案进行修改,或者对其中部分进行等同替换。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。上述虽然对本发明的具体实施方式进行了描述,但并非对本发明保护范围的限制,所属领域技术人员应该明白,在本发明的技术方案的基础上,本领域技术人员不需要付出创造性劳动即可做出的各种修改或变形仍在本发明的保护范围以内。

Claims (9)

1.一种治疗肺损伤的DPI-有机酸复盐,其特征在于,
所述肺损伤为低压低氧和LPS双重压力所引起的急性肺损伤;
DPI-有机酸复盐包括具有如Formula I结构通式:
所述DPI-有机酸复盐的制备方法,包括如下步骤:
(a)化合物1和化合物2经Sonogoshira 偶联反应得到化合物3;所述Sonogoshira 偶联反应在反应溶剂中,碱性条件下,经催化剂作用进行;
(b)化合物3经环化反应得到化合物4;环化反应为在有机溶剂中由环化剂在酸性条件下进行;
(c)化合物4经离子交换后得到DPI碱式盐即化合物5;离子交换反应为经离子交换树脂在水溶液中进行;
(d)化合物5与有机酸经酸碱中和反应得到复盐类化合物I;将化合物5与有机酸溶解于有机溶剂中,静置至晶体析出,干燥即得DPI-有机酸复盐;
其中,反应过程如下所示:
Scheme 1
Scheme 2 ;
其中,RCOO-为有机酸的酸根,所述有机酸为甘草次酸;R1、R2为H;m, n=0, 1, 2, 3, 4。
2.根据权利要求1所述DPI-有机酸复盐,其特征在于,步骤(a)中,所用反应溶剂为1:1体积的四氢呋喃和水;所述碱性条件由碳酸钾提供,所用催化剂为双三苯基磷二氯化钯。
3.根据权利要求1所述DPI-有机酸复盐,其特征在于,步骤(a)中,所述化合物1为1,2-二碘苯或取代的1,2-二碘苯;用量为2eq,化合物2为苯硼酸或者取代的苯硼酸;用量为1eq;所用催化剂的量为催化量;提供碱性条件所用的碳酸钾为4eq;反应溶剂的体积为20mL;反应温度为70ºC。
4.根据权利要求1所述DPI-有机酸复盐,其特征在于,步骤(b)中,所述的有机溶剂为二氯甲烷;所用环化剂为间氯过氧苯甲酸;所用酸为三氟乙酸;
步骤(b)中,所用有机溶剂的体积为40mL,化合物3的用量为1eq;所用环化剂的用量为1.5eq;所用酸的用量为3eq;反应温度为室温。
5.根据权利要求1所述DPI-有机酸复盐,其特征在于,步骤(c)中,所述水溶液为去离子水;所述离子交换树脂树脂为氢氧型强碱性阴离子交换树脂。
6.根据权利要求1所述DPI-有机酸复盐,其特征在于,步骤(d)中,化合物5与有机酸溶解于有机溶剂中进行超声溶解;步骤(d)中,化合物5与有机酸的摩尔比为1:1-2:1;
步骤(d)中, RCOO-为有机酸的酸根,所述有机酸为甘草次酸;所述有机溶剂为二甲基亚砜、甲醇、乙醇、乙腈、乙酸乙酯、四氢呋喃或二氯甲烷中的一种。
7.权利要求1-6任一项所述DPI-有机酸复盐在制备治疗肺损伤药物中的应用。
8.一种药物组合物,包括权利要求1-6任一项所述DPI-有机酸复盐以及药学上可接受的赋形剂。
9.如权利要求8所述的药物组合物,其特征在于,所述药物组合物的剂型为注射剂。
CN202210846446.0A 2022-07-19 2022-07-19 Dpi-有机酸复盐及其制备方法和应用 Active CN115259994B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202210846446.0A CN115259994B (zh) 2022-07-19 2022-07-19 Dpi-有机酸复盐及其制备方法和应用

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202210846446.0A CN115259994B (zh) 2022-07-19 2022-07-19 Dpi-有机酸复盐及其制备方法和应用

Publications (2)

Publication Number Publication Date
CN115259994A CN115259994A (zh) 2022-11-01
CN115259994B true CN115259994B (zh) 2024-02-13

Family

ID=83767120

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202210846446.0A Active CN115259994B (zh) 2022-07-19 2022-07-19 Dpi-有机酸复盐及其制备方法和应用

Country Status (1)

Country Link
CN (1) CN115259994B (zh)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4613620A (en) * 1966-08-17 1986-09-23 Eli Lilly And Company Novel oxiodinium and thiaiodinium compounds
KR20120003832A (ko) * 2011-11-22 2012-01-11 강원대학교산학협력단 Nadph 옥시데이즈 복합체 단백질을 유효성분으로 하는 암을 치료, 및 진단하기 위한 조성물
CN103172612A (zh) * 2013-03-06 2013-06-26 中山大学肿瘤防治中心 一种二苯并碘鎓盐及其抗癌应用
CN106905133A (zh) * 2017-01-23 2017-06-30 肇庆医学高等专科学校 一种螺环芴并茚二酮类化合物及其制备方法和应用
CN114685518A (zh) * 2020-12-29 2022-07-01 广州华睿光电材料有限公司 有机化合物、混合物、组合物及有机电子器件

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005030138A2 (en) * 2003-09-26 2005-04-07 Webb Waring Institute Methods of modulating inflammatory reactions by modulating xanthine oxidoreductase activity
EP3129102A1 (en) * 2014-04-07 2017-02-15 The U.S.A. As Represented By The Secretary, Department Of Health And Human Services Iodonium analogs as inhibitors of nadph oxidases and other flavin dehydrogenases; formulations thereof; and uses thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4613620A (en) * 1966-08-17 1986-09-23 Eli Lilly And Company Novel oxiodinium and thiaiodinium compounds
KR20120003832A (ko) * 2011-11-22 2012-01-11 강원대학교산학협력단 Nadph 옥시데이즈 복합체 단백질을 유효성분으로 하는 암을 치료, 및 진단하기 위한 조성물
CN103172612A (zh) * 2013-03-06 2013-06-26 中山大学肿瘤防治中心 一种二苯并碘鎓盐及其抗癌应用
CN106905133A (zh) * 2017-01-23 2017-06-30 肇庆医学高等专科学校 一种螺环芴并茚二酮类化合物及其制备方法和应用
CN114685518A (zh) * 2020-12-29 2022-07-01 广州华睿光电材料有限公司 有机化合物、混合物、组合物及有机电子器件

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
An almitrine analog acts as hypoxia in isolated rat lungs;E Robineau 等;Respiration Physiology;第105卷;225-233 *
Inhibition of Hypoxic Pulmonary Vasoconstriction in Isolated Rat Pulmonary Arteries by Diphenyleneiodonium (DPI);J. S. Thompson 等;Pulmonary Pharmacology & Therapeutics;第11卷;71-75 *
J.S.Thompson 等.Inhibition of Hypoxic Pulmonary Vasoconstriction in Isolated Rat Pulmonary Arteries by Diphenyleneiodonium (DPI).Pulmonary Pharmacology & Therapeutics.1998,第11卷(第1期),第71-75页. *
Protective effects of diphenyleneiodonium, an NADPH oxidase inhibitor, on lipopolysaccharide-induced acute lung injury;Sung Kyoung Kim 等;Clinical and Experimental Pharmacology and Physiology;第46卷(第2期);第153-162页 *
Redox-sensitive regulation of macrophage-inducible nitric oxide synthase expression in vitro does not correlate with the failure of apocynin to prevent lung inflammation induced by endotoxin;Daniela Viaˇcková 等;Immunobiology;第216卷;457–465 *
Through the Maze: Cross-Coupling Pathways to a Helical Hexaphenyl "Geländer" Molecule;Michel Rickhaus 等;European Journal of Organic Chemistry;第1-17页 *

Also Published As

Publication number Publication date
CN115259994A (zh) 2022-11-01

Similar Documents

Publication Publication Date Title
EP1800685B1 (en) Steroidal saponin pharmaceutical composition, its preparation method and use
RU2421443C2 (ru) Замещенная бета-фенил-альфа-гидроксил пропановая кислота, метод синтеза и использование
EP3321259B1 (en) New pyrazine derivative, and preparation method and medical application thereof
AU2006312117A1 (en) Pharmaceutical gallium compositions and methods
JPS60155141A (ja) ポリ置換ナフタレン化合物、その製造方法およびこれを含有する医薬および化粧料組成物
JP2019509332A (ja) バイカリンマグネシウム化合物、その製造方法及び使用
CN104650108B (zh) 连翘脂素硫酸酯及其衍生物、制备方法及其应用
CN113336704A (zh) 丹参素衍生物及其制备方法和医药用途
CN115259994B (zh) Dpi-有机酸复盐及其制备方法和应用
CN102391336B (zh) 一种化合物、其制备方法及用途
CN101367799B (zh) 苦参碱丹参酚酸b复盐和苦参素丹参酚酸b复盐及其制备方法和用途
CN115974832B (zh) 一种含有二硫键的n-乙酰- l-半胱氨酸衍生物及其制备方法与应用
CN108794473B (zh) 一种苝酰亚胺-野尻毒素衍生物及其制备方法与应用
CN104188978B (zh) 闭花木酮的o-(四氢吡咯基)乙基衍生物在制备治疗或预防肾纤维化药物中的应用
CN104945455B (zh) 香豆素苷类化合物、其制法和药物组合物与用途
CN108484709B (zh) 灯盏花乙素镁化合物、其制备方法及应用
CN111606917B (zh) 一种具c环骈合内酯环新颖骨架的松香烷类化合物及其制备方法与应用
CN103980341B (zh) 一种氨基酸丹参酮酚酯衍生物及其制备方法
CN102234284B (zh) 含氟的噻氯匹啶类似物及其制备方法和用途
CN108164476B (zh) 间苯二腈类化合物、其应用以及包含该化合物的药物
CN104447721A (zh) 坎格列净无水化合物
JPH0952899A (ja) ロイコトリエン拮抗剤
CN109096133A (zh) (s)-2-氨基-3-(2,4,5-三氟苯基)丙酸薄荷酯盐酸盐及其制备方法和应用
CN106822107A (zh) Psiguadial A的咪唑基和二羟乙胺基衍生物组合物用于抗急性肾衰
CN102199171B (zh) 以曲酸衍生物为配体的钒类配位化合物及制备方法与应用

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant