WO2023131349A1 - Dérivé de tréprostinil de type donneur d'oxyde nitrique, composition pharmaceutique associée et utilisation associée - Google Patents

Dérivé de tréprostinil de type donneur d'oxyde nitrique, composition pharmaceutique associée et utilisation associée Download PDF

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WO2023131349A1
WO2023131349A1 PCT/CN2023/072247 CN2023072247W WO2023131349A1 WO 2023131349 A1 WO2023131349 A1 WO 2023131349A1 CN 2023072247 W CN2023072247 W CN 2023072247W WO 2023131349 A1 WO2023131349 A1 WO 2023131349A1
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Prior art keywords
pharmaceutically acceptable
pharmaceutical composition
donor
acceptable salt
treprostinil derivative
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PCT/CN2023/072247
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English (en)
Chinese (zh)
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黄夏梦
鲁卓敏
吴晓川
王天雨
章翔宇
蒋晟
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广州楷石医药有限公司
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Publication of WO2023131349A1 publication Critical patent/WO2023131349A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C203/00—Esters of nitric or nitrous acid
    • C07C203/02—Esters of nitric acid
    • C07C203/04—Esters of nitric acid having nitrate groups bound to acyclic carbon atoms
    • 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
    • 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
    • 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
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/14—Benz[f]indenes; Hydrogenated benz[f]indenes
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of biomedicine, and specifically relates to a coupled NO donor treprostinil derivative or a pharmaceutically acceptable salt thereof, its pharmaceutical composition and application.
  • Pulmonary arterial hypertension is a malignant disease characterized by elevated pulmonary vascular resistance and right ventricular failure.
  • Prostaglandins in the body activate adenylyl cyclase by interacting with prostaglandin receptors on platelets or vascular smooth muscle, thereby increasing the concentration of intracellular cAMP, which can play a role in dilating blood vessels.
  • Prostacyclin (PGI2) drugs are one of the important types of targeted drugs for the treatment of PAH.
  • Treprostinil as a class of prostaglandin analogues, can specifically bind to prostaglandin receptors to relax vascular smooth muscle and reduce pulmonary artery Pressure and inhibition of pulmonary artery vascular remodeling and in situ thrombosis.
  • Treprostinil is currently the only prostacyclin drug that is used in the treatment of PAH abroad and has multiple drug methods, such as subcutaneous, intravenous, inhalation or oral subcutaneous/intravenous administration.
  • Nitric oxide is a messenger molecule widely present in the human body and has various physiological activities. At physiological concentrations, it can activate soluble guanylate cyclase in smooth muscle cells to increase The level of cGMP, which makes blood vessels dilate, plays a role in regulating blood pressure. NO is also a commonly used drug for pulmonary hypertension and pulmonary embolism (Fernanda Blasina, et al., Pulmonary Pharmacology & Therapeutics, 2019; Jeffrey A. Kline, Am Heart J.
  • NO and treprostinil have their own special advantages and are effective through two second messenger cGMP and cAMP pathways respectively, clinically there is also the experience of using combined administration to improve the therapeutic effect in the future (Stacy Mandras, et al., J of Cardiovascular Pharmacol and Therap, 2021), but because the two drugs have to be administered in different ways (NO must be inhaled in the hospital, Quqian can be taken orally or injected or inhaled), so the drug is very inconvenient to use and the patient's compliance is low It is difficult to obtain the desired therapeutic effect.
  • the present invention is a series of innovative drugs coupled with Treprostinil and NO donors.
  • This type of drug combines two characteristic components of Treprostinil and NO, which are decomposed into Treprostinil and NO donors in the body and then produced NO, on the one hand, provides treprostinil and prostaglandin receptor specific binding, and exerts the effect of dilating vascular smooth muscle; NO passes through different pathways of cGMPS and cAMP. Therefore, the two have a synergistic function, which strengthens the effect of dilating blood vessels. At the same time, it is more convenient to administer and solves the problem of patient compliance. Pulmonary hypertension, respiratory distress syndrome, chronic arterial occlusive disease and other diseases.
  • a coupling NO donor type treprostinil derivative or a pharmaceutically acceptable salt thereof is provided.
  • the coupled NO donor treprostinil derivative or its pharmaceutically acceptable salt can be used for the treatment of pulmonary arterial hypertension, respiratory distress syndrome, chronic arterial occlusive disease and the like.
  • n is 0-6, preferably 0, 1, 2, 3 or 4;
  • R is -X-ONO 2 , -OC(O)-X-ONO 2 , -OX-ONO 2 , or Wherein X is straight chain or branched C 1 -C 10 alkyl, C 5-7 cycloalkyl or -C 1 -C 10 alkyl-aromatic ring-; wherein C 1 -C 10 alkyl, C 5- 7 Cycloalkyl or aromatic ring can be substituted by one or more of the following substituents: halogen atom, hydroxyl, carboxyl, cyano or -(C 1 -C 10 alkyl)-ONO 2 .
  • the compound includes any one of the following structures:
  • the present invention also provides a pharmaceutical composition, which contains a therapeutically effective amount of coupled NO-donor treprostinil derivative or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the carrier of the present invention can be any one or A mixture of two or more.
  • the pharmaceutical composition is preferably any one of external preparations, oral preparations and injection preparations.
  • the oral preparation is any one of granules, capsules and tablets.
  • the coupling NO donor treprostinil derivative or its pharmaceutically acceptable salt described in the present invention includes its application as a procyclin analogue.
  • the coupling NO donor type treprostinil derivative or its pharmaceutically acceptable salt described in the present invention includes its application in the preparation of medicines for treating pulmonary hypertension, respiratory distress syndrome, chronic arterial occlusive disease and the like.
  • the present invention has the following advantages:
  • the invention provides a kind of coupled NO donor type treprostinil derivatives or pharmaceutically acceptable salts thereof, which solves the defects of weak curative effect of treprostinil and inconvenient dosage of NO administration, etc. Drug effectiveness and patient compliance, and drug effectiveness control have also been improved.
  • Fig. 1 is a comparison chart of hypoxic pulmonary arterial hypertension (mPAP) measured in vivo in rats.
  • Example 2 can be prepared.
  • Example 3 can be prepared.
  • Example 5 can be prepared.
  • compound 8 can be prepared.
  • Example 9 can be prepared.
  • Example 10 can be prepared.
  • 1 H NMR 300MHz, Chloroform-d
  • Example 11 can be prepared.
  • Example 12 can be prepared.
  • Example 13 can be prepared.
  • compound 20 can be prepared.
  • compound 21 can be prepared.
  • the released NO is instantaneously oxidized in aqueous solution and called NO2 - , NO2 - and Griess reagent form a complex, which has a strong ultraviolet absorption at 540nm, so as to determine the NO release amount of the compound.
  • L-cysteine solution after accurately weighing L-cysteine, add a certain amount of PBS to prepare a solution weighing 200 ⁇ M;
  • Test compound solution the test compound was accurately weighed, dissolved in DMSO and diluted to a concentration of 1 mM, and then diluted with PBS to make the concentration 200 ⁇ M.
  • HX-200 animal ventilator SD male rats used in the experiment were purchased from Yangzhou University. All the control groups were reared under normal conditions, and the intervention group and the model group were reared in a hypobaric hypoxic chamber (air pressure 50kPa, oxygen concentration 10%).

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (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)
  • Engineering & Computer Science (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Epidemiology (AREA)
  • Emergency Medicine (AREA)
  • Pulmonology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne un médicament donneur d'oxyde nitrique (NO) couplé au tréprostinil, qui est tel que représenté dans la formule I ci-dessous, une composition pharmaceutique de celui-ci et une utilisation de celui-ci.
PCT/CN2023/072247 2022-01-07 2023-01-16 Dérivé de tréprostinil de type donneur d'oxyde nitrique, composition pharmaceutique associée et utilisation associée WO2023131349A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210017004.5 2022-01-07
CN202210017004.5A CN116444377A (zh) 2022-01-07 2022-01-07 一种氧化氮供体型曲前列尼尔类衍生物及其药物组合物和用途

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1906159A (zh) * 2004-01-05 2007-01-31 尼考斯股份公司 前列腺素硝基氧衍生物
CN103857413A (zh) * 2011-08-12 2014-06-11 阿森迪斯药物股份有限公司 载体连接的曲罗尼尔前药
CN105848479A (zh) * 2013-10-25 2016-08-10 英斯梅德股份有限公司 前列环素化合物、其组合物及使用方法
CN106905313A (zh) * 2017-03-14 2017-06-30 中国药科大学 一氧化氮供体型原小檗碱类衍生物及其制备方法和用途
CN110678174A (zh) * 2016-09-26 2020-01-10 联合治疗学有限公司 曲前列环素的前药
WO2022194195A1 (fr) * 2021-03-16 2022-09-22 江苏恒瑞医药股份有限公司 Dérivé de tréprostinil et son utilisation
CN115959996A (zh) * 2022-01-28 2023-04-14 上海众强药业有限公司 No供体化合物及其药物组合物和应用

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1906159A (zh) * 2004-01-05 2007-01-31 尼考斯股份公司 前列腺素硝基氧衍生物
CN103857413A (zh) * 2011-08-12 2014-06-11 阿森迪斯药物股份有限公司 载体连接的曲罗尼尔前药
CN105848479A (zh) * 2013-10-25 2016-08-10 英斯梅德股份有限公司 前列环素化合物、其组合物及使用方法
CN110678174A (zh) * 2016-09-26 2020-01-10 联合治疗学有限公司 曲前列环素的前药
CN106905313A (zh) * 2017-03-14 2017-06-30 中国药科大学 一氧化氮供体型原小檗碱类衍生物及其制备方法和用途
WO2022194195A1 (fr) * 2021-03-16 2022-09-22 江苏恒瑞医药股份有限公司 Dérivé de tréprostinil et son utilisation
CN115959996A (zh) * 2022-01-28 2023-04-14 上海众强药业有限公司 No供体化合物及其药物组合物和应用

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