WO2022217481A1 - Application d'analogues nucléosidiques dans la préparation de médicaments pour la prévention et/ou le traitement de maladies cérébrovasculaires - Google Patents

Application d'analogues nucléosidiques dans la préparation de médicaments pour la prévention et/ou le traitement de maladies cérébrovasculaires Download PDF

Info

Publication number
WO2022217481A1
WO2022217481A1 PCT/CN2021/087130 CN2021087130W WO2022217481A1 WO 2022217481 A1 WO2022217481 A1 WO 2022217481A1 CN 2021087130 W CN2021087130 W CN 2021087130W WO 2022217481 A1 WO2022217481 A1 WO 2022217481A1
Authority
WO
WIPO (PCT)
Prior art keywords
halogen
alkyl
preparation
formula
stroke
Prior art date
Application number
PCT/CN2021/087130
Other languages
English (en)
Chinese (zh)
Inventor
陈新平
刘菁菁
赵文阳
Original Assignee
兰州大学
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 兰州大学 filed Critical 兰州大学
Priority to PCT/CN2021/087130 priority Critical patent/WO2022217481A1/fr
Publication of WO2022217481A1 publication Critical patent/WO2022217481A1/fr

Links

Images

Classifications

    • 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
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to the field of medical technology, and also relates to a class of novel small molecular compounds that can be used for cerebrovascular diseases, and more particularly to the preparation of nucleoside analogs such as lamivudine, zidovudine and acyclovir for cerebrovascular diseases.
  • nucleoside analogs such as lamivudine, zidovudine and acyclovir for cerebrovascular diseases.
  • Cerebrovascular disease refers to various diseases of the brain blood vessels, including atherosclerosis, thrombosis, stenosis, occlusion, cerebral arteritis, cerebral artery injury, cerebral aneurysm, intracranial vascular malformation, cerebral aneurysm
  • Typical cerebrovascular diseases include cerebral thrombosis, cerebral ischemia, and cerebral infarction.
  • Cerebral thrombosis is based on cerebral atherosclerosis and plaque. Under the conditions of slow blood flow and low blood pressure, the effective components of blood adhere to the intima of the artery to form a thrombus, which becomes a cerebral thrombosis. Clinically, hemiplegia is the main cause. clinical manifestations.
  • Stroke is an acute cerebrovascular disease, which is a group of diseases that damage brain tissue due to sudden rupture of blood vessels in the brain or blockage of blood vessels that prevent blood from flowing into the brain, including ischemic stroke and hemorrhagic stroke. Thrombosis can cause the formation of cerebral infarction, also known as ischemic stroke; cerebral thrombosis and cerebral infarction can ultimately be attributed to stroke.
  • Stroke is a major chronic non-communicable disease that seriously endangers the health of Chinese nationals. It has five characteristics of high morbidity, high disability rate, high mortality rate, high recurrence rate and high economic burden. With the aging of the population, the prevalence of risk factors for cerebrovascular disease is more obvious, resulting in a continuous increase in the incidence of cerebrovascular disease. At present, there is no effective treatment for this serious disease in clinical practice. Therefore, how to develop a new drug that can significantly treat ischemic stroke is an urgent problem to be solved.
  • nucleoside analogs mainly include lamivudine, acyclovir, adefovir dipivoxil, famciclovir, entecavir, gemcitabine, zidovudine, cytarabine, azacitidine, emtricil Tapin, telbivudine, clavudine, emtricitabine, etc., their functions are mainly anti-virus, anti-tumor, improve immunity and restore liver function.
  • Lamivudine is a cytosine nucleoside analog, which has a competitive inhibitory effect on the synthesis and extension of viral DNA chains.
  • cytarabine mainly acts on the pyrimidine antimetabolites in the cell S proliferation phase, by inhibiting the synthesis of cell DNA and interfering with the proliferation of cells, it is mainly used for the treatment of acute leukemia, and has the most curative effect on acute myeloid leukocytes. Yes, it is also effective for acute monocytic leukemia and acute lymphoblastic leukemia.
  • Gemcitabine is a new cytosine nucleoside derivative with the same mechanism of action as cytarabine. Its main metabolite is incorporated into DNA in cells and mainly acts on G1/S phase. Clinically, gemcitabine and cytarabine have different anti-tumor spectrums and are effective against a variety of solid tumors. They are used as second-line drugs for patients with advanced pancreatic cancer and can improve the quality of life of patients; as locally advanced and metastatic non-small cell First-line therapy for cell lung cancer.
  • Zidovudine is a thymidine analog used for the treatment of AIDS or AIDS-related syndromes and the immunodeficiency virus HIV infection. It is the first anti-AIDS drug approved by the US FDA in the world. Because of its exact curative effect, it has become the most basic component of "cocktail" therapy, and has high activity against retroviruses including human immunodeficiency virus in vitro.
  • Acyclovir is a synthetic guanosine nucleoside analog, which is mainly used for various infections caused by herpes simplex virus. viral (HSV) infection. As the drug of choice for the treatment of HSV encephalitis, it is superior to vidarabine in reducing morbidity and mortality. It can also be used for herpes zoster, EB virus, and immunocompromised persons complicated with chickenpox infection. Due to less skin absorption, only for topical skin.
  • patent CN101511375B discloses that L-cytosine analogs are prepared in Use in medicaments for the treatment of cancer and other disorders or disease states, primarily structural modification of nucleoside analogs, and the use of modified compounds in the treatment of colon, pancreatic and liver cancers.
  • Patent CN111741967A discloses nucleotide analogs, preparation methods and their applications in nucleic acid sequence determination, etc., which mainly relate to the preparation methods of nucleoside analogs, etc.
  • Patent CN109790196A discloses the use of reversibly blocked nucleoside analogs for nucleic acid detection.
  • Patent CN108671235A discloses a functional nucleic acid with nucleoside analogs integrated into the backbone and its derivatives and its preparation method, as well as its use in the combined treatment of diseases with gene therapy and chemotherapy;
  • Patent CN104211742A discloses cyclophosphamide The phosphoric acid N-fatty acid modified by the chemical group and connected to the fatty chain is used for the treatment of viral hepatitis and liver cancer;
  • the patent CN110643609A discloses the drug aptamer constructed by the nucleoside analog drug molecule, the preparation method and its application, etc.; however, At present, there is no literature on the application of nucleoside analogs to cerebrovascular diseases, nor does any literature suggest that those skilled in the art have new uses for nucleoside analogs in the treatment of cerebrovascular diseases.
  • the inventor unexpectedly discovered that the nucleoside analog has a significant curative effect on cerebrovascular diseases, and provides a new use of the nucleoside analog.
  • the present invention discloses a nucleoside analog represented by formula (I) or its tautomer, meso, racemate, enantiomer and diastereomer Use of isomers and mixtures thereof, and pharmaceutically acceptable salts thereof for the preparation of medicines for the treatment and/or prevention of cerebrovascular diseases;
  • X and Y are respectively selected from any one of S, O, NH or alkoxy;
  • R is any one of cytosine, thymine, adenine and guanine
  • R 1 is OH, NH 2 , CH 3 , CH 3 O, halogen, C 1 -C 6 alkyl, metal ion, etc.;
  • R 2 is OH, NH 2 , CH 3 , CH 3 O, halogen, C 1 -C 6 alkyl, metal ions, etc.;
  • the nucleoside analogs are lamivudine, acyclovir, adefovir dipivoxil, famciclovir, entecavir, gemcitabine, zidovudine, cytarabine, azacitidine, entrexine One of sitapine, telbivudine, clavudine, or emtricitabine.
  • the nucleoside analogs are lamivudine, zidovudine and acyclovir.
  • the cerebrovascular disease is cerebral thrombosis, cerebral ischemia and cerebral apoplexy.
  • the stroke includes hemorrhagic stroke and ischemic stroke.
  • the stroke is ischemic stroke.
  • the second object of the present invention is to disclose the nucleoside analogs of formula (I) or their tautomers, mesomers, racemates, enantiomers, diastereomers and Its mixture form, and the application of its pharmaceutically acceptable salts in the preparation of medicines for treating and/or preventing nerve function damage;
  • X and Y are respectively selected from any one of S, O, NH or alkoxy;
  • R is any one of cytosine, thymine, adenine and guanine
  • R 1 is OH, NH 2 , CH 3 , CH 3 O, halogen, C 1 -C 6 alkyl, metal ion, etc.;
  • R 2 is OH, NH 2 , CH 3 , CH 3 O, halogen, C 1 -C 6 alkyl, metal ions, etc.;
  • the third object of the present invention is to disclose the nucleoside analogs of formula (I) or their tautomers, mesomers, racemates, enantiomers, diastereomers and Use of its mixture form and its pharmaceutically acceptable salts for preparing medicines for treating and/or preventing cerebral ischemia-reperfusion injury;
  • X and Y are respectively selected from any one of S, O, NH or alkoxy;
  • R is any one of cytosine, thymine, adenine and guanine
  • R 1 is OH, NH 2 , CH 3 , CH 3 O, halogen, C 1 -C 6 alkyl, metal ion, etc.;
  • R 2 is OH, NH 2 , CH 3 , CH 3 O, halogen, C 1 -C 6 alkyl, metal ions, etc.;
  • the fourth object of the present invention is to disclose the nucleoside analogs of formula (I) or their tautomers, mesomers, racemates, enantiomers, diastereomers and
  • the mixture form, its pharmaceutically acceptable salt and one or more pharmaceutically acceptable carriers constitute a pharmaceutical composition, and the dosage form of the pharmaceutical composition is injection, tablet, capsule, granule, and pill.
  • the present invention provides a new use of nucleoside analogs, specifically providing nucleoside analogs such as lamivudine, zidovudine and acyclovir in the preparation and treatment of cerebrovascular diseases, especially It is an application for the treatment of ischemic stroke.
  • nucleoside analogs can significantly reduce the neurological deficit score of stroke patients, reduce infarction focus, and have neuroprotective effects on stroke patients. It has the effect of treating ischemic stroke and can be popularized and applied clinically.
  • A is the TTC staining map of the brain slice
  • B is the neurological deficit score map
  • C is the cerebral infarction volume ratio map.
  • A is the TTC staining map of the brain slice
  • B is the neurological deficit score map
  • C is the cerebral infarction volume ratio map.
  • lamivudine is a virus-inhibiting drug and cannot clear hepatitis B virus, because lamivudine has no effect on hepatitis B virus cccDNA, and the half-life of cccDNA in the human body is about 3-4 years , if cccDNA persists, the virus will not be cleared, and it will inevitably relapse after stopping the drug. Therefore, in the application of lamivudine, its efficacy is not entirely dependent on the drug itself, but also closely related to the patient's specific immune response to HBV and virus virulence. For patients with weak specific immune response, lamivudine is used alone. It is difficult to achieve the purpose of clearing the virus, and it is necessary to find ways to improve the body's specific immune response to HBV. Consider the combined application of thymosin, therapeutic vaccines and high-titer hepatitis B immunoglobulin.
  • zidovudine is a thymidine analog, which is used for the treatment of AIDS or AIDS-related syndrome patients and immunodeficiency virus HIV infection.
  • the approved anti-AIDS drug has become the most basic component of the "cocktail" therapy because of its precise efficacy, and has high activity against retroviruses including human immunodeficiency virus in vitro.
  • acyclovir is a synthetic guanosine nucleoside analog, which is mainly used for various infections caused by herpes simplex virus, and can be used for initial or recurrent skin, mucous membrane, and external genital infections. and immunodeficiency HSV infection.
  • acyclovir is superior to vidarabine in reducing morbidity and mortality.
  • Acyclovir can also be used for the treatment of herpes zoster, Epstein-Barr virus, and varicella infection in immunocompromised patients.
  • butylphthalide is mainly used to treat mild and moderate acute ischemic stroke.
  • butylphthalide is used as a positive drug.
  • MCAO refers to Middle Cerebral Artery Occlusion, middle cerebral artery ischemia.
  • Example 1 The therapeutic effect of lamivudine on ischemic stroke
  • Lamivudine (Lamivudine, 3-TC, HPLC ⁇ 98%), purchased from McLean Biotechnology Co., Ltd.; Butylphthalide Soft Capsules (NBP, NBP), purchased from NBP of CSPC Pu Pharmaceutical Co., Ltd.; 2,3,5-triphenyltetrazolium chloride (TTC), purchased from Solarbio Company.
  • NBP Butylphthalide Soft Capsules
  • TTC 2,3,5-triphenyltetrazolium chloride
  • butylphthalide group (NBP, intragastric administration of butylphthalide, 20mg/kg/day)
  • Lamivudine group (C1, lamivudine given by gavage, 2 mg/kg/day),
  • the suture method of Longa et al. (refer to Reversible middle cerebral artery occlusion without craniectomy in rats.) was used to create an animal model of right middle artery occlusion in rats.
  • Model group The anesthetized rats were fixed, the skin was prepared, the iodine povidone was sterilized, and the surgical instruments were sterilized.
  • the No. 5 thread for ligation was prepared.
  • the common carotid artery and the internal carotid artery were ligated with surgical suture.
  • a 0.32mm suture was inserted into the internal carotid artery through the incision. When the depth of the suture was about 18-20mm, the insertion was stopped and the ligature was fastened. After washing, layered sutures are performed.
  • the suture was removed, and the animal would wake up naturally, and then reperfused for 24 hours, and then the relevant indicators were detected.
  • the nylon suture was pulled out after 2 hours of blocking, the arterial stump was tied tightly, and the subcutaneous tissue and skin were sutured layer by layer after disinfection.
  • Sham operation group the operation was the same as the model group except that no suture was inserted. After the experimental animals were awake, drug intervention was carried out, and the animals were sacrificed 24 hours after administration.
  • the rats in each group were decapitated, the brain tissue was separated on ice, the olfactory bulb and brain stem were removed, rinsed with normal saline, and immediately placed in -20 °C for 15 min, then taken out, and the brain was uniformly sliced along the optic chiasm plane to the pituitary plane coronally.
  • 4 coronal sections were immersed in 1.5% TTC solution, incubated in a constant temperature water bath at 37°C for 45 min for staining (protected from light), and turned every 15 min to make the staining uniform, the reaction with deoxygenase in normal tissue was red, and the ischemic area was white. That is, the unstained area is the infarct area, and the infarct volume of the animal brain tissue was determined according to the percentage of the total brain volume in each coronal section of the brain tissue in the total brain volume.
  • Cerebral infarction volume (sum of the mean area of the ischemic side - sum of the mean of the contralateral area) ⁇ the thickness of the infarcted brain tissue
  • FIG. 1 The results of neurological deficit evaluation, TTC staining and cerebral infarction volume are shown in Figure 1.
  • Figure 1A and Figure 1B compared with the sham-operated group, the neurological function score of the model group was significantly increased ( ### p ⁇ 0.001), the TTC staining in the brain tissue was uniform red, and no ischemic white infarction was found.
  • the MCAO model group a large area of white infarction was seen, indicating that the rat MCAO model was successfully constructed.
  • the positive drugs butylphthalide and lamivudine could significantly reduce the neurological deficit score (*p ⁇ 0.05, Figure 1B), improve the infarction (**p ⁇ 0.001, Figure 1C), It shows that lamivudine has the same neuroprotective effect of stroke as butylphthalide, and the neuroprotective effect of lamivudine (80.38%) is stronger than that of clinical drug butylphthalide (60.71%), namely the present invention Lamivudine has a better effect on the treatment of nerve damage in ischemic stroke.
  • lamivudine is a classic nucleoside analog drug
  • the inventors speculate that other nucleoside analogs besides lamivudine also have the effect of treating ischemic stroke.
  • the inventors The therapeutic effects of zidovudine and acyclovir on ischemic stroke were evaluated. The specific experimental process is as follows.
  • SPF grade healthy male SD rats weighing 200-240g, have not used any drugs before the experiment, provided by Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, license number is SCXK (gan)-2020-0002, adaptive rearing for one week, given Animals were fed food and water ad libitum before being grouped for the experiment.
  • Drugs and reagents Zidovudine (Zidovudine, AZT, HPLC ⁇ 98%), purchased from Aladdin Biotechnology Co., Ltd.; Acyclovir (Acyclovir, ACV, HPLC ⁇ 98%), purchased from McLean Biotechnology Co., Ltd. Company; Butylphthalide Soft Capsules (NBP, NBP), purchased from NBP Pharmaceutical Co., Ltd. of CSPC; 2,3,5-triphenyltetrazolium chloride (TTC), purchased from Solarbio Company .
  • the experimental groups are as follows:
  • the sham operation group (SHAM, given the same volume of 0.9% NaCl by gavage);
  • butylphthalide group (NBP, intragastric administration of butylphthalide, 20mg/kg/day)
  • Zidovudine group (AZT, zidovudine given by gavage, 20mg/kg/day)
  • Acyclovir group (ACV, intragastric administration of acyclovir, 20mg/kg/day)
  • FIG. 2 The results of neurological deficit evaluation, TTC staining and cerebral infarction volume are shown in Figure 2.
  • the neurological function score of the model group was significantly increased ( ### p ⁇ 0.001), the TTC staining of the brain tissue was uniform red, and no ischemic white infarction was found.
  • the MCAO model group a large area of white infarction was seen, indicating that the rat MCAO model was successfully constructed.
  • the positive drugs butylphthalide, zidovudine and acyclovir can significantly reduce the neurological deficit score (*p ⁇ 0.05, Figure 2B), and reduce the infarction (**p ⁇ 0.001).
  • the present invention evaluates the therapeutic effect of lamivudine, zidovudine and acyclovir on ischemic stroke by using MCAO cerebral ischemia-reperfusion injury animal model.
  • zidovudine and acyclovir have the effect of treating ischemic stroke, and the therapeutic effect of zidovudine and acyclovir is better than that of lamivudine. Therefore, all nucleoside analogs have the effect of treating ischemic stroke, and have broad application prospects in clinical practice.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une application d'un analogue nucléosidique dans la préparation de médicaments pour la prévention ou le traitement de maladies cérébrovasculaires. La formule générale structurale de l'analogue nucléosidique est telle que représentée dans la formule (I), dans laquelle X et Y sont respectivement choisis parmi l'un quelconque de S, O, NH ou alcoxyle, et R est limité à l'une quelconque de la cytosine, la thymine, l'adénine et la guanine, R1 est OH, NH2, CH3, CH3O, halogène, alkyle en C1-C6, des ions métalliques, etc., et R2 est OH, NH2, CH3, CH3O, halogène, alkyle en C1-C6, des ions métalliques, etc., 0≤n≤3. L'analogue nucléosidique a un effet curatif remarquable sur un accident vasculaire cérébral ischémique, peut améliorer significativement les lésions de la fonction nerveuse, réduit la taille de l'infarctus, et présente une bonne perspective d'application clinique.
PCT/CN2021/087130 2021-04-14 2021-04-14 Application d'analogues nucléosidiques dans la préparation de médicaments pour la prévention et/ou le traitement de maladies cérébrovasculaires WO2022217481A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CN2021/087130 WO2022217481A1 (fr) 2021-04-14 2021-04-14 Application d'analogues nucléosidiques dans la préparation de médicaments pour la prévention et/ou le traitement de maladies cérébrovasculaires

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2021/087130 WO2022217481A1 (fr) 2021-04-14 2021-04-14 Application d'analogues nucléosidiques dans la préparation de médicaments pour la prévention et/ou le traitement de maladies cérébrovasculaires

Publications (1)

Publication Number Publication Date
WO2022217481A1 true WO2022217481A1 (fr) 2022-10-20

Family

ID=83639942

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/087130 WO2022217481A1 (fr) 2021-04-14 2021-04-14 Application d'analogues nucléosidiques dans la préparation de médicaments pour la prévention et/ou le traitement de maladies cérébrovasculaires

Country Status (1)

Country Link
WO (1) WO2022217481A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040014648A1 (en) * 2002-05-17 2004-01-22 Faust Pharmaceuticals Methods for the prevention and/or the treatment of neurological disorders
WO2004098627A1 (fr) * 2003-05-06 2004-11-18 Royal College Of Surgeons In Ireland Procede de modulation de l'activite plaquettaire ou neutrophile
CN101048164A (zh) * 2004-11-01 2007-10-03 柳署弘 降低肌萎缩性侧索硬化中神经变性的方法和组合物
US20090105168A1 (en) * 2004-11-30 2009-04-23 Gruber Peter J Use Of HDAC And/Or DNMT Inhibitors For Treatment Of Ischemic Injury
CN111569075A (zh) * 2020-05-13 2020-08-25 四川大学华西医院 一种核苷类抗病毒药在制备治疗梗死性疾病药物中的应用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040014648A1 (en) * 2002-05-17 2004-01-22 Faust Pharmaceuticals Methods for the prevention and/or the treatment of neurological disorders
WO2004098627A1 (fr) * 2003-05-06 2004-11-18 Royal College Of Surgeons In Ireland Procede de modulation de l'activite plaquettaire ou neutrophile
CN101048164A (zh) * 2004-11-01 2007-10-03 柳署弘 降低肌萎缩性侧索硬化中神经变性的方法和组合物
US20090105168A1 (en) * 2004-11-30 2009-04-23 Gruber Peter J Use Of HDAC And/Or DNMT Inhibitors For Treatment Of Ischemic Injury
CN111569075A (zh) * 2020-05-13 2020-08-25 四川大学华西医院 一种核苷类抗病毒药在制备治疗梗死性疾病药物中的应用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GUMENYUK A. V.; TYKHOMYROV A. A.; SAVOSKO S. I.; GUZYK M. M.; RYBALKO S. L.; RYZHA А. О.; CHAIKOVSKY YU. B.: "State of Astrocytes in the Mice Brain under Conditions ofHerpesViral Infection and Modeled Stroke", NEUROPHYSIOLOGY, KLUWER, NEW YORK, NY, US, vol. 50, no. 5, 28 January 2019 (2019-01-28), US , pages 326 - 331, XP036715104, ISSN: 0090-2977, DOI: 10.1007/s11062-019-09757-0 *
SIMRET BERAKI, LILY LITRUS, LIZA SORIANO, MARIE MONBUREAU, LILLIAN K. TO, STEVEN P. BRAITHWAITE, KAROLY NIKOLICH, ROMAN URFER, DON: "A Pharmacological Screening Approach for Discovery of Neuroprotective Compounds in Ischemic Stroke", PLOS ONE, vol. 8, no. 7, pages e69233, XP055106884, DOI: 10.1371/journal.pone.0069233 *

Similar Documents

Publication Publication Date Title
JP4959900B2 (ja) 抗ウイルスピリミジンヌクレオシド類
US20020169140A1 (en) Combination therapy for reduction of toxicity of chemotherapeutic agents
KR100256144B1 (ko) 아실화된 피리미딘 누클레오사이드를 이용한 화학요법제 및 항비루스제의 독성의 치료
RU2488591C2 (ru) Аналоги азацитидина и их применение
JPH10511682A (ja) ジドブジン、１５９２ｕ８９および３ｔｃまたはｆｔｃの相乗的組み合わせ
US20050250728A1 (en) Enhancing the efficacy of reverse transcriptase and dna polymerase inhibitors (nucleoside analogs) using pnp inhibitors and/or 2'-deoxyguanosine and/or prodrug thereof
AU728377C (en) Method of treating disorders characterized by overexpression of cytidine deaminase or deoxycytidine deaminase
AU2915095A (en) Pyrimidine nucleotide precursors for treatment of systemic inflammation and inflammatory hepatitis
WO2022217481A1 (fr) Application d'analogues nucléosidiques dans la préparation de médicaments pour la prévention et/ou le traitement de maladies cérébrovasculaires
CN113573736A (zh) 经修饰的微rna和它们在治疗癌症中的用途
CN113116900B (zh) 一类核苷类似物在制备预防和/或治疗脑血管疾病药物中的应用
CN106928298B (zh) 环二核苷酸cGAMP衍生物的结构组成、制备方法及其在抗肿瘤中的应用
WO2022099574A1 (fr) Application de prazosine dans la préparation de médicaments pour le traitement et/ou la prévention de maladies cérébrovasculaires
EP4175646A1 (fr) Adénosine nucléoside modifié destiné à être utilisé dans le traitement d'infections virales
WO2022160323A1 (fr) Application d'un analogue nucléosidique dans la préparation de médicaments pour la prévention ou le traitement de maladies gastro-intestinales
CN114533739B (zh) 核苷类似物在制备预防或治疗胃肠道疾病药物中的应用
EP0452360A1 (fr) Procedes et compositions pour la prophylaxie et le traitement d'infections dues au virus de l'hepatite b
CN115634228B (zh) 嘌呤合成抑制剂在制备治疗缺血和缺血再灌注损伤药物中的应用
CN112294834B (zh) 地西他滨在制备治疗单纯疱疹病毒的药物中的应用
CN116173056A (zh) 核苷类化合物在制备具有防醉、解酒功效的药物中的应用
JP2003525898A (ja) 医薬組成物
JP5581200B2 (ja) シチジン誘導体及びカルボプラチンを含有する抗腫瘍剤
CN115028594A (zh) 恩替他滨药用前体化合物及其制备方法和医学用途
WO2022206752A1 (fr) Combinaison médicamenteuse d'un agoniste du récepteur 7 de type toll et d'un anticorps anti-pd-l1
CN110354168A (zh) 一种治疗肾透明细胞癌的药物组合物及其制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21936374

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21936374

Country of ref document: EP

Kind code of ref document: A1