WO2022217481A1 - Application of nucleoside analogues in preparation of drugs for preventing and/or treating cerebrovascular diseases - Google Patents

Application of nucleoside analogues in preparation of drugs for preventing and/or treating cerebrovascular diseases Download PDF

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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
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halogen
alkyl
preparation
formula
stroke
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陈新平
刘菁菁
赵文阳
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兰州大学
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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
    • A61K31/33—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.

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Abstract

The present invention relates to an application of a nucleoside analogue in preparation of drugs for preventing or treating cerebrovascular diseases. The structural general formula of the nucleoside analogue is as shown in formula (I), wherein X and Y are respectively selected from any one of S, O, NH or alkoxyl, and R is limited to any one of cytosine, thymine, adenine and guanine, R1is OH, NH2, CH3, CH3O, halogen, C1-C6 alkyl, metal ions, etc., and R2 is OH, NH2, CH3, CH3O, halogen, C1-C6 alkyl, metal ions, etc., 0≤n≤3. The nucleoside analogue has a remarkable curative effect on ischemic stroke, can significantly improve nerve function damage, reduces the infarct size, and has good clinical application prospect in clinic.

Description

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Application of a class of nucleoside analogs in the preparation of drugs for preventing and/or treating cerebrovascular diseases 技术领域technical field
本发明涉及医药技术领域，还涉及一类可用于脑血管疾病的新型小分子化合物，更具体的涉及核苷类似物例如拉米夫定、齐多夫定和阿昔洛韦在制备用于脑血管疾病的药物中的应用。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. The use of drugs in vascular diseases.
背景技术Background technique
脑血管疾病(Cerebrovascular disease)，泛指脑部血管的各种疾病，包括动脉粥样硬化、血栓形成、狭窄、闭塞、脑动脉炎、脑动脉损伤、脑动脉瘤、颅内血管畸形、脑动静脉瘘等，其共同特点是引起脑组织的缺血或出血性意外。典型的脑血管疾病主要有脑血栓、脑缺血、脑梗塞等。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 The common feature of venous fistula is to cause brain tissue ischemia or hemorrhagic accident. Typical cerebrovascular diseases include cerebral thrombosis, cerebral ischemia, and cerebral infarction.
脑血栓是在脑动脉粥样硬化和斑块基础上，在血流缓慢和血压偏低的条件下，血液的有效成分附着在动脉的内膜形成血栓，成为脑血栓，临床上以偏瘫为主要临床表现。脑卒中是一种急性脑血管疾病，是由于脑部血管突然破裂或因血管阻塞导致血液不能流入大脑而引起脑组织损伤的一组疾病，包括缺血性卒中和出血性卒中。血栓可引起脑梗的形成，脑梗又称为缺血性脑卒中；脑血栓、脑梗塞最终均可归结于卒中。而卒中是严重危害中国国民健康的重大慢性非传染性疾病，具有高发病率、高致残率、高死亡率、高复发率和高经济负担五大特点。随着人口老龄化的加剧，脑血管病危险因素流行趋势更加明显，导致脑血管病的发病人数持续增加。目前，临床上面对这一危害严重的疾病，尚无有效的治疗方法。因此，如何开发出一种能够显著治疗缺血性脑卒中的新药物是目前亟待解决的问题。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.
常见的核苷类似物临床用药主要包括拉米夫定、阿昔洛韦、阿德福韦酯、泛昔洛韦、恩替卡韦、吉西他滨、齐多夫定、阿糖胞苷、阿扎胞苷、恩曲西他平、替比夫定、克拉夫定、恩曲他滨等，其功能主要为抗病毒、抗肿瘤、提高免疫和恢复肝功。其中。拉米夫定是一种胞嘧啶核苷类似物，对病毒DNA链的合成和延长有竞争性抑制作用，其主要用于乙型肝炎和肝胆疾病的治疗，是目前临床应用中最具代表性的核苷类似物；阿糖胞苷主要作用于细胞S增殖期的嘧啶类抗代谢药物，通过抑制细胞DNA的合成，干扰细胞的增殖，主要用于治疗急性白血病，对急性粒细胞白细胞疗效最好，对急性单核细胞白血病及急性淋巴细胞白血病也有效。对恶性淋巴瘤、肺癌、消化道癌、头颈部癌有一定的疗效，对病毒性角膜炎及流行性结膜炎等也有一定的疗效。吉西他滨为一种新的胞嘧啶核苷衍生物，作用机制和阿糖胞苷相同，其主要代谢物在细胞内掺入DNA，主要作用于G1/S期。在临床上，吉西他滨和阿糖胞苷的抗瘤谱不同，对多种实体瘤有效，用于晚期胰腺癌患者的二线用药，能改善患者的生活质量；作为局部晚期和已经有转移的非小细胞肺癌的一线用药。齐多夫定是一种胸腺嘧啶 核苷类似物，用于艾滋病或与艾滋病有关的综合症患者及免疫缺陷病毒HIV感染的治疗，是世界上第一个获得美国FDA批准生产的抗艾滋病药品，因其疗效确切，成为“鸡尾酒”疗法最基本的组合成分，在体外对逆转病毒包括人免疫缺陷病毒具有高度活性。阿昔洛韦是一种合成的鸟嘌呤核苷类似物，主要用于单纯疱疹病毒所致的各种感染，可用于初发或复发性皮肤、粘膜、外生殖器感染及免疫缺陷发生的单纯疱疹病毒(HSV)感染。为治疗HSV脑炎的首选药物，减少发病率及降低死亡率均优于阿糖腺苷。还可用于带状疱疹、EB病毒、及免疫缺陷者并发水痘感染。因皮肤吸收较少，仅用于局部皮肤。Common clinical drugs of 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. in. Lamivudine is a cytosine nucleoside analog, which has a competitive inhibitory effect on the synthesis and extension of viral DNA chains. It is mainly used for the treatment of hepatitis B and hepatobiliary diseases, and is the most representative in clinical applications. The nucleoside analogs; 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. It has a certain curative effect on malignant lymphoma, lung cancer, digestive tract cancer, head and neck cancer, and also has a certain curative effect on viral keratitis and epidemic conjunctivitis. 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.
目前，研究人员针对核苷及其类似物的研究中，更多的是关于其剂型、检测方法、制备方法、结构修饰等的研究，例如专利CN101511375B公开了L-胞嘧啶核苷类似物在制备用于治疗癌症和其它病症或疾病状态的药物中的应用，其主要是对于核苷类似物的结构修饰，并用修饰后的化合物治疗结肠癌、胰腺癌和肝癌。专利CN111741967A公开了核苷酸类似物、制备方法及其在核酸序列测定等方面的应用，其主要涉及核苷类似物的制备方法等；专利CN109790196A公开了使用可逆封闭核苷类似物进行核酸检测的方法；专利CN108671235A公开了一种骨架整合有核苷类似物药物的功能性核酸及其衍生物及其制备方法，以及用于基因疗法和化学疗法联合治疗疾病的用途；专利CN104211742A公开了环磷酰化基团修饰后并连接脂肪链的磷酸N-脂肪酸用于病毒性肝炎和肝癌的治疗；专利CN110643609A公开了核苷类似物药物分子构建的药物适配体、制备方法及其应用等；但是，目前并没有将核苷类似物应用于脑血管疾病的文献，亦没有任何文献提示本领域技术人员核苷类似物具有治疗脑血管疾病的新用途。At present, in the research of nucleosides and their analogs, researchers focus more on their formulations, detection methods, preparation methods, structural modifications, etc. For example, 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. Method; 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.
发明人在研究过程中意外的发现，核苷类似物对脑血管疾病具有显著的疗效，提供了核苷类似物的一种新用途。During the research process, 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.
发明内容SUMMARY OF THE INVENTION
针对上述技术问题，本发明公开了一种如式(Ⅰ)所示的核苷类似物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐用于制备治疗和/或预防脑血管疾病药物中的应用；In view of the above technical problems, 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;
Figure PCTCN2021087130-appb-000001
Figure PCTCN2021087130-appb-000001
其中，所述的结构式中X和Y分别选自S、O、NH或烷氧基中的任意一个；Wherein, in the described structural formula, X and Y are respectively selected from any one of S, O, NH or alkoxy;
R为胞嘧啶、胸腺嘧啶、腺嘌呤和鸟嘌呤中的任意一个；R is any one of cytosine, thymine, adenine and guanine;
R 1为OH、NH 2、CH 3、CH 3O、卤素、C 1-C 6烷基、金属离子等； R 1 is OH, NH 2 , CH 3 , CH 3 O, halogen, C 1 -C 6 alkyl, metal ion, etc.;
R 2为OH、NH 2、CH 3、CH 3O、卤素、C 1-C 6烷基、金属离子等； R 2 is OH, NH 2 , CH 3 , CH 3 O, halogen, C 1 -C 6 alkyl, metal ions, etc.;
0≤n≤3。0≤n≤3.
优选地，所述的核苷类似物为拉米夫定、阿昔洛韦、阿德福韦酯、泛昔洛韦、恩替卡韦、吉西他滨、齐多夫定、阿糖胞苷、阿扎胞苷、恩曲西他平、替比夫定、克拉夫定或恩曲他滨中的一种。Preferably, the nucleoside analogs are lamivudine, acyclovir, adefovir dipivoxil, famciclovir, entecavir, gemcitabine, zidovudine, cytarabine, azacitidine, entrexine One of sitapine, telbivudine, clavudine, or emtricitabine.
优选地，所述的核苷类似物为拉米夫定、齐多夫定和阿昔洛韦。Preferably, the nucleoside analogs are lamivudine, zidovudine and acyclovir.
优选地，所述的脑血管疾病为脑血栓、脑缺血和脑卒中。Preferably, the cerebrovascular disease is cerebral thrombosis, cerebral ischemia and cerebral apoplexy.
优选地，所述的脑卒中包括出血性脑卒中和缺血性脑卒中。Preferably, the stroke includes hemorrhagic stroke and ischemic stroke.
优选地，所述的脑卒中为缺血性脑卒中。Preferably, the stroke is ischemic stroke.
本发明的第二目的是公开式(Ⅰ)所述的核苷类似物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐在制备治疗和/或预防神经功能损伤药物中的应用；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;
Figure PCTCN2021087130-appb-000002
Figure PCTCN2021087130-appb-000002
其中，所述的结构式中X和Y分别选自S、O、NH或烷氧基中的任意一个；Wherein, in the described structural formula, X and Y are respectively selected from any one of S, O, NH or alkoxy;
R为胞嘧啶、胸腺嘧啶、腺嘌呤和鸟嘌呤中的任意一个；R is any one of cytosine, thymine, adenine and guanine;
R 1为OH、NH 2、CH 3、CH 3O、卤素、C 1-C 6烷基、金属离子等； R 1 is OH, NH 2 , CH 3 , CH 3 O, halogen, C 1 -C 6 alkyl, metal ion, etc.;
R 2为OH、NH 2、CH 3、CH 3O、卤素、C 1-C 6烷基、金属离子等； R 2 is OH, NH 2 , CH 3 , CH 3 O, halogen, C 1 -C 6 alkyl, metal ions, etc.;
0≤n≤3。0≤n≤3.
本发明的第三目的是公开式(Ⅰ)所述的核苷类似物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐用于制备治疗和/或预防脑缺血再灌注损伤药物中的应用；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;
Figure PCTCN2021087130-appb-000003
Figure PCTCN2021087130-appb-000003
其中，所述的结构式中X和Y分别选自S、O、NH或烷氧基中的任意一个；Wherein, in the described structural formula, X and Y are respectively selected from any one of S, O, NH or alkoxy;
R为胞嘧啶、胸腺嘧啶、腺嘌呤和鸟嘌呤中的任意一个；R is any one of cytosine, thymine, adenine and guanine;
R 1为OH、NH 2、CH 3、CH 3O、卤素、C 1-C 6烷基、金属离子等； R 1 is OH, NH 2 , CH 3 , CH 3 O, halogen, C 1 -C 6 alkyl, metal ion, etc.;
R 2为OH、NH 2、CH 3、CH 3O、卤素、C 1-C 6烷基、金属离子等； R 2 is OH, NH 2 , CH 3 , CH 3 O, halogen, C 1 -C 6 alkyl, metal ions, etc.;
0≤n≤3。0≤n≤3.
本发明的第四目的是公开式(Ⅰ)所述的核苷类似物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐和一种或多种药学上可接受的载体组成药物组合物，所述药物组合物的剂型为注射剂、片剂、胶囊剂、颗粒剂、丸剂。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.
本发明的有益效果是：本发明提供了一种核苷类似物的新用途，具体提供了核苷类似物例如拉米夫定、齐多夫定和阿昔洛韦在制备治疗脑血管疾病尤其是治疗缺血性脑卒中的应用，本发明的实验结果显示，所述的核苷类似物能显著降低脑卒中患者的神经功能缺损评分，降低梗死灶，对脑卒中患者具有神经保护作用，也具有治疗缺血性脑卒中的效果，可以在临床上推广应用。The beneficial effects of the present invention are as follows: 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. The experimental results of the present invention show that the 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.
附图说明Description of drawings
图1拉米夫定大鼠MCAO模型试验结果Figure 1 The results of the MCAO model test of lamivudine in rats
与“SHAM”相比， ###p﹤0.001；与“IR”相比，*p<0.05和***p<0.001 ### p<0.001 compared to "SHAM";*p<0.05 and ***p<0.001 compared to "IR"
其中“A”为脑片TTC染色图；“B”为神经功能缺损评分图；“C”为脑梗死体积比图。"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.
图2齐多夫定和阿昔洛韦大鼠MCAO模型试验结果Figure 2 The results of the MCAO model test of zidovudine and acyclovir in rats
与“SHAM”相比， ###p﹤0.001；与“IR”相比，*p<0.05和***p<0.001 ### p<0.001 compared to "SHAM";*p<0.05 and ***p<0.001 compared to "IR"
其中“A”为脑片TTC染色图；“B”为神经功能缺损评分图；“C”为脑梗死体积比图。"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.
具体实施方式Detailed ways
以下结合具体实施例对本发明的保护范围进行详细说明，但应当指出的是，本发明的保护范围并不限于以下实施例，同时保护核苷类似物的一类化合物在所有脑血管疾病尤其是脑卒中疾病中的治疗效果，包括不同剂型、剂量、联合用药等。凡本领域技术人员按照本发明的思路在现有技术上通过逻辑分析、推断和实验得出的技术方案，均属于本发明所请求保护的范围。The protection scope of the present invention will be described in detail below with reference to specific examples, but it should be pointed out that the protection scope of the present invention is not limited to the following examples, and a class of compounds that protect nucleoside analogs in all cerebrovascular diseases, especially brain Treatment effects in stroke diseases, including different dosage forms, doses, and combination drugs. All technical solutions obtained by those skilled in the art through logical analysis, inference and experimentation in the prior art according to the idea of the present invention belong to the scope of the claimed protection of the present invention.
本发明以下实施例中，拉米夫定是一个抑制病毒的药物，并不能清除乙肝病毒，这是因为拉米夫定对乙肝病毒cccDNA没有作用，cccDNA在人体内的半衰期大约为3-4年，如果cccDNA持续存在，病毒就不会得到清除，停药后必然复发。因此在应用拉米夫定时，其疗效并不完全取决于药物本身，还和病人对HBV的特异性免疫反应状态及病毒毒力密切相关，对于特异性免疫反应弱的病人单独应用拉米夫定很难达到清除病毒的目的，还要想办法提高机体对HBV特异性免疫反应，可以考虑联合应用胸腺肽、治疗性疫苗及高效价乙肝免疫球蛋白等。In the following examples of the present invention, 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.
本发明以下实施例中，齐多夫定是一种胸腺嘧啶核苷类似物，用于艾滋病或与艾滋病有关的综合症患者及免疫缺陷病毒HIV感染的治疗，是世界上第一个获得美国FDA批准生产的抗艾滋病药品，因其疗效确切，成为“鸡尾酒”疗法最基本的组合成分，在体外对逆转病毒包括人免疫缺陷病毒具有高度活性。In the following examples of the present invention, 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.
本发明以下实施例中，阿昔洛韦是一种合成的鸟嘌呤核苷类似物，主要用于单纯疱疹病毒所致的各种感染，可用于初发或复发性皮肤、粘膜、外生殖器感染及免疫缺陷发生的HSV感染。阿昔洛韦作为治疗HSV脑炎的首选药物，其减少发病率及降低死亡率均优于阿糖腺苷。阿昔洛韦还可用于带状疱疹、EB病毒、及免疫缺陷者并发水痘感染的治疗。In the following examples of the present invention, 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. As the drug of choice for the treatment of HSV encephalitis, 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.
应理解，上述简述和下文的详述为示例性且仅用于解释，而不对本文发明主题做任何限制。在本申请中，必须注意，除非文中另有清楚的说明，否则在本说明书和权利要求书中所用的单数形式包括所指事物的复数形式。还应注意，除非另有说明，否则所用“或”、“或者”表示“和/或”。此外，所用术语“包括”以及其他形式，例如“包含”、“含”和“含有”并非限制性。It is to be understood that both the foregoing brief description and the following detailed description are exemplary and explanatory only and are not intended to limit the subject matter herein. In this application, it must be noted that the singular forms used in this specification and the claims include the plural forms of referents unless the context clearly dictates otherwise. It should also be noted that the use of "or" and "or" means "and/or" unless stated otherwise. Furthermore, the use of the term "including" and other forms such as "comprising", "including" and "comprising" is not intended to be limiting.
本发明以下实施例中，丁苯酞主要用于治疗轻、中度急性缺血性脑卒中。本发明实施例将丁苯酞作为阳性药使用。In the following embodiments of the present invention, butylphthalide is mainly used to treat mild and moderate acute ischemic stroke. In the embodiment of the present invention, butylphthalide is used as a positive drug.
本发明以下实施例中，MCAO是指Middle Cerebral Artery Occlusion，大脑中动脉缺血。In the following embodiments of the present invention, MCAO refers to Middle Cerebral Artery Occlusion, middle cerebral artery ischemia.
实施例一、拉米夫定对缺血性脑卒中的治疗效果Example 1. The therapeutic effect of lamivudine on ischemic stroke
1.实验动物和药物1. Laboratory animals and drugs
SPF级健康雄性SD大鼠，体重200-240g，实验前未用过任何药物，由中国农业科学院兰州兽医研究所提供，动物许可证号为SCXK(甘)-2020-0002，适应性饲养一周，给予动物饮食并自由饮水，然后分组进行实验。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, animal license number is SCXK (gan)-2020-0002, adaptive feeding for one week, Animals were given chow and water ad libitum and were then grouped for experiments.
药物及试剂：拉米夫定(Lamivudine，3-TC，HPLC≥98％)，购自麦克林生物科技有限公司；丁苯酞软胶囊(恩必普，NBP)，购自石药集团恩必普药业有限公司；2，3，5-氯化三苯基四氮唑(TTC)，购自Solarbio公司。Drugs and reagents: 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.
2.MCAO模型的制备和给药时间：适应性饲养一周后，所有的SD大鼠随机分为4组，分组和给药剂量如下：2. Preparation and administration time of MCAO model: After one week of adaptive feeding, all SD rats were randomly divided into 4 groups, and the grouping and administration doses were as follows:
假手术组(SHAM，灌胃给予等体积0.5％CMC-Na)；Sham operation group (SHAM, given equal volume of 0.5% CMC-Na by gavage);
模型组(IR，灌胃给予等体积0.5％CMC-Na)；Model group (IR, intragastric administration of equal volume of 0.5% CMC-Na);
丁苯酞组(NBP，灌胃给予丁苯酞，20mg/kg/day)Butylphthalide group (NBP, intragastric administration of butylphthalide, 20mg/kg/day)
拉米夫定组(C1，灌胃给予拉米夫定，2mg/kg/day)，Lamivudine group (C1, lamivudine given by gavage, 2 mg/kg/day),
预给药3天，应用Longa等(参照文献Reversible middle cerebral artery occlusion without craniectomy in rats.)的线栓法制作大鼠右侧中动脉闭塞动物模型。Pre-administration for 3 days, 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.
模型组：将麻醉后的大鼠固定，备皮，碘伏消毒，并消毒手术器械，预备好结扎用的5号线，沿颈部正中偏右行纵向切口约1.5cm。小心分离右侧颈动脉和迷走神经后，用手术缝合线将颈总动脉与颈内动脉结扎，颈总动脉结扎位置在分岔口10mm处，之后在离颈总动脉分叉处5mm处切口，将直径为0.32mm的线栓经切口插入颈内动脉，线栓深度约为18-20mm时，停止插线，系紧结扎线。清洗后，进行分层缝合。在动物缺血2h后去除线栓，动物会自然苏醒，再灌注24h，进行相关指标检测。与永久性脑缺血不同的是，在阻断2h后拔出尼龙线栓，扎紧动脉残端，消毒后逐层缝合皮下组织和皮肤。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. After careful separation of the right carotid artery and vagus nerve, 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. After 2 hours of ischemia, the suture was removed, and the animal would wake up naturally, and then reperfused for 24 hours, and then the relevant indicators were detected. Different from permanent cerebral ischemia, 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.
假手术组：除不插入线栓外其余操作同模型组。待实验动物清醒后，再进行药物干预，给药24h后处死取材。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.
3.检测指标3. Detection indicators
3.1神经功能缺损评分3.1 Neurological deficit score
依据Zea Longa 5级评分：0分：无神经功能缺损；1分：病灶对侧前爪不能完全伸展；2分：向病灶对侧自发性旋转；3分：向病灶对侧倾倒；4分：无自发性行走且出现意识丧失。According to the Zea Longa 5 scale: 0 points: no neurological deficit; 1 point: inability to fully extend the forepaw on the opposite side of the lesion; 2 points: spontaneous rotation to the opposite side of the lesion; 3 points: dumping to the opposite side of the lesion; 4 points: No spontaneous walking and loss of consciousness.
3.2 TTC染色3.2 TTC staining
取每组大鼠，断头，冰上分离脑组织，去除嗅球和脑干，生理盐水冲洗后立即放入-20℃冷冻15min，取出，将大脑沿视交叉平面至垂体平面冠状切均匀切成4片冠状切片，浸入1.5％ TTC溶液，37℃恒温水浴中孵育染色(避光)45min，每15min翻一次，使染色均匀，与正常组织中的脱氧酶反应呈红色，缺血区呈白色，即未染色的区域为梗死区域，根据脑组织各冠状切片梗死体积总和占全脑体积百分比测定动物脑组织梗死体积。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.
脑梗死体积＝(缺血侧面积均值总和-对侧面积均值总和)×梗死脑组织厚度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
4.实验结果4. Experimental results
神经功能缺损评价、TTC染色和脑梗死体积结果如附图1所示。由图1A和图1B可知，与假手术组相比，模型组的神经功能评分显著升高( ###p﹤0.001)，脑组织TTC染色呈均匀的红色，未见缺血白色梗死灶，而MCAO模型组可见大区域的白色梗死灶，表明大鼠MCAO模型制作成功。与IR模型组相比，阳性药丁苯酞与拉米夫定均能显著的降低神经功能缺损评分(*p<0.05，图1B)，改善梗死灶(**p<0.001，图1C)，表明拉米夫定与丁苯酞一样具有脑卒中的神经保护作用，且拉米夫定的神经保护作用(80.38％)强于临床用药丁苯酞的神经保护作用(60.71％)，即本发明拉米夫定具备更佳的治疗缺血性脑卒中神经损伤的作用。 The results of neurological deficit evaluation, TTC staining and cerebral infarction volume are shown in Figure 1. As can be seen from 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. In the MCAO model group, a large area of white infarction was seen, indicating that the rat MCAO model was successfully constructed. Compared with the IR model group, 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.
由于拉米夫定属于经典的核苷类似物药物，因此，发明人推测，除了拉米夫定之外的其他核苷类似物也具有治疗缺血性脑卒中的效果，为了验证上述推测，发明人评价了齐多夫定和阿昔洛韦对缺血性脑卒中的治疗效果，具体实验过程如下。Since lamivudine is a classic nucleoside analog drug, the inventors speculate that other nucleoside analogs besides lamivudine also have the effect of treating ischemic stroke. In order to verify the above speculation, the inventors The therapeutic effects of zidovudine and acyclovir on ischemic stroke were evaluated. The specific experimental process is as follows.
实施例二、齐多夫定和阿昔洛韦对缺血性脑卒中的治疗效果Example 2. Therapeutic effect of zidovudine and acyclovir on ischemic stroke
1.实验动物1. Experimental animals
SPF级健康雄性SD大鼠，体重200-240g，实验前未用过任何药物，由中国农业科学院兰州兽医研究所提供，许可证号为SCXK(甘)-2020-0002，适应性饲养一周，给予动物饮食并自由饮水，然后分组进行实验。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.
2.试剂与实验方法2. Reagents and experimental methods
药物及试剂：齐多夫定(Zidovudine,AZT，HPLC≥98％)，购自阿拉丁生物科技有限公司；阿昔洛韦(Acyclovir,ACV，HPLC≥98％)，购自麦克林生物科技有限公司；丁苯酞软胶囊(恩必普，NBP)，购自石药集团恩必普药业有限公司；2，3，5-氯化三苯基四氮唑(TTC)，购自Solarbio公司。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 .
3.动物模型的制备与检测指标方法同实施例一3. The preparation of the animal model and the method for detecting the index are the same as those in Example 1
实验分组如下：The experimental groups are as follows:
假手术组(SHAM，灌胃给予等体积0.9％NaCl)；The sham operation group (SHAM, given the same volume of 0.9% NaCl by gavage);
模型组(IR，灌胃给予等体积0.9％NaCl)；Model group (IR, intragastric administration of equal volume of 0.9% NaCl);
丁苯酞组(NBP，灌胃给予丁苯酞，20mg/kg/day)Butylphthalide group (NBP, intragastric administration of butylphthalide, 20mg/kg/day)
齐多夫定组(AZT，灌胃给予齐多夫定，20mg/kg/day)Zidovudine group (AZT, zidovudine given by gavage, 20mg/kg/day)
阿昔洛韦组(ACV，灌胃给予阿昔洛韦，20mg/kg/day)Acyclovir group (ACV, intragastric administration of acyclovir, 20mg/kg/day)
4..实验结果4. Experimental results
神经功能缺损评价、TTC染色和脑梗死体积结果如附图2所示。由图2A和图2B可知，与假手术组相比，模型组的神经功能评分显著升高( ###p﹤0.001)，脑组织TTC染色呈均匀的红色，未见缺血白色梗死灶，而MCAO模型组可见大区域的白色梗死灶，表明大鼠MCAO模型制作成功。与IR模型组相比，阳性药丁苯酞与齐多夫定、阿昔洛韦均能显著的降低神经功能缺损评分(*p<0.05，图2B)，降低梗死灶(**p<0.001，图2C)，表明齐多夫定、阿昔洛韦和丁苯酞一样具有脑卒中的神经保护作用，且齐多夫定的神经保护作用(72.96％)强于临床用药丁苯酞的神经保护作用(59.44％)，阿昔洛韦的神经保护作用(61.80％)略强于临床用药丁苯酞的神经保护作用(59.44％)，即本发明齐多夫定、阿昔洛韦具备更佳的治疗缺血性脑卒中神经损伤的作用。 The results of neurological deficit evaluation, TTC staining and cerebral infarction volume are shown in Figure 2. As can be seen from Figure 2A and Figure 2B, compared with the sham-operated group, 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. In the MCAO model group, a large area of white infarction was seen, indicating that the rat MCAO model was successfully constructed. Compared with the IR model group, 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). , Figure 2C), indicating that zidovudine, acyclovir and butylphthalide have the same neuroprotective effect on stroke, and the neuroprotective effect of zidovudine (72.96%) is stronger than the neuroprotective effect of clinical drug butylphthalide The protective effect (59.44%), the neuroprotective effect of acyclovir (61.80%) is slightly stronger than the neuroprotective effect of the clinical drug butylphthalide (59.44%), that is, the zidovudine and acyclovir of the present invention have better neuroprotective effect. Optimal treatment of nerve damage in ischemic stroke.
综上所述，本发明通过采用MCAO脑缺血再灌注损伤动物模型评价拉米夫定、齐多夫定、阿昔洛韦对缺血性脑卒中治疗效果，实验结果显示拉米夫定、齐多夫定、阿昔洛韦均具有治疗缺血性脑卒中的作用，且齐多夫定和阿昔洛韦的治疗效果优于拉米夫定。因此，核苷类似物均具有治疗缺血性脑卒中的作用，在临床上具有广阔的应用前景。To sum up, the present invention evaluates the therapeutic effect of lamivudine, zidovudine and acyclovir on ischemic stroke by using MCAO cerebral ischemia-reperfusion injury animal model. Both 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.
本发明的保护范围不限于实施例。凡技术人员按照本发明的思路在现有技术上通过逻辑分析、推断和实验得出的技术方案，均属于权利要求书中保护的范围。The protection scope of the present invention is not limited to the embodiments. All technical solutions obtained by technical personnel through logical analysis, inference and experimentation in the prior art according to the idea of the present invention belong to the scope of protection in the claims.

Claims (9)

  1. 一种如式(Ⅰ)所示的核苷类似物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐在制备治疗和/或预防脑血管疾病药物中的应用；A nucleoside analog of formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer and mixture thereof, and The application of its pharmaceutically acceptable salt in the preparation of medicine for treating and/or preventing cerebrovascular disease;
    Figure PCTCN2021087130-appb-100001
    Figure PCTCN2021087130-appb-100001
    其中，所述的结构式中X和Y分别选自S、O、NH或烷氧基中的任意一个；Wherein, in the described structural formula, X and Y are respectively selected from any one of S, O, NH or alkoxy;
    R为胞嘧啶、胸腺嘧啶、腺嘌呤和鸟嘌呤中的任意一个；R is any one of cytosine, thymine, adenine and guanine;
    R 1为OH、NH 2、CH 3、CH 3O、卤素、C 1-C 6烷基、金属离子等； R 1 is OH, NH 2 , CH 3 , CH 3 O, halogen, C 1 -C 6 alkyl, metal ion, etc.;
    R 2为OH、NH 2、CH 3、CH 3O、卤素、C 1-C 6烷基、金属离子等； R 2 is OH, NH 2 , CH 3 , CH 3 O, halogen, C 1 -C 6 alkyl, metal ions, etc.;
    0≤n≤3。0≤n≤3.
  2. 如权利要求1所述的应用，其特征在于，所述的核苷类似物为拉米夫定、阿昔洛韦、阿德福韦酯、泛昔洛韦、恩替卡韦、吉西他滨、齐多夫定、阿糖胞苷、阿扎胞苷、恩曲西他平、替比夫定、克拉夫定或恩曲他滨中的一种。The application according to claim 1, wherein the nucleoside analog is lamivudine, acyclovir, adefovir dipivoxil, famciclovir, entecavir, gemcitabine, zidovudine, arabinoside One of cytidine, azacitidine, emtricitapine, telbivudine, clavudine, or emtricitabine.
  3. 如权利要求1所述的应用，其特征在于，所述的核苷类似物为拉米夫定、奇多夫定或阿昔洛韦中的任一种。The application according to claim 1, wherein the nucleoside analog is any one of lamivudine, chidovudine or acyclovir.
  4. 如权利要求1所述的应用，其特征在于，所述的脑血管疾病为脑血栓、脑缺血和脑卒中。The application according to claim 1, wherein the cerebrovascular disease is cerebral thrombosis, cerebral ischemia and cerebral apoplexy.
  5. 如权利要求4所述的应用，其特征在于，所述的脑卒中包括出血性脑卒中和缺血性脑卒中。The application according to claim 4, wherein the stroke includes hemorrhagic stroke and ischemic stroke.
  6. 如权利要求5所述的应用，其特征在于，所述的脑卒中为缺血性脑卒中。The application according to claim 5, wherein the stroke is ischemic stroke.
  7. 如式(Ⅰ)所示的核苷类似物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐在制备治疗和/或预防神经功能损伤药物中的应用；Nucleoside analogs represented by formula (I) or tautomers, mesomers, racemates, enantiomers, diastereomers and mixtures thereof, and The use of medicinal salts in the preparation of medicines for the treatment and/or prevention of neurological damage;
    Figure PCTCN2021087130-appb-100002
    Figure PCTCN2021087130-appb-100002
    其中，所述的结构式中X和Y分别选自S、O、NH或烷氧基中的任意一个；Wherein, in the described structural formula, X and Y are respectively selected from any one of S, O, NH or alkoxy;
    R为胞嘧啶、胸腺嘧啶、腺嘌呤和鸟嘌呤中的任意一个；R is any one of cytosine, thymine, adenine and guanine;
    R 1为OH、NH 2、CH 3、CH 3O、卤素、C 1-C 6烷基、金属离子等； R 1 is OH, NH 2 , CH 3 , CH 3 O, halogen, C 1 -C 6 alkyl, metal ion, etc.;
    R 2为OH、NH 2、CH 3、CH 3O、卤素、C 1-C 6烷基、金属离子等； R 2 is OH, NH 2 , CH 3 , CH 3 O, halogen, C 1 -C 6 alkyl, metal ions, etc.;
    0≤n≤3。0≤n≤3.
  8. 如式(Ⅰ)所示的核苷类似物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐在制备治疗和/或预防脑缺血再灌注损伤药物中的应用；Nucleoside analogs represented by formula (I) or tautomers, mesomers, racemates, enantiomers, diastereomers and mixtures thereof, and The application of medicinal salt in the preparation of medicine for treating and/or preventing cerebral ischemia-reperfusion injury;
    Figure PCTCN2021087130-appb-100003
    Figure PCTCN2021087130-appb-100003
    其中，所述的结构式中X和Y分别选自S、O、NH或烷氧基中的任意一个；Wherein, in the described structural formula, X and Y are respectively selected from any one of S, O, NH or alkoxy;
    R为胞嘧啶、胸腺嘧啶、腺嘌呤和鸟嘌呤中的任意一个；R is any one of cytosine, thymine, adenine and guanine;
    R 1为OH、NH 2、CH 3、CH 3O、卤素、C 1-C 6烷基、金属离子等； R 1 is OH, NH 2 , CH 3 , CH 3 O, halogen, C 1 -C 6 alkyl, metal ion, etc.;
    R 2为OH、NH 2、CH 3、CH 3O、卤素、C 1-C 6烷基、金属离子等； R 2 is OH, NH 2 , CH 3 , CH 3 O, halogen, C 1 -C 6 alkyl, metal ions, etc.;
    0≤n≤3。0≤n≤3.
  9. 如权利要求1、7或8任一项所述的应用，其特征在于，式(Ⅰ)所述的核苷类似物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式，及其可药用盐和一种或多种药学上可接受的载体组成药物组合物，所述药物组合物的剂型为注射剂、片剂、胶囊剂、颗粒剂、丸剂。The use according to any one of claims 1, 7 or 8, wherein the nucleoside analog of formula (I) or its tautomer, meso, racemate, para- Enantiomers, diastereomers and their mixture forms, their pharmaceutically acceptable salts and one or more pharmaceutically acceptable carriers form a pharmaceutical composition, and the dosage form of the pharmaceutical composition is injection, tablet doses, capsules, granules, pills.
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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 (en) * 2003-05-06 2004-11-18 Royal College Of Surgeons In Ireland Inhibition of platelet aggregation through acyclovir and two peptide antagonists
CN101048164A (en) * 2004-11-01 2007-10-03 柳署弘 Methods and compositions for reducing neurodegeneration in amyotrophic lateral sclerosis
US20090105168A1 (en) * 2004-11-30 2009-04-23 Gruber Peter J Use Of HDAC And/Or DNMT Inhibitors For Treatment Of Ischemic Injury
CN111569075A (en) * 2020-05-13 2020-08-25 四川大学华西医院 Application of nucleoside antiviral drug in preparation of drug for treating infarct disease

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 (en) * 2003-05-06 2004-11-18 Royal College Of Surgeons In Ireland Inhibition of platelet aggregation through acyclovir and two peptide antagonists
CN101048164A (en) * 2004-11-01 2007-10-03 柳署弘 Methods and compositions for reducing neurodegeneration in amyotrophic lateral sclerosis
US20090105168A1 (en) * 2004-11-30 2009-04-23 Gruber Peter J Use Of HDAC And/Or DNMT Inhibitors For Treatment Of Ischemic Injury
CN111569075A (en) * 2020-05-13 2020-08-25 四川大学华西医院 Application of nucleoside antiviral drug in preparation of drug for treating infarct disease

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 *

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