WO2016122288A2 - Formulation combinée comprenant un dérivé de verbénone et un agent thérapeutique pour une reperfusion pour la prévention ou le traitement de maladies cérébrovasculaires, de l'artériosclérose ou de maladies cardio-vasculaires - Google Patents

Formulation combinée comprenant un dérivé de verbénone et un agent thérapeutique pour une reperfusion pour la prévention ou le traitement de maladies cérébrovasculaires, de l'artériosclérose ou de maladies cardio-vasculaires Download PDF

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WO2016122288A2
WO2016122288A2 PCT/KR2016/001092 KR2016001092W WO2016122288A2 WO 2016122288 A2 WO2016122288 A2 WO 2016122288A2 KR 2016001092 W KR2016001092 W KR 2016001092W WO 2016122288 A2 WO2016122288 A2 WO 2016122288A2
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hept
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dimethylbicyclo
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WO2016122288A3 (fr
WO2016122288A9 (fr
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김원기
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Korea University Research and Business Foundation
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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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/13—Amines
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom

Definitions

  • the present invention relates to compositions and combination therapy for the treatment or prophylaxis of cerebrovascular disease, arteriosclerosis or cardiovascular disease.
  • the present invention provides a composition for the treatment or prevention of cerebrovascular disease, arteriosclerosis or cardiovascular disease, including a verbenone derivative or a pharmaceutically acceptable salt thereof and a reperfusion agent, and also a verbenone derivative or a pharmaceutical thereof.
  • a combination agent for the treatment or prevention of cerebrovascular disease, arteriosclerosis or cardiovascular disease comprising a composition comprising an acceptable salt and a composition comprising a reperfusion therapeutic agent.
  • the present invention provides a method of treating cerebrovascular disease, atherosclerosis or cardiovascular disease, comprising administering to a patient a composition comprising a verbenone derivative or a pharmaceutically acceptable salt thereof and a reperfusion therapeutic agent; And administering to the patient a composition comprising a verbenone derivative or a pharmaceutically acceptable salt thereof, and administering to the patient a composition comprising a reperfusion therapeutic agent to the cerebrovascular disease, atherosclerosis or cardiovascular disease. It relates to a method of treatment.
  • Degenerative brain disease is a disease associated with aging caused by the failure of brain neurons to function, and social interest in cerebrovascular disease is increasing along with the rapid growth of an aging population. Cerebrovascular diseases are distinguished by taking into account the main clinical manifestations and the involvement of the brain area and include stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis and proximal side-sighting. Amyotrophic lateral sclerosis and the like.
  • Cerebrovascular disease is known to be caused by the death of neurons, which are most important for the transmission of information from the brain nervous system, the formation or functioning of synapses that transmit information between brain cells and neurons, and the ideal symptoms or reduction of the electrical activity of the brain nerves. Still, the underlying treatment is difficult and the cause of the disease is not clear.
  • stroke is the single most common cause of death in Korea and is higher than that of developed countries such as the United States, Canada, and Australia. Stroke is impaired by exercise, sensory function, memory, learning, arithmetic, and reasoning. It causes high levels of functioning, destroys the quality of life, causes a lot of mental and physical pain for the patient and his family until death, and the rapid growth of the elderly population due to the aging of modern society. In light of recent trends, stroke incidence and increased survival time have emerged as a major social problem. Therefore, it is necessary to reduce the symptoms of stroke and to develop therapeutic drugs.
  • reperfusion treatment with tPA is the only treatment approved for ischemic stroke, the treatment range is very narrow and limited, and the risk of causing cerebral hemorrhage or fatal hemorrhagic transformation is very high. It usually takes a few hours for a patient to arrive at a hospital emergency room after a stroke, and within minutes to hours of the stroke, nerve cells are primarily damaged by excitatory neurotoxicity due to excessive release of glutamic acid. They are exposed to excessive production of oxygen and nitrogen radicals, resulting in secondary damage. After tens of hours, the inflammatory response is sustained and severely damaged, and therefore the use of excitatory neurotoxic agents is clinically insignificant.
  • the inventors of the present application have developed a derivative of (1S)-(-)-verbenone, confirming that such a verbenone derivative can be a therapeutic for stroke, and neuronal cell death of the verbenone derivatives.
  • a patent application for demonstrating a reduction in oxidative stress, an inhibitory effect on cerebral ischemic damage, and an inhibitory effect on migration of inflammatory cells (WO2013 / 183920).
  • stroke is not a disease caused by a single cause, but a disease causing brain damage according to various apoptosis paths and mechanisms.
  • Aspirin and dipyridamole may be administered together, or NMDA receptor blocking agent memantine and beta adrenergic ⁇ 2 receptor agonist Clenbuterol may be used together, or memantine and calcium ion blocking agent Combination administration of Topiramate has been attempted.
  • the results of these co-administration studies are mostly for the purpose of alleviating temporary symptoms and have not obtained synergistic effects based on brain tissue protection mechanisms.
  • thrombolysis results in brain injury (eg, enlargement of cerebral infarction and cerebral edema, neurobehavioral injury).
  • tPA delayed reperfusion therapy
  • brain injury eg, enlargement of cerebral infarction and cerebral edema, neurobehavioral injury.
  • the present invention has been shown to significantly increase the rate of cerebral hemorrhage and mortality, but the combination of berbenone derivatives can also significantly reduce brain tissue damage, cerebral hemorrhage and mortality, which are side effects caused by reperfusion drugs such as tPA. It was.
  • An object of the present invention is to prevent an increase in cerebral hemorrhage caused by side effects caused by a reperfusion therapy used in the treatment of stroke, and to provide an excellent cerebrovascular disease treatment effect.
  • the present invention provides a composition or method for treating a prolonged treatment time with a reperfusion agent by suppressing an increase in mortality caused by delayed application.
  • the present invention provides a cerebrovascular disease, atherosclerosis or cardiovascular system comprising (i) a verbenone derivative having the structure of formula (1) or a pharmaceutically acceptable salt thereof, and (ii) a reperfusion therapy
  • a cerebrovascular disease, atherosclerosis or cardiovascular system comprising (i) a verbenone derivative having the structure of formula (1) or a pharmaceutically acceptable salt thereof, and (ii) a reperfusion therapy
  • compositions for the treatment or prophylaxis of diseases :
  • R 1 , R 2 , R 3 , R 4 , and R 5 are each independently a hydrogen atom, a halogen atom selected from F, Cl, Br or I, a hydroxy group, a C 1 to C 3 lower alkyl group, C 1 to C 3 lower Alkoxy group, amino group, C 1 to C 3 lower alkylamine group, C 1 to C 3 lower alkyldiamine group, C 5 to 8 aromatic ring, C 5 to 8 aliphatic ring, and C 5 to 8 heteroaromatic ring At least one substituent selected from the group consisting of
  • X, Y and Z are each independently one or more heteroatoms selected from the group consisting of carbon atoms or N, O or S atoms,
  • ( ) Means a double bond or a single bond.
  • the invention also comprises the step of administering to a patient a composition comprising (i) a verbenone derivative having the structure of Formula 1 or a pharmaceutically acceptable salt thereof, and (ii) a reperfusion therapy agent, cerebrovascular disease To provide a method of treating atherosclerosis or cardiovascular disease.
  • the present invention comprises (i) a composition comprising a verbenone derivative having a structure of Formula 1 or a pharmaceutically acceptable salt thereof, and (ii) a composition comprising a reperfusion therapy, cerebrovascular disease, A combination agent for treating or preventing atherosclerosis or cardiovascular disease is provided.
  • the present invention comprises the steps of (i) administering to the patient a composition comprising a verbenone derivative having the structure of Formula 1 or a pharmaceutically acceptable salt thereof, and (ii) a composition comprising a reperfusion therapy to the patient It provides a method of treating cerebrovascular disease, atherosclerosis or cardiovascular disease, comprising administering.
  • the present invention relates to the treatment of cerebrovascular disease, atherosclerosis or cardiovascular disease of a composition comprising (i) a verbenone derivative having the structure of Formula 1 or a pharmaceutically acceptable salt thereof, and (ii) a reperfusion therapeutic agent or
  • a combination formulation comprising (i) a composition comprising a verbenone derivative having the structure of Formula 1 or a pharmaceutically acceptable salt thereof, and (ii) a reperfusion therapeutic agent Provided for the treatment or prevention of cerebrovascular disease, atherosclerosis or cardiovascular disease.
  • FIG. 1 is a diagram showing the stroke treatment mechanism using tPA and side effects by tPA.
  • FIG. 2 is a graph showing CBF changes after tPA administration in an embolic ischemic stroke animal model.
  • FIG. 3 shows the results of brain tissue observation, mortality, total cerebral infarct volume and edema volume, neurological deficits, and changes in bleeding over time after tPA alone administration in an ischemic stroke animal model:
  • Figure 4 shows the changes in brain tissue observation, mortality, total cerebral infarct volume and edema volume, neurological deficits and bleeding according to LMT356 (3h, iv bolus) + tPA (3h, iv infusion) administration in an ischemic stroke animal model. Confirmed results are shown: A: brain tissue observation, B: mortality, C: total cerebral infarction volume measurement, D: edema volume measurement, E: neurological deficit, F: bleeding volume excluding the dead animals.
  • 5A and 5B show brain tissue observation, mortality, total cerebral infarct volume, edema volume, neurological following LMT356 (3h or 4.5h, iv bolus) + tPA (4.5h, iv infusion) administration in an ischemic stroke animal model Results of the change in the degree of defect, bleeding volume and cerebral blood flow were shown: A: brain tissue observation, B: mortality, C: total cerebral infarction volume measurement, D: edema volume measurement, E: neurological deficit rate, F: bleeding volume excluding death, G: cerebral blood flow.
  • FIGS. 6A and 6B show changes in brain tissue observation, mortality, total cerebral infarct volume and edema volume following administration of LMT356 (3h, 4.5h, 5.15h or 6h, iv bolus) + tPA (6h, iv infusion) in an ischemic stroke animal model , Neurological deficiency, bleeding volume and cerebral blood flow were shown: A: brain tissue observation, B: mortality, C: total cerebral infarction volume measurement, D: edema volume measurement, E: neurological deficiency , F: bleeding volume excluding dead animals, G: cerebral blood flow.
  • Figure 7 shows the results of confirming mortality, total cerebral infarction volume, edema volume measurement and neurological deficiency according to LMT356 (4.5h or 7.5h, iv bolus) + tPA (6h, iv infusion) administration in an ischemic stroke animal model
  • A mortality
  • B cerebral infarction volumetric
  • C edema volumetric
  • D neurological deficit.
  • the present invention provides the treatment or prevention of cerebrovascular disease, arteriosclerosis or cardiovascular disease comprising (i) a verbenone derivative having the structure of Formula 1 or a pharmaceutically acceptable salt thereof and (ii) a reperfusion agent
  • the composition relates to:
  • R 1 , R 2 , R 3 , R 4 , and R 5 are each independently a hydrogen atom, a halogen atom selected from F, Cl, Br or I, a hydroxy group, a C 1 to C 3 lower alkyl group, C 1 to C 3 lower Alkoxy group, amino group, C 1 to C 3 lower alkylamine group, C 1 to C 3 lower alkyldiamine group, aromatic ring having 5 to 8 carbon atoms, aliphatic ring having 5 to 8 carbon atoms, and heterocyclic ring having 5 to 8 ring atoms At least one substituent selected from the group consisting of aromatic rings,
  • X, Y and Z are each independently one or more heteroatoms selected from the group consisting of carbon atoms or N, O or S atoms,
  • ( ) Means a double bond or a single bond.
  • R 1 , R 2 , R 3 , R 4 , and R 5 are each independently a halogen atom, a hydroxy group, a methyl group, an ethyl group, a methoxy group, selected from a hydrogen atom, F, Cl, Br and I, It may be at least one selected from the group consisting of an ethoxy group, an amino group, an aromatic ring having 5 to 6 carbon atoms, an aliphatic ring having 5 to 6 carbon atoms, and a heteroaromatic ring having 5 to 6 ring atoms.
  • R 1 , R 2 , R 3 , R 4 , and R 5 are each independently a halogen atom selected from a hydrogen atom, F, Cl, Br, and I, a hydroxy group, a methyl group, a methoxy group, a phenyl group, a pyrrole group And pyridine groups.
  • the X, Y and Z may be each independently C or N.
  • the verbenone derivative is
  • the reperfusion therapy is used to treat abnormal conditions caused by perfusion injury, for example, to revascularize, prevent the spread of blood clots and revascularization of blood vessels, restore perfusion, and at the same time prevent potential bleeding by pharmacological changes and mechanical manipulation of hemostasis.
  • Suitable agents are not particularly limited but may be, for example, one or more selected from the group consisting of thrombolytics, anticoagulants and antiplatelet agents.
  • the thrombolytic agent is not particularly limited as long as it is a substance that dissolves blood clots present in the blocked blood vessel, but may be, for example, a plasminogen activator.
  • the plasminogen activator may be, for example, Streptokinase (SK), Alteplase (tPA), Reteplase (rPA), Tenecteplase (TNK), or ansoylated plasminogen streptokinase activator complex (APSAC).
  • tPA may refer to an exogenous tissue-type plasminogen activator having two or more functional domains including a protease domain capable of converting plasminogen to plasmin and an N-terminus known to be responsible for fibrin binding.
  • the tissue plasminogen activator may be used without limitation, but may be, for example, a recombinant tissue plasminogen activator or commercially available tPA.
  • the anticoagulant is not particularly limited as long as it is a substance that prevents blood coagulation in blood vessels or the heart, for example, aspirin, warfarin, endoxaparin, heparin, cilostazol, clopidogrel, ticlopidine, tyropiban, absik MAP, dipyridamole, plasma protein fractions, human albumin, dextran, hetastarch, reteplasm,reteraz, streptokinase, urokinase, daltepharine, filplastin, immunoglobulin, gincolide B, hirudin, Poropaphan, Rosepapant, Vivalidine, Dermatan Sulfate Mediolanum, Eftirivatid, Tyropiban, Trombomodulin, Absmap, Low Molecular Weight Dermatan Sulfate-Opocrine, Eftacog Alpha, Arga Trovan, Fondafarix Sodium, Tifacozin, Repyrudine,
  • the antiplatelet agents are adenosine diphosphate (ADP) antagonists or P2Y12 antagonists, phosphodiesterase (PDE) inhibitors, adenosine reuptake inhibitors, vitamin K antagonists, heparin, heparin analogs, direct thrombin inhibitors, glycoprotein IIB / IIIA inhibitors, It may be an anticoagulant enzyme, but is not limited thereto.
  • ADP adenosine diphosphate
  • P2Y12 antagonists P2Y12 antagonists
  • PDE phosphodiesterase
  • adenosine reuptake inhibitors vitamin K antagonists
  • heparin heparin analogs
  • direct thrombin inhibitors glycoprotein IIB / IIIA inhibitors
  • It may be an anticoagulant enzyme, but is not limited thereto.
  • the antiplatelet agent may be sulfinpyrazone, ticlopidine, clopidogrel, prasugrel, R-99224 (manufactured by Sankyo), R-1381727, R-125690 (manufactured by Lilly), C-1330-7, C -50547 (Millennium Pharmaceuticals), INS-48821, INS-48824, INS-446056, INS-46060, INS-49162.
  • INS-49266, INS-50589 (manufacturer: Inspire Pharmaceuticals), Sch-572423 (manufacturer: Schering Plough), AZD6140 (manufacturer: AstraZeneca), asenokoumarol, chlorindione, dicumarol, diphenadione, ethyl bisco Umacetate, phenprocomon, pheninion, thioclomarol, warfarin, heparin, antithrombin III, bemiparin, dalteparin, danaparoid, enoxaparin , Fondaparinux (subcutaneous), Nadroparin, Parnaparin, Levivilin, Sulodexide, Tinzaparin, Abzaximab ), Eptifibatide, tirofiban, alteplase, ancrod, anistreplase, brinase, drotrecogin alfa ), Fibrinolysin, Protein C,
  • the cerebrovascular disease refers to a disease caused by the death of cerebral neurons, which are the most important for information transmission, the formation or function of synapses that transmit information between brain neurons and neurons, and the ideal symptoms or reduction of electrical activity of the brain nerves.
  • the cerebrovascular disease may include, for example, stroke, dementia, Alzheimer's disease, Parkinson's disease, or Huntington's disease, preferably stroke, more preferably ischemic stroke.
  • the cardiovascular disease includes, but is not limited to, myocardial infarction, angina pectoris and the like.
  • the composition is not particularly limited as long as the composition can produce a synergistic effect while maintaining stability between the verbenone derivative or a pharmaceutically acceptable salt thereof and a reperfusion therapeutic agent.
  • the verbenone derivative or a pharmaceutically acceptable salt thereof and the perfusion treatment agent may be included, for example, in a weight ratio of 0.02: 1 to 10: 1, preferably 0.1: 1 to 10: 1.
  • a verbenone derivative or a pharmaceutically acceptable salt thereof and a reperfusion agent are included in the above-defined range, the efficacy of both active ingredients is maintained to prevent or treat a cerebrovascular disease, arteriosclerosis, or cardiovascular disease. I can make it.
  • the invention comprises administering to a patient a composition comprising (i) a verbenone derivative having the structure of Formula 1 or a pharmaceutically acceptable salt thereof, and (ii) a reperfusion therapeutic agent A method of treating vascular disease, atherosclerosis or cardiovascular disease.
  • the composition comprising the verbenone derivative or a pharmaceutically acceptable salt thereof and a reperfusion therapy can be administered within 3 hours after the onset of cerebrovascular disease, such as ischemic stroke, and further after the onset of cerebrovascular disease 3 It can also be administered after time.
  • composition containing the verbenone derivative or a pharmaceutically acceptable salt thereof and a reperfusion therapeutic agent may be repeatedly administered as necessary.
  • the present invention also relates to the treatment of cerebrovascular disease, atherosclerosis or cardiovascular disease of a composition
  • a composition comprising (i) a verbenone derivative having the structure of Formula 1 or a pharmaceutically acceptable salt thereof, and (ii) a reperfusion therapeutic agent or To preventive use.
  • the present invention provides a cerebrovascular system comprising (i) a composition comprising a verbenone derivative having the structure of Formula 1 or a pharmaceutically acceptable salt thereof, and (ii) a reperfusion therapeutic agent
  • a cerebrovascular system comprising (i) a composition comprising a verbenone derivative having the structure of Formula 1 or a pharmaceutically acceptable salt thereof, and (ii) a reperfusion therapeutic agent
  • the present invention relates to a combination for treating or preventing a disease, atherosclerosis or cardiovascular disease.
  • a composition comprising a verbenone derivative having a structure of Formula 1 or a pharmaceutically acceptable salt thereof may include a composition including a verbenone derivative having a structure of Formula 1 or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient it means.
  • the composition may comprise a pharmaceutically acceptable carrier, the form is not particularly limited.
  • composition comprising the reperfusion therapeutic agent means a composition comprising the reperfusion therapeutic agent as a pharmacologically active ingredient.
  • the composition may comprise a pharmaceutically acceptable carrier, the form is not particularly limited.
  • the present invention comprises the steps of (i) administering to the patient a composition comprising a verbenone derivative having the structure of Formula 1 or a pharmaceutically acceptable salt thereof, and (ii) a composition comprising a reperfusion therapy to the patient It relates to a method of treating cerebrovascular disease, arteriosclerosis or cardiovascular disease, comprising administering.
  • arteries comprising a combination comprising (i) a composition comprising a verbenone derivative having the structure of Formula 1 or a pharmaceutically acceptable salt thereof, and (ii) a composition comprising a reperfusion therapeutic agent A therapeutic or prophylactic use of sclerosis or cardiovascular disease.
  • the inventors of the present application delay the application of thrombolysis using tPA, which is the only approved drug for ischemic stroke, through the combination of the verbenone derivative and the reperfusion therapy, and as a reperfusion therapy 3 hours after the onset of stroke. It was confirmed that the side effects and mortality such as cerebral infarction and hemorrhagic bleeding caused by treatment after bleeding, neurological deficit and reperfusion agent can be significantly reduced.
  • a verbenone derivative unlike the conventional use of the reperfusion therapy, which minimizes the side effects caused by the reperfusion therapy (e.g., tPA) and shows a significant ischemic stroke treatment effect only when treated within 3 hours of the onset of stroke.
  • the combination of and perfusion therapy can be used to extend the therapeutic range and treatment time using reperfusion therapy.
  • direct cerebral perfusion may be induced by removing cerebral thrombosis through surgery or procedure, which may lead to cerebral hemorrhage and brain injury.
  • the inventors of the present application have confirmed that the combination of the verbenone derivative and the reperfusion agent can prevent cerebral hemorrhage and brain damage that may occur when cerebral thrombosis is removed through surgery or procedure.
  • tPA a type of reperfusion drug
  • tPA is used within three hours in clinical practice and in some countries, up to 4.5 hours, and is used within three hours of tPA in embolic stroke animal models.
  • various indicators eg, cerebral infarction, cerebral edema, neurobehavioral indicators, mortality and cerebral hemorrhage
  • FIG. 3 cerebral hemorrhage and mortality
  • the combined dosage form is the simultaneous or separate administration of a composition comprising a verbenone derivative and a composition comprising tPA, and the separate administration is, for example, pretreatment of the verbenone derivative prior to tPA administration, As well as the therapeutic effect, it was confirmed that the effect of the pre treatment of the beverone derivatives is also very good.
  • pretreatment of berbenone derivatives can protect brain damage from reperfusion even in animal studies under the same conditions as surgically removing thrombi to induce reperfusion. That is, the verbenone derivative or its pharmaceutically acceptable salts and reperfusion therapy may be administered even when cerebral perfusion is induced by removing cerebral thrombosis through surgery or procedure, thereby preventing cerebral hemorrhage and brain injury.
  • composition comprising the verbenone derivative or a pharmaceutically acceptable salt thereof and the composition comprising a reperfusion agent may be administered simultaneously.
  • the composition containing the verbenone derivative or a pharmaceutically acceptable salt thereof and the composition comprising a reperfusion therapy may be administered separately at regular intervals.
  • a composition comprising the verbenone derivative or a pharmaceutically acceptable salt thereof may be administered separately before or after administration of the composition comprising a reperfusion therapeutic agent.
  • composition comprising the reperfusion therapy may be administered within 3 hours after the onset of cerebrovascular disease, such as ischemic stroke, and according to an embodiment of the present invention, may be administered even after 3 hours after the onset of cerebrovascular disease.
  • composition comprising the verbenone derivative or a pharmaceutically acceptable salt thereof may be, for example, 0.5-6 hours before or after, 0.5-4.5 hours before, or 0.5-3.5 hours before or after administering a composition comprising a reperfusion agent. Or after, before or after 0.5-3 hours, before or after 0.5-2.5 hours, before or after 0.5-2 hours, before or after 0.5-1.5 hours, before or after 0.85-3.5 hours, before or after 0.85-3 hours , Before or after 0.85-2.5 hours, before or after 0.85-2 hours, or before or after 0.85-1.5 hours, preferably before or after 1.5-3 hours, more preferably before or after 2-3 hours have.
  • a composition comprising a reperfusion therapy is administered within 3 hours or 3 hours after the onset of cerebrovascular disease, such as ischemic stroke, and a composition comprising a verbenone derivative or a pharmaceutically acceptable salt thereof, for example 0.5-6 Time interval, 0.5-4.5 hour interval, 0.5-3.5 hour interval, 0.5-3 hour interval, 0.5-2.5 hour interval, 0.5-2 hour interval, 0.5-1.5 hour interval, 0.85-3.5 hour interval, 0.85-3 hour interval Before or after administration of a composition comprising a reperfusion therapeutic agent at intervals of 0.85-2.5 hours, 0.85-2 hours, 0.85-1.5 hours, preferably 1.5-3 hours, more preferably 2-3 hours Can be.
  • composition containing the verbenone derivative or a pharmaceutically acceptable salt thereof may be administered two or more times before and after administering a composition comprising a reperfusion therapeutic agent.
  • a composition comprising a reperfusion therapeutic agent for example, 0.5-6 hours before, 0.35-4.5 hours, 0.5-3 hours, 1-3 hours, preferably 1.5-3 hours, more preferably before administering a composition comprising a reperfusion therapy.
  • composition comprising the verbenone derivative or a pharmaceutically acceptable salt thereof and the composition comprising a reperfusion agent may be repeatedly administered as necessary.
  • a composition comprising a verbenone derivative or a pharmaceutically acceptable salt thereof, it is possible to reduce the bleeding and mortality caused by reperfusion therapy, eg, commercially available tPA, which reduces the expression of MMPs. It is determined that through the.
  • reperfusion therapy eg, commercially available tPA
  • the verbenone derivative or a pharmaceutically acceptable salt thereof is approached to an ischemic site to have a neuroprotective effect.
  • the treatment time range in which the reperfusion therapy should be administered within 3 hours after the onset of cerebrovascular disease and no later than 4.5 hours is about 6 to 8 It can be extended to time, which may increase the clinical coverage of reperfusion therapy such as tPA by more than 10 times.
  • the verbenone derivative or pharmaceutically acceptable salt thereof may vary depending on the condition and weight of the patient, the extent of the disease, the form of the drug, the route of administration and the duration of administration, and may be appropriately selected and administered by a person skilled in the art. For example, from 0.01 mg / kg to 10 g / kg, preferably from 1 mg / kg to 1 g / kg.
  • the tissue plasminogen activator may also be appropriately selected and administered by those skilled in the art in consideration of the condition of the patient according to the approved dosage or the recommended dose, for example, 0.1-50 mg / kg, preferably 0.5-10 mg It may be administered at a dosage of / kg. Administration may be administered once a day or may be divided several times.
  • a composition for treating or preventing cerebrovascular disease, arteriosclerosis or cardiovascular disease comprising (i) a verbenone derivative having the structure of Formula 1 or a pharmaceutically acceptable salt thereof and (ii) a reperfusion agent according to the present invention;
  • reperfusion therapeutic agents can be used in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral formulations, suppositories, and sterile injectable solutions according to conventional methods.
  • Carriers, excipients and diluents that may be included therein include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, Methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, magnesium stearate and mineral oil. When formulated, it may be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc. which are commonly used.
  • Solid form preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, which form at least one or more excipients in the compound, at least cotton, starch, calcium carbonate, sucrose. Or lactose, gelatin, or the like is mixed. In addition to simple excipients, lubricants such as magnesium styrate talc are also used. Oral liquid preparations include suspending agents, liquid solutions, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. .
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like.
  • non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used.
  • base of the suppository witepsol, macrogol, tween, cacao butter, laurin butter, glycerogelatin and the like can be used.
  • Rats (between 270-300 g weight) were inhaled using 3% isoflurane gas mixed with 70% N 2 O and 30% O 2 (v / v) gas mixture, followed by 3% isoflurane It was maintained using.
  • a rectal thermometer was inserted and an automatic heating pad connected thereto maintained the body temperature of the rat at 37.0-37.9 ° C. during the surgery.
  • the common carotid artery (CCA), the right external carotid artery (ECA) and the right internal carotid artery (ICA) were separated to bind the external carotid artery and the whole carotid artery. .
  • the internal carotid artery was temporarily tightened using a curved microvascular clip.
  • the microvascular clip was removed and the catheter was carefully advanced 16-17 mm into the internal carotid artery to move about 2 mm from the start of the midbrain aorta. Embolization of the catheter was injected into the internal carotid artery (10 ⁇ l).
  • Nitrotyrosine is recognized as a marker of nitric oxide stress mediated by reactive nitrogen groups such as peroxynitrite and NO. Rats were sacrificed 24 hours after reperfusion and perfused with 4% Paraformaldehyde (PFA) in 0.1 M Phosphate buffer (PB). The whole brain was removed, fixed in 4% PFA for one day, and then lyophilized using 30% sucrose. A continuous 8 ⁇ m coronal section was made using a cryostat (Leica 1850, Leica, Germany). To reduce nonspecific binding, the fragments were first blocked with 5% normal goat serum for 1 hour, then anti-NeuN (A60; 1: 100) or anti-nitrotyrosine (1:50) antibody was added at 4 ° C. Stained overnight.
  • PFA Paraformaldehyde
  • PB Phosphate buffer
  • the fragments were incubated for 1 hour at room temperature with goat anti-rabbit or anti-mouse IgG antibody (2 ⁇ g / ml) conjugated with Alexa 488 and then stained with Hoechst 33258 for 20 minutes. Fluorescence intensity and number of immunoreactive cells were measured using confocal fluorescence microscopy (Zeiss LSM510; Zeiss, Oberkochen, Germany). For quantitation, four non-overlapping optical fragments (450 ⁇ 450 m 2 , 5.0 ⁇ m thick) were systematically screened from ligament injury sites around the cortex and cerebrospinal fluid, and the number of nitrotyrosine positive cells was double blinded. Counted.
  • Infarct sections between +4 mm (front) and -6 mm (rear) of bregma were measured with an analysis program (OPTIMAS 5.1 image analysis program, BioScan Inc. Edmonds, WA). The outer periphery of the infarct area for cerebral infarct size measurement was set manually.
  • Total cerebral infarction volume (mm3) is calculated by calibrating cerebral edema according to Equation 1 as described in J Neurosci Methods (1998) 84: 9-16; J Cereb Blood Flow Metab (1990) 10: 290-293 It was. Cerebral edema is calculated as a percentage increase in ipsilateral (V 1 ) / contralateral hemisphere area (V C ), as shown in Equation 2 below. All were measured by double blind method.
  • Total cerebral infarction volume (mm 3 ) ipsilateral volume (IVd) ⁇ [(hemilateral volume (V C )) / hemilateral volume (V C )] by direct measurement
  • Edema volume (%) [(ipsilateral volume (V 1 ) -hemilateral volume (V C )) / hemilateral volume (V C )] ⁇ 100.
  • the tissue was then frozen and cut into 10 or 30 mm carotid artery sections with a cutter (Leica 3050; Leica, Nussloch, Germany) and stored at -20 ° C.
  • Neurological deficits were measured 24 hours after ischemia and measured on a four-point scale (0: no neurological deficits, 1: forearm flexion, 2: forefoot flexion and reduced resistance to lateral push, no rotation) , 3: same as 2, but rotates).
  • Rats with focal cerebral ischemia were measured within 24 hours after surgery under the same conditions as before.
  • LDF Laser Doppler flowmetry, Transonic Systems Inc., Ithaca, NY; model BLF22
  • MCAO middle cerebral artery occlusion
  • An LDF probe Type N18, Transonic Systems Inc. was placed in the cranial cerebral cortical window of the upper right head of the rat.
  • Example One Embolic After tPA in an Ischemic Stroke Animal Model CBF change
  • CBF changes were observed after tPA administration.
  • Embolization of autologous blood was used to induce an embolic stroke induced by middle cerebral artery occlusion.
  • Recombinant tPA (10 mg / kg, i.v. infusion) was treated in rats at the indicated time after middle cerebral artery occlusion. Over time after tPA administration, it is expressed as relative CBF (%) relative to blood flow before embolization.
  • Embolism of autologous blood was used to induce embolic stroke induced by middle cerebral artery occlusion in an embolic ischemic stroke animal model.
  • Embolic stroke-induced rats were treated with recombinant tPA (10 mg / kg, i.v. infusion) 3 hours, 4.5 hours, and 6 hours after middle cerebral artery occlusion, respectively.
  • tPA recombinant tPA
  • FIG. 3A Brain tissue observation results are shown in Figure 3A, the total cerebral infarction volume measurement results in Figure 3C.
  • 3A and 3C brain injury increases after embolic ischemia.
  • tPA is treated at 3 hours after embolic ischemia, the size of cerebral infarction decreases, but delayed tPA treatment at 4.5 hours or 6 hours is performed. It was confirmed that the size does not decrease.
  • FIG. 3D The result of measuring the edema volume is shown in Figure 3D.
  • treatment with tPA at 3 hours after embolic ischemia showed no statistical significance but tended to suppress edema volume.
  • the delayed tPA treatment administered at 4.5 hours or 6 hours could not suppress the edema volume.
  • FIG. 3E The degree of neurological deficits was shown in FIG. 3E.
  • tPA treatment improved neurobehavioral function at 3 hours after embolic ischemia, but tPA was determined at 4.5 and 6 hours. In the case of administration, no improvement effect on neurobehavioral function was observed.
  • FIG. 3F The bleeding volume of the surviving rats except for animals that died during the experiment was measured and shown in FIG. 3F.
  • treatment of tPA at 3 hours after embolic ischemia does not affect the volume of bleeding, but 4.5 hours or Delayed tPA treatment administered at 6 hours showed a significant increase in cerebral hemorrhage.
  • Example 3 Embolic 3 hours after ischemia LMT Of the combination of -356 and tPA
  • Embolization of autologous blood was used to induce an embolic stroke induced by middle cerebral artery occlusion.
  • Rats were treated with LMT356 (3h, iv bolus), recombinant tPA (3h, iv infusion), and LMT356 (3h, iv bolus) + recombinant tPA (3h, iv infusion), respectively, 3 hours after middle cerebral artery occlusion.
  • Brain tissue observations after 24 hours of cerebral artery occlusion confirmed changes in mortality, total cerebral infarction volume, edema volume, neurological deficit, and bleeding (excluding values obtained from death animals).
  • FIGS. 4A and 4C Brain tissue observation results are shown in Figure 4A the total cerebral infarction volume measurement results in Figure 4C.
  • FIGS. 4A and 4C when tPA alone was administered at 3 hours after embolic ischemia, the size of cerebral infarction decreased, but administration of the berbenone derivative alone did not significantly reduce the size of cerebral infarction.
  • Edema volume was measured and shown in FIG. 4D.
  • treatment with tPA alone at 3 hours after embolic ischemia showed no statistical significance, but showed a tendency to suppress edema volume.
  • administration of the beverone derivative alone at 3 hours after embolic ischemia did not show an effect of suppressing edema volume.
  • Simultaneous treatment with verbenone derivatives and tPA at 3 hours after embolic ischemia showed a tendency to suppress edema volume, but no better results were obtained with tPA alone.
  • FIG. 4E The degree of neurological deficit was confirmed in FIG. 4E.
  • administration of tPA alone at 3 hours after embolic ischemia improved neurobehavioral function.
  • the treatment with berbenone derivative alone at 3 hours after embolic ischemia could not restore neurobehavioral function.
  • Simultaneous treatment of berbenone derivatives with tPA at 3 hours after embolic ischemia restored neurobehavioral function but did not yield better results than administration of tPA alone.
  • FIG. 4F The bleeding volume of the animals except the deceased animal was measured and shown in FIG. 4F.
  • treatment with tPA alone at 3 hours after embolic ischemia did not affect cerebral hemorrhage volume.
  • the treatment with berbenone derivative alone did not affect the hemorrhagic volume.
  • Six patients treated with verbenone derivatives and tPA at 3 hours after embolic ischemia did not affect cerebral hemorrhage volume.
  • Example 4 LMT To -356 After pretreatment with tPA LMT Comparison of effects of -356 and tPA at the same time (1)
  • Rats were treated with LMT356 (3h, iv bolus), LMT356 (4.5h, iv bolus), recombinant tPA (4.5h, iv infusion), and LMT356 (3h, iv bolus) + recombination after middle cerebral artery occlusion in the same manner as in Example 3.
  • tPA Treatment with tPA (4.5 h, iv infusion), and LMT356 (4.5 h, iv bolus) + recombinant tPA (4.5 h, iv infusion), brain tissue observation 24 h after middle cerebral artery occlusion, mortality, total cerebral infarct volume, edema Changes in volume, neurologic deficit, bleeding (excluding values obtained from dead animals), and cerebral blood flow were identified.
  • FIG. 5A Brain tissue observation results are shown in Figure 5A the total cerebral infarction volume measurement results in Figure 5C.
  • the treatment of tPA alone at 4.5 hours after embolic ischemia did not reduce the size of cerebral infarction.
  • the cerebral infarct size was not reduced when the beverone derivative was administered alone 3 hours or 4.5 hours after embolic ischemia.
  • cerebral infarct size decreased when the beverone derivative was administered at 3 hours or 4.5 hours after embolic ischemia and treated with tPA at 4.5 hours.
  • Edema volume was measured and shown in FIG. 5D.
  • the treatment with tPA alone at 4.5 hours after embolic ischemia showed no edema volume reduction.
  • the edema volume did not decrease when the verbenone derivative alone was administered 3 hours or 4.5 hours after embolic ischemia.
  • the mortality over time was confirmed and shown in Table 3 and FIG. 5B.
  • the mortality did not change when Verbenone derivatives were administered at 3 hours or 4.5 hours after embolic ischemia.
  • Treatment with tPA alone at 4.5 hours after embolic ischemia significantly increased mortality.
  • the mortality rate was significantly reduced when the verbenone derivative was first administered 3 hours after embolic ischemia and tPA was treated 4.5 hours after embolic ischemia.
  • the simultaneous treatment of verbenone derivatives with tPA at 4.5 hours after embolic ischemia did not reduce mortality rate significantly compared to the administration of tPA alone at 4.5 hours.
  • FIG. 5E The degree of neurological deficit was confirmed and shown in FIG. 5E.
  • treatment with tPA alone at 4.5 hours after embolic ischemia did not restore neurobehavioral function.
  • the neurobehavioral function was not restored when the beverone derivative was administered alone 3 hours or 4.5 hours after embolic ischemia.
  • neurobehavioral function was restored when Verbenone derivatives were administered 3 hours or 4.5 hours after embolic ischemia and tPA was treated at 4.5 hours.
  • FIG. 5F The bleeding volume was measured and shown in FIG. 5F.
  • treatment with tPA at 4.5 hours after embolic ischemia did not affect cerebral hemorrhage volume.
  • the treatment of the beverone derivatives at 3 hours or 4.5 hours after embolic ischemia did not significantly affect the hemorrhagic volume.
  • Pretreatment or co-treatment of the verbenone derivative 1.5 hours prior to tPA treatment did not affect the volume of cerebral hemorrhage observed after tPA treatment.
  • tPA treatment at 3 hours after embolic ischemia prevents blockage of blood flow by thrombus and restores blood flow, whereas embolism is observed.
  • Administration of the verbenone derivative alone 3 hours after ischemia did not appear to affect blood flow at all.
  • the treatment of tPA at 4.5 hours after the first administration of the berbenone derivative at 3 hours after embolic ischemia is not significantly different from the flow of tPA alone at 4.5 hours after embolic ischemia.
  • Verbenone derivatives do not appear to have an effect on improving blood flow.
  • Rats were treated with LMT356 (3h, iv bolus), LMT356 (4.5h, iv bolus), recombinant tPA (6h, iv infusion), and LMT356 (3h, iv bolus) + recombination after middle cerebral artery occlusion in the same manner as in Example 3.
  • FIGS. 6A and 6C show the results of brain tissue observation in FIG. 6A.
  • the treatment of tPA alone after 6 hours after embolic ischemia did not reduce the size of cerebral infarction.
  • cerebral infarction was not significantly reduced in size.
  • cerebral infarct size decreased when the beverone derivative was administered 3 hours or 4.5 hours after embolic ischemia and 6 hours of tPA treatment.
  • the administration of the verbenone derivative at 5.15 hours after embolic ischemia or simultaneous administration with tPA did not affect the volume of cerebral hemorrhage observed after tPA treatment.
  • Edema volume was measured and shown in FIG. 6D. Referring to FIG. 6D, it was confirmed that the edema volume did not decrease even after treatment with tPA alone for 6 hours after embolic ischemia. Likewise, the edema volume did not decrease when the beverone derivative was administered alone 3 hours or 4.5 hours after embolic ischemia. However, it was confirmed that the edema volume is significantly reduced when the beverone derivative is administered 3 hours after embolic ischemia and 6 hours after treatment with tPA.
  • the beverone derivative was first administered 4.5 hours or 5.15 hours after embolic ischemia and tPA was administered at 6 hours, or the beverone derivative was simultaneously administered with tPA at 6 hours after embolic ischemia, the volume of cerebral hemorrhage was It was found that the effect is not very large.
  • the mortality over time was confirmed and shown in Table 4 and FIG. 6B.
  • Table 4 and FIG. 6B there was no change in mortality when the beverone derivative was administered at 3 hours or 4.5 hours after embolic ischemia.
  • 6 hours after embolic ischemia alone treatment with tPA significantly increased mortality.
  • the mortality rate was 6 when the beverone derivative was first administered at 3 hours, 4.5 hours or 5.15 hours after embolic ischemia and tPA was administered at 6 hours, or when the beverone derivative was simultaneously administered with tPA at 6 hours after embolic ischemia. It was confirmed that the time was much lower than the tPA alone treatment.
  • FIG. 6E The degree of neurological deficits was shown in FIG. 6E.
  • treatment with tPA alone at 6 hours after embolic ischemia did not restore neurobehavioral function.
  • the neurobehavioral function was not restored when the beverone derivative was administered alone 3 hours or 4.5 hours after embolic ischemia.
  • beverone derivatives were first administered at 3 hours, 4.5 hours or 5.15 hours after embolic ischemia, and treated with tPA at 6 hours, neurobehavioral function was greatly improved.
  • the neurologic deficiency was less than that of tPA alone when 6 hours after embolic ischemia.
  • FIG. 6F The bleeding volume was measured and shown in FIG. 6F. Referring to FIG. 6F, it was confirmed that cerebral hemorrhage volume was significantly increased by treatment with tPA at 6 hours after embolic ischemia. However, it was confirmed that the administration of the beverone derivative at 3 hours or 4.5 hours after embolic ischemia does not affect the hemorrhagic volume. If tPA was first administered 45 minutes before, 1.5 hours, or 3 hours before administration of tPA and 6 hours after embolic ischemia, tPA alone was administered 6 hours after embolic ischemia. In comparison, the volume of cerebral hemorrhage was hardly increased.
  • tPA treatment at 3 hours after embolic ischemia prevents blockage of blood flow by thrombus and restores blood flow, while embolism is observed.
  • Administration of the verbenone derivative alone 3 hours after ischemia did not appear to affect blood flow at all.
  • the treatment of tPA at 6 hours after the first administration of the verbenone derivative at 3 hours after embolic ischemia has no significant difference in blood flow compared with the administration of tPA at 6 hours after embolic ischemia.
  • Verbenone derivatives do not appear to have an effect on improving blood flow.
  • Rats were treated with LMT356 (4.5 h and 7.5 h twice, iv bolus), recombinant tPA (6 h, iv infusion), LMT356 (4.5 h and 7.5 h twice) following mid-cerebral artery occlusion in the same manner as in Example 3 Administration, iv bolus) + recombinant tPA (6h, iv infusion), and changes in mortality, total cerebral infarct volume, edema volume and degree of neurologic deficit after 24 hours of middle cerebral artery occlusion.
  • the mortality over time was confirmed and shown in Table 5 and FIG. 7A.
  • the mortality rate was significantly increased by treatment with tPA alone at 6 hours after embolic ischemia.
  • the mortality rate can be significantly lowered if the verbenone derivative is administered 4.5 hours after embolic ischemia, and the Verbenone derivative is administered once more at 7.5 hours after tPA treatment at 6 hours.
  • FIG. 7B The results of measuring the total cerebral infarction are shown in Figure 7B.
  • treatment with tPA alone at 6 hours after embolic ischemia did not reduce the size of cerebral infarction.
  • the magnitude of cerebral infarction was also achieved when the beverone derivative was administered alone at 4.5 and 7.5 hours after embolic ischemia, or when the beverone derivative was administered at 4.5 and 7.5 hours after embolic ischemia and tPA was treated at 6 hours. Did not appear to have a significant effect.
  • FIG. 7C The result of measuring the edema volume is shown in Figure 7C. Looking at Figure 7C it can be seen that 6 hours after embolic ischemia alone treatment with tPA can not suppress the edema volume. The edema volume was not suppressed even when the beverone derivative was administered alone at 4.5 and 7.5 hours after embolic ischemia, or when the bebenone derivative was administered at 4.5 and 7.5 hours after embolic ischemia and 6 hours of tPA treatment. I could't.
  • FIG. 7D The results of evaluating the degree of neurological deficit are shown in FIG. 7D, and when treated with tPA alone at 6 hours after embolic ischemia from FIG. 7D, it could be confirmed that neurobehavioral function was not restored. However, neurobehavioral function was restored when the beverone derivatives were administered alone at 4.5 and 7.5 hours after embolic ischemia, or when the bebenone derivatives were administered at 4.5 and 7.5 hours after embolic ischemia and 6 hours of tPA treatment. It showed a tendency to.
  • a composition comprising a verbenone derivative according to the present invention and a reperfusion therapeutic agent a combination comprising: (i) a composition comprising said verbenone derivative or a pharmaceutically acceptable salt thereof, and (ii) a composition comprising a reperfusion therapeutic agent; Or through a treatment method including the combined administration thereof, it is possible to reduce cerebral infarction and cerebral edema caused by ischemia and to suppress cerebral hemorrhage and mortality.
  • Matrix metalloproteinases are known to be significantly associated with increased cerebral hemorrhage and mortality, which are side effects caused by treatment with reperfusion drugs, such as tPA.
  • MMPs Matrix metalloproteinases
  • MMP2 MMP2, MMP3 and MMP9
  • tPA reperfusion drugs

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Abstract

La présente invention concerne une composition et une thérapie d'administration combinée pour le traitement de maladies cérébrovasculaires. Plus particulièrement, la présente invention concerne : une composition comprenant un dérivé de verbénone ou son sel pharmaceutiquement acceptable, et un agent thérapeutique pour une reperfusion pour le traitement de maladies cérébrovasculaires, de l'artériosclérose ou de maladies cardio-vasculaires ; une formulation combinée pour la prévention ou le traitement de maladies cérébrovasculaires, de l'artériosclérose ou de maladies cardio-vasculaires, la formulation combinée comprenant (i) une composition comprenant un dérivé de verbénone ou son sel pharmaceutiquement acceptable, et (ii) une composition comprenant une étape d'un agent thérapeutique pour une reperfusion ; et une méthode de traitement de maladies cérébrovasculaires, de l'artériosclérose ou de maladies cardio-vasculaires, le procédé comprenant une étape consistant à administrer un dérivé de verbénone ou son sel pharmaceutiquement acceptable à un patient et une étape consistant à administrer un agent thérapeutique pour une reperfusion à un patient.
PCT/KR2016/001092 2015-01-30 2016-02-01 Formulation combinée comprenant un dérivé de verbénone et un agent thérapeutique pour une reperfusion pour la prévention ou le traitement de maladies cérébrovasculaires, de l'artériosclérose ou de maladies cardio-vasculaires Ceased WO2016122288A2 (fr)

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WO2023033517A1 (fr) * 2021-08-30 2023-03-09 신풍제약주식회사 Composition de traitement ou de prévention de l'obésité ou maladie hépatique associée à l'obésité, comprenant des dérivés de verbénone
CN116348445A (zh) * 2020-08-24 2023-06-27 阿布雷克萨制药公司 用于预防和治疗出血和脉管系统不稳定的化合物

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WO2025159459A1 (fr) * 2024-01-25 2025-07-31 재단법인대구경북과학기술원 Composition pharmaceutique pour la prévention ou le traitement de maladies cérébrales dégénératives, comprenant du prasugrel en tant que principe actif

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