WO2018062837A1 - Composé dérivé de la chalcone, isomère optique associé, ou sel pharmaceutiquement acceptable associé, et composition pharmaceutique comprenant ledit composé comme principe actif pour prévenir ou traiter une maladie provoquée par une diminution du taux de consommation d'oxygène par les mitochondries - Google Patents

Composé dérivé de la chalcone, isomère optique associé, ou sel pharmaceutiquement acceptable associé, et composition pharmaceutique comprenant ledit composé comme principe actif pour prévenir ou traiter une maladie provoquée par une diminution du taux de consommation d'oxygène par les mitochondries Download PDF

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WO2018062837A1
WO2018062837A1 PCT/KR2017/010701 KR2017010701W WO2018062837A1 WO 2018062837 A1 WO2018062837 A1 WO 2018062837A1 KR 2017010701 W KR2017010701 W KR 2017010701W WO 2018062837 A1 WO2018062837 A1 WO 2018062837A1
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compound
disease
oxygen consumption
consumption rate
pharmaceutical composition
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PCT/KR2017/010701
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English (en)
Korean (ko)
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허준영
김수정
이민정
권기량
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충남대학교산학협력단
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/227—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing halogen
    • C07C49/233—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings
    • C07C49/235—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings having unsaturation outside the aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/24—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing hydroxy groups
    • C07C49/245—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing hydroxy groups containing six-membered aromatic rings
    • C07C49/248—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing hydroxy groups containing six-membered aromatic rings having unsaturation outside the aromatic rings

Definitions

  • the present invention relates to a pharmaceutical composition for the prophylaxis or treatment of a disease caused by a reduction in oxygen consumption of mitochondria comprising a chalcone derivative compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof and an active ingredient thereof.
  • Mitochondria are one of the intracellular organelles that form the backbone of energy metabolism in cells and are surrounded by a nuclear membrane that is characteristic of eukaryotic cells. Mitochondria are also described as cell energy production plants because ATP, the most cellular energy required for cells, is produced. This ATP production process is also called cell breathing, mitochondria is activated as the respiration occurs actively.
  • Respiration refers to the action by which life breaks down nutrients and obtains the energy necessary for life.
  • the respiration of cells is a complex process that is broken down through various stages of oxidation in the cell, through glycolysis, the TCA circuit, and the electron transport system.
  • Respiration of mitochondria is an essential process for consuming oxygen and producing carbon dioxide through the electron transport chain (ETC), and about 85-90% of the total oxygen consumption is used for the oxidative phosphorylation required for the synthesis of ATP (Korzeniewski, B., Biochem Mol Biol Int., 39 (2), 415-419, 1996).
  • mitochondrial dysfunction can cause various diseases, and mitochondrial dysfunction changes oxygen consumption rate.
  • Alzheimer's disease As diseases related to mitochondrial dysfunction, Alzheimer's disease (Onyango, I. et al., J Alzheimers Dis., 9 (2), 183-193, 2006; Dumont, M. et al., J Alzheimers Dis., 20 (Suppl 2), S633-643, 2010), Parkinson's disease (Winklhofer, KF et al., Biochim Biophys Acta., 1802 (1), 29-44, 2010; Luo, Y. et al., Int J Mol Sci ., 16 (9), 20704-20730, 2015), chronic fatigue syndrome (Filler, K. et al., BBA Clin., 1, 12-23, 2014; Myhill, S. et al.
  • Neurodegenerative disease also known as neurodegenerative disease, is a disorder in which the brain or spinal cord causes abnormalities in the brain or spinal cord due to abnormal neuronal death, which decreases cognitive, gait, and motor skills.
  • Diseases Alzheimer's disease, stroke, etc. (Sagara, Y. et al., Free Radic Biol Med., 24 (9), 1375-1389, 1998; Jeong, GS et al., Biol Pharm Bull., 32 ( 5), 945-949, 2009; Parfenova, H. et al., Am J Physiol Cell Physiol., 290 (5), 1399-1410, 2006; Ha, JS et al., Neurosci Lett., 393, 165- 169, 2006).
  • Parkinson's disease a representative neurodegenerative disease, is a chronic progressive degenerative disease of the nervous system caused by sudden degeneration or a significant decrease in the number of cells that produce the neurotransmitter dopamine in the substantia nigra area of the midbrain. Is a representative refractory disease. Parkinson's disease reduces the balance of the neurotransmitter by reducing dopamine in neurotransmitters, resulting in tremor, rigidity, bradykinesia, and postural instability. symptoms such as postural instability.
  • Chronic renal failure is a disease in which the kidneys are damaged or renal function continues for more than three months. Even if the kidney function decreases by 35-50% of normal due to various causes, it does not cause any systemic symptoms. However, if the kidney function is bad enough that even the most basic functions such as waste excretion and electrolyte concentration control do not work properly, it leads to kidney failure. If renal failure progresses and reaches end stage renal failure, the diet or drug therapy alone can not be treated, so hemodialysis, peritoneal dialysis, or kidney transplants can be substituted for kidney function.
  • Hepatic encephalopathy is an unconscious or behavioral change in patients with liver dysfunction. If your consciousness changes frequently or changes day and night, starting with a slight change in your personality or behavior, it can range from deep coma to severely unresponsive pain. Hepatic encephalopathy develops in many cases, but when it does not recover early and in a deep coma, it may recover very slowly or not respond to treatment. It is important to find and treat appropriately when you begin to sleep poorly or do something different than usual. When hepatic encephalopathy is suspected, it is a key treatment method to take diarrhea or enemas to get rid of ammonia, and to take a lot of stool.Amino acid preparations or other medications can be used, and chronic hepatic encephalopathy is not well recovered. You can think of a liver transplant for its treatment.
  • liver diseases which usually causes inflammation of the liver, accounts for the majority of liver diseases.
  • acute hepatitis and chronic infection depending on the cause, viral hepatitis, alcoholic hepatitis, drug hepatitis, etc.
  • liver diseases caused by such abnormalities include fatty liver, hepatitis, cirrhosis, liver cancer, and the like.
  • the mechanism of the progression of liver disease is not fully understood, but it is thought to develop into advanced liver disease such as fatty liver disease and cirrhosis due to secondary cell damage after primary fatty liver development. If controllable, the development of more serious liver disease could be prevented.
  • exercise, alcoholism, diet and treatment are treated in parallel, but there are no treatment methods established to date and fundamentally complete healing is difficult.
  • It is an object of the present invention to provide a pharmaceutical composition for the prophylaxis or treatment of a disease caused by a reduction in the oxygen consumption rate of mitochondria comprising a chalcone derivative compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof and an active ingredient thereof.
  • the present invention provides a pharmaceutical for preventing or treating a disease caused by reducing oxygen consumption of mitochondria comprising a chalcone derivative compound represented by Formula 1 or Formula 2, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. It relates to a composition.
  • optical isomers include forms of R-form, S-form or racemic compounds, respectively.
  • Pharmaceutically acceptable salts of the chalcone derivative compounds of the present invention are preferably addition salts and citric acid formed by inorganic acids such as hydrochloride, sulfate, phosphate, hydrobromide, hydroiodide, nitrate, pyrosulfate, metaphosphate, etc.
  • Addition salts formed by organic acids such as salts, oxalates, benzoates, acetates, trifluoroacetates, propionates, succinates, fumarates, lactates, maleates, tartarates, glutarates, sulfonates, or Metal salts, such as lithium salts, sodium salts, potassium salts, magnesium salts, calcium salts, but are not limited thereto.
  • the disease caused by the reduced oxygen consumption rate of the mitochondria is selected from the group consisting of neurodegenerative diseases, attention deficit hyperactivity disorder, schizophrenia, drug addiction, chronic renal failure, hepatic encephalopathy and chronic liver disease.
  • the neurodegenerative disease is selected from the group consisting of Parkinson's disease, Alzheimer's disease, Lou Gehrig's disease, Pick disease, Huntington's disease, multiple sclerosis and dementia
  • the chronic liver disease is viral hepatitis, alcoholic hepatitis, drug hepatitis, Fatty liver, chronic hepatitis and cirrhosis.
  • the present invention provides ( E ) -1- (3-hydroxyphenyl) -3- (2- (trifluoromethyl) phenyl) prop-2-ene-1 represented by the following formula (3): -One (compound 1) and ( E ) -1- (4-hydroxyphenyl) -3- (3- (trifluoromethyl) phenyl) prop-2-en-1-one (compound 4)
  • the present invention relates to a chalcone derivative compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  • compositions according to the invention may be formulated in a suitable form with the pharmaceutically acceptable carriers generally used.
  • Pharmaceutically acceptable refers to a composition that is physiologically acceptable and does not cause an allergic or similar reaction, such as gastrointestinal disorders, dizziness, or the like, when administered to a human.
  • the compositions may be used in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral formulations, suppositories, and sterile injectable solutions, respectively, according to conventional methods.
  • Carriers, excipients and diluents that may be included in the composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl Cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl paraoxybenzoate, propyl paraoxybenzoate, talc, magnesium stearate and mineral oil, but are not limited thereto.
  • Solid form preparations for oral administration include tablets, pills, powders, granules, capsules and the like, and such solid form preparations include at least one excipient such as starch, microcrystalline cellulose, sucrose or lactose, It is prepared by mixing low-substituted hydroxypropyl cellulose, hypromellose and the like.
  • lubricants such as magnesium stearate and 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.
  • the non-aqueous solvent and the suspension solvent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used.
  • chalcone derivative compounds, optical isomers thereof, or pharmaceutically acceptable salts thereof are sterilized and / or preservatives, stabilizers, wetting or emulsifying accelerators, salts and / or buffers for the control of osmotic pressure for formulation into parenteral dosage forms.
  • adjuvant, and other therapeutically useful substances may be mixed into water to prepare a solution or suspension, which may be prepared in ampoules or in vial unit dosage forms.
  • the pharmaceutical composition comprising the chalcone derivative compound disclosed in the present invention as an active ingredient may be administered to mammals such as rats, livestock, humans, and the like by various routes. All modes of administration can be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or cerebrovascular injections. Dosage may include the age, sex, weight of the subject to be treated, the specific disease or pathology to be treated, the severity of the disease or pathology, the time of administration, the route of administration, the absorption, distribution and excretion of the drug, the type of drug used and the prescriber's It will vary depending on judgment.
  • Dosage determination based on these factors is within the level of skill in the art and generally dosages range from 0.01 mg / kg / day to approximately 2000 mg / kg / day. More preferred dosage is 1 mg / kg / day to 500 mg / kg / day. Administration may be administered once a day or may be divided several times. The dosage does not limit the scope of the invention in any aspect.
  • the present invention relates to a chalcone derivative compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for preventing or treating a disease caused by a reduced oxygen consumption rate of mitochondria including the same as an active ingredient.
  • a pharmaceutical composition for preventing or treating a disease caused by a reduced oxygen consumption rate of mitochondria including the same as an active ingredient.
  • the activity of increasing oxygen consumption in the mitochondria is excellent, and the oxygen consumption rate of mitochondria in neurodegenerative diseases, attention deficit hyperactivity disorder, schizophrenia, drug addiction, chronic renal failure, hepatic encephalopathy and chronic liver disease is reduced. It can be usefully used as a pharmaceutical composition for preventing or treating a disease caused.
  • FIG. 1 is a graph showing the measurement of oxygen consumption rate change (FIG. 1A and 1B) when Compound 4 of the present invention is treated with dopaminergic neurons in a short time.
  • FIG. 2 is a graph showing the change in oxygen consumption rate (FIGS. 2A and 2B) when Compound 4 of the present invention is treated with dopaminergic neurons for a long time.
  • FIG. 3 shows the relative dopaminergic neuron density when the compound 4 of the present invention is treated in a Parkinson's disease-induced mouse model.
  • FIG. 3A is a result of immunostaining dopaminergic neurons of the mouse model.
  • FIG. 3B Is a graph that quantifies this.
  • the compound 1-a or a-2 (1.0 equiv) was dissolved in ethanol, addition of LiOH and H 2 O (0.2 ⁇ 1.0 equivalent) and stirred at room temperature for 15 minutes. After 15 minutes, Compound 1-b, 2-b or 3-b (1.0-1.2 equivalents) was added thereto, stirred for 2 hours, and distilled water (100 mL) was added to terminate the reaction. Thereafter, the mixture was diluted with ethyl acetate (200 mL), washed with distilled water (200 mL ⁇ 2 times) and brine (200 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified using silica gel chromatography or recrystallization to obtain compounds 1 to 5 of the present invention.
  • the dopaminergic neuron line SN4741 was incubated at 33 ° C. and 5% CO 2 in d-MEM medium containing 10% FBS, 1% glucose, penicillin / streptomycin, and l-glutamine.
  • Example 3-2 Oxygen consumption rate measurement in short time treatment
  • oxygen consumption rate measurement by Seahorse's XF-analyzer is known.
  • a total of four ports (port A: target compound, port B: oligomycin A, an ATPase inhibitor, port C: carbonyl cyanide m-chlorophenyl hydrazone, uncoupler)
  • Port D Four different drugs were administered to rotenone, a mitochondrial complex 1 inhibitor, at different time intervals, and mitochondrial function was evaluated from the oxygen consumption rate change for each drug.
  • Example 3-1 a dopaminergic neuron cultured in Example 3-1, was dispensed at 20000 cells per well on an XF-plate. Then, after measuring the 3 rate (but one rate proceeds for 7 minutes) without drug treatment, the compound 1 to 5 of the present invention, the target compound is dissolved in DMSO and injected into the A port at a concentration of 5 ⁇ M, respectively, and 5 rate. was measured.
  • DMSO was used instead of the compound of the present invention as a control, and Comparative Compounds 1 to 5 were used as the comparative group.
  • oligomycin A in port B, CCCP in port C, and rotenone in the port D were measured sequentially, and then measured by 3 rates, respectively, to measure a change in oxygen consumption rate of a total of 17 rates.
  • the result of measuring the change in oxygen consumption rate was calculated by referring to the following formula and is shown in Table 2, in particular, the results for the compound 4 is shown in Figures 1A and 1B.
  • the compound 1 or 4 of the present invention having a hydroxy group substituent in the structure of the chalcone derivative compound has a higher effect of increasing the oxygen consumption rate than the comparative compound 1 or 2 having a methoxy group substituent, and also has a hydroxyl group substituent in the para or meta position.
  • Compounds 1 to 5 of the present invention were found to have an excellent effect of increasing the oxygen consumption rate compared to the comparative compounds 3 to 5 having a hydroxy group substituent in the ortho position, and it was found that there was a large difference in the oxygen consumption activity according to the substituents and positions of the chalcone derivatives.
  • Example 3-3 Oxygen consumption rate measurement at long time treatment
  • the compound 4 of the present invention was pretreated to SN4741, the dopaminergic neurons cultured in Example 3-1, at a concentration of 2.5 ⁇ M for 48 hours, and then placed on an XF-plate. Dispense at 20000 cells per well. Thereafter, after measuring 3 rates, oligomycin A in port A, CCCP in port B, and rotenone in C port were sequentially injected and measured by 3 rates (but one rate proceeded for 7 minutes). By measuring the change in oxygen consumption rate of a total of 12 rates, the oxygen consumption rate measurement results for the case of long-term treatment of the compound of the present invention is shown in Figures 2A and 2B.
  • the oxygen consumption rate was increased.
  • the compound of the present invention was treated for a long time rather than a short time. It was confirmed that a high maximum oxygen consumption rate change.
  • the brain was extracted through perfusion, and the extracted brain tissue was sectioned, and then the substantia nigra and striatum regions were labeled with tyrosine hydroxylase, a dopaminergic neuron marker.
  • Immunostaining with TH, tyrosine hydroxylase) antibody, the dopaminergic neuron density is shown in Figure 3 and Table 3.
  • the relative density of TH-positive cell fibers of Fig. 3B and Table 3 means that dopaminergic neuronal cell death increases as the value is lower.
  • the relative dopaminergic neuron density of the group induced Parkinson's disease by MPTP on the basis of the control group (normal group) showed a value of 0.25
  • MPTP and the compound 1 or 4 of the present invention Relative dopaminergic neuron density of the group treated with showed a value of 0.65, 0.66, confirming that the death of dopaminergic neurons more than two times.
  • the relative dopaminergic neuron density of the group treated with MPTP and Compound 5 of the present invention showed a value of 0.3 so that the potency values of dopaminergic neurons (in vitro) (see Table 2) were similar to those of Compound 1 or 4.
  • Parkinson's disease-induced animal model shows similar dopaminergic neuron killing effect as MPTP-induced Parkinson's disease-induced animal model. It was found that the use shows a better therapeutic effect.
  • Example 5-2 Long-term and tissue toxicity experiments in experimental and control groups
  • Compound 4 (( E ) -1- (4-hydroxyphenyl) -3- (3- (trifluoromethyl) phenyl) prop-2-en-1-one) 100 mg of the present invention, 100 microcrystalline cellulose Tablets were prepared by mixing mg, lactose monohydrate, 20 mg of low-substituted hydroxypropyl cellulose, and 2 mg of magnesium stearate, followed by compression according to a conventional method for preparing tablets.
  • Compound 4 (( E ) -1- (4-hydroxyphenyl) -3- (3- (trifluoromethyl) phenyl) prop-2-en-1-one) 100 mg of the present invention, 100 microcrystalline cellulose MG, lactose monohydrate 60mg, low-substituted hydroxypropyl cellulose 20mg and magnesium stearate 2mg were mixed, and the above ingredients were mixed and filled in gelatin capsules according to a conventional capsule preparation method to prepare a capsule.

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Abstract

La présente invention concerne un composé dérivé de la chalcone, un isomère optique associé, ou un sel pharmaceutiquement acceptable associé, et une composition pharmaceutique comprenant ledit composé comme principe actif pour prévenir ou traiter des maladies provoquées par la diminution du taux de consommation d'oxygène par les mitochondries. Une composition pharmaceutique, lorsqu'elle comprend le composé dérivé de la chalcone, exerce une excellente action d'augmentation du taux de consommation d'oxygène par les mitochondries et peut être utilement utilisée pour prévenir ou traiter des maladies provoquées par une diminution du taux de consommation d'oxygène par les mitochondries, telles que des maladies neurodégénératives, le trouble déficitaire de l'attention/hyperactivité, la schizophrénie, la toxicomanie, l'insuffisance rénale chronique, l'encéphalopathie hépatique, et la maladie hépatique chronique.
PCT/KR2017/010701 2016-09-27 2017-09-27 Composé dérivé de la chalcone, isomère optique associé, ou sel pharmaceutiquement acceptable associé, et composition pharmaceutique comprenant ledit composé comme principe actif pour prévenir ou traiter une maladie provoquée par une diminution du taux de consommation d'oxygène par les mitochondries WO2018062837A1 (fr)

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KR1020160123833A KR101855087B1 (ko) 2016-09-27 2016-09-27 칼콘 유도체 화합물, 이의 광학이성질체, 또는 이의 약학적으로 허용 가능한 염, 및 이를 유효성분으로 포함하는 미토콘드리아의 산소 소모율 감소에 의해 야기되는 질환의 예방 또는 치료용 약학 조성물
KR10-2016-0123833 2016-09-27

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Cited By (1)

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CN110028421A (zh) * 2018-12-11 2019-07-19 兰州市肺科医院 一种查耳酮类化合物及制备方法与用途

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Publication number Priority date Publication date Assignee Title
CN110028421A (zh) * 2018-12-11 2019-07-19 兰州市肺科医院 一种查耳酮类化合物及制备方法与用途

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