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WO2018111050A1 - Composition pharmaceutique comprenant un composé à base de phénanthrène-lactame comme ingrédient efficace destiné à la prévention ou au traitement de la maladie liée à dyrk - Google Patents

Composition pharmaceutique comprenant un composé à base de phénanthrène-lactame comme ingrédient efficace destiné à la prévention ou au traitement de la maladie liée à dyrk Download PDF

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Publication number
WO2018111050A1
WO2018111050A1 PCT/KR2017/014894 KR2017014894W WO2018111050A1 WO 2018111050 A1 WO2018111050 A1 WO 2018111050A1 KR 2017014894 W KR2017014894 W KR 2017014894W WO 2018111050 A1 WO2018111050 A1 WO 2018111050A1
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WIPO (PCT)
Prior art keywords
cancer
alkyl
alkoxy
disease
heterocycloalkyl
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Ceased
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PCT/KR2017/014894
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English (en)
Korean (ko)
Inventor
조성찬
최미리
이주연
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Korea Research Institute of Chemical Technology KRICT
Korea Research Institute of Bioscience and Biotechnology KRIBB
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Korea Research Institute of Chemical Technology KRICT
Korea Research Institute of Bioscience and Biotechnology KRIBB
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Priority claimed from KR1020170172213A external-priority patent/KR102419029B1/ko
Application filed by Korea Research Institute of Chemical Technology KRICT, Korea Research Institute of Bioscience and Biotechnology KRIBB filed Critical Korea Research Institute of Chemical Technology KRICT
Publication of WO2018111050A1 publication Critical patent/WO2018111050A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole

Definitions

  • the present invention relates to a pharmaceutical composition for preventing or treating DYRK-related diseases containing a phenanthran-lactam compound as an active ingredient.
  • Alzheimer's disease is accompanied by two types of neuropathology: amyloid plaque, the formation of intracellular neurofibrillary tangles composed of aggregates of hyperphosphorylated tau, and cellular accumulation of insoluble precipitates of amyloid ⁇ peptides.
  • DYRK1A is known to be associated with the development of Alzheimer's disease by directly phosphorylating Tau, amyloid ⁇ precursor protein (APP), and Presenilin 1 (PS1), which are key proteins for the formation of neuropathology.
  • DYRK1A plays an important role in other degenerative brain diseases.
  • the present inventors attempted to develop a drug targeting DYRK1A while studying a strategy for simultaneously controlling senile plaques and neurofibrillary tangles, and the phenanthran-lactam compound according to the present invention was previously known as a DYRK1A inhibitor. Structurally different from the above, it was confirmed that the inhibitory effect is superior, and the selectivity for DYRK is excellent and completed the present invention.
  • the present invention provides a pharmaceutical composition for the prevention or treatment of DYRK-related diseases comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are as defined herein).
  • Figure 1 is a schematic diagram showing a virtual screening (virtual screening) process for the discovery of DYRK1A inhibitor according to the present invention.
  • Figure 4 is a graph of the expression of NFAT signaling reporter confirming the concentration-dependent DYRK1A inhibitory effect of the compound represented by Formula 2,
  • Compound 1 represents a compound represented by the formula (2).
  • FIG. 5A is a photograph showing the Tau phosphorylation inhibitory effect of the compound represented by Formula 2 at the mammalian cell level
  • FIG. 5B is a graph showing the Tau phosphorylation inhibitory effect of the compound represented by Formula 2 at the mammalian cell level.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen, halogen, hydroxy, C 1 -C 5 alkyl or C 1 -C 5 may be alkoxy
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen, halogen, hydroxy, C 1 -C 3 alkyl or It may be C 1 -C 3 alkoxy, more specifically the R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 may be each independently C 1 -C 3 alkoxy. .
  • R 9 is hydrogen, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, perfluoro, hydroxy, halogen, C 1 -C 5 alkylamino, C 1 -C 5 dialkylamino, C 1 -C 5 acyloxy, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl, C 1 -C 5 alkyl substituted by an C 3 -C 8 heterocycloalkyl, C 3 -C 8 heterocycloalkyl alkylcarbonyl, C 3 -C 8 heterocycloalkyl C 1 -C 5 alkoxycarbonyl, C 3 -C 8 heteroaryl, aryl, and substituted with one or more substituents selected from the group consisting of Cy Iowa reel or unsubstituted C 1 -C 5 alkyl, C 1 -C 5 alkenyl, C 1 -C 5 alkynyl, C 1 -C 5 acyl,
  • Compound represented by Chemical Formula 1 may be a compound represented by the following Chemical Formula 2.
  • the compound represented by Formula 1 of the present invention has an effect of inhibiting the activity of DYRK.
  • the compound represented by Formula 1 strongly and selectively inhibits DYRK1A, and inhibits phosphorylation of Tau protein, which is a representative substrate protein of DYRK1A and a key factor in neurofibrillary tangle formation.
  • Molecular modeling confirmed that it inhibits ATP in a competitive manner. From the above results, it can be seen that the compound represented by the formula (1) of the present invention can be used as an active ingredient of the pharmaceutical composition for the prevention or treatment of DYRK-related diseases.
  • the present invention provides a pharmaceutical composition for the prevention or treatment of DYRK-related diseases comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • prevention refers to reducing the risk of developing a disease or disorder, that is, at least one clinical symptom of the disease is present in a subject that is susceptible to or at risk of disease but does not yet develop or exhibits symptoms of the disease. Indicates not to proceed.
  • treatment refers to alleviating the disease or disorder, ie to arrest or reduce the progression of the disease or one or more clinical symptoms thereof.
  • the DYRK-related disease refers to a disease caused by overexpression and overactivation of DYRK, and may be, for example, Down syndrome, degenerative brain disease, cancer disease, metabolic disease, and the like.
  • the degenerative brain disease is one or more diseases selected from the group consisting of Pick disease, vascular dementia, Alzheimer's, Parkinson's disease, Lewy body dementia, prefrontal lobe dementia, Creutzfeldt-Jakob disease, Huntington's disease- chorea, multiple sclerosis, Guillain-Barré syndrome It can be characterized.
  • Small bowel cancer endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penis cancer, prostate cancer, chronic or acute leukemia, lymphocyte lymphoma, bladder cancer, kidney or ureter cancer, renal cell cancer, renal cancer, central nervous system (CNS) tumor, primary CNS lymphoma, spinal cord tumor, brain stem glioma, and pituitary adenoma.
  • CNS central nervous system
  • the metabolic disease may be selected from the group consisting of obesity, diabetes, hypertension, hyperlipidemia, hypercholesterolemia, arteriosclerosis, fatty liver, heart disease, diabetes, myocardial infarction, angina.
  • the compound represented by Formula 1 of the present invention effectively inhibits DYRK1A, thereby forming nerve fiber entanglement, senile plaque, lewy body formation by phosphorylation regulation of Tau, APP, PS1, ⁇ -synuclein, HIP1, etc. It has been shown that it can be used to control and eventually prevent or treat DYRK related diseases such as Alzheimer's and several degenerative brain diseases.
  • salts refer to salts of compounds of the invention that are pharmaceutically acceptable and that have the desired pharmacological activity of the parent compound.
  • Such salts may be prepared by conventional methods in the art, for example salts with inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, nitric acid, carbonic acid, formic acid, acetic acid, propionic acid, Salts with organic acids such as oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gestyic acid, fumaric acid, lactobionic acid, salicylic acid, or acetylsalicylic acid (aspirin), Salts with amino acids such as glycine, alanine, vanillin, isoleucine, serine, cysteine, cystine, aspartic acid, glutamine, lysine, arg
  • the pharmaceutical composition according to the present invention may be formulated by adding a non-toxic and pharmaceutically acceptable carrier, adjuvant and excipient, etc. according to conventional methods, for example oral such as tablets, capsules, troches, solutions, suspensions, etc. It may be prepared as a preparation for administration or as a preparation for parenteral administration.
  • lactose for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth rubber, al A carboxylic acid, sodium alginate, methyl cellulose, sodium carboxymethyl cellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor and the like.
  • compositions of the present invention may be used in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral dosage forms, external preparations, suppositories, or sterile injectable solutions according to conventional methods. .
  • compositions comprising a compound of the present invention may further comprise a suitable carrier, excipient or diluent according to conventional methods. Specifically, when formulated, it may be formulated using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants and the like that are commonly used.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations may contain at least one excipient such as starch, calcium carbonate, sucrose, lactose, gelatin, or the like. Can be prepared by mixing. In addition to simple excipients, lubricants such as magnesium stearate, talc can also be used.
  • Oral liquid preparations include suspensions, solvents, emulsions, and syrups.In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. have.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations and suppositories.
  • non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate and the like can be used.
  • utopsol macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
  • the pharmaceutical composition of the present invention can be administered to mammals such as mice, mice, livestock, humans, etc. by various routes. All modes of administration may be administered by, for example, skin, oral, rectal, intravenous, abdominal, muscle, subcutaneous, intrauterine dural or intracerebroventricular injection, preferably either oral or intravenous It may be administered by the route of, but is not limited thereto.
  • the administration may contain one or more active ingredients exhibiting the same or similar function. It may further comprise one or more pharmaceutically acceptable carriers for administration.
  • Pharmaceutically acceptable carriers may be used in combination with saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol and one or more of these components, as necessary, including antioxidants, buffers, Other conventional additives such as bacteriostatic agents can be added.
  • the amount of the compound at the time of administration varies depending on the weight, age, sex, health condition, diet, time of administration, method of administration, excretion rate and severity of the disease.
  • the daily dosage of the compound of the present invention is 0.0001 to 100 mg / kg, preferably, the amount of 0.001 to 30 mg / kg may be administered once to several times a day. In addition, the administration period may be 1 day to 2 months, but may be administered without limitation until the prophylactic or therapeutic effect of the disease is exhibited.
  • the present invention provides a health functional food composition for preventing or ameliorating DYRK-related diseases comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the health functional food composition according to the present invention comprises a compound of Formula 1 or a pharmaceutically acceptable salt thereof for the purpose of preventing or ameliorating DYRK related diseases such as Down syndrome, degenerative brain disease, cancer disease, metabolic disease, etc.
  • the health functional food composition according to the present invention may be added to the compound of formula 1 or a pharmaceutically acceptable salt thereof for the purpose of preventing or improving DYRK-related diseases.
  • Examples of foods to which the above-mentioned substances may be added include dairy products, various soups, drinks, meat, sausages, breads, biscuits, rice cakes, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, ice cream, Beverages, alcoholic beverages and vitamin complexes, dairy products, dairy products and the like, and includes all the health functional foods in the conventional sense.
  • the compound of formula 1 of the present invention may be added to a food as it is or used with other food or food ingredients, and may be appropriately used according to a conventional method.
  • the mixing amount of the active ingredient can be suitably determined according to the purpose of use (prevention or improvement).
  • the amount of the compound in the health food can be added at 0.1 to 90 parts by weight of the total food weight.
  • the amount may be below the above range, and the active ingredient may be used in an amount above the above range because there is no problem in terms of safety. .
  • the health functional beverage composition of the present invention is not particularly limited to other ingredients except for containing the compound as an essential ingredient in the indicated ratios, and may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks.
  • natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • natural flavoring agents such as, tauumatin, stevia extract (e.g., Rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used.
  • the proportion of natural carbohydrates is generally from about 1 g to 20 g, preferably from about 5 g to 12 g per 100 g of the composition of the present invention.
  • the compound of formula 1 of the present invention may be used in various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors such as flavoring agents, coloring and neutralizing agents (such as cheese, chocolate), pectic acid and salts thereof, Alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks and the like.
  • the quinoline 4-one derivative of the present invention may contain fruit flesh for the production of natural fruit juices and fruit juice beverages and vegetable beverages. These components can be used independently or in combination. The proportion of such additives is not so critical but it is generally chosen that the quinoline 4-one derivative of the present invention is in the range of 0.1 to about 20 parts by weight per 100 parts by weight.
  • DYRK1A was selected using protein structure-based method (Structure-Based Virtual Screening, SBVS), and utilized 340,000 compound libraries owned by Korea Compound Bank.
  • the protein used to consider the spatial variation of the binding site, the conformational difference and the diversity of the inhibitor structure through the tertiary structure analysis of the protein is PDB code 4MQ1 (2.35).
  • c] quinoline carboxylic acid derivative is bound.
  • hydrogen bonding in the hinge region is expected to be an important functional pharmacophore. Therefore, in virtual search, two conditions are applied to each of the two selected protein structures. A total of 40,000 compound libraries were searched four times.
  • NFAT signaling reporter a well-established cell-based DYRK1A efficacy evaluation system, for 570 compounds derived as DYRK1A inhibition candidates through virtual screening (FIG. 3).
  • the NFAT signaling reporter is highly dependent on DYRK1A, and thus is effective in deriving DYRK1A inhibitor candidates.
  • DYRK1A is known to regulate calcineurin / nuclear factor of activated T cells (NFAT) signaling and play an important role in human developmental stages.
  • NFATc1 transcription factor is a protein that is usually phosphorylated in the cytoplasm. When the Ca 2+ concentration of the cell increases, NFATc1 is dephosphorylated by Ca 2+ dependent protein phosphatase calcineurin and NFATc1 is transferred into the nucleus. .
  • NFATc1 which enters the nucleus, forms a transcription complex with partner protein NFATn and binds to a promoter of the target gene to induce target gene expression.
  • DYRK1A phosphorylates NFATc1 to inhibit the migration of NFATc1 to the nucleus, resulting in suppression of target gene expression.
  • the compound is a phenanthran lactam compound and has a tetracycle structure.
  • the activity of luciferase gradually increased when treated with the concentration gradient under the same conditions (FIG. 4).
  • the luciferase increase effect of the compound represented by the formula (2) shows an EC 50 that is about 10 times lower than the previously reported DYRK1A inhibitor, harmine, CX-4945, which is more effective than these. It was confirmed (Fig. 4).
  • DYRK1A a representative substrate protein of DYRK1A and a major factor in the onset of Alzheimer's and Down syndrome.
  • Tau is a microtubule-associated protein.
  • DYRK1A phosphorylates Thr212 of Tau protein, and this phosphorylation has been clearly observed in hippocampal tissue of Down syndrome syndrome mice overexpressed DYRK1A.
  • Phosphorylation which did not appear when overexpressing only Tau protein in mammalian cells 293T, was clearly seen when DYRK1A was overexpressed. It was confirmed that the decrease (Fig. 5).
  • DYRK1A In order to confirm whether the compound represented by Formula 2 directly inhibits DYRK1A, an in vitro kinase assay using purely purified DYRK1A protein was performed, as well as DYRK family kinase such as DYRK1B, DYRK3, and DYRK4. As well as the representative CMGC kinase including the selective efficacy of DYRK1A was confirmed.
  • Compound represented by the formula (2) showed a strong inhibitory effect on DYRK1A, about 95% of inhibitory effect at a concentration of 100 nM, IC 50 less than about 10 nM is expected to be a strong inhibitory effect (Fig. 6).
  • the compound represented by Formula 2 showed high inhibitory effects on DYRK1B and DYRK3 in addition to DYRK1A, and showed a relatively 10-fold lower inhibitory effect on other similar CMGC kinases.
  • the compound represented by the formula (2) structurally fits to the ATP binding site of DYRK1A, and in particular, the nitrogen and carbonyl groups of the tetracycle ring (heterocycle ring) and DYRK1A
  • the three hydrogen bonds formed between Leu241, Glu239 and Lys188 are found to play an important role.

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  • Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne une composition pharmaceutique comprenant un composé à base de phénanthrène-lactame comme ingrédient efficace pour prévenir ou traiter une maladie liée à DYRK. Le composé à base de phénanthrène-lactame de la présente invention, qui est utilisé comme ingrédient efficace de la composition pharmaceutique, inhibe l'activité de DYRK à une efficacité et sélectivité très élevées et ainsi peut être efficacement utilisé dans la prévention ou le traitement des maladies liées à DYRK telles que le syndrome de Down, les maladies de neurodégénérescence, les cancers, les maladies métaboliques, etc.
PCT/KR2017/014894 2016-12-15 2017-12-15 Composition pharmaceutique comprenant un composé à base de phénanthrène-lactame comme ingrédient efficace destiné à la prévention ou au traitement de la maladie liée à dyrk Ceased WO2018111050A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR10-2016-0171492 2016-12-15
KR20160171492 2016-12-15
KR1020170172213A KR102419029B1 (ko) 2016-12-15 2017-12-14 페난트란-락탐계 화합물을 유효성분으로 함유하는 dyrk 관련 질환의 예방 또는 치료용 약학적 조성물
KR10-2017-0172213 2017-12-14

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WO2018111050A1 true WO2018111050A1 (fr) 2018-06-21

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4782077A (en) * 1987-08-20 1988-11-01 Monoclonetics International, Inc. Taliscanin and other aristolactams for treating neurological disorders, Parkinson's disease, Alzheimer disease and impotence
US20030045564A1 (en) * 2000-10-19 2003-03-06 Young-Joong Kim Saururus chinensis extract for prevention and treatment of neurodegenerative disease
KR20090039038A (ko) * 2007-10-17 2009-04-22 한국화학연구원 항암 활성을 갖는 페난트렌 락탐 유도체, 이의 제조방법 및이를 포함하는 약학 조성물
CN102247357A (zh) * 2011-05-19 2011-11-23 中国人民解放军第二军医大学 紫玉盘内酰胺和马兜铃内酰胺bi在制备抗癌药物中的应用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4782077A (en) * 1987-08-20 1988-11-01 Monoclonetics International, Inc. Taliscanin and other aristolactams for treating neurological disorders, Parkinson's disease, Alzheimer disease and impotence
US20030045564A1 (en) * 2000-10-19 2003-03-06 Young-Joong Kim Saururus chinensis extract for prevention and treatment of neurodegenerative disease
KR20090039038A (ko) * 2007-10-17 2009-04-22 한국화학연구원 항암 활성을 갖는 페난트렌 락탐 유도체, 이의 제조방법 및이를 포함하는 약학 조성물
CN102247357A (zh) * 2011-05-19 2011-11-23 中国人民解放军第二军医大学 紫玉盘内酰胺和马兜铃内酰胺bi在制备抗癌药物中的应用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
COUTURE, A. ET AL.: "Synthesis and Biological Evaluation of Aristolactams", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 12, 2002, pages 3557 - 3559, XP055510502 *
KUMAR, V. ET AL.: "Naturally Occurring Aristolactams, Aristolochic Acids and Dioxoaporphines and Their Biological Activities", NATURAL PRODUCT REPORTS, vol. 20, no. 6, 2003, pages 565 - 583, XP055510506 *

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