WO2021112620A1 - Composition pharmaceutique pour la prévention ou le traitement de la sarcopénie ou de l'atrophie musculaire - Google Patents

Composition pharmaceutique pour la prévention ou le traitement de la sarcopénie ou de l'atrophie musculaire Download PDF

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WO2021112620A1
WO2021112620A1 PCT/KR2020/017642 KR2020017642W WO2021112620A1 WO 2021112620 A1 WO2021112620 A1 WO 2021112620A1 KR 2020017642 W KR2020017642 W KR 2020017642W WO 2021112620 A1 WO2021112620 A1 WO 2021112620A1
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compound
hydrogen
pharmaceutical composition
alkyl
sarcopenia
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PCT/KR2020/017642
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Korean (ko)
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WO2021112620A9 (fr
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김용철
윌리엄스다런
정다운
이제헌
이지형
김현준
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광주과학기술원
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Publication of WO2021112620A9 publication Critical patent/WO2021112620A9/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system

Definitions

  • the present invention relates to a pharmaceutical composition for preventing or treating sarcopenia or muscular atrophy comprising an indirubin derivative as an active ingredient, and a method for treating sarcopenia or muscular atrophy using the same.
  • Skeletal muscle accounts for more than 30% of body mass. This tissue plays a pivotal role in motor and metabolic homeostasis such as glucose consumption. Skeletal muscle wasting (muscle atrophy) can be caused by a number of factors, including immobility and aging (sarcopenia). Sarcopenia, a geriatric disease, is on the rise due to the proportional increase in the elderly (over 60 years old), which is expected to account for 29% of the population in 2050. A person's physical decline begins in their 30s and accelerates when they reach their 50s. Thus, the percentage of skeletal muscle mass continues to decrease and falls below 25% at the age of 75-80 years.
  • E3 ubiquitin ligase Muscle-specific E3 ubiquitin ligase (E3 ubiquitin ligase), atrogin-1 (atrogin-1) mediates protein ubiquitination and is a marker of protein synthesis. Overexpression of atrogine-1 reduces the diameter of myotubes, and knockout of denovation opposite to atrogine-1 induces myotubes. It is presented as a signal of a potential therapeutic among anti-sarcopenia drug candidates.
  • small molecule drug therapies to prevent the progression of sarcopenia. This small molecule approach has advantages in drug development compared to protein or oligonucleotide therapy, such as ease of administration, structural manipulation, dose optimization and cost-effectiveness.
  • the present application describes the development of an indirubin-based small molecule to treat muscle loss associated with sarcopenia by reducing the expression of atrozin-1 in atrophic muscle fibers.
  • the present inventors made intensive research efforts to derive novel compounds having therapeutic efficacy for sarcopenia or muscular atrophy. As a result, it was found that certain indirubin derivative compounds can effectively inhibit muscle loss by reducing the expression of atrozin-1, increasing the diameter of the root canal, and preventing the effect of atrophy of the root canal.
  • the present invention has been completed.
  • Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of sarcopenia or muscular atrophy.
  • Another object of the present invention is to provide a method for preventing or treating sarcopenia or muscular atrophy using the composition.
  • the present invention relates to a treatment for sarcopenia or muscular atrophy, which is a novel use of an indirubin derivative, and the pharmaceutical composition provided in the present invention increases the diameter of the root canal, suppresses atrophy of the root canal, maintains the ratio of the root canal by diameter, and destroys the muscle protein. It can be usefully used for effective prevention or treatment of sarcopenia or muscular atrophy through suppression of the expression of atrozin-1 gene.
  • 1 relates to the effect of compounds 1 and 3 in a model of muscular atrophy induced by dexamethasone.
  • 1A is a representative image of a mitotracker of a stained root canal. Scale bar represents 100 ⁇ m (7C: compound 1, 13C: compound 3).
  • Figure 1b is a quantitative result of the average root canal diameter (7C: Compound 1, 13C: Compound 3).
  • Figure 1c shows the number of root canals according to the tube diameter (7C: Compound 1, 13C: Compound 3).
  • Figure 2 is a real-time qPCR-based mRNA expression analysis results of muscle E3 ligase atrogin-1 (E3 ligase atrogin-1) according to the treatment of compound 1 to confirm the molecular marker of muscle atrophy.
  • the present invention provides a compound represented by the following formula (1), a pharmaceutically acceptable salt, solvate or hydrate thereof:
  • R 1 is hydrogen, halogen, or halogen-substituted or unsubstituted C 1 -C 4 alkoxy;
  • n is a natural number of 2 or more and 4 or less
  • R 3 is hydrogen or halogen
  • X is CH or N
  • L is a single bond or NH
  • R 5 and R 6 are each independently hydrogen; C 1 -C 4 alkyl; Or unsubstituted or C 1 -C 4 alkyl substituted piperidinyl (piperidinyl) or piperazinyl (piperazinyl),
  • R 8 is hydrogen or C 1 -C 6 alkyl, hydroxyalkyl, alkylaminoalkyl, or aminoalkyl,
  • R 9 is C 1 -C 6 alkyl, hydroxyalkyl, alkylaminoalkyl, or aminoalkyl.
  • R 2 of Formula 1 may be a compound selected from the group consisting of the following compounds, a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • the compound represented by Formula 1 of the present invention may be any one selected from the group consisting of the following compounds:
  • the present invention provides a pharmaceutical composition for preventing or treating sarcopenia or muscular atrophy comprising (a) a compound represented by the following formula (1), a pharmaceutically acceptable salt, solvate or hydrate thereof provides:
  • R 1 is hydrogen, halogen, or halogen-substituted or unsubstituted C 1 -C 4 alkoxy;
  • n is a natural number of 2 or more and 4 or less
  • R 3 is hydrogen or halogen
  • X is CH or N
  • L is a single bond or NH
  • R 5 and R 6 are each independently hydrogen; C 1 -C 4 alkyl; Or unsubstituted or C 1 -C 4 alkyl substituted piperidinyl (piperidinyl) or piperazinyl (piperazinyl),
  • R 8 is hydrogen or C 1 -C 6 alkyl, hydroxyalkyl, alkylaminoalkyl, or aminoalkyl,
  • R 9 is C 1 -C 6 alkyl, hydroxyalkyl, alkylaminoalkyl, or aminoalkyl.
  • R 2 of Formula 1 may be a pharmaceutical composition, characterized in that it is selected from the group consisting of the following compounds:
  • the compound may be any one selected from the group consisting of the following compounds:
  • sarcopenia refers to a gradual weakening of muscle density and function, and the cause is known to cause progressive degeneration and destruction of motor neurons or muscle cells in the spinal nerve or diencephalon. In particular, muscle loss due to aging is called age-related sarcopenia.
  • muscle atrophy refers to a generic name for a disease in which the muscles of the extremities are gradually atrophied in an almost symmetrical manner, and when cancer, aging, kidney disease, hereditary disease, and various chronic diseases are induced It may be accompanied by amyotrophic lateral sclerosis (Lou Gehrig's disease), and is represented by progressive progressive muscular atrophy of the spinal cord.
  • the effect of inhibiting the expression of atrozin-1 gene for increasing the diameter of the pharmaceutical composition, suppressing root canal atrophy, maintaining the ratio of root canals by diameter, and destroying muscle proteins was confirmed. It was confirmed that it can be used as a therapeutic agent for sarcopenia or muscular atrophy.
  • treatment refers to any action of inhibiting or delaying sarcopenia or muscular atrophy by administering a pharmaceutical composition comprising the compound of Formula 1 and a pharmaceutically acceptable salt, solvate or hydrate thereof. .
  • prevention refers to any action in which the symptoms of sarcopenia or muscular atrophy are improved or beneficially changed by administration of a pharmaceutical composition comprising the compound of Formula 1 and a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • the pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier in addition to the active ingredient.
  • Pharmaceutically acceptable carriers included in the pharmaceutical composition of the present invention are commonly used in formulation, and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, and the like.
  • the pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like, in addition to the above components.
  • a lubricant e.g., a talc, a kaolin, a kaolin, a kaolin, a kaolin, kaolin, kaolin, kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, a talct, a talct, a talct, a talct, a sorbitol, mannitol, mannitol
  • a suitable dosage of the pharmaceutical composition of the present invention is variously prescribed depending on factors such as formulation method, administration method, age, weight, sex, pathological condition, food, administration time, administration route, excretion rate, and reaction sensitivity of the patient.
  • the dosage of the pharmaceutical composition of the present invention is preferably 1-1000 mg/kg (body weight) per day.
  • the pharmaceutical composition of the present invention may be administered orally or parenterally, and when administered parenterally, it may be administered by topical application to the skin, intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, etc. .
  • the administration is preferably made by intravenous or oral administration.
  • the pharmaceutical composition of the present invention is prepared in unit dosage form by formulating using a pharmaceutically acceptable carrier and/or excipient according to a method that can be easily carried out by a person of ordinary skill in the art to which the present invention pertains. Or it can be prepared by introducing into a multi-dose container.
  • the formulation may be in the form of a solution, suspension, or emulsion in oil or an aqueous medium, or may be in the form of an extract, powder, granule, tablet or capsule, and may additionally include a dispersant or stabilizer.
  • the pharmaceutical composition of the present invention can be administered orally, and solid preparations for oral administration include tablets, pills, powders, granules, capsules, troches, etc., and these solid preparations contain at least one compound of the present invention. It is prepared by mixing one or more excipients, for example, starch, calcium carbonate, sucrose or lactose or gelatin. In addition to simple excipients, lubricants such as magnesium stearate talc are also used.
  • Liquid preparations for oral administration include suspensions, oral solutions, emulsions, or 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. can
  • Formulations for oral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like.
  • Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
  • injectable esters such as ethyl oleate.
  • As the base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, gelatin, etc. may be used.
  • the pharmaceutical composition of the present invention is a composition for preventing or treating sarcopenia or muscular atrophy, it may be preferably administered parenterally, for example, intravenous administration, intraperitoneal administration, intramuscular administration, subcutaneous administration, or local administration. can be administered using
  • the indirubin derivative of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid may be used.
  • Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes.
  • non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids, and organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid and fumaric acid.
  • Such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, ioda.
  • the acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the indirubin derivative of Formula 1 in an organic solvent, for example, methanol, ethanol, acetone, methylene chloride, acetonitrile, or the like, and adding an organic or inorganic acid to the precipitate. It can be prepared by filtration and drying, or by drying or crystallization in an organic solvent after distilling the solvent and excess acid under reduced pressure.
  • an organic solvent for example, methanol, ethanol, acetone, methylene chloride, acetonitrile, or the like.
  • a pharmaceutically acceptable metal salt may be prepared using a base.
  • the alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate.
  • it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt.
  • the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg, silver nitrate).
  • the present invention includes all possible solvates, hydrates, stereoisomers, etc. that can be prepared therefrom, as well as indirubin derivatives represented by Formula 1 and pharmaceutically acceptable salts thereof.
  • the present invention provides a method of treating sarcopenia or muscular atrophy comprising administering the pharmaceutical composition to an individual having sarcopenia or muscular atrophy in a pharmaceutically effective amount or an individual at risk of developing sarcopenia or muscular atrophy do.
  • the term "individual” may include, without limitation, mammals, farmed fish, and the like, including mice, livestock, humans, etc. that are likely to or have developed sarcopenia or muscular atrophy.
  • the administration route of the pharmaceutical composition for the treatment of muscular atrophy or sarcopenia of the present invention may be administered through any general route as long as it can reach the target tissue.
  • the pharmaceutical composition of the present invention is not particularly limited thereto, but depending on the intended route, such as intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, intranasal administration, intrapulmonary administration, rectal administration, etc. can be administered through
  • the pharmaceutical composition containing the compound of Formula 1 may be denatured by gastric acid during oral administration, the oral composition should be formulated to coat the active agent or to protect it from degradation in the stomach.
  • the composition may be administered by any device capable of transporting the active agent to a target cell.
  • the present invention provides the use of the pharmaceutical composition in the manufacture of a medicament for the prevention or treatment of muscular atrophy or sarcopenia.
  • Methyl 3-bromopropionate was dissolved in DMF, and indirubin-3'-oxime 3a-d was added and stirred for 5 minutes. Next, TEA (2eq) was added and stirred at 80°C for 1 hour. The mixture was then cooled and neutralized with aqueous NH 4 Cl solution. The neutralized product was extracted using EA and concentrated by rotary evaporation. This extract was purified by column chromatography to obtain products 4a-d.
  • the obtained product 5a-d was dissolved in DMF, and EDC (1.5eq) and 4-Amino-1-Boc-piperidine (3eq) were added and stirred for 5 minutes. Next, TEA (2eq) was added and stirred at O/N at 60°C. The mixture was then cooled and neutralized with aqueous NH 4 Cl solution. The neutralized product was extracted using EA and concentrated by rotary evaporation. The obtained product was dissolved in DCM and TFA was added and stirred for 2 hours. Then, the mixture was neutralized with 1N aqueous NaOH solution, extracted using EA, and concentrated by rotary evaporation. This extract was purified by column chromatography to obtain products 8a-d.
  • the obtained product 11 was added to Indirubin-3'-oxime 3a-d dissolved in DMF and stirred for 5 minutes. Next, K 2 CO 3 (5eq) was added and stirred at O/N at 60°C. The mixture was then cooled and neutralized with aqueous NH 4 Cl solution. The neutralized product was extracted using EA and concentrated by rotary evaporation. The resulting mixture was dissolved in DCM and TFA was added and stirred for 2 hours. Then, the mixture was neutralized with 1N aqueous NaOH solution, extracted using EA, and concentrated by rotary evaporation. This extract was purified by column chromatography to obtain products 12a-d.
  • the obtained indirubin derivative 12a-d was dissolved in THF, 4N HCl in dioxane (6-18 eq) was added at 0° C., and stirred at room temperature for 2 hours. After confirming that the reaction was complete, the precipitate was washed several times with DCM through filtration and dried to obtain a clean solid.
  • the product 13a-d in the form of a salt was obtained from an indirubin derivative.
  • C2C12 mouse myoblasts were cultured in DMEM, 10% FBS and 1% penicillin streptomycin (GM), and differentiation was induced with DMEM, 2% horse serum and 1% penicillin streptomycin (DM). To make myotubes, differentiation medium was treated for 72 hours and further treatment was performed after the differentiation procedure.
  • DMEM penicillin streptomycin
  • C2C12 mouse myoblasts were seeded in 96-well plates and stabilized for 24 hours.
  • CMXRos (Invitrogen, M7512) and DAPI (Sigma, D9542) were added to myotubes treated with dexamethasone and chemicals at final concentrations of 50 nM and 1 ⁇ M, respectively. Cells were incubated for 30 min and then visualized by fluorescence microscopy (Leica DMI 3000B; Leica).
  • the myosin heavy chain was stained with a specific antibody (Santa cruz SC-53095). 30x10 4 C2C12 cells were seeded in 12 well plates and differentiated for 72 hours after stabilization for 24 hours. Differentiated myotubes were treated with individual drugs for 24 hours and fixed with 4% formaldehyde solution. Cells were permeabilized and blocked with 0.5% Triton-X and 1% BSA solutions, respectively. Myosin heavy chain antibody was exposed to O/N in a 1:50 ratio and conjugated with Alexa 488 (Thermo, A11001) for 1 h. The stained myotubes were confirmed with a fluorescence microscope (Leica DMI 3000B; Leica).
  • RNA from C2C12 myotubes was extracted using TRI solution (BIO Science Technology) according to the manufacturer's protocol.
  • the extracted RNA was quantified with Nanodrop One (Thermo) and reacted with RT-PCR premix (BIONEER, K-2044) to make cDNA.
  • RT-PCR premix BIONEER, K-2044
  • cDNA was mixed with SBR green master mix (Enzynomix) and detected with StepOnePlus real-time PCR system (Applied biosystems).
  • the dexamethasone-induced muscle atrophy model which is the most used model for this kind of study, was used. 10 ⁇ M of dexamethasone and the indicated concentrations of compounds were administered to the differentiated myotubes for 72 hours. Myotubes were visualized with a mitotracker indicating intracellular mitochondrial activity (Fig. 1a).
  • FIGS. 1B and 1C In a cell-based model of dexamethasone-induced muscle atrophy, changes in root canal diameter and root canal size distribution, which were reduced by dexamethasone alone treatment, were significantly alleviated by treatment with the compound of the present invention ( FIGS. 1B and 1C ).
  • the diameter of the root canal was reduced by about 30% by treatment with dexamethasone alone, whereas 98% and 88% and 88 of normal myotubes (control without dexamethasone) were treated with 7C (Compound 1) and 13C (Compound 3). % level, respectively.
  • Dexamethasone treatment alone changed the size distribution of root canals, increasing the number of relatively small ( ⁇ 15 ⁇ m) canals and decreasing large (> 30 ⁇ m) canals. However, the distribution of these small and large myotubes was normalized by treatment with compounds 1 and 3.
  • the compound of the present invention has an effect of alleviating muscle loss because it alleviates the decrease in the diameter of the root canal and the change in the size distribution of the root canal in the desamethasone-treated muscle atrophy model.
  • the dexamethasone-treated group showed a rapid increase in atrozin-1, and it was confirmed that representative compound 1 suppressed the expression of atrozin-1 induced by dexamethasone in a dose-dependent manner.
  • the compound of the present invention can be useful as a therapeutic agent for sarcopenia by inhibiting the expression of E3 ligase atrozin-1, a sarcopenia inducer.
  • MTT cell proliferation assay was performed to confirm the chemical toxicity of the compound of the present invention. Inhibition of muscle loss was effective in both compounds (compounds 1 and 3) at a concentration of 300 nM, and thus was evaluated in the range of less than 1 ⁇ M ( FIG. 3 ).
  • compounds 1 and 3 were all non-cytotoxic at concentrations of 125, 250, and 500 nM, confirming the stability as a therapeutic agent for muscle loss.
  • the present application has technical significance in identifying novel uses of previously unknown indirubin derivatives by confirming the therapeutic effect of indirubin derivatives on sarcopenia or muscular atrophy.

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Abstract

La présente invention concerne une composition pharmaceutique comprenant un dérivé de l'indirubine utilisé comme principe actif pour la prévention ou le traitement de la sarcopénie ou de l'atrophie musculaire ainsi qu'une méthode de traitement de la sarcopénie ou de l'atrophie musculaire à l'aide de celle-ci. La présente invention concerne une nouvelle utilisation d'un dérivé de l'indirubine dans le traitement de la sarcopénie ou de l'atrophie musculaire. La composition pharmaceutique selon la présente invention peut être avantageusement utilisée pour prévenir ou traiter efficacement la sarcopénie ou l'atrophie musculaire par l'augmentation des diamètres de myotubes, la suppression de l'atrophie des myotubes, le maintien de rapports entre les myotubes en fonction du diamètre, et la régulation à la baisse de l'expression du gène atrogine-1, qui détruit les protéines musculaires.
PCT/KR2020/017642 2019-12-06 2020-12-04 Composition pharmaceutique pour la prévention ou le traitement de la sarcopénie ou de l'atrophie musculaire WO2021112620A1 (fr)

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KR20240032299A (ko) * 2022-09-02 2024-03-12 단국대학교 천안캠퍼스 산학협력단 트리아졸로 티아디아진계 화합물 및 이를 유효성분으로 포함하는 근감소증 예방 또는 치료용 조성물

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KR20160006669A (ko) * 2013-03-14 2016-01-19 시티 오브 호프 5-브로모-인디루빈
WO2016114655A1 (fr) * 2015-01-12 2016-07-21 Ry Pharma B.V. Traitement de maladie neuromusculaire ou neurologique par réduction de la surstimulation des neurotransmetteurs inhibiteurs gabaergiques et/ou glycinergique
US20160243077A1 (en) * 2012-03-23 2016-08-25 Dennis M. Brown Compositions and methods to improve the therapeutic benefit of indirubin and analogs thereof, including meisoindigo
WO2017208211A1 (fr) * 2016-06-03 2017-12-07 The Regents Of The University Of California Identification de médicaments augmentant la masse musculaire
WO2018170870A1 (fr) * 2017-03-24 2018-09-27 Qualcomm Incorporated Techniques de communication de rétroaction dans des communications sans fil

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US20150259288A1 (en) * 2014-03-14 2015-09-17 City Of Hope 5-bromo-indirubins
AU2018358582B2 (en) * 2017-10-31 2021-06-10 Pelemed Co., Ltd. Pharmaceutical composition for prevention or treatment of acute myeloid leukemia or metastatic breast cancer

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160243077A1 (en) * 2012-03-23 2016-08-25 Dennis M. Brown Compositions and methods to improve the therapeutic benefit of indirubin and analogs thereof, including meisoindigo
KR20160006669A (ko) * 2013-03-14 2016-01-19 시티 오브 호프 5-브로모-인디루빈
WO2016114655A1 (fr) * 2015-01-12 2016-07-21 Ry Pharma B.V. Traitement de maladie neuromusculaire ou neurologique par réduction de la surstimulation des neurotransmetteurs inhibiteurs gabaergiques et/ou glycinergique
WO2017208211A1 (fr) * 2016-06-03 2017-12-07 The Regents Of The University Of California Identification de médicaments augmentant la masse musculaire
WO2018170870A1 (fr) * 2017-03-24 2018-09-27 Qualcomm Incorporated Techniques de communication de rétroaction dans des communications sans fil

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