[go: up one dir, main page]

WO2021107686A1 - Composé de promédicament d'edaravone et son utilisation pharmaceutique pour le traitement ou le soulagement de maladies neurodégénératives ou motoneuronales - Google Patents

Composé de promédicament d'edaravone et son utilisation pharmaceutique pour le traitement ou le soulagement de maladies neurodégénératives ou motoneuronales Download PDF

Info

Publication number
WO2021107686A1
WO2021107686A1 PCT/KR2020/017088 KR2020017088W WO2021107686A1 WO 2021107686 A1 WO2021107686 A1 WO 2021107686A1 KR 2020017088 W KR2020017088 W KR 2020017088W WO 2021107686 A1 WO2021107686 A1 WO 2021107686A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
piperazine
methyl
carboxylate
pyrazol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/KR2020/017088
Other languages
English (en)
Korean (ko)
Inventor
김재선
유형철
임지웅
권순진
류병환
오용호
동승명
장지원
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Theragen Etex Co Ltd
J2H Biotech Inc
Original Assignee
Theragen Etex Co Ltd
J2H Biotech Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Theragen Etex Co Ltd, J2H Biotech Inc filed Critical Theragen Etex Co Ltd
Publication of WO2021107686A1 publication Critical patent/WO2021107686A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to a novel precursor drug (prodrug) of edaravone compound known to be useful for the treatment or improvement of neurodegenerative and motor neuron diseases such as Lou Gehrig's disease or a pharmaceutically acceptable salt thereof.
  • the present invention also relates to a pharmaceutical composition comprising the novel precursor drug or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also relates to a pharmaceutical use of such a precursor drug or a pharmaceutically acceptable salt thereof.
  • Degenerative brain diseases or motor neuron diseases represented by Alzheimer's disease, Parkinson's disease, Huntington's disease, Lou Gehrig's disease; Amyotrophic lateral sclerosis, and multiple sclerosis are Currently, clinically available therapeutics are extremely limited. In order to treat or improve symptoms of these diseases, various approaches are being made for each disease.
  • a mechanism that can be commonly applied to the treatment of this disease group is a method of inhibiting oxidative damage to nerve cells by a causative protein. In other words, excessive production of radical oxygen species (ROS) causes neurotoxicity, and it is taking advantage of the fact that antioxidants can reduce neurodegeneration by reducing oxidative damage to neurons.
  • ROS radical oxygen species
  • edaravone is a drug newly approved as a treatment for Lou Gehrig's disease in the United States in 2017, and in clinical trials, it improves the revised ALS functional rating scale (ALSFRS-R) and, in particular, nitros in cerebrospinal fluid (CSF). It has been proven to be effective, such as dramatically reducing tyrosine (3-nitrotyrosine) levels.
  • ALSFRS-R ALS functional rating scale
  • CSF cerebrospinal fluid
  • amyloid-beta amyloid- ⁇
  • amyloid- ⁇ amyloid- ⁇
  • the edaravone inhibits the deposition of amyloid-beta and consequent oxidative damage, and has been reported to inhibit the progression of the disease.
  • a bar Proceedings of the National Academy of Sciences of the United States of America, 2015, 112 (16), 5225
  • edaravone was administered intraperitoneally in an animal test for Alzheimer's disease-induced APPswe/PS1 mice, Behavioral improvement effects were demonstrated along with reduction of amyloid-beta deposition and phosphorylation of tau protein, and reduction of neuronal inflammation and neuronal loss.
  • Edaravone is currently commercialized as an intravenous infusion (IV infusion), and is generally administered to patients in a repeat cycle of 28 days at a dose of 60 mg each time. That is, after daily administration for the first 14 days, there is a 14-day rest period, followed by a 14-day rest period after administration for 10 days out of 14.
  • each administration has to go to the hospital and undergo a very cumbersome process of receiving an injection for an hour.
  • considering the characteristics of ALS the movement of patients with mobility difficulties, injections, and frequent administration schedules, despite the clinical usefulness of the drug, it is very inappropriate in terms of patient convenience.
  • a precursor drug (prodrug) that is a piperazine derivative compound linked to a carbamate functional group in the edarabone structure is presented, and the antioxidant effect was measured by administering the compounds orally or by injection to an animal model.
  • the above patent does not disclose the pharmacokinetic aspects that appear after in vivo administration of the compounds, and there is no disclosure on the concentration of edaravone in the blood generated from the precursor material.
  • the precursor drugs disclosed in the Chinese patent were insufficient to improve the bioavailability of edaravone, so the present inventors determined that a drug with more dramatically improved absorption rate, bioavailability, etc. is needed did.
  • the problem to be solved by the present invention is a precursor drug of edarabone with improved absorption rate, bioavailability, etc., a pharmaceutical composition comprising such a drug, and the treatment or improvement of a neurodegenerative or / and motor neuron disease of the drug.
  • the present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
  • R 1 is selected from the group consisting of D- or L-amino acids, and N-acetyl derivatives thereof, wherein the amino acids are glycine, phenylglycine, leucine, methionine, valine, alanine, isoleucine, proline, tryptophan, tyrosine, phenylalanine, histidine , serine, cysteine, asparagine, threonine, t-leucine, glutamine, glutamic acid, aspartic acid, lysine, arginine, and 3,4-dihydroxyphenylalanine.
  • amino acids are glycine, phenylglycine, leucine, methionine, valine, alanine, isoleucine, proline, tryptophan, tyrosine, phenylalanine, histidine , serine, cysteine, asparagine, threonine, t-leucine, glutamine
  • N-acetyl derivative of the amino acid means that one hydrogen of the NH 2 group of the amino acid is substituted with a —CO—CH 3 group.
  • the present inventors showed very excellent effects in terms of absorption rate and bioavailability of the compound or a pharmaceutically acceptable salt thereof.
  • excellent physical properties or properties as a precursor drug The present invention was completed by confirming that the
  • the compounds are
  • (C x -C y ) when described as “C x -C y ”, this means that the number of carbon atoms is x to y.
  • (C 1 -C 3 )alkyl means alkyl having 1 to 3 carbon atoms.
  • alkyl includes both linear and branched types.
  • “Pharmaceutically acceptable salts” in the present invention include salts of the active compounds prepared with relatively non-toxic acids and bases depending on the particular substituents found on the compounds mentioned herein.
  • acidic addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, neat or with a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include acetic acid, propionic acid, isobutylic acid, oxalic acid, maleic, malonic, benzoic acid, succinic acid, suberic, fumaric.
  • salts derived from organic acids hydrogen chloride, hydrogen bromide, nitric acid, carbonic acid, monohydrogencarbonic, phosphoric, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydrogen iodide or phosphorous acid acid
  • salts of amino acids such as arginate and analogues thereof and analogues of organic acids such as glucuronic or galactunoric acids and analogues thereof.
  • salts are well-known literature in the art that the present invention is, for example, Remington's Pharmaceutical Sciences, l8 th eds, Mack Publishing, Easton PA (1990) or Remington:. The Science and Practice of Pharmacy, 19 th eds ., Mack Publishing, Easton PA (1995).
  • a compound of the present invention is meant to include compounds of Formula 1 as well as clathrates, hydrates, solvates, or (crystal) polymorphs thereof.
  • the term “compound of the present invention” is meant to include pharmaceutically acceptable salts of the compounds of the present invention unless a pharmaceutically acceptable salt thereof is mentioned.
  • a compound of the invention is a stereoisomerically pure compound (e.g., substantially free of other stereoisomers (e.g., at least 85% ee, at least 90% ee, at least 95% ee, 97% ee or more, or 99% ee or more)).
  • the compound of Formula 1 or a salt thereof according to the present invention is a tautomeric isomer and/or stereoisomer (eg, geometrical isomer and conformational isomers), their separated isomers and mixtures each are also included within the scope of the compounds of the present invention.
  • the compound of the present invention or a salt thereof has an asymmetric carbon in its structure, their optically active compounds and racemic mixtures are also included in the scope of the compound of the present invention.
  • polymorph refers to a solid crystalline form of a compound of the present invention or a complex thereof. Different polymorphs of the same compound exhibit different physical, chemical and/or spectral properties. Differences in physical properties include, but are not limited to, stability (eg, thermal or light stability), compressibility and density (important for formulation and product manufacturing), and dissolution rate (which may affect bioavailability).
  • stability eg, thermal or light stability
  • compressibility and density important for formulation and product manufacturing
  • dissolution rate which may affect bioavailability
  • Differences in stability may be due to chemical reactivity changes (e.g., differential oxidation, such as a faster discoloration when composed of one polymorph than when composed of another polymorph) or mechanical properties (e.g., kinetics) Tablet fragments stored as the preferred polymorph are converted to a thermodynamically more stable polymorph) or both (tablets of one polymorph are more susceptible to degradation at high humidity).
  • Other physical properties of polymorphs can affect their processing. For example, one polymorph may be more likely to form a solvate than another polymorph, for example due to its shape or particle size distribution, or it may be more difficult to filter or wash.
  • solvent compound refers to a compound of the present invention, or a pharmaceutically acceptable salt thereof, comprising a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces.
  • Preferred solvents are volatile, non-toxic, and can be administered in trace amounts to humans.
  • hydrate refers to a compound of the present invention, or a pharmaceutically acceptable salt thereof, comprising a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • clathrate refers to a compound of the present invention in the form of a crystal lattice containing spaces (eg, channels) that confine guest molecules (eg, solvent or water). or salts thereof.
  • the compound represented by Formula 1 of the present invention may be synthesized, for example, by the following route.
  • the first material used is piperazine compound I, which is reacted with t-leucine derivative II.
  • the t-leucine derivative used includes an amine protecting group, and a t-butoxycarbonyl (Boc) functional group commonly used for the amine group may be used.
  • the group-protected carboxybenzyl group (carboxybenzyl, Cbz) can be deprotected by hydrogenation to obtain the amide intermediate III.
  • Intermediate III can be activated by treatment with triphosgene, reacted with edaravone IV, and then deprotected with hydrochloric acid to obtain compound V.
  • compound V and an amino acid derivative that is, an amino acid protected with an amine group with Boc, are subjected to an amide condensation reaction, and then Boc is deprotected under acidic conditions to obtain a final compound VII.
  • the compound represented by Formula 1 of the present invention may be synthesized, for example, by the following route.
  • the final compound IX can be obtained through the amide condensation reaction of the above-described intermediate compound V and the acetylated amino acid compound VIII.
  • the present inventors modified the chemical structure of the edaravone compound, and invented and prepared a novel compound with a new structure that can dramatically increase the oral absorption rate during oral administration.
  • the concentration of edaravone substance exposed to blood after oral administration of the novel compound thus prepared in vivo is ultimately directly proportional to the efficacy of the drug for the treatment or improvement of various neurodegenerative and/or motor neuron diseases. This is based on the concentration of the edarabone substance exposed in the blood after intravenous administration of edarabone, and compares the concentration of the edarabone substance exposed to the blood through the metabolic process after oral administration of the novel compound according to the present invention, that is, the precursor drug. This means that the doses of intravenous and oral administration can be proportionally applied.
  • the present inventors prepared and evaluated compounds having various chemical structures in order to derive novel compounds with improved oral absorption of edarabone.
  • absorption of the drug is basically made by passive diffusion, it was evaluated whether it exhibits a certain degree of fat solubility, and in order to prevent a decrease in absorption due to excessively low water solubility, Whether it can show solubility was also evaluated.
  • some of the compounds according to the present invention may act as a substrate for amino acid transporters such as PepT1 and LAT1 among transmembrane transporters present in the intestinal mucosa. Therefore, while the original edaravone compound has low bioavailability due to PgP release, it is considered that some of the compounds according to the present invention significantly increase bioavailability due to active transport by amino acid transporters.
  • the present invention is not limited to such a theoretical mechanism.
  • the bioavailability of the orally administered compound of Example 2 is 54.3%, and the bioavailability of orally administered edaravone A remarkable increase of about 11 times compared to 4.9% was confirmed.
  • the bioavailability of the orally administered compound of Example 4 is 56.7%, which is a remarkable increase of about 12 times compared to 4.9% of the bioavailability of orally administered edaravone. was confirmed.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention, and a pharmaceutically acceptable carrier.
  • an “effective amount or effective amount” refers to slowing or minimizing neurodegenerative and/or motor neuron disease; or an amount of a compound of the invention sufficient to provide a therapeutic benefit in the treatment or management of a neurodegenerative and/or motor neuron disease.
  • the pharmaceutically acceptable carrier may be, for example, a carrier for oral administration or a carrier for parenteral administration.
  • Carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like.
  • the carrier for parenteral administration may include water, a suitable oil, saline, aqueous glucose and glycol, and the like, and may further include a stabilizer and a preservative. Suitable stabilizers include antioxidants such as sodium bisulfite, sodium sulfite or ascorbic acid. Suitable preservatives are benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol.
  • those described in the following literature may be referred to. (Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, PA, 1995)
  • the pharmaceutical composition of the present invention may be administered to mammals including humans by any route of administration. It can be administered orally or parenterally. However, the oral administration route is more preferable in view of the excellent oral absorption of the compounds of the present invention.
  • Parenteral administration may be, for example, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual or rectal administration.
  • the pharmaceutical composition of the present invention may be administered by preparing an injectable formulation and lightly pricking the skin with a 30-gauge thin injection needle, or by applying it directly to the skin.
  • the pharmaceutical composition of the present invention may be formulated as a formulation for oral administration or parenteral administration according to the administration route as described above.
  • the composition of the present invention may be formulated as a powder, granule, tablet, pill, dragee, capsule, liquid, gel, syrup, slurry, suspension, etc. using methods known in the art.
  • oral preparations can be obtained by combining the active ingredient with a solid excipient, grinding it, adding suitable adjuvants, and processing it into a granule mixture.
  • excipients include sugars including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol and maltitol, and starches, including corn starch, wheat starch, rice starch and potato starch, cellulose, Cellulose, including methyl cellulose, sodium carboxymethylcellulose and hydroxypropylmethyl-cellulose, and the like, fillers such as gelatin, polyvinylpyrrolidone, and the like may be included.
  • cross-linked polyvinylpyrrolidone, agar, alginic acid or sodium alginate may be added as a disintegrant if necessary.
  • the pharmaceutical composition of the present invention may further include an anti-aggregating agent, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent, and a preservative.
  • Formulations for parenteral administration may be formulated in the form of injections, creams, lotions, external ointments, oils, moisturizers, gels, aerosols and nasal inhalants by methods known in the art. These formulations are described in the literature, which is a commonly known formula for all pharmaceutical chemistry.
  • the total dose of the pharmaceutical composition of the present invention may be administered to a patient as a single dose, and may be administered by a fractionated treatment protocol in which multiple doses are administered for a long period of time.
  • the pharmaceutical composition of the present invention may vary the content of the active ingredient according to the symptoms of the disease.
  • the preferred total dose of the composition of the present invention may be about 0.01 ⁇ g to 1,000 mg, most preferably 0.1 ⁇ g to 100 mg per kg of patient body weight per day.
  • the dosage of the pharmaceutical composition of the present invention is determined by considering various factors such as the age, weight, health status, sex, severity of disease, diet, and excretion rate of the patient, as well as the route of administration and the number of treatments, according to common knowledge in the art A person with a knowledge of this will be able to determine an appropriate effective dosage.
  • the pharmaceutical composition according to the present invention is not particularly limited in its formulation, administration route and administration method as long as the effect of the present invention is exhibited.
  • the pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents.
  • the composition of the present invention and the other therapeutic agents may be administered simultaneously, separately, or sequentially.
  • the other therapeutic agent may be a substance already known to have an effect of treating or improving neurodegenerative and/or motor neuron diseases.
  • the composition of the present invention and the other therapeutic agent may be formulated separately in separate containers, or may be co-formulated together in the same dosage form.
  • composition 1 composition 2 active ingredient compound A30 compound B 60 lactose 20 30 Sodium Lauryl Sulfate (SLS) 5 10 Polyvinyl pyrrolidone (PVP) 2 2 Sodium Croscarmellose 5 5 Microcrystalline Cellulose - 10 magnesium stearate 3 3 total amount 65 120
  • the present invention also provides a pharmaceutical composition for treating or improving neurodegenerative or motor neuron disease, comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention as an active ingredient. That is, the present invention provides a pharmaceutical use of the compound of Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention for the treatment or improvement of neurodegenerative or motor neuron diseases.
  • the present invention provides a method for treating or ameliorating a neurodegenerative or motor neuron disease, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof
  • the neurodegenerative or motor neuron disease is Alzheimer's disease, Parkinson's disease, Huntington's disease, Lou Gehrig's disease, multiple sclerosis, dystonia, spinal muscular atrophy, inflammatory neuropathy, or alcoholic dementia.
  • the subject is a human.
  • the treatment is a preventative treatment.
  • the treatment is a palliative treatment.
  • the treatment is a restorative treatment.
  • the present invention provides a compound effective for the treatment or improvement of neurodegenerative or motor neuron disease, a pharmaceutical composition comprising the same as an active ingredient, a pharmaceutical use thereof, and a treatment method comprising administering them to an individual in need of treatment or prevention .
  • the compound according to the present invention or a pharmaceutically acceptable salt thereof is an active ingredient of a pharmaceutical, and has various advantages in terms of solubility, etc., and, in particular, has excellent bioavailability after oral administration.
  • Benzyl piperazine-1-carboxylate derivative was dissolved in 5 volumes of dichloromethane and 5 volumes of N-methyl-2-pyrrolidone (N-methyl-2-pyrrolidone, NMP), followed by t-butoxycarbo 1.0 equivalent of t-leucine protected by an amine group with a nyl (t-butoxycarbonyl, Boc) group, 1.1 equivalents of diisopropylcarbodiimide (DIPC), and 1.2 equivalents of triethylamine were added. After stirring for 2 hours at room temperature under an argon gas environment, the mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • NMP N-methyl-2-pyrrolidone
  • DIPC diisopropylcarbodiimide
  • the separated organic solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • the residue was purified by column chromatography using silica gel (eluent: a mixture of ethyl acetate and n-hexane), and then it was again dissolved in 10 times the volume of dichloromethane. Twice the volume of trifluoroacetic acid was added and stirred at room temperature for 2 hours.
  • the reaction solution was concentrated under reduced pressure, and then ethyl acetate and purified water were added thereto for distribution.
  • the organic solution layer was washed again with a saturated aqueous sodium hydrogen carbonate solution, and the separated organic solution was dried over anhydrous magnesium sulfate.
  • the filtered organic solution was dried under reduced pressure to obtain the title compound as an off-white solid. (Yield: 67%) Structural analysis of the obtained material is as described in Table 2 below.
  • Pharmacokinetic tests for the compounds of Examples and Reference Examples were performed as follows. That is, after a single oral administration of the test substance to SD (Sprague-Dawley) rats, the efficacy of the compound of the present invention was demonstrated by tracking the kinetics of the drug edaravone released into the blood by the metabolic process and comparing it with a standard substance. . Specifically, the concentration of edarabone in the blood was analyzed by oral administration of standard edarabone and test substances, respectively. After each standard and test substance were prepared in the same way, 0.1 mmol/kg dose was administered to rats, and blood was collected at a set time, and then plasma was separated.
  • the pretreatment method 100 ⁇ l of the plasma sample was transferred to a centrifuge tube, 10 ⁇ l of the internal standard solution and 300 ⁇ l of methanol were added and mixed for about 30 seconds. The tube was centrifuged at 3,000 xg (4°C) for about 5 minutes, and the supernatant was transferred to an LC vial and then injected into the instrument. And the concentration of the active ingredient in rat plasma, that is, edaravone, was quantified by applying a previously verified assay.
  • the mean AUC t was 1,868 hr*ng/ml
  • the mean AUC i was 1,963 hr*ng/ml
  • the mean C max was 206 ng/ml
  • the mean T max was 4.17 hours
  • the mean t 1/ 2 was 5.74 hours
  • the bioavailability was 54.3%.
  • the average AUC t is 1,949 hr * ng / ml
  • the average AUC i is 2,240 hr * ng / ml
  • the average C max is 754 ng / ml
  • the average T max is 0.67 hours
  • the average t 1 /2 was 5.47 hours
  • the bioavailability was 56.7%.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un nouveau promédicament d'un composé d'edaravone, ou un sel pharmaceutiquement acceptable de celui-ci, une composition pharmaceutique le comprenant en tant que principe actif, et une utilisation pharmaceutique de celui-ci pour traiter ou soulager des maladies neurodégénératives et/ou motoneuronales.
PCT/KR2020/017088 2019-11-28 2020-11-27 Composé de promédicament d'edaravone et son utilisation pharmaceutique pour le traitement ou le soulagement de maladies neurodégénératives ou motoneuronales Ceased WO2021107686A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020190156021A KR20210067005A (ko) 2019-11-28 2019-11-28 에다라본 전구체 약물 화합물 및 이들의 신경퇴행성 또는 운동신경 질환의 치료 또는 개선을 위한 의약 용도
KR10-2019-0156021 2019-11-28

Publications (1)

Publication Number Publication Date
WO2021107686A1 true WO2021107686A1 (fr) 2021-06-03

Family

ID=76129548

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2020/017088 Ceased WO2021107686A1 (fr) 2019-11-28 2020-11-27 Composé de promédicament d'edaravone et son utilisation pharmaceutique pour le traitement ou le soulagement de maladies neurodégénératives ou motoneuronales

Country Status (2)

Country Link
KR (1) KR20210067005A (fr)
WO (1) WO2021107686A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025087971A1 (fr) 2023-10-23 2025-05-01 Treeway Tw001 B.V. Traitement combiné de la maladie d'alzheimer
WO2025113038A1 (fr) * 2023-11-28 2025-06-05 郑州大学 Composé précurseur à base de structure d'édaravone et son procédé de préparation et son utilisation

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080312226A1 (en) * 2004-11-18 2008-12-18 Takeda Pharmaceutical Company Limited Amide Compound
CN102190622A (zh) * 2010-03-15 2011-09-21 李勤耕 依达拉奉的水溶性衍生物及其制备方法和应用
CN104098512A (zh) * 2013-04-03 2014-10-15 江苏先声药物研究有限公司 依达拉奉衍生物及其制备方法、检测方法和用途
WO2018133621A1 (fr) * 2017-01-18 2018-07-26 周意 Dérivé d'édaravone et son utilisation
WO2019183636A1 (fr) * 2018-03-23 2019-09-26 Pfizer Inc. Dérivés azaspiro de pipérazine
WO2019211585A1 (fr) * 2018-04-30 2019-11-07 University Of Leeds Inhibiteurs du facteur xiia

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080312226A1 (en) * 2004-11-18 2008-12-18 Takeda Pharmaceutical Company Limited Amide Compound
CN102190622A (zh) * 2010-03-15 2011-09-21 李勤耕 依达拉奉的水溶性衍生物及其制备方法和应用
CN104098512A (zh) * 2013-04-03 2014-10-15 江苏先声药物研究有限公司 依达拉奉衍生物及其制备方法、检测方法和用途
WO2018133621A1 (fr) * 2017-01-18 2018-07-26 周意 Dérivé d'édaravone et son utilisation
WO2019183636A1 (fr) * 2018-03-23 2019-09-26 Pfizer Inc. Dérivés azaspiro de pipérazine
WO2019211585A1 (fr) * 2018-04-30 2019-11-07 University Of Leeds Inhibiteurs du facteur xiia

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025087971A1 (fr) 2023-10-23 2025-05-01 Treeway Tw001 B.V. Traitement combiné de la maladie d'alzheimer
WO2025113038A1 (fr) * 2023-11-28 2025-06-05 郑州大学 Composé précurseur à base de structure d'édaravone et son procédé de préparation et son utilisation

Also Published As

Publication number Publication date
KR20210067005A (ko) 2021-06-08

Similar Documents

Publication Publication Date Title
EP4209494A1 (fr) Composé de peptide court de proline à cycle modifié et son utilisation
US20040235752A1 (en) 3-fluoro-pyrrolidines as antidiabetic agents
EP0536399B1 (fr) Nouveau derive d'arylalcanoylamine et medicament contenant ce derive
US6403624B1 (en) 8,8A-dihydroindeno[1,2-D] thiazole derivatives which are substituted in the 8A-position; processes for their preparation and their use as medicaments
BRPI0708071A2 (pt) derivados de catecolamina deuterada e medicamentos compreendendo os ditos compostos
KR102261931B1 (ko) 에다라본 전구체 약물 화합물 및 이들의 신경퇴행성 또는 운동신경 질환의 치료 또는 개선을 위한 의약 용도
WO2021107686A1 (fr) Composé de promédicament d'edaravone et son utilisation pharmaceutique pour le traitement ou le soulagement de maladies neurodégénératives ou motoneuronales
US20220184021A1 (en) Novel formulations comprising melflufen
CN111511737A (zh) 用于治疗细菌感染的单环β-内酰胺化合物
EP3722286B1 (fr) Sel d'un dérivé de phénylpropionamide et son procédé de préparation
IE65117B1 (en) 1-(Pyridinylamino)-2-pyrrolidinones a process for their preparation and their use as medicaments
US20090170937A1 (en) Amino Acid Derivatives
WO2020204624A1 (fr) Composé de promédicament de mirabegron, et utilisation pharmaceutique de celui-ci pour traiter ou soulager la maladie de la vessie hyperactive
CN104974221A (zh) 二肽及三肽类蛋白酶体抑制剂及其制法和药物用途
WO2011152657A2 (fr) Malate d'acétyle-l-carnitine, procédé permettant de la préparer et composition pharmaceutique la comprenant
SK30394A3 (en) Derivatives of 2,4-diamino-3-hydroxycarboxylic acid, method of their preparation, pharmaceutical compositions containing these derivatives and their use
WO2020159228A1 (fr) Composés de médicament précurseur de monométhylfumarate et compositions pharmaceutiques associées
WO2022211460A1 (fr) Composition pharmaceutique pour le traitement d'une infection au sras-cov-2
KR20230022874A (ko) (2s,5r)-5-(2-클로로페닐)-1-(2'-메톡시-[1,1'-비페닐]-4-카르보닐)피롤리딘-2-카르복실산의 합성
CN103739591B (zh) 7-(3-酰胺基-4-甲肟基-1-哌啶基)氟喹诺酮羧酸及其制备方法
EP4157266B1 (fr) Formes cristallines de solvates de dérivés de tryptophane, compositions les comprenant et leurs utilisations
EP4004013A1 (fr) Composés dinucléotidiques pour le traitement de cancers et leurs utilisations médicales
EP4660197A1 (fr) Composé polycyclique d'ester acyléthylique, et composition pharmaceutique et utilisation associées
EP2459550A2 (fr) Sel de l'acide r-7-(3-aminométhyl-4-méthoxyimino-3-méthyl-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylique et de l'acide l-aspartique, leur procédé de préparation et composition pharmaceutique les comprenant servant d'agent antimicrobien
WO2024029639A1 (fr) Promédicament à trois composants, composition pharmaceutique de celui-ci et utilisation médicale associée

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20891487

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20891487

Country of ref document: EP

Kind code of ref document: A1