WO2016108319A1 - Nouveau sel de promédicament du rébamipide et son utilisation - Google Patents

Nouveau sel de promédicament du rébamipide et son utilisation Download PDF

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Publication number
WO2016108319A1
WO2016108319A1 PCT/KR2015/000004 KR2015000004W WO2016108319A1 WO 2016108319 A1 WO2016108319 A1 WO 2016108319A1 KR 2015000004 W KR2015000004 W KR 2015000004W WO 2016108319 A1 WO2016108319 A1 WO 2016108319A1
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WO
WIPO (PCT)
Prior art keywords
acid
oxo
propionate
chlorobenzoylamino
dihydroquinolin
Prior art date
Application number
PCT/KR2015/000004
Other languages
English (en)
Korean (ko)
Inventor
조의환
최승주
이성우
신희종
권호석
이재웅
주정호
김현태
송우헌
윤종배
박기석
박호준
남호태
Original Assignee
삼진제약 주식회사
㈜에이에스텍
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 삼진제약 주식회사, ㈜에이에스텍 filed Critical 삼진제약 주식회사
Priority to PCT/KR2015/000004 priority Critical patent/WO2016108319A1/fr
Publication of WO2016108319A1 publication Critical patent/WO2016108319A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4

Definitions

  • the present invention relates to a pharmaceutically acceptable salt of a novel levamipid precursor and its use, and more particularly, the overall reaction process is simple and improved efficacy with the effects of the conventional levamifeed material.
  • Rebamipide is used as a therapeutic agent for peptic ulcer, and its chemical name is 2- (4-chlorobenzoylamino) -3- [2 (1H) -quinolon-4-yl] propionic acid.
  • Levamipid is a medicament that has an excellent effect in the treatment of gastric mucosal damage due to gastric ulcer, acute gastritis, or acute exacerbation of chronic gastritis.
  • the drug protects the gastric mucosa by promoting PGE2 biosynthesis, increasing mucus, promoting cell proliferation, and inhibiting gastritis by inhibiting bacterial adhesion and invasion to gastric mucosa cells, especially in patients infected with Helicobacter pylori. It is characterized by.
  • the action mechanism of levamifeed promotes biosynthesis of prostaglandin to enhance the defense factor and is the only antioxidant among the defense factor enhancers to simultaneously remove the inflammation caused by Helicobacter. Inflammation has two effects at the same time. Therefore, it is a very effective drug that can significantly reduce the recurrence rate and shorten the treatment period in ulcer or gastritis patients. In the experiments using rats that developed gastric ulcers with acetic acid, the treatment rate was improved, and the ulcer size and recurrence rate were all reduced by levamifeed.
  • Korean Patent No. 10-0669823 discloses a method for preparing 2- (4-chlorobenzoylamino) -3- [2 (1H) -quinolon-4-yl] propionic acid and intermediates thereof.
  • Korean Patent No. 10-1032600 discloses a method for producing high purity levamipid, which is capable of producing high quality levamipid with a purity of 99.95% by simultaneously performing a reaction and purification at a high yield and a low production cost.
  • levamipid is effective in preventing or treating gastric ulcer, acute gastritis, chronic gastritis, dry eye syndrome, cancer, osteoarthritis, rheumatoid arthritis, etc.
  • levamipid inhibits obesity It has shown an effect and has also attracted attention as an anti-obesity agent, and various therapeutic compositions including levamipid as an active ingredient have been developed.
  • Levamipid is soluble in dimethylformamide, slightly soluble in methanol and ethanol and hardly soluble in ether and water. Aqueous solubility of levamifeed is reported to be approximately 0.0001% (w / v) at pH 3 and 0.013% (w / v) at pH 7. Levamipid is rated as Class in the biopharmaceutiocs classification system (BCS) due to its low solubility and low membrane permeability, and its bioavailability is known to be around 5% because it is hardly absorbed by the circulatory system. Due to this low absorption rate and bioavailability, it is necessary to take a relatively large amount of levamifeed in the development of a pharmaceutical composition comprising levamifeed having various effects as described above.
  • BCS biopharmaceutiocs classification system
  • the present inventors have shown useful effects on the various symptoms as described above, but while trying to improve the level of revamifeed, which is significantly lowered in the body absorption rate, the salt of the revamipi precursor (prodrug) has a higher absorption rate in the body than the revamifeed. Confirmation of excellent and completed the present invention.
  • the present invention provides pharmaceutically acceptable salts of compounds of formula (I):
  • According to another object of the present invention is a gastric ulcer, acute gastritis, chronic gastritis, dry eye syndrome, cancer, osteoarthritis, rheumatoid arthritis, hyperlipidemia, hypertriglyceridemia, diabetes, hypersensitivity comprising the salt of the levamipid precursor as an active ingredient It provides a pharmaceutical composition having the effect of preventing or treating colon syndrome and treating and inhibiting obesity.
  • the present invention has the advantage of providing a salt of the levamifeed precursor, which is a novel material that has increased the absorption rate to the human body.
  • the salt of the novel levamipid precursor according to the present invention significantly increases the absorption rate in the body compared to levamifeed present as a free acid, so that even when a small amount is taken, gastric ulcer, acute gastritis, chronic gastritis, dry eye syndrome, and cancer , Osteoarthritis, rheumatoid arthritis, obesity, hyperlipidemia, hypertriglyceridemia, diabetes, irritable bowel syndrome and the like can be useful in preventing or treating various diseases.
  • the present invention provides salts of the precursors of levamipid, known for the prophylaxis or treatment of gastric ulcers, acute gastritis, chronic gastritis, dry eye syndrome, cancer, osteoarthritis, rheumatoid arthritis and the like.
  • X is any one of oxygen, nitrogen or sulfur
  • Y is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, (C 1 -C 3 alkyloxy) C 1 -C 6 alkyl, (C 2 -C 6 alkenyloxy) C 1 -C 6 alkyl, (C 1 -C 6 alkylcarbonyloxy) C 1 -C 6 alkyl, (C 1 -C 6 alkylsulfanyl) C 1 -C 6 alkyl, (arylsulfanyl) C 1 -C 6 alkyl, (arylsul Ponyl) C 1 -C 6 alkyl, (C 1 -C 6 alkylamino) C 1 -C 6 alkyl, [(C 1 -C 6 alkyl) (C 1 -C 6 alkyl) amino] C 1 -C 6 alkyl , [(C 1 -C 3 alkyl) (aryl) amino] C 1 -C 6 alkyl, [(C 1 -C
  • C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 oxoalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, C 3 -C 8 heterocycloalkenyl, aryl or heteroaryl is one or more substituents selected from the group consisting of C 1 -C 3 alkyl, fluoro, chloro, bromo, hydroxy groups, oxo, nitro groups and cyano groups Can be substituted.
  • heterocycloalkyl or “heterocycloalkenyl” is substituted for saturated carbon with either nitrogen, oxygen, or sulfur, or the same atoms or different atoms are single, two or three adjacent or It means skipped.
  • heterocycloalkyl or heterocycloalkenyl examples include aziridine, oxirane, azetidine, oxetane, pyrrolidine, pyrroline, pyrazolidine, pyrazoline, imidazolidine, imidazoline, triazolidine , Oxazolidine, tetrahydrofuran, tetrahydrothiophene, thiazolidine, dioxolane, dioxol, oxathiolane, morpholine. Thiomorpholine, dithiane, piperidine, piperazine, pyran, dioxane or azepan.
  • aryl as used herein include, but are not limited to, benzene, naphthalene, anthracene, or phenanthrene.
  • heteroaryl refers to aryl wherein any one of nitrogen, oxygen, or sulfur is substituted, or the same atom or different atoms are substituted with one, two or three neighbors or skipped.
  • the heteroaryl include pyrrole, imidazole, pyrazole, triazole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, pyridine, pyrimidine, Pyrazine, pyridazine, triazine, azepine, indole, benzimidazole, indazole, benzoxazole, benzoisoxazole, benzothiazole, benzotriazole, benzofuran, benzothiophene, quinoline, isoquinoline, quinox Saline, quinazoline, cynoline, naphthyridine, phthal
  • XY represents an amino acid or amino acid (C 1 -C 3 alkyl) ester.
  • Amino acids refer to, but are not limited to, glycine, leucine, methionine, valine, alanine, isoleucine, proline, tryptophan, phenylalanine, serine, threonine, asparagine, glutamic acid, lysine, histidine, or tyrosine.
  • the pharmaceutically acceptable salt of the levamifeed precursor according to the present invention is preferably an acid addition salt formed by a pharmaceutically acceptable free acid, and an organic acid and an inorganic acid may be used as the free acid.
  • the organic acid is, but is not limited to, citric acid, acetic acid, lactic acid, tartaric acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, adipic acid, ascorbic acid, Benzoic acid, 4-acetamidobenzoic acid, gluconic acid, sulfonic acid, methanesulfonic acid, capric acid, capronic acid, caprylic acid, carboxylic acid, cinnamic acid, cyclic acid, dodecylsulfonic acid, ethane-1,2-di Sulfonic acid, ethanesulfonic acid
  • Preferred salt compounds of the levamifeed precursors include, but are not limited to:
  • pharmaceutically acceptable salts of the compounds of formula (I) according to the invention can be prepared from compounds of formula (I) prepared by reacting compounds of formula (II) with compounds of formula (III).
  • X and Y are as described above, Z is hydroxy, amino, amine, halogen or leaving group.
  • Z is hydroxy, -NH 2 , Cl, Br, alkylsulfonyl or arylsulfonyl.
  • pharmaceutically acceptable salts of the compounds of formula (I) according to the present invention may be prepared from, but are not limited to, compounds of formula (I) prepared by the methods shown in Scheme 1 below.
  • X is any one of oxygen, nitrogen or sulfur
  • the compound of [Formula II] used as starting material in [Scheme 1] can be prepared by the method described in US Patent No. 4,578,381.
  • the inorganic salts represented in [Scheme 1] may be inorganic bases such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate or cesium carbonate, and the solvent is acetone, dimethylformamide, dimethyl sulfoxide, or It may be acetonitrile, the reaction may be carried out at 10 to 100 °C for 1 to 24 hours.
  • DCC is dicyclohexylcarbodiimide
  • DMAP is 4-dimethylaminopyridine
  • HOBT is 1-hydroxybenzotriazole
  • EDCI means 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloric acid
  • Y-OMs or Y-OTs are sulfonyl groups such as alkylsulfonyl groups such as methanesulfonyl group; Or arylsulfonyl groups such as paratoluenesulfonyl, benzenesulfonyl or 4-nitrobenzenesulfonyl groups.
  • Sodium hydrosulfide in [Scheme 2] may be used in an amount of 1 to 10 equivalents, preferably 4 to 6 equivalents, sodium sulfide may be used in an amount of 1 to 5 equivalents, preferably 2 to 3 equivalents.
  • Dimethylformamide, dimethyl sulfoxide or acetonitrile may be used as the solvent in [Scheme 2], and the reaction may be performed at 10 to 100 ° C. for 1 to 24 hours.
  • NCS in the above scheme refers to N-chlorosuccinimid.
  • pharmaceutically acceptable salts of the compounds of formula (I) according to the invention can be prepared from levamifeed precursors prepared according to the following general experimental methods.
  • 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) -thiopropionic acid in the levamifeed precursor represented by the formula (I) is an experimental method.
  • a or B is prepared as follows
  • the salt of the levamifeed precursor according to the present invention may be prepared according to the following general experimental method E, but is not limited thereto.
  • salts of the compounds of formula (I) of the present invention have better absorption in the body than levamipids in the free acid state, they can replace levamipids for gastric ulcer, acute gastritis, chronic gastritis, dry eye syndrome, cancer, osteoarthritis, rheumatoid arthritis or It can be usefully used to prevent or treat obesity.
  • the disease is already disclosed that the levamipid can be prevented or treated, the levamifeed precursor of the present invention will be used more effectively in the disease than levamifeed.
  • the present invention provides a pharmaceutical for the prevention or treatment of gastric ulcer, acute gastritis, chronic gastritis, dry eye syndrome, cancer, osteoarthritis, rheumatoid arthritis or obesity, comprising a pharmaceutically acceptable salt of the compound of formula (I) as an active ingredient To provide a composition.
  • the pharmaceutically effective amount of the salt of the levamifeed compound according to the invention is 0.5-100 mg / day, preferably 1-30 mg / day, per kg of body weight of the patient.
  • the pharmaceutically effective amount may be appropriately changed depending on the extent of disease symptoms, the age, weight, health condition, sex, route of administration and duration of treatment of the patient.
  • composition according to the invention may further comprise a pharmaceutically acceptable additive.
  • a pharmaceutically acceptable additive means that when administered physiologically and humanly, it usually does not cause an allergic reaction such as gastrointestinal disorder, dizziness or the like.
  • the additives include carriers, excipients and diluents.
  • Examples of such carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, Polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers and preservatives may be further included.
  • compositions of the present invention may be formulated using methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal.
  • the formulations may be in the form of powders, granules, tablets, emulsions, syrups, aerosols, soft or hard gelatin capsules, sterile injectable solutions, sterile powders.
  • the pharmaceutical composition according to the present invention can be administered through various routes including oral, transdermal, subcutaneous, intravenous or intramuscular, and the dosage of the active ingredient is determined by the route of administration, the age, sex, weight and severity of the patient. It may be appropriately selected according to various factors, and may be administered in combination with a compound which is known to have a prophylactic or therapeutic use in the disease, depending on the kind of disease to be treated.
  • the present invention comprises administering a pharmaceutically acceptable salt of a compound of formula (I) to a subject in need thereof, gastric ulcer, acute gastritis, chronic gastritis, dry eye syndrome, cancer, osteoarthritis, rheumatoid arthritis Or it provides a method of preventing or treating obesity.
  • the present invention provides the use of a pharmaceutically acceptable salt of a compound of formula (I) for the prevention or treatment of gastric ulcer, acute gastritis, chronic gastritis, dry eye syndrome, cancer, osteoarthritis, rheumatoid arthritis or obesity.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne un sel pharmaceutiquement acceptable d'un nouveau promédicament du rébamipide et une utilisation de celui-ci. Le nouveau sel de promédicament du rébamipide selon l'invention présente une excellente vitesse d'absorption dans le corps, par rapport au rébamipide, ce qui le rend utile dans la prévention ou le traitement des ulcères gastriques, de la gastrite aiguë, de la gastrite chronique, de la sécheresse oculaire, du cancer, de l'arthrose, de la polyarthrite rhumatoïde ou de l'obésité en remplaçant le rébamipide par le sel.
PCT/KR2015/000004 2015-01-02 2015-01-02 Nouveau sel de promédicament du rébamipide et son utilisation WO2016108319A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017138717A1 (fr) * 2016-02-11 2017-08-17 삼진제약주식회사 Composition pharmaceutique comprenant des promédicaments de rébamipide pour administration orale dans le traitement prophylactique ou thérapeutique d'une maladie immunitaire et d'une maladie métabolique
WO2020085760A1 (fr) * 2018-10-23 2020-04-30 삼진제약 주식회사 Composition pour prévenir ou traiter le syndrome de sjögren
RU2780509C1 (ru) * 2018-10-23 2022-09-26 Самдзин Фармасьютикал Ко., Лтд. Композиция для предупреждения или лечения синдрома шегрена

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002066436A1 (fr) * 2001-02-20 2002-08-29 Kyung Dong Pharm., Co., Ltd Procede de preparation d"acide propionique 2-(4-chlorobenzoylamino)-3-[2(1h)-quinolinon-4-yl]
WO2006059781A1 (fr) * 2004-12-01 2006-06-08 Otsuka Pharmaceutical Co., Ltd. Procédé amélioré de synthèse du rebamipide
WO2008074853A1 (fr) * 2006-12-21 2008-06-26 Novartis Ag Solution ophtalmique de rebamipide
KR20110100700A (ko) * 2010-03-05 2011-09-15 가톨릭대학교 산학협력단 유효성분으로서 레바미피드를 함유하는 골관절염 예방 또는 치료용 약학 조성물
WO2014003424A1 (fr) * 2012-06-26 2014-01-03 삼진제약 주식회사 Nouveau promédicament de rebamipide, son procédé de fabrication et son utilisation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002066436A1 (fr) * 2001-02-20 2002-08-29 Kyung Dong Pharm., Co., Ltd Procede de preparation d"acide propionique 2-(4-chlorobenzoylamino)-3-[2(1h)-quinolinon-4-yl]
WO2006059781A1 (fr) * 2004-12-01 2006-06-08 Otsuka Pharmaceutical Co., Ltd. Procédé amélioré de synthèse du rebamipide
WO2008074853A1 (fr) * 2006-12-21 2008-06-26 Novartis Ag Solution ophtalmique de rebamipide
KR20110100700A (ko) * 2010-03-05 2011-09-15 가톨릭대학교 산학협력단 유효성분으로서 레바미피드를 함유하는 골관절염 예방 또는 치료용 약학 조성물
WO2014003424A1 (fr) * 2012-06-26 2014-01-03 삼진제약 주식회사 Nouveau promédicament de rebamipide, son procédé de fabrication et son utilisation

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017138717A1 (fr) * 2016-02-11 2017-08-17 삼진제약주식회사 Composition pharmaceutique comprenant des promédicaments de rébamipide pour administration orale dans le traitement prophylactique ou thérapeutique d'une maladie immunitaire et d'une maladie métabolique
WO2020085760A1 (fr) * 2018-10-23 2020-04-30 삼진제약 주식회사 Composition pour prévenir ou traiter le syndrome de sjögren
JP2022505588A (ja) * 2018-10-23 2022-01-14 サムジン ファーマシューティカル カンパニー，リミテッド シェーグレン症候群の予防または治療用組成物
RU2780509C1 (ru) * 2018-10-23 2022-09-26 Самдзин Фармасьютикал Ко., Лтд. Композиция для предупреждения или лечения синдрома шегрена

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