WO2016108319A1 - Novel rebamipide prodrug salt and use thereof - Google Patents

Novel rebamipide prodrug salt and use thereof 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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WIPO (PCT)
Prior art keywords
acid
oxo
propionate
chlorobenzoylamino
dihydroquinolin
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PCT/KR2015/000004
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French (fr)
Korean (ko)
Inventor
조의환
최승주
이성우
신희종
권호석
이재웅
주정호
김현태
송우헌
윤종배
박기석
박호준
남호태
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삼진제약 주식회사
㈜에이에스텍
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Priority to PCT/KR2015/000004 priority Critical patent/WO2016108319A1/en
Publication of WO2016108319A1 publication Critical patent/WO2016108319A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—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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Abstract

The present invention relates to a pharmaceutically acceptable salt of a novel rebamipide prodrug and a use thereof. The novel rebamipide prodrug salt according to the present invention has an excellent absorption rate in the body, compared to rebamipide, and thus can be useful in preventing or treating gastric ulcers, acute gastritis, chronic gastritis, dry eye syndrome, cancer, osteoarthritis, rheumatoid arthritis, or obesity by substituting rebamipide with the salt.

Description

신규 레바미피드 전구체의 염 및 이의 용도Salts of New Levamifeed Precursors and Their Uses
본 발명은 신규 레바미피드 전구체(prodrug)의 약제학적으로 허용가능한 염 및 이의 용도에 관한 것으로서, 보다 상세하게는 전체적인 반응공정이 단순하면서도 기존의 레바미피드 물질이 가지는 효과와 더불어 개선된 효능을 보이는 신규 물질인 레바미피드 전구체의 약제학적으로 허용가능한 염 및 이의 용도에 관한 것이다. 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. A pharmaceutically acceptable salt of the levamifeed precursor, a novel novel material, and its use.
레바미피드(Rebamipide)는 소화성 궤양 치료제로 사용되고 있고, 화학명은 2-(4-클로로벤조일아미노)-3-[2(1H)-퀴놀론-4-일]프로피온산이다. 레바미피드는 위궤양, 급성위염, 또는 만성 위염의 급성 악화로 인한 위 점막 손상의 치료에 탁월한 효과를 가지는 의약이다. 이 약제는 PGE2 생합성을 촉진시켜 점액을 증가시킴으로써 위점막을 보호하고, 세포증식을 촉진시키며, 특히 헬리코박터 필로균에 감염된 환자에 있어서 위점막세포에 대한 균의 점착 및 침윤을 억제시킴으로써 위염증을 억제하는 특징을 갖는다.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.
레바미피드의 작용기전은 프로스타글라딘의 생합성을 촉진하여 방어인자를 증강시킴은 물론 방어인자증강제 중에서는 유일하게 항산화 작용이 있어서 헬리코박터에 의한 염증을 제거하는 작용을 동시에 나타냄으로써 방어인자증강과 염증억제의 두 가지 작용을 동시에 갖고 있다. 그러므로 궤양이나 위염환자에서 재발률을 현저히 낮추고 치료기간을 단축할 수 있는 매우 효과적인 약물이다. 아세트산을 투여하여 위궤양을 발생시킨 쥐를 이용한 실험에서도 치료율은 개선되면서 궤양의 크기, 재발율이 모두 레바미피드에 의해 감소되는 것을 확인할 수 있었다. 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.
종래에는 통상적으로 레바미피드의 제조 방법이나 고순도의 레바미피드를 얻는 방법들이 채택되었다. 그 예로서, 한국등록특허 제10-0669823호에는 2-(4-클로로벤조일아미노)-3-[2(1H)-퀴놀론-4-일]프로피온산의 제조방법 및 그 중간체가 개시되어 있고, 한국등록특허 제10-1032600호에는 수득률이 높고 저렴한 제조원가로 반응 및 정제를 동시에 수행하여 순도 99.95%수준의 고품질의 레바미피드를 제조할 수 있는 고순도 레바미피드의 제조방법이 개시되어 있다. Conventionally, the method of manufacturing levamifeed or the method of obtaining high purity levamifeed have been adopted. As an example, 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.
한편, 레바미피드는 위궤양, 급성 위염, 만성 위염, 안구 건조 증후군, 암, 골관절염, 류마티스 관절염 등을 예방 또는 치료하는데 유용한 효과를 보여주고 있으며, 최근의 연구결과에 의하면 레바미피드가 비만을 억제하는 효과를 보여 비만치료제로서도 관심을 불러 일으키고 있어, 레바미피드를 유효성분으로 포함하는 치료용 조성물이 다양하게 개발되고 있다. On the other hand, levamipid is effective in preventing or treating gastric ulcer, acute gastritis, chronic gastritis, dry eye syndrome, cancer, osteoarthritis, rheumatoid arthritis, etc. According to recent studies, 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.
레바미피드는 디메틸포름아미드에 용해되며, 메탄올, 에탄올에 약간 용해되며, 에테르와 물에는 거의 용해되지 않는다. 레바미피드의 수용성 용해도(aqueous solubility)는 대략적으로 pH 3에서 0.0001%(w/v)을, pH 7에서 0.013%(w/v)라고 보고되어 있다. 레바미피드는 낮은 용해도와 낮은 멤브레인 투과성으로 인하여 생물약제학 분류시스템(biopharmaceutiocs classification system : BCS)에서 Class로 등급이 매겨져 있으며, 체순환계에 거의 흡수 되지 않아 생체이용율(bioavailability)이 5% 내외로 알려져 있다. 이처럼 낮은 흡수율과 생체이용율로 인하여 상술한 것과 같은 다양한 효능을 가지는 레바미피드를 포함하는 약학 조성물을 개발하는데 있어 상대적으로 많은 양의 레바미피드를 복용하여야 하고, 때문에 투약시 환자들이 불편할 뿐만 아니라 약효도 투약량에 비해 현저하게 떨어지는 문제점이 남아 있었다. 이와 같이 낮은 수용성 용해도를 가지는 레바미피드의 경구 흡수율을 높이기 위해 다양한 노력들이 시도되고 있었으며, 특히 흡수촉진제(absorption enhancers)와 보조제의 도움을 받거나, 용해도를 증진시킨 다양한 형태의 염을 제조하는 기술들이 연구되어 왔으며, 대한민국공개특허 제10-2004-0104020호에서는 레바미피드 리지네이트와 레바미피드 아르기니네이트 및 이들을 유효성분으로 함유하는 약학적 제재에 대해 제안을 하였지만, 이의 인체에 대한 흡수율을 높이는 효과부분에 대해서는 의문이며, 이 이외에 유효하게 레바미피드의 체내 흡수율을 높일 수 있는 기술에 대해서는 제시되지 않고 있다. 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. The problem remained significantly lower compared to the dosage. Various efforts have been made to increase the oral absorption rate of levamifeed having low water solubility, and in particular, techniques for preparing various types of salts with the help of absorption enhancers and auxiliaries or enhancing solubility In the Republic of Korea Patent Publication No. 10-2004-0104020 has been proposed for levamipid ridgenate and levamipid arginate and pharmaceutical agents containing them as an active ingredient, but the absorption rate of the body It is questionable about the effective part, and there is no suggestion about a technology that can effectively increase the absorption rate of levamifeed in the body.
본 발명자들은 상술한 것과 같은 다양한 증상에 대해 유용한 효과를 보여주고 있으나 체내 흡수율이 현저히 떨어지는 레바미피드를 개선하기 위해 노력하던 중, 레바미피 전구체(prodrug)의 염이 레바미피드에 비해 체내 흡수율이 우수함을 확인하고 본 발명을 완성하였다. 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.
본 발명의 목적은 인체에 대한 흡수율을 증대시킨 신규 레바미피드 전구체의 약제학적으로 허용가능한 염을 제공하는 데 그 목적이 있다. It is an object of the present invention to provide a pharmaceutically acceptable salt of a novel levamipid precursor which has increased absorption in the human body.
상기 목적에 따라, 본 발명은 하기 화학식 I의 화합물의 약제학적으로 허용가능한 염이 제공된다:In accordance with this object, the present invention provides pharmaceutically acceptable salts of compounds of formula (I):
[화학식 I][Formula I]
Figure PCTKR2015000004-appb-I000001
Figure PCTKR2015000004-appb-I000001
상기 식에서, X 및 Y는 본원에서 정의한 바와 같다. Wherein X and Y are as defined herein.
상기 또 다른 목적에 따라 본 발명은 상기 레바미피드 전구체의 염을 유효성분으로 포함하는 위궤양, 급성 위염, 만성 위염, 안구 건조 증후군, 암, 골관절염, 류마티스 관절염, 고지혈증, 고중성지방증, 당뇨, 과민성대장증후군의 예방 또는 치료 및 비만 치료 및 억제효과를 가지는 약제학적 조성물을 제공한다. 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.
본 발명은 인체에 대한 흡수율을 증대시킨 신규 물질인 레바미피드 전구체의 염을 제공한다는 장점이 있다. 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.
또한, 본 발명에 의한 신규 레바미피드 전구체의 염은 유리산으로 존재하는 레바미피드에 비해 체내 흡수율을 현저하게 증대시킴으로써 적은 양을 복용하더라도 효과적으로 위궤양, 급성 위염, 만성 위염, 안구 건조 증후군, 암, 골관절염, 류마티스 관절염, 비만, 고지혈증, 고중성지방증, 당뇨, 과민성대장증후군 등의 각종 질환을 예방 또는 치료하는데 유용하게 사용될 수 있다는 장점이 있다.In addition, 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.
이하 본 발명을 상세히 설명한다. Hereinafter, the present invention will be described in detail.
본 발명은 위궤양, 급성 위염, 만성 위염, 안구 건조 증후군, 암, 골관절염, 류마티스 관절염 등의 예방 또는 치료 용도가 공지되어 있는 레바미피드의 전구체의 염을 제공한다. 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.
하나의 양태에 있어서, 하기 화학식 I의 화합물의 약제학적으로 허용가능한 염이 제공된다:In one embodiment there is provided a pharmaceutically acceptable salt of a compound of formula (I):
[화학식 I][Formula I]
Figure PCTKR2015000004-appb-I000002
Figure PCTKR2015000004-appb-I000002
상기 식에서, Where
X는 산소, 질소 또는 황 중 어느 하나이고;X is any one of oxygen, nitrogen or sulfur;
Y는 C1-C6알킬, C1-C6할로알킬, (C1-C3알킬옥시)C1-C6알킬, (C2-C6알켄일옥시)C1-C6알킬, (C1-C6알킬카르보닐옥시)C1-C6알킬, (C1-C6알킬설판일)C1-C6알킬, (아릴설판일)C1-C6 알킬, (아릴설폰일)C1-C6 알킬, (C1-C6알킬아미노)C1-C6알킬, [(C1-C6알킬)(C1-C6알킬)아미노]C1-C6알킬, [(C1-C3알킬)(아릴)아미노]C1-C6알킬, [(C1-C3알킬)(아릴)C1-C3알킬]아미노C1-C6알킬, [(C1-C3알킬)(헤테로아릴)아미노]C1-C6알킬, (아릴카르보닐아미노)C1-C6알킬,C2-C6알켄일, C2-C6알카인일, C2-C6옥소알킬, C3-C8사이클로알킬, (C3-C8사이클로알킬)C1-C6알킬, (C3-C8사이클로알켄일)C1-C6알킬, (C3-C8헤테로사이클로알킬)C1-C6알킬, [(C1-C3알킬)C3-C8헤테로사이클로알킬]C1-C6알킬, [(아릴)C1-C3알킬]C3-C8헤테로사이클로알킬C1-C6알킬, [(C1-C6알킬옥시카르보닐)C3-C8헤테로사이클로알킬]C1-C6알킬, [(C1-C3알킬옥시카르보닐)C3-C8헤테로사이클로알킬]C1-C6알킬, (C3-C8헤테로사이클로알킬)C1-C6알켄일, [(C1-C3알킬)C3-C8헤테로사이클로알켄일]C1-C6알킬, (아릴)C1-C6알킬, [(C1-C3알킬)아릴]C1-C6알킬, [(C1-C3알킬옥시)아릴]C1-C6알킬, [(아릴옥시)아릴]C1-C6알킬, [(C1-C3알킬설판일)아릴]C1-C6알킬, [(C1-C3알킬옥시카르보닐)아릴]C1-C6알킬, [(아릴옥시카르보닐)아릴]C1-C6알킬, (아릴)C3-C6알켄일, (헤테로아릴)C1-C6알킬, [(알킬옥시카르보닐)헤테로아릴]C1-C6알킬, [(C1-C3알킬)C3-C8헤테로아릴]C1-C6알킬, [(C3-C8사이클로알킬)헤테로아릴]C1-C6알킬, [(아릴)헤테로아릴]C1-C6알킬, [(C1-C3알킬)헤테로아릴]C1-C6알킬, [(아릴)C1-C3알킬]헤테로아릴C1-C6알킬, (C1-C6알킬옥시카르보닐)C1-C6알킬, [(C3-C8헤테로사이클로알킬)C1-C6알킬옥시카르보닐]C1-C6알킬, (C3-C8헤테로사이클로알킬카르보닐)C1-C6알킬, [(C1-C3알킬)C3-C8헤테로사이클로알킬카르보닐]C1-C6알킬, [(C1-C3알킬)C3-C8헤테로사이클로알킬카르보닐]C1-C6알킬, [(C3-C8사이클로알킬)옥시카르보닐옥시]C1-C6알킬, [(C3-C8헤테로사이클로알킬)옥시카르보닐옥시]C1-C6알킬, (유레이도)C1-C6알킬, (아릴유레이도)C1-C6알킬, [(아릴)(C1-C3알킬유레이도]C1-C6알킬, (C1-C6알킬아미노카르보닐)C1-C6알킬, [(C3-C8헤테로사이클로알킬)아미노카르보닐]C1-C6알킬, [(C1-C3알킬)C3-C8헤테로사이클로알킬]아미노카르보닐C1-C6알킬, [(C1-C3알킬)(C1-C3알킬옥시)아미노카르보닐]C1-C6알킬 또는 (옥소C3-C8헤테로사이클로알킬)C1-C6알킬일 수 있다. 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 3 alkyl) (aryl) C 1 -C 3 alkyl] aminoC 1 -C 6 alkyl, [ (C 1 -C 3 alkyl) (heteroaryl) amino] C 1 -C 6 alkyl, (arylcarbonylamino) 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 cycloalkyl) C 1 -C 6 alkyl, (C 3 -C 8 cycloalkenyl) C 1 -C 6 alkyl, (C 3 -C 8 heterocycloalkyl) C 1 -C 6 alkyl, [(C 1 -C 3 alkyl) C 3 -C 8 heterocycloalkyl] C 1 -C 6 alkyl, [(aryl) C 1 -C 3 alkyl] C 3 -C 8 heterocycloalkyl al C 1 -C 6 alkyl, [(C 1 -C 6 alkyloxycarbonyl) C 3 -C 8 heterocycloalkyl] C 1 -C 6 alkyl, [(C 1 -C 3 alkyloxycarbonyl) C 3 - C 8 heterocycloalkyl] C 1 -C 6 alkyl, (C 3 -C 8 heterocycloalkyl) C 1 -C 6 alkenyl, [(C 1 -C 3 alkyl) C 3 -C 8 heterocycloalkenyl] C 1 -C 6 alkyl, (aryl) C 1 -C 6 alkyl, [(C 1 -C 3 alkyl) aryl] C 1 -C 6 alkyl, [(C 1 -C 3 alkyloxy) aryl] C 1- C 6 alkyl, [(aryloxy) aryl] C 1 -C 6 alkyl, [(C 1 -C 3 alkylsulfanyl) aryl] C 1 -C 6 alkyl, [(C 1 -C 3 alkyloxycarbonyl) Aryl] C 1 -C 6 alkyl, [(aryloxycarbonyl) aryl] C 1 -C 6 alkyl, (aryl) C 3 -C 6 alkenyl, (heteroaryl) C 1 -C 6 alkyl, [(alkyl Oxycarbonyl) heteroaryl] C 1 -C 6 alkyl, [(C 1 -C 3 alkyl) C 3 -C 8 heteroaryl] C 1 -C 6 alkyl, [(C 3 -C 8 cycloalkyl) heteroaryl ] C 1 -C 6 alkyl, [(aryl) heteroaryl] C 1 -C 6 alkyl, [(C 1 -C 3 alkyl) heteroaryl] C 1 -C 6 alkyl, [(aryl) C 1- C 3 alkyl] heteroarylC 1 -C 6 alkyl, (C 1 -C 6 alkyloxycarbonyl) C 1 -C 6 alkyl, [(C 3 -C 8 heterocycloalkyl) C 1 -C 6 alkyloxycar Carbonyl] C 1 -C 6 alkyl, (C 3 -C 8 heterocycloalkylcarbonyl) C 1 -C 6 alkyl, [(C 1 -C 3 alkyl) C 3 -C 8 heterocycloalkylcarbonyl] C 1 -C 6 alkyl, [(C 1 -C 3 alkyl) C 3 -C 8 heterocycloalkyl-carbonyl] C 1 -C 6 alkyl, [(C 3 -C 8 cycloalkyl) oxy carbonyloxy] C 1 - C 6 alkyl, [(C 3 -C 8 heterocycloalkyl) oxycarbonyloxy] C 1 -C 6 alkyl, (ureido) C 1 -C 6 alkyl, (arylureido) C 1 -C 6 alkyl, [(Aryl) (C 1 -C 3 alkylureido) C 1 -C 6 alkyl, (C 1 -C 6 alkylaminocarbonyl) C 1 -C 6 alkyl, [(C 3 -C 8 heterocycloalkyl) Aminocarbonyl] C 1 -C 6 alkyl, [(C 1 -C 3 alkyl) C 3 -C 8 heterocycloalkyl] aminocarbonylC 1 -C 6 alkyl, [(C 1 -C 3 alkyl) (C 1 -C 3 alkyloxy) aminocarbonyl] C 1 -C 6 alkyl Or (oxoC 3 -C 8 heterocycloalkyl) C 1 -C 6 alkyl.
상기 C1-C6알킬, C2-C6알켄일, C2-C6알카인일, C2-C6옥소알킬, C3-C8사이클로알킬, C3-C8사이클로알켄일, C3-C8헤테로사이클로알켄일, 아릴 또는 헤테로아릴은 C1-C3알킬, 플루오로, 클로로, 브로모, 하이드록시기, 옥소, 니트로기 및 시아노기로 이루어진 군으로서 선택된 하나 이상의 치환기로 치환될 수 있다. 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.
본원에 사용된 용어 "헤테로사이클로알킬" 또는 "헤테로사이클로알켄일"은 포화탄소 대신에 질소, 산소, 또는 황 중 어느 하나가 치환되거나, 같은 원자 또는 서로 다른 원자가 단일, 둘 또는 셋이 이웃하거나 또는 건너뛰어 치환됨을 의미한다. 상기 헤테로사이클로알킬 또는 헤테로사이클로알켄일의 예로는 아지리딘, 옥시란, 아제티딘, 옥세탄, 피롤리딘, 피롤린, 피라졸리딘, 피라졸린, 이미다졸리딘, 이미다졸린, 트리아졸리딘, 옥사졸리딘, 테트라하이드로퓨란, 테트라하이드로티오펜, 티아졸리딘, 다이옥솔란, 다이옥솔, 옥사티올란, 모폴린. 티오모폴린, 다이티안, 피페리딘, 피페라진, 피란, 다이옥산 또는 아제판을 들 수 있으나, 이에 제한되지는 않는다. As used herein, the term "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. Examples of the heterocycloalkyl or heterocycloalkenyl 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.
또한, 본원에 사용된 용어 "아릴"의 구체적인 예로는 벤젠, 나프탈렌, 안트라센, 또는 페난트렌을 들 수 있으나, 이에 제한되지는 않는다. In addition, specific examples of the term “aryl” as used herein include, but are not limited to, benzene, naphthalene, anthracene, or phenanthrene.
나아가, 본원에 사용된 용어 "헤테로아릴"은 질소, 산소, 또는 황 중 어느 하나가 치환되거나, 같은 원자 또는 서로 다른 원자가 단일, 둘 또는 셋이 이웃하거나 또는 건너뛰어 치환된 아릴을 의미한다. 상기 헤테로아릴의 구체적인 예로는 피롤, 이미다졸, 피라졸, 트리아졸, 퓨란, 티오펜, 옥사졸, 아이소옥사졸, 티아졸, 아이소티아졸, 옥사다이아졸, 티아다이아졸, 피리딘, 피리미딘, 피라진, 피리다진, 트리아진, 아제핀, 인돌, 벤즈이미다졸, 인다졸, 벤조옥사졸, 벤조아이소옥사졸, 벤조티아졸, 벤조트리아졸, 벤조퓨란, 벤조티오펜, 퀴놀린, 아이소퀴놀린, 퀴녹살린, 퀴나졸린, 시놀린, 나프티리딘, 프탈라진, 벤조피란, 벤즈옥사진, 벤조트리아진, 크로만, 크로멘, 벤조다이옥산 아트리딘, 페노티아진, 페노옥사진 또는 카바졸을 들 수 있으나, 이에 제한되지 않는다. Further, as used herein, the term “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. Specific examples of 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, phthalazine, benzopyran, benzoxazine, benzotriazine, chromman, chromen, benzodioxane atridine, phenothiazine, phenooxazine or carbazole. However, the present invention is not limited thereto.
본원에서, X-Y는 아미노산 또는 아미노산 (C1-C3알킬)에스테르를 나타낸다. 아미노산은 이에 제한되는 것은 아니나, 글라이신, 류신, 메티오닌, 발린, 알라닌, 아이소류신, 프롤린, 트립토판, 페닐알라닌, 세린, 트레오닌, 아스파라긴, 글루탐산, 라이신, 히스티딘, 또는 타이로신을 말한다. In the present application, 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.
본 발명에 따른 레바미피드 전구체의 약제학적으로 허용가능한 염은 약제학적으로 허용가능한 유리산(free acid)에 의하여 형성된 산 부가염이 바람직하며, 상기 유리산으로는 유기산과 무기산을 사용할 수 있다. 상기 유기산은 이에 제한되는 것은 아니나, 구연산, 초산, 젖산, 주석산, 타르타르산, 말레인산, 푸마르산, 포름산, 프로피온산, 옥살산, 다이클로로아세트산, 트리클로로아세트산, 트리플로오로아세트산, 아디프산, 아스코브산, 벤조산, 4-아세트아미도벤조산, 글루콘산, 설폰산, 메탄설폰산, 카프르산, 카프론산, 카프릴산, 카르본산, 신남산, 사이클람산, 도데실설폰산, 에탄-1,2-다이설폰산, 에탄설폰산, 2-하이드록시에탄설폰산, 갈락타르산, 겐티스산, 글루타르산, 2-옥소글루타르산, 글리세로포스포르산, 히푸르산, 올레산, 오로트산, 팔미트산, 파모산, 파이로글루탐산, 세바스산, 스테아르산, 티오시안산, 운데실렌산, 아이소부티르산, 라우르산, 만델산, 나프탈렌-1,5-다이설폰산, 나프탈렌-2-설폰산, 나프토산, 니코틴산, 글리콜산, 석신산, 4-톨루엔설폰산, 캠퍼설폰산, 글루탐산, 아스파르트산, 살리실산, 4-아미노살리실산, 말론산, 말산 및 벤조설폰산을 포함한다. 또한 상기 무기산은 이에 제한되는 것은 아니나, 염산, 브롬산, 황산, 질산, 요오드산 및 인산을 포함한다.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, 2-hydroxyethanesulfonic acid, galactaric acid, gentisic acid, glutaric acid, 2-oxoglutaric acid, glycerophosphoric acid, hypofuric acid, oleic acid, orotic acid, Palmitic acid, pamoic acid, pyroglutamic acid, sebacic acid, stearic acid, thiocyanic acid, undecylenic acid, isobutyric acid, lauric acid, mandelic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfur Phonic acid, naphthoic acid, nicotinic acid, glycolic acid, succinic acid, 4-toluenesulfone Acids, camphorsulfonic acid, glutamic acid, aspartic acid, salicylic acid, 4-aminosalicylic acid, malonic acid, malic acid and benzosulfonic acid. In addition, the inorganic acid includes, but is not limited to, hydrochloric acid, bromic acid, sulfuric acid, nitric acid, iodic acid and phosphoric acid.
바람직한 레바미피드 전구체의 염 화합물로는 하기를 들 수 있으나, 이에 제한되는 것은 아니다: Preferred salt compounds of the levamifeed precursors include, but are not limited to:
1) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 글리콜레이트; 1) 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate glycolate;
2) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 락테이트;2) 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate lactate;
3) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 살리실레이트;3) 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate salicylate;
4) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 옥살레이트; 4) 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate oxalate;
5) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 말로네이트;5) 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate malonate;
6) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 말레이트; 6) 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate maleate;
7) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 타르타레이트;7) 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate tartarate;
8) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 말레에이트;8) 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate maleate;
9) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 푸마레이트;9) 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate fumarate;
10) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 시트레이트;10) 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate citrate;
11) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 벤젠설포네이트;11) 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate benzenesulfonate;
12) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 토실레이트;12) 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate tosylate;
13) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 하이드로클로레이트;13) 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate hydrochlorate;
14) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 설페이트;14) 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate sulfate;
15) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 포스포레이트;15) 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate phosphorate;
16) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 아세테이트;16) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate acetate;
17) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 다이클로로아세테이트;17) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate dichloroacetate;
18) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 아디페이트;18) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate adipate;
19) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 아스코베이트;19) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate ascorbate;
20) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 벤조에이트;20) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate benzoate;
21) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 4-아세트아미도벤조에이트;21) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate 4-acetamidobenzo Eight;
22) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 카프레이트;22) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate caprate;
23) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 카프로네이트;23) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate capronate;
24) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 카프릴레이트;24) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate caprylate;
25) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 카르보네이트;25) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate carbonate;
26) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 신나메이트;26) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate cinnamate;
27) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 사이클라메이트;27) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate cyclomate;
28) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 도데실설포네이트;28) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate dodecylsulfonate;
29) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 에탄-1,2-다이설포네이트;29) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate ethane-1,2- Disulfonates;
30) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 에탄설포네이트;30) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate ethanesulfonate;
31) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 2-하이드록시에탄설포네이트;31) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate 2-hydroxyethanesulfo Nate;
32) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 포르메이트;32) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate formate;
33) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 갈락타레이트;33) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate galactate;
34) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 겐티세이트;34) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate gentisate;
35) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 글루타메이트;35) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate glutamate;
36) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 글루타레이트;36) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate glutarate;
37) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 2-옥소글루타레이트;37) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate 2-oxoglutarate ;
38) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 글리세로포스포레이트;38) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate glycerophosphorate;
39) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 히푸레이트;39) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate hipurate;
40) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 올레에이트;40) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate oleate;
41) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 오로테이트41) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate orotate
42) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 팔미테이트;42) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate palmitate;
43) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 파모에이트;43) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate pamoate;
44) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 프로피오네이트;44) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate propionate;
45) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 파이로글루타메이트;45) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate pyroglutamate;
46) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 4-아미노살리실레이트;46) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate 4-aminosalicylate ;
47) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 세바세이트;47) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate sebacate;
48) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 스테아레이트;48) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate stearate;
49) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 티오시아네이트;49) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate thiocyanate;
50) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 운데실레네이트;50) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate undecylenate;
51) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 하이드로브로메이트;51) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate hydrobromate;
52) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 아이소부티레이트;52) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate isobutyrate;
53) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 라우레이트;53) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate laurate;
54) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 DL-만델레이트;54) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate DL-mandelate;
55) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 메탄설포네이트;55) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate methanesulfonate;
56) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 나프탈렌-1,5-다이설포네이트;56) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate naphthalene-1,5- Disulfonates;
57) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 나프탈렌-2-설포네이트;57) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate naphthalene-2-sulfonate ;
58) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 2-나프토에이트;58) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate 2-naphthoate;
59) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 니코티네이트;59) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate nicotinate;
60) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 니트레이트;60) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate nitrate;
61) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 석시네이트의 제조61) Preparation of 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate succinate
62) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 설퍼레이트; 및62) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate sulfate; And
63) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 L-아스파르테이트.63) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate L-aspartate.
한편, 본 발명에 따른 화학식 I의 화합물의 약제학적으로 허용가능한 염은 하기 화학식 II의 화합물을 하기 화학식 III의 화합물과 반응시켜 제조된 화학식 I의 화합물로부터 제조될 수 있다. On the other hand, 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).
[화학식 II][Formula II]
Figure PCTKR2015000004-appb-I000003
Figure PCTKR2015000004-appb-I000003
[화학식 III][Formula III]
Y-ZY-Z
상기 식에서, Where
X 및 Y는 전술한 바와 같으며, Z는 하이드록시, 아미노, 아민, 할로겐 또는 이탈기(Leaving group)이다. X and Y are as described above, Z is hydroxy, amino, amine, halogen or leaving group.
본 발명의 하나의 실시형태에서, Z는 하이드록시, -NH2, Cl, Br, 알킬설포닐 또는 아릴설포닐이다. In one embodiment of the invention, Z is hydroxy, -NH 2 , Cl, Br, alkylsulfonyl or arylsulfonyl.
구체적으로, 본 발명에 따른 화학식 I의 화합물의 약제학적으로 허용가능한 염는 하기 [반응식 1]에 표기한 방법으로 제조된 화학식 I의 화합물로부터 제조될 수 있지만, 이에 제한되는 것은 아니다.Specifically, 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.
[반응식 1] Scheme 1
[규칙 제91조에 의한 정정 04.03.2015]　
Figure WO-DOC-FIGURE-117
[Revision under Rule 91 04.03.2015]
Figure WO-DOC-FIGURE-117
(상기 식에서, X는 산소, 질소 또는 황 중 어느 하나이다)Wherein X is any one of oxygen, nitrogen or sulfur
상기 [반응식 1]에서 출발물질로 사용된 [화학식 II]의 화합물은 미국 특허 제4,578,381호에 기술된 방법에 의해 제조될 수 있다. 상기 [반응식 1]에 표기한 무기염은 소디움바이카보네이트, 소디움카보네이트, 포타슘바이카보네이트, 포타슘카보네이트 또는 세슘카보네이트와 같은 무기 염기일 수 있으며, 용매는 아세톤, 다이메틸포름아마이드, 다이메틸설폭사이드, 또는 아세토나이트릴일 수 있고, 반응은 10 내지 100℃에서 1 내지 24시간 동안 수행할 수 있다. 상기 반응식에서 DCC는 다이사이클로헥실카보다이이마이드; DMAP는 4-다이메틸아미노피리딘; HOBT는 1-하이드록시벤조트리아졸; 및 EDCI는 1-에틸-3-(3-다이메틸아미노프로필)카보다이이마이드 염산을 의미하며, Y-OMs 또는 Y-OTs은 설포닐기로서 메탄설포닐기와 같은 알킬설포닐기; 또는 파라톨루엔설포닐, 벤젠설포닐 또는 4-니트로벤젠설포닐기와 같은 아릴설포닐기를 포함한다.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 ℃ for 1 to 24 hours. In the above scheme, DCC is dicyclohexylcarbodiimide; DMAP is 4-dimethylaminopyridine; HOBT is 1-hydroxybenzotriazole; And EDCI means 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloric acid, and 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.
상기 [반응식 1]에서 X가 황인 [화학식 II]의 화합물은 하기 [반응식 2]의 과정에 따라 제조될 수 있다.The compound of [Chemical Formula II] wherein X is sulfur in [Scheme 1] may be prepared according to the following [Scheme 2].
[반응식 2]Scheme 2
[규칙 제91조에 의한 정정 04.03.2015]　
Figure WO-DOC-FIGURE-123
[Revision under Rule 91 04.03.2015]
Figure WO-DOC-FIGURE-123
상기 [반응식 2]에서 소디움하이드로설파이드는 1 내지 10 당량, 바람직하게는 4 내지 6당량의 양으로 사용될 수 있고, 소디움설파이드는 1 내지 5 당량, 바람직하게는 2 내지 3 당량의 양으로 사용될 수 있다. 상기 [반응식 2]에서 용매로서 다이메틸포름아마이드, 다이메틸설폭사이드 또는 아세토나이트릴이 사용될 수 있고, 반응은 10 내지 100℃에서 1 내지 24시간 동안 수행될 수 있다. 상기 반응식에서 NCS는 N-클로로석시니이마이드를 지칭한다. 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.
구체적으로, 본 발명에 따른 화학식 I의 화합물의 약제학적으로 허용가능한 염은 하기의 일반적인 실험방법에 따라 제조되는 레바미피드 전구체로부터 제조될 수 있다. Specifically, 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.
실험방법 AExperiment Method A
[규칙 제91조에 의한 정정 04.03.2015]　
Figure WO-DOC-FIGURE-128
[Revision under Rule 91 04.03.2015]
Figure WO-DOC-FIGURE-128
[화학식 II]의 화합물을 DMF(다이메틸포름아마이드, 화학식 II 화합물 무게의 8~10배 부피량)에 가열하여 녹인 후 0℃로 냉각시킨다. 상기 혼합물에 DCC(다이사이클로헥실카보다이이마이드, 1~1.5 당량) 및 DMAP(다이메틸아미노피리딘, 0.1~0.3 당량)를 첨가한다. 첨가 후 내부온도가 안정화되면 알콜 또는 아민(1~1.2 당량)을 천천히 첨가한다. 상기 혼합물을 실온에서 4 내지 24시간 동안 교반한 후, 생성된 부산물을 여과하여 제거하고, 감압 하에 DMF를 제거한다. 이후, 메틸렌클로라이드 : 메탄올 (9:1, v/v)을 이용한 컬럼 크로마토그래피를 수행하여 고체 상태의 [화학식 I]의 화합물을 수득한다. 필요한 경우 재결정을 수행한다.The compound of [Formula II] is dissolved in DMF (dimethylformamide, 8 to 10 times by volume of the weight of the compound of Formula II), dissolved and cooled to 0 ° C. To the mixture is added DCC (dicyclohexylcarbodiimide, 1-1.5 equiv) and DMAP (dimethylaminopyridine, 0.1-0.3 equiv). When the internal temperature stabilizes after addition, add alcohol or amine (1 to 1.2 equivalents) slowly. The mixture is stirred at room temperature for 4 to 24 hours, after which the resulting by-products are filtered off and DMF is removed under reduced pressure. Thereafter, column chromatography is performed with methylene chloride: methanol (9: 1, v / v) to obtain a compound of formula (I) in a solid state. If necessary, perform a recrystallization.
실험방법 BExperiment Method B
[규칙 제91조에 의한 정정 04.03.2015]　
Figure WO-DOC-FIGURE-132
[Revision under Rule 91 04.03.2015]
Figure WO-DOC-FIGURE-132
[화학식 II]의 화합물을 DMF(다이메틸포름아마이드, 화학식 II 화합물의 8~10배 부피량)에 가열하여 녹인 후 0℃로 냉각시킨다. 상기 혼합물에 EDCI(1-에틸-3-(3-다이메틸아미노프로필)카보다이이마이드 염산, 1~3 당량) 및 HOBT(1-하이드록시벤조트리아졸, 1~3 당량)를 첨가한다. 첨가 후 내부온도가 안정화되면 알콜 또는 아민(1~1.5 당량)을 천천히 첨가한다. 상기 혼합물을 실온에서 4 내지 24시간 동안 교반한 후, 생성된 부산물을 여과하여 제거하고, 감압 하에 DMF를 제거한다. 이후, 메틸렌클로라이드 : 메탄올 (9:1, v/v)을 이용한 컬럼 크로마토그래피를 수행하여 고체 상태의 [화학식 I]의 화합물을 수득한다. 필요한 경우 재결정을 수행한다.The compound of [Formula II] is dissolved in DMF (dimethylformamide, 8 to 10 times by volume of the compound of Formula II) and dissolved, and then cooled to 0 ° C. To the mixture are added EDCI (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloric acid, 1-3 equivalents) and HOBT (1-hydroxybenzotriazole, 1-3 equivalents). When the internal temperature stabilizes after addition, add alcohol or amine (1 to 1.5 equivalents) slowly. The mixture is stirred at room temperature for 4 to 24 hours, after which the resulting by-products are filtered off and DMF is removed under reduced pressure. Thereafter, column chromatography is performed with methylene chloride: methanol (9: 1, v / v) to obtain a compound of formula (I) in a solid state. If necessary, perform a recrystallization.
실험방법 CExperiment Method C
[규칙 제91조에 의한 정정 04.03.2015]　
Figure WO-DOC-FIGURE-136
[Revision under Rule 91 04.03.2015]
Figure WO-DOC-FIGURE-136
[화학식 II]의 화합물에 DMF(다이메틸포름아마이드, 화학식 II 화합물의 8~10배 부피량), 할로겐 화합물(1~1.5 당량) 및 무기염(1~2 당량)을 차례로 첨가하여 20~80℃에서 1~24시간 동안 반응시킨다. 반응 종료 후, 부산물을 여과하여 제거하고, 감압 하에 DMF를 제거한다. 이후, 메틸렌클로라이드 : 메탄올 (9:1, v/v)을 이용한 컬럼 크로마토그래피를 수행하여 고체 상태의 [화학식 I]의 화합물을 수득한다. 필요한 경우 재결정을 수행한다.DMF (dimethylformamide, 8 to 10 times the volume of the compound of formula II), a halogen compound (1 to 1.5 equivalents) and an inorganic salt (1 to 2 equivalents) are sequentially added to the compound of the formula [II] to 20 to 80 The reaction is carried out at 1 ° C. for 1 to 24 hours. After completion of the reaction, by-products are filtered off and DMF is removed under reduced pressure. Thereafter, column chromatography is performed with methylene chloride: methanol (9: 1, v / v) to obtain a compound of formula (I) in a solid state. If necessary, perform a recrystallization.
실험방법 DExperiment Method D
[규칙 제91조에 의한 정정 04.03.2015]　
Figure WO-DOC-FIGURE-140
[Revision under Rule 91 04.03.2015]
Figure WO-DOC-FIGURE-140
[화학식 II]의 화합물에 DMF(다이메틸포름아마이드, 화학식 II 화합물의 8~10배 부피량), 설포네이트 화합물(1~1.5 당량) 및 무기염(1~2 당량)을 차례로 첨가하여 20~80℃에서 1~24시간 동안 반응시킨다. 반응 종료 후, 부산물을 여과하여 제거하고, 감압 하에 DMF를 제거한다. 이후, 메틸렌클로라이드 : 메탄올 (9:1, v/v)을 이용한 컬럼 크로마토그래피를 수행하여 고체 상태의 [화학식 I]의 화합물을 수득한다. 필요한 경우 재결정을 수행한다.DMF (dimethylformamide, 8 to 10 times the volume of the compound of formula II), sulfonate compound (1 to 1.5 equivalents), and inorganic salt (1 to 2 equivalents) are sequentially added to the compound of the formula The reaction is performed at 80 ° C. for 1 to 24 hours. After completion of the reaction, by-products are filtered off and DMF is removed under reduced pressure. Thereafter, column chromatography is performed with methylene chloride: methanol (9: 1, v / v) to obtain a compound of formula (I) in a solid state. If necessary, perform a recrystallization.
더욱 구체적으로, 상기 화학식 I로 표시되는 레바미피드 전구체 중 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)-티오프로피온산은 실험방법 A 또는 B에 따라 다음과 같이 제조된다More specifically, 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. According to A or B is prepared as follows
실험방법 AExperiment Method A
레바미피드 50 g(134.8 mmol)을 DMF(다이메틸포름아마이드) 400 mL에 가열하여 녹인 후 실온으로 냉각시킨다. 상기 혼합물에 DCC(다이사이클로헥실카보다이이마이드) 28.1 g(1.0eq, 134.8 mmol)을 가한 후 30분간 교반한다. 상기 혼합물에 NaSH(소디움하이드로설파이드) 16.0 g(1.0eq, 134.8 mmol)을 가한 후 실온에서 15시간 동안 교반한다. 반응 종료 후, 상기 혼합물에 물 800 mL를 가한 다음, 에틸초산 800 mL로 3번 추출한다. 유기상에 무수 황산마그네슘을 가하여 건조하고 여과하고 농축한 다음, 잔류물에 에틸초산 800 mL을 가하여 실온에서 교반한다. 생성된 침전물을 여과하고 건조하여 노란색 고체의 표제화합물(42.0 g)을 수득한다. 50 g (134.8 mmol) of levamipid are dissolved in 400 mL of DMF (dimethylformamide), and then cooled to room temperature. 28.1 g (1.0eq, 134.8 mmol) of DCC (dicyclohexylcarbodiimide) was added to the mixture, followed by stirring for 30 minutes. 16.0 g (1.0eq, 134.8 mmol) of NaSH (sodium hydrosulfide) was added to the mixture, followed by stirring at room temperature for 15 hours. After the reaction was completed, 800 mL of water was added to the mixture, followed by extraction three times with 800 mL of ethyl acetate. Anhydrous magnesium sulfate was added to the organic phase, dried, filtered and concentrated. Then, 800 mL of ethyl acetate was added to the residue, followed by stirring at room temperature. The resulting precipitate is filtered and dried to give the title compound (42.0 g) as a yellow solid.
실험방법 BExperiment Method B
레바미피드 10 g(26.97 mmol)을 DMF(다이메틸포름아마이드) 80 mL에 가열하여 녹인 후 0℃로 냉각시킨다. 상기 혼합물에 EDCI(1-에틸-3-(3-다이메틸아미노프로필)카보다이이마이드 염산) 5.69 g(1.1eq, 29.67 mmol) 및 Na2S(소디움설파이드) 13.6 g (3.0eq, 80.9 mmol)을 가한 후 얼음 수조를 제거한 다음 실온에서 3시간 교반한다. 반응 종료 후, 상기 혼합물에 물 160 mL를 가한 다음, 에틸초산 160 mL로 3번 추출한다. 유기상에 무수 황산마그네슘을 가하여 건조하고 여과하고 농축한 다음, 잔류물에 에틸초산 200 mL을 가하여 실온에서 교반한다. 생성된 침전물을 여과하고 건조하여 노란색 고체의 표제화합물(6.5 g)을 수득한다. 10 g (26.97 mmol) of levamifeed are dissolved in 80 mL of DMF (dimethylformamide), and then cooled to 0 ° C. 5.69 g (1.1 eq, 29.67 mmol) of EDCI (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloric acid) and 13.6 g (3.0 eq, 80.9 mmol) of Na 2 S (sodium sulfide) were added to the mixture. After the addition of the ice bath was removed and stirred for 3 hours at room temperature. After the reaction was completed, 160 mL of water was added to the mixture, followed by extraction three times with 160 mL of ethyl acetate. Anhydrous magnesium sulfate was added to the organic phase, dried, filtered and concentrated, and 200 mL of ethyl acetate was added to the residue, followed by stirring at room temperature. The resulting precipitate is filtered and dried to give the title compound (6.5 g) as a yellow solid.
한편, 본 발명에 따른 레바미피드 전구체의 염은 하기의 일반적인 실험방법 E에 따라 제조될 수 있으나, 이에 제한되지 않는다. Meanwhile, 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.
실험방법 EExperimental Method E
[규칙 제91조에 의한 정정 04.03.2015]　
Figure WO-DOC-FIGURE-151
[Revision under Rule 91 04.03.2015]
Figure WO-DOC-FIGURE-151
[화학식 I]의 화합물을 다이메틸설폭사이드 또는 다이메틸포름아마이드([화학식 I]의 화합물 무게의 3~10배 부피)에 녹인다. 상기 혼합물에 유기산 또는 무기산([화학식 I]의 화합물의 1 당량)을 가하고 교반하여 고체화시켜 상기 [화학식 III]의 화합물을 수득한다.Dissolve the compound of Formula I in dimethylsulfoxide or dimethylformamide (3-10 times the volume by weight of the compound of Formula I). An organic acid or an inorganic acid (1 equivalent of the compound of [Formula I]) is added to the mixture, followed by solidification by stirring to obtain the compound of Formula III.
본 발명의 화학식 I의 화합물의 염은 유리산 상태의 레바미피드에 비해 체내 흡수율이 뛰어나므로, 레바미피드를 대체하여 위궤양, 급성 위염, 만성 위염, 안구 건조 증후군, 암, 골관절염, 류마티스 관절염 또는 비만을 예방 또는 치료하는데 유용하게 사용될 수 있다. 상기 질환은 레바미피드가 예방 또는 치료할 수 있는 것으로 이미 공개되어 있는 것으로서, 본 발명의 레바미피드 전구체는 레바미피드보다 상기 질환에 더 효과적으로 사용될 것이다. 이에, 본 발명은 화학식 I의 화합물의 약제학적으로 허용가능한 염을 유효성분으로 포함하는, 위궤양, 급성 위염, 만성 위염, 안구 건조 증후군, 암, 골관절염, 류마티스 관절염 또는 비만의 예방 또는 치료용 약제학적 조성물을 제공한다. Since 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. Accordingly, 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.
본 발명에 따른 레바미피드 화합물의 염의 약학적으로 유효한 양은 환자의 체중 1kg 당 0.5 ~ 100 mg/day, 바람직하게는 1 ~ 30 mg/day이다. 그러나 상기 약학적으로 유효한 양은 질환 증상의 정도, 환자의 연령, 체중, 건강상태, 성별, 투여 경로 및 치료기간 등에 따라 적절히 변화될 수 있다.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. However, 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.
또한, 본 발명에 따른 약제학적 조성물은 약제학적으로 허용가능한 첨가제를 추가로 포함할 수 있다. 상기에서 '약제학적으로 허용가능한'이란 생리학적으로 허용되고 인간에게 투여될 때, 통상적으로 위장 장애, 현기증과 같은 알레르기 반응 또는 이와 유사한 반응을 일으키지 않는 것을 의미한다. 상기 첨가제의 예로는 담체, 부형제 및 희석제 등을 들 수 있다. 상기 담체, 부형제 및 희석제의 예로는, 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 또한, 충진제, 항응집제, 윤활제, 습윤제, 향료, 유화제 및 방부제 등을 추가로 포함할 수 있다.In addition, the pharmaceutical composition according to the invention may further comprise a pharmaceutically acceptable additive. As used herein, 'pharmaceutically acceptable' means that when administered physiologically and humanly, it usually does not cause an allergic reaction such as gastrointestinal disorder, dizziness or the like. Examples of 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. In addition, fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers and preservatives may be further included.
또한, 본 발명의 약제학적 조성물은 포유동물에 투여된 후 활성 성분의 신속, 지속 또는 지연된 방출을 제공할 수 있도록 당업계에 공지된 방법을 사용하여 제형화될 수 있다. 제형은 분말, 과립, 정제, 에멀젼, 시럽, 에어로졸, 연질 또는 경질 젤라틴 캅셀, 멸균 주사용액, 멸균 분말의 형태일 수 있다.In addition, the pharmaceutical 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.
본 발명에 따른 약제학적 조성물은 경구, 경피, 피하, 정맥 또는 근육을 포함한 여러 경로를 통해 투여될 수 있으며, 활성 성분의 투여량은 투여 경로, 환자의 연령, 성별, 체중 및 환자의 중증도 등의 여러 인자에 따라 적절히 선택될 수 있고, 치료하고자 하는 질환의 종류에 따라 상기 질환에 예방 또는 치료 용도가 있다고 공지되어 있는 화합물과 병용하여 투여될 수 있다. 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.
또한, 본 발명은 화학식 I의 화합물의 약제학적으로 허용가능한 염을 이를 필요로 하는 대상에 투여하는 것을 포함하는, 대상에서의 위궤양, 급성 위염, 만성 위염, 안구 건조 증후군, 암, 골관절염, 류마티스 관절염 또는 비만의 예방 또는 치료방법을 제공한다. In addition, 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.
나아가, 본 발명은 위궤양, 급성 위염, 만성 위염, 안구 건조 증후군, 암, 골관절염, 류마티스 관절염 또는 비만의 예방 또는 치료를 위한 화학식 I의 화합물의 약제학적으로 허용가능한 염의 용도를 제공한다. Furthermore, 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.
이하 본 발명을 실시예를 들어 상세히 설명하고자 하나, 본 발명의 범주가 상기 실시예에 의해 한정되는 것은 아니다. Hereinafter, the present invention will be described in detail with reference to Examples, but the scope of the present invention is not limited by the above Examples.
실시예 1: 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 글리콜레이트의 제조 Example 1: 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate glycolate Manufacture
Figure PCTKR2015000004-appb-I000011
Figure PCTKR2015000004-appb-I000011
일반적인 실험방법 E에 따라, 2-모폴린-4-일에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 1 g(2.07 mmol) 및 글리콜산 0.16 g(2.07 mmol)을 반응시켜 백색 고체의 표제화합물(0.8 g)을 얻었다.1 g of 2-morpholin-4-ylethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate according to general test method E (2.07 mmol) and 0.16 g (2.07 mmol) of glycolic acid were reacted to obtain the title compound (0.8 g) as a white solid.
1H NMR (400MHz, DMSO-d6): 11.71(s, 1H), 9.06(d, 1H), 7.83(t, 3H), 7.59(s, 1H), 7.57(s, 1H), 7.52(t, 1H), 7.32(d, 1H), 7.24(t, 1H), 6.47(s, 1H), 4.76(m, 1H), 4.26-4.15(m, 2H), 3.50-3.45(m, 5H), 3.35(s, 2H), 3.29(q, 1H), 2.57-2.47(m, 4H), 2.35(br-s, 4H) 1 H NMR (400 MHz, DMSO-d 6 ): 11.71 (s, 1H), 9.06 (d, 1H), 7.83 (t, 3H), 7.59 (s, 1H), 7.57 (s, 1H), 7.52 (t , 1H), 7.32 (d, 1H), 7.24 (t, 1H), 6.47 (s, 1H), 4.76 (m, 1H), 4.26-4.15 (m, 2H), 3.50-3.45 (m, 5H), 3.35 (s, 2H), 3.29 (q, 1H), 2.57-2.47 (m, 4H), 2.35 (br-s, 4H)
실시예 2: 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 락테이트의 제조 Example 2: 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate lactate Manufacture
Figure PCTKR2015000004-appb-I000012
Figure PCTKR2015000004-appb-I000012
일반적인 실험방법 E에 따라, 2-모폴린-4-일에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 1 g(2.07 mmol) 및 락트산 0.19 g(2.07 mmol)을 반응시켜 백색 고체의 표제화합물(0.9 g)을 얻었다.1 g of 2-morpholin-4-ylethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate according to general test method E (2.07 mmol) and lactic acid 0.19 g (2.07 mmol) gave the title compound (0.9 g) as a white solid.
1H NMR (400MHz, DMSO-d6): 11.71(s, 1H), 9.06(d, 1H), 7.83(t, 3H), 7.59(s, 1H), 7.57(s, 1H), 7.52(t, 1H), 7.32(d, 1H), 7.24(t, 1H), 6.46(s, 1H), 4.75(m, 1H), 4.27-4.14(m, 2H), 3.50-3.45(m, 2H), 3.35-3.26(m, 5H), 2.58-2.46(m, 5H), 2.35(br-s, 4H) 1 H NMR (400 MHz, DMSO-d 6 ): 11.71 (s, 1H), 9.06 (d, 1H), 7.83 (t, 3H), 7.59 (s, 1H), 7.57 (s, 1H), 7.52 (t , 1H), 7.32 (d, 1H), 7.24 (t, 1H), 6.46 (s, 1H), 4.75 (m, 1H), 4.27-4.14 (m, 2H), 3.50-3.45 (m, 2H), 3.35-3.26 (m, 5H), 2.58-2.46 (m, 5H), 2.35 (br-s, 4H)
실시예 3: 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 살리실레이트의 제조 Example 3: 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate salicyl Manufacture of Rate
Figure PCTKR2015000004-appb-I000013
Figure PCTKR2015000004-appb-I000013
일반적인 실험방법 E에 따라, 2-모폴린-4-일에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 1 g(2.07 mmol) 및 살리실산 0.29 g(2.07 mmol)을 반응시켜 백색 고체의 표제화합물(0.8 g)을 얻었다.1 g of 2-morpholin-4-ylethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate according to general test method E (2.07 mmol) and 0.29 g (2.07 mmol) of salicylic acid were reacted to obtain the title compound (0.8 g) as a white solid.
1H NMR (400MHz, DMSO-d6): 11.71(s, 1H), 9.08(d, 1H), 7.83(t, 3H), 7.76(dd, 1H), 7.59(s, 1H), 7.56(s, 1H), 7.52(t, 1H), 7.42(m, 1H), 7.32(d, 1H), 7.23(t, 1H), 6.85(q, 1H), 6.46(s, 1H), 4.78(m, 1H), 4.32-4.21(m, 2H), 3.54-3.47(m, 5H), 3.29(q, 2H), 2.78-2.67(m, 2H), 2.54(br-s, 4H) 1 H NMR (400 MHz, DMSO-d 6 ): 11.71 (s, 1H), 9.08 (d, 1H), 7.83 (t, 3H), 7.76 (dd, 1H), 7.59 (s, 1H), 7.56 (s , 1H), 7.52 (t, 1H), 7.42 (m, 1H), 7.32 (d, 1H), 7.23 (t, 1H), 6.85 (q, 1H), 6.46 (s, 1H), 4.78 (m, 1H), 4.32-4.21 (m, 2H), 3.54-3.47 (m, 5H), 3.29 (q, 2H), 2.78-2.67 (m, 2H), 2.54 (br-s, 4H)
실시예 4: 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 옥살레이트의 제조 Example 4: 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate oxalate Manufacture
Figure PCTKR2015000004-appb-I000014
Figure PCTKR2015000004-appb-I000014
일반적인 실험방법 E에 따라, 2-모폴린-4-일에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 1 g(2.07 mmol) 및 옥살산 0.19 g(2.07 mmol)을 반응시켜 백색 고체의 표제화합물(1.0 g)을 얻었다.1 g of 2-morpholin-4-ylethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate according to general test method E (2.07 mmol) and 0.19 g (2.07 mmol) of oxalic acid were reacted to obtain the title compound (1.0 g) as a white solid.
1H NMR (400MHz, DMSO-d6): 11.71(s, 1H), 9.09(d, 1H), 7.83(t, 3H), 7.58(s, 1H), 7.56(s, 1H), 7.52(t, 1H), 7.32(d, 1H), 7.23(t, 1H), 6.46(s, 1H), 4.79(m, 1H), 4.34-4.25(m, 2H), 3.56(t, 4H), 3.49(dd, 1H), 3.29(q, 1H), 2.87-2.78(m, 2H), 2.65(br-s, 4H) 1 H NMR (400 MHz, DMSO-d 6 ): 11.71 (s, 1H), 9.09 (d, 1H), 7.83 (t, 3H), 7.58 (s, 1H), 7.56 (s, 1H), 7.52 (t , 1H), 7.32 (d, 1H), 7.23 (t, 1H), 6.46 (s, 1H), 4.79 (m, 1H), 4.34-4.25 (m, 2H), 3.56 (t, 4H), 3.49 ( dd, 1H), 3.29 (q, 1H), 2.87-2.78 (m, 2H), 2.65 (br-s, 4H)
실시예 5: 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 말로네이트의 제조 Example 5: 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate malonate Manufacture
Figure PCTKR2015000004-appb-I000015
Figure PCTKR2015000004-appb-I000015
일반적인 실험방법 E에 따라, 2-모폴린-4-일에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 1 g(2.07 mmol) 및 말론산 0.22 g(2.07 mmol)을 반응시켜 백색 고체의 표제화합물(1.1 g)을 얻었다.1 g of 2-morpholin-4-ylethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate according to general test method E (2.07 mmol) and 0.22 g (2.07 mmol) of malonic acid gave the title compound (1.1 g) as a white solid.
1H NMR (400MHz, DMSO-d6): 11.71(s, 1H), 9.06(d, 1H), 7.83(t, 3H), 7.59(s, 1H), 7.56(s, 1H), 7.52(t, 1H), 7.32(d, 1H), 7.24(t, 1H), 6.46(s, 1H), 4.77(m, 1H), 4.24(m, 2H), 3.51-3.46(m, 5H), 3.29(q, 1H), 3.19(s, 2H), 2.70-2.61(m, 2H), 2.51(t, 2H), 2.47(br-s, 4H) 1 H NMR (400 MHz, DMSO-d 6 ): 11.71 (s, 1H), 9.06 (d, 1H), 7.83 (t, 3H), 7.59 (s, 1H), 7.56 (s, 1H), 7.52 (t , 1H), 7.32 (d, 1H), 7.24 (t, 1H), 6.46 (s, 1H), 4.77 (m, 1H), 4.24 (m, 2H), 3.51-3.46 (m, 5H), 3.29 ( q, 1H), 3.19 (s, 2H), 2.70-2.61 (m, 2H), 2.51 (t, 2H), 2.47 (br-s, 4H)
실시예 6: 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 말레이트의 제조 Example 6: 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate maleate Manufacture
Figure PCTKR2015000004-appb-I000016
Figure PCTKR2015000004-appb-I000016
일반적인 실험방법 E에 따라, 2-모폴린-4-일에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 1 g(2.07 mmol) 및 말산 0.28 g(2.07 mmol)을 반응시켜 백색 고체의 표제화합물(0.6 g)을 얻었다.1 g of 2-morpholin-4-ylethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate according to general test method E (2.07 mmol) and 0.28 g (2.07 mmol) of malic acid gave the title compound (0.6 g) as a white solid.
1H NMR (700MHz, DMSO-d6): 11.70(s, 1H), 9.06(d, 1H), 7.85-7.82(m, 3H), 7.59-7.57(m, 2H), 7.52(t, 1H), 7.32(q, 1H), 7.23(t, 1H), 6.47(s, 1H), 4.78-4.75(m, 1H), 4.26-4.16(m, 3H), 3.49-3.47(m, 5H), 3.29(q, 2H), 2.63-2.51(m, 2H), 2.45-2.38(m, 5H) 1 H NMR (700 MHz, DMSO-d 6 ): 11.70 (s, 1H), 9.06 (d, 1H), 7.85-7.82 (m, 3H), 7.59-7.57 (m, 2H), 7.52 (t, 1H) , 7.32 (q, 1H), 7.23 (t, 1H), 6.47 (s, 1H), 4.78-4.75 (m, 1H), 4.26-4.16 (m, 3H), 3.49-3.47 (m, 5H), 3.29 (q, 2H), 2.63-2.51 (m, 2H), 2.45-2.38 (m, 5H)
실시예 7: 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 타르타레이트의 제조 Example 7: 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate tarta Manufacture of Rate
Figure PCTKR2015000004-appb-I000017
Figure PCTKR2015000004-appb-I000017
일반적인 실험방법 E에 따라, 2-모폴린-4-일에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 1 g(2.07 mmol) 및 타르타르산 0.31 g(2.07 mmol)을 반응시켜 백색 고체의 표제화합물(0.4 g)을 얻었다.1 g of 2-morpholin-4-ylethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate according to general test method E (2.07 mmol) and 0.31 g (2.07 mmol) of tartaric acid were reacted to obtain the title compound (0.4 g) as a white solid.
1H NMR (400MHz, DMSO-d6): 11.71(s, 1H), 9.06(d, 1H), 7.83(t, 3H), 7.58(s, 1H), 7.56(s, 1H), 7.52(t, 1H), 7.32(d, 1H), 7.23(t, 1H), 6.47(s, 1H), 4.75(m, 1H), 4.29-4.15(m, 4H), 3.51-3.46(m, 5H), 3.29(q, 1H), 2.60-2.48(m, 2H), 2.37(br-s, 4H) 1 H NMR (400 MHz, DMSO-d 6 ): 11.71 (s, 1H), 9.06 (d, 1H), 7.83 (t, 3H), 7.58 (s, 1H), 7.56 (s, 1H), 7.52 (t , 1H), 7.32 (d, 1H), 7.23 (t, 1H), 6.47 (s, 1H), 4.75 (m, 1H), 4.29-4.15 (m, 4H), 3.51-3.46 (m, 5H), 3.29 (q, 1H), 2.60-2.48 (m, 2H), 2.37 (br-s, 4H)
실시예 8: 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 말레에이트의 제조 Example 8: 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate maleate Manufacture
Figure PCTKR2015000004-appb-I000018
Figure PCTKR2015000004-appb-I000018
일반적인 실험방법 E에 따라, 2-모폴린-4-일에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 1 g(2.07 mmol) 및 말레산 0.24 g(2.07 mmol)을 반응시켜 백색 고체의 표제화합물(0.8 g)을 얻었다.1 g of 2-morpholin-4-ylethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate according to general test method E (2.07 mmol) and 0.24 g (2.07 mmol) of maleic acid were reacted to obtain the title compound (0.8 g) as a white solid.
1H NMR (400MHz, DMSO-d6): 11.71(s, 1H), 9.09(d, 1H), 7.83(m, 3H), 7.59(s, 1H), 7.57(s, 1H), 7.52(t, 1H), 7.32(d, 1H), 7.23(t, 1H), 6.45(s, 1H), 6.11(s, 2H), 4.82(m, 1H), 4.37(m, 2H), 3.65(br-s, 4H), 3.49(dd, 1H), 3.31(q, 1H), 3.14(br-s, 2H), 2.95(br-s, 4H), 2.51(t, 2H) 1 H NMR (400 MHz, DMSO-d 6 ): 11.71 (s, 1H), 9.09 (d, 1H), 7.83 (m, 3H), 7.59 (s, 1H), 7.57 (s, 1H), 7.52 (t , 1H), 7.32 (d, 1H), 7.23 (t, 1H), 6.45 (s, 1H), 6.11 (s, 2H), 4.82 (m, 1H), 4.37 (m, 2H), 3.65 (br- s, 4H), 3.49 (dd, 1H), 3.31 (q, 1H), 3.14 (br-s, 2H), 2.95 (br-s, 4H), 2.51 (t, 2H)
실시예 9: 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 푸마레이트의 제조 Example 9: 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate fumarate Manufacture
Figure PCTKR2015000004-appb-I000019
Figure PCTKR2015000004-appb-I000019
일반적인 실험방법 E에 따라, 2-모폴린-4-일에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 1 g(2.07 mmol) 및 푸말산 0.16 g(2.07 mmol)을 반응시켜 백색 고체의 표제화합물(0.9 g)을 얻었다.1 g of 2-morpholin-4-ylethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate according to general test method E (2.07 mmol) and 0.16 g (2.07 mmol) of fumaric acid were reacted to obtain the title compound (0.9 g) as a white solid.
1H NMR (400MHz, DMSO-d6): 11.71(s, 1H), 9.08(d, 1H), 7.83(m, 3H), 7.59(s, 1H), 7.56(s, 1H), 7.52(t, 1H), 7.32(d, 1H), 7.24(t, 1H), 6.46(s, 1H), 6.12(s, 2H), 4.82(m, 1H), 4.37(m, 2H), 3.65(br-s, 4H), 3.48(dd, 1H), 3.32(q, 1H), 3.15(br-s, 2H), 2.96(br-s, 4H), 2.52(t, 2H) 1 H NMR (400 MHz, DMSO-d 6 ): 11.71 (s, 1H), 9.08 (d, 1H), 7.83 (m, 3H), 7.59 (s, 1H), 7.56 (s, 1H), 7.52 (t , 1H), 7.32 (d, 1H), 7.24 (t, 1H), 6.46 (s, 1H), 6.12 (s, 2H), 4.82 (m, 1H), 4.37 (m, 2H), 3.65 (br- s, 4H), 3.48 (dd, 1H), 3.32 (q, 1H), 3.15 (br-s, 2H), 2.96 (br-s, 4H), 2.52 (t, 2H)
실시예 10: 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 시트레이트의 제조 Example 10: 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2 -dihydroquinolin-4-yl) propionate citrate Produce
Figure PCTKR2015000004-appb-I000020
Figure PCTKR2015000004-appb-I000020
일반적인 실험방법 E에 따라, 2-모폴린-4-일에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 1 g(2.07 mmol) 및 시트르산 0.40 g(2.07 mmol)을 반응시켜 백색 고체의 표제화합물(0.7 g)을 얻었다.1 g of 2-morpholin-4-ylethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate according to general test method E (2.07 mmol) and 0.40 g (2.07 mmol) of citric acid were reacted to obtain the title compound (0.7 g) as a white solid.
1H NMR (400MHz, DMSO-d6): 11.71(s, 1H), 9.06(d, 1H), 7.83(t, 3H), 7.59(s, 1H), 7.56(s, 1H), 7.52(t, 1H), 7.32(d, 1H), 7.24(t, 1H), 6.47(s, 1H), 4.77(m, 1H), 4.28-4.18(m, 2H), 3.50-3.46(m, 5H), 3.29(q, 1H), 2.65(dd, 2H), 2.64-2.57(m, 2H), 2.51(t, 2H), 2.43(br-s, 4H) 1 H NMR (400 MHz, DMSO-d 6 ): 11.71 (s, 1H), 9.06 (d, 1H), 7.83 (t, 3H), 7.59 (s, 1H), 7.56 (s, 1H), 7.52 (t , 1H), 7.32 (d, 1H), 7.24 (t, 1H), 6.47 (s, 1H), 4.77 (m, 1H), 4.28-4.18 (m, 2H), 3.50-3.46 (m, 5H), 3.29 (q, 1H), 2.65 (dd, 2H), 2.64-2.57 (m, 2H), 2.51 (t, 2H), 2.43 (br-s, 4H)
실시예 11: 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 벤젠설포네이트의 제조 Example 11: 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2 -dihydroquinolin-4-yl) propionate benzenesulfonate Manufacture
Figure PCTKR2015000004-appb-I000021
Figure PCTKR2015000004-appb-I000021
일반적인 실험방법 E에 따라, 2-모폴린-4-일에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 1 g(2.07 mmol) 및 벤젠설폰산 0.33 g(2.07 mmol)을 반응시켜 백색 고체의 표제화합물(1.0 g)을 얻었다. 1 g of 2-morpholin-4-ylethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate according to general test method E (2.07 mmol) and 0.33 g (2.07 mmol) of benzenesulfonic acid gave the title compound (1.0 g) as a white solid.
1H NMR (700MHz, DMSO-d6): 11.71(s, 1H), 9.80(br-s, 1H), 9.11(d, 1H), 7.84-7.81(m, 3H), 7.62-7.61(m, 2H), 7.60-7.57(m, 2H), 7.52(t, 1H), 7.35-7.30(m, 4H), 7.23(t, 1H), 6.45(s, 1H), 6.11(s, 2H), 4.89-4.85(m, 1H), 4.52-4.42(m, 2H), 3.89(t, 2H), 3.62(t, 2H), 3.54-3.52(m, 3H), 3.44(t, 2H), 3.33(q, 1H), 3.15(br-s, 2H) 1 H NMR (700 MHz, DMSO-d 6 ): 11.71 (s, 1H), 9.80 (br-s, 1H), 9.11 (d, 1H), 7.84-7.81 (m, 3H), 7.62-7.61 (m, 2H), 7.60-7.57 (m, 2H), 7.52 (t, 1H), 7.35-7.30 (m, 4H), 7.23 (t, 1H), 6.45 (s, 1H), 6.11 (s, 2H), 4.89 -4.85 (m, 1H), 4.52-4.42 (m, 2H), 3.89 (t, 2H), 3.62 (t, 2H), 3.54-3.52 (m, 3H), 3.44 (t, 2H), 3.33 (q , 1H), 3.15 (br-s, 2H)
실시예 12: 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 토실레이트의 제조 Example 12: 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2 -dihydroquinolin-4-yl) propionate tosylate Produce
Figure PCTKR2015000004-appb-I000022
Figure PCTKR2015000004-appb-I000022
일반적인 실험방법 E에 따라, 2-모폴린-4-일에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 1 g(2.07 mmol) 및 톨루엔설폰산 모노하이드레이트 0.39 g(2.07 mmol)을 반응시켜 백색 고체의 표제화합물(0.9 g)을 얻었다.1 g of 2-morpholin-4-ylethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate according to general test method E (2.07 mmol) and 0.39 g (2.07 mmol) of toluenesulfonic acid monohydrate were reacted to obtain the title compound (0.9 g) as a white solid.
1H NMR (400MHz, DMSO-d6): 11.71(s, 1H), 9.78(br-s, 1H), 9.10(d, 1H), 7.84-7.81(m, 3H), 7.59-7.47(m, 5H), 7.32(d, 1H), 7.23(t, 1H), 7.11(d, 2H), 6.45(s, 1H), 6.11(s, 2H), 4.86(m, 1H), 4.52-4.40(m, 2H), 4.02(m, 2H), 3.62(t, 2H), 3.55-3.29(m, 6H), 3.14(m, 2H), 2.29(s, 3H) 1 H NMR (400 MHz, DMSO-d 6 ): 11.71 (s, 1H), 9.78 (br-s, 1H), 9.10 (d, 1H), 7.84-7.81 (m, 3H), 7.59-7.47 (m, 5H), 7.32 (d, 1H), 7.23 (t, 1H), 7.11 (d, 2H), 6.45 (s, 1H), 6.11 (s, 2H), 4.86 (m, 1H), 4.52-4.40 (m , 2H), 4.02 (m, 2H), 3.62 (t, 2H), 3.55-3.29 (m, 6H), 3.14 (m, 2H), 2.29 (s, 3H)
실시예 13: 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 하이드로클로레이트의 제조 Example 13: 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2 -dihydroquinolin-4-yl) propionate hydrochlorate Manufacture
Figure PCTKR2015000004-appb-I000023
Figure PCTKR2015000004-appb-I000023
일반적인 실험방법 E에 따라, 2-모폴린-4-일에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 1 g(2.07 mmol) 및 염산 0.19 mL(2.07 mmol)을 반응시켜 백색 고체의 표제화합물(0.4 g)을 얻었다.1 g of 2-morpholin-4-ylethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate according to general test method E (2.07 mmol) and 0.19 mL (2.07 mmol) in hydrochloric acid gave the title compound (0.4 g) as a white solid.
1H NMR (400MHz, DMSO-d6): 11.69(s, 1H), 11.52(br-s, 1H), 9.24(d, 1H), 7.89-7.86(m, 3H), 7.57(t, 1H), 7.55(t, 1H), 7.51(m, 1H), 7.32(dd, 1H), 7.22(m, 1H), 6.46(s, 1H), 4.93(m, 1H), 4.60-4.47(m, 2H), 3.87-3.82(m, 4H), 3.57(dd, 1H), 3.60-3.33(m, 5H), 3.12(m, 2H) 1 H NMR (400 MHz, DMSO-d 6 ): 11.69 (s, 1H), 11.52 (br-s, 1H), 9.24 (d, 1H), 7.89-7.86 (m, 3H), 7.57 (t, 1H) , 7.55 (t, 1H), 7.51 (m, 1H), 7.32 (dd, 1H), 7.22 (m, 1H), 6.46 (s, 1H), 4.93 (m, 1H), 4.60-4.47 (m, 2H ), 3.87-3.82 (m, 4H), 3.57 (dd, 1H), 3.60-3.33 (m, 5H), 3.12 (m, 2H)
실시예 14: 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 설페이트의 제조 Example 14 Preparation of 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2 -dihydroquinolin-4-yl) propionate sulfate
Figure PCTKR2015000004-appb-I000024
Figure PCTKR2015000004-appb-I000024
일반적인 실험방법 E에 따라, 2-모폴린-4-일에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 1 g(2.07 mmol) 및 황산 0.20 g(2.07 mmol)을 반응시켜 백색 고체의 표제화합물(0.4 g)을 얻었다.1 g of 2-morpholin-4-ylethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate according to general test method E (2.07 mmol) and 0.20 g (2.07 mmol) of sulfuric acid were reacted to obtain the title compound (0.4 g) as a white solid.
1H NMR (400MHz, DMSO-d6): 11.71(s, 1H), 9.09(d, 1H), 7.83(t, 3H), 7.59(s, 1H), 7.56(s, 1H), 7.52(t, 1H), 7.32(d, 1H), 7.23(t, 1H), 6.46(s, 1H), 4.82(m, 1H), 4.35(t, 2H), 3.63(s, 4H), 3.50(dd, 1H), 3.1(q, 1H), 3.05(br-s, 2H), 2.86(br-s, 4H), 2.55(s, 1H), 2.51(s, 1H) 1 H NMR (400 MHz, DMSO-d 6 ): 11.71 (s, 1H), 9.09 (d, 1H), 7.83 (t, 3H), 7.59 (s, 1H), 7.56 (s, 1H), 7.52 (t , 1H), 7.32 (d, 1H), 7.23 (t, 1H), 6.46 (s, 1H), 4.82 (m, 1H), 4.35 (t, 2H), 3.63 (s, 4H), 3.50 (dd, 1H), 3.1 (q, 1H), 3.05 (br-s, 2H), 2.86 (br-s, 4H), 2.55 (s, 1H), 2.51 (s, 1H)
실시예 15: 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 포스포레이트의 제조 Example 15 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2 -dihydroquinolin-4-yl) propionate phosphorate Manufacture
*
Figure PCTKR2015000004-appb-I000025
*
Figure PCTKR2015000004-appb-I000025
일반적인 실험방법 E에 따라, 2-모폴린-4-일에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 1 g(2.07 mmol) 및 인산 0.17 g(2.07 mmol)을 반응시켜 백색 고체의 표제화합물(0.6 g)을 얻었다.1 g of 2-morpholin-4-ylethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate according to general test method E (2.07 mmol) and 0.17 g (2.07 mmol) of phosphoric acid were reacted to obtain the title compound (0.6 g) as a white solid.
1H NMR (700MHz, DMSO-d6): 11.72(br-s, 1H), 9.08(d, 1H), 7.86-7.82(m, 3H), 7.58-7.57(m, 2H), 7.52(t, 1H), 7.33(dd, 1H), 7.24(m, 1H), 6.47(s, 1H), 4.77-4.75(m, 1H), 4.27-4.17(m, 2H), 3.50-3.47(m, 5H), 3.30(dd, 1H), 2.60-2.57(m, 2H), 2.56-2.50(m, 1H), 2.39(br-s, 4H) 1 H NMR (700 MHz, DMSO-d 6 ): 11.72 (br-s, 1 H), 9.08 (d, 1 H), 7.86-7.82 (m, 3 H), 7.58-7.57 (m, 2H), 7.52 (t, 1H), 7.33 (dd, 1H), 7.24 (m, 1H), 6.47 (s, 1H), 4.77-4.75 (m, 1H), 4.27-4.17 (m, 2H), 3.50-3.47 (m, 5H) , 3.30 (dd, 1H), 2.60-2.57 (m, 2H), 2.56-2.50 (m, 1H), 2.39 (br-s, 4H)
실시예 16 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 아세테이트의 제조 Example 16 Preparation of 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2 -dihydroquinolin-4-yl) propionate acetate
1H-NMR(d, DMSO-d6) : 9.13(d,1H), 7.83(t,3H), 7.53(m,3H), 7.22(d,1H), 7.18(t,1H), 4.84-4.89(m,1H), 4.39-4.49(m,2H), 3.9(t,2H), 3.7(t,2H), 3.3-3.5(m,6H), 3.15(bs,2H) 1 H-NMR (d, DMSO-d 6 ): 9.13 (d, 1H), 7.83 (t, 3H), 7.53 (m, 3H), 7.22 (d, 1H), 7.18 (t, 1H), 4.84- 4.89 (m, 1H), 4.39-4.49 (m, 2H), 3.9 (t, 2H), 3.7 (t, 2H), 3.3-3.5 (m, 6H), 3.15 (bs, 2H)
실시예 17: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 다이클로로아세테이트의 제조 Example 17 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate dichloroacetate Manufacture
1H-NMR(d, DMSO-d6) : 9.10(d,1H), 7.85(t,3H), 7.53(m,3H), 7.22(d,1H), 7.18(t,1H), 6.33(s,2H), 4.87-4.89(m,1H), 4.36-4.46(m,2H), 3.43-3.58(m,5H), 3.32-3.34(m,1H), 2.63-2.68(m,2H), 2.49(bs,4H) 1 H-NMR (d, DMSO-d 6 ): 9.10 (d, 1H), 7.85 (t, 3H), 7.53 (m, 3H), 7.22 (d, 1H), 7.18 (t, 1H), 6.33 ( s, 2H), 4.87-4.89 (m, 1H), 4.36-4.46 (m, 2H), 3.43-3.58 (m, 5H), 3.32-3.34 (m, 1H), 2.63-2.68 (m, 2H), 2.49 (bs, 4H)
실시예 18: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 아디페이트의 제조 Example 18 of 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate adipate Produce
1H-NMR(d, DMSO-d6) : 9.02(d,1H), 7.83(t,3H), 7.53(m,3H), 7.22(d,1H), 7.18(t,1H), 6.33(s,2H), 4.84-4.89(m,1H), 4.41-4.49(m,2H), 3.47-3.55(m,5H), 3.38-3.34(m,1H), 2.63-2.68(m,2H), 2.49(bs,4H), 2.23(t,4H), 1.52-1.56(m,4H) 1 H-NMR (d, DMSO-d 6 ): 9.02 (d, 1H), 7.83 (t, 3H), 7.53 (m, 3H), 7.22 (d, 1H), 7.18 (t, 1H), 6.33 ( s, 2H), 4.84-4.89 (m, 1H), 4.41-4.49 (m, 2H), 3.47-3.55 (m, 5H), 3.38-3.34 (m, 1H), 2.63-2.68 (m, 2H), 2.49 (bs, 4H), 2.23 (t, 4H), 1.52-1.56 (m, 4H)
실시예 19: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 아스코베이트의 제조 Example 19 of 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate ascorbate Produce
1H-NMR(d, DMSO-d6) : 9.22(d,1H), 7.80(t,3H), 7.51(m,3H), 7.22(d,1H), 7.18(t,1H), 6.33(s,2H), 5.01(d,1H), 4.81-4.87(m,1H), 4.38-4.49(m,2H), 3.91-3.95(m,1H), 3.80-3.82(m,1H), 3.54-3.56(m,1H), 3.47-3.52(m,5H), 3.32-3.34(m,1H), 2.63-2.68(m,2H), 2.49(bs,4H) 1 H-NMR (d, DMSO-d 6 ): 9.22 (d, 1H), 7.80 (t, 3H), 7.51 (m, 3H), 7.22 (d, 1H), 7.18 (t, 1H), 6.33 ( s, 2H), 5.01 (d, 1H), 4.81-4.87 (m, 1H), 4.38-4.49 (m, 2H), 3.91-3.95 (m, 1H), 3.80-3.82 (m, 1H), 3.54- 3.56 (m, 1H), 3.47-3.52 (m, 5H), 3.32-3.34 (m, 1H), 2.63-2.68 (m, 2H), 2.49 (bs, 4H)
실시예 20: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 벤조에이트의 제조 Example 20 of 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate benzoate Produce
1H-NMR(d, DMSO-d6) : 9.05(d,1H), 8.13-7.83(m,8H), 7.52(m,3H), 7.25(d,1H), 7.16(t,1H), 4.84-4.89(m,1H), 4.39-4.49(m,2H), 3.47-3.52(m,5H), 3.32-3.34(m,1H), 2.63-2.68(m,2H), 2.49(bs,4H) 1 H-NMR (d, DMSO-d 6 ): 9.05 (d, 1H), 8.13-7.83 (m, 8H), 7.52 (m, 3H), 7.25 (d, 1H), 7.16 (t, 1H), 4.84-4.89 (m, 1H), 4.39-4.49 (m, 2H), 3.47-3.52 (m, 5H), 3.32-3.34 (m, 1H), 2.63-2.68 (m, 2H), 2.49 (bs, 4H )
실시예 21: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 4-아세트아미도벤조에이트의 제조 Example 21: 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate 4-acet Preparation of Amidobenzoate
1H-NMR(d, DMSO-d6) : 9.31(d,1H), 8.04(d,2H), 7.92-7.83(m,5H), 7.53(m,3H), 7.22(d,1H), 7,18(t,1H), 4.84-4.90(m,1H), 4.37-4.49(m,2H), 3.50-3.52(m,5H), 3.31-3.34(m,1H), 2.63-2.68(m,2H), 2.49(bs,4H), 2.03(s,3H) 1 H-NMR (d, DMSO-d 6 ): 9.31 (d, 1H), 8.04 (d, 2H), 7.92-7.83 (m, 5H), 7.53 (m, 3H), 7.22 (d, 1H), 7,18 (t, 1H), 4.84-4.90 (m, 1H), 4.37-4.49 (m, 2H), 3.50-3.52 (m, 5H), 3.31-3.34 (m, 1H), 2.63-2.68 (m , 2H), 2.49 (bs, 4H), 2.03 (s, 3H)
실시예 22: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 카프레이트의 제조 Example 22 of 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate caprate Produce
1H-NMR(d, DMSO-d6) : 9.16(d,1H), 7.88(t,3H), 7.55(m,3H), 7.19(d,1H), 7.09(t,1H), 4.80-4.88(m,1H), 4.33-4.38(m,2H), 3.47-3.52(m,5H), 3.32-3.34(m,1H), 2.63-2.68(m,2H), 2.49(bs,4H), 2.21(d,2H), 1.52-1.55(m,2H), 1.30-1.41(m,12H), 0.88(s,3H) 1 H-NMR (d, DMSO-d 6 ): 9.16 (d, 1H), 7.88 (t, 3H), 7.55 (m, 3H), 7.19 (d, 1H), 7.09 (t, 1H), 4.80- 4.88 (m, 1H), 4.33-4.38 (m, 2H), 3.47-3.52 (m, 5H), 3.32-3.34 (m, 1H), 2.63-2.68 (m, 2H), 2.49 (bs, 4H), 2.21 (d, 2H), 1.52-1.55 (m, 2H), 1.30-1.41 (m, 12H), 0.88 (s, 3H)
실시예 23: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 카프로네이트의 제조 Example 23 of 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate capronate Produce
1H-NMR(d, DMSO-d6) : 9.17(d,1H), 7.83(t,3H), 7.53(m,3H), 7.22(d,1H), 7.18(t,1H), 4.84-4.89(m,1H), 4.39-4.49(m,2H), 3.47-3.52(m,5H), 3.32-3.34(m,1H), 2.63-2.68(m,2H), 2.49(bs,4H), 2.23(d,2H), 1.57-1.65(m,2H), 1.32-1.39(m,2H), 1.22-1.26(m,2H), 0.90(s,3H) 1 H-NMR (d, DMSO-d 6 ): 9.17 (d, 1H), 7.83 (t, 3H), 7.53 (m, 3H), 7.22 (d, 1H), 7.18 (t, 1H), 4.84- 4.89 (m, 1H), 4.39-4.49 (m, 2H), 3.47-3.52 (m, 5H), 3.32-3.34 (m, 1H), 2.63-2.68 (m, 2H), 2.49 (bs, 4H), 2.23 (d, 2H), 1.57-1.65 (m, 2H), 1.32-1.39 (m, 2H), 1.22-1.26 (m, 2H), 0.90 (s, 3H)
실시예 24: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 카프릴레이트의 제조 Example 24 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate caprylate Manufacture
1H-NMR(d, DMSO-d6) : 9.11(d,1H), 7.87(t,3H), 7.52(m,3H), 7.11(d,1H), 6.91(t,1H), 4.84-4.89(m,1H), 4.39-4.49(m,2H), 3.47-3.52(m,5H), 3.32-3.34(m,1H), 2.63-2.68(m,2H), 2.49(bs,4H), 2.15(d,2H), 1.52-1.55(m,2H), 1.22-1.25(m,8H), 0.81(s,3H) 1 H-NMR (d, DMSO-d 6 ): 9.11 (d, 1H), 7.87 (t, 3H), 7.52 (m, 3H), 7.11 (d, 1H), 6.91 (t, 1H), 4.84- 4.89 (m, 1H), 4.39-4.49 (m, 2H), 3.47-3.52 (m, 5H), 3.32-3.34 (m, 1H), 2.63-2.68 (m, 2H), 2.49 (bs, 4H), 2.15 (d, 2H), 1.52-1.55 (m, 2H), 1.22-1.25 (m, 8H), 0.81 (s, 3H)
실시예 25: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 카르보네이트의 제조 Example 25 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate carbonate Manufacture
1H-NMR(d, DMSO-d6) : 9.18(d,1H), 7.80(t,3H), 7.58(m,3H), 7.33(d,1H), 7.21(t,1H), 4.74-4.79(m,1H), 4.24-4.33(m,2H), 3.50-3.52(m,5H), 3.32-3.34(m,1H), 2.63-2.68(m,2H), 2.51(bs,4H) 1 H-NMR (d, DMSO-d 6 ): 9.18 (d, 1H), 7.80 (t, 3H), 7.58 (m, 3H), 7.33 (d, 1H), 7.21 (t, 1H), 4.74- 4.79 (m, 1H), 4.24-4.33 (m, 2H), 3.50-3.52 (m, 5H), 3.32-3.34 (m, 1H), 2.63-2.68 (m, 2H), 2.51 (bs, 4H)
실시예 26: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 신나메이트의 제조 Example 26 of 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate cinnamate Produce
1H-NMR(d, DMSO-d6) : 9.10(d,1H), 7.80(t,3H),7.53-7.33(m,8H), 7.24(d,1H), 7.12(d,1H), 7.08(t,1H), 6.24(d,1H), 4.84-4.89(m,1H), 4.39-4.49(m,2H), 3.47-3.52(m,5H), 3.32-3.34(m,1H), 2.63-2.68(m,2H), 2.55(bs,4H) 1 H-NMR (d, DMSO-d 6 ): 9.10 (d, 1H), 7.80 (t, 3H), 7.53-7.33 (m, 8H), 7.24 (d, 1H), 7.12 (d, 1H), 7.08 (t, 1H), 6.24 (d, 1H), 4.84-4.89 (m, 1H), 4.39-4.49 (m, 2H), 3.47-3.52 (m, 5H), 3.32-3.34 (m, 1H), 2.63-2.68 (m, 2H), 2.55 (bs, 4H)
실시예 27: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 사이클라메이트의 제조 Example 27 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate cyclomate Manufacture
1H-NMR(d, DMSO-d6) : 9.11(d,1H), 7.83(t,3H), 7.55(m,3H), 7.22(d,1H), 7.18(t,1H), 4.84-4.89(m,1H), 4.35-4.45(m,2H), 3.47-3.52(m,5H), 3.32-3.34(m,1H), 2.63-2.68(m,2H), 2.49(bs,4H), 2.0-2.11(m,2H), 1.11-1.44(m,10H) 1 H-NMR (d, DMSO-d 6 ): 9.11 (d, 1H), 7.83 (t, 3H), 7.55 (m, 3H), 7.22 (d, 1H), 7.18 (t, 1H), 4.84- 4.89 (m, 1H), 4.35-4.45 (m, 2H), 3.47-3.52 (m, 5H), 3.32-3.34 (m, 1H), 2.63-2.68 (m, 2H), 2.49 (bs, 4H), 2.0-2.11 (m, 2H), 1.11-1.44 (m, 10H)
실시예 28: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 도데실설포네이트의 제조 Example 28: 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate dodecylsulfo Preparation of Nate
1H-NMR(d, DMSO-d6) : 9.15(d,1H), 7.86(t,3H), 7.50(m,3H), 7.22(d,1H), 7.10(t,1H), 4.85-4.87(m,1H), 4.39-4.49(m,2H), 3.47-3.52(m,5H), 3.32-3.34(m,1H), 2.63-2.68(m,2H), 2.49(bs,4H), 2.21(d,2H), 1.52-1.57(m,2H), 1.25-1.31(m,18H), 0.86(s,3H) 1 H-NMR (d, DMSO-d 6 ): 9.15 (d, 1H), 7.86 (t, 3H), 7.50 (m, 3H), 7.22 (d, 1H), 7.10 (t, 1H), 4.85- 4.87 (m, 1H), 4.39-4.49 (m, 2H), 3.47-3.52 (m, 5H), 3.32-3.34 (m, 1H), 2.63-2.68 (m, 2H), 2.49 (bs, 4H), 2.21 (d, 2H), 1.52-1.57 (m, 2H), 1.25-1.31 (m, 18H), 0.86 (s, 3H)
실시예 29: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 에탄-1,2-다이설포네이트의 제조 Example 29: 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate ethane-1 Of 2-, disulfonate
1H-NMR(d, DMSO-d6) : 9.11(d,1H), 7.83(t,3H), 7.53(m,3H), 7.22(d,1H), 7,18(t,1H), 4.84-4.89(m,1H), 4.39-4.49(m,2H), 3.97(d,4H), 3.50-3.52(m,5H), 3.37-3.41(m,1H), 2.63-2.69(m,2H), 2.51(bs,4H) 1 H-NMR (d, DMSO-d 6 ): 9.11 (d, 1H), 7.83 (t, 3H), 7.53 (m, 3H), 7.22 (d, 1H), 7,18 (t, 1H), 4.84-4.89 (m, 1H), 4.39-4.49 (m, 2H), 3.97 (d, 4H), 3.50-3.52 (m, 5H), 3.37-3.41 (m, 1H), 2.63-2.69 (m, 2H ), 2.51 (bs, 4H)
실시예 30: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 에탄설포네이트의 제조 Example 30 2-Molinolin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate ethanesulfonate Manufacture
1H-NMR(d, DMSO-d6) : 9.14(d,1H), 7.83(t,3H), 7.53(m,3H), 7.22(d,1H), 7.11(t,1H), 4.84-4.89(m,1H), 4.39-4.49(m,2H), 3.47-3.52(m,7H), 3.32-3.34(m,1H), 2.63-2.68(m,2H), 2.49(bs,4H), 1.45(d,3H) 1 H-NMR (d, DMSO-d 6 ): 9.14 (d, 1H), 7.83 (t, 3H), 7.53 (m, 3H), 7.22 (d, 1H), 7.11 (t, 1H), 4.84- 4.89 (m, 1H), 4.39-4.49 (m, 2H), 3.47-3.52 (m, 7H), 3.32-3.34 (m, 1H), 2.63-2.68 (m, 2H), 2.49 (bs, 4H), 1.45 (d, 3H)
실시예 31: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 2-하이드록시에탄설포네이트의 제조 Example 31 2-Molinolin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate 2-hydro Preparation of Roxyethanesulfonate
1H-NMR(d, DMSO-d6) : 9.09(d,1H), 7.81(t,3H), 7.53(m,3H) ,7.22(d,1H), 7.20(t,1H), 4.84-4.89(m,1H), 4.39-4.49(m,2H), 4.01-4.11(m,2H), 3.57-3.61(m,2H), 3.47-3.52(m,5H), 3.32-3.38(m,1H), 2.60-2.65(m,2H), 2.55(bs,4H) 1 H-NMR (d, DMSO-d 6 ): 9.09 (d, 1H), 7.81 (t, 3H), 7.53 (m, 3H), 7.22 (d, 1H), 7.20 (t, 1H), 4.84- 4.89 (m, 1H), 4.39-4.49 (m, 2H), 4.01-4.11 (m, 2H), 3.57-3.61 (m, 2H), 3.47-3.52 (m, 5H), 3.32-3.38 (m, 1H ), 2.60-2.65 (m, 2H), 2.55 (bs, 4H)
실시예 32: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 포르메이트의 제조 Example 32: 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate formate Produce
1H-NMR(d, DMSO-d6) : 9.65(s,1H), 9.13(d,1H), 7.83(t,3H), 7.53(m,3H), 7.22(d,1H), 7.08(t,1H), 4.84-4.89(m,1H), 4.39-4.49(m,2H), 3.47-3.52(m,5H), 3.32-3.34(m,1H), 2.63-2.68(m,2H), 2.57(bs,4H) 1 H-NMR (d, DMSO-d 6 ): 9.65 (s, 1H), 9.13 (d, 1H), 7.83 (t, 3H), 7.53 (m, 3H), 7.22 (d, 1H), 7.08 ( t, 1H), 4.84-4.89 (m, 1H), 4.39-4.49 (m, 2H), 3.47-3.52 (m, 5H), 3.32-3.34 (m, 1H), 2.63-2.68 (m, 2H), 2.57 (bs, 4H)
실시예 33: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 갈락타레이트의 제조 Example 33 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate galactate Manufacture
1H-NMR(d, DMSO-d6) : 9.17(d,1H), 7.82(t,3H), 7.53(m,3H), 7.22(d,1H), 7,18(t.1H), 4.84-4.89(m,1H), 4.39-4.49(m,4H), 3.78(s,2H), 3.48-3.52(m,5H), 3.32-3.34(m,1H), 2.63-2.68(m,2H), 2.49(bs,4H) 1 H-NMR (d, DMSO-d 6 ): 9.17 (d, 1H), 7.82 (t, 3H), 7.53 (m, 3H), 7.22 (d, 1H), 7,18 (t.1H), 4.84-4.89 (m, 1H), 4.39-4.49 (m, 4H), 3.78 (s, 2H), 3.48-3.52 (m, 5H), 3.32-3.34 (m, 1H), 2.63-2.68 (m, 2H ), 2.49 (bs, 4H)
실시예 34: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 겐티세이트의 제조 Example 34 of 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate gentisate Produce
1H-NMR(d, DMSO-d6) : 9.01(d,1H), 7.83(t,3H), 7.53(m,3H), 7.22(d,1H), 7.11-6.90(m,4H), 4.85-4.89(m,1H), 4.39-4.49(m,2H), 3.47-3.52(m,5H), 3.32-3.34(m,1H), 2.63-2.68(m,2H), 2.45(bs,4H) 1 H-NMR (d, DMSO-d 6 ): 9.01 (d, 1H), 7.83 (t, 3H), 7.53 (m, 3H), 7.22 (d, 1H), 7.11-6.90 (m, 4H), 4.85-4.89 (m, 1H), 4.39-4.49 (m, 2H), 3.47-3.52 (m, 5H), 3.32-3.34 (m, 1H), 2.63-2.68 (m, 2H), 2.45 (bs, 4H )
실시예 35: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 글루타메이트의 제조 Example 35 Preparation of 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate glutamate
1H-NMR(d, DMSO-d6) : 9.15(d,1H), 7.83(t,3H), 7.53(m,3H), 7.22(d,1H), 7.18(t,1H), 4.84-4.89(m,1H), 4.39-4.49(m,2H), 3.47-3.52(m,6H), 3.32-3.34(m,1H), 2.63-2.68(m,2H), 2.49(bs,4H), 2.33(d,2H), 2.05(d,2H) 1 H-NMR (d, DMSO-d 6 ): 9.15 (d, 1H), 7.83 (t, 3H), 7.53 (m, 3H), 7.22 (d, 1H), 7.18 (t, 1H), 4.84- 4.89 (m, 1H), 4.39-4.49 (m, 2H), 3.47-3.52 (m, 6H), 3.32-3.34 (m, 1H), 2.63-2.68 (m, 2H), 2.49 (bs, 4H), 2.33 (d, 2H), 2.05 (d, 2H)
실시예 36: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 글루타레이트의 제조 Example 36 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate glutarate Manufacture
1H-NMR(d, DMSO-d6) : 9.10(d,1H), 7.85(t,3H), 7.53(m,3H), 7.22(d,1H), 7.18(t,1H), 4.84-4.89(m,1H), 4.39-4.49(m,2H), 3.47-3.52(m,5H), 3.32-3.34(m,1H), 2.63-2.68(m,2H), 2.49(bs,4H), 2.20-2.24(m,4H), 1.83(t,2H) 1 H-NMR (d, DMSO-d 6 ): 9.10 (d, 1H), 7.85 (t, 3H), 7.53 (m, 3H), 7.22 (d, 1H), 7.18 (t, 1H), 4.84- 4.89 (m, 1H), 4.39-4.49 (m, 2H), 3.47-3.52 (m, 5H), 3.32-3.34 (m, 1H), 2.63-2.68 (m, 2H), 2.49 (bs, 4H), 2.20-2.24 (m, 4H), 1.83 (t, 2H)
실시예 37: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 2-옥소글루타레이트의 제조 Example 37: 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate 2-oxo Preparation of Glutarate
1H-NMR(d, DMSO-d6) : 9.11(d,1H), 7.83(t,3H), 7.53(m,3H), 7.22(d,1H), 7.15(t,1H), 4.84-4.89(m,1H), 4.39-4.49(m,2H), 3.79(d,2H), 3.47-3.52(m,5H), 3.32-3.34(m,1H), 2.63-2.68(m,4H), 2.49(bs,4H) 1 H-NMR (d, DMSO-d 6 ): 9.11 (d, 1H), 7.83 (t, 3H), 7.53 (m, 3H), 7.22 (d, 1H), 7.15 (t, 1H), 4.84- 4.89 (m, 1H), 4.39-4.49 (m, 2H), 3.79 (d, 2H), 3.47-3.52 (m, 5H), 3.32-3.34 (m, 1H), 2.63-2.68 (m, 4H), 2.49 (bs, 4H)
실시예 38: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 글리세로포스포레이트의 제조 Example 38 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate glycerophosphate Preparation of Forrate
1H-NMR(d, DMSO-d6) : 9.14(d,1H), 7.83(t,3H), 7.53(m,3H), 7.22(d,1H), 7.17(t,1H), 4.84-4.89(m,1H), 4.39-4.49(m,2H), 4.20-4.25(m,2H), 4.15-4.18(m,1H), 3.47-3.52(m,5H), 3.32-3.34(m,1H), 2.63-2.68(m,2H), 2.49(bs,4H) 1 H-NMR (d, DMSO-d 6 ): 9.14 (d, 1H), 7.83 (t, 3H), 7.53 (m, 3H), 7.22 (d, 1H), 7.17 (t, 1H), 4.84- 4.89 (m, 1H), 4.39-4.49 (m, 2H), 4.20-4.25 (m, 2H), 4.15-4.18 (m, 1H), 3.47-3.52 (m, 5H), 3.32-3.34 (m, 1H ), 2.63-2.68 (m, 2H), 2.49 (bs, 4H)
실시예 39: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 히푸레이트의 제조 Example 39: 2-morpholin-4- yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate hypofurate Produce
1H-NMR(d, DMSO-d6) : 9.17(d,1H), 7.85-7.70(m,8H), 7.53(m,3H), 7.22(d,1H), 7.15(t,1H), 4.84-4.89(m,1H), 4.39-4.49(m,2H), 3.84(s,2H), 3.47-3.52(m,5H), 3.32-3.34(m,1H), 2.63-2.68(m,2H), 2.49(bs,4H) 1 H-NMR (d, DMSO-d 6 ): 9.17 (d, 1H), 7.85-7.70 (m, 8H), 7.53 (m, 3H), 7.22 (d, 1H), 7.15 (t, 1H), 4.84-4.89 (m, 1H), 4.39-4.49 (m, 2H), 3.84 (s, 2H), 3.47-3.52 (m, 5H), 3.32-3.34 (m, 1H), 2.63-2.68 (m, 2H ), 2.49 (bs, 4H)
실시예 40: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 올레에이트의 제조 Example 40 of 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate oleate Produce
1H-NMR(d, DMSO-d6) : 9.11(d,1H), 7.87(t,3H), 7.49(m,3H), 7.23(d,1H), 7.03(t,1H), 5.42(d,2H), 4.84-4.89(m,1H), 4.39-4.50(m,2H), 3.47-3.52(m,5H), 3.32-3.34(m,1H), 2.63-2.68(m,2H), 2.49(bs,4H), 2.23(d,2H), 1.93-1.96(m,4H), 1.52-1.55(m,2H), 1.29-1.31(m,20H), 0.90(s,3H) 1 H-NMR (d, DMSO-d 6 ): 9.11 (d, 1H), 7.87 (t, 3H), 7.49 (m, 3H), 7.23 (d, 1H), 7.03 (t, 1H), 5.42 ( d, 2H), 4.84-4.89 (m, 1H), 4.39-4.50 (m, 2H), 3.47-3.52 (m, 5H), 3.32-3.34 (m, 1H), 2.63-2.68 (m, 2H), 2.49 (bs, 4H), 2.23 (d, 2H), 1.93-1.96 (m, 4H), 1.52-1.55 (m, 2H), 1.29-1.31 (m, 20H), 0.90 (s, 3H)
실시예 41: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 오로테이트의 제조 Example 41: 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate orotate Produce
1H-NMR(d, DMSO-d6) : 9.10(d,1H), 7.89(t,3H), 7.53(m,3H), 7.22(d,1H), 7.18(t,1H), 6.74(s,1H), 4.87-4.89(m,1H), 4.44-4.49(m,2H), 3.47-3.52(m,5H), 3.32-3.34(m,1H), 2.63-2.68(m,2H), 2.45(bs,4H) 1 H-NMR (d, DMSO-d 6 ): 9.10 (d, 1H), 7.89 (t, 3H), 7.53 (m, 3H), 7.22 (d, 1H), 7.18 (t, 1H), 6.74 ( s, 1H), 4.87-4.89 (m, 1H), 4.44-4.49 (m, 2H), 3.47-3.52 (m, 5H), 3.32-3.34 (m, 1H), 2.63-2.68 (m, 2H), 2.45 (bs, 4H)
실시예 42: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 팔미테이트의 제조 Example 42: 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate palmitate Produce
1H-NMR(d, DMSO-d6) : 9.12(d,1H), 7.82(t,3H), 7.55(m,3H), 7.22(d,1H), 7.11(t,1H), 4.84-4.89(m,1H), 4.39-4.49(m,2H), 3.47-3.52(m,5H), 3.32-3.34(m,1H), 2.65-2.68(m,2H), 2.49(bs,4H), 2.25(d,2H), 1.52-1.55(m,2H), 1.28-1.33(m,24H), 0.81(s,3H) 1 H-NMR (d, DMSO-d 6 ): 9.12 (d, 1H), 7.82 (t, 3H), 7.55 (m, 3H), 7.22 (d, 1H), 7.11 (t, 1H), 4.84- 4.89 (m, 1H), 4.39-4.49 (m, 2H), 3.47-3.52 (m, 5H), 3.32-3.34 (m, 1H), 2.65-2.68 (m, 2H), 2.49 (bs, 4H), 2.25 (d, 2H), 1.52-1.55 (m, 2H), 1.28-1.33 (m, 24H), 0.81 (s, 3H)
실시예 43: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 파모에이트의 제조 Example 43 of 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate pamoate Produce
1H-NMR(d, DMSO-d6) : 9.09(d,1H), 8.55-7.77(m,13H), 7.53(m,3H), 7.22(d,1H), 7.18(t,1H), 4.88-4.92(m,3H), 4.39-4.45(m,2H), 3.47-3.52(m,5H), 3.32-3.34(m,1H), 2.63-2.68(m,2H), 2.51(bs,4H) 1 H-NMR (d, DMSO-d 6 ): 9.09 (d, 1H), 8.55-7.77 (m, 13H), 7.53 (m, 3H), 7.22 (d, 1H), 7.18 (t, 1H), 4.88-4.92 (m, 3H), 4.39-4.45 (m, 2H), 3.47-3.52 (m, 5H), 3.32-3.34 (m, 1H), 2.63-2.68 (m, 2H), 2.51 (bs, 4H )
실시예 44: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 프로피오네이트의 제조 Example 44 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate propionate Manufacture
1H-NMR(d, DMSO-d6) : 9.12(d,1H), 7.83(t,3H), 7.53(m,3H), 7.22(d,1H), 7.18(t,1H), 4.84-4.89(m,1H), 4.39-4.49(m,2H), 3.47-3.52(m,5H), 3.32-3.37(m,1H), 2.63-2.68(m,2H), 2.45(bs,4H), 2.27(d,2H), 1.09(d,3H) 1 H-NMR (d, DMSO-d 6 ): 9.12 (d, 1H), 7.83 (t, 3H), 7.53 (m, 3H), 7.22 (d, 1H), 7.18 (t, 1H), 4.84- 4.89 (m, 1H), 4.39-4.49 (m, 2H), 3.47-3.52 (m, 5H), 3.32-3.37 (m, 1H), 2.63-2.68 (m, 2H), 2.45 (bs, 4H), 2.27 (d, 2H), 1.09 (d, 3H)
실시예 45: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 파이로글루타메이트의 제조 Example 45 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate pyroglutamate Manufacture
1H-NMR(d, DMSO-d6) : 9.07(d,1H), 7.83(t,3H), 7.53(m,3H), 7.24(d,1H), 6.99(t,1H), 4.85-4.89(m,1H), 4.39-4.49(m,2H), 4.05-4.1(m,1H), 3.47-3.52(m,5H), 3.32-3.34(m,1H), 2.63-2.68(m,2H), 2.11-2.44(m,8H) 1 H-NMR (d, DMSO-d 6 ): 9.07 (d, 1H), 7.83 (t, 3H), 7.53 (m, 3H), 7.24 (d, 1H), 6.99 (t, 1H), 4.85- 4.89 (m, 1H), 4.39-4.49 (m, 2H), 4.05-4.1 (m, 1H), 3.47-3.52 (m, 5H), 3.32-3.34 (m, 1H), 2.63-2.68 (m, 2H ), 2.11-2.44 (m, 8H)
실시예 46: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 4-아미노살리실레이트의 제조 Example 46: 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate 4-amino Preparation of Salicylate
1H-NMR(d, DMSO-d6) : 9.17(d,1H), 7.71-7.75(m,4H), 7.53(m,3H), 7.22(d,1H), 6.88(t,1H), 6.11-6.2(m,2H), 4.84-4.89(m,1H), 4.39-4.49(m,2H), 3.47-3.52(m,5H), 3.32-3.34(m,1H), 2.63-2.68(m,2H), 2.50(bs,4H) 1 H-NMR (d, DMSO-d 6 ): 9.17 (d, 1H), 7.71-7.75 (m, 4H), 7.53 (m, 3H), 7.22 (d, 1H), 6.88 (t, 1H), 6.11-6.2 (m, 2H), 4.84-4.89 (m, 1H), 4.39-4.49 (m, 2H), 3.47-3.52 (m, 5H), 3.32-3.34 (m, 1H), 2.63-2.68 (m , 2H), 2.50 (bs, 4H)
실시예 47: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 세바세이트의 제조 Example 47 of 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate sebacate Produce
1H-NMR(d, DMSO-d6) : 9.11(d,1H), 7.83(t,3H), 7.53(m,3H), 7.22(d,1H), 7.02(t,1H), 4.78-4.84(m,1H), 4.39-4.41(m,2H), 3.47-3.52(m,5H), 3.33-3.34(m,1H), 2.63-2.68(m,2H), 2.49(bs,4H), 2.23(d,4H), 1.52-1.55(m,4H), 1.21-1.29(m,8H) 1 H-NMR (d, DMSO-d 6 ): 9.11 (d, 1H), 7.83 (t, 3H), 7.53 (m, 3H), 7.22 (d, 1H), 7.02 (t, 1H), 4.78- 4.84 (m, 1H), 4.39-4.41 (m, 2H), 3.47-3.52 (m, 5H), 3.33-3.34 (m, 1H), 2.63-2.68 (m, 2H), 2.49 (bs, 4H), 2.23 (d, 4H), 1.52-1.55 (m, 4H), 1.21-1.29 (m, 8H)
실시예 48: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 스테아레이트의 제조 Example 48 of 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate stearate Produce
1H-NMR(d, DMSO-d6) : 9.08(d,1H), 7.85(t,3H), 7.53(m,3H), 7.22(d,1H), 7.15(t,1H), 4.84-4.89(m,1H), 4.44-4.49(m,2H), 3.47-3.52(m,5H), 3.32-3.38(m,1H), 2.63-2.65(m,2H), 2.49(bs,4H), 2.21(d,2H), 1.52-1.55(m,2H), 1.25-1.30(m,28H), 0.90(m,3H) 1 H-NMR (d, DMSO-d 6 ): 9.08 (d, 1H), 7.85 (t, 3H), 7.53 (m, 3H), 7.22 (d, 1H), 7.15 (t, 1H), 4.84- 4.89 (m, 1H), 4.44-4.49 (m, 2H), 3.47-3.52 (m, 5H), 3.32-3.38 (m, 1H), 2.63-2.65 (m, 2H), 2.49 (bs, 4H), 2.21 (d, 2H), 1.52-1.55 (m, 2H), 1.25-1.30 (m, 28H), 0.90 (m, 3H)
실시예 49: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 티오시아네이트의 제조 Example 49: 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate thiocyanate Manufacture
1H-NMR(d, DMSO-d6) : 9.17(d,1H), 7.83(t,3H), 7.53(m,3H), 7.22(d,1H), 7.18(t,1H), 4.84-4.92(m,1H), 4.39-4.49(m,2H), 3.9(t,2H), 3.7(t,2H), 3.3-3.5(m,6H), 3.15(bs,2H) 1 H-NMR (d, DMSO-d 6 ): 9.17 (d, 1H), 7.83 (t, 3H), 7.53 (m, 3H), 7.22 (d, 1H), 7.18 (t, 1H), 4.84- 4.92 (m, 1H), 4.39-4.49 (m, 2H), 3.9 (t, 2H), 3.7 (t, 2H), 3.3-3.5 (m, 6H), 3.15 (bs, 2H)
실시예 50: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 운데실레네이트의 제조 Example 50: 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate undecylenate Manufacture
1H-NMR(d, DMSO-d6) : 9.01(d,1H), 7.83(t,3H), 7.53(m,3H), 7.22(d,1H), 7.02(t,1H), 6.41(d,1H), 5.95(d,1H), 4.84-4.89(m,1H), 4.39-4.44(m,2H), 3.47-3.52(m,5H), 3.32-3.34(m,1H), 2.63-2.68(m,2H), 2.49(bs,4H), 1.96(d,2H), 1.28-1.32(m,12H), 0.86(m,3H) 1 H-NMR (d, DMSO-d 6 ): 9.01 (d, 1H), 7.83 (t, 3H), 7.53 (m, 3H), 7.22 (d, 1H), 7.02 (t, 1H), 6.41 ( d, 1H), 5.95 (d, 1H), 4.84-4.89 (m, 1H), 4.39-4.44 (m, 2H), 3.47-3.52 (m, 5H), 3.32-3.34 (m, 1H), 2.63- 2.68 (m, 2H), 2.49 (bs, 4H), 1.96 (d, 2H), 1.28-1.32 (m, 12H), 0.86 (m, 3H)
실시예 51: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 하이드로브로메이트의 제조 Example 51: 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate hydrobromate Manufacture
1H-NMR(d, DMSO-d6) : 9.13(d,1H), 7.85(t,3H), 7.55(m,3H), 7.33(d,1H), 7.23(t,1H), 6.45(s,1H), 4.90-4.85(m,1H), 4.56-4.45(m,2H), 3.91-3.86(m,2H), 3.74-3.68(m,2H), 3.57-3.32(m,6H), 3.16(s,1H) 1 H-NMR (d, DMSO-d 6 ): 9.13 (d, 1H), 7.85 (t, 3H), 7.55 (m, 3H), 7.33 (d, 1H), 7.23 (t, 1H), 6.45 ( s, 1H), 4.90-4.85 (m, 1H), 4.56-4.45 (m, 2H), 3.91-3.86 (m, 2H), 3.74-3.68 (m, 2H), 3.57-3.32 (m, 6H), 3.16 (s, 1H)
실시예 52: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 아이소부티레이트의 제조 Example 52 of 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate isobutyrate Produce
1H-NMR(d, DMSO-d6) : 9.22(d,1H), 7.87-7.83(m,3H), 7.52-7.47(m,3H), 7.32(d,1H), 7.24(t,1H), 6.48(s,1H), 4.82-4.77(m,1H), 4.35-4.24(m,2H), 3.55-3.48(m,5H), 3.34-3.29(m,1H), 2.73-2.62(m,3H), 2.56-2.50(m,4H), 1.18(d,6H) 1 H-NMR (d, DMSO-d 6 ): 9.22 (d, 1H), 7.87-7.83 (m, 3H), 7.52-7.47 (m, 3H), 7.32 (d, 1H), 7.24 (t, 1H ), 6.48 (s, 1H), 4.82-4.77 (m, 1H), 4.35-4.24 (m, 2H), 3.55-3.48 (m, 5H), 3.34-3.29 (m, 1H), 2.73-2.62 (m , 3H), 2.56-2.50 (m, 4H), 1.18 (d, 6H)
실시예 53: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 라우레이트의 제조 Example 53 of 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate laurate Produce
1H-NMR(d, DMSO-d6) : 9.22(d,1H), 7.87-7.83(m,3H), 7.52-7.47(m,3H), 7.32(d,1H), 7.24(t,1H), 6.48(s,1H), 4.82-4.77(m,1H), 4.35-4.24(m,3H), 3.55-3.48(m,5H), 3.34-3.29(m,1H), 2.73-2.62(m,2H), 2.56-2.50(m,4H), 1.26(m,20H), 0.86(d,3H) 1 H-NMR (d, DMSO-d 6 ): 9.22 (d, 1H), 7.87-7.83 (m, 3H), 7.52-7.47 (m, 3H), 7.32 (d, 1H), 7.24 (t, 1H ), 6.48 (s, 1H), 4.82-4.77 (m, 1H), 4.35-4.24 (m, 3H), 3.55-3.48 (m, 5H), 3.34-3.29 (m, 1H), 2.73-2.62 (m , 2H), 2.56-2.50 (m, 4H), 1.26 (m, 20H), 0.86 (d, 3H)
실시예 54: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 DL-만델레이트의 제조 Example 54 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate DL-mandel Manufacture of Rate
1H-NMR(d, DMSO-d6) : 9.07(d,1H), 7.87-7.82(m,3H), 7.58-7.50(m,3H), 7.44-7.22(m,7H), 6.48(s,1H), 5.03(s,1H), 4.81-4.75(m,1H), 4.27-4.18(m,2H), 3.52-3.46(m,5H), 3.34-3.28(m,1H), 2.59-2.50(m,2H), 2.37(brs,4H) 1 H-NMR (d, DMSO-d 6 ): 9.07 (d, 1H), 7.87-7.82 (m, 3H), 7.58-7.50 (m, 3H), 7.44-7.22 (m, 7H), 6.48 (s , 1H), 5.03 (s, 1H), 4.81-4.75 (m, 1H), 4.27-4.18 (m, 2H), 3.52-3.46 (m, 5H), 3.34-3.28 (m, 1H), 2.59-2.50 (m, 2H), 2.37 (brs, 4H)
실시예 55: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 메탄설포네이트의 제조 Example 55 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate methanesulfonate Manufacture
1H-NMR(d, DMSO-d6) : 9.13(d,1H), 7.85-7.82(m,3H), 7.58-7.50(m,3H), 7.34-7.21(m,2H), 6.46(s,1H), 4.87(brs,1H), 4.50-4.46(m,2H), 3.88(brs,2H), 3.69-3.66(m,2H), 3.57-3.31(m,6H), 3.15(brs,2H), 3.40(t,3H) 1 H-NMR (d, DMSO-d 6 ): 9.13 (d, 1H), 7.85-7.82 (m, 3H), 7.58-7.50 (m, 3H), 7.34-7.21 (m, 2H), 6.46 (s , 1H), 4.87 (brs, 1H), 4.50-4.46 (m, 2H), 3.88 (brs, 2H), 3.69-3.66 (m, 2H), 3.57-3.31 (m, 6H), 3.15 (brs, 2H ), 3.40 (t, 3H)
실시예 56: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 나프탈렌-1,5-다이설포네이트의 제조 Example 56 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate naphthalene-1 Of 5,5-disulfonate
1H-NMR(d, DMSO-d6) : 9.13(d,1H), 8.94(d,1H), 8.03(d,2H), 7.92(s,4H), 7.86-7.82(m,2H), 7.52-7.47(m,4H), 7.38(d,1H), 7.21(t,1H), 6.56(s,1H), 4.95-4.89(m,1H), 4.52-4.42(m,2H), 3.80-3.75(m,2H), 3.61-3.51(m,4H), 3.43-3.37(m,3H), 3.12(brs,3H) 1 H-NMR (d, DMSO-d 6 ): 9.13 (d, 1H), 8.94 (d, 1H), 8.03 (d, 2H), 7.92 (s, 4H), 7.86-7.82 (m, 2H), 7.52-7.47 (m, 4H), 7.38 (d, 1H), 7.21 (t, 1H), 6.56 (s, 1H), 4.95-4.89 (m, 1H), 4.52-4.42 (m, 2H), 3.80- 3.75 (m, 2H), 3.61-3.51 (m, 4H), 3.43-3.37 (m, 3H), 3.12 (brs, 3H)
실시예 57: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 나프탈렌-2-설포네이트의 제조 Example 57 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate naphthalene-2 Preparation of Sulfonates
1H-NMR(d, DMSO-d6) : 9.12(d,1H), 8.97(d,1H), 8.06(d,2H), 7.92(s,4H), 7.86-7.82(m,2H), 7.52-7.47(m,5H), 7.40(d,1H), 7.27(t,1H), 6.56(s,1H), 4.95-4.87(m,1H), 4.50-4.42(m,2H), 3.81-3.75(m,2H), 3.62-3.50(m,4H), 3.43-3.37(m,3H), 3.12(brs,3H) 1 H-NMR (d, DMSO-d 6 ): 9.12 (d, 1H), 8.97 (d, 1H), 8.06 (d, 2H), 7.92 (s, 4H), 7.86-7.82 (m, 2H), 7.52-7.47 (m, 5H), 7.40 (d, 1H), 7.27 (t, 1H), 6.56 (s, 1H), 4.95-4.87 (m, 1H), 4.50-4.42 (m, 2H), 3.81- 3.75 (m, 2H), 3.62-3.50 (m, 4H), 3.43-3.37 (m, 3H), 3.12 (brs, 3H)
실시예 58: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 2-나프토에이트의 제조 Example 58: 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate 2-naph Preparation of Toate
1H-NMR(d, DMSO-d6) : 9.12(d,1H), 8.97(d,1H), 8.06(d,2H), 7.92(s,4H), 7.86-7.82(m,2H), 7.52-7.47(m,5H), 7.40(d,1H), 7.27(t,1H), 6.56(s,1H), 4.95-4.87(m,1H), 4.50-4.42(m,2H), 3.81-3.75(m,2H), 3.62-3.50(m,4H), 3.43-3.37(m,3H), 3.12(brs,3H) 1 H-NMR (d, DMSO-d 6 ): 9.12 (d, 1H), 8.97 (d, 1H), 8.06 (d, 2H), 7.92 (s, 4H), 7.86-7.82 (m, 2H), 7.52-7.47 (m, 5H), 7.40 (d, 1H), 7.27 (t, 1H), 6.56 (s, 1H), 4.95-4.87 (m, 1H), 4.50-4.42 (m, 2H), 3.81- 3.75 (m, 2H), 3.62-3.50 (m, 4H), 3.43-3.37 (m, 3H), 3.12 (brs, 3H)
실시예 59: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 니코티네이트의 제조 Example 59 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate nicotinate Manufacture
1H-NMR(d, DMSO-d6) : 9.10-9.04(m,2H), 7.89-7.80(m,5H), 7.56-7.44(m,4H), 7.24-7.17(m,2H), 6.49(s,1H), 4.81-4.75(m,1H), 4.32-4.26(m,2H), 3.58-3.50(m,5H), 3.39-3.29(m,1H), 2.75-2.62(m,2H), 2.54-2.47(m,4H) 1 H-NMR (d, DMSO-d 6 ): 9.10-9.04 (m, 2H), 7.89-7.80 (m, 5H), 7.56-7.44 (m, 4H), 7.24-7.17 (m, 2H), 6.49 (s, 1H), 4.81-4.75 (m, 1H), 4.32-4.26 (m, 2H), 3.58-3.50 (m, 5H), 3.39-3.29 (m, 1H), 2.75-2.62 (m, 2H) , 2.54-2.47 (m, 4H)
실시예 60: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 니트레이트의 제조 Example 60 of 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate nitrate Produce
1H-NMR(d, DMSO-d6) : 9.11(d,1H), 7.84-7.81(m,3H), 7.59-7.50(m,3H), 7.34-7.21(m,2H), 6.44(s,1H), 4.88-4.83(m,1H), 4.52-4.41(m,2H), 3.88(brs,1H), 3.64-3.59(m,2H), 3.50-3.43(m,5H), 3.35-3.29(m,1H), 3.14(brs,2H) 1 H-NMR (d, DMSO-d 6 ): 9.11 (d, 1H), 7.84-7.81 (m, 3H), 7.59-7.50 (m, 3H), 7.34-7.21 (m, 2H), 6.44 (s , 1H), 4.88-4.83 (m, 1H), 4.52-4.41 (m, 2H), 3.88 (brs, 1H), 3.64-3.59 (m, 2H), 3.50-3.43 (m, 5H), 3.35-3.29 (m, 1H), 3.14 (brs, 2H)
실시예 61: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 석시네이트의 제조 Example 61 of 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate succinate Produce
1H-NMR(d, DMSO-d6) : 9.09(d,1H), 7.89-7.83(m,3H), 7.60-7.51(m,3H), 7.37-7.22(m,2H), 6.51(s,1H), 4.83-4.78(m,1H), 4.29-4.16(m,2H), 3.53-3.47(m,5H), 3.36-3.30(m,1H), 2.59-2.48(m,4H), 2.37-2.31(m,4H), 2.11-2.09(m,2H) 1 H-NMR (d, DMSO-d 6 ): 9.09 (d, 1H), 7.89-7.83 (m, 3H), 7.60-7.51 (m, 3H), 7.37-7.22 (m, 2H), 6.51 (s , 1H), 4.83-4.78 (m, 1H), 4.29-4.16 (m, 2H), 3.53-3.47 (m, 5H), 3.36-3.30 (m, 1H), 2.59-2.48 (m, 4H), 2.37 -2.31 (m, 4H), 2.11-2.09 (m, 2H)
실시예 62: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 설퍼레이트의 제조 Example 62 of 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate sulfate Produce
1H-NMR(d, DMSO-d6) : 9.10(d,1H), 7.84-7.80(m,3H), 7.54-7.47(m,3H), 7.33-7.18(m,2H), 6.46(s,1H), 4.90-4.84(m,1H), 4.50-4.40(m,2H), 3.73(brs,4H), 3.58-3.51(m,1H), 3.39-3.31(m,3H), 3.18(brs,4H) 1 H-NMR (d, DMSO-d 6 ): 9.10 (d, 1H), 7.84-7.80 (m, 3H), 7.54-7.47 (m, 3H), 7.33-7.18 (m, 2H), 6.46 (s , 1H), 4.90-4.84 (m, 1H), 4.50-4.40 (m, 2H), 3.73 (brs, 4H), 3.58-3.51 (m, 1H), 3.39-3.31 (m, 3H), 3.18 (brs , 4H)
실시예 63: 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 L-아스파르테이트의 제조 Example 63 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- dihydroquinolin-4-yl) propionate L-as Preparation of Partate
1H-NMR(d, DMSO-d6) : 7.98(d,1H), 7.71-7.67(m,3H), 7.57-7.55(m,3H), 7.48-7.42(m,2H), 6.68(s,1H), 5.09-5.05(m,1H), 4.63-4.52(m,2H), 3.88-3.85(m,5H), 3.76-3.72(m,1H), 3.52-3.46(m,3H), 3.25(brs,3H), 2.89-2.83(m,1H), 2.75-2.68(m,2H) 1 H-NMR (d, DMSO-d 6 ): 7.98 (d, 1H), 7.71-7.67 (m, 3H), 7.57-7.55 (m, 3H), 7.48-7.42 (m, 2H), 6.68 (s , 1H), 5.09-5.05 (m, 1H), 4.63-4.52 (m, 2H), 3.88-3.85 (m, 5H), 3.76-3.72 (m, 1H), 3.52-3.46 (m, 3H), 3.25 (brs, 3H), 2.89-2.83 (m, 1H), 2.75-2.68 (m, 2H)

Claims (8)

  1. 하기 화학식 I의 화합물의 약제학적으로 허용가능한 염:Pharmaceutically acceptable salts of compounds of formula (I)
    [화학식 I][Formula I]
    Figure PCTKR2015000004-appb-I000026
    Figure PCTKR2015000004-appb-I000026
    상기 식에서, Where
    X는 산소, 질소 또는 황 중 어느 하나이고;X is any one of oxygen, nitrogen or sulfur;
    Y는 C1-C6알킬, C1-C6할로알킬, (C1-C3알킬옥시)C1-C6알킬, (C2-C6알켄일옥시)C1-C6알킬, (C1-C6알킬카르보닐옥시)C1-C6알킬, (C1-C6알킬설판일)C1-C6알킬, (아릴설판일)C1-C6 알킬, (아릴설폰일)C1-C6 알킬, (C1-C6알킬아미노)C1-C6알킬, [(C1-C6알킬)(C1-C6알킬)아미노]C1-C6알킬, [(C1-C3알킬)(아릴)아미노]C1-C6알킬, [(C1-C3알킬)(아릴)C1-C3알킬]아미노C1-C6알킬, [(C1-C3알킬)(헤테로아릴)아미노]C1-C6알킬, (아릴카르보닐아미노)C1-C6알킬,C2-C6알켄일, C2-C6알카인일, C2-C6옥소알킬, C3-C8사이클로알킬, (C3-C8사이클로알킬)C1-C6알킬, (C3-C8사이클로알켄일)C1-C6알킬, (C3-C8헤테로사이클로알킬)C1-C6알킬, [(C1-C3알킬)C3-C8헤테로사이클로알킬]C1-C6알킬, [(아릴)C1-C3알킬]C3-C8헤테로사이클로알킬C1-C6알킬, [(C1-C6알킬옥시카르보닐)C3-C8헤테로사이클로알킬]C1-C6알킬, [(C1-C3알킬옥시카르보닐)C3-C8헤테로사이클로알킬]C1-C6알킬, (C3-C8헤테로사이클로알킬)C1-C6알켄일, [(C1-C3알킬)C3-C8헤테로사이클로알켄일]C1-C6알킬, (아릴)C1-C6알킬, [(C1-C3알킬)아릴]C1-C6알킬, [(C1-C3알킬옥시)아릴]C1-C6알킬, [(아릴옥시)아릴]C1-C6알킬, [(C1-C3알킬설판일)아릴]C1-C6알킬, [(C1-C3알킬옥시카르보닐)아릴]C1-C6알킬, [(아릴옥시카르보닐)아릴]C1-C6알킬, (아릴)C3-C6알켄일, (헤테로아릴)C1-C6알킬, [(알킬옥시카르보닐)헤테로아릴]C1-C6알킬, [(C1-C3알킬)C3-C8헤테로아릴]C1-C6알킬, [(C3-C8사이클로알킬)헤테로아릴]C1-C6알킬, [(아릴)헤테로아릴]C1-C6알킬, [(C1-C3알킬)헤테로아릴]C1-C6알킬, [(아릴)C1-C3알킬]헤테로아릴C1-C6알킬, (C1-C6알킬옥시카르보닐)C1-C6알킬, [(C3-C8헤테로사이클로알킬)C1-C6알킬옥시카르보닐]C1-C6알킬, (C3-C8헤테로사이클로알킬카르보닐)C1-C6알킬, [(C1-C3알킬)C3-C8헤테로사이클로알킬카르보닐]C1-C6알킬, [(C1-C3알킬)C3-C8헤테로사이클로알킬카르보닐]C1-C6알킬, [(C3-C8사이클로알킬)옥시카르보닐옥시]C1-C6알킬, [(C3-C8헤테로사이클로알킬)옥시카르보닐옥시]C1-C6알킬, (유레이도)C1-C6알킬, (아릴유레이도)C1-C6알킬, [(아릴)(C1-C3알킬유레이도]C1-C6알킬, (C1-C6알킬아미노카르보닐)C1-C6알킬, [(C3-C8헤테로사이클로알킬)아미노카르보닐]C1-C6알킬, [(C1-C3알킬)C3-C8헤테로사이클로알킬]아미노카르보닐C1-C6알킬, [(C1-C3알킬)(C1-C3알킬옥시)아미노카르보닐]C1-C6알킬 또는 (옥소C3-C8헤테로사이클로알킬)C1-C6알킬이고, 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 3 alkyl) (aryl) C 1 -C 3 alkyl] aminoC 1 -C 6 alkyl, [ (C 1 -C 3 alkyl) (heteroaryl) amino] C 1 -C 6 alkyl, (arylcarbonylamino) 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 cycloalkyl) C 1 -C 6 alkyl, (C 3 -C 8 cycloalkenyl) C 1 -C 6 alkyl, (C 3 -C 8 heterocycloalkyl) C 1 -C 6 alkyl, [(C 1 -C 3 alkyl) C 3 -C 8 heterocycloalkyl] C 1 -C 6 alkyl, [(aryl) C 1 -C 3 alkyl] C 3 -C 8 heterocycloalkyl al C 1 -C 6 alkyl, [(C 1 -C 6 alkyloxycarbonyl) C 3 -C 8 heterocycloalkyl] C 1 -C 6 alkyl, [(C 1 -C 3 alkyloxycarbonyl) C 3 - C 8 heterocycloalkyl] C 1 -C 6 alkyl, (C 3 -C 8 heterocycloalkyl) C 1 -C 6 alkenyl, [(C 1 -C 3 alkyl) C 3 -C 8 heterocycloalkenyl] C 1 -C 6 alkyl, (aryl) C 1 -C 6 alkyl, [(C 1 -C 3 alkyl) aryl] C 1 -C 6 alkyl, [(C 1 -C 3 alkyloxy) aryl] C 1- C 6 alkyl, [(aryloxy) aryl] C 1 -C 6 alkyl, [(C 1 -C 3 alkylsulfanyl) aryl] C 1 -C 6 alkyl, [(C 1 -C 3 alkyloxycarbonyl) Aryl] C 1 -C 6 alkyl, [(aryloxycarbonyl) aryl] C 1 -C 6 alkyl, (aryl) C 3 -C 6 alkenyl, (heteroaryl) C 1 -C 6 alkyl, [(alkyl Oxycarbonyl) heteroaryl] C 1 -C 6 alkyl, [(C 1 -C 3 alkyl) C 3 -C 8 heteroaryl] C 1 -C 6 alkyl, [(C 3 -C 8 cycloalkyl) heteroaryl ] C 1 -C 6 alkyl, [(aryl) heteroaryl] C 1 -C 6 alkyl, [(C 1 -C 3 alkyl) heteroaryl] C 1 -C 6 alkyl, [(aryl) C 1- C 3 alkyl] heteroarylC 1 -C 6 alkyl, (C 1 -C 6 alkyloxycarbonyl) C 1 -C 6 alkyl, [(C 3 -C 8 heterocycloalkyl) C 1 -C 6 alkyloxycar Carbonyl] C 1 -C 6 alkyl, (C 3 -C 8 heterocycloalkylcarbonyl) C 1 -C 6 alkyl, [(C 1 -C 3 alkyl) C 3 -C 8 heterocycloalkylcarbonyl] C 1 -C 6 alkyl, [(C 1 -C 3 alkyl) C 3 -C 8 heterocycloalkyl-carbonyl] C 1 -C 6 alkyl, [(C 3 -C 8 cycloalkyl) oxy carbonyloxy] C 1 - C 6 alkyl, [(C 3 -C 8 heterocycloalkyl) oxycarbonyloxy] C 1 -C 6 alkyl, (ureido) C 1 -C 6 alkyl, (arylureido) C 1 -C 6 alkyl, [(Aryl) (C 1 -C 3 alkylureido) C 1 -C 6 alkyl, (C 1 -C 6 alkylaminocarbonyl) C 1 -C 6 alkyl, [(C 3 -C 8 heterocycloalkyl) Aminocarbonyl] C 1 -C 6 alkyl, [(C 1 -C 3 alkyl) C 3 -C 8 heterocycloalkyl] aminocarbonylC 1 -C 6 alkyl, [(C 1 -C 3 alkyl) (C 1 -C 3 alkyloxy) aminocarbonyl] C 1 -C 6 alkyl Or (oxoC 3 -C 8 heterocycloalkyl) C 1 -C 6 alkyl,
    이 때, 상기 C1-C6알킬, C2-C6알켄일, C2-C6알카인일, C2-C6옥소알킬, C3-C8사이클로알킬, C3-C8사이클로알켄일, C3-C8헤테로사이클로알켄일, 아릴 또는 헤테로아릴은 C1-C3알킬, 플루오로, 클로로, 브로모, 하이드록시기, 옥소, 니트로기 및 시아노기로 이루어진 군으로서 선택된 하나 이상의 치환기로 치환될 수 있다. Wherein 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 cyclo Alkenyl, C 3 -C 8 heterocycloalkenyl, aryl or heteroaryl is one selected from the group consisting of C 1 -C 3 alkyl, fluoro, chloro, bromo, hydroxy, oxo, nitro and cyano groups It may be substituted with the above substituents.
  2. 제1항에 있어서, 상기 염은 약제학적으로 허용가능한 유리산(free acid)에 의하여 형성된 산 부가염인 것을 특징으로 하는, 화학식 I의 화합물의 약제학적으로 허용가능한 염.A pharmaceutically acceptable salt of a compound of formula I according to claim 1, wherein the salt is an acid addition salt formed by a pharmaceutically acceptable free acid.
  3. 제3항에 있어서, 상기 유리산은 유기산 또는 무기산인 것을 특징으로 하는, 화학식 I의 화합물의 약제학적으로 허용가능한 염.4. A pharmaceutically acceptable salt of a compound of formula (I) according to claim 3, wherein the free acid is an organic or inorganic acid.
  4. 제4항에 있어서, 상기 유기산은 구연산, 초산, 젖산, 주석산, 말레인산, 푸마르산, 포름산, 프로피온산, 옥살산, 다이클로로아세트산, 트리플로오로아세트산, 아디프산, 아스코브산, 벤조산, 4-아세트아미도벤조산, 글루콘산, 설폰산, 메탄설폰산, 카프르산, 카프론산, 카프릴산, 카르본산, 신남산, 사이클람산, 도데실설폰산, 에탄-1,2-다이설폰산, 에탄설폰산, 2-하이드록시에탄설폰산, 갈락타르산, 겐티스산, 글루타르산, 2-옥소글루타르산, 글리세로포스포르산, 히푸르산, 올레산, 오로트산, 팔미트산, 파모산, 파이로글루탐산, 세바스산, 스테아르산, 티오시안산, 운데실렌산, 아이소부티르산, 라우르산, 만델산, 나프탈렌-1,5-다이설폰산, 나프탈렌-2-설폰산, 나프토산, 니코틴산, 글리콜산, 석신산, 4-톨루엔설폰산, 캠퍼설폰산, 글루탐산, 아스파르트산, 살리실산, 4-아미노살리실산, 말론산, 말산 및 벤조설폰산으로 이루어진 군으로부터 선택되며, 상기 무기산은 염산, 브롬산, 황산, 질산 및 인산으로 이루어진 군으로부터 선택되는 것을 특징으로 하는, 화학식 I의 화합물의 약제학적으로 허용가능한 염.The method of claim 4, wherein the organic acid is citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, dichloroacetic acid, trifluoroacetic acid, adipic acid, ascorbic acid, benzoic acid, 4-acetami Dobenzoic acid, gluconic acid, sulfonic acid, methanesulfonic acid, capric acid, caproic acid, caprylic acid, carboxylic acid, cinnamic acid, cyclamic acid, dodecylsulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid , 2-hydroxyethanesulfonic acid, galactaric acid, gentisic acid, glutaric acid, 2-oxoglutaric acid, glycerophosphoric acid, hypofuric acid, oleic acid, orotic acid, palmitic acid, pamoic acid , Pyroglutamic acid, sebacic acid, stearic acid, thiocyanic acid, undecylenic acid, isobutyric acid, lauric acid, mandelic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, naphthoic acid, nicotinic acid , Glycolic acid, succinic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glutamic acid, aspartic acid, salicylic acid Compound selected from the group consisting of silicic acid, 4-aminosalicylic acid, malonic acid, malic acid and benzosulfonic acid, wherein said inorganic acid is selected from the group consisting of hydrochloric acid, bromic acid, sulfuric acid, nitric acid and phosphoric acid. Pharmaceutically acceptable salts thereof.
  5. 제1항에 있어서, 상기 염이 하기로 이루어진 군으로부터 선택되는 것을 특징으로 하는 화학식 I의 화합물의 약제학적으로 허용가능한 염:The pharmaceutically acceptable salt of a compound of formula (I) according to claim 1, wherein the salt is selected from the group consisting of:
    1) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 글리콜레이트; 1) 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate glycolate;
    2) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 락테이트;2) 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate lactate;
    3) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 살리실레이트;3) 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate salicylate;
    4) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 옥살레이트; 4) 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate oxalate;
    5) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 말로네이트;5) 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate malonate;
    6) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 말레이트; 6) 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate maleate;
    7) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 타르타레이트;7) 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate tartarate;
    8) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 말레에이트;8) 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate maleate;
    9) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 푸마레이트;9) 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate fumarate;
    10) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 시트레이트;10) 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate citrate;
    11) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 벤젠설포네이트;11) 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate benzenesulfonate;
    12) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 토실레이트;12) 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate tosylate;
    13) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 하이드로클로레이트;13) 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate hydrochlorate;
    14) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 설페이트;14) 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate sulfate;
    15) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 포스포레이트;15) 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate phosphorate;
    16) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 아세테이트;16) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate acetate;
    17) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 다이클로로아세테이트;17) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate dichloroacetate;
    18) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 아디페이트;18) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate adipate;
    19) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 아스코베이트;19) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate ascorbate;
    20) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 벤조에이트;20) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate benzoate;
    21) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 4-아세트아미도벤조에이트;21) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate 4-acetamidobenzo Eight;
    22) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 카프레이트;22) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate caprate;
    23) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 카프로네이트;23) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate capronate;
    24) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 카프릴레이트;24) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate caprylate;
    25) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 카르보네이트;25) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate carbonate;
    26) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 신나메이트;26) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate cinnamate;
    27) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 사이클라메이트;27) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate cyclomate;
    28) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 도데실설포네이트;28) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate dodecylsulfonate;
    29) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 에탄-1,2-다이설포네이트;29) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate ethane-1,2- Disulfonates;
    30) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 에탄설포네이트;30) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate ethanesulfonate;
    31) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 2-하이드록시에탄설포네이트;31) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate 2-hydroxyethanesulfo Nate;
    32) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 포르메이트;32) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate formate;
    33) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 갈락타레이트;33) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate galactate;
    34) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 겐티세이트;34) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate gentisate;
    35) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 글루타메이트;35) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate glutamate;
    36) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 글루타레이트;36) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate glutarate;
    37) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 2-옥소글루타레이트;37) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate 2-oxoglutarate ;
    38) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 글리세로포스포레이트;38) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate glycerophosphorate;
    39) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 히푸레이트;39) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate hipurate;
    40) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 올레에이트;40) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate oleate;
    41) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 오로테이트41) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate orotate
    42) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 팔미테이트;42) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate palmitate;
    43) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 파모에이트;43) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate pamoate;
    44) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 프로피오네이트;44) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate propionate;
    45) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 파이로글루타메이트;45) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate pyroglutamate;
    46) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 4-아미노살리실레이트;46) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate 4-aminosalicylate ;
    47) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 세바세이트;47) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate sebacate;
    48) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 스테아레이트;48) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate stearate;
    49) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 티오시아네이트;49) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate thiocyanate;
    50) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 운데실레네이트;50) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate undecylenate;
    51) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 하이드로브로메이트;51) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate hydrobromate;
    52) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 아이소부티레이트;52) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate isobutyrate;
    53) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 라우레이트;53) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate laurate;
    54) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 DL-만델레이트;54) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate DL-mandelate;
    55) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 메탄설포네이트;55) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate methanesulfonate;
    56) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 나프탈렌-1,5-다이설포네이트;56) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate naphthalene-1,5- Disulfonates;
    57) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 나프탈렌-2-설포네이트;57) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate naphthalene-2-sulfonate ;
    58) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 2-나프토에이트;58) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate 2-naphthoate;
    59) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 니코티네이트;59) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate nicotinate;
    60) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 니트레이트;60) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate nitrate;
    61) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 석시네이트의 제조61) Preparation of 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate succinate
    62) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 설퍼레이트; 및62) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate sulfate; And
    63) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 L-아스파르테이트.63) 2-morpholin-4-yl-ethyl2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate L-aspartate.
  6. 제1항의 화학식 I의 화합물의 약제학적으로 허용가능한 염을 유효성분으로 포함하는, 위궤양, 급성 위염, 만성 위염, 안구 건조 증후군, 암, 골관절염, 류마티스 관절염, 고지혈증, 고중성지방증, 당뇨, 과민성대장증후군 또는 비만의 예방 또는 치료용 약제학적 조성물. Gastric ulcer, acute gastritis, chronic gastritis, dry eye syndrome, cancer, osteoarthritis, rheumatoid arthritis, hyperlipidemia, hypertriglyceridemia, diabetes, irritable bowel, comprising pharmaceutically acceptable salts of compounds of formula (I) as claimed in claim 1 Pharmaceutical compositions for the prevention or treatment of syndromes or obesity.
  7. 제1항의 화학식 I의 화합물의 약제학적으로 허용가능한 염을 이를 필요로 하는 대상에 투여하는 것을 포함하는, 대상에서의 위궤양, 급성 위염, 만성 위염, 안구 건조 증후군, 암, 골관절염, 류마티스 관절염, 고지혈증, 고중성지방증, 당뇨, 과민성대장증후군 또는 비만의 예방 또는 치료방법. Gastric ulcer, acute gastritis, chronic gastritis, dry eye syndrome, cancer, osteoarthritis, rheumatoid arthritis, hyperlipidemia in a subject comprising administering to a subject in need thereof a pharmaceutically acceptable salt of the compound of formula (I) , Hypertriglyceridemia, diabetes, irritable bowel syndrome or obesity.
  8. 위궤양, 급성 위염, 만성 위염, 안구 건조 증후군, 암, 골관절염, 류마티스 관절염, 고지혈증, 고중성지방증, 당뇨, 과민성대장증후군 또는 비만의 예방 또는 치료를 위한 제1항의 화학식 I의 화합물의 약제학적으로 허용가능한 염의 용도. Pharmaceutically acceptable compound of formula I of claim 1 for the prevention or treatment of gastric ulcer, acute gastritis, chronic gastritis, dry eye syndrome, cancer, osteoarthritis, rheumatoid arthritis, hyperlipidemia, hypertriglyceridemia, diabetes, irritable bowel syndrome or obesity Use of possible salts.
PCT/KR2015/000004 2015-01-02 2015-01-02 Novel rebamipide prodrug salt and use thereof WO2016108319A1 (en)

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WO2017138717A1 (en) * 2016-02-11 2017-08-17 삼진제약주식회사 Pharmaceutical composition comprising rebamipide prodrugs for oral administration for preventing or treating immune disease and metabolic disease
WO2020085760A1 (en) * 2018-10-23 2020-04-30 삼진제약 주식회사 Composition for preventing or treating sjogren's syndrome
RU2780509C1 (en) * 2018-10-23 2022-09-26 Самдзин Фармасьютикал Ко., Лтд. Composition for the prevention or treatment of sjogren's syndrome

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