KR20150075443A - Novel salts of rebamipide prodrugs and use thereof - Google Patents

Novel salts of rebamipide prodrugs and use thereof Download PDF

Info

Publication number
KR20150075443A
KR20150075443A KR1020130163399A KR20130163399A KR20150075443A KR 20150075443 A KR20150075443 A KR 20150075443A KR 1020130163399 A KR1020130163399 A KR 1020130163399A KR 20130163399 A KR20130163399 A KR 20130163399A KR 20150075443 A KR20150075443 A KR 20150075443A
Authority
KR
South Korea
Prior art keywords
oxo
alkyl
propionate
chlorobenzoylamino
acid
Prior art date
Application number
KR1020130163399A
Other languages
Korean (ko)
Other versions
KR102132162B1 (en
Inventor
조의환
최승주
이성우
신희종
권호석
이재웅
주정호
김현태
송우헌
윤종배
박기석
박호준
남호태
Original Assignee
삼진제약주식회사
(주)에이에스텍
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 삼진제약주식회사, (주)에이에스텍 filed Critical 삼진제약주식회사
Priority to KR1020130163399A priority Critical patent/KR102132162B1/en
Priority to TW103145460A priority patent/TW201533029A/en
Publication of KR20150075443A publication Critical patent/KR20150075443A/en
Application granted granted Critical
Publication of KR102132162B1 publication Critical patent/KR102132162B1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2

Abstract

The present invention relates to a pharmaceutically acceptable salt of a novel rebamipide precursor and a use of the same. The salt of a novel rebamipide precursor of the present invention has excellent in vivo absorptivity compared to rebamipide, so as to be usefully used in preventing or treating gastric ulcer, acute gastritis, chronic gastritis, scheroma, cancer, ostarthritis, proliferative arthritis, or obesity, in place of rebamipide.

Description

신규 레바미피드 전구체의 염 및 이의 용도{NOVEL SALTS OF REBAMIPIDE PRODRUGS AND USE THEREOF}BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to salts of novel rebamipide precursors and to their use. BACKGROUND OF THE INVENTION < RTI ID = 0.0 >

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 rebamipide prodrug and to its use, and more particularly to a process for the preparation of a novel rebamipide prodrug wherein the overall reaction process is simple but has improved efficacy To pharmaceutically acceptable salts of rebamipide precursors and to their 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 treatment for peptic ulcer, and its chemical name is 2- (4-chlorobenzoylamino) -3- [2 (1H) -quinolin-4-yl] propionic acid. Levamipide is an effective drug for the treatment of gastric mucosal damage caused by acute exacerbation of gastric ulcer, acute gastritis, or chronic gastritis. This drug protects the gastric mucosa by promoting PGE2 biosynthesis and increases mucus, promotes cell proliferation, and inhibits stomach inflammation by inhibiting the adhesion and infiltration of bacteria to gastric mucosal cells in patients infected with Helicobacter pylori. .

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 mechanism of action of rebamipide is to promote the biosynthesis of prostaglandin, thereby enhancing the protective factor. In addition, it has the antioxidative action, which is the only defense factor enhancer, which acts to remove the inflammation by the helicobacter, It has two actions of inhibiting inflammation at the same time. Therefore, it is a very effective drug to reduce the recurrence rate and shorten the treatment period in patients with ulcer or gastritis. It was also confirmed that the size and recurrence rate of ulcer were reduced by rebamipide as the treatment rate was improved in rats fed with acetic acid.

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, methods for producing rebamipide and methods for obtaining high purity rebamipide have been conventionally adopted. As an example, Korean Patent Registration No. 10-0669823 discloses a process for producing 2- (4-chlorobenzoylamino) -3- [2 (1H) -quinolin-4-yl] Patent No. 10-1032600 discloses a process for producing high purity rebamipide which can produce rebamipide of high quality at a purity of 99.95% by simultaneously performing reaction and purification at a low yield and a low yield.

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, levamipide has shown beneficial effects in preventing or treating gastric ulcer, acute gastritis, chronic gastritis, dry eye syndrome, cancer, osteoarthritis and rheumatoid arthritis. Recent studies have shown that rebamipide inhibits obesity As a result, it has attracted interest as a therapeutic agent for obesity, and various therapeutic compositions containing rebamipide as an active ingredient have been developed variously.

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.
Levamipide is soluble in dimethylformamide, slightly soluble in methanol and ethanol, and almost insoluble in ether and water. The aqueous solubility of rebamipide is reported to be approximately 0.0001% (w / v) at pH 3 and 0.013% (w / v) at pH 7. Levamipide is classified as Class in the biopharmaceutical classification system (BCS) due to its low solubility and low membrane permeability, and bioavailability is estimated to be about 5% because it is not absorbed in the body circulation system. Due to such low absorption rate and bioavailability, it is necessary to take a relatively large amount of rebamipide in the development of a pharmaceutical composition containing the rebamipide having various effects as described above. Therefore, There was a problem in that the dosage was significantly lowered. Various attempts have been made to increase the oral absorption rate of rebamipide having such a low water solubility, and in particular, techniques for producing various types of salts with the aid of absorption enhancers and adjuvants or improving solubility Korean Patent Laid-Open No. 10-2004-0104020 proposes rebamipide ridinate and rebamipide arginate and a pharmaceutical agent containing them as an active ingredient. However, it has been proposed to increase the absorption rate of human body There is no question about the effect part, and there is not provided a technique for effectively increasing the absorption rate of rebamipide 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 a beneficial effect on various symptoms as described above. However, in attempting to improve rebamipide, which has a remarkably low absorption rate in the body, the salt of the rebamipide prodrug has a higher absorption rate than the rebamipide And the present invention has been completed.

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 rebamipide precursor which increases the absorption rate to the human body.

상기 목적에 따라, 본 발명은 하기 화학식 I의 화합물의 약제학적으로 허용가능한 염이 제공된다:According to this object, the present invention provides a pharmaceutically acceptable salt of a compound of formula (I)

[화학식 I](I)

Figure pat00001
Figure pat00001

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 aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating gastric ulcer, acute gastritis, chronic gastritis, ocular dryness syndrome, cancer, osteoarthritis, rheumatoid arthritis, hyperlipidemia, There is provided a pharmaceutical composition having the effect of preventing or treating bowel 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 a rebamipide precursor, which is a novel substance that increases the absorption rate to 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 rebamipide precursor according to the present invention significantly increases the absorption rate of the body in comparison with rebamipide present in free acid, so that the salt of the novel rebamipide precursor according to the present invention can be effectively used for the treatment of gastric ulcer, acute gastritis, , Osteoarthritis, rheumatoid arthritis, obesity, hyperlipidemia, hypertriglyceridemia, diabetes, irritable bowel syndrome, and the like.

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 a salt of a precursor of rebamipide, which is known to prevent or treat gastric ulcer, 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 aspect, there is provided a pharmaceutically acceptable salt of a compound of formula I:

[화학식 I](I)

Figure pat00002
Figure pat00002

상기 식에서, In this formula,

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, sulfonyl) 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) (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 alkane , C 2 -C 6 alkyl, oxo, C 3 -C 8 cycloalkyl, (C 3 -C 8 cycloalkyl) C 1 -C 6 alkyl, (C 3 -C 8 cyclo-alkenyl) 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 heterocycloalkyl-alkenyl; 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 alkyl ylsulfanyl) aryl] C 1 -C 6 alkyl, [(C 1 -C 3 alkyloxy-carbonyl) 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 (C 3 -C 8 cycloalkyl) 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) ] 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; heteroaryl C 1 -C 6 alkyl, (C 1 -C 6 alkyloxycarbonyl) C 1 -C 6 alkyl, [(C 3 -C 8 heterocycloalkyl) C 1 -C 6 alkyl-oxy-carboxylic carbonyl] C 1 -C 6 alkyl, (C 3 -C 8 heterocycloalkyl-carbonyl) C 1 -C 6 alkyl, [(C 1 -C 3 alkyl) C 3 -C 8 heterocycloalkyl-carbonyl] 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) oxy carbonyloxy] C 1 -C 6 alkyl, (Fig yureyi) C 1 -C 6 alkyl, (aryl yureyi Figure) C 1 -C 6 alkyl, [(aryl) (C 1 -C 3 alkyl yureyi FIG] C 1 -C 6 alkyl, (C 1 -C 6 alkylamino-carbonyl) C 1 -C 6 alkyl, [(C 3 -C 8 heterocycloalkyl) amino carbonyl; C 1 -C 6 alkyl, [(C 1 -C 3 alkyl) C 3 -C 8 heterocycloalkyl; aminocarbonyl-C 1 -C 6 alkyl, [(C 1 -C 3 alkyl) (C 1 -C 3 alkyloxy) aminocarbonyl] C 1 -C 6 alkyl Or (oxo C 3 -C 8 heterocycloalkyl), it may be a 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.
Said 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 optionally substituted with one or more substituents selected from the group consisting of C 1 -C 3 alkyl, fluoro, chloro, bromo, hydroxyl, oxo, nitro and cyano .

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. The term "heterocycloalkyl" or "heterocycloalkenyl ", as used herein, refers to a saturated or unsaturated, saturated or unsaturated, saturated or unsaturated, This means skipping over. Examples of said heterocycloalkyl or heterocycloalkenyl include aziridine, oxirane, azetidine, oxetane, pyrrolidine, pyrroline, pyrazolidine, pyrazoline, imidazolidine, imidazoline, triazolidine , Oxazolidine, tetrahydrofuran, tetrahydrothiophene, thiazolidine, dioxolane, dioxole, oxathiolane, morpholine. But are not limited to, thiomorpholine, dithiane, piperidine, piperazine, pyran, dioxane or azepane.

또한, 본원에 사용된 용어 "아릴"의 구체적인 예로는 벤젠, 나프탈렌, 안트라센, 또는 페난트렌을 들 수 있으나, 이에 제한되지는 않는다. As used herein, the term "aryl" includes, but is 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.
Furthermore, the term "heteroaryl " as used herein means an aryl in which either nitrogen, oxygen, or sulfur is substituted, or the same or different atoms are replaced by a single, double or triple neighboring or skipped substituent. Specific examples of the heteroaryl include pyrrole, imidazole, pyrazole, triazole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, pyridine, pyrimidine, Benzothiazole, benzothiazole, benzofuran, benzothiophene, quinoline, isoquinoline, quinoxine, pyrazine, pyridazine, triazine, azepine, indole, benzimidazole, indazole, benzooxazole, Benzothiophene, benzothiophene, benzothiophene, benzothiophene, benzothiophene, benzothiophene, benzothiophene, benzothiophene, benzothiophene, benzothiophene, benzothiazine, chroman, chromene, benzodioxanthridine, phenothiazine, But 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.
Herein, XY represents an amino acid or amino acid (C 1 -C 3 alkyl) ester. Amino acids include, 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 rebamipide precursor according to the present invention is preferably an acid addition salt formed by a pharmaceutically acceptable free acid, and the free acid may be an organic acid or an inorganic acid. The organic acids include but are not limited to citric acid, acetic acid, lactic 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, cyclamic acid, dodecylsulfonic acid, ethane- But are not limited to, sulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, galactaric acid, gentisic acid, glutaric acid, 2-oxoglutaric acid, glycerophosphoric acid, But are not limited to, palmitic, palmoic, pyroglutamic, sebacic, stearic, thiocyanic, undecylenic, isobutyric, lauric, mandelic, naphthalene- P-toluenesulfonic acid, p-toluenesulfonic acid, p-toluenesulfonic acid, p-toluenesulfonic acid, Acid, camphorsulfonic acid, glutamic acid, aspartic acid, salicylic acid, 4-aminosalicylic acid, malonic acid, malic acid and benzosulfonic acid. 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: The salt compounds of the preferred rebamipide 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 tartrate;

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 hydrochloride;

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-ethyl 2- (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-ethyl 2- (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-ethyl 2- (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-ethyl 2- (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-ethyl 2- (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- (4-Chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate 2-Morpholin- Eight;

22) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 카프레이트;22) 2-Morpholin-4-yl-ethyl 2- (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-ethyl 2- (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-ethyl 2- (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-ethyl 2- (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-ethyl 2- (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-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate cyclamate;

28) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 도데실설포네이트;28) 2-Morpholin-4-yl-ethyl 2- (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- (4-Chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate A mixture of 2-morpholin- Disulfonate;

30) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 에탄설포네이트;30) 2-Morpholin-4-yl-ethyl 2- (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- (4-Chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate 2-Morpholin- Nate;

32) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 포르메이트;32) 2-Morpholin-4-yl-ethyl 2- (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-ethyl 2- (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-ethyl 2- (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-ethyl 2- (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-ethyl 2- (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- (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-ethyl 2- (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-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate hydrate;

40) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 올레에이트;40) 2-Morpholin-4-yl-ethyl 2- (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- (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-ethyl 2- (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-ethyl 2- (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-ethyl 2- (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-ethyl 2- (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- (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-ethyl 2- (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-ethyl 2- (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-ethyl 2- (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-ethyl 2- (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-ethyl 2- (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-ethyl 2- (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-ethyl 2- (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-ethyl 2- (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-ethyl 2- (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-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate Naphthalene- Disulfonate;

57) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 나프탈렌-2-설포네이트;57) 2- (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-ethyl 2- (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-ethyl 2- (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-ethyl 2- (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 제조Preparation of 2-morpholin-4-yl-ethyl 2- (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-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate Sulfurate; 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-ethyl 2- (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. Alternatively, a pharmaceutically acceptable salt of a compound of formula (I) according to the present invention can be prepared from a compound of formula (I) prepared by reacting a compound of formula (II)

[화학식 II]≪ RTI ID = 0.0 &

Figure pat00003
Figure pat00003

[화학식 III](III)

Y-ZY-Z

상기 식에서, In this formula,

X 및 Y는 전술한 바와 같으며, Z는 하이드록시, 아미노, 아민, 할로겐 또는 이탈기(Leaving group)이다. X and Y are as defined above, and Z is hydroxy, amino, amine, halogen or a leaving group.

본 발명의 하나의 실시형태에서, Z는 하이드록시, -NH2, Cl, Br, 알킬설포닐 또는 아릴설포닐이다.
In one embodiment of the invention, Z is selected from the group consisting of hydroxy, -NH 2, Cl, Br, an 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, the pharmaceutically acceptable salts of the compounds of formula (I) according to the present invention can be prepared from the compounds of formula (I) prepared by the method shown in scheme 1 below, but are not limited thereto.

[반응식 1] [Reaction Scheme 1]

Figure pat00004
Figure pat00004

(상기 식에서, X는 산소, 질소 또는 황 중 어느 하나이다)(Wherein X is any one of oxygen, nitrogen and 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 the starting material in the above Reaction Scheme 1 may be prepared by the method described in U.S. Patent No. 4,578,381. The inorganic salt represented in the above Reaction Scheme 1 may be an inorganic base such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate or cesium carbonate, and the solvent may be acetone, dimethylformamide, dimethylsulfoxide, or Acetonitrile, and the reaction may be carried out at 10 to 100 DEG C 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 is an alkylsulfonyl group such as a methanesulfonyl group as a sulfonyl 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 the formula (II) wherein X is sulfur in the above Reaction Scheme 1 can be prepared according to the process of the following Reaction Scheme 2.

[반응식 2][Reaction Scheme 2]

Figure pat00005
Figure pat00005

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 may be used in an amount of 1 to 10 equivalents, preferably 4 to 6 equivalents, and sodium sulfite may be used in an amount of 1 to 5 equivalents, preferably 2 to 3 equivalents . Dimethylformamide, dimethylsulfoxide, or acetonitrile may be used as a solvent in the above Reaction Scheme 2, and the reaction may be carried out at 10 to 100 ° C for 1 to 24 hours. In the above scheme NCS refers to N-chloro succinimide.

구체적으로, 본 발명에 따른 화학식 I의 화합물의 약제학적으로 허용가능한 염은 하기의 일반적인 실험방법에 따라 제조되는 레바미피드 전구체로부터 제조될 수 있다. In particular, pharmaceutically acceptable salts of compounds of formula (I) according to the present invention can be prepared from rebamipide precursors prepared according to the following general experimental procedures.

실험방법 AExperimental Method A

Figure pat00006
Figure pat00006

[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 by heating in DMF (dimethyl formamide, 8 to 10 times the weight of the compound of formula (II)) and then cooled to 0 占 폚. DCC (dicyclohexylcarbodiimide, 1 to 1.5 eq.) And DMAP (dimethylaminopyridine, 0.1 to 0.3 eq.) Are added to the mixture. If the internal temperature stabilizes after addition, add alcohol or amine (1 to 1.2 equivalents) slowly. After stirring the mixture at room temperature for 4 to 24 hours, the resulting by-product is removed by filtration, and DMF is removed under reduced pressure. Thereafter, column chromatography using methylene chloride: methanol (9: 1, v / v) is carried out to obtain a compound of the formula (I) in solid state. If necessary, perform recrystallization.

실험방법 BExperimental Method B

Figure pat00007
Figure pat00007

[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 by heating in DMF (dimethyl formamide, 8 to 10 times the volume of compound of formula (II)) and then cooled to 0 占 폚. To this mixture is added EDCI (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1-3 equivalents) and HOBT (1-hydroxybenzotriazole, 1-3 equivalents). If the internal temperature stabilizes after addition, add alcohol or amine (1 to 1.5 equivalents) slowly. After stirring the mixture at room temperature for 4 to 24 hours, the resulting by-product is removed by filtration, and DMF is removed under reduced pressure. Thereafter, column chromatography using methylene chloride: methanol (9: 1, v / v) is carried out to obtain a compound of the formula (I) in solid state. If necessary, perform recrystallization.

실험방법 CExperimental Method C

Figure pat00008
Figure pat00008

[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.
To the compound of formula (II), DMF (dimethylformamide, 8-10 times volume of compound of formula II), a halogen compound (1-1.5 equivalents) and inorganic salt (1-2 equivalents) Deg.] C for 1 to 24 hours. After completion of the reaction, the by-product is removed by filtration, and DMF is removed under reduced pressure. Thereafter, column chromatography using methylene chloride: methanol (9: 1, v / v) is carried out to obtain a compound of the formula (I) in solid state. If necessary, perform recrystallization.

실험방법 DExperimental Method D

Figure pat00009
Figure pat00009

[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.
To the compound of formula (II), DMF (dimethylformamide, 8-10 times volume of compound of formula II), sulfonate compound (1-1.5 equivalents) and inorganic salt (1-2 equivalents) The reaction is carried out at 80 ° C for 1 to 24 hours. After completion of the reaction, the by-product is removed by filtration, and DMF is removed under reduced pressure. Thereafter, column chromatography using methylene chloride: methanol (9: 1, v / v) is carried out to obtain a compound of the formula (I) in solid state. If necessary, perform 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, the 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) -thiopropionic acid of the rebamipide precursor represented by the above- According to A or B, it is prepared as follows

실험방법 AExperimental 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 rebamipide are dissolved in 400 mL of DMF (dimethylformamide) by heating and then cooled to room temperature. 28.1 g (1.0 eq, 134.8 mmol) of DCC (dicyclohexylcarbodiimide) was added to the mixture, followed by stirring for 30 minutes. 16.0 g (1.0 eq, 134.8 mmol) of NaSH (sodium hydrosulfide) was added to the mixture, followed by stirring at room temperature for 15 hours. After completion of the reaction, 800 mL of water is added to the mixture, and the mixture is extracted three times with 800 mL of ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated. To the residue was added 800 mL of ethyl acetic acid, and the mixture was stirred at room temperature. The resulting precipitate was filtered off and dried to give the title compound (42.0 g) as a yellow solid.

실험방법 BExperimental 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.
Rebamipide 10 g (26.97 mmol) is dissolved in 80 mL of DMF (dimethylformamide) by heating and then cooled to 0 占 폚. EDCI in the mixture (1-ethyl-3- (3-dimethylaminopropyl) carbonyl dayiyi polyimide hydrochloride) 5.69 g (1.1eq, 29.67 mmol ) and Na 2 S (sodium sulfide) 13.6 g (3.0eq, 80.9 mmol ) After the ice bath was removed, the mixture was stirred at room temperature for 3 hours. After completion of the reaction, 160 mL of water is added to the mixture, and the mixture is extracted three times with 160 mL of ethyl acetate. Anhydrous magnesium sulfate was added to the organic phase, and the organic phase was dried, filtered and concentrated, and 200 mL of ethyl acetate was added to the residue, followed by stirring at room temperature. The resulting precipitate was filtered off and dried to give the title compound as a yellow solid (6.5 g).

한편, 본 발명에 따른 레바미피드 전구체의 염은 하기의 일반적인 실험방법 E에 따라 제조될 수 있으나, 이에 제한되지 않는다. The salt of the rebamipide precursor according to the present invention may be prepared according to the following general method E but is not limited thereto.

실험방법 EExperimental Method E

Figure pat00010
Figure pat00010

[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.
The compound of formula (I) is dissolved in dimethylsulfoxide or dimethylformamide (3 to 10 times the weight of the compound of formula (I)). To the mixture is added an organic or inorganic acid (1 equivalent of the compound of formula (I)) and solidified 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.
The salt of the compound of formula I of the present invention is superior to the free acid levamipide in that it has superior absorption in the body so it can be used in place of rebamipide for the treatment of ulcers, acute gastritis, chronic gastritis, dry eye syndrome, cancer, osteoarthritis, rheumatoid arthritis Can be useful for preventing or treating obesity. The disease is already disclosed as being capable of preventing or treating rebamipide, and the rebamipide precursor of the present invention will be used more effectively for the disease than rebamipide. Accordingly, the present invention provides a pharmaceutical composition for preventing or treating gastric ulcer, acute gastritis, chronic gastritis, dry eye syndrome, cancer, osteoarthritis, rheumatoid arthritis or obesity, which comprises a pharmaceutically acceptable salt of the compound of formula Lt; / RTI >

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 rebamipide compound according to the present invention is 0.5 to 100 mg / day, preferably 1 to 30 mg / day, per kg body weight of the patient. However, the pharmaceutically effective amount may be appropriately changed depending on the severity of the disease symptoms, the age, body weight, health condition, sex, administration route and treatment period 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 present invention may further comprise a pharmaceutically acceptable additive. &Quot; Pharmaceutically acceptable " as used herein means physiologically acceptable and when administered to humans, does not normally cause an allergic reaction such as gastrointestinal disorder, dizziness, or the like. Examples of the additive include a carrier, an excipient, and a diluent. Examples of the carrier, excipient and diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, Polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. Further, it may further include a filler, an anticoagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent and an antiseptic agent.

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 so as to provide rapid, sustained or delayed release of the active ingredient after administration to the mammal. The formulations may be in the form of powders, granules, tablets, emulsions, syrups, aerosols, soft or hard gelatine 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 may be administered through various routes including oral, transdermal, subcutaneous, intravenous or muscular, and the dose of the active ingredient may be appropriately determined depending on the administration route, age, sex, May be appropriately selected according to various factors, and may be administered in combination with a compound known to have a prophylactic or therapeutic use for the disease according to the type 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. The present invention also relates to the use of a compound of formula I in the manufacture of a medicament for the treatment or prophylaxis of gastric ulcers, acute gastritis, chronic gastritis, dry eye syndrome, cancer, osteoarthritis, rheumatoid arthritis Or 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.
Further, the present invention provides the use of a pharmaceutically acceptable salt of a compound of formula I for the prophylaxis 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. However, the scope of the present invention is not limited to the above embodiments.

실시예Example 1: 2-( 1: 2- ( 모폴린Morpholine -4-일)에틸 2-(4-Yl) ethyl 2- (4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다All 이하이드로퀴놀린-4-일)Lt; / RTI > quinolin-4-yl) 프로피오네이트Propionate 글리콜레이트의Glycolate 제조 Produce

Figure pat00011
Figure pat00011

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.According to the general method E, 1 g of 2-morpholin-4-ylethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate (2.07 mmol) and glycolic acid (0.16 g, 2.07 mmol) 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 (400MHz, 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, IH), 7.24 (t, IH), 6.47 (s, IH), 4.76 (m, IH), 4.26-4. 2H), 3.29 (q, 1H), 2.57-2.47 (m, 4H), 2.35 (br-

실시예Example 2: 2-( 2: 2- ( 모폴린Morpholine -4-일)에틸 2-(4-Yl) ethyl 2- (4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다All 이하이드로퀴놀린-4-일)Lt; / RTI > quinolin-4-yl) 프로피오네이트Propionate 락테이트의Lactate 제조 Produce

Figure pat00012
Figure pat00012

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.According to the general method E, 1 g of 2-morpholin-4-ylethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate (2.07 mmol) and lactic acid (0.19 g, 2.07 mmol) were reacted to obtain 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 (400MHz, 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 (M, 2H), 7.32 (d, IH), 7.24 (t, IH), 6.46 3.35-3.26 (m, 5H), 2.58-2.46 (m, 5H), 2.35 (br-s,

실시예Example 3: 2-( 3: 2- ( 모폴린Morpholine -4-일)에틸 2-(4-Yl) ethyl 2- (4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다All 이하이드로퀴놀린-4-일)Lt; / RTI > quinolin-4-yl) 프로피오네이트Propionate 살리실레이트의Salicylate 제조 Produce

Figure pat00013
Figure pat00013

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.According to the general method E, 1 g of 2-morpholin-4-ylethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate (2.07 mmol) and salicylic acid (0.29 g, 2.07 mmol) were reacted to obtain the titled 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 (400MHz, 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 , 7.52 (t, 1 H), 7.42 (m, 1 H), 7.32 (d, 1 H), 7.23 2H), 2.54 (br-s, 4H), 2.32-2.27 (m,

실시예Example 4: 2-( 4: 2- ( 모폴린Morpholine -4-일)에틸 2-(4-Yl) ethyl 2- (4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다All 이하이드로퀴놀린-4-일)Lt; / RTI > quinolin-4-yl) 프로피오네이트Propionate 옥살레이트의Oxalate 제조 Produce

Figure pat00014
Figure pat00014

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.According to the general method E, 1 g of 2-morpholin-4-ylethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate (2.07 mmol) and oxalic acid (0.19 g, 2.07 mmol) were reacted to obtain the titled 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 (400MHz, 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, IH), 7.23 (t, IH), 6.46 (s, IH), 4.79 (m, 2H), 2.65 (br-s, 4H)

실시예Example 5: 2-( 5: 2- ( 모폴린Morpholine -4-일)에틸 2-(4-Yl) ethyl 2- (4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다All 이하이드로퀴놀린-4-일)Lt; / RTI > quinolin-4-yl) 프로피오네이트Propionate 말로네이트의Malonate 제조 Produce

Figure pat00015
Figure pat00015

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.According to the general method E, 1 g of 2-morpholin-4-ylethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate (2.07 mmol) of malonic acid and 0.22 g (2.07 mmol) of malonic acid were reacted to obtain 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 (400MHz, 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, IH), 7.24 (t, IH), 6.46 (s, IH), 4.77 (m, IH), 4.24 (m, 2H), 3.51-3.46 (m, 2H), 2.51 (t, 2H), 2.47 (br-s, 4H)

실시예Example 6: 2-( 6: 2- ( 모폴린Morpholine -4-일)에틸 2-(4-Yl) ethyl 2- (4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다All 이하이드로퀴놀린-4-일)Lt; / RTI > quinolin-4-yl) 프로피오네이트Propionate 말레이트의Malrate 제조 Produce

Figure pat00016
Figure pat00016

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.According to the general method E, 1 g of 2-morpholin-4-ylethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate (2.07 mmol) and malic acid (0.28 g, 2.07 mmol) were reacted to give 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 (700MHz, 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, IH), 7.23 (t, IH), 6.47 (s, IH), 4.78-4.75 (m, IH), 4.26-4.16 (m, 3H), 3.49-3.47 (q, 2H), 2.63-2.51 (m, 2H), 2.45-2.38 (m, 5H)

실시예Example 7: 2-( 7: 2- ( 모폴린Morpholine -4-일)에틸 2-(4-Yl) ethyl 2- (4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다All 이하이드로퀴놀린-4-일)Lt; / RTI > quinolin-4-yl) 프로피오네이트Propionate 타르타레이트의Tartarate 제조 Produce

Figure pat00017
Figure pat00017

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.According to the general method E, 1 g of 2-morpholin-4-ylethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate (2.07 mmol) and tartaric acid (0.31 g, 2.07 mmol) were reacted to give 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 (400MHz, 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, IH), 7.23 (t, IH), 6.47 (s, IH), 4.75 (m, IH), 4.29-4.15 (m, 4H), 3.51-3.46 3.29 (q, 1 H), 2.60-2.48 (m, 2H), 2.37 (br-s,

실시예Example 8: 2-( 8: 2- ( 모폴린Morpholine -4-일)에틸 2-(4-Yl) ethyl 2- (4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다All 이하이드로퀴놀린-4-일)Lt; / RTI > quinolin-4-yl) 프로피오네이트Propionate 말레에이트의Maleate 제조 Produce

Figure pat00018
Figure pat00018

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.According to the general method E, 1 g of 2-morpholin-4-ylethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate (2.07 mmol) and maleic acid (0.24 g, 2.07 mmol) were reacted to obtain the titled 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 (400MHz, 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, IH), 7.23 (t, IH), 6.45 (s, IH), 6.11 (s, 2H), 4.82 (m, 2H), 2.95 (br-s, 4H), 2.51 (t, 2H)

실시예Example 9: 2-( 9: 2- ( 모폴린Morpholine -4-일)에틸 2-(4-Yl) ethyl 2- (4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다All 이하이드로퀴놀린-4-일)Lt; / RTI > quinolin-4-yl) 프로피오네이트Propionate 푸마레이트의Fumarate 제조 Produce

Figure pat00019
Figure pat00019

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.According to the general method E, 1 g of 2-morpholin-4-ylethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate (2.07 mmol) and fumaric acid (0.16 g, 2.07 mmol) 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 (400MHz, 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, IH), 7.24 (t, IH), 6.46 (s, IH), 6.12 (s, 2H), 4.82 (m, 2H), 2.96 (br-s, 4H), 2.52 (t, 2H)

실시예Example 10: 2-( 10: 2- ( 모폴린Morpholine -4-일)에틸 2-(4-Yl) ethyl 2- (4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)) -3- (2-oxo-1,2-dihydroquinolin-4-yl) 프로피오네이트Propionate 시트레이트의Citrate 제조 Produce

Figure pat00020
Figure pat00020

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.According to the general method E, 1 g of 2-morpholin-4-ylethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate (2.07 mmol) and citric acid (0.40 g, 2.07 mmol) were reacted to give 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 (400MHz, 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, IH), 7.24 (t, IH), 6.47 (s, IH), 4.77 (m, IH), 4.28-4.18 (m, 2H), 3.50-3.46 2H), 2.43 (br s, 4H), 2.32 (s, 2H)

실시예Example 11: 2-( 11: 2- ( 모폴린Morpholine -4-일)에틸 2-(4-Yl) ethyl 2- (4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)) -3- (2-oxo-1,2-dihydroquinolin-4-yl) 프로피오네이트Propionate 벤젠설포네이트의Benzenesulfonate 제조 Produce

Figure pat00021
Figure pat00021

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. According to the general method E, 1 g of 2-morpholin-4-ylethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate (2.07 mmol) and benzenesulfonic acid (0.33 g, 2.07 mmol) were reacted to obtain the titled 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 (700MHz, 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 2H), 3.39 (t, 2H), 3.62 (m, 2H), 3.84 (m, , ≪ / RTI > 1H), 3.15 (br-s, 2H)

실시예Example 12: 2-( 12: 2- ( 모폴린Morpholine -4-일)에틸 2-(4-Yl) ethyl 2- (4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)) -3- (2-oxo-1,2-dihydroquinolin-4-yl) 프로피오네이트Propionate 토실레이트의Tosylate 제조 Produce

Figure pat00022
Figure pat00022

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.According to the general method E, 1 g of 2-morpholin-4-ylethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate (2.07 mmol) and toluene sulfonic acid monohydrate (0.39 g, 2.07 mmol) were reacted to give 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 (400MHz, 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, 1H), 7.32 (d, IH), 7.23 (t, IH), 7.11 (d, 2H), 6.45 (s, 2H), 2.29 (s, 3H), 2.29 (m, 2H)

실시예Example 13: 2-( 13: 2- ( 모폴린Morpholine -4-일)에틸 2-(4-Yl) ethyl 2- (4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)) -3- (2-oxo-1,2-dihydroquinolin-4-yl) 프로피오네이트Propionate 하이드로클로레이트의Hydrochloric 제조 Produce

Figure pat00023
Figure pat00023

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.According to the general method E, 1 g of 2-morpholin-4-ylethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate (2.07 mmol) and hydrochloric acid 0.19 mL (2.07 mmol) were reacted to obtain 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, 1 H), 11.52 (br-s, 1 H), 9.24 , 7.55 (t, IH), 7.51 (m, IH), 7.32 (dd, IH), 7.22 (m, IH), 6.46 ), 3.87-3.82 (m, 4H), 3.57 (dd,

실시예Example 14: 2-( 14: 2- ( 모폴린Morpholine -4-일)에틸 2-(4-Yl) ethyl 2- (4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)) -3- (2-oxo-1,2-dihydroquinolin-4-yl) 프로피오네이트Propionate 설페이트의Sulphate 제조 Produce

Figure pat00024
Figure pat00024

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.According to the general method E, 1 g of 2-morpholin-4-ylethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate (2.07 mmol) and sulfuric acid (0.20 g, 2.07 mmol) 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 (400MHz, 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 2H), 3.63 (s, 4H), 3.50 (d, 1H), 7.32 (d, 2H), 2.86 (br-s, 4H), 2.55 (s, IH), 2.51 (s,

실시예Example 15: 2-( 15: 2- ( 모폴린Morpholine -4-일)에틸 2-(4-Yl) ethyl 2- (4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)) -3- (2-oxo-1,2-dihydroquinolin-4-yl) 프로피오네이트Propionate 포스포레이트의Phosphorate 제조  Produce

Figure pat00025
Figure pat00025

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.According to the general method E, 1 g of 2-morpholin-4-ylethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate (2.07 mmol) and phosphoric acid (0.17 g, 2.07 mmol) were reacted to obtain the titled 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 (700MHz, DMSO- d 6): 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 (d, 1H), 7.24 (m, 1H), 6.47 (s, 1H), 4.77-4.75 (m, , 3.30 (dd, 1 H), 2.60-2.57 (m, 2H), 2.56-2.50 (m,

실시예Example 16 2- 16 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 아세테이트의 제조 Preparation of 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, 1 H), 7.83 (t, 3H), 7.53 (m, 3H), 7.22 2H), 3.9 (t, 2H), 3.7 (t, 2H), 3.3-3.5 (m, 6H), 3.15 (bs, 2H)

실시예Example 17: 2- 17: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 다이클로로아세테이트의Of dichloroacetate 제조 Produce

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 ( (m, 2H), 4.87-4.89 (m, IH), 4.36-4.46 (m, 2H), 3.43-3.58 2.49 (bs, 4H)

실시예Example 18: 2- 18: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 아디페이트의Adipate 제조 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 ( 2H), 4.84-4.89 (m, 1H), 4.41-4.49 (m, 2H), 3.47-3.55 (m, 2.49 (bs, 4H), 2.23 (t, 4H), 1.52 - 1.56 (m, 4H)

실시예Example 19: 2- 19: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 아스코베이트의Ascorbate 제조 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 ( (m, 2H), 3.91-3.95 (m, 1H), 3.80-3.82 (m, 1H), 3.54- (M, 2H), 2.49 (bs, 4H), 3.65-3.

실시예Example 20: 2- 20: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 벤조에이트의Benzoate 제조 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, 1 H), 8.13-7.83 (m, 8H), 7.52 2H), 2.49 (bs, 4H, m), 4.84-4.89 (m, )

실시예Example 21: 2- 21: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 4- 4- 아세트아미도벤조에이트의Acetamidobenzoate 제조 Produce

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), 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)

실시예Example 22: 2- 22: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 카프레이트의Caprate 제조 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- (M, 2H), 2.49 (bs, 4H), 3.48-3. 25 2H), 1.52-1.55 (m, 2H), 1.30-1.41 (m, 12H), 0.88 (s, 3H)

실시예Example 23: 2- 23: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 카프로네이트의Capronate 제조 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, 1 H), 7.83 (t, 3H), 7.53 (m, 3H), 7.22 2H), 2.49 (bs, 4H), 2.49 (m, IH) 2H), 1.50-1.65 (m, 2H), 1.32-1.39 (m, 2H), 1.22-1.26

실시예Example 24: 2- 24: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 카프릴레이트의Caprylate 제조 Produce

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- 2H), 2.49 (bs, 4H), 2.49 (m, IH) 2H), 1.52-1.55 (m, 2H), 1.22-1.25 (m, 8H), 0.81 (s, 3H)

실시예Example 25: 2- 25: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 카르보네이트의Carbonate 제조 Produce

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- 2H), 2.51 (bs, 4H), 4.79 (m, 1H), 4.24-4.33 (m, 2H), 3.50-3.52

실시예Example 26: 2- 26: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 신나메이트의Cinnamate 제조 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), 2H), 3.47-3.52 (m, 5H), 3.32-3.34 (m, IH), 7.08 (t, 2.63-2.68 (m, 2H), 2.55 (bs, 4H)

실시예Example 27: 2- 27: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 사이클라메이트의Cyclamate 제조 Produce

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, 1 H), 7.83 (t, 3H), 7.55 (m, 3H), 7.22 (M, 2H), 2.49 (bs, 4H), 2.49 (m, 2.0-2.11 (m, 2H), 1.11-1.44 (m, 10H)

실시예Example 28: 2- 28: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 도데실설포네이트의Dodecylsulfonate 제조 Produce

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- 2H), 2.49 (bs, 4H), 2.47 (m, IH) 2H), 1.52-1.57 (m, 2H), 1.25-1.31 (m, 18H), 0.86 (s, 3H)

실시예Example 29: 2- 29: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 에탄-1,2- Ethane-l, 2- 다이설포네이트의Disulfonate 제조 Produce

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 2H), 3.97 (d, 4H), 3.50-3.52 (m, 5H), 3.37-3.41 (m, 1H), 2.63-2.69 ), 2.51 (bs, 4H)

실시예Example 30: 2- 30: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 에탄설포네이트의Ethane sulfonate 제조 Produce

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, 1 H), 7.83 (t, 3H), 7.53 (m, 3H), 7.22 2H), 2.49 (bs, 4H), 2.49 (m, IH) 1.45 (d, 3H)

실시예Example 31: 2- 31: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 2- 2- 하이드록시에탄설포네이트의Of hydroxyethanesulfonate 제조 Produce

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- 2H), 3.57-3.61 (m, 2H), 3.47-3.52 (m, 5H), 3.32-3.38 ), 2.60-2.65 (m, 2H), 2.55 (bs, 4H)

실시예Example 32: 2- 32: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 포르메이트의Formate 제조 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 ( 2H), 3.47-3.52 (m, 5H), 3.32-3.34 (m, 1H), 2.63-2.68 (m, 2H) 2.57 (bs, 4H)

실시예Example 33: 2- 33: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 갈락타레이트의Galactalate 제조 Produce

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 2H), 3.48-3.52 (m, 5H), 3.32-3.34 (m, 1H), 2.63-2.68 (m, 2H), 4.84-4.89 ), 2.49 (bs, 4H)

실시예Example 34: 2- 34: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 겐티세이트의Gentisate 제조 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), 2H), 2.45 (bs, 4H), 3.45-3.52 (m, 2H) )

실시예Example 35: 2- 35: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 글루타메이트의Glutamate 제조 Produce

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- 2H), 2.49 (bs, 4H), 2.49 (m, 2H) 2.33 (d, 2 H), 2.05 (d, 2 H)

실시예Example 36: 2- 36: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 글루타레이트의Glutarate 제조 Produce

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, 1 H), 7.85 (t, 3H), 7.53 (m, 3H), 7.22 2H), 2.49 (bs, 4H), 2.49 (m, IH) 2.20 - 2.24 (m, 4 H), 1.83 (t, 2 H)

실시예Example 37: 2- 37: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 2- 2- 옥소글루타레이트의Oxoglutarate 제조 Produce

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- 2H), 3.79-3.52 (m, 5H), 3.32-3.34 (m, 1H), 2.63-2.68 (m, 4H) 2.49 (bs, 4H)

실시예Example 38: 2- 38: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 글리세로포스포레이트의Glycerophosphate 제조 Produce

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- 2H), 4.15-4.18 (m, 1H), 3.47-3.52 (m, 5H), 3.32-3.34 ), 2.63-2.68 (m, 2H), 2.49 (bs, 4H)

실시예Example 39: 2- 39: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 히푸레이트의Hippurate 제조 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), 2H), 3.84-3.52 (m, 5H), 3.32-3.34 (m, 1H), 2.63-2.68 (m, 2H), 4.84-4.89 (m, ), 2.49 (bs, 4H)

실시예Example 40: 2- 40: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 올레에이트의Oleate 제조 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 ( 2H), 4.84-4.89 (m, 1H), 4.39-4.50 (m, 2H), 3.47-3.52 (m, 5H), 3.32-3.34 2H), 1.29-1.31 (m, 20H), 0.90 (s, 3H), 2.49 (m, 2H)

실시예Example 41: 2- 41: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 오로테이트의Orotate 제조 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 ( 2H), 3.47-3.52 (m, 5H), 3.32-3.34 (m, 1H), 2.63-2.68 (m, 2H) 2.45 (bs, 4H)

실시예Example 42: 2- 42: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 팔미테이트의Palmitate 제조 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- 2H), 2.49 (bs, 4H), 2.49 (m, 2H) 2H), 1.52-1.55 (m, 2H), 1.28-1.33 (m, 24H), 0.81 (s, 3H)

실시예Example 43: 2- 43: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 파모에이트의Pamoite 제조 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), (M, 2H), 2.51 (bs, 4H), 3.48-3.44 (m, )

실시예Example 44: 2- 44: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 프로피오네이트의Propionate 제조 Produce

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- (M, 2H), 2.45 (bs, 4H), 3.45-3.52 2.27 (d, 2 H), 1.09 (d, 3 H)

실시예Example 45: 2- 45: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 파이로글루타메이트의Pyroglutamate 제조 Produce

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- 1H), 2.63-2.68 (m, 2H), 3.39-3. 44 (m, ), 2.11-2.44 (m, 8H)

실시예Example 46: 2- 46: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 4- 4- 아미노살리실레이트의Aminosalicylate 제조 Produce

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), 1H), 2.63-2.68 (m, 2H), 3.63-3.64 (m, 2H) , 2H), 2.50 (bs, 4H)

실시예Example 47: 2- 47: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 세바세이트의Sebacate 제조 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, 1 H), 7.83 (t, 3H), 7.53 (m, 3H), 7.22 (M, 2H), 2.49 (bs, 4H), 3.94-3.44 (m, 2.23 (d, 4H), 1.52 - 1.55 (m, 4H), 1.21 - 1.29 (m, 8H)

실시예Example 48: 2- 48: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 스테아레이트의Stearate 제조 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- 2H), 2.49 (bs, 4H), 2.49 (m, 2H) 2.21 (d, 2H), 1.52-1.55 (m, 2H), 1.25-1.30 (m, 28H), 0.90 (m, 3H)

실시예Example 49: 2- 49: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 티오시아네이트의Thiocyanate 제조 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), 4.84-4.92(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, 1 H), 7.83 (t, 3H), 7.53 (m, 3H), 7.22 2H), 3.9 (t, 2H), 3.7 (t, 2H), 3.3-3.5 (m, 6H), 3.15 (bs,

실시예Example 50: 2- 50: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 운데실레네이트의Undecylenate 제조 Produce

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 ( 2H), 3.47-3.52 (m, 5H), 3.32-3.34 (m, 1H), 2.63-3.44 (m, (D, 2H), 1.28-1.32 (m, 12H), 0.86 (m, 3H)

실시예Example 51: 2- 51: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 하이드로브로메이트의Hydrobromate 제조 Produce

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 ( (m, 2H), 3.74-3.68 (m, 2H), 3.57-3.32 (m, 6H) 3.16 (s, 1 H)

실시예Example 52: 2- 52: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 아이소부티레이트의Isobutyrate 제조 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, IH), 4.82-4.77 (m, IH), 4.35-4.24 (m, 2H), 3.55-3.48 (m, 5H), 3.34-3.29 , 3H), 2.56-2.50 (m, 4H), 1.18 (d, 6H)

실시예Example 53: 2- 53: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 라우레이트의Laurate 제조 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 , 2H), 2.56-2.50 (m, 4H), 1.26 (m, 20H), 0.86 (d,

실시예Example 54: 2- 54: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate DLDL -- 만델레이트의Mandela's 제조 Produce

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 2H), 3.52-3.46 (m, 5H), 3.34-3.28 (m, IH), 2.59-2.50 (m, IH) (m, 2H), 2.37 (brs, 4H)

실시예Example 55: 2- 55: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 메탄설포네이트의Methanesulfonate 제조 Produce

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 2H), 3.69-3.66 (m, 2H), 3.57-3.31 (m, 6H), 3.15 (brs, 2H), 4.87 ), 3.40 (t, 3H)

실시예Example 56: 2- 56: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 나프탈렌-1,5- Naphthalene-1,5- 다이설포네이트의Disulfonate 제조 Produce

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), (M, 2H), 3.80 (d, IH), 7.52-7.47 (m, 4H), 7.38 3H), 3.12 (brs, 3H), 3.75 (m, 2H), 3.61-3.51 (m, 4H)

실시예Example 57: 2- 57: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 나프탈렌-2- Naphthalene-2- 설포네이트의Sulfonate 제조 Produce

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), 1H), 7.50-7.47 (m, 5H), 7.40 (d, 1H), 7.27 3H), 3.12 (brs, 3H), 3.75-3.55 (m, 2H)

실시예Example 58: 2- 58: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 2- 2- 나프토에이트의Naphthoate 제조 Produce

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), 1H), 7.50-7.47 (m, 5H), 7.40 (d, 1H), 7.27 3H), 3.12 (brs, 3H), 3.75-3.55 (m, 2H)

실시예Example 59: 2- 59: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 니코티네이트의Nicotinate 제조 Produce

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 (m, 2H), 3.58-3.50 (m, 5H), 3.39-3.29 (m, 1H), 2.75-2.62 , 2.54-2.47 (m, 4H)

실시예Example 60: 2- 60: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 니트레이트의Nitrate 제조 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 (M, 2H), 3.50-4.41 (m, 5H), 3.35-3.29 (m, 2H) (m, 1 H), 3.14 (brs, 2 H)

실시예Example 61: 2- 61: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 석시네이트의Seishin Nate's 제조 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 (M, 4H), 2.37 (m, IH), 4.83-4.78 (m, IH), 4.29-4.16 (m, 2H), 3.53-3.47 -2.31 (m, 4H), 2.11-2.09 (m, 2H)

실시예Example 62: 2- 62: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate 설퍼레이트의Sulferrate 제조 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 (M, 1H), 4.90-4.84 (m, 1H), 4.50-4.40 (m, 2H), 3.73 (brs, 4H), 3.58-3.51 , 4H)

실시예Example 63: 2- 63: 2- 모폴린Morpholine -4-일-Yl- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-) -3- (2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)Yl) 프로피오네이트Propionate L- L- 아스파르테이트의Aspartate 제조 Produce

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, 1 H), 7.71-7.67 (m, 3H), 7.57-7.55 (m, 3H), 7.48-7.42 (M, 3H), 3.25 (m, IH), 5.09-5.05 (m, IH), 4.63-4.52 (m, 2H), 3.88-3.85 (br s, 3H), 2.89-2.83 (m, IH), 2.75-2.68 (m, 2H)

Claims (8)

하기 화학식 I의 화합물의 약제학적으로 허용가능한 염:
[화학식 I]
Figure pat00026

상기 식에서,
X는 산소, 질소 또는 황 중 어느 하나이고;
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,
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.
A pharmaceutically acceptable salt of a compound of formula (I)
(I)
Figure pat00026

In this formula,
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, sulfonyl) 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) (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 alkane , C 2 -C 6 alkyl, oxo, C 3 -C 8 cycloalkyl, (C 3 -C 8 cycloalkyl) C 1 -C 6 alkyl, (C 3 -C 8 cyclo-alkenyl) 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 heterocycloalkyl-alkenyl; 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 alkyl ylsulfanyl) aryl] C 1 -C 6 alkyl, [(C 1 -C 3 alkyloxy-carbonyl) 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 (C 3 -C 8 cycloalkyl) 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) ] 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; heteroaryl C 1 -C 6 alkyl, (C 1 -C 6 alkyloxycarbonyl) C 1 -C 6 alkyl, [(C 3 -C 8 heterocycloalkyl) C 1 -C 6 alkyl-oxy-carboxylic carbonyl] C 1 -C 6 alkyl, (C 3 -C 8 heterocycloalkyl-carbonyl) C 1 -C 6 alkyl, [(C 1 -C 3 alkyl) C 3 -C 8 heterocycloalkyl-carbonyl] 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) oxy carbonyloxy] C 1 -C 6 alkyl, (Fig yureyi) C 1 -C 6 alkyl, (aryl yureyi Figure) C 1 -C 6 alkyl, [(aryl) (C 1 -C 3 alkyl yureyi FIG] C 1 -C 6 alkyl, (C 1 -C 6 alkylamino-carbonyl) C 1 -C 6 alkyl, [(C 3 -C 8 heterocycloalkyl) amino carbonyl; C 1 -C 6 alkyl, [(C 1 -C 3 alkyl) C 3 -C 8 heterocycloalkyl; aminocarbonyl-C 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,
Wherein said 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 heterocycloalkyl alkenyl, aryl, or heteroaryl C 1 -C 3 alkyl, fluoro, chloro, bromo, hydroxy, oxo, one selected as the group consisting of a nitro group and a cyano group Lt; / RTI >
제1항에 있어서, 상기 염은 약제학적으로 허용가능한 유리산(free acid)에 의하여 형성된 산 부가염인 것을 특징으로 하는, 화학식 I의 화합물의 약제학적으로 허용가능한 염.
The pharmaceutically acceptable salt of a compound of formula I according to claim 1, wherein said salt is an acid addition salt formed by a pharmaceutically acceptable free acid.
제3항에 있어서, 상기 유리산은 유기산 또는 무기산인 것을 특징으로 하는, 화학식 I의 화합물의 약제학적으로 허용가능한 염.
The pharmaceutically acceptable salt of the compound of formula (I) according to claim 3, wherein the free acid is an organic acid or an inorganic acid.
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 selected from the group consisting of citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, dichloroacetic acid, tripleurooacetic acid, adipic acid, ascorbic acid, There may be mentioned acid addition salts such as benzoic acid, gluconic acid, sulfonic acid, methanesulfonic acid, capric acid, capronic acid, caprylic acid, carboxylic acid, cinnamic acid, cyclamic acid, dodecylsulfonic acid, ethane- , 2-hydroxyethanesulfonic acid, galactaric acid, gentisic acid, glutaric acid, 2-oxoglutaric acid, glycerophosphoric acid, hippuric acid, oleic acid, orotic acid, palmitic acid, , Pyroglutamic acid, sebacic acid, stearic acid, thioxanic acid, undecylenic acid, isobutyric acid, lauric acid, mandelic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, , Glycolic acid, succinic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glutamic acid, aspartic acid, salicylic acid Wherein the inorganic acid is selected from the group consisting of acetic acid, 4-amino salicylic acid, malonic acid, malic acid and benzosulfonic acid, wherein the inorganic acid is selected from the group consisting of hydrochloric acid, bromic acid, sulfuric acid, nitric acid and phosphoric acid. Or a pharmaceutically acceptable salt thereof.
제1항에 있어서, 상기 염이 하기로 이루어진 군으로부터 선택되는 것을 특징으로 하는 화학식 I의 화합물의 약제학적으로 허용가능한 염:
1) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 글리콜레이트;
2) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 락테이트;
3) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 살리실레이트;
4) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 옥살레이트;
5) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 말로네이트;
6) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 말레이트;
7) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 타르타레이트;
8) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 말레에이트;
9) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 푸마레이트;
10) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 시트레이트;
11) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 벤젠설포네이트;
12) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 토실레이트;
13) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 하이드로클로레이트;
14) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 설페이트;
15) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 포스포레이트;
16) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 아세테이트;
17) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 다이클로로아세테이트;
18) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 아디페이트;
19) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 아스코베이트;
20) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 벤조에이트;
21) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 4-아세트아미도벤조에이트;
22) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 카프레이트;
23) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 카프로네이트;
24) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 카프릴레이트;
25) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 카르보네이트;
26) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 신나메이트;
27) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 사이클라메이트;
28) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 도데실설포네이트;
29) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 에탄-1,2-다이설포네이트;
30) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 에탄설포네이트;
31) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 2-하이드록시에탄설포네이트;
32) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 포르메이트;
33) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 갈락타레이트;
34) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 겐티세이트;
35) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 글루타메이트;
36) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 글루타레이트;
37) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 2-옥소글루타레이트;
38) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 글리세로포스포레이트;
39) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 히푸레이트;
40) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 올레에이트;
41) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 오로테이트
42) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 팔미테이트;
43) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 파모에이트;
44) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 프로피오네이트;
45) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 파이로글루타메이트;
46) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 4-아미노살리실레이트;
47) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 세바세이트;
48) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 스테아레이트;
49) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 티오시아네이트;
50) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 운데실레네이트;
51) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 하이드로브로메이트;
52) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 아이소부티레이트;
53) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 라우레이트;
54) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 DL-만델레이트;
55) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 메탄설포네이트;
56) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 나프탈렌-1,5-다이설포네이트;
57) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 나프탈렌-2-설포네이트;
58) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 2-나프토에이트;
59) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 니코티네이트;
60) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 니트레이트;
61) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 석시네이트의 제조
62) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 설퍼레이트; 및
63) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 L-아스파르테이트.
A pharmaceutically acceptable salt of a compound of formula I as claimed in claim 1, wherein said salt is selected from the group consisting of:
1) 2- (Morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate glycolate;
2) 2- (Morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate lactate;
3) 2- (Morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate salicylate;
4) 2- (Morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate oxalate;
5) 2- (Morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate Malonate;
6) 2- (Morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate maleate;
7) 2- (Morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate tartrate;
8) 2- (Morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate maleate;
9) 2- (Morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate fumarate;
10) 2- (Morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate citrate;
11) 2- (Morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate benzenesulfonate;
12) 2- (Morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate tosylate;
13) 2- (Morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate hydrochloride;
14) 2- (Morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate sulfate;
15) 2- (Morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate phosphorate;
16) 2-Morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate acetate;
17) 2-Morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate dichloroacetate;
18) 2-Morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate adipate;
19) 2-morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate ascorbate;
20) 2-Morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate benzoate;
21) 2- (4-Chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate 2-Morpholin- Eight;
22) 2-Morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate caprate;
23) 2-Morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate capronate;
24) 2-Morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate caprylate;
25) 2-Morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate carbonate;
26) 2-Morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate cinnamate;
27) 2-Morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate cyclamate;
28) 2-Morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate dodecylsulfonate;
29) 2- (4-Chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate A mixture of 2-morpholin- Disulfonate;
30) 2-Morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate ethanesulfonate;
31) 2- (4-Chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate 2-Morpholin- Nate;
32) 2-Morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate formate;
33) 2-morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate galactate;
34) 2-Morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate gentisate;
35) 2-morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate glutamate;
36) 2-Morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate glutarate;
37) 2- (4-Chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate 2-oxoglutarate ;
38) 2-Morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate glycerophosphorate;
39) 2-Morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate hydrate;
40) 2-Morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate oleate;
41) 2- (4-Chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate Orotate
42) 2-Morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate palmitate;
43) 2-Morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate pamoate;
44) 2-Morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate propionate;
45) 2-morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate pyroglutamate;
46) 2- (4-Chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate 4-Aminosalicylate ;
47) 2-Morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate sebacate;
48) 2-Morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate stearate;
49) 2-Morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate thiocyanate;
50) 2-Morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate undecylenate;
51) 2-Morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate hydrobromate;
52) 2-Morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate isobutyrate;
53) 2-Morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate laurate;
54) 2-morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate DL-mandelate;
55) 2-Morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate methanesulfonate;
56) 2-Morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate Naphthalene- Disulfonate;
57) 2- (4-Chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate naphthalene-2-sulfonate ;
58) 2-Morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate 2-naphthoate;
59) 2-Morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate nicotinate;
60) 2-Morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate nitrate;
Preparation of 2-morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate succinate
62) 2-Morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate Sulfurate; And
63) 2-morpholin-4-yl-ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate L-aspartate.
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.
Inflammatory bowel disease, acute gastritis, chronic gastritis, dry eye syndrome, cancer, osteoarthritis, rheumatoid arthritis, hyperlipidemia, hyperglycemia, diabetes mellitus, irritable bowel syndrome, Syndrome or a pharmaceutical composition for the prevention or treatment of obesity.
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.
Acute gastritis, chronic gastritis, dry eye syndrome, cancer, osteoarthritis, rheumatoid arthritis, hyperlipidemia, hyperlipidemia, hyperlipidemia, hyperlipidemia, , Hypertriglyceridemia, diabetes, irritable bowel syndrome or obesity.
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. For the prophylaxis or treatment of gastric ulcer, acute gastritis, chronic gastritis, dry eye syndrome, cancer, osteoarthritis, rheumatoid arthritis, hyperlipidemia, hypertonicity, diabetes, irritable bowel syndrome or obesity. Possible use of salts.
KR1020130163399A 2013-12-25 2013-12-25 Novel salts of rebamipide prodrugs and use thereof KR102132162B1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
KR1020130163399A KR102132162B1 (en) 2013-12-25 2013-12-25 Novel salts of rebamipide prodrugs and use thereof
TW103145460A TW201533029A (en) 2013-12-25 2014-12-25 Novel salts of rebamipide prodrugs and use thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
KR1020130163399A KR102132162B1 (en) 2013-12-25 2013-12-25 Novel salts of rebamipide prodrugs and use thereof

Publications (2)

Publication Number Publication Date
KR20150075443A true KR20150075443A (en) 2015-07-06
KR102132162B1 KR102132162B1 (en) 2020-07-10

Family

ID=53788551

Family Applications (1)

Application Number Title Priority Date Filing Date
KR1020130163399A KR102132162B1 (en) 2013-12-25 2013-12-25 Novel salts of rebamipide prodrugs and use thereof

Country Status (2)

Country Link
KR (1) KR102132162B1 (en)
TW (1) TW201533029A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020085760A1 (en) * 2018-10-23 2020-04-30 삼진제약 주식회사 Composition for preventing or treating sjogren's syndrome

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6019767A (en) * 1983-07-11 1985-01-31 Otsuka Pharmaceut Co Ltd Carbostyryl derivative
KR20040104020A (en) * 2003-06-02 2004-12-10 진양제약주식회사 A new rebamipide lysinate, rebamipide argininate and pharmaceutical preparation containing the same as active substance
KR100669823B1 (en) * 2001-02-20 2007-01-17 경동제약 주식회사 Process for Preparing 2-4-Chlorobenzoylamino-3-[21?- quinolinon-4-yl]propionic acid and intermediate thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6019767A (en) * 1983-07-11 1985-01-31 Otsuka Pharmaceut Co Ltd Carbostyryl derivative
KR100669823B1 (en) * 2001-02-20 2007-01-17 경동제약 주식회사 Process for Preparing 2-4-Chlorobenzoylamino-3-[21?- quinolinon-4-yl]propionic acid and intermediate thereof
KR20040104020A (en) * 2003-06-02 2004-12-10 진양제약주식회사 A new rebamipide lysinate, rebamipide argininate and pharmaceutical preparation containing the same as active substance

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020085760A1 (en) * 2018-10-23 2020-04-30 삼진제약 주식회사 Composition for preventing or treating sjogren's syndrome

Also Published As

Publication number Publication date
TW201533029A (en) 2015-09-01
KR102132162B1 (en) 2020-07-10

Similar Documents

Publication Publication Date Title
ES2377661T3 (en) New compounds III
JP2017039730A (en) Pochoxime conjugates useful for treatment of hsp90 related pathologies
CN114430743A (en) Thyroid hormone receptor beta agonist compounds
EP2814820B1 (en) Anti-malarial agents
RU2612509C2 (en) New rebamipide prodrugs, method for their preparation and application
TW202235072A (en) Heterocycle derivatives for treating trpm3 mediated disorders
US20220348591A1 (en) Solid Forms of 3-(5-Fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)pyrrole-2,5-dione
CN111718332B (en) 2-substituted pyrazol amino-4-substituted amino-5-pyrimidine formamide compound, composition and application thereof
JP2021102645A (en) Novel inhibitor of meprin alpha and beta
KR102132162B1 (en) Novel salts of rebamipide prodrugs and use thereof
CA2972746C (en) Production method of thiazole derivative
TW202012414A (en) Tricyclic ask1 inhibitors
JP7279134B2 (en) Method for producing prolinamide compound
KR101750680B1 (en) Pharmaceutical composition comprising novel revamipide prodrugs
OA17194A (en) Novel rebamipide prodrug, method for producing same, and usage thereof.
TW202321215A (en) Polymorphic forms of aurora a selective inhibitors and uses thereof
JP2023100917A (en) Method for producing prolinamide compound
CN116987073A (en) PI3K alpha/HDAC 6 subtype selective dual inhibitor and application thereof
KR20230083276A (en) autotaxin inhibitor compounds
JP2006052138A (en) Proline derivative
JPH0343272B2 (en)

Legal Events

Date Code Title Description
E902 Notification of reason for refusal
E701 Decision to grant or registration of patent right