KR102132162B1 - Novel salts of rebamipide prodrugs and use thereof - Google Patents

Novel salts of rebamipide prodrugs and use thereof Download PDF

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KR102132162B1
KR102132162B1 KR1020130163399A KR20130163399A KR102132162B1 KR 102132162 B1 KR102132162 B1 KR 102132162B1 KR 1020130163399 A KR1020130163399 A KR 1020130163399A KR 20130163399 A KR20130163399 A KR 20130163399A KR 102132162 B1 KR102132162 B1 KR 102132162B1
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oxo
propionate
chlorobenzoylamino
acid
alkyl
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KR20150075443A (en
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조의환
최승주
이성우
신희종
권호석
이재웅
주정호
김현태
송우헌
윤종배
박기석
박호준
남호태
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삼진제약주식회사
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    • 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

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Abstract

본 발명은 신규 레바미피드 전구체의 약제학적으로 허용가능한 염 및 이의 용도에 관한 것으로서, 본 발명의 신규 레바미피드 전구체의 염은 레바미피드에 비해 체내 흡수율이 우수하므로, 레바미피드를 대체하여 위궤양, 급성 위염, 만성 위염, 안구 건조 증후군, 암, 골관절염, 류마티스 관절염 또는 비만을 예방 또는 치료하는데 유용하게 사용될 수 있다. The present invention relates to a pharmaceutically acceptable salt of a new rebamipide precursor and its use, and since the salt of the novel rebamipide precursor of the present invention has a higher absorption rate in the body than rebamipide, it replaces rebamipide It can be useful for preventing or treating gastric ulcer, acute gastritis, chronic gastritis, dry eye syndrome, cancer, osteoarthritis, rheumatoid arthritis or obesity.

Description

신규 레바미피드 전구체의 염 및 이의 용도{NOVEL SALTS OF REBAMIPIDE PRODRUGS AND USE THEREOF}Salt of novel rebamipide precursor and its use{NOVEL SALTS OF REBAMIPIDE PRODRUGS AND USE THEREOF}

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 precursor (prodrug) and the use thereof, more specifically, the overall reaction process is simple, but with the effect of the existing rebamipide material and improved efficacy The novel material shown relates to a pharmaceutically acceptable salt of a rebamipide precursor and its use.

레바미피드(Rebamipide)는 소화성 궤양 치료제로 사용되고 있고, 화학명은 2-(4-클로로벤조일아미노)-3-[2(1H)-퀴놀론-4-일]프로피온산이다. 레바미피드는 위궤양, 급성위염, 또는 만성 위염의 급성 악화로 인한 위 점막 손상의 치료에 탁월한 효과를 가지는 의약이다. 이 약제는 PGE2 생합성을 촉진시켜 점액을 증가시킴으로써 위점막을 보호하고, 세포증식을 촉진시키며, 특히 헬리코박터 필로균에 감염된 환자에 있어서 위점막세포에 대한 균의 점착 및 침윤을 억제시킴으로써 위염증을 억제하는 특징을 갖는다.Rebamipide is used as a therapeutic agent for peptic ulcer, and the chemical name is 2-(4-chlorobenzoylamino)-3-[2(1H)-quinol-4-yl]propionic acid. Rebamipide is a medicine that has an excellent effect in the treatment of gastric mucosal injury due to gastric ulcer, acute gastritis, or acute exacerbation of chronic gastritis. This agent promotes PGE2 biosynthesis to protect the gastric mucosa by increasing mucus, promote cell proliferation, and inhibit gastritis by inhibiting the adhesion and infiltration of bacteria to gastric mucosal cells, especially in patients infected with Helicobacter pylori. It has a characteristic.

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 promotes the biosynthesis of prostaglandins, enhances the defense factor, and has the only antioxidant effect among defense factor enhancers, thereby simultaneously showing the effect of removing inflammation caused by Helicobacter, thereby enhancing the defense factor. It has two effects of inflammation suppression at the same time. Therefore, it is a very effective drug that can significantly reduce the recurrence rate and shorten the treatment period in patients with ulcer or gastritis. Even in experiments using rats that generated stomach ulcers by administering acetic acid, it was confirmed that both the size of the ulcer and the recurrence rate were reduced by rebamipide while the treatment rate was improved.

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, a method of manufacturing a rebamipide or a method of obtaining a high purity rebamipide has been adopted. As an example, Korean Patent Registration No. 10-0669823 discloses a method for producing 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolon-4-yl]propionic acid and its intermediate, and Korea Patent No. 10-1032600 discloses a method for producing high-purity rebamipide capable of producing high-quality rebamipide having a purity of 99.95% by simultaneously performing reaction and purification at a high yield and low manufacturing cost.

한편, 레바미피드는 위궤양, 급성 위염, 만성 위염, 안구 건조 증후군, 암, 골관절염, 류마티스 관절염 등을 예방 또는 치료하는데 유용한 효과를 보여주고 있으며, 최근의 연구결과에 의하면 레바미피드가 비만을 억제하는 효과를 보여 비만치료제로서도 관심을 불러 일으키고 있어, 레바미피드를 유효성분으로 포함하는 치료용 조성물이 다양하게 개발되고 있다.
On the other hand, rebamipide shows a useful effect in preventing or treating gastric ulcer, acute gastritis, chronic gastritis, dry eye syndrome, cancer, osteoarthritis, rheumatoid arthritis, and recent studies show that rebamipide inhibits obesity. As it shows an effect, it is also attracting attention as a treatment for obesity, and various therapeutic compositions including rebamipide as an active ingredient have been developed.

레바미피드는 디메틸포름아미드에 용해되며, 메탄올, 에탄올에 약간 용해되며, 에테르와 물에는 거의 용해되지 않는다. 레바미피드의 수용성 용해도(aqueous solubility)는 대략적으로 pH 3에서 0.0001%(w/v)을, pH 7에서 0.013%(w/v)라고 보고되어 있다. 레바미피드는 낮은 용해도와 낮은 멤브레인 투과성으로 인하여 생물약제학 분류시스템(biopharmaceutiocs classification system : BCS)에서 Class로 등급이 매겨져 있으며, 체순환계에 거의 흡수 되지 않아 생체이용율(bioavailability)이 5% 내외로 알려져 있다. 이처럼 낮은 흡수율과 생체이용율로 인하여 상술한 것과 같은 다양한 효능을 가지는 레바미피드를 포함하는 약학 조성물을 개발하는데 있어 상대적으로 많은 양의 레바미피드를 복용하여야 하고, 때문에 투약시 환자들이 불편할 뿐만 아니라 약효도 투약량에 비해 현저하게 떨어지는 문제점이 남아 있었다. 이와 같이 낮은 수용성 용해도를 가지는 레바미피드의 경구 흡수율을 높이기 위해 다양한 노력들이 시도되고 있었으며, 특히 흡수촉진제(absorption enhancers)와 보조제의 도움을 받거나, 용해도를 증진시킨 다양한 형태의 염을 제조하는 기술들이 연구되어 왔으며, 대한민국공개특허 제10-2004-0104020호에서는 레바미피드 리지네이트와 레바미피드 아르기니네이트 및 이들을 유효성분으로 함유하는 약학적 제재에 대해 제안을 하였지만, 이의 인체에 대한 흡수율을 높이는 효과부분에 대해서는 의문이며, 이 이외에 유효하게 레바미피드의 체내 흡수율을 높일 수 있는 기술에 대해서는 제시되지 않고 있다.
Lebamide is soluble in dimethylformamide, slightly soluble in methanol and ethanol, and almost insoluble in ether and water. The water solubility of rebamipide is reported to be approximately 0.0001% (w/v) at pH 3 and 0.013% (w/v) at pH 7. Rebamipide is classified as a class in the biopharmaceutiocs classification system (BCS) due to its low solubility and low membrane permeability, and it is known that bioavailability is around 5% because it is hardly absorbed by the systemic circulation. Due to the low absorption rate and bioavailability, a relatively large amount of rebamipide should be taken in developing a pharmaceutical composition comprising rebamipide having various effects as described above, and thus, the patient is not only uncomfortable but also uncomfortable during administration. The problem remained that it was significantly lower than the dose. Various efforts have been attempted to increase the oral absorption rate of rebamipide having such low water solubility. In particular, techniques for preparing various types of salts with the help of absorption enhancers and auxiliaries or enhancing solubility It has been studied, and Korean Patent Publication No. 10-2004-0104020 has proposed rebamipide liginate and rebamipide arginate and pharmaceutical preparations containing them as an active ingredient, but increasing its absorption rate to the human body The effect part is questionable, and no technique has been proposed to effectively increase 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 show a useful effect on various symptoms as described above, but while trying to improve rebamipide, the absorption rate of which is significantly lower in the body, the salt of the rebamipide precursor (prodrug) has a higher absorption rate in the body than rebamipide. It confirmed the excellence and completed the present invention.

본 발명의 목적은 인체에 대한 흡수율을 증대시킨 신규 레바미피드 전구체의 약제학적으로 허용가능한 염을 제공하는 데 그 목적이 있다.
It is an object of the present invention to provide a pharmaceutically acceptable salt of a novel rebamipide precursor that has increased absorption to the human body.

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

[화학식 I][Formula I]

Figure 112013118680282-pat00001
Figure 112013118680282-pat00001

상기 식에서, X 및 Y는 본원에서 정의한 바와 같다.
In the above formula, X and Y are as defined herein.

상기 또 다른 목적에 따라 본 발명은 상기 레바미피드 전구체의 염을 유효성분으로 포함하는 위궤양, 급성 위염, 만성 위염, 안구 건조 증후군, 암, 골관절염, 류마티스 관절염, 고지혈증, 고중성지방증, 당뇨, 과민성대장증후군의 예방 또는 치료 및 비만 치료 및 억제효과를 가지는 약제학적 조성물을 제공한다.
According to another object of the present invention, gastric ulcer, acute gastritis, chronic gastritis, dry eye syndrome, cancer, osteoarthritis, rheumatoid arthritis, hyperlipidemia, hypertriglyceridemia, diabetes, hypersensitivity, including the salt of the rebamipide precursor as an active ingredient Provided is a pharmaceutical composition having a prophylactic or therapeutic effect for treating and suppressing obesity or bowel syndrome.

본 발명은 인체에 대한 흡수율을 증대시킨 신규 물질인 레바미피드 전구체의 염을 제공한다는 장점이 있다. The present invention has an advantage of providing a salt of a rebamipide precursor, which is a new material that increases the absorption rate for the human body.

또한, 본 발명에 의한 신규 레바미피드 전구체의 염은 유리산으로 존재하는 레바미피드에 비해 체내 흡수율을 현저하게 증대시킴으로써 적은 양을 복용하더라도 효과적으로 위궤양, 급성 위염, 만성 위염, 안구 건조 증후군, 암, 골관절염, 류마티스 관절염, 비만, 고지혈증, 고중성지방증, 당뇨, 과민성대장증후군 등의 각종 질환을 예방 또는 치료하는데 유용하게 사용될 수 있다는 장점이 있다.
In addition, the salt of the novel rebamipide precursor according to the present invention effectively increases gastric absorption rate in the body compared to the rebamipide present as free acid, effectively taking gastric ulcer, acute gastritis, chronic gastritis, dry eye syndrome, cancer , Osteoarthritis, rheumatoid arthritis, obesity, hyperlipidemia, hypertriglyceridemia, diabetes, irritable bowel syndrome, and the like can be usefully used to prevent or treat various diseases.

이하 본 발명을 상세히 설명한다.
Hereinafter, the present invention will be described in detail.

본 발명은 위궤양, 급성 위염, 만성 위염, 안구 건조 증후군, 암, 골관절염, 류마티스 관절염 등의 예방 또는 치료 용도가 공지되어 있는 레바미피드의 전구체의 염을 제공한다.
The present invention provides a salt of a precursor of rebamipide, which is known for prophylactic or therapeutic uses such as 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 embodiment, pharmaceutically acceptable salts of the compounds of Formula I are provided:

[화학식 I][Formula I]

Figure 112013118680282-pat00002
Figure 112013118680282-pat00002

상기 식에서, In the above 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, (arylsulfuryl Fonyl)C 1 -C 6 alkyl, (C 1 -C 6 alkylamino)C 1 -C 6 alkyl, [(C 1 -C 6 alkyl)(C 1 -C 6 alkyl)amino]C 1 -C 6 alkyl , [(C 1 -C 3 alkyl)(aryl)amino]C 1 -C 6 alkyl, [(C 1 -C 3 alkyl)(aryl)C 1 -C 3 alkyl]aminoC 1 -C 6 alkyl, [ (C 1 -C 3 alkyl)(heteroaryl)amino]C 1 -C 6 alkyl, (arylcarbonylamino)C 1 -C 6 alkyl,C 2 -C 6 alkenyl, C 2 -C 6 alkynyl , C 2 -C 6 oxoalkyl, C 3 -C 8 cycloalkyl, (C 3 -C 8 cycloalkyl)C 1 -C 6 alkyl, (C 3 -C 8 cycloalkenyl)C 1 -C 6 alkyl, (C 3 -C 8 heterocycloalkyl)C 1 -C 6 alkyl, [(C 1 -C 3 alkyl)C 3 -C 8 heterocycloalkyl]C 1 -C 6 alkyl, [(aryl)C 1 -C 3 alkyl]C 3 -C 8 heterocycloalkylC 1 -C 6 alkyl, [(C 1 -C 6 alkyloxycarbonyl)C 3 -C 8 heterocycloalkyl]C 1 -C 6 alkyl, [(C 1 -C 3 alkyloxycarbonyl)C 3 -C 8 heterocycloalkyl]C 1 -C 6 alkyl, (C 3 -C 8 heterocycloalkyl)C 1 -C 6 alkenyl, [(C 1 -C 3 alkyl )C 3 -C 8 heterocycloalkenyl]C 1 -C 6 alkyl, (aryl)C 1 -C 6 alkyl, [(C 1 -C 3 alkyl)aryl]C 1 -C 6 alkyl, [(C 1 -C 3 alkyloxy)aryl]C 1 -C 6 alkyl, [(aryloxy)aryl]C 1 -C 6 alkyl, [(C 1 -C 3 alkylsulfanyl)aryl]C 1 -C 6 alkyl, [ (C 1 -C 3 alkyloxycarbonyl)aryl]C 1 -C 6 alkyl, [(aryloxycarbonyl)aryl]C 1 -C 6 alkyl, (aryl)C 3 -C 6 alkenyl, (heteroaryl)C 1 -C 6 alkyl, [(alkyloxycarbonyl) Heteroaryl]C 1 -C 6 alkyl, [(C 1 -C 3 alkyl)C 3 -C 8 heteroaryl]C 1 -C 6 alkyl, [(C 3 -C 8 cycloalkyl)heteroaryl]C 1- C 6 alkyl, [(aryl)heteroaryl]C 1 -C 6 alkyl, [(C 1 -C 3 alkyl)heteroaryl]C 1 -C 6 alkyl, [(aryl)C 1 -C 3 alkyl]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 alkyloxycarbonyl]C 1 -C 6 alkyl, (C 3 -C 8 heterocycloalkylcarbonyl)C 1 -C 6 alkyl, [(C 1 -C 3 alkyl)C 3 -C 8 heterocycloalkylcarbonyl]C 1 -C 6 alkyl, [ (C 1 -C 3 alkyl)C 3 -C 8 heterocycloalkylcarbonyl]C 1 -C 6 alkyl, [(C 3 -C 8 cycloalkyl)oxycarbonyloxy]C 1 -C 6 alkyl, [( C 3 -C 8 heterocycloalkyl)oxycarbonyloxy]C 1 -C 6 alkyl, (ureido) C 1 -C 6 alkyl, (arylureido) C 1 -C 6 alkyl, [(aryl)(C 1 -C 3 alkylureido]C 1 -C 6 alkyl, (C 1 -C 6 alkylaminocarbonyl)C 1 -C 6 alkyl, [(C 3 -C 8 heterocycloalkyl)aminocarbonyl]C 1 -C 6 alkyl, [(C 1 -C 3 alkyl)C 3 -C 8 heterocycloalkyl]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.

상기 C1-C6알킬, C2-C6알켄일, C2-C6알카인일, C2-C6옥소알킬, C3-C8사이클로알킬, C3-C8사이클로알켄일, C3-C8헤테로사이클로알켄일, 아릴 또는 헤테로아릴은 C1-C3알킬, 플루오로, 클로로, 브로모, 하이드록시기, 옥소, 니트로기 및 시아노기로 이루어진 군으로서 선택된 하나 이상의 치환기로 치환될 수 있다.
C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 oxoalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, C 3 -C 8 heterocycloalkenyl, aryl or heteroaryl is one or more substituents selected from the group consisting of C 1 -C 3 alkyl, fluoro, chloro, bromo, hydroxy groups, oxo, nitro groups and cyano groups. Can be substituted.

본원에 사용된 용어 "헤테로사이클로알킬" 또는 "헤테로사이클로알켄일"은 포화탄소 대신에 질소, 산소, 또는 황 중 어느 하나가 치환되거나, 같은 원자 또는 서로 다른 원자가 단일, 둘 또는 셋이 이웃하거나 또는 건너뛰어 치환됨을 의미한다. 상기 헤테로사이클로알킬 또는 헤테로사이클로알켄일의 예로는 아지리딘, 옥시란, 아제티딘, 옥세탄, 피롤리딘, 피롤린, 피라졸리딘, 피라졸린, 이미다졸리딘, 이미다졸린, 트리아졸리딘, 옥사졸리딘, 테트라하이드로퓨란, 테트라하이드로티오펜, 티아졸리딘, 다이옥솔란, 다이옥솔, 옥사티올란, 모폴린. 티오모폴린, 다이티안, 피페리딘, 피페라진, 피란, 다이옥산 또는 아제판을 들 수 있으나, 이에 제한되지는 않는다. As used herein, the term "heterocycloalkyl" or "heterocycloalkenyl" is substituted for either nitrogen, oxygen, or sulfur in place of saturated carbon, or the same atom or different atoms are single, two or three neighboring, or It means skipping and replacing. Examples of the heterocycloalkyl or heterocycloalkenyl include aziridine, oxirane, azetidine, oxetane, pyrrolidine, pyrroline, pyrazolidine, pyrazoline, imidazolidine, imidazoline, triazolidine , Oxazolidine, tetrahydrofuran, tetrahydrothiophene, thiazolidine, dioxolane, dioxol, oxathiolane, morpholine. Thiomorpholine, dithiane, piperidine, piperazine, pyran, dioxane or azepanes, but is not limited thereto.

또한, 본원에 사용된 용어 "아릴"의 구체적인 예로는 벤젠, 나프탈렌, 안트라센, 또는 페난트렌을 들 수 있으나, 이에 제한되지는 않는다. Further, specific examples of the term “aryl” as used herein include, but are not limited to, benzene, naphthalene, anthracene, or phenanthrene.

나아가, 본원에 사용된 용어 "헤테로아릴"은 질소, 산소, 또는 황 중 어느 하나가 치환되거나, 같은 원자 또는 서로 다른 원자가 단일, 둘 또는 셋이 이웃하거나 또는 건너뛰어 치환된 아릴을 의미한다. 상기 헤테로아릴의 구체적인 예로는 피롤, 이미다졸, 피라졸, 트리아졸, 퓨란, 티오펜, 옥사졸, 아이소옥사졸, 티아졸, 아이소티아졸, 옥사다이아졸, 티아다이아졸, 피리딘, 피리미딘, 피라진, 피리다진, 트리아진, 아제핀, 인돌, 벤즈이미다졸, 인다졸, 벤조옥사졸, 벤조아이소옥사졸, 벤조티아졸, 벤조트리아졸, 벤조퓨란, 벤조티오펜, 퀴놀린, 아이소퀴놀린, 퀴녹살린, 퀴나졸린, 시놀린, 나프티리딘, 프탈라진, 벤조피란, 벤즈옥사진, 벤조트리아진, 크로만, 크로멘, 벤조다이옥산 아트리딘, 페노티아진, 페노옥사진 또는 카바졸을 들 수 있으나, 이에 제한되지 않는다.
Furthermore, as used herein, the term "heteroaryl" refers to aryl in which either nitrogen, oxygen, or sulfur is substituted, or the same atom or different atoms are single, two or three adjacent or skipped. Specific examples of the heteroaryl include pyrrole, imidazole, pyrazole, triazole, furan, thiophene, oxazole, isooxazole, thiazole, isothiazole, oxadiazole, thiadiazole, pyridine, pyrimidine, Pyrazine, pyridazine, triazine, azepine, indole, benzimidazole, indazole, benzoxazole, benzoisoxazole, benzothiazole, benzotriazole, benzofuran, benzothiophene, quinoline, isoquinoline, quinox Examples include saline, quinazoline, cynoline, naphthyridine, phthalazine, benzopyran, benzoxazine, benzotriazine, chroman, chroman, benzodioxate atridine, phenothiazine, phenooxazine, or carbazole. However, it 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.
Here, 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 an organic acid and an inorganic acid can be used as the free acid. The organic acid is not limited thereto, citric acid, acetic acid, lactic acid, tartaric acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, adipic acid, ascorbic acid, Benzoic acid, 4-acetamidobenzoic acid, gluconic acid, sulfonic acid, methanesulfonic acid, capric acid, capric acid, caprylic acid, carboxylic acid, cinnamic acid, cyclamic acid, dodecylsulfonic acid, ethane-1,2-di Sulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, galactaric acid, gentisic acid, glutaric acid, 2-oxoglutaric acid, glycerophosphoric acid, hypuric acid, oleic acid, orotic acid, Palmitic acid, pamoic acid, pyroglutamic acid, sebacic acid, stearic acid, thiocyanic acid, undecylenic acid, isobutyric acid, lauric acid, mandelic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulf Phonic acid, naphthoic acid, nicotinic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glutamic acid, aspartic acid, salicylic acid, 4-aminosalicylic acid, malonic acid, malic acid and benzosulfonic acid. In addition, the inorganic acids include, but are not limited to, hydrochloric acid, bromic acid, sulfuric acid, nitric acid, iodic acid and phosphoric acid.

바람직한 레바미피드 전구체의 염 화합물로는 하기를 들 수 있으나, 이에 제한되는 것은 아니다: Preferred salt compounds of 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 hydrochlorate;

14) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 설페이트;14) 2-(morpholin-4-yl)ethyl 2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate sulfate;

15) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 포스포레이트;15) 2-(morpholin-4-yl)ethyl 2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate phosphorate;

16) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 아세테이트;16) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate acetate;

17) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 다이클로로아세테이트;17) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate dichloroacetate;

18) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 아디페이트;18) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate adipate;

19) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 아스코베이트;19) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate ascorbate;

20) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 벤조에이트;20) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate benzoate;

21) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 4-아세트아미도벤조에이트;21) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate 4-acetamidobenzo Eight;

22) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 카프레이트;22) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate caprate;

23) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 카프로네이트;23) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate capronate;

24) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 카프릴레이트;24) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate caprylate;

25) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 카르보네이트;25) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate carbonate;

26) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 신나메이트;26) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate cinnamate;

27) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 사이클라메이트;27) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate cyclamate;

28) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 도데실설포네이트;28) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate dodecylsulfonate;

29) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 에탄-1,2-다이설포네이트;29) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate ethane-1,2- Disulfonate;

30) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 에탄설포네이트;30) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate ethanesulfonate;

31) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 2-하이드록시에탄설포네이트;31) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate 2-hydroxyethanesulfo Nate;

32) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 포르메이트;32) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate formate;

33) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 갈락타레이트;33) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate galactarate;

34) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 겐티세이트;34) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate gentisate;

35) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 글루타메이트;35) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate glutamate;

36) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 글루타레이트;36) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate glutarate;

37) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 2-옥소글루타레이트;37) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate 2-oxoglutarate ;

38) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 글리세로포스포레이트;38) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate glycerophosphorate;

39) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 히푸레이트;39) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate hiprate;

40) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 올레에이트;40) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate oleate;

41) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 오로테이트41) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate orotate

42) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 팔미테이트;42) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate palmitate;

43) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 파모에이트;43) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate pamoate;

44) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 프로피오네이트;44) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate propionate;

45) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 파이로글루타메이트;45) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate pyroglutamate;

46) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 4-아미노살리실레이트;46) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate 4-aminosalicylate ;

47) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 세바세이트;47) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate sebacate;

48) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 스테아레이트;48) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate stearate;

49) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 티오시아네이트;49) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate thiocyanate;

50) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 운데실레네이트;50) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate undecylenate;

51) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 하이드로브로메이트;51) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate hydrobromate;

52) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 아이소부티레이트;52) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate isobutyrate;

53) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 라우레이트;53) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate laurate;

54) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 DL-만델레이트;54) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate DL-mandelate;

55) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 메탄설포네이트;55) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate methanesulfonate;

56) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 나프탈렌-1,5-다이설포네이트;56) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate naphthalene-1,5- Disulfonate;

57) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 나프탈렌-2-설포네이트;57) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate naphthalene-2-sulfonate ;

58) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 2-나프토에이트;58) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate 2-naphthoate;

59) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 니코티네이트;59) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate nicotinate;

60) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 니트레이트;60) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate nitrate;

61) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 석시네이트의 제조61) Preparation of 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate succinate

62) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 설퍼레이트; 및62) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate 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-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate L-aspartate.

한편, 본 발명에 따른 화학식 I의 화합물의 약제학적으로 허용가능한 염은 하기 화학식 II의 화합물을 하기 화학식 III의 화합물과 반응시켜 제조된 화학식 I의 화합물로부터 제조될 수 있다. On the other hand, pharmaceutically acceptable salts of compounds of formula I according to the present invention can be prepared from compounds of formula I prepared by reacting a compound of formula II with a compound of formula III:

[화학식 II][Formula II]

Figure 112013118680282-pat00003
Figure 112013118680282-pat00003

[화학식 III][Formula III]

Y-ZY-Z

상기 식에서, In the above formula,

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

본 발명의 하나의 실시형태에서, Z는 하이드록시, -NH2, Cl, Br, 알킬설포닐 또는 아릴설포닐이다.
In one embodiment of the invention, Z is hydroxy, -NH 2 , Cl, Br, alkylsulfonyl or arylsulfonyl.

구체적으로, 본 발명에 따른 화학식 I의 화합물의 약제학적으로 허용가능한 염는 하기 [반응식 1]에 표기한 방법으로 제조된 화학식 I의 화합물로부터 제조될 수 있지만, 이에 제한되는 것은 아니다.Specifically, the pharmaceutically acceptable salt of the compound of formula (I) according to the present invention may be prepared from the compound of formula (I) prepared by the method shown in [Reaction Scheme 1], but is not limited thereto.

[반응식 1] [Scheme 1]

Figure 112013118680282-pat00004
Figure 112013118680282-pat00004

(상기 식에서, X는 산소, 질소 또는 황 중 어느 하나이다)(In the above formula, X is any one of oxygen, nitrogen or sulfur)

상기 [반응식 1]에서 출발물질로 사용된 [화학식 II]의 화합물은 미국 특허 제4,578,381호에 기술된 방법에 의해 제조될 수 있다. 상기 [반응식 1]에 표기한 무기염은 소디움바이카보네이트, 소디움카보네이트, 포타슘바이카보네이트, 포타슘카보네이트 또는 세슘카보네이트와 같은 무기 염기일 수 있으며, 용매는 아세톤, 다이메틸포름아마이드, 다이메틸설폭사이드, 또는 아세토나이트릴일 수 있고, 반응은 10 내지 100℃에서 1 내지 24시간 동안 수행할 수 있다. 상기 반응식에서 DCC는 다이사이클로헥실카보다이이마이드; DMAP는 4-다이메틸아미노피리딘; HOBT는 1-하이드록시벤조트리아졸; 및 EDCI는 1-에틸-3-(3-다이메틸아미노프로필)카보다이이마이드 염산을 의미하며, Y-OMs 또는 Y-OTs은 설포닐기로서 메탄설포닐기와 같은 알킬설포닐기; 또는 파라톨루엔설포닐, 벤젠설포닐 또는 4-니트로벤젠설포닐기와 같은 아릴설포닐기를 포함한다.
The compound of [Formula II] used as a starting material in [Scheme 1] may be prepared by the method described in US Pat. No. 4,578,381. The inorganic salt indicated in [Scheme 1] may be an inorganic base such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate or cesium carbonate, and the solvent is acetone, dimethylformamide, dimethyl sulfoxide, or It may be acetonitrile, and the reaction may be performed at 10 to 100°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 are sulfonyl groups such as alkylsulfonyl groups such as methanesulfonyl groups; Or arylsulfonyl groups such as paratoluenesulfonyl, benzenesulfonyl or 4-nitrobenzenesulfonyl groups.

상기 [반응식 1]에서 X가 황인 [화학식 II]의 화합물은 하기 [반응식 2]의 과정에 따라 제조될 수 있다.The compound of [Chemical Formula II] in which X is sulfur in [Scheme 1] may be prepared according to the following [Scheme 2].

[반응식 2][Scheme 2]

Figure 112013118680282-pat00005
Figure 112013118680282-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.
In [Scheme 2], sodium hydrosulfide may be used in an amount of 1 to 10 equivalents, preferably 4 to 6 equivalents, and sodium sulfide may be used in an amount of 1 to 5 equivalents, preferably 2 to 3 equivalents . In [Reaction Scheme 2], dimethylformamide, dimethylsulfoxide or acetonitrile may be used as a solvent, and the reaction may be performed at 10 to 100°C for 1 to 24 hours. In the above scheme, NCS refers to N-chlorosuccinimide.

구체적으로, 본 발명에 따른 화학식 I의 화합물의 약제학적으로 허용가능한 염은 하기의 일반적인 실험방법에 따라 제조되는 레바미피드 전구체로부터 제조될 수 있다. Specifically, the pharmaceutically acceptable salt of the compound of formula I according to the present invention can be prepared from a rebamipide precursor prepared according to the following general experimental method.

실험방법 AExperimental Method A

Figure 112013118680282-pat00006
Figure 112013118680282-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 in DMF (dimethylformamide, 8 to 10 times the volume of the compound of Formula II) by weight, and then cooled to 0°C. To the mixture, DCC (dicyclohexylcarbodiimide, 1 to 1.5 equivalents) and DMAP (dimethylaminopyridine, 0.1 to 0.3 equivalents) are added. When the internal temperature stabilizes after the addition, alcohol or amine (1 to 1.2 equivalents) is slowly added. After stirring the mixture for 4 to 24 hours at room temperature, the resulting by-product is filtered off and DMF is removed under reduced pressure. Thereafter, column chromatography using methylene chloride:methanol (9:1, v/v) is performed to obtain a solid compound of [Formula I]. Re-determination is performed if necessary.

실험방법 BExperimental Method B

Figure 112013118680282-pat00007
Figure 112013118680282-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 heated in DMF (dimethylformamide, 8 to 10 times the volume of the compound of Formula II), dissolved and cooled to 0°C. EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloric acid, 1-3 equivalents) and HOBT (1-hydroxybenzotriazole, 1-3 equivalents) are added to the mixture. When the internal temperature stabilizes after the addition, alcohol or amine (1 to 1.5 equivalents) is slowly added. After stirring the mixture for 4 to 24 hours at room temperature, the resulting by-product is filtered off and DMF is removed under reduced pressure. Thereafter, column chromatography using methylene chloride:methanol (9:1, v/v) is performed to obtain a solid compound of [Formula I]. Re-determination is performed if necessary.

실험방법 CExperimental Method C

Figure 112013118680282-pat00008
Figure 112013118680282-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.
DMF (dimethylformamide, 8 to 10 times the volume of the compound of formula II), halogen compound (1 to 1.5 eq.) and inorganic salt (1 to 2 eq.) were added to the compound of [Formula II] in order, 20 to 80. The reaction is carried out for 1 to 24 hours at ℃. After completion of the reaction, by-products are removed by filtration and DMF is removed under reduced pressure. Thereafter, column chromatography using methylene chloride:methanol (9:1, v/v) is performed to obtain a solid compound of [Formula I]. Re-determination is performed if necessary.

실험방법 DExperimental Method D

Figure 112013118680282-pat00009
Figure 112013118680282-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.
DMF (dimethylformamide, 8 to 10 times the volume of the compound of formula II), sulfonate compound (1 to 1.5 eq.) and inorganic salt (1 to 2 eq.) were added to the compound of [Formula II] in turn, and 20 to 20. The reaction was carried out at 80°C for 1 to 24 hours. After completion of the reaction, by-products are removed by filtration and DMF is removed under reduced pressure. Thereafter, column chromatography using methylene chloride:methanol (9:1, v/v) is performed to obtain a solid compound of [Formula I]. Re-determination is performed if necessary.

더욱 구체적으로, 상기 화학식 I로 표시되는 레바미피드 전구체 중 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)-티오프로피온산은 실험방법 A 또는 B에 따라 다음과 같이 제조된다More specifically, 2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)-thiopropionic acid in the rebamipide precursor represented by Chemical Formula I is an experimental method Manufactured as follows according to A or B

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 is dissolved in 400 mL of DMF (dimethylformamide), dissolved, and cooled to room temperature. DCC (dicyclohexylcarbodiimide) 28.1 g (1.0eq, 134.8 mmol) was added to the mixture, followed by stirring for 30 minutes. 16.0 g (1.0eq, 134.8 mmol) of NaSH (sodium hydrosulfide) was added to the mixture, followed by stirring at room temperature for 15 hours. After completion of the reaction, 800 mL of water was added to the mixture, followed by extraction three times with 800 mL of ethyl acetate. Anhydrous magnesium sulfate was added to the organic phase, dried, filtered and concentrated, and 800 mL of ethyl acetate was added to the residue, followed by stirring at room temperature. The resulting precipitate was filtered and dried to give the titled 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.
10 g (26.97 mmol) of rebamipide is dissolved in 80 mL of DMF (dimethylformamide), dissolved, and cooled to 0°C. To the mixture, 5.69 g (1.1 eq, 29.67 mmol) of EDCI (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride) and 13.6 g (3.0 eq, 80.9 mmol) of Na 2 S (sodium sulfide) After adding, the ice bath was removed and stirred at room temperature for 3 hours. After completion of the reaction, 160 mL of water was added to the mixture, followed by extraction three times with 160 mL of ethyl acetate. Anhydrous magnesium sulfate was added to the organic phase, dried, filtered and concentrated, and 200 mL of ethyl acetate was added to the residue, followed by stirring at room temperature. The resulting precipitate was filtered and dried to give the titled compound (6.5 g) as a yellow solid.

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

실험방법 EExperimental Method E

Figure 112013118680282-pat00010
Figure 112013118680282-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 dimethyl sulfoxide or dimethylformamide (3 to 10 times the volume of the compound of [Formula I]). To the mixture, an organic acid or an inorganic acid (1 equivalent of the compound of [Formula I]) is added and stirred to solidify to obtain the compound of [Formula III].

본 발명의 화학식 I의 화합물의 염은 유리산 상태의 레바미피드에 비해 체내 흡수율이 뛰어나므로, 레바미피드를 대체하여 위궤양, 급성 위염, 만성 위염, 안구 건조 증후군, 암, 골관절염, 류마티스 관절염 또는 비만을 예방 또는 치료하는데 유용하게 사용될 수 있다. 상기 질환은 레바미피드가 예방 또는 치료할 수 있는 것으로 이미 공개되어 있는 것으로서, 본 발명의 레바미피드 전구체는 레바미피드보다 상기 질환에 더 효과적으로 사용될 것이다. 이에, 본 발명은 화학식 I의 화합물의 약제학적으로 허용가능한 염을 유효성분으로 포함하는, 위궤양, 급성 위염, 만성 위염, 안구 건조 증후군, 암, 골관절염, 류마티스 관절염 또는 비만의 예방 또는 치료용 약제학적 조성물을 제공한다.
Since the salt of the compound of the formula (I) of the present invention has a higher absorption rate in the body than levamipid in the free acid state, gastric ulcer, acute gastritis, chronic gastritis, dry eye syndrome, cancer, osteoarthritis, rheumatoid arthritis or It can be usefully used to prevent or treat obesity. The disease has already been disclosed that rebamipide can be prevented or treated, and the rebamipide precursor of the present invention will be used more effectively for the disease than rebamipide. Accordingly, the present invention includes a pharmaceutically acceptable salt of the compound of formula I as an active ingredient, gastric ulcer, acute gastritis, chronic gastritis, dry eye syndrome, cancer, osteoarthritis, rheumatoid arthritis or obesity Provided is a composition.

본 발명에 따른 레바미피드 화합물의 염의 약학적으로 유효한 양은 환자의 체중 1kg 당 0.5 ~ 100 mg/day, 바람직하게는 1 ~ 30 mg/day이다. 그러나 상기 약학적으로 유효한 양은 질환 증상의 정도, 환자의 연령, 체중, 건강상태, 성별, 투여 경로 및 치료기간 등에 따라 적절히 변화될 수 있다.
The pharmaceutically effective amount of the salt of the rebamipide compound according to the present invention is 0.5 to 100 mg/day, preferably 1 to 30 mg/day per 1 kg of body weight of the patient. However, the pharmaceutically effective amount may be appropriately changed according to the degree of disease symptoms, the patient's age, weight, health status, sex, administration route, and treatment period.

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 include a pharmaceutically acceptable additive. As used herein,'pharmaceutically acceptable' means that when physiologically acceptable and administered to humans, it does not usually cause an allergic reaction such as gastrointestinal disorders, dizziness or similar reactions. Examples of the additives include carriers, excipients and diluents. Examples of the carrier, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, Polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In addition, fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers and preservatives may be further included.

또한, 본 발명의 약제학적 조성물은 포유동물에 투여된 후 활성 성분의 신속, 지속 또는 지연된 방출을 제공할 수 있도록 당업계에 공지된 방법을 사용하여 제형화될 수 있다. 제형은 분말, 과립, 정제, 에멀젼, 시럽, 에어로졸, 연질 또는 경질 젤라틴 캅셀, 멸균 주사용액, 멸균 분말의 형태일 수 있다.In addition, the pharmaceutical compositions of the present invention can be formulated using methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal. Formulations may be in the form of powders, granules, tablets, emulsions, syrups, aerosols, soft or hard gelatin capsules, sterile injectable solutions, sterile powders.

본 발명에 따른 약제학적 조성물은 경구, 경피, 피하, 정맥 또는 근육을 포함한 여러 경로를 통해 투여될 수 있으며, 활성 성분의 투여량은 투여 경로, 환자의 연령, 성별, 체중 및 환자의 중증도 등의 여러 인자에 따라 적절히 선택될 수 있고, 치료하고자 하는 질환의 종류에 따라 상기 질환에 예방 또는 치료 용도가 있다고 공지되어 있는 화합물과 병용하여 투여될 수 있다.
The pharmaceutical composition according to the present invention can be administered through various routes including oral, transdermal, subcutaneous, intravenous or intramuscular, and the dosage of the active ingredient is the route of administration, the age of the patient, sex, weight, and the severity of the patient. It 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 in 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. In addition, the present invention comprises administering a pharmaceutically acceptable salt of a compound of Formula I to a subject in need thereof, gastric ulcer, acute gastritis, chronic gastritis, dry eye syndrome, cancer, osteoarthritis, rheumatoid arthritis Or it provides a method for preventing or treating obesity.

나아가, 본 발명은 위궤양, 급성 위염, 만성 위염, 안구 건조 증후군, 암, 골관절염, 류마티스 관절염 또는 비만의 예방 또는 치료를 위한 화학식 I의 화합물의 약제학적으로 허용가능한 염의 용도를 제공한다.
Furthermore, the present invention provides the use of a pharmaceutically acceptable salt of a compound of formula I for the prevention or treatment of gastric ulcer, acute gastritis, chronic gastritis, dry eye syndrome, cancer, osteoarthritis, rheumatoid arthritis or obesity.

이하 본 발명을 실시예를 들어 상세히 설명하고자 하나, 본 발명의 범주가 상기 실시예에 의해 한정되는 것은 아니다.
Hereinafter, the present invention will be described in detail with reference to examples, but the scope of the present invention is not limited by the examples.

실시예Example 1: 2-( 1: 2-( 모폴린Morpholine -4-일)에틸 2-(4--4-yl)ethyl 2-(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다All 이하이드로퀴놀린-4-일)Dihydroquinolin-4-yl) 프로피오네이트Propionate 글리콜레이트의Glycolate 제조 Produce

Figure 112013118680282-pat00011
Figure 112013118680282-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 General Experimental 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, 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)

실시예Example 2: 2-( 2: 2-( 모폴린Morpholine -4-일)에틸 2-(4--4-yl)ethyl 2-(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다All 이하이드로퀴놀린-4-일)Dihydroquinolin-4-yl) 프로피오네이트Propionate 락테이트의Lactate 제조 Produce

Figure 112013118680282-pat00012
Figure 112013118680282-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 General Experimental 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 0.19 g (2.07 mmol) of lactic acid were reacted to obtain the title compound (0.9 g) as a white solid.

1H NMR (400MHz, DMSO-d6): 11.71(s, 1H), 9.06(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 , 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)

실시예Example 3: 2-( 3: 2-( 모폴린Morpholine -4-일)에틸 2-(4--4-yl)ethyl 2-(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다All 이하이드로퀴놀린-4-일)Dihydroquinolin-4-yl) 프로피오네이트Propionate 살리실레이트의Salicylate 제조 Produce

Figure 112013118680282-pat00013
Figure 112013118680282-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 General Experimental 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 title compound (0.8 g) as a white solid.

1H NMR (400MHz, DMSO-d6): 11.71(s, 1H), 9.08(d, 1H), 7.83(t, 3H), 7.76(dd, 1H), 7.59(s, 1H), 7.56(s, 1H), 7.52(t, 1H), 7.42(m, 1H), 7.32(d, 1H), 7.23(t, 1H), 6.85(q, 1H), 6.46(s, 1H), 4.78(m, 1H), 4.32-4.21(m, 2H), 3.54-3.47(m, 5H), 3.29(q, 2H), 2.78-2.67(m, 2H), 2.54(br-s, 4H)
 1 H NMR (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 , 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)

실시예Example 4: 2-( 4: 2-( 모폴린Morpholine -4-일)에틸 2-(4--4-yl)ethyl 2-(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다All 이하이드로퀴놀린-4-일)Dihydroquinolin-4-yl) 프로피오네이트Propionate 옥살레이트의Oxalate 제조 Produce

Figure 112013118680282-pat00014
Figure 112013118680282-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 General Experimental 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 0.19 g (2.07 mmol) of oxalic acid were reacted to obtain the title compound (1.0 g) as a white solid.

1H NMR (400MHz, DMSO-d6): 11.71(s, 1H), 9.09(d, 1H), 7.83(t, 3H), 7.58(s, 1H), 7.56(s, 1H), 7.52(t, 1H), 7.32(d, 1H), 7.23(t, 1H), 6.46(s, 1H), 4.79(m, 1H), 4.34-4.25(m, 2H), 3.56(t, 4H), 3.49(dd, 1H), 3.29(q, 1H), 2.87-2.78(m, 2H), 2.65(br-s, 4H)
 1 H NMR (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, 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)

실시예Example 5: 2-( 5: 2-( 모폴린Morpholine -4-일)에틸 2-(4--4-yl)ethyl 2-(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다All 이하이드로퀴놀린-4-일)Dihydroquinolin-4-yl) 프로피오네이트Propionate 말로네이트의Malonate 제조 Produce

Figure 112013118680282-pat00015
Figure 112013118680282-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 General Experimental 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 malonic acid 0.22 g (2.07 mmol) 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, 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)

실시예Example 6: 2-( 6: 2-( 모폴린Morpholine -4-일)에틸 2-(4--4-yl)ethyl 2-(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다All 이하이드로퀴놀린-4-일)Dihydroquinolin-4-yl) 프로피오네이트Propionate 말레이트의Malate 제조 Produce

Figure 112013118680282-pat00016
Figure 112013118680282-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 General Experimental 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 0.28 g (2.07 mmol) of malic acid were reacted to obtain 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, 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)

실시예Example 7: 2-( 7: 2-( 모폴린Morpholine -4-일)에틸 2-(4--4-yl)ethyl 2-(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다All 이하이드로퀴놀린-4-일)Dihydroquinolin-4-yl) 프로피오네이트Propionate 타르타레이트의Tartarate 제조 Produce

Figure 112013118680282-pat00017
Figure 112013118680282-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 General Experimental 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 obtain the title compound (0.4 g) as a white solid.

1H NMR (400MHz, DMSO-d6): 11.71(s, 1H), 9.06(d, 1H), 7.83(t, 3H), 7.58(s, 1H), 7.56(s, 1H), 7.52(t, 1H), 7.32(d, 1H), 7.23(t, 1H), 6.47(s, 1H), 4.75(m, 1H), 4.29-4.15(m, 4H), 3.51-3.46(m, 5H), 3.29(q, 1H), 2.60-2.48(m, 2H), 2.37(br-s, 4H)
 1 H NMR (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, 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)

실시예Example 8: 2-( 8: 2-( 모폴린Morpholine -4-일)에틸 2-(4--4-yl)ethyl 2-(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다All 이하이드로퀴놀린-4-일)Dihydroquinolin-4-yl) 프로피오네이트Propionate 말레에이트의Maleate 제조 Produce

Figure 112013118680282-pat00018
Figure 112013118680282-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 General Experimental 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 title compound (0.8 g) as a white solid.

1H NMR (400MHz, DMSO-d6): 11.71(s, 1H), 9.09(d, 1H), 7.83(m, 3H), 7.59(s, 1H), 7.57(s, 1H), 7.52(t, 1H), 7.32(d, 1H), 7.23(t, 1H), 6.45(s, 1H), 6.11(s, 2H), 4.82(m, 1H), 4.37(m, 2H), 3.65(br-s, 4H), 3.49(dd, 1H), 3.31(q, 1H), 3.14(br-s, 2H), 2.95(br-s, 4H), 2.51(t, 2H)
 1 H NMR (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, 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)

실시예Example 9: 2-( 9: 2-( 모폴린Morpholine -4-일)에틸 2-(4--4-yl)ethyl 2-(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다All 이하이드로퀴놀린-4-일)Dihydroquinolin-4-yl) 프로피오네이트Propionate 푸마레이트의Fumarate 제조 Produce

Figure 112013118680282-pat00019
Figure 112013118680282-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 General Experimental 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 0.16 g (2.07 mmol) of fumaric acid were reacted to obtain the title compound (0.9 g) as a white solid.

1H NMR (400MHz, DMSO-d6): 11.71(s, 1H), 9.08(d, 1H), 7.83(m, 3H), 7.59(s, 1H), 7.56(s, 1H), 7.52(t, 1H), 7.32(d, 1H), 7.24(t, 1H), 6.46(s, 1H), 6.12(s, 2H), 4.82(m, 1H), 4.37(m, 2H), 3.65(br-s, 4H), 3.48(dd, 1H), 3.32(q, 1H), 3.15(br-s, 2H), 2.96(br-s, 4H), 2.52(t, 2H)
 1 H NMR (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, 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)

실시예Example 10: 2-( 10: 2-( 모폴린Morpholine -4-일)에틸 2-(4--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 112013118680282-pat00020
Figure 112013118680282-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 General Experimental 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 obtain the title compound (0.7 g) as a white solid.

1H NMR (400MHz, DMSO-d6): 11.71(s, 1H), 9.06(d, 1H), 7.83(t, 3H), 7.59(s, 1H), 7.56(s, 1H), 7.52(t, 1H), 7.32(d, 1H), 7.24(t, 1H), 6.47(s, 1H), 4.77(m, 1H), 4.28-4.18(m, 2H), 3.50-3.46(m, 5H), 3.29(q, 1H), 2.65(dd, 2H), 2.64-2.57(m, 2H), 2.51(t, 2H), 2.43(br-s, 4H)
 1 H NMR (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, 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)

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

Figure 112013118680282-pat00021
Figure 112013118680282-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 General Experimental 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 title compound (1.0 g) as a white solid.

1H NMR (700MHz, DMSO-d6): 11.71(s, 1H), 9.80(br-s, 1H), 9.11(d, 1H), 7.84-7.81(m, 3H), 7.62-7.61(m, 2H), 7.60-7.57(m, 2H), 7.52(t, 1H), 7.35-7.30(m, 4H), 7.23(t, 1H), 6.45(s, 1H), 6.11(s, 2H), 4.89-4.85(m, 1H), 4.52-4.42(m, 2H), 3.89(t, 2H), 3.62(t, 2H), 3.54-3.52(m, 3H), 3.44(t, 2H), 3.33(q, 1H), 3.15(br-s, 2H)
 1 H NMR (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(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)

실시예Example 12: 2-( 12: 2-( 모폴린Morpholine -4-일)에틸 2-(4--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 112013118680282-pat00022
Figure 112013118680282-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 General Experimental 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 toluenesulfonic acid monohydrate 0.39 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), 9.78(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, 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)

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

Figure 112013118680282-pat00023
Figure 112013118680282-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 General Experimental 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, 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)

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

Figure 112013118680282-pat00024
Figure 112013118680282-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 General Experimental 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 0.20 g (2.07 mmol) of sulfuric acid were reacted to obtain the title compound (0.4 g) as a white solid.

1H NMR (400MHz, DMSO-d6): 11.71(s, 1H), 9.09(d, 1H), 7.83(t, 3H), 7.59(s, 1H), 7.56(s, 1H), 7.52(t, 1H), 7.32(d, 1H), 7.23(t, 1H), 6.46(s, 1H), 4.82(m, 1H), 4.35(t, 2H), 3.63(s, 4H), 3.50(dd, 1H), 3.1(q, 1H), 3.05(br-s, 2H), 2.86(br-s, 4H), 2.55(s, 1H), 2.51(s, 1H)
 1 H NMR (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 , 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)

실시예Example 15: 2-( 15: 2-( 모폴린Morpholine -4-일)에틸 2-(4--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 112013118680282-pat00025
Figure 112013118680282-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 General Experimental 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 0.17 g (2.07 mmol) of phosphoric acid were reacted to obtain the title compound (0.6 g) as a white solid.

1H NMR (700MHz, DMSO-d6): 11.72(br-s, 1H), 9.08(d, 1H), 7.86-7.82(m, 3H), 7.58-7.57(m, 2H), 7.52(t, 1H), 7.33(dd, 1H), 7.24(m, 1H), 6.47(s, 1H), 4.77-4.75(m, 1H), 4.27-4.17(m, 2H), 3.50-3.47(m, 5H), 3.30(dd, 1H), 2.60-2.57(m, 2H), 2.56-2.50(m, 1H), 2.39(br-s, 4H)
 1 H NMR (700 MHz, DMSO-d 6 ): 11.72 (br-s, 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)

실시예Example 16 2- 16 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 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,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)

실시예Example 17: 2- 17: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 프로피오네이트Propionate 다이클로로아세테이트의Dichloroacetate 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( 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)

실시예Example 18: 2- 18: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 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( 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)

실시예Example 19: 2- 19: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 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( 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)

실시예Example 20: 2- 20: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 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,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) )

실시예Example 21: 2- 21: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 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), 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)

실시예Example 22: 2- 22: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 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- 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)

실시예Example 23: 2- 23: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 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,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)

실시예Example 24: 2- 24: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 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- 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)

실시예Example 25: 2- 25: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 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- 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)

실시예Example 26: 2- 26: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 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), 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)

실시예Example 27: 2- 27: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 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,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)

실시예Example 28: 2- 28: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 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- 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)

실시예Example 29: 2- 29: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 프로피오네이트Propionate 에탄-1,2- Ethane-1,2- 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(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)

실시예Example 30: 2- 30: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 프로피오네이트Propionate 에탄설포네이트의Ethanesulfonate 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,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)

실시예Example 31: 2- 31: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 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- 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)

실시예Example 32: 2- 32: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 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( 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)

실시예Example 33: 2- 33: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 프로피오네이트Propionate 갈락타레이트의Galactarate 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 (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)

실시예Example 34: 2- 34: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 프로피오네이트Propionate 겐티세이트의Gentian 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), 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) )

실시예Example 35: 2- 35: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 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- 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)

실시예Example 36: 2- 36: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 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,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)

실시예Example 37: 2- 37: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 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- 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)

실시예Example 38: 2- 38: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 프로피오네이트Propionate 글리세로포스포레이트의Glycerophosphorate 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- 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)

실시예Example 39: 2- 39: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 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), 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)

실시예Example 40: 2- 40: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 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( 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)

실시예Example 41: 2- 41: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 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( 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)

실시예Example 42: 2- 42: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 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- 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)

실시예Example 43: 2- 43: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 프로피오네이트Propionate 파모에이트의Pamoate 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), 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) )

실시예Example 44: 2- 44: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 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- 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)

실시예Example 45: 2- 45: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 프로피오네이트Propionate 파이로글루타메이트의Of pyroglutamate 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- 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)

실시예Example 46: 2- 46: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 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), 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)

실시예Example 47: 2- 47: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 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,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)

실시예Example 48: 2- 48: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 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- 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)

실시예Example 49: 2- 49: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 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,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)

실시예Example 50: 2- 50: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 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( 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)

실시예Example 51: 2- 51: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 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( 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)

실시예Example 52: 2- 52: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 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,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)

실시예Example 53: 2- 53: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 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(m,1H), 2.73-2.62(m ,2H), 2.56-2.50(m,4H), 1.26(m,20H), 0.86(d,3H)

실시예Example 54: 2- 54: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 프로피오네이트Propionate DLDL -- 만델레이트의Mandelate 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 ,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)

실시예Example 55: 2- 55: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 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 ,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)

실시예Example 56: 2- 56: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 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), 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)

실시예Example 57: 2- 57: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 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), 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)

실시예Example 58: 2- 58: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 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), 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)

실시예Example 59: 2- 59: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 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 (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)

실시예Example 60: 2- 60: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 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 ,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)

실시예Example 61: 2- 61: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 프로피오네이트Propionate 석시네이트의Succinate 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 ,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)

실시예Example 62: 2- 62: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 프로피오네이트Propionate 설퍼레이트의Sulfurate 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 ,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)

실시예Example 63: 2- 63: 2- 모폴린Morpholine -4-일--4-day- 에틸2Ethyl 2 -(4--(4- 클로로벤조일아미노Chlorobenzoylamino )-3-(2-옥소-1,2-)-3-(2-oxo-1,2- 다이하이드로퀴놀린Dihydroquinoline -4-일)-4-day) 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,1H), 7.71-7.67(m,3H), 7.57-7.55(m,3H), 7.48-7.42(m,2H), 6.68(s ,1H), 5.09-5.05(m,1H), 4.63-4.52(m,2H), 3.88-3.85(m,5H), 3.76-3.72(m,1H), 3.52-3.46(m,3H), 3.25 (brs,3H), 2.89-2.83(m,1H), 2.75-2.68(m,2H)

Claims (8)

하기 화학식 I의 화합물의 약제학적으로 허용가능한 염:
[화학식 I]
Figure 112020055775915-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.)
으로서,
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.
Pharmaceutically acceptable salts of the compounds of formula I:
[Formula I]
Figure 112020055775915-pat00026

(In the above 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, (arylsulfuryl Fonyl)C 1 -C 6 alkyl, (C 1 -C 6 alkylamino)C 1 -C 6 alkyl, [(C 1 -C 6 alkyl)(C 1 -C 6 alkyl)amino]C 1 -C 6 alkyl , [(C 1 -C 3 alkyl)(aryl)amino]C 1 -C 6 alkyl, [(C 1 -C 3 alkyl)(aryl)C 1 -C 3 alkyl]aminoC 1 -C 6 alkyl, [ (C 1 -C 3 alkyl)(heteroaryl)amino]C 1 -C 6 alkyl, (arylcarbonylamino)C 1 -C 6 alkyl,C 2 -C 6 alkenyl, C 2 -C 6 alkynyl , C 2 -C 6 oxoalkyl, C 3 -C 8 cycloalkyl, (C 3 -C 8 cycloalkyl)C 1 -C 6 alkyl, (C 3 -C 8 cycloalkenyl)C 1 -C 6 alkyl, (C 3 -C 8 heterocycloalkyl)C 1 -C 6 alkyl, [(C 1 -C 3 alkyl)C 3 -C 8 heterocycloalkyl]C 1 -C 6 alkyl, [(aryl)C 1 -C 3 alkyl]C 3 -C 8 heterocycloalkylC 1 -C 6 alkyl, [(C 1 -C 6 alkyloxycarbonyl)C 3 -C 8 heterocycloalkyl]C 1 -C 6 alkyl, [(C 1 -C 3 alkyloxycarbonyl)C 3 -C 8 heterocycloalkyl]C 1 -C 6 alkyl, (C 3 -C 8 heterocycloalkyl)C 1 -C 6 alkenyl, [(C 1 -C 3 alkyl )C 3 -C 8 heterocycloalkenyl]C 1 -C 6 alkyl, (aryl)C 1 -C 6 alkyl, [(C 1 -C 3 alkyl)aryl]C 1 -C 6 alkyl, [(C 1 -C 3 alkyloxy)aryl]C 1 -C 6 alkyl, [(aryloxy)aryl]C 1 -C 6 alkyl, [(C 1 -C 3 alkylsulfanyl)aryl]C 1 -C 6 alkyl, [ (C 1 -C 3 alkyloxycarbonyl)aryl]C 1 -C 6 alkyl, [(aryloxycarbonyl)aryl]C 1 -C 6 alkyl, (aryl)C 3 -C 6 alkenyl, (heteroaryl)C 1 -C 6 alkyl, [(alkyloxycarbonyl) Heteroaryl]C 1 -C 6 alkyl, [(C 1 -C 3 alkyl)C 3 -C 8 heteroaryl]C 1 -C 6 alkyl, [(C 3 -C 8 cycloalkyl)heteroaryl]C 1- C 6 alkyl, [(aryl)heteroaryl]C 1 -C 6 alkyl, [(C 1 -C 3 alkyl)heteroaryl]C 1 -C 6 alkyl, [(aryl)C 1 -C 3 alkyl]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 alkyloxycarbonyl]C 1 -C 6 alkyl, (C 3 -C 8 heterocycloalkylcarbonyl)C 1 -C 6 alkyl, [(C 1 -C 3 alkyl)C 3 -C 8 heterocycloalkylcarbonyl]C 1 -C 6 alkyl, [ (C 1 -C 3 alkyl)C 3 -C 8 heterocycloalkylcarbonyl]C 1 -C 6 alkyl, [(C 3 -C 8 cycloalkyl)oxycarbonyloxy]C 1 -C 6 alkyl, [( C 3 -C 8 heterocycloalkyl)oxycarbonyloxy]C 1 -C 6 alkyl, (ureido) C 1 -C 6 alkyl, (arylureido) C 1 -C 6 alkyl, [(aryl)(C 1 -C 3 alkylureido]C 1 -C 6 alkyl, (C 1 -C 6 alkylaminocarbonyl)C 1 -C 6 alkyl, [(C 3 -C 8 heterocycloalkyl)aminocarbonyl]C 1 -C 6 alkyl, [(C 1 -C 3 alkyl)C 3 -C 8 heterocycloalkyl]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,
At this time, the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 oxoalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cyclo Alkenyl, C 3 -C 8 heterocycloalkenyl, aryl or heteroaryl is one selected from the group consisting of C 1 -C 3 alkyl, fluoro, chloro, bromo, hydroxy, oxo, nitro and cyano groups. It may be substituted with the above substituents.
As,
Pharmaceutically acceptable salts of compounds of formula I, characterized in that the salts are 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 hydrochlorate;
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-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate acetate;
17) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate dichloroacetate;
18) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate adipate;
19) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate ascorbate;
20) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate benzoate;
21) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate 4-acetamidobenzo Eight;
22) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate caprate;
23) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate capronate;
24) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate caprylate;
25) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate carbonate;
26) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate cinnamate;
27) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate cyclamate;
28) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate dodecylsulfonate;
29) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate ethane-1,2- Disulfonate;
30) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate ethanesulfonate;
31) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate 2-hydroxyethanesulfo Nate;
32) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate formate;
33) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate galactarate;
34) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate gentisate;
35) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate glutamate;
36) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate glutarate;
37) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate 2-oxoglutarate ;
38) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate glycerophosphorate;
39) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate hiprate;
40) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate oleate;
41) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate orotate
42) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate palmitate;
43) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate pamoate;
44) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate propionate;
45) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate pyroglutamate;
46) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate 4-aminosalicylate ;
47) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate sebacate;
48) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate stearate;
49) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate thiocyanate;
50) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate undecylenate;
51) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate hydrobromate;
52) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate isobutyrate;
53) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate laurate;
54) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate DL-mandelate;
55) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate methanesulfonate;
56) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate naphthalene-1,5- Disulfonate;
57) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate naphthalene-2-sulfonate ;
58) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate 2-naphthoate;
59) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate nicotinate;
60) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate nitrate;
61) Preparation of 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate succinate
62) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate sulfurate; And
63) 2-morpholin-4-yl-ethyl2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate L-aspartate.
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 the compound of formula I according to claim 1, wherein the salt is an acid addition salt formed by a pharmaceutically acceptable free acid.
제2항에 있어서, 상기 유리산은 유기산 또는 무기산인 것을 특징으로 하는, 화학식 I의 화합물의 약제학적으로 허용가능한 염.
3. A pharmaceutically acceptable salt of a compound of Formula I according to claim 2, wherein the free acid is an organic or inorganic acid.
제3항에 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 3, wherein the organic acid is citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, dichloroacetic acid, trifluoroacetic acid, adipic acid, ascorbic acid, benzoic acid, 4-acetami Dobenzoic acid, gluconic acid, sulfonic acid, methanesulfonic acid, capric acid, capronic acid, caprylic acid, carboxylic acid, cinnamic acid, cyclamic acid, dodecylsulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid , 2-hydroxyethanesulfonic acid, galactaric acid, gentisic acid, glutaric acid, 2-oxoglutaric acid, glycerophosphoric acid, hippuric acid, oleic acid, orotic acid, palmitic acid, pamoic acid , Pyroglutamic acid, sebacic acid, stearic acid, thiocyanic acid, undecylenic acid, isobutyric acid, lauric acid, mandelic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, naphthoic acid, nicotinic acid , Glycolic acid, succinic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glutamic acid, aspartic acid, salicylic acid, 4-aminosalicylic acid, malonic acid, malic acid and benzosulfonic acid.The inorganic acid is hydrochloric acid, bromine A pharmaceutically acceptable salt of the compound of formula I, characterized in that it is selected from the group consisting of acids, sulfuric acid, nitric acid and phosphoric acid.
삭제delete 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.
A gastric ulcer, acute gastritis, chronic gastritis, dry eye syndrome, cancer, osteoarthritis, rheumatoid arthritis, hyperlipidemia, hypertriglyceridemia, diabetes, irritable bowel, comprising the pharmaceutically acceptable salt of the compound of formula I of claim 1 as an active ingredient. A pharmaceutical composition for the prevention or treatment of syndrome or obesity.
삭제delete 삭제delete
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