KR100463993B1 - Novel quinolone derivative with an antibacterial activity and preparation thereof - Google Patents

Novel quinolone derivative with an antibacterial activity and preparation thereof Download PDF

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KR100463993B1
KR100463993B1 KR10-2001-0088822A KR20010088822A KR100463993B1 KR 100463993 B1 KR100463993 B1 KR 100463993B1 KR 20010088822 A KR20010088822 A KR 20010088822A KR 100463993 B1 KR100463993 B1 KR 100463993B1
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KR20030058394A (en
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박태호
이상호
한철
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한국화학연구원
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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Abstract

본 발명은 하기 화학식 1의 퀴놀론 유도체, 이의 제조방법 및 이를 함유하는 항생제 조성물에 관한 것으로, 본 발명의 퀴놀론 유도체 또는 이의 약제학적으로 허용가능한 염은 우수한 항균작용과 광범위한 항균 스펙트럼을 갖는 항균제로서 유용하게 사용될 수 있다.The present invention relates to a quinolone derivative of the formula (1), a method for preparing the same and an antibiotic composition containing the same, wherein the quinolone derivative or a pharmaceutically acceptable salt thereof is useful as an antibacterial agent having excellent antimicrobial activity and broad antibacterial spectrum. Can be used.

상기 식에서,Where

R1은 C1-4알킬기, 할로겐 원자로 치환되거나 치환되지 않은 페닐기, 또는 할로겐 원자로 치환되거나 치환되지 않은 C3-6사이클로알킬기이고;R 1 is a C 1-4 alkyl group, a phenyl group substituted or unsubstituted with a halogen atom, or a C 3-6 cycloalkyl group substituted or unsubstituted with a halogen atom;

R2는 수소 원자, 아미노기 또는 C1-4알킬기이고;R 2 is a hydrogen atom, an amino group or a C 1-4 alkyl group;

R3는 수소 원자, C1-4알킬기, C1-4알킬기로 치환되거나 치환되지 않은 아미노기, 또는 C1-4알킬기로 치환되거나 치환되지 않은 아미노메틸기 또는 아미노에틸기이며;R 3 is an amino group unsubstituted or substituted with a hydrogen atom, a C 1-4 alkyl group, a C 1-4 alkyl group, or an aminomethyl group or aminoethyl group unsubstituted or substituted with a C 1-4 alkyl group;

W는 질소 원자, CH 또는 CY(이때, Y는 할로겐 원자, 또는 할로겐 원자로 치환되거나 치환되지 않은 C1-4알킬기 또는 C1-4알콕시기이다)이고;W is a nitrogen atom, CH or CY, wherein Y is a halogen atom, or a C 1-4 alkyl group or a C 1-4 alkoxy group unsubstituted or substituted with a halogen atom;

Pyr은 2-, 3- 또는 4-피리딜기이며;Pyr is a 2-, 3- or 4-pyridyl group;

단, W가 CH인 경우, W와 R1은 함께 COCH2CH(CH3), CCH2CH2CH(CH3) 또는 CSCH2CH(CH3)을 형성할 수 있다.However, when W is CH, W and R 1 may together form COCH 2 CH (CH 3 ), CCH 2 CH 2 CH (CH 3 ) or CSCH 2 CH (CH 3 ).

Description

신규한 퀴놀론계 항균제 및 이의 제조방법{NOVEL QUINOLONE DERIVATIVE WITH AN ANTIBACTERIAL ACTIVITY AND PREPARATION THEREOF}Novel quinolone antibacterial agent and preparation method thereof {NOVEL QUINOLONE DERIVATIVE WITH AN ANTIBACTERIAL ACTIVITY AND PREPARATION THEREOF}

본 발명은 우수한 항균활성을 갖는, 신규한 퀴놀론 유도체, 이의 제조방법 및 이를 함유하는 항생제 조성물에 관한 것이다.The present invention relates to a novel quinolone derivative having a good antibacterial activity, a method for preparing the same, and an antibiotic composition containing the same.

현재 임상에서 사용되고 있는 퀴놀론계 항균제로서 우수한 항균력을 가진 것들이 많이 보고되어 있으나, 이들 대부분은 시프로플록사신(미국 특허 제 4,670,444 호 참조)처럼 그램음성균에 비해 그램양성균에 대한 항균력이 열세이거나, 또는 스파플록사신(미국 특허 제 4,795,751 호 참조)처럼 둘다에 대해 항균력은 우수하나 물에 대한 용해도가 나빠 생체이용률이 떨어지거나 세포독성 또는 광독성 등을 발현하는 것으로 알려져 있다.There are many reports of quinolone-based antimicrobial agents that are currently used in clinical practice, but most of them have inferior antimicrobial activity against Gram-positive bacteria, such as ciprofloxacin (see US Patent No. 4,670,444), or spafloxacin ( It is known that the antimicrobial activity is good for both, such as U.S. Patent No. 4,795,751, but the solubility in water causes poor bioavailability or expression of cytotoxicity or phototoxicity.

이에 본 발명자들은 항균력이 우수하고 항균 스펙트럼이 넓으며 물에 대한 용해도가 개선되고 세포독성이 적은 퀴놀론계 항균제를 개발하기 위해 계속 연구를 진행한 결과, 퀴놀론 모핵의 7-위치가 피리딜아민기로 치환된, 신규한 퀴놀론 유도체를 개발함으로써 본 발명을 완성하게 되었다.Accordingly, the present inventors have continued to develop a quinolone antibacterial agent having excellent antimicrobial activity, broad antibacterial spectrum, improved solubility in water and low cytotoxicity. As a result, the 7-position of the quinolone mother core is substituted with a pyridylamine group. The present invention has been completed by developing novel quinolone derivatives.

따라서, 본 발명의 목적은 우수한 항균작용과 광범위한 항균 스펙트럼을 갖는, 7-위치가 피리딜아민기로 치환된 퀴놀론 유도체 및 이의 제조 방법을 제공하는 것이다.Accordingly, it is an object of the present invention to provide a quinolone derivative substituted with a pyridylamine group at the 7-position having excellent antibacterial action and a broad antibacterial spectrum, and a method for preparing the same.

본 발명의 다른 목적은 상기 퀴놀론 유도체를 유효성분으로 함유하는 항생제 조성물을 제공하는 것이다.Another object of the present invention to provide an antibiotic composition containing the quinolone derivative as an active ingredient.

상기 목적을 달성하기 위하여, 본 발명에서는 하기 화학식 1의 퀴놀론 유도체 또는 이의 약제학적으로 허용가능한 염을 제공한다:In order to achieve the above object, the present invention provides a quinolone derivative of formula (1) or a pharmaceutically acceptable salt thereof:

화학식 1Formula 1

상기 식에서,Where

R1은 C1-4알킬기, 할로겐 원자로 치환되거나 치환되지 않은 페닐기, 또는 할로겐 원자로 치환되거나 치환되지 않은 C3-6사이클로알킬기이고;R 1 is a C 1-4 alkyl group, a phenyl group substituted or unsubstituted with a halogen atom, or a C 3-6 cycloalkyl group substituted or unsubstituted with a halogen atom;

R2는 수소 원자, 아미노기 또는 C1-4알킬기이고;R 2 is a hydrogen atom, an amino group or a C 1-4 alkyl group;

R3는 수소 원자, C1-4알킬기, C1-4알킬기로 치환되거나 치환되지 않은 아미노기, 또는 C1-4알킬기로 치환되거나 치환되지 않은 아미노메틸기 또는 아미노에틸기이며;R 3 is an amino group unsubstituted or substituted with a hydrogen atom, a C 1-4 alkyl group, a C 1-4 alkyl group, or an aminomethyl group or aminoethyl group unsubstituted or substituted with a C 1-4 alkyl group;

W는 질소 원자, CH 또는 CY(이때, Y는 할로겐 원자, 또는 할로겐 원자로 치환되거나 치환되지 않은 C1-4알킬기 또는 C1-4알콕시기이다)이고;W is a nitrogen atom, CH or CY, wherein Y is a halogen atom, or a C 1-4 alkyl group or a C 1-4 alkoxy group unsubstituted or substituted with a halogen atom;

Pyr은 2-, 3- 또는 4-피리딜기이며;Pyr is a 2-, 3- or 4-pyridyl group;

단, W가 CH인 경우, W와 R1은 함께 COCH2CH(CH3), CCH2CH2CH(CH3) 또는 CSCH2CH(CH3)을 형성할 수 있다.However, when W is CH, W and R 1 may together form COCH 2 CH (CH 3 ), CCH 2 CH 2 CH (CH 3 ) or CSCH 2 CH (CH 3 ).

또한, 본 발명에서는 하기 화학식 2의 화합물을 하기 화학식 3의 화합물과 축합반응시키는 것을 포함하는, 상기 화학식 1의 퀴놀론 유도체의 제조방법을 제공한다:In addition, the present invention provides a method for preparing a quinolone derivative of Formula 1, comprising condensing a compound of Formula 2 with a compound of Formula 3:

상기 식에서,Where

R1, R2, R3, W 및 Pyr는 상기한 바와 같은 의미를 가지며;R 1 , R 2 , R 3 , W and Pyr have the same meaning as described above;

X는 할로겐 원자이고;X is a halogen atom;

HA는 염화수소 또는 삼불화아세트산이고, n은 0, 2 또는 3이다.HA is hydrogen chloride or trifluoroacetic acid and n is 0, 2 or 3.

상기 다른 목적을 달성하기 위하여, 본 발명에서는 유효량의 화학식 1의 퀴놀론 유도체 또는 이의 약제학적으로 허용가능한 염 및 약제학적으로 허용되는 담체를 포함하는 항생제 조성물을 제공한다.In order to achieve the above another object, the present invention provides an antibiotic composition comprising an effective amount of the quinolone derivative of formula (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

이하 본 발명을 좀더 상세하게 설명한다.Hereinafter, the present invention will be described in more detail.

본 발명에 따른 상기 화학식 1의 퀴놀론 유도체에 있어서, 바람직하게는, R1은에틸기, t-부틸기, 사이클로프로필기, 2,4-디플루오로페닐기 또는 2-(S)-플루오로사이클로프로필기이고; R2는 수소 원자, 아미노기 또는 메틸기이며; R3는 수소 원자, 메틸기, 아미노기, 메틸아미노기, 아미노메틸기, 메틸아미노메틸기 또는 1-아미노에틸기이고; W는 질소 원자, CH, CF, CCl, CCH3, COCH3, COCH2F 또는 COCHF2이며; Pyr은 2-, 3- 또는 4-피리딜기이고; 상기 W와 R1은 함께 COCH2CH(CH3), CCH2CH2CH(CH3) 또는 CSCH2CH(CH3)을 형성한다.In the quinolone derivative of Chemical Formula 1 according to the present invention, preferably, R 1 is an ethyl group, t-butyl group, cyclopropyl group, 2,4-difluorophenyl group or 2- (S) -fluorocyclopropyl Group; R 2 is a hydrogen atom, an amino group or a methyl group; R 3 is a hydrogen atom, a methyl group, an amino group, a methylamino group, an aminomethyl group, a methylaminomethyl group or a 1-aminoethyl group; W is nitrogen atom, CH, CF, CCl, CCH 3 , COCH 3 , COCH 2 F or COCHF 2 ; Pyr is a 2-, 3- or 4-pyridyl group; W and R 1 together form COCH 2 CH (CH 3 ), CCH 2 CH 2 CH (CH 3 ) or CSCH 2 CH (CH 3 ).

본 발명에서, 화학식 1의 퀴놀론 유도체는, 화학식 2의 화합물과 화학식 3의 화합물을 물 또는 유기용매에 녹이거나 현탁시킨 후 무기염기 또는 유기염기 존재 하에서 20 내지 120℃에서 6 내지 14시간 동안 축합반응시켜 제조할 수 있다.In the present invention, the quinolone derivative of Formula 1 is a condensation reaction for 6 to 14 hours at 20 to 120 ℃ in the presence of an inorganic or organic base after dissolving or suspending the compound of Formula 2 and the compound of Formula 3 in water or an organic solvent Can be prepared.

화학식 1의 화합물의 제조에 사용되는 화학식 3의 화합물은 통상적인 방법(문헌[Chem. Pharm. Bull., 1986, 34, 4098, 2], [J. Hetero. Chem., 1987, 24, 181, 3], [J. Med. Chem., 1988, 31, 503, 4], EP 특허 제115,841,5호 및 일본 특개평62-252772호 참조)으로 용이하게 제조가능하고 구입(알드리치(Aldrich)사 등)하여 사용할 수도 있다. 한편, 화학식 2의 화합물은 치환된 피리딘 유도체로부터 제조되는 신규한 화합물로서 이 화합물 및 이의 제조방법이 본 발명과 동일자로 출원되어진다.The compounds of formula 3 used in the preparation of compounds of formula 1 may be prepared by conventional methods (Chem. Pharm. Bull., 1986, 34, 4098, 2), J. Hetero. Chem., 1987, 24, 181, 3], [J. Med. Chem., 1988, 31, 503, 4], EP Patent Nos. 115,841, 5 and Japanese Patent Laid-Open No. 62-252772, and are readily available (Aldrich). Etc.) may be used. On the other hand, the compound of formula (2) is a novel compound prepared from substituted pyridine derivatives, the compound and its preparation method is filed with the same as the present invention.

본 발명에 사용되는 유기용매로는 아세토니트릴, 디메틸포름아미드, 디메틸설폭시드 및 피리딘 등이 있으며; 염기로서 CaCO3및 NaHCO3와 같은 무기염기, 및 트리에틸아민, 피리딘, 디아자비사이클로[5,4,0]운덱-7-엔 및 디이소프로필에틸아민과 같은 유기염기를 사용할 수 있다.Organic solvents used in the present invention include acetonitrile, dimethylformamide, dimethyl sulfoxide and pyridine; As the base, inorganic bases such as CaCO 3 and NaHCO 3 and organic bases such as triethylamine, pyridine, diazabicyclo [5,4,0] undec-7-ene and diisopropylethylamine can be used.

이와 같이 제조된, 본 발명의 화학식 1의 퀴놀론 유도체 및 이의 약제학적으로 허용가능한 염은 우수한 항균력 및 그램음성균과 그램양성균 둘다에 대해 광범위한 항균 스펙트럼을 가지며 물에 대한 용해도가 높고 세포독성이 적다.Thus prepared, the quinolone derivatives of formula 1 of the present invention and pharmaceutically acceptable salts thereof have excellent antimicrobial activity and broad antimicrobial spectrum against both Gram-negative and Gram-positive bacteria, have high solubility in water and low cytotoxicity.

따라서, 본 발명에서는 유효성분으로서의 화학식 1의 화합물 또는 이의 약제학적으로 허용가능한 염, 및 약제학적으로 허용되는 담체를 포함하는 항생제 조성물을 제공한다. 본 발명의 약학 조성물에는 활성 성분인 화학식 1의 화합물이 조성물의 총중량을 기준으로 하여 0.1 내지 75 중량%, 바람직하게는 1 내지 50 중량%의 양으로 함유될 수 있다.Accordingly, the present invention provides an antibiotic composition comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier as an active ingredient. The pharmaceutical composition of the present invention may contain the compound of formula 1 as an active ingredient in an amount of 0.1 to 75% by weight, preferably 1 to 50% by weight, based on the total weight of the composition.

본 발명의 약학 조성물은 다양한 경구 또는 비경구 투여 형태로 제형화할 수 있다. 경구 투여용 제형으로는 예를 들면 정제, 환제, 경.연질 캅셀제, 액제, 현탁제, 유화제, 시럽제, 과립제 등이 있는데, 이들 제형은 유효성분 이외에 희석제(예: 락토즈, 덱스트로즈, 수크로즈, 만니톨, 솔비톨, 셀룰로즈 및/ 또는 글리신), 활택제(예: 실리카, 탈크, 스테아르산 및 그의 마그네슘 또는 칼슘염 및/ 또는 폴리에틸렌 글리콜)를 함유하고 있다. 정제는 또한 마그네슘 알루미늄 실리케이트, 전분 페이스트, 젤라틴, 트라가칸스, 메틸셀룰로즈, 나트륨 카복시메틸셀룰로즈 및/또는 폴리비닐피롤리딘과 같은 결합제를 함유할 수 있으며, 경우에 따라 전분, 한천, 알긴산 또는 그의 나트륨 염과 같은 붕해제 또는 비등 혼합물 및/또는 흡수제, 착색제, 향미제, 및 감미제를 함유할 수 있다. 상기 제형은 통상적인 혼합, 과립화 또는 코팅 방법에 의해 제조될 수 있다. 또한 비경구 투여용 제형의 대표적인 것은 주사용 제형으로 등장성 수용액 또는 현탁액이 바람직하다.The pharmaceutical compositions of the invention can be formulated in a variety of oral or parenteral dosage forms. Formulations for oral administration include, for example, tablets, pills, hard and soft capsules, solutions, suspensions, emulsifiers, syrups, and granules. These formulations may contain, in addition to the active ingredients, diluents (e.g., lactose, dextrose, water, Cross, mannitol, sorbitol, cellulose and / or glycine), lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols. Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, optionally starch, agar, alginic acid or its Disintegrants or boiling mixtures such as sodium salts and / or absorbents, colorants, flavors, and sweeteners. The formulations may be prepared by conventional mixing, granulating or coating methods. Also representative of parenteral formulations are injectable formulations, preferably aqueous isotonic solutions or suspensions.

상기 조성물은 멸균되고/되거나 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 및/또는 완충제 등의 보조제 및 기타 치료적으로 유용한 물질을 함유할 수 있으며, 통상적인 방법인 혼합, 과립화 또는 코팅 방법에 따라 제제화할 수 있다.The composition may contain sterile and / or auxiliaries such as preservatives, stabilizers, hydrating or emulsifying accelerators, salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, which are conventional methods of mixing, granulating Or according to a coating method.

유효 성분으로서 화학식 1의 화합물은 사람을 포함하는 포유동물에 대해 하루에 2.5 내지 100 ㎎/㎏(체중), 바람직하게는 5 내지 60 ㎎/㎏(체중)의 양으로 1일 1회 또는 분할하여 경구 또는 비경구적 경로를 통해 투여할 수 있다.As an active ingredient, the compound of formula 1 may be divided or divided once a day in an amount of 2.5 to 100 mg / kg body weight, preferably 5 to 60 mg / kg body weight, per day for mammals including humans. Administration can be via oral or parenteral routes.

이하, 하기 실시예에 의하여 본 발명을 좀더 상세하게 설명하고자 한다.단, 하기 실시예는 본 발명을 예시하기 위한 것일 뿐 본 발명의 범위가 이들만으로 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only for illustrating the present invention and the scope of the present invention is not limited thereto.

실시예 1: 1-사이클로프로필-6,8-디플루오로-7-[{3-아미노메틸-3-(피리딘-2-일)피롤리딘}-1-일]-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 1)의 제조Example 1: 1-cyclopropyl-6,8-difluoro-7-[{3-aminomethyl-3- (pyridin-2-yl) pyrrolidin} -1-yl] -4-oxo-1 Preparation of 4,4-dihydroquinoline-3-carboxylic acid (Compound 1)

1-사이클로프로필-6,7,8-트리플루오로-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 3, 알드리치사제) 283mg, 3-아미노메틸-3-(피리딘-2-일)피롤리딘 삼염산염(화합물 2, 당사제) 315mg 및 염기로서 디아자비사이클로[5.4.0]운덱-7-엔 200mg을 아세토니트릴 10ml에 넣고 6시간동안 환류시킨 후, 반응혼합물을 냉각, 여과 및 건조하여 연노란색의 목적 화합물 334mg을 얻었다.1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Compound 3, available from Aldrich), 283 mg, 3-aminomethyl-3- (pyridine-2 -Yl) pyrrolidin trihydrochloride (Compound 2, manufactured by Company) and 200 mg of diazabicyclo [5.4.0] undec-7-ene as a base were added to 10 ml of acetonitrile and refluxed for 6 hours, and then the reaction mixture was cooled. Filtration and drying yielded 334 mg of the pale yellow target compound.

원소분석 (C23H22N4O3F2)Elemental Analysis (C 23 H 22 N 4 O 3 F 2 )

측정치(%) ; C: 62.61 H: 5.18 N: 12.54Measured value (%); C: 62.61 H: 5.18 N: 12.54

이론치(%) ; C: 62.72 H: 5.03 N: 12.72Theoretical value (%); C: 62.72 H: 5.03 N: 12.72

실시예 2: 1-사이클로프로필-6-플루오로-8-클로로-7-[{3-아미노메틸-3-(피리딘-2-일)피롤리딘}-1-일]-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 1)의 제조Example 2: 1-cyclopropyl-6-fluoro-8-chloro-7-[{3-aminomethyl-3- (pyridin-2-yl) pyrrolidin} -1-yl] -4-oxo- Preparation of 1,4-dihydroquinoline-3-carboxylic acid (Compound 1)

1-사이클로프로필-6,7-디플루오로-8-클로로-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 3) 298mg 및 3-아미노메틸-3-(피리딘-2-일)피롤리딘 삼염산염(화합물 2) 315mg을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 흰색 고체의 목적 화합물 406mg을 얻었다.298 mg of 1-cyclopropyl-6,7-difluoro-8-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Compound 3) and 3-aminomethyl-3- (pyridine-2- (1) Except for using 315 mg of pyrrolidine trichloride (Compound 2), the same procedure as in Example 1 was carried out to obtain 406 mg of the target compound as a white solid.

원소분석 (C23H22N4O3FCl)Elemental Analysis (C 23 H 22 N 4 O 3 FCl)

측정치(%) ; C: 60.41 H: 4.81 N: 12.30Measured value (%); C: 60.41 H: 4.81 N: 12.30

이론치(%) ; C: 60.46 H: 4.85 N: 12.26Theoretical value (%); C: 60.46 H: 4.85 N: 12.26

실시예 3: 1-사이클로프로필-6-플루오로-8-메톡시-7-[{3-아미노메틸-3-(피리딘-2-일)피롤리딘}-1-일]-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 1)의 제조Example 3: 1-cyclopropyl-6-fluoro-8-methoxy-7-[{3-aminomethyl-3- (pyridin-2-yl) pyrrolidin} -1-yl] -4-oxo Preparation of -1,4-dihydroquinoline-3-carboxylic acid (Compound 1)

1-사이클로프로필-6,7-디플루오로-8-메톡시-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 3) 293mg 및 3-아미노메틸-3-(피리딘-2-일)피롤리딘 염산염(화합물 2) 315mg을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 목적 화합물 382mg을 얻었다.293 mg of 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Compound 3) and 3-aminomethyl-3- (pyridine-2 382 mg of the target compound were obtained in the same manner as in Example 1 except that 315 mg of -yl) pyrrolidine hydrochloride (Compound 2) was used.

원소분석 (C24H25N4O4F)Elemental Analysis (C 24 H 25 N 4 O 4 F)

측정치(%) ; C: 63.66 H: 5.59 N: 12.37Measured value (%); C: 63.66 H: 5.59 N: 12.37

이론치(%) ; C: 63.71 H: 5.57 N: 12.38Theoretical value (%); C: 63.71 H: 5.57 N: 12.38

실시예 4: 1-사이클로프로필-5-아미노-6,8-디플루오로-7-[{3-아미노메틸-3-(피리딘-2-일)피롤리딘}-1-일]-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 1)의 제조Example 4: 1-cyclopropyl-5-amino-6,8-difluoro-7-[{3-aminomethyl-3- (pyridin-2-yl) pyrrolidin} -1-yl] -4 Preparation of oxo-1,4-dihydroquinoline-3-carboxylic acid (compound 1)

1-사이클로프로필-5-아미노-6,7,8-트리플루오로-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 3) 295mg 및 3-아미노메틸-3-(피리딘-2-일)피롤리딘 염산염(화합물 2) 315mg을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 노란색의 목적 화합물 396mg을 얻었다.295 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Compound 3) and 3-aminomethyl-3- (pyridine- Except for using 315 mg of 2-yl) pyrrolidine hydrochloride (Compound 2), the same procedure as in Example 1 was carried out to obtain 396 mg of a yellow target compound.

원소분석 (C23H23N5O3F2)Elemental Analysis (C 23 H 23 N 5 O 3 F 2 )

측정치(%) ; C: 60.71 H: 5.06 N: 15.41Measured value (%); C: 60.71 H: 5.06 N: 15.41

이론치(%) ; C: 60.65 H: 5.09 N: 15.38Theoretical value (%); C: 60.65 H: 5.09 N: 15.38

실시예 5: 1-사이클로프로필-6-플루오로-7-[(3-아미노메틸-3-(피리딘-2-일)피롤리딘)-1-일]-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 1)의 제조Example 5: 1-cyclopropyl-6-fluoro-7-[(3-aminomethyl-3- (pyridin-2-yl) pyrrolidin) -1-yl] -4-oxo-1,4- Preparation of Dihydroquinoline-3-carboxylic Acid (Compound 1)

1-사이클로프로필-6,7-디플루오로-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 3) 263mg 및 3-아미노메틸-3-(피리딘-2-일)피롤리딘 염산염(화합물 2) 315mg을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 흰색 고체의 목적 화합물 361mg을 얻었다.263 mg of 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Compound 3) and 3-aminomethyl-3- (pyridin-2-yl) pyrroli Except for using 315 mg of Dean hydrochloride (Compound 2), the same procedure as in Example 1 was carried out to obtain 361 mg of the target compound as a white solid.

원소분석 (C23H23N4O3F)Elemental Analysis (C 23 H 23 N 4 O 3 F)

측정치(%) ; C: 65.41 H: 5.46 N: 13.21Measured value (%); C: 65.41 H: 5.46 N: 13.21

이론치(%) ; C: 65.39 H: 5.49 N: 13.26Theoretical value (%); C: 65.39 H: 5.49 N: 13.26

실시예 6: 9-플루오로-2,3-디히드로-3-(S)-메틸-10-[(3-아미노메틸-3-(피리딘-2-일)피롤리딘)-1-일]-7-옥소-7H-피리도[1.2.3-데]-1,4-벤조옥사진-6-카복실산(화합물 1)의 제조Example 6 9-Fluoro-2,3-dihydro-3- (S) -methyl-10-[(3-aminomethyl-3- (pyridin-2-yl) pyrrolidin) -1-yl ] -7-oxo-7H-pyrido [1.2.3-dec] -1,4-benzooxazine-6-carboxylic acid (Compound 1)

9,10-디플루오로-2,3-디히드로-3-(S)-메틸-7-옥소-7H-피리도[1.2.3-데]-1,4-벤조옥사진-6-카복실산(화합물 3) 287mg 및 3-아미노메틸-3-(피리딘-2-일)피롤리딘 염산염(화합물 2) 315mg을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 목적 화합물 386mg을 얻었다.9,10-difluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido [1.2.3-dec] -1,4-benzooxazine-6-carboxylic acid (Compound 3) The same procedure as in Example 1 was repeated except that 287 mg and 315 mg of 3-aminomethyl-3- (pyridin-2-yl) pyrrolidine hydrochloride (Compound 2) were used to obtain 386 mg of the target compound. Got it.

원소분석 (C23H23N4O3F)Elemental Analysis (C 23 H 23 N 4 O 3 F)

측정치(%) ; C: 63.06 H: 5.26 N: 12.81Measured value (%); C: 63.06 H: 5.26 N: 12.81

이론치(%) ; C: 63.00 H: 5.29 N: 12.78Theoretical value (%); C: 63.00 H: 5.29 N: 12.78

실시예 7: 1-사이클로프로필-6-플루오로-7-[(3-아미노메틸-3-(피리딘-2-일)피롤리딘)-1-일]-4-옥소-1,4-디히드로-1,8-나프티리딘-3-카복실산(화합물 1)의 제조Example 7: 1-cyclopropyl-6-fluoro-7-[(3-aminomethyl-3- (pyridin-2-yl) pyrrolidin) -1-yl] -4-oxo-1,4- Preparation of Dihydro-1,8-naphthyridine-3-carboxylic Acid (Compound 1)

1-사이클로프로필-6,7-디플루오로-4-옥소-1,4-디히드로-1,8-나프티리딘-3-카복실산(화합물 3) 264mg 및 3-아미노메틸-3-(피리딘-2-일)피롤리딘 염산염(화합물 2) 315mg을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 목적 화합물 393mg을 얻었다.264 mg of 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (Compound 3) and 3-aminomethyl-3- (pyridine- Except for using 315 mg of 2-yl) pyrrolidine hydrochloride (Compound 2), the same procedure as in Example 1 was carried out to obtain 393 mg of the target compound.

원소분석 (C22H22N5O3F)Elemental Analysis (C 22 H 22 N 5 O 3 F)

실측치(%) ; C: 62.45 H: 5.21 N: 15.51Found (%); C: 62.45 H: 5.21 N: 15.51

이론치(%) ; C: 62.40 H: 5.24 N: 16.54Theoretical value (%); C: 62.40 H: 5.24 N: 16.54

실시예 8: 1-(2,4-디플루오로페닐)-6-플루오로-7-[(3-아미노메틸-3-(피리딘-2-일)피롤리딘)-1-일]-4-옥소-1,4-디히드로-1,8-나프티리딘-3-카복실산(화합물 1)의 제조Example 8: 1- (2,4-difluorophenyl) -6-fluoro-7-[(3-aminomethyl-3- (pyridin-2-yl) pyrrolidin) -1-yl]- Preparation of 4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (compound 1)

1-(2,4-디플루오로페닐)-6,7-디플루오로-4-옥소-1,4-디히드로-1,8-나프티리딘-3-카복실산(화합물 3) 334mg 및 3-아미노메틸-3-(피리딘-2-일)피롤리딘 염산염(화합물 2) 315mg을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 목적 화합물 433mg을 얻었다.334 mg of 1- (2,4-difluorophenyl) -6,7-difluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (compound 3) and 3- 433 mg of the target compound was obtained by the same method as Example 1 except that 315 mg of aminomethyl-3- (pyridin-2-yl) pyrrolidine hydrochloride (Compound 2) was used.

원소분석 (C25H20N5O3F3)Elemental Analysis (C 25 H 20 N 5 O 3 F 3 )

측정치(%) ; C: 60.63 H: 4.06 N: 14.15Measured value (%); C: 60.63 H: 4.06 N: 14.15

이론치(%) ; C: 60.60 H: 4.07 N: 14.14Theoretical value (%); C: 60.60 H: 4.07 N: 14.14

실시예 9: 1-사이클로프로필-6,8-디플루오로-7-[(3-메틸아미노-3-(피리딘-2-일)피롤리딘)-1-일]-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 1)의 제조Example 9: 1-cyclopropyl-6,8-difluoro-7-[(3-methylamino-3- (pyridin-2-yl) pyrrolidin) -1-yl] -4-oxo-1 Preparation of 4,4-dihydroquinoline-3-carboxylic acid (Compound 1)

1-사이클로프로필-6,7,8-트리플루오로-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 3) 280mg 및 3-메틸아미노-3-(피리딘-2-일)피롤리딘 염산염(화합물 2) 315mg을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 목적 화합물 340mg을 얻었다.280 mg of 1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Compound 3) and 3-methylamino-3- (pyridin-2-yl) 340 mg of the target compound was obtained in the same manner as in Example 1, except that 315 mg of pyrrolidine hydrochloride (Compound 2) was used.

원소분석 (C23H22N4O3F2)Elemental Analysis (C 23 H 22 N 4 O 3 F 2 )

측정치(%) ; C: 62.61 H: 5.18 N: 12.54Measured value (%); C: 62.61 H: 5.18 N: 12.54

이론치(%) ; C: 62.72 H: 5.03 N: 12.72Theoretical value (%); C: 62.72 H: 5.03 N: 12.72

실시예 10: 1-사이클로프로필-6-플루오로-8-메톡시-7-[(3-아미노메틸-3-(피리딘-4-일)피롤리딘)-1-일]-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 1)의 제조Example 10 1-cyclopropyl-6-fluoro-8-methoxy-7-[(3-aminomethyl-3- (pyridin-4-yl) pyrrolidin) -1-yl] -4-oxo Preparation of -1,4-dihydroquinoline-3-carboxylic acid (Compound 1)

1-사이클로프로필-6,7-디플루오로-8-메톡시-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 3) 295mg 및 3-아미노메틸-3-(피리딘-4-일)피롤리딘 염산염(화합물 2) 315mg을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 흰색 고체의 목적 화합물 401mg을 얻었다.295 mg of 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Compound 3) and 3-aminomethyl-3- (pyridine-4 401 mg of the white solid target compound was obtained in the same manner as in Example 1 except that 315 mg of -yl) pyrrolidine hydrochloride (Compound 2) was used.

원소분석 (C24H25N4O4F)Elemental Analysis (C 24 H 25 N 4 O 4 F)

측정치(%) ; C: 63.68 H: 5.57 N: 12.41Measured value (%); C: 63.68 H: 5.57 N: 12.41

이론치(%) ; C: 63.71 H: 5.57 N: 12.38Theoretical value (%); C: 63.71 H: 5.57 N: 12.38

실시예 11: 1-사이클로프로필-6-플루오로-8-메톡시-7-[(3-아미노-3-(피리딘-4-일)피롤리딘)-1-일]-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 1)의 제조Example 11: 1-cyclopropyl-6-fluoro-8-methoxy-7-[(3-amino-3- (pyridin-4-yl) pyrrolidin) -1-yl] -4-oxo- Preparation of 1,4-dihydroquinoline-3-carboxylic acid (Compound 1)

1-사이클로프로필-6,7-디플루오로-8-메톡시-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 3) 295mg 및 3-아미노-3-(피리딘-4-일)피롤리딘 염산염(화합물 2) 315mg을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 흰색 고체의 목적 화합물 407mg을 얻었다.295 mg of 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Compound 3) and 3-amino-3- (pyridine-4- 407 mg of the target compound as a white solid was obtained in the same manner as in Example 1 except that 315 mg of 1) pyrrolidine hydrochloride (Compound 2) was used.

원소분석 (C23H23N4O4F)Elemental Analysis (C 23 H 23 N 4 O 4 F)

측정치(%) ; C: 63.05 H: 5.31 N: 12.75Measured value (%); C: 63.05 H: 5.31 N: 12.75

이론치(%) ; C: 63.00 H: 5.29 N: 12.78Theoretical value (%); C: 63.00 H: 5.29 N: 12.78

실시예 12: 1-사이클로프로필-5-아미노-6,8-디플루오로-7-[(3-아미노메틸-3-(피리딘-4-일)피롤리딘)-1-일]-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 1)의 제조Example 12 1-cyclopropyl-5-amino-6,8-difluoro-7-[(3-aminomethyl-3- (pyridin-4-yl) pyrrolidin) -1-yl] -4 Preparation of oxo-1,4-dihydroquinoline-3-carboxylic acid (compound 1)

1-사이클로프로필-5-아미노-6,7,8-트리플루오로-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 3) 298mg 및 3-아미노메틸-3-(피리딘-4-일)피롤리딘 염산염(화합물 2) 315mg을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 목적 화합물 401mg을 얻었다.298 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Compound 3) and 3-aminomethyl-3- (pyridine- 401 mg of the target compound was obtained in the same manner as in Example 1, except that 315 mg of 4-yl) pyrrolidine hydrochloride (Compound 2) was used.

원소분석 (C23H23N5O3F2)Elemental Analysis (C 23 H 23 N 5 O 3 F 2 )

측정치(%) ; C: 60.67 H: 5.12 N: 15.35Measured value (%); C: 60.67 H: 5.12 N: 15.35

이론치(%) ; C: 60.65 H: 5.09 N: 15.38Theoretical value (%); C: 60.65 H: 5.09 N: 15.38

실시예 13: 9-플루오로-2,3-디히드로-3-(S)-메틸-10-[(3-아미노-3-(피리딘-4-일)피롤리딘)-1-일]-7-옥소-7H-피리도[1.2.3-데]-1,4-벤조옥사진-6-카복실산(화합물 1)의 제조Example 13: 9-Fluoro-2,3-dihydro-3- (S) -methyl-10-[(3-amino-3- (pyridin-4-yl) pyrrolidin) -1-yl] Preparation of -7-oxo-7H-pyrido [1.2.3-dec] -1,4-benzooxazine-6-carboxylic acid (Compound 1)

9,10-디플루오로-2,3-디히드로-3-(S)-메틸-7-옥소-7H-피리도[1.2.3-데]-1,4-벤조옥사진-6-카복실산(화합물 3) 281mg 및 3-아미노-3-(피리딘-4-일)피롤리딘 염산염(화합물 2) 300mg을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 목적 화합물 375mg을 얻었다.9,10-difluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido [1.2.3-dec] -1,4-benzooxazine-6-carboxylic acid (Compound 3) Except for using 281 mg and 3-mg of 3-amino-3- (pyridin-4-yl) pyrrolidine hydrochloride (Compound 2), the same procedure as in Example 1 was carried out to obtain 375 mg of the target compound. .

원소분석 (C22H21N4O4F)Elemental Analysis (C 22 H 21 N 4 O 4 F)

측정치(%) ; C: 62.24 H: 5.01 N: 13.20Measured value (%); C: 62.24 H: 5.01 N: 13.20

이론치(%) ; C: 62.26 H: 4.99 N: 13.20Theoretical value (%); C: 62.26 H: 4.99 N: 13.20

실시예 14: 1-사이클로프로필-6-플루오로-7-[(3-아미노-3-(피리딘-3-일)피롤리딘)-1-일]-4-옥소-1,4-디히드로-1,8-나프티리딘-3-카복실산(화합물 1)의 제조Example 14 1-cyclopropyl-6-fluoro-7-[(3-amino-3- (pyridin-3-yl) pyrrolidin) -1-yl] -4-oxo-1,4-di Preparation of Hydro-1,8-naphthyridine-3-carboxylic acid (Compound 1)

1-사이클로프로필-6-플루오로-7-클로로-4-옥소-1,4-디히드로-1,8-나프티리딘-3-카복실산(화합물 3) 282mg 및 3-아미노-3-(피리딘-3-일)피롤리딘 염산염(화합물 2) 300mg을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 목적 화합물 382mg을 얻었다.282 mg of 1-cyclopropyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (Compound 3) and 3-amino-3- (pyridine- Except for using 300 mg of 3-yl) pyrrolidine hydrochloride (Compound 2), the same procedure as in Example 1 was carried out to obtain 382 mg of the target compound.

원소분석 (C21H20N5O3F)Elemental Analysis (C 21 H 20 N 5 O 3 F)

실측치(%) ; C: 61.65 H: 4.89 N: 17.14Found (%); C: 61.65 H: 4.89 N: 17.14

이론치(%) ; C: 61.61 H: 4.92 N: 17.11Theoretical value (%); C: 61.61 H: 4.92 N: 17.11

실시예 15: 1-사이클로프로필-6-플루오로-7-[(3-아미노메틸-3-(피리딘-3-일)피롤리딘)-1-일]-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 1)의 제조Example 15 1-cyclopropyl-6-fluoro-7-[(3-aminomethyl-3- (pyridin-3-yl) pyrrolidin) -1-yl] -4-oxo-1,4- Preparation of Dihydroquinoline-3-carboxylic Acid (Compound 1)

1-사이클로프로필-6,7-디플루오로-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 3) 295mg 및 3-아미노메틸-3-(피리딘-3-일)피롤리딘 염산염(화합물 2) 315mg을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 목적 화합물 367mg을 얻었다.295 mg of 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Compound 3) and 3-aminomethyl-3- (pyridin-3-yl) pyrroli Except for using 315 mg of Dean hydrochloride (Compound 2), the same procedure as in Example 1 was carried out to obtain 367 mg of the target compound.

원소분석 (C23H23N4O3F)Elemental Analysis (C 23 H 23 N 4 O 3 F)

측정치(%) ; C: 65.39 H: 5.51 N: 13.31Measured value (%); C: 65.39 H: 5.51 N: 13.31

이론치(%) ; C: 65.39 H: 5.49 N: 13.26Theoretical value (%); C: 65.39 H: 5.49 N: 13.26

실시예 16: 1-사이클로프로필-6,8-디플루오로-7-[(3-아미노-3-(피리딘-4-일)피롤리딘)-1-일]-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 1)의 제조Example 16: 1-cyclopropyl-6,8-difluoro-7-[(3-amino-3- (pyridin-4-yl) pyrrolidin) -1-yl] -4-oxo-1, Preparation of 4-dihydroquinoline-3-carboxylic acid (Compound 1)

1-사이클로프로필-6,7,8-트리플루오로-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 3) 295mg 및 3-아미노-3-(피리딘-4-일)피롤리딘 염산염(화합물 2) 300mg을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 목적 화합물 367mg을 얻었다.295 mg of 1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Compound 3) and 3-amino-3- (pyridin-4-yl) pi 367 mg of the target compound was obtained in the same manner as in Example 1, except that 300 mg of lollidine hydrochloride (Compound 2) was used.

원소분석 (C22H20N4O3F2)Elemental Analysis (C 22 H 20 N 4 O 3 F 2 )

측정치(%) ; C: 61.98 H: 4.71 N: 13.11Measured value (%); C: 61.98 H: 4.71 N: 13.11

이론치(%) ; C: 61.97 H: 4.73 N: 13.14Theoretical value (%); C: 61.97 H: 4.73 N: 13.14

실시예 17: 1-사이클로프로필-6-플루오로-8-메톡시-7-[(3-메틸아미노메틸-3-(피리딘-4-일)피롤리딘)-1-일]-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 1)의 제조Example 17 1-cyclopropyl-6-fluoro-8-methoxy-7-[(3-methylaminomethyl-3- (pyridin-4-yl) pyrrolidin) -1-yl] -4- Preparation of oxo-1,4-dihydroquinoline-3-carboxylic acid (compound 1)

1-사이클로프로필-6,7-디플루오로-8-메톡시-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 3) 295mg 및 3-메틸아미노메틸-3-(피리딘-4-일)피롤리딘 염산염(화합물 2) 320mg을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 흰색 고체의 목적 화합물 376mg을 얻었다.295 mg of 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Compound 3) and 3-methylaminomethyl-3- (pyridine- Except for using 320 mg of 4-yl) pyrrolidine hydrochloride (Compound 2), the same procedure as in Example 1 was carried out to obtain 376 mg of the target compound as a white solid.

원소분석 (C24H25N4O4F)Elemental Analysis (C 24 H 25 N 4 O 4 F)

측정치(%) ; C: 64.41 H: 5.81 N: 12.00Measured value (%); C: 64.41 H: 5.81 N: 12.00

이론치(%) ; C: 64.37 H: 5.83 N: 12.01Theoretical value (%); C: 64.37 H: 5.83 N: 12.01

실시예 18: 1-사이클로프로필-6-플루오로-8-메톡시-7-[(3-메틸아미노-3-(피리딘-3-일)피롤리딘)-1-일]-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 1)의 제조Example 18 1-cyclopropyl-6-fluoro-8-methoxy-7-[(3-methylamino-3- (pyridin-3-yl) pyrrolidin) -1-yl] -4-oxo Preparation of -1,4-dihydroquinoline-3-carboxylic acid (Compound 1)

1-사이클로프로필-6,7-디플루오로-8-메톡시-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 3) 295mg 및 3-메틸아미노-3-(피리딘-3-일)피롤리딘 염산염(화합물 2) 315mg을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 흰색 고체의 목적 화합물 381mg을 얻었다.295 mg of 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Compound 3) and 3-methylamino-3- (pyridine-3 -81) Pyrrolidine hydrochloride (Compound 2) was treated in the same manner as in Example 1, except that 315 mg of a white solid target compound was obtained.

원소분석 (C24H25N4O4F)Elemental Analysis (C 24 H 25 N 4 O 4 F)

측정치(%) ; C: 63.75 H: 5.59 N: 12.42Measured value (%); C: 63.75 H: 5.59 N: 12.42

이론치(%) ; C: 63.71 H: 5.57 N: 12.38Theoretical value (%); C: 63.71 H: 5.57 N: 12.38

실시예 19: 1-사이클로프로필-5-아미노-6,8-디플루오로-7-[(3-아미노메틸-3-(피리딘-3-일)피롤리딘)-1-일]-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 1)의 제조Example 19 1-cyclopropyl-5-amino-6,8-difluoro-7-[(3-aminomethyl-3- (pyridin-3-yl) pyrrolidin) -1-yl] -4 Preparation of oxo-1,4-dihydroquinoline-3-carboxylic acid (compound 1)

1-사이클로프로필-5-아미노-6,7,8-트리플루오로-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 3) 298mg 및 3-아미노메틸-3-(피리딘-3-일)피롤리딘 염산염(화합물 2) 315mg을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 목적 화합물 370mg을 얻었다.298 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Compound 3) and 3-aminomethyl-3- (pyridine- 370 mg of the target compound were obtained in the same manner as in Example 1, except that 315 mg of 3-yl) pyrrolidine hydrochloride (Compound 2) was used.

원소분석 (C23H23N5O3F2)Elemental Analysis (C 23 H 23 N 5 O 3 F 2 )

측정치(%) ; C: 60.61 H: 5.11 N: 15.39Measured value (%); C: 60.61 H: 5.11 N: 15.39

이론치(%) ; C: 60.65 H: 5.09 N: 15.38Theoretical value (%); C: 60.65 H: 5.09 N: 15.38

실시예 20: 9-플루오로-2,3-디히드로-3-(S)-메틸-10-[(3-메틸아미노-3-(피리딘-3-일)피롤리딘)-1-일]-7-옥소-7H-피리도[1.2.3-데]-1,4-벤조옥사진-6-카복실산(화합물 1)의 제조Example 20 9-Fluoro-2,3-dihydro-3- (S) -methyl-10-[(3-methylamino-3- (pyridin-3-yl) pyrrolidin) -1-yl ] -7-oxo-7H-pyrido [1.2.3-dec] -1,4-benzooxazine-6-carboxylic acid (Compound 1)

9,10-플루오로-2,3-디히드로-3-(S)-메틸-7-옥소-7H-피리도[1.2.3-데]-1,4-벤조옥사진-6-카복실산(화합물 3) 281mg 및 3-메틸아미노-3-(피리딘-3-일)피롤리딘 염산염(화합물 2) 315mg을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 목적 화합물 391mg을 얻었다.9,10-Fluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido [1.2.3-dec] -1,4-benzooxazine-6-carboxylic acid ( 391 mg of the target compound was obtained by the same method as Example 1, except that 281 mg of compound 3) and 315 mg of 3-methylamino-3- (pyridin-3-yl) pyrrolidine hydrochloride (Compound 2) were used. .

원소분석 (C23H23N4O4F)Elemental Analysis (C 23 H 23 N 4 O 4 F)

측정치(%) ; C: 63.02 H: 5.30 N: 12.74Measured value (%); C: 63.02 H: 5.30 N: 12.74

이론치(%) ; C: 63.00 H: 5.29 N: 12.78Theoretical value (%); C: 63.00 H: 5.29 N: 12.78

실시예 21: 1-(2-(S)-플루오로사이클로프로필)-6-플루오로-8-메톡시-7-[(3-아미노-3-(피리딘-4-일)피롤리딘)-1-일]-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 1)의 제조Example 21: 1- (2- (S) -fluorocyclopropyl) -6-fluoro-8-methoxy-7-[(3-amino-3- (pyridin-4-yl) pyrrolidine) -1-yl] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Compound 1)

1-(2-(S)-플루오로사이클로프로필)-6,7-디플루오로-8-메톡시-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 3) 313mg 및 3-아미노-3-(피리딘-4-일)피롤리딘(화합물 2) 141mg을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 목적 화합물 417mg을 얻었다.313 mg and 1- (2- (S) -fluorocyclopropyl) -6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Compound 3) 3 417 mg of the target compound was obtained in the same manner as in Example 1 except that 141 mg of -amino-3- (pyridin-4-yl) pyrrolidine (Compound 2) was used.

원소분석 (C23H22N4O4F2)Elemental Analysis (C 23 H 22 N 4 O 4 F 2 )

실측치(%) ; C: 60.56 H: 4.83 N: 12.31Found (%); C: 60.56 H: 4.83 N: 12.31

이론치(%) ; C: 60.52 H: 4.86 N: 12.27Theoretical value (%); C: 60.52 H: 4.86 N: 12.27

실시예 22: 1-사이클로프로필-6-플루오로-8-메톡시-7-[(3-아미노-4-N-메틸아미노메틸피롤리딘)-1-일]-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 1)의 제조Example 22 1-cyclopropyl-6-fluoro-8-methoxy-7-[(3-amino-4-N-methylaminomethylpyrrolidin) -1-yl] -4-oxo-1, Preparation of 4-dihydroquinoline-3-carboxylic acid (Compound 1)

1-사이클로프로필-6,7-디플루오로-8-메톡시-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 3) 295mg 및 3-아미노-4-N-메틸아미노메틸피롤리딘(화합물 2) 141mg을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 목적 화합물 397mg을 얻었다.295 mg of 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Compound 3) and 3-amino-4-N-methylaminomethyl Except for using 141 mg of pyrrolidine (Compound 2), the same procedure as in Example 1 was carried out to obtain 397 mg of the target compound.

원소분석 (C21H20N5O3F)Elemental Analysis (C 21 H 20 N 5 O 3 F)

측정치(%) ; C: 61.58 H: 4.91 N: 17.11Measured value (%); C: 61.58 H: 4.91 N: 17.11

이론치(%) ; C: 61.61 H: 4.92 N: 17.11Theoretical value (%); C: 61.61 H: 4.92 N: 17.11

실시예 23: 1-사이클로프로필-5-메틸-6-플루오로-7-[(3-아미노-3-(피리딘-4-일)피롤리딘)-1-일]-4-옥소-1,4-디히드로-1,8-나프티리딘-3-카복실산(화합물 1)의 제조Example 23 1-cyclopropyl-5-methyl-6-fluoro-7-[(3-amino-3- (pyridin-4-yl) pyrrolidin) -1-yl] -4-oxo-1 Preparation of, 4-dihydro-1,8-naphthyridine-3-carboxylic acid (Compound 1)

1-사이클로프로필-5-메틸-6-플루오로-7-클로로-4-옥소-1,4-디히드로-1,8-나프티리딘-3-카복실산(화합물 3) 291mg 및 3-아미노-3-(피리딘-4-일)피롤리딘 염산염(화합물 2) 300mg을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 목적 화합물 423mg을 얻었다.291 mg of 1-cyclopropyl-5-methyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (compound 3) and 3-amino-3 423 mg of the target compound were obtained in the same manner as in Example 1, except that 300 mg of-(pyridin-4-yl) pyrrolidine hydrochloride (Compound 2) was used.

원소분석 (C22H22N5O3F)Elemental Analysis (C 22 H 22 N 5 O 3 F)

실측치(%) ; C: 62.35 H: 5.21 N: 16.51Found (%); C: 62.35 H: 5.21 N: 16.51

이론치(%) ; C: 62.40 H: 5.24 N: 16.54Theoretical value (%); C: 62.40 H: 5.24 N: 16.54

실시예 24: 1-t-부틸-6-플루오로-7-[(3-아미노-3-(피리딘-4-일)피롤리딘)-1-일]-4-옥소-1,4-디히드로-1,8-나프티리딘-3-카복실산(화합물 1)의 제조Example 24 1-t-butyl-6-fluoro-7-[(3-amino-3- (pyridin-4-yl) pyrrolidin) -1-yl] -4-oxo-1,4- Preparation of Dihydro-1,8-naphthyridine-3-carboxylic Acid (Compound 1)

1-t-부틸-6-플루오로-7-클로로-4-옥소-1,4-디히드로-1,8-나프티리딘-3-카복실산(화합물 3) 291mg 및 3-아미노-3-(피리딘-4-일)피롤리딘 염산염(화합물 2) 300mg을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 목적 화합물 423mg을 얻었다.291 mg of 1-t-butyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (Compound 3) and 3-amino-3- (pyridine 423 mg of the target compound were obtained in the same manner as in Example 1, except that 300 mg of 4-yl) pyrrolidine hydrochloride (Compound 2) was used.

원소분석 (C22H24N5O3F)Elemental Analysis (C 22 H 24 N 5 O 3 F)

실측치(%) ; C: 62.08 H: 5.71 N: 16.41Found (%); C: 62.08 H: 5.71 N: 16.41

이론치(%) ; C: 62.11 H: 5.69 N: 16.46Theoretical value (%); C: 62.11 H: 5.69 N: 16.46

실시예 25: 1-사이클로프로필-6-플루오로-8-메톡시-7-[(3-(피리딘-4-일)피롤리딘)-1-일]-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 3)의 제조Example 25 1-cyclopropyl-6-fluoro-8-methoxy-7-[(3- (pyridin-4-yl) pyrrolidin) -1-yl] -4-oxo-1,4- Preparation of Dihydroquinoline-3-carboxylic Acid (Compound 3)

1-사이클로프로필-6,7-디플루오로-8-메톡시-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 3) 295mg 및 3-(피리딘-4-일)피롤리딘 염산염(화합물 1) 230mg을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 목적 화합물 347mg을 얻었다.295 mg of 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Compound 3) and 3- (pyridin-4-yl) pyrroli Except that 230 mg of Dean hydrochloride (Compound 1) was used, the same procedure as in Example 1 was carried out to obtain 347 mg of the target compound.

원소분석 (C23H22N3O4F)Elemental Analysis (C 23 H 22 N 3 O 4 F)

측정치(%) ; C: 65.18 H: 5.21 N: 9.91Measured value (%); C: 65.18 H: 5.21 N: 9.91

이론치(%) ; C: 65.24 H: 5.24 N: 9.92Theoretical value (%); C: 65.24 H: 5.24 N: 9.92

실시예 26: 1-사이클로프로필-6-플루오로-8-메톡시-7-[(3-메틸-3-(피리딘-4-일)피롤리딘)-1-일]-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 1)의 제조Example 26 1-cyclopropyl-6-fluoro-8-methoxy-7-[(3-methyl-3- (pyridin-4-yl) pyrrolidin) -1-yl] -4-oxo- Preparation of 1,4-dihydroquinoline-3-carboxylic acid (Compound 1)

1-사이클로프로필-6,7-디플루오로-8-메톡시-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 3) 295mg 및 3-메틸-3-(피리딘-4-일)피롤리딘 염산염(화합물 2) 230mg을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 목적 화합물 351mg을 얻었다.295 mg of 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Compound 3) and 3-methyl-3- (pyridine-4- 351 mg of the target compound was obtained in the same manner as in Example 1, except that 230 mg of i) pyrrolidine hydrochloride (Compound 2) was used.

원소분석 (C24H24N3O4F)Elemental Analysis (C 24 H 24 N 3 O 4 F)

측정치(%) ; C: 65.88 H: 5.51 N: 9.61Measured value (%); C: 65.88 H: 5.51 N: 9.61

이론치(%) ; C: 65.89 H: 5.53 N: 9.63Theoretical value (%); C: 65.89 H: 5.53 N: 9.63

실시예 27: 1-사이클로프로필-6-플루오로-8-메톡시-7-[(3-메틸-3-(피리딘-2-일)피롤리딘)-1-일]-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 1)의 제조Example 27 1-cyclopropyl-6-fluoro-8-methoxy-7-[(3-methyl-3- (pyridin-2-yl) pyrrolidin) -1-yl] -4-oxo- Preparation of 1,4-dihydroquinoline-3-carboxylic acid (Compound 1)

1-사이클로프로필-6,7-디플루오로-8-메톡시-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 3) 295mg 및 3-메틸-3-(피리딘-2-일)피롤리딘 염산염(화합물 2) 230mg을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 목적 화합물 365mg을 얻었다.295 mg of 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Compound 3) and 3-methyl-3- (pyridine-2- I) 365 mg of the target compound was obtained in the same manner as in Example 1, except that 230 mg of pyrrolidine hydrochloride (Compound 2) was used.

원소분석 (C24H24N3O4F)Elemental Analysis (C 24 H 24 N 3 O 4 F)

측정치(%) ; C: 65.88 H: 5.51 N: 9.57Measured value (%); C: 65.88 H: 5.51 N: 9.57

이론치(%) ; C: 65.89 H: 5.53 N: 9.61Theoretical value (%); C: 65.89 H: 5.53 N: 9.61

실시예 28: 1-사이클로프로필-6-플루오로-8-메톡시-7-[(3-(1-아미노에틸)-3-(피리딘-2-일)피롤리딘)-1-일]-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 1)의 제조Example 28 1-cyclopropyl-6-fluoro-8-methoxy-7-[(3- (1-aminoethyl) -3- (pyridin-2-yl) pyrrolidin) -1-yl] Preparation of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (compound 1)

1-사이클로프로필-6,7-디플루오로-8-메톡시-4-옥소-1,4-디히드로퀴놀린-3-카복실산(화합물 3) 295mg 및 3'-(1"-아미노에틸)-3'-(피리딘-2"-일)피롤리딘 염산염(화합물 2) 340mg을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 목적 화합물 415mg을 얻었다.295 mg of 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Compound 3) and 3 '-(1 "-aminoethyl)- 415 mg of the target compound was obtained in the same manner as in Example 1, except that 340 mg of 3 '-(pyridin-2 "-yl) pyrrolidine hydrochloride (Compound 2) was used.

원소분석 (C25H27N4O4F)Elemental Analysis (C 25 H 27 N 4 O 4 F)

측정치(%) ; C: 64.38 H: 5.81 N: 12.05Measured value (%); C: 64.38 H: 5.81 N: 12.05

이론치(%) ; C: 64.37 H: 5.83 N: 12.01Theoretical value (%); C: 64.37 H: 5.83 N: 12.01

시험예 : 시험관내 항균력, 세포독성 및 선택독성 측정 시험Test Example: In Vitro Antibacterial Activity, Cytotoxicity and Selective Toxicity Test

뮬러-힌톤(Muller-Hinton) 한천을 사용하여 아가 희석법(agar dilution, Hoechst 345)에 따라 최소성장 억제농도(Minimum Inhibitory Concentration, MIC)를 측정함으로써, 실시예 3 및 11에서 제조된, 본 발명의 퀴놀론 유도체, 및 대조군으로서 기존의 시프로플록사신 및 스파플록사신의 균주들에 대한 항균력을 평가하여, 그 결과를 하기 표 1에 나타내었다; 시험조건 - 용매 : H2O 또는 1N-NaOH, 접종 크기 : 107colony forming unit / ml medium, 온도 : 37℃, 배양 시간 : 18시간.Of the present invention, prepared in Examples 3 and 11 by measuring the Minimum Inhibitory Concentration (MIC) according to agar dilution (Hoechst 345) using Muller-Hinton agar. The antimicrobial activity of the quinolone derivatives, and strains of existing ciprofloxacin and spafloxacin as controls, was evaluated and the results are shown in Table 1 below; Test conditions-solvent: H 2 O or 1N-NaOH, inoculation size: 10 7 colony forming unit / ml medium, temperature: 37 ℃, incubation time: 18 hours.

또한, 실시예 3 및 11에서 제조된, 본 발명의 퀴놀론 유도체, 및 대조군으로서 기존의 시프로플록사신 및 스파플록사신의 세포독성 및 선택독성(selectivity index)을 측정하여 그 결과를 하기 표 2에 나타내었다.In addition, the quinolone derivatives of the present invention prepared in Examples 3 and 11, and the cytotoxicity and selectivity index of the existing ciprofloxacin and spafloxacin as a control was measured and the results are shown in Table 2 below.

균 주Strain 실시예 3Example 3 실시예 11Example 11 시프로플록사신Ciprofloxacin 스파플록사신Spafloxacin 1One Streptococcus pyogenes 308aStreptococcus pyogenes 308a 0.0130.013 0.0250.025 3.1253.125 0.3910.391 22 Streptococcus pyogenes 77AStreptococcus pyogenes 77A 0.0070.007 0.0130.013 0.7810.781 0.1950.195 33 Streptococcus faecium MD 8bStreptococcus faecium MD 8b 0.0070.007 0.0250.025 0.3910.391 0.3910.391 44 Staphylococcus aureus SG 511Staphylococcus aureus SG 511 0.0070.007 0.0130.013 0.1950.195 0.0980.098 55 Staphylococcus aureus 285Staphylococcus aureus 285 0.0130.013 0.0130.013 0.7810.781 0.0490.049 66 Staphylococcus aureus 503Staphylococcus aureus 503 0.0070.007 0.0070.007 0.3910.391 0.0490.049 77 Escherichia coli 078Escherichia coli 078 <0.002<0.002 <0.002<0.002 0.0040.004 0.0040.004 88 Escherichia coli DC OEscherichia coli DC O 0.0490.049 0.0490.049 0.1950.195 0.1950.195 99 Escherichia coli DC 2Escherichia coli DC 2 0.0130.013 0.0130.013 0.0490.049 0.0250.025 1010 Escherichia coli TEMEscherichia coli tem 0.0070.007 0.0070.007 0.0070.007 0.0130.013 1111 Escherichia coli 1507EEscherichia coli 1507E 0.0070.007 0.0130.013 0.0070.007 0.0250.025 1212 Pseudomonas aeruginosa 9027Pseudomonas aeruginosa 9027 0.1950.195 0.1950.195 0.1950.195 0.7810.781 1313 Pseudomonas aeruginosa1592EPseudomonas aeruginosa1592E 0.1950.195 0.1950.195 0.1950.195 0.7810.781 1414 Pseudomonas aeruginosa 1771Pseudomonas aeruginosa 1771 0.0980.098 0.1950.195 0.1950.195 0.7810.781 1515 Pseudomonas aeruginosa1771MPseudomonas aeruginosa1771M 0.0980.098 0.0980.098 0.0490.049 0.1950.195 1616 Salmonella typhymuriumSalmonella typhymurium 0.0070.007 0.0070.007 0.0070.007 0.0070.007 1717 Klebsiella oxytoca 1082EKlebsiella oxytoca 1082E <0.002<0.002 0.0020.002 <0.002 <0.002 <0.002<0.002 1818 Klebsiella aerogenes 1522 EKlebsiella aerogenes 1522 E 0.0130.013 0.0130.013 0.0130.013 0.0250.025 1919 Enterobacter cloacae P99Enterobacter cloacae P99 0.0070.007 0.0040.004 0.0070.007 0.0070.007 2020 Enterobacter cloacae 1321 EEnterobacter cloacae 1321 E <0.002<0.002 0.0020.002 <0.002<0.002 0.0040.004

IC100, Topo II(㎍/㎖)IC 100, Topo II (µg / mL) IC100, Gyrase(㎍/㎖)IC 100, Gyrase (μg / ml) 선택 독성Select toxicity 화합물 3Compound 3 1,0001,000 0.20.2 5,0005,000 화합물 11Compound 11 1,0001,000 0.40.4 2,5002,500 시프로플록사신Ciprofloxacin 500500 0.50.5 1,0001,000 스파플록사신Spafloxacin 500500 1.01.0 500500

본 발명의 퀴놀론 유도체 및 이의 약제학적으로 허용가능한 염은 우수한 항균력 및 그램음성균과 그램양성균 둘다에 대해 광범위한 항균 스펙트럼을 가지며 물에 대한 용해도가 높고 세포독성이 적어, 항균제로서 유용하게 사용될 수 있다.Quinolone derivatives and pharmaceutically acceptable salts thereof of the present invention have excellent antimicrobial activity and broad antimicrobial spectrum against both Gram-negative and Gram-positive bacteria, have high solubility in water and low cytotoxicity, and thus can be usefully used as antibacterial agents.

Claims (5)

하기 화학식 1의 퀴놀론 유도체 또는 이의 약제학적으로 허용가능한 염:Quinolone derivatives of Formula 1 or pharmaceutically acceptable salts thereof: 화학식 1Formula 1 상기 식에서,Where 상기 식에서,Where R1은 C1-4알킬기, 할로겐 원자로 치환되거나 치환되지 않은 페닐기, 또는 할로겐 원자로 치환되거나 치환되지 않은 C3-6사이클로알킬기이고;R 1 is a C 1-4 alkyl group, a phenyl group substituted or unsubstituted with a halogen atom, or a C 3-6 cycloalkyl group substituted or unsubstituted with a halogen atom; R2는 수소 원자, 아미노기 또는 C1-4알킬기이고;R 2 is a hydrogen atom, an amino group or a C 1-4 alkyl group; R3는 C1-4알킬기, C1-4알킬기로 치환되거나 치환되지 않은 아미노기, 또는 C1-4알킬기로 치환되거나 치환되지 않은 아미노메틸기 또는 아미노에틸기이며;R 3 is C 1-4 alkyl, which is unsubstituted or substituted with a C 1-4 alkyl group, or substituted with a C 1-4 alkyl group or unsubstituted amino group or amino group and; W는 질소 원자, CH 또는 CY(이때, Y는 할로겐 원자, 또는 할로겐 원자로 치환되거나 치환되지 않은 C1-4알킬기 또는 C1-4알콕시기이다)이고;W is a nitrogen atom, CH or CY, wherein Y is a halogen atom, or a C 1-4 alkyl group or a C 1-4 alkoxy group unsubstituted or substituted with a halogen atom; Pyr은 2-, 3- 또는 4-피리딜기이며;Pyr is a 2-, 3- or 4-pyridyl group; 단, W가 CH인 경우, W와 R1은 함께 COCH2CH(CH3), CCH2CH2CH(CH3) 또는 CSCH2CH(CH3)을 형성할 수 있다.However, when W is CH, W and R 1 may together form COCH 2 CH (CH 3 ), CCH 2 CH 2 CH (CH 3 ) or CSCH 2 CH (CH 3 ). 제 1 항에 있어서,The method of claim 1, R1이에틸기, t-부틸기, 사이클로프로필기, 2,4-디플루오로페닐기 또는 2-(S)-플루오로사이클로프로필기이고; R2가 수소 원자, 아미노기 또는 메틸기이며; R3가 메틸기, 아미노기, 메틸아미노기, 아미노메틸기, 메틸아미노메틸기 또는 1-아미노에틸기이고; W가 질소 원자, CH, CF, CCl, CCH3, COCH3, COCH2F 또는 COCHF2이며; Pyr가 2-, 3- 또는 4-피리딜기이고; 상기 W와 R1가 함께 COCH2CH(CH3), CCH2CH2CH(CH3) 또는 CSCH2CH(CH3)을 형성한 유도체, 또는 이의 약제학적으로 허용가능한 염.R 1 is an ethyl group, t-butyl group, cyclopropyl group, 2,4-difluorophenyl group or 2- (S) -fluorocyclopropyl group; R 2 is a hydrogen atom, an amino group or a methyl group; R 3 is a methyl group, an amino group, a methylamino group, an aminomethyl group, a methylaminomethyl group or a 1-aminoethyl group; W is nitrogen atom, CH, CF, CCl, CCH 3 , COCH 3 , COCH 2 F or COCHF 2 ; Pyr is a 2-, 3- or 4-pyridyl group; A derivative wherein W and R 1 together form COCH 2 CH (CH 3 ), CCH 2 CH 2 CH (CH 3 ) or CSCH 2 CH (CH 3 ), or a pharmaceutically acceptable salt thereof. 하기 화학식 2의 화합물을 하기 화학식 3의 화합물과 축합반응시키는 것을 포함하는, 제 1 항의 퀴놀론 유도체의 제조방법:A process for preparing the quinolone derivative of claim 1 comprising condensing a compound of Formula 2 with a compound of Formula 3: 화학식 2Formula 2 화학식 3Formula 3 상기 식에서,Where R1, R2, R3, W 및 Pyr는 제 1 항에서 정의한 바와 같으며;R 1 , R 2 , R 3 , W and Pyr are as defined in claim 1; X는 할로겐 원자이고;X is a halogen atom; HA는 염화수소 또는 삼불화아세트산이고, n=0, 2 또는 3이다.HA is hydrogen chloride or trifluoroacetic acid and n = 0, 2 or 3. 제 3 항에 있어서,The method of claim 3, wherein 물 또는 유기용매 중에서 무기염기 또는 유기염기 존재 하에 화학식 2의 화합물을 화학식 3의 화합물과 20 내지 120℃에서 6 내지 14시간 동안 반응시키는 것을 특징으로 하는 방법.The compound of formula (2) is reacted with the compound of formula (3) at 20 to 120 ℃ for 6 to 14 hours in the presence of an inorganic or organic base in water or an organic solvent. 유효성분으로의 제 1 항의 화학식 1의 퀴놀론 유도체 또는 이의 약제학적으로 허용가능한 염, 및 약제학적으로 허용되는 담체를 포함하는 항생제 조성물.An antibiotic composition comprising the quinolone derivative of formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier.
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Citations (3)

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Publication number Priority date Publication date Assignee Title
US5342844A (en) * 1992-02-06 1994-08-30 Warner-Lambert Company 7-substituted quinolones and naphthyridones as antibacterial agents
KR960001720A (en) * 1994-06-13 1996-01-25 기타구치 료이치 level
KR19990052328A (en) * 1997-12-22 1999-07-05 이서봉 New Quinolone Carboxylic Acid Derivatives

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5342844A (en) * 1992-02-06 1994-08-30 Warner-Lambert Company 7-substituted quinolones and naphthyridones as antibacterial agents
KR960001720A (en) * 1994-06-13 1996-01-25 기타구치 료이치 level
KR19990052328A (en) * 1997-12-22 1999-07-05 이서봉 New Quinolone Carboxylic Acid Derivatives

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