KR0131990B1 - Novel antibiotic quinoline derivatives and process for preparing thereof - Google Patents

Novel antibiotic quinoline derivatives and process for preparing thereof

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KR0131990B1
KR0131990B1 KR1019940016988A KR19940016988A KR0131990B1 KR 0131990 B1 KR0131990 B1 KR 0131990B1 KR 1019940016988 A KR1019940016988 A KR 1019940016988A KR 19940016988 A KR19940016988 A KR 19940016988A KR 0131990 B1 KR0131990 B1 KR 0131990B1
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남두현
최훈
장재혁
김영관
김세호
홍창용
송헤경
정이나
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성재갑
주식회사엘지화학
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • C07—ORGANIC CHEMISTRY
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    • 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
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    • 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
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

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Abstract

The quinoline carboxylic acid derivatives(I; Q= C-H, C-F, C-Cl or N; R1= ethyl, cyclopropyl or phenyl substituted with a fluorine atom more than 1; R2= H, methyl or amino; n= 0,1,2; R3= H or C1-4 alkyl; R4= C1-4 alkyl, C1-2 alkylene is formed by a linkage of R1 and R2) were prepared. Thus, 41 mg 1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydro- quinoline -3-carboxylic acid and 35 mg 4-methylsulfonyl-pyrrolidin-3-ylamine dihydrochloride were suspended in 0.5 ml dried acetonitrile, followed by refluxing 40 mg 1,8-diaza- bicyclo[5,4,0 undec-7-ene for 4 hours to give 17 mg 7-(3-amino-4-methylsulfonyl-pyrrolidin-1-yl)-1-cyclopropyl -6,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.

Description

신규한 퀴놀론계 항생제 및 그의 제조방법Novel quinolone antibiotics and preparation method thereof

본 발명의 탁월한 항균력을 나타내는 신규 퀴놀린계 화합물에 관한 것이다. 본 발명은 특히, 퀴놀론 모핵의 7-번 위치에 아미노기와 설파이드기가 치환된 피롤리딘 그룹의 유도체를 갖는 화합물로서, 우수한 항균작용과 광범위한 항균 스펙트럼을 갖는 하기 일반식(Ⅰ)의 신규한 퀴놀린 및 나트티리딘 카르복실산 유도체, 약제학적으로 허용가능한 그의 염, 그의 용매화물, 및 그의 제조방법에 관한 것이다.It relates to a novel quinoline compound exhibiting excellent antimicrobial activity of the present invention. In particular, the present invention is a compound having a derivative of a pyrrolidine group substituted with an amino group and a sulfide group at the 7-position of the quinolone mother nucleus, and having a novel quinoline of formula (I) having excellent antibacterial activity and broad antibacterial spectrum, and Natrithydine carboxylic acid derivatives, pharmaceutically acceptable salts thereof, solvates thereof, and methods for preparing the same.

상기식에서, Q는 C-H, C-F, C-Cl, 또는 N이고, R1은 에틸, 사이클로프로필 또는 1개이상의 불소 원자로 치환된 페닐이며, R2는 수소, 메틸 또는 아미노이고, n은 0,1, 또는 2이며, R3는 수소 또는 C1-C4알킬이고(단, n이 0일때 R3는 수소가 아니다), R4는 Cl-C4알킬이거나, R3및 R4는 서로 연결되어 5 내지 8환의 하기 구조를 형성한다.Wherein Q is CH, CF, C-Cl, or N, R 1 is ethyl, cyclopropyl or phenyl substituted with one or more fluorine atoms, R 2 is hydrogen, methyl or amino, n is 0,1 Or 2, R 3 is hydrogen or C 1 -C 4 alkyl (where R 3 is not hydrogen when n is 0), R 4 is C 1 -C 4 alkyl, or R 3 and R 4 are Connected to form the following structures of 5 to 8 rings.

(여기서, m은 1 내지 4의 정수이다).(Wherein m is an integer from 1 to 4).

1962년 요로감염부의 치료제로서 날리딕신산(G. Y. Lesher, et al., J. Med. Chem. 5, 1063-1065 (1962))이 처음 등장한 이래 많은 퀴놀린 카르복실산계 항균제, 즉 옥솔리닉산(Oxolinic acid), 로속사신(Rosoxacin), 피페미딕산(Pipemidic acid)들이 개발되었는데, 이들 초기의 항균제(Albrecht R.,Prog. Drug Res., 21, 9(1977))들은 그람 양성균에 대해서는 활성이 거의 없어 주로 그람 음성균의 항균제로서 사용되어 왔다.Since the emergence of nalidic acid (GY Lesher, et al., J. Med. Chem. 5, 1063-1065 (1962)) in 1962 as a therapeutic agent for urinary tract infections, many quinoline carboxylic acid-based antimicrobials, oxolinic acid (Oxolinic acid) acid, Rosoxacin, and Pipemidic acid were developed, and these early antimicrobial agents (Albrecht R., Prog. Drug Res., 21, 9 (1977)) showed little activity against Gram-positive bacteria. It has been used mainly as an antimicrobial agent of Gram-negative bacteria.

최근에 6번 위치에 불소를 포함하는 새로운 세대의 퀴놀론계 화합물인 노플록사신(Norfloxacin; H. Koga, et al., J, Med. Chem. 23, 1358-63(1980))이 개발되면서 퀴놀론계 항생제에 대한 연구가 매우 광범위하게 시도되었다. 그러나, 노플록사신은 그람양성균에 대한 항균력이 비교적 약하고 분포 및 흡수가 우수하지 못하여 그람 음성균들에 의하여 야기되는 요로 감염증(urinary tract infections), 위장감염(gastro-intestinal infections)이나 성적전달감염(sexually transmitted desease)에 대해서만 주로 사용되었다. 그러나, 그후 스프로플록사신(Ciprofloxacin: R. Wise. et al., J. Antimicrob. Agents Chemother, 23, 559(1983)), 오플록사신(Ofloxacin: K. Sata, et al., Antimictob. Agents Chemother., 22, 548(1982))등이 개발되었으며, 이러한 항균제들은 초기의 항균제들 보다 광범위한 항균력을 갖는 것으로서, 오늘날 실제로 임상에 널리 사용되고 있다.Recently, a new generation of quinolones-containing nofloxacin (H. Koga, et al., J, Med. Chem. 23, 1358-63 (1980)) containing fluorine at position 6 has been developed. Research on antibiotics has been very extensively attempted. However, nofloxacin has a relatively low antimicrobial activity against Gram-positive bacteria and does not have good distribution and absorption, resulting in urinary tract infections, gastro-intestinal infections or sexually transmitted infections caused by Gram-negative bacteria. It is mainly used for transmitted desease. However, thereafter, sprofloxacin (Ciprofloxacin: R. Wise. Et al., J. Antimicrob. Agents Chemother, 23, 559 (1983)), ofloxacin (K. Sata, et al., Antimictob. Agents Chemother., 22, 548 (1982), and the like, which have a broader antimicrobial activity than earlier antimicrobials, and are widely used in practice today.

한편, 퀴놀론 모핵의 7번 위치에는 시프로플록사신이나 오플록사신에서와 같이 피페라진이 치환되어 있는 유도체가 주를 이루고 있으나 보다 강력하고 광범위한 항균력을 갖는 퀴놀론계 항생제 개발을 위한 지속적인 노력의 결과, 7번 위치에 3-아미노 또는 3-아미노메틸피롤리딘 그룹이 도입된 화합물은 7번 위치에 피페라진 그룹을 갖는 화합물들에 비해 그랍음성균에 대한 항균력을 유지하는 동시에 그람양성균에 대한 항균력이 증가되는 것이 발견되었다.On the other hand, the position 7 of the quinolone mother nucleus is mainly derived from derivatives substituted with piperazine, such as ciprofloxacin or oploxacin, but as a result of continuous efforts to develop more powerful and broader antibacterial quinolone antibiotics, position 7 The compound introduced with 3-amino or 3-aminomethylpyrrolidine group was found to have increased antibacterial activity against Gram-positive bacteria while maintaining antimicrobial activity against Gram-positive bacteria compared to compounds having piperazine group at position 7. It became.

그러나 불행하게도 일반적으로 피롤리딘 치환제를 갖는 화합물들은 피페라진 치환제를 갖는 화합물에 비해 물에 대한 낮은 용해도 등의 이유로 인해 생체외에서의 항균력과 같은 강력한 항균성을 생체내에서 보여주지 못하는 단점이 있다.Unfortunately, however, compounds with pyrrolidine substituents generally do not show strong antimicrobial properties such as antimicrobial activity in vitro due to low solubility in water compared to compounds with piperazine substituents. .

따라서, 피롤리딘 치환체를 갖는 화합물의 이러한 단점을 개선하여 물에 대한 용해도를 증가시키고 또한 약동력학적 성질을 개선시키기 위한 노력이 계속되었으며, 이러한 연구의 예는 여러 보고에서 나타나고 있다.Thus, efforts have been made to improve these shortcomings of compounds with pyrrolidine substituents to increase their solubility in water and also to improve their pharmacokinetic properties, examples of which are shown in several reports.

예를들면 ((2S, 4S)-4-아미노-2-메틸피롤리디닐)나프티리딘 유도체(Rosen, T; Chu, D.T.W. etc. J. Med. Chem. 1988, 31. 1598-1611) 또는 (트란스-3-아미노-4-메틸피롤리디닐)나프티리딘 유도체(Matsumoto, J etc. Proceedings of the 14th International Congress of Chemdthera-py; Ishigami, J., Ed. ; University of Tokyo Press : Tokyo, 1985; pp 1519-1520)들은 피롤리딘에 메틸그룹이 없는 화합물에 비해 생체의 항균력은 유사하면서 물에 대한 용해도가 각각 20배와 40배가 증가함으로써, 경구 흡수율이 증가하고 약동력학적 성질이 개선되었음을 보여주고 있다.For example, ((2S, 4S) -4-amino-2-methylpyrrolidinyl) naphthyridine derivatives (Rosen, T; Chu, DTW etc. J. Med. Chem. 1988, 31. 1598-1611) or ( Trans-3-amino-4-methylpyrrolidinyl) naphthyridine derivatives (Matsumoto, J etc. Proceedings of the 14th International Congress of Chemdthera-py; Ishigami, J., Ed .; University of Tokyo Press: Tokyo, 1985; pp 1519-1520) showed that the antimicrobial activity of the body was similar to that of the compound without methyl group in pyrrolidine and the solubility in water increased by 20 and 40 times, respectively, resulting in increased oral absorption and improved pharmacokinetic properties. Giving.

한편, 피롤리딘이나 피페라진에 다른 작용기를 도입시켜 퀴놀론계 화합물들이 가지고 있는 단점, 즉 그람양성균에 대해 상대적으로 약한 항균력과 물에 대한 용해도가 낮은 점들을 개선하여 약동력학적 성질을 개선하려는 노력들도 진행되었다. 예를들어 독일 특허 제 012143(1985)호 (WO 8606630)에는 하기 일반식[A]로 표시되는 퀴놀론계 화합물이 기술되어 있다.On the other hand, efforts to improve pharmacokinetic properties by introducing other functional groups into pyrrolidine or piperazine by improving the disadvantages of quinolone compounds, that is, relatively weak antimicrobial activity and low solubility in water against gram-positive bacteria Also proceeded. For example, German Patent No. 012143 (1985) (WO 8606630) describes a quinolone compound represented by the following general formula [A].

상기식에서, R은 수소 또는 가수분해 가능한 저급알킬기이고; R1은 에틸, 사이클로프로필 또는 불소가 치환된 페닐기이며; X는 할로겐기이고; n은 0,1, 또는 2이다. 또한, 한국특허 제 9212474호 (WO 9303026)에는 하기 일반식[B]의 퀴놀론계 화합물이 기술되어 있다.Wherein R is hydrogen or a hydrolyzable lower alkyl group; R 1 is a phenyl group substituted with ethyl, cyclopropyl or fluorine; X is a halogen group; n is 0, 1, or 2. In addition, Korean Patent No. 9212474 (WO 9303026) describes a quinolone compound of the following general formula [B].

상기식에서, R은 수소 또는 가수분해가 가능한 저급알킬기이며; X는 할로겐기를 나타낸다. 또 다른 예로는 일본 특허 제 2-69474호에 하기 일반식[C]와 같은 퀴놀론계 화합물이 기술되어 있다.Wherein R is hydrogen or a lower alkyl group capable of hydrolysis; X represents a halogen group. As another example, Japanese Patent No. 2-69474 describes a quinolone compound such as the following general formula [C].

상기식에서, R은 수소 또는 가수분해가 가능한 저급알킬기이며;Wherein R is hydrogen or a lower alkyl group capable of hydrolysis;

X는 불소와 같은 할로겐기이다.X is a halogen group such as fluorine.

상기의 일반식들에서 언급된 퀴놀론계 화합물들의 구조적 특징은 황원자(S) 또는 산화된 형태의 황원자가 피롤리딘환 구조에 직접 치환되어 있거나, 피롤리딘에 아미노기에 함께 저급알킬의 설파이드가 동시에 치환되어 있다는 것이다.The structural characteristics of the quinolone compounds mentioned in the above general formulas are that sulfur atom (S) or oxidized sulfur atom is directly substituted with pyrrolidine ring structure, or pyrrolidin is substituted with lower alkyl sulfide simultaneously with amino group. Is that it is.

이에 본 발명자들은, 이러한 선행기술을 바탕으로하여 개선된 물성을 보이는 퀴놀론계 화합물을 개발하려는 노력을 거듭한 결과, 상기 화합물들과는 다르게 아미노기와 함께 설파이드기가 피롤리딘기에 직접 연결되어 환 구조를 형성하므로써 전체 분자가 좀더 밀집된 형태를 갖거나, 아미노기가 저급알킬기 그중에서도 메틸기에 의해 치환되거나, 산화된 설폰그룹이 피롤리딘기에 직접 치환됨으로써 좀더 친수성을 갖게된 퀴놀론계 화합물이 그람양성균 및 그람음성균 뿐아니라, 내성균을 포함하여 광범위한 병원균에 대해 강력한 항균력을 나타낸다는 사실을 발견함으로써 본 발명을 완성하게 되었다.Accordingly, the present inventors have made efforts to develop a quinolone compound showing improved properties based on such prior art, and thus, unlike the above compounds, a sulfide group together with an amino group is directly connected to a pyrrolidine group to form a ring structure. Not only gram-positive bacteria and gram-negative bacteria, the quinolone compounds having a more compact form, the amino group being substituted by a methyl group among lower alkyl groups, or the oxidized sulfone group directly substituted by a pyrrolidine group, have become more hydrophilic. The present invention has been completed by the discovery of strong antimicrobial activity against a wide range of pathogens, including resistant bacteria.

따라서, 본 발명은 하기 일반식(Ⅰ)의 신규한 퀴놀론계 화합물, 약제학적으로 허용가능한 그의 무독성염, 생리학적으로 가수분해 가능한 에스테르, 용매화물 및 이들의 이성체를 제공하는 것을 목적으로 한다.It is therefore an object of the present invention to provide novel quinolone compounds of the general formula (I), pharmaceutically acceptable nontoxic salts thereof, physiologically hydrolysable esters, solvates and isomers thereof.

상기식에서, Q는 C-H, C-F, C-Cl, 또는 N이고, R1은 에틸, 사이클로프로필 또는 1개이상의 불소 원자로 치환된 페닐이며, R2는 수소, 메틸, 또는 아미노이고, n은 0, 1, 또는 2이며, R3는 수소 또는 C1-C4알킬이고(단, n이 0일 때 R3는 수소가 아니다), R4는 C1-C4알킬이거나, R3및 R4는 서로 연결되어 5 내지 8환의 하기구조를 형성한다.Wherein Q is CH, CF, C-Cl, or N, R 1 is ethyl, cyclopropyl or phenyl substituted with one or more fluorine atoms, R 2 is hydrogen, methyl, or amino, n is 0, 1, or 2, R 3 is hydrogen or C 1 -C 4 alkyl (where R 3 is not hydrogen when n is 0) and R 4 is C 1 -C 4 alkyl or R 3 and R 4 Are connected to each other to form the following structure of 5 to 8 rings.

(여기서, m은 1 내지 4의 정수이다).(Wherein m is an integer from 1 to 4).

탁월한 항균 작용 및 광범위한 항균 스펙트럼을 나타내는 상기 일반식(Ⅰ)의 화합물 중에서도 바람직한 화합물은 Q는 C-H, C-F, C-Cl, 또는 N이고, R1은 에틸, 사이클로프로필 또는 2,4-디플루오로페닐이며, R2는 수소이고, n은 0, 1, 또는 2이며, R3는 수소이고, R4는 메틸이거나, R3및 R4는 서로 연결되어 5 내지 6환의 하기 구조를 형성하는 화합물이다.Among the compounds of the general formula (I) showing excellent antimicrobial activity and broad antimicrobial spectrum, preferred compounds are Q, CH, CF, C-Cl, or N, and R 1 is ethyl, cyclopropyl or 2,4-difluoro Phenyl, R 2 is hydrogen, n is 0, 1, or 2, R 3 is hydrogen, R 4 is methyl, or R 3 and R 4 are linked to each other to form the following structures of 5-6 rings: to be.

(여기서, m은 1 내지 2의 정수이다).(Wherein m is an integer of 1 to 2).

더욱 바람직한 화합물은 Q는 C-F이고, R1은 사이클로프로필미여, R2는 수소이고, n은 0 또는 2이며, R3는 수소이고, R4는 메틸이거나, R3 및 R4는 서로 연결되어 5 내지 6환의 하기 구조를 형성하는 화합물이다.More preferred compounds are Q is CF, R1 is cyclopropylme, R2 is hydrogen, n is 0 or 2, R3 is hydrogen, R4 is methyl or R3 and R4 are linked to each other to form a 5-6 ring of To form a compound.

(여기서, m은 1 내지 2의 정수이다).(Wherein m is an integer of 1 to 2).

상기 일반식(Ⅰ)의 피롤리딘 그룹에서 아미노, 저급알킬설파이드, 또는 저급알킬설폰 그룹이 치환된 피롤리딘 그룹의 3번 및 4번 위치는 비대칭탄소로서 각각 R 또는 S형태이거나, R 및 S의 혼합물 형태를 포함하고 있으며, 따라서 본 발명에서는 이들 각 이성체 및 이들의 혼합물도 포함한다.In the pyrrolidine group of the general formula (I), positions 3 and 4 of the pyrrolidine group substituted with amino, lower alkyl sulfide, or lower alkyl sulfone group are each asymmetric carbon, R or S form, or R and It includes the form of a mixture of S, and therefore, the present invention also includes each of these isomers and mixtures thereof.

본 발명에 따른 일반식(Ⅰ)화합물의 약제학적으로 허용되는 무독성 염은, 염산, 브롬산, 인산, 황산 등의 무기산, 아세트산, 트리플루오로아세트산, 구연산, 말레인산, 수산, 호박산, 벤조산, 주석산, 푸말산, 만데린산, 아스코르빈산 또는 말린산 등의 유기 카르복실산 또는 메탄설폰산, 파라-톨루엔설폰산 등의 설폰산과의 염 및 퀴놀론계 화합물 기술분야에서 공지되어 사용되고 있는 기타 다른 산들과의 염을 포함한다. 이들 산부가염은 통상의 전환공정에 의하여 제조될 수 있다.Pharmaceutically acceptable non-toxic salts of the general formula (I) compounds according to the present invention are inorganic acids such as hydrochloric acid, bromic acid, phosphoric acid, sulfuric acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, hydroxyl, succinic acid, benzoic acid, tartaric acid Salts with organic carboxylic acids such as fumaric acid, manderic acid, ascorbic acid or dried acid, or sulfonic acids such as methanesulfonic acid and para-toluenesulfonic acid, and other acids known and used in the art of quinolone compounds. Contains salts. These acid addition salts can be prepared by conventional conversion processes.

본 발명에 따른 일반식(Ⅰ)의 화합물은 하기 반응도식 1의 방법에 따라 일반식(Ⅱ)의 화합물과 일반식(Ⅲ)의 화합물을 용매 존재하에서 적당한 염기를 첨가하고 실온 내지 200℃의 온도로 1 내지 20시간 동안 교반시킴으로써 제조할 수 있으며, 따라서 신규한 일반식(Ⅰ)의 화합물을 제조하는 방법을 제공함도 본 발명의 목적이 된다.Compound of formula (I) according to the present invention is added to the compound of formula (II) and compound of formula (III) in the presence of a solvent according to the method of Scheme 1 below and the temperature of room temperature to 200 ℃ It can also be prepared by stirring for 1 to 20 hours, and thus it is an object of the present invention to provide a method for preparing a new compound of general formula (I).

[반응식 1]Scheme 1

상기식에서, Q, R1, R2, R3, R4, 및 n은 전술한 바와 동일하고; X는 할로겐원자(바람직하게는 염소, 브롬 또는 불소)이며; 일반식(Ⅲ)의 화합물은 그 자체로 또는 염산, 브롬산 또는 트리플루오로아세트산 등과의 염의 형태로도 사용할 수 있다.Wherein Q, R 1 , R 2 , R 3 , R 4 , and n are the same as described above; X is a halogen atom (preferably chlorine, bromine or fluorine); The compound of general formula (III) may be used on its own or in the form of a salt with hydrochloric acid, bromic acid or trifluoroacetic acid or the like.

상기 반응에서 사용되는 용매로는 아세토니트릴, 디메틸포름아미드(DMF), 디메틸설폭시드(DMSO), 피리딘 또는 헥사메틸포스포아미드(HMPA) 등이 바람직하며, 반응을 진행시킴예 있어서는 상대적으로 고가인 출발물질(Ⅱ)의 반응효율을 높이기 위해서 반응물질(Ⅲ)을 출발물질(Ⅱ)에 대해 동몰량 내지 10 몰배량 사용하고, 바람직하게는 동몰량 내지 5 몰배량 사용하여 반응시키는 것이 좋다. 또한 상기 반응은 산수용체의 존재하에서 진행되는데, 이때 사용 가능한 산수용체로는 탄산수소나트륨, 탄산칼륨 등의 무기염기 및 트리에틸아민, 디이소프로필에틸아민, 피리딘, N,N-디메틸아닐린, N,N-디메틸아미노피리딘, 1,8-디아자비사이클로[5,4,0]운데세-7-엔(DBU), 1,4-디아자비사이클로[2,2,2]옥탄(DABCO) 등의 유기염기가 바람직하다.As the solvent used in the reaction, acetonitrile, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), pyridine or hexamethylphosphoamide (HMPA) and the like are preferable. In order to increase the reaction efficiency of the starting material (II), it is preferable to react the reacting material (III) by using an equimolar amount to 10 molar times with respect to the starting material (II), preferably using an equimolar amount to 5 molar times. In addition, the reaction proceeds in the presence of an acid acceptor, which may be used as inorganic acceptors such as sodium hydrogen carbonate and potassium carbonate and triethylamine, diisopropylethylamine, pyridine, N, N-dimethylaniline, N , N-dimethylaminopyridine, 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU), 1,4-diazabicyclo [2,2,2] octane (DABCO), etc. The organic base of is preferable.

본 발명에 따른 일반식(Ⅰ)의 화합물은 반응도식 1에 따라 제조할 수 있으나, 경우에 따라서는 하기 반응도식 2에 나타내는 바와 같이 일반식(Ⅲ)의 화합물에서 4-아미노메틸의 R3및 R4가 수소인 경우에 아미노기가 보호된 형태인 일반식(Ⅲ′)의 화합물을 사용하여 상기 반응도식 1에서와 같은 조건에서 반응시킨 후, 수득된 일반식(Ⅰ′)의 화합물을 탈 보호기화시켜 원하는 일반식(Ⅰ)의 화합물을 획득할 수 있다.The compound of formula (I) according to the present invention may be prepared according to Scheme 1, but in some cases R 3 and 4-aminomethyl in the compound of formula (III) as shown in Scheme 2 below. When R 4 is hydrogen, reacted under the same conditions as in Scheme 1 using the compound of formula (III ′) in which the amino group is protected, and then the compound of formula (I ′) obtained is deprotected. Vaporization can yield the desired compound of formula (I).

[반응식 2]Scheme 2

상기식에서, Q, R1, R2, R4, 및 n은 전술한 바와 동일하고;Wherein Q, R1, R2, R4, and n are the same as described above;

X는 할로겐원자(바람직하게는 염소, 브롬 또는 불소)이며;X is a halogen atom (preferably chlorine, bromine or fluorine);

P는 아미노보호기를 나타낸다. 이때 사용가능한 아미노보호기는 유기화학 분야에서 통상 사용되는 것으로서 반응 결과 수득되는 목적 화합물의 구조를 파괴함이 없이 용이하게 제거될 수 있는 것이면 어떠한 것이라도 무방하다. 그의 구체적인 예로는 포르밀, 아세틸, 트리플루오로아세틸, 메톡시카르보닐, 벤질옥시카르보닐, 파라-메톡시벤질옥시카르보닐, 트리틸, 트리메틸실릴, 디페닐포스피닐, 테트라하이드로피라닐, t-부틸옥시카르보닐 등이 있다.P represents an aminoprotecting group. The amino protecting group which can be used at this time may be any thing as long as it is commonly used in the field of organic chemistry and can be easily removed without destroying the structure of the target compound obtained by the reaction. Specific examples thereof include formyl, acetyl, trifluoroacetyl, methoxycarbonyl, benzyloxycarbonyl, para-methoxybenzyloxycarbonyl, trityl, trimethylsilyl, diphenylphosphinyl, tetrahydropyranyl, t -Butyloxycarbonyl and the like.

반응을 완료시킨 후 수득된 화합물(Ⅰ′)에 들어 있는 아미노보호기의 제거는 해당기의 성질에 따라서, 가수분해를 비롯한 가용매분해 또는 환원 반응을 이용하여 수행할 수 있는데, 예컨대, 0 내지 130℃의 온도의 용매중에서 산 또는 염기 존재하 또는 부재하에 수행된다. 이때 사용가능한 무기산으로 염산, 브롬산, 황산, 인산 등을 들 수 있고, 아세트산, 트리플루오로아세트산, 포름산, 톨루엔설폰산과 같은 유기산이나 삼브롬화붕소, 염화알루미늄 등의 루이스산도 사용될 수 있다. 또한 염기로는 수산화나트륨, 수산화바륨 등의 알칼리금속 또는 알칼리토금속의 수산화물이나, 탄산나트륨, 탄산칼륨 등의 알칼리금속 탄산염 또는 나트륨메톡사이드, 나트륨에톡사이드 등의 알칼리금속 알콕사이드나 아세트산나트륨 등을 사용할 수 있다.After completion of the reaction, the removal of the amino protecting group contained in the obtained compound (I ′) may be carried out using a solubilization or reduction reaction including hydrolysis, for example, 0 to 130, depending on the nature of the group. In the presence or absence of an acid or a base in a solvent at a temperature of < RTI ID = 0.0 > In this case, hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, and the like may be used, and organic acids such as acetic acid, trifluoroacetic acid, formic acid, toluenesulfonic acid, or Lewis acids such as boron tribromide and aluminum chloride may also be used. As the base, hydroxides of alkali metals or alkaline earth metals such as sodium hydroxide and barium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate or alkali metal alkoxides such as sodium methoxide and sodium ethoxide, sodium acetate and the like can be used. have.

용매로는 물 또는, 화합물의 종류에 따라 에탄올, 디옥산, 에틸렌글리콜, 아세트산 등의 용매 또는 이들 용매와 물의 혼합용매를 사용할 수도 있고, 경우에 따라서는 용매없이 반응시킬 수도 있다. 또한, 보호기가 파라-톨루엔설포닐, 벤질, 트리틸, 벤질카르보닐, 벤질옥시카르보닐, 파라-메톡시벤질옥시카르보닐, 트리클로로에톡시카르보닐, 베타-요오드에톡시카르보닐 등일 때에는 환원 반응을 이용하여 효과적으로 제거할 수 있다. 환원 반응에 의한 보호기의 제거는 보호기의 성질에 따라 반응 조건이 조금씩 다를 수 있으나, 불활성 용매내에서 백금, 팔라듐, 라니니켈 등과 같은 촉매의 존재하에 10 내지 100℃의 온도로 수소기류를 불어넣어 수행하거나 -50 내지 -10℃ 온도의 액체 암모니아 중에서 금속나트륨이나 금속리튬으로 처리하여 수행하는 것이 일반적이다.As a solvent, a solvent such as ethanol, dioxane, ethylene glycol, acetic acid, or a mixed solvent of these solvents and water may be used depending on the kind of the compound, and in some cases, the reaction may be carried out without a solvent. Further, when the protecting group is para-toluenesulfonyl, benzyl, trityl, benzylcarbonyl, benzyloxycarbonyl, para-methoxybenzyloxycarbonyl, trichloroethoxycarbonyl, beta-iodineethoxycarbonyl or the like, reduction The reaction can be used to effectively remove it. Removal of the protecting group by the reduction reaction may be slightly different depending on the nature of the protecting group, but is carried out by blowing a hydrogen stream at a temperature of 10 to 100 ℃ in the presence of a catalyst such as platinum, palladium, nickel and the like in an inert solvent Or by treatment with metallic sodium or metallic lithium in liquid ammonia at a temperature of -50 to -10 ° C.

본 발명에서 출발 물질로 사용된 일반식(Ⅱ)의 화합물은 선행 문헌(J. M. Domagala, et al., J. Med. Chem. 34, 1142(1991); J. M. Domagala, et al., J. Med. Chem. 31, 991(1998); D. Bouzard, et al., J. Med. Chem. 35, 518(1992)등)에 공지된 방법에 따라 반응을 진행시킴으로써 용이하게 제조할 수 있다.Compounds of general formula (II) used as starting materials in the present invention are described in JM Domagala, et al., J. Med. Chem. 34, 1142 (1991); JM Domagala, et al., J. Med. Chem. 31, 991 (1998); D. Bouzard, et al., J. Med. Chem. 35, 518 (1992) and the like) can be prepared easily by proceeding the reaction.

한편, 본 발명에서 반응물질로 사용된 일반식(Ⅲ)의 화합물은 하기 반응도식들과 같은 방법에 의해 용이하게 제조할 수 있으며, 그 예로써 인덴 유도체는 반응도식 3의 방법에 의해 제조할 수 있다.On the other hand, the compound of the general formula (III) used as a reactant in the present invention can be easily prepared by the same method as the following schemes, for example, indene derivative can be prepared by the method of Scheme 3 have.

[반응식 3]Scheme 3

상기식에서, Boc는 t-부톡시카르보닐을 나타내며, 이하에서도 동일한 의미로 사용된다.In the above formula, Boc represents t-butoxycarbonyl and is used in the same sense below.

상기 반응도식 3에 따르면, t-부톡시카르보닐로 아민 그룹이 보호된 3-피롤린화합물[1]은 일반적으로 에폭사이드를 만드는데 산화제로 많이 사용되는 메타-클로로퍼옥시벤조산(mCPBA)이나 과산화수소(H2O2)를 사용하고 클로로포름과 같은 유기용매, 물 또는 그 혼합액중에서 반응시킴으로써 에폭사이드 화합물[2]로 용이하게 전환시킬 수 있으며, 생성된 에폭사이드 화합물[2]을 아세톤이나 물 또는 그 혼합액중에서 염화아지드를 이용하여 공지의 방법(J. Org. Chem, 1985, 50, 5696)에 따라 실온 또는 가열 환류 조건에서 반응시키면 아지도화합물[3]을 정량적으로 수득할 수 있다.According to Scheme 3, 3-pyrroline compound [1] in which t-butoxycarbonylamine group is protected is generally meta-chloroperoxybenzoic acid (mCPBA) or hydrogen peroxide, which is commonly used as an oxidizing agent to form epoxides. By using (H 2 O 2 ) and reacting in an organic solvent such as chloroform, water or a mixture thereof, it can be easily converted into an epoxide compound [2]. The resulting epoxide compound [2] can be converted into acetone, water or its The azido compound [3] can be obtained quantitatively by reacting azide in the mixture at room temperature or under reflux according to a known method (J. Org. Chem, 1985, 50, 5696).

화합물[3]의 아지도 그룹은 팔라듐이나 플라티늄과 같은 금속 촉매의 존재하에서 수소를 이용하거나(M. K. Eberhardt, Tetrahedron 1967, 23, 3029), 리튬알루미늄하이드리드(J. H. Boyer, J. Am. Chem. Soc., 1951, 73, 5865), 염화나트륨(B. A. Belinka and A. J. Hassner, J. Org. Chem., 1979, 44, 4712) 또는 트리페닐포스핀(R. Carrie, et c., Tetrahedron Letters 1983, 24, 763) 등을 이용하여 쉽게 아민 그룹으로 환원시켜 아민 유도체인 화합물[4]을 얻을 수 있으며, 계속해서 화합물[4]의 아미노기는 무수프탈산(T. Sasaki, K. Minamoto and H. Ito, J. Org. Chem., 1978, 43, 2320)이나 N-카보에톡시프탈이미드(C. R. McArthur, P. M. Worster and A. U. Okon, Synth. Commun., 1983, 13, 311)를 이용하여 프탈아미드기로 보호시킴으로써 하이드록시화합물[5]을 높은 수율로 수득할 수 있다.The azido group of compound [3] can be prepared using hydrogen in the presence of a metal catalyst such as palladium or platinum (MK Eberhardt, Tetrahedron 1967, 23, 3029) or lithium aluminum hydride (JH Boyer, J. Am. Chem. Soc). , 1951, 73, 5865), sodium chloride (BA Belinka and AJ Hassner, J. Org. Chem., 1979, 44, 4712) or triphenylphosphine (R. Carrie, et c., Tetrahedron Letters 1983, 24, 763), etc., can be easily reduced to an amine group to obtain an amine derivative compound [4]. Subsequently, the amino group of the compound [4] is phthalic anhydride (T. Sasaki, K. Minamoto and H. Ito, J. Org. Chem., 1978, 43, 2320) or N-carboethoxyphthalimide (CR McArthur, PM Worster and AU Okon, Synth. Commun., 1983, 13, 311) to protect phthalamide groups The hydroxy compound [5] can be obtained in high yield.

트리페닐포스틴 및 디에틸아조디카르복실레이트(DEAD)를 이용하여 화합물[5]에 티오아세트산 그룹을 도입시킴으로써 화합물[6]을 합성하고, 합성된 화합물[6]을 가수분해시켜 티올화합물[7]을 높은 수율로 수득하였다. 티올화합물[7]을 염기 존재하에 에틸클로로아세테이트와 반응시켜 화합물[8]을 정량적으로 얻을 수 있는데, 이때 사용할 수 있는 염기로는 앞에서 언급된 무기 또는 유기 염기를 들 수 있다.Compound [6] was synthesized by introducing thioacetic acid group into compound [5] using triphenylphosphine and diethyl azodicarboxylate (DEAD), and hydrolyzed synthesized compound [6] to thiol compound [ 7] was obtained in high yield. The thiol compound [7] can be reacted with ethylchloroacetate in the presence of a base to obtain the compound [8] quantitatively. Examples of the base that can be used include the above-mentioned inorganic or organic bases.

화합물[8]의 아미노기의 보호 그룹인 프탈이미노 그룹은 공지의 방법들, 즉 하이드라진(T. Sasaki, K. Minamoto and H. Ito, J. Org. Chem., 1978, 43, 2320)이나 페닐하이드라진(I. Schumann and R. A. Boissonnas, Helv. Chim. Acta, 1953, 35, 2235) 또는 황화나트륨(S. Kukolja and S. R. Lammert, J. Am. Chem. Soc., 1975, 97, 5582) 등을 이용하여 탈보호화시키는 방법들을 이용하여 용이하게 탄보호기화시킬 수 있으며, 탈보호기화된 아미노 그룹이 반응하여 환 구조의 화합물[9]을 형성할 수 있다. 또한, 환형 아미드화합물[9]의 아미드기를 리튬알루미늄하이드라이드로 환원시키면 환형 아민화합물[10]을 얻게 되며, 화합물[10]의 피롤리딘환에서 아미노 보호기는 앞에서 언급한 방법들을 이용하여 쉽게 탈보호기화시켜 목적화합물(Ⅲa)을 정량적인 수율로 수득할 수 있다.The phthalimino group, which is a protecting group of the amino group of compound [8], is known methods such as hydrazine (T. Sasaki, K. Minamoto and H. Ito, J. Org. Chem., 1978, 43, 2320) or phenyl Hydrazine (I. Schumann and RA Boissonnas, Helv. Chim. Acta, 1953, 35, 2235) or sodium sulfide (S. Kukolja and SR Lammert, J. Am. Chem. Soc., 1975, 97, 5582) It can be easily carbon-protected group using the deprotection method, and the deprotected amino group can be reacted to form the compound [9] of the ring structure. In addition, reduction of the amide group of the cyclic amide compound [9] to lithium aluminum hydride gives a cyclic amine compound [10], and the amino protecting group in the pyrrolidine ring of compound [10] is easily deprotected using the aforementioned methods. Vaporization can yield the desired compound (IIIa) in quantitative yield.

아민의 또 다른 예로서, 설폰 형태의 인덴 유도체 화합물(Ⅲb)은 화합물[10]을 이용하여 반응도식 C의 방법으로 합성할 수 있다.As another example of the amine, the sulfone type indene derivative compound (IIIb) can be synthesized by the method of Scheme C using the compound [10].

[반응식 4]Scheme 4

상기 반응도식 4에 따르면, 먼저 반응도식 3에서 제조한 화합물[10]의 아미노 그룹을 t-부틸카보네이트로 보호화시키는 동시에 설파이드 그룹을 설폰 그룹이로 산화시켜 화합물[11]을 정량적으로 수득하게 된다. 이때 사용하는 산화제로는 옥손(Ttost, B. M. and Curran, D. P. Tetrahedron Lett. 1981, 22, 1287)이나 메타-클로로퍼옥시벤조산(Holmes, R. R., Bayer, R. P. J. Am. Chem. Soc. 1960, 82, 3454)을 들수 있다. 또한, 화합물[11]의 아미노보호기를 앞에서 언급한 방법으로 탈보호화시키면 목적 화합물(Ⅲb)을 높은 수율로 수득할 수 있다.According to Scheme 4, first, the amino group of the compound [10] prepared in Scheme 3 is protected with t-butylcarbonate, and the sulfide group is oxidized to a sulfone group to quantitatively obtain the compound [11]. Oxidants used at this time are oxone (Ttost, BM and Curran, DP Tetrahedron Lett. 1981, 22, 1287) or meta-chloroperoxybenzoic acid (Holmes, RR, Bayer, RPJ Am. Chem. Soc. 1960, 82, 3454 ). In addition, deprotection of the aminoprotecting group of compound [11] by the above-mentioned method can give the desired compound (IIIb) in high yield.

또다른 아민의 예로 펜탈렌 유도체 화합물(Ⅲc)은 반응도식 3에서 합성한 화합물[7]를 이용하여 반응도식 5와 같은 방법으로 제조할 수 있다.As another example of the amine, pentalene derivative compound (IIIc) may be prepared by the same method as in Scheme 5, using compound [7] synthesized in Scheme 3.

[반응식 5]Scheme 5

상기 반응도식 5에 따르면, 화합물[7]의 아미노 보호기인 프탈아미드기를 반응도식 3에서와 동일한 방법으로 탈보호화시켜 디설파이드 화합물[12]를 정량적인 수율로 수득하고, 디설파이드 화합물[12]의 아미노기를 페닐옥시카르보닐을 보호기화시켜 화합물[13]을 높은 수율로 얻으며, 계속하여 디설파이드기를 환원시킴으로써 환 구조의 화합물[14]를 수득할 수 있는데, 이때 디설파이드 그룹을 환원시키는데 이용할 수 있는 환원제로는 리튬알루미늄하이드리드(Arnold, R. C., Lien, A. P., Alm, R. M., J. Am. Chem. Soc. 1950, 72, 731)이나 트리부틸포스핀과 같은 트리알킬포스핀 또는 트리알릴포스핀(Overman, L. E., Smoot, J., Overman, J. D., Synthesis 1974, 59; Field, L. In Organic Compound of Sulfur(S. Oae, ed.), Plenum Press, New York, 1977)을 사용할 수 있다.According to Scheme 5, the phthalamide group, an amino protecting group of Compound [7], was deprotected in the same manner as in Scheme 3 to obtain disulfide Compound [12] in quantitative yield, and the amino group of Disulfide Compound [12] By protecting the phenyloxycarbonyl, compound [13] can be obtained in high yield, and the compound [14] having a ring structure can be obtained by subsequently reducing the disulfide group, wherein a reducing agent which can be used to reduce the disulfide group is lithium. Trialkylphosphines or triallylphosphines such as aluminum hydride (Arnold, RC, Lien, AP, Alm, RM, J. Am. Chem. Soc. 1950, 72, 731) or tributylphosphine (Overman, LE , Smoot, J., Overman, JD, Synthesis 1974, 59; Field, L. In Organic Compound of Sulfur (S. Oae, ed.), Plenum Press, New York, 1977.

화합물[14]에 있는 아미노 그룹의 아민기는 디-t-부톡시카르보닐디카보네이트, 염기, 및 N,N-디메틸아미노피리딘을 이용하여 t-부톡시카르보닐기로 보호기화 시킨 다음 보론디메틸설파이드로 테트라하이드로퓨란과 같은 유기용매하에서 환원시키면 화합물[15]를 높은 수율로 수득할 수 있다.The amine group of the amino group in the compound [14] is protected with a t-butoxycarbonyl group using di-t-butoxycarbonyldicarbonate, a base, and N, N-dimethylaminopyridine, followed by tetramethyl boridedimethylsulfide tetra Reduction under an organic solvent such as hydrofuran can give compound [15] in high yield.

화합물[15]의 아미노 보호기들은 앞에서 이미 언급한 방법을 사용하여 쉽게 탈보호기화시켜 목적하는 화합물(Ⅲc)을 무기 또는 유기산의 염이나 그 자체로서 그의 정량적인 수율로 수득할 수 있다.The amino protecting groups of compound [15] can be readily deprotected using the methods already mentioned above to give the desired compound (IIIc) in quantitative yield as a salt of an inorganic or organic acid or as such.

반응도식 5의 목적 화합물(Ⅲc)의 산화된 형태로서 펜탈렌 유도체인 화합물(Ⅲd)은 반응도식 4와 유사한 방법으로 반응도식 6과 같이 합성할 수 있다.Compound (IIId), which is a pentalene derivative as an oxidized form of the target compound (IIIc) of Scheme 5, may be synthesized as in Scheme 6 by a method similar to Scheme 4.

[반응식 6]Scheme 6

상기 반응도식 6에 따르면, 화합물[15]를 반응도식 4에서와 같은 방법으로 산화시켜 설폰 유도체 화합물[16]을 높은 수율로 수득하고, 계속하여 화합물[16]의 보호기들은 앞에서 언급된 방법들을 이용하여 탈보호기화 시킴으로써 목적화합물(Ⅲd)을 염 또는 그 자체의 형태로서 높은 수율로 수득할 수 있다.According to Scheme 6, the compound [15] was oxidized in the same manner as in Scheme 4 to obtain a sulfone derivative compound [16] in high yield, and the protecting groups of compound [16] were then used using the aforementioned methods. By deprotection, the desired compound (IIId) can be obtained in high yield in the form of a salt or itself.

아민의 또 다른 예로서 피롤리딘 유도체인 화합물(Ⅲe)은 반응도식 7의 방법으로 합성할 수 있다.As another example of the amine, compound (IIIe), which is a pyrrolidine derivative, can be synthesized by the method of Scheme 7.

[반응식 7]Scheme 7

상기 반응도식 7에 따르면, 먼저 아미노피롤리딘 유도체[4]의 아미노기를 디-t-부틸디카보네이트로 보호기화 시켜 화합물[17]을 높은 수율로 수득하고, 계속하여 화합물[17]의 하이드록시기를 메탄설포닐클로라이드와 반응시켜 화합물[18]을 높은 수율로 수득한다.According to Scheme 7, the amino group of the aminopyrrolidine derivative [4] was first protected with di-t-butyldicarbonate to obtain compound [17] in high yield, followed by hydroxy of compound [17]. The group is reacted with methanesulfonylchloride to give compound [18] in high yield.

화합물[18]을 소듐티오메톡사이드와 반응시키면 메틸설파이드 그룹에 의해 치환된 화합물[19]을 수득할 수 있고 화합물[19]의 설파이드 그룹은 반응도식 4에서와 동일한 방법으로 산화시켜 설폰 유도체 화합물[20]을 거의 정량적인 수율로 얻을 수 있는데, 이 화합물[20]의 보호기들은 앞에서 이미 언급된 방법들을 사용하여 탈보호기화 시킴으로써 목적화합물(Ⅲe)을 염 또는 그 자체의 형태로 수득할 수 있다.By reacting compound [18] with sodium thiomethoxide, compound [19] substituted by methyl sulfide group can be obtained, and the sulfide group of compound [19] is oxidized in the same manner as in Scheme 4 to form a sulfone derivative compound. [20] can be obtained in almost quantitative yield, and the protecting groups of this compound [20] can be obtained in the form of salts or themselves by deprotection using the methods already mentioned above. .

본 발명에 따라 제조된 화합물은 여러 가지 경구, 비경구 및 국소 투여형태로 투여될 수 있는데, 이때 활성성분으로서 일반식(Ⅰ)의 화합물에 상응하는 약제학적으로 허용가능한 염이 구성될 수도 있음은 물론이다. 본 발명에 기술된 일반식(Ⅰ)의 화합물로부터 약제학적 조성물을 제조하기 위한 불활성인 동시에 약제학적으로 허용가능한 담체는 고체이거나 액체일 수 있다. 고체 형태의 제제는 분말, 정제, 분산 가능한 과립, 캡슐, 카세, 좌약 및 연고를 포함하며, 이중에서도 경구 투여에 적당한 고체 투약 형태로는 정제, 분말, 카세 및 캡슐을 들 수 있다. 고체 담체는 희석제, 향미제, 가용화제, 윤활제, 현탁제, 결합체, 정제팽화제로 작용할 수 있는 물질 또느너 캡슐화 물질 중에서 하나 이상 선택된다. 분말의 경우에 있어, 담체는 미분된 활성성분을 5 내지 70%, 바람직하게는 10 내지 70% 함유하며, 적당한 고체 담체로는 탄산마그네슘, 스테아린산마그네슘, 탈크, 설탕, 락토오즈, 펙틴, 덱스트린, 전분, 젤라틴, 트리가칸트, 메틸셀룰로오즈, 소듐카르복시메틸셀룰로오즈, 저융점 왁스, 코코아 버터 등을 들 수 있다. 액체 형태의 제제는 용액, 현탄액 및 유탁액을 포함한다. 예를들면, 비경구 주사용으로는 물 또는 물-프로필렌글리콜의 혼합 용액이 사용될 수 있는데, 그러한 용액은 등장성, pH 등이 생체계에 적합하도록 제조된다. 액체 제제는 또한 폴리에틸렌글리콜 수용액으로 형성될 수도 있다. 경구용으로 적당한 수용액은 활성 성분을 물에 녹이고 적당한 착색제, 향미제, 안정제 및 농후제를 부가함으로서 제조될 수 있다. 경구용으로 적당한 수성 현탁제는 미분된 활성성분을 천연 또는 합성검, 수지, 메틸셀룰로오즈, 소듐카르복시메틸셀룰로오즈 및 공지의 현탁제와 같은 점성 물질에 분산시킴으로서 제조될 수 있다.The compounds prepared according to the invention can be administered in a variety of oral, parenteral and topical dosage forms, in which the active ingredient may comprise a pharmaceutically acceptable salt corresponding to the compound of formula (I). Of course. Inert and pharmaceutically acceptable carriers for the preparation of pharmaceutical compositions from the compounds of general formula (I) described herein can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, suppositories, and ointments, among which solid dosage forms suitable for oral administration include tablets, powders, cachets, and capsules. The solid carrier is selected from one or more of diluents, flavors, solubilizers, lubricants, suspensions, binders, tablet encapsulants or encapsulating materials. In the case of powders, the carrier contains from 5 to 70%, preferably from 10 to 70%, of finely divided active ingredients, and suitable solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, Starch, gelatin, trigacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter and the like. Formulations in liquid form include solutions, suspensions, and emulsions. For example, water or a mixed solution of water-propylene glycol may be used for parenteral injection, which is prepared such that isotonicity, pH, etc. are suitable for the biological system. Liquid formulations may also be formed from aqueous polyethylene glycol solutions. Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers and thickening agents. Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active component in a viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and known suspending agents.

바람직한 약학적 제제는 단위 투약 형태이다. 그러한 형태에서, 제제는 활성성분의 적당한 양을 포함하는 단위 형태로 세분된다. 단위 투약 형태는 제제의 분리된 양을 함유하는 포장된 제제일 수 있으며, 예를들면, 바이알 또는 앰플내의 포장된 정제, 캡슐, 분말 및 튜브나 병내의 고약이다. 단위 투약의 형태는 또는 캡슐, 카세, 정제, 겔 또는 크림이거나 이러한 포장 형태의 몇가지 종류의 적당한 수 일 수 있다. 제제의 단위 투약량내의 활성 화합물의 양은 가변적이며, 특정한 활성 성분의 효능에 따라 1 내지 100㎎까지 조정할 수 있다. 세균성 전염병을 치료하기 위한 목적으로 사용되는데, 본 발명에 따른 화합물은 초기에는 킬로그람당 약 6 내지 14㎎의 투약량이 바람직하다. 그러나 투약량은 환자의 필요정도, 치료되어야 할 상태의 정도, 사용될 화합물에 따라 가변적이다. 특정한 상태에서 바람직한 투약량을 결정하는 것은 공지의 기술이다. 일반적으로 치료는 화합물의 최적량보다 적은 투약량으로 시작한다. 그런 다음 상황에 따라 최적 효과가 나타날 때 까지 조금씩 투약량을 증가시킨다. 또한, 편의에 따라 하루 총 투약량을 부분적으로 나누어 하루동안 투여하는 것도 가능하다.Preferred pharmaceutical preparations are in unit dosage form. In such forms, the preparation is subdivided into unit forms containing the appropriate amount of active ingredient. The unit dosage form can be a packaged preparation containing discrete amounts of the preparation, for example packaged tablets, capsules, powders and vials in vials or ampoules, or plasters in a bottle. The unit dosage form can also be capsules, cachets, tablets, gels or creams or can be any suitable number of several types of such packaging forms. The amount of active compound in the unit dosage of the formulation is variable and can be adjusted from 1 to 100 mg depending on the efficacy of the particular active ingredient. Used for the purpose of treating bacterial infectious diseases, the compounds according to the invention are initially preferred with a dosage of about 6-14 mg per kilogram. Dosages, however, vary depending on the needs of the patient, the extent of the condition to be treated, and the compound to be used. It is known to determine the desired dosage in a particular state. In general, treatment begins with a dosage less than the optimal amount of the compound. Then increase the dosage in small increments until the optimum effect occurs. In addition, it is also possible to partially divide the total daily dose for the day for convenience.

이상 언급된 본 발명에 따른 화합물은 여러 가지 그람양성균 및 그람음성균을 포함하는 병원균에 대하여 광범위한 항균 스펙트럼과 보다 강력한 항균작용을 나타내는데, 그람음성균에 대해서는 기존의 약제(예를들면 오플록사신)와 동등 또는 그 이상의 항균활성을 나타내고, 특히 그람양성균에 대해서는 기존 약제에 비하여 탁월한 활성을 보이며, 또한 퀴놀론계 화합물에 대해 내성을 나타내는 균주에 대해서도 매우 우수한 항균력을 보이고 있다. 더욱이 본 발명에 따른 화합물은 약동력학적인 면에서도 기존의 퀴놀론계 화합물보다 흡수가 잘되고, 독성이 적어 인간을 포함한 동물의 박테리아 감염에 의한 질명의 예방 및 치료 목적으로 매우 효과적으로 사용될 수 있다.The above-mentioned compounds according to the present invention exhibit a broad spectrum of antimicrobial spectrum and stronger antimicrobial activity against various gram-positive and gram-negative pathogens, and for gram-negative bacteria, they are equivalent to conventional drugs (e.g., oploxacin). Or more than the antimicrobial activity, especially for Gram-positive bacteria shows excellent activity compared to the existing drugs, and also shows a very good antimicrobial activity against strains that are resistant to quinolone compounds. Moreover, the compound according to the present invention is better absorbed than conventional quinolone compounds in terms of pharmacokinetics, and is less toxic and thus can be very effectively used for the purpose of preventing and treating vaginal infection caused by bacterial infection in animals including humans.

이하, 본 발명을 실시예에 의거하여 보다 구체적으로 설명한다. 그러나, 하기의 제조예 및 실시예들은 본 발명에 대한 이해를 돕기 위한 것일 뿐, 주요 구성이 변경되지 않는 한 본 밞영의 범위가 이에 국한되는 것은 아니다.EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated more concretely based on an Example. However, the following Preparation Examples and Examples are only to help understanding of the present invention, the scope of the present invention is not limited thereto unless the main configuration is changed.

[제조예 1][Production Example 1]

1-t-부톡시카르보닐-3-피롤린의 합성Synthesis of 1-t-butoxycarbonyl-3-pyrroline

클로로포름 130㎖에 3-피롤린 18g(0.26몰)을 가하고 50㎖의 클로로포름에 디-t-부틸디카보네이트 62.51g(0.28몰)을 용해시켜 첨가한 후 실온에서 1.5시간동안 교반시켰다. 반응물을 묽은 염산 수용액, 물, 및 소금물로 세척해준 다음 무수마그네슘설페이트로 건조, 여과시키고 여과액을 감압증류시켜 표제화합물을 거의 정량적(수율 99%)으로 수득하였다.18 g (0.26 mol) of 3-pyrroline was added to 130 ml of chloroform, and 62.51 g (0.28 mol) of di-t-butyldicarbonate was added to 50 ml of chloroform, followed by stirring at room temperature for 1.5 hours. The reaction was washed with dilute aqueous hydrochloric acid solution, water, and brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was distilled under reduced pressure to give the title compound almost quantitatively (yield 99%).

1H NMR(CDCl3, ppm): δ5.77(2H, d, J=7.29㎐), 1.48(9H, s) 1 H NMR (CDCl 3 , ppm): δ 5.77 (2H, d, J = 7.29 Hz), 1.48 (9H, s)

Mass(FAB, m/e): 170(M+H)Mass (FAB, m / e): 170 (M + H)

[제조예 2][Production Example 2]

1-t-부톡시카르보닐-6-옥사-3-아자비사이클로[3,1,0]헥산의 합성Synthesis of 1-t-butoxycarbonyl-6-oxa-3-azabicyclo [3,1,0] hexane

1-t-부톡시카르보닐-3-피롤린 49.8g(0.26몰)을 클로로포름 250㎖에 용해시킨 다음 클로로포름 1ℓ에 메타-클로로퍼옥시벤조산(mCPBA) 97.21g (0.34몰)을 용해시켜 첨가하였다. 반응물을 실온에서 10시간동안 교반시키고 5%나트륨하이드로설파이트 수용액으로 세척해준 다음 포화 탄산수소나트륨 수용액으로 세척하였다. 유기층을 물과 소금물로 세척해준 후 무수마그네슘설페이트로 건조, 여과시키고 감압증류시켜 표제화합물을 82%의 수율로 수득하였다.49.8 g (0.26 mol) of 1-t-butoxycarbonyl-3-pyrroline was dissolved in 250 ml of chloroform, and then 97.21 g (0.34 mol) of meta-chloroperoxybenzoic acid (mCPBA) was added to 1 liter of chloroform. . The reaction was stirred at room temperature for 10 hours, washed with 5% aqueous sodium hydrosulfite solution and then with saturated aqueous sodium hydrogen carbonate solution. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure to obtain the title compound in a yield of 82%.

1H NMR(CDCl3, ppm) :δ3.9-3.6(4H, m), 3.32(2H, dd), 1.46(9H, s) 1 H NMR (CDCl 3 , ppm): δ3.9-3.6 (4H, m), 3.32 (2H, dd), 1.46 (9H, s)

Mass(FAB, m/e): 186(M+H)Mass (FAB, m / e): 186 (M + H)

[제조예 3][Manufacture example 3]

1-t-부톡시카르보닐-4-아지도-3-피롤리디놀의 합성Synthesis of 1-t-butoxycarbonyl-4-azido-3-pyrrolidinol

제조예 2에서 합성한 화합물 7.41g (0.04몰)을 아세톤:무(1:1)의 혼합용액 60㎖에 가하고, 여기에 나트륨아지드 13g (0.2몰)과 암모늄클로라이드 4.28g (0.008몰)을 첨가한 다음 15시간 동안 가열 환류시켰다. 반응물을 에틸아세테이트 50㎖로 희석시킨 다음 포화 소금물을 가하여 유기층을 추출하였다. 추출한 유기층을 무수마그네슘설페이트로 건조, 여과시키고 여과액을 감압증류시켜 표제화합물을 96%의 수율로 수득하였다.7.41 g (0.04 mol) of the compound synthesized in Preparation Example 2 was added to 60 ml of a mixed solution of acetone: radish (1: 1), and 13 g (0.2 mol) of sodium azide and 4.28 g (0.008 mol) of ammonium chloride were added thereto. After the addition, the mixture was heated to reflux for 15 hours. The reaction was diluted with 50 ml of ethyl acetate, and then saturated brine was added to extract the organic layer. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate was distilled under reduced pressure to obtain the title compound in a yield of 96%.

1H NMR(CDCl3, ppm): δ 4.25(1H, s), 3.92(1H, s), 3.8-3.2(2H, m), 3.5-3.2(2H, m), 2.6-2.3(1H, d), 1.46(9H, s) 1 H NMR (CDCl 3 , ppm): δ 4.25 (1H, s), 3.92 (1H, s), 3.8-3.2 (2H, m), 3.5-3.2 (2H, m), 2.6-2.3 (1H, d ), 1.46 (9H, s)

Mass(FAB, m/e): 229(M+H)Mass (FAB, m / e): 229 (M + H)

[제조예 4][Production Example 4]

1-t-부톡시카르보닐-4-아미노-3-피롤리디놀의 합성Synthesis of 1-t-butoxycarbonyl-4-amino-3-pyrrolidinol

제조예 3에서 합성한 화합물 8.57g (37.5 밀리몰)을 테트라하이드로퓨란 85㎖에 용해시키고, 여기에 트리페닐포스핀 9.84g (37.5 밀리몰)을 가한 다음 상온에서 1.5시간동안 교반시켰다.8.57 g (37.5 mmol) of the compound synthesized in Preparation Example 3 was dissolved in 85 mL of tetrahydrofuran, and 9.84 g (37.5 mmol) of triphenylphosphine was added thereto, followed by stirring at room temperature for 1.5 hours.

반응물에 물 3㎖를 가하고 13시간동안 더 교반시킨 후 반응물을 감압증류시켜 수득한 잔류물을 컬럼 크로마토그라피로 정제하여 표제 화합물 6.86g (수율 90%)을 수득하였다.3 ml of water was added to the reaction, followed by further stirring for 13 hours, and the residue obtained by distillation under reduced pressure was purified by column chromatography to give 6.86 g (yield 90%) of the title compound.

1H NMR(CDCl3, ppm): δ 3.98(1H, m), 3.70(2H, m), 3.40-3.05(3H, m), 1.80(3H, br), 1.47(9H, s) 1 H NMR (CDCl 3 , ppm): δ 3.98 (1H, m), 3.70 (2H, m), 3.40-3.05 (3H, m), 1.80 (3H, br), 1.47 (9H, s)

Mass(FAB, m/e): 203(M+H)Mass (FAB, m / e): 203 (M + H)

[제조예 5]Production Example 5

1-t-부톡시카르보닐-4-(1,3-디옥소-1,3-디하이드로-이소인돌-2-일)-3-피롤리디놀의 합성Synthesis of 1-t-butoxycarbonyl-4- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -3-pyrrolidinol

제조예 4에서 합성한 화합물 20㎎ (0.1 밀리몰) 및 N-카르보에톡시프탈이미드 22㎎ (0.1 밀리몰)을 톨루엔 3㎖에 가하고 6시간 동안 가열 환류시킨 다음 헥산으로 희석시켜서 생성된 고체를 여과하였다. 여과된 고체를 건조시켜 표제화합무 28㎎ (수율 : 84%)을 수득하였다.20 mg (0.1 mmol) of the compound synthesized in Preparation Example 4 and 22 mg (0.1 mmol) of N-carboethoxyphthalimide were added to 3 ml of toluene, heated to reflux for 6 hours, and diluted with hexane to give a solid. Was filtered. The filtered solid was dried to give 28 mg (yield: 84%) of the title compound.

1H NMR(CDCl3, ppm): δ 7.79(4H, m), 5.00(1H, m), 4.61(1H, m), 3.90(2H, m), 3.69(1H, t, J=9.2㎐), 3.27(1H, dd, J=7.3㎐), 2.42(1H, d, J=4.9㎐), 1.46(9H, s) 1 H NMR (CDCl 3 , ppm): δ 7.79 (4H, m), 5.00 (1H, m), 4.61 (1H, m), 3.90 (2H, m), 3.69 (1H, t, J = 9.2 Hz) , 3.27 (1H, dd, J = 7.3 kPa), 2.42 (1H, d, J = 4.9 kPa), 1.46 (9H, s)

Mass(FAB, m/e): 333(M+H), 665(2M+H)Mass (FAB, m / e): 333 (M + H), 665 (2M + H)

[제조예 6][Manufacture example 6]

1-t-부톡시카르보닐-3-아세틸티오-4-(1,3-디옥소-1,3-디하이드로-이소인돌-2-일)피롤리디놀의 합성Synthesis of 1-t-butoxycarbonyl-3-acetylthio-4- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) pyrrolidinol

트리페닐포스핀 525㎎ (2 밀리몰)의 테트라하이드로퓨란 10㎖용액을 0℃로 냉각시키고 디에틸아조디카르복실레이트 (DEAD) 0.32㎖ (2 밀리몰)을 첨가한후 20분간 교반시킨 다음 제조예 5에서 합성한 화합물 332㎎ (1 밀리몰)과 티오아세트산 0.14㎖(2 밀리몰)을 첨가하였다. 반응물을 실온에서 17시간 동안 교반시키고 감압증류시켜 수득한 잔류물을 컬럼 크로마토그래피로 정제하여 표제화합물을 305㎎(수율 : 78%) 수득하였다.10 ml of 525 mg (2 mmol) of tetrahydrofuran solution of triphenylphosphine was cooled to 0 ° C., 0.32 ml (2 mmol) of diethylazodicarboxylate (DEAD) was added thereto, followed by stirring for 20 minutes. 332 mg (1 mmol) of the compound synthesized in 5 and 0.14 mL (2 mmol) of thioacetic acid were added. The reaction was stirred at room temperature for 17 hours and distilled under reduced pressure to purify the residue by column chromatography to give 305 mg (yield: 78%) of the title compound.

1H NMR(CDCl3, ppm): δ 7.81(4H, m), 5.08(1H, m), 4.50-4.15(2H, m), 3.92(3H, m), 3.57(1H, t, J=11.07㎐), 2.25(3H, s), 1.50(9H, s) 1 H NMR (CDCl 3 , ppm): δ 7.81 (4H, m), 5.08 (1H, m), 4.50-4.15 (2H, m), 3.92 (3H, m), 3.57 (1H, t, J = 11.07 I), 2.25 (3H, s), 1.50 (9H, s)

Mass(FAB, m/e): 391(M+H), 781(2M+H)Mass (FAB, m / e): 391 (M + H), 781 (2M + H)

[제조예 7][Manufacture example 7]

1-t-부톡시카르보닐-3-(1,3-디옥소-1,3-디하이드로-이소인돌-2-일)-4-머캅토-피롤리딘의 합성Synthesis of 1-t-butoxycarbonyl-3- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -4-mercapto-pyrrolidine

제조예 6에서 합성한 화합물 1.56g (4밀리몰)을 테트라하이드로퓨란 25㎖에 가하고 메탄올 2㎖ 첨가후 0℃로 냉각시켰다. 나트륨메톡사이드 216㎎(4밀리몰)을 반응물에 가하고 20분간 교반시킨후, 아세트산을 소량 첨가하고 감압증류시켜 잔류물을 수득하였다. 잔류물을 컬럼 크로마토그래피로 정제하여 표제화합물을 1.115g(수율 : 80%)수득하였다.1.56 g (4 mmol) of the compound synthesized in Preparation Example 6 were added to 25 ml of tetrahydrofuran, and 2 ml of methanol was added and cooled to 0 ° C. 216 mg (4 mmol) of sodium methoxide was added to the reaction and stirred for 20 minutes, and then a small amount of acetic acid was added and distilled under reduced pressure to obtain a residue. The residue was purified by column chromatography to give 1.115 g (yield: 80%) of the title compound.

1H NMR(CDCl3, ppm): δ 7.82(4H, m), 4.91(1H, m), 3.97(3H, m), 3.74(1H, m), 3.48(1H, m), 2.10(1H, s), 1.49(9H, s) 1 H NMR (CDCl 3 , ppm): δ 7.82 (4H, m), 4.91 (1H, m), 3.97 (3H, m), 3.74 (1H, m), 3.48 (1H, m), 2.10 (1H, s), 1.49 (9H, s)

Mass(FAB, m/e): 349(M+H), 679(2M+H)Mass (FAB, m / e): 349 (M + H), 679 (2M + H)

[제조예 8][Manufacture example 8]

1-t-부톡시카르보닐-3-(1,3-디옥소-1,3-디하이드로-이소인돌-2-일)-4-에톡시카르보닐메틸티오-피롤리디놀의 합성Synthesis of 1-t-butoxycarbonyl-3- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -4-ethoxycarbonylmethylthio-pyrrolidinol

테트라하이드로퓨란 5㎖에 수소화나트륨(60%) 111㎎(2.77밀리몰) 및 에틀클로로아세테이트 1.412g(11.55밀리몰)을 가하고 0℃로 냉각시킨 다음 제조예 7에서 합성한 화합물 0.805g(2.31밀리몰)을 테트라하이드로퓨란 15㎖에 용해시켜 첨가하였다. 반응물에 0℃에서 30분간 교반시키고, 계속하여 실온에서 3시간 동안 교반시켰다. 반응물에 물을 가하여 수소화나트륨을 비활성화시키고 에틸아세테이트로 희석시킨 다음 소금물로 세척해주고 무수마그네슘설페이트로 건조, 여과시켰다. 여과액을 감압증류시켜 표제화합물 0.984g(수율 : 98%)을 수득하였다.To 5 ml of tetrahydrofuran, 111 mg (2.77 mmol) of sodium hydride (60%) and 1.412 g (11.55 mmol) of ethyl chloroacetate were added and cooled to 0 ° C., followed by 0.805 g (2.31 mmol) of the compound synthesized in Preparation Example 7. It was added by dissolving in 15 ml of tetrahydrofuran. The reaction was stirred at 0 ° C. for 30 minutes and then stirred at room temperature for 3 hours. Water was added to the reaction to deactivate sodium hydride, diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure to give 0.984 g (yield: 98%) of the title compound.

1H NMR(CDCl3, ppm): δ 7.84(4H, m), 5.10(1H, m), 4.20(2H, q, J=7.20㎐), 4.05-3.80(1H, m), 3.30(1H, m), 3.14(1H, d, J=14.76㎐), 1.55(9H, s), 1.26(3H, t, J=7.02㎐) 1 H NMR (CDCl 3 , ppm): δ 7.84 (4H, m), 5.10 (1H, m), 4.20 (2H, q, J = 7.20 Hz), 4.05-3.80 (1H, m), 3.30 (1H, m), 3.14 (1H, d, J = 14.76 Hz), 1.55 (9H, s), 1.26 (3H, t, J = 7.02 Hz)

Mass(FAB, m/e): 435(M+H)Mass (FAB, m / e): 435 (M + H)

[제조예 9][Manufacture example 9]

2-t-부톡시카르보닐-옥타하이드로-4-티아-2,7-디아자-인덴-6-온의 합성Synthesis of 2-t-butoxycarbonyl-octahydro-4-thia-2,7-diaza-inden-6-one

제조예 8에서 합성한 화합물 43㎎ (0.1 밀리몰)을 테트라하이드로퓨란 2.5㎖에 가하고, 여기에 다시 하이드라진(80%) 22㎎ (0.35 밀리몰)을 가하고 24시간 동안 가열환류시킨 다음 에틸아세테이트로 희석시켰다. 이 용액을 5%탄산나트륨 수용액 및 소금물로 세척해 준 후 무수마그네슘설페이트로 건조, 여과시켰다. 여과액을 감압증류시킨 후 잔류물을 컬럼 크로마토그래피로 정제하여 표제화합물 20㎎ (수율 : 77%)을 수득하였다.43 mg (0.1 mmol) of the compound synthesized in Preparation Example 8 was added to 2.5 ml of tetrahydrofuran, and 22 mg (0.35 mmol) of hydrazine (80%) was added thereto, heated to reflux for 24 hours, and diluted with ethyl acetate. . The solution was washed with 5% aqueous sodium carbonate solution and brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and the residue was purified by column chromatography to give 20 mg (yield: 77%) of the title compound.

1H NMR(CDCl3, ppm): δ 5.86(1H, s), 4.14(1H, m), 3.78(1H, m), 3.67(1H, m), 3.60-3.40(3H, m), 3.29(2H, dd), 1.46(9Hs) 1 H NMR (CDCl 3 , ppm): δ 5.86 (1H, s), 4.14 (1H, m), 3.78 (1H, m), 3.67 (1H, m), 3.60-3.40 (3H, m), 3.29 ( 2H, dd), 1.46 (9Hs)

Mass(FAB, m/e): 259(M+H), 517(2M+H)Mass (FAB, m / e): 259 (M + H), 517 (2M + H)

제조예 10 : 2-t-부톡시카르보닐-옥타하이드로-4-티아-2,7-디아자-인덴의 합성Preparation Example 10 Synthesis of 2-t-butoxycarbonyl-octahydro-4-thia-2,7-diaza-indene

제조예 9에서 합성한 화합물 454㎎ (1.76 밀리몰)을 테트라하이드로퓨란 10㎖에 가하고 여기에 다시 리튬알루미늄하이드리드 100㎎(2.64밀리몰)을 0℃에 첨가하였다. 반응물을 실온에서 1.5시간동안 교반시키고 0℃로 냉각시킨 다음 물 및 15%수산화나트륨 수용액으로 처리한 후 여과하였다. 여과액을 감압증류시켜 수득한 잔류물을 컬럼 크로마토그래피로 정제하여 표제화합물을 215㎎ (수율 : 50%)을 수득하였다.454 mg (1.76 mmol) of the compound synthesized in Preparation Example 9 was added to 10 ml of tetrahydrofuran, and 100 mg (2.64 mmol) of lithium aluminum hydride was added thereto at 0 ° C. The reaction was stirred at room temperature for 1.5 hours, cooled to 0 ° C., treated with water and 15% aqueous sodium hydroxide solution, and filtered. The filtrate was distilled under reduced pressure and the residue was purified by column chromatography to give 215 mg (yield: 50%) of the title compound.

1H NMR(CDCl3, ppm): δ 3.70-3.55(2H, m), 3.44(2H, m), 2.98(2H, m), 2.82(1H, m), 2.27(1H, m), 1.46(9H, s) 1 H NMR (CDCl 3 , ppm): δ 3.70-3.55 (2H, m), 3.44 (2H, m), 2.98 (2H, m), 2.82 (1H, m), 2.27 (1H, m), 1.46 ( 9H, s)

Mass(FAB, m/e): 245(M+H), 489(2M+H)Mass (FAB, m / e): 245 (M + H), 489 (2M + H)

제조예 11 : 옥타하이드로-4-티아-2,7-디아자-인덴 트리플루오로아세테이트산염의 합성Preparation Example 11 Synthesis of Octahydro-4-thia-2,7-diaza-indene trifluoroacetate

제조예 10에서 합성한 화합물 60㎎ (0.25 밀리몰)을 0℃로 냉각시킨 트리플루오로아세트산 1㎖에 가하고 30분간 교반시켰다. 이 용액을 감압증류시켜 수득한 잔류물을 에탄올:에틸아세테르(1:20) 혼합액으로 세척해준 후 건조시켜 표제화합물 83㎎ (수율 : 91%)을 수득하였다.60 mg (0.25 mmol) of the compound synthesized in Preparation Example 10 was added to 1 ml of trifluoroacetic acid cooled to 0 ° C., and stirred for 30 minutes. The residue obtained by distillation under reduced pressure was washed with a mixture of ethanol: ethyl acetate (1:20) and dried to give 83 mg (yield: 91%) of the title compound.

1H NMR(DMSO-d6, ppm) : δ 9.20(2H, s), 3.39(1H, s), 3.65-3.25(6H, m), 3.10(1H, m), 2.82(1H, m), 2.63(1H, m) 1 H NMR (DMSO-d 6 , ppm): δ 9.20 (2H, s), 3.39 (1H, s), 3.65-3.25 (6H, m), 3.10 (1H, m), 2.82 (1H, m), 2.63 (1 H, m)

Mass(FAB, m/e): 145(M+H)Mass (FAB, m / e): 145 (M + H)

[제조예 12][Manufacture example 12]

2,7-디-t-부톡시카르보닐-옥타하이드로-4-티아-2,7-디아자-인덴의 합성Synthesis of 2,7-di-t-butoxycarbonyl-octahydro-4-thia-2,7-diaza-indene

제조예 10에서 합성한 화합물 132㎎ (0.54 밀리몰) 및 트리에틸아민 82㎎(0.81 밀리몰)을 클로로포름 2㎖에 가하고, 클로로포름 1㎖에 용해시킨 디-t-부틸디카보네이트 142㎎(0.65밀리몰)을 첨가하였다. 반응물을 실온에서 3.5시간동안 교반시킨후 감압증류시켜 수득한 잔류물을 컬럼 크로마토그래피로 정제하여 표제화합물을 170㎎ (수율 : 91%)을 수득하였다.132 mg (0.54 mmol) of the compound synthesized in Preparation Example 10 and 82 mg (0.81 mmol) of triethylamine were added to 2 ml of chloroform, and 142 mg (0.65 mmol) of di-t-butyldicarbonate dissolved in 1 ml of chloroform was added. Added. The reaction was stirred at room temperature for 3.5 hours, and then the residue obtained by distillation under reduced pressure was purified by column chromatography to give 170 mg (yield: 91%) of the title compound.

1H NMR(CDCl3, ppm): δ 4.85(1H, s), 4.24(1H, m), 3.07(1H, m), 2.72(1H, m), 2.44(1H, m), 1.47(18H, s) 1 H NMR (CDCl 3 , ppm): δ 4.85 (1H, s), 4.24 (1H, m), 3.07 (1H, m), 2.72 (1H, m), 2.44 (1H, m), 1.47 (18H, s)

Mass(FAB, m/e): 345(M+H)Mass (FAB, m / e): 345 (M + H)

[제조예 13][Production Example 13]

2,7-디-t-부톡시카르보닐-4,4-디옥소-옥타하이드로-4-티아-2,7-디아자-인덴의 합성Synthesis of 2,7-di-t-butoxycarbonyl-4,4-dioxo-octahydro-4-thia-2,7-diaza-indene

제조예 12에서 합성한 화합물 170㎎ (0.49 밀리몰)을 디클로로메탄 3㎖에 가한 다음 물-얼음 용기로 냉각시키고, 여기에 메타클로로퍼옥시벤조산(mCPBA)(60%) 426㎎(1.48밀리몰)을 디클로로메탄 2㎖에 혼탁시켜 첨가하였다. 반응물을 30분간 교반시켜 준 후 10%소디움하이드로설파이트 수용액, 탄산수소 나트륨 수용액 및 물로 세척하였다. 유기층을 무수마그네슘설페이트로 건조, 여과시킨 후 감압증류시켜 표제화합물을 180㎎ (수율 : 97%)을 수득하였다.170 mg (0.49 mmol) of the compound synthesized in Preparation Example 12 were added to 3 ml of dichloromethane, and then cooled in a water-ice container, to which 426 mg (1.48 mmol) of metachloroperoxybenzoic acid (mCPBA) (60%) was added. It was added turbidly to 2 ml of dichloromethane. The reaction was stirred for 30 minutes and then washed with 10% aqueous sodium hydrosulfite solution, aqueous sodium hydrogen carbonate solution and water. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure to obtain 180 mg (yield: 97%) of the title compound.

1H NMR(CDCl3, ppm): δ 5.24(1H, m), 4.60(1H, m), 4.16(1H, t, J=13.0㎐), 3.70-3.40(5H, m), 3.06(2H, m), 1.49(9H, s), 1.47(9H, s) 1 H NMR (CDCl 3 , ppm): δ 5.24 (1H, m), 4.60 (1H, m), 4.16 (1H, t, J = 13.0 Hz), 3.70-3.40 (5H, m), 3.06 (2H, m), 1.49 (9H, s), 1.47 (9H, s)

Mass(FAB, m/e): 377(M+H)Mass (FAB, m / e): 377 (M + H)

[제조예 14]Production Example 14

4,4-디옥소-옥타하이드로-4-티아-2,7-디아자-인덴, 이염산염의 합성Synthesis of 4,4-dioxo-octahydro-4-thia-2,7-diaza-indene, dihydrochloride

메탄올 6㎖를 물-얼음 용기로 냉각시킨 다음, 여기에 아세틸클로라이드 3㎖를 첨가하고 실온에서 20분간 교반시켰다. 제조예 13에서 합성한 화합물 180㎎ (0.48 밀리몰)을 메탄올 4㎖에 용해시켜 상기 용액에 첨가한 후 1.5시간동안 실온에서 교반시켜 주었다. 반응물을 감압증류시킨 다음 에탄올:에틸에테르(1:10)의 혼합용액으로 잔류물을 세척해주고 건조시켜 표제화합물을 109㎎ (수율 : 91%)을 수득하였다.6 ml of methanol was cooled in a water-ice vessel, and then 3 ml of acetylchloride was added thereto and stirred at room temperature for 20 minutes. 180 mg (0.48 mmol) of the compound synthesized in Preparation Example 13 was dissolved in 4 ml of methanol, added to the solution, and stirred at room temperature for 1.5 hours. The reaction was distilled under reduced pressure, and then the residue was washed with a mixed solution of ethanol: ethyl ether (1:10) and dried to give 109 mg (yield: 91%) of the title compound.

1H NMR(CDCl3, ppm): δ 10.00-9.20(1H, m), 6.50-5.00(2H, s), 4.0(2H, m), 3.90-3.20(8H, m) 1 H NMR (CDCl 3 , ppm): δ 10.00-9.20 (1H, m), 6.50-5.00 (2H, s), 4.0 (2H, m), 3.90-3.20 (8H, m)

Mass(FAB, m/e): 177(M+H)Mass (FAB, m / e): 177 (M + H)

[제조예 15][Production Example 15]

1-t-부톡시카르보닐-4-(N-t-부톡시카르보닐)아미노-3-피롤리디놀의 합성Synthesis of 1-t-butoxycarbonyl-4- (N-t-butoxycarbonyl) amino-3-pyrrolidinol

제조예 4에서 합성한 화합물 6.86㎎(33.9 밀리몰)과 트리에틸아민 6.65㎖(47.5밀리몰)를 클로로포름 20㎖에 용해시키고, 여기에 디-t-부틸디카보네이트 8.98g(40.7밀리몰)을 용해시킨 클로로포름 20㎖용액을 첨가하였다. 반응 혼합물을 상온에서 2시간동안 교반시키고 디클로로메탄 30㎖를 가하여 희석시킨 다음 묽은 염산 수용액, 물 및 소금물로 세척하였다. 유기층을 무수마그네슘설페이트로 건조, 여과시킨 후 감압증류시켜 표제화합물을 92%의 수율로 수득하였다.6.86 mg (33.9 mmol) of the compound synthesized in Preparation Example 4 and 6.65 mL (47.5 mmol) of triethylamine were dissolved in 20 mL of chloroform, and 8.98 g (40.7 mmol) of di-t-butyldicarbonate was dissolved therein. 20 ml solution was added. The reaction mixture was stirred at room temperature for 2 hours, diluted with 30 ml of dichloromethane and washed with dilute aqueous hydrochloric acid solution, water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure to obtain the title compound in a yield of 92%.

1H NMR(CDCl3, ppm): δ 4.72(1H, s), 3.91(1H, s), 3.85-3.60(3H, m), 3.40-3.10(2H, m), 1.46(18H, s) 1 H NMR (CDCl 3 , ppm): δ 4.72 (1H, s), 3.91 (1H, s), 3.85-3.60 (3H, m), 3.40-3.10 (2H, m), 1.46 (18H, s)

Mass(FAB, m/e): 303(M+H)Mass (FAB, m / e): 303 (M + H)

[제조예 16][Production Example 16]

1-t-부톡시카르보닐-4-메탄설포닐옥시-3-(N,t-부톡시카르보닐)아미노 피롤리딘의 합성Synthesis of 1-t-butoxycarbonyl-4-methanesulfonyloxy-3- (N, t-butoxycarbonyl) amino pyrrolidine

제조예 15에서 합성한 화합물 2.12g(7.42밀리몰)과 트리에탄아민 1.45㎖(10.36밀리몰)을 디클로로메탄 23㎖에 가하고 0℃로 냉각시킨 다음, 여기에 메탄설포닐클로라이드 0.69㎖(8.90밀리몰)을 천천히 첨가하였다. 반응 혼합물을 실온에서 1시간동안 교반시킨 후 디클로로메탄으로 희석시키고 1N염산 수용액, 물, 및 포화 탄산수소나트륨 수용액의 순으로 세척해준 다음 무수마그네슘설페이트로 건조, 여과시켰다. 여과액을 감압증류시켜 표제화합물 2.60g (수율 : 96%)을 수득하였다.2.12 g (7.42 mmol) of the compound synthesized in Preparation Example 15 and 1.45 mL (10.36 mmol) of triethanamine were added to 23 mL of dichloromethane, and cooled to 0 ° C. Then, 0.69 mL (8.90 mmol) of methanesulfonyl chloride was added thereto. Added slowly. The reaction mixture was stirred at room temperature for 1 hour, diluted with dichloromethane, washed with 1N aqueous hydrochloric acid solution, water, and saturated aqueous sodium hydrogen carbonate solution in that order, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure to give 2.60 g (yield: 96%) of the title compound.

1H NMR(CDCl3, ppm): δ 5.02(1H, s), 3.80-3.60(3H, m), 3.45-3.20(1H, m), 3.13(3H, s), 1.45(9H, s) 1 H NMR (CDCl 3 , ppm): δ 5.02 (1H, s), 3.80-3.60 (3H, m), 3.45-3.20 (1H, m), 3.13 (3H, s), 1.45 (9H, s)

Mass(FAB, m/e): 365(M+H)Mass (FAB, m / e): 365 (M + H)

[제조예 17][Production Example 17]

1-t-부톡시카르보닐-3-(N-t-부톡시카르보닐)아미드-4-메틸설포닐-피롤리딘의 합성Synthesis of 1-t-butoxycarbonyl-3- (N-t-butoxycarbonyl) amide-4-methylsulfonyl-pyrrolidine

제조예 16에서 합성한 화합물 114㎎ (0.3 밀리몰)을 N,N-디메틸포름아미드 1㎖에 가하고, 여기에 소디움티오메톡사이드 46㎎(6.56밀리몰)을 첨가한 후 실온에서 1시간동안 교반시켰다. 반응물을 감압증류시키고, 디클로로메탄으로 잔류물을 희석시킨 다음 1N염산수용액, 물 및 소금물로 세척해주고 무수마그네슘설페이트로 건조, 여과시켰다. 여과액을 감압증류시킨 다음 디클로로메탄 3㎖에 잔류물을 용해시킨 후 0℃로 냉각시키고 메타클로로퍼옥시벤조산(60%) 259㎎(0.9밀리몰)을 첨가하였다. 반응물을 30분간 교반시키고 10%소디움하이드로설파이트 수용액, 탄산수소나트륨 수용액, 및 물로 세척해준 후 소금물로 더 세척하고 무수마그네슘설페이트로 건조, 여과시켰다. 여과액을 감압증류시킨 다음 컬럼 크로마토그래피로 정제하여 표제화합물을 50㎎ (수율 : 46%)을 수득하였다.114 mg (0.3 mmol) of the compound synthesized in Preparation Example 16 were added to 1 mL of N, N-dimethylformamide, and 46 mg (6.56 mmol) of sodium thiomethoxide was added thereto, followed by stirring at room temperature for 1 hour. . The reaction was distilled under reduced pressure, the residue was diluted with dichloromethane, washed with 1N aqueous hydrochloric acid solution, water and brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure, the residue was dissolved in 3 ml of dichloromethane, cooled to 0 ° C., and 259 mg (0.9 mmol) of metachloroperoxybenzoic acid (60%) was added. The reaction was stirred for 30 minutes, washed with 10% aqueous sodium hydrosulfite solution, aqueous sodium bicarbonate solution, and water, further washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and then purified by column chromatography to give 50 mg (yield: 46%) of the title compound.

1H NMR(CDCl3, ppm): δ (2개의 이성체)5.35(1H, m), 4.88(1H, s), 4.75(1H, m), 4.39(1H, s), 4.10(1H, s), 4.00-3.65(6H, m), 3.43(3H, m), 3.10(3H, s) 1.46(18H, s) 1 H NMR (CDCl 3 , ppm): δ (two isomers) 5.35 (1H, m), 4.88 (1H, s), 4.75 (1H, m), 4.39 (1H, s), 4.10 (1H, s) , 4.00-3.65 (6H, m), 3.43 (3H, m), 3.10 (3H, s) 1.46 (18H, s)

Mass(FAB, m/e): 356(M+H)Mass (FAB, m / e): 356 (M + H)

[제조예 18][Production Example 18]

4-메틸설포닐-피롤리딘-3-일아민, 이염산염의 합성Synthesis of 4-methylsulfonyl-pyrrolidin-3-ylamine, dihydrochloride

제조예 17에서 합성한 화합물 50㎎ (0.14 밀리몰)을 제조예 14와 동일한 방법으로하여 표제화합물을 31㎎(수율 : 94%)을 수득하였다.50 mg (0.14 mmol) of the compound synthesized in Preparation Example 17 was obtained in the same manner as in Preparation Example 31, to obtain 31 mg (yield: 94%) of the title compound.

1H NMR(CDCl3, ppm): δ 8.90(3H, s), 4.39(1H, m), 4.00-3.50(5H, m), 3.31(3H, s) 1 H NMR (CDCl 3 , ppm): δ 8.90 (3H, s), 4.39 (1H, m), 4.00-3.50 (5H, m), 3.31 (3H, s)

Mass(FAB, m/e): 165(M+H)Mass (FAB, m / e): 165 (M + H)

[제조예 19][Production Example 19]

1-t-부톡시카르보닐-3-아미노-피롤리딘-4-일-디설파이드의 합성Synthesis of 1-t-butoxycarbonyl-3-amino-pyrrolidin-4-yl-disulfide

제조예 7에서 합성한 화합물 1.40g (4.02 밀리몰)을 테트라하이드로퓨한 15㎖에 가하고, 여기에 하이드라진(80%) 1.01g(20밀리몰)을 첨가한 다음 18시간동안 가열 환류시켰다. 반응물을 감압증류시켜 수득한 잔류물을 에틸에테르로 혼탁용액으로 만든 후 여과하였다. 여과액을 감압증류시켜 표제화합물을 0.861g(수율: 99%) 수득하였다.1.40 g (4.02 mmol) of the compound synthesized in Preparation Example 7 was added to 15 mL of tetrahydrofuran, and 1.01 g (20 mmol) of hydrazine (80%) was added thereto, followed by heating to reflux for 18 hours. The residue obtained by distillation under reduced pressure was made into a turbid solution with ethyl ether and filtered. The filtrate was distilled under reduced pressure to give 0.861 g (yield: 99%) of the title compound.

1H NMR(CDCl3, ppm): δ 3.71(4H, m), 3.45(6H, m), 3.20(2H, m), 1.46(18H, s) 1 H NMR (CDCl 3 , ppm): δ 3.71 (4H, m), 3.45 (6H, m), 3.20 (2H, m), 1.46 (18H, s)

Mass(FAB, m/e): 435(M+H)Mass (FAB, m / e): 435 (M + H)

[제조예 20][Production Example 20]

1-t-부톡시카르보닐-3-(N-페녹시카르보닐)아미노-4-일-디설파이드의 합성Synthesis of 1-t-butoxycarbonyl-3- (N-phenoxycarbonyl) amino-4-yl-disulfide

제조예 19에서 합성한 화합물 0.728㎎(1.67 밀리몰)과 클로로포름 10㎖에 가하고, 여기에 탄산수소나트륨 0.492g(5.86밀리몰)을 첨가한 후 실온에서 교반시키면서 페닐클로로포르메이트 0.918g(5.86밀리몰)을 첨가하였다. 반응물을 4시간동안 교반시킨 후 물과 소금물로 세척해주고 무수마그네슘설페이트로 건조, 여과하여 수득한 여과액을 감압증류시켰다. 잔류물을 컬럼 크로마토그래피로 정제하여 표제화합물 1.055g(수율 : 93%)수득하였다.0.728 mg (1.67 mmol) of the compound synthesized in Preparation Example 19 and 10 ml of chloroform were added thereto, and 0.918 g (5.86 mmol) of phenylchloroformate was added thereto while 0.492 g (5.86 mmol) of sodium hydrogencarbonate was added thereto. Added. The reaction was stirred for 4 hours, washed with water and brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure. The residue was purified by column chromatography to give 1.055 g (yield: 93%) of the title compound.

1H NMR(CDCl3, ppm): δ 7.35(4H, m), 7.20(6H, m), 4.55(2H, s) 1 H NMR (CDCl 3 , ppm): δ 7.35 (4H, m), 7.20 (6H, m), 4.55 (2H, s)

Mass(FAB, m/e): 675(M+H)Mass (FAB, m / e): 675 (M + H)

제조예 21 : 5-t-부톡시카르보닐-2-옥소-옥타하이드로-1-티아-3,5-디아자-펜탈렌의 합성Preparation Example 21 Synthesis of 5-t-butoxycarbonyl-2-oxo-octahydro-1-thia-3,5-diaza-pentalene

제조예 20에서 합성한 화합물 75㎎(0.11 밀리몰)과 탄산수소나트륨 28㎎(0.33밀리몰)을 테트라하이드로퓨란 3㎖에 가하고, 여기에 트리-n-부틸포스핀 55㎕(0.22밀리몰)를 첨가한 후 실온에서 20시간동안 교반시켰다. 반응혼합물을 감압증류시켜 수득한 잔류물을 컬럼 크로마토그래피로 정제하여 표제화합물을 41㎎(수율 : 76%)수득하였다.75 mg (0.11 mmol) of the compound synthesized in Preparation Example 20 and 28 mg (0.33 mmol) of sodium bicarbonate were added to 3 ml of tetrahydrofuran, and 55 µl (0.22 mmol) of tri-n-butylphosphine was added thereto. After stirring at room temperature for 20 hours. The residue obtained by distillation under reduced pressure was purified by column chromatography to obtain 41 mg (yield: 76%) of the title compound.

1H NMR(CDCl3, ppm): δ 5.63(1H, s), 4.39(1H, m), 3.93(1H, m), 3.63(3H, m), 1.47(9H, s) 1 H NMR (CDCl 3 , ppm): δ 5.63 (1H, s), 4.39 (1H, m), 3.93 (1H, m), 3.63 (3H, m), 1.47 (9H, s)

Mass(FAB, m/e): 245(M+H)Mass (FAB, m / e): 245 (M + H)

[제조예 22][Production Example 22]

3,5-디-t-부톡시카르보닐-2-옥소-옥타하이드로-1-티아-3,5-디아자-펜탈렌의 합성Synthesis of 3,5-di-t-butoxycarbonyl-2-oxo-octahydro-1-thia-3,5-diaza-pentalene

제조예 21에서 합성한 화합물 40㎎(0.16 밀리몰)과 4-N,N-디메틸아미노피리딘 5㎎(0.004밀리몰)을 아세토니트릴 1.5㎖에 가하고, 여기에 트리에틸아민 20㎎(0.20밀리몰)을 첨가한 후 실온에서 교반시키면서 디-t-부틸디카보네이트 54㎎(0.25밀리몰)을 첨가하였다. 반응물을 실온에서 20분간 교반시키고, 감압증류시킨 다음 잔류물을 컬럼 크로마토그래피로 정제하여 표제화합물을 56㎎(수율 : 99%)수득하였다.40 mg (0.16 mmol) of the compound synthesized in Preparation Example 21 and 5 mg (0.004 mmol) of 4-N, N-dimethylaminopyridine were added to 1.5 ml of acetonitrile, and 20 mg (0.20 mmol) of triethylamine was added thereto. Then, 54 mg (0.25 mmol) of di-t-butyldicarbonate was added while stirring at room temperature. The reaction was stirred at room temperature for 20 minutes, distilled under reduced pressure and the residue was purified by column chromatography to give 56 mg (yield: 99%) of the title compound.

1H NMR(CDCl3, ppm): δ 4.84(1H, m), 4.16(1H, m), 3.96(1H, m), 3.81(1H, dd), 3.68(1H, m), 3.55(1H, m), 1.53(9H, s), 1.46(9H, s) 1 H NMR (CDCl 3 , ppm): δ 4.84 (1H, m), 4.16 (1H, m), 3.96 (1H, m), 3.81 (1H, dd), 3.68 (1H, m), 3.55 (1H, m), 1.53 (9H, s), 1.46 (9H, s)

Mass(FAB, m/e): 345(M+H)Mass (FAB, m / e): 345 (M + H)

[제조예 23][Manufacture example 23]

3,5-디-t-부톡시카르보닐-옥타하이드로-1-티아-3,5-디아자-펜탈렌의 합성Synthesis of 3,5-di-t-butoxycarbonyl-octahydro-1-thia-3,5-diaza-pentalene

제조예 22에서 합성한 화합물 625㎎(1.81 밀리몰)을 테트라하이드로퓨란 45㎎에 용해시킨 다음 보란-디메틸설파이드((BH3, Me2S); 10M) 414㎎(5.44밀리몰)을 첨가한 후 5시간동안 가열 환류시켰다. 반응물을 0℃로 냉각시킨 후 물을 가하고 에틸아세테이트로 추출하였다. 유기층을 무수마그네슘설페이트로 건조, 여과한 후 감압증류시켜 수득한 잔류물을 컬럼 크로마토그래피로 정제하여 표제화합물을 493㎎(수율 : 82%)수득하였다.625 mg (1.81 mmol) of the compound synthesized in Preparation Example 22 was dissolved in 45 mg of tetrahydrofuran, followed by heating for 5 hours after addition of 414 mg (5.44 mmol) of borane-dimethylsulfide ((BH3, Me2S); 10M). It was refluxed. After cooling the reaction to 0 ℃ water was added and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and the residue obtained by distillation under reduced pressure was purified by column chromatography to obtain 493 mg (yield: 82%) of the title compound.

1H NMR(CDCl3, ppm): δ 4.72(2H, m), 4.41(1H, d), 3.98(1H, m), 3.75(2H, m), 3.40(2H, m), 1.48(9H, s), 1.45(9H, s) 1 H NMR (CDCl 3 , ppm): δ 4.72 (2H, m), 4.41 (1H, d), 3.98 (1H, m), 3.75 (2H, m), 3.40 (2H, m), 1.48 (9H, s), 1.45 (9H, s)

Mass(FAB, m/e): 331(M+H)Mass (FAB, m / e): 331 (M + H)

[제조예 24][Manufacture example 24]

옥타하이드로-1-티아-3,5-디아자-펜탈렌, 디트리플루오로아세트산염의 합성Synthesis of Octahydro-1-thia-3,5-diaza-pentalene, ditrifluoroacetic acid salt

제조예 23에서 합성한 화합물 204㎎(0.62 밀리몰)을 0℃롤 냉각된 트리플루오로아세트산 3㎖에 가하고 20분간 교반시켰다. 반응물을 감압증류시켜 수득한 잔류물을 에틸에테르로 세척하고 건조시켜 표제화합물을 152㎎(수율 : 70%)수득하였다.204 mg (0.62 mmol) of the compound synthesized in Preparation Example 23 was added to 3 ml of 0 ° C roll-cooled trifluoroacetic acid, followed by stirring for 20 minutes. The residue obtained by distillation under reduced pressure was washed with ethyl ether and dried to give 152 mg (yield: 70%) of the title compound.

1H NMR(CDCl3, ppm): δ 9.00(2H, s), 4.41(1H, m), 4.27(2H, dd, J=10.14㎐), 4.03(1H, m), 3.59(1H, m), 3.46(1H, m), 2.92(1H, m) 1 H NMR (CDCl 3 , ppm): δ 9.00 (2H, s), 4.41 (1H, m), 4.27 (2H, doublet of doublets, J = 10.14 Hz), 4.03 (1H, m), 3.59 (1H, m) , 3.46 (1H, m), 2.92 (1H, m)

Mass(FAB, m/e): 131(M+H)Mass (FAB, m / e): 131 (M + H)

[제조예 25]Production Example 25

3,5-디-t-부톡시카르보닐-1,1-디옥소-옥타하이드로-1-티아-3,5-디아자-펜탈렌의 합성Synthesis of 3,5-di-t-butoxycarbonyl-1,1-dioxo-octahydro-1-thia-3,5-diaza-pentalene

제조예 23에서 합성한 화합물 289㎎(0.87 밀리몰)을 디클로로메탄 10㎖에 가하고, 여기에 메타클로로퍼옥시벤조산 755㎎(2.62밀리몰)을 첨가한 후 실온에서 30분동안 교반시켰다. 반응물에 10%소디움하이드로설파이트 수용액을 첨가하고 탄산수소나트륨 수용액, 물 및 소금물로 세척해준 후 무수마그네슘설페이트로 건조, 여과하였다. 여과액을 감압증류시켜 수득한 잔류물을 컬럼 크로마토그래피로 정제하여 표제화합물을 169㎎(수율 : 53%)수득하였다.289 mg (0.87 mmol) of the compound synthesized in Preparation Example 23 was added to 10 ml of dichloromethane, and 755 mg (2.62 mmol) of metachloroperoxybenzoic acid was added thereto, followed by stirring at room temperature for 30 minutes. An aqueous 10% sodium hydrosulfite solution was added to the reaction mixture, washed with an aqueous sodium bicarbonate solution, water and brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and the residue was purified by column chromatography to give 169 mg (yield: 53%) of the title compound.

1H NMR(CDCl3, ppm): δ 5.30-4.70(2H, m), 4.13(2H, m), 3.85-3.50(4H, m), 1.50(9H, s), 1.47(9H, s) 1 H NMR (CDCl 3 , ppm): δ 5.30-4.70 (2H, m), 4.13 (2H, m), 3.85-3.50 (4H, m), 1.50 (9H, s), 1.47 (9H, s)

Mass(FAB, m/e): 363(M+H)Mass (FAB, m / e): 363 (M + H)

[제조예 26]Production Example 26

옥타하이드로-1,1-디옥소-1-티아-3,5-디아자-펜탈렌, 디트리플루오로아세트산염의 합성Synthesis of octahydro-1,1-dioxo-1-thia-3,5-diaza-pentalene, ditrifluoroacetic acid salt

제조예 25에서 합성한 화합물 168㎎(0.47 밀리몰)을 0℃로 냉각된 트리플루오로아세트산 3㎖에 가하고 30분간 교반시켰다. 반응물을 감압증류시켜 수득한 잔류물을 에틸에테르로 세척하고 건조시켜 표제화합물을 150㎎(수율 : 82%)수득하였다.168 mg (0.47 mmol) of the compound synthesized in Preparation Example 25 was added to 3 ml of trifluoroacetic acid cooled to 0 ° C, and stirred for 30 minutes. The residue obtained by distillation under reduced pressure was washed with ethyl ether and dried to give 150 mg (yield: 82%) of the title compound.

1H NMR(CDCl3, ppm): δ 9.12(2H, s), 4.50(1H, m), 4.02(2H, dd, J=12, 43, 11.70), 3.60(2H, m), 3.40(2H, m), 3.20(1H, dd, J=4.32, 4.23) 1 H NMR (CDCl 3 , ppm): δ 9.12 (2H, s), 4.50 (1H, m), 4.02 (2H, dd, J = 12, 43, 11.70), 3.60 (2H, m), 3.40 (2H , m), 3.20 (1H, doublet of doublets, J = 4.32, 4.23)

Mass(FAB, m/e): 163(M+H)Mass (FAB, m / e): 163 (M + H)

[실시예 1]Example 1

7-(3-아미노-4-메틸설포닐-피롤리딘-1-일)-1-사이클로피로필-6,8-디플루오르-4-옥소-1,4-디하이드로-퀴놀린-3-카르복실산의 합성7- (3-amino-4-methylsulfonyl-pyrrolidin-1-yl) -1-cyclopyrophyll-6,8-difluoro-4-oxo-1,4-dihydro-quinoline-3- Synthesis of Carboxylic Acids

1-사이클로피로필-6,7,8-트리플루오로-4-옥소-1,4-디하이드로-퀴놀린-3-카르복실산(41㎎, 0.145밀리몰) 및 4-메틸설포닐-피롤리딘-3-일아민 이염산염(35㎎, 0.148밀리몰)을 건조된 아세토니트릴 0.5㎖에 현탁시킨 후 1,8-디아자비사이클로[5,4,0]운데세-7-엔(40㎎, 0.263밀리몰)을 첨가하고 4시간 동안 가열 환류시켰다. 반응물을 상온으로 냉각시키고 감압, 농축시킨 뒤 아세토니트릴-물(8:2)의 혼합액 5㎖를 가해 고체를 형성시킨 뒤, 여과하여 표제화합물을 17㎎(수율 27%)수득하였다.1-cyclopyrophyll-6,7,8-trifluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (41 mg, 0.145 mmol) and 4-methylsulfonyl-pyrroli Din-3-ylamine dihydrochloride (35 mg, 0.148 mmol) was suspended in 0.5 ml of dried acetonitrile and then 1,8-diazabicyclo [5,4,0] undec-7-ene (40 mg, 0.263 mmol) was added and heated to reflux for 4 hours. The reaction was cooled to room temperature, depressurized and concentrated, and 5 ml of acetonitrile-water (8: 2) was added to form a solid, which was then filtered to obtain 17 mg (yield 27%) of the title compound.

1H NMR(DMSO-d6, ppm): δ 8.6(1H, s), 7.75(1H, d), 4.25(1H, m), 4.1(2H, m), 3.95(2H, m), 3.9-3.5(2H, m), 3.2(2H, s), 3.1(1H, s), 1.15(4H, s) 1 H NMR (DMSO-d 6 , ppm): δ 8.6 (1H, s), 7.75 (1H, d), 4.25 (1H, m), 4.1 (2H, m), 3.95 (2H, m), 3.9- 3.5 (2H, m), 3.2 (2H, s), 3.1 (1H, s), 1.15 (4H, s)

Mass(FAB, m/e): 428(M+H)Mass (FAB, m / e): 428 (M + H)

[실시예 2]Example 2

1-사이클로프로필-6,8-디플루오르-4-(옥타하이드로-7-티아-2,4-디아자-인덴-2-일)-4-옥소-1,4-디하이드로-퀴놀린-3-카르복실산의 합성1-cyclopropyl-6,8-difluoro-4- (octahydro-7-thia-2,4-diaza-inden-2-yl) -4-oxo-1,4-dihydro-quinoline-3 Synthesis of Carboxylic Acids

1-사이클로피로필-6,7,8-트리플루오로-4-옥소-1,4-디하이드로-퀴놀린-3-카르복실산(57㎎, 0.2밀리몰) 및 옥타하이드로-7-티아-2,4-디아자-인덴 디트리플루오로아세트산염(80㎎, 0.234밀리몰)을 건조된 아세토니트릴 1㎖에 현탁시킨 후 2.5시간 동안 가열 환류시켰다. 상온으로 식힌 뒤 물 1㎖를 가하여 고체를 형성시킨 뒤, 여과하여 표제화합물을 50㎎(수율 61%)수득하였다.1-cyclopyrophyll-6,7,8-trifluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (57 mg, 0.2 mmol) and octahydro-7-thia-2 , 4-diaza-indene ditrifluoroacetate (80 mg, 0.234 mmol) was suspended in 1 ml of dried acetonitrile and heated to reflux for 2.5 hours. After cooling to room temperature, 1 ml of water was added to form a solid, followed by filtration to obtain 50 mg (yield 61%) of the title compound.

1H NMR(DMSO-d6, ppm): δ 8.6(1H, s), 7.75(1H, d), 4.25(1H, m), 4.1(2H, m), 3.95(2H, m), 3.9-3.5(2H, m), 3.2(2H, s), 3.1(1H, s), 1.15(4H, s) 1 H NMR (DMSO-d 6 , ppm): δ 8.6 (1H, s), 7.75 (1H, d), 4.25 (1H, m), 4.1 (2H, m), 3.95 (2H, m), 3.9- 3.5 (2H, m), 3.2 (2H, s), 3.1 (1H, s), 1.15 (4H, s)

Mass(FAB, m/e): 428(M+H)Mass (FAB, m / e): 428 (M + H)

[실시예 3]Example 3

1-사이클로프로필-7-(7,7-디옥소-옥타하이드로-7-티아-2,4-디아자-인덴-2-일)-6,8-디플루오로-4-옥소-1,4-디하이드로-퀴놀린-3-카르복실산의 합성1-cyclopropyl-7- (7,7-dioxo-octahydro-7-thia-2,4-diaza-inden-2-yl) -6,8-difluoro-4-oxo-1, Synthesis of 4-dihydro-quinoline-3-carboxylic acid

1-사이클로피로필-6,7,8-트리플루오로-4-옥소-1,4-디하이드로-퀴놀린-3-카르복실산(114㎎, 0.4밀리몰) 및 옥타하이드로-7-티아-2,4-디아자-인덴-7,7-디옥사이드이염산염(110㎎, 0.44밀리몰)을 실시예 2와 동일한 방법으로하여 4시간 동안 반응시켜 표제화합물을 102㎎(수율 58%)수득하였다.1-cyclopyrophyll-6,7,8-trifluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (114 mg, 0.4 mmol) and octahydro-7-thia-2 , 4-diaza-indene-7,7-dioxide dihydrochloride (110 mg, 0.44 mmol) was reacted for 4 hours in the same manner as in Example 2 to obtain 102 mg (yield 58%) of the title compound.

1H NMR(DMSO-d6, ppm): δ 8.6(1H, s), 7.75(1H, d), 4.3(1H, m), 4.1(2H, m), 3.9-3.7(3H, m), 3.6(1H, d), 3.2(1H, d), 3.1-2.9(2H, m), 2.85(1H, m), 1.15(4H, m) 1 H NMR (DMSO-d 6 , ppm): δ 8.6 (1H, s), 7.75 (1H, d), 4.3 (1H, m), 4.1 (2H, m), 3.9-3.7 (3H, m), 3.6 (1H, d), 3.2 (1H, d), 3.1-2.9 (2H, m), 2.85 (1H, m), 1.15 (4H, m)

Mass(FAB, m/e): 440(M+H)Mass (FAB, m / e): 440 (M + H)

[실시예 4]Example 4

1-사이클로프로필-6,8-디플루오르-7-(옥타하이드로-1-티아-3,5-디아자-펜탈렌-5-일)-4-옥소-1,4-디하이드로-퀴놀린-3-카르복실산의 합성1-Cyclopropyl-6,8-difluoro-7- (octahydro-1-thia-3,5-diaza-pentalen-5-yl) -4-oxo-1,4-dihydro-quinoline- Synthesis of 3-carboxylic Acid

1-사이클로피로필-6,7,8-트리플루오로-4-옥소-1,4-디하이드로-퀴놀린-3-카르복실산(108㎎, 0.38밀리몰)과 옥타하이드로-1-티아-3,5-디아자-펜탈렌 디트리플루오로아세트산염(150㎎, 0.42밀리몰)을 실시예 1과 동일한 방법으로하여 1.5시간 반응시켜 표제화합물을 92㎎(수율 61%)수득하였다.1-cyclopyrophyll-6,7,8-trifluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (108 mg, 0.38 mmol) and octahydro-1-thia-3 , 5-Diaza-pentalene ditrifluoroacetic acid salt (150 mg, 0.42 mmol) was reacted for 1.5 hours in the same manner as in Example 1 to obtain 92 mg (yield 61%) of the title compound.

1H NMR(DMSO-d6, ppm): δ 8.65(1H, s), 7.8(1H, d), 4.3(3H, m), 4.1(2H, m), 4.0-3.8(2H, m), 3.6(1H, m), 3.5(2H, m), 1.2(4H, s) 1 H NMR (DMSO-d 6 , ppm): δ 8.65 (1H, s), 7.8 (1H, d), 4.3 (3H, m), 4.1 (2H, m), 4.0-3.8 (2H, m), 3.6 (1H, m), 3.5 (2H, m), 1.2 (4H, s)

Mass(FAB, m/e): 394(M+H)Mass (FAB, m / e): 394 (M + H)

[실시예 5]Example 5

1-사이클로프로필-7-(1,1-디옥소-옥타하이드로-1-티아-3,5-디아자-펜탈렌-5-일)-6,8-디플루오로-4-옥소-1,4-디하이드로-퀴놀린-3-카르복실산의 합성1-cyclopropyl-7- (1,1-dioxo-octahydro-1-thia-3,5-diaza-pentalen-5-yl) -6,8-difluoro-4-oxo-1 Synthesis of, 4-dihydro-quinoline-3-carboxylic acid

1-사이클로피로필-6,8-디플루오로-7-(옥타하이드로-1-티아-3.5-디아자-펜탈렌-5-일)-4-옥소-1,4-디하이드로-퀴놀린-3-카르복실산(39㎎, 0.1밀리몰)을 클로로포름 1.5㎖에 현탁시킨 뒤 메타-클로로퍼옥시벤조산(72㎎, 0.25밀리몰)을 첨가하고 50℃에서 10시간동안 반응시킨다. 반응물에 에테르를 가하여 고체를 형성한 뒤, 여과하고 과량의 에테르로 세척하여 표제화합물을 40㎎(수율 94%)수득하였다.1-cyclopyrophil-6,8-difluoro-7- (octahydro-1-thia-3.5-diaza-pentalen-5-yl) -4-oxo-1,4-dihydro-quinoline- 3-carboxylic acid (39 mg, 0.1 mmol) is suspended in 1.5 ml of chloroform, and then meta-chloroperoxybenzoic acid (72 mg, 0.25 mmol) is added and reacted at 50 DEG C for 10 hours. Ether was added to the reaction to form a solid, which was filtered and washed with excess ether to give 40 mg (94% yield) of the title compound.

1H NMR(DMSO-d6, ppm): δ 8.65(1H, s), 7.8(1H, d), 4.1(3H, m), 4.0-3.7(4H, m), 3.5-3.3(3H, m), 1.15(4H, m) 1 H NMR (DMSO-d 6 , ppm): δ 8.65 (1H, s), 7.8 (1H, d), 4.1 (3H, m), 4.0-3.7 (4H, m), 3.5-3.3 (3H, m ), 1.15 (4H, m)

Mass(FAB, m/e): 426(M+H)Mass (FAB, m / e): 426 (M + H)

[실시예 6]Example 6

1-사이클로프로필-6,8-디플루오르-4-옥소-7-(1-옥소-옥타하이드로-1-티아-3,5-디아자-펜탈렌-5-일)-1,4-디하이드로-퀴놀린-3-카르복실산의 합성1-cyclopropyl-6,8-difluoro-4-oxo-7- (1-oxo-octahydro-1-thia-3,5-diaza-pentalen-5-yl) -1,4-di Synthesis of Hydro-Quinoline-3-carboxylic Acid

실시예 4에서 합성한 화합물(39㎎, 0.1밀리몰)을 메탄올 3㎖에 현탁시킨 뒤, 여기에 증류수 1㎖에 용해시킨 과산화요오드산나트륨(NaIO4, 23.5㎎, 0.11밀리몰)을 첨가하고, 0℃에서 8시간 동안 교반시켰다. 반응물을 여과한 뒤, 증류수로 세척하고 건조시켜 표제화합물을 33㎎(수율 81%)수득하였다.The compound (39 mg, 0.1 mmol) synthesized in Example 4 was suspended in 3 ml of methanol, and thereto was added sodium iodide peroxide (NaIO 4, 23.5 mg, 0.11 mmol) dissolved in 1 ml of distilled water, followed by 0 ° C. Stirred for 8 h. The reaction was filtered, washed with distilled water and dried to give 33 mg (yield 81%) of the title compound.

1H NMR(DMSO-d6, ppm): δ 8.65(1H, s), 7.8(1H, d), 4.3-4.0(5H, m), 4.0-3.6(2H, m), 3.2(2H, s), 1.15(4H, s) 1 H NMR (DMSO-d 6 , ppm): δ 8.65 (1H, s), 7.8 (1H, d), 4.3-4.0 (5H, m), 4.0-3.6 (2H, m), 3.2 (2H, s ), 1.15 (4H, s)

Mass(FAB, m/e): 410(M+H)Mass (FAB, m / e): 410 (M + H)

[실시예 7]Example 7

1-사이클로프로필-6-플루오르-7-(옥타하이드로-7-티아-2,4-디아자-인덴-2-일)-4-옥소-1,4-디하이드로[1,8]나프티리딘-3-카르복실산의 합성1-cyclopropyl-6-fluoro-7- (octahydro-7-thia-2,4-diaza-inden-2-yl) -4-oxo-1,4-dihydro [1,8] naphthyridine Synthesis of 3-carboxylic Acid

7-클로로-1-사이클로피로필-6-플루오로-4-옥소-1,4-디하이드로[1,8]나프티리딘-3 카르복실산(56㎎, 0.2밀리몰)과 옥타하이드로-7-티아-2,4-디아자-인덴 디트리플루오로아세트산염(74㎎, 0.2밀리몰)을 실시예 2와 동일한 방법으로하여 1시간동안 반응시켜 표제화합물을 43㎎(수율 55%)수득하였다.7-chloro-1-cyclopyrophil-6-fluoro-4-oxo-1,4-dihydro [1,8] naphthyridine-3 carboxylic acid (56 mg, 0.2 mmol) and octahydro-7- Thia-2,4-diaza-indene ditrifluoroacetic acid salt (74 mg, 0.2 mmol) was reacted for 1 hour in the same manner as in Example 2 to obtain 43 mg (yield 55%) of the title compound.

1H NMR(DMSO-d6, ppm): δ 8.55(1H, s), 7.75(1H, d), 4.2-4.0(3H, m), 3.8(1H, m), 3.4(2H, m), 3.2(2H, m), 2.75(2H, d), 2.3(1H, m), 1.2(2H, d), 1.05(2H, s) 1 H NMR (DMSO-d 6 , ppm): δ 8.55 (1H, s), 7.75 (1H, d), 4.2-4.0 (3H, m), 3.8 (1H, m), 3.4 (2H, m), 3.2 (2H, m), 2.75 (2H, d), 2.3 (1H, m), 1.2 (2H, d), 1.05 (2H, s)

Mass(FAB, m/e): 391(M+H)Mass (FAB, m / e): 391 (M + H)

[실시예 8]Example 8

1-(2,4-디플루오로페닐-)-6-플루오로-7-(옥타하이드로-7-티아-2,4-디아자-인덴-2-일)-4-옥소-1,4-디하이드로[1,8]나프티리딘-3-카르복실산의 합성1- (2,4-difluorophenyl-)-6-fluoro-7- (octahydro-7-thia-2,4-diaza-inden-2-yl) -4-oxo-1,4 Synthesis of Dihydro [1,8] naphthyridine-3-carboxylic Acid

7-클로로-1-(2,4-디플루오로페닐)-6-플루오로-4-옥소-1,4-디하이드로[1,8]나프티리딘-3-카르복실산(71㎎, 0.2밀리몰)과 옥타하이드로-7-티아-2,4-디아자-인덴 디트리플루오로아세트산염(74㎎, 0.2밀리몰)을 실시예 2와 동일한 방법으로하여 1시간동안 반응시켜 표제화합물을 41㎎(수율 45%)수득하였다.7-chloro-1- (2,4-difluorophenyl) -6-fluoro-4-oxo-1,4-dihydro [1,8] naphthyridine-3-carboxylic acid (71 mg, 0.2 Mmol) and octahydro-7-thia-2,4-diaza-indene ditrifluoroacetate (74 mg, 0.2 mmol) were reacted for 1 hour in the same manner as in Example 2 to obtain 41 mg of the title compound. (Yield 45%) was obtained.

1H NMR(DMSO-d6, ppm): δ 8.85(1H, s), 8.15(1H, d), 7.8(1H, dd), 7.6(1H, dd), 7.35(1H, dd), 4.3-4.05(3H, m), 3.8(1H, m), 3.45(2H, m), 3.2(2H, m), 2.8(2H, d), 2.3(1H, m) 1 H NMR (DMSO-d 6 , ppm): δ 8.85 (1H, s), 8.15 (1H, d), 7.8 (1H, dd), 7.6 (1H, dd), 7.35 (1H, dd), 4.3- 4.05 (3H, m), 3.8 (1H, m), 3.45 (2H, m), 3.2 (2H, m), 2.8 (2H, d), 2.3 (1H, m)

Mass(FAB, m/e): 463(M+H)Mass (FAB, m / e): 463 (M + H)

[실시예 9]Example 9

8-클로로-1-사이클로프로필-6-플루오르-4-(옥타하이드로-1-티아-3,5-디아자-펜탈렌-5-일)-4-옥소-1,4-디하이드로-퀴놀린-3-카르복실산의 합성8-chloro-1-cyclopropyl-6-fluoro-4- (octahydro-1-thia-3,5-diaza-pentalen-5-yl) -4-oxo-1,4-dihydro-quinoline Synthesis of 3-carboxylic Acid

8-클로로-1-사이클로피로필-6,7-디플루오로-4-옥소-1,4-디하이드로-퀴놀린-3-카르복실산(150㎎, 0.5밀리몰)과 옥타하이드로-1-티아-3,5-디아자-펜탈렌 디트리플루오로아세트산염(215㎎, 0.6밀리몰)을 실시예 4와 동일한 방법으로하여 2시간동안 반응시켜 표제화합물을 74㎎(수율 36%)수득하였다.8-Chloro-1-cyclopyrophyll-6,7-difluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (150 mg, 0.5 mmol) and octahydro-1-thia -3,5-diaza-pentalene ditrifluoroacetic acid salt (215 mg, 0.6 mmol) was reacted in the same manner as in Example 4 for 2 hours to obtain 74 mg (yield 36%) of the title compound.

1H NMR(DMSO-d6, ppm): δ 8.8(1H, s), 7.8(1H, d), 4.3-4.2(3H, m), 4.1(2H, m), 4.0-3.85(2H, m), 3.65(2H, m), 1.2-1.05(4H, m) 1 H NMR (DMSO-d 6 , ppm): δ 8.8 (1H, s), 7.8 (1H, d), 4.3-4.2 (3H, m), 4.1 (2H, m), 4.0-3.85 (2H, m ), 3.65 (2H, m), 1.2-1.05 (4H, m)

Mass(FAB, m/e): 410(M+H)Mass (FAB, m / e): 410 (M + H)

[실시예 10]Example 10

1-사이클로프로필-6-플루오르-7-(옥타하이드로-1-티아-3,5-디아자-펜탈렌-5-일)-4-옥소-1,4-디하이드로-퀴놀린-3-카르복실산의 합성1-cyclopropyl-6-fluoro-7- (octahydro-1-thia-3,5-diaza-pentalen-5-yl) -4-oxo-1,4-dihydro-quinoline-3-carr Synthesis of Acids

1-사이클로피로필-6,7-디플루오로-4-옥소-1,4-디하이드로-퀴놀린-3-카르복실산(133㎎, 0.5밀리몰)과 옥타하이드로-1-티아-3,5-디아자-펜탈렌 디트리플루오로아세트산염(215㎎, 0.6밀리몰)을 실시예 4와 동일한 방법으로하여 4시간동안 반응시켜 표제화합물을 60㎎(수율 32%)수득하였다.1-cyclopyrophyll-6,7-difluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (133 mg, 0.5 mmol) with octahydro-1-thia-3,5 Diaza-pentalene ditrifluoroacetate (215 mg, 0.6 mmol) was reacted for 4 hours in the same manner as in Example 4 to obtain 60 mg (yield 32%) of the title compound.

1H NMR(DMSO-d6, ppm): δ 8.7(1H, s), 7.85(1H, d), 7.55(1H, d), 4.3(3H, m), 4.05(2H, m), 4.0-3.8(1H, m), 3.6(1H, m), 3.5(2H, m), 1.2-1.1(4H, s) 1 H NMR (DMSO-d 6 , ppm): δ 8.7 (1H, s), 7.85 (1H, d), 7.55 (1H, d), 4.3 (3H, m), 4.05 (2H, m), 4.0- 3.8 (1H, m), 3.6 (1H, m), 3.5 (2H, m), 1.2-1.1 (4H, s)

Mass(FAB, m/e): 376(M+H)Mass (FAB, m / e): 376 (M + H)

[실시예 11]Example 11

시험관내(in vitro) 항균력 검정In vitro antibacterial activity assay

본 발명에 따른 화합물들의 유용성은 공지의 화합물인 오플록사신(ofloxa-cin)을 대조약제로하여 표준균주, 임상적으로 분리된 균주, 일부항생제에 내성을 갖는 균주에 대한 최소억제농도(Minimum Inhibitory Concentration; MIC, ㎍/㎖)를 구하여 평가하였다. 최소 억제 농도는 시험화합물을 2배 희석법에 의해 희석시킨 후 뮐러-힌톤 아가(Mueller-Hinton agar) 배지에 분산시킨 다음 ㎖당 107 CFU를 갖는 표준균주를 5㎕씩 접종하고 37℃에서 18시간동안 배양하여 구하였으며, 그 결과는 표 1에 나타내었다.The usefulness of the compounds according to the present invention is the minimum inhibitory concentration (Minimum Inhibitory) against standard strains, clinically isolated strains, strains resistant to some antibiotics using the known compound ofloxa-cin as a control agent Concentration (MIC, μg / ml) was obtained and evaluated. The minimum inhibitory concentration was obtained by diluting the test compound by a 2-fold dilution method, dispersing it in Mueller-Hinton agar medium, inoculating 5 μl of standard strain with 107 CFU / ml for 18 hours at 37 ° C. Cultures were obtained and the results are shown in Table 1.

[실시예 12]Example 12

급성 경구 독성시험Acute Oral Toxicity Test

본 발명에 따른 화합물중에서 화합물 1 및 2의 급성 경구독성을 조사하기 위해 화합물을 각기 다른 여러 농도로 함유하는 용액을 ICR 계통의 수컷 생쥐에게 체중 1㎏ 당 10㎖의 투약양으로 경구 투약하였다. 경구투여 후 치사율 및 7일 동안의 증상을 관측하고, 리츠필드-윌콕슨(Litchfield-Wilcoxon)방법에 따라 중독 치사량치(LD50, ㎍/㎏)를 계산하고 그 결과를 표 2에 나타내었다.In order to investigate the acute oral toxicity of Compounds 1 and 2 among the compounds according to the present invention, a solution containing the compound in various concentrations was orally administered to a male mouse of the ICR line at a dose of 10 ml / kg body weight. The mortality and symptoms for 7 days after oral administration were observed, and the poisoning lethal dose (LD50, μg / kg) was calculated according to the Litchfield-Wilcoxon method and the results are shown in Table 2.

Claims (11)

하기 일반식(Ⅰ)의 퀴놀린 카르복실산 유도체, 약학적으로 허용가능한 그의 염 및 그의 용매화물 ;Quinoline carboxylic acid derivatives of the general formula (I), pharmaceutically acceptable salts thereof and solvates thereof; 상기식에서, Q는 C-H, C-F, C-Cl, 또는 N이고, R1은 에틸, 사이클로프로필 또는 1개 이상의 불소원자로 치환된 페닐이며, R2는 수소, 메틸 또는 아미노이고, n은 0, 1 또는 2이며, R3는 수소 또는 C1-4알킬이고(단, n이 0일 때 R3는 수소가 아니다), R4는 C1-4알킬이거나, R3및 R4는 서로 연결되어 함께 C1-2알킬렌을 형성한다.Wherein Q is CH, CF, CC 1 , or N, R 1 is ethyl, cyclopropyl or phenyl substituted with one or more fluorine atoms, R 2 is hydrogen, methyl or amino, n is 0, 1 or 2 and, R 3 is hydrogen or C 1 - 4 alkyl (where, n is 0 when R3 is not hydrogen), or R 4 is C 1-4 alkyl, R 3 and R 4 are connected to each other with a C To form 1-2 alkylene. 제1항에 있어서, Q는 C-H, C-F, C-Cl, 또는 N이고, R1은 사이클로프로필 또는 2,4-디플루오로페닐이며, R2는 수소이고, n은 0, 1 또는 2이며, R3는 수소이고, R4는 메틸이거나, R3및 R4는 서로 연결되어 함께 C1-2알킬렌을 형성하는 화합물.The compound of claim 1, wherein Q is CH, CF, C-Cl, or N, R 1 is cyclopropyl or 2,4-difluorophenyl, R 2 is hydrogen, n is 0, 1 or 2 , R 3 is hydrogen, R 4 is methyl, or R 3 and R 4 are linked to each other to form C 1-2 alkylene. 제2항에 있어서, Q는 C-F이고, R1은 사이클로프로필이며, R2는 수소이고, n은 0, 1 또는 2이며, R3는 수소이고, R4는 메틸이거나, R3및 R4는 서로 연결되어 함께 C1-2알킬렌을 형성하는 화합물.The compound of claim 2, wherein Q is CF, R 1 is cyclopropyl, R 2 is hydrogen, n is 0, 1 or 2, R 3 is hydrogen, R 4 is methyl, or R 3 and R 4 Are compounds linked together to form C 1-2 alkylene together. 하기 일반식(Ⅱ)의 화합물을 용매중에서 산수용체의 존재하에 하기 일반식(Ⅲ)의 화합물 또는 R3가 수소인 경우 아미노기가 보호된 일반식(Ⅲ)의 화합물과 반응시킴을 특징으로하여 일반식(Ⅰ)의 화합물을 제조하는 방법 ;The compound of formula (II) is reacted with a compound of formula (III) wherein an amino group is protected when R 3 is hydrogen in the presence of an acid acceptor in a solvent A method for producing the compound of formula (I); 상기식에서, Q, R1, R2, n, R3, 및 R4는 제 1항에서 언급한 바와 같고, X는 할로겐을 나타낸다.Wherein Q, R 1 , R 2 , n, R 3 , and R 4 are as mentioned in claim 1, and X represents halogen. 제4항에 있어서, 일반식(Ⅲ)의 화합물은 염산, 브롬산, 또는 트리플루오로아세트산과의 염 형태로 사용됨을 특징으로 하는 방법.The process according to claim 4, wherein the compound of general formula (III) is used in the form of a salt with hydrochloric acid, bromic acid, or trifluoroacetic acid. 제4항에 있어서, 일반식(Ⅲ)의 화합물을 일반식(Ⅱ)의 화합물에 대해 동몰량 내지 10몰래량 사용함을 특징으로 하는 방법.The method according to claim 4, wherein the compound of formula (III) is used in an amount of from 10 to 10 sneak to the compound of formula (II). 제4항에 있어서, 용매는 아세토니트릴, 디메틸포름아미드, 디메틸설폭시드, 피리딘, 및 헥사메틸포스포아미드 중에서 선택됨을 특징으로 하는 방법.The method of claim 4 wherein the solvent is selected from acetonitrile, dimethylformamide, dimethylsulfoxide, pyridine, and hexamethylphosphoamide. 제4항에 있어서, 산수용체는 탄산수소나트륨, 탄산칼륨, 트리에틸아민, 디이소프로필에틸아민, 피리딘, N,N-디메틸아닐린, N,N-디메틸아미노피리딘, 1,8-디아자비사이클로[5,4,0]운데세-7-엔, 1,4-디아자비사이클로[2,2,2]옥탄 중에서 선택됨을 특징으로 하는 방법.5. The acid acceptor according to claim 4, wherein the acid acceptor is sodium hydrogen carbonate, potassium carbonate, triethylamine, diisopropylethylamine, pyridine, N, N-dimethylaniline, N, N-dimethylaminopyridine, 1,8-diazabicyclo [5,4,0] undec-7-ene, 1,4-diazabicyclo [2,2,2] octane. 제4항에 있어서, 아미노기가 보호된 일반식(Ⅲ)의 화합물은 하기 일반식(Ⅲ＇)의 형태이고 일반식(Ⅱ)의 화합물과 반응시킨 후에는 아미노보호기를 제거시킴을 특징으로하여 일반식(Ⅰ)의 화합물을 제조하는 방법 ;The compound of general formula (III) in which the amino group is protected is in the form of the following general formula (III '), and after reacting with the compound of general formula (II), the amino protecting group is removed. A method for producing the compound of formula (I); 상기식에서, R4는 제1항에서 언급한 바와 같고, P는 아미노보호기를 나타낸다.Wherein R 4 is as mentioned in claim 1 and P represents an aminoprotecting group. 활성물질로서 제1항에 따른 일반식(Ⅰ)의 화합물, 약제학적으로 허용가능한 그의 염, 또는 그의 용매화물을 함유함을 특징으로 하는 항균제 조성물.An antimicrobial composition comprising as an active substance a compound of formula (I) according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof. 제10항에 있어서, 활성물질을 단위 투약량내에 1 내지 100㎎함유량을 특징으로 하는 조성물.The composition of claim 10, wherein the active substance is contained in a unit dosage of 1 to 100 mg.
KR1019940016988A 1994-07-14 1994-07-14 Novel antibiotic quinoline derivatives and process for preparing thereof KR0131990B1 (en)

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