KR100377558B1 - Selective thrombin inhibitors with piperidine group - Google Patents

Selective thrombin inhibitors with piperidine group Download PDF

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KR100377558B1
KR100377558B1 KR10-1999-0004971A KR19990004971A KR100377558B1 KR 100377558 B1 KR100377558 B1 KR 100377558B1 KR 19990004971 A KR19990004971 A KR 19990004971A KR 100377558 B1 KR100377558 B1 KR 100377558B1
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carbon atoms
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piperidinyl
hydrogen
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KR20000055994A (en
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박태교
이태희
장혜경
권오환
박희동
김현성
유영준
윤미경
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주식회사 엘지생명과학
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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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine

Abstract

본 발명은 트롬빈 억제활성이 우수하고 경구투여가능한 화학식 1의 신규 트롬빈 억제제, 그의 제조방법 및 그를 유효성분으로 함유하는 혈액응고 예방 및 혈전증 치료용 약제학적 조성물에 관한 것이다:The present invention relates to a novel thrombin inhibitor of formula (1) having excellent thrombin inhibitory activity and oral administration, a method for preparing the same, and a pharmaceutical composition for preventing blood coagulation and thrombosis containing the same as an active ingredient:

상기식에서, R1은 수소, R2NCOCO-, RCO-, RSO2-, ROCO-, R2NCOCH2-, RNHSO2- 또는 ROSO2-이고, R은 수소, 탄소원자수 1∼8의 저급알킬, 탄소원자수 6∼10의 아릴, 탄소원자수 5∼12의 아릴알킬, 탄소원자수 4∼10의 헤테로아릴, 탄소원자수 5∼11의 헤테로아릴알킬 또는 탄소원자수 3∼8의 시클로알킬이며, R2는 수소, 불소, 염소, 브롬, 요오드, 하이드록시 또는 메톡시이고, X 및 X'은 각각 독립적으로 수소, 불소, 염소, 브롬, 요오드, 포르밀, 시아노, 하이드록시 또는 메톡시이며, n은 0, 1 또는 2이고, m은 1 또는 2이다.Wherein R 1 is hydrogen, R 2 NCOCO-, RCO-, RSO 2- , ROCO-, R 2 NCOCH 2- , RNHSO 2 -or ROSO 2- , R is hydrogen, lower alkyl having 1 to 8 carbon atoms , Aryl having 6 to 10 carbon atoms, arylalkyl having 5 to 12 carbon atoms, heteroaryl having 4 to 10 carbon atoms, heteroarylalkyl having 5 to 11 carbon atoms, or cycloalkyl having 3 to 8 carbon atoms, R 2 is Hydrogen, fluorine, chlorine, bromine, iodine, hydroxy or methoxy, X and X 'are each independently hydrogen, fluorine, chlorine, bromine, iodine, formyl, cyano, hydroxy or methoxy, n is 0, 1 or 2 and m is 1 or 2.

Description

피페리딘 작용기를 갖는 선택적 트롬빈 억제제{Selective thrombin inhibitors with piperidine group}Selective thrombin inhibitors with piperidine group

본 발명은 신규한 트롬빈 억제제(thrombin inhibitor)에 관한 것으로서, 더욱 상세하게는, 트롬빈 억제활성이 우수하고 경구투여가능한 화학식 1의 트롬빈 억제제, 그의 제조방법 및 그를 유효성분으로 함유하는 혈액응고 예방 및 혈전증 치료용 약제학적 조성물에 관한 것이다.The present invention relates to a novel thrombin inhibitor, and more particularly, to a thrombin inhibitor having a high thrombin inhibitory activity and orally administrable thereof, a method for preparing the same, and a blood clotting prevention and thrombosis containing the same as an active ingredient. The present invention relates to a therapeutic pharmaceutical composition.

[화학식 1][Formula 1]

상기식에서, R1은 수소, R2NCOCO-, RCO-, RSO2-, ROCO-, R2NCOCH2-, RNHSO2- 또는 ROSO2-이고, R은 수소, 탄소원자수 1∼8의 저급알킬, 탄소원자수 6∼10의 아릴, 탄소원자수 5∼12의 아릴알킬, 탄소원자수 4∼10의 헤테로아릴, 탄소원자수 5∼11의 헤테로아릴알킬 또는 탄소원자수 3∼8의 시클로알킬이며,Wherein R 1 is hydrogen, R 2 NCOCO-, RCO-, RSO 2- , ROCO-, R 2 NCOCH 2- , RNHSO 2 -or ROSO 2- , R is hydrogen, lower alkyl having 1 to 8 carbon atoms , Aryl having 6 to 10 carbon atoms, arylalkyl having 5 to 12 carbon atoms, heteroaryl having 4 to 10 carbon atoms, heteroarylalkyl having 5 to 11 carbon atoms, or cycloalkyl having 3 to 8 carbon atoms,

R2는 수소, 불소, 염소, 브롬, 요오드, 하이드록시 또는 메톡시이고,R 2 is hydrogen, fluorine, chlorine, bromine, iodine, hydroxy or methoxy,

X 및 X'은 각각 독립적으로 수소, 불소, 염소, 브롬, 요오드, 포르밀, 시아노, 하이드록시 또는 메톡시이며,X and X 'are each independently hydrogen, fluorine, chlorine, bromine, iodine, formyl, cyano, hydroxy or methoxy,

n은 0, 1 또는 2이고, m은 1 또는 2이다.n is 0, 1 or 2 and m is 1 or 2.

혈액응고 과정에는 여러가지 복잡한 효소반응이 관여하고 있는 것으로 알려져 있다. 혈액응고 과정의 마지막 단계는 프로트롬빈(prothrombin)을 트롬빈으로 전환하는 반응을 포함하고 있다. 이 단계에서 생성된 트롬빈은 혈소판을 활성화시키고, 섬유소원을 섬유소로 바꾸는 등의 역할을 수행하는데, 섬유소는 중합반응에 의해 고분자물질로 바뀌고, 활성화된 혈액인자 XⅢ에 의해 교차결합되어 불용성 응혈이 된다. 트롬빈은 또한 혈액응고 과정에 참여하는 혈액인자 Ⅴ 및 VⅢ을 활성화시키는 역할도 하여 혈액응고 반응을 더욱 가속화시킨다. 따라서, 트롬빈 억제제는 효과적인 항응혈제로 작용하는 동시에, 혈소판 활성을 억제하고 섬유소 생성 및 안정화를 방지할 수 있다. 따라서 오래전부터 트롬빈 활성을 억제할 수 있는 물질을 개발함으로써 혈액응고를 예방하고 각종 혈전증을 치료하고자 하는 방법이 모색되어 왔다.Many complex enzymatic reactions are known to be involved in the coagulation process. The final stage of the coagulation process involves the conversion of prothrombin to thrombin. Thrombin produced at this stage activates platelets, converts fibrinogen to fibrin, and the like. Fibrin is converted into a polymer by a polymerization reaction and crosslinked by activated blood factor XIII to become insoluble coagulation. Thrombin also acts to activate blood factors V and VIII, which participate in the coagulation process, further accelerating the coagulation response. Thus, thrombin inhibitors can act as effective anticoagulants, while inhibiting platelet activity and preventing fibrin production and stabilization. Therefore, there has been a search for a method for preventing blood coagulation and treating various thrombosis by developing a substance capable of inhibiting thrombin activity for a long time.

한편, 혈전으로 인한 여러가지 질병의 치료 뿐만 아니라 예방 차원의 항응혈제의 필요성이 대두됨에 따라, 주사제 이외에 사용이 간편한 경구투여용 트롬빈 억제제를 개발하고자 하는 노력이 활발히 진행되고 있다.On the other hand, as the need for preventive anticoagulant as well as the treatment of various diseases caused by blood clots has emerged, efforts are being actively made to develop thrombin inhibitors for oral administration that are easy to use in addition to injections.

효과적인 트롬빈 억제제로서 개발된 대표적인 화합물로는 첫째, 아릴설포닐아르기닌계 화합물인 화학식 1d의 아가트로반(Argatroban, Ki=1.9nM)을 들 수 있다 (미국특허 제 4258192 호 및 제 4201863 호).With representative compounds developed as effective thrombin inhibitors. First, there may be mentioned arylsulfonyl arginine-based compound, a half (Argatroban, K i = 1.9nM) to ahgateu of formula 1d (U.S. Patent No. 4,258,192 and No. 4,201,863 No.).

상기 화합물은 이미 1990년에 일본에서 주사용 제제로 상품화되었다(문헌[Biochemistry 1984, 23, 85-90]).The compound has already been commercialized as an injectable preparation in Japan in 1990 (Biochemistry 1984, 23, 85-90).

또한 트롬빈 억제제로서 벤즈아미딘계 아릴설포닐 화합물인 화학식 1e의 NAPAP도 개발되어 있는데, 이 화합물은 합성이 용이할 뿐만 아니라 효과적인 트롬빈 억제제임에도 불구하고(Ki=6.0nM) 선택성이 좋지 못하다는 문제점이 있다(문헌[J. Biol. Chem. 1991. 266, 20085-20093]).In addition, as a thrombin inhibitor, NAPAP of Formula 1e, a benzamidine-based arylsulfonyl compound, has been developed, which is not only easy to synthesize but also has a problem of poor selectivity despite being an effective thrombin inhibitor (K i = 6.0 nM). (J. Biol. Chem. 1991. 266, 20085-20093).

한편 선택성이 개선된 화학식 1f의 Ro46-6240 화합물이 강력한 트롬빈 억제제로서 보고되었는데(Ki=0.2nM), 이 화합물은 정맥주사용 제제로서 개발 가능성을 보여주고 있으나, 혈중 반감기가 짧아서 경구투여제로서의 개발 가능성은 없다(문헌[J. Med. Chem. 1994, 37, 3889-3901]).Meanwhile, Ro46-6240 compound of formula (1f) with improved selectivity has been reported as a potent thrombin inhibitor (K i = 0.2 nM). Although this compound has been shown to be developed as an intravenous infusion, it has a short half-life in blood and can be used as an oral administration. There is no possibility of development (J. Med. Chem. 1994, 37, 3889-3901).

경구투여가능하면서 효과적인 트롬빈 억제제로는 코바스(Corvas)사에서 개발한 화학식 1g의 CVS-1123이 있다(Ki=1.4nM).An orally administrable and effective thrombin inhibitor is CVS-1123 of Formula 1g, developed by Corvas Corporation (K i = 1.4 nM).

상기 화합물은 쥐에서 뿐만 아니라 개와 원숭이에서도 경구투여가 가능한 것으로 보고되었으나, 선택성이 저조한 것이 큰 단점이다(문헌[국제공개특허 제 WO 9315756 호 및 제 WO 9408941 호]).The compound has been reported to be orally administered in dogs and monkeys as well as in mice, but the lack of selectivity is a major drawback (WO 9315756 and WO 9408941).

한편, 엘리 릴리(Eli Lilly)사에서 개발한 화학식 1h의 화합물은 선택성과 경구흡수율이 저조하다는 단점을 갖는다(국제공개특허 제 WO 9523609 호).On the other hand, the compound of formula (1h) developed by Eli Lilly has a disadvantage that the selectivity and oral absorption is low (WO 9523609).

이에 본 발명자들은 트롬빈 억제활성이 우수할 뿐만 아니라 경구투여가 가능한 신규한 화합물을 개발하기 위한 연구를 집중적으로 수행해 온 결과, 상기 정의된 화학식 1의 화합물이 이러한 목적에 부합함을 확인하고 본 발명을 완성하기에 이르렀다.Therefore, the present inventors have intensively researched to develop novel compounds capable of oral administration as well as excellent thrombin inhibitory activity, and confirmed that the compound of Formula 1 as defined above meets these objectives. It was completed.

따라서, 본 발명의 목적은 첫째, 트롬빈 억제활성이 우수하고 경구투여가능한 화학식 1의 신규 트롬빈 억제제를 제공하는 것이고, 둘째, 상기 화합물을 제조하는 방법을 제공하는 것이며, 셋째, 상기 화합물을 유효성분으로 함유하는 혈액응고 예방 및 혈전증 치료용 약제학적 조성물을 제공하는 것이다.Accordingly, an object of the present invention is to provide a novel thrombin inhibitor of formula (1) which is excellent in thrombin inhibitory activity and orally administrable, and second, to provide a method for preparing the compound, and third, to convert the compound into an active ingredient. It is to provide a pharmaceutical composition for the prevention of blood clotting and thrombosis containing.

본 발명은 화학식 1의 화합물, 약제학적으로 허용되는 그의 염, 수화물, 용매화물 및 이성체을 제공한다:The present invention provides a compound of formula 1, pharmaceutically acceptable salts, hydrates, solvates and isomers thereof:

[화학식 1][Formula 1]

상기식에서, R1은 수소, R2NCOCO-, RCO-, RSO2-, ROCO-, R2NCOCH2-, RNHSO2- 또는 ROSO2-이고, R은 수소, 탄소원자수 1∼8의 저급알킬, 탄소원자수 6∼10의 아릴, 탄소원자수 5∼12의 아릴알킬, 탄소원자수 4∼10의 헤테로아릴, 탄소원자수 5∼11의 헤테로아릴알킬 또는 탄소원자수 3∼8의 시클로알킬이며,Wherein R 1 is hydrogen, R 2 NCOCO-, RCO-, RSO 2- , ROCO-, R 2 NCOCH 2- , RNHSO 2 -or ROSO 2- , R is hydrogen, lower alkyl having 1 to 8 carbon atoms , Aryl having 6 to 10 carbon atoms, arylalkyl having 5 to 12 carbon atoms, heteroaryl having 4 to 10 carbon atoms, heteroarylalkyl having 5 to 11 carbon atoms, or cycloalkyl having 3 to 8 carbon atoms,

R2는 수소, 불소, 염소, 브롬, 요오드, 하이드록시 또는 메톡시이고,R 2 is hydrogen, fluorine, chlorine, bromine, iodine, hydroxy or methoxy,

X 및 X'은 각각 독립적으로 수소, 불소, 염소, 브롬, 요오드, 포르밀, 시아노, 하이드록시 또는 메톡시이며,X and X 'are each independently hydrogen, fluorine, chlorine, bromine, iodine, formyl, cyano, hydroxy or methoxy,

n은 0, 1 또는 2이고, m은 1 또는 2이다.n is 0, 1 or 2 and m is 1 or 2.

상기 화합물중, R은 수소, 탄소원자수 1∼8의 저급알킬, 탄소원자수 6∼10의 아릴 또는 탄소원자수 5∼12의 아릴알킬이고, R2는 수소이며, X 및 X'은 수소인 화합물이 바람직하며, 그중에서도 R1은 RSO2-, R2NCOCH2- 또는 RNHSO2-이고, R은 수소, 탄소원자수 1∼3의 저급알킬, 탄소원자수 6의 아릴 또는 탄소원자수 5∼12의 아릴알킬이며, n은 1이고, m은 1인 화합물이 더욱 바람직하다. 상기 화합물중 대표적인 예로는,In the compound, R is hydrogen, lower alkyl having 1 to 8 carbon atoms, aryl having 6 to 10 carbon atoms or arylalkyl having 5 to 12 carbon atoms, R 2 is hydrogen, and X and X 'are hydrogen. Preferably, R 1 is RSO 2- , R 2 NCOCH 2 -or RNHSO 2- , R is hydrogen, lower alkyl of 1 to 3 carbon atoms, aryl of 6 carbon atoms or arylalkyl of 5 to 12 carbon atoms and more preferably, n is 1 and m is 1. Representative examples of the compound,

tert-부틸(1R)-1-벤즈히드릴-2-옥소-2-[2-({[2-(4-피페리디닐)에틸]아미노}카르보닐)-1-피롤리디닐]에틸카바메이트;tert-butyl (1R) -1-benzhydryl-2-oxo-2- [2-({[2- (4-piperidinyl) ethyl] amino} carbonyl) -1-pyrrolidinyl] ethylcarba Mate;

tert-부틸(1R)-1-벤즈히드릴-2-옥소-2-[2-({[2-(4-피페리디닐)에틸]아미노}카르보닐)-1-피페리디닐]에틸카바메이트;tert-butyl (1R) -1-benzhydryl-2-oxo-2- [2-({[2- (4-piperidinyl) ethyl] amino} carbonyl) -1-piperidinyl] ethylcarba Mate;

1-{(2R)-2-[(메틸설포닐)아미노]-3,3-디페닐프로파노일}-N-[2-(4-피페리디닐)에틸]-2-피롤리딘카르복사미드;1-{(2R) -2-[(methylsulfonyl) amino] -3,3-diphenylpropanoyl} -N- [2- (4-piperidinyl) ethyl] -2-pyrrolidinecar Radiation mid;

1-[(2R)-2-(벤질설포닐아미노)-3,3-디페닐프로파노일]-N-[2-(4-피페리디닐)에틸]-2-피롤리딘카르복사미드;1-[(2R) -2- (benzylsulfonylamino) -3,3-diphenylpropanoyl] -N- [2- (4-piperidinyl) ethyl] -2-pyrrolidinecarboxamide ;

tert-부틸(1R)-1-벤즈히드릴-2-옥소-2-[2-({[3-(4-피페리디닐)프로필]아미노}카르보닐)-1-피롤리디닐]에틸카바메이트;tert-butyl (1R) -1-benzhydryl-2-oxo-2- [2-({[3- (4-piperidinyl) propyl] amino} carbonyl) -1-pyrrolidinyl] ethylcarba Mate;

tert-부틸(1R)-1-벤즈히드릴-2-옥소-2-[2-({[3-(4-피페리디닐)프로필]아미노}카르보닐)-1-피페리디닐]에틸카바메이트;tert-butyl (1R) -1-benzhydryl-2-oxo-2- [2-({[3- (4-piperidinyl) propyl] amino} carbonyl) -1-piperidinyl] ethylcarba Mate;

tert-부틸(1R)-1-벤즈히드릴-2-옥소-2-{2-[3-(4-피페리디닐)프로파노일]-1-아제티디닐}에틸카바메이트;tert-butyl (1R) -1-benzhydryl-2-oxo-2- {2- [3- (4-piperidinyl) propanoyl] -1-azetidinyl} ethyl carbamate;

1-{(2R)-2-[(아닐리노설포닐)아미노]-3,3-디페닐프로파노일}-N-[2-(4-피페리디닐)에틸]-2-피롤리딘카르복사미드; 또는1-{(2R) -2-[(anilinosulfonyl) amino] -3,3-diphenylpropanoyl} -N- [2- (4-piperidinyl) ethyl] -2-pyrrolidine Carboxamides; or

1-((2R)-2-{[2-(디에틸아미노)-2-옥소에틸]아미노}-3,3-디페닐프로파노일)-N-[2-(4-피페리디닐)에틸]-2-피롤리딘카르복사미드를 들 수 있다.1-((2R) -2-{[2- (diethylamino) -2-oxoethyl] amino} -3,3-diphenylpropanoyl) -N- [2- (4-piperidinyl) Ethyl] -2-pyrrolidine carboxamide.

본 발명은 또한 (a) 화학식 2의 알라닌 유도체를 화학식 3의 프롤린 메틸에스테르 염산염 또는 그 유사체와 반응시켜 화학식 4의 에스테르 유도체를 수득하고,The present invention also relates to (a) reacting an alanine derivative of formula 2 with a proline methylester hydrochloride of formula 3 or an analog thereof to obtain an ester derivative of formula 4,

화학식 4의 에스테르 유도체를 가수분해하여 화학식 5의 카르복실산 유도체를 수득하고,Hydrolyzing the ester derivative of formula 4 to obtain a carboxylic acid derivative of formula 5,

화학식 5의 카르복실산 유도체를 화학식 6의 피페리딘 유도체와 커플링시켜 화학식 7의 화합물을 수득하고,Coupling a carboxylic acid derivative of formula 5 with a piperidine derivative of formula 6 to obtain a compound of formula 7,

화학식 7의 화합물을 직접 탈보호화하거나, 화학식 7의 화합물로부터 ROCO- 그룹을 제거하여 탈보호화하거나, 화학식 7의 화합물로부터 ROCO- 그룹을 제거하고 설포닐화 또는 아실화하여 탈보호화함으로써, 화학식 1a의 화합물을 수득하거나;A compound of formula 1a by deprotecting the compound of formula 7 directly, or by deprotection by removing the ROCO- group from the compound of formula 7, or by deprotection by removing the ROCO- group from the compound of formula 7 and sulfonylating or acylating To obtain;

(b) 화학식 8의 아제티딘 카르복실산 유도체를 화학식 6의 피페리딘 유도체와 커플링시켜 화학식 9의 화합물을 수득하고,(b) coupling the azetidine carboxylic acid derivative of formula 8 with a piperidine derivative of formula 6 to obtain a compound of formula 9,

화학식 9의 화합물로부터 ROCO- 그룹을 제거하고 화학식 2의 알라닌 유도체와 커플링시켜 화학식 10의 화합물을 수득하고,Removing the ROCO- group from the compound of formula 9 and coupling with an alanine derivative of formula 2 to obtain a compound of formula 10,

화학식 10의 화합물을 직접 탈보호화하거나, 화학식 10의 화합물로부터 ROCO- 그룹을 제거하여 탈보호화하거나, 화학식 10의 화합물로부터 ROCO- 그룹을 제거하고 설포닐화 또는 아실화하여 탈보호화함으로써, 화학식 1b의 화합물을 수득하거나;A compound of formula 1b by directly deprotecting the compound of formula 10, or by deprotection by removing the ROCO- group from the compound of formula 10, or by deprotection by removing the ROCO- group from the compound of formula 10 and sulfonylating or acylating To obtain;

(c) 화학식 4의 에스테르 유도체를 화학식 11의 아미드 유도체와 커플링시키고 가수분해하여 화학식 12의 화합물을 수득하고,(c) coupling and hydrolyzing the ester derivative of formula 4 with an amide derivative of formula 11 to obtain a compound of formula 12,

화학식 12의 화합물을 화학식 6의 피페리딘 유도체와 커플링시켜 ROCO- 그룹 을 제거하고 탈보호화함으로써, 화학식 1c의 화합물을 수득하는 것을 특징으로 하는, 제 1 항에 따른 화합물의 제조방법:A process for the preparation of a compound according to claim 1, characterized in that the compound of formula 12 is coupled with a piperidine derivative of formula 6 to remove and deprotect the ROCO— group, thereby obtaining a compound of formula 1c.

[화학식 1a][Formula 1a]

[화학식 1b][Formula 1b]

[화학식 1c][Formula 1c]

[화학식 2][Formula 2]

[화학식 3][Formula 3]

[화학식 4][Formula 4]

[화학식 5][Formula 5]

[화학식 6][Formula 6]

[화학식 7][Formula 7]

[화학식 8][Formula 8]

[화학식 9][Formula 9]

[화학식 10][Formula 10]

[화학식 11][Formula 11]

[화학식 12][Formula 12]

상기식에서, W는 수소, R2NCOCO-, RCO-, RSO2-, ROCO-, RNHSO2- 또는 ROSO2-이고, R은 상기에서 정의한 바와 동일하며, m 및 n'은 1 또는 2이다.Wherein W is hydrogen, R 2 NCOCO-, RCO-, RSO 2- , ROCO-, RNHSO 2 -or ROSO 2- , R is as defined above and m and n 'are 1 or 2.

본 발명은 또한 상기 화합물을 유효성분으로 함유하는 것을 특징으로 하는 혈액응고 예방 및 혈전증 치료용 약제학적 조성물을 제공한다. 상기 약제학적 조성물은 주사용 제제 또는 경구투여용 제제로 제형화되는 것이 바람직하다.The present invention also provides a pharmaceutical composition for preventing blood coagulation and thrombosis, characterized in that it contains the compound as an active ingredient. The pharmaceutical composition is preferably formulated as an injectable or oral preparation.

이하, 본 발명을 상세히 설명하면 하기와 같다.Hereinafter, the present invention will be described in detail.

본 명세서에서 저급알킬은 메틸, 에틸, 이소프로필, 이소부틸, t-부틸을 포함하는 직쇄 또는 측쇄알킬을 의미한다.Lower alkyl herein means straight or branched chain alkyl including methyl, ethyl, isopropyl, isobutyl, t-butyl.

본 명세서에서 사용되는 약어들은 아래 의미를 갖는 것으로 정의한다.Abbreviations used herein are defined to have the following meanings.

boc(또는 Boc): 부톡시카르보닐Ph: 페닐boc (or Boc): butoxycarbonylPh: phenyl

Me: 메틸Et: 에틸Me: Methyl Et: Ethyl

n-Pr: n-프로필Ac: 아세틸n-Pr: n-propylAc: acetyl

Ms: 메틸설포닐Bn: 벤질Ms: Methylsulfonyl Bn: Benzyl

diphe: 디페닐Ala: 알라닌diphe: diphenylAla: alanine

Pro: 프롤린Arg: 아르기닌Pro: Proline Arg: Arginine

Aze: L-2-아제티딘 카르복실산Pip : DL-피페콜산Aze: L-2-azetidine carboxylic acidPip: DL-Pipecolic acid

Cbz: 벤질옥시카르복실Cbz: benzyloxycarboxyl

또한, 본 명세서에서는 사용하는 시약을 아래의 약어로 기술하고자 한다.In addition, in the present specification, the reagent to be used is described by the following abbreviations.

DMF : 디메틸포름아미드DMF: Dimethylformamide

THF : 테트라하이드로푸란THF: Tetrahydrofuran

TEA : 트리에틸아민TEA: Triethylamine

DIPEA : 디이소프로필에틸아민DIPEA: Diisopropylethylamine

EDC : 1-(3-디메틸아미노프로필)-3-에틸카보디이미드 하이드로클로라이드EDC: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

HOBt : 하이드록시벤조트리아졸HOBt: hydroxybenzotriazole

DEAD : 디에틸 아조디카르복실레이트DEAD: diethyl azodicarboxylate

DPPA : 디페닐포스포릴 아지드DPPA: diphenylphosphoryl azide

NMM : N-메틸모르폴린NMM: N-methylmorpholine

TFA : 트리플루오로아세트산TFA: trifluoroacetic acid

본 발명에 따른 대표적인 화합물로는 표 1a 내지 1c에 나타낸 화합물들을 들 수 있다.Representative compounds according to the present invention include the compounds shown in Tables 1a to 1c.

본 발명에 따른 화학식 1의 화합물은 약제학적으로 허용되는 염을 형성할 수도 있다. 이러한 약제학적으로 허용되는 염에는 약제학적으로 허용되는 음이온을 함유하는 무독성 산부가염을 형성하는 산, 예를 들면 염산, 황산, 질산, 인산, 브롬화수소산, 요오드화수소산 등과 같은 무기산, 타르타르산, 포름산, 시트르산, 아세트산, 트리클로로아세트산, 트리플루오로아세트산, 글루콘산, 벤조산, 락트산,푸마르산, 말레인산 등과 같은 유기 카본산, 메탄설폰산, 벤젠설폰산, p-톨루엔설폰산 또는 나프탈렌설폰산 등과 같은 설폰산 등에 의해 형성된 산부가염이 포함된다.The compounds of formula 1 according to the invention may also form pharmaceutically acceptable salts. Such pharmaceutically acceptable salts include acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as inorganic acids, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, tartaric acid, formic acid, citric acid And organic carbon acids such as acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid and maleic acid, sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalenesulfonic acid, and the like. Acid addition salts formed by

한편 본 발명에 따른 화합물들은 비대칭 탄소중심을 가질 수 있으므로 라세미 화합물, 부분입체이성체 혼합물 및 개개의 부분입체이성체로서 존재할 수 있으며, 이들 모든 이성체 형태는 본 발명의 범위에 포함된다.On the other hand, the compounds according to the invention may have an asymmetric carbon center and therefore may exist as racemic compounds, diastereomeric mixtures and individual diastereomers, all of these isomeric forms are included within the scope of the invention.

본 발명은 또한 화학식 1의 화합물의 수화물, 용매화물 및 화학식 1의 화합물로 전환되는 프로드럭을 포함한다.The invention also includes hydrates, solvates of compounds of formula 1 and prodrugs that are converted to compounds of formula 1.

본 발명에서 화학식 1의 화합물을 제조하는 방법의 대표적인 예를 하기 반응식 1 내지 4에 나타내었다.Representative examples of the method for preparing the compound of Formula 1 in the present invention are shown in Schemes 1 to 4.

반응식 1은 D-(diphe)Ala-Pro-피페리딘 유도체 화합물 합성을 나타내고 있는것으로서, N-boc-D-(diphe)Ala-OH(화학식 2a)를 프롤린 메틸에스테르 염산염 또는 그 유사체(화학식 3)와 반응시켜 에스테르 유도체(화학식 4a)를 얻고 이를 가수분해하여 카르복실산 유도체(화학식 5a)를 얻는다. 이를 다시 피페리딘 유도체(화학식 6)와 커플링시켜 화학식 7a의 화합물을 얻는다. 화학식 7a의 화합물을 직접 탈보호화하면(즉, Cbz 그룹을 제거하면) 화학식 1a'의 최종화합물을 얻게 되고, 화학식 7a의 화합물에서 boc 그룹을 제거하여 화학식 7a'의 화합물을 얻은 다음 탈보호화하면 화학식 1a"의 최종화합물을 얻게 되며, 화학식 7a'의 화합물을 아실화 또는 설포닐화하여 얻은 화학식 7a"의 화합물을 탈보호화하면 화학식 1a"'의 최종화합물을 얻게 된다.Scheme 1 shows the synthesis of D- (diphe) Ala-Pro-piperidine derivative compound, wherein N-boc-D- (diphe) Ala-OH (Formula 2a) is converted to proline methyl ester hydrochloride or an analog thereof (Formula 3) ) To obtain an ester derivative (Formula 4a) and hydrolyze it to obtain a carboxylic acid derivative (Formula 5a). This is then coupled with the piperidine derivative (Formula 6) to obtain a compound of Formula 7a. Direct deprotection of the compound of Formula 7a (ie, removal of the Cbz group) yields the final compound of Formula 1a ', removal of the boc group from the compound of Formula 7a to obtain the compound of Formula 7a', followed by deprotection A final compound of Formula 1a "is obtained, and deprotection of the compound of Formula 7a" obtained by acylation or sulfonylation of the compound of Formula 7a 'gives a final compound of Formula 1a "'.

반응식 2는 화학식 6의 피페리딘 유도체의 합성을 나타내는 것인데, 4-피리딘카르복사알데히드를 디메틸 말로네이트와 반응시키고 이것을 수소화 반응시키고(Boc)2O로 보호한다. 이것을 염화나트륨과 물과 반응시키고 이것으로부터 Boc 그룹을 Cbz 그룹으로 전환하여 가수분해하여 카르복실산 유도체를 얻는다. 이것을 DPPA, TEA와 반응시켜(방법 A 또는 B) 피페리딘 유도체 화합물을 얻거나, 이것을 알콜 유도체로 변환시킨 후 프탈이미드 유도체를 거쳐 피페리딘 유도체 화합물을 얻게 된다.Scheme 2 illustrates the synthesis of piperidine derivatives of formula 6, wherein 4-pyridinecarboxaldehyde is reacted with dimethyl malonate, which is hydrogenated (Boc) and protected with 2 O. This is reacted with sodium chloride and water and from this the Boc group is converted to Cbz group and hydrolyzed to obtain a carboxylic acid derivative. This is reacted with DPPA, TEA (Method A or B) to obtain a piperidine derivative compound or to convert it to an alcohol derivative followed by a phthalimide derivative to obtain a piperidine derivative compound.

반응식 3은 D-(diphe)Ala-Aze-피페리딘 유도체 화합물 합성을 나타내고 있는 것으로서, 먼저 N-boc-Aze(화학식 8b)를 피페리딘 유도체(화학식 6b)와 커플링시켜 화학식 9b의 화합물을 얻은 후, boc 그룹을 제거하고 N-boc-D-(diphe)Ala-OH(화학식 2a)와 커플링시켜 화학식 10b의 화합물을 얻는다. 화학식 10b의 화합물에서 Cbz 그룹을 제거하여 화학식 1b'의 최종화합물을 얻는다.Scheme 3 shows the synthesis of D- (diphe) Ala-Aze-piperidine derivative compound, wherein N-boc-Aze (Formula 8b) is coupled with a piperidine derivative (Formula 6b) to give a compound of Formula 9b. After obtaining the boc group is removed and coupled with N-boc-D- (diphe) Ala-OH (Formula 2a) to obtain a compound of formula (10b). The Cbz group is removed from the compound of Formula 10b to obtain the final compound of Formula 1b '.

반응식 4는 알킬 유도체를 도입한 화합물의 합성을 나타내고 있는 것으로서, 먼저 N-Boc-(diphe)Ala-Pro-OMe(화학식 4a)를 브로모아세틸 디에틸아미드(화학식 11c)와 커플링시켜 화학식 12c의 화합물을 얻고, 이를 가수분해하여 화학식 6b의 피페리딘 유도체와 커플링시킨 후 boc 그룹과 Cbz 그룹을 제거하여 화학식 1c'의 최종화합물을 얻는다.Scheme 4 illustrates the synthesis of a compound incorporating an alkyl derivative. First, by coupling N-Boc- (diphe) Ala-Pro-OMe (Formula 4a) with bromoacetyl diethylamide (Formula 11c), To obtain a compound of the compound of the formula 6b is hydrolyzed and coupled with the piperidine derivative of formula 6b and the boc group and the Cbz group is removed to obtain a final compound of formula (1c ').

아미노 그룹의 커플링 반응을 위해 사용될 수 있는 공지의 커플링 시약에는 디사이클로헥실카보디이미드(DCC), 1-(3-디메틸아미노프로필)-3-에틸카보디이미드 (EDC), 비스-(2-옥소-3-옥사졸리디닐)-포스핀산 클로라이드(BOP-Cl), 디페닐포스포릴아지드(DPPA), 이소부틸클로로포메이트 등이 포함되나, 이들로 제한되는 것은 아니다.Known coupling reagents that can be used for the coupling reaction of amino groups include dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC), bis- ( 2-oxo-3-oxazolidinyl) -phosphinic acid chloride (BOP-Cl), diphenylphosphoryl azide (DPPA), isobutylchloroformate and the like, but are not limited to these.

상기 언급한 바와 같이 본 발명에 따른 화학식 1의 화합물은 공지의 화합물들에 비해 트롬빈 억제활성이 우수하며 경구투여가 가능하다. 따라서 본 발명의 화합물은 혈액응고 예방 및 혈전증의 치료에 유용한 바, 본 발명은 화학식 1의 화합물을 유효성분으로 함유하는 혈액응고 예방 및 혈전증 치료용 약제학적 조성물을 제공한다.As mentioned above, the compound of Formula 1 according to the present invention is superior in thrombin inhibitory activity and known to be orally administered as compared with known compounds. Therefore, the compound of the present invention is useful for the prevention of blood coagulation and treatment of thrombosis. The present invention provides a pharmaceutical composition for preventing blood coagulation and thrombosis containing the compound of Formula 1 as an active ingredient.

본 발명의 화합물을 임상적인 목적으로 투여시에 숙주에게 투여되는 총 1일 용량은 단일용량 또는 분리용량으로 체중 1kg 당 0.001∼10mg이 바람직하나, 특정 환자에 대한 특이 용량 수준은 사용될 특정 화합물, 체중, 성, 건강상태, 식이, 투여시간, 투여방법, 배설율, 약제혼합 및 질환의 중증도에 따라 변화될 수 있다.The total daily dose administered to the host when administering a compound of the present invention for clinical purposes is preferably from 0.001 to 10 mg / kg body weight in a single dose or in separate doses, but the specific dose level for a particular patient is determined by the specific compound, body weight to be used. May vary with sex, health status, diet, time of administration, method of administration, rate of excretion, drug mixture and severity of disease.

본 발명의 화합물은 목적하는 바에 따라 주사용 제제 또는 경구투여용 제제로 투여될 수 있다. 주사용 제제, 예를 들면 멸균 주사용 수성 또는 유성 현탁액은 공지의 기술에 따라 적합한 분산제, 습윤제 또는 현탁제를 사용하여 제조될 수 있다. 사용가능한 용매에는 물, 링거액 또는 등장성 NaCl 용액이 있으며, 멸균 고정 오일은 통상적으로 용매 또는 현탁매질로서 사용된다. 모노, 디글리세라이드를 포함하여 어떠한 무자극성 고정오일도 이러한 목적으로 사용될 수 있으며, 올레산과 같은 지방산은 주사용 제제에 사용된다. 경구투여용 고체 투여형태는 캅셀제, 정제, 환제, 산제 또는 입제가 가능하고, 특히 캅셀제와 정제가 유용하다. 정제 및 환제는 장피제로 제조하는 것이 바람직하다. 고체 투여형태에는 본 발명에 따른 화학식 1의 화합물을 슈크로스, 락토오스, 전분 등과 같은 하나 이상의 불활성 희석제 및 마그네슘 스테아레이트와 같은 윤활제, 붕해제, 결합제 등과 같은 담체와 혼합시킴으로써 제조될 수 있다.The compounds of the present invention can be administered in preparations for injection or oral administration as desired. Injectable preparations, for example sterile injectable aqueous or oleaginous suspensions, can be prepared using suitable dispersing agents, wetting agents or suspending agents according to the known art. Solvents that can be used include water, Ringer's solution or isotonic NaCl solution, and sterile fixed oils are commonly used as a solvent or suspending medium. Any non-irritating fixed oil may be used for this purpose, including mono, diglycerides, and fatty acids such as oleic acid are used in the preparation of injectables. Solid dosage forms for oral administration may be capsules, tablets, pills, powders, or granules, and capsules and tablets are particularly useful. Tablets and pills are preferably prepared with enteric agents. Solid dosage forms can be prepared by mixing the compound of formula 1 according to the invention with one or more inert diluents such as sucrose, lactose, starch and the like and carriers such as lubricants such as magnesium stearate, disintegrants, binders and the like.

본 발명에 따른 화학식 1의 화합물의 특장점중의 하나는 이를 함유하는 약제학적 조성물을 경구투여용 제제로 제형화하여 경구투여하는 경우에도 약효를 나타낸다는 점으로서, 이러한 사실은 쥐를 실험동물로 하여 약물동력학 실험을 수행한 결과 본 발명의 약제학적 조성물을 경구로 투여한 경우 약물의 농도가 혈중에서 장기간 유지되는 특성이 있음을 확인함으로써 입증된다. 따라서, 본 발명의 화합물은 기존의 트롬빈 억제제와는 달리 경구투여용 제제로서 유효하게 사용될 수 있다는 점에서 더욱 유용하다.One of the advantages of the compound of Formula 1 according to the present invention is that the pharmaceutical composition containing the same has an effect even when formulated orally administered by oral administration. The results of pharmacokinetic experiments demonstrate that oral administration of the pharmaceutical composition of the present invention confirms that the concentration of the drug is characterized by long-term maintenance in the blood. Therefore, the compound of the present invention is more useful in that it can be effectively used as a preparation for oral administration, unlike conventional thrombin inhibitors.

한편, 본 발명의 화합물을 임상적으로 투여함으로써 목적하는 항응혈 효과 및 혈전용해 효과를 얻고자 하는 경우, 본 발명에 따른 화학식 1의 화합물은 혈전 용해제 및 혈소판 활성 억제제 중에서 선택된 1종 이상의 성분과 동시에 투여될 수 있다. 본 발명의 화합물과 혼합하여 투여될 수 있는 혈전용해제로는 티피에이(t-PA), 유로키나아제(Urokinase), 스트렙토키나아제(Streptokinase) 등이 포함될 수 있으며, 혈소판 활성 억제제는 아스피린, 티클로피딘(Ticlopidin), 클로피드로겔(Clopidrogel), 7E3 단일항체 등이 포함된다. 그러나, 혈전증의 치료 및 예방을 목적으로 본 발명에 따른 화합물을 함유하는 제제는 상기한 것으로 제한되는 것은 아니며, 혈전증의 치료 및 예방에 유용한 제제라면 어떠한 것도 포함될 수 있다.On the other hand, in the case of obtaining the desired anticoagulant effect and thrombolytic effect by clinically administering the compound of the present invention, the compound of the formula (1) according to the present invention simultaneously with at least one component selected from thrombolytic agents and platelet activity inhibitors May be administered. Thrombolytic agents that can be administered in combination with a compound of the present invention may include t-PA, urokinase, streptokinase, and the like, and platelet activity inhibitors include aspirin, ticlopidin , Clopidrogel, 7E3 monoantibody, and the like. However, preparations containing the compounds according to the invention for the purpose of the treatment and prevention of thrombosis are not limited to those described above, and any preparations useful for the treatment and prevention of thrombosis may be included.

[실시예]EXAMPLE

본 발명은 하기 실시예 및 실험예에 의해 더욱 구체적으로 설명되나, 본 발명의 범위가 이들에 의해 어떤 식으로든 제한되는 것은 아니다.The present invention is explained in more detail by the following examples and experimental examples, but the scope of the present invention is not limited in any way by these.

[제조예][Production example]

[제조예 1-1] (2S)-1-{(2R)-2-[(tert-부톡시카르보닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복실산의 합성Production Example 1-1 (2S) -1-{(2R) -2-[(tert-butoxycarbonyl) amino] -3,3-diphenylpropanoyl} -2-pyrrolidinecarboxyl Acid synthesis

Boc-D-(diphe)Ala-OH(3.01g, 8.82밀리몰), 프롤린 메틸에스테르 하이드로클로라이드(1.75g, 1.2당량), EDC(2.54g, 1.5당량), HOBt(1.79g, 1.5당량)를 약 40㎖의 DMF에 용해시키고 0℃를 유지한 다음 TEA(4.92㎖, 4.0당량)를 가해준 후 하루동안 상온에서 교반하였다. 저압에서 농축하고 잔류물을 에틸아세테이트에 용해시킨 후 통상적인 방법으로 추출-건조-농축하였다. 관 크로마토그래피(30% 에틸아세테이트/헥산)를 사용하여 분리-정제하여 3.88g(수율: 97%)의 표제 화합물을 담황색의 오일로 얻었다.Boc-D- (diphe) Ala-OH (3.01 g, 8.82 mmol), proline methylester hydrochloride (1.75 g, 1.2 equiv), EDC (2.54 g, 1.5 equiv), HOBt (1.79 g, 1.5 equiv) approx. The solution was dissolved in 40 ml of DMF, maintained at 0 ° C., and then stirred at room temperature for one day after adding TEA (4.92 ml, 4.0 equiv). Concentrated at low pressure and the residue was dissolved in ethyl acetate and then extracted-dried-condensed by conventional methods. Separation-purification using column chromatography (30% ethyl acetate / hexanes) gave 3.88 g (yield: 97%) of the title compound as a pale yellow oil.

상기 수득한 화합물을 혼합용매(THF:MeOH:H2O=3:2:1) 50㎖에 용해시키고 리튬하이드록사이드(0.51g, 1.4당량)를 가해주어 3시간 동안 상온에서 교반하였다. 6N HCl(2.2㎖)로 중화한 후 저압에서 농축하고, 잔류물을 에틸아세테이트에 용해시킨 후 통상적인 방법으로 추출-건조-농축하여 3.76g의 표제 화합물을 백색 분말로 정량적으로 얻었다.The obtained compound was dissolved in 50 ml of a mixed solvent (THF: MeOH: H 2 O = 3: 2: 1), and lithium hydroxide (0.51 g, 1.4 equivalents) was added thereto, followed by stirring at room temperature for 3 hours. Neutralized with 6N HCl (2.2 mL), concentrated at low pressure, the residue was dissolved in ethyl acetate and extracted-dried-concentrated by conventional method to yield 3.76 g of the title compound as a white powder quantitatively.

1H-NMR (CDCl3, 500MHz) δ 7.30-7.15 (m, 10H), 5.12 (m, 2H), 4.36 (m,1H), 4.14 (m, 1H), 3.75 (m, 1H), 2.70 (m, 1H), 2.22 (m, 1H), 1.81 (m, 1H), 1.53 (m, 1H), 1.33 (s, 9H). 1 H-NMR (CDCl 3 , 500 MHz) δ 7.30-7.15 (m, 10H), 5.12 (m, 2H), 4.36 (m, 1H), 4.14 (m, 1H), 3.75 (m, 1H), 2.70 ( m, 1H), 2.22 (m, 1H), 1.81 (m, 1H), 1.53 (m, 1H), 1.33 (s, 9H).

[제조예 1-2] (2S)-1-{(2R)-2-[(tert-부톡시카르보닐)아미노]-3,3-디페닐프로파노일}-2-피페리딘카르복실산(부분입체이성체)의 합성Production Example 1-2 (2S) -1-{(2R) -2-[(tert-butoxycarbonyl) amino] -3,3-diphenylpropanoyl} -2-piperidinecarboxyl Synthesis of Acids (Diastereoisomers)

제조예 1-1과 유사한 방법으로 표제 화합물을 얻었다.The title compound was obtained in a similar manner to Preparation Example 1-1.

1H-NMR (CDCl3, 500MHz) δ 7.38-7.19 (m, 10H), 5.55-5.04 (m, 2H), 5.19 ( m, 0.5H), 4.61 (m, 0.5H), 4.44 (m, 1H), 4.01 및 3.83 (br d, 1H), 3.09 및 2.50 (m, 1H), 2.16 및 1.88 (m, 1H), 1.69-1.20 (m, 14H). 1 H-NMR (CDCl 3 , 500 MHz) δ 7.38-7.19 (m, 10H), 5.55-5.04 (m, 2H), 5.19 (m, 0.5H), 4.61 (m, 0.5H), 4.44 (m, 1H ), 4.01 and 3.83 (br d, 1H), 3.09 and 2.50 (m, 1H), 2.16 and 1.88 (m, 1H), 1.69-1.20 (m, 14H).

[제조예 2-1] 디메틸 2-(4-피리디닐메틸렌)말로네이트의 합성Preparation Example 2-1 Synthesis of Dimethyl 2- (4-pyridinylmethylene) malonate

4-피리딘카르복사알데히드(21.4g, 0.2몰), 디메틸 말로네이트(26.4g, 0.2몰), 피페리딘(1.70g, 0.1당량), 아세트산(0.60g, 0.05당량)을 벤젠 250㎖에 용해시킨 후 딘스탁으로 물을 제거하면서 20시간동안 환류하였다. 100㎖의 에틸아세테이트에 용해시킨 후 포화 중탄산나트륨, 포화 염화나트륨으로 세척하고 건조-감압농축하였다. 이것을 관 크로마토그래피(20% 에틸아세테이트-헥산-55% 에틸아세테이트-헥산)하여 분리-정제하여 38.5g(수율: 87%)의 표제 화합물을 백색 결정으로 얻었다.4-pyridinecarboxaldehyde (21.4 g, 0.2 mole), dimethyl malonate (26.4 g, 0.2 mole), piperidine (1.70 g, 0.1 equiv) and acetic acid (0.60 g, 0.05 equiv) dissolved in 250 ml of benzene The mixture was refluxed for 20 hours while removing water with Dean Stark. After dissolving in 100 ml of ethyl acetate, the mixture was washed with saturated sodium bicarbonate and saturated sodium chloride, and then concentrated under reduced pressure. This was purified by column chromatography (20% ethyl acetate-hexane-55% ethyl acetate-hexane) to obtain 38.5 g (yield: 87%) of the title compound as white crystals.

1H-NMR (CDCl3, 500MHz) δ 8.65 (m, 2H), 7.68 (s, 1H), 7.25 (m, 2H), 3.86 (s, 3H), 3.83 (s, 3H). 1 H-NMR (CDCl 3 , 500 MHz) δ 8.65 (m, 2H), 7.68 (s, 1H), 7.25 (m, 2H), 3.86 (s, 3H), 3.83 (s, 3H).

[제조예 2-2] 디메틸 2-{[1-(tert-부톡시카르보닐)-4-피페리디닐]메틸}말로네이트의 합성Preparation Example 2-2 Synthesis of Dimethyl 2-{[1- (tert-butoxycarbonyl) -4-piperidinyl] methyl} malonate

제조예 2-1의 화합물(22g, 99.5밀리몰)을 아세트산(10㎖)과 메탄올(150㎖)에 용해시킨 후 PtO2(1.03g)를 가하고 파 하이드로지네이터(Parr Hydrogenator)에서 55-70psi의 수소 기압하에서 24시간동안 교반하였다. 셀라이트를 통과시킨 후 메탄올로 세척하고 농축하여 얻은 오일을 물 200㎖-디옥산 50㎖에 용해시킨 후 탄산나트륨(29.1g, 0.274몰)과 (Boc)2O(23.9g, 1.1당량)을 가하고 2시간동안 상온에서 교반하였다. 감압하에서 농축하여 생성된 잔류물을 에틸아세테이트(300㎖×3)에 용해시킨 후 포화 중탄산나트륨, 포화 염화나트륨으로 세척하고 건조-감압농축하였다. 이것을 관 크로마토그래피(15% 에틸아세테이트-헥산)로 분리-정제하여 32.3g(수율: 99%)의 표제 화합물을 황색 오일로 얻었다.After dissolving the compound of Preparation Example 2-1 (22 g, 99.5 mmol) in acetic acid (10 mL) and methanol (150 mL), PtO 2 (1.03 g) was added, and 55-70 psi was added in Parr Hydrogenator. Stirred for 24 hours under hydrogen atmosphere. After passing through celite, washing with methanol and concentrating, the oil obtained was dissolved in 200 ml of water-50 ml of dioxane, and sodium carbonate (29.1 g, 0.274 mol) and (Boc) 2 O (23.9 g, 1.1 equiv) were added thereto. Stir at room temperature for 2 hours. The residue produced by concentration under reduced pressure was dissolved in ethyl acetate (300 mL × 3), washed with saturated sodium bicarbonate, saturated sodium chloride, and concentrated under reduced pressure. This was separated-purified by column chromatography (15% ethyl acetate-hexane) to give 32.3 g (yield: 99%) of the title compound as a yellow oil.

1H-NMR (CDCl3, 500MHz) δ 4.09 (bs, 2H), 3.73 (s, 6H), 3.46 (t, J=7.4Hz, 1H), 2.64 (bs, 2H), 1.85 (t, J=6.9Hz, 2H), 1.64 (m, 3H), 1.43 (s, 9H), 1.10 (m, 2H). 1 H-NMR (CDCl 3 , 500 MHz) δ 4.09 (bs, 2H), 3.73 (s, 6H), 3.46 (t, J = 7.4 Hz, 1H), 2.64 (bs, 2H), 1.85 (t, J = 6.9 Hz, 2H), 1.64 (m, 3H), 1.43 (s, 9H), 1.10 (m, 2H).

[제조예 2-3] tert-부틸 4-(3-메톡시-3-옥소프로필)-1-피페리딘카르복실레이트의 합성Preparation Example 2-3 Synthesis of tert-Butyl 4- (3-methoxy-3-oxopropyl) -1-piperidinecarboxylate

제조예 2-2의 화합물(25.1g, 76.2밀리몰)을 물(2.74g, 2.0당량)과 디메틸설폭사이드 50㎖에 용해시킨 후 염화나트륨(5.34g, 1.2당량)을 가하고 3시간동안 환류하였다. 에틸아세테이트-헥산(1:1, 300㎖×3)으로 추출하고 물(200㎖×2), 포화 염화나트륨으로 세척하고 건조-감압농축하였다. 이것을 관 크로마토그래피(12% 에틸아세테이트-헥산)으로 분리-정제하여 16.25g(수율: 72%)의 표제 화합물을 황색 오일로 얻었다.The compound of Preparation Example 2-2 (25.1 g, 76.2 mmol) was dissolved in water (2.74 g, 2.0 equivalents) and 50 ml of dimethyl sulfoxide, followed by addition of sodium chloride (5.34 g, 1.2 equivalents) and refluxed for 3 hours. Extracted with ethyl acetate-hexane (1: 1, 300 mL × 3), washed with water (200 mL × 2), saturated sodium chloride and concentrated to dryness-decompression. This was separated-purified by column chromatography (12% ethyl acetate-hexane) to give 16.25 g (yield: 72%) of the title compound as a yellow oil.

1H-NMR (CDCl3, 500MHz) δ 4.03 (bs, 2H), 3.62 (s, 3H), 2.61 (bs, 2H), 2.28 (t, J=7.4Hz, 2H), 1.62-1.31 (m, 5H), 1.43 (s, 9H). 1.03 (m, 2H). 1 H-NMR (CDCl 3 , 500 MHz) δ 4.03 (bs, 2H), 3.62 (s, 3H), 2.61 (bs, 2H), 2.28 (t, J = 7.4 Hz, 2H), 1.62-1.31 (m, 5H), 1.43 (s, 9H). 1.03 (m, 2 H).

[제조예 2-4] 벤질 4-(3-메톡시-3-옥소프로필)-1-피페리딘카르복실레이트의 합성Preparation Example 2-4 Synthesis of Benzyl 4- (3-methoxy-3-oxopropyl) -1-piperidinecarboxylate

제조예 2-3의 화합물(11.25g, 41.5밀리몰)을 40㎖의 CH2Cl2에 용해시킨 후 0℃에서 TFA 20㎖를 가하고 1시간동안 교반하였다. 감압하에서 농축한 후 얻은 잔류물을 에틸아세테이트에 용해시키고 포화 중탄산나트륨, 포화 염화나트륨으로 세척하고 건조-감압농축하였다. 이로부터 얻은 오일을 물 100㎖-디옥산 25㎖에 용해시킨 후 0℃에서 탄산나트륨(4.4g, 1.0당량)과 CbzCl(6.5㎖, 1.1당량)을 가하고 2시간동안 서서히 온도를 상온으로 상승시키면서 교반하였다. 감압하에서 농축하여 얻은 잔류물을 에틸아세테이트(300㎖)에 용해시킨 후, 포화 중탄산나트륨, 포화 염화나트륨으로 세척하고 건조-감압농축하였다.The compound of Preparation Example 2-3 (11.25 g, 41.5 mmol) was dissolved in 40 mL of CH 2 Cl 2 , and then 20 mL of TFA was added at 0 ° C. and stirred for 1 hour. The residue obtained after concentration under reduced pressure was dissolved in ethyl acetate, washed with saturated sodium bicarbonate, saturated sodium chloride and concentrated to dry-pressure. The oil thus obtained was dissolved in 100 ml of water-25 ml of dioxane, and sodium carbonate (4.4 g, 1.0 equivalent) and CbzCl (6.5 ml, 1.1 equivalent) were added at 0 ° C., and the mixture was slowly stirred for 2 hours while the temperature was raised to room temperature. It was. The residue obtained by concentration under reduced pressure was dissolved in ethyl acetate (300 mL), washed with saturated sodium bicarbonate, saturated sodium chloride, and concentrated under reduced pressure.

1H-NMR (CDCl3, 500MHz) δ 7.36-7.28 (m, 5H), 5.11 (s, 2H), 4.16 (bs, 2H), 3.67 (s, 3H), 2.74 (bs, 2H), 2.33 (t, J=7.4Hz, 2H), 1.72-1.55 (m, 4H), 1.43 (m, 1H), 1.10 (m, 2H). 1 H-NMR (CDCl 3 , 500 MHz) δ 7.36-7.28 (m, 5H), 5.11 (s, 2H), 4.16 (bs, 2H), 3.67 (s, 3H), 2.74 (bs, 2H), 2.33 ( t, J = 7.4 Hz, 2H), 1.72-1.55 (m, 4H), 1.43 (m, 1H), 1.10 (m, 2H).

[제조예 2-5] 3-{1-[(벤질옥시)카르보닐]-4-피페리디닐}프로피온산의 합성Preparation Example 2-5 Synthesis of 3- {1-[(benzyloxy) carbonyl] -4-piperidinyl} propionic acid

제조예 2-4의 화합물을 THF(230㎖)에 용해시키고 1N NaOH(57㎖, 1.5당량)을 가하고 상온에서 3시간동안 교반하였다. 6N HCl로 중화한 후 감압하에서 농축하여얻은 잔류물을 에틸아세테이트(300㎖)에 용해시키고 포화 염화나트륨으로 세척하여 건조-감압농축하였다. 이것을 관 크로마토크래피(20% 에틸아세테이트/헥산-에틸아세테이트)로 분리-정제하여 9.36g(제조예 2-4 내지 2-5의 총수율: 77%)을 황색 오일로 얻었다.The compound of Preparation Example 2-4 was dissolved in THF (230 mL), 1N NaOH (57 mL, 1.5 equiv) was added, and the mixture was stirred at room temperature for 3 hours. The residue obtained by neutralization with 6N HCl and then concentrated under reduced pressure was dissolved in ethyl acetate (300 mL), washed with saturated sodium chloride, and concentrated to dryness under reduced pressure. This was purified by column chromatography (20% ethyl acetate / hexane-ethyl acetate) to give 9.36 g (total yield: 77% of Production Examples 2-4 to 2-5) as a yellow oil.

1H-NMR (CDCl3, 500MHz) δ 7.35-7.29 (m, 5H), 5.11 (s, 2H), 4.19 (bs, 2H), 2.75 (bs, 2H), 2.38 (t, J=7.3Hz, 2H), 1.68 (bs, 2H), 1.60 (t, J=7.3Hz, 2H), 1.45 (m, 1H), 1.12 (bs, 2H). 1 H-NMR (CDCl 3 , 500 MHz) δ 7.35-7.29 (m, 5H), 5.11 (s, 2H), 4.19 (bs, 2H), 2.75 (bs, 2H), 2.38 (t, J = 7.3 Hz, 2H), 1.68 (bs, 2H), 1.60 (t, J = 7.3 Hz, 2H), 1.45 (m, 1H), 1.12 (bs, 2H).

[제조예 2-6] 벤질 4-(2-아미노에틸)-1-피페리딘카르복실레이트의 합성Preparation Example 2-6 Synthesis of Benzyl 4- (2-aminoethyl) -1-piperidinecarboxylate

[방법 A][Method A]

제조예 2-5의 화합물(3.29g, 11.3밀리몰)을 120㎖의 벤젠에 용해시키고 딘스탁으로 물을 제거하면서 1시간동안 환류하였다. 상온으로 냉각시킨 후 DPPA(3.42g, 1.1당량), TEA(1.37g, 1.2당량)과 t-부탄올(4.18g, 5.0당량)을 가하고 하루동안 환류하였다. t-부탄올 50㎖을 가하고 하루동안 재환류하였다. 통상적인 방법으로 추출-건조-감압농축하여 잔류물을 얻고 이를 다시 관 크로마토그래피(25% 에틸아세테이트-헥산)으로 분리-정제하여 2.70g(수율: 66%)의 N-Cbz-피페리딘-4-CH2CH2NHBoc를 담황색의 오일로 얻었다.The compound of Preparation Example 2-5 (3.29 g, 11.3 mmol) was dissolved in 120 mL of benzene and refluxed for 1 hour while removing water with Dean Stark. After cooling to room temperature, DPPA (3.42 g, 1.1 equiv), TEA (1.37 g, 1.2 equiv) and t-butanol (4.18 g, 5.0 equiv) were added and refluxed for one day. 50 ml of t-butanol was added and refluxed for one day. Extract-dry-depressurize and concentrate the residue in the usual manner to obtain the residue, which was then purified by column chromatography (25% ethyl acetate-hexane) to give 2.70 g (yield: 66%) of N-Cbz-piperidine-. 4-CH 2 CH 2 NHBoc was obtained as a pale yellow oil.

1H-NMR (CDCl3, 500MHz) δ 7.35-7.29 (m, 5H), 5.11 (s, 2H), 4.47 (bs, 1H), 4.16 (bs, 2H), 3.15 (bs, 2H), 2.76 (bs, 2H), 1.69-1.14 (m, 7H), 1.43 (s, 9H). 1 H-NMR (CDCl 3 , 500 MHz) δ 7.35-7.29 (m, 5H), 5.11 (s, 2H), 4.47 (bs, 1H), 4.16 (bs, 2H), 3.15 (bs, 2H), 2.76 ( bs, 2H), 1.69-1.14 (m, 7H), 1.43 (s, 9H).

상기 화합물(1.51g, 4.17밀리몰)을 6㎖의 CH2Cl2에 용해시킨 후 0℃에서 TFA(3㎖)를 가하고 1시간동안 교반하였다. 감압하에서 농축한 후 얻은 잔류물을 에틸아세테이트에 용해시키고 포화 탄산나트륨, 포화 염화나트륨으로 세척하고 건조한 후 4N HCl/디옥산을 가하고 감압농축하여 표제 화합물(정량적인 수율)을 황색 분말로 얻었다.The compound (1.51 g, 4.17 mmol) was dissolved in 6 mL of CH 2 Cl 2 and then TFA (3 mL) was added at 0 ° C. and stirred for 1 hour. The residue obtained after concentration under reduced pressure was dissolved in ethyl acetate, washed with saturated sodium carbonate, saturated sodium chloride, dried, 4N HCl / dioxane and concentrated under reduced pressure to give the title compound (quantitative yield) as a yellow powder.

1H-NMR (CDCl3, 500MHz) δ 8.23 (bs, 2H), 7.34-7.29 (m, 5H), 5.10 (s, 2H), 4.15 (bs, 2H), 2.97 (bs, 2H), 2.74 (bs, 2H), 1.67-1.49 (m, 5H), 1.26 (bs, 3H). 1 H-NMR (CDCl 3 , 500 MHz) δ 8.23 (bs, 2H), 7.34-7.29 (m, 5H), 5.10 (s, 2H), 4.15 (bs, 2H), 2.97 (bs, 2H), 2.74 ( bs, 2H), 1.67-1.49 (m, 5H), 1.26 (bs, 3H).

[방법 B][Method B]

제조예 2-5의 화합물(2.06g, 7.07밀리몰)을 100㎖의 벤젠에 용해시키고 딘스탁으로 물을 제거하면서 1시간동안 환류하였다. 상온으로 냉각한 후 DPPA(2.14g, 1.1당량), TEA(0.86g, 1.2당량)을 가하고 3시간동안 환류하였다. 통상적인 방법으로 추출-건조-감압농축하여 잔류물을 얻고, 이를 THF/1N HCl(1/1. 150㎖)에 용해시켜 상온에서 교반하였다. 감압하에서 농축한 후 얻은 잔류물을 에틸아세테이트에 용해시키고 포화 탄산나트륨, 포화 염화나트륨으로 세척하고 건조한 후 4N HCl/디옥산을 가하고 감압농축하여 2.08g(수율: 88%)의 표제 화합물(순도: 90%)을 황색 분말로 얻었다.The compound of Preparation Example 2-5 (2.06 g, 7.07 mmol) was dissolved in 100 mL of benzene and refluxed for 1 hour while removing water with Dean Stark. After cooling to room temperature, DPPA (2.14 g, 1.1 equiv) and TEA (0.86 g, 1.2 equiv) were added and refluxed for 3 hours. Extraction-drying-decompression concentration was carried out in a conventional manner to obtain a residue, which was dissolved in THF / 1N HCl (1 / 1.150 mL) and stirred at room temperature. The residue obtained after concentration under reduced pressure was dissolved in ethyl acetate, washed with saturated sodium carbonate, saturated sodium chloride, dried, 4N HCl / dioxane and concentrated under reduced pressure to give 2.08 g (yield: 88%) of the title compound (purity: 90%). ) Was obtained as a yellow powder.

[제조예 2-7] 벤질 4-(3-하이드록시프로필)-1-피페리딘카르복실레이트의 합성Preparation Example 2-7 Synthesis of Benzyl 4- (3-hydroxypropyl) -1-piperidinecarboxylate

제조예 2-5의 화합물(2.01g, 6.90밀리몰)과 N-메틸모르폴린(770mg, 1.1당량)을 무수 THF에 용해시키고 -20℃, 질소하에서 i-부틸클로로포메이트(990mg, 1.05당량)를 가하였다. 20분동안 교반한 후 현탁액을 여과하여 NaBH4(522mg, 2.0몰당량)의 THF-메탄올(40㎖-10㎖) 현탁액에 -78℃에서 가하고 상기 온도에서 2시간동안 교반한 후 아세트산(1.66g, 4.0몰당량)과 수 ㎖의 아세톤을 가하였다. 감압농축하여 얻은 잔류물을 에틸아세테이트에 용해시키고 물, 포화 중탄산나트륨, 포화 염화나트륨으로 세척하고 건조한 후 감압농축하였다. 이것을 관 크로마토그래피(30% 에틸아세테이트-헥산 50% 에틸아세테이트-헥산)로 분리-정제하여 1.74g(수율: 91%)의 표제 화합물을 무색 오일로 얻었다.The compound of Preparation Example 2-5 (2.01 g, 6.90 mmol) and N-methylmorpholine (770 mg, 1.1 equiv) were dissolved in anhydrous THF and i-butylchloroformate (990 mg, 1.05 equiv) at -20 ° C under nitrogen. Was added. After stirring for 20 minutes, the suspension was filtered and added to a suspension of THB-methanol (40 mL-10 mL) in NaBH 4 (522 mg, 2.0 molar equivalents) at −78 ° C., stirred at this temperature for 2 hours, and then acetic acid (1.66 g). , 4.0 molar equivalents) and several ml of acetone were added. The residue obtained by concentration under reduced pressure was dissolved in ethyl acetate, washed with water, saturated sodium bicarbonate and saturated sodium chloride, dried and concentrated under reduced pressure. This was separated-purified by column chromatography (30% ethyl acetate-hexane 50% ethyl acetate-hexane) to give 1.74 g (yield: 91%) of the title compound as a colorless oil.

1H-NMR (CDCl3, 500MHz) δ 7.35-7.29 (m, 5H), 5.11 (s, 2H), 4.17 (bs, 2H), 3.63 (t, J=6.9Hz, 2H), 2.75 (bs, 2H), 1.67 (bs, 2H), 1.57 (m, 2H), 1.41 (m, 1H), 1.31 (m, 2H), 1.12 (bs, 2H). 1 H-NMR (CDCl 3 , 500 MHz) δ 7.35-7.29 (m, 5H), 5.11 (s, 2H), 4.17 (bs, 2H), 3.63 (t, J = 6.9 Hz, 2H), 2.75 (bs, 2H), 1.67 (bs, 2H), 1.57 (m, 2H), 1.41 (m, 1H), 1.31 (m, 2H), 1.12 (bs, 2H).

[제조예 2-8] 벤질 4-[3-(1,3-디옥소-1,3-디하이드로-2H-이소인돌-2-일)프로필]-1-피페리딘카르복실레이트의 합성 Preparation Example 2-8 Synthesis of Benzyl 4- [3- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) propyl] -1-piperidinecarboxylate

제조예 2-7의 화합물(1.69g, 6.08밀리몰)과 프탈이미드(1.07g, 1.2당량), 트리페닐포스핀(1.92g, 1.2당량)을 무수 THF 50㎖에 용해시킨 후 0℃에서 DEAD(1.27g, 1.2당량)을 가하였다. 반응온도를 상온으로 천천히 상승시키면서 16시간동안 교반하였다. 감압농축하여 얻은 잔류물을 관 크로마토그래피(20% 에틸아세테이트-헥산)으로 분리-정제하여 2.40g(수율: 97%)의 표제 화합물을 백색 분말로 얻었다.The compound of Preparation Example 2-7 (1.69 g, 6.08 mmol), phthalimide (1.07 g, 1.2 equiv) and triphenylphosphine (1.92 g, 1.2 equiv) were dissolved in 50 mL of dry THF and then DEAD at 0 ° C. (1.27 g, 1.2 equiv) was added. The reaction temperature was stirred for 16 hours while slowly rising to room temperature. The residue obtained by concentration under reduced pressure was purified by column chromatography (20% ethyl acetate-hexane) to give 2.40 g (yield: 97%) of the title compound as a white powder.

1H-NMR (CDCl3, 500MHz) δ 7.83 (dd, J=3.2, 5.5Hz, 2H), 7.70 (dd, J=3.2, 5.5Hz, 2H), 5.10 (s, 2H), 4.15 (bs, 2H), 3.66 (t, J=6.3Hz, 2H), 2.73 (bs, 2H), 1.69 (m, 2H), 1.59 (s, 2H), 1.43 (m, 1H), 1.29 (m, 2H), 1.08 (bs, 2H). 1 H-NMR (CDCl 3 , 500 MHz) δ 7.83 (dd, J = 3.2, 5.5 Hz, 2H), 7.70 (dd, J = 3.2, 5.5 Hz, 2H), 5.10 (s, 2H), 4.15 (bs, 2H), 3.66 (t, J = 6.3 Hz, 2H), 2.73 (bs, 2H), 1.69 (m, 2H), 1.59 (s, 2H), 1.43 (m, 1H), 1.29 (m, 2H), 1.08 (bs, 2 H).

[제조예 2-9] 벤질 4-(3-아미노프로필)-1-피페리딘카르복실레이트의 합성Preparation Example 2-9 Synthesis of Benzyl 4- (3-aminopropyl) -1-piperidinecarboxylate

제조예 2-8의 화합물(2.37g, 5.83밀리몰)을 에탄올 40㎖에 용해시킨 후 하이드라진 일수화물(순도 80%, 350mg)을 가하고 2시간동안 환류하였다. 다시 하이드라진 일수화물(순도 80%, 350mg)을 가하고 1시간동안 환류하였다. 디클로로메탄 100㎖를 가하고 여과한 후 농축하여 얻은 잔류물을 다시 디클로로메탄/헥산(1/1, 100㎖)에 트리튜레이션하고 여과하여 잔여 프탈하이드라지드를 제거하고 생성된 용액을 농축하였다. 잔류물을 디클로로메탄에 용해시키고 4N HCl/디옥산 2㎖를 가하고 농축한 후 헥산 50㎖로 트리튜레이션하여 1.62g(수율: 89%)의 표제 화합물을 백색 분말로 얻었다.The compound of Preparation Example 2-8 (2.37 g, 5.83 mmol) was dissolved in 40 ml of ethanol, and then hydrazine monohydrate (purity 80%, 350 mg) was added and refluxed for 2 hours. Again hydrazine monohydrate (purity 80%, 350 mg) was added and refluxed for 1 hour. 100 ml of dichloromethane was added, filtered and the residue obtained was triturated again in dichloromethane / hexane (1/1, 100 ml) and filtered to remove residual phthalhydrazide and the resulting solution was concentrated. The residue was dissolved in dichloromethane, 2 ml of 4N HCl / dioxane was added, concentrated and triturated with 50 ml of hexane to give 1.62 g (yield: 89%) of the title compound as a white powder.

1H-NMR (CDCl3, 500MHz) δ 8.27 (bs, 3H), 7.35-7.28 (m, 5H), 5.10 (s, 2H), 4.15 (bs, 2H), 2.96 (bs, 2H), 2.73 (bs, 2H), 2.02-1.09 (m, 9H). 1 H-NMR (CDCl 3 , 500 MHz) δ 8.27 (bs, 3H), 7.35-7.28 (m, 5H), 5.10 (s, 2H), 4.15 (bs, 2H), 2.96 (bs, 2H), 2.73 ( bs, 2H), 2.02-1.09 (m, 9H).

[제조예 3-1] 벤질 4-(2-{[((2S)-1-{(2R)-2-[(tert-부톡시카르보닐)아미노]-3,3-디페닐프로파노일}피롤리디닐)카르보닐]아미노}에틸)-1-피페리딘카르복실레이트의 합성Preparation Example 3-1 Benzyl 4- (2-{[((2S) -1-{(2R) -2-[(tert-butoxycarbonyl) amino] -3,3-diphenylpropanoyl } Synthesis of pyrrolidinyl) carbonyl] amino} ethyl) -1-piperidinecarboxylate

제조예 1-1의 화합물, 제조예 2-6의 화합물(298mg, 1.14당량), EDC(288mg, 1.5당량), HOBt(203mg, 1.5당량)을 약 5㎖의 DMF에 용해시키고 0℃를 유지시킨 다음 TEA(0.42㎖, 3.0당량)를 가한 후 하루동안 상온에서 교반하였다. 저압하에서 농축하여 잔류물을 에틸아세테이트에 용해시킨 후 통상적인 방법으로 추출-건조-농축하였다. 관 크로마토그래피(80% 에틸아세테이트/헥산)를 사용하여 분리-정제하여 547mg(수율: 80%)의 표제 화합물을 백색 폼으로 얻었다.The compound of Preparation Example 1-1, the compound of Preparation Example 2-6 (298 mg, 1.14 equiv), EDC (288 mg, 1.5 equiv), and HOBt (203 mg, 1.5 equiv) were dissolved in about 5 mL of DMF and maintained at 0 ° C. After adding TEA (0.42 mL, 3.0 equiv), the mixture was stirred at room temperature for one day. Concentrate under low pressure to dissolve the residue in ethyl acetate and extract-dry-concentrate in a conventional manner. Separation-purification using tube chromatography (80% ethyl acetate / hexanes) gave 547 mg (yield: 80%) of the title compound as a white foam.

1H-NMR (CDCl3, 500MHz) δ 7.40-7.17 (m, 15H), 7.05 (bs, 1H), 5.10 (s, 2H), 4.91 (d, J=5.0Hz, 1H), 4.85 및 4.84 (2d, J=11.5Hz, 1H), 4.35(d, J=10.4Hz, 1H), 4.27 (d, J=7.8Hz, 1H), 4.13 (bs, 2H), 3.62 (m, 1H), 3.28 (m, 1H), 3.10 (m, 1H), 2.73 (bs, 2H), 2.50 (qt, J=8.2Hz, 1H), 2.10 (bs, 1H), 1.63-1.09 (m, 10H), 1.35 (s, 9H). 1 H-NMR (CDCl 3 , 500 MHz) δ 7.40-7.17 (m, 15H), 7.05 (bs, 1H), 5.10 (s, 2H), 4.91 (d, J = 5.0 Hz, 1H), 4.85 and 4.84 ( 2d, J = 11.5 Hz, 1H), 4.35 (d, J = 10.4 Hz, 1H), 4.27 (d, J = 7.8 Hz, 1H), 4.13 (bs, 2H), 3.62 (m, 1H), 3.28 ( m, 1H), 3.10 (m, 1H), 2.73 (bs, 2H), 2.50 (qt, J = 8.2 Hz, 1H), 2.10 (bs, 1H), 1.63-1.09 (m, 10H), 1.35 (s , 9H).

[제조예 3-2] 벤질 4-(3-{[((2S)-1-{(2R)-2-[(tert-부톡시카르보닐)아미노]-3,3-디페닐프로파노일}피롤리디닐)카르보닐]아미노}프로필)-1-피페리딘카르복실레이트의 합성Preparation Example 3-2 Benzyl 4- (3-{[((2S) -1-{(2R) -2-[(tert-butoxycarbonyl) amino] -3,3-diphenylpropanoyl } Synthesis of pyrrolidinyl) carbonyl] amino} propyl) -1-piperidinecarboxylate

제조예 3-1과 유사한 방법으로 표제 화합물을 얻었다.The title compound was obtained in a similar manner to Preparation Example 3-1.

1H-NMR (CDCl3, 500MHz) δ 7.39-7.17 (m, 15H), 7.06 (bs, 1H), 5.10 (s, 2H), 4.93 (d, J=5.0Hz, 1H), 4.84 (dd, J=5.0, 11.0Hz, 1H), 4.35 (d, J=11.0Hz, 1H), 4.27 (d, J=7.8Hz, 1H), 4.13 (bs, 2H), 3.63 (t, J=8.3Hz, 2H), 3.22 (m, 1H), 3.04 (m, 1H), 2.72 (bs, 2H), 2.49 (m, 1H), 2.09 (m, 1H), 1.76-1.05 (m, 13H), 1.35 (s, 9H). 1 H-NMR (CDCl 3 , 500 MHz) δ 7.39-7.17 (m, 15H), 7.06 (bs, 1H), 5.10 (s, 2H), 4.93 (d, J = 5.0 Hz, 1H), 4.84 (dd, J = 5.0, 11.0 Hz, 1H), 4.35 (d, J = 11.0 Hz, 1H), 4.27 (d, J = 7.8 Hz, 1H), 4.13 (bs, 2H), 3.63 (t, J = 8.3 Hz, 2H), 3.22 (m, 1H), 3.04 (m, 1H), 2.72 (bs, 2H), 2.49 (m, 1H), 2.09 (m, 1H), 1.76-1.05 (m, 13H), 1.35 (s , 9H).

[제조예 3-3] 벤질 4-(2-{[((2S)-1-{(2R)-2-[(tert-부톡시카르보닐)아미노]-3,3-디페닐프로파노일}피페리디닐)카르보닐]아미노}에틸)-1-피페리딘카르복실레이트(부분입체이성체)의 합성Preparation Example 3-3 Benzyl 4- (2-{[((2S) -1-{(2R) -2-[(tert-butoxycarbonyl) amino] -3,3-diphenylpropanoyl } Synthesis of piperidinyl) carbonyl] amino} ethyl) -1-piperidinecarboxylate (diastereomer)

제조예 3-1과 유사한 방법으로 표제 화합물을 얻었다.The title compound was obtained in a similar manner to Preparation Example 3-1.

1H-NMR (CDCl3, 500MHz) δ 7.39-7.15 (m, 15H), 5.68-4.93 (m, 4H), 4.67-4.21 (m, 2H), 4.15 (bs, 2H), 3.73-2.93 (m, 2H), 2.74 (bs, 2H), 2.32 (m, 1H), 1.66-1.14 (m, 13H), 1.35, 1.34 및 1.26 (3s, 9H). 1 H-NMR (CDCl 3 , 500 MHz) δ 7.39-7.15 (m, 15H), 5.68-4.93 (m, 4H), 4.67-4.21 (m, 2H), 4.15 (bs, 2H), 3.73-2.93 (m , 2H), 2.74 (bs, 2H), 2.32 (m, 1H), 1.66-1.14 (m, 13H), 1.35, 1.34 and 1.26 (3s, 9H).

[제조예 3-4] 벤질 4-(3-{[((2S)-1-{(2R)-2-[(tert-부톡시카르보닐)아미노]-3,3-디페닐프로파노일}피페리디닐)카르보닐]아미노}프로필)-1-피페리딘카르복실레이트(부분입체이성체)의 합성Preparation Example 3-4 Benzyl 4- (3-{[((2S) -1-{(2R) -2-[(tert-butoxycarbonyl) amino] -3,3-diphenylpropanoyl } Synthesis of piperidinyl) carbonyl] amino} propyl) -1-piperidinecarboxylate (diastereomer)

제조예 3-1과 유사한 방법으로 표제 화합물을 얻었다.The title compound was obtained in a similar manner to Preparation Example 3-1.

1H-NMR (CDCl3, 500MHz) δ 7.36-7.12 (m, 15H), 5.67-4.94 (m, 4H), 4.71-4.23 (m, 2H), 4.16 (bs, 2H), 3.73-2.93 (m, 2H), 2.75 (bs, 2H), 2.33 (m, 1H), 1.61-1.08 (m, 13H), 1.35, 1.34 및 1.25 (3s, 9H). 1 H-NMR (CDCl 3 , 500 MHz) δ 7.36-7.12 (m, 15H), 5.67-4.94 (m, 4H), 4.71-4.23 (m, 2H), 4.16 (bs, 2H), 3.73-2.93 (m , 2H), 2.75 (bs, 2H), 2.33 (m, 1H), 1.61-1.08 (m, 13H), 1.35, 1.34 and 1.25 (3s, 9H).

[제조예 4-1] 벤질 4-{2-[({(2S)-1-[(2R)-2-아미노-3,3-디페닐프로파노일]피롤리디닐}카르보닐)아미노]에틸}-1-피페리딘카르복실레이트의 합성Preparation Example 4-1 Benzyl 4- {2-[({(2S) -1-[(2R) -2-amino-3,3-diphenylpropanoyl] pyrrolidinyl} carbonyl) amino] Synthesis of ethyl} -1-piperidinecarboxylate

제조예 3-1의 화합물(302mg, 0.442밀리몰)에 30%의 트리플루오로아세트산:디클로로메탄 용액 6㎖를 0℃에서 가한 후 상온에서 2시간동안 교반하였다. 저압하에서 농축하여 잔류물을 에틸아세테이트에 용해시킨 후 포화 중탄산나트륨, 포화 염화나트륨으로 세척하고 건조-감압농축하여 258mg(수율: 100%)의 표제 화합물을 백색 폼으로 얻었다.6 ml of a 30% trifluoroacetic acid: dichloromethane solution was added to the compound of Preparation Example 3-1 (302 mg, 0.442 mmol) at 0 ° C. and stirred at room temperature for 2 hours. Concentrated under low pressure, the residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate, saturated sodium chloride, and dried under reduced pressure to give 258 mg (yield: 100%) of the title compound as a white foam.

[제조예 4-2] 벤질 4-(2-{[((2S)-1-{(2R)-2-[(메틸설포닐)아미노]-3,3-디페닐프로파노일}피롤리디닐)카르보닐]아미노}에틸)-1-피페리딘카르복실레이트의 합성Production Example 4-2 Benzyl 4- (2-{[((2S) -1-{(2R) -2-[(methylsulfonyl) amino] -3,3-diphenylpropanoyl} pyrroli Synthesis of diyl) carbonyl] amino} ethyl) -1-piperidinecarboxylate

제조예 4-1의 화합물(85mg, 0.146밀리몰)와 TEA(41mg, 3.0당량)을 4㎖의 디클로메탄에 용해시킨 후 0℃에서 메틸설포닐 클로라이드(35mg, 2.0당량)를 가하였다. 1시간동안 교반한 후 통상적인 방법으로 추출-건조-감압농축하여 잔류물을 얻고 이것을 관 크로마토그래피(60% 에틸아세테이트-헥산-에틸아세테이트)로 분리-정제하여 97mg(수율: 100%)의 표제 화합물을 무색 폼으로 얻었다.The compound of Preparation Example 4-1 (85 mg, 0.146 mmol) and TEA (41 mg, 3.0 equiv) were dissolved in 4 mL of dichloromethane, and methylsulfonyl chloride (35 mg, 2.0 equiv) was added at 0 ° C. After stirring for 1 hour, extraction-drying-condensation concentration was carried out in a conventional manner to obtain a residue, which was separated-purified by column chromatography (60% ethyl acetate-hexane-ethyl acetate) to give 97 mg (yield: 100%) of the title. The compound was obtained as a colorless foam.

1H-NMR (CDCl3, 500MHz) δ 7.41-7.21 (m, 15H), 6.59 (t, J=5.0Hz, 1H), 5.11 (d, J=8.7Hz, 1H), 5.10 (s, 2H), 4.79 (dd, J=8.7, 11.4Hz, 1H), 4.32 (d, J=11.4Hz, 1H), 4.22 (d, J=8.3Hz, 1H), 4.12 (bs, 2H), 3.57 (dt, J=2.7, 8.7Hz, 1H), 3.19 (m, 2H), 2.82 (s, 3H), 2.74 (bs, 2H), 2.55 (m, 1H), 2.04 (m, 1H), 1.66-1.07 (m, 10H). 1 H-NMR (CDCl 3 , 500 MHz) δ 7.41-7.21 (m, 15H), 6.59 (t, J = 5.0 Hz, 1H), 5.11 (d, J = 8.7 Hz, 1H), 5.10 (s, 2H) , 4.79 (dd, J = 8.7, 11.4 Hz, 1H), 4.32 (d, J = 11.4 Hz, 1H), 4.22 (d, J = 8.3 Hz, 1H), 4.12 (bs, 2H), 3.57 (dt, J = 2.7, 8.7 Hz, 1H), 3.19 (m, 2H), 2.82 (s, 3H), 2.74 (bs, 2H), 2.55 (m, 1H), 2.04 (m, 1H), 1.66-1.07 (m , 10H).

[제조예 4-3] 벤질 4-(2-{[((2S)-1-{(2R)-2-[(벤질설포닐)아미노]-3,3-디페닐프로파노일}피롤리디닐)카르보닐]아미노}에틸)-1-피페리딘카르복실레이트의합성 Production Example 4-3 Benzyl 4- (2-{[((2S) -1-{(2R) -2-[(benzylsulfonyl) amino] -3,3-diphenylpropanoyl} pyrroli Synthesis of diyl) carbonyl] amino} ethyl) -1-piperidinecarboxylate

제조예 4-1의 화합물(84mg, 0.144밀리몰)와 TEA(40mg, 3.0당량)을 4㎖의 디클로로메탄에 용해시킨 후 0℃에서 α-톨루엔설포닐클로라이드(56mg, 2.0당량)를 가하였다. 1시간동안 교반한 후 통상적인 방법으로 추출-건조-감압농축하여 잔류물을 얻고 이것을 관 크로마토그래피(60% 에틸아세테이트-헥산-에틸아세테이트)로 분리-정제하여 88mg(수율: 84%)의 표제 화합물을 무색 폼으로 얻었다.The compound of Preparation Example 4-1 (84 mg, 0.144 mmol) and TEA (40 mg, 3.0 equiv) were dissolved in 4 mL of dichloromethane, and α-toluenesulfonylchloride (56 mg, 2.0 equiv) was added at 0 ° C. After stirring for 1 hour, extraction-drying-condensation concentration was carried out in a conventional manner to obtain a residue, which was separated and purified by column chromatography (60% ethyl acetate-hexane-ethyl acetate) to give 88 mg (yield: 84%) of the title. The compound was obtained as a colorless foam.

1H-NMR (CDCl3, 500MHz) δ 7.45-7.19 (m, 18H), 7.04 (m, 2H), 6.64 (t, J=5.0Hz, 1H), 5.10 (s, 2H), 4.86 및 4.85 (2d, J=11.0Hz, 1H), 4.75 및 4.74 (2s, 2H), 4.30 및 4.28 (2s, 1H), 4.15 및 4.01 (ABq, J=13.7Hz, 2H), 4.08 (bs, 2H), 3.59 (m, 1H), 3.17 (m, 2H), 2.69 (bs, 2H), 2.56 (m, 1H), 2.07 (m, 1H), 1.71-1.03 (m, 10H), 1.25 (s, 9H). 1 H-NMR (CDCl 3 , 500 MHz) δ 7.45-7.19 (m, 18H), 7.04 (m, 2H), 6.64 (t, J = 5.0 Hz, 1H), 5.10 (s, 2H), 4.86 and 4.85 ( 2d, J = 11.0 Hz, 1H), 4.75 and 4.74 (2s, 2H), 4.30 and 4.28 (2s, 1H), 4.15 and 4.01 (ABq, J = 13.7 Hz, 2H), 4.08 (bs, 2H), 3.59 (m, 1H), 3.17 (m, 2H), 2.69 (bs, 2H), 2.56 (m, 1H), 2.07 (m, 1H), 1.71-1.03 (m, 10H), 1.25 (s, 9H).

[제조예 4-4] 벤질 4-(2-{[((2S)-1-{(2R)-2-[(아닐리노설포닐)아미노]-3,3-디페닐프로파노일}피롤리디닐)카르보닐]아미노}에틸)-1-피페리딘카르복실레이트의 합성Preparation Example 4-4 Benzyl 4- (2-{[((2S) -1-{(2R) -2-[(anilinosulfonyl) amino] -3,3-diphenylpropanoyl}} Synthesis of Lolidinyl) Carbonyl] amino} ethyl) -1-piperidinecarboxylate

제조예 4-1의 화합물(80mg, 0.137밀리몰), TEA(69mg, 5.0당량)을 4㎖의 디클로로메탄에 용해시킨 후 문헌[J.A. Kloek et al., J. Org. Chem. 1976, 41, 4028-4029]에 기재된 방법에 따라 합성한 페닐설파모일 클로라이드(79mg, 3.0당량)를 0℃에서 가하였다. 1시간동안 교반한 후 통상적인 방법으로 추출-건조-감압농축하여 잔류물을 얻고 이것을 관 크로마토그래피(60% 에틸아세테이트-헥산-에틸아세테이트)로 분리-정제하여 95mg(수율: 94%)의 표제 화합물을 무색 폼으로 얻었다.The compound of Preparation Example 4-1 (80 mg, 0.137 mmol) and TEA (69 mg, 5.0 equiv) were dissolved in 4 mL of dichloromethane and then described in J.A. Kloek et al., J. Org. Chem. 1976, 41, 4028-4029 was added phenylsulfamoyl chloride (79 mg, 3.0 equiv) synthesized according to the method described at 0 ° C. After stirring for 1 hour, extraction-drying-condensation concentration was carried out in a conventional manner to obtain a residue, which was separated-purified by column chromatography (60% ethyl acetate-hexane-ethyl acetate) to give 95 mg (yield: 94%) of the title. The compound was obtained as a colorless foam.

1H-NMR (CDCl3, 500MHz) δ 7.40-7.05 (m, 20H + 2NH), 6.50 (br m, 1H), 5.20 (d, J=8.3Hz, 1H), 5.10 (s, 2H), 4.86 (m, 1H), 4.31 (d, J=11.0Hz, 1H), 4.21-4.18 (m, 3H), 4.08 (bs, 2H), 3.65 (m, 1H), 3.16 (m, 2H), 2.89-2.60 (m, 3H), 2.01 (m, 1H), 1.72-0.88 (m, 9H). 1 H-NMR (CDCl 3 , 500 MHz) δ 7.40-7.05 (m, 20H + 2NH), 6.50 (br m, 1H), 5.20 (d, J = 8.3 Hz, 1H), 5.10 (s, 2H), 4.86 (m, 1H), 4.31 (d, J = 11.0 Hz, 1H), 4.21-4.18 (m, 3H), 4.08 (bs, 2H), 3.65 (m, 1H), 3.16 (m, 2H), 2.89- 2.60 (m, 3H), 2.01 (m, 1H), 1.72-0.88 (m, 9H).

[제조예 5-1] 벤질 4-[2-({[(2S)-1-(tert-부톡시카르보닐)아제티디닐]카르보닐}아미노)에틸]-1-피페리딘카르복실레이트의 합성Production Example 5-1 Benzyl 4- [2-({[(2S) -1- (tert-butoxycarbonyl) azetidinyl] carbonyl} amino) ethyl] -1-piperidinecarboxylate Synthesis of

Boc-Aze-OH(146mg, 1.00밀리몰), 제조예 2-6의 화합물(282mg, 1.3당량), EDC(209mg, 1.5당량), HOBt(147mg, 1.5당량)을 약 4㎖의 DMF에 용해시키고 0℃를 유지시킨 후 TEA(0.41㎖, 4.0당량)를 가하고 하루동안 상온에서 교반하였다. 저압하에서 농축하여 잔류물을 에틸아세테이트에 용해시키고 통상적인 방법으로 추출-건조-농축하였다. 관 크로마토그래피(40% 에틸아세테이트/헥산)를 사용하여 분리-정제하여 323mg(수율: 100%)의 표제 화합물을 백색 폼으로 얻었다.Boc-Aze-OH (146 mg, 1.00 mmol), the compound of Preparation Example 2-6 (282 mg, 1.3 equiv), EDC (209 mg, 1.5 equiv) and HOBt (147 mg, 1.5 equiv) were dissolved in about 4 mL of DMF and After maintaining at 0 ° C., TEA (0.41 mL, 4.0 equiv) was added and stirred at room temperature for one day. Concentrate under low pressure to dissolve the residue in ethyl acetate and extract-dry-concentrate in conventional manner. Separation-purification using column chromatography (40% ethyl acetate / hexanes) gave 323 mg (yield: 100%) of the title compound as a white foam.

1H-NMR (CDCl3, 500MHz) δ 7.38-7.28 (m, 6H), 5.11 (s, 2H), 4.62 (t, J=7.8Hz, 1H), 4.15 (bs, 2H), 3.88 (qt, J=8.2Hz, 1H), 3.76 (qt, J=8.2Hz, 1H), 3.31 (m, 2H), 2.74 (bs, 2H), 2.42 (bs, 2H), 1.69-1.12 (m, 7H), 1.24 (s, 9H). 1 H-NMR (CDCl 3 , 500 MHz) δ 7.38-7.28 (m, 6H), 5.11 (s, 2H), 4.62 (t, J = 7.8 Hz, 1H), 4.15 (bs, 2H), 3.88 (qt, J = 8.2 Hz, 1H), 3.76 (qt, J = 8.2 Hz, 1H), 3.31 (m, 2H), 2.74 (bs, 2H), 2.42 (bs, 2H), 1.69-1.12 (m, 7H), 1.24 (s, 9 H).

[제조예 5-2] 벤질 4-(2-{[((2S)-1-{(2R)-2-[(tert-부톡시카르보닐)아미노]-3,3-디페닐프로파노일}아제티디닐)카르보닐]아미노}에틸)-1-피페리딘카르복실레이트의 합성Preparation Example 5-2 Benzyl 4- (2-{[((2S) -1-{(2R) -2-[(tert-butoxycarbonyl) amino] -3,3-diphenylpropanoyl Synthesis of azetidinyl) carbonyl] amino} ethyl) -1-piperidinecarboxylate

제조예 4-1 및 3-1과 유사한 방법으로 표제 화합물을 얻었다.The title compound was obtained in a similar manner to Preparation Examples 4-1 and 3-1.

1H-NMR (CDCl3, 500MHz) δ 7.59 및 7.05 (2bs, 1H), 7.36-7.23 (m, 15H), 5.95 및 4.63 (2m, 1H), 5.11 (bs, 2H), 4.89 (bs, 1H), 4.40-4.31 (m, 2H), 4.15(bs, 2H), 3.98 (m, 1H), 3.25 (bs, 2H), 2.95 (m, 1H), 2.83 및 2.57 (2m, 1H), 2.73 (bs, 2H), 2.24 (m, 1H), 1.92 (m, 1H), 1.67-1.12 (m, 7H), 1.33 (s, 9H). 1 H-NMR (CDCl 3 , 500 MHz) δ 7.59 and 7.05 (2bs, 1H), 7.36-7.23 (m, 15H), 5.95 and 4.63 (2m, 1H), 5.11 (bs, 2H), 4.89 (bs, 1H ), 4.40-4.31 (m, 2H), 4.15 (bs, 2H), 3.98 (m, 1H), 3.25 (bs, 2H), 2.95 (m, 1H), 2.83 and 2.57 (2m, 1H), 2.73 ( bs, 2H), 2.24 (m, 1H), 1.92 (m, 1H), 1.67-1.12 (m, 7H), 1.33 (s, 9H).

[제조예 6-1] 메틸 (2S)-1-((2R)-2-{(tert-부톡시카르보닐)[2-(디에틸아미노)-2-옥소에틸]아미노}-3,3-디페닐프로파노일)-2-피롤리디닐카르복실레이트의 합성Production Example 6-1 Methyl (2S) -1-((2R) -2-{(tert-butoxycarbonyl) [2- (diethylamino) -2-oxoethyl] amino} -3,3 Synthesis of -diphenylpropanoyl) -2-pyrrolidinylcarboxylate

Boc-D-(diphe)Ala-Pro-OMe(205mg, 0.453밀리몰)을 무수 THF(4㎖)에서 용해시킨 후 0℃에서 1M LiHMDS(0.46㎖, 1.0당량)를 가하고 10분동안 교반하였다. 여기에 브로모아세틸 N,N-디에틸아미드(97mg, 0.498밀리몰)을 가하고 1시간동안 교반하였다. 에틸아세테이트를 가한 후 통상적인 방법으로 추출-건조-농축하였다. 관 크로마토그래피(40% 에틸아세테이트/헥산)를 사용하여 분리-정제하여 42mg(수율: 18%)의 표제 화합물을 백색 폼으로 얻었다.Boc-D- (diphe) Ala-Pro-OMe (205 mg, 0.453 mmol) was dissolved in anhydrous THF (4 mL), then 1M LiHMDS (0.46 mL, 1.0 equiv) was added at 0 ° C. and stirred for 10 minutes. Bromoacetyl N, N-diethylamide (97 mg, 0.498 mmol) was added thereto and stirred for 1 hour. Ethyl acetate was added and extracted, dried and concentrated in a conventional manner. Separation-purification using tube chromatography (40% ethyl acetate / hexanes) gave 42 mg (yield: 18%) of the title compound as a white foam.

1H-NMR (CDCl3, 500MHz) rotameric mixture δ 7.40-7.10 (m, 10H), [5.90 (d, J=11.9Hz), 5.76 (d, J=11.5Hz), 5.75 (d, J=11.5 Hz), 5.41 (d, J=11.0Hz), 5.24 (m), 5.06(Ψt, J=7.8 및 8.3Hz), 4.71 (d, J=11.5Hz), 4.70 (d, J=11.5Hz), 4.60 (d, J=11.5Hz), 4.58(d, J=12.0Hz)](all integrated to 4H), 4.30-3.30 (m,7H), 3.80 및 3.67 및 3.60 (three singlets, 3H), 2.58-0.88 (m, 19H). 1 H-NMR (CDCl 3 , 500 MHz) rotameric mixture δ 7.40-7.10 (m, 10H), [5.90 (d, J = 11.9 Hz), 5.76 (d, J = 11.5 Hz), 5.75 (d, J = 11.5 Hz), 5.41 (d, J = 11.0 Hz), 5.24 (m), 5.06 (Ψt, J = 7.8 and 8.3 Hz), 4.71 (d, J = 11.5 Hz), 4.70 (d, J = 11.5 Hz), 4.60 (d, J = 11.5 Hz), 4.58 (d, J = 12.0 Hz)] (all integrated to 4H), 4.30-3.30 (m, 7H), 3.80 and 3.67 and 3.60 (three singlets, 3H), 2.58- 0.88 (m, 19 H).

[제조예 6-2] 벤질 4-[2-({[(2S)-1-((2R)-2-{(tert-부톡시카르보닐)[2-(디에틸아미노)-2-옥소에틸]아미노}-3,3-디페닐프로파노일)피롤리디닐]카르보닐}아미노}에틸]-1-피페리딘카르복실레이트의 합성Production Example 6-2 Benzyl 4- [2-({[(2S) -1-((2R) -2-{(tert-butoxycarbonyl) [2- (diethylamino) -2-oxo Synthesis of ethyl] amino} -3,3-diphenylpropanoyl) pyrrolidinyl] carbonyl} amino} ethyl] -1-piperidinecarboxylate

Boc-D-(diphe)Ala-Pro-OMe(42mg, 0.074밀리몰)을 THF-메탄올-H2O(3:2:1, 2㎖)에 용해시킨 후 LiOH 일수화물(4.7mg, 1.5당량)를 가하고 1시간동안 교반하였다. 1N HCl(0.12㎖)로 중화한 후 에틸아세테이트를 가하여 통상적인 방법으로 추출-건조-농축하였다. 이것을 제조예 2-6의 피페리딘 유도체(29mg, 1.3당량), EDC(21mg, 1.5당량), HOBt(15mg, 1.5당량)를 DMF(2㎖)에 용해시키고 0℃에서 TEA(30mg, 4.0당량)를 가한 후 16시간동안 상온에서 교반하였다. 통상적인 방법으로 추출-건조-농축하였다. 관 크로마토그래피(70% 에틸아세테이트/헥산-에틸아세테이트)를 사용하여 분리-정제하여 43mg(수율: 73%)의 표제 화합물을 백색 폼으로 얻었다.Boc-D- (diphe) Ala-Pro-OMe (42 mg, 0.074 mmol) was dissolved in THF-methanol-H 2 O (3: 2: 1, 2 mL) followed by LiOH monohydrate (4.7 mg, 1.5 equiv) Was added and stirred for 1 hour. After neutralization with 1N HCl (0.12 mL), ethyl acetate was added, followed by extraction, drying, and concentration. The piperidine derivative (29 mg, 1.3 equiv), EDC (21 mg, 1.5 equiv) and HOBt (15 mg, 1.5 equiv) of Preparation Example 2-6 were dissolved in DMF (2 mL) and TEA (30 mg, 4.0) at 0 ° C. Equivalent weight) and then stirred at room temperature for 16 hours. Extraction-drying-concentration was carried out by conventional methods. Separation-purification using column chromatography (70% ethyl acetate / hexane-ethyl acetate) gave 43 mg (yield: 73%) of the title compound as a white foam.

1H-NMR (CDCl3, 500MHz) δ 7.45-7.11 (m, 15H + NH), 5.94 (d, J=11.5Hz, 0.5H), 5.10 (br d, 2H), 5.75 (d, J=11.5Hz), 5.41 (d, J=11.0Hz), 5,24 (m),5.06 (Ψt, J=7.8 및 8.3Hz), 4.58 (d, J=12.0Hz, 0.5H), 4.28-2.70 (m, 16H), 2.40-1.04 (m, 26H). 1 H-NMR (CDCl 3 , 500 MHz) δ 7.45-7.11 (m, 15H + NH), 5.94 (d, J = 11.5 Hz, 0.5H), 5.10 (br d, 2H), 5.75 (d, J = 11.5 Hz), 5.41 (d, J = 11.0 Hz), 5,24 (m), 5.06 (Ψt, J = 7.8 and 8.3 Hz), 4.58 (d, J = 12.0 Hz, 0.5H), 4.28-2.70 (m , 16H), 2.40-1.04 (m, 26H).

[실시예]EXAMPLE

[실시예 1] tert-부틸(1R)-1-벤즈히드릴-2-옥소-2-[2-({[2-(4-피페리디닐)에틸]아미노}카르보닐)-1-피롤리디닐]에틸카바메이트(화합물 1)의 합성Example 1 tert-Butyl (1R) -1-benzhydryl-2-oxo-2- [2-({[2- (4-piperidinyl) ethyl] amino} carbonyl) -1-pi Synthesis of Lolidinyl] ethyl Carbamate (Compound 1)

제조예 3-1의 화합물(118mg, 0.173밀리몰)을 10㎖의 에탄올에 용해시키고 Pd/C(100mg, 10%, Degussa E101), 1N HCl/디옥산(0.18㎖, 1.0당량)을 가한 후 상온에서 수소하에 3시간동안 교반하였다. 셀라이트를 통과시키고 저압하에서 농축하여 잔류물을 헥산으로 트리튜레이션하여 100mg(수율: 99%)의 표제 화합물을 백색 분말로 얻었다.The compound of Preparation Example 3-1 (118 mg, 0.173 mmol) was dissolved in 10 ml of ethanol, Pd / C (100 mg, 10%, Degussa E101), 1N HCl / dioxane (0.18 ml, 1.0 equiv) was added thereto, and then at room temperature. Stir under hydrogen for 3 h. Passed through celite and concentrated under low pressure, the residue was triturated with hexane to give 100 mg (yield: 99%) of the title compound as a white powder.

1H-NMR (CDCl3, 500MHz) δ 9.55 (br, 1H), 9.13 (br, 1H), 7.41-7.05 (m, 10H + NH), 4.96 (d, J=4.1Hz, 1H), 4.79 (dd, J=5.1 및 11.5Hz, 1H), 4,34 (d, J=11.5Hz, 1H), 4.25 (d, J=8.3Hz, 1H), 3.62 (m, 1H), 3.41 (m, 2H), 3.23 (m, 1H), 3.15 (m, 1H), 2.,82 (m, 2H), 2.,47 (m, 1H), 2.08-1.23 (m, 10H), 1.35 (s, 9H). 1 H-NMR (CDCl 3 , 500 MHz) δ 9.55 (br, 1H), 9.13 (br, 1H), 7.41-7.05 (m, 10H + NH), 4.96 (d, J = 4.1 Hz, 1H), 4.79 ( dd, J = 5.1 and 11.5 Hz, 1H), 4,34 (d, J = 11.5 Hz, 1H), 4.25 (d, J = 8.3 Hz, 1H), 3.62 (m, 1H), 3.41 (m, 2H ), 3.23 (m, 1H), 3.15 (m, 1H), 2., 82 (m, 2H), 2., 47 (m, 1H), 2.08-1.23 (m, 10H), 1.35 (s, 9H ).

HR-MASS계산치: M+H+(C32H45N4O4): 549.3441, 실측치: 549. 3440.HR-MASS calculated: M + H + (C 32 H 45 N 4 O 4 ): 549.3441. Found: 549. 3440.

[실시예 2 내지 8][Examples 2 to 8]

실시예 1과 유사한 방법으로 하기 표 2a 및 2b에 열거한 화합물들을 얻었다.In a similar manner to Example 1, the compounds listed in Tables 2A and 2B were obtained.

[실시예 9] 1-((2R)-2-{[2-(디에틸아미노)-2-옥소에틸]아미노}-3,3-디페닐프로파노일)-N-[2-(4-피페리디닐)에틸]-2-피롤리딘카르복사미드(화합물 9)의 합성Example 9 1-((2R) -2-{[2- (diethylamino) -2-oxoethyl] amino} -3,3-diphenylpropanoyl) -N- [2- (4 -Piperidinyl) ethyl] -2-pyrrolidinecarboxamide (Compound 9)

제조예 6-2의 화합물(43mg, 0.054밀리몰)을 4㎖의 포화 HCl/에틸아세테이트에 용해시켜 1시간 동안 상온에서 교반하여 저압하에서 농축하였다. 이 잔류물에 실시예 1과 유사한 방법으로 행하여 34mg(수율: 100%)의 표제 화합물을 백색 분말로 얻었다.The compound of Preparation Example 6-2 (43 mg, 0.054 mmol) was dissolved in 4 ml of saturated HCl / ethyl acetate, stirred at room temperature for 1 hour, and concentrated under low pressure. This residue was carried out in the same manner as in Example 1 to obtain 34 mg (yield: 100%) of the title compound as a white powder.

NMR: 복잡NMR: Complex

HR-MASS계산치: M+H+(C33H48N5O3): 562.3757, 실측치: 562.3761.HR-MASS calculated: M + H + (C 33 H 48 N 5 0 3 ): 562.3757. Found: 562.3761.

[실험예]Experimental Example

[실험예 1] 트롬빈 억제제의 억제활성Experimental Example 1 Inhibitory Activity of a Thrombin Inhibitor

본 발명에 따른 화학식 1의 화합물의 트롬빈 억제효과를 문헌[Methods in Enzymology Vol. 80 pp341-361; Biochemistry 27 pp2144-2151, 1988]에 기재된 방법에 따라 하기식을 이용하여 해리상수 Ki 값을 결정함으로써 측정하였다.The thrombin inhibitory effect of the compound of formula 1 according to the present invention is described in Methods in Enzymology Vol. 80 pp341-361; Biochemistry 27 pp 2144-2151, 1988] was determined by determining the dissociation constant Ki value using the following formula.

Ki= [E][I]/[EI]Ki = [E] [I] / [EI]

[E]: 억제제와 결합하고 있지 않은 효소의 농도[E]: concentration of enzyme not bound to inhibitor

[I]: 효소와 결합하고 있지 않은 억제제의 농도[I]: concentration of inhibitor not bound to enzyme

[EI]: 효소와 억제제의 결합물의 농도[EI]: concentration of the combination of enzyme and inhibitor

해리상수 Ki는 효소와 트롬빈 억제제의 해리정도를 나타내는 것이므로 해리상수값이 작을수록 효소에 대한 억제제의 결합능력이 큰 것을 의미하므로 억제활성이 큰 것으로 평가될 수 있다. 이러한 해리상수는 트롬빈의 작용을 받아 가수분해되면 발색하는 특정 기질과 반응시키고 그 발색정도를 분광도법에 따라 시간의 함수로 측정함으로써 구할 수 있다.Since the dissociation constant Ki indicates the degree of dissociation between the enzyme and the thrombin inhibitor, the smaller the dissociation constant, the greater the binding capacity of the inhibitor to the enzyme. This dissociation constant can be obtained by reacting with a specific substrate that develops upon hydrolysis under the action of thrombin and measuring the degree of color development as a function of time according to spectrophotometry.

본 실험예에서는 트롬빈의 기질로서 트롬빈의 작용을 받아 가수분해되면 발색하는 물질로 크로모자임 TH(Chromozyme TH: Tosyl-Gly-Pro-Arg-4-nitroanilide acetate)를 사용하였다. 크로모자임 TH가 트롬빈에 의해 가수분해되면 황색의 파라-니트로아닐리드가 생성된다. 따라서, 생성되는 파라-니트로아닐린의 양을 시간에 따른 흡광도의 변화로 측정함으로써 본 발명에 따른 화합물의 트롬빈 억제활성을 측정할 수 있다. 즉, 흡광도의 변화로부터 효소의 활성을 측정할 수 있으며, 이는 바로 트롬빈 억제제의 효소활성 억제능력과 연관될 수 있다.In this experimental example, chromozyme TH (Chromozyme TH: Tosyl-Gly-Pro-Arg-4-nitroanilide acetate) was used as a substance for the coloration upon hydrolysis under the action of thrombin. Chromozyme TH is hydrolyzed by thrombin to produce yellow para-nitroanilide. Therefore, the thrombin inhibitory activity of the compound according to the present invention can be measured by measuring the amount of para-nitroaniline produced by the change in absorbance with time. That is, the activity of the enzyme can be measured from the change in absorbance, which may be directly related to the ability of the thrombin inhibitor to inhibit the enzyme activity.

구체적으로는, 하기하는 바에 따라 본 발명에 따른 화합물의 트롬빈 활성에 대한 억제능력을 측정하였다.Specifically, the ability to inhibit thrombin activity of the compounds according to the present invention was measured as follows.

1.5㎖ 큐벳에 150mM NaCl, 0.1% PEG 8000(폴리에틸렌글리콜, 분자량 약 8,000)이 함유되어 있는 0.1M 트리스 완충용액(pH 7.8)을 1160㎕씩 가하였다. 기질용액으로는 크로모자임 TH를 디메틸설폭사이드(DMSO)에 10mM 농도로 용해시킨 후 상기 완충용액으로 희석시켜 0.1mM 농도가 되도록 제조한 것을 사용하였다. 이렇게 제조한 0.1mM 기질용액 225㎕를 큐벳에 가하였다. 억제제 용액으로는 본 발명에 따른 억제제 화합물을 디메틸설폭사이드로 10mg/㎖ 되게 용해시킨 후 상기 완충용액으로 희석시켜 0.1mg/㎖, 0.01mg/㎖, 0.001mg/㎖ 농도로 만든 것을 0-10㎍의 양이 되게 취한 후 트리스 완충용액으로 전체 부피가 100㎕가 되도록 하여 큐벳에 가하였다.1160 μl of 0.1M Tris buffer (pH 7.8) containing 150 mM NaCl and 0.1% PEG 8000 (polyethylene glycol, molecular weight about 8,000) was added to a 1.5 mL cuvette. The substrate solution was prepared by dissolving Chromozyme TH in dimethyl sulfoxide (DMSO) at a concentration of 10 mM and diluting with the buffer solution to a concentration of 0.1 mM. 225 µl of the 0.1 mM substrate solution thus prepared was added to the cuvette. As an inhibitor solution, the inhibitor compound according to the present invention was dissolved in dimethyl sulfoxide to 10 mg / ml and diluted with the buffer solution at a concentration of 0.1 mg / ml, 0.01 mg / ml, and 0.001 mg / ml. The solution was taken up to the amount of 3, and the total volume was added to the cuvette with 100 μl of Tris buffer solution.

실온에서 반응용액이 들어있는 큐벳에 각각 상기 트리스 완충용액에 0.1mg/㎖ 농도로 용해시킨 인간 트롬빈(human thrombin) 15㎕을 가하여 효소 가수분해 반응을 개시하였다. 효소를 가한 순간부터 2분동안 반응에 의해 생성되는 파라-니트로아닐리드의 양을 381nm에서의 흡광도의 변화로 모니터하여, 반응시간 대 흡광도의 연속 스펙트럼을 도시하였다. 여러 종류의 억제제 농도에 대해 위 실험을 수행하여 연속 스펙트럼을 얻었다.15 μl of human thrombin dissolved in the Tris buffer solution at a concentration of 0.1 mg / ml was added to the cuvette containing the reaction solution at room temperature to initiate the enzymatic hydrolysis reaction. The amount of para-nitroanilide produced by the reaction for two minutes from the moment of addition of the enzyme was monitored by the change in absorbance at 381 nm, showing the continuous spectrum of reaction time versus absorbance. The above experiments were performed on different inhibitor concentrations to obtain continuous spectra.

각 스펙트럼에서 반응시간 초기 30초 이내의 기울기로부터 초기속도 Vi를 구한 후, 억제제 농도 대비 초기속도의 역수(1/Vi) 그래프를 도시하였다. 그래프 위의 점들을 만족하는 1차식을 계산해낸 후 그 식의 x 절편으로부터 효소 반응식을 사용하여 Ki를 계산하였다. 이 계산에 사용된 Km값은 5.2μM로 일정효소 농도에서 기질 농도를 변화시킴으로써 구한 것이다.After obtaining the initial velocity Vi from the slope within the initial 30 seconds of the reaction time in each spectrum, an inverse graph of the initial velocity versus the inhibitor concentration (1 / Vi) is shown. After calculating the first equation satisfying the points on the graph, Ki was calculated from the x-intercept of the equation using the enzyme reaction equation. The K m value used in this calculation was 5.2 μM, determined by varying the substrate concentration at a constant enzyme concentration.

상기한 방법에 따라 트롬빈에 대해 측정된 본 발명에 따른 억제제의 각 효소활성 능력을 Ki값으로 나타내었다. 그 결과를 하기 표 3 [본 발명에 따른 화합물의 트롬빈과 트립신에 대한 억제능력]에 나타내었다.Each enzyme activity capacity of the inhibitor according to the present invention, measured for thrombin according to the method described above, is represented by Ki value. The results are shown in Table 3 [Inhibition of Thrombin and Trypsin of Compounds According to the Present Invention].

[실험예 2] 동물에서의 혈전형성 억제효과Experimental Example 2 Inhibitory Effect on Thrombus Formation in Animals

본 발명에 따른 화합물의 혈전형성에 대한 억제능력을 동물모델에서 측정하였다. 사용한 동물은 엘지화학 기술연구원 실험동물실에서 온도 20-22℃, 12시간 간격의 명암조건에서 시판 표준사료를 사용하여 사육된, 체중 250-300g의 웅성 흰쥐(Sprague Dawley)이며, 실험군당 3-4마리를 사용하였다. 먼저 쥐에 체중 kg당 1.3g 용량으로 우레탄(urethane)을 복강주사하여 마취하였다. 쥐의 복부를 절개하여 하대정맥(inferior vena cava)을 노출시킨 다음, 좌측 신정맥(left renal vein) 바로 아래 부위와 1.6cm 아래 부위의 정맥에 봉합사를 걸쳐놓았다. 실시예의 화합물을 체중 kg당 5mg 용량으로 좌측 대퇴정맥(left femoral vein)을 통하여 주입하고 5분 후에 트롬보플라스틴(thromboplastin)을 역시 대퇴정맥을 통하여 주입하였다. 이어서 30초 후에 걸쳐놓았던 봉합사를 결찰하였다. 봉합사를 결찰한 지 15분 후에 정맥을 적출하여 생성된 혈전을 취하여 무게를 측정하였다.Inhibition of the compounds according to the present invention against thrombus formation was measured in animal models. Animals used were Sprague Dawley, weighing 250-300 g, which were bred using commercial standard feed at a temperature of 20-22 ° C and 12-hour contrast in the laboratory of laboratory of LG Chem Institute of Technology. Four were used. First, rats were anesthetized by intraperitoneal injection of urethane at a dose of 1.3 g / kg body weight. The abdomen of the rat was incised to expose the inferior vena cava, and then sutures were applied to the vein just below the left renal vein and 1.6 cm below. The compound of the example was injected through the left femoral vein at a dose of 5 mg / kg body weight and 5 minutes later, thromboplastin was also injected through the femoral vein. Subsequently, the sutures laid down after 30 seconds were ligated. Fifteen minutes after the suture was ligated, the veins were removed and the thrombus produced was taken and weighed.

본 발명에 따른 실시예 4 화합물의 혈전형성 억제효과를 동일한 용적의 10% HPCD(hydroxypropyl β-cyclodextrin) 용액을 투여한 대조군의 혈전형성 정도와 비교하여 산출한 결과, 81%의 혈전형성 억제효과를 나타내었다.The thrombus formation inhibitory effect of the compound according to the present invention was calculated by comparing the degree of thrombus formation of the control group administered with the same volume of 10% HPCD (hydroxypropyl β-cyclodextrin) solution. Indicated.

[실험예 3] 본 발명에 따른 화합물의 약물동력학Experimental Example 3 Pharmacokinetics of Compounds According to the Present Invention

본 발명에 따른 화합물의 경구투여시 흡수효과를 하기와 같은 실험방법에 따라 혈중약물농도를 측정함으로써 결정하였다. 웅성 쥐와 개를 각각 18시간씩 절식시킨 후 실험에 사용하였다. 적당한 용해보조제를 사용하여 실시예 화합물의 1%(10mg/㎖) 용액을 조제한 후 경구로 투여하였다. 정해진 시간간격으로 혈액을 채취한 후, 메틸렌클로라이드로 액상추출하고 다시 묽은 염산용액으로 역추출하여 고압액체크로마토그래피(HPLC)로 혈중약물농도를 측정하였다. 그 결과, 일례로서실시예 1 화합물은 체중 kg 당 30mg으로 경구투여하였을 때 혈중농도가 760ng/㎖까지 측정되었다.The absorption effect upon oral administration of the compound according to the present invention was determined by measuring blood drug concentration according to the following experimental method. Male rats and dogs were fasted for 18 hours each and used for the experiment. A 1% (10 mg / ml) solution of the example compound was prepared using an appropriate dissolution aid and then administered orally. Blood was collected at a predetermined time interval, followed by liquid extraction with methylene chloride and back extraction with dilute hydrochloric acid solution to measure blood drug concentration by high pressure liquid chromatography (HPLC). As a result, as an example, the compound of Example 1 was measured to a blood concentration of 760 ng / ml when orally administered at 30 mg / kg body weight.

본 발명에 따른 트롬빈 억제제는 트롬빈 억제활성이 우수하고 경구투여가능하므로, 혈액응고 예방 및 혈전증 치료에 유용하게 사용될 수 있다.The thrombin inhibitor according to the present invention is excellent in thrombin inhibitory activity and orally administrable, and thus may be usefully used for preventing blood clotting and treating thrombosis.

Claims (4)

화학식 1의 화합물, 약제학적으로 허용되는 그의 염, 수화물, 용매화물 및 이성체:Compounds of Formula 1, pharmaceutically acceptable salts, hydrates, solvates and isomers thereof: [화학식 1][Formula 1] 상기식에서, R1은 수소, R2NCOCO-, RCO-, RSO2-, ROCO-, R2NCOCH2-, RNHSO2- 또는 ROSO2-이고, R은 수소, 탄소원자수 1∼8의 저급알킬, 탄소원자수 6∼10의 아릴, 탄소원자수 5∼12의 아릴알킬, 탄소원자수 4∼10의 헤테로아릴, 탄소원자수 5∼11의 헤테로아릴알킬 또는 탄소원자수 3∼8의 시클로알킬이며,Wherein R 1 is hydrogen, R 2 NCOCO-, RCO-, RSO 2- , ROCO-, R 2 NCOCH 2- , RNHSO 2 -or ROSO 2- , R is hydrogen, lower alkyl having 1 to 8 carbon atoms , Aryl having 6 to 10 carbon atoms, arylalkyl having 5 to 12 carbon atoms, heteroaryl having 4 to 10 carbon atoms, heteroarylalkyl having 5 to 11 carbon atoms, or cycloalkyl having 3 to 8 carbon atoms, R2는 수소, 불소, 염소, 브롬, 요오드, 하이드록시 또는 메톡시이며,R 2 is hydrogen, fluorine, chlorine, bromine, iodine, hydroxy or methoxy, X 및 X'은 각각 독립적으로 수소, 불소, 염소, 브롬, 요오드, 포르밀, 시아노, 하이드록시 또는 메톡시이며,X and X 'are each independently hydrogen, fluorine, chlorine, bromine, iodine, formyl, cyano, hydroxy or methoxy, n은 0, 1 또는 2이며,n is 0, 1 or 2, m은 1 또는 2이다.m is 1 or 2. 제 1 항에 있어서, R은 수소, 탄소원자수 1∼8의 저급알킬, 탄소원자수 6∼10의 아릴 또는 탄소원자수 5∼12의 아릴알킬이고, R2는 수소이며, X 및 X'은 수소인 화합물.The compound of claim 1, wherein R is hydrogen, lower alkyl of 1 to 8 carbon atoms, aryl of 6 to 10 carbon atoms, or arylalkyl of 5 to 12 carbon atoms, R 2 is hydrogen, and X and X 'are hydrogen compound. 제 2 항에 있어서, R1은 RSO2-, R2NCOCH2- 또는 RNHSO2-이고, R은 수소, 탄소원자수 1∼3의 저급알킬, 탄소원자수 6의 아릴 또는 탄소원자수 5∼12의 아릴알킬이며, n 및 m이 1인 화합물.3. R 1 is RSO 2- , R 2 NCOCH 2 -or RNHSO 2- , R is hydrogen, lower alkyl of 1 to 3 carbon atoms, aryl of 6 carbon atoms or aryl of 5 to 12 carbon atoms An alkyl, wherein n and m are 1; 제 1 항 내지 제 3 항중 어느 한 항에 있어서,The method according to any one of claims 1 to 3, tert-부틸(1R)-1-벤즈히드릴-2-옥소-2-[2-({[2-(4-피페리디닐)에틸]아미노}카르보닐)-1-피롤리디닐]에틸카바메이트;tert-butyl (1R) -1-benzhydryl-2-oxo-2- [2-({[2- (4-piperidinyl) ethyl] amino} carbonyl) -1-pyrrolidinyl] ethylcarba Mate; tert-부틸(1R)-1-벤즈히드릴-2-옥소-2-[2-({[2-(4-피페리디닐)에틸]아미노}카르보닐)-1-피페리디닐]에틸카바메이트;tert-butyl (1R) -1-benzhydryl-2-oxo-2- [2-({[2- (4-piperidinyl) ethyl] amino} carbonyl) -1-piperidinyl] ethylcarba Mate; 1-{(2R)-2-[(메틸설포닐)아미노]-3,3-디페닐프로파노일}-N-[2-(4-피페리디닐)에틸]-2-피롤리딘카르복사미드;1-{(2R) -2-[(methylsulfonyl) amino] -3,3-diphenylpropanoyl} -N- [2- (4-piperidinyl) ethyl] -2-pyrrolidinecar Radiation mid; 1-[(2R)-2-(벤질설포닐아미노)-3,3-디페닐프로파노일]-N-[2-(4-피페리디닐)에틸]-2-피롤리딘카르복사미드;1-[(2R) -2- (benzylsulfonylamino) -3,3-diphenylpropanoyl] -N- [2- (4-piperidinyl) ethyl] -2-pyrrolidinecarboxamide ; tert-부틸(1R)-1-벤즈히드릴-2-옥소-2-[2-({[3-(4-피페리디닐)프로필]아미노}카르보닐)-1-피롤리디닐]에틸카바메이트;tert-butyl (1R) -1-benzhydryl-2-oxo-2- [2-({[3- (4-piperidinyl) propyl] amino} carbonyl) -1-pyrrolidinyl] ethylcarba Mate; tert-부틸(1R)-1-벤즈히드릴-2-옥소-2-[2-({[3-(4-피페리디닐)프로필]아미노}카르보닐)-1-피페리디닐]에틸카바메이트;tert-butyl (1R) -1-benzhydryl-2-oxo-2- [2-({[3- (4-piperidinyl) propyl] amino} carbonyl) -1-piperidinyl] ethylcarba Mate; tert-부틸(1R)-1-벤즈히드릴-2-옥소-2-{2-[3-(4-피페리디닐)프로파노일]-1-아제티디닐}에틸카바메이트;tert-butyl (1R) -1-benzhydryl-2-oxo-2- {2- [3- (4-piperidinyl) propanoyl] -1-azetidinyl} ethyl carbamate; 1-{(2R)-2-[(아닐리노설포닐)아미노]-3,3-디페닐프로파노일}-N-[2-(4-피페리디닐)에틸]-2-피롤리딘카르복사미드; 또는1-{(2R) -2-[(anilinosulfonyl) amino] -3,3-diphenylpropanoyl} -N- [2- (4-piperidinyl) ethyl] -2-pyrrolidine Carboxamides; or 1-((2R)-2-{[2-(디에틸아미노)-2-옥소에틸]아미노}-3,3-디페닐프로파노일)-N-[2-(4-피페리디닐)에틸]-2-피롤리딘카르복사미드인 화합물.1-((2R) -2-{[2- (diethylamino) -2-oxoethyl] amino} -3,3-diphenylpropanoyl) -N- [2- (4-piperidinyl) Ethyl] -2-pyrrolidinecarboxamide.
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