KR100405650B1 - Orally available peptidic thrombin inhibitors - Google Patents

Orally available peptidic thrombin inhibitors Download PDF

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KR100405650B1
KR100405650B1 KR10-1999-0064851A KR19990064851A KR100405650B1 KR 100405650 B1 KR100405650 B1 KR 100405650B1 KR 19990064851 A KR19990064851 A KR 19990064851A KR 100405650 B1 KR100405650 B1 KR 100405650B1
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amino
methyl
compound
alkyl
formula
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KR20000052621A (en
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이구
박철원
정원혁
이승학
이상구
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주식회사 엘지생명과학
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
    • C07K5/0222—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2 with the first amino acid being heterocyclic, e.g. Pro, Trp
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic

Abstract

본 발명은 혈전생성 억제효과가 매우 뛰어나며 경구투여시 흡수가 높은 하기 화학식 1의 신규한 트롬빈 억제제 및 이 화합물을 유효성분으로 함유하는 혈액응고 예방 또는 각종 혈전증 치료를 위한 트롬빈 억제제 조성물에 관한 것이다.The present invention relates to a novel thrombin inhibitor of the general formula (1) having a very excellent antithrombotic effect and high absorption upon oral administration, and a thrombin inhibitor composition for preventing blood coagulation or treating various thrombosis containing the compound as an active ingredient.

상기식에서In the above formula

n, m, A, B, D, E, F, G 및 H는 명세서중에 정의된 바와 같다.n, m, A, B, D, E, F, G and H are as defined in the specification.

Description

경구흡수가 뛰어난 펩티드성 트롬빈 억제제 {Orally available peptidic thrombin inhibitors}Orally available peptidic thrombin inhibitors

본 발명은 혈전생성 억제효과가 매우 뛰어나며 경구흡수가 가능한 하기 화학식 1의 화합물, 약제학적으로 허용되는 그의 염, 수화물, 용매화물 및 이성체에 관한 것이다:The present invention relates to a compound of formula (1), a pharmaceutically acceptable salt, hydrate, solvate and isomer thereof having excellent antithrombotic effect and capable of oral absorption:

화학식 1Formula 1

상기식에서,In the above formula,

n은 0 내지 2의 정수를 나타내고,n represents an integer of 0 to 2,

m은 1 내지 3의 정수를 나타내며,m represents an integer of 1 to 3,

A는 수소, C1-C6-알킬, C3-C7-사이클로알킬, 아릴, -SO2-R1, -SO3-R1, -(CH2)m-SO2-R1, -(CH2)m-SO3-R1, -CO-R1, -CO2-R2, -(CH2)m-CO2-R1, -PO(R1)2, -PO(OR1)2, 또는-(CH2)m-PO(OR1)2을 나타내고, 여기에서 R1은 수소, C1-C6-알킬, C3-C7-사이클로알킬, 아릴, -(CH2)m-아릴 또는 -NR3R4를 나타내며, R2는 C1-C6-알킬, C3-C7-사이클로알킬, 아릴, 또는 -(CH2)m-아릴을 나타내고, R3및 R4는 각각 독립적으로 수소, C1-C6-알킬, 또는 C3-C7-사이클로알킬을 나타내며,A is hydrogen, COne-C6Alkyl, C3-C7-Cycloalkyl, aryl, -SO2-ROne, -SO3-ROne, -(CH2)m-SO2-ROne,-(CH2)m-SO3-ROne, -CO-ROne, -CO2-R2,-(CH2)m-CO2-ROne, -PO (ROne)2, -PO (OROne)2, Or-(CH2)m-PO (OROne)2Where R isOneSilver hydrogen, COne-C6Alkyl, C3-C7-Cycloalkyl, aryl,-(CH2)m-Aryl or -NR3R4, R2COne-C6Alkyl, C3-C7-Cycloalkyl, aryl, or-(CH2)m-Aryl, R3And R4Are each independently hydrogen, COne-C6-Alkyl, or C3-C7-Cycloalkyl,

B는 C1-C4-알킬, 할로겐, 하이드록시, C1-C4-알킬옥시, -CO2-C1-C4-알킬 및 아미노로 구성된 그룹중에서 선택된 1개 이상의 치환체에 의해 치환되거나 비치환된 페닐, 나프틸, 비페닐, 헤테로아릴, C1-C6-알킬, C3-C7-사이클로알킬, C5-C12-비사이클로알킬, C11-C16-트리사이클로알킬을 나타내거나, -CH(R5)2을 나타내며, 여기에서 R5는 수소를 나타내거나, C1-C4-알킬, 할로겐, 하이드록시, C1-C4-알킬옥시, -CO2-C1-C4-알킬 및 아미노로 구성된 그룹중에서 선택된 1개 이상의 치환체에 의해 치환되거나 비치환된 페닐, 헤테로아릴, C1-C4-알킬 또는 C3-C7-사이클로알킬을 나타내고,B is substituted by one or more substituents selected from the group consisting of C 1 -C 4 -alkyl, halogen, hydroxy, C 1 -C 4 -alkyloxy, -CO 2 -C 1 -C 4 -alkyl and amino Unsubstituted phenyl, naphthyl, biphenyl, heteroaryl, C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 5 -C 12 -bicycloalkyl, C 11 -C 16 -tricycloalkyl Or -CH (R 5 ) 2 , wherein R 5 represents hydrogen, or C 1 -C 4 -alkyl, halogen, hydroxy, C 1 -C 4 -alkyloxy, -CO 2- Phenyl, heteroaryl, C 1 -C 4 -alkyl or C 3 -C 7 -cycloalkyl substituted or unsubstituted by one or more substituents selected from the group consisting of C 1 -C 4 -alkyl and amino,

D는 -C(NH)NH2(아미딘), -CH2NH2(아미노메틸) 또는 -C(NH2)NOH(하이드록시아미딘)을 나타내며,D represents —C (NH) NH 2 (amidine), —CH 2 NH 2 (aminomethyl) or —C (NH 2 ) NOH (hydroxyamidine),

E, F, G 및 H는 각각 독립적으로 CR6또는 N을 나타내나, 단 E, F, G 및 H가동시에 N이 될 수 없고, 여기에서 R6는 수소, 할로겐, C1-C4-알킬, C1-C4-알킬옥시, 하이드록시 또는 아미노를 나타낸다.E, F, G and H each independently represent CR 6 or N, provided that E, F, G and H cannot be N at operation, where R 6 is hydrogen, halogen, C 1 -C 4 -Alkyl, C 1 -C 4 -alkyloxy, hydroxy or amino.

본 발명은 또한, 상기 화학식 1의 화합물의 제조방법 및 이 화합물을 유효성분으로 함유함을 특징으로 하는 혈액응고 예방 또는 각종 혈전증 치료를 위한 트롬빈 억제제 조성물에 관한 것이다.The present invention also relates to a method for preparing the compound of Formula 1 and a thrombin inhibitor composition for preventing blood coagulation or treating various thrombosis, characterized in that it contains the compound as an active ingredient.

일반적으로 혈액응고 과정에는 여러가지 복잡한 효소반응이 관여하고 있는 것으로 알려져 있다. 그리고 그 마지막 단계는 프로트롬빈을 트롬빈으로 전환시키는 반응을 포함하고 있다. 이 과정에서 생성된 트롬빈은 혈소판을 활성화시키고, 섬유소원을 섬유소로 바꾸는 등의 역할을 수행하는데, 섬유소는 중합반응에 의해 고분자물질로 바뀌고, 활성화된 혈액인자 XIII 에 의해 교차결합되어 불용성 응혈이 된다. 트롬빈은 또한 혈액응고 과정에 참여하는 혈액인자 V와 VIII를 활성화시키는 역할도 하여 혈액응고 반응을 더욱 가속화시킨다. 따라서, 트롬빈의 억제제는 효과적인 항응혈제로 작용하는 동시에, 혈소판 활성을 억제하고 섬유소 생성 및 안정화를 막을 수 있으므로 각종 혈전증을 예방하고 치료할 수 있다.In general, it is known that various complex enzyme reactions are involved in the coagulation process. The final step involves the conversion of prothrombin to thrombin. Thrombin generated in this process activates platelets, converts fibrinogens to fibrin, and the like, and the fibrin is converted into a polymer by a polymerization reaction and crosslinked by activated blood factor XIII to become insoluble coagulation. Thrombin also plays a role in activating the blood factors V and VIII involved in the coagulation process, further accelerating the coagulation reaction. Thus, inhibitors of thrombin can act as an effective anticoagulant, while inhibiting platelet activity and preventing fibrin production and stabilization, thereby preventing and treating various thrombosis.

현재 주사용 항혈액응고제로 가장 많이 쓰이고 있는 헤파린(heparin)은 안티트롬빈을 억제함으로서 트롬빈을 간접적으로 억제하는 기작을 바탕으로 한다. 따라서 헤파린은 동맥혈전에 효과가 적을 뿐 아니라 출혈과 연관된 안정성이 낮아 치료중 환자를 주의깊게 관찰해야 하는 어려움이 있다. 또한 경구용 항혈액응고제로 가장 많이 쓰이고 있는 쿠마린은 비타민 K의 길항제로서 복용후 매우 늦게(6-24 시간) 효과가 나타나는 단점이 있을 뿐아니라 헤파린과 마찬가지로 출혈을 배제할 수 없기 때문에 환자를 주의깊게 관찰해야 하는 어려움이 있다.Heparin, the most widely used anticoagulant for injection, is based on a mechanism that indirectly inhibits thrombin by inhibiting antithrombin. Therefore, heparin is not only effective in arterial thrombosis but also has low stability associated with bleeding. In addition, coumarin, the most commonly used oral anticoagulant, is a vitamin K antagonist that has a very late effect (6-24 hours) after taking it, and, like heparin, bleeding cannot be ruled out. There is a difficulty to observe.

저분자 트롬빈 억제제의 연구는 혈전 치료제로서 매우 각광을 받아 왔으며, 하기 화학식 2의 아가트로반(Argatroban)은 이미 1990년에 일본에서 상품화되었다 (참조: USP4,258,192; USP4,201,863; Biochemistry 1984, 23, 85-90). 그러나 이 화합물은 주사제로만 사용되며 경구투여용으로는 전혀 활성이 없다.Research of small molecule thrombin inhibitors has been very popular as a thrombus therapeutic agent, and Argatroban of Formula 2 has already been commercialized in Japan in 1990 (US Pat. No. 4,258,192; USP4,201,863; Biochemistry 1984, 23, 85-90). However, this compound is used only as an injection and has no activity for oral administration.

저분자 트롬빈 억제제의 등장은 트롬빈의 천연기질인 피브리노겐의 서열을 모방한 D-Phe-Pro-Arg 구조의 연구로 부터 시작되었으며, 따라서 이를 바탕으로 하는 트리펩티드 유도체가 가장 많이 연구되어 왔다. 초기 연구에서는 P1 위치에 알기닌알(Argininal)을 함유한 화합물이 많았는데, 하기 화학식 3의 화합물(Effegatran)은 그 대표적인 것으로 효과적인 트롬빈 억제제임이 입증되었다(참조: Eli Lilly, J. Med. Chem. 1990, 33, 1729; Circulation 1994, 90, I-231).The emergence of small molecule thrombin inhibitors began with the study of the structure of D-Phe-Pro-Arg, which mimics the sequence of fibrinogen, a natural substrate of thrombin, and therefore the tripeptide derivatives based thereon have been studied the most. In early studies, there were many compounds containing argininal at the P1 position, and the compound of formula 3 (Effegatran) was a representative one and proved to be an effective thrombin inhibitor (see Eli Lilly, J. Med. Chem. 1990). , 33, 1729; Circulation 1994, 90, I-231).

그 후, P1 위치에 알데히드 또는 그와 유사한 친핵성 그룹이 결여된 D-Phe-Pro-아그마틴과 그 유사체가 보고되었고, 대표적인 것으로는 하기 화학식 4 및 5의 이노가트란(Inogatran)과 멜라가트란(Melagatran)을 들 수 있다(참조: Astra, WO9311152, 1993; Thromb. Haemost. 1995, 73, 1325; WO9429336, 1994; Thromb. Haemost. 1998, 79, 110). 이들 트롬빈 억제제들은 스위스의 아스트라사에 의해 주사용 항응고제로 개발되고 있지만 그 효과가 기존의 항응혈치료제인 헤파린보다 우수하지 못한 것이 단점이다.Thereafter, D-Phe-Pro-agmatine and its analogs, which lack an aldehyde or similar nucleophilic group at the P1 position, have been reported, and representative examples thereof include Inogatran and Mela of Formulas 4 and 5 Melagatran (Astra, WO9311152, 1993; Thromb. Haemost. 1995, 73, 1325; WO9429336, 1994; Thromb. Haemost. 1998, 79, 110). These thrombin inhibitors have been developed as anticoagulants for injection by Astrasa in Switzerland, but their effects are not as good as the conventional anticoagulant heparin.

이들 트리펩티드 계열의 트롬빈 억제제 중에는 N-터미날에 부톡시카보닐 그룹을 함유함으로써 경구흡수가 증가된 경우가 있으며, 그 예로는 머크사에서 개발한 하기 화학식 6의 화합물을 들 수 있다. 그러나 이 화합물은 또한 혈전생성 억제효과가 매우 저조하다는 것이 단점이다(참조: J. Med. Chem. 1997, 40, 1565).Among these tripeptide-based thrombin inhibitors, oral absorption is increased by the inclusion of butoxycarbonyl groups in the N-terminal, and examples thereof include compounds represented by the following formula (6) developed by Merck. However, this compound also has the disadvantage that the effect of inhibiting thrombogenesis is very low (J. Med. Chem. 1997, 40, 1565).

이에 본 발명자들은 트롬빈 억제활성이 뛰어나며, 전술한 화학식 2 내지 6의 화합물들이 가지는 각각의 단점이 개선된 새로운 트롬빈 억제제를 개발하기 위해 예의 연구하였으며, 그 결과 상기 정의된 화학식 1의 화합물이 혈전생성 억제효과가 매우 우수함을 물론이고 경구투여시 혈중으로 흡수되는 농도가 높아서 소기의 목적에 부합됨을 발견하고 본 발명을 완성하게 되었다.Accordingly, the present inventors intensively studied to develop novel thrombin inhibitors which are excellent in thrombin inhibitory activity and each of the disadvantages of the compounds of Formulas 2 to 6 are improved, and as a result, the compound of Formula 1 as defined above inhibits thrombus formation. Of course, the effect is very excellent, and the concentration is absorbed into the blood during oral administration was found to meet the desired purpose to complete the present invention.

따라서, 본 발명의 목적은 혈전생성 억제효과가 우수할 뿐아니라 경구투여가 가능한 하기 화학식 1의 화합물, 약제학적으로 허용되는 그의 염, 수화물, 용매화물 및 이성체에 관한 것이다:Accordingly, an object of the present invention relates to a compound of formula (1), a pharmaceutically acceptable salt, hydrate, solvate and isomer thereof having an excellent antithrombotic effect as well as oral administration:

화학식 1Formula 1

상기식에서,In the above formula,

n은 0 내지 2의 정수를 나타내고,n represents an integer of 0 to 2,

m은 1 내지 3의 정수를 나타내며,m represents an integer of 1 to 3,

A는 수소, C1-C6-알킬, C3-C7-사이클로알킬, 아릴, -SO2-R1, -SO3-R1, -(CH2)m-SO2-R1, -(CH2)m-SO3-R1, -CO-R1, -CO2-R2, -(CH2)m-CO2-R1, -PO(R1)2, -PO(OR1)2, 또는 -(CH2)m-PO(OR1)2을 나타내고, 여기에서 R1은 수소, C1-C6-알킬, C3-C7-사이클로알킬, 아릴, -(CH2)m-아릴 또는 -NR3R4를 나타내며, R2는 C1-C6-알킬, C3-C7-사이클로알킬, 아릴, 또는 -(CH2)m-아릴을 나타내고, R3및 R4는 각각 독립적으로 수소, C1-C6-알킬, 또는 C3-C7-사이클로알킬을 나타내며,A is hydrogen, COne-C6Alkyl, C3-C7-Cycloalkyl, aryl, -SO2-ROne, -SO3-ROne,-(CH2)m-SO2-ROne,-(CH2)m-SO3-ROne, -CO-ROne, -CO2-R2,-(CH2)m-CO2-ROne, -PO (ROne)2, -PO (OROne)2, Or-(CH2)m-PO (OROne)2Where R isOneSilver hydrogen, COne-C6Alkyl, C3-C7-Cycloalkyl, aryl,-(CH2)m-Aryl or -NR3R4, R2COne-C6Alkyl, C3-C7-Cycloalkyl, aryl, or-(CH2)m-Aryl, R3And R4Are each independently hydrogen, COne-C6-Alkyl, or C3-C7-Cycloalkyl,

B는 C1-C4-알킬, 할로겐, 하이드록시, C1-C4-알킬옥시, -CO2-C1-C4-알킬 및 아미노로 구성된 그룹중에서 선택된 1개 이상의 치환체에 의해 치환되거나 비치환된 페닐, 나프틸, 비페닐, 헤테로아릴, C1-C6-알킬, C3-C7-사이클로알킬, C5-C12-비사이클로알킬, C11-C16-트리사이클로알킬을 나타내거나, -CH(R5)2을 나타내며, 여기에서 R5는 수소를 나타내거나, C1-C4-알킬, 할로겐, 하이드록시, C1-C4-알킬옥시, -CO2-C1-C4-알킬 및 아미노로 구성된 그룹중에서 선택된 1개 이상의 치환체에 의해 치환되거나 비치환된 페닐, 헤테로아릴, C1-C4-알킬 또는 C3-C7-사이클로알킬을 나타내고,B is substituted by one or more substituents selected from the group consisting of C 1 -C 4 -alkyl, halogen, hydroxy, C 1 -C 4 -alkyloxy, -CO 2 -C 1 -C 4 -alkyl and amino Unsubstituted phenyl, naphthyl, biphenyl, heteroaryl, C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 5 -C 12 -bicycloalkyl, C 11 -C 16 -tricycloalkyl Or -CH (R 5 ) 2 , wherein R 5 represents hydrogen, or C 1 -C 4 -alkyl, halogen, hydroxy, C 1 -C 4 -alkyloxy, -CO 2- Phenyl, heteroaryl, C 1 -C 4 -alkyl or C 3 -C 7 -cycloalkyl substituted or unsubstituted by one or more substituents selected from the group consisting of C 1 -C 4 -alkyl and amino,

D는 -C(NH)NH2(아미딘), -CH2NH2(아미노메틸) 또는 -C(NH2)NOH(하이드록시아미딘)을 나타내며,D represents —C (NH) NH 2 (amidine), —CH 2 NH 2 (aminomethyl) or —C (NH 2 ) NOH (hydroxyamidine),

E, F, G 및 H는 각각 독립적으로 CR6또는 N을 나타내나, 단 E, F, G 및 H가 동시에 N이 될 수 없고, 여기에서 R6는 수소, 할로겐, C1-C4-알킬, C1-C4-알킬옥시, 하이드록시 또는 아미노를 나타낸다.E, F, G and H each independently represent CR 6 or N, provided that E, F, G and H cannot be N at the same time, where R 6 is hydrogen, halogen, C 1 -C 4- Alkyl, C 1 -C 4 -alkyloxy, hydroxy or amino.

본 발명에 따른 화학식 1의 화합물의 치환기에 대한 정의에서 용어 "알킬"은 단독으로 또는 "알킬옥시"와 같이 조합하여 사용되는 경우에 각각 직쇄 또는 측쇄 탄화수소 라디칼을 의미하며, 용어 "사이클로알킬"은 사이클로헥실을 포함한 환상 알킬을 의미한다.The term "alkyl" in the definition of the substituent of the compound of formula 1 according to the invention, when used alone or in combination with "alkyloxy" means a straight or branched chain hydrocarbon radical, respectively, and the term "cycloalkyl" It means cyclic alkyl including cyclohexyl.

용어 "아릴"은 6 내지 14-원 모노사이클릭, 비사이클릭 또는 트리사이클릭 방향족 그룹을 의미하며, 용어 "헤테로아릴"은 산소, 질소 및 황중에서 선택된 헤테로원자를 함유하는 모노사이클릭 또는 비사이클릭 방향족 그룹을 의미한다.The term "aryl" refers to a 6-14 membered monocyclic, bicyclic or tricyclic aromatic group, and the term "heteroaryl" refers to monocyclic or non-containing heteroatoms selected from oxygen, nitrogen and sulfur. It means a cyclic aromatic group.

용어 "비사이클로알킬"은 2개 이상의 공통된 원자(atoms in common)를 가지며 2개의 환으로 구성된 포화 환을 나타내고, 용어 "트리사이클로알킬"은 3개의 환으로 구성된 포화 환을 나타낸다.The term "bicycloalkyl" refers to a saturated ring having two or more atoms in common and consisting of two rings, and the term "tricycloalkyl" refers to a saturated ring consisting of three rings.

본 발명에 따른 화학식 1의 화합물중에서도 바람직한 화합물은Among the compounds of Formula 1 according to the present invention, preferred compounds are

i) B가 C1-C4-알킬, 할로겐, 하이드록시, C1-C4-알킬옥시, -CO2-C1-C4-알킬 및 아미노로 구성된 그룹중에서 선택된 1개 이상의 치환체에 의해 치환되거나 비치환된 페닐, C1-C4-알킬, C3-C7-사이클로알킬을 나타내거나 -CH(R5)2을 나타내며, 여기에서 R5는 수소, 페닐, 헤테로아릴, C1-C4-알킬 또는 C3-C7-사이클로알킬을 나타내거나,i) B is substituted by one or more substituents selected from the group consisting of C 1 -C 4 -alkyl, halogen, hydroxy, C 1 -C 4 -alkyloxy, —CO 2 -C 1 -C 4 -alkyl and amino Substituted or unsubstituted phenyl, C 1 -C 4 -alkyl, C 3 -C 7 -cycloalkyl or —CH (R 5 ) 2 , wherein R 5 represents hydrogen, phenyl, heteroaryl, C 1 -C 4 -alkyl or C 3 -C 7 -cycloalkyl, or

ii) E 및 F중 하나가 N이고 G 및 H중 하나가 N이며 나머지는 CR6이고, 여기에서 R6는 수소, 할로겐, C1-C4-알킬, C1-C4-알킬옥시, 하이드록시 또는 아미노를 나타내거나,ii) one of E and F is N, one of G and H is N and the other is CR 6 , wherein R 6 is hydrogen, halogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkyloxy, Hydroxy or amino, or

iii) E, F, G 및 H중 하나가 N이고 나머지는 CR6이며, 여기에서 R6는 수소, 할로겐, C1-C4-알킬, C1-C4-알킬옥시, 하이드록시 또는 아미노를 나타내는 화합물이다.iii) one of E, F, G and H is N and the other is CR 6 , wherein R 6 is hydrogen, halogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkyloxy, hydroxy or amino It is a compound which represents.

상기 i)의 화합물 중에서도 특히 바람직한 화합물은 B가 할로겐 및 하이드록시로 구성된 그룹중에서 선택된 1개 이상의 치환체에 의해 치환되거나 비치환된 페닐, C1-C4-알킬, C3-C7-사이클로알킬을 나타내거나 -CH(R5)2을 나타내며, 여기에서 R5는 페닐, C1-C4-알킬 또는 사이클로헥실을 나타내는 화합물이다.Among the compounds of i), particularly preferred compounds are phenyl, C 1 -C 4 -alkyl, C 3 -C 7 -cycloalkyl, wherein B is unsubstituted or substituted by one or more substituents selected from the group consisting of halogen and hydroxy. Or -CH (R 5 ) 2 , wherein R 5 is a compound representing phenyl, C 1 -C 4 -alkyl or cyclohexyl.

보다 특히 바람직한 화합물은 n은 0 내지 2의 정수를 나타내고, m은 1 내지 3의 정수를 나타내며, A는 수소, 아릴, -SO2-R1, -CO-R1, -CO2-R2, -(CH2)m-CO2-R1, -PO(R1)2또는 -PO(OR1)2를 나타내고, 여기에서 R1은 수소, C1-C6-알킬, 아릴, -(CH2)m-아릴 또는 -NR3R4를 나타내며, R2는 C1-C6-알킬, 아릴, 또는 -(CH2)m-아릴을 나타내고, R3및 R4는 각각 독립적으로 수소 또는 C1-C6-알킬을 나타내며, B는 할로겐 및 하이드록시로 구성된 그룹중에서 선택된 1개 이상의 치환체에 의해 치환되거나 비치환된 페닐, C1-C4-알킬, C3-C7-사이클로알킬을 나타내거나 -CH(R5)2을 나타내며, 여기에서 R5는 페닐, C1-C4-알킬 또는 사이클로헥실을 나타내고, D는 -C(NH)NH2(아미딘), -CH2NH2(아미노메틸) 또는 -C(NH2)NOH(하이드록시아미딘)을 나타내며, E 및 F중 하나가 N이고 G 및 H중 하나가 N이며 나머지는 CR6이거나, E, F, G 및 H중 하나가 N이고 나머지는 CR6이며, 여기에서 R6는 수소, 할로겐, C1-C4-알킬, C1-C4-알킬옥시 또는 아미노를 나타내는 화합물이다.More particularly preferred compounds n represents an integer from 0 to 2, m represents an integer from 1 to 3, A represents hydrogen, aryl, -SO 2 -R 1 , -CO-R 1 , -CO 2 -R 2 ,-(CH 2 ) m -CO 2 -R 1 , -PO (R 1 ) 2 or -PO (OR 1 ) 2 , wherein R 1 is hydrogen, C 1 -C 6 -alkyl, aryl,- (CH 2 ) m -aryl or -NR 3 R 4 , R 2 represents C 1 -C 6 -alkyl, aryl, or-(CH 2 ) m -aryl, and R 3 and R 4 are each independently Hydrogen or C 1 -C 6 -alkyl, B is phenyl, C 1 -C 4 -alkyl, C 3 -C 7 -unsubstituted or substituted by one or more substituents selected from the group consisting of halogen and hydroxy Cycloalkyl or —CH (R 5 ) 2 where R 5 represents phenyl, C 1 -C 4 -alkyl or cyclohexyl, and D is —C (NH) NH 2 (amidine), — CH 2 NH 2 represents an (aminomethyl) or -C (NH 2) NOH (hydroxy-amidine), one of E and F One of the N and G and H are N and the others are 6 or CR, E, F, G and H, and one of the remaining N is CR 6, R 6 is hydrogen, halogen, C 1 -C 4 here -alkyl , C 1 -C 4 -alkyloxy or amino.

가장 바람직한 화합물은 상기 보다 특히 바람직한 화합물 중에서도 B가 -CH(R5)2을 나타내며, 여기에서 R5는 페닐인 화합물이다.Most preferred compounds are those wherein B represents -CH (R 5 ) 2 , among which more particularly preferred compounds, wherein R 5 is phenyl.

본 발명에 따르는 화학식 1의 대표적인 화합물에는 다음과 같은 화합물이 포함된다:Representative compounds of Formula 1 according to the present invention include the following compounds:

1. (2S)-N-{4-[아미노(이미노)메틸]벤질}-1-{(2R)-2-[(아미노설포닐)아미노] -3,3-디페닐프로파노일}-2-피롤리딘카르복사미드;1. ( 2S ) -N- {4- [amino (imino) methyl] benzyl} -1-{( 2R ) -2-[(aminosulfonyl) amino] -3,3-diphenylpropano Il} -2-pyrrolidinecarboxamide;

2. (2S)-N-{4-[아미노메틸]벤질}-1-{(2R)-2-[(아미노설포닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드;2. ( 2S ) -N- {4- [aminomethyl] benzyl} -1-{( 2R ) -2-[(aminosulfonyl) amino] -3,3-diphenylpropanoyl} -2 -Pyrrolidinecarboxamide;

3. (2S)-N-{4-[아미노(이미노)메틸]벤질}-1-{(2R)-2-[(아미노설포닐)아미노] -3-(3,4-디클로로페닐)프로파노일}-2-피롤리딘카르복사미드; 3. (2 S) - N - {4- [ amino (imino) methyl] benzyl} -1 - {(2 R) -2 - [( aminosulfonyl) amino] -3- (3,4-dichloro Phenyl) propanoyl} -2-pyrrolidinecarboxamide;

4. (2S)-N-{4-[아미노(이미노)메틸]벤질}-1-{(2R)-2-[(아미노설포닐)아미노] -3,3-디사이클로헥실프로파노일}-2-피롤리딘카르복사미드;4. (2 S) - N - to [(aminosulfonyl) amino] 3,3-cyclohexylene silpeu {4- [amino (imino) methyl] benzyl} -1 - {(2 R) -2 Panoyl} -2-pyrrolidinecarboxamide;

5. (2S)-N-{4-[아미노(이미노)메틸]벤질}-1-{(2R)-2-[(아미노설포닐)아미노] -3,3-디페닐프로파노일}-2-아제티딘카르복사미드;5. ( 2S ) -N- {4- [amino (imino) methyl] benzyl} -1-{( 2R ) -2-[(aminosulfonyl) amino] -3,3-diphenylpropano Il} -2-azetidinecarboxamide;

6. (2S)-N-{4-[아미노(이미노)메틸]벤질}-1-{(2R)-2-[(아미노설포닐)아미노] -2-사이클로헥실에타노일}-2-피롤리딘카르복사미드; 6. (2 S) - N - {4- [ amino (imino) methyl] benzyl} -1 - {(2 R) -2 - [( aminosulfonyl) amino] -2-cyclohexyl} other Russo -2-pyrrolidinecarboxamide;

7. (2S)-N-{4-[아미노(이미노)메틸]벤질}-1-{(2R)-2-[(아미노설포닐)아미노] -3-사이클로헥실프로파노일}-2-피롤리딘카르복사미드; 7. (2 S) - N - {4- [ amino (imino) methyl] benzyl} -1 - {(2 R) -2 - [( aminosulfonyl) amino] -3-cyclohexyl propanoyl} -2-pyrrolidinecarboxamide;

8. (2S)-N-{4-[아미노(이미노)메틸]벤질}-1-{(2R)-2-[(아미노설포닐)아미노] -3-메틸부타노일}-2-피롤리딘카르복사미드; 8. (2 S) - N - {4- [ amino (imino) methyl] benzyl} -1 - {(2 R) -2 - [( aminosulfonyl) amino] -3-methyl-butanoyl} -2 -Pyrrolidinecarboxamide;

9. (2S)-N-({6-[아미노(이미노)메틸]-3-피리디닐}메틸)-1-{(2R)-2-[(아미노 설포닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드;9. ( 2S ) -N -({6- [amino (imino) methyl] -3-pyridinyl} methyl) -1-{( 2R ) -2-[(amino sulfonyl) amino] -3 , 3-diphenylpropanoyl} -2-pyrrolidinecarboxamide;

10. (2S)-N-({6-[아미노메틸]-3-피리디닐}메틸)-1-{(2R)-2-[(아미노설포닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드;10. ( 2S ) -N -({6- [aminomethyl] -3-pyridinyl} methyl) -1-{( 2R ) -2-[(aminosulfonyl) amino] -3,3-di Phenylpropanoyl} -2-pyrrolidinecarboxamide;

11. (2S)-N-({6-[아미노(이미노)메틸]-3-피리디닐}메틸)-1-{(2R)-2-[(아미노 설포닐)아미노]-3,3-디사이클로헥실프로파노일}-2-피롤리딘카르복사미드;11. ( 2S ) -N -({6- [amino (imino) methyl] -3-pyridinyl} methyl) -1-{( 2R ) -2-[(amino sulfonyl) amino] -3 , 3-dicyclohexylpropanoyl} -2-pyrrolidinecarboxamide;

12. (2S)-N-({6-[아미노(이미노)메틸]-3-피리디닐}메틸)-1-{(2R)-2-[(아미노 설포닐)아미노]-3-사이클로헥실프로파노일}-2-피롤리딘카르복사미드;12. ( 2S ) -N -({6- [amino (imino) methyl] -3-pyridinyl} methyl) -1-{( 2R ) -2-[(amino sulfonyl) amino] -3 -Cyclohexylpropanoyl} -2-pyrrolidinecarboxamide;

13. (2S)-N-({5-[아미노(이미노)메틸]-2-피리디닐}메틸)-1-{(2R)-2-[(아미노 설포닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드;13. ( 2S ) -N -({5- [amino (imino) methyl] -2-pyridinyl} methyl) -1-{( 2R ) -2-[(amino sulfonyl) amino] -3 , 3-diphenylpropanoyl} -2-pyrrolidinecarboxamide;

14. (2S)-N-({2-[아미노(이미노)메틸]-5-피리미디닐}메틸)-1-{(2R)-2-[(아 미노설포닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드;14. ( 2S ) -N -({2- [amino (imino) methyl] -5-pyrimidinyl} methyl) -1-{( 2R ) -2-[(aminosulfonyl) amino] -3,3-diphenylpropanoyl} -2-pyrrolidinecarboxamide;

15. (2S)-N-{4-[아미노(이미노)메틸]-3-플루오로벤질}-1-{(2R)-2-[(아미노 설포닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드; 15. (2 S) - N - {4- [ amino (imino) methyl] -3-fluoro-benzyl} -1 - {(2 R) -2 - [( aminosulfonyl) amino] 3,3 -Diphenylpropanoyl} -2-pyrrolidinecarboxamide;

16. (2S)-N-{4-[아미노(이미노)메틸]-2-플루오로벤질}-1-{(2R)-2-[(아미노 설포닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드; 16. (2 S) - N - {4- [ amino (imino) methyl] benzyl-2-fluoro} -1 - {(2 R) -2 - [( aminosulfonyl) amino] 3,3 -Diphenylpropanoyl} -2-pyrrolidinecarboxamide;

17. (2S)-N-{4-[아미노(이미노)메틸]-3-메틸벤질}-1-{(2R)-2-[(아미노 설포닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드; 17. (2 S) - N - {4- [ amino (imino) methyl] -3-methyl-benzyl} -1 - {(2 R) -2 - [( aminosulfonyl) amino] -3,3- Diphenylpropanoyl} -2-pyrrolidinecarboxamide;

18. (2S)-N-{4-[아미노(이미노)메틸]-3-아미노벤질}-1-{(2R)-2-[(아미노 설포닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드; 18. (2 S) - N - {4- [ amino (imino) methyl] -3-amino-benzyl} -1 - {(2 R) -2 - [( aminosulfonyl) amino] -3,3- Diphenylpropanoyl} -2-pyrrolidinecarboxamide;

19. (2S)-N-{4-[아미노(이미노)메틸]-2-메틸옥시벤질}-1-{(2R)-2-[(아미노 설포닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드; 19. (2 S) - N - {4- [ amino (imino) methyl] -2-methyl-benzyl oxy} -1 - {(2 R) -2 - [( aminosulfonyl) amino] 3,3 -Diphenylpropanoyl} -2-pyrrolidinecarboxamide;

20. (2S)-N-{4-[아미노(이미노)메틸]벤질}1-{(2R)-2-[(아미노설포닐)아미노] -3-(4-하이드록시페닐)프로파노일}-2-피롤리딘카르복사미드; 20. (2 S) - N - {4- [ amino (imino) methyl] benzyl} 1 - {(2 R) -2 - [( aminosulfonyl) amino] -3- (4-hydroxyphenyl) Propanoyl} -2-pyrrolidinecarboxamide;

21. (2S)-N-{4-[아미노(이미노)메틸]벤질}-1-{(2R)-2-[(t-부틸옥시카보닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드; 21. (2 S) - N - {4- [ amino (imino) methyl] benzyl} -1 - {(2 R) -2 - [(t- butyloxycarbonyl) amino] -3,3-di Phenylpropanoyl} -2-pyrrolidinecarboxamide;

22. (2S)-N-{4-[아미노(이미노)메틸]벤질}-1-{(2R)-2-[(메틸옥시카보닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드; 22. (2 S) - N - {4- [ amino (imino) methyl] benzyl} -1 - {(2 R) -2 - [( methyloxy-carbonyl) amino] -3,3-diphenyl-pro Panoyl} -2-pyrrolidinecarboxamide;

23. (2S)-N-{4-[아미노(이미노)메틸]벤질}-1-{(2R)-2-[(프로필옥시카보닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드; 23. (2 S) - N - {4- [ amino (imino) methyl] benzyl} -1 - {(2 R) -2 - [( propyloxy-carbonyl) amino] -3,3-diphenyl-pro Panoyl} -2-pyrrolidinecarboxamide;

24. (2S)-N-{4-[아미노(이미노)메틸]벤질}-1-{(2R)-2-[(벤질옥시카보닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드; 24. (2 S) - N - {4- [ amino (imino) methyl] benzyl} -1 - {(2 R) -2 - [( benzyloxycarbonyl) amino] -3,3-diphenyl-pro Panoyl} -2-pyrrolidinecarboxamide;

25. (2S)-N-{4-[아미노(이미노)메틸]벤질}-1-{(2R)-2-[(페닐옥시카보닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드; 25. (2 S) - N - {4- [ amino (imino) methyl] benzyl} -1 - {(2 R) -2 - [( phenyloxy-carbonyl) amino] -3,3-diphenyl-pro Panoyl} -2-pyrrolidinecarboxamide;

26. (2S)-N-{4-[아미노(이미노)메틸]벤질}-1-{(2R)-2-[(메틸옥시카보닐)아미노]-3-(3,4-디클로로페닐)프로파노일}-2-피롤리딘카르복사미드; 26. (2 S) - N - {4- [ amino (imino) methyl] benzyl} -1 - {(2 R) -2 - [( methyloxy carbonyl) amino] -3- (3,4- Dichlorophenyl) propanoyl} -2-pyrrolidinecarboxamide;

27. (2S)-N-{4-[아미노(이미노)메틸]벤질}-1-{(2R)-2-[(메틸옥시카보닐)아미노]-3,3-디사이클로헥실프로파노일}-2-피롤리딘카르복사미드; 27. (2 S) - N - {4- [ amino (imino) methyl] benzyl} -1 - {(2 R) -2 - [( methyloxy-carbonyl) amino] -3,3-dicyclohexyl Propanoyl} -2-pyrrolidinecarboxamide;

28. (2S)-N-{4-[아미노(이미노)메틸]벤질}-1-{(2R)-2-[(메틸옥시카보닐)아미노]-3,3-디페닐프로파노일}-2-아제티딘카르복사미드; 28. (2 S) - N - {4- [ amino (imino) methyl] benzyl} -1 - {(2 R) -2 - [( methyloxy-carbonyl) amino] -3,3-diphenyl-pro Panoyl} -2-azetidinecarboxamide;

29. (2S)-N-{4-[아미노(이미노)메틸]벤질}-1-{(2R)-2-[(메틸옥시카보닐)아미노]-2-사이클로헥실에탄오일}-2-피롤리딘카르복사미드; 29. (2 S) - N - {4- [ amino (imino) methyl] benzyl} -1 - {(2 R) -2 - [( methyloxy-carbonyl) amino] -2-cyclohexyl-ethane} five days -2-pyrrolidinecarboxamide;

30. (2S)-N-{4-[아미노(이미노)메틸]벤질}-1-{(2R)-2-[(메틸옥시카보닐)아미노]-3-사이클로헥실프로파노일}-2-피롤리딘카르복사미드; 30. (2 S) - N - {4- [ amino (imino) methyl] benzyl} -1 - {(2 R) -2 - [( methyloxy-carbonyl) amino] -3-cyclohexyl-propanoyl } -2-pyrrolidinecarboxamide;

31. (2S)-N-({6-[아미노(이미노)메틸]-3-피리디닐}메틸)-1-{(2R)-2-[(메틸옥시카보닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드; 31. (2 S) - N - ({6- [ amino (imino) methyl] -3-pyridinyl} methyl) -1 - {(2 R) -2 - [( methyloxy-carbonyl) amino] - 3,3-diphenylpropanoyl} -2-pyrrolidinecarboxamide;

32. (2S)-N-({6-[아미노(이미노)메틸]-3-피리디닐}메틸)-1-{(2R)-2-[(메틸옥시카보닐)아미노]-3,3-디사이클로헥실프로파노일}-2-피롤리딘카르복사미드; 32. (2 S) - N - ({6- [ amino (imino) methyl] -3-pyridinyl} methyl) -1 - {(2 R) -2 - [( methyloxy-carbonyl) amino] - 3,3-dicyclohexylpropanoyl} -2-pyrrolidinecarboxamide;

33. (2S)-N-({5-[아미노(이미노)메틸]-2-피리디닐}메틸)-1-{(2R)-2-[(메틸옥시카보닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드; 33. (2 S) - N - ({5- [ amino (imino) methyl] -2-pyridinyl} methyl) -1 - {(2 R) -2 - [( methyloxy-carbonyl) amino] - 3,3-diphenylpropanoyl} -2-pyrrolidinecarboxamide;

34. (2S)-N-({2-[아미노(이미노)메틸]-5-피리미디닐}메틸)-1-{(2R)-2-[(메틸옥시카보닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드; 34. (2 S) - N - ({2- [ amino (imino) methyl] -5-pyrimidinyl} methyl) -1 - {(2 R) -2 - [( methyloxy-carbonyl) amino] -3,3-diphenylpropanoyl} -2-pyrrolidinecarboxamide;

35. (2S)-N-{4-[아미노(이미노)메틸]-3-플루오로벤질}-1-{(2R)-2-[(메틸옥시카보닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드; 35. (2 S) - N - {4- [ amino (imino) methyl] -3-fluorobenzyl} -1 - {(2 R) -2 - [( methyloxy-carbonyl) amino] -3, 3-diphenylpropanoyl} -2-pyrrolidinecarboxamide;

36. (2S)-N-{4-[아미노(이미노)메틸]-2-메틸옥시벤질}-1-{(2R)-2-[(메틸옥시카보닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드; 36. (2 S) - N - {4- [ amino (imino) methyl] -2-methyl-benzyl oxy} -1 - {(2 R) -2 - [( methyloxy-carbonyl) amino] -3, 3-diphenylpropanoyl} -2-pyrrolidinecarboxamide;

37. (2S)-N-{4-[아미노(이미노)메틸]-3-메틸벤질}-1-{(2R)-2-[(메틸옥시카보닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드; 37. (2 S) - N - {4- [ amino (imino) methyl] -3-methyl-benzyl} -1 - {(2 R) -2 - [( methyloxy-carbonyl) amino] 3,3 -Diphenylpropanoyl} -2-pyrrolidinecarboxamide;

38. (2S)-N-{4-[아미노(이미노)메틸]벤질}-1-{(2R)-2-(아세틸아미노)-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드; 38. (2 S) - N - {4- [ amino (imino) methyl] benzyl} -1 - {(2 R) -2- ( acetylamino) -3,3-diphenyl-propanoyl} -2 -Pyrrolidinecarboxamide;

39. (2S)-N-{4-[아미노(이미노)메틸]벤질}-1-[(2R)-2-아미노-3,3-디페닐프로판오일]-2-피롤리딘카르복사미드; 39. (2 S) - N - {4- [ amino (imino) methyl] benzyl} -1 - [(2 R) -2- amino-3,3-diphenyl propane five days] -2-pyrrolidine Carboxamides;

40. (2S)-N-{4-[아미노(이미노)메틸]벤질}-1-{(2R)-2-[(메틸설포닐)아미노] -3,3-디페닐프로파노일}-2-피롤리딘카르복사미드; 40. (2 S) - N - {4- [ amino (imino) methyl] benzyl} -1 - {(2 R) -2 - [( methylsulfonyl) amino] -3,3-diphenyl-propanoate Il} -2-pyrrolidinecarboxamide;

41. (2S)-N-{4-[아미노(이미노)메틸]벤질}-1-{(2R)-2-[(벤질설포닐)아미노] -3,3-디페닐프로파노일}-2-피롤리딘카르복사미드; 41. (2 S) - N - {4- [ amino (imino) methyl] benzyl} -1 - {(2 R) -2 - [( benzyl-sulfonyl) amino] -3,3-diphenyl-propanoate Il} -2-pyrrolidinecarboxamide;

42. (2S)-N-{4-[아미노(이미노)메틸]벤질}-1-{(2R)-2-[(디메틸아미노설포닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드; 42. (2 S) - N - {4- [ amino (imino) methyl] benzyl} -1 - {(2 R) -2 - [( dimethylamino sulfonyl) amino] -3,3-diphenyl-pro Panoyl} -2-pyrrolidinecarboxamide;

43. (2S)-N-{4-[아미노(이미노)메틸]벤질}-1-{(2R)-2-[(디메톡시포스포릴)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드; 43. (2 S) - N - {4- [ amino (imino) methyl] benzyl} -1 - {(2 R) -2 - [( dimethoxy-phosphoryl) amino] -3,3-diphenyl-pro Panoyl} -2-pyrrolidinecarboxamide;

44. (2S)-N-{4-[아미노(이미노)메틸]벤질}-1-{(2R)-2-[(디메틸포스포릴)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드; 44. (2 S) - N - {4- [ amino (imino) methyl] benzyl} -1 - {(2 R) -2 - [( dimethyl-phosphoryl) amino] -3,3-diphenyl-propanoate Il} -2-pyrrolidinecarboxamide;

45. (2S)-N-{4-[아미노(이미노)메틸]벤질}-1-{(2R)-2-[(카르복시메틸)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드; 및 45. (2 S) - N - {4- [ amino (imino) methyl] benzyl} -1 - {(2 R) -2 - [( carboxymethyl) amino] -3,3-diphenyl-propanoyl } -2-pyrrolidinecarboxamide; And

46. (2S)-N-{4-[아미노(이미노)메틸]벤질}-1-{(2R)-2-[페닐아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드. 46. (2 S) - N - {4- [ amino (imino) methyl] benzyl} -1 - {(2 R) -2- [ phenyl-amino] -3,3-diphenyl-propanoyl} -2 Pyrrolidinecarboxamide.

본 발명에 따른 화학식 1의 화합물은 또한 약제학적으로 허용되는 염을 형성할 수도 있다. 이러한 약제학적으로 허용되는 염에는 약제학적으로 허용되는 음이온을 함유하는 무독성 산부가염을 형성하는 산, 예를들면 염산, 황산, 질산, 인산, 브롬화수소산, 요오드화수소산 등과 같은 무기산, 타타르산, 포름산, 시트르산, 아세트산, 트리클로로아세트산 또는 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, Organic carbonic acid such as citric acid, acetic acid, trichloroacetic acid or trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, etc., sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalenesulfonic acid Acid addition salts formed by and the like are included.

한편, 본 발명에 따른 화합물들은 비대칭 탄소중심을 가질 수 있으므로 R 또는 S 이성체, 라세미화합물, 부분입체이성체 혼합물 및 개개의 부분입체이성체로서 존재할 수 있으며, 이들 모든 이성체는 본 발명의 범위에 포함된다.On the other hand, the compounds according to the invention may have an asymmetric carbon center and therefore exist as R or S isomers, racemic compounds, diastereomeric mixtures and individual diastereomers, all of these isomers being included in the scope of the invention. .

본 발명의 또다른 목적은 상기 정의된 화학식 1의 화합물을 제조하는 방법을 제공하는 것이다.Another object of the present invention is to provide a method for preparing the compound of formula 1 as defined above.

본 발명에 따른 화학식 1의 화합물은 a) 하기 화학식 7의 시아노 화합물을 황화수소, 요오드화메탄 및 암모늄아세테이트와 차례로 반응시켜 하기 화학식 1a의 아미딘 화합물을 제조하거나, b) 화학식 7의 화합물을 산촉매 존재하에 수소를 사용하여 환원반응시켜 하기 화학식 1b의 아미노메틸 화합물을 제조하거나, c) 하기 화학식 8의 화합물을 탈보호기화시켜 화학식 1a의 아미딘 화합물을 제조함을 특징으로 하여 제조할 수 있다:The compound of formula 1 according to the present invention may be prepared by a) reacting a cyano compound of formula 7 with hydrogen sulfide, methane iodide and ammonium acetate in order to prepare an amidine compound of formula 1a, or b) presenting an acid catalyst in the presence of an acid catalyst. It can be prepared by reducing the reaction with hydrogen to prepare an aminomethyl compound of Formula 1b or c) deprotecting the compound of Formula 8 to produce an amidine compound of Formula 1a:

상기식에서In the above formula

n, m, A, B, E, F, G 및 H는 앞에서 정의한 바와 같고,n, m, A, B, E, F, G and H are as defined above,

P 는 아미노보호기, 바람직하게는 t-부톡시카보닐, 벤질옥시카보닐, 파라톨루엔설포닐 등을 나타낸다.P represents an aminoprotecting group, preferably t-butoxycarbonyl, benzyloxycarbonyl, paratoluenesulfonyl and the like.

본 발명에 따른 상기 방법 a) 내지 c)에서 각 단계의 반응은 바람직하게는 반응에 악영향을 끼치지 않는 통상적인 용매중에서 수행될 수 있으며, 공지의 반응조건을 참조할 수 있다.In the above methods a) to c) according to the present invention, the reaction of each step may be preferably performed in a conventional solvent which does not adversely affect the reaction, and known reaction conditions may be referred to.

먼저 시아노 그룹을 아미디노 그룹으로 전환시키는 방법 (a)에서 황화수소는 시아노 그룹을 티오아미드 그룹으로 전환시키고, 요오드화메탄은 티오아미드 그룹을 메틸티오이미데이트 그룹으로 전환시키며, 암모늄아세테이트는 최종적으로 메틸티오이미데이트 그룹을 아미디노 그룹으로 전환시킨다. 이때, 황화수소를 사용하는 단계에서는 피리딘을, 요오드화메탄을 사용하는 단계에서는 아세톤 또는 아세토니트릴을, 암모늄아세테이트를 사용하는 단계에서는 메탄올과 같은 알콜류 또는 아세토니트릴을 바람직한 용매로서 사용할 수 있다.First, in the method (a) of converting a cyano group to an amidino group, hydrogen sulfide converts a cyano group to a thioamide group, methane iodide converts a thioamide group to a methylthioimide group, and ammonium acetate finally The methylthioimidate group is converted to an amidino group. At this time, pyridine may be used in the step of using hydrogen sulfide, acetone or acetonitrile in the step of using methane iodide, and alcohols such as methanol or acetonitrile in the step of using ammonium acetate may be used as a preferred solvent.

방법 a)에서는 임의로 수율을 향상시킬 목적으로 트리에틸아민 염기존재하에 반응을 수행할 수 있으며, 변법으로서 하이드록실아민 염산염 및 염기 존재하에 가열처리하여 하이드록실아미딘을 제조한 다음 촉매수소반응을 통해 하이드록시기를 제거함으로서 아미딘을 제조하는 방법을 이용할 수도 있다. 방법 b)에서 사용가능한 산촉매로는 염산, 황산, 질산, 트리플루오로아세트산과 같은 강산중에서 선택된 1 종 이상을 들 수 있으며, 가압수소하에 반응을 진행시키는 경우 바람직한 수소압력은 30 내지 70psi이다. 또한, 방법 c)에서 탈보호기화 반응은 HCl 존재하에 수행하거나, 수소첨가반응에 의하거나, 트리플루오로아세트산을 사용하는 방법을 사용할 수 있고, 구체적인 반응조건은 문헌(T.W. Green G.M. Wuts, "Protective Groups in Organic Synthesis", Chapter 7, pp309-405)에 기재된 것을 참조할 수 있다.In method a), the reaction can optionally be carried out in the presence of triethylamine base for the purpose of improving the yield. As a variant, the reaction is carried out in the presence of hydroxylamine hydrochloride and base to prepare hydroxylamidine, followed by catalytic hydrogenation. The method of manufacturing amidine can also be used by removing a hydroxyl group. Acid catalysts usable in process b) include at least one selected from strong acids such as hydrochloric acid, sulfuric acid, nitric acid and trifluoroacetic acid, and the preferred hydrogen pressure is 30 to 70 psi when the reaction is carried out under pressurized hydrogen. In addition, the deprotection gasification reaction in method c) may be carried out in the presence of HCl, by hydrogenation, or by using trifluoroacetic acid, and specific reaction conditions are described in TW Green GM Wuts, "Protective. Groups in Organic Synthesis ", Chapter 7, pp309-405.

본 발명의 방법에 따라 제조된 화학식 1의 화합물은 통상적인 방법에 의해 그의 염으로 전환시킬 수 있다.Compounds of formula (1) prepared according to the process of the invention can be converted to their salts by conventional methods.

상기한 본 발명의 방법에 따른 반응이 완결된 후에 생성물은 통상적인 후처리 방법, 예를들면 크로마토그래피, 재결정화 등의 방법에 의해 분리 및 정제할 수 있다.After completion of the reaction according to the process of the present invention described above, the product can be separated and purified by conventional post-treatment methods such as chromatography, recrystallization and the like.

한편, 화학식 1의 화합물을 제조하는 상기 방법에서 출발물질로 사용된 화학식 7의 화합물 및 화학식 8의 화합물은 하기 반응식 1 내지 3에 도시한 방법에 따라 제조하여 사용할 수 있다.Meanwhile, the compound of Formula 7 and the compound of Formula 8 used as starting materials in the method for preparing the compound of Formula 1 may be prepared and used according to the methods shown in Schemes 1 to 3 below.

먼저, 화학식 7의 시아노 화합물에서 n이 0이고, m이 2이며, B가 -CH(ph)2인 화합물은 N-말단에 보호기가 있는 아미노산 화합물을 출발물질로 하여 하기 반응식 1의 방법에 따라 디펩티드 화합물의 형성, 가수분해, 커플링반응, 탈보호기화 및 A그룹의 도입반응을 통해 제조하거나, 반응식 2의 방법에 따라 디펩티드 화합물의 형성, 탈보호기화, A그룹의 도입반응, 가수분해 및 커플링반응을 통해 제조할 수 있다:First, in the cyano compound of Formula 7, n is 0, m is 2, and B is -CH (ph) 2 is a compound of the following reaction scheme 1 using an amino acid compound having a protecting group at the N-terminus as a starting material. According to the method of Scheme 2, or the formation of the dipeptide compound, the deprotection group, the introduction of the A group, It can be prepared through hydrolysis and coupling reactions:

상기식에서,In the above formula,

EDC는 1-(3-디메틸아미노프로필)-3-에틸카보디이미드 염산염을 나타내고,EDC stands for 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride,

HOBT는 1-하이드록시벤조트리아졸을 나타내며,HOBT stands for 1-hydroxybenzotriazole,

DMF는 디메틸포름아미드를 나타내고 이하 동일한 의미로 사용되며,DMF stands for dimethylformamide and is used hereinafter with the same meaning,

P'는 아미노보호기를 나타낸다.P 'represents an aminoprotecting group.

또한, 화학식 8의 화합물에서 n이 0이고, m이 2이며, B가 -CH(ph)2인 화합물은 하기 반응식 3에 도시한 바에 따라 가수분해 및 커플링반응을 통해 제조할 수 있다:In addition, in the compound of Formula 8, n is 0, m is 2, and B is -CH (ph) 2 may be prepared by hydrolysis and coupling reaction as shown in Scheme 3 below:

상기식에서In the above formula

A, E, F, G, H 및 P는 앞에서 정의한 바와 같다.A, E, F, G, H and P are as defined above.

상기 반응식 1 내지 3에서 커플링반응에 사용될 수 있는 공지의 커플링제로는 디사이클로헥실카보디이미드(DCC), 1-(3-디메틸아미노프로필)-3-에틸카보디이미드(EDC), 1,1'-디카보닐디이미다졸(CDI) 등의 카르보이미드류를 1-하이드록시벤조트리아졸(HOBT)과 혼합된 상태로 사용하거나, 또는 비스-(2-옥소-3-옥사졸리디닐)-포스핀산 클로라이드(BOP-Cl), 디페닐포스포릴아지드(DPPA) 등을 사용할 수 있으나, 단 이들로 제한되는 것은 아니다. 이 반응에는 디메틸포름아미드 이외에 디메틸아세트아미드, 테트라하이드로푸란, 메틸렌클로라이드, 클로로포름 등과 같은 통상의 용매를 사용한다.Known coupling agents that can be used in the coupling reactions in Schemes 1 to 3 include dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC), 1 Carbodiimides, such as 1'- dicarbonyl diimidazole (CDI), are used mixed with 1-hydroxybenzotriazole (HOBT), or bis- (2-oxo-3-oxazolidinyl ) -Phosphinic acid chloride (BOP-Cl), diphenylphosphoryl azide (DPPA) and the like can be used, but is not limited thereto. In addition to dimethylformamide, this reaction uses conventional solvents such as dimethylacetamide, tetrahydrofuran, methylene chloride, chloroform and the like.

상기 반응식 1 내지 3에서 커플링 반응에 사용된 카복실산 화합물은 그대로 사용할 수도 있으나, 바람직하게는 그의 반응성 유도체, 예를들면 산할라이드 또는 그밖의 다른 활성화 에스테르 유도체로 전환시켜 커플링 반응에 사용함으로써 반응을 촉진시킬 수 있다. 카복실산의 활성화 유도체는 아민과의 커플링 반응에 의해 아미드 결합을 형성하거나, 알콜과의 커플링 반응에 의해 에스테르 결합을 형성시키기 위해 필요하다. 이러한 반응성 유도체는 당해 기술분야에서 통상적인 방법에 의해 제조할 수 있는 통상적인 유도체들이 포함되는데, 예를들어 산할라이드에는 산클로라이드가 포함되고, 활성화 에스테르에는 메톡시카보닐클로라이드, 이소부틸옥시카보닐클로라이드 등의 알콕시카보닐할라이드와 커플링 시약으로부터 유도된 카복실산의 무수물, N-하이드록시프탈이미드-유도된 에스테르, N-하이드록시숙신이미드-유도된 에스테르, N-하이드록시-5-노보넨-2',3'-디카복시이미드-유도된 에스테르, 2,4,5-트리클로로페놀-유도된 에스테르 등이 포함되나, 이들로 제한되는 것은 아니다.The carboxylic acid compound used in the coupling reaction in Schemes 1 to 3 may be used as it is, but is preferably converted into a reactive derivative thereof, for example, an acid halide or other activated ester derivative, and used in the coupling reaction. Can be promoted. Activated derivatives of carboxylic acids are necessary to form amide bonds by coupling reactions with amines or to form ester bonds by coupling reactions with alcohols. Such reactive derivatives include conventional derivatives that may be prepared by conventional methods in the art, for example acid halides include acid chlorides, and activated esters include methoxycarbonyl chloride, isobutyloxycarbonyl Anhydrides of carboxylic acids derived from alkoxycarbonyl halides and coupling reagents such as chlorides, N-hydroxyphthalimide-derived esters, N-hydroxysuccinimide-derived esters, N-hydroxy-5-novo Nene-2 ', 3'-dicarboxyimide-derived esters, 2,4,5-trichlorophenol-derived esters, and the like.

본 발명에 따른 화학식 1의 화합물의 트롬빈 억제효과는 문헌(참조: Methods in Enzymology V.80 p341-361; Biochemistry 27, p2144-2151,1988)에 기재된 방법에 따라 하기 수학식 1을 이용하여 해리상수 Ki 값을 결정함으로써 측정한다.The thrombin inhibitory effect of the compound of formula 1 according to the present invention is dissociation constant using the following equation 1 according to the method described in Methods in Enzymology V.80 p341-361; Biochemistry 27, p2144-2151,1988 Measure by determining Ki value.

상기식에서In the above formula

[E]는 억제제와 결합하고 있지 않은 효소의 농도이고,[E] is the concentration of enzyme that is not bound to the inhibitor,

[I]는 효소와 결합하고 있지 않은 억제제의 농도이며,[I] is the concentration of inhibitor that is not bound to the enzyme

[EI]는 효소와 억제제 결합물의 농도이다.[EI] is the concentration of the enzyme and inhibitor combination.

해리상수 Ki는 효소와 트롬빈 억제제 화합물의 해리정도를 나타내는 것이므로 해리상수 값이 작을수록 효소에 대한 억제제의 결합성이 큰 것을 의미하며 따라서 억제활성이 큰 것으로 평가될 수 있다. 이러한 해리상수는 트롬빈의 작용을 받아 가수분해되면 발색성을 나타내는 특정 기질과 반응시키고 그 발색정도를 분광도법에 따라 시간의 함수로 측정함으로서 구할 수 있다.Since the dissociation constant Ki indicates the degree of dissociation between the enzyme and the thrombin inhibitor compound, the smaller the dissociation constant value, the greater the binding of the inhibitor to the enzyme, and thus the higher the inhibitory activity. These dissociation constants can be obtained by reacting with a specific substrate that exhibits color development when hydrolyzed by the action of thrombin and measuring the color development as a function of time according to spectrophotometry.

본 발명에서는 트롬빈의 기질로서 트롬빈의 작용을 받아 가수분해되면 발색하는 물질로 크로모자임 TH(Chromozyme TH: 토실-Gly-Pro-Arg-4-니트로아닐리드아세테이트)를 사용한다. 크로모자임 TH가 트롬빈에 의해 가수분해되면 노란색의 파라-니트로아닐리드가 생성된다. 따라서, 생성되는 파라-니트로아닐리드의 양을 시간에 따른 흡광도의 변화로 측정함으로써 본 발명에 따른 화합물의 트롬빈 억제활성을 측정할 수 있다. 즉, 흡광도의 변화로부터 효소의 활성을 측정할 수 있으며, 이는 곧바로 트롬빈 억제제의 효소활성 억제능력과 연관될 수 있다.In the present invention, chromozyme TH (Chromozyme TH: tosyl-Gly-Pro-Arg-4-nitroanilide acetate) is used as a material for thrombin, which develops upon hydrolysis. Chromozyme TH is hydrolyzed by thrombin to produce yellow para-nitroanilide. Therefore, the thrombin inhibitory activity of the compounds according to the invention can be measured by measuring the amount of para-nitroanilides produced by the change in absorbance over time. That is, the activity of the enzyme can be measured from the change in absorbance, which can be directly related to the ability of the thrombin inhibitor to inhibit the enzyme activity.

이와 같이 트롬빈에 대해 본 발명에 따른 화학식 1의 화합물의 억제활성을 측정한 결과, 본 발명의 화합물은 공지의 트롬빈 억제제인 이노가트란 또는 아가트로반에 비해 우수한 트롬빈 억제활성을 나타냄을 확인할 수 있었다(실험예 1 참조). 또한, 화학식 1의 화합물은 혈전생성 억제력에 있어서도 공지의 아가트로반에 비해 우수한 것으로 확인되었으며(실험예 3 참조), 경구투여에 의해서도 고유의 효과를 나타낼 수 있는 장점을 지니고 있다(실험예 2 참조). 따라서, 본 발명의 화합물은 혈액응고 예방 및 혈전증의 치료에 유용하게 사용될 수 있다.As a result of measuring the inhibitory activity of the compound of formula 1 according to the present invention with respect to thrombin, it was confirmed that the compound of the present invention exhibits superior thrombin inhibitory activity compared to inogartran or agatroban, which are known thrombin inhibitors (See Experimental Example 1). In addition, the compound of Formula 1 was found to be superior to the known agatroban also in the ability to inhibit thrombogenesis (see Experimental Example 3), and has the advantage of exhibiting inherent effects by oral administration (see Experimental Example 2). ). Therefore, the compounds of the present invention can be usefully used for the prevention of blood clotting and the treatment of thrombosis.

따라서, 본 발명은 또한 약제학적으로 허용되는 담체와 함께 화학식 1의 화합물 또는 그의 약제학적으로 허용되는 염을 유효성분으로 함유하는 혈액응고 예방 및 혈전증 치료용 약제학적 조성물을 제공하는 것을 또다른 목적으로 한다.Accordingly, the present invention also provides a pharmaceutical composition for the prevention of blood coagulation and thrombosis containing a compound of formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier for another object. do.

본 발명의 화합물을 임상적인 목적으로 투여시에 단일용량 또는 분리용량으로 숙주에게 투여될 총 일일용량은 체중 1㎏ 당 0.001 내지 10㎎의 범위가 바람직하나, 개개 환자에 대한 특이적인 용량 수준은 사용될 특정 화합물, 환자의 체중, 성, 건강상태, 식이, 약제의 투여시간, 투여방법, 배설률, 약제혼합 및 질환의 중증도 등에 따라 변화될 수 있다.The total daily dose to be administered to the host in a single dose or in separate doses when administering a compound of the present invention for clinical purposes is preferably in the range of 0.001-10 mg / kg body weight, but specific dose levels for individual patients may be used. It may vary depending on the specific compound, the weight of the patient, sex, health condition, diet, the time of administration of the drug, the method of administration, the rate of excretion, the mixing of the drug and the severity of the disease.

본 발명의 화합물은 목적하는 바에 따라 주사용 제제 및 경구용 제제로 투여할 수 있다.The compounds of the present invention can be administered in injectable and oral formulations as desired.

주사용 제제, 예를들면 멸균 주사용 수성 또는 유성 현탁액은 공지된 기술에 따라 적합한 분산제, 습윤제, 또는 현탁제를 사용하여 제조할 수 있다. 이를 위해 사용될 수 있는 용매에는 물, 링거액 및 등장성 NaCl 용액이 있으며, 멸균 고정오일도 통상적으로 용매 또는 현탁 매질로서 사용한다. 모노-, 디-글리세라이드를 포함하여 어떠한 무자극성 고정오일도 이러한 목적으로 사용될 수 있으며, 또한 올레산과 같은 지방산도 주사용 제제에 사용할 수 있다.Injectable preparations, for example sterile injectable aqueous or oleaginous suspensions, can be prepared using suitable dispersing agents, wetting agents, or suspending agents according to known techniques. Solvents that can be used for this are water, Ringer's solution and isotonic NaCl solution, and sterile fixed oils are also commonly used as solvents or suspending media. Any non-irritating fixed oil may be used for this purpose, including mono- and diglycerides, and fatty acids such as oleic acid may also be used in the preparation of injectables.

경구투여용 고체투여 형태로는 캅셀제, 정제, 환제, 산제 및 입제가 있으며, 특히 캅셀제와 정제가 유용하다. 정제 및 환제는 장피제로 제조하는 것이 바람직하다. 고체투여 형태는 본 발명에 따른 화학식 1의 활성화합물을 수크로오즈, 락토오즈, 전분 등과 같은 하나 이상의 불활성 희석제 및 마그네슘스테아레이트와 같은 윤활제, 붕해제, 결합제 등과 같은 담체와 혼합시킴으로서 제조할 수 있다.Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. Particularly, capsules and tablets are useful. Tablets and pills are preferably prepared with enteric agents. Solid dosage forms can be prepared by mixing the active compound of formula 1 according to the invention with one or more inert diluents such as sucrose, lactose, starch and the like and a carrier such as a lubricant such as magnesium stearate, a disintegrant, a binder and the like. .

본 발명에 따른 화학식 1의 화합물의 커다란 특징중의 하나는 이를 함유하는 약제학적 조성물을 경구형 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 오랫동안 유지되는 특성이 있음을 확인함으로서 입증되었다. 따라서, 기존의 트롬빈 억제제와는 달리 경구용 제제로서 효과적으로 사용될 수 있다는 점에서 더욱 유용하다.One of the great features 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 as an oral preparation. Results of pharmacokinetic experiments demonstrated that oral administration of the pharmaceutical composition of the present invention confirms that the concentration of the drug is maintained in the blood for a long time. Therefore, it is more useful in that it can be effectively used as an oral preparation, unlike conventional thrombin inhibitors.

한편, 본 발명의 화합물을 임상적으로 투여하여 목적하는 항응혈효과 및 혈전용해효과를 얻고자 하는 경우에, 본 발명에 따른 화학식 1의 활성화합물은 혈전용해제 및 혈소판 활성 억제제중에서 선택된 1종 이상의 성분과 동시에 투여를 할 수 있다. 이러한 방식으로 본 발명의 화합물과 혼합하여 투여될 수 있는 혈전용해제로는 t-PA, 유로키나제(Urokinase), 스트렙토키나제(Streptokinase) 등이 포함될 수 있으며, 혈소판 활성 억제제로는 아스피린, 티클로피딘(Ticlopidin), 클로피드로겔(Clopidrogel), 7E3 단일항체 등이 포함된다.On the other hand, when clinically administering the compound of the present invention to obtain the desired anticoagulant and thrombolytic effect, the active compound of formula 1 according to the present invention is one or more components selected from thrombolytic agents and platelet activity inhibitors It can be administered at the same time. Thrombolytic agents that can be administered in combination with a compound of the present invention in this manner may include t-PA, urokinase, streptokinase, and the like, and platelet activity inhibitors include aspirin, ticlopidin, Clopidrogel, 7E3 monoclonal antibody, and the like.

그러나, 혈전의 치료 및 예방을 목적으로 본 발명에 따른 화합물을 함유하는 제제는 상술된 것으로 제한되는 것은 아니며, 혈전의 치료 및 예방에 유용한 제제라면 어떠한 것도 포함될 수 있다.However, the preparations containing the compounds according to the invention for the purpose of the treatment and prevention of thrombi are not limited to those described above, and any preparations useful for the treatment and prevention of thrombi can be included.

본 발명을 하기 실시예 및 실험예에 의거하여 보다 구체적으로 설명한다. 그러나, 이들 실시예 및 실험예는 본 발명에 대한 이해를 돕기위한 것일 뿐, 어떤 의미로든 본 발명의 범위가 이들에 의해 한정되는 것은 아니다.The present invention will be described in more detail based on the following Examples and Experimental Examples. However, these Examples and Experimental Examples are only for better understanding of the present invention, and the scope of the present invention is not limited by them in any sense.

하기 실시예에서 화합물의 명칭에 사용되는 약어와 용어의 설명은 다음과 같다:Explanations of abbreviations and terms used in the names of compounds in the following examples are as follows:

amd: 아미디노 (amidino)amd: amidino

hydroxyamd: 하이드록시아미디노 (hydroxyamidino)hydroxyamd: hydroxyamidino

Aze: 아제티딘카르복산 (Azetidinecarboxylic acid)Aze: Azetidinecarboxylic acid

Bn: 벤질 (benzyl)Bn: benzyl

bnamd: 벤질아미드 (benzylamide)bnamd: benzylamide

Boc: t-부틸옥시카보닐 (t-butoxycarbonyl)Boc: t-butyloxycarbonyl

Br: 브로모 (bromo)Br: bromo

Cha: 사이클로헥실알라닌 (Cyclohexylalanine)Cha: Cyclohexylalanine

Chg: 사이클로헥실글리신 (Cyclohexylglycine)Chg: Cyclohexylglycine

Dcha: 디사이클로헥실알라닌 (Dicyclohexylalanine)Dcha: Dicyclohexylalanine

Dcpa: 3,4-디클로로페닐알라닌 (3,4-Dichlorophenylalanine9Dcpa: 3,4-Dichlorophenylalanine (3,4-Dichlorophenylalanine9

Dpa: 디페닐알라닌 (Diphenylalanine)Dpa: Diphenylalanine

F: 플루오로 (fluoro)F: fluoro

piamd: 피콜릴아미드 (picolylamide)piamd: picolylamide

Ph: 페닐 (phenyl)Ph: phenyl

Pro: 프롤린 (Proline)Pro: Proline

TFA: 트리플루오로아세트산 (trifluoroacetic acid)TFA: trifluoroacetic acid

Val: 발린 (Valine)Val: Valine

실시예 1: (2Example 1: (2 SS )-)- NN -{4-[아미노(이미노)메틸]벤질}-1-{(2-{4- [amino (imino) methyl] benzyl} -1-{(2 RR )-2-[(아미노설포닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성Synthesis of) -2-[(aminosulfonyl) amino] -3,3-diphenylpropanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid salt

a) NH2SO2-D-Dpa-Pro-OMe의 제조a) Preparation of NH 2 SO 2 -D-Dpa-Pro-OMe

클로로설포닐이소시아네이트(chlorosulfonylisocyanate, 6.36g, 45mmol)의 디클로로메탄(25㎖)용액에 포름산(formic acid, 2.13g, 45mmol)을 서서히 가하고 상온에서 1시간 동안 교반하였다. 반응액을 1시간 이상 끓인 다음 냉각시켜 1.8N 의 설파모일클로라이드(sulfamoyl chloride) 용액을 수득하였다. D-Dpa-Pro-OMe·HCl(2.5g, 6.47mmol)의 디클로로메탄(100㎖) 용액을 5℃로 냉각시킨 후, 여기에 상기 수득한 1.8N 설파모일클로라이드 용액(6㎖)을 가하고 트리에틸아민(2.7㎖)을 가하였다. 이때 용액이 약간 염기성(pH=8-9)이 되도록 조절하고 이를 pH지로 확인하였다. 반응 완결 후 용액을 디클로로메탄(40㎖)으로 희석하고 포화 소금물로 씻어준 다음, 무수 마그네슘설페이트로 건조, 여과 및 농축시켰다. 잔류물을 칼럼 크로마토그래피(용리액: 에틸아세테이트/n-헥산=2/1, 부피비)로 정제하여 표제화합물 1.88g(수율 67%)을 수득하였다.Formic acid (formic acid, 2.13 g, 45 mmol) was slowly added to a dichloromethane (25 mL) solution of chlorosulfonyl isocyanate (chlorosulfonylisocyanate, 6.36 g, 45 mmol) and stirred at room temperature for 1 hour. The reaction solution was boiled for at least 1 hour and then cooled to obtain a solution of sulfamoyl chloride of 1.8N. After cooling a dichloromethane (100 mL) solution of D-Dpa-Pro-OMe.HCl (2.5 g, 6.47 mmol) to 5 ° C., the obtained 1.8N sulfamoyl chloride solution (6 mL) was added thereto, and Ethylamine (2.7 mL) was added. At this time, the solution was adjusted to be slightly basic (pH = 8-9) and confirmed by pH. After completion of the reaction, the solution was diluted with dichloromethane (40 mL), washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (eluent: ethyl acetate / n-hexane = 2/1, volume ratio) to give 1.88 g (yield 67%) of the title compound.

1H NMR (CDCl3) δ 7.38 - 7.20 (m, 4H), 7.18 (m, 6H), 5.85 (d, 1H), 5.29(s, 2H), 4.95 (dd, 1H), 4.75 (m, 1H), 4.14 (d, 1H), 3.67 (s, 3H), 2.70 (m, 1H), 1.74 (m, 3H), 1.38 (m, 1H) 1 H NMR (CDCl 3 ) δ 7.38-7.20 (m, 4H), 7.18 (m, 6H), 5.85 (d, 1H), 5.29 (s, 2H), 4.95 (dd, 1H), 4.75 (m, 1H ), 4.14 (d, 1H), 3.67 (s, 3H), 2.70 (m, 1H), 1.74 (m, 3H), 1.38 (m, 1H)

FAB MS: 432 [M+1]+ FAB MS: 432 [M + 1] +

b) NH2SO2-D-Dpa-Pro-OH의 제조b) preparation of NH 2 SO 2 -D-Dpa-Pro-OH

단계 a)에서 수득한 화합물(1.88g, 4.36mmol)을 물(100㎖)과 메탄올(150㎖)에 현탁시키고 여기에 0.5N의 리튬하이드록사이드(LiOH) 수용액(40㎖)을 가한 다음 반나절 동안 교반하였다. 1N 염산 수용액을 사용하여 반응액의 pH를 약 2로 산성화시킨 후, 감압증류하여 농축시켰다. 생성된 백색 침전물을 여과, 건조시켜 표제화합물 1.5g을 수득하였다. 한편, 여액을 디클로로메탄(100㎖)으로 추출하여 표제화합물 0.18g을 수득하였다(전체 수율 92%).The compound (1.88 g, 4.36 mmol) obtained in step a) was suspended in water (100 mL) and methanol (150 mL), to which 0.5 N aqueous lithium hydroxide (LiOH) solution (40 mL) was added, followed by half a day. Was stirred. The pH of the reaction solution was acidified to about 2 using 1N aqueous hydrochloric acid solution, and then concentrated by distillation under reduced pressure. The resulting white precipitate was filtered and dried to yield 1.5 g of the title compound. Meanwhile, the filtrate was extracted with dichloromethane (100 mL) to give 0.18 g of the title compound (total yield 92%).

1H NMR (CD3OD) δ 7.40 (m, 2H), 7.33 (m, 2H), 7.24 (m, 6H), 4.95 (dd, 1H), 4.29 (d, 1H), 4.05 (m, 1H), 3.75 (m, 1H), 2.87 (m, 1H), 1.83 - 1.72 (m, 3H), 1.43 (m, 1H) 1 H NMR (CD 3 OD) δ 7.40 (m, 2H), 7.33 (m, 2H), 7.24 (m, 6H), 4.95 (dd, 1H), 4.29 (d, 1H), 4.05 (m, 1H) , 3.75 (m, 1H), 2.87 (m, 1H), 1.83-1.72 (m, 3H), 1.43 (m, 1H)

FAB MS: 418 [M+1]+ FAB MS: 418 [M + 1] +

c) NH2SO2-D-Dpa-Pro-(4-CN)-bnamd의 제조c) preparation of NH 2 SO 2 -D-Dpa-Pro- (4-CN) -bnamd

단계 b)에서 수득한 화합물(0.7g, 1.4mmol)을 디메틸포름아미드(10㎖)에 녹인 후, 0℃로 냉각시켰다. 여기에 1-(3-디메틸아미노프로필)-3-에틸카보디이미드 염산염(EDC, 0.54g, 2.8mmol)과 1-하이드록시벤조트리아졸 수화물(HOBT, 0.3g, 2.1mmol)을 가하고 완전히 녹을 때까지 교반하였다. 이 용액에 4-시아노벤질아민 염산염(0.26g, 1.56mmol)과 N-메틸모폴린(0.6㎖, 4.26mmol)을 가하고 상온으로 서서히 승온시킨 후 2시간 동안 교반하였다. 반응 완결 후 감압증류하여 휘발성 물질을 제거하였다. 수득된 잔액을 에틸아세테이트로 희석한 후, 포화 탄산수소나트륨 수용액, 묽은 염산 및 포화 소금물을 사용하여 차례로 씻어주었다. 무수 마그네슘설페이트로 건조, 여과 및 농축시켰다. 잔류물을 칼럼 크로마토그래피(용리액: 에틸아세테이트/n-헥산=1/1, 부피비)로 정제하여 표제화합물 0.65g(수율 87%)을 수득하였다.The compound (0.7 g, 1.4 mmol) obtained in step b) was dissolved in dimethylformamide (10 mL) and then cooled to 0 ° C. To this was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC, 0.54g, 2.8mmol) and 1-hydroxybenzotriazole hydrate (HOBT, 0.3g, 2.1mmol) and completely dissolved. Stir until. 4-cyanobenzylamine hydrochloride (0.26g, 1.56mmol) and N-methylmorpholine (0.6ml, 4.26mmol) were added to the solution, and the temperature was slowly raised to room temperature, followed by stirring for 2 hours. After completion of the reaction, distillation under reduced pressure was carried out to remove volatiles. The obtained residue was diluted with ethyl acetate and washed sequentially with saturated aqueous sodium hydrogen carbonate solution, diluted hydrochloric acid and saturated brine. Dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1/1, volume ratio) to give 0.65 g (87% yield) of the title compound.

1H NMR (CDCl3) δ 1.42 (m, 1H), 1.52 (m, 1H), 1.75 (m, 1H), 1.98 (m, 1H), 2.63 (m, 1H), 3.63 (m, 1H), 4.17 (m, 1H), 4.28-4.49 (m, 3H), 4.86-4.90 (m, 3H), 5.51 (m, 1H), 7.20-7.45 (m, 12H), 7.58 (m, 2H) 1 H NMR (CDCl 3 ) δ 1.42 (m, 1H), 1.52 (m, 1H), 1.75 (m, 1H), 1.98 (m, 1H), 2.63 (m, 1H), 3.63 (m, 1H), 4.17 (m, 1H), 4.28-4.49 (m, 3H), 4.86-4.90 (m, 3H), 5.51 (m, 1H), 7.20-7.45 (m, 12H), 7.58 (m, 2H)

FAB MS: 532[M+1]+ FAB MS: 532 [M + 1] +

d) NH2SO2-D-Dpa-Pro-(4-amd)-bnamd·TFA의 제조d) Preparation of NH 2 SO 2 -D-Dpa-Pro- (4-amd) -bnamdTFA

단계 c)에서 수득한 화합물(0.64g, 1.37mmol)을 피리딘(10㎖)에 녹여서 가한 다음, 여기에 트리에틸아민(2㎖)을 가했다. 플라스크 한쪽 가지를 통하여 황화수소(H2S) 가스를 용액내로 약 20분간 버블링(bubbling)시키면서 용액의 색깔이 초록빛 또는 진한 갈색으로 변화될 때까지 포화시켰다. 그 후, 마개로 막고 1일간 상온에서 방치하였다. 반응 완결후 감압증류하여 휘발성 물질을 제거하고 진공펌프로 건조시켰다. 수득된 노란색 고체에 아세톤(10㎖)과 요오드화메탄(MeI, 0.26㎖, 4.18mmol)을 함께 가하고 2시간 동안 가열환류시켰다. 이를 다시 감압증류하여 휘발성 물질을 제거하고 진공펌프로 건조시킨 다음 얻어진 잔류물을 아세토니트릴 (5㎖)에 녹여 교반하였다. 여기에 암모늄아세테이트(NH4OAc, 0.32g, 4.15mmol)를 넣고 1시간 동안 가열환류시켰다. 반응 완결 후 농축하고 분취용 HPLC(용리액: TFA 0.1%가 포함된 물/메탄올=75/25→20/80 구배, v/v)로 정제하여 표제화합물 0.27g(수율 41%)을 수득하였다.The compound (0.64 g, 1.37 mmol) obtained in step c) was dissolved in pyridine (10 mL), and then triethylamine (2 mL) was added thereto. Hydrogen sulfide (H 2 S) gas was bubbled through one branch of the flask into the solution for about 20 minutes and saturated until the color of the solution turned green or dark brown. Then, it was plugged and left to stand at room temperature for 1 day. After completion of the reaction, the product was distilled under reduced pressure to remove volatiles and dried with a vacuum pump. Acetone (10 mL) and methane iodide (MeI, 0.26 mL, 4.18 mmol) were added together to the obtained yellow solid, and the mixture was heated to reflux for 2 hours. It was distilled under reduced pressure again to remove volatiles, dried with a vacuum pump, and the resulting residue was dissolved in acetonitrile (5 mL) and stirred. Ammonium acetate (NH 4 OAc, 0.32 g, 4.15 mmol) was added thereto, and the mixture was heated to reflux for 1 hour. After completion of the reaction, the reaction mixture was concentrated and purified by preparative HPLC (eluent: water / methanol containing 0.1% TFA = 75/25 → 20/80 gradient, v / v) to obtain 0.27 g (41% yield) of the title compound.

1H NMR (CD3OD) δ 1.46 (m, 1H), 1.61 (m, 1H), 1.71 (m, 1H), 1.85 (m, 1H), 2.91 (m, 1H), 3.78 (m, 1H), 4.09 (m, 1H), 4.31-4.39 (m, 2H), 4.45 (m, 1H), 4.91 (m, 1H), 7.18-7.55 (m, 12H), 7.73 (m, 2H) 1 H NMR (CD 3 OD) δ 1.46 (m, 1H), 1.61 (m, 1H), 1.71 (m, 1H), 1.85 (m, 1H), 2.91 (m, 1H), 3.78 (m, 1H) , 4.09 (m, 1H), 4.31-4.39 (m, 2H), 4.45 (m, 1H), 4.91 (m, 1H), 7.18-7.55 (m, 12H), 7.73 (m, 2H)

FAB MS: 549 [M+1]+ FAB MS: 549 [M + 1] +

실시예 2: (2Example 2: (2 SS )-)- NN -{4-[아미노메틸]벤질}-1-{(2-{4- [aminomethyl] benzyl} -1-{(2 RR )-2-[(아미노설포닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드 염산염의 합성) -2-[(aminosulfonyl) amino] -3,3-diphenylpropanoyl} -2-pyrrolidinecarboxamide hydrochloride

실시예 1의 단계 c)에서 수득한 화합물(200mg, 0.43mmol)을 메탄올(2㎖)에 녹이고 여기에 10% 팔라듐-탄소 및 진한 염산 5방울을 가한 다음, Parr 수소반응기를 사용하여 50psi의 수소압력하에 6시간 동안 반응시켰다. 생성된 용액을 셀라이트(Celite) 패드로 걸러 불용성 탄소를 제거하고 용매를 감압증류하여 농축시켰다. 생성된 잔류물을 분취용 HPLC(용리액: 물/메탄올=75/25→20/80 구배, v/v)로 정제하여 표제화합물 170mg(수율 86%)을 수득하였다.The compound (200 mg, 0.43 mmol) obtained in step c) of Example 1 was dissolved in methanol (2 mL), and 5% of 10% palladium-carbon and concentrated hydrochloric acid were added thereto, followed by 50 psi of hydrogen using a Parr hydrogen reactor. The reaction was carried out under pressure for 6 hours. The resulting solution was filtered through a pad of Celite to remove insoluble carbon and the solvent was concentrated by distillation under reduced pressure. The resulting residue was purified by preparative HPLC (eluent: water / methanol = 75/25 → 20/80 gradient, v / v) to give 170 mg (86% yield) of the title compound.

1H NMR (CD3OD) δ 1.36 (m, 1H), 1.61 (m, 1H), 2.76 (m, 2H), 2.92 (m, 1H), 3.70 (m, 1H), 4.07 (m, 3H), 4.35 (m, 3H), 5.02 (m, 1H), 7.20-7.54 (m, 14H) 1 H NMR (CD 3 OD) δ 1.36 (m, 1H), 1.61 (m, 1H), 2.76 (m, 2H), 2.92 (m, 1H), 3.70 (m, 1H), 4.07 (m, 3H) , 4.35 (m, 3H), 5.02 (m, 1H), 7.20-7.54 (m, 14H)

FAB MS: 536 [M+1]+ FAB MS: 536 [M + 1] +

실시예 3: (2Example 3: (2 SS )-)- NN -{4-[아미노(이미노)메틸]벤질}-1-{(2-{4- [amino (imino) methyl] benzyl} -1-{(2 RR )-2-[(아미노설포닐)아미노]-3-(3,4-디클로로페닐)프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성Synthesis of) -2-[(aminosulfonyl) amino] -3- (3,4-dichlorophenyl) propanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid salt

a) NH2SO2-D-Dcpa-Pro-OH의 제조a) Preparation of NH 2 SO 2 -D-Dcpa-Pro-OH

D-Dcpa-Pro-OMe·HCl에 대해 실시예 1의 단계 a) 및 b)에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 60%).The reaction was carried out on D-Dcpa-Pro-OMe.HCl in the same manner as in steps a) and b) of Example 1 to give the title compound (yield 60%).

1H NMR (CD3OD) δ 1.30 (m, 1H), 1.74 (m, 1H), 1.88-1.93 (m, 2H), 2.78 (m, 3H), 3.71 (m, 1H), 4.30-4.42 (m, 2H), 5.23 (m, 1H), 7.11-7.42 (m, 3H) 1 H NMR (CD 3 OD) δ 1.30 (m, 1H), 1.74 (m, 1H), 1.88-1.93 (m, 2H), 2.78 (m, 3H), 3.71 (m, 1H), 4.30-4.42 ( m, 2H), 5.23 (m, 1H), 7.11-7.42 (m, 3H)

FAB MS: 411 [M+1]+ FAB MS: 411 [M + 1] +

b) NH2SO2-D-Dcpa-Pro-(4-CN)-bnamd의 제조b) preparation of NH 2 SO 2 -D-Dcpa-Pro- (4-CN) -bnamd

단계 a)에서 수득한 화합물에 대해 실시예 1의 단계 c)에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 71%).The reaction was carried out on the compound obtained in step a) in the same manner as in step c) of Example 1, to obtain the title compound (yield 71%).

1H NMR (CD3OD) δ 1.35 (m, 1H), 1.77 (m, 1H), 1.89 (m, 1H), 1.99 (m, 1H), 2.81-3.02 (m, 3H), 3.71 (m, 1H), 4.28-4.50 (m, 4H), 7.05 (m, 1H), 7.25-7.55 (m, 4H), 7.68 (m, 2H) 1 H NMR (CD 3 OD) δ 1.35 (m, 1H), 1.77 (m, 1H), 1.89 (m, 1H), 1.99 (m, 1H), 2.81-3.02 (m, 3H), 3.71 (m, 1H), 4.28-4.50 (m, 4H), 7.05 (m, 1H), 7.25-7.55 (m, 4H), 7.68 (m, 2H)

FAB MS: 525 [M+1]+ FAB MS: 525 [M + 1] +

c) NH2SO2-D-Dcpa-Pro-(4-amd)-bnamd·TFA의 제조c) Preparation of NH 2 SO 2 -D-Dcpa-Pro- (4-amd) -bnamdTFA

단계 b)에서 수득한 화합물에 대해 실시예 1의 단계 d)에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 42%).The reaction was carried out for the compound obtained in step b) in the same manner as in step d) of Example 1, to obtain the title compound (yield 42%).

1H NMR (CD3OD) δ 1.28 (m, 1H), 1.75 (m, 1H), 1.90 (m, 1H), 2.00 (m, 1H), 2.98 (m, 2H), 3.07 (m, 1H), 3.82 (m, 1H), 4.36-4.61 (m, 4H), 7.23 (m, 1H), 7.44-7.53 (m, 4H), 7.78 (m, 2H) 1 H NMR (CD 3 OD) δ 1.28 (m, 1H), 1.75 (m, 1H), 1.90 (m, 1H), 2.00 (m, 1H), 2.98 (m, 2H), 3.07 (m, 1H) , 3.82 (m, 1H), 4.36-4.61 (m, 4H), 7.23 (m, 1H), 7.44-7.53 (m, 4H), 7.78 (m, 2H)

FAB MS: 542 [M+1]+ FAB MS: 542 [M + 1] +

실시예 4: (2Example 4: (2 SS )-)- NN -{4-[아미노(이미노)메틸]벤질}-1-{(2-{4- [amino (imino) methyl] benzyl} -1-{(2 RR )-2-[(아미노설포닐)아미노]-3,3-디사이클로헥실프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성Synthesis of) -2-[(aminosulfonyl) amino] -3,3-dicyclohexylpropanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid salt

D-Dcha-Pro-OMe·HCl(참조: J. Med. Chem. 1997, 40, 1565)에 대해 실시예 1과 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 16%).The title compound was obtained in the same manner as in Example 1 against D-Dcha-Pro-OMe.HCl (J. Med. Chem. 1997, 40, 1565) (yield 16%).

1H NMR (CD3OD) δ 1.07-2.18 (m, 27H), 3.31 (m, 1H), 3.79 (m, 1H), 4.18-4.53 (m, 3H), 5.07 (m, 1H), 7.50 (m, 2H), 7.71 (m, 2H) 1 H NMR (CD 3 OD) δ 1.07-2.18 (m, 27H), 3.31 (m, 1H), 3.79 (m, 1H), 4.18-4.53 (m, 3H), 5.07 (m, 1H), 7.50 ( m, 2H), 7.71 (m, 2H)

FAB MS: 561 [M+1]+ FAB MS: 561 [M + 1] +

실시예 5: (2Example 5: (2 SS )-)- NN -{4-[아미노(이미노)메틸]벤질}-1-{(2-{4- [amino (imino) methyl] benzyl} -1-{(2 RR )-2-[(아미노설포닐)아미노]-3,3-디페닐프로파노일}-2-아제티딘카르복사미드 트리플루오로아세트산염의 합성) -2-[(aminosulfonyl) amino] -3,3-diphenylpropanoyl} -2-azetidinecarboxamide trifluoroacetic acid salt

D-Dpa-Aze-OMe·HCl(참조: Liebigs Ann. Chem. 1990, 687)에 대해 실시예 1과 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 25%).The title compound was obtained in the same manner as in Example 1 with respect to D-Dpa-Aze-OMe.HCl (see Liebigs Ann. Chem. 1990, 687) (yield 25%).

1H NMR (CD3OD) δ 2.54 (m, 1H), 2.83 (m, 2H), 2.89 (m, 1H), 3.75 (m, 1H), 4.02 (m, 1H), 4.30-4.37 (m, 2H), 4.41 (m, 1H), 4.87 (m, 1H), 7.16-7.52 (m, 12H), 7.70 (m, 2H) 1 H NMR (CD 3 OD) δ 2.54 (m, 1H), 2.83 (m, 2H), 2.89 (m, 1H), 3.75 (m, 1H), 4.02 (m, 1H), 4.30-4.37 (m, 2H), 4.41 (m, 1H), 4.87 (m, 1H), 7.16-7.52 (m, 12H), 7.70 (m, 2H)

FAB MS: 535 [M+1]+ FAB MS: 535 [M + 1] +

실시예 6: (2Example 6: (2 SS )-)- NN -{4-[아미노(이미노)메틸]벤질}-1-{(2-{4- [amino (imino) methyl] benzyl} -1-{(2 RR )-2-[(아미노설포닐)아미노]-2-사이클로헥실에타노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성Synthesis of) -2-[(aminosulfonyl) amino] -2-cyclohexylethanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid salt

D-Chg-Pro-OMe·HCl에 대해 실시예 1과 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 17%).The reaction was performed with D-Chg-Pro-OMe.HCl in the same manner as in Example 1 to obtain the title compound (yield 17%).

1H NMR (CD3OD) δ 0.93-1.88 (m, 14H), 2.15 (m, 1H), 3.12 (m, 1H), 3.95(m, 1H), 4.37-4.62 (m, 3H), 4.92 (m, 1H), 7.40 (m, 2H), 7.72 (m, 2H) 1 H NMR (CD 3 OD) δ 0.93-1.88 (m, 14H), 2.15 (m, 1H), 3.12 (m, 1H), 3.95 (m, 1H), 4.37-4.62 (m, 3H), 4.92 ( m, 1H), 7.40 (m, 2H), 7.72 (m, 2H)

FAB MS: 465[M+1]+ FAB MS: 465 [M + 1] +

실시예 7: (2Example 7: (2 SS )-)- NN -{4-[아미노(이미노)메틸]벤질}-1-{(2-{4- [amino (imino) methyl] benzyl} -1-{(2 RR )-2-[(아미노설포닐)아미노]-3-사이클로헥실프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성Synthesis of) -2-[(aminosulfonyl) amino] -3-cyclohexylpropanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid salt

D-Cha-Pro-OMe·HCl에 대해 실시예 1과 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 22%).The title compound was obtained by performing the reaction for D-Cha-Pro-OMe.HCl in the same manner as in Example 1 (yield 22%).

1H NMR (CD3OD) δ 0.78-1.0 (m, 2H), 1.10-1.81 (m, 10H), 1.85-2.23 (m, 5H), 3.49 (m, 1H), 3.83 (m, 1H), 4.30-4.55 (m, 3H), 5.05 (m, 1H), 7.42 (m, 2H), 7.68 (m, 2H) 1 H NMR (CD 3 OD) δ 0.78-1.0 (m, 2H), 1.10-1.81 (m, 10H), 1.85-2.23 (m, 5H), 3.49 (m, 1H), 3.83 (m, 1H), 4.30-4.55 (m, 3H), 5.05 (m, 1H), 7.42 (m, 2H), 7.68 (m, 2H)

FAB MS: 479 [M+1]+ FAB MS: 479 [M + 1] +

실시예 8: (2Example 8: (2 SS )-)- NN -{4-[아미노(이미노)메틸]벤질}-1-{(2-{4- [amino (imino) methyl] benzyl} -1-{(2 RR )-2-[(아미노설포닐)아미노]-3-메틸부타노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성Synthesis of) -2-[(aminosulfonyl) amino] -3-methylbutanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid salt

D-Val-Pro-OMe·HCl에 대해 실시예 1과 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 26%).The reaction was performed with D-Val-Pro-OMe.HCl in the same manner as in Example 1 to obtain the title compound (yield 26%).

1H NMR (CD3OD) δ 1.15 (m, 6H), 1.40 (m, 1H), 1.68-1.72 (m, 2H), 1.87 (m, 1H), 2.38 (m, 1H), 3.25 (m, 1H), 3.81 (m, 1H), 4.25-4.63 (m, 3H), 5.20 (m, 1H), 7.47 (m, 2H), 7.70 (m, 2H) 1 H NMR (CD 3 OD) δ 1.15 (m, 6H), 1.40 (m, 1H), 1.68-1.72 (m, 2H), 1.87 (m, 1H), 2.38 (m, 1H), 3.25 (m, 1H), 3.81 (m, 1H), 4.25-4.63 (m, 3H), 5.20 (m, 1H), 7.47 (m, 2H), 7.70 (m, 2H)

FAB MS: 425 [M+1]+ FAB MS: 425 [M + 1] +

실시예 9: (2Example 9: (2 SS )-)- NN -({6-[아미노(이미노)메틸]-3-피리디닐}메틸)-1-{(2-({6- [amino (imino) methyl] -3-pyridinyl} methyl) -1-{(2 RR ) -2-[(아미노설포닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성) -2-[(aminosulfonyl) amino] -3,3-diphenylpropanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid salt

a) 6-시아노-3-피콜린의 제조a) Preparation of 6-cyano-3-picolin

6-브로모-3-피콜린(3g, 17.44mmol)을 디메틸포름아미드(60㎖)에 녹였다. 여기에 시아노구리(2.3g, 26.16mmol)를 가하고 1시간 30분동안 가열환류시켰다. 반응 완결 후 감압증류하여 휘발성 물질을 제거하였다. 잔액을 디에틸에테르로 희석한 후, 암모니아수 및 포화 소금물을 사용하여 차례로 씻어주었다. 무수 마그네슘설페이트로 건조, 여과 및 농축시켰다. 잔류물을 칼럼 크로마토그래피(용리액: 에틸아세테이트/n-헥산=1/9, 부피비)로 정제하여 표제화합물 1.6g(수율 78%)을 수득하였다.6-Bromo-3-picolin (3 g, 17.44 mmol) was dissolved in dimethylformamide (60 mL). Cyano copper (2.3 g, 26.16 mmol) was added thereto, and the mixture was heated to reflux for 1 hour 30 minutes. After completion of the reaction, distillation under reduced pressure was carried out to remove volatiles. The residue was diluted with diethyl ether and washed sequentially with ammonia water and saturated brine. Dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1/9, volume ratio) to give 1.6 g (78% yield) of the title compound.

1H NMR (CDCl3) δ 8.51 (s, 1H), 7.66 (d, 1H), 7.40 (d, 1H), 2.41 (s, 3H) 1 H NMR (CDCl 3 ) δ 8.51 (s, 1H), 7.66 (d, 1H), 7.40 (d, 1H), 2.41 (s, 3H)

FAB MS: 119 [M+1]+ FAB MS: 119 [M + 1] +

b) 6-시아노-3-피콜릴브로마이드의 제조b) Preparation of 6-cyano-3-picolyl bromide

단계 a)에서 수득한 화합물(1.32g, 11.19mmol)을 사염화탄소(30㎖)에 녹인 다음, 여기에 N-브로모숙신이미드(NBS, 2.8g, 15.7mmol) 및 벤조일퍼옥사이드 ((PhCO)2O2, 540mg, 2.24mmol)을 가하고 2시간동안 가열환류시켰다. 반응 완결 후 감압증류하여 휘발성 물질을 제거하였다. 잔류물을 칼럼 크로마토그래피(용리액: 에틸아세테이트/n-헥산=1/9, 부피비)로 정제하여 표제화합물 1.12g(수율 51%)을 수득하였다.The compound obtained in step a) (1.32 g, 11.19 mmol) was dissolved in carbon tetrachloride (30 mL), and then N-bromosuccinimide (NBS, 2.8 g, 15.7 mmol) and benzoyl peroxide ((PhCO) 2 O 2 , 540 mg, 2.24 mmol) was added and heated to reflux for 2 hours. After completion of the reaction, distillation under reduced pressure was performed to remove volatiles. The residue was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1/9, volume ratio) to give 1.12 g (51% yield) of the title compound.

1H NMR (CDCl3) δ 8.64 (s, 1H), 7.76 (d, 1H), 7.63 (d, 1H), 4.55 (s, 2H) 1 H NMR (CDCl 3 ) δ 8.64 (s, 1H), 7.76 (d, 1H), 7.63 (d, 1H), 4.55 (s, 2H)

FAB MS: 197 [M+1]+ FAB MS: 197 [M + 1] +

c) 6-시아노-3-피콜릴아민 염산염의 제조c) preparation of 6-cyano-3-picolylamine hydrochloride

소듐하이드리드(NaH, 240mg, 6mmol)와 THF(10㎖)의 혼합액을 0℃로 냉각시킨후 교반하면서 이미노디카복실산 디-t-부틸에스테르((Me3COCO)2NH, 650mg, 3mmol)를 THF(10㎖)에 녹인 용액을 서서히 적가한 후 30분간 교반하였다. 여기에 단계 b)에서 수득한 화합물(1.06g, 5.4mmol)을 THF(10㎖)에 녹여서 천천히 가한 후 상온으로 승온시켜 2시간 동안 교반하였다. 반응 완결 후 냉각시켜 물(5㎖)을 가하고 감압 증류하여 휘발성 물질을 제거하였다. 잔액을 에틸아세테이트로 묽힌 후, 포화 소금물로 씻어주었다. 무수 마그네슘설페이트로 건조, 여과 및 농축시켰다. 잔류물을 칼럼 크로마토그래피(용리액: 에틸아세테이트/n-헥산=1/9, 부피비)로 정제하여 수득한 화합물(580mg, 1.74mmol)을 메탄올(20㎖)에 녹인 후, 0℃로 냉각시켰다. 여기에 아세틸클로라이드(MeCOCl, 30당량)를 천천히 넣어주었다. 반응액을 상온으로 승온시켜 1시간 동안 교반하였다. 감압하에 휘발성 물질을 제거하여 표제화합물 293mg(수율 53%)을 흰색 고체로 수득하였다.The mixture of sodium hydride (NaH, 240 mg, 6 mmol) and THF (10 mL) was cooled to 0 ° C., and then iminodicarboxylic acid di- t -butyl ester ((Me 3 COCO) 2 NH, 650 mg, 3 mmol) was stirred. The solution dissolved in THF (10 mL) was slowly added dropwise and stirred for 30 minutes. Here, the compound (1.06 g, 5.4 mmol) obtained in step b) was dissolved in THF (10 mL), slowly added thereto, and then heated to room temperature and stirred for 2 hours. After completion of the reaction, the mixture was cooled, water (5 ml) was added thereto, and distillation under reduced pressure was carried out to remove volatiles. The residue was diluted with ethyl acetate and washed with saturated brine. Dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1/9, volume ratio) to dissolve the compound (580 mg, 1.74 mmol) in methanol (20 mL), and then cooled to 0 ° C. Acetyl chloride (MeCOCl, 30 equivalents) was slowly added thereto. The reaction solution was heated to room temperature and stirred for 1 hour. The volatiles were removed under reduced pressure to give 293 mg (53% yield) of the title compound as a white solid.

1H NMR (CD3OD) δ 8.54 (s, 1H), 7.56 (d, 1H), 7.43 (d, 1H), 4.80 (s, 2H) 1 H NMR (CD 3 OD) δ 8.54 (s, 1H), 7.56 (d, 1H), 7.43 (d, 1H), 4.80 (s, 2H)

FAB MS: 133 [M+1]+ FAB MS: 133 [M + 1] +

d) NH2SO2-D-Dpa-Pro-(6-CN)-3-piamd의 제조d) preparation of NH 2 SO 2 -D-Dpa-Pro- (6-CN) -3-piamd

단계 c)에서 수득한 화합물과 실시예 1의 단계 b)에서 수득한 화합물에 대해 실시예 1의 단계 c)에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 65%).The title compound was obtained by performing the reaction of the compound obtained in step c) with the compound obtained in step b) of Example 1 in the same manner as in step c) of Example 1 (yield 65%).

1H NMR (CDCl3) δ 8.28(s, 1H), 7.60 (d, 1H), 7.44 (m, 3H), 7.30-7.23 (m, 7H), 7.05(m, 1H), 6.58(d, 1H), 5.52(s, 2H), 4.90( dd, 1H), 4.68(d, 1H), 4.41(dd, 1H), 4.11(m, 2H), 3.65(m, 1H), 2.64(m, 1H), 2.00- 1.41(m, 4H) 1 H NMR (CDCl 3 ) δ 8.28 (s, 1H), 7.60 (d, 1H), 7.44 (m, 3H), 7.30-7.23 (m, 7H), 7.05 (m, 1H), 6.58 (d, 1H ), 5.52 (s, 2H), 4.90 (dd, 1H), 4.68 (d, 1H), 4.41 (dd, 1H), 4.11 (m, 2H), 3.65 (m, 1H), 2.64 (m, 1H) , 2.00- 1.41 (m, 4H)

FAB MS: 533[M+1]+ FAB MS: 533 [M + 1] +

e) NH2SO2-D-Dpa-Pro-(6-amd)-3-piamd·TFA의 제조e) Preparation of NH 2 SO 2 -D-Dpa-Pro- (6-amd) -3-piamdTFA

단계 d)에서 수득한 화합물에 대해 실시예 1의 단계 d)에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 68%).The reaction was carried out on the compound obtained in step d) in the same manner as in step d) of Example 1, to obtain the title compound (yield 68%).

1H NMR (CD3OD) δ 8.72(s, 1H), 8.08 (d, 1H), 7.99(d, 1H), 7.44- 7.35(m, 4H), 7.26- 7.24 (m, 6H), 4.98 (d, 1H), 4.55( dd, 1H), 4.33-4.30 (m, 2H), 4.06(dd, 1H), 3.76(m, 1H), 2.90(m, 1H), 1.84- 1.45(m, 4H) 1 H NMR (CD 3 OD) δ 8.72 (s, 1H), 8.08 (d, 1H), 7.99 (d, 1H), 7.44-7.35 (m, 4H), 7.26- 7.24 (m, 6H), 4.98 ( d, 1H), 4.55 (dd, 1H), 4.33-4.30 (m, 2H), 4.06 (dd, 1H), 3.76 (m, 1H), 2.90 (m, 1H), 1.84- 1.45 (m, 4H)

FAB MS: 550 [M+1]+ FAB MS: 550 [M + 1] +

실시예 10: (2Example 10: (2 SS )-)- NN -({6-[아미노메틸]-3-피리디닐}메틸)-1-{(2-({6- [aminomethyl] -3-pyridinyl} methyl) -1-{(2 RR )-2-[(아미노설포닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드 염산염의 합성) -2-[(aminosulfonyl) amino] -3,3-diphenylpropanoyl} -2-pyrrolidinecarboxamide hydrochloride

실시예 9의 단계 d)에서 수득한 화합물에 대해 실시예 2에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 75%).The title compound was obtained by the reaction of the compound obtained in step d) of Example 9 in the same manner as in Example 2 (yield 75%).

1H NMR (CD3OD) δ 8.26 (s, 1H), 8.07 (d, 1H), 8.00(d, 1H), 7.52 (m, 4H), 7.36-7.19 (m, 6H), 5.02(d, 1H), 4.64 (m, 3H), 4.31 (m, 1H), 4.09 (s, 2H), 3.75 (m, 1H), 2.80(m, 1H), 1.90-1.45(m, 4H) 1 H NMR (CD 3 OD) δ 8.26 (s, 1H), 8.07 (d, 1H), 8.00 (d, 1H), 7.52 (m, 4H), 7.36-7.19 (m, 6H), 5.02 (d, 1H), 4.64 (m, 3H), 4.31 (m, 1H), 4.09 (s, 2H), 3.75 (m, 1H), 2.80 (m, 1H), 1.90-1.45 (m, 4H)

FAB MS: 537 [M+1]+ FAB MS: 537 [M + 1] +

실시예 11: (2Example 11: (2 SS )-)- NN -({6-[아미노(이미노)메틸]-3-피리디닐}메틸)-1-{(2-({6- [amino (imino) methyl] -3-pyridinyl} methyl) -1-{(2 RR )-2-[(아미노설포닐)아미노]-3,3-디사이클로헥실프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성Synthesis of) -2-[(aminosulfonyl) amino] -3,3-dicyclohexylpropanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid salt

D-Dcha-Pro-OMe·HCl(참조: J. Med. Chem. 1997, 40, 1565)에 대해 실시예 1의 단계 a) 및 b)에서와 동일한 반응을 수행하여 NH2SO2-D-Dcha-Pro-OH를 수득한 후, 이 화합물을 실시예 1의 단계 b)에서 수득한 화합물 대신 사용하는 것을 제외하고는 실시예 1의 단계 c) 및 d)에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 62%).NH 2 SO 2 -D- was carried out on D-Dcha-Pro-OMe.HCl (see J. Med. Chem. 1997, 40, 1565) in the same manner as in steps a) and b) of Example 1 After obtaining Dcha-Pro-OH, the reaction was carried out in the same manner as in steps c) and d) of Example 1, except that this compound was used instead of the compound obtained in step b) of Example 1 The title compound was obtained (yield 62%).

1H NMR (CD3OD) δ 8.72(s, 1H), 8.08 (d, 1H), 7.99(d, 1H), 5.07(m, 1H), 4.18-4.53 (m, 3H), 3.79 (m, 1H), 3.31(m, 1H), 2.18-1.07(m, 27H) 1 H NMR (CD 3 OD) δ 8.72 (s, 1H), 8.08 (d, 1H), 7.99 (d, 1H), 5.07 (m, 1H), 4.18-4.53 (m, 3H), 3.79 (m, 1H), 3.31 (m, 1H), 2.18-1.07 (m, 27H)

FAB MS: 562 [M+1]+ FAB MS: 562 [M + 1] +

실시예 12: (2Example 12: (2 SS )-)- NN -({6-[아미노(이미노)메틸]-3-피리디닐}메틸)-1-{(2-({6- [amino (imino) methyl] -3-pyridinyl} methyl) -1-{(2 RR )-2-[(아미노설포닐)아미노]-3-사이클로헥실프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성Synthesis of) -2-[(aminosulfonyl) amino] -3-cyclohexylpropanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid salt

D-Cha-Pro-OMe·HCl에 대해 실시예 1의 단계 a) 및 b)에서와 동일한 반응을 수행하여 NH2SO2-D-Cha-Pro-OH를 수득한 후, 이 화합물을 실시예 1의 단계 b)에서 수득한 화합물 대신 사용하는 것을 제외하고는 실시예 1의 단계 c) 및 d)에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 54%).The same reaction as in step a) and b) of Example 1 was carried out on D-Cha-Pro-OMe.HCl to obtain NH 2 SO 2 -D-Cha-Pro-OH, which was then prepared in Example The title compound was obtained in the same manner as in step c) and d) of Example 1, except that the compound was used instead of the compound obtained in step b) (yield 54%).

1H NMR (CD3OD) δ 8.67(s, 1H), 8.04 (d, 1H), 7.89(d, 1H), 5.05(m, 1H), 4.55-4.30 (m, 3H), 3.83(m, 1H), 3.49(m, 1H), 2.23-1.85(m, 5H), 1.81-1.10(m,10H), 1.01-0.78(m, 2H) 1 H NMR (CD 3 OD) δ 8.67 (s, 1H), 8.04 (d, 1H), 7.89 (d, 1H), 5.05 (m, 1H), 4.55-4.30 (m, 3H), 3.83 (m, 1H), 3.49 (m, 1H), 2.23-1.85 (m, 5H), 1.81-1.10 (m, 10H), 1.01-0.78 (m, 2H)

FAB MS: 480 [M+1]+ FAB MS: 480 [M + 1] +

실시예 13: (2Example 13: (2 SS )-)- NN -({5-[아미노(이미노)메틸]-2-피리디닐}메틸)-1-{(2-({5- [amino (imino) methyl] -2-pyridinyl} methyl) -1-{(2 RR )-2-[(아미노설포닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성Synthesis of) -2-[(aminosulfonyl) amino] -3,3-diphenylpropanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid salt

a) 5-시아노-2-피콜릴아민 염산염의 제조a) Preparation of 5-cyano-2-picolylamine hydrochloride

5-시아노-2-피콜린에 대해 실시예 9의 단계 b) 및 c)에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 41%).The reaction was carried out on 5-cyano-2-picoline in the same manner as in steps b) and c) of Example 9 to give the title compound (yield 41%).

1H NMR (CD3OD) δ 8.70 (s, 1H), 7.76 (d, 1H), 7.53 (d, 1H), 4.80 (s, 2H) 1 H NMR (CD 3 OD) δ 8.70 (s, 1H), 7.76 (d, 1H), 7.53 (d, 1H), 4.80 (s, 2H)

FAB MS: 133 [M+1]+ FAB MS: 133 [M + 1] +

b) NH2SO2-D-Dpa-Pro-(5-amd)-2-piamd·TFA의 제조b) Preparation of NH 2 SO 2 -D-Dpa-Pro- (5-amd) -2-piamdTFA

단계 a)에서 수득한 화합물과 실시예 1의 단계 b)에서 수득한 화합물에 대해 실시예 1의 단계 c) 및 d)에서와 동일한 방법으로 반응을 수행하여 표제화합물을수득하였다(수율 52%).The title compound was obtained by performing the reaction of the compound obtained in step a) and the compound obtained in step b) of Example 1 in the same manner as in steps c) and d) of Example 1 (yield 52%). .

1H NMR (CD3OD) δ 8.82(s, 1H), 8.18 (d, 1H), 8.03(d, 1H), 7.44- 7.35(m, 4H), 7.26- 7.24 (m, 6H), 5.01 (d, 1H), 4.55(dd, 1H), 4.33-4.30 (m, 2H), 4.06(dd, 1H), 3.76(m, 1H), 2.90(m, 1H), 1.84- 1.45(m, 4H) 1 H NMR (CD 3 OD) δ 8.82 (s, 1H), 8.18 (d, 1H), 8.03 (d, 1H), 7.44-7.35 (m, 4H), 7.26- 7.24 (m, 6H), 5.01 ( d, 1H), 4.55 (dd, 1H), 4.33-4.30 (m, 2H), 4.06 (dd, 1H), 3.76 (m, 1H), 2.90 (m, 1H), 1.84- 1.45 (m, 4H)

FAB MS: 550 [M+1]+ FAB MS: 550 [M + 1] +

실시예 14: (2Example 14: (2 SS )-)- NN -({2-[아미노(이미노)메틸]-5-피리미디닐}메틸)-1- {(2-({2- [amino (imino) methyl] -5-pyrimidinyl} methyl) -1- {(2 RR )-2-[(아미노설포닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성Synthesis of) -2-[(aminosulfonyl) amino] -3,3-diphenylpropanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid salt

실시예 1의 단계 c)에서 4-시아노벤질아민 염산염 대신에 5-아미노메틸-2-시아노-피리미딘염산염(WO9625426)을 사용하는 것을 제외하고는 실시예 1의 단계 c) 및 d)에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 46%).Example c steps and d) except that 5-aminomethyl-2-cyano-pyrimidine hydrochloride (WO9625426) is used instead of 4-cyanobenzylamine hydrochloride in step c) of Example 1 The reaction was carried out in the same manner as in to give the title compound (yield 46%).

1H NMR (CD3OD) δ 8.72(m, 2H), 7.44- 7.35(m, 4H),7.26- 7.24 (m, 6H), 5.02 (d, 1H), 4.55( dd, 1H), 4.33-4.30 (m, 2H), 4.06(dd, 1H), 3.76(m, 1H),2.90(m, 1H), 1.84- 1.45(m, 4H) 1 H NMR (CD 3 OD) δ 8.72 (m, 2H), 7.44-7.35 (m, 4H), 7.26- 7.24 (m, 6H), 5.02 (d, 1H), 4.55 (dd, 1H), 4.33- 4.30 (m, 2H), 4.06 (dd, 1H), 3.76 (m, 1H), 2.90 (m, 1H), 1.84- 1.45 (m, 4H)

FAB MS: 551 [M+1]+ FAB MS: 551 [M + 1] +

실시예 15: (2Example 15: (2 SS )-)- NN -{4-[아미노(이미노)메틸]-3-플루오로벤질}-1-{(2-{4- [amino (imino) methyl] -3-fluorobenzyl} -1-{(2 RR )- 2-[(아미노설포닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성)-Synthesis of 2-[(aminosulfonyl) amino] -3,3-diphenylpropanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid salt

a) 2-플루오로-4-메틸벤조니트릴의 제조a) Preparation of 2-fluoro-4-methylbenzonitrile

4-브로모-3-플루오로-톨루엔(2g, 10.6mmol)과 시아노구리(1.4g, 15.9mmol)를 디메틸포름아미드(DMF, 15㎖)와 함께 반응용기에 가하였다. 반응액을 200℃로 가열환류시키면서 4시간 동안 반응시킨 후 0℃로 냉각시키고 에틸아세테이트(100㎖)를 가하였다. 녹지 않는 고체를 여과한 후 암모니아수(100㎖)로 세척하고, 무수 마그네슘설페이트로 건조, 여과 및 농축시켰다. 잔류물을 칼럼 크로마토그래피(용리액: 에틸아세테이트/n-헥산=1/4, 부피비)로 정제하여 표제화합물 1.0g(수율 70%)을 수득하였다.4-Bromo-3-fluoro-toluene (2 g, 10.6 mmol) and cyano copper (1.4 g, 15.9 mmol) were added to the reaction vessel together with dimethylformamide (DMF, 15 mL). The reaction solution was reacted for 4 hours while heating to reflux at 200 ° C., cooled to 0 ° C., and ethyl acetate (100 mL) was added thereto. The insoluble solid was filtered off, washed with ammonia water (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1/4, volume ratio) to obtain 1.0 g (yield 70%) of the title compound.

1H NMR (CDCl3) δ 7.50 (m, 1H), 7.08 (m, 2H), 2.45 (s, 3H) 1 H NMR (CDCl 3 ) δ 7.50 (m, 1H), 7.08 (m, 2H), 2.45 (s, 3H)

FAB MS: 136 [M+1]+ FAB MS: 136 [M + 1] +

b) 4-브로모메틸-2-플루오로벤조니트릴의 제조b) Preparation of 4-bromomethyl-2-fluorobenzonitrile

단계 a)에서 수득한 화합물(1g, 7.4mmol)과 N-브로모숙신이미드(NBS, 1.9g, 10.6mmol)를 사염화탄소(100㎖)와 함께 반응용기에 가한 다음, 벤조일퍼옥사이드 ((PhCO)2O2, 0.39g, 1.6mmol)를 가하고 3시간 동안 가열환류시켰다. 반응액을 0℃로 냉각시킨 후 녹지 않는 고체를 여과하였다. 여액을 디클로로메탄(400㎖)으로 희석시키고 포화 탄산수소나트륨 수용액을 사용하여 2회 세척하였다. 무수 마그네슘설페이트로 건조, 여과 및 농축시켰다. 잔류물을 칼럼 크로마토그래피(용리액: 에틸아세테이트/n-헥산=1/9, 부피비)로 정제하여 표제화합물 0.9g(수율 56%)을 수득하였다.Compound (1 g, 7.4 mmol) and N-bromosuccinimide (NBS, 1.9 g, 10.6 mmol) obtained in step a) were added to the reaction vessel together with carbon tetrachloride (100 mL), followed by benzoyl peroxide ((PhCO ) 2 O 2 , 0.39 g, 1.6 mmol) was added and heated to reflux for 3 hours. After cooling the reaction solution to 0 ℃ solid that was not filtered was filtered. The filtrate was diluted with dichloromethane (400 mL) and washed twice with saturated aqueous sodium hydrogen carbonate solution. Dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1/9, volume ratio) to give 0.9 g (56% yield) of the title compound.

1H NMR (CDCl3) δ 7.41 (m, 1H), 7.30 (m, 2H), 4.55 (s, 2H) 1 H NMR (CDCl 3 ) δ 7.41 (m, 1H), 7.30 (m, 2H), 4.55 (s, 2H)

FAB MS: 215 [M+1]+ FAB MS: 215 [M + 1] +

c) 4-시아노-3-플루오로벤질아민 염산염의 제조c) preparation of 4-cyano-3-fluorobenzylamine hydrochloride

단계 b)에서 수득한 화합물에 대해 실시예 9의 단계 c)에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 78%).The reaction was carried out on the compound obtained in step b) in the same manner as in step c) of Example 9, to obtain the title compound (yield 78%).

1H NMR (CD3OD) δ 7.49 (m, 1H), 7.20 (m, 2H), 4.12 (s, 2H) 1 H NMR (CD 3 OD) δ 7.49 (m, 1H), 7.20 (m, 2H), 4.12 (s, 2H)

FAB MS: 151 [M+1]+ FAB MS: 151 [M + 1] +

d) NH2SO2-D-Dpa-Pro-(6-amd-3-F)-bnamd·TFA의 제조d) Preparation of NH 2 SO 2 -D-Dpa-Pro- (6-amd-3-F) -bnamdTFA

단계 c)에서 수득한 화합물과 실시예 1의 단계 b)에서 수득한 화합물에 대해 실시예 1의 단계 c) 및 d)에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 41%).Reaction was carried out for the compound obtained in step c) and the compound obtained in step b) of Example 1 in the same manner as in steps c) and d) of Example 1 to obtain the title compound (yield 41%). .

1H NMR (CD3OD) δ 1.47 (m, 1H), 1.61 (m, 1H), 1.72 (m, 1H), 1.85 (m, 1H), 2.88 (m, 1H), 3.78 (m, 1H), 4.07 (m, 1H), 4.35 (m, 2H), 4.50 (m, 1H), 5.05 (m, 1H), 7.21-7.45 (m, 12H), 7.60 (m, 1H) 1 H NMR (CD 3 OD) δ 1.47 (m, 1H), 1.61 (m, 1H), 1.72 (m, 1H), 1.85 (m, 1H), 2.88 (m, 1H), 3.78 (m, 1H) , 4.07 (m, 1H), 4.35 (m, 2H), 4.50 (m, 1H), 5.05 (m, 1H), 7.21-7.45 (m, 12H), 7.60 (m, 1H)

FAB MS: 567 [M+1]+ FAB MS: 567 [M + 1] +

실시예 16: (2Example 16: (2 SS )-)- NN -{4-[아미노(이미노)메틸]-2-플루오로벤질}-1-{(2-{4- [amino (imino) methyl] -2-fluorobenzyl} -1-{(2 RR )- 2-[(아미노설포닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성)-Synthesis of 2-[(aminosulfonyl) amino] -3,3-diphenylpropanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid salt

실시예 15의 단계 a)에서 4-브로모-3-플루오로-톨루엔 대신에 4-브로모-2-플루오로-톨루엔을 사용하는 것을 제외하고는 실시예 15에서와 동일한 방법에 따라 반응을 수행하여 표제화합물을 수득하였다.The reaction was carried out according to the same method as in Example 15, except that 4-bromo-2-fluoro-toluene was used instead of 4-bromo-3-fluoro-toluene in step a) of Example 15. To give the title compound.

1H NMR (CD3OD) δ 1.47 (m, 1H), 1.61 (m, 1H), 1.75 (m, 1H), 1.84 (m,1H), 2.90 (m, 1H), 3.78 (m, 1H), 4.08 (m, 1H), 4.35 (m, 2H), 4.56 (m, 1H), 4.98 (m, 1H), 7.21-7.71 (m, 13H) 1 H NMR (CD 3 OD) δ 1.47 (m, 1H), 1.61 (m, 1H), 1.75 (m, 1H), 1.84 (m, 1H), 2.90 (m, 1H), 3.78 (m, 1H) , 4.08 (m, 1H), 4.35 (m, 2H), 4.56 (m, 1H), 4.98 (m, 1H), 7.21-7.71 (m, 13H)

FAB MS: 567 [M+1]+ FAB MS: 567 [M + 1] +

실시예 17: (2Example 17: (2 SS )-)- NN -{4-[아미노(이미노)메틸]-3-메틸벤질}-1-{(2-{4- [amino (imino) methyl] -3-methylbenzyl} -1-{(2 RR )-2- [(아미노설포닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성) -2-[(aminosulfonyl) amino] -3,3-diphenylpropanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid salt

a) 4-브로모-3-메틸벤질아민 염산염의 제조a) Preparation of 4-bromo-3-methylbenzylamine hydrochloride

보란 용액(1.0M BH3/THF, 42㎖)을 완전 건조된 500㎖의 둥근 플라스크에 넣고 여기에 무수 THF(20㎖)에 녹인 4-브로모-3-메틸벤즈아미드(1.3g, 6.0mmol) 용액을 적가한 다음 6시간 동안 상온에서 교반하였다. 반응액에 6N 염산(30 ㎖)을 천천히 적가하고 물(30㎖)과 메탄올(150㎖)을 차례로 가한 다음 12시간동안 교반하였다. 용액을 50㎖까지 감압농축시키고 생성된 침전물을 여과하여 제거하였다. 여액은 다시 감압농축하고 얻어진 잔류물을 칼럼 크로마토그래피(용리액: 메탄올/메틸렌클로라이드=1/4, 부피비)로 정제하여 표제화합물 810mg(수율 57%)을 수득하였다.Boran solution (1.0 M BH 3 / THF, 42 ml) was placed in a fully dried 500 ml round flask and dissolved in anhydrous THF (20 ml) 4-bromo-3-methylbenzamide (1.3 g, 6.0 mmol). ) Was added dropwise and stirred at room temperature for 6 hours. 6N hydrochloric acid (30 mL) was slowly added dropwise to the reaction solution, water (30 mL) and methanol (150 mL) were added sequentially, followed by stirring for 12 hours. The solution was concentrated under reduced pressure to 50 ml and the resulting precipitate was filtered off. The filtrate was concentrated under reduced pressure again and the residue was purified by column chromatography (eluent: methanol / methylene chloride = 1/4, volume ratio) to give 810 mg (yield 57%) of the title compound.

1H NMR (CD3OD) δ 7.60 (d, 1H), 7.37 (s, 2H), 7.18 (d, 1H), 4.04 (s,2H), 2.41 (s, 3H) 1 H NMR (CD 3 OD) δ 7.60 (d, 1H), 7.37 (s, 2H), 7.18 (d, 1H), 4.04 (s, 2H), 2.41 (s, 3H)

FAB MS: 201 [M+1]+ FAB MS: 201 [M + 1] +

b) 4-시아노-3-메틸벤질아민 염산염의 제조b) Preparation of 4-cyano-3-methylbenzylamine hydrochloride

단계 a)에서 수득한 화합물(810mg, 3.4mmol)에 대해 실시예 15의 단계 a)에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 44%).The reaction was carried out for the compound obtained in step a) (810 mg, 3.4 mmol) in the same manner as in step a) of Example 15, to obtain the title compound (yield 44%).

1H NMR (CD3OD) δ 8.12 (d, 1H), 7.45 (s, 2H), 7.36 (d, 1H), 4.08 (s, 2H) , 2.40 (s, 3H) 1 H NMR (CD 3 OD) δ 8.12 (d, 1H), 7.45 (s, 2H), 7.36 (d, 1H), 4.08 (s, 2H), 2.40 (s, 3H)

FAB MS: 147 [M+1]+ FAB MS: 147 [M + 1] +

c) NH2SO2-D-Dpa-Pro-(4-amd-3-Me)-bnamd·TFA의 제조c) Preparation of NH 2 SO 2 -D-Dpa-Pro- (4-amd-3-Me) -bnamdTFA

단계 b)에서 수득한 화합물과 실시예 1의 단계 b)에서 수득한 화합물에 대해 실시예 1의 단계 c) 및 d)에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 48%).The reaction of the compound obtained in step b) and the compound obtained in step b) of Example 1 was carried out in the same manner as in steps c) and d) of Example 1 to obtain the title compound (yield 48%). .

1H NMR (CD3OD) δ 1.46 (m, 1H), 1.61 (m, 1H), 1.71 (m, 1H), 1.85 (m, 1H), 2.35 (s, 3H), 2.91 (m, 1H), 3.78 (m, 1H), 4.09 (m, 1H), 4.31-4.39 (m, 2H), 4.45 (m, 1H), 4.91 (m, 1H), 7.18-7.55 (m, 11H), 7.73 (m, 2H) 1 H NMR (CD 3 OD) δ 1.46 (m, 1H), 1.61 (m, 1H), 1.71 (m, 1H), 1.85 (m, 1H), 2.35 (s, 3H), 2.91 (m, 1H) , 3.78 (m, 1H), 4.09 (m, 1H), 4.31-4.39 (m, 2H), 4.45 (m, 1H), 4.91 (m, 1H), 7.18-7.55 (m, 11H), 7.73 (m , 2H)

FAB MS: 563 [M+1]+ FAB MS: 563 [M + 1] +

실시예 18: (2Example 18: (2 SS )-)- NN -{4-[아미노(이미노)메틸]-3-아미노벤질}-1-{(2-{4- [amino (imino) methyl] -3-aminobenzyl} -1-{(2 RR )- 2-[(아미노설포닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성)-Synthesis of 2-[(aminosulfonyl) amino] -3,3-diphenylpropanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid salt

a) 4-브로모메틸-2-니트로벤조니트릴의 제조a) Preparation of 4-bromomethyl-2-nitrobenzonitrile

4-메틸-2-니트로벤조니트릴에 대해 실시예 9의 단계 b)에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 42%).The reaction was carried out on the 4-methyl-2-nitrobenzonitrile in the same manner as in step b) of Example 9 to give the title compound (yield 42%).

1H NMR (CDCl3) δ 8.34 (s, 1H), 7.90 (d, 1H), 7.84 (d, 1H), 4.54 (s, 2H) 1 H NMR (CDCl 3 ) δ 8.34 (s, 1H), 7.90 (d, 1H), 7.84 (d, 1H), 4.54 (s, 2H)

FAB MS: 242 [M+1]+ FAB MS: 242 [M + 1] +

b) 3-니트로-4-시아노벤질아민 염산염의 제조b) Preparation of 3-nitro-4-cyanobenzylamine hydrochloride

단계 a)에서 수득한 화합물에 대해 실시예 9의 단계 c)에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 85%).The reaction was carried out on the compound obtained in step a) in the same manner as in step c) of Example 9, to obtain the title compound (yield 85%).

1H NMR (CD3OD) δ 8.25 (s, 1H), 7.85 (d, 1H), 7.74 (d, 1H), 4.80 (s, 2H) 1 H NMR (CD 3 OD) δ 8.25 (s, 1H), 7.85 (d, 1H), 7.74 (d, 1H), 4.80 (s, 2H)

FAB MS: 178 [M+1]+ FAB MS: 178 [M + 1] +

c) NH2SO2-D-Dpa-Pro-(4-CN-3-NO2)-bnamd의 제조c) Preparation of NH 2 SO 2 -D-Dpa-Pro- (4-CN-3-NO 2 ) -bnamd

단계 b)에서 수득한 화합물과 실시예 1의 단계 b)에서 수득한 화합물에 대해 실시예 1의 제조 c)에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 70%).The title compound was obtained by performing the reaction of the compound obtained in step b) and the compound obtained in step b) of Example 1 in the same manner as in Preparation c) of Example 1 (yield 70%).

1H NMR (CDCl3) δ 8.19(s, 1H), 7.76 (d, 1H), 7.68 (d, 1H), 7.38- 7.24 (m, 10H), 5.49(m, 1H), 5.10(s, 2H), 4.79(dd, 1H), 4.58(dd, 1H), 4.39-4.36(m, 2H), 3.62(m, 1H), 2.59(m, 1H), 1.75- 1.47(m, 4H) 1 H NMR (CDCl 3 ) δ 8.19 (s, 1H), 7.76 (d, 1H), 7.68 (d, 1H), 7.38-7.24 (m, 10H), 5.49 (m, 1H), 5.10 (s, 2H ), 4.79 (dd, 1H), 4.58 (dd, 1H), 4.39-4.36 (m, 2H), 3.62 (m, 1H), 2.59 (m, 1H), 1.75-1.47 (m, 4H)

FAB MS: 576[M+1]+ FAB MS: 576 [M + 1] +

d) NH2SO2-D-Dpa-Pro-(4-CN-3-NH2)-bnamd의 제조d) preparation of NH 2 SO 2 -D-Dpa-Pro- (4-CN-3-NH 2 ) -bnamd

단계 c)에서 수득한 화합물(200mg, 0.35mmol)을 메탄올(6㎖)에 녹이고 여기에 10% 팔라듐-탄소를 가한 다음, Parr 수소 반응기를 이용하여 20psi의 수소압력하에 3시간 동안 반응시켰다. 생성된 용액을 셀라이트(Celite) 패드로 걸러 불용성 탄소를 제거하고 용매를 감압증류하여 농축시켰다. 잔류물을 칼럼 크로마토그래피(용리액: 에틸아세테이트/n-헥산=4/1, 부피비)로 정제하여 표제화합물 170mg (수율 89%)을 수득하였다.The compound (200 mg, 0.35 mmol) obtained in step c) was dissolved in methanol (6 mL) and 10% palladium-carbon was added thereto, followed by reaction under a hydrogen pressure of 20 psi using a Parr hydrogen reactor for 3 hours. The resulting solution was filtered through a pad of Celite to remove insoluble carbon and the solvent was concentrated by distillation under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate / n-hexane = 4/1, volume ratio) to give 170 mg (yield 89%) of the title compound.

1H NMR (CDCl3) δ 7.51(s, 1H), 7.32- 7.20 (m, 10H), 6.91 (d, 1H), 6.80 (d, 1H), 5.39(m, 1H), 5.05(s, 2H), 4.89(dd, 1H), 4.47(dd, 1H), 4.34-4.25(m, 2H), 3.51(m, 1H), 2.49(m, 1H), 1.65- 1.45(m, 4H). 1 H NMR (CDCl 3 ) δ 7.51 (s, 1H), 7.32-7.20 (m, 10H), 6.91 (d, 1H), 6.80 (d, 1H), 5.39 (m, 1H), 5.05 (s, 2H ), 4.89 (dd, 1H), 4.47 (dd, 1H), 4.34-4.25 (m, 2H), 3.51 (m, 1H), 2.49 (m, 1H), 1.65- 1.45 (m, 4H).

FAB MS: 546[M+1]+ FAB MS: 546 [M + 1] +

e) NH2SO2-D-Dpa-Pro-(4-amd-3-NH2)-bnamd·TFA의 제조e) Preparation of NH 2 SO 2 -D-Dpa-Pro- (4-amd-3-NH 2 ) -bnamdTFA

단계 d)에서 수득한 화합물에 대해 실시예 1의 제조 d)에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 66%).The reaction was carried out for the compound obtained in step d) in the same manner as in Preparation d) of Example 1, to obtain the title compound (yield 66%).

1H NMR (CD3OD) δ 7.50(m, 2H), 7.37(m, 2H), 7.27-7.17 (m, 7H), 6.84 (d, 1H), 6.76(d, 1H), 5.05(s, 2H), 4.33(d, 1H), 4.31(s, 2H), 3.69(m, 1H), 2.92(m, 1H), 1.79- 1.40(m, 4H) 1 H NMR (CD 3 OD) δ 7.50 (m, 2H), 7.37 (m, 2H), 7.27-7.17 (m, 7H), 6.84 (d, 1H), 6.76 (d, 1H), 5.05 (s, 2H), 4.33 (d, 1H), 4.31 (s, 2H), 3.69 (m, 1H), 2.92 (m, 1H), 1.79-1.40 (m, 4H)

FAB MS: 564[M+1]+ FAB MS: 564 [M + 1] +

실시예 19: (2Example 19: (2 SS )-)- NN -{4-[아미노(이미노)메틸]-2-메틸옥시벤질}-1-{(2-{4- [amino (imino) methyl] -2-methyloxybenzyl} -1-{(2 RR )- 2-[(아미노설포닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성)-Synthesis of 2-[(aminosulfonyl) amino] -3,3-diphenylpropanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid salt

4-아미노메틸-3-메톡시벤조니트릴 염산염(WO9625426)과 실시예 1의 단계 b)에서 수득한 화합물에 대해 실시예 1의 단계 c) 및 d)에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 54%).The reaction of 4-aminomethyl-3-methoxybenzonitrile hydrochloride (WO9625426) with the compound obtained in step b) of Example 1 was carried out in the same manner as in step c) and d) of Example 1, to obtain the title compound. Was obtained (yield 54%).

1H NMR (CD3OD) δ 1.45 (m, 1H), 1.62 (m, 1H), 1.73 (m, 1H), 1.88 (m, 1H), 2.93 (m, 1H), 3.78-3.85 (m, 4H), 4.12 (m, 1H), 4.28-4.33 (m, 2H), 4.51 (m, 1H), 4.98 (m, 1H), 7.18-7.73 (m, 13H) 1 H NMR (CD 3 OD) δ 1.45 (m, 1H), 1.62 (m, 1H), 1.73 (m, 1H), 1.88 (m, 1H), 2.93 (m, 1H), 3.78-3.85 (m, 4H), 4.12 (m, 1H), 4.28-4.33 (m, 2H), 4.51 (m, 1H), 4.98 (m, 1H), 7.18-7.73 (m, 13H)

FAB MS: 579 [M+1]+ FAB MS: 579 [M + 1] +

실시예 20: (2Example 20: (2 SS )-)- NN -{4-[아미노(이미노)메틸]벤질}-1-{(2-{4- [amino (imino) methyl] benzyl} -1-{(2 RR )-2-[(아미노설포닐)아미노]-3-(4-하이드록시페닐)프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성Synthesis of) -2-[(aminosulfonyl) amino] -3- (4-hydroxyphenyl) propanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid salt

a) NH2SO2-D-Tyr-Pro-OH의 제조a) Preparation of NH 2 SO 2 -D-Tyr-Pro-OH

D-Tyr-Pro-OMe 에 대해 실시예 1의 단계 a) 및 b)에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 69%).The reaction was carried out on D-Tyr-Pro-OMe in the same manner as in steps a) and b) of Example 1 to give the title compound (yield 69%).

1H NMR (CD3OD) δ 7.58(d, 2H), 7.49(d, 2H), 4.41-4.35(m, 2H), 3.64(m, 1H), 3.40(m, 1H), 3.11(m, 1H), 2.97(m, 1H), 2.60 (m, 1H), 1.93- 1.40(m, 4H) 1 H NMR (CD 3 OD) δ 7.58 (d, 2H), 7.49 (d, 2H), 4.41-4.35 (m, 2H), 3.64 (m, 1H), 3.40 (m, 1H), 3.11 (m, 1H), 2.97 (m, 1H), 2.60 (m, 1H), 1.93-1.40 (m, 4H)

FAB MS: 358 [M+1]+ FAB MS: 358 [M + 1] +

b) NH2SO2-D-Tyr-Pro-(4-CN)-bnamd의 제조b) preparation of NH 2 SO 2 -D-Tyr-Pro- (4-CN) -bnamd

단계 a)에서 수득한 화합물에 대해 실시예 1의 단계 c)에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 60%).The reaction was carried out on the compound obtained in step a) in the same manner as in step c) of Example 1, to obtain the title compound (yield 60%).

1H NMR (CD3OD) δ 7.66(d, 2H), 7.45(d, 2H), 7.06(d, 2H), 6.71(d, 2H) 4.58(m, 1H), 4.40(d, 2H), 4.39-4.28(m, 2H), 3.64(m, 1H), 2.92-2.87(m, 2H), 2.72 (m, 1H), 2.00- 1.52(m, 4H) 1 H NMR (CD 3 OD) δ 7.66 (d, 2H), 7.45 (d, 2H), 7.06 (d, 2H), 6.71 (d, 2H) 4.58 (m, 1H), 4.40 (d, 2H), 4.39-4.28 (m, 2H), 3.64 (m, 1H), 2.92-2.87 (m, 2H), 2.72 (m, 1H), 2.00- 1.52 (m, 4H)

FAB MS: 472 [M+1]+ FAB MS: 472 [M + 1] +

c) NH2SO2-D-Tyr-Pro-(4-amd)-bnamd·TFA의 제조c) preparation of NH 2 SO 2 -D-Tyr-Pro- (4-amd) -bnamdTFA

단계 b)에서 수득한 화합물에 대해 실시예 1의 단계 d)에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 55%).The reaction was carried out on the compound obtained in step b) in the same manner as in step d) of Example 1, to obtain the title compound (yield 55%).

1H NMR (CD3OD) δ 7.76(d, 2H), 7.51(d, 2H), 7.07(d, 2H), 6.73(d, 2H) 4.43-4.30(m, 4H), 3.66(m, 1H), 2.94-2.85(m, 2H), 2.73 (m, 1H), 1.90- 1.55(m, 4H) 1 H NMR (CD 3 OD) δ 7.76 (d, 2H), 7.51 (d, 2H), 7.07 (d, 2H), 6.73 (d, 2H) 4.43-4.30 (m, 4H), 3.66 (m, 1H ), 2.94-2.85 (m, 2H), 2.73 (m, 1H), 1.90-1.55 (m, 4H)

FAB MS: 489 [M+1]+ FAB MS: 489 [M + 1] +

실시예 21: (2Example 21: (2 SS )-)- NN -{4-[아미노(이미노)메틸]벤질}-1-{(2-{4- [amino (imino) methyl] benzyl} -1-{(2 RR )-2-[(t-부틸옥시카보닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성Synthesis of) -2-[(t-butyloxycarbonyl) amino] -3,3-diphenylpropanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid salt

a) Boc-D-Dpa-Pro-(4-CN)-bnamd의 제조a) Preparation of Boc-D-Dpa-Pro- (4-CN) -bnamd

Boc-D-Dpa-Pro-OH(참조: J. Med. Chem. 1997, 40, 3726)(2g, 4.5mmol)을 디메틸포름아미드(DMF, 50㎖)에 녹였다. 여기에 1-(3-디메틸아미노프로필)-3-에틸카보디이미드 염산염(EDC, 1.14g, 5.9mmol)과 1-하이드록시벤조트리아졸 수화물 (HOBT, 0.74g, 5.4mmol) 및 4-시아노벤질아민 염산염(0.84g, 5.0mmol)을 가하고 완전히 녹을 때까지 교반하였다. 이 용액을 0℃로 냉각시킨 후 트리에틸아민(2㎖, 13.7mmol)을 가하고 상온으로 서서히 승온시킨 후 2시간 동안 교반하였다. 반응 완결 후 감압증류하여 휘발성 물질을 제거하였다. 얻어진 잔액을 에틸아세테이트로 희석한 후, 포화 탄산수소나트륨 수용액, 묽은 염산 및 포화 소금물로 차례로 씻어주었다. 무수 마그네슘설페이트로 건조, 여과 및 농축시켰다. 잔류물을 칼럼 크로마토그래피(용리액: 에틸아세테이트/n-헥산=2/1, 부피비)로 정제하여 표제화합물 2.1g(수율 84%)을 수득하였다.Boc-D-Dpa-Pro-OH (J. Med. Chem. 1997, 40, 3726) (2 g, 4.5 mmol) was dissolved in dimethylformamide (DMF, 50 mL). It contains 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC, 1.14g, 5.9mmol) and 1-hydroxybenzotriazole hydrate (HOBT, 0.74g, 5.4mmol) and 4-sia Nobenzylamine hydrochloride (0.84 g, 5.0 mmol) was added and stirred until it dissolved completely. After the solution was cooled to 0 ° C., triethylamine (2 mL, 13.7 mmol) was added thereto, and the temperature was slowly raised to room temperature, followed by stirring for 2 hours. After completion of the reaction, distillation under reduced pressure was carried out to remove volatiles. The resulting residue was diluted with ethyl acetate and washed sequentially with saturated aqueous sodium hydrogen carbonate solution, diluted hydrochloric acid and saturated brine. Dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (eluent: ethyl acetate / n-hexane = 2/1, volume ratio) to give 2.1 g (yield 84%) of the title compound.

1H NMR (CDCl3) δ 1.35-1.48 (m, 11H), 1.67 (m, 1H), 2.02 (m, 1H), 2.45 (m, 1H), 3.62 (m, 1H), 4.20 (m, 1H), 4.40 (m, 2H), 4.61 (m, 1H), 4.86 (m, 1H), 5.19 (m, 1H), 7.15-7.48 (m, 11H), 7.62 (m, 3H) 1 H NMR (CDCl 3 ) δ 1.35-1.48 (m, 11H), 1.67 (m, 1H), 2.02 (m, 1H), 2.45 (m, 1H), 3.62 (m, 1H), 4.20 (m, 1H ), 4.40 (m, 2H), 4.61 (m, 1H), 4.86 (m, 1H), 5.19 (m, 1H), 7.15-7.48 (m, 11H), 7.62 (m, 3H)

FAB MS: 553 [M+1]+ FAB MS: 553 [M + 1] +

b) Boc-D-Dpa-Pro-(4-amd)-bnamd·TFA의 제조b) Preparation of Boc-D-Dpa-Pro- (4-amd) -bnamdTFA

단계 a)에서 수득한 화합물(0.15g, 0.27mmol)을 피리딘(2㎖)에 녹여서 가지달린 플라스크에 가한 다음, 여기에 트리에틸아민(0.4㎖)을 가했다. 플라스크 한쪽 가지를 통하여 황화수소(H2S) 가스를 용액내로 약 20분간 버블링(bubbling)시키면서 용액의 색깔이 초록빛 또는 진한 갈색으로 변화될 때까지 포화시켰다. 그 후, 마개로 막고 1일간 상온에서 방치하였다. 반응 완결후 감압증류하여 휘발성 물질을 제거하고 진공펌프로 건조시켰다. 수득된 노란색 고체에 아세톤(2㎖)과 요오드화메탄(MeI, 0.05㎖, 0.81mmol)을 함께 가하고 3시간 동안 가열환류시켰다. 이를 다시 감압증류하여 휘발성 물질을 제거하고 진공펌프로 건조시킨 다음 얻어진 잔류물을 아세토니트릴(2㎖)에 녹여 교반하였다. 여기에 암모늄아세테이트(NH4OAc, 0.06g, 0.81mmol)를 넣고 1시간 동안 가열환류시켰다. 반응 완결 후 농축하고 분취용 HPLC(용리액: TFA 0.1%가 포함된 물/메탄올=75/25→20/80 구배, v/v)로 정제하여 표제화합물 0.11g(수율 60%)을 수득하였다.The compound (0.15 g, 0.27 mmol) obtained in step a) was dissolved in pyridine (2 mL) and added to a flask equipped with triethylamine (0.4 mL). Hydrogen sulfide (H 2 S) gas was bubbled through one branch of the flask into the solution for about 20 minutes and saturated until the color of the solution turned green or dark brown. Then, it was plugged and left to stand at room temperature for 1 day. After completion of the reaction, the product was distilled under reduced pressure to remove volatiles and dried with a vacuum pump. Acetone (2 mL) and methane iodide (MeI, 0.05 mL, 0.81 mmol) were added together to the obtained yellow solid, and the mixture was heated to reflux for 3 hours. It was distilled under reduced pressure again to remove volatiles, dried with a vacuum pump, and the residue was dissolved in acetonitrile (2 ml) and stirred. Ammonium acetate (NH 4 OAc, 0.06 g, 0.81 mmol) was added thereto, and the mixture was heated to reflux for 1 hour. After completion of the reaction, the reaction mixture was concentrated and purified by preparative HPLC (eluent: water / methanol containing 0.1% TFA = 75/25 → 20/80 gradient, v / v) to obtain 0.11 g (yield 60%) of the title compound.

1H NMR (CD3OD) δ 1.38-1.65 (m, 11H), 1.84 (m, 2H), 2.80 (m, 1H), 3.75 (m, 1H), 4.12 (m, 1H), 4.42 (m, 2H), 4.57 (m, 1H), 5.08 (m, 1H), 7.15-7.55 (m, 12H), 7.74 (m, 2H) 1 H NMR (CD 3 OD) δ 1.38-1.65 (m, 11H), 1.84 (m, 2H), 2.80 (m, 1H), 3.75 (m, 1H), 4.12 (m, 1H), 4.42 (m, 2H), 4.57 (m, 1H), 5.08 (m, 1H), 7.15-7.55 (m, 12H), 7.74 (m, 2H)

FAB MS: 570 [M+1]+ FAB MS: 570 [M + 1] +

실시예 22: (2Example 22: (2 SS )-)- NN -{4-[아미노(이미노)메틸]벤질}-1-{(2-{4- [amino (imino) methyl] benzyl} -1-{(2 RR )-2-[(메틸옥시카보닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성) -2-[(methyloxycarbonyl) amino] -3,3-diphenylpropanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid

a) MeO2C-D-Dpa-Pro-(4-CN)-bnamd의 제조a) Preparation of MeO 2 CD-Dpa-Pro- (4-CN) -bnamd

실시예 21의 단계 a)에서 수득한 화합물(0.17g, 0.30mmol)을 메탄올(3㎖)에 녹인 후, 여기에 아세틸클로라이드(MeCOCl, 0.3㎖)를 실온에서 가하였다. 이 용액을 2시간동안 교반한 후 감압증류하여 휘발성 물질을 제거하고 진공펌프로 건조시켰다. 수득된 잔류물을 디클로로메탄(2㎖)에 녹여 교반하고, 용액을 0℃로 냉각시켰다. 여기에 트리에틸아민(0.13㎖, 0.92mmol)과 메틸클로로포메이트(MeOCOCl, 0.04㎖, 0.46mmol)를 가하고 상온으로 서서히 승온시킨 후 2시간 동안 교반하였다. 반응 완결 후 농축하고 잔류물을 칼럼 크로마토그래피(용리액: 에틸아세테이트/n-헥산=2/1, 부피비)로 정제하여 표제화합물 0.13g(수율 81%)을 수득하였다.The compound obtained in step a) of Example 21 (0.17 g, 0.30 mmol) was dissolved in methanol (3 mL), and acetyl chloride (MeCOCl, 0.3 mL) was added thereto at room temperature. After stirring for 2 hours, the solution was distilled under reduced pressure to remove volatiles and dried with a vacuum pump. The obtained residue was dissolved in dichloromethane (2 mL) and stirred, and the solution was cooled to 0 ° C. Triethylamine (0.13 mL, 0.92 mmol) and methylchloroformate (MeOCOCl, 0.04 mL, 0.46 mmol) were added thereto, and the temperature was slowly raised to room temperature, followed by stirring for 2 hours. After completion of the reaction was concentrated and the residue was purified by column chromatography (eluent: ethyl acetate / n- hexane = 2/1, volume ratio) to give 0.13g (yield 81%) of the title compound.

1H NMR (CDCl3) δ 1.45 (m, 2H), 1.70 (m, 1H), 2.19 (m, 1H), 2.51 (m, 1H), 3.20 (s, 3H), 3.68 (m, 1H), 4.25 (m, 1H), 4.40 (m, 2H), 4.77 (m, 1H), 4.88 (m, 1H), 5.24 (m, 1H), 7.28-7.48 (m, 11H), 7.68 (m, 3H) 1 H NMR (CDCl 3 ) δ 1.45 (m, 2H), 1.70 (m, 1H), 2.19 (m, 1H), 2.51 (m, 1H), 3.20 (s, 3H), 3.68 (m, 1H), 4.25 (m, 1H), 4.40 (m, 2H), 4.77 (m, 1H), 4.88 (m, 1H), 5.24 (m, 1H), 7.28-7.48 (m, 11H), 7.68 (m, 3H)

FAB MS: 511 [M+1]+ FAB MS: 511 [M + 1] +

b) MeO2C-D-Dpa-Pro-(4-amd)-bnamd·TFA의 제조b) Preparation of MeO 2 CD-Dpa-Pro- (4-amd) -bnamdTFA

단계 a)에서 수득한 화합물(0.13g, 0.25mmol)에 대해 실시예 1의 단계 d)에서와 동일한 방법으로 반응을 수행하여 표제화합물 0.10g(수율 62%)을 수득하였다.The reaction (0.13 g, 0.25 mmol) obtained in step a) was carried out in the same manner as in step d) of Example 1 to obtain 0.10 g (yield 62%) of the title compound.

1H NMR (CD3OD) δ 1.49 (m, 1H), 1.65 (m, 1H), 1.84 (m, 2H), 2.89 (m, 1H), 3.29 (s, 3H), 3.83 (m, 1H), 4.12 (m, 1H), 4.38 (m, 2H), 4.57 (m, 1H), 5.12 (m, 1H), 7.18-7.52 (m, 12H), 7.83 (m, 2H) 1 H NMR (CD 3 OD) δ 1.49 (m, 1H), 1.65 (m, 1H), 1.84 (m, 2H), 2.89 (m, 1H), 3.29 (s, 3H), 3.83 (m, 1H) , 4.12 (m, 1H), 4.38 (m, 2H), 4.57 (m, 1H), 5.12 (m, 1H), 7.18-7.52 (m, 12H), 7.83 (m, 2H)

FAB MS: 528 [M+1]+ FAB MS: 528 [M + 1] +

실시예 23: (2Example 23: (2 SS )-)- NN -{4-[아미노(이미노)메틸]벤질}-1-{(2-{4- [amino (imino) methyl] benzyl} -1-{(2 RR )-2-[(프로필옥시카보닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성) -2-[(propyloxycarbonyl) amino] -3,3-diphenylpropanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid salt

실시예 22의 단계 a)에서 메틸클로로포메이트 대신에 프로필클로로포메이트를 사용하여 PrO2C-D-Dpa-Pro-(4-CN)-bnamd 를 수득한 다음, 이 화합물에 대해 실시예 1의 단계 d)에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 57%).In step a) of Example 22, PrO 2 CD-Dpa-Pro- (4-CN) -bnamd was obtained using propylchloroformate instead of methylchloroformate, followed by the steps of Example 1 for this compound The reaction was carried out in the same manner as in d) to give the title compound (yield 57%).

1H NMR (CD3OD) δ 0.91 (t, 3H), 1.35-1.51 (m, 3H), 1.67 (m, 1H), 1.88 (m, 2H), 2.85 (m, 1H), 3.35 (s, 3H), 3.89 (m, 1H), 4.02-4.15 (m, 3H), 4.35 (m, 2H), 4.62 (m, 1H), 5.11 (m, 1H), 7.18-7.60 (m, 12H), 7.82 (m, 2H) 1 H NMR (CD 3 OD) δ 0.91 (t, 3H), 1.35-1.51 (m, 3H), 1.67 (m, 1H), 1.88 (m, 2H), 2.85 (m, 1H), 3.35 (s, 3H), 3.89 (m, 1H), 4.02-4.15 (m, 3H), 4.35 (m, 2H), 4.62 (m, 1H), 5.11 (m, 1H), 7.18-7.60 (m, 12H), 7.82 (m, 2H)

FAB MS: 556 [M+1]+ FAB MS: 556 [M + 1] +

실시예 24: (2Example 24: (2 SS )-)- NN -{4-[아미노(이미노)메틸]벤질}-1-{(2-{4- [amino (imino) methyl] benzyl} -1-{(2 RR )-2-[(벤질옥시카보닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성Synthesis of) -2-[(benzyloxycarbonyl) amino] -3,3-diphenylpropanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid salt

실시예 22의 단계 a)에서 메틸클로로포메이트 대신에 벤질클로로포메이트를 사용하여 BnO2C-D-Dpa-Pro-(4-CN)-bnamd를 수득한 다음, 이 화합물에 대해 실시예 1의 단계 d)에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 41%).In step a) of Example 22, BnO 2 CD-Dpa-Pro- (4-CN) -bnamd was obtained using benzylchloroformate instead of methylchloroformate, followed by the steps of Example 1 for this compound The reaction was carried out in the same manner as in d) to give the title compound (yield 41%).

1H NMR (CD3OD) δ 1.53 (m, 1H), 1.71 (m, 1H), 1.89 (m, 2H), 2.81 (m, 1H), 3.25 (s, 3H), 3.85 (m, 1H), 4.22 (m, 1H), 4.38 (m, 2H), 4.51 (m, 1H),5.07 (m, 3H), 7.15-7.62 (m, 17H), 7.80 (m, 2H) 1 H NMR (CD 3 OD) δ 1.53 (m, 1H), 1.71 (m, 1H), 1.89 (m, 2H), 2.81 (m, 1H), 3.25 (s, 3H), 3.85 (m, 1H) , 4.22 (m, 1H), 4.38 (m, 2H), 4.51 (m, 1H), 5.07 (m, 3H), 7.15-7.62 (m, 17H), 7.80 (m, 2H)

FAB MS: 604 [M+1]+ FAB MS: 604 [M + 1] +

실시예 25: (2Example 25: (2 SS )-)- NN -{4-[아미노(이미노)메틸]벤질}-1-{(2-{4- [amino (imino) methyl] benzyl} -1-{(2 RR )-2-[(페닐옥시카보닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성Synthesis of) -2-[(phenyloxycarbonyl) amino] -3,3-diphenylpropanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid salt

실시예 22의 단계 a)에서 메틸클로로포메이트 대신에 페닐클로로포메이트를 사용하여 PhO2C-D-Dpa-Pro-(4-CN)-bnamd를 수득한 다음, 이 화합물에 대해 실시예 1의 단계 d)에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율: 63%).In step a) of Example 22, PhO 2 CD-Dpa-Pro- (4-CN) -bnamd was obtained using phenylchloroformate instead of methylchloroformate, followed by the steps of Example 1 for this compound. The reaction was carried out in the same manner as in d) to give the title compound (yield: 63%).

1H NMR (CD3OD) δ 1.51 (m, 1H), 1.60 (m, 1H), 1.73 (m, 1H), 1.88 (m, 1H), 2.93 (m, 1H), 3.31 (s, 3H), 3.88 (m, 1H), 4.17 (m, 1H), 4.29 (m, 1H), 4.43 (m, 1H), 4.57 (m, 1H), 5.12 (m, 1H), 7.10-7.58 (m, 17H), 7.79 (m, 2H) 1 H NMR (CD 3 OD) δ 1.51 (m, 1H), 1.60 (m, 1H), 1.73 (m, 1H), 1.88 (m, 1H), 2.93 (m, 1H), 3.31 (s, 3H) , 3.88 (m, 1H), 4.17 (m, 1H), 4.29 (m, 1H), 4.43 (m, 1H), 4.57 (m, 1H), 5.12 (m, 1H), 7.10-7.58 (m, 17H ), 7.79 (m, 2 H)

FAB MS: 590 [M+1]+ FAB MS: 590 [M + 1] +

실시예 26: (2Example 26: (2 SS )-)- NN -{4-[아미노(이미노)메틸]벤질}-1-{(2-{4- [amino (imino) methyl] benzyl} -1-{(2 RR )-2-[(메틸옥시카보닐)아미노]-3-(3,4-디클로로페닐)프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성Synthesis of) -2-[(methyloxycarbonyl) amino] -3- (3,4-dichlorophenyl) propanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid salt

a) Boc-D-Dcpa-Pro-(4-CN)-bnamd의 제조a) Preparation of Boc-D-Dcpa-Pro- (4-CN) -bnamd

Boc-D-Dcpa-Pro-OH(참조: J. Med. Chem. 1997, 40, 3726)에 대해 실시예 21의 단계 a)에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 91%).The reaction was carried out on Boc-D-Dcpa-Pro-OH (J. Med. Chem. 1997, 40, 3726) in the same manner as in step a) of Example 21 to obtain the title compound (Yield 91 %).

1H NMR (CD3OD) δ 1.43 (m, 1H), 1.75 (m, 1H), 1.88 (m, 1H), 2.09 (m, 1H), 2.88-3.12 (m, 3H), 3.29 (s, 3H), 3.75 (m, 1H), 4.25-4.55 (m, 4H), 7.15-7.55 (m, 5H), 7.78 (m, 2H) 1 H NMR (CD 3 OD) δ 1.43 (m, 1H), 1.75 (m, 1H), 1.88 (m, 1H), 2.09 (m, 1H), 2.88-3.12 (m, 3H), 3.29 (s, 3H), 3.75 (m, 1H), 4.25-4.55 (m, 4H), 7.15-7.55 (m, 5H), 7.78 (m, 2H)

FAB MS: 504 [M+1]+ FAB MS: 504 [M + 1] +

b) MeO2C-D-Dcpa-Pro-(4-amd)-bnamd·TFA의 제조b) Preparation of MeO 2 CD-Dcpa-Pro- (4-amd) -bnamdTFA

단계 a)에서 수득한 화합물에 대해 실시예 22의 단계 a) 및 b)에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 52%).The reaction was carried out for the compound obtained in step a) in the same manner as in steps a) and b) of Example 22 to obtain the title compound (yield 52%).

1H NMR (CD3OD) δ 1.31 (m, 1H), 1.70 (m, 1H), 1.95-2.05 (m, 2H), 2.95(m, 2H), 3.04 (m, 1H), 3.35 (s, 3H), 3.87 (m, 1H), 4.32-4.58 (m, 4H), 7.18 (m, 1H), 7.40-7.58 (m, 4H), 7.75 (m, 2H) 1 H NMR (CD 3 OD) δ 1.31 (m, 1H), 1.70 (m, 1H), 1.95-2.05 (m, 2H), 2.95 (m, 2H), 3.04 (m, 1H), 3.35 (s, 3H), 3.87 (m, 1H), 4.32-4.58 (m, 4H), 7.18 (m, 1H), 7.40-7.58 (m, 4H), 7.75 (m, 2H)

FAB MS: 521 [M+1]+ FAB MS: 521 [M + 1] +

실시예 27: (2Example 27: (2 SS )-)- NN -{4-[아미노(이미노)메틸]벤질}-1-{(2-{4- [amino (imino) methyl] benzyl} -1-{(2 RR )-2-[(메틸옥시카보닐)아미노]-3,3-디사이클로헥실프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성) -2-[(methyloxycarbonyl) amino] -3,3-dicyclohexylpropanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid

Boc-D-Dcha-Pro-OH(참조: J. Med. Chem. 1997, 40, 1565)에 대해 실시예 21의 단계 a) 및 실시예 22에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 21%).The reaction was carried out on Boc-D-Dcha-Pro-OH (see J. Med. Chem. 1997, 40, 1565) in the same manner as in step a) and Example 22 of Example 21, to obtain the title compound. (Yield 21%).

1H NMR (CD3OD) δ 1.12-2.20 (m, 27H), 3.27-3.35 (m, 4H), 3.83 (m, 1H), 4.22-4.48 (m, 3H), 5.12 (m, 1H), 7.52 (m, 2H), 7.68 (m, 2H) 1 H NMR (CD 3 OD) δ 1.12-2.20 (m, 27H), 3.27-3.35 (m, 4H), 3.83 (m, 1H), 4.22-4.48 (m, 3H), 5.12 (m, 1H), 7.52 (m, 2H), 7.68 (m, 2H)

FAB MS: 540 [M+1]+ FAB MS: 540 [M + 1] +

실시예 28: (2Example 28: (2 SS )-)- NN -{4-[아미노(이미노)메틸]벤질}-1-{(2-{4- [amino (imino) methyl] benzyl} -1-{(2 RR )-2-[(메틸옥시카보닐)아미노]-3,3-디페닐프로파노일}-2-아제티딘카르복사미드 트리플루오로아세트산염의 합성) -2-[(methyloxycarbonyl) amino] -3,3-diphenylpropanoyl} -2-azetidinecarboxamide trifluoroacetic acid

Boc-D-Dpa-Aze-OH(참조: Liebigs Ann. Chem. 1990, 687)에 대해 실시예 21의 단계 a) 및 실시예 22에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 33%).The reaction was carried out on Boc-D-Dpa-Aze-OH (Liebigs Ann. Chem. 1990, 687) in the same manner as in step a) and Example 22 of Example 21 to obtain the title compound (yield). 33%).

1H NMR (CD3OD) δ 2.55 (m, 1H), 2.85 (m, 2H), 3.35 (s, 3H), 3.82 (m, 1H), 3.95 (m, 1H), 4.10 (m, 2H), 4.35 (m, 2H), 4.55 (m, 1H), 4.85 (m, 1H), 7.15-7.50 (m, 12H), 7.73 (m, 2H) 1 H NMR (CD 3 OD) δ 2.55 (m, 1H), 2.85 (m, 2H), 3.35 (s, 3H), 3.82 (m, 1H), 3.95 (m, 1H), 4.10 (m, 2H) , 4.35 (m, 2H), 4.55 (m, 1H), 4.85 (m, 1H), 7.15-7.50 (m, 12H), 7.73 (m, 2H)

FAB MS: 514 [M+1]+ FAB MS: 514 [M + 1] +

실시예 29: (2Example 29: (2 SS )-)- NN -{4-[아미노(이미노)메틸]벤질}-1-{(2-{4- [amino (imino) methyl] benzyl} -1-{(2 RR )-2-[(메틸옥시카보닐)아미노]-2-사이클로헥실에탄오일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성Synthesis of) -2-[(methyloxycarbonyl) amino] -2-cyclohexylethanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid salt

Boc-D-Chg-Pro-OH 에 대해 실시예 21의 단계 a) 및 실시예 22에서와 동일한방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 25%).The reaction was carried out on Boc-D-Chg-Pro-OH in the same manner as in step a) and Example 22 of Example 21, to obtain the title compound (yield 25%).

1H NMR (CD3OD) δ 0.90-1.91 (m, 14H), 2.11 (m, 1H), 3.19 (m, 1H), 3.35 (s, 3H), 3.88 (m, 1H), 4.32-4.60 (m, 3H), 5.01 (m, 1H), 7.45 (m, 2H), 7.70 (m, 2H) 1 H NMR (CD 3 OD) δ 0.90-1.91 (m, 14H), 2.11 (m, 1H), 3.19 (m, 1H), 3.35 (s, 3H), 3.88 (m, 1H), 4.32-4.60 ( m, 3H), 5.01 (m, 1H), 7.45 (m, 2H), 7.70 (m, 2H)

FAB MS: 444 [M+1]+ FAB MS: 444 [M + 1] +

실시예 30: (2Example 30: (2 SS )-)- NN -{4-[아미노(이미노)메틸]벤질}-1-{(2-{4- [amino (imino) methyl] benzyl} -1-{(2 RR )-2-[(메틸옥시카보닐)아미노]-3-사이클로헥실프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성Synthesis of) -2-[(methyloxycarbonyl) amino] -3-cyclohexylpropanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid salt

Boc-D-Cha-Pro-OH 에 대해 실시예 21의 단계 a) 및 실시예 22에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 40%).The reaction was carried out on Boc-D-Cha-Pro-OH in the same manner as in step a) and Example 22 of Example 21 to obtain the title compound (yield 40%).

1H NMR (CD3OD) δ 0.82-1.77 (m, 12H), 1.89-2.18 (m, 5H), 3.29 (s, 3H), 3.42 (m, 1H), 3.91 (m, 1H), 4.25-4.49 (m, 3H), 5.01 (m, 1H), 7.45 (m, 2H), 7.72 (m, 2H) 1 H NMR (CD 3 OD) δ 0.82-1.77 (m, 12H), 1.89-2.18 (m, 5H), 3.29 (s, 3H), 3.42 (m, 1H), 3.91 (m, 1H), 4.25- 4.49 (m, 3H), 5.01 (m, 1H), 7.45 (m, 2H), 7.72 (m, 2H)

FAB MS: 458 [M+1]+ FAB MS: 458 [M + 1] +

실시예 31: (2Example 31: (2 SS )-)- NN -({6-[아미노(이미노)메틸]-3-피리디닐}메틸)-1-{(2-({6- [amino (imino) methyl] -3-pyridinyl} methyl) -1-{(2 RR )-2-[(메틸옥시카보닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성) -2-[(methyloxycarbonyl) amino] -3,3-diphenylpropanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid

a) 6-시아노-3-피콜린의 제조a) Preparation of 6-cyano-3-picolin

6-브로모-3-피콜린(3g, 17.44mmol)을 디메틸포름아미드(60㎖)에 녹인 후, 여기에 시아노구리(2.3g, 26.16mmol)를 가하고 1시간 30분간 가열환류시켰다. 반응 완결 후 감압증류하여 휘발성 물질을 제거하였다. 수득된 잔액을 디에틸에테르로 희석한 후, 암모니아수 및 포화 소금물을 사용하여 차례로 씻어주었다. 무수 마그네슘설페이트로 건조, 여과 및 농축시켰다. 잔류물을 칼럼 크로마토그래피(용리액: 에틸아세테이트/n-헥산=1/9, 부피비)로 정제하여 표제화합물 1.6g(수율 78%)을 수득하였다.6-bromo-3-picolin (3 g, 17.44 mmol) was dissolved in dimethylformamide (60 mL), and cyano copper (2.3 g, 26.16 mmol) was added thereto, followed by heating to reflux for 1 hour 30 minutes. After completion of the reaction, distillation under reduced pressure was carried out to remove volatiles. The resulting residue was diluted with diethyl ether and washed sequentially with aqueous ammonia and saturated brine. Dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1/9, volume ratio) to give 1.6 g (78% yield) of the title compound.

1H NMR (CDCl3) δ 8.51 (s, 1H), 7.66 (d, 1H), 7.40 (d, 1H), 2.41 (s, 3H) 1 H NMR (CDCl 3 ) δ 8.51 (s, 1H), 7.66 (d, 1H), 7.40 (d, 1H), 2.41 (s, 3H)

FAB MS: 119 [M+1]+ FAB MS: 119 [M + 1] +

b) 6-시아노-3-피콜릴브로마이드의 제조b) Preparation of 6-cyano-3-picolyl bromide

단계 a)에서 수득한 화합물(1.32g, 11.19mmol)을 사염화탄소(30㎖)에 녹였다. 여기에 N-브로모숙신이미드(NBS, 2.8g, 15.7mmol)와 벤조일퍼옥사이드 ((PhCO)2O2, 540mg, 24mmol)을 가하고 2시간동안 가열환류시켰다. 반응 완결 후 감압증류하여 휘발성 물질을 제거하였다. 잔류물을 칼럼 크로마토그래피(용리액: 에틸아세테이트/n-헥산=1/9, 부피비)로 정제하여 표제화합물 1.12g(수율 51%)을 수득하였다.The compound (1.32 g, 11.19 mmol) obtained in step a) was dissolved in carbon tetrachloride (30 mL). N-bromosuccinimide (NBS, 2.8 g, 15.7 mmol) and benzoyl peroxide ((PhCO) 2 O 2 , 540 mg, 24 mmol) were added thereto, followed by heating to reflux for 2 hours. After completion of the reaction, distillation under reduced pressure was performed to remove volatiles. The residue was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1/9, volume ratio) to give 1.12 g (51% yield) of the title compound.

1H NMR (CDCl3) δ 8.64 (s, 1H), 7.76 (d, 1H), 7.63 (d, 1H), 4.55 (s, 2H) 1 H NMR (CDCl 3 ) δ 8.64 (s, 1H), 7.76 (d, 1H), 7.63 (d, 1H), 4.55 (s, 2H)

FAB MS: 197 [M+1]+ FAB MS: 197 [M + 1] +

c) 6-시아노-3-피콜릴아민 염산염의 제조c) preparation of 6-cyano-3-picolylamine hydrochloride

소듐하이드리드(NaH, 240mg, 6.0mmol)와 테트라하이드로푸란(THF, 10㎖)의 혼합액을 0℃로 냉각시킨 후 교반하면서 이미노디카복실산 디-t-부틸에스테르 ((Me3COCO)2NH, 650mg, 3mmol)를 테트라하이드로푸란(THF, 10㎖)에 녹인 용액을 서서히 적가한 후 30분간 교반하였다. 여기에 단계 b)에서 수득한 화합물(1.06g, 5.4mmol)을 테트라하이드로푸란(THF, 10㎖)에 녹여서 천천히 가한 후 상온으로 올려 2시간 동안 교반시켰다. 반응 완결 후 냉각시켜 물(5㎖)을 가하고 감압증류하에 휘발성 물질을 제거하였다. 잔액을 에틸아세테이트로 묽힌 후, 포화 소금물로 씻어주었다. 무수 마그네슘술페이트로 건조, 여과 및 농축시켰다. 잔류물을 칼럼크로마토그래피(용리액: 에틸아세테이트/n-헥산=1/9, 부피비)로 정제하여 수득한 화합물(580mg, 1.74mmol)을 메탄올(20㎖)에 녹인 후, 0℃로 냉각시켰다. 여기에 아세틸클로라이드(MeCOCl, 30당량)를 천천히 넣어주었다. 용액의 온도를 상온으로 승온시켜 1시간 동안 교반하였다. 감압하에 휘발성 물질을 제거하여 표제화합물 293mg(수율 53%)을 흰색 고체로 수득하였다.The mixture of sodium hydride (NaH, 240 mg, 6.0 mmol) and tetrahydrofuran (THF, 10 mL) was cooled to 0 ° C., followed by stirring with iminodicarboxylic acid di- t -butyl ester ((Me 3 COCO) 2 NH, 650 mg, 3 mmol) was slowly added dropwise into a solution of tetrahydrofuran (THF, 10 mL) and stirred for 30 minutes. Here, the compound (1.06 g, 5.4 mmol) obtained in step b) was dissolved in tetrahydrofuran (THF, 10 mL) and slowly added thereto, followed by stirring at room temperature for 2 hours. After completion of the reaction, the mixture was cooled, water (5 mL) was added thereto, and volatiles were removed under reduced pressure distillation. The residue was diluted with ethyl acetate and washed with saturated brine. Dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1/9, volume ratio) to dissolve the compound (580 mg, 1.74 mmol) in methanol (20 mL), and then cooled to 0 ° C. Acetyl chloride (MeCOCl, 30 equivalents) was slowly added thereto. The temperature of the solution was raised to room temperature and stirred for 1 hour. The volatiles were removed under reduced pressure to give 293 mg (53% yield) of the title compound as a white solid.

1H NMR (CD3OD) δ 8.54 (s, 1H), 7.56 (d, 1H), 7.43 (d, 1H), 4.80 (s, 2H) 1 H NMR (CD 3 OD) δ 8.54 (s, 1H), 7.56 (d, 1H), 7.43 (d, 1H), 4.80 (s, 2H)

FAB MS: 133 [M+1]+ FAB MS: 133 [M + 1] +

d) MeO2C-D-Dpa-Pro-(6-amd)-3-piamd·TFA의 제조d) Preparation of MeO 2 CD-Dpa-Pro- (6-amd) -3-piamdTFA

4-시아노벤질아민 염산염 대신에 단계 c)에서 수득한 화합물을 사용하는 것을 제외하고는 실시예 21의 단계 a) 및 실시예 22에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 31%).The reaction was carried out in the same manner as in step a) and Example 22 of Example 21, except that the compound obtained in step c) was used instead of 4-cyanobenzylamine hydrochloride to give the title compound (yield) 31%).

1H NMR (CD3OD) δ 8.78 (s, 1H), 8.10(d, 1H), 7.96 (d, 1H), 7.39 (m, 2H), 7.33 (m, 2H), 7.25 (m, 6H), 5.15 (d, 1H), 4.56 (dd, 1H), 4.45 (dd, 1H), 4.38 (d, 1H), 4.09 (m, 1H), 3.82 (m, 1H), 3.29, (s, 3H), 2.93(m, 1H), 1.84-1.48 (m, 4H) 1 H NMR (CD 3 OD) δ 8.78 (s, 1H), 8.10 (d, 1H), 7.96 (d, 1H), 7.39 (m, 2H), 7.33 (m, 2H), 7.25 (m, 6H) , 5.15 (d, 1H), 4.56 (dd, 1H), 4.45 (dd, 1H), 4.38 (d, 1H), 4.09 (m, 1H), 3.82 (m, 1H), 3.29, (s, 3H) , 2.93 (m, 1 H), 1.84-1.48 (m, 4 H)

FAB MS: 529 [M+1]+ FAB MS: 529 [M + 1] +

실시예 32: (2Example 32: (2 SS )-)- NN -({6-[아미노(이미노)메틸]-3-피리디닐}메틸)-1-{(2-({6- [amino (imino) methyl] -3-pyridinyl} methyl) -1-{(2 RR )-2-[(메틸옥시카보닐)아미노]-3,3-디사이클로헥실프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성) -2-[(methyloxycarbonyl) amino] -3,3-dicyclohexylpropanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid

D-Dcha-Pro-OMe·HCl (참조: J. Med. Chem. 1997, 40, 1565)와 실시예 31의 단계 c)에서 수득한 6-시아노-3-피콜릴아민 염산염에 대해 실시예 21의 단계 a) 및 실시예 22에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 13%).Example for 6-cyano-3-picolylamine hydrochloride obtained in D-Dcha-Pro-OMe.HCl (J. Med. Chem. 1997, 40, 1565) and step c) of Example 31. The reaction was carried out in the same manner as in step a) of 21 and Example 22, to obtain the title compound (yield 13%).

1H NMR (CD3OD) δ 8.72(s, 1H), 8.08 (d, 1H), 7.99(d, 1H), 5.07(m, 1H), 4.18-4.53 (m, 3H), 3.79 (m, 1H), 3.42 (s, 3H), 3.31(m, 1H), 2.18-1.07(m, 27H) 1 H NMR (CD 3 OD) δ 8.72 (s, 1H), 8.08 (d, 1H), 7.99 (d, 1H), 5.07 (m, 1H), 4.18-4.53 (m, 3H), 3.79 (m, 1H), 3.42 (s, 3H), 3.31 (m, 1H), 2.18-1.07 (m, 27H)

FAB MS: 541 [M+1]+ FAB MS: 541 [M + 1] +

실시예 33: (2Example 33: (2 SS )-)- NN -({5-[아미노(이미노)메틸]-2-피리디닐}메틸)-1-{(2-({5- [amino (imino) methyl] -2-pyridinyl} methyl) -1-{(2 RR )-2-[(메틸옥시카보닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성) -2-[(methyloxycarbonyl) amino] -3,3-diphenylpropanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid

a) 5-시아노-2-피콜릴아민 염산염의 제조a) Preparation of 5-cyano-2-picolylamine hydrochloride

5-시아노-2-피콜린에 대해 실시예 31의 단계 b) 및 c)에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 41%).The reaction was carried out on 5-cyano-2-picoline in the same manner as in steps b) and c) of Example 31 to give the title compound (yield 41%).

1H NMR (CD3OD) δ 8.70 (s, 1H), 7.76 (d, 1H), 7.53 (d, 1H), 4.80 (s, 2H) 1 H NMR (CD 3 OD) δ 8.70 (s, 1H), 7.76 (d, 1H), 7.53 (d, 1H), 4.80 (s, 2H)

FAB MS: 133 [M+1]+ FAB MS: 133 [M + 1] +

b) MeO2C-D-Dpa-Pro-(5-amd)-2-piamd·TFA의 제조b) Preparation of MeO 2 CD-Dpa-Pro- (5-amd) -2-piamdTFA

4-시아노벤질아민 염산염 대신에 단계 a)에서 수득한 화합물을 사용하는 것을 제외하고는 실시예 21의 단계 a) 및 실시예 22에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 31%).The reaction was carried out in the same manner as in step a) and Example 22 of Example 21, except that the compound obtained in step a) was used instead of 4-cyanobenzylamine hydrochloride to give the title compound (yield) 31%).

1H NMR (CD3OD) δ 8.67 (s, 1H), 8.05(d, 1H), 7.89(d, 1H), 7.29 (m, 2H), 7.23 (m, 2H), 7.21 (m, 6H), 5.11 (d, 1H), 4.46 (dd, 1H), 4.40 (dd, 1H), 4.28 (d, 1H), 4.02 (m, 1H), 3.72 (m, 1H), 3.31, (s, 3H), 2.90(m, 1H), 1.79-1.45 (m, 4H) 1 H NMR (CD 3 OD) δ 8.67 (s, 1H), 8.05 (d, 1H), 7.89 (d, 1H), 7.29 (m, 2H), 7.23 (m, 2H), 7.21 (m, 6H) , 5.11 (d, 1H), 4.46 (dd, 1H), 4.40 (dd, 1H), 4.28 (d, 1H), 4.02 (m, 1H), 3.72 (m, 1H), 3.31, (s, 3H) , 2.90 (m, 1 H), 1.79-1.45 (m, 4 H)

FAB MS: 529 [M+1]+ FAB MS: 529 [M + 1] +

실시예 34: (2Example 34: (2 SS )-)- NN -({2-[아미노(이미노)메틸]-5-피리미디닐}메틸)-1-{ (2-({2- [amino (imino) methyl] -5-pyrimidinyl} methyl) -1- {(2 RR )-2-[(메틸옥시카보닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성) -2-[(methyloxycarbonyl) amino] -3,3-diphenylpropanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid

4-시아노벤질아민 염산염 대신에 5-아미노메틸-2-시아노-피리미딘 염산염 (5-Aminomethyl-2-cyano-pyrimidine·HCl, WO9625426)을 사용하는 것을 제외하고는 실시예 21의 단계 a) 및 실시예 22에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 33%).Step a of Example 21, except that 5-aminomethyl-2-cyano-pyrimidine hydrochloride (5-Aminomethyl-2-cyano-pyrimidine.HCl, WO9625426) is used instead of 4-cyanobenzylamine hydrochloride. And the same method as in Example 22 to give the title compound (yield 33%).

1H NMR (CD3OD) δ 8.72(m,, 2H), 7.44- 7.35(m, 4H),7.26- 7.24 (m, 6H), 4.55( dd, 1H), 4.33-4.30 (m, 2H), 4.06(dd, 1H), 3.76(m, 1H), 3.28 (s, 3H), 2.90(m, 1H), 1.84- 1.45(m, 4H) 1 H NMR (CD 3 OD) δ 8.72 (m, 2H), 7.44-7.35 (m, 4H), 7.26- 7.24 (m, 6H), 4.55 (dd, 1H), 4.33-4.30 (m, 2H) , 4.06 (dd, 1H), 3.76 (m, 1H), 3.28 (s, 3H), 2.90 (m, 1H), 1.84- 1.45 (m, 4H)

FAB MS: 530 [M+1]+ FAB MS: 530 [M + 1] +

실시예 35: (2Example 35: (2 SS )-)- NN -{4-[아미노(이미노)메틸]-3-플루오로벤질}-1-{(2-{4- [amino (imino) methyl] -3-fluorobenzyl} -1-{(2 RR )-2-[(메틸옥시카보닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성) -2-[(methyloxycarbonyl) amino] -3,3-diphenylpropanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid

a) 2-플루오로-4-메틸벤조니트릴의 제조a) Preparation of 2-fluoro-4-methylbenzonitrile

4-브로모-3-플루오로-톨루엔(2g, 10.6mmol)과 시아노구리(CuCN, 1.4g, 15.9 mmol)을 디메틸포름아미드(DMF, 15㎖)와 함께 반응용기에 가하였다. 반응액을 200℃로 가열환류시키면서 4시간 동안 반응시킨 후 0℃로 냉각시키고 에틸아세테이트(100㎖)를 가하였다. 녹지 않는 고체를 여과한 후 암모니아수(100㎖)로 세척하고, 무수 마그네슘설페이트로 건조, 여과 및 농축시켰다. 잔류물을 칼럼 크로마토그래피(용리액: 에틸아세테이트/n-헥산=1/4, 부피비)로 정제하여 표제화합물 1.0g(수율 70%)을 수득하였다.4-Bromo-3-fluoro-toluene (2 g, 10.6 mmol) and cyano copper (CuCN, 1.4 g, 15.9 mmol) were added to the reaction vessel together with dimethylformamide (DMF, 15 mL). The reaction solution was reacted for 4 hours while heating to reflux at 200 ° C., cooled to 0 ° C., and ethyl acetate (100 mL) was added thereto. The insoluble solid was filtered off, washed with ammonia water (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1/4, volume ratio) to obtain 1.0 g (yield 70%) of the title compound.

1H NMR (CDCl3) δ 7.50 (m, 1H), 7.08 (m, 2H), 2.45 (s, 3H) 1 H NMR (CDCl 3 ) δ 7.50 (m, 1H), 7.08 (m, 2H), 2.45 (s, 3H)

FAB MS: 135 [M+1]+ FAB MS: 135 [M + 1] +

b) 4-브로모메틸-2-플루오로벤조니트릴의 제조b) Preparation of 4-bromomethyl-2-fluorobenzonitrile

단계 a)에서 수득한 화합물(1g, 7.4mmol)과 N-브로모숙신이미드(NBS, 1.9g, 10.6mmol)를 사염화탄소(100㎖)와 함께 반응용기에 가하였다. 여기에 벤조일퍼옥사이드((PhCO)2O2, 0.39g, 1.6mmol)를 가하고 3시간 동안 가열환류시켰다. 반응액을 0℃로 냉각시킨 후 녹지 않는 고체를 여과하였다. 여액을 디클로로메탄(400㎖)으로 희석시키고 포화 탄산수소나트륨 수용액으로 2회 세척하였다. 무수 마그네슘설페이트로 건조, 여과 및 농축시켰다. 잔류물을 칼럼 크로마토그래피(용리액: 에틸아세테이트/n-헥산=1/9, 부피비)로 정제하여 표제화합물 0.9g(수율 56%)을 수득하였다.Compound (1 g, 7.4 mmol) and N-bromosuccinimide (NBS, 1.9 g, 10.6 mmol) obtained in step a) were added to the reaction vessel together with carbon tetrachloride (100 mL). Benzoyl peroxide ((PhCO) 2 O 2 , 0.39 g, 1.6 mmol) was added thereto, and the mixture was heated to reflux for 3 hours. After cooling the reaction solution to 0 ℃ solid that was not filtered was filtered. The filtrate was diluted with dichloromethane (400 mL) and washed twice with saturated aqueous sodium hydrogen carbonate solution. Dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1/9, volume ratio) to give 0.9 g (56% yield) of the title compound.

1H NMR (CDCl3) δ 7.41 (m, 1H), 7.30 (m, 2H), 4.55 (s, 2H) 1 H NMR (CDCl 3 ) δ 7.41 (m, 1H), 7.30 (m, 2H), 4.55 (s, 2H)

FAB MS: 214 [M+1]+ FAB MS: 214 [M + 1] +

c) 4-시아노-3-플루오로벤질아민 염산염의 제조c) preparation of 4-cyano-3-fluorobenzylamine hydrochloride

디메틸포름아미드(50㎖)에 소듐하이드리드(NaH, 60%, 0.2g, 5.0mmol)를 가하고 여기에 이미노디카복실산 디-t-부틸에스테르((Me3COCO)2NH, 0.99g, 4.62mmol)를 천천히 가한 다음 상온에서 30분간 교반하였다. 여기에 디메틸포름아미드(5㎖)에 단계 b)에서 수득한 화합물(0.9g, 4.2mmol)을 녹인 용액을 천천히 가하고 상온에서 2시간 동안 교반하였다. 반응 완결 후 메탄올(10㎖)을 가하고 감압증류하여 휘발성 물질을 제거하였다. 수득된 잔액을 에틸아세테이트로 희석하고 물로 세척한 다음, 무수 마그네슘설페이트로 건조, 여과 및 농축시켰다. 잔류물을 칼럼 크로마토그래피(용리액: 에틸아세테이트/n-헥산=1/4, 부피비)로 정제하여 수득한 화합물 (1.2g, 수율 82%)을 메탄올(50㎖)에 녹이고 아세틸클로라이드(MeCOCl, 5㎖)를 천천히 가하여 실온에서 3시간 동안 교반하였다. 반응 완결 후 감압증류하여 휘발성 물질을 제거하고 진공펌프로 건조시켜 표제화합물 0.6g(수율 94%)을 수득하였다.Sodium hydride (NaH, 60%, 0.2 g, 5.0 mmol) was added to dimethylformamide (50 mL) and iminodicarboxylic acid di- t -butyl ester ((Me 3 COCO) 2 NH, 0.99 g, 4.62 mmol) was added. ) Was added slowly and stirred at room temperature for 30 minutes. To the dimethylformamide (5 ml) was slowly added a solution of the compound (0.9 g, 4.2 mmol) obtained in step b) and stirred at room temperature for 2 hours. After completion of the reaction, methanol (10 mL) was added and distilled under reduced pressure to remove volatiles. The obtained residue was diluted with ethyl acetate and washed with water, then dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1/4, volume ratio), and the obtained compound (1.2 g, yield 82%) was dissolved in methanol (50 mL), and acetyl chloride (MeCOCl, 5 Ml) was slowly added and stirred at room temperature for 3 hours. After completion of the reaction, distillation under reduced pressure to remove volatiles and drying with a vacuum pump yielded 0.6 g (yield 94%) of the title compound.

1H NMR (CD3OD) δ 7.49 (m, 1H), 7.20 (m, 2H), 4.12 (s, 2H) 1 H NMR (CD 3 OD) δ 7.49 (m, 1H), 7.20 (m, 2H), 4.12 (s, 2H)

FAB MS: 151 [M+1]+ FAB MS: 151 [M + 1] +

d) MeO2C-D-Dpa-Pro-(4-amd-3-F)-bnamd·TFA의 제조d) Preparation of MeO 2 CD-Dpa-Pro- (4-amd-3-F) -bnamdTFA

4-시아노벤질아민 염산염 대신에 단계 c)에서 수득한 화합물을 사용하는 것을 제외하고는 실시예 21의 단계 a) 및 실시예 22에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 38%).The reaction was carried out in the same manner as in step a) and Example 22 of Example 21, except that the compound obtained in step c) was used instead of 4-cyanobenzylamine hydrochloride to give the title compound (yield) 38%).

1H NMR (CD3OD) δ 1.52 (m, 1H), 1.63 (m, 1H), 1.73-1.88 (m, 2H), 2.92 (m, 1H), 3.45(s, 3H), 3.82 (m, 1H), 4.18 (m, 1H), 4.41 (m, 2H), 4.52 (m, 1H), 5.02 (m, 1H), 7.20-7.51 (m, 12H), 7.62 (m, 1H) 1 H NMR (CD 3 OD) δ 1.52 (m, 1H), 1.63 (m, 1H), 1.73-1.88 (m, 2H), 2.92 (m, 1H), 3.45 (s, 3H), 3.82 (m, 1H), 4.18 (m, 1H), 4.41 (m, 2H), 4.52 (m, 1H), 5.02 (m, 1H), 7.20-7.51 (m, 12H), 7.62 (m, 1H)

FAB MS: 547 [M+1]+ FAB MS: 547 [M + 1] +

실시예 36: (2Example 36: (2 SS )-)- NN -{4-[아미노(이미노)메틸]-2-메틸옥시벤질}-1-{(2-{4- [amino (imino) methyl] -2-methyloxybenzyl} -1-{(2 RR )- 2-[(메틸옥시카보닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성)-Synthesis of 2-[(methyloxycarbonyl) amino] -3,3-diphenylpropanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid salt

4-시아노벤질아민 염산염 대신에 4-아미노메틸-3-메틸옥시벤조니트릴 염산염 (WO9625426)을 사용하는 것을 제외하고는 실시예 21의 단계 a) 및 실시예 22에서와동일한 방법으로 반응을 수행하여 표제 화합물을 수득하였다(수율 29%).The reaction was carried out in the same manner as in step a) and Example 22 of Example 21, except that 4-aminomethyl-3-methyloxybenzonitrile hydrochloride (WO9625426) was used instead of 4-cyanobenzylamine hydrochloride. To give the title compound (yield 29%).

1H NMR (CD3OD) δ 1.51 (m, 1H), 1.63 (m, 1H), 1.72-1.86 (m, 2H), 3.01 (m, 1H), 3.42 (s, 3H), 3.75-3.83 (m, 4H), 4.11 (m, 1H), 4.25-4.36 (m, 2H), 4.52 (m, 1H), 5.03 (m, 1H), 7.20-7.75 (m, 13H) 1 H NMR (CD 3 OD) δ 1.51 (m, 1H), 1.63 (m, 1H), 1.72-1.86 (m, 2H), 3.01 (m, 1H), 3.42 (s, 3H), 3.75-3.83 ( m, 4H), 4.11 (m, 1H), 4.25-4.36 (m, 2H), 4.52 (m, 1H), 5.03 (m, 1H), 7.20-7.75 (m, 13H)

FAB MS: 558 [M+1]+ FAB MS: 558 [M + 1] +

실시예 37: (2Example 37: (2 SS )-)- NN -{4-[아미노(이미노)메틸]-3-메틸벤질}-1-{(2-{4- [amino (imino) methyl] -3-methylbenzyl} -1-{(2 RR )-2-[(메틸옥시카보닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성) -2-[(methyloxycarbonyl) amino] -3,3-diphenylpropanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid

a) 4-브로모-3-메틸벤질아민 염산염의 제조a) Preparation of 4-bromo-3-methylbenzylamine hydrochloride

보란(1.0M BH3/THF, 42㎖) 용액을 완전히 건조된 500㎖의 둥근 플라스크에 넣고 여기에 무수 테트라하이드로푸란(THF, 20㎖)에 녹인 4-브로모-3-메틸벤즈아미드(1.3g, 6.0mmol) 용액을 적가한 다음 6시간 동안 상온에서 교반하였다. 여기에 6N 염산(30㎖)을 천천히 적가하고 물(30㎖)과 메탄올(150㎖)을 차례로 가한 다음 12시간동안 교반하였다. 용액을 50㎖가 될 때까지 감압 농축시키고 생성된 침전물을 여과하여 제거하였다. 여액을 다시 감압농축하여 수득된 잔류물을 칼럼 크로마토그래피(용리액: 메탄올/메틸렌클로라이드=1/4, 부피비)로 정제하여 표제화합물 810mg(수율 57%)을 수득하였다.Boran (1.0M BH 3 / THF, 42 mL) solution was placed in a completely dried 500 mL round flask and dissolved in anhydrous tetrahydrofuran (THF, 20 mL) in 4-bromo-3-methylbenzamide (1.3 g, 6.0 mmol) was added dropwise and stirred at room temperature for 6 hours. 6N hydrochloric acid (30 mL) was slowly added dropwise thereto, water (30 mL) and methanol (150 mL) were added sequentially, followed by stirring for 12 hours. The solution was concentrated under reduced pressure until 50 ml and the resulting precipitate was filtered off. The filtrate was concentrated under reduced pressure again and the residue was purified by column chromatography (eluent: methanol / methylene chloride = 1/4, volume ratio) to give 810 mg (yield 57%) of the title compound.

1H NMR (CD3OD) δ 7.60 (d, 1H), 7.37 (s, 2H), 7.18 (d, 1H), 4.04 (s, 2H), 2.41 (s, 3H) 1 H NMR (CD 3 OD) δ 7.60 (d, 1H), 7.37 (s, 2H), 7.18 (d, 1H), 4.04 (s, 2H), 2.41 (s, 3H)

FAB MS: 201 [M+1]+ FAB MS: 201 [M + 1] +

b) 4-시아노-3-메틸벤질아민 염산염의 제조b) Preparation of 4-cyano-3-methylbenzylamine hydrochloride

단계 a)에서 수득한 화합물(810mg, 3.4mmol)에 대해 실시예 35의 단계 c)에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 44%).The reaction was carried out for the compound obtained in step a) (810 mg, 3.4 mmol) in the same manner as in step c) of Example 35, to obtain the title compound (yield 44%).

1H NMR (CD3OD) δ 8.12 (d, 1H), 7.45 (s, 2H), 7.36 (d, 1H), 4.08 (s, 2H), 2.40 (s, 3H) 1 H NMR (CD 3 OD) δ 8.12 (d, 1H), 7.45 (s, 2H), 7.36 (d, 1H), 4.08 (s, 2H), 2.40 (s, 3H)

FAB MS: 147 [M+1]+ FAB MS: 147 [M + 1] +

c) MeO2C-D-Dpa-Pro-(4-amd-3-Me)-bnamd·TFA의 제조c) Preparation of MeO 2 CD-Dpa-Pro- (4-amd-3-Me) -bnamdTFA

4-시아노벤질아민 염산염 대신에 단계 b)에서 수득한 화합물(249mg, 0.4 mmol)을 사용하는 것을 제외하고는 실시예 21의 단계 a) 및 실시예 22에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 37%).The reaction was carried out in the same manner as in Step a) and Example 22 of Example 21, except that the compound (249 mg, 0.4 mmol) obtained in step b) was used instead of 4-cyanobenzylamine hydrochloride. Compound was obtained (yield 37%).

1H NMR (CD3OD) δ 1.47 (m, 1H), 1.60 (m, 1H), 1.85 (m, 2H), 2.30 (s, 3H), 2.86 (m, 1H), 3.23 (s, 3H), 3.83 (m, 1H), 4.15 (m, 1H), 4.36 (m, 2H),4.53 (m, 1H), 5.10 (m, 1H), 7.18-7.52 (m, 11H), 7.82 (m, 2H) 1 H NMR (CD 3 OD) δ 1.47 (m, 1H), 1.60 (m, 1H), 1.85 (m, 2H), 2.30 (s, 3H), 2.86 (m, 1H), 3.23 (s, 3H) , 3.83 (m, 1H), 4.15 (m, 1H), 4.36 (m, 2H), 4.53 (m, 1H), 5.10 (m, 1H), 7.18-7.52 (m, 11H), 7.82 (m, 2H )

FAB MS: 542 [M+1]+ FAB MS: 542 [M + 1] +

실시예 38: (2Example 38: (2 SS )-)- NN -{4-[아미노(이미노)메틸]벤질}-1-{(2-{4- [amino (imino) methyl] benzyl} -1-{(2 RR )-2-(아세틸아미노)-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성) -2- (acetylamino) -3,3-diphenylpropanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid salt

실시예 22의 단계 a)에서 메틸클로로포메이트 대신에 아세틸클로라이드 (MeCOCl)를 사용하여 MeOC-D-Dpa-Pro-(4-CN)-bnamd를 수득하고, 이 화합물에 대해 실시예 22의 단계 b)에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 54%).In step a) of Example 22, acetylchloride (MeCOCl) was used instead of methylchloroformate to give MeOC-D-Dpa-Pro- (4-CN) -bnamd, and the step of Example 22 for this compound The reaction was carried out in the same manner as in b) to give the title compound (yield 54%).

1H NMR (CD3OD) δ 1.51 (m, 1H), 1.68 (m, 1H), 1.87 (m, 2H), 2.15 (s, 3H), 2.92 (m, 1H), 3.84 (m, 1H), 4.15 (m, 1H), 4.42 (m, 2H), 4.61 (m, 1H), 5.12 (m, 1H), 7.18-7.57 (m, 12H), 7.72 (m, 2H) 1 H NMR (CD 3 OD) δ 1.51 (m, 1H), 1.68 (m, 1H), 1.87 (m, 2H), 2.15 (s, 3H), 2.92 (m, 1H), 3.84 (m, 1H) , 4.15 (m, 1H), 4.42 (m, 2H), 4.61 (m, 1H), 5.12 (m, 1H), 7.18-7.57 (m, 12H), 7.72 (m, 2H)

FAB MS: 512 [M+1]+ FAB MS: 512 [M + 1] +

실시예 39: (2Example 39: (2 SS )-)- NN -{4-[아미노(이미노)메틸]벤질}-1-[(2-{4- [amino (imino) methyl] benzyl} -1-[(2 RR )-2-아미노-3, 3-디페닐프로판오일]-2-피롤리딘카르복사미드 트리플루오로아세트산 염의 합성) -2-amino-3, 3-diphenylpropane oil] -2-pyrrolidinecarboxamide trifluoroacetic acid salt

실시예 21에서 수득한 화합물(208㎎, 0.365mmol)을 디클로로메탄(1㎖)에 녹이고 트리플루오르아세트산(TFA; 2㎖)을 가한 후 상온에서 30분간 교반하였다. 반응 완결을 확인한 후 감압하여 농축하고 생성된 잔류물을 HPLC로 정제하여 표제화합물 200㎎(수율 69%)을 수득하였다.The compound (208 mg, 0.365 mmol) obtained in Example 21 was dissolved in dichloromethane (1 mL), trifluoroacetic acid (TFA; 2 mL) was added, and the mixture was stirred at room temperature for 30 minutes. After confirming the completion of the reaction, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by HPLC to obtain 200 mg (yield 69%) of the title compound.

1H NMR (CD3OD) δ 7.78 (d, 2H), 7.62 (d, 2H), 7.55 (d, 2H), 7.47 (t, 2H), 7.39-7.21 (m, 6H), 5.18 (d, 1H), 4.50 (m, 3H), 4.11 (dd, 1H), 3.62 (m, 1H), 2.81 (m, 1H), 1.77 (m, 3H), 1.31 (m, 1H) 1 H NMR (CD 3 OD) δ 7.78 (d, 2H), 7.62 (d, 2H), 7.55 (d, 2H), 7.47 (t, 2H), 7.39-7.21 (m, 6H), 5.18 (d, 1H), 4.50 (m, 3H), 4.11 (dd, 1H), 3.62 (m, 1H), 2.81 (m, 1H), 1.77 (m, 3H), 1.31 (m, 1H)

FAB MS: 470 [M+1]+ FAB MS: 470 [M + 1] +

실시예 40: (2Example 40: (2 SS )-)- NN -{4-[아미노(이미노)메틸]벤질}-1-{(2-{4- [amino (imino) methyl] benzyl} -1-{(2 RR )-2-[(메틸설포닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성) -2-[(methylsulfonyl) amino] -3,3-diphenylpropanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid salt

a) MeSO2-D-Dpa-Pro-(4-CN)-bnamd의 제조a) Preparation of MeSO 2 -D-Dpa-Pro- (4-CN) -bnamd

실시예 22의 단계 a)에서 메틸클로로포메이트 대신 메탄설포닐클로라이드를 사용하는 것을 제외하고는 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다.The reaction was carried out in the same manner as in Example 22, except that methanesulfonylchloride was used instead of methylchloroformate to obtain the title compound.

FAB MS: 531 [M+1]+ FAB MS: 531 [M + 1] +

b) MeSO2-D-Dpa-Pro-(4-amd)-bnamd·TFA의 제조b) Preparation of MeSO 2 -D-Dpa-Pro- (4-amd) -bnamdTFA

단계 a)에서 수득한 화합물에 대해 실시예 1의 단계 d)에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 82%).The reaction was carried out on the compound obtained in step a) in the same manner as in step d) of Example 1, to obtain the title compound (yield 82%).

1H NMR (CD3OD) δ 8.24 (m, 1H), 7.76 (m, 2H), 7.52 (m, 4H), 7.48-7.18 (m, 8H), 5.02 (d, 1H), 4.44 (m, 2H), 4.34 (d, 1H), 4.09 (m, 1H), 3.72 (m, 1H), 2.98 (m, 1H), 2.84 (s, 3H), 1.80 (m, 2H), 1.67 (m, 1H), 1.40 (m, 1H) 1 H NMR (CD 3 OD) δ 8.24 (m, 1H), 7.76 (m, 2H), 7.52 (m, 4H), 7.48-7.18 (m, 8H), 5.02 (d, 1H), 4.44 (m, 2H), 4.34 (d, 1H), 4.09 (m, 1H), 3.72 (m, 1H), 2.98 (m, 1H), 2.84 (s, 3H), 1.80 (m, 2H), 1.67 (m, 1H ), 1.40 (m, 1 H)

FAB MS: 548 [M+1]+ FAB MS: 548 [M + 1] +

실시예 41: (2Example 41: (2 SS )-)- NN -{4-[아미노(이미노)메틸]벤질}-1-{(2-{4- [amino (imino) methyl] benzyl} -1-{(2 RR )-2-[(벤질설포닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성) -2-[(benzylsulfonyl) amino] -3,3-diphenylpropanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid

a) BnSO2-D-Dpa-Pro-(4-CN)-bnamd의 제조a) Preparation of BnSO 2 -D-Dpa-Pro- (4-CN) -bnamd

실시예 22 의 단계 a)에서 메틸클로로포메이트 대신 벤질설포닐클로라이드를 사용하는 것을 제외하고는 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 81%).The title compound was obtained in the same manner as in Example 22, except for using benzylsulfonylchloride instead of methylchloroformate in step a) (yield 81%).

1H NMR (CDCl3) δ 7.52-7.42 (m, 6H), 7.38-7.18 (m,11H), 6.96 (d, 2H), 5.11 (d, 1H), 4.88 (t, 1H), 4.36 (d, 1H), 4.35 (d, 2H), 4.06 (d, 1H), 3.93 (d, 1H), 3.61 (m, 1H), 2.58 (m, 1H), 2.09-1.31 (m, 4H) 1 H NMR (CDCl 3 ) δ 7.52-7.42 (m, 6H), 7.38-7.18 (m, 11H), 6.96 (d, 2H), 5.11 (d, 1H), 4.88 (t, 1H), 4.36 (d , 1H), 4.35 (d, 2H), 4.06 (d, 1H), 3.93 (d, 1H), 3.61 (m, 1H), 2.58 (m, 1H), 2.09-1.31 (m, 4H)

FAB MS: 607 [M+1]+ FAB MS: 607 [M + 1] +

b) BnSO2-D-Dpa-Pro-(4-amd)-bnamd·TFA의 제조b) Preparation of BnSO 2 -D-Dpa-Pro- (4-amd) -bnamdTFA

단계 a)에서 수득한 화합물에 대해 실시예 1의 단계 d)에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 82%).The reaction was carried out on the compound obtained in step a) in the same manner as in step d) of Example 1, to obtain the title compound (yield 82%).

1H NMR (CD3OD) δ 7.65 (m, 2H), 7.48 (m, 4H), 7.40-7.12(m, 13H), 5.08 (d, 2H), 4.37 (d, 2H), 4.35 (d, 1H), 4.19 (s, 2H), 4.05 (m, 1H), 3.77 (m, 1H), 2.97 (m, 1H), 1.82 (m, 2H), 1.61-1.28 (m, 2H) 1 H NMR (CD 3 OD) δ 7.65 (m, 2H), 7.48 (m, 4H), 7.40-7.12 (m, 13H), 5.08 (d, 2H), 4.37 (d, 2H), 4.35 (d, 1H), 4.19 (s, 2H), 4.05 (m, 1H), 3.77 (m, 1H), 2.97 (m, 1H), 1.82 (m, 2H), 1.61-1.28 (m, 2H)

FAB MS: 624 [M+1]+ FAB MS: 624 [M + 1] +

실시예 42: (2Example 42: (2 SS )-)- NN -{4-[아미노(이미노)메틸]벤질}-1-{(2-{4- [amino (imino) methyl] benzyl} -1-{(2 RR )-2-[(디메틸아미노설포닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성Synthesis of) -2-[(dimethylaminosulfonyl) amino] -3,3-diphenylpropanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid salt

a) Me2NSO2-D-Dpa-Pro-(4-CN)-bnamd의 제조a) Preparation of Me 2 NSO 2 -D-Dpa-Pro- (4-CN) -bnamd

실시예 22의 단계 a)에서 메틸클로로포메이트 대신 디메틸설파모일클로라이드를 사용하는 것을 제외하고는 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다.The reaction was carried out in the same manner as in Example 22, except that dimethylsulfamoylchloride was used instead of methylchloroformate to obtain the title compound.

1H NMR (CDCl3) δ 7.53 (d, 2H), 7.36 (m, 8H), 7.24 (m,4H), 4.94 (d,1H), 4.66 (t, 1H), 4.48 (dd, 1H), 4.30 (m, 3H), 3.57 (m, 1H), 2.61 (m, 1H), 2.56 (s, 6H), 2.05-1.41 (m, 4H) 1 H NMR (CDCl 3 ) δ 7.53 (d, 2H), 7.36 (m, 8H), 7.24 (m, 4H), 4.94 (d, 1H), 4.66 (t, 1H), 4.48 (dd, 1H), 4.30 (m, 3H), 3.57 (m, 1H), 2.61 (m, 1H), 2.56 (s, 6H), 2.05-1.41 (m, 4H)

FAB MS: 560 [M+1]+ FAB MS: 560 [M + 1] +

b) Me2NSO2-D-Dpa-Pro-(4-amd)-bnamd의 제조b) Preparation of Me 2 NSO 2 -D-Dpa-Pro- (4-amd) -bnamd

단계 a)에서 수득한 화합물에 대해 실시예 1의 단계 d)에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 75%).The reaction was carried out on the compound obtained in step a) in the same manner as in step d) of Example 1, to obtain the title compound (yield 75%).

1H NMR (CD3OD) δ 7.97 (m, 1H), 7.72 (d, 2H), 7.51 (m, 4H), 7.37-7.18 (m, 8H), 4.94 (d,1H), 4.45 (m, 2H), 4.29 (d, 1H), 4.05 (d, 1H), 3.68 (m, 1H), 3.02 (m, 1H), 2.58 (s, 6H), 1.88-1.41 (m, 4H) 1 H NMR (CD 3 OD) δ 7.97 (m, 1H), 7.72 (d, 2H), 7.51 (m, 4H), 7.37-7.18 (m, 8H), 4.94 (d, 1H), 4.45 (m, 2H), 4.29 (d, 1H), 4.05 (d, 1H), 3.68 (m, 1H), 3.02 (m, 1H), 2.58 (s, 6H), 1.88-1.41 (m, 4H)

FAB MS: 577 [M+1]+ FAB MS: 577 [M + 1] +

실시예 43: (2Example 43: (2 SS )-)- NN -{4-[아미노(이미노)메틸]벤질}-1-{(2-{4- [amino (imino) methyl] benzyl} -1-{(2 RR )-2-[(디메톡시포스포릴)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성Synthesis of) -2-[(dimethoxyphosphoryl) amino] -3,3-diphenylpropanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid salt

a) (MeO)2OP-D-Dpa-Pro-(4-CN)-bnamd의 제조a) Preparation of (MeO) 2 OP-D-Dpa-Pro- (4-CN) -bnamd

실시예 22의 단계 a)에서 메틸클로로포메이트 대신 디메틸클로로포스페이트를 사용하는 것을 제외하고는 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 99%).The reaction was carried out in the same manner as in Example 22, except for using dimethylchlorophosphate instead of methylchloroformate to give the title compound (yield 99%).

1H NMR (CDCl3) δ 8.18 (m, 1H), 7.55 (d, 2H), 7.39-7.23 (m, 12H), 4.59 (m, 2H), 4.35 (d,1H), 4.33 (d, 1H), 4.11 (dd, 1H), 3.65 (m,1H), 3.43 (d, 3H),3.27 (d, 3H), 2.99 (m, 1H), 2.57(m, 1H), 2.06 (m, 1H), 1.45 (m, 2H) 1 H NMR (CDCl 3 ) δ 8.18 (m, 1H), 7.55 (d, 2H), 7.39-7.23 (m, 12H), 4.59 (m, 2H), 4.35 (d, 1H), 4.33 (d, 1H ), 4.11 (dd, 1H), 3.65 (m, 1H), 3.43 (d, 3H), 3.27 (d, 3H), 2.99 (m, 1H), 2.57 (m, 1H), 2.06 (m, 1H) , 1.45 (m, 2H)

FAB MS: 561 [M+1]+ FAB MS: 561 [M + 1] +

b) (MeO)2OP-D-Dpa-Pro-(4-amd)-bnamd·TFA의 제조b) Preparation of (MeO) 2 OP-D-Dpa-Pro- (4-amd) -bnamdTFA

단계 a)에서 수득한 화합물에 대해 실시예 1의 단계 d)에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 75%).The reaction was carried out on the compound obtained in step a) in the same manner as in step d) of Example 1, to obtain the title compound (yield 75%).

1H NMR (CD3OD) δ 7.74 (d, 2H), 7.51-7.25 (m, 12H), 5.02 (d, 1H), 4.78 (dd, 1H), 4.44 (q, 2H), 4.32 (d, 1H), 4.07 (dd, 1H), 3.75 (m, 1H), 3.38 (d, 3H), 3.28 (d, 3H), 3.01 (m, 1H), 1.89-1.48 (m, 4H) 1 H NMR (CD 3 OD) δ 7.74 (d, 2H), 7.51-7.25 (m, 12H), 5.02 (d, 1H), 4.78 (dd, 1H), 4.44 (q, 2H), 4.32 (d, 1H), 4.07 (dd, 1H), 3.75 (m, 1H), 3.38 (d, 3H), 3.28 (d, 3H), 3.01 (m, 1H), 1.89-1.48 (m, 4H)

FAB MS: 578 [M+1]+ FAB MS: 578 [M + 1] +

실시예 44: (2Example 44: (2 SS )-)- NN -{4-[아미노(이미노)메틸]벤질}-1-{(2-{4- [amino (imino) methyl] benzyl} -1-{(2 RR )-2-[(디메틸포스포릴)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성Synthesis of) -2-[(dimethylphosphoryl) amino] -3,3-diphenylpropanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid salt

a) Me2OP-D-Dpa-Pro-(4-CN)-bnamd의 제조a) Preparation of Me 2 OP-D-Dpa-Pro- (4-CN) -bnamd

실시예 22의 단계 a)에서 메틸클로로포메이트 대신 디메틸포스피닉클로라이드를 사용하는 것을 제외하고는 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 76%).The reaction was carried out in the same manner as in Example 22, except for using dimethylphosphonic chloride instead of methylchloroformate to give the title compound (yield 76%).

1H NMR (CDCl3) δ 8.63 (m, 1H), 7.55 (d, 2H), 7.32-7.22 (m, 12H), 4.71 (dd, 1H), 4.41 (m, 1H), 4.30 (m, 2H), 4.09 (dd, 1H),3.68 (m, 1H), 3.23 (m, 1H), 2.57 (m, 1H), 1.97-1.43 (m, 4H), 1.41 (d, 3H), 0.99 (d, 3H) 1 H NMR (CDCl 3 ) δ 8.63 (m, 1H), 7.55 (d, 2H), 7.32-7.22 (m, 12H), 4.71 (dd, 1H), 4.41 (m, 1H), 4.30 (m, 2H ), 4.09 (dd, 1H), 3.68 (m, 1H), 3.23 (m, 1H), 2.57 (m, 1H), 1.97-1.43 (m, 4H), 1.41 (d, 3H), 0.99 (d, 3H)

FAB MS: 546 [M+1]+ FAB MS: 546 [M + 1] +

b) Me2OP-D-Dpa-Pro-(4-amd)-bnamd·TFA의 제조b) Preparation of Me 2 OP-D-Dpa-Pro- (4-amd) -bnamdTFA

단계 a)에서 수득한 화합물에 대해 실시예 1의 단계 d)에서와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 68%).The reaction was carried out on the compound obtained in step a) in the same manner as in step d) of Example 1, to obtain the title compound (yield 68%).

1H NMR (CD3OD) δ 7.75 (d, 2H), 7.53- 7.19 (m, 12 H), 4.85 (dd, 4H), 4.59 (d, 1H), 4.31 (s, 2H), 4.09 (dd, 1H), 3.86 (m, 1H), 3.08 (m, 1H), 1.83-1.52 (m, 4H), 1.41 (d, 3H), 1.14 (d, 3H) 1 H NMR (CD 3 OD) δ 7.75 (d, 2H), 7.53- 7.19 (m, 12 H), 4.85 (dd, 4H), 4.59 (d, 1H), 4.31 (s, 2H), 4.09 (dd , 1H), 3.86 (m, 1H), 3.08 (m, 1H), 1.83-1.52 (m, 4H), 1.41 (d, 3H), 1.14 (d, 3H)

FAB MS: 529 [M+1]+ FAB MS: 529 [M + 1] +

실시예 45: (2Example 45: (2 SS )-)- NN -{4-[아미노(이미노)메틸]벤질}-1-{(2-{4- [amino (imino) methyl] benzyl} -1-{(2 RR )-2-[(카르복시메틸)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성) -2-[(carboxymethyl) amino] -3,3-diphenylpropanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid salt

a) t-BuO2CCH2-D-Dpa-Pro-(4-CN)-bnamd의 제조a) Preparation of t-BuO 2 CCH 2 -D-Dpa-Pro- (4-CN) -bnamd

실시예 22의 단계 a) 과정 도중에 수득한 화합물 D-Dpa-Pro-(4-CN)-bnamd (400㎎, 0.818mmol)을 아세토니트릴(10㎖)에 녹여 0℃로 냉각시킨 후 디이소프로필에틸아민(0.58㎖, 3.27mmol)과 t-부틸브로모아세테이트(t-BuO2CCH2Br; 0.16㎖, 1.06 mmol)를 가하고 상온으로 서서히 올린 후 20시간 동안 교반하였다. 반응 완결 후 농축하고 잔류물을 칼럼 크로마토그래피(용리액: 에틸아세테이트/n-헥산=6/4, 부피비)로 정제하여 표제화합물 445㎎(수율 96%)을 수득하였다.Example a) Compound D-Dpa-Pro- (4-CN) -bnamd (400 mg, 0.818 mmol) obtained in the course of step a) was dissolved in acetonitrile (10 mL), cooled to 0 ° C., and diisopropyl. Ethylamine (0.58 mL, 3.27 mmol) and t-butylbromoacetate (t-BuO 2 CCH 2 Br; 0.16 mL, 1.06 mmol) were added thereto, and then slowly raised to room temperature, followed by stirring for 20 hours. After completion of the reaction was concentrated and the residue was purified by column chromatography (eluent: ethyl acetate / n- hexane = 6/4, volume ratio) to give 445 mg (96% yield) of the title compound.

1H NMR (CDCl3) δ 8.01 (m, 1H), 7.57 (d, 2H), 7.37 (m, 6H), 7.28- 7.13 (m, 6H), 4.52 (dd, 1H), 4.41(dd, 1H), 4.28 (dd, 2H), 4.14 (d, 1H), 3.27 (m, 1H), 3.21 (dd, 2H), 2.69 (m, 1H), 2.12 (m, 2H), 1.67 (m, 1H), 1.43 (m, 1H), 1.37 (s, 9H) 1 H NMR (CDCl 3 ) δ 8.01 (m, 1H), 7.57 (d, 2H), 7.37 (m, 6H), 7.28-7.13 (m, 6H), 4.52 (dd, 1H), 4.41 (dd, 1H ), 4.28 (dd, 2H), 4.14 (d, 1H), 3.27 (m, 1H), 3.21 (dd, 2H), 2.69 (m, 1H), 2.12 (m, 2H), 1.67 (m, 1H) , 1.43 (m, 1H), 1.37 (s, 9H)

FAB MS: 567[M+1]+ FAB MS: 567 [M + 1] +

b) t-BuO2CCH2-D-Dpa-Pro-(4-amd)-bnamd의 제조b) Preparation of t-BuO 2 CCH 2 -D-Dpa-Pro- (4-amd) -bnamd

단계 a)에서 수득한 화합물(100㎎, 0.176mmol)을 메탄올(6㎖)에 녹인 후 하이드록실아민 염산염(NH2OH·HCl; 24.5㎎, 0.352mmol)과 포타슘 t-부톡사이드(KOC(CH3)3; 40㎎, 0.352mmol)를 가하고 60℃에서 10시간 동안 교반하였다. 반응 완결 후 감압 증류하여 휘발성 물질을 제거하였다. 잔액을 에틸아세테이트로 희석시킨 후 포화 소금물로 세척하였다. 무수 마그네슘설페이트로 건조시킨 후, 여과하고 농축하였다. 잔류물을 칼럼 크로마토그래피(용리액: 메탄올/디클로로메탄= 2/23, 부피비)로 정제하여 t-BuO2CCH2-D-Dpa-Pro-(4-hydroxyamd)-bnamd를 95㎎(수율 90%) 수득하였다. 수득된 화합물(93㎎, 0.155mmol)을 메탄올(5㎖)에 녹이고 여기에 아세트산무수물(CH3CO2COCH3; 0.03㎖, 0.31mmol), 아세트산(CH3CO2H; 0.044㎖, 0.775mmol) 및 10% 팔라듐-탄소(20㎎)를 가한 다음 이 용액을 Parr 수소반응기를 사용하여 20psi의 수소하에서 24시간 동안 반응시켰다. 생성용액을 셀라이트 패드로 걸러 불용성 탄소를 제거하고 용매를 감압증류하여 농축시켰다. 잔류물을 HPLC로 정제하여 표제화합물 90㎎(수율 90%)을 수득하였다.The compound (100 mg, 0.176 mmol) obtained in step a) was dissolved in methanol (6 mL), followed by hydroxylamine hydrochloride (NH 2 OH.HCl; 24.5 mg, 0.352 mmol) and potassium t-butoxide (KOC (CH). 3 ) 3 ; 40 mg, 0.352 mmol) was added and stirred at 60 ° C. for 10 hours. After completion of the reaction, distillation under reduced pressure to remove volatiles. The residue was diluted with ethyl acetate and washed with saturated brine. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The residue was purified by column chromatography (eluent: methanol / dichloromethane = 2/23, volume ratio) to give 95 mg of t-BuO 2 CCH 2 -D-Dpa-Pro- (4-hydroxyamd) -bnamd (90% yield). ) Obtained. The obtained compound (93 mg, 0.155 mmol) was dissolved in methanol (5 mL), and acetic anhydride (CH 3 CO 2 COCH 3 ; 0.03 mL, 0.31 mmol) and acetic acid (CH 3 CO 2 H; 0.044 mL, 0.775 mmol) ) And 10% palladium-carbon (20 mg) were added and the solution was then reacted for 24 hours under 20 psi hydrogen using a Parr hydrogen reactor. The resulting solution was filtered through a pad of celite to remove insoluble carbon, and the solvent was concentrated by distillation under reduced pressure. The residue was purified by HPLC to give 90 mg (90% yield) of the title compound.

1H NMR (CD3OD) δ 7.76 (d, 2H), 7.55 (d, 2H), 7.50 (d, 2H), 7.37 (t, 2H), 7.26-7.16 (m, 6H), 4.50 (m, 3H), 4.22(d, 1H), 4.08 (dd, 1H), 3.53 (m, 1H), 3.34 (s, 2H), 2.98 (m, 1H), 2.02- 1.70 (m, 3H), 1.41 (s, 9H), 1.40(m, 1H) 1 H NMR (CD 3 OD) δ 7.76 (d, 2H), 7.55 (d, 2H), 7.50 (d, 2H), 7.37 (t, 2H), 7.26-7.16 (m, 6H), 4.50 (m, 3H), 4.22 (d, 1H), 4.08 (dd, 1H), 3.53 (m, 1H), 3.34 (s, 2H), 2.98 (m, 1H), 2.02- 1.70 (m, 3H), 1.41 (s , 9H), 1.40 (m, 1H)

FAB MS: 584 [M+1]+ FAB MS: 584 [M + 1] +

c) HO2CCH2-D-Dpa-Pro-(4-amd)-bnamd·2TFA의 제조c) preparation of HO 2 CCH 2 -D-Dpa-Pro- (4-amd) -bnamd.2TFA

단계 b)에서 수득한 화합물(100㎎, 0.17mmol)을 디클로로메탄(2.5㎖)에 녹이고 트리플루오르아세트산(2.5㎖)을 가한 후 상온에서 3시간 30분동안 교반하였다. 반응 완결을 확인한 후 감압하여 농축하고 생성된 잔류물을 HPLC로 정제하여 표제화합물 102㎎(수율 80%)을 수득하였다.The compound (100 mg, 0.17 mmol) obtained in step b) was dissolved in dichloromethane (2.5 mL), trifluoroacetic acid (2.5 mL) was added, and the mixture was stirred at room temperature for 3 hours 30 minutes. After confirming the completion of the reaction, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by HPLC to obtain 102 mg (yield 80%) of the title compound.

1H NMR (CD3OD) δ 7.77 (d, 2H), 7.67 (d, 2H), 7.57 (d, 2H), 7.51 (t, 2H), 7.41-7.26 (m, 6H), 5.33 (d, 2H), 4.52 (dd, 2H), 4.10 (dd, 1H), 3.83 (dd, 2H), 3.49 (m, 1H), 2.87 (m, 1H), 1.91- 1.72 (m, 3H), 1.30(m, 1H) 1 H NMR (CD 3 OD) δ 7.77 (d, 2H), 7.67 (d, 2H), 7.57 (d, 2H), 7.51 (t, 2H), 7.41-7.26 (m, 6H), 5.33 (d, 2H), 4.52 (dd, 2H), 4.10 (dd, 1H), 3.83 (dd, 2H), 3.49 (m, 1H), 2.87 (m, 1H), 1.91-1.72 (m, 3H), 1.30 (m , 1H)

FAB MS: 528 [M+1]+ FAB MS: 528 [M + 1] +

실시예 46: (2Example 46: (2 SS )-)- NN -{4-[아미노(이미노)메틸]벤질}-1-{(2-{4- [amino (imino) methyl] benzyl} -1-{(2 RR )-2-[페닐아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드 트리플루오로아세트산염의 합성) -2- [phenylamino] -3,3-diphenylpropanoyl} -2-pyrrolidinecarboxamide trifluoroacetic acid salt

a) Ph-D-Dpa의 제조a) Preparation of Ph-D-Dpa

D-디페닐알라닌 염산염(0.5g, 1.3mmol)을 디메틸포름아미드(3.6㎖)와 함께 반응용기에 넣었다. 여기에 요오드화벤젠(0.16㎖, 1.43mmol), 테트라키스(트리페닐포스핀)팔라듐(Pd(PPh3)4; 72㎎, 0.062mmol), 요오드화구리(CuI; 12.2㎎, 0.064 mmol), 칼륨카보네이트(K2CO3; 0.18g, 1.3mmol), 트리에틸벤질암모늄클로라이드(PhCH2NEt3Cl; 44㎎, 0.19mmol), 트리에틸아민(0.36㎖, 2.58mmol) 및 물(0.36㎖)을 함께 가하고 100℃에서 4시간 동안 교반하였다. 반응 완결 후 1N 수산화나트륨 수용액을 사용하여 pH를 10으로 조정하고 에틸아세테이트 20㎖로 세척해주었다. 1N 염산을 사용하여 수층의 pH를 2로 조정하고 에틸아세테이트(10㎖)로 2회 추출하였다. 유기층을 모아 무수 마그네슘설페이트로 건조시킨 후, 여과 및 농축하고 진공펌프로 다시 건조시켜 표제화합물 0.21g(수율 86%)을 수득하였다.D-diphenylalanine hydrochloride (0.5 g, 1.3 mmol) was added to the reaction vessel together with dimethylformamide (3.6 mL). Benzene iodide (0.16 mL, 1.43 mmol), tetrakis (triphenylphosphine) palladium (Pd (PPh 3 ) 4 ; 72 mg, 0.062 mmol), copper iodide (CuI; 12.2 mg, 0.064 mmol), potassium carbonate (K 2 CO 3 ; 0.18 g, 1.3 mmol), triethylbenzylammonium chloride (PhCH 2 NEt 3 Cl; 44 mg, 0.19 mmol), triethylamine (0.36 mL, 2.58 mmol) and water (0.36 mL) together It was added and stirred at 100 ℃ for 4 hours. After completion of the reaction, the pH was adjusted to 10 using 1N aqueous sodium hydroxide solution and washed with 20 ml of ethyl acetate. The pH of the aqueous layer was adjusted to 2 with 1N hydrochloric acid and extracted twice with ethyl acetate (10 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, concentrated and dried again with a vacuum pump to give 0.21 g (yield 86%) of the title compound.

1H NMR (CD3OD) δ 7.51-7.15 (m, 11H), 7.07 (m, 2H), 6.60 (m, 2H), 4.74 (d, 1H), 4.42 (d, 1H) 1 H NMR (CD 3 OD) δ 7.51-7.15 (m, 11H), 7.07 (m, 2H), 6.60 (m, 2H), 4.74 (d, 1H), 4.42 (d, 1H)

FAB MS: 318 [M+1]+ FAB MS: 318 [M + 1] +

b) Ph-D-Dpa-Pro-OMe의 제조b) Preparation of Ph-D-Dpa-Pro-OMe

단계 a)에서 수득한 화합물(0.21g, 0.66mmol)에 대해 실시예 1의 단계 c)에서와 유사한 방법으로 아미드 결합반응을 수행하여 표제화합물 0.10g(수율 36%)을 수득하였다.The amide coupling reaction was carried out for the compound obtained in step a) (0.21 g, 0.66 mmol) in a similar manner as in step c) of Example 1 to obtain 0.10 g (yield 36%) of the title compound.

1H NMR (CDCl3) δ 7.47-7.03 (m, 13H), 6.73 (t, 1H), 6.58 (m, 2H), 4.76 (dd, 1H), 4.44 (d, 1H), 4.19 (t, 1H), 4.07 (m, 1H), 3.55 (m, 1H), 3.48 (s, 3H), 2.83 (m, 1H), 1.73 (m, 3H), 1.27 (m, 1H) 1 H NMR (CDCl 3 ) δ 7.47-7.03 (m, 13H), 6.73 (t, 1H), 6.58 (m, 2H), 4.76 (dd, 1H), 4.44 (d, 1H), 4.19 (t, 1H ), 4.07 (m, 1H), 3.55 (m, 1H), 3.48 (s, 3H), 2.83 (m, 1H), 1.73 (m, 3H), 1.27 (m, 1H)

FAB MS: 429 [M+1]+ FAB MS: 429 [M + 1] +

c) Ph-D-Dpa-Pro-OH의 제조c) preparation of Ph-D-Dpa-Pro-OH

단계 b)에서 수득한 화합물(0.13g, 0.25mmol)에 대해 실시예 1의 단계 b)에서와 동일한 방법으로 가수분해 반응을 수행하여 표제화합물 0.10g(수율 97%)을 수득하였다.The hydrolysis reaction was carried out for the compound obtained in step b) (0.13 g, 0.25 mmol) in the same manner as in step b) of Example 1, to obtain 0.10 g (yield 97%) of the title compound.

1H NMR (CD3OD) δ 7.51-7.10 (m, 12H), 6.71 (m, 1H), 6.60 (m, 2H), 4.77 (m, 1H), 4.40 (m, 1H), 4.22 (m, 1H), 4.02 (m, 1H), 3.50 (m, 1H), 2.80 (m, 1H), 1.83 (m, 3H), 1.30 (m, 1H) 1 H NMR (CD 3 OD) δ 7.51-7.10 (m, 12H), 6.71 (m, 1H), 6.60 (m, 2H), 4.77 (m, 1H), 4.40 (m, 1H), 4.22 (m, 1H), 4.02 (m, 1H), 3.50 (m, 1H), 2.80 (m, 1H), 1.83 (m, 3H), 1.30 (m, 1H)

FAB MS: 415 [M+1]+ FAB MS: 415 [M + 1] +

d) Ph-D-Dpa-Pro-(4-CN)-bnamd의 제조d) preparation of Ph-D-Dpa-Pro- (4-CN) -bnamd

단계 c)에서 수득한 화합물(0.10g, 0.24mmol)에 대해 실시예 1의 단계 c)에서와 동일한 방법으로 반응을 수행하여 표제화합물 0.12g(수율 52%)을 수득하였다.The reaction was carried out for the compound obtained in step c) (0.10 g, 0.24 mmol) in the same manner as in step c) of Example 1, to obtain 0.12 g (yield 52%) of the title compound.

1H NMR (CDCl3) δ 7.50-6.99 (m, 13H), 6.95 (m, 1H), 6.69 (m, 1H), 6.53 (m, 2H), 4.87 (m, 1H), 4.55 (d, 1H), 4.44 (d, 1H), 4.19 (dd, 1H), 4.16 (m, 1H), 4.01 (dd, 1H), 3.50 (m, 1H), 2.72 (m, 1H), 2.16 (m, 1H), 1.74 (m, 1H), 1.38 (m, 2H) 1 H NMR (CDCl 3 ) δ 7.50-6.99 (m, 13H), 6.95 (m, 1H), 6.69 (m, 1H), 6.53 (m, 2H), 4.87 (m, 1H), 4.55 (d, 1H ), 4.44 (d, 1H), 4.19 (dd, 1H), 4.16 (m, 1H), 4.01 (dd, 1H), 3.50 (m, 1H), 2.72 (m, 1H), 2.16 (m, 1H) , 1.74 (m, 1H), 1.38 (m, 2H)

FAB MS: 529 [M+1]+ FAB MS: 529 [M + 1] +

e) Ph-D-Dpa-Pro-(4-amd)-bnamd·TFA의 제조e) Preparation of Ph-D-Dpa-Pro- (4-amd) -bnamdTFA

단계 d)에서 수득한 화합물(0.13g, 0.25mmol)에 대해 실시예 1의 단계 d)에서와 동일한 방법으로 반응을 수행하여 표제화합물 0.10g(수율 53%)을 수득하였다.The reaction was carried out for the compound obtained in step d) (0.13 g, 0.25 mmol) in the same manner as in step d) of Example 1, to obtain 0.10 g (yield 53%) of the title compound.

1H NMR (CD3OD) δ 7.59 (m, 2H), 7.51-7.25 (m, 12H), 7.02 (m, 2H), 6.75-6.63 (m, 3H), 5.06 (m, 1H), 4.43 (m, 1H), 4.25 (m, 2H), 4.12 (m, 1H), 3.66 (m, 1H), 3.07 (m, 1H), 1.93-1.57 (m, 3H), 1.35 (m, 1H) 1 H NMR (CD 3 OD) δ 7.59 (m, 2H), 7.51-7.25 (m, 12H), 7.02 (m, 2H), 6.75-6.63 (m, 3H), 5.06 (m, 1H), 4.43 ( m, 1H), 4.25 (m, 2H), 4.12 (m, 1H), 3.66 (m, 1H), 3.07 (m, 1H), 1.93-1.57 (m, 3H), 1.35 (m, 1H)

FAB MS: 546 [M+1]+ FAB MS: 546 [M + 1] +

실험예 1: 트롬빈 억제활성Experimental Example 1: Thrombin Inhibitory Activity

하기 설명하는 바에 따라 본 발명에 따른 화합물의 트롬빈 활성에 대한 억제 능력을 측정하였다.The inhibitory capacity for thrombin activity of the compounds according to the invention was measured as described below.

1.5㎖ 큐벳에 150mM NaCl, 0.1% PEG8000(폴리에틸렌글리콜, 분자량 약 8,000)이 함유되어 있는 0.1M 트리스 완충용액(pH 7.8)을 1160㎕ 씩 가하였다. 억제제 용액으로는 본 발명에 따른 화합물을 디메틸설폭사이드로 10㎎/㎖ 되게 용해시킨 후 상기 완충용액으로 희석시켜 0.1㎎/㎖, 0.01㎎/㎖, 0.001㎎/㎖ 농도로 만든 것을 화합물의 양이 0 내지 10㎍ 사이가 되게 취한 후 트리스 완충용액으로 전체 부피가 100㎕ 되도록 하여 큐벳에 가하였다. 기질용액으로는 크로모자임 TH 를 디메틸설폭사이드(DMSO)에 10mM 농도로 용해시킨 후 상기 완충용액으로 희석시켜 0.1mM 농도가 되도록 제조한 것을 사용하였다.To the 1.5 mL cuvette was added 1160 μl of 0.1 M Tris buffer (pH 7.8) containing 150 mM NaCl and 0.1% PEG8000 (polyethylene glycol, molecular weight about 8,000). As an inhibitor solution, the compound according to the present invention was dissolved in dimethyl sulfoxide to 10 mg / ml, and then diluted with the buffer solution to make 0.1 mg / ml, 0.01 mg / ml, or 0.001 mg / ml. Taken between 0 and 10 μg and added to the cuvette with a total volume of 100 μl with Tris buffer. The substrate solution was prepared by dissolving chromozyme TH in dimethylsulfoxide (DMSO) at a concentration of 10 mM and diluting with the buffer solution to a concentration of 0.1 mM.

완충용액과 억제제 용액이 들어 있는 큐벳에 상기 트리스 완충용액에 0.1㎎/㎖ 농도로 용해시킨 트롬빈(human thrombin) 용액 15㎕를 가하여 실온에서 15분 동안 방치한 후 0.1mM 기질용액 225㎕를 가하면서 2분 동안 반응에 의해 생성되는 파라-니트로아닐리드의 양을 381nm 에서의 흡광도의 변화로 모니터하여, 반응시간 대 흡광도의 연속 스펙트럼을 도시하였다. 여러 종류의 억제제 농도에 대해 위의 실험을 수행하여 연속 스펙트럼을 얻었다.15 μl of a thrombin solution dissolved in the Tris buffer solution at a concentration of 0.1 mg / ml was added to a cuvette containing a buffer solution and an inhibitor solution, and allowed to stand at room temperature for 15 minutes, followed by adding 225 μl of 0.1 mM substrate solution. The amount of para-nitroanilide produced by the reaction for 2 minutes was monitored by the change in absorbance at 381 nm, showing the continuous spectrum of reaction time versus absorbance. The above experiments were performed for different inhibitor concentrations to obtain continuous spectra.

각 스펙트럼에서 기울기를 측정하여 속도 V를 구한 후, 억제제 농도 대비 속도의 역수(1/V) 그래프를 도시하였다. 그래프상의 점들을 만족하는 1차식을 계산해낸 후 그 식의 X 절편으로 부터 효소 반응식을 사용하여 Ki 를 계산해낼 수 있다. 이 계산에 사용된 Km 값은 5.2μM로 일정효소 농도에서 기질의 농도를 변화시킴으로써 구한 것이다.Velocity V was determined by measuring the slope in each spectrum, and then an inverse (1 / V) graph of velocity versus inhibitor concentration was shown. After calculating the linear equation that satisfies the points on the graph, Ki can be calculated using the enzyme reaction from the X intercept of the equation. The Km value used in this calculation was 5.2 μM, determined by varying the substrate concentration at a constant enzyme concentration.

이상 설명한 방법에 따라 트롬빈에 대해 측정된 본 발명에 따른 억제제의 효소활성 억제능력을 Ki 값으로 나타내었으며, 그 결과는 하기 표 1에 기재한 바와 같다.According to the method described above, the inhibitory activity of the inhibitor according to the present invention measured for thrombin was expressed as Ki value, and the results are shown in Table 1 below.

트롬빈에 대한 억제능력Inhibitory ability to thrombin 실시예화합물Example Compound 트롬빈에 대한억제능력Inhibition of thrombin 실시예화합물Example Compound 트롬빈에 대한억제능력Inhibition of thrombin 1One Ki = 0.018 nMKi = 0.018 nM 2525 Ki = 0.150 nMKi = 0.150 nM 22 Ki = 4.2 nMKi = 4.2 nM 2626 Ki = 0.47 nMKi = 0.47 nM 33 Ki = 0.16 nMKi = 0.16 nM 2727 Ki = 0.020 nMKi = 0.020 nM 44 Ki = 0.029 nMKi = 0.029 nM 2828 Ki = 0.060 nMKi = 0.060 nM 55 Ki = 0.035 nMKi = 0.035 nM 2929 Ki = 0.52 nMKi = 0.52 nM 66 Ki = 0.38 nMKi = 0.38 nM 3030 Ki = 0.91 nMKi = 0.91 nM 77 Ki = 0.66 nMKi = 0.66 nM 3131 Ki = 0.015 nMKi = 0.015 nM 88 Ki = 43 nMKi = 43 nM 3232 Ki = 0.020 nMKi = 0.020 nM 99 Ki = 0.027 nMKi = 0.027 nM 3333 Ki = 0.040 nMKi = 0.040 nM 1010 Ki = 4.2 nMKi = 4.2 nM 3434 Ki = 0.040 nMKi = 0.040 nM 1111 Ki = 0.046 nMKi = 0.046 nM 3535 Ki = 0.050 nMKi = 0.050 nM 1212 Ki = 2.1 nMKi = 2.1 nM 3636 Ki = 0.090 nMKi = 0.090 nM 1313 Ki = 0.055 nMKi = 0.055 nM 3737 Ki = 0.44 nMKi = 0.44 nM 1414 Ki = 0.023 nMKi = 0.023 nM 3838 Ki = 0.26 nMKi = 0.26 nM 1515 Ki = 0.030 nMKi = 0.030 nM 3939 Ki = 0.036 nMKi = 0.036 nM 1616 Ki = 0.016 nMKi = 0.016 nM 4040 Ki = 0.005 nMKi = 0.005 nM 1717 Ki = 0.32 nMKi = 0.32 nM 4141 Ki = 0.01 nMKi = 0.01 nM 1818 Ki = 0.20 nMKi = 0.20 nM 4242 Ki = 0.002 nMKi = 0.002 nM 1919 Ki = 0.060 nMKi = 0.060 nM 4343 Ki = 0.011 nMKi = 0.011 nM 2020 Ki = 0.39 nMKi = 0.39 nM 4444 Ki = 0.15 nMKi = 0.15 nM 2121 Ki = 0.080 nMKi = 0.080 nM 4545 Ki = 0.02 nMKi = 0.02 nM 2222 Ki = 0.030 nMKi = 0.030 nM 4646 Ki = 0.045 nMKi = 0.045 nM 2323 Ki = 0.035 nMKi = 0.035 nM 이노가트란Inogartran Ki = 15 nMKi = 15 nM 2424 Ki = 0.040 nMKi = 0.040 nM 아가트로반Agatrovan Ki = 2.5 nMKi = 2.5 nM

트롬빈에 대해 본 발명에 따른 화학식 1 화합물의 억제 활성을 측정한 결과, 본 발명의 화합물은 트롬빈에 대한 억제능이 매우 우수한 것으로 확인되었다. 특히 대부분의 실시예 화합물은 공지의 트롬빈 억제제인 화학식 2의 아가트로반 및 화학식 4의 이노가트란에 비해 훨씬 뛰어난 효과를 지니고 있다.As a result of measuring the inhibitory activity of the compound of formula (I) according to the present invention with respect to thrombin, the compound of the present invention was found to have a very good inhibitory activity against thrombin. In particular, most of the example compounds have a much better effect than the known thrombin inhibitors, agatroban of formula (2) and inogatran of formula (4).

실험예 2: 약물동력학Experimental Example 2: Pharmacokinetics

본 발명에 따른 화학식 1 화합물의 경구투여시 흡수효과는 하기 실험방법에따라 혈중약물농도를 측정함으로써 결정하였다.The absorption effect upon oral administration of the compound of formula 1 according to the present invention was determined by measuring blood drug concentration according to the following experimental method.

실험군당 3 내지 4마리의 웅성 쥐를 20시간동안 절식시킨 후 실험하였다. 생리식염수를 사용하여 실시예 화합물의 1%(10㎎/㎖) 용액을 조제한 후 경구투여하였다. 정해진 시간간격에 따라서 혈액을 채취하여 혈장을 분리한 후, 메탄올과 3:1(v/v)의 비율로 혼합하고 상층액에 대해 고압액체크로마토그래피(HPLC)를 사용하여 205nm에서 혈중약물농도를 측정하였다.Three to four male mice per experimental group were fasted for 20 hours and then tested. Physiological saline was used to prepare a 1% (10 mg / ml) solution of the compound, followed by oral administration. Plasma is separated by taking blood at a predetermined time interval, and then mixed with methanol at a ratio of 3: 1 (v / v). Measured.

실험결과, 본 발명에 따른 대부분의 실시예 화합물은 동물에서 높은 경구흡수 경향을 보여 주었다. 그 예로서 실시예 1, 9, 15, 21, 31, 39, 40, 43 및 45 화합물의 결과를 하기 표 2에 나타내었다. 표 2의 결과로부터 쥐에서 흡수된 실시예의 약물들이 혈중에서 고농도로 검출됨을 알 수 있다.As a result, most of the example compounds according to the present invention showed high oral absorption tendency in animals. As examples, the results of Examples 1, 9, 15, 21, 31, 39, 40, 43, and 45 compounds are shown in Table 2 below. From the results in Table 2, it can be seen that the drugs of the examples absorbed in the rats are detected at high concentrations in the blood.

쥐에 실시예의 화합물을 30mg/kg으로 경구투여한 경우 혈중약물농도 계수Blood drug concentration coefficient when oral administration of 30 mg / kg of the compound of Example 실시예 번호Example number Cmax(㎍/㎖)Cmax (μg / ml) Tmax(분)Tmax (minutes) AUC(㎍·분/㎖)AUC (μgmin / ml) 1One 2.82.8 4040 272272 99 1.61.6 6060 246246 1515 1.71.7 3030 206206 2121 3.23.2 3030 594594 3131 14.114.1 3030 15641564 3939 1.11.1 1515 107107 4040 2.72.7 4040 265265 4343 4.14.1 3030 271271 4545 1.21.2 1010 120120

상기 표 2에서 Cmax는 최고혈중농도이고, Tmax는 최고 혈중농도를 나타내는 시간이며, AUC는 혈중농도의 시간에 따른 적분값이다.In Table 2, Cmax is the highest blood concentration, Tmax is the time indicating the highest blood concentration, and AUC is the integral value of the blood concentration over time.

Claims (10)

하기 화학식 1의 화합물, 약제학적으로 허용되는 그의 염, 수화물, 용매화물 및 이성체:Compounds of Formula 1, pharmaceutically acceptable salts, hydrates, solvates and isomers thereof: 화학식 1Formula 1 상기식에서,In the above formula, n은 0 내지 2의 정수를 나타내고,n represents an integer of 0 to 2, m은 1 내지 3의 정수를 나타내며,m represents an integer of 1 to 3, A는 수소, C1-C6-알킬, C3-C7-사이클로알킬, 아릴, -SO2-R1, -SO3-R1, -(CH2)m-SO2-R1, -(CH2)m-SO3-R1, -CO-R1, -CO2-R2, -(CH2)m-CO2-R1, -PO(R1)2, -PO(OR1)2, 또는 -(CH2)m-PO(OR1)2을 나타내고, 여기에서 R1은 수소, C1-C6-알킬, C3-C7-사이클로알킬, 아릴, -(CH2)m-아릴 또는 -NR3R4를 나타내며, R2는 C1-C6-알킬, C3-C7-사이클로알킬, 아릴, 또는 -(CH2)m-아릴을 나타내고, R3및 R4는 각각 독립적으로 수소, C1-C6-알킬, 또는 C3-C7-사이클로알킬을 나타내며,A is hydrogen, COne-C6Alkyl, C3-C7-Cycloalkyl, aryl, -SO2-ROne, -SO3-ROne,-(CH2)m-SO2-ROne,-(CH2)m-SO3-ROne, -CO-ROne, -CO2-R2,-(CH2)m-CO2-ROne, -PO (ROne)2, -PO (OROne)2, Or-(CH2)m-PO (OROne)2Where R isOneSilver hydrogen, COne-C6Alkyl, C3-C7-Cycloalkyl, aryl,-(CH2)m-Aryl or -NR3R4, R2COne-C6Alkyl, C3-C7-Cycloalkyl, aryl, or-(CH2)m-Aryl, R3And R4Are each independently hydrogen, COne-C6-Alkyl, or C3-C7-Cycloalkyl, B는 -CH(R5)2을 나타내며, 여기에서 R5는 C1-C4-알킬, 할로겐, 하이드록시, C1-C4-알킬옥시, -CO2-C1-C4-알킬 및 아미노로 구성된 그룹중에서 선택된 1개 이상의 치환체에 의해 치환되거나 비치환된 페닐, 헤테로아릴, C1-C4-알킬 또는 C3-C7-사이클로알킬을 나타내고,B represents -CH (R 5 ) 2 , wherein R 5 is C 1 -C 4 -alkyl, halogen, hydroxy, C 1 -C 4 -alkyloxy, -CO 2 -C 1 -C 4 -alkyl And phenyl, heteroaryl, C 1 -C 4 -alkyl or C 3 -C 7 -cycloalkyl unsubstituted or substituted by one or more substituents selected from the group consisting of amino, D는 -C(NH)NH2(아미딘), -CH2NH2(아미노메틸) 또는 -C(NH2)NOH(하이드록시아미딘)을 나타내며,D represents —C (NH) NH 2 (amidine), —CH 2 NH 2 (aminomethyl) or —C (NH 2 ) NOH (hydroxyamidine), E, F, G 및 H는 각각 독립적으로 CR6또는 N을 나타내나, 단 E, F, G 및 H가 동시에 N이 될 수 없으며, 적어도 하나가 N이 되어야 하고, 여기에서 R6는 수소, 할로겐, C1-C4-알킬, C1-C4-알킬옥시, 하이드록시 또는 아미노를 나타낸다.E, F, G and H each independently represent CR 6 or N, provided that E, F, G and H cannot be N at the same time, at least one must be N, where R 6 is hydrogen, Halogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkyloxy, hydroxy or amino. 제1항에 있어서, B가 -CH(R5)2을 나타내며, 여기에서 R5는 페닐, 헤테로아릴, C1-C4-알킬 또는 C3-C7-사이클로알킬을 나타내는 화합물.The compound of claim 1, wherein B represents -CH (R 5 ) 2 , wherein R 5 represents phenyl, heteroaryl, C 1 -C 4 -alkyl or C 3 -C 7 -cycloalkyl. 제2항에 있어서, B가 -CH(R5)2을 나타내며, 여기에서 R5는 페닐, C1-C4-알킬 또는 사이클로헥실을 나타내는 화합물.The compound of claim 2, wherein B represents -CH (R 5 ) 2 , wherein R 5 represents phenyl, C 1 -C 4 -alkyl or cyclohexyl. 제1항에 있어서, E 및 F중 하나가 N이고 G 및 H중 하나가 N이며 나머지는 CR6이거나, E, F, G 및 H중 하나가 N이고 나머지는 CR6이며, 여기에서 R6는 수소, 할로겐, C1-C4-알킬, C1-C4-알킬옥시, 하이드록시 또는 아미노를 나타내는 화합물.The compound of claim 1, wherein one of E and F is N and one of G and H is N and the other is CR 6, or one of E, F, G and H is N and the other is CR 6 , wherein R 6 Is hydrogen, halogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkyloxy, hydroxy or amino. 제2항 또는 제4항에 있어서, n은 0 내지 2의 정수를 나타내고, m은 1 내지 3의 정수를 나타내며, A는 수소, 아릴, -SO2-R1, -CO-R1, -CO2-R2, -(CH2)m-CO2-R1, -PO(R1)2또는 -PO(OR1)2를 나타내고, 여기에서 R1은 수소, C1-C6-알킬, 아릴, -(CH2)m-아릴 또는 -NR3R4를 나타내며, R2는 C1-C6-알킬, 아릴, 또는 -(CH2)m-아릴을 나타내고, R3및 R4는 각각 독립적으로 수소 또는 C1-C6-알킬을 나타내며, B는 -CH(R5)2을 나타내며, 여기에서 R5는 페닐, C1-C4-알킬 또는 사이클로헥실을 나타내고, D는 -C(NH)NH2(아미딘), -CH2NH2(아미노메틸) 또는 -C(NH2)NOH(하이드록시아미딘)을 나타내며, E 및 F중 하나가 N이고 G 및 H중 하나가 N이며 나머지는 CR6이거나, E, F, G 및 H중 하나가 N이고 나머지는 CR6이며, 여기에서 R6는 수소, 할로겐, C1-C4-알킬, C1-C4-알킬옥시 또는 아미노를 나타내는 화합물.The method of claim 2 or 4, wherein n represents an integer of 0 to 2, m represents an integer of 1 to 3, A represents hydrogen, aryl, -SO 2 -R 1 , -CO-R 1 ,- CO 2 -R 2 ,-(CH 2 ) m -CO 2 -R 1 , -PO (R 1 ) 2 or -PO (OR 1 ) 2 , wherein R 1 is hydrogen, C 1 -C 6- Alkyl, aryl,-(CH 2 ) m -aryl or -NR 3 R 4 , R 2 represents C 1 -C 6 -alkyl, aryl, or-(CH 2 ) m -aryl, R 3 and R 4 each independently represents hydrogen or C 1 -C 6 -alkyl, B represents —CH (R 5 ) 2 , wherein R 5 represents phenyl, C 1 -C 4 -alkyl or cyclohexyl, D Represents -C (NH) NH 2 (amidine), -CH 2 NH 2 (aminomethyl) or -C (NH 2 ) NOH (hydroxyamidine), wherein one of E and F is N and G and H One is N and the other is CR 6 or one of E, F, G and H is N and the other is CR 6 , where R 6 is hydrogen, halogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkyloxy Or a compound representing amino. 제5항에 있어서, B가 -CH(R5)2을 나타내며, 여기에서 R5는 페닐인 화합물.6. The compound of claim 5, wherein B represents —CH (R 5 ) 2 , wherein R 5 is phenyl. 제6항에 있어서,The method of claim 6, (2S)-N-({6-[아미노(이미노)메틸]-3-피리디닐}메틸)-1-{(2R)-2-[(아미노설포닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드; (2 S) - N - ( {6- [ amino (imino) methyl] -3-pyridinyl} methyl) -1 - {(2 R) -2 - [( aminosulfonyl) amino] 3,3 -Diphenylpropanoyl} -2-pyrrolidinecarboxamide; (2S)-N-({6-[아미노메틸]-3-피리디닐}메틸)-1-{(2R)-2-[(아미노설포닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드;( 2S ) -N -({6- [aminomethyl] -3-pyridinyl} methyl) -1-{( 2R ) -2-[(aminosulfonyl) amino] -3,3-diphenylprop Panoyl} -2-pyrrolidinecarboxamide; (2S)-N-({5-[아미노(이미노)메틸]-2-피리디닐}메틸)-1-{(2R)-2-[(아미노설포닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드; (2 S) - N - ( {5- [ amino (imino) methyl] -2-pyridinyl} methyl) -1 - {(2 R) -2 - [( aminosulfonyl) amino] 3,3 -Diphenylpropanoyl} -2-pyrrolidinecarboxamide; (2S)-N-({2-[아미노(이미노)메틸]-5-피리미디닐}메틸)-1-{(2R)-2-[(아미노설포닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드;( 2S ) -N -({2- [amino (imino) methyl] -5-pyrimidinyl} methyl) -1-{( 2R ) -2-[(aminosulfonyl) amino] -3, 3-diphenylpropanoyl} -2-pyrrolidinecarboxamide; (2S)-N-({6-[아미노(이미노)메틸]-3-피리디닐}메틸)-1-{(2R)-2-[(메틸옥시카보닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드;( 2S ) -N -({6- [amino (imino) methyl] -3-pyridinyl} methyl) -1-{( 2R ) -2-[(methyloxycarbonyl) amino] -3, 3-diphenylpropanoyl} -2-pyrrolidinecarboxamide; (2S)-N-({5-[아미노(이미노)메틸]-2-피리디닐}메틸)-1-{(2R)-2-[(메틸옥시카보닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드; 및( 2S ) -N -({5- [amino (imino) methyl] -2-pyridinyl} methyl) -1-{( 2R ) -2-[(methyloxycarbonyl) amino] -3, 3-diphenylpropanoyl} -2-pyrrolidinecarboxamide; And (2S)-N-({2-[아미노(이미노)메틸]-5-피리미디닐}메틸)-1-{(2R)-2-[(메틸옥시카보닐)아미노]-3,3-디페닐프로파노일}-2-피롤리딘카르복사미드로 구성된 그룹중에서 선택된 화합물.( 2S ) -N -({2- [amino (imino) methyl] -5-pyrimidinyl} methyl) -1-{( 2R ) -2-[(methyloxycarbonyl) amino] -3 , 3-diphenylpropanoyl} -2-pyrrolidinecarboxamide. a) 하기 화학식 7의 시아노 화합물을 황화수소, 요오드화메탄 및 암모늄아세테이트와 차례로 반응시켜 하기 화학식 1a의 아미딘 화합물을 제조하거나, b) 화학식 7의 화합물을 산촉매 존재하에 수소를 사용하여 환원반응시켜 하기 화학식 1b의 아미노메틸 화합물을 제조하거나, c) 하기 화학식 8의 화합물을 탈보호기화시켜 화학식 1a의 아미딘 화합물을 제조함을 특징으로 하여 제1항에 정의된 화학식 1의 화합물을 제조하는 방법:a) reacting a cyano compound of formula 7 with hydrogen sulfide, methane iodide and ammonium acetate in order to prepare an amidine compound of formula 1a, or b) reducing the compound of formula 7 with hydrogen in the presence of an acid catalyst A process for preparing the compound of formula 1 as defined in claim 1, characterized in that to prepare an aminomethyl compound of formula 1b, or c) deprotecting the compound of formula 8 to produce an amidine compound of formula 1a: 화학식 7Formula 7 화학식 1aFormula 1a 화학식 1bFormula 1b 화학식 8Formula 8 상기식에서In the above formula n, m, A, B, E, F, G 및 H는 제1항에서 정의한 바와 같고,n, m, A, B, E, F, G and H are as defined in claim 1, P 는 아미노보호기를 나타낸다.P represents an aminoprotecting group. 약제학적으로 허용되는 담체와 함께 유효성분으로서 제1항에 정의된 화학식 1의 화합물을 함유함을 특징으로 하는 혈액응고 예방 또는 혈전증 치료를 위한 트롬빈 억제제 조성물.A thrombin inhibitor composition for preventing coagulation or treating thrombosis, comprising a compound of formula 1 as defined in claim 1 together with a pharmaceutically acceptable carrier. 제9항에 있어서, 경구투여형 제제로 제형화된 조성물.The composition of claim 9 formulated as an oral dosage form.
KR10-1999-0064851A 1998-12-29 1999-12-29 Orally available peptidic thrombin inhibitors KR100405650B1 (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100596897B1 (en) * 2006-02-21 2006-07-04 주식회사 탑스코 Hanger inspection unit and the establishment method of bridge

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