KR20000049048A - Aspartate Ester Inhibitors of Interleukin-1Beta Converting Enzyme - Google Patents

Aspartate Ester Inhibitors of Interleukin-1Beta Converting Enzyme Download PDF

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KR20000049048A
KR20000049048A KR1019990703117A KR19997003117A KR20000049048A KR 20000049048 A KR20000049048 A KR 20000049048A KR 1019990703117 A KR1019990703117 A KR 1019990703117A KR 19997003117 A KR19997003117 A KR 19997003117A KR 20000049048 A KR20000049048 A KR 20000049048A
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South Korea
Prior art keywords
oxo
pentanoic acid
acetoxy
naphthalen
phenyl
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KR1019990703117A
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Korean (ko)
Inventor
한스 페. 알브레히트
해미쉬 존 알렌
케니쓰 데일 브래디
브래들리 윌리암 캐프레이드
존 로쥐 길모어
윌리암 글렌 하터
쉐릴 진 헤이스
캐서린 로즈 코스틀란
엘리자베쓰 앤 루니
킴벌리 수잔 파라
앤쏘니 제롬 토마스
니겔 워커
Original Assignee
로즈 암스트롱, 크리스틴 에이. 트러트웨인
워너-램버트 캄파니
스타르크, 카르크
바스프 악티엔게젤샤프트
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Application filed by 로즈 암스트롱, 크리스틴 에이. 트러트웨인, 워너-램버트 캄파니, 스타르크, 카르크, 바스프 악티엔게젤샤프트 filed Critical 로즈 암스트롱, 크리스틴 에이. 트러트웨인
Publication of KR20000049048A publication Critical patent/KR20000049048A/en

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Abstract

PURPOSE: Provided are compounds which are inhibitors of interleukin-1ss converting enzyme. Also a method of treatment of stroke, reperfusion injury, Alzheimer's disease, shigellosis, inflammatory diseases, and a pharmaceutically acceptable composition containing the compound are provided. CONSTITUTION: Compounds which are inhibitors of interleukin-1 beta converting enzyme that have formula (I) wherein R¬1 is R¬3CO-, R¬3SO2-, each R¬a is independently hydrogen, C1-C6 alkyl, or -(CH2)n aryl; R¬2 is -(CRR)n-aryl, -(CRR)n-X-aryl, -(CRR)n-heteroaryl, -(CRR)n-X-heteroaryl, -(CRR)n-(substituted-heteroaryl), -(CRR)n-(substituted-aryl), -(CRR)n-X-(substituted-aryl), -(CRR)n-aryl-aryl, -(CRR)n-aryl-heteroaryl, -(CRR)n-aryl-(CH2)n-aryl, -(CRR)n-CH(aryl)2, -(CRR)n-cycloalkyl, -(CRR)n-X-cycloalkyl, -(CRR)n-heterocycle, -(CRR)n-X-heterocycle, -(CRR)n substituted heterocycle, each R is independently hydrogen, C1-C6 alkyl, halogen or hydroxy; X is O or S; R3 is C1 -C6 alkyl, aryl heteroaryl, -(CHR)n-aryl, -(CHR)n-heteroaryl, -(CHR)n-substituted heteroaryl, -(CHR)n-substituted aryl, -(CRR)nS(CH2)n-aryl, cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, each R¬1 is independently C1-C6 alkyl, C1 -C6 alkylaryl, aryl, or hydrogen; each J is independently -C02R¬b, -CONR¬bR¬b, -SO2NR¬bR¬b, or -SO2R¬b; each R¬b is independently hydrogen, C1-C6 alkyl, aryl, substituted aryl; arylalkyl, heteroarylalkyl, substituted arylalkyl, or substituted heteroarylalkyl; R4 is hydrogen, C1-C6 alkyl, -phenyl, R6 is hydrogen, C 1 -C6 alkyl, -(CH2)n aryl, -(CH2)nCO2Ra, hydroxyl substituted C1-C6 alkyl, or imidazole substituted C1-C6 alkyl; each n is independently 0 to 3, and the pharmaceutically acceptable, salts, esters, amides, and prodrugs thereof.

Description

인터루킨-1β 전환 효소의 아스파르테이트 에스테르 억제제 {Aspartate Ester Inhibitors of Interleukin-1Beta Converting Enzyme}Aspartate Ester Inhibitors of Interleukin-1 Beta Converting Enzyme

본 발명의 화합물은 인터루킨-1β 전환 효소 (ICE; 카스파제 (Caspase-1))의 억제제이며, 인터루킨-1이 관여하는 질병의 치료에 유용하다.The compounds of the present invention are inhibitors of interleukin-1β converting enzyme (ICE; Caspase-1) and are useful for the treatment of diseases involving interleukin-1.

ICE는 프로-인터루킨-1β (pro-IL-1β)에 작용하여, 염증성 사이토킨인 인터루킨-1β (IL-1β)를 생성시킨다. 또한 ICE (카스파제-1)는 적어도 4 개의 사이토킨을 조절한다. ICE는 IL-β 및 IL-18을 활성화시켜서, IL-1∝ 및 IFNγ의 생성을 간접적으로 조절한다. 인터루킨 활성과 관련된 질병에는 여러 가지가 있다. 인터루킨-1이 관련된 질병의 예로는 루마티스성 관절염 및 염증성 장 질환 등의 염증성 질환, 발작 등의 신경염증성 장애 (neuroinflammatory disorder) 등이 있다. 기타 질병으로는 패혈성 쇼크, 재관류 손상, 알쯔하이머병, 시겔라증 등이 있다.ICE acts on pro- interleukin-1β (pro-IL-1β) to produce the inflammatory cytokine interleukin-1β (IL-1β). ICE (Caspase-1) also regulates at least four cytokines. ICE activates IL-β and IL-18 to indirectly regulate the production of IL-1 ′ and IFNγ. There are several diseases associated with interleukin activity. Examples of diseases associated with interleukin-1 include inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease, and neuroinflammatory disorders such as seizures. Other diseases include septic shock, reperfusion injury, Alzheimer's disease, and shigellosis.

IL-1β 활성을 조절하는 작용제가 유익한 생체내 효과를 갖는 것으로 입증되었다. 예를 들어 인터루킨-1 수용체 길항제인 화합물은 쥐의 뇌에서 허혈성 및 흥분독성 손상을 억제하는 것으로 입증되었다. 참고문헌의 예로는 문헌 (Relton J. K., et al., Brain Research Bulletin, 1992; 29: 243-246)이 있다. 또한 ICE 억제제는 쥐에게서 염증 및 발열을 억제하는 것으로 밝혀졌다. 문헌 (Elford P. R., et al., British Journal of Pharmacology, 1995; 115: 601-606)을 참고한다.Agents that modulate IL-1β activity have been demonstrated to have beneficial in vivo effects. For example, compounds that are interleukin-1 receptor antagonists have been shown to inhibit ischemic and excitatory damage in the rat brain. An example of a reference is Relton J. K., et al., Brain Research Bulletin, 1992; 29: 243-246. ICE inhibitors have also been shown to inhibit inflammation and fever in mice. See Elford P. R., et al., British Journal of Pharmacology, 1995; 115: 601-606.

본 발명의 화합물은 또한 ICE 패밀리 중 나머지 시스테인 프로테아제의 억제제이기도 하다. 이들 프로테아제 중 많은 것이 최근에서야 문헌을 통해 설명되었다. 명명법은 아직까지 결정되지 않았으나, 이런 종류의 효소에 속하는 대표적인 것으로는 Ich-2 (Tx 또는 ICErel-II로도 불림), ICErel-III, Ich-I (Nedd-2로도 불림), CPP-32 (아포파인 및 야마로도 불림), Mch-2, Mch-3 (ICE-lap3, CMH-1로도 불림) 및 Ced-3 등의 프로테아제가 있다 (Henkart P. A., Immunity, 1996; 4: 195-201). 이런 효소 패밀리에 속하는 것들은 염증 및 세포소멸 (apoptosis (계획된 세포사; programmed cell death))에서 중요한 생물학적 기능을 하는 것으로 인식되고 있다. 특히 카스파제-4는 IL-1β 및 IL-18을 활성화시킬 수 있다. 카스파제-4의 쥐의 동족체 (homolog)가 ICE를 활성화시킬 수 있음이 입증되었다. 따라서 카스파제-4를 억제하면, ICE가 억제될 것이다 (Thornberry N.A., et al., Perspectives in Drug Discovery and Design, 1994; 2 : 389-399).The compounds of the invention are also inhibitors of the remaining cysteine proteases in the ICE family. Many of these proteases have only recently been described in the literature. Nomenclature has not yet been determined, but representatives of this class of enzymes include Ich-2 (also called Tx or ICErel-II), ICErel-III, Ich-I (also called Nedd-2), CPP-32 (apopo) Also called pine and Yamaro), Mch-2, Mch-3 (also called ICE-lap3, CMH-1) and Ced-3 (Henkart PA, Immunity, 1996; 4: 195-201). Those belonging to this family of enzymes are recognized to play important biological functions in inflammation and apoptosis (programmed cell death). Caspase-4 in particular can activate IL-1β and IL-18. It has been demonstrated that the mouse homolog of caspase-4 can activate ICE. Thus, inhibition of caspase-4 will inhibit ICE (Thornberry N.A., et al., Perspectives in Drug Discovery and Design, 1994; 2: 389-399).

IL-1β 생성에 대한 작용 이외에도, ICE는 염증 매개 인터페론-γ를 생성시키는 기능을 하는 것으로 밝혀졌다 (Ghayur, et al., Nature, 1997; 386 (6625): 619-623). ICE는 불활성 프로 형태 (proform)의 인터페론-γ 유도 인자 (IGIF; 인터루킨-18)를 프로세싱하여, T 세포 및 천연 킬러 세포로 하여금 인터페론-γ을 생성시키도록 유도하는 단백질인 활성 IGIF를 만든다. 인터페론-γ는 염증성 장애 및 패혈성 쇼크 등의 질병의 병리 상태에 관련되어 있다. 따라서, ICE 억제제는 인터페론-γ에 작용하여 그러한 질병 상태에 유익한 효과를 가질 것으로 예상된다.In addition to its action on IL-1β production, ICE has been shown to function to produce inflammatory mediated interferon-γ (Ghayur, et al., Nature, 1997; 386 (6625): 619-623). ICE processes the inactive proform of interferon-γ inducing factor (IGIF; interleukin-18) to produce active IGIF, a protein that induces T cells and natural killer cells to produce interferon-γ. Interferon- [gamma] is associated with pathological conditions of diseases such as inflammatory disorders and septic shock. Thus, ICE inhibitors are expected to act on interferon-γ and have a beneficial effect on such disease states.

최근, ICE 패밀리 (카스파제로도 알려져 있음. ICE는 카스파제-1으로 알려짐)내의 이들 시스테인 프로테아제의 명명법이 추가로 정해졌다. 문헌 (Alnemri, et al, Cell, 1996; 87: 171)에 기재된 명명법을 사용하면, 이런 종류의 효소에 속하는 대표적인 것으로는 카스파제-2 (Ich-1으로도 알려짐), 카스파제-3 (CPP32, 야마 및 아포파인으로도 알려짐), 카스파제-4 (TX, Ich-2 및 ICE rel-II로도 알려져 있음), 카스파제-5 (ICE rel-III로도 알려짐), 카스파제-6 (Mch2로도 알려짐), 카스파제-7 (Mch3으로도 알려짐), 카스파제-8 (FLICE 및 Mch5로도 알려짐), 카스파제-9 (ICE-LAP6 및 Mch6으로도 알려짐), 카스파제-10 (Mch4로도 알려짐) 등이 있다.Recently, nomenclature of these cysteine proteases in the ICE family (also known as caspase. ICE is known as caspase-1) has been further defined. Using the nomenclature described in Alnemri, et al, Cell, 1996; 87: 171, representatives of this class of enzymes are caspase-2 (also known as Ich-1), caspase-3 (CPP32). , Also known as yama and apopain), caspase-4 (also known as TX, Ich-2 and ICE rel-II), caspase-5 (also known as ICE rel-III), caspase-6 (also referred to as Mch2) Caspase-7 (also known as Mch3), caspase-8 (also known as FLICE and Mch5), caspase-9 (also known as ICE-LAP6 and Mch6), caspase-10 (also known as Mch4) Etc.

발명의 요약Summary of the Invention

본 발명은 하기 화학식 I의 화합물 및 제약상 허용가능한 그의 염, 에스테르, 아미드 및 프로드럭을 제공한다.The present invention provides compounds of formula I and pharmaceutically acceptable salts, esters, amides and prodrugs thereof.

식 중, R1은, R3CO-, R3SO2-,,,,,, 또는(식 중, 각각의 Ra는 서로 독립적으로 수소, C1-C6알킬 또는 -(CH2)n아릴임)이고,Wherein R 1 is , R 3 CO-, R 3 SO 2- , , , , , , or Wherein each R a is, independently of each other, hydrogen, C 1 -C 6 alkyl, or — (CH 2 ) n aryl,

R2는 -(CRR)n-아릴, -(CRR)n-X-아릴, -(CRR)n-헤테로아릴, -(CRR)n-X-헤테로아릴, -(CRR)n-(치환된 헤테로아릴), -(CRR)n-(치환된 아릴), -(CRR)n-X-(치환된 아릴), -(CRR)n-아릴-아릴, -(CRR)n-아릴-헤테로아릴, -(CRR)n-아릴-(CH2)n-아릴, -(CRR)n-CH(아릴)2, -(CRR)n-시클로알킬, -(CRR)n-X-시클로알킬, -(CRR)n-헤테로사이클, -(CRR)n-X-헤테로사이클, -(CRR)n치환된 헤테로사이클,,,,,,,,,,,,,,,, 또는또는이다.R 2 is-(CRR) n -aryl,-(CRR) n -X-aryl,-(CRR) n -heteroaryl,-(CRR) n -X-heteroaryl,-(CRR) n- (substituted Heteroaryl),-(CRR) n- (substituted aryl),-(CRR) n -X- (substituted aryl),-(CRR) n -aryl-aryl,-(CRR) n -aryl-heteroaryl ,-(CRR) n -aryl- (CH 2 ) n -aryl,-(CRR) n -CH (aryl) 2 ,-(CRR) n -cycloalkyl,-(CRR) n -X-cycloalkyl,- (CRR) n -heterocycle,-(CRR) n -X-heterocycle,-(CRR) n substituted heterocycle, , , , , , , , , , , , , , , , or or to be.

여기서 각각의 R은 서로 독립적으로 수소, C1-C6-알킬, 할로겐 또는 히드록시이고,Wherein each R is, independently from each other, hydrogen, C 1 -C 6 -alkyl, halogen or hydroxy,

X는 산소 또는 황이며,X is oxygen or sulfur,

R3은 C1-C6알킬, 아릴, 헤테로아릴, -(CHR)n-아릴, -(CHR)n-헤테로아릴, -(CHR)n-치환된 헤테로아릴, -(CHR)n-치환된 아릴,, -(CRR)nS(CH2)n-아릴, 시클로알킬, 치환된 시클로알킬, 헤테로사이클, 치환된 헤테로사이클,,,,,,,,,,,,, R 3 is C 1 -C 6 alkyl, aryl, heteroaryl,-(CHR) n -aryl,-(CHR) n -heteroaryl,-(CHR) n -substituted heteroaryl,-(CHR) n -substituted Aryl, ,-(CRR) n S (CH 2 ) n -aryl, cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, , , , , , , , , , , , ,

각각의 R'은 서로 독립적으로 C1-C6알킬, C1-C6알킬아릴, 아릴 또는 수소이고,Each R 'is independently of each other C 1 -C 6 alkyl, C 1 -C 6 alkylaryl, aryl or hydrogen,

각각의 J는 서로 독립적으로 -CO2Rb, -CONRbRb, -SO2NRbRb또는 -SO2Rb(여기서 각각의 Rb는 서로 독립적으로 수소, C1-C6알킬, 아릴, 치환된 아릴, 아릴알킬, 헤테로아릴알킬, 치환된 아릴알킬 또는 치환된 헤테로아릴알킬임)이고,Each J is, independently from each other, -CO 2 R b , -CONR b R b , -SO 2 NR b R b or -SO 2 R b , wherein each R b is independently of each other hydrogen, C 1 -C 6 alkyl , Aryl, substituted aryl, arylalkyl, heteroarylalkyl, substituted arylalkyl or substituted heteroarylalkyl,

R4는 수소, C1-C6알킬,, -페닐 또는이고,R 4 is hydrogen, C 1 -C 6 alkyl, , -Phenyl or ego,

R5는 C1-C6알킬-CO-, -(CH2)n아릴,, C1-C6알킬-X-(CH2)nCO,,,,,,,,,, -(CH2)nX(CH2)n-아릴, -C1-C6알킬X-C1-C6알킬아릴, 또는이고,R 5 is C 1 -C 6 alkyl-CO—, — (CH 2 ) n aryl, , C 1 -C 6 alkyl-X- (CH 2 ) n CO, , , , , , , , , ,-(CH 2 ) n X (CH 2 ) n -aryl, -C 1 -C 6 alkylXC 1 -C 6 alkylaryl, or ego,

R5a는,,,,또는이고,R 5a is , , , , or ego,

R6은 수소, C1-C6알킬, -(CH2)n아릴, -(CH2)nCO2Ra, 히드록실 치환된 C1-C6알킬, 또는 이미다졸 치환된 C1-C6알킬이고,R 6 is hydrogen, C 1 -C 6 alkyl, — (CH 2 ) n aryl, — (CH 2 ) n CO 2 R a , hydroxyl substituted C 1 -C 6 alkyl, or imidazole substituted C 1- C 6 alkyl,

각각의 n은 서로 독립적으로 0 내지 3이다.Each n is 0 to 3 independently of each other.

화학식 I의 화합물의 바람직한 실시태양에서, R1은이다.In a preferred embodiment of the compound of formula (I), R 1 is to be.

화학식 I의 화합물의 또다른 실시태양에서, R1은 페닐-SO2이다.In another embodiment of compounds of Formula (I), R 1 is phenyl-SO 2 .

화학식 I의 화합물의 또다른 실시태양에서, R1은이다.In another embodiment of the compound of formula (I), R 1 is to be.

화학식 I의 화합물의 또다른 실시태양에서, R1은 페닐-CH2CH2-CO-이다.In another embodiment of compounds of Formula (I), R 1 is phenyl-CH 2 CH 2 -CO-.

화학식 I의 화합물의 또다른 실시태양에서, R1은이다.In another embodiment of the compound of formula (I), R 1 is to be.

화학식 I의 화합물의 또다른 실시태양에서, R1은이다.In another embodiment of the compound of formula (I), R 1 is to be.

화학식 I의 화합물의 또다른 실시태양에서, R1은 페닐-CH2-CO-이다.In another embodiment of compounds of Formula (I), R 1 is phenyl-CH 2 -CO-.

화학식 I의 화합물의 또다른 실시태양에서, R1은이다.In another embodiment of the compound of formula (I), R 1 is to be.

화학식 I의 화합물의 또다른 실시태양에서, Ra는 수소이다.In another embodiment of compounds of Formula (I), R a is hydrogen.

화학식 I의 화합물의 또다른 실시태양에서, R2는 -(CH2)n-페닐이다.In another embodiment of compounds of Formula (I), R 2 is — (CH 2 ) n -phenyl.

화학식 I의 화합물의 또다른 실시태양에서, R2는 -(CH2)n-나프틸이다.In another embodiment of compounds of Formula (I), R 2 is — (CH 2 ) n -naphthyl.

화학식 I의 화합물의 또다른 실시태양에서, R2는 -(CH2)n-O-페닐이다.In another embodiment of compounds of Formula (I), R 2 is — (CH 2 ) n —O-phenyl.

화학식 I의 화합물의 또다른 실시태양에서, R2는 -(CH2)n-O-나프틸이다.In another embodiment of compounds of Formula (I), R 2 is — (CH 2 ) n —O-naphthyl.

화학식 I의 화합물의 또다른 실시태양에서, R2는 -(CH2)n-S-페닐이다.In another embodiment of compounds of Formula (I), R 2 is — (CH 2 ) n —S-phenyl.

화학식 I의 화합물의 또다른 실시태양에서, R2는 -(CH2)n-CH(페닐)2이다.In another embodiment of compounds of Formula (I), R 2 is — (CH 2 ) n —CH (phenyl) 2 .

화학식 I의 화합물의 또다른 실시태양에서는, Ra가 수소이고, R1이 벤질옥시카르보닐이고, R2가 아릴-X(CRR)n-, 아릴-(CRR)n-, 헤테로아릴-(CRR)n-, 또는 시클로알킬-(CRR)n-이고, n이 1, 2 또는 3이고, X가 산소 또는 황이고, R이 수소, 메틸 또는 벤질이다.In another embodiment of compounds of Formula (I), R a is hydrogen, R 1 is benzyloxycarbonyl, R 2 is aryl-X (CRR) n −, aryl- (CRR) n −, heteroaryl- ( CRR) n -or cycloalkyl- (CRR) n- , n is 1, 2 or 3, X is oxygen or sulfur and R is hydrogen, methyl or benzyl.

화학식 I의 화합물의 또다른 실시태양에서는, Ra가 수소이고, R1이 벤질옥시카르보닐이고, R2가 -(CH2)n-나프틸, -(CH2)n-페닐, -(CH2)n-시클로알킬, -(CH2)nO(CH2)n-나프틸, -(CH2)nO(CH2)n-페닐, 또는 -(CH2)nS(CH2)n-페닐이다.In another embodiment of a compound of Formula (I), R a is hydrogen, R 1 is benzyloxycarbonyl, R 2 is — (CH 2 ) n -naphthyl, — (CH 2 ) n -phenyl,-( CH 2 ) n -cycloalkyl,-(CH 2 ) n O (CH 2 ) n -naphthyl,-(CH 2 ) n O (CH 2 ) n -phenyl, or-(CH 2 ) n S (CH 2) n -phenyl.

화학식 I의 화합물의 또다른 실시태양에서는, Ra가 수소이고, R1이 벤질옥시카르보닐이고, R2가 -CH2-나프틸이다.In another embodiment of compounds of Formula (I), R a is hydrogen, R 1 is benzyloxycarbonyl and R 2 is —CH 2 -naphthyl.

화학식 I의 화합물의 또다른 실시태양에서는, Ra가 수소이고, R2이 벤질옥시카르보닐,,,,또는이다.In another embodiment of compounds of Formula (I), R a is hydrogen, R 2 is benzyloxycarbonyl, , , , or to be.

또한, 인터루킨-1β 전환 효소의 억제를 필요로하는 환자에게 화학식 I의 화합물의 치료학적 유효량을 투여하는 것을 포함하는, 인터루킨-1β 전환 효소의 억제 방법이 제공된다.Also provided are methods of inhibiting interleukin-1β converting enzyme, comprising administering a therapeutically effective amount of a compound of Formula I to a patient in need thereof.

또한, 카스파제-4의 억제를 필요로하는 환자에게 화학식 I의 화합물의 카스파제-4 억제량을 투여하는 것을 포함하는, 카스파제-4의 억제 방법이 제공된다.Also provided is a method of inhibiting caspase-4, comprising administering a caspase-4 inhibitory amount of a compound of Formula I to a patient in need thereof.

또한, 발작이 일어난 환자 또는 발작이 일어난 적이 있는 환자에게 화학식 I의 화합물의 치료학적 유효량을 투여하는 것을 포함하는, 발작의 치료 방법이 제공된다.Also provided are methods of treating seizures, comprising administering a therapeutically effective amount of a compound of Formula (I) to a patient who has had or has had a seizure.

또한, 염증성 질환에 걸린 환자에게 화학식 I의 화합물의 치료학적 유효량을 투여하는 것을 포함하는, 염증성 질환의 치료 방법이 제공된다.Also provided is a method of treating an inflammatory disease comprising administering to a patient with an inflammatory disease a therapeutically effective amount of a compound of formula (I).

염증성 질환의 치료 방법의 바람직한 실시태양에서는, 상기 염증성 질환이 관절염이다.In a preferred embodiment of the method of treating an inflammatory disease, the inflammatory disease is arthritis.

염증성 질환의 치료 방법의 또다른 바람직한 실시태양에서는, 상기 염증성 질환이 염증성 장 질환이다.In another preferred embodiment of the method of treating an inflammatory disease, the inflammatory disease is an inflammatory bowel disease.

또한, 재관류 손상을 당한 환자에게 화학식 I의 화합물의 치료학적 유효량을 투여하는 것을 포함하는, 재관류 손상의 치료 방법이 제공된다.Also provided are methods of treating reperfusion injury comprising administering to a patient suffering from reperfusion injury a therapeutically effective amount of a compound of formula (I).

또한, 알쯔하이머병에 걸린 환자에게 화학식 I의 화합물의 치료학적 유효량을 투여하는 것을 포함하는, 알쯔하이머병의 치료 방법이 제공된다.Also provided is a method of treating Alzheimer's disease, comprising administering to a patient with Alzheimer's disease a therapeutically effective amount of a compound of formula (I).

또한, 시겔라증에 걸린 환자에게 화학식 I의 화합물의 치료학적 유효량을 투여하는 것을 포함하는, 시겔라증의 치료 방법이 제공된다.Also provided is a method of treating shigellosis comprising administering a therapeutically effective amount of a compound of Formula (I) to a patient with Shigellosis.

또한 제1항의 화합물을 함유하는 제약적으로 허용가능한 조성물이 제공된다.Also provided is a pharmaceutically acceptable composition containing the compound of claim 1.

또한 다음 화합물,Also the following compounds,

3-벤질옥시카르보닐아미노-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3-benzyloxycarbonylamino-5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-벤질옥시카르보닐아미노-4-옥소-5-(3-페닐프로피오닐옥시)-펜탄산,3-benzyloxycarbonylamino-4-oxo-5- (3-phenylpropionyloxy) -pentanoic acid,

3-벤질옥시카르보닐아미노-5-(3-시클로헥실-프로피오닐옥시)-4-옥소-펜탄산,3-benzyloxycarbonylamino-5- (3-cyclohexyl-propionyloxy) -4-oxo-pentanoic acid,

3-벤질옥시카르보닐아미노-5-[(나프탈렌-1-일-옥시)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(naphthalen-1-yl-oxy) -acetoxy] -4-oxo-pentanoic acid,

3-벤질옥시카르보닐아미노-4-옥소-5-페녹시아세톡시-펜탄산,3-benzyloxycarbonylamino-4-oxo-5-phenoxyacetoxy-pentanoic acid,

3-벤질옥시카르보닐아미노-4-옥소-5-페닐술파닐아세톡시-펜탄산,3-benzyloxycarbonylamino-4-oxo-5-phenylsulfanylacetoxy-pentanoic acid,

3-벤질옥시카르보닐아미노-5-[(6-메톡시-나프탈렌-1-일)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(6-methoxy-naphthalen-1-yl) -acetoxy] -4-oxo-pentanoic acid,

3-벤질옥시카르보닐아미노-5-(나프탈렌-2-일-아세톡시)-4-옥소-펜탄산,3-benzyloxycarbonylamino-5- (naphthalen-2-yl-acetoxy) -4-oxo-pentanoic acid,

3-벤질옥시카르보닐아미노-5-(3-나프탈렌-2-일-프로피오닐옥시)-4-옥소-펜탄산,3-benzyloxycarbonylamino-5- (3-naphthalen-2-yl-propionyloxy) -4-oxo-pentanoic acid,

3-벤질옥시카르보닐아미노-5-(3,3-디페닐-프로피오닐옥시)-4-옥소-펜탄산,3-benzyloxycarbonylamino-5- (3,3-diphenyl-propionyloxy) -4-oxo-pentanoic acid,

3-벤질옥시카르보닐아미노-5-[(1H-인돌-3-일)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(1H-indol-3-yl) -acetoxy] -4-oxo-pentanoic acid,

3-벤질옥시카르보닐아미노-5-(인돌-1-일-아세톡시)-4-옥소-펜탄산,3-benzyloxycarbonylamino-5- (indol-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-벤질옥시카르보닐아미노-5-(2-나프탈렌-1-일-프로피오닐옥시)-4-옥소-펜탄산,3-benzyloxycarbonylamino-5- (2-naphthalen-1-yl-propionyloxy) -4-oxo-pentanoic acid,

3-벤질옥시카르보닐아미노-4-옥소-5-[(2-옥소-피롤리딘-1-일)-아세톡시]-펜탄산,3-benzyloxycarbonylamino-4-oxo-5-[(2-oxo-pyrrolidin-1-yl) -acetoxy] -pentanoic acid,

5-[(아세틸-페닐-아미노)-아세톡시]-3-벤질옥시카르보닐-아미노-4-옥소-펜탄산,5-[(acetyl-phenyl-amino) -acetoxy] -3-benzyloxycarbonyl-amino-4-oxo-pentanoic acid,

3-벤질옥시카르보닐아미노-5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-펜탄산,3-benzyloxycarbonylamino-5- (2-benzyl-3-phenyl-propionyloxy) -4-oxo-pentanoic acid,

3-벤질옥시카르보닐아미노-5-(히드록시-나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3-benzyloxycarbonylamino-5- (hydroxy-naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-벤질옥시카르보닐아미노-4-옥소-5-[(페닐-아미노)-아세톡시]-펜탄산,3-benzyloxycarbonylamino-4-oxo-5-[(phenyl-amino) -acetoxy] -pentanoic acid,

3-벤질옥시카르보닐아미노-5-[(6-히드록시-나프탈렌-1-일)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(6-hydroxy-naphthalen-1-yl) -acetoxy] -4-oxo-pentanoic acid,

3-벤질옥시카르보닐아미노-5-[3-(4-히드록시-페닐)-2-나프탈렌-1-일-프로피오닐옥시)-4-옥소-펜탄산,3-benzyloxycarbonylamino-5- [3- (4-hydroxy-phenyl) -2-naphthalen-1-yl-propionyloxy) -4-oxo-pentanoic acid,

(S)-3-벤질옥시카르보닐아미노-4-옥소-5-페닐아세톡시-펜탄산,(S) -3-benzyloxycarbonylamino-4-oxo-5-phenylacetoxy-pentanoic acid,

(S)-3-벤질옥시카르보닐아미노-4-옥소-5-(4-페닐-부티릴옥시)-펜탄산,(S) -3-benzyloxycarbonylamino-4-oxo-5- (4-phenyl-butyryloxy) -pentanoic acid,

3-벤질옥시카르보닐아미노-4-옥소-5-[(4-페닐-나프탈렌-1-일)-아세톡시]-펜탄산,3-benzyloxycarbonylamino-4-oxo-5-[(4-phenyl-naphthalen-1-yl) -acetoxy] -pentanoic acid,

3-벤질옥시카르보닐아미노-5-[(4-메틸-나프탈렌-1-일)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(4-methyl-naphthalen-1-yl) -acetoxy] -4-oxo-pentanoic acid,

3-벤질옥시카르보닐아미노-4-옥소-5-[(4-티오펜-2-일-나프탈렌-1-일)-아세톡시]-펜탄산,3-benzyloxycarbonylamino-4-oxo-5-[(4-thiophen-2-yl-naphthalen-1-yl) -acetoxy] -pentanoic acid,

3-벤질옥시카르보닐아미노-5-[(4-플루오로-나프탈렌-1-일)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(4-fluoro-naphthalen-1-yl) -acetoxy] -4-oxo-pentanoic acid,

3-벤질옥시카르보닐아미노-5-[(2-메틸-나프탈렌-1-일)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(2-methyl-naphthalen-1-yl) -acetoxy] -4-oxo-pentanoic acid,

3-벤질옥시카르보닐아미노-5-[(2-플루오로-나프탈렌-1-일)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(2-fluoro-naphthalen-1-yl) -acetoxy] -4-oxo-pentanoic acid,

5-(벤조푸란-4-일-아세톡시)-3-벤질옥시카르보닐아미노-4-옥소-펜탄산,5- (benzofuran-4-yl-acetoxy) -3-benzyloxycarbonylamino-4-oxo-pentanoic acid,

5-(벤조[b]티오펜-7-일-아세톡시)-3-벤질옥시카르보닐아미노-4-옥소-펜탄산,5- (benzo [b] thiophen-7-yl-acetoxy) -3-benzyloxycarbonylamino-4-oxo-pentanoic acid,

5-(벤조[b]티오펜-4-일-아세톡시)-3-벤질옥시카르보닐아미노-4-옥소-펜탄산,5- (benzo [b] thiophen-4-yl-acetoxy) -3-benzyloxycarbonylamino-4-oxo-pentanoic acid,

5-[(4-벤질-나프탈렌-1-일)-아세톡시]-3-벤질옥시카르보닐아미노-4-옥소-펜탄산,5-[(4-benzyl-naphthalen-1-yl) -acetoxy] -3-benzyloxycarbonylamino-4-oxo-pentanoic acid,

3-벤질옥시카르보닐아미노-5-[(3,4-디히드로-나프탈렌-1-일)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(3,4-dihydro-naphthalen-1-yl) -acetoxy] -4-oxo-pentanoic acid,

3-벤질옥시카르보닐아미노-5-[(5-브로모-1H-인돌-3-일)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(5-bromo-1H-indol-3-yl) -acetoxy] -4-oxo-pentanoic acid,

3-벤질옥시카르보닐아미노-5-(3,4-디페닐-부티릴옥시)-4-옥소-펜탄산,3-benzyloxycarbonylamino-5- (3,4-diphenyl-butyryloxy) -4-oxo-pentanoic acid,

3-벤질옥시카르보닐아미노-4-옥소-5-(3-페닐-3-페닐아미노-프로피오닐옥시)-펜탄산,3-benzyloxycarbonylamino-4-oxo-5- (3-phenyl-3-phenylamino-propionyloxy) -pentanoic acid,

3-벤질옥시카르보닐아미노-4-옥소-5-[(1,2,3,4-테트라히드로나프탈렌-2-일)-아세톡시]-펜탄산,3-benzyloxycarbonylamino-4-oxo-5-[(1,2,3,4-tetrahydronaphthalen-2-yl) -acetoxy] -pentanoic acid,

3-벤질옥시카르보닐아미노-5-[(1-메탄술포닐-피페리딘-4-일)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(1-methanesulfonyl-piperidin-4-yl) -acetoxy] -4-oxo-pentanoic acid,

3-벤질옥시카르보닐아미노-4-옥소-5-[(2,3,5,6-테트라메틸-페닐)-아세톡시]-펜탄산3-Benzyloxycarbonylamino-4-oxo-5-[(2,3,5,6-tetramethyl-phenyl) -acetoxy] -pentanoic acid

5-(벤조티아졸-4-일-아세톡시)-3-벤질옥시카르보닐아미노-4-옥소-펜탄산,5- (benzothiazol-4-yl-acetoxy) -3-benzyloxycarbonylamino-4-oxo-pentanoic acid,

5-(벤조푸란-3-일-아세톡시)-3-벤질옥시카르보닐아미노-4-옥소-펜탄산,5- (benzofuran-3-yl-acetoxy) -3-benzyloxycarbonylamino-4-oxo-pentanoic acid,

5-(벤조[b]티오펜-3-일-아세톡시)-3-벤질옥시카르보닐아미노-4-옥소-펜탄산,5- (benzo [b] thiophen-3-yl-acetoxy) -3-benzyloxycarbonylamino-4-oxo-pentanoic acid,

3-벤질옥시카르보닐아미노-4-옥소-5-(3-페닐-3-피리딘-2-일-프로피오닐옥시)-펜탄산,3-benzyloxycarbonylamino-4-oxo-5- (3-phenyl-3-pyridin-2-yl-propionyloxy) -pentanoic acid,

3-벤질옥시카르보닐아미노-5-[(2,3-디클로로-페닐)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(2,3-dichloro-phenyl) -acetoxy] -4-oxo-pentanoic acid,

3-벤질옥시카르보닐아미노-5-[(5-메틸-나프탈렌-1-일)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(5-methyl-naphthalen-1-yl) -acetoxy] -4-oxo-pentanoic acid,

3-벤질옥시카르보닐아미노-5-[(2-요오도-페닐)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(2-iodo-phenyl) -acetoxy] -4-oxo-pentanoic acid,

3-벤질옥시카르보닐아미노-4-옥소-5-(3-피리딘-3-일-프로피오닐옥시)-펜탄산,3-benzyloxycarbonylamino-4-oxo-5- (3-pyridin-3-yl-propionyloxy) -pentanoic acid,

3-벤질옥시카르보닐아미노-5-[(5-메톡시-나프탈렌-1-일)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(5-methoxy-naphthalen-1-yl) -acetoxy] -4-oxo-pentanoic acid,

3-벤질옥시카르보닐아미노-5-[(8-메틸-나프탈렌-1-일)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(8-methyl-naphthalen-1-yl) -acetoxy] -4-oxo-pentanoic acid,

3-벤질옥시카르보닐아미노-5-[(9H-플루오렌-9-일)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(9H-fluoren-9-yl) -acetoxy] -4-oxo-pentanoic acid,

3-벤질옥시카르보닐아미노-5-[(10,11-디히드로-5H-디벤조[a,d]시클로헵텐-5-일)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) -acetoxy] -4-oxo-pentanoic acid,

5-옥소-1-(톨루엔-4-술포닐)-피롤리딘-2-카르복실산 3-벤질옥시카르보닐아미노-4-카르복시-2-옥소-부틸 에스테르,5-oxo-1- (toluene-4-sulfonyl) -pyrrolidine-2-carboxylic acid 3-benzyloxycarbonylamino-4-carboxy-2-oxo-butyl ester,

5-옥소-피롤리딘-1,2-디카르복실산 1-벤질 에스테르 2-(3-벤질옥시카르보닐아미노-4-카르복시-2-옥소-부틸)에스테르,5-oxo-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2- (3-benzyloxycarbonylamino-4-carboxy-2-oxo-butyl) ester,

1-벤조일-피롤리딘-2-카르복실산 3-벤질옥시카르보닐아미노-4-카르복시-2-옥소-부틸 에스테르,1-benzoyl-pyrrolidine-2-carboxylic acid 3-benzyloxycarbonylamino-4-carboxy-2-oxo-butyl ester,

피롤리딘-1,2-디카르복실산 1-벤질 에스테르 2-(3-벤질옥시카르보닐아미노-4-카르복시-2-옥소-부틸)에스테르,Pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2- (3-benzyloxycarbonylamino-4-carboxy-2-oxo-butyl) ester,

3-벤질옥시카르보닐아미노-5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-펜탄산,3-benzyloxycarbonylamino-5- (2-benzyl-3-phenyl-propionyloxy) -4-oxo-pentanoic acid,

3-벤질옥시카르보닐아미노-5-[(5-시아노-나프탈렌-1-일)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(5-cyano-naphthalen-1-yl) -acetoxy] -4-oxo-pentanoic acid,

3-벤질옥시카르보닐아미노-4-옥소-5-(3-페닐-3-피리딘-3-일-프로피오닐옥시)-펜탄산,3-benzyloxycarbonylamino-4-oxo-5- (3-phenyl-3-pyridin-3-yl-propionyloxy) -pentanoic acid,

3-벤질옥시카르보닐아미노-4-옥소-5-(3-페닐-3-피리딘-4-일-프로피오닐옥시)-펜탄산 및3-benzyloxycarbonylamino-4-oxo-5- (3-phenyl-3-pyridin-4-yl-propionyloxy) -pentanoic acid and

3-벤질옥시카르보닐아미노-4-옥소-5-[(1-옥소-3,4-디히드로-1H-이소퀴놀린-2-일)-아세톡시]-펜탄산이 제공된다.3-Benzyloxycarbonylamino-4-oxo-5-[(1-oxo-3,4-dihydro-1 H-isoquinolin-2-yl) -acetoxy] -pentanoic acid is provided.

또한 다음의 화합물,In addition, the following compound,

3-벤젠술포닐아미노-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3-benzenesulfonylamino-5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-메톡시카르보닐아미노-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3-methoxycarbonylamino-5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

5-(나프탈렌-1-일-아세톡시)-4-옥소-3-(3-페닐-프로피오닐아미노)-펜탄산,5- (naphthalen-1-yl-acetoxy) -4-oxo-3- (3-phenyl-propionylamino) -pentanoic acid,

3-메톡시카르보닐아미노-4-옥소-5-페녹시아세톡시-펜탄산 및3-methoxycarbonylamino-4-oxo-5-phenoxycetoxy-pentanoic acid and

3-(2-메탄술포닐-1-메틸-에틸술파닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산이 제공된다.3- (2-Methanesulfonyl-1-methyl-ethylsulfanylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid is provided.

또한 다음의 화합물,In addition, the following compound,

[S-(R*,R*)]-3-(2-아세틸아미노-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,[S- (R * , R * )]-3- (2-acetylamino-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

5-(나프탈렌-1-일-아세톡시)-4-옥소-3-[(티오펜-3-카르보닐)-아미노]-펜탄산,5- (naphthalen-1-yl-acetoxy) -4-oxo-3-[(thiophen-3-carbonyl) -amino] -pentanoic acid,

3-[(푸란-3-카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3-[(furan-3-carbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

5-(나프탈렌-1-일-아세톡시)-4-옥소-3-[2-(4-페닐-부티릴아미노)-프로필아미노]-펜탄산,5- (naphthalen-1-yl-acetoxy) -4-oxo-3- [2- (4-phenyl-butyrylamino) -propylamino] -pentanoic acid,

3-(2-메탄술포닐아미노-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (2-methanesulfonylamino-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-[2-(2-아세틸아미노-4-페닐-부티릴아미노)-프로피오닐아미노]-5-(나프탈렌1-일-아세톡시)-4-옥소-펜탄산,3- [2- (2-acetylamino-4-phenyl-butyrylamino) -propionylamino] -5- (naphthalen1-yl-acetoxy) -4-oxo-pentanoic acid,

3-(2-아세틸아미노-부티릴아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (2-acetylamino-butyrylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-[2-(4-카르바모일-부티릴아미노)-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- [2- (4-carbamoyl-butyrylamino) -propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-(2-벤질옥시카르보닐아미노-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (2-benzyloxycarbonylamino-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

5-(나프탈렌-1-일-아세톡시)-4-옥소-3-(2-우레이도-프로피오닐아미노)-펜탄산,5- (naphthalen-1-yl-acetoxy) -4-oxo-3- (2-ureido-propionylamino) -pentanoic acid,

3-(2-아세틸아미노-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (2-acetylamino-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-[(1-아세틸-피롤리딘-2-카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3-[(1-acetyl-pyrrolidine-2-carbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-(2-메틸-3-옥소-3-티오펜-2-일-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (2-Methyl-3-oxo-3-thiophen-2-yl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-(2-아세틸아미노-아세틸아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (2-acetylamino-acetylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-(2-아세틸아미노-프로피오닐아미노)-5-(3,3-디페닐-프로피오닐옥시)-4-옥소-펜탄산,3- (2-acetylamino-propionylamino) -5- (3,3-diphenyl-propionyloxy) -4-oxo-pentanoic acid,

3-[2-(2-아세틸아미노-4-카르복시-부티릴아미노)-프로피오닐아미노]-5-나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- [2- (2-acetylamino-4-carboxy-butyrylamino) -propionylamino] -5-naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

5-(나프탈렌-1-일-아세톡시)-4-옥소-3-[2-(3-페닐-프로피오닐아미노)-프로피오닐아미노]-펜탄산,5- (naphthalen-1-yl-acetoxy) -4-oxo-3- [2- (3-phenyl-propionylamino) -propionylamino] -pentanoic acid,

3-[2-(3-메틸-부티릴아미노)-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- [2- (3-Methyl-butyrylamino) -propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-[(1-아세틸-4-벤질옥시-피롤리딘-2-카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3-[(1-acetyl-4-benzyloxy-pyrrolidine-2-carbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-(4-카르바모일-부티릴아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 및3- (4-Carbamoyl-butyrylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid and

3-[2-(1-메틸-1H-이미다졸-4-일)-아세틸아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산이 제공된다.3- [2- (1-Methyl-1H-imidazol-4-yl) -acetylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid is provided.

또한 다음의 화합물,In addition, the following compound,

(S)-5-(나프탈렌-1-일-아세톡시)-4-옥소-3-페닐아세틸아미노-펜탄산,(S) -5- (naphthalen-1-yl-acetoxy) -4-oxo-3-phenylacetylamino-pentanoic acid,

(S)-5-(나프탈렌-1-일-아세톡시)-4-옥소-3-(2-티오펜-2-일-아세틸아미노)-펜탄산,(S) -5- (naphthalen-1-yl-acetoxy) -4-oxo-3- (2-thiophen-2-yl-acetylamino) -pentanoic acid,

3-[(2-카르바모일-시클로펜탄카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3-[(2-Carbamoyl-cyclopentanecarbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-[(3-(카르바모일-비시클로[2.2.1]헵탄-2-카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3-[(3- (carbamoyl-bicyclo [2.2.1] heptan-2-carbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-(3-메탄술포닐-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (3-methanesulfonyl-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-(3-벤젠술포닐-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (3-benzenesulfonyl-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-부티릴아미노-5-(나프탈렌-2-일-아세톡시)-4-옥소-펜탄산,3-butyrylamino-5- (naphthalen-2-yl-acetoxy) -4-oxo-pentanoic acid,

3-아세틸아미노-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3-acetylamino-5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-(3-메탄술포닐-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (3-methanesulfonyl-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-(3-메틸-부티릴아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (3-Methyl-butyrylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-(3-카르바모일-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (3-Carbamoyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

[S-(R*,R*)]-3-(3-아세틸술파닐-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 및[S- (R * , R * )]-3- (3-acetylsulfanyl-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid and

트랜스-3-[(3-카르바모일-시클로펜탄카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산이 제공된다.Trans-3-[(3-carbamoyl-cyclopentanecarbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid is provided.

또한 다음의 화합물,In addition, the following compound,

3-(1,2,3,4-테트라히드로-1-옥소-이소퀴놀린-2-일)-아세트아미노-5-(나프탈렌-1-일 아세톡시)-4-옥소-펜탄산,3- (1,2,3,4-tetrahydro-1-oxo-isoquinolin-2-yl) -acetamino-5- (naphthalen-1-yl acetoxy) -4-oxo-pentanoic acid,

3-(2-메틸-3-펜에틸카르바모일-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (2-Methyl-3-phenethylcarbamoyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

5-(나프탈렌-2-일-아세톡시)-4-옥소-3-[2-(2-옥소-6-페닐-피페리딘-1-일)-아세틸아미노]-펜탄산,5- (naphthalen-2-yl-acetoxy) -4-oxo-3- [2- (2-oxo-6-phenyl-piperidin-1-yl) -acetylamino] -pentanoic acid,

5-(나프탈렌-1-일-아세톡시)-4-옥소-3-[2-(2-옥소-6-페닐-피페리딘-1-일)-아세틸아미노]-펜탄산,5- (naphthalen-1-yl-acetoxy) -4-oxo-3- [2- (2-oxo-6-phenyl-piperidin-1-yl) -acetylamino] -pentanoic acid,

3-[3-메틸-2-(3-페닐-프로피오닐아미노)-부티릴아미노]-4-옥소-5-[(1-옥소-1,2,3,4-테트라히드로-나프탈렌-2-일)-아세톡시]-펜탄산,3- [3-methyl-2- (3-phenyl-propionylamino) -butyrylamino] -4-oxo-5-[(1-oxo-1,2,3,4-tetrahydro-naphthalene-2 -Yl) -acetoxy] -pentanoic acid,

5-(나프탈렌-2-일-아세톡시)-4-옥소-3-[2-(1-옥소-3,4-디히드로-1H-이소퀴놀린-2-일)-아세틸아미노]-펜탄산,5- (Naphthalen-2-yl-acetoxy) -4-oxo-3- [2- (1-oxo-3,4-dihydro-1 H-isoquinolin-2-yl) -acetylamino] -pentanoic acid ,

5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-3-[2-(1-옥소-3,4-디히드로-1H-이소퀴놀린-2-일)-아세틸아미노]-펜탄산,5- (2-benzyl-3-phenyl-propionyloxy) -4-oxo-3- [2- (1-oxo-3,4-dihydro-1 H-isoquinolin-2-yl) -acetylamino] Pentanoic acid,

5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-3-[2-(2-옥소-6-페닐-피페리딘-1-일)-아세틸아미노]-펜탄산5- (2-Benzyl-3-phenyl-propionyloxy) -4-oxo-3- [2- (2-oxo-6-phenyl-piperidin-1-yl) -acetylamino] -pentanoic acid

5-(나프탈렌-1-일-아세톡시)-4-옥소-3-[2-(1-옥소-1,2,3,4-테트라히드로-나프탈렌-2-일)-아세틸아미노]-펜탄산,5- (naphthalen-1-yl-acetoxy) -4-oxo-3- [2- (1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl) -acetylamino] -phen Carbonated,

5-(나프탈렌-1-일-아세톡시)-4-옥소-3-[2-(1-옥소-3,4-디히드로-1H-이소퀴놀린-2-일)-프로피오닐아미노]-펜탄산,5- (naphthalen-1-yl-acetoxy) -4-oxo-3- [2- (1-oxo-3,4-dihydro-1 H-isoquinolin-2-yl) -propionylamino] -phen Carbonated,

5-(나프탈렌-2-일-아세톡시)-4-옥소-3-[2-(1-옥소-3,4-디히드로-1H-이소퀴놀린-2-일)-프로피오닐아미노]-펜탄산,5- (naphthalen-2-yl-acetoxy) -4-oxo-3- [2- (1-oxo-3,4-dihydro-1 H-isoquinolin-2-yl) -propionylamino] -phen Carbonated,

3-[4-(1-벤젠술포닐-1H-피롤-2-일)-4-옥소-부티릴아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- [4- (1-benzenesulfonyl-1H-pyrrole-2-yl) -4-oxo-butyrylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-3-[2-(1-옥소-1,2,3,4-테트라히드로-나프탈렌-2-일)-아세틸아미노]-펜탄산,5- (2-Benzyl-3-phenyl-propionyloxy) -4-oxo-3- [2- (1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl) -acetylamino ] -Pentanoic acid,

5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-3-[2-(1-옥소-3,4-디히드로-1H-이소퀴놀린-2-일)-프로피오닐아미노]-펜탄산,5- (2-Benzyl-3-phenyl-propionyloxy) -4-oxo-3- [2- (1-oxo-3,4-dihydro-1 H-isoquinolin-2-yl) -propionylamino ] -Pentanoic acid,

4-옥소-3-[2-(1-옥소-3,4-디히드로-1H-이소퀴놀린-2-일)-프로피오닐아미노]-5-[(1-옥소-1,2,3,4-테트라히드로-나프탈렌-2-일)-아세톡시]-펜탄산,4-oxo-3- [2- (1-oxo-3,4-dihydro-1 H-isoquinolin-2-yl) -propionylamino] -5-[(1-oxo-1,2,3, 4-tetrahydro-naphthalen-2-yl) -acetoxy] -pentanoic acid,

3-[4-(1-벤젠술포닐-1H-피롤-2-일)-4-옥소-부티릴아미노]-5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-펜탄산,3- [4- (1-benzenesulfonyl-1H-pyrrole-2-yl) -4-oxo-butyrylamino] -5- (2-benzyl-3-phenyl-propionyloxy) -4-oxo- Pentanic Acid,

4-옥소-5-[(1-옥소-1,2,3,4-테트라히드로-나프탈렌-2-일)-아세톡시]-3-[2-(1-옥소-1,2,3,4-테트라히드로-나프탈렌-2-일)-아세틸아미노]-펜탄산,4-oxo-5-[(1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl) -acetoxy] -3- [2- (1-oxo-1,2,3, 4-tetrahydro-naphthalen-2-yl) -acetylamino] -pentanoic acid,

5-(나프탈렌-1-일-아세톡시)-4-옥소-3-[2-(2-옥소-3-페닐-이미다졸리딘-1-일)-프로피오닐아미노]-펜탄산,5- (naphthalen-1-yl-acetoxy) -4-oxo-3- [2- (2-oxo-3-phenyl-imidazolidin-1-yl) -propionylamino] -pentanoic acid,

5-(나프탈렌-1-일-아세톡시)-4-옥소-3-[2-(2-옥소-3-페닐-테트라히드로-피리미딘-1-일)-프로피오닐아미노]-펜탄산,5- (naphthalen-1-yl-acetoxy) -4-oxo-3- [2- (2-oxo-3-phenyl-tetrahydro-pyrimidin-1-yl) -propionylamino] -pentanoic acid,

5-(나프탈렌-1-일-아세톡시)-4-옥소-3-[2-(2-옥소-3-페닐-테트라히드로-피리미딘-1-일)-아세틸아미노]-펜탄산,5- (naphthalen-1-yl-acetoxy) -4-oxo-3- [2- (2-oxo-3-phenyl-tetrahydro-pyrimidin-1-yl) -acetylamino] -pentanoic acid,

3-(2-아세틸아미노-3-메틸-부티릴아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (2-acetylamino-3-methyl-butyrylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-(2-아세틸아미노-3-메틸-부티릴아미노)-5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-펜탄산,3- (2-Acetylamino-3-methyl-butyrylamino) -5- (2-benzyl-3-phenyl-propionyloxy) -4-oxo-pentanoic acid,

3-(2-아세틸아미노-3-메틸-부티릴아미노)-5-(3-벤질-4-페닐-부티릴옥시)-4-옥소-펜탄산,3- (2-acetylamino-3-methyl-butyrylamino) -5- (3-benzyl-4-phenyl-butyryloxy) -4-oxo-pentanoic acid,

3-(2-아세틸아미노-3-메틸-부티릴아미노)-5-(4-벤질-5-페닐-펜타노일옥시)-4-옥소-펜탄산,3- (2-acetylamino-3-methyl-butyrylamino) -5- (4-benzyl-5-phenyl-pentanoyloxy) -4-oxo-pentanoic acid,

3-(2-아세틸아미노-3-메틸-부티릴아미노)-4-옥소-5-[(1-옥소-1,2,3,4-테트라히드로-나프탈렌-2-일)-아세톡시]-펜탄산,3- (2-acetylamino-3-methyl-butyrylamino) -4-oxo-5-[(1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl) -acetoxy] Pentanoic acid,

5-(3-벤질-4-페닐-부티릴옥시)-3-[3-메틸-2-(3-페닐-프로피오닐아미노)-부티릴아미노]-4-옥소-펜탄산,5- (3-benzyl-4-phenyl-butyryloxy) -3- [3-methyl-2- (3-phenyl-propionylamino) -butyrylamino] -4-oxo-pentanoic acid,

3-[2-(3-아세틸아미노-2-옥소-2H-피리딘-1-일)-아세틸아미노]-5-(3,3-디페닐-프로피오닐옥시)-4-옥소-펜탄산 및3- [2- (3-Acetylamino-2-oxo-2H-pyridin-1-yl) -acetylamino] -5- (3,3-diphenyl-propionyloxy) -4-oxo-pentanoic acid and

3-[2-(3-아세틸아미노-2-옥소-2H-피리딘-1-일)-아세틸아미노]-5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-펜탄산이 제공된다.3- [2- (3-acetylamino-2-oxo-2H-pyridin-1-yl) -acetylamino] -5- (2-benzyl-3-phenyl-propionyloxy) -4-oxo-pentanoic acid This is provided.

또한 다음의 화합물,In addition, the following compound,

3-[2-(2-벤질옥시카르보닐아미노-4-카르복시-부티릴아미노)-3-메틸-부티릴아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- [2- (2-benzyloxycarbonylamino-4-carboxy-butyrylamino) -3-methyl-butyrylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-phen Carbonated,

3-[2-(2-벤질옥시카르보닐아미노-3-메틸-부티릴아미노)-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- [2- (2-benzyloxycarbonylamino-3-methyl-butyrylamino) -propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-(2-아세틸아미노-3-메틸-부티릴아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (2-acetylamino-3-methyl-butyrylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-[2-(2-벤질옥시카르보닐아미노-3-메틸-부티릴아미노)-프로피오닐아미노]-5-(3,3-디페닐-프로피오닐옥시)-4-옥소-펜탄산,3- [2- (2-benzyloxycarbonylamino-3-methyl-butyrylamino) -propionylamino] -5- (3,3-diphenyl-propionyloxy) -4-oxo-pentanoic acid,

3-[2-(2-벤질옥시카르보닐아미노-3-메틸-부티릴아미노)-프로피오닐아미노]-5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-펜탄산,3- [2- (2-Benzyloxycarbonylamino-3-methyl-butyrylamino) -propionylamino] -5- (2-benzyl-3-phenyl-propionyloxy) -4-oxo-pentanoic acid ,

3-[2-(2-벤질옥시카르보닐아미노-3-메틸-부티릴아미노)-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- [2- (2-benzyloxycarbonylamino-3-methyl-butyrylamino) -propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

5-(2-벤질-3-페닐-프로피오닐옥시)-3-{2-[4-카르복시-2-(3-페닐-프로피오닐아미노)-부티릴아미노]-3-메틸-부티릴아미노}-4-옥소-펜탄산,5- (2-Benzyl-3-phenyl-propionyloxy) -3- {2- [4-carboxy-2- (3-phenyl-propionylamino) -butyrylamino] -3-methyl-butyrylamino } -4-oxo-pentanoic acid,

3-(2-벤질옥시카르보닐아미노-3-메틸-부티릴아미노)-5-(3,3-디페닐-프로피오닐옥시)-4-옥소-펜탄산,3- (2-benzyloxycarbonylamino-3-methyl-butyrylamino) -5- (3,3-diphenyl-propionyloxy) -4-oxo-pentanoic acid,

3-(2-아세틸아미노-3-히드록시-부티릴아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (2-acetylamino-3-hydroxy-butyrylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-(2-아세틸아미노-3-히드록시-부티릴아미노)-5-(3,3-디페닐-프로피오닐옥시)-4-옥소-펜탄산,3- (2-acetylamino-3-hydroxy-butyrylamino) -5- (3,3-diphenyl-propionyloxy) -4-oxo-pentanoic acid,

3-(2-{2-[2-아세틸아미노-3-(1H-인돌-3-일)-프로피오닐아미노]-4-카르복시-부티릴아미노}-3-메틸-부티릴아미노)-5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-펜탄산 및3- (2- {2- [2-acetylamino-3- (1H-indol-3-yl) -propionylamino] -4-carboxy-butyrylamino} -3-methyl-butyrylamino) -5 -(2-benzyl-3-phenyl-propionyloxy) -4-oxo-pentanoic acid and

5-(3,3-디페닐-프로피오닐옥시)-4-옥소-3-[2-(4-페닐-부티릴아미노)-프로피오닐아미노]-펜탄산이 제공된다.5- (3,3-Diphenyl-propionyloxy) -4-oxo-3- [2- (4-phenyl-butyrylamino) -propionylamino] -pentanoic acid is provided.

또한 다음의 화합물,In addition, the following compound,

3-(2-{2-[2-아세틸아미노-3-(1H-인돌-3-일)-프로피오닐아미노]-4-카르복시-부티릴아미노}-3-메틸-부티릴아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 및3- (2- {2- [2-acetylamino-3- (1H-indol-3-yl) -propionylamino] -4-carboxy-butyrylamino} -3-methyl-butyrylamino) -5 -(Naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid and

3-(2-{2-[2-아세틸아미노-3-(4-히드록시-페닐)-프로피오닐아미노]-4-카르복시-부티릴아미노}-3-메틸-부티릴아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산이 제공된다.3- (2- {2- [2-acetylamino-3- (4-hydroxy-phenyl) -propionylamino] -4-carboxy-butyrylamino} -3-methyl-butyrylamino) -5- (Naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid is provided.

또한 다음의 화합물,In addition, the following compound,

3-[(2-카르복시-시클로헥산카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3-[(2-carboxy-cyclohexanecarbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-[(2-메톡시카르보닐-시클로헥산카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 및3-[(2-methoxycarbonyl-cyclohexanecarbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid and

3-[(2-카르바모일-시클로헥산카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산이 제공된다.3-[(2-Carbamoyl-cyclohexanecarbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid is provided.

또한 다음의 화합물,In addition, the following compound,

3-(3-벤질술파닐-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (3-benzylsulfanyl-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-(2-메틸-3-페닐메탄술포닐-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (2-Methyl-3-phenylmethanesulfonyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-[3-(2-카르복시-에탄술파닐)-2-메틸-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- [3- (2-carboxy-ethanesulfanyl) -2-methyl-propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

5-(2-벤질-3-페닐-프로피오닐옥시)-3-[3-(2-카르복시-에탄술포닐)-2-메틸-프로피오닐아미노]-4-옥소-펜탄산,5- (2-benzyl-3-phenyl-propionyloxy) -3- [3- (2-carboxy-ethanesulfonyl) -2-methyl-propionylamino] -4-oxo-pentanoic acid,

5-(2-벤질-3-페닐-프로피오닐옥시)-3-[3-(3-카르복시-프로판-1-술피닐)-2-메틸-프로피오닐아미노]-4-옥소-펜탄산,5- (2-benzyl-3-phenyl-propionyloxy) -3- [3- (3-carboxy-propane-1-sulfinyl) -2-methyl-propionylamino] -4-oxo-pentanoic acid,

5-(나프탈렌-1-일-아세톡시)-4-옥소-3-(2-페닐메탄술파닐-프로피오닐아미노)-펜탄산,5- (naphthalen-1-yl-acetoxy) -4-oxo-3- (2-phenylmethanesulfanyl-propionylamino) -pentanoic acid,

3-(2-메틸-3-페닐술파닐-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (2-Methyl-3-phenylsulfanyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

5-(2-벤질-3-페닐-프로피오닐옥시)-3-(2-메틸-3-페닐술파닐-프로피오닐아미노)-4-옥소-펜탄산,5- (2-Benzyl-3-phenyl-propionyloxy) -3- (2-methyl-3-phenylsulfanyl-propionylamino) -4-oxo-pentanoic acid,

3-(2-메틸-3-펜에틸술파닐-프로피오닐옥시)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (2-Methyl-3-phenethylsulfanyl-propionyloxy) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

5-(2-벤질-3-페닐-프로피오닐옥시)-3-(2-메틸-3-펜에틸술파닐-프로피오닐아미노)-4-옥소-펜탄산,5- (2-benzyl-3-phenyl-propionyloxy) -3- (2-methyl-3-phenethylsulfanyl-propionylamino) -4-oxo-pentanoic acid,

5-(2-벤질-3-페닐-프로피오닐옥시)-3-(3-벤질술파닐-2-메틸-프로피오닐아미노)-4-옥소-펜탄산,5- (2-benzyl-3-phenyl-propionyloxy) -3- (3-benzylsulfanyl-2-methyl-propionylamino) -4-oxo-pentanoic acid,

5-(2-벤질-3-페닐-프로피오닐옥시)-3-(2-벤질술파닐-프로피오닐아미노)-4-옥소-펜탄산,5- (2-benzyl-3-phenyl-propionyloxy) -3- (2-benzylsulfanyl-propionylamino) -4-oxo-pentanoic acid,

3-[2-메틸-3-(3-페닐-프로필술파닐)-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- [2-Methyl-3- (3-phenyl-propylsulfanyl) -propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-(3-벤젠술포닐-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (3-benzenesulfonyl-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-(3-벤젠술포닐-2-메틸-프로피오닐아미노)-5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-펜탄산,3- (3-benzenesulfonyl-2-methyl-propionylamino) -5- (2-benzyl-3-phenyl-propionyloxy) -4-oxo-pentanoic acid,

5-(2-벤질-3-페닐-프로피오닐옥시)-3-[2-메틸-3-(2-페닐-에탄술포닐)-프로피오닐아미노]-4-옥소-펜탄산,5- (2-Benzyl-3-phenyl-propionyloxy) -3- [2-methyl-3- (2-phenyl-ethanesulfonyl) -propionylamino] -4-oxo-pentanoic acid,

3-[2-메틸-3-(2-페닐-에탄술포닐)-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- [2-Methyl-3- (2-phenyl-ethanesulfonyl) -propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

5-(나프탈렌-1-일-아세톡시)-4-옥소-3-(2-페닐메탄술포닐-프로피오닐아미노)-펜탄산,5- (naphthalen-1-yl-acetoxy) -4-oxo-3- (2-phenylmethanesulfonyl-propionylamino) -pentanoic acid,

5-(2-벤질-3-페닐-프로피오닐옥시)-3-(2-메틸-3-페닐메탄술포닐-프로피오닐아미노)-4-옥소-펜탄산,5- (2-benzyl-3-phenyl-propionyloxy) -3- (2-methyl-3-phenylmethanesulfonyl-propionylamino) -4-oxo-pentanoic acid,

5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-3-(2-페닐메탄술포닐-프로피오닐아미노)-펜탄산,5- (2-benzyl-3-phenyl-propionyloxy) -4-oxo-3- (2-phenylmethanesulfonyl-propionylamino) -pentanoic acid,

3-[2-메틸-3-(3-페닐-프로판-1-술포닐)-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- [2-Methyl-3- (3-phenyl-propane-1-sulfonyl) -propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

5-(2-벤질-3-페닐-프로피오닐옥시)-3-[2-메틸-3-(3-페닐-프로판-1-술포닐)-프로피오닐아미노]-4-옥소-펜탄산,5- (2-Benzyl-3-phenyl-propionyloxy) -3- [2-methyl-3- (3-phenyl-propane-1-sulfonyl) -propionylamino] -4-oxo-pentanoic acid,

5-(2-벤질-3-페닐-프로피오닐옥시)-3-[3-(2-카르복시-에틸술파닐)-2-메틸-프로피오닐아미노]-4-옥소-펜탄산,5- (2-Benzyl-3-phenyl-propionyloxy) -3- [3- (2-carboxy-ethylsulfanyl) -2-methyl-propionylamino] -4-oxo-pentanoic acid,

3-[3-(3-카르복시-프로필술파닐)-2-메틸-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- [3- (3-carboxy-propylsulfanyl) -2-methyl-propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

5-(2-벤질-3-페닐-프로피오닐옥시)-3-[3-(3-카르복시-프로필술파닐)-2-메틸-프로피오닐아미노]-4-옥소-펜탄산,5- (2-Benzyl-3-phenyl-propionyloxy) -3- [3- (3-carboxy-propylsulfanyl) -2-methyl-propionylamino] -4-oxo-pentanoic acid,

3-(3-카르복시메틸술파닐-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (3-carboxymethylsulfanyl-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

5-(2-벤질-3-페닐-프로피오닐옥시)-3-(3-카르복시메틸술파닐-2-메틸-프로피오닐아미노)-4-옥소-펜탄산,5- (2-benzyl-3-phenyl-propionyloxy) -3- (3-carboxymethylsulfanyl-2-methyl-propionylamino) -4-oxo-pentanoic acid,

3-[3-(2-카르복시-에탄술포닐)-2-메틸-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- [3- (2-carboxy-ethanesulfonyl) -2-methyl-propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-[3-(3-카르복시-프로판-1-술포닐)-2-메틸-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- [3- (3-carboxy-propane-1-sulfonyl) -2-methyl-propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-(3-카르복시메탄술포닐-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (3-carboxymethanesulfonyl-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

5-(2-벤질-3-페닐-프로피오닐옥시)-3-[3-(3-카르복시-프로판-1-술포닐)-2-메틸-프로피오닐아미노]-4-옥소-펜탄산,5- (2-benzyl-3-phenyl-propionyloxy) -3- [3- (3-carboxy-propane-1-sulfonyl) -2-methyl-propionylamino] -4-oxo-pentanoic acid,

5-(2-벤질-3-페닐-프로피오닐옥시)-3-(3-카르복시메탄술포닐-2-메틸-프로피오닐아미노)-4-옥소-펜탄산,5- (2-benzyl-3-phenyl-propionyloxy) -3- (3-carboxymethanesulfonyl-2-methyl-propionylamino) -4-oxo-pentanoic acid,

3-[3-(3-카르복시-프로판-1-술피닐)-2-메틸-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- [3- (3-carboxy-propane-1-sulfinyl) -2-methyl-propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-[2-메틸-3-(3-페닐-프로판-1-술피닐)-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 및3- [2-Methyl-3- (3-phenyl-propane-1-sulfinyl) -propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid and

5-(2-벤질-3-페닐-프로피오닐옥시)-3-[2-메틸-3-(3-페닐-프로판-1-술피닐)-프로피오닐아미노]-4-옥소-펜탄산.5- (2-Benzyl-3-phenyl-propionyloxy) -3- [2-methyl-3- (3-phenyl-propane-1-sulfinyl) -propionylamino] -4-oxo-pentanoic acid.

또한, 3-[3-메틸-2-(펜에틸카르바모일-메틸)-부티릴아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 및Furthermore, 3- [3-methyl-2- (phenethylcarbamoyl-methyl) -butyrylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid and

3-(3-카르복시-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산이 제공된다.3- (3-carboxy-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid is provided.

또한, 3-(2-메틸-3-술파모일-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산이 제공된다.Also provided is 3- (2-methyl-3-sulfamoyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid.

또한, 다음의 화합물,In addition, the following compounds,

3-(3-카르바모일-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (3-Carbamoyl-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-(2-벤질옥시카르보닐아미노-3-메틸-나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (2-benzyloxycarbonylamino-3-methyl-naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-[(2-카르바모일-시클로펜탄카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3-[(2-Carbamoyl-cyclopentanecarbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-[(1-카르바모일-피롤리딘-2-카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3-[(1-Carbamoyl-pyrrolidine-2-carbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-[(2-{2-[2-아세틸아미노-3-(4-히드록시-페닐)-프로피오닐아미노]-4-카르복시-부티릴아미노}-3-메틸-부티릴아미노)-5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-펜탄산,3-[(2- {2- [2-acetylamino-3- (4-hydroxy-phenyl) -propionylamino] -4-carboxy-butyrylamino} -3-methyl-butyrylamino) -5 -(2-benzyl-3-phenyl-propionyloxy) -4-oxo-pentanoic acid,

3-(3-카르바모일-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (3-Carbamoyl-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-(2-카르바모일메틸-3-메틸-부티릴아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (2-Carbamoylmethyl-3-methyl-butyrylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-(3-벤질옥시-2-우레이도-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (3-benzyloxy-2-ureido-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid,

3-[2-(2-벤질옥시카르보닐아미노-4-카르복시-부티릴아미노)-3-메틸-부티릴아미노]-5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-펜탄산,3- [2- (2-benzyloxycarbonylamino-4-carboxy-butyrylamino) -3-methyl-butyrylamino] -5- (2-benzyl-3-phenyl-propionyloxy) -4- Oxo-Pentanoic Acid,

3-{2-[4-카르복시-2-(3-페닐-프로피오닐아미노)-부티릴아미노]-3-메틸-부티릴아미노}-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 및3- {2- [4-carboxy-2- (3-phenyl-propionylamino) -butyrylamino] -3-methyl-butyrylamino} -5- (naphthalen-1-yl-acetoxy) -4 Oxo-pentanoic acid and

3-[2-(2-아세틸아미노-4-카르복시-부티릴아미노)-3-메틸-부티릴아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산이 제공된다.Provided by 3- [2- (2-acetylamino-4-carboxy-butyrylamino) -3-methyl-butyrylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid do.

또한, 하기 화학식 I의 화합물 및 제약상 허용가능한 그의 염, 에스테르, 아미드 및 프로드럭이 제공된다.Also provided are compounds of formula (I) and pharmaceutically acceptable salts, esters, amides and prodrugs thereof.

<화학식 I><Formula I>

식 중, R1은,,,,, , , -(CH2)3페닐,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 또는이고,Wherein R 1 is , , , , , , ,-(CH 2 ) 3 phenyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ego,

R2는 -CH2CH2-페닐, -CH2-나프틸, -CH2CH2-시클로헥실, -CH2O-나프틸, -CH2O-페닐, -CH2S-페닐, -CH2-치환된 나프틸, -CH2CH(페닐)2, -CH2-이미다졸, -(CH2)3-페닐,,,, -CH[CH2페닐]2,, -CH2-NH페닐,, -CH2-나프틸-페닐, -CH2-플루오레닐, -CH2-나프틸-티에닐,,, -CH2-벤조푸라닐, -CH2-벤조티에닐, -CH2-나프틸-CH2-페닐, -CH2-치환된 페닐,, -CH2-치환된 인돌릴,,,,,,,,,, -(CH2)2-피리딜, 또는이고,R 2 is —CH 2 CH 2 -phenyl, -CH 2 -naphthyl, -CH 2 CH 2 -cyclohexyl, -CH 2 O-naphthyl, -CH 2 O-phenyl, -CH 2 S-phenyl,- CH 2 -substituted naphthyl, -CH 2 CH (phenyl) 2 , -CH 2 -imidazole,-(CH 2 ) 3 -phenyl, , , , -CH [CH 2 phenyl] 2 , , -CH 2 -NHphenyl, , -CH 2 -naphthyl-phenyl, -CH 2 -fluorenyl, -CH 2 -naphthyl-thienyl, , , -CH 2 -benzofuranyl, -CH 2 -benzothienyl, -CH 2 -naphthyl-CH 2 -phenyl, -CH 2 -substituted phenyl, , -CH 2 -substituted indolyl, , , , , , , , , ,-(CH 2 ) 2 -pyridyl, or ego,

각각의 n은 서로 독립적으로 0 내지 3이다.Each n is 0 to 3 independently of each other.

본 발명은 인터루킨-1β 전환 효소의 억제제 화합물에 관한 것이다. 본 발명은 또한 발작, 재관류 손상, 알쯔하이머병, 시겔라증, 염증성 질환의 치료 방법 및 인터루킨-1β 전환 효소의 억제제 화합물을 함유하는 제약상 허용가능한 조성물에 관한 것이다.The present invention relates to inhibitor compounds of interleukin-1β converting enzymes. The invention also relates to methods of treating seizures, reperfusion injury, Alzheimer's disease, shigellosis, inflammatory diseases and pharmaceutically acceptable compositions containing inhibitor compounds of interleukin-1β converting enzymes.

"알킬"이란 용어는 직쇄 또는 분지쇄 탄화수소를 의미한다. 알킬기의 대표적인 예로는 메틸, 에틸, 프로필, 이소프로필, 이소부틸, 부틸, tert-부틸, sec-부틸, 펜틸 및 헥실이다.The term "alkyl" means a straight or branched chain hydrocarbon. Representative examples of alkyl groups are methyl, ethyl, propyl, isopropyl, isobutyl, butyl, tert-butyl, sec-butyl, pentyl and hexyl.

"알콕시"란 용어는 산소 원자에 연결된 알킬기를 의미한다. 알콕시기의 대표적인 예로는, 메톡시, 에톡시, tert-부톡시, 프로폭시 및 이소부톡시 등이 있다.The term "alkoxy" means an alkyl group linked to an oxygen atom. Representative examples of alkoxy groups include methoxy, ethoxy, tert-butoxy, propoxy and isobutoxy.

"할로겐"이란 용어는 염소, 불소, 브롬 및 요오드를 포괄한다.The term "halogen" encompasses chlorine, fluorine, bromine and iodine.

"아릴"이란 용어는 방향족 탄화수소를 의미한다. 아릴기의 대표적인 예로는 페닐과 나프틸이 있다.The term "aryl" means an aromatic hydrocarbon. Representative examples of aryl groups include phenyl and naphthyl.

"헤테로원자"라는 용어는 산소, 질소, 황 및 인을 포괄한다.The term "heteroatom" encompasses oxygen, nitrogen, sulfur and phosphorus.

"헤테로아릴"이란 용어는 방향족 탄화수소 중에서 하나 이상의 탄소 원자가 헤테로원자로 대체된 아릴기를 의미한다. 헤테로아릴기의 예로는 푸란, 티오펜, 피롤, 티아졸, 피리딘, 피리미딘, 피라진, 벤조푸란, 인돌, 코우마린, 퀴놀린, 이소퀴놀린, 및 나프티리딘 등이 있다.The term "heteroaryl" means an aryl group in which one or more carbon atoms in an aromatic hydrocarbon is replaced by a heteroatom. Examples of heteroaryl groups include furan, thiophene, pyrrole, thiazole, pyridine, pyrimidine, pyrazine, benzofuran, indole, coumarin, quinoline, isoquinoline, naphthyridine and the like.

아릴 또는 헤테로아릴기는 하나 이상의 동일하거나 상이한 치환체로 치환될 수 있다. 적절한 치환체의 예로는 알킬, 알콕시, 티오알콕시, 히드록시, 할로겐, 트리플루오로메틸, 아미노, 알킬아미노, 디알킬아미노, -NO2, -CN, -CO2H, -CO2알킬, -SO3H, -CHO, -CO알킬, -CONH2, -CONH-알킬, -CONHRｑ, -CON(알킬)2, -(CH2)n-NH2, -(CH2)nOH, -(CH2)n-NH-알킬, -NHRｑ, 또는 -NHCORｑ (여기서 n은 1 내지 5이고, Rｑ는 수소 또는 알킬임) 등이 있다.Aryl or heteroaryl groups may be substituted with one or more identical or different substituents. Examples of suitable substituents include alkyl, alkoxy, thioalkoxy, hydroxy, halogen, trifluoromethyl, amino, alkylamino, dialkylamino, -NO 2 , -CN, -CO 2 H, -CO 2 alkyl, -SO 3 H, -CHO, -COalkyl, -CONH 2 , -CONH-alkyl, -CONHR ', -CON (alkyl) 2 ,-(CH 2 ) n -NH 2 ,-(CH 2 ) n OH,-(CH 2 ) n- NH-alkyl, -NHR ', or -NHCOR', where n is 1 to 5 and R 'is hydrogen or alkyl.

"시클로알킬"이란 용어는 고리형 알킬기를 의미한다. 시클로알킬기의 예로는 시클로프로판, 시클로부탄, 시클로펜탄, 시클로헥산 등이 있다.The term "cycloalkyl" refers to a cyclic alkyl group. Examples of cycloalkyl groups include cyclopropane, cyclobutane, cyclopentane, cyclohexane and the like.

"헤테로사이클"이란 용어는 하나 이상의 탄소 원자가 헤테로원자로 대체된 시클로알킬기를 의미한다. 헤테로사이클의 예로는 피페라진, 모르폴리노, 피페리딘 등이 있다.The term "heterocycle" refers to a cycloalkyl group in which one or more carbon atoms is replaced with a heteroatom. Examples of heterocycles include piperazine, morpholino, piperidine and the like.

본원에 사용된 용어 아릴, 헤테로아릴, 시클로알킬, 헤테로사이클은 치환된 아릴, 치환된 헤테로아릴, 치환된 시클로알킬, 치환된 헤테로사이클을 포괄한다.The term aryl, heteroaryl, cycloalkyl, heterocycle, as used herein, encompasses substituted aryl, substituted heteroaryl, substituted cycloalkyl, substituted heterocycle.

기호 "-"는 결합을 의미한다.The symbol "-" means a bond.

화학식 I의 화합물은 단독으로 또는 제약상 허용되는 조성물의 일부로서 환자에게 투여될 수 있다. 이 조성물은 사람 및 동물 등의 환자에게, 경구, 직장, 비경구 (정맥내, 근육내, 또는 피하), 지망막하조내, 질(膣)내, 복강내, 방광내로, 국소 부위로 (분말제, 연고 또는 점적제 (drops)), 또는 협측 또는 코 스프레이 중 어느 하나로 투여할 수 있다.The compound of formula (I) may be administered to the patient alone or as part of a pharmaceutically acceptable composition. The composition is orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), in subretinal alveolar, intravaginal, intraperitoneal, into the bladder, topically (powdered) to patients such as humans and animals. Agents, ointments or drops, or buccal or nasal sprays.

비경구 주입을 위한 적절한 조성물은 생리적으로 허용가능한 멸균 수성 또는 비수성 용액, 분산액, 현탁액 또는 에멀젼, 및 멸균 주입 용액 또는 분산액에 용해시켜 원상태로 되는 (reconstitution) 멸균 분말을 함유할 수 있다. 적절한 수성 및 비수성 담체, 희석제, 용매 또는 비히클의 예로는 물, 에탄올, 폴리올 (프로필렌글리콜, 폴리에틸렌글리콜, 글리세롤 등), 이들의 적절한 혼합물, 식물성 오일 (예: 올리브유), 및 에틸 올레에이트 등의 주입가능한 유기 에스테르 등이 있다. 레시틴 등의 코팅제를 사용하거나, 분산액의 경우에는 필요한 입자 크기를 유지하고, 계면활성제를 사용하는 등의 수단을 통해 적절한 유동성을 유지할 수 있다.Suitable compositions for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders which are dissolved in sterile infusion solutions or dispersions and undoped. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), suitable mixtures thereof, vegetable oils (e.g. olive oil), and ethyl oleate. Injectable organic esters and the like. Appropriate fluidity can be maintained by means such as using a coating such as lecithin, in the case of dispersions, by maintaining the required particle size, and by using surfactants.

이들 조성물은 또한 방부제, 습윤제, 유화제, 분산제 등의 보조제를 함유할 수도 있다. 미생물의 작용을 확실히 방지하기 위해서는, 파라벤, 클로로부탄올, 페놀, 소르브산 등의 각종 항세균제 및 항진균제를 사용할 수 있다. 당, 염화나트륨 등의 등장제를 첨가하는 것도 필요할 수 있다. 주입가능한 제약 형태의 장기간 흡수 (prolonged absorption)는 모노스테아르산 알루미늄 및 젤라틴 등의 흡수지연제를 사용함으로써 이루어질 수 있다.These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers, dispersants and the like. In order to reliably prevent the action of microorganisms, various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, and sorbic acid can be used. It may also be necessary to add isotonic agents, such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be achieved by the use of absorption retardants such as aluminum monostearate and gelatin.

경구 투여용 고체 투여형은 캡슐, 정제, 환제, 분말제 및 과립 등이 있다. 이러한 고체 투여형에서, 활성 화합물은 시트르산 나트륨 또는 인산이칼슘 또는Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is sodium citrate or dicalcium phosphate or

(a) 전분, 락토오즈, 수크로오즈, 포도당, 만니톨 및 규산 등과 같은 충전제 또는 증량제,(a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and silicic acid, etc.,

(b) 카르복시메틸셀룰로오즈, 알리그네이트, 젤라틴, 폴리비닐피롤리돈, 수크로오즈 및 아카시아 등의 결합제,(b) binders such as carboxymethylcellulose, aligates, gelatin, polyvinylpyrrolidone, sucrose and acacia,

(c) 글리세롤 등의 보습제 (humectant),(c) humectants such as glycerol,

(d) 아가-아가, 탄산칼슘, 감자 또는 타피오카 전분, 알긴산, 특정한 복합 실리케이트, 및 탄산칼슘 등의 붕해제(d) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and calcium carbonate

(e) 파라핀 등의 용액 지연제 (solution retarder),(e) solution retarders such as paraffin,

(f) 4급 암모늄 화합물 등의 흡수 촉진제,(f) absorption accelerators such as quaternary ammonium compounds,

(g) 세틸 알코올 및 모노스테아르산 글리세롤 등의 습윤제 (wetting agent),(g) wetting agents, such as cetyl alcohol and glycerol monostearate,

(h) 카올린 및 벤토나이트 등의 흡착제,(h) adsorbents such as kaolin and bentonite,

(i) 활석, 스테아르산 칼슘, 스테아르산 마그네슘, 고체 폴리에틸렌 글리콜, 라우릴 황산 나트륨, 또는 이들의 혼합물 등의 윤활제 등의 통상적인 불활성 부형제 (또는 담체) 하나 이상과 혼합한다. 캡슐, 정제 및 환제의 경우에는, 투여형에 완충제도 함유될 수 있다.(i) one or more conventional inert excipients (or carriers) such as lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also contain buffering agents.

락토오즈 또는 젖당 등의 부형제 및 고분자량 폴리에틸렌글리콜 등을 사용하는 연질 및 경질 충전 젤라틴 캡슐에 충전제로서 유사한 종류의 고체 조성물을 사용할 수도 있다.Similar types of solid compositions can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or lactose and high molecular weight polyethylene glycols and the like.

정제, 당의정, 캡슐, 환제 및 과립 등의 고체 투여형은 장 코팅 (enteric coatings) 및 당분야에 잘 알려진 것 등의 코팅 및 외피 (shell)를 갖도록 제조할 수 있다. 이들은 혼탁제 (opacifying agent)를 포함할 수 있으며, 또한 지연된 방식으로 장 관의 특정 부위에서 활성 화합물 또는 화합물들을 방출하는 조성일 수도 있다. 사용할 수 있는 포매 조성물의 예로는 중합 물질 및 왁스가 있다. 활성 화합물은 또한 적절하다면 상기한 부형제 하나 이상을 포함하는 마이크로-캡슐화된 형태일 수 있다.Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and those well known in the art. These may include opacifying agents and may also be compositions which release the active compound or compounds at specific sites of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compound may also be in micro-encapsulated form comprising one or more of the excipients described above as appropriate.

경구 투여용 액체 투여형으로는 제약상 허용가능한 에멀젼, 용액제, 현탁액제, 시럽제 및 엘릭서 등이 있다. 액체 투여형은 활성 물질 이외에도 당업계에 일반적으로 알려진 물 또는 다른 용매 등의 불활성 희석제, 가용화제 (solubilizing agent) 및 유화제, 예를 들면, 에틸 알코올, 이소프로필 알코올, 에틸 카르보네이트, 에틸 아세테이트, 벤질 알코올, 벤질 벤조에이트, 프로필렌글리콜, 1,3-부틸렌글리콜, 디메틸포름아미드, 오일류 구체적으로는, 목화씨유, 땅콩유, 옥수수 배(胚)유, 올리브유, 캐스터유, 및 참기름, 글리세롤, 테트라히드로푸르푸릴 알코올, 폴리에틸렌글리콜, 및 소르비탄의 지방산 에스테르 또는 이들 물질의 혼합물 등을 함유할 수 있다.Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. Liquid dosage forms, in addition to the active substance, include inert diluents, solubilizing agents and emulsifiers such as water or other solvents commonly known in the art, for example ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, Benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, specifically, cottonseed oil, peanut oil, corn pear oil, olive oil, castor oil, and sesame oil, glycerol, Fatty acid esters of tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan, mixtures of these substances, and the like.

이러한 불활성 희석제 이외에도 조성물은 습윤제, 유화제 및 현탁제, 감미제, 풍미제, 및 향료 등을 함유할 수 있다.In addition to these inert diluents, the composition may contain wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, flavoring agents, and the like.

현탁액제는 활성 화합물 이외에, 에톡실화 이소스테아릴 알코올, 폴리옥시에틸렌 소르비톨 및 소르비탄 에스테르, 미세결정 셀룰로오즈, 알루미늄 메타히드록시드, 벤토나이트, 아가-아가 및 트라가칸트, 이들 물질의 혼합물 등과 같은 현탁제를 함유할 수 있다.Suspensions, in addition to the active compounds, are suspended, such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, mixtures of these substances, and the like. It may contain an agent.

직장 투여용 조성물은 바람직하게는 본 발명의 화합물을, 코코아 버터, 폴리에틸렌글리콜 또는 좌제 왁스 등과 같이 상온에서는 고체이지만 체온에서는 액체로 변해 직장 또는 질강에서 용융되어 활성 성분을 방출하는 무자극 (non-irritating) 부형제 또는 담체와 혼합함으로써 제조할 수 있는 좌제이다.The composition for rectal administration is preferably a non-irritating compound of the present invention, such as cocoa butter, polyethylene glycol or suppository wax, which is solid at room temperature but liquid at body temperature and melts in the rectum or vaginal cavity to release the active ingredient. ), Suppositories that can be prepared by mixing with an excipient or a carrier.

본 발명의 화합물의 국소 투여용 투여형은 연고, 분말제, 스프레이 및 흡입제 등이 있다. 활성 성분은 생리학적으로 허용가능한 담체 및 임의의 방부제, 완충제, 또는 필요하다면 추진제 (propellant)와 멸균 상태에서 혼합한다. 눈 제제, 눈 연고, 분말제 및 용액제도 본 발명의 범위내에 속하는 것으로 간주된다.Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active ingredient is mixed in sterile form with a physiologically acceptable carrier and any preservatives, buffers, or propellants, if necessary. Eye preparations, eye ointments, powders and solutions are also considered to be within the scope of the present invention.

본 발명의 화합물은 하루에 약 0.1 내지 약 1,000 mg의 투여량 수준으로 환자에게 투여될 수 있다. 체중이 약 70 kg인 정상적인 성인의 경우에는 하루에 약 0.01 내지 약 100 mg/kg의 투여량이 바람직하다. 그러나 사용되는 개별적인 투여량은 달라질 수 있다. 예를 들면 투여량은 환자의 요구, 치료할 증세, 사용되는 화합물의 약리 활성 등을 비롯한 많은 요인들에 따라 달라질 수 있기 때문이다. 특정 환자에게 최적의 투여량을 결정하는 것은 당업자에게 잘 알려져 있다.Compounds of the invention may be administered to a patient at a dosage level of about 0.1 to about 1,000 mg per day. For normal adults weighing about 70 kg, dosages of about 0.01 to about 100 mg / kg per day are preferred. However, the individual dosages used may vary. For example, the dosage may vary depending on many factors, including the needs of the patient, the condition to be treated, the pharmacological activity of the compound used, and the like. It is well known to those skilled in the art to determine the optimal dosage for a particular patient.

본원에 사용된 "제약상 허용가능한 염, 에스테르, 아미드 및 프로드럭"이란 용어는, 건전한 의학적 판단의 범위내에서 심한 독성, 자극, 알레르기 반응 등이 없이 환자의 피부와 접촉해서 사용하는데 적합하며, 합리적인 이익/위험 비율이 적절하며, 의도한 목적에 효과적인, 본 발명의 화합물의 카르복실산염, 아미노산 부가염, 에스테르, 아미드 및 프로드럭 뿐만 아니라 가능하다면 본 발명의 화합물의 양쪽성 이온형을 가리킨다. "염"이란 용어는 본 발명의 화합물의 비교적 비독성인 무기 및 유기 산 부가 염을 가리킨다. 이들 염은 본 발명의 화합물의 최종 단리 및 정제 동안 계내에서 제조되거나 또는 유리 염기 형태로 정제된 화합물을 적절한 유기 또는 무기산과 별도로 반응시킨 후 생성된 염을 단리함으로써 제조할 수 있다. 대표적인 염으로는, 브롬화수소염, 염화수소염, 황산염, 중황산염, 질산염, 아세트산염, 옥살산염, 발레르산염, 올레산염, 팔미트산염, 스테아르산염, 라우르산염, 붕산염, 벤조산염, 락트산염, 인산염, 토실산염, 시트르산염, 말레산염, 푸마르산염, 숙신산염, 타르타르산염, 나프틸산염, 메실산염, 글루코헵톤산염, 락토비온산염 및 라우릴술폰산염 등이 있다. 이들은 나트륨, 리튬, 칼륨, 칼슘, 마그네슘 등의 알칼리 금속 및 알칼리토금속을 기재로한 양이온 뿐만 아니라 암모늄, 트리메틸아민, 테트라에틸암모늄, 메틸아민, 디메틸아민, 트리메틸아민, 트리에틸아민, 에틸아민 등을 포함하나 이들로 제한되지 않는 비독성 암모늄, 4급 암모늄, 및 아민 양이온도 포함할 수 있다. 본원에 참고로 도입된 문헌(Berge S. M., et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1 - 19)를 참조한다.As used herein, the term "pharmaceutically acceptable salts, esters, amides and prodrugs" is suitable for use in contact with the skin of a patient without severe toxicity, irritation, allergic reactions, etc. within the scope of sound medical judgment, A rational benefit / risk ratio is appropriate and refers to the carboxylic acid salts, amino acid addition salts, esters, amides and prodrugs of the compounds of the invention, which are effective for the intended purpose, as well as the amphoteric ion form of the compounds of the invention, if possible. The term "salts" refers to relatively nontoxic inorganic and organic acid addition salts of the compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the present invention or by reacting the compounds purified in the free base form separately with the appropriate organic or inorganic acid followed by isolating the resulting salts. Representative salts include hydrobromide, hydrogen chloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, Phosphates, tosylates, citrates, maleates, fumarates, succinates, tartarates, naphthylates, mesylates, glucoheptonates, lactobionic acid salts and laurylsulfonate salts. These include ammonium, trimethylamine, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, as well as cations based on alkali metals and alkaline earth metals such as sodium, lithium, potassium, calcium and magnesium. Non-toxic ammonium, quaternary ammonium, and amine cations may also be included, including but not limited to these. See Berge S. M., et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977; 66: 1-19, incorporated herein by reference.

본 발명의 화합물의 제약상 허용가능한 비독성 에스테르의 예로는, C1-C6알킬 에스테르 (여기서 알킬은 직쇄 또는 분지쇄임) 등이 있다. 또한 허용가능한 에스테르로는 C5-C7시클로알킬 에스테르와, 벤질로 제한되지는 않으나 벤질과 같은 아르알킬 에스테르 등이 있다. 바람직한 것은 C1-C4알킬 에스테르이다. 본 발명의 화합물의 에스테르는 종래 방법에 따라 제조할 수 있다.Examples of pharmaceutically acceptable non-toxic esters of the compounds of the present invention include C 1 -C 6 alkyl esters, wherein alkyl is straight or branched chain. Acceptable esters also include C 5 -C 7 cycloalkyl esters and aralkyl esters such as, but not limited to, benzyl. Preferred are C 1 -C 4 alkyl esters. Esters of the compounds of the present invention can be prepared according to conventional methods.

본 발명의 화합물의 제약상 허용가능한 비독성 아미드의 예로는 암모니아, 1급 C1-C6알킬 아민 및 2급 C1-C6디알킬 아민 (기서 알킬기는 직쇄 또는 분지쇄일 수 있음)으로부터 유도된 아미드가 있다. 2급 아민의 경우에는 하나의 질소 원자 를 포함하는 5- 또는 6-원 헤테로사이클의 형태일 수 있다. 암모니아로부터 유도된 아미드, C1-C3알킬 1급 아민, C1-C2디알킬 2급 아민이 바람직하다. 본 발명의 화합물의 아미드는 종래의 방법에 따라 제조할 수 있다.Examples of pharmaceutically acceptable non-toxic amides of the compounds of the present invention are derived from ammonia, primary C 1 -C 6 alkyl amines and secondary C 1 -C 6 dialkyl amines, where the alkyl groups may be straight or branched chains. Amides. In the case of secondary amines it may be in the form of a 5- or 6-membered heterocycle comprising one nitrogen atom. Preferred are amides derived from ammonia, C 1 -C 3 alkyl primary amines, C 1 -C 2 dialkyl secondary amines. Amides of the compounds of the present invention can be prepared according to conventional methods.

"프로드럭 (prodrug)"이란 용어는 생체내에서 급속하게 변형되어 (예를 들면, 혈액 내에서 가수분해에 의해) 상기 화학식의 모(母)화합물을 생성시키는 화합물이다. 이에 관한 충분한 설명은, 본원에 참고로 도입된 문헌 (Higuchi T. and Stella V., "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series) 및 문헌 (Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987)에 기재되어 있다.The term "prodrug" is a compound that is rapidly modified in vivo (eg, by hydrolysis in blood) to produce the parent compound of the formula. A full description of this can be found in Higuchi T. and Stella V., “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the ACS Symposium Series and Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987).

또한, 본 발명의 화합물은 비용매화 형태 및 물, 에탄올 등의 제약상 허용가능한 용매와의 용매화된 형태로 존재할 수 있다. 일반적으로 용매화된 형태는 본 발명의 목적에 있어서 비용매화 형태와 동등한 것으로 간주된다.In addition, the compounds of the present invention may exist in unsolvated form and in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.

본 발명의 화합물은 화합물 내에 비대칭 중심이 존재하기 때문에 (즉, 각각의 비대칭 탄소는 R 또는 S 입체배열을 가질 수 있음) 상이한 입체이성질체 형태로 존재할 수 있다. 본 발명의 화합물의 모든 입체이성질체 형태 뿐만 아니라 라세미체 혼합물을 비롯한 이의 혼합물도 본 발명의 일부를 이루는 것으로 간주한다.Compounds of the present invention may exist in different stereoisomeric forms because of the presence of asymmetric centers in the compound (ie, each asymmetric carbon may have an R or S stereoconfiguration). All stereoisomeric forms of the compounds of the invention as well as mixtures thereof, including racemic mixtures, are considered to be part of the invention.

본 발명의 화합물은 ICE 또는 카스파제-4의 억제를 필요로하는 환자에게 투여할 수 있다. 일반적으로 ICE 또는 카스파제-4를 억제할 필요가 있는 환자는 ICE 또는 카스파제-4가 관여하는 질병 또는 상태에 처해 있는 환자들이다. 그러한 질병의 예로는 루마티스성 관절염 및 염증성 장 질환 등의 염증성 질병, 발작 등의 신경 염증성 장애, 및 패혈성 쇼크 등이 있으나 이것으로 제한되지는 않는다. 다른 질병으로는 재관류 손상, 알쯔하이머병 및 시겔라증이 있다.The compounds of the present invention can be administered to patients in need of inhibition of ICE or caspase-4. In general, patients in need of inhibiting ICE or caspase-4 are patients who have a disease or condition involving ICE or caspase-4. Examples of such diseases include, but are not limited to, inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease, neuroinflammatory disorders such as seizures, and septic shock. Other diseases include reperfusion injury, Alzheimer's disease and shigellosis.

"치료학적 유효량"은 화학식 I의 화합물로 치료할 수 있는 질병에 걸린 환자에게 투여할 때 질병의 증상을 완화시킬 수 있는 화학식 I의 화합물의 양이다. 화학식 I의 화합물의 치료학적 유효량은 환자에게 화학식 I의 화합물을 투여하고 결과를 관찰함으로써 당업자에 의해 용이하게 결정된다.A "therapeutically effective amount" is an amount of a compound of formula I that can alleviate the symptoms of the disease when administered to a patient with a disease that can be treated with a compound of formula I. A therapeutically effective amount of a compound of formula I is readily determined by one skilled in the art by administering a compound of formula I to the patient and observing the result.

다음의 실시예는 본 발명의 특정한 실시태양을 예시하는 것이며, 어떤 식으로든 명세서 및 청구의 범위의 범위를 제한하려는 것이 아니다.The following examples illustrate certain embodiments of the invention and are not intended to limit the scope of the specification and claims in any way.

다음의 반응식 1 내지 11은 본 발명의 화합물이 어떻게 제조되는지를 개괄적으로 보여준다.The following schemes 1 to 11 show in general how the compounds of the invention are prepared.

Z-Asp(OtBu)-브로모메틸케톤으로 알려진 3-벤질옥시카르보닐아미노-5-브로모-4-옥소-펜토조산 tert-부틸 에스테르는 구입할 수 있거나 문헌 (Dolle, et al., J. Med. Chem., 1994; 37: 563-564)의 방법에 따라 제조할 수 있다. 이 메틸브로모케톤을 적절히 치환된 카르복실산 및 불화칼륨 등의 염기로 처리한다. 이와 다르게는, 염화칼륨, 탄산세슘, 또는 칼륨 t-부톡시드 등의 다른 염기를 사용할 수 있다. 이 시약은 디메틸 포름아미드 (DMF), 디메틸아세트아미드 (DMA), 디메틸 술폭시드 (DMSO), 아세토니트릴 또는 다른 적절한 용매에 혼합하고 8 내지 24 시간 동안 실온에서 교반시킬 수 있다. t-부틸 에스테르 보호기는 산성 매질, 바람직하게는 트리플루오로아세트산에서 제거하여 반응식 1에 보인 카르보벤족시 아스파르틸 에스테르를 제조할 수 있다.3-benzyloxycarbonylamino-5-bromo-4-oxo-pentozoic acid tert-butyl ester known as Z-Asp (OtBu) -bromomethylketone can be purchased or described in Dolle, et al., J. Med. Chem., 1994; 37: 563-564). This methyl bromoketone is treated with a base such as carboxylic acid and potassium fluoride which are appropriately substituted. Alternatively, other bases such as potassium chloride, cesium carbonate, or potassium t-butoxide may be used. This reagent can be mixed in dimethyl formamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), acetonitrile or other suitable solvent and stirred at room temperature for 8 to 24 hours. The t-butyl ester protecting group can be removed in an acidic medium, preferably trifluoroacetic acid, to prepare the carbobenzoxyl aspartyl ester shown in Scheme 1.

카르보벤족시 아스파르틸 t-부틸 에스테르의 적절히 치환된 아실옥시메틸 케톤의 혼합물을 탄소상 팔라듐과 같은 촉매의 존재하에 1 당량의 염산 또는 다른 산을 사용하여 수소첨가하여, 아민 염을 얻었다. 이 염을 적절히 치환된 이소시아네이트, 술포닐 클로라이드, 클로로포르메이트 또는 페닐프로피오닐 클로라이드로 아실화하여 N-치환된 유도체를 얻을 수 있다. 이들 이소시아네이트, 술포닐 클로라이드 또는 클로로포르메이트는 구입할 수 있거나 화학 문헌에 기재된 방법으로 합성할 수도 있다. t-부틸 에스테르 보호기는 산성 매질, 바람직하게는 트리플루오로아세트산을 사용하여 최종 단계에서 제거하여, 반응식 2에 도시한 바와 같이 아실옥시 메틸케톤 유도체를 제조할 수 있다.A mixture of appropriately substituted acyloxymethyl ketones of carbobenzoic aspartyl t-butyl ester was hydrogenated using 1 equivalent of hydrochloric acid or another acid in the presence of a catalyst such as palladium on carbon to obtain an amine salt. This salt may be acylated with an appropriately substituted isocyanate, sulfonyl chloride, chloroformate or phenylpropionyl chloride to obtain N-substituted derivatives. These isocyanates, sulfonyl chlorides or chloroformates can be purchased or synthesized by the methods described in the chemical literature. The t-butyl ester protecting group can be removed in the final step using an acidic medium, preferably trifluoroacetic acid, to prepare acyloxy methyl ketone derivatives as shown in Scheme 2.

실시예 2와 유사한 방식으로, Z-Asp(Ot-Bu)OH의 아실옥시메틸케톤 아민염을 합성하고, 이를 적절히 치환된 카르복실산 및 커플링제로 처리했다. 커플링제는 1,3-디시클로헥실카르보디이미드 (DCC), 1-(3-디메틸아미노프로필)-3-메틸카르보디이미드 히드로클로라이드 (EDCI), 1,1'-카르보닐디이미다졸 (CDI), 1,1'-카르보닐비스(3-메틸이미다졸리움)트리플레이트 (CBMIT), 이소부틸클로로포르메이트, 벤조트리아졸-1-일옥시트리스(디메틸아미노)-포스포늄 헥사플루오로포스페이트 (BOP), 2-(3,4-디히드로-4-옥소-1,2,3-벤조트리아진-3-일)-1,1,3,3-테트라메틸우로늄 테트라플루오로보레이트 (TDBTU), 및 2-(1H-벤조트리아졸-1-일)-1,1,3,3-테트라메틸우로늄 헥사플루오로포스페이트 (HBTU)일 수 있으나, 이들로 제한되는 것은 아니다. 1-히드록시벤조트리아졸 수화물을 반응에 첨가하여, 수율을 향상시키고 이성질화를 제한해야 하며, 염기, 바람직하게는 트리메틸아민 또는 메틸 모르폴린 등의 아민을 산 스캐벤져로서 첨가하여야 한다. 생성된 아미드 생성물을 산성 매질, 바람직하게는 트리플루오로아세트산으로 처리하여 t-부틸 에스테르를 제거하고, 반응식 3에 나타낸 바와 같은 최종 생성물을 얻었다.In a manner similar to Example 2, acyloxymethylketone amine salts of Z-Asp (Ot-Bu) OH were synthesized and treated with appropriately substituted carboxylic acids and coupling agents. The coupling agent is 1,3-dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-methylcarbodiimide hydrochloride (EDCI), 1,1'-carbonyldiimidazole ( CDI), 1,1'-carbonylbis (3-methylimidazolium) triplate (CBMIT), isobutylchloroformate, benzotriazol-1-yloxytris (dimethylamino) -phosphonium hexafluoro Phosphate (BOP), 2- (3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TDBTU), and 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), but is not limited to these. 1-hydroxybenzotriazole hydrate should be added to the reaction to improve yield and limit isomerization, and bases, preferably amines such as trimethylamine or methyl morpholine, should be added as acid scavengers. The resulting amide product was treated with an acidic medium, preferably trifluoroacetic acid, to remove the t-butyl ester, giving a final product as shown in Scheme 3.

실시예 2와 유사한 방식으로, Cbz-Asp(OtBu)OH의 아실옥시메틸케톤 아민염을 합성하고, 이를 적절히 치환된 산 클로라이드 또는 산 플루오라이드로 처리하여 아미드 생성물을 발생시켰다. 산 클로라이드는 구입하거나 티오닐 클로라이드, 삼브롬화인 또는 옥살릴 클로라이드/DMF와 같은 제제로 카르복실산을 처리함으로써 제조했다. 산 플루오라이드는 불화시아누르산으로 카르복실산을 처리함으로써 제조했다. 페눌티메이트 아미드 생성물을 산성 매질, 바람직하게는 트리플루오로아세트산으로 처리하여 t-부틸 에스테르를 제거하고 반응식 4에 기재된 최종 생성물을 얻었다.In an analogous manner to Example 2, acyloxymethylketone amine salts of Cbz-Asp (OtBu) OH were synthesized and treated with appropriately substituted acid chlorides or acid fluorides to give the amide product. Acid chlorides were purchased or prepared by treating carboxylic acids with agents such as thionyl chloride, phosphorus tribromide or oxalyl chloride / DMF. Acid fluorides were prepared by treating carboxylic acids with cyanuric fluoride. The phenultimate amide product was treated with an acidic medium, preferably trifluoroacetic acid, to remove the t-butyl ester and to give the final product described in Scheme 4.

H-Asp(OtBu)OMe의 히드로클로라이드 염을 적절히 치환된 카르복실산 및 커플링제로 처리했다. 커플링제는 실시예 3에 기재된 시약들일 수 있으나, 이것으로 제한되지는 않는다. 1-히드록시벤조트리아졸 수화물을 반응물에 첨가하여 수율을 향상시키고 이성질화를 제한해야 하며, 염기, 바람직하게는 트리메틸아민 또는 메틸 모르폴린 등의 아민을 산 스캐벤져로서 첨가해야 한다. 생성된 아미드 생성물을 수산화나트륨 등의 알칼리성 시약으로 처리하여 메틸 에스테르를 카르복실산으로 가수분해했다. 생성된 산을 이소부틸클로로포르메이트 등의 클로로포르메이트로 처리한 후, 디아조메탄 및 브롬화수소산을 사용하여 차례로 처리하여, 메틸브로모케톤을 얻었다. 메틸브로모케톤을 적절히 치환된 카르복실산 및 불화칼륨 등의 염기로 (실시예 1에 기재된 바와 같이) 처리하여, 원하는 아실옥시메틸케톤을 얻었으며, 이를 트리플루오로아세트산을 사용하여 상기한 바와 같이 탈보호시켜, 반응식 5에 나타낸 최종 화합물을 얻었다.The hydrochloride salt of H-Asp (OtBu) OMe was treated with an appropriately substituted carboxylic acid and coupling agent. The coupling agent may be, but is not limited to, the reagents described in Example 3. 1-hydroxybenzotriazole hydrate should be added to the reaction to improve yield and limit isomerization, and bases, preferably amines such as trimethylamine or methyl morpholine, should be added as acid scavengers. The resulting amide product was treated with an alkaline reagent such as sodium hydroxide to hydrolyze the methyl ester with carboxylic acid. The resulting acid was treated with chloroformate such as isobutylchloroformate and then treated sequentially with diazomethane and hydrobromic acid to obtain methyl bromoketone. Methylbromoketone was treated (as described in Example 1) with an appropriately substituted base of carboxylic acid and potassium fluoride to afford the desired acyloxymethylketone, which was described above using trifluoroacetic acid. Deprotection was performed to obtain the final compound shown in Scheme 5.

H-Asp(OtBu)OMe의 히드로클로라이드 염을 적절히 보호된 아미노산 및 커플링제로 처리했다. 커플링제는 실시예 3에 기재된 시약들일 수 있으나, 이것으로 제한되지는 않는다. 1-히드록시벤조트리아졸 수화물을 반응물에 첨가하여 수율을 향상시키고 이성질화를 제한해야 하며, 염기, 바람직하게는 트리메틸아민 또는 메틸 모르폴린 등의 아민을 산 스캐벤져로서 첨가해야 한다. 생성된 아미드 생성물을 수산화나트륨 등의 알칼리성 시약으로 처리하여 메틸 에스테르를 카르복실산으로 가수분해했다. Cbz-아민 보호기는 촉매적 수소첨가 표준 조건을 사용하여 제거했으며, 또다른 보호된 아미노산의 커플링은 상기한 바와 같이 진행할 수 있다. 이 공정을 원하는 길이의 펩티드가 될 때까지 반복했다. 생성된 펩티드 생성물을 수산화나트륨 등의 알칼리성 시약으로 처리하여 메틸 에스테르를 카르복실산으로 가수분해했다. 생성된 산을 계속해서 이소부틸클로로포르메이트 등의 클로로포르메이트로 처리한 후, 디아조메탄 및 브롬화수소산으로 차례로 처리하여 메틸브로모케톤을 얻었다. 메틸브로모케톤을 적절히 치환된 카르복실산 및 불화칼륨 등의 염기로 (실시예 1에 기재된 바와 같이) 처리하여 원하는 아실옥시메틸케톤을 제조했으며, 이를 상기한 바와 같이 트리플루오로아세트산으로 탈보호시켜, 반응식 6에 나타낸 바와 같은 최종 화합물을 얻었다.The hydrochloride salt of H-Asp (OtBu) OMe was treated with suitably protected amino acids and coupling agents. The coupling agent may be, but is not limited to, the reagents described in Example 3. 1-hydroxybenzotriazole hydrate should be added to the reaction to improve yield and limit isomerization, and bases, preferably amines such as trimethylamine or methyl morpholine, should be added as acid scavengers. The resulting amide product was treated with an alkaline reagent such as sodium hydroxide to hydrolyze the methyl ester with carboxylic acid. Cbz-amine protecting groups were removed using catalytic hydrogenation standard conditions, and the coupling of another protected amino acid can proceed as described above. This process was repeated until a peptide of the desired length was obtained. The resulting peptide product was treated with an alkaline reagent such as sodium hydroxide to hydrolyze the methyl ester with carboxylic acid. The resulting acid was subsequently treated with chloroformate such as isobutylchloroformate, and subsequently treated with diazomethane and hydrobromic acid to obtain methylbromoketone. Methylbromoketone was treated with an appropriately substituted base such as carboxylic acid and potassium fluoride (as described in Example 1) to give the desired acyloxymethylketone, which was deprotected with trifluoroacetic acid as described above. The final compound as shown in Scheme 6 was obtained.

보호된 아미노산의 적절히 치환된 아실옥시메틸케톤을 실시예 7에 기재된 바와 같이 합성했다. Cbz-아민 보호기를 촉매적 수소첨가 표준 조건을 사용하여 제거했으며, 아민 생성물을 적절히 치환된 카르복실산 및 커플링제로 처리했다. 커플링제는 실시예 3에 기재된 시약과 같은 것이나 이것으로 제한되지는 않는다. 1-히드록시벤조트리아졸 수화물을 첨가하여 수율을 증가시키고 이성질화를 제한해야 하며, 염기, 바람직하게는 트리메틸 아민이나 메틸 모르폴린 등의 아민을 산 스캐벤져로서 첨가해야 한다. 페눌티메이트 아미드 생성물을 산성 매질, 바람직하게는 트리플루오로아세트산으로 처리하여 t-부틸 에스테르를 제거하고 반응식 7에 기재된 바와 같이 최종 생성물을 얻었다.Properly substituted acyloxymethylketones of protected amino acids were synthesized as described in Example 7. The Cbz-amine protecting group was removed using catalytic hydrogenation standard conditions and the amine product was treated with appropriately substituted carboxylic acid and coupling agent. The coupling agent is the same as, but not limited to, the reagent described in Example 3. 1-hydroxybenzotriazole hydrate should be added to increase yield and limit isomerization, and bases, preferably amines such as trimethyl amine or methyl morpholine, should be added as acid scavengers. The phenultimate amide product was treated with an acidic medium, preferably trifluoroacetic acid, to remove the t-butyl ester and to give the final product as described in Scheme 7.

트랜스-1,2-시클로헥산디카르복실산 무수물을 아스파르틸 t-부틸 에스테르의 적절히 치환된 아실옥시메틸케톤 아민염으로 피리딘 및 4-디메틸아미노피리딘 (DMAP)의 존재하에 처리하여 아민 생성물을 얻었다. 이 카르복실산은 적절히 치환된 아민 또는 알코올과 실시예 3에 기재된 커플링제를 사용하여 관능화시켜 아미드 및 에스테르 생성물을 얻을 수 있다. 이 페눌티메이트 생성물을 산성 매질, 바람직하게는 트리플루오로아세트산으로 처리하여, t-부틸 에스테르를 제거하고 반응식 8에 나타낸 바와 같은 최종 생성물을 얻었다.The trans-1,2-cyclohexanedicarboxylic anhydride is treated with an appropriately substituted acyloxymethylketone amine salt of aspartyl t-butyl ester in the presence of pyridine and 4-dimethylaminopyridine (DMAP) to treat the amine product. Got it. This carboxylic acid can be functionalized using a coupling agent as described in Example 3 with an appropriately substituted amine or alcohol to obtain amide and ester products. This fenultimate product was treated with an acidic medium, preferably trifluoroacetic acid, to remove the t-butyl ester and to give the final product as shown in Scheme 8.

메틸 메타크릴레이트를 적절히 치환된 술피드 음이온으로 처리하여 미카엘 (Michael) 부가물을 얻고, 이를 수산화나트륨과 같은 염기성 매질 내에서 가수분해하여 카르복실산을 제조했다. 이 산을 아스파르틸 t-부틸 에스테르의 아실옥시메틸케톤 아민염 및 실시예 3에 기재한 바와 같은 커플링제과 합하여 아미드 생성물을 얻었다. 술피드 (n=0)가 원하는 생성물이라면, 산화단계는 사용하지 않으며, 아미드 t-부틸 에스테르를 산성 매질, 바람직하게는 트리플루로오아세트산에서 탈보호시켜 최종 생성물을 얻는다. 이와 다르게는, 술폭시드 (n=1) 또는 술폰 (n=2)가 최종 생성물인 경우에는 아미드 중간체를 산화제로 처리하여 원하는 산화 생성물을 얻는데, 여기서 산화제는 m-클로로퍼벤조산, 칼륨 모노퍼옥시술페이트, 과붕산나트륨일 수 있으나 이것으로 제한되는 않는다. 페눌티메이트 중간체의 t-부틸 에스테르를 산성 매질, 바람직하게는 트리플루오로아세트산에서 탈보호시켜 반응식 9에 나타낸 바와 같은 최종 화합물을 얻었다.Methyl methacrylate was treated with an appropriately substituted sulfide anion to obtain the Michael adduct, which was hydrolyzed in a basic medium such as sodium hydroxide to prepare a carboxylic acid. This acid was combined with the acyloxymethylketone amine salt of aspartyl t-butyl ester and the coupling agent as described in Example 3 to obtain an amide product. If sulfide (n = 0) is the desired product, no oxidation step is used, and the amide t-butyl ester is deprotected in acidic medium, preferably trifluoroacetic acid to obtain the final product. Alternatively, if sulfoxide (n = 1) or sulfone (n = 2) is the final product, the amide intermediate is treated with an oxidant to obtain the desired oxidation product, where the oxidant is m-chloroperbenzoic acid, potassium monoperoxysulfate. Pate, sodium perborate, but is not limited thereto. The t-butyl ester of the phenultimate intermediate was deprotected in acidic medium, preferably trifluoroacetic acid, to give the final compound as shown in Scheme 9.

문헌 (Evans, et al., J. Org. Chem., 1985; 50: 1830)에 기재된 바와 같은 4-치환된-2-옥사졸리디논 키랄 보조물을 n-부틸 리튬 (이것으로 제한되지 않음) 등의 염기와 혼합한 후, 적절히 치환된 산 클로라이드 또는 다른 활성화된 카르복실산으로 처리하여 N-아실화 생성물을 얻는다. 이 생성물을 이어서 나트륨 비스(트리메틸실릴)아미드 및 t-부틸 브로모아세테이트로 제한되지 않으나 이와 같은 염기로 처리하여 알킬화된 키랄 생성물을 생성시킨다. 키랄 보조물을 수산화리튬 및 과산화수소로 처리하여 제거하고 키랄산을 얻었다. 산을 H-Asp(OBz)O-알릴 및 실시예 3에 기재한 바와 같은 커플링제의 아민염으로 처리하여 숙시닐 아미드 생성물을 얻었다.4-substituted-2-oxazolidinone chiral auxiliaries as described in Evans, et al., J. Org. Chem., 1985; 50: 1830, include, but are not limited to, n-butyl lithium, etc. After mixing with a base of N, it is treated with an appropriately substituted acid chloride or other activated carboxylic acid to obtain an N-acylated product. This product is then treated with, but not limited to, sodium bis (trimethylsilyl) amide and t-butyl bromoacetate to yield an alkylated chiral product. The chiral auxiliaries were removed by treatment with lithium hydroxide and hydrogen peroxide to give chiral acid. The acid was treated with H-Asp (OBz) O-allyl and the amine salt of the coupling agent as described in Example 3 to give succinyl amide product.

공정의 이 단계에서, 생성물을 두 가지 방식 중 하나로 제조할 수 있다. 첫번째, t-부틸 에스테르를 산성 매질, 바람직하게는 트리플루오로아세트산에서 제거한 후 생성된 산을 적절히 치환된 아민과 실시예 3에 기재된 것과 같은 커플링제의 존재하에 커플링시켜서 새로운 아미드 생성물을 제조했다. 이 알릴 에스테르를 페닐실란 및 테트라키스(트리페닐-포스핀)팔라듐 또는 다른 Pd(0) 촉매를 사용하여 제거함으로써 카르복실산을 얻었으며, 이 산을 실시예 5에 기재한 바와 같이 메틸브로모케톤으로 전환시킨 후, 아실옥시메틸케톤으로 전환시켰다. 페눌티메이트 중간체를 촉매적 수소첨가 반응을 시켜서 벤질 에스테르를 제거하여 반응식 10에 나타낸 바와 같은 최종 아미드 생성물을 얻었다.At this stage of the process, the product can be prepared in one of two ways. First, the t-butyl ester was removed in an acidic medium, preferably trifluoroacetic acid, and the resulting acid was then coupled with an appropriately substituted amine in the presence of a coupling agent as described in Example 3 to prepare a new amide product. . This allyl ester was removed using phenylsilane and tetrakis (triphenyl-phosphine) palladium or other Pd (0) catalyst to give a carboxylic acid, the acid being methylbromo as described in Example 5. After conversion to ketone, conversion to acyloxymethylketone. The penultimate intermediate was subjected to catalytic hydrogenation to remove the benzyl ester to afford the final amide product as shown in Scheme 10.

이와 다르게 최종 생성물을 제조하는 제2 경로에서는, 알릴 에스테르를 페닐실란 및 테트라키스테트라키스(트리페닐포스핀)팔라듐 또는 다른 Pd(0) 촉매를 사용하여 제거하여 카르복실산을 얻는다. 이 산을 실시예 5에 기재된 바와 같이 메틸브로모케톤으로 전환시킨 후 아실옥시메틸케톤으로 전환시킨다. 아실옥시메틸케톤의 t-부틸 에스테르를 트리플루오로아시드산을 사용하여 제거한 후 생성된 카르복실산을 에스테르로 전환하여 새로운 에스테르 생성물을 얻었다. 에스테르화는 커플링제의 존재하에 적절히 치환된 알코올로 카르복실산을 처리하는 것을 비롯한 (이것으로 제한되지 않음) 각종 문헌에 소개된 기술을 통해 수행할 수 있다. 페눌티메이트 중간체를 촉매적 수소첨가 반응을 시켜서 벤질 에스테르를 제거하고 반응식 10에 나타낸 바와 같은 최종 에스테르 생성물을 얻었다.Alternatively, in the second route of preparing the final product, the allyl ester is removed using phenylsilane and tetraquistetrakis (triphenylphosphine) palladium or other Pd (0) catalysts to obtain carboxylic acids. This acid is converted to methylbromoketone and then to acyloxymethylketone as described in Example 5. The t-butyl ester of acyloxymethylketone was removed using trifluoroacidic acid and then the resulting carboxylic acid was converted to an ester to give a new ester product. The esterification can be carried out via techniques introduced in various documents, including but not limited to treating carboxylic acids with alcohols which are suitably substituted in the presence of a coupling agent. The penultimate intermediate was subjected to catalytic hydrogenation to remove the benzyl ester and to give the final ester product as shown in Scheme 10.

적절히 치환된 S-아세틸 메르캅토 카르복실산을 벤질 브로마이드 및 1,8-디아조비시클로[5.4.0]운데크-7-엔 (DBU)로 처리하여 벤질 에스테를 제조하고, 이어서 이를 염소 기체와 반응시켜 술포닐 클로라이드를 얻었다. 술포닐 클로라이드를 N,N-비스(p-메톡시벤질)아민으로 처리하여 술폰아미드를 얻고, 이를 촉매적 수소첨가하고 중간체 카르복실산을 얻었다. 이 산을 불화시아누르산을 사용하여 활성화시킨 후 H-Asp(Ot-Bu)OMe의 아민염과 혼합하여 아미드 생성물을 얻었다. 이 메틸 에스테르를 수산화나트륨으로 가수분해하고, 카르복실산을 실시예 5에 기재된 화학적 방법으로 아실옥시메틸케톤으로 전환시켰다. 술폰아미드의 p-메톡시벤질 보호기를 질산세륨암모늄으로 제한되지 않지만 바람직하게는 이와 같은 산화 조건을 사용하여 제거했으며, t-부틸 에스테르 보호기는 산성 매질, 바람직하게는 트리플루오로아세트산으로 제거하여 반응식 11에 나타낸 바와 같은 원하는 술폰아미드 생성물을 얻었다.Properly substituted S-acetyl mercapto carboxylic acid is treated with benzyl bromide and 1,8-diazobicyclo [5.4.0] undec-7-ene (DBU) to produce benzyl esters, which are then combined with chlorine gas. Reaction gave sulfonyl chloride. Sulfonyl chloride was treated with N, N-bis (p-methoxybenzyl) amine to give sulfonamide, which was catalytically hydrogenated to give an intermediate carboxylic acid. This acid was activated with cyanuric acid fluoride and then mixed with the amine salt of H-Asp (Ot-Bu) OMe to give the amide product. This methyl ester was hydrolyzed with sodium hydroxide and the carboxylic acid was converted to acyloxymethylketone by the chemical method described in Example 5. The p-methoxybenzyl protecting group of sulfonamide is not limited to cerium ammonium nitrate but is preferably removed using such oxidation conditions, and the t-butyl ester protecting group is removed by acidic medium, preferably trifluoroacetic acid. The desired sulfonamide product was obtained as shown in 11.

<실시예 1><Example 1>

3-벤질옥시카르보닐아미노-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3-benzyloxycarbonylamino-5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

단계 AStep A

디메틸포름아미드 (DMF) 10 ml 중의 Z-Asp(OtBu)-브로모메틸케톤 (Z는 카르보벤족시이며 cbz로도 알려져 있고, Asp는 아스파르트산이고, tBu는 tert-부틸임) (BACHEM Bioscience Inc.에서 구입하거나 문헌 (Dolle R.E. et al., J. Med. Chem., 1994; 37:563-564)에 따라 제조함) (2.03 g, 5.07 mmol), 1-나프틸아세트산 (1.00 g, 5.37 mmol), 불화칼륨 (0.74 g, 12.74 mmol)의 혼합물을 12 시간 동안 실온에서 교반시켰다. 이 혼합물을 에틸 아세테이트 및 NaHCO3포화용액 사이에 분배했다. 에틸 아세테이트 추출물을 KH2PO4포화용액 및 염수로 세척하고, 건조 (MgSO4)하고 여과 및 농축했다. 오일 조생성물을 중간 압력 크로마토그래피 (실리카 겔, 75 % 헥산-25 % 에틸 아세테이트) 처리하여 3-벤질옥시카르보닐아미노-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르를 무색 오일로서 얻었다.Z-Asp (OtBu) -bromomethylketone in 10 ml of dimethylformamide (DMF) (Z is carbobenzox and also known as cbz, Asp is aspartic acid and tBu is tert-butyl) (BACHEM Bioscience Inc Purchased from Dolle RE et al., J. Med. Chem., 1994; 37: 563-564) (2.03 g, 5.07 mmol), 1-naphthylacetic acid (1.00 g, 5.37 mmol), potassium fluoride (0.74 g, 12.74 mmol) was stirred at room temperature for 12 hours. This mixture was partitioned between ethyl acetate and saturated NaHCO 3 solution. The ethyl acetate extract was washed with saturated KH 2 PO 4 solution and brine, dried (MgSO 4 ), filtered and concentrated. The crude oil product was subjected to medium pressure chromatography (silica gel, 75% hexane-25% ethyl acetate) to 3-benzyloxycarbonylamino-5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid tert-butyl ester was obtained as a colorless oil.

단계 BStep B

디클로로메탄 20 ml 중의 3-벤질옥시카르보닐아미노-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르 (실시예 1의 단계 A, 0.500 g, 0.989 mmol) 및 트리플루오로아세트산 (10 ml, 0.13 몰) 용액을 2 시간 동안 실온에서 교반시켰다. 이 용액을 농축하여 표제 화합물을 발포성 백색 고체로 얻었다.3-benzyloxycarbonylamino-5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid tert-butyl ester in 20 ml of dichloromethane (step A of Example 1, 0.500 g, 0.989 mmol) And trifluoroacetic acid (10 ml, 0.13 mol) solution was stirred for 2 hours at room temperature. This solution was concentrated to give the title compound as an effervescent white solid.

C25H23NO7·0.70H2O(462.075)에 대한 분석:Analysis for C 25 H 23 NO 7 · 0.70H 2 O (462.075):

이론치 : C, 64.98; H, 5.32; N, 3.03Theoretical: C, 64.98; H, 5. 32; N, 3.03

실측치 : C, 64.94; H, 5.01; N, 3.01.Found: C, 64.94; H, 5.01; N, 3.01.

실시예 1과 유사한 방법으로 상응하는 아래 화합물들을 제조했다.In the same manner as in Example 1, the following compounds were prepared.

<실시예 1a><Example 1a>

3-벤질옥시카르보닐아미노-4-옥소-5-(3-페닐-프로피오닐옥시)-펜탄산 (백색 고체)3-benzyloxycarbonylamino-4-oxo-5- (3-phenyl-propionyloxy) -pentanoic acid (white solid)

C22H23NO7·0.25H2O(417.935)에 대한 분석:Analysis for C 22 H 23 NO 7 · 0.25H 2 O (417.935):

이론치 : C, 63.23; H, 5.67, N, 3.35Theoretical: C, 63.23; H, 5.67, N, 3.35

실측치 : C, 63.19; H, 5.55; N, 3.27.Found: C, 63.19; H, 5.55; N, 3.27.

<실시예 1b><Example 1b>

3-벤질옥시카르보닐아미노-5-(3-시클로헥실-프로피오닐옥시)-4-옥소-펜탄산 (백색 발포성 고체)3-benzyloxycarbonylamino-5- (3-cyclohexyl-propionyloxy) -4-oxo-pentanoic acid (white effervescent solid)

C22H29NO7·0.67H2O(431.489)에 대한 분석:Analysis for C 22 H 29 NO 7 · 0.67H 2 O (431.489):

이론치 : C, 61.24; H, 7.09; N, 3.25Theoretical: C, 61.24; H, 7.09; N, 3.25

실측치 : C, 61.25; H, 6.85; N, 3.21.Found: C, 61.25; H, 6. 85; N, 3.21.

<실시예 1c><Example 1c>

3-벤질옥시카르보닐아미노-5-[(나프탈렌-1-일-옥시)-아세톡시]-4-옥소-펜탄산 (백색 발포성 고체)3-benzyloxycarbonylamino-5-[(naphthalen-1-yl-oxy) -acetoxy] -4-oxo-pentanoic acid (white foamable solid)

C25H23NO8·0.40H2O(472.670)에 대한 분석:Analysis for C 25 H 23 NO 8 · 0.40H 2 O (472.670):

이론치 : C, 63.53; H, 5.08; N, 2.96Theoretic value: C, 63.53; H, 5.08; N, 2.96

실측치 : C, 63.55; H, 4.87; N, 2.77.Found: C, 63.55; H, 4.87; N, 2.77.

<실시예 1d>Example 1d

3-벤질옥시카르보닐아미노-4-옥소-5-페녹시아세톡시-펜탄산 (발포성 백색 고체)3-benzyloxycarbonylamino-4-oxo-5-phenoxycetoxy-pentanoic acid (foamable white solid)

C21H21NO8·0.67H2O(427.414)에 대한 분석:Analysis for C 21 H 21 NO 8 · 0.67H 2 O (427.414):

이론치 : C, 59.01; H, 5.27; N, 3.28Theoretical: C, 59.01; H, 5. 27; N, 3.28

실측치 : C, 58.99; H, 4.91; N, 3.15.Found: C, 58.99; H, 4.91; N, 3.15.

<실시예 1e><Example 1e>

3-벤질옥시카르보닐아미노-4-옥소-5-페닐술파닐아세톡시-펜탄산 (백색 고체)3-benzyloxycarbonylamino-4-oxo-5-phenylsulfanylacetoxy-pentanoic acid (white solid)

C21H21NO7S(431.468)에 대한 분석:Analysis for C 21 H 21 NO 7 S (431.468):

이론치 : C, 58.46; H, 4.91; N, 3.25Theoretic value: C, 58.46; H, 4.91; N, 3.25

실측치 : C, 58.08; H, 4.83; N, 3.14.Found: C, 58.08; H, 4.83; N, 3.14.

<실시예 1f><Example 1f>

3-벤질옥시카르보닐아미노-5-[(6-메톡시-나프탈렌-1-일)-아세톡시]-4-옥소-펜탄산 (회백색 고체)3-Benzyloxycarbonylamino-5-[(6-methoxy-naphthalen-1-yl) -acetoxy] -4-oxo-pentanoic acid (grey-white solid)

C26H25NO8·H2O(497.506)에 대한 분석:Analysis for C 26 H 25 NO 8 · H 2 O (497.506):

이론치 : C, 62.77; H, 5.47; N, 2.82Theoretic value: C, 62.77; H, 5.47; N, 2.82

실측치 : C, 62.73; H, 5.24; N, 2.61.Found: C, 62.73; H, 5. 24; N, 2.61.

<실시예 1g><Example 1g>

3-벤질옥시카르보닐아미노-5-(나프탈렌-2-일-아세톡시)-4-옥소-펜탄산 (회백색 고체)3-benzyloxycarbonylamino-5- (naphthalen-2-yl-acetoxy) -4-oxo-pentanoic acid (grey-white solid)

C25H23NO7·0.80H2O(463.877)에 대한 분석:Analysis for C 25 H 23 NO 7 · 0.80H 2 O (463.877):

이론치 : C, 64.73; H, 5.34; N, 3.02Theoretical: C, 64.73; H, 5. 34; N, 3.02

실측치 : C, 64.64; H, 4.94; N, 2.88.Found: C, 64.64; H, 4.94; N, 2.88.

<실시예 1h><Example 1h>

3-벤질옥시카르보닐아미노-5-(3-나프탈렌-2-일-프로피오닐옥시)-4-옥소-펜탄산 (백색 고체)3-benzyloxycarbonylamino-5- (3-naphthalen-2-yl-propionyloxy) -4-oxo-pentanoic acid (white solid)

C26H25NO7(463.492)에 대한 분석:Analysis for C 26 H 25 NO 7 (463.492):

이론치 : C, 67.38; H, 5.44; N, 3.02Theoretic value: C, 67.38; H, 5. 44; N, 3.02

실측치 : C, 64.39; H, 5.10; N, 2.76.Found: C, 64.39; H, 5. 10; N, 2.76.

<실시예 1i><Example 1i>

3-벤질옥시카르보닐아미노-5-(3,3-디페닐-프로피오닐옥시)-4-옥소-펜탄산 (발포성 황갈색 고체)3-benzyloxycarbonylamino-5- (3,3-diphenyl-propionyloxy) -4-oxo-pentanoic acid (foamable tan solid)

C28H27NO7(489.530)에 대한 분석:Analysis for C 28 H 27 NO 7 (489.530):

이론치 : C, 68.70; H, 5.56; N, 2.86Theoretic value: C, 68.70; H, 5.56; N, 2.86

실측치 : C, 66.68; H, 5.72; N, 3.07.Found: C, 66.68; H, 5.72; N, 3.07.

<실시예 1j><Example 1j>

3-벤질옥시카르보닐아미노-5-[(1H-인돌-3-일)-아세톡시]-4-옥소-펜탄산 (회백색 고체)3-benzyloxycarbonylamino-5-[(1H-indol-3-yl) -acetoxy] -4-oxo-pentanoic acid (grey-white solid)

C23H22N2O7·0.90H2O(454.655)에 대한 분석:Analysis for C 23 H 22 N 2 O 7 · 0.90H 2 O (454.655):

이론치 : C, 60.76; H, 5.28; N, 6.16Theoretical: C, 60.76; H, 5. 28; N, 6.16

실측치 : C, 60.76; H, 4.88; N, 5.65.Found: C, 60.76; H, 4.88; N, 5.65.

<실시예 1k><Example 1k>

3-벤질옥시카르보닐아미노-5-(인돌-1-일-아세톡시)-4-옥소-펜탄산 (담자주색 고체)3-benzyloxycarbonylamino-5- (indol-1-yl-acetoxy) -4-oxo-pentanoic acid (pale purple solid)

C23H22N2O7·0.75H2O(451.952)에 대한 분석:Analysis of C 23 H 22 N 2 O 7 0.75H 2 O (451.952):

이론치 : C, 61.12; H, 5.24; N, 6.20Theoretical: C, 61.12; H, 5. 24; N, 6.20

실측치 : C, 61.20; H, 5.11; N, 5.90.Found: C, 61.20; H, 5.11; N, 5.90.

<실시예 1l><Example 1l>

3-벤질옥시카르보닐아미노-5-(2-나프탈렌-1-일-프로피오닐옥시)-4-옥소-펜탄산 (백색 고체)3-benzyloxycarbonylamino-5- (2-naphthalen-1-yl-propionyloxy) -4-oxo-pentanoic acid (white solid)

C26H25NO7·0.20H2O(467.095)에 대한 분석:Analysis for C 26 H 25 NO 7 0.20 H 2 O (467.095):

이론치 : C, 66.86; H, 5.48; N, 3.00Theoretic value: C, 66.86; H, 5. 48; N, 3.00

실측치 : C, 66.87; H, 5.61; N, 2.71.Found: C, 66.87; H, 5.61; N, 2.71.

<실시예 1m><Example 1m>

3-벤질옥시카르보닐아미노-4-옥소-5-[(2-옥소-피롤리딘-1-일)-아세톡시]-펜탄산 (백색 고체)3-benzyloxycarbonylamino-4-oxo-5-[(2-oxo-pyrrolidin-1-yl) -acetoxy] -pentanoic acid (white solid)

C19H22N2O8·0.50H2O(415.403)에 대한 분석: C 19 H 22 N 2 O 8 · 0.50H 2 O analysis for (415.403):

이론치 : C, 54.94; H, 5.58; N, 6.74Theoretical: C, 54.94; H, 5.58; N, 6.74

실측치 : C, 55.18; H, 5.72; N, 6.36.Found: C, 55.18; H, 5.72; N, 6.36.

<실시예 1n><Example 1n>

5-[(아세틸-페닐-아미노)-아세톡시]-3-벤질옥시카르보닐-아미노-4-옥소-펜탄산 (회백색 고체)5-[(acetyl-phenyl-amino) -acetoxy] -3-benzyloxycarbonyl-amino-4-oxo-pentanoic acid (grey-white solid)

C23H24N2O8·0.70NaHCO3(515.264)에 대한 분석:Analysis of C 23 H 24 N 2 O 8 .0.70 NaHCO 3 (515.264):

이론치 : C, 55.25; H, 4.83; N, 5.44Theoretical: C, 55.25; H, 4.83; N, 5.44

실측치 : C, 55.03; H, 4.86; N, 5.41.Found: C, 55.03; H, 4.86; N, 5.41.

<실시예 1o><Example 1o>

3-벤질옥시카르보닐아미노-5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-펜탄산, 칼륨염 (흡습성 백색 고체)3-benzyloxycarbonylamino-5- (2-benzyl-3-phenyl-propionyloxy) -4-oxo-pentanoic acid, potassium salt (hygroscopic white solid)

C29H28NO7·K·0.90H2O(557.865)에 대한 분석:Analysis for C 29 H 28 NO 7 · K · 0.90H 2 O (557.865):

이론치 : C, 62.44; H, 5.38; N, 2.51Theoretical: C, 62.44; H, 5. 38; N, 2.51

실측치 : C, 62.40; H, 5.19; N, 2.17.Found: C, 62.40; H, 5. 19; N, 2.17.

<실시예 1p><Example 1p>

3-벤질옥시카르보닐아미노-5-(히드록시-나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 (백색 고체)3-benzyloxycarbonylamino-5- (hydroxy-naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid (white solid)

C25H23NO8·0.30H2O(470.869)에 대한 분석:Analysis for C 25 H 23 NO 8 · 0.30H 2 O (470.869):

이론치 : C, 63.77; H, 5.05; N, 2.98Theoretic value: C, 63.77; H, 5.05; N, 2.98

실측치 : C, 63.73; H, 4.87; N, 2.93.Found: C, 63.73; H, 4.87; N, 2.93.

<실시예 1q><Example 1q>

3-벤질옥시카르보닐아미노-4-옥소-5-[(페닐-아미노)-아세톡시]-펜탄산 트리플루오로아세트산 염 (갈색 고체)3-benzyloxycarbonylamino-4-oxo-5-[(phenyl-amino) -acetoxy] -pentanoic acid trifluoroacetic acid salt (brown solid)

C21H22N2O7·0.50CF3CO2H(471.431)에 대한 분석:Analysis of C 21 H 22 N 2 O 7 0.50CF 3 CO 2 H (471.431):

이론치 : C, 56.05; H, 4.81; N, 5.94Theoretic value: C, 56.05; H, 4.81; N, 5.94

실측치 : C, 55.72; H, 4.98; N, 5.78.Found: C, 55.72; H, 4.98; N, 5.78.

<실시예 1r><Example 1r>

3-벤질옥시카르보닐아미노-5-[(6-히드록시-나프탈렌-1-일)-아세톡시]-4-옥소-펜탄산 (백색 고체)3-benzyloxycarbonylamino-5-[(6-hydroxy-naphthalen-1-yl) -acetoxy] -4-oxo-pentanoic acid (white solid)

C25H23NO8·0.40H2O(472.670)에 대한 분석:Analysis for C 25 H 23 NO 8 · 0.40H 2 O (472.670):

이론치 : C, 63.53; H, 5.08; N, 2.96Theoretic value: C, 63.53; H, 5.08; N, 2.96

실측치 : C, 63.53; H, 5.25; N, 2.83.Found: C, 63.53; H, 5. 25; N, 2.83.

<실시예 1s><Example 1s>

3-벤질옥시카르보닐아미노-5-[3-(4-히드록시-페닐)-2-나프탈렌-1-일-프로피오닐옥시)-4-옥소-펜탄산 (백색 고체)3-benzyloxycarbonylamino-5- [3- (4-hydroxy-phenyl) -2-naphthalen-1-yl-propionyloxy) -4-oxo-pentanoic acid (white solid)

C32H29NO8·0.5H2O(564.598)에 대한 분석:Analysis for C 32 H 29 NO 8 · 0.5H 2 O (564.598):

이론치 : C, 68.08; H, 5.36; N, 2.48Theoretic value: C, 68.08; H, 5. 36; N, 2.48

실측치 : C, 67.98; H, 5.40; N, 2.34.Found: C, 67.98; H, 5.40; N, 2.34.

<실시예 1t><Example 1t>

(S)-3-벤질옥시카르보닐아미노-4-옥소-5-페닐아세톡시-펜탄산(S) -3-benzyloxycarbonylamino-4-oxo-5-phenylacetoxy-pentanoic acid

1H NMR(400 MHz, d6DMSO) 7.31(m, 10H), 5.05(s, 2H), 4.92(m, 2H), 4.45(m, 1H), 3.75(s, 2H), 2.71(dd, 1H), 2.52(dd, 1H) 1 H NMR (400 MHz, d 6 DMSO) 7.31 (m, 10H), 5.05 (s, 2H), 4.92 (m, 2H), 4.45 (m, 1H), 3.75 (s, 2H), 2.71 (dd, 1H), 2.52 (dd, 1H)

<실시예 1u><Example 1u>

(S)-3-벤질옥시카르보닐아미노-4-옥소-5-(4-페닐-부티릴옥시)-펜탄산(S) -3-benzyloxycarbonylamino-4-oxo-5- (4-phenyl-butyryloxy) -pentanoic acid

1H NMR(400 MHz, d6DMSO) 7.86(bs, 1H), 7.27(m, 10H), 5.05(s, 2H), 4.91(m, 2H), 4.46(m, 1H), 2.72(dd, 1H), 2.61(t, 2H), 2.52(dd, 1H), 2.36(t, 2H), 1.83(m, 2H). 1 H NMR (400 MHz, d 6 DMSO) 7.86 (bs, 1H), 7.27 (m, 10H), 5.05 (s, 2H), 4.91 (m, 2H), 4.46 (m, 1H), 2.72 (dd, 1H), 2.61 (t, 2H), 2.52 (dd, 1H), 2.36 (t, 2H), 1.83 (m, 2H).

<실시예 1v><Example 1v>

3-벤질옥시카르보닐아미노-4-옥소-5-[(4-페닐-나프탈렌-1-일)-아세톡시]-펜탄산 (백색 고체, 융점 111-119 ℃ (분해))3-benzyloxycarbonylamino-4-oxo-5-[(4-phenyl-naphthalen-1-yl) -acetoxy] -pentanoic acid (white solid, melting point 111-119 ° C. (decomposition))

C31H27NO7(525.563)에 대한 분석:Analysis for C 31 H 27 NO 7 (525.563):

이론치 : C, 70.85; H, 5.18; N, 2.67Theoretical: C, 70.85; H, 5. 18; N, 2.67

실측치 : C, 70.60; H, 5.11; N, 2.64.Found: C, 70.60; H, 5.11; N, 2.64.

<실시예 1w><Example 1w>

3-벤질옥시카르보닐아미노-5-[(4-메틸-나프탈렌-1-일)-아세톡시]-4-옥소-펜탄산 (백색 고체, 융점 94-100 ℃ (분해))3-benzyloxycarbonylamino-5-[(4-methyl-naphthalen-1-yl) -acetoxy] -4-oxo-pentanoic acid (white solid, melting point 94-100 ° C. (decomposition))

C26H25NO7·0.15H2O(466.194)에 대한 분석:Analysis of C 26 H 25 NO 7 0.15H 2 O (466.194):

이론치 : C, 66.99; H, 5.47; N, 3.00Theoretical: C, 66.99; H, 5.47; N, 3.00

실측치 : C, 66.95; H, 5.32; N, 2.94.Found: C, 66.95; H, 5. 32; N, 2.94.

<실시예 1x><Example 1x>

3-벤질옥시카르보닐아미노-4-옥소-5-[(4-티오펜-2-일-나프탈렌-1-일)-아세톡시]-펜탄산 (회백색 고체, 융점 63-68 ℃ (분해))3-Benzyloxycarbonylamino-4-oxo-5-[(4-thiophen-2-yl-naphthalen-1-yl) -acetoxy] -pentanoic acid (grey-white solid, melting point 63-68 ° C. (decomposition) )

C29H25NO7S(531.589)에 대한 분석:Analysis for C 29 H 25 NO 7 S (531.589):

이론치 : C, 65.52; H, 4.74; N, 2.63Theoretic value: C, 65.52; H, 4. 74; N, 2.63

실측치 : C, 65.32; H, 5.08; N, 2.47.Found: C, 65.32; H, 5.08; N, 2.47.

<실시예 1y><Example 1y>

3-벤질옥시카르보닐아미노-5-[(4-플루오로-나프탈렌-1-일)-아세톡시]-4-옥소-펜탄산 (백색 고체, 융점 100-103 ℃ (분해))3-benzyloxycarbonylamino-5-[(4-fluoro-naphthalen-1-yl) -acetoxy] -4-oxo-pentanoic acid (white solid, melting point 100-103 ° C. (decomposition))

C25H22FNO7(467.455)에 대한 분석:Analysis for C 25 H 22 FNO 7 (467.455):

이론치 : C, 64.24; H, 4.74; N, 3.00Theoretical: C, 64.24; H, 4. 74; N, 3.00

실측치 : C, 63.98; H, 4.52; N, 2.89.Found: C, 63.98; H, 4.52; N, 2.89.

<실시예 1z><Example 1z>

3-벤질옥시카르보닐아미노-5-[(2-메틸-나프탈렌-1-일)-아세톡시]-4-옥소-펜탄산 (백색 고체, 융점 139-144 ℃)3-Benzyloxycarbonylamino-5-[(2-methyl-naphthalen-1-yl) -acetoxy] -4-oxo-pentanoic acid (white solid, melting point 139-144 ° C.)

C26H25NO7(463.492)에 대한 분석:Analysis for C 26 H 25 NO 7 (463.492):

이론치 : C, 67.38; H, 5.44; N, 3.02Theoretic value: C, 67.38; H, 5. 44; N, 3.02

실측치 : C, 67.09; H, 5.44; N, 2.84.Found: C, 67.09; H, 5. 44; N, 2.84.

<실시예 1aa>Example 1aa

3-벤질옥시카르보닐아미노-5-[(2-플루오로-나프탈렌-1-일)-아세톡시]-4-옥소-펜탄산 (백색 고체, 융점 98-102 ℃)3-benzyloxycarbonylamino-5-[(2-fluoro-naphthalen-1-yl) -acetoxy] -4-oxo-pentanoic acid (white solid, melting point 98-102 ° C.)

C25H22FNO7(467.455)에 대한 분석:Analysis for C 25 H 22 FNO 7 (467.455):

이론치 : C, 64.24; H, 4.74; N, 3.00Theoretical: C, 64.24; H, 4. 74; N, 3.00

실측치 : C, 63.57; H, 4.47; N, 2.85.Found: C, 63.57; H, 4. 47; N, 2.85.

<실시예 1bb><Example 1bb>

5-(벤조푸란-4-일-아세톡시)-3-벤질옥시카르보닐아미노-4-옥소-펜탄산 (담황색 오일)5- (Benzofuran-4-yl-acetoxy) -3-benzyloxycarbonylamino-4-oxo-pentanoic acid (pale yellow oil)

C23H21NO8·0.65H2O(451.136)에 대한 분석:Analysis for C 23 H 21 NO 8 · 0.65H 2 O (451.136):

이론치 : C, 61.24; H, 4.98; N, 3.10Theoretical: C, 61.24; H, 4.98; N, 3.10

실측치 : C, 61.22; H, 4.80; N, 2.98.Found: C, 61.22; H, 4.80; N, 2.98.

<실시예 1cc><Example 1cc>

5-(벤조[b]티오펜-7-일-아세톡시)-3-벤질옥시카르보닐아미노-4-옥소-펜탄산 (담황색 오일)5- (Benzo [b] thiophen-7-yl-acetoxy) -3-benzyloxycarbonylamino-4-oxo-pentanoic acid (pale yellow oil)

C23H21NO7S·1.5H2O(482.513)에 대한 분석:Analysis of C 23 H 21 NO 7 S1.5H 2 O (482.513):

이론치 : C, 57.25; H, 5.01; N, 2.90Theoretic value: C, 57.25; H, 5.01; N, 2.90

실측치 : C, 57.35; H, 4.82; N, 2.76.Found: C, 57.35; H, 4. 82; N, 2.76.

<실시예 1dd><Example 1dd>

5-(벤조[b]티오펜-4-일-아세톡시)-3-벤질옥시카르보닐아미노-4-옥소-펜탄산 (발포성 회백색 고체)5- (Benzo [b] thiophen-4-yl-acetoxy) -3-benzyloxycarbonylamino-4-oxo-pentanoic acid (foamable off-white solid)

C23H21NO7S(455.490)에 대한 분석:Analysis of C 23 H 21 NO 7 S (455.490):

이론치 : C, 60.65; H, 4.65; N, 3.08Theoretical: C, 60.65; H, 4.65; N, 3.08

실측치 : C, 60.90; H, 4.90; N, 2.92.Found: C, 60.90; H, 4. 90; N, 2.92.

<실시예 1ee><Example 1ee>

5-[(4-벤질-나프탈렌-1-일)-아세톡시]-3-벤질옥시카르보닐아미노-4-옥소-펜탄산 (백색 고체, 융점 66-77 ℃ (분해))5-[(4-benzyl-naphthalen-1-yl) -acetoxy] -3-benzyloxycarbonylamino-4-oxo-pentanoic acid (white solid, melting point 66-77 ° C. (decomposition))

C32H29NO7·0.30H2O(544.995)에 대한 분석:Analysis for C 32 H 29 NO 7 0.30H 2 O (544.995):

이론치 : C, 70.52; H, 5.48; N, 2.57Theoretic value: C, 70.52; H, 5. 48; N, 2.57

실측치 : C, 70.55; H, 5.35; N, 2.49.Found: C, 70.55; H, 5. 35; N, 2.49.

<실시예 1ff><Example 1ff>

3-벤질옥시카르보닐아미노-5-[(3,4-디히드로-나프탈렌-1-일)-아세톡시]-4-옥소-펜탄산 (발포성 담황색 고체)3-benzyloxycarbonylamino-5-[(3,4-dihydro-naphthalen-1-yl) -acetoxy] -4-oxo-pentanoic acid (foamable pale yellow solid)

C25H25NO7·0.20H2O(455.084)에 대한 분석:Analysis for C 25 H 25 NO 7 0.20 H 2 O (455.084):

이론치 : C, 65.98; H, 5.63; N, 3.08Theoretic value: C, 65.98; H, 5.63; N, 3.08

실측치 : C, 66.06; H, 5.74; N, 3.04.Found: C, 66.06; H, 5. 74; N, 3.04.

<실시예 1gg><Example 1gg>

3-벤질옥시카르보닐아미노-5-[(5-브로모-1H-인돌-3-일)-아세톡시]-4-옥소-펜탄산 (황갈색 고체, 융점 122-129 ℃ (분해))3-benzyloxycarbonylamino-5-[(5-bromo-1H-indol-3-yl) -acetoxy] -4-oxo-pentanoic acid (tan solid, melting point 122-129 ° C. (decomposition))

C23H21BrN2O7(517.342)에 대한 분석:Anal for C 23 H 21 BrN 2 O 7 (517.342):

이론치 : C, 53.40; H, 4.09; N, 5.41Theoretical: C, 53.40; H, 4.09; N, 5.41

실측치 : C, 53.77; H, 3.94; N, 5.25.Found: C, 53.77; H, 3.94; N, 5.25.

<실시예 1hh><Example 1hh>

3-벤질옥시카르보닐아미노-5-(3,4-디페닐-부티릴옥시)-4-옥소-펜탄산 (흡습성 백색 고체)3-benzyloxycarbonylamino-5- (3,4-diphenyl-butyryloxy) -4-oxo-pentanoic acid (hygroscopic white solid)

C29H29NO7·0.30H2O(508.962)에 대한 분석:Analysis of C 29 H 29 NO 7 0.30H 2 O (508.962):

이론치 : C, 68.44; H, 5.86; N, 2.75Theoretic value: C, 68.44; H, 5. 86; N, 2.75

실측치 : C, 68.41; H, 5.92; N, 2.56.Found: C, 68.41; H, 5.92; N, 2.56.

<실시예 1ii>Example 1ii

3-벤질옥시카르보닐아미노-4-옥소-5-(3-페닐-3-페닐아미노-프로피오닐옥시)-펜탄산 (흡습성 담녹색 고체)3-benzyloxycarbonylamino-4-oxo-5- (3-phenyl-3-phenylamino-propionyloxy) -pentanoic acid (hygroscopic pale green solid)

C28H28N2O7·0.50H2O(513.552)에 대한 분석:Analysis for C 28 H 28 N 2 O 7 · 0.50H 2 O (513.552):

이론치 : C, 65.49; H, 5.69; N, 5.46Theoretical: C, 65.49; H, 5.69; N, 5.46

실측치 : C, 65.58; H, 5.62; N, 5.19.Found: C, 65.58; H, 5.62; N, 5.19.

<실시예 1jj><Example 1jj>

3-벤질옥시카르보닐아미노-4-옥소-5-[(1,2,3,4-테트라히드로나프탈렌-2-일)-아세톡시]-펜탄산 (백색 고체, 융점 75-83 ℃ (분해))3-benzyloxycarbonylamino-4-oxo-5-[(1,2,3,4-tetrahydronaphthalen-2-yl) -acetoxy] -pentanoic acid (white solid, melting point 75-83 ° C. (decomposition) ))

C25H27NO7(453.496)에 대한 분석:Analysis for C 25 H 27 NO 7 (453.496):

이론치 : C, 66.21; H, 6.00; N, 3.09Theoretical: C, 66.21; H, 6.00; N, 3.09

실측치 : C, 66.02; H, 5.89; N, 2.96.Found: C, 66.02; H, 5.89; N, 2.96.

<실시예 1kk><Example 1kk>

3-벤질옥시카르보닐아미노-5-[(1-메탄술포닐-피페리딘-4-일)-아세톡시]-4-옥소-펜탄산 (황색 무정질 고체)3-benzyloxycarbonylamino-5-[(1-methanesulfonyl-piperidin-4-yl) -acetoxy] -4-oxo-pentanoic acid (yellow amorphous solid)

C21H28N2O9S·0.25 EtOAc(506.556)에 대한 분석:Anal for C 21 H 28 N 2 O 9 S.0.25 EtOAc (506.556):

이론치 : C, 52.16; H, 5.97; N, 5.53Theoretical: C, 52.16; H, 5.97; N, 5.53

실측치 : C, 51.96; H, 6.09; N, 5.22.Found: C, 51.96; H, 6.09; N, 5.22.

<실시예 1ll><Example 1ll>

3-벤질옥시카르보닐아미노-4-옥소-5-[(2,3,5,6-테트라메틸-페닐)-아세톡시]-펜탄산 (융점 139-145 ℃)3-Benzyloxycarbonylamino-4-oxo-5-[(2,3,5,6-tetramethyl-phenyl) -acetoxy] -pentanoic acid (melting point 139-145 ° C.)

C25H29NO7에 대한 분석:Analysis of C 25 H 29 NO 7 :

이론치 : C, 65.92; H, 6.42; N, 3.07Theoretic value: C, 65.92; H, 6. 42; N, 3.07

실측치 : C, 65.66; H, 6.30; N, 2.97.Found: C, 65.66; H, 6. 30; N, 2.97.

<실시예 1mm><Example 1mm>

5-(벤조티아졸-4-일-아세톡시)-3-벤질옥시카르보닐아미노-4-옥소-펜탄산 (백색 고체)5- (Benzothiazol-4-yl-acetoxy) -3-benzyloxycarbonylamino-4-oxo-pentanoic acid (white solid)

C22H20N2O7S·0.15CF3CO2H(473.582)에 대한 분석:Analysis of C 22 H 20 N 2 O 7 S0.15CF 3 CO 2 H (473.582):

이론치 : C, 56.56; H, 4.29; N, 5.92Theoretic value: C, 56.56; H, 4. 29; N, 5.92

실측치 : C, 56.52; H, 4.09; N, 6.02.Found: C, 56.52; H, 4.09; N, 6.02.

<실시예 1nn><Example 1nn>

5-(벤조푸란-3-일-아세톡시)-3-벤질옥시카르보닐아미노-4-옥소-펜탄산 (발포성 백색 고체)5- (Benzofuran-3-yl-acetoxy) -3-benzyloxycarbonylamino-4-oxo-pentanoic acid (foamable white solid)

C23H21NO8·0.14CF3CO2H(455.389)에 대한 분석:Analysis of C 23 H 21 NO 8 0.14 CF 3 CO 2 H (455.389):

이론치 : C, 61.40; H, 4.68; N, 3.08Theoretical: C, 61.40; H, 4.68; N, 3.08

실측치 : C, 61.49; H, 4.86; N, 3.13.Found: C, 61.49; H, 4.86; N, 3.13.

<실시예 1oo><Example 1oo>

5-(벤조[b]티오펜-3-일-아세톡시)-3-벤질옥시카르보닐아미노-4-옥소-펜탄산 (융점 110-111 ℃)5- (Benzo [b] thiophen-3-yl-acetoxy) -3-benzyloxycarbonylamino-4-oxo-pentanoic acid (melting point 110-111 ° C.)

C23H21NO7S에 대한 분석:Analysis of C 23 H 21 NO 7 S:

이론치 : C, 60.65; H, 4.65; N, 3.08; S, 7.04Theoretical: C, 60.65; H, 4.65; N, 3.08; S, 7.04

실측치 : C, 60.45; H, 4.67; N, 3.02; S, 7.07.Found: C, 60.45; H, 4.67; N, 3.02; S, 7.07.

<실시예 1pp><Example 1 pp>

3-벤질옥시카르보닐아미노-4-옥소-5-(3-페닐-3-피리딘-2-일-프로피오닐옥시)-펜탄산 (무정질 백색 고체)3-benzyloxycarbonylamino-4-oxo-5- (3-phenyl-3-pyridin-2-yl-propionyloxy) -pentanoic acid (amorphous white solid)

C27H26N2O7·CF3CO2H(604.542)에 대한 분석:Anal for C 27 H 26 N 2 O 7 CF 3 CO 2 H (604.542):

이론치 : C, 57.62; H, 4.50; N, 4.63Theoretic value: C, 57.62; H, 4.50; N, 4.63

실측치 : C, 57.32; H, 4.65; N, 4.46.Found: C, 57.32; H, 4.65; N, 4.46.

<실시예 1qq><Example 1qq>

3-벤질옥시카르보닐아미노-5-[(2,3-디클로로-페닐)-아세톡시]-4-옥소-펜탄산 (백색 고체)3-benzyloxycarbonylamino-5-[(2,3-dichloro-phenyl) -acetoxy] -4-oxo-pentanoic acid (white solid)

C21H19Cl2NO7·0.18CF3CO2H(488.818)에 대한 분석:Anal for C 21 H 19 Cl 2 NO 7 0.18 CF 3 CO 2 H (488.818):

이론치 : C, 52.48; H, 3.96; N, 2.86Theoretical: C, 52.48; H, 3.96; N, 2.86

실측치 : C, 52.46; H, 4.03; N, 2.80.Found: C, 52.46; H, 4.03; N, 2.80.

<실시예 1rr><Example 1rr>

3-벤질옥시카르보닐아미노-5-[(5-메틸-나프탈렌-1-일)-아세톡시]-4-옥소-펜탄산 (회색 고체)3-benzyloxycarbonylamino-5-[(5-methyl-naphthalen-1-yl) -acetoxy] -4-oxo-pentanoic acid (grey solid)

C26H25NO7·0.20CF3CO2H(486.296)에 대한 분석:Analysis of C 26 H 25 NO 7 0.20CF 3 CO 2 H (486.296):

이론치 : C, 65.21; H, 5.22; N, 2.88Theoretical: C, 65.21; H, 5. 22; N, 2.88

실측치 : C, 65.21; H, 5.30; N, 2.88.Found: C, 65.21; H, 5. 30; N, 2.88.

<실시예 1ss><Example 1ss>

3-벤질옥시카르보닐아미노-5-[(2-요오도-페닐)-아세톡시]-4-옥소-펜탄산 (회백색 흡습성 고체)3-benzyloxycarbonylamino-5-[(2-iodo-phenyl) -acetoxy] -4-oxo-pentanoic acid (grey-white hygroscopic solid)

C21H20INO7(525.300)에 대한 분석:Analysis for C 21 H 20 INO 7 (525.300):

이론치 : C, 48.02; H, 3.84; N, 2.67.Theoretic value: C, 48.02; H, 3. 84; N, 2.67.

실측치 : C, 48.33; H, 3.88; N, 2.66.Found: C, 48.33; H, 3.88; N, 2.66.

<실시예 1tt><Example 1tt>

3-벤질옥시카르보닐아미노-4-옥소-5-(3-피리딘-3-일-프로피오닐옥시)-펜탄산, 트리플루오로아세트산염 (회백색 고체)3-benzyloxycarbonylamino-4-oxo-5- (3-pyridin-3-yl-propionyloxy) -pentanoic acid, trifluoroacetic acid salt (grey-white solid)

C21H22N2O7·CF3CO2H(528.443)에 대한 분석:Anal for C 21 H 22 N 2 O 7 CF 3 CO 2 H (528.443):

이론치 : C, 52.28; H, 4.39; N, 5.30.Theoretical: C, 52.28; H, 4. 39; N, 5.30.

실측치 : C, 52.26; H, 4.36; N, 5.19.Found: C, 52.26; H, 4. 36; N, 5.19.

<실시예 1uu><Example 1 uu>

3-벤질옥시카르보닐아미노-5-[(5-메톡시-나프탈렌-1-일)-아세톡시]-4-옥소-펜탄산 (백색 고체)3-benzyloxycarbonylamino-5-[(5-methoxy-naphthalen-1-yl) -acetoxy] -4-oxo-pentanoic acid (white solid)

C26H25NO8·0.03CF3CO2H(482.912)에 대한 분석:Analysis of C 26 H 25 NO 8 .0.03CF 3 CO 2 H (482.912):

이론치 : C, 64.82; H, 5.22; N, 2.90.Theoretic value: C, 64.82; H, 5. 22; N, 2.90.

실측치 : C, 64.86; H, 5.22; N, 2.92.Found: C, 64.86; H, 5. 22; N, 2.92.

<실시예 1vv><Example 1vv>

3-벤질옥시카르보닐아미노-5-[(8-메틸-나프탈렌-1-일)-아세톡시]-4-옥소-펜탄산 (황갈색 고체)3-Benzyloxycarbonylamino-5-[(8-methyl-naphthalen-1-yl) -acetoxy] -4-oxo-pentanoic acid (tan solid)

C26H25NO7·0.2CF3CO2H(486.297)에 대한 분석:Analysis of C 26 H 25 NO 7 0.2CF 3 CO 2 H (486.297):

이론치 : C, 65.21; H, 5.22; N, 2.88.Theoretical: C, 65.21; H, 5. 22; N, 2.88.

실측치 : C, 65.16; H, 5.38; N, 2.73.Found: C, 65.16; H, 5. 38; N, 2.73.

<실시예 1ww><Example 1ww>

3-벤질옥시카르보닐아미노-5-[(9H-플루오렌-9-일)-아세톡시]-4-옥소-펜탄산3-Benzyloxycarbonylamino-5-[(9H-fluoren-9-yl) -acetoxy] -4-oxo-pentanoic acid

MS (APCI) m/z 488.4 (M+1)MS (APCI) m / z 488.4 (M + l)

<실시예 1xx><Example 1xx>

3-벤질옥시카르보닐아미노-5-[(10,11-디히드로-5H-디벤조[a,d]시클로헵텐-5-일)-아세톡시]-4-옥소-펜탄산3-benzyloxycarbonylamino-5-[(10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) -acetoxy] -4-oxo-pentanoic acid

MS (APCI) m/z 515.8 (M+1)MS (APCI) m / z 515.8 (M + 1)

<실시예 1yy><Example 1yy>

5-옥소-1-(톨루엔-4-술포닐)-피롤리딘-2-카르복실산 3-벤질옥시카르보닐아미노-4-카르복시-2-옥소-부틸 에스테르5-oxo-1- (toluene-4-sulfonyl) -pyrrolidine-2-carboxylic acid 3-benzyloxycarbonylamino-4-carboxy-2-oxo-butyl ester

MS (APCI) m/z 547.3 (M+1)MS (APCI) m / z 547.3 (M + 1)

<실시예 1zz><Example 1zz>

5-옥소-피롤리딘-1,2-디카르복실산 1-벤질 에스테르 2-(3-벤질옥시카르보닐아미노-4-카르복시-2-옥소-부틸)에스테르5-oxo-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2- (3-benzyloxycarbonylamino-4-carboxy-2-oxo-butyl) ester

MS (APCI) m/z 527.3 (M+1)MS (APCI) m / z 527.3 (M + 1)

<실시예 1aaa><Example 1aaa>

1-벤조일-피롤리딘-2-카르복실산 3-벤질옥시카르보닐아미노-4-카르복시-2-옥소-부틸 에스테르1-benzoyl-pyrrolidine-2-carboxylic acid 3-benzyloxycarbonylamino-4-carboxy-2-oxo-butyl ester

MS (APCI) m/z 483.0 (M+1)MS (APCI) m / z 483.0 (M + 1)

<실시예 1bbb><Example 1 bbb>

피롤리딘-1,2-디카르복실산 1-벤질 에스테르 2-(3-벤질옥시카르보닐아미노-4-카르복시-2-옥소-부틸)에스테르Pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2- (3-benzyloxycarbonylamino-4-carboxy-2-oxo-butyl) ester

MS (APCI) m/z 469.1 (M-43)MS (APCI) m / z 469.1 (M-43)

<실시예 1ccc><Example 1ccc>

3-벤질옥시카르보닐아미노-5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-펜탄산3-benzyloxycarbonylamino-5- (2-benzyl-3-phenyl-propionyloxy) -4-oxo-pentanoic acid

MS (ESI) m/z 502.4 (M-H)MS (ESI) m / z 502.4 (M-H)

<실시예 1ddd><Example 1ddd>

3-벤질옥시카르보닐아미노-5-[(5-시아노-나프탈렌-1-일)-아세톡시]-4-옥소-펜탄산 (황갈색 고체)3-benzyloxycarbonylamino-5-[(5-cyano-naphthalen-1-yl) -acetoxy] -4-oxo-pentanoic acid (tan solid)

C26H22N2O7·0.07CF3CO2H(482.456)에 대한 분석:Anal for C 26 H 22 N 2 O 7 .7CF 3 CO 2 H (482.456):

이론치 : C, 65.08; H, 4.61; N, 5.81.Theoretic value: C, 65.08; H, 4.61; N, 5.81.

실측치 : C, 65.03; H, 4.79; N, 5.64.Found: C, 65.03; H, 4.79; N, 5.64.

<실시예 1eee><Example 1eee>

3-벤질옥시카르보닐아미노-4-옥소-5-(3-페닐-3-피리딘-3-일-프로피오닐옥시)-펜탄산 (오렌지색 고체)3-benzyloxycarbonylamino-4-oxo-5- (3-phenyl-3-pyridin-3-yl-propionyloxy) -pentanoic acid (orange solid)

C27H26H2O7·1.02CF3CO2H(606.822)에 대한 분석:Anal for C 27 H 26 H 2 O 7 .1.02CF 3 CO 2 H (606.822):

이론치 : C, 57.48; H, 4.49; N, 4.62.Theoretic value: C, 57.48; H, 4. 49; N, 4.62.

실측치 : C, 57.45; H, 4.69; N, 4.29.Found: C, 57.45; H, 4.69; N, 4.29.

<실시예 1fff><Example 1fff>

3-벤질옥시카르보닐아미노-4-옥소-5-(3-페닐-3-피리딘-4-일-프로피오닐옥시)-펜탄산 (황갈색 고체)3-benzyloxycarbonylamino-4-oxo-5- (3-phenyl-3-pyridin-4-yl-propionyloxy) -pentanoic acid (tan solid)

C27H26N2O7·1.23CF3CO2H(630.767)에 대한 분석:C 27 H 26 N 2 O 7 1.21.2 CF 3 CO 2 H (630.767) for analysis:

이론치 : C, 56.10; H, 4.35; N, 4.44.Theoretical: C, 56.10; H, 4. 35; N, 4.44.

실측치 : C, 56.10; H, 4.50; N, 4.25.Found: C, 56.10; H, 4.50; N, 4.25.

<실시예 1ggg><Example 1ggg>

3-벤질옥시카르보닐아미노-4-옥소-5-[(1-옥소-3,4-디히드로-1H-이소퀴놀린-2-일)-아세톡시]-펜탄산3-benzyloxycarbonylamino-4-oxo-5-[(1-oxo-3,4-dihydro-1 H-isoquinolin-2-yl) -acetoxy] -pentanoic acid

MS (ESI) m/z 469.1 (M+1). (1-옥소-3,4-디히드로-1H-이소퀴놀린-2-일)-아세트산을 문헌 (W.K. Anderson, et al., J. Med. Chem. 1988; 31: 2097)의 순서에 따라 제조했다.MS (ESI) m / z 469.1 (M + l). (1-oxo-3,4-dihydro-1H-isoquinolin-2-yl) -acetic acid was prepared according to the sequence of WK Anderson, et al., J. Med. Chem. 1988; 31: 2097. did.

<실시예 2><Example 2>

3-벤젠술포닐아미노-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3-Benzenesulfonylamino-5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

단계 AStep A

에탄올 25 ml 중의 3-벤젠술포닐아미노-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르 (1.495 g, 2.956 mmol, 실시예 1의 단계 A), 20 % Pd/C (0.50 g), 진한 염산 (1.00 ml, 12.1 mmol)의 혼합물을 2 시간 동안 실온에서 기구 압력하에서 수소첨가시켰다. 이 혼합물을 셀라이트 패드를 통과시켜 여과하고, 여액을 농축하여 3-아미노-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르 히드로클로라이드를 발포성 회백색 고체로 얻었다.3-benzenesulfonylamino-5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid tert-butyl ester in 25 ml of ethanol (1.495 g, 2.956 mmol, step A of Example 1), 20 A mixture of% Pd / C (0.50 g), concentrated hydrochloric acid (1.00 ml, 12.1 mmol) was hydrogenated under instrument pressure at room temperature for 2 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated to give 3-amino-5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid tert-butyl ester hydrochloride as an effervescent off-white solid. Got it.

단계 BStep B

질소 상태의 0 ℃에서 아세토니트릴 10 ml 중의 3-아미노-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르 히드로클로라이드 (0.239 g, 0.587 mmol, 실시예 2의 단계 A)의 용액에 벤젠술포닐 클로라이드 (0.075 ml, 0.588 mmol)를 (주사기를 통해) 적가한 후, 4-메틸모르폴린 (0.20 ml, 1.819 mmol)을 적가했다. 용액을 실온에서 밤새 서서히 가온했다. 이 용액을 농축하고 에틸 아세테이트 내로 재용해시키고, NaHCO3포화용액, KH2PO4포화용액, 염수로 세척했다. 에틸 아세테이트 추출물을 건조 (MgSO4)하고 여과하고, 농축 및 크로마토그래피 (실리카 겔, 80 % 헥산-20 % 에틸 아세테이트) 처리하여 3-벤젠술포닐아미노-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르를 담황색 오일로서 얻었다.3-amino-5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid tert-butyl ester hydrochloride (0.239 g, 0.587 mmol, Example 2 in 10 ml of acetonitrile at 0 ° C. in nitrogen) To the solution of step A) was added benzenesulfonyl chloride (0.075 ml, 0.588 mmol) dropwise (via syringe) followed by dropwise 4-methylmorpholine (0.20 ml, 1.819 mmol). The solution was allowed to slowly warm up at room temperature overnight. The solution was concentrated and redissolved in ethyl acetate and washed with saturated NaHCO 3 solution, KH 2 PO 4 saturated solution, brine. The ethyl acetate extract was dried (MgSO 4 ), filtered, concentrated and chromatographed (silica gel, 80% hexane-20% ethyl acetate) to give 3-benzenesulfonylamino-5- (naphthalen-1-yl-acetoxy ) -4-oxo-pentanoic acid tert-butyl ester was obtained as a pale yellow oil.

단계 CStep C

디클로로메탄 20 ml 중의 3-벤젠술포닐아미노-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르 (0.136 g, 0.266 mmol, 실시예 2의 단계 B) 및 트리플루오로아세트산 10 ml의 용액을 실온에서 1 시간 동안 교반시켰다. 이 용액을 농축하여 표제 화합물을 발포성 회백색 고체로서 얻었다.3-benzenesulfonylamino-5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid tert-butyl ester (0.136 g, 0.266 mmol, step B of Example 2) in 20 ml of dichloromethane and A solution of 10 ml of trifluoroacetic acid was stirred at room temperature for 1 hour. This solution was concentrated to give the title compound as effervescent off-white solid.

C23H21NO7S·0.75H2O(469.002)에 대한 분석:Analysis of C 23 H 21 NO 7 S.0.75H 2 O (469.002):

이론치 : C, 58.90; H, 4.84; N, 2.99Theoretical: C, 58.90; H, 4. 84; N, 2.99

실측치 : C, 58.94; H, 4.73; N, 3.02.Found: C, 58.94; H, 4.73; N, 3.02.

실시예 2와 유사한 방법으로 적절히 치환된 이소시아네이트, 적절히 치환된 술포닐 클로라이드, 적절히 치환된 클로로포르메이트, 적절히 치환된 산 클로라이드 중 어느 하나와 3-아미노-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르 히드로클로라이드 (실시예 2의 단계 A)를 사용하여 아래의 상응하는 화합물을 제조했다.In a manner similar to Example 2, 3-amino-5- (naphthalen-1-yl-acetoxy with any of an appropriately substituted isocyanate, an appropriately substituted sulfonyl chloride, an appropriately substituted chloroformate, an appropriately substituted acid chloride ) -4-oxo-pentanoic acid tert-butyl ester hydrochloride (step A of Example 2) was used to prepare the corresponding compounds below.

<실시예 2a><Example 2a>

3-메톡시카르보닐아미노-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 (회백색 고체)3-methoxycarbonylamino-5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid (grey-white solid)

C19H19HO7(373.366)에 대한 분석:Analysis for C 19 H 19 HO 7 (373.366):

이론치 : C, 61.12; H, 5.13; N, 3.75.Theoretical: C, 61.12; H, 5.13; N, 3.75.

실측치 : C, 60.85; H, 5.25; N, 3.58.Found: C, 60.85; H, 5. 25; N, 3.58.

<실시예 2b><Example 2b>

5-(나프탈렌-1-일-아세톡시)-4-옥소-3-(3-페닐-프로피오닐아미노)-펜탄산 (백색 고체)5- (Naphthalen-1-yl-acetoxy) -4-oxo-3- (3-phenyl-propionylamino) -pentanoic acid (white solid)

C26H25NO6·0.25H2O(451.996)에 대한 분석:Analysis for C 26 H 25 NO 6 · 0.25H 2 O (451.996):

이론치 : C, 69.09; H, 5.69; N, 3.10.Theoretical: C, 69.09; H, 5.69; N, 3.10.

실측치 : C, 69.06; H, 5.45; N, 2.91.Found: C, 69.06; H, 5. 45; N, 2.91.

<실시예 2c><Example 2c>

3-메톡시카르보닐아미노-4-옥소-5-페녹시아세톡시-펜탄산 (발포성 회백색 고체)3-methoxycarbonylamino-4-oxo-5-phenoxyacetoxy-pentanoic acid (foamable off-white solid)

C15H17NO8·0.80NaHCO3(406.510)에 대한 분석:Analysis for C 15 H 17 NO 8 · 0.80NaHCO 3 (406.510):

이론치 : C, 46.68; H, 4.41; N, 3.45.Theoretic value: C, 46.68; H, 4.41; N, 3.45.

실측치 : C, 46.89; H, 4.44; N, 3.43.Found: C, 46.89; H, 4. 44; N, 3.43.

<실시예 2d>Example 2d

3-(2-메탄술포닐-에탄술포닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 (고체, 융점 131-135 ℃)3- (2-Methanesulfonyl-ethanesulfonylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid (solid, melting point 131-135 ° C.)

C20H23NO9S2(485.536)에 대한 분석:Analysis for C 20 H 23 NO 9 S 2 (485.536):

이론치 : C, 49.48; H, 4.78; N, 2.88.Theoretical: C, 49.48; H, 4.78; N, 2.88.

실측치 : C, 49.26; H, 4.60; N, 2.88.Found: C, 49.26; H, 4. 60; N, 2.88.

<실시예 2e><Example 2e>

3-(2-메탄술포닐-1-메틸-에틸술파닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- (2-Methanesulfonyl-1-methyl-ethylsulfanylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

C21H25NO9S2·1.0H2O (517.578)에 대한 분석:Analysis for C 21 H 25 NO 9 S 2 · 1.0H 2 O (517.578):

이론치 : C, 48.73; H, 5.26; N, 2.71Theoretic value: C, 48.73; H, 5. 26; N, 2.71

실측치 : C, 48.90; H, 5.60; N, 2.78.Found: C, 48.90; H, 5. 60; N, 2.78.

<실시예 3><Example 3>

[S-(R*,R*)]-3-(2-아세틸아미노-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산[S- (R * , R * )]-3- (2-acetylamino-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

단계 AStep A

0 ℃의 질소 상태에서 디클로로메탄 15 ml 중의 N-아세틸 알라닌 (0.176 g, 1.34 mmol), 3-아미노-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르 히드로클로라이드 (0.500 g, 1.22 mmol, 실시예 2의 단계 A), 2-(1H-벤조트리아졸-1-일)-1,1,3,3-테트라메틸우로니움 테트라플루오로보레이트 (0.431 g, 1.34 mmol), 1-히드록시벤조트리아졸 (0.214 g, 1.58 mmol)의 용액에 N,N-디이소프로필에틸아민 (0.531 ml, 3.05 mmol)을 (주사기를 통해) 적가했다. 이 용액을 실온으로 밤새 가온시켰다. 그 다음 이용액을 에틸 아세테이트에 용해시키고, 2 x 5 % 시트르산 용액, 2 x NaHCO3포화용액 및 1 x 염수로 세척했다. 에틸아세테이트 추출물을 건조 (MgSO4), 여과, 농축 및 크로마토그래피 (실리카 겔, 30 % 테트라히드로푸란-70 % 디클로로메탄) 처리하여, [S-(R*,R*)]-3-(2-아세틸아미노-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르를 담황색 진한 오일로서 얻었다.N-acetyl alanine (0.176 g, 1.34 mmol), 3-amino-5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid tert-butyl ester in 15 ml of dichloromethane at 0 ° C. nitrogen Hydrochloride (0.500 g, 1.22 mmol, step A of Example 2), 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate (0.431 g, 1.34 mmol), N, N-diisopropylethylamine (0.531 ml, 3.05 mmol) was added dropwise (via syringe) to a solution of 1-hydroxybenzotriazole (0.214 g, 1.58 mmol). This solution was allowed to warm to room temperature overnight. The solution was then dissolved in ethyl acetate and washed with 2 x 5% citric acid solution, 2 x NaHCO 3 saturated solution and 1 x brine. The ethyl acetate extract was dried (MgSO 4 ), filtered, concentrated and chromatographed (silica gel, 30% tetrahydrofuran-70% dichloromethane) to give [S- (R * , R * )]-3- (2 Acetylamino-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid tert-butyl ester was obtained as a pale yellow dark oil.

단계 BStep B

디클로로메탄 7.5 ml 중의 [S-(R*,R*)]-3-(2-아세틸아미노-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르 (0.467 g, 0.96 mmol) 및 트리플루오로아세트산 7.5 ml의 용액을 2 시간 동안 실온에서 교반시켰다. 이 용액을 농축하고, 크로마토그래피 (실리카 겔, 94 % 디클로로메탄-5 % 메탄올- 1% 아세트산) 처리하여 표제 화합물을 오일성 발포체로서 얻었다. 표제 화합물을 이어서 아세토니트릴 및 물로부터 고체 형태로 동결건조했다.[S- (R * , R * )]-3- (2-acetylamino-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid tert in 7.5 ml of dichloromethane A solution of -butyl ester (0.467 g, 0.96 mmol) and 7.5 ml of trifluoroacetic acid was stirred for 2 hours at room temperature. The solution was concentrated and chromatographed (silica gel, 94% dichloromethane-5% methanol-1% acetic acid) to afford the title compound as an oily foam. The title compound was then lyophilized in a solid form from acetonitrile and water.

1H NMR (400 MHz, d6DMSO), 12.43 (bs, 1H), 8.44 (d, 1H), 7.95 (m, 2H), 7.87 (m, 1H), 7.51 (m, 4H), 4.87 (m, 2H), 4.56 (m, 1H), 4.23 (s, 2H), 4.18 (m, 1H) 2.72 (dd, 1H), 2.54 (dd, 1H), 1.81 (s, 3H), 1.17 (d, 3H). 1 H NMR (400 MHz, d 6 DMSO), 12.43 (bs, 1H), 8.44 (d, 1H), 7.95 (m, 2H), 7.87 (m, 1H), 7.51 (m, 4H), 4.87 (m , 2H), 4.56 (m, 1H), 4.23 (s, 2H), 4.18 (m, 1H) 2.72 (dd, 1H), 2.54 (dd, 1H), 1.81 (s, 3H), 1.17 (d, 3H ).

실시예 3과 유사한 방법으로 상응하는 화합물들을 제조했다.Corresponding compounds were prepared in a similar manner to Example 3.

<실시예 3a><Example 3a>

5-(나프탈렌-1-일-아세톡시)-4-옥소-3-[(티오펜-3-카르보닐)-아미노]-펜탄산 (발포성 회백색 고체)5- (Naphthalen-1-yl-acetoxy) -4-oxo-3-[(thiophen-3-carbonyl) -amino] -pentanoic acid (foamable off-white solid)

C22H19NO6S·0.45H2O(433.571)에 대한 분석:Analysis of C 22 H 19 NO 6 S0.45H 2 O (433.571):

이론치 : C, 60.95; H, 4.63; N, 3.23.Theoretical: C, 60.95; H, 4.63; N, 3.23.

실측치 : C, 60.98; H, 4.81; N, 3.29.Found: C, 60.98; H, 4.81; N, 3.29.

<실시예 3b><Example 3b>

3-[(푸란-3-카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 (백색 고체)3-[(furan-3-carbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid (white solid)

C22H19NO7·0.25H2O(413.903)에 대한 분석:C 22 H 19 NO 7 .0.25H 2 O (413.903) for analysis:

이론치 : C, 63.84; H, 4.75; N, 3.38.Theoretic value: C, 63.84; H, 4.75; N, 3.38.

실측치 : C, 63.86; H, 4.50; N, 3.39.Found: C, 63.86; H, 4.50; N, 3.39.

<실시예 3c><Example 3c>

5-(나프탈렌-1-일-아세톡시)-4-옥소-3-[2-(4-페닐-부티릴아미노)-프로필아미노]-펜탄산5- (Naphthalen-1-yl-acetoxy) -4-oxo-3- [2- (4-phenyl-butyrylamino) -propylamino] -pentanoic acid

MS(CI) m/z 533 (M+1)MS (CI) m / z 533 (M + 1)

<실시예 3d>Example 3d

3-(2-메탄술포닐아미노-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- (2-Methanesulfonylamino-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

MS (APCI) m/z 465 (M+1)MS (APCI) m / z 465 (M + 1)

<실시예 3e><Example 3e>

3-[2-(2-아세틸아미노-4-페닐-부티릴아미노)-프로피오닐아미노]-5-(나프탈렌1-일-아세톡시)-4-옥소-펜탄산3- [2- (2-Acetylamino-4-phenyl-butyrylamino) -propionylamino] -5- (naphthalen1-yl-acetoxy) -4-oxo-pentanoic acid

MS (APCI) m/z 590.4 (M+1)MS (APCI) m / z 590.4 (M + 1)

<실시예 3f><Example 3f>

3-(2-아세틸아미노-부티릴아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- (2-Acetylamino-butyrylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

MS (APCI) m/z 443.5 (M+1)MS (APCI) m / z 443.5 (M + 1)

<실시예 3g><Example 3g>

3-[2-(4-카르바모일-부티릴아미노)-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- [2- (4-Carbamoyl-butyrylamino) -propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

MS (APCI) m/z 500.5 (M+1)MS (APCI) m / z 500.5 (M + 1)

<실시예 3h><Example 3h>

3-(2-벤질옥시카르보닐아미노-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- (2-Benzyloxycarbonylamino-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

MS (APCI) m/z 521.4 (M+1)MS (APCI) m / z 521.4 (M + 1)

<실시예 3i><Example 3i>

5-(나프탈렌-1-일-아세톡시)-4-옥소-3-(2-우레이도-프로피오닐아미노)-펜탄산5- (Naphthalen-1-yl-acetoxy) -4-oxo-3- (2-ureido-propionylamino) -pentanoic acid

MS (APCI) m/z 430.5 (M+1)MS (APCI) m / z 430.5 (M + l)

<실시예 3j><Example 3j>

3-(2-아세틸아미노-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- (2-Acetylamino-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

MS (APCI) m/z 429.5 (M+1)MS (APCI) m / z 429.5 (M + 1)

<실시예 3k><Example 3k>

3-[(1-아세틸-피롤리딘-2-카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3-[(1-acetyl-pyrrolidine-2-carbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

MS (APCI) m/z 455.5 (M+1)MS (APCI) m / z 455.5 (M + 1)

<실시예 3l><Example 3l>

3-(2-메틸-3-옥소-3-티오펜-2-일-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- (2-Methyl-3-oxo-3-thiophen-2-yl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

MS (APCI) m/z 482.4 (M+1)MS (APCI) m / z 482.4 (M + 1)

<실시예 3m><Example 3m>

3-(2-아세틸아미노-아세틸아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- (2-Acetylamino-acetylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

MS (APCI) m/z 415.5 (M+1)MS (APCI) m / z 415.5 (M + 1)

<실시예 3n><Example 3n>

3-(2-아세틸아미노-프로피오닐아미노)-5-(3,3-디페닐-프로피오닐옥시)-4-옥소-펜탄산3- (2-Acetylamino-propionylamino) -5- (3,3-diphenyl-propionyloxy) -4-oxo-pentanoic acid

MS (APCI) m/z 469.2 (M+1)MS (APCI) m / z 469.2 (M + l)

<실시예 3o><Example 3o>

3-[2-(2-아세틸아미노-4-카르복시-부티릴아미노)-프로피오닐아미노]-5-나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- [2- (2-Acetylamino-4-carboxy-butyrylamino) -propionylamino] -5-naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

MS (APCI) m/z 596.1 (M-1)MS (APCI) m / z 596.1 (M-1)

<실시예 3p><Example 3p>

5-(나프탈렌-1-일-아세톡시)-4-옥소-3-[2-(3-페닐-프로피오닐아미노)-프로피오닐아미노]-펜탄산5- (Naphthalen-1-yl-acetoxy) -4-oxo-3- [2- (3-phenyl-propionylamino) -propionylamino] -pentanoic acid

MS (APCI) m/z 518.8 (M+1)MS (APCI) m / z 518.8 (M + l)

<실시예 3q><Example 3q>

3-[2-(3-메틸-부티릴아미노)-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- [2- (3-Methyl-butyrylamino) -propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

MS (APCI) m/z 470.8 (M+1)MS (APCI) m / z 470.8 (M + 1)

<실시예 3r><Example 3r>

3-[(1-카르바모일-피롤리딘-2-카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3-[(1-Carbamoyl-pyrrolidine-2-carbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

<실시예 3s><Example 3s>

3-(3-벤질옥시-2-우레이도-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- (3-Benzyloxy-2-ureido-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

<실시예 3t><Example 3t>

3-[(1-아세틸-4-벤질옥시-피롤리딘-2-카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3-[(1-acetyl-4-benzyloxy-pyrrolidine-2-carbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

<실시예 3u><Example 3u>

3-(4-카르바모일-부티릴아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- (4-Carbamoyl-butyrylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

<실시예 3v><Example 3v>

3-(3-카르바모일-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- (3-Carbamoyl-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

<실시예 3w><Example 3w>

3-[2-(1-메틸-1H-이미다졸-4-일)-아세틸아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- [2- (1-Methyl-1H-imidazol-4-yl) -acetylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

<실시예 4><Example 4>

(S)-5-(나프탈렌-1-일-아세톡시)-4-옥소-3-페닐아세틸아미노-펜탄산(S) -5- (naphthalen-1-yl-acetoxy) -4-oxo-3-phenylacetylamino-pentanoic acid

단계 AStep A

실온의 질소 상태에서 아세토니트릴 25 ml 중의 페닐아세틸 클로라이드 (0.160 ml, 1.22 mmol), 3-아미노-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르 히드로클로라이드 (0.500 g, 1.22 mmol, 실시예 2의 단계 A), 4-디메틸아미노피리딘 (촉매)의 용액에 N,N-디이소프로필에틸아민 (0.471 ml, 2.69 mmol)을 (주사기를 통해) 적가했다. 이 용액을 밤새 교반시켰다. 이어서 용액을 에틸 아세테이트에 용해시키고, 2 x 5 % 시트르산 용액, 2 x NaHCO3포화용액 및 1 x 염수로 세척했다. 에틸 아세테이트 추출물을 건조 (MgSO4), 여과, 농축 및 크로마토그래피 (실리카 겔, 40 % 에틸 아세테이트-60 % 헥산) 처리를 하여 (S)-5-(나프탈렌-1-일-아세톡시)-4-옥소-3-페닐아세틸아미노-펜탄산 tert-부틸 에스테르를 진한 오일로서 얻었다.Phenylacetyl chloride (0.160 ml, 1.22 mmol), 3-amino-5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid tert-butyl ester hydrochloride in 25 ml of acetonitrile at room temperature in nitrogen (0.500 g, 1.22 mmol, Step A of Example 2), N, N-diisopropylethylamine (0.471 ml, 2.69 mmol) was added dropwise (via syringe) to a solution of 4-dimethylaminopyridine (catalyst) . This solution was stirred overnight. The solution was then dissolved in ethyl acetate and washed with 2 x 5% citric acid solution, 2 x NaHCO 3 saturated solution and 1 x brine. The ethyl acetate extract was dried (MgSO 4 ), filtered, concentrated and chromatographed (silica gel, 40% ethyl acetate-60% hexanes) to give (S) -5- (naphthalen-1-yl-acetoxy) -4 -Oxo-3-phenylacetylamino-pentanoic acid tert-butyl ester was obtained as a thick oil.

단계 BStep B

디클로로메탄 7.5 ml 중에서 (S)-5-(나프탈렌-1-일-아세톡시)-4-옥소-3-페닐아세틸아미노-펜탄산 tert-부틸 에스테르 (0.300 g, 0.61 mmol, 실시예 4의 단계 A) 및 트리플루오로아세트산 7.5 ml를 실온에서 2 시간 동안 교반시켰다. 용액을 농축하고 크로마토그래피 (실리카 겔, 40 % 에틸 아세테이트 - 59 % 헥산 - 1 % 아세트산) 처리하여 표제 화합물을 오일성 발포체로서 얻었다. 그 다음 표제 화합물을 아세토니트릴 및 물로부터 고체 형태로 동결 건조했다.(S) -5- (naphthalen-1-yl-acetoxy) -4-oxo-3-phenylacetylamino-pentanoic acid tert-butyl ester (0.300 g, 0.61 mmol, step of Example 4 in 7.5 ml of dichloromethane A) and 7.5 ml of trifluoroacetic acid were stirred at room temperature for 2 hours. The solution was concentrated and chromatographed (silica gel, 40% ethyl acetate-59% hexanes-1% acetic acid) to afford the title compound as an oily foam. The title compound was then lyophilized in a solid form from acetonitrile and water.

1H NMR (400 MHz, d6DMSO), 12.49 (bs, 1H), 8.64 (bs, 1H), 7.94 (m, 2H), 7.84 (m, 1H), 7.49 (m, 4H), 7.27 (m, 5H), 4.85 (bs, 2H), 4.62 (m, 1H), 4.21 (s, 2H), 3.47 (s, 2H), 2.69 (dd, 1H), 2.59 (dd, 1H). 1 H NMR (400 MHz, d 6 DMSO), 12.49 (bs, 1H), 8.64 (bs, 1H), 7.94 (m, 2H), 7.84 (m, 1H), 7.49 (m, 4H), 7.27 (m , 5H), 4.85 (bs, 2H), 4.62 (m, 1H), 4.21 (s, 2H), 3.47 (s, 2H), 2.69 (dd, 1H), 2.59 (dd, 1H).

실시예 4와 유사한 방식으로 상응하는 화합물들을 제조했다.Corresponding compounds were prepared in a similar manner to Example 4.

<실시예 4a><Example 4a>

(S)-5-(나프탈렌-1-일-아세톡시)-4-옥소-3-(2-티오펜-2-일-아세틸아미노)-펜탄산(S) -5- (naphthalen-1-yl-acetoxy) -4-oxo-3- (2-thiophen-2-yl-acetylamino) -pentanoic acid

1H NMR (400 MHz, d6DMSO), 12.52 (bs, 1H), 8.67 (bs, 1H), 7.89 (m, 3H), 7.49 (m, 4H), 7.34 (m, 1H), 6.93 (m, 2H), 4.88 (bs, 2H), 4.62 (m, 1H), 4.22 (s, 2H), 3.71 (s, 2H), 2.69 (dd, 1H), 2.60 (dd, 1H). 1 H NMR (400 MHz, d 6 DMSO), 12.52 (bs, 1H), 8.67 (bs, 1H), 7.89 (m, 3H), 7.49 (m, 4H), 7.34 (m, 1H), 6.93 (m , 2H), 4.88 (bs, 2H), 4.62 (m, 1H), 4.22 (s, 2H), 3.71 (s, 2H), 2.69 (dd, 1H), 2.60 (dd, 1H).

<실시예 4b 및 4c><Examples 4b and 4c>

3-[(2-카르바모일-시클로펜탄카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산, 부분입체이성질체 A 및 B3-[(2-Carbamoyl-cyclopentanecarbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, diastereomers A and B

아세토니트릴 (100 ml) 중의 트랜스-2-카르바모일-시클로펜탄카르복실산 (130 mg, 0.83 mmol) 및 피리딘 (65 mg, 0.83 mmol)의 용액에 불화시아누르산 (110 mg, 0.83 mmol)을 첨가하고, 이 반응 혼합물을 3 시간 동안 실온에서 교반시켰다. 얼음물 (10 ml)을 첨가하고, 반응 혼합물을 5 분 동안 교반시켰다. 이를 메틸렌 클로라이드 (75 ml)로 추출하고, 유기층을 증발시켜, 중간체 산 플루오라이드 조생성물 (50 mg)을 얻었다. 메틸렌 클로라이드 : 아세토니트릴 1 : 1 (20 ml) 중의 산 플루오라이드 용액을 3-아미노-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르의 히드로클라이드 염 (100 mg, 0.25 mmol, 실시예 2의 단계 A) 및 N-메틸모르폴린 (0.5 mmol)로 처리했다. 이 반응 혼합물을 실온에서 2 시간 동안 교반시킨 후 용매를 증발시켰다. 플래시 크로마토그래피 (실리카 겔, 에틸 아세테이트)로 정제하여 3-[(2-카르바모일-시클로펜탄카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르의 2 개의 부분입체 이성질체 [부분입체이성질체 A (높은 Rf) MS (AP+): 510.9 및 부분입체이성질체 B (낮은 Rf) MS (APCI) m/z 510.9 (M+1)]를 얻었다.Cyanuric acid fluoride (110 mg, 0.83 mmol) in a solution of trans-2-carbamoyl-cyclopentanecarboxylic acid (130 mg, 0.83 mmol) and pyridine (65 mg, 0.83 mmol) in acetonitrile (100 ml) Was added and the reaction mixture was stirred for 3 hours at room temperature. Ice water (10 ml) was added and the reaction mixture was stirred for 5 minutes. It was extracted with methylene chloride (75 ml) and the organic layer was evaporated to give the intermediate acid fluoride crude product (50 mg). Methylene chloride: A solution of acid fluoride in acetonitrile 1: 1 (20 ml) was added to a hydroclide salt of 3-amino-5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid tert-butyl ester ( 100 mg, 0.25 mmol, step A) of Example 2 and N-methylmorpholine (0.5 mmol). The reaction mixture was stirred at rt for 2 h before the solvent was evaporated. Purification by flash chromatography (silica gel, ethyl acetate) gave 3-[(2-carbamoyl-cyclopentanecarbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-phene Two diastereomers of carbonic acid tert-butyl ester [diastereomer A (high Rf) MS (AP +): 510.9 and diastereomer B (low Rf) MS (APCI) m / z 510.9 (M + 1)] Got it.

단계 BStep B

부분입체이성질체 A 또는 B를 실시예 4에 기재된 바와 같이 트리플루오로아세트산과 반응시켜 3-[(2-카르바모일-시클로펜탄카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 4b (부분입체이성질체 A) (융점 171-185 ℃) 및 3-[(2-카르바모일-시클로펜탄카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 4c (부분입체이성질체 B) (융점 208-210 ℃)을 얻었다.Diastereomers A or B are reacted with trifluoroacetic acid as described in Example 4 to 3-[(2-carbamoyl-cyclopentanecarbonyl) -amino] -5- (naphthalen-1-yl-ace Methoxy) -4-oxo-pentanoic acid 4b (diastereomer A) (melting point 171-185 ° C.) and 3-[(2-carbamoyl-cyclopentanecarbonyl) -amino] -5- (naphthalene-1- Mono-acetoxy) -4-oxo-pentanoic acid 4c (diastereomer B) (melting point 208-210 ° C.) was obtained.

<실시예 4d><Example 4d>

3-[(3-(카르바모일-비시클로[2.2.1]헵탄-2-카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3-[(3- (Carbamoyl-bicyclo [2.2.1] heptan-2-carbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

3-[(3-(카르바모일-비시클로[2.2.1]헵탄-2-카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르를 실시예 4b 및 4c의 방법으로 (1R, 2S, 3S, 4S)-3-카르바모일-2-카르복시비시클로[2.2.1]헵탄 (Ohtani, et al., JOC, 1991; 562: 122-2177)로부터 47 %의 수율로 얻었다.3-[(3- (Carbamoyl-bicyclo [2.2.1] heptan-2-carbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid tert- Butyl ester was prepared by the methods of Examples 4b and 4c (1R, 2S, 3S, 4S) -3-carbamoyl-2-carboxybicyclo [2.2.1] heptane (Ohtani, et al., JOC, 1991; 562). : 122-2177) in a yield of 47%.

<실시예 4e><Example 4e>

3-(3-카르바모일-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- (3-Carbamoyl-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

단계 AStep A

-78 ℃에서 디클로로메탄 25 ml 및 테트라히드로푸란 25 ml 중의 (S)-(-)-2-메틸숙시남산 (0.160 g, 1.22 mmol, 문헌 (Chem. Pharm. Bull., 1991; 39 (10): 2706-2708)에 기재된 방법에 따라 제조됨)의 용액에 N-메틸피페리딘 (0.163 ml, 1.34 mmol)을 첨가한 후 이소부틸 클로로포르메이트 (0.166 ml, 1.26 mmol)을 적가했다. 이 반응 혼합물을 1 시간 동안 -78 ℃에서 교반시켰다. 디클로로메탄 (25 ml) 및 테트라히드로푸란 (25 ml) 중의 3-아미노-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르 히드로클로라이드 (0.500 g, 1.22 mmol, 실시예 2의 단계 A)의 용액을 적가하면서 동시에 제2 깔대기를 사용하여 N-메틸피페리딘 (0.163 ml, 1.34 mmol)을 적가했다. 이 반응 혼합물을 실온으로 서서히 가온하고 밤새 교반시켰다. 이 반응 혼합물을 에틸 아세테이트로 희석하고, 5 % 시트르산, 중탄산나트륨 포화용액, 마지막으로 염화나트륨 포화용액으로 세척했다. 유기층을 황산마그네슘 상에서 건조하고, 여과하고, 진공 농축시켰다. 생성된 고체를 디에틸 에테르에 현탁시키고, 여과로 모아서 디에틸 에테르로 세척하고, 감압하에 건조시켜 중간체 3-(3-카르바모일-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르 294 mg (49 %)을 얻었다.(S)-(-)-2-methylsuccinic acid (0.160 g, 1.22 mmol, in Chem. Pharm. Bull., 1991; 39 (10) in 25 ml of dichloromethane and 25 ml of tetrahydrofuran at −78 ° C. N-methylpiperidine (0.163 ml, 1.34 mmol) was added dropwise to a solution of the same method as described in (2706-2708). The reaction mixture was stirred for 1 h at -78 ° C. 3-Amino-5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid tert-butyl ester hydrochloride (0.500 g, 1.22 mmol) in dichloromethane (25 ml) and tetrahydrofuran (25 ml) , The solution of step A) of Example 2 was added dropwise while N-methylpiperidine (0.163 ml, 1.34 mmol) was added dropwise using a second funnel. The reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with 5% citric acid, saturated sodium bicarbonate solution and finally saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting solid is suspended in diethyl ether, collected by filtration, washed with diethyl ether and dried under reduced pressure to afford intermediate 3- (3-carbamoyl-2-methyl-propionylamino) -5- (naphthalene-1 294 mg (49%) of -yl-acetoxy) -4-oxo-pentanoic acid tert-butyl ester were obtained.

단계 BStep B

4 N 염산/디옥산 10 ml 중의 3-(3-카르바모일-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르 (0.150 g, 0.309 mmol, 실시예 4e의 단계 A)의 용액을 실온에서 2 시간 동안 교반시켰다. 용액을 농축시키고 생성물을 역상 HPLC로 정제했다. 아세토니트릴 및 물로부터 동결건조하여 3-(3-카르바모일-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산을 고체로서 얻었다.3- (3-carbamoyl-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid tert-butyl ester in 10 ml of 4N hydrochloric acid / dioxane The solution of (0.150 g, 0.309 mmol, step A of Example 4e) was stirred at room temperature for 2 hours. The solution was concentrated and the product was purified by reverse phase HPLC. Lyophilization from acetonitrile and water gave 3- (3-carbamoyl-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid as a solid.

1H NMR (400 MHz, DMSO), 12.38 (bs, 1H), 8.49 (d, 1H), 7.88 (m, 1H), 7.54 (m, 4H), 7.28 (s, 1H), 6.76 (s, 1H), 4.89 (s, 2H), 4.46 (m, 1H), 4.22 (s, 2H), 2.71 (m, 2H), 2.74 (m, 2H), 2.32 (dd, 1H), 2.08 (dd, 1H), 0.98 (d,3H). MS (APCI) m/z 429.1 (M+H) 1 H NMR (400 MHz, DMSO), 12.38 (bs, 1H), 8.49 (d, 1H), 7.88 (m, 1H), 7.54 (m, 4H), 7.28 (s, 1H), 6.76 (s, 1H ), 4.89 (s, 2H), 4.46 (m, 1H), 4.22 (s, 2H), 2.71 (m, 2H), 2.74 (m, 2H), 2.32 (dd, 1H), 2.08 (dd, 1H) , 0.98 (d, 3 H). MS (APCI) m / z 429.1 (M + H)

<실시예 4f><Example 4f>

3-(3-메탄술포닐-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- (3-Methanesulfonyl-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

단계 AStep A

티오닐 클로라이드 10 ml 중의 2(S)-메틸-3-메틸술포닐)프로피온산 (250 mg, 1.5 mmol, 문헌 (Vazquez, M. L., et al., WO94/10136)의 방법에 따라서 제조됨)의 용액을 2 시간 동안 질소 상태의 55 ℃에서 교반시켰다. 용매를 감압하에서 제거하고, 벤젠으로 세척하고, 재농축시켜 회백색 고체를 얻었다. 생성된 고체를 40 ml THF 및 N-메틸모르폴린 (300 mg, 3.0 mmol)에 용해시키고 4-디메틸아미노피리딘 (120 mg, 1.0 mmol)을 첨가한 후 3-아미노-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르 히드로클로라이드 (실시예 2의 단계 A)(407 mg, 1.0 mmol)를 한번에 첨가했다. 이 혼합물을 실온에서 16 시간 동안 교반시켰다. 이 용액을 에틸 아세테이트로 희석시키고, NaHCO3포화용액, KHPO4포화용액, 염수로 세척하고, 건조 (MgSO4), 여과 및 농축했다. 오일 조생성물을 중간 압력 크로마토그래피 (실리카 겔, 75 % 헥산-25 % 에틸 아세테이트 내지 60 % 헥산-40 % 에틸 아세테이트) 처리하여 [S-(R*,R*)]-3-(3-메탄술포닐-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르를 오일 조생성물로 얻었다.Solution of 2 (S) -methyl-3-methylsulfonyl) propionic acid (250 mg, 1.5 mmol, prepared according to the method of Vazquez, ML, et al., WO94 / 10136) in 10 ml of thionyl chloride Was stirred at 55 ° C. under nitrogen for 2 hours. The solvent was removed under reduced pressure, washed with benzene and concentrated again to give an off white solid. The resulting solid was dissolved in 40 ml THF and N-methylmorpholine (300 mg, 3.0 mmol) and 4-dimethylaminopyridine (120 mg, 1.0 mmol) was added followed by 3-amino-5- (naphthalene-1- Mono-acetoxy) -4-oxo-pentanoic acid tert-butyl ester hydrochloride (Step A of Example 2) (407 mg, 1.0 mmol) was added in one portion. This mixture was stirred at rt for 16 h. The solution was diluted with ethyl acetate, washed with saturated NaHCO 3 solution, saturated KHPO 4 solution, brine, dried (MgSO 4 ), filtered and concentrated. The crude oil was subjected to medium pressure chromatography (silica gel, 75% hexane-25% ethyl acetate to 60% hexane-40% ethyl acetate) to give [S- (R * , R * )]-3- (3-methane Sulfonyl-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid tert-butyl ester was obtained as an oil crude product.

단계 BStep B

디클로로메탄 5 ml 중의 [S-(R*,R*)]-3-(3-메탄술포닐-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르 (232 mg, 0.45 mmol) 및 트리플루오로아세트산 (5 ml, 0.065 몰)의 용액을 실온에서 2 시간 동안 교반시켰다. 이 용액을 진공 농축시키고 물에 현탁시켜 표제 화합물을 회백색 고체로서 얻었다.[S- (R * , R * )]-3- (3-methanesulfonyl-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4- in 5 ml of dichloromethane A solution of oxo-pentanoic acid tert-butyl ester (232 mg, 0.45 mmol) and trifluoroacetic acid (5 ml, 0.065 mol) was stirred at room temperature for 2 hours. The solution was concentrated in vacuo and suspended in water to afford the title compound as an off white solid.

C22H25NO8S·H2O(481.51)에 대한 분석:Analysis of C 22 H 25 NO 8 SH 2 O (481.51):

이론치: C, 58.87; H, 5.65; N, 2.91.Theoretical: C, 58.87; H, 5.65; N, 2.91.

실측치: C, 54.78; H, 5.42; N, 2.78Found: C, 54.78; H, 5. 42; N, 2.78

<실시예 4g><Example 4g>

3-(3-벤젠술포닐-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- (3-Benzenesulfonyl-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

단계 AStep A

아세트산 100 ml 중의 2-메틸-3-(티오벤젠)프로피온산 메틸 에스테르 (4 g, 19 mmol, 문헌 (J. Org. Chem., 1981; 46: 235-9)의 방법에 따라 제조됨)의 용액에 과붕산나트륨 (7.33 g, 47.6 mmol)을 첨가하고 혼합물을 17 시간 동안 55 ℃로 가열했다. 반응물을 물에 붓고 메틸렌 클로라이드로 추출하고 중탄산 수용액으로 세척하고 건조 (MgSO4)하고 농축하여 2-메틸-3-(벤젠술포닐)프로피온산 메틸 에스테르를 무색 오일로서 얻었다.Solution of 2-methyl-3- (thiobenzene) propionic acid methyl ester (4 g, 19 mmol, prepared according to the method of J. Org. Chem., 1981; 46: 235-9) in 100 ml of acetic acid To sodium perborate (7.33 g, 47.6 mmol) was added and the mixture was heated to 55 ° C for 17 h. The reaction was poured into water, extracted with methylene chloride, washed with aqueous bicarbonate solution, dried (MgSO 4 ) and concentrated to afford 2-methyl-3- (benzenesulfonyl) propionic acid methyl ester as a colorless oil.

단계 BStep B

THF 60 ml 중의 2-메틸-3-(벤젠술포닐)프로피온산 메틸 에스테르 (4.47 g, 18.5 mmol)의 용액에 물 (30 ml) 중의 수산화리튬 (0.93 g, 22.2 mmol) 용액을 첨가했다. 용액을 실온에서 16 시간 동안 교반시킨 후 1 N KHSO4를 사용하여 pH 1로 산성화시키고, 용액을 에틸 아세테이트로 3회 추출했다. 합한 유기 용액을 건조 (MgSO4)하고 농축하여 무색 오일을 얻고 이를 방치하여 고체화시켜 2-메틸-3-(벤젠술포닐)프로피온산을 얻었다.To a solution of 2-methyl-3- (benzenesulfonyl) propionic acid methyl ester (4.47 g, 18.5 mmol) in 60 ml of THF was added a solution of lithium hydroxide (0.93 g, 22.2 mmol) in water (30 ml). The solution was stirred at rt for 16 h and then acidified to pH 1 with 1 N KHSO 4 and the solution was extracted three times with ethyl acetate. The combined organic solution was dried (MgSO 4 ) and concentrated to give a colorless oil which was left to solidify to give 2-methyl-3- (benzenesulfonyl) propionic acid.

단계 CStep C

티오닐 클로라이드 10 ml 중의 2-메틸-3-(벤젠술포닐)프로피온산 (300 mg, 1.3 mmol)의 용액을 55 ℃의 질소 상태에서 16 시간 동안 교반시켰다. 용매를 감압하에서 제거하고 벤젠으로 세척하고 재농축시켜 황색 오일을 얻었다. 생성된 오일을 THF 40 ml에 용해시키고, N-메틸모르폴린 (300 mg, 3.0 mmol) 및 4-디메틸아미노피리딘 (120 mg, 1.0 mmol)를 첨가한 후 3-아미노-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르 히드로클로라이드 (407 mg, 1.0 mmol, 실시예 2의 단계 A)를 한번에 첨가했다. 이 혼합물을 실온에서 36 시간 동안 교반시켰다. 이 용액을 에틸 아세테이트로 희석하고 NaHCO3포화용액, KHPO4포화용액, 염수로 세척하고, 건조 (MgSO4), 여과 및 농축했다. 오일 조생성물을 중간 압력 크로마토그래피 (실리카 겔, 75 % 헥산-25 % 에틸 아세테이트 내지 60 % 헥산-40 % 에틸 아세테이트) 처리하여 3-(3-벤젠술포닐-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르를 얻었다.A solution of 2-methyl-3- (benzenesulfonyl) propionic acid (300 mg, 1.3 mmol) in 10 ml of thionyl chloride was stirred for 16 h at 55 ° C. under nitrogen. The solvent was removed under reduced pressure, washed with benzene and concentrated again to give a yellow oil. The resulting oil was dissolved in 40 ml of THF, N-methylmorpholine (300 mg, 3.0 mmol) and 4-dimethylaminopyridine (120 mg, 1.0 mmol) were added followed by 3-amino-5- (naphthalene-1 -Yl-acetoxy) -4-oxo-pentanoic acid tert-butyl ester hydrochloride (407 mg, 1.0 mmol, step A of Example 2) was added in one portion. This mixture was stirred at rt for 36 h. The solution was diluted with ethyl acetate and washed with saturated NaHCO 3 solution, saturated KHPO 4 solution, brine, dried (MgSO 4 ), filtered and concentrated. The crude oil was subjected to medium pressure chromatography (silica gel, 75% hexane-25% ethyl acetate to 60% hexane-40% ethyl acetate) to give 3- (3-benzenesulfonyl-2-methyl-propionylamino)- 5- (Naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid tert-butyl ester was obtained.

단계 DStep D

디클로로메탄 5 ml 중의 3-(3-벤젠술포닐-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르 (216 mg, mmol) 및 트리플루오로아세트산 (5 ml, 0.065 mmol)의 용액을 실온에서 2 시간 동안 교반시켰다. 이 용액을 진공 농축하고 에틸 아세테이트에 현탁시키고, 표제 화합물을 회백색 고체로 얻었다.3- (3-benzenesulfonyl-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid tert-butyl ester (216 mg, in 5 ml of dichloromethane) mmol) and trifluoroacetic acid (5 ml, 0.065 mmol) were stirred at room temperature for 2 hours. The solution was concentrated in vacuo and suspended in ethyl acetate to afford the title compound as an off-white solid.

C27H27NO8S·C2HF3O2(611.10)에 대한 분석:Analysis for C 27 H 27 NO 8 SC 2 HF 3 O 2 (611.10):

이론치: C, 56.01; H, 4.58; N, 2.29.Theoretical: C, 56.01; H, 4.58; N, 2.29.

실측치: C, 56.12; H, 4.86; N, 2.40Found: C, 56.12; H, 4.86; N, 2.40

실시예 4와 유사한 방법으로 상응하는 화합물을 제조했다.The corresponding compound was prepared in a similar manner as in Example 4.

<실시예 4h><Example 4h>

3-부티릴아미노-5-(나프탈렌-2-일-아세톡시)-4-옥소-펜탄산3-Butyrylamino-5- (naphthalen-2-yl-acetoxy) -4-oxo-pentanoic acid

MS (CI) m/z 386 (M+1)MS (CI) m / z 386 (M + 1)

<실시예 4i><Example 4i>

3-아세틸아미노-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 (발포성 회백색 고체)3-Acetylamino-5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid (foamable off-white solid)

C19H19NO6·H2O(375.382)에 대한 분석:Analysis for C 19 H 19 NO 6 · H 2 O (375.382):

이론치: C, 60.80; H, 5.64; N, 3.73Theoretical: C, 60.80; H, 5. 64; N, 3.73

실측치: C, 61.07; H, 5.70; N, 3.57Found: C, 61.07; H, 5. 70; N, 3.57

<실시예 4j><Example 4j>

3-(3-메탄술포닐-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- (3-Methanesulfonyl-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

C22H25NO8S·1.0H2O(481.526)에 대한 분석:Analysis of C 22 H 25 NO 8 S.1.0H 2 O (481.526):

이론치: C, 54.88; H, 5.65; N, 2.91.Theoretical: C, 54.88; H, 5.65; N, 2.91.

실측치: C, 54.78; H, 5.42; N, 2.78Found: C, 54.78; H, 5. 42; N, 2.78

<실시예 4k><Example 4k>

3-(3-메틸-부티릴아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- (3-Methyl-butyrylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

MS (APCI) m/z 399.8 (M+1)MS (APCI) m / z 399.8 (M + 1)

<실시예 4l><Example 4l>

3-(3-카르바모일-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- (3-Carbamoyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

1H NMR (400 Mhz, DMSO) 12.38(bs,1H), 8.44(d,1H), 7.93(m,3H), 7.50 (m,4H), 7.28(s,1H), 6.75(s,1H), 4.92(dd,2H), 4.56(m,1H), 4.23(s,2H), 2.68 (dd,1H), 2.52(dd,1H), 2.49(m,4H). 1 H NMR (400 Mhz, DMSO) 12.38 (bs, 1H), 8.44 (d, 1H), 7.93 (m, 3H), 7.50 (m, 4H), 7.28 (s, 1H), 6.75 (s, 1H) , 4.92 (dd, 2H), 4.56 (m, 1H), 4.23 (s, 2H), 2.68 (dd, 1H), 2.52 (dd, 1H), 2.49 (m, 4H).

MS(APCI) m/z 415.5(M+H)MS (APCI) m / z 415.5 (M + H)

<실시예 4m><Example 4m>

[S-(R*,R*)]-3-(3-아세틸술파닐-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산[S- (R * , R * )]-3- (3-acetylsulfanyl-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

C23H25NO7S·0.1 CF3CO2H(470.925)에 대한 분석:Analysis of C 23 H 25 NO 7 S.0.1 CF 3 CO 2 H (470.925):

이론치: C, 59.17; H, 5.37; N, 2.97.Theoretical: C, 59.17; H, 5. 37; N, 2.97.

실측치: C, 59.39; H, 5.59; N, 3.01.Found: C, 59.39; H, 5.59; N, 3.01.

<실시예 4n><Example 4n>

트랜스-3-[(3-카르바모일-시클로펜탄카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산Trans-3-[(3-carbamoyl-cyclopentanecarbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

C24H26N2O7·1.5H2O에 대한 분석:Analysis of C 24 H 26 N 2 O 7 1.5H 2 O:

이론치: C, 59.86; H, 6.07; N, 5.82.Theoretical: C, 59.86; H, 6.07; N, 5.82.

실측치: C, 59.74; H, 5.80; N, 5.48Found: C, 59.74; H, 5.80; N, 5.48

<실시예 5>Example 5

3-(1,2,3,4-테트라히드로-1-옥소-이소퀴놀린-2-일)-아세트아미노-5-(나프탈렌-1-일 아세톡시)-4-옥소-펜탄산3- (1,2,3,4-Tetrahydro-1-oxo-isoquinolin-2-yl) -acetamino-5- (naphthalen-1-yl acetoxy) -4-oxo-pentanoic acid

단계 AStep A

0 ℃에서 디메틸포름아미드 (40 ml) 중의 (1,2,3,4-테트라히드로-1-옥소-이소퀴놀린-2-일)아세트산 (2.7 g, 13.0 mmol, 문헌 (Anderson W.K., et al., J. Med. Chem., 1988; 31: 2097)의 방법에 따라 제조됨) 및 H-Asp(OtBu)OMe·HCl (2.9 g, 12.0 mmol)의 용액에 1-에틸-3-(3'-디메틸아미노프로필)카르보디이미드 x HCl (2.5 g, 13.0 mmol) 및 트리에틸아민 (4.05 g, 40 mmol)을 첨가했다. 이 혼합물을 실온에서 16 시간 동안 교반시켰다. 용매 대부분을 감압하에서 제거하고, 잔류물을 에틸 아세테이트에 용해시켰다. 유기상을 탄산수소나트륨 수용액과 물로 연속적으로 세척하고, 황산나트륨 상에서 건조하고 농축하여 무정질 잔류물 4.5 g을 얻었다.(1,2,3,4-tetrahydro-1-oxo-isoquinolin-2-yl) acetic acid (2.7 g, 13.0 mmol, in Anderson WK, et al. At 0 ° C. in dimethylformamide (40 ml). , J. Med. Chem., 1988; 31: 2097) and 1-ethyl-3- (3 ') in a solution of H-Asp (OtBu) OMe.HCl (2.9 g, 12.0 mmol). -Dimethylaminopropyl) carbodiimide x HCl (2.5 g, 13.0 mmol) and triethylamine (4.05 g, 40 mmol) were added. This mixture was stirred at rt for 16 h. Most of the solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. The organic phase was washed successively with aqueous sodium hydrogen carbonate solution and water, dried over sodium sulfate and concentrated to give 4.5 g of amorphous residue.

이 잔류물을 디옥산/물 (1:1) 40 ml에 용해시키고, 티모프탈레인의 존재하에 1 N NaOH (12.0 ml)을 적가하여 가수분해시켰다. 대부분의 디옥산을 증발시키고, 물로 희석시킨 후 수용액을 에테르로 추출하고 묽은 HCl로 pH 2-3으로 산성화하고 생성물을 에틸 아세테이트로 추출했다. 유기상을 물로 세척하고 황산나트륨 상에서 건조하고 감압하에서 농축시켜 결정성 N-(1,2,3,4-테트라히드로-1-옥소-이소퀴놀린-2-일)-아세틸 아스파르트산 4-tert-부틸 에스테르 3.4 g을 얻었다.This residue was dissolved in 40 ml of dioxane / water (1: 1) and hydrolyzed by the dropwise addition of 1 N NaOH (12.0 ml) in the presence of timophthalein. Most of the dioxane was evaporated, diluted with water, the aqueous solution was extracted with ether, acidified to pH 2-3 with dilute HCl and the product extracted with ethyl acetate. The organic phase was washed with water, dried over sodium sulfate and concentrated under reduced pressure to afford crystalline N- (1,2,3,4-tetrahydro-1-oxo-isoquinolin-2-yl) -acetyl aspartic acid 4-tert-butyl ester 3.4 g was obtained.

단계 BStep B

-15 ℃에서 테트라히드로푸란 (40 ml) 중의 N-(1,2,3,4-테트라히드로-1-옥소-이소퀴놀린-2-일)-아세틸 아스파르트산 4-tert-부틸 에스테르 (2.8 g, 7.4 mmol)의 용액에 N-메틸모르폴린 (0.75 ml, 8 mmol)을 첨가한 후, 에틸 클로로포르메이트 (0.79 ml, 8 mmol)를 적가했다. 15 분 후 -10 ℃에서 에테르 중의 디아조메탄 0.2 N 용액 50 ml를 적가했다. 반응물을 2 시간 동안 실온에 놓아둔 후 빙초산 중의 48 % HBr (1:1) 용액 15 ml를 0 ℃에서 적가했다. 15 분 동안 교반시킨 후, 반응 혼합물을 에틸 아세테이트에 부었다. 유기상을 탄산수소나트륨 포화수용액과 물로 연속적으로 세척하고 황산나트륨 상에서 건조하고 감압하에서 농축시켜, 3-(1,2,3,4-테트라히드로-1-옥소-이소퀴놀린-2-일)-아세트아미노-5-브로모-4-옥소-펜탄산 tert-부틸 에스테르 (3.1 g)를 얻었다.N- (1,2,3,4-tetrahydro-1-oxo-isoquinolin-2-yl) -acetyl aspartic acid 4-tert-butyl ester in 2.8 g tetrahydrofuran (40 ml) (2.8 g) , 7.4 mmol) was added N-methylmorpholine (0.75 ml, 8 mmol), and then ethyl chloroformate (0.79 ml, 8 mmol) was added dropwise. After 15 minutes 50 ml of a diazomethane 0.2 N solution in ether was added dropwise at -10 ° C. The reaction was left at room temperature for 2 hours before 15 ml of a 48% HBr (1: 1) solution in glacial acetic acid was added dropwise at 0 ° C. After stirring for 15 minutes, the reaction mixture was poured into ethyl acetate. The organic phase was washed successively with saturated aqueous sodium hydrogen carbonate solution and water, dried over sodium sulfate and concentrated under reduced pressure to afford 3- (1,2,3,4-tetrahydro-1-oxo-isoquinolin-2-yl) -acetamino -5-Bromo-4-oxo-pentanoic acid tert-butyl ester (3.1 g) was obtained.

단계 CStep C

디메틸포름아미드 (30 ml) 중의 3-(1,2,3,4-테트라히드로-1-옥소-이소퀴놀린-2-일)-아세트아미노-5-브로모-4-옥소-펜탄산 tert-부틸 에스테르 (0.7 g, 1.5 mmol) 및 불화칼륨 (0.26 g, 4.5 mmol)의 혼합물에 1-나프틸아세트산 (0.28 g, 1.5 mmol)을 첨가했다. 이 혼합물을 실온에서 16 시간 동안 교반시켰다. 대부분의 용매를 감압하에서 증발시키고, 잔류물을 에틸 아세테이트와 물 사이에 분배했다. 유기상을 탄산수소나트륨 수용액 및 물로 연속적으로 세척하고 황산나트륨 상에서 건조했다. 감압하에서 증발시킨 후, 실리카 (디클로로메탄/아세톤 20 : 1로 용출) 상에서 크로마토그래피하여 3-(1,2,3,4-테트라히드로-1-옥소-이소퀴놀린-2-일)-아세트아미노-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르 0.31 g을 얻었다.3- (1,2,3,4-tetrahydro-1-oxo-isoquinolin-2-yl) -acetamino-5-bromo-4-oxo-pentanoic acid tert- in dimethylformamide (30 ml) To a mixture of butyl ester (0.7 g, 1.5 mmol) and potassium fluoride (0.26 g, 4.5 mmol) was added 1-naphthylacetic acid (0.28 g, 1.5 mmol). This mixture was stirred at rt for 16 h. Most of the solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was washed successively with aqueous sodium hydrogen carbonate solution and water and dried over sodium sulfate. After evaporation under reduced pressure, chromatography on silica (eluted with dichloromethane / acetone 20: 1) to 3- (1,2,3,4-tetrahydro-1-oxo-isoquinolin-2-yl) -acetamino 0.31 g of -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid tert-butyl ester was obtained.

단계 DStep D

디클로로메탄 : 트리플루오로아세트산 1 : 1 혼합물 중의 3-(1,2,3,4-테트라히드로-1-옥소-이소퀴놀린-2-일)-아세트아미노-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르 (0.28 g, 0.5 mmol)를 실온에서 45 분 동안 교반시켰다. 감압하에서 증발시키고 디클로로메탄/에테르/헥산으로부터 결정화하여 3-(1,2,3,4-테트라히드로-1-옥소-이소퀴놀린-2-일)-아세트아미노-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 (0.19 g)을 얻었다.Dichloromethane: trifluoroacetic acid 1: 1 mixture 3- (1,2,3,4-tetrahydro-1-oxo-isoquinolin-2-yl) -acetamino-5- (naphthalen-1-yl- Acetoxy) -4-oxo-pentanoic acid tert-butyl ester (0.28 g, 0.5 mmol) was stirred at room temperature for 45 minutes. Evaporate under reduced pressure and crystallize from dichloromethane / ether / hexane to give 3- (1,2,3,4-tetrahydro-1-oxo-isoquinolin-2-yl) -acetamino-5- (naphthalen-1-yl -Acetoxy) -4-oxo-pentanoic acid (0.19 g) was obtained.

융점 117℃-124℃; NMR(d6-DMSO, ppm): 12.5(bs,1H), 8.5(d,1H), 8.1-7.8(m,4H), 7.6-7.4(m,5H), 7.4-7.2(m,2H), 5.0(m,2H), 4.65(dd,1H), 4.25(s,2H), 4.18(dd,2H), 3.6(m,2H), 3.0 (m, 2H), 2.75-2.5(2m,2H)Melting point 117 ° C-124 ° C; NMR (d 6 -DMSO, ppm): 12.5 (bs, 1H), 8.5 (d, 1H), 8.1-7.8 (m, 4H), 7.6-7.4 (m, 5H), 7.4-7.2 (m, 2H) , 5.0 (m, 2H), 4.65 (dd, 1H), 4.25 (s, 2H), 4.18 (dd, 2H), 3.6 (m, 2H), 3.0 (m, 2H), 2.75-2.5 (2m, 2H )

<실시예 5a><Example 5a>

3-(2-메틸-3-펜에틸카르바모일-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- (2-Methyl-3-phenethylcarbamoyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

단계 AStep A

아세토니트릴 100 ml 중의 이타콘산 무수물 (5.00 g, 44.6 mmol) 및 펜에틸아민 (5.95 g, 49.1 mmol)의 용액을 실온의 질소 상태에서 72 시간 동안 교반시켰다. 이 혼합물 (고체가 형성됨)을 농축한 후 EtOAc와 1 N HCl 사이에 분배했다. 유기 추출물을 염수로 세척하고, 건조 (MgSO4)하고 농축하고 잔류물을 디에틸 에테르로부터 결정화하고, 2-(펜에틸카르바모일-메틸)-아크릴산 5.24 g (50 %)을 백색 고체로서 얻었다 (융점 133-140 ℃)A solution of itaconic anhydride (5.00 g, 44.6 mmol) and phenethylamine (5.95 g, 49.1 mmol) in 100 ml of acetonitrile was stirred for 72 hours at room temperature under nitrogen. This mixture (solid formed) was concentrated and then partitioned between EtOAc and 1N HCl. The organic extract was washed with brine, dried (MgSO 4 ) and concentrated and the residue was crystallized from diethyl ether to give 5.24 g (50%) of 2- (phenethylcarbamoyl-methyl) -acrylic acid as a white solid. (Melting point 133-140 ° C)

C13H15NO3S(233.269)에 대한 분석:Analysis of C 13 H 15 NO 3 S (233.269):

이론치: C, 66.94; H, 6.48; N, 6.00Theoretical: C, 66.94; H, 6. 48; N, 6.00

실측치: C, 66.74; H, 6.56; N, 6.00Found: C, 66.74; H, 6.56; N, 6.00

단계 BStep B

THF 100 ml 중의 2-(펜에틸카르바모일-메틸)-아크릴산 (2.76 g, 11.8 mmol, 단계 A)의 용액을 5 % Pd/C (0.2 g)으로 처리하고 실온에서 수소압 52 psi하에서 2.5 시간 동안 수소첨가시켰다. 이 혼합물을 여과하고 농축하여 2-(펜에틸카르보닐-메틸)-프로피온산을 회백색 고체로서 2.39 g (86 %)을 얻었다.A solution of 2- (phenethylcarbamoyl-methyl) -acrylic acid (2.76 g, 11.8 mmol, step A) in 100 ml of THF was treated with 5% Pd / C (0.2 g) and 2.5 at 52 psi hydrogen pressure at room temperature. Hydrogenation for time. This mixture was filtered and concentrated to give 2.39 g (86%) of 2- (phenethylcarbonyl-methyl) -propionic acid as off-white solid.

C13H17NO3(235.285)에 대한 분석:Anal for C 13 H 17 NO 3 (235.285):

이론치: C, 66.36; H, 7.28; N, 5.95Theoretical: C, 66.36; H, 7. 28; N, 5.95

실측치: C, 65.31; H, 7.05; N, 5.80Found: C, 65.31; H, 7.05; N, 5.80

단계 CStep C

디클로로메탄 100 ml 중의 2-(펜에틸카르바모일-메틸)-프로피온산 (1.63 g, 6.93 mmol, 단계 B), H-Asp (OtBu)-OMe·HCl (1.83 g, 7.64 mmol, Bachem Bioscience Inc.에서 구입), 1-히드록시벤조트리아졸 수화물 (1.17 g, 7.64 mmol), N-에틸-N'-(3-디메틸아미노프로필)-카르보디이미드 히드로클로라이드 (1.46 g, 7.62 mmol) 및 4-메틸모르폴린 (0.95 ml, 8.64 mmol)을 24 시간 동안 실온에서 교반시켰다. 이 혼합물을 농축시킨 후 EtOAc와 NaHCO3포화용액 사이에 분배했다. 유기 추출물을 KH2PO4포화용액 및 염수로 세척한 후 건조 (MgSO4)하고, 여과, 농축 및 크로마토그래피 (실리카 겔, 25 % 헥산 - 75 % EtOAc)한 후, 2-(2-메틸-3-펜에틸카르바모일-프로피오닐아미노)-숙신산 4-tert-부틸 에스테르 1-메틸 에스테르 2.54 g (87 %)을 왁스형 백색 고체로서 얻었다.2- (phenethylcarbamoyl-methyl) -propionic acid (1.63 g, 6.93 mmol, step B), H-Asp (OtBu) -OMe.HCl (1.83 g, 7.64 mmol, Bachem Bioscience Inc. in 100 ml of dichloromethane. Purchased from), 1-hydroxybenzotriazole hydrate (1.17 g, 7.64 mmol), N-ethyl-N '-(3-dimethylaminopropyl) -carbodiimide hydrochloride (1.46 g, 7.62 mmol) and 4- Methylmorpholine (0.95 ml, 8.64 mmol) was stirred for 24 hours at room temperature. The mixture was concentrated and partitioned between EtOAc and saturated NaHCO 3 solution. The organic extracts were washed with saturated KH 2 PO 4 solution and brine, dried (MgSO 4 ), filtered, concentrated and chromatographed (silica gel, 25% hexanes-75% EtOAc), then 2- (2-methyl- 2.54 g (87%) of 3-phenethylcarbamoyl-propionylamino) -succinic acid 4-tert-butyl ester 1-methyl ester was obtained as a waxy white solid.

C22H32N2O6(420.510)에 대한 분석:Analysis for C 22 H 32 N 2 O 6 (420.510):

이론치: C, 62.84; H, 7.67; N, 6.66Theoretical: C, 62.84; H, 7.67; N, 6.66

실측치: C, 62.68; H, 7.69; N, 6.54Found: C, 62.68; H, 7.69; N, 6.54

단계 DStep D

에탄올 60 ml 중의 2-(2-메틸-3-펜에틸카르바모일-프로피오닐아미노)-숙신산 4-tert-부틸 에스테르 1-메틸 에스테르 (2.11 g, 5.01 mmol, 단계 C) 및 0.1 N 수산화나트륨 용액 (60.1 ml, 6.01 mmol)의 용액을 12 시간 동안 실온에서 교반시켰다. 용액을 농축하고 KH2PO4포화용액으로 pH 약 5로 산성화하고 클로로포름 (2 x 100 ml)으로 추출했다. 합한 클로로포름 추출물을 건조 (MgSO4), 여과 및 농축하여 2-(2-메틸-3-펜에틸카르바모일-프로피오닐아미노)-숙신산 4-tert-부틸 에스테르 2.23 g (약 100 %)을 무색 오일로서 얻고, 이를 추가의 정제없이 사용했다.2- (2-Methyl-3-phenethylcarbamoyl-propionylamino) -succinic acid 4-tert-butyl ester 1-methyl ester in 60 ml of ethanol (2.11 g, 5.01 mmol, step C) and 0.1 N sodium hydroxide A solution of solution (60.1 ml, 6.01 mmol) was stirred for 12 hours at room temperature. The solution was concentrated, acidified to pH about 5 with saturated KH 2 PO 4 solution and extracted with chloroform (2 × 100 ml). The combined chloroform extracts were dried (MgSO 4 ), filtered and concentrated to give 2.23 g (about 100%) of 2- (2-methyl-3-phenethylcarbamoyl-propionylamino) -succinic acid 4-tert-butyl ester as colorless. Obtained as an oil and used without further purification.

THF 50 ml 중의 2-(2-메틸-3-펜에틸카르바모일-프로피오닐아미노)-숙신산 4-tert-부틸 에스테르 (2.23 g, 5.49 mmol) 및 4-메틸모르폴린 (0.61 ml, 5.73 mmol)의 용액을 클리어-실 (Clear-Seal) 연결 (joint) 250 ml 둥근 플라스크에서 약 -45 ℃ (드라이 아이스-아세토니트릴 슬러리)로 냉각하고, 이소부틸 클로로포르메이트 (0.75 ml, 5.78 mmol)로 처리했다. 즉시 고체가 형성되었으며, 이 혼합물을 15 분 동안 교반시킨 후, 에테르 용액 중의 0.5 M 디아조메탄 (55 ml, 27.5 mmol, Diazald로부터 생성)으로 처리했다. 냉각조를 제거하고, 담황색 용액을 실온에서 2 시간 동안 교반시키고, 0 ℃로 냉각시키고 아세트산 10 ml 중의 48 % 브롬화수소산 (10 ml, 184 mmol)의 용액을 적가했다. 무색 용액을 실온에서 30 분 동안 교반시킨 후 EtOAc와 물 (각각 약 200 ml) 사이에 분배했다. 유기 추출물을 물, NaHCO3및 염수로 세척하고, 건조 (MgSO4), 여과 및 농축하여 2-(2-메틸-3-펜에틸카르바모일-프로피오닐아미노)-5-브로모-4-옥소-펜탄산 tert-부틸 에스테르 1.40 g (53 %)을 담황색 고체로서 얻었다.2- (2-Methyl-3-phenethylcarbamoyl-propionylamino) -succinic acid 4-tert-butyl ester (2.23 g, 5.49 mmol) and 4-methylmorpholine (0.61 ml, 5.73 mmol in 50 ml THF) ) Is cooled to about -45 ° C (dry ice-acetonitrile slurry) in a Clear-Seal joint 250 ml round flask and isobutyl chloroformate (0.75 ml, 5.78 mmol) Processed. A solid formed immediately and the mixture was stirred for 15 minutes and then treated with 0.5 M diazomethane (55 ml, 27.5 mmol, generated from Diazald) in ether solution. The cooling bath was removed and the pale yellow solution was stirred at room temperature for 2 hours, cooled to 0 ° C. and a solution of 48% hydrobromic acid (10 ml, 184 mmol) in 10 ml of acetic acid was added dropwise. The colorless solution was stirred at room temperature for 30 minutes and then partitioned between EtOAc and water (about 200 ml each). The organic extract was washed with water, NaHCO 3 and brine, dried (MgSO 4 ), filtered and concentrated to 2- (2-methyl-3-phenethylcarbamoyl-propionylamino) -5-bromo-4- 1.40 g (53%) of oxo-pentanoic acid tert-butyl ester were obtained as a pale yellow solid.

단계 EStep E

DMF 2.5 ml 중의 2-(2-메틸-3-펜에틸카르바모일-프로피오닐아미노)-5-브로모-4-옥소-펜탄산, tert-부틸 에스테르 (0.70 g, 1.45 mmol, 단계 D), 1-나프틸아세트산 (0.34 g, 1.81 mmol) 및 불화칼륨 (0.21 g, 3.61 mmol)의 혼합물을 12 시간 동안 실온에서 교반시켰다. 이 샘플을 EtOAc 및 NaHCO3포화용액 사이에 분배했다. 유기 추출물을 KH2PO4포화용액 및 염수로 세척하고 건조 (MgSO4), 여과 및 농축했다. 잔류물을 크로마토그래피 (실리카 겔, 25 % 헥산- 75 % EtOAc)하여, 3-(2-메틸-3-펜에틸카르바모일-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르 0.65 g (77 %)을 얻었다.2- (2-Methyl-3-phenethylcarbamoyl-propionylamino) -5-bromo-4-oxo-pentanoic acid, tert-butyl ester (0.70 g, 1.45 mmol, step D) in 2.5 ml of DMF , A mixture of 1-naphthylacetic acid (0.34 g, 1.81 mmol) and potassium fluoride (0.21 g, 3.61 mmol) was stirred at room temperature for 12 hours. This sample was partitioned between EtOAc and saturated NaHCO 3 solution. The organic extract was washed with saturated KH 2 PO 4 solution and brine, dried (MgSO 4 ), filtered and concentrated. The residue is chromatographed (silica gel, 25% hexanes-75% EtOAc) to give 3- (2-methyl-3-phenethylcarbamoyl-propionylamino) -5- (naphthalen-1-yl-acetoxy 0.65 g (77%) of 4-oxo-pentanoic acid tert-butyl ester was obtained.

단계 FStep F

디클로로메탄 20 ml 중의 3-(2-메틸-3-펜에틸카르바모일-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르 (0.62 g, 1.06 mmol, 단계 E) 및 트리플루오로아세트산 (5 ml)의 용액을 1 시간 동안 실온에서 교반시킨 후, 황색 오일로 농축했다. 이 샘플을 EtOAc 및 KH2PO4포화용액 사이에서 분배했다. 유기 추출물을 염수로 세척하고 건조 (MgSO4)하고 여과 및 농축하여 3-(2-메틸-3-펜에틸카르바모일-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 0.51 g (91 %)을 백색 고체로서 얻었다.3- (2-Methyl-3-phenethylcarbamoyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid tert-butyl ester (0.62) in 20 ml of dichloromethane A solution of g, 1.06 mmol, step E) and trifluoroacetic acid (5 ml) was stirred for 1 hour at room temperature and then concentrated to a yellow oil. This sample was partitioned between EtOAc and saturated KH 2 PO 4 solution. The organic extract was washed with brine, dried (MgSO 4 ), filtered and concentrated to 3- (2-methyl-3-phenethylcarbamoyl-propionylamino) -5- (naphthalen-1-yl-acetoxy)- 0.51 g (91%) of 4-oxo-pentanoic acid was obtained as a white solid.

C30H32N2O7·1/3H2O(538.604)에 대한 분석:Analysis for C 30 H 32 N 2 O 7 1 / 3H 2 O (538.604):

이론치: C, 66.90; H, 6.11; N, 5.20Theoretical: C, 66.90; H, 6. 11; N, 5.20

실측치: C, 66.90; H, 6.14; N, 5.10Found: C, 66.90; H, 6. 14; N, 5.10

실시예 5와 유사한 방법으로 상응하는 화합물들을 제조했다.Corresponding compounds were prepared in a similar manner to Example 5.

<실시예 5b><Example 5b>

5-(나프탈렌-2-일-아세톡시)-4-옥소-3-[2-(2-옥소-6-페닐-피페리딘-1-일)-아세틸아미노]-펜탄산 (부분입체이성질체의 혼합물로서 얻음)5- (Naphthalen-2-yl-acetoxy) -4-oxo-3- [2- (2-oxo-6-phenyl-piperidin-1-yl) -acetylamino] -pentanoic acid (diastereomer Obtained as a mixture of

1H NMR (d6-DMSO):δ12.5(1H,s), 8.38(1H,2d), 7.90-7.75(4H,m), 7.50-7.10(8H,m), 4.90(2H,dd), 4.70-4.50(2H,m), 4.40(1H,m), 3.90(2H,s), 3.0(1H,dd), 2.7(1H,m), 2.40-2.30(2H,m), 2.20(1H,m) 1.8-1.5(4H,m) 출발산인 6-페닐-피페리딘-2-온은 문헌 (L.D. Desaubry, C. G. Wermuth and J.J. Bourguignon, Tetrahedron Lett., 1995; 36: 4249)에 따라서 제조한 후 에틸 브로모아세테이트로 알킬화 (NaH/톨루엔; 110 ℃에서 1 시간)한 후, 알칼리성 가수분해시켰다. 1 H NMR (d 6 -DMSO): δ12.5 (1H, s), 8.38 (1H, 2d), 7.90-7.75 (4H, m), 7.50-7.10 (8H, m), 4.90 (2H, dd) , 4.70-4.50 (2H, m), 4.40 (1H, m), 3.90 (2H, s), 3.0 (1H, dd), 2.7 (1H, m), 2.40-2.30 (2H, m), 2.20 (1H , m) 6-phenyl-piperidin-2-one, a 1.8-1.5 (4H, m) starting acid, was prepared according to LD Desaubry, CG Wermuth and JJ Bourguignon, Tetrahedron Lett., 1995; 36: 4249 Then alkylated with ethyl bromoacetate (NaH / toluene; 1 h at 110 ° C.) followed by alkaline hydrolysis.

<실시예 5c><Example 5c>

5-(나프탈렌-1-일-아세톡시)-4-옥소-3-[2-(2-옥소-6-페닐-피페리딘-1-일)-아세틸아미노]-펜탄산 (부분입체이성질체의 혼합물로서 얻어짐)5- (Naphthalen-1-yl-acetoxy) -4-oxo-3- [2- (2-oxo-6-phenyl-piperidin-1-yl) -acetylamino] -pentanoic acid (diastereomer Obtained as a mixture of

1H NMR (d6-DMSO):δ13.0-12.0(1H,bs), 8.4(1H,m), 8.1-7.8(3H,m), 7.6-7.0(9H,m), 5.05-4.8(2H,m), 4.70-4.50(2H,m), 4.45-4.35(1H,m), 4.25(2H,s), 3.0(1H,m), 2.7(1H,m), 2.5(DMSO+1H,m), 2.40(2H,m), 2.10(1H,m) 1.8-1.5(3H,m) 출발산인 6-페닐-피페리딘-2-온은 실시예 5b에 기재된 바와 같이 제조했다. 1 H NMR (d 6 -DMSO): δ13.0-12.0 (1H, bs), 8.4 (1H, m), 8.1-7.8 (3H, m), 7.6-7.0 (9H, m), 5.05-4.8 ( 2H, m), 4.70-4.50 (2H, m), 4.45-4.35 (1H, m), 4.25 (2H, s), 3.0 (1H, m), 2.7 (1H, m), 2.5 (DMSO + 1H, m), 2.40 (2H, m), 2.10 (1H, m) 1.8-1.5 (3H, m) starting acid 6-phenyl-piperidin-2-one was prepared as described in Example 5b.

<실시예 5d>Example 5d

3-[3-메틸-2-(3-페닐-프로피오닐아미노)-부티릴아미노]-4-옥소-5-[(1-옥소-1,2,3,4-테트라히드로-나프탈렌-2-일)-아세톡시]-펜탄산3- [3-methyl-2- (3-phenyl-propionylamino) -butyrylamino] -4-oxo-5-[(1-oxo-1,2,3,4-tetrahydro-naphthalene-2 -Yl) -acetoxy] -pentanoic acid

MS (ESI) m/z 565.2 (M+1)MS (ESI) m / z 565.2 (M + 1)

<실시예 5e><Example 5e>

5-(나프탈렌-2-일-아세톡시)-4-옥소-3-[2-(1-옥소-3,4-디히드로-1H-이소퀴놀린-2-일)-아세틸아미노]-펜탄산5- (Naphthalen-2-yl-acetoxy) -4-oxo-3- [2- (1-oxo-3,4-dihydro-1 H-isoquinolin-2-yl) -acetylamino] -pentanoic acid

1H NMR (d6-DMSO):δ12.5(1H,m) 8.6(1H,d), 8.0-7.8(5H,m), 7.55-7.25(6H,2m), 4.95(2H,dd), 4.65(1H,dd), 4.15(2H,s), 3.95(2H,s), 3.55(2H,dd), 3.0(2H,m), 2.75(1H,dd), 2.6(1H,m). 출발산인 1-옥소-3,4-디히드로-1H-이소퀴놀린-2-일)-아세트산은 실시예 5에 기재된 바와 같이 제조했다. 1 H NMR (d 6 -DMSO): δ12.5 (1H, m) 8.6 (1H, d), 8.0-7.8 (5H, m), 7.55-7.25 (6H, 2m), 4.95 (2H, dd), 4.65 (1H, dd), 4.15 (2H, s), 3.95 (2H, s), 3.55 (2H, dd), 3.0 (2H, m), 2.75 (1H, dd), 2.6 (1H, m). Starting acid 1-oxo-3,4-dihydro-1H-isoquinolin-2-yl) -acetic acid was prepared as described in Example 5.

<실시예 5f><Example 5f>

5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-3-[2-(1-옥소-3,4-디히드로-1H-이소퀴놀린-2-일)-아세틸아미노]-펜탄산5- (2-benzyl-3-phenyl-propionyloxy) -4-oxo-3- [2- (1-oxo-3,4-dihydro-1 H-isoquinolin-2-yl) -acetylamino] -Pentanoic acid

MS (ESI) m/z 557.2 (M+1)MS (ESI) m / z 557.2 (M + 1)

출발산 (1-옥소-3,4-디히드로-1H-이소퀴놀린-2-일)-아세트산은 실시예 5에 기재된 바와 같이 제조했다.Starting acid (1-oxo-3,4-dihydro-1H-isoquinolin-2-yl) -acetic acid was prepared as described in Example 5.

<실시예 5g><Example 5g>

5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-3-[2-(2-옥소-6-페닐-피페리딘-1-일)-아세틸아미노]-펜탄산 (부분입체이성질체의 혼합물로서 얻어짐)5- (2-Benzyl-3-phenyl-propionyloxy) -4-oxo-3- [2- (2-oxo-6-phenyl-piperidin-1-yl) -acetylamino] -pentanoic acid ( Obtained as a mixture of diastereomers)

1H NMR (d6-DMSO):δ12.5(1H,bs), 8.35(1H, 2d), 7.4-7.1(15H,m), 4.75(2H,dd), 4.6(2H,m), 4.40(1H,m), 3.1-2.5(8H,m), 2.35(2H,m), 2.10(1H,m) 1.8-1.5(3H,m) 출발산인 6-페닐-피페리딘-2-온은 실시예 5b에 기재된 바와 같이 제조했다. 1 H NMR (d 6 -DMSO): δ12.5 (1H, bs), 8.35 (1H, 2d), 7.4-7.1 (15H, m), 4.75 (2H, dd), 4.6 (2H, m), 4.40 (1H, m), 3.1-2.5 (8H, m), 2.35 (2H, m), 2.10 (1H, m) 1.8-1.5 (3H, m) starting acid 6-phenyl-piperidin-2-one Prepared as described in Example 5b.

<실시예 5h><Example 5h>

5-(나프탈렌-1-일-아세톡시)-4-옥소-3-[2-(1-옥소-1,2,3,4-테트라히드로-나프탈렌-2-일)-아세틸아미노]-펜탄산5- (naphthalen-1-yl-acetoxy) -4-oxo-3- [2- (1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl) -acetylamino] -phen Carbonic acid

MS (ESI) m/z 483.5 (M-H2O). 출발산인 (1-옥소-3,4-디히드로-1H-이소퀴놀린-2-일)-아세트산은 실시예 5에 기재된 바와 같이 제조했다.MS (ESI) m / z 483.5 (M-H 2 O). Starting acid (1-oxo-3,4-dihydro-1H-isoquinolin-2-yl) -acetic acid was prepared as described in Example 5.

<실시예 5i><Example 5i>

5-(나프탈렌-1-일-아세톡시)-4-옥소-3-[2-(1-옥소-3,4-디히드로-1H-이소퀴놀린-2-일)-프로피오닐아미노]-펜탄산5- (naphthalen-1-yl-acetoxy) -4-oxo-3- [2- (1-oxo-3,4-dihydro-1 H-isoquinolin-2-yl) -propionylamino] -phen Carbonic acid

MS (ESI) m/z 517.4 (M+1). 출발산인 2-(1-옥소-3,4-디히드로-1H-이소퀴놀린-2-일)-프로피온산은 에틸 2-브로모프로피오네이트로부터 출발하여 실시예 5의 문헌 공정과 유사하게 제조했다.MS (ESI) m / z 517.4 (M + l). The starting acid 2- (1-oxo-3,4-dihydro-1H-isoquinolin-2-yl) -propionic acid was prepared analogously to the literature process of Example 5 starting from ethyl 2-bromopropionate. .

<실시예 5j><Example 5j>

5-(나프탈렌-2-일-아세톡시)-4-옥소-3-[2-(1-옥소-3,4-디히드로-1H-이소퀴놀린-2-일)-프로피오닐아미노]-펜탄산5- (naphthalen-2-yl-acetoxy) -4-oxo-3- [2- (1-oxo-3,4-dihydro-1 H-isoquinolin-2-yl) -propionylamino] -phen Carbonic acid

MS (ESI) m/z 517.3 (M+1). 출발산인 2-(1-옥소-3,4-디히드로-1H-이소퀴놀린-2-일)-프로피온산은 실시예 5i에 기재된 바와 같이 제조했다.MS (ESI) m / z 517.3 (M + l). The starting acid 2- (1-oxo-3,4-dihydro-1H-isoquinolin-2-yl) -propionic acid was prepared as described in Example 5i.

<실시예 5k><Example 5k>

3-[4-(1-벤젠술포닐-1H-피롤-2-일)-4-옥소-부티릴아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- [4- (1-Benzenesulfonyl-1H-pyrrole-2-yl) -4-oxo-butyrylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

MS (ESI) m/z 605.4 (M+1). 출발산인 4-(1-벤젠술포닐-1H-피롤-2-일)-4-옥소-부틸산은 문헌 (M. Kakushima, et al., J. Org. Chem., 1983; 48: 3214)의 공정에 따라서 제조했다.MS (ESI) m / z 605.4 (M + l). The starting acid 4- (1-benzenesulfonyl-1H-pyrrole-2-yl) -4-oxo-butyl acid is described in M. Kakushima, et al., J. Org. Chem., 1983; 48: 3214. It manufactured according to the process.

<실시예 5l><Example 5l>

5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-3-[2-(1-옥소-1,2,3,4-테트라히드로-나프탈렌-2-일)-아세틸아미노]-펜탄산5- (2-Benzyl-3-phenyl-propionyloxy) -4-oxo-3- [2- (1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl) -acetylamino ] -Pentanoic acid

MS (ESI) m/z 556.4 (M+1). 출발산인 (1-옥소-3,4-디히드로-1H-이소퀴놀린-2-일)-아세트산은 실시예 5에 기재된 바와 같이 제조했다.MS (ESI) m / z 556.4 (M + l). Starting acid (1-oxo-3,4-dihydro-1H-isoquinolin-2-yl) -acetic acid was prepared as described in Example 5.

<실시예 5m><Example 5m>

5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-3-[2-(1-옥소-3,4-디히드로-1H-이소퀴놀린-2-일)-프로피오닐아미노]-펜탄산 (부분입체이성질체의 혼합물로서 얻어짐)5- (2-Benzyl-3-phenyl-propionyloxy) -4-oxo-3- [2- (1-oxo-3,4-dihydro-1 H-isoquinolin-2-yl) -propionylamino ] -Pentanoic acid (obtained as a mixture of diastereomers)

1H NMR (d6-DMSO):δ12.5(1H,m), 8.5(1H,m), 7.9(1H,m), 7.45-7.10(13H,m), 5.2(1H,m), 4.8(2H,m), 4.65(2H,m), 3.55(2H,m), 3.1-2.65(9H,m), 1.3(3H,d). 출발산인 2-(1-옥소-3,4-디히드로-1H-이소퀴놀린-2-일)-프로피온산을 실시예 5i에 기재된 바와 같이 제조했다. 1 H NMR (d 6 -DMSO): δ12.5 (1H, m), 8.5 (1H, m), 7.9 (1H, m), 7.45-7.10 (13H, m), 5.2 (1H, m), 4.8 (2H, m), 4.65 (2H, m), 3.55 (2H, m), 3.1-2.65 (9H, m), 1.3 (3H, d). Starting acid, 2- (1-oxo-3,4-dihydro-1H-isoquinolin-2-yl) -propionic acid, was prepared as described in Example 5i.

<실시예 5n><Example 5n>

4-옥소-3-[2-(1-옥소-3,4-디히드로-1H-이소퀴놀린-2-일)-프로피오닐아미노]-5-[(1-옥소-1,2,3,4-테트라히드로-나프탈렌-2-일)-아세톡시]-펜탄산 (부분입체이성질체의 혼합물로서 얻어짐)4-oxo-3- [2- (1-oxo-3,4-dihydro-1 H-isoquinolin-2-yl) -propionylamino] -5-[(1-oxo-1,2,3, 4-tetrahydro-naphthalen-2-yl) -acetoxy] -pentanoic acid (obtained as a mixture of diastereomers)

1H NMR (d6-DMSO):δ12.5(1H,s), 8.6-8.5(1H,2d), 7.9(2H, m), 7.6-7.2(6H,m), 5.3-5.1(1H,m), 4.9(2H,s), 4.7(1H,m), 3.45(2H,m), 3.2-2.5(9H,m), 2.2(1H,m), 1.95(1H,m), 1.3(3H,d). 출발산인 2-(1-옥소-3,4-디히드로-1H-이소퀴놀린-2-일)-프로피온산을 실시예 5i에 기재된 바와 같이 제조했다. 1 H NMR (d 6 -DMSO): δ12.5 (1H, s), 8.6-8.5 (1H, 2d), 7.9 (2H, m), 7.6-7.2 (6H, m), 5.3-5.1 (1H, m), 4.9 (2H, s), 4.7 (1H, m), 3.45 (2H, m), 3.2-2.5 (9H, m), 2.2 (1H, m), 1.95 (1H, m), 1.3 (3H , d). Starting acid, 2- (1-oxo-3,4-dihydro-1H-isoquinolin-2-yl) -propionic acid, was prepared as described in Example 5i.

<실시예 5o><Example 5o>

3-[4-(1-벤젠술포닐-1H-피롤-2-일)-4-옥소-부티릴아미노]-5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-펜탄산3- [4- (1-benzenesulfonyl-1H-pyrrole-2-yl) -4-oxo-butyrylamino] -5- (2-benzyl-3-phenyl-propionyloxy) -4-oxo- Pentanic acid

MS (ESI) m/z 659.4 (M+1). 출발산인 4-(1-벤젠술포닐-1H-피롤-2-일)-4-옥소-부틸산을 실시예 5k에 대해 기재된 바와 같이 제조했다.MS (ESI) m / z 659.4 (M + l). Starting acid, 4- (1-benzenesulfonyl-1H-pyrrole-2-yl) -4-oxo-butyl acid, was prepared as described for Example 5k.

<실시예 5p><Example 5p>

4-옥소-5-[(1-옥소-1,2,3,4-테트라히드로-나프탈렌-2-일)-아세톡시]-3-[2-(1-옥소-1,2,3,4-테트라히드로-나프탈렌-2-일)-아세틸아미노]-펜탄산4-oxo-5-[(1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl) -acetoxy] -3- [2- (1-oxo-1,2,3, 4-tetrahydro-naphthalen-2-yl) -acetylamino] -pentanoic acid

MS (ESI) m/z 520.2 (M+1). 출발산 (1-옥소-3,4-디히드로-1H-이소퀴놀린-2-일)-아세트산을 실시예 5에 기재된 바와 같이 제조했다.MS (ESI) m / z 520.2 (M + l). Starting acid (1-oxo-3,4-dihydro-1 H-isoquinolin-2-yl) -acetic acid was prepared as described in Example 5.

<실시예 5q><Example 5q>

5-(나프탈렌-1-일-아세톡시)-4-옥소-3-[2-(2-옥소-3-페닐-이미다졸리딘-1-일)-프로피오닐아미노]-펜탄산5- (Naphthalen-1-yl-acetoxy) -4-oxo-3- [2- (2-oxo-3-phenyl-imidazolidin-1-yl) -propionylamino] -pentanoic acid

MS (ESI) m/z 518.2 (M+1). 출발산 2-(2-옥소-3-페닐-이미다졸리딘-1-일)-프로피온산은 바샤 (Basha)의 문헌 (실시예 5s 참조)의 방법에 따라 제조한 후 알킬화하고 이어서 알칼리성 가수분해시켰다.MS (ESI) m / z 518.2 (M + l). Starting acid 2- (2-oxo-3-phenyl-imidazolidin-1-yl) -propionic acid was prepared according to the method of Basha's literature (see Example 5s), followed by alkylation followed by alkaline hydrolysis. I was.

<실시예 5r><Example 5r>

5-(나프탈렌-1-일-아세톡시)-4-옥소-3-[2-(2-옥소-3-페닐-테트라히드로-피리미딘-1-일)-프로피오닐아미노]-펜탄산5- (Naphthalen-1-yl-acetoxy) -4-oxo-3- [2- (2-oxo-3-phenyl-tetrahydro-pyrimidin-1-yl) -propionylamino] -pentanoic acid

MS (ESI) m/z 546.3 (M+1). 출발산인 2-(2-옥소-3-페닐-테트라히드로피리딘-2-일)-프로피온산은 2-옥소-3-페닐-테트라히드로피리미딘으로부터 제조 (바샤의 문헌 참조, 실시예 5s)한 후, 에틸 2-브로모-프로피오네이트로 알킬화한 후 알칼리성 가수분해시켰다.MS (ESI) m / z 546.3 (M + l). Starting acid, 2- (2-oxo-3-phenyl-tetrahydropyridin-2-yl) -propionic acid, was prepared from 2-oxo-3-phenyl-tetrahydropyrimidine (see, eg, Basha, Example 5s). And alkylated with ethyl 2-bromo-propionate followed by alkaline hydrolysis.

<실시예 5s><Example 5s>

5-(나프탈렌-1-일-아세톡시)-4-옥소-3-[2-(2-옥소-3-페닐-테트라히드로-피리미딘-1-일)-아세틸아미노]-펜탄산5- (Naphthalen-1-yl-acetoxy) -4-oxo-3- [2- (2-oxo-3-phenyl-tetrahydro-pyrimidin-1-yl) -acetylamino] -pentanoic acid

MS (ESI) m/z 532.3 (M+1). 1-페닐-테트라히드로피리미딘-2-온은 문헌 (A. Basha, Tetrahedron Lett., 1988; 29: 2525)의 공정에 따라서 제조한 후 에틸 브로모아세테이트로 알킬화한 후 (NaH/DMF; 실온에서 16 시간), 알칼리성 가수분해시켰다.MS (ESI) m / z 532.3 (M + l). 1-phenyl-tetrahydropyrimidin-2-one was prepared according to the process of A. Basha, Tetrahedron Lett., 1988; 29: 2525 and then alkylated with ethyl bromoacetate (NaH / DMF; room temperature). 16 hours), alkaline hydrolysis.

<실시예 5t><Example 5t>

3-(2-아세틸아미노-3-메틸-부티릴아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- (2-Acetylamino-3-methyl-butyrylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

MS (ESI) m/z 455.3 (M-H)MS (ESI) m / z 455.3 (M-H)

<실시예 5u><Example 5u>

3-(2-아세틸아미노-3-메틸-부티릴아미노)-5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-펜탄산3- (2-Acetylamino-3-methyl-butyrylamino) -5- (2-benzyl-3-phenyl-propionyloxy) -4-oxo-pentanoic acid

MS (ESI) m/z 511.3 (M+1)MS (ESI) m / z 511.3 (M + 1)

<실시예 5v><Example 5v>

3-(2-아세틸아미노-3-메틸-부티릴아미노)-5-(3-벤질-4-페닐-부티릴옥시)-4-옥소-펜탄산3- (2-Acetylamino-3-methyl-butyrylamino) -5- (3-benzyl-4-phenyl-butyryloxy) -4-oxo-pentanoic acid

MS (ESI) m/z 525.3 (M+1)MS (ESI) m / z 525.3 (M + 1)

<실시예 5w><Example 5w>

3-(2-아세틸아미노-3-메틸-부티릴아미노)-5-(4-벤질-5-페닐-펜타노일옥시)-4-옥소-펜탄산3- (2-Acetylamino-3-methyl-butyrylamino) -5- (4-benzyl-5-phenyl-pentanoyloxy) -4-oxo-pentanoic acid

MS (ESI) m/z 537.3 (M-1)MS (ESI) m / z 537.3 (M-1)

<실시예 5x><Example 5x>

3-(2-아세틸아미노-3-메틸-부티릴아미노)-4-옥소-5-[(1-옥소-1,2,3,4-테트라히드로-나프탈렌-2-일)-아세톡시]-펜탄산3- (2-acetylamino-3-methyl-butyrylamino) -4-oxo-5-[(1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl) -acetoxy] -Pentanoic acid

MS (ESI) m/z 475.3 (M+1)MS (ESI) m / z 475.3 (M + 1)

<실시예 5y><Example 5y>

5-(3-벤질-4-페닐-부티릴옥시)-3-[3-메틸-2-(3-페닐-프로피오닐아미노)-부티릴아미노]-4-옥소-펜탄산5- (3-Benzyl-4-phenyl-butyryloxy) -3- [3-methyl-2- (3-phenyl-propionylamino) -butyrylamino] -4-oxo-pentanoic acid

MS (ESI) m/z 601.3 (M+1)MS (ESI) m / z 601.3 (M + 1)

<실시예 5z><Example 5z>

3-[2-(3-아세틸아미노-2-옥소-2H-피리딘-1-일)-아세틸아미노]-5-(3,3-디페닐-프로피오닐옥시)-4-옥소-펜탄산 (핑크빛 조분말)3- [2- (3-acetylamino-2-oxo-2H-pyridin-1-yl) -acetylamino] -5- (3,3-diphenyl-propionyloxy) -4-oxo-pentanoic acid ( Pink powder)

출발산은 문헌 (Bioorganic & Medicinal Chemistry Letters, 1997; 7: 1337-1342)에 기재된 바와 같이 제조했다.Starting acids were prepared as described in Bioorganic & Medicinal Chemistry Letters, 1997; 7: 1337-1342.

C29H29N3O8·0.585CF3CO2H(614.274)에 대한 분석:Analysis of C 29 H 29 N 3 O 8 0.585CF 3 CO 2 H (614.274):

이론치: C, 58.99; H, 4.86; N, 6.84.Theoretical: C, 58.99; H, 4.86; N, 6.84.

실측치: C, 59.38; H, 5.16; N, 6.20Found: C, 59.38; H, 5. 16; N, 6.20

<실시예 5aa>Example 5aa

3-[2-(3-아세틸아미노-2-옥소-2H-피리딘-1-일)-아세틸아미노]-5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-펜탄산 (갈색 미분말)3- [2- (3-acetylamino-2-oxo-2H-pyridin-1-yl) -acetylamino] -5- (2-benzyl-3-phenyl-propionyloxy) -4-oxo-pentanoic acid (Brown fine powder)

출발산은 문헌 (Bioorganic & Medicinal Chemistry Letters, 1997; 7: 1337-1342)에 기재된 바와 같이 제조했다.Starting acids were prepared as described in Bioorganic & Medicinal Chemistry Letters, 1997; 7: 1337-1342.

C30H31N3O8·0.468CF3CO2H(614.960)에 대한 분석:C 30 H 31 N 3 O 8 .0.468CF 3 CO 2 H (614.960) for analysis:

이론치: C, 60.42; H, 5.16; N, 6.83Theoretical: C, 60.42; H, 5. 16; N, 6.83

실측치: C, 60.82; H, 5.39; N, 6.42Found: C, 60.82; H, 5.39; N, 6.42

<실시예 6><Example 6>

3-[2-(2-벤질옥시카르보닐아미노-4-카르복시-부티릴아미노)-3-메틸-부티릴아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- [2- (2-benzyloxycarbonylamino-4-carboxy-butyrylamino) -3-methyl-butyrylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-phen Carbonic acid

단계 AStep A

디클로로메탄 500 ml중의 HCl·H-Asp(OtBu)-OMe (13.1 g, 54.6 mmol), Z-Val-OH (15.1 g, 60.1 mmol), HOBT·H2O (9.2 g, 60.0 mmol), 1-에틸-3-(3'-디메틸아미노프로필)카르보디이미드 히드로클로라이드 (EDCl·HCl, 11.5 g, 60.0 mmol) 및 4-메틸모르폴린 (7.5 ml, 68.2 mmol)의 혼합물을 12 시간 동안 질소 상태의 실온에서 교반시켰다. 이 혼합물을 농축한 후 에틸 아세테이트와 NaHCO3포화용액 사이에 분배했다. 유기 추출물을 KH2PO4포화용액 및 염수로 세척하고 건조 (MgSO4), 여과 및 농축하여 2-(2-벤질옥시-카르보닐아미노-3-메틸-부티릴아미노)-숙신산 4-tert-부틸 에스테르 1-메틸 에스테르 23.9 g (약 100 %)을 백색 고체로 얻었다. MS (APCI) m/z (상대 강도) 436.9 (M+, 100), 380.9 (M-56, 94).HCl.H-Asp (OtBu) -OMe (13.1 g, 54.6 mmol), Z-Val-OH (15.1 g, 60.1 mmol), HOBT.H 2 O (9.2 g, 60.0 mmol) in 500 ml of dichloromethane, 1 A mixture of -ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (EDCl.HCl, 11.5 g, 60.0 mmol) and 4-methylmorpholine (7.5 ml, 68.2 mmol) was nitrogen for 12 hours. Stirred at room temperature. The mixture was concentrated and partitioned between ethyl acetate and saturated NaHCO 3 solution. The organic extract was washed with saturated KH 2 PO 4 solution and brine, dried (MgSO 4 ), filtered and concentrated to 2- (2-benzyloxy-carbonylamino-3-methyl-butyrylamino) -succinic acid 4-tert- 23.9 g (about 100%) of butyl ester 1-methyl ester were obtained as a white solid. MS (APCI) m / z (relative intensity) 436.9 (M +, 100), 380.9 (M-56, 94).

단계 BStep B

EtOH : THF (5 : 1) 600 ml 중의 2-(2-벤질옥시카르보닐아미노-3-메틸-부티릴아미노)-숙신산 4-tert-부틸 에스테르 1-메틸 에스테르 (23.8 g, 54.5 mmol, 실시예 6의 단계 A) 및 진한 염산 (5.0 ml, 60.5 mmol)의 용액을 20 % Pd/C (2.0 g)으로 처리하고, 실온의 수소압 50 psig에서 1.2 시간 동안 수소첨가했다. 이 샘플을 여과 및 농축했다. 생성된 오일을 디에틸 에테르로 세척하고, 여과 및 진공 건조하여 2-(2-아미노-3-메틸-부티릴아미노)-숙신산 4-tert-부틸 에스테르 1-메틸 에스테르 히드로클로라이드 16.5 g을 백색 고체로서 얻었다 (융점 166 - 167 ℃) MS (APCI) m/z (상대세기) 302.1 (M, 20), 301.1 (M-1, 100).EtOH: 2- (2-benzyloxycarbonylamino-3-methyl-butyrylamino) -succinic acid 4-tert-butyl ester 1-methyl ester in 600 ml of THF (5: 1) (23.8 g, 54.5 mmol, carried out Example A) and a solution of concentrated hydrochloric acid (5.0 ml, 60.5 mmol) in Example 6 were treated with 20% Pd / C (2.0 g) and hydrogenated at 50 psig hydrogen pressure at room temperature for 1.2 hours. This sample was filtered and concentrated. The resulting oil was washed with diethyl ether, filtered and vacuum dried to afford 16.5 g of 2- (2-amino-3-methyl-butyrylamino) -succinic acid 4-tert-butyl ester 1-methyl ester hydrochloride as a white solid. Obtained as (melting point 166-167 ° C) MS (APCI) m / z (relative strength) 302.1 (M, 20), 301.1 (M-1, 100).

C14H26N2O5·HCl(338.835)에 대한 분석:Anal for C 14 H 26 N 2 O 5 HCl (338.835):

이론치: C, 49.63; H, 8.03; N, 8.27.Theoretical: C, 49.63; H, 8.03; N, 8.27.

실측치: C, 49.62; H, 8.19; N, 8.21.Found: C, 49.62; H, 8. 19; N, 8.21.

단계 CStep C

디클로로메탄 500 ml 중의 HCl·H-ValAsp (OtBu)-OMe (2-(2-아미노-3-메틸-부티릴아미노)-숙신산 4-tert-부틸 에스테르 1-메틸 에스테르 히드로클로라이드 (15.4 g, 45.6 mmol, 실시예 6의 단계 B), Z-Glu(OtBu)-OH (15.8 g, 46.9 mmol), HOBT·H2O (7.7 g, 50.1 mmol), EDCl·HCl (9.6 g, 50.1 mmol) 및 4-메틸모르폴린 (6.3 ml, 57.3 mmol)의 혼합물을 실온에서 12 시간 동안 질소 상태에서 교반시켰다. 이 혼합물을 농축시킨 후 에틸 아세테이트 및 NaHCO3포화용액 사이에 분배했다. 이 유기 추출물을 KH2PO4포화용액 및 염수로 세척하고, 건조 (MgSO4), 여과 및 농축하여 Z-Glu(OtBu)ValAsp(OtBu)-OMe[2-[2-(2-벤질옥시카르보닐아미노-4-tert-부톡시카르보닐-부티릴아미노)-3-메틸-부티릴아미노]-숙신산 4-tert-부틸 에스테르 1-메틸 에스테르] 26.3 g (93 %)을 백색 고체로서 얻었다. MS (APCI) m/z (상대 세기) 622.0 (M, 100), 565.9 (M-56, 68)HClH-ValAsp (OtBu) -OMe (2- (2-amino-3-methyl-butyrylamino) -succinic acid 4-tert-butyl ester 1-methyl ester hydrochloride in 500 ml of dichloromethane (15.4 g, 45.6 mmol, step B) of Example 6, Z-Glu (OtBu) -OH (15.8 g, 46.9 mmol), HOBT.H 2 O (7.7 g, 50.1 mmol), EDCl.HCl (9.6 g, 50.1 mmol) and 4-methylmorpholine and the mixture of (6.3 ml, 57.3 mmol) for 12 hours at room temperature and stirred under a nitrogen condition. after the mixture was concentrated and partitioned between ethyl acetate and NaHCO 3 saturated solution. the organic extract KH 2 Washed with saturated PO 4 solution and brine, dried (MgSO 4 ), filtered and concentrated to Z-Glu (OtBu) ValAsp (OtBu) -OMe [2- [2- (2-benzyloxycarbonylamino-4-tert -Butoxycarbonyl-butyrylamino) -3-methyl-butyrylamino] -succinic acid 4-tert-butyl ester 1-methyl ester] 26.3 g (93%) was obtained as a white solid MS (APCI) m / z (relative century) 622.0 (M, 100), 565.9 (M-56, 68)

C31H47N3O10(621.734)에 대한 분석:Anal for C 31 H 47 N 3 O 10 (621.734):

이론치: C, 59.89; H, 7.62; N, 6.76.Theoretical: C, 59.89; H, 7.62; N, 6.76.

실측치: C, 59.88; H, 7.63; N, 6.70.Found: C, 59.88; H, 7.63; N, 6.70.

단계 DStep D

에탄올 300 ml 중의 Z-Glu(OtBu)ValAsp(OtBu)ValAsp(OtBu)-OMe (17.2 g, 27.6 mmol, 실시예 6의 단계 C) 및 0.1 N 수산화나트륨 (330 ml, 33.0 mmol)의 용액을 실온에서 1 시간 동안 질소 상태에서 교반시켰다. 약간 흐린 용액을 농축시키고 (대부분의 에탄올 제거), KH2PO4포화용액을 사용하여 pH 약 5로 산성화하고 클로로포름 : 메탄올 (9 : 1) 500 ml로 2회 추출했다. 합한 유기 추출물을 건조 (MgSO4)하고, 여과하고 농축하여 Z-Glu(OtBu)ValAsp(OtBu)-OH 15.0 g (89 %)을 발포성 백색 고체로 얻었다.A solution of Z-Glu (OtBu) ValAsp (OtBu) ValAsp (OtBu) -OMe (17.2 g, 27.6 mmol, step C of Example 6) and 0.1 N sodium hydroxide (330 ml, 33.0 mmol) in 300 ml of ethanol was room temperature Stirred under nitrogen for 1 hour. The slightly cloudy solution was concentrated (most of the ethanol removed), acidified to pH about 5 with saturated KH 2 PO 4 solution and extracted twice with 500 ml of chloroform: methanol (9: 1). The combined organic extracts were dried (MgSO 4 ), filtered and concentrated to give 15.0 g (89%) of Z-Glu (OtBu) ValAsp (OtBu) -OH as an effervescent white solid.

C30N45N3O10(607.707)에 대한 분석:Analysis for C 30 N 45 N 3 O 10 (607.707):

이론치: C, 59.29; H, 7.46; N, 6.91.Theoretical: C, 59.29; H, 7. 46; N, 6.91.

실측치: C, 59.26; H, 7.57; N, 6.54.Found: C, 59.26; H, 7.57; N, 6.54.

단계 EStep E

약 -40 ℃ (드라이 아이스 CH3CN 조)에서 THF 200 ml 중의 Z-Glu(OtBu)ValAsp(OtBu)-OH (14.9 g, 24.6 mmol) 및 4-메틸모르폴린 (2.7 ml, 24.6 mmol)의 용액을 이소-부틸 클로로포르메이트 (3.2 ml, 24.6 mmol)로 처리했다. 즉시 고체가 형성되었다. 이 샘플을 15 분 동안 교반시킨 후, 냉각 디아조메탄 (에테르 용액 300 ml, Diazald 대신에 새로히 제조됨)으로 처리했다. 이 샘플을 2 시간 동안 실온에서 교반시키고, 0 ℃로 냉각하고, 48 % 브롬산 - 아세트산 용액 (각각 35 ml)을 적가하여 반응을 중지시켰다. 얼음조를 제거하고, 샘플을 30 분 동안 실온에서 교반시킨 후 에틸 아세테이트-물 (각각 500 ml)로 추출했다. 유기 추출물을 물, NaHCO3포화용액 및 염수로 세척하고 건조 (MgSO4), 여과 및 농축했다. 잔류물을 디클로로메탄-헥산으로부터 결정화하여 3-[2-(2-벤질옥시카르보닐아미노-4-tert-부톡시카르보닐-부티릴아미노)-3-메틸-부티릴아미노]-5-브로모-4-옥소-펜탄산 tert-부틸 에스테르 (Z-Glu(OtBu)ValAsp(OtBu)CH2Br) 10.5 g (63 %)을 백색 고체로서 얻었다.Of Z-Glu (OtBu) ValAsp (OtBu) -OH (14.9 g, 24.6 mmol) and 4-methylmorpholine (2.7 ml, 24.6 mmol) in 200 ml THF at about -40 ° C (dry ice CH 3 CN crude). The solution was treated with iso-butyl chloroformate (3.2 ml, 24.6 mmol). A solid formed immediately. The sample was stirred for 15 minutes and then treated with cold diazomethane (300 ml ether solution, freshly prepared instead of Diazald). The sample was stirred for 2 hours at room temperature, cooled to 0 ° C. and the reaction was stopped by dropwise addition of a 48% bromic acid-acetic acid solution (35 ml each). The ice bath was removed and the sample was stirred for 30 minutes at room temperature and then extracted with ethyl acetate-water (500 ml each). The organic extract was washed with water, saturated NaHCO 3 solution and brine, dried (MgSO 4 ), filtered and concentrated. The residue was crystallized from dichloromethane-hexane to give 3- [2- (2-benzyloxycarbonylamino-4-tert-butoxycarbonyl-butyrylamino) -3-methyl-butyrylamino] -5-bro 10.5 g (63%) of mother-4-oxo-pentanoic acid tert-butyl ester (Z-Glu (OtBu) ValAsp (OtBu) CH 2 Br) was obtained as a white solid.

C31N46BrN3O9(684.636)에 대한 분석:Anal for C 31 N 46 BrN 3 O 9 (684.636):

이론치: C, 54.39; H, 6.77; N, 6.14.Theoretical: C, 54.39; H, 6. 77; N, 6.14.

실측치: C, 54.24; H, 6.63; N, 6.08.Found: C, 54.24; H, 6.63; N, 6.08.

단계 FStep F

DMF 20 ml 중의 Z-Glu(OtBu)ValAsp(OtBu)CH2Br (9.4 g, 13.8 mmol, 실시예 6의 단계 E), 1-나프틸아세트산 (3.2 g, 17.2 mmol) 및 불화칼륨 (2.0 g, 34.4 mmol)의 혼합물을 12 시간 동안 실온에서 교반시켰다. 이 혼합물을 에틸 아세테이트 및 NaHCO3포화용액 사이에 분배했다. 유기 추출물을 KH2PO4포화용액과 염수로 세척하고, 건조 (MgSO4)하고, 여과 및 농축하여 3-[2-(2-벤질옥시-카르보닐아미노-4-tert-부톡시카르보닐-부티릴아미노)-3-메틸-부티릴아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르를 백색 고체로서 얻었다 (융점 92 - 105 ℃).Z-Glu (OtBu) ValAsp (OtBu) CH 2 Br (9.4 g, 13.8 mmol, step E of Example 6), 1-naphthylacetic acid (3.2 g, 17.2 mmol) and potassium fluoride (2.0 g) in 20 ml of DMF , 34.4 mmol) was stirred at rt for 12 h. This mixture was partitioned between ethyl acetate and saturated NaHCO 3 solution. The organic extract was washed with saturated KH 2 PO 4 solution and brine, dried (MgSO 4 ), filtered and concentrated to 3- [2- (2-benzyloxy-carbonylamino-4-tert-butoxycarbonyl- Butyrylamino) -3-methyl-butyrylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid tert-butyl ester was obtained as a white solid (melting point 92-105 ° C.).

C43H55N3O11(789.931)에 대한 분석:Anal for C 43 H 55 N 3 O 11 (789.931):

이론치: C, 65.38; H, 7.02; N, 5.32.Theoretical: C, 65.38; H, 7.02; N, 5.32.

실측치: C, 65.13; H, 7.20; N, 5.36.Found: C, 65.13; H, 7. 20; N, 5.36.

단계 GStep G

디클로로메탄 20 ml 중의 3-[2-(2-벤질옥시카르보닐아미노-4-tert-부톡시카르보닐-부티릴아미노)-3-메틸-부티릴아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르 (1.0 g, 1.27 mmol, 실시예 6의 단계 F) 및 트리플루오로아세트산 10 ml의 용액을 1 시간 동안 실온에서 교반시켰다. 이 용액을 담황색 오일로 농축했다. 에테르 (약 50 ml)를 첨가하면 이 오일은 서서히 고체화되었다. 이 혼합물을 여과하고 진공건조하여 3-[2-(2-벤질옥시카르보닐아미노-4-카르복시-부티릴아미노)-3-메틸-부티릴아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 0.81 g (95 %)을 백색 고체로서 얻었다.3- [2- (2-benzyloxycarbonylamino-4-tert-butoxycarbonyl-butyrylamino) -3-methyl-butyrylamino] -5- (naphthalen-1-yl in 20 ml of dichloromethane A solution of -acetoxy) -4-oxo-pentanoic acid tert-butyl ester (1.0 g, 1.27 mmol, step F of Example 6) and 10 ml of trifluoroacetic acid was stirred at room temperature for 1 hour. This solution was concentrated to a pale yellow oil. The oil slowly solidified when ether (about 50 ml) was added. The mixture was filtered and dried in vacuo to afford 3- [2- (2-benzyloxycarbonylamino-4-carboxy-butyrylamino) -3-methyl-butyrylamino] -5- (naphthalen-1-yl-ace 0.81 g (95%) of methoxy) -4-oxo-pentanoic acid was obtained as a white solid.

C35H39N3O11·0.70H20(690.325)에 대한 분석: C 35 H 39 N 3 O 11 · 0.70H 2 Analysis of the 0 (690.325):

이론치: C, 60.90; H, 5.90; N, 6.09.Theoretical: C, 60.90; H, 5. 90; N, 6.09.

실측치: C, 60.90; H, 5.90; N, 6.30.Found: C, 60.90; H, 5. 90; N, 6.30.

실시예 6과 유사한 방법으로 상응하는 화합물을 제조했다.The corresponding compound was prepared in a similar manner as in Example 6.

<실시예 6a><Example 6a>

3-[2-(2-벤질옥시카르보닐아미노-3-메틸-부티릴아미노)-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 (백색 고체, 융점 160 - 163 ℃)3- [2- (2-Benzyloxycarbonylamino-3-methyl-butyrylamino) -propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid (white solid Melting point 160-163 ℃)

C33H37N3O9·0.50H20(628.685)에 대한 분석:Analysis for C 33 H 37 N 3 O 9 · 0.50H 2 0 (628.685):

이론치: C, 63.05; H, 6.09; N, 6.68.Theoretical: C, 63.05; H, 6.09; N, 6.68.

실측치: C, 63.13; H, 5.96; N, 6.68.Found: C, 63.13; H, 5.96; N, 6.68.

<실시예 6b><Example 6b>

3-(2-아세틸아미노-3-메틸-부티릴아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- (2-Acetylamino-3-methyl-butyrylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

MS (APCI) m/z 457.5 (M+1)MS (APCI) m / z 457.5 (M + 1)

<실시예 6c><Example 6c>

3-[2-(2-벤질옥시카르보닐아미노-3-메틸-부티릴아미노)-프로피오닐아미노]-5-(3,3-디페닐-프로피오닐옥시)-4-옥소-펜탄산 (백색 고체, 융점 99 - 104 ℃)3- [2- (2-Benzyloxycarbonylamino-3-methyl-butyrylamino) -propionylamino] -5- (3,3-diphenyl-propionyloxy) -4-oxo-pentanoic acid ( White solid, melting point 99-104 ℃)

C36H41N3O9(659.743)에 대한 분석:Analysis for C 36 H 41 N 3 O 9 (659.743):

이론치: C, 65.54; H, 6.26; N, 6.37.Theoretical: C, 65.54; H, 6. 26; N, 6.37.

실측치: C, 65.25; H, 6.23; N, 6.25.Found: C, 65.25; H, 6. 23; N, 6.25.

<실시예 6d><Example 6d>

3-(2-벤질옥시카르보닐아미노-3-메틸-나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- (2-Benzyloxycarbonylamino-3-methyl-naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

MS (APCI) m/z 549.0 (M+1)MS (APCI) m / z 549.0 (M + l)

<실시예 6e><Example 6e>

3-[2-(2-벤질옥시카르보닐아미노-4-카르복시-부티릴아미노)-3-메틸-부티릴아미노]-5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-펜탄산 (백색 고체)3- [2- (2-benzyloxycarbonylamino-4-carboxy-butyrylamino) -3-methyl-butyrylamino] -5- (2-benzyl-3-phenyl-propionyloxy) -4- Oxo-pentanoic acid (white solid)

C39H45N3O11·0.50H2O(740.815)에 대한 분석:Analysis for C 39 H 45 N 3 O 11 · 0.50H 2 O (740.815):

이론치: C, 63.23; H, 6.26; N, 5.67.Theoretical: C, 63.23; H, 6. 26; N, 5.67.

실측치: C, 63.14; H, 6.16; N, 5.55.Found: C, 63.14; H, 6. 16; N, 5.55.

<실시예 6f><Example 6f>

3-[2-(2-벤질옥시카르보닐아미노-3-메틸-부티릴아미노)-프로피오닐아미노]-5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-펜탄산 (백색 고체)3- [2- (2-Benzyloxycarbonylamino-3-methyl-butyrylamino) -propionylamino] -5- (2-benzyl-3-phenyl-propionyloxy) -4-oxo-pentanoic acid (White solid)

C37H43N3O9·0.13CF3CO2H(688.593)에 대한 분석:Analysis for C 37 H 43 N 3 O 9 0.13 CF 3 CO 2 H (688.593):

이론치: C, 64.99; H, 6.31; N, 6.10.Theoretical: C, 64.99; H, 6. 31; N, 6.10.

실측치: C, 64.98; H, 6.50; N, 6.10.Found: C, 64.98; H, 6. 50; N, 6.10.

<실시예 6g><Example 6g>

3-[2-(2-벤질옥시카르보닐아미노-3-메틸-부티릴아미노)-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 (백색 고체)3- [2- (2-Benzyloxycarbonylamino-3-methyl-butyrylamino) -propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid (white solid )

C33H37N3O9·0.25CF3CO2H(648.184)에 대한 분석:Anal for C 33 H 37 N 3 O 9 0.25C 3 CO 2 H (648.184):

이론치: C, 62.08; H, 5.79; N, 6.48.Theoretical: C, 62.08; H, 5.79; N, 6.48.

실측치: C, 62.07; H, 5.85; N, 6.68.Found: C, 62.07; H, 5.85; N, 6.68.

<실시예 6h><Example 6h>

3-(2-{2-[2-아세틸아미노-3-(4-히드록시-페닐)-프로피오닐아미노]-4-카르복시-부티릴아미노}-3-메틸-부티릴아미노)-5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-펜탄산 (백색 고체, 융점 156-168 ℃ (분해))3- (2- {2- [2-acetylamino-3- (4-hydroxy-phenyl) -propionylamino] -4-carboxy-butyrylamino} -3-methyl-butyrylamino) -5- (2-benzyl-3-phenyl-propionyloxy) -4-oxo-pentanoic acid (white solid, melting point 156-168 ° C. (decomposition))

C42H50N4O12·H2O(820.902)에 대한 분석:Analysis for C 42 H 50 N 4 O 12 · H 2 O (820.902):

이론치: C, 61.45; H, 6.38; N, 6.82.Theoretical: C, 61.45; H, 6. 38; N, 6.82.

실측치: C, 61.43; H, 6.27; N, 6.76.Found: C, 61.43; H, 6. 27; N, 6.76.

<실시예 6i><Example 6i>

5-(2-벤질-3-페닐-프로피오닐옥시)-3-{2-[4-카르복시-2-(3-페닐-프로피오닐아미노)-부티릴아미노]-3-메틸-부티릴아미노}-4-옥소-펜탄산 (백색 고체)5- (2-Benzyl-3-phenyl-propionyloxy) -3- {2- [4-carboxy-2- (3-phenyl-propionylamino) -butyrylamino] -3-methyl-butyrylamino } -4-oxo-pentanoic acid (white solid)

C40H47N3O10·0.13CF3CO2H(744.658)에 대한 분석:Analysis of C 40 H 47 N 3 O 10 0.13 CF 3 CO 2 H (744.658):

이론치: C, 64.94; H, 6.38; N, 5.64.Theoretical: C, 64.94; H, 6. 38; N, 5.64.

실측치: C, 64.93; H, 6.63; N, 5.61.Found: C, 64.93; H, 6.63; N, 5.61.

<실시예 6j><Example 6j>

3-{2-[4-카르복시-2-(3-페닐-프로피오닐아미노)-부티릴아미노]-3-메틸-부티릴아미노}-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 (백색 고체)3- {2- [4-carboxy-2- (3-phenyl-propionylamino) -butyrylamino] -3-methyl-butyrylamino} -5- (naphthalen-1-yl-acetoxy) -4 Oxo-pentanoic acid (white solid)

C36H41N3O10·0.44CF3CO2H(725.913)에 대한 분석:Analysis for C 36 H 41 N 3 O 10 0.44 CF 3 CO 2 H (725.913):

이론치: C, 61.02; H, 5.75; N, 5.79.Theoretical: C, 61.02; H, 5.75; N, 5.79.

실측치: C, 61.04; H, 6.04; N, 6.19.Found: C, 61.04; H, 6.04; N, 6.19.

<실시예 6k><Example 6k>

3-(2-벤질옥시카르보닐아미노-3-메틸-부티릴아미노)-5-(3,3-디페닐-프로피오닐옥시)-4-옥소-펜탄산3- (2-Benzyloxycarbonylamino-3-methyl-butyrylamino) -5- (3,3-diphenyl-propionyloxy) -4-oxo-pentanoic acid

MS (APCI) m/z 588.9 (M-1)MS (APCI) m / z 588.9 (M-1)

<실시예 6l><Example 6l>

3-(2-아세틸아미노-3-히드록시-부티릴아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- (2-Acetylamino-3-hydroxy-butyrylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

MS (APCI) m/z 456.9 (M-1)MS (APCI) m / z 456.9 (M-1)

<실시예 6m><Example 6m>

3-(2-아세틸아미노-3-히드록시-부티릴아미노)-5-(3,3-디페닐-프로피오닐옥시)-4-옥소-펜탄산3- (2-Acetylamino-3-hydroxy-butyrylamino) -5- (3,3-diphenyl-propionyloxy) -4-oxo-pentanoic acid

MS (APCI) m/z 496.9 (M-1)MS (APCI) m / z 496.9 (M-1)

<실시예 6n><Example 6n>

3-(2-{2-[2-아세틸아미노-3-(1H-인돌-3-일)-프로피오닐아미노]-4-카르복시-부티릴아미노}-3-메틸-부티릴아미노)-5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-펜탄산 (오렌지색 고체)3- (2- {2- [2-acetylamino-3- (1H-indol-3-yl) -propionylamino] -4-carboxy-butyrylamino} -3-methyl-butyrylamino) -5 -(2-benzyl-3-phenyl-propionyloxy) -4-oxo-pentanoic acid (orange solid)

C44H51N5O11·1.33H2O(849.944)에 대한 분석:Analysis of C 44 H 51 N 5 O 11 .1.33H 2 O (849.944):

이론치: C, 62.18; H, 6.36; N, 8.24.Theoretical: C, 62.18; H, 6. 36; N, 8.24.

실측치: C, 62.16; H, 6.24; N, 8.18.Found: C, 62.16; H, 6. 24; N, 8.18.

<실시예 6o><Example 6o>

5-(3,3-디페닐-프로피오닐옥시)-4-옥소-3-[2-(4-페닐-부티릴아미노)-프로피오닐아미노]-펜탄산5- (3,3-Diphenyl-propionyloxy) -4-oxo-3- [2- (4-phenyl-butyrylamino) -propionylamino] -pentanoic acid

MS (APCI) m/z 573.2 (M+1)MS (APCI) m / z 573.2 (M + l)

<실시예 7><Example 7>

3-(2-{2-[2-아세틸아미노-3-(1H-인돌-3-일)-프로피오닐아미노]-4-카르복시-부티릴아미노}-3-메틸-부티릴아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- (2- {2- [2-acetylamino-3- (1H-indol-3-yl) -propionylamino] -4-carboxy-butyrylamino} -3-methyl-butyrylamino) -5 -(Naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

단계 AStep A

에탄올 : THF (2:1) 300 ml 중의 3-[2-(2-벤질옥시카르보닐아미노-4-tert-부톡시카르보닐-부티릴아미노)-3-메틸-부티릴아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르 (5.3 g, 6.7 mmol, 실시예 6의 단계 F)의 용액을 20 % Pd/C 0.6 g으로 처리하고 실온에서 3 시간 동안 기구 압력으로 수소 첨가시켰다. 이 샘플을 여과하고 농축하여 3-[2-(2-아미노-4-tert-부톡시카르보닐-부티릴아미노)-3-메틸-부티릴아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르 5.0 g (> 100 %)을 황색 오일로서 얻었다.Ethanol: 3- [2- (2-benzyloxycarbonylamino-4-tert-butoxycarbonyl-butyrylamino) -3-methyl-butyrylamino] -5- in 300 ml of THF (2: 1) A solution of (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid tert-butyl ester (5.3 g, 6.7 mmol, step F of Example 6) was treated with 0.6 g of 20% Pd / C and at room temperature Hydrogenated to instrument pressure for 3 hours. The sample was filtered and concentrated to 3- [2- (2-amino-4-tert-butoxycarbonyl-butyrylamino) -3-methyl-butyrylamino] -5- (naphthalen-1-yl-ace 5.0 g (> 100%) of oxy) -4-oxo-pentanoic acid tert-butyl ester was obtained as a yellow oil.

단계 BStep B

디클로로메탄 25 ml 중의 3-[2-(2-아미노-4-tert-부톡시카르보닐-부티릴아미노)-3-메틸-부티릴아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르 (1.25 g, 1.91 mmol, 실시예 7의 단계 A), AcTrp-OH (0.52 g, 2.10 mmol), HOBT·H2O (0.32 g, 2.10 mmol), EDCl·HCl (0.40 g, 2.10 mmol) 및 4-메틸모르폴린 (0.26 ml, 2.36 mmol)의 혼합물을 실온에서 12 시간 동안 교반시켰다. 이 샘플을 농축시킨 후 에틸 아세테이트와 NaHCO3포화용액 사이에서 분배시켰다. 유기 추출물을 KH2PO4포화용액, 염수로 세척하고 건조 (MgSO4), 여과 및 농축했다. 잔류물을 크로마토그래피 (MPLC, 실리카 겔, 25 % 헥산-75 % 에틸 아세테이트)하여, 3-(2-{2-[2-아세틸아미노-3-(1H-인돌-3-일)-프로피오닐아미노]-4-tert-부톡시카르보닐-부티릴아미노}-3-메틸-부티릴아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르 0.95 g (56 %)을 백색 고체로서 얻었다.3- [2- (2-amino-4-tert-butoxycarbonyl-butyrylamino) -3-methyl-butyrylamino] -5- (naphthalen-1-yl-acetoxy) in 25 ml of dichloromethane 4-oxo-pentanoic acid tert-butyl ester (1.25 g, 1.91 mmol, step A of Example 7), AcTrp-OH (0.52 g, 2.10 mmol), HOBT.H 2 O (0.32 g, 2.10 mmol), A mixture of EDCl.HCl (0.40 g, 2.10 mmol) and 4-methylmorpholine (0.26 ml, 2.36 mmol) was stirred at rt for 12 h. The sample was concentrated and partitioned between ethyl acetate and saturated NaHCO 3 solution. The organic extract was washed with saturated KH 2 PO 4 solution, brine, dried (MgSO 4 ), filtered and concentrated. The residue is chromatographed (MPLC, silica gel, 25% hexanes-75% ethyl acetate) to give 3- (2- {2- [2-acetylamino-3- (1H-indol-3-yl) -propionyl Amino] -4-tert-butoxycarbonyl-butyrylamino} -3-methyl-butyrylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid tert-butyl ester 0.95 g (56%) was obtained as a white solid.

단계 CStep C

디클로로메탄 20 ml 중의 3-(2-{2-[2-아세틸아미노-3-(1H-인돌-1-일)-프로피오닐아미노]-4-tert-부톡시카르보닐-부티릴아미노}-3-메틸-부티릴아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르 (0.93 g, 1.05 mmol, 실시예 7의 단계 B) 및 트리플루오로아세트산 10 ml의 용액을 2 시간 동안 실온에서 교반시켰다. 이 샘플을 자주색 오일로 농축했다. 에테르 (약 50 ml)을 첨가하면 오일은 서서히 고체화되었다. 이 샘플을 여과하고 진공 건조하여 3-(2-{2-[2-아세틸아미노-3-(1H-인돌-1-3-일)-프로피오닐아미노]-4-카르복시-부티릴아미노}-3-메틸-부티릴아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 0.78 g (96 %)을 담자주색 고체로서 얻었다.3- (2- {2- [2-acetylamino-3- (1H-indol-1-yl) -propionylamino] -4-tert-butoxycarbonyl-butyrylamino}-in 20 ml of dichloromethane 3-Methyl-butyrylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid tert-butyl ester (0.93 g, 1.05 mmol, step B of Example 7) and trifluoro A solution of 10 ml of acetic acid was stirred for 2 hours at room temperature. This sample was concentrated to purple oil. The oil slowly solidified when ether (about 50 ml) was added. The sample was filtered and dried in vacuo to afford 3- (2- {2- [2-acetylamino-3- (1H-indol-1-3-yl) -propionylamino] -4-carboxy-butyrylamino}- 0.78 g (96%) of 3-methyl-butyrylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid was obtained as a pale orange solid.

C40H45N5O11·0.50H2O(780.839)에 대한 분석:Analysis for C 40 H 45 N 5 O 11 · 0.50H 2 O (780.839):

이론치: C, 61.53; H, 5.94; N, 8.97.Theoretical: C, 61.53; H, 5.94; N, 8.97.

실측치: C, 61.45; H, 6.12; N, 8.81.Found: C, 61.45; H, 6. 12; N, 8.81.

실시예 7과 유사한 방법으로 상응하는 화합물들을 제조했다.Corresponding compounds were prepared in a similar manner to Example 7.

<실시예 7a><Example 7a>

3-[2-(2-아세틸아미노-4-카르복시-부티릴아미노)-3-메틸-부티릴아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 (회백색 고체)3- [2- (2-Acetylamino-4-carboxy-butyrylamino) -3-methyl-butyrylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid (grey-white solid)

C29H35N3O10·H2O(603.632)에 대한 분석:Analysis for C 29 H 35 N 3 O 10 · H 2 O (603.632):

이론치: C, 57.70; H, 6.18; N, 6.96.Theoretical: C, 57.70; H, 6. 18; N, 6.96.

실측치: C, 57.59; H, 6.11; N, 7.28.Found: C, 57.59; H, 6. 11; N, 7.28.

<실시예 7b><Example 7b>

3-(2-{2-[2-아세틸아미노-3-(4-히드록시-페닐)-프로피오닐아미노]-4-카르복시-부티릴아미노}-3-메틸-부티릴아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 (백색 고체)3- (2- {2- [2-acetylamino-3- (4-hydroxy-phenyl) -propionylamino] -4-carboxy-butyrylamino} -3-methyl-butyrylamino) -5- (Naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid (white solid)

C38H44N4O12·H2O(766.809)에 대한 분석:Analysis for C 38 H 44 N 4 O 12 · H 2 O (766.809):

이론치: C, 59.52; H, 6.00; N, 7.31.Theoretical: C, 59.52; H, 6.00; N, 7.31.

실측치: C, 59.36; H, 5.79; N, 7.24.Found: C, 59.36; H, 5.79; N, 7.24.

<실시예 8><Example 8>

3-[(2-카르복시-시클로헥산카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3-[(2-carboxy-cyclohexanecarbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

단계 AStep A

메틸렌 클로라이드 30 ml 중의 3-아미노-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르의 히드로클로라이드 염 (1.7 g, 4.6 mmol) (실시예 2의 단계 A) 및 1,2-트랜스-시클로헥산디카르복실산 무수물 (0.79 g, 5.1 mmol)을 피리딘 (5 ml) 및 디메틸아미노피리딘 (DMAP)의 촉매량으로 처리했다. 이 반응 혼합물을 실온에서 밤새 교반시키고 용매를 증발시켰다. 이 잔류물을 디에틸 에테르와 5 % HCl 사이에 분배하고, 각 층을 분리했다. 유기층을 5 % HCl로 세척하고 건조 (MgSO4), 여과 및 농축했다. 조생성물을 플래시 크로마토그래피 (실리카 겔, 15 % 아세톤/1 % 포름산/ 메틸렌 클로라이드)로 정제하여 순수한 3-[(2-카르복시-시클로헥산카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르 0.3 g을 두 부분입체이성질체의 혼합물로서 얻었다.Hydrochloride salt of 3-amino-5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid tert-butyl ester in 1.7 ml of methylene chloride (1.7 g, 4.6 mmol) (step A of Example 2 ) And 1,2-trans-cyclohexanedicarboxylic anhydride (0.79 g, 5.1 mmol) were treated with catalytic amounts of pyridine (5 ml) and dimethylaminopyridine (DMAP). The reaction mixture was stirred at rt overnight and the solvent was evaporated. This residue was partitioned between diethyl ether and 5% HCl and each layer was separated. The organic layer was washed with 5% HCl, dried (MgSO 4 ), filtered and concentrated. The crude product was purified by flash chromatography (silica gel, 15% acetone / 1% formic acid / methylene chloride) to give pure 3-[(2-carboxy-cyclohexanecarbonyl) -amino] -5- (naphthalen-1-yl 0.3 g of -acetoxy) -4-oxo-pentanoic acid tert-butyl ester was obtained as a mixture of two diastereomers.

MS (APCI) m/z 524 (M-1)MS (APCI) m / z 524 (M-1)

단계 BStep B

메틸렌 클로라이드 6 ml 중의 3-[(2-카르복시-시클로헥산카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르 (0.181 g, 0.3444 mmol)의 용액을 50 % 트리플루오로아세트산 (메틸렌 클로라이드 중) 4 ml로 처리했다. 반응 혼합물을 실온에서 4 시간 동안 교반시키고, 톨루엔 (50 ml)로 희석하고 감압하에서 농축하여 3-[(2-카르복시-시클로헥산카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시-4-옥소-펜탄산을 무색 고체 (두 부분입체이성질체의 혼합물)로서 얻었다.3-[(2-carboxy-cyclohexanecarbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid tert-butyl ester in 0.1 ml of methylene chloride (0.181 g, 0.3444 mmol) was treated with 4 ml of 50% trifluoroacetic acid (in methylene chloride). The reaction mixture was stirred at rt for 4 h, diluted with toluene (50 ml) and concentrated under reduced pressure to afford 3-[(2-carboxy-cyclohexanecarbonyl) -amino] -5- (naphthalen-1-yl-ace Toxy-4-oxo-pentanoic acid was obtained as a colorless solid (mixture of two diastereomers).

MS (APCI) m/z 470 (M+1)MS (APCI) m / z 470 (M + 1)

<실시예 8a><Example 8a>

3-[(2-메톡시카르보닐-시클로헥산카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3-[(2-Methoxycarbonyl-cyclohexanecarbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

단계 AStep A

메틸렌 클로라이드 5 ml 중의 3-[(2-카르복시-시클로헥산카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르 (2.3 mmol) (실시예 8의 단계 A)의 용액을 에테르 중의 디아조메탄 과량으로 처리했다. 이 반응 혼합물을 3 시간 동안 실온에서 교반시킨 후 빙초산을 적가하여 반응을 중지시켰다. 용매를 감압하에서 증발시켜 3-[(2-메톡시카르보닐-시클로헥산카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르를 얻었다.3-[(2-carboxy-cyclohexanecarbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid tert-butyl ester (2.3 mmol) in 5 ml of methylene chloride ( The solution of step A) of Example 8 was treated with an excess of diazomethane in ether. The reaction mixture was stirred for 3 hours at room temperature and then the reaction was stopped by dropwise addition of glacial acetic acid. The solvent was evaporated under reduced pressure to afford 3-[(2-methoxycarbonyl-cyclohexanecarbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid tert-butyl ester Got it.

MS (APCI) m/z 540 (M+1)MS (APCI) m / z 540 (M + 1)

단계 BStep B

대상 화합물은 실시예 8의 단계 B에 기재된 상응하는 tert-부틸 에스테르로부터 제조하여 3-[(2-메톡시카르보닐-시클로헥산카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산을 얻었다.The subject compound was prepared from the corresponding tert-butyl ester described in step B of Example 8 and prepared 3-[(2-methoxycarbonyl-cyclohexanecarbonyl) -amino] -5- (naphthalen-1-yl-ace Methoxy) -4-oxo-pentanoic acid was obtained.

MS (APCI) m/z 484 (M+1)MS (APCI) m / z 484 (M + l)

<실시예 8b><Example 8b>

3-[(2-카르바모일-시클로헥산카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3-[(2-Carbamoyl-cyclohexanecarbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

단계 AStep A

메틸렌 클로라이드 20 ml 중의 DCC (0.18 g, 0.88 mmol) 및 HOBT (0.12 g, 0.88 mmol)의 용액을 메틸렌 클로라이드 25 ml 중의 3-[(2-카르복시-시클로헥산카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르 (0.45 g, 0.85 mmol) (실시예 2의 단계 A) 및 트리에틸아민 (0.099 g, 0.98 mmol)의 용액에 적가하고, 반응 혼합물을 30 분 동안 실온에서 교반시켰다. 헥사메틸디실라잔 (0.80 g, 4.9 mmol)을 첨가하고, 반응 혼합물을 실온에서 밤새 교반시켰다. 반응 혼합물을 에테르 100 ml에 붓고 5 % HCl로 3 회 추출한 후, NaCl 포화용액으로 세척했다. 유기층을 건조 (MgSO4), 여과하고 감압하에서 농축시켰다. 잔류물을 에테르/헥산에 용해시키고, 여과 및 농축하여 점성 발포체를 얻었다. 플래시 크로마토그래피로 정제한 후, 3-[(2-카르바모일-시클로헥산카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르 (0.086 g)를 두 부분입체이성질체의 혼합물로서 얻었다.A solution of DCC (0.18 g, 0.88 mmol) and HOBT (0.12 g, 0.88 mmol) in 20 ml of methylene chloride was added to 3-[(2-carboxy-cyclohexanecarbonyl) -amino] -5- (in 25 ml of methylene chloride. Naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid tert-butyl ester (0.45 g, 0.85 mmol) (step A of Example 2) and dropwise addition to a solution of triethylamine (0.099 g, 0.98 mmol) The reaction mixture was stirred for 30 minutes at room temperature. Hexamethyldisilazane (0.80 g, 4.9 mmol) was added and the reaction mixture was stirred at rt overnight. The reaction mixture was poured into 100 ml of ether, extracted three times with 5% HCl, and washed with saturated NaCl solution. The organic layer was dried (MgSO 4 ), filtered and concentrated under reduced pressure. The residue was dissolved in ether / hexane, filtered and concentrated to give a viscous foam. After purification by flash chromatography, 3-[(2-carbamoyl-cyclohexanecarbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid tert-butyl ester (0.086 g) was obtained as a mixture of two diastereomers.

MS (APCI) m/z 525 (M+1)MS (APCI) m / z 525 (M + 1)

단계 BStep B

대상 화합물은 실시예 8의 단계 B에 기재된 상응하는 tert-부틸 에스테로부터 제조하여 3-[(2-카르바모일-시클로헥산카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산을 얻었다.The subject compound was prepared from the corresponding tert-butyl ester described in step B of Example 8 and prepared 3-[(2-carbamoyl-cyclohexanecarbonyl) -amino] -5- (naphthalen-1-yl-acetoxy ) -4-oxo-pentanoic acid was obtained.

MS (APCI) m/z 467 (M-1)MS (APCI) m / z 467 (M-1)

<실시예 9>Example 9

3-(3-벤질술파닐-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- (3-Benzylsulfanyl-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

단계 AStep A

0 ℃에서 디메틸포름아미드 (50 ml) 중의 3-벤질술파닐-2-메틸-프로피온산 (3.3 g, 15.8 mmol) 및 H-Asp(OtBu)OMe·HCl (3.7 g, 15.8 mmol)의 용액에 1-에틸-3-(3'-디메틸아미노프로필)카르보디이미드·HCl (3.25 g, 17.0 mmol) 및 트리에틸아민 (4.4 g, 43.8 mmol)을 첨가했다. 이 혼합물을 실온에서 16 시간 동안 교반시켰다. 대부분의 용매를 감압하에서 제거하고, 잔류물을 에틸 아세테이트와 5 % 시트르산 사이에 분배시켰다. 에틸 아세테이트 추출물을 탄산수소나트륨과 물로 세척하고 황산나트륨 상에서 건조하고 농축하고 무정질 잔류물 6.3 g을 얻었다. 이 잔류물을 디옥산/물 (1 : 1) 100 ml 중에 용해시키고 티모프탈레인의 존재하에 1 N NaOH (15.0 ml)을 적가하여 가수분해시켰다. 대부분의 디옥산을 증발시키고, 물로 희석한 후 수용액을 에테르로 추출하고 묽은 HCl로 산성화하여 pH 2-3으로 조절하고, 생성물을 에틸 아세테이트로 추출했다. 에틸 아세테이트 추출물을 물로 세척하고, 황산나트륨 상에서 건조하고 농축하여 조생성물 6.3 g을 얻었다. 실리카 겔 상에서 크로마토그래피 (디클로로메탄/메탄올 30: 1)하여 N-(3-벤질술파닐-2-메틸-프로피오닐)-아스파르트산 4-tert-부틸 에스테르 5.5 g을 얻었다.To a solution of 3-benzylsulfanyl-2-methyl-propionic acid (3.3 g, 15.8 mmol) and H-Asp (OtBu) OMe.HCl (3.7 g, 15.8 mmol) in dimethylformamide (50 ml) at 0 ° C. -Ethyl-3- (3'-dimethylaminopropyl) carbodiimide.HCl (3.25 g, 17.0 mmol) and triethylamine (4.4 g, 43.8 mmol) were added. This mixture was stirred at rt for 16 h. Most of the solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and 5% citric acid. The ethyl acetate extract was washed with sodium bicarbonate and water, dried over sodium sulfate and concentrated to give 6.3 g of amorphous residue. This residue was dissolved in 100 ml of dioxane / water (1: 1) and hydrolyzed by the dropwise addition of 1 N NaOH (15.0 ml) in the presence of timophthalein. Most of the dioxane was evaporated, diluted with water, the aqueous solution was extracted with ether, acidified with diluted HCl, adjusted to pH 2-3, and the product extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over sodium sulfate and concentrated to give 6.3 g of crude product. Chromatography (dichloromethane / methanol 30: 1) on silica gel gave 5.5 g of N- (3-benzylsulfanyl-2-methyl-propionyl) -aspartic acid 4-tert-butyl ester.

단계 BStep B

-15 ℃에서 테트라히드로푸란 (670 ml) 중의 N-(3-벤질 술파닐-2-메틸-프로피오닐)-아스파르트산 4-tert-부틸 에스테르 (5.4 g, 14.2 mmol)의 용액에 N-메틸모르폴린 (1.5 ml, 16.0 mmol)을 첨가한 후, 에틸 클로로포르메이트 (1.6 ml, 16.0 mmol)을 적가했다. -10 ℃에서 15 분 후, 에테르 중의 디아조메탄 0.2 N 용액 110 ml를 적가했다. 반응물을 2 시간 동안 실온에 놓아둔 후, 빙초산 중의 48 % HBr (1 : 1) 용액 40 ml을 0 ℃에서 적가했다. 15 분 동안 교반시킨 후, 반응 혼합물을 에틸 아세테이트로 부었다. 유기상을 탄산수소나트륨 수용액으로 3 회 세척한 후 물로 세척하고 황산나트륨 상에서 건조하고 감압하에서 농축하여 3-(3-벤질술파닐-2-메틸-프로피온-1-일)아미노-5-브로모-4-옥소-펜탄산 tert-부틸 에스테르 (4.2 g)를 얻었다.N-methyl in a solution of N- (3-benzyl sulfanyl-2-methyl-propionyl) -aspartic acid 4-tert-butyl ester (5.4 g, 14.2 mmol) in tetrahydrofuran (670 ml) at −15 ° C. After adding morpholine (1.5 ml, 16.0 mmol), ethyl chloroformate (1.6 ml, 16.0 mmol) was added dropwise. After 15 minutes at −10 ° C., 110 ml of a 0.2 N solution of diazomethane in ether was added dropwise. After the reaction was left at room temperature for 2 hours, 40 ml of a 48% HBr (1: 1) solution in glacial acetic acid was added dropwise at 0 ° C. After stirring for 15 minutes, the reaction mixture was poured into ethyl acetate. The organic phase is washed three times with aqueous sodium hydrogen carbonate solution, then with water, dried over sodium sulfate and concentrated under reduced pressure to afford 3- (3-benzylsulfanyl-2-methyl-propion-1-yl) amino-5-bromo-4 Oxo-pentanoic acid tert-butyl ester (4.2 g) was obtained.

단계 CStep C

디메틸포름아미드 (40 ml) 중의 3-(3-벤질술파닐-2-메틸-프로피오닐)아미노-5-브로모-4-옥소-펜탄산 tert-부틸 에스테르 (0.92 g, 2.0 mmol) 및 불화칼륨 (0.35 g, 6.0 mmol)의 혼합물을 1-나프탈렌아세트산 (0.37 g, 2.0 mmol)을 얻었다. 이 혼합물을 실온에서 16 시간 동안 교반시켰다. 대부분의 용매를 감압하에서 증발시키고, 잔류물을 에틸 아세테이트와 물 사이에 분배했다. 유기상을 탄산수소나트륨 수용액 및 물로 연속적으로 세척하고 황산나트륨 상에서 건조하고 감압하에서 증발시켰다. 실리카 상에서 크로마토그래피 (디클로로메탄/아세톤 40 : 1)를 실시하여 3-(3-벤질술파닐-2-메틸-프로피오닐)아미노-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르 0.46 g을 얻었다.3- (3-benzylsulfanyl-2-methyl-propionyl) amino-5-bromo-4-oxo-pentanoic acid tert-butyl ester (0.92 g, 2.0 mmol) in dimethylformamide (40 ml) and fluorinated A mixture of potassium (0.35 g, 6.0 mmol) gave 1-naphthaleneacetic acid (0.37 g, 2.0 mmol). This mixture was stirred at rt for 16 h. Most of the solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was washed successively with aqueous sodium hydrogen carbonate solution and water, dried over sodium sulfate and evaporated under reduced pressure. Chromatography (dichloromethane / acetone 40: 1) on silica gives 3- (3-benzylsulfanyl-2-methyl-propionyl) amino-5- (naphthalen-1-yl-acetoxy) -4-oxo 0.46 g of -pentanoic acid tert-butyl ester was obtained.

단계 DStep D

아니솔 0.1 ml을 함유하는 디클로로메탄/트리플루오로아세트산 1 : 1의 혼합물 10 ml 중의 3-(3-벤질술파닐-2-메틸-프로피오닐)아미노-5-(나프탈렌-1-일)아세톡시-4-옥소-펜탄산 tert-부틸 에스테르 (0.12 g, 0.21 mmol)를 45 분 동안 실온에서 교반시켰다. 감압하에서 증발시킨 후, 실리카 상에서 크로마토그래피 (디클로로메탄/메탄올 40 : 1 내지 20 : 1)를 실시하여 3-(3-벤질술파닐-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 (0.11 g)을 얻었다.3- (3-benzylsulfanyl-2-methyl-propionyl) amino-5- (naphthalen-1-yl) acetate in 10 ml of a mixture of dichloromethane / trifluoroacetic acid 1: 1 containing 0.1 ml of anisole Toxy-4-oxo-pentanoic acid tert-butyl ester (0.12 g, 0.21 mmol) was stirred at room temperature for 45 minutes. After evaporation under reduced pressure, chromatography on silica was carried out (dichloromethane / methanol 40: 1 to 20: 1) to give 3- (3-benzylsulfanyl-2-methyl-propionylamino) -5- (naphthalene-1 -Yl-acetoxy) -4-oxo-pentanoic acid (0.11 g) was obtained.

MS (ESI) m/z 508.4 (M+1)MS (ESI) m / z 508.4 (M + 1)

<실시예 9a><Example 9a>

3-(2-메틸-3-페닐메탄술포닐-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- (2-Methyl-3-phenylmethanesulfonyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

단계 AStep A

에탄올 10 ml중의 실시예 9의 단계 C로부터 얻은 에탄올 10 ml 중의 3-(3-페닐메탄술파닐-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르 (0.33 g, 0.58 mmol)에, 0 ℃에서 교반시키면서 칼륨 모노퍼옥시술페이트 (물 2 ml 중의 옥손 0.54 g의 용액으로서 1.74 mmol)를 첨가했다. 생성된 슬러리를 4 시간 동안 실온에서 교반시켰다. 반응 혼합물을 디클로로메탄 및 물 사이에 분배했다. 유기상을 탄산수소나트륨 수용액 및 물로 세척하고, 황산나트륨 상에서 건조하고, 감압하에서 증발시켰다. 실리카 (디클로로메탄/아세톤 40 : 1) 상에서 크로마토그래피를 실시하여 3-(3-페닐메탄술파닐-2-메틸-프로피오닐)아미노-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르 0.25 g을 얻었다.3- (3-phenylmethanesulfanyl-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4- in 10 ml of ethanol obtained from step C of Example 9 in 10 ml of ethanol To oxo-pentanoic acid tert-butyl ester (0.33 g, 0.58 mmol) was added potassium monoperoxysulfate (1.74 mmol as a solution of 0.54 g of oxone in 2 ml of water) with stirring at 0 ° C. The resulting slurry was stirred for 4 hours at room temperature. The reaction mixture was partitioned between dichloromethane and water. The organic phase was washed with aqueous sodium hydrogen carbonate solution and water, dried over sodium sulfate and evaporated under reduced pressure. Chromatography on silica (dichloromethane / acetone 40: 1) to give 3- (3-phenylmethanesulfanyl-2-methyl-propionyl) amino-5- (naphthalen-1-yl-acetoxy) -4- 0.25 g of oxo-pentanoic acid tert-butyl ester was obtained.

단계 BStep B

아니솔 0.2 ml을 함유하는 디클로로메탄/트리플루오로아세트산 1 : 1의 혼합물 20 ml 중의 3-(3-페닐메탄술파닐-2-메틸-프로피오닐)아미노-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르 (0.21 g, 0.35 mmol)를 45 분 동안 실온에서 교반시켰다. 감압하에서 증발시켜 디클로로메탄/에테르/헥산으로부터 결정화하여 3-(2-메틸-3-페닐메탄술포닐-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 (0.16 g)을 얻었다.3- (3-phenylmethanesulfanyl-2-methyl-propionyl) amino-5- (naphthalen-1-yl-) in 20 ml of a mixture of dichloromethane / trifluoroacetic acid 1: 1 containing 0.2 ml of anisole Acetoxy) -4-oxo-pentanoic acid tert-butyl ester (0.21 g, 0.35 mmol) was stirred for 45 minutes at room temperature. Evaporate under reduced pressure to crystallize from dichloromethane / ether / hexane to afford 3- (2-methyl-3-phenylmethanesulfonyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-phene Carbonic acid (0.16 g) was obtained.

MS (ESI) m/z 540.2 (M+1)MS (ESI) m / z 540.2 (M + l)

<실시예 9b><Example 9b>

3-[3-(2-카르복시-에탄술파닐)-2-메틸-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- [3- (2-carboxy-ethanesulfanyl) -2-methyl-propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

단계 AStep A

디메틸포름아미드 (60 ml) 중의 3-(2-tert-부톡시카르보닐)에탄술파닐-2-메틸-프로피온산 (5.0 g, 20.0 mmol) 및 H-Asp(OtBu)OMe·HCl (4.8 g, 20.0 mmol)의 용액을 0 ℃에서 1-에틸-3-(3'-디메틸아미노프로필)카르보디이미드·HCl (3.85 g, 20.0 mmol) 및 트리에틸아민 (6.0 g, 60 mmol)을 첨가했다. 혼합물을 16 시간 동안 실온에서 교반시켰다. 대부분의 용매를 감압하에서 제거하고, 잔류물을 에틸 아세테이트와 5 % 시트르산 사이에 분배했다. 에틸 아세테이트 추출물을 탄산수소나트륨과 물로 세척하고 황산나트륨 상에서 건조하고 농축하여 실리카 겔 크로마토그래피 (디클로로메탄/아세톤 15 : 1)한 후, 무정질 잔류물 5.5 g을 얻었다. 이 잔류물을 디옥산/물 (4 : 1) 50 ml 중에 용해시키고, 티모프탈레인의 존재하에 1 N NaOH (12.5 ml)를 적가하여 가수분해시켰다. 대부분의 디옥산을 증발시키고 물로 희석한 후, 수용액을 에테르로 추출하고 묽은 HCl로 산성화하여 pH 2-3으로 조절하고, 생성물을 에틸 아세테이트로 추출했다. 에틸 아세테이트 추출물을 물로 세척하고 황산나트륨으로 건조하고 농축하여 N-(3-(2-tert-부톡시카르보닐)에탄술파닐-2-메틸-프로피오닐)-아스파르트산 4-tert-부틸 에스테르 5.2 g을 얻었다.3- (2-tert-butoxycarbonyl) ethanesulfanyl-2-methyl-propionic acid (5.0 g, 20.0 mmol) and H-Asp (OtBu) OMe-HCl (4.8 g, in dimethylformamide (60 ml) 20.0 mmol) was added 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide.HCl (3.85 g, 20.0 mmol) and triethylamine (6.0 g, 60 mmol) at 0 ° C. The mixture was stirred at rt for 16 h. Most of the solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and 5% citric acid. The ethyl acetate extract was washed with sodium bicarbonate and water, dried over sodium sulfate and concentrated to silica gel chromatography (dichloromethane / acetone 15: 1) to give 5.5 g of amorphous residue. This residue was dissolved in 50 ml of dioxane / water (4: 1) and hydrolyzed by the dropwise addition of 1 N NaOH (12.5 ml) in the presence of timophthalein. After most of the dioxane was evaporated and diluted with water, the aqueous solution was extracted with ether, acidified with dilute HCl, adjusted to pH 2-3, and the product extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over sodium sulfate and concentrated to give 5.2 g of N- (3- (2-tert-butoxycarbonyl) ethanesulfanyl-2-methyl-propionyl) -aspartic acid 4-tert-butyl ester Got.

단계 BStep B

테트라히드로푸란 60 ml 중의 N-(3-(2-tert-부톡시카르보닐)에탄술파닐-2-메틸-프로피오닐)-아스파르트산 4-tert-부틸 에스테르 (4.5 g, 10.7 mmol)의 용액에 - 15 ℃에서, N-메틸모르폴린 (1.65 ml, 15.0 mmol)을 첨가한 후 에틸 클로로포르메이트 (1.35 ml, 13.5 mmol)을 적가했다. - 10 ℃에서 15 분 후, 에테르 중의 디아조메탄 약 0.2 N의 용액 105 ml를 적가했다. 반응물을 2 시간 동안 실온에서 방치해 둔 후, 빙초산 중의 48 % HBr (1 : 1) 용액 30 ml를 0 ℃에서 적가했다. 15 분 동안 교반시킨 후, 반응 혼합물을 에틸 아세테이트로 부었다. 유기상을 탄산수소나트륨 포화수용액으로 3 회 세척한 후 물로 세척하고, 황산나트륨 상에서 건조하고 감압하에서 농축하여 3-(3-(2-tert-부틸옥시카르보닐)에탄술파닐-2-메틸-프로피온-1-일)아미노-5-브로모-4-옥소-펜탄산 tert-부틸 에스테르 (4.2 g)를 얻었다.Solution of N- (3- (2-tert-butoxycarbonyl) ethanesulfanyl-2-methyl-propionyl) -aspartic acid 4-tert-butyl ester (4.5 g, 10.7 mmol) in 60 ml of tetrahydrofuran To -15 ° C, N-methylmorpholine (1.65 ml, 15.0 mmol) was added followed by dropwise addition of ethyl chloroformate (1.35 ml, 13.5 mmol). After 15 minutes at 10 ° C., 105 ml of a solution of about 0.2 N of diazomethane in ether was added dropwise. After the reaction was left at room temperature for 2 hours, 30 ml of a 48% HBr (1: 1) solution in glacial acetic acid was added dropwise at 0 ° C. After stirring for 15 minutes, the reaction mixture was poured into ethyl acetate. The organic phase was washed three times with saturated aqueous sodium hydrogen carbonate solution and then with water, dried over sodium sulfate and concentrated under reduced pressure to afford 3- (3- (2-tert-butyloxycarbonyl) ethanesulfanyl-2-methyl-propion- 1-yl) amino-5-bromo-4-oxo-pentanoic acid tert-butyl ester (4.2 g) was obtained.

단계 CStep C

디메틸포름아미드 (50 ml) 중의 3-(3-(2-tert-부톡시카르보닐)에탄술파닐-2-메탄-프로피오닐)아미노-5-브로모-4-옥소-펜탄산 tert-부틸 에스테르 (1.65 g, 3.3 mmol) 및 불화칼륨 (0.58 g, 10.0 mmol)의 혼합물에 1-나프탈렌아세트산 (0.75 g, 4.0 mmol)을 첨가했다. 혼합물을 16 시간 동안 실온에서 교반시켰다. 대부분의 용매를 감압하에서 증발시키고, 잔류물을 에틸 아세테이트와 물 사이에 분배했다. 유기상을 탄산수소나트륨 수용액 및 물로 세척하고 황산나트륨 상에서 건조하고, 감압하에서 증발시켰다. 실리카 (디클로로메탄/아세톤 40 : 1) 상에서 크로마토그래피를 실시하여 3-(3-(2-tert-부톡시카르보닐)-에탄술파닐-2-메틸-프로피오닐)아미노-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 tert-부틸 에스테르 0.89 g을 얻었다.3- (3- (2- (2-tert-butoxycarbonyl) ethanesulfanyl-2-methane-propionyl) amino-5-bromo-4-oxo-pentanoic acid tert-butyl in dimethylformamide (50 ml) To a mixture of ester (1.65 g, 3.3 mmol) and potassium fluoride (0.58 g, 10.0 mmol) was added 1-naphthaleneacetic acid (0.75 g, 4.0 mmol). The mixture was stirred at rt for 16 h. Most of the solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was washed with aqueous sodium hydrogen carbonate solution and water, dried over sodium sulfate and evaporated under reduced pressure. Chromatography on silica (dichloromethane / acetone 40: 1) to give 3- (3- (2-tert-butoxycarbonyl) -ethanesulfanyl-2-methyl-propionyl) amino-5- (naphthalene- 0.89 g of 1-yl-acetoxy) -4-oxo-pentanoic acid tert-butyl ester was obtained.

단계 DStep D

아니솔 0. 1 ml를 함유하는 디클로로메탄/트리플루오로아세트산 1 : 1의 혼합물 중의 3-(3-(2-tert-부톡시카르보닐)에탄술파닐-2-메틸-프로피오닐)아미노-5-(나프탈렌-1-일)아세톡시-4-옥소-펜탄산 tert-부틸 에스테르 (0.21 g, 0.33 mmol)를 45 분 동안 실온에서 교반시켰다. 감압하에서 증발시키고 잔류물을 디클로로메탄/에테르/헥산으로 처리하여 3-[(3-(2-카르브에톡시-에탄술파닐)-2-메틸-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 0.08 g을 얻었다 (0.11 g).3- (3- (2- (2-tert-butoxycarbonyl) ethanesulfanyl-2-methyl-propionyl) amino- in a mixture of dichloromethane / trifluoroacetic acid 1: 1 containing 0.1 ml of anisole 5- (naphthalen-1-yl) acetoxy-4-oxo-pentanoic acid tert-butyl ester (0.21 g, 0.33 mmol) was stirred at room temperature for 45 minutes. Evaporation under reduced pressure and the residue was treated with dichloromethane / ether / hexane to give 3-[(3- (2-carbroethoxy-ethanesulfanyl) -2-methyl-propionylamino] -5- (naphthalene-1 0.08 g of -yl-acetoxy) -4-oxo-pentanoic acid was obtained (0.11 g).

MS (ESI) m/z 490.3 (M+1)MS (ESI) m / z 490.3 (M + 1)

<실시예 9c><Example 9c>

5-(2-벤질-3-페닐-프로피오닐옥시)-3-[3-(2-카르복시-에탄술포닐)-2-메틸-프로피오닐아미노]-4-옥소-펜탄산5- (2-Benzyl-3-phenyl-propionyloxy) -3- [3- (2-carboxy-ethanesulfonyl) -2-methyl-propionylamino] -4-oxo-pentanoic acid

단계 AStep A

에탄올 15 ml 중의 5-(2-벤질-3-페닐-프로피오닐옥시)-3-[3-(2-카르복시-에탄술파닐)-2-메틸-프로피오닐아미노]-4-옥소-펜탄산 tert-부틸 에스테르 (0.59 g, 0.9 mmol, 실시예 3에 기재된 바와 같이 제조됨)에 0 ℃에서 교반시키면서, 칼륨 모노퍼옥시술페이트 (2.8 mmol, 물 3 ml 중의 옥손 0.86 g의 용액)를 첨가했다. 생성된 슬러리를 3 시간 동안 실온에서 교반시켰다. 반응 혼합물을 디클로로메탄 및 물 사이에 분배했다. 유기상을 탄산수소나트륨 수용액 및 물로 세척하고 황산나트륨 상에서 건조하고, 감압하에서 증발시켰다. 실리카 상에서 크로마토그래피 (디클로로메탄/아세톤 30 : 1)하여, 5-(2-벤질-3-페닐-프로피오닐옥시)-3-[3-(2-카르복시-에탄술포닐)-2-메틸-프로피오닐아미노]-4-옥소-펜탄산 tert-부틸에스테르 0.39 g을 얻었다.5- (2-benzyl-3-phenyl-propionyloxy) -3- [3- (2-carboxy-ethanesulfanyl) -2-methyl-propionylamino] -4-oxo-pentanoic acid in 15 ml of ethanol To tert-butyl ester (0.59 g, 0.9 mmol, prepared as described in Example 3) was added potassium monoperoxysulfate (2.8 mmol, solution of 0.86 g of oxone in 3 ml of water) with stirring at 0 ° C. . The resulting slurry was stirred for 3 hours at room temperature. The reaction mixture was partitioned between dichloromethane and water. The organic phase was washed with aqueous sodium hydrogen carbonate solution and water, dried over sodium sulfate and evaporated under reduced pressure. Chromatography on silica (dichloromethane / acetone 30: 1) to give 5- (2-benzyl-3-phenyl-propionyloxy) -3- [3- (2-carboxy-ethanesulfonyl) -2-methyl- 0.39 g of propionylamino] -4-oxo-pentanoic acid tert-butyl ester was obtained.

단계 BStep B

아니솔 0.1 ml을 함유하는 디클로로메탄/트리플루오로아세트산 1 : 1 혼합물 20 ml 중의 5-(2-벤질-3-페닐-프로피오닐옥시)-3-[3-(2-카르복시-에탄술포닐)-2-메틸-프로피오닐아미노]-4-옥소-펜탄산 tert-부틸 에스테르 (0.33 g, 0.48 mmol)를 45 분 동안 실온에서 교반시켰다. 감압하에서 증발시킨 후, 에테르/헥산으로부터 결정화하여 5-(2-벤질-3-페닐-프로피오닐옥시)-3-[3-(2-카르복시-에탄술포닐)-2-메틸-프로피오닐아미노]-4-옥소-펜탄산 tert-부틸 에스테르 (0.12 g)를 얻었다.5- (2-benzyl-3-phenyl-propionyloxy) -3- [3- (2-carboxy-ethanesulfonyl) in 20 ml of dichloromethane / trifluoroacetic acid 1: 1 mixture containing 0.1 ml of anisole ) -2-methyl-propionylamino] -4-oxo-pentanoic acid tert-butyl ester (0.33 g, 0.48 mmol) was stirred at room temperature for 45 minutes. After evaporation under reduced pressure, crystallization from ether / hexanes afforded 5- (2-benzyl-3-phenyl-propionyloxy) -3- [3- (2-carboxy-ethanesulfonyl) -2-methyl-propionylamino ] -4-oxo-pentanoic acid tert-butyl ester (0.12 g) was obtained.

MS (ESI) m/z 576.3 (M+1)MS (ESI) m / z 576.3 (M + 1)

<실시예 9d>Example 9d

5-(2-벤질-3-페닐-프로피오닐옥시)-3-[3-(3-카르복시-프로판-1-술피닐)-2-메틸-프로피오닐아미노]-4-옥소-펜탄산5- (2-Benzyl-3-phenyl-propionyloxy) -3- [3- (3-carboxy-propane-1-sulfinyl) -2-methyl-propionylamino] -4-oxo-pentanoic acid

단계 AStep A

디클로로메탄 4 ml 중의 5-(2-벤질-3-페닐-프로피오닐옥시)-3-[3-(3-카르복시-프로판술파닐)-2-메틸-프로피오닐아미노]-4-옥소-펜탄산 tert-부틸 에스테르 (0.28 g, 0.42 mmol, 실시예 3에서 제조됨)에 -50 ℃에서 교반시키면서 70 % 3-클로로퍼벤조산 (0.53 mmol) 0.13을 첨가했다. 이 반응 혼합물을 1 시간 동안 - 30 ℃에서 놓아둔 후, 디클로로메탄과 물 사이에 분배했다. 유기상을 탄산수소나트륨 수용액 (2 회)과 물로 세척하고, 황산나트륨 상에서 건조하고, 감압하에서 증발시켰다. 실리카 상에서 크로마토그래피 (디클로로메탄/아세톤 10 : 1)하여 5-(2-벤질-3-페닐-프로피오닐옥시)-3-[3-(3-카르복시-프로판-1-술피닐)-2-메틸-프로피오닐아미노]-4-옥소-펜탄산 tert-부틸 에스테르 0.15 g을 얻었다.5- (2-benzyl-3-phenyl-propionyloxy) -3- [3- (3-carboxy-propanesulfanyl) -2-methyl-propionylamino] -4-oxo-phene in 4 ml of dichloromethane To carbonic acid tert-butyl ester (0.28 g, 0.42 mmol, prepared in Example 3) was added 0.13 of 70% 3-chloroperbenzoic acid (0.53 mmol) with stirring at -50 ° C. The reaction mixture was left at -30 ° C for 1 hour and then partitioned between dichloromethane and water. The organic phase was washed with aqueous sodium hydrogen carbonate solution (twice) and water, dried over sodium sulfate and evaporated under reduced pressure. Chromatography on silica (dichloromethane / acetone 10: 1) 5- (2-benzyl-3-phenyl-propionyloxy) -3- [3- (3-carboxy-propane-1-sulfinyl) -2- Methyl-propionylamino] -4-oxo-pentanoic acid tert-butyl ester was obtained.

단계 BStep B

아니솔 0.1 ml을 함유하는 디클로로메탄/트리플루오로아세트산의 1 : 1 혼합물 중의 5-(2-벤질-3-페닐-프로피오닐옥시)-3-[3-(3-카르복시-프로판-1-술피닐)-2-메틸-프로피오닐아미노]-4-옥소-펜탄산 tert-부틸 에스테르 (0.40 g, 0.57 mmol)를 45 분 동안 실온에서 교반시켰다. 감압하에서 증발시킨 후 에테르/헥산으로부터 결정화하여 표제 화합물 (0.14 g)을 얻었다.5- (2-benzyl-3-phenyl-propionyloxy) -3- [3- (3-carboxy-propane-1- in a 1: 1 mixture of dichloromethane / trifluoroacetic acid containing 0.1 ml of anisole Sulfinyl) -2-methyl-propionylamino] -4-oxo-pentanoic acid tert-butyl ester (0.40 g, 0.57 mmol) was stirred for 45 minutes at room temperature. Evaporation under reduced pressure followed by crystallization from ether / hexane gave the title compound (0.14 g).

MS (ESI) m/z 574.3 (M+1)MS (ESI) m / z 574.3 (M + 1)

실시예 9와 유사한 방법으로 적절히 치환된 술파닐 카르복실산을 사용하여 상응하는 화합물들을 제조했다.Corresponding compounds were prepared using appropriately substituted sulfanyl carboxylic acids in a similar manner as in Example 9.

<실시예 9e><Example 9e>

5-(나프탈렌-1-일-아세톡시)-4-옥소-3-(2-페닐메탄술파닐-프로피오닐아미노)-펜탄산5- (Naphthalen-1-yl-acetoxy) -4-oxo-3- (2-phenylmethanesulfanyl-propionylamino) -pentanoic acid

MS (ESI) m/z 494.3 (M+1)MS (ESI) m / z 494.3 (M + 1)

<실시예 9f><Example 9f>

3-(2-메틸-3-페닐술파닐-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- (2-Methyl-3-phenylsulfanyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

MS (EI) m/z 493 (M+1)MS (EI) m / z 493 (M + 1)

<실시예 9g><Example 9g>

5-(2-벤질-3-페닐-프로피오닐옥시)-3-(2-메틸-3-페닐술파닐-프로피오닐아미노)-4-옥소-펜탄산5- (2-Benzyl-3-phenyl-propionyloxy) -3- (2-methyl-3-phenylsulfanyl-propionylamino) -4-oxo-pentanoic acid

MS (ESI) m/z 548.3 (M+1)MS (ESI) m / z 548.3 (M + l)

<실시예 9h><Example 9h>

3-(2-메틸-3-펜에틸술파닐-프로피오닐옥시)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- (2-Methyl-3-phenethylsulfanyl-propionyloxy) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

MS (ESI) m/z 522.2 (M+1)MS (ESI) m / z 522.2 (M + l)

<실시예 9i><Example 9i>

5-(2-벤질-3-페닐-프로피오닐옥시)-3-(2-메틸-3-펜에틸술파닐-프로피오닐아미노)-4-옥소-펜탄산5- (2-Benzyl-3-phenyl-propionyloxy) -3- (2-methyl-3-phenethylsulfanyl-propionylamino) -4-oxo-pentanoic acid

MS (ESI) m/z 576.3 (M+1)MS (ESI) m / z 576.3 (M + 1)

<실시예 9j><Example 9j>

5-(2-벤질-3-페닐-프로피오닐옥시)-3-(3-벤질술파닐-2-메틸-프로피오닐아미노)-4-옥소-펜탄산5- (2-Benzyl-3-phenyl-propionyloxy) -3- (3-benzylsulfanyl-2-methyl-propionylamino) -4-oxo-pentanoic acid

MS (ESI) m/z 562.3 (M+1)MS (ESI) m / z 562.3 (M + 1)

<실시예 9k><Example 9k>

5-(2-벤질-3-페닐-프로피오닐옥시)-3-(2-벤질술파닐-프로피오닐아미노)-4-옥소-펜탄산5- (2-Benzyl-3-phenyl-propionyloxy) -3- (2-benzylsulfanyl-propionylamino) -4-oxo-pentanoic acid

MS (ESI) m/z 546.3 (M+1)MS (ESI) m / z 546.3 (M + 1)

<실시예 9l><Example 9l>

3-[2-메틸-3-(3-페닐-프로필술파닐)-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- [2-Methyl-3- (3-phenyl-propylsulfanyl) -propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

MS (ESI) m/z 536.4 (M+1)MS (ESI) m / z 536.4 (M + 1)

실시예 9a와 유사한 방법으로, 적절히 치환된 술폰 카르복실산을 사용하여 상응하는 화합물을 제조했다.In a similar manner to Example 9a, the corresponding compounds were prepared using suitably substituted sulfone carboxylic acids.

<실시예 9m><Example 9m>

3-(3-벤젠술포닐-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- (3-Benzenesulfonyl-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

(ESI) MS m/z 526.4 (M+1)(ESI) MS m / z 526.4 (M + 1)

<실시예 9n><Example 9n>

3-(3-벤젠술포닐-2-메틸-프로피오닐아미노)-5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-펜탄산3- (3-Benzenesulfonyl-2-methyl-propionylamino) -5- (2-benzyl-3-phenyl-propionyloxy) -4-oxo-pentanoic acid

MS (ESI) m/z 580.2 (M+1)MS (ESI) m / z 580.2 (M + l)

<실시예 9o><Example 9o>

5-(2-벤질-3-페닐-프로피오닐옥시)-3-[2-메틸-3-(2-페닐-에탄술포닐)-프로피오닐아미노]-4-옥소-펜탄산5- (2-Benzyl-3-phenyl-propionyloxy) -3- [2-methyl-3- (2-phenyl-ethanesulfonyl) -propionylamino] -4-oxo-pentanoic acid

MS (ESI) m/z 608.2 (M+1)MS (ESI) m / z 608.2 (M + l)

<실시예 9p><Example 9p>

3-[2-메틸-3-(2-페닐-에탄술포닐)-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- [2-Methyl-3- (2-phenyl-ethanesulfonyl) -propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

MS (ESI) m/z 554.2 (M+1)MS (ESI) m / z 554.2 (M + l)

<실시예 9q><Example 9q>

5-(나프탈렌-1-일-아세톡시)-4-옥소-3-(2-페닐메탄술포닐-프로피오닐아미노)-펜탄산5- (Naphthalen-1-yl-acetoxy) -4-oxo-3- (2-phenylmethanesulfonyl-propionylamino) -pentanoic acid

MS (ESI) m/z 526.2 (M+1)MS (ESI) m / z 526.2 (M + 1)

<실시예 9r><Example 9r>

5-(2-벤질-3-페닐-프로피오닐옥시)-3-(2-메틸-3-페닐메탄술포닐-프로피오닐아미노)-4-옥소-펜탄산5- (2-Benzyl-3-phenyl-propionyloxy) -3- (2-methyl-3-phenylmethanesulfonyl-propionylamino) -4-oxo-pentanoic acid

MS (ESI) m/z 594.2 (M+1)MS (ESI) m / z 594.2 (M + l)

<실시예 9s><Example 9s>

5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-3-(2-페닐메탄술포닐-프로피오닐아미노)-펜탄산5- (2-Benzyl-3-phenyl-propionyloxy) -4-oxo-3- (2-phenylmethanesulfonyl-propionylamino) -pentanoic acid

MS (ESI) m/z 580.1 (M+1)MS (ESI) m / z 580.1 (M + l)

<실시예 9t><Example 9t>

3-[2-메틸-3-(3-페닐-프로판-1-술포닐)-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- [2-Methyl-3- (3-phenyl-propane-1-sulfonyl) -propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

MS (ESI) m/z 568.2 (M+1)MS (ESI) m / z 568.2 (M + l)

<실시예 9u><Example 9u>

5-(2-벤질-3-페닐-프로피오닐옥시)-3-[2-메틸-3-(3-페닐-프로판-1-술포닐)-프로피오닐아미노]-4-옥소-펜탄산5- (2-Benzyl-3-phenyl-propionyloxy) -3- [2-methyl-3- (3-phenyl-propane-1-sulfonyl) -propionylamino] -4-oxo-pentanoic acid

MS (ESI) m/z 622.3 (M+1)MS (ESI) m / z 622.3 (M + 1)

실시예 9b와 유사한 방법으로 적절히 치환된 술파닐 카르복실산을 사용하여 상응하는 화합물들을 제조했다.Corresponding compounds were prepared using appropriately substituted sulfanyl carboxylic acids in a similar manner as in Example 9b.

<실시예 9v><Example 9v>

5-(2-벤질-3-페닐-프로피오닐옥시)-3-[3-(2-카르복시-에틸술파닐)-2-메틸-프로피오닐아미노]-4-옥소-펜탄산5- (2-Benzyl-3-phenyl-propionyloxy) -3- [3- (2-carboxy-ethylsulfanyl) -2-methyl-propionylamino] -4-oxo-pentanoic acid

MS (ESI) m/z 544.4 (M+1)MS (ESI) m / z 544.4 (M + l)

<실시예 9w><Example 9w>

3-[3-(3-카르복시-프로필술파닐)-2-메틸-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- [3- (3-carboxy-propylsulfanyl) -2-methyl-propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

MS (ESI) m/z 504.2 (M+1)MS (ESI) m / z 504.2 (M + l)

<실시예 9x><Example 9x>

5-(2-벤질-3-페닐-프로피오닐옥시)-3-[3-(3-카르복시-프로필술파닐)-2-메틸-프로피오닐아미노]-4-옥소-펜탄산5- (2-Benzyl-3-phenyl-propionyloxy) -3- [3- (3-carboxy-propylsulfanyl) -2-methyl-propionylamino] -4-oxo-pentanoic acid

MS (ESI) m/z 558.2 (M+1)MS (ESI) m / z 558.2 (M + l)

<실시예 9y><Example 9y>

3-(3-카르복시메틸술파닐-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- (3-carboxymethylsulfanyl-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

MS (ESI) m/z 476.1 (M+1)MS (ESI) m / z 476.1 (M + 1)

<실시예 9z><Example 9z>

5-(2-벤질-3-페닐-프로피오닐옥시)-3-(3-카르복시메틸술파닐-2-메틸-프로피오닐아미노)-4-옥소-펜탄산5- (2-Benzyl-3-phenyl-propionyloxy) -3- (3-carboxymethylsulfanyl-2-methyl-propionylamino) -4-oxo-pentanoic acid

MS (ESI) m/z 530.1 (M+1)MS (ESI) m / z 530.1 (M + 1)

실시예 9c와 유사한 방법으로, 적절히 치환된 술포닐 카르복실산을 사용하여 상응하는 화합물을 제조했다.In a similar manner to Example 9c, the corresponding compounds were prepared using suitably substituted sulfonyl carboxylic acids.

<실시예 9aa><Example 9aa>

3-[3-(2-카르복시-에탄술포닐)-2-메틸-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- [3- (2-carboxy-ethanesulfonyl) -2-methyl-propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

MS (ESI) m/z 522.3 (M+1)MS (ESI) m / z 522.3 (M + 1)

<실시예 9bb><Example 9bb>

3-[3-(3-카르복시-프로판-1-술포닐)-2-메틸-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- [3- (3-carboxy-propane-1-sulfonyl) -2-methyl-propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

MS (ESI) m/z 536.3 (M+1)MS (ESI) m / z 536.3 (M + 1)

<실시예 9cc><Example 9cc>

3-(3-카르복시메탄술포닐-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- (3-carboxymethanesulfonyl-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

MS (ESI) m/z 508.3 (M+1)MS (ESI) m / z 508.3 (M + 1)

<실시예 9dd><Example 9dd>

5-(2-벤질-3-페닐-프로피오닐옥시)-3-[3-(3-카르복시-프로판-1-술포닐)-2-메틸-프로피오닐아미노]-4-옥소-펜탄산5- (2-Benzyl-3-phenyl-propionyloxy) -3- [3- (3-carboxy-propane-1-sulfonyl) -2-methyl-propionylamino] -4-oxo-pentanoic acid

MS (ESI) m/z 588.3 (M-H)MS (ESI) m / z 588.3 (M-H)

<실시예 9ee><Example 9ee>

5-(2-벤질-3-페닐-프로피오닐옥시)-3-(3-카르복시메탄술포닐-2-메틸-프로피오닐아미노)-4-옥소-펜탄산5- (2-Benzyl-3-phenyl-propionyloxy) -3- (3-carboxymethanesulfonyl-2-methyl-propionylamino) -4-oxo-pentanoic acid

MS (ESI) m/z 560.2 (M-H)MS (ESI) m / z 560.2 (M-H)

실시예 9d와 유사한 방법으로, 적절히 치환된 술피닐 카르복실산을 사용하여 상응하는 화합물들을 제조했다.In a similar manner to Example 9d, the corresponding compounds were prepared using suitably substituted sulfinyl carboxylic acids.

<실시예 9ff><Example 9ff>

3-[3-(3-카르복시-프로판-1-술피닐)-2-메틸-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- [3- (3-carboxy-propane-1-sulfinyl) -2-methyl-propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

MS (ESI) m/z 520.4 (M+1)MS (ESI) m / z 520.4 (M + 1)

<실시예 9gg><Example 9gg>

3-[2-메틸-3-(3-페닐-프로판-1-술피닐)-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- [2-Methyl-3- (3-phenyl-propane-1-sulfinyl) -propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

MS (ESI) m/z 552.2 (M+1)MS (ESI) m / z 552.2 (M + 1)

<실시예 9hh><Example 9hh>

5-(2-벤질-3-페닐-프로피오닐옥시)-3-[2-메틸-3-(3-페닐-프로판-1-술피닐)-프로피오닐아미노]-4-옥소-펜탄산5- (2-Benzyl-3-phenyl-propionyloxy) -3- [2-methyl-3- (3-phenyl-propane-1-sulfinyl) -propionylamino] -4-oxo-pentanoic acid

MS (ESI) m/z 606.3 (M+1)MS (ESI) m / z 606.3 (M + 1)

<실시예 10><Example 10>

3-(2-카르바모일메틸-3-메틸-부티릴아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- (2-Carbamoylmethyl-3-methyl-butyrylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

단계 AStep A

-78 ℃의 질소 상태에서 THF 400 ml 중의 (4S)-(-)-4-이소프로필-2-옥사졸리디논 (19.85 g, 0.154 몰)의 용액을 n-부틸 리튬 (64.5 ml, 0.161 몰, 헥산 중의 2.5 M 용액)으로 적가 처리했다. 고체가 생성되었다. 이 혼합물을 30 분 동안 -78 ℃에서 교반시킨 후 이소-발레릴 클로라이드 (20.6 ml, 0.169 몰)로 적가 처리했다. 이 반응물을 실온까지 서서히 밤새 가온시켰다. 샘플을 농축한 후 EtOAc와 KH2PO4포화용액 사이에 분배했다. 유기 추출물을 염수로 세척하고 건조 (MgSO4)하고, 생성된 황색 오일을 크로마토그래피 (MPLC, 실리카 겔, 헥산 중의 10 % EtOAc)하여 N-아실옥사졸리돈 29.8 g (91 %)을 담황색 오일로 얻었다.A solution of (4S)-(-)-4-isopropyl-2-oxazolidinone (19.85 g, 0.154 mol) in 400 ml THF in nitrogen at −78 ° C. was converted to n-butyl lithium (64.5 ml, 0.161 mol, 2.5 M solution in hexane) dropwise. A solid was produced. The mixture was stirred for 30 min at -78 ° C and then treated dropwise with iso-valeryl chloride (20.6 ml, 0.169 mol). The reaction was slowly warmed up to room temperature overnight. The sample was concentrated and partitioned between EtOAc and saturated KH 2 PO 4 solution. The organic extract was washed with brine and dried (MgSO 4 ), and the resulting yellow oil was chromatographed (MPLC, silica gel, 10% EtOAc in hexanes) to give 29.8 g (91%) of N-acyloxazolidone to pale yellow oil. Got it.

단계 BStep B

THF 500 ml 중의 N-아실옥사졸리돈 (20.8 g, 97.5 mmol, 실시예 10의 단계 A)의 용액을 질소 상태의 -78 ℃에서 나트륨 비스(트리메틸실릴)아미드 (107 ml, 107 mmol, THF 중의 1.0 M 용액)으로 적가 처리했다. 이 용액을 30 분 동안 -78 ℃에서 교반시킨 후, THF 100 ml 중의 tert-부틸 브로모아세테이트 (18.0 ml, 121.9 mmol) 용액으로 적가 처리했다. 샘플을 1 시간 동안 -78 ℃에서 교반시킨 후 KH2PO4용액 (약 125 ml)을 적가하여 반응을 중단시켰다. 이 혼합물을 실온으로 가온하고 농축하여 (THF 대부분 제거), 에테르로 추출했다. 이 유기 추출물을 NaHCO3및 염수로 세척하고 건조 (MgSO4), 농축하고 에테르-펫 에테르로부터 결정화하여, [(S-(R*,R*)]-3-(4-이소프로필-2-옥소-옥사졸리딘-3-카르보닐)-4-메틸-펜탄산 tert-부틸 에스테르 21.1 g (66 %)을 백색 고체로서 얻었다.A solution of N-acyloxazolidone (20.8 g, 97.5 mmol, step A of Example 10) in 500 ml of THF was dissolved in sodium bis (trimethylsilyl) amide (107 ml, 107 mmol, THF at −78 ° C. under nitrogen). 1.0 M solution) dropwise. The solution was stirred for 30 min at −78 ° C. and then treated dropwise with a solution of tert-butyl bromoacetate (18.0 ml, 121.9 mmol) in 100 ml of THF. The sample was stirred for 1 h at -78 ° C and then the reaction was stopped by dropwise addition of KH 2 PO 4 solution (about 125 ml). The mixture was warmed to room temperature and concentrated (most of THF removed), extracted with ether. This organic extract was washed with NaHCO 3 and brine, dried (MgSO 4 ), concentrated and crystallized from ether-pet ether to give [(S- (R * , R * )]-3- (4-isopropyl-2- 21.1 g (66%) of oxo-oxazolidine-3-carbonyl) -4-methyl-pentanoic acid tert-butyl ester were obtained as a white solid.

C17H29NO5(327.424)에 대한 분석:Analysis for C 17 H 29 NO 5 (327.424):

이론치: C, 62.36; H, 8.93; N, 4.28.Theoretical: C, 62.36; H, 8.93; N, 4.28.

실측치: C, 62.30; H, 9.07; N, 4.09.Found: C, 62.30; H, 9.07; N, 4.09.

단계 CStep C

N-아실옥사졸리돈의 가수분해는 문헌 (Evans D. A., et al., Tet. Lett. 1987; 28: 6141-6144)의 공정에 따라서 과산화수소리튬을 사용하여 수행했다. THF 250 ml 중의 [(S-(R*,R*)]-3-(4-이소프로필-2-옥소-옥사졸리딘-3-카르보닐)-4-메틸-펜탄산 tert-부틸 에스테르 (9.05 g, 27.64 mmol, 실시예 10의 단계 B)의 0 ℃ 교반 용액에 과산화수소 (14.1 ml, 138 mmol, 물 중의 30 중량% 용액)를 적가한 후, 1.0 M 수산화리튬 용액 (55.3 ml, 55.3 mmol)을 첨가했다. 반응물을 실온에서 서서히 밤새 가온시켰다. 반응물을 농축시키고 (THF 대부분 제거), 염기성 용액을 CH2Cl2(2 x 100 ml)로 세척했다. 수상을 냉각시키고 KH2PO4포화용액으로 산성화하여 pH 약 5로 조절하고, EtOAc로 추출했다. 유기 추출물을 염수로 세척하고 건조 (MgSO4), 농축하여 (S)-2-이소프로필 숙신산 4-tert-부틸 에스테르 5.66 g (95 %)을 무색 오일로 얻고 이를 추가의 정제없이 사용했다.Hydrolysis of N-acyloxazolidone was carried out using lithium peroxide, according to the process of Evans DA, et al., Tet. Lett. 1987; 28: 6141-6144. [(S- (R * , R * )]-3- (4-isopropyl-2-oxo-oxazolidine-3-carbonyl) -4-methyl-pentanoic acid tert-butyl ester in 250 ml of THF ( Hydrogen peroxide (14.1 ml, 138 mmol, 30 wt% solution in water) was added dropwise to 9.05 g, 27.64 mmol, step B) of Example 10), followed by 1.0 M lithium hydroxide solution (55.3 ml, 55.3 mmol The reaction was allowed to slowly warm at room temperature overnight The reaction was concentrated (mostly removed THF) and the basic solution was washed with CH 2 Cl 2 (2 × 100 ml) The aqueous phase was cooled and saturated with KH 2 PO 4. Acidified with solution to pH to about 5. and extracted with EtOAc The organic extracts were washed with brine, dried (MgSO 4 ) and concentrated to give 5.66 g (95) (S) -2-isopropyl succinic acid 4-tert-butyl ester %) Was obtained as a colorless oil and used without further purification.

단계 DStep D

CH2Cl2250 ml 중의 (S)-2-이소프로필 숙신산 4-tert-부틸 에스테르 (10.77 g, 49.80 mmol), (S)-2-아미노-숙신산 1-알릴 에스테르 4-벤질 에스테르 히드로클로라이드 (14.93 g, 49.81 mmol), HOBT·H2O (8.4 g, 74.6 mmol), EDCl·HCl (10.5 g, 54.8 mmol) 및 4-메틸모르폴린 (8.2 ml, 74.6 mmol)의 혼합물을 실온에서 12 시간 동안 교반시켰다. 이 혼합물을 농축시킨 후 EtOAc 및 NaHCO3포화용액 사이에서 분배했다. EtOAc 추출물을 KH2PO4포화용액 및 염수로 세척하고 건조 (MgSO4)하고, 여과 및 농축하고, 크로마토그래피 (MPLC, 실리카 겔, 헥산 중의 20 % EtOAc)하여 [(S-(R*,R*)]-2-(2-tert-부톡시카르보닐메틸-3-메틸-부티릴아미노)-숙신산 1-알릴 에스테르 4-벤질 에스테르 19.21 g (84 %)을 담황색 오일로서 얻었다.(S) -2-isopropyl succinic acid 4-tert-butyl ester (10.77 g, 49.80 mmol) in 250 ml CH 2 Cl 2 , (S) -2-amino-succinic acid 1-allyl ester 4-benzyl ester hydrochloride ( 14.93 g, 49.81 mmol), a mixture of HOBT.H 2 O (8.4 g, 74.6 mmol), EDCl.HCl (10.5 g, 54.8 mmol) and 4-methylmorpholine (8.2 ml, 74.6 mmol) at room temperature for 12 hours. Was stirred. The mixture was concentrated and partitioned between EtOAc and saturated NaHCO 3 solution. EtOAc extract was washed with saturated KH 2 PO 4 solution and brine, dried (MgSO 4 ), filtered and concentrated, chromatographed (MPLC, silica gel, 20% EtOAc in hexanes) to [(S- (R * , R). * )]-2- (2-tert-butoxycarbonylmethyl-3-methyl-butyrylamino) -succinic acid 1-allyl ester 4-benzyl ester 19.21 g (84%) was obtained as a pale yellow oil.

단계 EStep E

CH2Cl235 ml 중의 [(S-(R*,R*)]-2-(2-tert-부톡시카르보닐메틸-3-메틸-부티릴아미노)-숙신산 1-알릴 에스테르 4-벤질 에스테르 (9.3 g, 23.0 mmol, 실시예 10의 단계 D) 및 트리플루오로아세트산 (35 ml)의 용액을 실온에서 2 시간 동안 질소 상태에서 교반시켰다. 이 샘플을 농축시킨 후 CH2Cl2에 재용해하고, EDCI·HCl (8.8 g, 46.0 mmol), HOBT·H2O (6.2 g, 46.0 mmol) 및 O-벤질히드록시아민 히드로클로라이드 (7.3 g, 46.0 mmol)로 처리했다. 4-메틸모르폴린 (11.6 g, 115 mmol)을 적가하고 반응 혼합물을 실온에서 밤새 교반시켰다. 샘플을 CH2Cl2로 희석하고 5 % HCl 및 NaHCO3포화용액으로 연속적으로 세척했다. 유기 추출물을 건조 (Na2SO4)하고 농축하여 O-벤질 히드록사메이트 10.25 g (88 %)을 백색 고체로서 얻고 이를 추가의 정제없이 다음 단계에서 수행했다.[(S- (R * , R * )]-2- (2-tert-butoxycarbonylmethyl-3-methyl-butyrylamino) -succinic acid 1-allyl ester 4-benzyl in 35 ml CH 2 Cl 2 A solution of ester (9.3 g, 23.0 mmol, step D of Example 10) and trifluoroacetic acid (35 ml) was stirred under nitrogen for 2 hours at room temperature The sample was concentrated and reused in CH 2 Cl 2 . Dissolved and treated with EDCI.HCl (8.8 g, 46.0 mmol), HOBT.H 2 O (6.2 g, 46.0 mmol) and O-benzylhydroxyamine hydrochloride (7.3 g, 46.0 mmol). Pauline (11.6 g, 115 mmol) was added dropwise and the reaction mixture was stirred at rt overnight The sample was diluted with CH 2 Cl 2 and washed successively with 5% HCl and saturated NaHCO 3 solution The organic extract was dried (Na 2 SO 4 ) and concentrated to give 10.25 g (88%) of O-benzyl hydroxamate as a white solid, which was carried out in the next step without further purification.

단계 FStep F

알릴 에스테르는 문헌 (Dessolin M., et al., Tet. Lett., 1995; 36: 5741-5744)의 공정을 사용하여 절단했다. CH2Cl2중의 알릴 에스테르 (10.25 g, 19.7 mmol, 실시예 10의 단계 E) 및 테트라키스(트리페닐포스핀)팔라듐 (0) (0.462 g, 0.40 mmol)의 용액을 페닐실란 (4.26 g, 39.4 mmol)으로 적가 처리했다. 이 반응 혼합물을 1 시간에 걸쳐 실온으로 가온시킨 후, KH2PO4포화용액으로 세척했다. 유기층을 0.5 N NaOH로 추출했다. 염기성 수상을 진한 HCl로 산성화하고 EtOAc로 추출했다. 유기 추출물을 건조 (Na2SO4), 여과 및 농축하여 치환된 숙신산 4-벤질 에스테르 6.2 g (72 %)를 발포성 백색 고체로서 얻었다.Allyl esters were cleaved using the process of Dessolin M., et al., Tet. Lett., 1995; 36: 5741-5744. A solution of allyl ester (10.25 g, 19.7 mmol, step E of Example 10) and tetrakis (triphenylphosphine) palladium (0) (0.462 g, 0.40 mmol) in CH 2 Cl 2 was charged with phenylsilane (4.26 g, 39.4 mmol) dropwise. The reaction mixture was allowed to warm to room temperature over 1 hour and then washed with saturated KH 2 PO 4 solution. The organic layer was extracted with 0.5 N NaOH. The basic aqueous phase was acidified with concentrated HCl and extracted with EtOAc. The organic extract was dried (Na 2 SO 4 ), filtered and concentrated to give 6.2 g (72%) of substituted succinic acid 4-benzyl ester as effervescent white solid.

THF (50 ml) 중의 상기의 산 (6.0 g, 12.8 mmol) 및 4-메틸모르폴린 (1.3 g, 12.8 mmol)의 용액에 -42 ℃에서 이소부틸 클로로포르메이트 (1.8 g, 12.8 mmol)를 적가했다. 30 분 동안 교반시킨 후, 반응 혼합물을 디에틸 에테르 (약 0.5 M, 200 ml) 중의 디아조메탄 용액에 0 ℃에서 첨가했다. 반응 혼합물을 2 시간 동안 실온에서 교반시킨 후 0 ℃로 냉각시켰다. 48 % HBr (20 ml) 및 HOAc (20 ml)의 용액을 적가하고, 반응물을 0 ℃에서 30 분 동안 교반시켰다. 샘플을 디에틸 에테르로 희석하고, 물 (2 회) 및 NaHCO3용액 (2 회)으로 세척했다. 유기층을 건조 (Na2SO4)하고 농축했다. 잔류물을 CH2Cl2에 용해시키고, 생성물을 헥산으로 침전시켰다. 이 고체를 여과하여 모으고, 헥산으로 잘 세척하고 건조하여, 브로모메틸 케톤 1.5 g (15 %)을 백색 고체로서 얻었다.To a solution of the above acid (6.0 g, 12.8 mmol) and 4-methylmorpholine (1.3 g, 12.8 mmol) in THF (50 ml) was added dropwise isobutyl chloroformate (1.8 g, 12.8 mmol) at -42 ° C. did. After stirring for 30 minutes, the reaction mixture was added to a solution of diazomethane in diethyl ether (about 0.5 M, 200 ml) at 0 ° C. The reaction mixture was stirred for 2 hours at room temperature and then cooled to 0 ° C. A solution of 48% HBr (20 ml) and HOAc (20 ml) was added dropwise and the reaction stirred at 0 ° C. for 30 minutes. The sample was diluted with diethyl ether and washed with water (twice) and NaHCO 3 solution (twice). The organic layer was dried (Na 2 SO 4 ) and concentrated. The residue was dissolved in CH 2 Cl 2 and the product was precipitated with hexanes. This solid was collected by filtration, washed well with hexane and dried to give 1.5 g (15%) of bromomethyl ketone as a white solid.

DMF 2.0 ml 중의 브로모메틸 케톤 (0.440 g, 0.82 mmol), 1-나프틸아세트산 (0.300 g, 1.61 mmol) 및 불화칼륨 (0.116 g, 2.0 mmol)의 혼합물을 12 시간 동안 실온에서 교반시켰다. 반응 혼합물을 EtOAc로 희석하고 물 (2 회) 및 NaHCO3용액 (2 회)으로 세척했다. 유기층을 건조 (Na2SO4)하고 농축했다. 잔류물을 CH2Cl2-헥산으로부터 결정화하여 나프틸 아세트산 에스테르 메틸 케톤 0.430 g (80 %)을 백색 고체로서 얻었다.A mixture of bromomethyl ketone (0.440 g, 0.82 mmol), 1-naphthylacetic acid (0.300 g, 1.61 mmol) and potassium fluoride (0.116 g, 2.0 mmol) in 2.0 ml of DMF was stirred at room temperature for 12 hours. The reaction mixture was diluted with EtOAc and washed with water (2 times) and NaHCO 3 solution (2 times). The organic layer was dried (Na 2 SO 4 ) and concentrated. The residue was crystallized from CH 2 Cl 2 -hexanes to give 0.430 g (80%) of naphthyl acetate ester methyl ketone as a white solid.

단계 GStep G

THF 75 ml 중의 치환된 숙신산 4-벤질 에스테르 (0.43 g, 실시예 10의 단계 F)의 용액에 Pd/C (0.050 g)로 처리하고, 2 시간 동안 실온에서 혼합물을 수소압 50 psi에서 수소첨가했다. 이 반응 혼합물을 여과하고 라니 니켈 (Raney Nickel) (0.10 g)를 첨가했다. 반응 혼합물을 다시 17 시간 동안 50 psi에서 수소첨가했다. 샘플을 여과했다. 여액을 농축하고, 잔류물을 아세톤-헥산으로부터 결정화하여, 3-(2-카르바모일메틸-3-메틸-부티릴아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 0.111 g (45 %)을 백색 고체로서 얻었다.To a solution of substituted succinic acid 4-benzyl ester (0.43 g, step F of Example 10) in 75 ml of THF was treated with Pd / C (0.050 g) and the mixture was hydrogenated at 50 psi hydrogen pressure at room temperature for 2 hours. did. The reaction mixture was filtered and Raney Nickel (0.10 g) was added. The reaction mixture was again hydrogenated at 50 psi for 17 hours. The sample was filtered. The filtrate was concentrated and the residue was crystallized from acetone-hexane to give 3- (2-carbamoylmethyl-3-methyl-butyrylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo 0.111 g (45%) of -pentanoic acid was obtained as a white solid.

C24H28N2O7·0.74H2O에 대한 분석:Analysis for C 24 H 28 N 2 O 7 · 0.74H 2 O:

이론치: C, 61.30; H, 6.32; N, 5.96.Theoretical: C, 61.30; H, 6. 32; N, 5.96.

실측치: C, 61.30; H, 6.37; N, 5.94.Found: C, 61.30; H, 6. 37; N, 5.94.

실시예 10과 유사한 방법으로 상응하는 화합물들을 제조했다.Corresponding compounds were prepared in a similar manner to Example 10.

<실시예 10a><Example 10a>

3-[3-메틸-2-(펜에틸카르바모일-메틸)-부티릴아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 (백색 고체)3- [3-Methyl-2- (phenethylcarbamoyl-methyl) -butyrylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid (white solid)

C32H36N2O7·1.5H2O(587.676)에 대한 분석:Analysis for C 32 H 36 N 2 O 7 1.5H 2 O (587.676):

이론치: C, 65.40; H, 6.69; N, 4.77.Theoretical: C, 65.40; H, 6. 69; N, 4.77.

실측치: C, 65.23; H, 6.69; N, 4.74.Found: C, 65.23; H, 6. 69; N, 4.74.

<실시예 10b><Example 10b>

3-(3-카르복시-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- (3-Carboxy-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

<실시예 11><Example 11>

3-(2-메틸-3-술파모일-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산3- (2-Methyl-3-sulfamoyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid

0 ℃의 질소 상태에서, 톨루엔 125 ml 중의 D-(-)-S-아세틸-β-메르캅토이소부티릴산 (14.0 g, 86.4 mmol)의 용액에 1,8-디아자비시클로[5.4.0]운데크-7-엔 (DBU, 13.6 g, 89.5 mmol)을 적가한 후 벤질 브로마이드 (15.3 g, 89.5 mmol)를 5 분에 걸쳐 적가했다. 반응물을 실온에서 밤새 가온시켰다. 반응물을 농축시킨 후 NaHCO3포화용액으로 희석하고, EtOAc (3 회)로 추출했다. 합한 유기 추출물을 염수로 세척하고 건조 (MgSO4), 여과 및 농축하여 D-(-)-S-아세틸-β-메르캅토이소부틸산 벤질 에스테르를 얻고 이를 추가의 정제없이 사용했다.1,8-diazabicyclo [5.4.0 in a solution of D-(-)-S-acetyl-β-mercaptoisobutyryl acid (14.0 g, 86.4 mmol) in 125 ml of toluene at 0 ° C. ] Undec-7-ene (DBU, 13.6 g, 89.5 mmol) was added dropwise followed by benzyl bromide (15.3 g, 89.5 mmol) dropwise over 5 minutes. The reaction was allowed to warm overnight at room temperature. The reaction was concentrated and then diluted with saturated NaHCO 3 solution and extracted with EtOAc (3 times). The combined organic extracts were washed with brine, dried (MgSO 4 ), filtered and concentrated to give D-(-)-S-acetyl-β-mercaptoisobutyl acid benzyl ester which was used without further purification.

사염화탄소 : 에탄올 (9 : 1) 80 ml 중의 D-(-)-S-아세틸-β-메르캅토이소부틸산 벤질 에스테르 (7.1 g, 20.5 mmol)의 용액을 통해 90 분 동안 염소 기체로 거품을 일으켰다. 이 용액을 농축했다. 생성된 술포닐 클로라이드를 CH2Cl270 ml에 용해시키고 0 ℃에서 농축시키고, CH2Cl210 ml 중의 트리에틸아민 (2.4 g, 24.6 mmol) 및 비스(p-메톡시-벤질)아민 (5.5 g, 21.5 mmol, J. Org. Chem., 1992; 57: 7065) 용액으로 적가 처리했다. 이 용액을 3 시간 동안 0 ℃에서 교반시키고, 농축시키고, 물로 희석하고, EtOAc (3 회)로 추출했다. 합한 유기 추출물을 염수로 세척하고 건조 (MgSO4), 여과 및 농축했다. 생성된 갈색 오일을 크로마토그래피 (MPLC, 실리카 겔, 헥산 중의 30 % EtOAc)하여 술폰아미드를 담황색 오일로서 얻었다.Carbon tetrachloride: foamed with chlorine gas for 90 minutes through a solution of D-(-)-S-acetyl-β-mercaptoisobutyl acid benzyl ester (7.1 g, 20.5 mmol) in 80 ml of ethanol (9: 1) Caused. This solution was concentrated. The resulting sulfonyl chloride CH 2 Cl 2 and concentrated in dissolved 0 ℃ to 70 ml, CH 2 Cl 2 10 ml of triethylamine (2.4 g, 24.6 mmol) and bis (p- methoxy-benzyl) -amine ( 5.5 g, 21.5 mmol, J. Org.Chem., 1992; 57: 7065) dropwise. This solution was stirred for 3 h at 0 ° C., concentrated, diluted with water and extracted with EtOAc (3 times). The combined organic extracts were washed with brine, dried (MgSO 4 ), filtered and concentrated. The resulting brown oil was chromatographed (MPLC, silica gel, 30% EtOAc in hexanes) to give sulfonamide as a pale yellow oil.

THF 중의 이 술폰아미드 (8.45 g, 17 mmol)의 용액을 20 % Pd/C로 처리하고 수소압 50 psig로 실온에서 4 시간 동안 수소첨가시켰다. 샘플을 셀라이트 패드를 통해 여과하고 농축하여 술폰아미드 산을 무색 오일로서 얻었고 이것은 방치해 두면 고체화되었다.A solution of this sulfonamide (8.45 g, 17 mmol) in THF was treated with 20% Pd / C and hydrogenated at 50 psig for 4 hours at room temperature. The sample was filtered through a pad of celite and concentrated to give sulfonamide acid as a colorless oil which solidified upon standing.

0 ℃에서 CH2Cl2100 ml 중의 이 술폰아미드산 (4.1 g, 10 mmol) 및 피리딘 (0.8 g, 10 mmol)의 용액에 불화시아누르산 (2.76 g, 20 mmol)을 적가했다. 샘플을 2 시간 동안 0 ℃에서 교반시키고, 물로 희석하고, CH2Cl2(2 회)로 추출했다. 합한 CH2Cl2추출물을 건조 (MgSO4), 여과 및 농축했다. 생성된 오일을 CH2Cl2100 ml에 용해하고 H-Asp(OtBu)OMe·HCl (4.08 g, 17 mmol)로 처리하고 4-메틸-모르폴린 (2.0 g, 20 mmol)을 적가했다. 용액을 12 시간 동안 실온에서 교반시킨 후 EtOAc와 NaHCO3포화용액 사이에 분배했다. 유기 추출물을 NaH2PO4포화용액 및 염수로 세척하고, 건조 (MgSO4) 및 농축하여 오일을 얻고, 이를 방치하여 고체화했다.To a solution of this sulfonamic acid (4.1 g, 10 mmol) and pyridine (0.8 g, 10 mmol) in 100 ml of CH 2 Cl 2 at 0 ° C. was added dropwise cyanuric acid fluoride (2.76 g, 20 mmol). The sample was stirred for 2 h at 0 ° C., diluted with water and extracted with CH 2 Cl 2 (twice). The combined CH 2 Cl 2 extracts were dried (MgSO 4 ), filtered and concentrated. The resulting oil was dissolved in 100 ml of CH 2 Cl 2 , treated with H-Asp (OtBu) OMe.HCl (4.08 g, 17 mmol) and 4-methyl-morpholine (2.0 g, 20 mmol) was added dropwise. The solution was stirred at rt for 12 h and then partitioned between EtOAc and saturated NaHCO 3 solution. The organic extract was washed with saturated NaH 2 PO 4 solution and brine, dried (MgSO 4 ) and concentrated to give an oil which was left to solidify.

실온에서 메틸 에스테르 (4.58 g, 7.73 mmol)를 메탄올 (50 ml) 및 0.5 N NaOH 수용액 (20 ml) 중에서 밤새 교반시켰다. 메탄올을 진공 상태에서 제거하고 잔류물을 물 (100 ml)로 희석시킨 후 진한 HCl로 산성화하고 EtOAc로 추출했다. 유기층을 건조 (Na2SO4)하고 농축하여 유리 산 3.7 g (83 %)을 발포성 황색 고체를 얻었다.Methyl ester (4.58 g, 7.73 mmol) was stirred overnight at room temperature in methanol (50 ml) and 0.5 N aqueous NaOH solution (20 ml). Methanol was removed in vacuo and the residue diluted with water (100 ml), acidified with concentrated HCl and extracted with EtOAc. The organic layer was dried (Na 2 SO 4 ) and concentrated to give 3.7 g (83%) of the free acid as an effervescent yellow solid.

THF 50 ml 중의 상기 산 (3.7 g, 6.4 mmol) 및 4-메틸모르폴린 (0.65 g, 6.4 mmol)의 용액에 이소부틸 클로로포르메이트 (0.89 g, 6.4 mmol)을 적가했다. 30 분 동안 교반시킨 후, 반응 혼합물을 디에틸 에테르 중의 디아조메탄 용액 (약 0.3 M, 100 ml)에 0 ℃에서 첨가했다. 반응 혼합물을 2 시간 동안 실온에서 교반한 후, 0 ℃로 냉각했다. 48 HBr (15 ml) 및 HOAc (15 ml)의 용액을 적가하고, 반응물을 30 분 동안 0 ℃에서 교반시켰다. 샘플을 디에틸 에테르로 희석하고 물 (2회) 및 NaHCO3포화용액 (2회)으로 세척했다. 유기층을 건조 (Na2SO4)하고 농축하여 브로모메틸 케톤 3.88 g (97 %)을 황색 고체로서 얻었다.To a solution of the acid (3.7 g, 6.4 mmol) and 4-methylmorpholine (0.65 g, 6.4 mmol) in 50 ml of THF was added dropwise isobutyl chloroformate (0.89 g, 6.4 mmol). After stirring for 30 minutes, the reaction mixture was added to a solution of diazomethane (about 0.3 M, 100 ml) in diethyl ether at 0 ° C. The reaction mixture was stirred for 2 hours at room temperature and then cooled to 0 ° C. A solution of 48 HBr (15 ml) and HOAc (15 ml) was added dropwise and the reaction was stirred at 0 ° C. for 30 minutes. The sample was diluted with diethyl ether and washed with water (twice) and saturated NaHCO 3 solution (twice). The organic layer was dried (Na 2 SO 4 ) and concentrated to give 3.88 g (97%) bromomethyl ketone as a yellow solid.

무수 DMF 2.0 ml 중의 브로모메틸 케톤 (0.624 g, 1.0 mmol), 1-나프틸아세트산 (0.372 g, 2.0 mmol) 및 불화칼륨 (0.145 g, 2.5 mmol)의 혼합물을 12 시간 동안 실온에서 교반시켰다. 반응 혼합물을 EtOAc로 희석하고 물 (2회) 및 NaHCO3포화용액으로 연속적으로 세척했다. 유기층을 건조 (Na2SO4), 농축하고, 잔류물을 크로마토그래피 (MPLC, 실리카 겔, 헥산-EtOAc [2:1])하여 디-p-메톡시벤질 술폰아미드 0.470 g (62 %)을 백색 고체로서 얻었다.A mixture of bromomethyl ketone (0.624 g, 1.0 mmol), 1-naphthylacetic acid (0.372 g, 2.0 mmol) and potassium fluoride (0.145 g, 2.5 mmol) in 2.0 ml of anhydrous DMF was stirred at room temperature for 12 hours. The reaction mixture was diluted with EtOAc and washed successively with water (twice) and saturated NaHCO 3 solution. The organic layer was dried (Na 2 SO 4 ), concentrated and the residue was chromatographed (MPLC, silica gel, hexane-EtOAc [2: 1]) to afford 0.470 g (62%) of di-p-methoxybenzyl sulfonamide. Obtained as a white solid.

디-p-메톡시벤질 술폰아미드 (0.760 g, 1.0 mmol) 및 질산암모늄세륨 (IV) (CAN, 4.39 g, 8.0 mmol)의 혼합물을 95 % CH3CN 및 5 % H2O (20 ml) 중에 18 시간 동안 교반시켰다. CH3CN을 진공 제거하고 샘플을 EtOAc로 희석하고 NaHCO3포화용액 (2회)으로 세척했다. 유기층을 건조 (Na2SO4), 농축하고 잔류물을 크로마토그래프 (MPLC, 실리카 겔, 50 % EtOAc-50 % 헥산)하여 원하는 1급 술폰아미드 tert-부틸 에스테르 0.280 g (54 %)을 얻었다.A mixture of di-p-methoxybenzyl sulfonamide (0.760 g, 1.0 mmol) and cerium ammonium nitrate (IV) (CAN, 4.39 g, 8.0 mmol) was added to 95% CH 3 CN and 5% H 2 O (20 ml). Stirred for 18 hours. CH 3 CN was removed in vacuo and the sample was diluted with EtOAc and washed with saturated NaHCO 3 solution (twice). The organic layer was dried (Na 2 SO 4 ), concentrated and the residue was chromatographed (MPLC, silica gel, 50% EtOAc-50% hexanes) to give 0.280 g (54%) of the desired primary sulfonamide tert-butyl ester.

이 1급 술폰아미드 tert-부틸 에스테르 (0.375 g, 0.72 mmol)을 트리플루오로아세트산 (5 ml) 및 CH2Cl2(5 ml)로 1 시간 동안 실온에서 처리했다. 용매를 진공 상태에서 제거하여 황색 고체를 얻었다. 잔류물을 CH2Cl2-헥산으로부터 재결정하여 3-(2-메틸-3-술파모일-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 0.090 g (27 %)을 회백색 고체로서 얻었다.This primary sulfonamide tert-butyl ester (0.375 g, 0.72 mmol) was treated with trifluoroacetic acid (5 ml) and CH 2 Cl 2 (5 ml) for 1 hour at room temperature. The solvent was removed in vacuo to yield a yellow solid. The residue was recrystallized from CH 2 Cl 2 -hexanes to give 0.090 g of 3- (2-methyl-3-sulfamoyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid (27%) was obtained as an off-white solid.

C21H24N2O8S1·0.27CF3CO2H에 대한 분석:Analysis for C 21 H 24 N 2 O 8 S 1 · 0.27CF 3 CO 2 H:

이론치: C, 52.23; H, 4.94; N, 5.66.Theoretical: C, 52.23; H, 4.94; N, 5.66.

실측치: C, 52.23; H, 5.07; N, 5.54.Found: C, 52.23; H, 5.07; N, 5.54.

<억제 활성 연구>Inhibitory Activity Studies

화학식 I의 화합물은 본원에 기재된 프로토콜을 사용하여 Ki(μM) 및 IC50(μM)을 측정하여 입증한 바와 같이 ICE의 억제제이다. ICE (0.24 nM 최종 농도)를 15 μM의 기질 (Ac-Tyr-Val-Ala-Asp-AMC; KM= 15 μM)과 비히클 (DMSO) 또는 Ki블랭킷 농도의 억제제를 함유하는 HGDE 완충액 (100 mM HEPES, 20 % 글리세롤, 5 mM DTT, 0.5 mM EDTA) 400 ㎕에 첨가했다. 기질 가수분해를 380 nm 여기 및 460 nm 발광을 사용하여 방출된 AMC의 형광을 관측함으로써 300 초 동안 관찰했다. 기질 가수분해의 평균 속도는 형광 대 시간 궤적에 대해 선형회귀법으로 평가했다. Ki를 측정하기 위해, 억제율 (%) 대 억제제 농도의 그래프를 비선형 회귀법으로 가역적, 경쟁적 모델로 최적화한다.Compounds of formula (I) are inhibitors of ICE as demonstrated by measuring K i (μM) and IC 50 (μM) using the protocol described herein. ICE (0.24 nM final concentration) was added to HGDE buffer (100 containing 15 μM substrate (Ac-Tyr-Val-Ala-Asp-AMC; K M = 15 μM) and inhibitor of vehicle (DMSO) or K i blanket concentration. mM HEPES, 20% glycerol, 5 mM DTT, 0.5 mM EDTA) was added to 400 μl. Substrate hydrolysis was observed for 300 seconds by observing the fluorescence of the AMC emitted using 380 nm excitation and 460 nm emission. The average rate of substrate hydrolysis was assessed by linear regression for fluorescence versus time trajectory. To determine K i , the graph of% inhibition versus inhibitor concentration is optimized with a nonlinear regression to a reversible, competitive model.

상기 식에서 경쟁 인수 (1 + [S]/KM)는 2 이다.In the above formula, the competition factor (1 + [S] / K M ) is 2.

<PBMC 세포 분석 - IC50결정><PBMC Cell Analysis-IC 50 Determination>

화학식 I의 화합물이 ICE의 억제제라는 또다른 증거는 본원에 기재된 바와 같이, 사람의 말초혈 단핵 세포 (PBMC)에서 IL-Iβ 생성을 억제하는 이들의 능력이다. PBMC는 피콜 쿠션 (Ficoll cushion) 상에서 헤파린 처리된 혈액으로부터 원심분리한 후 인산 완충 염수로 3회 세척했다. PBMC를 글루타민, 페니실린, 스트렙토마이신 및 2 % 사람 AB 혈청과 함께 RPMI 1640을 함유하는 배지에 현탁시키고, 96 웰 평판 플레이트에 웰당 106세포로 플레이팅했다. PBMC를 화학식 I의 화합물이 존재 또는 부재하에 밤새 리포폴리사카라이드 (LPS, 대장균 균주 0111:B4; Calbiochem) 10 ng/ml로 자극했다. 배지로부터 회수하여 성숙한 IL-1β의 양을 ELISA 키트 (R & D Systems)를 사용하여 측정했다. 화합물 억제율 (IC50)은 IL-1β의 양이 50 %까지 감소되는 제제의 농도를 측정하여 평가했다. 세포를 3-(4,5-디메틸티아졸-2-일)-2,5-디페닐테트라졸륨 브로마이드 (MTT)의 존재하에 추가로 4 시간 더 배양하여 생존 여부를 관찰했다. 화합물 독성은 세포 50 %를 죽이는 제제의 농도 (TC50)를 측정하여 평가했다.Another evidence that compounds of Formula I are inhibitors of ICE is their ability to inhibit IL-Iβ production in human peripheral blood mononuclear cells (PBMC), as described herein. PBMC was centrifuged from heparinized blood on a Ficoll cushion and then washed three times with phosphate buffered saline. PBMCs were suspended in medium containing RPMI 1640 with glutamine, penicillin, streptomycin and 2% human AB serum and plated at 10 6 cells per well in 96 well plate plates. PBMC was stimulated with lipopolysaccharide (LPS, E. coli strain 0111: B4; Calbiochem) 10 ng / ml overnight with or without the compound of formula (I). The amount of mature IL-1β recovered from the medium was measured using an ELISA kit (R & D Systems). Compound inhibition (IC 50 ) was assessed by measuring the concentration of the agent where the amount of IL-1β was reduced by 50%. The cells were further incubated for an additional 4 hours in the presence of 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT) to observe survival. Compound toxicity was assessed by measuring the concentration of the agent killing 50% of cells (TC 50 ).

<ICE 색도계 용량-반응 (IC50) 분석>ICE colorimeter dose-response (IC 50 ) analysis

희석된 억제제 스톡을 선택된 농도 (스트리닝 결과 또는 IC50평가 1차 시도를 근거로 선택됨)의 1차 스톡으로부터 가장 진한 웰에서 대략 95 %의 억제율이 얻어지도록 2 배로 연속 희속시켜 제조했다. 각 희석액의 분액을 마이크로타이터 플레이트로 3회 옮겼다.Diluted inhibitor stocks were prepared by continuous doubling in series so that approximately 95% inhibition was obtained in the darkest wells from the primary stock at the selected concentration (selected on the basis of the screening results or the IC 50 evaluation first attempt). Aliquots of each dilution were transferred to a microtiter plate three times.

ICE 효소를 HGE 완충액 (100 mM HEPES pH 7.5, 0.5 mM EDTA, 20 % 글리세롤, 0.1 % 소혈청 알부민 (BSA)) 내에 대략 24 nM로 희석하고, 최종 농도가 5 mM가 되도록 디티오트레이톨 (DTT)를 첨가하여 활성화시켰다. 활성화된 효소를 억제제 또는 비히클이 담긴 웰로 나누어 옮기고, 플레이트를 60 분 동안 주변 온도에서 예비인큐베이션시켰다. 기질 (Ac-Tyr-Val-Ala-Asp-pNA)를 최종 농도가 50 μM가 되도록 각 웰에 첨가하고 플레이트를 마이크로타이터 25 ℃로 온도가 맞춰진 마이크로타이터 플레이트-판독기 내에 놓았다. 기질을 첨가한지 5 분이 되면 웰의 흡광 (405 nm)을 1 시간 동안 관찰하고 이 기간 동안의 흡광도 변화의 평균 비율로 활성을 계산했다.Dilute the ICE enzyme to approximately 24 nM in HGE buffer (100 mM HEPES pH 7.5, 0.5 mM EDTA, 20% glycerol, 0.1% bovine serum albumin (BSA)) and bring the final concentration to 5 mM ) Was activated by addition. The activated enzyme was transferred to the wells containing the inhibitor or vehicle and the plates were preincubated for 60 minutes at ambient temperature. Substrate (Ac-Tyr-Val-Ala-Asp-pNA) was added to each well to a final concentration of 50 μM and the plate was placed in a microtiter plate-reader temperatured to microtiter 25 ° C. Five minutes after the addition of the substrate, the absorbance of the wells (405 nm) was observed for 1 hour and the activity was calculated as the average rate of change in absorbance during this period.

<Ich-2(카스파제-4) 색도계 용량-반응 (IC50) 분석><Ich-2 (Caspase-4) Colorimeter Dose-Response (IC 50 ) Analysis>

Ich-2 효소의 억제율은 ICE에 대해 기재한 바와 같이 평가하되, 단 효소는 64 nM의 농도로 사용하며 Ich-2 특이적 기질 Ac-Leu-Glu-Val-Asp-pNA 60 μM를 ICE 기질 Ac-Tyr-Val-Ala-Asp-pNA 대신에 사용한다. 이 시험의 결과는 표 1에 나타낸다.Inhibition rate of Ich-2 enzyme was evaluated as described for ICE, except that the enzyme was used at a concentration of 64 nM and 60 μM of Ich-2 specific substrate Ac-Leu-Glu-Val-Asp-pNA Use instead of -Tyr-Val-Ala-Asp-pNA. The results of this test are shown in Table 1.

HEPES = 4-(2-히드록시메틸)-1-피페라진 에탄 술폰산HEPES = 4- (2-hydroxymethyl) -1-piperazine ethane sulfonic acid

DTT = 디티오트레이톨DTT = dithiothreitol

EDTA = 에틸렌 디아민 테트라 아세트산EDTA = ethylene diamine tetra acetic acid

Ac = 아세틸Ac = acetyl

Glu = 글루탐산Glu = glutamic acid

Leu = 루이신Leu = Leucine

Tyr = 티로신Tyr = Tyrosine

Val = 발린Val = valine

Ala = 알라닌Ala = alanine

Asp = 아스파르트산Asp = aspartic acid

AMC = 7-아미노-4-메틸 코우마린AMC = 7-amino-4-methyl coumarin

pNA = 파라 니트로아닐린pNA = para nitroaniline

HOBT = 1-히드록시 벤조트리아졸HOBT = 1-hydroxy benzotriazole

AA = 아미노산AA = amino acid

Me = 메틸Me = methyl

Et = 에틸Et = ethyl

DMF = 디메틸 포름아미드DMF = Dimethyl Formamide

EDCI = N-에틸-N'-디메틸 아미노프로필 카르보디이미드EDCI = N-ethyl-N'-dimethyl aminopropyl carbodiimide

Claims (43)

하기 화학식 I의 화합물 및 제약상 허용가능한 그의 염, 에스테르, 아미드 및 프로드럭.Compounds of formula (I) and pharmaceutically acceptable salts, esters, amides and prodrugs thereof. <화학식 I><Formula I> 식 중, R1은, R3CO-, R3SO2-,,,,,, 또는(식 중, 각각의 Ra는 서로 독립적으로 수소, C1-C6알킬 또는 -(CH2)n아릴임)이고,Wherein R 1 is , R 3 CO-, R 3 SO 2- , , , , , , or Wherein each R a is, independently of each other, hydrogen, C 1 -C 6 alkyl, or — (CH 2 ) n aryl, R2는 -(CRR)n-아릴, -(CRR)n-X-아릴, -(CRR)n-헤테로아릴, -(CRR)n-X-헤테로아릴, -(CRR)n-(치환된 헤테로아릴), -(CRR)n-(치환된 아릴), -(CRR)n-X-(치환된 아릴), -(CRR)n-아릴-아릴, -(CRR)n-아릴-헤테로아릴, -(CRR)n-아릴-(CH2)n-아릴, -(CRR)n-CH(아릴)2, -(CRR)n-시클로알킬, -(CRR)n-X-시클로알킬, -(CRR)n-헤테로사이클, -(CRR)n-X-헤테로사이클, -(CRR)n치환된 헤테로사이클,,,,,,,,,,,,,,,, 또는또는이다.R 2 is-(CRR) n -aryl,-(CRR) n -X-aryl,-(CRR) n -heteroaryl,-(CRR) n -X-heteroaryl,-(CRR) n- (substituted Heteroaryl),-(CRR) n- (substituted aryl),-(CRR) n -X- (substituted aryl),-(CRR) n -aryl-aryl,-(CRR) n -aryl-heteroaryl ,-(CRR) n -aryl- (CH 2 ) n -aryl,-(CRR) n -CH (aryl) 2 ,-(CRR) n -cycloalkyl,-(CRR) n -X-cycloalkyl,- (CRR) n -heterocycle,-(CRR) n -X-heterocycle,-(CRR) n substituted heterocycle, , , , , , , , , , , , , , , , or or to be. 여기서 각각의 R은 서로 독립적으로 수소, C1-C6-알킬, 할로겐 또는 히드록시이고,Wherein each R is, independently from each other, hydrogen, C 1 -C 6 -alkyl, halogen or hydroxy, X는 산소 또는 황이며,X is oxygen or sulfur, R3은 C1-C6알킬, 아릴, 헤테로아릴, -(CHR)n-아릴, -(CHR)n-헤테로아릴, -(CHR)n-치환된 헤테로아릴, -(CHR)n-치환된 아릴,, -(CRR)nS(CH2)n-아릴, 시클로알킬, 치환된 시클로알킬, 헤테로사이클, 치환된 헤테로사이클,,,,,,,,,,,,, R 3 is C 1 -C 6 alkyl, aryl, heteroaryl,-(CHR) n -aryl,-(CHR) n -heteroaryl,-(CHR) n -substituted heteroaryl,-(CHR) n -substituted Aryl, ,-(CRR) n S (CH 2 ) n -aryl, cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, , , , , , , , , , , , , 각각의 R'은 서로 독립적으로 C1-C6알킬, C1-C6알킬아릴, 아릴 또는 수소이고,Each R 'is independently of each other C 1 -C 6 alkyl, C 1 -C 6 alkylaryl, aryl or hydrogen, 각각의 J는 서로 독립적으로 -CO2Rb, -CONRbRb, -SO2NRbRb또는 -SO2Rb(여기서 각각의 Rb는 서로 독립적으로 수소, C1-C6알킬, 아릴, 치환된 아릴, 아릴알킬, 헤테로아릴알킬, 치환된 아릴알킬 또는 치환된 헤테로아릴알킬임)이고,Each J is, independently from each other, -CO 2 R b , -CONR b R b , -SO 2 NR b R b or -SO 2 R b , wherein each R b is independently of each other hydrogen, C 1 -C 6 alkyl , Aryl, substituted aryl, arylalkyl, heteroarylalkyl, substituted arylalkyl or substituted heteroarylalkyl, R4는 수소, C1-C6알킬,, -페닐 또는이고,R 4 is hydrogen, C 1 -C 6 alkyl, , -Phenyl or ego, R5는 C1-C6알킬-CO-, -(CH2)n아릴,, C1-C6알킬-X-(CH2)nCO,,,,,,,,,, -(CH2)nX(CH2)n-아릴, -C1-C6알킬X-C1-C6알킬아릴, 또는이고,R 5 is C 1 -C 6 alkyl-CO—, — (CH 2 ) n aryl, , C 1 -C 6 alkyl-X- (CH 2 ) n CO, , , , , , , , , ,-(CH 2 ) n X (CH 2 ) n -aryl, -C 1 -C 6 alkylXC 1 -C 6 alkylaryl, or ego, R5a는,,,,또는이고,R 5a is , , , , or ego, R6은 수소, C1-C6알킬, -(CH2)n아릴, -(CH2)nCO2Ra, 히드록실 치환된 C1-C6알킬, 또는 이미다졸 치환된 C1-C6알킬이고,R 6 is hydrogen, C 1 -C 6 alkyl, — (CH 2 ) n aryl, — (CH 2 ) n CO 2 R a , hydroxyl substituted C 1 -C 6 alkyl, or imidazole substituted C 1- C 6 alkyl, 각각의 n은 서로 독립적으로 0 내지 3이다.Each n is 0 to 3 independently of each other. 제1항에 있어서, R1이인 화합물.The compound of claim 1, wherein R 1 is Phosphorus compounds. 제1항에 있어서, R1이 페닐-SO2인 화합물.The compound of claim 1, wherein R 1 is phenyl-SO 2 . 제1항에 있어서, R1이인 화합물.The compound of claim 1, wherein R 1 is Phosphorus compounds. 제1항에 있어서, R1이 페닐-CH2CH2-CO-인 화합물.The compound of claim 1, wherein R 1 is phenyl-CH 2 CH 2 -CO-. 제1항에 있어서, R1이인 화합물.The compound of claim 1, wherein R 1 is Phosphorus compounds. 제1항에 있어서, R1이인 화합물.The compound of claim 1, wherein R 1 is Phosphorus compounds. 제1항에 있어서, R1이 페닐-CH2-CO-인 화합물.The compound of claim 1, wherein R 1 is phenyl-CH 2 —CO—. 제1항에 있어서, R1이인 화합물.The compound of claim 1, wherein R 1 is Phosphorus compounds. 제1항에 있어서, 각각의 Ra가 수소인 화합물.The compound of claim 1, wherein each R a is hydrogen. 제1항에 있어서, R2가 -(CH2)n-페닐인 화합물.The compound of claim 1, wherein R 2 is — (CH 2 ) n -phenyl. 제1항에 있어서, R2가 -(CH2)n-나프틸인 화합물.The compound of claim 1, wherein R 2 is — (CH 2 ) n -naphthyl. 제1항에 있어서, R2가 -(CH2)n-O-페닐인 화합물.The compound of claim 1, wherein R 2 is — (CH 2 ) n —O-phenyl. 제1항에 있어서, R2가 -(CH2)n-O-나프틸인 화합물.The compound of claim 1, wherein R 2 is — (CH 2 ) n —O-naphthyl. 제1항에 있어서, R2가 -(CH2)n-S-페닐인 화합물.The compound of claim 1, wherein R 2 is — (CH 2 ) n —S-phenyl. 제1항에 있어서, R2가 -(CH2)n-CH(페닐)2인 화합물.The compound of claim 1, wherein R 2 is — (CH 2 ) n —CH (phenyl) 2 . 제1항에 있어서, 각각의 Ra가 수소이고, R1이 벤질옥시카르보닐이고, R2가 아릴-X(CRR)n-, 아릴-(CRR)n-, 헤테로아릴-(CRR)n-, 또는 시클로알킬-(CRR)n-이고, n이 1, 2 또는 3이고, X가 산소 또는 황이고, R이 수소, 메틸 또는 벤질인 화합물.The compound of claim 1, wherein each R a is hydrogen, R 1 is benzyloxycarbonyl, R 2 is aryl-X (CRR) n −, aryl- (CRR) n −, heteroaryl- (CRR) n -Or cycloalkyl- (CRR) n- , n is 1, 2 or 3, X is oxygen or sulfur and R is hydrogen, methyl or benzyl. 제1항에 있어서, 각각의 Ra가 수소이고, R1이 벤질옥시카르보닐이고, R2가 -(CH2)n-나프틸, -(CH2)n-페닐, -(CH2)n-시클로알킬, -(CH2)nO(CH2)n-나프틸, -(CH2)nO(CH2)n-페닐, 또는 -(CH2)nS(CH2)n-페닐인 화합물.The compound of claim 1, wherein each R a is hydrogen, R 1 is benzyloxycarbonyl, and R 2 is-(CH 2 ) n -naphthyl,-(CH 2 ) n -phenyl,-(CH 2 ) n -cycloalkyl,-(CH 2 ) n O (CH 2 ) n -naphthyl,-(CH 2 ) n O (CH 2 ) n -phenyl, or-(CH 2 ) n S (CH 2 ) n- Phenyl. 제1항에 있어서, 각각의 Ra가 수소이고, R1이 벤질옥시카르보닐이고, R2가 -CH2-나프틸인 화합물.The compound of claim 1, wherein each R a is hydrogen, R 1 is benzyloxycarbonyl, and R 2 is —CH 2 -naphthyl. 제1항에 있어서, 각각의 Ra가 수소이고, R2이 벤질옥시카르보닐,,,,또는인 화합물.The compound of claim 1, wherein each R a is hydrogen, R 2 is benzyloxycarbonyl, , , , or Phosphorus compounds. 인터루킨-1β 전환 효소의 억제를 필요로하는 환자에게 제1항의 화합물의 치료학적 유효량을 투여하는 것을 포함하는, 인터루킨-1β 전환 효소의 억제 방법.A method of inhibiting interleukin-1β converting enzyme, comprising administering a therapeutically effective amount of the compound of claim 1 to a patient in need of inhibition of the interleukin-1β converting enzyme. 카스파제-4의 억제를 필요로하는 환자에게 제1항의 화합물의 카스파제-4 억제량을 투여하는 것을 포함하는, 카스파제-4의 억제 방법.A method of inhibiting caspase-4, comprising administering a caspase-4 inhibitory amount of the compound of claim 1 to a patient in need of inhibition of caspase-4. 발작이 일어난 환자 또는 발작이 일어난 적이 있는 환자에게 제1항의 화합물의 치료학적 유효량을 투여하는 것을 포함하는, 발작의 치료 방법.A method of treating seizures, comprising administering a therapeutically effective amount of the compound of claim 1 to a patient having a seizure or to a patient having a seizure. 염증성 질환에 걸린 환자에게 제1항의 화합물의 치료학적 유효량을 투여하는 것을 포함하는, 염증성 질환의 치료 방법.A method of treating an inflammatory disease comprising administering to a patient with an inflammatory disease a therapeutically effective amount of the compound of claim 1. 제24항에 있어서, 상기 염증성 질환이 관절염인 방법.The method of claim 24, wherein the inflammatory disease is arthritis. 제24항에 있어서, 상기 염증성 질환이 염증성 장 질환인 방법.The method of claim 24, wherein the inflammatory disease is an inflammatory bowel disease. 재관류 손상을 당한 환자에게 제1항의 화합물의 치료학적 유효량을 투여하는 것을 포함하는, 재관류 손상의 치료 방법.A method of treating reperfusion injury comprising administering a therapeutically effective amount of a compound of claim 1 to a patient suffering from reperfusion injury. 알쯔하이머병에 걸린 환자에게 제1항의 화합물의 치료학적 유효량을 투여하는 것을 포함하는, 알쯔하이머병의 치료 방법.A method of treating Alzheimer's disease, comprising administering a therapeutically effective amount of the compound of claim 1 to a patient with Alzheimer's disease. 시겔라증에 걸린 환자에게 제1항의 화합물의 치료학적 유효량을 투여하는 것을 포함하는, 시겔라증의 치료 방법.A method of treating shigellosis, comprising administering a therapeutically effective amount of the compound of claim 1 to a patient with Shigellosis. 제1항의 화합물을 함유하는 제약적으로 허용가능한 조성물.A pharmaceutically acceptable composition containing the compound of claim 1. 3-벤질옥시카르보닐아미노-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3-benzyloxycarbonylamino-5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-벤질옥시카르보닐아미노-4-옥소-5-(3-페닐프로피오닐옥시)-펜탄산,3-benzyloxycarbonylamino-4-oxo-5- (3-phenylpropionyloxy) -pentanoic acid, 3-벤질옥시카르보닐아미노-5-(3-시클로헥실-프로피오닐옥시)-4-옥소-펜탄산,3-benzyloxycarbonylamino-5- (3-cyclohexyl-propionyloxy) -4-oxo-pentanoic acid, 3-벤질옥시카르보닐아미노-5-[(나프탈렌-1-일-옥시)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(naphthalen-1-yl-oxy) -acetoxy] -4-oxo-pentanoic acid, 3-벤질옥시카르보닐아미노-4-옥소-5-페녹시아세톡시-펜탄산,3-benzyloxycarbonylamino-4-oxo-5-phenoxyacetoxy-pentanoic acid, 3-벤질옥시카르보닐아미노-4-옥소-5-페닐술파닐아세톡시-펜탄산,3-benzyloxycarbonylamino-4-oxo-5-phenylsulfanylacetoxy-pentanoic acid, 3-벤질옥시카르보닐아미노-5-[(6-메톡시-나프탈렌-1-일)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(6-methoxy-naphthalen-1-yl) -acetoxy] -4-oxo-pentanoic acid, 3-벤질옥시카르보닐아미노-5-(나프탈렌-2-일-아세톡시)-4-옥소-펜탄산,3-benzyloxycarbonylamino-5- (naphthalen-2-yl-acetoxy) -4-oxo-pentanoic acid, 3-벤질옥시카르보닐아미노-5-(3-나프탈렌-2-일-프로피오닐옥시)-4-옥소-펜탄산,3-benzyloxycarbonylamino-5- (3-naphthalen-2-yl-propionyloxy) -4-oxo-pentanoic acid, 3-벤질옥시카르보닐아미노-5-(3,3-디페닐-프로피오닐옥시)-4-옥소-펜탄산,3-benzyloxycarbonylamino-5- (3,3-diphenyl-propionyloxy) -4-oxo-pentanoic acid, 3-벤질옥시카르보닐아미노-5-[(1H-인돌-3-일)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(1H-indol-3-yl) -acetoxy] -4-oxo-pentanoic acid, 3-벤질옥시카르보닐아미노-5-(인돌-1-일-아세톡시)-4-옥소-펜탄산,3-benzyloxycarbonylamino-5- (indol-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-벤질옥시카르보닐아미노-5-(2-나프탈렌-1-일-프로피오닐옥시)-4-옥소-펜탄산,3-benzyloxycarbonylamino-5- (2-naphthalen-1-yl-propionyloxy) -4-oxo-pentanoic acid, 3-벤질옥시카르보닐아미노-4-옥소-5-[(2-옥소-피롤리딘-1-일)-아세톡시]-펜탄산,3-benzyloxycarbonylamino-4-oxo-5-[(2-oxo-pyrrolidin-1-yl) -acetoxy] -pentanoic acid, 5-[(아세틸-페닐-아미노)-아세톡시]-3-벤질옥시카르보닐-아미노-4-옥소-펜탄산,5-[(acetyl-phenyl-amino) -acetoxy] -3-benzyloxycarbonyl-amino-4-oxo-pentanoic acid, 3-벤질옥시카르보닐아미노-5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-펜탄산,3-benzyloxycarbonylamino-5- (2-benzyl-3-phenyl-propionyloxy) -4-oxo-pentanoic acid, 3-벤질옥시카르보닐아미노-5-(히드록시-나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3-benzyloxycarbonylamino-5- (hydroxy-naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-벤질옥시카르보닐아미노-4-옥소-5-[(페닐-아미노)-아세톡시]-펜탄산,3-benzyloxycarbonylamino-4-oxo-5-[(phenyl-amino) -acetoxy] -pentanoic acid, 3-벤질옥시카르보닐아미노-5-[(6-히드록시-나프탈렌-1-일)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(6-hydroxy-naphthalen-1-yl) -acetoxy] -4-oxo-pentanoic acid, 3-벤질옥시카르보닐아미노-5-[3-(4-히드록시-페닐)-2-나프탈렌-1-일-프로피오닐옥시)-4-옥소-펜탄산,3-benzyloxycarbonylamino-5- [3- (4-hydroxy-phenyl) -2-naphthalen-1-yl-propionyloxy) -4-oxo-pentanoic acid, (S)-3-벤질옥시카르보닐아미노-4-옥소-5-페닐아세톡시-펜탄산,(S) -3-benzyloxycarbonylamino-4-oxo-5-phenylacetoxy-pentanoic acid, (S)-3-벤질옥시카르보닐아미노-4-옥소-5-(4-페닐-부티릴옥시)-펜탄산,(S) -3-benzyloxycarbonylamino-4-oxo-5- (4-phenyl-butyryloxy) -pentanoic acid, 3-벤질옥시카르보닐아미노-4-옥소-5-[(4-페닐-나프탈렌-1-일)-아세톡시]-펜탄산,3-benzyloxycarbonylamino-4-oxo-5-[(4-phenyl-naphthalen-1-yl) -acetoxy] -pentanoic acid, 3-벤질옥시카르보닐아미노-5-[(4-메틸-나프탈렌-1-일)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(4-methyl-naphthalen-1-yl) -acetoxy] -4-oxo-pentanoic acid, 3-벤질옥시카르보닐아미노-4-옥소-5-[(4-티오펜-2-일-나프탈렌-1-일)-아세톡시]-펜탄산,3-benzyloxycarbonylamino-4-oxo-5-[(4-thiophen-2-yl-naphthalen-1-yl) -acetoxy] -pentanoic acid, 3-벤질옥시카르보닐아미노-5-[(4-플루오로-나프탈렌-1-일)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(4-fluoro-naphthalen-1-yl) -acetoxy] -4-oxo-pentanoic acid, 3-벤질옥시카르보닐아미노-5-[(2-메틸-나프탈렌-1-일)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(2-methyl-naphthalen-1-yl) -acetoxy] -4-oxo-pentanoic acid, 3-벤질옥시카르보닐아미노-5-[(2-플루오로-나프탈렌-1-일)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(2-fluoro-naphthalen-1-yl) -acetoxy] -4-oxo-pentanoic acid, 5-(벤조푸란-4-일-아세톡시)-3-벤질옥시카르보닐아미노-4-옥소-펜탄산,5- (benzofuran-4-yl-acetoxy) -3-benzyloxycarbonylamino-4-oxo-pentanoic acid, 5-(벤조[b]티오펜-7-일-아세톡시)-3-벤질옥시카르보닐아미노-4-옥소-펜탄산,5- (benzo [b] thiophen-7-yl-acetoxy) -3-benzyloxycarbonylamino-4-oxo-pentanoic acid, 5-(벤조[b]티오펜-4-일-아세톡시)-3-벤질옥시카르보닐아미노-4-옥소-펜탄산,5- (benzo [b] thiophen-4-yl-acetoxy) -3-benzyloxycarbonylamino-4-oxo-pentanoic acid, 5-[(4-벤질-나프탈렌-1-일)-아세톡시]-3-벤질옥시카르보닐아미노-4-옥소-펜탄산,5-[(4-benzyl-naphthalen-1-yl) -acetoxy] -3-benzyloxycarbonylamino-4-oxo-pentanoic acid, 3-벤질옥시카르보닐아미노-5-[(3,4-디히드로-나프탈렌-1-일)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(3,4-dihydro-naphthalen-1-yl) -acetoxy] -4-oxo-pentanoic acid, 3-벤질옥시카르보닐아미노-5-[(5-브로모-1H-인돌-3-일)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(5-bromo-1H-indol-3-yl) -acetoxy] -4-oxo-pentanoic acid, 3-벤질옥시카르보닐아미노-5-(3,4-디페닐-부티릴옥시)-4-옥소-펜탄산,3-benzyloxycarbonylamino-5- (3,4-diphenyl-butyryloxy) -4-oxo-pentanoic acid, 3-벤질옥시카르보닐아미노-4-옥소-5-(3-페닐-3-페닐아미노-프로피오닐옥시)-펜탄산,3-benzyloxycarbonylamino-4-oxo-5- (3-phenyl-3-phenylamino-propionyloxy) -pentanoic acid, 3-벤질옥시카르보닐아미노-4-옥소-5-[(1,2,3,4-테트라히드로나프탈렌-2-일)-아세톡시]-펜탄산,3-benzyloxycarbonylamino-4-oxo-5-[(1,2,3,4-tetrahydronaphthalen-2-yl) -acetoxy] -pentanoic acid, 3-벤질옥시카르보닐아미노-5-[(1-메탄술포닐-피페리딘-4-일)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(1-methanesulfonyl-piperidin-4-yl) -acetoxy] -4-oxo-pentanoic acid, 3-벤질옥시카르보닐아미노-4-옥소-5-[(2,3,5,6-테트라메틸-페닐)-아세톡시]-펜탄산3-Benzyloxycarbonylamino-4-oxo-5-[(2,3,5,6-tetramethyl-phenyl) -acetoxy] -pentanoic acid 5-(벤조티아졸-4-일-아세톡시)-3-벤질옥시카르보닐아미노-4-옥소-펜탄산,5- (benzothiazol-4-yl-acetoxy) -3-benzyloxycarbonylamino-4-oxo-pentanoic acid, 5-(벤조푸란-3-일-아세톡시)-3-벤질옥시카르보닐아미노-4-옥소-펜탄산,5- (benzofuran-3-yl-acetoxy) -3-benzyloxycarbonylamino-4-oxo-pentanoic acid, 5-(벤조[b]티오펜-3-일-아세톡시)-3-벤질옥시카르보닐아미노-4-옥소-펜탄산,5- (benzo [b] thiophen-3-yl-acetoxy) -3-benzyloxycarbonylamino-4-oxo-pentanoic acid, 3-벤질옥시카르보닐아미노-4-옥소-5-(3-페닐-3-피리딘-2-일-프로피오닐옥시)-펜탄산,3-benzyloxycarbonylamino-4-oxo-5- (3-phenyl-3-pyridin-2-yl-propionyloxy) -pentanoic acid, 3-벤질옥시카르보닐아미노-5-[(2,3-디클로로-페닐)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(2,3-dichloro-phenyl) -acetoxy] -4-oxo-pentanoic acid, 3-벤질옥시카르보닐아미노-5-[(5-메틸-나프탈렌-1-일)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(5-methyl-naphthalen-1-yl) -acetoxy] -4-oxo-pentanoic acid, 3-벤질옥시카르보닐아미노-5-[(2-요오도-페닐)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(2-iodo-phenyl) -acetoxy] -4-oxo-pentanoic acid, 3-벤질옥시카르보닐아미노-4-옥소-5-(3-피리딘-3-일-프로피오닐옥시)-펜탄산,3-benzyloxycarbonylamino-4-oxo-5- (3-pyridin-3-yl-propionyloxy) -pentanoic acid, 3-벤질옥시카르보닐아미노-5-[(5-메톡시-나프탈렌-1-일)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(5-methoxy-naphthalen-1-yl) -acetoxy] -4-oxo-pentanoic acid, 3-벤질옥시카르보닐아미노-5-[(8-메틸-나프탈렌-1-일)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(8-methyl-naphthalen-1-yl) -acetoxy] -4-oxo-pentanoic acid, 3-벤질옥시카르보닐아미노-5-[(9H-플루오렌-9-일)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(9H-fluoren-9-yl) -acetoxy] -4-oxo-pentanoic acid, 3-벤질옥시카르보닐아미노-5-[(10,11-디히드로-5H-디벤조[a,d]시클로헵텐-5-일)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) -acetoxy] -4-oxo-pentanoic acid, 5-옥소-1-(톨루엔-4-술포닐)-피롤리딘-2-카르복실산 3-벤질옥시카르보닐아미노-4-카르복시-2-옥소-부틸 에스테르,5-oxo-1- (toluene-4-sulfonyl) -pyrrolidine-2-carboxylic acid 3-benzyloxycarbonylamino-4-carboxy-2-oxo-butyl ester, 5-옥소-피롤리딘-1,2-디카르복실산 1-벤질 에스테르 2-(3-벤질옥시카르보닐아미노-4-카르복시-2-옥소-부틸)에스테르,5-oxo-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2- (3-benzyloxycarbonylamino-4-carboxy-2-oxo-butyl) ester, 1-벤조일-피롤리딘-2-카르복실산 3-벤질옥시카르보닐아미노-4-카르복시-2-옥소-부틸 에스테르,1-benzoyl-pyrrolidine-2-carboxylic acid 3-benzyloxycarbonylamino-4-carboxy-2-oxo-butyl ester, 피롤리딘-1,2-디카르복실산 1-벤질 에스테르 2-(3-벤질옥시카르보닐아미노-4-카르복시-2-옥소-부틸)에스테르,Pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2- (3-benzyloxycarbonylamino-4-carboxy-2-oxo-butyl) ester, 3-벤질옥시카르보닐아미노-5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-펜탄산,3-benzyloxycarbonylamino-5- (2-benzyl-3-phenyl-propionyloxy) -4-oxo-pentanoic acid, 3-벤질옥시카르보닐아미노-5-[(5-시아노-나프탈렌-1-일)-아세톡시]-4-옥소-펜탄산,3-benzyloxycarbonylamino-5-[(5-cyano-naphthalen-1-yl) -acetoxy] -4-oxo-pentanoic acid, 3-벤질옥시카르보닐아미노-4-옥소-5-(3-페닐-3-피리딘-3-일-프로피오닐옥시)-펜탄산,3-benzyloxycarbonylamino-4-oxo-5- (3-phenyl-3-pyridin-3-yl-propionyloxy) -pentanoic acid, 3-벤질옥시카르보닐아미노-4-옥소-5-(3-페닐-3-피리딘-4-일-프로피오닐옥시)-펜탄산 및3-benzyloxycarbonylamino-4-oxo-5- (3-phenyl-3-pyridin-4-yl-propionyloxy) -pentanoic acid and 3-벤질옥시카르보닐아미노-4-옥소-5-[(1-옥소-3,4-디히드로-1H-이소퀴놀린-2-일)-아세톡시]-펜탄산 화합물.3-Benzyloxycarbonylamino-4-oxo-5-[(1-oxo-3,4-dihydro-1 H-isoquinolin-2-yl) -acetoxy] -pentanoic acid compound. 3-벤젠술포닐아미노-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3-benzenesulfonylamino-5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-메톡시카르보닐아미노-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3-methoxycarbonylamino-5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 5-(나프탈렌-1-일-아세톡시)-4-옥소-3-(3-페닐-프로피오닐아미노)-펜탄산,5- (naphthalen-1-yl-acetoxy) -4-oxo-3- (3-phenyl-propionylamino) -pentanoic acid, 3-메톡시카르보닐아미노-4-옥소-5-페녹시아세톡시-펜탄산 및3-methoxycarbonylamino-4-oxo-5-phenoxycetoxy-pentanoic acid and 3-(2-메탄술포닐-1-메틸-에틸술파닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산인 화합물.3- (2-Methanesulfonyl-1-methyl-ethylsulfanylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid. [S-(R*,R*)]-3-(2-아세틸아미노-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,[S- (R * , R * )]-3- (2-acetylamino-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 5-(나프탈렌-1-일-아세톡시)-4-옥소-3-[(티오펜-3-카르보닐)-아미노]-펜탄산,5- (naphthalen-1-yl-acetoxy) -4-oxo-3-[(thiophen-3-carbonyl) -amino] -pentanoic acid, 3-[(푸란-3-카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3-[(furan-3-carbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 5-(나프탈렌-1-일-아세톡시)-4-옥소-3-[2-(4-페닐-부티릴아미노)-프로필아미노]-펜탄산,5- (naphthalen-1-yl-acetoxy) -4-oxo-3- [2- (4-phenyl-butyrylamino) -propylamino] -pentanoic acid, 3-(2-메탄술포닐아미노-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (2-methanesulfonylamino-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-[2-(2-아세틸아미노-4-페닐-부티릴아미노)-프로피오닐아미노]-5-(나프탈렌1-일-아세톡시)-4-옥소-펜탄산,3- [2- (2-acetylamino-4-phenyl-butyrylamino) -propionylamino] -5- (naphthalen1-yl-acetoxy) -4-oxo-pentanoic acid, 3-(2-아세틸아미노-부티릴아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (2-acetylamino-butyrylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-[2-(4-카르바모일-부티릴아미노)-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- [2- (4-carbamoyl-butyrylamino) -propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-(2-벤질옥시카르보닐아미노-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (2-benzyloxycarbonylamino-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 5-(나프탈렌-1-일-아세톡시)-4-옥소-3-(2-우레이도-프로피오닐아미노)-펜탄산,5- (naphthalen-1-yl-acetoxy) -4-oxo-3- (2-ureido-propionylamino) -pentanoic acid, 3-(2-아세틸아미노-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (2-acetylamino-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-[(1-아세틸-피롤리딘-2-카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3-[(1-acetyl-pyrrolidine-2-carbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-(2-메틸-3-옥소-3-티오펜-2-일-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (2-Methyl-3-oxo-3-thiophen-2-yl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-(2-아세틸아미노-아세틸아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (2-acetylamino-acetylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-(2-아세틸아미노-프로피오닐아미노)-5-(3,3-디페닐-프로피오닐옥시)-4-옥소-펜탄산,3- (2-acetylamino-propionylamino) -5- (3,3-diphenyl-propionyloxy) -4-oxo-pentanoic acid, 3-[2-(2-아세틸아미노-4-카르복시-부티릴아미노)-프로피오닐아미노]-5-나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- [2- (2-acetylamino-4-carboxy-butyrylamino) -propionylamino] -5-naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 5-(나프탈렌-1-일-아세톡시)-4-옥소-3-[2-(3-페닐-프로피오닐아미노)-프로피오닐아미노]-펜탄산,5- (naphthalen-1-yl-acetoxy) -4-oxo-3- [2- (3-phenyl-propionylamino) -propionylamino] -pentanoic acid, 3-[2-(3-메틸-부티릴아미노)-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- [2- (3-Methyl-butyrylamino) -propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-[(1-아세틸-4-벤질옥시-피롤리딘-2-카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3-[(1-acetyl-4-benzyloxy-pyrrolidine-2-carbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-(4-카르바모일-부티릴아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 및3- (4-Carbamoyl-butyrylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid and 3-[2-(1-메틸-1H-이미다졸-4-일)-아세틸아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산인 화합물.3- [2- (1-Methyl-1H-imidazol-4-yl) -acetylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid. (S)-5-(나프탈렌-1-일-아세톡시)-4-옥소-3-페닐아세틸아미노-펜탄산,(S) -5- (naphthalen-1-yl-acetoxy) -4-oxo-3-phenylacetylamino-pentanoic acid, (S)-5-(나프탈렌-1-일-아세톡시)-4-옥소-3-(2-티오펜-2-일-아세틸아미노)-펜탄산,(S) -5- (naphthalen-1-yl-acetoxy) -4-oxo-3- (2-thiophen-2-yl-acetylamino) -pentanoic acid, 3-[(2-카르바모일-시클로펜탄카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3-[(2-Carbamoyl-cyclopentanecarbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-[(3-(카르바모일-비시클로[2.2.1]헵탄-2-카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3-[(3- (carbamoyl-bicyclo [2.2.1] heptan-2-carbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-(3-메탄술포닐-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (3-methanesulfonyl-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-(3-벤젠술포닐-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (3-benzenesulfonyl-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-부티릴아미노-5-(나프탈렌-2-일-아세톡시)-4-옥소-펜탄산,3-butyrylamino-5- (naphthalen-2-yl-acetoxy) -4-oxo-pentanoic acid, 3-아세틸아미노-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3-acetylamino-5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-(3-메탄술포닐-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (3-methanesulfonyl-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-(3-메틸-부티릴아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (3-Methyl-butyrylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-(3-카르바모일-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (3-Carbamoyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, [S-(R*,R*)]-3-(3-아세틸술파닐-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 및[S- (R * , R * )]-3- (3-acetylsulfanyl-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid and 트랜스-3-[(3-카르바모일-시클로펜탄카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산인 화합물.Trans-3-[(3-carbamoyl-cyclopentanecarbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid. 3-(1,2,3,4-테트라히드로-1-옥소-이소퀴놀린-2-일)-아세트아미노-5-(나프탈렌-1-일 아세톡시)-4-옥소-펜탄산,3- (1,2,3,4-tetrahydro-1-oxo-isoquinolin-2-yl) -acetamino-5- (naphthalen-1-yl acetoxy) -4-oxo-pentanoic acid, 3-(2-메틸-3-펜에틸카르바모일-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (2-Methyl-3-phenethylcarbamoyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 5-(나프탈렌-2-일-아세톡시)-4-옥소-3-[2-(2-옥소-6-페닐-피페리딘-1-일)-아세틸아미노]-펜탄산,5- (naphthalen-2-yl-acetoxy) -4-oxo-3- [2- (2-oxo-6-phenyl-piperidin-1-yl) -acetylamino] -pentanoic acid, 5-(나프탈렌-1-일-아세톡시)-4-옥소-3-[2-(2-옥소-6-페닐-피페리딘-1-일)-아세틸아미노]-펜탄산,5- (naphthalen-1-yl-acetoxy) -4-oxo-3- [2- (2-oxo-6-phenyl-piperidin-1-yl) -acetylamino] -pentanoic acid, 3-[3-메틸-2-(3-페닐-프로피오닐아미노)-부티릴아미노]-4-옥소-5-[(1-옥소-1,2,3,4-테트라히드로-나프탈렌-2-일)-아세톡시]-펜탄산,3- [3-methyl-2- (3-phenyl-propionylamino) -butyrylamino] -4-oxo-5-[(1-oxo-1,2,3,4-tetrahydro-naphthalene-2 -Yl) -acetoxy] -pentanoic acid, 5-(나프탈렌-2-일-아세톡시)-4-옥소-3-[2-(1-옥소-3,4-디히드로-1H-이소퀴놀린-2-일)-아세틸아미노]-펜탄산,5- (Naphthalen-2-yl-acetoxy) -4-oxo-3- [2- (1-oxo-3,4-dihydro-1 H-isoquinolin-2-yl) -acetylamino] -pentanoic acid , 5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-3-[2-(1-옥소-3,4-디히드로-1H-이소퀴놀린-2-일)-아세틸아미노]-펜탄산,5- (2-benzyl-3-phenyl-propionyloxy) -4-oxo-3- [2- (1-oxo-3,4-dihydro-1 H-isoquinolin-2-yl) -acetylamino] Pentanoic acid, 5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-3-[2-(2-옥소-6-페닐-피페리딘-1-일)-아세틸아미노]-펜탄산5- (2-Benzyl-3-phenyl-propionyloxy) -4-oxo-3- [2- (2-oxo-6-phenyl-piperidin-1-yl) -acetylamino] -pentanoic acid 5-(나프탈렌-1-일-아세톡시)-4-옥소-3-[2-(1-옥소-1,2,3,4-테트라히드로-나프탈렌-2-일)-아세틸아미노]-펜탄산,5- (naphthalen-1-yl-acetoxy) -4-oxo-3- [2- (1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl) -acetylamino] -phen Carbonated, 5-(나프탈렌-1-일-아세톡시)-4-옥소-3-[2-(1-옥소-3,4-디히드로-1H-이소퀴놀린-2-일)-프로피오닐아미노]-펜탄산,5- (naphthalen-1-yl-acetoxy) -4-oxo-3- [2- (1-oxo-3,4-dihydro-1 H-isoquinolin-2-yl) -propionylamino] -phen Carbonated, 5-(나프탈렌-2-일-아세톡시)-4-옥소-3-[2-(1-옥소-3,4-디히드로-1H-이소퀴놀린-2-일)-프로피오닐아미노]-펜탄산,5- (naphthalen-2-yl-acetoxy) -4-oxo-3- [2- (1-oxo-3,4-dihydro-1 H-isoquinolin-2-yl) -propionylamino] -phen Carbonated, 3-[4-(1-벤젠술포닐-1H-피롤-2-일)-4-옥소-부티릴아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- [4- (1-benzenesulfonyl-1H-pyrrole-2-yl) -4-oxo-butyrylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-3-[2-(1-옥소-1,2,3,4-테트라히드로-나프탈렌-2-일)-아세틸아미노]-펜탄산,5- (2-Benzyl-3-phenyl-propionyloxy) -4-oxo-3- [2- (1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl) -acetylamino ] -Pentanoic acid, 5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-3-[2-(1-옥소-3,4-디히드로-1H-이소퀴놀린-2-일)-프로피오닐아미노]-펜탄산,5- (2-Benzyl-3-phenyl-propionyloxy) -4-oxo-3- [2- (1-oxo-3,4-dihydro-1 H-isoquinolin-2-yl) -propionylamino ] -Pentanoic acid, 4-옥소-3-[2-(1-옥소-3,4-디히드로-1H-이소퀴놀린-2-일)-프로피오닐아미노]-5-[(1-옥소-1,2,3,4-테트라히드로-나프탈렌-2-일)-아세톡시]-펜탄산,4-oxo-3- [2- (1-oxo-3,4-dihydro-1 H-isoquinolin-2-yl) -propionylamino] -5-[(1-oxo-1,2,3, 4-tetrahydro-naphthalen-2-yl) -acetoxy] -pentanoic acid, 3-[4-(1-벤젠술포닐-1H-피롤-2-일)-4-옥소-부티릴아미노]-5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-펜탄산,3- [4- (1-benzenesulfonyl-1H-pyrrole-2-yl) -4-oxo-butyrylamino] -5- (2-benzyl-3-phenyl-propionyloxy) -4-oxo- Pentanic Acid, 4-옥소-5-[(1-옥소-1,2,3,4-테트라히드로-나프탈렌-2-일)-아세톡시]-3-[2-(1-옥소-1,2,3,4-테트라히드로-나프탈렌-2-일)-아세틸아미노]-펜탄산,4-oxo-5-[(1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl) -acetoxy] -3- [2- (1-oxo-1,2,3, 4-tetrahydro-naphthalen-2-yl) -acetylamino] -pentanoic acid, 5-(나프탈렌-1-일-아세톡시)-4-옥소-3-[2-(2-옥소-3-페닐-이미다졸리딘-1-일)-프로피오닐아미노]-펜탄산,5- (naphthalen-1-yl-acetoxy) -4-oxo-3- [2- (2-oxo-3-phenyl-imidazolidin-1-yl) -propionylamino] -pentanoic acid, 5-(나프탈렌-1-일-아세톡시)-4-옥소-3-[2-(2-옥소-3-페닐-테트라히드로-피리미딘-1-일)-프로피오닐아미노]-펜탄산,5- (naphthalen-1-yl-acetoxy) -4-oxo-3- [2- (2-oxo-3-phenyl-tetrahydro-pyrimidin-1-yl) -propionylamino] -pentanoic acid, 5-(나프탈렌-1-일-아세톡시)-4-옥소-3-[2-(2-옥소-3-페닐-테트라히드로-피리미딘-1-일)-아세틸아미노]-펜탄산,5- (naphthalen-1-yl-acetoxy) -4-oxo-3- [2- (2-oxo-3-phenyl-tetrahydro-pyrimidin-1-yl) -acetylamino] -pentanoic acid, 3-(2-아세틸아미노-3-메틸-부티릴아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (2-acetylamino-3-methyl-butyrylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-(2-아세틸아미노-3-메틸-부티릴아미노)-5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-펜탄산,3- (2-Acetylamino-3-methyl-butyrylamino) -5- (2-benzyl-3-phenyl-propionyloxy) -4-oxo-pentanoic acid, 3-(2-아세틸아미노-3-메틸-부티릴아미노)-5-(3-벤질-4-페닐-부티릴옥시)-4-옥소-펜탄산,3- (2-acetylamino-3-methyl-butyrylamino) -5- (3-benzyl-4-phenyl-butyryloxy) -4-oxo-pentanoic acid, 3-(2-아세틸아미노-3-메틸-부티릴아미노)-5-(4-벤질-5-페닐-펜타노일옥시)-4-옥소-펜탄산,3- (2-acetylamino-3-methyl-butyrylamino) -5- (4-benzyl-5-phenyl-pentanoyloxy) -4-oxo-pentanoic acid, 3-(2-아세틸아미노-3-메틸-부티릴아미노)-4-옥소-5-[(1-옥소-1,2,3,4-테트라히드로-나프탈렌-2-일)-아세톡시]-펜탄산,3- (2-acetylamino-3-methyl-butyrylamino) -4-oxo-5-[(1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl) -acetoxy] Pentanoic acid, 5-(3-벤질-4-페닐-부티릴옥시)-3-[3-메틸-2-(3-페닐-프로피오닐아미노)-부티릴아미노]-4-옥소-펜탄산,5- (3-benzyl-4-phenyl-butyryloxy) -3- [3-methyl-2- (3-phenyl-propionylamino) -butyrylamino] -4-oxo-pentanoic acid, 3-[2-(3-아세틸아미노-2-옥소-2H-피리딘-1-일)-아세틸아미노]-5-(3,3-디페닐-프로피오닐옥시)-4-옥소-펜탄산 및3- [2- (3-Acetylamino-2-oxo-2H-pyridin-1-yl) -acetylamino] -5- (3,3-diphenyl-propionyloxy) -4-oxo-pentanoic acid and 3-[2-(3-아세틸아미노-2-옥소-2H-피리딘-1-일)-아세틸아미노]-5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-펜탄산인 화합물.3- [2- (3-acetylamino-2-oxo-2H-pyridin-1-yl) -acetylamino] -5- (2-benzyl-3-phenyl-propionyloxy) -4-oxo-pentanoic acid Phosphorus compounds. 3-[2-(2-벤질옥시카르보닐아미노-4-카르복시-부티릴아미노)-3-메틸-부티릴아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- [2- (2-benzyloxycarbonylamino-4-carboxy-butyrylamino) -3-methyl-butyrylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-phen Carbonated, 3-[2-(2-벤질옥시카르보닐아미노-3-메틸-부티릴아미노)-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- [2- (2-benzyloxycarbonylamino-3-methyl-butyrylamino) -propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-(2-아세틸아미노-3-메틸-부티릴아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (2-acetylamino-3-methyl-butyrylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-[2-(2-벤질옥시카르보닐아미노-3-메틸-부티릴아미노)-프로피오닐아미노]-5-(3,3-디페닐-프로피오닐옥시)-4-옥소-펜탄산,3- [2- (2-benzyloxycarbonylamino-3-methyl-butyrylamino) -propionylamino] -5- (3,3-diphenyl-propionyloxy) -4-oxo-pentanoic acid, 3-[2-(2-벤질옥시카르보닐아미노-3-메틸-부티릴아미노)-프로피오닐아미노]-5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-펜탄산,3- [2- (2-Benzyloxycarbonylamino-3-methyl-butyrylamino) -propionylamino] -5- (2-benzyl-3-phenyl-propionyloxy) -4-oxo-pentanoic acid , 3-[2-(2-벤질옥시카르보닐아미노-3-메틸-부티릴아미노)-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- [2- (2-benzyloxycarbonylamino-3-methyl-butyrylamino) -propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 5-(2-벤질-3-페닐-프로피오닐옥시)-3-{2-[4-카르복시-2-(3-페닐-프로피오닐아미노)-부티릴아미노]-3-메틸-부티릴아미노}-4-옥소-펜탄산,5- (2-Benzyl-3-phenyl-propionyloxy) -3- {2- [4-carboxy-2- (3-phenyl-propionylamino) -butyrylamino] -3-methyl-butyrylamino } -4-oxo-pentanoic acid, 3-(2-벤질옥시카르보닐아미노-3-메틸-부티릴아미노)-5-(3,3-디페닐-프로피오닐옥시)-4-옥소-펜탄산,3- (2-benzyloxycarbonylamino-3-methyl-butyrylamino) -5- (3,3-diphenyl-propionyloxy) -4-oxo-pentanoic acid, 3-(2-아세틸아미노-3-히드록시-부티릴아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (2-acetylamino-3-hydroxy-butyrylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-(2-아세틸아미노-3-히드록시-부티릴아미노)-5-(3,3-디페닐-프로피오닐옥시)-4-옥소-펜탄산,3- (2-acetylamino-3-hydroxy-butyrylamino) -5- (3,3-diphenyl-propionyloxy) -4-oxo-pentanoic acid, 3-(2-{2-[2-아세틸아미노-3-(1H-인돌-3-일)-프로피오닐아미노]-4-카르복시-부티릴아미노}-3-메틸-부티릴아미노)-5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-펜탄산 및3- (2- {2- [2-acetylamino-3- (1H-indol-3-yl) -propionylamino] -4-carboxy-butyrylamino} -3-methyl-butyrylamino) -5 -(2-benzyl-3-phenyl-propionyloxy) -4-oxo-pentanoic acid and 5-(3,3-디페닐-프로피오닐옥시)-4-옥소-3-[2-(4-페닐-부티릴아미노)-프로피오닐아미노]-펜탄산인 화합물.5- (3,3-Diphenyl-propionyloxy) -4-oxo-3- [2- (4-phenyl-butyrylamino) -propionylamino] -pentanoic acid. 3-(2-{2-[2-아세틸아미노-3-(1H-인돌-3-일)-프로피오닐아미노]-4-카르복시-부티릴아미노}-3-메틸-부티릴아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 및3- (2- {2- [2-acetylamino-3- (1H-indol-3-yl) -propionylamino] -4-carboxy-butyrylamino} -3-methyl-butyrylamino) -5 -(Naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid and 3-(2-{2-[2-아세틸아미노-3-(4-히드록시-페닐)-프로피오닐아미노]-4-카르복시-부티릴아미노}-3-메틸-부티릴아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산인 화합물.3- (2- {2- [2-acetylamino-3- (4-hydroxy-phenyl) -propionylamino] -4-carboxy-butyrylamino} -3-methyl-butyrylamino) -5- A compound that is (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid. 3-[(2-카르복시-시클로헥산카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3-[(2-carboxy-cyclohexanecarbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-[(2-메톡시카르보닐-시클로헥산카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 및3-[(2-methoxycarbonyl-cyclohexanecarbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid and 3-[(2-카르바모일-시클로헥산카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산인 화합물.3-[(2-Carbamoyl-cyclohexanecarbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid. 3-(3-벤질술파닐-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (3-benzylsulfanyl-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-(2-메틸-3-페닐메탄술포닐-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (2-Methyl-3-phenylmethanesulfonyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-[3-(2-카르복시-에탄술파닐)-2-메틸-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- [3- (2-carboxy-ethanesulfanyl) -2-methyl-propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 5-(2-벤질-3-페닐-프로피오닐옥시)-3-[3-(2-카르복시-에탄술포닐)-2-메틸-프로피오닐아미노]-4-옥소-펜탄산,5- (2-benzyl-3-phenyl-propionyloxy) -3- [3- (2-carboxy-ethanesulfonyl) -2-methyl-propionylamino] -4-oxo-pentanoic acid, 5-(2-벤질-3-페닐-프로피오닐옥시)-3-[3-(3-카르복시-프로판-1-술피닐)-2-메틸-프로피오닐아미노]-4-옥소-펜탄산,5- (2-benzyl-3-phenyl-propionyloxy) -3- [3- (3-carboxy-propane-1-sulfinyl) -2-methyl-propionylamino] -4-oxo-pentanoic acid, 5-(나프탈렌-1-일-아세톡시)-4-옥소-3-(2-페닐메탄술파닐-프로피오닐아미노)-펜탄산,5- (naphthalen-1-yl-acetoxy) -4-oxo-3- (2-phenylmethanesulfanyl-propionylamino) -pentanoic acid, 3-(2-메틸-3-페닐술파닐-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (2-Methyl-3-phenylsulfanyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 5-(2-벤질-3-페닐-프로피오닐옥시)-3-(2-메틸-3-페닐술파닐-프로피오닐아미노)-4-옥소-펜탄산,5- (2-Benzyl-3-phenyl-propionyloxy) -3- (2-methyl-3-phenylsulfanyl-propionylamino) -4-oxo-pentanoic acid, 3-(2-메틸-3-펜에틸술파닐-프로피오닐옥시)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (2-Methyl-3-phenethylsulfanyl-propionyloxy) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 5-(2-벤질-3-페닐-프로피오닐옥시)-3-(2-메틸-3-펜에틸술파닐-프로피오닐아미노)-4-옥소-펜탄산,5- (2-benzyl-3-phenyl-propionyloxy) -3- (2-methyl-3-phenethylsulfanyl-propionylamino) -4-oxo-pentanoic acid, 5-(2-벤질-3-페닐-프로피오닐옥시)-3-(3-벤질술파닐-2-메틸-프로피오닐아미노)-4-옥소-펜탄산,5- (2-benzyl-3-phenyl-propionyloxy) -3- (3-benzylsulfanyl-2-methyl-propionylamino) -4-oxo-pentanoic acid, 5-(2-벤질-3-페닐-프로피오닐옥시)-3-(2-벤질술파닐-프로피오닐아미노)-4-옥소-펜탄산,5- (2-benzyl-3-phenyl-propionyloxy) -3- (2-benzylsulfanyl-propionylamino) -4-oxo-pentanoic acid, 3-[2-메틸-3-(3-페닐-프로필술파닐)-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- [2-Methyl-3- (3-phenyl-propylsulfanyl) -propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-(3-벤젠술포닐-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (3-benzenesulfonyl-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-(3-벤젠술포닐-2-메틸-프로피오닐아미노)-5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-펜탄산,3- (3-benzenesulfonyl-2-methyl-propionylamino) -5- (2-benzyl-3-phenyl-propionyloxy) -4-oxo-pentanoic acid, 5-(2-벤질-3-페닐-프로피오닐옥시)-3-[2-메틸-3-(2-페닐-에탄술포닐)-프로피오닐아미노]-4-옥소-펜탄산,5- (2-Benzyl-3-phenyl-propionyloxy) -3- [2-methyl-3- (2-phenyl-ethanesulfonyl) -propionylamino] -4-oxo-pentanoic acid, 3-[2-메틸-3-(2-페닐-에탄술포닐)-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- [2-Methyl-3- (2-phenyl-ethanesulfonyl) -propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 5-(나프탈렌-1-일-아세톡시)-4-옥소-3-(2-페닐메탄술포닐-프로피오닐아미노)-펜탄산,5- (naphthalen-1-yl-acetoxy) -4-oxo-3- (2-phenylmethanesulfonyl-propionylamino) -pentanoic acid, 5-(2-벤질-3-페닐-프로피오닐옥시)-3-(2-메틸-3-페닐메탄술포닐-프로피오닐아미노)-4-옥소-펜탄산,5- (2-benzyl-3-phenyl-propionyloxy) -3- (2-methyl-3-phenylmethanesulfonyl-propionylamino) -4-oxo-pentanoic acid, 5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-3-(2-페닐메탄술포닐-프로피오닐아미노)-펜탄산,5- (2-benzyl-3-phenyl-propionyloxy) -4-oxo-3- (2-phenylmethanesulfonyl-propionylamino) -pentanoic acid, 3-[2-메틸-3-(3-페닐-프로판-1-술포닐)-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- [2-Methyl-3- (3-phenyl-propane-1-sulfonyl) -propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 5-(2-벤질-3-페닐-프로피오닐옥시)-3-[2-메틸-3-(3-페닐-프로판-1-술포닐)-프로피오닐아미노]-4-옥소-펜탄산,5- (2-Benzyl-3-phenyl-propionyloxy) -3- [2-methyl-3- (3-phenyl-propane-1-sulfonyl) -propionylamino] -4-oxo-pentanoic acid, 5-(2-벤질-3-페닐-프로피오닐옥시)-3-[3-(2-카르복시-에틸술파닐)-2-메틸-프로피오닐아미노]-4-옥소-펜탄산,5- (2-Benzyl-3-phenyl-propionyloxy) -3- [3- (2-carboxy-ethylsulfanyl) -2-methyl-propionylamino] -4-oxo-pentanoic acid, 3-[3-(3-카르복시-프로필술파닐)-2-메틸-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- [3- (3-carboxy-propylsulfanyl) -2-methyl-propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 5-(2-벤질-3-페닐-프로피오닐옥시)-3-[3-(3-카르복시-프로필술파닐)-2-메틸-프로피오닐아미노]-4-옥소-펜탄산,5- (2-Benzyl-3-phenyl-propionyloxy) -3- [3- (3-carboxy-propylsulfanyl) -2-methyl-propionylamino] -4-oxo-pentanoic acid, 3-(3-카르복시메틸술파닐-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (3-carboxymethylsulfanyl-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 5-(2-벤질-3-페닐-프로피오닐옥시)-3-(3-카르복시메틸술파닐-2-메틸-프로피오닐아미노)-4-옥소-펜탄산,5- (2-benzyl-3-phenyl-propionyloxy) -3- (3-carboxymethylsulfanyl-2-methyl-propionylamino) -4-oxo-pentanoic acid, 3-[3-(2-카르복시-에탄술포닐)-2-메틸-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- [3- (2-carboxy-ethanesulfonyl) -2-methyl-propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-[3-(3-카르복시-프로판-1-술포닐)-2-메틸-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- [3- (3-carboxy-propane-1-sulfonyl) -2-methyl-propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-(3-카르복시메탄술포닐-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (3-carboxymethanesulfonyl-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 5-(2-벤질-3-페닐-프로피오닐옥시)-3-[3-(3-카르복시-프로판-1-술포닐)-2-메틸-프로피오닐아미노]-4-옥소-펜탄산,5- (2-benzyl-3-phenyl-propionyloxy) -3- [3- (3-carboxy-propane-1-sulfonyl) -2-methyl-propionylamino] -4-oxo-pentanoic acid, 5-(2-벤질-3-페닐-프로피오닐옥시)-3-(3-카르복시메탄술포닐-2-메틸-프로피오닐아미노)-4-옥소-펜탄산,5- (2-benzyl-3-phenyl-propionyloxy) -3- (3-carboxymethanesulfonyl-2-methyl-propionylamino) -4-oxo-pentanoic acid, 3-[3-(3-카르복시-프로판-1-술피닐)-2-메틸-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- [3- (3-carboxy-propane-1-sulfinyl) -2-methyl-propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-[2-메틸-3-(3-페닐-프로판-1-술피닐)-프로피오닐아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 및3- [2-Methyl-3- (3-phenyl-propane-1-sulfinyl) -propionylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid and 5-(2-벤질-3-페닐-프로피오닐옥시)-3-[2-메틸-3-(3-페닐-프로판-1-술피닐)-프로피오닐아미노]-4-옥소-펜탄산인 화합물.5- (2-benzyl-3-phenyl-propionyloxy) -3- [2-methyl-3- (3-phenyl-propane-1-sulfinyl) -propionylamino] -4-oxo-pentanoic acid compound. 3-[3-메틸-2-(펜에틸카르바모일-메틸)-부티릴아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 및3- [3-Methyl-2- (phenethylcarbamoyl-methyl) -butyrylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid and 3-(3-카르복시-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산인 화합물.3- (3-carboxy-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid. 3-(2-메틸-3-술파모일-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산인 화합물.3- (2-Methyl-3-sulfamoyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid. 3-(3-카르바모일-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (3-Carbamoyl-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-(2-벤질옥시카르보닐아미노-3-메틸-나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (2-benzyloxycarbonylamino-3-methyl-naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-[(2-카르바모일-시클로펜탄카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3-[(2-Carbamoyl-cyclopentanecarbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-[(1-카르바모일-피롤리딘-2-카르보닐)-아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3-[(1-Carbamoyl-pyrrolidine-2-carbonyl) -amino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-[(2-{2-[2-아세틸아미노-3-(4-히드록시-페닐)-프로피오닐아미노]-4-카르복시-부티릴아미노}-3-메틸-부티릴아미노)-5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-펜탄산,3-[(2- {2- [2-acetylamino-3- (4-hydroxy-phenyl) -propionylamino] -4-carboxy-butyrylamino} -3-methyl-butyrylamino) -5 -(2-benzyl-3-phenyl-propionyloxy) -4-oxo-pentanoic acid, 3-(3-카르바모일-2-메틸-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (3-Carbamoyl-2-methyl-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-(2-카르바모일메틸-3-메틸-부티릴아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (2-Carbamoylmethyl-3-methyl-butyrylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-(3-벤질옥시-2-우레이도-프로피오닐아미노)-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산,3- (3-benzyloxy-2-ureido-propionylamino) -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid, 3-[2-(2-벤질옥시카르보닐아미노-4-카르복시-부티릴아미노)-3-메틸-부티릴아미노]-5-(2-벤질-3-페닐-프로피오닐옥시)-4-옥소-펜탄산,3- [2- (2-benzyloxycarbonylamino-4-carboxy-butyrylamino) -3-methyl-butyrylamino] -5- (2-benzyl-3-phenyl-propionyloxy) -4- Oxo-Pentanoic Acid, 3-{2-[4-카르복시-2-(3-페닐-프로피오닐아미노)-부티릴아미노]-3-메틸-부티릴아미노}-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산 및3- {2- [4-carboxy-2- (3-phenyl-propionylamino) -butyrylamino] -3-methyl-butyrylamino} -5- (naphthalen-1-yl-acetoxy) -4 Oxo-pentanoic acid and 3-[2-(2-아세틸아미노-4-카르복시-부티릴아미노)-3-메틸-부티릴아미노]-5-(나프탈렌-1-일-아세톡시)-4-옥소-펜탄산인 화합물.3- [2- (2-acetylamino-4-carboxy-butyrylamino) -3-methyl-butyrylamino] -5- (naphthalen-1-yl-acetoxy) -4-oxo-pentanoic acid . 하기 화학식 I의 화합물 및 제약상 허용가능한 그의 염, 에스테르, 아미드 및 프로드럭.Compounds of formula (I) and pharmaceutically acceptable salts, esters, amides and prodrugs thereof. <화학식 I><Formula I> 식 중, R1은,,,,, , , -(CH2)3페닐,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 또는이고,Wherein R 1 is , , , , , , ,-(CH 2 ) 3 phenyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ego, R2는 -CH2CH2-페닐, -CH2-나프틸, -CH2CH2-시클로헥실, -CH2O-나프틸, -CH2O-페닐, -CH2S-페닐, -CH2-치환된 나프틸, -CH2CH(페닐)2, -CH2-이미다졸, -(CH2)3-페닐,,,, -CH[CH2페닐]2,, -CH2-NH페닐,, -CH2-나프틸-페닐, -CH2-플루오레닐, -CH2-나프틸-티에닐,,, -CH2-벤조푸라닐, -CH2-벤조티에닐, -CH2-나프틸-CH2-페닐, -CH2-치환된 페닐,, -CH2-치환된 인돌릴,,,,,,,,,, -(CH2)2-피리딜, 또는이고,R 2 is —CH 2 CH 2 -phenyl, -CH 2 -naphthyl, -CH 2 CH 2 -cyclohexyl, -CH 2 O-naphthyl, -CH 2 O-phenyl, -CH 2 S-phenyl,- CH 2 -substituted naphthyl, -CH 2 CH (phenyl) 2 , -CH 2 -imidazole,-(CH 2 ) 3 -phenyl, , , , -CH [CH 2 phenyl] 2 , , -CH 2 -NHphenyl, , -CH 2 -naphthyl-phenyl, -CH 2 -fluorenyl, -CH 2 -naphthyl-thienyl, , , -CH 2 -benzofuranyl, -CH 2 -benzothienyl, -CH 2 -naphthyl-CH 2 -phenyl, -CH 2 -substituted phenyl, , -CH 2 -substituted indolyl, , , , , , , , , ,-(CH 2 ) 2 -pyridyl, or ego, 각각의 n은 서로 독립적으로 0 내지 3이다.Each n is 0 to 3 independently of each other.
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