KR20010052518A - Alpha-Keto Oxadiazoles As Serine Protease Inhibitors - Google Patents
Alpha-Keto Oxadiazoles As Serine Protease Inhibitors Download PDFInfo
- Publication number
- KR20010052518A KR20010052518A KR1020007013659A KR20007013659A KR20010052518A KR 20010052518 A KR20010052518 A KR 20010052518A KR 1020007013659 A KR1020007013659 A KR 1020007013659A KR 20007013659 A KR20007013659 A KR 20007013659A KR 20010052518 A KR20010052518 A KR 20010052518A
- Authority
- KR
- South Korea
- Prior art keywords
- oxadiazolyl
- methylpropyl
- pyrimidinyl
- dihydro
- carbonyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 57
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 40
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Abstract
본 발명은 세린 프로테아제, 예를 들면 인간 호중구 엘라스타제(HNE)의 저해제로서 유용한, 발린 및 프롤린 잔기를 함유하는 치환된 몇몇 옥사디아졸, 티아디아졸 및 트리아졸 펩티드 및 피리미디논 잔기를 함유하는 비펩티드에 관한 것이다. 본 발명의 화합물은 성인 호흡 곤란 증후군, 패혈증 쇼크 및 다중 장기 부전증의 증세를 치료하거나 완화시키는데 유용하다. HNE에 의해 매개되는 과정은 관절염, 치주 질환, 사구체신염, 방광 섬유증과 같은 질환과 관련된다.The present invention relates to the use of some substituted oxadiazoles, thiadiazoles and triazole peptides containing valine and proline residues and pyrimidone residues, which are useful as inhibitors of serine proteases, for example human neutrophil elastase (HNE) ≪ / RTI > The compounds of the present invention are useful for treating or alleviating symptoms of adult respiratory distress syndrome, sepsis shock and multiple organ failure. The process mediated by HNE is associated with diseases such as arthritis, periodontal disease, glomerulonephritis, and bladder fibrosis.
Description
본 발명은 본원에서 참고로 인용되는, 1998년 6월 3일 출원된 미국 특허 출원 제 09/090,046 호 및 미국 특허 출원 제 09/090,274 호를 우선권으로 주장한다.The present application claims priority from U.S. Patent Application Serial No. 09 / 090,046 and U.S. Patent Application Serial No. 09 / 090,274, filed June 3, 1998, which are incorporated herein by reference.
세린 프로테아제는 엘라스타제, 키모트립신, 카텝신 G, 트립신 및 트롬빈을 포함하는 효소군이다. 이들 프로테아제는 공통적으로 세린-195, 히스티딘-57 및 아스파르트산-102(키모트립신 넘버링 시스템)로 이루어진 촉매 트리아드(triad)를 갖는다. 인간 호중구 엘라스타제(HNE)는 다형핵성 백혈구(PMN)가 다양한 염증 자극에 반응하여 분비하는 단백질 분해 효소이다. 이러한 HNE 방출 및 그의 세포외 단백질분해 활성은 고도로 조절되고, PMN의 정상적이며 유익한 기능이다. 정상적인 환경에서의 HNE의 분해 능력은 α1-프로테이나제 저해제(α-PI)의 비교적 높은 혈장 농도에 의해 조절된다. 그러나, 자극된 PMN은 활성 산소 대사물질을 대량 생산하고 그중 일부 (예를 들어, 차아염소산)는 α- PI 내의 중요한 메티오닌 잔기를 산화시킬 수 있다. 산화된 α-PI는 HNE 저해제로서의 효능이 제한되는 것으로 밝혀졌고, 이러한 프로테아제/항프로테아제 균형이 변경됨으로써 HNE가 국소의 조절된 환경에서 그의 분해 기능을 수행하게 된다는 것이 제안되었다.Serine proteases are a family of enzymes including elastase, chymotrypsin, cathepsin G, trypsin and thrombin. These proteases commonly have a catalytic triad of serine-195, histidine-57 and aspartic acid-102 (chymotrysin numbering system). Human neutrophil elastase (HNE) is a proteolytic enzyme secreted by polymorphonuclear leukocytes (PMN) in response to various inflammatory stimuli. This HNE release and its extracellular proteolytic activity are highly regulated and are a normal and beneficial function of PMN. The ability of HNE to degrade under normal circumstances is controlled by the relatively high plasma concentration of the α 1 -proteinase inhibitor (α-PI). However, stimulated PMNs produce massive amounts of active oxygen metabolites and some (e. G., Hypochlorous acid) of them can oxidize important methionine residues in a-PI. Oxidized α-PI has been shown to have limited efficacy as an HNE inhibitor, and it has been proposed that this protease / anti-protease balance is altered so that HNE performs its degradative function in a local controlled environment.
프로테아제/항프로테아제 활성이 균형을 이루어도, 이러한 조절 대사의 파괴가 질병의 원인이 되는 여러 인간의 질병이 있다. HNE 활성의 부적절한 조절이 성인 호흡 곤란 증후군, 패혈증 쇼크 및 다중 장기 부전증에 원인이 되는 인자라는 것이 제안되었다. 일련의 연구 결과, PMN 및 호중구 엘라스타제가 심근 허혈 재관류 손상과 관련된다는 것을 알 수 있었다. 정상보다 낮은 수준의 α1-PI를 갖는 사람은 폐기종이 발생할 가능성이 높아진다. HNE-매개된 과정은 관절염, 치주 질환, 사구체신염, 피부염, 건선, 방광 섬유증, 만성 기관지염, 아테롬성 동맥 경화증, 알쯔하이머병, 장기 이식, 각막 궤양 및 악성 종양의 침윤과 같은 기타 질병과도 관련이 있다.Even when the protease / anti-protease activity is balanced, there are many human diseases in which the destruction of such regulated metabolism is the cause of the disease. It has been suggested that inadequate regulation of HNE activity is a causative factor in adult respiratory distress syndrome, sepsis shock, and multiple organ failure. A series of studies have shown that PMN and neutrophil elastase are associated with myocardial ischemia reperfusion injury. People with lower than normal levels of alpha 1 -PI are more likely to develop emphysema. The HNE-mediated process is also associated with other diseases such as arthritis, periodontal disease, glomerulonephritis, dermatitis, psoriasis, bladder fibrosis, chronic bronchitis, atherosclerosis, Alzheimer's disease, organ transplantation, corneal ulcers and malignant tumor invasion .
엘라스타제-매개된 문제를 치료 및/또는 예방하기 위한 치료제 및 예방약으로서 HNE의 유효한 저해제가 요구된다.Effective inhibitors of HNE are required as therapeutic and preventive agents for treating and / or preventing elastase-mediated problems.
발명의 요약SUMMARY OF THE INVENTION
한 실시양태에서, 본 발명은 하기 화학식 I의 화합물을 제공한다.In one embodiment, the invention provides compounds of formula (I)
상기 식에서,In this formula,
X 및 Y는 독립적으로 O 또는 N이고,X and Y are independently O or N,
R1은 알킬, α,α-디알킬알킬아릴 또는 α,α-디알킬알킬 융합된 아릴-사이클로알킬 (여기서, 사이클로알킬기는 2개 이상의 O 원자로 임의로 치환됨)이고,R 1 is alkyl, alpha, alpha-dialkyl alkylaryl or alpha, alpha-dialkyl alkyl fused aryl-cycloalkyl, wherein the cycloalkyl group is optionally substituted with at least two O atoms,
R2및 R3은 독립적으로 H 또는 알킬이거나, 또는 함께 3 내지 5개의 탄소로 이루어진 고리를 형성하는데, 여기서 고리의 하나 이상의 탄소 원자는 O, S 또는 N (여기서, N은 H 또는 알킬로 임의로 치환됨)으로부터 선택된 헤테로원자로 임의로 치환될 수 있고, 바람직하게는 R2와 R3중 하나는 H이고, 다른 하나는 이소-프로필이고,R 2 and R 3 are independently H or alkyl or together form a ring of 3 to 5 carbons wherein at least one carbon atom of the ring is optionally replaced by O, S or N, wherein N is H or optionally alkyl Lt; 2 > and R < 3 > are H, and the other is iso-propyl,
R4는 알킬옥시카르보닐이다.R 4 is alkyloxycarbonyl.
바람직하게는, 본 발명의 화합물은 1,3,4-옥사디아졸 고리(즉, X는 N이고, Y는 O임)를 포함한다.Preferably, the compounds of the present invention comprise a 1,3,4-oxadiazole ring (i.e., X is N and Y is O).
본 발명의 바람직한 실시양태에서, R1은 알킬, 예를 들면 t-부틸이다. 또다른 실시양태에서, R1은 α,α-디알킬알킬아릴, 예를 들면 α,α-디메틸벤질기이다. 또다른 바람직한 실시양태에서, R1은 사이클로알킬기가 2개의 O 원자로 치환된 α,α- 디알킬알킬 융합된 아릴-사이클로알킬, 예를 들면 α,α-디메틸-(3,4-메틸렌디옥시)벤질기이다. 또다른 바람직한 실시양태에서, R2및 R3은 독립적으로 알킬, 예를 들면 이소프로필이거나 또는 H이다. 바람직하게는 R2는 이소프로필이고, R3는 H이다.In a preferred embodiment of the present invention, R < 1 > is alkyl, for example t-butyl. In another embodiment, R < 1 > is an alpha, alpha-dialkyl alkylaryl, e.g., alpha, alpha -dimethylbenzyl group. In another preferred embodiment, R < 1 > is an alpha, alpha -dialkylalkyl fused aryl-cycloalkyl wherein the cycloalkyl group is substituted with two O atoms, such as alpha, alpha -dimethyl- (3,4-methylenedioxy ) Benzyl group. In another preferred embodiment, R 2 and R 3 are independently alkyl, such as isopropyl, or H. Preferably, R < 2 > is isopropyl and R < 3 >
또다른 실시양태에서, 본 발명은 하기 화학식 II의 화합물 또는 그의 약학적으로 허용되는 염을 제공한다.In another embodiment, the invention provides a compound of formula II: < EMI ID = 2.1 >
상기 식에서,In this formula,
X 및 Y는 독립적으로 O 또는 N이고,X and Y are independently O or N,
R1, R2및 R3은 상기에 정의된 바와 같고,R 1 , R 2 and R 3 are as defined above,
R'2및 R'3은 독립적으로 H 또는 알킬이거나, 또는 함께 3 내지 5개의 탄소원자로 이루어진 고리를 형성하는데, 여기서 고리의 하나 이상의 탄소 원자는 O, S 또는 N (여기서, N은 H 또는 알킬로 임의 치환됨)으로부터 선택된 헤테로원자로 임의로 치환될 수 있고,R ' 2 and R' 3 are independently H or alkyl, or together form a ring of 3 to 5 carbon atoms, wherein at least one carbon atom of the ring is replaced by O, S or N, wherein N is H or alkyl , ≪ / RTI > optionally substituted with one or more < RTI ID = 0.0 >
A는 직접 결합, -NH- 또는 -OC(O)-NH-이고,A is a direct bond, -NH- or -OC (O) -NH-,
R4는 H 또는 할로겐이고,R < 4 > is H or halogen,
R5는 H, 알킬 또는 아릴알킬이다.R < 5 > is H, alkyl or arylalkyl.
바람직하게는, 본 발명의 실시양태의 화합물은 1,3,4-옥사디아졸 고리(즉, X는 N이고, Y는 O임)를 포함한다.Preferably, the compounds of embodiments of the present invention include a 1,3,4-oxadiazole ring (i.e., X is N and Y is O).
본 발명의 바람직한 실시양태에서, R1은 알킬, 예를 들면 t-부틸이다. 또다른 실시양태에서, R1은 사이클로알킬기가 2개의 O 원자로 치환된 α,α- 디알킬알킬 융합된 아릴-사이클로알킬, 예를 들면 α,α-디메틸-(3,4-메틸렌디옥시)벤질기이다. 또다른 실시양태에서, R1은 α,α-디알킬알킬아릴, 예를 들면 α,α-디메틸벤질기이다. 또다른 바람직한 실시양태에서, R2및 R3은 독립적으로 알킬, 예를 들면 이소프로필 또는 H이다. 더욱 바람직한 실시양태에서, R2는 이소프로필이고, R3은 H이고, R2' 및 R3'은 모두 H이다. R4가 할로겐일 경우, R4는 Cl, F, I 또는 Br일 수 있고, F가 바람직하다.In a preferred embodiment of the present invention, R < 1 > is alkyl, for example t-butyl. In another embodiment, R < 1 > is an alpha, alpha-dialkylalkyl fused aryl-cycloalkyl wherein the cycloalkyl group is substituted with two O atoms, for example, alpha, alpha -dimethyl- (3,4-methylenedioxy) Benzyl group. In another embodiment, R < 1 > is an alpha, alpha-dialkyl alkylaryl, e.g., alpha, alpha -dimethylbenzyl group. In another preferred embodiment, R 2 and R 3 are independently alkyl, such as isopropyl or H. In a more preferred embodiment, R 2 is isopropyl, R 3 is H, R 2 'and R 3 ' are all H. When R 4 is halogen, R 4 can be Cl, F, I or Br, with F being preferred.
본원에서 사용된 "임의로 치환된"이라는 용어는 치환시 1개 내지 전체가 치환됨을 의미한다.The term " optionally substituted " as used herein means that one to all of the substituents are substituted.
본원에서 사용된 "독립적으로"라는 용어는 치환체가 동일하거나 상이할 수 있음을 의미한다.As used herein, the term " independently " means that the substituents may be the same or different.
본원에서 사용된 용어 "알킬"은 C1-C15, 바람직하게는 C1-C8을 의미한다. 알킬기는 선형이거나 분지형일 수 있는 것으로 이해된다.The term " alkyl " as used herein means C 1 -C 15 , preferably C 1 -C 8 . It is understood that the alkyl group may be linear or branched.
본원에서 사용된 용어 "α,α-디알킬알킬아릴"은 알킬기가 옥사디아졸 고리 또는 아릴기 또는 둘다에 대해 α-위치에서 치환됨을 의미한다. 한가지 예로, α-치환체가 바람직하게는 메틸, 에틸 또는 프로필인 α,α-디알킬벤질이 있다. 구체적인 예로 α,α-디메틸벤질이 있다. 용어 "α,α- 디알킬알킬 융합된 아릴-사이클로알킬"은 알킬기가 옥사디아졸 고리 또는 아릴기에 대해 α-위치에서 치환되고 아릴 고리에 사이클로알킬이 융함됨을 의미한다. "α,α- 디알킬알킬 융합된 아릴-사이클로알킬"의 한 예는 α-치환체가 메틸, 에틸 또는 프로필이고 바람직하게는 메틸인 α,α-디알킬-3,4-메틸렌디옥시벤질기이다. 구체적인 예로는 α,α- 디메틸-3,4-메틸렌디옥시벤질기가 있다.As used herein, the term "α, α-dialkylalkylaryl" means that the alkyl group is substituted at the α-position to the oxadiazole ring or aryl group, or both. As an example, there is an alpha, alpha -dialkylbenzyl wherein the alpha-substituent is preferably methyl, ethyl or propyl. Specific examples include?,? - dimethylbenzyl. The term "α, α-dialkylalkyl fused aryl-cycloalkyl" means that the alkyl group is substituted in the α-position to the oxadiazole ring or aryl group and the cycloalkyl is fused to the aryl ring. An example of " alpha, alpha-dialkyl alkyl fused aryl-cycloalkyl " is the alpha, alpha -dialkyl-3,4-methylenedioxybenzyl group in which the alpha-substituent is methyl, to be. A specific example is?,? -Dimethyl-3,4-methylenedioxybenzyl group.
본원에서 사용된 알킬옥시카르보닐은 알킬-O-C(O)- (여기서, 알킬은 상기 정의된 바와 같음)를 의미한다. 알킬옥시카르보닐의 한 예로는 메틸옥시카르보닐이고, 이것은 일반식 CH3-O-C(O)-로 나타내어진다.Alkyloxycarbonyl as used herein means alkyl-OC (O) -, wherein alkyl is as defined above. An example of alkyloxycarbonyl is methyloxycarbonyl, which is represented by the general formula CH 3 -OC (O) -.
도 1은 본 발명에서 사용된 Boc 보호된 아미노 알콜의 중간체 합성 과정을 보여주는 도면이다.BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a diagram showing a process for synthesizing intermediates of Boc-protected aminoalcohols used in the present invention. FIG.
도 2는 본 발명의 한 실시양태의 화합물의 합성 과정을 보여주는 도면이다.2 is a diagram showing a process of synthesizing a compound of one embodiment of the present invention.
도 3은 본 발명의 또다른 실시양태의 화합물의 합성 과정을 보여주는 도면이다.Figure 3 is a diagram illustrating a process for synthesizing a compound of another embodiment of the present invention.
본 발명의 화합물은 세린 프로테아제 인간 호중구 엘라스타제(HNE)의 효능있는 저해제인 것으로 밝혀졌다. 이들은 활성 부위 세린 잔기와 전이상태 중간체를 형성하는 것으로 추측되는 가역성(reversible) 저해제이다. 이 화합물은 분자량이 낮고, HNE에 대해 선택성이 높고, 생리학적 상태와 관련해 안정성을 가짐을 특징으로 한다. 따라서, 이 화합물은 HNE의 존재와 관련된 분해 효과에 의해 매개되는 질병을 예방, 완화 및/또는 치료할 수 있을 것으로 생각된다. 이 화합물은 생체내 다양한 인간 질환의 치료에 사용될 뿐만 아니라 시험관 내에서 진단 시약으로서도 사용될 수 있다는 점에서 특히 중요하다.The compounds of the present invention have been found to be potent inhibitors of serine protease human neutrophil elastase (HNE). These are reversible inhibitors which are presumed to form transition state intermediates with active site serine residues. This compound is characterized by low molecular weight, high selectivity for HNE, and stability with respect to its physiological state. Thus, it is believed that this compound is capable of preventing, alleviating and / or treating a disease mediated by the degradative effect associated with the presence of HNE. This compound is particularly important in that it can be used not only for the treatment of various human diseases in vivo but also as a diagnostic reagent in vitro.
본 발명은 실시예에 기재된 특정 실시양태 뿐만 아니라 하기 실시양태를 제공하지만 여기에만 국한되지는 않는다.The present invention provides, but is not limited to, the specific embodiments described in the examples as well as the following embodiments.
실시양태에서 사용된 명명법은 다음과 같다 (개시된 실시양태가 2-메틸프로필기의 입체화학을 (S)-배열이라고 하였어도, 에난티오머상(enantiomerically) 순수한 (R) 및 라세미 (R,S) 배열도 본 발명의 범주 내에 있는 것으로 이해된다).The nomenclature used in the embodiments is as follows (although the disclosed embodiment enantiomerically encompasses both pure (R) and racemic (R, S) structures, even if the stereochemistry of the 2- Arrangement is also understood to be within the scope of the present invention).
실시예 1: 메틸옥시카르보닐-L-발릴-N-[1-(2-[5-(t-부틸)-옥사디아졸릴]카르보닐)-2-(S)-메틸프로필]-L-프롤린아미드.Example 1: Methyloxycarbonyl-L-valyl-N- [1- (2- [5- (t-butyl) -oxadiazolyl] carbonyl) -2- (S) Proline amide.
실시예 2: 메틸옥시카르보닐-L-발릴-N-[1-(2-[5-(α,α-디메틸벤질)-옥사디아졸릴]카르보닐)-2-(S)-메틸프로필]-L-프롤린아미드.Example 2: Methyloxycarbonyl-L-valyl-N- [1- (2- [5- (α, α-dimethylbenzyl) -oxadiazolyl] carbonyl) -2- (S) Lt; / RTI >
실시예 3: 메틸옥시카르보닐-L-발릴-N-[1-(2-[5-(α,α-디메틸-3,4-메틸렌디옥시벤질)-1,3,4-옥사디아졸릴]카르보닐)-2-(S)-메틸프로필]-L-프롤린아미드.Example 3: Synthesis of methyloxycarbonyl-L-valyl-N- [1- (2- [5- (?,? -Dimethyl-3,4-methylenedioxybenzyl) -1,3,4-oxadiazolyl ] Carbonyl) -2- (S) -methylpropyl] -L-prolinamide.
실시예 4: 2-[6-옥소-2-(4-플루오로페닐)-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-t-부틸-1,3,4-옥사디아졸릴]카르보닐)-2-(S)-메틸프로필]아세트아미드.Example 4: Preparation of 2- [6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [ 1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide.
실시예 5: 2-[5-벤질옥시카르보닐아미노-6-옥소-2-(4-플루오로페닐)-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-(α,α-디메틸-3,4-메틸렌디옥시벤질)-1,3,4-옥사디아졸릴]카르보닐)-2-(S)-메틸프로필]아세트아미드.Example 5: Synthesis of 2- [5-benzyloxycarbonylamino-6-oxo-2- (4-fluorophenyl) -1, 6-dihydro-1-pyrimidinyl] - [5- (α, α-dimethyl-3,4-methylenedioxybenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide.
실시예 6: 2-[5-아미노-6-옥소-2-(4-플루오로페닐)-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-(α,α-디메틸-3,4-메틸렌디옥시벤질)-1,3,4-옥사디아졸릴]카르보닐)-2-(R,S)-메틸프로필]아세트아미드.Example 6: 2- [5-Amino-6-oxo-2- (4-fluorophenyl) -1, 6- dihydro- 1 -pyrimidinyl] -N- [ (α, α-dimethyl-3,4-methylenedioxybenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide.
실시예 7: 2-[5-벤질옥시카르보닐아미노-6-옥소-2-페닐-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-(α,α-디메틸-3,4-메틸렌디옥시벤질)-1,3,4-옥사디아졸릴]카르보닐)-2-(S)-메틸프로필]아세트아미드.Example 7: Preparation of 2- [5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- ,? -dimethyl-3,4-methylenedioxybenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide.
실시예 8: 2-[5-아미노-6-옥소-2-페닐-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-(α,α-디메틸-3,4-메틸렌디옥시벤질)-1,3,4-옥사디아졸릴]카르보닐)-2-(R,S)-메틸프로필]아세트아미드.Example 8: 2- [5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- -3,4-methylenedioxybenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide.
실시예 9: 2-[6-옥소-2-페닐-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-(α,α-디메틸-3,4-메틸렌디옥시벤질)-1,3,4-옥사디아졸릴]카르보닐)-2-(R,S)-메틸프로필]아세트아미드.Example 9: 2- [6-Oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- - methylenedioxybenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide.
실시예 10: 2-[6-옥소-2-(4-플루오로페닐)-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-(α,α-디메틸-3,4-메틸렌디옥시벤질)-1,3,4-옥사디아졸릴]카르보닐)-2-(R,S)-메틸프로필]아세트아미드.Example 10: 2- [6-Oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- -Dimethyl-3,4-methylenedioxybenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide.
실시예 11: 2-[6-옥소-2-(4-플루오로페닐)-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-(α,α-디메틸벤질)-1,3,4-옥사디아졸릴]카르보닐)-2-(R,S)-메틸프로필]아세트아미드.Example 11: 2- [6-Oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- -Dimethylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide.
실시예 12: 2-[6-옥소-2-페닐-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-(α,α-디메틸벤질)-1,3,4-옥사디아졸릴]카르보닐)-2-(R,S)-메틸프로필]아세트아미드.Example 12: 2- [6-Oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- , 3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide.
실시예 13: 2-[5-메틸옥시카르보닐아미노-6-옥소-2-페닐-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-(t-부틸)-1,3,4-옥사디아졸릴]카르보닐)-2-(R,S)-메틸프로필]아세트아미드.Example 13: 2- [5-Methyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- -Butyl) -1,3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide.
본 발명의 화합물은 인간 엘라스타제의 저해에만 그 용도가 제한되지는 않는다. 엘라스타제는 세린 프로테아제라고 공지된 효소군에 속하는 구성원이다. 또한, 이 효소군에는 예를 들어 키모트립신, 카텝신 G, 트립신 및 트롬빈이 포함된다. 이들 프로테아제는 공통적으로 세린-195, 히스티딘-57 및 아스파르트산-102(키모트립신 넘버링 시스템)로 이루어진 촉매 트리아드를 갖는다. 이러한 아미노산 잔기들 사이에 존재하는 정밀한 수소 결합 네트워크로 인해서 세린-195 히드록실기는 아미드 기질의 카르보닐과 함께 사면체의 중간체를 형성한다. 이러한 중간체가 분해되면서 유리 아민과 아실화된 효소가 방출된다. 그 다음 단계에서, 이 새로이 형성된 에스테르가 가수분해되어 본래의 효소 및 카르복실산이 생성된다. 효소의 특이성을 특성화하도록 돕는 것은 카르복실 성분이다 . 카르복실 성분이 펩티드인 경우, 아미노산의 알파-치환체가 효소에 대한 특이성과 주로 관련이 있다. 섹터(Schechter) 및 베르거(Berger)의 문헌[Biochem. Biophy. Res. Commun., 27:157(1967)] 및 [Biochem. Biophys. Res. Commun., 32:898(1968)]에서 인증된 명명법을 사용하면, 절단되는 기질내 아미노산 잔기는 N-말단에 대해서 P1…Pn라고 정의되고, C-말단에 대해서 P1'…Pn'라고 정의된다. 따라서, 펩티드 서브유닛의 P1잔기와 P1'잔기 사이의 결합은 끊어지기 쉬운 결합(scissile bond)이다. 기질의 서브유닛을 수용하는 결합 포켓(binding pocket)을 구성하는 효소의 아미노산 잔기에 대해서도 이와 유사한 명명법이 사용되고, 효소의 결합 포켓은 기질에 대해서 P1…Pn대신에 S1…Sn으로 표시된다.The compounds of the present invention are not limited only to the inhibition of human elastase. Elastases are members of the enzyme family known as serine proteases. This enzyme group also includes, for example, chymotrypsin, cathepsin G, trypsin and thrombin. These proteases commonly have a catalytic triad consisting of serine-195, histidine-57 and aspartic acid-102 (chymotrysin numbering system). Due to the precise hydrogen bonding network present between these amino acid residues, the serine-195 hydroxyl group forms a tetrahedral intermediate with the carbonyl of the amide substrate. These intermediates decompose, releasing free amines and acylated enzymes. In the next step, this newly formed ester is hydrolyzed to produce the native enzyme and carboxylic acid. It is the carboxyl component that helps characterize the enzyme's specificity. When the carboxyl component is a peptide, the alpha-substituent of the amino acid is mainly related to the specificity for the enzyme. Sectors (Schechter and Berger, Biochem. Biophy. Res. Commun., 27: 157 (1967) and Biochem. Biophys. Res. Commun., 32: 898 (1968)), the amino acid residues in the substrate to be cleaved can be cleaved at the P 1 ... P n , and P 1 'for the C-terminal. P n '. Thus, the bond between the P 1 residue and the P 1 'residue of the peptide subunit is a scissile bond. Also in binding amino acid residues of the enzyme that make up the pocket (binding pocket) for accommodating the subunits of the substrate is similar nomenclature is used, the binding pocket of the enzyme with respect to the substrate P 1 ... Instead of P n , S 1 ... S n .
세린 프로테이나제 특이성을 결정짓는 P1잔기의 특징은 잘 규명되어 있다. 프로테이나제는 P1잔기의 차이에 따라 엘라스타제, 키마제 및 트립타제의 세개의 하위 군(subclass)으로 분류된다. 엘라스타제는 발린과 같은 작은 지방족 잔기를 우선적으로 갖는 반면에, 키마제 및 트립타제는 각각 큰 방향족 소수성 잔기 및 양 하전된 잔기를 우선적으로 갖는다.The characteristics of the P 1 residue that determines the serine protease specificity are well characterized. Proteinases are classified into three subclasses: elastase, chymase, and tryptase, depending on the difference in P 1 residues. Elastases preferentially have small aliphatic moieties such as valine, while chymase and tryptase preferentially have large aromatic hydrophobic moieties and positively charged moieties, respectively.
이러한 카테고리에 속하지 않는 또다른 프로테이나제는 프로필 엔도펩티다제이다. 특이성을 결정짓는 P1잔기는 프롤린이다. 이 효소는 알쯔하이머병 환자의 기억력 상실의 진행에 관여한다. 근래에 α-케토 헤테로사이클로 이루어지는 저해제가 프로필 엔도펩티다제를 저해한다는 것으로 밝혀졌다[Tsutsumi et al. J. Med. Chem., 37, 3492-3502(1994)]. 부연 설명하면, 여기서 정의된 α-케토 헤테로사이클은 효소의 P' 영역에서의 결합을 증가시킨다.Another proteinase not belonging to this category is the profile endopeptidase. The P 1 residue that determines the specificity is proline. This enzyme is involved in the progression of memory loss in Alzheimer's disease patients. It has recently been found that inhibitors consisting of? -Ketoheterocycles inhibit the profile endopeptidase (Tsutsumi et al. J. Med. Chem., 37, 3492-3502 (1994)). In other words, the [alpha] -ketoheterocycle defined herein increases binding in the P ' region of the enzyme.
P1잔기가 기질의 특이성을 우선적으로 결정짓기 때문에, 본 발명은 P1-Pn'의 변형, 특히 1,2,4-옥사디아졸 및 1,3,4-옥사디아졸을 포함하는 특정 알파-치환된 케토 헤테로사이클에 관한 것이다. 알파-치환체를 케톤으로 변경시키고 헤테로사이클상의 치환체를 어느 정도 변경시킴으로써, 본 발명의 화합물의 특이성을 목적하는 프로테이나제에 맞출 수 있다 (예를 들면, 엘라스타제에 대해서는 작은 지방족 기).Since the P 1 residue predominantly determines the specificity of the substrate, the present invention relates to a modification of P 1 -P n ', particularly to a specific one comprising 1,2,4-oxadiazole and 1,3,4-oxadiazole Alpha-substituted ketoheterocycle. By varying the alpha-substituent to the ketone and to some extent the substituents on the heterocycle, the specificity of the compounds of the invention can be tailored to the desired proteinase (e. G., A small aliphatic group for elastase).
다양한 질병을 치료하기 위한 화합물의 효능은 당업계에 공지된 과학적인 방법에 의해 결정될 수 있다. HNE 매개된 질환의 예는 다음과 같다:The efficacy of compounds for treating various diseases can be determined by scientific methods known in the art. Examples of HNE mediated diseases include:
- 급성 호흡 곤란 증후군: 인간 호중구 엘라스타제(HNE) 모델(AARD, 141:227-677(1990))에 따른 방법; 미니 돼지(minipig)에서의 엔도톡신 유도된 급성 폐 손상 모델(AARD, 142:782-788(1990))에 따른 방법; 또는 햄스터에서의 인간 다형핵성 엘라스타제-유도된 폐 출혈 모델(유럽 특허 공개 제 0769498 호)에 따른 방법이 사용될 수 있다;- acute respiratory distress syndrome: a method according to the human neutrophil elastase (HNE) model (AARD, 141: 227-677 (1990)); A method according to the endotoxin induced acute lung injury model (AARD, 142: 782-788 (1990)) in a minipig; Or a method according to a human polymorphonuclear elastase-induced pulmonary hemorrhage model in a hamster (European Patent Publication No. 0769498) can be used;
- 허혈/재관류: 재관류 손상의 개 모델 (J. Clin. Invest., 81:624-629(1988))에 따른 방법이 사용될 수 있다.- Ischemia / reperfusion: a method according to the dog model of reperfusion injury (J. Clin. Invest., 81: 624-629 (1988)) may be used.
본 발명의 화합물, 그의 염 및 그의 중간체를 본원에 기술된 방법 또는 화학 분야에 공지된 다양한 방법으로 제조할 수 있다(WO 96/16080을 참조).The compounds of the present invention, salts thereof and intermediates thereof can be prepared by the methods described herein or by various methods known in the chemical arts (see WO 96/16080).
한편으로는, 본 발명의 화합물을 도 1, 2 및 3에 도시된 바와 같이 제조할 수 있다. 도 1은 본 발명에서 사용된 Boc 보호된 아미노 알콜 중간체의 합성에 관한 것이다. 도 2 및 도 3은 이 중간체를 사용하여 본 발명의 화합물을 합성하는 과정을 보여준다.On the other hand, the compounds of the present invention can be prepared as shown in FIGS. 1, 2 and 3. Figure 1 relates to the synthesis of the Boc protected aminoalcohol intermediates used in the present invention. Figures 2 and 3 show the process of synthesizing the compounds of the present invention using this intermediate.
2-치환된 1,3,4-옥사디아졸 (3)은 예를 들면 염화티오닐 및 메탄올을 이용하여 상응하는 산 (1)으로부터 메틸 에스테르를 생성시킨 후, 적합한 용매 중에서 히드라진으로 처리함으로써 히드라존산 (2)을 생성시켜 제조할 수 있다. 별법으로, 에스테르는 당업자에게 공지된 방법 또는 문헌[Comprehensive Organic Transformations(R. Larock, VCH Publishers 1989, 966-972)]에 기술된 방법으로 제조할 수 있다. 트리에틸 오르토포르메이트 또는 트리메틸 오르토포르메이트와 TsOH의 반응 (2)에 의해서 목적하는 2-치환된 1,3,4-옥사디아졸 (3)이 생성된다.The 2-substituted 1,3,4-oxadiazole (3) can be obtained, for example, by using thionyl chloride and methanol to produce the methyl ester from the corresponding acid (1), followed by treatment with hydrazine in a suitable solvent, (2). ≪ / RTI > Alternatively, the esters can be prepared by methods known to those skilled in the art or by the methods described in Comprehensive Organic Transformations (R. Larock, VCH Publishers 1989, 966-972). The desired 2-substituted 1,3,4-oxadiazole (3) is produced by the reaction (2) of triethylorthoformate or trimethylorthoformate with TsOH.
표준 조건(예를 들면 저온에서 극성 비양성자성 용매 중에서 부틸리튬 또는 기타 공지된 알킬 리튬 시약을 사용하고, 경우에 따라 추가로 MgBr·OEt2와 반응시킴)을 사용하여 중간체 (3')를 형성한 후, 이를 알데히드 (4)에 첨가하여 알콜 (5)을 얻을 수 있다.Forming the intermediate layer 3 'by using the standard conditions (e. G. A polar non-positive at low magnetic solvents, butyl lithium or other known alkyl, a lithium reagent, additional MgBr · OEt 2 and reaction in some cases Sikkim) , Which can then be added to the aldehyde (4) to give the alcohol (5).
알데히드 (4)를 도 1에 도시된 3가지 방법 중 어느 한 방법으로 제조할 수 있다. 그중 한 방법에서는 Boc-Val-OH와 이소-프로필클로로포르메이트 사이에 형성된 중간체를 수소화붕소나트륨으로써 환원시켜 Boc-발리놀 (12)을 얻는다. 다음 단계에서 Boc-발리놀을 DMSO 중에서 SO3-Py로 산화시켜 알데히드 (4)를 얻는다. 또다른 방법에서는 Boc-Val-OH (11)로부터 제조된 웨인렙(Weinreb) 아미드 (13)를 취하고 이를 디이소부틸알루미늄 히드라이드(DIBAL)를 이용하여 환원시켜 알데히드를 얻는다. 별법으로, 아미노산의 에스테르(14)를 생성시킨 후, DIBAL로 환원시켜 알데히드 (14)를 얻을 수도 있다.The aldehyde (4) can be prepared by any one of the three methods shown in Fig. In one of these methods, an intermediate formed between Boc-Val-OH and iso-propyl chloroformate is reduced with sodium borohydride to give Boc-valinol (12). In the next step, Boc-valinol is oxidized with SO 3 -Py in DMSO to give aldehyde (4). In another method, Weinreb amide (13) prepared from Boc-Val-OH (11) is taken and reduced with diisobutyl aluminum hydride (DIBAL) to obtain aldehyde. Alternatively, an ester 14 of an amino acid can be generated and then reduced to DIBAL to give the aldehyde 14.
도 2 및 도 3에 도시된 바와 같이, 디옥산 중의 염산을 사용하여 아민 (5)을 탈보호시켜 아미노 히드로클로라이드 (6)를 얻고, 이를 당업자에게 공지된 방법을 사용해 목적하는 산 (7) 또는 (7')으로 커플링시켜 중간체 (8) 또는 (8')를 얻는다. 스원(Swern) 산화법, 데스-마틴의 페리오디난(Dess-Martin's Periodinane) 또는 문헌[Oxidation in Organic Chemistry (M. Hudlicky, ACS Monograph 186(1990)]에 기술된 기타 산화 방법을 사용하여 목적하는 케톤 (9) 또는 (9')를 얻는다.As shown in Figures 2 and 3, the amine 5 is deprotected using hydrochloric acid in dioxane to give the amino hydrochloride 6, which can be converted to the desired acid 7 using the methods known to those skilled in the art, (7 ') to give intermediate (8) or (8'). Other oxidation methods as described in Swern oxidation, Dess-Martin's Periodinane, or Oxidation in Organic Chemistry (M. Hudlicky, ACS Monograph 186 (1990)), (9) or (9 ').
화합물이 피리미디논기의 5번 위치에서 벤질옥시카르보닐아미노기로 치환된 경우, 도 3에 도시된 바와 같이 탈보호 단계를 수행할 수 있다. 이 단계에서는 아민으로부터 보호기를 제거해야 하며, 이는 많은 방법으로 수행할 수 있다. 예를 들면, 디클로로메탄과 같은 적합한 용매 중에서 알루미늄 클로라이드, 아니솔 및 니트로메탄을 사용하여 5-아미노 화합물 (10')을 얻을 수 있다. 당업계에서 사용되는 또다른 탈보호 방법을 사용할 수도 있다.When the compound is substituted with the benzyloxycarbonylamino group at the 5-position of the pyrimidone group, the deprotection step can be performed as shown in FIG. In this step the protecting group must be removed from the amine, which can be done in a number of ways. For example, the 5-amino compound (10 ') can be obtained using aluminum chloride, anisole and nitromethane in a suitable solvent such as dichloromethane. Other deprotection methods used in the art may also be used.
본원에서 기술된 화합물을 순수한 화합물로서 투여할 수도 있지만, 활성 성분을 약학 조성물로 제공하는 것이 바람직하다. 따라서, 본 발명은 하나 이상의 화합물과 함께 하나 이상의 약학적으로 허용되는 담체 및 임의의 기타 치료 및/또는 예방 성분을 포함하는 약학 조성물을 제공한다. 담체는 조성물의 다른 성분들과 혼화성이고 투여 대상에게 해로운 것이 아니어야 한다는 점에서 "허용가능한" 것이어야 한다.While the compounds described herein may be administered as a pure compound, it is desirable to provide the active ingredient in a pharmaceutical composition. Accordingly, the present invention provides pharmaceutical compositions comprising one or more compounds together with one or more pharmaceutically acceptable carriers and any other therapeutic and / or prophylactic component. The carrier should be " acceptable " in the sense that it must be miscible with the other ingredients of the composition and not deleterious to the subject of administration.
약학 조성물은 경구 투여 또는 비경구 투여(근육내, 피하 및 정맥내 투여를 포함)에 적합한 조성물을 포함한다. 조성물은 경우에 따라서는 개별 단위 제형으로서 간편하게 제공되거나, 약학 분야에 공지된 임의의 방법에 의해 제조될 수 있다. 이러한 방법에는 활성 화합물을 액체 담체, 고체 매트릭스, 반고체 담체, 미분된 고체 담체 또는 이들의 혼합물과 조합하고, 이어서 경우에 따라 생성물을 목적하는 전달 시스템으로 성형시키는 단계가 포함된다.The pharmaceutical compositions include compositions suitable for oral or parenteral administration, including intramuscular, subcutaneous and intravenous administration. The compositions may conveniently be provided as individual unit dosage forms, or may be prepared by any method known in the art of pharmacy. Such methods include combining the active compound with a liquid carrier, a solid matrix, a semi-solid carrier, a finely divided solid carrier or a mixture thereof, and then optionally shaping the product into the desired delivery system.
경구 투여에 적합한 약학 조성물은 각각 소정량의 활성 성분을 함유하는 경질 또는 연질 젤라틴 캡슐, 카세제(cachet) 또는 정제와 같은 개별 단위 제형; 분말 또는 과립; 용액, 현탁액 또는 유화액으로서 제공될 수 있다. 활성 성분은 볼러스(bolus), 지제(electuary) 또는 패이스트로서 제공될 수 있다. 경구 투여를 위한 정제 및 캡슐은 결합제, 충전제, 윤활제, 붕해제 또는 습윤제와 같은 통상적인 부형제를 함유할 수 있다. 정제는 당업계에 공지된 방법에 따라 코팅될 수 있다(예를 들면 장용성 코팅).Pharmaceutical compositions suitable for oral administration may be presented as discrete unit dosage forms, such as hard or soft gelatine capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; Powder or granules; Solution, suspension or emulsion. The active ingredient may be provided as a bolus, an electuary or a paste. Tablets and capsules for oral administration may contain conventional excipients such as binders, fillers, lubricants, disintegrating or wetting agents. The tablets may be coated according to methods known in the art (e. G. Enteric coatings).
경구용 액체 제제는 예를 들면 수성 또는 유성 현탁액, 용액, 유화액, 시럽 또는 엘릭시르제(elixir)의 형태일 수 있고, 사용 전에 물 또는 기타 적합한 비히클에 타서 사용하기 위한 건조 제품으로서 제공될 수도 있다. 이러한 액체 제제는 현탁제, 유화제, 비-수성 비히클(식용 오일을 포함할 수도 있다) 또는 보존제와 같은 통상적인 첨가제를 함유할 수도 있다.Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, and may be presented as a dry product for use in water or other suitable vehicles prior to use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils) or preservatives.
본 발명의 화합물은 비경구 투여(예를 들면 주사, 예를 들면 볼러스 주사 또는 연속 주입)용으로도 제제화될 수 있으며, 앰퓰, 기충전된 주사기, 소형 볼러스 주입 용기 또는 다회-투여 용기 내에 보존제와 함께 담긴 단위 투여 제형으로서 제공될 수도 있다. 조성물은 유성 또는 수성 비히클 중의 현탁액, 용액 또는 유화액과 같은 형태를 취할 수도 있고, 현탁제, 안정화제 및/또는 분산제와 같은 배합제를 함유할 수 있다. 별법으로, 활성 성분은 사용 전에 적합한 비히클, 예를 들면 발열 물질을 함유하지 않는 멸균수에 타서 사용하는, 멸균 고체의 무균 단리 또는 용액으로부터의 동결건조에 의해 얻어진 분말 형태일 수 있다.The compounds of the present invention may also be formulated for parenteral administration (e. G., Injection, e. G., Bolus injection or continuous infusion) and may be administered in ampoules, pre-filled syringes, small bolus injection containers, or multi- May also be presented as unit dosage forms packed with a preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form obtained by aseptic isolation of sterile solid or lyophilization from solution, which is used in a suitable vehicle, e. G., Sterile water free of pyrogen, prior to use.
표피에 국소 투여하기 위해서, 화합물은 연고, 크림 또는 로션으로서, 또는 경피 패치제의 활성 성분으로서 제제화될 수도 있다. 적합한 경피 전달 시스템이 예를 들면 피셔(Fisher) 등의 미국 특허 제 4,788,603호 또는 바와스(Bawas) 등의 미국 특허 제 4,931,279 호, 제 4,668,504 호 및 제 4,713,224 호에 개시되어 있다. 연고 및 크림은 예를 들면, 적합한 증점제 및/또는 겔화제가 첨가된 수성 또는 유성 베이스와 제제화될 수 있다. 로션은 수성 또는 유성 베이스와 제제화될 수 있고, 일반적으로는 1종 이상의 유화제, 안정화제, 분산제, 현탁제, 증점제 또는 착색제를 함유한다. 활성 성분은 예를 들면 미국 특허 제 4,140,122호, 제 4,383,529호 또는 제 4,051,842호에 개시된 바와 같이, 이온영동법(iontophoresis)에 의해 전달될 수 있다.For topical administration to the epidermis, the compound may be formulated as an ointment, cream or lotion, or as an active ingredient in a transdermal patch. Suitable transdermal delivery systems are described, for example, in US Pat. No. 4,788,603 to Fisher et al. Or US Pat. Nos. 4,931,279, 4,668,504 and 4,713,224 to Bawas et al. Ointments and creams may, for example, be formulated with an aqueous or oily base to which suitable thickening and / or gelling agents have been added. Lotions may be formulated with an aqueous or oily base and generally contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents or coloring agents. The active ingredient may be delivered by iontophoresis, for example, as disclosed in U.S. Patent Nos. 4,140,122, 4,383,529 or 4,051,842.
구강 내에 국소 투여하기에 적합한 조성물에는, 활성 성분을 향미 베이스, 통상적으로는 수크로스 및 아카시아 또는 트라가칸트(tragacanth) 내에 포함하는 로젠지제와 같은 단위 제형; 활성 성분을 젤라틴 및 글리세린 또는 수크로스 및 아카시아와 같은 불활성 베이스 내에 포함하는 트로키제(pastille); 점착성 겔 및 활성 성분을 적합한 액체 담체 내에 포함하는 구강세정제(mouthwashes)가 포함된다.Compositions suitable for topical administration in the mouth include unit dosage forms such as lozenges comprising the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; Pastilles wherein the active ingredient is contained in an inert base such as gelatin and glycerin or sucrose and acacia; Mouthwashes comprising a viscous gel and an active ingredient in a suitable liquid carrier.
경우에 따라서는, 상기한 조성물은 예를 들어 천연 겔, 합성 중합체 겔 또는 그의 혼합물을 포함하는 특정 친수성 중합체 매트릭스와 조합하여, 이용되는 활성 성분을 서서히 방출하도록 배합될 수 있다.In some cases, the composition may be formulated to release the active ingredient used in combination with a particular hydrophilic polymer matrix, including, for example, a natural gel, a synthetic polymer gel, or a mixture thereof.
본 발명에 따른 약학 조성물은 향미제, 착색제, 항균제 또는 보존제와 같은 기타 보조제를 함유할 수도 있다.The pharmaceutical compositions according to the invention may also contain other adjuvants such as flavors, coloring agents, antimicrobial agents or preservatives.
치료에 사용되도록 요구되는 화합물, 또는 그의 활성 염 또는 유도체의 양은 선택된 특정 염뿐만 아니라 투여 경로, 치료할 질환의 성질, 환자의 연령 및 상태에 따라 달라질 것이며 궁극적으로는 담당 의사 또는 임상의의 판단에 따른다는 것을 알아야 한다.The amount of a compound, or an active salt or derivative thereof, which is required to be used in the treatment will vary depending on the route of administration, the nature of the disease to be treated, the age and condition of the patient and ultimately the judgment of the attending physician or clinician .
그러나, 일반적으로는 적합한 투여량은 약 0.5 내지 약 100 ㎎/㎏/일, 예를 들면 1일당 체중 1 ㎏당 약 1 내지 약 75 ㎎, 예를 들면 1일당 환자의 체중 1 ㎏당 3 내지 약 50 ㎎의 범위 내에 있으며, 바람직하게는 6 내지 90 ㎎/㎏/일, 가장 바람직하게는 15 내지 60 ㎎/㎏/일의 범위에 있다.In general, however, a suitable dosage is about 0.5 to about 100 mg / kg / day, for example about 1 to about 75 mg / kg of body weight per day, such as about 3 to about 100 mg / 50 mg, preferably in the range of 6 to 90 mg / kg / day, most preferably in the range of 15 to 60 mg / kg / day.
화합물은 편리하게는 단위 제형으로서 투여되는데, 예를 들면 단위 제형당 활성 성분을 0.5 내지 1000 ㎎, 편리하게는 5 내지 750 ㎎, 가장 편리하게는 10 내지 500 ㎎ 포함하는 형태로 투여된다.The compound is conveniently administered as a unit dosage form, for example in the form of containing 0.5 to 1000 mg, conveniently 5 to 750 mg, most conveniently 10 to 500 mg of active ingredient per unit dosage form.
이상적으로는 활성 성분은 약 0.5 내지 약 75 μM, 더욱 바람직하게는 약 1 내지 50 μM, 가장 바람직하게는 약 2 내지 약 30 μM의 최대 혈장 농도에 이르도록 투여되어야 한다. 이는 예를 들면, 활성 성분을 임의로 식염수 중 0.05 내지 5% 용액으로서 정맥내 주사하거나, 활성 성분을 약 0.5 내지 500 ㎎ 함유하는 볼러스로서 경구 투여하여 달성할 수 있다. 활성 성분을 약 0.01 내지 5.0 ㎎/㎏/hr을 제공하기 위해 연속 주입하거나 활성 성분을 약 0.4 내지 15 ㎎/㎏ 함유하는 간헐적 주입에 의해 목적 혈액 수준을 유지할 수 있다.Ideally, the active ingredient should be administered to reach a maximum plasma concentration of about 0.5 to about 75 [mu] M, more preferably about 1 to 50 [mu] M, and most preferably about 2 to about 30 [mu] M. This can be achieved, for example, by intravenous injection of the active ingredient optionally as a 0.05 to 5% solution in saline or by oral administration as a bolus containing about 0.5 to 500 mg of active ingredient. May be continuously injected to provide about 0.01 to 5.0 mg / kg / hr of the active ingredient, or the target blood level may be maintained by intermittent infusion containing about 0.4 to 15 mg / kg of the active ingredient.
목적하는 투여량을 1회 투여하거나 적당한 시간 간격으로 분할 투여, 예를 들어 소단위-투여량(sub-dose)을 하루에 2, 3, 4 또는 그 이상으로 나누어 투여함으로써 편리하게 제공할 수 있다. 소단위-투여량 자체를 더욱 분할하여 투여할 수도 있는데, 예를 들어 흡입기로부터 여러번 흡입하는 방법 또는 안구에 여러번 적하하는 방법과 같이 개별적으로 여러번 넓은 시간 간격을 두고 투여할 수 있다.It may conveniently be provided by administering the desired dose in a single dose or in divided doses at appropriate time intervals, for example by subdosing two, three, four or more sub-doses per day. The sub-dose-dose itself may be administered in divided doses, such as multiple inhalation doses from an inhaler or multiple drops in the eye, each at multiple time intervals.
본 발명을 그의 특정 실시양태과 관련하여 기술하였지만, 이를 추가로 변경할 수 있으며, 일반적으로 본 발명의 원리를 따르고, 본 발명의 관련 분야 내의 공지된 또는 통상적인 실시에 포함되고, 이제까지 기술된 필수 사항에 적용되고, 첨부된 청구항의 범위에 따르는 것들을 포함하는, 본 발명의 임의의 변경, 사용 또는 변형을 망라하도록 의도된 것으로 이해된다.Although the present invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and is to be accorded the widest scope consistent with the principles of the invention, It is to be understood that the invention is intended to cover any modifications, uses, or variations of the present invention, including those that are applicable and conform to the scope of the appended claims.
다음의 실시예는 본 발명을 예시하려는 것이지 어떠한 방식으로라도 제한하고자 하는 것은 아니다.The following examples are intended to illustrate the invention and not to limit it in any way.
본 발명의 화합물, 그의 염 및 그의 중간체를 본원에서 기술된 방법 또는 화학 분야에 공지된 다양한 방법으로 제조할 수 있다. 예를 들면, 본원에서 정의된 공정의 최종 단계는 2°알콜을 케톤으로 산화시키는 것이다. 본원에서 기술된 바와 같이, 이러한 알콜에서 케톤으로의 산화는, 디메틸설폭사이드 및 옥살릴 클로라이드를 사용한 후 염기를 사용하는 스원 산화법으로 공지된 방법을 사용하여 수행하였다. 그러나, 이러한 스원 산화법의 변형법도 당업계에 공지되어 있으며, 본 발명에서도 허용된다. 디사이클로헥실카르보디이미드, 아세트산 무수물, 트리플루오로아세트산 무수물 또는 설퍼 트리옥사이드와 같은 기타 친전자성 분자가 옥살릴 클로라이드 대신에 사용될 수 있다는 것이 알려져 있다(만쿠소(Mancuso) 등의 문헌[Synthesis 165(1981)]을 참조). 별법으로, 본 발명의 발명자의 미국 특허 제 5,618,792호에 기술된 바와 같이, N-클로로숙신이미드(NCS) 사용후 염기를 사용하는 방법 또는 데스-마틴 시약과 같은 페리오디난과 같은 기타 산화 방법을 사용할 수도 있다. 문헌[앰 후들릭키(M.Hudlicky), Oxidation in Organic Chemistry, ACS Monograph 186(1990)]에 기술된 또다른 방법들이 적당할 수도 있다.The compounds of the present invention, salts thereof and intermediates thereof can be prepared by the methods described herein or by various methods known in the chemical arts. For example, the final step of the process defined herein is to oxidize the 2 ° alcohol to the ketone. As described herein, the oxidation of these alcohols to ketones was carried out using dimethylsulfoxide and oxalyl chloride followed by known methods for the Sueon oxidation using bases. However, such a modification of the Suwon oxidation method is also known in the art and is allowed in the present invention. It is known that other electrophilic molecules such as dicyclohexylcarbodiimide, acetic anhydride, trifluoroacetic anhydride or sulfur trioxide can be used instead of oxalyl chloride (Mancuso et al., Synthesis 165 (1981)]. Alternatively, as described in U.S. Patent No. 5,618,792 to the inventors of the present invention, a method of using a base after the use of N-chlorosuccinimide (NCS) or other oxidation methods such as periodin May be used. Other methods described in M. Hudlicky, Oxidation in Organic Chemistry, ACS Monograph 186 (1990), may be suitable.
후술될 방법외에 다른 방법을 사용해서, 치환된 옥사디아졸 비펩티드를 제조할 수 있다. 본원에서 참고로 인용된 미국 특허 제 5,807,829 호는 치환된 옥사디아졸 비펩티드를 제조하는 또다른 몇가지 방법들을 교시한다.Substituted oxadiazole non-peptides can be prepared using methods other than those described below. U.S. Patent No. 5,807,829, which is incorporated herein by reference, teaches several other methods for preparing substituted oxadiazole non-peptides.
숙련된 기술자들이라면 특정 에난티오머가 언급된 경우에서 에난티오머 또는 에난티오머의 혼합물이 사용될 수 있음을 알 것이다.It will be appreciated by those skilled in the art that mixtures of enantiomers or enantiomers may be used where a particular enantiomer is mentioned.
기호들은 당업자들이 잘 알고 있는 표준 의미를 가지며, 예를 들면 ㎖는 밀리리터, g는 그램, TLC는 박막 크로마토그래피, Rf는 TLC 플레이트상에서 동일한 시간 동안 화합물이 이동한 거리 대 용매 머리가 이동한 거리의 비,1H NMR은 양성자 핵 자기 공명, DMSO-d6은 듀테로디메틸설폭사이드이고 CDCl3는 듀테로클로로로포름이다.The symbols have standard meanings well known to those skilled in the art, such as ml, milligrams, grams, TLC, thin film chromatography, R f is the distance that the compound migrated over the same time on the TLC plate, , 1 H NMR is proton nuclear magnetic resonance, DMSO-d 6 is diterodimethyl sulfoxide and CDCl 3 is deuterochloroform.
＜실시예 1: 메틸옥시카르보닐-L-발릴-N-[1-(2-[5-(t-부틸)-옥사디아졸릴]카르보닐)-2-(S)-메틸프로필]-L-프롤린아미드＞Example 1: Methyloxycarbonyl-L-valyl-N- [1- (2- [5- (t-butyl) -oxadiazolyl] carbonyl) -2- (S) - proline amide>
2차 알콜인 메틸옥시카르보닐-L-발릴-N-[1-(2-[5-(t-부틸)-옥사디아졸릴]히드록시메틸)-2-(S)-메틸프로필]-L-프롤린아미드를 스원 산화법과 같이 당업자에게 공지된 방법 중 하나를 사용하여 산화시켰다. 중간체인 메틸옥시카르보닐-L-발릴-N-[1-(2-[5-(t-부틸)-옥사디아졸릴]히드록시메틸)-2-(S)-메틸프로필]-L-프롤린아미드를 다음과 같이 제조하였다:2- (S) -methylpropyl] -L (2- [5- (t-butyl) -oxadiazolyl] hydroxymethyl) -2- -Pro- < / RTI > amide was oxidized using one of the methods known to those skilled in the art, such as the Suwon oxidation. 2- (S) -methylpropyl] -L-proline < / RTI > Amide was prepared as follows:
A. t-부틸카르보히드라존산A. t-Butyl Carbohydrazone
메틸 트리메틸아세테이트 (230㎖)와 히드라진 모노히드레이트 (170㎖)의 혼합물을 24시간 동안 환류시켰다. 반응물을 실온으로 냉각시키고, 감압 하에서 농축시켰다. 잔여물을 톨루엔으로 수시간에 걸쳐 공비시키고, 염화나트륨 포화 수용액에 용해시키고, 클로로포름으로 4회 추출시켰다. 추출물을 무수 황산나트륨 상에서 건조시키고, 감압 하에서 농축시켜 하기 물리적 데이타를 나타내는 t-부틸카르보히드라존산 (176g)을 수득하였다.A mixture of methyl trimethyl acetate (230 ml) and hydrazine monohydrate (170 ml) was refluxed for 24 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was azeotroped with toluene over several hours, dissolved in a saturated aqueous solution of sodium chloride and extracted four times with chloroform. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give t-butylcarbhydrazonic acid (176 g) which exhibited the following physical data.
TLC: Rf=0.59, 클로로포름:메탄올(10:1)TLC: Rf = 0.59, chloroform: methanol (10: 1)
1H NMR(DMSO-d6):δ8.78(1H,brs), 4.15(2H, brs), 1.08(9H,s). 1 H NMR (DMSO-d 6 ): δ8.78 (1H, brs), 4.15 (2H, brs), 1.08 (9H, s).
B. 2-t-부틸-1,3,4-옥사디아졸B. 2-t-Butyl-1,3,4-oxadiazole
t-부틸카르보히드라존산 (176g), 트리메틸 오르토포르메이트 (250㎖)와 p-톨루엔설폰산 모노히드레이트(4.3g)로 이루어진 혼합물을 가열하고 90 내지 110℃의 온도에서 증류시켜 메탄올을 제거하였다. 트리메틸 오르토포르메이트를 제거하고 (50℃/43mmHg), 잔여물을 120℃/23mmHg에서 증류시켜 하기 물리적 데이타를 나타내는 2-t-부틸-1,3,4-옥사디아졸(131g)을 수득하였다.A mixture of t-butylcarbhydrazonic acid (176 g), trimethylorthoformate (250 ml) and p-toluenesulfonic acid monohydrate (4.3 g) was heated and distilled at 90-110 ° C to remove methanol Respectively. The trimethylorthoformate was removed (50 C / 43 mm Hg) and the residue was distilled at 120 C / 23 mm Hg to give 2-t-butyl-1,3,4-oxadiazole (131 g) .
TLC: Rf=0.68, 클로로포름:메탄올(10:1)TLC: Rf = 0.68, chloroform: methanol (10: 1)
1H NMR(DMSO-d6):δ9.12(1H,s), 1.36(9H,s). 1 H NMR (DMSO-d 6 ): δ9.12 (1H, s), 1.36 (9H, s).
C. 1-[2-(5-t-부틸)-1,3,4-옥사디아졸릴]-2-(S)-(t-부톡시카르보닐아미노)-3-메틸부탄-1-올C. Synthesis of 1- [2- (5-t-butyl) -1,3,4-oxadiazolyl] -2- (S) - (t-butoxycarbonylamino)
-78℃에서 아르곤 대기 중에서, 테트라히드로푸란 (1650㎖) 중 2-t-부틸-1,3,4-옥사디아졸 (62.1g)의 용액에 헥산중 n-부틸리튬 용액 (1.6M, 307.8㎖)을 적가하였다. 이 혼합물을 -78℃에서 40분동안 교반하고, 마그네슘 브로마이드 디에틸 에테레이트(127.2g)를 첨가하고, 이렇게 얻은 혼합물을 -45℃로 가온시켰다. 1시간 30분이 지난 후, -45℃에서 테트라히드로푸란 (60㎖) 중 2-(S)-[N-(t-부톡시카르보닐)아미노]-3-메틸부탄알(90g)을 적가하고 -15℃로 가온시켰다. 이 반응 혼합물에 암모늄 클로라이드 포화 수용액을 첨가하여 급냉시키고, 에틸 아세테이트로 추출시켰다. 추출물을 물로 3회 세척하고 염화나트륨 포화 수용액으로 세척하고, 무수 황산나트륨상에서 건조시키고, 농축시켰다. 그 잔여물을 실리카겔상에서 칼럼 크로마토그래피(머크(Merck) 7734)(에틸 아세테이트:헥산=1:20 내지 1:1)에 의해 정제하여 하기 물리적 데이타를 나타내는 1-[2-(5-t-부틸)-1,3,4-옥사디아졸릴]-2-(S)-(t-부톡시카르보닐아미노)-3-메틸부탄-1-올 (78.6g)을 수득하였다.To a solution of 2-t-butyl-1,3,4-oxadiazole (62.1 g) in tetrahydrofuran (1650 ml) was added n-butyllithium solution in hexanes (1.6 M, 307.8 ML) was added dropwise. The mixture was stirred at -78 < 0 > C for 40 minutes, magnesium bromide diethyl etherate (127.2 g) was added and the mixture thus obtained was warmed to -45 < 0 > C. After 1 hour and 30 minutes, 2- (S) - [N- (t-butoxycarbonyl) amino] -3-methylbutanal (90 g) in tetrahydrofuran (60 ml) Lt; RTI ID = 0.0 > 15 C. < / RTI & The reaction mixture was quenched by the addition of a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The extracts were washed with water three times, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (Merck 7734) (ethyl acetate: hexane = 1: 20 to 1: 1) to give 1- [2- (5-t-butyl ) -1,3,4-oxadiazolyl] -2- (S) - (t-butoxycarbonylamino) -3-methylbutan-1-ol (78.6 g).
TLC: Rf=0.42, 헥산:에틸 아세테이트(1:1)TLC: Rf = 0.42, hexane: ethyl acetate (1: 1)
1H NMR(CDCl3):δ5.16-4.90(2H,m), 4.67(1H,m), 4.23(1H,m), 3.90(1H,m), 3.66(1H,m), 1.98(1H,m), 1.42, 1.41 및 1.36(총 18H, 각 s), 1.13-0.90(6H,m). 1 H NMR (CDCl 3): δ5.16-4.90 (2H, m), 4.67 (1H, m), 4.23 (1H, m), 3.90 (1H, m), 3.66 (1H, m), 1.98 (1H , m), 1.42, 1.41 and 1.36 (total 18H, angle s), 1.13-0.90 (6H, m).
D. 1-[2-(5-t-부틸)-1,3,4-옥사디아졸릴]-2-(S)-아미노-3-메틸부탄-1-올 히드로클로라이드D. Synthesis of 1- [2- (5-t-butyl) -1,3,4-oxadiazolyl] -2- (S) -amino-3-methylbutan-1-ol hydrochloride
0℃에서, 디옥산 (200㎖) 중 1-[2-(5-t-부틸)-1,3,4-옥사디아졸릴]-2-(S)-(t-부톡시카르보닐아미노)-3-메틸부탄-1-올 (76.3g)의 용액에 디옥산 (1000㎖)중 4N 염산 용액을 첨가하였다. 이 반응 혼합물을 감압 하에서 농축시켰다. 잔여물을 디에틸 에테르로 응고시켰다. 이렇게 얻은 고체를 벤젠으로 수시간에 걸쳐 공비시켜 하기 물리적 데이타를 나타내는 1-[2-(5-t-부틸)-1,3,4-옥사디아졸릴]-2-(S)-아미노-3-메틸부탄-1-올 히드로클로라이드 (66.1g)를 수득하였다.(5-t-butyl) -1,3,4-oxadiazolyl] -2- (S) - (t-butoxycarbonylamino) -3-methylbutan-1-ol (76.3 g) in dioxane (1000 ml) was added a solution of 4N hydrochloric acid in dioxane (1000 ml). The reaction mixture was concentrated under reduced pressure. The residue was coagulated with diethyl ether. The resulting solid was azeotroped with benzene over several hours to give 1- [2- (5-t-butyl) -1,3,4-oxadiazolyl] -2- (S) -Methylbutan-1-ol hydrochloride (66.1 g).
TLC: Rf=0.30, 클로로포름:메탄올(10:1)TLC: Rf = 0.30, chloroform: methanol (10: 1)
1H NMR(CDCl3):δ8.50-8.10(2H,br), 7.10-6.80(1H,br), 5.55-5.35(1H,m), 3.95-3.60(2H,m), 2.10(1H,m), 1.41(9H,s), 1.20-1.00(6H,m). 1 H NMR (CDCl 3): δ8.50-8.10 (2H, br), 7.10-6.80 (1H, br), 5.55-5.35 (1H, m), 3.95-3.60 (2H, m), 2.10 (1H, m), 1.41 (9H, s), 1.20-1.00 (6H, m).
E. 메틸옥시카르보닐-L-발릴-N-[1-(2-[5-(t-부틸)-옥사디아졸릴]히드록시메틸)-2-(S)-메틸프로필]-L-프롤린아미드E. Preparation of methyloxycarbonyl-L-valyl-N- [1- (2- [5- (t-butyl) -oxadiazolyl] hydroxymethyl) -2- (S) amides
메틸옥시카르보닐-L-Val-Pro-OH 및 1-[2-(5-t-부틸)-1,3,4-옥사디아졸릴]-2-(S)-아미노-3-메틸부탄-1-올 히드로클로라이드를 사용하고 당업자에게 공지된 커플링 방법을 사용하여 본 화합물을 제조하였다.(5-t-butyl) -1,3,4-oxadiazolyl] -2- (S) -amino-3-methylbutane- This compound was prepared using the coupling method known to one skilled in the art using 1-ol hydrochloride.
생성물은 하기 물리적 데이타를 나타내었다.The product showed the following physical data.
TLC: Rf=0.58, 에틸 아세테이트TLC: Rf = 0.58, ethyl acetate
1H NMR(200MHz,CDCl3): δ7.53(brd., J=6.2Hz,1H,NH), δ5.45-5.29(m,2H,NH 및 P1Val의 α CH), δ4.79-4.62(m,1H,Pro의 α CH), 4.32(m,1H,P3-Val의 α CH), 3.83-3.51(m,2H,Pro의 NCH2), 3.68(s,3H,CH3O), 2.55-1.80(m,6H,이소-Pr의 CH, 및 Pro의 CH2CH2), 1.47(s,9H,t-Bu의 CH3),1.16-0.86(m,12H,이소-Pr의 CH3). 1 H NMR (200MHz, CDCl 3 ): δ7.53 (. Brd, J = 6.2Hz, 1H, NH), δ5.45-5.29 (m, 2H, α CH NH of Val and P 1), δ4.79 -4.62 (m, 1H, α CH of Pro), 4.32 (m, 1H, P 3 -Val of α CH), 3.83-3.51 (m, 2H, Pro of NCH 2), 3.68 (s, 3H, CH 3 O), 2.55-1.80 (m, 6H , CH of iso -Pr, and Pro CH 2 CH 2), 1.47 (s, 9H, t-Bu of CH 3), 1.16-0.86 (m, 12H, iso- Pr CH 3 ).
＜실시예 2: 메틸옥시카르보닐-L-발릴-N-[1-(2-[5-(α,α-디메틸벤질)-옥사디아졸릴]카르보닐)-2-(S)-메틸프로필]-L-프롤린아미드＞Example 2 Methyloxycarbonyl-L-valyl-N- [1- (2- [5- (α, α-dimethylbenzyl) -oxadiazolyl] carbonyl) -2- (S) ] -L-prolinamide < / RTI >
메틸옥시카르보닐-L-발릴-N-[1-(2-[5-(α,α-디메틸벤질)-옥사디아졸릴]히드록시메틸)-2-(S)-메틸프로필]-L-프롤린아미드를 스원 산화법과 같이 당업자에게 공지된 방법 중 하나를 사용하여 산화시킴으로써 본 화합물을 제조하였다.2- (S) -methylpropyl] -L-valyl-L-valyl-N- [1- (2- [5- (?,? - dimethylbenzyl) oxadiazolyl] hydroxymethyl) -2- The present compounds were prepared by oxidizing proline amides using one of the methods known to those skilled in the art, such as Suwon oxidation.
중간체인 메틸옥시카르보닐-L-발릴-N-[1-(2-[5-(α,α-디메틸벤질)-옥사디아졸릴]히드록시메틸)-2-(S)-메틸프로필]-L-프롤린아미드를 메틸옥시카르보닐-L-Val-Pro-OH 및 1-[2-(α,α-디메틸벤질)-1,3,4-옥사디아졸릴]-2-(S)-아미노-3-메틸부탄-1-올 히드로클로라이드를 사용하고 당업자에게 공지된 커플링 방법을 사용하여 제조하였다. 중간체인 1-(2-(α,α-디메틸벤질)-1,3,4-옥사디아졸릴]-2-(S)-아미노-3-메틸부탄-1-올 히드로클로라이드를 메틸 트리메틸아세테이트 대신에 메틸 페닐이소부티레이트를 사용한다는 것만 제외하고 실시예 1에 기술된 방법과 유사한 방법으로 제조하였다.(S) -methylpropyl] - < RTI ID = 0.0 > methyl- L-Val-Pro-OH and 1- [2- (alpha, alpha -dimethylbenzyl) -1,3,4-oxadiazolyl] -2- (S) -amino -3-methylbutan-1-ol hydrochloride and using coupling methods known to those skilled in the art. (S) -amino-3-methylbutan-1-ol hydrochloride was obtained in the same manner as in the synthesis of Intermediate 1- (2- (α, α-dimethylbenzyl) -1,3,4-oxadiazolyl] -2- Was prepared in a manner analogous to that described in Example 1, but using methyl phenyl isobutyrate.
생성물은 하기 물리적 데이타를 가졌다.The product had the following physical data.
TLC: Rf=0.64, 에틸 아세테이트TLC: Rf = 0.64, ethyl acetate
1H NMR(200MHz,CDCl3): 7.84 및 7.49(각 brd.,J=7.6Hz,총 1H,NH), 7.40-7.20(m,5H 방향족 H), 5.46-5.29(m,2H,NH 및 P1Val의 αCH), 4.77-4.60(m,1H,Pro의 αCH), 4.40-4.25(m,1H, P3Val의 αCH), 3.84-3.55(m,2H,Pro의 NCH2), 3.68(s,3H,CH3O), 2.55-1.76(m,6H,이소-Pr의 CH, 및 Pro의 CH2CH2), 1.88(s,6H,hetC(CH3)2Ph), 1.12-0.82(m,12H,이소-Pr의 CH3). 1 H NMR (200MHz, CDCl 3 ): 7.84 and 7.49 (each brd, J = 7.6Hz, total 1H, NH), 7.40-7.20 (m , 5H aromatic H), 5.46-5.29 (m, 2H , NH and αCH) of P 1 Val, 4.77-4.60 (m, 1H, Pro of αCH), 4.40-4.25 (m, 1H , P 3 Val of αCH), 3.84-3.55 (m, 2H , NCH 2 of Pro), 3.68 (s, 3H, CH 3 O ), 2.55-1.76 (m, 6H, CH of iso -Pr, and Pro CH 2 CH 2), 1.88 (s, 6H, hetC (CH 3) 2 Ph), 1.12- 0.82 (m, 12H, CH 3 of iso -Pr).
＜실시예 3: 메틸옥시카르보닐-L-발릴-N-[1-(2-[5-(α,α-디메틸-3,4-메틸렌디옥시벤질)-1,3,4-옥사디아졸릴]카르보닐)-2-(S)-메틸프로필]-L-프롤린아미드＞Example 3: Methyloxycarbonyl-L-valyl-N- [1- (2- [5- (?,? -Dimethyl-3,4-methylenedioxybenzyl) -1,3,4-oxadiazole Carbonyl) -2- (S) -methylpropyl] -L-prolinamide < / RTI >
메틸옥시카르보닐-L-발릴-N-[1-(2-[5-(α,α-디메틸-3,4-메틸렌디옥시벤질)-옥사디아졸릴]히드록시메틸)-2-(S)-메틸프로필]-L-프롤린아미드를 스원 산화법과 같이 당업자에게 공지된 방법을 사용하여 산화시킴으로써 본 화합물을 제조하였다.Methyloxycarbonyl-L-valyl-N- [1- (2- [5- (?,? - dimethyl-3,4-methylenedioxybenzyl) oxadiazolyl] hydroxymethyl) -2- ) -Methylpropyl] -L-prolinamide was oxidized using methods known to those skilled in the art, such as the Suwon oxidation.
중간체인 메틸옥시카르보닐-L-발릴-N-[1-(2-[5-(α,α-디메틸-3,4-메틸렌디옥시벤질)-옥사디아졸릴]히드록시메틸)-2-(S)-메틸프로필]-L-프롤린아미드를 메틸옥시카르보닐-L-Val-Pro-OH 및 1-[2-(α,α-디메틸-3,4-메틸렌디옥시벤질)-1,3,4-옥사디아졸릴]-2-(S)-아미노-3-메틸부탄-1-올 히드로클로라이드를 사용하고 당업자에게 공지된 커플링 방법을 사용하여 제조하였다. 중간체인 1-[2-(α,α-디메틸-3,4-메틸렌디옥시벤질)-1,3,4-옥사디아졸릴]-2-(S)-아미노-3-메틸부탄-1-올 히드로클로라이드를 메틸 트리메틸아세테이트 대신에 메틸 3,4-메틸렌디옥시페닐이소부티레이트를 사용한다는 것만 제외하고 실시예 1에 기술된 방법과 유사한 방법으로 제조하였다.The process for the preparation of the intermediate methyloxycarbonyl-L-valyl-N- [1- (2- [5- (?,? - dimethyl-3,4-methylenedioxybenzyl) oxadiazolyl] hydroxymethyl) -2- (S) -methylpropyl] -L-prolinamide was reacted with methyloxycarbonyl-L-Val-Pro-OH and 1- [2- (?,? -Dimethyl-3,4-methylenedioxybenzyl) Oxadiazolyl] -2- (S) -amino-3-methylbutan-1-ol hydrochloride and using coupling methods known to those skilled in the art. (S) -amino-3-methylbutane-l- [2- (?,? - dimethyl-3,4- methylenedioxybenzyl) -1,3,4-oxadiazolyl] -2- Was prepared in a manner analogous to that described in Example 1, but using methyl 3,4-methylenedioxyphenylisobutyrate instead of methyl trimethylacetate.
생성물은 하기 물리적 데이타를 나타내었다.The product showed the following physical data.
TLC: Rf=0.63, 에틸 아세테이트TLC: Rf = 0.63, ethyl acetate
1H NMR(200MHz,CDCl3): 7.49(d,J=6.4Hz,1H,NH), 6.85-6.73(m,3H 방향족 H), 5.95(s,2H,OCH2O), 5.46-5.28(m,1H,Pro의 αCH), 4.30(m,1H, P3Val의 αCH), 3.84-3.54(m,2H,Pro의 NCH2), 3.68(s,3H,CH3O), 2.55-1.78(m,6H,이소 -Pr의 CH, 및 Pro의 CH2CH2), 1.83(s,6H,HetC(CH3)2Ph), 1.11-0.85(m,12H,이소-Pr의 CH3). 1 H NMR (200MHz, CDCl 3 ): 7.49 (d, J = 6.4Hz, 1H, NH), 6.85-6.73 (m, 3H aromatic H), 5.95 (s, 2H , OCH 2 O), 5.46-5.28 ( of m, 1H, Pro αCH), 4.30 (m, 1H, P 3 Val of αCH), 3.84-3.54 (m, 2H , NCH 2) of Pro, 3.68 (s, 3H, CH 3 O), 2.55-1.78 (m, 6H, CH 2 CH 2 of the iso -Pr CH, and Pro), 1.83 (s, 6H , HetC (CH 3) 2 Ph), 1.11-0.85 (m, 12H, CH 3 of iso -Pr) .
＜실시예 4: 2-[6-옥소-2-(4-플루오로페닐)-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-t-부틸-1,3,4-옥사디아졸릴]카르보닐)-2-(S)-메틸프로필]아세트아미드＞Example 4: 2- [6-Oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [ -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide>
-78℃에서 아르곤 대기 중에서, 디클로로메탄 (160㎖) 중 옥살릴 클로라이드 (5.80㎖)의 용액에 디클로로메탄 (16㎖)중 디메틸설폭사이드 (9.44㎖)의 용액을 서서히 적가하였다. 이 혼합물을 78℃에서 30분동안 교반하였다. -78℃에서, 상기 혼합물에, 디클로로메탄 (160㎖)중 2-[6-옥소-2-(4-플루오로페닐)-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-t-부틸-1,3,4-옥사디아졸릴]히드록시메틸)-2-(S)-메틸프로필]아세트아미드(15.2g)의 용액을 적가하였다. 이 혼합물을 -78℃에서 2시간 동안 교반하였다. 이렇게 얻은 용액에, -78℃에서 트리에틸아민 (97.2㎖)을 첨가하였다. 반응 혼합물을 실온으로 가온하고, 그 온도에서 34시간 동안 교반하였다. 반응 혼합물에 2N 염산 수용액을 첨가하여 산성화시키고, 디클로로메탄으로 추출시켰다. 추출물을 2N 염산 수용액, 물 및 염화나트륨 포화 수용액으로 세척하고, 무수 황산나트륨상에서 건조시키고, 농축시켰다. 잔여물을, 66 내지 100%의 구배를 갖는 에틸 아세테이트/헥산의 용리액을 사용하여 실리카겔상에서 칼럼 크로마토그래피시켜 정제하여 하기 물리적 데이타를 나타내는 2-[6-옥소-2-(4-플루오로페닐)-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-t-부틸-1,3,4-옥사디아졸릴]카르보닐)-2-(S)-메틸프로필]아세트아미드 (10.92g)을 수득하였다.A solution of dimethylsulfoxide (9.44 ml) in dichloromethane (16 ml) was slowly added dropwise to a solution of oxalyl chloride (5.80 ml) in dichloromethane (160 ml) at-78 C in an argon atmosphere. The mixture was stirred at 78 占 폚 for 30 minutes. To a mixture of 2- [6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [ 2- (S) -methylpropyl] acetamide (15.2 g) in tetrahydrofuran (5 ml) was added dropwise. The mixture was stirred at -78 < 0 > C for 2 hours. To this solution was added triethylamine (97.2 mL) at -78 < 0 > C. The reaction mixture was allowed to warm to room temperature and stirred at that temperature for 34 hours. The reaction mixture was acidified by addition of aqueous 2N hydrochloric acid and extracted with dichloromethane. The extract was washed with a 2N aqueous hydrochloric acid solution, water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel using an eluant of ethyl acetate / hexanes having a gradient from 66 to 100% to give 2- [6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5-t- butyl- 1,3,4-oxadiazolyl] carbonyl) -2- (S) Methylpropyl] acetamide (10.92 g) was obtained.
TLC: Rf=0.63, 클로로포름:메탄올(10:1)TLC: Rf = 0.63, chloroform: methanol (10: 1)
1H NMR(CDCl3): δ8.00(1H,d,J=6.5Hz), 7.64(2H,dd,J=8.6, 5.4Hz), 7.17(2H,t,J=8.6Hz), 6.95(1H,brd,J=8.4Hz), 6.50(1H,d,J=6.5Hz), 5.43(1H,dd,J=8.4, 4.8Hz), 4.63 및 4.58(각 1H, 각 d, J=15.4Hz), 2.53(1H,m), 1.48(9H,s), 1.09(3H,d,J=6.8Hz), 0.90(3H,d,J=6.8Hz). 1 H NMR (CDCl 3): δ8.00 (1H, d, J = 6.5Hz), 7.64 (2H, dd, J = 8.6, 5.4Hz), 7.17 (2H, t, J = 8.6Hz), 6.95 ( D, J = 8.4, 4.8 Hz), 4.63 and 4.58 (each 1H, each d, J = 15.4 Hz, 1H, brd, J = 8.4 Hz), 6.50 ), 2.53 (1H, m), 1.48 (9H, s), 1.09 (3H, d, J = 6.8Hz), 0.90 (3H, d, J = 6.8Hz).
중간체인 2-[6-옥소-2-(4-플루오로페닐)-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-t-부틸-1,3,4-옥사디아졸릴]히드록시메틸)-2-(S)-메틸프로필]아세트아미드를 다음과 같이 제조하였다:1- [2- (5-t-Butyl-1, 2-dihydro-1-pyrimidinyl] 3,4-oxadiazolyl] hydroxymethyl) -2- (S) -methylpropyl] acetamide was prepared as follows:
A. t-부틸카르보히드라존산A. t-Butyl Carbohydrazone
t-부틸카르보히드라존산을 전술된 바와 같이 제조하였다.t-Butylcarbhydrazonic acid was prepared as described above.
TLC: Rf=0.59, 클로로포름:메탄올(10:1)TLC: Rf = 0.59, chloroform: methanol (10: 1)
1H NMR(DMSO-d6): δ8.78(1H,brs), 4.15(2H,brs),1.08(9H,s). 1 H NMR (DMSO-d 6 ): δ8.78 (1H, brs), 4.15 (2H, brs), 1.08 (9H, s).
B. 2-t-부틸-1,3,4-옥사디아졸B. 2-t-Butyl-1,3,4-oxadiazole
2-t-부틸-1,3,4-옥사디아졸을 전술된 바와 같이 제조하였다.2-t-Butyl-1,3,4-oxadiazole was prepared as described above.
C. 1-[2-(5-t-부틸)-1,3,4-옥사디아졸릴]-2-(S)-(t-부톡시카르보닐아미노)-3-메틸부탄-1-올C. Synthesis of 1- [2- (5-t-butyl) -1,3,4-oxadiazolyl] -2- (S) - (t-butoxycarbonylamino)
-78℃에서 아르곤 대기중에서, 테트라히드로푸란 (1650㎖)중 2-t-부틸-1,3,4-옥사디아졸(62.1g)의 용액에 헥산중 n-부틸리튬 (1.6M,307.8㎖)을 적가하였다. 이 혼합물을 -78℃에서 40분동안 교반하고, 마그네슘 브로마이드 디에틸 에테레이트 (127.2g)를 첨가하고, 이렇게 얻은 혼합물을 -45℃로 가온시켰다. 1시간 30분이 지난 후, -45℃에서 테트라히드로푸란 (60㎖)중 2-(S)-[N-(t-부톡시카르보닐)아미노]-3-메틸부탄알 (90g)의 용액을 적가하고 -15℃로 가온시켰다. 반응 혼합물에 암모늄 클로라이드 포화 수용액을 첨가하여 급냉시키고, 에틸 아세테이트로 추출시켰다. 추출물을 물로 3회 세척하고 염화나트륨 포화 수용액으로 세척하고, 무수 황산나트륨상에서 건조시키고, 농축시켰다. 그 잔여물을 실리카겔상에서 칼럼 크로마토그래피(머크 7734)(에틸 아세테이트:헥산=1:20 내지 1:1)에 의해 정제하여 하기 물리적 데이타를 나타내는 1-[2-(5-t-부틸)-1,3,4-옥사디아졸릴]-2-(S)-(t-부톡시카르보닐아미노)-3-메틸부탄-1-올 (78.6g)을 수득하였다.To a solution of 2-t-butyl-1,3,4-oxadiazole (62.1 g) in tetrahydrofuran (1650 ml) in n-butyllithium (1.6 M, 307.8 ml, ) Was added dropwise. The mixture was stirred at -78 < 0 > C for 40 minutes, magnesium bromide diethyl etherate (127.2 g) was added and the mixture thus obtained was warmed to -45 < 0 > C. After 1 hour 30 minutes, a solution of 2- (S) - [N- (t-butoxycarbonyl) amino] -3-methylbutanal (90 g) in tetrahydrofuran (60 ml) Lt; RTI ID = 0.0 > -15 C. < / RTI > The reaction mixture was quenched by the addition of a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The extracts were washed with water three times, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (Merck 7734) (ethyl acetate: hexane = 1:20 to 1: 1) to give 1- [2- (5-t-butyl) -1 , 3,4-oxadiazolyl] -2- (S) - (t-butoxycarbonylamino) -3-methylbutan-1-ol (78.6 g).
TLC: Rf=0.42, 헥산:에틸 아세테이트(1:1)TLC: Rf = 0.42, hexane: ethyl acetate (1: 1)
1H NMR(CDCl3):δ5.16-4.90(2H,m), 4.67(1H,m), 4.23(1H,m), 3.90(1H,m), 3.66(1H,m), 1.98(1H,m), 1.42, 1.41 및 1.36(총 18H, 각 s), 1.13-0.90(6H,m). 1 H NMR (CDCl 3): δ5.16-4.90 (2H, m), 4.67 (1H, m), 4.23 (1H, m), 3.90 (1H, m), 3.66 (1H, m), 1.98 (1H , m), 1.42, 1.41 and 1.36 (total 18H, angle s), 1.13-0.90 (6H, m).
D. 1-[2-(5-t-부틸)-1,3,4-옥사디아졸릴]-2-(S)-아미노-3-메틸부탄-1-올 히드로클로라이드D. Synthesis of 1- [2- (5-t-butyl) -1,3,4-oxadiazolyl] -2- (S) -amino-3-methylbutan-1-ol hydrochloride
0℃에서, 디옥산(200㎖)중 1-[2-(5-t-부틸)-1,3,4-옥사디아졸릴]-2-(S)-(t-부톡시카르보닐아미노)-3-메틸부탄-1-올(76.3g)의 용액에 디옥산(1000㎖)중 4N 염산 용액을 첨가하였다. 이 반응 혼합물을 감압하에서 농축시켰다. 잔여물을 디에틸 에테르로 응고시켰다. 이렇게 얻은 고체를 벤젠으로 수시간에 걸쳐 공비시켜 하기 물리적 데이타를 나타내는 1-[2-(5-t-부틸)-1,3,4-옥사디아졸릴]-2-(S)-아미노-3-메틸부탄-1-올 히드로클로라이드(66.1g)를 수득하였다.(5-t-butyl) -1,3,4-oxadiazolyl] -2- (S) - (t-butoxycarbonylamino) -3-methylbutan-1-ol (76.3 g) in dioxane (1000 ml) was added a solution of 4N hydrochloric acid in dioxane (1000 ml). The reaction mixture was concentrated under reduced pressure. The residue was coagulated with diethyl ether. The resulting solid was azeotroped with benzene over several hours to give 1- [2- (5-t-butyl) -1,3,4-oxadiazolyl] -2- (S) -Methylbutan-1-ol hydrochloride (66.1 g).
TLC: Rf=0.30, 클로로포름:메탄올(10:1)TLC: Rf = 0.30, chloroform: methanol (10: 1)
1H NMR(CDCl3):δ8.50-8.10(2H,br), 7.10-6.80(1H,br), 5.55-5.35(1H,m), 3.95-3.60(2H,m), 2.10(1H,m), 1.41(9H,s), 1.20-1.00(6H,m). 1 H NMR (CDCl 3): δ8.50-8.10 (2H, br), 7.10-6.80 (1H, br), 5.55-5.35 (1H, m), 3.95-3.60 (2H, m), 2.10 (1H, m), 1.41 (9H, s), 1.20-1.00 (6H, m).
E. 2-[6-옥소-2-(4-플루오로페닐)-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-t-부틸-1,3,4-옥사디아졸]히드록시메틸)-2-(S)-메틸프로필]아세트아미드E. 2- [6-Oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [ 3,4-oxadiazole] hydroxymethyl) -2- (S) -methylpropyl] acetamide
-0℃에서, 디메틸포름아미드 (100㎖)에 1-[2-(5-t-부틸)-1,3,4-옥사디아졸릴]-2-(S)-아미노-3-메틸부탄-1-올 히드로클로라이드 (10.76g)와 [6-옥소-2-(4-플루오로페닐)-1,6-디히드로-1-피리미디닐]아세트산 (8.63g)과 1-히드록시벤조트리아졸 (5.85g)이 용해된 용액에 1-에틸-3-[3-(디메틸아미노)프로필]카르보디이미드 (7.33g)를 첨가하였다. 이 온도에서 이 혼합물에 4-메틸모르폴린 (4.21㎖)을 첨가하였다. 이 반응 혼합물을 실온에서 17시간 동안 교반하였다. 반응물에 물을 첨가하여 급냉시키고 에틸 아세테이트로 3회 추출시켰다. 추출물을 10% 시트르산 수용액, 탄산수소나트륨 포화 수용액, 물 및 염화나트륨 포화 수용액으로 세척하였다. 유기상을 무수 황산나트륨상에서 건조시키고 감압하에서 농축시켜 하기 물리적 데이타를 나타내는 2-[6-옥소-2-(4-플루오로페닐)-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-t-부틸-1,3,4-옥사디아졸릴]히드록시메틸)-2-(S)-메틸프로필]아세트아미드(14.6g)를 수득하였다.To a solution of 1- [2- (5-t-butyl) -1,3,4-oxadiazolyl] -2- (S) -amino-3-methylbutane- 1-ol hydrochloride (10.76 g), [6-oxo-2- (4-fluorophenyl) -1,6-dihydro- 1 -pyrimidinyl] acetic acid (8.63 g) and 1-hydroxybenzotri Ethyl-3- [3- (dimethylamino) propyl] carbodiimide (7.33 g) was added to a solution in which a sol (5.85 g) was dissolved. To this mixture was added 4-methylmorpholine (4.21 ml) at this temperature. The reaction mixture was stirred at room temperature for 17 hours. The reaction was quenched by the addition of water and extracted three times with ethyl acetate. The extract was washed with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution, water and saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2- [6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] 1- (2- [5-t-butyl-1,3,4-oxadiazolyl] hydroxymethyl) -2- (S) -methylpropyl] acetamide (14.6 g).
TLC: Rf=0.40, 클로로포름:메탄올(10:1)TLC: Rf = 0.40, chloroform: methanol (10: 1)
1H NMR(DMSO-d6): δ8.00 및 7.94(각 1H,각 d,J=6.6Hz), 7.71 및 7.55(각 2H,각 m), 7.19 및 7.18(각 2H, 각 J=6.6Hz), 6.43 및 6.38(각 1H, 각 d, J=6.6Hz), 5.13(1H,d,J=2.2Hz), 5.05(1H,d,J=4.4Hz), 4.54(2H,s), 4.43(2H,m), 4.31(1H,m), 4.04(1H,m), 2.20-1.52(1H,m), 1.41 및 1.37(각 9H, 각 s), 1.08, 1.00, 0.94 및 0.92(각 3H, 각 d, J=6.6Hz). 1 H NMR (DMSO-d 6 ): δ8.00 and 7.94 (each 1H, each d, J = 6.6Hz), 7.71 and 7.55 (each 2H, each m), 7.19 and 7.18 (each 2H, each J = 6.6 D, J = 2.2 Hz), 5.05 (1H, d, J = 4.4 Hz), 4.54 (2H, s) (2H, m), 4.31 (1H, m), 4.04 (1H, m), 2.20-1.52 (1H, m), 1.41 and 1.37 (each 9H, s), 1.08, 1.00, 0.94 and 0.92 3H, angle d, J = 6.6 Hz).
＜실시예 5: 2-[5-벤질옥시카르보닐아미노-6-옥소-2-(4-플루오로페닐)-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-(α,α-디메틸-3,4-메틸렌디옥시벤질)-1,3,4-옥사디아졸릴]카르보닐)-2-(S)-메틸프로필]아세트아미드＞Example 5: Synthesis of 2- [5-benzyloxycarbonylamino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] (S) -methylpropyl] acetamide < / RTI > < RTI ID = 0.0 >
2°알콜로서 2-[5-벤질옥시카르보닐아미노-6-옥소-2-(4-플루오로페닐)-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-(α,α-디메틸-3,4-메틸렌디옥시벤질)-1,3,4-옥사디아졸릴]히드록시메틸)-2-(S)-메틸프로필]아세트아미드를 사용하여 실시예 1에 기술된 것과 유사한 산화 방법을 사용하여 본 화합물을 제조하였다. 표제 화합물인 2-[5-벤질옥시카르보닐아미노-6-옥소-2-(4-플루오로페닐)-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-(α,α-디메틸-3,4-메틸렌디옥시벤질)-1,3,4-옥사디아졸릴]카르보닐)-2-(S)-메틸프로필]아세트아미드는 하기 물리적 데이타를 나타내었다.2- [5-benzyloxycarbonylamino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (S) -methylpropyl] acetamide, which was used in place of [5- (α, α-dimethyl-3,4-methylenedioxybenzyl) -1,3,4-oxadiazolyl] hydroxymethyl) -2- This compound was prepared using an oxidation method analogous to that described in Example < RTI ID = 0.0 > 1. < / RTI > The title compound, 2- [5-benzyloxycarbonylamino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro- 1- pyrimidinyl] [5- (?,? - dimethyl-3,4-methylenedioxybenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide has the following physical data Respectively.
TLC: Rf=0.66, 클로로포름:메탄올(10:1)TLC: Rf = 0.66, chloroform: methanol (10: 1)
1H NMR(CDCl3):δ8.76(1H,brs), 7.63-7.52(2H,m), 7.49(1H,brs), 7.38(5H,brs), 7.13(2H,t,J=8.6Hz), 6.82-6.74(3H,m), 6.71(1H,brd,J=8.6Hz), 5.94(2H,s), 5.42(1H,dd,J=8.6, 5.0Hz), 5.22(2H,s), 4.58(2H,brs), 2.50(1H,m), 1.83(6H,s), 1.05 및 0.86(각 3H, 각 d,J=7.0Hz). 1 H NMR (CDCl 3): δ8.76 (1H, brs), 7.63-7.52 (2H, m), 7.49 (1H, brs), 7.38 (5H, brs), 7.13 (2H, t, J = 8.6Hz ), 6.82-6.74 (3H, m), 6.71 (1H, brd, J = 8.6 Hz), 5.94 (2H, s), 5.42 (1H, dd, J = , 4.58 (2H, brs), 2.50 (1H, m), 1.83 (6H, s), 1.05 and 0.86 (3H each, d, J = 7.0Hz).
중간체인 2-[5-벤질옥시카르보닐아미노-6-옥소-2-(4-플루오로페닐)-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-(α,α-디메틸-3,4-메틸렌디옥시벤질)-1,3,4-옥사디아졸릴]히드록시메틸)-2-(S)-메틸프로필]아세트아미드를 [5-벤질옥시카르보닐아미노-6-옥소-2-(4-플루오로페닐)-1,6-디히드로-1-피리미디닐]아세트산과 1-[2-(α,α-디메틸-3,4-메틸렌디옥시벤질)-1,3,4-옥사디아졸릴]-2-(S)-아미노-3-메틸부탄-1-올 히드로클로라이드를 사용하여 실시예 1 E에 기술된 것과 유사한 방법으로 제조하였다. 중간체인 1-[2-(α,α-디메틸-3,4-메틸렌디옥시벤질)-1,3,4-옥사디아졸릴]-2-(S)-아미노-3-메틸부탄-1-올 히드로클로라이드를 실시예 1D에 기술된 것과 유사한 방법으로 제조하였다. 헤테로사이클 중간체인 2-(α,α-디메틸-3,4-메틸렌디옥시벤질)-1,3,4-옥사디아졸은 하기 물리적 데이타를 나타내었다.2- [5-benzyloxycarbonylamino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [ 5- (α, α-dimethyl-3,4-methylenedioxybenzyl) -1,3,4-oxadiazolyl] hydroxymethyl) -2- (S) -methylpropyl] acetamide was reacted with [ Oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] acetic acid and 1- [2- (α, Prepared in a similar manner to that described in Example 1E using methylenedioxybenzyl) -1,3,4-oxadiazolyl] -2- (S) -amino-3-methylbutan-1-ol hydrochloride Respectively. (S) -amino-3-methylbutane-l- [2- (?,? - dimethyl-3,4- methylenedioxybenzyl) -1,3,4-oxadiazolyl] -2- Ol hydrochloride was prepared by a method similar to that described in Example 1D. The heterocycle intermediate 2- (α, α-dimethyl-3,4-methylenedioxybenzyl) -1,3,4-oxadiazole exhibited the following physical data.
TLC: Rf=0.69, 클로로포름:메탄올(10:1)TLC: Rf = 0.69, chloroform: methanol (10: 1)
1H NMR(CDCl3):δ8.30(1H,s), 6.78(1H,brs), 6.74(2H,brs), 5.94(2H,s), 1.81(6H,s). 1 H NMR (CDCl 3): δ8.30 (1H, s), 6.78 (1H, brs), 6.74 (2H, brs), 5.94 (2H, s), 1.81 (6H, s).
＜실시예 6: 2-[5-아미노-6-옥소-2-(4-플루오로페닐)-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-(α,α-디메틸-3,4-메틸렌디옥시벤질)-1,3,4-옥사디아졸릴]카르보닐)-2-(R,S)-메틸프로필]아세트아미드＞Example 6: Synthesis of 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [ - (?,? -dimethyl-3,4-methylenedioxybenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl]
2-[5-(벤질옥시카르보닐아미노)-6-옥소-2-(4-플루오로페닐)-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-(α,α-디메틸-3,4-메틸렌디옥시벤질)-1,3,4-옥사디아졸릴]카르보닐)-2-(S)-메틸프로필]아세트아미드 (1.42g)에, 브롬화수소산이 아세트산에 30%로 용해되어 있는 용액 (50㎖)을 첨가하였다. 이 반응 혼합물을 실온에서 1시간 동안 교반하였다. 반응 혼합물에 얼음물을 첨가하여 급냉시키고, 에틸 아세테이트로 2회 추출시켰다. 추출물을 합하고, 이것을 물로 2회 세척하고, 염화나트륨 포화 수용액으로 세척하였다. 유기상을 무수 황산나트륨상에서 건조시키고, 여과하고, 감압하에서 농축시켰다. 잔여물을 50 내지 100%의 구배를 갖는 에틸 아세테이트/헥산의 용리액을 사용하여 실리카겔상에서 칼럼 크로마토그래피시켜 정제하여 하기 물리적 데이타를 나타내는 2-[5-아미노-6-옥소-2-(4-플루오로페닐)-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-(α,α-디메틸-3,4-메틸렌디옥시벤질)-1,3,4-옥사디아졸릴]카르보닐)-2-(R,S)-메틸프로필]아세트아미드 (457㎎)를 수득하였다.1- [2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [ Carbonyl) -2- (S) -methylpropyl] acetamide (1.42 g) in tetrahydrofuran was added dropwise to a solution of 4- (4-methylphenyl) A solution (50 ml) in which hydrobromic acid was dissolved in acetic acid at 30% was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched by the addition of ice water and extracted twice with ethyl acetate. The extracts were combined, washed twice with water, and washed with saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using an eluent of ethyl acetate / hexanes with a gradient of 50-100% to give 2- [5-amino-6-oxo-2- (4- -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (?,? - dimethyl-3,4-methylenedioxybenzyl) 4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide (457 mg).
TLC: Rf=0.39, 에틸 아세테이트TLC: Rf = 0.39, ethyl acetate
1H NMR(CDCl3):δ7.53(2H,dd,J=8.8, 5.3Hz), 7.48(1H,s), 7.06(2H,t,J=8.8Hz), 6.90(1H,brd,J=8.4Hz), 6.84-6.70(3H,m), 5.95(2H,s), 5.43(1H,dd,J=8.4, 4.8Hz), 4.63 및 4.54(각 1H Abq,J=15.0Hz), 4.05(2H,brs), 2.51(1H,m), 1.84(6H,s), 1.06 및 0.87(각 3H,각 d,J=7.0Hz). 1 H NMR (CDCl 3): δ7.53 (2H, dd, J = 8.8, 5.3Hz), 7.48 (1H, s), 7.06 (2H, t, J = 8.8Hz), 6.90 (1H, brd, J J = 8.4 Hz), 6.84-6.70 (3H, m), 5.95 (2H, s), 5.43 (1H, dd, J = 8.4,4.8Hz), 4.63 and 4.54 (2H, brs), 2.51 (1H, m), 1.84 (6H, s), 1.06 and 0.87 (3H each, d, J = 7.0Hz).
＜실시예 7: 2-[5-벤질옥시카르보닐아미노-6-옥소-2-페닐-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-(α,α-디메틸-3,4-메틸렌디옥시벤질)-1,3,4-옥사디아졸릴]카르보닐)-2-(R,S)-메틸프로필]아세트아미드＞Example 7: 2- [5-Benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- -1,3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide,
2°알콜로서 2-[5-벤질옥시카르보닐아미노-6-옥소-2-페닐-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-(α,α-디메틸-3,4-메틸렌디옥시벤질)-1,3,4-옥사디아졸릴]히드록시메틸)-2-(S)-메틸프로필]아세트아미드를 사용하여 실시예 1에 기술된 것과 유사한 산화 방법을 사용하여 본 화합물을 제조하였다. 표제 화합물인 2-[5-벤질옥시카르보닐아미노-6-옥소-2-페닐-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-(α,α-디메틸-3,4-메틸렌디옥시벤질)-1,3,4-옥사디아졸릴]카르보닐)-2-(R,S)-메틸프로필]아세트아미드는 하기 물리적 데이타를 나타내었다.2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- -methylenedioxybenzyl) -1,3,4-oxadiazolyl] hydroxymethyl) -2- (S) -methylpropyl] acetamide as a starting material, This compound was prepared using an oxidation method similar to that described above. The title compound, 2- [5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- dimethyl-3,4-methylenedioxybenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide showed the following physical data.
TLC: Rf=0.34, 헥산:에틸 아세테이트(1:1)TLC: Rf = 0.34, hexane: ethyl acetate (1: 1)
1H NMR(CDCl3):δ8.78(1H,brs), 7.60-7.30(1H,m), 6.78(3H,m), 6.68(1H,d,J=8.8Hz), 5.94(2H,s), 5.42(1H,dd,J=8.8, 4.8Hz), 5.23(2H,s), 4.65 및 4.57(2H,Abq,J=15.0Hz), 2.49(1H,m), 1.83(6H,s), 1.04(3H,d,J=6Hz), 0.84(3H,d,J=5.8Hz). 1 H NMR (CDCl 3): δ8.78 (1H, brs), 7.60-7.30 (1H, m), 6.78 (3H, m), 6.68 (1H, d, J = 8.8Hz), 5.94 (2H, s ), 5.42 (1H, dd, J = 8.8,4.8Hz), 5.23 (2H, s), 4.65 and 4.57 (2H, Abq, J = 15.0Hz), 2.49 , 1.04 (3H, d, J = 6 Hz), 0.84 (3H, d, J = 5.8 Hz).
중간체인 2-[5-벤질옥시카르보닐아미노-6-옥소-2-페닐-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-(α,α-디메틸-3,4-메틸렌디옥시벤질)-1,3,4-옥사디아졸릴]히드록시메틸)-2-(S)-메틸프로필]아세트아미드를 5-벤질옥시카르보닐아미노-6-옥소-2-페닐-1,6-디히드로-1-피리미디닐]아세트산 및 1-[2-(α,α-디메틸-3,4-메틸렌디옥시벤질)-1,3,4-옥사디아졸릴]-2-(S)-아미노-3-메틸부탄-1-올 히드로클로라이드를 사용하여 실시예 1 E에 기술된 것과 유사한 방법으로 제조하였다. 중간체인 1-[2-(α,α-디메틸-3,4-메틸렌디옥시벤질)-1,3,4-옥사디아졸릴]-2-(S)-아미노-3-메틸부탄-1-올 히드로클로라이드를 실시예 1 D에 기술된 것과 유사한 방법으로 제조하였다. 헤테로사이클 중간체인 2-(α,α-디메틸-3,4-메틸렌디옥시벤질)-1,3,4-옥사디아졸은 하기 물리적 데이타를 나타내었다.Preparation of intermediate 2- [5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- -Dimethyl-3,4-methylenedioxybenzyl) -1,3,4-oxadiazolyl] hydroxymethyl) -2- (S) -methylpropyl] acetamide was reacted with 5-benzyloxycarbonylamino- Oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] acetic acid and 1- [2- (?,? -Dimethyl-3,4-methylenedioxybenzyl) (S) -amino-3-methylbutan-1-ol hydrochloride, the title compound was prepared in analogy to that described in Example 1E. (S) -amino-3-methylbutane-l- [2- (?,? - dimethyl-3,4- methylenedioxybenzyl) -1,3,4-oxadiazolyl] -2- Ol hydrochloride was prepared by a method similar to that described in Example < RTI ID = 0.0 > 1D. ≪ / RTI > The heterocycle intermediate 2- (α, α-dimethyl-3,4-methylenedioxybenzyl) -1,3,4-oxadiazole exhibited the following physical data.
TLC: Rf=0.69, 클로로포름:메탄올(10:1)TLC: Rf = 0.69, chloroform: methanol (10: 1)
1H NMR(CDCl3):δ8.30(1H,s), 6.78(1H,brs), 6.74(2H,brs), 5.94(2H,s), 1.81(6H,s). 1 H NMR (CDCl 3): δ8.30 (1H, s), 6.78 (1H, brs), 6.74 (2H, brs), 5.94 (2H, s), 1.81 (6H, s).
＜실시예 8: 2-[5-아미노-6-옥소-2-페닐-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-(α,α-디메틸-3,4-메틸렌디옥시벤질)-1,3,4-옥사디아졸릴]카르보닐)-2-(R,S)-메틸프로필]아세트아미드＞Example 8: 2- [5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- Dimethyl-3,4-methylenedioxybenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl]
2-[5-벤질옥시카르보닐아미노-6-옥소-2-페닐-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-(α,α-디메틸-3,4-메틸렌디옥시벤질)-1,3,4-옥사디아졸릴]카르보닐)-2-(S)-메틸프로필]아세트아미드를 사용하여 실시예 3에 기술된 것과 유사한 방법을 사용하여 본 화합물을 제조하였다. 표제 화합물인 2-[5-아미노-6-옥소-2-페닐-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-(α,α-디메틸-3,4-메틸렌디옥시벤질)-1,3,4-옥사디아졸릴]카르보닐)-2-(S)-메틸프로필]아세트아미드는 하기 물리적 데이타를 나타내었다.2- [5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- -3,4-methylenedioxybenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide was used the method analogous to that described in Example 3 To give the present compound. The title compound, 2- [5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- Methylenedioxybenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide showed the following physical data.
TLC: Rf=0.40, 에틸 아세테이트TLC: Rf = 0.40, ethyl acetate
1H NMR(CDCl3):δ7.59-7.34(5H,m), 7.50(1H,s), 6.86(1H,d,J=8.2Hz), 6.86-6.72(3H,m), 5.95(2H,s), 5.43(1H,dd,J=8.2 및 4.8Hz), 4.66(1H,d,J=15.4Hz), 4.56(2H,f,J=15.4Hz), 4.05(2H,brs), 2.62-2.36(1H,m), 1.84(6H,s), 1.05(3H,d,J=7.0Hz), 0.85(3H,d,J=7.0Hz). 1 H NMR (CDCl 3): δ7.59-7.34 (5H, m), 7.50 (1H, s), 6.86 (1H, d, J = 8.2Hz), 6.86-6.72 (3H, m), 5.95 (2H d, J = 8.2 and 4.8 Hz), 4.66 (1H, d, J = 15.4 Hz), 4.56 (2H, (1H, m), 1.84 (6H, s), 1.05 (3H, d, J = 7.0Hz), 0.85 (3H, d, J = 7.0Hz).
＜실시예 9: 2-[6-옥소-2-페닐-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-(α,α-디메틸-3,4-메틸렌디옥시벤질)-1,3,4-옥사디아졸릴]카르보닐)-2-(R,S)-메틸프로필]아세트아미드＞Example 9: Preparation of 2- [6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [ (4-methylenedioxybenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl]
TLC: Rf=0.46, 에틸 아세테이트TLC: Rf = 0.46, ethyl acetate
1H NMR(CDCl3):δ8.01(1H,d,J=6.6Hz), 7.65-7.35(5H,m), 6.87(1H,d,J=8.6Hz), 6.85-6.70(3H,m), 6.49(1H,d,J=6.6Hz), 5.95(2H,s), 5.42(1H,dd,J=8.6 및 5.0Hz), 4.67(1H,d,J=15.2Hz), 4.54(1H,d,J=15.2Hz), 2.63-2.37(1H,m), 1.84(6H,s), 1.05(3H,d,J=6.8Hz), 0.85(3H,d,J=6.8Hz). 1 H NMR (CDCl 3): δ8.01 (1H, d, J = 6.6Hz), 7.65-7.35 (5H, m), 6.87 (1H, d, J = 8.6Hz), 6.85-6.70 (3H, m D, J = 8.6 and 5.0 Hz), 4.67 (1H, d, J = 15.2 Hz), 4.54 (1H, d, J = 15.2 Hz), 2.63-2.37 (1H, m), 1.84 (6H, s), 1.05 (3H, d, J = 6.8Hz), 0.85 (3H, d, J = 6.8Hz).
＜실시예 10: 2-[6-옥소-2-(4-플루오로페닐)-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-(α,α-디메틸-3,4-메틸렌디옥시벤질)-1,3,4-옥사디아졸릴]카르보닐)-2-(R,S)-메틸프로필]아세트아미드＞Example 10: 2- [6-Oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- -1,3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide,
TLC: Rf=0.43, 에틸 아세테이트TLC: Rf = 0.43, ethyl acetate
1H NMR(CDCl3):δ7.99(1H,d,J=6.6Hz), 7.63(2H,dd,J=8.6, 5.2Hz), 7.14(2H,t,J=8.6Hz), 6.93(1H,brd,J=8.6Hz), 6.84-6.70(3H,m), 6.49(1H,d,J=6.6Hz), 5.95(2H,s), 5.41(1H,dd,J=8.6, 5.0Hz), 4.64 및 4.53(각 1H Abq,J=15.0Hz), 2.50(1H,m), 1.84(6H,s), 1.06 및 0.87(각 3H,각 d,J=7.0Hz). 1 H NMR (CDCl 3): δ7.99 (1H, d, J = 6.6Hz), 7.63 (2H, dd, J = 8.6, 5.2Hz), 7.14 (2H, t, J = 8.6Hz), 6.93 ( (2H, s), 5.41 (1H, dd, J = 8.6, 5.0Hz, 1H, brd, J = 8.6Hz), 6.84-6.70 (3H, m), 6.49 ), 4.64 and 4.53 (each 1H Abq, J = 15.0 Hz), 2.50 (1H, m), 1.84 (6H, s), 1.06 and 0.87 (3H each d, J = 7.0 Hz).
＜실시예 11: 2-[6-옥소-2-(4-플루오로페닐)-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-(α,α-디메틸벤질)-1,3,4-옥사디아졸릴]카르보닐)-2-(R,S)-메틸프로필]아세트아미드＞Example 11: 2- [6-Oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- -dimethylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide>
2°알콜로서 2-[6-옥소-2-(4-플루오로페닐)-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-(α,α-디메틸벤질)-1,3,4-옥사디아졸릴]히드록시메틸)-2-(S)-메틸프로필]아세트아미드를 사용하여 실시예 1에 기술된 것과 유사한 산화 방법을 사용하여 본 화합물을 제조하였다. 표제 화합물인 2-[6-옥소-2-(4-플루오로페닐)-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-(α,α-디메틸벤질)-1,3,4-옥사디아졸릴]카르보닐)-2-(S)-메틸프로필]아세트아미드는 하기 물리적 데이타를 나타내었다.1-pyrimidinyl] -N- [1- (2- [5- (α, α-dihydro- -Dimethylbenzyl) -1,3,4-oxadiazolyl] hydroxymethyl) -2- (S) -methylpropyl] acetamide, the title compound was prepared . The title compound, 2- [6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- Dimethylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide showed the following physical data.
TLC: Rf=0.42, 에틸 아세테이트TLC: Rf = 0.42, ethyl acetate
1H NMR(CDCl3):δ7.99(1H,d,J=6.5Hz), 7.62(2H,m), 7.40-7.20(5H,m), 7.14(2H,t,J=8.8Hz), 6.89(1H,brd,J=8.6Hz), 6.49(1H,d,J=6.5Hz), 5.42(1H,dd,J=8.6, 5.0Hz), 4.61 및 4.54(각 1H,각 d,J=15.0Hz), 2.50(1H,m), 1.88(6H,s), 1.06 및 0.86(각 3H,각 d,J=6.7Hz). 1 H NMR (CDCl 3): δ7.99 (1H, d, J = 6.5Hz), 7.62 (2H, m), 7.40-7.20 (5H, m), 7.14 (2H, t, J = 8.8Hz), J = 8.6 Hz), 6.49 (1H, d, J = 6.5 Hz), 5.42 (1H, dd, J = 8.6, 5.0 Hz), 4.61 and 4.54 15.0 Hz), 2.50 (1H, m), 1.88 (6H, s), 1.06 and 0.86 (3H each, d, J = 6.7Hz).
중간체인 2-[6-옥소-2-(4-플루오로페닐)-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-(α,α-디메틸벤질)-1,3,4-옥사디아졸릴]히드록시메틸)-2-(S)-메틸프로필]아세트아미드를 [6-옥소-2-(4-플루오로페닐)-1,6-디히드로-1-피리미디닐]아세트산과 1-[2-(α,α-디메틸벤질)-1,3,4-옥사디아졸릴]-2-(S)-아미노-3-메틸부탄-1-올 히드로클로라이드를 사용하여 실시예 1 E에 기술된 것과 유사한 방법으로 제조하였다. 중간체인 1-[2-(α,α-디메틸-3,4-메틸렌디옥시벤질)-1,3,4-옥사디아졸릴]-2-(S)-아미노-3-메틸부탄-1-올 히드로클로라이드를 실시예 1 D에 기술된 것과 유사한 방법으로 제조하였다. 헤테로사이클 중간체인 2-(α,α-디메틸벤질)-1,3,4-옥사디아졸은 하기 물리적 데이타를 나타내었다.2- [4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (a, 2- (4-fluorophenyl) -1, 6-di (benzyl) -1,3,4-oxadiazolyl] hydroxymethyl) -2- -1,3,4-oxadiazolyl] -2- (S) -amino-3-methylbutane-l- Lt; / RTI > The title compound was prepared by a method similar to that described in Example 1E using < RTI ID = 0.0 > (S) -amino-3-methylbutane-l- [2- (?,? - dimethyl-3,4- methylenedioxybenzyl) -1,3,4-oxadiazolyl] -2- Ol hydrochloride was prepared by a method similar to that described in Example < RTI ID = 0.0 > 1D. ≪ / RTI > The heterocycle intermediate 2- (α, α-dimethylbenzyl) -1,3,4-oxadiazole exhibited the following physical data.
TLC: Rf=0.43, 에틸 아세테이트:헥산(1:2)TLC: Rf = 0.43, ethyl acetate: hexane (1: 2)
1H NMR(CDCl3):δ8.31(1H,s), 7.40-7.14(5H,m), 1.86(6H,s). 1 H NMR (CDCl 3 ):? 8.31 (1H, s), 7.40-7.14 (5H, m), 1.86 (6H, s).
＜실시예 12: 2-[6-옥소-2-페닐-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-(α,α-디메틸벤질)-1,3,4-옥사디아졸릴]카르보닐)-2-(R,S)-메틸프로필]아세트아미드＞Example 12: 2- [6-Oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- 1,3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide>
2°알콜로서 2-[6-옥소-2-페닐-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-(α,α-디메틸벤질)-1,3,4-옥사디아졸릴]히드록시메틸)-2-(S)-메틸프로필]아세트아미드를 사용하여 실시예 4에 기술된 것과 유사한 산화 방법을 사용하여 본 화합물을 제조하였다. 표제 화합물인 2-[6-옥소-2-페닐-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-(α,α-디메틸벤질)-1,3,4-옥사디아졸릴]카르보닐)-2-(S)-메틸프로필]아세트아미드는 하기 물리적 데이타를 나타내었다.2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (?,? - dimethylbenzyl) -1 , 3,4-oxadiazolyl] hydroxymethyl) -2- (S) -methylpropyl] acetamide, the title compound was prepared using an oxidation method similar to that described in Example 4. The title compound, 2- [6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- 3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide showed the following physical data.
TLC: Rf=0.44, 에틸 아세테이트TLC: Rf = 0.44, ethyl acetate
1H NMR(CDCl3):δ8.02(1H,d,J=6.5Hz), 7.64-7.24(10H,m), 6.82(1H,brd,J=8.4Hz), 6.50(1H,d,J=6.5Hz), 5.44(1H,dd,J=8.4, 4.8Hz), 4.63 및 4.56(각 1H,각 d,J=15.4Hz), 2.50(1H,m), 1.89(6H,s), 1.06 및 0.86(각 3H,각 d,J=6.8Hz). 1 H NMR (CDCl 3): δ8.02 (1H, d, J = 6.5Hz), 7.64-7.24 (10H, m), 6.82 (1H, brd, J = 8.4Hz), 6.50 (1H, d, J = 6.5 Hz), 5.44 (1H, dd, J = 8.4, 4.8 Hz), 4.63 and 4.56 (each 1H, d, J = 15.4 Hz), 2.50 (1H, m), 1.89 And 0.86 (3H each, d, J = 6.8Hz).
중간체인 2-[6-옥소-2-페닐-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-(α,α-디메틸벤질)-1,3,4-옥사디아졸릴]히드록시메틸)-2-(S)-메틸프로필]아세트아미드를 [6-옥소-2-페닐-1,6-디히드로-1-피리미디닐]아세트산과 1-[2-(α,α-디메틸벤질)-1,3,4-옥사디아졸릴]-2-(S)-아미노-3-메틸부탄-1-올 히드로클로라이드를 사용하여 실시예 1 E에 기술된 것과 유사한 방법으로 제조하였다.The intermediate, 2- [6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (4-oxadiazolyl) hydroxymethyl) -2- (S) -methylpropyl] acetamide was reacted with [6-oxo-2-phenyl-1,6-dihydro- 1- pyrimidinyl] acetic acid and 1- The title compound was prepared in analogy to Example 1E using [2- (α, α-dimethylbenzyl) -1,3,4-oxadiazolyl] -2- (S) -amino- ≪ / RTI >
＜실시예 13: 2-[5-메틸옥시카르보닐아미노-6-옥소-2-페닐-1,6-디히드로-1-피리미디닐]-N-[1-(2-[5-(t-부틸)-1,3,4-옥사디아졸릴]카르보닐)-2-(R,S)-메틸프로필]아세트아미드＞Example 13: 2- [5-Methyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- t-butyl) -1,3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl]
실시예 7과 유사한 방법으로 제조하였다. 생성물은 하기 물리적 데이타를 나타내었다.Prepared in a similar manner to Example 7. The product showed the following physical data.
TLC: Rf=0.57, 메탄올:클로로포름(1:10)TLC: Rf = 0.57, methanol: chloroform (1:10)
1H NMR(200MHz,CDCl3): 8.78(brs,1H,피리미디논의 H), 7.62-7.40(m,6H,NH 및 방향족 H), 6.73(brd,J=8.4Hz,1H,CONH), 5.45(dd, J=8.4, 5.0Hz, 1H, Val의 αCH), 4.67 및 4.61(각 d,J=15.0Hz,각 1H, Gly의 CH2), 3.81(s,3H,CH3O), 2.51(m,1H,이소-Pr의 CH), 1.48(s,9H,t-Bu의 CH3), 1.07 및 0.88(각 d,J=6.8Hz,각 3H,이소-Pr의 CH3). 1 H NMR (200MHz, CDCl 3 ): 8.78 (brs, 1H, pyrimidinyl discussion H), 7.62-7.40 (m, 6H , NH and aromatic H), 6.73 (brd, J = 8.4Hz, 1H, CONH), (D, J = 8.4, 5.0 Hz, 1H, Val of? CH), 4.67 and 4.61 (d, J = 15.0 Hz, each 1H, CH 2 of Gly), 3.81 (s, 3H, CH 3 O) 2.51 (m, 1H, iso -Pr CH), 1.48 (s, 9H, t-Bu of CH 3), 1.07 and 0.88 (each d, J = 6.8Hz, each 3H, the iso -Pr CH 3).
＜실시예 14: 시험관내에서의 엘라스타제 저해 실험＞≪ Example 14: Elastase inhibition experiment in vitro >
다음 프로토콜을 사용하여 본원에서 기술된 화합물들의 저해 활성을 결정하였다. 프로토콜에서 사용된 엘라스타제는 인간 객담(HSE)에서 유래된 것이다. 시판 HSE(875U/㎎ 단백질, SE-563, 미국 미주리주 엘라스틴 프로덕트 캄파니 인코포레이티드(Elastin Product Co.,Inc.)를 식염수로 1000U/㎖가 되게 희석시켜 HSE 효소의 모액을 제조하고, 이를 사용전에 0℃에서 2U/㎖가 되게 추가로 희석시켰다.The following protocols were used to determine the inhibitory activity of the compounds described herein. The elastase used in the protocol is derived from human sputum (HSE). A mother liquor of HSE enzyme was prepared by diluting commercially available HSE (875 U / mg protein, SE-563, Elastin Product Co., Inc., Missouri, USA) with saline to 1000 U / It was further diluted to 2 U / ml at 0 ° C before use.
0.2M HEPES-NaOH 완충액(pH 8.0) 100㎕, 2.5M NaCl 40㎕, 1% 폴리에틸렌글리콜 6000 20㎕, 증류수 8㎕, 저해제가 DMSO에 용해되어 있는 용액 10㎕ 및 N-메톡시숙시닐-Ala-Ala-Pro-Val-p-니트로아닐린(농도 100, 200 및 400μM)의 용액 2㎕을 혼합함으로써 용액을 제조하였다. 이 용액을 37℃에서 10분동안 배양시켰다. 여기에 HSE(인간 객담에서 유래된 엘라스타제)의 효소 용액을 첨가하였다. 이렇게 얻은 혼합물을 하기와 같이 속도 분석하였다.100 μl of 0.2 M HEPES-NaOH buffer (pH 8.0), 40 μl of 2.5 M NaCl, 20 μl of 1% polyethylene glycol 6000, 8 μl of distilled water, 10 μl of the solution in which the inhibitor was dissolved in DMSO, -Ala-Pro-Val-p-nitroaniline (concentrations 100, 200 and 400 [mu] M). This solution was incubated at 37 占 폚 for 10 minutes. To this, an enzyme solution of HSE (Elastase derived from human sputum) was added. The thus obtained mixture was subjected to a speed analysis as follows.
효소 반응에 의해 생성된 p-니트로아닐린으로 인한 광학 밀도(SPECTRA MAX 250, 몰레큘라 디바이스(Molecular Devices))를 405㎚에서 37℃에서 측정하여, p-니트로아닐린의 생성 속도가 선형인 기간 동안 반응 속도를 측정하였다. 효소 용액을 첨가한 직후에 30초 간격으로 10분동안 속도 mO.D/분을 측정하였다. 로그-로짓(log-logit) 방법을 사용하여 IC50값을 결정하였고 딕손(Dixson) 플롯(plot) 방법을 사용하여 K1값으로 전환시켰다. HNE에 대해 저해 활성을 나타내는(K1값, nM) 화합물들을 하기 표 2에 나타내었다.The optical density (SPECTRA MAX 250, Molecular Devices) due to p-nitroaniline produced by the enzymatic reaction was measured at 405 nm at 37 ° C to determine the reaction rate during the linearity of the rate of formation of p-nitroaniline The speed was measured. Immediately after addition of the enzyme solution, the velocity mO.D / min was measured for 10 minutes at 30 second intervals. IC 50 values were determined using a log-logit method and converted to K 1 values using the Dixson plot method. The compounds (K 1 value, nM) exhibiting inhibitory activity against HNE are shown in Table 2 below.
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