KR100405914B1 - Biphenyl Butyric Acid Derivative as a Matrix Metalloproteinase Inhibitor - Google Patents
Biphenyl Butyric Acid Derivative as a Matrix Metalloproteinase Inhibitor Download PDFInfo
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- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
- C07C235/76—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
- C07C235/78—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
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- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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- C—CHEMISTRY; METALLURGY
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- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
Abstract
본 발명은 신규한 비페닐 부티릭산 유도체에 관한 것이다. 본 발명은 메트릭스 메탈로프로테이나제의 저해제로서 유용한 하기 일반식(Ⅰ)의 신규한 비페닐 부티릭산 유도체, 그의 약학적으로 허용되는 염 및 이들의 제조방법을 제공한다. 본 발명의 비페닐 부티릭산 유도체 화합물은 시험관내(in vitro) 조건에서 MMP(matrix metalloproteinase)의 활성을 선택적으로 억제하는 바, 전기 비페닐 부티릭산 유도체를 유효성분으로 하는 MMP 억제제는 MMP의 과발현 및 과도한 활성화에 의해서 유발되는 각종질병의 예방 및 치료에 유용하게 사용될 수 있을 것이다.The present invention relates to novel biphenyl butyric acid derivatives. The present invention provides novel biphenyl butyric acid derivatives of the general formula (I), pharmaceutically acceptable salts thereof, and methods for their preparation, which are useful as inhibitors of matrix metalloproteinases. The biphenyl butyric acid derivative compound of the present invention selectively inhibits the activity of matrix metalloproteinase (MMP) under in vitro conditions. The MMP inhibitor comprising the biphenyl butyric acid derivative as an active ingredient is an overexpression of MMP and It may be useful for the prevention and treatment of various diseases caused by excessive activation.
Description
본 발명은 신규한 비페닐 부티릭산 유도체에 관한 것이다. 좀 더 구체적으로, 본 발명은 메트릭스 메탈로프로테이나제의 저해제로서 유용한 하기 일반식(Ⅰ)의 신규한 비페닐 부티릭산 유도체, 그의 약학적으로 허용되는 염 및 이들의 제조방법에 관한 것이다.The present invention relates to novel biphenyl butyric acid derivatives. More specifically, the present invention relates to novel biphenyl butyric acid derivatives of the general formula (I), pharmaceutically acceptable salts thereof, and methods for their preparation, useful as inhibitors of matrix metalloproteinases.
메트릭스 메탈로프로테이나제(matrix metalloproteinase, 이하 'MMP'라 함)는 활성부위에 아연(Zn2+)을 함유하고 칼슘(Ca2+) 의존적인 프로테이나제로서, 스트로멜리신, 콜라게나제 및 젤라티나제의 페밀리 등 약 18가지가 알려져 있다. 이들 MMP 효소들은 생물학적 조건하에서 결합조직의 단백질 성분 즉, 콜라겐, 라미닌, 프로테오글리칸, 피브로넥틴, 엘라스틴, 젤라틴 등을 분해시켜, 관절조직, 골조직, 결합조직의 성장 및 조직의 리모델링을 야기시킨다. 이들 효소들은 공통적으로 활성부위에 아연을 함유하고 칼슘에 따라 활성이 달라지며, 불활성 전효소의 형태로 분비되어 세포의 외부에서 활성화되고, TIMP(tissue inhibitor of metalloproteinase)라는 천연 저해제와 함께 분비된다.Matrix metalloproteinase (MMP) is a calcium (Ca 2+ ) dependent proteinase that contains zinc (Zn 2+ ) at its active sites and is a stromelysin and collagenase. About 18 are known, including families of agents and gelatinases. These MMP enzymes degrade the protein components of the connective tissue, namely collagen, laminin, proteoglycan, fibronectin, elastin, gelatin, etc. under biological conditions, leading to the growth and remodeling of joint tissue, bone tissue, connective tissue. These enzymes commonly contain zinc in their active sites and vary in activity depending on calcium, are secreted in the form of inactive preenzymes, activated outside of cells, and secreted with a natural inhibitor called TIMP (tissue inhibitor of metalloproteinase).
한편, MMP 억제제는 MMP의 과발현 및 과도한 활성화에 의해서 유발되는 각종질병의 예방 및 치료에 유용하다. 상기 질병의 예로는 류마토이드, 관절골염, 비정상 골흡수증, 골다공증, 치주염, 간질성 신염, 동맥경화증, 폐기종, 경변증, 각막손상, 종양세포의 전이, 침범, 또는 성장, 자가면역질병, 혈관유지, 또는 백혈구의 침범에 의해 유발되는 질병, 동맥혈화를 들 수 있다(참조: Beeley et al., Curr. Opin. Ther. Patents, 4(1):7-16, 1994). 예를 들면, 합성한 MMP 저해제가 난소암의 쥐 모델에서 기질의 리모델링의 저해작용과 함께 생체내(in vivo)에서 항암효과가 있음이 보고되었다(참조: Cancer Res., 53:2087, 1993). 특히, 암세포 성장에 필수적으로 요구되는 신혈관생성(angiogenesis) 단계에서 위의 MMP 효소 중 MMP-2와 MMP-9가 필수적으로 관여함이 알려져 있고(참조: Biochim. Biophys. Acta, 695, 1983), 또한, MMP 효소 중 MMP-1과 MMP-3는 류마티스성 관절염 환자의 활막(synovium)과 연골(cartilage)에서 정상치보다 아주 높은 농도로 발견되어, 상기한 MMP-1/MMP-3가 관절염의 진행에 중요한 역할을 한다고 알려져 있으므로(참조:Arthritis Rheum., 35:35-42, 1992), MMP-1/MMP-2에의 선택성이 관절통증 등의 부작용을 줄이는데 중요한 역할을 할 것으로 여겨지고 있다. 따라서, 최근의 연구는 선택적인 저해제의 개발에 집중되고 있으며, 이러한 MMP 저해제의 설계 및 합성에 대해서는 다각도로 연구되고 있다(참조: J. Enzyme Inhibitor, 2:1-22, 1987; Current Medicinal Chemistry, 2:743-762, 1995; Progress in Medicinal Chemistry, 29:271-334, 1992; Exp. Opin. Ther. Patents, 5:1287-1296, 1995; Drug Discovery Today, 1:16-26, 1996; Chem. Rev. 99:2735-2776, 1999).On the other hand, MMP inhibitors are useful for the prevention and treatment of various diseases caused by overexpression and excessive activation of MMP. Examples of the disease include rheumatoid, osteoarthritis, abnormal osteoporosis, osteoporosis, periodontitis, interstitial nephritis, arteriosclerosis, emphysema, cirrhosis, corneal injury, tumor cell metastasis, invasion, or growth, autoimmune disease, vascular maintenance, Or diseases caused by invasion of leukocytes, arterialization (Beeley et al., Curr. Opin. Ther. Patents, 4 (1): 7-16, 1994). For example, it has been reported that the synthesized MMP inhibitor has an anti-cancer effect in vivo along with the inhibitory effect of substrate remodeling in a rat model of ovarian cancer (Cancer Res., 53: 2087, 1993). . In particular, it is known that MMP-2 and MMP-9 of the above MMP enzymes are essentially involved in the angiogenesis stage required for cancer cell growth (Biochim. Biophys. Acta, 695, 1983). In addition, MMP-1 and MMP-3 in the MMP enzymes were found to be higher than normal levels in synoviium and cartilage of rheumatoid arthritis patients. Since it is known to play an important role in progression (Arthritis Rheum., 35: 35-42, 1992), selectivity to MMP-1 / MMP-2 is believed to play an important role in reducing side effects such as joint pain. Thus, recent research has focused on the development of selective inhibitors, and the design and synthesis of such MMP inhibitors has been studied at various angles (J. Enzyme Inhibitor, 2: 1-22, 1987; Current Medicinal Chemistry, 2: 743-762, 1995; Progress in Medicinal Chemistry, 29: 271-334, 1992; Exp.Opin.Ther. Patents, 5: 1287-1296, 1995; Drug Discovery Today, 1: 16-26, 1996; Chem Rev. 99: 2735-2776, 1999).
일반적으로, MMP 효소들의 활성부위에 아연 금속과 잘 배위하는 작용기를 가지는 화합물은 MMP의 촉매활성을 저해한다. 이와 같은 작용기로는 히드록사믹산(hydroxamic acid), 카르복실산, 포스포린산, 포스핀산, 티올 등이 알려져 있으며, 이러한 작용기를 이용하여 고안되고 합성된 MMP 저해제가 이미 공지되어 있다. 특히, 초기의 저해제로 기질유사체인 펩티드 골격을 가진 여러종의 숙신산 유도체가 합성되었는 바(참조: British Biotech, WO 9925693; Zeneca, WO 9843959, WO 9824759; Abbott, WO 9830551, WO9830541; PU, WO9732846; Roche, WO9901428, EP 897908; GW, WO 9838179; Sankyo, JP 95002797; DuPont, WO 9918074; Ono, WO 9919296; 및, Otsuka, EP 641323), 이러한 기질유사체 저해제들은 모두 Zn-배위기로 히드록사믹산을 가지는 것으로 알려져 있으나, 전기 저해제들은 펩티드 유도체가 가지는 낮은 경구흡수도 및 MMP-1/MMP-2의 선택성이 낮다는 문제점을 가지고 있다.In general, compounds having functional groups that coordinate well with zinc metal in the active site of MMP enzymes inhibit the catalytic activity of MMP. Such functional groups are known as hydroxamic acid, carboxylic acid, phosphoric acid, phosphinic acid, thiol, and the like, and MMP inhibitors designed and synthesized using such functional groups are already known. In particular, various succinic acid derivatives with peptide backbones, substrate migratory compounds, have been synthesized as early inhibitors (British Biotech, WO 9925693; Zeneca, WO 9843959, WO 9824759; Abbott, WO 9830551, WO9830541; PU, WO9732846; Roche, WO9901428, EP 897908; GW, WO 9838179; Sankyo, JP 95002797; DuPont, WO 9918074; Ono, WO 9919296; and, Otsuka, EP 641323), all of these substrate-like inhibitors use hydroxamic acids as Zn-coordinates. Although known to have, the electrical inhibitors have problems of low oral absorption and low selectivity of MMP-1 / MMP-2 possessed by the peptide derivative.
전술한 문제점을 해결한 저해제로서 1996년에 설포닐아미노산 유도체가 개발된 이후(참조: USP 5,506,242; J. Med. Chem., 40:2525-2532, 1997) 다양한 설포닐아미노산 유도체가 합성되어 보고되었다(참조: WO 9720824, JP 98316662, WO 9808825, EP 877018, JP 98204059, WO 9906410, JP 98204054, EP 895988, EP 9918076, WO 9832748, WO 9809934 및 WO 9808823). 상기 저해제들은 비교적 높은 MMP 활성억제 효과를 가지고 있으나, MMP-1/MMP-2의 선택성은 높지 않았고(참조: Drugs of the Future, 24(1):16-21, 1999), 임상실험에서 부작용으로서 관절통증이 보고되었으므로, 상기 부작용 문제를 해결하기 위한 다각적인 연구결과, 전술한 문제점을 해결한 저해제로서 하기와 같은 구조식의 비페닐 부티릭산 화합물(Bay12-9566)이 보고된 바 있다(참조: WO 9615096).Since sulfonylamino acid derivatives were developed in 1996 as inhibitors to solve the aforementioned problems (see USP 5,506,242; J. Med. Chem., 40: 2525-2532, 1997), various sulfonylamino acid derivatives have been synthesized and reported. (See WO 9720824, JP 98316662, WO 9808825, EP 877018, JP 98204059, WO 9906410, JP 98204054, EP 895988, EP 9918076, WO 9832748, WO 9809934 and WO 9808823). The inhibitors have a relatively high inhibitory effect on MMP activity, but the selectivity of MMP-1 / MMP-2 was not high (Drugs of the Future, 24 (1): 16-21, 1999) and as a side effect in clinical trials. Since arthralgia has been reported, a multi-faceted study for solving the above-mentioned side effects has been reported as a biphenyl butyric acid compound (Bay12-9566) having the following structural formula as an inhibitor for solving the above-mentioned problems (WO: WO 9615096).
Bay12-9566은 상기 기질유사체 숙신산 유도체나 설포닐아미노산 유도체에 비하여 시험관내 MMP 저해 활성은 크게 떨어지나 MMP-1/MMP-2의 선택성은 크게 향상된 결과를 보여주었고(참조: Drugs of the Future, 24(1):16-21, 1999), 임상실험에서 관절통증 등의 부작용은 거의 없는 것으로 나타났다. 그러나, Bay 12-9566은 MMP-2(IC50:11nM)/MMP-9(IC50:301nM)에 대한 활성이 크게 낮은 문제점을 가지고 있어서, 이후로 MMP 저해제로서 다양한 비페닐 부티릭산 유도체가 보고되었다(참조: USP 5789434, USP 5854277, USP 5859047, USP 5861427, USP 5861428, USP 5874473,USP 5886022, USP 5886024 및 USP 5886043).Bay12-9566 showed a significantly lower in vitro MMP inhibitory activity compared to the substrate-like succinic acid derivative or sulfonylamino acid derivative, but significantly improved the selectivity of MMP-1 / MMP-2 (see Drugs of the Future, 24 ( 1): 16-21, 1999), clinical trials showed little side effects such as joint pain. However, Bay 12-9566 has a problem of significantly lower activity against MMP-2 (IC 50 : 11 nM) / MMP-9 (IC 50 : 301 nM), and various biphenyl butyric acid derivatives have been reported as MMP inhibitors. (USP 5789434, USP 5854277, USP 5859047, USP 5861427, USP 5861428, USP 5874473, USP 5886022, USP 5886024 and USP 5886043).
또한, 하기와 같은 구조식의 부티릭산 유도체가 보고되었으나(참조: WO 9809940, WO 9806711), MMP-1/ MMP-2의 선택성은 증가하지만 위의 기질유사체 숙신산 유도체나 설포닐아미노산 유도체에 비해 시험관내 MMP 저해 활성은 크게 떨어지는 문제점을 가지고 있었다.In addition, butyric acid derivatives of the following structural formulas have been reported (see WO 9809940, WO 9806711), but the selectivity of MMP-1 / MMP-2 is increased, but in vitro compared to the above substrate-like succinic or sulfonylamino acid derivatives. MMP inhibitory activity had a problem of greatly falling.
따라서, MMP저해활성과 MMP-1/MMP-2에의 선택성을 증가시켜, 부작용을 줄일 수 있는 신물질을 개발하여야 할 필요성이 끊임없이 대두되었다.Therefore, there is a constant need to develop new substances that can reduce side effects by increasing MMP inhibitory activity and selectivity to MMP-1 / MMP-2.
이에, 본 발명자들은 MMP저해활성과 MMP-1/ MMP-2에의 선택성을 증가시켜 부작용을 줄일 수 있는 신물질을 개발하고자 예의 연구노력한 결과, 새로이 합성된 비페닐 부티릭산 유도체가 시험관내(in vitro) 조건에서 MMP의 활성을 선택적으로 억제하는 것을 확인하고, 본 발명을 완성하게 되었다.Accordingly, the present inventors have diligently researched to develop a new substance that can reduce side effects by increasing MMP inhibitory activity and selectivity to MMP-1 / MMP-2, and as a result, newly synthesized biphenyl butyric acid derivatives are in vitro. It was confirmed that selectively inhibiting the activity of MMP under the conditions, the present invention was completed.
결국, 본 발명의 주된 목적은 MMP의 활성을 저해하는 비페닐 부티릭산 유도체를 제공하는 것이다.After all, the main object of the present invention is to provide a biphenyl butyric acid derivative that inhibits the activity of MMP.
본 발명의 다른 목적은 전기 유도체의 제조방법을 제공하는 것이다.Another object of the present invention is to provide a method for producing an electrical derivative.
본 발명은 MMP의 작용을 억제하는 다음 일반식(I)의 비페닐 부티릭산 유도체 화합물, 그의 이성질체 및 이들의 약학적으로 허용되는 염과 전기 물질들의 제조방법을 제공한다.The present invention provides a method for preparing biphenyl butyric acid derivative compounds of general formula (I), isomers thereof, and pharmaceutically acceptable salts and electrical substances thereof which inhibit the action of MMP.
상기 식에서,Where
R1은 수소, 알킬, 씨클로알킬, 할로겐, 니트로, 시아노, -OCF3,R 1 is hydrogen, alkyl, cycloalkyl, halogen, nitro, cyano, -OCF 3 ,
, -OCH2F, -OCH2F, , -OCH 2 F, -OCH 2 F,
-OR4, -SR4, -S(O)R4또는 -S(O)2이고(이때, R4및 R4 a는 서-OR 4 , -SR 4 , -S (O) R 4 or -S (O) 2 , where R 4 and R 4 a are
로 같거나 다른 것으로, 알킬, 아릴, 아릴알킬, 헤테로아Equal to or different from, alkyl, aryl, arylalkyl, heteroa
릴 또는 씨클로알킬이다);Reel or cycloalkyl);
R2및 R3는 서로 같거나 다른 것으로, 수소, 알킬, 아릴, 아릴알R 2 and R 3 are the same as or different from each other, hydrogen, alkyl, aryl, arylal
킬, 헤테로아릴 또는 씨클로알킬이며; 및,Ke, heteroaryl or cycloalkyl; And,
n은 1 또는 2이다.n is 1 or 2.
또한, R2와 R3가 서로 탄소, 질소, 산소 또는 황으로 연결되어 5, 6의 고리를 형성할 수 있으며, 이때기는 구체적으로 하기의 구조를 포함한다.In addition, R 2 and R 3 may be connected to each other by carbon, nitrogen, oxygen or sulfur to form a ring of 5, 6, wherein The group specifically includes the following structure.
상기 식에서,Where
R5는 수소, 알킬, 아릴, 아릴알킬, 헤테로아릴, 또는R 5 is hydrogen, alkyl, aryl, arylalkyl, heteroaryl, or
씨클로알킬이며; 및,Cycloalkyl; And,
X는 O 또는 S이다.X is O or S.
특별한 언급이 없는 한, 전기 설폰아미드 화합물의 모든 이성질체들은 본 발명의 범주에 속한다. 예를 들면, 알킬, 알콕시 알켄, 및 알킨의 경우, 이의 직쇄 및 분지쇄는 물론, 비대칭 탄소에 의해서 발생하는 이성체, 예컨대 분지된 알킬 또한 본 발명에 속한다.Unless otherwise noted, all isomers of the foregoing sulfonamide compounds are within the scope of the present invention. For example, in the case of alkyls, alkoxy alkenes, and alkynes, the straight and branched chains thereof, as well as isomers such as branched alkyls generated by asymmetric carbons, also belong to the invention.
본 발명의 약학적으로 허용되는 염에는 산 부가염, 수화물염이 포함된다. 본 발명의 일반식(I)의 화합물은 상응하는 염으로 전환시킬 수 있는데, 알칼리금속의 염(나트륨, 칼륨 등), 알칼리토금속의 염(칼슘, 마그네슘 등), 암모늄염, 약학적 유기아민의 비독성염 및 수용성염이 바람직하다. 본 발명의 일반식(I)의 화합물은 무기산의 염(염산염, 브롬화수소염, 요드화수소염, 황산염, 인산염, 질산염 등), 유기산의 염(아세트산, 락테이트, 타르타레이트, 옥살레이트, 푸마레이트, 글루쿠로네이트 등)의 상응하는 산 부가염으로 전환시킬 수 있는데, 비독성염 및 수용성염이 바람직하다. 본 발명의 일반식(I)의 화합물 및 이의 염은 당업계의 통상적인 방법에 의하여 상응하는 수화물로도 전환시킬 수 있다.Pharmaceutically acceptable salts of the present invention include acid addition salts, hydrate salts. Compounds of general formula (I) of the present invention can be converted to the corresponding salts, including salts of alkali metals (sodium, potassium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), ammonium salts, non-toxic organic amines Preferred salts and water soluble salts are preferred. Compounds of the general formula (I) of the present invention are salts of inorganic acids (hydrochloride, hydrogen bromide, hydrogen iodide, sulfate, phosphate, nitrate, etc.), salts of organic acids (acetic acid, lactate, tartarate, oxalate, puma) Lysates, glucuronates, etc.), which can be converted to the corresponding acid addition salts, with non-toxic and water-soluble salts being preferred. The compounds of formula (I) and salts thereof of the present invention can also be converted to the corresponding hydrates by conventional methods in the art.
특히, 일반식(I)의 화합물 중에서 상기에 정의된 R2,R3에 따라 다양한 비페닐 부티릭산 유도체들을 포함하지만, 하기 일반식의 비페닐 부티릭산 유도체가 바람직하다.In particular, although various biphenyl butyric acid derivatives according to R 2 and R 3 as defined above among the compounds of the general formula (I) are preferred, biphenyl butyric acid derivatives of the following general formula are preferred.
상기 식에서,Where
R1및 R5는 일반식(Ⅰ)에서 이미 정의한 바와 동일하고; 및,R 1 and R 5 are the same as previously defined in general formula (I); And,
R6은 수소, 알킬, 아릴, 아릴알킬, 헤테로아릴, 또는R 6 is hydrogen, alkyl, aryl, arylalkyl, heteroaryl, or
씨클로알킬이다.Cycloalkyl.
이하에서는, 일반식(Ⅰ)의 화합물의 제조방법을 공정별로 나누어 설명한다.Below, the manufacturing method of the compound of general formula (I) is demonstrated according to process.
제조방법 1:Preparation Method 1:
상기 식에서,Where
R1, R2및 R3는 일반식(Ⅰ)에서 정의한 바와 동일하다.R 1 , R 2 and R 3 are the same as defined in the general formula (I).
제 1공정: First step :
공지된 방법을 일부 수정하여 출발물질(II)와 (III)으로부터 삼차부틸에스테르(IV)를 수득한다(참조: WO 9615096): 이때, 출발물질(II)는 상업적으로 구입이가능하거나, 공지된 방법에 의하여 제조할 수 있고(참조: B.S. Furniss, et al., VOGEL's Textbook of Practical Organic Chemistry, 5th, ed., pp942-943, 1988), 출발물질(III)은 공지된 방법을 일부 수정하여 제조할 수 있다(참조: WO 9615096).Some modifications to the known methods give tertiary butyl ester (IV) from the starting materials (II) and (III) (see WO 9615096): wherein starting material (II) is commercially available or known It can be prepared by the method (BS Furniss, et al., VOGEL's Textbook of Practical Organic Chemistry, 5th, ed., Pp942-943, 1988), and starting material (III) is prepared by modifying some known methods. It may be done (see WO 9615096).
제 2공정: Second process :
삼차부틸에스테르(IV)를 탈보호기반응시켜 화합물(V)를 수득한다.Deprotective group reaction of the tertiary butyl ester (IV) affords compound (V).
제 3공정: Third process :
화합물(V)과 아민을 축합반응시켜 디에틸 에스테르(Ⅵ)를 수득한다: 이때, 바람직하게는 EDC/Et3N을 이용하여 축합반응을 수행한다.Condensation of compound (V) with an amine gives diethyl ester (VI): Condensation is preferably carried out using EDC / Et 3 N.
제 4공정: 4th process :
공지된 방법을 일부 수정하여, 디에틸 에스테르(Ⅵ)를 가수분해 및 탈탄산 반응시켜 화합물(I)을 제조한다(참조: WO 9615096).With some modification of the known methods, the compound (I) is prepared by hydrolysis and decarboxylation of diethyl ester (VI) (see WO 9615096).
제조방법 2:Preparation Method 2:
상술한 제조방법을 일부 변형하여 일반식(Ⅰ)의 화합물을 제조할 수 있다.The compound of general formula (I) can be manufactured by changing a manufacturing method mentioned above in part.
상기 식에서,Where
R1, R2및 R3는 일반식(Ⅰ)에서 정의한 바와 동일하다.R 1 , R 2 and R 3 are the same as defined in the general formula (I).
제 1공정: First step :
전기 제조방법의 제 1공정에서 수득한 삼차부틸에스테르(IV)에 있는 에스테르 하나만을 선택적으로 가수분해하여 탈탄산 반응시킴으로써 화합물(VII)을 수득한다.Compound (VII) is obtained by selectively hydrolyzing and decarboxylating only one ester in tertiary butyl ester (IV) obtained in the first step of the above-mentioned manufacturing method.
제 2공정: Second process :
전기 제조방법 1의 제 2공정과 동일한 방법으로, 화합물(VII)을 탈보호기 반응시켜 화합물(Ⅷ)을 수득한다.Compound (VII) is subjected to a deprotection group reaction in the same manner as in the second step of Preparation Method 1 to obtain compound (VII).
제 3공정: Third process :
화합물(Ⅷ)과 아민을 축합반응시켜 에틸 에스테르(Ⅸ)를 수득한다: 이때, 축합반응 방법은 HOBT/DCC 등의 활성화 에스테르 중간체를 사용하는 것이 바람직하다.Condensation reaction of compound (VII) with an amine yields ethyl ester (IX): At this time, the condensation reaction method preferably uses an activated ester intermediate such as HOBT / DCC.
제 4공정: 4th process :
공지된 방법을 일부 수정하여 에틸 에스테르(Ⅸ)를 가수분해시킴으로써 화합물(I)을 제조한다(참조: WO 9615096).Compound (I) is prepared by hydrolyzing ethyl ester (IV) with some modifications of known methods (see WO 9615096).
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention in more detail, it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples in accordance with the gist of the present invention. .
실시예 1: 5-(비페닐-4-일)-5-옥소-3,3-디에틸카르복실발레릭산 t-부틸에스테르(IV, R1=H)의 제조 Example 1 : Preparation of 5- (biphenyl-4-yl) -5-oxo-3,3-diethylcarboxylic valeric acid t-butyl ester (IV, R 1 = H)
100ml 플라스크에 NaH(95%, 505mg, 20.0mmol)와 정제된 THF(15mL)를 넣고 -10℃까지 냉각하였다. 이에, THF(10mL)에 용해시킨 에틸, t-부틸-2-에틸카르복실숙시네이트(III, 4.9g, 18.17mmol)을 천천히 가한 후, 30분간 상온에서 교반하였다. 여기에 THF(15mL)에 용해시킨 2-(비페닐-4-일)-1-브로모에탄(II, R1=H, 5g, 18.17mmol)을 천천히 가하고, 상온에서 1시간 30분동안 교반한 다음, 1N HCl용액(30mL)과 에틸초산(30mL)을 넣고 추출하였다. 유기층을 물(10mL)로 세척하고, 무수 MgSO4를 넣고 5분간 교반한 다음, 여과 및 감압 증류하여 표제화합물(8.65g, 95%)을 제조하였다.NaH (95%, 505mg, 20.0mmol) and purified THF (15mL) were added to a 100ml flask and cooled to -10 ° C. Ethyl and t-butyl-2-ethylcarboxyl succinate (III, 4.9 g, 18.17 mmol) dissolved in THF (10 mL) were slowly added thereto, followed by stirring at room temperature for 30 minutes. To this was slowly added 2- (biphenyl-4-yl) -1-bromoethane (II, R 1 = H, 5 g, 18.17 mmol) dissolved in THF (15 mL) and stirred at room temperature for 1 hour 30 minutes. Then, 1N HCl solution (30 mL) and ethyl acetate (30 mL) were added and extracted. The organic layer was washed with water (10 mL), anhydrous MgSO 4 was added thereto, stirred for 5 minutes, filtered and distilled under reduced pressure to obtain the title compound (8.65 g, 95%).
1H NMR(300MHz, CDCl3): δ1.24(t, 6H), 1.38(s, 9H), 3.39(s, 2H), 1 H NMR (300 MHz, CDCl 3 ): δ 1.24 (t, 6H), 1.38 (s, 9H), 3.39 (s, 2H),
3.97(s, 2H), 4.24(q, 4H), 7.45(m, 3H),3.97 (s, 2H), 4.24 (q, 4H), 7.45 (m, 3H),
7.61(d, 2H), 7.69(d, 2H), 8.04(d, 2H)7.61 (d, 2H), 7.69 (d, 2H), 8.04 (d, 2H)
실시예 2: 5-(4'-메톡시비페닐-4-일)-5-옥소-3,3-디에틸카르복실발레릭산 t-부틸에스테르(IV, R1=OMe)의 제조 Example 2 : Preparation of 5- (4'-methoxybiphenyl-4-yl) -5-oxo-3,3-diethylcarboxylic valeric acid t-butylester (IV, R 1 = OMe)
2-(4'-브로모비페닐-4-일)-1-브로모에탄(II, R1=OMe)을 사용하는 것을 제외하고는, 실시예 1과 동일한 방법으로 표제 화합물을 제조하였다.The title compound was prepared in the same manner as in Example 1 except for using 2- (4'-bromobiphenyl-4-yl) -1-bromoethane (II, R 1 = OMe).
1H NMR(300MHz, CDCl3): δ1.24(t, 6H), 1.38(s, 9H), 3.21(s, 2H), 1 H NMR (300 MHz, CDCl 3 ): δ 1.24 (t, 6H), 1.38 (s, 9H), 3.21 (s, 2H),
3.86(s, 3H), 3.94(s, 2H), 4.24(q, 4H),3.86 (s, 3H), 3.94 (s, 2H), 4.24 (q, 4H),
7.0(d, 2H), 7.58(d, 2H), 7.65(d, 2H),7.0 (d, 2H), 7.58 (d, 2H), 7.65 (d, 2H),
8.02(d, 2H)8.02 (d, 2H)
실시예 3: 5-(4'-브로모비페닐-4-일)-5-옥소-3,3-디에틸카르복실발레릭산 t-부틸에스테르(IV, R1=Br)의 제조 Example 3 Preparation of 5- (4'-Bromobiphenyl-4-yl) -5-oxo-3,3-diethylcarboxyvaleric acid t-butylester (IV, R 1 = Br)
2-(4'-브로모비페닐-4-일)-1-브로모에탄(II, R1=Br)을 사용하는 것을 제외하고는, 실시예 1과 동일한 방법으로 표제 화합물을 제조하였다.The title compound was prepared in the same manner as in Example 1 except for using 2- (4'-bromobiphenyl-4-yl) -1-bromoethane (II, R 1 = Br).
1H NMR(300MHz, CDCl3): δ1.24(t, 6H), 1.39(s, 9H), 3.21(s, 2H), 1 H NMR (300 MHz, CDCl 3 ): δ 1.24 (t, 6H), 1.39 (s, 9H), 3.21 (s, 2H),
3.95(s, 2H), 4.24(q, 4H), 7.48(d, 2H),3.95 (s, 2H), 4.24 (q, 4H), 7.48 (d, 2H),
7.60(d, 2H), 7.65(d, 2H), 8.04(d, 2H)7.60 (d, 2H), 7.65 (d, 2H), 8.04 (d, 2H)
실시예 4: 5-(4'-클로로비페닐-4-일)-5-옥소-3,3-디에틸카르복실발레릭산 t-부틸에스테르(IV, R1=Cl)의 제조 Example 4 Preparation of 5- (4'-Chlorobiphenyl-4-yl) -5-oxo-3,3-diethylcarboxylic valeric acid t-butylester (IV, R 1 = Cl)
2-(4'-브로모비페닐-4-일)-1-브로모에탄(II, R1=Cl)을 사용하는 것을 제외하고는, 실시예 1과 동일한 방법으로 표제 화합물을 제조하였다.The title compound was prepared in the same manner as in Example 1 except for using 2- (4'-bromobiphenyl-4-yl) -1-bromoethane (II, R 1 = Cl).
1H NMR(300MHz, CDCl3): δ1.25(t, 6H), 1.39(s, 9H), 3.21(s, 2H), 1 H NMR (300 MHz, CDCl 3 ): δ 1.25 (t, 6H), 1.39 (s, 9H), 3.21 (s, 2H),
3.95(s, 2H), 4.24(q, 4H), 7.44(d, 2H),3.95 (s, 2H), 4.24 (q, 4H), 7.44 (d, 2H),
7.56(d, 2H), 7.65(d, 2H), 8.06(d, 2H)7.56 (d, 2H), 7.65 (d, 2H), 8.06 (d, 2H)
실시예 5: 5-(비페닐-4-일)-5-옥소-3,3-디에틸카르복실발레릭산(V, R1=H)의 제조 Example 5 Preparation of 5- (biphenyl-4-yl) -5-oxo-3,3-diethylcarboxylic valeric acid (V, R 1 = H)
5-(비페닐-4-일)-5-옥소-3,3-디에틸카르복실발레릭산 t-부틸에스테르(IV, R1=H, 1.5g, 3.2mmol)를 MC(20mL)에 분산시킨 후, TFA(2mL)를 넣고 상온에서 24시간교반한 다음, MC를 감압제거하였다. 이에, 에틸초산(20mL)를 넣고, 1N NaOH용액을 천천히 가한 다음, 10분간 교반한 후, 물로 추출하였다. 여기에 1N HCl용액을 넣고 에틸초산으로 추출한 후, 무수 MgSO4로 건조, 여과, 감압 증류하여 표제화합물(1.2g, 91%)을 제조하였다.5- (biphenyl-4-yl) -5-oxo-3,3-diethylcarboxylic valeric acid t-butyl ester (IV, R 1 = H, 1.5 g, 3.2 mmol) was dispersed in MC (20 mL) After TFA (2 mL) was added and the mixture was stirred at room temperature for 24 hours, and MC was removed under reduced pressure. Ethyl acetate (20 mL) was added thereto, 1N NaOH solution was added slowly, stirred for 10 minutes, and then extracted with water. 1N HCl solution was added thereto, extracted with ethyl acetate, dried over anhydrous MgSO 4 , filtered, and distilled under reduced pressure to obtain the title compound (1.2g, 91%).
1H NMR(300MHz, CDCl3): δ1.24(t, 6H), 3.39(s, 2H), 3.97(s, 2H), 1 H NMR (300 MHz, CDCl 3 ): δ 1.24 (t, 6H), 3.39 (s, 2H), 3.97 (s, 2H),
4.24(q, 4H), 7.45(m, 3H), 7.61(d, 2H),4.24 (q, 4H), 7.45 (m, 3H), 7.61 (d, 2H),
7.69(d, 2H), 8.04(d, 2H)7.69 (d, 2H), 8.04 (d, 2H)
실시예 6: 5-(4'-메톡시비페닐-4-일)-5-옥소-3,3-디에틸카르복실발레릭산(V, R1=OMe)의 제조 Example 6 : Preparation of 5- (4'-methoxybiphenyl-4-yl) -5-oxo-3,3-diethylcarboxylic valeric acid (V, R 1 = OMe)
5-(4'-메톡시비페닐-4-일)-5-옥소-3,3-디에틸카르복실발레릭산 t-부틸에스테르(IV, R1=OMe)을 사용하는 것을 제외하고는, 실시예 5와 동일한 방법으로 표제 화합물을 제조하였다.Except that 5- (4'-methoxybiphenyl-4-yl) -5-oxo-3,3-diethylcarboxylic valeric acid t-butylester (IV, R 1 = OMe) was used. The title compound was prepared in the same manner as in Example 5.
1H NMR(300MHz, CDCl3): δ1.24(t, 6H), 3.21(s, 2H), 3.86(s, 3H), 1 H NMR (300 MHz, CDCl 3 ): δ 1.24 (t, 6H), 3.21 (s, 2H), 3.86 (s, 3H),
3.94(s, 2H), 4.24(q, 4H), 7.0(d, 2H),3.94 (s, 2H), 4.24 (q, 4H), 7.0 (d, 2H),
7.58(d, 2H), 7.65(d, 2H), 8.02(d, 2H)7.58 (d, 2H), 7.65 (d, 2H), 8.02 (d, 2H)
실시예 7: 5-(4'-브로모비페닐-4-일)-5-옥소-3,3-디에틸카르복실발레릭산(V, R1=Br)의 제조 Example 7 Preparation of 5- (4′-Bromobiphenyl-4-yl) -5-oxo-3,3-diethylcarboxyvaleric acid (V, R 1 = Br)
5-(4'-브로모비페닐-4-일)-5-옥소-3,3-디에틸카르복실발레릭산 t-부틸에스테르(IV, R1=Br)을 사용하는 것을 제외하고는, 실시예 5와 동일한 방법으로 표제 화합물을 제조하였다.Except that 5- (4'-bromobiphenyl-4-yl) -5-oxo-3,3-diethylcarboxylic valeric acid t-butyl ester (IV, R 1 = Br) is used. The title compound was prepared in the same manner as in Example 5.
1H NMR(300MHz, CDCl3): δ1.24(t, 6H), 3.21(s, 2H), 3.95(s, 2H), 1 H NMR (300 MHz, CDCl 3 ): δ 1.24 (t, 6H), 3.21 (s, 2H), 3.95 (s, 2H),
4.24(q, 4H), 7.48(d, 2H), 7.60(d, 2H),4.24 (q, 4H), 7.48 (d, 2H), 7.60 (d, 2H),
7.65(d, 2H), 8.04(d, 2H)7.65 (d, 2H), 8.04 (d, 2H)
실시예 8: N-페닐-5-(비페닐-4-일)-5-옥소-3,3-디에틸카르복실발레릭아미드 (VI, R1=H)의 제조 Example 8 Preparation of N-phenyl-5- (biphenyl-4-yl) -5-oxo-3,3-diethylcarboxyvalerericamide (VI, R 1 = H)
5-(비페닐-4-일)-5-옥소-3,3-디에틸카르복실발레릭산(V, R1=H, 0.5g, 1.2mmol), EDC(0.23g, 1.2mmol) 및 HOBt(0.16g, 1.2mmol)를 MC(5mL)에 용해시킨후, 0℃로 냉각하였다. 여기에 TEA(170mL, 1.2mmol)를 넣고 10분간 교반한 다음, 아닐린(122mL, 1.3mmol)을 넣고 상온에서 2시간 30분동안 다시 교반하였다. 여기에 1N HCl용액을 넣고 MC로 추출한 다음, 무수 MgSO4로 건조, 여과, 감압 증류하여 표제화합물을 제조하고, 컬럼 크로마토그래피(Hx/EA=4/1)로 정제하여, 0.365g(62%)의 표제화합물을 제조하였다.5- (biphenyl-4-yl) -5-oxo-3,3-diethylcarboxyvaleric acid (V, R 1 = H, 0.5 g, 1.2 mmol), EDC (0.23 g, 1.2 mmol) and HOBt (0.16 g, 1.2 mmol) was dissolved in MC (5 mL) and then cooled to 0 ° C. TEA (170mL, 1.2mmol) was added thereto and stirred for 10 minutes. Then, aniline (122mL, 1.3mmol) was added thereto and stirred again at room temperature for 2 hours 30 minutes. To this was added 1N HCl solution, extracted with MC, dried over anhydrous MgSO 4 , filtered and distilled under reduced pressure to obtain the title compound, which was purified by column chromatography (Hx / EA = 4/1) and purified by 0.365 g (62%). ), The title compound was prepared.
1H NMR(300MHz, CDCl3): δ1.24(t, 6H), 3.32(s, 2H), 4.05(s, 2H), 1 H NMR (300 MHz, CDCl 3 ): δ 1.24 (t, 6H), 3.32 (s, 2H), 4.05 (s, 2H),
4.24(q, 4H), 7.07(t, 1H), 7.26(m, 1H),4.24 (q, 4H), 7.07 (t, 1H), 7.26 (m, 1H),
7.45(m, 5H), 7.65(m, 5H), 8.04(d, 2H)7.45 (m, 5H), 7.65 (m, 5H), 8.04 (d, 2H)
실시예 9: N-씨클로프로필-5-(비페닐-4-일)-5-옥소-3,3-디에틸카르복실발레릭아미드(VI, R1=H)의 제조 Example 9 Preparation of N-cyclopropyl-5- (biphenyl-4-yl) -5-oxo-3,3-diethylcarboxyvaleramide (VI, R 1 = H)
5-(비페닐-4-일)-5-옥소-3,3-디에틸카르복실발레릭산(V, R1=H)과 씨클릭프로필아민을 사용하는 것을 제외하고는, 실시예 8과 동일한 방법으로 표제 화합물을 제조하였다.Example 8, except that 5- (biphenyl-4-yl) -5-oxo-3,3-diethylcarboxyvaleric acid (V, R 1 = H) and cyclicpropylamine were used. In the same manner, the title compound was prepared.
1H NMR(300MHz, CDCl3): δ0.41(m, 2H), 0.69(m, 2H), 2.62(m, 1H), 1 H NMR (300 MHz, CDCl 3 ): δ 0.41 (m, 2H), 0.69 (m, 2H), 2.62 (m, 1H),
3.08(s, 2H), 4.00(s, 2H), 4.24(q, 4H),3.08 (s, 2H), 4.00 (s, 2H), 4.24 (q, 4H),
5.9(s, 1H), 7.45(m, 3H), 7.61(d, 2H),5.9 (s, 1H), 7.45 (m, 3H), 7.61 (d, 2H),
7.69(d, 2H), 8.04(d, 2H)7.69 (d, 2H), 8.04 (d, 2H)
실시예 10: N-(α-메틸벤질)-5-(비페닐-4-일)-5-옥소-3,3-디에틸카르복실발레릭아미드(VI, R1=H)의 제조(VI) Example 10 Preparation of N- (α-Methylbenzyl) -5- (biphenyl-4-yl) -5-oxo-3,3-diethylcarboxyvalerericamide (VI, R 1 = H) VI)
5-(비페닐-4-일)-5-옥소-3,3-디에틸카르복실발레릭산(V, R1=H)과 α-메틸벤질아민을 사용하는 것을 제외하고는, 실시예 8과 동일한 방법으로 표제 화합물을 제조하였다.Example 8, except that 5- (biphenyl-4-yl) -5-oxo-3,3-diethylcarboxyvaleric acid (V, R 1 = H) and α-methylbenzylamine are used In the same manner as in the title compound was prepared.
1H NMR(300MHz, CDCl3): δ1.24(t, 6H), 1.41(d, 3H), 3.17(d, 2H), 1 H NMR (300 MHz, CDCl 3 ): δ 1.24 (t, 6H), 1.41 (d, 3H), 3.17 (d, 2H),
3.97(d, 2H), 4.21(q, 4H), 5.0(m, 1H),3.97 (d, 2H), 4.21 (q, 4H), 5.0 (m, 1H),
5.95(d, 1H), 7.19(m, 5H), 7.46(m, 3H),5.95 (d, 1 H), 7.19 (m, 5 H), 7.46 (m, 3 H),
7.61(d, 2H), 7.67(d, 2H), 8.04(d, 2H)7.61 (d, 2H), 7.67 (d, 2H), 8.04 (d, 2H)
실시예 11: N-페닐-5-(4'-메톡시비페닐-4-일)-5-옥소-3,3-디에틸카르복실발레릭아미드(VI, R1=OMe)의 제조 Example 11 Preparation of N-phenyl-5- (4'-methoxybiphenyl-4-yl) -5-oxo-3,3-diethylcarboxyvaleramide (VI, R 1 = OMe)
5-(4'-메톡시비페닐-4-일)-5-옥소-3,3-디에틸카르복실발레릭산(V, R1=OMe)과 아닐린을 사용하는 것을 제외하고는, 실시예 8과 동일한 방법으로 표제 화합물을 제조하였다.Example 8, except using 5- (4'-methoxybiphenyl-4-yl) -5-oxo-3,3-diethylcarboxyvaleric acid (V, R 1 = OMe) and aniline In the same manner as in the title compound was prepared.
1H NMR(300MHz, CDCl3): δ1.24(t, 6H), 3.34(s, 2H), 3.86(s, 3H), 1 H NMR (300 MHz, CDCl 3 ): δ 1.24 (t, 6H), 3.34 (s, 2H), 3.86 (s, 3H),
4.04(s, 2H), 4.24(q, 4H), 7.0(d, 2H),4.04 (s, 2H), 4.24 (q, 4H), 7.0 (d, 2H),
7.05(t, 1H), 7.26(t, 2H), 7.44(d, 2H),7.05 (t, 1H), 7.26 (t, 2H), 7.44 (d, 2H),
7.54(d, 2H), 7.62(d, 2H), 8.02(d, 2H)7.54 (d, 2H), 7.62 (d, 2H), 8.02 (d, 2H)
실시예 12: N-[1,5-디옥소-5-(4'-메톡시비페닐-4-일)-3,3-디에틸카르복실펜탄-1-일]-4-메틸피페라진(VI, R1=OMe)의 제조(VI) Example 12 N- [1,5-dioxo-5- (4'-methoxybiphenyl-4-yl) -3,3-diethylcarboxypentan-1-yl] -4-methylpiperazine ( VI, R 1 = OMe) Preparation (VI)
5-(4'-메톡시비페닐-4-일)-5-옥소-3,3-디에틸카르복실발레릭산(V, R1=OMe)과 N-메틸피페라진을 사용하는 것을 제외하고는, 실시예 8과 동일한 방법으로 표제 화합물을 제조하였다.Except for using 5- (4'-methoxybiphenyl-4-yl) -5-oxo-3,3-diethylcarboxyvaleric acid (V, R 1 = OMe) and N-methylpiperazine In the same manner as in Example 8, the title compound was prepared.
1H NMR(300MHz, CDCl3): δ1.24(t, 6H), 2.30(s, 3H), 2.34(br, 4H), 1 H NMR (300 MHz, CDCl 3 ): δ 1.24 (t, 6H), 2.30 (s, 3H), 2.34 (br, 4H),
3.35(s, 2H), 3.55(br, 4H), 3.86(s, 3H),3.35 (s, 2H), 3.55 (br, 4H), 3.86 (s, 3H),
4.10(s, 2H), 4.24(q, 4H), 7.0(d, 2H),4.10 (s, 2H), 4.24 (q, 4H), 7.0 (d, 2H),
7.58(d, 2H), 7.65(d, 2H), 8.02(d, 2H)7.58 (d, 2H), 7.65 (d, 2H), 8.02 (d, 2H)
실시예 13: N-페닐-5-(4'-브로모비페닐-4-일)-5-옥소-3,3-디에틸카르복실발레릭아미드(VI, R1=Br)의 제조 Example 13 Preparation of N-phenyl-5- (4'-bromobiphenyl-4-yl) -5-oxo-3,3-diethylcarboxyvaleramide (VI, R 1 = Br)
5-(4'-브로모비페닐-4-일)-5-옥소-3,3-디에틸카르복실발레릭산(V, R1=OMe)과 아닐린을 사용하는 것을 제외하고는, 실시예 8과 동일한 방법으로 표제 화합물을 제조하였다.Example 8, except using 5- (4'-bromobiphenyl-4-yl) -5-oxo-3,3-diethylcarboxyvaleric acid (V, R 1 = OMe) and aniline In the same manner as in the title compound was prepared.
1H NMR(300MHz, CDCl3): δ1.24(t, 6H), 3.33(s, 2H), 4.05(s, 2H), 1 H NMR (300 MHz, CDCl 3 ): δ 1.24 (t, 6H), 3.33 (s, 2H), 4.05 (s, 2H),
4.26(q, 4H), 7.07(t, 1H), 7.24(m, 2H),4.26 (q, 4H), 7.07 (t, 1H), 7.24 (m, 2H),
7.48(m, 4H), 7.60(d, 2H), 7.65(d, 2H),7.48 (m, 4H), 7.60 (d, 2H), 7.65 (d, 2H),
8.04(d, 2H)8.04 (d, 2H)
실시예 14: N-[1,5-디옥소-5-(4'-브로모비페닐-4-일)-3,3-디에틸카르복실펜탄-1-일]피페리딘(VI, R1=Br)의 제조 Example 14 N- [1,5-dioxo-5- (4'-bromobiphenyl-4-yl) -3,3-diethylcarboxypentan-1-yl] piperidine (VI, R Preparation of 1 = Br)
5-(4'-브로모비페닐-4-일)-5-옥소-3,3-디에틸카르복실발레릭산(V, R1=Br)과 피페리딘을 사용하는 것을 제외하고는, 실시예 8과 동일한 방법으로 표제 화합물을 제조하였다.Except that 5- (4'-bromobiphenyl-4-yl) -5-oxo-3,3-diethylcarboxyvaleric acid (V, R 1 = Br) and piperidine are used The title compound was prepared in the same manner as in Example 8.
1H NMR(300MHz, CDCl3): δ1.24(t, 6H), 2.85(Br, 4H), 3.37(s, 2H), 1 H NMR (300 MHz, CDCl 3 ): δ 1.24 (t, 6H), 2.85 (Br, 4H), 3.37 (s, 2H),
3.64(br, 4H), 4.00(s, 2H), 4.26(q, 4H),3.64 (br, 4H), 4.00 (s, 2H), 4.26 (q, 4H),
7.48(d, 2H), 7.59(d, 2H), 7.66(d, 2H),7.48 (d, 2H), 7.59 (d, 2H), 7.66 (d, 2H),
8.04(d, 2H)8.04 (d, 2H)
실시예 15: N-[1,5-디옥소-5-(4'-브로모비페닐-4-일)-3,3-디에틸카르복실펜탄-1-일]-4-벤조일피페라진(VI, R1=Br)의 제조(VI) Example 15 N- [1,5-dioxo-5- (4'-bromobiphenyl-4-yl) -3,3-diethylcarboxypentan-1-yl] -4-benzoylpiperazine ( Preparation of VI, R 1 = Br) (VI)
N-벤조일피페라진(Kondo, K. et al, J. Chem. Soc, Perkin Trans 1, 1998, 2973-2974의 방법으로 합성)과 5-(4'-브로모비페닐-4-일)-5-옥소-3,3-디에틸카르복실발레릭산(V, R1=Br)을 사용하는 것을 제외하고는, 실시예 8과 동일한 방법으로 표제 화합물을 제조하였다.N-benzoylpiperazine (synthesized by Kondo, K. et al, J. Chem. Soc, Perkin Trans 1, 1998, 2973-2974) and 5- (4'-bromobiphenyl-4-yl) -5 The title compound was prepared in the same manner as in Example 8, except that -oxo-3,3-diethylcarboxylic valeric acid (V, R 1 = Br) was used.
1H NMR(300MHz, CDCl3): δ1.24(t, 6H), 3.18(s, 2H), 3.54(br, 4H), 1 H NMR (300 MHz, CDCl 3 ): δ 1.24 (t, 6H), 3.18 (s, 2H), 3.54 (br, 4H),
3.75(br, 4H), 4.00(s, 2H), 4.24(q, 4H),3.75 (br, 4H), 4.00 (s, 2H), 4.24 (q, 4H),
7.40(m, 4H), 7.42(d, 2H), 7.62(m, 4H),7.40 (m, 4H), 7.42 (d, 2H), 7.62 (m, 4H),
7.86(d, 1H), 8.02(d, 2H)7.86 (d, 1 H), 8.02 (d, 2 H)
실시예 16: N-페닐-5-(비페닐-4-일)-5-옥소-3-카르복실발레릭아미드(I, R1=H)의 제조 Example 16 Preparation of N-phenyl-5- (biphenyl-4-yl) -5-oxo-3-carboxyvaleramide (I, R 1 = H)
N-페닐-5-(비페닐-4-일)-5-옥소-3,3-디에틸카르복실발레릭아미드(VI, R1=H,0.36g, 0.74mmol)를 에탄올(10mL)에 용해시킨 후, 1N NaOH(1.55mL, 1.55mmol)을 넣고 상온에서 2시간동안 교반하였다. 에탄올을 감압제거한 다음, 물을 넣고 에틸초산으로 세척하였다. 여기에 1N HCl용액으로 산성화하여, 에틸초산으로 추출한 후, 무수 MgSO4로 건조, 여과, 감압 증류하였다. 이렇게 합성된 물질을 1,4-디옥산(dioxane, 10mL)에 용해시킨 후, 3시간동안 가열 환류시키고 용매를 감압제거시켜 수득한 물질을 MC/MeOH(19/1)용액(v/v)과 헥산으로 재 결정화하여 표제화합물(0.17g, 60%)을 제조하였다.N-phenyl-5- (biphenyl-4-yl) -5-oxo-3,3-diethylcarboxyvaleramide (VI, R 1 = H, 0.36 g, 0.74 mmol) in ethanol (10 mL) After dissolution, 1N NaOH (1.55 mL, 1.55 mmol) was added thereto, and the resultant was stirred at room temperature for 2 hours. After ethanol was removed under reduced pressure, water was added and the mixture was washed with ethyl acetate. The mixture was acidified with 1N HCl solution, extracted with ethyl acetate, dried over anhydrous MgSO 4 , filtered, and distilled under reduced pressure. The synthesized material was dissolved in 1,4-dioxane (10 mL), heated to reflux for 3 hours, and the solvent was evaporated under reduced pressure to obtain a MC / MeOH (19/1) solution (v / v). Recrystallized with hexane to give the title compound (0.17g, 60%).
1H NMR(300MHz, CDCl3): δ2.76(dd, 1H), 2.90(dd, 1H), 3.42(dd, 1H), 1 H NMR (300 MHz, CDCl 3 ): δ 2.76 (dd, 1H), 2.90 (dd, 1H), 3.42 (dd, 1H),
3.49(m, 1H), 3.58(dd, 1H), 7.10(t, 1H),3.49 (m, 1 H), 3.58 (dd, 1 H), 7.10 (t, 1 H),
7.26(m, 1H), 7.45(m, 5H), 7.65(m, 5H),7.26 (m, 1 H), 7.45 (m, 5 H), 7.65 (m, 5 H),
8.07(d, 2H)8.07 (d, 2 H)
실시예 17: N-씨클로프로필-5-(비페닐-4-일)-5-옥소-3-카르복실발레릭아미드 (I, R1=H)의 제조 Example 17 Preparation of N-cyclopropyl-5- (biphenyl-4-yl) -5-oxo-3-carboxyvalerericamide (I, R 1 = H)
N-씨클로프로필-5-(비페닐-4-일)-5-옥소-3,3-디에틸카르복실발레릭아미드(VI, R1=H)을 사용하는 것을 제외하고는, 실시예 16과 동일한 방법으로 표제 화합물을 제조하였다.Example 16, except using N-cyclopropyl-5- (biphenyl-4-yl) -5-oxo-3,3-diethylcarboxyvaleramide (VI, R 1 = H) In the same manner as in the title compound was prepared.
1H NMR(300MHz, CDCl3): δ0.47(m, 2H), 0.73(m, 2H), 2.48(dd, 1H), 1 H NMR (300 MHz, CDCl 3 ): δ 0.47 (m, 2H), 0.73 (m, 2H), 2.48 (dd, 1H),
2.68(m, 2H), 3.39(m, 2H), 3.54(dd, 1H),2.68 (m, 2H), 3.39 (m, 2H), 3.54 (dd, 1H),
7.40(m, 3H), 7.61(d, 2H), 7.69(d, 2H),7.40 (m, 3H), 7.61 (d, 2H), 7.69 (d, 2H),
8.02(d, 2H)8.02 (d, 2H)
실시예 18: N-(α-메틸벤질)-5-(비페닐-4-일)-5-옥소-3-카르복실발레릭아미드(I, R1=H)의 제조 Example 18 Preparation of N- (α-Methylbenzyl) -5- (biphenyl-4-yl) -5-oxo-3-carboxyvaleramide (I, R 1 = H)
N-(α-메틸벤질)-5-(비페닐-4-일)-5-옥소-3,3-디에틸카르복실발레릭아미드(VI, R1=H)을 사용하는 것을 제외하고는, 실시예 16과 동일한 방법으로 표제 화합물을 제조하였다.Except for using N- (α-methylbenzyl) -5- (biphenyl-4-yl) -5-oxo-3,3-diethylcarboxyvaleramide (VI, R 1 = H) In the same manner as in Example 16, the title compound was prepared.
1H NMR(300MHz, CDCl3): δ1.44(d, 3H), 2.48(dd, 1H), 2.68(m, 2H), 1 H NMR (300 MHz, CDCl 3 ): δ 1.44 (d, 3H), 2.48 (dd, 1H), 2.68 (m, 2H),
3.39(m, 2H), 3.54(dd, 1H), 4.98(m, 1H),3.39 (m, 2H), 3.54 (dd, 1H), 4.98 (m, 1H),
7.40(m, 3H), 7.61(d, 2H), 7.69(d, 2H),7.40 (m, 3H), 7.61 (d, 2H), 7.69 (d, 2H),
8.02(d, 2H)8.02 (d, 2H)
실시예 19: N-페닐-5-(4'-메톡시비페닐-4-일)-5-옥소-3-카르복실발레릭아미드(I, R1=OMe)의 제조(I) Example 19 Preparation of N-phenyl-5- (4'-methoxybiphenyl-4-yl) -5-oxo-3-carboxyvaleramide (I, R 1 = OMe) (I)
N-페닐-5-(4'-메톡시비페닐-4-일)-5-옥소-3,3-디에틸카르복실발레릭아미드(VI, R1=OMe)를 사용하는 것을 제외하고는, 실시예 16과 동일한 방법으로 표제 화합물을 제조하였다.Except for using N-phenyl-5- (4'-methoxybiphenyl-4-yl) -5-oxo-3,3-diethylcarboxyvaleramide (VI, R 1 = OMe), In the same manner as in Example 16, the title compound was prepared.
1H NMR(300MHz, CDCl3): δ2.70(dd, 1H), 2.91(dd, 1H), 3.40(dd, 1H), 1 H NMR (300 MHz, CDCl 3 ): δ2.70 (dd, 1H), 2.91 (dd, 1H), 3.40 (dd, 1H),
3.49(m, 1H), 3.55(dd, 1H), 3.84(s, 3H),3.49 (m, 1 H), 3.55 (dd, 1 H), 3.84 (s, 3 H),
6.98(d, 2H), 7.06(t, 1H), 7.30(m, 2H),6.98 (d, 2H), 7.06 (t, 1H), 7.30 (m, 2H),
7.50(m, 4H), 7.62(d, 2H), 8.01(d, 2H)7.50 (m, 4H), 7.62 (d, 2H), 8.01 (d, 2H)
실시예 20: N-[1,5-디옥소-5-(4'-메톡시비페닐-4-일)-3-카르복실펜탄-1-일]-4-메틸피페라진(I, R1=OMe)의 제조(VI) Example 20 N- [1,5-dioxo-5- (4'-methoxybiphenyl-4-yl) -3-carboxypentan-1-yl] -4-methylpiperazine (I, R 1 OMe) Preparation (VI)
N-[1,5-디옥소-5-(4'-메톡시비페닐-4-일)-3,3-디에틸카르복실펜탄-1-일]-4-메틸피페라진(VI, R1=OMe)을 사용하는 것을 제외하고는, 실시예 16과 동일한 방법으로 표제 화합물을 제조하였다.N- [1,5-dioxo-5- (4'-methoxybiphenyl-4-yl) -3,3-diethylcarboxypentan-1-yl] -4-methylpiperazine (VI, R 1 The title compound was prepared in the same manner as in Example 16, except for using = OMe).
1H NMR(300MHz, CDCl3): δ1.20(s, 3H), 2.45(s, 1H), 2.65(m, 4H), 1 H NMR (300 MHz, CDCl 3 ): δ 1.20 (s, 3H), 2.45 (s, 1H), 2.65 (m, 4H),
2.82(dd, 1H), 3.28(dd, 1H), 3.39(br, 4H),2.82 (dd, 1H), 3.28 (dd, 1H), 3.39 (br, 4H),
3.65(dd, 1H), 3.84(s, 3H), 4.13(m, 1H),3.65 (dd, 1H), 3.84 (s, 3H), 4.13 (m, 1H),
6.98(d, 2H), 7.54(d, 2H), 7.62(d, 2H),6.98 (d, 2H), 7.54 (d, 2H), 7.62 (d, 2H),
8.00(d, 2H)8.00 (d, 2H)
실시예 21: N-페닐-5-(4'-브로모비페닐-4-일)-5-옥소-3-카르복실발레릭아미드(I, R1=OMe)의 제조(I) Example 21 Preparation of N-phenyl-5- (4′-bromobiphenyl-4-yl) -5-oxo-3-carboxyvaleramideamide (I, R 1 = OMe) (I)
N-페닐-5-(4'-브로모비페닐-4-일)-5-옥소-3,3-디에틸카르복실발레릭아미드(VI, R1=Br)를 사용하는 것을 제외하고는, 실시예 1과 동일한 방법으로 표제 화합물을 제조하였다.Except for using N-phenyl-5- (4'-bromobiphenyl-4-yl) -5-oxo-3,3-diethylcarboxyvaleramide (VI, R 1 = Br), The title compound was prepared in the same manner as in Example 1.
1H NMR(300MHz, CDCl3+DMSO): δ2.73(dd, 1H), 2.89(dd, 1H), 3.33(dd, 2H), 1 H NMR (300 MHz, CDCl 3 + DMSO): δ2.73 (dd, 1H), 2.89 (dd, 1H), 3.33 (dd, 2H),
3.55(m, 1H), 7.05(t, 1H), 7.28(t, 2H),3.55 (m, 1 H), 7.05 (t, 1 H), 7.28 (t, 2 H),
7.52(m, 6H), 7.65(d, 2H), 8.04(d, 2H)7.52 (m, 6H), 7.65 (d, 2H), 8.04 (d, 2H)
실시예 22: N-[1,5-디옥소-5-(4'-브로모비페닐-4-일)-3-카르복실펜탄-1-일]피페리딘(I, R1=Br) Example 22 N- [1,5-dioxo-5- (4'-bromobiphenyl-4-yl) -3-carboxypentan-1-yl] piperidine (I, R 1 = Br)
N-[1,5-디옥소-5-(4'-브로모비페닐-4-일)-3,3-디에틸카르복실펜탄-1-일]피페리딘(VI, R1=Br)을 사용하는 것을 제외하고는, 실시예 16과 동일한 방법으로 표제 화합물을 제조하였다.N- [1,5-dioxo-5- (4'-bromobiphenyl-4-yl) -3,3-diethylcarboxypentan-1-yl] piperidine (VI, R 1 = Br) Except for using the title compound in the same manner as in Example 16 was prepared.
H NMR(300MHz, CDCl3): δ2.85(Br, 4H), 3.37(m, 2H), 3.64(br, 4H),H NMR (300 MHz, CDCl 3 ): δ 2.85 (Br, 4H), 3.37 (m, 2H), 3.64 (br, 4H),
4.00(m, 2H), 4.13(m, 1H), 7.48(d, 2H),4.00 (m, 2H), 4.13 (m, 1H), 7.48 (d, 2H),
7.59(d, 2H), 7.66(d, 2H), 8.04(d, 2H)7.59 (d, 2H), 7.66 (d, 2H), 8.04 (d, 2H)
실시예 23: N-[1,5-디옥소-5-(4'-브로모비페닐-4-일)-3-카르복실펜탄-1-일]-4-벤조일피페라진(I, R1=Br) Example 23 N- [1,5-dioxo-5- (4'-bromobiphenyl-4-yl) -3-carboxypentan-1-yl] -4-benzoylpiperazine (I, R 1 = Br)
N-[1,5-디옥소-5-(4'-브로모비페닐-4-일)-3,3-디에틸카르복실펜탄-1-일]-4-벤조일피페라진(VI, R1=Br)을 사용하는 것을 제외하고는, 실시예 16과 동일한 방법으로 표제 화합물을 제조하였다.N- [1,5-dioxo-5- (4'-bromobiphenyl-4-yl) -3,3-diethylcarboxypentan-1-yl] -4-benzoylpiperazine (VI, R 1 The title compound was prepared in the same manner as in Example 16, except for using = Br).
1H NMR(300MHz, CDCl3): δ2.59(dd, 1H), 2.86(br, 4H), 3.10(dd, 1H), 1 H NMR (300 MHz, CDCl 3 ): δ 2.59 (dd, 1H), 2.86 (br, 4H), 3.10 (dd, 1H),
3.42(dd, 2H), 3.62(Br, 4H), 3.80(m, 1H),3.42 (dd, 2H), 3.62 (Br, 4H), 3.80 (m, 1H),
7.40(m, 4H), 7.42(d, 2H), 7.62(m, 4H),7.40 (m, 4H), 7.42 (d, 2H), 7.62 (m, 4H),
7.86(d, 1H), 8.02(d, 2H)7.86 (d, 1 H), 8.02 (d, 2 H)
실시예 24: 5-(4'-클로로비페닐-4-일)-5-옥소-3-에틸카르복실발레릭산,t-부틸에스테르(VII, R1=Cl)의 제조 Example 24 Preparation of 5- (4'-Chlorobiphenyl-4-yl) -5-oxo-3-ethylcarboxyvaleric acid, t-butyl ester (VII, R 1 = Cl)
KOH(85%, 0.72g, 11.0mmol)를 에탄올(30mL)에 용해시킨 용액을 5-(4'-클로로비페닐-4-일)-5-옥소-3,3-디에틸카르복실발레릭산,t-부틸에스테르(IV, R1=Cl, 5.26g, 10.46mmol)를 에탄올(30mL)에 용해시킨 용액에 천천히 넣고 상온에서 6시간동안 교반한 다음, 1N HCl용액으로 산성화시키고 에틸초산으로 추출하고, 무수 MgSO4로 건조, 여과, 감압 증류하였다. 이렇게 합성된 물질을 1,4-디옥산(10mL)에 용해시키고, 3시간동안 가열 환류시키고, 용매를 감압제거하여 표제화합물(3.51g, 78%)을 제조하였다.A solution of KOH (85%, 0.72 g, 11.0 mmol) in ethanol (30 mL) was dissolved in 5- (4'-chlorobiphenyl-4-yl) -5-oxo-3,3-diethylcarboxylic valeric acid. , t-butyl ester (IV, R 1 = Cl, 5.26g, 10.46mmol) was slowly added to a solution of ethanol (30 mL), stirred at room temperature for 6 hours, acidified with 1N HCl solution and extracted with ethyl acetate. The mixture was dried over anhydrous MgSO 4 , filtered, and distilled under reduced pressure. The synthesized material was dissolved in 1,4-dioxane (10 mL), heated to reflux for 3 hours, and the solvent was removed under reduced pressure to obtain the title compound (3.51 g, 78%).
1H NMR(300MHz, CDCl3): δ1.24(t, 3H), 1.45(s, 9H), 2.66(ddd, 2H), 1 H NMR (300 MHz, CDCl 3 ): δ 1.24 (t, 3H), 1.45 (s, 9H), 2.66 (ddd, 2H),
3.24(dd, 1H), 3.45(m, 1H), 3.53(dd, 1H),3.24 (dd, 1H), 3.45 (m, 1H), 3.53 (dd, 1H),
4.16(q, 2H), 7.42(d, 2H), 7.55(d, 2H),4.16 (q, 2H), 7.42 (d, 2H), 7.55 (d, 2H),
7.65(m, 2H), 8.03(d, 2H)7.65 (m, 2H), 8.03 (d, 2H)
실시예 25: 5-(비페닐-4-일)-5-옥소-3-에틸카르복실발레릭산,t-부틸에스테르 (VII, R1=H)의 제조 Example 25 Preparation of 5- (biphenyl-4-yl) -5-oxo-3-ethylcarboxylic valeric acid, t-butyl ester (VII, R 1 = H)
5-(비페닐-4-일)-5-옥소-3,3-디에틸카르복실발레릭산,t-부틸에스테르(IV, R1=H)을 사용하는 것을 제외하고는, 실시예 24와 동일한 방법으로 표제 화합물을 제조하였다.Example 24, except that 5- (biphenyl-4-yl) -5-oxo-3,3-diethylcarboxylic valeric acid, t-butyl ester (IV, R 1 = H) was used. In the same manner, the title compound was prepared.
1H NMR(300MHz, CDCl3): δ1.24(t, 3H), 1.45(s, 9H), 2.66(ddd, 2H), 1 H NMR (300 MHz, CDCl 3 ): δ 1.24 (t, 3H), 1.45 (s, 9H), 2.66 (ddd, 2H),
3.24(dd, 1H), 3.45(m, 1H), 3.53(dd, 1H),3.24 (dd, 1H), 3.45 (m, 1H), 3.53 (dd, 1H),
4.16(q, 2H), 7.45(m, 3H), 7.61(d, 2H),4.16 (q, 2H), 7.45 (m, 3H), 7.61 (d, 2H),
7.69(d, 2H), 8.04(d, 2H)7.69 (d, 2H), 8.04 (d, 2H)
실시예 26: 5-(4'-브로모비페닐-4-일)-5-옥소-3-에틸카르복실발레릭산,t-부틸에스테르(VII, R1=Br)의 제조 Example 26 Preparation of 5- (4'-Bromobiphenyl-4-yl) -5-oxo-3-ethylcarboxylic valeric acid, t-butyl ester (VII, R 1 = Br)
5-(4'-브로모비페닐-4-일)-5-옥소-3,3-디에틸카르복실발레릭산,t-부틸에스테르(IV, R1=Br)을 사용하는 것을 제외하고는, 실시예 24와 동일한 방법으로 표제 화합물을 제조하였다.Except for using 5- (4'-bromobiphenyl-4-yl) -5-oxo-3,3-diethylcarboxylic valeric acid, t-butyl ester (IV, R 1 = Br), In the same manner as in Example 24, the title compound was prepared.
1H NMR(300MHz, CDCl3): δ1.24(t, 3H), 1.45(s, 9H), 2.66(ddd, 2H), 1 H NMR (300 MHz, CDCl 3 ): δ 1.24 (t, 3H), 1.45 (s, 9H), 2.66 (ddd, 2H),
3.24(dd, 1H), 3.45(m, 1H), 3.53(dd, 1H),3.24 (dd, 1H), 3.45 (m, 1H), 3.53 (dd, 1H),
4.16(q, 2H), 7.48(d, 2H), 7.60(d, 2H),4.16 (q, 2H), 7.48 (d, 2H), 7.60 (d, 2H),
7.65(d, 2H), 8.04(d, 2H)7.65 (d, 2H), 8.04 (d, 2H)
실시예 27: 5-(4'-클로로비페닐-4-일)-5-옥소-3-에틸카르복실발레릭산(VIII, R1=Cl)의 제조 Example 27 Preparation of 5- (4'-Chlorobiphenyl-4-yl) -5-oxo-3-ethylcarboxyvaleric acid (VIII, R 1 = Cl)
5-(4'-클로로비페닐-4-일)-5-옥소-3-에틸카르복실발레릭산,t-부틸에스테르(VII, R1=Cl, 3.51g, 8.14mmol)를 MC(50mL)에 분산시킨 후, TFA(7.4mL)를 넣고 상온에서 24시간 교반하였다. 이후, MC를 감압제거하고 에틸초산(20mL)을 넣은 후, 1N NaOH용액을 천천히 넣고 10분간 교반한 다음, 물로 추출하였다. 여기에 1N HCl용액을 넣고 에틸초산으로 추출한 후, 무수 MgSO4로 건조, 여과, 감압 증류하고 CHCl3와 헥산으로 재결정하여, 표제화합물 2.7g(88%)을 제조하였다.5- (4'-Chlorobiphenyl-4-yl) -5-oxo-3-ethylcarboxylic valeric acid, t-butyl ester (VII, R 1 = Cl, 3.51 g, 8.14 mmol) in MC (50 mL) After dispersed in, TFA (7.4 mL) was added and stirred at room temperature for 24 hours. Then, MC was removed under reduced pressure, ethyl acetate (20 mL) was added thereto, 1N NaOH solution was slowly added thereto, stirred for 10 minutes, and then extracted with water. 1N HCl solution was added thereto, extracted with ethyl acetate, dried over anhydrous MgSO 4 , filtered, distilled under reduced pressure, and recrystallized with CHCl 3 and hexane to obtain 2.7 g (88%) of the title compound.
1H NMR(300MHz, CDCl3): δ1.24(t, 3H), 2.84(ddd, 2H), 3.30(dd, 1H), 1 H NMR (300 MHz, CDCl 3 ): δ 1.24 (t, 3H), 2.84 (ddd, 2H), 3.30 (dd, 1H),
3.48(m, 1H), 3.57(dd, 1H), 4.18(q, 2H),3.48 (m, 1 H), 3.57 (dd, 1 H), 4.18 (q, 2H),
7.42(d, 2H), 7.55(d, 2H), 7.65(m, 2H),7.42 (d, 2H), 7.55 (d, 2H), 7.65 (m, 2H),
8.03(d, 2H)8.03 (d, 2H)
실시예 28: 5-(비페닐-4-일)-5-옥소-3-에틸카르복실발레릭산(VIII, R1=H)의 제조 Example 28 Preparation of 5- (biphenyl-4-yl) -5-oxo-3-ethylcarboxyvaleric acid (VIII, R 1 = H)
5-(비페닐-4-일)-5-옥소-3-에틸카르복실발레릭산,t-부틸에스테르(VII, R1=H)을 사용하는 것을 제외하고는, 실시예 27과 동일한 방법으로 표제 화합물을 제조하였다.In the same manner as in Example 27, except that 5- (biphenyl-4-yl) -5-oxo-3-ethylcarboxylic valeric acid, t-butyl ester (VII, R 1 = H) was used. The title compound was prepared.
1H NMR(300MHz, CDCl3): δ1.24(t, 3H), 2.84(ddd, 2H), 3.30(dd, 1H), 1 H NMR (300 MHz, CDCl 3 ): δ 1.24 (t, 3H), 2.84 (ddd, 2H), 3.30 (dd, 1H),
3.48(m,1H), 3.57(dd, 1H), 4.18(q, 2H),3.48 (m, 1H), 3.57 (dd, 1H), 4.18 (q, 2H),
7.45(m, 3H), 7.61(d, 2H), 7.69(d, 2H),7.45 (m, 3H), 7.61 (d, 2H), 7.69 (d, 2H),
8.04(d, 2H)8.04 (d, 2H)
실시예 29: 5-(4'-브로모비페닐-4-일)-5-옥소-3-에틸카르복실발레릭산(VIII, R1=Br)의 제조 Example 29 Preparation of 5- (4'-Bromobiphenyl-4-yl) -5-oxo-3-ethylcarboxyvaleric acid (VIII, R 1 = Br)
5-(4'-브로모비페닐-4-일)-5-옥소-3-에틸카르복실발레릭산,t-부틸에스테르(VII, R1=Br)를 사용하는 것을 제외하고는, 실시예 27과 동일한 방법으로 표제 화합물을 제조하였다.Example 27, except using 5- (4'-bromobiphenyl-4-yl) -5-oxo-3-ethylcarboxylic valeric acid, t-butyl ester (VII, R 1 = Br) In the same manner as in the title compound was prepared.
1H NMR(300MHz, CDCl3): δ1.24(t, 3H), 2.84(ddd, 2H), 3.30(dd, 1H), 1 H NMR (300 MHz, CDCl 3 ): δ 1.24 (t, 3H), 2.84 (ddd, 2H), 3.30 (dd, 1H),
3.48(m, 1H), 3.57(dd, 1H), 4.18(q, 2H),3.48 (m, 1 H), 3.57 (dd, 1 H), 4.18 (q, 2H),
7.48(d, 2H), 7.60(d, 2H), 7.65(d, 2H),7.48 (d, 2H), 7.60 (d, 2H), 7.65 (d, 2H),
8.04(d, 2H)8.04 (d, 2H)
실시예 30: N-(3-시아노페닐)-5-[(비페닐-4-일)-5-옥소-3-에틸카르보닐]발레익아미드(IX, R1=H)의 제조 Example 30 Preparation of N- (3-cyanophenyl) -5-[(biphenyl-4-yl) -5-oxo-3-ethylcarbonyl] valericamide (IX, R 1 = H)
5-(비페닐-4-일)-5-옥소-3-에틸카르복실발레릭산(VIII, R1=H, 50mg, 0.147mmol)을 THF(3mL)에 용해시키고 0℃로 냉각하였다. 여기에 N-메틸모포린(35mL, 0.323mmol) 및 에틸 클로로포메이트(16mL, 0.162mmol)를 가하고 30분간 교반한 후, 3-아미노벤조니트릴을 THF(1mL)에 용해시킨 용액을 가하였다. 이를 상온에서 3시간 30분동안 교반한 후, 여과하고 여액을 감압 증류하였다. 이를 클로로포름으로 희석하고, 1N HCl 용액, 10% NaHCO3용액 및 물로 차례로 세척한 후, 무수 MgSO4로 건조, 여과, 감압 증류하여 표제화합물(55.5mg, 86%)을 제조하였다.5- (biphenyl-4-yl) -5-oxo-3-ethylcarboxyvaleric acid (VIII, R 1 = H, 50 mg, 0.147 mmol) was dissolved in THF (3 mL) and cooled to 0 ° C. N-methylmorpholine (35 mL, 0.323 mmol) and ethyl chloroformate (16 mL, 0.162 mmol) were added thereto, stirred for 30 minutes, and then a solution obtained by dissolving 3-aminobenzonitrile in THF (1 mL) was added thereto. This was stirred for 3 hours and 30 minutes at room temperature, filtered and the filtrate was distilled under reduced pressure. It was diluted with chloroform, washed sequentially with 1N HCl solution, 10% NaHCO 3 solution and water, and then dried over anhydrous MgSO 4 , filtered, and distilled under reduced pressure to obtain the title compound (55.5 mg, 86%).
1H NMR(300MHz, CDCl3): δ1.22(t, 3H), 2.74(dd, 1H), 3.01(dd, 1H), 1 H NMR (300 MHz, CDCl 3 ): δ 1.22 (t, 3H), 2.74 (dd, 1H), 3.01 (dd, 1H),
3.54(m, 3H), 4.22(q, 2H), 7.42(m, 4H),3.54 (m, 3H), 4.22 (q, 2H), 7.42 (m, 4H),
7.65(m, 5H), 8.01(m, 3H), 8.20(s, 1H)7.65 (m, 5H), 8.01 (m, 3H), 8.20 (s, 1H)
실시예 31: N-(3-아세틸페닐)-5-[(비페닐-4-일)-5-옥소-3-에틸카르보닐]발레익아미드(IX, R1=H)의 제조(IX) Example 31 Preparation of N- (3-acetylphenyl) -5-[(biphenyl-4-yl) -5-oxo-3-ethylcarbonyl] valericamide (IX, R 1 = H) )
5-(비페닐-4-일)-5-옥소-3-에틸카르복실발레릭산(VIII, R1=H) 및 3-아미노아세토페논을 사용하는 것을 제외하고는, 실시예 30과 동일한 방법으로 표제 화합물을 제조하였다.Same method as in Example 30, except using 5- (biphenyl-4-yl) -5-oxo-3-ethylcarboxyvaleric acid (VIII, R 1 = H) and 3-aminoacetophenone The title compound was prepared.
1H NMR(300MHz, CDCl3): δ1.23(t, 3H), 2.59(s, 3H), 2.80(dd, 1H), 1 H NMR (300 MHz, CDCl 3 ): δ 1.23 (t, 3H), 2.59 (s, 3H), 2.80 (dd, 1H),
3.00(dd, 1H), 3.56(m, 3H), 4.20(q, 2H),3.00 (dd, 1H), 3.56 (m, 3H), 4.20 (q, 2H),
7.40(m, 4H), 7.60(m, 5H), 8.03(m, 3H),7.40 (m, 4H), 7.60 (m, 5H), 8.03 (m, 3H),
8.20(s, 1H)8.20 (s, 1 H)
실시예 32: N-(3-아세틸페닐)-5-[(4'-클로로비페닐-4-일)-5-옥소-3-에틸카르보닐]발레익아미드(IX, R1=H)의 제조 Example 32 N- (3-Acetylphenyl) -5-[(4'-chlorobiphenyl-4-yl) -5-oxo-3-ethylcarbonyl] valericamide (IX, R 1 = H) Manufacture
5-(4'-클로로비페닐-4-일)-5-옥소-3-에틸카르복실발레릭산(VIII, R1=Cl) 및3-아미노아세토페논을 사용하는 것을 제외하고는, 실시예 30과 동일한 방법으로 표제 화합물을 제조하였다.Example, except using 5- (4'-chlorobiphenyl-4-yl) -5-oxo-3-ethylcarboxyvaleric acid (VIII, R 1 = Cl) and 3-aminoacetophenone The title compound was prepared in the same manner as 30.
1H NMR(300MHz, CDCl3): δ1.24(t, 3H), 2.60(s, 3H), 2.80(dd, 1H), 1 H NMR (300 MHz, CDCl 3 ): δ 1.24 (t, 3H), 2.60 (s, 3H), 2.80 (dd, 1H),
2.94(dd, 1H), 3.56(m, 3H), 4.20(q, 2H),2.94 (dd, 1H), 3.56 (m, 3H), 4.20 (q, 2H),
7.44(m, 3H), 7.54(d, 2H), 7.66(m, 3H),7.44 (m, 3H), 7.54 (d, 2H), 7.66 (m, 3H),
7.82(s, 1H), 8.04(m, 3H)7.82 (s, 1 H), 8.04 (m, 3 H)
실시예 33: N-(2-클로로페닐)-5-[(비페닐-4-일)-5-옥소-3-에틸카르보닐]발레익아미드(IX, R1=H)의 제조 Example 33 Preparation of N- (2-Chlorophenyl) -5-[(biphenyl-4-yl) -5-oxo-3-ethylcarbonyl] valericamide (IX, R 1 = H)
5-(비페닐-4-일)-5-옥소-3-에틸카르복실발레릭산(VIII, R1=H) 및 2-클로로아닐린을 사용하는 것을 제외하고는, 실시예 30과 동일한 방법으로 표제 화합물을 제조하였다.In the same manner as in Example 30, except for using 5- (biphenyl-4-yl) -5-oxo-3-ethylcarboxylic valeric acid (VIII, R 1 = H) and 2-chloroaniline The title compound was prepared.
1H NMR(300MHz, CDCl3): δ1.24(t, 3H), 2.88(dd, 1H), 3.03(dd, 1H), 1 H NMR (300 MHz, CDCl 3 ): δ 1.24 (t, 3H), 2.88 (dd, 1H), 3.03 (dd, 1H),
3.48~3.66(m, 3H), 4.24(q, 2H), 7.05(t, 1H),3.48-3.66 (m, 3H), 4.24 (q, 2H), 7.05 (t, 1H),
7.43(m, 4H), 7.62(d, 2H), 7.70(d, 2H),7.43 (m, 4H), 7.62 (d, 2H), 7.70 (d, 2H),
7.90(s, 1H), 8.06(d, 2H), 8.30(s, 1H)7.90 (s, 1H), 8.06 (d, 2H), 8.30 (s, 1H)
실시예 34: N-(3-클로로페닐)-5-[(비페닐-4-일)-5-옥소-3-에틸카르보닐]발레익아미드(IX, R1=H)의 제조 Example 34 Preparation of N- (3-chlorophenyl) -5-[(biphenyl-4-yl) -5-oxo-3-ethylcarbonyl] valericamide (IX, R 1 = H)
5-(비페닐-4-일)-5-옥소-3-에틸카르복실발레릭산(VIII, R1=H) 및 3-클로로아닐린을 사용하는 것을 제외하고는, 실시예 30과 동일한 방법으로 표제 화합물을 제조하였다.In the same manner as in Example 30, except that 5- (biphenyl-4-yl) -5-oxo-3-ethylcarboxyvaleric acid (VIII, R 1 = H) and 3-chloroaniline were used The title compound was prepared.
1H NMR(300MHz, MeOH-d4): δ1.24(t, 3H), 2.88(dd, 1H), 3.03(dd, 1H), 1 H NMR (300 MHz, MeOH-d 4 ): δ 1.24 (t, 3H), 2.88 (dd, 1H), 3.03 (dd, 1H),
3.48~3.66(m, 3H), 4.24(q, 2H), 7.23(d, 2H),3.48-3.66 (m, 3H), 4.24 (q, 2H), 7.23 (d, 2H),
7.42(m, 3H), 7.48(d, 2H), 7.62(d, 2H),7.42 (m, 3H), 7.48 (d, 2H), 7.62 (d, 2H),
7.69(d, 2H), 8.04(d, 2H)7.69 (d, 2H), 8.04 (d, 2H)
실시예 35: N-(4-클로로페닐)-5-[(비페닐-4-일)-5-옥소-3-에틸카르보닐]발레익아미드(IX, R1=H)의 제조(IX) Example 35 Preparation of N- (4-chlorophenyl) -5-[(biphenyl-4-yl) -5-oxo-3-ethylcarbonyl] valericamide (IX, R 1 = H) (IX )
5-(비페닐-4-일)-5-옥소-3-에틸카르복실발레릭산(VIII, R1=H) 및 4-클로로아닐린을 사용하는 것을 제외하고는, 실시예 30과 동일한 방법으로 표제 화합물을 제조하였다.In the same manner as in Example 30, except for using 5- (biphenyl-4-yl) -5-oxo-3-ethylcarboxylic valeric acid (VIII, R 1 = H) and 4-chloroaniline The title compound was prepared.
1H NMR(300MHz, DMSO-d6): δ1.24(t, 3H), 2.76(dd, 1H), 2.90(dd, 1H), 1 H NMR (300 MHz, DMSO-d 6 ): δ 1.24 (t, 3H), 2.76 (dd, 1H), 2.90 (dd, 1H),
3.53(m, 3H), 4.20(q, 2H), 7.06(d, 2H),3.53 (m, 3H), 4.20 (q, 2H), 7.06 (d, 2H),
7.21(t, 1H), 7.44(m, 4H), 7.62(d, 2H),7.21 (t, 1 H), 7.44 (m, 4 H), 7.62 (d, 2H),
7.68(d, 2H), 8.04(d, 2H)7.68 (d, 2H), 8.04 (d, 2H)
실시예 36: N-[3-(N,N-디에틸아미노키르복실)페닐]-5-[(4'-클로로비페닐-4-일)-5-옥소-3-에틸카르보닐]발레익아미드(IX, R1=Cl)의 제조(IX) Example 36 N- [3- (N, N-diethylaminokixyl) phenyl] -5-[(4'-chlorobiphenyl-4-yl) -5-oxo-3-ethylcarbonyl] ballet Preparation of Ixamide (IX, R 1 = Cl) (IX)
5-(4'-클로로비페닐-4-일)-5-옥소-3-에틸카르복실발레릭산(VIII, R1=Cl) 및 3-(N,N-디에틸아미노키르복실)아닐린을 사용하는 것을 제외하고는, 실시예 30과 동일한 방법으로 표제 화합물을 제조하였다.5- (4'-chlorobiphenyl-4-yl) -5-oxo-3-ethylcarboxyvaleric acid (VIII, R 1 = Cl) and 3- (N, N-diethylaminokixyl) aniline Except for the use of the title compound in the same manner as in Example 30.
1H NMR(300MHz, CDCl3): δ1.11(t, 3H), 1.23(t, 6H), 2.73(dd, 1H), 1 H NMR (300 MHz, CDCl 3 ): δ 1.11 (t, 3H), 1.23 (t, 6H), 2.73 (dd, 1H),
2.90(dd, 1H), 3.26(br, 2H), 3.52(m, 5H),2.90 (dd, 1H), 3.26 (br, 2H), 3.52 (m, 5H),
4.22(q, 2H), 7.08(d, 1H), 7.32(t, 1H),4.22 (q, 2H), 7.08 (d, 1H), 7.32 (t, 1H),
7.44(d, 2H), 7.54(m, 3H), 7.65(d, 2H),7.44 (d, 2H), 7.54 (m, 3H), 7.65 (d, 2H),
7.80(s, 1H), 8.03(d, 2H)7.80 (s, 1H), 8.03 (d, 2H)
실시예 37: N-[3-(N-페닐아미노키르복실)페닐]-5-[(4'-클로로비페닐-4-일)-5-옥소-3-에틸카르보닐]발레익아미드(IX, R1=Cl)의 제조 Example 37 N- [3- (N-phenylaminokiloxyl) phenyl] -5-[(4'-chlorobiphenyl-4-yl) -5-oxo-3-ethylcarbonyl] valericamide ( IX, R 1 = Cl)
5-(4'-클로로비페닐-4-일)-5-옥소-3-에틸카르복실발레릭산(VIII, R1=Cl) 및 3-(N-페닐아미노키르복실)아닐린을 사용하는 것을 제외하고는, 실시예 30과 동일한 방법으로 표제 화합물을 제조하였다.The use of 5- (4'-chlorobiphenyl-4-yl) -5-oxo-3-ethylcarboxyvaleric acid (VIII, R 1 = Cl) and 3- (N-phenylaminokiloxyl) aniline Except for the title compound, in the same manner as in Example 30.
1H NMR(300MHz, CDCl3): δ1.17(t, 3H), 2.85(dd, 1H), 3.10(dd, 1H), 1 H NMR (300 MHz, CDCl 3 ): δ 1.17 (t, 3H), 2.85 (dd, 1H), 3.10 (dd, 1H),
3.56(d, 2H), 3.65(m, 1H), 4.15(q, 2H),3.56 (d, 2H), 3.65 (m, 1H), 4.15 (q, 2H),
7.15(t, 1H), 7.34(m, 4H), 7.50(d, 3H),7.15 (t, 1 H), 7.34 (m, 4 H), 7.50 (d, 3 H),
7.61(d, 3H), 7.75(d, 3H), 8.00(d, 2H),7.61 (d, 3H), 7.75 (d, 3H), 8.00 (d, 2H),
8.35(s, 1H), 8.50(s, 1H)8.35 (s, 1H), 8.50 (s, 1H)
실시예 38: 5-(4'-클로로비페닐-4-일)-5-옥소-3-카르복실발레릭산(IX, R1=Cl)의 제조 Example 38 Preparation of 5- (4'-Chlorobiphenyl-4-yl) -5-oxo-3-carboxyvaleric acid (IX, R 1 = Cl)
5-(4'-클로로비페닐-4-일)-5-옥소-3-에틸카르복실발레릭산(VIII, R1=Cl, 40mg, 0.107mmol)을 에탄올(3mL)에 용해시킨 후, 1N NaOH(1mL)를 가하고 상온에서 4시간동안 교반한 다음, 다시 물을 가하고 에틸초산으로 세척하였다. 이를 1N HCl용액으로 산성화하고 MC로 추출한 후, 무수 MgSO4로 건조, 여과, 감압 증류하여 표제화합물을 제조하고, CHCl3/MeOH(4/1)용액(v/v)과 헥산으로 재결정하여 30mg(81%)을 제조하였다.5- (4'-Chlorobiphenyl-4-yl) -5-oxo-3-ethylcarboxyvaleric acid (VIII, R 1 = Cl, 40 mg, 0.107 mmol) was dissolved in ethanol (3 mL), followed by 1 N NaOH (1 mL) was added and stirred at room temperature for 4 hours, then water was added again and washed with ethyl acetate. This was acidified with 1N HCl solution, extracted with MC, dried over anhydrous MgSO 4 , filtered, and distilled under reduced pressure to obtain the title compound, which was recrystallized with CHCl 3 / MeOH (4/1) solution (v / v) and hexane and 30 mg ( 81%) was prepared.
1H NMR(300MHz, DMSO-d6): δ2.63(dd, 1H), 2.78(dd, 1H), 3.28(dd, 1H), 1 H NMR (300 MHz, DMSO-d 6 ): δ 2.63 (dd, 1H), 2.78 (dd, 1H), 3.28 (dd, 1H),
3.39(m, 1H), 3.52(dd, 1H), 7.38(d, 2H),3.39 (m, 1 H), 3.52 (dd, 1 H), 7.38 (d, 2H),
7.50(d, 2H), 7.58(d, 2H), 8.00(d, 2H)7.50 (d, 2H), 7.58 (d, 2H), 8.00 (d, 2H)
실시예 39: 5-(비페닐-4-일)-5-옥소-3-카르복실발레릭산(IX, R1=H)의 제조 Example 39 Preparation of 5- (biphenyl-4-yl) -5-oxo-3-carboxyvaleric acid (IX, R 1 = H)
5-(비페닐-4-일)-5-옥소-3-에틸카르복실발레릭산(VIII, R1=H)을 사용하는 것을 제외하고는, 실시예 38과 동일한 방법으로 표제 화합물을 제조하였다.The title compound was prepared in the same manner as in Example 38, except that 5- (biphenyl-4-yl) -5-oxo-3-ethylcarboxyvaleric acid (VIII, R 1 = H) was used. .
1H NMR(300MHz, DMSO-d6): δ2.63(dd, 1H), 2.78(dd, 1H), 3.28(dd, 1H), 1 H NMR (300 MHz, DMSO-d 6 ): δ 2.63 (dd, 1H), 2.78 (dd, 1H), 3.28 (dd, 1H),
3.39(m, 1H), 3.52(dd, 1H), 7.46(m, 3H),3.39 (m, 1 H), 3.52 (dd, 1 H), 7.46 (m, 3 H),
7.61(d, 2H), 7.67(d, 2H), 8.04(d, 2H)7.61 (d, 2H), 7.67 (d, 2H), 8.04 (d, 2H)
실시예 40: 5-(4'-브로모비페닐-4-일)-5-옥소-3-카르복실발레릭산(IX, R1=Br)의 제조 Example 40 Preparation of 5- (4'-bromobiphenyl-4-yl) -5-oxo-3-carboxyvaleric acid (IX, R 1 = Br)
5-(4'-클로로비페닐-4-일)-5-옥소-3-에틸카르복실발레릭산(VIII, R1=Br)을 사용하는 것을 제외하고는, 실시예 38과 동일한 방법으로 표제 화합물을 제조하였다.Heading in the same manner as in Example 38, except for using 5- (4'-chlorobiphenyl-4-yl) -5-oxo-3-ethylcarboxyvaleric acid (VIII, R 1 = Br) The compound was prepared.
1H NMR(300MHz, DMSO-d6): δ2.63(dd, 1H), 2.78(dd, 1H), 3.28(dd, 1H), 1 H NMR (300 MHz, DMSO-d 6 ): δ 2.63 (dd, 1H), 2.78 (dd, 1H), 3.28 (dd, 1H),
3.39(m, 1H), 3.52(dd, 1H), 7.48(d, 2H),3.39 (m, 1 H), 3.52 (dd, 1 H), 7.48 (d, 2H),
7.59(d, 2H), 7.66(d, 2H), 8.04(d, 2H)7.59 (d, 2H), 7.66 (d, 2H), 8.04 (d, 2H)
실시예 41: N-(3-시아노페닐)-5-[(비페닐-4-일)-5-옥소-3-카르보닐]발레익아미드(I, R1=H)의 제조 Example 41 Preparation of N- (3-cyanophenyl) -5-[(biphenyl-4-yl) -5-oxo-3-carbonyl] valericamide (I, R 1 = H)
N-(3-시아노페닐)-5-[(비페닐-4-일)-5-옥소-3-에틸카르보닐]발레익아미드(IX, R1=H, 11.8mg, 0.0268mmol)을 에탄올(2mL)에 용해시킨 후, 1N NaOH(0.5 mL)를 가하고 상온에서 1시간 30분 동안 교반한 다음, 물을 가하고 에틸초산으로 세척하고 1N HCl용액으로 산성화하였다. MC로 추출한 후 무수 MgSO4로 건조, 여과, 감압 증류하여 표제화합물을 제조하고, CHCl3/MeOH(19/1)용액(v/v)과 헥산으로 재결정하여 10.4mg(94%)을 제조하였다.N- (3-cyanophenyl) -5-[(biphenyl-4-yl) -5-oxo-3-ethylcarbonyl] valericamide (IX, R 1 = H, 11.8 mg, 0.0268 mmol) After dissolving in ethanol (2 mL), 1N NaOH (0.5 mL) was added and stirred at room temperature for 1 hour and 30 minutes, then water was added, washed with ethyl acetate and acidified with 1N HCl solution. Extracted with MC, dried over anhydrous MgSO 4 , filtered, and distilled under reduced pressure to obtain the title compound, and recrystallized with CHCl 3 / MeOH (19/1) solution (v / v) and hexane to prepare 10.4 mg (94%). .
1H NMR(300MHz, CDCl3): δ2.74(dd, 1H), 3.01(dd, 1H), 3.54(m, 3H), 1 H NMR (300 MHz, CDCl 3 ): δ2.74 (dd, 1H), 3.01 (dd, 1H), 3.54 (m, 3H),
7.42(m, 4H), 7.65(m, 5H), 8.01(m, 3H),7.42 (m, 4H), 7.65 (m, 5H), 8.01 (m, 3H),
8.20(s, 1H)8.20 (s, 1 H)
실시예 42: N-(3-아세틸페닐)-5-[(비페닐-4-일)-5-옥소-3-카르보닐]발레익아미드(I, R1=H)의 제조 Example 42 Preparation of N- (3-Acetylphenyl) -5-[(biphenyl-4-yl) -5-oxo-3-carbonyl] valericamide (I, R 1 = H)
N-(3-아세틸페닐)-5-[(비페닐-4-일)-5-옥소-3-에틸카르보닐]발레익아미드(IX, R1=H)을 사용하는 것을 제외하고는, 실시예 41과 동일한 방법으로 표제 화합물을 제조하였다.Except for using N- (3-acetylphenyl) -5-[(biphenyl-4-yl) -5-oxo-3-ethylcarbonyl] valericamide (IX, R 1 = H), In the same manner as in Example 41, the title compound was prepared.
1H NMR(300MHz, CDCl3): δ2.59(s, 3H), 2.80(dd, 1H), 3.00(dd, 1H), 1 H NMR (300 MHz, CDCl 3 ): δ 2.59 (s, 3H), 2.80 (dd, 1H), 3.00 (dd, 1H),
3.56(m, 3H), 7.40(m, 4H), 7.60(m, 5H),3.56 (m, 3H), 7.40 (m, 4H), 7.60 (m, 5H),
8.03(m, 3H), 8.20(s, 1H)8.03 (m, 3H), 8.20 (s, 1H)
실시예 43: N-(3-아세틸페닐)-5-[(4'-클로로비페닐-4-일)-5-옥소-3-카르보닐]발레익아미드(I, R1=H)의 제조 Example 43 : N- (3-acetylphenyl) -5-[(4'-chlorobiphenyl-4-yl) -5-oxo-3-carbonyl] valleamide (I, R 1 = H) Produce
N-(3-아세틸페닐)-5-[(4'-클로로비페닐-4-일)-5-옥소-3-에틸카르보닐]발레익아미드(IX, R1=H)을 사용하는 것을 제외하고는, 실시예 41과 동일한 방법으로 표제 화합물을 제조하였다.The use of N- (3-acetylphenyl) -5-[(4'-chlorobiphenyl-4-yl) -5-oxo-3-ethylcarbonyl] valericamide (IX, R 1 = H) Except for the title compound, in the same manner as in Example 41.
1H NMR(300MHz, CDCl3): δ2.60(s, 3H), 2.80(dd, 1H), 2.94(dd, 1H), 1 H NMR (300 MHz, CDCl 3 ): δ 2.60 (s, 3H), 2.80 (dd, 1H), 2.94 (dd, 1H),
3.56(m, 3H), 7.44(m, 3H), 7.54(d, 2H),3.56 (m, 3H), 7.44 (m, 3H), 7.54 (d, 2H),
7.66(m, 3H), 7.82(s, 1H), 8.04(m, 3H)7.66 (m, 3H), 7.82 (s, 1H), 8.04 (m, 3H)
실시예 44: N-(2-클로로페닐)-5-[(비페닐-4-일)-5-옥소-3-카르보닐]발레익아미드(I, R1=H)의 제조 Example 44 Preparation of N- (2-chlorophenyl) -5-[(biphenyl-4-yl) -5-oxo-3-carbonyl] valericamide (I, R 1 = H)
N-(2-클로로페닐)-5-[(비페닐-4-일)-5-옥소-3-에틸카르보닐]발레익아미드(IX, R1=H)을 사용하는 것을 제외하고는, 실시예 41과 동일한 방법으로 표제 화합물을 제조하였다.Except for using N- (2-chlorophenyl) -5-[(biphenyl-4-yl) -5-oxo-3-ethylcarbonyl] valericamide (IX, R 1 = H), In the same manner as in Example 41, the title compound was prepared.
1H NMR(300MHz, CDCl3): δ2.88(dd, 1H), 3.03(dd, 1H), 3.48~3.66(m, 3H), 1 H NMR (300 MHz, CDCl 3 ): δ 2.88 (dd, 1H), 3.03 (dd, 1H), 3.48-3.66 (m, 3H),
7.05(t, 1H), 7.43(m, 4H), 7.62(d, 2H),7.05 (t, 1H), 7.43 (m, 4H), 7.62 (d, 2H),
7.70(d, 2H), 7.90(s, 1H), 8.06(d, 2H),7.70 (d, 2H), 7.90 (s, 1H), 8.06 (d, 2H),
8.30(s, 1H)8.30 (s, 1 H)
실시예 45: N-(3-클로로페닐)-5-[(비페닐-4-일)-5-옥소-3-카르보닐]발레익아미드(I, R1=H)의 제조 Example 45 Preparation of N- (3-chlorophenyl) -5-[(biphenyl-4-yl) -5-oxo-3-carbonyl] valericamide (I, R 1 = H)
N-(3-클로로페닐)-5-[(비페닐-4-일)-5-옥소-3-에틸카르보닐]발레익아미드(IX, R1=H)을 사용하는 것을 제외하고는, 실시예 41과 동일한 방법으로 표제 화합물을 제조하였다.Except for using N- (3-chlorophenyl) -5-[(biphenyl-4-yl) -5-oxo-3-ethylcarbonyl] valericamide (IX, R 1 = H), In the same manner as in Example 41, the title compound was prepared.
1H NMR(300MHz, MeOH-d4): δ2.88(dd, 1H), 3.03(dd, 1H), 1 H NMR (300 MHz, MeOH-d 4 ): δ 2.88 (dd, 1H), 3.03 (dd, 1H),
3.48~3.66(m, 3H), 7.23(d, 2H), 7.42(m, 3H),3.48-3.66 (m, 3H), 7.23 (d, 2H), 7.42 (m, 3H),
7.48(d, 2H), 7.62(d, 2H), 7.69(d, 2H),7.48 (d, 2H), 7.62 (d, 2H), 7.69 (d, 2H),
8.04(d, 2H)8.04 (d, 2H)
실시예 46: N-(4-클로로페닐)-5-[(비페닐-4-일)-5-옥소-3-카르보닐]발레익아미드(I, R1=H)의 제조 Example 46 Preparation of N- (4-chlorophenyl) -5-[(biphenyl-4-yl) -5-oxo-3-carbonyl] valericamide (I, R 1 = H)
N-(2-클로로페닐)-5-[(비페닐-4-일)-5-옥소-3-에틸카르보닐]발레익아미드(IX, R1=H)을 사용하는 것을 제외하고는, 실시예 41과 동일한 방법으로 표제 화합물을 제조하였다.Except for using N- (2-chlorophenyl) -5-[(biphenyl-4-yl) -5-oxo-3-ethylcarbonyl] valericamide (IX, R 1 = H), In the same manner as in Example 41, the title compound was prepared.
1H NMR(300MHz, DMSO-d6): δ2.76(dd, 1H), 2.90(dd, 1H), 3.53(m, 3H), 1 H NMR (300 MHz, DMSO-d 6 ): δ 2.76 (dd, 1H), 2.90 (dd, 1H), 3.53 (m, 3H),
7.06(d, 2H), 7.21(t, 1H), 7.44(m, 4H),7.06 (d, 2H), 7.21 (t, 1H), 7.44 (m, 4H),
7.62(d, 2H), 7.68(d, 2H), 8.04(d, 2H)7.62 (d, 2H), 7.68 (d, 2H), 8.04 (d, 2H)
실시예 47: N-[3-(N,N-디에틸아미노키르복실)페닐]-5-[(4'-클로로비페닐-4-일)-5-옥소-3-카르보닐]발레익아미드(I, R1=Cl)의 제조 Example 47 N- [3- (N, N-diethylaminokixyl) phenyl] -5-[(4'-chlorobiphenyl-4-yl) -5-oxo-3-carbonyl] valleic Preparation of Amides (I, R 1 = Cl)
N-[3-(N,N-디에틸아미노키르복실)페닐]-5-[(4'-클로로비페닐-4-일)-5-옥소-3-에틸카르보닐]발레익아미드(IX, R1=Cl)을 사용하는 것을 제외하고는, 실시예 41과 동일한 방법으로 표제 화합물을 제조하였다.N- [3- (N, N-diethylaminokiloxyl) phenyl] -5-[(4'-chlorobiphenyl-4-yl) -5-oxo-3-ethylcarbonyl] valericamide (IX , Title compound was prepared in the same manner as in Example 41, except that R 1 = Cl).
1H NMR(300MHz, CDCl3): δ1.23(t, 6H), 2.73(dd, 1H), 2.90(dd, 1H), 1 H NMR (300 MHz, CDCl 3 ): δ 1.23 (t, 6H), 2.73 (dd, 1H), 2.90 (dd, 1H),
3.26(br, 2H), 3.52(m, 5H), 7.08(d, 1H),3.26 (br, 2H), 3.52 (m, 5H), 7.08 (d, 1H),
7.32(t, 1H), 7.44(d, 2H), 7.54(m, 3H),7.32 (t, 1 H), 7.44 (d, 2 H), 7.54 (m, 3 H),
7.65(d, 2H), 7.80(s, 1H), 8.03(d, 2H)7.65 (d, 2H), 7.80 (s, 1H), 8.03 (d, 2H)
실시예 48: N-[3-(N-페닐아미노키르복실)페닐]-5-[(4'-클로로비페닐-4-일)-5-옥소-3-카르보닐]발레익아미드(IX, R1=Cl)의 제조 Example 48 N- [3- (N-phenylaminokixyl) phenyl] -5-[(4'-chlorobiphenyl-4-yl) -5-oxo-3-carbonyl] valericamide (IX , R 1 = Cl)
N-[3-(N-페닐아미노키르복실)페닐]-5-[(4'-클로로비페닐-4-일)-5-옥소-3-에틸카르보닐]발레익아미드(IX, R1=Cl)을 사용하는 것을 제외하고는, 실시예 41과 동일한 방법으로 표제 화합물을 제조하였다.N- [3- (N-phenylaminokiloxyl) phenyl] -5-[(4'-chlorobiphenyl-4-yl) -5-oxo-3-ethylcarbonyl] valericamide (IX, R 1 Except for using = Cl), the title compound was prepared in the same manner as in Example 41.
1H NMR(300MHz, CDCl3): δ2.85(dd, 1H), 3.10(dd, 1H), 3.56(d, 2H), 1 H NMR (300 MHz, CDCl 3 ): δ 2.85 (dd, 1H), 3.10 (dd, 1H), 3.56 (d, 2H),
3.65(m, 1H), 7.15(t, 1H), 7.34(m, 4H),3.65 (m, 1 H), 7.15 (t, 1 H), 7.34 (m, 4 H),
7.50(d, 3H), 7.61(d, 3H), 7.75(d, 3H),7.50 (d, 3H), 7.61 (d, 3H), 7.75 (d, 3H),
8.00(d, 2H), 8.35(s, 1H), 8.50(s, 1H)8.00 (d, 2H), 8.35 (s, 1H), 8.50 (s, 1H)
실시예 49: 시험관내에서의 젤라티나제 A(MMP-2)억제 Example 49 Inhibition of Gelatinase A (MMP-2) in Vitro
본 검정은 형광합성펩티드 기질((7-methoxycoumarin-4-acetyl-Pro-Leu-Gly-Leu-β-(2,4-dinitrophenylamino)Ala-Ala-Arg-NH2(Sigma Chem. Co., U.S.A.))을 젤라티나제 A(Boehringer Mannheim, cat# 1782916, from human fibrosarcoma cells)가 절단하여 생성되는 형광물질(7-methoxycoumarin-4-acetyl-Pro-Leu-Gly)의 형광량을 측정하여 수행하였다. 형광합성기질을 이용한 효소반응은 96웰 플레이트에 탐색시료와 TNBC(25mM Tris-HCl, pH 7.5, 0.1M NaCl, 0.01% Brij-35, 5mM CaCl2)완충용액, 효소반응 직전 1mM의 APMA(aminophenylmercuric acetate)로 37℃에서 30분간 활성화시킨 젤라티나제 A(웰내 최종농도: 4.17nM) 및 기질인 형광합성펩티드(웰내 최종농도: 9.15uM)를 넣어 37℃에서 30분간 반응시킨 후, 웰플레이트 리더가 장착된 형광분석기(spectrofluorimeter, Fmax(molecular device))로 여기(excitation) 328nm, 발광(emission) 393nm에서 형광량을 측정하였다. 저해역가(%)는 저해제를 넣은 것의 반응전 형광량(A)과 반응후의 형광량(B), 저해제를 넣지 않은 것의 반응전 형광량(C)과 반응후 형광량(D)으로부터 다음과 같이 계산하였다.This assay was performed using a fluoropeptide substrate ((7-methoxycoumarin-4-acetyl-Pro-Leu-Gly-Leu-β- (2,4-dinitrophenylamino) Ala-Ala-Arg-NH 2 (Sigma Chem. Co., USA) )) Was performed by measuring the amount of fluorescence of the fluorescent substance (7-methoxycoumarin-4-acetyl-Pro-Leu-Gly) produced by cleaving gelatinase A (Boehringer Mannheim, cat # 1782916, from human fibrosarcoma cells). Enzyme reaction using fluorescence synthesis substrate was performed in 96-well plate with probe and TNBC (25 mM Tris-HCl, pH 7.5, 0.1M NaCl, 0.01% Brij-35, 5 mM CaCl 2 ) buffer solution, 1 mM APMA ( gelatinase A (activated in the well: 4.17nM) and the substrate was synthesized with aminophenylmercuric acetate for 30 minutes and the fluorescent synthetic peptide (final concentration in the well: 9.15uM) was added and reacted at 37 ° C for 30 minutes. The amount of fluorescence was measured at 328 nm of excitation and 393 nm of emission using a spectrofluorimeter (Fmax (molecular device)) equipped with a reader. The amount of fluorescent light before reaction (A) with the inhibitor, the amount of fluorescent light after the reaction (B), the amount of fluorescent light before the reaction (C) with no inhibitor and the amount of fluorescent light after the reaction (D) were calculated as follows.
실시예 50: 시험관내에서의 젤라티나제 B(MMP-9)억제 Example 50 Inhibition of Gelatinase B (MMP-9) in Vitro
젤라티나제 B 효소(Boehringer Mannheim cat# 1758896, from Human blood)를 사용하고, 젤라티나제 B 효소의 농도(웰내 최종농도: 2.715nM) 및 기질인 형광합성펩타이드의 농도(웰내 최종농도: 4.575uM)를 달리하는 것을 제외하고는, 실시예 49와 동일한 방법으로 시험관내에서의 젤라티나제 B(MMP-9)의 저해율을 측정하였다.Using gelatinase B enzyme (Boehringer Mannheim cat # 1758896, from Human blood), concentration of gelatinase B enzyme (final concentration in wells: 2.715 nM) and concentration of fluorescent synthetic peptide as substrate (final concentration in 4.5 wells) Except for), the inhibition rate of gelatinase B (MMP-9) was measured in vitro in the same manner as in Example 49.
실시예 51: 시험관내에서의 콜라게나제(MMP-1)억제 Example 51 Inhibition of Collagenase (MMP-1) in Vitro
콜라게나제 효소(AngioLab. Co.Ltd)를 사용하고, 콜라게나제 효소의 농도(웰내 최종농도: 7.25nM)를 달리하는 것을 제외하고는, 실시예 49와 동일한 방법으로 시험관내에서의 콜라게나제(MMP-1)의 저해율을 측정하였다.Using collagenase enzyme (AngioLab. Co. Ltd.) and collagenase enzyme concentration (final concentration in the well: 7.25 nM), except collagen in vitro in the same manner as in Example 49 Inhibition rate of the first agent (MMP-1) was measured.
상기 표의 비교물질은 Bay12-9566으로서 MMP-2에 대한 저해활성이 IC5011nM, MMP-9에 대한 저해활성이 IC50301nM이고, MMP-1/MMP-2의 선택성이 500인 것으로 알려져 있다(참조: Drugs of the Future, 24(1):16-21, 1999). 지금까지 가장 우수한 것으로 보고되고 있는 전기 비교물질과 비교하여 볼 때, 본 발명의 화합물은 보다 탁월한 MMP 저해활성을 나타내고, 10000배 이상의 MMP-1/MMP-2 선택성을 나타냄을 알 수 있다.The table compares substance is known to have inhibitory activity against MMP-2 as Bay12-9566 the IC 50 11nM, and the inhibitory activity against MMP-9 IC 50 301nM, selectivity 500 of MMP-1 / MMP-2 ( See Drugs of the Future, 24 (1): 16-21, 1999). Compared with the electrical comparative material which is reported to be the best so far, it can be seen that the compound of the present invention exhibits more excellent MMP inhibitory activity and exhibits MMP-1 / MMP-2 selectivity of 10000 times or more.
이상에서 상세히 설명하고 입증하였듯이, 본 발명은 MMP의 작용을 억제하는 비페닐 부티릭산 유도체 화합물, 그의 이성질체 및 이들의 약학적으로 허용되는 염과 전기 물질들의 제조방법을 제공하였다. 본 발명의 비페닐 부티릭산 유도체 화합물은 시험관내(in vitro) 조건에서 MMP의 활성을 선택적으로 억제하는 바, 전기 비페닐 부티릭산 유도체를 유효성분으로 하는 MMP 억제제는 MMP의 과발현 및 과도한 활성화에 의해서 유발되는 각종질병의 예방 및 치료에 유용하게 사용될 수 있을 것이다.As described and demonstrated in detail above, the present invention provides a biphenyl butyric acid derivative compound, an isomer thereof, and a pharmaceutically acceptable salt thereof and a method for preparing the electrical substances that inhibit the action of MMP. The biphenyl butyric acid derivative compound of the present invention selectively inhibits the activity of MMP under in vitro conditions, and the MMP inhibitor containing the biphenyl butyric acid derivative as an active ingredient is characterized by overexpression and excessive activation of MMP. It may be useful for the prevention and treatment of various diseases caused.
Claims (6)
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| KR10-2000-0021835A KR100405914B1 (en) | 2000-04-25 | 2000-04-25 | Biphenyl Butyric Acid Derivative as a Matrix Metalloproteinase Inhibitor |
| CA002377629A CA2377629A1 (en) | 2000-04-25 | 2001-04-24 | Biphenyl butyric acid derivative as a matrix metalloproteinase inhibitor |
| AU52759/01A AU5275901A (en) | 2000-04-25 | 2001-04-24 | Biphenyl butyric acid derivative as a matrix metalloproteinase inhibitor |
| EP01926225A EP1189882A1 (en) | 2000-04-25 | 2001-04-24 | Biphenyl butyric acid derivative as a matrix metalloproteinase inhibitor |
| JP2001580874A JP2003531894A (en) | 2000-04-25 | 2001-04-24 | Biphenylbutyric acid derivatives as matrix metalloprotease inhibitors |
| CN01801067A CN1366518A (en) | 2000-04-25 | 2001-04-24 | Biphenyl butyric acid derivative as matrix metalloproteinase inhibitor |
| PCT/KR2001/000687 WO2001083445A1 (en) | 2000-04-25 | 2001-04-24 | Biphenyl butyric acid derivative as a matrix metalloproteinase inhibitor |
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| US5177204A (en) * | 1990-06-18 | 1993-01-05 | Vyzkumng, USTAV pro farmacii a biochemii, Statni podnik | Derivatives of 4-(2,4-difluorbiphenylyl)-2-methyl-4-oxobutanoic acid |
| WO1996015096A1 (en) * | 1994-11-15 | 1996-05-23 | Bayer Corporation | Substituted 4-biarylbutyric or 5-biarylpentanoic acids and derivatives as matrix metalloprotease inhibitiors |
| WO1998009940A1 (en) * | 1996-09-04 | 1998-03-12 | Warner-Lambert Company | Biphenyl butyric acids and their derivatives as inhibitors of matrix metalloproteinases |
| WO1999018079A1 (en) * | 1997-10-06 | 1999-04-15 | Warner-Lambert Company | Heteroaryl butyric acids and their derivatives as inhibitors of matrix metalloproteinases |
| WO2001083445A1 (en) * | 2000-04-25 | 2001-11-08 | Samsung Electronics Co., Ltd. | Biphenyl butyric acid derivative as a matrix metalloproteinase inhibitor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5177204A (en) * | 1990-06-18 | 1993-01-05 | Vyzkumng, USTAV pro farmacii a biochemii, Statni podnik | Derivatives of 4-(2,4-difluorbiphenylyl)-2-methyl-4-oxobutanoic acid |
| WO1996015096A1 (en) * | 1994-11-15 | 1996-05-23 | Bayer Corporation | Substituted 4-biarylbutyric or 5-biarylpentanoic acids and derivatives as matrix metalloprotease inhibitiors |
| WO1998009940A1 (en) * | 1996-09-04 | 1998-03-12 | Warner-Lambert Company | Biphenyl butyric acids and their derivatives as inhibitors of matrix metalloproteinases |
| WO1999018079A1 (en) * | 1997-10-06 | 1999-04-15 | Warner-Lambert Company | Heteroaryl butyric acids and their derivatives as inhibitors of matrix metalloproteinases |
| WO2001083445A1 (en) * | 2000-04-25 | 2001-11-08 | Samsung Electronics Co., Ltd. | Biphenyl butyric acid derivative as a matrix metalloproteinase inhibitor |
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