KR100264158B1 - [(aryl)isoxazolyl]methylene-azabicyclic compounds and preparation thereof - Google Patents
[(aryl)isoxazolyl]methylene-azabicyclic compounds and preparation thereof Download PDFInfo
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- KR100264158B1 KR100264158B1 KR1019980023118A KR19980023118A KR100264158B1 KR 100264158 B1 KR100264158 B1 KR 100264158B1 KR 1019980023118 A KR1019980023118 A KR 1019980023118A KR 19980023118 A KR19980023118 A KR 19980023118A KR 100264158 B1 KR100264158 B1 KR 100264158B1
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
일반식 (II)로 표시되는 카르보닐 화합물을 용매와 염기 존재하에 일반식 (III)으로 표시되는 포스포늄염 화합물이나 또는 일반식 (IV)로 표시되는 포스포네이트 화합물과 반응시켜 새로운 일반식 (I)로 표시되는 [(아릴)이소옥소졸릴]메틸렌-아자비시클로 화합물을 제조하는 것으로, 본 발명 화합물은 무스카린성 아세틸콜린 수용체에 높은 결합 친화도를 나타내므로 알쯔하이머씨 병 등의 뇌신경 질환 치료제로 유용하다.A carbonyl compound represented by formula (II) is reacted with a phosphonium salt compound represented by formula (III) or a phosphonate compound represented by formula (IV) in the presence of a solvent and a base to form a new formula ( The compound of the present invention exhibits a high binding affinity for the muscarinic acetylcholine receptor, and thus is used as a therapeutic agent for cerebral neurological diseases such as Alzheimer's disease, by preparing the [(aryl) isooxozolyl] methylene-azabicyclo compound represented by I). useful.
상기 식들에서, R은 각각 수소, 할로, 알콕시, 시아노, 알킬, 알케닐, 알키닐, 히드록시, 아미노, 니트로, 4-메톡시벤질옥시, 3급-부톡시카르보닐아미노 또는 약제학적으로 가능한 염을, R1,R2및RR는 각각 알킬, 아릴 또는 아랄킬을, X는 할로겐 원자를 각각 표시하며, n은 1 또는 2의 정수이다.Wherein R is hydrogen, halo, alkoxy, cyano, alkyl, alkenyl, alkynyl, hydroxy, amino, nitro, 4-methoxybenzyloxy, tert-butoxycarbonylamino or pharmaceutically Possible salts are R 1 , R 2 and R R , respectively, alkyl, aryl or aralkyl, X represents a halogen atom, respectively, n is an integer of 1 or 2.
Description
본 발명은 무스카린성 아세틸콜린 수용체에 좋은 친화도를 나타내는 질소를 포함하는 새로운 두고리 화합물 및 이의 제조방법에 관한 것이다.The present invention relates to a new bicyclic compound comprising nitrogen showing good affinity for a muscarinic acetylcholine receptor and a method for preparing the same.
중추신경계에 존재하는 무스카린성 아세틸콜린 수용체에 작용하는 화합물들은 콜린 결핍에 의해 일어나는 알쯔하이머씨 병, 헌팅톤씨 병, 운동 장애와 운동 과다증 등의 신경질환에 좋은 효과를 나타내는 것으로 알려지고 있다. 알쯔하이머씨 병이라는 것은 기억력, 집중력, 언어 및 시각 인식 능력의 뚜렷한 부족에 의해 특징 지워지는 질병으로서 점진적으로 진행하는 퇴행성 뇌신경질환의 하나이다. 이러한 알쯔하이머씨 병을 치료하기 위해서, 과거에는 인식 향상제(nootropics)와 같은 증상 개선제를 주로 사용하여 왔으나 최근에는 이와 관련된 생화학적이고 신경 화학적인 발견을 토대로 콜린성 신경계의 손상과 관련지어 설명하는 콜린성 가설에 입각하여, 이 신경계를 보강해주는 무스카린성 효능제 및 아세틸 콜린 분해효소 억제제를 사용하는 접근방법이 연구되고 있다. 그 중, 무스카린성 아세틸콜린 수용체에 작용함으로써 콜린 결핍을 복구시켜주는 화합물로는 옥사디아졸계 화합물(유럽 특허 공고번호 0 307 140), 탈사클리딘 퓨마레이트(유럽특허 공고번호 0 370 415) 등 많은 화합물들이 보고된 바 있다.Compounds that act on the muscarinic acetylcholine receptors present in the central nervous system are known to have good effects on neurological diseases such as Alzheimer's disease, Huntington's disease, dyskinesia and hyperactivity caused by choline deficiency. Alzheimer's disease is a disease characterized by a marked lack of memory, concentration, language and visual perception, and is one of progressive progressive neurodegenerative diseases. In order to treat Alzheimer's disease, symptom enhancers such as cognitive enhancers have been used in the past, but recently, based on the biochemical and neurochemical findings related to this, it is based on the cholinergic hypothesis that explains the damage to the cholinergic nervous system. Thus, approaches using muscarinic agonists and acetylcholinease inhibitors that enhance this nervous system have been studied. Among them, compounds that repair choline deficiency by acting on the muscarinic acetylcholine receptor include oxadiazole compounds (European Patent Publication No. 0 307 140), dexaclidine fumarate (European Patent Publication No. 0 370 415), and the like. Many compounds have been reported.
본 발명은 무스카린성 아세틸콜린 수용체에 좋은 친화도를 나타내는 질소를 포함하는 새로운 [(아릴)이소옥소졸릴]메틸렌-아자비시클로 화합물 및 이의 제조방법에 관한 것이다.The present invention relates to a novel [(aryl) isoxozolyl] methylene-azabicyclo compound comprising nitrogen showing good affinity for a muscarinic acetylcholine receptor and a process for preparing the same.
본 발명은 이러한 무스카린성 아세틸콜린 수용체에 높은 결합 친화도를 가짐으로써 알쯔하이머씨 병을 포함한 콜린성 신경전달의 이상에서 기인하는 뇌신경 질환 치료제로서 유용 가능한 질소를 포함하는 두고리 화합물 및 이의 제조방법에 관한 것으로서, 구체적으로는 다음 일반식 (I)로 표시되는 [(아릴)이소옥소졸릴]메틸렌-아자비시클로 화합물에 관한 것이다.The present invention relates to a bicyclic compound containing nitrogen which is useful as a therapeutic agent for cerebral nerve disease resulting from abnormalities in cholinergic neurotransmission, including Alzheimer's disease, by having a high binding affinity to such a muscarinic acetylcholine receptor. More specifically, it relates to the [(aryl) isoxozolyl] methylene-azabicyclo compound represented by the following general formula (I).
일반식 (I)에서 n은 1 또는 2의 정수이며, R은 수소, 플루오로, 클로로, 메톡시, 헤테로 원자, 3,4-디메톡시, 2,4-디메톡시, 시아노, 탄소수 1 ∼ 6개의 알킬, 탄소수 2 ∼ 6개의 알케닐, 탄소수 2 ∼ 6개의 알키닐, 탄소수 3 ∼ 7개의 시클로알킬, 히드록시, 아미노, 니트로, 4-메톡시벤질옥시, 3급-부톡시카르보닐아미노 또는 약제학적으로 가능한 염을 이루는 유기산 및 무기산 등을 포함한다. 약제학적으로 가능한 염을 이루는 산으로는 일반적으로, 염산, 브롬산, 황산, 인산, 아세트산, 트리플루오로초산, 푸마르산, 말레산, 시트르산, 락트산, 옥살산 등을 들 수 있다.In general formula (I), n is an integer of 1 or 2, R is hydrogen, fluoro, chloro, methoxy, hetero atom, 3,4-dimethoxy, 2,4-dimethoxy, cyano, C1-C 6 alkyl, alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, hydroxy, amino, nitro, 4-methoxybenzyloxy, tert-butoxycarbonylamino Or organic and inorganic acids that make up pharmaceutically acceptable salts, and the like. Acids which form pharmaceutically possible salts generally include hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, fumaric acid, maleic acid, citric acid, lactic acid, oxalic acid and the like.
본 발명의 일반식 (I)로 표시되는 [(아릴)이소옥소졸릴]메틸렌-아자비시클로 화합물은 기하 이성질체인 일반식 (Ia)와 (Ib), 및 그 혼합물을 포함하며, 이들 이성질체는 크로마토그래피법에 의해서 분리하고, 각각의 염은 재결정하여 얻을 수 있다.[(Aryl) isoxozozolyl] methylene-azabicyclo compounds represented by general formula (I) of the present invention include the general isomers of general formulas (Ia) and (Ib), and mixtures thereof, and these isomers are chromatographed. Separate by the method, each salt can be obtained by recrystallization.
특히, 본 발명의 일반식 (I)로 표시되는 [(아릴)이소옥소졸릴]메틸렌-아자비시클로 화합물에 있어서, n=1인 경우에는 위의 구조와 같이 일반식(Ia)와 일반식(Ib)로 표시되는 기하 이성질체로 나타낼 수 있으며, 물론 이들 각각은 라세미 혼합물이다.In particular, in the [(aryl) isooxozolyl] methylene-azabicyclo compound represented by the general formula (I) of the present invention, when n = 1, general formula (Ia) and general formula (Ib) as in the above structure And geometric isomers represented by), each of which is of course a racemic mixture.
본 발명의 제조공정을 간단히 설명하면, 일반식 (II)로 표시되는 카르보닐 화합물을 용매와 염기 존재하에 일반식 (III)으로 표시되는 포스포늄염 화합물이나 또는 일반식 (IV)로 표시되는 포스포네이트 화합물과 반응시켜 새로운 화합물인 일반식 (I)로 표시되는 [(아릴)이소옥소졸릴]메틸렌-아자비시클로 화합물을 제조하는 것으로 이의 반응과정을 표시하면 다음과 같다.Briefly describing the production process of the present invention, the carbonyl compound represented by the general formula (II) is a phosphonium salt compound represented by the general formula (III) in the presence of a solvent and a base, or a phosphine represented by the general formula (IV) By reacting with a ponate compound to prepare a [(aryl) isoxozozolyl] methylene-azabicyclo compound represented by the general formula (I), the reaction process is as follows.
일반식 (II)에 있어서, n은 일반식 (I)의 것과 같다. 일반식 (III)과 일반식 (IV)에 있어서, 각각의 R은 일반식 (I)의 것과 같으며, R1,R2는 각각 탄소수 1 ∼ 6개의 알킬, 아릴 또는 아랄킬을 표시한다. 그리고, 일반식(III)에 있어서, R3는 위의 R1또는 R2와 같으며, X는 할로겐 원자를 나타낸다In general formula (II), n is the same as that of general formula (I). In general formula (III) and general formula (IV), each R is the same as that of general formula (I), R <1> , R <2> represents a C1-C6 alkyl, aryl, or aralkyl, respectively. In General Formula (III), R 3 is the same as R 1 or R 2 above, and X represents a halogen atom.
본 발명의 제조방법을 보다 자세히 설명하면, 일반식 (II)로 표시되는 카르보닐 화합물과 물, 아세톤, 디옥산, 아세토니트릴, 클로로포름, 디클로로메탄, 테트라히드로퓨란, 에틸 아세테이트, N,N-디메틸포름아미드 등으로 이루어진 군 중에서 한가지 또는 두가지 이상의 혼합용매와 탄산 나트륨, 탄산수소 나트륨, 알칼리금속 히드리드, 알칼리금속 아미드, 알칼리금속 히드록시드, 알칼리금속 알킬 및 알칼리금속 알콕시드 등의 염기 존재하에 일반식 (III)으로 표시되는 포스포늄염 화합물이나 또는 일반식 (IV)로 표시되는 포스포네이트 화합물을 -40℃ ∼ 25℃의 반응온도에서 10분 ∼ 48시간 동안, 바람직하게는 30분동안 반응시켜 새로운 화합물인 일반식 (I)로 표시되는 [(아릴)이소옥소졸릴]메틸렌-아자비시클로 화합물을 제조하는 것이다. 이때에, 일반식(II)의 카르보닐 화합물에 대한 일반식(III)의 포스포늄염 화합물 또는 일반식(IV)의 포스포네이트 화합물의 사용량은 1당량 ∼ 5당량이 가능하나, 바람직하게는 1.5 당량이다.In more detail, the carbonyl compound represented by the general formula (II) and water, acetone, dioxane, acetonitrile, chloroform, dichloromethane, tetrahydrofuran, ethyl acetate, N, N-dimethyl One or two or more mixed solvents of the group consisting of formamide and the like in the presence of bases such as sodium carbonate, sodium bicarbonate, alkali metal hydride, alkali metal amide, alkali metal hydroxide, alkali metal alkyl, and alkali metal alkoxide The phosphonium salt compound represented by the formula (III) or the phosphonate compound represented by the general formula (IV) is reacted at a reaction temperature of -40 ° C to 25 ° C for 10 minutes to 48 hours, preferably for 30 minutes. This is to prepare [(aryl) isoxozolyl] methylene-azabicyclo compound represented by general formula (I) which is a new compound. At this time, the amount of the phosphonium salt compound of the general formula (III) or the phosphonate compound of the general formula (IV) to the carbonyl compound of the general formula (II) may be 1 to 5 equivalents, preferably 1.5 equivalents.
다음 화합물들은 본 발명에서 얻어진 일반식(I)로 표시되는 [(아릴)이소옥소졸릴]메틸렌-아자비시클로 화합물의 구조를 나타내는 대표적인 화합물들을 표시한 것이다.The following compounds represent the representative compounds which show the structure of the [(aryl) isooxozolyl] methylene-azabicyclo compound represented by General Formula (I) obtained in the present invention.
화합물 1.Compound 1.
(Z)-3-[3-(4-메틸페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.2.]옥탄 및 이의 옥살산 염.(Z) -3- [3- (4-methylphenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.2.] Octane and oxalic acid salts thereof.
화합물 2.Compound 2.
(E)-3-[3-(4-메틸페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.2]옥탄 및 이의 옥살산 염.(E) -3- [3- (4-methylphenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.2] octane and oxalic acid salts thereof.
화합물 3.Compound 3.
(Z)-3-(3-페닐이소옥사졸-5-일)메틸렌-1-아자비시클로[2.2.2]옥탄 및 이의 옥살산 염.(Z) -3- (3-phenylisoxazol-5-yl) methylene-1-azabicyclo [2.2.2] octane and oxalic acid salts thereof.
화합물 4.Compound 4.
(E)-3-(3-페닐이소옥사졸-5-일)메틸렌-1-아자비시클로[2.2.2]옥탄 및 이의 옥살산염.(E) -3- (3-phenylisoxazol-5-yl) methylene-1-azabicyclo [2.2.2] octane and its oxalate salts.
화합물 5.Compound 5.
(Z)-3-[3-(4-메톡시페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.2]옥탄 및 이의 옥살산 염.(Z) -3- [3- (4-methoxyphenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.2] octane and oxalic acid salts thereof.
화합물 6.Compound 6.
(E)-3-[3-(4-메톡시페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.2]옥탄 및 이의 옥살산 염.(E) -3- [3- (4-methoxyphenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.2] octane and oxalic acid salts thereof.
화합물 7.Compound 7.
(Z)-3-[3-(4-플루오로페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.2]옥탄 및 이의 옥살산 염.(Z) -3- [3- (4-fluorophenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.2] octane and oxalic acid salts thereof.
화합물 8.Compound 8.
(E)-3-[3-(4-플루오로페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.2]옥탄 및 이의 옥살산 염.(E) -3- [3- (4-fluorophenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.2] octane and oxalic acid salts thereof.
화합물 9.Compound 9.
(Z)-3-[3-(4-클로로페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.2]옥탄 및 이의 옥살산 염.(Z) -3- [3- (4-chlorophenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.2] octane and oxalic acid salts thereof.
화합물 10.Compound 10.
(E)-[3-(4-클로로페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.2]옥탄 및 이의 옥살산 염.(E)-[3- (4-chlorophenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.2] octane and oxalic acid salts thereof.
화합물 11.Compound 11.
(Z)-3-[3-(3,4-디메톡시페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.2] 옥탄 및 이의 옥살산 염.(Z) -3- [3- (3,4-dimethoxyphenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.2] octane and oxalic acid salts thereof.
화합물 12.Compound 12.
(E)-3-[3-(3,4-디메톡시페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.2]옥탄 및 이의 옥살산 염.(E) -3- [3- (3,4-dimethoxyphenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.2] octane and oxalic acid salts thereof.
화합물 13.Compound 13.
(Z)-3-[3-(4-시아노페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.2]옥탄 및 이의 옥살산 염.(Z) -3- [3- (4-cyanophenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.2] octane and oxalic acid salts thereof.
화합물 14.Compound 14.
(E)-3-[3-(4-시아노페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.2]옥탄 및 이의 옥살산 염.(E) -3- [3- (4-cyanophenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.2] octane and oxalic acid salts thereof.
화합물 15.Compound 15.
(Z)-3-[3-(2,4-디메톡시페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.2]옥탄 및 이의 옥살산 염.(Z) -3- [3- (2,4-dimethoxyphenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.2] octane and oxalic acid salts thereof.
화합물 16.Compound 16.
(E)-3-[3-(2,4-디메톡시페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.2]옥탄 및 이의 옥살산 염.(E) -3- [3- (2,4-dimethoxyphenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.2] octane and oxalic acid salts thereof.
화합물 17.Compound 17.
(Z)-3-{3-[3,4-비스(4-메톡시벤질옥시)페닐]이소옥사졸-5-일}메틸렌-1-아자비시클로[2.2.2]옥탄 및 이의 옥살산 염.(Z) -3- {3- [3,4-bis (4-methoxybenzyloxy) phenyl] isoxazol-5-yl} methylene-1-azabicyclo [2.2.2] octane and oxalic acid salts thereof.
화합물 18.Compound 18.
(E)-3-{3-[3,4-비스(4-메톡시벤질옥시)페닐]이소옥사졸-5-일}메틸렌-1-아자비시클로[2.2.2]옥탄 및 이의 옥살산 염.(E) -3- {3- [3,4-bis (4-methoxybenzyloxy) phenyl] isoxazol-5-yl} methylene-1-azabicyclo [2.2.2] octane and oxalic acid salts thereof.
화합물 19.Compound 19.
(Z)-3-[3-(4-t-부톡시카르보닐아미노페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.2]옥탄 및 이의 옥살산 염.(Z) -3- [3- (4-t-butoxycarbonylaminophenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.2] octane and oxalic acid salts thereof.
화합물 20.Compound 20.
(E)-3-[3-(4-t-부톡시카르보닐아미노페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.2]옥탄 및 이의 옥살산 염.(E) -3- [3- (4-t-butoxycarbonylaminophenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.2] octane and oxalic acid salts thereof.
화합물 21.Compound 21.
(Z)-3-{3-[4-(4-메톡시벤질옥시)페닐]이소옥사졸-5-일}메틸렌-1-아자비시클로[2.2.2]옥탄 및 이의 옥살산 염.(Z) -3- {3- [4- (4-methoxybenzyloxy) phenyl] isoxazol-5-yl} methylene-1-azabicyclo [2.2.2] octane and oxalic acid salts thereof.
화합물 22.Compound 22.
(E)-3-{3-[4-(4-메톡시벤질옥시)페닐]이소옥사졸-5-일}메틸렌-1-아자비시클로[2.2.2]옥탄 및 이의 옥살산 염.(E) -3- {3- [4- (4-methoxybenzyloxy) phenyl] isoxazol-5-yl} methylene-1-azabicyclo [2.2.2] octane and oxalic acid salts thereof.
화합물 23.Compound 23.
(Z)-3-[3-(4-메톡시페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.1]헵탄 및 이의 옥살산 염.(Z) -3- [3- (4-methoxyphenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.1] heptane and oxalic acid salts thereof.
화합물 24.Compound 24.
(E)-3-[3-(4-메톡시페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.1]헵탄 및 이의 옥살산 염.(E) -3- [3- (4-methoxyphenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.1] heptane and oxalic acid salts thereof.
화합물 25.Compound 25.
(Z)-3-{3-[3,4-비스(4-메톡시벤질옥시)페닐]이소옥사졸-5-일}메틸렌-1-아자비시클로[2.2.1] 헵탄 및 이의 옥살산 염.(Z) -3- {3- [3,4-bis (4-methoxybenzyloxy) phenyl] isoxazol-5-yl} methylene-1-azabicyclo [2.2.1] heptane and oxalic acid salts thereof.
화합물 26.Compound 26.
(E)-3-{3-[3,4-비스(4-메톡시벤질옥시)페닐]이소옥사졸-5-일}메틸렌-1-아자비시클로[2.2.1]헵탄 및 이의 옥살산 염.(E) -3- {3- [3,4-bis (4-methoxybenzyloxy) phenyl] isoxazol-5-yl} methylene-1-azabicyclo [2.2.1] heptane and oxalic acid salts thereof.
화합물 27.Compound 27.
(Z)-3-[3-(4-t-부톡시카르보닐아미노페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.1]헵탄 및 이의 옥살산 염.(Z) -3- [3- (4-t-butoxycarbonylaminophenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.1] heptane and oxalic acid salts thereof.
화합물 28.Compound 28.
(E)-3-[3-(4-t-부톡시카르보닐아미노페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.1]헵탄 및 이의 옥살산 염.(E) -3- [3- (4-t-butoxycarbonylaminophenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.1] heptane and oxalic acid salts thereof.
화합물 29.Compound 29.
(Z)-3-{3-[4-(4-메톡시벤질옥시)페닐]이소옥사졸-5-일}메틸렌-1-아자비시클로[2.2.1]헵탄 및 이의 옥살산 염.(Z) -3- {3- [4- (4-methoxybenzyloxy) phenyl] isoxazol-5-yl} methylene-1-azabicyclo [2.2.1] heptane and oxalic acid salts thereof.
화합물 30.Compound 30.
(E)-3-{3-[4-(4-메톡시벤질옥시)페닐]이소옥사졸-5-일}메틸렌-1-아자비시클로[2.2.1]헵탄 및 이의 옥살산 염.(E) -3- {3- [4- (4-methoxybenzyloxy) phenyl] isoxazol-5-yl} methylene-1-azabicyclo [2.2.1] heptane and oxalic acid salts thereof.
화합물 31.Compound 31.
(Z)-3-[3-(4-히드록시페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.2]옥탄 및 이의 트리플루오로아세트산 염.(Z) -3- [3- (4-hydroxyphenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.2] octane and trifluoroacetic acid salts thereof.
화합물 32.Compound 32.
(E)-3-[3-(4-히드록시페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.2]옥탄 및 이의 트리플루오로아세트산 염.(E) -3- [3- (4-hydroxyphenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.2] octane and trifluoroacetic acid salts thereof.
화합물 33.Compound 33.
(Z)-3-[3-(3,4-디히드록시페닐)이소옥사졸-5-일]메틸렌-1아자비시클로[2.2.2]옥탄 및 이의 트리플루오로아세트산 염.(Z) -3- [3- (3,4-dihydroxyphenyl) isoxazol-5-yl] methylene-1azabicyclo [2.2.2] octane and its trifluoroacetic acid salt.
화합물 34.Compound 34.
(E)-3-[3-(3,4-디히드록시페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.2]옥탄 및 이의 트리플루오로아세트산 염.(E) -3- [3- (3,4-dihydroxyphenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.2] octane and trifluoroacetic acid salts thereof.
화합물 35.Compound 35.
(Z)-3-[3-(4-아미노페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.2]옥탄 및 이의 트리플루오로아세트산 염.(Z) -3- [3- (4-aminophenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.2] octane and its trifluoroacetic acid salt.
화합물 36.Compound 36.
(E)-3-[3-(4-아미노페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.2]옥탄 및 이의 트리플루오로아세트산 염.(E) -3- [3- (4-aminophenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.2] octane and trifluoroacetic acid salts thereof.
화합물 37.Compound 37.
(Z)-3-[3-(4-히드록시페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.1]헵탄 및 이의 트리플루오로아세트산 염.(Z) -3- [3- (4-hydroxyphenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.1] heptane and its trifluoroacetic acid salt.
화합물 38.Compound 38.
(E)-3-[3-(4-디히드록시페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.1]헵탄 및 이의 트리플루오로아세트산 염.(E) -3- [3- (4-dihydroxyphenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.1] heptane and its trifluoroacetic acid salt.
화합물 39.Compound 39.
(Z)-3-[3-(3,4-디히드록시페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.1]헵탄 및 이의 트리플루오로아세트산 염.(Z) -3- [3- (3,4-dihydroxyphenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.1] heptane and its trifluoroacetic acid salt.
화합물 40.Compound 40.
(E)-3-[3-(3,4-디히드록시페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.1]헵탄 및 이의 트리플루오로아세트산 염.(E) -3- [3- (3,4-dihydroxyphenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.1] heptane and its trifluoroacetic acid salt.
화합물 41.Compound 41.
(Z)-3-[3-(4-아미노페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.1]헵탄 및 이의 트리플루오로아세트산 염.(Z) -3- [3- (4-aminophenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.1] heptane and its trifluoroacetic acid salt.
화합물 42.Compound 42.
(E)-3-[3-(4-아미노페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.1]헵탄 및 이의 트리플루오로아세트산 염.(E) -3- [3- (4-aminophenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.1] heptane and its trifluoroacetic acid salt.
다음 실시 예는 본 발명을 더욱 상세히 예증하고 있으나, 본 발명의 범위가 이에 국한된다는 것이다.The following examples illustrate the invention in more detail, but the scope of the invention is limited thereto.
참고예 1Reference Example 1
디에틸 3-(4-메틸페닐)-5-이소옥사졸릴메틸포스포네이트의 제조.Preparation of Diethyl 3- (4-methylphenyl) -5-isoxazolylmethylphosphonate.
(1) 3-(4-메틸페닐)-5-히드록시메틸이소옥사졸의 제조.(1) Preparation of 3- (4-methylphenyl) -5-hydroxymethylisoxazole.
N-클로로숙신이미드 6.81 g (50.94 mmol)과 4-메틸페닐알독심 5.3 g (39.2 mmol)을 80 mL의 무수 테트라히드로퓨란 용액에 가하였다. 이 반응 혼합물에 촉매량의 피리딘을 가하고 50℃에서 30분간 교반시켰다. 이 반응 혼합물을 21℃로 냉각하여 프로파질 알콜 5.84 g (78.42 mmol)을 가한 후, 80 mL의 무수 테트라히드로퓨란 용매에 묽힌 트리에틸아민 7.1 mL (50.97 mmol)를 10분간 적가하고 50℃에서 1시간 교반하였다. 불용물을 여과하여 제거하고, 감압 증류하여 농축하여 얻어진 잔여물을 관 크로마토그래피 (전개용액 , 노르말 헥산 : 에틸아세테이트 = 3 : 1)로 정제하여 목적 화합물 5.1 g (수득률 : 68%)을 얻었다.6.81 g (50.94 mmol) of N-chlorosuccinimide and 5.3 g (39.2 mmol) of 4-methylphenylaldoxim were added to 80 mL of anhydrous tetrahydrofuran solution. A catalytic amount of pyridine was added to the reaction mixture, which was stirred for 30 minutes at 50 ° C. After cooling the reaction mixture to 21 ° C., 5.84 g (78.42 mmol) of propazyl alcohol was added, and then 7.1 mL (50.97 mmol) of triethylamine diluted in 80 mL of anhydrous tetrahydrofuran solvent was added dropwise for 10 minutes, followed by 1 Stirred for time. The insolubles were removed by filtration, and the residue obtained by distillation under reduced pressure was purified by column chromatography (developing solution, normal hexane: ethyl acetate = 3: 1) to obtain the title compound (5.1 g, yield: 68%).
1H NMR (CDCl3, 300MHz): δ 2.47 (3H, s, CH3), 4.80 (2H, s, CH2OH), 6.52 (1H, s, 이소옥사졸-H), 7.22 (2H, d, 페닐-H), 7.66 (2H, d, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 2.47 (3H, s, CH 3 ), 4.80 (2H, s, CH 2 OH), 6.52 (1H, s, isoxazole-H), 7.22 (2H, d , Phenyl-H), 7.66 (2H, d, phenyl-H).
(2) 3-(4-메틸페닐)-5-브로모메틸이소옥사졸의 제조.(2) Preparation of 3- (4-methylphenyl) -5-bromomethylisoxazole.
3-(4-메틸페닐)-5-히드록시메틸이소옥사졸 4 g (21.14 mmol)을 40mL의 무수 테트라히드로퓨란 용매에 녹이고 트리페닐포스핀 6.65 g (25.37 mmol)과 카본 테트라브로미드 8.41 g (25.37 mmol)을 가하여 21℃에서 1.5시간 교반시켰다. 반응 혼합물을 감압 증류하여 농축하고, 잔여물을 관 크로마토그래피 (전개용액 , 노르말 헥산 : 에틸 아세테이트 = 1 : 1)로 정제하여 목적 화합물 4.8 g (수득률 : 90%)을 얻었다.4 g (21.14 mmol) of 3- (4-methylphenyl) -5-hydroxymethylisoxazole are dissolved in 40 mL of anhydrous tetrahydrofuran solvent, 6.65 g (25.37 mmol) of triphenylphosphine and 8.41 g (25.37) of carbon tetrabromide mmol) was added and stirred at 21 ° C for 1.5 hours. The reaction mixture was concentrated by distillation under reduced pressure, and the residue was purified by column chromatography (developing solution, normal hexane: ethyl acetate = 1: 1) to obtain 4.8 g (yield: 90%) of the title compound.
1H NMR (CDCl3, 300MHz): δ 2.40 (3H, s, CH3), 4.50 (2H, s, CH2Br), 6.60 (1H, s, 이소옥사졸-H), 7.25 (2H, d, 페닐-H), 7.66 (2H, d, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 2.40 (3H, s, CH 3 ), 4.50 (2H, s, CH 2 Br), 6.60 (1H, s, isoxazole-H), 7.25 (2H, d , Phenyl-H), 7.66 (2H, d, phenyl-H).
(3) 디에틸 3-(4-메틸페닐)-5-이소옥사졸릴메틸포스포네이트의 제조.(3) Preparation of diethyl 3- (4-methylphenyl) -5-isoxazolylmethylphosphonate.
트리에틸포스파이트 6.10 g (36.69 mmol)에 3-(4-메틸페닐)-5-브로모메틸이소옥사졸 3.7 g (14.68 mmol)을 가하고 150℃에서 4시간 동안 교반 시켰다. 반응 혼합물을 감압 증류하여 농축하고, 잔여물을 관 크로마토그래피 (전개용액 , 노르말 헥산 : 에틸 아세테이트 = 1 : 1)로 정제하여 목적 화합물 4.1 g (수득률 : 90%)을 얻었다.3.7 g (14.68 mmol) of 3- (4-methylphenyl) -5-bromomethylisoxazole was added to 6.10 g (36.69 mmol) of triethylphosphite, followed by stirring at 150 ° C for 4 hours. The reaction mixture was concentrated by distillation under reduced pressure, and the residue was purified by column chromatography (developing solution, normal hexane: ethyl acetate = 1: 1) to obtain 4.1 g (yield: 90%) of the title compound.
1H NMR (CDCl3, 300MHz): δ 1.30 ∼ 1.40 (6H, m, 2 CH3), 2.23 (3H, s, CH3), 3.25 (2H, d, CH2), 3.85 ∼ 4.06 (4H, m, 2 CH2), 6.42 (1H, s, 이소옥사졸-H), 7.12 (2H, d, 페닐-H), 7.54 (2H, d, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.30-1.40 (6H, m, 2 CH 3 ), 2.23 (3H, s, CH 3 ), 3.25 (2H, d, CH 2 ), 3.85-4.06 (4H, m, 2 CH 2 ), 6.42 (1H, s, isoxazole-H), 7.12 (2H, d, phenyl-H), 7.54 (2H, d, phenyl-H).
참고예 2Reference Example 2
상기 참고예 1과 같은 방법으로, 해당하는 이소옥사졸 화합물로부터 다음과 같은 화합물들을 제조하였다.In the same manner as in Reference Example 1, the following compounds were prepared from the corresponding isoxazole compound.
(1) 디에틸 3-페닐-5-이소옥사졸릴메틸포스포네이트.(1) diethyl 3-phenyl-5-isooxazolylmethylphosphonate.
1H NMR (CDCl3, 300MHz): δ 1.32 ∼ 1.40 (6H, m, 2 CH3), 3.40 (2H, d, CH2), 4.00 ∼ 4.20 (4H, m, 2 CH2), 6.60 (1H, s, 이소옥사졸-H), 7.40 ∼ 7.50 (3H, m, 페닐-H), 7.75 ∼ 7.83 (2H, m, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.32-1.40 (6H, m, 2 CH 3 ), 3.40 (2H, d, CH 2 ), 4.00-4.20 (4H, m, 2 CH 2 ), 6.60 (1H , s, isoxazole-H), 7.40 to 7.50 (3H, m, phenyl-H), 7.75 to 7.83 (2H, m, phenyl-H).
(2) 디에틸 3-(4-플루오로페닐)-5-이소옥사졸릴메틸포스포네이트.(2) diethyl 3- (4-fluorophenyl) -5-isoxazolylmethylphosphonate.
1H NMR (CDCl3, 300MHz): δ 1.21 ∼ 1.34 (6H, m, 2 CH3), 3.35 (2H, d, CH2), 4.00 ∼ 4.18 (4H, m, 2 CH2), 6.50 (1H, s, 이소옥사졸-H), 7.03 ∼ 7.12 (2H, m, 페닐-H), 7.70 ∼ 7.78 (2H, m, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.21-1.34 (6H, m, 2 CH 3 ), 3.35 (2H, d, CH 2 ), 4.00-4.18 (4H, m, 2 CH 2 ), 6.50 (1H , s, isoxazole-H), 7.03 to 7.12 (2H, m, phenyl-H), 7.70 to 7.78 (2H, m, phenyl-H).
(3) 디에틸 3-(4-메톡시페닐)-5-이소옥사졸릴메틸포스포네이트.(3) diethyl 3- (4-methoxyphenyl) -5-isoxazolylmethylphosphonate.
1H NMR (CDCl3, 300MHz): δ 1.25 ∼ 1.34 (6H, m, 2 CH3), 3.37 (2H, d, CH2), 3.81 (3H, s, OCH3), 4.00 ∼ 4.20 (4H, m, 2 CH2), 6.51 (1H, s, 이소옥사졸-H), 6.94 (2H, d, 페닐-H), 7.70 (2H, d, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.25-1.34 (6H, m, 2 CH 3 ), 3.37 (2H, d, CH 2 ), 3.81 (3H, s, OCH 3 ), 4.00-4.20 (4H, m, 2 CH 2 ), 6.51 (1H, s, isoxazole-H), 6.94 (2H, d, phenyl-H), 7.70 (2H, d, phenyl-H).
(4) 디에틸 3-(4-클로로페닐)-5-이소옥사졸릴메틸스포네이트.(4) diethyl 3- (4-chlorophenyl) -5-isoxazolylmethyl phosphate.
1H NMR (CDCl3, 300MHz): δ 1.21 ∼ 1.32 (6H, m, 2 CH3), 3.35 (2H, d, CH2), 3.98 ∼ 4.15 (4H, m, 2 CH2), 6.52 (1H, s, 이소옥사졸-H), 7.37 (2H, d, 페닐-H), 7.69 (2H, d, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.21-1.32 (6H, m, 2 CH 3 ), 3.35 (2H, d, CH 2 ), 3.98-4.15 (4H, m, 2 CH 2 ), 6.52 (1H , s, isoxazole-H), 7.37 (2H, d, phenyl-H), 7.69 (2H, d, phenyl-H).
(5) 디에틸 3-(3,4-디메톡시페닐)-5-이소옥사졸릴메틸포스포네이트.(5) Diethyl 3- (3,4-dimethoxyphenyl) -5-isoxazolylmethylphosphonate.
1H NMR (CDCl3, 300MHz): δ 1.22 ∼ 1.35 (6H, m, 2 CH3), 3.36 (2H, d, CH2), 3.80 (3H, s, OCH3), 3.85 (3H, s, OCH3), 4.01 ∼ 4.15 (4H, m, 2 CH2), 6.54 (1H, s, 이소옥사졸-H), 6.90 (1H, d, 페닐-H), 7.25 (1H, d, 페닐-H), 7.40 (1H, s, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.22-1.35 (6H, m, 2 CH 3 ), 3.36 (2H, d, CH 2 ), 3.80 (3H, s, OCH 3 ), 3.85 (3H, s, OCH 3 ), 4.01 to 4.15 (4H, m, 2 CH 2 ), 6.54 (1H, s, isoxazole-H), 6.90 (1H, d, phenyl-H), 7.25 (1H, d, phenyl-H ), 7.40 (1H, s, phenyl-H).
(6) 디에틸 3-(4-시아노페닐)-5-이소옥사졸릴메틸포스포네이트.(6) diethyl 3- (4-cyanophenyl) -5-isoxazolylmethylphosphonate.
1H NMR (CDCl3, 300MHz): δ 1.19 ∼ 1.32 (6H, m, 2 CH3), 3.36 (2H, d, CH2), 3.96 ∼ 4.16 (4H, m, 2 CH2), 6.59 (1H, s, 이소옥사졸-H), 7.68 (2H, d, 페닐-H), 7.85 (2H, d, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.19-1.32 (6H, m, 2 CH 3 ), 3.36 (2H, d, CH 2 ), 3.96-4.16 (4H, m, 2 CH 2 ), 6.59 (1H , s, isoxazole-H), 7.68 (2H, d, phenyl-H), 7.85 (2H, d, phenyl-H).
(7) 디에틸 3-(2,4-디메톡시페닐)-5-이소옥사졸릴메틸포스포네이트.(7) diethyl 3- (2,4-dimethoxyphenyl) -5-isooxazolylmethylphosphonate.
1H NMR (CDCl3, 300MHz): δ 1.23 ∼ 1.38 (6H, m, 2CH3), 3.34 (2H, d, CH2), 3.75 (3H, s, OCH3), 3.80 (3H, s, OCH3), 3.98 ∼ 4.16 (4H, m, 2 CH2), 6.55 (1H, s, 이소옥사졸-H), 6.90 (1H, d, 페닐-H), 7.65 (1H, d, 페닐-H), 7.70 (1H, s, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.23-1.38 (6H, m, 2CH 3 ), 3.34 (2H, d, CH 2 ), 3.75 (3H, s, OCH 3 ), 3.80 (3H, s, OCH 3 ), 3.98-4.16 (4H, m, 2 CH 2 ), 6.55 (1H, s, isoxazole-H), 6.90 (1H, d, phenyl-H), 7.65 (1H, d, phenyl-H) , 7.70 (1H, s, phenyl-H).
(8) 디에틸 3-[3,4-비스(4-디메톡시벤질옥시)페닐]-5-이소옥사졸릴메틸포스포네이트.(8) diethyl 3- [3,4-bis (4-dimethoxybenzyloxy) phenyl] -5-isoxazolylmethylphosphonate.
1H NMR (CDCl3, 300MHz): δ 1.23 ∼ 1.32 (6H, m, 2 CH3), 3.33 (2H, d, CH2), 3.75 (6H, s, 2 OCH3), 3.99 ∼ 4.16 (4H, m, 2 CH2), 5.09 (4H, s, 2 CH2), 6.47 (1H, s, 이소옥사졸-H), 6.81 ∼ 6.97 (5H, m, 페닐-H), 7.21 ∼ 7.38 (5H, m, 페닐-H), 7.44 (1H, s, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.23 to 1.32 (6H, m, 2 CH 3 ), 3.33 (2H, d, CH 2 ), 3.75 (6H, s, 2 OCH 3 ), 3.99 to 4.16 (4H , m, 2 CH 2 ), 5.09 (4H, s, 2 CH 2 ), 6.47 (1H, s, isoxazole-H), 6.81-6.97 (5H, m, phenyl-H), 7.21-7.38 (5H , m, phenyl-H), 7.44 (1H, s, phenyl-H).
(9) 디에틸 3-(4-t-부톡시카르보닐아미노페닐)-5-이소옥사졸릴메틸포스포네이트.(9) Diethyl 3- (4-t-butoxycarbonylaminophenyl) -5-isoxazolylmethylphosphonate.
1H NMR (CDCl3, 300MHz): δ 1.20 ∼ 1.36 (6H, m, 2 CH3), 1.46 [9H, s, C(CH3)3], 3.32 (2H, d, CH2), 3.97 ∼ 4.15 (4H, m, 2 CH2), 6.49 (1H, s, 이소옥사졸-H), 7.46 (2H, d, 페닐-H), 7.64 (2H, d, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.20-1.36 (6H, m, 2 CH 3 ), 1.46 [9H, s, C (CH 3 ) 3 ], 3.32 (2H, d, CH 2 ), 3.97- 4.15 (4H, m, 2 CH 2), 6.49 (1H, s, iso-oxazole -H), 7.46 (2H, d , phenyl -H), 7.64 (2H, d , phenyl -H).
(10) 디에틸 3-[4-(4-메톡시벤질옥시)페닐]-5-이소옥사졸릴메틸포스포네이트.(10) diethyl 3- [4- (4-methoxybenzyloxy) phenyl] -5-isoxazolylmethylphosphonate.
1H NMR (CDCL3, 300MHz): δ 1.29 ∼ 1.38 (6H, m, 2 CH3), 3.39 (2H, d, CH2), 3.82 (3H, s, OCH3), 4.10 ∼ 4.12 (4H, m, 2 CH2), 5.03 (2H, s, CH2), 6.62 (1H, s, 이소옥사졸-H), 6.93 (2H, d, 페닐-H), 7.03 (2H, d, 페닐-H). 7.38 (2H, d, 페닐-H), 7.74 (2H, d, 페닐-H). 1 H NMR (CDCL 3 , 300 MHz): δ 1.29-1.38 (6H, m, 2 CH 3 ), 3.39 (2H, d, CH 2 ), 3.82 (3H, s, OCH 3 ), 4.10-4.12 (4H, m, 2 CH 2 ), 5.03 (2H, s, CH 2 ), 6.62 (1H, s, isoxazole-H), 6.93 (2H, d, phenyl-H), 7.03 (2H, d, phenyl-H ). 7.38 (2H, d, phenyl-H), 7.74 (2H, d, phenyl-H).
실시예 1Example 1
3-[3-(4-메틸페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.2]옥탄 옥살산 염.3- [3- (4-methylphenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.2] octane oxalic acid salt.
칼륨 3급-부톡시드 188 mg (1.68 mmol)을 2mL의 무수 테트라히드로퓨란 용매에 용해시키고, 이 용액에 디에틸 3-(4-메틸페닐)-5-이소옥사졸릴메틸포스포네이트 482 mg (1.56 mmol)을 2 mL의 무수 테트라히드로퓨란 용매에 녹인 용액을 천천히 적가하고 22℃에서 30분간 교반시켰다. 이 반응 혼합액에 3-퀴누클리디논 150 mg (1.20 mmol)을 2 mL의 무수 테트라히드로퓨란 용매에 녹인 용액을 천천히 적가하고 22℃에서 1시간 동안 교반시켰다. 감압 증류하여 농축하고 잔여물에 6N 염산을 가하여 산성화(pH = 3)한 후 에틸 아세테이트 용매로 추출하였다. 물층을 2N 나트륨 히드록시드 용액으로 염기화(pH = 9) 한 다음 에틸 아세테이트 용매로 추출하고 유기층을 무수 황산 마그네슘으로 건조시켰다. 건조된 유기층을 걸르고, 이 용액을 다시 감압 증류하여 농축하고 잔여물을 관 크로마토그래피 (전개용액 , 에틸아세테이트 : 메탄올 : 암모니움 히드록시드 = 3 : 1 : 2)로 정제하여 목적화합물인 (Z)-이성질체 80 mg과 (E)-이성질체 60 mg (수득률 : 총 90%)을 각각 얻었다. 이들 이성질체를 옥살산으로 처리하여 옥살산 염을 제조하였다.188 mg (1.68 mmol) of potassium tert-butoxide are dissolved in 2 mL of anhydrous tetrahydrofuran solvent, and 482 mg (1.56) of diethyl 3- (4-methylphenyl) -5-isooxazolylmethylphosphonate in this solution mmol) was slowly added dropwise into 2 mL of anhydrous tetrahydrofuran solvent and stirred at 22 ° C for 30 minutes. To the reaction mixture, a solution of 150 mg (1.20 mmol) of 3-quinuclidinone dissolved in 2 mL of anhydrous tetrahydrofuran solvent was slowly added dropwise and stirred at 22 ° C for 1 hour. After distillation under reduced pressure, 6N hydrochloric acid was added to the residue and acidified (pH = 3), followed by extraction with an ethyl acetate solvent. The water layer was basified with 2N sodium hydroxide solution (pH = 9) and then extracted with ethyl acetate solvent and the organic layer was dried over anhydrous magnesium sulfate. The dried organic layer was filtered and the solution was concentrated by distillation under reduced pressure again and the residue was purified by column chromatography (developing solution, ethyl acetate: methanol: ammonium hydroxide = 3: 1: 2) to obtain the target compound ( 80 mg of Z) -isomer and 60 mg of (E) -isomer (yield: 90% in total) were obtained, respectively. These isomers were treated with oxalic acid to prepare oxalic acid salts.
(Z)-이성질체(Z) -isomer
11H NMR (CDCl3, 300MHz): δ 1.75 ∼ 1.92 (4H, m, 2 CH2), 2.40 (3H, s, CH2), 2.58 ∼ 2.61 (1H, m, CH), 2.88 ∼ 3.11 (4H, m, 2 CH2), 3.92 (2H, s, CH2), 6.30 (2H, 2s, C=CH, 이소옥사졸-H), 7.28 (2H, d, 페닐-H), 7.70 (2H, d, 페닐-H). 1 1 H NMR (CDCl 3 , 300 MHz): δ 1.75 to 1.92 (4H, m, 2 CH 2 ), 2.40 (3H, s, CH 2 ), 2.58 to 2.61 (1H, m, CH), 2.88 to 3.11 (4H , m, 2 CH 2 ), 3.92 (2H, s, CH 2 ), 6.30 (2H, 2s, C = CH, isoxazole-H), 7.28 (2H, d, phenyl-H), 7.70 (2H, d, phenyl-H).
(E)-이성질체(E) -isomer
1H NMR (CDCl3, 300MHz): δ 2.00 ∼ 2.13 (4H, m, 2 CH2), 2.41 (3H, s, CH3), 3.20 ∼ 3.38 (4H, m, 2 CH2), 3.86 ∼ 3.91 (1H, m, CH), 3.97 (2H, s, CH2), 6.27 (1H, s, C=CH), 6.42 (1H, s, 이소옥사졸-H), 7.27 (2H, d, 페닐-H), 7.69 (2H, d, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 2.00 to 2.13 (4H, m, 2 CH 2 ), 2.41 (3H, s, CH 3 ), 3.20 to 3.38 (4H, m, 2 CH 2 ), 3.86 to 3.91 (1H, m, CH), 3.97 (2H, s, CH 2), 6.27 (1H, s, C = CH), 6.42 (1H, s, iso-oxazole -H), 7.27 (2H, d , phenyl- H), 7.69 (2H, d, phenyl-H).
실시예 2Example 2
3-(3-페닐이소옥사졸-5-일)메틸렌-1-아자비시클로[2. 2. 2]옥탄.3- (3-phenylisoxazol-5-yl) methylene-1-azabicyclo [2. 2. 2] octane.
상기 실시예 1과 같은 제조방법으로 THF 용매를 사용하여 칼륨 3급-부톡시드 85 mg (0.75 mmol), 디에틸 3-페닐-5-이소옥사졸릴메틸포스포네이트 207 mg (0.70 mmol) 및 3-퀴누클리디논 67.5 mg (0.54 mmol)을 22℃에서 5시간 동안 반응시킨 후 관 크로마토그래피로 분리하여 목적화합물인 (Z)-이성질체 67 mg과 (E)-이성질체 46 mg (수득률 : 총 81%)을 각각 얻었다.85 mg (0.75 mmol) of potassium tert-butoxide, 207 mg (0.70 mmol) of diethyl 3-phenyl-5-isoxazolylmethylphosphonate and 3 using THF solvent in the same preparation method as in Example 1 above 67.5 mg (0.54 mmol) of quinuclidinone was reacted at 22 ° C. for 5 hours and separated by column chromatography to obtain 67 mg of the target compound (Z) -isomer and 46 mg of the (E) -isomer (yield: 81% in total). ), Respectively.
(Z)-이성질체(Z) -isomer
1H NMR (CDCl3, 300MHz): δ1.72 ∼ 1.98 (4H, m, 2 CH2), 2.55 ∼ 2.62 (1H, m, CH), 2.87 ∼ 3.14 (4H, m, 2 CH2), 3.95 (2H, s, CH2), 6.30 (2H, 2s, C=CH, 이소옥사졸-H), 7.40 ∼ 7.51 (3H, m, 페닐-H), 7.75 ∼ 7.65 (2H, m, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ1.72 to 1.98 (4H, m, 2 CH 2 ), 2.55 to 2.62 (1H, m, CH), 2.87 to 3.14 (4H, m, 2 CH 2 ), 3.95 (2H, s, CH2), 6.30 (2H, 2s, C = CH, isoxazole-H), 7.40-7.51 (3H, m, phenyl-H), 7.75-7.65 (2H, m, phenyl-H) .
(E)-이성질체(E) -isomer
1H NMR (CDCl3, 300MHz): δ 1.73 ∼ 1.98 (4H, m, 2 CH2), 2.86 ∼ 3.12 (4H, m, 2 CH2), 3.65 ∼ 3.71 (3H, m, CH, CH2), 6.25 (1H, s, C=CH), 6.35 (1H, s, 이소옥사졸-H), 7.35 ∼ 7.50 (3H, m, 페닐-H), 7.75 ∼ 7.82 (2H, d, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.73-1.98 (4H, m, 2 CH 2 ), 2.86-3.12 (4H, m, 2 CH 2 ), 3.65-3.71 (3H, m, CH, CH 2 ) , 6.25 (1H, s, C = CH), 6.35 (1H, s, isoxazole-H), 7.35-7.50 (3H, m, phenyl-H), 7.75-7.82 (2H, d, phenyl-H) .
실시예 3Example 3
3-[3-(4-메톡시페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.2]옥탄.3- [3- (4-methoxyphenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.2] octane.
상기 실시예 1과 같은 제조방법으로 THF 용매를 사용하여 칼륨 3급-부톡시드 350 mg (3.12 mmol), 디에틸 3-(4-메톡시페닐)-5-이소옥사졸릴메틸포스포네이트 936 mg (2.88 mmol) 및 3-퀴누클리디논 300 mg (2.40 mmol)을 22℃에서 3.5시간 동안 반응시킨 후 관 크로마토그래피로 분리하여 목적화합물인 (Z)-이성질체 285 mg과 (E)-이성질체 247 mg (수득률 : 총 75%)을 각각 얻었다.350 mg (3.12 mmol) of potassium tert-butoxide, 936 mg of diethyl 3- (4-methoxyphenyl) -5-isooxazolylmethylphosphonate using THF solvent in the same method as in Example 1 above (2.88 mmol) and 300 mg (2.40 mmol) of 3-quinuclidinone were reacted at 22 ° C. for 3.5 hours, and then separated by column chromatography to obtain 285 mg of the target compounds (Z) -isomer and (E) -isomer 247 mg. (Yield: 75% in total) were obtained.
(Z)-이성질체(Z) -isomer
1H NMR (CDCl3, 300MHz): δ 1.66 ∼ 1.88 (4H, m, 2 CH2), 2.50 ∼ 2.57 (1H, m, CH), 2.80 ∼ 3.03 (4H, m, 2 CH2), 3.82 (3H, s, OCH3), 3.89 (2H, s, CH2), 6.24 (2H, 2s, C=CH, 이소옥사졸-H), 6.94 (2H, d, 페닐-H), 7.72 (2H, d, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.66-1.88 (4H, m, 2 CH 2 ), 2.50-2.57 (1H, m, CH), 2.80-3.03 (4H, m, 2 CH 2 ), 3.82 ( 3H, s, OCH 3 ), 3.89 (2H, s, CH 2 ), 6.24 (2H, 2s, C = CH, isoxazole-H), 6.94 (2H, d, phenyl-H), 7.72 (2H, d, phenyl-H).
(E)-이성질체(E) -isomer
1H NMR (CDCl3, 300MHz): δ 1.70 ∼ 1.95 (4H, m, 2 CH2), 2.86 ∼ 3.10 (4H, m, 2 CH2), 3.54 ∼ 3.60 (1H, m, CH), 3.62 (2H, s, CH2), 3.82 (2H, s, OCH3), 6.12 (1H, s, C=CH), 6.30 (1H, s, 이소옥사졸-H), 6.94 (2H, d, 페닐-H), 7.72 (2H, d, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.70-1.95 (4H, m, 2 CH 2 ), 2.86-3.10 (4H, m, 2 CH 2 ), 3.54-3.60 (1H, m, CH), 3.62 ( 2H, s, CH 2 ), 3.82 (2H, s, OCH 3 ), 6.12 (1H, s, C = CH), 6.30 (1H, s, isoxazole-H), 6.94 (2H, d, phenyl- H), 7.72 (2H, d, phenyl-H).
실시예 4Example 4
3-[3-(4-플루오로페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.2]옥탄.3- [3- (4-fluorophenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.2] octane.
상기 실시예 1과 같은 제조방법으로 THF 용매를 사용하여 칼륨 3급-부톡시드 233 mg (2.08 mmol), 디에틸 3-(4-플루오로페닐)-5-이소옥사졸릴메틸포스포네이트 600 mg (1.92 mmol) 및 3-퀴누클리디논 200 mg (1.60 mmol)을 22℃에서 3.5시간 동안 반응시킨 후 관 크로마토그래피로 분리하여 목적화합물인 (Z)-이성질체 67 mg과 (E)-이성질체 46 mg (수득률 : 총 71%)을 각각 얻었다.233 mg (2.08 mmol) of potassium tert-butoxide, 600 mg of diethyl 3- (4-fluorophenyl) -5-isoxazolylmethylphosphonate using THF solvent in the same manner as in Example 1 above (1.92 mmol) and 200 mg (1.60 mmol) of 3-quinuclidinone were reacted at 22 ° C. for 3.5 hours, and then separated by column chromatography to obtain 67 mg of the target compounds (Z) -isomer and 46 mg of the (E) -isomer. (Yield: Total 71%) were obtained, respectively.
(Z)-이성질체(Z) -isomer
1H NMR (CDCl3, 300MHz): δ 1.65 ∼ 1.92 (4H, m, 2 CH2), 2.52 ∼ 2.60 (1H, m, CH), 2.80 ∼ 3.06 (4H, m, 2 CH2), 3.84 (2H, s, CH2), 6.22 (2H, s, C=CH, 이소옥사졸-H), 7.11 (2H, d, 페닐-H), 7.75 (2H, d, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.65-1.92 (4H, m, 2 CH 2 ), 2.52-2.60 (1H, m, CH), 2.80-3.06 (4H, m, 2 CH 2 ), 3.84 ( 2H, s, CH 2 ), 6.22 (2H, s, C = CH, isoxazole-H), 7.11 (2H, d, phenyl-H), 7.75 (2H, d, phenyl-H).
(E)-이성질체:(E) -isomers:
1H NMR (CDCl3, 300MHz): δ 1.76 ∼ 1.98 (4H, m, 2 CH2), 2.87 ∼ 3.09 (4H, m, 2 CH2), 3.53 ∼ 3.59 (1H, m, CH), 3.68 (2H, s, CH2), 6.15 (1H, s, C=CH), 6.35 (1H, s, 이소옥사졸-H), 7.25 (2H, d, 페닐-H), 7.72 (2H, d, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.76-1.98 (4H, m, 2 CH 2 ), 2.87-3.09 (4H, m, 2 CH 2 ), 3.53-3.59 (1H, m, CH), 3.68 ( 2H, s, CH 2 ), 6.15 (1H, s, C = CH), 6.35 (1H, s, isoxazole-H), 7.25 (2H, d, phenyl-H), 7.72 (2H, d, phenyl -H).
실시예 5Example 5
3-[3-(4-클로로페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.2]옥탄.3- [3- (4-chlorophenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.2] octane.
상기 실시예 1과 같은 제조방법으로 THF 용매를 사용하여 칼륨 3급-부톡시드 116 mg (1.04 mmol), 디에틸 3-(4-플루오로페닐)-5-이소옥사졸릴메틸포스포네이트 316 mg (0.96 mmol) 및 3-퀴누클리디논 100 mg (0.80 mmol)을 22℃에서 45분간 반응시킨 후 관 크로마토그래피로 분리하여 목적화합물인 (Z)-이성질체 85 mg과 (E)-이성질체 78 mg (수득률 : 총 68%)을 각각 얻었다.116 mg (1.04 mmol) of potassium tert-butoxide and 316 mg of diethyl 3- (4-fluorophenyl) -5-isooxazolylmethylphosphonate using THF solvent in the same method as in Example 1 above (0.96 mmol) and 100 mg (0.80 mmol) of 3-quinuclidinone were reacted for 45 minutes at 22 ° C. and separated by column chromatography to obtain 85 mg of the target compounds (Z) -isomer and 78 mg of the (E) -isomer. Yield: 68% in total).
(Z)-이성질체(Z) -isomer
1H NMR (CDCl3, 300MHz): δ 1.80 ∼ 1.98 (4H, m, 2 CH2), 2.6 ∼ 2.68 (1H, m, CH), 2.90 ∼ 3.20 (4H, m, 2 CH2), 3.99 (2H, s, CH2), 6.31 (2H, s, C=CH, 이소옥사졸-H), 7.40 (2H, d, 페닐-H), 7.71 (2H, d, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.80-1.98 (4H, m, 2 CH 2 ), 2.6-2.68 (1H, m, CH), 2.90-3.20 (4H, m, 2 CH 2 ), 3.99 ( 2H, s, CH 2 ), 6.31 (2H, s, C = CH, isoxazole-H), 7.40 (2H, d, phenyl-H), 7.71 (2H, d, phenyl-H).
(E)-이성질체(E) -isomer
1H NMR (CDCl3, 300MHz): δ 1.80 ∼ 2.01 (4H, m, 2 CH2), 3.00 ∼ 3.20 (4H, m, 2 CH2), 3.60 ∼ 3.70 (1H, m, CH), 3.79 (2H, s, CH2), 6.18 (1H, s, C=CH), 6.38 (1H, s, 이소옥사졸-H), 7.40 (2H, d, 페닐-H), 7.68 (2H, d, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.80 to 2.01 (4H, m, 2 CH 2 ), 3.00 to 3.20 (4H, m, 2 CH 2 ), 3.60 to 3.70 (1H, m, CH), 3.79 ( 2H, s, CH 2 ), 6.18 (1H, s, C = CH), 6.38 (1H, s, isoxazole-H), 7.40 (2H, d, phenyl-H), 7.68 (2H, d, phenyl -H).
실시예 6Example 6
3-[3-(3,4-디메톡시페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.2]옥탄.3- [3- (3,4-dimethoxyphenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.2] octane.
상기 실시예 1과 같은 제조방법으로 THF 용매를 사용하여 칼륨 3급-부톡시드 126 mg (1.12 mmol), 디에틸 3-(3,4-디메톡시페닐)-5-이소옥사졸릴메틸포스포네이트 369 mg (1.04 mmol) 및 3-퀴누클리디논 100 mg (0.80 mmol)을 22℃에서 1.5시간 동안 반응시킨 후 관 크로마토그래피로 분리하여 목적화합물인 (Z)-이성질체 135 mg과 (E)-이성질체 65 mg (수득률 : 총 77%)을 각각 얻었다.126 mg (1.12 mmol) of potassium tert-butoxide, diethyl 3- (3,4-dimethoxyphenyl) -5-isooxazolylmethylphosphonate using a THF solvent in the same method as in Example 1 above 369 mg (1.04 mmol) and 100 mg (0.80 mmol) of 3-quinuclidinone were reacted at 22 ° C. for 1.5 hours and separated by column chromatography to obtain 135 mg of the target compound (Z) -isomer and (E) -isomer. 65 mg (yield: 77% total) were obtained, respectively.
(Z)-이성질체(Z) -isomer
1H NMR (CDCl3, 300MHz): δ 1.70 ∼ 1.95 (4H, m, 2 CH2), 2.50 ∼ 2.60 (1H, m, CH), 2.88 (4H, m, 2 CH2), 3.85 (2H, s, CH2), 3.90 (3H, s, OCH3), 3.96 (3H, s, OCH3), 6.23 (2H, 2s, C=CH, 이소옥사졸-H), 6.88 (1H, d, 페닐-H), 7.25 (1H, d, 페닐-H), 7.40 (1H, s, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.70-1.95 (4H, m, 2 CH 2 ), 2.50-2.60 (1H, m, CH), 2.88 (4H, m, 2 CH 2 ), 3.85 (2H, s, CH 2 ), 3.90 (3H, s, OCH 3 ), 3.96 (3H, s, OCH 3 ), 6.23 (2H, 2s, C = CH, isoxazole-H), 6.88 (1H, d, phenyl -H), 7.25 (1H, d, phenyl-H), 7.40 (1H, s, phenyl-H).
(E)-이성질체(E) -isomer
1H NMR (CDCl3, 300MHz): δ 1.78 ∼ 1.96 (4H, m, 2 CH2), 2.90 ∼ 3.09 (4H, m, 2 CH2), 3.58 ∼ 3.62 (1H, m, CH), 3.68 (2H, s, CH2), 3.89 (3H, s, OCH3), 3.91 (3H, s, OCH3), 6.13 (1H, s, C=CH), 6.32 (1H, s, 이소옥사졸-H), 6.87 (1H, d, 페닐-H), 7.23 (1H, d, 페닐-H), 7.38 (1H, s, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.78-1.96 (4H, m, 2 CH 2 ), 2.90-3.09 (4H, m, 2 CH 2 ), 3.58-3.62 (1H, m, CH), 3.68 ( 2H, s, CH 2 ), 3.89 (3H, s, OCH 3 ), 3.91 (3H, s, OCH 3), 6.13 (1H, s, C = CH), 6.32 (1H, s, isoxazole-H) , 6.87 (1H, d, phenyl-H), 7.23 (1H, d, phenyl-H), 7.38 (1H, s, phenyl-H).
실시예 7Example 7
3-[3-(4-시아노페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.2]옥탄.3- [3- (4-cyanophenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.2] octane.
상기 실시예 1과 같은 제조방법으로 THF 용매를 사용하여 칼륨 3급-부톡시드 188 mg (1.68 mmol), 디에틸 3-(4-시아노페닐)-5-이소옥사졸릴메틸포스포네이트 499 mg (1.56 mmol) 및 3-퀴누클리디논 150 mg (1.20 mmol)을 22℃에서 1.5시간 동안 반응시킨 후 관 크로마토그래피로 분리하여 목적화합물인 (Z)-이성질체 120 mg과 (E)-이성질체 93 mg (수득률 : 총 61%)을 각각 얻었다.188 mg (1.68 mmol) of potassium tert-butoxide, 499 mg of diethyl 3- (4-cyanophenyl) -5-isooxazolylmethylphosphonate using a THF solvent in the same method as in Example 1 above (1.56 mmol) and 150 mg (1.20 mmol) of 3-quinuclidinone were reacted at 22 ° C. for 1.5 hours, and then separated by column chromatography to obtain 120 mg of the (Z) -isomer and 93 mg of the (E) -isomer. (Yield: 61% in total) were obtained.
(Z)-이성질체(Z) -isomer
1H NMR (CDCl3, 300MHz): δ 1.95 ∼ 2.20 (4H, m, 2 CH2), 2.85 ∼ 2.90 (1H, m, CH), 3.25 ∼ 3.39 (4H, m, 2 CH2), 4.31 (2H, s, CH2), 6.48 (2H, 2s, C=CH, 이소옥사졸-H), 7.76 (2H, d, 페닐-H), 7.94 (2H, d, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.95-2.20 (4H, m, 2 CH 2 ), 2.85-2.90 (1H, m, CH), 3.25-3.39 (4H, m, 2 CH 2 ), 4.31 ( 2H, s, CH 2 ), 6.48 (2H, 2s, C = CH, isoxazole-H), 7.76 (2H, d, phenyl-H), 7.94 (2H, d, phenyl-H).
(E)-이성질체(E) -isomer
1H NMR (CDCl3, 300MHz): δ 1.80 ∼ 2.01 (4H, m, 2 CH2), 3.02 ∼ 3.20 (4H, m, 2 CH2), 3.60 ∼ 3.70 (1H, m, CH), 3.78 (2H, s, CH2), 6.20 (1H, s, C=CH), 6.41 (1H, s, 이소옥사졸-H), 7.75 (2H, d, 페닐-H), 7.92 (2H, d, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.80 to 2.01 (4H, m, 2 CH 2 ), 3.02 to 3.20 (4H, m, 2 CH 2 ), 3.60 to 3.70 (1H, m, CH), 3.78 ( 2H, s, CH 2 ), 6.20 (1H, s, C = CH), 6.41 (1H, s, isoxazole-H), 7.75 (2H, d, phenyl-H), 7.92 (2H, d, phenyl -H).
실시예 8Example 8
3-[3-(2,4-디메톡시페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.2]옥탄.3- [3- (2,4-dimethoxyphenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.2] octane.
상기 실시예 1과 같은 제조방법으로 THF 용매를 사용하여 칼륨 3급-부톡시드 126 mg (1.12 mmol), 디에틸 3-(2,4-디메톡시페닐)-5-이소옥사졸릴메틸포스포네이트 369 mg (1.04 mmol) 및 3-퀴누클리디논 100 mg (0.80 mmol)을 22℃에서 1.5시간 동안 반응시킨 후 관 크로마토그래피로 분리하여 목적화합물인 (Z)-이성질체 95 mg과 (E)-이성질체 82 mg (수득률 : 총 68%)을 각각 얻었다.126 mg (1.12 mmol) of potassium tert-butoxide, diethyl 3- (2,4-dimethoxyphenyl) -5-isooxazolylmethylphosphonate using THF solvent in the same preparation method as in Example 1 above 369 mg (1.04 mmol) and 100 mg (0.80 mmol) of 3-quinuclidinone were reacted at 22 ° C. for 1.5 hours, and then separated by column chromatography to obtain 95 mg of the target compound (Z) -isomer and (E) -isomer. 82 mg (yield yield: 68% of total) were obtained, respectively.
(Z)-이성질체(Z) -isomer
1H NMR (CDCl3, 300MHz): δ 1.83 ∼ 1.98 (4H, m, 2 CH2), 2.55 ∼ 2.65 (1H, m, CH), 2.95 ∼ 3.18 (4H, m, 2 CH2), 3.85 (3H, s, CH2), 3.87 (3H, 2s, OCH3),3.92 (2H, s, CH2), 6.28 (1H, s, C=CH), 6.49 (1H, s, 이소옥사졸-H), 6.53 ∼ 6.59 (2H, m, 페닐-H), 7.79 (1H, d, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.83-1.98 (4H, m, 2 CH 2 ), 2.55-2.65 (1H, m, CH), 2.95-3.18 (4H, m, 2 CH 2 ), 3.85 ( 3H, s, CH 2 ), 3.87 (3H, 2s, OCH 3 ), 3.92 (2H, s, CH 2 ), 6.28 (1H, s, C = CH), 6.49 (1H, s, isoxazole-H ), 6.53-6.59 (2H, m, phenyl-H), 7.79 (1H, d, phenyl-H).
(E)-이성질체(E) -isomer
1H NMR (CDCl3, 300MHz): δ 1.82 ∼ 1.99 (4H, m, 2 CH2), 2.94 ∼ 3.15 (4H, m, 2 CH2), 3.61 ∼ 3.69 (1H, m CH), 3.83 (2H, s, CH2), 3.85 (3H, s, OCH3), 3.86 (3H, s, OCH3), 6.13 (1H, s, C=CH), 6.51 ∼ 6.54 (3H, m, 이소옥사졸-H, 페닐-H), 7.75 (1H, d, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.82-1.99 (4H, m, 2 CH 2 ), 2.94-3.15 (4H, m, 2 CH 2 ), 3.61-3.69 (1H, m CH), 3.83 (2H , s, CH 2 ), 3.85 (3H, s, OCH 3 ), 3.86 (3H, s, OCH 3 ), 6.13 (1H, s, C = CH), 6.51 to 6.54 (3H, m, isoxazole- H, phenyl-H), 7.75 (1H, d, phenyl-H).
실시예 9Example 9
3-{3-[3,4-비스(4-메톡시벤질옥시)페닐]이소옥사졸-5-일}메틸렌-1-아자비시클로[2.2.2]옥탄.3- {3- [3,4-bis (4-methoxybenzyloxy) phenyl] isoxazol-5-yl} methylene-1-azabicyclo [2.2.2] octane.
상기 실시예 1과 같은 제조방법으로 THF 용매를 사용하여 칼륨 3급-부톡시드 117 mg (1.04 mmol), 디에틸 3-[3,4-비스(4-메톡시벤질옥시)페닐]-5-이소옥사졸릴메틸포스포네이트 589 mg (1.04 mmol) 및 3-퀴누클리디논 100 mg (0.80 mmol)을 22℃에서 1.5시간 동안 반응시킨 후 관 크로마토그래피로 분리하여 목적화합물인 (Z)-이성질체 190 mg과 (E)-이성질체 60 mg (수득률 : 총 58%)을 각각 얻었다.117 mg (1.04 mmol) of potassium tert-butoxide, diethyl 3- [3,4-bis (4-methoxybenzyloxy) phenyl] -5- using a THF solvent in the same method as in Example 1 above 589 mg (1.04 mmol) of isooxazolylmethylphosphonate and 100 mg (0.80 mmol) of 3-quinuclidinone were reacted at 22 ° C. for 1.5 hours, and then separated by column chromatography to obtain (Z) -isomer 190 as a target compound. mg and (E) -isomer 60 mg (yield: total 58%) were obtained, respectively.
(Z)-이성질체(Z) -isomer
1H NMR (CDCl3, 300MHz): δ 1.72 ∼ 1.95 (4H, m, 2 CH2), 2.54 ∼ 2.59 (1H, m, CH), 2.85 ∼ 3.08 (4H, m, 2 CH2), 3.79 (6H, s, 2 OCH3), 3.89 (2H, s, CH2), 5.09 - 5.12 (4H, s, 2 CH2), 6.21 (1H, s, C=CH), 6.24 (1H, s, 이소옥사졸-H), 6.87 (4H, d, 페닐-H), 6.96 (1H, d, 페닐-H), 7.25 ∼ 7.40 (5H, m, 페닐-H), 7.48 (1H, s, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.72-1.95 (4H, m, 2 CH 2 ), 2.54-2.59 (1H, m, CH), 2.85-3.08 (4H, m, 2 CH 2 ), 3.79 ( 6H, s, 2 OCH 3 ), 3.89 (2H, s, CH 2 ), 5.09-5.12 (4H, s, 2 CH 2 ), 6.21 (1H, s, C = CH), 6.24 (1H, s, iso Oxazole-H), 6.87 (4H, d, phenyl-H), 6.96 (1H, d, phenyl-H), 7.25-7.40 (5H, m, phenyl-H), 7.48 (1H, s, phenyl-H ).
(E)-이성질체(E) -isomer
1H NMR (CDCl3, 300MHz): δ 1.72 ∼ 1.99 (4H, m 2 CH2), 2.85 ∼ 3.09 (4H, m, 2 CH2), 3.51 ∼ 3.58 (1H, m, CH), 3.64 (2H, s, CH2), 3.78 (6H, s, 2 OCH3), 5.05 ∼ 5.11 (4H, m, 2 CH2), 6.08 (1H, s, C=CH), 6.24 (1H, s, 이소옥사졸-H), 6.84 (4H, d, 페닐-H), 6.94 (1H, d, 페닐-H), 7.20 ∼ 7.40 (5H, m, 페닐-H), 7.45 (1H, s, 페닐-H).1 H NMR (CDCl 3, 300 MHz): δ 1.72-1.99 (4H, m 2 CH 2 ), 2.85-3.09 (4H, m, 2 CH 2), 3.51-3.58 (1H, m, CH), 3.64 (2H, s, CH 2 ), 3.78 (6H, s, 2 OCH 3 ), 5.05 to 5.11 (4H, m, 2 CH 2 ), 6.08 (1H, s, C = CH), 6.24 (1H, s, isoxazole-H ), 6.84 (4H, d, phenyl-H), 6.94 (1H, d, phenyl-H), 7.20-7.40 (5H, m, phenyl-H), 7.45 (1H, s, phenyl-H).
실시예 10Example 10
3-[3-(4-t-부톡시카르보닐아미노페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.2]옥탄.3- [3- (4-t-butoxycarbonylaminophenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.2] octane.
상기 실시예 1과 같은 제조방법으로 THF 용매를 사용하여 칼륨 3급-부톡시드 117 mg (1.04 mmol), 디에틸 3-(4-t-부톡시카르보닐아미노페닐)-5-이소옥사졸릴메틸포스포네이트 426 mg (1.04 mmol) 및 3-퀴누클리디논 100 mg (0.80 mmol)을 22℃에서 1.2시간 동안 반응시킨 후 관 크로마토그래피로 분리하여 목적화합물인 (Z)-이성질체 105 mg과 (E)-이성질체 90 mg (수득률 : 총 64%)을 각각 얻었다.117 mg (1.04 mmol) of potassium tert-butoxide, diethyl 3- (4-t-butoxycarbonylaminophenyl) -5-isoxazolylmethyl using THF solvent in the same method as in Example 1 above 426 mg (1.04 mmol) of phosphonate and 100 mg (0.80 mmol) of 3-quinuclidinone were reacted at 22 ° C. for 1.2 hours, and then separated by column chromatography to obtain 105 mg of the target compound (Z) -isomer and (E ) -Isomer 90 mg (yield: total 64%) were obtained respectively.
(Z)-이성질체(Z) -isomer
1H NMR (CDCl3, 300MHz): δ 1.54 [9H, s, C(CH3)3], 1.70 ∼ 1.90 (4H, m, 2 CH2), 2.52 ∼ 2.60 (1H, m, CH), 2.85 ∼ 3.09 (4H, m, 2 CH2), 3.89 (2H, s, CH2), 6.27 (2H, 2s, C=CH, 이소옥사졸-H), 6.65 (1H, s, NH), 7.46 (2H, d, 페닐-H), 7.73 (2H, d, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.54 [9H, s, C (CH 3 ) 3 ], 1.70 to 1.90 (4H, m, 2 CH 2 ), 2.52 to 2.60 (1H, m, CH), 2.85 -3.09 (4H, m, 2 CH 2 ), 3.89 (2H, s, CH 2 ), 6.27 (2H, 2s, C = CH, isoxazole-H), 6.65 (1H, s, NH), 7.46 ( 2H, d, phenyl-H), 7.73 (2H, d, phenyl-H).
(E)-이성질체(E) -isomer
1H NMR (CDCl3, 300MHz): δ 1.54 [9H, s, C(CH3)3], 1.70 ∼ 1.98 (4H, m, 2 CH2), 2.87 ∼ 3.10 (4H, m, 2 CH2), 3.52 ∼ 3.60 (1H, m CH), 3.64 (2H, s, CH2), 6.14 (1H, s, C=CH), 6.32 (1H, s, 이소옥사졸-H), 6.68 (1H, s, NH), 7.45 (2H, d, 페닐-H), 7.72 (2H, d, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.54 [9H, s, C (CH 3 ) 3 ], 1.70 to 1.98 (4H, m, 2 CH 2 ), 2.87 to 3.10 (4H, m, 2 CH 2 ) , 3.52 to 3.60 (1H, m CH), 3.64 (2H, s, CH 2 ), 6.14 (1H, s, C = CH), 6.32 (1H, s, isoxazole-H), 6.68 (1H, s , NH), 7.45 (2H, d, phenyl-H), 7.72 (2H, d, phenyl-H).
실시예 11Example 11
3-{3-[4-(4-메톡시벤질옥시)페닐]이소옥사졸-5-일}메틸렌-1-아자비시클로[2.2.2]옥탄.3- {3- [4- (4-methoxybenzyloxy) phenyl] isoxazol-5-yl} methylene-1-azabicyclo [2.2.2] octane.
상기 실시예 1과 같은 제조방법으로 THF 용매를 사용하여 칼륨 3급-부톡시드 215 mg (1.92 mmol), 디에틸 3-[4-(4-메톡시벤질옥시)페닐]-5-이소옥사졸릴메틸포스포네이트 827 mg (1.92 mmol) 및 3-퀴누클리디논 200 mg (1.60 mmol)을 22℃에서 1.5시간 동안 반응시킨 후 관 크로마토그래피로 분리하여 목적화합물인 (Z)-이성질체 250 mg과 (E)-이성질체 168 mg (수득률 : 총 65%)을 각각 얻었다.215 mg (1.92 mmol) of potassium tert-butoxide, diethyl 3- [4- (4-methoxybenzyloxy) phenyl] -5-isoxazolyl using THF solvent in the same method as in Example 1 above 827 mg (1.92 mmol) of methylphosphonate and 200 mg (1.60 mmol) of 3-quinuclidinone were reacted at 22 ° C. for 1.5 hours and separated by column chromatography to obtain 250 mg of the (Z) -isomer as the target compound ( E) -isomer 168 mg (yield: 65% total) were obtained respectively.
(Z)-이성질체(Z) -isomer
1H NMR (CDCl3, 300MHz): δ 1.70 ∼ 1.91 (4H, m, 2 CH2), 2.53 ∼ 2.60 (1H, m, CH), 2.85 ∼ 3.09 (4H, m, 2 CH2), 3.83 (3H, s, OCH3), 3.87 (2H, s, CH2), 5.05 (2H, s, CH2), 6.24 ∼ 6.28 (2H, 2s, C=CH, 이소옥사졸-H), 6.92 (2H, d, 페닐-H), 7.03 (2H, d, 페닐-H), 7.36 (2H, d, 페닐-H), 7.73 (2H, d, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.70-1.91 (4H, m, 2 CH 2 ), 2.53-2.60 (1H, m, CH), 2.85-3.09 (4H, m, 2 CH 2 ), 3.83 ( 3H, s, OCH 3 ), 3.87 (2H, s, CH 2 ), 5.05 (2H, s, CH 2 ), 6.24 to 6.28 (2H, 2s, C = CH, isoxazole-H), 6.92 (2H , d, phenyl-H), 7.03 (2H, d, phenyl-H), 7.36 (2H, d, phenyl-H), 7.73 (2H, d, phenyl-H).
(E)-이성질체(E) -isomer
1H NMR (CDCl3, 300MHz): δ 1.75 ∼ 1.97 (4H, m, 2 CH2), 2.90 ∼ 3.10 (4H, m, 2 CH2), 3.55 ∼ 3.60 (1H, m, CH), 3.65 (2H, s, CH2), 3.83 (3H, s, OCH3), 5.05 (2H, s, CH2), 6.14 (1H, S, C=CH), 6.30 (1H, s, 이소옥사졸-H), 6.92 (2H, d, 페닐-H), 7.02 (2H, d, 페닐-H), 7.36 (2H, d, 페닐-H), 7.72 (2H, D, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.75-1.97 (4H, m, 2 CH 2 ), 2.90-3.10 (4H, m, 2 CH 2 ), 3.55-3.60 (1H, m, CH), 3.65 ( 2H, s, CH 2 ), 3.83 (3H, s, OCH 3 ), 5.05 (2H, s, CH 2 ), 6.14 (1H, S, C = CH), 6.30 (1H, s, isoxazole-H ), 6.92 (2H, d, phenyl-H), 7.02 (2H, d, phenyl-H), 7.36 (2H, d, phenyl-H), 7.72 (2H, D, phenyl-H).
실시예 12Example 12
3-[3-(4-메톡시페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.1]헵탄 옥살산 염.3- [3- (4-methoxyphenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.1] heptane oxalic acid salt.
칼륨 3급-부톡시드 131 mg (1.17 mmol)을 1.5mL의 무수 테트라히드로퓨란 용매에 녹이고 이 용액에 디에틸 3-(3-메틸페닐)-5-이소옥사졸릴메틸포스포네이트 416 mg (1.17 mmol)을 2 mL의 무수 테트라히드로퓨란 용매에 녹인 용액을 천천히 적가하고 22℃에 30분간 교반시켰다. 반응 혼합물에 1-아자비시클로[2.2.1]헵탄-3-온 100 mg (0.90 mmol)을 2 mL의 무수 테트라히드로퓨란 용액에 녹여 천천히 적가하고, 22℃에 1시간 동안 교반하였다. 감압 증류하여 농축하고 잔여물에 6N 염산을 가하여 산성화(pH = 3)하여 에틸 아세테이트 용매로 추출하였다. 물층을 2N 나트륨 히드록시드 용액으로 염기화(pH = 9)한 다음, 에틸 아세테이트 용매로 추출하고 무수 황산 마그네슘으로 건조시켰다. 건조된 용액을 걸르고, 이 용액을 다시 감압 증류하여 농축하여 잔여물을 관 크로마토그래피 (전개용액 ; 에틸 아세테이트/메탄올/암모늄 히드록시드 = 3/1/2)로 정제하여 목적화합물인 (Z)-이성질체 70 mg과 (E)-이성질체 75 mg (수득률 : 총 85%)을 얻었다. 이들 이성질체를 옥살산으로 처리하여 옥살산 염을 제조 하였다.131 mg (1.17 mmol) of potassium tert-butoxide are dissolved in 1.5 mL of anhydrous tetrahydrofuran solvent and 416 mg (1.17 mmol of diethyl 3- (3-methylphenyl) -5-isoxazolylmethylphosphonate in this solution. ) Was slowly added dropwise into 2 mL of anhydrous tetrahydrofuran solvent and stirred at 22 ° C for 30 minutes. To the reaction mixture, 100 mg (0.90 mmol) of 1-azabicyclo [2.2.1] heptan-3-one was dissolved in 2 mL of anhydrous tetrahydrofuran solution and slowly added dropwise, and stirred at 22 ° C. for 1 hour. After distillation under reduced pressure, 6N hydrochloric acid was added to the residue, acidified (pH = 3), and extracted with an ethyl acetate solvent. The water layer was basified with 2N sodium hydroxide solution (pH = 9), then extracted with ethyl acetate solvent and dried over anhydrous magnesium sulfate. The dried solution was filtered, and the solution was distilled under reduced pressure again and concentrated. The residue was purified by column chromatography (developing solution; ethyl acetate / methanol / ammonium hydroxide = 3/1/2) to obtain the target compound (Z). 70 mg of) -isomer and 75 mg of (E) -isomer were obtained (85% yield). These isomers were treated with oxalic acid to prepare oxalic acid salts.
(Z)-이성질체(Z) -isomer
1H NMR (CDCl3, 300MHz): δ 1.48 ∼ 1.58 (1H, m), 1.90 ∼ 2.10 (1H, m), 2.55 ∼ 2.73 (3H, m), 2.96 ∼ 3.08 (1H, m), 3.19 (1H, d), 3.51 (2H, ABq), 3.82 (3H, s, OCH3), 6.24 (1H, s, C=CH), 6.40 (1H, s, 이소옥사졸-H), 6.94 (2H, d, 페닐-H), 7.70 (2H, d, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.48-1.58 (1H, m), 1.90-2.10 (1H, m), 2.55-2.73 (3H, m), 2.96-3.08 (1H, m), 3.19 (1H , d), 3.51 (2H, ABq), 3.82 (3H, s, OCH 3 ), 6.24 (1H, s, C = CH), 6.40 (1H, s, isoxazole-H), 6.94 (2H, d , Phenyl-H), 7.70 (2H, d, phenyl-H).
(E)-이성질체(E) -isomer
1H NMR (CDCl3, 300MHz): δ 1.53 ∼ 1.65 (1H, m, CH), 2.00 ∼ 2.11 (1H, m), 2.60 ∼ 2.80 (3H, m), 3.02 ∼ 3.15 (1H, m), 3.42 (2H, ABq), 3.86 (3H, s, OCH3), 3.96 (1H, d), 6.11 (1H, s, C=CH), 6.33 (1H, s, 이소옥사졸-H), 6.98 (2H, d, 페닐-H), 7.75 (2H, O, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.53 to 1.65 (1H, m, CH), 2.00 to 2.11 (1H, m), 2.60 to 2.80 (3H, m), 3.02 to 3.15 (1H, m), 3.42 (2H, ABq), 3.86 (3H, s, OCH 3 ), 3.96 (1H, d), 6.11 (1H, s, C = CH), 6.33 (1H, s, isoxazole-H), 6.98 (2H , d, phenyl-H), 7.75 (2H, O, phenyl-H).
실시예 13Example 13
상기 실시예 12와 같은 제조방법으로 THF 용매를 사용하여 칼륨 3급-부톡시드 262 mg (2.34 mmol), 디에틸 3-[3,4-비스(4-메톡시벤질옥시)페닐]-5-이소옥사졸릴메틸포스포네이트 1.33 mg (2.34 mmol) 및 1-아자비시클로[2. 2. 1]헵탄-3-온 200 mg (1.80 mmol)을 22℃에서 1.2시간 동안 반응시킨 후 관 크로마토그래피로 분리하여 목적화합물인 (Z)-이성질체 279 mg과 (E)-이성질체 250 mg (수득률 : 총 56%)을 각각 얻었다.262 mg (2.34 mmol) of potassium tert-butoxide, diethyl 3- [3,4-bis (4-methoxybenzyloxy) phenyl] -5- using a THF solvent in the same preparation method as in Example 12 1.33 mg (2.34 mmol) and 1-azabicyclo [2. Isoxazolylmethylphosphonate] 2. 1] heptan-3-one 200 mg (1.80 mmol) was reacted at 22 ° C. for 1.2 hours and separated by column chromatography to obtain 279 mg of the target compound (Z) -isomer and 250 mg of the (E) -isomer. Yield: 56% in total).
(Z)-이성질체(Z) -isomer
1H NMR (CDCl3, 300MHz); δ 1.43 ∼ 1.54 (1H, m), 1.85 ∼ 2.00 (1H, m), 2.49 ∼∼ 2.70 (3H, m), 2.90 ∼ 3.04 (1H, m), 3.15 (1H, d), 3.55 (2H, ABq), 3.79 (6H, s, 2 OCH3), 5.09 (2H, s, CH2O), 5.11 (2H, s, CH2O), 6.15 (1H, s, C=CH), 6.40 (1H, s, 이소옥사졸-H), 6.86 (4H, d, 페닐-H), 6.95 (1H, d, 페닐-H), 7.23 (1H, d, 페닐-H), 7.30 ∼ 7.40 (4H, m, 페닐-H), 7.47 (1H, s, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz); δ 1.43 to 1.54 (1H, m), 1.85 to 2.00 (1H, m), 2.49 to 2.70 (3H, m), 2.90 to 3.04 (1H, m), 3.15 (1H, d), 3.55 (2H, ABq ), 3.79 (6H, s, 2 OCH 3 ), 5.09 (2H, s, CH 2 O), 5.11 (2H, s, CH 2 O), 6.15 (1H, s, C = CH), 6.40 (1H, s, isoxazole-H), 6.86 (4H, d, phenyl-H), 6.95 (1H, d, phenyl-H), 7.23 (1H, d, phenyl-H), 7.30-7.40 (4H, m, Phenyl-H), 7.47 (1H, s, phenyl-H).
(E)-이성질체(E) -isomer
1H NMR (CDCl3, 300MHz): δ 1.45 ∼ 1.55 (1H, m), 1.91 ∼ 2.01 (1H, m), 2.50 ∼- 2.70 (3H, m), 2.90 ∼ 3.03 (1H, m), 3.33 (2H, ABq), 3.78 (6H, s, 2OCH3), 3.83 (1H, d), 5.09 (2H, s, CH2O), 5.10 (2H, s, CH2O), 6.04 (1H, s, C=CH), 6.25 (1H, s, 이소옥사졸-H), 6.86 (4H, d, 페닐-H), 6.94 (1H, d, 페닐-H), 7.24 (1H, d, 페닐-H), 7.32 ∼ 7.40 (4H, m, 페닐-H), 7.49 (1H, s, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.45-1.55 (1H, m), 1.91-2.01 (1H, m), 2.50-2.70 (3H, m), 2.90-3.03 (1H, m), 3.33 ( 2H, ABq), 3.78 (6H, s, 20CH 3 ), 3.83 (1H, d), 5.09 (2H, s, CH 2 O), 5.10 (2H, s, CH 2 O), 6.04 (1H, s, C = CH), 6.25 (1H, s, isoxazole-H), 6.86 (4H, d, phenyl-H), 6.94 (1H, d, phenyl-H), 7.24 (1H, d, phenyl-H) , 7.32-7.40 (4H, m, phenyl-H), 7.49 (1H, s, phenyl-H).
실시예 14Example 14
3-[3-(4-t-부톡시카르보닐아미노페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.1]헵탄.3- [3- (4-t-butoxycarbonylaminophenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.1] heptane.
상기 실시예 12와 같은 제조방법으로 THF 용매를 사용하여 칼륨 3급-부톡시드 262 mg (2.34 mmol), 디에틸 3-(4-t-부톡시카르보닐아미노페닐)-5-이소옥사졸릴메틸포스포네이트 960 mg (2.34 mmol) 및 1-아자비시클로[2. 2. 1]헵탄-3-온 200 mg (1.80 mmol)을 22℃에서 1.2시간 동안 반응시킨 후 관 크로마토그래피로 분리하여 목적화합물인 (Z)-이성질체 268 mg과 (E)-이성질체 182 mg (수득률 : 총 68%)을 각각 얻었다.262 mg (2.34 mmol) of potassium tert-butoxide, diethyl 3- (4-t-butoxycarbonylaminophenyl) -5-isoxazolylmethyl using THF solvent in the same preparation method as in Example 12 960 mg (2.34 mmol) phosphonate and 1-azabicyclo [2. 2. 1] Heptane-3-one 200 mg (1.80 mmol) was reacted at 22 ° C. for 1.2 hours and separated by column chromatography to obtain 268 mg of the target compound (Z) -isomer and 182 mg of (E) -isomer ( Yield: 68% in total).
(Z)-이성질체(Z) -isomer
1H NMR (CDCl3, 300MHz): δ 1.45 ∼ 1.60 [10H, m, CH, C(CH3)3], 1.90 ∼ 2.01 (1H, m), 2.50 ∼ 2.75 (3H, m), 2.94 ∼ 3.06 (1H, m), 3.20 (1H, d), 3.60 (2H, ABq), 6.22 (1H, s, C=CH), 6.42 (1H, s, 이소옥사졸-H), 6.67 (1H, s, NH), 7.44 (2H, d, 페닐-H), 7.71 (2H, d, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.45-1.60 [10H, m, CH, C (CH 3 ) 3 ], 1.90-2.01 (1H, m), 2.50-2.75 (3H, m), 2.94-3.06 (1H, m), 3.20 (1H, d), 3.60 (2H, ABq), 6.22 (1H, s, C = CH), 6.42 (1H, s, isoxazole-H), 6.67 (1H, s, NH), 7.44 (2H, d, phenyl-H), 7.71 (2H, d, phenyl-H).
(E)-이성질체(E) -isomer
1H NMR (CDCl3, 300MHz): δ 1.50 ∼ 1.65 [10H, s, CH, C(CH3)3], 2.00 ∼ 2.11 (1H, m), 2.60 ∼ 2.80 (3H, m), 3.02 ∼ 3.15 (1H, m), 3.45 (2H, ABq), 3.96 (1H, d), 6.11 (1H, s, C=CH), 6.35 (1H, s, 이소옥사졸-H), 6.77 (1H, s, NH), 7.45 (2H, d, 페닐-H), 7.72 (2H, d, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.50 to 1.65 [10H, s, CH, C (CH 3 ) 3 ], 2.00 to 2.11 (1H, m), 2.60 to 2.80 (3H, m), 3.02 to 3.15 (1H, m), 3.45 (2H, ABq), 3.96 (1H, d), 6.11 (1H, s, C = CH), 6.35 (1H, s, isoxazole-H), 6.77 (1H, s, NH), 7.45 (2H, d, phenyl-H), 7.72 (2H, d, phenyl-H).
실시예 15Example 15
3-{3-[4-(4-메톡시벤질옥시)페닐]이소옥사졸-5-일}메틸렌-1-아자비시클로[2.2.1]헵탄.3- {3- [4- (4-methoxybenzyloxy) phenyl] isoxazol-5-yl} methylene-1-azabicyclo [2.2.1] heptane.
상기 실시예 12와 같은 제조방법으로 THF 용매를 사용하여 칼륨 3급-부톡시드 242 mg (2.16 mmol), 디에틸 3-[4-(4-메톡시벤질옥시)페닐]-5-이소옥사졸릴메틸포스포네이트 932 mg (2.16 mmol) 및 1-아자비시클로[2. 2. 1]헵탄-3-온 200 mg (1.80 mmol)을 22℃에서 1.5시간 동안 반응시킨 후 관 크로마토그래피로 분리하여 목적화합물인 (Z)-이성질체 120 mg과 (E)-이성질체 300 mg (수득률 : 총 60%)을 각각 얻었다.Potassium tert-butoxide 242 mg (2.16 mmol), diethyl 3- [4- (4-methoxybenzyloxy) phenyl] -5-isoxazolyl using THF solvent in the same preparation method as in Example 12 932 mg (2.16 mmol) of methylphosphonate and 1-azabicyclo [2. 2. 1] Heptane-3-one 200 mg (1.80 mmol) was reacted at 22 ° C. for 1.5 hours and separated by column chromatography to obtain 120 mg of the (Z) -isomer and 300 mg of the (E) -isomer. Yield: 60% total).
(Z)-이성질체(Z) -isomer
1H NMR (CDCl3, 300MHz): δ 1.48 ∼ 1.59 (1H, m), 1.92 ∼ 2.08 (1H, m), 2.51 ∼ 2.75 (3H, m), 2.95 ∼ 3.08 (1H, m), 3.20 (1H, d), 3.60 (2H, ABq), 3.83 (3H, s, OCH3), 5.04 (2H, s, CH2), 6.21 (1H, s, C=CH), 6.42 (1H, s, 이소옥사졸-H), 6.92 (2H, d, 페닐-H), 7.01 (2H, d, 페닐-H), 7.35 (2H, d, 페닐-H), 7.70 (H, d, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.48-1.59 (1H, m), 1.92-2.08 (1H, m), 2.51-2.75 (3H, m), 2.95-3.08 (1H, m), 3.20 (1H , d), 3.60 (2H, ABq), 3.83 (3H, s, OCH 3 ), 5.04 (2H, s, CH 2 ), 6.21 (1H, s, C = CH), 6.42 (1H, s, isooxa Sol-H), 6.92 (2H, d, phenyl-H), 7.01 (2H, d, phenyl-H), 7.35 (2H, d, phenyl-H), 7.70 (H, d, phenyl-H).
(E)-이성질체(E) -isomer
1H NMR (CDCl3, 300MHz): δ 1.50 ∼ 1.60 (1H, m), 1.95 ∼ 2.09 (1H, m), 2.55 ∼ 2.72 (3H, m), 2.95 ∼ 3.09 (1H, m), 3.35 (2H, ABq), 3.83 (3H, s, OCH3), 3.90 (1H, d), 5.05 (2H, s, CH2), 6.08 (1H, s, C=CH), 6.32 (1H, s, 이소옥사졸-H), 6.92 (2H, d, 페닐-H), 7.02 (2H, d, 페닐-H), 7.36 (2H, d, 페닐-H), 7.73 (2H, d, 페닐-H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.50-1.60 (1H, m), 1.95-2.09 (1H, m), 2.55-2.72 (3H, m), 2.95-3.09 (1H, m), 3.35 (2H , ABq), 3.83 (3H, s, OCH 3 ), 3.90 (1H, d), 5.05 (2H, s, CH 2 ), 6.08 (1H, s, C = CH), 6.32 (1H, s, isoxa Sol-H), 6.92 (2H, d, phenyl-H), 7.02 (2H, d, phenyl-H), 7.36 (2H, d, phenyl-H), 7.73 (2H, d, phenyl-H).
실시예 16Example 16
3-[3-(4-히드록시페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.2]옥탄 트리플루오로아세트산 염의 제조.Preparation of 3- [3- (4-hydroxyphenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.2] octane trifluoroacetic acid salt.
(1) (Z)-이성질체(1) (Z) -isomer
(Z)-3-[3-(4-메톡시벤질옥시페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.2]옥탄 70mg (0.17 mmol)을 0.2 mL의 아니솔에 녹인 후 이 용액에 트리플루오로아세트산 0.8 mL를 가하고 22℃에서 2시간 동안 교반시켰다. 이 반응 혼합물에 디에틸에테르를 천천히 적가하고 생성된 고체를 여과하여 얻은 다음 진공 건조하여 목적 화합물 49 mg (수득률 : 71%)을 얻었다.70 mg (0.17 mmol) of (Z) -3- [3- (4-methoxybenzyloxyphenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.2] octane in 0.2 mL of anisole After dissolving, 0.8 mL of trifluoroacetic acid was added to the solution, followed by stirring at 22 ° C. for 2 hours. Diethyl ether was slowly added dropwise to this reaction mixture, the resulting solid was filtered off and dried in vacuo to yield 49 mg (yield: 71%) of the title compound.
1H NMR (D2O. 300MHz): δ 2.08 ∼ 2.35 (4H, m, 2 CH2), 2.98 ∼ 3.03 (1H, m, CH), 3.40 ∼ 3.65 (4H, m, 2 CH2), 4.50 (2H, s, CH2), 6.58 (1H, s, C=CH), 6.64 (1H, s, 이소옥사졸-H), 7.05 (2H, d, 페닐-H), 7.73 (2H, d, 페닐-H). 1 H NMR (D 2 O. 300 MHz): δ 2.08 to 2.35 (4H, m, 2 CH 2 ), 2.98 to 3.03 (1H, m, CH), 3.40 to 3.65 (4H, m, 2 CH 2 ), 4.50 (2H, s, CH 2 ), 6.58 (1H, s, C = CH), 6.64 (1H, s, isoxazole-H), 7.05 (2H, d, phenyl-H), 7.73 (2H, d, Phenyl-H).
(2) (E)-이성질체(2) (E) -isomer
상기 (1)과 같은 방법으로 (E)-3-[3-(4-메톡시페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.2]옥탄 100mg (0.25 mmol)을 사용하여 목적화합물 80 mg (82%)을 얻었다.In the same manner as in (1), 100 mg (0.25 mmol) of (E) -3- [3- (4-methoxyphenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.2] octane was added. 80 mg (82%) of the title compound were obtained.
1H NMR (D2O, 300MHz): δ 1.92 ∼ 2.22 (4H, m, 2 CH2), 3.28 ∼ 3.55 (4H, m, 2 CH2), 3.60 ∼ 3.69 (1H, m, CH), 4.09 (2H, s, CH2), 6.25 (1H, s, C=CH), 6.64 (1H, s, 이소옥사졸-H), 6.94 (2H, d, 페닐-H), 7.60 (2H, d, 페닐-H). 1 H NMR (D 2 O, 300 MHz): δ 1.92-2.22 (4H, m, 2 CH 2 ), 3.28-3.55 (4H, m, 2 CH 2 ), 3.60-3.69 (1H, m, CH), 4.09 (2H, s, CH 2 ), 6.25 (1H, s, C = CH), 6.64 (1H, s, isoxazole-H), 6.94 (2H, d, phenyl-H), 7.60 (2H, d, Phenyl-H).
실시예 17Example 17
3-[3-(3,4-디히드록시페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.2]옥탄 트리플루오로아세트산 염.3- [3- (3,4-dihydroxyphenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.2] octane trifluoroacetic acid salt.
(1) (Z)이성질체(1) (Z) isomer
상기 실시예 16의 (1)과 같은 방법으로 (Z)-3-｛3-[3,4-비스(4-메톡시벤질옥시)페닐]이소옥사졸-5-일｝메틸렌-1-아자비시클로[2. 2. 2]옥탄 70 mg (0.13 mmol)을 사용하여 목적 화합물 27 mg (수득률 : 50%)을 얻었다.(Z) -3- (3- [3,4-bis (4-methoxybenzyloxy) phenyl] isoxazol-5-yl｝ methylene-1-azabi by the same method as in Example (1) above Cyclo [2. 2. 2] Octane 70 mg (0.13 mmol) was used to obtain 27 mg of the target compound (yield: 50%).
1H NMR (D2O, 300MHz): δ 1.95 ∼ 2.25 (4H, m, 2 CH2), 2.79 ∼ 2.85 (1H, m, CH), 3.25 ∼ 3.55 (4H, m, 2 CH2), 4.24 (2H, s, CH2), 6.25 (2H, 2s, C=CH, 이소옥사졸-H), 7.88 (2H, d, 페닐H), 7.05 (2H, d, 페닐-H). 1 H NMR (D 2 O, 300 MHz): δ 1.95-2.25 (4H, m, 2 CH 2 ), 2.79-2.85 (1H, m, CH), 3.25-3.55 (4H, m, 2 CH 2 ), 4.24 (2H, s, CH 2 ), 6.25 (2H, 2s, C═CH, isoxazole-H), 7.88 (2H, d, phenylH), 7.05 (2H, d, phenyl-H).
(2) (E)-이성질체(2) (E) -isomer
상기 (1)과 같은 방법으로 (E)-3-｛3-[3,4-비스(4-메톡시벤질옥시)페닐]이소옥사졸-5-일｝메틸렌-1-아자비시클로[2. 2. 2]옥탄 100 mg (0.19 mmol)을 사용하여 목적 화합물 45 mg (수득률 : 63%)을 얻었다.(E) -3-'3- [3,4-bis (4-methoxybenzyloxy) phenyl] isoxazol-5-yl'methylene-1-azabicyclo [2. 2. 2] Octane 100 mg (0.19 mmol) was used to obtain 45 mg of the target compound (yield: 63%).
1H NMR (D2O, 300MHz): δ 1.95 ∼ 2.25 (4H, m, 2 CH2), 3.30 ∼ 3.60 (4H, m, 2 CH2), 3.62 ∼ 3.72 (1H, m, CH), 4.13 (2H, s, CH2), 6.29 (1H, s, C=CH), 6.60 (1H, s, 이소옥사졸-H), 7.00 (1H, d, 페닐-H), 7.20 ∼ 7.32 (2H, m, 페닐-H). 1 H NMR (D 2 O, 300 MHz): δ 1.95-2.25 (4H, m, 2 CH 2 ), 3.30-3.60 (4H, m, 2 CH 2 ), 3.62-3.72 (1H, m, CH), 4.13 (2H, s, CH 2 ), 6.29 (1H, s, C = CH), 6.60 (1H, s, isoxazole-H), 7.00 (1H, d, phenyl-H), 7.20-7.32 (2H, m, phenyl-H).
실시예 18Example 18
3-[3-(4-아미노페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.2]옥탄 트리플루오로아세트산 염.3- [3- (4-aminophenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.2] octane trifluoroacetic acid salt.
(1) (Z)-이성질체(1) (Z) -isomer
상기 실시예 16의 (1)과 같은 방법으로 (Z)-3-[3-(4-t-부톡시카르보닐아미노페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2. 2. 2]옥탄 120 mg (0.31 mmol)을 사용하여 목적 화합물 112 mg (수득률 : 90%)을 얻었다.In the same manner as in (1) of Example 16, (Z) -3- [3- (4-t-butoxycarbonylaminophenyl) isoxazol-5-yl] methylene-1-azabicyclo [2. 2. 2] Octane 120 mg (0.31 mmol) was used to obtain 112 mg of the target compound (yield: 90%).
1H NMR (D2O, 300MHz): δ 2.06 ∼ 2.31 (4H, m, 2 CH2), 2.98 ∼ 3.03 (1H, m, CH), 3.38 ∼ 3.63 (4H, m, 2 CH2), 4.58 (2H, s, CH2), 6.65 (1H, s, C=CH), 6.80 (1H, s, 이소옥사졸-H), 7.49 (2H, d, 페닐-H), 7.95 (2H, d, 페닐-H). 1 H NMR (D 2 O, 300 MHz): δ 2.06-2.31 (4H, m, 2 CH 2 ), 2.98-3.03 (1H, m, CH), 3.38-3.63 (4H, m, 2 CH 2 ), 4.58 (2H, s, CH 2 ), 6.65 (1H, s, C = CH), 6.80 (1H, s, isoxazole-H), 7.49 (2H, d, phenyl-H), 7.95 (2H, d, Phenyl-H).
(2) (E)-이성질체(2) (E) -isomer
상기 (1)과 같은 방법으로 (E)-3-[3-(4-t-부톡시카르보닐아미노페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2. 2. 2]옥탄 100 mg (0.26 mmol)을 사용하여 목적 화합물 95 mg (수득률 : 77%)을 얻었다.In the same manner as in (1), (E) -3- [3- (4-t-butoxycarbonylaminophenyl) isoxazol-5-yl] methylene-1-azabicyclo [2. 2. 2] Octane 100 mg (0.26 mmol) was used to obtain 95 mg of the target compound (yield: 77%).
1H NMR (D2O, 300MHz): δ 1.99 ∼ 2.26 (4H, m, 2 CH2), 3.30 ∼ 3.56 (4H, m, 2 CH2), 3.70 ∼ 3.76 (1H, m, CH), 4.12 (2H, s, CH2), 6.34 (1H, s, C=CH), 6.69 (1H, s, 이소옥사졸-H), 6.94 (2H, d, 페닐-H), 7.64 (2H, d, 페닐-H). 1 H NMR (D 2 O, 300 MHz): δ 1.99 to 2.26 (4H, m, 2 CH 2 ), 3.30 to 3.56 (4H, m, 2 CH 2 ), 3.70 to 3.76 (1H, m, CH), 4.12 (2H, s, CH 2 ), 6.34 (1H, s, C = CH), 6.69 (1H, s, isoxazole-H), 6.94 (2H, d, phenyl-H), 7.64 (2H, d, Phenyl-H).
실시예 19Example 19
3-[3-(4-히드록시페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.1]헵탄 트리플루오로아세트산 염의 제조.Preparation of 3- [3- (4-hydroxyphenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.1] heptane trifluoroacetic acid salt.
(1) (Z)-이성질체(1) (Z) -isomer
(Z)-3-{3-[4-(4-메톡시벤질옥시)페닐]이소옥사졸-5-일}메틸렌-1-아자비시클로[2.2.1]헵탄 40mg (0.10 mmol)을 0.2 mL의 아니솔에 녹인 다음 이 용액에 트리플루오로아세트산 0.8 mL를 가하고 22℃에서 2시간 동안 교반시켰다. 이 반응 혼합물에 디에틸 에테르를 천천히 적가하고 생성된 고체를 여과하여 분리한 후, 진공 건조하여 목적 화합물 33 mg (수득률 : 85%)을 얻었다.0.2 mL of 40 mg (0.10 mmol) of (Z) -3- {3- [4- (4-methoxybenzyloxy) phenyl] isoxazol-5-yl} methylene-1-azabicyclo [2.2.1] heptane After dissolving in anisole, 0.8 mL of trifluoroacetic acid was added to the solution, and the mixture was stirred at 22 ° C for 2 hours. Diethyl ether was slowly added dropwise to the reaction mixture, the resulting solid was separated by filtration and dried in vacuo to give 33 mg (yield: 85%) of the title compound.
1H NMR (D2O, 300MHz): δ 1.89 ∼ 2.00 (1H, m), 2.35 ∼ 2.49 (1H, m), 3.35 ∼ 3.46 (3H, m), 3.58 ∼ 3.72 (2H, m), 4.38 (2H, ABq), 6.59 (1H, s, C=CH), 6.62 (1H, s, 이소옥사졸-H), 6.99 (2H, d, 페닐-H), 7.68 (2H, d, 페닐-H).1 H NMR (D2O, 300 MHz): δ 1.89-2.00 (1H, m), 2.35-2.49 (1H, m), 3.35-3.46 (3H, m), 3.58-3.72 (2H, m), 4.38 (2H, ABq ), 6.59 (1H, s, C = CH), 6.62 (1H, s, isoxazole-H), 6.99 (2H, d, phenyl-H), 7.68 (2H, d, phenyl-H).
(2) (E)-이성질체(2) (E) -isomer
상기 (1)과 같은 방법으로 (E)-3-}3-[4-(4-메톡시벤질옥시)페닐]이소옥사졸-5-일}메틸렌-1-아자비시클로[2.2.1]헵탄 80 mg (0.21 mmol)을 사용하여 목적 화합물 55mg (수득률 : 수득률 : 90%)을 얻었다.(E) -3-} 3- [4- (4-methoxybenzyloxy) phenyl] isoxazol-5-yl} methylene-1-azabicyclo [2.2.1] heptane in the same manner as in (1) above. 80 mg (0.21 mmol) was used to obtain 55 mg of the target compound (yield: yield: 90%).
1H NMR (D2O, 300MHz): δ 1.90 ∼ 2.03 (1H, m), 2.40 ∼ 2.56 (1H, m), 3.35 ∼ 3.55 (3H, m), 3.62 ∼ 3.76 (1H, m), 4.02 ∼ 4.36 (3H, m), 6.40 (1H, s, C=CH), 6.69 (1H, s, 이소옥사졸-H), 7.04 (2H, d, 페닐-H), 7.71 (2H, d, 페닐-H). 1 H NMR (D 2 O, 300 MHz): δ 1.90-2.03 (1H, m), 2.40-2.56 (1H, m), 3.35-3.55 (3H, m), 3.62-3.76 (1H, m), 4.02- 4.36 (3H, m), 6.40 (1H, s, C = CH), 6.69 (1H, s, isoxazole-H), 7.04 (2H, d, phenyl-H), 7.71 (2H, d, phenyl- H).
실시예 20Example 20
3-[3-(3,4-디히드록시페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.1]헵탄 트리플루오르아세트산 염.3- [3- (3,4-dihydroxyphenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.1] heptane trifluoroacetic acid salt.
(1) (Z)-이성질체(1) (Z) -isomer
상기 실시예 19의 (1)과 같은 방법으로 (Z)-3-｛3-[3,4-비스(4-메톡시벤질옥시)페닐]이소옥사졸-5-일｝메틸렌-1-아자비시클로[2. 2. 1]헵탄 40 mg (0.08 mmol)을 사용하여 목적 화합물 26 mg (수득률 : 87%)을 얻었다.(Z) -3- (3- [3,4-bis (4-methoxybenzyloxy) phenyl] isoxazol-5-ylmethylene-1-azabi by the same method as in Example (1) above Cyclo [2. 2. 1] heptane 40 mg (0.08 mmol) gave 26 mg of the target compound (yield: 87%).
1H NMR (D2O, 300MHz): δ 1.81 ∼ 1.94 (1H, m), 2.28 ∼ 2.41 (1H, m), 3.25 ∼ 3.40 (3H, m), 3.51 ∼ 3.66 (2H, m), 4.25 (2H, ABq), 6.38 (1H, s, C=CH), 6.46 (1H, s, 이소옥사졸-H), 6.90 (1H, d, 페닐-H), 7.05 ∼ 7.20 (2H, m, 페닐-H). 1 H NMR (D 2 O, 300 MHz): δ 1.81-1.94 (1H, m), 2.28-2.41 (1H, m), 3.25-3.40 (3H, m), 3.51-3.66 (2H, m), 4.25 ( 2H, ABq), 6.38 (1H, s, C = CH), 6.46 (1H, s, isoxazole-H), 6.90 (1H, d, phenyl-H), 7.05-7.20 (2H, m, phenyl- H).
(2) (E)-이성질체(2) (E) -isomer
상기 (1)과 같은 방법으로 (E)-3-｛3-[3,4-비스(4-메톡시벤질옥시)페닐]이소옥사졸-5-일｝메틸렌-1-아자비시클로[2. 2. 1]헵탄 80 mg (0.15 mmol)을 사용하여 목적 화합물 54 mg (수득률 : 89%)을 얻었다.(E) -3-'3- [3,4-bis (4-methoxybenzyloxy) phenyl] isoxazol-5-yl'methylene-1-azabicyclo [2. 2. 80 mg (0.15 mmol) of 1] heptane was used to obtain 54 mg of the target compound (yield: 89%).
1H NMR (D2O, 300MHz): δ 1.74 ∼ 1.98 (1H, m), 2.30 ∼ 2.45 (1H, m), 3.21 ∼ 3.40 (3H, m), 3.51 ∼ 3.68 (1H, m, CH), 3.88 ∼ 4.22 (3H, m), 6.17 (1H, s, C=CH), 6.43 (1H, s, 이소옥사졸-H), 6.90 (1H, d, 페닐-H), 7.08 ∼ 7.18 (2H, m, 페닐-H). 1 H NMR (D 2 O, 300 MHz): δ 1.74-1.98 (1H, m), 2.30-2.45 (1H, m), 3.21-3.40 (3H, m), 3.51-3.68 (1H, m, CH), 3.88-4.22 (3H, m), 6.17 (1H, s, C = CH), 6.43 (1H, s, isoxazole-H), 6.90 (1H, d, phenyl-H), 7.08-7.18 (2H, m, phenyl-H).
실시예 21Example 21
3-[3-(4-아미노페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2.2.1]헵탄 트리플루오로아세트산 염.3- [3- (4-aminophenyl) isoxazol-5-yl] methylene-1-azabicyclo [2.2.1] heptane trifluoroacetic acid salt.
(1) (Z)-이성질체(1) (Z) -isomer
상기 실시예 19의 (1)과 같은 방법으로 (Z)-3-[3-(4-t-부톡시카르보닐아미노페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2. 2. 1]헵탄 40 mg (0.11 mmol)을 사용하여 목적 화합물 22 mg (수득률 : 52%)을 얻었다.In the same manner as in (1) of Example 19, (Z) -3- [3- (4-t-butoxycarbonylaminophenyl) isoxazol-5-yl] methylene-1-azabicyclo [2. 2. 1] heptane 40 mg (0.11 mmol) was used to obtain 22 mg of the target compound (yield: 52%).
1H NMR (D2O, 300MHz): δ 1.89 ∼ 2.00 (1H, m), 2.32 ∼ 2.50 (1H, m), 3.35 ∼ 3.48 (3H, m), 3.53 ∼ 3.72 (2H, m), 4.45 (2H, ABq), 6.71 (1H, s, C=CH), 6.78 (1H, s, 이소옥사졸-H), 7.45 (2H, d, 페닐-H), 7.90 (2H, d, 페닐-H). 1 H NMR (D 2 O, 300 MHz): δ 1.89-2.00 (1H, m), 2.32-2.50 (1H, m), 3.35-3.48 (3H, m), 3.53-3.72 (2H, m), 4.45 ( 2H, ABq), 6.71 (1H, s, C = CH), 6.78 (1H, s, isoxazole-H), 7.45 (2H, d, phenyl-H), 7.90 (2H, d, phenyl-H) .
(2) (E)-이성질체(2) (E) -isomer
상기 실시예 (1)과 같은 방법으로 (E)-3-[3-(4-t-부톡시카르보닐아미노페닐)이소옥사졸-5-일]메틸렌-1-아자비시클로[2. 2. 1]헵탄 35 mg (0.10 mmol)을 사용하여 목적 화합물 15 mg (수득률 : 42%)을 얻었다.In the same manner as in Example (1), (E) -3- [3- (4-t-butoxycarbonylaminophenyl) isoxazol-5-yl] methylene-1-azabicyclo [2. 2. 1] heptane 35 mg (0.10 mmol) was used to obtain 15 mg of the target compound (yield: 42%).
1H NMR (D2O, 300MHz): δ 1.90 ∼ 2.04 (1H, m), 2.39 ∼ 2.52 (1H, m), 3.32 ∼ 3.50 (3H, m), 3.58 ∼ 3.70 (1H, m), 4.03 ∼ 4.34 (3H, m), 6.48 (1H, s, C=CH), 6.84 (1H, s, 이소옥사졸-H), 7.51 (2H, d, 페닐-H), 7.95 (2H, d, 페닐-H). 1 H NMR (D 2 O, 300 MHz): δ 1.90 to 2.04 (1H, m), 2.39 to 2.52 (1H, m), 3.32 to 3.50 (3H, m), 3.58 to 3.70 (1H, m), 4.03 to 4.34 (3H, m), 6.48 (1H, s, C = CH), 6.84 (1H, s, isoxazole-H), 7.51 (2H, d, phenyl-H), 7.95 (2H, d, phenyl- H).
일반식 (I)의 목적 화합물의 유용성을 나타내기 위해서 본 발명의 대표적인 화합물들의 무스카린성 아세틸콜린 수용체 결합 친화력의 시험결과를 아래에 나타내었다.In order to show the usefulness of the target compound of general formula (I), the test result of the muscarinic acetylcholine receptor binding affinity of the representative compounds of this invention is shown below.
[약물효과 측정][Drug effect measurement]
1) 수용체 현탁액의 조제1) Preparation of Receptor Suspension
-70℃에 냉동 보관된 수용체 세포 분획을 50mL당 4.5mL의 트리스 완충용액 (50mM Trizma base, 10mM MgCl2, 1 nM EDTA, pH 7.4)으로 현탁시키고 단백질 함량을 측정(Bio-Rad DC Protein Assay Kit)한 후 70 ∼ 74mg/mL 농도로 조정하였다. 이때 수용체의 함량으로 대변되는 단백질 농도의 설정은 기초실험을 통하여 결정한 것이며 그후 알맞은 부피씩 분주하여 -70℃에 냉동보관하였다. 이렇게 보관하였을 때 6개월까지 결합 활성에는 변함이 없었다.The cryopreserved receptor cell fraction at -70 ℃ tris buffer solution of 4.5mL per 50mL (50mM Trizma base, 10mM MgCl 2, 1 nM EDTA, pH 7.4) to the suspension and the protein content measured (Bio-Rad DC Protein Assay Kit ), And then adjusted to a concentration of 70 ~ 74 mg / mL. At this time, the protein concentration represented by the content of the receptor was determined through the basic experiment, and then dispensed by appropriate volume and stored at -70 ℃ frozen. There was no change in binding activity until 6 months when stored.
2) 결합 분석2) binding analysis
모든 시료의 시험은 2회 반복 또는 4회 반복하여 실험하였으며 분석 완충욕액으로는 10 nM MgCl2와 1 mM EDTA를 함유하는 50 mM 완충용액 (pH 7.2)을 사용하였다. 반응의 최종 부피는 0.25 mL 이었으며 여기에 50 mL의 hot-리간드와 10 mL의 시험약물이 포함되게 하였다. 반응의 시작은 100 mL의 수용체 서스펜션을 첨가하는 것으로부터하여 27℃에서 60분간 흔들 배양기에서 반응시켰다. 평형결합 분석에서는 [3H]-N-메틸스코폴아민의 12단계 농도 구배를 사용하였는데 비선택성 결합은 1 mM의 아트로핀 설페이트로 측정하였다. 경쟁분석에서는 1 nM의 [3H]-N-메틸스코폴아민과 10단계 농도 구배의 표준약물로 결합 친화도를 측정하였다.All samples were tested twice or four times and 50 mM buffer (pH 7.2) containing 10 nM MgCl 2 and 1 mM EDTA was used as the assay buffer. The final volume of the reaction was 0.25 mL, which included 50 mL of hot ligand and 10 mL of test drug. The start of the reaction was allowed to react in an incubator shaken at 27 ° C. for 60 minutes by adding 100 mL of receptor suspension. In the equilibrium binding assay, a 12-step concentration gradient of [ 3 H] -N-methylscopolamine was used, with non-selective binding measured by 1 mM atropine sulfate. In the competitive analysis, binding affinity was measured with 1 nM of [ 3 H] -N-methylscopolamine and a standard drug of 10-step concentration gradient.
다음 표는 [3H]-N-메틸스코폴아민의 쥐의 피질 수용체에의 결합에 의해 측정된 본 발명의 대표적인 화합물들의 무스카린성 아세틸콜린 수용체에 대한 친화도를 예시한 것이다. 이 때에 그 친화도는 수용체에 대한 [3H]-N-메틸스코폴아민의 특이성 결합을 50% 저해하는 기질 화합물의 농도인 IC50로 나타내었다.The following table illustrates the affinity for muscarinic acetylcholine receptors of representative compounds of the invention as measured by binding of [ 3 H] -N-methylscopolamine to the mouse cortical receptor. The affinity was then expressed as IC 50 , the concentration of the substrate compound that inhibits 50% of the specific binding of [ 3 H] -N-methylscopolamine to the receptor.
[표 1]TABLE 1
대표적 화합물들의 수용체에 대한 친화도 (IC50)Affinity to Receptors of Representative Compounds (IC 50 )
본 발명에 따른 새로운 일반식 (I)로 표시되는 [(아릴)이소옥소졸릴]메틸렌-아자비시클로 화합물을 제조함으로써,알쯔하이머씨 병 등 뇌신경 질환 치료제로 유용하게 사용될 수 있다.By preparing the [(aryl) isoxozozolyl] methylene-azabicyclo compound represented by the new general formula (I) according to the present invention, it can be usefully used as a therapeutic agent for cerebral neurological diseases such as Alzheimer's disease.
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| KR100441404B1 (en) * | 2002-01-24 | 2004-07-23 | 한국과학기술연구원 | A novel alkenyl azabicyclic compound and preparation method thereof |
| KR100448002B1 (en) * | 2002-02-01 | 2004-09-13 | 한국과학기술연구원 | Novel quinuclidine compounds and preparation method thereof |
| KR100465277B1 (en) * | 2002-01-24 | 2005-01-13 | 한국과학기술연구원 | Novel azabicyclic compounds having an oxime moiety and preparation method thereof |
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| KR100441404B1 (en) * | 2002-01-24 | 2004-07-23 | 한국과학기술연구원 | A novel alkenyl azabicyclic compound and preparation method thereof |
| KR100465277B1 (en) * | 2002-01-24 | 2005-01-13 | 한국과학기술연구원 | Novel azabicyclic compounds having an oxime moiety and preparation method thereof |
| KR100448002B1 (en) * | 2002-02-01 | 2004-09-13 | 한국과학기술연구원 | Novel quinuclidine compounds and preparation method thereof |
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