公开(公告)号：KR1020030034823A

公开(公告)日：2003-05-09

申请号：KR1020010066579

申请日：2001-10-27

Applicant: 한국과학기술연구원

Inventor： 김유승 ,  강순방 ,  금교창 ,  장민석 ,  장택수 ,  공재양 ,  정대영

IPC: C07D413/04

Abstract: PURPOSE: Isoxazole or isoxazoline substituted 1,2,5,6-tetrahydropyridine derivative having high affinity for an acetylcholine receiptor is provided, which compound is useful as a muscarine type acetylcholine receiptor agonist, a recognition improving agent and a treating agent of cerebral nervous disease such as Alzheimer's disease. CONSTITUTION: The isoxazole or isoxazoline substituted 1,2,5,6-tetrahydropyridine derivative represented by formula(1) and a pharmaceutically acceptable salt thereof are provided, wherein R2 is C1-4 alkyl; one of R3 and R4 is one functional group in claim 1 and another of them is H; R5 is hydrogen, hydroxy, hydroxy C1-6 alkyl, C1-6 alkoxymethyl, C1-6 alkoxy, acetoxy, C1-4 alkyl ester, nitrile, aryl, phenylthio, methylthiomethyl, phenylsulfoxide, dimethylthiomethyl, C1-4 alkylketo, C1-4 alkylketo oxime, C1-4 alkylketo C1-5 alkyl oxime, and N-pyrrolidine-2-on; R6 is hydrogen; and R5 and F6 form -CH2OCH2 together. The process for preparing the isoxazole or isoxazoline substituted 1,2,5,6-tetrahydropyridine derivative represented by formula comprises the steps of: reacting 3- or 4-pyridine aldehyde oxime compound of formula(2) with chlorox to prepare nitrile oxide of formula(4); and cycloadddition reaction of nitrile oxide of formula(4) with alkene or alkyne compound of formula(8) or formula(9) to prepare a compound of formula(5) or formula(6); reacting the compound of formula(5) or formula(6) with alkyl iodide to prepare alkyl pyridine salt of formula(7); and reducing the alkyl pyridine salt of formula(7).

Abstract translation: 目的：提供对乙酰胆碱受体具有高亲和力的异恶唑或异恶唑啉取代的1,2,5,6-四氢吡啶衍生物，该化合物可用作毒蕈碱型乙酰胆碱受体激动剂，识别改善剂和脑神经系统疾病的治疗剂 如阿尔茨海默病。 构成：提供由式（1）表示的异恶唑或异恶唑啉取代的1,2,5,6-四氢吡啶衍生物及其药学上可接受的盐，其中R 2为C 1-4烷基; R3和R4之一是权利要求1中的一个官能团，另一个是H; R5是氢，羟基，羟基C1-6烷基，C1-6烷氧基甲基，C1-6烷氧基，乙酰氧基，C1-4烷基酯，腈，芳基，苯硫基，甲硫基甲基，苯基亚砜，二甲硫甲基，C1-4烷基酮，C1-4 烷基酮肟，C 1-4烷基酮C 1-5烷基肟和N-吡咯烷-2-酮; R6是氢; R5和F6一起形成-CH 2 OCH 2。 制备由式表示的异恶唑或异恶唑啉取代的1,2,5,6-四氢吡啶衍生物的方法包括以下步骤：使式（2）的3-或4-吡啶醛肟化合物与氯氧反应制备式 （4）; 和式（4）的氧化腈与式（8）或式（9）的烯烃或炔化合物的环加成反应以制备式（5）或式（6）的化合物; 使式（5）或式（6）的化合物与烷基碘反应制备式（7）的烷基吡啶盐; 和还原式（7）的烷基吡啶盐。

公开(公告)号：KR1020030034822A

公开(公告)日：2003-05-09

申请号：KR1020010066578

申请日：2001-10-27

Applicant: 한국과학기술연구원

Inventor： 김유승 ,  강순방 ,  금교창 ,  장민석 ,  공재양 ,  정대영

IPC: C07D413/14

CPC classification number: C07D413/14

Abstract: PURPOSE: Pyrrolidone derivative, a preparation process thereof and a pharmaceutical composition containing the same are provided, which pyrrolidone derivatives are useful as a muscarine type acetylcholine receiptor agonist, a recognition improving agent and a treating agent of cerebral nervous disease such as Alzheimer's disease. CONSTITUTION: The pyrrolidone derivative represented by formula(1) and a pharmaceutically acceptable salt thereof are provided, wherein n is 0 or 1; Aza is C1-4 alkyl substituted or unsubstituted heterocycle, or heterocycle substituted C1-4 alkyl; and heterocycle is hetero atom and saturated or unsaturated 5-membered ring or 5-membered ring containing nitrogen. The process for preparing the pyrrolidone derivative of formula(1) comprises the steps of: reacting azacyclo aldehyde oxime compound of formula(2) with chlorox to prepare nitrile oxide of formula(4); and cycloadddition reaction of nitrile oxide of formula(4) with pyrrolidone containing alkene or alkyne compound of formula(5).

Abstract translation: 目的：提供吡咯烷酮衍生物及其制备方法和含有该吡咯烷酮衍生物的药物组合物，该吡咯烷酮衍生物可用作毒蕈碱型乙酰胆碱受体激动剂，识别改善剂和脑神经疾病如阿尔茨海默病的治疗剂。 构成：提供由式（1）表示的吡咯烷酮衍生物及其药学上可接受的盐，其中n为0或1; 氮杂是C 1-4烷基取代或未取代的杂环，或杂环取代的C 1-4烷基; 杂环是杂原子和含氮的饱和或不饱和的5元环或5元环。 制备式（1）的吡咯烷酮衍生物的方法包括以下步骤：使式（2）的唑烷酮肟化合物与氯氧化反应制备式（4）的氧化腈; 和式（4）的氧化腈与含有式（5）的烯烃或炔化合物的吡咯烷酮的环加成反应。

公开(公告)号：KR1020020043918A

公开(公告)日：2002-06-12

申请号：KR1020000073121

申请日：2000-12-04

Applicant: 한국과학기술연구원 ,  한국과학기술원 ,  한국화학연구원

Inventor： 고훈영 ,  최경일 ,  조용서 ,  배애님 ,  강경호 ,  차미영 ,  공재양 ,  정대영 ,  이희윤

IPC: C07D413/14

CPC classification number: C07D413/04 ,  C07D261/08 ,  C07D413/14

Abstract: PURPOSE: Provided are novel isoxazolylalkylpiperazine derivatives having selective activity for dopamine D3 and D4 receptor represented by the formula(1) and their manufacturing method by reductive amination in the presence of a reductant. The derivatives and their pharmaceutically acceptable salts are useful in the treatment of mental illness. CONSTITUTION: The novel isoxazolylalkylpiperazine derivative of the formula(1) is prepared by reacting amine compound represented by the chemical formula(2) with aldehyde compound shown in the chemical formula(3) in the presence of a reductant selected from NaBH(OAc)3, NaBH3CN and NaBH4 in a reductive amination reaction. In the formulae, R1,R2,R3,R4, and R5 are same or different each other and are hydrogen atom, halogen atom, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, hydroxy, hydroxymethyl, aryl, heteroaryl, amino group, C1-C6 alkylamino, carbonyl, C3-C8 cycloalkyl, or C3-C8 heterocyclic group; R6 is hydrogen atom, halogen atom, alkyl, C1-C6 alkoxy, aryl, pyridyl, heterocyclic, pyrimidyl group; X is CH or nitrogen atom; and n is 3 or 4.

Abstract translation: 目的：提供具有式（1）表示的多巴胺D3和D4受体选择性活性的新型异恶唑基烷基哌嗪衍生物及其制备方法，在还原胺存在下还原胺化。 衍生物及其药学上可接受的盐可用于治疗精神疾病。 构成：式（1）的新型异恶唑基烷基哌嗪衍生物通过使化学式（2）表示的胺化合物与化学式（3）所示的醛化合物在选自NaBH（OAc）3的还原剂存在下反应来制备 ，NaBH 3 CN和NaBH 4在还原胺化反应中。 在式中，R 1，R 2，R 3，R 4和R 5相同或不同，为氢原子，卤原子，C 1 -C 6烷基，C 1 -C 6烷氧基，C 2 -C 6烯基，羟基，羟甲基，芳基，杂芳基 ，氨基，C1-C6烷基氨基，羰基，C3-C8环烷基或C3-C8杂环基; R6是氢原子，卤素原子，烷基，C1-C6烷氧基，芳基，吡啶基，杂环基，嘧啶基; X是CH或氮原子; n为3或4。

公开(公告)号：KR1020020041711A

公开(公告)日：2002-06-03

申请号：KR1020000071399

申请日：2000-11-28

Applicant: 한국과학기술연구원

Inventor： 고훈영 ,  조용서 ,  최경일 ,  배애님 ,  강경호 ,  이희윤 ,  손정훈 ,  공재양 ,  정대영

IPC: C07D401/04

Abstract: PURPOSE: A 4-aminopiperidine analogue and a producing method thereof are provided, therefore the compound can be useful as a ligand of a muscarine receptor, and it is thus used in study on Alzheimer disease. CONSTITUTION: The 4-aminopiperidine analogue is represented by formula(I), wherein R1, R2, R3, R4, R5, R6 and R7 are hydrogen, cycloalkyl having carbon number of 1 to 6, alkoxy, halogen, hydroxy, hydroxymethyl, aryl, heteroaryl, amino, alkylamino, alkenyl, carbonyl or hetero ring having carbon number of 5 to 7 wherein aryl is a ring having 6 atoms, two rings having 10 atoms or a stable resonance form having double bond to adjacent carbon; heteroaryl is a single ring aromatic group having carbon number of 5 to 6 or a double ring aromatic group having carbon number of 10 in which the heteroaryl has at least one hetero atom of N, O or S; hetero ring consists of 5 to 7 atoms having 1 to 3 of N, O or S; X is carbon or sulfur; and n is an integer of 1 to 2 wherein n is 1 when X is carbon and is 2 when X is sulfur. The 4-aminopiperidine analogue is produced by reacting piperidine or amine(II) with piperazine with ketone(III) in the presence of 1 to 3 equivalent of acetic acid, 2 to 10 equivalent of reducing agent and solvent at room temperature for 3 to 24 hours to produce 4-aminopiperidine(I) and adding NaHCO3 solution and organic solvent to 4-aminopiperidine(I); and drying the extracted 4-aminopiperidine(I), dissolving it, adding 1 to 10 equivalent of hydrogen chloride to the solution, and separating, washing and drying the hydrochloride of 4-aminopiperidine.

Abstract translation: 目的：提供4-氨基哌啶类似物及其制备方法，因此该化合物可用作毒蕈碱受体的配体，因此用于阿尔茨海默病的研究。 构成：4-氨基哌啶类似物由式（I）表示，其中R 1，R 2，R 3，R 4，R 5，R 6和R 7为氢，碳数为1至6的环烷基，烷氧基，卤素，羟基，羟甲基，芳基 碳原子数为5〜7的杂芳基，氨基，烷基氨基，烯基，羰基或杂环，其中芳基为6原子的环，2个环为10个原子或具有与相邻碳原子双键的稳定共振形式; 杂芳基是碳数为5至6的单环芳基或碳数为10的双环芳基，其中杂芳基具有至少一个杂原子为N，O或S; 杂环由5至7个具有1至3个N，O或S的原子组成; X是碳或硫; n为1〜2的整数，X为碳时n为1，X为硫时为2。 4-氨基哌啶类似物通过哌啶或胺（II）与哌嗪与酮（III）在1至3当量的乙酸，2至10当量的还原剂和溶剂的存在下在室温下反应3至24 小时以产生4-氨基哌啶（I）并将NaHCO 3溶液和有机溶剂加入到4-氨基哌啶（I）中; 并将提取的4-氨基哌啶（I）干燥，溶解，向溶液中加入1〜10当量的氯化氢，分离，洗涤和干燥4-氨基哌啶的盐酸盐。

公开(公告)号：KR1020010029025A

公开(公告)日：2001-04-06

申请号：KR1019990041613

申请日：1999-09-28

Applicant: 한국과학기술연구원

Inventor： 고훈영 ,  조용서 ,  최경일 ,  배애님 ,  강경호 ,  이지은 ,  이희윤 ,  공재양 ,  정대영 ,  정선호

IPC: C07D413/06

Abstract: PURPOSE: Provided is a method for manufacturing an iso-oxazole piperazin compound and its salts which can end up developing a lead compound for new drugs. CONSTITUTION: An isooxazol compound is manufactured by the next step: reacting the compound of the formula (2) with the compound of the formula (3) at room temperature, at 0-7 deg.C, in the presence of organic solvent, 0.1-2 equivalent, preferably 1 equivalent of base, and chlorinating agent for 30 minutes-4 hours, preferably 2 hours. Wherein, organic solvent is selected from benzene, methylene chloride, and tetrahydrofuran; a base is selected from methyl amine, ethyl amine, diethyl amine, dimethyl amine, trimethyl amine, cyclohexylamine, diethylisopropylamine, pyridine, or preferably triethylamine; And chlorinating agent is one of chlorine, N-chlorosuccinimide, and sodium hypochlorite. In the formula (1), (2), and (3), R1 and R6 are a phenyl group, benzyl group, halide phenyl group, phenyl group having substituted C1-C6 alkyl group, phenyl group having substituted C1-C6 alkoxy group, methyl phenyl group, or pyridyl group. R2-R5 is hydrogen, and X is nitrogen.

Abstract translation: 目的：提供一种制造异恶唑哌嗪化合物及其盐的方法，其可以最终形成用于新药的铅化合物。 构成：通过下一步骤制备异恶唑化合物：在室温，0-7℃，有机溶剂存在下，将式（2）化合物与式（3）化合物反应，得到0.1 -2当量，优选1当量碱和氯化剂30分钟-4小时，优选2小时。 其中有机溶剂选自苯，二氯甲烷和四氢呋喃; 碱选自甲胺，乙胺，二乙胺，二甲胺，三甲胺，环己胺，二乙基异丙胺，吡啶，或优选三乙胺; 而氯化剂是氯，N-氯代琥珀酰亚胺和次氯酸钠之一。 在式（1），（2）和（3）中，R 1和R 6是苯基，苄基，卤化苯基，具有取代的C 1 -C 6烷基的苯基，具有取代的C 1 -C 6烷氧基的苯基 ，甲基苯基或吡啶基。 R2-R5是氢，X是氮。

公开(公告)号：KR100264158B1

公开(公告)日：2000-08-16

申请号：KR1019980023118

申请日：1998-06-19

Applicant: 한국과학기술연구원

Inventor： 고훈영 ,  장문호 ,  김유승 ,  최경일 ,  조용서 ,  배애님 ,  차주환 ,  공재양 ,  천혜경 ,  정대영

IPC: C07D453/00 ,  C07D261/20

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.

상기 식들에서, R은 각각 수소, 할로, 알콕시, 시아노, 알킬, 알케닐, 알키닐, 히드록시, 아미노, 니트로, 4-메톡시벤질옥시, 3급-부톡시카르보닐아미노 또는 약제학적으로 가능한 염을, R
1 ,R
2 및R
R 는 각각 알킬, 아릴 또는 아랄킬을, X는 할로겐 원자를 각각 표시하며, n은 1 또는 2의 정수이다.