公开(公告)号：KR100432283B1

公开(公告)日：2004-05-22

申请号：KR1020010066568

申请日：2001-10-27

Applicant: 한국과학기술연구원

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

IPC: C07D401/06 ,  A61K31/435 ,  A61K31/40

CPC classification number: C07D401/06

Abstract: The present invention relates to novel tetrahydropyridine derivatives of formula 1 having an appropriately substituted pyrrolidinone and oxime, wherein m is 0 or 1, n is 1 or 2, R1 is hydrogen, C1-4 alkyl, C2-4 alkynyl or aryl, R3 is C1-4 alkyl, which show high efficacy, low cholinergic adverse effects and high affinity for muscarinic acetylcholine receptor; and pharmaceutically acceptable salts thereof; processes for the preparation thereof; and pharmaceutical compositions comprising these compounds or salts.

Abstract translation: 本发明涉及具有适当取代的吡咯烷酮和肟的式1的四氢吡啶衍生物，其中m为0或1，n为1或2，R 1为氢，C 1-4烷基，C 2-4炔基或芳基，R 3为 它表现出高效力，低胆碱能不良作用和对毒蕈碱乙酰胆碱受体的高亲和力; 和其药学上可接受的盐; 其制备方法; 和包含这些化合物或盐的药物组合物。

公开(公告)号：KR1020040095889A

公开(公告)日：2004-11-16

申请号：KR1020030026907

申请日：2003-04-29

Applicant: 한국과학기술연구원

Inventor： 김유승 ,  강순방 ,  금교창 ,  장민석 ,  모길웅 ,  오희영

IPC: C12P17/12

Abstract: PURPOSE: Methods for preparing tetrasubstitued pyrazines using baker's yeast are provided, thereby easily and environment-friendly preparing tetrasubstitued pyrazines in water under mild condition. CONSTITUTION: The method for preparing tetrasubstitued pyrazines of formula (2) using baker's yeast comprises the steps of: (1) preparing a solution of baker's yeast; and (2) dissolving beta-keto alpha-oxime carbonyl derivatives of formula (1) in hydrophilic organic solvent and adding the solution into the baker's yeast solution to carry out chemoselective microbial reduction, wherein R1 is methyl, ethyl or phenyl; R2 is hydrogen, methyl or benzyl; R3 is methoxy, ethoxy, benzyloxy or phenylamine; the organic solvent is selected from benzene, toluene and hexane.

Abstract translation: 目的：提供使用面包酵母制备四取代吡嗪的方法，由此在温和条件下在水中制备四取代吡嗪容易且环境友好。 构成：使用面包酵母制备式（2）的四取代吡嗪的方法包括以下步骤：（1）制备面包酵母溶液; 将式（1）的β-酮基α-肟羰基衍生物溶解在亲水性有机溶剂中，并将溶液加入面包酵母溶液中进行化学选择性微生物还原，其中R1为甲基，乙基或苯基; R2是氢，甲基或苄基; R3是甲氧基，乙氧基，苄氧基或苯胺; 有机溶剂选自苯，甲苯和己烷。

公开(公告)号：KR100437973B1

公开(公告)日：2004-07-02

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：提供了对乙酰胆碱接受者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接受者激动剂，识别改善剂和脑神经疾病治疗剂 如阿尔茨海默病。 本发明提供了由式（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R2为C1-4烷基; R 3和R 4中的一个是权利要求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，二甲基硫代甲基，C1-4烷基酮基，C1-4 烷基酮肟，C 1-4烷基酮基C 1-5烷基肟和N-吡咯烷-2-酮; R6是氢; R5和F6一起形成-CH2OCH2。 制备由下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化氧反应以制备式 （4）; 和式（4）的氧化腈与式（8）或式（9）的烯烃或炔烃化合物的环加成加成反应以制备式（5）或式（6）的化合物; 使式（5）或式（6）的化合物与烷基碘反应以制备式（7）的烷基吡啶盐; 和还原式（7）的烷基吡啶盐。

公开(公告)号：KR100758317B1

公开(公告)日：2007-09-13

申请号：KR1020060039225

申请日：2006-05-01

Applicant: 한국과학기술연구원

Inventor： 금교창 ,  김유승 ,  강순방 ,  임혜원 ,  장민석 ,  구일회

IPC: A61K31/5375 ,  A61P9/04

CPC classification number: A61K31/5375

Abstract: A composition for blocking T-type calcium channel comprising morpholin-2-one derivatives is provided to block the T-type calcium channel in the same level as the conventional T-type calcium channel blocker, mibefradil, without side effects. A composition for blocking T-type calcium channel comprises morpholin-2-one derivatives represented by the formula(1), or pharmaceutically acceptable salts thereof, wherein R^1 and R^2 are each independently hydrogen, C1-C6 alkyl, C1-C6 cycloalkyl, or phenyl optionally substituted by halogen, nitro, hydroxyl or C1-C6 alkoxy; and R^3 and R^4 are each independently hydrogen, C1-C6 alkyl, C1-C6 thioalkyl, amino or phenyl optionally substituted by halogen, nitro, hydroxyl or C1-C6 alkoxy. The composition prevents or treats diseases caused by overexpression of T-type calcium channel including angina pectoris, hypertension, myocardiac infarction, pain and epilepsy.

Abstract translation: 提供一种用于阻断包含吗啉-2-酮衍生物的T型钙通道的组合物，以阻断与常规T型钙通道阻滞剂米非司酮相同水平的T型钙通道，无副作用。 用于阻断T型钙通道的组合物包括由式（1）表示的吗啉-2-酮衍生物或其药学上可接受的盐，其中R 1和R 2各自独立地为氢，C 1 -C 6烷基， C 6环烷基或任选被卤素，硝基，羟基或C 1 -C 6烷氧基取代的苯基; R 3和R 4各自独立地为氢，C 1 -C 6烷基，C 1 -C 6硫代烷基，任选被卤素，硝基，羟基或C 1 -C 6烷氧基取代的氨基或苯基。 该组合物预防或治疗由过度表达T型钙通道引起的疾病，包括心绞痛，高血压，心肌梗塞，疼痛和癫痫。

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：KR100466371B1

公开(公告)日：2005-01-13

申请号：KR1020030026907

申请日：2003-04-29

Applicant: 한국과학기술연구원

Inventor： 김유승 ,  강순방 ,  금교창 ,  장민석 ,  모길웅 ,  오희영

IPC: C12P17/12

Abstract: PURPOSE: Methods for preparing tetrasubstitued pyrazines using baker's yeast are provided, thereby easily and environment-friendly preparing tetrasubstitued pyrazines in water under mild condition. CONSTITUTION: The method for preparing tetrasubstitued pyrazines of formula (2) using baker's yeast comprises the steps of: (1) preparing a solution of baker's yeast; and (2) dissolving beta-keto alpha-oxime carbonyl derivatives of formula (1) in hydrophilic organic solvent and adding the solution into the baker's yeast solution to carry out chemoselective microbial reduction, wherein R1 is methyl, ethyl or phenyl; R2 is hydrogen, methyl or benzyl; R3 is methoxy, ethoxy, benzyloxy or phenylamine; the organic solvent is selected from benzene, toluene and hexane.

Abstract translation: 目的：提供使用面包酵母制备四取代吡嗪的方法，由此在温和条件下容易且环境友好地制备四取代吡嗪在水中。 构成：使用面包酵母制备式（2）的四取代吡嗪的方法包括以下步骤：（1）制备面包酵母溶液; （2）将式（1）的β-酮基α-肟羰基衍生物溶解于亲水性有机溶剂中，并将该溶液加入面包酵母溶液中进行化学选择性微生物还原，其中R1为甲基，乙基或苯基; R2是氢，甲基或苄基; R3是甲氧基，乙氧基，苄氧基或苯胺; 有机溶剂选自苯，甲苯和己烷。

公开(公告)号：KR100437972B1

公开(公告)日：2004-07-02

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: The present invention relates to substituted pyrrolidinone compounds of formula 1, wherein n is 0 or 1; Aza is a heterocycle optionally substituted with C1-4 alkyl, or C1-4 alkyl substituted with a heterocycle, which represents a saturated or unsaturated five- or six-membered ring having nitrogen(s) as a heteroatom, which are muscarinic acetylcholine receptor agonists and useful as nootropics and therapeutic agents for cerebral neural diseases such as Alzheimer's disease; and pharmaceutically acceptable salts thereof; processes for the preparation thereof; and pharmaceutical compositions comprising these compounds or salts.

Abstract translation: 本发明涉及式1的取代的吡咯烷酮化合物，其中n是0或1; Aza是任选被C1-4烷基或被杂环取代的C1-4烷基取代的杂环，所述杂环代表具有氮作为杂原子的饱和或不饱和五元或六元环，其为蕈毒碱乙酰胆碱受体激动剂 作为阿尔茨海默病等脑神经疾病的促智药和治疗药有用; 和其药学上可接受的盐; 其制备方法; 和包含这些化合物或盐的药物组合物。

公开(公告)号：KR1020030034816A

公开(公告)日：2003-05-09

申请号：KR1020010066568

申请日：2001-10-27

Applicant: 한국과학기술연구원

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

IPC: C07D401/06 ,  A61K31/435 ,  A61K31/40

CPC classification number: C07D401/06

Abstract: PURPOSE: A tetrahydropyridine derivative having high affinity for muscarine type acetylcholine receiptor is provided, thereby the tetrahydropyridine derivative can be useful as a recognition improving agent and a nervous disease treating agent. CONSTITUTION: The tetrahydropyridine derivative having high affinity for a muscarine type acetylcholine receiptor is represented by formula(1), wherein m is 0 or 1; n is 1 or 2; R1 is hydrogen, C1-4 alkyl, C2-4 alkynyl or aryl; and R3 is C1-4 alkyl. The process for preparing the tetrahydropyridine derivative comprises (i) condensation of a compound of formula(5) with R1ONH2-HCl to prepare a compound of formula(8); and (ii) reacting the compound of formula(8) with alkyl iodide to prepare alkyl pyrimidine salt and reducing the alkyl pyrimidine salt.

Abstract translation: 目的：提供对毒蕈碱型乙酰胆碱受体具有高亲和力的四氢吡啶衍生物，由此四氢吡啶衍生物可用作识别改善剂和神经疾病处理剂。 构成：对毒蕈碱型乙酰胆碱受体具有高亲和力的四氢吡啶衍生物由式（1）表示，其中m为0或1; n为1或2; R1是氢，C1-4烷基，C2-4炔基或芳基; 并且R 3是C 1-4烷基。 制备四氢吡啶衍生物的方法包括（i）式（5）化合物与R1ONH2-HCl缩合以制备式（8）化合物; 和（ii）使式（8）化合物与烷基碘反应制备烷基嘧啶盐并还原烷基嘧啶盐。