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：KR1020030065890A

公开(公告)日：2003-08-09

申请号：KR1020020005946

申请日：2002-02-01

Applicant: 한국과학기술연구원

Inventor： 고훈영 ,  최경일 ,  조용서 ,  배애님 ,  차주환 ,  석미영 ,  공재양 ,  정대영

IPC: C07D453/02

Abstract: PURPOSE: Provided are Quinuclidine compounds which are useful for treatment of brain-nervous diseases caused by cholinergic neurotransmission such as Alzheimer's disease and a preparation method thereof. CONSTITUTION: A quinuclidine compounds of the formula (I) and pharmaceutically acceptable salts thereof are provided, wherein n is an integer of 1 to 5; R is a substituent on a benzene ring, hydrogen, F, Cl, methoxy, OH, NH2, NO2, 3,4-dimethoxy, 2,4-dimethoxy, cyano, C1-6 alkyl, 1,2 or 3 fluorine substituted C1-6 alkyl, 4-methoxybenzyloxy, t-butoxycarbonyl, C2-6 alkenyl, 1,2 or 3 fluorine substituted C2-6 alkenyl, C2-6 alkynyl, 1,2 or 3 fluorine substituted C2-6 alkynyl, and C3-7 cycloalkyl. A method for preparing the quinuclidine compounds of the formula (I) comprises reacting a compound of the formula (II) with a compound of the formula (III) or (IV), wherein R1 and R2 are independently C1-6 alkyl, aryl or arylalkyl.

Abstract translation: 目的：提供可用于治疗由胆碱能神经传递如阿尔茨海默病引起的脑神经疾病的奎宁环化合物及其制备方法。 构成：提供式（I）的奎宁环化合物及其药学上可接受的盐，其中n为1至5的整数; R是苯环上的取代基，氢，F，Cl，甲氧基，OH，NH2，NO2,3,4-二甲氧基，2,4-二甲氧基，氰基，C1-6烷基，1,2或3个氟取代的C1 -6烷基，4-甲氧基苄氧基，叔丁氧基羰基，C2-6烯基，1,2或3个氟取代的C2-6烯基，C2-6炔基，1,2或3个氟取代的C2-6炔基，C3-7 环。 制备式（I）的奎宁环化合物的方法包括使式（II）的化合物与式（III）或（IV）的化合物反应，其中R 1和R 2独立地为C 1-6烷基，芳基或 芳。

公开(公告)号：KR100465277B1

公开(公告)日：2005-01-13

申请号：KR1020020004200

申请日：2002-01-24

Applicant: 한국과학기술연구원

Inventor： 고훈영 ,  최경일 ,  조용서 ,  배애님 ,  차주환 ,  공재양 ,  정대영

IPC: C07D453/02 ,  C07D471/08 ,  C07D261/06

Abstract: PURPOSE: Azabicyclic compounds having an oxime moiety and a preparation method thereof are provided, which can be useful for treatment of cerebral nervous diseases caused by choline neurotransmission disorders including Alzheimer's disease. CONSTITUTION: An azabicyclic compounds having an oxime moiety represented by the formula(I) and pharmaceutically acceptable salts thereof are provided, wherein n is 1 or 2; m is 0 or 1; and R is at least one substituent selected from the group consisting of hydrogen, F, Cl, methoxy, OH, NH2, NO2, 3, 4-dimethoxy, 2, 4-dimethoxy, cyano, C1-C6 alkyl, 1, 2 or 3 fluorine atom substituted C1-C6 alkyl, 4-methoxybenzyloxy, t-butoxycarbonyl, C2-C6 alkenyl, 1, 2 or 3 fluorine atom substituted C2-C6 alkynyl, C3-C7 cycloalkyl and aromatic atom group, in which the aromatic atom group is selected from phenyl, 2- or 3-thienyl, 2- or 3-puridyl, 2- or 3-pyrrolyl; and the substituent of the aromatic atom group is selected from the group consisting of Cl, Br, F, trifluoromethyl, NH2, NO2 and C1-C4 straight or branched chain alkyl.

Abstract translation: 目的：提供具有肟部分的氮杂双环化合物及其制备方法，其可用于治疗由包括阿尔茨海默病在内的胆碱神经传递障碍引起的脑神经疾病。 构成：提供了具有由式（I）表示的肟部分的氮杂双环化合物及其药学上可接受的盐，其中n是1或2; m是0或1; 和R是至少一个选自氢，F，Cl，甲氧基，OH，NH 2，NO 2，3,4-二甲氧基，2,4-二甲氧基，氰基，C 1 -C 6烷基，1,2或3个 3个氟原子取代的C 1 -C 6烷基，4-甲氧基苄氧基，叔丁氧基羰基，C 2 -C 6烯基，1,2或3个氟原子取代的C 2 -C 6炔基，C 3 -C 7环烷基和芳族原子基团， 选自苯基，2-或3-噻吩基，2-或3-嘌呤基，2-或3-吡咯基; 并且芳族原子基团的取代基选自Cl，Br，F，三氟甲基，NH 2，NO 2和C 1 -C 4直链或支链烷基。

公开(公告)号：KR100441404B1

公开(公告)日：2004-07-23

申请号：KR1020020004199

申请日：2002-01-24

Applicant: 한국과학기술연구원

Inventor： 고훈영 ,  최경일 ,  조용서 ,  배애님 ,  차주환 ,  공재양 ,  정대영

IPC: C07D453/02 ,  C07D471/08 ,  C07D261/06

Abstract: PURPOSE: An alkenyl azabicyclic compound and a preparation method thereof are provided, which can be useful for treatment of cerebral nervous diseases caused by choline neurotransmission disorders. CONSTITUTION: An alkenyl azabicyclic compound represented by the formula(I) and pharmaceutically acceptable salts thereof are provided, wherein n is 1 or 2; and R is selected from the group consisting of hydrogen, F, Cl, methoxy, OH, NH2, NO2, 3,4-dimethoxy, 2,4-dimethoxy, cyano, C1-C6 alkyl, 1, 2 or 3 fluorine substituted C1-C6 alkyl, 4-methoxybenzyloxy, t-butoxycarbonyl, C2-C6 alkenyl, 1, 2 or 3 fluorine substituted C2-C6 alkynyl and C3-C7 cyloalkyl. A method for preparing the alkenyl azabicyclic compound of the formula(I) comprises a compound of the formula(II) with a compound of the formula(III) or formula(IV), wherein R1, R2 and R3 are independently C1-C6 alkyl, aryl or arylalkyl.

Abstract translation: 目的：提供烯基氮杂双环化合物及其制备方法，其可用于治疗由胆碱神经传递紊乱引起的脑神经疾病。 构成：提供由式（I）表示的烯基氮杂双环化合物及其药学上可接受的盐，其中n是1或2; 并且R选自氢，F，Cl，甲氧基，OH，NH 2，NO 2，3,4-二甲氧基，2,4-二甲氧基，氰基，C 1 -C 6烷基，1,2或3个氟取代的C 1 -C 6烷基，4-甲氧基苄氧基，叔丁氧基羰基，C 2 -C 6烯基，1,2或3个氟取代的C 2 -C 6炔基和C 3 -C 7环烷基。 用于制备式（I）的烯基氮杂双环化合物的方法包括式（II）的化合物与式（III）或式（IV）的化合物，其中R 1，R 2和R 3独立地为C 1 -C 6烷基 ，芳基或芳基烷基。

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：KR1020030063854A

公开(公告)日：2003-07-31

申请号：KR1020020004200

申请日：2002-01-24

Applicant: 한국과학기술연구원

Inventor： 고훈영 ,  최경일 ,  조용서 ,  배애님 ,  차주환 ,  공재양 ,  정대영

IPC: C07D453/02 ,  C07D471/08 ,  C07D261/06

Abstract: PURPOSE: Azabicyclic compounds having an oxime moiety and a preparation method thereof are provided, which can be useful for treatment of cerebral nervous diseases caused by choline neurotransmission disorders including Alzheimer's disease. CONSTITUTION: An azabicyclic compounds having an oxime moiety represented by the formula(I) and pharmaceutically acceptable salts thereof are provided, wherein n is 1 or 2; m is 0 or 1; and R is at least one substituent selected from the group consisting of hydrogen, F, Cl, methoxy, OH, NH2, NO2, 3, 4-dimethoxy, 2, 4-dimethoxy, cyano, C1-C6 alkyl, 1, 2 or 3 fluorine atom substituted C1-C6 alkyl, 4-methoxybenzyloxy, t-butoxycarbonyl, C2-C6 alkenyl, 1, 2 or 3 fluorine atom substituted C2-C6 alkynyl, C3-C7 cycloalkyl and aromatic atom group, in which the aromatic atom group is selected from phenyl, 2- or 3-thienyl, 2- or 3-puridyl, 2- or 3-pyrrolyl; and the substituent of the aromatic atom group is selected from the group consisting of Cl, Br, F, trifluoromethyl, NH2, NO2 and C1-C4 straight or branched chain alkyl.

Abstract translation: 目的：提供具有肟部分的氮杂双环化合物及其制备方法，其可用于治疗由胆碱神经传递障碍（包括阿尔茨海默氏病）引起的脑神经疾病。 构成：提供具有由式（I）表示的肟部分及其药学上可接受的盐的氮杂双环化合物，其中n为1或2; m为0或1; R为至少一个选自氢，F，Cl，甲氧基，OH，NH2，NO2,3,4-二甲氧基，2,4-二甲氧基，氰基，C1-C6烷基，1,2或 3个氟原子取代的C1-C6烷基，4-甲氧基苄氧基，叔丁氧基羰基，C2-C6烯基，1,2或3个氟原子取代的C2-C6炔基，C3-C7环烷基和芳族原子基团，其中芳族原子团 选自苯基，2-或3-噻吩基，2-或3-取代基，2-或3-吡咯基; 芳基原子的取代基选自Cl，Br，F，三氟甲基，NH 2，NO 2和C 1 -C 4直链或支链烷基。

公开(公告)号：KR100355343B1

公开(公告)日：2002-10-12

申请号：KR1019990050823

申请日：1999-11-16

Applicant: 한국과학기술연구원

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

IPC: C07D261/14

Abstract: 본발명은신규삼차아미노에틸이소옥사졸유도체및 그제조방법에관한것으로서, 상기이소옥사졸유도체는여러가지중추신경계장애와관련이있는도파민-1 수용체의길항제로서작용하며, 그구조는화학식 1과같다. [화학식 1] 그제조방법은아래의화학식 2의아민과화학식 3의토실레이트의치환반응을이용한것으로서, 그반응은반응식 1과같다. [화학식 2] [화학식 3] [반응식 1] 상기화학식 1, 2, 3 및반응식 1에서, R는페닐, 할로겐원자에의해치환된페닐, 트리플루오로메틸에의해치환된페닐, 페닐기의 2, 3 또는 4 위치에트리플루오로메틸에의해치환된페닐메틸, 디페닐메틸, 페닐기의 2, 3 또는 4 위치에할로겐원자에의해치환된디페닐메틸, 벤질, 3-히드로벤즈이미다졸-2-온이며; R내지 R는모두수소이며; R는니트로기, 페녹시기, 메톡시기, 트리플루오로메틸기및 할로겐기로구성되는군에서선택되는하나이상에의해치환된페닐, 페닐기에의해치환된비닐또는 O, S 및 N으로구성되는군에서선택되는한가지원자에의해치환된 5환또는 6환의불포화또는포화헤테로고리화합물이며; X는질소또는 C-H이다.

公开(公告)号：KR100343947B1

公开(公告)日：2002-07-22

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: 본발명은화학식 1을갖는이소옥사졸피페라진계열의화합물또는그 염의제조방법및 상기방법에의해만들어진라이브러리에관한것으로, 상기방법은화학식 2의화합물과화학식 3의화합물을염기및 염소화제의존재하에 1,3-쌍극자고리화첨가반응시켜화학식 1 또는그 염의화합물을제조하는것으로구성된다. 그화학식 1, 2, 3과반응식 1은다음과같다. 상기화학식 1, 2, 3과반응식 1에서, R및 R는페닐, 벤질, 할로겐화페닐, C-C의알킬기로치환된페닐, C-C의알콕시기로치환된페닐, (트리플루오로)메틸페닐, 피리딜등의페닐유도체를말하며, R-R는수소이며, X는질소이며,는이중결합또는삼중결합을의미하며,는이중결합또는단일결합을의미한다.

公开(公告)号：KR1020020043413A

公开(公告)日：2002-06-10

申请号：KR1020000073122

申请日：2000-12-04

Applicant: 한국과학기술연구원 ,  한국과학기술원 ,  한국화학연구원 ,  학교법인 성신학원

Inventor： 고훈영 ,  최경일 ,  조용서 ,  배애님 ,  공재양 ,  정대영 ,  정선호 ,  정지영 ,  이희윤

IPC: C07D413/14

CPC classification number: C07D413/04 ,  C07D261/08

Abstract: PURPOSE: Provided are novel 4,5-dihydroisoxazolylalkylpiperazine derivatives having selective biological activity to dopamine D3 and D4 receptors, and their preparation method by reductive amination in the presence of reductant. CONSTITUTION: 4,5-dihydroisoxazolylalkylpiperazine derivative is represented by the formula(1), wherein R1, R2, R3, R4 and R5 are identical or different from each other, and represents individually hydrogen atom, halogen atom, C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, hydroxy group , hydroxymethyl group, aryl group, heteroaryl group, amino group, C1-C6 alkyl amino group, carbonyl group, C3-C8 cycloalkyl group, or C3-C8 heterocyclic group; R6 represents hydrogen atom, halogen atom, alkyl group, C1-C6 alkoxy group, aryl group, pyridyl group, heterocyclic group or pyrimidyl group; X represents CH or nitrogen atom; and n is 3 or 4.

Abstract translation: 目的：提供对多巴胺D3和D4受体具有选择性生物活性的新型4,5-二氢异恶唑烷基哌嗪衍生物及其在还原剂存在下还原胺化的制备方法。 构成：4,5-二氢异恶唑基烷基哌嗪衍生物由式（1）表示，其中R 1，R 2，R 3，R 4和R 5彼此相同或不同，并且表示单独的氢原子，卤素原子，C1-C6烷基， C1-C6烷氧基，C2-C6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表示氢原子，卤素原子，烷基，C1-C6烷氧基，芳基，吡啶基，杂环基或嘧啶基; X表示CH或氮原子; n为3或4。

公开(公告)号：KR1020010046868A

公开(公告)日：2001-06-15

申请号：KR1019990050823

申请日：1999-11-16

Applicant: 한국과학기술연구원

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

IPC: C07D261/14

Abstract: PURPOSE: A novel tertiary aminoethyl isooxazol derivative is provided, which acts as an antagonist of dopamine-1 receptor relating to various central nervous system disorders. And a method for preparing the same is also provided. CONSTITUTION: The tertiary aminoethyl isooxazol derivative is represented by the formula (1) and is prepared by dissolving a compound represented by the formula (2) and a compound represented by the formula (3) in a solvent to react them with each other in the presence of base. In the formulae 1-3, R1 is phenyl, phenyl substituted by halogen atom, phenyl substituted by trifluoromethyl, phenyl methyl having a trifluoromethyl substituent in 2, 3 or 4 position of the phenyl group, diphenylmethyl having a halogen atom substituent in 2, 3 or 4 position of the phenyl group, benzyl or 3-hydrobenzimidazole-2-one, each R2-R5 is hydrogen, R6 is phenyl substituted by at least one selected from the group consisting of nitro group, phynoxy group, methoxy group, trifluoromethyl group and halogen group, vinyl substituted by phenyl group or C5 or C6 unsaturated or saturated hetero cyclic compound substituted by O, S or N, and X is nitrogen or carbon.

Abstract translation: 目的：提供一种新的叔氨基乙基异恶唑衍生物，其作为与各种中枢神经系统疾病有关的多巴胺-1受体的拮抗剂。 还提供了制备该方法。 构成：叔氨基乙基异恶唑衍生物由式（1）表示，通过将式（2）表示的化合物和式（3）表示的化合物溶解在溶剂中，使其在 存在基地 式1-3中，R 1为苯基，被卤素原子取代的苯基，被三氟甲基取代的苯基，苯基2,3或4位中具有三氟甲基取代基的苯基甲基，2,3或4位的卤素原子取代基的二苯基甲基 或4位，苯基或3-氢苯并咪唑-2-酮，每个R 2 -R 5是氢，R 6是被选自硝基，环氧基，甲氧基，三氟甲基中的至少一个取代的苯基 卤素基，被苯基取代的乙烯基或被O，S或N取代的C5或C6不饱和或饱和杂环化合物，X是氮或碳。