公开(公告)号：KR100843352B1

公开(公告)日：2008-07-03

申请号：KR1020070009627

申请日：2007-01-30

Applicant: 한국과학기술연구원 ,  주식회사 디비하이텍

Inventor： 배애님 ,  조용서 ,  추현아 ,  차주환 ,  김지혜 ,  고훈영 ,  박우규 ,  공재양 ,  채명윤 ,  조인선 ,  황봉운 ,  이동하

IPC: C07D401/12 ,  A61K31/502

CPC classification number: C07D237/32

Abstract: A 1,2-dihydro-1-oxophthalazinyl piperazine derivative is provided to show selective antagonistic activity on serotonin 5-HT2a or 5-HT2c receptor, thereby being used for a pharmaceutical composition for treating and preventing central nervous system diseases. A 1,2-dihydro-1-oxophthalazinyl piperazine derivative is represented by a formula(1) and is prepared by reacting an amine compound represented by a formula(2) with a carboxylic acid compound represented by a formula(3). In the formulae, R1 is H, halogen, C1-10 alkyl, C1-10 alkoxy, phenyl, pyridyl or pyrimidyl; R2 is aryl selected from the group consisting of phenyl, pyridyl and pyrimidyl which may be substituted or unsubstituted by a substituent selected from the group consisting of halogen, nitro, C1-10 alkyl, C1-10 haloalkyl, C1-10 alkoxy, C1-10 haloalkoxy, and C1-6 acyl; and n is an integer from 0 to 5. A pharmaceutical composition for treating and preventing diseases such as anxiety, depression, stroke, obsessive neurosis, psychosis, schizophrenia, suicidal tendency, sleep disorders, appetite disorders, withdrawal symptoms caused by drug abuse, and migraine comprises the 1,2-dihydro-1-oxophthalazinyl piperazine derivative represented by the formula(1) or a pharmaceutically acceptable salt thereof.

Abstract translation: 提供1,2-二氢-1-氧酞嗪哌嗪衍生物以显示对5-羟色胺5-HT2a或5-HT2c受体的选择性拮抗活性，从而用于治疗和预防中枢神经系统疾病的药物组合物。 1,2-二氢-1-氧代吖嗪基哌嗪衍生物由式（1）表示，通过使由式（2）表示的胺化合物与由式（3）表示的羧酸化合物反应制备。 式中，R 1为H，卤素，C 1-10烷基，C 1-10烷氧基，苯基，吡啶基或嘧啶基; R 2是选自苯基，吡啶基和嘧啶基的芳基，其可以被选自卤素，硝基，C 1-10烷基，C 1-10卤代烷基，C 1-10烷氧基，C 1-10烷氧基， 10个卤代烷氧基和C1-6酰基; n为0〜5的整数。用于治疗和预防焦虑，抑郁，中风，强迫神经症，精神病，精神分裂症，自杀倾向，睡眠障碍，食欲障碍，药物滥用引起的戒断症状的药物组合物，以及 偏头痛包含由式（1）表示的1,2-二氢-1-氧代嗪嗪哌嗪衍生物或其药学上可接受的盐。

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。

公开(公告)号：KR1020000002400A

公开(公告)日：2000-01-15

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: PURPOSE: The compound is provided which exhibits a high affinity for muscarinic acetylcholine receptor and is useful as therapeutic agent of cerebral nerve disease such as Alzheimer's disease. CONSTITUTION: The carbonyl compound of the formula (II), wherein, n is integer 1 or 2, is reacted with phosphonium salt compound of formula (III), in which R is H, halo, alkoxy, cyano, alkyl, alkenyl, alkinyl, hydroxy, amino, nitro, 4-methoxybenzyloxy, t-butoxycarbonylamino or its salt; R1, R2 and R3 are alkyl, aryl or aralkyl, respectively; X is halogen, or with phosphonate compound of the formula (IV) in the presence of solvent and base to give £(aryl) isooxozolyl| methylene-azabicyclo compound of the formula (I). Thus, 188mg of potassium t-butoxide and 482mg of diethyl 3-(4-methylphenyl)-5-isooxazolylmethylphosphonate being dissolved in tetrahydrofuran are stirred for 30 minutes at 22°C to give 3-£3-(4-methylphenyl)isooxazol-5-yl|methylene-1-azabicyclo£2.2.2|octane oxalic acid salt.

Abstract translation: 目的：提供对毒蕈碱性乙酰胆碱受体具有高亲和力的化合物，并且可用作脑神经疾病如阿尔茨海默病的治疗剂。 构成：其中n为1或2的式（II）的羰基化合物与式（III）的鏻盐化合物反应，其中R为H，卤素，烷氧基，氰基，烷基，烯基，炔基 ，羟基，氨基，硝基，4-甲氧基苄氧基，叔丁氧基羰基氨基或其盐; R1，R2和R3分别是烷基，芳基或芳烷基; X为卤素，或与式（IV）的膦酸酯化合物在溶剂和碱存在下反应，得到（芳基）异恶唑基| 式（I）的亚甲基 - 氮杂二环化合物。 因此，将188mg叔丁醇钾和482mg 3-（4-甲基苯基）-5-异恶唑甲基膦酸二乙酯溶于四氢呋喃中，在22℃下搅拌30分钟，得到3- {3-（4-甲基苯基）异恶唑-4-基） 5-基|亚甲基-1-氮杂双环{2.2.2 |辛酸草酸盐。

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。