公开(公告)号：KR100820173B1

公开(公告)日：2008-04-08

申请号：KR1020070024124

申请日：2007-03-12

Applicant: 한국화학연구원

Inventor： 이규양 ,  이선경 ,  윤성준 ,  이병호 ,  오광석 ,  정이숙

IPC: C07D233/90 ,  A61K31/4164

CPC classification number: C07D233/90

Abstract: A novel 4-methylimidazol-5-ylcarbonylguanidine derivative is provided to show strong inhibitory activity on NHE-1, a sodium and hydrogen exchange passage, and show excellent heart protecting effect, thereby being usefully used as a therapeutic agent of ischemic heart diseases or a heat protecting agent such as a fibrinolytic enzyme. A 4-methylimidazol-5-ylcarbonylguanidine derivative represented by the formula(1) is at least one selected from the group consisting of (2-(2,3-dichlorophenyl)-4-methyl-1H-imidazol-5-ylcarbonyl)guanidine bis-methanesulfonate, (2-(2,5-dichlorophenyl)-4-methyl-1H-imidazol-5-ylcarbonyl)guanidine bis-methanesulfonate, (2-(3,5-dichlorophenyl)-4-methyl-1H-imidazol-5-ylcarbonyl)guanidine, (2-(2-methoxy-5-chlorophenyl)-4-methyl-1H-imidazol-5-ylcarbonyl)guanidine bis-methanesulfonate, and (2-(2-methoxy-5-fluorophenyl)-4-methyl-1H-imidazol-5-ylcarbonyl)guanidine bis-methanesulfonate and is prepared by reacting a carboxylic acid derivative having a leaving group(L) represented by the formula(2) with guanidine, wherein each R^1 and R^2 is independently H, halogen, trihalomethyl, mesyl, nitro, amino, C1-5 linear or branched alkyl or OR^3(wherein R^3 is H, trihalomethyl, C1-5 linear or branched alkyl or phenyl); X is H, C1-5 linear or branched alkyl or phenyl; and L is halogen, hydroxy, alkoxy, mesylate, or tosylate. A pharmaceutical composition for preventing and treating ischemic cardiac diseases comprises the 4-methylimidazol-5-ylcarbonylguanidine derivative or a pharmaceutically acceptable salt thereof as an effective ingredient.

Abstract translation: 提供了一种新的4-甲基咪唑-5-基羰基胍衍生物，以显示对NHE-1，钠和氢交换通道的强抑制活性，并且显示出优异的心脏保护作用，从而可用作缺血性心脏病的治疗剂或 热保护剂如纤维蛋白溶解酶。 由式（1）表示的4-甲基咪唑-5-基羰基胍衍生物是选自（2-（2,3-二氯苯基）-4-甲基-1H-咪唑-5-基羰基）胍 （2-（2,5-二氯苯基）-4-甲基-1H-咪唑-5-基羰基）双 - 甲磺酸胍，（2-（3,5-二氯苯基）-4-甲基-1H-咪唑 （2-（2-甲氧基-5-氯苯基）-4-甲基-1H-咪唑-5-基羰基） - 双 - 甲磺酸胍和（2-（2-甲氧基-5-氟苯基） -4-甲基-1H-咪唑-5-基羰基）双 - 甲磺酸胍，通过使具有式（2）表示的离去基团（L）的羧酸衍生物与胍反应制备，其中每个R 1和R ^ 2独立地是H，卤素，三卤代甲基，甲磺酰基，硝基，氨基，C 1-5直链或支链烷基或OR 3（其中R 3是H，三卤代甲基，C 1-5直链或支链烷基或苯基）; X是H，C 1-5直链或支链烷基或苯基; 和L是卤素，羟基，烷氧基，甲磺酸酯或甲苯磺酸酯。 用于预防和治疗缺血性心脏病的药物组合物包含4-甲基咪唑-5-基羰基胍衍生物或其药学上可接受的盐作为有效成分。

公开(公告)号：KR1020080030146A

公开(公告)日：2008-04-04

申请号：KR1020060095840

申请日：2006-09-29

Applicant: 한국화학연구원

Inventor： 이규양 ,  이선경 ,  윤성준 ,  이병호 ,  오광석

IPC: C07D263/34 ,  A61K31/42

Abstract: An oxazol-4-yl-carbonylguanidine derivative is provided to show strong inhibitory activity on NHE-1, which is a sodium/hydrogen exchanger, promote recovery of heart function damage caused by ischemia/reperfusion in an isolated ischemic heart model, and show excellent heat protecting effect by significantly decreasing the size of myocardial infarction, thereby being usefully used in order to prevent and treat ischemic heart diseases such as myocardial infarction, arrhythmia and angina pectoris and used as a heart protecting agent for surgical operation of heart. An oxazol-4-yl-carbonylguanidine derivative is represented by the formula(1), wherein each R^1 and R^2 is independently H, halogen, C1-5 linear or branched alkyl, halogen substituted C1-5 linear or branched alkyl, nitro, amino, methyl sulfonyl, or alkoxy(OR^3(where R^3 is H, trifluoromethyl, C1-5 linear or branched alkyl or phenyl)); and X is H or C1-5 linear or branched alkyl, and is prepared by reacting a carboxylic acid derivative represented by the formula(2) with guanidine or reacting the carboxylic acid of the formula(2) with guanidine in the presence of a base. In the formula(2), R^1, R^2, and X are same as defined above, and L is a group easily left by the guanidine and is one selected from the group consisting of halide, hydroxy, mesylate and tosylate. A pharmaceutical composition for preventing and treating ischemic heart diseases comprises the compound of the formula(1) or a pharmaceutically acceptable salt thereof as an effective ingredient.

Abstract translation: 提供了恶唑-4-基 - 羰基胍衍生物，以显示对作为钠/氢交换器的NHE-1的强抑制活性，促进在分离的缺血性心脏模型中由缺血/再灌注引起的心脏功能损伤的恢复，并显示出优异的 通过显着降低心肌梗死的大小，从而有效地利用了预防和治疗心肌梗塞，心律失常和心绞痛等缺血性心脏病的热保护作用，并用作心脏外科手术的心脏保护剂。 恶唑-4-基 - 羰基胍衍生物由式（1）表示，其中每个R 1和R 2独立地是H，卤素，C 1-5直链或支链烷基，卤素取代的C 1-5直链或支链烷基 ，硝基，氨基，甲基磺酰基或烷氧基（OR 3）（其中R 3是H，三氟甲基，C 1-5直链或支链烷基或苯基））; 并且X是H或C 1-5直链或支链烷基，并且通过使式（2）表示的羧酸衍生物与胍反应或使式（2）的羧酸与胍在碱的存在下反应来制备 。 在式（2）中，R 1，R 2和X与上述定义相同，且L是易于被胍留下并且选自卤化物，羟基，甲磺酸酯和甲苯磺酸酯的基团。 用于预防和治疗缺血性心脏病的药物组合物包含式（1）化合物或其药学上可接受的盐作为有效成分。

公开(公告)号：KR100863336B1

公开(公告)日：2008-10-15

申请号：KR1020060095840

申请日：2006-09-29

Applicant: 한국화학연구원

Inventor： 이규양 ,  이선경 ,  윤성준 ,  이병호 ,  오광석

IPC: C07D263/34 ,  A61K31/42

Abstract: 본 발명은 하기 화학식 1로 표시되는 신규 옥사졸-4-카르보닐구아니딘 유도체, 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 함유하는 허혈성 심장질환의 예방 및 치료용 약학적 조성물에 관한 것으로, 본 발명에 따른 옥사졸-4-카르보닐구아니딘 유도체는 나트륨/수소 교환통로인 NHE-1에 대하여 강력한 억제작용을 나타내고, 적출 허혈심장모델에서 허혈/재관류에 의한 심장기능 손상의 회복을 증진시키며, 생체 내 허혈동물 모델에서 심근경색의 크기를 유의성있게 감소시켜 우수한 심장보호효과를 나타내므로 심근경색, 부정맥, 협심증 등의 허혈성 심장질환의 예방 및 치료에 유용하게 사용될 수 있으며, 관동맥우회술, 관동맥경피성형술 등 심장시술 시 또는 혈전용해제 등의 재관류요법에 대한 심장보호제 등으로 유용하게 사용될 수 있다.


(상기 식에서, R
1 , R
2 및 X는 본 명세서에서 정의한 바와 같다)
옥사졸-4-카르보닐구아니딘 유도체, NHE-1, 허혈성 심장질환, 심장보호제