Benzopyranes as potassium channel openersThe present invention relates to compounds of formula (I) and the pharmaceutically acceptable salts thereof, wherein the dashed line represents an optional covalent bond; X is O, NH, S or a direct link; R is hydroxy when the dashed line does not represent a covalent bond and R is absent when the dashed line represents a covalent bond; R is (a) when X is O, a group of formula (i), (b) when X is O, NH or S, optionally substituted hydroxyphenyl, (c) an optionally substituted 4- to 7-membered heterocyclic ring, or (d) when X is NH, a group of formula (ii). The compounds are useful for the treatment of disease associated with the altered tone or motility of smooth muscle.The compound shown in the following formula or its pharmaceutically acceptable salt: dotted line is represented an optional covalence key in the formula; x is o, nh, s or a direct bond;r and r 1perhaps be selected from h independently of one another, fluorine (c 1-c 4) alkyl and c 1-c 4alkyl perhaps lumps together and represents c 2-c 6alkylidene group; r 2be h or c 1-c 4alkyl; r 3when dotted line is not represented a covalent linkage is hydroxyl, and when dotted line is represented a covalent linkage r 3do not exist; r 4， (a) when x is o, be the group of following chemical formula: w and w in the formula 1lump together and represent c 1-c 4alkylidene group is as w and w 1lump together and represent c 2-c 4described alkylidene group is randomly benzo-fused during alkylidene group, and is that replacement is randomly arranged, and being included in benzo-fused part has c 1-c 6alkyl, hydroxyl ,-or 8, halogen ,-n (r 8) 2,-sr 8or halogen (c 1-c 4) alkyl substituent, (b) when x is o, nh or s, be hydroxyphenyl, c is randomly arranged 1-c 6alkyl ,-or 8, halogen ,-n (r 8) 2,-sr 8or halogen (c 1-c 4) alkyl substituent, (c) be one or contain 1～3 n heteroatoms or contain 1 n heteroatoms and 1 o or 1 heteroatomic 4～7 yuan of heterocycle of s that described ring is randomly benzo-fused or c 3-c 7cycloalkylfused, and be that replacement is randomly arranged, be included in benzo-fused or c 3-c 7replaced c on the cycloalkyl blending part 1-c 6alkyl, hydroxyl, hydroxyl (c 1-c 4) alkyl, or 8, r 8o (c 1-c 4) alkyl, halogen, halogen (c 1-c 4) alkyl ,-s (o) mr 8, r 8s (o) m (c 1-c 4) alkyl, oxo, n-cyanoimino, amino, amino (c 1-c 4) alkyl ,-nhr 8, r 8nh (c 1-c 4) alkyl ,-n (r 8) 2, (r 8) 2n (c 1-c 4) alkyl, cyano group, cyano group (c 1-c 4) alkyl ,-co 2r 8, r 8o 2c (c 1-c 4) alkyl ,-conh 2, h 2nco (c 1-c 4) alkyl ,-conhr 8, r 8nhco (c 1-c 4) alkyl ,-con (r 8) 2or (r 8) 2nco (c 1-c 4) alkyl, under suitable situation, be a kind of cyclic n nitroso compound oxide compound of described heterocyclic or s oxide derivative perhaps, its prerequisite is, when x was o, nh or s, described heterocycle was connected by carbon atom on the ring, or (d) when x is nh, be the group of following chemical formula: r in the formula 6be-or 8,-nhr 8,-sr 8,-nh (aryl) or-nh (pyridyl), and r 7be cyano group, nitro or c 2-c 6alkanoyl; r 5be aryl, c 1-c 12alkyl, c 2-c 12alkenyl or c 2-c 12alkynyl group, described c 1-c 12alkyl, c 2-c 12alkenyl and c 2-c 12randomly replaced c on the alkynyl group 4-c 7cycloalkyl, hydroxyl ,-or 8, c 2-c 5alkanoyloxy, halogen, cyano group, nitro, amino ,-nhr 8,-n (r 8) 2,-s (o) mr 8,-nhso 2r 8,-nhcor 8,-cor 8,-conh 2,-conhr 8,-con (r 8) 2,-oco 2r 8,-conh (c 1-c 6) alkyl co 2r 8,-conr 8(c 1-c 6) alkyl co 2r 8,-co 2r 9, aryl, aryloxy, aromatic carbonyl, fragrant carbonyl oxygen base, virtue (c 1-c 6) alkoxyl group, virtue (c 1-c 6) carbalkoxy, phthaloyl imino, or the group of following chemical formula: r 8be c 1-c 6alkyl; r 9be 2,3-indanyl, aryl, c 1-c 12alkyl, c 2-c 12alkenyl or c 2-c 12alkynyl group, described c 1-c 12alkyl, c 2-c 12alkenyl and c 2-c 12randomly replaced c on the alkynyl group 4-c 7cycloalkyl, hydroxyl ,-or 8, c 2-c 6alkanoyloxy, halogen, cyano group, nitro, amino ,-nhr 8,-n (r 8) 2,-s (o) mr 8,-nhso 2r 8,-nhcor 8,-cor 8,-conh 2,-conhr 8,-con (r 8) 2,-oco 2r 8,-conh (c 1-c 6) alkyl co 2r 8,-conr 8(c 1-c 6) alkyl co 2r 8,-co 2(c 1-c 12alkyl), aryl, aryloxy, aromatic carbonyl, fragrant carbonyl oxygen base, virtue (c 1-c 6) alkoxyl group, virtue (c 1-c 6) carbalkoxy, phthaloyl imino, or the group of following chemical formula: r 5, r 6and r 9definition in and ' aryl ' that use in this definition mean phenyl, c is randomly arranged 1-c 6alkyl, c 2-c 6alkenyl, c 2-c 6alkynyl group, hydroxyl, hydroxyl (c 1-c 6) alkyl ,-or 8, r 8o (c 1-c 6) alkyl, r 8o (c 1-c 6) alkoxyl group, r 8o (c 1-c 6) alcoxyl (c 1-c 6) alkyl, halogen, halogen (c 1-c 6) alkyl, cyano group, cyano group (c 1-c 6) alkyl, nitro, nitro (c 1-c 6) alkyl, amino, amino (c 1-c 6) alkyl ,-nhr 8, r 8nh (c 1-c 6) alkyl ,-n (r 8) 2, (r 8) 2n (c 1-c 6) alkyl ,-s (o) mr 8, r 8s (o) m (c 1-c 6) alkyl ,-nhcor 8, r 8conh (c 1-c 6) alkyl ,-cor 8, r 8co (c 1-c 6) alkyl ,-conh 2, h 2nco (c 1-c 6) alkyl ,-conhr 8, r 8nhco (c 1-c 6) alkyl ,-con (r 8) 2, (r 8) 2nco (c 1-c 6) alkyl ,-conh (c 1-c 6) alkyl co 2r 8, r 8o 2c (c 1-c 6) alkyl nhco (c 1-c 6) alkyl ,-conr 8(c 1-c 6) alkyl co 2r 8, r 8o 2c (c 1-c 6) alkyl nr 8co (c 1-c 6) alkyl ,-co 2r 9a, r 9ao 2c (c 1-c 6) alkyl, aryl, virtue (c 1-c 6) alkyl, virtue (c 1-c 6) alkoxyl group or virtue (c 1-c 6) alcoxyl (c 1-c 6) alkyl substituent; r 9abe 2,3-indanyl, phenyl, c 1-c 12alkyl, c 2-c 12alkenyl or c 2-c 12alkynyl group, described c 1-c 12alkyl, c 2-c 12alkenyl and c 2-c 12alkynyl group randomly just like the front to r 9the substituting group of those definition defineds, and described phenyl randomly has 1～3 substituting group, each substituting group all is independently selected from c 1-c 6alkyl, hydroxyl ,...
칼륨 채널 개방제로서의 벤조피란(Benzopyranes as Potassium Channel Openers)본 발명은 하기 일반식(I)의 화합물 및 그의 제약적으로 허용되는 염에 관한 것이다. 식 중 점선은 임의의 공유 결합을 나타내고; X는 0, NH, S 또는 직접 결합하며, R3는 점선이 공유 결합을 나타내지 않을 때 히드록시이고, 점선이 공유 결합일 때 존재하지 않으며, R4는 (a) X가 O일 때, 하기 일반식(i)의 기이고,(b)X가O, NH 또는 S일 때, 임의 치환된 히드록시 페닐이며, (c)임의 치환된 4-내지 7원 헤테로시클릭 고리이거나, 또는(d) X가NH일 때, 하기 일반식(ii)의 기이다. 본 발병의 화합물은 평활근의 긴장 또는 운동성의 변화와 관련되는 질병에 치료에 유용하다.하기 일반식(I)의 호합물 또는 그의 제약학적으로 허용되는 염. [이미지]상기 식에서, 점선은 임의의 공유 결합을 나타내고; X는 O, NH, S 또는 직접 결합이며; R 및 R1은 각기 독립적으로 H, 플루오르(C1-C4)알킬 및 C1-C4알칼에서 선택되거나, 또는 물이 함께 C2-C5알킬렌을 나타내고;R2 H 또는 C1-C4알킬이며; R3는 점선이 공유 결합을 나타내지 않을 때 히드록시이고, 점선이 공유 결합을 나타낼 때 존재하지 않으며; R4는 (a)X가 0일 때, 하기 일반식 [이미지]의 기 (여기서, W 및 W1은 둘이 함께 C1-C4알킬렌을 나타내며, 아 알킬렌은 W 및 W1이 함께 C2-C4알킬렌을 나타낼 때 임의로 벤조 융합되며 벤조 융합된 부분을 포함하여 C1-C4알킬, 히드록시, -OR8, 할로, -N(R8)2, -SR8, 할로(1-C4)알킬로 ㅇㅁ의 치환된 히드록시페닐, (C) 1 내지 3개의 N 헤테로 원자 또는 1개의 헤테로 원자와 1개의 0 또는 S 헤테로 원자를 함유하는 4- 내지 7-원 헤테로시클릭 고리 (이 고리는 임의로 벤조융합 또는 C3-C7시클로알킬 융합되며, 벤조 융합 또는 C3-C7시클로알킬 융합된 부분을 포함하여, C1-C6알킬, 히드록시, 히드록시(C1-C4)알킬, -OR8,R8O(C1-C4)알킬, 할로, 할로(C1-C4)알킬, -S(O)mR8, R8S(O)m(C1-C4)알킬, 옥소 N-시아노이미노, 아미노, 아미노(C1-C4)알킬, -NH8,R6NH(C1-C4)알킬, -N(R8)2N(C1-C4)알킬, -CO2R8, R8O2C(C1-C4)알킬, -CONH2, H2NCO(C1-C4)알킬, -CONHCO(C1-C4)알킬, -CON(R8)2또는 (R8)2NCO(C1-C4)알킬로 임의 치환됨), 또는 적합한 경우 상기 헤테로시클릭 고리의 N-옥사이드 또는 S-옥사이드 유도체 고리 (단, X가 O, NH 또는 S일 때 상기 헤테로시클릭 고리는 고리 탄소 원자에 의해 결합됨), 또는(d) X 가 NH일때, 하기일반식 [이미지] 의기(여기서, R6은 -OR8, -NHR8, -SR8, -NH(아릴) 또는 -NH(피리디닐)이며, R7은 시아노, 니트로 또는 C2-C6알카노일임)이고; R5는 아릴, C1-C12알킬, C2-C12알케닐 또는 C2-C12알키닐이며, 여기서 C1-C12알킬, C2-C12알케닐 또는 C2-C12알키닐은 C4-C7시클로알킬, 히드록시, -OR8, C2-C6알카노일옥시, 할로, 시아노, 니트로, 아미노, -NHR8, -N(R8)2, -S(O)mR8, -NHSO2R8, -NHCOR8,-COR8,-CONH2, -CONHR8, -CON(R8)2,-OCO2R8, -CONH(C1-C6)알킬CO2R8,-CONR8(C1-C6)알콕시카르보닐, 프탈이미도, 또는 하기 일반식 의 기로 임의 치환되며; R8은 C1-C6알킬이고; R9은 인다닐, 아릴 C1-C12알킬, C1-C12알케닐 또는 C2-C12알키닐이며, 여기서C1-C12알킬, C2-C12알키닐은 C4-C7시클로알킬, 히드록시, -OR8,C2-C6알카노일옥시, 할로, 시아노, 니트로, 아미노, NHR8, -N(R8)2 -S(O)mR8, -NHSO2R8, -NHCOR8, -COR8, -CONHR8, -CON(R8)2-OCO2R8, -CONH(C1-C6)알킬CO2R8, -CONR8(C1-C6)알킬CO2R8, -CO2(C1-C12알킬),아릴, 아릴옥시, 아릴카르보닐, 아릴카르보닐옥시, 아릴(C1-C6)알콕시, 아릴(C1-C6)알콕시카르보닐, 프탈이미도 또는 하기 일반식 [이미지] 기로 임의 치화뇌며; R5,R6 및 R9의 정의 및 본 정의에서 사용되는 "아릴"은 C1-C6알킬, C2-C6알케닐, C2-C6알키닐, 히드록시, 히드록시(C1-C6)알키닐, 히드록시, 히드록시(C1-C6)알킬, -OR8,R8O(C1-C6)알킬, R8O(C1-C6)알콕시, R8O(C1-C6)알콕시(C1-C6)알킬, 할로, 할로(C1-C6)알킬, 시아노, 시아노(C1-C6알킬, 니트로, 니트로(C1-C6)알킬, 아미노, 아미노(C1-C6)알킬, -NHR8,R8NH(C1-C6)알킬, -N(R8)2, (R8)2, (R8)2N(C1-C6)알킬, -S(O)mR8, R8S(O)m(C1-C6)알킬, -NHCHR8, R8CONH(C1-C6)알킬, -COR8,R8CO(C1-C6)알킬, -CONH2 H2NCO(C1-C6),알킬,-CONHR8,R8NHCO(C1-C6),알킬, -CON(R8)2, (R8)2NCO(C1-C6)알킬, -CONH(C1-C6)알킬, CO2-R8, R8O2C(C1-C6)알킬NHCO(C1-C6)알킬, -CONR8(C1-C6)알킬, CO2R8, R8O2C(C1-C6)알킬,NR8CO(C1-C6)알킬, -CO2R9A,R9A02C(C1-C6-알킬),아릴,아릴(C1-C6)알킬, 아릴(C1-C6)알콕시 또는 아릴(C1-C6)알콕시(C1-C6)알킬로 임의 치환된 페닐을 의미하고; R9A는 인다닐, 페닐, C1-C12알킬, C2-C12알케닐 또는 C2-C12알키닐이며, 여기서 상기C2-C12알킬,C2-C12알케닐 또는 C2-C12알키닐은 R9에 대해 상기 정의한 바와 같이 임의 치환되며, 상기 페닐은 C1-C6알킬, 히드록시, -OR8, 할로, 할로(C1-C)6알킬, 니트로 및 시아노에서 각기 독립적으로 선택된 1 내지 3개의 치환기로 임의 치환되고; m은 0.1 또는 2이며, n은 1,2 또는 3이다.