申请人:MERCK FROSST CANADA INC.
公开号:EP0219308A2
公开(公告)日:1987-04-22
Novel compounds have the formula:
or are pharmaceutically acceptable salts thereof. In the formula:
Y is -(CR²=CR²)n-, -(C≡C)n-, -CR²R²-X-, -X-CR²R²-, -CR²R²-X-CR²R²-,
X, C=O, -NR²--, or --NR²-;
R¹ is H, halogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, -CF₃, -OR², -SR², -SOR², -SO₂R², -NR²R², -CHO, -COOR², -(C=O)R², -C(OH)R²R², -CN, -NO₂, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, or substituted or unsubstituted phenethyl;
R² is H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, -CF₃, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, or substituted or unsubstituted phenethyl;
R³ is -(A)m-(CR⁶=CR⁶)p-(CR²R⁴)m-Q;
R⁴ is H, halogen, -NO₂, -CN, -OR², -SR², NR²R², or C1-8 alkyl;
R⁵ is
R⁶ is H or C1-4 alkyl;
R⁷ is A) a monocyclic or bicyclic heterocyclic radical containing from 3 to 12 nuclear carbon atoms and 1 or 2 nuclear heteroatoms from N, S or O, each ring in the hererocyclic radical being formed of 5 or 6 atoms, or
B) the radical W-R⁸;
R⁸ contains up to 21 carbon atoms and is (1) a hydrocarbon radical or (2) an acyl radical of an organic acyclic or monocyclic carboxylic acid containing not more than 1 heteroatom in the ring;
R⁹ is -OR¹⁰, -SR¹⁰, or NR¹⁰R¹⁰;
R¹⁰ is H, C1-6 alkyl, -(C=O)R¹¹, unsubstituted phenyl or unsubstituted benzyl;
R¹¹ is H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, -CF₃, or unsubstituted phenyl, benzyl, or phenethyl;
R¹² is R² or halogen;
m is 0-8;
n is 1 or 2;
p is 0 or 1;
s is 0-3;
A is -CR⁴R⁴-, or =C=O;
Q is -COOR², tetrazole, -COOR⁵, -CONHSO₂R¹¹, -CN, -CONR¹⁰R¹⁰, -NHSO₂R¹¹ (but only when the sum of m, m and P in R³ is greater than 0); or if Q is COOH and R³ contains an R⁴ which is -OH, -SH, or -NHR² then Q and R⁴ and the carbons through which they are attached may form a heterocyclic ring with loss of water;
w is O, S, or NH; and
X is O, S, -SO, -SO₂, or -NR².
The compounds are antagonists of leukotrienes and inhibitors of their biosynthesis and are useful as anti-asthmatic, anti-allergic, anti-inflammatory, and cytoprotective agents.
新型化合物的化学式为
或其药学上可接受的盐类。式中
Y是-(CR²=CR²)n-、-(C≡C)n-、-CR²R²-X-、-X-CR²R²-、-CR²R²-X-CR²R²-、
X、C=O、-NR²-或--NR²-;
R¹ 是 H、卤素、C1-8 烷基、C2-8 烯基、C2-8 炔基、-CF₃、-OR²、-SR²、-SOR²、-SO₂R²、-NR²R²、-CHO、-COOR²、-(C=O)R²、-C(OH)R²R²、-CN、-NO₂、取代或未取代的苯基、取代或未取代的苄基或取代或未取代的苯乙基;
R² 是 H、C1-8 烷基、C2-8 烯基、C2-8 炔基、-CF₃、取代或未取代的苯基、取代或未取代的 苄基、取代或未取代的苯乙基;
R³ 是-(A)m-(CR⁶=CR⁶)p-(CR²R⁴)m-Q;
R⁴ 是 H、卤素、-NO₂、-CN、-OR²、-SR²、NR²R² 或 C1-8 烷基;
R⁵ 是
R⁶ 是 H 或 C1-4 烷基;
R⁷ 是 A) 单环或双环杂环基,含有 3 至 12 个核碳原子和 1 或 2 个来自 N、S 或 O 的核杂原子,杂环基中的每个环由 5 或 6 个原子组成,或
B) 自由基 W-R⁸;
R⁸ 含有多达 21 个碳原子,并且(1)是烃基或(2)是有机无环或单环羧酸的酰基,在环中含有不超过 1 个杂原子;
R⁹ 是-OR¹⁰、-SR¹⁰ 或 NR¹⁰R¹⁰;
R¹⁰ 是 H、C1-6 烷基、-(C=O)R¹¹、未取代苯基或未取代苄基;
R¹¹ 是 H、C1-8 烷基、C2-8 烯基、C2-8 炔基、-CF₃ 或未取代苯基、苄基或苯乙基;
R¹² 是 R² 或卤素;
m 是 0-8
n 是 1 或 2
p 为 0 或 1
s 为 0-3;
A 是-CR⁴R⁴-,或 =C=O;
Q 是-COOR²、四唑、-COOR⁵、-CONHSO₂R¹¹、-CN、-CONR¹⁰R¹⁰、-NHSO₂R¹¹(但仅当 R³ 中 m、m 和 P 之和大于 0 时);或如果 Q 为 COOH 且 R³ 中包含一个-OH、-SH 或-NHR²的 R⁴,则 Q 和 R⁴ 以及连接它们的碳可以形成一个杂环,但会失去水分;
w 是 O、S 或 NH;以及
X 是 O、S、-SO、-SO₂ 或 -NR²。
这些化合物是白三烯的拮抗剂和白三烯生物合成的抑制剂,可用作抗哮喘、抗过敏、抗炎和细胞保护剂。