公开(公告)号：EP0301692A2

公开(公告)日：1989-02-01

申请号：EP88305388.6

申请日：1988-06-13

申请人： MERCK FROSST CANADA INC.

发明人： Adams, Julian ,  Belanger, Patrice C. ,  Rokach, Joshua ,  Guindon, Yvan ,  Belly, Michel L.

IPC分类号： C07D307/06 ,  C07D407/06 ,  C07D407/04 ,  C07D407/12 ,  A61K31/34 ,  A61K31/36

CPC分类号： C07D407/06 ,  C07D307/86

摘要： 4,7-Benzofurandione derivatives of Formula I, pharmaceutical compositions, and methods of treatment are disclosed. These compounds are useful as inhibitors of mammalian leukotriene biosynthesis. As such, these compounds are useful therapeutic agents for treating allergic conditions, asthma, cardio­vascular disorders, inflammation, psoriasis and allergic conjunctivitis. The compounds are also useful as analgesics and as cytoprotective agents. Also disclosed are novel intermediates useful for the preparation of the 4,7-benzofurandiones of this invention.

摘要翻译： 公开了式I的4,7-苯并呋喃二酮衍生物，药物组合物和治疗方法。 这些化合物可用作哺乳动物白三烯生物合成的抑制剂。 因此，这些化合物是治疗过敏性疾病，哮喘，心血管疾病，炎症，牛皮癣和过敏性结膜炎的有用的治疗剂。 这些化合物也可用作止痛剂和细胞保护剂。 还公开了可用于制备本发明的4,7-苯并呋喃二酸的新型中间体。 v

公开(公告)号：EP0338782A1

公开(公告)日：1989-10-25

申请号：EP89303838.0

申请日：1989-04-18

申请人： MERCK FROSST CANADA INC.

发明人： Belanger, Patrice C. ,  Rokach, Joshua ,  Scheigetz, John

IPC分类号： C07D307/78 ,  C07D333/52 ,  C07D405/06 ,  A61K31/34 ,  A61K31/38

CPC分类号： C07D307/79 ,  C07D307/80 ,  C07D307/81 ,  C07D307/86 ,  C07D333/54 ,  C07D333/56 ,  C07D405/06 ,  C07D409/06 ,  C07D417/06 ,  C07D493/04 ,  C07F9/65517

摘要： Benzofuran derivatives are useful as inhibitors of mammalian leuktoriene biosynthesis. As such, these compounds are useful therapeutic agents for treating allergic conditions, asthma, cardiovascular disorders, inflammation. The compounds are also useful as analgesics and as cytoprotective agents, and for these uses are made into pharmaceutical compositions. The compounds of the invention have the formula
wherein:

each R 1 is independently hydrogen or C 1 to C 6 alkyl;
R 2 is hydrogen, C 1 to C 8 alkyl, -(CH 2 ) n -het-Y, -(CH 2 ) n -Q or - CH- Q, C H 3 where Q is

R3 is hydroxyl,
, OCOCH 2 CH 2 COOH, OSO 3 H, or OPO 3 H 2 ; each R 4 is independently C 1 to C 6 alkyl;
each R 5 is independently H, C 1 to C 6 alkyl, or both R 5 s join to form a 5- or 6-membered ring with the N to which they are attached;
Het is a heterocyclic group selected from pyridine, pyrazine, pyrimidine, oxazole, pyrazole, oxadiazole, tetrazole, quinoline, thiophene, furan, pyrrole, thiazole, thiadiazole, or imidazole;
X is 0, S, SO, SO 2 ;
Y, Y 1 , Y 2 , Y 3 , Y 4 and Z are each independently H, halogen, OH.
C 1 to C 6 alkyl, C 2 to C 6 alkenyl, C 1-6 hydroxyalkyl, -COOR 1 , -COR 1 , nitro, carboxy (C 1-6 alkyl), C 1 to C 6 alkoxy, C 1 to C 6 alkylthio, -CH 2 SR 1 , OCH 2 CO 2 R 1 ,

and each n is independently 0 to 10; with the provisos that:

(a) not all of R 1 , R 2 , Y, Y 1 , Y 2 , Y 3 , Y 4 , and Z are simultaneously H;
(b) when up to 2 of R 1 , R 2 , Y, Y 1 , and Z are C 1 to C 2 alkyl, and the others of R 1 , R 2 , Y, Y 1 , and Z are H, then R 3 is not OH; and
(c) when n in
is O and one of R 3 , Y, Y 1 or Z is OH, then R i is not H or C i to C 2 alkyl; or are acid-addition salts thereof.

摘要翻译： 苯并呋喃衍生物可用作哺乳动物白念珠菌生物合成的抑制剂。 因此，这些化合物是治疗过敏性疾病，哮喘，心血管疾病，炎症的有用的治疗剂。 这些化合物也可用作止痛剂和作为细胞保护剂，并且将这些用途制成药物组合物。 本发明的化合物具有式CHEM，其中：每个R 1独立地是氢或C 1至C 6烷基; R 2是氢，C 1至C 8烷基， - （CH 2）n - het-Y， - （CH 2）n Q或 - @ @ Q，其中Q是 R 3是羟基， -R 1，O - ， - OR 4，OCOCH 2 CH 2 COOH，OSO 3 H或OPO 3 H 2; 每个R 4独立地为C 1 -C 6烷基; 每个R 5独立地为H，C 1至C 6烷基，或两个R 5连接以与它们所连接的N形成5-或6-元环; Het是选自吡啶，吡嗪，嘧啶，恶唑，吡唑，恶二唑，四唑，喹啉，噻吩，呋喃，吡咯，噻唑，噻二唑或咪唑的杂环基。 X是O，S，SO，SO2; Y，Y 1，Y 2，Y 3，Y 4和Z各自独立地为H，卤素，OH。 C1〜C6烷基，C2〜C6烯基，C1-6羟烷基，-COOR1，-COR1，硝基，羧基（C1-6烷基），C1〜C6烷氧基，C1〜C6烷硫基，-CH2SR1 ，OCH 2 CO 2 R 1，CHEM，各n独立地为0〜10; 条件是：（a）不是全部R 1，R 2，Y，Y 1，Y 2，Y 3，Y 4和Z同时为H; （b）当R 2最多2个时，R 2，Y，Y 1和Z分别是C 1〜C 2烷基，R 1，R 2，Y，Y <1>，Z为H，则R 3不为OH; 和（c）当中的n为O且R 3，Y，Y 1中的一个或Z为OH时，R 1不为H或C 1至C 2烷基; 或其酸加成盐。 ÿ

公开(公告)号：EP0252639A1

公开(公告)日：1988-01-13

申请号：EP87305526.3

申请日：1987-06-22

申请人： MERCK FROSST CANADA INC.

发明人： Belanger, Patrice C. ,  Fortin, Rejean ,  Guindon, Yvan ,  Rokach, Joshua ,  Yoakim, Christiane

IPC分类号： C07C149/40 ,  C07C149/36 ,  C07C147/14 ,  C07C147/10 ,  C07C149/415 ,  A61K31/19

CPC分类号： C07C323/00 ,  C07C317/00

摘要： Compounds of the Formulae:
and
are antagonists of leukotrienes of C 4 , D 4 and E 4 , the slow reacting substance of anaphylaxis. These compounds are useful as anti-asthmatic, anti-allergic, anti-inflammatory, and cytoprotective agents.

摘要翻译： 下式化合物：是C4，D4和E4的白三烯，慢性过敏反应物质的拮抗剂。 这些化合物可用作抗哮喘，抗过敏，抗炎和细胞保护剂。

公开(公告)号：EP0140709A3

公开(公告)日：1986-03-05

申请号：EP84307480

申请日：1984-10-30

申请人： MERCK FROSST CANADA INC.

发明人： Atkinson, Joseph G. ,  Belanger, Patrice C. ,  Guindon, Yvan ,  Rokach, Joshua

IPC分类号： A61K31/54 ,  A61K31/535 ,  A61K31/495 ,  C07D513/04 ,  C07D498/04 ,  C07D513/16 ,  C07D241/18 ,  C07D279/00 ,  C07D241/00

CPC分类号： C07D513/04 ,  A61K31/495 ,  A61K31/535 ,  A61K31/54 ,  C07D241/18

摘要： Compounds of the Formula I:
and their pharmaceutically acceptable salts are inhibitors of the mammalian 5-lipoxygenase enzyme system of the arachidonic acid cascade. As such, these compounds are useful therapeutic agents for treating allergic conditions, asthma, cardiovascular disorders and inflammation and are incorporated into pharmaceutical compositions. Certain of the compounds are novel. In the formula,
Z is O, NCN, SO or SO 2 ; R, is H, C 1-6 alkyl, benzyl, C 1-6 acyl, C 1-6 aminoacyl, (C 1-6 alkylacyloxy)-(C 1-6 alkyl), (C 1-6 alkoxy)-(C 1-6 alkyl), -(CH 2 ) n COOR 6 where n is, 0, 1, 2, 3 or 4, CN, (C 1-6 alkyl)acyloxy-(C 1-6 alkoxy)carbonyl, -C(R 7 ) = C(R 7 )COOR 6 or SO 2 R 10 ; each of R 2 , R 3 , R 4 and R 5 , independently of the others, is hydrogen, C 1-6 alkyl, C 2-6 alkenyl or -(CH 2 ) n M, where n is 0 or an integer from 1 to 6 and M is(a) OR 16 (b) halogen; (c) CF 3 . (d) SR 16 ; (e) phenyl; (f) substituted phenyl where the substituents(s) is/are C 1-3 alkyl, halogen, CN, C 1-3 alkoxy, OH, (CH 2 ) n NR 8 R 9 where n is 0, 1 or 2, CF 3 , COOR 6 or CH 2 COOR 6 ; (herein called «substituted phenyl as defined»); (g) COOR 6 ; (h) -CO-R 14 ; (i) tetrazolyl; (j) NH-CO-R 7 ; (k) NR 8 R 9 ; (I) NHSO 2 R 10 ; (m) -CO-CH 2 0H; (n) SOR 11 where R 11 is C 1-6 alkyl, phenyl, substituted phenyl as defined, (CH 2 ) m COOR 6 , where m is an integer from 1 to 6, or CF 3 ; (o) CONR 8 R 9 ; (p) SO 2 NR 8 R 9 ; (q) S0 2 R 13 where R 13 is OH, C 1-6 alkyl, H phenyl, substituted phenyl as defined, (CH 2 ) m COOR 6 or CF 3 ; (r) N0 2 ; (s) -OCO-R 14 ; (t) -OCO-NR 8 R 9 ; (u)-OCO-OR 7 ; or (v) -CN; each R 16 , independently of any other, is H; (C 1-6 alkoxy)-(C 1-6 alkyl); (C 1-6 alkyl)acyloxy(C 1-6 alkyl); C 1-6 alkyl; substituted phenyl as defined; -CH 2 ) m COOR 6 ; CN: C 1-5 alkylacyl; C 1-4 perfluoroalkyl; phenyl; benzyl; or CH 2 -R 12 where R 12 is C 1-5 alkyldimethylamino; each R 6 , independently of any other, is H, C 1-6 alkyl, benzyl or phenyl; each R 14 , independently of any other, is H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl)acyloxy(C 1-6 alkoxy), (CH 2 ) n COOR 6 where n is 0 or an integer from 1 to 4, phenyl or substituted phenyl as defined or is such that R 14 COOH is an essential amino acid; each of R 8 and R 9 , independently of the others, is H, phenyl, substituted phenyl as defined or C 1-4 alkyl, or NR 8 R 9 is a heterocycloalkyl of 5 to 8 ring atoms; and each R 7 , independently of the others, is H, C 1-6 alkyl, benzyl, phenyl or (C 1-6 alkyl)acyloxy-(C 1-6 alkoxy); each R 10 is independently OH, C 1-6 alkyl, C 1-6 alkoxy, phenyl or p-tolyl; or any two of R,, R 2 , R 3 , R 4 or R 5 are joined to form an additional ring of 5 to 7 members that optionally contains a carbonyl group and/or a hydroxyl group as substituent(s), and that has 0, 1 or 2 double bonds, and such that, if R, is a constituent of the ring, one member is nitrogen and the others are carbon and if R 1 is not a constituent of the ring, all the members are carbon; and T is hydrogen or OR 15 where R 15 is hydrogen, C 1-6 alkyl, C 1-6 alkylacyl, phenyl-(C 1-8 alkyl)acyl, SO 2 R 10 , arylsulfonyl, -CO-phenyl or substituted phenyl as defined.

摘要翻译： 式I化合物及其药学上可接受的盐是花生四烯酸级联的哺乳动物5-脂氧合酶系统的抑制剂。 这样，这些化合物是用于治疗过敏性疾病，哮喘，心血管疾病和炎症的有用的治疗剂，并且被掺入到药物组合物中。 某些化合物是新颖的。 在该式中，Z是O，NCN，SO或SO 2; （C1-6烷基） - （C1-6烷基），（C1-6烷氧基） - （C1-6烷基），（C1-6烷基） - （C1-6烷基） - （CH 2）n COOR 6其中n是0,1,2,3或4，CN，（C 1-6烷基）酰氧基 - （C 1-6烷氧基）羰基，-C（R 7）= C（R 7）COOR 6或 SO 2 R; R 2，R 3，R 4和R 5各自独立地为氢，C 1-6烷基，C 2-6烯基或 - （CH 2）n M，其中n为0或1至6的整数，且M为（a ）OR16（b）卤素; （c）CF3。 （d）SR16; （e）苯基; （f）其中取代基为C 1-3烷基，卤素，CN，C 1-3烷氧基，OH，（CH 2）n NR 8 R 9，其中n为0,1或2，CF 3，COOR 6或CH 2 COOR 6的取代的苯基; （在此称为“定义的取代苯基”）; （g）COOR6; （h）-CO-R14; （i）四唑基; （j）NH-CO-R7; （k）NR8R9; （I）NHSO2R10; （m）-CO-CH 2 OH; （n）SOR11，其中R11是C1-6烷基，苯基，如所定义的取代的苯基，（CH2）mCOOR6，其中m是1至6的整数，或CF3; （o）CONR8R9; （p）SO2NR8R9; （q）SO 2 R 13，其中R 13是OH，C 1-6烷基，H苯基，如所定义的取代的苯基，（CH 2）m COOR 6或CF 3; （r）NO 2; （s）-OCO-R14; （t）-OCO-NR 8 R 9; （U）-OCO-OR7; 或（v）-CN; 每个R16独立于任何其他，是H; （C 1-6烷氧基） - （C 1-6烷基）; （C 1-6烷基）酰氧基（C 1-6烷基）; C 1-6烷基; 如定义的取代的苯基; -CH 2）mCOOR6; CN：C 1-5烷基酰基; C1-4全氟烷基; 苯基; 苄基; 或CH 2 -R 12，其中R 12是C 1-5烷基二甲基氨基; 每个R6彼此独立地为H，C1-6烷基，苄基或苯基; 每个R 14彼此独立地为H，C 1-6烷基，C 1-6烷氧基，C 1-6烷基）酰氧基（C 1-6烷氧基），（CH 2）n COOR 6，其中n为0或1至4的整数， 苯基或取代的苯基，或者是这样的，即R 14 COOH是必需氨基酸; R8和R9中的每一个相互独立地为H，苯基，如所定义的取代的苯基或C1-4烷基，或NR8R9为具有5至8个环原子的杂环烷基; 并且每个R 7相互独立地为H，C 1-6烷基，苄基，苯基或（C 1-6烷基）酰氧基 - （C 1-6烷氧基）; 每个R 10独立地为OH，C 1-6烷基，C 1-6烷氧基，苯基或对甲苯基; 或者R 1，R 2，R 3，R 4或R 5中的任意两个连接形成另外的5至7元环，其任选地含有羰基和/或羟基作为取代基，并且具有0,1 或2个双键，并且如果R 1是环的组分，则一个成员是氮并且其他是碳，并且如果R 1不是环的组成部分，则所有成员都是碳; 和T是氢或OR 15，其中R 15是氢，C 1-6烷基，C 1-6烷基酰基，苯基 - （C 1-8烷基）酰基，SO 2 R 10，芳基磺酰基，-CO-苯基或取代的苯基。

公开(公告)号：EP0140709B1

公开(公告)日：1991-04-03

申请号：EP84307480.8

申请日：1984-10-30

申请人： MERCK FROSST CANADA INC.

发明人： Atkinson, Joseph G. ,  Belanger, Patrice C. ,  Guindon, Yvan ,  Rokach, Joshua

IPC分类号： A61K31/54 ,  A61K31/535 ,  A61K31/495 ,  C07D513/04

CPC分类号： C07D513/04 ,  A61K31/495 ,  A61K31/535 ,  A61K31/54 ,  C07D241/18

公开(公告)号：EP0106565B1

公开(公告)日：1986-09-10

申请号：EP83305587.4

申请日：1983-09-21

申请人： MERCK FROSST CANADA INC.

发明人： Belanger, Patrice C. ,  Fortin, Rejean ,  Guindon, Yvan ,  Rokach, Joshua ,  Yoakim, Christiane

IPC分类号： C07C149/40 ,  C07C147/14 ,  C07C147/107 ,  C07C59/90 ,  C07C59/64 ,  C07C51/347 ,  A61K31/19

CPC分类号： C07C255/00 ,  C07C45/46 ,  C07C45/71 ,  C07C49/84 ,  C07C59/90 ,  C07C317/00 ,  C07C323/00

公开(公告)号：EP0165810A2

公开(公告)日：1985-12-27

申请号：EP85304382.6

申请日：1985-06-19

申请人： MERCK FROSST CANADA INC.

发明人： Belanger, Patrice C. ,  Scheigetz, John ,  Rokach, Joshua

IPC分类号： C07D307/79 ,  C07D405/06 ,  C07D409/06 ,  C07D417/06 ,  C07D333/54 ,  A61K31/34 ,  A61K31/38 ,  A61K31/47 ,  A61K31/40 ,  A61K31/44 ,  A61K31/41

CPC分类号： C07D307/79 ,  C07D307/80 ,  C07D307/81 ,  C07D307/86 ,  C07D333/54 ,  C07D333/56 ,  C07D405/06 ,  C07D409/06 ,  C07D417/06 ,  C07D493/04 ,  C07F9/65517

摘要： Novel benzofuran compounds have the formula
in which

each R 1 is independently hydrogen or C 1 to C 6 alkyl;
R 2 is hydrogen, C, to C 6 alkyl, -(CH 2 ) n -Het-Y, or

R 3 is hydroxyl,

OS0 3 H, or OP0 3 H 2 ; each R 4 is independently C 1 to C 6 alkyl; each R 5 is independently H, C, to C 6 alkyl, or both R 5 s join to form a 5- or 6-membered ring with the N to which they are attached; Het is a heterocyclic group selected from pyridine, pyrazine, pyrimidine, oxazole, pyrazole, oxadiazole, tetrazole, quinoline, thiophene, furan, pyrrole, thiazole, thiadiazole, or imidazole;
X is O, S, SO, SO 2 ;
Y, Y 1 , Y 2 , Y 3 , Y 4 and Z are each independently H, halogen, OH.
C 1 to C 6 alkyl, C 2 to C 6 alkenyl,
-COOR 1 , -COR 1 , nitro,
C 1 to C 6 alkoxy, C 1 to C 6 alkylthio,
-CH 2 SR 1 , OCH 2 CO 2 R 1 ,

and each n is independently 0 to 10; with the provisos that:
(a) not all of R 1 , R 2 , Y, Y 1 , Y 2 , Y 3 , Y 4 , and Z are simultaneously H;
(b) when up to 2 of R 1 , R 2 , Y, Y 1 , and Z are C 1 to C 2 alkyl, and the others of R 1 , R 2 , Y, Y', and Z are H, then R3 is not OH; and
(c) when n in
is O and one of R 3 , Y, Y 1 or Z is OH, then R 1 is not H or C 1 to C 2 alkyl.

Their pharmaceutically acceptable salts are also novel. These compounds are useful as inhibitors of mammalian leukotriene biosynthesis and are therefore useful therapeutic agents for treating allergic conditions, asthma, cardiovascu-Iar disorders, inflammation. The compounds are also useful as analgesics and as cytoprotective agents. They are made into pharmaceutical compositions for such uses.

摘要翻译： 新颖苯并呋喃化合物具有下式其中各R <1>是unabhängig氢或C1-C6烷基; [R <2>为氢，C1-C6烷基， - （CH 2）N -Het-Y，或每个R <4>独立地是C1-C6烷基; 每个R <5>是unabhängigH，C1-C6烷基，或两个R <5>取值加入，以形成与它们所连接的N个5-或6-元环; Het为选自吡啶，吡嗪，嘧啶，恶唑，吡唑，中选出的杂环基恶二唑，四唑，喹啉，噻吩，呋喃，吡咯，噻唑，噻二唑或咪唑; X是O，S，SO，SO 2; Y，Y <1>，Y <2>，Y <3>，Y <4>和Z各自独立地为H，卤素，OH。 C1-C6烷基，C2至C6链烯基，COOR <1>，-COR <1>，硝基，C1至C6烷氧基，C1至C6烷硫基， - CH 2 SR <1>，OCH2CO2R <1>，并且每个 n是unabhängig0至10; 但条件是：（a）不是所有的R <1>，R <2>，Y，Y <1>，Y <2>，Y <3>，Y <4>，和Z同时为H; （B）当达到的R 2 <1>，R <2>，Y，Y <1>，和Z是C 1至C 2烷基，且R <1>，R <2>，Y，Y的其他 <1>，和Z为H时，则R <3>不为OH; 和（c）当n在是O且R中的一个<3>，Y，Y <1>或Z为OH，则R <1>不是H或C1到C2的烷基。 因此，它们的phamaceutically上可接受的盐是新的。 这些化合物可用作哺乳动物白细胞三烯生物合成的抑制剂，并因此适用于治疗过敏性疾病，哮喘，心血管疾病，炎症有用的治疗剂。 所述化合物因此作为止痛药和作为细胞保护剂是有用的。 它们制作成搜索用途的药物组合物。

公开(公告)号：EP0106565A1

公开(公告)日：1984-04-25

申请号：EP83305587.4

申请日：1983-09-21

申请人： MERCK FROSST CANADA INC.

发明人： Belanger, Patrice C. ,  Fortin, Rejean ,  Guindon, Yvan ,  Rokach, Joshua ,  Yoakim, Christiane

IPC分类号： C07C149/40 ,  C07C147/14 ,  C07C147/107 ,  C07C59/90 ,  C07C59/64 ,  C07C51/347 ,  A61K31/19

CPC分类号： C07C255/00 ,  C07C45/46 ,  C07C45/71 ,  C07C49/84 ,  C07C59/90 ,  C07C317/00 ,  C07C323/00

摘要： Compounds of the formulae:

and their pharmaceutically acceptable (including acid- addition) salts, which are novel, are antagonists of leukotrienes of C 4 , D 4 and E 4 , the slow reacting substance of anaphylaxis. They can be made into pharmaceutical compositions by incorporating them in a pharmaceutical carrier.
In the formulae, each R is H, OH, SH, C, 6 alkyl, C 2 .B 6 alkenyl, CF 3 , C, 6 alkoxy, C, 6 alkylthio, phenyl, phenyl having C, 3 alkyl or halogen substitution, benzyl, phenethyl, halogen, amino, N(R 4 ) 2 , COOR 4 or CH 2 OR 4 where R 4 is H or C, 6 alkyl, formyl, CN, CF 3 S or NO 2 ;

each R' is R 4 ; OR 4 ; COOR 4 ; N(R 4 ) 2 ; SR 4 ; CH 2 OR 4 or CHO; or together R' and R' are O, CH 2 or

Y' is sulfur, sulfoxide, sulfone,
= NR 12 , = N - CO - R 3 ,- N - CN. CH 2 or C = O where R 11 is H, C 1-4 alkyl, C 1-4 4 alkanoyl, phenylsulfonyl or p-totuenesutfonyt, R 12 is H or C 1-4 alkyl and R 13 is C 1-4 alkyl or C 1-4 alkoxy;
Y is of the type defined for Y' or oxygen;
each R, is hydrogen or C 1-3 alkyl; each m is 0 or an integer from 1 to 6;
where each R 6 is H or C 1-4 alkyl; each R 7 is H, OH or C 1-4 alkyl; and each R 8 is H or C 1-4 alkyl and is absent when the two indicated carbons are triply bonded;
R 5 is COOR 4 ; CH 2 0H, CHO: tetrazole; NHSO 2 R 14 ; CON-HSO 2 R 14 ; hydroxymethylketone; CN; CON(R 7 ) 2 ; a monocyclic or bicyclic heterocyclic ring containing an acidic hydroxyl group; or COOR, s where R, 5 is:
where each s is independently 0-3. R 6 is as defined above and R 16 is

(A) a monocyclic or bicyclic heterocyclic radical containing from 3 to 12 nuclear carbon atoms and 1 or 2 N heteroatoms or one N and one S heteratom, each ring in the heterocyclic radical being formed of 5 or 6 atoms, or
(B) W-R 17 where W is 0, S or NH and R 17 contains up to 21 carbon atoms and is (1) a hydrocarbon radical or (2) an acyl radical or an organic acyclic or monocyclic carboxylic acid containing not more than 1 heteroatom in the ring;

each of r and q is 0-20 but r + q does not exceed 20; and
p is 0 or 1;
R 3 is C 1-6 alkyl or C 3-6 alkenyl;
R 9 is C, 1-6 alkyl, C, 6 alkoxy or (CN 2 ) r R 5 , where r and R 5 are as defined above; and
R 10 is H, C 1-6 alkyl; R 4 CO- or R 4 OCH 2 , where R 4 is as defined above and R 14 is OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 acyl, phenyl, phenyl having C 1-3 alkyl or C 1-3 alkoxy substitution, halogen, halogenated alkyl, carboxy, cyano or formyl.

摘要翻译： 下式的化合物及其药学上可接受的（包括酸加成的）盐是新颖的，它们是C4，D4和E4（即过敏反应的缓慢反应物质）的白三烯的拮抗剂。 它们可以通过将它们掺入药物载体制成药物组合物。 在式中，每个R为H，OH，SH，C 1-6烷基，C 2-6链烯基，CF 3，C 1-6烷氧基，C 1-6烷硫基，苯基，具有C 1-3烷基或卤素取代基的苯基，苄基， ，卤素，氨基，N（R4）2，COOR4或CH2OR4，其中R4是H或C1-6烷基，甲酰基，CN，CF3S或NO2; 每个R'是R4; OR 4; COOR4; N（R 4）2; SR4; CH2OR4或CHO; 或一起R'和R'是O，CH2或Y'是硫，亚砜，砜，= NR12，= N-CO-R3，-N-CN。 CH2或C = O，其中R11为H，C1-4烷基，C1-4烷酰基，苯磺酰基或对甲苯磺酰基，R12为H或C1-4烷基，R13为C1-4烷基或C1-4烷氧基; Y是为Y'或氧定义的类型; 每个R 1是氢或C 1-3烷基; 每个m为0或1至6的整数; 其中每个R 6是H或C 1-4烷基; 每个R 7是H，OH或C 1-4烷基; 并且每个R 8是H或C 1-4烷基并且当两个指定的碳被三重键合时不存在; R5是COOR4; CH 2 OH，CHO：四唑; NHSO2R14; CON-HSO2R14; hydroxymethylketone; CN; CON（R7）2; 含有酸性羟基的单环或双环杂环; 或COOR，其中R，5是：其中每个s独立地是0-3。 R6如上所定义且R16为（A）含有3-12个核碳原子和1或2个N杂原子或一个N和一个杂原子的单环或双环杂环基团，杂环基团中的每个环由5或 （B）W-R17，其中W是O，S或NH，并且R17含有至多21个碳原子，并且是（1）一种烃基或（2）一种酰基或一种有机无环或单环羧酸， 环中不超过1个杂原子; r和q各为0-20，但r + q不超过20; 并且p是0或1; R3是C1-6烷基或C3-6链烯基; R9是C1-6烷基，C1-6烷氧基或（CN2）rR5，其中r和R5如上所定义; 和R 10是H，C 1-6烷基; R 4 CO-或R 4 OCH 2，其中R 4如上所定义且R 14是OH，C 1-6烷基，C 1-6烷氧基，C 1-6酰基，苯基，具有C 1-3烷基或C 1-3烷氧基取代基的苯基，卤素，卤代烷基 ，羧基，氰基或甲酰基。

公开(公告)号：EP0165810A3

公开(公告)日：1986-06-25

申请号：EP85304382

申请日：1985-06-19

申请人： MERCK FROSST CANADA INC.

发明人： Belanger, Patrice C. ,  Scheigetz, John ,  Rokach, Joshua

IPC分类号： C07D307/79 ,  C07D405/06 ,  C07D409/06 ,  C07D417/06 ,  C07D333/54 ,  A61K31/34 ,  A61K31/38 ,  A61K31/47 ,  A61K31/40 ,  A61K31/44 ,  A61K31/41

CPC分类号： C07D307/79 ,  C07D307/80 ,  C07D307/81 ,  C07D307/86 ,  C07D333/54 ,  C07D333/56 ,  C07D405/06 ,  C07D409/06 ,  C07D417/06 ,  C07D493/04 ,  C07F9/65517

摘要： Novel benzofuran compounds have the formula
in which
each R 1 is independently hydrogen or C 1 to C 6 alkyl; R 2 is hydrogen, C, to C 6 alkyl, -(CH 2 ) n -Het-Y, or
R 3 is hydroxyl,
OS0 3 H, or OP0 3 H 2 ; each R 4 is independently C 1 to C 6 alkyl; each R 5 is independently H, C, to C 6 alkyl, or both R 5 s join to form a 5- or 6-membered ring with the N to which they are attached; Het is a heterocyclic group selected from pyridine, pyrazine, pyrimidine, oxazole, pyrazole, oxadiazole, tetrazole, quinoline, thiophene, furan, pyrrole, thiazole, thiadiazole, or imidazole; X is O, S, SO, SO 2 ; Y, Y 1 , Y 2 , Y 3 , Y 4 and Z are each independently H, halogen, OH. C 1 to C 6 alkyl, C 2 to C 6 alkenyl, -COOR 1 , -COR 1 , nitro, C 1 to C 6 alkoxy, C 1 to C 6 alkylthio, -CH 2 SR 1 , OCH 2 CO 2 R 1 , and each n is independently 0 to 10; with the provisos that: (a) not all of R 1 , R 2 , Y, Y 1 , Y 2 , Y 3 , Y 4 , and Z are simultaneously H; (b) when up to 2 of R 1 , R 2 , Y, Y 1 , and Z are C 1 to C 2 alkyl, and the others of R 1 , R 2 , Y, Y', and Z are H, then R3 is not OH; and (c) when n in
is O and one of R 3 , Y, Y 1 or Z is OH, then R 1 is not H or C 1 to C 2 alkyl. Their pharmaceutically acceptable salts are also novel. These compounds are useful as inhibitors of mammalian leukotriene biosynthesis and are therefore useful therapeutic agents for treating allergic conditions, asthma, cardiovascu-Iar disorders, inflammation. The compounds are also useful as analgesics and as cytoprotective agents. They are made into pharmaceutical compositions for such uses.

公开(公告)号：EP0104885A1

公开(公告)日：1984-04-04

申请号：EP83305588.2

申请日：1983-09-21

申请人： MERCK FROSST CANADA INC.

发明人： Belanger, Patrice C. ,  Fortin, Rejean ,  Guindon, Yvan ,  Rokach, Joshua ,  Yoakim, Christiane

IPC分类号： C07C149/40 ,  C07C147/14 ,  C07C147/107 ,  C07D317/14 ,  C07D233/78 ,  C07D207/404 ,  C07D303/02 ,  C07C59/90 ,  A61K31/19 ,  C07C59/64 ,  C07C51/347

CPC分类号： C07D207/26 ,  C07C45/71 ,  C07C59/90 ,  C07C317/00 ,  C07C323/00 ,  C07D207/33 ,  C07D233/74 ,  C07D257/04 ,  C07D307/58 ,  C07D317/34 ,  C07C49/84

摘要： Compounds of the formulae:

and their pharmaceutically acceptable (including acid- addition) salts, which are novel, are antagonists of leukotrienes of C 4 , D 4 and E 4 , the slow reacting substance of anaphylaxis. They can be made into pharmaceutical compositions by incorporating them in a pharmaceutical carrier.
In the formulae, each R is H, OH, SH, C 1-8 alkyl, C 2-8 alkenyl, CF 3 , C 1-8 alkoxy, C 1-8 alkylthio, phenyl, phenyl having C 1-3 alkyl or halogen substitution, phen (C 2-4 alkyl), halogen, amino, N(R 4 ) 2 , COOR 4 or CH 2 OR 4 where R 4 is H or C 1-8 alkyl, formyl, CN, CF 3 S or NO 2 ;
each R' is R 4 ; OR 4 ; COOR 4 ; N(R 4 ) 2 ; SR 4 ; CH 2 OR 4 orCHO; , or together R' and R' are 0, CH 2 or
Y is oxyge, sulfur, sulfoxide, sulfone,
= NR 12 , = N - CO - R 13 or - N - CN, where R 11 is C 1-4 alkyl, R 12 is H or C 1-4 atkyl and R 13 is C 1-4 alkyl or C 1-4 alkoxy;

Y' is Y,
each R 1 is hydrogen or C 1-3 alkyl; each m is an integer from 0 to 6;
R 2 is
where Z is O. S, CH 2 , H and OH, C 1-4 alkenyl, or = N - R 14 , where R 14 is OH, CN, COOH, halogen, formyl, C 1-8 acyl, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 halogenated alkyl, phenyl, or phenyl having C 1-3 alkyl or C 1-3 alkoxy substitution; each R e is H or C 1-4 alkyl; each R 7 is H, OH or C 1-4 alkyl; each R 8 is H or C 1-4 alkyl and is absent when the two indicated carbons are triply bonded;
R 5 is COOR 4 ; CH 2 OH; CHO; tetrazole; NHSO 2 R 14 ; CON-HSO 2 R 14 hydroxymethylketone; CN; CON(R 7 ) 2 ; a monocyclic or bicyclic heterocyclic ring containing an acidic hydroxyl group; or COOR 15 where R 15 is:
where each s is independently 0-3, R 6 is as defined above and R 16 is

(A) a monocyclic or bicyclic heterocyclic radical containing from 3 to 12 nuclear carbon atoms and 1 or 2 N heteroatoms or one N and one S heteratom, each ring in the heterocyclic radical being formed of 5 or 6 atoms, or
(B) W-R 17 where W is O, S or NH and R 17 contains up to 21 carbon atoms and is (1) a hydrocarbon radical or (2) an acyl radical or an organic acyclic or monocyclic carboxylic acid containing not more than 1 heteroatom in the ring;

each of r and q is 0-20 but r + q does not exceed 20; and
p is 0 or 1;
R 3 is C 1-6 alkyl or C 3-8 alkenyl;
R 9 is C 1-8 alkyl, C 1-8 alkoxy or (CH 2 ) r R 5 , where r and R s are as defined above: and
R 10 is H, C 1-8 alkyl; R 4 CO- or R 4 OCH 2 , where R 4 is as defined above.

The compounds are prepared by condensing together two compounds having appropriately substituted benzene rings, one of which contains a halogen atom in the chain containing Y and Y', which removes a hydrogen atom from the ring of the other compound.

摘要翻译： 下列化合物：及其药学上可接受的（包括酸加成）盐，它们是C4，D4和E4的白三烯拮抗剂，其是过敏反应的缓慢反应物质。 它们可以通过将其并入药物载体中而制成药物组合物。 式中，R为H，OH，SH，C 1-6烷基，C 2-6烯基，CF 3，C 1-6烷氧基，C 1-6链炔基，苯基，具有C1-3烷基或卤素取代基的苯基，苯基（C2 -4烷基），卤素，氨基，N（R4）2，COOR4或CH2OR4，其中R4是H或C1-6烷基，甲酰基，CN，CF3S或NO2; 每个R 1是R 4; OR 4; COOR4; N（R 4）2; SR4; CH2OR4或CHO; 或R 1和R 2分别为O，CH 2或CH 2 Y，是氧，硫，亚砜，砜，= NR 11，= NR 12，= N-CO-R 13或-N-CN，其中R 11为C 1-4 烷基，R 12为H或C 1-4烷基，R 13为C 1-4烷基或C 1-4烷氧基; Y min为Y，-CH 2 - 或 - 每个R 1是氢或C 1-3烷基; 每个m是0至6的整数; 其中Z是O，S，CH2，H和OH，C1-4链烯基或= N-R14，其中R14是OH，CN，COOH，卤素，甲酰基，C1-6酰基，C1-6烷基， C 1-6烷氧基，C 1-6卤代烷基，苯基或具有C 1-3烷基或C 1-3烷氧基取代基的苯基; 每个R 6是H或C 1-4烷基; 每个R 7是H，OH或C 1-4烷基; 每个R 8为H或C 1-4烷基，当两个表示的碳原子键合时不存在; R5为COOR4; CH2OH; CHO; 四唑; NHSO2R14; CONHSO2R14羟甲基酮; CN; CON（R7）2; 含有酸性羟基的单环或双环杂环; 或COOR 15，其中R 15为：其中各s独立地为0-3，R 6如上所定义，R 16为（A）含有3至12个核碳原子和1或2个N杂原子的单环或双环杂环基，或 一个N和一个S杂原子，杂环基中的每个环由5或6个原子形成，或（B）W-R 17，其中W是O，S或NH，R 17含有最多21个碳原子，并且是（1）a 烃基或（2）环中含有不超过1个杂原子的酰基或有机酰基或单环羧酸; r和q各自为0-20，但r + q不超过20; p为0或1; R3是C1-6烷基或C3-6烯基; R 9是C 1-6烷基，C 1-6烷氧基或（CH 2）r R 5，其中r和R 5如上所定义; R 10为H，C 1-6烷基; R4CO-或R4OCH2，其中R4如上所定义。 通过将具有适当取代的苯边缘的两种化合物冷凝在一起制备化合物，其中一个在含有Y和Ymin的链中含有卤素原子，其从另一种化合物的环除去氢原子。