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    Conjugates of leukotrienes with proteins
    2.
    发明公开
    Conjugates of leukotrienes with proteins 失效
    枸橼酸钠。

    公开(公告)号：EP0179959A1

    公开(公告)日：1986-05-07

    申请号：EP84307569.8

    申请日：1984-11-02

    申请人： MERCK FROSST CANADA INC. ,  Merck & Co., Inc.

    发明人： Hayes, Edward C. ,  Rokach, Joshua ,  Young, Robert N.

    IPC分类号： C07K15/00 ,  C07K5/02 ,  C07C109/093 ,  A61K37/02 ,  C07C103/173 ,  G01N33/531

    CPC分类号： C07K5/0606 ,  A61K38/00 ,  A61K47/62 ,  A61K47/643 ,  C07C243/00 ,  C07D207/416 ,  C07D207/456 ,  C07D309/30 ,  C07K1/1077 ,  C07K14/00 ,  C07K16/18 ,  C07K17/06 ,  G01N33/531 ,  G01N33/60 ,  G01N33/88

    摘要： Leukotrienes B 4 , C 4 , D 4 and E 4 are conjugated with various proteins, viz. Bovine Serum Albumin, Hemocyanin from Giant Keyhole Limpets, human serum albumin, tetanus antigen, diphtheriae toxoid and CRM 197 using 1,5-difluoro-2,4-dinitrobenzene or 6-N-maleimido(C 2-8 alkanoic acid)-chloride as coupling agent.
    These conjugates are useful as reagents in a newly developed immunoassay for leukotrienes, as well as having potential utility as chemical immunotherapeutic agents in the treatment of various allergic and chronic inflammatory diseases of the skin, lung, and airways, including asthma, allergic rhinitis, rheumatoid arthritis, and skin diseases such as psoriasis and eczema. They may be made into pharmaceutical compositions.
    Certain novel intermediate compounds are also provided.

    摘要翻译： 白三烯B4，C4，D4和E4与各种蛋白质缀合， 使用1,5-二氟-2,4-二硝基苯或6-N-马来酰亚胺（C 2-8链烷酸）氯化物的牛血清白蛋白，来自巨孔锁孔的血蓝蛋白，人血清白蛋白，破伤风抗原，白喉类毒素和CRM 197 偶联剂。 这些缀合物可用作新开发的白三烯免疫测定中的试剂，以及作为化学免疫治疗剂用于治疗皮肤，肺和气道的各种过敏性和慢性炎性疾病，包括哮喘，过敏性鼻炎，类风湿病 关节炎和皮肤疾病如牛皮癣和湿疹。 它们可以制成药物组合物。 还提供某些新的中间体化合物。

    4,7-Benzofurandione derivatives
    5.
    发明公开
    4,7-Benzofurandione derivatives 失效
    4,7- Benzofurandion衍。

    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

    Leukotriene antagonists
    7.
    发明公开
    Leukotriene antagonists 失效
    白三烯拮抗剂

    公开(公告)号：EP0140684A3

    公开(公告)日：1986-07-23

    申请号：EP84307390

    申请日：1984-10-26

    申请人： MERCK FROSST CANADA INC.

    发明人： Frenette, Richard ,  Rokach, Joshua ,  Young, Robert N. ,  Kakushima, Masatoshi

    IPC分类号： C07C69/738 ,  C07C59/90 ,  C07D307/93 ,  C07C149/40 ,  C07C147/14 ,  A61K31/34 ,  A61K31/35 ,  A61K31/215 ,  C07C149/437

    CPC分类号： C07D307/93 ,  C07C59/90 ,  C07C317/00 ,  C07C323/00

    摘要： Compounds having the formula:
    and their salts, including acid-addition salts, are novel. These compounds are antagonists of leukotrienes of C 4 , D 4 and E 4 , the slow reacting substance of anaphylaxis. The compounds are useful as anti-asthmatic, anti-allergic, anti-inflammatory and cytoprotective agents and are made into suitable pharmaceutical compositions.
    In the formula, each R, independently of the other(s), is H, OH or OR 2 , or C(R) 2 represents C=C(R 4 ) 2 ; R 1 is H, OH, acyl, formyl, R 5 CO; or R 5 OCO; each of R 2 and R 3 , independently of the others, is H, OH, C 1-6 alkyl, C 2-6 alkenyl, trifluoromethyl, C 1-6 alkoxy, SH, C 1-6 thioalkyl, phenyl, phenyl having C 1-3 alkyl halogen substitution, benzyl, phenethyl, halogen, amino, N(R 4 ) 2 , COOR 4 , CH 2 0R 4 , formyl, CN, trifluoromethylthio or nitro; .each of X 1 and X 2 , independently of the other, is oxygen, sulfur, sulfoxide, sulfone, -SO=NR 5 , NR e , N-CO-R 7 , N-CN or NCONHR 6 ; each of R 4 and R 6 , independently of the other(s), is H or C 1-6 alkyl; each R 5 is C 1-6 alkyl; each R 7 , independently of the other, if any, is C 1-6 alkyl or C 1-6 alkoxy; W is H or C 1-6 alkyl or is combined with Y to form an unsaturated bond; Z is H, OH or C 1-6 alkoxy, or is combined with Y to form an oxo residue; Y, of not combined with Z or W, is hydrogen; A is -[C(R 4 ) 2]s- R 8 where S is 0,1, 2, or 3 and R 8 isCOOR 4 , CH 2 0H, CHO, tetrazolyl, NHSO 2 R 9 , CONHSO 2 R 9 , hydroxymethylketone, CN, CON(R 7 ) 2 , a monocyclic heterocyclic ring containing an acidic hydroxyl group, or
    where each s, independently, of the others, is 0, 1, 2 or 3 and R 10 is (A) a monocyclic or bicyclic radical containing from 3 to 12 nuclear carbon atoms and, as nuclear heteroatoms, two Ns or one N and one S, and with each ring in the heterocyclic radical being formed of 5 or 6 atoms, or (B) the radical X'-R 11 where X' is O, S or NH and R 11 contains up to 21 carbon atoms and is a hydrocarbon radical or an acryl radical of an organic acyclic or monocyclic carboxylic acid containing not more than 1 heteroatom in the ring; each n, independently of the others, is 0,1, or 3; R 9 is OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 perfluoroalkyl, phenyl, or phenyl having one or more R 2 substituents.

    摘要翻译： 具有下式的化合物及其盐包括酸加成盐是新颖的。 这些化合物是C4，D4和E4白三烯拮抗剂，即过敏反应的缓慢反应物质。 这些化合物可用作抗哮喘剂，抗过敏剂，抗炎剂和细胞保护剂，并制成合适的药物组合物。 在该式中，每个R独立于其它的一个或多个是H，OH或OR 2，或C（R）2表示C = C（R 4）2; R1是H，OH，酰基，甲酰基，R5CO; 或R5OCO; R2和R3各自独立地为H，OH，C1-6烷基，C2-6链烯基，三氟甲基，C1-6烷氧基，SH，C1-6硫代烷基，苯基，具有C1-3烷基卤素取代基的苯基 ，苄基，苯乙基，卤素，氨基，N（R 4）2，COOR 4，CH 2 OR 4，甲酰基，CN，三氟甲硫基或硝基; 每个X1和X2相互独立地为氧，硫，亚砜，砜，-SO = NR5，NRe，N-CO-R7，N-CN或NCONHR6; R 4和R 6中的每一个独立于另一个或多个，为H或C 1-6烷基; 每个R5是C1-6烷基; 如果有的话，每个R7独立于另一个是C1-6烷基或C1-6烷氧基; W是H或C 1-6烷基或与Y结合形成不饱和键; Z是H，OH或C 1-6烷氧基，或者与Y结合形成氧代残基; 未与Z或W结合的Y是氢; A是 - [C（R 4）2] s -R 8其中S是0,1,2或3且R 8是COOR 4，CH 2 OH，CHO，四唑基，NHSO 2 R 9，CONHSO 2 R 9，羟甲基酮，CN，CON（R 7）2，单环 含有酸性羟基的杂环，或其中每一个独立地为其它的为0,1,2或3，且R 10为（A）含有3至12个核碳原子的单环或双环基团，并且作为核 杂原子，两个N或一个N和一个S，并且杂环基团中的每个环由5或6个原子形成，或（B）基团X'-R11，其中X'是O，S或NH且R11含有 至21个碳原子并且是环中含有不超过1个杂原子的有机无环或单环羧酸的烃基或丙烯酰基; 每个n彼此独立地为0,1或3; R9是OH，C1-6烷基，C1-6烷氧基，C1-6全氟烷基，苯基或具有一个或多个R2取代基的苯基。

    Benzo[a]phenothiazines and hydro-derivatives and pharmaceutical compositions containing them
    8.
    发明公开
    Benzo[a]phenothiazines and hydro-derivatives and pharmaceutical compositions containing them 失效
    苯并咪唑和水解衍生物及含有它们的药物组合物

    公开(公告)号：EP0136893A3

    公开(公告)日：1985-05-08

    申请号：EP84306641

    申请日：1984-09-28

    申请人： MERCK FROSST CANADA INC.

    发明人： Fortin, Rejean ,  Girard, Yves ,  Guindon, Yvan ,  Lau, Cheuk K. ,  Rokach, Joshua ,  Yoakim, Christiane

    IPC分类号： A61K31/54 ,  A61K31/535 ,  C07D279/36 ,  C07D265/34 ,  C07F09/65

    CPC分类号： C07F9/6547 ,  A61K31/535 ,  A61K31/54 ,  C07D265/34 ,  C07D279/36

    摘要： Pharmaceutical compositions contain a compound for the Formula
    or a pharmaceutically acceptable salt thereof. Certain compounds of Formula I are novel. Compounds of Formula I are useful in treating allergic conditions, asthma, cardrovascular disorders, inflammation and pain and are useful as cytoprotective agents.
    In Formula 1. X is O, S, SO or SO 2 ; R, is H; C,- 6 alkyl; C, - 6 acyl; C 1-6 aminoacyl; (C 1-6 acyloxy)-(C 1-6 alkyl); (C 1-6 alkoxy)-(C l - 6 alkyl); benzoyl; substituted benzoyl in which the substitution in the phenyl ring (herein called "substituted as herein defined") is halogen, C 1-3 alkyl, C 1-3 alkoxy, CN, CF 3 , COOR 6 , OH, CH 2 COOR 6 or (CH 2 ) n NR 8 R 9 where n is 0, 1 or 2; carbamoyl; CONHR 7 ; COOR 7 ; p-toluenesulfonyl; methane sulfonyl; or an acyl group such that R,-OH is an essential amino acid; 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; -(CHR 6 ) p COOR 6 , p being 0 or an integer from 1 to 4; or -(CH 2 ) m M where m is 0 or an integer from 1 to 6 and M is (a) OR, s ; (b) halogen; (c) CF 3 ; (d) SR 15 ; (e) phenyl or substituted phenyl as herein defined; (f) COOR 6 ; (g) CO-R 14 ; (h) tetrazolyl; (i) -NH-CO-R 7 ; (j) -NR 8 R 9 ; (k) -NHSO 2 R 10 where R 10 is OH, C 1-6 alkyl, C 1-6 alkoxy, or phenyl; (I) -COCH 2 0H; (m) -SOR 11 where R 11 is C 1-6 alkyl; phenyl; substituted phenyl as herein defined; (CH 2 ) m COOR 6 ;CN; formyl or C 1-4 perfluoroalkyl; (n) -CONR 8 R 9 ; (o) -SO 2 NR 8 R 9 ; (p) -SO 2 R 13 where R 13 is a hydrogen atom or a radical of the type defined for R 11 ; (q) NO 2 ; (r) O-CO-R 14 ; (s) O-CO-NR 8 R 9 ; (t) -CN; or (u) -OPO(OR 6 ) 2 : each R 6 , independently of any other, is H, phenyl or C 1-6 alkyl; each R 7 , independently of any other, is C 1-6 alkyl, benzyl, phenyl or (C 1-6 acyloxyl-(C 1-6 alkyl); each R 8 and each R 9 , independently of any other, is phenyl, substituted phenyl as herein defined, or C 1-4 alkyl, or NR 8 R 9 represents a heterocycloalkyl radical of 5 to 8 ring atoms; each R 14 , independently of any other, is H. (CH 2 ) p COOR 6 , C, 6 alkyl, C 1-6 alkoxy, (C 1-6 acyloxy)-(C 1-6 alkoxy), phenyl, substituted phenyl as herein defined, or C, -6 aminoalkyl, or R 14 is such that R 14 CO 2 H is an essential amino acid; R 15 is H, (C 1-6 alkoxy)-(C 1-6 alkyl), (C, 6 acyloxyl-(C 1-6 alkyl), C 1-6 alkyl, benzyl, -(CH 2 ) m COOR 6 , CN, formyl, C 1-4 perfluoroalkyl, CH 2 -R 12 where R 12 is C 1-5 alkyldimethylamino or phenyl, phenyl, or substituted phenyl as herein defined; the broken lines in ring A represent optional double bonds; R 2 , R 3 , R 4 and R 5 may be positioned anywhere in the structure.