US 5,314,900 AGranted

Aryl thiopyrano[2,3,4-C,D]indoles as inhibitors of leukotriene biosynthesis

AssigneeMerck Frosst Canada, Inc.

InventorsYves Girard, John H. Hutchinson, Michel Therien, Daniel Delorme

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Abstract

Compounds having the formula I: ##STR1## are inhibitors of 5-lipoxygenase and inhibitors of leukotriene biosynthesis. These compounds are useful as anti-asthmatic, anti-allergic, anti-inflammatory, and cytoprotective agents. They are also useful in treating angina, cerebral spasm, glomerular nephritis, hepatitis, endotoxemia, psoriasis, uveitis, and allograft rejection and in preventing the formation of atherosclerotic plaques.

Claims9

Dependent claims

A compound of the formula:

##STR13## wherein the substituents are as follows:
______________________________________ EX. NO. R.sup.4 Z (CR.sup.2 R.sup.3).sub.m Y(CR.sup.2 R.sup.3).sub. n ______________________________________ 1 4-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 S 2 3-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 S 3 4-FC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 S 4 4-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 S 5 4-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 O 6 4-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 O 7 4-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 O 8 4-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 O 9 4-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 O 10 4-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 S 11 3-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 O 12 3-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 O 13 4-FC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 O 14 4-FC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 O 15 3-Cl-4FC.sub.6 H.sub.3 CH.sub.2 CH.sub.2 O 16 C.sub.6 H.sub.5 CH.sub.2 O 17* 3-(C.sub.5 H.sub.7 O)C.sub.6 H.sub.4 CH.sub. 2 CH.sub.2 O 18 4-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 OCH.sub.2 19 4-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 OCH.sub.2 20 4-ClC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 OCH.sub.2 21 4-ClC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 S 22 4-ClC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 O 23 4-C;C.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 O 24 4-ClC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 O 25 4-ClC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 O 26 4-ClC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 O 27 3-ClC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 O 28 4-ClC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 S 29 4-ClC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 O 30 4-ClC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 O 31 4-ClC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 O 32 3-ClC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 O 33 3-ClC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 O (-)-enantiomer 34 3-ClC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 O (+)-enantiomer 35 4-FC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 O 36 4-FC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 O (-)-enantiomer 37 4-FC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 O (+)-enantiomer 38 4-FC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 O 39 3-FC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 O 40 4-ClC.sub.6 H.sub.4 CH.sub.2 S 41 4-ClC.sub.6 H.sub.4 CH.sub.2 S 42 4-ClC.sub.6 H.sub.4 CH.sub.2 CH.dbd.CH (E&Z isomers) 43 4-ClC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 44 4-ClC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 58 4-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 O (+)-enantiomer 59 4-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 O (-)enantiomer 60 4-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 O (-)enantiomer 61 4-FC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 O (+)enantiomer 62 4-FC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 O (-)enantiomer 63 3-I-4-N.sub.3 C.sub.6 H.sub.3 S(O).sub.2 CH.sub.2 S 64 3-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 O (-)enantiomer 65 3-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 O (+)enantiomer ______________________________________ EX. NO. (CR.sup.2 R.sup.3).sub.p Q ______________________________________ 1 -- CO.sub.2 H, 2 -- CO.sub.2 H, 3 -- CO.sub.2 H, 4 -- CONHS(O).sub.2 Me, 5 CH.sub.2 CO.sub.2 H, 6 CH.sub.2 CONHS(O).sub.2 Me, 7 CH(Me) CO.sub.2 H, 8 CH(Me) CONHS(O).sub.2 Me, 9 CH(Et) CO.sub.2 H, 10 CH.sub.2 CO.sub.2 H, 11 CH.sub.2 CO.sub.2 H, 12 CH(Me) CO.sub.2 H, 13 CH.sub.2 CO.sub.2 H, 14 CH(Me) CO.sub.2 H, 15 CH.sub.2 CO.sub.2 H, 16 CH.sub.2 CO.sub.2 H, 17* CH.sub.2 CO.sub.2 H, 18 -- CO.sub.2 H, 19 -- CN.sub.4 H, 20 -- CN.sub.4 H, 21 -- CO.sub.2 H, 22 -- CO.sub.2 H, 23 -- CONHS(O).sub.2 Me, 24 -- CN.sub.4 H, 25 -- S(O).sub.2 NHCOMe, 26 -- S(O).sub.2 NHCOPh, 27 -- CO.sub.2 H, 28 CH.sub.2 CO.sub.2 H, 29 CH.sub.2 CO.sub.2 H, 30 CH(Me) CO.sub.2 H, 31 CH(Et) CO.sub.2 H, 32 CH.sub.2 CO.sub.2 H, 33 CH.sub.2 CO.sub.2 H, (-)enantiomer 34 CH.sub.2 CO.sub.2 H, (+)enantiomer 35 CH.sub.2 CO.sub.2 H, 36 CH.sub.2 CO.sub.2 H, (-)enantiomer 37 CH.sub.2 CO.sub.2 H, (+)enantiomer 38 CH(Me) CO.sub.2 H, 39 CH.sub.2 CO.sub.2 H, 40 -- CO.sub.2 H, 41 CH.sub.2 CO.sub.2 H, 42 -- CN.sub.4 H, 43 -- CO.sub.2 H, 44 -- CN.sub.4 H, 58 CH.sub.2 CO.sub.2 H, (+)enantiomer 59 CH.sub.2 CO.sub.2 H, (-)enantiomer 60 CH(Me) CO.sub.2 H, (-)enantiomer 61 CH(Me) CO.sub.2 H, (+)enantiomer 62 CH(Me) CO.sub.2 H, (-)enantiomer 63 -- CO.sub.2 H, 64 CH.sub.2 CO.sub.2 H, or (-)enantiomer 65 CH.sub.2 CO.sub.2 H, (+)enantiomer ______________________________________ *EX 17:
C.sub.5 H.sub.7 O is 2H5,6-dihydropyran-4-yl

Dependencies are inferred from the claim text.

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Abstract

A compound of the formula:

##STR13## wherein the substituents are as follows:
______________________________________ EX. NO. R.sup.4 Z (CR.sup.2 R.sup.3).sub.m Y(CR.sup.2 R.sup.3).sub. n ______________________________________ 1 4-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 S 2 3-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 S 3 4-FC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 S 4 4-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 S 5 4-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 O 6 4-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 O 7 4-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 O 8 4-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 O 9 4-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 O 10 4-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 S 11 3-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 O 12 3-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 O 13 4-FC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 O 14 4-FC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 O 15 3-Cl-4FC.sub.6 H.sub.3 CH.sub.2 CH.sub.2 O 16 C.sub.6 H.sub.5 CH.sub.2 O 17* 3-(C.sub.5 H.sub.7 O)C.sub.6 H.sub.4 CH.sub. 2 CH.sub.2 O 18 4-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 OCH.sub.2 19 4-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 OCH.sub.2 20 4-ClC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 OCH.sub.2 21 4-ClC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 S 22 4-ClC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 O 23 4-C;C.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 O 24 4-ClC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 O 25 4-ClC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 O 26 4-ClC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 O 27 3-ClC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 O 28 4-ClC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 S 29 4-ClC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 O 30 4-ClC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 O 31 4-ClC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 O 32 3-ClC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 O 33 3-ClC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 O (-)-enantiomer 34 3-ClC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 O (+)-enantiomer 35 4-FC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 O 36 4-FC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 O (-)-enantiomer 37 4-FC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 O (+)-enantiomer 38 4-FC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 O 39 3-FC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 O 40 4-ClC.sub.6 H.sub.4 CH.sub.2 S 41 4-ClC.sub.6 H.sub.4 CH.sub.2 S 42 4-ClC.sub.6 H.sub.4 CH.sub.2 CH.dbd.CH (E&Z isomers) 43 4-ClC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 44 4-ClC.sub.6 H.sub.4 CH.sub.2 (CH.sub.2).sub.2 58 4-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 O (+)-enantiomer 59 4-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 O (-)enantiomer 60 4-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 O (-)enantiomer 61 4-FC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 O (+)enantiomer 62 4-FC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 O (-)enantiomer 63 3-I-4-N.sub.3 C.sub.6 H.sub.3 S(O).sub.2 CH.sub.2 S 64 3-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 O (-)enantiomer 65 3-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 O (+)enantiomer ______________________________________ EX. NO. (CR.sup.2 R.sup.3).sub.p Q ______________________________________ 1 -- CO.sub.2 H, 2 -- CO.sub.2 H, 3 -- CO.sub.2 H, 4 -- CONHS(O).sub.2 Me, 5 CH.sub.2 CO.sub.2 H, 6 CH.sub.2 CONHS(O).sub.2 Me, 7 CH(Me) CO.sub.2 H, 8 CH(Me) CONHS(O).sub.2 Me, 9 CH(Et) CO.sub.2 H, 10 CH.sub.2 CO.sub.2 H, 11 CH.sub.2 CO.sub.2 H, 12 CH(Me) CO.sub.2 H, 13 CH.sub.2 CO.sub.2 H, 14 CH(Me) CO.sub.2 H, 15 CH.sub.2 CO.sub.2 H, 16 CH.sub.2 CO.sub.2 H, 17* CH.sub.2 CO.sub.2 H, 18 -- CO.sub.2 H, 19 -- CN.sub.4 H, 20 -- CN.sub.4 H, 21 -- CO.sub.2 H, 22 -- CO.sub.2 H, 23 -- CONHS(O).sub.2 Me, 24 -- CN.sub.4 H, 25 -- S(O).sub.2 NHCOMe, 26 -- S(O).sub.2 NHCOPh, 27 -- CO.sub.2 H, 28 CH.sub.2 CO.sub.2 H, 29 CH.sub.2 CO.sub.2 H, 30 CH(Me) CO.sub.2 H, 31 CH(Et) CO.sub.2 H, 32 CH.sub.2 CO.sub.2 H, 33 CH.sub.2 CO.sub.2 H, (-)enantiomer 34 CH.sub.2 CO.sub.2 H, (+)enantiomer 35 CH.sub.2 CO.sub.2 H, 36 CH.sub.2 CO.sub.2 H, (-)enantiomer 37 CH.sub.2 CO.sub.2 H, (+)enantiomer 38 CH(Me) CO.sub.2 H, 39 CH.sub.2 CO.sub.2 H, 40 -- CO.sub.2 H, 41 CH.sub.2 CO.sub.2 H, 42 -- CN.sub.4 H, 43 -- CO.sub.2 H, 44 -- CN.sub.4 H, 58 CH.sub.2 CO.sub.2 H, (+)enantiomer 59 CH.sub.2 CO.sub.2 H, (-)enantiomer 60 CH(Me) CO.sub.2 H, (-)enantiomer 61 CH(Me) CO.sub.2 H, (+)enantiomer 62 CH(Me) CO.sub.2 H, (-)enantiomer 63 -- CO.sub.2 H, 64 CH.sub.2 CO.sub.2 H, or (-)enantiomer 65 CH.sub.2 CO.sub.2 H, (+)enantiomer ______________________________________ *EX 17:
C.sub.5 H.sub.7 O is 2H5,6-dihydropyran-4-yl