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US 5,093,356 AGranted
Indenyl hydroxamic acids and hydroxy ureas as inhibitors of 5-lipoxygenase
AssigneeMerck Frosst Canada, Inc.
InventorsYves Girard, Pierre Hamel, Daniel Delorme
Life of this patent
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Abstract
Compounds having the formula I: ##STR1## are inhibitors of the 5-lipoxygenase enzyme. These compounds are useful as anti-asthmatic, anti-allergic, anti-inflammatory, and cytoprotective agents. They are also useful in treating diarrhea, hypertension, angina, platelet aggregation, cerebral spasm, premature labor, spontaneous abortion, dysmenorrhea, and migraine.
Claims14
A compound of the formula I:
- ##STR14## wherein:
- R.sup.1 and R.sup.5 are independently:
- a) hydrogen;
- b) lower alkyl;
- R.sup.2 and R.sup.3 are independently
- c) hydrogen;
- d) lower alkyl;
- e) phenyl substituted with c)-d) hereinabove or R.sup.7 ;
- where R.sup.7 is --OR.sup.8, --SR.sup.9, --S(O).sub.2 R.sup.9, --CN, --CO.sub.2 R.sup.8, or halogen;
- wherein R.sup.8 is hydrogen or R.sup.9 ;
- R.sup.9 is lower alkyl;
- f) heteroaryl substituted with c)-d) hereinabove or R.sup.7 ;
- g) lower alkyl monosubstituted with e) to f) hereinabove;
- R4 is hydrogen, lower alkyl, lower alkynyl, lower alkenyl, --OR.sup.8, --C(O)R.sup.8, --NO.sub.2, N(R.sup.8).sub.2, --NR.sup.8 C(O)R.sup.8, --R.sup.10 N(R.sup.8.sub.2), SO.sub.2 N(R.sup.8).sub.2, --SR.sup.9, --R.sup.10 OH, --S(O).sub.2 R.sup.9, --CN, --CO.sub.2 R.sup.8, --CON(R.sup.8).sub.2, halogen, cycloalkyl, --R.sup.10 --halogen, or cycloalkoxy;
- where R.sup.8 and R.sup.9 are defined hereinabove and R.sup.10 is lower alkyl;
- R.sup.6 is hydrogen or OM;
- M is hydrogen, a pharmacetically acceptable cation or --C(O)R.sup.11 ;
- where R.sup.11 is lower alkyl, or phenyl substituted with hydrogen, lower alkyl or R.sup.7 ;
- m is 1 to 4;
- n is 0 or 1;
- p is 0 to 2;
- Z is lower alkyl or NR.sup.12 R.sup.13 ;
- where R.sup.12 is --OM or R.sup.13 ;
- R.sup.13 is hydrogen, lower alkyl or R.sup.12 and R.sup.13 are joined to form a heterocyclic ring of 3 to 6 carbon atoms and 1 or 2 heteroatoms selected from N, S or O, provided that R.sup.12 is --OM when R.sup.6 is hydrogen or n is 0;
- and the dotted line between positions 3 and 3' indicates an optional double bond;
- and the pharmaceutically acceptable salts thereof.
23 more elements
A compound of the formula Ia wherein the substituents are as follows:
- __________________________________________________________________________ ##STR15## Ia [CR.sub.2.sup.5 ].sub.m Y Z R.sup.1 R.sup.2 R.sup.3 R.sup.4 __________________________________________________________________________ CH.sub.2 -- N(OH)CH.sub.3 CH.sub.3 H C.sub.6 H.sub.4 -4-SCH.sub.3 F, (CH.sub.2).sub.2 NOH CH.sub.3 CH.sub.3 H C.sub.6 H.sub.4 -4-SCH.sub.3 F, (CH.sub.2).sub.2 NOH NH.sub.2 CH.sub.3 H C.sub.6 H.sub.4 -4-SCH.sub.3 F, (CH.sub.2).sub.2 NOH NHCH.sub.3 CH.sub.3 H C.sub.6 H.sub.4 -4-SCH.sub.3 F, (CH.sub.2).sub.2 NOH NH(CH.sub.3).sub.3 CH.sub.3 H C.sub.6 H.sub.4 -4-SCH.sub.3 F, CH.sub.2 NH N(OH)CH.sub.3 CH.sub.3 H C.sub.6 H.sub.4 -4-SCH.sub.3 F, (CH.sub.2).sub.2 NOH NH.sub.2 CH.sub.3 H C.sub.6 H.sub.4 -4-S(O)CH.sub.3 F, (CH.sub.2).sub.2 NOH NH.sub.2 CH.sub.3 H C.sub.6 H.sub.4 -4-S(O).sub.2 CH.sub.3 F, CH.sub.2 NOH NH.sub.2 CH.sub.3 H C.sub.6 H.sub.4 -4-SCH.sub.3 F, CHCH.sub.3 NOH NH.sub.2 CH.sub.3 H C.sub.6 H.sub.4 -4-SCH.sub.3 F, (CH.sub.2).sub.3 NOH NH.sub.2 CH.sub.3 H C.sub.6 H.sub.4 -4-SCH.sub.3 F, (CH.sub.2).sub.4 NOH NH.sub.2 CH.sub.3 H C.sub.6 H.sub.4 -4-SCH.sub.3 F, (CH.sub.2).sub.2 NOH NH.sub.2 H C.sub.6 H.sub.4 -4-SCH.sub.3 H H, -(CH.sub.2).sub.2 NOH NH.sub.2 H C.s ub.4 H.sub.3 O* H H or (CH.sub.2).sub.2 NOH NH.sub.2 H C.sub.4 H.sub.3 S** H H __________________________________________________________________________ *2-FURYL **2-THIENYL.
A compound of the Formula Ib:
- ##STR16## wherein:
- R.sup.3 is:
- a) hydrogen;
- b) lower alkyl;
- c) phenyl substituted with a)-b) hereinabove or R.sup.7 ;
- where R.sup.7 is --OR.sup.8, --SR.sup.9, --S(O).sub.2 R.sup.9, --CN, --CO.sub.2 R.sup.8, or halogen;
- wherein R.sup.8 is hydrogen or R.sup.9 ;
- R.sup.9 is lower alkyl;
- d) heteroaryl substituted with c)-d) hereinabove or R.sup.7 ;
- e) lower alkyl monosubstituted with c) to d) hereinabove.
7 more elements
A compound of the Formula Ic:
- ##STR17## wherein:
- R.sup.1 is:
- a) hydrogen;
- b) lower alkyl;
- R.sup.3 is:
- c) hydrogen;
- d) lower alkyl;
- e) phenyl substituted with c)-d) hereinabove or R.sup.7 ;
- where R.sup.7 is --OR.sup.8, --SR.sup.9, --S(O).sub.2 R.sup.9, --CN, --CO.sub.2 R.sup.8, or halogen;
- wherein R.sup.8 is hydrogen or R.sup.9 ;
- R.sup.9 is lower alkyl;
- f) heteroaryl substituted with c)-d) hereinabove or R.sup.7 ;
- g) lower alkyl monosubstituted with e) to f) hereinabove.
10 more elements
Dependencies are inferred from the claim text.