Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders
AssigneeCytomed, Inc.
InventorsXiong Cai, Aberra Fura, Changgeng Qian
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Abstract
Tetrahydrofurans, tetrahydrothiophenes, pyrrolidines and cyclopentanes are disclosed that reduce the chemotaxis and respiratory burst leading to the formation of damaging oxygen radicals of polymorphonuclear leukocytes during an inflammatory or immune response. It has been determined that 5-lipoxygenase activity, oral availability, and stability in vivo (for example, glucuronidation rate) can vary significantly among the optical isomers of the disclosed compounds.
Claims22
A compound of formula:
- ##STR30## wherein:
- Ar is an aryl or heteroaryl group that is optionally substituted with halo, lower alkoxy, lower aryloxy, W, cyano, or R.sup.3 ;
- m is 0 or 1;
- n is 1-6;
- W is independently --AN(OM)C(O)N(R.sup.3)R.sup.4, --N(OM)C(O)N(R.sup.3)R.sup.4, --AN(R.sup.3)C(O)N(OM)R.sup.4, --N(R.sup.3)C(O)N(OM)R.sup.4, --AN(OM)C(O)R.sup.4, --N(OM)C(O)R.sup.4 --, AC(O)N(OM)R.sup.4, --C(O)N(OM)R.sup.4, --C(O)NHA;
- A is lower alkylene, lower alkenylene, lower alkynylene, alkylarylene or aryl alkylene, or a hetero derivative thereof, wherein one or more carbons optionally can be replaced by O, N, or S (with valence completed with hydrogen or oxygen as necessary), however, --Y--A--, --A--, and --AW-- must not include two adjacent heteroatoms;
- M is hydrogen, a pharmaceutically acceptable cation, or a metabolically cleavable leaving group;
- X is O, S, S(O), S(O).sub.2, NR.sup.3, or CHR.sup.5 ;
- Y is O, S, S(O), S(O).sub.2, NR.sup.3, or CHR.sup.5 ;
- Z is O, S, S(O), S(O).sub.2, NR.sup.3 ;
- R.sup.1 and R.sup.2 are independently hydrogen, lower alkyl, cyclopropylmethyl, ethyl, isopropyl, butyl, pentyl hexyl, and C.sub.3-8 cycloalkyl, for example, cyclopentyl;
- halo lower alkyl, halo;
- or --COOH;
- R.sup.3 and R.sup.4 are independently hydrogen or alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, C.sub.1-6 alkoxy-C.sub.1-10 alkyl, C.sub.1-6 alkylthio-C.sub.1-10 alkyl, heteroaryl, or heteroarylalkyl-;
- R.sup.5 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, arylalkyl, alkylaryl, --AN(OM)C(O)N(R.sup.3)R.sup.4, --AN(R.sup.3)C(O)N(OM)R.sup.4, --AN(OM)C(O)R.sup.4, --AC(O)N(OM)R.sup.4, --AS(O)xR.sup.3, --AS(O).sub.x H.sub.2 C(O)R.sup.3, --AS(O)xCH.sub.2 CH(OH)R.sup.3, or --AC(O)NHR.sup.3 ;
- wherein x is 0-2.
A compound selected from the group consisting of 2S,5S-trans-2-(4-fluorophenoxymethyl)-5-(4-protectedoxy-1-butynyl)tetrahyd rofuran and 2S,5R-cis-2-(4-fluorophenoxymethly)-5-(4-protectedoxy-1-butynyl) tetrahydr ofuran.
Dependencies are inferred from the claim text.