Substituted phenyl phenol leukotriene antagonists
AssigneeEli Lilly and Company
InventorsS. Richard Baker, Robert D. Dillard, Paul E. Floreancig, J. Scott Sawyer, Michael J. Sofia
Life of this patent
Estimating the term…
Abstract
Antagonists having a substituted phenyl phenol or a substituted phenolic biphenyl structure, and various derivatives thereof, are specific leukotriene antagonists. Their structures, use and synthesis are disclosed. Also, pharmaceutical formulations are disclosed for use in applications treating diseases or conditions characterized by excessive release of leukotriene B.sub.4, one of the metabolites of arachidonic acid. The primary LTB.sub.4 antagonistic structures are represented as: ##STR1##
Claims38
A compound of the formula:
- ##STR94## or a pharmaceutically acceptable base addition salt thereof, wherein:
- R.sub.1 is C.sub.1 -C.sub.5 alkyl, C.sub.2 -C.sub.5 alkenyl, C.sub.2 -C.sub.5 alkynyl, C.sub.1 -C.sub.4 alkoxy, (C.sub.1 -C.sub.4 alkyl)thio, halo, or R.sub.2 -substitutedphenyl;
- each R.sub.2 and R.sub.3 are each independently hydrogen, halo, hydroxy, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, (C.sub.1 -C.sub.4 alkyl)--S(O).sub.q --, trifluoromethyl, or di-(C.sub.1 -C.sub.3 alkyl) amino;
- X is --O--, --S--, --C(.dbd.O), or --CH.sub.2 --;
- Y is --O-- or --CH.sub.2 --;
- or when taken together, --X--Y-- is --CH.dbd.CH-- or --C.tbd.C--;
- Z is a straight or branched chain C.sub.1 -C.sub.10 alkylidenyl;
- A is a bond, --O--, --S--, --CH.dbd.CH--, or CR.sub.a R.sub.b --, where R.sub.a and R.sub.b are each independently hydrogen, C.sub.1 -C.sub.5 alkyl, or R.sub.7 -substitutedphenyl, or when taken together with the carbon atom to which they are attached form a C.sub.4 -C.sub.8 cycloalkyl ring;
- R.sub.4 is R.sub.6, ##STR95## where each R.sub.6 is independently --COOH, 5-tetrazolyl, --CON(R.sub.9).sub.2, or --CONHSO.sub.2 R.sub.10 ;
- each R.sub.7 is hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.5 alkenyl, C.sub.2 -C.sub.5 alkynyl, benzyl, methoxy, --W--R.sub.6, --T--G--R.sub.6, (C.sub.1 -C.sub.4 alkyl)--T-- (C.sub.1 -C.sub.4 alkylidenyl)--O--, or hydroxy;
- R.sub.8 is hydrogen or halo;
- each R.sub.9 is independently hydrogen, phenyl, or C.sub.1 -C.sub.4 alkyl, or when taken together with the nitrogen atom form a morpholino, piperidino, piperazino, or pyrrolidino group;
- R.sub.10 is C.sub.1 -C.sub.4 alkyl or phenyl;
- R.sub.11 is R.sub.2, --W--R.sub.6, or --T--G--R.sub.6 ;
- each W is a bond or straight or branched chain divalent hydrocarbyl radical of one to eight carbon atoms;
- each G is a straight or branched chain divalent hydrocarbyl radical of one to eight carbon atoms;
- each T is a bond, --CH.sub.2 --, --O--, --NH--, --NHCO--, --C(.dbd.O)--, or --S(O)q--;
- K is --C(.dbd.O)-- or --CH(OH)--;
- each q is independently 0, 1, or 2;
- p is 0 or 1;
- and
- t is 0 or 1;
- provided when X is --O-- or --S--, Y is not --O--;
- provided when A is --O-- or --S--, R.sub.4 is not R.sub.6 ;
- and provided W is not a bond when p is 0.
The compound which is 2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]propoxy]phen oxy]benzoic acid or a pharmaceutically acceptable base addition salt thereof.
The compound which is 3(2(3(2ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy)propoxy)-6-(4-carboxyphen oxy)phenyl)propionic acid or a pharmaceutically acceptable base addition salt thereof.
The compound which is 1-(4-(carboxymethoxy)phenyl)-1-(1H-tetrazol-5-yl)-6-(2-ethyl-4-(4-fluoroph enyl)-5-hydroxyphenoxy)hexane or a pharmaceutically acceptable base addition salt thereof.
The compound which is 3-[4-[7-carboxy-9-oxo-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]-p ropoxy]-9H-xanthene]]propanoic acid or a pharmaceutically acceptable base addition salt thereof.
The compound which is 5-[3-[2-(1-carboxy)ethyl]-4-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenox y]propoxy]phenyl]-4-pentynoic acid or a pharmaceutically acceptable base addition salt thereof.
The compound which is 3-(5-(6-(4-(4-fluoro-phenyl)-5-hydroxy-2-ethylphenoxy)propoxy)-2-carboxyme thyl-1,2,3,4-tetrahydronaphthalen-1(2H)-one)propanoic acid or a pharmaceutically acceptable base addition salt thereof.
A pharmaceutical formulation comprising 2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]-propoxy]phe noxy]benzoic acid or a pharmaceutically acceptable base addition salt thereof with a pharmaceutically acceptable carrier.
A pharmaceutical formulation comprising 3-(2-(3-(2-ethyl-4-(4-fluorophenyl)-5-hdyroxyphenoxy)propoxy)-6-(4-carboxy phenoxy)phenyl)propionic acid or a pharmaceutically acceptable base addition salt thereof with a pharmaceutically acceptable carrier.
A pharmaceutical formulation comprising 1-(4-(carboxymethoxyphenyl)-1-(1H-tetrazol-5-yl)-6-(2-ethyl-4-(4-fluorophe nyl)-5-hydroxyphenoxy)hexane or a pharmaceutically acceptable base addition salt thereof with a pharmaceutically acceptable carrier.
A compound of the formula:
- ##STR97## or a pharmaceutically acceptable base addition salt thereof, where
- R.sub.1 is C.sub.1 -C.sub.5 alkyl, C.sub.2 -C.sub.5 alkenyl, C.sub.2 -C.sub.5 alkynyl, C.sub.1 -C.sub.4 alkoxy, (C.sub.1 -C.sub.4 alkyl)thio, halo, or R.sub.2 -substitutedphenyl;
- each R.sub.2 and R.sub.3 are each independently hydrogen, halo, hydroxy, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, (C.sub.1 -C.sub.4 alkyl)--S(O)q--, trifluoromethyl, or di-(C.sub.1 -C.sub.3 alkyl) amino;
- X is --O--, --S--, -C(.dbd.O), or --CH.sub.2 --;
- Y is --O-- or --CH.sub.2 --;
- or when taken together, --X--Y-- is --CH.dbd.CH-- or --C.tbd.C--;
- Z is a straight or branched chain C.sub.1 -C.sub.10 alkylidenyl;
- A is a bond, --O--, --S--, --CH.dbd.CH--, or CR.sub.a R.sub.b --, where R.sub.a and R.sub.b are each independently hydrogen, C.sub.1 -C.sub.5 alkyl, or R.sub.7 -substitutedphenyl, or when taken together with the carbon atom to which they are attached form a C.sub.4 -C.sub.8 cycloalkyl ring;
- R.sub.4 ' is R.sub.6 ', ##STR98## where each R.sub.6 is independently --COOH, 5-tetrazolyl, --CON(R.sub.9).sub.2, --CONHSO.sub.2 R.sub.10, --COOR, or --CN;
- each R.sub.7 is hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.5 alkenyl, C.sub.2 -C.sub.5 alkynyl, benzyl, methoxy, --W--R.sub.6, --T--G--R.sub.6, (C.sub.1 -C.sub.4 alkyl)--T-- (C.sub.1 -C.sub.4 alkylidenyl)--O--, or hydroxy;
- R.sub.8 is hydrogen or halo;
- each R.sub.9 is independently hydrogen, phenyl, or C.sub.1 -C.sub.4 alkyl, or when taken together with the nitrogen atom form a morpholino, piperidino, piperazino, or pyrrolidino group;
- R.sub.10 is C.sub.1 -C.sub.4 alkyl or phenyl;
- R.sub.11 is R.sub.2, --W--R.sub.6, or --T--G--R.sub.6 ;
- each W is a bond or straight or branched chain divalent hydrocarbyl radical of one to eight carbon atoms;
- each G is a straight or branched chain divalent hydrocarbyl radical of one to eight carbon atoms;
- each T is a bond, --CH.sub.2 --, --O--, --NH--, --NHCO--, -C(.dbd.O)--, or --S(O)q--;
- K is --C(.dbd.O)-- or --CH(OH)--;
- each q is independently 0, 1, or 2;
- p is 0 or 1;
- and
- t is 0 or 1;
- provided when X is --O-- or --S--, Y is not --O--;
- provided when A is --O-- or --S--, R.sub.4 ' is not R.sub.6 ';
- provided W is not a bond when p is 0;
- and provided that at least one R.sub.6 ' must be --COOR or --CN.
A compound which is a C.sub.1 -C.sub.6 alkyl ester of 2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]propoxy]phen oxy]benzoic acid.
The compound which is 2-[2-propyl-3-[3-2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]propoxy]pheno xy]-benzoic acid methyl ester.
A compound which is a C.sub.1 -C.sub.6 alkyl ester of 3-(2-(3-(2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy)propoxy)-6-(4-carboxy phenoxy)phenyl)propionic acid.
A compound which is a C.sub.1 -C.sub.6 alkyl ester of 1-(4-(carboxymethoxy)phenyl)-1-(1H-tetrazol-5-yl)-6-(2-ethyl-4-(4-fluoroph enyl)-5-hydroxyphenoxy)hexane.
A method of treating a mammal to regress or prevent the inflammation or allergic disorders of psoriasis, arthritis, chronic lung disease, acute respiratory distress syndrome, shock, asthma, and inflammatory bowel disease;
- wherein the method comprises administering to said mammal a therapeutically effective amount of a compound of the formula:
- ##STR104## or a pharmaceutically acceptable base addition salt thereof, wherein:
- R.sub.1 is C.sub.1 -C.sub.5 alkyl, C.sub.2 -C.sub.5 alkenyl, C.sub.2 -C.sub.5 alkynyl, C.sub.1 -C.sub.4 alkoxy, (C.sub.1 -C.sub.4 alkyl)thio, halo, or R.sub.2 -substitutedphenyl;
- each R.sub.2 and R.sub.3 are each independently hydrogen, halo, hydroxy, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, (C.sub.1 -C.sub.4 alkyl)--S(O).sub.q --, trifluoromethyl, or di-(C.sub.1 -C.sub.3 alkyl) amino;
- X is --O--, --S--, -C(.dbd.O), or --CH.sub.2 --;
- Y is --O-- or --CH.sub.2 --;
- or when taken together, --X--Y-- is --CH.dbd.CH-- or --C.tbd.C--;
- Z is a straight or branched chain C.sub.1 -C.sub.10 alkylidenyl;
- A is a bond, --O--, --S--, --CH.dbd.CH--, or CR.sub.a R.sub.b --, where R.sub.a and R.sub.b are each independently hydrogen, C.sub.1 -C.sub.5 alkyl, or R.sub.7 -substitutedphenyl, or when taken together with the carbon atom to which they are attached form a C.sub.4 -C.sub.8 cycloalkyl ring;
- R.sub.4 is R.sub.6, ##STR105## where each R.sub.6 is independently --COOH, 5-tetrazolyl, --CON(R.sub.9).sub.2, or --CONHSO.sub.2 R.sub.10 ;
- each R.sub.7 is hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.5 alkenyl, C.sub.2 -C.sub.5 alkynyl, benzyl, methoxy, --W--R.sub.6, --T--G--R.sub.6, (C.sub.1 -C.sub.4 alkyl)--T-- (C.sub.1 -C.sub.4 alkylidenyl)--O--, or hydroxy;
- R.sub.8 is hydrogen or halo;
- each R.sub.9 is independently hydrogen, phenyl, or C.sub.1 -C.sub.4 alkyl, or when taken together with the nitrogen atom form a morpholino, piperidino, piperazino, or pyrrolidino group;
- R.sub.10 is C.sub.1 -C.sub.4 alkyl or phenyl;
- R.sub.11 is R.sub.2, --W--R.sub.6, or --T--G--R.sub.6 ;
- each W is a bond or straight or branched chain divalent hydrocarbyl radical of one to eight carbon atoms;
- each G is a straight or branched chain divalent hydrocarbyl radical of one to eight carbon atoms;
- each T is a bond, --CH.sub.2 --, --O--, --NH--, --NHCO--, --C(.dbd.O)--, or --S(O)q--;
- K is -C(.dbd.O)-- or --CH(OH)--;
- each q is independently 0, 1, or 2;
- p is 0 or 1;
- and
- t is 0 or 1;
- provided when X is --O--or --S--, Y is not --O--;
- provided when A is --O--or --S--, R.sub.4 is not R.sub.6 ;
- and provided W is not a bond when p is 0.
A method of treating a mammal to regress or prevent the inflammation or allergic disorders of psoriasis, arthritis, chronic lung disease, acute respiratory distress syndrome, shock, asthma, and inflammatory bowel disease;
- wherein the method comprises administering to said mammal a therapeutically effective amount of a compound of the formula:
- ##STR106## or a pharmaceutically acceptable base addition salt thereof, where
- R.sub.1 is C.sub.1 -C.sub.5 alkyl, C.sub.2 -C.sub.5 alkenyl, C.sub.2 -C.sub.5 alkynyl, C.sub.1 -C.sub.4 alkoxy, (C.sub.1 -C.sub.4 alkyl)thio, halo, or R.sub.2 -substitutedphenyl;
- each R.sub.2 and R.sub.3 are each independently hydrogen, halo, hydroxy, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, (C.sub.1 -C.sub.4 alkyl)--S(O).sub.q --, trifluoromethyl, or di-(C.sub.1 -C.sub.3 alkyl) amino;
- X is --O--, --S--, -C(.dbd.O), or --CH.sub.2 --;
- Y is --O-- or --CH.sub.2 --;
- or when taken together, --X--Y-- is --CH.dbd.CH-- or --C.tbd.C--;
- Z is a straight or branched chain C.sub.1 -C.sub.10 alkylidenyl;
- A is a bond, --O--, --S--, --CH.dbd.CH--, or CR.sub.a R.sub.b --, where R.sub.a and R.sub.b are each independently hydrogen, C.sub.1 -C.sub.5 alkyl, or R.sub.7 -substitutedphenyl, or when taken together with the carbon atom to which they are attached form a C.sub.4 -C.sub.8 cycloalkyl ring;
- R.sub.4 'is R.sub.6 ', ##STR107## where each R.sub.6 ' is independently --COOH, 5-tetrazolyl, --CON(R.sub.9).sub.2, --CONHSO.sub.2 R.sub.10, --COOR, or --CN;
- each R.sub.7 is hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.5 alkenyl, C.sub.2 -C.sub.5 alkynyl, benzyl, methoxy, --W--R.sub.6, --T--G--R.sub.6, (C.sub.1 -C.sub.4 alkyl)--T-- (C.sub.1 -C.sub.4 alkylidenyl)--O--, or hydroxy;
- R.sub.8 is hydrogen or halo;
- each R.sub.9 is independently hydrogen, phenyl, or C.sub.1 -C.sub.4 alkyl, or when taken together with the nitrogen atom form a morpholino, piperidino, piperazino, or pyrrolidino group;
- R.sub.10 is C.sub.1 -C.sub.4 alkyl or phenyl;
- R.sub.11 is R.sub.2, --W--R.sub.6 ', or --T--G--R.sub.6 ';
- each W is a bond or straight or branched chain divalent hydrocarbyl radical of one to eight carbon atoms;
- each G is a straight or branched chain divalent hydrocarbyl radical of one to eight carbon atoms;
- each T is a bond, --CH.sub.2 --, --O--, --NH--, --NHCO--, --C(.dbd.O)--, or --S(O)q--;
- K is -C(.dbd.O)-- or --CH(OH)--;
- each q is independently 0, 1, or 2;
- p is 0 or 1;
- and
- t is 0 or 1;
- provided when X is --O-- or --S--, Y is not --O--;
- provided when A is --O-- or --S--, R.sub.4 is not R.sub.6 ;
- provided W is not a bond when p is 0;
- and provided that at least one R.sub.6 must be --COOR or --CN.
A method of treating a mammal to regress or prevent the inflammation or allergic disorders of psoriasis, arthritis, chronic lung disease, acute respiratory distress synfrome, shock, asthma, and inflammatory bowel disease;
- wherein the method comprises administering to said mammal a therapeutically effective amount of the compound;
- 2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]propoxy]phen oxy]-benzoic acid or a pharmaceutically acceptable base addition salt thereof.
A method of treating a human to regress or prevent the inflammation or allergic disorders of psoriasis, arthritis, or asthma;
- wherein the method comprises administering to said human a therapeutically effective amount of the compound;
- 2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]propoxy]phen oxy]-benzoic acid or a pharmaceutically acceptable base addition salt thereof.
Dependencies are inferred from the claim text.