Substituted phenyl compounds and derivatives thereof that modulate the activity of endothelin

Abstract

Methods, compositions, and compounds for modulating the activity of an endothelin peptide are provided. The methods use compositions that contain compounds of formula (I): where X and Y are selected from groups that include O, S, and NH; and Ar 1 , Ar 2 and Ar 3 are independently selected from substituted or unsubstituted groups that include 5 to 6 membered aryl groups and heteroaryl groups that contain one or two heteroatom(s). The methods are effected by contacting endothelin receptors with one or more of the compounds or with compositions containing one or more of the compounds prior to, simultaneously with, or subsequent to contacting the receptors with an endothelin peptide.

We claim:  
     
         1 . A compound that has the formula (I):  
                   
       or a pharmaceutically acceptable salt or ester thereof, wherein: 
 X and Y are independently selected from O, S, NR 28 , —(CH 2 ) v —, —NR 28 (CH 2 ) v —, —S—(CH 2 ) v — or —O—(CH 2 ) v — where v is 0 to 12, provided that, when Ar 3  is phenyl, at least one of X and Y is O, S or NR 28 ;  
 R 28  is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl;  
 Ar 1  and Ar 2  are independently selected from among aryl and heteroaryl groups containing one to three fused rings and from 3 up to about 21 members in the ring(s), in which the heteroaryl groups contain one to three heteroatoms selected from O, S and N; and  
 Ar 3  is independently selected from the aryl and heteroaryl groups set forth for Ar 1  and Ar 2 ,  
 X, Y, Ar 1 , Ar 2  and Ar 3  are selected with the proviso that the resulting compound does not have the formula (IV):  
                 
 
 in which R′ is lower alkyl, COOH, C(O)NR a R b , where R a  is hydrogen or alkyl containing 1 to 6 carbon atoms in the chain, R b  is alkyl containing 1 to 6 carbon atoms in the chain, OH, methoxy, cyanomethyl, or R a  and R b  together form —(CH 2 ) x —, where x is 1 to 6.  
 
     
     
         2 . The compound of    claim 1    that has the formula (I):  
                 
 
       or a pharmaceutically acceptable salt or ester thereof, wherein: 
 Ar 3  is pyrazinyl, pyridazinyl, pyridyl, oxazolyl, isoxazolyl or imiazolyl;  
 X and Y are independently selected from O, S, NR 28 , —(CH 2 ) v —, —NR 28 (CH 2 ) v —, —S—(CH 2 ) v — or —O—(CH 2 ) v — where v is 0 to 12;  
 R 28  is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocyclyl, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl;  
 Ar 1  and Ar 2  are independently selected from among aryl and heteroaryl groups containing one or two to three fused rings and from 3 up to about 21 members in the ring(s), in which the heteroaryl groups contain one to three heteroatoms selected from O, S and N.  
 
     
     
         3 . The compound of    claim 2   , wherein Ar 1  and Ar 2  are each independently selected from among aryl groups that contain 5 to 6 members in the ring and heteroaryl groups that contain 5 to 6 members in the ring and one or two heteroatom(s).  
     
     
         4 . The compound of    claim 2   , wherein Ar 1  and Ar 2  are independently selected from naphthyl, phenyl, biphenyl, quinolyl, thienyl, furyl, isoquinolyl, pyrrolyl, pyridyl, indolyl, oxadiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyrimidyl, benzo[b]furyl and benzo[b]thienyl.  
     
     
         5 . The compound of    claim 4   , wherein Ar 1  and Ar 2  are unsubstituted or are substituted with one or more substituents selected from among alkyl, alkoxy, alkenyl, alkynyl, halo, pseudohalo, (CH 2 ) q COR 16  in which q is 0 to 6, (alkenyl) r COR 15  in which alkenyl is a straight or branched carbon chain containing at least two carbons and one unsaturated bond so that r, which is the number of carbons in the chain, is 0 or 2 to 6, (CH 2 ) t OH in which t is 0 to 6, (alkenyl) u OH in which alkenyl is a straight or branched carbon chain containing at least two carbons and one unsaturated bond so that u is 0 or 2 to 6; 
 R 15  and R 16  are each independently hydrogen, alkyl, haloalkyl, aryl, aryloxy, heterocyclyl, arylalkyl, arylalkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, R 20 , C(O)R 20 , CO 2 R 20 , SH, S(O) n R 20  in which n is 0-2, HNOH, (CH 2 ) s R 20  in which s is 1-6, NR 20 R 21 , OR 20 , R 21 NCOR 20  or R 21 NSO 2 R 20 ;    R 20  is selected from among hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, arylalkyl, cycloalkyl, cycloalkenyl or cycloalkynyl; and    R 21  is selected from among hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxy, aryloxy, heterocyclyl, arylalkyl, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl.    
     
     
         6 . The compound of    claim 4   , wherein Ar 3  is selected from among pyrazinyl and pyridyl groups.  
     
     
         7 . The compound of    claim 2   , wherein Ar 3  is selected from among pyrazinyl and pyridyl groups.  
     
     
         8 . The compound of    claim 6   , wherein Ar 3  is a pyrazinyl group.  
     
     
         9 . The compound of    claim 6   , wherein Ar 3  is a pyridyl group.  
     
     
         10 . The compound of    claim 7   , wherein Ar 3  is a pyrazinyl group.  
     
     
         11 . The compound of    claim 7   , wherein Ar 3  is a pyridyl group.  
     
     
         12 . The compound of    claim 2   , wherein Ar 1  and Ar 2  are selected from phenyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazolyl, isoxazolyl, isothiazolyl and pyrimidyl.  
     
     
         13 . The compound of    claim 6   , wherein Ar 1  and Ar 2  are selected from phenyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazolyl, isoxazolyl, isothiazolyl and pyrimidyl.  
     
     
         14 . The compound of    claim 7   , wherein Ar 1  and Ar 2  are selected from phenyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazolyl, isoxazolyl, isothiazolyl and pyrimidyl.  
     
     
         15 . The compound of    claim 2   , wherein Ar 3  is substituted with a carboxyl group or an isostere thereof.  
     
     
         16 . The compound of    claim 6   , wherein at least one of Ar 1  and Ar 2  is substituted phenyl and at least one of X and Y is O or S.  
     
     
         17 . A pharmaceutical composition, comprising a compound of    claim 1    or a pharmaceutically acceptable salt or ester of a compound of    claim 1    in a pharmaceutically acceptable carrier.  
     
     
         18 . The pharmaceutical composition of    claim 17    that is formulated for single dosage administration.  
     
     
         19 . A method for treating endothelin-mediated disorders, comprising administering a therapeutically effective amount of a compound of    claim 1    or a pharmaceutically acceptable salt or ester thereof, wherein the effective amount is sufficient to ameliorate one or more of the symptoms of the disorder.  
     
     
         20 . The method of    claim 19   , wherein the disorder is selected from the group consisting of hypertension, cardiovascular disease, asthma, pulmonary hypertension, inflammatory diseases, ophthalmologic disease, menstrual disorders, obstetric conditions, wounds, gastroenteric disease, renal failure, immunosuppressant-mediated renal vasoconstriction, erythropoietin-mediated vasoconstriction, endotoxin shock, anaphylactic shock and hemorrhagic shock.  
     
     
         21 . The method of    claim 19   , wherein the disorder is selected from the group consisting of asthma and inflammatory diseases.  
     
     
         22 . A method for inhibiting the binding of an endothelin peptide to an endothelin receptor, comprising contacting the receptor with an endothelin peptide and with one or more compounds of    claim 1    or pharmaceutically acceptable salts or esters thereof, wherein the contacting is effected prior to, simultaneously with or subsequent to contacting the receptors with the endothelin peptide.  
     
     
         23 . The method of    claim 22   , wherein the endothelin receptor is an endothelin A  (ET A ) or endothelin B  (ET B ) receptor.  
     
     
         24 . An article of manufacture, comprising packaging material and a compound of    claim 1    or a pharmaceutically acceptable salt or ester thereof, wherein the compound is contained within the packaging material; the compound, or salt or ester thereof, is effective for antagonizing the effects of endothelin, ameliorating the symptoms of an endothelin-mediated disorder, or inhibiting the binding of an endothelin peptide to an endothelin receptor with an IC 50  of less than about 10 μM, and the packaging material includes a label that indicates that the compound or salt thereof is used for antagonizing the effects of endothelin, ameliorating the symptoms of an endothelin-mediated disorder, or inhibiting the binding of endothelin to an endothelin receptor with an IC 50  of less than about 10 μM.