Sulfonamides and derivatives thereof that modulate the activity of endothelin

Abstract

Thienyl-, furyl- and pyrrolyl-sulfonamides, formulations of pharmaceutically-acceptable salts thereof and methods for modulating or altering the activity of the endothelin family of peptides are provided. In particular, N-(isoxazolyl)thienylsulfonamides, N-(isoxazolyl)furylsulfonamides and N-(isoxazolyl)pyrrolylsulfonamides, formulations thereof and methods using these sulfonamides for inhibiting the binding of an endothelin peptide to an endothelin receptor by contacting the receptor with the sulfonamide are provided. Methods for treating endothelin-mediated disorders by administering effective amounts of one or more of these sulfonamides or prodrugs thereof that inhibit the activity of endothelin are also provided.

What is claimed is:  
     
         1 . A sulfonamide compound of formula (A):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, acid or ester thereof, wherein: 
 Ar 1  is a substituted with one or more substituents or an unsubstituted monocyclic or polycyclic aryl group in which each substituent is independently selected from the group consisting of H, NH 2 , halide, pseudohalide, alkyl, alkylcarbonyl, formyl, aryl, heteroaryl, alkoxyalkyl, alkylamino, alkylthio, arylcarbonyl, aryloxy, arylamino, arylthio, haloalkyl, haloaryl, and carbonyl, in which the aryl and alkyl portions are unsubstituted or substituted with any of the preceeding groups, or straight or branched chains of from about 1 up to about 12 carbons;  
 Ar 2  has the formula:  
                     
 in which M is (CH 2 ) m C(O)(CH 2 ) r , (CH 2 ) m C(O)NH(CH 2 ) r , (CH 2 ) m (CH═CH)(CH 2 ) r , (CH 2 ) m C(O)(CH 2 ) s NH(CH 2 ) r , (CH 2 ) m (CH═CH)(CH 2 ) r , C═N(OH)(CH 2 ) r , (CH 2 ) m C(O)(CH═CH) s NH(CH 2 ) r , CH(OH)(CH 2 ) r , CH(CH 3 )C(O)(CH 2 ) r , CH(CH 3 )C(O)(CH 2 ) m (CH═CH)(CH 2 ) r , (CH 2 ) r , (CH 2 ) r O, (CH 2 )S(O) n  wherein n is 0-2, C(O)O, in which m, s and r are each independently 0 to 6; and  
 R 1 , R 2 , R 3 , R 4  and R 5  are each independently selected from (i) or (ii) as follows: 
 (i) R 1 , R 2 , R 3 , R 4  and R 5  are each independently selected from among H, OH, NHR 38 , CONR 38 R 39 , NO 2 , cyano, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, haloalkyl, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, alkenylthio, alkenylamino, alkenyloxy, alkenylsulfinyl, alkenylsulfonyl, alkoxycarbonyl, arylaminocarbonyl, alkylaminocarbonyl, aminocarbonyl, (alkyl-aminocarbonyl)alkyl, acetoxy, hydroxyl, carboxyl, carboxyalkyl, carboxyalkenyl, alkylsulfonylaminoalkyl, cyanoalkyl, acetyl, acetoxyalkyl, hydroxyalkyl, alkyoxyalkoxy, hydroxyalkyl, (acetoxy)alkoxy, (hydroxy)alkoxy, formyl, sulfonyl chlorides, amino acids, hexoses, O-glycosides, riboses, lower alkyl, CN, —(CH 2 ) x C(O)(CH 2 ) x , —(CH 2 ) x , (CH 2 ) x N-lower alkyl, —(CH 2 ) x C(O)NH 2 , a D-, L- or racemic amino acid, a primary or secondary amide, O-glycoside, a hexose or ribose, —S(O) 2 NH 2 , hydroxy, alkoxy, alkoxycarbonyl, acetoxyalkyl, —(CH 2 ) x COOH; —(CH 2 ) x COOH—, CO 2 -lower alkyl, CN, heteroaryl, —COC(O)(CH 2 ) x CH 3 , —(CH 2 ) x N(CH 3 ) 2 , a sulfonyl chloride, S(O) 2 NHR 50 , alkylaryl, alkylheteroaryl, C(O)NHR 50 , —(CH 2 ) x OH or —C(O)N(H)N(H)M; or  
 (ii) at least two of R 1 , R 2 , R 3 , R 4  and R 5 , which substitute adjacent carbons on the ring, together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, which is unsubstituted or substituted by replacing one or more hydrogens with halide, loweralkyl, loweralkoxy or halo loweralkyl, and the others of R 1 , R 2 , R 3 , R 4  and R 5  are selected as in (i);  
 
 at least four of R 1 , R 2 , R 3 , R 4  and R 5  are not hydrogen, unless: 
 (a) R 1  and R 3  are alkyl and R 5  is R 20 , which is selected from the group consisting of aryl, heteroaryl, heterocyclyl, OH, CN, C(O)R 16 , CO 2 R 16 , SH, S(O) n R 16  in which n is 0-2, a D, L or racemic amino acid, a ribose or hexose, an O-glycoside, a sulfonyl chloride, —(CH 2 ) x OH, NHOH, NR 12 R 16 , NO 2 , N 3 , OR 16 , R 12 NCOR 16  and CONR 12 R 16 , then R 2  and R 4  may be H; or  
 (b) when M is —CONHC(R 12 )(R 16 )—, then R 1 , R 2 , R 3 , R 4  and R 5  may all be H;  
 (c) when M is —COCHR 6 —, Ar 1  is not an isoxazolyl, R 1  is alkyl, and R 3  and R 4  form alkylenedioxy, then R 2  and R 5  may be H;  
 
 R 38  and R 39  are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl alkylaryl, heterocyclyl, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl;  
 R 6  is H, or substituted or unsubstituted alkyl or aryl;  
 X is S, O or NR 11 , where R 11  contains up to about 30 carbon atoms and is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R 15  and S(O) n R 15  in which n is 0-2;  
 R 15  is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, or cycloalkynyl;  
 R 11  and R 15  are unsubstituted or are substituted with one or more substituents each selected independently from Z;  
 Z is hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, amino acids, primary and secondary amides, O-glycosides, hexoses, riboses, alkylaryl, alkylheteroaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(O)R 16 , OC(O)R 16 , CO 2 R 16 , OCO 2 R 16 , SH, S(O) n R 16  in which n is 0-2, NHOH, NR 12 R 16 , NO 2 , N 3 , OR 16 , R 12 NCOR 16  and CONR 12 R 16 ; R 16  is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, chloride, NHR 50 , alkylaryl, alkylheteroaryl, or —(CH 2 ) x OH; R 50  is a substituent such as hydrogen, lower alkyl, or lower alkoxy; R 12 , which is selected independently from R 11  and Z, is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R 17  and S(O) n R 17  in which n is 0-2; R 17  is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; R 12  and R 16  may together form alkylene; each of R 12 , R 15  and R 16  may be further substituted with any group set forth for Z.  
 
     
     
         2 . A compound or pharmaceutically acceptable salt, acid or ester thereof of  claim 1 , wherein M is  
       
         
           
           
               
               
           
         
       
       in which R 40  is hydrogen, alkyl, alkoxy, alkoxyalkyl, haloalkyl.  
     
     
         3 . A compound or pharmaceutically acceptable salt, acid or ester thereof of  claim 1 , wherein M is C(O)CH 2 , C(O)NH, —CH═CH—, CH 2 CH 2 C(O)(CH) 2  or CH 2 CHC(O)CH 2 .  
     
     
         4 . A compound or pharmaceutically acceptable salt, acid or ester thereof of  claim 1 , wherein M is selected from among:  
       
         
           
           
               
               
           
         
       
     
     
         5 . A sulfonamide compound or pharmaceutically acceptable salt, acid or ester thereof of  claim 1  that has formula (I):  
       
         
           
           
               
               
           
         
       
       wherein: 
 Ar 1  is a substituted with one or more substituents or an unsubstituted monocyclic or polycyclic aryl group in which each substituent is independently selected from the group consisting of H, NH 2 , halide, pseudohalide, alkyl, alkylcarbonyl, formyl, aryl, heteroaryl, alkoxyalkyl, alkylamino, alkylthio, arylcarbonyl, aryloxy, arylamino, arylthio, haloalkyl, haloaryl, and carbonyl, in which the aryl and alkyl portions are unsubstituted or substituted with any of the preceeding groups, and straight or branched chains of from about 1 up to about 12 carbons;  
 X is S;  
 R 15  is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, or cycloalkynyl;  
 R 11  and R 15  are unsubstituted or are substituted with one or more substituents each selected independently from Z;  
 Z is selected from the group consisting of hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, amino acids, primary and secondary amides, O-glycosides, hexoses, riboses, alkylaryl, alkylheteroaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(O)R 16 , OC(O)R 16 , CO 2 R 16 , OCO 2 R 16 , SH, S(O) n R 16  in which n is 0-2, NHOH, NR 12 R 16 , NO 2 , N 3 , OR 16 , R 12 NCOR 16  and CONR 12 R 16 ;  
 R 16  is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, chloride, NHR 50 , alkylaryl, alkylheteroaryl, or —(CH 2 ) x OH;  
 R 50  is hydrogen, lower alkyl, or lower alkoxy;  
 R 12 , which is selected independently from R 11  and Z, is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R 17  and S(O) n R 17  in which n is 0-2;  
 R 17  is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl;  
 R 12  and R 16  may together form alkylene;  
 each of R 11 , R 12 , R 15  and R 16  may be further substituted with the any of the appropriate groups of those set forth for Z;  
 W is ═C(halo) 2 , —(CH 2 ) x —, ═N(lower alkyl), —C(O)—, ═C(lower alkyl) 2 , —NH—, ═NCOR 16 , —NHC(R 12 )(R 16 )—, ═NCO 2 R 16 , —CH 2 — or ═CHR 6 ; and  
 each  x  is 0-3.  
 
     
     
         6 . A sulfonamide or pharmaceutically acceptable salt, acid or ester thereof of  claim 1 , wherein the compounds of formula (A) are of formula (II):  
       
         
           
           
               
               
           
         
       
       wherein: 
 Ar 1  is a substituted or unsubstituted monocyclic or polycyclic aryl group with one or more substituents, selected from the group consisting of H, NH 2 , halide, pseudohalide, alkyl, alkylcarbonyl, formyl, aryl, heteroaryl, alkoxyalkyl, alkylamino, alkylthio, arylcarbonyl, aryloxy, arylamino, arylthio, haloalkyl, haloaryl, and carbonyl, in which the aryl and alkyl portions are unsubstituted or substituted with any of the preceeding groups, and straight or branched chains of from about 1 up to about 10-12 carbons;  
 R 7  is R 1 , R 8  is R 3 , R 9  is R 4  and R 10  is R 5 .  
 
     
     
         7 . A sulfonamide or pharmaceutically acceptable salt, acid or ester thereof of  claim 6 , wherein R 7 , R 8  and R 10  are alkyl, haloalkyl, polyhaloalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl.  
     
     
         8 . A sulfonamide or pharmaceutically acceptable salt, acid or ester thereof of  claim 7 , wherein R 7 , R 8  and R 10  are lower alkyl, lower alkenyl, lower alkynyl, or aryl.  
     
     
         9 . A sulfonamide or pharmaceutically acceptable salt, acid or ester thereof of  claim 8 , wherein R 7 , R 8  and R 10  are methyl.  
     
     
         10 . A sulfonamide or pharmaceutically acceptable salt, acid or ester thereof of  claim 6 , wherein R 7 , R 8 , R 9  and R 10  do not contain cyano groups, and W is not —CH 2 —.  
     
     
         11 . A sulfonamide or pharmaceutically acceptable salt, acid or ester thereof of  claim 6 , wherein: 
 W is —NH—, ═NCO 2 R 16 , or is —CH 2 — when R 9  is hydroxyl;    R 7 , R 8  and R 10  are methyl; and    R 9  is selected from the group consisting of Z-substituted and unsubstituted alkyl, hydroxyl, substituted and unsubstituted alkoxy, OC(O)R 16 , OCO 2 R 16 , NR 12 R 16  and S(O) n R 16  in which n is 0-2.    
     
     
         12 . A sulfonamide or pharmaceutically acceptable salt, acid or ester thereof of  claim 11 , wherein R 9  is selected from the group consisting of methoxy, methoxycarbonylmethoxy, 2-(2-methoxyethoxy)ethoxyacetoxy, 2-hydroxyethoxy, N,N-dimethylthiocarbonyloxy, N,N-dimethylthiocarbonyloxymethyl, dimethylamino, pyrrolidinyl, acetoxy, hydroxy, cyanomethyl, acetoxymethyl, hydroxymethyl, carboxylmethyl, methanesulfonylamino, N,N-dimethylaminomethyl, SO 2 NH 2 , and methoxycarbonylmethyl.  
     
     
         13 . A sulfonamide or pharmaceutically acceptable salt, acid or ester thereof of  claim 11 , wherein R 9  does not contain a cyano group.  
     
     
         14 . A sulfonamide or pharmaceutically acceptable salt, acid or ester thereof of  claim 11 , wherein R 9  is selected from the group consisting of methoxy, methoxycarbonylmethoxy, 2-(2-methoxyethoxy)ethoxyacetoxy, 2-hydroxyethoxy, N,N-dimethylthiocarbonyloxy, N,N-dimethylthiocarbonyloxymethyl, dimethylamino, pyrrolidinyl, acetoxymethyl, methoxycarbonylmethyl, hydroxy and acetoxy.  
     
     
         15 . A sulfonamide compound or pharmaceutically acceptable salt, acid or ester thereof of  claim 1  that is a thiophene-3-sulfonamide.  
     
     
         16 . A sulfonamide compound or pharmaceutically acceptable salt, acid or ester thereof of  claim 6  that is a thiophene-3-sulfonamide.  
     
     
         17 . A sulfonamide compound or pharmaceutically acceptable salt, acid or ester thereof of  claim 1  that has formula III:  
       
         
           
           
               
               
           
         
       
       wherein: 
 X is S, O or NR 11 ;  
 each G and R is independently selected from lower alkyl, CN, —(CH 2 ) x C(O)(CH 2 ) x , —(CH 2 ) x , (CH 2 ) x N-lower alkyl, —(CH 2 ) x C(O)NH 2 , a D-, L- or racemic amino acid, a primary or secondary amide, O-glycoside, a hexose or ribose, —S(O) 2 NH 2 , hydroxy, alkoxy, alkoxycarbonyl, acetoxyalkyl, —(CH 2 ) x COOH; —(CH 2 ) x COOH—, CO 2 -lower alkyl, CN, heteroaryl, —COC(O)(CH 2 ) x CH 3 , —(CH 2 ) x N(CH 3 ) 2 , a sulfonyl chloride, S(O) 2 NHR 50 , alkylaryl, alkylheteroaryl, C(O)NHR 50 , —(CH 2 ) x OH and —C(O)N(H)N(H)M;  
 R 50  is hydrogen, lower alkyl, or lower alkoxy;  
 M is H or R 50 ;  
 R′ is independently selected from hydrogen, G and R;  
 W is ═C(halo) 2 , ═N(H), —(CH 2 ) x —, ═N(lower alkyl), —C(O)—, ═C(lower alkyl) 2 ; and  
 each x is independently is 0-3.  
 
     
     
         18 . The sulfonamides of  claim 17 , wherein Ar 1  is a phenyl group.  
     
     
         19 . The sulfonamides of  claim 17 , wherein: R, G and R′ are selected where the amino acid is L-Asp or L-Glu; the hexose is D-mannose, the heteroaryl is triazolyl, and X is S.  
     
     
         20 . The sulfonamides of  claim 17 , wherein: 
 W is ═CH 2 , ═NH, ═NCH 3 , ═NCH 2 CH 3 , ═C(CH 3 ) 2  or CF 2 ; and    G is —CH 3 , —CN, —COCH 3 , —CH 2 CH 3 , —(CH 2 ) x CO 2 H.    
     
     
         21 . The sulfonamides of  claim 18 , wherein: 
 W is ═CH 2 , ═NH, ═NCH 3 , ═NCH 2 CH 3 , ═C(CH 3 ) 2  or CF 2 ; and    G is —CH 3 , —CN, —COCH 3 , —CH 2 CH 3 , —(CH 2 ) x CO 2 H.    
     
     
         22 . A sulfonamide compound or pharmaceutically acceptable salt, acid or ester thereof of  claim 17  that is a thiophene-3-sulfonamide.  
     
     
         23 . A sulfonamide or pharmaceutically acceptable salt, acid or ester thereof of  claim 1 , wherein the compounds of formula (A) are of formula (IV):  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 6  is H, or substituted or unsubstituted alkyl or aryl.  
 
     
     
         24 . A sulfonamide or pharmaceutically acceptable salt, acid or ester thereof of  claim 23 , wherein: 
 R 6  is H, or substituted or unsubstituted alkyl.    
     
     
         25 . A sulfonamide or pharmaceutically acceptable salt, acid or ester thereof of  claim 23 , wherein R 6  is methyl or carboxymethyl.  
     
     
         26 . A sulfonamide compound or pharmaceutically acceptable salt, acid or ester thereof of  claim 23  that is a thiophene-3-sulfonamide.  
     
     
         27 . A sulfonamide or pharmaceutically acceptable salt, acid or ester thereof of  claim 1 , wherein the compounds of formula (A) are of formula (V):  
       
         
           
           
               
               
           
         
       
       wherein: 
 W is —NH—; and  
 R 20  is selected from the group consisting of aryl, heteroaryl, heterocyclyl, OH, CN, C(O)R 16 , CO 2 R 16 , SH, S(O) n R 16  in which n is 0-2, a D, L or racemic amino acid, a ribose or hexose, an O-glycoside, a sulfonyl chloride, —(CH 2 ) x OH, NHOH, NR 12 R 16 , NO 2 , N 3 , OR 16 , R 12 NCOR 16  and CONR 12 R 16 ;  
 R 16  is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl;  
 R 12  is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R 17  and S(O) n R 17  in which n is 0-2;  
 R 17  is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; and  
 each of R 12 , R 15  and R 16  may be further substituted with the any of the groups set forth for Z.  
 
     
     
         28 . A sulfonamide compound or pharmaceutically acceptable salt, acid or ester thereof of  claim 27  that is a thiophene-3-sulfonamide.  
     
     
         29 . The compounds of  claim 1  that are pharmaceutically acceptable sodium salts.  
     
     
         30 . A pharmaceutical composition, comprising an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt, acid or ester thereof in a pharmaceutically acceptable carrier, wherein the amount is effective for ameliorating the symptoms of an endothelin-mediated disease.  
     
     
         31 . The composition of  claim 30  that is formulated for single or multiple dosage administration.  
     
     
         32 . An article of manufacture, comprising packaging material and a compound or a pharmaceutically acceptable salt, acid or ester thereof of  claim 1  contained within the packaging material, wherein the compound 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 ET receptor with an IC 50  of less than about 10 μM, and the packaging material includes a label that indicates that the sulfonamide or salt thereof is used for antagonizing the effects of endothelin, inhibiting the binding of endothelin to an endothelin receptor or treating an endothelin-mediated disorder.  
     
     
         33 . A method for the treatment of endothelin-mediated diseases, comprising administering to a subject an effective amount the pharmaceutical composition of  claim 1 , wherein the effective amount is sufficient to ameliorate one or more of the symptoms of the disease.  
     
     
         34 . The method of  claim 33 , wherein the disease 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, pulmonary hypertension, anaphylactic shock and hemorrhagic shock.  
     
     
         35 . The method of  claim 34 , wherein the disease is selected from the group consisting of asthma and inflammatory diseases.  
     
     
         36 . A method for inhibiting the binding of an endothelin peptide to endothelin A  (ET A ) or endothelin B  (ET B ) receptors, comprising contacting the receptors an endothelin peptide and with a compound or pharmaceutically acceptable salt, acid or ester thereof of  claim 1 , wherein: 
 the contacting is effected prior to, simultaneously with or subsequent to contacting the receptors with the endothelin peptide.    
     
     
         37 . A method for altering endothelin receptor-mediated activity, comprising contacting endothelin receptors with a compound or pharmaceutically acceptable salt, acid or ester thereof of  claim 1 .  
     
     
         38 . The pharmaceutical composition of  claim 30 , that comprises a sodium phosphate buffer solution containing a sugar and the compound, or a pharmaceutically acceptable salt, acid or ester thereof, dissolved therein.  
     
     
         39 . The pharmaceutical formulation of  claim 38 , wherein the sulfonamide is a pharmaceutically-acceptable salt that is an alkali metal.  
     
     
         40 . A lyophilized powder, comprising a salt of compound of  claim 1 .  
     
     
         41 . The lyophilized powder of  claim 40  produced by a process, comprising: 
 (a) dissolving a pharmaceutically-acceptable salt of the sulfonamide compound in a sodium phosphate buffer solution containing a sugar or carbohydrate;  
 (b) sterile-filtering the resulting solution; and  
 (c) lyophilizing the filtered solution under standard conditions to produce a sterile powder.  
 
     
     
         42 . The powder of  claim 41 , wherein the sugar or carbohydrate is dextrose.  
     
     
         43 . An article of manufacture, comprising packaging material and a the powder of  claim 40 , contained within the packaging material, wherein the compound 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 ET receptor with an IC 50  of less than about 1 μM, and the packaging material includes a label that indicates that the sulfonamide or salt thereof is used for antagonizing the effects of endothelin, inhibiting the binding of endothelin to an endothelin receptor or treating an endothelin-mediated disorder.  
     
     
         44 . The combination comprising: 
 a sterile vial containing the pharmaceutical formulation of  claim 40 .    
     
     
         45 . The combination of  claim 44 , wherein the sterile vial contains an amount of the powder that is for single dose administration.  
     
     
         46 . The combination of  claim 44 , wherein the sterile vial also contains an amount of sterile water for injection; and the final concentration of the sulfonamide sodium salt is between about 1 and 250 mg/mL.  
     
     
         47 . The pharmaceutical composition of  claim 30  that is formulated as a tablet or capsule.  
     
     
         48 . A composition of  claim 47 , further comprising an enteric coating.  
     
     
         49 . The composition of  claim 47 , wherein the coating is selected from cellulose acetate phthalate, polyethylene glycol, polyoxyethylene sorbitan, castor oil, ethyl cellulose pseudolatex, phenyl salicylate, n-butyl stearate, stearic acid and carnuba wax.  
     
     
         50 . A sulfonamide or pharmaceutically acceptable salt, acid or ester thereof of  claim 1 , wherein Ar 1  is phenyl.  
     
     
         51 . A sulfonamide or pharmaceutically acceptable salt, acid or ester thereof of  claim 6 , wherein Ar 1  is phenyl.  
     
     
         52 . A sulfonamide or pharmaceutically acceptable salt, acid or ester thereof of  claim 1 , wherein M is (CH 2 ) m C(O)(CH 2 ) r , (CH 2 ) m C(O)NH(CH 2 ) r , (CH 2 ) m (CH═CH)(CH 2 ) r , (CH 2 ) m C(O)(CH 2 ) s NH(CH 2 ) r , (CH 2 ) m (CH═CH)(CH 2 ) r , C═N(OH)(CH 2 ) r , CH(OH)(CH 2 ) r , (CH 2 ) r , (CH 2 ) r O, (CH 2 )S(O) n , C(O)O.  
     
     
         53 . A sulfonamide or pharmaceutically acceptable salt, acid or ester thereof of  claim 27 , wherein: 
 W is —NH—; and    R 20  is CONH 2 , COOH, or phenyl.