Substituted phenyl compounds and derivatives thereof that modulate the activity of endothelin
First Claim
Patent Images
1. A compound that has the formula (I):
- ##STR14## or a pharmaceutically acceptable salt or ester thereof, wherein;
Ar3 is phenyl;
X and Y are independently selected from O, S, --N(R28)--, --(CH2)v --, --N(R28)(CH2)v --, --S--(CH2)v -- and --O--(CH2)v -- where v is 0 to 12, provided that at least one of X and Y is O, S or --N(R28)--;
R28 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl, wherein the heterocycle groups are rings containing 3 to 7 members and one heteroatom selected from S, O and N;
Ar1 and Ar2 are independently selected from among aryl and heteroaryl groups containing one ring 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; and
X, Y, Ar1, Ar2 and Ar3 are selected with the proviso that the resulting compound does not have the formula (IV);
##STR15## in which R'"'"' is lower alkyl, COOH, C(O)NRa Rb, where Ra is hydrogen or alkyl containing 1 to 6 carbon atoms in the chain, Rb is alkyl containing 1 to 6 carbon atoms in the chain, OH, methoxy, cyanomethyl, or Ra and Rb together form --(CH2)x --, where x is 1 to 6.
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Accused Products
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): ##STR1## where X and Y are selected from groups that include O, S, and NH; and Ar1, Ar2 and Ar3 are independently selected from substituted or unsubstituted groups that include 5 to 6 membered aryl groups and heteraryl 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.
123 Citations
73 Claims
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1. A compound that has the formula (I):
- ##STR14## or a pharmaceutically acceptable salt or ester thereof, wherein;
Ar3 is phenyl; X and Y are independently selected from O, S, --N(R28)--, --(CH2)v --, --N(R28)(CH2)v --, --S--(CH2)v -- and --O--(CH2)v -- where v is 0 to 12, provided that at least one of X and Y is O, S or --N(R28)--; R28 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl, wherein the heterocycle groups are rings containing 3 to 7 members and one heteroatom selected from S, O and N; Ar1 and Ar2 are independently selected from among aryl and heteroaryl groups containing one ring 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; and X, Y, Ar1, Ar2 and Ar3 are selected with the proviso that the resulting compound does not have the formula (IV);
##STR15## in which R'"'"' is lower alkyl, COOH, C(O)NRa Rb, where Ra is hydrogen or alkyl containing 1 to 6 carbon atoms in the chain, Rb is alkyl containing 1 to 6 carbon atoms in the chain, OH, methoxy, cyanomethyl, or Ra and Rb together form --(CH2)x --, where x is 1 to 6. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)
- ##STR14## or a pharmaceutically acceptable salt or ester thereof, wherein;
-
15. A compound that has formula (II):
- ##STR16## or a pharmaceutically acceptable salt or ester thereof wherein;
X and Y are independently selected from O, S, --N(R28)--, --(CH2)v --, --N(R28)(CH2)v --, --S--(CH2)v -- and --O--(CH2)v -- where v is 0 to 12, provided that at least one of X and Y is O, S or --N(R28)--; R28 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl, wherein the heterocycle groups are rings containing 3 to 7 members and one heteroatom selected from S, O and N; Ar1 and Ar2 are independently selected from among aryl and heteroaryl groups containing one ring 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; X, Y, Ar1, and Ar2 are selected with the proviso that the resulting compound does not have the formula (IV);
##STR17## in which R'"'"' is lower alkyl, COOH, C(O)NRa Rb, where Ra is hydrogen or alkyl containing 1 to 6 carbon atoms in the chain, Rb is alkyl containing 1 to 6 carbon atoms in the chain, OH, methoxy, cyanomethyl, or Ra and Rb together form --(CH2)x --, where x is 1 to 6;R1 is selected from hydrogen, --(CH2)n --A in which n is 0 to 6, --(CH2)q (CO2 R4), --(CH2)q (OH), CN, --C(R7)═
NOR8, NO2, --(CH2)q R9, --C.tbd.CR10, --CR11 ═
C(R12)(R13), tetrazolyl, CONR27 R26, --CH═
CH--Z, --C(R4)═
C(R4)--Z, --C.tbd.CZ, --O--(CH2)q Z, --CO2 H, --S--(CH2)q Z, --(CH2)q C(O)Z, --(CH2)q C(═
O)CH2 C(═
O)CO2 H, --CO(R14), alkylthio, alkylsulfinyl, alkylsulfonyl, carbamoyl, thiocarbamoyl, and nitrogen-containing rings, wherein the nitrogen-containing rings are selected from heterocycles containing 3 to 7 members in the ring including at least one nitrogen atom and optionally containing one or more additional heteroatoms selected from nitrogen, oxygen and sulfur in addition to the carbon atom(s) present;A is selected from among CO2 R4, carboxylic acid, alkylthioic acid, alkyldithoic acid, alkylimidic acid, sulfinic acid, sulfonic acid, phosphonic, sulfinimidic acid, sulfonimidic acid, sulfonamide, alkylhydroxamic acid, hydrazide, amide, hydroxyl, and hydrogen; Z is carboxylic acid, alkylthioic acid, alkyldithioic acid, alkylimidic acid, sulfinic acid, sulfonic acid, phosphonic, sulfinimidic acid, sulfonimidic acid, sulfonamide, alkylhydroxamic acid, hydrazide, amide, hydroxyl, hydrogen, alkyl, alkenyl, or tetrazolyl; q is 0 to 6; R4 is hydrogen, lower alkyl or haloalkyl; R7 is selected from hydrogen, alkyl and haloalkyl; R8 is hydrogen, arylalkyl or --(lower alkyl)CO2 R17 ; R9 is --CN, --CO2 R19, --CH2 OH, or carbamoyl; R10 is --CO2 H or carboxyphenyl; R11 is hydrogen, alkyl or arylalkyl; R12 and R13 are independently hydrogen, --CO2 R 18, --CN, aryl, lower alkyl, heteroaryl, lower alkyl or --NHC(O)aryl, provided that one of R12 and R13 is --CO2 H; R14 is hydrogen, alkyl, --(lower alkyl)carboxy, arylalkenyl, heteroarylalkenyl or --CO2 H; R17, R18 and R19 are independently selected from hydrogen, alkyl and haloalkyl; R26 and R27 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl; j, o and p are each independently 0 or 1; R2, R3 and R22 are each independently selected from alkyl, alkenyl, halo, haloalkyl, alkoxy, --S-alkyl, --NR29 -alkyl, aryl and heteroaryl; R29 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; the heterocycle groups are rings containing 3 to 7 members and at least on heteroatom selected from S, O and N; and the heteroaryl and aryl groups contain one ring 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. - View Dependent Claims (16, 17, 18, 19, 20, 21, 22, 23, 24)
- ##STR16## or a pharmaceutically acceptable salt or ester thereof wherein;
-
25. A compound that has formula (V):
- ##STR19## or a pharmaceutically acceptable salt or ester thereof, wherein;
X and Y are independently selected from O, S, --N(R28)--, --(CH2)v --, --N(R28)(CH2)v --, --S--(CH2)v -- and --O--(CH2)v -- where v is 0 to 12, provided that at least one of X and Y is O, S or --N(R28)--;R28 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl, wherein the heterocycle groups are rings containing 3 to 7 members and one heteroatom selected from S, O and N; R1 is selected from hydrogen, --(CH2)n --A in which n is 0 to 6, --(CH2)q (CO2 R4), --(CH2)q (OH), CN, --C(R7)═
NOR8, NO2, --(CH2)q R9, --C.tbd.CR10, --CR11 ═
C(R12)(R13), tetrazolyl, CONR27 R26, --CH═
CH--Z, --C(R4)═
C(R4)--Z, --C.tbd.CZ, --O--(CH2)q Z, --CO2 H, --S--(CH2)q Z, --(CH2)q C(O)Z, --(CH2)q C(═
O)CH2 C(═
O)CO2 H, --CO(R14), alkylthio, alkylsulfinyl, alkylsulfonyl, carbamoyl, thiocarbamoyl, and nitrogen-containing rings, wherein the nitrogen-containing rings are selected from heterocycles containing 3 to 7 members in the ring including at least one nitrogen atom and optionally containing one or more additional heteroatoms selected from nitrogen, oxygen and sulfur in addition to the carbon atom(s) present;A is selected from among CO2 R4, carboxylic acid, alkylthioic acid, alkyldithoic acid, alkylimidic acid, sulfinic acid, sulfonic acid, phosphonic, sulfinimidic acid, sulfonimidic acid, sulfonamide, alkylhydroxamic acid, hydrazide, amide, hydroxyl, and hydrogen; Z is carboxylic acid, alkylthioic acid, alkylthioic acid, alkylimidic acid, sulfinic acid, sulfonic acid, phosphonic, sulfinimidic acid, sulfonimidic acid, sulfonamide, alkylhydroxamic acid, hydrazide, amide, hydroxyl, hydrogen, alkyl, alkenyl, or tetrazolyl; q is 0 to 6; R4 is hydrogen, lower alkyl or haloalkyl; R7 is selected from hydrogen, alkyl and haloalkyl; R8 is hydrogen, arylalkyl or --(lower alkyl)CO2 R17 ; R9 is --CN, --CO2 R19, --CH2 OH, or carbamoyl; R10 is --CO2 H or carboxyphenyl; R11 is hydrogen, alkyl or arylalkyl; R12 and R13 are independently hydrogen, --CO2 R18, --CN, aryl, lower alkyl, heteroaryl, lower alkyl or --NHC(O)aryl, provided that one of R12 and R13 is --CO2 H; R14 is hydrogen, alkyl, --(lower alkyl)carboxy, arylalkenyl, heteroarylalkenyl or --CO2 H; R17, R18 and R19 are independently selected from hydrogen, alkyl and haloalkyl; R26 and R27 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl; R32, R33, R34, R35, R36 and R37 are each independently selected from (i), (ii) and (iii) as follows; (i) R32, R33, R34, R35, R36 and R37 are each independently selected from among H, NHR38, CONR38, NO2, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxy, haloalkyl, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, alkenylthio, alkenylamino, alkenyloxy, alkenylsulfinyl, alkenylsulfonyl, aminocarbonyl, carboxy, carboxyalkyl, carboxyalkenyl, and formyl;
or(ii) any two of R32, R33, and R34, R35, R36 and R37 substitute adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, containing 1 to 4 carbons in the alkyl portion, and which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and the others of R32, R33, R34, R35, R36 and R37 are selected as in (i);
or(iii) at least two of R32, R33 and R34 substitute adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, containing 1 to 4 carbons in the alkyl portion and which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and at least two of R35, R36 and R37 substitute adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, containing 1 to 4 carbons in the alkyl portion and which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and the others of R32, R33, R34, R35, R36 and R37 are selected as in (i); and R38 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl; with the proviso that the resulting compound does not have the formula (IV);
##STR20## in which R'"'"' is lower alkyl, COOH, C(O)NRa Rb, where Ra is hydrogen or alkyl containing 1 to 6 carbon atoms in the chain, Rb is alkyl containing 1 to 6 carbon atoms in the chain, OH, methoxy, cyanomethyl, or Ra and Rb together form --(CH2)x --, where x is 1 to 6. - View Dependent Claims (26, 27, 28, 29, 30, 31, 32)
- ##STR19## or a pharmaceutically acceptable salt or ester thereof, wherein;
-
33. A pharmaceutical composition, comprising a compound of formula (I):
- or a pharmaceutically acceptable salt or ester thereof, in a pharmaceutically acceptable carrier, wherein;
Ar3 is phenyl or pyrimidyl; X and Y are independently selected from O, S, --N(R28)--, --(CH2)v --, --N(R28)(CH2)v --, --S--(CH2)v -- and --O--(CH2)v -- where v is 0 to 12, provided that at least one of X and Y is O, S or --N(R28)--; R28 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl, wherein the heterocycle groups are rings containing 3 to 7 members and one heteroatom selected from S, O and N; and Ar1 and Ar2 are independently selected from among aryl and heteroaryl groups containing one ring 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. - View Dependent Claims (34, 35)
- or a pharmaceutically acceptable salt or ester thereof, in a pharmaceutically acceptable carrier, wherein;
-
36. A method for treating endothelin-mediated disorders, comprising administering a therapeutically effective amount of a compound of formula (I):
- ##STR23## or a pharmaceutically acceptable salt or ester thereof, wherein;
Ar3 is phenyl or pyrimidyl;X and Y are independently selected from O, S, --N(R28)--, --(CH2)v --, --N(R28)(CH2)v --, --S--(CH2)v -- and --O--(CH2)v -- where v is 0 to 12, provided that at least one of X and Y is O, S or --N(R28)--; R28 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl, wherein the heterocycle groups are rings containing 3 to 7 members and one heteroatom selected from S, O and N; Ar1 and Ar2 are independently selected from among aryl and heteroaryl groups containing one ring 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; and the effective amount is sufficient to ameliorate one or more of the symptoms of the disorder. - View Dependent Claims (37, 38)
- ##STR23## or a pharmaceutically acceptable salt or ester thereof, wherein;
-
39. A method for treating endothelin-mediated disorders, comprising administering a therapeutically effective amount of a compound of formula (II):
- ##STR24## or a pharmaceutically acceptable salt or ester thereof, wherein;
Ar1 and Ar2 are independently selected from among aryl and heteroaryl groups containing one ring 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;X and Y are independently selected from O, S, --N(R28)--, --(CH2)v --, --N(R28)(CH2)v --, --S--(CH2)v -- and --O--(CH2)v -- where v is 0 to 12, provided that at least one of X and Y is O, S or --N(R28)--; R28 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl, wherein the heterocycle groups are rings containing 3 to 7 members and one heteroatom selected from S, O and N; R1 is selected from hydrogen, --(CH2)n --A in which n is 0 to 6, --(CH2)q (CO2 R4), --(CH2)q (OH), CN, --C(R7)═
NOR8, NO2, --(CH2)q R9, --C.tbd.CR10, --CR11 ═
C(R12)(R13), tetrazolyl, CONR27 R26, --CH═
CH--Z, --C(R4)═
C(R4)--Z, --C.tbd.CZ, --O--(CH2)q Z, --CO2 H, --S--(CH2)q Z, --(CH2)q C(O)Z, --(CH2)q C(═
O)CH2 C(═
O)CO2 H, --CO(R14), alkylthio, alkylsulfinyl, alkylsulfonyl, carbamoyl, thiocarbamoyl, and nitrogen-containing rings, wherein the nitrogen-containing rings are selected from heterocycles containing 3 to 7 members in the ring including at least one nitrogen atom and optionally containing one or more additional heteroatoms selected from nitrogen, oxygen and sulfur in addition to the carbon atom(s) present;A is selected from among CO2 R4, carboxylic acid, alkylthioic acid, alkyldithoic acid, alkylimidic acid, sulfinic acid, sulfonic acid, phosphonic, sulfinimidic acid, sulfonimidic acid, sulfonamide, alkylhydroxamic acid, hydrazide, amide, hydroxyl, and hydrogen; Z is carboxylic acid, alkylthioic acid, alkyldithoic acid, alkylimidic acid, sulfinic acid, sulfonic acid, phosphonic, sulfinimidic acid, sulfonimidic acid, sulfonamide, alkylhydroxamic acid, hydrazide, amide, hydroxyl, hydrogen, alkyl, alkenyl, or tetrazolyl; q is 0 to 6; R4 is hydrogen, lower alkyl or haloalkyl; R7 is selected from hydrogen, alkyl and haloalkyl; R3 is hydrogen, arylalkyl or --(lower alkyl)CO2 R17 ; R9 is --CN, --CO2 R19, --CH2 OH, or carbamoyl; R10 is --CO2 H or carboxyphenyl; R11 is hydrogen, alkyl or arylalkyl; R12 and R13 are independently hydrogen, --CO2 R18, --CN, aryl, lower alkyl, heteroaryl lower alkyl or --NHC(O)aryl, provided that one of R12 and R13 is --CO2 H; R14 is hydrogen, alkyl, --(lower alkyl)carboxy, arylalkenyl, heteroarylalkenyl or --CO2 H; R17, R18 and R19 are independently selected from hydrogen, alkyl and haloalkyl; R26 and R27 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o and p are independently 0 or 1; R2 and R3 are independently selected from alkyl, alkenyl, halo, haloalkyl, alkoxy, --S-alkyl, --NR29 -alkyl, aryl and heteroaryl; and R29 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; and the effective amount is sufficient to ameliorate one or more of the symptoms of the disorder. - View Dependent Claims (40)
- ##STR24## or a pharmaceutically acceptable salt or ester thereof, wherein;
-
41. A method for treating endothelin-mediated disorders, comprising administering a therapeutically effective amount of a compound of formula (V):
- or a pharmaceutically acceptable salt or ester thereof, wherein;
X and Y are independently selected from O, S, --N(R28)--, --(CH2)v --, --N(R28)(CH2)v --, --S--(CH2)v -- and --O--(CH2)v -- where v is 0 to 12, provided that at least one of X and Y is O, S or --N(R28)--; R28 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl, wherein the heterocycle groups are rings containing 3 to 7 members and one heteroatom selected from S, O and N; R1 is hydrogen, --(CH2)q (CO2 R4), --(CH2)q (OH), CN, --C(R7)═
NOR8, NO2,--(CH2)q R9, --C.tbd.CR10, --CR11 ═
C(R12) (R13), tetrazolyl, --(CH2)q C(═
O)CH2 C(═
O)CO2 H, --CO(R14), CONR27 R26, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamoyl, thiocarbamoyl, or a nitrogen-containing ring, wherein the nitrogen-containing ring is selected from heterocycles containing 3 to 7 members in the ring including at least one nitrogen atom and optionally containing one or more additional heteroatoms selected from nitrogen, oxygen and sulfur in addition to the carbon atom(s) present;q is 0 to 6; R4 is hydrogen, lower alkyl or haloalkyl; R7 is selected from hydrogen, alkyl and haloalkyl; R8 is hydrogen, arylalkyl or --(lower alkyl)CO2 R17 ; R9 is --CN, --CO2 R19, --CH2 OH, or carbamoyl; R10 is --CO2 H or carboxyphenyl; R11 is hydrogen, alkyl or arylalkyl; R12 and R13 are independently hydrogen, --CO2 R18, --CN, aryl, lower alkyl, heteroaryl, lower alkyl or --NHC(O)aryl, provided that one of R12 and R13 is --CO2 H; R14 is hydrogen, alkyl, --(lower alkyl)carboxy, arylalkenyl, heteroarylalkenyl or --CO2 H; R17, R18 and R19 are independently selected from hydrogen, alkyl and haloalkyl; R26 and R27 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl; R32, R33, R34, R35, R36 and R37 are each independently selected from (i), (ii) and (iii) as follows; (i) R32, R33, R34, R35, R36 and R37 are each independently selected from among H, NHR38, CONR38, NO2, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxy, haloalkyl, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, alkenylthio, alkenylamino, alkenyloxy, alkenylsulfinyl, alkenylsulfonyl, aminocarbonyl, carboxy, carboxyalkyl, carboxyalkenyl, and formyl;
or(ii) at least two of R32, R33 and R34 or R35, R36 and R37 substitute adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, containing 1 to 4 carbons in the alkyl portion and which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and the others of R32, R33, R34, R35, R36 and R37 are selected as in (i);
or(iii) at least two of R32, R33 and R34 substitute adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, containing 1 to 4 carbons in the alkyl portion and which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and at least two of R35, R36 and R37 substitute adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, containing 1 to 4 carbons in the alkyl portion and which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and the others of R32, R33, R34, R35, R36 and R37 are selected as in (i); and R38 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl; and the effective amount is sufficient to ameliorate one or more of the symptoms of the disorder. - View Dependent Claims (42)
- or a pharmaceutically acceptable salt or ester thereof, wherein;
-
43. A method for treating endothelin-mediated disorders, comprising administering a therapeutically effective amount of a compound of formula (VII):
- or a pharmaceutically acceptable salt or ester thereof, wherein;
X and Y are independently selected from O, S, --N(R28)--, --(CH2)v --, --N(R28)(CH2)v --, --S--(CH2)v -- and --O--(CH2)v -- where v is 0 to 12, provided that at least one of X and Y is O, S or --N(R28)--; R28 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl, wherein the heterocycle groups are rings containing 3 to 7 members and one heteroatom selected from S, O and N; R1 is selected from hydrogen, --(CH2)n --A in which n is 0 to 6, --(CH2)q (CO2 R4), --(CH2)q (OH), CN, --C(R7)═
NOR8, NO2, --(CH2)q R9, --C.tbd.--CR10, --CR11 ═
C(R12)(R13), tetrazolyl, CONR27 R26, --CH═
CH--Z, --C(R4)═
C(R4)--Z, --C.tbd.CZ, --O--(CH2)q Z, --CO2 H, --S--(CH2)q Z, --(CH2)q C(O)Z, --(CH2)q C(═
O)CH2 C(═
O)CO2 H, --CO(R14), alkylthio, alkylsulfinyl, alkylsulfonyl, carbamoyl, thiocarbamoyl and nitrogen-containing rings, wherein the nitrogen-containing rings are selected from heterocycles containing 3 to 7 members in the ring including at least one nitrogen atom and optionally containing one or more additional heteroatoms selected from nitrogen, oxygen and sulfur in addition to the carbon atom(s) present;A is selected from among CO2 R4, carboxylic acid, alkylthioic acid, alkyldithoic acid, alkylimidic acid, sulfinic acid, sulfonic acid, phosphonic, sulfinimidic acid, sulfonimidic acid, sulfonamide, alkylhydroxamic acid, hydrazide, amide, hydroxyl, and hydrogen; Z is carboxylic acid, alkylthioic acid, alkyldithoic acid, alkylimidic acid, sulfinic acid, sulfonic acid, phosphonic, sulfinimidic acid, sulfonimidic acid, sulfonamide, alkylhydroxamic acid, hydrazide, amide, hydroxyl, hydrogen, alkyl, alkenyl, or tetrazolyl; q is 0 to 6; R4 is hydrogen, lower alkyl or haloalkyl; R7 is selected from hydrogen, alkyl and haloalkyl; R8 is hydrogen, arylalkyl or --(lower alkyl)CO2 R17 ; R9 is --CN, --CO2 R19, --CH2 OH, or carbamoyl; R10 is --CO2 H or carboxyphenyl; R11 is hydrogen, alkyl or arylalkyl; R12 and R13 are independently hydrogen, --CO2 R18, --CN, aryl, lower alkyl, heteroaryl lower alkyl or --NHC(O)aryl, provided that one of R12 and R13 is --CO2 H; R14 is hydrogen, alkyl, --(lower alkyl)carboxy, arylalkenyl, heteroarylalkenyl or --CO2 H; R17, R18 and R19 are independently selected from hydrogen, alkyl and haloalkyl; R26 and R27 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl; R32, R33, R34, R35, R36 and R37 are each independently selected from (i), (ii) and (iii) as follows; (i) R32, R33, R34, R35, R36 and R37 are each independently selected from among H, NHR38, CONR38, NO2, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxy, haloalkyl, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, alkenylthio, alkenylamino, alkenyloxy, alkenylsulfinyl, alkenylsulfonyl, aminocarbonyl, carboxy, carboxyalkyl, carboxyalkenyl, and formyl;
or(ii) at least two of R32, R33 and R34 or R35, R36 and R37 substitute adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, containing 1 to 4 carbons in the alkyl portion and which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and the others of R32, R33, R34, R35, R36 and R37 are selected as in (i);
or(iii) at least two of R32, R33 and R34 substitute adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, containing 1 to 4 carbons in the alkyl portion and which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and at least two of R35, R36 and R37 substitute adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, containing 1 to 4 carbons in the alkyl portion and which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and the others of R32, R33, R34, R35, R36 and R37 are selected as in (i); and R38 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl; and the effective amount is sufficient to ameliorate one or more of the symptoms of the disorder. - View Dependent Claims (44)
- or a pharmaceutically acceptable salt or ester thereof, wherein;
-
45. 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 formula (I):
- or pharmaceutically acceptable salts or esters thereof, wherein;
Ar3 is phenyl or pyrimidyl; X and Y are independently selected from O, S, --N(R28)--, --(CH2)v --, --N(R28)(CH2)v --, --S--(CH2)v -- and --O--(CH2)v -- where v is 0 to 12, provided that at least one of X and Y is O, S or --N(R28)--; R28 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl, wherein the heterocycle groups are rings containing 3 to 7 members and one heteroatom selected from S, O and N; Ar1 and Ar2 are independently selected from among aryl and heteroaryl groups containing one ring 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; and the contacting is effected prior to, simultaneously with or subsequent to contacting the receptors with the endothelin peptide.
- or pharmaceutically acceptable salts or esters thereof, wherein;
-
46. 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 formula (V):
- ##STR28## or pharmaceutically acceptable salts or esters thereof, wherein;
X and Y are independently selected from O, S, --N(R28)--, --(CH2)v --, --N(R28)(CH2)v --, --S--(CH2)v -- and --O--(CH2)v -- where v is 0 to 12, provided that at least one of X and Y is O, S or --N(R28)--;R28 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl, wherein the heterocycle groups are rings containing 3 to 7 members and one heteroatom selected from S, O and N; R1 is hydrogen, --(CH2)q (CO2 R4), --(CH2)q (OH), CN, --C(R7)═
NOR8, NO2, --(CH2)q R9, --C.tbd.CR10, --CR11 ═
C(R12)(R13), tetrazolyl, --(CH2)q C(═
O)CH2 C(═
O)CO2 H, --CO(R14), CONR27 R26, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamoyl, thiocarbamoyl, or a nitrogen-containing ring, wherein the nitrogen-containing ring is selected from heterocycles containing 3 to 7 members in the ring including at least one nitrogen atom and optionally containing one or more additional heteroatoms selected from nitrogen, oxygen and sulfur in addition to the carbon atom(s) present;q is 0 to 6; R4 is hydrogen, lower alkyl or haloalkyl; R7 is selected from hydrogen, alkyl and haloalkyl; R8 is hydrogen, arylalkyl or --(lower alkyl)CO2 R17 ; R9 is --CN, --CO2 R19, --CH2 OH, or carbamoyl; R10 is --CO2 H or carboxyphenyl; R11 is hydrogen, alkyl or arylalkyl; R12 and R13 are independently hydrogen, --CO2 R18, --CN, aryl, lower alkyl, heteroaryl, lower alkyl or --NHC(O)aryl, provided that one of R12 and R13 is --CO2 H; R14 is hydrogen, alkyl, --(lower alkyl)carboxy, arylalkenyl, heteroarylalkenyl or --CO2 H; R17, R18 and R19 are independently selected from hydrogen, alkyl and haloalkyl; R26 and R27 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl; R32, R33, R34, R35, R36 and R37 are each independently selected from (i), (ii) and (iii) as follows; (i) R32, R33, R34, R35, R36 and R37 are each independently selected from among H, NHR38, CONR38, NO2, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxy, haloalkyl, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, alkenylthio, alkenylamino, alkenyloxy, alkenylsulfinyl, alkenylsulfonyl, aminocarbonyl, carboxy, carboxyalkyl, carboxyalkenyl, and formyl;
or(ii) at least two of R32, R33 and R34 or R35, R36 and R37 substitute adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, containing 1 to 4 carbons in the alkyl portion and which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and the others of R32, R33, R34, R35, R36 and R37 are selected as in (i);
or(iii) at least two of R32, R33 and R34 substitute adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, containing 1 to 4 carbons in the alkyl portion and which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and at least two of R35, R36 and R37 substitute adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, containing 1 to 4 carbons in the alkyl portion and which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and the others of R32, R33, R34, R35, R36 and R37 are selected as in (i); and R38 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl; and the contacting is effected prior to, simultaneously with or subsequent to contacting the receptors with the endothelin peptide. - View Dependent Claims (47)
- ##STR28## or pharmaceutically acceptable salts or esters thereof, wherein;
-
48. 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 formula (VIII):
- or pharmaceutically acceptable salts or esters thereof, wherein;
X and Y are independently selected from O, S, --N(R28)--, --(CH2)v --, --N(R28)(CH2)v --, --S--(CH2)v -- and --O--(CH2)v -- where v is 0 to 12, provided that at least one of X and Y is O, S or --N(R28)--; R28 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl, wherein the heterocycle groups are rings containing 3 to 7 members and one heteroatom selected from S, O and N; R1 is hydrogen, --(CH2)q (CO2 R4), --(CH2)q (OH), CN, --C(R7)═
NOR8, NO2, --(CH2)q R9, --C.tbd.CR10, --CR11 ═
C(R12)(R13), tetrazolyl, --(CH2)q C(═
O)CH2 C(═
O)CO2 H, --CO(R14), CONR27 R26, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamoyl, thiocarbamoyl, or a nitrogen-containing ring, wherein the nitrogen-containing ring is selected from heterocycles containing 3 to 7 members in the ring including at least one nitrogen atom and optionally containing one or more additional heteroatoms selected from nitrogen, oxygen and sulfur in addition to the carbon atom(s) present;q is 0 to 6; R4 is hydrogen, lower alkyl or haloalkyl; R7 is selected from hydrogen, alkyl and haloalkyl; R8 is hydrogen, arylalkyl or --(lower alkyl)CO2 R17 ; R9 is --CN, --CO2 R19, --CH2 OH, or carbamoyl; R10 is --CO2 H or carboxyphenyl; R11 is hydrogen, alkyl or arylalkyl; R12 and R13 are independently hydrogen, --CO2 R18, --CN, aryl, lower alkyl, heteroaryl, lower alkyl or --NHC(O)aryl, provided that one of R12 and R13 is --CO2 H; R14 is hydrogen, alkyl, --(lower alkyl)carboxy, arylalkenyl, heteroarylalkenyl or --CO2 H; R17, R18 and R19 are independently selected from hydrogen, alkyl and haloalkyl; R26 and R27 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl; R32, R33, R34, R35, R36 and R37 are each independently selected from (i), (ii) and (iii) as follows; (i) R32, R33, R34, R35, R36 and R37 are each independently selected from among H, NHR38, CONR38, NO2, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxy, haloalkyl, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, alkenylthio, alkenylamino, alkenyloxy, alkenylsulfinyl, alkenylsulfonyl, aminocarbonyl, carboxy, carboxyalkyl, carboxyalkenyl, and formyl;
or(ii) at least two of R32, R33 and R34 or R35, R36 and R37 substitute adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, containing 1 to 4 carbons in the alkyl portion and which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and the others of R32, R33, R34, R35, R36 and R37 are selected as in (i);
or(iii) at least two of R32, R33 and R34 substitute adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, containing 1 to 4 carbons in the alkyl portion and which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and at least two of R35, R36 and R37 substitute adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, containing 1 to 4 carbons in the alkyl portion and which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and the others of R32, R33, R34, R35, R36 and R37 are selected as in (i); and R38 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl; and the contacting is effected prior to, simultaneously with or subsequent to contacting the receptors with the endothelin peptide.
- or pharmaceutically acceptable salts or esters thereof, wherein;
-
49. A method for inhibiting the binding of an endothelin peptide to endothelinA (ETA) or endothelinB (ETB) receptors, comprising contacting the receptors an endothelin peptide and with one or more compounds formula (I):
- ##STR30## or pharmaceutically acceptable salts or esters thereof, wherein;
Ar3 is phenyl or pyrimidyl;X and Y are independently selected from O, S, --N(R28)--, --(CH2)v --, --N(R28)(CH2)v --, --S--(CH2)v -- and --O--(CH2)v -- where v is 0 to 12, provided that at least one of X and Y is O, S or --N(R28)--; R28 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl, wherein the heterocycle groups are rings containing 3 to 7 members and one heteroatom selected from S, O and N; Ar1 and Ar2 are independently selected from among aryl and heteroaryl groups containing one ring 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; and the contacting is effected prior to, simultaneously with or subsequent to contacting the receptors with the endothelin peptide.
- ##STR30## or pharmaceutically acceptable salts or esters thereof, wherein;
-
50. A pharmaceutical composition formulated for single dosage administration, comprising an effective amount of one or more compounds of formula (I):
- ##STR31## or a pharmaceutically acceptable salt or ester thereof, wherein;
Ar3 is phenyl or pyrimidyl;X and Y are independently selected from O, S, --N(R28)--, --(CH2)v --, --N(R28)(CH2)v --, --S--(CH2)v -- and --O--(CH2)v -- where v is 0 to 12, provided that at least one of X and Y is O, S or --N(R28)--; R28 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl, wherein the heterocycle groups are rings containing 3 to 7 members and one heteroatom selected from S, O and N; Ar1 and Ar2 are independently selected from among aryl and heteroaryl groups containing one ring 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; and the amount is effective for ameliorating the symptoms of an endothelin-mediated disease.
- ##STR31## or a pharmaceutically acceptable salt or ester thereof, wherein;
-
51. A pharmaceutical composition formulated for single dosage administration, comprising an effective amount of one or more compounds of formula (V):
- ##STR32## or pharmaceutically acceptable salt or ester thereof, wherein;
X and Y are independently selected from O, S, --N(R28)--, --(CH2)v --, --N(R28)(CH2)v --, --S--(CH2)v -- and --O--(CH2)v -- where v is 0 to 12, provided that at least one of X and Y is O, S or --N(R28)--;R28 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl, wherein the heterocycle groups are rings containing 3 to 7 members and one heteroatom selected from S, O and N; R1 is hydrogen, --(CH2)q (CO2 R4), --(CH2)q (OH), CN, --C(R7)═
NOR8, NO2, --(CH2)q R9, --C.tbd.CR10, --CR11 ═
C(R12)(R13), tetrazolyl, (CH2)q C(═
O)CH2 C(═
O)CO2 H, --CO(R14), CONR27 R26, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamoyl, thiocarbamoyl, or a nitrogen-containing ring, wherein the nitrogen-containing ring is selected from heterocycles containing 3 to 7 members in the ring including at least one nitrogen atom and optionally containing one or more additional heteroatoms selected from nitrogen, oxygen and sulfur in addition to the carbon atom(s) present;q is 0 to 6; R4 is hydrogen, lower alkyl or haloalkyl; R7 is selected from hydrogen, alkyl and haloalkyl; R8 is hydrogen, arylalkyl or --(lower alkyl)CO2 R17 ; R9 is --CN, --CO2 R19, --CH2 OH, or carbamoyl; R10 is --CO2 H or carboxyphenyl; R11 is hydrogen, alkyl or arylalkyl; R12 and R13 are independently hydrogen, --CO2 R18, --CN, aryl, lower alkyl, heteroaryl, lower alkyl or --NHC(O)aryl, provided that one of R12 and R13 is --CO2 H; R14 is hydrogen, alkyl, --(lower alkyl)carboxy, arylalkenyl, heteroarylalkenyl or --CO2 H; R17, R18 and R19 are independently selected from hydrogen, alkyl and haloalkyl; R26 and R27 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl; R32, R33, R34, R35, R36 and R37 are each independently selected from (i), (ii) and (iii) as follows; (i) R32, R33, R34, R35, R36 and R37 are each independently selected from among H, NHR38, CONR38, NO2, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxy, haloalkyl, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, alkenylthio, alkenylamino, alkenyloxy, alkenylsulfinyl, alkenylsulfonyl, aminocarbonyl, carboxy, carboxyalkyl, carboxyalkenyl, and formyl;
or(ii) at least two of R32, R33, and R34 or R35, R36 and R37 substitute adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, containing 1 to 4 carbons in the alkyl portion and which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and the others of R32, R33, R34, R35, R36 and R37 are selected as in (i);
or(iii) at least two of R32, R33 and R34 substitute adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, containing 1 to 4 carbons in the alkyl portion and which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and at least two of R35, R36 and R37 substitute adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, containing 1 to 4 carbons in the alkyl portion and which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and the others of R32, R33, R34, R35, R36 and R37 are selected as in (i); and R38 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl; and the amount is effective for ameliorating the symptoms of an endothelin-mediated disease. - View Dependent Claims (52)
- ##STR32## or pharmaceutically acceptable salt or ester thereof, wherein;
-
53. A pharmaceutical composition formulated for single dosage administration, comprising an effective amount of one or more compounds of formula (VIII):
- or pharmaceutically acceptable salt or ester thereof, wherein;
X and Y are independently selected from O, S, --N(R28)--, --(CH2)v --, --N(R28)(CH2)v --, --S--(CH2)v -- and --O--(CH2)v -- where v is 0 to 12, provided that at least one of X and Y is O, S or --N(R28)--; R28 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl, wherein the heterocycle groups are rings containing 3 to 7 members and one heteroatom selected from S, O and N; R1 is hydrogen, --(CH2)q (CO2 R4), --(CH2)q (OH), CN, --C(R7)═
NOR8, NO2, --(CH2)q R9, --C.tbd.CR10, --CR11 ═
C(R12)(R13), tetrazolyl, --(CH2)q C(═
O)CH2 C(═
O)CO2 H, --CO(R14), CONR27 R26, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamoyl, thiocarbamoyl, or a nitrogen-containing ring, wherein the nitrogen-containing ring is selected from heterocycles containing 3 to 7 members in the ring including at least one nitrogen atom and optionally containing one or more additional heteroatoms selected from nitrogen, oxygen and sulfur in addition to the carbon atom(s) present;q is 0 to 6; R4 is hydrogen, lower alkyl or haloalkyl; R7 is selected from hydrogen, alkyl and haloalkyl; R8 is hydrogen, arylalkyl or --(lower alkyl)CO2 R17 ; R9 is --CN, --CO2 R19, --CH2 OH, or carbamoyl; R10 is --CO2 H or carboxyphenyl; R11 is hydrogen, alkyl or arylalkyl; R12 and R13 are independently hydrogen, --CO2 R18, --CN, aryl, lower alkyl, heteroaryl, lower alkyl or --NHC(O)aryl, provided that one of R12 and R13 is --CO2 H; R14 is hydrogen, alkyl, --(lower alkyl)carboxy, arylalkenyl, heteroarylalkenyl or --CO2 H; R17, R18 and R19 are independently selected from hydrogen, alkyl and haloalkyl; R26 and R27 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl; R32, R33, R34, R35, R36 and R37 are each independently selected from (i), (ii) and (iii) as follows; (i) R32, R33, R34, R35, R36 and R37 are each independently selected from among H, NHR38, CONR38, NO2, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxy, haloalkyl, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, alkenylthio, alkenylamino, alkenyloxy, alkenylsulfinyl, alkenylsulfonyl, aminocarbonyl, carboxy, carboxyalkyl, carboxyalkenyl, and formyl;
or(ii) at least two of R32, R33 and R34 or R35, R36 and R37 substitute adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, containing 1 to 4 carbons in the alkyl portion and which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and the others of R32, R33, R34, R35, R36 and R37 are selected as in (i);
or(iii) at least two of R32, R33 and R34 substitute adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, containing 1 to 4 carbons in the alkyl portion and which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and at least two of R35, R36 and R37 substitute adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, containing 1 to 4 carbons in the alkyl portion and which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and the others of R32, R33, R34, R35, R36 and R37 are selected as in (i); and R38 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl; and the amount is effective for ameliorating the symptoms of an endothelin-mediated disease.
- or pharmaceutically acceptable salt or ester thereof, wherein;
-
54. An article of manufacture, comprising packaging material and a compound of formula (I):
- ##STR34## or a pharmaceutically acceptable salt or ester thereof, wherein;
Ar3 is phenyl or pyrimidyl;X and Y are independently selected from O, S, --N(R28)--, --(CH2)v --, --N(R28)(CH2)v --, --S--(CH2)v -- and --O--(CH2)v -- where v is 0 to 12, provided that at least one of X and Y is O, S or --N(R28)--; R28 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl, wherein the heterocycle groups are rings containing 3 to 7 members and one heteroatom selected from S, O and N; Ar1 and Ar2 are independently selected from among aryl and heteroaryl groups containing one ring 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; and
wherein;the compound is contained within the packaging material; the compound or salt 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 ET receptor with an IC50 of less than about 10 μ
M, and the article of manufacture comprises a label that indicates that the compound 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.
- ##STR34## or a pharmaceutically acceptable salt or ester thereof, wherein;
-
55. An article of manufacture, comprising packaging material and a compound of formula (V):
- ##STR35## or a pharmaceutically acceptable salt or ester thereof, wherein;
X and Y are independently selected from O, S, --N(R28)--, --(CH2)v --, --N(R28)(CH2)v --, --S--(CH2)v -- and --O--(CH2)v -- where v is 0 to 12, provided that at least one of X and Y is O, S or --N(R28)--;R28 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl, wherein the heterocycle groups are rings containing 3 to 7 members and one heteroatom selected from S, O and N; R1 is selected from hydrogen, --(CH2)n --A in which n is 0 to 6, --(CH2)q (CO2 R4), --(CH2)q (OH), CN, --C(R7)═
NOR8, NO2, --(CH2)q R9, --C.tbd.CR10, --CR11 ═
C(R12)(R13), tetrazolyl, CONR27 R26, --CH═
CH--Z, --C(R4)═
C(R4)--Z, --C.tbd.CZ, --O--(CH2)q Z, --CO2 H, --S--(CH2)q Z, --(CH2)q C(O)Z, --(CH2)q C(═
O)CH2 C(═
O)CO2 H, --CO(R14), alkylthio, alkylsulfinyl, alkylsulfonyl, carbamoyl, thiocarbamoyl, and nitrogen-containing rings, wherein the nitrogen-containing rings are selected from heterocycles containing 3 to 7 members in the ring including at least one nitrogen atom and optionally containing one or more additional heteroatoms selected from nitrogen, oxygen and sulfur in addition to the carbon atom(s) present;A is selected from among CO2 R4, carboxylic acid, alkylthioic acid, alkyldithoic acid, alkylimidic acid, sulfinic acid, sulfonic acid, phosphonic, sulfinimidic acid, sulfonimidic acid, sulfonamide, alkylhydroxamic acid, hydrazide, amide, alkylamide, alkyl-N-alkyl, alkyl-OH, hydroxyl, and hydrogen; Z is a carboxylic acid, alkylthioic acid, alkyldithoic acid, alkylimidic acid, sulfinic acid, sulfonic acid, phosphonic, sulfinimidic acid, sulfonimidic acid, sulfonamide, alkylhydroxamic acid, hydrazide, amide, hydroxyl, hydrogen, alkyl, alkenyl, or tetrazolyl; q is 0 to 6; R4 is hydrogen, lower alkyl or haloalkyl; R7 is selected from hydrogen, alkyl and haloalkyl; R8 is hydrogen, arylalkyl or --(lower alkyl)CO2 R17 ; R9 is --CN, --CO2 R19, --CH2 OH, or carbamoyl; R10 is --CO2 H or carboxyphenyl; R11 is hydrogen, alkyl or arylalkyl; R12 and R13 are independently hydrogen, --CO2 R18, --CN, aryl, lower alkyl, heteroaryl, lower alkyl or --NHC(O)aryl, provided that at least one of R12 and R13 is --CO2 H; R14 is hydrogen, alkyl, --(lower alkyl)carboxy, arylalkenyl, heteroarylalkenyl or --CO2 H; R17, R18 and R19 are independently selected from hydrogen, alkyl and haloalkyl; R26 and R27 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl; R32, R33, R34, R35, R36 and R37 are each independently selected from (i), (ii) and (iii) as follows; (i) R32, R33, R34, R35, R36 and R37 are each independently selected from among H, NHR38, CONR38, NO2, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxy, haloalkyl, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, alkenylthio, alkenylamino, alkenyloxy, alkenylsulfinyl, alkenylsulfonyl, aminocarbonyl, carboxy, carboxyalkyl, carboxyalkenyl, and formyl;
or(ii) at least two of R32, R33 and R34 or R35, R36 and R37 substitute adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, containing 1 to 4 carbons in the alkyl portion and which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and the others of R32, R33, R34, R35, R36 and R37 are selected as in (i);
or(iii) at least two of R32, R33 and R34 substitute adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, containing 1 to 4 carbons in the alkyl portion and which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and at least two of R35, R36 and R37 substitute adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, containing 1 to 4 carbons in the alkyl portion and which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and the others of R32, R33, R34, R35, R36 and R37 are selected as in (i); and R38 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl; and
wherein;the compound is contained within the packaging material; the compound or salt 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 ET receptor with an IC50 of less than about 10 μ
M; andthe article of manufacture comprises a label that indicates that the compound 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. - View Dependent Claims (56)
- ##STR35## or a pharmaceutically acceptable salt or ester thereof, wherein;
-
57. An article of manufacture, comprising packaging material and a compound of formula (III):
- or a pharmaceutically acceptable salt or ester thereof, wherein;
X and Y are independently selected from O, S, --N(R28)--, --(CH2)v --, --N(R28)(CH2)v --, --S--(CH2)v -- and --O--(CH2)v -- where v is 0 to 12, provided that at least one of X and Y is O, S or --N(R28)--; R28 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl, wherein the heterocycle grouns are rings containing 3 to 7 members and one heteroatom selected from S, O and N; R1 is hydrogen, --(CH2)q (CO2 R4), --(CH2)q (OH), CN, --C(R7)═
NOR8, NO2, --(CH2)q R9, --C.tbd.CR10, --CR11 ═
C(R12)(R13), tetrazolyl, (CH2)q C(═
O)CH2 C(═
O)CO2 H, --CO(R14), CONR27 R26, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamoyl, thiocarbamoyl, or a nitrogen-containing ring, wherein the nitrogen-containing ring is selected from heterocycles containing 3 to 7 members in the ring including at least one nitrogen atom and optionally containing one or more additional heteroatoms selected from nitrogen, oxygen and sulfur in addition to the carbon atom(s) present;q is 0 to 6; R4 is hydrogen, lower alkyl or haloalkyl; R7 is selected from hydrogen, alkyl and haloalkyl; R8 is hydrogen, arylalkyl or --(lower alkyl)CO2 R17 ; R9 is --CN, --CO2 R19, --CH2 OH, or carbamoyl; R10 is --CO2 H or carboxyphenyl; R11 is hydrogen, alkyl or arylalkyl; R12 and R13 are independently hydrogen, --CO2 R18, --CN, aryl, lower alkyl, heteroaryl, lower alkyl or --NHC(O)aryl, provided that one of R12 and R13 is --CO2 H; R14 is hydrogen, alkyl, --(lower alkyl)carboxy, arylalkenyl, heteroarylalkenyl or --CO2 H; R17, R18 and R19 are independently selected from hydrogen, alkyl and haloalkyl; R26 and R27 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl; R32, R33, R34, R35, R36 and R37 are each independently selected from (i), (ii) and (iii) as follows; (i) R32, R33, R34, R35, R36 and R37 are each independently selected from among H, NHR38, CONR38, NO2, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxy, haloalkyl, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, alkenylthio, alkenylamino, alkenyloxy, alkenylsulfinyl, alkenylsulfonyl, aminocarbonyl, carboxy, carboxyalkyl, carboxyalkenyl, and formyl;
or(ii) at least two of R32, R33 and R34 or R35, R36 and R37 substitute adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, containing 1 to 4 carbons in the alkyl portion and which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and the others of R32, R33, R34, R35, R36 and R37 are selected as in (i);
or(iii) at least two of R32, R33 and R34 substitute adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, containing 1 to 4 carbons in the alkyl portion and which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and at least two of R35, R36 and R37 substitute adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, containing 1 to 4 carbons in the alkyl portion and which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and the others of R32, R33, R34, R35, R36 and R37 are selected as in (i); and R38 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl; and
wherein;the compound is contained within the packaging material; the compound or salt 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 ET receptor with an IC50 of less than about 10 μ
M; andthe article of manufacture comprises a label that indicates that the compound 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.
- or a pharmaceutically acceptable salt or ester thereof, wherein;
-
58. A compound of formula (I):
- ##STR37## or a pharmaceutically acceptable salt or ester thereof, wherein;
Ar3 is phenyl;Ar1 and Ar2 are independently alkylenedioxyphenyl, alkylenethioxyoxyphenyl, or alkylenedithioxy phenyl; and X and Y are independently selected from O, S, --N(R28)--, --(CH2)v --, --N(R28)(CH2)v --, --S--(CH2)v -- and --O--(CH2)v --, where v is 0 to 12 provided that at least one of X and Y is O, S or --N(R28)--;
whereR28 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl, wherein the heterocycle groups are rings containing 3 to 7 members and one heteroatom selected from S, O and N. - View Dependent Claims (59, 60, 61, 62, 63)
- ##STR37## or a pharmaceutically acceptable salt or ester thereof, wherein;
-
64. A compound of formula (I):
- ##STR38## or a pharmaceutically acceptable salt or ester thereof, wherein;
Ar3 is pyrimidyl; X and Y are independently selected from O, S, --N(R28)--, --(CH2)v --, --N(R 28) (CH2)v --, --S--(CH2)v -- and --O--(CH2)v -- where v is 0 to 12; R28 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl, wherein the heterocycle groups are rings containing 3 to 7 members and one heteroatom selected from S, O and N; and Ar1 and Ar2 are independently selected from among aryl and heteroaryl groups containing one ring 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. - View Dependent Claims (65, 66, 67)
- ##STR38## or a pharmaceutically acceptable salt or ester thereof, wherein;
-
68. A pharmaceutical composition for treating endothelin-mediated disorders, comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt or ester thereof in a pharmaceutically acceptable carrier, wherein:
-
the compound has formula (II);
##STR39## X and Y are independently selected from O, S, --N(R28)--, --(CH2)v --, --N(R28)(CH2)v --, --S--(CH2)v -- and --O--(CH2)v -- where v is 0 to 12, provided that at least one of X and Y is O, S or --N(R28)--;R28 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl, wherein the heterocycle groups are rings containing 3 to 7 members and one heteroatom selected from S, O and N; Ar1 and Ar2 are independently selected from among aryl and heteroaryl groups containing one ring 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; R1 is selected from hydrogen, --(CH2)n --A in which n is 0 to 6, --(CH2)q (CO2 R4), --(CH2)q (OH), CN, --C(R7)═
NOR8, NO2, --(CH2)q R9, --C.tbd.--CR11 ═
C(R12)(R13), tetrazolyl, CONR27 R26, --CH═
CH--Z, --C(R4)═
C(R4)--Z, --C.tbd.CZ, --O--(CH2)q Z, --CO2 H, --S--(CH2)q Z, --(CH2)q C(O)Z, --(CH2)q C(═
O)CH2 C(═
O)CO2 H, --CO(R14), alkylthio, alkylsulfinyl, alkylsulfonyl, carbamoyl, thiocarbamoyl, and nitrogen-containing rings, wherein the nitrogen-containing rings are selected from heterocycles containing 3 to 7 members in the ring including at least one nitrogen atom and optionally containing one or more additional heteroatoms selected from nitrogen, oxygen and sulfur in addition to the carbon atom(s) present;A is selected from among CO2 R4, carboxylic acid, alkylthioic acid, alkyldithoic acid, alkylimidic acid, sulfinic acid, sulfonic acid, phosphonic, sulfinimidic acid, sulfonimidic acid, sulfonamide, alkylhydroxamic acid, hydrazide, amide, hydroxyl and hydrogen; Z is carboxylic acid, alkylthioic acid, alkyldithoic acid, alkylimidic acid, sulfinic acid, sulfonic acid, phosphonic, sulfinimidic acid, sulfonimidic acid, sulfonamide, alkylhydroxamic acid, hydrazide, amide, hydroxyl, hydrogen, alkyl, alkenyl, or tetrazolyl; q is 0 to 6; R4 is hydrogen, lower alkyl or haloalkyl; R7 is selected from hydrogen, alkyl and haloalkyl; R8 is hydrogen, arylalkyl or --(lower alkyl)CO2 R17 ; R9 is --CN, --CO2 R19, --CH2 OH, or carbamoyl; R10 is --CO2 H or carboxyphenyl; R11 is hydrogen, alkyl or arylalkyl; R12 and R13 are independently hydrogen, --CO2 R18, --CN, aryl, lower alkyl, heteroaryl, lower alkyl or --NHC(O)aryl, provided that one of R12 and R13 is --CO2 H; R14 is hydrogen, alkyl, --(lower alkyl)carboxy, arylalkenyl, heteroarylalkenyl or --CO2 H; R17, R18 and R19 are independently selected from hydrogen, alkyl and haloalkyl; R26 and R27 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o and p are independently 0 or 1; R2 and R3 are independently selected from alkyl, alkenyl, halo, haloalkyl, alkoxy, --S-alkyl, --NR29 -alkyl, aryl and heteroaryl; and R29 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl. - View Dependent Claims (69, 70)
-
-
71. A pharmaceutical composition for treating endothelin-mediated disorders, comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt or ester thereof in a pharmaceutically acceptable carrier, wherein:
- the compound has formula (V);
##STR41## X and Y are independently selected from O, S, --N(R28)--, --(CH2)v --, --N(R28)(CH2)v --, --S--(CH2)v -- and --O--(CH2)v -- where v is 0 to 12, provided that at least one of X and Y is O, S or --N(R28)--;R28 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl, wherein the heterocycle groups are rings containing 3 to 7 members and one heteroatom selected from S, O and N; R1 is hydrogen, --(CH2)q (CO2 R4), --(CH2)q (OH), CN, --C(R7)═
NOR8, NO2,--(CH2)q R9, --C.tbd.CR10, --CR11 ═
C(R12)(R13), tetrazolyl, --(CH2)q C(═
O)CH2 C(═
O)CO2 H, --CO(R14), CONR27 R26, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamoyl, thiocarbamoyl, or a nitrogen-containing ring, wherein the nitrogen-containing rings are selected from heterocycles containing 3 to 7 members in the ring including at least one nitrogen atom and optionally containing one or more additional heteroatoms selected from nitrogen, oxygen and sulfur in addition to the carbon atom(s) present;A is selected from among CO2 R4, carboxylic acid, alkylthioic acid, alkyldithoic acid, alkylimidic acid, sulfinic acid, sulfonic acid, phosphonic, sulfinimidic acid, sulfonimidic acid, sulfonamide, alkylhydroxamic acid, hydrazide, amide, hydroxyl and hydrogen; Z is carboxylic acid, alkylthioic acid, alkyldithoic acid, alkylimidic acid, sulfinic acid, sulfonic acid, phosphonic, sulfinimidic acid, sulfonimidic acid, sulfonamide, alkylhydroxamic acid, hydrazide, amide, hydroxyl, hydrogen, alkyl, alkenyl, or tetrazolyl; q is 0 to 6; R4 is hydrogen, lower alkyl or haloalkyl; R7 is selected from hydrogen, alkyl and haloalkyl; R8 is hydrogen, arylalkyl or --(lower alkyl)CO2 R17 ; R9 is --CN, --CO2 R19, --CH2 OH, or carbamoyl; R10 is --CO2 H or carboxyphenyl; R11 is hydrogen, alkyl or arylalkyl; R12 and R13 are independently hydrogen, --CO2 R18, --CN, aryl, lower alkyl, heteroaryl, lower alkyl or --NHC(O)aryl, provided that one of R12 and R13 is --CO2 H; R14 is hydrogen, alkyl, --(lower alkyl)carboxy, arylalkenyl, heteroarylalkenyl or --CO2 H; R17, R18 and R19 are independently selected from hydrogen, alkyl and haloalkyl; R26 and R27 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl; R32, R33, R34, R35, R36 and R37 are each independently selected from (i), (ii) and (iii) as follows; (i) R32, R33, R34, R35, R36 and R37 are each independently selected from among H, NHR38, CONR38, NO2, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxy, haloalkyl, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, alkenylthio, alkenylamino, alkenyloxy, alkenylsulfinyl, alkenylsulfonyl, aminocarbonyl, carboxy, carboxyalkyl, carboxyalkenyl, and formyl;
or(ii) at least two of R32, R33 and R34 or R35, R36 and R37 substitute adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, containing 1 to 4 carbons in the alkyl portion and which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and the others of R32, R33, R34, R35, R36 and R37 are selected as in (i);
or(iii) at least two of R32, R33 and R34 substitute adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, containing 1 to 4 carbons in the alkyl portion and which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and at least two of R35, R36 and R37 substitute adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, containing 1 to 4 carbons in the alkyl portion and which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and the others of R32, R33, R34, R35, R36 and R37 are selected as in (i); and R38 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl.
- the compound has formula (V);
-
72. A pharmaceutical composition for treating endothelin-mediated disorders, comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt or ester thereof in a pharmaceutically acceptable carrier, wherein:
-
the compound has formula (VII);
##STR42## wherein;
X and Y are independently selected from O, S, --N(R28)--, --(CH2)v --, --N(R28)(CH2)--, --S--(CH2)v -- and --O--(CH2)v -- where v is 0 to 12, provided that at least one of X and Y is O, S or --N(R28)--;R28 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl, wherein the heterocvcle groups are rings containing 3 to 7 members and one heteroatom selected from S, O and N; R1 is hydrogen, --(CH2)q (CO2 R4), --(CH2)q (OH), CN, --C(R7)═
NOR8, NO2,--(CH2)q R9, --C.tbd.CR10, --CR11 ═
C(R12)(R13), tetrazolyl, --(CH2)q C(═
O)CH2 C(═
O)CO2 H, --CO(R14), CONR27 R26, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamoyl, thiocarbamoyl, or a nitrogen-containing ring, wherein the nitrogen-containing rings are selected from heterocycles containing 3 to 7 members in the ring including at least one nitrogen atom and optionally containing one or more additional heteroatoms selected from nitrogen, oxygen and sulfur in addition to the carbon atom(s) present;A is selected from among CO2 R4, carboxylic acid, alkylthioic acid, alkyldithoic acid, alkylimidic acid, sulfinic acid, sulfonic acid, phosphonic, sulfinimidic acid, sulfonimidic acid, sulfonamide, alkylhydroxamic acid, hydrazide, amide, hydroxyl and hydrogen; Z is carboxylic acid, alkylthioic acid, alkyldithoic acid, alkylimidic acid, sulfinic acid, sulfonic acid, phosphonic, sulfinimidic acid, sulfonimidic acid, sulfonamide, alkylhydroxamic acid, hydrazide, amide, hydroxyl, hydrogen, alkyl, alkenyl, or tetrazolyl; q is 0 to 6; R4 is hydrogen, lower alkyl or haloalkyl; R7 is selected from hydrogen, alkyl and haloalkyl; R8 is hydrogen, arylalkyl or --(lower alkyl)CO2 R17 ; R9 is --CN, --CO2 R19, --CH2 OH, or carbamoyl; R10 is --CO2 H or carboxyphenyl; R11 is hydrogen, alkyl or arylalkyl; R12 and R13 are independently hydrogen, --CO2 R18, --CN, aryl, lower alkyl, heteroaryl, lower alkyl or --NHC(O)aryl, provided that one of R12 and R13 is --CO2 H; R14 is hydrogen, alkyl, --(lower alkyl)carboxy, arylalkenyl, heteroarylalkenyl or --CO2 H; R17, R18 and R19 are independently selected from hydrogen, alkyl and haloalkyl; R26 and R27 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl; R32, R33, R34, R35, R36 and R37 are each independently selected from (i), (ii) and (iii) as follows; (i) R32, R33, R34, R35, R36 and R37 are each independently selected from among H, NHR38, CONR38, NO2, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxy, haloalkyl, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, alkenylthio, alkenylamino, alkenyloxy, alkenylsulfinyl, alkenylsulfonyl, aminocarbonyl, carboxy, carboxyalkyl, carboxyalkenyl, and formyl;
or(ii) at least two of R32, R33 and R34 or R35, R36 and R37 substitute adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, containing 1 to 4 carbons in the alkyl portion and which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and the others of R32, R33, R34, R35, R36 and R37 are selected as in (i);
or(iii) at least two of R32, R33 and R34 substitute adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, containing 1 to 4 carbons in the alkyl portion and which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and at least two of R35, R36 and R37 substitute adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, containing 1 to 4 carbons in the alkyl portion and which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and the others of R32, R33, R34, R35, R36 and R37 are selected as in (i); and R38 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl. - View Dependent Claims (73)
-
Specification
-
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Current AssigneeEncysive Pharmaceuticals Incorporated (Pfizer Inc.)
-
Original AssigneeEncysive Pharmaceuticals Incorporated (Pfizer Inc.)
-
InventorsKois, Adam, Wu, Chengde, Chan, Ming Fai, Raju, Bore Gowda, Balaji, Vitukudi Narayanaiyengar, Castillo, Rosario Silvestre
-
Primary Examiner(s)Richter, Johann
-
Assistant Examiner(s)Oswecki, Jane C.
-
Application NumberUS08/590,139Time in Patent Office1,379 DaysField of Search549/435, 549/440, 549/443, 549/444, 549/447, 514/452, 514/464, 514/466, 514/450, 514/256, 514/381, 514/784, 544/335, 548/250, 548/253, 562/405, 562/462, 562/473, 562/474US Class Current514/256CPC Class CodesA61K 31/192 having aromatic groups, e.g...A61K 31/36 Compounds containing methyl...A61K 31/505 Pyrimidines; Hydrogenated p...A61K 31/506 not condensed and containin...A61P 29/00 Non-central analgesic, anti...C07D 239/60 Three or more oxygen or sul...C07D 317/64 Oxygen atomsC07D 405/14 containing three or more he...Y10S 206/828 Medicinal content
