Phosphoramidates, phosphinic amides and related compounds and the use thereof to modulate the activity of endothelin

• US 5,958,905 A
• Filed: 03/26/1996
• Issued: 09/28/1999
• Est. Priority Date: 03/26/1996
• Status: Expired due to Fees

• Current Assignee: Encysive Pharmaceuticals Incorporated (Pfizer Inc.)
• Original Assignee: Encysive Pharmaceuticals Incorporated (Pfizer Inc.)
• Inventors: Chan, Ming Fai, Verner, Erik Joel
• Primary Examiner(s): McKane, Joseph K.
• Application Number:
  US08/624,706
• Time in Patent Office: 1,281 Days
• Field of Search: 548/115, 548/113, 548/413, 514/92, 514/80, 514/91, 514/94, 514/82, 514/89, 514/95, 514/96, 514/99, 514/100, 514/85, 546/22, 546/23, 549/6, 549/218, 549/220, 544/243
• US Class Current: 514/92
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07F 9/247 of aromatic amines (N-C aromatic linkage)
• CPC Class Codes: C07F 9/650905 having the nitrogen atoms in the positions 1 and 2
• CPC Class Codes: C07F 9/6512 having the nitrogen atoms in positions 1 and 3
• CPC Class Codes: C07F 9/653 Five-membered rings

Abstract

Phosphoramidates and phosphinic amides and related compounds are provided. Also provided are methods that use the compounds for modulating the activity of the endothelin family of peptides are provided. In particular, compounds having formula: ##STR1## in which A, B, R¹ and R² are as described are provided. Also provided are methods for treating endothelin-mediated disorders by administering effective amounts of one or more of these compounds or prodrugs thereof. Methods for elucidating the physiological and pathophysiological roles of endothelin, as well as isolating endothelin receptors are also provided.

Claims

1. A compound of formula I:

##STR10## or a pharmaceutically acceptable salt or ester thereof, wherein;

Ar¹ is an optionally substituted heteroaryl group selected from the group consisting of quinolyl, thienyl, furyl, isoquinolyl, pyrrolyl, indolyl, oxadiazolyl, isoxazolyl, isothiazolyl, benzofuranyl and benzothienyl; and

A and B are independently selected from among halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, thioalkoxy, alkylamino, alkylthio, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, heteroaryloxy, heteroarylamino, heteroarylthio, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, amido and ureido, in which the alkyl, alkenyl and alkynyl groups have from 1 up to about 14 carbon atoms, and are either straight or branched chains or cyclic, and in which the aryl and heteroaryl groups have from 4 to 16 atoms in the ring.

2. A compound of claim 1, wherein:

Ar¹ is a 5 to 6 membered heteroaryl group that has one or two heteroatom(s).

3. A compound of claim 1, wherein Ar¹ is unsubstituted or is substituted with one or more substituents selected from among NH₂, NO₂, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl groups have from 1 up to about 14 carbon atoms and are either straight or branched chains or cyclic, and the aryl and heteroaryl groups have from about 4 to about 16 atoms in the ring.

4. A compound of claim 1, wherein Ar¹ is selected from among thienyl, furyl, isoquinolyl, pyrrolyl, indolyl, oxadiazolyl, isoxazolyl, isothiazolyl and.

22. A compound of claim 1 that is N-(4-bromo-3-methyl-5-isoxazolyl)diethylphosphoramidate.

23. A compound of claim 1 that is N-(3,4-dimethyl-5-isoxazolyl)diphenylphosphoramidate.

24. A compound of claim 1 that is N-(3,4-dimethyl-5-isoxazolyl)diphenylphosphinic amide.

25. A compound of claim 1 that is N-(4-bromo-3-methyl-5-isoxazolyl)diphenylphosphoramidate.

26. A compound of claim 1 that is N-(4-bromo-3-methyl-5-isoxazolyl)diphenylphosphinic amide.

43. A method for inhibiting the binding of an endothelin peptide to endothelin_A or endothelin_B receptors, comprising contacting the receptors an endothelin peptide and with one or more compounds of claim 1, wherein:

the contacting is effected prior to, simultaneously with or subsequent to contacting the receptors with the endothelin peptide.

44. A method for altering endothelin receptor-mediated activity, comprising contacting endothelin receptors with one or more compounds of claim 1.

46. An article of manufacture, comprising packaging material and a compound of claim 1 or pharmaceutically acceptable salt of a compound of claim 1 contained within the packaging material, wherein 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 packaging material includes 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.

82. A pharmaceutical composition, comprising a compound of claim 1,

or a pharmaceutically acceptable salt or ester of a compound of claim 1 in a pharmaceutically acceptable carrier, wherein:

Ar¹ is selected from among thienyl, furyl, isoquinolyl, pyrrolyl, pyridyl, indolyl, oxadiazolyl, pyrazolyl, isoxazolyl, isothiazolyl and pyrimidyl.

88. The compound of claim 1, wherein:

Ar¹ is thienyl, furyl, isoquinolyl, pyrrolyl, oxadiazolyl, isothiazolyl, pyridazinyl, benzofuryl or benzothienyl; and

A and B are independently selected from among halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, thioalkoxy, alkylamino, alkylthio, alkyloxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, heteroaryloxy, heteroarylamino, heteroarylthio, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, amido and ureido, in which the alkyl, alkenyl and alkynyl portions have from 1 up to about 14 carbon atoms, and are either straight or branched chains or cyclic, and in which the aryl and heteroaryl portions have from 4 to 16 members in the ring.

89. The compound of claim 1, wherein:

A and B are independently selected from among halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, thioalkoxy, alkylamino, alkylthio, alkyloxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, heteroaryloxy, heteroarylamino, heteroarylthio, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, amido and ureido, in which the alkyl, alkenyl and alkynyl portions have from 1 up to about 14 carbon atoms, and are either straight or branched chains or cyclic, and in which the aryl and heteroaryl portions have from 4 to 16 members in the ring;

Ar¹ is an isoxazolyl group of formula;

##STR32## R¹ is selected from among lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, halide or pseudohalide; and

R² is selected from among lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl or H.

5. A compound of formula I:

##STR11## or a pharmaceutically acceptable salt or ester thereof, wherein;

Ar¹ is selected from;

##STR12## in which each group is unsubstituted or substituted with one or more substituents R; and

each R, which may be the same or different, is independently selected from H, NH₂, NO₂, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl groups have from 1 up to about 14 carbon atoms and are either straight or branched chains or cyclic, and the aryl and heteroaryl groups have from about 4 to about 16 atoms;

A and B are each independently selected from among halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, thioalkoxy, alkylamino, alkylthio, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, heteroaryloxy, heteroarylamino, heteroarylthio, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, amido and ureido, in which the alkyl, alkenyl and alkynyl groups have from 1 up to about 14 carbon atoms, and are either straight or branched chains or cyclic, and in which the aryl and heteroaryl groups have from 4 to 16 atoms in the ring.

6. A compound of claim 5, wherein each R is selected from among H, halide, pseudohalide, alkyl, alkoxy, alkenyl or alkynyl.

7. A compound of formula I:

##STR13## or a pharmaceutically salt or ester thereof, wherein;

Ar¹ is an optionally substituted heteroaryl group selected from the group consisting of quinolyl, thienyl, furyl, isoquinolyl, pyrrolyl, indolyl, oxadiazolyl, isoxazolyl, isothiazolyl, benzofuranyl and benzothienyl;

A has the formula Ar² --X_p ;

B has the formula Ar³ --Y_o in which o and p are 0 or 1;

Ar² and Ar³ are each independently selected from aryl and heteroaryl groups; and

X and Y are each independently selected from among O, N, NR¹³, S or (CH₂)_n in which n is 0 to 10;

R¹³ has up to about 30 carbon atoms and is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, aralkyl, aralkoxy, halide, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R¹⁴ and S(O)_n R¹⁴ in which n is 0-2; and

R¹⁴ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl;

R¹³ and R¹⁴ are unsubstituted or are substituted with one or more substituents each selected independently from Z, which is hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, or cycloalkynyl.

8. A compound of claim 7, wherein Ar² and Ar³ are each independently selected from among phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrrolyl, pyrazinyl, thienyl and furyl.

35. A compound of claim 7, wherein Ar¹ is unsubstituted or is substituted with one or more substituents selected from among NH₂, NO₂, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl groups have from 1 up to about 14 carbon atoms and are either straight or branched chains or cyclic, and the aryl and heteroaryl groups have from about 4 to about 16 atoms in the ring.

36. A compound of claim 7, wherein Ar¹ is selected from among thienyl, furyl, isoquinolyl, pyrrolyl, indolyl, oxadiazolyl, isoxazolyl, and isothiazolyl.

47. A method for the treatment of endothelin-mediated diseases, comprising administering an effective amount of one or more compounds of claim 7 or pharmaceutically acceptable salts of the compounds of claim 7, wherein the effective amount is sufficient to ameliorate one or more of the symptoms of the disease.

48. The method of claim 47, 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, anaphylactic shock and hemorrhagic shock.

49. The method of claim 47, wherein the disease is selected from the group consisting of asthma and inflammatory diseases.

50. A method for inhibiting the binding of an endothelin peptide to endothelin_A or endothelin_B receptors, comprising contacting the receptors an endothelin peptide and with one or more compounds of claim 7, wherein:

the contacting is effected prior to, simultaneously with or subsequent to contacting the receptors with the endothelin peptide.

51. A method for altering endothelin receptor-mediated activity, comprising contacting endothelin receptors with one or more compounds of claim 7.

53. An article of manufacture, comprising packaging material and a compound of claim 7 or pharmaceutically acceptable salt of a compound of claim 7 contained within the packaging material, wherein 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 packaging material includes 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.

60. An article of manufacture, comprising packaging material and a compound of claim 7 or pharmaceutically acceptable salt of a compound of claim 7 contained within the packaging material, wherein 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 packaging material includes 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.

61. A method for the treatment of endothelin-mediated diseases, comprising administering an effective amount of one or more compounds of claim 7 or pharmaceutically acceptable salts of the compounds of claim 7, wherein the effective amount is sufficient to ameliorate one or more of the symptoms of the disease.

62. The method of claim 61, 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, anaphylactic shock and hemorrhagic shock.

63. The method of claim 61, wherein the disease is selected from the group consisting of asthma and inflammatory diseases.

64. A method for inhibiting the binding of an endothelin peptide to endothelin_A or endothelin_B receptors, comprising contacting the receptors an endothelin peptide and with one or more compounds of claim 7, wherein:

the contacting is effected prior to, simultaneously with or subsequent to contacting the receptors with the endothelin peptide.

65. A method for altering endothelin receptor-mediated activity, comprising contacting endothelin receptors with one or more compounds of claim 7.

84. A pharmaceutical composition, comprising a compound of claim 7, or a pharmaceutically acceptable salt or ester of a compound of claim 7 in a pharmaceutically acceptable carrier, wherein:

Ar¹ is selected from among thienyl, furyl, isoquinolyl, pyrrolyl, pyridyl, indolyl, oxadiazolyl, pyrazolyl, isoxazolyl, isothiazolyl and pyrimidyl.

9. A compound of formula I:

##STR14## or a pharmaceutically acceptable salt or ester thereof, wherein;

Ar¹ is an optionally substituted isoxazolyl or N-pyridazinyl; and

A and B are independently selected from among halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, thioalkoxy, alkylamino, alkylthio, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, heteroaryloxy, heteroarylamino, heteroarylthio, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, amido and ureido, in which the alkyl, alkenyl and alkynyl groups have from 1 up to about 14 carbon atoms, and are either straight or branched chains or cyclic, and in which the aryl and heteroaryl groups have from 4 to 16 atoms in the ring.

11. A compound of claim 9, wherein Ar¹ is an isoxazolyl.

12. A compound of claim 11 that has formula II:

##STR16## R¹ and R² are independently selected from H, NH₂, NO₂, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyloxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl groups have from 1 up to about 14 carbon atoms and are either straight or branched chains or cyclic, and the aryl groups have from about 4 to about 16 carbons, with the proviso that R² is not halide, pseudohalide, alkylsufinyl, alkylsulfonyl, arylsufinyl, arylsulfonyl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl or arylcarbonyl.

13. A compound of claim 12, wherein R¹ and R² are independently selected from among lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, halide, pseudohalide or H;

with the proviso that R² is not halide or pseudohalide.

14. A compound of claim 11 that has formula III:

##STR17## wherein X and Y are each independently selected from among O, N, NR¹³, S or (CH₂)_n in which n is 0 to 10;

o and p are independently 0 or 1;

R¹³ has up to about 30 carbon atoms and is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, aralkyl, aralkoxy, halide, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R¹⁴ and S(O)_n R¹⁴ in which n is 0-2;

R¹⁴ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl;

R¹³ and R¹⁴ are unsubstituted or are substituted with one or more substituents each selected independently from Z, which is hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl;

R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are each independently selected from among any of (i), (ii), (iii), (iv) or (v);

(i) R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are each independently selected from among H, NHOH, NH₂, NO₂, N₃, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, amido, ureido, or at least two of R³, R⁴, R⁵, R⁶ and R⁷ or R⁸, R⁹, R¹⁰, R¹¹ and R¹² form alkylenedioxy, in which the alkyl, alkenyl, alkynyl groups are straight or branched chains of from about 1 up to about 10 carbons, and in which the aryl groups have from 3 up to about 10 carbons;

(ii) R⁴ and R⁷ and/or R¹⁰ and R¹¹ together are substituted or unsubstituted 1,3-butadienyl, 4-dimethylamino-1,3butadienyl, 1-chloro-1,3-butadienyl, 1-aza-1,3-butadienyl or 2-aza-1,3-butadienyl groups; and

the others of R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are as defined in (i) above;

or alternatively,

(iii) R⁷ and R³ and/or R¹¹ and R¹² together are substituted or unsubstituted 1,3-butadienyl, 4-dimethylamino-1,3butadienyl, 1-chloro-1,3-butadienyl, 1-aza-1,3-butadienyl or 2-aza-1,3-butadienyl groups; and

the others of R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are as defined in (i) above;

or

(iv) R³, R⁵, and R⁷ and R¹⁰, R¹¹ and R⁸ are H are as defined in (i); and

R⁴ and R⁶ and/or R⁹ and R¹² are each independently selected from alkyl, alkoxy, halide, aminoalkyl, dialkylaminoalkyl, in which the alkyl and alkoxy groups have from 1 to 10, preferably 1 to 6 carbons, and are straight or branched chains, and the others of R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are as defined in (i) above;

or

(v) any two of R³, R⁴, R⁵, R⁶, and R⁷, and/or any two of R⁸, R⁹, R¹⁰, R¹¹ and R¹², which are each selected as in (i) form a ring or fused rings.

15. A compound of claim 14, wherein R¹³ is alkyl, halide, alkoxyalkyl, or haloalkyl in which the alkyl group is a straight or branched carbon chain.

16. A compound of claim 15, wherein R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are independently selected from among H, NH₂, halide, pseudohalide, lower alkyl, lower alkenyl and lower haloalkyl and at least three of R³, R⁴, R⁵, R⁶ and R⁷ are hydrogen and at least three of R⁸, R⁹, R¹⁰, R¹¹ and R¹² are hydrogen.

17. A compound of claim 14 that has formula IV:

##STR18##

18. A compound of claim 14, wherein R¹³ is a straight or branched carbon chain halide, alkoxyalkyl, or haloalkyl.

19. A compound of claim 17, wherein R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are independently selected from among H, NH₂, halide, pseudohalide, lower alkyl, lower alkenyl and lower haloalkyl and at least three of R³, R⁴, R⁵, R⁶ and R⁷ are hydrogen and at least three of R⁸, R⁹, R¹⁰, R¹¹ and R¹² are hydrogen.

20. A compound of claim 14 that has formula V:

21. A compound of claim 20, wherein R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are independently selected from among H, NH₂, halide, pseudohalide, lower alkyl, lower alkenyl and lower haloalkyl and at least three of R³, R⁴, R⁵, R⁶ and R⁷ are hydrogen and at least three of R⁸, R⁹, R¹⁰, R¹¹ and R¹² are hydrogen.

39. A compound of claim 18, wherein R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are independently selected from among H, NH₂, halide, pseudohalide, lower alkyl, lower alkenyl and lower haloalkyl and at least three of R³, R⁴, R⁵, R⁶ and R⁷ are hydrogen and at least three of R⁸, R⁹, R¹⁰, R¹¹ and R¹² are hydrogen.

85. A pharmaceutical composition, comprising a compound of claim 9 or a pharmaceutically acceptable salt or ester thereof in a pharmaceutically acceptable carrier.

90. The compound of claim 9 that has formula III:

##STR33## wherein;

X and Y are each independently selected from among O, N, NR¹³, S and (CH₂)_n, in which n is 0 to 10;

o and p are independently 0 or 1;

R¹³ is alkyl, alkoxyalkyl or haloalkyl, in which the alkyl group is a straight or branched carbon chain;

R¹³ is unsubstituted or substituted with one or more substituents each selected independently from Z, which is hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl;

R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are each independently selected from among any of (i), (ii), (iii), (iv) or (v);

(i) R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are each independently selected from among H, NHOH, NH₂, NO₂, N₃, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, amido, ureido, or at least two of R³, R⁴, R⁵, R⁶ and R⁷ or R⁸, R⁹, R¹⁰, R¹¹ and R¹² form alkylenedioxy, in which the alkyl, alkenyl, alkynyl groups are straight or branched chains from about 1 up to about 10 carbons, and in which the aryl groups have from 3 up to about 10 carbons;

(ii) R⁴ and R⁷ and/or R¹⁰ and R¹¹ together are substituted or unsubstituted 1,3-butadienyl, 4-dimethylamino-1,3butadienyl, 1-chloro-1,3-butadienyl, 1-aza-1,3-butadienyl or 2-aza-1,3-butadienyl groups; and

the others of R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are as defined in (i) above;

or alternatively,

(iii) R⁷ and R³ and/or R¹¹ and R¹² together are substituted or unsubstituted 1,3-butadienyl, 4-dimethylamino-1,3 butadienyl, 1-chloro-1,3-butadienyl, 1-aza-1,3-butadienyl or 2-aza-1,3-butadienyl groups; and

the others of R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are as defined in (i) above;

or

(iv) R³, R⁵, and R⁷ and R¹⁰, R¹¹ and R⁸ are H are as defined in (i); and

R⁴ and R⁶ and/or R⁹ and R¹² are each independently selected from alkyl, alkoxy, halide, aminoalkyl, dialkylaminoalkyl, in which the alkyl and alkoxy groups have from 1 to 10, and are straight or branched chains, and the others of R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are as defined in (i) above;

or

(v) any two of R³, R⁴, R⁵, R⁶, and R⁷, and/or any two of R⁸, R⁹, R¹⁰, R¹¹ and R¹², which are each selected as in (i) form fused or unfused carbocyclic or heterocyclic rings;

R¹ is selected from NH₂, NO₂, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyloxy, haloalkyl, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions have from 1 up to about 14 carbon atoms and are either straight or branched chains or cyclic, and the aryl portions have from about 4 to about 16 carbons; and

R² is selected from H, NH₂, NO₂, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyloxy, haloalkyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloaryl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions have from 1 up to about 14 carbon atoms and are either straight or branched chains or cyclic, and the aryl portions contain from about 4 to about 16 carbons, with the proviso that R² is not halide, pseudohalide, alkylsufinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl or arylcarbonyl.

91. The compound of claim 9 that has formula III:

##STR34## wherein;

X and Y are each independently selected from among O, N, NR¹³, S and (CH₂)_n, in which n is 0 to 10;

o and p are independently 0 or 1;

R¹, R² and R¹⁶ are independently selected from H, NH₂, NO₂, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, haloalkyl, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl groups have from 1 up to about 14 carbon atoms and are either straight or branched chains or cyclic, and the aryl groups have from about 4 to about 16 carbons, with the proviso that R² is not halide, pseudohalide, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl or arylcarbonyl;

R¹⁵ is selected from NH₂, NO₂, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, haloalkyl, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl groups have from 1 up to about 14 carbon atoms and are either straight or branched chains or cyclic, and the aryl groups have from about 4 to about 16 carbons, with the proviso that R² is not halide, pseudohalide, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl or arylcarbonyl;

R¹³ has up to about 30 carbon atoms and is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, aralkyl, aralkoxy, halide, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R¹⁴ and S(O)_n R¹⁴, in which n is 0-2;

R¹⁴ is selected from among hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl;

R¹³ and R¹⁴ are unsubstituted or are substituted with one or more substituents each selected independently from Z, which is hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl;

R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are each independently selected from among any of (i), (ii), (iii), (iv) or (v);

(i) R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are each independently selected from among H, NHOH, NH₂, NO₂, N₃, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, amido, ureido, or at least two of R³, R⁴, R⁵, R⁶ and R⁷ or R⁸, R⁹, R¹⁰, R¹¹ and R¹² form alkylenedioxy, in which the alkyl, alkenyl, alkynyl groups are straight or branched chains from about 1 up to about 10 carbons, and in which the aryl groups have from 3 up to about 10 carbons;

(ii) R⁴ and R⁷ and/or R¹⁰ and R¹¹ together are substituted or unsubstituted 1,3-butadienyl, 4-dimethylamino-1,3-butadienyl, 1-chloro-1,3-butadienyl, 1-aza-1,3-butadienyl or 2-aza-1,3-butadienyl groups; and

the others of R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are as defined in (i) above;

or alternatively,

(iii) R⁷ and R³ and/or R¹¹ and R¹² together are substituted or unsubstituted 1,3-butadienyl, 4-dimethylamino-1,3-butadienyl, 1-chloro-1,3-butadienyl, 1-aza-1,3-butadienyl or 2-aza-1,3-butadienyl groups; and

the others of R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are as defined in (i) above;

or

(iv) R³, R⁵, and R⁷ and R¹⁰, R¹¹ and R⁸ are H are as defined in (i); and

R⁴ and R⁶ and/or R⁹ and R¹² are each independently selected from alkyl, alkoxy, halide, aminoalkyl, dialkylaminoalkyl, in which the alkyl and alkoxy groups have from 1 to 10, and are straight or branched chains, and the others of R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are as defined in (i) above;

or

(v) any two of R³, R⁴, R⁵, R⁶, and R⁷, and/or any two of R⁸, R⁹, R¹⁰, R¹¹ and R¹², which are each selected as in (i) form fused or unfused carbocyclic or heterocyclic rings.

92. The compound of claim 9 that has formula V:

##STR35## wherein;

R¹ and R² are independently selected from H, NH₂, NO₂, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, haloalkyl, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl groups have from 1 up to about 14 carbon atoms and are either straight or branched chains or cyclic, and the aryl groups have from about 4 to about 16 carbons, with the proviso that R² is not halide, pseudohalide, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl or arylcarbonyl;

R¹³ has up to about 30 carbon atoms and is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, aralkyl, aralkoxy, halide, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R¹⁴ and S(O)_n R¹⁴, in which n is 0-2;

R¹⁴ is selected from among hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl;

R¹³ and R¹⁴ are unsubstituted or are substituted with one or more substituents each selected independently from Z, which is hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl;

R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are each independently selected from among any of (i), (ii), (iii), (iv) or (v);

(i) R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are each independently selected from among H, NHOH, NH₂, NO₂, N₃, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, amido, ureido, or at least two of R³, R⁴, R⁵, R⁶ and R⁷ or R⁸, R⁹, R¹⁰, R¹¹ and R¹² form alkylenedioxy, in which the alkyl, alkenyl, alkynyl groups are straight or branched chains of from about 1 up to about 10 carbons, and in which the aryl groups have from 3 up to about 10 carbons;

(ii) R⁴ and R⁷ and/or R¹⁰ and R¹¹ together are substituted or unsubstituted 1,3-butadienyl, 4-dimethylamino-1,3-butadienyl, 1-chloro-1,3-butadienyl, 1-aza-1,3-butadienyl or 2-aza-1,3-butadienyl groups; and

the others of R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are as defined in (i) above;

or alternatively,

(iii) R⁷ and R³ and/or R¹¹ and R¹² together are substituted or unsubstituted 1,3-butadienyl, 4-dimethylamino-1,3-butadienyl, 1-chloro-1,3-butadienyl, 1-aza-1,3-butadienyl or 2-aza-1,3-butadienyl groups; and

the others of R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are as defined in (i) above;

or

(iv) R³, R⁵, and R⁷ and R¹⁰, R¹¹ and R⁸ are H are as defined in (i); and

R⁴ and R⁶ and/or R⁹ and R¹² are each independently selected from alkyl, alkoxy, halide, aminoalkyl, dialkylaminoalkyl, in which the alkyl and alkoxy groups have from 1 to 10, and are straight or branched chains, and the others of R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are as defined in (i) above;

or

(v) any two of R³, R⁴, R⁵, R⁶, and R⁷, and/or any two of R⁸, R⁹, R¹⁰, R¹¹ and R¹², which are each selected as in (i) form fused or unfused carbocyclic or heterocyclic rings.

10. A compound of formula I:

##STR15## or a pharmaceutically acceptable salt or ester thereof, wherein;

Ar¹ is an optionally substituted isoxazolyl or N-pyridazinyl;

A has the formula Ar² --X_p ;

B has the formula Ar³ --Y_o in which o and p are 0 or 1;

Ar² and Ar³ are each independently selected from among phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrrolyl, pyrazinyl, thienyl and furyl; and

X and Y are each independently selected from among O, N, NR¹³, S or (CH₂)_n in which n is 0 to 10;

R¹³ has up to about 30 carbon atoms and is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, aralkyl, aralkoxy, halide, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R¹⁴ and S(O)_n R¹⁴ in which n is 0-2; and

R¹⁴ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl;

R¹³ and R¹⁴ are unsubstituted or are substituted with one or more substituents each selected independently from Z, which is hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl.

86. A pharmaceutical composition, comprising a compound of claim 10 or a pharmaceutically acceptable salt or ester thereof in a pharmaceutically acceptable carrier.

27. A pharmaceutical composition, comprising an effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt or ester of a compound of formula (I) in a pharmaceutically acceptable carrier, wherein;

Ar¹ is an optionally substituted heteroaryl group having one ring or two or three fused or unfused rings and from 3 up to about 21 atoms in the ring(s), in which the heteroaryl groups have one to three heteroatoms selected from O, S, and N;

A and B are independently selected from among alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, thioalkoxy, alkylamino, alkylthio, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, heteroaryloxy, heteroarylamino, heteroarylthio, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, amido and ureido, in which the alkyl, alkenyl and alkynyl groups have from 1 up to about 14 carbon atoms, and are either straight or branched chains or cyclic, and in which the aryl and heteroaryl groups have from 4 to 16 atoms in the ring; and

the amount is effective for ameliorating the symptoms of an endothelin-mediated disorder when a single dose of the composition is administered.

54. The composition of claim 27, wherein Ar¹ is a 5 to 6 membered heteroaryl group that has one or two heteroatom(s).

75. The composition of claim 27 that is formulated for single dosage administration.

76. The composition of claim 27 that is formulated for systemic administration .

77. The composition of claim 27 that contains about 0.1 ng/ml to about 100 μ

g/ml of the compound.

78. The composition of claim 27 that is formulated for parenteral administration.

79. The composition of claim 27 that is formulated for administration topical or local administration to the eye.

80. The composition of claim 27 that is formulated for oral administration.

81. The composition of claim 80 that is formulated as a tablet.

28. A method for the treatment of endothelin-mediated diseases, comprising administering an effective amount of one or more compounds of formula (I):

##STR19## or pharmaceutically acceptable salts of the compounds of formula (I), wherein;

Ar¹ is an optionally substituted heteroaryl group having one ring or two to three fused or unfused rings and from 3 up to about 21 atoms in the ring(s), in which the heteroaryl groups have one to three heteroatoms selected from among O, S and N; and

A and B are independently selected from among halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, thioalkoxy, alkylamino, alkylthio, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, heteroaryloxy, heteroarylamino, heteroarylthio, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, amido and ureido, in which the alkyl, alkenyl and alkynyl portions have from 1 up to about 14 carbon atoms, and are either straight or branched chains or cyclic, and in which the aryl and heteroaryl groups have from 4 to 16 atoms in the ring; and

the effective amount is sufficient to ameliorate one or more of the symptoms of the disease.

29. The method of claim 28, 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, anaphylactic shock and hemorrhagic shock.

30. The method of claim 28, wherein the disease is selected from the group consisting of asthma and inflammatory diseases.

57. The method of claim 28, wherein Ar¹ is a 5 to 6 membered heteroaryl group that has one or two heteroatom(s).

31. A method for inhibiting the binding of an endothelin peptide to endothelin_A or endothelin_B receptors, comprising contacting the receptors with an endothelin peptide and with one or more compounds of formula (I):

##STR20## or pharmaceutically acceptable salts of the compounds of formula (I), wherein;

Ar¹ is an optionally substituted heteroaryl group having one ring or two to three fused or unfused rings and from 3 up to about 21 atoms in the ring(s), in which the heteroaryl groups have one to three heteroatoms selected from among O, S and N; and

A and B are independently selected from among halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, thioalkoxy, alkylamino, alkylthio, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, heteroaryloxy, heteroarylamino, heteroarylthio, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, amido and ureido, in which the alkyl, alkenyl and alkynyl groups have from 1 up to about 14 carbon atoms, and are either straight or branched chains or cyclic, and in which the aryl and heteroaryl groups have from 4 to 16 atoms in the ring; and

the contacting is effected prior to, simultaneously with or subsequent to contacting the receptors with the endothelin peptide.

58. The method of claim 31, wherein Ar¹ is a 5 to 6 membered heteroaryl group that has one or two heteroatom(s).

32. A method for altering endothelin receptor-mediated activity, comprising contacting endothelin receptors with one or more compounds of formula (I):

##STR21## or pharmaceutically acceptable salts of the compounds of formula (I), wherein;

Ar¹ is an optionally substituted heteroaryl group, having one ring or two to three fused or unfused rings and from 3 up to about 21 atoms in the ring(s), in which the heteroaryl groups have one to three heteroatoms selected from among O, S and N; and

A and B are independently selected from among halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, thioalkoxy, alkylamino, alkylthio, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, heteroaryloxy, heteroarylamino, heteroarylthio, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, amido and ureido, in which the alkyl, alkenyl and alkynyl groups have from 1 up to about 14 carbon atoms, and are either straight or branched chains or cyclic, and in which the aryl and heteroaryl groups have from 4 to 16 atoms in the ring.

59. The method of claim 32, wherein Ar¹ is a 5 to 6 membered heteroaryl group that has one or two heteroatom(s).

33. A pharmaceutical composition formulated for single dosage administration, comprising an effective amount of one or more compounds of formula (I):

##STR22## or pharmaceutically acceptable salts or esters of the compounds of formula (I), wherein;

Ar¹ is an optionally substituted heteroaryl group having one ring or two to three fused or unfused rings and from 3 up to about 21 atoms in the ring(s), in which the heteroaryl groups have one to three heteroatoms selected from among O, S and N; and

A and B are independently selected from among alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, thioalkoxy, alkylamino, alkylthio, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, heteroaryloxy, heteroarylamino, heteroarylthio, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, amido and ureido, in which the alkyl, alkenyl and alkynyl groups have from 1 up to about 14 carbon atoms, and are either straight or branched chains or cyclic, and in which the aryl and heteroaryl groups have from 4 to 16 atoms in the ring; and

the amount is effective for ameliorating the symptoms of an endothelin-mediated disease.

55. The composition of claim 33, wherein Ar¹ is a 5 to 6 membered heteroaryl group that has one or two heteroatom(s).

34. An article of manufacture, comprising packaging material and a compound of formula (I):

##STR23## or a pharmaceutically acceptable salt of a compound of formula (I) contained within the packaging material, wherein;

Ar¹ is an optionally substituted heteroaryl group having one ring or two to three fused or unfused rings and from 3 up to about 21 atoms in the ring(s), in which the heteroaryl groups have one to three heteroatoms selected from among O, S and N; and

A and B are independently selected from among halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, thioalkoxy, alkylamino, alkylthio, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, heteroaryloxy, heteroarylamino, heteroarylthio, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, amido and ureido, in which the alkyl, alkenyl and alkynyl groups have from 1 up to about 14 carbon atoms, and are either straight or branched chains or cyclic, and in which the aryl and heteroaryl groups have from 4 to 16 atoms in the ring; and

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 packaging material includes 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.

56. The article of manufacture claim 34, wherein Ar¹ is a 5 to 6 membered heteroaryl group that has one or two heteroatom(s).

37. A compound of formula I:

##STR24## or a pharmaceutically acceptable salt or ester thereof, wherein;

Ar¹ is selected from;

##STR25## in which each group is unsubstituted or substituted with one or more substituents R; and

each R, which may be the same or different, is independently selected from H, NH₂, NO₂, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl groups have from 1 up to about 14 carbon atoms and are either straight or branched chains or cyclic, and the aryl and heteroaryl groups have from about 4 to about 16 atoms;

A has the formula Ar² --X_p ;

B has the formula Ar³ --Y_o in which o and p are 0 or 1;

Ar² and Ar³ are each independently selected from aryl and heteroaryl groups; and

X and Y are each independently selected from among O, N, NR¹³, S or (CH₂)_n in which n is 0 to 10;

R¹³ has up to about 30 carbon atoms and is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, aralkyl, aralkoxy, halide, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R¹⁴ and S(O)_n R¹⁴ in which n is 0-2; and

R¹⁴ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl;

R¹³ and R¹⁴ are unsubstituted or are substituted with one or more substituents each selected independently from Z, which is hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, or cycloalkynyl.

38. A compound of claim 37, wherein each R is selected from among H, halide, pseudohalide, alkyl, alkoxy, alkenyl or alkynyl.

40. A method for the treatment of endothelin-mediated diseases, comprising administering an effective amount of one or more compounds of formula I:

##STR26## or pharmaceutically acceptable salts or esters thereof, wherein;

Ar¹ is an optionally substituted heteroaryl group selected from the group consisting of quinolyl, thienyl, furyl, isoquinolyl, pyrrolyl, pyridyl, indolyl, oxadiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyrimidyl, benzofuranyl and benzothienyl;

A and B are independently selected from among halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, thioalkoxy, alkylamino, alkylthio, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, heteroaryloxy, heteroarylamino, heteroarylthio, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, amido and ureido, in which the alkyl, alkenyl and alkynyl groups have from 1 up to about 14 carbon atoms, and are either straight or branched chains or cyclic, and in which the aryl and heteroaryl groups have from 4 to 16 atoms in the ring; and

the effective amount is sufficient to ameliorate one or more of the symptoms of the disease.

41. The method of claim 40, 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, anaphylactic shock and hemorrhagic shock.

42. The method of claim 40, wherein the disease is selected from the group consisting of asthma and inflammatory diseases.

45. A pharmaceutical composition formulated for single dosage administration, comprising an effective amount of one or more compounds of formula I:

##STR27## or pharmaceutically acceptable salts or esters thereof, wherein;

Ar¹ is an optionally substituted heteroaryl group selected from the group consisting of quinolyl, thienyl, furyl, isoquinolyl, pyrrolyl, pyridyl, indolyl, oxadiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyrimidyl, benzofuranyl and benzothienyl;

A and B are independently selected from among halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, thioalkoxy, alkylamino, alkylthio, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, heteroaryloxy, heteroarylamino, heteroarylthio, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, amido and ureido, in which the alkyl, alkenyl and alkynyl groups have from 1 up to about 14 carbon atoms, and are either straight or branched chains or cyclic, and in which the aryl and heteroaryl groups have from 4 to 16 atoms in the ring; and

the amount is effective for ameliorating the symptoms of an endothelin-mediated disease.

52. A pharmaceutical composition formulated for single dosage administration, comprising an effective amount of one or more compounds of formula (I):

##STR28## or pharmaceutically acceptable salts or esters thereof, wherein;

Ar¹ is an optionally substituted heteroaryl group having one ring or two to three fused or unfused rings and from 3 up to about 21 atoms in the ring(s), in which the heteroaryl groups have one to three heteroatoms selected from among O, S and N;

A has the formula Ar² --X_p ;

B has the formula Ar³ --Y_o in which o and p are 0 or 1;

Ar² and Ar³ are each independently selected from aryl and heteroaryl groups; and

X and Y are each independently selected from among O, N, NR¹³, S or (CH₂)_n in which n is 0 to 10;

R¹³ has up to about 30 carbon atoms and is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, aralkyl, aralkoxy, halide, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R¹⁴ and S(O)_n R¹⁴ in which n is 0-2;

R¹⁴ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl;

R¹³ and R¹⁴ are unsubstituted or are substituted with one or more substituents each selected independently from Z, which is hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl; and

the amount is effective for ameliorating the symptoms of an endothelin-mediated disease.

66. A pharmaceutical composition formulated for single dosage administration, comprising an effective amount of one or more compounds of formula (I):

##STR29## or pharmaceutically acceptable salts or esters thereof, wherein;

Ar¹ is an optionally substituted heteroaryl group having one ring or two to three fused or unfused rings and from 3 up to about 21 atoms in the ring(s), in which the heteroaryl groups have one to three heteroatoms selected from among O, S and N;

A has the formula Ar² --X_p ;

B has the formula Ar³ --Y_o in which o and p are 0 or 1;

Ar² and Ar³ are each independently selected from aryl and heteroaryl groups; and

X and Y are each independently selected from among O, N, NR¹³, S or (CH₂)_n in which n is 0 to 10;

R¹³ has up to about 30 carbon atoms and is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, aralkyl, aralkoxy, halide, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R¹⁴ and S(O)_n R¹⁴ in which n is 0-2;

R¹⁴ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl;

R¹³ and R¹⁴ are unsubstituted or are substituted with one or more substituents each selected independently from Z, which is hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl; and

the amount is effective for ameliorating the symptoms of an endothelin-mediated disease.

67. A pharmaceutical composition, comprising an effective amount of a compound of formula I:

##STR30## or a pharmaceutically acceptable salt or ester of a compound of formula I in a pharmaceutially acceptable carrier, wherein;

Ar¹ is an optionally substituted heteroaryl group selected from the group consisting of quinolyl, thienyl, furyl, isoquinolyl, pyrrolyl, pyridyl, indolyl, oxadiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyrimidyl, benzofuranyl and benzothienyl;

A and B are independently selected from among halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, thioalkoxy, alkylamino, alkylthio, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, heteroaryloxy, heteroarylamino, heteroarylthio, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, amido and ureido, in which the alkyl, alkenyl and alkynyl groups have from 1 up to about 14 carbon atoms, and are either straight or branched chains or cyclic, and in which the aryl and heteroaryl groups have from 4 to 16 atoms in the ring;

the amount is effective for ameliorating the symptoms of an endothelin-mediated disorder when a single dose of the composition is administered.

68. The composition of claim 67 that is formulated for single dosage administration.

69. The composition of claim 67 that is formulated for systemic administration.

70. The composition of claim 67 that contains about 0.1 ng/ml to about 100 μ

g/ml of the compound.

71. The composition of claim 67 that is formulated for parenteral administration.

72. The composition of claim 67 that is formulated for administration topical or local administration to the eye.

73. The composition of claim 67 that is formulated for oral administration.

74. The composition of claim 73 that is formulated as a tablet.

87. A pharmaceutical composition of claim 67, wherein the compound is selected from the group consisting of N-(4-bromo-3-methyl-5-isoxazolyl)diethylphosphoramidate, N-(3,4-dimethyl-5-isoxazolyl)diphenylphosphoramidate, N-(3,4-dimethyl-5-isoxazolyl)diphenylphosphinic amide, N-(4-bromo-3-methyl-5-isoxazolyl)diphenylphosphoramidate and N-(4-bromo-3-methyl-5-isoxazolyl)diphenylphosphinic amide or a pharmaceutically acceptable salt, acid or ester thereof.

83. A pharmaceutical composition, comprising a compound of formula (I):

##STR31## or a pharmaceutically acceptable salt or ester of a compound of formula I in a pharmaceutically acceptable carrier, wherein;

Ar¹ is an optionally substituted heteroaryl group having one ring or two to three fused or unfused rings and from 3 up to about 21 atoms in the ring(s), in which the heteroaryl groups have one to three heteroatoms selected from among O, S and N;

A has the formula Ar² --X_p ;

B has the formula Ar³ --Y_o in which o and p are 1;

Ar² and Ar³ are each independently selected from aryl and heteroaryl groups; and

X and Y are each independently selected from among O, N, NR¹³, S or (CH₂)_n in which n is 0 to 10;

R¹³ has up to about 30 carbon atoms and is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, aralkyl, aralkoxy, halide, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R¹⁴ and S(O)_n R¹⁴ in which n is 0-2; and

R¹⁴ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl;

R¹³ and R¹⁴ are unsubstituted or are substituted with one or more substituents each selected independently from Z, which is hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl.