Claims
- 1. A compound that has the formula (I):
14
- 2. The compound of claim 1 that has the formula (I):
16
- 3. The compound of claim 2, wherein Ar1 and Ar2 are each independently selected from among aryl groups that contain 5 to 6 members in the ring and heteroaryl groups that contain 5 to 6 members in the ring and one or two heteroatom(s).
- 4. The compound of claim 2, wherein Ar1 and Ar2 are independently selected from naphthyl, phenyl, biphenyl, quinolyl, thienyl, furyl, isoquinolyl, pyrrolyl, pyridyl, indolyl, oxadiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyrimidyl, benzo[b]furyl and benzo[b]thienyl.
- 5. The compound of claim 4, wherein Ar1 and Ar2 are unsubstituted or are substituted with one or more substituents selected from among alkyl, alkoxy, alkenyl, alkynyl, halo, pseudohalo, (CH2)qCOR16 in which q is 0 to 6, (alkenyl)rCOR15 in which alkenyl is a straight or branched carbon chain containing at least two carbons and one unsaturated bond so that r, which is the number of carbons in the chain, is 0 or 2 to 6, (CH2)tOH in which t is 0 to 6, (alkenyl)uOH in which alkenyl is a straight or branched carbon chain containing at least two carbons and one unsaturated bond so that u is 0 or 2 to 6;
R15 and R16 are each independently hydrogen, alkyl, haloalkyl, aryl, aryloxy, heterocyclyl, arylalkyl, arylalkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, R20, C(O)R20, CO2R20, SH, S(O)nR20 in which n is 0-2, HNOH, (CH2)sR20 in which s is 1-6, NR20R21, OR20, R21NCOR20 or R21NSO2R20; R20 is selected from among hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, arylalkyl, cycloalkyl, cycloalkenyl or cycloalkynyl; and R21 is selected from among hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxy, aryloxy, heterocyclyl, arylalkyl, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl.
- 6. The compound of claim 4, wherein Ar3 is selected from among pyrazinyl and pyridyl groups.
- 7. The compound of claim 2, wherein Ar3 is selected from among pyrazinyl and pyridyl groups.
- 8. The compound of claim 6, wherein Ar3 is a pyrazinyl group.
- 9. The compound of claim 6, wherein Ar3 is a pyridyl group.
- 10. The compound of claim 7, wherein Ar3 is a pyrazinyl group.
- 11. The compound of claim 7, wherein Ar3 is a pyridyl group.
- 12. The compound of claim 2, wherein Ar1 and Ar2 are selected from phenyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazolyl, isoxazolyl, isothiazolyl and pyrimidyl.
- 13. The compound of claim 6, wherein Ar1 and Ar2 are selected from phenyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazolyl, isoxazolyl, isothiazolyl and pyrimidyl.
- 14. The compound of claim 7, wherein Ar1 and Ar2 are selected from phenyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazolyl, isoxazolyl, isothiazolyl and pyrimidyl.
- 15. The compound of claim 2, wherein Ar3 is substituted with a carboxyl group or an isostere thereof.
- 16. The compound of claim 6, wherein at least one of Ar1 and Ar2 is substituted phenyl and at least one of X and Y is O or S.
- 17. A pharmaceutical composition, comprising a compound of claim 1 or a pharmaceutically acceptable salt or ester of a compound of claim 1 in a pharmaceutically acceptable carrier.
- 18. The pharmaceutical composition of claim 17 that is formulated for single dosage administration.
- 19. A method for treating endothelin-mediated disorders, comprising administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt or ester thereof, wherein the effective amount is sufficient to ameliorate one or more of the symptoms of the disorder.
- 20. The method of claim 19, wherein the disorder is selected from the group consisting of hypertension, cardiovascular disease, asthma, pulmonary hypertension, inflammatory diseases, ophthalmologic disease, menstrual disorders, obstetric conditions, wounds, gastroenteric disease, renal failure, immunosuppressant-mediated renal vasoconstriction, erythropoietin-mediated vasoconstriction, endotoxin shock, anaphylactic shock and hemorrhagic shock.
- 21. The method of claim 19, wherein the disorder is selected from the group consisting of asthma and inflammatory diseases.
- 22. A method for inhibiting the binding of an endothelin peptide to an endothelin receptor, comprising contacting the receptor with an endothelin peptide and with one or more compounds of claim 1 or pharmaceutically acceptable salts or esters thereof, wherein the contacting is effected prior to, simultaneously with or subsequent to contacting the receptors with the endothelin peptide.
- 23. The method of claim 22, wherein the endothelin receptor is an endothelinA (ETA) or endothelinB (ETB) receptor.
- 24. An article of manufacture, comprising packaging material and a compound of claim 1 or a pharmaceutically acceptable salt or ester thereof, wherein the compound is contained within the packaging material; the compound, or salt or ester thereof, is effective for antagonizing the effects of endothelin, ameliorating the symptoms of an endothelin-mediated disorder, or inhibiting the binding of an endothelin peptide to an endothelin receptor with an IC50 of less than about 10 μM, and the packaging material includes a label that indicates that the compound or salt thereof is used for antagonizing the effects of endothelin, ameliorating the symptoms of an endothelin-mediated disorder, or inhibiting the binding of endothelin to an endothelin receptor with an IC50 of less than about 10 μM.
Parent Case Info
[0001] This application is a continuation of U.S. application Ser. No. 09/327,661, filed Jun. 8, 1999, entitled “SUBSTITUTED PHENYL COMPOUNDS AND DERIVATIVES THEREOF THAT MODULATE THE ACTIVITY OF ENDOTHELIN” to Chan et al.
[0002] U.S. application Ser. No. 09/327,661 is a continuation of U.S. application Ser. No. 08/590,139, filed Jan. 23, 1996, entitled “SUBSTITUTED PHENYL COMPOUNDS AND DERIVATIVES THEREOF THAT MODULATE THE ACTIVITY OF ENDOTHELIN” to Chan et al., now U.S. Pat. No. 5,977,117, which is a continuation-in-part of U.S. application Ser. No. 08/583,871, filed Jan. 5, 1996, entitled “SUBSTITUTED PHENYL COMPOUNDS AND DERIVATIVES THEREOF THAT MODULATE THE ACTIVITY OF ENDOTHELIN” to Chan et al., now abandoned.
Continuations (2)
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Number |
Date |
Country |
Parent |
09327661 |
Jun 1999 |
US |
Child |
09808771 |
Mar 2001 |
US |
Parent |
08590139 |
Jan 1996 |
US |
Child |
09327661 |
Jun 1999 |
US |
Continuation in Parts (1)
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Number |
Date |
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Parent |
08583871 |
Jan 1996 |
US |
Child |
08590139 |
Jan 1996 |
US |