Claims
- 1. A compound of Formula (I): wherein (Z) is P is tetrazol-5-yl, CO2R6 or C(O)N(R6)S(O)qR10; Ra is independently hydrogen or C1-6alkyl; R1 is independently hydrogen, Ar, C1-6alkyl, or C1-6 alkoxy; R2 is Ar, R3 and R5 are independently R13OH, C1-8alkoxy, S(O)qR11, N(R6)2, NO2, Br, F, I, Cl, CF3, NHCOR6, R13CO2R7, —X—R9—Y, —X(C(R6)2)OR6, —(CH2)mX—R8 or —X(CH2)nR8 wherein each methylene group within —X(CH2)nR8 may be unsubstituted or substituted by one or two —(CH2)nAr groups; R4 is independently R11, OH, C1-5alkoxy, S(O)qR11, N(R6)2, Br, F, I, Cl or NHCOR6, wherein the C1-5alkoxy may be unsubstituted or substituted by OH, methoxy or halogen; R6 is independently hydrogen or C1-8alkyl; R7 is independently hydrogen, C1-10alkyl, C2-10alkenyl or C2-8alkynyl, all of which may be unsubstituted or substituted by one or more OH, N(R6)2, CO2R12, halogen or XC1-10 alkyl; or R7 is (CH2)nAr; R8 is independently R11, CO2R7, CO2C(R11)2O(CO)XR7, PO3(R7)2, SO2NR7R11, NR7SO2R11, CONR7SO2R11, SO3R7, SO2R7, P(O)(OR7)R7, CN, CO2(CH2)mC(O)N(R6)2, C(R11)2N(R7)2, C(O)N(R6)2, NR7C(O)NR7SO2R11, OR6, or tetrazole which is substituted or unsubstituted by C1-6alkyl; R9 is independently a bond, C1-10alkylene, C1-10alkenylene, C1-10alkylidene, C1-10alkynylene, all of which may be linear or branched, or phenylene, all of which may be unsubstituted or substituted by one of more OH, N(R6)2, COOH or halogen; R10 is independently C1-10alkyl, N(R6)2 or Ar; R11 is independently hydrogen, Ar, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, all of which may be unsubstituted or substituted by one or more OH, CH2OH, N(R6)2 or halogen; R12 is independently hydrogen, C1-6alkyl, C2-6alkenyl or C2-7alkynyl; R13 is independently divalent Ar, C1-10alkylene, C1-10alkylidene, C2-10alkenylene, all of which may be unsubstituted or substituted by one or more OH, CH2OH, N(R6)2 or halogen; R14 is independently hydrogen, C1-10alkyl, XC1-10alkyl, Ar or XAr; R15 is independently hydrogen, Ar, C1-6alkyl, or XAr; R16 is independently C1-6alkyl or phenyl substituted by one or more C1-6alkyl, OH, C1-5alkoxy, S(O)qR6, N(R6)2, Br, F, I, Cl, CF3 or NHCOR6; X is independently (CH2)n, O, NR6 or S(O)q; X′ is independently O, NR6 or S(O)q; Y is independently CH3 or X(CH2)nAr; Ar is: both of which may be unsubstituted or substituted by one or more Z1 or Z2 groups;A is independently C═O, or (C(R6)2)m; B is independently —CH2— or —O—; Z1 and Z2 are independently hydrogen, XR6, C1-8alkyl, (CH2)qCO2R6, C(O)N(R6)2, CN, (CH2)nOH, NO2, F, Cl, Br, I, N(R6)2, NHC(O)R6, O(CH2)mC(O)NRaSO2R16, (CH2)mOC(O)NRaSO2R16, O(CH2)mNRaC(O)NRaSO2R16 or tetrazolyl which may be substituted or unsubstituted by C1-6alkyl, CF3 or C(O)R6; m is independently 1 to 3; n is independently 0 to 6; q is independently 0, 1 or 2; provided R3, R4 and R5 are not O—O(CH2)nAr or —O—O R6; and further provided that R2 is not dihydrobenzofuran; or a pharmaceutically acceptable salt thereof.
- 2. A compound of Formula (I) wherein P is CO2R6; R1 is hydrogen; R2 is Ar; R3 and R5 are independently hydrogen, CO2R7, OH, C1-8alkoxy, C1-8alkyl, N(R6)2, NO2, Br, F, Cl, I, R13CO2R7, X(CH2)nR8, (CH2)mX′R8, or X(C(R6)2)OR6; R4 is hydrogen, OH, C1-5alkoxy, N(R6)2, Br, F, Cl, I, NHCOCH3, or S(O)qC1-5alkyl wherein the C1-5alkyl may be unsubstituted or substituted by OH, methoxy or halogen; R6 is hydrogen, methyl or ethyl; R7 is hydrogen, C1-10alkyl, C2-10alkenyl or C2-8alkynyl, all of which may be unsubstituted or substituted by one or more OH, N(R6)2, CO2R12, halogen, or R7 is (CH2)nAr wherein n is zero or 1 and Ar is substituted phenyl; R11 is hydrogen or phenyl, which may be substituted or unsubstituted by one or two C1-4alkyl groups; C1-8alkyl, C2-8alkenyl, C2-8alkynyl, all of which may be substituted or unsubstituted by one or more OH, CH2OH, N(R6)2, or halogen; R12 is hydrogen or C1-6alkyl; R13 is phenyl or C2-10alkylene, both of which may be unsubstituted or substituted by one or more OH, CH2OH, N(R6)2, or halogen, and the phenyl may be additionally unsubstituted or substituted with CO2R6; R15 is hydrogen or C1-6alkyl; and (Z) is (d).
- 3. A compound of claim 2 wherein P is CO2H; R1 is hydrogen; R2 is a group Ar wherein Ar is a group (a) or (b) and in said group (a) or (b), Z1 and Z2 are independently hydrogen, CO2R6, (CH2)nOH, C1-4alkyl or C1-6 alkoxy and A is CH2, and both Bs are O; R3 is Br, Cl, C1-8alkoxy or X(CH2)nR8, wherein X is O, n is 0, 1, or 2, and R8 is selected from: CO2H, OH, tetrazolyl optionally substituted by C1-6alkyl; CONR7SO2R11 wherein R7 is H or C1-8alkyl, R11 is C1-8alkyl or phenyl optionally substituted by Br, Cl, F, C1-8alkyl; or R8 is phenyl substituted by one or more Br, Cl, CO2H, CH2OH; R5 is methoxy or N(R6)2 wherein R6 is H or methyl; R4 is hydrogen; R6 is hydrogen, methyl or ethyl; R7 is hydrogen, C1-10alkyl, C2-10alkenyl or C2-8alkynyl, all of which may be unsubstituted or substituted by one or more OH, N(R6)2, CO2R12, halogen, or R7 is (CH2)nAr wherein R7 is (CH2)nAr and n is zero or 1 and Ar is phenyl substituted or unsubstituted by halogen or C1-5 alkoxy; R11 is hydrogen, phenyl, wherein the phenyl may be substituted or unsubstituted by one or two C1-4alkyl groups; C1-8alkyl, C2-8alkenyl, C2-8alkynyl, all of which may be substituted or unsubstituted by one or more OH, CH2OH, N(R6)2, or halogen; R12 is hydrogen or C1-6alkyl; R13 is phenyl or C2-10alkylene, both of which may be unsubstituted or substituted by one or more OH, CH2OH, N(R6)2, or halogen, and the phenyl may be additionally unsubstituted or substituted with CO2R6; R15 is hydrogen, ethyl, isopropyl, n-butyl, or cyclopropylethyl; and (Z) is (d).
- 4. A compound of claim 1 selected from:(E)-alpha-[[5-[2-[(2-carboxyphenyl)methoxy]-4-methoxyphenyl]-1-ethyl-1H-pyrazol-4-yl]methylene]-6-methoxy-1,3-benzodioxole-5-propanoic acid; (E)-alpha-[[1-Allyl-5-[2-[(2-carboxyphenyl)methoxy]-4methoxyphenyl]-1H-pyrazol-4-yl]methylene]-6-methoxy-1,3-benzodioxole-5-propanoic acid; (E)-alpha-[[1-Butyl-5-(2-[(2-carboxyphenyl)methoxy]-4-chlorophenyl]-1H-pyrazol-4-yl]methylene]-6-methoxy-1,3-benzodioxole-5-propanoic acid; (E)-alpha-[[1-Butyl-5-[4-methoxy-2-[[N-(phenylsulfonyl)]carboxamidomethoxy]phenyl]-1H-pyrazol-4-yl]methylene]-6-methoxy-1,3-benzodioxole-5-propanoic acid; (E)-3-[1-Butyl-5-[2-[2-carboxyphenyl)methoxy]-4-methoxyphenyl]-1H-pyrazol-4-yl]-2-[(2,5-dimethoxyphenyl)methyl]-prop-2-enoic acid; (E)-alpha-[[1-Butyl-5-[2-[(2-hydroxymethylphenyl)methoxy]-4-methoxyphenyl]-1H-pyrazol-4-yl]methylene]-6-methoxy-1,3-benzodioxole-5-propanoic acid; (E)-alpha-[[1-Butyl-5-[2-[(2-carboxyphenyl)methoxy-4-methoxyphenyl]-1H-pyrazol-4-yl]methylene]-7-methoxy-1,4-benzodioxan-6-propanoic acid; (E)-alpha-[[5-[2-[(2-Carboxyphenyl)methoxy]-4-methoxyphenyl]-1-cyclopropylmethyl-1H-pyrazol-4-yl]methylene]-6-methoxy-1,3-benzodioxole-5-propanoic acid; (E)-alpha-[[1-(3-Butenyl)-5-[2-[(2-hydroxymethylphenyl)methoxy]-4-methoxyphenyl]-1H-pyrazol-4-yl]methylene]-6-methoxy-1,3-benzodioxole-5-propanoic acid; (E)-alpha-[[5-[2-[(2-Carboxyphenyl)methoxy]-4-methoxyphenyl]-1H-cyclopropylethyl-1H-pyrazol-4-yl]methylene]-6-methoxy-1,3-benzodioxole-5-propanoic acid; (E)-alpha-[[1-Butyl-5-[2-[(2-carboxyphenoxy]methyl)-4-methoxyphenyl]-1H-pyrazol-4-yl]methylene]-6-methoxy-1,3-benzodioxole-5-propanoic acid.
- 5. A compound of claim 1 which is (E)-alpha-[[1-Butyl-5-[2-[(2-carboxyphenyl)methoxy]-4-methoxyphenyl]-1H-pyrazol-4-yl]methylene]-6-methoxy-1,3-benzodioxole-5-propanoic acid.
- 6. A compound of claim 5 which is the disodium salt thereof.
- 7. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
- 8. A method of treatment of diseases caused by an excess of endothelin comprising administering to a subject in need thereof, an effective amount of an endothelin receptor antagonist of claim 1.
- 9. A method of treating renal failure or cerebrovascular disease which comprises administering to a subject in need thereof, an effective amount of a compound of claim 1.
- 10. A method for the prophylaxis and treatment of radiocontrast induced renal failure which comprises administering to a subject in need thereof, an effective amount of a compound of claim 1.
- 11. A method of treatment of congestive heart failure which comprises administering to a subject in need thereof, an effective amount of a compound of claim 1.
- 12. A method of treatment of unstable angina, coronary vasospasm and myocardial salvage which comprises administering to a subject in need thereof, an effective amount of a compound of claim 1.
- 13. A method of preventing or treating restenosis which comprises administering to a subject in need thereof, an effective amount of a compound of claim 1.
- 14. A method of treatment of pulmonary hypertension which comprises administering to a subject in need thereof, an effective amount of a compound of claim 1.
- 15. A method of treatment of stroke or subarachnoid hemorrhage which comprises administering to a subject in need thereof, an effective amount of a compound of claim 1.
- 16. A process for preparing a compound of Formula (Id) by:(a) Reaction of a compound of Formula (II) or a protected form or precursor thereof with a compound of Formula (8) (wherein R2 and R16 are as defined in claim 1 for Formula (Id) hereinabove); followed if necessary or desired by: (b) deprotection and alkylation and hydrolysis of the R3, R4, R5, R15, R16, Z1 and Z2 groups as required and; (c) salt formation.
Parent Case Info
This is a continuation of application Ser. No. 09/249,392 filed Feb. 12, 1999; now abandoned which is a continuation of application Ser. No. 08/718,565 filed Feb. 2, 1998; now abandoned which is a 371 of International Application No. PCT/US96/12661, filled Aug. 2, 1996, which claims benefit from the following provisional applications: 60/001,792, filed Aug. 2, 1995 and 60/010,982, filed Feb. 1, 1996.
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Number |
Name |
Date |
Kind |
3703513 |
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Nov 1972 |
A |
4965282 |
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A |
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Foreign Referenced Citations (2)
Number |
Date |
Country |
0 714 897 |
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WO |
Provisional Applications (2)
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Number |
Date |
Country |
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60/001792 |
Aug 1995 |
US |
|
60/010982 |
Feb 1996 |
US |
Continuations (2)
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Number |
Date |
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Parent |
09/249392 |
Feb 1999 |
US |
Child |
09/699951 |
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US |
Parent |
08/718565 |
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US |
Child |
09/249392 |
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US |