Claims
- 1. 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 Formula (I): E is O, S or NR15; P is tetrazol-5-yl, CO2R6 or C(O)NR6)S(O)qR10; Ra is independently hydrogen or C1-6alkyl; R1 is independently hydrogen, Ar, C1-6alkyl, or C1-6 alkoxy; R2 is Ar, C1-8alkyl, C(O)R14 or 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′R9 or —X(CH2)nR9 wherein each methylene group within —X(CH2)nR9 may be unsubstituted or substituted by one or two —(CH2)nAr groups; R4 is independently R11, OH, C15alkoxy, 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 XC1-10alkyl; 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)NR6)2, C(R11)2N(R7)2, C(O)N(R6)2, NR7C(O)NR7SO2R11, OR6, or tetrazole which is unsubstituted or substituted 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: naphthyl, indolyl, pyridyl, thienyl, oxazolidinyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, piperazinyl, pyrrolyl, or pyrimidyl; all of which may be unsubstituted or substituted by one or more Z1 or Z2 groups; A is independently C═O, or (CR6)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, 1, N(R6)2, NHC(O)R6, O(CH2)mC(O)NRaSO2R1 6, (CH2)mOC(O)NRaSO2R16, O(CH2)mNRaC(O)NRaSO2R16 or tetrazolyl which may be substituted or unsubstituted by one or two 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—OR6; or a pharmaceutically acceptable salt thereof.
- 2. A method according to claim 1 wherein P is CO2R6; R1 is hydrogen; R2 is Ar, cyclohexyl or C1-4alkyl; R3 and R5 are independently hydrogen, CO2R6, OH, C1-8alkoxy, C1-8alkyl, N(R6)2, NO2, Br, F, Cl, I, R13CO2R7, X(CH2)nR8, (CH2)mXR8, or X(CR6)2)mOR6; 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, phenyl, pyridyl all of 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, pyridyl, or C2-10alkylene, all of which may be unsubstituted or substituted by one or more CO2R6, OH, CH2OH, N(R6)2, or halogen; and R15 is hydrogen or C1-6alkyl.
- 3. A method according to 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 one or 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 C1-8alkyl; 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 or pyridyl 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 by halogen or C1-5 alkoxy; R11 is hydrogen, phenyl, pyridyl wherein the phenyl or pyridyl 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, pyridyl, or C2-10alkylene, all of which may be unsubstituted or substituted by one or more CO2R6, OH, CH2OH, N(R6)2, or halogen; and R15 is hydrogen, ethyl, isopropyl, n-butyl, cyclopropylmethyl or cyclopropylethyl.
- 4. 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 Formula I of claim 1.
- 5. A method of preventing or treating restenosis which comprises administering to a subject in need thereof, an effective amount of a compound of Formula I of claim 1.
- 6. A method of treatment of pulmonary hypertension which comprises administering to a subject in need thereof, an effective amount of a compound of Formula I of claim 1.
- 7. 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 Formula I of claim 1.
- 8. A compound which is(E)-3-[ 1-n-Butyl-5-[2-(2-carboxyphenyl)methoxy-4-methoxyphenyl]-1H-imidazol-4-yl]-2-[(2-methoxy-4,5-methylenedioxy)phenylmethyl]-prop-2-enoic acid.
Parent Case Info
This is a divisional of application Ser. No. 08/750,018 filed Feb. 2, 1998 now U.S. Pat. No. 6,030,970; which is a 371 of International Application No. PCT/US96/12584, filed Aug. 2, 1996; which claims the benefit of the following provisional applications: Ser. No. 60/001,794, filed Aug. 2, 1995 and Ser. No. 60/011,009, filed Feb. 1, 1996.
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Provisional Applications (2)
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Number |
Date |
Country |
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60/001794 |
Aug 1995 |
US |
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60/011009 |
Feb 1996 |
US |