Claims
- 1. A compound of Formula (I): ##STR48## wherein (Z) is ##STR49## P is �tetrazol-5-yl,! CO.sub.2 R.sub.6 or C(O)N(R.sub.6)S(O).sub.q R.sub.10 ;
- R.sup.a is independently hydrogen or C.sub.1-6 alkyl;
- R.sub.1 is independently hydrogen, Ar, C.sub.1-6 alkyl or C.sub.1-6 alkoxy;
- R.sub.2 is ##STR50## R.sub.3 and R.sub.5 are independently R.sub.13 OH, C.sub.1-8 alkoxy, S(O).sub.q R.sub.11, N(R.sub.6).sub.2, NO.sub.2, Br, F, I, Cl, CF.sub.3, NHCOR.sub.6, R.sub.13 CO.sub.2 R.sub.7, --X--R.sub.9 --Y, --X(C(R.sub.6) .sub.2)OR.sub.6, --(CH.sub.2) .sub.m X'R.sub.8 or --X(CH.sub.2).sub.n R.sub.8 wherein each methylene group within --X(CH.sub.2) .sub.n R.sub.8 may be unsubstituted or substituted by one or two --(CH.sub.2).sub.n Ar groups;
- R.sub.4 is independently R.sub.11, OH, C.sub.1-5 alkoxy, S(O).sub.q R.sub.11, N(R.sub.6).sub.2, Br, F, I, Cl or NHCOR.sub.6, wherein the C.sub.1-5 alkoxy may be unsubstituted or substituted by OH, methoxy or halogen;
- R.sub.6 is independently hydrogen or C.sub.1-8 alkyl;
- R.sub.7 is independently hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl or C.sub.2-8 alkynyl, all of which may be unsubstituted or substituted by one or more OH, N(R.sub.6).sub.2, CO.sub.2 R.sub.12, halogen or XC.sub.1-10 alkyl; or R.sub.7 is (CH.sub.2).sub.n Ar;
- R.sub.8 is independently R.sub.11, CO.sub.2 R.sub.7, CO.sub.2 C(R.sub.11).sub.2 O(CO)XR.sub.7, PO.sub.3 (R.sub.7).sub.2, SO.sub.2 NR.sub.7 R.sub.11, NR.sub.7 SO.sub.2 R.sub.11, CONR.sub.7 SO.sub.2 R.sub.11, SO.sub.3 R.sub.7, SO.sub.2 R.sub.7, P(O)(OR.sub.7)R.sub.7, CN, CO.sub.2 (CH.sub.2).sub.m C(O)N(R.sub.6).sub.2, C(R.sub.11).sub.2 N(R.sub.7).sub.2, C(O)N(R.sub.6).sub.2, NR.sub.7 C(O)NR.sub.7 SO.sub.2 R.sub.11, OR.sub.6, or tetrazole which is substituted or unsubstituted by C.sub.1-6 alkyl;
- R.sub.9 is independently a bond, C.sub.1-10 alkylene, C.sub.1-10 alkenylene, C.sub.1-10 alkylidene, C.sub.1-10 alkynylene, all of which may be linear or branched, or phenylene, all of which may be unsubstituted or substituted by one of more OH, N(R.sub.6).sub.2, COOH or halogen;
- R.sub.10 is independently C.sub.1-10 alkyl, N(R.sub.6).sub.2 or Ar;
- R.sub.11 is independently hydrogen, Ar, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, all of which may be substituted or unsubstituted by one or more OH, CH.sub.2 OH, N(R.sub.6).sub.2, or halogen;
- R.sub.12 is independently hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl or C.sub.2-7 alkynyl;
- R.sub.13 is independently divalent Ar, C.sub.1-10 alkylene, C.sub.1-10 alkylidene, C.sub.2-10 alkenylene, all of which may be unsubstituted or substituted by one or more OH, CH.sub.2 OH, N(R.sub.6).sub.2 or halogen;
- R.sub.14 is independently hydrogen, C.sub.1-10 alkyl, XC.sub.1-10 alkyl, Ar or XAr;
- R.sub.15 is independently hydrogen, Ar, C.sub.1-6 alkyl, or XAr;
- R.sub.16 is independently C.sub.1-6 alkyl or phenyl substituted by one or more C.sub.1-6 alkyl, OH, C.sub.1-5 alkoxy, S(O).sub.q R.sub.6, N(R.sub.6).sub.2, Br, F, I, Cl, CF.sub.3 or NHCOR.sub.6 ;
- X is independently (CH.sub.2).sub.n, O, NR.sub.6 or S(O).sub.q ;
- X' is independently O, NR.sub.6 or S(O).sub.q ;
- Y is independently CH.sub.3 or X(CH.sub.2).sub.n Ar;
- Ar is; ##STR51## naphthyl; all of which may be unsubstituted or substituted by one or more Z.sub.1 or Z.sub.2 groups;
- A is independently C.dbd.O , or (C(R.sub.6).sub.2).sub.m ;
- B is independently --CH.sub.2 -- or --O--;
- Z.sub.1 and Z.sub.2 are independently hydrogen, XR.sub.6, C.sub.1-8 alkyl, (CH.sub.2).sub.q CO.sub.2 R.sub.6, C(O)N(R.sub.6).sub.2, CN, (CH.sub.2).sub.n OH, NO.sub.2, F, Cl, Br, I, N(R.sub.6).sub.2, NHC(O)R.sub.6, O(CH.sub.2).sub.m C(O)NR.sub.a SO.sub.2 R.sub.16, (CH.sub.2).sub.m OC(O)NR.sub.a SO.sub.2 R.sub.16, O(CH.sub.2).sub.m NR.sub.a C(O)NR.sub.a SO.sub.2 R.sub.16 tetrazolyl which may be substituted or unsubstituted by C.sub.1-6 alkyl, CF.sub.3 or C(O)R.sub.6 ;
- m is independently 1 to 3;
- n is independently 0 to 6;
- q is independently 0, 1 or 2;
- provided R.sub.3, R.sub.4 and R.sub.5 are not O--O(CH.sub.2).sub.n Ar or O--OR.sub.6 ;
- or a pharmaceutically acceptable salt thereof.
- 2. A compound of Formula (I) of claim 1 wherein P is CO.sub.2 R.sub.6 ; R.sub.1 is hydrogen; R.sub.3 and R.sub.5 are independently hydrogen, CO.sub.2 R.sub.6, OH, C.sub.1-8 alkoxy, C.sub.1-8 alkyl, N(R.sub.6).sub.2, NO.sub.2, Br, F, Cl, I, R.sub.13 CO.sub.2 R.sub.7, X(CH.sub.2).sub.n R.sub.8, (CH.sub.2)mX'R.sub.8, or X(C(R.sub.6).sub.2).sub.m OR.sub.6 ; R.sub.4 is hydrogen, OH, C.sub.1-5 alkoxy, N(R.sub.6).sub.2, Br, F, Cl, I, NHCOCH.sub.3, or S(O).sub.q C.sub.1-5 alkyl wherein the C.sub.1-5 alkyl may be unsubstituted or substituted by OH, methoxy or halogen; R.sub.6 is hydrogen, methyl or ethyl; R.sub.7 is hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl or C.sub.2-8 alkynyl, all of which may be unsubstituted or substituted by one or more OH, N(R.sub.6).sub.2, CO.sub.2 R.sub.12, halogen, or R.sub.7 is (CH.sub.2).sub.n Ar wherein n is zero or 1 and Ar is substituted phenyl; R.sub.11 is hydrogen, phenyl, all of which may be substituted or unsubstituted by one or two C.sub.1-4 alkyl groups; C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, all of which may be substituted or unsubstituted by one or more OH, CH.sub.2 OH, N(R.sub.6).sub.2, or halogen; R.sub.12 is hydrogen or C.sub.1-6 alkyl; R.sub.13 is phenyl, or C.sub.2-10 alkylene, all of which may be unsubstituted or substituted by one or more CO.sub.2 R.sub.6, OH, CH.sub.2 OH, N(R.sub.6).sub.2, or halogen; and R.sub.15 is hydrogen or C.sub.1-6 alkyl.
- 3. A compound of claim 2 wherein P is CO.sub.2 H; R.sub.1 is hydrogen; Z.sub.1 and Z.sub.2 are independently hydrogen, CO.sub.2 R.sub.6, (CH.sub.2).sub.n OH, C.sub.1-4 alkyl or C.sub.1-6 alkoxy; R.sub.3 is Br, Cl, C.sub.1-8 alkoxy or X(CH.sub.2).sub.n R.sub.8, wherein X is O, n is 0, 1, or 2, and R.sub.8 is selected from; CO.sub.2 H, OH, tetrazolyl optionally substituted by C.sub.1-8 alkyl; CONR.sub.7 SO.sub.2 R.sub.11 wherein R.sub.7 is H or C.sub.1-8 alkyl, R.sub.11 is C.sub.1-8 alkyl or phenyl optionally substituted by Br, Cl, F, C.sub.1-8 alkyl; or R.sub.8 is phenyl substituted by one or more Br, Cl, CO.sub.2 H, CH.sub.2 OH; R.sub.5 is methoxy or N(R.sub.6).sub.2 wherein R.sub.6 is H or methyl; R.sub.4 is hydrogen; R.sub.6 is hydrogen, methyl or ethyl; R.sub.7 is hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl or C.sub.2-8 alkynyl, all of which may be unsubstituted or substituted by one or more OH, N(R.sub.6).sub.2, CO.sub.2 R.sub.12, halogen, or R.sub.7 is (CH.sub.2).sub.n Ar wherein R.sub.7 is (CH.sub.2).sub.n Ar and n is preferably zero or 1 and Ar is preferably phenyl substituted or unsubstituted by halogen or C.sub.1-5 alkoxy; R.sub.11 is hydrogen, phenyl, all of which may be substituted or unsubstituted by one or two C.sub.1-4 alkyl groups; C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, all of which may be substituted or unsubstituted by one or more OH, CH.sub.2 OH, N(R.sub.6).sub.2, or halogen; R.sub.12 is hydrogen or C.sub.1-6 alkyl; R.sub.13 is phenyl or C.sub.2-10 alkylene, all of which may be unsubstituted or substituted by one or more CO.sub.2 R.sub.6, OH, CH.sub.2 OH, N(R.sub.6).sub.2, or halogen; and R.sub.15 is hydrogen, ethyl, isopropyl, n-butyl, cyclopropylmethyl or cyclopropylethyl.
- 4. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
- 5. 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.
- 6. A method of treating hypertension, renal failure or cerebrovascular disease which comprises administering to a subject in need thereof, an effective amount of a compound of claim 1.
- 7. A method for the treatment of chronic renal failure which comprises administering to a subject in need thereof, an effective amount of a compound of claim 1.
- 8. A method of treatment of benign prostatic hypertrophy which comprises administering to a subject in need thereof, an effective amount of a compound of claim 1.
- 9. 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.
- 10. 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.
- 11. 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.
- 12. 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.
- 13. A method of treatment of atherosclerosis which comprises administering to a subject in need thereof, an effective amount of a compound of claim 1.
- 14. A method of preventing and treating the sequelae of diabetes 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.
Parent Case Info
This is a divisional of application Ser. No. 09/121,545 filed Jul. 23, 1998, which is a continuation of prior application Ser. No. 08/718,562, filed Feb. 2, 1998 now abandoned; which is a 371 of International Application No. PCT/US96/12581, filed Aug. 2, 1996; which claims the benefit of priority from the following provisional applications: 60/001,792, filed Aug. 2, 1995 and 60/010,982, filed Feb. 1, 1996.
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3703513 |
Yamamoto et al. |
Nov 1972 |
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4965282 |
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Foreign Referenced Citations (2)
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Divisions (1)
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Number |
Date |
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Parent |
121545 |
Jul 1998 |
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Continuations (1)
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Number |
Date |
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Parent |
718562 |
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