Claims
- 1. A compound of Formula (I): ##STR49## wherein Z is ##STR50## D is O or S; 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 Ar, C.sub.1-8 alkyl, C(O)R.sub.14 or ##STR51## 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.27 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 unsubstituted or substituted 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.1-6 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: ##STR52## 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 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.1-10 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).sub.n R.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 or tetrazolyl which may be substituted or unsubstituted by one or two 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 claim 1 wherein P is CO.sub.2 R.sub.6 ; R.sub.1 is hydrogen; R.sub.2 is Ar, cyclohexyl or C.sub.1-4 alkyl; 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).sub.m X'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, pyridyl 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, pyridyl, 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; R.sub.2 is a group Ar wherein Ar is a group (a) or (b) and in said group (a) or (b), 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 and A is CH.sub.2, and one or both Bs are O; 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 or pyridyl 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, pyridyl wherein the phenyl or pyridyl 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, pyridyl, 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 compound of claim 1 selected from:
- (E)-alpha-[[5-[2-[(2-carboxyphenyl)methoxy]-4-methoxyphenyl]isoxazol-4-yl]methylene]-6-methoxy-1,3-benzodioxole-5-propanoic acid;
- (E)-alpha-[[3-[2-[(2-carboxyphenyl)methoxy]-4-methoxyphenyl]isoxazol-4-yl]methylene]-6-methoxy-1,3-benzodioxole-5-propanoic acid; and
- (E)-alpha-[[3-Butyl-4-[2-[(2-carboxyphenyl)methoxy]-4-methoxyphenyl]isoxazol-5-yl]methylene]-6-methoxy-1,3-benzodioxole-5-propanoic acid.
- 5. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
- 6. 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.
- 7. 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.
- 8. 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.
- 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 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 application is a 371 of PCT/US96/12584 filed Aug. 2, 1996, which claims the benefit of U.S. Provisional Application Ser. No. 60/001,794 filed Aug. 2, 1995 and Ser. No. 60/011,009 filed Feb. 2, 1996
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
102e Date |
371c Date |
PCT/US96/12584 |
8/2/1996 |
|
|
2/2/1998 |
2/2/1998 |
Publishing Document |
Publishing Date |
Country |
Kind |
WO97/04774 |
2/13/1997 |
|
|
US Referenced Citations (2)
Number |
Name |
Date |
Kind |
3700661 |
Saucy et al. |
Oct 1972 |
|
4376862 |
Junek et al. |
Mar 1983 |
|
Foreign Referenced Citations (2)
Number |
Date |
Country |
WO 9514863 |
Jun 1995 |
WOX |
WO 9607653 |
Mar 1996 |
WOX |