Claims
- 1. A compound of Formula (I): ##STR26## wherein Z is ##STR27## D is O; P is CO.sub.2 H;
- R.sup.a is hydrogen;
- R.sub.1 is independently hydrogen, Ar or C.sub.1-6 alkyl;
- R.sub.2 is Ar, C.sub.1-8 alkyl, C(O)R.sub.14 or ##STR28## 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, Br, F, I, Cl, CF.sub.3, NHCOR.sub.6 R.sub.13 CO.sub.2 R.sub.7, --X--R.sub.9 Y 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, tetrazole or OR.sub.6 ;
- 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 C.sub.1-6 alkyl or phenyl substituted by one or two 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 ;
- Y is independently CH.sub.3 or X(CH.sub.2).sub.n Ar;
- Ar is independently: ##STR29## naphthyl, furyl, oxozolyl, 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.1-8 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, X(CH.sub.2).sub.n R.sub.8, O(CH.sub.2).sub.m C(O)NR.sub.a SO.sub.2 R.sub.15, (CH.sub.2).sub.m OC(O)NR.sub.a SO.sub.2 R.sub.15, O(CH.sub.2).sub.m NR.sub.a C(O)NR.sub.1 SO.sub.2 R.sub.15, or tetrazolyl which may be substituted or unsubstituted by C.sub.1-6 alkyl, CF.sub.3 or C(O)R.sub.6 ;
- Ar' is pyridyl or thienyl; all of which may be unsubstituted or substituted by one or more XR.sub.9 --Y, Z.sub.1 or Z.sub.2 groups;
- 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 a pharmaceutically acceptable salt thereof.
- 2. A compound of claim 1 chosen from the group consisting of:
- (E)-alpha-[[5-[4-[(2-carboxyphenyl)methoxy]-2-methoxypyrid-5-yl]isoxazol-4-yl]methylene]-6-methoxy-1,3-benzodioxole-5-propanoic acid;
- (E)-alpha-[[5-(3-carboxy-5-chlorothien-2-yl)isoxazol-4-yl]methylene]-6-methoxy-1,3-benzodioxole-5-propanoic acid;
- (E)-alpha-[[3-[4-[(2-carboxyphenyl)methoxy]-2-methoxypyrid-5-yl]isoxazol-4-yl]methylene]-6-methoxy-1,3-benzodioxole-5-propanoic acid;
- (E)-alpha-[[3-(3-carboxy-5-chlorothien-2-yl)isoxazol-4-yl]methylene]-6-methoxy-1,3-benzodioxole-5-propanoic acid;
- (E)-alpha-[[3-Butyl-4-[4-[(2-carboxyphenyl)methoxy]-2-methoxypyrid-5-yl]isoxazol-5-yl]methylene]-6-methoxy-1,3-benzodioxole-5-propanoic acid;
- (E)-alpha-[[5-Butyl-4-[4-[(2-carboxyphenyl)methoxy]-2-methoxypyrid-5-yl]isoxazol-3-yl]methylene]-6-methoxy-1,3-benzodioxole-5-propanoic acid.
- 3. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
- 4. 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.
- 5. A method of treating renal failure, hypertension, pulmonary hypertension or heart failure which comprises administering to a subject in need thereof, an effective amount of a compound of claim 1.
Parent Case Info
This application claims the benefit of Provisional application Ser. No. 60/010,992 filed Feb. 1, 1996.
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
102e Date |
371c Date |
PCT/US97/00955 |
1/31/1997 |
|
|
7/31/1998 |
7/31/1998 |
Publishing Document |
Publishing Date |
Country |
Kind |
WO97/28160 |
8/7/1997 |
|
|
US Referenced Citations (2)
Number |
Name |
Date |
Kind |
3277105 |
Schmidt et al. |
Oct 1966 |
|
3700105 |
Saucy et al. |
Oct 1972 |
|
Foreign Referenced Citations (1)
Number |
Date |
Country |
WO 9607653 |
Mar 1996 |
WOX |