Claims
- 1. A compound of Formula (I): ##STR14## D is O; P is 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 ##STR15## R.sub.3 and R.sub.5 are independently hydrogen CO.sub.2, R.sub.6, OH, R.sub.13 OH, C.sub.1-8 alkoxy, C.sub.1-8 alkyl, 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(CR.sub.6).sub.2)OR.sub.6, (CH.sub.2).sub.m XR.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 unsubstitutcd 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, wherein R.sub.11 is C.sub.1-5 alkyl is may be unsubstituted or substiteted by OH, methoxy, or halogen; 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 ;
- 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 two CO.sub.2 R.sub.6, 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, cyclopropylmethyl, cyclopropylethyl 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 ;
- X' is independently O, NR.sub.6 or S(O).sub.q ;
- Y is independently CH.sub.3 or X(CH2).sub.n Ar;
- Ar is: ##STR16## both of which may be unsubstituted or substituted by one or two 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, C.sub.1-6 alkoxy, (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.15, (CH.sub.2).sub.m OC(O)NR.sub.a SO.sub.2 R.sub.15, or O(CH.sub.2).sub.m R.sub.a C(O)NR.sub.a SO.sub.2 R.sub.15 ;
- 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 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, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, or 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; 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, 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, or 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 n is zero or 1 and Ar is phenyl substituted or unsubstituted by halogen or C.sub.1-5 alkoxy; 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.5 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 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 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.
- 8. 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.
- 9. 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.
- 10. 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.
- 11. 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.
- 12. 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.
- 13. A process for preparing a compound of Formula (I) of claim 1 by:
- (a) Reaction of a compound of Formula (II) ##STR17## or a protected form or precursor thereof with a compound of Formula (7) ##STR18## 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 ##STR19## R.sub.3 and R.sub.5 are independently hydrogen, CO.sub.2 R.sub.6, OH, R.sub.13, OH, C.sub.1-8 alkyl, 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 XR.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 hydrogen, R.sub.11, OH, C.sub.1-5 alkoxy, S(O).sub.q R.sub.11, wherein R.sub.11 is C.sub.1-5 alkyl it may be unsubstituted or substituted by OH, methoxy or halogen; 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;
- D is O;
- n is independently 0 to 6; and
- m is independently 1 to 3; and
- (b) optional saponification of the ester group;
- (c) optional salt formation.
- 14. A compound of claim 1 selected from:
- E-3-[3-[2-(2-carboxyphenyl)methoxy-4-methoxy]phenyl-fur-2-yl]-2-[2-methoxy-4,5-methylenedioxyphenyl]methyl-prop-2-enoic acid, and
- E-3-[4-[2-(2-carboxyphenyl)methoxy-4-methoxy]phenyl-fur-3-yl]-2-[2-methoxy-4,5-methylenedioxyphenyl]methyl-prop-2-enoic acid.
Parent Case Info
This application claims the benefit of Provisional Application Ser. No. 60/010,983 filed Feb. 1, 1996 and Provisional Application Ser. No. 60/001,793 filed Aug. 2, 1995.
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
102e Date |
371c Date |
PCT/US96/12583 |
8/2/1996 |
|
|
11/25/1996 |
11/25/1996 |
Publishing Document |
Publishing Date |
Country |
Kind |
WO97/04769 |
2/13/1997 |
|
|
US Referenced Citations (3)
Number |
Name |
Date |
Kind |
4402971 |
Edwards |
Sep 1983 |
|
5691373 |
Berryman et al. |
Nov 1997 |
|
5719182 |
Cousins et al. |
Feb 1998 |
|