Claims
- 1. A compound of the formula (Ia, Ib and Ic) ##STR30## wherein: R.sub.1 is --X(CH2).sub.n Ar
- dihydrobenzofuranyl, benzodioxanyl, or cyclohexyl;
- R.sub.2 is Ar or (c);
- P.sub.1 is --X(CH.sub.2).sub.n R.sub.8 ;
- P.sub.2 is --X(CH.sub.2).sub.n R.sub., or --XR.sub.9 Y;
- R.sub.3 and R.sub.5 are independently hydrogen, R.sub.11, 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.12 CO.sub.2 R.sub.7, --XR.sub.9 --Y or --X(CH.sub.2).sub.n R.sub.8 ;
- R.sub.4 is hydrogen, R.sub.11, OH, C.sub.1-5 alkoxy, S(O).sub.q R.sub.11,N(R.sub.6).sub.2, --X(R.sub.11), 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.1-4 alkyl;
- R.sub.7 is independently hydrogen, C.sub.1-6 alkyl or (CH.sub.2).sub.n Ar;
- R.sub.8 is hydrogen, R.sub.11, CO.sub.2 R.sub.7, PO.sub.3 H.sub.2, P(O)(OH)R.sub.7, CN, --C(O)N(R.sub.6).sub.2, tetrazole or OR.sub.6 ;
- R.sub.9 is divalent C.sub.1-10 alkylene, C.sub.2-10 alkenylene or phenylene all of which may be unsubstituted or substituted by one or more OH, N(R.sub.6).sub.2, COOH, halogen or XC.sub.1-5 alkyl;
- R.sub.10 is R.sub.3 or R.sub.4 ;
- R.sub.11 is monovalent or divalent 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 C.sub.1-8 alkylene, C.sub.2-8 alkenylene or C.sub.2-8 alkynylene;
- X is (CH.sub.2).sub.n, O, NR.sub.6 or S(O).sub.q ;
- Y is CH.sub.3 or --CH.sub.2 X(CH.sub.2).sub.n Ar;
- Ar is: ##STR31## naphthyl, indolyl, pyridyl, thienyl, oxazolidinyl, oxazolyl, 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 R.sub.3 or R.sub.4 groups;
- A is C.dbd.O, or (C(R.sub.6).sub.2).sub.m ;
- B is --CH.sub.2 -- or --O--;
- q is zero, one or two;
- n is an integer from 0 to six;
- m is 1, 2or3;
- and the dotted line indicates the optional presence of a double bond; or a pharmaceutically acceptable salt thereof; provided that when the optional double bond is present there is no P.sub.1 or R.sub.10 ; and further provided that P.sub.1 and P.sub.2 are not methyl and P.sub.1 and P.sub.2 are not both hydrogen; and further provided that when R.sub.11, R.sub.8 or Y are Ar, the Ar is not substituted bv another Ar which is further substituted by yet another Ar.
- 2. A compound of claim 1 wherein R.sub.2 is (a), (b), or indolyl; R.sub.3 and R.sub.5 are independently hydrogen, OH, C.sub.1-5 alkoxy, halogen, R.sub.11 CO.sub.2 R.sub.7, C.sub.1-4 alkyl, N(R.sub.6).sub.2, NH(CO)CH.sub.3, --X(CH.sub.2).sub.n R.sub.8, or S(O).sub.p C.sub.1-5 alkyl; R.sub.4 is hydrogen, OH, C.sub.1-5 alkoxy, halogen, C.sub.1-4 alkyl, N(R.sub.6).sub.2, NH(CO)CH.sub.3 or S(O).sub.p C.sub.1-5 alkyl; P.sub.1 and P.sub.2 are independently hydrogen, CO.sub.2 H or tetrazole; A.sub.r is (a), (b) or pyridyl; and X is (CH.sub.2).sub.n or oxygen.
- 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 to antagonize endothelin receptors of a compound of claim 1.
- 5. A method of treating hypertension which comprises administering to a subject in need thereof an effective amount of a compound of claim 1.
- 6. A method of treating renal failure which comprises administering to a subject in need thereof, an effective amount of a compound of claim 1.
- 7. A method of treating cerebrovascular disease which comprises administering to a subject in need thereof, an effective amount of a compound of claim 1.
Parent Case Info
This application claims priority under 35 U.S.C. .sctn.371 from PCT/US95/07904, filed 07 Jun. 1995, which is a CIP of U.S. application Ser. No. 08/255,623, filed 09 Jun. 1994, now abandoned.
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
102e Date |
371c Date |
PCT/US95/07904 |
6/7/1995 |
|
|
6/7/1995 |
6/7/1995 |
Publishing Document |
Publishing Date |
Country |
Kind |
WO95/33752 |
12/14/1995 |
|
|
US Referenced Citations (14)
Foreign Referenced Citations (4)
Number |
Date |
Country |
705107 |
Mar 1965 |
CAX |
705417 |
Mar 1965 |
CAX |
WO8803142 |
May 1988 |
WOX |
WO 8803142 |
May 1988 |
WOX |
Continuation in Parts (1)
|
Number |
Date |
Country |
Parent |
255623 |
Jun 1994 |
|