Claims
- 1. A compound of Formula (I): ##STR18## wherein Z is ##STR19## wherein D, E, F and G may be N, or CR.sub.1 provided: 1) no more than two are nitrogens;
- 2) not all are CR.sub.1 ;
- 3) the ring formed is not pyrimidine or pyridine;
- P is tetraxol-2-yl, CO.sub.2 R.sub.6 or C(O)N(R.sub.6)S(O).sub.1 R.sub.10 ;
- R.sub.a is 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 ##STR20## 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 with --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.1 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 unsubsidized 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 C(O)NR.sub.7 SO.sub.2 R.sub.11, OR.sub.6, or tetraxole 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 alkenylene, all of which may be linear or branched, or phenylene, all of which may be unsubsidized or substituted by one or 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 unstubsituted or substituted by one or more OH, CH.sub.2 OH, N(R.sub.6).sub.2 or hydrogen;
- R.sub.12 is independently hydrogen, C.sub.1-6 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 substituted by one ore 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 X Ar;
- 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.1 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 X(CH.sub.2).sub.n Ar;
- Ar is independently: ##STR21## naphtyl, indoyly, pyridyl, thienyl, ozaolidinyl, thiazolyl, isothiazolyl, pyraxolyl, triazolyl, tetrazoly, imidazolyl, imidazolindinyl, thiazolindinyl, 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, 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.a 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 ;
- m is independently 1 to 3;
- n is independently 0 to 6;
- q is independently 0, 1 or 2;
- provided R.sub.3 and R.sub.5 are not O--O--(CH.sub.2).sub.n Ar or O--0 R.sub.6 ; or a pharmaceutically acceptable salt thereof.
- 2. A compound of Formula (I) wherein P is CO.sub.2 R.sub.6 :R.sub.1 is hydrogen, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy; 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)mX'R.sub.8, or X(C(R.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, 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: R.sub.15 is hydrogen or C.sub.1-6 alkyl; and D, E, F and G are N, or CR.sub.1 provided no more than two are nitrogens.
- 3. A compound of claim 2 wherein P is CO.sub.2 H:R.sub.1 is hydrogen, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy; 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 Rg 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 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 pryidyl substituted by one or more Br, Cl, CO.sub.2 H, CO.sub.2 OH; R.sub.5 is methoxy or N(R.sub.6).sub.2 wherein R.sub.6 is 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 zero or 1 and Ar is 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; R.sub.15 is hydrogen, ethyl, isopropyl, n-butyl, cyclopropylmethyl or cyclopropylenthyl; and D, E, F and G are N, or CR.sub.1 provided no more than two are nitrogens.
- 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 vasopasm 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): ##STR22## wherein R.sub.3a, R.sub.4a and R.sub.5a represent the groups, R.sub.3, R.sub.4 and R.sub.5 are defined for Formula (I) hereinabove, or a protected form or precursor thereof and R.sub.1a represents a group R.sub.1 as defined for Formula (I) hereinabove or a protected form or precursor thereof;
- with a compound of Formula (III) ##STR23## wherein R.sub.2 and P are defined for formula (I) hereinabove and n is 5; followed if necessary or desired by;
- (b) functional group interconversion of a compound of formula (I) into a different compound of formula (I) and or
- (c) salt formation.
Parent Case Info
This is a divisional of application Ser. No. 09/097,756, filed Jun. 16, 1998; which is a divisional of application Ser. No. 08/716,347 filed Sep. 27, 1996 now U.S. Pat. No. 5,942,516; which is a 371 of PCT/US96/12582, filed Aug. 2, 1996; which claims priority from application Ser. No. 60/001,791, filed Aug. 2, 1995 and application Ser. No. 60/011,148, filed Feb. 1, 1996.
US Referenced Citations (1)
Number |
Name |
Date |
Kind |
5942516 |
Elliott et al. |
Aug 1999 |
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Divisions (2)
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Number |
Date |
Country |
Parent |
097756 |
Jun 1998 |
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Parent |
716347 |
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