Patent EA-001471-B1 (EA)
Title: Indole derivatives useful as endothelinreceptor antagonists
Inventor: RAWSON DAVID JAMES
IPC: C07D405/06
Filed: 1997-04-11
Abstract: 1. A compound of formula I   wherein R<1> and R<2> are optional substituents and independently represent C1-6 alkyl, C3-6 cycloalkyl, C2-6alkenyl [optionally substituted by CO2H or CO2(C1-6 alkyl) or CO2(C3-6 cycloalkyl)], C2-6 alkynyl, halogen, C1-3 perfluoroalkyl, C3 perfluorocycloalkyl, (CH2)mAR<1>, (CH2)mHet<1>, (CH2)mCONR<7>R<8>, (CH2)mCO2R<8>, O(CH2)qCO2R<8>, (CH2)mCOR<8>, (CH2)mOR<8>, O(CH2)pOR<8>, (CH2)mNR<7>R<8>, CO2(CH2)qNR<7>R<8>, (CH2)mCN, S(O)nR<8>, SO2NR<7>R<8>, CONH(CH2)mAR<1> or CONH(CH2)mHet<1>; R<3> represents H, C1-6 alkyl, C3-6 cycloalkyl, (CH2)pNR<9>R<10>, SO2R<10>, SO2NR<9>R<10>, (CH2)mCOR<10>, C2-6 alkenyl, C2-6 alkynyl, (CH2)mCONR<9>R<10>, (CH2)m CO2R<10>, (CH2)pCN, (CH2)pR<10> or (CH2)pOR<10>; R<4> and R<9> independently represent H, C1-6 alkyl or C3-6 cycloalkyl; R<7> represents H, C1-6 alkyl, C3-6 cycloalkyl, or C1-6 alkoxy; R<5> represents H or OH; R<6> represents phenyl optionally fused to a saturated or unsaturated 5- or 6-memb ered heterocyclic ring containing 1 or 2 heteroatoms selected from N, S and O, the group as a whole being optionally substituted by one or more groups selected from C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy and halogen, and wherein any members of the heterocyclic ring which are S, may be substituted by one or two oxygen atoms; R<8> and R<10> independently represent H, C1-6 alkyl, C3-6 cycloalkyl, AR<2>, Het<2> or substituted AR<2> or Het<2> C1-6 alkyl or C3-6 cycloalkyl; Z represents CO2H, CONH(tetrazol-5-yl), CONHSO2O(C1-4 alkyl), CONHSO2O(C3-4 cycloalkyl), CO2AR<3>, CO2(C1-6 alkyl), CO2(C3-6 cycloalkyl), tetrazol-5-yl, CONHSO2Ar<3>, CONHSO2(CH2)qAr<3> or CONHSO2(C1-6 alkyl) or CONHSO2(C3-6 cycloalkyl); m represents 0, 1, 2 or 3; n represents 0, 1 or 2; p represents 2, 3 or 4; q represents 1, 2 or 3; Ar<1-3> independently represent phenyl, naphthyl, or an aromatic heterocycle having 5 or 6 ring members up to 4 of which are selected from N, S and O, which aromatic heterocycle is optionally fused to a benzene ring, and which phenyl group is optionally fused to an aromatic heterocycle as defined immediately above, the group as a whole being optionally substituted by one or more groups falling within the definition of R<1> above; and  Het<1> and Het<2> independently represent a non-aromatic heterocycle having 5 or 6 ring members up to 4 of which are selected from N, S and O, which group is optionally substituted by one or more groups falling within the definition of R<1> above, and is further optionally substituted by =O or =S; provided that: (1) when R<1> represents methoxy or is absent, R<2> is absent, R<3> represents H, R<4> represents H, methyl or ethyl, and R<6> represents unsubstituted phenyl, then Z does not represent CO2H or CO2(C1-6 alkyl) or CO2(C3-6 cycloalkyl); (2) when R<1> and R<2> are absent, R<3> represents CO(p-CIC6H4), R<4> represents H, and R<6> represents unsubstituted phenyl, then Z does not represent CO2(C1-6 alkyl) or CO2(C3-6 cycloalkyl), and (3) when R<1> represents methoxy, R<2> is absent, R<3> represents CO(p-CIC6H4), R<4> represents methyl, and R<6> represents unsubstituted phenyl, then Z does not represent CO2H; or a pharmaceutically acceptable derivative thereof which is a prodrug or a pharmaceutically acceptable salt thereof. 2. A compound as claimed in claim 1, wherein R<1> represents halogen, (CH2)m CONR<7>R<8>, (CH2)mCO2R<8>, (CH2)mCOR<8>, (CH2)mOR<8> or (CH2)mCN. 3. A compound as claimed in claim 1 or claim 2, wherein R<2> is absent. 4. A compound as claimed in any one of claims 1-3, wherein R<3> represents H, C1-6 alkyl, C3-6 cycloalkyl or (CH2)pOR<10>. 5. A compound as claimed in any one of claims 1-4, wherein R<4> represents H. 6. A compound as claimed in any one of claims 1-5, wherein R<5> represents H. 7. A compound as claimed in any one of claims 1-6 wherein R<6> represents phenyl fused to a saturated 5-membered heterocyclic ring. 8. A compound as claimed in any one of claims 1-7, wherein Z represents CO2H or CONHSO2Ar<3>. 9. A compound of formula I, as defined in claim 1, but without provisos (1) and (2), or a pharmaceutically acceptable derivative thereof which is a prodrug or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical. 10. A pharmaceutical formulation comprising a compound of formula I, as defined in claim 1, but without provisos (1) and (2), or a pharmaceutically acceptable derivative thereof which is a prodrug or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier. 11. Use of a compound of formula I, as defined in claim 1, but without provisos (1)-(3), or a pharmaceutically acceptable derivative thereof which is a prodrug or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of restenosis, renal failure, pulmonary hypertension, benign prostatic hypertrophy, congestive heart failure, stroke, stenocardia, atherosclerosis, cerebral and cardiac ischaemia or cyclosporin induced nephrotoxicity. 12. A method of treatment of restenosis, renal failure, pulmonary hypertension, benign prostatic hypertrophy, congestive heart failure, stroke, stenocardia, atherosclerosis , cerebral and cardiac ischaemia or cyclosporin induced nephrotoxicity, which comprises administering a therapeutically effective amount of a compound of formula I, as defined in claim 1, but without provisos (1)-(3), or a pharmaceutically acceptable derivative thereof which is a prodrug or a pharmaceutically acceptable salt thereof, to a patient in need of such treatment. 13. A process for the production of a compound of formula I, as defined in claim 1, or a pharmaceutically acceptable derivative thereof which is a prodrug or a pharmaceutically acceptable salt thereof, which comprises: when R<5> represents H, reaction of a compound of formula IIA   wherein R<1-4> are as defined in claim 1, with a compound of formula III   wherein R<6> and Z are as defined in claim 1, in the presence of a Lewis acid or trifluoroacetic acid and a tri(C1-6 alkyl)silane; and if desired or it is necessary the obtained compound of formula I is converted into pharmaceutically acceptable derivative thereof which is a prodrug or a pharmaceutically acceptable salt thereof or vice versa. 14. A process for the production of a compound of formula I, as defined in claim 1, or a pharmaceutically acceptable derivative thereof which is a prodrug or a pharmaceutically acceptable salt thereof, wherein: when R<5> represents OH, reaction of a compound of formula IIA, as defined above with a compound of formula III, as defined above, is carried out in the presence of a Lewis acid and if desired or it is necessary the obtained compound of formula I is converted into pharmaceutically acceptable derivative thereof which is a prodrug or a pharmaceutically acceptable salt thereof or vice versa. 15. A process for the production of a compound of formula I, as defined in claim 1, or a pharmaceutically acceptable derivative thereof which is a prodrug or a pharmaceutically acceptable salt thereof, wherein: when R<3> represents H and R<5> represents H, treatment of a compound of formula IIB   wherein R<1>, R<2> and R<4> are as defined in claim 1, with a Grignard reagent, followed by reaction with a compound of formula III, as defined above, followed by treatment with a Lewis acid or trifluoroacetic acid, and a tri(C1-6 alkyl)silane; and if desired or it is necessary the obtained compound of formula I is converted into pharmaceutically acceptable derivative thereof which is a prodrug or a pharmaceutically acceptable salt thereof or vice versa. 16. A process for the production of a compound of formula I, as defined in claim 1, or a pharmaceutically acceptable derivative thereof which is a prodrug or a pharmaceutically acceptable salt thereof, wherein: when R<3> represents H and R<5> represents H, treatment of a compound of formula IIB, as defined above, with a Grignard reagent, is followed by reaction with a compound of formula IV   wherein R<6> and Z are as defined in claim 1, and Hal represents halogen, and if desired or it is necessary the obtained compound of formula I is converted into pharmaceutically acceptable derivative thereof which is a prodrug or a pharmaceutically acceptable salt thereof or vice versa. 17. A process for the production of a compound of formula I, as defined in claim 1, or a pharmaceutically acceptable derivative thereof which is a prodrug or a pharmaceutically acceptable salt thereof, wherein: when R<5> represents H, treatment of a compound of formula IIA, as defined above, with a compound of formula IV, as defined above, in the presence of a hindered non-nucleophilic base; is carried out and if desired or it is necessary the obtained compound of formula I is converted into pharmaceutically acceptable derivative thereof which is a prodrug or a pharmaceutically acceptable salt thereof or vice versa. 18. A process for the production of a compound of formula I, as defined in claim 1, or a pharmaceutically acceptable derivative thereof which is a prodrug or a pharmaceutically acceptable salt thereof, wherein reacting a compound of formula I, in which R<1> represents Br, is carried out with CO gas in the presence of a palladium catalyst and a reducing agent, to provide the corresponding compound of formula I in which R<1> represents CHO; and if desired or it is necessary the obtained compound of formula I is converted into pharmaceutically acceptable derivative thereof which is a prodrug or a pharmaceutically acceptable salt thereof or vice versa. 19. A process for the production of a compound of formula I, as defined in claim 1, or a pharmaceutically acceptable derivative thereof which is a prodrug or a pharmaceutically acceptable salt thereof, wherein reacting a compound of formula I, in which R<1> represents Br, is carried out with CO gas in the presence of a palladium catalyst and a C1-6 alkanol, to provide the corresponding compound of formula I in which