Patent ID: 6225315
Filing Date: 2001-05-01
Classification: A61K,A61P

Abstract:
A method of treating nitrate-induced tolerance in a mammal comprising administering to said mammal a nitrate-induced tolerance treating amount ofa compound of formula (I) ##STR13##and the pharmaceutically acceptable salts, prodrugs, polymorphs, hydrates, solvates, active metabolites and stereoisomers thereof; wherein:R.sup.1 is H, C.sub.1 -C.sub.3 alkyl, C.sub.3 -C.sub.5 cycloalkyl or C.sub.1 -C.sub.3 perfluoroalkyl;R.sup.2 is H, C.sub.1 -C.sub.6 alkyl optionally substituted by OH, C.sub.1 -C.sub.3 alkoxy or C.sub.3 -C.sub.6 cycloalkyl, or C.sub.1 -C.sub.3 perfluoroalkyl;R.sup.3 is C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 alkenyl, C.sub.3 -C.sub.6 alkynyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.1 -C.sub.6 perfluoroalkyl or (C.sub.3 -C.sub.6 cycloalkyl)C.sub.1 -C.sub.6 alkyl;R.sup.4 taken together with the nitrogen atom to which it is attached completes a 4-N--(R.sup.6)-piperazinyl group;R.sup.5 is H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.3 alkoxy, NR.sup.7 R.sup.8 or CONR.sup.7 R.sup.8 ;R.sup.6 is H, C.sub.1 -C.sub.6 alkyl, (C.sub.1 -C.sub.3 alkoxy)C.sub.2 -C.sub.6 alkyl, hydroxy C.sub.2 -C.sub.6 alkyl, (R.sup.7 R.sup.8 N)C.sub.2 -C.sub.6 alkyl, (R.sup.7 R.sup.8 NCO)C.sub.1 -C.sub.6 alkyl, CONR.sup.7 R.sup.8, CSNR.sup.7 R.sup.8 or C(NH)NR.sup.7 R.sup.8 ; andR.sup.7 and R.sup.8 are each independently H, C.sub.1 -C.sub.4 alkyl, (C.sub.1 -C.sub.3 alkoxy)C.sub.2 -C.sub.4 alkyl or hydroxy C.sub.2 -C.sub.4 alkyl;a compound of formula (II) ##STR14##and the pharmaceutically acceptable salts, prodrugs, polymorphs, hydrates, solvates, active metabolites and stereoisomers thereof; wherein:R.sup.9 is H, C.sub.1 -C.sub.3 alkyl optionally substituted with one or more fluoro substituents, or C.sub.3 -C.sub.5 cycloalkyl;R.sup.10 is H or C.sub.1 -C.sub.6 alkyl optionally substituted with one or more fluoro substituents or with C.sub.3 -C.sub.6 cycloalkyl;R.sup.11 is C.sub.1 -C.sub.6 alkyl optionally substituted with one or more fluoro substituents or with C.sub.3 -C.sub.6 cycloalkyl, or C.sub.3 -C.sub.5 cycloalkyl, or C.sub.3 -C.sub.6 alkenyl, or C.sub.3 -C.sub.6 alkynyl;R.sup.12 is C.sub.1 -C.sub.4 alkyl optionally substituted with OH, NR.sup.13 R.sup.14, CN, CONR.sup.13 R.sup.14 or with CO.sub.2 R.sup.15, or C.sub.2 -C.sub.4 alkenyl optionally substituted with CN, CONR.sup.13 R.sup.14 or with CO.sub.2 R.sup.15, or C.sub.2 -C.sub.4 alkanoyl optionally substituted with NR.sup.13 R.sup.14, or hydroxy C.sub.2 -C.sub.4 alky optionally substituted with NR.sup.13 R.sup.14, or (C.sub.2 -C.sub.3 alkoxy)C.sub.1 -C.sub.2 alkyl optionally substituted with OH or NR.sup.13 R.sup.14, or CONR.sup.13 R.sup.14, or CO.sub.2 R.sup.15, or halo, or NR.sup.13 R.sup.14, or NHSO.sub.2 NR.sup.13 R.sup.14, or NHSO.sub.2 R.sup.16, or phenyl or heterocyclyl either of which is optionally substituted with methyl;R.sup.13 and R.sup.14 are each independently H, C.sub.1 -C.sub.4 alkyl, or together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidino, morpholino, 4-(NR.sup.17)-piperazinyl or imidazolyl group wherein said group is optionally substituted with methyl or hydroxy;R.sup.15 is H or C.sub.1 -C.sub.4 alkyl;R.sup.16 is C.sub.1 -C.sub.3 alkyl optionally substituted with NR.sup.13 R.sup.14 ; andR.sup.17 is H, C.sub.1 -C.sub.3 alkyl optionally substituted with phenyl, or hydroxy C.sub.2 -C.sub.3 alkyl, or C.sub.1 -C.sub.4 alkanoyl;a compound of formula (III) ##STR15##and the pharmaceutically acceptable salts, prodrugs, polymorphs, hydrates, solvates, active metabolites and stereoisomers thereof; wherein: R.sup.1, R.sup.2, R.sup.3 and R.sup.5 are as previously described for said formula (I); R.sup.18 taken together with the nitrogen to which it is attached completes a pyrrolidinyl, piperidino or morpholino group;a compound of formula (IV) ##STR16##and the pharmaceutically acceptable salts, prodrugs, polymorphs, hydrates, solvates, active metabolites and stereoisomers thereof; wherein:R.sup.19 is C.sub.1 -C.sub.4 alkyl;R.sup.20 is C.sub.2 -C.sub.4 alkyl;R.sup.21 is H or SO.sub.2 NR.sup.22 R.sup.23 ;R.sup.22 and R.sup.23 together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino, morpholino or 4-N--(R.sup.24)-1-piperazinyl group; andR.sup.24 is H or C.sub.1 -C.sub.3 alkyl;a compound of formula (V) ##STR17##and the pharmaceutically acceptable salts, prodrugs, polymorphs, hydrates, solvates, active metabolites and stereoisomers thereof; wherein:R.sup.25 is H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy or CONR.sup.29 R.sup.30 ;R.sup.26 is H or C.sub.1 -C.sub.4 alkyl;R.sup.27 is C.sub.2 -C.sub.4 alkyl;R.sup.28 is H, C.sub.2 -C.sub.4 alkanoyl optionally substituted with NR.sup.31 R.sup.32, or (hydroxy)C.sub.2 -C.sub.4 alkyl optionally substituted with NR.sup.31 R.sup.32, or CH.dbd.CHCO.sub.2 R.sup.33, or CH.dbd.CHCONR.sup.31 R.sup.32, or CH.sub.2 CH.sub.2 CO.sub.2 R.sup.33, or CH.sub.2 CH.sub.2 CONR.sup.31 R.sup.32, or SO.sub.2 NR.sup.31 R.sup.32, or SO.sub.2 NH(CH.sub.2).sub.n NR.sup.31 R.sup.32 or imidazolyl;R.sup.29 and R.sup.30 are each independently H or C.sub.1 -C.sub.4 alkyl;R.sup.31 and R.sup.32 are each independently H or C.sub.1 -C.sub.4 alkyl, or together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino, morpholino or 4-(NR.sup.34)-1-piperazinyl group wherein any of said groups is optionally substituted with CONR.sup.29 R.sup.30 ;R.sup.33 is H or C.sub.1 -C.sub.4 alkyl;R.sup.34 is H, C.sub.1 -C.sub.3 alkyl or (hydroxy)C.sub.2 -C.sub.3 alkyl; andn is 2, 3 or 4; and provided that R.sup.28 is not H when R.sup.25 is H, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy;a compound of formula (VI) ##STR18##and the pharmaceutically acceptable salts, prodrugs, polymorphs, hydrates, solvates, active metabolites and stereoisomers thereof; wherein:R.sup.35 is H, C.sub.1 -C.sub.4 alkyl, CN or CONR.sup.29 R.sup.30 ;R.sup.36 is C.sub.2 -C.sub.4 alkyl;R.sup.37 is SO.sub.2 NR.sup.38 R.sup.39, NO.sub.2, NH.sub.2, NHCOR.sup.42, NHSO.sub.2 R.sup.42 or N(SO.sub.2 R.sup.42).sub.2 ;R.sup.38 and R.sup.39 are each independently selected from H and C.sub.1 -C.sub.4 alkyl optionally substituted with CO.sub.2 R.sup.43, OH, pyridyl, 5-isoxazolin-3-onyl, morpholino or 1-imidazolidin-2-onyl, or together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino, morpholino, 1-pyrazolyl or 4-(NR.sup.44)-1-piperazinyl group wherein any of said groups may optionally be substituted with one or two substituents selected from C.sub.1 -C.sub.4 alkyl, CO.sub.2 R.sup.43, NH.sub.2 and OH;R.sup.42 is C.sub.1 -C.sub.4 alkyl or pyridyl;R.sup.43 is H or C.sub.1 -C.sub.4 alkyl; andR.sup.44 is H, C.sub.1 -C.sub.4 alkyl or (hydroxy)C.sub.2 -C.sub.3 alkyl;a compound of formula (VII) ##STR19##and the pharmaceutically acceptable salts, prodrugs, polymorphs, hydrates, solvates, active metabolites and stereoisomers thereof; wherein:R.sup.45 is C.sub.1 -C.sub.6 alkyl;R.sup.46 is H, methyl or ethyl;R.sup.47 is C.sub.2 -C.sub.4 alkyl;R.sup.48 is C.sub.1 -C.sub.4 alkyl optionally substituted with NR.sup.49 R.sup.50, CN, CONR.sup.49 R.sup.50 or CO.sub.2 R.sup.51 ; C.sub.2 -C.sub.4 alkenyl optionally substituted with CN, CONR.sup.49 R.sup.50 or CO.sub.2 R.sup.51 ; C.sub.2 -C.sub.4 alkanoyl optionally substituted with NR.sup.49 R.sup.50 ; SO.sub.2 NR.sup.49 R.sup.50 ; CONR.sup.49 R.sup.50 ; CO.sub.2 R.sup.51 ; or halo;R.sup.49 and R.sup.50 are each independently H or C.sub.1 -C.sub.4 alkyl, or together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino, morpholino, 4-(NR.sup.52)-1-piperazinyl or 1-imidazolyl group wherein said group is optionally substituted by one or two C.sub.1 -C.sub.4 alkyl groups;R.sup.51 is H or C.sub.1 -C.sub.4 alkyl; andR.sup.52 is H, C.sub.1 -C.sub.3 alkyl or hydroxy C.sub.2 -C.sub.3 alkyl;a compound of formula (VIII) ##STR20##and the pharmaceutically acceptable salts, prodrugs, polymorphs, hydrates, solvates, active metabolites and stereoisomers thereof; wherein:R.sup.53 is methyl or ethyl;R.sup.54 is ethyl or n-propyl;R.sup.55 and R.sup.56 are each independently H or C.sub.1 -C.sub.6 alkyl optionally substituted with C.sub.5 -C.sub.7 cycloalkyl or with morpholino; ora compound of formula (IX) ##STR21##and the pharmaceutically acceptable salts, prodrugs, polymorphs, hydrates, solvates, active metabolites and stereoisomers thereof; wherein:R.sup.57 is hydrogen, halogen or C.sub.1-6 alkyl;R.sup.58 is hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halo C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkyl C.sub.1-3 alkyl, aryl C.sub.1-3 alkyl or heteroaryl C.sub.1-3 alkyl;R.sup.59 is an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan and pyridine or an optionally substituted bicyclic ring ##STR22##attached to the rest of the molecule via one of the benzene ring carbon atoms and wherein the fused ring A is a 5- or 6-membered ring which may be saturated or partially or fully unsaturated and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulphur and nitrogen; andR.sup.60 is hydrogen or C.sub.1-3 alkyl, or R.sup.58 and R.sup.60 together represent a 3- or 4-membered alkyl or alkenyl chain; ora compound of formulae (XA) or (XB) ##STR23##and the pharmaceutically acceptable salts, prodrugs, polymorphs, hydrates, solvates, active metabolites and stereoisomers thereof; wherein:R.sup.61 is C.sub.1 -C.sub.3 alkyl substituted with C.sub.3 -C.sub.6 cycloalkyl, CONR.sup.65 R.sup.66 or a N-linked heterocyclic group selected from pyrazolyl, imidazolyl, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl and 4-R.sup.67 -piperazinyl; (CH.sub.2).sub.p Het or (CH.sub.2).sub.q Ar;R.sup.62 is C.sub.1 -C.sub.6 alkyl;R.sup.63 is C.sub.1 -C.sub.6 alkyl optionally substituted with C.sub.1 -C.sub.4 alkoxy;R.sup.64 is SO.sub.2 NR.sup.68 R.sup.69 ;R.sup.65 and R.sup.66 are each independently selected from H and C.sub.1 -C.sub.4 alkyl optionally substituted with C.sub.1 -C.sub.4 alkoxy, or, together with the nitrogen atom to which they are attached, form a pyrrolidinyl, piperidinyl, morpholinyl or 4-R.sup.67 -piperazinyl group;R.sup.68 and R.sup.69, together with the nitrogen atom to which they are attached, form a 4-R.sup.70 -piperazinyl group;R.sup.67 is C.sub.1 -C.sub.4 alkyl;R.sup.70 is H or C.sub.1 -C.sub.4 alkyl optionally substituted with OH, C.sub.1 -C.sub.4 alkoxy or CONH.sub.2 ;Het is a C-linked 6-membered heterocyclic group containing one or two nitrogen atoms, optionally in the form of of its mono-N-oxide, or a C-linked 5-membered heterocyclic group containing from one to four heteroatoms selected from nitrogen, oxygen and sulfur, wherein either of said heterocyclic groups is optionally substituted with one or two substituents selected from C.sub.1 -C.sub.4 alkyl optionally substituted with C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkoxy, halo and NH.sub.2 ;Ar is phenyl optionally substituted with one or two substituents selected from C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halo, CN, CONH.sub.2, NO.sub.2, NH.sub.2, NHSO.sub.2 (C.sub.1 -C.sub.4 alkyl) and SO.sub.2 NH.sub.2 ; andp and q are each independently 0 or 1.