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New oxabispidine compounds useful in the treatment of cardiac arrhythmiasRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Six-membered And Includes At Least Nitrogen And Oxygen As Ring Hetero Atoms (e.g., Monocyclic 1,2- And 1,3-oxazines, Etc.), Polycyclo Ring System Having The Six-membered Hetero Ring As One Of The Cyclos (e.g., Maytansinoids, Etc.), Bicyclo Ring System Having The Six-membered Hetero Ring As One Of The Cyclos (e.g., 1,4-benzoxazines, Etc.)New oxabispidine compounds useful in the treatment of cardiac arrhythmias description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060166980, New oxabispidine compounds useful in the treatment of cardiac arrhythmias. Brief Patent Description - Full Patent Description - Patent Application Claims
FIELD OF THE INVENTION [0001] This invention relates to novel pharmaceutically useful compounds, in particular compounds which are useful in the treatment of cardiac arrhythmias. BACKGROUND AND PRIOR ART [0002] Cardiac arrhythmias may be defined as abnormalities in the rate, regularity, or site of origin of the cardiac impulse or as disturbances in conduction which causes an abnormal sequence of activation. Arrhythmias may be is classified clinically by means of the presumed site of origin (i.e. as supraventricular, including atrial and atrioventricular, arrhythmias and ventricular arrhythmias) and/or by means of rate (i.e., bradyarrhythmias (slow) and tachyarrhythmias (fast)). [0003] In the treatment of cardiac arrhythmias, the negative outcome in clinical trials (see, for example, the outcome of the Cardiac Arrhythmia Suppression Trial (CAST) reported in New England Journal of Medicine, 321, 406 (1989)) with "traditional" antiarrhythmic drugs, which act primarily by slowing the conduction velocity (class I antiarrhythmic drugs), has prompted drug development towards compounds which selectively delay cardiac repolarization, thus prolonging the QT interval. Class III antiarrrhythmic drugs may be defined as drugs which prolong the trans-membrane action potential duration (which can be caused by a block of outward K.sup.+ currents or from an increase of inward ion currents) and refractoriness, without affecting cardiac conduction. [0004] One of the key disadvantages of hitherto known drugs which act by delaying repolarization (class III or otherwise) is that they all are known to exhibit a unique form of proarrhythmia known as torsades de pointes (turning of points), which may, on occasion be fatal. From the point of view of safety, the minimisation of this phenomenon (which has also been shown to be exhibited as a result of administration of non-cardiac drugs such as phenothiazines, tricyclic antidepressants, antihistamines and antibiotics) is a key problem to be solved in the provision of effective antiarrthythmic drugs. [0005] Antiarrhythmic drugs based on bispidines (3,7-diazabicyclo[3.3.1]nonanes), are known from inter alia international patent applications WO 91/07405 and WO 99/31100, European patent applications 306 871, 308 843 and 655 228 and U.S. Pat. Nos. 3,962,449, 4,556,662, 4,550,112, 4,459,301 and 5,468,858, as well as journal articles including inter alia J. Med. Chem. 39, 2559, (1996), Pharmacol. Res., 24, 149 (1991), Circulation, 90, 2032 (1994) and Anal. Sci. 9, 429, (1993). Oxabispidine compounds are neither disclosed nor suggested in any of these documents. [0006] Certain oxabispidine compounds are disclosed as chemical curiosities in Chem. Ber., 96, 2872 (1963). That these compounds may be used in the treatment of arrhythmias is neither mentioned nor suggested. [0007] We have surprisingly found that a novel group of oxabispidine-based compounds exhibit electrophysiological activity, preferably class III electrophysiological activity, and are therefore expected to be useful in the treatment of cardiac arrhythmias. DISCLOSURE OF THE INVENTION [0008] According to the invention there is provided compounds of formula I, wherein R.sup.1 represents C.sub.1-12 alkyl (which alkyl group is optionally substituted and/or terminated by one or more groups selected from halo, cyano, nitro, aryl, Het.sup.1, C(O)R.sup.5a, OR.sup.5b, N(R.sup.6)R.sup.5c, --C(O)XR.sup.7, --C(O)N(R.sup.8)R.sup.5d, and --S(O).sub.2R.sup.9), or R.sup.1 represents --C(O)XR.sup.7, --C(O)N(R.sup.8)R.sup.5d or --S(O).sub.2R.sup.9; R.sup.5a to R.sup.5d independently represent, at each occurrence, H, C.sub.1-6 alkyl (which latter group is optionally substituted and/or terminated by one or more substituents selected from --OH, halo, cyano, nitro, aryl and Het.sup.2), aryl or Het.sup.3, or R.sup.5d, together with R.sup.8, represents C.sub.3-6 alkylene (which alkylene group is optionally interrupted by an O atom and/or is optionally substituted by one or more C.sub.1-3 alkyl groups); R.sup.6 represents H, C.sub.1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from --OH, halo, cyano, nitro and aryl), aryl, --C(O)R.sup.10a, --C(O)OR.sup.10b or --C(O)N(H)R.sup.10c; R.sup.10a, R.sup.10b and R.sup.10c independently represent C.sub.1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from --OH, halo, cyano, nitro and aryl), aryl, or R.sup.10a represents H; R.sup.7 represents C.sub.1-12 alkyl (optionally substituted and/or terminated by one or more substituents selected from --OH, halo, cyano, nitro, aryl, C.sub.1-6 alkoxy and Het.sup.4); R.sup.8 represents H, C.sub.1-12 alkyl, C.sub.1-6 alkoxy (which latter two groups are optionally substituted and/or terminated by one or more substituents selected from --OH, halo, cyano, nitro, C.sub.1-4, alkyl and C.sub.1-4, alkoxy), -D-aryl, -D-aryloxy, -D-Het.sup.5, -D-N(H)C(O)R.sup.11a, -D-S(O).sub.2R.sup.12a, -D-C(O)R.sup.11b, -D-C(O)OR.sup.12b, -D-C(O)N(R.sup.11c)R.sup.11d, or R.sup.8, together with R.sup.5d, represents C.sub.3-6 alkylene (which alkylene group is optionally interrupted by an O atom and/or is optionally substituted by one or more C.sub.1-3 alkyl groups); R.sup.11a to R.sup.11d independently represent H, C.sub.1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from --OH, halo, cyano, nitro and aryl), aryl, or R.sup.11c and R.sup.11d together represent C.sub.3-6 alkylene; R.sup.9, R.sup.12a and R.sup.12b independently represent C.sub.1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from --OH, halo, cyano, nitro and aryl) or aryl; D represents a direct bond or C.sub.1-6 alkylene; X represents O or S; R.sup.2 represents H, halo, C.sub.1-6 alkyl, --OR.sup.13, -E-N(R.sup.14)R.sup.15 or, together with R.sup.3, represents .dbd.O; R.sup.3 represents H, C.sub.1-6 alkyl or, together with R.sup.2, represents .dbd.O; R.sup.13 represents H, C.sub.1-6 alkyl, -E-aryl, -E-Het.sup.6, --C--(O)R.sup.16a, --C(O)OR.sup.16b or --C(O)N(R.sup.17a)R.sup.17b; R.sup.14 represents H, C.sub.1-6 alkyl, -E-aryl, -E-Het.sup.6, --C(O)R.sup.16a, --C(O)OR.sup.16b, --S(O).sub.2R.sup.16c, --[C(O)].sub.pN(R.sup.17a)R.sup.17b or --C(NH)NH.sub.2; R.sup.15 represents H, C.sub.1-6 alkyl, -E-aryl or --C(O)R.sup.16d; R.sup.16a to R.sup.16d independently represent, at each occurrence when used herein, C.sub.1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from halo, aryl and Het.sup.7), aryl, Het.sup.8, or R.sup.16a and R.sup.16d independently represent H; R.sup.17a and R.sup.17b independently represent, at each occurrence when used herein, H or C.sub.1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from halo, aryl and Het.sup.9), aryl, Het.sup.10, or together represent C.sub.3-6 alkylene, optionally interrupted by an O atom; E represents, at each occurrence when used herein, a direct bond or C.sub.1-4, alkylene; p represents 1 or 2; Het.sup.1 to Het.sup.10 independently represent five- to twelve-membered heterocyclic groups containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, which groups are optionally substituted by one or more substituents selected from --OH, oxo, halo, cyano, nitro, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, aryl, aryloxy, --N(R.sup.18a)R.sup.18b, --C(O)R.sup.18c, C(O)OR.sup.18d, --C(O)N(R.sup.18e)R.sup.18f, --N(R.sup.18g)C(O)R.sup.18h and --N(R.sup.18i)S(O).sub.2R.sup.18j; R.sup.18a to R.sup.18j independently represent C.sub.1-6 alkyl, aryl or R.sup.18a to R.sup.18i independently represent H; A represents a direct bond, -J-, -J-N(R.sup.19)-- or -J-O-- (in which latter two groups, N(R.sup.19)-- or O-- is attached to the carbon atom bearing R.sup.2 and R.sup.3); B represents -Z-, -Z-N(R.sup.20)--, --N(R.sup.20)-Z-, -Z-S(O).sub.n--, -Z-O-- (in which latter two groups, Z is attached to the carbon atom bearing R.sup.2 and R.sup.3), --N(R.sup.20)C(O)O-Z-, (in which latter group, --N(R.sup.20) is attached to the carbon atom bearing R.sup.2 and R.sup.3) or --C(O)N(R.sup.20)-- (in which latter group, --C(O) is attached to the carbon atom bearing R.sup.2 and R.sup.3); J represents C.sub.1-6 alkylene optionally substituted by one or more substituents selected from --OH, halo and amino; Z represents a direct bond or C.sub.1-4 alkylene; n represents 0, 1 or 2; R.sup.19 and R.sup.20 independently represent H or C.sub.1-6 alkyl; G represents CH or N; R.sup.4 represents one or more optional substituents selected from --OH, cyano, halo, nitro, C.sub.1-6 alkyl (optionally terminated by --N(H)C(O)OR.sup.21a), C.sub.1-6 alkoxy, --N(R.sup.22a)R.sup.22b, --C(O)R.sup.22c, --C(O)OR.sup.22d, --C(O)N(R.sup.22e)R.sup.22f, --N(R.sup.22g)C(O)N(R.sup.22i)R.sup.22k, --N(R.sup.22m)S(O).sub.2R.sup.21b, --S(O)R.sup.21cR and/or --OS(O).sub.2R.sup.21d; R.sup.21a to R.sup.21d independently represent C.sub.1-6 alkyl; R.sup.22a and R.sup.22b independently represent H, C.sub.1-6 alkyl or together represent C.sub.3-6 alkylene, resulting in a four- to seven-membered nitrogen-containing ring; R.sup.22c to R.sup.22m independently represent H or C.sub.1-6 alkyl; and R.sup.41 to R.sup.46 independently represent H or C.sub.1-3 alkyl; wherein each aryl and aryloxy group, unless otherwise specified, is optionally substituted; provided that (a) the compound is not: [0009] 3,7-dibenzoyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane; (b) when A represents -J-N(R.sup.19)-- or -J-O--, then: [0010] (i) J does not represent C.sub.1 alkylene; and [0011] (ii) B does not represent --N(R.sup.20)--, --NR.sup.20)-Z- (in which latter group N(R.sup.20) is attached to the carbon atom bearing R.sup.2 and R.sup.3), --S(O).sub.n--, --O-- or --N(R.sup.20)C(O)O-Z- when R.sup.2 and R.sup.3 do not together represent .dbd.O; and (c) when R.sup.2 represents --OR.sup.13 or --N(R.sup.14)(R.sup.15), then: [0012] (i) A does not represent -J-N(R.sup.19)-- or -J-O--; and [0013] (ii) B does not represent --N(R.sup.20)--, --N(R.sup.20)-Z- (in which latter group N(R.sup.20) is attached to the carbon atom bearing R.sup.2 and R.sup.3), --S(O).sub.n--, --O-- or --N(R.sup.20)C(O)O-Z-; or a pharmaceutically acceptable derivative thereof; which compounds are referred to hereinafter as "the compounds of the invention". [0014] Unless otherwise specified, alkyl groups and alkoxy groups as defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of three) of carbon atoms be branched-chain, and/or cyclic. Further, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, such alkyl and alkoxy groups may also be part cyclic/acyclic. Such alkyl and alkoxy groups may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated and/or interrupted by one or more oxygen and/or sulfur atoms. Unless otherwise specified, alkyl and alkoxy groups may also be substituted by one or more halo, and especially fluoro, atoms. [0015] Unless otherwise specified, alkylene groups as defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be branched-chain. Such alkylene chains may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated and/or interrupted by one or more oxygen and/or sulfur atoms. Unless otherwise specified, alkylene groups may also be substituted by one or more halo atoms. [0016] The term "aryl", when used herein, includes C.sub.6-10 aryl groups such as phenyl, naphthyl and the like. The term "aryloxy", when used herein includes C.sub.6-10 aryloxy groups such as phenoxy, naphthoxy and the like. For the avoidance of doubt, aryloxy groups referred to herein are attached to the rest of the molecule via the O-atom of the oxy-group. Unless otherwise specified, aryl and aryloxy groups may be substituted by one or more substituents including --OH, halo, cyano, nitro, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, --N(R.sup.22a)R.sup.22b, --C(O)R.sup.22c, --C(O)OR.sup.22d, --C(O)N(R.sup.22e)R.sup.22f, --N(R.sup.22g)C(O)R.sup.22h, --N(R.sup.22m)S(O).sub.2R.sup.21b, --S(O).sub.2R.sup.21c, and/or --OS(O).sub.2R.sup.21d (wherein R.sup.21b to R.sup.21d and R.sup.22a to R.sup.22m are as hereinbefore defined). When substituted, aryl and aryloxy groups are preferably substituted by between one and three substitutents. [0017] The term "halo", when used herein, includes fluoro, chloro, bromo and iodo. [0018] Het (Het.sup.1, Het.sup.2, Het.sup.3, Het.sup.4, Het.sup.5, Het.sup.6, Het.sup.7, Het.sup.8, Het.sup.9 and Het.sup.10) groups that may be mentioned include those containing 1 to 4 heteroatoms (selected from the group oxygen, nitrogen and/or sulfur) and in which the total number of atoms in the ring system are between five and twelve. Het (Het.sup.1, Het.sup.2, Het.sup.3, Het.sup.4, Het.sup.5, Het.sup.6, Het.sup.7, Het.sup.8, Het.sup.9 and Het.sup.10) groups may be fully saturated, wholly aromatic, partly aromatic and/or bicyclic in character. Heterocyclic groups that may be mentioned include benzodioxanyl, benzodioxepanyl, benzodioxolyl, benzofuranyl, benzimidazolyl, benzomorpholinyl, benzoxazinonyl, benzothiophenyl, chromanyl, cinnolinyl, dioxanyl, furanyl, imidazolyl, imidazo[1,2-a]pyridinyl, indolyl, isoquinolinyl, isoxazolyl, morpholinyl, oxazolyl, phthalazinyl, piperazinyl, piperidinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimindinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, tetrahydropyranyl, tetrahydrofuranyl, thiazolyl, thienyl, thiochromanyl, triazolyl and the like. Values of Het.sup.1 that may be mentioned include pyridinyl, benzodioxanyl, imidazolyl, imidazo[1,2-a]pyridinyl, piperazinyl, pyrazolyl, pyrrolyl, pyrrolidinyl, tetrahydropyranyl and thiazolyl. Values of Het.sup.3 that may be mentioned include benzodioxanyl and benzomorpholinyl. Values of Het.sup.4 that may be mentioned include piperazinyl. Substituents on Het (Het.sup.1, Het.sup.2, Het.sup.3, Het.sup.4, Het.sup.5, Het.sup.6, Het.sup.7, Het.sup.8, Het.sup.9 and Het.sup.10) groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of Het (Het.sup.1, Het.sup.2, Het.sup.3, Het.sup.4, Het.sup.5, Het.sup.6, Het.sup.7, Het.sup.8, Het.sup.9 and Het.sup.10) groups may be via any atom in the ring system including (where appropriate) a heteroatom, or an atom on any fused carbocyclic ring that may be present as part of the ring system. Het (Het.sup.1, Het.sup.2, Het.sup.3, Het.sup.4, Het.sup.5, Het.sup.6, Het.sup.7, Het.sup.8, Het.sup.9 and Het.sup.10) groups may also be in the N- or S-oxidised form. [0019] Pharmaceutically acceptable derivatives include salts and solvates. Salts which may be mentioned include acid addition salts. Specific salts that may be mentioned include arylsulfonate salts, such as toluenesulfonate and, especially, benzenesulfonate salts. Solvates that may be mentioned include hydrates, such as monohydrates of the compounds of the invention. [0020] Pharmaceutically acceptable derivatives also include, at the oxabispidine or (when G represents N) pyridyl nitrogens, C.sub.1-4 alkyl quaternary ammonium salts and N-oxides, provided that when a N-oxide is present: [0021] (a) no Het (Het.sup.1, Het.sup.2, He.sup.3, Het.sup.4, He.sup.5, He.sup.6, Het.sup.7, Het.sup.8, Het.sup.9 and Het.sup.10) group contains an unoxidised S-atom; and/or [0022] (b) n does not represent 0 when B represents -Z-S(O).sub.n--. [0023] The compounds of the invention may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention. [0024] The compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric esters by conventional means (e.g. HPLC, chromatography over silica). All stereoisomers are included within the scope of the invention. [0025] Abbreviations are listed at the end of this specification. [0026] Compounds of formula I that may be mentioned include those in which, when R.sup.2 and R.sup.3 together represent .dbd.O, then A and B do not simultaneously represent direct bonds. [0027] Preferred compounds of the invention include those in which: [0028] R.sup.1 represents C.sub.1-8 alkyl (which alkyl group is optionally substituted and/or terminated by one or more groups selected from halo, optionally substituted aryl, optionally substituted Het.sup.1, --C(O)R.sup.5a, --OR.sup.5b, N(R.sup.6)R.sup.5c, --C(O)N(R.sup.8)R.sup.5d, and --S(O).sub.2R.sup.9), or R.sup.1 represents --C(O)OR.sup.7, --C(O)N(R.sup.8)R.sup.5d or --S(O).sub.2R.sup.9; Continue reading about New oxabispidine compounds useful in the treatment of cardiac arrhythmias... Full patent description for New oxabispidine compounds useful in the treatment of cardiac arrhythmias Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this New oxabispidine compounds useful in the treatment of cardiac arrhythmias patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. 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