Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/08—Bridged systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/06—Antiarrhythmics

Definitions

• This invention relates to novel pharmaceutically useful compounds, in particular compounds which are useful in the treatment of cardiac arrhythmias.
• 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 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)).
• Class III antiarrhythmic drugs may be defined as drugs which prolong the trans-membrane action potential duration (which can be caused by a block of outward K + currents or from an increase of inward ion currents) and refractoriness, without affecting cardiac conduction.
• Antiarrhythmic drugs based on bispidines are known from inter alia international patent application WO 91/07405, European patent applications 306 871, 308 843 and 655 228 and US patents 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).
• Known bispidine-based antiarrhythmic compounds include bisaramil (3-methyl-7-ethyl-9 ⁇ ,4'-(Cl-benzoyloxy)-3,7- diazabicyclo[3.3.1]nonane), tedisamil (3',7'-bis(cyclopropylmethyl)spiro- (cyclopentane-l,9')-3,7-diazabicyclo[3.3.1]nonane), SAZ-NII-22 (3-(4- chlorobenzoyl)-7-/s ⁇ -propyl-3,7-diazabicyclo[3.3.1]nonane), SAZ-NII-23 (3-benzoyl-7- 5c>-propyl-3,7-diazabicyclo[3.3.
• R 1 and R 2 independently represent H, C alkyl, OR 2b or N(R 2c )R 2d , or together form -0-(CH 2 ) 2 -0-, -(CH 2 ) 3 -, -(CH 2 ) 4 - or -(CH 2 ) r ;
• R 2b , R 2c and R 2d independently represent H or Cj. 6 alkyl;
• R 3 represents H, C ⁇ alkyl or, together with R 4 , represents C 3 . 6 alkylene (which alkylene group is optionally interrupted by an O atom and/or is optionally substituted by one or more Cj. 3 alkyl groups);
• R 4 represents H, C 2 alkyl, C ⁇ alkoxy (which latter two groups are both optionally substituted and/or terminated by one or more substituents selected from -OH, halo, cyano, nitro, C alkyl and/or C alkoxy), -(CH 2 ) q -aryl, -(CH 2 ) q -oxyaryl, -(CH 2 ) q -Het 1 (which latter three groups are optionally substituted (at the -(CH 2 ) q - part and/or the aryl/Het 1 part) by one or more substituents selected from -OH, halo, cyano, nitro, -C(0)R 10 , -C(0)OR n , -N(H)S(0) 2 R lla , C ⁇ .
• R 41 , R 42 , R 4 ⁇ R 44 , R 45 or R 4 ° independently represent H or C ⁇ alkyl
• R 12 represents H, C ⁇ . 6 alkyl, -S(0) 2 -C M -alkyl, -C(0)R 14 , -C(0)OR 14 , -C(0)N(R 15 )R 1 a or aryl (which latter group is optionally substituted and/or terminated by one or more substituents selected from -OH, halo, cyano, nitro, -C(0)R 10 , -C(0)OR u , -N(H)S(0) 2 R lla , C 6 alkyl and/or C w alkoxy);
• R 13 represents H or C alkyl;
• R 14 represents H or C ⁇ alkyl;
• R 15 and R 15a independently represent H or C alkyl, or together represent
• A represents a single bond, C ⁇ 6 alkylene, -N(R 16 )(CH 2 ) r - or -0(CH 2 ) r - (in which two latter groups, the -(CH 2 ) r - group is attached to the bispidine nitrogen atom);
• B represents a single bond, C M alkylene, -(CH 2 ) n N(R 17 )-, -(CH 2 ) n S(0) p -, -(CH 2 ) n O- (in which three latter groups, the -(CH 2 ) n - group is attached to the carbon atom bearing R 5 and R 6 ), -C(0)N(R 17 )- (in which latter group, the -C(O)- group is attached to the carbon atom bearing R 5 and R 6 ), -N(R 17 )C(0)0(CH 2 ) n -, -N(R 17 )(CH 2 ) n - (in which two latter groups, the N(R 17 ) group is attached to the carbon atom bearing R 5 and R 6 ) or -(CH 2 ) m C(H)(OH)(CH 2 ) n - (in which latter group, the -(CH 2 ) m - group is attached to the carbon atom bearing
• R 7 represents C j . 6 alkyl, aryl or Het 2 , all of which groups are optionally substituted and/or terminated (as appropriate) by one or more substituents selected from -OH, cyano, halo, amino, nitro, Het 3 , -C(0)R 10 , -C(0)OR n , Q.
• R 18 , R 19 and R 20 independently represent C ⁇ alkyl
• R 21 and R 22 independently represent H or C ⁇ alkyl (optionally terminated by cyano);
• R 10 and R 11 independently represent, at each individual occurrence, H or
• R lla represents, at each individual occurrence, C ⁇ alkyl
• A does not represent -N(R 16 )(CH 2 ) r - or -0(CH 2 ) r -; and/or (ii) n does not represent 0 when B represents -(CH 2 ) n N(R 17 )-,
• Aryl groups that may be mentioned include C 6 . 10 aryl groups, such as phenyl, naphthyl and the like.
• Oxyaryl groups that may be mentioned include C 6 . 10 oxyaryl groups, such as oxyphenyl (phenoxy), oxynaphthyl (naphthoxy) and the like. When substituted, aryl and aryloxy groups are preferably substituted by one to three substituents.
• Het 1 , Het 2 and Het 3 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 1 , Het 2 and Het 3 ) groups may be wholly/partly aromatic in character and may be bicyclic.
• Heterocyciic groups that may be mentioned include morpholinyl, thiazolyl, oxazolyl, isoxazolyl, cinnolinyl, quinazolinyl, phthalazinyl, purinyl, benzimidazolyl, pyrimindinyl, piperazinyl, pyrazinyl, piperidinyl, pyridinyl, triazolyl, imidazolyl, quinolinyl, isoquinolinyl, dioxanyl, benzodioxanyl, benzodioxolyl, benzodioxepanyl, benzomorpholinyl, indolyl, pyrazolyl, pyrrolyl, benzothiophenyl, thiophenyl, chromanyl, thiochromanyl, benzofuranyl, pyranyl, tetrahydropyranyl, tetrahydrofurany
• Het 1 values of Het 1 that may be mentioned include tetrahydropyranyl, isoxazolyl, benzodioxolyl, benzodioxepanyl and thiophenyl.
• Values of Het 2 that may be mentioned include quinolinyl, isoquinolinyl, benzomorpholinyl, benzodioxanyl, piperazinyl, indolyl and pyrazolyl.
• Values of Het 3 values include imidazolyl.
• Substituents on Het (Het 1 , Het 2 and Het 3 ) groups may, where appropriate, be located on any atom in the ring system including a heteroatom.
• Het (Het 1 , Het 2 and Het 3 ) groups may be via any atom in the ring system including (where appropriate) a heteroatom.
• Het (Het 1 , Het 2 and Het 3 ) groups may also be in the N- or S-oxidised form.
• Pharmaceutically acceptable derivatives include salts and solvates. Salts which may be mentioned include acid addition salts. Pharmaceutically acceptable derivatives also include, at the bispidine nitrogens, i alkyl quaternary ammonium salts and N-oxides, provided that when a N-oxide is present:
• (b) p does not represent 0 when B represents -(CH 2 ) n S(0) p -.
• the compounds of the invention may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention.
• 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.
• 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.
• R 42 , R 43 , R 44 , R 45 and R 46 may represent, that R 12 may include, and with which R 3 , R 4 , R 7 , R 8 and R 12 may be substituted; and alkoxy groups that R 4 may represent, and with which R 4 , R 7 , R 8 and R 12 may be substituted; may be linear or, when there is a sufficient number (i.e. three) of carbon atoms, be branched and/or cyclic. Further, when there is a sufficient number (i.e. 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. two) of carbon atoms, be unsaturated and/or interrupted by oxygen.
• Alkylene groups that R 3 and R 4 , R 8 and R 9 , R 15 and R 15a , A, and B, may represent; and -(CH 2 ) m -, -(CH 2 ) n -, -(CH 2 ) q - and -(CH 2 ) r - chains that A, B and R 4 (as appropriate) may include, may be linear or, when there is a sufficient number (i.e. two) of carbon atoms, be branched.
• Such alkylene groups and -(CH 2 )- containing chains may also be saturated or, when there is a sufficient number (i.e. two) of carbon atoms, be unsaturated and/or interrupted by oxygen.
• Halo groups that R 5 may represent, and with which R 4 , R 7 , R 8 and R 12 may be substituted, include fluoro, chloro, bromo and iodo.
• each R 10 , R 11 , and R lla , group identified herein is independent of other R 10 , R 11 , and R lla , groups, respectively.
• R 4 and R 7 both represent aryl substituted by -C(0)R 10
• the two individual -C(0)R 10 substituents are independent of one another, and are not necessarily identical (though this possibility is not excluded).
• Preferred compounds of the invention include those in which: R 1 represents H; R 2 represents H; R 3 represents
• R 4 represents C 4 . 5 alkylene, optionally interrupted by an
• R 4 represents
• R 5 represents H; fluoro; OR 12 (in which R 12 represents H, phenyl (optionally substimted by one or more methoxy groups) or C(0)N(H)R 15a (in which R 15 represents linear or branched C alkyl));
• A represents a single bond, linear or branched C alkylene (which group is also optionally interrupted by O), -N(H)(CH 2 ) r - or -0(CH 2 ) r - (in which latter two groups r is 1 or 2);
• B represents a single bond, C alkylene, -(CH 2 ) n O-, -(CH 2 ) n S(0) 2 -,
• R 7 represents linear or branched and/or acyclic, cyclic and/or part cyclic/acyclic C x _ 6 alkyl (optionally substimted and/or terminated by OH);
• More preferred compounds of the invention include those in which:
• R 3 represents H
• R 5 represents H, OH or -N(H)C(0)N(R 15 )(R 15a );
• R 6 represents H
• A represents -CH 2 - or -(CH 2 ) 2 -;
• B represents a single bond, -CH 2 N(H)- or -CH 2 0- (where, for the avoidance of doubt, the -CH 2 - part is attached to the carbon atom bearing R 5 and R 6 );
• R 7 represents phenyl (substimted by a cyano group (preferably in the 4- position relative to B) and by one or more optional C(0)N(H)R 22 substituent).
• Preferred compounds of the invention include the compounds of the Examples disclosed hereinafter. Preparation
• R 1 , R 2 , R 5 , R 6 , R 7 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , A and B are as hereinbefore defined with a compound of formula III,
• an appropriate organic solvent e.g. dichloromethane
• R 3 represents a leaving group such as halo, imidazole or R 23 0- (wherein R 23 represents, for example, C lQ alkyl, aryl or C [ . 3 alkylaryl, which groups are optionally substimted by one or more halo or nitro groups) and R 3 and R 4 are as hereinbefore defined, for example at between room and reflux temperamre in the presence of a suitable base (e.g. triethylamine or potassium carbonate) and an appropriate organic solvent (e.g. dichloromethane, THF, acetonitrile, toluene, or mixtures thereof);
• a suitable base e.g. triethylamine or potassium carbonate
• an appropriate organic solvent e.g. dichloromethane, THF, acetonitrile, toluene, or mixtures thereof
• R 1 , R 2 , R 5 , R 6 , R 7 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , A, B and L 1 are as hereinbefore defined with a compound of formula VA,
• R 3 and R 4 are as hereinbefore defined, for example at between room and reflux temperamre in the presence of a suitable base (e.g. triethylamine or potassium carbonate) and an appropriate organic solvent (e.g. dichloromethane, THF, acetonitrile, toluene, or mixtures thereof), or via solid phase synthesis under conditions known to those skilled in the art; (d) for compounds of formula I in which A represents CH 2 and R 5 represents -OH or -N(H)R 12 , wherein R 12 is as hereinbefore defined, reaction of a compound of formula VI,
• a suitable base e.g. triethylamine or potassium carbonate
• an appropriate organic solvent e.g. dichloromethane, THF, acetonitrile, toluene, or mixtures thereof
• R 1 , R 2 , R 3 , R 4 , R 41 , R 42 , R 43 , R 44 , R 45 and R 46 are as hereinbefore defined, with a compound of formula VII,
• X represents O or N(R 12 ) and R 6 , R 7 , R 12 and B are as hereinbefore defined, for example at elevated temperamre (e.g. 60°C to reflux) in the presence of a suitable solvent (e.g. a lower alkyl alcohol (e.g. IPA), acetonitrile, or a mixture of a lower alkyl alcohol and water);
• a suitable solvent e.g. a lower alkyl alcohol (e.g. IPA), acetonitrile, or a mixture of a lower alkyl alcohol and water
• L 2 represents a leaving group (e.g. mesylate, tosylate or halo) and R 5 , R 6 , R 7 , A and B are as hereinbefore defined, for example at elevated temperamre (e.g. between 35°C and reflux temperamre) in the presence of a suitable base (e.g. triethylamine or K 2 C0 3 ) and an appropriate organic solvent (e.g. acetonitrile or DMSO);
• a suitable base e.g. triethylamine or K 2 C0 3
• an appropriate organic solvent e.g. acetonitrile or DMSO
• a suitable reducing agent e.g. sodium borohydride or sodium cyanoborohydride
• an appropriate organic solvent e.g.
• a lower alkyl alcohol such as methanol, ethanol or IP A
• the reducing agent may be added to the reaction mixture and the reduction carried out at between 60 °C and reflux, advantageously in the presence of a suitable organic acid (e.g. acetic acid);
• R 1 , R 2 , R 3 , R ⁇ R 5 , R 6 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , A and n are as hereinbefore defined, with a compound of formula XIA,
• R 7 OH XIA in which R 7 is as hereinbefore defined, for example under Mitsunobu-type conditions e.g. at between ambient (e.g. 25 °C) and reflux temperamre in the presence of a tertiary phosphine (e.g. tributylphosphine or triphenylphosphine), an azodicarboxylate derivative (e.g. diethylazodicarboxylate or l ,l '-(azodicarbonyl)dipiperidine) and an appropriate organic solvent (e.g.
• a tertiary phosphine e.g. tributylphosphine or triphenylphosphine
• an azodicarboxylate derivative e.g. diethylazodicarboxylate or l ,l '-(azodicarbonyl)dipiperidine
• an appropriate organic solvent e.g.
• R L 3 XII wherein R b represents C alkyl and L 3 is a leaving group such as halo, alkane sulfonate or aryl sulfonate, for example at room temperamre in the presence of an appropriate organic solvent (e.g. DMF), followed by purification (using e.g. HPLC) in the presence of a suitable counter- ion provider (e.g. NH 4 OAc);
• an appropriate organic solvent e.g. DMF
• purification using e.g. HPLC
• a suitable counter- ion provider e.g. NH 4 OAc
• a a represents C w alkylene and R 1 , R 2 , R 3 , R 4 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 and R 17 are as hereinbefore defined with a compound of formula XIV,
• R 7 -(CH 2 ) n -L 2 XIV wherein R 7 , n and L 2 are as hereinbefore defined, for example at 40 °C in the presence of a suitable organic solvent (e.g. acetonitrile);
• a suitable organic solvent e.g. acetonitrile
• R ⁇ R 2 , R 3 , R 4 , R 6 , R 7 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , A and B are as hereinbefore defined, for example by hydrogenation at a suitable pressure in the presence of a suitable catalyst (e.g. palladium on carbon) and an appropriate solvent (e.g. a water-ethanol mixture);
• a suitable catalyst e.g. palladium on carbon
• an appropriate solvent e.g. a water-ethanol mixture
• R 15 is as hereinbefore defined, for example at ambient temperamre (e.g. 25°C) in the presence of a suitable solvent (e.g. benzene); (o) for compounds of formula I in which R 5 represents -N(R 13 )C(0)R 14 , reaction of a corresponding compound of formula I in which R 5 represents -N(R 13 )H with a compound of formula XVII,
• R 14 C(0)R x XVII wherein R x represents a suitable leaving group, such as C alkoxy, halo (e.g. Cl, Br) or /7-nitrophenyl, and R 14 is as hereinbefore defined, for example at between ambient and reflux temperamre in the presence of a suitable solvent (e.g. dichloromethane or acetonitrile) and optionally in the presence of a suitable base (e.g. triethylamine or potassium carbonate);
• a suitable solvent e.g. dichloromethane or acetonitrile
• a suitable base e.g. triethylamine or potassium carbonate
• R 12 OH XIX wherein R 12a represents C w alkyl or optionally substimted aryl, for example at between ambient (e.g. 25 °C) and reflux temperamre, under Mitsunobu- type conditions (i.e. in the presence of e.g. triphenylphosphine, an azodicarboxylate derivative (e.g. l , l '-(azodicarbonyl)dipiperidine) and a suitable organic solvent (e.g. dichloromethane)); (r) for compounds of formula I in which R 5 represents -OR 12 , in which R 12 represents C w alkyl or optionally substimted aryl, reaction of a compound of formula XX,
• L 2 , R 1 , R 2 , R 3 , R ⁇ R 6 , R 7 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , A and B are as hereinbefore defined with a compound of formula XIX as hereinbefore defined, for example at between ambient (e.g. 25 °C) and reflux temperamre, under Williamson-type conditions (i.e. in the presence of an appropriate base (e.g. KOH or NaH) and a suitable organic solvent (e.g. dimethylsulfoxide or DMF));
• an appropriate base e.g. KOH or NaH
• a suitable organic solvent e.g. dimethylsulfoxide or DMF
• R 14 C0 2 H XXI wherein R 14 is as hereinbefore defined, for example at ambient temperamre (e.g. 25°C) in the presence of a suitable coupling agent (e.g. l-(3- dimethylaminopropyl)-3-ethylcarbodiimide), an appropriate catalyst (e.g. 4- dimethylaminopyridine) and a reaction- inert organic solvent (e.g. THF); (t) for compounds of formula I in which R 5 represents halo, substitution of a corresponding compound of formula I in which R 5 represents -OH, using an appropriate halogenating agent (e.g. , for compounds in which R 5 represents fluoro, reaction with diethylaminosulfurtrifluoride);
• a suitable coupling agent e.g. l-(3- dimethylaminopropyl)-3-ethylcarbodiimide
• an appropriate catalyst e.g. 4- dimethylaminopyridine
• R 3 and/or R 4 as appropriate represent alkyl groups (e.g. C w or C l 2 alkyl, as appropriate), alkylation of a corresponding compound of formula I, in which R 3 and/or R 4 (as appropriate) represent H under conditions well known to those skilled in the art;
• R 3 , R 4 , R 5 , R 6 , R 7 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , A and B are as hereinbefore defined, in the presence of a suitable reducing agent (e.g. LiAlH 4 ), for example under conditions that are well known to those skilled in the art;
• a suitable reducing agent e.g. LiAlH 4
• R 2e L XXIB wherein R 2e represents C ⁇ alkyl and L 1 is as hereinbefore defined, for example under conditions that are well known to those skilled in the art; or
• R 1 , R 2 , R 41 , R 42 , R 43 , R 44 , R 45 and R 46 are as hereinbefore defined, with a compound of formula VIII as hereinbefore defined, for example as described hereinbefore for synthesis of compounds of formula I (process step (e)), or, in the case of compounds of formula II wherein A represents CH 2 and R 5 represents OH or N(H)R 12 , with a compound of formula VII as hereinbefore defined, for example as described hereinbefore for synthesis of compounds of formula I (process step (d)).
• an appropriate agent such as tosylhydrazine
• L 1 is as hereinbefore defined, and in which the two L 1 groups may be the same or different, for example at between 0°C and reflux temperamre in the presence of a suitable base (e.g. triethylamine or potassium carbonate) and an appropriate organic solvent (e.g. toluene or dichloromethane) .
• a suitable base e.g. triethylamine or potassium carbonate
• an appropriate organic solvent e.g. toluene or dichloromethane
• Compounds of formula V may be prepared by reaction of a compound of formula II, as hereinbefore defined, with a compound of formula XXIV, as hereinbefore defined, for example as described hereinbefore for the synthesis of compounds of formula IV.
• Compounds of formula VI may be prepared by reaction of a compound of formula XXII, as hereinbefore defined, with a compound of formula III, as hereinbefore defined, for example as described hereinbefore for synthesis of compounds of formula I (process step (a)), or with a compound of formula IV, as hereinbefore defined, for example as described hereinbefore for synthesis of compounds of formula I (process step (b)).
• Compounds of formula VI may alternatively be prepared by reaction of a compound of formula XXII, as hereinbefore defined, with a compound of formula XXIV, as hereinbefore defined, for example as described hereinbefore for synthesis of compounds of formula IV, followed by reaction of the resultant intermediate with a compound of formula VA, as hereinbefore defined, for example as described hereinbefore for the synthesis of compounds of formula I (process step (c)).
• R 41 , R 42 , R 45 and/or R 46 represent Cj. 3 alkyl
• an appropriate alkylating agent e.g. dimethyl sulfate
• a suitable strong base e.g. s-BuLi
• N,N,N' ,N'- tetramethylethylenediamine e.g. THF
• a reaction-inert solvent e.g. THF
• B represents -CH 2 0- and X represents O may be prepared by reaction of a compound of formula XIA as hereinbefore defined, with a compound of formula XXVI,
• R 6 and L 2 are as hereinbefore defined, for example at elevated temperamre (e.g. between 60°C and reflux temperamre) in the presence of a suitable base (e.g. K 2 C0 3 or NaOH) and an appropriate organic solvent (e.g. acetonitrile or toluene/ water), or as otherwise described in the prior art;
• a suitable base e.g. K 2 C0 3 or NaOH
• an appropriate organic solvent e.g. acetonitrile or toluene/ water
• R 6 represents H and X represents O may be prepared by reduction of a compound of formula XXVII,
• R 7 and B are as hereinbefore defined, for example at between -15°C and room temperamre in the presence of a suitable reducing agent (e.g. NaBH 4 ) and an appropriate organic solvent (e.g. THF), followed by an internal displacement reaction in the resultant intermediate, for example at room temperamre in the presence of a suitable base (e.g. K 2 C0 3 ) and an appropriate organic solvent (e.g. acetonitrile);
• a suitable reducing agent e.g. NaBH 4
• an appropriate organic solvent e.g. THF
• a suitable base e.g. K 2 C0 3
• an appropriate organic solvent e.g. acetonitrile
• B represents C M alkylene, -(CH 2 ) n N(R 17 )-, -(CH 2 ) n S(0) 2 - or -(CH 2 ) n O- (in which latter three groups n represents 1 , 2, 3 or 4) or -(CH 2 ) m C(H)(OH)(CH 2 ) n - and X represents O may be prepared by oxidation of a compound of formula XXVIII,
• B a represents a single bond, C ⁇ alkylene, -(CH 2 ) n . 1 N(R 17 )-, -(CH 2 ) n . 1 S(0) 2 - or -(CH 2 ) n . ! ⁇ - (in which latter three groups n represents 1 , 2, 3 or 4) or -(CH 2 ) m . 1 C(H)(OH)(CH 2 ) n - (in which latter group n is as hereinbefore defined), and in all cases R 17 and m are as hereinbefore defined, in the presence of a suitable oxidising agent (e.g. CPBA), for example by refluxing in the presence of a suitable organic solvent (e.g. DCM); or
• a suitable oxidising agent e.g. CPBA
• a suitable organic solvent e.g. DCM
• B represents -(CH 2 ) n O- and X represents N(R 12 ) and R 12 represents -S(0) 2 -C -alkyl or -C(0)OR 14 may be prepared by cyclisation of a compound of formula XXVIIIA,
• R 12a represents -S(0) 2 -C -alkyl or -C(0)OR 14 and n, R 6 , R 7 , R 14 and L 2 are as hereinbefore defined, for example at between 0°C and reflux temperamre in the presence of a suitable base (e.g. sodium hydroxide), an appropriate solvent (e.g. dichloromethane, water, or a mixture thereof) and, if necessary a phase transfer catalyst (such as tetrabutylammonium hydrogensulfate).
• a suitable base e.g. sodium hydroxide
• an appropriate solvent e.g. dichloromethane, water, or a mixture thereof
• phase transfer catalyst such as tetrabutylammonium hydrogensulfate
• (2) represents -(CH 2 ) n O- may be prepared by coupling a compound of formula XIA, as hereinbefore defined, to a compound of formula XXIX,
• L 4 -(CH 2 ) n -C(R 5 )(R 6 )-A-L 2 XXIX wherein L 4 represents a suitable leaving group (e.g. halo) and n, R 5 , R 6 , A and L 2 are as hereinbefore defined; or
• (2) B represents -C(0)N(R 17 )- may be prepared by coupling a compound of formula XXX, R 7 N(H)R 17 XXX wherein R 7 and R 17 are as hereinbefore defined, to a compound of formula XXXI,
• R 7 wherein R represents C alkyl or aryl (which two groups are optionally substimted with one or more substituents selected from C l alkyl or halo) and R 6 , R 7 and B are as hereinbefore defined, for example at between ambient temperamre (e.g. 25 °C) and reflux temperamre in the presence of a suitable base (e.g. K 2 C0 3 ) and an appropriate organic solvent (e.g. acetonitrile), followed by conversion of the ester functionality to an L 2 group (in which L 2 is as hereinbefore defined), under conditions that are well known to those skilled in the art.
• a suitable base e.g. K 2 C0 3
• an appropriate organic solvent e.g. acetonitrile
• Compounds of formulae VII and VIII in which B represents -(CH 2 ) n S(0)- or -(CH 2 ) ⁇ S(0) 2 - may be prepared by oxidation of corresponding compounds of formulae VII and VIII wherein B represents -(CH 2 ) ⁇ S-, wherein n is as hereinbefore defined, in the presence of an appropriate amount of a suitable oxidising agent (e.g. CPBA) and an appropriate organic solvent.
• a suitable oxidising agent e.g. CPBA
• compounds of formula IX in which A represents C 2 alkylene may be prepared by reaction of a compound of formula VI, as hereinbefore defined with a compound of formula XXXII,
• R 7 -B-C(0)-CH CH 2 XXXII
• B and R 7 are as hereinbefore defined, for example a room temperamre in the presence of a suitable organic solvent (e.g. ethanol).
• a suitable organic solvent e.g. ethanol.
• ' Compounds of formula XIII may be prepared by removing an optionally substimted benzyloxycarbonyl unit from (i.e. deprotecting) a corresponding compound of formula I in which R 7 represents optionally substimted phenyl, R 5 and R 6 both represent H, B represents
• A represents A a and A a is as hereinbefore defined under conditions which are well known to those skilled in the art.
• R 5 represents -OH, with a compound of formula XXXIII
• R y S(0) 2 Cl XXXIII wherein R y is as hereinbefore defined, for example at between -10 and
• a suitable solvent e.g. dichloromethane
• a suitable source of the azide ion e.g. sodium azide
• an appropriate solvent e.g. DMF
• a suitable base e.g.
• Compounds of formula XXIA may be prepared by reaction of a corresponding compound of formula X with hydroxylamine, for example at elevated temperamre (e.g. at reflux) in the presence of a suitable organic solvent (e.g. methanol).
• a suitable organic solvent e.g. methanol
• R la and R 2a together represent -0-(CH 2 ) 2 -0-, -(CH 2 ) 3 -, -(CH 2 ) 4 - or -(CH 2 ) 5 -, in the presence of a suitable reducing agent (e.g. LiAlH 4 ) under conditions which are well known to those skilled in the art.
• a suitable reducing agent e.g. LiAlH 4
• Compounds of formula XXXIIIA may be prepared in analogous fashion to compounds of formula XV (i.e. from the corresponding alcohol).
• Compounds of formulae X, XXIII and XXV (in which, in all cases, R 45 and R 46 both represent H), may be prepared, advantageously, by reaction of (as appropriate) either (i) a compound of formula XXXV,
• R z represents C 0 alkyl or . 3 alkylaryl (e.g. alkylphenyl, such as benzyl) and R 41 , R 42 , R 43 and R 44 are as hereinbefore defined, or (ii) 4- piperidone (or a protected derivative thereof), with (as appropriate) either (1) a compound of formula XXXVI,
• R 5 , R 6 , R 7 , A and B are as hereinbefore defined, or (2) NH 3 (or a protected (e.g. benzyl) derivative thereof), in all cases in the presence of a formaldehyde (i.e. an appropriate source of formaldehyde, such as paraformaldehyde or formalin solution) and, in the case of compounds of formulae X and XXV, conversion of the C(0)OR z group in the resultant intermediate to a C(0)N(R 3 )(R 4 ) group using techniques such as those described herein (e.g. process step (c) above).
• a formaldehyde i.e. an appropriate source of formaldehyde, such as paraformaldehyde or formalin solution
• R l ' and R 2a' together represent -(CH 2 ) 3 -, -(CH 2 ) 4 - or -(CH 2 ) 5 -, with a mixture of phosphoric acid and sulfuric acid, for example at 120°C.
• aryl e.g. phenyl
• heterocyciic, group(s) in compounds defined herein may be converted to other claimed substiments using techniques well known to those skilled in the art. For example, nitrobenzene may be reduced to an aminobenzene, hydroxy may be converted to alkoxy, alkoxy may be hydrolysed to hydroxy, etc.
• the compounds of the invention may be isolated from their reaction mixtures using conventional techniques.
• the functional groups of intermediate compounds may be, or may need to be, protected by protecting groups.
• Functional groups which it is desirable to protect include hydroxy, amino and carboxyiic acid.
• Suitable protecting groups for hydroxy include trialkylsilyl and diarylalkylsilyl groups (e.g. ferr-butyldimethylsilyl, tert- butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl and alkylcarbonyloxy groups (e.g. methyl- and ethylcarbonyloxy groups).
• Suitable protecting groups for amino include benzyl, ret ⁇ -butyloxy carbonyl, 9-fluorenylmethoxycarbonyl or benzyloxycarbonyl.
• Suitable protecting groups for carboxyiic acid include C ⁇ alkyl or benzyl esters.
• the compounds of the invention are useful because they possess pharmacological activity. They are therefore indicated as pharmaceuticals.
• the compounds of the invention for use as pharmaceuticals.
• the compounds of the invention exhibit myocardial electrophysiological activity, for example as demonstrated in the test described below.
• the compounds of the mvention are thus expected to be useful in both the prophylaxis and the treatment of arrhythmias, and in particular atrial and ventricular arrhythmias.
• the compounds of the invention are thus indicated in the treatment or prophylaxis of cardiac diseases, or in indications related to cardiac diseases, in which arrhythmias are believed to play a major role, including ischaemic heart disease, sudden heart attack, myocardial infarction, heart failure, cardiac surgery and thromboembolic events.
• compounds of the invention In the treatment of arrhythmias, compounds of the invention have been found to selectively delay cardiac repolarization, thus prolonging the QT interval, and, in particular, to exhibit class III activity. Although compounds of the invention have been found to exhibit class III activity in particular, in the treatment of arrhythmias, their mode(s) of activity is/are not necessarily restricted to this class.
• a method of treatment of an arrhythmia which method comprises administration of a therapeutically effective amount of a compound of the invention to a person suffering from, or susceptible to, such a condition.
• the compounds of the invention will normally be administered orally, subcutaneously, intravenously, intraarterially, transdermally, intranasally, by inhalation, or by any other parenteral route, in the form of pharmaceutical preparations comprising the active ingredient either as a free base, a pharmaceutically acceptable ion exchanger or a non-toxic organic or inorganic acid addition salt, in a pharmaceutically acceptable dosage form.
• the compositions may be administered at varying doses.
• the compounds of the invention may also be combined with any other drugs useful in the treatment of arrhythmias and/or other cardiovascular disorders.
• a pharmaceutical formulation including a compound of the invention in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
• Suitable daily doses of the compounds of the invention in therapeutic treatment of humans are about 0.05 to 5.0 mg/kg body weight at parenteral admimstration.
• the compounds of the invention have the advantage that they are effective against cardiac arrhythmias.
• Compounds of the invention may also have the advantage that they may be more efficacious than, be less toxic than, have a broader range of activity (including exhibiting any combination of class I, class II, class III and/or class IV activity (especially class I, class II and/or class IV activity in addition to class III activity)) than, be more potent than, be longer acting than, produce fewer side effects (including a lower incidence of proarrhythmias such as torsades de pointes) than, be more easily absorbed than, or that they may have other useful pharmacological properties over, compounds known in the prior art.
• Guinea pigs weighing between 660 an 1100 g were used. The animals were housed for at least one week before the experiment and had free access to food and tap water during that period.
• Anaesthesia was induced by an intraperitoneal injection of pentobarbital (40 to 50 mg/kg) and catheters were introduced into one carotid artery (for blood pressure recording and blood sampling) and into one jugular vein (for drug infusions). Needle electrodes were placed on the limbs for recording of ECGs (lead II). A thermistor was placed in the rectum and the animal was placed on a heating pad, set to a rectal temperamre of between 37.5 and 38.5°C.
• a tracheotomy was performed and the animal was artificially ventilated with room air by use of a small animal ventilator, set to keep blood gases within the normal range for the species.
• a small animal ventilator set to keep blood gases within the normal range for the species.
• both vagi were cut in the neck, and 0.5 mg/kg of propranolol was given intravenously, 15 minutes before the start of the experiment.
• the left ventricular epicardium was exposed by a left-sided thoracotomy, and a custom-designed suction electrode for recording of the monophasic action potential (MAP) was applied to the left ventricular free wall.
• the electrode was kept in position as long as an acceptable signal could be recorded, otherwise it was moved to a new position.
• a bipolar electrode for pacing was clipped to the left atrium. Pacing (2 ms duration, twice the diastolic threshold) was performed with a custom-made constant current stimulator.
• the heart was paced at a frequency just above the normal sinus rate during 1 minute every fifth minute throughout the study.
• the blood pressure, the MAP signal and the lead II ECG were recorded on a Mingograph ink-jet recorder (Siemens-Elema, Sweden). All signals were collected (sampling frequency 1000 Hz) on a PC during the last 10 seconds of each pacing sequence and the last 10 seconds of the following minute of sinus rhythm. The signals were processed using a custom-made program developed for acquisition and analysis of physiological signals measured in experimental animals (see Axenborg and Hirsch, Comput. Methods Programs Biomed. 41, 55 (1993)).
• test procedure consisted of taking two basal control recordings, 5 minutes apart, during both pacing and sinus rhythm. After the second control recording, the first dose of the test substance was infused in a volume of 0.2 mL into the jugular vein catheter for 30 seconds. Three minutes later, pacing was started and a new recording was made. Five minutes after the previous dose, the next dose of test substance was administered. Six to ten consecutive doses were given during each experiment.
• the three variables selected were the MAP duration at 75 percent repolarization during pacing, the atrio- ventricular (AV) conduction time (defined as the interval between the atrial pace pulse and the start of the ventricular MAP) during pacing, and the heart rate (defined as the RR interval during sinus rhythm).
• AV atrio- ventricular
• AV atrio- ventricular
• RR interval the heart rate
• Systolic and diastolic blood pressure were measured in order to judge the haemodynamic status of the anaesthetised animal. Further, the ECG was checked for arrhythmias and/or morphological changes.
• the hepatic S-9 fraction from dog, man, rabbit and rat with NADPH as co- factor was used.
• the assay conditions were as follows: S-9 (3 mg/mL), NADPH (0.83 mM), Tris-HCl buffer (50 mM) at pH 7.4 and 10 ⁇ M of test compound.
• test compound was started by addition of test compound and terminated after 0, 1, 5, 15 and 30 minutes by raising the pH in the sample to above 10 (NaOH; 1 mM). After solvent extraction, the concentration of test compound was measured against an internal standard by LC (fluorescence/UV detection).
• test compound remaining after 30 minutes were calculated and used as a measure for metabolic stability.
• Mass spectra were recorded on a Finnigan MAT TSQ 700 triple quadrupole mass spectrometer equipped with an electrospray interface (FAB-MS) and VG Platform II mass spectrometer equipped with an electrospray interface (LC-MS), a Hewlett Packard model 6890 gas chromatograph connected to a Hewlett-Packard model 5973A mass spectrometer via a Hewlett Packard HP-5-MS GC column, or a Shimadzu QP-5000 GC/mass spectrometer (CI, methane).
• l K NMR and 13 C NMR measurements were performed on a BRUKER ACP 300 and Varian UNITY plus 400 and 500 spectrometers, operating at !
• Rotamers may or may not be denoted in spectra depending upon ease of interpretation of spectra. Unless otherwise stated, chemical shifts are given in ppm with the solvent as internal standard.
• the sub-title compound was prepared according to the method described in J. Org. Chem. 41, 1593, (1976) except that 3,7-dibenzyl-3,7- diazabicyclo[3.3.1]nonan-9-one (also prepared according to the method described in J. Org. Chem. 41, 1593 (1976)) was used instead of N- benzyl-N-methylbispidone .
• Benzylamine (6.51 g; 60.2 mmol), acetic acid (72.3 g, 1200 mmol), paraformaldehyde (3.71 g; 120 mmol) and l-rgrr-butoxycarbonyl-4- piperidone (12.0 g; 60.2 mmol), were added to ethanol (300 mL). The solution was heated to 65°C and stirred at this temperamre for 2 hours. The same work-up procedure as that described in step (a) above was performed, yielding 15.78 g of material with a purity of 92 area% (HPLC) and a yield of 70% .
• Methanesulfonyl chloride (17.5 g, 153 mmol) was slowly added to a cooled (-10°C) solution of 4-(3-amino-2-hydroxypropoxy)benzonitrile (13.3 g, 69 mmol, from step (a) above) and 4-(dimethylamino)pyridine (0.2 g, 1.64 mmol) in pyridine (100 mL).
• the yellow solution was stirred at rt for 1.5 hours, concentrated in vacuo and then redissolved in DCM. This solution was washed twice with 2 M HCl and once with NaHC0 3 solution before the organic phase was separated, dried (MgS0 4 ) and concentrated in vacuo to yield 23.5 g (100%) of the sub-title compound.
• R 7 and R 8 independently represent H, C ⁇ alkyl or -(CH 2 ) b -aryl (which latter two groups are optionally substimted and/or terminated by one or more substiments selected from -OH, halo, cyano, nitro, C alkyl and/or C alkoxy); R 7a and R 7 independently represent H or C 6 alkyl; b represents 0, 1 , 2, 3 or 4;
• R 4 represents H or C ⁇ alkyl
• D represents H, C M alkyl, -OR 9 , or -(CH 2 ) C N(R 10 )(R U );
• R 9 represents H, C w alkyl, -C(0)R 12 , -(CH 2 ) d -aryl or -(CH 2 ) d -Het 2 (which latter three groups are optionally substimted by one or more substiments selected from -OH, halo, cyano, nitro, C alkyl, C M alkoxy, C(0)R 13 ,
• R 10 represents H, C ⁇ alkyl, -(CH 2 ) r aryl, -C(NH)NH 2 ,
• R 11 represents H, C w alkyl, -C(0)R 20 or -(CH 2 ) h -aryl (which latter group is optionally substimted and/or terminated (as appropriate) by one or more substiments selected from -OH, cyano, halo, amino, nitro, C ⁇ alkyl and/or C ⁇ alkoxy);
• R 12 , R 13 , R 14 , R 16 , R 17 , R 18 , R 19 and R 20 independently represent H, C w alkyl, Het 3 or -(CH 2 ) j -aryl (which latter three groups are optionally 0.84 mmol) to give a clear solution.
• the mixmre was stirred for 1 h at rt, concentrated in vacuo and then purified by column chromatography, eluting with 5 % MeOH in DCM, to give the title compound in 73 % yield.
• the title compound was prepared in 26% yield (counting steps (a) and (b) together) according to procedure described in Example 2(b) above, using cyanomethyl isocyanate (from step (a) above) in place of cyclopropylmethyl isocyanate.
• Example 12 7- [3-(4-Cyanophenoxy)-2-hydroxypropy 1] -N- [2-oxo-2-(propylamino)- ethyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide
• Example 13 7- ⁇ 3-(4-Cyanophenoxy)-2-[(4-morpholinylcarbonyl)amino]propyl ⁇ -N- ethyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide
• reaction mixmre was concentrated in vacuo to give 7.4 g of a yellow oil, which was purified by column chromatography, eluting with a gradient of DCM:MeOH (100:0 to 90: 10), to yield 3.33 g of the sub-title compound.
• the sub-title compound was prepared by way of a reaction between 3- benzyl-3,7-diazabicyclo[3.3.1]nonane (see Example E above) and 1- piperidinecarbonyl chloride (Boon, J. Chem. Soc , (1947) 307, 313).
• 1,3-Dibromopropane (1.02 L; 10 mol) was added to a stirred suspension of -cyanophenol (238 g; 2 mol), K 2 C0 3 (276.4 g; 2 mol) in MeCN (2.7 L). The reaction mixmre was refluxed for 4 h, filtered and concentrated. The residue was recrystallized from tsc-propyl ether to give the sub-title compound in a 69% yield.
• the sub-title compound was prepared according to the procedure described in Example 14(b) above, using 7-benzyl-3,7- diazabicyclo [3.3.1] nonane-3 -ethanol (from step (d) above) in place of 3- benzyl-7-[3-(2-propyl-l ,3-dioxolan-2-yl)propyl]-3,7-diazabicyclo[3.3.1]- nonane.
• the title compound was prepared in 83 % yield according to the procedure described in Example 19 above, using 2-(2-isocyanatoethyl)thiophene in place of -toluenesulfonyl isocyanate.
• the sub-title compound was prepared in 90% yield according to the procedure described in Example 12(a) above, using ethyl 3- isocyanatopropanoate in place of ethyl 2-isocyanatoacetate.
• the title compound was prepared in 22 % yield according to the procedure described in Example 12(b) above, using ethyl 3-[( ⁇ 7-[3-(4- cyanophenoxy)-2-hydroxypropyl] -3 ,7-diazabicyclo [3.3.1] non-3 -y 1 ⁇ - carbonyl)amino]propanoate (from step (a) above) and ethylamine in place of ethyl 2-[( ⁇ 7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3 ,7-diazabicyclo- [3.3. l]non-3-yl ⁇ carbonyl)amino] acetate and propylamine, respectively.
• the sub-title compound was prepared in 99% yield according to the procedure described in Example 5(a) above, using 4-[3-(3,7-diazabicyclo[3.3.1]non-3-yl)-2-hydroxypropoxy]benzonitrile (see Example G above) and ethyl 2-isocyanatoacetate in place of 3-benzyl-3,7- diazabicyclo [3.3.1] nonane and wo-propyl isocyanate, respectively.
• the sub-title compound was prepared according to the method described in Example 7(b) above using 2-oxiranylmethyl 3-nitrobenzenesulfonate (prepared analogously to the method described in Example B above).
• reaction mixmre was poured into a warm aqueous solution of sodium cyanide (8.10 g, 165 mmol of NaCN in 25 mL H 2 0).
• the resulting mixmre was extracted with toluene and DCM.
• the combined organic layers were washed with water and then brine, dried and concentrated in vacuo.
• the residue so obtained was crystallised from toluene and DCM to yield 2.8 g (35 %) of the sub-title compound.
• Example 36 were also prepared, using analogous methods to those described herein:
• CDI carbonyl diimidazole
• HPLC high performance liquid chromatography
• wCPBA mgr ⁇ -chloroperbenzoic acid
• NADPH nicotinamide adenine dinucleotide phosphate, reduced form
• pTSA ⁇ r ⁇ -toluenesulfonic acid
• n-, s-, i-, iso-, t- and tert- have their usual meanings: normal, iso, secondary and tertiary.

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