EP1301510A1 - Nouveaux composes de bispidine et leur utilisation dans le traitement des arythmies cardiaques - Google Patents

Nouveaux composes de bispidine et leur utilisation dans le traitement des arythmies cardiaques

Info

Publication number
EP1301510A1
EP1301510A1 EP01950132A EP01950132A EP1301510A1 EP 1301510 A1 EP1301510 A1 EP 1301510A1 EP 01950132 A EP01950132 A EP 01950132A EP 01950132 A EP01950132 A EP 01950132A EP 1301510 A1 EP1301510 A1 EP 1301510A1
Authority
EP
European Patent Office
Prior art keywords
formula
compound
alkyl
het
optionally substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01950132A
Other languages
German (de)
English (en)
Inventor
Kjell Andersson
Annika Björe
Magnus Björsne
Fritiof Ponten
Gert Strandlund
Peder Svensson
Louise Tottie
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca AB
Original Assignee
AstraZeneca AB
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from SE0002603A external-priority patent/SE0002603D0/xx
Priority claimed from SE0002788A external-priority patent/SE0002788D0/xx
Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Publication of EP1301510A1 publication Critical patent/EP1301510A1/fr
Withdrawn legal-status Critical Current

Links

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
    • 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 tachy arrhythmias (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 applications WO 91/07405 and WO 99/31100, European patent applications 000 074, 301 245, 306 871, 308 843, 461 574 and 665 228, German patent applications DE 24 28 792, DE 26 58 558 and DE 27 44 248 and US patents 3,962,449, 4,556,662, 4,550,112, 4,459,301, 5,468,858 and 5,786,481, as well as journal articles including inter alia: J. Med. Chem. 39, 2559 (1996); Pharmacol. Res.
  • bispidine-based antiarrhythmic compounds include bisaramil (syn-9-(4-chlorobenzoyloxy)- 3-methyl-7-ethyl-3,7-diazabicyclo[3.3.1]nonane), tedisamil (3,7-di-(cyclo- pro ⁇ ylmethyl)-9,9-tetramethylene-3,7-diazabicyclo[3.3.1]nonane), SAZ- VII-22 (3-(4-chlorobenzoyl)-7-zso- ⁇ ropyl-3,7-diazabicyclo[3.3.1 jnonane), SAZ-VII-23 (3-benzoyl-7-wo-propyl-3,7-diazabicyclo[3.3.ljnonane), GLG- V-13 (3-[4-(4-chlorobenzoyloxy)- 3-methyl-7-ethyl-3,7-diazabicyclo[3.3.1]nonane), tedisam
  • KMC-IV-84 (7-[4'-(lH-imidazolo-l-yl)-benzenesulfonyl]- 3-t5O-propyl-3 ,7-diazabicyclo[3.3.ljnonane dihydroperchlorate and ambasilide (3-(4-aminobenzoyl)-7-benzyl-3,7-diazabicyclo[3.3.ljnonane).
  • Further bispidine compounds are known from inter alia: Eur. J. Med. Chem. 25, 1 (1990); Bull Polish Acad. Sci. Chem. 34(5-6), 205 (1986); J. Org. Chem. 60, 8148 (1995); Eur.
  • R 1 represents a structural fragment of formula la
  • D represents a direct bond or C 1- alkylene
  • R 7 represents H, C 1-6 alkyl, -E-aryl, -E-Het 1 , -C(O)R 10a , -C(O)OR 10b or
  • R 8 represents H, C 1-6 alkyl, -E-aryl, -E-Het 1 , -C(O)R 10a , -C(O)OR 10b ,
  • R 9 represents H, C I-6 alkyl, -E-aryl, or -C(O)R 10d ;
  • E represents, at each occurrence when used herein, a direct bond or C 1-4 alkylene; R 10a to R 10d independently represent, at each occurrence when used herein,
  • Ci -6 alkyl (optionally substituted and/or terminated by one or more substituents selected from halo, aryl and Het 2 ), aryl, Het 3 , or R l0a and R 10d independently represent H;
  • R l la and R l lb independently represent, at each occurrence when used herein, H, C ⁇ . 6 alkyl (optionally substituted and/or terminated by one or more substituents selected from halo, aryl and Het 4 ), aryl, Het 5 , or R l la and R l lb together represent C 3-7 alkylene, which alkylene group is optionally interrupted by an oxygen atom; n represents 1 or 2;
  • A represents -G-, -J-N(R )- or -J-O- (in which latter two groups, J is attached to the bispidine nitrogen atom);
  • B represents -L-, -L-N(R 13 )-, -N(R 13 )-L-, -L-S(0) p - or -L-O- (in which latter two groups, L is attached to the carbon atom bearing R 4 and R 5 );
  • G represents a direct bond or C 1-6 alkylene;
  • J represents C 2-6 alkylene;
  • L represents a direct bond or C 1-4 alkylene;
  • p represents 0, 1 or 2;
  • R and R independently represent H or C 1-4 alkyl;
  • R represents aryl, Het (both of which groups are optionally substituted and/or terminated (as appropriate) by one or more substituents selected from -OH, cyano, halo, nitro, C 1-6 alkyl (optionally terminated by -N(H)C(0)OR 14a ), C 1-6 alkoxy, aryl, Het 7 , -N(R 15a )R 15b , -C(0)R
  • R 16 represents H, aryl, Het 10 or C ⁇ -6 alkyl (which alkyl group is optionally substituted and/or terminated by one or more substituents selected from halo, -OH, -CN, -N(R 34 )R 35 , aryl and Het 11 );
  • R 34 represents, H, C 1-6 alkyl, aryl, Het 12 , -C(0)R 36a or -C(0)OR 36b ;
  • R 18 represents H, aryl, Het 13 , -C(0)R 36a , -C(0)OR 36 or C 1-6 alkyl (which alkyl group is optionally substituted and/or terminated by one or more substituents selected from halo, -OH, -CN, -C(0)R 36a and -C(0)OR 36b );
  • R 22 represents Het 14 , aryl, or C ⁇ -6 alkyl (which alkyl group is optionally substituted and/or terminated by one or more substituents selected from halo, -OH, -CN, Het 15 and aryl);
  • R 23 represents H, C 1-6 alkyl, aryl, Het 16 , -C(0)R 36a , -C(0)OR 36 or -C(0)SR 36b ;
  • R represents H or C 1-6 alkyl (which alkyl group is optionally substituted and/or terminated by one or more substituents selected from halo, -OH, -CN, C ⁇ -6 alkyl (which alkyl group is optionally substituted and/or terminated by one or more substituents selected from C 1- alkyl and -OH), C ⁇ -6 alkoxy and aryl);
  • R 27 represents C 1-6 alkyl or aryl
  • R represents H, C 1-6 alkyl, aryl or Het ;
  • R 29a and R 29b independently represent H, C 1-6 alkyl, aryl or Het 18 ;
  • R 30 represents H, C 1-6 alkyl, aryl, Het 19 , -C(0)R 37a , -C(0)OR 37b or
  • R 31 represents H, C ]-6 alkyl, aryl or Het 20 ;
  • R' represents H, C 1-6 alkyl, aryl, He .21 1 , -C(0)R J /a , -C(0)OR J /D or -C(0)N(R 37c )R 37d ;
  • R represents C ⁇ -6 alkyl, aryl or Het ; r represents 0, 1 or 2;
  • R 36a and R 36b independently represent, at each occurrence when used herein, C 1-6 alkyl, or R 36a represents H;
  • R a to R independently represent, at each occurrence when used herein, C 1-6 alkyl, aryl or Het 23 , or R 37a , R 37c and R 37d independently represent H; Het 1 to Het 23 independently represent, at each occurrence when used herein, five- to twelve-membered heterocyclic groups containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur;
  • R 3a and R 3b independently represent H, C M alkyl, -OR 38a , -SR 38b , -N(R 39 )R 38c , or R 3a and R 3b together represent C 3-5 alkylene, -0-Z-0-, -O-Z-S- or -S-Z-S-;
  • R represents H, . 6 alkyl or a structural fragment of formula la as defined above;
  • Z represents C 2-3 alkylene optionally substituted by one or more C 1-4 alkyl groups;
  • R 41 to R 6 independently represent H or C J-3 alkyl
  • R 14a to R 14d , R 17 and R 21 independently represent C 1-6 alkyl
  • R 15a to R 15p , R 19 , R 20a , R 20b , R 24 , R 26 , R 35 and R 38a to R 38c independently represent H or C ⁇ -6 alkyl;
  • B does not represent a direct bond, -N(R )-L- (in which group -N(R 13 )- is attached to the carbon atom bearing R 4 and R 5 ), -N(R 13 )-, -S(0) p - or -0-; (b) when R 5 represents H or C M alkyl; and A represents -J-N(R 12 )- or -J-0-; then B does not represent -N(R 13 )-L-, -N(R 13 )-, -S(0) p - or -0-;
  • (ii) B does not represent -N(R l3 )-L-, -N(R 13 )-, -S(0) p - or -0-;
  • 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 of carbon atoms (i.e. a minimum of four), 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 of carbon atoms (i.e. a minimum of two), 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.
  • alkylene groups as defined herein may be straight-chain or, when there is a sufficient number of carbon atoms (i.e. a minimum of two), be branched-chain. Such alkylene chains may also be saturated or, when there is a sufficient number of carbon atoms (i.e. a minimum of two), 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.
  • aryl when used herein, includes C 6- ⁇ o aryl groups such as phenyl, naphfhyl and the like. Unless otherwise specified, aryl groups may be substituted by one or more substituents including -OH, cyano, halo, nitro, C I-6 alkyl (optionally terminated by -N(H)C(0)OR 14a ), C 1-6 alkoxy, Het 1 , aryl (which aryl group may not be substituted with any further aryl groups), -N(R 15a )R 15b , -C(0)R 15c , -C(0)OR 15d , -C(0)N(R 15e R 15f , -N(R 15g )C(0)R 15h , -N(R 15i )C(0)N(R 15j )R 15k , -N(R 15m )S(0) 2 R 14b -S(0) q R 14c , -OS(0) 2 R 14d and -
  • halo when used herein, includes fluoro, chloro, bromo and iodo. 1 9 " ⁇
  • Het (Het to Het ) 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
  • Het (Het to Het ) groups may be fully saturated, partly unsaturated, wholly aromatic, partly aromatic and/or bicyclic in character.
  • Heterocyclic groups that may be mentioned include benzodioxanyl, benzodioxepanyl, benzodioxolyl, benzofuranyl, benzo-furazanyl, benzimidazolyl, benzomorpholinyl, .
  • Het 1 that may be mentioned include pyridyl.
  • Values of Het 6 that may be mentioned include benzodioxanyl, benzomorpholinyl, furanyl, isoquinolinyl, isoxazolyl, 2-oxazolidonyl, piperazinyl, pyrazolyl, pyrrolidinonyl and 1,2,3- thiadiazolyl.
  • Values of Het that may be mentioned include pyrimidyl, quinazolinyl, tetrazolyl, thiazolyl and 1,2,4-triazolyl.
  • Values of Het 9 that may be mentioned include benzomorpholinyl, 2-oxazolidonyl and piperazinyl.
  • Het 10 furanyl, isoxazolyl, pyrazolyl, pyrrolidinonyl and 1,2,3-thiadiazolyl.
  • Values of Het 14 that may be mentioned include imidazolyl, sulfolanyl, thienyl and quinolinyl.
  • Values of Het 15 that may be mentioned include mo ⁇ holinyl.
  • Het 1 to Het 23 When a Het (Het 1 to Het 23 ) group is substituted by one or more Het 1 and/or aryl group(s), that (those) said Het 1 and/or aryl substituent(s) may not itself (themselves) be substituted by any aryl and/or
  • Het group(s). Substituents on Het (Het to Het ) groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of Het (Het to Het ) groups may be via any atom in the ring system including (where appropriate) a heteroatom. Het (Het 1 to Het 23 ) 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 3,7-diazabicyclo[3.3.1]nonane nitrogen, C 1-4 alkyl quaternary ammonium salts and N-oxides, provided that when a N-oxide is present:
  • (c) q does not represent 0 when the group -S(0) q R 14c is present as a substituent on aryl, Het (Het to Het ) or R ; and/or
  • (d) r does not represent 0 when the group -S(0) r R is present as a substituent on an alkyl group that R represents.
  • 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 7 represents H, C 1-6 alkyl or -C(O)R I0a ;
  • R represents aryl; then B does not represent -L-; and/or
  • R 3a and R 3b independently represent H or Cj- alkyl; and R represents aryl; then A and B do not simultaneously represent direct bonds, in which above provisos aryl groups, unless otherwise specified, are optionally substituted as described hereinbefore.
  • R and R independently represent H, C 1-6 alkyl or C 3-8 cycloalkyl;
  • Het 9 represents an unsubstituted, saturated 3- to 8-membered heterocycle containing one nitrogen atom (via which atom the heterocyclic group is attached to the rest of the molecule);
  • R 4 arid R 5 both represent H
  • R 6 represents phenyl substituted in the meta- or/? ⁇ r ⁇ - ⁇ osition (relative to the group B) by C0 2 H or NH 2 , then:
  • Het 6 represents an unsubstituted, saturated 3- to 8-membered heterocycle containing one nitrogen atom (via which atom the heterocyclic group is attached to the rest of the molecule); and the group -A-C(R 4 )(R 5 )-B- represents C 1-6 n-alkylene; then R 2 does not represent:
  • R 23 represents phenyl substituted in the meta-- or /? r ⁇ -position (relative to the point of attachment) by C0 2 H or NH 2 ; and R 24 represents H or C ]-6 alkyl; and (v) C 3-4 n-alkyl, which alkyl group is terminated by phenyl, which phenyl group is substituted in the meta- or/?flr ⁇ -position (relative to the point of attachment) by C0 2 H or NH 2 , and which alkyl group is interrupted at the ⁇ -position (relative to the point of attachment of the phenyl group) by O.
  • Further compounds of the invention that may be mentioned include compounds of formula I, as defined above, with the additional proviso that: R does not represent:
  • Preferred compounds of the invention also include those in which: R 4 represents H, C 1-2 alkyl, -OR 7 or N(H)R 8 , or R 4 , together with R 5 , represents — O;
  • R 7 represents H, C 1-4 alkyl, optionally substituted phenyl, -C(O)R 10a , or
  • R 8 represents H, C 1-4 alkyl, -C(O)R 10a , -C(O)OR 10b or -C(0)N(R' la )R 1 lb ;
  • R 10a and R 10 independently represent, at each occurrence when used herein,
  • R 10a represents H
  • R 1 l a and R 11 independently represent, at each occurrence when used herein, H or C 1-5 alkyl (optionally substituted and/or terminated by one or more substituents selected from halo and phenyl)
  • A represents -G- or -J-N(R 12 )-
  • B represents a direct bond, Cj, alkylene, -L-N(H)-, -L-S(0) 2 - or -L-O- (in which latter three groups, L is attached to the carbon atom bearing R 4 and
  • G represents a direct bond or C 1-4 alkylene
  • J represents C 2- alkylene
  • L represents C 1-4 alkylene
  • R 16 represents optionally substituted phenyl, Het 1 or C ⁇ -6 alkyl (which alkyl group is optionally unsaturated and/or optionally substituted and/or terminated by one or more substituents selected from halo, -CN, -N(H)R 34 and optionally substituted phenyl);
  • R 34 represents, H, C M alkyl, -C(0)R 36a or -C(0)OR 36b ;
  • R 18 represents H, -C(0)OR 36b or C ⁇ -6 alkyl (which alkyl group is optionally substituted and/or terminated by one or more substituents selected from halo and -C(0)OR 6b );
  • R 22 represents Het 14 , optionally substituted phenyl or C ⁇ -4 alkyl (which alkyl group is optionally substituted and/or terminated by one or more substituents selected from halo, Het 15 and optionally substituted phenyl);
  • R 23 represents H, C 1-4 alkyl
  • R 28 represents C 1-5 alkyl, optionally substituted phenyl or Het 17 ;
  • R 29b represents H, C 1-4 alkyl or optionally substituted phenyl
  • R 30 represents H, optionally substituted phenyl, -C(0)R 37a or -C(0)OR 37b ;
  • R 31 represents H, C ⁇ -2 alkyl or optionally substituted phenyl
  • R 32 represents H, C 1- alkyl (which alkyl group is optionally interrupted by
  • R 33 represents C 1-6 alkyl or optionally substituted phenyl
  • R 37a and R 37b independently represent, at each occurrence when used herein,
  • R 37a represents H
  • R 3a and R 3b independently represent H, C 1-2 alkyl, -SR 38b , -N(R 39 )R 38c , or
  • R 3a and R 3b together represent C 3- alkylene or -0-Z-0-;
  • R represents H, C 1-2 alkyl or a structural fragment of formula la;
  • Z represents C 2-3 alkylene
  • R 41 to R 46 independently represent H or C ⁇ -2 alkyl
  • R 14b , R 14c , R 17 and R 21 independently represent C M alkyl
  • R 15b to R 15p , R 20b , R 24 , R 26 , R 38b and R 38c independently represent H or C 1-5 alkyl; optional substituents on phenyl groups are one or more substituents selected from cyano, halo, nitro, C ⁇ -2 alkyl, C ⁇ -2 alkoxy, Het 1 , -NH 2 , -C(0)R 15c , -C(0)N(H)R 15f , -N(H)C(0)R 15h , -N(H)C(0)N(H)R 15k , -N(H)S(0) 2 R 14b and -S(0) 2 N(R 15n )R 15p .
  • R 3a and/or R 3b represent(s) -N(R 39 )R 38c in which R 39 represents a structural fragment of formula la
  • preferred compounds of formula I include those in which, in that R group:
  • R represents H, phenyl (which group is optionally substituted by one to three methoxy groups), -C(0)CH 3 , or -C(0)N(H)-C 1-4 alkyl;
  • R 8 represents H, -C(0)0-C M alkyl or -C(0)N(H)CH 3 ;
  • A represents C ⁇ -3 alkylene or -C 2-3 alkylene-N(H)-;
  • B represents a direct bond, -CH 2 -, -CH 2 -N(H)-, -CH 2 -S(0) 2 -, -CH 2 -0- (in which latter, three groups, CH 2 is attached to the carbon atom bearing R 4 and R 5 ) or -0-;
  • R 6 represents phenyl optionally substituted by up to three substituents (in the para- and or ortho- positions) selected from cyano,
  • More preferred compounds of the invention include those in which:
  • R 7 represents H, C 1-2 alkyl, optionally substituted phenyl, -C(O)R 10a , or
  • R 8 represents H, C 1-2 alkyl, -C(O)OR 1 1 0 0 b o _r_
  • R 10a and R 10b independently represent, at each occurrence when used herein, Ci -5 alkyl (optionally substituted or terminated by phenyl), optionally substituted phenyl, or R 10a represents H; R a and R 1 lb independently represent, at each occurrence when used herein, H or C ⁇ -5 alkyl (optionally substituted or terminated by phenyl); A represents -G- or -J-N(R 12 )-;
  • B represents a direct bond, C ⁇ -4 alkylene, -L-N(H)-, -L-S(0) 2 - or -L-O- (in which latter three groups, L is attached to the carbon atom bearing R 4 and
  • G represents a direct bond or C 1- alkylene
  • J represents C 2-4 alkylene
  • L represents C 1- alkylene
  • R 6 represents phenyl or Het 6 (which two groups are optionally substituted by one or more substituents selected from cyano, halo, C ⁇ _ 2 alkyl, C 1- alkoxy, -C(0)R 15c , -N(H)C(0)R 15h , -N(H)C(0)N(H)R 15k , -N(H)S(0) 2 R 14b , -S(0) 2 R 14c and -S(0) 2 N(R 15n )R 15p ).
  • R represents -S(0) 2 R
  • 1 A represents -G-, -J-N(R )- or -J-O- (in which latter two groups, J is attached to the bispidine nitrogen atom);
  • G represents Cj -6 alkylene
  • R 2 represents -CN, Het 8 , -C(0)R 16 , -C(S)OR 17 , -C(S)N(R 18 )R 19 , -[C(O)j 2 N(R 0a )R 20b , -[C(0)] 2 OR 21 , -S(0) 2 R 22 , -S(0) 2 N(R 23 )R 24 ,
  • R 16 represents H, Het 10 or C 1-6 alkyl (which alkyl group is optionally substituted and/or terminated by one or more substituents selected from halo, -OH, -CN, -N(R 34 )R 35 , aryl and Het 11 );
  • R 6 represents aryl, Het 6 (both of which groups are substituted and/or terminated (as appropriate) by one or more substituents selected from -OH, cyano, halo, nitro, C 1-6 alkyl (optionally terminated by -N(H)C(0)OR 14a ), C 1-6 alkoxy, aryl, Het 7 , -N(R 15a )R 15b , -C(0)R 15c , -C(0)OR 15d , -C(0)N(R 15e )R 15f , -N(R 15g )C(0)R 15h , -N(R 15i )C(0)N(R 15j )R 15k
  • R may represent C ⁇ -6 alkyl.
  • Preferred compounds of the invention include the compounds of the Examples disclosed hereinafter.
  • R 2 , R 3a , R 3b and R 41 to R 46 are as hereinbefore defined, with a compound of formula III, wherein L 1 represents a leaving group (e.g. mesylate, tosylate or halo) and R 4 , R 5 , R 6 , A and B are as hereinbefore defined, for example at between -10°C and reflux temperature in the presence of a suitable base (e.g. triethylamine or K 2 C0 3 ) and an appropriate organic solvent (e.g. dichloromethane, acetonitrile or DMSO);
  • a suitable base e.g. triethylamine or K 2 C0 3
  • an appropriate organic solvent e.g. dichloromethane, acetonitrile or DMSO
  • R and B are as hereinbefore defined, for example at room temperature in the presence of a suitable organic solvent (e.g. ethanol);
  • a suitable organic solvent e.g. ethanol
  • a suitable reducing agent e.g. LiAlH 4
  • THF an appropriate solvent
  • 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);
  • a suitable organic acid e.g. acetic acid
  • R 1 , R 2 and R 41 to R 46 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 a -L 1 VIII wherein R a represents C 1-6 alkyl and L 1 is as hereinbefore defined, for example under conditions that are well known to those skilled in the art;
  • R 2 , R 3a , R 3b , R 4 , R 5 , R 41 to R 46 , A and L are as hereinbefore defined, with a compound of formula X,
  • R 6 OH X in which R is as hereinbefore defined, for example under Mitsunobu-type conditions e.g. at between ambient (e.g. 25°C) and reflux temperature in the presence of a tertiary phosphine (e.g. tributylphosphine or triphenyl- phosphine), an azodicarboxylate derivative (e.g. diethylazodicarboxylate or l,l '-(azodicarbonyl)dipiperidine) and an appropriate organic solvent (e.g. dichloromethane or toluene);
  • a tertiary phosphine e.g. tributylphosphine or triphenyl- phosphine
  • an azodicarboxylate derivative e.g. diethylazodicarboxylate or l,l '-(azodicarbonyl)dipiperidine
  • an appropriate organic solvent e.g. dichlor
  • a a represents C 1-6 alkylene and R 2 , R 3a , R 3b , R 4 , R 5 , R 13 and R 41 to R 46 are as hereinbefore defined with a compound of formula XII,
  • R 6 -L-L 2 XII wherein L 2 represents a leaving group such as halo, alkane sulfonate, perfluoroalkane sulfonate or arenesulfonate, and R and L 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 10a to R 10c are as hereinbefore defined, for example under conditions that are well known to those skilled in the art;
  • R 7a OH XVI wherein R 7a represents C 1- alkyl, -E-aryl or -E-Het 1 , wherein Het 1 is as hereinbefore defined, for example at between ambient (e.g. 25°C) and reflux temperature, under Mitsunobu-type conditions (i.e. in the presence of e.g. triphenylphosphine, an azodicarboxylate derivative (e.g. 1,1'- (azodicarbonyl)dipiperidine) and a suitable organic solvent (e.g. dichloromethane)) ;
  • Mitsunobu-type conditions i.e. in the presence of e.g. triphenylphosphine, an azodicarboxylate derivative (e.g. 1,1'- (azodicarbonyl)dipiperidine) and a suitable organic solvent (e.g. dichloromethane)
  • a suitable organic solvent e.g. dichloromethane
  • R 7b -L 4 XVIII wherein R 7b represents R 7 as hereinbefore defined, except that it does not represent H, and L 4 represents a leaving group such as OH, halo, alkane sulfonate, arene sulfonate or -OC(O)R 10 , wherein R 10a is as hereinbefore defined, for example at between room and reflux temperature, optionally in the presence of a reaction-inert organic solvent (e.g. THF or CH 2 C1 2 ), a suitable base (e.g. triethylamine or K 2 C0 3 ) and/or an appropriate coupling agent (e.g.
  • a reaction-inert organic solvent e.g. THF or CH 2 C1 2
  • a suitable base e.g. triethylamine or K 2 C0 3
  • an appropriate coupling agent e.g.
  • 1,3-dicyclohexylcarbodiimide or l-(3-dimethylaminopropy ⁇ )-3- ethylcarbodiimide optionally combined with a suitable catalyst such as 4- dimethylaminopyridine)
  • a suitable catalyst such as 4- dimethylaminopyridine
  • R 7b represents -C(0)R 10a
  • L represents OH
  • this reaction may be performed at ambient temperature (e.g. 25°C) in the presence of a coupling agent such as l-(3-dimethylamino- propyl)-3-ethylcarbodiimide, an appropriate catalyst such as 4-(dimethyl- amino)pyridine and a solvent such as THF);
  • R 1 , R 3a , R 3b and R 41 to R 46 are as hereinbefore defined, with a compound of formula XX,
  • R 2 -L 5 XX wherein L 5 represents a leaving group such as halo, OH, alkane sulfonate, arene sulfonate, C alkoxy, phenoxy, -OC(0)R 16 , -OC(0)OR 21 or -OS(0) 2 R 22 , and R 2 , R 16 , R 21 and R 22 are as hereinbefore defined, for example at between -10°C and reflux temperature, optionally in the presence of a suitable solvent (e.g. CHC1 3 , CH 3 CN, 2-propanol, diethyl ether, or mixtures thereof) and/or an appropriate base (e.g. K 2 C0 3 , pyridine or triethylamine);
  • a suitable solvent e.g. CHC1 3 , CH 3 CN, 2-propanol, diethyl ether, or mixtures thereof
  • an appropriate base e.g. K 2 C0 3 , pyridine or triethylamine
  • X a represents O or N(R 30 ) and R 2a represents C MO alkyl, optionally substituted with one or more substituents as specified hereinbefore for R , for example as described hereinbefore for preparation of compounds of formula I (process step (d));
  • R b -L 2 XXI wherein R b represents C 1-4 alkyl and L 2 is as hereinbefore defined, for example at room temperature 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
  • R 3a , R 3b and R 41 to R 46 are as hereinbefore defined, with a compound of formula XX as hereinbefore defined, for example as described hereinbefore for synthesis of compounds of formula I (process step (x)).
  • R alk -Mg-Hal XXIV wherein R al represents C 1-4 alkyl and Hal represents chloro, bromo or iodo, for example at between -25°C and ambient temperature in the presence of a suitable solvent (e.g. diethyl ether).
  • a suitable solvent e.g. diethyl ether
  • L 6 -C(0)-A-L 1 XXVII wherein L 6 , A and L 1 are as hereinbefore defined;
  • R 7 7 1 represents -OR , in which R represents C ⁇ _ 6 alkyl, -E-aryl or -E-Het may alternatively be prepared by reaction of a compound of formula XVI as hereinbefore defined with a compound of formula XXVIII,
  • R y represents C ' alkyl or aryl (which two groups are optionally substituted with one or more substituents selected from C 1-4 alkyl or halo) and R 5 , R 6 and B are as hereinbefore defined, for example at between ambient temperature (e.g. 25°C) and reflux temperature 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 1 group (in which L 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
  • a b represents a direct bond or C 1- alkylene
  • R 4 , R 5 , R 6 and B are as hereinbefore defined, with a suitable borane or borane-Lewis base complex (e.g. borane-dimethyl sulfide) in the presence of an appropriate solvent (e.g. diethyl ether, THF, or a mixture thereof), followed by oxidation of the resulting borane adduct with a suitable oxidising agent (e.g. sodium perborate) and then conversion of the resulting OH group to an L 1 group under conditions known to those skilled in the art.
  • a suitable borane or borane-Lewis base complex e.g. borane-dimethyl sulfide
  • an appropriate solvent e.g. diethyl ether, THF, or a mixture thereof
  • a suitable oxidising agent e.g. sodium perborate
  • Compounds of formula III in which B represents -L-S(O)- or -L-S(0) 2 - may be prepared by oxidation of corresponding compounds of formula III in which B represents -L-S-, wherein L 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
  • B represents -CH 2 0- and X represents O may be prepared by reaction of a compound of formula X, as hereinbefore defined, with a compound of formula XXXII,
  • R and L are as hereinbefore defined, for example at elevated temperature (e.g. between 60°C and reflux temperature) 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 5 represents H and X represents O may be prepared by reduction of a compound of formula XXXIII,
  • R 6 and B are as hereinbefore defined, for example at between -15°C and room temperature 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 temperature 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 -L-, -L-N(R 13 )-, -L-S(0) 2 - or -L-O- (in all four of which groups L represents C ⁇ - alkylene) and X represents O may be prepared by oxidation of a compound of formula XXXIV,
  • B a represents -L-, -L-N(R 13 )-, -L-S(0) 2 - or -L-O- (in all four of which groups L represents a single bond or C 1-3 alkylene), and R , R and R 13 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
  • B represents -L-O- (in which group L represents C 1-4 alkylene) and X , represents N(R 8 ) (wherein R 8 represents -C(O)OR 10b or -S(O) 2 R 10c ) may be prepared by cyclisation of a compound of formula XXXV,
  • R 8b represents -C(O)OR 10b or -S(O) 2
  • R 10c and R 5 , R 6 , R 10b , R 10c , L a and L 2 are as hereinbefore defined, for example at between 0°C and reflux temperature 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
  • a phase transfer catalyst such as tetrabutylammonium hydrogensulfate
  • Compounds of formula VII may be prepared by reaction of a corresponding compound of formula VI with hydroxylamine, for example at elevated temperature (e.g. at reflux) in the presence of a suitable organic solvent (e
  • R y S(0) 2 Cl XXXVI wherein R y is as hereinbefore defined, for example at between -10 and 25 °C in the presence of a suitable solvent (e.g. dichloromethane), followed by reaction with a suitable source of the azide ion (e.g. sodium azide) for example at between ambient and reflux temperature in the presence of an appropriate solvent (e.g. DMF) and a suitable base (e.g. NaHC0 3 ).
  • 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. NaHC0 3
  • Compounds of formulae II and XIX in which one or more of R 41 , R 42 , R 45 and/or R 46 represent C 1-3 alkyl may alternatively be prepared by reaction of a compound of formula II or XIX (as appropriate) in which R 41 , R 42 , R 45 and/or R 46 (as appropriate) represent H, with an appropriate alkylating agent (e.g. dimethyl sulfate), for example in the presence of a suitable strong base (e.g. s- BuLi), N,N,N',N'-tetramethylethylenediamine and a reaction-inert solvent (e.g. THF).
  • an appropriate alkylating agent e.g. dimethyl sulfate
  • a suitable strong base e.g. s- BuLi
  • N,N,N',N'-tetramethylethylenediamine e.g. THF
  • R c and R d together represent C 3-5 alkylene, -0-Z-0-, -O-Z-S- or -S-Z-S-, wherein Z is as hereinbefore defined, in the presence of a suitable reducing agent (e.g. LiAlH 4 ) under conditions that are well known to those skilled in the art.
  • a suitable reducing agent e.g. LiAlH 4
  • Compounds of formula XXIX in which B represents C ⁇ -4 alkylene may be prepared by coupling a compound of formula XL, wherein B b represents C 1-4 alkylene and Hal, A b , R 4 and R 5 are as hereinbefore defined, with a compound of formula XXX, as hereinbefore defined, for example at between -25°C and room temperature in the presence of a suitable zinc(II) salt (e.g. anhydrous ZnBr 2 ), an appropriate catalyst (e.g. Pd(PPh 3 ) 4 ) and a reaction-inert organic solvent (e.g. THF, toluene or diethyl ether).
  • a suitable zinc(II) salt e.g. anhydrous ZnBr 2
  • an appropriate catalyst e.g. Pd(PPh 3 ) 4
  • a reaction-inert organic solvent e.g. THF, toluene or diethyl ether
  • R z represents C ⁇ -10 alkyl or C 1-3 alkylaryl (e.g. alkylphenyl, such as benzyl) and R 43 to R 46 are as hereinbefore defined, or (ii) 4-piperidone (or a protected derivative thereof), with (as appropriate) either (1) a compound of formula XLII,
  • R 6 -B-C(R 4 )(R 5 )-A-NH 2 XLII wherein R 4 , R 5 , R 6 , 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 VI and XXIII, conversion of the C(0)OR z group in the resultant intermediate to an R 2 group using techniques such as those described herein (e.g. removal of the C(0)OR z group followed by carrying out a coupling, e.g. according to process step (x) above).
  • a formaldehyde i.e. an appropriate source of formaldehyde, such as paraformaldehyde or formalin solution
  • this process may also be used to prepare compounds of formula I in which R 45 and R are H, and R and/or R 42 are other than H, for example by: (i) reacting a compound of formula XLI in which R 45 and/or R 46 is/are other than H with, for example, benzylamine or a derivative thereof; (ii) removal of the -C(0)OR z unit; (iii) reaction at the free bispidine nitrogen of the resultant compound with a compound of formula III, IV or V (as appropriate), as hereinbefore defined; (iv) removal of the benzyl protecting group; and
  • R e and R together represent C 3-5 alkylene, with a mixture of phosphoric acid and sulfuric acid, for example at 120°C.
  • aryl e.g. phenyl
  • heterocyclic, group(s) in compounds defined herein may be converted to other claimed substituents using techniques well known to those skilled in the art. For example, hydroxy may be converted to alkoxy, phenyl may be halogenated to give halophenyl, nitro may be reduced to give amino, amino may be acetylated to give acetylamino, 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 carboxylic acid.
  • Suitable protecting groups for hydroxy include trialkylsilyl and diarylalkylsilyl groups (e.g. tert-butyldimethylsilyl, tert- butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl and alkylcarbonyl groups (e.g. methyl- and ethylcarbonyl groups).
  • Suitable protecting groups for amino include benzyl, tert-butyloxycarbonyl, 9-fluorenylmethoxy- carbonyl or benzyloxycarbonyl.
  • Suitable protecting groups for amidino and guanidino include benzyloxycarbonyl.
  • Suitable protecting groups for carboxylic acid include C 1- alkyl or benzyl esters.
  • R 39 represents H or C 1-6 alkyl; then R does not represent: (i) CN; (ii) C 1-6 alkyl optionally substituted by OH, N(R 30 )R 31 or Het 9 ; wherein
  • R 30 and R 31 independently represent H, C 1-6 alkyl or C 3-8 cycloalkyl
  • Het 9 represents an unsubstituted, saturated . 3- to 8-membered heterocycle containing one nitrogen atom (via which atom the heterocyclic group is attached to the rest of the molecule);
  • R represents H or phenyl substituted in the meta- or flra-position
  • R 16 represents H or phenyl substituted in the meta- or ?fl7-fl-position (relative to the point of attachment) by C0 2 H or NH 2 ; 99 99
  • R represents phenyl substituted in the meta- or ? ⁇ ra-position (relative to the point of attachment) by C0 2 H or NH 2 ;
  • R represents H or C 1-6 alkyl
  • R 4 and R 5 both represent H; then R 2 does not represent CN, -C(0)R 16 , -S(0) 2 R 22 , -S(0) 2 N(R 23 )R 2 '
  • R 22 represents Het 14 or C 1-6 alkyl (which alkyl group is optionally, substituted and/or terminated by one or more substituents selected from halo, -OH, -CN, Het 15 and aryl);
  • R 23 represents H, C 1-6 alkyl, Het 16 , -C(0)R 36a , -C(0)OR 36b or -C(0)SR 36b ;
  • R 30 represents Het 19 , -C(0)R 37a , -C(0)OR 37b or -C(0)N(R 37c )R 37d ;
  • R 32 represents C 1-6 alkyl, Het 21 , -C(0)R 37a , -C(0)OR 37b or -C(0)N(R 37c )R 37d .
  • the compounds of the invention are useful because they possess pharmacological activity. They are therefore indicated as pharmaceuticals.
  • the compounds of the invention exhibit myocardial electrophysiological activity, for example as demonstrated in the test described below.
  • the compounds of the invention 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 HI 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 0.005 to 10.0 mg/kg body weight at oral administration and about 0.005 to 5.0 mg/kg body weight at parenteral administration.
  • 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 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 and 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 temperature 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
  • 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 mo ⁇ hological changes.
  • the mean of the two control recordings was set to zero and the effects recorded after consecutive doses of test substance were expressed as percentage changes from this value. By plotting these percentage values against the cumulative dose administered before each recording, it was possible to construct dose-response curves. In this way, each experiment generated three dose-response curves, one for MAP duration, one for AV- conduction time and one for the sinus frequency (RR interval). A mean curve of all experiments performed with a test substance was calculated, and potency values were derived from the mean curve. All dose-response curves in these experiments were constructed by linear connection of the data points obtained. The cumulative dose prolonging the MAP duration by 10% from the baseline was used as an index to assess the class III electrophysiological potency of the agent under investigation (D j 0 ) .
  • Glucocorticoid-treated mouse fibroblasts as a model to detect blockers of the delayed rectifier K current IC50 for K channel blockade was determined using a microtitre plate based screen method, based on membrane potential changes of glucocorticoid- treated mouse fibroblasts.
  • the membrane potential of glucocorticoid- treated mouse fibroblasts was measured using fluorescence of the bisoxonol dye DiBac 4(3) , which could be reliably detected using a fluorescence laser imaging plate reader (FLIPR).
  • FLIPR fluorescence laser imaging plate reader
  • Expression of a delayed rectifier potassium channel was induced in mouse fibroblasts by 24 hours exposure to the glucocorticoide dexamehasone (5 ⁇ M). Blockade of these potassium channels depolarised the fibroblasts, resulting in increased fluorescence of DiBac 4(3) .
  • Mouse ltk fibroblasts were purchased from American Type Culture Collection (ATCC, Manassa, VA), and were cultured in Dulbeccos modified eagle medium supplemented with fetal calf serum (5% vol/vol), penicillin (500 units/mL), streptomycin (500 ⁇ g/mL) and L-alanine-L- glutamine (0.862 mg/mL). The cells were passaged every 3-4 days using trypsin (0.5 mg/mL in calcium- free phosphate buffered saline, Gibco BRL). Three days prior to experiments, cell-suspension was pipetted out into clear- bottom, black plastic, 96-well plates (Costar) at 25 000 cells/well.
  • ATCC American Type Culture Collection
  • VA Manassa, VA
  • Dulbeccos modified eagle medium supplemented with fetal calf serum (5% vol/vol)
  • penicillin 500 units/mL
  • streptomycin 500 ⁇ g/m
  • DiBac 4(3) (DiBac Molecular probes) was used to measure membrane potential.
  • DiBac (3) maximally absorbs at 488 nM and emits at 513 nM.
  • DiBac 4(3) is a bisoxonol, and thus is negatively charged at pH 7. Due to its negative charge, the distribution of DiBac 4(3) across the membrane is dependent upon the transmembrane potential: if the cell depolarizes (i.e. the cell interior becomes less negative relative to cell exterior), the DiBac 4(3) concentration inside the cell increases, due to electrostatic forces. Once inside the cell, DiBac 4(3) molecules can bind to lipids and proteins, which causes an increase in fluorescence emission. Thus, a depolarization will be reflected by an increase in DiBac 4(3) fluorescence. The change in DiBac 4(3) fluorescence was detected by a FLIPR.
  • the cells Prior to each experiment, the cells were washed 4 times in phosphate- buffered saline (PBS) to remove all culture media. The cells were then treated with 5 ⁇ M DiBac 4(3) (in 180 ⁇ L of PBS) at 35°C. Once a stable fluorescence was reached (usually after 10 min), 20 ⁇ L of the test substance was added, using FLIPR' s internal 96 well pipetting system. Fluorescence measurements were then taken every 20 sec for a further 10 min. All experiments were carried out at 35°C, due to the high temperature sensitivity of both delayed rectifier potassium channel conductance and
  • DiBac 4(3) fluorescence Test substances were prepared in a second 96 well plate, in PBS containing 5 ⁇ M DiBac 4(3) .
  • the concentration of substance prepared was 10 times that of the desired concentration in the experiment as an additional 1:10 dilution occurred during addition of substance during the experiment.
  • Dofetilide (10 ⁇ M) was used as a positive control, i.e. to determine the maximum increase in fluorescence.
  • 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 (and thus t ⁇ ) was calculated and used as a measure for metabolic stability.
  • Mass spectra were recorded on one of the following instruments: a Finnigan MAT TSQ 700 triple quadrupole mass spectrometer equipped with an electrospray interface (FAB-MS); a Perkin-Elmer SciX API 150ex spectrometer; a VG Quattro II triple quadrupole; a VG Platform II single quadrupole; or a Micromass Platform LCZ single quadrupole mass spectrometer (the latter three instruments were equipped with a pneumatically assisted electrospray interface (LC-MS)).
  • FAB-MS electrospray interface
  • LC-MS Micromass Platform LCZ single quadrupole mass spectrometer
  • H NMR and C NMR measurements were performed on a BRUKER ACP 300 and Varian 300, 400 and 500 spectrometers, operating at 1H frequencies of 300, 400 and 500 MHz respectively, and at C frequencies of 75.5, 100.6 and 125.7 MHz respectively.
  • C NMR measurements were performed on a BRUKER ACE 200 spectrometer at a frequency of 50.3 MHz.
  • Rotamers may or may not be denoted in spectra depending upon ease of inte ⁇ retation 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 procedure described in J. Org. Chem., 41(9), 1976, pp. 1593-1597, using 3,7-dibenzyl-3,7- diazabicyclo[3.3.1]nonane-9-one (see step (i) above) in place of N-benzyl- N'-methylbispidone.
  • step (ii) 4-[2-(2-Oxiranyl)ethoxyjbenzonitrile 4-(3-Butenyloxy)benzonitrile (see step (i) above; 37 g, 0.21 mol) was mixed with CPBA (61.6 g, 0.25 mol) and DCM (700 mL) and stirred at r.t. for 4 h. The reaction mixture was filtered and 2 mL of DMSO was added to destroy the excess mCPBA. The mixture was washed with NaHC0 3 , then separated, dried and evaporated to give 38.7 g (97%) of the sub-title compound.
  • step (viii) 3-(Butylsulfony ⁇ )-3,7-diazabicyclo[3.3.1 jnonane 3-Benzyl-7-(butylsulfonyl)-3,7-diazabicyclo[3.3.1jnonane (see step (vii) above; 12.7 g, 38 mmol) was dissolved in ethanol (150 mL of 95%) and hydrogenated over 5% Pd/C at 1 atm. overnight. TLC analysis showed that no reaction had occurred. The catalyst was filtered off and new catalyst (5% Pd/C) was added, together with H 2 0 (10 mL) and acetic acid (2 mL). The mixture was then hydrogenated at 1 atm. overnight. The catalyst was filtered off, 2 N NaOH was added and the mixture was extracted with toluene. Evaporation of the toluene solution gave 8 g (85%) of the sub-title compound.
  • API atmospheric pressure ionisation (in relation to MS)
  • HEPES 4-(2-hy droxy ethyl)- 1 -piperazmeethanesulfonic acid
  • NADPH nicotinamide adenine dinucleotide phosphate, reduced form

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Cardiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne des composés de formule (I), dans laquelle R?1, R2, R3a, R3b et, R41 à R46¿ ont les significations mentionnées dans le descriptif, lesdits composés étant utilisés en prophylaxie et dans le traitement des arythmies, notamment des arythmies auriculaires et ventriculaires.
EP01950132A 2000-07-07 2001-07-04 Nouveaux composes de bispidine et leur utilisation dans le traitement des arythmies cardiaques Withdrawn EP1301510A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
SE0002603 2000-07-07
SE0002603A SE0002603D0 (sv) 2000-07-07 2000-07-07 New compounds
SE0002788A SE0002788D0 (sv) 2000-07-27 2000-07-27 New compounds
SE0002788 2000-07-27
PCT/SE2001/001544 WO2002004446A1 (fr) 2000-07-07 2001-07-04 Nouveaux composes de bispidine et leur utilisation dans le traitement des arythmies cardiaques

Publications (1)

Publication Number Publication Date
EP1301510A1 true EP1301510A1 (fr) 2003-04-16

Family

ID=26655177

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01950132A Withdrawn EP1301510A1 (fr) 2000-07-07 2001-07-04 Nouveaux composes de bispidine et leur utilisation dans le traitement des arythmies cardiaques

Country Status (20)

Country Link
EP (1) EP1301510A1 (fr)
JP (1) JP2004502772A (fr)
KR (1) KR20030014426A (fr)
CN (1) CN1440407A (fr)
AR (1) AR030302A1 (fr)
AU (1) AU2001271161A1 (fr)
BR (1) BR0112267A (fr)
CA (1) CA2412848A1 (fr)
CZ (1) CZ200332A3 (fr)
EE (1) EE200300013A (fr)
HU (1) HUP0301304A2 (fr)
IL (1) IL153485A0 (fr)
IS (1) IS6660A (fr)
MX (1) MXPA02012942A (fr)
NO (1) NO20030057L (fr)
NZ (1) NZ523540A (fr)
PL (1) PL360474A1 (fr)
RU (1) RU2002134450A (fr)
SK (1) SK42003A3 (fr)
WO (1) WO2002004446A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004103991A1 (fr) * 2003-05-20 2004-12-02 'chemical Diversity Research Institute', Ltd. Piperidines 2-substituees, bibliotheque focalisee et composition pharmaceutique
US7399765B2 (en) 2003-09-19 2008-07-15 Abbott Laboratories Substituted diazabicycloalkane derivatives
SE0302775D0 (sv) * 2003-10-20 2003-10-20 Astrazeneca Ab Chemical compound and assay
RU2472793C1 (ru) * 2011-07-20 2013-01-20 Федеральное государственное бюджетное образовательное учреждение высшего профессионального образования "Московский государственный университет тонких химических технологий имени М.В. Ломоносова" (МИТХТ им.М.В.Ломоносова) 1,5-бис[(трет-бутиламино)метил]-n,n'-ди-трет-бутилбиспидин-9-она и способ его получения

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3732094A1 (de) * 1987-09-24 1989-04-06 Basf Ag Bispidinderivate als klasse iii-antiarrhythmika
US5110933A (en) * 1989-11-13 1992-05-05 Board Of Regents Of Oklahoma State University Salts of 3-azabicyclo[3.3.1]nonanes as antiarrhythmic agents, and precursors thereof
US5468858A (en) * 1993-10-28 1995-11-21 The Board Of Regents Of Oklahoma State University Physical Sciences N-alkyl and n-acyl derivatives of 3,7-diazabicyclo-[3.3.1]nonanes and selected salts thereof as multi-class antiarrhythmic agents
DE4402931A1 (de) * 1994-02-01 1995-08-03 Kali Chemie Pharma Gmbh Neue 3-Phenylsulfonyl-3,7-diazabicyclo[3,3,1] nonan-Verbindungen enthaltende Arzneimittel
DE4402933A1 (de) * 1994-02-01 1995-08-03 Kali Chemie Pharma Gmbh Neue 3-Benzoyl-3,7-diazabicyclo[3,3,1] nonan-Verbindungen enthaltende Arzneimittel
SE9704709D0 (sv) * 1997-12-17 1997-12-17 Astra Ab Pharmaceutically active compounds
SE9902268D0 (sv) * 1999-06-16 1999-06-16 Astra Ab Pharmaceutically active compounds
SE9902271D0 (sv) * 1999-06-16 1999-06-16 Astra Ab Pharmaceutically active compounds
SE9902269D0 (sv) * 1999-06-16 1999-06-16 Astra Ab Pharmaceutically active compounds
SE9902270D0 (sv) * 1999-06-16 1999-06-16 Astra Ab Pharmaceutically active compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0204446A1 *

Also Published As

Publication number Publication date
NO20030057L (no) 2003-01-31
AU2001271161A1 (en) 2002-01-21
RU2002134450A (ru) 2004-07-10
AR030302A1 (es) 2003-08-20
IS6660A (is) 2002-12-19
KR20030014426A (ko) 2003-02-17
EE200300013A (et) 2004-10-15
WO2002004446A1 (fr) 2002-01-17
CA2412848A1 (fr) 2002-01-17
PL360474A1 (en) 2004-09-06
CZ200332A3 (cs) 2003-04-16
NO20030057D0 (no) 2003-01-06
JP2004502772A (ja) 2004-01-29
IL153485A0 (en) 2003-07-06
MXPA02012942A (es) 2003-10-06
CN1440407A (zh) 2003-09-03
SK42003A3 (en) 2003-07-01
HUP0301304A2 (hu) 2003-08-28
BR0112267A (pt) 2003-05-20
NZ523540A (en) 2004-07-30

Similar Documents

Publication Publication Date Title
MXPA02003848A (es) Nuevos compuestos de oxabispidina utiles en el tratamiento de arritmias cardiacas.
EP1360187B1 (fr) 3,7-diazabicyclo(3.3.0)octanes et leur utilisation dans le traitement de l'arythmie cardiaque
EP1330461A1 (fr) Nouveau compose d'oxabispidine utile pour traiter les arythmies cardiaques
US7012074B2 (en) 3,8-Diazabicyclo[3.2.1]octanes and their use in the treatment of cardiac arrhythmias
WO2002004446A1 (fr) Nouveaux composes de bispidine et leur utilisation dans le traitement des arythmies cardiaques
AU761576B2 (en) New bispidine compounds useful in the treatment of cardiac arrhythmias
US20030212095A1 (en) New bispidine compounds and their use in the treatment of cardiac arrhythmias
US20040229900A1 (en) Bispidine compounds useful in the treatment of cardiac arrythmias
EP1192154B1 (fr) Composes de bispidine utiles dans le traitement des arythmies cardiaques
AU2002226854A1 (en) 3,7-diazabicyclo[3.30]octanes and their use in the treatment of cardiac arrhythmias
SK18292001A3 (sk) Bispidínové zlúčeniny užitočné pri liečbe srdcových arytmií

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20030207

AK Designated contracting states

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

RIN1 Information on inventor provided before grant (corrected)

Inventor name: TOTTIE, LOUISE

Inventor name: SVENSSON, PEDER

Inventor name: STRANDLUND, GERT

Inventor name: PONTEN, FRITIOF

Inventor name: BJOERSNE, MAGNUS

Inventor name: BJOERE, ANNIKA

Inventor name: ANDERSSON, KJELL

17Q First examination report despatched

Effective date: 20030725

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20050825

REG Reference to a national code

Ref country code: HK

Ref legal event code: WD

Ref document number: 1053647

Country of ref document: HK