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WO2002004446A1 - New bispidine compounds and their use in the treatment of cardiac arrhythmias - Google Patents

New bispidine compounds and their use in the treatment of cardiac arrhythmias Download PDF

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Publication number
WO2002004446A1
WO2002004446A1 PCT/SE2001/001544 SE0101544W WO0204446A1 WO 2002004446 A1 WO2002004446 A1 WO 2002004446A1 SE 0101544 W SE0101544 W SE 0101544W WO 0204446 A1 WO0204446 A1 WO 0204446A1
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WIPO (PCT)
Prior art keywords
formula
compound
alkyl
het
optionally substituted
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Application number
PCT/SE2001/001544
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French (fr)
Inventor
Kjell Andersson
Annika Björe
Magnus Björsne
Fritiof Pontén
Gert Strandlund
Peder Svensson
Louise Tottie
Original Assignee
Astrazeneca Ab
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Publication date
Priority claimed from SE0002603A external-priority patent/SE0002603D0/en
Priority claimed from SE0002788A external-priority patent/SE0002788D0/en
Priority to PL36047401A priority Critical patent/PL360474A1/en
Priority to EEP200300013A priority patent/EE200300013A/en
Priority to MXPA02012942A priority patent/MXPA02012942A/en
Priority to KR10-2003-7000248A priority patent/KR20030014426A/en
Priority to AU2001271161A priority patent/AU2001271161A1/en
Priority to US10/332,103 priority patent/US20030212095A1/en
Priority to EP01950132A priority patent/EP1301510A1/en
Priority to HU0301304A priority patent/HUP0301304A2/en
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Priority to BR0112267-3A priority patent/BR0112267A/en
Priority to IL15348501A priority patent/IL153485A0/en
Priority to CA002412848A priority patent/CA2412848A1/en
Priority to JP2002509311A priority patent/JP2004502772A/en
Priority to SK4-2003A priority patent/SK42003A3/en
Priority to NZ523540A priority patent/NZ523540A/en
Publication of WO2002004446A1 publication Critical patent/WO2002004446A1/en
Priority to IS6660A priority patent/IS6660A/en
Priority to NO20030057A priority patent/NO20030057L/en

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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

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Abstract

There is provided compounds of formula (I), wherein R?1, R2, R3a, R3b and R41 to R46¿ have meanings given in the description, which are useful in the prophylaxis and in the treatment of arrhythmias, in particular atrial and ventricular arrhythmias.

Description

NEW BISPIDINE COMPOUNDS AND THEIR USE IN THE TREATMENT OF CARDIAC ARRHYTHMIAS
Field of the Invention
This invention relates to novel pharmaceutically useful compounds, in particular compounds which are useful in the treatment of cardiac arrhythmias.
Background and Prior Art
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)).
In the treatment of cardiac arrhythmias, the negative outcome in clinical trials (see, for example, the outcome of the Cardiac Arrhythmia Suppression Trial (CAST) reported in New England Journal of Medicine, 321, 406 (1989)) with "traditional" antiarrhythmic drugs, which act primarily by slowing the conduction velocity (class I antiarrhythmic drugs), has prompted drug development towards compounds which selectively delay cardiac repolarization, thus prolonging the QT interval. Class III 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. One of the key disadvantages of hitherto known drugs which act by delaying repolarization (class III or otherwise) is that they all are known to exhibit a unique form of proarrhythmia known as torsades de pointes (turning of points), which may, on occasion be fatal. From the point of view of safety, the minimisation of this phenomenon (which has also been shown to be exhibited as a result of administration of non-cardiac drugs such as phenothiazines, tricyclic antidepressants, antihistamines . and antibiotics) is a key problem to be solved in the provision of effective antiarrhythmic drugs.
Antiarrhythmic drugs based on bispidines (3,7-diazabicyclo[3.3.1]nonanes), are known from inter alia international patent applications WO 91/07405 and WO 99/31100, European patent applications 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. 24, 149 (1991); Circulation, 90, 2032 (1994); Anal Sci. 9, 429, (1993); and J. Med Chem. 20, 1668 (1977).- Known 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- proρylmethyl)-9,9-tetramethylene-3,7-diazabicyclo[3.3.1]nonane), SAZ- VII-22 (3-(4-chlorobenzoyl)-7-zso-ρropyl-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-(lH-imidazol-l-yl)benzoyl]-7-trø-propyl-3,7-diazabicyclo-
[3.3.1]nonane), 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. J. Med. Chem. - Chimica Therapeutica 12(4), 301 (1977); Phosphorous, Sulfur and Silicon 123, 385 (1997); J. Org Chem. 42(6), 937 (1977); and J. Molecular Structure 127, 185 (1985).
We have surprisingly found that a novel group of 3,7-diazabicyclo[3.3.1]- nonane-based compounds exhibit electrophysiological activity, preferably class III electrophysiological activity, and are therefore expected to be useful in the treatment of cardiac arrhythmias.
Disclosure of the Invention
According to the invention there is provided compounds of formula I,
Figure imgf000004_0001
wherein
R1 represents a structural fragment of formula la,
Figure imgf000004_0002
R4 represents H, halo, C1-4 alkyl, -D-OR7, -D-N(R8)R9, or R4, together with R5, represents =0; R5 represents H, C1-4 alkyl, or R5, together with R4, represents =0;
D represents a direct bond or C1- alkylene;
R7 represents H, C1-6 alkyl, -E-aryl, -E-Het1, -C(O)R10a, -C(O)OR10b or
-C(0)N(Rl la)Rl lb; R8 represents H, C1-6 alkyl, -E-aryl, -E-Het1, -C(O)R10a, -C(O)OR10b,
-S(O)2RI0c, -[C(0)jnN(Rl la)Rl lb or -C(NH)NH2;
R9 represents H, CI-6 alkyl, -E-aryl, or -C(O)R10d;
E represents, at each occurrence when used herein, a direct bond or C1-4 alkylene; R10a to R10d 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 Het2), aryl, Het3, or Rl0a and R10d independently represent H;
Rl la and Rl lb independently represent, at each occurrence when used herein, H, Cι.6 alkyl (optionally substituted and/or terminated by one or more substituents selected from halo, aryl and Het4), aryl, Het5, or Rl la and Rl lb together represent C3-7 alkylene, which alkylene group is optionally interrupted by an oxygen atom; n represents 1 or 2;
1
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(R13)-, -N(R13)-L-, -L-S(0)p- or -L-O- (in which latter two groups, L is attached to the carbon atom bearing R4 and R5); G represents a direct bond or C1-6 alkylene; J represents C2-6 alkylene; L represents a direct bond or C1-4 alkylene; p represents 0, 1 or 2; R and R independently represent H or C1-4 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, C1-6 alkyl (optionally terminated by -N(H)C(0)OR14a), C1-6 alkoxy, aryl, Het7, -N(R15a)R15b, -C(0)R15c, -C(0)OR,5d, -C(0)N(R15e)R15f, -N(R15g)C(0)RI5h, -N(R15i)C(0)N(R15j)R15k, -N(R15m)S(0)2R14b, -S(0)qR14c, -OS(0)2Rl4d and -S(0)2N(R15n)R15p) or, when R4 and R5 together represent =0, Rό may represent Cι- alkyl; q represents 0, 1 or 2;
R2 represents -CN, Het8, -C(0)R16, -C(S)OR17, -C(S)N(R18)R19, -[C(O)]2N(R20a)R20b, ' -[C(0)j2OR21, -S(0)2R22, -S(0)2N(R23)R24, -C(=N-CN)N(R25)R26, -C(=N-CN)OR27 or C1-12 alkyl (which alkyl group is optionally substituted and/or terminated by one or more substituents selected from -C(0)R28, -C(0)N(R29a)R29b, -N(R30)R31, -OR32, -S(0)rR33, halo, -CN, nitro, aryl and Het9);
R16 represents H, aryl, Het10 or Cι-6 alkyl (which alkyl group is optionally substituted and/or terminated by one or more substituents selected from halo, -OH, -CN, -N(R34)R35, aryl and Het11); R34 represents, H, C1-6 alkyl, aryl, Het12, -C(0)R36a or -C(0)OR36b;
R18 represents H, aryl, Het13, -C(0)R36a, -C(0)OR36 or C1-6 alkyl (which alkyl group is optionally substituted and/or terminated by one or more substituents selected from halo, -OH, -CN, -C(0)R36a and -C(0)OR36b);
R22 represents Het14, aryl, or Cι-6 alkyl (which alkyl group is optionally substituted and/or terminated by one or more substituents selected from halo, -OH, -CN, Het15 and aryl); R23 represents H, C1-6 alkyl, aryl, Het16, -C(0)R36a, -C(0)OR36 or -C(0)SR36b;
R represents H or C1-6 alkyl (which alkyl group is optionally substituted and/or terminated by one or more substituents selected from halo, -OH, -CN, Cι-6 alkyl (which alkyl group is optionally substituted and/or terminated by one or more substituents selected from C1- alkyl and -OH), Cι-6 alkoxy and aryl);
R27 represents C1-6 alkyl or aryl;
R represents H, C1-6 alkyl, aryl or Het ;
R29a and R29b independently represent H, C1-6 alkyl, aryl or Het18;
R30 represents H, C1-6 alkyl, aryl, Het19, -C(0)R37a, -C(0)OR37b or
-C(0)N(R37c)R37d;
R31 represents H, C]-6 alkyl, aryl or Het20;
R' represents H, C1-6 alkyl, aryl, He .211, -C(0)RJ /a, -C(0)ORJ /D or -C(0)N(R37c)R37d;
τ-3 oτ
R represents Cι-6 alkyl, aryl or Het ; r represents 0, 1 or 2;
R36a and R36b independently represent, at each occurrence when used herein, C1-6 alkyl, or R36a represents H;
R a to R independently represent, at each occurrence when used herein, C1-6 alkyl, aryl or Het23, or R37a, R37c and R37d independently represent H; Het1 to Het23 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;
R3a and R3b independently represent H, CM alkyl, -OR38a, -SR38b, -N(R39)R38c, or R3a and R3b together represent C3-5 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 C2-3 alkylene optionally substituted by one or more C1-4 alkyl groups;
R41 to R 6 independently represent H or CJ-3 alkyl;
R14a to R14d, R17 and R21 independently represent C1-6 alkyl;
R15a to R15p, R19, R20a, R20b, R24, R26, R35 and R38a to R38c independently represent H or Cι-6 alkyl;
wherein each aryl and Het (Het1 to Het23) group, unless otherwise specified, is optionally substituted;
or a pharmaceutically acceptable derivative thereof;
provided that: (a) when R1 represents a structural fragment of formula la in which: R4 and R5 together represent =0; A represents a direct bond;
1 "X then B does not represent a direct bond, -N(R )-L- (in which group -N(R13)- is attached to the carbon atom bearing R4 and R5), -N(R13)-, -S(0)p- or -0-; (b) when R5 represents H or CM alkyl; and A represents -J-N(R12)- or -J-0-; then B does not represent -N(R13)-L-, -N(R13)-, -S(0)p- or -0-;
(c) when R4 represents -D-OR7, -D-N(R8)R9 in which D represents a direct bond, then:
19
(i) A does not represent -J-N(R )- or -J-0-; and
(ii) B does not represent -N(Rl3)-L-, -N(R13)-, -S(0)p- or -0-;
(d) when R3a and R3b and both represent H; and R1 represents unsubstituted benzyl; then R does not represent unsubstituted benzyl or optionally substituted benzoyl; and
(e) the compound is not:
(i) N1-phenyl-3-(7-benzyl-3,7-diazabicyclo[3.3.1 jnon-3-yl)- propanamide; (ii) 3-benzyl-7-[3-(4-cyanophenoxy)-2-hydroxypropylj-6,8- dimethyl-3 ,7-diazabicyclo[3.3.1 jnonane; (iii) 3-benzyl-7-[3-(4-cyanophenoxy)-2-hydroxypropylj-6-methyl-
3,7-diazabicyclo[3.3.1 jnonane; (iv) N- {2-(7-benzyl-3 ,7-diazabicyclo[3.3.1 jnon-3-yl)- 1 -[(4-cyano- phenoxy)methylj ethyl jmethanesulfonamide;
(v) 3-benzyl-7-[3-(2-propyl-l,3-dioxolan-2-yι)propyιj-3,7-diaza- bicyclo[3.3.1 jnonane; or (vi) 7-benzyl-3 ,7-diazabicyclo[3.3. l]nonane-3 -ethanol;
which compounds are referred to hereinafter as "the compounds of the invention".
Unless otherwise specified, alkyl groups and alkoxy groups as defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of three) of carbon atoms, be branched-chain and/or cyclic. Further, when there is a sufficient number 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.
Unless otherwise specified, 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.
The term "aryl", when used herein, includes C6-ιo 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, CI-6 alkyl (optionally terminated by -N(H)C(0)OR14a), C1-6 alkoxy, Het1, aryl (which aryl group may not be substituted with any further aryl groups), -N(R15a)R15b, -C(0)R15c, -C(0)OR15d, -C(0)N(R15e R15f, -N(R15g)C(0)R15h, -N(R15i)C(0)N(R15j)R15k, -N(R15m)S(0)2R14b -S(0)qR14c, -OS(0)2R14d and -S(0)2N(R15n)R15p) (wherein Het1, R14a to R14d, R15ato R15p and q are as hereinbefore defined). When substituted, aryl groups are preferably substituted by between one and three substituents.
The term "halo", when used herein, includes fluoro, chloro, bromo and iodo. 1 9"ϊ
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
1 T and twelve. 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, . benzothiophenyl, chromanyl, cinnolinyl, dioxanyl, furanyl, hydantoinyl, imidazolyl, imidazo[l,2- fljpyridinyl, indolyl, isoquinolinyl, isoxazolyl, maleimido, morpholinyl, 2-oxazolidonyl, oxazolyl, phthalazinyl, piperazinyl, piperidinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, sulfolanyl, 3-sulfolenyl, tetrahydropyranyl, tetrahydrofuranyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, thiochromanyl, triazolyl and the like. Values of Het1 that may be mentioned include pyridyl. Values of Het6 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 Het9 that may be mentioned include benzomorpholinyl, 2-oxazolidonyl and piperazinyl. Values of Het10 that may be mentioned include furanyl, isoxazolyl, pyrazolyl, pyrrolidinonyl and 1,2,3-thiadiazolyl. Values of Het14 that may be mentioned include imidazolyl, sulfolanyl, thienyl and quinolinyl. Values of Het15 that may be mentioned include moφholinyl.
1 *7
Values of Het that may be mentioned include benzomoφholinyl. Values
91 of Het that may be mentioned include isoquinolinyl.
Unless otherwise specified, Het (Het1 to Het23) groups may be substituted by one or more substituents including =0, -OH, cyano, halo, nitro, Cι_6 alkyl (optionally terminated by -N(H)C(0)OR14a), C1-6 alkoxy, Het1, aryl, -N(R15a)R15b, -C(0)R15c, -C(0)OR15d, -C(0)N(R15e)R15f, -N(R15g)C(0)R15h, -N(R15i)C(0)N(R15j)R15k, -N(R15m)S(0)2R14b, -S(0)qR14c, -OS(0)2R14d and -S(0)2N(R15n)R15p) (wherein Het1, aryl, R14a to R14d, R15a to R15p and q are as hereinbefore defined). When a Het (Het1 to Het23) group is substituted by one or more Het1 and/or aryl group(s), that (those) said Het1 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 (Het1 to Het23) 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, C1-4 alkyl quaternary ammonium salts and N-oxides, provided that when a N-oxide is present:
(a) no Het (Het1 to Het23) group contains an unoxidised S-atom; (b) • p does not represent 0 when B represents -L-S(0)p-;
(c) q does not represent 0 when the group -S(0)qR14c 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)rR 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. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric esters by conventional means (e.g. HPLC, chromatography over silica). All stereoisomers are included within the scope of the invention.
Abbreviations are listed at the end of this specification.
Compounds of the invention that may be mentioned include compounds of formula I, as defined above, with the additional provisos that: (i) when R represents C1-6 alkyl (optionally substituted by one or two aryl groups), then:
(I) when R4 represents H, C alkyl, -OR7, or R4, together with R5 represents =0;
R7 represents H, C1-6 alkyl or -C(O)RI0a; and
R represents aryl; then B does not represent -L-; and/or
(II) when A represents a single bond; and R and R5 together represent =0; then R3 and R3b do not both represent C1-4 alkyl or they do not together represent C3-5 alkylene; (ii) when R2 represents -C(0)R16 and the group -A-C(R4)(R5)-B- represents C1-6 alkylene, then: (I) R16 does not represent aryl; and or (II) R3a and R3b do not both represent Cj- alkyl or they do not together represent C3-5 alkylene; and (iii) when R2 represents -S(0)2R22;
R3a and R3b 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.
Compounds of the invention that may also be mentioned include compounds of formula I, as defined above, with the additional provisos that: when R3a and R3b independently represent H, d-4 alkyl, OH or N(R39)R38c; and represents H or C1-6 alkyl, then: (a) when R2 represents CN or C1-6 alkyl optionally substituted by OH, N(R30)R31 or Het9;
R and R independently represent H, C1-6 alkyl or C3-8 cycloalkyl; Het9 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);
R4 arid R5 both represent H; and
R6 represents phenyl substituted in the meta- or/?αrα-ρosition (relative to the group B) by C02H or NH2, then:
(i) when A represents a direct bond, C1-6 n-alkylene or -J-0-; and J represents C2-3 «-alkylene; then B does not represent -L-N(R13)- or -L-O- (in which latter two groups, L represents a direct bond or Cι- n-alkylene and is attached to the carbon atom bearing R4 and R5); and (ii) when A represents -J-0-; and J represents C2-3 n-alkylene; then B does not represent a direct bond; and (b) when R6 represents Het6;
Het6 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(R4)(R5)-B- represents C1-6 n-alkylene; then R2 does not represent:
(i) C1-6 n-alkyl, which alkyl group is optionally interrupted by O and is terminated by N(R30)R31 or OR32; wherein one of R30 and R31 represents H or phenyl substituted in the meta- or >flrα-position (relative to the point of attachment) by C02H or NH2 and the other represents H or C1-6 alkyl; and R32 represents H or phenyl substituted in the meta- or para- position (relative to the point of attachment) by C02H or NH2; (ii) -C(0)R16, wherein R16 represents H or phenyl substituted in the metfl- or arα-position (relative to the point of attachment) by C02H or NH2; (iii) -S(0)2R22, wherein R22 represents phenyl substituted in the meta- or jpαrø-position (relative to the point of attachment) by C02H or NH2;
(iv) -S(0)2N(R23)R24; wherein
R23 represents phenyl substituted in the meta-- or /? rα-position (relative to the point of attachment) by C02H or NH2; and R24 represents H or C]-6 alkyl; and (v) C3-4 n-alkyl, which alkyl group is terminated by phenyl, which phenyl group is substituted in the meta- or/?flrø-position (relative to the point of attachment) by C02H or NH2, and which alkyl group is interrupted at the β-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:
(i) 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); or (ii) phenyl substituted in the meta- or ?αrfl-position (relative to the group
B) by C02H or NH2.
Further compounds of the invention that may also be mentioned include those in which R6 represents aryl, which group is optionally substituted and/or terminated (as appropriate) by one or more substituents selected from -OH, cyano, halo, nitro, C1-6 alkyl (optionally terminated by -N(H)C(0)OR14a), C1-6 alkoxy, aryl, Het7, -C(0)R15c, -C(0)N(R15e)R15f, -N(R15g)C(0)R15h, -N(R151)C(0)N(R15j)R15k, -N(R15m)S(0)2R14b -S(0)qR14c, -OS(0)2R14d and -S(0)2N(R15n)R15p, or, when R4 and R5 together represent =0, R6 may represent C1-6 alkyl.
Preferred compounds of the invention also include those in which: R4 represents H, C1-2 alkyl, -OR7 or N(H)R8, or R4, together with R5, represents — O;
R5 represents H, or R5, together with R4, represents =0;
R7 represents H, C1-4 alkyl, optionally substituted phenyl, -C(O)R10a, or
-C(0)N(Rl la)Rl lb; R8 represents H, C1-4 alkyl, -C(O)R10a, -C(O)OR10b or -C(0)N(R' la)R1 lb;
R10a and R10 independently represent, at each occurrence when used herein,
Cι-5 alkyl (optionally substituted and/or terminated by one or more substituents selected from halo and phenyl), optionally substituted phenyl, or R10a represents H; R1 l a and R11 independently represent, at each occurrence when used herein, H or C1-5 alkyl (optionally substituted and/or terminated by one or more substituents selected from halo and phenyl); A represents -G- or -J-N(R12)-; 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 R4 and
R5);
G represents a direct bond or C1-4 alkylene; J represents C2- alkylene; L represents C1-4 alkylene;
R represents phenyl, Het (both of which groups are optionally substituted by one or more substituents selected from cyano, halo, nitro, Cι- alkyl, Cι- alkoxy, optionally substituted phenyl, -N(H)R15b, -C(0)R15c, -C(0)N(H)R15f, -N(H)C(0)R15h, N(H)C(0)N(H)R15\ -N(H)S(0)2R14b -S(0)2R14c and -S(0)2N(R15n)R15p), or, when R4 and R5 together represent =0, R6 may represent .5 alkyl;
R2 represents -CN, Het8, -C(0)R16, -C(S)OR17, -C(S)N(H)R18, -[C(O)j2N(H)R20b, -[C(0)]2OR21, -S(0)2R22, -S(0)2N(R23)R24, -C(=N-CN)N(R25)R26, -C(=N-CN)OR27 or C1-6 alkyl (which alkyl group is optionally substituted and/or terminated by one or more substituents selected from -C(0)R28, -C(0)N(H)R29b, -N(R30)R31, -OR32, -S(0)2R33, halo, -CN, optionally substituted phenyl and Het9);
R16 represents optionally substituted phenyl, Het1 or Cι-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)R34 and optionally substituted phenyl); R34 represents, H, CM alkyl, -C(0)R36a or -C(0)OR36b; R18 represents H, -C(0)OR36b or Cι-6 alkyl (which alkyl group is optionally substituted and/or terminated by one or more substituents selected from halo and -C(0)OR 6b); R22 represents Het14, optionally substituted phenyl or Cι-4 alkyl (which alkyl group is optionally substituted and/or terminated by one or more substituents selected from halo, Het15 and optionally substituted phenyl); R23 represents H, C1-4 alkyl, -C(0)OR36b or -C(0)SR36b; R25 represents H or Cι-6 alkyl (which alkyl group is optionally substituted and/or terminated by one or more substituents selected from halo, -OH, C1-6 alkyl (which alkyl group is optionally substituted and/or terminated by one or more substituents selected from C1-4 alkyl and -OH), C1-4 alkoxy, naphthyl and optionally substituted phenyl); R represents optionally substituted phenyl;
R28 represents C1-5 alkyl, optionally substituted phenyl or Het17;
R29b represents H, C1-4 alkyl or optionally substituted phenyl;
R30 represents H, optionally substituted phenyl, -C(0)R37a or -C(0)OR37b;
R31 represents H, Cι-2 alkyl or optionally substituted phenyl; R32 represents H, C1- alkyl (which alkyl group is optionally interrupted by
91 oxygen), optionally substituted phenyl or Het ;
R33 represents C1-6 alkyl or optionally substituted phenyl;
R37a and R37b independently represent, at each occurrence when used herein,
C1-5 alkyl, optionally substituted phenyl, or R37a represents H; R3a and R3b independently represent H, C1-2 alkyl, -SR38b, -N(R39)R38c, or
R3a and R3b together represent C3- alkylene or -0-Z-0-;
R represents H, C1-2 alkyl or a structural fragment of formula la;
Z represents C2-3 alkylene;
R41 to R46 independently represent H or Cι-2 alkyl; R14b, R14c, R17 and R21 independently represent CM alkyl;
R15b to R15p, R20b, R24, R26, R38b and R38c independently represent H or C1-5 alkyl; optional substituents on phenyl groups are one or more substituents selected from cyano, halo, nitro, Cι-2 alkyl, Cι-2 alkoxy, Het1, -NH2, -C(0)R15c, -C(0)N(H)R15f, -N(H)C(0)R15h, -N(H)C(0)N(H)R15k, -N(H)S(0)2R14b and -S(0)2N(R15n)R15p.
When R3a and/or R3b represent(s) -N(R39)R38c in which R39 represents a structural fragment of formula la, preferred compounds of formula I include those in which, in that R group:
R4 represents H, -OR7 or N(H)R8, or R4, together with R5, represents =0;
R5 represents H, or R5, together with R4, represents =0;
R represents H, phenyl (which group is optionally substituted by one to three methoxy groups), -C(0)CH3, or -C(0)N(H)-C1-4 alkyl;
R8 represents H, -C(0)0-CM alkyl or -C(0)N(H)CH3;
A represents Cι-3 alkylene or -C2-3 alkylene-N(H)-;
B represents a direct bond, -CH2-, -CH2-N(H)-, -CH2-S(0)2-, -CH2-0- (in which latter, three groups, CH2 is attached to the carbon atom bearing R4 and R5) or -0-;
R6 represents phenyl optionally substituted by up to three substituents (in the para- and or ortho- positions) selected from cyano,
-N(H)C(0)N(H)CH3, -N(H)S(0)2CH3 and -S(0)2N(CH3)2.
More preferred compounds of the invention include those in which:
R4 represents H, -OR7 or N(H)R8, or R4, together with R5, represents =0;
R5 represents H, or R5, together with R4, represents =0;
R7 represents H, C1-2 alkyl, optionally substituted phenyl, -C(O)R10a, or
-C(0)N(Rl la)R1 !b; R8 represents H, C1-2 alkyl, -C(O)OR 1100b o _r_
Figure imgf000019_0001
R10a and R10b independently represent, at each occurrence when used herein, Ci-5 alkyl (optionally substituted or terminated by phenyl), optionally substituted phenyl, or R10a represents H; R a and R1 lb independently represent, at each occurrence when used herein, H or Cι-5 alkyl (optionally substituted or terminated by phenyl); A represents -G- or -J-N(R12)-;
B represents a direct bond, Cι-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 R4 and
R5); G represents a direct bond or C1- alkylene; J represents C2-4 alkylene; L represents C1- alkylene;
R6 represents phenyl or Het6 (which two groups are optionally substituted by one or more substituents selected from cyano, halo, Cι_2 alkyl, C1- alkoxy, -C(0)R15c, -N(H)C(0)R15h, -N(H)C(0)N(H)R15k, -N(H)S(0)2R14b, -S(0)2R14c and -S(0)2N(R15n)R15p).
9 99
When R represents -S(0)2R , more preferred compounds of the invention also include those in which: R4, together with R5, represents =0; A represents C1-4 alkylene;
B represents a direct bond or Cι-4 alkylene; R6 represents Cι-5 alkyl.
Further preferred compounds of the invention include those in which:
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;
R4 represents -D-OR7, -D-N(R8)R9, or R4, together with R5, represents =0;
R2 represents -CN, Het8, -C(0)R16, -C(S)OR17, -C(S)N(R18)R19, -[C(O)j2N(R 0a)R20b, -[C(0)]2OR21, -S(0)2R22, -S(0)2N(R23)R24,
-C(=N-CN)N(R25)R26, -C(=N-CN)OR27 or C 2 alkyl (which alkyl group is substituted and/or terminated by one or more substituents selected from
-C(0)R28, -C(0)N(R29a)R29b, -N(R30)R31, -OR32, -S(0)rR33, halo, -CN, nitro and Het ); R16 represents H, Het10 or C1-6 alkyl (which alkyl group is optionally substituted and/or terminated by one or more substituents selected from halo, -OH, -CN, -N(R34)R35, aryl and Het11);
R6 represents aryl, Het6 (both of which groups are substituted and/or terminated (as appropriate) by one or more substituents selected from -OH, cyano, halo, nitro, C1-6 alkyl (optionally terminated by -N(H)C(0)OR14a), C1-6 alkoxy, aryl, Het7, -N(R15a)R15b, -C(0)R15c, -C(0)OR15d, -C(0)N(R15e)R15f, -N(R15g)C(0)R15h, -N(R15i)C(0)N(R15j)R15k
-N(R15m)S(0)2R14b, -S(0)qR14c, -OS(0)2R14d and -S(0)2N(R15n)R15p) or, when R4 and R5 together represent =0, R may represent Cι-6 alkyl.
Preferred compounds of the invention include the compounds of the Examples disclosed hereinafter.
Preparation
According to the invention there is also provided a process for the preparation of compounds of formula I which comprises:
(a) reaction of a corresponding compound of formula II,
Figure imgf000021_0001
wherein R2, R3a, R3b and R41 to R46 are as hereinbefore defined, with a compound of formula III,
Figure imgf000022_0001
wherein L1 represents a leaving group (e.g. mesylate, tosylate or halo) and R4, R5, R6, 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 K2C03) and an appropriate organic solvent (e.g. dichloromethane, acetonitrile or DMSO);
(b) for compounds of formula I in which R1 represents a structural fragment of formula la in which A represents C2 alkylene and R4 and R5 together represent =0, reaction of a corresponding . compound of formula II, as hereinbefore defined, with a compound of formula IV,
Figure imgf000022_0002
wherein R and B are as hereinbefore defined, for example at room temperature in the presence of a suitable organic solvent (e.g. ethanol);
(c) for compounds of formula I in which R3a or R3b represents -N(R39)R38c- and R represents a structural fragment of formula la, reaction of a corresponding compound of formula I in which R3a or R (as appropriate) represents -N(H)R38c, wherein R38c is as hereinbefore defined, with a compound of formula III as hereinbefore defined, for example under conditions described hereinbefore (see process step (a));
(d) for compounds of formula I in which R represents a fragment of formula la in which A represents CH2 and R4 represents -OH or -N(H)R8, reaction of a corresponding compound of formula II, as hereinbefore defined, with a compound of formula V,
Figure imgf000023_0001
wherein X represents O or N(R ) and R , R , R and B are as hereinbefore defined, for example at elevated temperature (e.g. 60°C to reflux) in the presence of a suitable solvent (e.g. a lower alkyl alcohol (e.g. IP A), acetonitrile, or a mixture of a lower alkyl alcohol and water);
(e) for compounds of formula I in which R3a or R3 represents -N(R39)R38c and R39 represents a structural fragment of formula la in which A represents CH2 and R represents -OH or -N(H)R , reaction of a corresponding compound of formula I in which R3a or R (as appropriate) represents -N(H)R38c, wherein R38c is as hereinbefore defined, with a compound of formula V as hereinbefore defined, for example under conditions described hereinbefore (see process step (d));
(f) for compounds of formula I in which A represents C1-6 alkylene, B represents Cμ alkylene and R4 and R5 both represent H, reduction of a corresponding compound of formula I in which R4 and R5 together represent =0, in the presence of a suitable reducing agent and under appropriate reaction conditions, for example by activating the relevant C=0 group using an appropriate agent (such as tosylhydrazine) in the presence of a suitable reducing agent (e.g. sodium borohydride or sodium cyanoborohydride) and an appropriate organic solvent (e.g. a lower (e.g. C1-6) alkyl alcohol);
(g) for compounds of formula I in which R4 and R5 both represent H and (1)
1 9 A represents a single bond or -J-N(R ) and B represents Cj-4 alkylene, or (2) A represents C1-6 alkylene and B represents N(R13) or -N(R13)-L-, reduction of a corresponding compound of formula I in which R4 and R5 together represent =0, in the presence of a suitable reducing agent (e.g. LiAlH4) and an appropriate solvent (e.g. THF);
(h) for compounds of formula I in which A represents C1-6 alkylene, B represents a direct bond, CM alkylene, -L-N(R 13 )-, -L-S(0)p- or -L-O- (in which latter three groups L represents Cι-4 alkylene), R4 represents OH and R5 represents H, reduction of a corresponding compound of formula I in which R and R5 together represent =0, in the presence of a suitable reducing agent (e.g. NaBH ) and an appropriate organic solvent (e.g. THF);
(i) for compounds of formula I in which R3a and R3b both represent H, reduction of a corresponding compound of formula VI,
Figure imgf000024_0001
wherein R1, R2 and R41 to R46 are as hereinbefore defined, and in which the bridgehead C=0 group may be activated using an appropriate agent, such as tosylhydrazine, in the presence of a suitable reducing agent (e.g. sodium borohydride, sodium cyanoborohydride) and an appropriate organic solvent (e.g. a lower alkyl alcohol), or under standard Wolff-Kischner conditions known to those skilled in the art; when the C=0 group is activated, the activation step may be carried out at between room and reflux temperature in the presence of an appropriate organic solvent (e.g. a lower alkyl alcohol such as methanol, ethanol or IP A), whereafter 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);
(j) for compounds of formula I in which one of R3a and R3b represents H, and the other represents -OH, reduction of a corresponding compound of formula VI, as hereinbefore defined, in the presence of a mild reducing agent, e.g. sodium borohydride, and an appropriate organic solvent (e.g. a lower alcohol such as methanol or ethanol);
(k) for compounds of formula I in which R3a and R3b both represent -OR38a or -SR38b, or in which R3a and R3b together represent -0-Z-0-, -O-Z-S- or -S-Z-S-, reaction of a corresponding compound of formula VI, as hereinbefore defined, with a compound of formula HOR38a, HSR38b, HO-Z-OH, HO-Z-SH or HS-Z-SH (as appropriate), wherein R38a, R38b and Z are as hereinbefore defined, under appropriate reaction conditions, for example by refluxing in the presence of a suitable protic or Lewis acid catalyst (e.g. pTSA, trimefhylsilyl chloride or boron trifluoride) and an appropriate organic solvent (e.g. toluene or diethyl ether);
(1) for compounds of formula I in which one of R a and R represents -NH2 and the other represents H, reduction of a compound of formula VII,
Figure imgf000025_0001
wherein R1, R2 and R41 to R46 are as hereinbefore defined, in the presence of a suitable reducing agent (e.g. LiAlH4), for example under conditions that are well known to those skilled in the art;
(m) for compounds of formula I in which one or both of R3a and R3b represent -N(R39)R38c in which one or both of R39 and R38c represents Cι-6 alkyl, alkylation of a corresponding compound of formula I in which R3a and or R3b represent -N(R39)R38c (as appropriate) in which R39 and/or R38c
(as appropriate) represent H, using a compound of formula VIII,
Ra-L1 VIII wherein Ra represents C1-6 alkyl and L1 is as hereinbefore defined, for example under conditions that are well known to those skilled in the art;
(n) for compounds of formula I in which R1 represents a structural fragment of formula la in which B represents -L-0-, reaction of a compound of formula IX,
Figure imgf000026_0001
wherein R2, R3a, R3b, R4, R5, R41 to R46, A and L are as hereinbefore defined, with a compound of formula X,
R6OH 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);
(o) for compounds of formula I in which R1 represents a structural fragment of formula la in which A represents C1-6 alkylene and B represents -N(R13)-L- (wherein the group -N(R13)- is attached to the carbon atom bearing R4 and R5), reaction of a compound of formula XI,
Figure imgf000027_0001
wherein Aa represents C1-6 alkylene and R2, R3a, R3b, R4, R5, R13 and R41 to R46 are as hereinbefore defined with a compound of formula XII,
R6-L-L2 XII wherein L2 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);
(p) for compounds of formula I in which R1 represents a structural fragment of formula la in which R4 represents -D-NH2, reduction of a corresponding compound of formula XIII,
Figure imgf000028_0001
wherein R2, R3a, R3b, R5, R6, R41 to R46, A, B and D 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);
(q) for compounds of formula I in which R 4 represents -D-N(R9)C(0)NH(Rl lb), reaction of a corresponding compound of formula I in which R represents -D-N(R )H with a compound of formula XIV, RnbN=C=0 XIV wherein R is as hereinbefore defined, for example at ambient temperature (e.g. 25°C) in the presence of a suitable solvent (e.g. benzene);
(r) for compounds of formula I in which R4 represents -D-N(H)[C(0)j2NH2, reaction of a corresponding compound of formula I in which R4 represents -D-NH2 with oxalic acid diamide, for example at between -10 and 25°C in the presence of a suitable coupling agent (e.g. l-(3-dimethylaminoprόpyl)-3- ethylcarbodiimide), an appropriate activating agent (e.g. 1-hydroxybenzo- triazole), a suitable base (e.g. triethylamine) and a reaction-inert organic solvent (e.g. DMF); (s) for compounds of formula I in which R4 represents -D-N(R8)R9, wherein R8 and R9 are as hereinbefore defined, provided that R8 does not represent H, reaction of a corresponding compound of formula I, in which R4 represents -D-N(H)R9 with a compound of formula XV, R8a-L3 XV wherein R represents R as hereinbefore defined except that it does not represent H, and L represents a leaving group such as halo (e.g. chloro or bromo), ^-nitrophenolate, C1-4 alkoxide, C1-4 alkylfhiolate, -OC(O)R10a, -OC(O)OR10b, or -OS(O)2R10c, wherein R10a to R10c are as hereinbefore defined, for example under conditions that are well known to those skilled in the art;
(t) for compounds of formula I in which R4 represents -D-OR7 in which R7 represents C[-6 alkyl, -E-aryl or -E-Het , reaction of a corresponding compound of formula I in which R4 represents -D-OH with a compound of formula XVI,
R7aOH XVI wherein R7a represents C1- alkyl, -E-aryl or -E-Het1, wherein Het1 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)) ;
(u) for compounds of formula I in which R represents a structural fragment of formula la in which R4 represents -D-OR7 (in which R7 represents C[-6 alkyl, -E-aryl or -E-Het1), reaction of a corresponding compound of formula XVII,
Figure imgf000030_0001
wherein L2, R2, R3a, R3b, R5, R6, R41 to R , A, B and D are as hereinbefore defined with a compound of formula XVI as hereinbefore defined, for example at between ambient (e.g. 25°C) and reflux temperature, under Williams on- 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));
4 7 7
(v) for compounds of formula I in which R represents -D-OR , wherein R is as hereinbefore defined, provided that it does not represent H, reaction of a corresponding compound of formula I in which R4 represents -D-OH with a compound of formula XVIII,
R7b-L4 XVIII wherein R7b represents R7 as hereinbefore defined, except that it does not represent H, and L4 represents a leaving group such as OH, halo, alkane sulfonate, arene sulfonate or -OC(O)R10 , wherein R10a 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 CH2C12), a suitable base (e.g. triethylamine or K2C03) and/or an appropriate coupling agent (e.g. 1,3-dicyclohexylcarbodiimide or l-(3-dimethylaminopropyι)-3- ethylcarbodiimide, optionally combined with a suitable catalyst such as 4- dimethylaminopyridine) (for example, when R 7b represents -C(0)R 10a and 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);
(w) for compounds of formula I in which R4 represents halo, substitution of a corresponding compound of formula I in which R4 represents -OH, using an appropriate halogenating agent (e.g., for compounds in which R4 represents fluoro, reaction with diethylaminosulfurtrifluoride);
(x) reaction of a corresponding compound of formula XIX,
Figure imgf000031_0001
wherein R1, R3a, R3b and R41 to R46 are as hereinbefore defined, with a compound of formula XX,
R2-L5 XX wherein L5 represents a leaving group such as halo, OH, alkane sulfonate, arene sulfonate, C alkoxy, phenoxy, -OC(0)R16, -OC(0)OR21 or -OS(0)2R22, and R2, R16, R21 and R22 are as hereinbefore defined, for example at between -10°C and reflux temperature, optionally in the presence of a suitable solvent (e.g. CHC13, CH3CN, 2-propanol, diethyl ether, or mixtures thereof) and/or an appropriate base (e.g. K2C03, pyridine or triethylamine);
(y) for compounds of formula I in which R2 represent Cι-12 alkyl, which alkyl group is substituted at the C-2 carbon (relative to the bispidine nitrogen) with OH or N(H)R , and is otherwise optionally substituted with one or more further substituents as specified hereinbefore for R2, reaction of a compound of formula XIX as hereinbefore defined with a compound of formula XXA
Figure imgf000032_0001
wherein Xa represents O or N(R30) and R2a represents CMO 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));
(z). for compounds of formula I in which R represents tetrazol-5-yl, reaction of a corresponding compound of formula I in which R2 represents -CN with a suitable source of the azide ion (e.g. sodium azide), for example at elevated temperature (e.g. 100°C) in the presence of an appropriate solvent (e.g. DMF) and optionally in the presence of a suitable proton source (e.g. NH4CΪ);
(aa) for compounds of formula I which are bispidine-nitrogen N-oxide derivatives, oxidation of the corresponding bispidine nitrogen of a corresponding compound of formula I, in the presence of a suitable oxidising agent (e.g. CPBA), for example at 0°C in the presence of a suitable organic solvent (e.g. DCM);
(ab) for compounds of formula I which are CM alkyl quaternary ammonium salt derivatives, in which the alkyl group is attached to a bispidine nitrogen, reaction, at the bispidine nitrogen, of a corresponding compound of formula I with a compound of formula XXI,
Rb-L2 XXI wherein Rb represents C1-4 alkyl and L2 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. NH4OAc);
(ac) conversion of one substituent on R6 to another using techniques well known to those skilled in the art; or
(ad) conversion of one R2 group to another using techniques well known to those skilled in the art.
Compounds of formula II may be prepared by reaction of a corresponding compound of formula XXII,
Figure imgf000033_0001
wherein R3a, R3b and R41 to R46 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)).
Compounds of formula II in which R3a and R3b both represent H may be prepared by reduction of a corresponding compound of formula XXIII, XXIII
Figure imgf000034_0001
wherein R2 and R41 to R46 are as hereinbefore defined, and in which the C=0 group may be activated using an appropriate agent, such as tosylhydrazine, for example as described hereinbefore for the synthesis of compounds of formula I (process step (i)).
Compounds of formula II in which one of R3a and R3b represents -OH and the other represents C1- alkyl may be prepared by reaction of a compound of formula XXIII, or a protected derivative thereof, with a compound of formula XXIV,
Ralk-Mg-Hal XXIV wherein Ral represents C1-4 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).
Compounds of formula III may be prepared by standard techniques. For example compounds of formula III in which:
(1) B represents -L-O- may be prepared by coupling a compound of formula X, as hereinbefore defined, to a compound of formula XXV, L6-L-C(R4)(R5)-A-L1 XXV wherein L represents a suitable leaving group (e.g. halo) and R4, R5, A, L and L1 are as hereinbefore defined; or (2) B represents -N(R13)-L- and R4 and R5 together represent =0 may be prepared by coupling a compound of formula XXVI,
R6-L-N(R13)H XXVI wherein R , R and L are as hereinbefore defined, to a compound of formula XXVII,
L6-C(0)-A-L1 XXVII wherein L6, A and L1 are as hereinbefore defined;
in both cases, under conditions which are well known to those skilled in the art.
Compounds of formula III in which A represents C2-alkylene and R4
7 7 1 represents -OR , in which R represents Cι_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,
XXVIII
Figure imgf000035_0001
wherein Ry represents C ' alkyl or aryl (which two groups are optionally substituted with one or more substituents selected from C1-4 alkyl or halo) and R5, R6 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. K2C03) and an appropriate organic solvent (e.g. acetonitrile), followed by conversion of the ester functionality to an L1 group (in which L is as hereinbefore defined), under conditions that are well known to those skilled in the art. Compounds of formula III in which A represents C2-6 alkylene may be prepared by reduction of a corresponding compound of formula XXIX,
Figure imgf000036_0001
wherein Ab represents a direct bond or C1- alkylene, and R4, R5, R6 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 L1 group under conditions known to those skilled in the art.
Compounds of formula III in which A represents C2-6 alkylene and B represents -L-N(R13)- (wherein L represents CM alkylene) may be prepared by coupling a compound of formula XXX, R6-L6 XXX wherein R6 and L6 are as hereinbefore defined, with a compound of formula
XXXI,
HN(R13)-La-C(R4)(R5)-Ac-OH XXXI wherein La represents C1- alkylene, Ac represents C2-6 alkylene, and R4, R5 and R13 are as hereinbefore defined, for example at between room and reflux temperature, optionally in the presence of a suitable solvent and/or an appropriate base, followed by conversion of the OH group to an L1 group under conditions known to those skilled in the art.
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.
Compounds of formula V may be prepared in accordance with techniques which are known to those skilled in the art. For example, compounds of formula V in which:
(1) B represents -CH20- and X represents O may be prepared by reaction of a compound of formula X, as hereinbefore defined, with a compound of formula XXXII,
R5 A
\/ \ XXXII 2-^—o wherein 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. K2C03 or NaOH) and an appropriate organic solvent (e.g. acetonitrile or toluene/ water), or as otherwise described in the prior art;
(2) R5 represents H and X represents O may be prepared by reduction of a compound of formula XXXIII,
XXXIII
Figure imgf000037_0001
wherein R6 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. NaBH4) 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. K2C03) and an appropriate organic solvent (e.g. acetonitrile);
(3) B represents -L-, -L-N(R13)-, -L-S(0)2- or -L-O- (in all four of which groups L represents Cι- alkylene) and X represents O may be prepared by oxidation of a compound of formula XXXIV,
XXXIV
Figure imgf000038_0001
wherein Ba represents -L-, -L-N(R13)-, -L-S(0)2- or -L-O- (in all four of which groups L represents a single bond or C1-3 alkylene), and R , R and R13 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
(4) B represents -L-O- (in which group L represents C1-4 alkylene) and X , represents N(R8) (wherein R8 represents -C(O)OR10b or -S(O)2R10c) may be prepared by cyclisation of a compound of formula XXXV,
Figure imgf000038_0002
wherein R8b represents -C(O)OR10b or -S(O)2R10c and R5, R6, R10b, R10c, La and L2 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) . 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.g. methanol).
Compounds of formulae IX, XI, XIII and XVII may be prepared in a similar fashion to compounds of formula I (see, for example, process steps (a), (b) and (x)).
Compounds of formula XIII may alternatively be prepared by reaction of a corresponding compound of formula I in which R4 represents -D-OH, with a compound of formula XXXVI,
RyS(0)2Cl XXXVI wherein Ry 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. NaHC03).
Compounds of formula XVII may alternatively be prepared by replacement of the OH group of a compound of formula I in which R4 represents -D-OH with an L2 group under conditions that are well known to those skilled in the art.
Compounds of formula XIX may be prepared by reaction of a corresponding compound of formula XXII, as hereinbefore defined, with a compound of formula III, as hereinbefore defined.
Compounds of formula XIX in which A represents C2 alkylene and R4 and R together represent =0 may be prepared by reaction of a corresponding compound of formula XXII, as hereinbefore defined, 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 XIX in which A represents CH2 and R4 represents -OH or -N(H)R8 may be prepared by reaction of a corresponding compound of formula XXII, as hereinbefore defined, with a compound of formula V as hereinbefore defined, for example as described hereinbefore for synthesis of compounds of formula I (process step (d)).
Compounds of formula XIX in which R3a and R b both represent H may alternatively be prepared by reduction of a corresponding compound of formula XXXVII,
XXXVII
Figure imgf000040_0001
wherein R1 and R41 to R46 are as hereinbefore defined, and in which the C=0 group may be activated using an appropriate agent, such as tosylhydrazine, for example as described hereinbefore for the synthesis of compounds of formula I (process step (i)).
Compounds of formulae II and XIX in which one or more of R41, R42, R45 and/or R46 represent C1-3 alkyl may alternatively be prepared by reaction of a compound of formula II or XIX (as appropriate) in which R41, R42, R45 and/or R46 (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).
Compounds of formula XX in which R2 represents -C(=N-CN)N(R25)R26 and L5 represents phenoxy may be prepared by reaction of a corresponding compound of formula XXXVIII,
H-N(R25)R26 XXXVIII wherein R and R are - as hereinbefore defined, with diphenyl cyanocarbonimidoate, for example at between -10°C and room temperature in the presence of an appropriate solvent (e.g. isopropanol).
Compounds of formula XXII are known in the literature or are readily available using known techniques. For example, compounds of formula XXII in which R3a and R3b together represent C3-5 alkylene, -0-Z-0-, -O-Z-S- or -S-Z-S- and R41 to R46 all represent H, may be prepared by reduction of a compound of formula XXXIX,
XXXIX
Figure imgf000041_0001
wherein Rc and Rd together represent C3-5 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. LiAlH4) under conditions that are well known to those skilled in the art.
Compounds of formula XXIX in which B represents Cι-4 alkylene may be prepared by coupling a compound of formula XL,
Figure imgf000042_0001
wherein Bb represents C1-4 alkylene and Hal, Ab, R4 and R5 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 ZnBr2), an appropriate catalyst (e.g. Pd(PPh3)4) and a reaction-inert organic solvent (e.g. THF, toluene or diethyl ether).
Compounds of formulae VI, XXIII and XXXVII (in which, in all cases, R41 and R42 both represent H), may be prepared, advantageously, by reaction of (as appropriate) either (i) a compound of formula XLI,
Figure imgf000042_0002
wherein Rz represents Cι-10 alkyl or C1-3 alkylaryl (e.g. alkylphenyl, such as benzyl) and R43 to R46 are as hereinbefore defined, or (ii) 4-piperidone (or a protected derivative thereof), with (as appropriate) either (1) a compound of formula XLII,
R6-B-C(R4)(R5)-A-NH2 XLII wherein R4, R5, R6, A and B are as hereinbefore defined, or (2) NH3 (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)ORz group in the resultant intermediate to an R2 group using techniques such as those described herein (e.g. removal of the C(0)ORz group followed by carrying out a coupling, e.g. according to process step (x) above).
The formation of compounds of formulae VI, XXIII and XXXVII may be carried out in this way for example at between room temperature and reflux (depending upon the concentration of the reactahts) in the presence of an appropriate solvent (e.g. ethanol or methanol) and, preferably, in the presence of an organic acid (e.g. a Q-6 carboxylic acid, especially acetic acid).
It will be also appreciated by those skilled in the art that compounds of formula XXII in which R3a and R3b both represent H may also be prepared via this method (i.e. by reaction of a 4-piperidone (or a protected derivative thereof) with NH3 (or a protected derivative thereof) in the presence of a formaldehyde), provided that the intermediate so formed is subsequently reduced under appropriate reaction conditions.
The skilled person will also appreciate that this process may also be used to prepare compounds of formula I in which R45 and R are H, and R and/or R42 are other than H, for example by: (i) reacting a compound of formula XLI in which R45 and/or R46 is/are other than H with, for example, benzylamine or a derivative thereof; (ii) removal of the -C(0)ORz 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
(v) reaction at the free bispidine nitrogen of the resultant compound with a compound of formula XX as hereinbefore defined, under conditions well known to those skilled in the art including those described hereinbefore. This reaction will be accompanied by, at some point, conversion of the bridgehead carbonyl functionality to the desired R3a/R3b groups.
Compounds of formula XXXIX may be prepared in accordance with techniques which are well known to those skilled in the art. For example, compounds of formula XXXIX in which Rc and Rd together represent C3-5 alkylene may be prepared by reaction of a compound of formula XLIII,
XLIII
Figure imgf000044_0001
wherein Re and R together represent C3-5 alkylene, with a mixture of phosphoric acid and sulfuric acid, for example at 120°C.
Compounds of formula XLII are well known in the literature or are readily available using known techniques. For example, compounds of formula XLII in which R4 represents OH, R5 represents H and A represents CH2 may be prepared by reaction of a corresponding compound of formula V wherein R5 represents H and X represents 0 with ammonium hydroxide under conditions which are well known to those skilled in the art.
Compounds of formulae IV, VIII, X, XII, XIV, XV, XVI, XVIII, XX (in which R2 represents other than -C(=N-CN)N(R25)R26 and or L5 represents other than phenoxy), XXA, XXI, XXIV, XXV, XXVI, XXVII, XXVIII, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVIII, XL, XLI, XLIII and derivatives thereof, are either commercially available, are known in the literature, or may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from readily available starting materials using appropriate reagents and reaction conditions.
Substituents on the aryl (e.g. phenyl), and (if appropriate) 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 skilled person will also appreciate that various standard substituent or functional group interconversions and transformations within certain compounds of formula I will provide other compounds of formula I. For example, carbonyl may be reduced to hydroxy or alkylene, hydroxy may be acylated to give alkylcarbonyloxy, nitro may be reduced to amino, amido may be reduced to amino, amino may be sulfonated or acylated to give sulfonylamino or acylamino (respectively), and certain acyclic groups may be converted to certain heterocyclic groups under conditions known to those skilled in the art, for example as described in Comprehensive Heterocyclic Chemistry II, edited by AR Katritsky, CW Rees and EFV Scriven, 1st Edition, Elsevier Science Ltd., Volumes 1-11 (1996).
The compounds of the invention may be isolated from their reaction mixtures using conventional techniques.
It will be appreciated by those skilled in the art that, in the process described above, 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 C1- alkyl or benzyl esters.
The protection and deprotection of functional groups may take place before or after any of the reaction steps described hereinbefore.
Protecting groups may be removed in accordance with techniques which are well known to those skilled in the art and as described hereinafter.
The use of protecting groups is fully described in "Protective Groups in Organic Chemistry", edited by J.W.F. McOmie, Plenum Press (1973), and "Protective Groups in Organic Synthesis", 3rd edition, T.W. Greene & P.G.M. Wutz, Wiley-Interscience (1999).
Persons skilled in the art will appreciate that, in order to obtain compounds of the invention in an alternative, and, on some occasions, more convenient, manner, the individual process steps mentioned herein may be performed in a different order, and/or the individual reactions may be performed at a different stage in the overall route (i.e. substituents may be added to and/or chemical transformations performed upon, different intermediates to those associated hereinbefore with a particular reaction). This will depend inter alia on factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediates and the protecting group strategy (if any) to be adopted. Clearly, the type of chemistry involved will influence the choice of reagent that is used in the said synthetic steps, the need, and type, of protecting groups that are employed, and the sequence for accomplishing the synthesis.
It will also be appreciated by those skilled in the art that, although certain protected derivatives of compounds of formula I, which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, they may be administered parenterally or orally and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". Moreover, certain compounds of formula I may act as prodrugs of other compounds of formula I.
All prodrugs of compounds of formula I are included within the scope of the invention.
Some of the intermediates referred to hereinbefore are novel. According to a further aspect of the invention there is thus provided: (a) a compound of formula II, as hereinbefore defined, or a protected derivative thereof; (b) a compound of formula VI, as hereinbefore defined, or a protected derivative thereof; (c) a compound of formula VII, as hereinbefore defined, or a protected derivative thereof; (d) a compound of formula IX, as hereinbefore defined, or a protected derivative thereof; (e) a compound of formula XI, as hereinbefore defined, or a protected derivative thereof; (f) a compound of formula XIII, as hereinbefore defined, or a protected derivative thereof; (g) a compound of formula XVII, as hereinbefore defined, or a protected derivative thereof; (h) a compound of formula XIX, as hereinbefore defined (provided that at least one of R3a and R3b represents -N(R39)R38c, wherein R39 represents a structural fragment of formula la, as hereinbefore defined), or a protected derivative thereof; (i) a compound of formula XXII, as hereinbefore defined (provided that at least one of R3a and R3b represents -N(R39)R38c, wherein R39 represents a structural fragment of formula la, as hereinbefore defined), or a protected derivative thereof; and (j) a compound of formula XXIII, as hereinbefore defined, or a protected derivative thereof.
Compounds of formula II that may be mentioned include those in which: when R3a and R3b independently represent H, C1-4 alkyl, OH or N(R39)R38c; and
R39 represents H or C1-6 alkyl; then R does not represent: (i) CN; (ii) C1-6 alkyl optionally substituted by OH, N(R30)R31 or Het9; wherein
R30 and R31 independently represent H, C1-6 alkyl or C3-8 cycloalkyl); and
Het9 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);
(iii) C1-6 n-alkyl, which alkyl group is optionally interrupted by 0 and is terminated by N(R30)R31 or OR32; wherein one of R30 and R31 represents H or phenyl substituted in the meta- or ?αrα-position (relative to the point of attachment) by C02H or NH2 and the other represents H or Cι-6 alkyl; and
R represents H or phenyl substituted in the meta- or flra-position
(relative to the point of attachment) by C02H or NH2;
-C(0)R16, wherein R16 represents H or phenyl substituted in the meta- or ?fl7-fl-position (relative to the point of attachment) by C02H or NH2; 99 99
(v) -S(0)2R , wherein R represents phenyl substituted in the meta- or /?fl -position (relative to the point of attachment) by C02H or NH2;
(vi) -S(0)2N(R23)R24; wherein
R represents phenyl substituted in the meta- or ?αra-position (relative to the point of attachment) by C02H or NH2; and
R represents H or C1-6 alkyl; and
(vii) C3-4 n-alkyl, which alkyl group is terminated by phenyl, which phenyl group is substituted in the meta- or αra-position (relative to the point of attachment) by C02H or NH2, and which alkyl group is interrupted at the β-position (relative to the point of attachment of the phenyl group) by O.
Compounds of formula II, IX and XI that may be mentioned include those in which: when R3a and R3b independently represent H, C1-4 alkyl, OH or N(R39)R38c; R39 represents H or C1-6 alkyl; and
R4 and R5 both represent H; then R2 does not represent CN, -C(0)R16, -S(0)2R22, -S(0)2N(R23)R2'
Cι-6 alkyl optionally substituted as defined hereinbefore in respect of R .
Further compounds of formulae II, IX and XI that may be mentioned include those in which:
R2 represents Het8, -C(0)R16, -C(S)OR17, -C(S)N(R18)R19, -[C(O)]2N(R20a)R20b, -[C(0)j2OR21, -S(0)2R22, -S(0)2N(R23)R24, -C(=N-CN)N(R25)R26, -C(=N-CN)OR27 or C1-12 alkyl (which alkyl group is substituted and/or terminated by one or more substituents selected from -C(0)R28, -C(0)N(R29a)R29b, -N(R30)R31, -OR32, -S(0)rR33, halo, -CN and nitro); R16 represents Het10 or C1-6 alkyl (which alkyl group is optionally substituted and/or terminated by one or more substituents selected from halo, -OH, -CN, -N(R34)R35, aryl and Het11);
R22 represents Het14 or C1-6 alkyl (which alkyl group is optionally, substituted and/or terminated by one or more substituents selected from halo, -OH, -CN, Het15 and aryl);
R23 represents H, C1-6 alkyl, Het16, -C(0)R36a, -C(0)OR36b or -C(0)SR36b; R30 represents Het19, -C(0)R37a, -C(0)OR37b or -C(0)N(R37c)R37d; R32 represents C1-6 alkyl, Het21, -C(0)R37a, -C(0)OR37b or -C(0)N(R37c)R37d.
Medical and pharmaceutical use
The compounds of the invention are useful because they possess pharmacological activity. They are therefore indicated as pharmaceuticals.
Thus, according to a further aspect of the invention there is provided the compounds of the invention for use as pharmaceuticals.
In particular, 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.
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.
According to a further aspect of the invention, there is provided 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.
Pharmaceutical preparations
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. Depending upon the disorder and patient to be treated, as well as the route of administration, 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. According to a further aspect of the invention there is thus provided 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.
Biological Tests
Test A Primary Electrophysiological Effects In Anaesthetised Guinea Pigs
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. In order to reduce autonomic influences 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)).
The 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.
Data analysis
Of the numerous variables measured in this analysis, three were selected as the most important for comparison and selection of active compounds. 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). 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 moφhological 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) .
Test B
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 DiBac4(3), which could be reliably detected using a fluorescence laser imaging plate reader (FLIPR). Expression of a delayed rectifier potassium channel was induced in mouse fibroblasts by 24 hours exposure to the glucocorticoide dexamehasone (5 μM). Blockade of these potassium channels depolarised the fibroblasts, resulting in increased fluorescence of DiBac4(3).
Mouse ltk fibroblasts (L-cells) 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 μg/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. The fluorescence probe DiBac4(3) (DiBac Molecular probes) was used to measure membrane potential. DiBac (3) maximally absorbs at 488 nM and emits at 513 nM. DiBac4(3) is a bisoxonol, and thus is negatively charged at pH 7. Due to its negative charge, the distribution of DiBac4(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 DiBac4(3) concentration inside the cell increases, due to electrostatic forces. Once inside the cell, DiBac4(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 DiBac4(3) fluorescence. The change in DiBac4(3) fluorescence was detected by a FLIPR.
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 μM DiBac4(3) (in 180 μL of PBS) at 35°C. Once a stable fluorescence was reached (usually after 10 min), 20 μL 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
DiBac4(3) fluorescence. Test substances were prepared in a second 96 well plate, in PBS containing 5 μM DiBac4(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 μM) was used as a positive control, i.e. to determine the maximum increase in fluorescence. Curve-fitting, used to determine the IC50 values, was performed with the Graphpad Prism program (Graphpad Software Inc., San Diego, CA).
Test C Metabolic Stability of Test Compounds
An in vitro screen was set up to determine the metabolic stability of the compounds of the invention.
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 μM of test compound.
The reaction 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).
The percentage of test compound remaining after 30 minutes (and thus t^) was calculated and used as a measure for metabolic stability.
The invention is illustrated by way of the following examples.
Examples
General Experimental Procedures
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)). 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. Alternatively, 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 inteφretation of spectra. Unless otherwise stated, chemical shifts are given in ppm with the solvent as internal standard.
Example 1 tert-Butyl 2-{7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo- [3.3.1 ]non-3-yl} ethylcarbamate
(i) tert-Butyl 2-bromoefhylcarbamate A mixture of 2-bromoethylamine hydrobromide (10.0 g, 0.049 mol), NaOH (1.84 g, 0.046 mol), water (50 mL) and THF (200 mL) was cooled to 0°C. Di-tert-butyl dicarbonate (10.1 g, 0.046 mol) was added slowly to the mixture, which was then stirred at it overnight. The mixture was concentrated in vacuo and the residue dissolved in DCM. This organic solution was washed with water and purified by chromatography on silica, eluting with DCM, to give 5.6 g (50%) of the title compound.
(ii) 4-[3-(3,7-Diazabicyclo[3.3.1jnon-3-yl)-2-hydroxypropoxyjbenzonitrile HCl-saturated EtOAc (600 mL) was added to a solution of tert-butyl 7-[3- (4-cyanophenoxy)-2-hydroxypropylj-3,7-diazabicyclo[3.3.1jnonane-3- carboxylate (62 g; see Example 2 of international patent application No. PCT/SE98/02276) in EtOAc (600 mL) and the mixture was stirred at rt. for 4 h. The solvent was removed under reduced pressure, the residue was dissolved in MeCN (1.3 L) and K2C03 (100 g) was added. The suspension was stirred for 12 h and filtered. Concentration of the filtrate gave the title compound in a 90% yield.
13C NMR (CDC13) : δ 28.9, 29.2, 32.3, 50.9, 57.7, 60.8, 62.1, 66.0, 71.2, 104.0, 115.3, 119.1, 133.9, 162.1.
(iii) tert-Butyl 2- {7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diaza- bicyclo[3.3.1 jnon-3-yl) ethylcarbamate
4-[3-(3,7-Diazabicyclo[3.3.1]non-3-yl)-2-hydroxypropoxy]benzonitrile (see step (ii) above; 7.7 g, 25.6 mmol) and tert-butyl 2-bromoethylcarbamate (see step (i) above; 5.7 g, 2.56 mmol) and K2C03 (3.5 g, 2.56 mmol) were mixed in CH3CN (50 mL) and stirred at 60°C for 60 h. The reaction mixture was filtered and evaporated. The residue was purified using column chromatography (DCM: 10-20% MeOH saturated with NH3 (g)), to yield 8 g (71%) of the title compound. 13C NMR (CDCI3) : δ 28.4, 29.6, 30.3, 32.0, 36.9, 54.8, 58.4, 58.6, 59.5, 64.8, 71.1, 78.8, 104.1, 115.3, 119.2, 133.9, 156.4, 162.2. FAB-MS (M+l)+ = 445 (m/z)
Example 2
4-{3-[7-(3,3-Dimethyl-2-oxobutyl)-3,7-diazabicyclo[3.3.1jnon-3-ylj-2- hydroxypropoxy}benzonitrile
4-[3-(3,7-Diazabicyclo[3.3.1]non-3-yl)-2-hydroxypropoxyjbenzonitrile (see Example 1 (ii) above; 0.6 g, 2.0 mmol) and 1-chloropinacolone (0.27 g, 2.0 mmol) and K2C03 (0.27 g, 20 mmol) were mixed in CH3CN and stirred at 60°C for 1 h, and then at r.t. overnight. The reaction mixture was filtered and evaporated, giving 0.7 g (90%) of the title compound. 13C NMR (CDC13) : δ 26.2, 30.0, 30.6, 31.9, 43.5, 55.1, 57.3, 57.6, 59.2, 59.8, 61.7, 64.8, 71.1, 103.9, 115.3, 119.2, 133.9, 162.3, 212.2. FAB-MS (M+l)+ = 400 (m z)
Example 3
4-{3-r7-(2-Ethyl-2H-l,2,3,4-tetrazol-5-yl)-3,7-diazabicyclor3.3.1jnon-3- yl j -2-hy droxypropoxy } benzonitrile
(i) 3,7-Dibenzyl-3,7-diazabicyclo[3.3.1jnonane-9-one
The sub-title compound was prepared according to the procedure described in J. Org. Chem., 41(9), 1976, pp. 1593-1597.
(ii) 3,7-Dibenzyl-3,7-diazabicyclo[3.3.1 jnonane
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.
(iii) 3-Benzyl-3,7-diazabicyclo[3.3.1]nonane
A solution of 3,7-dibenzyl-3,7-diazabicyclo[3.3.1jnonane (see step (ii) above; 97 g, 6.4 mmol) in aqueous ethanol (95%) was hydrogenated over 5% Pd/C at 1 atm. until tic indicated that the reaction was complete. The catalyst was removed by filtration through a pad of Celite®, and the filtrate concentrated under reduced pressure to give the sub-title compound in quantitative yield.
13C ΝMR (CDCI3) : δ 30.1, 33.4, 36.0, 52.5, 59.6, 64.3, 126.9, 128.3, 128.7, 138.8 (iv) 3-Benzyl-7-cyano-3 ,7-diazabicyclo[3.3.1 jnonane 3-Benzyl-3,7-diazabicyclo[3.3.1jnonane (see step (iii) above; 20 g, 92 mmol) was dissolved in ether (120 mL). Cyanogen bromide (9.8 g, 92 mmol) dissolved in ether (80 mL) was added dropwise at 0°C. The * mixture was stirred at 0°C for 15 minutes, and then at r.t. overnight, after which a white precipitate formed. The ether was evaporated. Water and a saturated Na2C03 (aq) solution were added. The mixture was extracted with ether. The ether layer was separated and dried (MgS0 ), giving 20.3 g (91%) of the sub-title compound.
(v) 3-Benzyl-7-(2H-l,2,3,4-tetrazol-5-yl)-3,7-diazabicyclo[3.3.1]nonane, ammonium salt
A mixture of 3-benzyl-7-cyano-3,7-diazabicyclo[3.3.1jnonane (see step (iv) above; 10.2 g, 42 mmol), NaN3 (2.92 g, 45 mmol), NH4C1 (2.41 g, 45 mmol) and DMF (50 mL) was stirred at 100°C for 22 h. DMF was evaporated, toluene was added and evaporated, which resulted in 12 g of an orange-coloured powder. The product was purified by preparative reversed phase HPLC, giving 5.8 g (46%) of the sub-title compound.
(vi) 3-Benzyl-7-(2-ethyl-2H-l ,2,3,4-tetrazol-5-yl)-3,7-diazabicyclo[3.3.1]- nonane
A mixture of 3-benzyl-7-(2H-l,2,3,4-tetrazol-5-yl)-3,7-diazabicyclo- [3.3.1 jnonane, ammonium salt (see step (v) above; 4 g, 13 mmol), ethyl iodide (2.20 mL, 26 mmol) and NaOH (0.62 g, 15.6 mmol ) was refluxed for 2 h. The solvent was evaporated and the residue purified by flash chromatography (hexane:ethyl acetate (1 : 1), MeOH (NH3) 0-32%), giving 1.5 g (37%>) of the sub-title compound. (vii) 3-(2-Ethyl-2H-l,2,3,4-tetrazol-5-yl)-3,7-diazabicyclo[3.3.1 jnonane 3-Benzyl-7-(2-ethyl-2H-l,2,3,4-tetrazol-5-yl)-3,7-diazabicyclo[3.3.1j- nonane (see step (vi) above; 0.5 g, 1.6 mmol) dissolved in ethanol (5 mL of 95%) was hydrogenated over 5% Pd/C at 1 atm overnight. The catalyst was filtered over a pad of Celite®, and the residue was evaporated to give 0.2 g (56%) of the sub-title compound.
(viii) 4-{3-[7-(2-Ethyl-2H-l,2,3,4-tetrazol-5-yl)-3,7-diazabicyclor3.3.11- non-3-ylj-2-hydroxypropoxy}benzonitrile 4-(2-Oxiranylmethoxy)benzonitrile (see international patent application WO 99/31100; 0.18 g, 1 mmol) and 3-(2-ethyl-2H-l,2,3,4-tetrazol-5-yl)- 3,7-diazabicyclo[3.3.1]nonane (see step (vii) above; 0.2 g, 0.9 mmol) were mixed in isopropanol:Η20 (1.1 mL of 10: 1) and the mixture was stirred at 60°C overnight. The solvent was evaporated and the residue was purified by chromatography (hexane:ethyl acetate (1:1), MeOH (NH3) 0-32%), giving 0.28 g (77%) of the title compound.
13C NMR (CD3CN) : δ 14.4, 29.7, 30.0, 31.2, 48.6, 51.2, 51.3, 58.6, 60.8, 61.0, 66.3, 71.9, 104.3, 116.2, 118.2, 119.9, 134.9, 163.3, 170.1.
Example 4
4-{2-Hydroxy-3-[7-(l,3-thiazol-2-yl)-3,7-diazabicyclor3.3.1jnon-3-ylj- propoxy}benzonitrile
4-[3-(3,7-Diazabicyclo[3.3.1]non-3-yl)-2-hydroxyρropoxy]benzonitrile (see Example 1 (ii) above; 1 g, 3.3 mmol) 2-bromofhiazole (0.54 g, 3.3 mmol) and K2C03 (0.91 g, 6.5 mmol) were mixed in DMF (15 mL). The mixture was stirred overnight at 60°C. The solvent was evaporated, toluene was added and then evaporated. The residue was dissolved in ethyl acetate and washed with NaOH solution (2 M). The organic layer was separated and dried (Na2S04). The residue was purified by chromatography (hexane:ethyl acetate (1 : 1)). Yield: 0.57 g (45%). 13C NMR (CDCI3) : δ 29.1, 29.4, 30.5, 52.8, 53.0, 57.9, 60.7, 65.3, 70.4, 104.1, 105.6, 115.3, 119.2, 133.9, 139.7, 162.0, 171.2.
Example 5 N,-Cyano-7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N-(3,4,5-trimethoxy- benzyl)-3,7-diazabicyclo[3.3.1jnonane-3-carboximidamide
(i) Phenyl 7Λp-cyano-N-(3,4,5-trimethoxybenzyl)carbamimidoate 3,4,5-Trimethoxybenzylamine (1.08 mL, 6.3 mmol) was dissolved in isopropanol (10 mL). The mixture was cooled to 0°C before diphenyl cyanocarbonimidoate (1.5 g, 6.3 mmol) was added in portions. The reaction mixture was allowed to reach r.t. and then stirred overnight at that temperature. The precipitate that formed was filtered off and was then purified by chromatography DCM:MeOH (gradient 100:0 to 99:1). Yield: 1.37 g (63.5%)
(ii) N,-Cyano-7-[3-(4-cyanophenoxy)-2-hydroxypropylj-N-(3,4,5-tri- methoxybenzyl)-3,7-diazabicyclo[3.3.1jnonane-3-carboximidamide
4-[3-(3,7-Diazabicyclo[3.3.1jnon-3-yl)-2-hydroxyproρoxy]benzonitrile (see Example l(ii) above; 1 g, 3.3 mmol) and phenyl N'-cyano-N-(3,4,5- trimethoxybenzyl)carbamimidoate (see step (i) above; 1.13 g, 3.3 mmol) were mixed with isopropanol (15 mL) and then stirred at reflux for 3 h. The mixture was cooled to r.t. and the product that formed was filtered off. The product was purified by chromatography (DCM:MeOH (gradient 0 to 1%), giving 1.67 g (92%) of the title compound.
13C ΝMR (CDCI3) : δ 29.0, 29.3, 31.2, 47.9, 50.9, 51.3, 56.1, 57.1 , 60.0, 60.7, 61.3, 65.6, 70.6, 103.9, 105.1, 115.2, 118.3, 119.1, 133.2, 133.9, 137.4, 153.3, 160.2, 161.9, 176.3, 176.4. Example 6
4-{3-Amino-4-[7-(butylsulfonyl)-3,7-diazabicyclo[3.3.1jnon-3-yl]butoxy}- benzonitrile
(i) 4-(3 -Buteny loxy )benzonitrile
4-Cyanoρhenol (30 g, 250 mmol) was mixed with K2C03 (72.5 g, 525 mmol) and stirred for 60 min. 4-Bromo- 1-butene (50 g, 370 mmol) was added dropwise, and then the reaction mixture was stirred at 60°C overnight. The solids were filtered of and then the solvents were evaporated. The residue was dissolved in DCM and washed with 1 N ΝaOH. The organic layer was separated, dried (Νa2S04) and evaporated, giving 37 g (58 %) of the sub-title compound.
(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 NaHC03, then separated, dried and evaporated to give 38.7 g (97%) of the sub-title compound.
(iii) 4-(4-Amino-3-hydroxybutoxy)benzonitrile
4-[2-(2-Oxiranyl)ethoxyjbenzonitrile (see step (ii) above; 38.5 g, 204 mmol) was mixed with aqueous NH3 (1200 mL, cone.) and isopropanol (450 mL). The mixture was stirred at r.t. for 24 h. The solid (by-product) was filtered off, and the solvents were evaporated, giving 39.1 g (93%) of the sub-title compound. (iv) tert-Butyl 4-(4-cyanophenoxy)-2-hydroxybutylcarbamate 4-(4-Amino-3-hydroxybutoxy)benzonitrile (see step (iii) above; 34.3 g, 166 mmol) was dissolved in THF:H20 (600 mL of 8:2). Di-tert-butyl dicarbonate (36.3 g, 166 mmol) was added at 0°C. The mixture was then stirred at r.t. overnight before being evaporated to give 50 g (100%) of the sub-title compound (which was used in the next step without further purification).
(v) 1 - { [(tert-Butoxycarbonyl)aminojmethyl} -3-(4-cyanophenoxy)propyl methanesulfonate tert-Butyl 4-(4-cyanophenoxy)-2-hydroxybutylcarbamate (see step (iv) above; 38.1 g, 120 mmol) and 4-(dimethylamino)pyridine (10 mol%) were dissolved in pyridine (200 mL). The mixture was cooled to 0°C. Methanesulfonyl chloride (10.7 mL, 0.136 mol) was then added dropwise at 0°C. The mixture was allowed to reach r.t. before the pyridine was evaporated. DCM was added and the solution was washed with 2 M HC1 and water before being dried and evaporated. The compound was purified by chromatography on silica, eluting with DCM (5% ethyl acetate), to give 27 g of the sub-title compound.
(vi) tert-Butyl 2-[2-(4-cyanophenoxy)ethylj- 1 -aziridinecarboxylate 1 - { [(tert-Butoxycarbonyl)aminojmethyl} -3-(4-cyanophenoxy)propyl methanesulfonate (see step (v) above; 25.3 g, 0.066 mol) was mixed with tetrabutylammonium hydrogen sulphate (2.7 g; 7.8 mmol) and DCM (170 mL). The mixture was cooled to 0°C and NaOH (50% (aq)) was added slowly. The mixture was then allowed to reach r.t. before water and DCM were added. The organic layer was separated, washed with water, dried and then evaporated to give the sub-title compound. Yield: 19 g (99%). The product was used in the next step without further purification. (vii) 3-Benzyl-7-(butylsulfonyl)-3,7-diazabicyclo[3.3.1 jnonane Butanesulfonyl chloride was added dropwise at 0°C to a mixture of 3- benzyl-3,7-diazabicyclo[3.3.1 jnonane (see Example 3(iii) above; 13 g, 60 mmol), K2C03 (60 mmol) and MeCN (100 mL). The mixture was allowed to reach r.t. and was then stirred overnight at r.t. The reaction mixture was filtered through a plug of silica, which was then eluted with ethyl acetate to give 15 g (75%) of the sub-title compound.
(viii) 3-(Butylsulfonyι)-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 H20 (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.
(ix) tert-Butyl 1 - { [7-(butylsulfonyl)-3,7-diazabicyclo[3.3.1 jnon-3-ylj- methyl}-3-(4-cyanophenoxy)ρropylcarbamate tert-Butyl 2-[2-(4-cyanophenoxy)ethylj-l-aziridinecarboxylate (see step (vi) above; 1 g, 3.5 mmol) was mixed with 3-(butylsulfonyl)-3,7- diazabicyclo [3.3.1 jnonane (see step (viii) above; 0.85 g, 3.5 mmol) in isopropanol (25 mL). The mixture was stirred at 60°C overnight. Evaporation and purification of the residue on silica (DCM, 2% MeOH) gave 1.5 g (81 %) of the sub-title compound.
Η NMR (CDCI3) : δ 1.44 (3H, t), 1.91 (9H, s), 2.08 (2H, m), 2.1 (2H, m), 2.2 (2H, m), 2.4 (2H, s (broad)), 2.6 (2H, m), 2.8 (2H, d), 2.9 (2H, dd), 3.3- 3.6 (6H, m), 4.3 (3H, m), 4.6 (2H, m), 5.7 (1H, s (broad)), 7.4 (2H, dd), 8.0 (2H, dd).
(x) 4- { 3 - Amino-4- [7-(butylsulfonyl)-3 ,7-diazabicyclo [3.3.1 ]non-3 -ylj- butoxy } benzonitrile tert-Butyl 1 - { [7-(butylsulfonyl)-3,7-diazabicyclo[3.3. l]non-3-yljmethyl} -3- (4-cyanophenoxy)propylcarbamate (see step (ix) above; 0.9 g,
1.7 mmol) was dissolved in ethyl acetate (20 mL). Ethyl acetate saturated with HC1 (g) (50 mL) was added at 0°C. The resulting mixture was allowed to reach r.t. for 2 h. The solvent was evaporated and the resulting residue was dissolved in water to give a solution that was freeze-dried. This gave the dihydrochloride salt of the title compound. ES-MS (M + H)+ = 435 (m/z)
Example 7
The compounds listed below were prepared either in accordance with, or analogously to, methods described herein, or were otherwise prepared according to the following procedure: The appropriate 3- or 7-unsubstituted bispidine (dissolved in CHC13) was reacted with 2 eq. of the appropriate electrophile (dissolved in CH3CN) in the presence of a base (2.5 eq. of K2C03). The reaction mixtures were warmed to 50-100°C. When the reaction was ready (as determined by mass spectral analysis), the inorganic salts were filtered off and the reaction mixture was added to an ion exchange solid phase extraction plug (CBA). The plug was washed with CHC13 and the product was finally eluted with CHCl3:MeOH:Et3N (8: 1 : 1). The products were analysed by HPLC and MS. Compounds with a purity less then 90% were purified by preparative HPLC.
Mass spectra of the compounds, where recorded, are in brackets: 4-(3- {7-[3-(4-cyanophenoxy)-2-hydroxypropylj-3,7-diazabicyclo[3.3.1]- non-3-yl} -2-hydroxypropoxy)benzonitrile;
4-(3-{7-[3-(4-cyanophenoxy)-2-hydroxypropylj-9-(l,2-ethylenedioxy)-3,7- diazabicyclo[3.3. l]non-3-yl} -2-hydroxypropoxy)benzonitrile; 4- { 3 - [7- [3 -(4-cyanophenoxy)-2-hydroxypropylj -9,9-bis(propylsulfanyl)-
3,7-diazabicyclo[3.3.1]non-3-ylj-2-hydroxypropoxy}benzonitrile;
3 ,7-bis(4-nitrophenethyl)-3 ,7-diazabicyclo[3.3.1 jnonane;
4-(3-{7-[3-(4-cyanophenoxy)-2-hydroxypropylj-9,9-tetramethylene-3,7- diazabicyclo[3.3. l]non-3-yl} -2-hydroxypropoxy)benzonitrile; 4-{2-[7-(4-cyanophenethyl)-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}benzo- nitrile;
N- {4-[(7- {4-[(methylsulfonyl)amino]benzyl} -3 ,7-diazabicyclo[3.3.1 jnon-3- yl)methyl]phenyl}methanesulfonamide;
4-cyano-N-[2-(7- {2-[(4-cyanobenzoyl)amino]ethyl} -3 ,7-diazabicyclo- [3.3.1 jnon-3-yl)ethyljbenzamide;
4-(2- {7-[2-(4-cyanophenyl)-2-hydroxyethyl]-3 ,7-diazabicyclo[3.3.1 ] non-3 - yl} - 1 -hydroxyethyl)benzonitrile;
4-{3-[(3,7-dibenzyl-3,7-diazabicyclo[3.3.1jnon-9-yl)(methyl)aminoj-2- hy droxypropoxy } b enzonitrile ; 2- [(7- { [6-cy ano-4-(methylsulfonyl)-3 ,4-dihy dro-2H- 1 ,4-benzoxazin-2-yl j - methyl} -3,7-diazabicyclo[3.3.1 jnon-3-yl)methylj-4-(methylsulfonyl)-3 ,4- dihy dro-2H- 1 ,4-benzoxazine-6-carbonitrile;
4-[2-hydroxy-3-(7-methyl-3 ,7-diazabicyclo[3.3.1 ]non-3-yl)propoxyjbenzo- nitrile; 2-[(7-methyl-3,7-diazabicyclo[3.3.1]non-3-yl)methyl]-4-(methylsulfonyl)-
3 ,4-dihydro-2H- 1 ,4-benzoxazine-6-carbonitrile;
4-[3-(7-benzyl-3,7-diazabicyclo[3.3.1jnon-3-yl)-2-hydroxypropoxyjbenzo- nitrile;
4- { 2-hydroxy-3 - [7-(4-oxoheptyl)-3 ,7-diazabicy clo [3.3.1 jnon-3 -yl j - propoxyjbenzonitrile; 4-[((2R)-3-{7-[(2R)-3-(4-cyanophenoxy)-2-hydroxypropylj-3,7-diaza- bicyclo[3.3.1 ]non-3 -yl} -2-hydroxypropyl)oxy]benzonitrile;
4-[((2S)-3-{7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diaza- bicyclo[3.3.1]non-3-yl}-2-hydroxypropyl)oxy]benzonitrile; 4-[3-(7-butyryl-3,7-diazabicyclo[3.3.1jnon-3-yl)-2-hydroxypropoxyj- benzonitrile;
4-{3-[7-(ethylsulfonyl)-3,7-diazabicyclo[3.3.1jnon-3-yl]-2-hydroxy- propoxy}benzonitrile;
4-[((2S)-3-{7-[(2R)-3-(4-cyanoρhenoxy)-2-hydroxyρropyl]-3,7-diaza- bicyclo[3.3. l]non-3-yl}-2-hydroxyproρyl)oxy]benzonitrile;
4-{[(2S)-2-hydroxy-3-(7-propionyl-3,7-diazabicyclo[3.3.1]non-3-yl)- propyl] oxy } benzonitrile;
4-{[(2R)-2-hydroxy-3-(7-propionyl-3,7-diazabicyclo[3.3.1]non-3-yl)- propyl] oxy } benzonitrile; 2-{7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo[3.3.1]- non-3 -yl} -N-ethyl-2-oxoacetamide;
2- {7-[(2R)-3-(4-cyanophenoxy)-2-hydroxypropyl]-3 ,7-diazabicyclo[3.3.1]- non-3 -yl} -N-ethyl-2-oxoacetamide; tert-butyl (lS)-2-(7-benzyl-3,7-diazabicyclo[3.3.1]non-3-yl)-l-[(4-cyano- phenoxy)methyl]ethylcarbamate; tert-butyl (lS)-2-(4-cyanophenoxy)-l-({7-[(ethylamino)carbothioyl]-3,7- diazabicyclo[3.3.1 ]non-3-yl} methyl)ethylcarbamate;
7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-N-ethyl-3,7-diazabicyclo-
[3.3.1 ]nonane-3-carbothioamide; tert-butyl (lS)-l-({7-[(2S)-3-(4-cyanophenoxy)-2-hydroxyproρyl]-3,7- diazabicyclo[3.3. l]non-3-yl} carbonyl)-2-methylpropylcarbamate;
2-(4-cyanophenoxy)- 1 - { [7-(ethylsulfonyl)-3 ,7-diazabicyclo[3.3.1 ]non-3- yljmethyl} ethyl tert-butylcarbamate;
4-[((2S)-3-{7-[(2S -2-amino-3-methylbutanoyl]-3,7-diazabicyclo[3.3.1]- non-3-yl} -2-hydroxypropyl)oxy]benzonitrile; 4-{[(2S)-2-hydroxy-3-(7-{[(2S)-5-oxoρyrrolidinyl]carbonyl}-3,7-diaza- bicyclo[3.3.1 ]non-3 -yl)propyl]oxy} benzonitrile;
N-(5-cyano-2-{3-[7-(ethylsulfonyl)-3,7-diazabicyclo[3.3.1]non-3-yl]-2- hydroxypropoxy } phenyl)-N-ethylurea; N-(2- {2-amino-3-[7-(ethylsulfonyl)-3,7-diazabicyclo[3.3. l]non-3-yl]- propoxy } -5-cyanoρhenyl)-N-ethylurea;
4-{3-[7-(3,3-dimethylbutanoyl)-3,7-diazabicyclo[3.3.1]non-3-yl]-2- hydroxypropoxy } benzonitrile;
N-(2- {7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3 ,7-diazabicyclo[3.3.1 ]- non-3-yl} -2-oxoethyl)acetamide; tert-butyl (lS)-2-{7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7- diazabicyclo[3.3.1 ]non-3-yl} -1 -(4-methoxybenzyl)-2-oxoethylcarbamate;
4-[((2S)-3-{7-[(2S)-2-amino-3-(4-methoxyphenyl)propanpyl]-3,7-diaza- bicyclo[3.3.1 ]non-3-yl} -2-hydroxypropyl)oxy]benzonitrile; 2-{7-[3-(4-cyanophenoxy)-2-hydroxypropyι]-3,7-diazabicyclo[3.3.1]non-3- yl}-N-(2,6-dimethylphenyl)acetamide (m/z - 463); tert-butyl 2-{7-[3-(4-cyanophenoxy)-2-hydroxyρropyl]-3,7-diazabicyclo-
[3.3.1 ]non-3-yl} -2-oxoethylcarbamate (m/z = 344);
4- {3-[7-(2-aminoethyl)-3,7-diazabicyclo[3.3. l]non-3-yl]-2-hydroxy- propoxy} benzonitrile (m/z =345);
N-(2-{7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo[3.3.1]- non-3-yl} ethyl)-4-nitrobenzamide (m/z = 494); 4-amino-N=-(2- {7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3 ,7-diazabicyclo-
[3.3.1]non-3-yl}ethyl)benzamide (m/z = 464); N-(2-{7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo[3.3.1]- non-3-yl}ethyl)-4-[(methylsulfonyl)amino]benzamide (m/z =542);
4-(acetylamino)-N-(2-{7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7- diazabicyclo[3.3.1]non-3-yl}ethyl)benzamide (m/z = 506);
2-[7-(2- {[4-(acetylamino)benzoyl]amino}ethyl)-3,7-diazabicyclo[3.3.1]- non-3-yl]-l-[(4-cyanophenoxy)methyl]ethyl acetate (m/z = 548); 4-(3-{7-[(3,5-dimethyl-4-isoxazolyl)carbonyl]-3,7-diazabicyclo[3.3.1]non-
3-yl}-2-hydroxypropoxy)benzonitrile (m/z = 425);
4-{2-hydroxy-3-[7-(2-isopropyl-2H-l,2,3,4-tetraazol-5-yl)-3,7-diaza- bicyclo[3.3.1]non-3-yl]ρropoxy}benzonitrile (m/z = 412); 4-(2-hydroxy-3-{7-[(5-methyl-3-isoxazolyl)carboήyl]-3,7-diazabicyclo-
[3.3.1]non-3-yl}propoxyjbenzonitrile (m/z = 411);
4-[3-(7-{[3-(tert-butyl)-l-methyl-lH-pyrazol-5-yl]carbonyl}-3,7-diaza- bicyclo[3.3.1]non-3-yl)-2-hydroxypropoxy]benzonitrile (m/z = 466);
4-(2-hydroxy-3-{7-[(4-methyl-l,2,3-thiadiazol-5-yl)carbonyl]-3,7-diaza- bicyclo[3.3. l]non-3-yl}propoxy)benzonitrile (m/z - 428);
4-[3-(7-cyano-3,7-diazabicyclo[3.3.1]non-3-yl)-2-hydroxyρropoxy]benzo- nitrile (m/z = 327);
2-{7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo[3.3.1]non-3- yl}-2-oxoacetamide (m/z = 373); N-(3-{7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo[3.3.1]- non-3-yl}propyl)-N-(3,4-dimethoxyphenyl)-4-nitrobenzamide (m/z = 644);
4-{[7-(4-oxoheptyl)-3,7-diazabicyclo[3.3.1]non-3-yl]sulfonyl}benzonitrile
(m/z = 404);
4-{2-hydroxy-3-[7-(l-phenyl-lH-l,2,3,4-tetraazol-5-yl)-3,7-diazabicyclo- [3.3.1]non-3-yl]propoxy}benzonitrile (m/z = 446);
4-{2-hydroxy-3-[7-(l-methyl-lH-l,2,3,4-tetraazol-5-yl)-3,7-diazabicyclo-
[3.3.1]non-3-yl]propoxy}benzonitrile (m/z = 384);
4-{2-hydroxy-3-[7-(2-methyl-2H-l,2,3,4-tetraazol-5-yl)-3,7-diazabicyclo-
[3.3.1]non-3-yl]propoxy}benzonitrile (m/z = 384); N-cyano-7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N-cycloproρyl-3,7- diazabicyclo[3.3.1 ]nonane-3-carboximidamide;
S-propyl {7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo-
[3.3.1]non-3-yl}sulfonylcarbamothioate (m/z = 483);
4-((£)-3-{7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo- [3.3.1]non-3-yl}-3-oxo-l-propenyl)benzonitrile (m/z = 457); ethyl {7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo[3.3.1]- non-3 -yl} carbothioylcarbamate;
4-(2-hydroxy-3-{7-[(2-oxo-l,3-oxazolidin-4-yl)methyl]-3,7-diazabicyclo-
[3.3.1]non-3-yl}propoxy)benzonitrile; tert-butyl 2- {7- [2-amino-3 -(4-cy anophenoxy)propyl] -3 ,7-diazabicyclo-
[3.3.1]non-3-yl}ethylcarbamate (m/z - 444); tert-butyl 3-[({7-[3-(4-cyanophenoxy)-2-hydroxyproρyl]-3,7-diazabicyclo-
[3.3.1]non-3-yl}carbothioyl)amino]propanoate; tert-butyl 2-{7-[3-(4-cyanoanilino)propyl]-3,7-diazabicyclo[3.3.1]non-3- y 1 } ethylcarb amate (m/z = 428) ;
4-(3-{7-[(£ -3-(3,4-dimethoxyphenyl)-2-propenoyl]-3,7-diazabicyclo-
[3.3.1 ]non-3 -yl } -2-hydroxypropoxy)benzonitrile;
4-(3-{7-[(£)-3-(4-fluorophenyl)-2-propenoyl]-3,7-diazabicyclo[3.3.1]non-3- yl}-2-hydroxypropoxy)benzonitrile (m/z = 450); 2-{7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo[3.3.1]non-3- . yl}-N-isopropylacetamide (m/z = 401);
4-({(2S)-3-[7-(cyclopropylmethyl)-9,9-tetramethylen-3,7-diazabicyclo-
[3.3.1]non-3-yl]-2-hydroxypropyl}oxy)benzonitrile (m/z = 410); phenyl N-cyano-7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diaza- bicyclo[3.3. l]nonane-3-carboximidoate (m/z = 446);
4-{[7-(3,4-dimethoxyphenethyl)-3,7-diazabicyclo[3.3.1]non-3-yl]- carbonyl}benzonitrile (m/z = 420);
4-{3-[7-(3-amino-lH-l,2,4-triazol-5-yl)-3,7-diazabicyclo[3.3.1]non-3-yl]-2- hydroxypropoxy}benzonitrile (m/z = 384); N-cyano-7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N-(2-hydroxyethyl)-
3,7-diazabicyclo[3.3.1]nonane-3-carboximidamide (m/z = 413); tert-butyl 3-{7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo-
[3.3. l]non-3-yl}-l-methyl-3-oxopropylcarbamate; N-cyano-7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N-[(5-hydroxy-l,3,3- trimethylcyclohexyl)methyl]-3,7-diazabicyclo[3.3.1]nonane-3- carboximidamide (m/z = 523);
4-[2-hydroxy-3-(7- {2-hydroxy-3-[(2-methyl- 1 -oxo- 1 ,2-dihydro-4-iso- quinolinyl)oxy]ρropyl} -3,7-diazabicyclo[3.3. l]non-3-yl)propoxy]benzo- nitrile;
4-(3-{7-[(3,4-dimethoxyphenyl)sulfonyl]-3,7-diazabicyclo[3.3.1]non-3-yl}-
2-hydroxypropoxy)benzonitrile (m/z - 502);
4- {3-[7-(benzylsulfonyl)-3,7-diazabicyclo[3.3.1 ]non-3-yl]-2-hydroxy- propoxy} benzonitrile (m/z - 456);
4-{3-[7-(butylsulfonyl)-3,7-diazabicyclo[3.3.1]non-3-yl]-2-hydroxy- propoxy} benzonitrile (m/z = 422);
7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N,N-dimethyl-3,7-diazabicyclo-
[3.3.1 ]nonane-3-sulfonamide; 4- {3-[7-(3-aminobutanoyl)-3,7-diazabicyclo[3.3. l]non-3-yl]-2-hydroxy- propoxy}benzonitrile;
4-{3-[7-(l,3-dimethyl-2,6-dioxo-l,2,3,6-tetrahydro-4-pyrimidinyl)-3,7- diazabicyclo[3.3.1]non-3-yl]-2-hydroxypropoxy}benzonitrile (m/z = 440);
N-cyano-7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N-(2-methoxyethyl)- 3,7-diazabicyclo[3.3.1]nonane-3-carboximidamide ( /z = 427);
4-{2-hydroxy-3-[7-(2,2,2-trifluoroacetyl)-3,7-diazabicyclo[3.3.1]non-3- yl]propoxy} benzonitrile (m/z = 398);
4-{2-hydroxy-3-[7-(3,3,3-trifluoropropanoyl)-3,7-diazabicyclo[3.3.1]non-3- yljpropoxy} benzonitrile; N-cyano-7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N-[(lS)-l-(l- naphthyl)ethyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboximidamide (m/z =
523);
N-cyano-7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N-isopropyl-N-methyl-
3,7-diazabicyclo[3.3.1]nonane-3-carboximidamide (m/z = 425); N-cyano-7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N-(3,4-dimethoxy- phenethyl)-3 ,7-diazabicyclo[3.3.1 ]nonane-3-carboximidamide;
N-cyano-7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N-(3,4-dimethoxy- phenethyl)-N-methyl-3,7-diazabicyclo[3.3.1]nonane-3-carboximidamide (m/z = 547);
4-(2-hydroxy-3-{7-[(3-methyl-8-quinolinyl)sulfonyl]-3,7-diazabicyclo-
[3.3.1]non-3-yl}propoxy)benzonitrile (m/z = 507);
4-(2-hydroxy-3-{7-[(l-methyl-lH-imidazol-4-yl)sulfonyl]-3,7-diaza- bicyclo[3.3.1]non-3-yl}propoxy)benzonitrile (m/z = 446); 4-(2-hydroxy-3- {7-[(trifluoromethyl)sulfonyl]-3,7-diazabicyclo[3.3.1 ]non-
3-yl}propoxy)benzonitrile (m/z = 434);
4-{2-hydroxy-3-[7-(2-oxobutyl)-3,7-diazabicyclo[3.3.1]non-3-yl]- proρoxy}benzonitrile (m/z = 372);
4-{3-[7-(2-furoyl)-3,7-diazabicyclo[3.3.1]non-3-yl]-2-hydroxypropoxy}- benzonitrile (m/z = 396);
4-[2-hydroxy-3-(7-{[5-(2-pyridinyl)-2-thienyl]sulfonyl}-3,7-diazabicyclo-
[3.3.1]non-3-yl)propoxy]benzonitrile (m/z = 525);
N-[4-(2-{7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo-
[3.3.1]non-3-yl}acetyl)phenyl]methanesulfonamide (m/z = 513); 4-[2-hydroxy-3-(7- { [2-(4-moφholinyl)ethyl]sulfonyl} -3 ,7-diazabicyclo-
[3.3.1 ]non-3-yl)propoxy]benzonitrile;
4-{3-[7-(4-amino-6,7-dimethoxy-2-quinazolinyl)-3,7-diazabicyclo[3.3.1]- non-3-yl]-2-hydroxypropoxy}benzonitrile;
3,7-bis[3-(4-cyanophenoxy)-2-hydroxypropyl]-7-aza-3-azoniabicyclo- [3.3.1]nonan-3-olate (m/z = 493);
4-(3-{7-[(3-fluorophenyl)sulfonyl]-3,7-diazabicyclo[3.3.1]non-3-yl}-2- hydroxypropoxy)benzonitrile (m/z = 460);
4-{3-[7-(3,4-dimethoxyphenethyl)-3,7-diazabicyclo[3.3.1]non-3-yl]-2- hydroxypropoxy} benzonitrile (m/z = 466); 4-[4-(7-butyryl-3,7-diazabicyclo[3.3.1]non-3-yl)-l-(3,4-dimethoxy- phenoxy)butyl]benzonitrile (m/z = 506);
4-[4-[7-(butylsulfonyl)-3,7-diazabicyclo[3.3.1]non-3-yl]-l-(3,4-dimethoxy- phenoxy)butyl]benzonitrile (m/z = 556); 4- { l-(3,4-dimethoxyphenoxy)-4-[7-(3,3-dimethyl-2-oxobutyl)-3,7-diaza- bicyclo[3.3.1]non-3-yl]butyl}benzonitrile (m/z - 534);
4-[4-[7-(3 ,4-dimethoxyphenethyl)-3,7=-diazabicyclo[3.3. l]non-3-yl]- 1 -(3,4- dimethoxyphenoxy)butyl]benzonitrile (m/z = 600);
4-[4-(7-butyryl-3,7-diazabicyclo[3.3.1]non-3-yl)butyl]benzonitrile (m/z - 354);
4- {2-[7-(butylsulfonyl)-3,7-diazabicyclo[3.3. l]non-3-yl] ethoxy }benzo- nitrile (m/z = 404);
4-{4-[7-(3,3-dimethyl-2-oxobutyl)-3,7-diazabicyclo[3.3.1]non-3-yl]butyl}- benzonitrile (m/z = 382); 4-{4-[7-(3,4-dimethoxyphenethyl)-3,7-diazabicyclo[3.3.1]non-3-yl]butyl}- benzonitrile (m/z - 448);
4-[2-(7-butyryl-3,7-diazabicyclo[3.3.1]non-3-yl)ethoxy]benzonitrile (m/z =
342);
4-{2-[7-(3,3-dimethyl-2-oxobutyl)-3,7-diazabicyclo[3.3.1]non-3-yl]- ethoxy} benzonitrile (m/z = 370);
4-{2-[7-(3,4-dimethoxyphenethyl)-3,7-diazabicyclo[3.3.1]non-3-yl]- ethoxy} benzonitrile (m/z = 436);
O-ethyl 7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo[3.3.1]- nonane-3-carbothioate; benzonitrile, 4-[2-hydroxy-3-[7-[(tetrahydro-3-thienyl)sulfonyl]-3,7-diaza- bicyclo[3.3. l]non-3-yl]propoxy]-, S,S-dioxide;
4-({(2S)-2-amino-3-[7-(3,3-dimethyl-2-oxobutyl)-3,7-diazabicyclo[3.3.1]- non-3-yl]propyl} oxy)benzonitrile;
4-{2-[7-(l,3-thiazol-2-yl)-3,7-diazabicyclo[3.3.1]non-3-yl]ethoxy}benzo- nitrile (m/z = 355); 4-{l-(3,4-dimethoxyphenoxy)-4-[7-(l,3-thiazol-2-yl)-3,7-diazabicyclo-
[3.3. l]non-3-yl]butyl} benzonitrile (m/z - 519);
4-({3-[7-(l,3-thiazol-2-yl)-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}- sulfonyl)benzonitrile (m/z = 417); 4-cyano-N- {3-[7-( 1 ,3-thiazol-2-yl)-3,7-diazabicyclo[3.3. l]non-3-yl]- propyl}benzamide (m/z = 396);
4-{3-[7-(cyclopropylmethyl)-3,7-diazabicyclo[3.3.1]non-3-yl]-2-hydroxy- propoxy} benzonitrile (m/z = 356);
4- {2-[7-(cyclopropylmethyl)-3 ,7-diazabicyclo[3.3. l]non-3-yl] ethoxy} - benzonitrile (m/z = 326);
4-[4-[7-(cyclopropylmethyl)-3,7-diazabicyclo[3.3.1]non-3-yl]-l-(3,4- dimethoxyphenoxy)butyl]benzonitrile (m/z = 490);
4-({3-[7-(cyclopropylmethyl)-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}- amino)benzonitrile (m/z = 339); 4-{3-[7-(cycloρropylmethyl)-3,7-diazabicyclo[3.3.1]non-3-yl]-2-hydroxy- ρropoxy}-N,N-dimethylbenzenesulfonamide (m/z = 438);
4-({3-[7-(3,3-dimethyl-2-oxobutyl)-3,7-diazabicyclo[3.3.1]non-3-yl]- propyl}amino)benzonitrile (m/z = 383);
4-(4-(4-cyanophenyl)- 1 - {2- [7-(3 ,3-dimethyl-2-oxobutyl)-3 ,7-diazabicyclo- [3.3.1]non-3-yl]-2-oxoethyl}-lH-pyrazol-5-yl)benzonitrile (m/z = 535);
4-{3-[7-(3,3-dimethyl-2-oxobutyl)-3,7-diazabicyclo[3.3.1]non-3-yl]-2- hydroxypropoxy}-N,N-dimethylbenzenesulfonamide (m/z - 482);
4-(2- {7-[2-(2-methoxyethoxy)ethyl]-3,7-diazabicyclo[3.3. l]non-3-yl} - ethoxy)benzonitrile (m/z = 374); N-[2-(4-cyanophenoxy)-l-({7-[2-(2-methoxyethoxy)ethyl]-3,7-diaza- bicyclo[3.3.1]non-3-yl}methyl)ethyl]-N-methylurea (m/z = 460);
4-[(3- {7-[2-(2-methoxyethoxy)ethyl]-3,7-diazabicyclo[3.3. l]non-3-yl} - propyl)amino]benzonitrile (m/z = 387); 4-[4-(4-cyanophenyl)- 1 -(2- {7-[2-(2-methoxyethoxy)ethyl]-3 ,7-diaza- bicyclo[3.3. l]non-3-yl}-2-oxoethyl)-lH-pyrazol-5-yl]benzonitrile (m/z -
539);
4-{3-[7-(4-fluorobenzyl)-3,7-diazabicyclo[3.3.1]non-3-yl]-2-hydroxy- propoxy}benzonitrile (m/z = 410);
4-{2-[7-(4-fluorobenzyl)-3,7-diazabicyclo[3.3.1]non-3-yl]ethoxy}benzo- nitrile (ra/z = 380);
4- { 1 -(3,4-dimethoxyphenoxy)-4-[7-(4-fluorobenzyl)-3,7-diazabicyclo-
[3.3. l]non-3-yl]butyl}benzonitrile (m/z = 544); 4-({3-[7-(4-fluorobenzyl)-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}amino)- benzonitrile (m/z = 393);
4-({3-[7-(4-fluorobenzyl)-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}- sulfonyl)benzonitrile (m/z = 442);
4-cyano-N-{3-[7-(4-fluorobenzyl)-3,7-diazabicyclo[3.3.1]non-3-yl]- propyl } benzamide (m/z — 421 ) ;
4- {3-[7-(4-fluorobenzyl)-3,7-diazabicyclo[3.3. l]non-3-yl]-2-hydroxy- propoxy}-NrN-dimethylbenzenesulfonamide (m/z = 492);
4-{2-hydroxy-3-[7-(isopropylsulfonyl)-3,7-diazabicyclo[3.3.1]non-3-yl]- propoxy} benzonitrile; 4-{3-[7-(l-cyanoethyl)-3,7-diazabicyclo[3.3.1]non-3-yl]-2-hydroxy- propoxy} benzonitrile;
4- {2-[7-( 1 -cyanoethyl)-3 , 7-diazabicy clo[3.3.1 ]non-3 -yl] ethoxy} benzonitrile;
4-[4-[7-(l-cyanoethyl)-3,7-diazabicyclo[3.3.1]non-3-yl]-l-(3,4-dimethoxy- phenoxy)butyl]benzonitrile (m/z = 489);
4-{3-[7-(2-cyanoρropyl)-3,7-diazabicyclo[3.3.1]non-3-yl]-2-hydroxy- propoxy}-N,N-dimethylbenzenesulfonamide (m/z = 451);
4-({3-[7-(3,4-dimethoxyphenethyl)-3,7-diazabicyclo[3.3.1]non-3-yl]- propyl}amino)benzonitrile (m/z = 449); 4-({3-[7-(3,4-dimethoxyphenethyl)-3,7-diazabicyclo[3.3.1]non-3-yl]- propyl}sulfonyl)benzonitrile (m/z = 498);
4-(4-(4-cyanophenyl)- 1 - {2-[7-(3 ,4-dimethoxyphenethyl)-3,7-diazabicyclo-
[3.3.1]non-3-yl]-2-oxoethyl}-lH-pyrazol-5-yl)benzonitrile (m/z = 601); 4-cyano-N-{3-[7-(3,4-dimethoxyphenethyl)-3,7-diazabicyclo[3.3.1]non-3- yl]propyl}benzamide (m/z = 477);
4-{ l-(3,4-dimethoxyphenoxy)-4-[7-(4-oxoheptyl)-3,7-diazabicyclo[3.3.1]- non-3-yl]butyl}benzonitrile (m/z = 548);
4-(4-(4-cyanoρhenyl)-l-{2-oxo-2-[7-(4-oxoheptyl)-3,7-diazabicyclo[3.3.1]- non-3-yl]ethyl}-lH-pyrazol-5-yl)benzonitrile (m/z = 549);
4-cy ano-N- { 3 - [7-(4-oxoheptyl)-3 ,7-diazabicy clo [3.3.1 ]non-3 -yl]proρyl } - benzamide (m/z = 425);
4-(3-{7-[2-(2,3-dihydro-l,4-benzodioxin-6-yl)-2-oxoethyl]-3,7-diaza- bicyclo[3.3.1]non-3-yl}-2-hydroxypropoxy)benzonitrile (m/z = 478); 4-[(3-{7-[2-(2,3-dihydro-l,4-benzodioxin-6-yl)-2-oxoethyl]-3,7-diaza- bicyclo[3.3.1]non-3-yl}propyl)amino]benzonitrile (m/z = 461);
4-(3-{7-[3-(ethylsulfonyl)propyl]-3,7-diazabicyclo[3.3.1]non-3-yl}-2- hydroxypropoxy)benzonitrile (m/z = 436);
4-(l-(3,4-dimethoxyphenoxy)-4-{7-[3-(ethylsulfonyl)propyl]-3,7-diaza- bicyclo[3.3.1]non-3-yl}butyl)benzonitrile (m/z = 570);
N-{2-{7-[3-(4-acetyl-l-piperazinyl)propyl]-3,7-diazabicyclo[3.3.1]non-3- yl}-l-[(4-cyanophenoxy)methyl]ethyl}-N-methylurea (m/z = 526);
4-[l-(2-{7-[3-(4-acetyl-l-piperazinyl)propyl]-3,7-diazabicyclo[3.3.1]non-3- yl} -2-oxoethyl)-4-(4-cyanophenyl)- lH-pyrazol-5-yl]benzonitrile (m/z = 605);
4-( {3-[7-( 1 ,3-thiazol-2-yl)-3,7-diazabicyclo[3.3. l]non-3-yl]propyl} amino)- benzonitrile (m/z ~ 368);
4- {2-hydroxy-3-[7-( 1 ,3-thiazol-2-yl)-3 ,7-diazabicy clo [3.3.1 ]non-3-yl]- propoxy}-N,N-dimethylbenzenesulfonamide (m/z = 467); N-(2-(4-cyanophenoxy)- 1 - { [7-(cycloproρylmethyl)-3 ,7-diazabicyclo-
[3.3.1]non-3-yl]methyl}ethyl)-N-methylurea (m/z = 412);
4-({3-[7-(cyclopropylmethyl)-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}- sulfonyl)benzonitrile (m/z = 388); 4-(2- {7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo[3.3.1]- non-3-yl} acetyl)benzonitrile;
N-(2-(4-cyanophenoxy)- 1 - { [7-(3 ,3 -dimethyl-2-oxobutyl)-3 ,7-diazabicy clo-
[3.3.1]non-3-yl]methyl}ethyl)-N-methylurea (m/z = 456);
4-({3-[7-(3,3-dimethyl-2-oxobutyl)-3,7-diazabicyclo[3.3.1]non-3-yl]- propyl} sulfonyl)benzonitrile (m/z = 432);
4-cyano-N- {3-[7-(3,3-dimethyl-2-oxobutyl)-3,7-diazabicyclo[3.3. l]non-3- yl]propyl}benzamide (m/z = 411);
4-(2-hydroxy-3-{7-[2-(2-methoxyethoxy)ethyl]-3,7-diazabicyclo[3.3.1]- non-3-yl}propoxy)benzonitrile (m/z = 404); 4-(l-(3,4-dimethoxyphenoxy)-4-{7-[2-(2-methoxyethoxy)ethyl]-3,7-diaza- bicyclo[3.3.1]non-3-yl}butyl)benzonitrile (m/z - 538);
4-[(3-{7-[2-(2-methoxyethoxy)ethyl]-3,7-diazabicyclo[3.3.1]non-3-yl}- propyI)sulfonyl]benzonitrile (m/z = 436);
4-cyano-N-(3-{7-[2-(2-methoxyethoxy)ethyl]-3,7-diazabicyclo[3.3.1]non-3- yl}propyl)benzamide (m/z = 415);
4-(2-hydroxy-3-{7-[2-(2-methoxyethoxy)ethyl]-3,7-diazabicyclo[3.3.1]- non-3-yl}ρropoxy)-N,N-dimethylbenzenesulfonamide (m/z = 486);
N-{2-[7-(l-cyanoethyl)-3,7-diazabicyclo[3.3.1]non-3-yl]-l-[(4-cyano- phenoxy)methyl]ethyl}-N-methylurea; 4-cyano-N-{3-[7-(2-cyanopropyl)-3,7-diazabicyclo[3.3.1]non-3-yl]- propyl}benzamide (m/z = 380);
N-(2-(4-cyanophenoxy)-l-{[7-(3,4-dimethoxyphenethyl)-3,7-diazabicyclo-
[3.3.1]non-3-yl]methyl}ethyl)-N-methylurea (m/z = 522);
4-{3-[7-(3,4-dimethoxyphenethyl)-3,7-diazabicyclo[3.3.1]non-3-yl]-2- hydroxypropoxy}-N,N-dimethylbenzenesulfonamide (m/z - 548); 4- {2-[7-(4-oxoheptyl)-3,7-diazabicyclo[3.3. l]non-3-yl] ethoxy} benzonitrile
(m/z = 384);
4-{2-hydroxy-3-[7-(4-oxoheptyl)-3,7-diazabicyclo[3.3.1]non-3-yι]- propoxy}-N,N-dimethylbenzenesulfonamide (m/z = 496); N-[2-(4-cyanophenoxy)-l-({7-[2-(2,3-dihydro-l,4-benzodioxin-6-yl)-2- oxoethyl]-3 ,7-diazabicyclo [3.3.1 ]non-3-yl}methyl)ethyl]-N-methylurea
(m/z = 496);
4-[(3- {7-[2-(2,3-dihydro- 1 ,4-benzodioxin-6-yl)-2-oxoethyl]-3,7-diaza- bicyclo[3.3.1]non-3-yl}propyl)sulfonyl]benzonitrile (m/z = 510); 4-[4-(4-cyanoρhenyl)- 1 -(2- {7-[2-(2,3-dihydro- 1 ,4-benzodioxin-6-yl)-2- oxoethyl]-3 ,7-diazabicyclo[3.3. l]non-3-yl} -2-oxoethyl)- lH-pyrazol-5-yl]- benzonitrile (m/z = 510);
4-cyano-N-(3-{7-[2-(2,3-dihydro-l,4-benzodioxin-6-yl)-2-oxoethyl]-3,7- diazabicyclo[3.3.1]non-3-yl}propyl)benzamide (m/z = 489); 4-(3-{7-[2-(2,3-dihydro-l,4-benzodioxin-6-yl)-2-oxoethyl]-3,7-diaza- bicyclo[3.3.1]non-3-yl}-2-hydroxypropoxy)-N,N-dimethylbenzene- sulfonamide (m/z = 560);
4-(2-{7-[3-(ethylsulfonyl)propyl]-3,7-diazabicyclo[3.3.1]non-3-yl}ethoxy)- benzonitrile (m/z — 406); N-[2-(4-cyanophenoxy)- 1 -( {7-[3-(ethylsulfonyl)propyl]-3 ,7-diazabicyclo-
[3.3.1]non-3-yl}methyl)ethyl]-N-methylurea (m/z = 492);
4- [(3 - {7- [3 -(ethylsulfony ι)proρyl] -3 ,7-diazabicy clo [3.3.1 ]non-3 -yl} - propyl)amino]benzonitrile (m/z = 419);
4-[(3- {7-[3-(ethylsulfonyl)propyl]-3,7-diazabicyclo[3.3. l]non-3-yl} - propyl)sulfonyl]benzonitrile (m/z = 468);
4-[4-(4-cyanophenyl)- 1 -(2- {7-[3-(ethylsulfonyl)propyl]-3 ,7-diazabicyclo-
[3.3. l]non-3-yl} -2-oxoethyl)- lH-pyrazol-5-yl]benzonitrile (m/z = 571);
4-cyano-N-(3-{7-[3-(ethylsulfonyl)propyl]-3,7-diazabicyclo[3.3.1]non-3- yl}propyl)benzamide (m/z = 447); 4-(3-{7-[3-(ethylsulfonyl)propyl]-3,7-diazabicyclo[3.3.1]non-3-yl}-2- hydroxypropoxy)-N,N-dimethylbenzenesulfonamide (m/z = 518);
4-(2- {7- [3 -(4- acetyl- 1 -piperazinyl)propyl]-3,7-diazabicyclo[3.3.1 ]non-3- yl}ethoxy)benzonitrile (m/z = 440); 4- [4- {7-[3 -(4-acetyl- 1 -piρerazinyl)propyl] -3 ,7-diazabicyclo [3.3.1 ]non-3 - yl}-l-(3,4-dimethoxyphenoxy)butyl]benzonitrile (m/z = 604);
4-[(3-{7-[3-(4-acetyl-l-piperazinyl)propyl]-3,7-diazabicyclo[3.3.1]non-3- yl}propyl)amino]benzonitrile (m/z - 453);
4- [(3 - {7- [3 -(4-acetyl- l-piperazinyl)propyl] -3 ,7-diazabicyclo [3.3.1 ]non-3 - yl}propyl)sulfonyl]benzonitrile (m/z = 502);
4-(3-{7-[3-(4-acetyl-l-piperazinyl)propyl]-3,7-diazabicyclo[3.3.1]non-3- yl}-2-hydroxypropoxy)-N,N-dimethylbenzenesulfonamide (m/z = 552);
4-(3-{7-[3-(4-acetyl-l-piperazinyl)ρropyl]-3,7-diazabicyclo[3.3.1]non-3- yl}-2-hydroxypropoxy)benzonitrile; N-(2-(4-cyanophenoxy)-l-{[7-(l,3-thiazol-2-yl)-3,7-diazabicyclo[3.3.1]- non-3-yl]methyl}ethyl)-N-methylurea (m/z = 441);
4-{l-(3,4-dimethoxyphenoxy)-4-[7-(2-ethyl-2H-l,2,3,4-tetraazol-5-yl)-3,7- diazabicyclo[3.3.1]non-3-yl]butyl}benzonitrile; and
4-({3-[7-(2-ethyl-2H-l,2,3,4-tetraazol-5-yl)-3,7-diazabicyclo[3.3.1]non-3- yl]propyl} amino)benzonitrile.
Example 8
Title compounds of the above Examples were tested in Test A above and were found to exhibit D10 values of at least 6.0.
Example 9
Title compounds of the above Examples were tested in Test B above and were found to exhibit pIC50 values of at least 5.5. Abbreviation; 5
Ac = acetyl
API = atmospheric pressure ionisation (in relation to MS) aq. = aqueous br = broad (in relation to NMR)
Bt = benzotriazole t-BuOH •= tert-butanol
CI = chemical ionisation (in relation to MS) mCPBA = metα-chloroperoxybenzoic acid d = doublet (in relation to NMR)
DBU = diazabicyclo[5.4.0]undec-7-ene
DCM = dichloromethane dd = doublet of doublets (in relation to NMR)
DMAP = 4-dimethylaminopyridine
DMF = N,N-dimethylformamide
DMSO = dimethylsulfoxide
EDC = 1 - [3 -(dimethylamino)propyl] -3 -ethylcarbodiimide
Et == ethyl
EtOAc = ethyl acetate eq. = equivalents
ES == electrospray (in relation to MS)
FAB _ fast atom bombardment (in relation to MS) h = hour(s)
HC1 = hydrochloric acid
HEPES = 4-(2-hy droxy ethyl)- 1 -piperazmeethanesulfonic acid
HPLC = high performance liquid chromatography
IPA = wo-propyl alcohol (propan-2-ol) m = multiplet (in relation to ΝMR)
Me = methyl MeCN = acetonitrile
MeOH = methanol min. = minute(s) m.p. = melting point
; MS = mass spectroscopy
NADPH = nicotinamide adenine dinucleotide phosphate, reduced form
OAc = acetate
Pd/C = palladium on carbon q . = quartet (in relation to NMR)
' rt = room temperature s = singlet (in relation to NMR) t = triplet (in relation to NMR)
TEA = triethylamine
THF = tetrahydrofuran tic = thin layer chromatography
Prefixes «-, s-, i-, t- and tert- have their usual meanings: normal, secondary, iso, and tertiary.

Claims

Claims
1. A compound of formula I,
Figure imgf000084_0001
wherein
R1 represents a structural fragment of formula la,
Figure imgf000084_0002
R4 represents H, halo, C1-4 alkyl, -D-OR7, -D-N(R8)R9, or R4, together with
R5, represents =0;
R5 represents H, CM alkyl, or R5, together with R , represents =0;
D represents a direct bond or CM alkylene;
R7 represents H, C1-6 alkyl, -E-aryl, -E-Het1, -C(O)R10a, -C(O)OR10b or -C(0)N(Rl la)Rl lb;
R8 represents H, C1-6 alkyl, -E-aryl, -E-Het1, -C(O)R10a, -C(O)OR10b,
-S(0)2R , 110UcC, -[C(0)]nN(R lulaa)rR» l1 l1bD or -C(NH)NH2
Ry represents H, C1-6 alkyl, -E-aryl, or -C(0)Rι Oυdα;.
E represents, at each occurrence when used herein, a direct bond or, C alkylene;
R a to R independently represent, at each occurrence when used herein, C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from halo, aryl and Het2), aryl, Het3, or R10a and R10d independently represent H;
Rl la and Rl lb independently represent, at each occurrence when used herein, H, Cι-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from halo, aryl and Het ), aryl, Het5, or Rl la and Rllb together represent C3-7 alkylene, which alkylene group is optionally interrupted by an oxygen atom; n represents 1 or 2;
1 9 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(R13)-, -N(R13)-L-, -L-S(0)p- or -L-O- (in which latter two groups, L is attached to the carbon atom bearing R4 and R5);
G represents a direct bond or C1-6 alkylene; J represents C2- alkylene;
L represents a direct bond or CM alkylene; p represents 0, 1 or 2;
R12 and R13 independently represent H or C1-4 alkyl;
R6 represents aryl, Het6 (both of which groups are optionally substituted and/or terminated (as appropriate) by one or more substituents selected from -OH, cyano, halo, nitro, Cj.6 alkyl (optionally terminated by -N(H)C(0)OR14a), Cι.6 alkoxy, aryl, Het7, -N(R15a)R15b, -C(0)R15c, -C(0)OR15d, -C(0)N(Rl5e)R15f, -N(R15g)C(0)R15h, -N(R15i)C(0)N(R15j)R15k, -N(R15m)S(0)2R14b, -S(0)qR14c, -OS(0)2R14d and -S(0)2N(R15n)R15p) or, when R4 and R5 together represent =0, R may represent Cι-6 alkyl; q represents 0, 1 or 2;
R2 represents -CN, Het8, -C(0)R16, -C(S)OR17, -C(S)N(R18)R19, -[C(O)]2N(R20a)R20b, -[C(0)]2OR21, -S(0)2R22, -S(0)2N(R23)R24, -C(=N-CN)N(R25)R26, -C(=N-CN)OR27 or C 2 alkyl (which alkyl group is optionally substituted and/or terminated by one or more substituents selected from -C(0)R28, -C(0)N(R29a)R29b, -N(R30)R31, -OR32, -S(0)rR33, halo, -CN, nitro, aryl and Het9);
R16 represents H, aryl, Het10 or Cι-6 alkyl (which alkyl group is optionally substituted and/or terminated by one or more substituents selected from halo, -OH, -CN, -N(R34)R35, aryl and Het11);
R34 represents, H, C1-6 alkyl, aryl, Het12, -C(0)R36a or -C(0)OR36b;
R18 represents H, aryl, Het13, -C(0)R36a, -C(0)OR36b or C1-6 alkyl (which alkyl group is optionally substituted and/or terminated by one or more substituents selected from halo, -OH, -CN, -C(0)R36a and -C(0)OR36b);
R22 represents Het14, aryl, or Cι-6 alkyl (which alkyl group is optionally substituted and/or terminated by one or more substituents selected from halo, -OH, -CN, Het15 and aryl);
R23 represents H, C1-6 alkyl, aryl, Het16, -C(0)R36a, -C(0)OR36b or -C(0)SR36b;
R represents H or C1-6 alkyl (which alkyl group is optionally substituted and/or terminated by one or more substituents selected from halo, -OH, -CN, C1-6 alkyl (which alkyl group is optionally substituted and/or terminated by one or more substituents selected from C1-4 alkyl and -OH), Cι-6 alkoxy and aryl);
97
R represents Cι-6 alkyl or aryl;
R28 represents H, C1-6 alkyl, aryl or Het17; R29a and R29b independently represent H, C[,6 alkyl, aryl or Het18;
R30 represents H, Cι-6 alkyl, aryl, Het19, -C(0)R37a, -C(0)OR37b or -C(0)N(R37c)R37d; R31 represents H, C1-6 alkyl, aryl or Het
R32 represents H, C1-6 alkyl, aryl, Het21, -C(0)R37a, -C(0)OR37b or
-C(0)N(R37c)R37d;
R33 represents Cι-6 alkyl, aryl or Het ; r represents 0, 1 or 2;
R36a and R36 independently represent, at each occurrence when used herein, Cι-6 alkyl, or R36a represents H; R37a to R37d independently represent, at each occurrence when used herein, C1-6 alkyl, aryl or Het23, or R37a, R37c and R37d independently represent H;
Het1 to Het23 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;
R3a and R3b independently represent H, CM alkyl, -OR38a, -SR38b, -N(R39)R38c, or R3a and R3b together represent C3-5 alkylene, -0-Z-0-, -O-Z-S- or -S-Z-S-; R39 represents H, Cι-6 alkyl or a structural fragment of formula la as defined above;
Z represents C2.3 alkylene optionally substituted by one or more -4 alkyl groups;
R41 to R46 independently represent H or C[-3 alkyl; R14a to R14d, R17 and R21 independently represent C1-6 alkyl;
R15a tQ R.5Pj Rl9j R20a5 R20bj R24? RM R35 ^ R38a tø R38c independently
represent H or C1-6 alkyl;
1 9T wherein each aryl and Het (Het to Het ) group, unless otherwise specified, is optionally substituted;
or a pharmaceutically acceptable derivative thereof;
provided that:
(a) when R1 represents a structural fragment of formula la in which: R4 and R5 together represent =0;
A represents a direct bond; then B does not represent a direct bond, -N(R13)-L- (in which group -N(R13)- is attached to the carbon atom bearing R4 and R5), -N(R13)-, -
S(0)p- or -0-;
(b) when R5 represents H or C1-4 alkyl; and A represents -J-N(R12)- or -J-0-; then B does not represent -N(R13)-L-, -N(R13)-, -S(0)p- or -0-; (c) when R4 represents -D-OR7, -D-N(R8)R9 in which D represents a direct bond, then:
(i) A does not represent -J-N(R12)- or -J-0-; and (ii) B does not represent -N(R13)-L-, -N(R13)-, -S(0)p- or -0-;
(d) when R3a and R3b and both represent H; and R1 represents unsubstituted benzyl; then R2 does not represent unsubstituted benzyl or optionally substituted benzoyl; and
(e) the compound is not:
(i) N'-phenyl-3-(7-benzyl-3,7-diazabicyclo[3.3.1]non-3-yl)- propanamide; (ii) 3-benzyl-7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-6,8- dimethyl-3 ,7-diazabicy clo[3.3.1 ]nonane; (iii) 3 -benzyl-7- [3 -(4-cy anophenoxy)-2-hydroxypropyl] -6-methyl-
3,7-diazabicyclo[3.3.1]nonane; (iv) N- {2-(7-benzyl-3,7-diazabicyclo[3.3.1 ]non-3-yl)- 1 -[(4-cyano- phenoxy)methy 1] ethyl } methanesulfonamide; (v) 3 -benzyl-7- [3 -(2 -propyl- 1 ,3-dioxolan-2-yl)propyl]-3,7-diaza- bicyclo[3.3.1]nonane; or (vi) 7-benzyl-3,7-diazabicyclo[3.3.1]nonane-3-ethanol.
2. A compound as claimed in Claim 1, wherein R4 represents H, C1-2 alkyl, -OR7 or Ν(H)R8, or R4, together with R5, represents =0.
3. A compound as claimed in Claim 1 or Claim 2, wherein R5 represents H, or R5, together with R4, represents =0.
4. A compound as claimed in any one of Claims 1 to 3, wherein R7 represents H, Cι- alkyl, optionally substituted phenyl, -C(O)R10a, or -C(0)N(Rl la)Rl lb.
5. A compound as claimed in any one of Claims 1 to 3, wherein R represents H, C1-4 alkyl, -C(O)R10a, -C(O)OR10b or -C(0)N(Rl la)Rl lb
6. A compound as claimed in any one of Claims 1 to 5, wherein R10a and R10b independently represent, at each occurrence when used herein, Cι-5 alkyl (optionally substituted and/or terminated by one or more substituents selected from halo and phenyl), optionally substituted phenyl, or R10a represents H.
7. A compound as claimed in Claim 4 or Claim 5, wherein RUa and Rl lb independently represent, at each occurrence when used herein, H or C1.5 alkyl (optionally substituted and/or terminated by one or more substituents selected from halo and phenyl). '
8. A compound as claimed in any one of Claims 1 to 7, wherein A
1 9 represents -G- or -J-N(R )-.
9. A compound as claimed in Claim 8, wherein G represents a direct bond or C1-4 alkylene.
10. A compound as claimed in any one of Claims 1 to 8, wherein J represents C -4 alkylene.
11. A compound as claimed in any one of Claims 1 to 10, wherein B represents a direct bond, C1-4 alkylene, -L-N(H)-, -L-S(0)2- or -L-O- (in which latter three groups, L is attached to the carbon atom bearing R4 and
R5).
12. A compound as claimed in any one of Claims 1 to 11, wherein L represents C alkylene.
13. A compound as claimed in any one of Claims 1 to 12, wherein R represents phenyl, Het6 (both of which groups are optionally substituted by one or more substituents selected from cyano, halo, nitro, C1- alkyl, C)-4 alkoxy, optionally substituted phenyl, -N(H)R15b, -C(0)RI5c, -C(0)N(H)R15f, -N(H)C(0)R15h, -N(H)C(0)N(H)R15k, -N(H)S(0)2R14b, -S(0)2R14c and -S(0)2N(R15n)R15p), or, when R4 and R5 together represent =0, R may represent Cι-5 alkyl.
14. A compound as claimed in any one of Claims 1 to 13, wherein R represents -CN, Het8, -C(0)R16, -C(S)OR17, -C(S)N(H)R18, -[C(O)]2N(H)R20b, -[C(0)]2OR21, -S(0)2R22, -S(0)2N(R23)R24, -C(=N-CN)N(R25)R26, -C(=N-CN)OR27 or C1-6 alkyl (which alkyl group is optionally substituted and/or terminated by one or more substituents selected from -C(0)R28, -C(0)N(H)R29b, -N(R30)R31, -OR32, -S(0)2R33, halo, -CN, optionally substituted phenyl and Het9).
15. A compound as claimed in Claim 14, wherein R16 represents optionally substituted phenyl, Het10 or Cι-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)R34 and optionally substituted phenyl).
16. A compound as claimed in Claim 15, wherein R34 represents, H, Cj-4 alkyl, -C(0)R36a or -C(0)OR36b.
17. A compound as claimed in Claim 14, wherein R18 represents H, -C(0)OR36b or C1-6 alkyl (which alkyl group is optionally substituted and/or terminated by one or more substituents selected from halo and -C(0)OR ).
18. A compound as claimed in Claim 14, wherein R22 represents Het14, optionally substituted phenyl or C[- alkyl (which alkyl group is optionally substituted and/or terminated by one or more substituents selected from halo, Het15 and optionally substituted phenyl).
19. A compound as claimed in Claim 14, wherein R 23 represents H, Cι- alkyl, -C(0)OR36b or -C(0)SR36b. S
20. A compound as claimed in Claim 14, wherein R represents H or Cι_6 alkyl (which alkyl group is optionally substituted and/or terminated by one or more substituents selected from halo, -OH, Cι-6 alkyl (which alkyl group is optionally substituted and/or terminated by one or more substituents selected from Cι-4 alkyl and -OH), C1- alkoxy, naphthyl and optionally substituted phenyl).
97
21. A compound as claimed in Claim 14, wherein R represents optionally substituted phenyl.
98
22. A compound as claimed in Claim 14, wherein R represents C1-5 ι n alkyl, optionally substituted phenyl or Het .
23. A compound as claimed in any one of Claims 1 to 14 or 22, wherein
9 Oh R represents H, C[-4 alkyl or optionally substituted phenyl.
24. A compound as claimed in any one of Claims 14, 22 and 23, wherein R30 represents H, optionally substituted phenyl, -C(0)R37a or -C(0)OR37b.
25. A compound as claimed in any one of Claims 14 or 22 to 24, wherein R31 represents H, C1-2 alkyl or optionally substituted phenyl.
26. A compound as claimed in any one of Claims 14 or 22 to 25, wherein
T
R represents H, Cι- alkyl (which alkyl group is optionally interrupted by oxygen), optionally substituted phenyl or Het 21
27. A compound as claimed in any one of Claims 14 or 22 to 26, wherein R33 represents Cι_6 alkyl or optionally substituted phenyl.
28. A compound as claimed in any one of Claims 1 to 14 or 22 to 27, wherein R37a and R37b independently represent, at each occurrence when used herein, C1.5 alkyl, optionally substituted phenyl, or R37a represents H.
29. A compound as claimed in any one of Claims 1 to 28, wherein R3a and R3b independently represent H, C1-2 alkyl, -SR38b, -N(R39)R38c, or R3a and R together represent C3-4 alkylene or -O-Z-O-.
30. A compound as claimed in Claim 29, wherein R represents H, Cj.2 alkyl or a structural fragment of formula la.
31. A compound as claimed in any one of Claims 1 to 30, wherein Z represents C2-3 alkylene.
32. A compound as claimed in any one of Claims 1 to 31, wherein R41 to R4 independently represent H or C1-2 alkyl.
33. A compound as claimed in Claim 13 or Claim 14, wherein R 14b , r R> 14c
17 91
R and R independently represent C1-4 alkyl.
34. A compound as claimed in any one of Claims 13, 14 and 29, wherein R15b to R15p, R20b, R24, R26, R38b and R38c independently represent H or C1-5 alkyl.
35. A compound as claimed in any one of Claims 1 to 34, wherein optional substituents on phenyl groups are one or more substituents selected from cyano, halo, nitro, Cι-2 alkyl, Cι-2 alkoxy, Het1, -NH2, -C(0)R15c, -C(0)N(H)R15f, -N(H)C(0)R15h, -N(H)C(0)N(H)R15k, -N(H)S(0)2R14b and -S(0)2N(R15n)R15p.
36. A pharmaceutical formulation including a compound as defined in any one of Claims 1 to 35 in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.
37. A pharmaceutical formulation for use in the prophylaxis or the treatment of an arrhythmia, comprising a compound as defined in any one of Claims 1 to 35.
38. A compound as defined in any one of Claims 1 to 35, but without proviso (e), for use as a pharmaceutical.
39. A compound as defined in any one of Claims 1 to 35, but without proviso (e), for use in the prophylaxis or the treatment of an arrhythmia.
40. The use of a compound as defined in any of one Claims 1 to 35, but without proviso (e), as active ingredient for the manufacture of a medicament for use in the prophylaxis or the treatment of an arrhythmia.
41. The use as claimed in Claim 40, wherein the arrhythmia is an atrial or a ventricular arrhythmia.
42. A method of prophylaxis or treatment of an arrhythmia which method comprises administration of a therapeutically effective amount of a compound as defined in any one of Claims 1 to 35, but without proviso (e), to a person suffering from, or susceptible to, such a condition.
43. A process for the preparation of a compound of formula I as defined in Claim 1 which comprises:
(a) reaction of a corresponding compound of formula II,
Figure imgf000095_0001
wherein R2, R3a, R3b and R41 to R46 are as defined in Claim 1, with a compound of formula III,
Figure imgf000095_0002
wherein L1 represents a leaving group and R , R5, R , A and B are as defined in Claim 1;
(b) for compounds of formula I in which R1 represents a structural fragment of formula la in which A represents C2 alkylene and R4 and R5 together represent =0, reaction of a corresponding compound of formula II, as defined above, with a compound of formula IV,
Figure imgf000095_0003
wherein R and B are as defined in Claim 1 ;
(c) for compounds of formula I in which R 3a or R » 3b represents -N(R , 39Λ )-RΓ) 3" 8C and R >39 represents a structural fragment of formula la, reaction of a corresponding compound of formula I in which R 3a or R > 3b (as appropriate) represents -N(H)R38c, wherein R38c is as defined in Claim 1, with a compound of formula III as defined above;
(d) for compounds of formula I in which R represents a fragment of formula la in which A represents CH2 and R4 represents -OH or -N(H)R8, reaction of a corresponding compound of formula II, as defined above, with a compound of formula V,
Figure imgf000096_0001
o o wherein X represents O or N(R ) and R , R , R and B are as defined in
Claim 1;
(e) for compounds of formula I in which R a or R represents -N(R )R c and R represents a structural fragment of formula la in which A represents
CH2 and R4 represents -OH or -N(H)R8, reaction of a corresponding compound of formula I in which R3a or R3 (as appropriate) represents
-N(H)R38c, wherein R38c is as defined in Claim 1, with a compound of formula V as defined above; (f) for compounds of formula I in which A represents Cι,6 alkylene, B represents C1-4 alkylene and R4 and R5 both represent H, reduction of a corresponding compound of formula I in which R and R together represent
=0;
(g) for compounds of formula I in which R4 and R5 both represent H and (1)
1 A represents a single bond or -J-N(R ) and B represents C1-4 alkylene, or (2) A represents Cι-6 alkylene and B represents N(R13) or -N(R13)-L-, reduction of a corresponding compound of formula f in which R4 and R5 together represent =0; (h) for compounds of formula I in which A represents C1-6 alkylene, B
1 n represents a direct bond, C1-4 alkylene, -L-N(R )-, -L-S(0)p- or -L-O- (in which latter three groups L represents C1- alkylene), R4 represents OH and R5 represents H, reduction of a corresponding compound of formula I in which R and R together represent =0; (i) for compounds of formula I in which R3a and R3b both represent H, reduction of a corresponding compound of formula VI,
Figure imgf000097_0001
wherein R1, R2 and R41 to R46 are as defined in Claim 1, and in which the bridgehead C=0 group may be activated;
(j) for compounds of formula I in which one of R3a and R3b represents H, and the other represents -OH, reduction of a corresponding compound of formula VI, as defined above;
(k) for compounds of formula I in which R3a and R3b both represent -OR38a or -SR38b, or in which R3a and R3b together represent -0-Z-O-, -O-Z-S- or -S-Z-S-, reaction of a corresponding compound of formula VI, as defined above, with a compound of formula HOR38a, HSR38b, HO-Z-OH, HO-Z-SH or HS-Z-SH (as appropriate), wherein R38a, R38b and Z are as defined in Claim 1 ;
(1) for compounds of formula I in which one of R3a and R3b represents -NH2 and the other represents H, reduction of a compound of formula VII,
Figure imgf000097_0002
wherein R1, R2 and R41 to R46 are as defined in Claim 1; (m) for compounds of formula I in which one or both of R3 and R3b represent -N(R39)R38c in which one or both of R .3j9y and R » 3J8δcC represents C1-6 alkyl, alkylation of a corresponding compound of formula I in which R and/or R3b represent -N(R39)R38c (as appropriate) in which R39 and/or R38c (as appropriate) represent H, using a compound of formula VIII,
Ra-L! VIII wherein Ra represents C1-6 alkyl and L1 is as defined above; (n) for compounds of formula I in which R1 represents a structural fragment of formula la in which B represents -L-O-, reaction of a compound of formula IX,
Figure imgf000098_0001
wherein R2, R3a, R3b, R4, R5, R41 to R46, A and L are as defined in Claim 1, with a compound of formula X,
R6OH X in which R is as defined in Claim 1 ;
(o) for compounds of formula I in which R1 represents a structural fragment of formula la in which A represents Cι-6 alkylene and B represents -N(R13)- L- (wherein the group -N(R13)- is attached to the carbon atom bearing R4 and R ), reaction of a compound of formula XI,
Figure imgf000099_0001
wherein A represents C1-6 alkylene and R2, R3a, R3b, R4, R5, R13 and R41 to R46 are as defined in Claim 1, with a compound of formula XII,
R6-L-L2 XII wherein L
Figure imgf000099_0002
and L are as defined in Claim
(p) for compounds of formula I in which R represents a structural fragment of formula la in which R4 represents -D-NH2, reduction of a corresponding compound of formula XIII,
Figure imgf000099_0003
wherein R2, R3a, R3b, R5, R6, R41 to R46, A, B and D are as defined in Claim i;
(q) for compounds of formula I in which R4 represents -D-N(R9)C(0)NH(R1 lb), reaction of a corresponding compound of formula I in which R4 represents -D-N(R9)H with a compound of formula XIV,
Figure imgf000099_0004
wherein R , 11b is as defined in Claim 1;
(r) for compounds of formula I in which R represents -D-N(H)[C(0)]2NH2, reaction of a corresponding compound of formula I in which R4 represents
-D-NH2 with oxalic acid diamide;
(s) for compounds of formula I in which R4 represents -D-N(R8)R9, wherein
R8 and R9 are as defined in Claim 1, provided that R8 does not represent H, reaction of a corresponding compound of formula I, in which R4 represents
-D-N(H)R with a compound of formula XV,
R8a-L3 XV wherein R ,8a represents R as defined in Claim 1 except that it does not represent H, and L3 represents a leaving group;
(t) for compounds of formula I in which R represents -D-OR7 in which R7 represents Cj_6 alkyl, -E-aryl or -E-Het , reaction of a corresponding compound of formula I in which R4 represents -D-OH with a compound of formula XVI, .
R7aOH XVI wherein R7a represents C1-6 alkyl, -E-aryl or -E-Het1, wherein Het1 is as defined in Claim 1 ;
(u) for compounds of formula I in which R represents a structural fragment 7 7 of formula la in which R represents -D-OR (in which R represents Cι-6 alkyl, -E-aryl or -E-Het1), reaction of a corresponding compound of formula XVII,
Figure imgf000100_0001
wherein R2, R3a, R3b, R5, R6, R41 to R46, A, B and D are as defined in Claim
1 and L2 is as defined above, with a compound of formula XVI as defined above;
(v) for compounds of formula I in which R4 represents -D-OR7, wherein R7 is as defined in Claim 1, provided that it does not represent H, reaction of a corresponding compound of formula I in which R4 represents -D-OH with a compound of formula XVIII,
R7b-L4 XVIII wherein R7b represents R7 as defined in Claim 1, except that it does not represent H, and L4 represents a leaving group;
(w) for compounds of formula I in which R4 represents halo, substitution of a corresponding compound of formula I in which R4 represents -OH, using an appropriate halogenating agent;
(x) reaction of a corresponding compound of formula XIX,
Figure imgf000101_0001
wherein R1, R3a, R3b and R41 to R46 are as defined in Claim 1, with a compound of formula XX,
R2-L5 XX wherein L represents a leaving group and R is as defined in Claim 1 ; (y) for compounds of formula I in which R2 represent Cι_ι2 alkyl, which alkyl group is substituted at the C-2 carbon (relative to the bispidine nitrogen) with OH or N(H)R , and is otherwise optionally substituted with one or more further substituents as specified in Claim 1 for R2, reaction of a compound of formula XIX as defined above with a compound of formula XXA
Figure imgf000102_0001
wherein Xa represents O or N(R30) and R a represents Cι_ιo alkyl, optionally substituted with one or more substituents as specified in Claim 1 for R ; (z) for compounds of formula I in which R2 represents tetrazol-5-yl, reaction of a corresponding compound of formula I in which R2 represents -CN with a source of the azide ion;
(aa) for compounds of formula I which are bispidine-nitrogen N-oxide derivatives, oxidation of the corresponding bispidine nitrogen of a corresponding compound of formula I, in the presence of a suitable oxidising agent;
(ab) for compounds of formula I which are C1- alkyl quaternary ammonium salt derivatives, in which the alkyl group is attached to a bispidine nitrogen, reaction, at the bispidine nitrogen, of a corresponding compound of formula I with a compound of formula XXI,
Rb-L2 XXI wherein Rb represents C1- alkyl and L2 is as defined above;
(ac) conversion of one substituent on R to another; (ad) conversion of one R group to another; or
(ae) deprotection of a protected derivative of a compound of formula I as defined in Claim 1.
44. A compound of formula II, as defined in Claim 43, or a protected derivative thereof.
45. A compound of formula VI, as defined in Claim 43, or a protected derivative thereof.
46. A compound of formula VII, as defined in Claim 43, or a protected derivative thereof.
47. A compound of formula IX, as defined in Claim 43, or a protected derivative thereof.
48. A compound of formula XI, as defined in Claim 43, or a protected derivative thereof.
49. A compound of formula XIII, as defined in Claim 43, or a protected derivative thereof.
50. A compound of formula XVII, as defined in Claim 43, or a protected derivative thereof.
51. A compound of formula XIX, as defined in Claim 43 (provided that at least one of R3a and R3b represents -N(R39)R38c, wherein R39 represents a structural fragment of formula la, as defined in Claim 1), or a protected derivative thereof.
52. A compound of formula XXII,
Figure imgf000103_0001
wherein R3a, R3b and R4! to R46 are as defined in Claim 1 (provided that at least one of R » 3a and R , 3b represents -N(R 39 )-Rn 38cc, wherein R .39 represents a structural fragment of formula la, as defined in Claim 1), or a protected derivative thereof.
53. A compound of formula XXIII,
XXIII
Figure imgf000104_0001
wherein R and R to R are as defined in Claim 1, or a protected derivative thereof.
PCT/SE2001/001544 2000-07-07 2001-07-04 New bispidine compounds and their use in the treatment of cardiac arrhythmias WO2002004446A1 (en)

Priority Applications (16)

Application Number Priority Date Filing Date Title
SK4-2003A SK42003A3 (en) 2000-07-07 2001-07-04 New bispidine compounds and their use in the treatment of cardiac arrhythmias
NZ523540A NZ523540A (en) 2000-07-07 2001-07-04 New bispidine compounds and their use in the treatment of cardiac arrhythmias
BR0112267-3A BR0112267A (en) 2000-07-07 2001-07-04 Compound, pharmaceutical formulation, use of a compound, method of prophylaxis or treatment of an arrhythmia, and process for the preparation of a compound
MXPA02012942A MXPA02012942A (en) 2000-07-07 2001-07-04 New bispidine compounds and their use in the treatment of cardiac arrhythmias.
KR10-2003-7000248A KR20030014426A (en) 2000-07-07 2001-07-04 New bispidine compounds and their use in the treatment of cardiac arrhythmias
AU2001271161A AU2001271161A1 (en) 2000-07-07 2001-07-04 New bispidine compounds and their use in the treatment of cardiac arrhythmias
US10/332,103 US20030212095A1 (en) 2000-07-07 2001-07-04 New bispidine compounds and their use in the treatment of cardiac arrhythmias
EP01950132A EP1301510A1 (en) 2000-07-07 2001-07-04 New bispidine compounds and their use in the treatment of cardiac arrhythmias
HU0301304A HUP0301304A2 (en) 2000-07-07 2001-07-04 New bispidine compounds and their use in the treatment of cardiac arrhythmias, process for their preparation
PL36047401A PL360474A1 (en) 2000-07-07 2001-07-04 New bispidine compounds and their use in the treatment of cardiac arrhythmias
EEP200300013A EE200300013A (en) 2000-07-07 2001-07-04 Novel bispidine compounds and their use in the treatment of cardiac arrhythmias
IL15348501A IL153485A0 (en) 2000-07-07 2001-07-04 New bispidine compounds and their use in the treatment of cardiac arrhythmias
CA002412848A CA2412848A1 (en) 2000-07-07 2001-07-04 New bispidine compounds and their use in the treatment of cardiac arrhythmias
JP2002509311A JP2004502772A (en) 2000-07-07 2001-07-04 Novel bispidine compounds and their use in the treatment of cardiac arrhythmias
IS6660A IS6660A (en) 2000-07-07 2002-12-19 New bispidine compounds and their use in the treatment of arrhythmias
NO20030057A NO20030057L (en) 2000-07-07 2003-01-06 New bispidine compounds and their use in the treatment of cardiac arrhythmias

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SE0002603A SE0002603D0 (en) 2000-07-07 2000-07-07 New compounds
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US7399765B2 (en) 2003-09-19 2008-07-15 Abbott Laboratories Substituted diazabicycloalkane derivatives
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RU2472793C1 (en) * 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-bis[(tert-butylamino)methyl]-n,n'-di-tert-butylbispidin-9-one and method for production thereof

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