ZA200109796B

ZA200109796B - New bispidine compounds useful in the treatment of cardiac arrhythmias.

Info

Publication number: ZA200109796B
Application number: ZA200109796A
Authority: ZA
Inventors: Christer Alstermark; Annika Bjoere; Eva-Lotte Lindstedt Alstermark; Magnus Polla; Ylva Oertengren; Kjell Andersson; Magnus Bjoersne; Goeran Nilsson; Gert Strandlund
Original assignee: Astrazeneca Ab
Priority date: 1999-06-16
Filing date: 2001-11-28
Publication date: 2003-02-28
Also published as: IL146754A0; BR0011660A; SK18272001A3; WO2000077000A9; HK1045520A1; PL354032A1; RU2250903C2; TR200103663T2; AU761576B2; CN1370167A; HUP0203959A2; KR20020010713A; AU6032400A; JP2003502329A; CZ20014495A3; NZ516013A; AR024577A1; EE200100675A; HUP0203959A3; CN1144805C

Description

NEW BISPIDINE COMPOUNDS USEFUL 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 tachyarrhythmias (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 :

So oo PCT/SE00/01254 . | 5 ~~ or from an increase of inward ion currents) and refractoriness, without ~ affecting cardiac conduction.’ : oo :

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 proarthythmia known. as forsades 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 oo phenothiazines, micyclic antidepressants, antihistamines and antibiotics) is a oo key problem to be solved in the provision of effective antiarrhythmic drugs.

Co | ‘Antiarrhythmic drugs based on bispidines (3 7-diazabicyclo[3.3.1]nonanes), : oo are known from inter alia international patent -application WO 91/07405, a

European patent applications 306 871, 308 843 and 665 228 and US patents © 3,962,449, 4,556,662, 4,550,112, 4,459,301 and 5,468,858, as well as journal articles including inter alia J. Med. Chem. 39, 2559, (1996), . Pharmacol. Res, 24, 149 (1991), Circulation, 90, 2032 (1994) and Anal. Co

Sci. 9, 429, (1993). Known bispidine-based antiarrhythmic compounds © 2 include bisaramil (3-methyl-7-ethyl-9c, 4'-(Cl-benzoyloxy)-3,- oo diazabicyclo[3.3.1]oonane), tedisamil (3',7'-bis(cyclopropylmethyl)spiro- oo (cyclopentane-1,9')-3,7-diazabicyclo[3.3.1]nonane), SAZ-VII-22 (3-(4- chlorobenzoyl)-7-iso-propyl-3,7-diazabicyclo[3.3.1]nonane), SAZ-VII-23 : (3-benzoyl-T-iso-propyl-3,7-diazabicyclo[3.3. 1]nonane), GLG-V-13 (3-[4- (1H-imidazol-1 -yl)benzoyl] -7-iso-propyl-3,7-diazabicyclo[3.3.1]nonane), :

KMC-IV-84 (7-[4'-(1H-imidazolo-1 -yl)benzenesulfonyl] 3-iso-propyl-3 J7- diazabicyclo[3.3. 1]nonane dihydroperchlorate and ambasilide (3-(4- aminobenzoyl)-7-benzyl-3,7-diazabicyclo[3.3. 1]nonane). oo 3

I © AMENDED SHEET = So

We have surprisingly found that a novel group of bispidine-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, -

RS R44 fe)

R46! R42 N

RIC AN

B A \

Re J OK

R3 wherein

R! and R? independently represent H, C,, alkyl, OR? or N(R*)R¥, or together form -O-(CH,),-O-, (CH,)s-, -(CH.,),- or -(CH,)s-;

R?*, R* and R* independently represent H or C4 alkyl;

R3 represents H, C,, alkyl or, together with R*, represents C,¢ alkylene (which alkylene group is optionally interrupted by an O atom and/or is optionally substituted by one or more C,_; alkyl groups); - R* represents H, C,_,, alkyl, C,, alkoxy (which latter two groups are both optionally substituted and/or terminated by one or more substituents selected from -OH, halo, cyano, nitro, C, alkyl and/or C,_, alkoxy),

-AVO0 00/77000 . PCT/SE00/01254 -(CH,) aryl, -(CHp) -oxyaryl, (CHa Het (which latter three groups are } optionally substituted (at the -(CH,),- part and/or the aryl/Het' part) by one or more substituents selected from -OH, halo, cyano, nitro, -C(O)R', -C(O)OR!Y, -N(H)S(0),R!"?, C4 alkyl and/or C, 4 alkoxy), 5s -(CH,);N(H)C(O)R®, -(CH,);S(0),R?, -(CH,),C(O)R®, -(CH,),C(O)OR®, -(CH,),C(O)N(R*)R® or, together with R’, represents Cs alkylene (which alkylene group is optionally interrupted by an O atom and/or is optionally substituted by one or more C, 5 alkyl groups); q represents 0, 1, 2, 3, 4, 5 or 6;

R® represents H, C,¢ alkyl, aryl (which latter group is optionally substituted and/or terminated by one or more substituents selected from : -OH, halo, cyano, nitro, -C(O)R!, -C(O)OR", -N(H)S(0),R"*, C, alkyl and/or C, alkoxy) or, together with R’, represents Cs; alkylene;

R® represents H, C,, alkyl or, together with R®, represents Cj, alkylene;

Het! represents a five to twelve-membered heterocyclic ring containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, and which also optionally includes one or more =O substituents;

R*, R%, R®, R¥, R* or R* independently represent H or C,, alkyl,

RS represents H, halo, C,; alkyl, -OR", -N(R*)R" or, together with R®, represents =0;

R® represents H, C,_, alkyl or, together with R’, represents =O;

R" represents H, C, 4 alkyl, -S(0).-C, 4-alkyl, -C(O)R", -C(O)OR", -C(O)N(R¥)R™ or aryl (which latter group is optionally substituted and/or terminated by one or more substituents selected from -OH, halo, cyano, nitro, -C(O)RY, -C(O)OR!, -N(H)S(O),R"3, C,; alkyl and/or C4 alkoxy);

R! represents H or C,, alkyl;

R" represents H or C, alkyl,

R" and R'* independently represent H or C,, alkyl, or together represent

C,. alkylene, optionally interrupted by an O atom;

A represents a single bond, C4 alkylene, -N(R'®)(CH,),- or -O(CH,),.- (in which two latter groups, the -(CH,),- group is attached to the bispidine nitrogen atom);

B represents a single bond, C,, alkylene, -(CH,),N(R")-, -(CH,),S(O),-, -(CH,),O- (in which three latter groups, the -(CH,),- group is attached to the carbon atom bearing R® and R®), -C(O)N(R')- (in which latter group, the -C(O)- group is attached to the carbon atom bearing R’ and R®), -NR")C(0)O(CH,),-, -N(R)CH,),- (in which two latter groups, the

N(R") group is attached to the carbon atom bearing R® and R®) or -(CHy),C(H)(OH)(CH,),- (in which latter group, the -(CH,),- group is attached to the carbon atom bearing R’ and R®); " mrepresents 1, 2 or 3; n and r independently represent 0, 1, 2, 3 or 4; p represents 0, 1 or 2;

R' and RY independently represent H or C,, alkyl,

R’ represents C,; alkyl, aryl or Het?, all of which groups are optionally substituted and/or terminated (as appropriate) by one or more substituents selected from -OH, cyano, halo, amino, nitro, Het’, -C(O)R'®, -C(O)ORY, C4 alkyl, C, 4 alkoxy, -N(H)S(O),R'3, -S(O),R", -OS(0),R®, -NH)C(O)N(H)R?, -C(O)N(H)R* and/or aryl (which latter group is optionally substituted by one or more cyano groups);

Het? and Het® independently represent a five to twelve-membered heterocyclic group containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, and ich also optionally includes one or more =O substituents;

R'®¥, R! and R? independently represent C, ¢ alkyl;

R?* and R* independently represent H or C4 alkyl (optionally terminated s by cyano); and

R! and R! independently represent, at each individual occurrence, H or

C,. alkyl;

R'"* represents, at each individual occurrence, C,; alkyl; : or a pharmaceutically acceptable derivative thereof; provided that: (a) when.A and B are both single bonds and R’ is optionally substituted . aryl, then R® and R® do not both represent H; (b) when A represents a single bond, then R® and R® do not together represent =O; and (c) when R’ represents -OR" or ~-N(R*)R!?, then:- (i) A does not represent -N(R!®)(CH,),- or -O(CH,),-; and/or (ii) n does not represent 0 when B represents -(CH,),N(R")-, ~(CH,),S(0),- or ~(CH,),0-, which compounds are referred to hereinafter as “the compounds of the invention”.

Aryl groups that may be mentioned include Cg, aryl groups, such as phenyl, naphthyl and the like. Oxyaryl groups that may be mentioned “include Cq jy oxyaryl groups, such as oxyphenyl (phenoxy), oxynaphthyl

(naphthoxy) and the like. When substinuted, aryl and aryloxy groups are preferably substituted by one to three substituents.

Het'!, Het’? and Het’ groups that may be mentioned include those 5s containing 1 to 4 heteroatoms (selected from the group oxygen, nitrogen and/or sulfur) and in which the total number of atoms in the ring system are between five and twelve. Het (Het!, Het’ and Het’) groups may be wholly/partly aromatic in character and may be bicyclic. Heterocyclic groups that may be mentioned include morpholinyl, thiazolyl, oxazolyl, isoxazolyl, cinnolinyl, quinazolinyl, phthalazinyl, purinyl, benzimidazolyl, pyrimindinyl, piperazinyl, pyrazinyl, piperidinyl, pyridinyl, triazolyl, imidazolyl, quinolinyl, isoquinolinyl, dioxanyl, benzodioxanyl, benzodioxolyl, benzodioxepanyl, benzomorpholinyl, indolyl, pyrazolyl, pyrrolyl, benzothiophenyl, thiophenyl, chromanyl, thiochromanyl, benzofuranyl, pyranyl, tetrahydropyranyl, tetrahydrofuranyl, furanyl and the like. Values of Het! that may be mentioned include tetrahydropyranyl, isoxazolyl, benzodioxolyl, benzodioxepanyl and thiophenyl. Values of

Het that may be mentioned include quinolinyl, isoquinolinyl, benzomorpholinyl, benzodioxanyl, piperazinyl, indolyl and pyrazolyl.

Values of Het? that may be mentioned include imidazolyl. Substituents on

Het (Het!, Het® and Het’) groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of Het (Het!, Het> and Het’) groups may be vig any atom in the ring system including (where appropriate) a heteroatom. Het (Het!, Het? and Het’) groups may also be in the N- or S-oxidised form.

Pharmaceutically acceptable derivatives include salts and solvates. Salts which may be mentioned include acid addition salts. Pharmaceutically acceptable derivatives also include, at the bispidine nitrogens, C, alkyl quaternary ammonium salts and N-oxides, provided that when a N-oxide 1S present: (2) no Het (Het!, Het?, Het?) group contains an unoxidised S-atom; and/or (b) p does not represent O when B represents -(CH,),S(O),-.

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.

Alkyl groups that R!, R?, R®, R*, R¥ R’, RY R’, RS, R’, R%, R’ RY,

RY, R12, R, RS, RY, RY, R12 RS, RY, R!8 RY, R®, R*, R%, R*,

R*, R*®, R*, R* and R* may represent, that R' may include, and with which R3, R%, R’, R® and R'? may be substituted; and alkoxy groups that

R* may represent, and with which R*, R’, R® and R" may be substituted; may be linear or, when there is a sufficient number (i.e. three) of carbon atoms, be branched and/or cyclic. Further, when there is a sufficient number (i.e. four) of carbon atoms, such alkyl and alkoxy groups may also be part cyclic/acyclic. Such alky! and alkoxy groups may also be saturated or, when there is a sufficient number (i.e. two) of carbon atoms, be unsaturated and/or interrupted by oxygen.

Alkylene groups that R® and R*, R® and R®, R" and R'®, A, and B, may represent; and -(CH,),,-, -(CH,),-, -(CH,),- and -(CH,),- chains that A, B and R* (as appropriate) may include, may be linear or, when there is a sufficient number (i.e. two) of carbon atoms, be branched. Such alkylene groups and -(CH,)- containing chains may also be saturated or, when there is a sufficient number (i.e. two) of carbon atoms, be unsaturated and/or interrupted by oxygen.

Halo groups that R® may represent, and with which R*, R7, R® and R*? may be substituted, include fluoro, chloro, bromo and iodo.

For the avoidance of doubt, each R'®, R!, and R!'?, group identified herein is independent of other R', RY, and RM, groups, respectively. For example, when.R* and R’ both represent aryl substituted by -C(O)R', the two individual -C(O)R' substituents are independent of one another, and are not necessarily identical (though this possibility is not excluded).

Abbreviations are listed at the end of this specification.

According to a further aspect of the invention there is provided compounds of formula I as hereinbefore defined, but with the further provisos that: (a) when A represents -N(R'®)(CH,),- or -O(CH,),-, then r does not represent O or 1; and

(b) when R® represents -OH or NRHRE. then B does not represent -NR)C(0)O(CH,),- or -N(R")(CH,),-.

Preferred compounds of the invention include those in which:

R! represents H;

R? represents H;

R? represents

H;

C,, alkyl; or, together with R* represents C, 5 alkylene, optionally interrupted by an

O atom and/or optionally substituted by one or more methyl groups;

R* represents

H; linear or branched and/or saturated or unsaturated and/or cyclic, acyclic and/or part cyclic/acyclic C, 3 alkyl (which alkyl group is optionally substituted by one or more cyano or halo groups and/or interrupted by an 0] atom);

C, alkoxy; -(CH,)S(0),R®, -(CH,),C(O)OR?, (CH) N(H)C(O)R?, -(CH,),C(O)R®, (in which latter four groups, q represents 0, 1 or 2 and R® represents linear or branched and/or acyclic, cyclic and/or part cyclic/acyclic C,, alkyl, or phenyl (which phenyl group is optionally substituted by one or more cyano and/or C,; alkyl groups)); ~(CH,),C(O)N(R’)R® (in which latter group, q represents 0, 1 or 2 and R® and R’ independently represent H, linear or branched and/or acyclic, cyclic and/or part cyclic/acyclic C,, alkyl, or together represent Cg alkylene); -(CH,),-phenyl, -(CH),-oxyphenyl or ~(CH,)-Het' (in which latter three groups, q represents 0, 1, 2 or 3, the -(CH,),- part is optionally substituted by a cyano group, and ihe phenyl, or Het', part is optionally substituted with one or more substituents selected from cyano, nitro, linear or branched C,, alkyl, linear or branched C,, alkoxy and N(H)S(O),R!"); or, together with R?, represents C,, alkylene, optionally interrupted by an O atom and/or optionally substituted by one or more methyl groups;

R® represents

H; fluoro;

OR" (in which R" represents H, phenyl (optionally substituted by one or more methoxy groups) or C(O)N(H)R'® (in which R'® represents linear or branched C, alkyl)); ~-NR")(R") (in which R* represents H, C,,, alkyl, -S(0),-C, , alkyl, -C(O)R'™ (in which R" represents C,, alkyl), -C(O)OR™ (in which R* represents linear or branched C,s alkyl) or -C(O)N(R*)(R!*®) (in which RY and R'* independently represent H or linear or branched C,, alkyl or together represent C,s alkylene, which alkylene group is optionally interrupted by an O atom) and R* represents H or C, , alkyl); or, together with R®, represents =O (especially in the case where R’ represents alkyl or Het?);

R® represents H or C,, alkyl or together with R® represents =O (especially in the case where R’ represents alkyl or Het?);

A represents a single bond, linear or branched C,, alkylene (which group is also optionally interrupted by O), -N(H)(CH,),- or -O(CH,),- (in which latter two groups ris 1 or 2);

B represents a single bond, C, 4 alkylene, -(CH,),0-, -(CH,),S(O),-, -(CHp),N(H)- or -N(H)(CH,),- (in which latter four cases nis 0, 1, 2 or 3);

R’ represents linear or branched and/or acyelic, cyclic and/or part cyclic/acyclic

C, alkyl (optionally substituted and/or terminated by OH);

Het? (optionally substituted by one or more substituents selected from cyano, C,, alkyl, phenyl (which latter group is optionally substituted with 5s one or more cyano groups), =0, C(O)R' (in which R! is linear or branched C, ; alkyl) or S(O),R" (in which RY is C,, alkyl)); or phenyl (optionally substituted by one or more substituents selected from cyano, nitro, linear or branched C,; alkyl, linear or branched C,, alkoxy, fluoro, chloro, C(O)N(H)R* (in which R* represents linear or branched and/or acyclic, cyclic and/or part cyclic/acyclic C,_, alkyl, which alkyl group is optionally terminated by cyano), N(H)S(O),R'® (in which R'® represents C,, alkyl) or Het’);

RY, R%, R*, R*, R* and R* all represent H.

More preferred compounds of the invention include those in which:

R? represents H; :

R’ represents H, OH or -N(H)C(O)NR)(R"™);

R® represents H;

A represents -CH,- or -(CH,),-;

B represents a single bond, -CH,N(H)- or -CH,0- (where, for the avoidance of doubt, the ~CH,- part is attached to the carbon atom bearing R® and R%);

R’ represents phenyl (substituted by a cyano group (preferably in the 4- position relative to B) and by ome or more optional C(O)N(H)R> substituent).

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) for compounds of formula I in which R? is H, reaction of a compound of formula II, 1 R2 ll

RS R34 v2 . RI~_ AN id N * ) a

B A

Re wherein R!, R?, R®, R%, R7, R¥, R*®, R®, R®, R¥, R%, A and B are as hereinbefore defined with a compound of formula III,

R*-N=C=0 II 15s wherein R* is as hereinbefore defined, for example at between 0°C and reflux temperature in the presence of an appropriate organic solvent (e.g. dichloromethane), or via solid phase synthesis under conditions known to those skilled in the art; (b) reaction of a compound of formula II, as hereinbefore defined, with a carbonic acid derivative of formula IV, (R)R)NC(0)-L! IV

Claims

- 106 PCT/SE00/01254 Claims

N 1. A compound of formula I, . 1 R2 45 R43 R41 } BN . : N E

RS . : R44 Le ree N\ o R7 AN IR Sp AT \ RS ya ) . 5 . R3 : wherein Rand R? independently represent H, C,, alkyl, OR® or NR*)R¥, or BN oo together form -O-(CH,),-O-, ~(CH,);-, ~(CH,),- or -(CH,)s-; R?®, R*:and R* independently represent H or C, 4 alkyl; R? represents H, C,¢ alkyl or, together with R¥, represents C,, alkylene a 15 (which alkylene group is optionally interrupted by an O atom and/or is optionally substituted by one or more C,; alkyl groups); ~ Rfrepresents H, C,, alkyl, C,¢ alkoxy (which latter two groups are both “optionally ‘substituted and/or terminated by one or more substituents selected from -OH, halo, cyano, nitro, C,, alkyl and/or C, alkoxy), -(CHy) aryl, -(CH,),-0xyaryl, -(CH,)-Het! (which latter three groups are optionally substituted (at the -(CH,),- part and/or the aryl/Het' part) by one or more substituents selected from -OH, halo, cyano, nitro, -C(O)R?, -C(O)OR", -N(H)S(O),R'™, C, alkyl and/or C, alkoxy), CLEAN COPY

107 PCT/SE00/01254 ® -(CH,)N(H)C(O)R?, -(CH,),S(0),R*, ~(CH,){C(O)R®, -(CH,),C(O)OR?, -(CH,),C(O)N(R’R® or, together with R?, represents C,4 alkylene (which alkylene group is optionally interrupted by an O atom and/or is optionally substituted by one or more C, ; alkyl groups); qrepresents 0, 1,2, 3,4, 50r 6;

R® represents H, C4 alkyl, aryl (which latter group is optionally substituted and/or terminated by one or more substituents selected from -OH, halo, cyano, nitro, -C(O)R'?, -C(O)OR", -N(H)S(0),R!?, C, alkyl and/or C, 4 alkoxy) or, together with R®, represents C, , alkylene;

R’ represents H, C, alkyl or, together with R®, represents Cs, alkylene; - Het' represents a five to twelve-membered heterocyclic ring containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, and which also optionally includes one or more =O substituents;

1s RY, R*, R*®, R*, R* or R* independently represent H or C,, alkyl; R® represents H, halo, C,; alkyl, -OR®, -N(R**)R® or, together with RS,

represents =O, RS represents H, C,, alkyl or, together with R®, represents =O;

R" represents H, C, alkyl, -S(O),-C,,-alkyl, -C(O)R*, -C(O)OR, -C(O)N(R'*)R" or aryl (which latter group is optionally substituted and/or terminated by one or more substituents selected from -OH, halo, cyano, nitro, -C(O)R', -C(O)OR!, -N(H)S(O),R'*, C,, alkyl and/or C, alkoxy);

RP represents H or C, alkyl; R' represents H or C, alkyl; RY and R'** independently represent H or C, alkyl, or together represent C, alkylene, optionally interrupted by an O atom;

CLEAN COPY

108 PCT/SE00/01254 hd A represents a single bond, C, alkylene, -N(R')(CH,),- or -O(CH,).- (in which two latter groups, the -(CH,),- group is attached to the bispidine nitrogen atom); B represents a single bond, C,, alkylene, -(CH,) N(R!?)-, ~(CH,),S(0),-, oo -(CH,),O- (m which three latter groups, the -(CH,),- group is attached to the carbon atom bearing R® and R®), -C(O)N(R!")- (in which latter group, the -C(O)- group is attached to the carbon atom bearing R? and RY), -NR'MC(0)O(CHy),-, -N(R")(CH,),~ (in which two latter groups, the : N(R") group is attached to the carbon atom bearing R® and R®) or ~(CH,),C(H)OH)(CH,),- (in which latter group, the ~(CH,),- group is attached © the carbon atom bearing R? and RY); _ In represents 1, 2 or 3; nandr independently represent 0, 1, 2,3 0r4; Co p represents 0, 1 or 2; 13 R'® and R' independently represent H or C,, alkyl; oo oo R’ represents C,¢ alkyl, aryl or Het?, all of which groups are optionally substituted and/or terminated (as appropriate) by one or more substituents selected from -OH, cyano, halo, amino, nitro, Het?, -C(O)R™, : a 20 -C(O)ORY, C, 4 alkyl, C4 alkoxy, -N(H)S(O),R*, -S(0),RY, -0S(0),R®, ) -N(H)C(O)N (HRY, -C(O)N(H)R* and/or aryl (which latter group is optionally substituted by one or more cyano groups); ‘Het® and Het’ independently represent a five to twelve-membered heterocyclic group containing ome or more heteroatoms selected from oo : 25 oxygen, nitrogen and/or sulfur, and which also optionally includes one or oo more =0 substituents; I R', RY and R™ independently represent C, , alkyl; - - 5 R* and R” independently represent H or C, alkyl (optionally terminated Co Co | by cyano); and : | . CLEAN COPY

109 PCT/SE00/01254 R' and R'' independently represent, at each individual occurrence, H or C, alkyl; R'" represents, at each individual occurrence, C, alkyl; or a pharmaceutically acceptable derivative thereof; provided that: : : (a) when A and B are both single bonds and R7 is optionally substituted aryl, then R® and R® do not both represent H; : (b) when A represents a single bond, then R® and R® do not together represent =O; and (c) when R® represents -OR" or ~-N(R'*)R®, then:- (i) A does not represent ~-N(R!$)(CH,),- or ~O(CH,),~; and/or (ii) n does not represent 0 when B represents —(CH,) N(R!")-, -(CH,),S(0),- or -(CH,),0-. Co

~ 2. A compound as claimed in Claim 1, wherein R! represents H.

3. A compound as claimed in Claim 1 or Claim 2, wherein R? represents H.

4. A compound as claimed in any one of the preceding claims, wherein R* represents H; C,, alkyl; or, together with R* represents C,; alkylene, optionally interrupted by an O atom and/or optionally substituted by one or more methyl groups.

5. A compound as claimed in Claim 4, wherein R® represents H. CLEAN COPY

110 PCTI/SE00/01254 -® SE

6. A compound as claimed in any one of the preceding claims, wherein R* represents H; linear or branched and/or saturated or unsaturated and/or cyclic, acyclic and/or part cyclic/acyclic C,; alkyl (which alkyl group is optionally substituted by one or more cyano or halo groups and/or = : 5 interrupted by an O atom); C, alkoxy; -(CH,),S(O).R®, -(CHp),C(O)OR?, -(CHy) N(EH)C(O)R®, -(CH,),C(O)R®, (in which lamer four groups, q B represents 0, 1 or 2 and R® represents linear or branched and/or acyclic, cyclic and/or part cyclic/acyclic C,, alkyl, or phenyl (which phenyl group 1s optionally substituted by one or more cyano and/or C 3 alkyl groups)); ~(CH,){C(O)N(R”)R® (in which latter group, q represents 0, 1 or 2 and R® and R’ independently represent H, linear or branched and/or acyclic, cyclic and/or part cyclic/acyclic C, 4 alkyl, or together represent C, « alkylene); _— -(CH,)-phenyl, -(CH,),-oxyphenyl or -(CHy,-Het' (in which latter three groups, q represents 0, 1, 2 or 3, the -(CH,),- part is optionally substituted 1s by a cyano group, and the phenyl, or Het', part is optionally substituted oo no | with one or more substituents selected from cyano, nitro, linear or branched - Cy, alkyl, linear or branched C, alkoxy and NH)S(0),R!13); or, together - with R’, represents C,s alkylene, optionally interrupted by an O atom : and/or optionally substituted by one or more methyl groups. - | : : : :

7. A compound as claimed in any one of the preceding claims, wherein R® . represents H; fluoro; OR" (in which R™ represents H, phenyl (optionally substituted by one or more methoxy groups) or C(O)NH)R (in which R represents linear or branched C,, alkyl)); ~-NR™)R2) (in which R? represents H, Cy, alkyl, -S(0),-C,, alkyl, -C(O)R" (in which R' represents

C.. alkyl), -C(O)OR™ (in which R™ fepresents linear or branched C,; alkyl) or _C(O)N(R¥)(R**) (in which R® and R': independently represent - ) Hor Ynsar or branched C, ; alkyl or together represent Cs alkylene, which CLEAN COPY

111 PCT/SE00/01254 alkylene group is optionally interrupted by an O atom) and R!3 represents H or C,, alkyl); or, together with RS, represents =O.

8. A compound as claimed in Claim 7, wherein R® represents H, OH or 5s -NHCONRHRS).

9. A compound as claimed in any one of the preceding claims, wherein R® represents H or C,, alkyl or together with R® represents =0.

10. A compound as claimed in Claim 9, wherein R® represents H.

11. A compound as claimed in any one of the preceding claims, wherein A represents a single bond, linear or branched C, alkylene (which group Is also optionally interrupted by O), -N(H)(CH,),- or -O(CH,),- (in which latter two cases rislor?2).

12. A compound as claimed in Claim 11, wherein A represents -CH,- or -(CHy)s-.

13. A compound as claimed in any one of the preceding claims, wherein B represents a single bond, C,, alkylene, -(CH,),O-, -(CH,),S(0),-, -(CH,) N(H)- or -N(H)(CH,),- (in which latter four cases n is 0, 1, 2 or 3).

14. A compound as claimed in Claim 13, wherein B represents a single bond, -CH,N(H)- or -CH,0-.

15. A compound as claimed in any one of the preceding claims, wherein R’ represents linear or branched and/or acyclic, cyclic and/or part cyclic/acyclic C4 alkyl (optionally substituted and/or terminated by OH); CLEAN COPY

112 PCT/SE00/01254 ed Hee? (opuonally substituted by one or more substituents selected from cyano, C5 alkyl, phenyl (which latter group is optionally substituted with one Or more cyano groups), =0, C(O)RY (in which R' is linear or . branched C,; alkyl) or S(O),R" (in which R? is C,, alkyl): or phenyl (optionally substituted by one or more substituents selected from cyano, oo nitro, linear or branched C,. alkyl, linear or branched C3 alkoxy, fluoro, chloro, C(O)N(H)R* (in which RZ represents linear or branched and/or acyclic, cyclic and/or part cyclic/acyclic C,, alkyl, which alkyl group is optionally terminated by cyano), N(H)S(O),R'® (in which R'® represents C,, alkyl) or Het). | LT : : - 16. A compound as claimed in Claim 15, wherein R’ represents phenyl (substituted by a cyano group (preferably in the 4-position relative to B) and by one or more optional C(O)N(H)R? substituent). oo : . 15 | } .

17. A compound as claimed in any one of the preceding claims, wherein . “RR? RS, R¥, R% and R* all represent H. : wT

18. A pharmaceutical formulation including a compound as defined in any one of Claims 1 to 17 in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.

10. A pharmaceutical formulation for use in the prophylaxis or the treatment of an arrhythmia, comprising a compound as defined in any one . 25 of Claims 1 to. 17. : 20. A compound as defined in any ome of Claims 1 to 17 for use as a : pharmaceutical. CLEAN COPY

- PCT/SE00/01254

.21. A compound as defined in any one of Claims 1 to 17 for use in the prophylaxis or the treatment of an arrhythmia.

22. The use of a compound as defined in any one of Claims 1 to 17 ‘as active ingredient in the manufacture of a medicament for use in the prophylaxis or the : treatment of an arrhythmia. :

23. The use as claimed in Claim 22, wherein the arrhythmia is an atrial or a ventricular arrhythmia. : 24. A method of prophylaxis of an arrhythmia which method comprises administration of an effective amount of a compound as defined in any one of Claims 1 to 17 to a person susceptible to such a condition.

25. A process for the preparation of a compound of formula I as defined in Claim © 1 which comprises: (a) for compounds of formula I in which R3 is H, reaction of a compound of formula II, Co . . 1 R2 : 45 Re3 R41 . . y Co oo EE . RS R# : R42 RT yd N Ree N—y, : Co Sg A Rs E AMENDED SHEET

114 PCT/SE00/01254

@®. wherein R!, R?, R®, RS, R7, R*, R®, R®, R® R* R% A and B are as I defined in Claim 1 with a compound of formula III, R“N=C=0 | II wherein R* is as defined in Claim 1; (b) reaction of a compound of formula II, as defined above, with a carbonic acid derivative of formula Iv, : (R’)R*)NC(O)-L! AA wherein L' represents a leaving group and R*and R* are as defined in Claim CL | | - (c) reaction of a compound of formula V, - RL i : | E A Rés ™ Ra N__O oe AN AR B A l, Re ‘wherein and L' is as defined above and R!, R?, R?, RS, R, R*, R*, R*, 1s R¥%, R® R* A and B are as defined in Claim 1, with a compound of formula VA, oo | So : . ~ R)RYNH | VA wherein R? and R* are as defined in Claim 1; (d) for compounds of formula I in which A represents CH, and RS represents -OH or -N(H)R®Y, reaction of a compound of formula VI, oo - CLEAN COPY oo

115 PCT/SE00/01254 ° : 1 R2 45 R42 R41 Vi R44 No Re RZ N ° H SR R3 wherein R!, R?, R?, R*, RY, R*?, R®, R% R% and R* are as defined in Claim 1, with a compound of formula VII,

5 . Re wherein X represents O or N(R) and RS, R’, R™ and B are as defined in Claim 1; : (e) reaction of a compound of formula VI, as defined above, with a compound of formula VIII, S ay Rs Vil wherein L? represents a leaving group and R’, R6, R’, A and B are as defined in Claim 1; (f) for compounds of formula I in which R® represents H or OH and R® represents H, reduction of a compound of formula IX, . CLEAN COPY

116 PCT/SE00/01254

®. 1 R2 : ss RSS = ! | | | x . R44 : i Re Re nd .\ Sp nd STR or . wherein R!, R?, R?, R*, R7, R*, R™ R*, R*, R*, R% A and B are as + defined in Claim 1; (g) for compounds of formula I in which one of R! and R® represents H or : OH and the other represents H, reduction of a corresponding compound of oo formula X : ws R22 R41 ’ 7 : x

RS . R44 : J Re Rez nd R? oo ~g Id \ Rs yd OR 4 - wherein B®, RY, R?, RY, R’, R¥, R?, R¥, R* R® R% A and B are as defined in Claim 1; ol - (h) for compounds of formula I in which R' and R? together represent -O(CH,),0-, reaction of a corresponding compound of formula X as defined above with ethane-1,2-diol; : CLEAN COPY

: 117 PCT/SE00/01254 (1) for compounds of formula I in which B represents -(CH,),0-, reaction of * a compound of formula XI, 1 R? 5s Re R41 XI RS an Ree 1 y 0 BIEN Rd ~ le Nw RP s wherein R', R?, R?, RY, R®, R¢, R*, R¥, R*, R*%, R* R%_ A and n are as defined in Claim 1, with a compound of formula XIA, R’OH XIA in which R’is as defined in Claim 1; () 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; (k) for compounds of formula I which are C,, 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 XII, RPL | XII wherein R® represents C,, alkyl and L3 is a leaving group; () for compounds of formula I in which R® and R® represent H, A - represents C,¢ alkylene and B represents -N(R'”)(CH,),-, reaction of a compound of formula XIII, CLEAN COPY

' 118 PCT/SE00/01254

@. 45 R43 R41 . oo oo Xi Re 0 mir y Res R42 N \ ~ N— CH; —A? / In H STR ‘R3 - : wherein A® represents C, 4 alkylene and R!, R?, R®, R*, R*, R¥?, R¥ R#, E 5s R¥, R* and RY are as defined in Claim 1 with a compound of formula - XIV, N : R-(CHy),-L? Xv wherein L? is as defined above and R” and n are as defined in Claim 1; - : : (m) for compounds of formula I in which R® represents -NH,, reduction of a : 10 corresponding compound of formula XV, : | me oo 45 R23 R41 : XV N R44 ’ ] 3 N R46 R42 ~ . R? Co . Sp nd : \ Rs J OR go ~ wherein R', R%, R?, RY, R%, R’, R*, R®, R®, R%, R¥, R%, A and B are as defined in Claim 1; CLEAN COPY :

119 PCT/SE00/01254 ® (n) for compounds of formula I in which R’ represents -N(R")C(O)NH(R"), reaction of a corresponding compound of formula I in which R® represents -N(R**)H with a compound of formula XVI, RPN=C=0 XVI s wherein RY is as defined in Claim I; (0) for compounds of formula I in which R® represents -N(R)C(O)RY, reaction of a corresponding compound of formula I in which R® represents -N(R")H with a compound of formula XVII, RM™C(O)R* XVII wherein R* represents a suitable leaving group and R' is as defined in Claim 1; (p) for compounds of formula I in which R® represents -N(H)R'?, wherein R" is as defined in Claim 1 provided that it does not represent H, reaction of a corresponding compound of formula I, in which R® represents -NH, with a compound of formula XVIII, R21! Xvi wherein R'? represents R" as defined in Claim 1 provided that it does not represent Hand L is as defined above; (q) for compounds of formula I in which R® represents -OR'? in which R*? represents C,, alkyl or optionally substituted aryl, reaction of a corresponding compound of formula I in which R® represents -OH with a compound of formula XIX, ROH XIX wherein R'* represents C, alkyl or optionally substituted aryl; (r) for compounds of formula I in which R® represents -OR'?, in which R* represents C, 4 alkyl or optionally substituted aryl, reaction of a compound of formula XX, CLEAN.COPY

120 PCT/SE00/01254 ON ~ So ss R® © R® : XX : We N R46 Re R42 N © : PUA CE Rs J OR Co R3 Ee wherein L is as defined above and R', R?, R’, RE RORY R*, R%? R®, s R*, R® R¥% A and.B are as defined in Claim 1 with a compound of formula XIX as defined above; oo (s) for compounds of formula I in which R® represents.

OR? and R!? oo represents C(O)RY, reaction of a corresponding compound of formula I in a which R® represents OH with a compound of formula XX, . wo RICOH XXI oo wherein RY is as defined in Claim 1; | SE oo (t) for compounds of formula 1 in which R’ represents halo, substitution of a corresponding compound of formula I in which R® represents LOH, using an appropriate halogenating agent; oo 15 (u) for compounds of formula I in which R® and/or R* as appropriate . represent alkyl groups, alkylation of a corresponding compound of formula I, in which R® and/or R* (as appropriate) represent H; (v) conversion of one R* group to another; ° (w) for compounds of formula I in which one of R* and R® represents "20 -NH, and the other represents H, reduction of a compound of formula i.

XXIA, © CLEAN COPY

. h Co ~ PCT/SE00/01254 - C121 oo SE | NOH oo : : | he RE Re oo - oo \ N Re ha RZ ON ° . PN oo ~ Co oo : : | rR N wherein R?, R%, R, RY, R7, R*, R®2, R”, R*, R®, R%, A and B are as defied in Claim; : (x) for compounds of formula 1 in which one or both of R! and R2 . : represent _N(R*)R™ in which one or both of R* and R™ represents Crs oo alkyl, alkylation of a corresponding compound of formula I in which R! oo and/or R?2 represent _NR*)R¥ (as appropriate) in which R* and/or R* Co E 10 (as appropriate) represent H, using a compound of formula XXIB, oo rer xx® oo wherein R* represents C,¢alkyl and L' is as defined above; : k ~~ (y) conversion of one substituent on R” to another; or : CL } : (2) deprotection of a protected derivative of a compound of formula Ias oo - defined in Claim 1. | oo EE

26. A compound of formula II, as defined in Claim 25, or a protected derivative thereof, provided that R’ does not represent optionally substituted phenyl, or C, 4 alkyl. - oo | : ~~ AMENDED SHEET

Co 122 PCT/SE00/01254 hal 27. A compound of formula V, as defined in Claim 25, or a protected . : derivative thereof, provided that R7 does not represent optionally substituted phenyl. | :

28. A compound of formula X as defined in Claim 25, or a protected derivative thereof. : 29. A compound of formula XI as defined in Claim 25, or a protected derivative thereof. : Co 30. A compound of formula XIII, as defined in Claim 25, or a protected derivative thereof.

31. A compound of formula XV, as defined in Claim 25, or a protected derivative thereof. oo

32. A compound of formula XX, as defined in Claim 25, or a protected : derivative thereof. ~ 20 33. A compound of formula XXIII, o sis R#* R41 oo | | | | XXII oo RS Ras R? | N Ree A Nn . pg A - . Re CLEAN COPY oo | 123 : PCT/SE00/01254 a wherein R?, RY, R’, R*, R®, R®, R* R% R*, A and B are as defined in Claim 1, or a protected derivative thereof, provided that R” does not represent C,_ alkyl or optionally substituted phenyl.

34. A compound of formula XXV, | oo o 7 : oo s RY Ret oo - | XXV SE . : } R44 . ) . ’ N Re Re2 —~ oo s oo RR oo : wherein R?, R*, RY, R?, R®, R*, R¥ and R* are as defined in Claim 1, or : © a protected derivative thereof. - Co Co

35. A process for the preparation of a compound of formula X, of formula | oo ~ XXII, or of formula XXV (in which, in all cases, R* and R* both" represent H), which comprises (as appropriate) reaction of either: =~ : E (i) a compound of formula XXXV, | a Co : R43 R44 } Rei NT Rez | oo : PY OR: CC BE wherein R? represents Cj alkyl or C,; alkylaryl and R*, R?, R® and R* are as defined in Claim 1, or Co _ 2 AMENDED SHEET : : -

PCT/SE00/01254 (ii) 4-piperidone (or a protected derivative thereof), with (as appropriate) either: (1) a compound of formula XXXVI, ~ R-B-C(R’(R%-A-NH, XXXVI wherein R%, R®, R7, A and B are as defined in Claim 1, or (2) NH; (or a protected derivative thereof), in all cases in the presence of a formaldehyde and, in the case of compounds of formulae X and XXV, followed by conversion of the C(O)OR? group in the resultant intermediate to a CONER3)RY group.

36. A process as claimed in Claim 35, in which the reaction is carried out in the . oo presence of an organic acid. : oo : _

37. A process as claimed in Claim 36, in which the organic acid is acetic acid.

38.. A compound as defined in any one of Claims 1 to 17, or a pharmaceutical formulation comprising a compound as defined in any one of Claims 1 to 17, for use in a method for the prophylaxis or the treatment of an arrhythmia, said method comprising administering an effective amount of said compound.

39. A compound as claimed in any one -of Claims 1 to 17 or 26 to 34, substantially as herein described and illustrated. -

40. A formulation as claimed in Claim 18, substantially as herein described and illustrated. | - ~ 41. Use as claimed in Claim 22 or Claim 23, substantially as herein described and illustrated.

42. A method as claimed in Claim 24, substantially as herein described and illustrated. : AMENDED SHEET ’ :

PCT/SE00/01254

43. A process as claimed in Claim 25 or Claim 35, substantially as herein - described and illustrated.

44. A substance or composition for use in treatment, or in a method of treatment, as claimed in Claim 19 or Claim 21 or Claim 38, substantially as herein described and illustrated.

45. A new compound; a new formulation; a new use of a compound as defined in any one of Claims 1 to 17, or of a composition comprising a compound as defined in any one of Claims 1 to 17; a new non-therapeutic method of treatment; a new process for the preparation of a compound; or a substance or composition for a new use in a method of treatment, substantially as herein described. AMENDED SHEET