US 2003/0153564 A1Published application

New oxabispidine compounds useful in the treatment of cardiac arrhythmias

AssigneeAstraZeneca AB

InventorsAnnika Bjore, Magnus Bjorsne, David Cladingboel, Kurt-Jurgen Hoffmann, John Pavey, Fritiof Ponten, Gert Strandlund, Peder Svensson, Colin Thomson, Michael Wilsterman

Life of this patent

Estimating the term…

Abstract

There is provided compounds of formula I, 1 wherein R1, R2, R3, R4, R41 to R46, A, B and G have meanings given in the description, which are useful in the prophylaxis and in the treatment of arrhythmias, in particular atrial and ventricular arrhythmias.

Claims75

Dependent claims

A compound of formula I,

46
wherein
R1 represents C1-12 alkyl (which alkyl group is optionally substituted and/or terminated by one or more groups selected from halo, cyano, nitro, aryl, Het1, —C(O)R5a, —OR5b, —N(R6)R5c, —C(O)XR7, —C(O)N(R8)R5d, and —S(O)2R9), or R1 represents —C(O)XR7, —C(O)N(R8)R5d or —S(O)2R9;
R5a to R5d independently represent, at each occurrence, H, C1-6 alkyl (which latter group is optionally substituted and/or terminated by one or more substituents selected from —OH, halo, cyano, nitro, aryl and Het2), aryl or Het3, or R5d, together with R8, represents C3-6 alkylene (which alkylene group is optionally interrupted by an O atom and/or is optionally substituted by one or more C1-3 alkyl groups);
R6 represents H, C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from —OH, halo, cyano, nitro and aryl), aryl, —C(O)R10a, —C(O)OR10b or —C(O)N(H)R10c;
R10a, R10b and R10c independently represent C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from —OH, halo, cyano, nitro and aryl), aryl, or R10a represents H;
R7 represents C1-12 alkyl (optionally substituted and/or terminated by one or more substituents selected from -OH, halo, cyano, nitro, aryl, C1-6 alkoxy and Het4);
R8 represents H, C1-12 alkyl, C1-6 alkoxy (which latter two groups are optionally substituted and/or terminated by one or more substituents selected from —OH, halo, cyano, nitro, C1-4 alkyl and C1-4 alkoxy), -D-aryl, -D-aryloxy, -D-Het5, -D-N(H)C(O)R11a, -D-S(O)2R12a, -D-C(O)R11b, -D-C(O)OR12b, -D-C(O)N(R11c)R11d, or R8, together with R5d, represents C3-6 alkylene (which alkylene group is optionally interrupted by an O atom and/or is optionally substituted by one or more C1-3 alkyl groups);
R11a to R11d independently represent H, C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from —OH, halo, cyano, nitro and aryl), aryl, or R11c and R11d together represent C3-6 alkylene;
R9, R12a and R12b independently represent C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from —OH, halo, cyano, nitro and aryl) or aryl;
D represents a direct bond or C1-6 alkylene;
X represents O or S;
R2 represents H, halo, C1-6 alkyl, —OR13, -E-N(R14)R15 or, together with
R3, represents ═O;
R3 represents H, C1-6 alkyl or, together with R2, represents ═O;
R13 represents H, C1-6 alkyl, -E-aryl, -E-Het6, —C(O)R16a, —C(O)OR16b or —C(O)N(R17a)R17b;
R14 represents H, C1-6 alkyl, -E-aryl, -E-Het6, —C(O)R16a, —C(O)OR16b, —S(O)2R16c, —[C(O)]pN(R17a)R17b or —C(NH)NH2;
R15 represents H, C1-6 alkyl, -E-aryl or —C(O)R16d;
R16a to R16d 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 Het7), aryl, Het8, or R16a and R16d independently represent H;
R17a and R17b independently represent, at each occurrence when used herein, H or C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from halo, aryl and Het9), aryl, Het10, or together represent C3-6 alkylene, optionally interrupted by an O atom;
E represents, at each occurrence when used herein, a direct bond or C1-4 alkylene;
p represents 1 or 2;
Het1 to Het10 independently represent five- to twelve-membered heterocyclic groups containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, which groups are optionally substituted by one or more substituents selected from —OH, oxo, halo, cyano, nitro, C1-6 alkyl, C1-6 alkoxy, aryl, aryloxy, —N(R18a)R18b, —C(O)R18c, —C(O)OR18d, —C(O)N(R18e)R18f, —N(R18g)C(O)R18h and —N(R18i)S(O)2R18j;
R18a to R18j independently represent C1-6 alkyl, aryl or R18a to R18i independently represent H.;
A represents a direct bond, -J-, -J-N(R19)— or -J-O— (in which latter two groups, N(R19)— or O— is attached to the carbon atom bearing R2 and R3);
B represents -Z-, -Z-N(R20)—, —N(R20)-Z-, -Z-S(O)n—, -Z-O— (in which latter two groups, Z is attached to the carbon atom bearing R2 and R3), —N(R20)C(O)O-Z-, (in which latter group, —N(R20) is attached to the carbon atom bearing R2 and R3) or —C(O)N(R20)— (in which latter group, —C(O) is attached to the carbon atom bearing R2 and R3);
J represents C1-6 alkylene optionally substituted by one or more substituents selected from —OH, halo and amino;
Z represents a direct bond or C1-4 alkylene;
n represents 0, 1 or 2;
R19 and R20 independently represent H or C1-6 alkyl;
G represents CH or N;
R4 represents one or more optional substituents selected from —OH, cyano, halo, nitro, C1-6 alkyl (optionally terminated by —N(H)C(O)OR21a), C1-6 alkoxy, —N(R22a)R22b, —C(O)R22c, —C(O)OR22d, —C(O)N(R22e)R22f, —N(R22g)C(O)R22h, —N(R22i)C(O)N(R22j)R22k, —N(R22m)S(O)2R21b, —S(O)2R21c, and/or —OS(O)2R21d;
R21a to R21d independently represent C1-6 alkyl;
R22a and R22b independently represent H, C1-6 alkyl or together represent C3-6 alkylene, resulting in a four- to seven-membered nitrogen-containing ring;
R22c to R22m independently represent H or C1-6 alkyl;
and
R41 to R46 independently represent H or C1-3 alkyl;
wherein each aryl and aryloxy group, unless otherwise specified, is optionally substituted;
provided that
(a) the compound is not:
3,7-dibenzoyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
(b) when A represents -J-N(R19)— or -J-O—, then:
(i) J does not represent C1 alkylene;
and
(ii) B does not represent —N(R20)—, —N(R20)-Z- (in which latter group N(R20) is attached to the carbon atom bearing R2 and R3), —S(O)n—, —O— or —N(R20)C(O)O-Z- when R2 and R3 do not together represent ═O;
and
(c) when R2 represents —OR13 or —N(R14)(R15), then:
(i) A does not represent -J-N(R19)— or -J-O—;
and
(ii) B does not represent —N(R20)—, —N(R20)-Z- (in which latter group N(R20) is attached to the carbon atom bearing R2 and R3), —S(O)n—, —O— or —N(R20)C(O)O-Z-;
or a pharmaceutically acceptable derivative thereof.

48 more elements

A compound which is:

4-{2-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}benzonitrile;
7-[4-(4-cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl]-N-ethyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide;
4-({3-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}amino)benzonitrile;
4-{3-[7-(4-fluorobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-2-hydroxypropoxy}benzonitrile;
4-(2-{7-[2-(4-methoxyphenyl)-2-oxoethyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}ethoxy)benzonitrile;
4-[((2S)-2-amino-3-{7-[2-(1H-pyrrol-1-yl)ethyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}propyl)oxy]benzonitrile;
tert-butyl 2-{7-[3-(4-cyanoanilino)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}ethylcarbamate;
tert-butyl 2-{7-[4-(4-cyanophenyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}ethylcarbamate;
tert-butyl 2-{7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-di-azabicyclo[3.3.1]non-3-yl}ethylcarbamate;
4-(2-{7-[4-(4-pyridinyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-ethoxy)benzonitrile
tert-butyl 2-{7-(4-(4-pyridinyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamate;
4-{3-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-2-hydroxypropoxy}benzonitrile;
4-{3-[7-(3,4-dimethoxyphenethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-2-hydroxypropoxy}benzonitrile;
4-{2-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-ethoxy}benzonitrile;
4-({3-[7-(butylsulfonyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}-amino)benzonitrile;
4-({3-[7-(3,4-dimethoxyphenethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}amino)benzonitrile;
4-[4-[7-(butylsulfonyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-1-(3,4-dimethoxyphenoxy)butyl]benzonitrile;
4-{1-(3,4-dimethoxyphenoxy)-4-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]butyl}benzonitrile;
4-[4-[7-(3,4-dimethoxyphenethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-1-(3,4-dimethoxyphenoxy)butyl]benzonitrile;
2-(4-acetyl-1-piperazinyl)ethyl 7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate;
7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N-ethyl-9-oxa-3,7-diazabicyclo-[3.3.1]nonane-3-carboxamide;
4-{3-[7-(butylsulfonyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-2-hydroxy-propoxy}benzonitrile;
2-(4-acetyl-1-piperazinyl)ethyl 7-[2-(4-cyanophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate;
7-[2-(4-cyanophenoxy)ethyl]-N-ethyl-9-oxa-3,7-diazabicyclo[3.3.1]-nonane-3-carboxamide;
4-{2-[7-(butylsulfonyl)-9-oxa-3,7diazabicyclo[3.3.1]non-3-yl]ethoxy}-benzonitrile;
4-{2-[7-(3,4-dimethoxyphenethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethoxy}benzonitrile;
2-(4-acetyl-1-piperazinyl)ethyl 7-[3-(4-cyanoanilino)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate;
7-[3-(4-cyanoanilino)propyl]-N-ethyl-9-oxa-3,7-diazabicyclo[3.3.1]-nonane-3-carboxamide;
2-(4-acetyl-1-piperazinyl)ethyl 7-[4-(4-cyanophenyl)-4-(3,4-dimethoxy-phenoxy)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate;
4-{3-[7-(cyclopropylmethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-2-hydroxypropoxy}benzonitrile;
4-(3-{7-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-oxoethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-2-hydroxypropoxy)benzonitrile;
4-(3-{7-[3-(4-acetyl-1-piperazinyl)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}-2-hydroxypropoxy)benzonitrile;
2-{7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}-N-isopropylacetamide;
4-(3-{7-[3-(ethylsulfonyl)propyl]-9-oxa-3,7-diazabicyclo([3.3.1]non-3-yl}-2-hydroxypropoxy)benzonitrile;
4-(2-hydroxy-3-{7-[2-(2-methoxyethoxy)ethyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}propoxy)benzonitrile;
4-(2-hydroxy-3-{7-[2-(4-methoxyphenyl)-2-oxoethyl]-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl}propoxy)benzonitrile;
4-({3-[7-(cyclopropylmethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-propyl}amino)benzonitrile.
4-[(3-{7-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-oxoethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propyl)amino]benzonitrile;
4-[(3-{7-[2-(4-methyl-1,3-thiazol-5-yl)ethyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}propyl)amino]benzonitrile;
4-[(3-{7-[3-(4-acetyl-1-piperazinyl)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}propyl)amino]benzonitrile;
2-{7-[3-(4-cyanoanilino)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-N-isopropylacetamide;
4-[(3-{7-[3-(ethylsulfonyl)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-propyl)amino]benzonitrile;
4-[(3-{7-[2-(2-methoxyethoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propyl)amino]benzonitrile;
4-({3-[7-(4-fluorobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}-amino)benzonitrile;
4-[(3-{7-[2-(4-methoxyphenyl)-2-oxoethyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}propyl)amino]benzonitrile;
4-{2-[7-(cyclopropylmethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-ethoxy}benzonitrile;
4-(2-{7-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-oxoethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethoxy)benzonitrile;
4-(2-{7-[2-(4-methyl-1,3-thiazol-5-yl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}echoxy)benzonitrile;
4-(2-{7-[3-(4-acetyl-1-piperazinyl)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}ethoxy)benzonitrile;
2-{7-[2-(4-cyanophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-N-isopropylacetamide;
4-(2-{7-[3-(ethylsulfonyl)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-ethoxy)benzonitrile;
4-(2-{7-[2-(2-methoxyethoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethoxy)benzonitrile;
4-{2-[7-(4-fluorobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethoxy}-benzonitrile;
4-({3-[7-(3,3dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}sulfonyl)benzonitrile;
4-({3-[7-(cyclopropylmethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-propyl}sulfonyl)benzonitrile;
4-[(3-{7-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-oxoethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propyl)sulfonyl]benzonitrile;
4-[(3-{7-[2-(4-methyl-1,3-thiazol-5-yl)ethyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}propyl)sulfonyl]benzonitrile;
4-[(3-{7-[3-(4-acetyl-1-piperazinyl)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}propyl)sulfonyl]benzonitrile;
2-(7-{3-[(4-cyanophenyl)sulfonyl]propyl}-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl)-N-isopropylacetamide;
4-[(3-{7-[3-(ethylsulfonyl)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-propyl)sulfonyl]benzonitrile;
4-[(3-{7-[2-(2-methoxyethoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propyl)sulfonyl]benzonitrile;
4-({3-[7-(4-fluorobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}-sulfonyl)benzonitrile;
4-[(3-{7-[2-(4-methoxyphenyl)-2-oxoethyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}propyl)sulfonyl]benzonitrile;
4-[(3-{7-[2-(4-fluorophenyl)-2-oxoethyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}propyl)amino]benzonitrile;
4-(2-{7-[2-(4-fluorophenyl)-2-oxoethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethoxy)benzonitrile;
4-{2-[7-(tetrahydro-2H-pyran-2-ylmethyl)-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl]ethoxy}benzonitrile;
4-(3-{7-[2-(4-fluorophenyl)-2-oxoethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-2-hydroxypropoxy)benzonitrile;
4-{2-hydroxy-3-[7-(tetrahydro-2H-pyran-2-ylmethyl)-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl]propoxy}benzonitrile;
4-({3-[7-(2-fluoro-3,3-dimethylbutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}amino)benzonitrile;
4-({3-[7-(2-hydroxy-3,3-dimethylbutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}amino)benzonitrile;
4-({3-[7-(3,3-dimethylbutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-propyl}amino)benzonitrile;
4-({3-[7-(2-oxopropyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}-amino)benzonitrile;
4-(2-{7-[3-(4-cyanoanilino)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethoxy)benzonitrile;
4-(2-{7-[2-(4-cyanophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethoxy)benzonitrile;
4-(2-{7-[2-(4-cyanophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzonitrile;
4-{4-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-butyl}benzonitrile;
4-{2-[7-(2-phenoxyethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethoxy}-benzonitrile;
2-{7-[2-(4-cyanophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-N,N-diethylacetamide;
4-[(3-{7-[4-(4-fluorophenyl)-4-oxobutyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}propyl)amino]benzonitrile;
4-({7-[3-(4-cyanoanilino)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-methyl)benzonitrile;
4-{2-[7-(2,4 difluorobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-ethoxy}benzonitrile;
4-[(3-{7-[4-(difluoromethoxy)benzyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propyl)amino]benzonitrile;
4-[(3-{7-[2-(1H-pyrrol-1-yl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-propyl)amino]benzonitrile;
4-[(3-{7-[3-(4-bromophenyl)-3-oxopropyl]-9-oxa-3,7diazabicyclo[3.3.1]-non-3-yl}propyl)amino]benzonitrile;
4-{2-[7-(2,2-difluoroethyl)-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl]ethoxy}-benzonitrile;
4-({3-[7-(2-phenoxyethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}-amino)benzonitrile;
4-(2-{7-[2-(1H-pyrrol-1-yl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-ethoxy)benzonitrile;
4-[((2S)-3-{7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-2-hydroxypropyl)oxy]benzonitrile;
4-[((2S)-2-hydroxy-3-{7-[2-(1H-pyrrol-1-yl)ethyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}propyl)oxy]benzonitrile;
4-{2-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-ethoxy}isophthalonitrile;
4-(2-{7-[2-(4-methoxyphenyl)-2-oxoethyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}ethoxy)isophthalonitrile;
4-(2-{7-[2-(1H-pyrrol-1-yl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-ethoxy)isophthalonitrile;
tert-butyl 2-{7-[2-(2,4-dicyanophenoxy)ethyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}ethylcarbamate;
4-({(2S)-2-amino-3-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl]propyl}oxy)benzonitrile;
4-[((2S)-2-amino-3-{7-[2-(4-methoxyphenyl)-2-oxoethyl]-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl}propyl)oxy]benzonitrile;
4-{3-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-propoxy}benzonitrile;
4-(3-{7-[2-(4-fluorophenyl)-2-oxoethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propoxy)benzonitrile;
4-(3-{7-[2-(1H-pyrrol-1-yl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-propoxy)benzonitrile;
4-(4-{7-[2-(1H-pyrrol-1-yl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-butyl)benzonitrile;
4-{[(2S)-3-(7-{2-[4-(tert-butoxy)phenoxy]ethyl}-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl)-2-hydroxypropyl]oxy}benzonitrile;
4-[((2S)-3-{7-[2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl}-2-hydroxypropyl)oxy]benzonitrile;
4-{3-[7-(imidazo[1,2-a]pyridin-2-ylmethyl)-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl]propoxy}benzonitrile;
4-{3-[7-(2-phenoxyethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propoxy}-benzonitrile;
4-(3-{7-[2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}propoxy)benzonitrile;
4-({3-[7-(imidazo[1,2-a]pyridin-2-ylmethyl)-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl]propyl}amino)benzonitrile;
4-({3-[7-(2,4-difluorobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-propyl}amino)benzonitrile;
4-{[3-(7-{2-[4-(tert-butoxy)phenoxy]ethyl}-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl)propyl]amino}benzonitrile;
4-{2-[7-(imidazo[1.2-a]pyridin-2-ylmethyl)-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl]ethoxy}benzonitrile;
tert-butyl 2-{7-[2-(4-cyanophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}ethylcarbamate;
4-{[3-(7-{2-[4-(tert-butoxy)phenoxy]ethyl}-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl)propyl]sulfonyl}benzonitrile;
4-[(3-{7-[2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}propyl)sulfonyl]benzonitrile;
4-({3-[7-(2,4-difluorobenzyl)-9-oxa-3,7-diazabicyclo[3 3.1]non-3-yl]-propyl}sulfonyl)benzonitrile;
4-{2-[7-(imidazo[1,2-a]pyridin-2-ylmethyl)-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl]ethoxy}isophthalonitrile;
4-[2-(7-{2-[4-(tert-butoxy)phenoxy]ethyl}-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl)ethoxy]isophthalonitrile;
4-(2-{7-[2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}ethoxy)isophthalonitrile;
4-(4-{7-[2-(1H-imidazol-4-yl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}butyl)benzonitrile;
4-{4-[7-(imidazo[1,2-a]pyridin-2-ylmethyl)-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl]butyl}benzonitrile;
4-{4-[7-(2-phenoxyethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]butyl}-benzonitrile;
4-(4-{7-[2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}butyl)benzonitrile;
4-[3-(7-{2-oxo-2-[4-(1-pyrrolidinyl)phenyl]ethyl}-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl)propoxy]benzonitrile;
4-(3-{7-[2-(4-hydroxyphenyl)-2-oxoethyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}propoxy)benzonitrile;
4-(3-{7-[2-(4-methylphenyl)-2-oxoethyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}propoxy)benzonitrile;
4-(3-{7-[2-(4-methoxyphenyl)-2-oxoethyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}propoxy)benzonitrile;
4-(3-{7-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-oxoethyl]-9-oxa-3,7-di-azabicyclo[3.3.1]non-3-yl}propoxy)benzonitrile;
4-(2-{7-[2-(2,6-dimethylphenoxy)-1-methylethyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}ethoxy)benzonitrile;
4-(3-{7-[2-oxo-2-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propoxy)benzonitrile;
tert-butyl 2-{7-[3-(4-cyanophenoxy)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}ethylcarbamate;
N-(tert-butyl)-N′-(2-{7-[3-(4-cyanophenoxy)propyl]-9-oxa-3,7-diazabi-cyclo[3.3.1]non-3-yl}ethyl)urea;
tert-butyl 2-({7-[2-(4-cyanophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}methyl)-1-pyrrolidinecarboxylate;
4-{[3-(7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)propyl]amino}-benzonitrile;
4-[(3-{7-[3-(4-cyanoanilino)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propyl)amino]benzonitrile;
tert-butyl 2-{7-[2-(4-nitrophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}ethylcarbamate (m/z=437);
tert-butyl 2-[7-(2-{4-[(methylsulfonyl)amino]phenoxy}ethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethylcarbamate;
tert-butyl 2-{7-[2-(4-aminophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}ethylcarbamate;
4-({3-[7-(phenylsulfonyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}-amino)benzonitrile;
or
4-({3-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}amino)benzamide.

134 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/317,195Filed 12 Dec 2002
Priority: SE 9903759-018 Oct 1999
Published: 14 Aug 2003
Term ends: Not estimatedThe source records don’t support an estimate.

Classification5 codes

C07D 498/08
In which the condensed system contains two hetero rings: bridged systems
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 9/06
Drugs for disorders of the cardiovascular system: antiarrhythmics
C07D
Heterocyclic compounds

Family

Application09/688,251Division · filed 16 Oct 2000
Application10/317,195Division · filed 12 Dec 2002
US 6,559,143 B1Related patent
US 7,164,017 B2Related patent
US 2003/0153564 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of formula I,

46
wherein
R1 represents C1-12 alkyl (which alkyl group is optionally substituted and/or terminated by one or more groups selected from halo, cyano, nitro, aryl, Het1, —C(O)R5a, —OR5b, —N(R6)R5c, —C(O)XR7, —C(O)N(R8)R5d, and —S(O)2R9), or R1 represents —C(O)XR7, —C(O)N(R8)R5d or —S(O)2R9;
R5a to R5d independently represent, at each occurrence, H, C1-6 alkyl (which latter group is optionally substituted and/or terminated by one or more substituents selected from —OH, halo, cyano, nitro, aryl and Het2), aryl or Het3, or R5d, together with R8, represents C3-6 alkylene (which alkylene group is optionally interrupted by an O atom and/or is optionally substituted by one or more C1-3 alkyl groups);
R6 represents H, C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from —OH, halo, cyano, nitro and aryl), aryl, —C(O)R10a, —C(O)OR10b or —C(O)N(H)R10c;
R10a, R10b and R10c independently represent C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from —OH, halo, cyano, nitro and aryl), aryl, or R10a represents H;
R7 represents C1-12 alkyl (optionally substituted and/or terminated by one or more substituents selected from -OH, halo, cyano, nitro, aryl, C1-6 alkoxy and Het4);
R8 represents H, C1-12 alkyl, C1-6 alkoxy (which latter two groups are optionally substituted and/or terminated by one or more substituents selected from —OH, halo, cyano, nitro, C1-4 alkyl and C1-4 alkoxy), -D-aryl, -D-aryloxy, -D-Het5, -D-N(H)C(O)R11a, -D-S(O)2R12a, -D-C(O)R11b, -D-C(O)OR12b, -D-C(O)N(R11c)R11d, or R8, together with R5d, represents C3-6 alkylene (which alkylene group is optionally interrupted by an O atom and/or is optionally substituted by one or more C1-3 alkyl groups);
R11a to R11d independently represent H, C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from —OH, halo, cyano, nitro and aryl), aryl, or R11c and R11d together represent C3-6 alkylene;
R9, R12a and R12b independently represent C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from —OH, halo, cyano, nitro and aryl) or aryl;
D represents a direct bond or C1-6 alkylene;
X represents O or S;
R2 represents H, halo, C1-6 alkyl, —OR13, -E-N(R14)R15 or, together with
R3, represents ═O;
R3 represents H, C1-6 alkyl or, together with R2, represents ═O;
R13 represents H, C1-6 alkyl, -E-aryl, -E-Het6, —C(O)R16a, —C(O)OR16b or —C(O)N(R17a)R17b;
R14 represents H, C1-6 alkyl, -E-aryl, -E-Het6, —C(O)R16a, —C(O)OR16b, —S(O)2R16c, —[C(O)]pN(R17a)R17b or —C(NH)NH2;
R15 represents H, C1-6 alkyl, -E-aryl or —C(O)R16d;
R16a to R16d 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 Het7), aryl, Het8, or R16a and R16d independently represent H;
R17a and R17b independently represent, at each occurrence when used herein, H or C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from halo, aryl and Het9), aryl, Het10, or together represent C3-6 alkylene, optionally interrupted by an O atom;
E represents, at each occurrence when used herein, a direct bond or C1-4 alkylene;
p represents 1 or 2;
Het1 to Het10 independently represent five- to twelve-membered heterocyclic groups containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, which groups are optionally substituted by one or more substituents selected from —OH, oxo, halo, cyano, nitro, C1-6 alkyl, C1-6 alkoxy, aryl, aryloxy, —N(R18a)R18b, —C(O)R18c, —C(O)OR18d, —C(O)N(R18e)R18f, —N(R18g)C(O)R18h and —N(R18i)S(O)2R18j;
R18a to R18j independently represent C1-6 alkyl, aryl or R18a to R18i independently represent H.;
A represents a direct bond, -J-, -J-N(R19)— or -J-O— (in which latter two groups, N(R19)— or O— is attached to the carbon atom bearing R2 and R3);
B represents -Z-, -Z-N(R20)—, —N(R20)-Z-, -Z-S(O)n—, -Z-O— (in which latter two groups, Z is attached to the carbon atom bearing R2 and R3), —N(R20)C(O)O-Z-, (in which latter group, —N(R20) is attached to the carbon atom bearing R2 and R3) or —C(O)N(R20)— (in which latter group, —C(O) is attached to the carbon atom bearing R2 and R3);
J represents C1-6 alkylene optionally substituted by one or more substituents selected from —OH, halo and amino;
Z represents a direct bond or C1-4 alkylene;
n represents 0, 1 or 2;
R19 and R20 independently represent H or C1-6 alkyl;
G represents CH or N;
R4 represents one or more optional substituents selected from —OH, cyano, halo, nitro, C1-6 alkyl (optionally terminated by —N(H)C(O)OR21a), C1-6 alkoxy, —N(R22a)R22b, —C(O)R22c, —C(O)OR22d, —C(O)N(R22e)R22f, —N(R22g)C(O)R22h, —N(R22i)C(O)N(R22j)R22k, —N(R22m)S(O)2R21b, —S(O)2R21c, and/or —OS(O)2R21d;
R21a to R21d independently represent C1-6 alkyl;
R22a and R22b independently represent H, C1-6 alkyl or together represent C3-6 alkylene, resulting in a four- to seven-membered nitrogen-containing ring;
R22c to R22m independently represent H or C1-6 alkyl;
and
R41 to R46 independently represent H or C1-3 alkyl;
wherein each aryl and aryloxy group, unless otherwise specified, is optionally substituted;
provided that
(a) the compound is not:
3,7-dibenzoyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
(b) when A represents -J-N(R19)— or -J-O—, then:
(i) J does not represent C1 alkylene;
and
(ii) B does not represent —N(R20)—, —N(R20)-Z- (in which latter group N(R20) is attached to the carbon atom bearing R2 and R3), —S(O)n—, —O— or —N(R20)C(O)O-Z- when R2 and R3 do not together represent ═O;
and
(c) when R2 represents —OR13 or —N(R14)(R15), then:
(i) A does not represent -J-N(R19)— or -J-O—;
and
(ii) B does not represent —N(R20)—, —N(R20)-Z- (in which latter group N(R20) is attached to the carbon atom bearing R2 and R3), —S(O)n—, —O— or —N(R20)C(O)O-Z-;
or a pharmaceutically acceptable derivative thereof.

48 more elements

Facts

Application

10/317,195Filed 12 Dec 2002

Priority

SE 9903759-018 Oct 1999

Published

14 Aug 2003

Term ends

Not estimatedThe source records don’t support an estimate.

Classification5 codes

C07D 498/08
In which the condensed system contains two hetero rings: bridged systems
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 9/06
Drugs for disorders of the cardiovascular system: antiarrhythmics
C07D
Heterocyclic compounds