SK8912002A3 - New azabicyclooctane derivatives useful in the treatment of cardiac arrhythmias - Google Patents

New azabicyclooctane derivatives useful in the treatment of cardiac arrhythmias Download PDF

Info

Publication number: SK8912002A3
Authority: SK; Slovakia
Prior art keywords: group; formula; alkyl; aryl; compound
Prior art date: 1999-12-23

Application number

SK891-2002A

Other languages

English (en)

Slovak (sk)

Inventor

Magnus Bjorsne

Fritiof Ponten

Gert Strandlund

Peder Svensson

Original Assignee

Astrazeneca Ab

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1999-12-23

Filing date

2000-12-19

Publication date

2003-02-04

2000-12-19 Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab

2003-02-04 Publication of SK8912002A3 publication Critical patent/SK8912002A3/sk

Links

206010003119 arrhythmia Diseases 0.000 title claims abstract description 23
QUIJMHDIAFOPRK-UHFFFAOYSA-N 1-cyclooctylazocane Chemical class C1CCCCCCC1N1CCCCCCC1 QUIJMHDIAFOPRK-UHFFFAOYSA-N 0.000 title claims 38
238000011282 treatment Methods 0.000 title abstract description 10
150000001875 compounds Chemical class 0.000 claims abstract description 333
238000000034 method Methods 0.000 claims abstract description 29
230000006793 arrhythmia Effects 0.000 claims abstract description 14
206010047281 Ventricular arrhythmia Diseases 0.000 claims abstract description 4
230000001746 atrial effect Effects 0.000 claims abstract description 4
206010003130 Arrhythmia supraventricular Diseases 0.000 claims abstract description 3
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 255
125000004432 carbon atom Chemical group C* 0.000 claims description 153
-1 3-benzyl-3-azabicyclo [3.2.1] oct-8-yl Chemical group 0.000 claims description 124
125000000217 alkyl group Chemical group 0.000 claims description 102
125000003118 aryl group Chemical group 0.000 claims description 87
125000001424 substituent group Chemical group 0.000 claims description 75
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 60
229910052736 halogen Inorganic materials 0.000 claims description 56
239000001257 hydrogen Substances 0.000 claims description 56
229910052739 hydrogen Inorganic materials 0.000 claims description 56
150000002367 halogens Chemical class 0.000 claims description 54
125000002947 alkylene group Chemical group 0.000 claims description 45
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 45
125000004093 cyano group Chemical group *C#N 0.000 claims description 40
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 37
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 33
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 30
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 30
229910052799 carbon Inorganic materials 0.000 claims description 28
150000002431 hydrogen Chemical class 0.000 claims description 26
238000006243 chemical reaction Methods 0.000 claims description 25
125000005843 halogen group Chemical group 0.000 claims description 25
150000001721 carbon Chemical group 0.000 claims description 24
125000003545 alkoxy group Chemical group 0.000 claims description 23
229910052757 nitrogen Inorganic materials 0.000 claims description 23
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 21
125000004430 oxygen atom Chemical group O* 0.000 claims description 19
125000003107 substituted aryl group Chemical group 0.000 claims description 19
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
239000012634 fragment Substances 0.000 claims description 16
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 11
229920006395 saturated elastomer Polymers 0.000 claims description 11
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 10
125000004104 aryloxy group Chemical group 0.000 claims description 10
239000003814 drug Substances 0.000 claims description 10
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
125000004434 sulfur atom Chemical group 0.000 claims description 9
125000005842 heteroatom Chemical group 0.000 claims description 8
229910052760 oxygen Inorganic materials 0.000 claims description 8
125000000623 heterocyclic group Chemical group 0.000 claims description 7
230000009467 reduction Effects 0.000 claims description 7
DIVQZLMEZFLSED-UHFFFAOYSA-N [N].C1C2CCC1CNC2 Chemical group [N].C1C2CCC1CNC2 DIVQZLMEZFLSED-UHFFFAOYSA-N 0.000 claims description 6
239000008186 active pharmaceutical agent Substances 0.000 claims description 6
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
239000001301 oxygen Substances 0.000 claims description 6
229910052717 sulfur Inorganic materials 0.000 claims description 6
125000004429 atom Chemical group 0.000 claims description 5
239000003638 chemical reducing agent Substances 0.000 claims description 5
239000003795 chemical substances by application Substances 0.000 claims description 5
239000008194 pharmaceutical composition Substances 0.000 claims description 5
125000002619 bicyclic group Chemical group 0.000 claims description 4
230000003647 oxidation Effects 0.000 claims description 4
238000007254 oxidation reaction Methods 0.000 claims description 4
125000004043 oxo group Chemical group O=* 0.000 claims description 4
125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 3
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
150000001204 N-oxides Chemical class 0.000 claims description 3
125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 2
125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
125000006833 (C1-C5) alkylene group Chemical group 0.000 claims description 2
125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 2
YOLLCWCYOPYWGQ-UHFFFAOYSA-N CCCCCCCC.[N] Chemical group CCCCCCCC.[N] YOLLCWCYOPYWGQ-UHFFFAOYSA-N 0.000 claims description 2
YIKSCQDJHCMVMK-UHFFFAOYSA-N Oxamide Chemical compound NC(=O)C(N)=O YIKSCQDJHCMVMK-UHFFFAOYSA-N 0.000 claims description 2
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
239000004480 active ingredient Substances 0.000 claims description 2
239000003085 diluting agent Substances 0.000 claims description 2
230000002140 halogenating effect Effects 0.000 claims description 2
239000007800 oxidant agent Substances 0.000 claims description 2
239000000546 pharmaceutical excipient Substances 0.000 claims description 2
238000006467 substitution reaction Methods 0.000 claims description 2
239000011593 sulfur Substances 0.000 claims description 2
238000004519 manufacturing process Methods 0.000 claims 2
KKWGCRIBOPNFTQ-UHFFFAOYSA-N 3-[2-[4-(6-aminopyridin-2-yl)phenyl]ethyl]-3-azabicyclo[3.2.1]octan-8-amine Chemical compound NC1C(C2)CCC1CN2CCC(C=C1)=CC=C1C1=CC=CC(N)=N1 KKWGCRIBOPNFTQ-UHFFFAOYSA-N 0.000 claims 1
SFKAYSQAVXEORK-UHFFFAOYSA-N 3-azabicyclo[3.2.1]octan-8-amine Chemical compound C1NCC2CCC1C2N SFKAYSQAVXEORK-UHFFFAOYSA-N 0.000 claims 1
QHPWRLXAKMANSW-UHFFFAOYSA-N 3-benzyl-3-azabicyclo[3.2.1]octan-8-amine Chemical compound NC1C(C2)CCC1CN2CC1=CC=CC=C1 QHPWRLXAKMANSW-UHFFFAOYSA-N 0.000 claims 1
OMNZTTYSHLWCDQ-UHFFFAOYSA-N 3-methyl-3-azabicyclo[3.2.1]octan-8-amine Chemical compound C1N(C)CC2CCC1C2N OMNZTTYSHLWCDQ-UHFFFAOYSA-N 0.000 claims 1
SHYSXJBPBGOXED-UHFFFAOYSA-N 3-propan-2-yl-3-azabicyclo[3.2.1]octan-8-amine Chemical compound C1N(C(C)C)CC2CCC1C2N SHYSXJBPBGOXED-UHFFFAOYSA-N 0.000 claims 1
YFMZIYWNJGCILU-BRICXYORSA-N 4-amino-n-(3-benzyl-3-azabicyclo[3.2.1]octan-8-yl)-5-chloro-2-[(2s)-pent-3-yn-2-yl]oxybenzamide Chemical compound CC#C[C@H](C)OC1=CC(N)=C(Cl)C=C1C(=O)NC1C2CCC1CN(CC=1C=CC=CC=1)C2 YFMZIYWNJGCILU-BRICXYORSA-N 0.000 claims 1
XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 claims 1
238000002360 preparation method Methods 0.000 abstract description 48
230000008569 process Effects 0.000 abstract description 3
238000011321 prophylaxis Methods 0.000 abstract 1
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 123
239000000203 mixture Substances 0.000 description 106
JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 101
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 74
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 71
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 65
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 55
239000000243 solution Substances 0.000 description 49
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 45
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 42
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 41
ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 39
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 31
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
235000019439 ethyl acetate Nutrition 0.000 description 25
239000000741 silica gel Substances 0.000 description 25
229910002027 silica gel Inorganic materials 0.000 description 25
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 24
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 23
239000003480 eluent Substances 0.000 description 22
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 22
238000010992 reflux Methods 0.000 description 22
239000002904 solvent Substances 0.000 description 22
229910000027 potassium carbonate Inorganic materials 0.000 description 20
238000005160 1H NMR spectroscopy Methods 0.000 description 19
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 19
229910052938 sodium sulfate Inorganic materials 0.000 description 19
235000011152 sodium sulphate Nutrition 0.000 description 19
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 17
239000010410 layer Substances 0.000 description 17
239000003960 organic solvent Substances 0.000 description 17
238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 16
125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 description 16
239000012044 organic layer Substances 0.000 description 16
238000000262 chemical ionisation mass spectrometry Methods 0.000 description 15
OAJBTRKIJSZUFA-UHFFFAOYSA-N 4-[3-[8-(methylamino)-3-azabicyclo[3.2.1]octan-3-yl]propylsulfonyl]benzonitrile Chemical compound CNC1C(C2)CCC1CN2CCCS(=O)(=O)C1=CC=C(C#N)C=C1 OAJBTRKIJSZUFA-UHFFFAOYSA-N 0.000 description 14
FVIGODVHAVLZOO-UHFFFAOYSA-N Dixanthogen Chemical compound CCOC(=S)SSC(=S)OCC FVIGODVHAVLZOO-UHFFFAOYSA-N 0.000 description 14
239000002253 acid Substances 0.000 description 13
239000002585 base Substances 0.000 description 13
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 12
239000000706 filtrate Substances 0.000 description 12
125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 12
XHPDBJOCQNTAHJ-FCOWATRHSA-N tert-butyl n-[(2s)-1-(4-cyanophenoxy)-3-[8-(methylamino)-3-azabicyclo[3.2.1]octan-3-yl]propan-2-yl]carbamate Chemical compound C([C@H](CN1CC2CCC(C1)C2NC)NC(=O)OC(C)(C)C)OC1=CC=C(C#N)C=C1 XHPDBJOCQNTAHJ-FCOWATRHSA-N 0.000 description 12
238000012360 testing method Methods 0.000 description 12
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
238000001914 filtration Methods 0.000 description 11
238000003786 synthesis reaction Methods 0.000 description 11
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
230000015572 biosynthetic process Effects 0.000 description 10
125000004122 cyclic group Chemical group 0.000 description 10
239000000543 intermediate Substances 0.000 description 10
239000003921 oil Substances 0.000 description 10
238000005481 NMR spectroscopy Methods 0.000 description 9
239000000284 extract Substances 0.000 description 9
125000006239 protecting group Chemical group 0.000 description 9
239000007787 solid Substances 0.000 description 9
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 8
IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
239000000908 ammonium hydroxide Substances 0.000 description 8
PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 8
238000004587 chromatography analysis Methods 0.000 description 8
239000012043 crude product Substances 0.000 description 8
150000003840 hydrochlorides Chemical class 0.000 description 8
239000011541 reaction mixture Substances 0.000 description 8
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 8
NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 7
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
239000012267 brine Substances 0.000 description 7
210000004027 cell Anatomy 0.000 description 7
230000000694 effects Effects 0.000 description 7
GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 7
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 7
238000003756 stirring Methods 0.000 description 7
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
125000005233 alkylalcohol group Chemical group 0.000 description 6
239000012298 atmosphere Substances 0.000 description 6
HQMRIBYCTLBDAK-UHFFFAOYSA-M bis(2-methylpropyl)alumanylium;chloride Chemical compound CC(C)C[Al](Cl)CC(C)C HQMRIBYCTLBDAK-UHFFFAOYSA-M 0.000 description 6
239000003054 catalyst Substances 0.000 description 6
229940079593 drug Drugs 0.000 description 6
238000002474 experimental method Methods 0.000 description 6
210000002950 fibroblast Anatomy 0.000 description 6
GTCAXTIRRLKXRU-UHFFFAOYSA-N methyl carbamate Chemical compound COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 description 6
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
239000012074 organic phase Substances 0.000 description 6
125000004193 piperazinyl group Chemical group 0.000 description 6
238000010898 silica gel chromatography Methods 0.000 description 6
239000000126 substance Substances 0.000 description 6
FUSWHBHFBQQMCH-UHFFFAOYSA-N tert-butyl n-(3-azabicyclo[3.2.1]octan-8-yl)-n-methylcarbamate Chemical compound C1NCC2CCC1C2N(C)C(=O)OC(C)(C)C FUSWHBHFBQQMCH-UHFFFAOYSA-N 0.000 description 6
DVTMMXLIROMMOX-UHFFFAOYSA-N 3-benzyl-n-methyl-3-azabicyclo[3.2.1]octan-8-amine Chemical compound CNC1C(C2)CCC1CN2CC1=CC=CC=C1 DVTMMXLIROMMOX-UHFFFAOYSA-N 0.000 description 5
FTFKVOZESKOQIS-UHFFFAOYSA-N 4-[3-[8-(methylamino)-3-azabicyclo[3.2.1]octan-3-yl]propylamino]benzonitrile Chemical compound CNC1C(C2)CCC1CN2CCCNC1=CC=C(C#N)C=C1 FTFKVOZESKOQIS-UHFFFAOYSA-N 0.000 description 5
125000002015 acyclic group Chemical group 0.000 description 5
239000003416 antiarrhythmic agent Substances 0.000 description 5
230000000747 cardiac effect Effects 0.000 description 5
238000007796 conventional method Methods 0.000 description 5
LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 5
238000001704 evaporation Methods 0.000 description 5
230000008020 evaporation Effects 0.000 description 5
125000002883 imidazolyl group Chemical group 0.000 description 5
239000002953 phosphate buffered saline Substances 0.000 description 5
239000002244 precipitate Substances 0.000 description 5
239000000047 product Substances 0.000 description 5
150000003254 radicals Chemical class 0.000 description 5
150000003839 salts Chemical class 0.000 description 5
RKUPSPIXMNFDSA-UHFFFAOYSA-N tert-butyl n-[3-[2-(4-cyanophenoxy)ethyl]-3-azabicyclo[3.2.1]octan-8-yl]-n-methylcarbamate Chemical compound CC(C)(C)OC(=O)N(C)C1C(C2)CCC1CN2CCOC1=CC=C(C#N)C=C1 RKUPSPIXMNFDSA-UHFFFAOYSA-N 0.000 description 5
IVKAPFWKLFIYCG-UHFFFAOYSA-N 4-(2-bromoethoxy)benzonitrile Chemical compound BrCCOC1=CC=C(C#N)C=C1 IVKAPFWKLFIYCG-UHFFFAOYSA-N 0.000 description 4
YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 4
ACFIXJIJDZMPPO-NNYOXOHSSA-N NADPH Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](OP(O)(O)=O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 ACFIXJIJDZMPPO-NNYOXOHSSA-N 0.000 description 4
DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 4
239000012230 colorless oil Substances 0.000 description 4
125000000524 functional group Chemical group 0.000 description 4
238000004128 high performance liquid chromatography Methods 0.000 description 4
SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 4
238000002844 melting Methods 0.000 description 4
230000008018 melting Effects 0.000 description 4
239000012528 membrane Substances 0.000 description 4
125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 4
125000004433 nitrogen atom Chemical group N* 0.000 description 4
238000000746 purification Methods 0.000 description 4
125000004076 pyridyl group Chemical group 0.000 description 4
125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
XINQFOMFQFGGCQ-UHFFFAOYSA-L (2-dodecoxy-2-oxoethyl)-[6-[(2-dodecoxy-2-oxoethyl)-dimethylazaniumyl]hexyl]-dimethylazanium;dichloride Chemical compound [Cl-].[Cl-].CCCCCCCCCCCCOC(=O)C[N+](C)(C)CCCCCC[N+](C)(C)CC(=O)OCCCCCCCCCCCC XINQFOMFQFGGCQ-UHFFFAOYSA-L 0.000 description 3
XLHUBROMZOAQMV-UHFFFAOYSA-N 1,4-benzosemiquinone Chemical group [O]C1=CC=C(O)C=C1 XLHUBROMZOAQMV-UHFFFAOYSA-N 0.000 description 3
LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
KKFDCBRMNNSAAW-UHFFFAOYSA-N 2-(morpholin-4-yl)ethanol Chemical compound OCCN1CCOCC1 KKFDCBRMNNSAAW-UHFFFAOYSA-N 0.000 description 3
DMKUNHJZZHMFFE-UHFFFAOYSA-N 3-(4-cyanoanilino)propyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCCCNC1=CC=C(C#N)C=C1 DMKUNHJZZHMFFE-UHFFFAOYSA-N 0.000 description 3
CJQNJRRDTPULTL-UHFFFAOYSA-N 3-azabicyclo[3.2.1]octane Chemical class C1C2CCC1CNC2 CJQNJRRDTPULTL-UHFFFAOYSA-N 0.000 description 3
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125000000719 pyrrolidinyl group Chemical group 0.000 description 1
125000001422 pyrrolinyl group Chemical group 0.000 description 1
125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
125000005493 quinolyl group Chemical group 0.000 description 1
230000006340 racemization Effects 0.000 description 1
238000007363 ring formation reaction Methods 0.000 description 1
239000000523 sample Substances 0.000 description 1
230000035945 sensitivity Effects 0.000 description 1
229940076279 serotonin Drugs 0.000 description 1
239000002002 slurry Substances 0.000 description 1
239000012312 sodium hydride Substances 0.000 description 1
239000012418 sodium perborate tetrahydrate Substances 0.000 description 1
IBDSNZLUHYKHQP-UHFFFAOYSA-N sodium;3-oxidodioxaborirane;tetrahydrate Chemical compound O.O.O.O.[Na+].[O-]B1OO1 IBDSNZLUHYKHQP-UHFFFAOYSA-N 0.000 description 1
238000010532 solid phase synthesis reaction Methods 0.000 description 1
239000012453 solvate Substances 0.000 description 1
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229960005322 streptomycin Drugs 0.000 description 1
239000000758 substrate Substances 0.000 description 1
150000003462 sulfoxides Chemical class 0.000 description 1
230000001629 suppression Effects 0.000 description 1
238000003419 tautomerization reaction Methods 0.000 description 1
FMXZMAVYUFPAPE-UHFFFAOYSA-N tert-butyl 8-[3-(4-cyanoanilino)propyl-methylamino]-3-azabicyclo[3.2.1]octane-3-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC2CCC1C2N(C)CCCNC1=CC=C(C#N)C=C1 FMXZMAVYUFPAPE-UHFFFAOYSA-N 0.000 description 1
IASKTAVVDJDXOB-UHFFFAOYSA-N tert-butyl n-(3-benzyl-3-azabicyclo[3.2.1]octan-8-yl)-n-methylcarbamate Chemical compound CC(C)(C)OC(=O)N(C)C1C(C2)CCC1CN2CC1=CC=CC=C1 IASKTAVVDJDXOB-UHFFFAOYSA-N 0.000 description 1
ZTAFRGLEWLBFRK-LJYGWVNYSA-N tert-butyl n-[3-[(2s)-3-(4-cyanophenoxy)-2-(methoxycarbonylamino)propyl]-3-azabicyclo[3.2.1]octan-8-yl]-n-methylcarbamate Chemical compound C([C@@H](NC(=O)OC)CN1CC2CCC(C2N(C)C(=O)OC(C)(C)C)C1)OC1=CC=C(C#N)C=C1 ZTAFRGLEWLBFRK-LJYGWVNYSA-N 0.000 description 1
125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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238000004809 thin layer chromatography Methods 0.000 description 1
YSPWSQNKRBSICH-UHFFFAOYSA-N thiophene-3-sulfonyl chloride Chemical compound ClS(=O)(=O)C=1C=CSC=1 YSPWSQNKRBSICH-UHFFFAOYSA-N 0.000 description 1
230000009424 thromboembolic effect Effects 0.000 description 1
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JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
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239000012588 trypsin Substances 0.000 description 1
238000000825 ultraviolet detection Methods 0.000 description 1
DYWSVUBJGFTOQC-UHFFFAOYSA-N xi-2-Ethylheptanoic acid Chemical compound CCCCCC(CC)C(O)=O DYWSVUBJGFTOQC-UHFFFAOYSA-N 0.000 description 1
239000011701 zinc Substances 0.000 description 1
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Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/22—Bridged ring systems
- C07D221/24—Camphidines
- 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
- 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

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

SK891-2002A 1999-12-23 2000-12-19 New azabicyclooctane derivatives useful in the treatment of cardiac arrhythmias SK8912002A3 (en)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
SE9904765A SE9904765D0 (sv)	1999-12-23	1999-12-23	Pharmaceutically-useful compounds
PCT/SE2000/002604 WO2001047893A1 (en)	1999-12-23	2000-12-19	New azabicyclooctane derivatives useful in the treatment of cardiac arrhythmias

Publications (1)

Publication Number	Publication Date
SK8912002A3 true SK8912002A3 (en)	2003-02-04

Family

ID=20418291

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
SK891-2002A SK8912002A3 (en)	1999-12-23	2000-12-19	New azabicyclooctane derivatives useful in the treatment of cardiac arrhythmias

Country Status (26)

Country	Link
US (1)	US6559162B2 (et)
EP (1)	EP1244631A1 (et)
JP (1)	JP2003519128A (et)
KR (1)	KR20020063261A (et)
CN (1)	CN1229350C (et)
AR (1)	AR026925A1 (et)
AU (1)	AU777069B2 (et)
BR (1)	BR0016678A (et)
CA (1)	CA2394097A1 (et)
CO (1)	CO5261611A1 (et)
CZ (1)	CZ20022174A3 (et)
EE (1)	EE200200305A (et)
HU (1)	HUP0301030A3 (et)
IL (1)	IL150212A0 (et)
IS (1)	IS6438A (et)
MX (1)	MXPA02006249A (et)
MY (1)	MY133785A (et)
NO (1)	NO20023038L (et)
NZ (1)	NZ519497A (et)
PL (1)	PL357098A1 (et)
RU (1)	RU2262505C2 (et)
SE (1)	SE9904765D0 (et)
SK (1)	SK8912002A3 (et)
UA (1)	UA75057C2 (et)
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1999
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2000
- 2000-12-12 AR ARP000106579A patent/AR026925A1/es not_active Application Discontinuation
- 2000-12-18 CO CO00095911A patent/CO5261611A1/es not_active Application Discontinuation
- 2000-12-19 US US09/763,892 patent/US6559162B2/en not_active Expired - Fee Related
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- 2000-12-19 WO PCT/SE2000/002604 patent/WO2001047893A1/en not_active Ceased
- 2000-12-19 MX MXPA02006249A patent/MXPA02006249A/es active IP Right Grant
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- 2000-12-19 RU RU2002114821/04A patent/RU2262505C2/ru not_active IP Right Cessation
- 2000-12-19 CZ CZ20022174A patent/CZ20022174A3/cs unknown
- 2000-12-19 KR KR1020027008151A patent/KR20020063261A/ko not_active Ceased
- 2000-12-19 HU HU0301030A patent/HUP0301030A3/hu unknown
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- 2000-12-19 AU AU25659/01A patent/AU777069B2/en not_active Ceased
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- 2000-12-19 CN CNB008190860A patent/CN1229350C/zh not_active Expired - Fee Related
- 2000-12-19 JP JP2001549365A patent/JP2003519128A/ja active Pending
- 2000-12-19 PL PL00357098A patent/PL357098A1/xx not_active Application Discontinuation
- 2000-12-19 UA UA2002064618A patent/UA75057C2/uk unknown
- 2000-12-19 CA CA002394097A patent/CA2394097A1/en not_active Abandoned
- 2000-12-21 MY MYPI20006092A patent/MY133785A/en unknown
2002
- 2002-05-29 ZA ZA200204310A patent/ZA200204310B/en unknown
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Publication number	Publication date
NO20023038D0 (no)	2002-06-21
MXPA02006249A (es)	2004-09-06
AU777069B2 (en)	2004-09-30
CN1229350C (zh)	2005-11-30
CO5261611A1 (es)	2003-03-31
AU2565901A (en)	2001-07-09
NO20023038L (no)	2002-08-22
KR20020063261A (ko)	2002-08-01
ZA200204310B (en)	2003-08-29
US20020137766A1 (en)	2002-09-26
IL150212A0 (en)	2002-12-01
NZ519497A (en)	2004-02-27
CN1434802A (zh)	2003-08-06
HUP0301030A3 (en)	2007-03-28
CZ20022174A3 (cs)	2002-09-11
RU2002114821A (ru)	2004-01-20
RU2262505C2 (ru)	2005-10-20
PL357098A1 (en)	2004-07-12
BR0016678A (pt)	2002-10-15
WO2001047893A1 (en)	2001-07-05
MY133785A (en)	2007-11-30
SE9904765D0 (sv)	1999-12-23
CA2394097A1 (en)	2001-07-05
HUP0301030A2 (hu)	2003-08-28
US6559162B2 (en)	2003-05-06
AR026925A1 (es)	2003-03-05
EE200200305A (et)	2003-06-16
UA75057C2 (en)	2006-03-15
EP1244631A1 (en)	2002-10-02
IS6438A (is)	2002-06-20
JP2003519128A (ja)	2003-06-17

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US20090176856A1 (en)	2009-07-09	Muscarinic receptor antagonists
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AU761576B2 (en)	2003-06-05	New bispidine compounds useful in the treatment of cardiac arrhythmias
SK18282001A3 (sk)	2002-12-03	Bispidínové zlúčeniny užitočné pri liečbe srdcových arytmií
HK1056364A (en)	2004-02-13	New azabicyclooctane derivatives useful in the treatment of cardiac arrhythmias
SK18292001A3 (sk)	2002-12-03	Bispidínové zlúčeniny užitočné pri liečbe srdcových arytmií