HUP0301304A2 - Új biszpidinvegyületek és felhasználásuk szívritmuszavarok kezelésére és ezeket tartalmazó gyógyszerkészítmények - Google Patents

Új biszpidinvegyületek és felhasználásuk szívritmuszavarok kezelésére és ezeket tartalmazó gyógyszerkészítmények Download PDF

Info

Publication number: HUP0301304A2
Authority: HU; Hungary
Prior art keywords: group; formula; compounds; alkyl; hydrogen atom
Prior art date: 2000-07-07

Application number

HU0301304A

Other languages

English (en)

Hungarian (hu)

Inventor

Kjell Andersson

Annika Björe

Magnus Björsne

Fritiof Pontén

Gert Strandlund

Peder Svensson

Louise Tottie

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.)

2000-07-07

Filing date

2001-07-04

Publication date

2003-08-28

2000-07-07 Priority claimed from SE0002603A external-priority patent/SE0002603D0/xx

2000-07-27 Priority claimed from SE0002788A external-priority patent/SE0002788D0/xx

2001-07-04 Application filed by Astrazeneca Ab, filed Critical Astrazeneca Ab,

2003-08-28 Publication of HUP0301304A2 publication Critical patent/HUP0301304A2/hu

Links

PTPQJKANBKHDPM-UHFFFAOYSA-N 3,7-diazabicyclo[3.3.1]nonane Chemical class C1NCC2CNCC1C2 PTPQJKANBKHDPM-UHFFFAOYSA-N 0.000 title claims abstract description 21
238000002360 preparation method Methods 0.000 title claims description 61
238000000034 method Methods 0.000 title claims description 39
206010003119 arrhythmia Diseases 0.000 title claims description 18
230000008569 process Effects 0.000 title claims description 15
150000001875 compounds Chemical class 0.000 claims abstract description 403
125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 159
125000000217 alkyl group Chemical group 0.000 claims abstract description 127
125000004432 carbon atom Chemical group C* 0.000 claims abstract description 95
125000002947 alkylene group Chemical group 0.000 claims abstract description 76
125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 55
150000002367 halogens Chemical class 0.000 claims abstract description 44
229910052736 halogen Inorganic materials 0.000 claims abstract description 43
-1 nitro- Chemical class 0.000 claims abstract description 40
238000004519 manufacturing process Methods 0.000 claims abstract 3
125000003118 aryl group Chemical group 0.000 claims description 77
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 71
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 67
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 64
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 44
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 42
125000001424 substituent group Chemical group 0.000 claims description 42
239000001257 hydrogen Substances 0.000 claims description 27
229910052739 hydrogen Inorganic materials 0.000 claims description 27
229910052757 nitrogen Inorganic materials 0.000 claims description 25
229910052799 carbon Inorganic materials 0.000 claims description 22
230000002829 reductive effect Effects 0.000 claims description 21
125000004433 nitrogen atom Chemical group N* 0.000 claims description 19
125000005843 halogen group Chemical group 0.000 claims description 16
125000004429 atom Chemical group 0.000 claims description 15
239000003814 drug Substances 0.000 claims description 15
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 14
125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 13
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
125000003545 alkoxy group Chemical group 0.000 claims description 12
150000001721 carbon Chemical group 0.000 claims description 11
MNLAVFKVRUQAKW-UHFFFAOYSA-N VR nerve agent Chemical compound CCN(CC)CCSP(C)(=O)OCC(C)C MNLAVFKVRUQAKW-UHFFFAOYSA-N 0.000 claims description 8
125000004430 oxygen atom Chemical group O* 0.000 claims description 8
230000006793 arrhythmia Effects 0.000 claims description 7
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
239000003795 chemical substances by application Substances 0.000 claims description 6
125000000623 heterocyclic group Chemical group 0.000 claims description 6
125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 5
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
239000007800 oxidant agent Substances 0.000 claims description 5
229910052760 oxygen Inorganic materials 0.000 claims description 5
239000001301 oxygen Substances 0.000 claims description 5
239000008194 pharmaceutical composition Substances 0.000 claims description 5
230000002265 prevention Effects 0.000 claims description 5
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
230000002861 ventricular Effects 0.000 claims description 4
125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 3
125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
IVRMZWNICZWHMI-UHFFFAOYSA-N Azide Chemical compound [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 claims description 3
206010047281 Ventricular arrhythmia Diseases 0.000 claims description 3
239000004480 active ingredient Substances 0.000 claims description 3
125000001624 naphthyl group Chemical group 0.000 claims description 3
125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 2
SIHVSPXVPKLFAB-UHFFFAOYSA-N 2-(3-benzyl-3,7-diazabicyclo[3.3.1]nonan-7-yl)ethanol Chemical compound C1N(CCO)CC(C2)CC1CN2CC1=CC=CC=C1 SIHVSPXVPKLFAB-UHFFFAOYSA-N 0.000 claims description 2
MHCWBLYCXZVTPV-UHFFFAOYSA-N 3-(3-benzyl-3,7-diazabicyclo[3.3.1]nonan-7-yl)-n-phenylpropanamide Chemical compound C=1C=CC=CC=1NC(=O)CCN(C1)CC(C2)CC1CN2CC1=CC=CC=C1 MHCWBLYCXZVTPV-UHFFFAOYSA-N 0.000 claims description 2
LHUWGMIFIFULPE-UHFFFAOYSA-N 3-benzyl-7-[3-(2-propyl-1,3-dioxolan-2-yl)propyl]-3,7-diazabicyclo[3.3.1]nonane Chemical compound C1C(CN(CC=2C=CC=CC=2)C2)CC2CN1CCCC1(CCC)OCCO1 LHUWGMIFIFULPE-UHFFFAOYSA-N 0.000 claims description 2
ASVNRQFCHFLEPS-UHFFFAOYSA-N 4-[3-(7-benzyl-2,4-dimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)-2-hydroxypropoxy]benzonitrile Chemical compound CC1N(CC(O)COC=2C=CC(=CC=2)C#N)C(C)C(C2)CC1CN2CC1=CC=CC=C1 ASVNRQFCHFLEPS-UHFFFAOYSA-N 0.000 claims description 2
SEOQYNBBMGIYOF-UHFFFAOYSA-N 4-[3-(7-benzyl-4-methyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)-2-hydroxypropoxy]benzonitrile Chemical compound C1N(CC(O)COC=2C=CC(=CC=2)C#N)C(C)C(C2)CC1CN2CC1=CC=CC=C1 SEOQYNBBMGIYOF-UHFFFAOYSA-N 0.000 claims description 2
206010003130 Arrhythmia supraventricular Diseases 0.000 claims description 2
YIKSCQDJHCMVMK-UHFFFAOYSA-N Oxamide Chemical compound NC(=O)C(N)=O YIKSCQDJHCMVMK-UHFFFAOYSA-N 0.000 claims description 2
239000002671 adjuvant Substances 0.000 claims description 2
125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
239000003085 diluting agent Substances 0.000 claims description 2
230000002140 halogenating effect Effects 0.000 claims description 2
CUIFDVJEFHYCEM-UHFFFAOYSA-N n-[1-(7-benzyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)-3-(4-cyanophenoxy)propan-2-yl]methanesulfonamide Chemical compound C1C(CN(CC=2C=CC=CC=2)C2)CC2CN1CC(NS(=O)(=O)C)COC1=CC=C(C#N)C=C1 CUIFDVJEFHYCEM-UHFFFAOYSA-N 0.000 claims description 2
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 claims description 2
125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 2
239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 75
238000006243 chemical reaction Methods 0.000 description 56
239000000203 mixture Substances 0.000 description 52
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 26
239000000243 solution Substances 0.000 description 26
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 23
239000003960 organic solvent Substances 0.000 description 23
239000011541 reaction mixture Substances 0.000 description 23
239000002904 solvent Substances 0.000 description 23
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 17
238000010992 reflux Methods 0.000 description 16
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
239000002585 base Substances 0.000 description 13
HQMRIBYCTLBDAK-UHFFFAOYSA-M bis(2-methylpropyl)alumanylium;chloride Chemical compound CC(C)C[Al](Cl)CC(C)C HQMRIBYCTLBDAK-UHFFFAOYSA-M 0.000 description 13
230000000694 effects Effects 0.000 description 13
229910000027 potassium carbonate Inorganic materials 0.000 description 13
241001465754 Metazoa Species 0.000 description 12
125000003277 amino group Chemical group 0.000 description 12
239000003054 catalyst Substances 0.000 description 12
238000012360 testing method Methods 0.000 description 12
WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 11
210000004027 cell Anatomy 0.000 description 10
239000003638 chemical reducing agent Substances 0.000 description 10
229940079593 drug Drugs 0.000 description 10
239000000706 filtrate Substances 0.000 description 10
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 9
238000004587 chromatography analysis Methods 0.000 description 9
229920006395 saturated elastomer Polymers 0.000 description 9
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 8
150000002431 hydrogen Chemical class 0.000 description 8
239000000047 product Substances 0.000 description 8
239000000126 substance Substances 0.000 description 8
210000002950 fibroblast Anatomy 0.000 description 7
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
230000003213 activating effect Effects 0.000 description 6
239000003416 antiarrhythmic agent Substances 0.000 description 6
239000003153 chemical reaction reagent Substances 0.000 description 6
239000003480 eluent Substances 0.000 description 6
238000004128 high performance liquid chromatography Methods 0.000 description 6
239000000543 intermediate Substances 0.000 description 6
230000000144 pharmacologic effect Effects 0.000 description 6
150000003839 salts Chemical class 0.000 description 6
239000000741 silica gel Substances 0.000 description 6
229910002027 silica gel Inorganic materials 0.000 description 6
NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 5
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 5
230000000747 cardiac effect Effects 0.000 description 5
238000007796 conventional method Methods 0.000 description 5
238000005859 coupling reaction Methods 0.000 description 5
125000004122 cyclic group Chemical group 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
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
238000002474 experimental method Methods 0.000 description 5
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
239000002953 phosphate buffered saline Substances 0.000 description 5
125000006239 protecting group Chemical group 0.000 description 5
230000009467 reduction Effects 0.000 description 5
239000012279 sodium borohydride Substances 0.000 description 5
229910000033 sodium borohydride Inorganic materials 0.000 description 5
DLQGGZNCJPLPQJ-UHFFFAOYSA-N 4-[3-(3,7-diazabicyclo[3.3.1]nonan-3-yl)-2-hydroxypropoxy]benzonitrile Chemical compound C1C(C2)CNCC2CN1CC(O)COC1=CC=C(C#N)C=C1 DLQGGZNCJPLPQJ-UHFFFAOYSA-N 0.000 description 4
VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-piperidinone Chemical compound O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 description 4
238000004458 analytical method Methods 0.000 description 4
239000012298 atmosphere Substances 0.000 description 4
UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 4
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
239000000460 chlorine Substances 0.000 description 4
239000007822 coupling agent Substances 0.000 description 4
239000003862 glucocorticoid Substances 0.000 description 4
210000002216 heart Anatomy 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
210000004379 membrane Anatomy 0.000 description 4
239000012528 membrane Substances 0.000 description 4
150000002829 nitrogen Chemical class 0.000 description 4
125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 4
230000002336 repolarization Effects 0.000 description 4
230000033764 rhythmic process Effects 0.000 description 4
125000004434 sulfur atom Chemical group 0.000 description 4
238000003786 synthesis reaction Methods 0.000 description 4
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 4
238000004809 thin layer chromatography Methods 0.000 description 4
RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
KAAITWOSDOCHEH-UHFFFAOYSA-N 3-benzyl-3,7-diazabicyclo[3.3.1]nonane Chemical compound C1C(C2)CNCC2CN1CC1=CC=CC=C1 KAAITWOSDOCHEH-UHFFFAOYSA-N 0.000 description 3
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 3
ICGLPKIVTVWCFT-UHFFFAOYSA-N 4-methylbenzenesulfonohydrazide Chemical compound CC1=CC=C(S(=O)(=O)NN)C=C1 ICGLPKIVTVWCFT-UHFFFAOYSA-N 0.000 description 3
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
102000004257 Potassium Channel Human genes 0.000 description 3
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
230000015572 biosynthetic process Effects 0.000 description 3
230000000903 blocking effect Effects 0.000 description 3
229910052794 bromium Inorganic materials 0.000 description 3
229910052801 chlorine Inorganic materials 0.000 description 3
230000008878 coupling Effects 0.000 description 3
238000010168 coupling process Methods 0.000 description 3
150000002148 esters Chemical class 0.000 description 3
OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 3
238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 3
125000000524 functional group Chemical group 0.000 description 3
125000002541 furyl group Chemical group 0.000 description 3
125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 3
210000004731 jugular vein Anatomy 0.000 description 3
239000012280 lithium aluminium hydride Substances 0.000 description 3
230000002503 metabolic effect Effects 0.000 description 3
229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 3
230000003287 optical effect Effects 0.000 description 3
150000007524 organic acids Chemical class 0.000 description 3
230000001590 oxidative effect Effects 0.000 description 3
125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 3
125000004193 piperazinyl group Chemical group 0.000 description 3
108020001213 potassium channel Proteins 0.000 description 3
239000000651 prodrug Substances 0.000 description 3
229940002612 prodrug Drugs 0.000 description 3
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
125000003226 pyrazolyl group Chemical group 0.000 description 3
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
230000004044 response Effects 0.000 description 3
235000017557 sodium bicarbonate Nutrition 0.000 description 3
229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
238000001228 spectrum Methods 0.000 description 3
125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 3
229910052717 sulfur Inorganic materials 0.000 description 3
230000009466 transformation Effects 0.000 description 3
125000006527 (C1-C5) alkyl group Chemical group 0.000 description 2
USVVENVKYJZFMW-ONEGZZNKSA-N (e)-carboxyiminocarbamic acid Chemical class OC(=O)\N=N\C(O)=O USVVENVKYJZFMW-ONEGZZNKSA-N 0.000 description 2
125000004511 1,2,3-thiadiazolyl group Chemical group 0.000 description 2
VDPCIZXWEQHOJC-UHFFFAOYSA-N 3,7-dibenzyl-3,7-diazabicyclo[3.3.1]nonan-9-one Chemical compound C1C(CN(CC=2C=CC=CC=2)C2)C(=O)C2CN1CC1=CC=CC=C1 VDPCIZXWEQHOJC-UHFFFAOYSA-N 0.000 description 2
AOELDAGSFOHVFW-UHFFFAOYSA-N 3,7-dibenzyl-3,7-diazabicyclo[3.3.1]nonane Chemical compound C=1C=CC=CC=1CN(C1)CC(C2)CC1CN2CC1=CC=CC=C1 AOELDAGSFOHVFW-UHFFFAOYSA-N 0.000 description 2
CLFSRXWETMSTNT-UHFFFAOYSA-N 3-butylsulfonyl-3,7-diazabicyclo[3.3.1]nonane Chemical compound C1NCC2CN(S(=O)(=O)CCCC)CC1C2 CLFSRXWETMSTNT-UHFFFAOYSA-N 0.000 description 2
ZQTRICNUAXVYPU-UHFFFAOYSA-N 4-(4-amino-3-hydroxybutoxy)benzonitrile Chemical compound NCC(O)CCOC1=CC=C(C#N)C=C1 ZQTRICNUAXVYPU-UHFFFAOYSA-N 0.000 description 2
XZGQQCFEIDXEAI-UHFFFAOYSA-N 4-[2-(oxiran-2-yl)ethoxy]benzonitrile Chemical compound C1=CC(C#N)=CC=C1OCCC1OC1 XZGQQCFEIDXEAI-UHFFFAOYSA-N 0.000 description 2
KRTAVQKUTUYWGI-UHFFFAOYSA-N 4-but-3-enoxybenzonitrile Chemical compound C=CCCOC1=CC=C(C#N)C=C1 KRTAVQKUTUYWGI-UHFFFAOYSA-N 0.000 description 2
CGFWWSKNMUPDGW-UHFFFAOYSA-N 7-benzyl-3,7-diazabicyclo[3.3.1]nonane-3-carbonitrile Chemical compound C1N(C#N)CC(C2)CC1CN2CC1=CC=CC=C1 CGFWWSKNMUPDGW-UHFFFAOYSA-N 0.000 description 2
NDQFHDJESHWKGW-UHFFFAOYSA-N 7-benzyl-3-(2-ethyltetrazol-5-yl)-3,7-diazabicyclo[3.3.1]nonane Chemical compound CCN1N=NC(N2CC3CC(CN(CC=4C=CC=CC=4)C3)C2)=N1 NDQFHDJESHWKGW-UHFFFAOYSA-N 0.000 description 2
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PGFLPQKUAKHQIJ-UHFFFAOYSA-N 4-[1-[2-[7-[3-(4-acetylpiperazin-1-yl)propyl]-3,7-diazabicyclo[3.3.1]nonan-3-yl]-2-oxoethyl]-5-(4-cyanophenyl)pyrazol-4-yl]benzonitrile Chemical compound C1CN(C(=O)C)CCN1CCCN1CC(CN(C2)C(=O)CN3C(=C(C=N3)C=3C=CC(=CC=3)C#N)C=3C=CC(=CC=3)C#N)CC2C1 PGFLPQKUAKHQIJ-UHFFFAOYSA-N 0.000 description 1
XAHHUPRFWZTTLD-UHFFFAOYSA-N 4-[2-(3-butanoyl-3,7-diazabicyclo[3.3.1]nonan-7-yl)ethoxy]benzonitrile Chemical compound C1N(C(=O)CCC)CC(C2)CC1CN2CCOC1=CC=C(C#N)C=C1 XAHHUPRFWZTTLD-UHFFFAOYSA-N 0.000 description 1
LASJJXLJWPZDGD-UHFFFAOYSA-N 4-[2-(3-butylsulfonyl-3,7-diazabicyclo[3.3.1]nonan-7-yl)ethoxy]benzonitrile Chemical compound C1N(S(=O)(=O)CCCC)CC(C2)CC1CN2CCOC1=CC=C(C#N)C=C1 LASJJXLJWPZDGD-UHFFFAOYSA-N 0.000 description 1
ZCKXMWGOIVLEED-UHFFFAOYSA-N 4-[2-[3-(1,3-thiazol-2-yl)-3,7-diazabicyclo[3.3.1]nonan-7-yl]ethoxy]benzonitrile Chemical compound C1=CC(C#N)=CC=C1OCCN1CC(CN(C2)C=3SC=CN=3)CC2C1 ZCKXMWGOIVLEED-UHFFFAOYSA-N 0.000 description 1
AHFZFNILUKWOLE-UHFFFAOYSA-N 4-[2-[3-(1-cyanoethyl)-3,7-diazabicyclo[3.3.1]nonan-7-yl]ethoxy]benzonitrile Chemical compound C1N(C(C#N)C)CC(C2)CC1CN2CCOC1=CC=C(C#N)C=C1 AHFZFNILUKWOLE-UHFFFAOYSA-N 0.000 description 1
BNADZJMESNCDFS-UHFFFAOYSA-N 4-[2-[3-(3,3-dimethyl-2-oxobutyl)-3,7-diazabicyclo[3.3.1]nonan-7-yl]ethoxy]benzonitrile Chemical compound C1N(CC(=O)C(C)(C)C)CC(C2)CC1CN2CCOC1=CC=C(C#N)C=C1 BNADZJMESNCDFS-UHFFFAOYSA-N 0.000 description 1
JHQAWCXMUUVNRU-UHFFFAOYSA-N 4-[2-[3-(cyclopropylmethyl)-3,7-diazabicyclo[3.3.1]nonan-7-yl]ethoxy]benzonitrile Chemical compound C1=CC(C#N)=CC=C1OCCN1CC(CN(CC2CC2)C2)CC2C1 JHQAWCXMUUVNRU-UHFFFAOYSA-N 0.000 description 1
YNYUDSQXJRNOBV-UHFFFAOYSA-N 4-[2-[3-[(4-fluorophenyl)methyl]-3,7-diazabicyclo[3.3.1]nonan-7-yl]ethoxy]benzonitrile Chemical compound C1=CC(F)=CC=C1CN1CC(CN(CCOC=2C=CC(=CC=2)C#N)C2)CC2C1 YNYUDSQXJRNOBV-UHFFFAOYSA-N 0.000 description 1
ORCGMDQFKRRQIE-UHFFFAOYSA-N 4-[2-[3-[2-(4-cyanophenyl)-2-hydroxyethyl]-3,7-diazabicyclo[3.3.1]nonan-7-yl]-1-hydroxyethyl]benzonitrile Chemical compound C=1C=C(C#N)C=CC=1C(O)CN(C1)CC(C2)CC1CN2CC(O)C1=CC=C(C#N)C=C1 ORCGMDQFKRRQIE-UHFFFAOYSA-N 0.000 description 1
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ONLMCIVYACQOBS-UHFFFAOYSA-N 4-[2-[7-(3-ethylsulfonylpropyl)-3,7-diazabicyclo[3.3.1]nonan-3-yl]ethoxy]benzonitrile Chemical compound C1N(CCCS(=O)(=O)CC)CC(C2)CC1CN2CCOC1=CC=C(C#N)C=C1 ONLMCIVYACQOBS-UHFFFAOYSA-N 0.000 description 1
AHQLCFNKWBJDLW-UHFFFAOYSA-N 4-[2-[7-(4-oxoheptyl)-3,7-diazabicyclo[3.3.1]nonan-3-yl]ethoxy]benzonitrile Chemical compound C1N(CCCC(=O)CCC)CC(C2)CC1CN2CCOC1=CC=C(C#N)C=C1 AHQLCFNKWBJDLW-UHFFFAOYSA-N 0.000 description 1
QXXJAHXFUPJEBB-UHFFFAOYSA-N 4-[2-[7-[2-(2-methoxyethoxy)ethyl]-3,7-diazabicyclo[3.3.1]nonan-3-yl]ethoxy]benzonitrile Chemical compound C1N(CCOCCOC)CC(C2)CC1CN2CCOC1=CC=C(C#N)C=C1 QXXJAHXFUPJEBB-UHFFFAOYSA-N 0.000 description 1
FQJFQMDKQAAUDR-UHFFFAOYSA-N 4-[2-[7-[2-(3,4-dimethoxyphenyl)ethyl]-3,7-diazabicyclo[3.3.1]nonan-3-yl]ethoxy]benzonitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN1CC(CN(CCOC=2C=CC(=CC=2)C#N)C2)CC2C1 FQJFQMDKQAAUDR-UHFFFAOYSA-N 0.000 description 1
DJEUWFQTFXXVIC-UHFFFAOYSA-N 4-[2-[7-[3-(4-acetylpiperazin-1-yl)propyl]-3,7-diazabicyclo[3.3.1]nonan-3-yl]ethoxy]benzonitrile Chemical compound C1CN(C(=O)C)CCN1CCCN1CC(CN(CCOC=2C=CC(=CC=2)C#N)C2)CC2C1 DJEUWFQTFXXVIC-UHFFFAOYSA-N 0.000 description 1
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YNJOLPRIECATMA-UHFFFAOYSA-N 4-[2-hydroxy-3-(3-propan-2-ylsulfonyl-3,7-diazabicyclo[3.3.1]nonan-7-yl)propoxy]benzonitrile Chemical compound C1N(S(=O)(=O)C(C)C)CC(C2)CC1CN2CC(O)COC1=CC=C(C#N)C=C1 YNJOLPRIECATMA-UHFFFAOYSA-N 0.000 description 1
YDXMICMAZYUOIJ-UHFFFAOYSA-N 4-[2-hydroxy-3-[3-(2,2,2-trifluoroacetyl)-3,7-diazabicyclo[3.3.1]nonan-7-yl]propoxy]benzonitrile Chemical compound C1C(CN(C2)C(=O)C(F)(F)F)CC2CN1CC(O)COC1=CC=C(C#N)C=C1 YDXMICMAZYUOIJ-UHFFFAOYSA-N 0.000 description 1
FUJTXANDMPRVFG-UHFFFAOYSA-N 4-[2-hydroxy-3-[3-(2-oxobutyl)-3,7-diazabicyclo[3.3.1]nonan-7-yl]propoxy]benzonitrile Chemical compound C1N(CC(=O)CC)CC(C2)CC1CN2CC(O)COC1=CC=C(C#N)C=C1 FUJTXANDMPRVFG-UHFFFAOYSA-N 0.000 description 1
LWFYPESAVOTMHL-UHFFFAOYSA-N 4-[2-hydroxy-3-[3-(3,3,3-trifluoropropanoyl)-3,7-diazabicyclo[3.3.1]nonan-7-yl]propoxy]benzonitrile Chemical compound C1C(CN(C2)C(=O)CC(F)(F)F)CC2CN1CC(O)COC1=CC=C(C#N)C=C1 LWFYPESAVOTMHL-UHFFFAOYSA-N 0.000 description 1
LVVIIODNNZDOGL-UHFFFAOYSA-N 4-[2-hydroxy-3-[3-(3-methylquinolin-8-yl)sulfonyl-3,7-diazabicyclo[3.3.1]nonan-7-yl]propoxy]benzonitrile Chemical compound C=1C=CC2=CC(C)=CN=C2C=1S(=O)(=O)N(C1)CC(C2)CC1CN2CC(O)COC1=CC=C(C#N)C=C1 LVVIIODNNZDOGL-UHFFFAOYSA-N 0.000 description 1
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RBVHDTDFIYCQBW-UHFFFAOYSA-N 4-[2-hydroxy-3-[3-(5-methyl-1,2-oxazole-3-carbonyl)-3,7-diazabicyclo[3.3.1]nonan-7-yl]propoxy]benzonitrile Chemical compound O1C(C)=CC(C(=O)N2CC3CC(CN(CC(O)COC=4C=CC(=CC=4)C#N)C3)C2)=N1 RBVHDTDFIYCQBW-UHFFFAOYSA-N 0.000 description 1
BCBLYTTYBLBHHA-UHFFFAOYSA-N 4-[2-hydroxy-3-[3-[2-hydroxy-3-(2-methyl-1-oxoisoquinolin-4-yl)oxypropyl]-3,7-diazabicyclo[3.3.1]nonan-7-yl]propoxy]benzonitrile Chemical compound C12=CC=CC=C2C(=O)N(C)C=C1OCC(O)CN(C1)CC(C2)CC1CN2CC(O)COC1=CC=C(C#N)C=C1 BCBLYTTYBLBHHA-UHFFFAOYSA-N 0.000 description 1
VZEDRNLJNMUOBX-UHFFFAOYSA-N 4-[2-hydroxy-3-[7-[(2-oxo-1,3-oxazolidin-4-yl)methyl]-3,7-diazabicyclo[3.3.1]nonan-3-yl]propoxy]benzonitrile Chemical compound C1C(CN(CC2NC(=O)OC2)C2)CC2CN1CC(O)COC1=CC=C(C#N)C=C1 VZEDRNLJNMUOBX-UHFFFAOYSA-N 0.000 description 1
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RTAYLFCDYMAOTB-UHFFFAOYSA-N 4-[3-(3-butanoyl-3,7-diazabicyclo[3.3.1]nonan-7-yl)-2-hydroxypropoxy]benzonitrile Chemical compound C1N(C(=O)CCC)CC(C2)CC1CN2CC(O)COC1=CC=C(C#N)C=C1 RTAYLFCDYMAOTB-UHFFFAOYSA-N 0.000 description 1
FXDFOCYWWDANPI-UHFFFAOYSA-N 4-[3-(3-butylsulfonyl-3,7-diazabicyclo[3.3.1]nonan-7-yl)-2-hydroxypropoxy]benzonitrile Chemical compound C1N(S(=O)(=O)CCCC)CC(C2)CC1CN2CC(O)COC1=CC=C(C#N)C=C1 FXDFOCYWWDANPI-UHFFFAOYSA-N 0.000 description 1
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WKSIROOSLVKOPH-UHFFFAOYSA-N 4-[3-[3-[(4-fluorophenyl)methyl]-3,7-diazabicyclo[3.3.1]nonan-7-yl]propylamino]benzonitrile Chemical compound C1=CC(F)=CC=C1CN1CC(CN(CCCNC=2C=CC(=CC=2)C#N)C2)CC2C1 WKSIROOSLVKOPH-UHFFFAOYSA-N 0.000 description 1
WKGBFMGQJOASIO-UHFFFAOYSA-N 4-[3-[3-[(4-fluorophenyl)methyl]-3,7-diazabicyclo[3.3.1]nonan-7-yl]propylsulfonyl]benzonitrile Chemical compound C1=CC(F)=CC=C1CN1CC(CN(CCCS(=O)(=O)C=2C=CC(=CC=2)C#N)C2)CC2C1 WKGBFMGQJOASIO-UHFFFAOYSA-N 0.000 description 1
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CRZUARZDYOTXTI-UHFFFAOYSA-N 4-[3-[3-[2-(3,4-dimethoxyphenyl)ethyl]-3,7-diazabicyclo[3.3.1]nonan-7-yl]propylsulfonyl]benzonitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN1CC(CN(CCCS(=O)(=O)C=2C=CC(=CC=2)C#N)C2)CC2C1 CRZUARZDYOTXTI-UHFFFAOYSA-N 0.000 description 1
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239000013067 intermediate product Substances 0.000 description 1
238000001361 intraarterial administration Methods 0.000 description 1
239000007928 intraperitoneal injection Substances 0.000 description 1
238000001990 intravenous administration Methods 0.000 description 1
238000011835 investigation Methods 0.000 description 1
229910052740 iodine Inorganic materials 0.000 description 1
HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
238000005342 ion exchange Methods 0.000 description 1
210000005246 left atrium Anatomy 0.000 description 1
210000005240 left ventricle Anatomy 0.000 description 1
239000011968 lewis acid catalyst Substances 0.000 description 1
230000000670 limiting effect Effects 0.000 description 1
150000002632 lipids Chemical class 0.000 description 1
WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
238000001819 mass spectrum Methods 0.000 description 1
230000010534 mechanism of action Effects 0.000 description 1
239000002609 medium Substances 0.000 description 1
230000028161 membrane depolarization Effects 0.000 description 1
HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 1
QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
229940087646 methanolamine Drugs 0.000 description 1
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 description 1
125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
150000007522 mineralic acids Chemical class 0.000 description 1
239000003068 molecular probe Substances 0.000 description 1
230000004660 morphological change Effects 0.000 description 1
208000031225 myocardial ischemia Diseases 0.000 description 1
210000004165 myocardium Anatomy 0.000 description 1
PQDCSCHJYFYCGY-UHFFFAOYSA-N n'-cyano-7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-n-methyl-n-propan-2-yl-3,7-diazabicyclo[3.3.1]nonane-3-carboximidamide Chemical compound C1N(C(=NC#N)N(C)C(C)C)CC(C2)CC1CN2CC(O)COC1=CC=C(C#N)C=C1 PQDCSCHJYFYCGY-UHFFFAOYSA-N 0.000 description 1
OTAWSFIAOAJZDE-UHFFFAOYSA-N n-[2-[3-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo[3.3.1]nonan-7-yl]ethyl]-4-(methanesulfonamido)benzamide Chemical compound C1=CC(NS(=O)(=O)C)=CC=C1C(=O)NCCN1CC(CN(CC(O)COC=2C=CC(=CC=2)C#N)C2)CC2C1 OTAWSFIAOAJZDE-UHFFFAOYSA-N 0.000 description 1
GJJNIEAYDFRHRV-UHFFFAOYSA-N n-[2-[3-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo[3.3.1]nonan-7-yl]ethyl]-4-nitrobenzamide Chemical compound C1C(CN(CCNC(=O)C=2C=CC(=CC=2)[N+]([O-])=O)C2)CC2CN1CC(O)COC1=CC=C(C#N)C=C1 GJJNIEAYDFRHRV-UHFFFAOYSA-N 0.000 description 1
UMQUFJULMQHMTL-UHFFFAOYSA-N n-[2-[7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo[3.3.1]nonan-3-yl]-2-oxoethyl]acetamide Chemical compound C1N(C(=O)CNC(=O)C)CC(C2)CC1CN2CC(O)COC1=CC=C(C#N)C=C1 UMQUFJULMQHMTL-UHFFFAOYSA-N 0.000 description 1
KFAWWPIHKRFIMH-UHFFFAOYSA-N n-[3-[3-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo[3.3.1]nonan-7-yl]propyl]-n-(3,4-dimethoxyphenyl)-4-nitrobenzamide Chemical compound C1=C(OC)C(OC)=CC=C1N(C(=O)C=1C=CC(=CC=1)[N+]([O-])=O)CCCN1CC(CN(CC(O)COC=2C=CC(=CC=2)C#N)C2)CC2C1 KFAWWPIHKRFIMH-UHFFFAOYSA-N 0.000 description 1
SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
JCMDMJYRJNTTMM-UHFFFAOYSA-N n-cyano-7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-n'-[(3,4,5-trimethoxyphenyl)methyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboximidamide Chemical compound COC1=C(OC)C(OC)=CC(CNC(=NC#N)N2CC3CC(CN(CC(O)COC=4C=CC(=CC=4)C#N)C3)C2)=C1 JCMDMJYRJNTTMM-UHFFFAOYSA-N 0.000 description 1
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
231100000252 nontoxic Toxicity 0.000 description 1
230000003000 nontoxic effect Effects 0.000 description 1
125000002971 oxazolyl group Chemical group 0.000 description 1
BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 1
229910052763 palladium Inorganic materials 0.000 description 1
NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
229920002866 paraformaldehyde Polymers 0.000 description 1
238000007911 parenteral administration Methods 0.000 description 1
229940049954 penicillin Drugs 0.000 description 1
229960001412 pentobarbital Drugs 0.000 description 1
210000003516 pericardium Anatomy 0.000 description 1
239000012071 phase Substances 0.000 description 1
239000003444 phase transfer catalyst Substances 0.000 description 1
125000001484 phenothiazinyl group Chemical class C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
UXOFXTUCXRNLFA-UHFFFAOYSA-N phenyl-(7-propan-2-yl-3,7-diazabicyclo[3.3.1]nonan-3-yl)methanone Chemical compound C1N(C(C)C)CC(C2)CC1CN2C(=O)C1=CC=CC=C1 UXOFXTUCXRNLFA-UHFFFAOYSA-N 0.000 description 1
ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
229910000073 phosphorus hydride Inorganic materials 0.000 description 1
125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
125000003386 piperidinyl group Chemical group 0.000 description 1
239000013641 positive control Substances 0.000 description 1
239000000843 powder Substances 0.000 description 1
238000002953 preparative HPLC Methods 0.000 description 1
230000001536 pro-arrhythmogenic effect Effects 0.000 description 1
XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 description 1
229960003712 propranolol Drugs 0.000 description 1
108090000623 proteins and genes Proteins 0.000 description 1
102000004169 proteins and genes Human genes 0.000 description 1
125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
125000003373 pyrazinyl group Chemical group 0.000 description 1
125000000719 pyrrolidinyl group Chemical group 0.000 description 1
125000001422 pyrrolinyl group Chemical group 0.000 description 1
125000000168 pyrrolyl group Chemical group 0.000 description 1
230000006340 racemization Effects 0.000 description 1
239000000376 reactant Substances 0.000 description 1
230000008707 rearrangement Effects 0.000 description 1
210000000664 rectum Anatomy 0.000 description 1
238000004007 reversed phase HPLC Methods 0.000 description 1
238000007363 ring formation reaction Methods 0.000 description 1
239000000523 sample Substances 0.000 description 1
238000005070 sampling Methods 0.000 description 1
238000012216 screening Methods 0.000 description 1
238000007423 screening assay Methods 0.000 description 1
229910052710 silicon Inorganic materials 0.000 description 1
239000010703 silicon Substances 0.000 description 1
239000012312 sodium hydride Substances 0.000 description 1
229910000104 sodium hydride Inorganic materials 0.000 description 1
229960001922 sodium perborate Drugs 0.000 description 1
YKLJGMBLPUQQOI-UHFFFAOYSA-M sodium;oxidooxy(oxo)borane Chemical compound [Na+].[O-]OB=O YKLJGMBLPUQQOI-UHFFFAOYSA-M 0.000 description 1
239000007790 solid phase Substances 0.000 description 1
239000012453 solvate Substances 0.000 description 1
238000000638 solvent extraction Methods 0.000 description 1
241000894007 species Species 0.000 description 1
238000010183 spectrum analysis Methods 0.000 description 1
229960005322 streptomycin Drugs 0.000 description 1
238000007920 subcutaneous administration Methods 0.000 description 1
125000003107 substituted aryl group Chemical group 0.000 description 1
125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 description 1
239000011593 sulfur Substances 0.000 description 1
239000000725 suspension Substances 0.000 description 1
230000035488 systolic blood pressure Effects 0.000 description 1
230000006794 tachycardia Effects 0.000 description 1
239000008399 tap water Substances 0.000 description 1
235000020679 tap water Nutrition 0.000 description 1
229960002926 tedisamil Drugs 0.000 description 1
CTIRHWCPXYGDGF-HDICACEKSA-N tedisamil Chemical compound [H][C@]12CN(CC3CC3)C[C@]([H])(CN(CC3CC3)C1)C21CCCC1 CTIRHWCPXYGDGF-HDICACEKSA-N 0.000 description 1
ICNWQSARBNRXSN-UHFFFAOYSA-N tert-butyl 3-[[7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo[3.3.1]nonane-3-carbothioyl]amino]propanoate Chemical compound C1N(C(=S)NCCC(=O)OC(C)(C)C)CC(C2)CC1CN2CC(O)COC1=CC=C(C#N)C=C1 ICNWQSARBNRXSN-UHFFFAOYSA-N 0.000 description 1
FFDOXSIZJSGXOQ-UHFFFAOYSA-N tert-butyl 7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC(C2)CC1CN2CC(O)COC1=CC=C(C#N)C=C1 FFDOXSIZJSGXOQ-UHFFFAOYSA-N 0.000 description 1
OMJXIMJLBUMUJI-UHFFFAOYSA-N tert-butyl n-[1-(3-butylsulfonyl-3,7-diazabicyclo[3.3.1]nonan-7-yl)-4-(4-cyanophenoxy)butan-2-yl]carbamate Chemical compound C1N(S(=O)(=O)CCCC)CC(C2)CC1CN2CC(NC(=O)OC(C)(C)C)CCOC1=CC=C(C#N)C=C1 OMJXIMJLBUMUJI-UHFFFAOYSA-N 0.000 description 1
YWBADHLGYONUAC-UHFFFAOYSA-N tert-butyl n-[2-[3-[2-amino-3-(4-cyanophenoxy)propyl]-3,7-diazabicyclo[3.3.1]nonan-7-yl]ethyl]carbamate Chemical compound C1N(CCNC(=O)OC(C)(C)C)CC(C2)CC1CN2CC(N)COC1=CC=C(C#N)C=C1 YWBADHLGYONUAC-UHFFFAOYSA-N 0.000 description 1
MYOHDFYCJARIJO-UHFFFAOYSA-N tert-butyl n-[2-[3-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo[3.3.1]nonan-7-yl]ethyl]carbamate Chemical compound C1N(CCNC(=O)OC(C)(C)C)CC(C2)CC1CN2CC(O)COC1=CC=C(C#N)C=C1 MYOHDFYCJARIJO-UHFFFAOYSA-N 0.000 description 1
XIHYHBDKJKJBBZ-UHFFFAOYSA-N tert-butyl n-[2-[7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo[3.3.1]nonan-3-yl]-2-oxoethyl]carbamate Chemical compound C1N(C(=O)CNC(=O)OC(C)(C)C)CC(C2)CC1CN2CC(O)COC1=CC=C(C#N)C=C1 XIHYHBDKJKJBBZ-UHFFFAOYSA-N 0.000 description 1
IUVINUVWJBACBQ-UHFFFAOYSA-N tert-butyl n-[4-(4-cyanophenoxy)-2-hydroxybutyl]carbamate Chemical compound CC(C)(C)OC(=O)NCC(O)CCOC1=CC=C(C#N)C=C1 IUVINUVWJBACBQ-UHFFFAOYSA-N 0.000 description 1
OSTGEMHVUNCMFA-UHFFFAOYSA-N tert-butyl n-[4-[7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo[3.3.1]nonan-3-yl]-4-oxobutan-2-yl]carbamate Chemical compound C1N(C(=O)CC(C)NC(=O)OC(C)(C)C)CC(C2)CC1CN2CC(O)COC1=CC=C(C#N)C=C1 OSTGEMHVUNCMFA-UHFFFAOYSA-N 0.000 description 1
ISTGQSQWSKCNFJ-UHFFFAOYSA-N tert-butyl n-ethylcarbamate Chemical compound CCNC(=O)OC(C)(C)C ISTGQSQWSKCNFJ-UHFFFAOYSA-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
125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
125000001113 thiadiazolyl group Chemical group 0.000 description 1
125000005490 tosylate group Chemical group 0.000 description 1
230000001988 toxicity Effects 0.000 description 1
231100000419 toxicity Toxicity 0.000 description 1
238000000844 transformation Methods 0.000 description 1
125000004665 trialkylsilyl group Chemical group 0.000 description 1
125000001425 triazolyl group Chemical group 0.000 description 1
TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
239000003029 tricyclic antidepressant agent Substances 0.000 description 1
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
239000012588 trypsin Substances 0.000 description 1
238000005303 weighing Methods 0.000 description 1
229940102001 zinc bromide Drugs 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics

Landscapes

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

HU0301304A 2000-07-07 2001-07-04 Új biszpidinvegyületek és felhasználásuk szívritmuszavarok kezelésére és ezeket tartalmazó gyógyszerkészítmények HUP0301304A2 (hu)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
SE0002603A SE0002603D0 (sv)	2000-07-07	2000-07-07	New compounds
SE0002788A SE0002788D0 (sv)	2000-07-27	2000-07-27	New compounds
PCT/SE2001/001544 WO2002004446A1 (en)	2000-07-07	2001-07-04	New bispidine compounds and their use in the treatment of cardiac arrhythmias

Publications (1)

Publication Number	Publication Date
HUP0301304A2 true HUP0301304A2 (hu)	2003-08-28

Family

ID=26655177

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
HU0301304A HUP0301304A2 (hu)	2000-07-07	2001-07-04	Új biszpidinvegyületek és felhasználásuk szívritmuszavarok kezelésére és ezeket tartalmazó gyógyszerkészítmények

Country Status (20)

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

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* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
WO2004103991A1 (en) *	2003-05-20	2004-12-02	'chemical Diversity Research Institute', Ltd.	2-substituted piperidines, focused library and a pharmaceutical compound
US7399765B2 (en)	2003-09-19	2008-07-15	Abbott Laboratories	Substituted diazabicycloalkane derivatives
SE0302775D0 (sv) *	2003-10-20	2003-10-20	Astrazeneca Ab	Chemical compound and assay
RU2472793C1 (ru) *	2011-07-20	2013-01-20	Федеральное государственное бюджетное образовательное учреждение высшего профессионального образования "Московский государственный университет тонких химических технологий имени М.В. Ломоносова" (МИТХТ им.М.В.Ломоносова)	1,5-бис[(трет-бутиламино)метил]-n,n'-ди-трет-бутилбиспидин-9-она и способ его получения
CN116444556A (zh) *	2023-03-24	2023-07-18	苏州威迈芯材半导体有限公司	一种有机硅中间体4-苯甲腈基氧烷基三烷氧基硅烷的制备方法

Family Cites Families (10)

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

2001
- 2001-06-28 AR ARP010103085A patent/AR030302A1/es not_active Application Discontinuation
- 2001-07-04 CA CA002412848A patent/CA2412848A1/en not_active Abandoned
- 2001-07-04 RU RU2002134450/04A patent/RU2002134450A/ru not_active Application Discontinuation
- 2001-07-04 JP JP2002509311A patent/JP2004502772A/ja active Pending
- 2001-07-04 PL PL36047401A patent/PL360474A1/xx not_active Application Discontinuation
- 2001-07-04 HU HU0301304A patent/HUP0301304A2/hu unknown
- 2001-07-04 CZ CZ200332A patent/CZ200332A3/cs unknown
- 2001-07-04 CN CN01812475A patent/CN1440407A/zh active Pending
- 2001-07-04 AU AU2001271161A patent/AU2001271161A1/en not_active Abandoned
- 2001-07-04 BR BR0112267-3A patent/BR0112267A/pt not_active IP Right Cessation
- 2001-07-04 EE EEP200300013A patent/EE200300013A/xx unknown
- 2001-07-04 WO PCT/SE2001/001544 patent/WO2002004446A1/en not_active Ceased
- 2001-07-04 IL IL15348501A patent/IL153485A0/xx unknown
- 2001-07-04 KR KR10-2003-7000248A patent/KR20030014426A/ko not_active Withdrawn
- 2001-07-04 SK SK4-2003A patent/SK42003A3/sk unknown
- 2001-07-04 NZ NZ523540A patent/NZ523540A/en unknown
- 2001-07-04 MX MXPA02012942A patent/MXPA02012942A/es unknown
- 2001-07-04 EP EP01950132A patent/EP1301510A1/en not_active Withdrawn
2002
- 2002-12-19 IS IS6660A patent/IS6660A/is unknown
2003
- 2003-01-06 NO NO20030057A patent/NO20030057L/no not_active Application Discontinuation

Also Published As

Publication number	Publication date
SK42003A3 (en)	2003-07-01
AR030302A1 (es)	2003-08-20
CA2412848A1 (en)	2002-01-17
EP1301510A1 (en)	2003-04-16
IS6660A (is)	2002-12-19
MXPA02012942A (es)	2003-10-06
CN1440407A (zh)	2003-09-03
NO20030057L (no)	2003-01-31
WO2002004446A1 (en)	2002-01-17
BR0112267A (pt)	2003-05-20
KR20030014426A (ko)	2003-02-17
JP2004502772A (ja)	2004-01-29
RU2002134450A (ru)	2004-07-10
NZ523540A (en)	2004-07-30
NO20030057D0 (no)	2003-01-06
CZ200332A3 (cs)	2003-04-16
PL360474A1 (en)	2004-09-06
EE200300013A (et)	2004-10-15
IL153485A0 (en)	2003-07-06
AU2001271161A1 (en)	2002-01-21

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Date	Code	Title	Description
2006-04-28	FD9A	Lapse of provisional protection due to non-payment of fees

Publication	Publication Date	Title
EP1047695B1 (en)	2004-03-17	Novel bispidine antiarrhythmic compounds
HUP0302538A2 (hu)	2003-11-28	3,7-diaza-biciklo[3.3.0]oktán-vegyületek, eljárás az előállításukra, ezeket tartalmazó gyógyszerkészítmények és felhasználásuk szívritmus-zavarok kezelésére
KR20030032060A (ko)	2003-04-23	심부정맥의 치료에 유용한 신규 옥사비스피딘 화합물
US7012074B2 (en)	2006-03-14	3,8-Diazabicyclo[3.2.1]octanes and their use in the treatment of cardiac arrhythmias
JP2004502772A (ja)	2004-01-29	新規ビスピジン化合物および心不整脈の処置における前記化合物の使用
AU761576B2 (en)	2003-06-05	New bispidine compounds useful in the treatment of cardiac arrhythmias
EP1192154B1 (en)	2004-03-17	Bispidine compounds useful in the treatment of cardiac arrhythmias
US20030212095A1 (en)	2003-11-13	New bispidine compounds and their use in the treatment of cardiac arrhythmias
US20040229900A1 (en)	2004-11-18	Bispidine compounds useful in the treatment of cardiac arrythmias
EP1192156B1 (en)	2004-02-18	Bispidine compounds useful in the treatment of cardiac arrhythmias
HUP0202328A2 (en)	2002-10-28	Novel bispidine compounds useful in the treatment of cardiac arrhythmias, process for their preparation, pharmaceutical compositions containing them and intermediates