EP0639973A1 - Diamines pour le traitement de l'arythmie - Google Patents
Diamines pour le traitement de l'arythmieInfo
- Publication number
- EP0639973A1 EP0639973A1 EP93909965A EP93909965A EP0639973A1 EP 0639973 A1 EP0639973 A1 EP 0639973A1 EP 93909965 A EP93909965 A EP 93909965A EP 93909965 A EP93909965 A EP 93909965A EP 0639973 A1 EP0639973 A1 EP 0639973A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- dimethoxyphenyl
- alkyl
- pharmaceutically acceptable
- ethyl
- formula
- Prior art date
- Legal status (The legal status 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 status listed.)
- Withdrawn
Links
- 206010003119 arrhythmia Diseases 0.000 title claims abstract description 17
- 230000006793 arrhythmia Effects 0.000 title claims abstract description 14
- 150000004985 diamines Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 143
- 238000000034 method Methods 0.000 claims abstract description 48
- 150000003839 salts Chemical class 0.000 claims abstract description 42
- 239000012453 solvate Substances 0.000 claims abstract description 32
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 27
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 25
- -1 cyano, hydroxy Chemical group 0.000 claims abstract description 21
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 10
- 239000001257 hydrogen Substances 0.000 claims abstract description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 8
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 8
- 150000001336 alkenes Chemical class 0.000 claims abstract description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 4
- 231100000252 nontoxic Toxicity 0.000 claims abstract description 4
- 230000003000 nontoxic effect Effects 0.000 claims abstract description 4
- 125000004423 acyloxy group Chemical group 0.000 claims abstract description 3
- 125000005530 alkylenedioxy group Chemical group 0.000 claims abstract description 3
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 3
- 150000002367 halogens Chemical class 0.000 claims abstract description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 58
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 25
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 18
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 7
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 6
- 230000000302 ischemic effect Effects 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 125000006317 cyclopropyl amino group Chemical group 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000003232 p-nitrobenzoyl group Chemical group [N+](=O)([O-])C1=CC=C(C(=O)*)C=C1 0.000 claims description 3
- 238000007911 parenteral administration Methods 0.000 claims description 3
- 230000033764 rhythmic process Effects 0.000 claims description 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- IUUOJGSZVRNPDP-UHFFFAOYSA-N n-(3,4-dimethoxyphenyl)-n-[3-[2-(3,4-dimethoxyphenyl)ethyl-propan-2-ylamino]propyl]-4-nitrobenzamide Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C(C)C)CCCN(C=1C=C(OC)C(OC)=CC=1)C(=O)C1=CC=C([N+]([O-])=O)C=C1 IUUOJGSZVRNPDP-UHFFFAOYSA-N 0.000 claims description 2
- IWVWAKUJWCBAER-UHFFFAOYSA-N 4-amino-n-(3,4-dimethoxyphenyl)-n-[3-[2-(3,4-dimethoxyphenyl)ethyl-methylamino]propyl]benzamide Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCN(C=1C=C(OC)C(OC)=CC=1)C(=O)C1=CC=C(N)C=C1 IWVWAKUJWCBAER-UHFFFAOYSA-N 0.000 claims 1
- LQNIPXRLVAJFNA-UHFFFAOYSA-N n-(3,4-dichlorophenyl)-n-[3-[2-(3,4-dimethoxyphenyl)ethyl-methylamino]propyl]-4-nitrobenzamide Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCN(C=1C=C(Cl)C(Cl)=CC=1)C(=O)C1=CC=C([N+]([O-])=O)C=C1 LQNIPXRLVAJFNA-UHFFFAOYSA-N 0.000 claims 1
- QYFCGLVAIQWXLS-UHFFFAOYSA-N n-(3,4-dimethoxyphenyl)-n-[3-[2-(3,4-dimethoxyphenyl)ethyl-prop-2-enylamino]propyl]-4-nitrobenzamide Chemical compound C1=C(OC)C(OC)=CC=C1CCN(CC=C)CCCN(C=1C=C(OC)C(OC)=CC=1)C(=O)C1=CC=C([N+]([O-])=O)C=C1 QYFCGLVAIQWXLS-UHFFFAOYSA-N 0.000 claims 1
- QCIOYDQFPCXWSK-UHFFFAOYSA-N n-[3-[2-(3,4-dimethoxyphenyl)ethyl-methylamino]propyl]-4-nitro-n-(3,4,5-trimethoxyphenyl)benzamide Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCN(C=1C=C(OC)C(OC)=C(OC)C=1)C(=O)C1=CC=C([N+]([O-])=O)C=C1 QCIOYDQFPCXWSK-UHFFFAOYSA-N 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 abstract description 2
- 101100440695 Dictyostelium discoideum corB gene Proteins 0.000 abstract 2
- BGCPLWWYPZAURQ-UHFFFAOYSA-N 5-[[5-chloro-2-(2,2,6,6-tetramethylmorpholin-4-yl)pyrimidin-4-yl]amino]-3-(3-hydroxy-3-methylbutyl)-1-methylbenzimidazol-2-one Chemical compound ClC=1C(=NC(=NC=1)N1CC(OC(C1)(C)C)(C)C)NC1=CC2=C(N(C(N2CCC(C)(C)O)=O)C)C=C1 BGCPLWWYPZAURQ-UHFFFAOYSA-N 0.000 abstract 1
- 101100148545 Caenorhabditis elegans snr-5 gene Proteins 0.000 abstract 1
- 125000006355 carbonyl methylene group Chemical group [H]C([H])([*:2])C([*:1])=O 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 132
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 99
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 88
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 72
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 70
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 63
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 52
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 49
- 239000000243 solution Substances 0.000 description 48
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 40
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- 239000000203 mixture Substances 0.000 description 38
- 238000005160 1H NMR spectroscopy Methods 0.000 description 34
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 33
- 239000000741 silica gel Substances 0.000 description 31
- 229910002027 silica gel Inorganic materials 0.000 description 31
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
- 229940093499 ethyl acetate Drugs 0.000 description 29
- 235000019439 ethyl acetate Nutrition 0.000 description 29
- 239000003921 oil Substances 0.000 description 29
- 235000019198 oils Nutrition 0.000 description 29
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 26
- 239000011541 reaction mixture Substances 0.000 description 23
- 229960004132 diethyl ether Drugs 0.000 description 22
- 239000012074 organic phase Substances 0.000 description 19
- 238000004587 chromatography analysis Methods 0.000 description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 230000036982 action potential Effects 0.000 description 14
- 230000000694 effects Effects 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- 208000003663 ventricular fibrillation Diseases 0.000 description 13
- 229960002370 sotalol Drugs 0.000 description 12
- 241000282472 Canis lupus familiaris Species 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 238000003818 flash chromatography Methods 0.000 description 11
- 239000003981 vehicle Substances 0.000 description 11
- SKDHHIUENRGTHK-UHFFFAOYSA-N 4-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=C(C(Cl)=O)C=C1 SKDHHIUENRGTHK-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 238000001816 cooling Methods 0.000 description 9
- 239000013078 crystal Substances 0.000 description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 9
- 230000010410 reperfusion Effects 0.000 description 9
- YKPQUSLRUFLVDA-UHFFFAOYSA-N $l^{2}-azanylmethane Chemical compound [NH]C YKPQUSLRUFLVDA-UHFFFAOYSA-N 0.000 description 8
- 208000028867 ischemia Diseases 0.000 description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 6
- 239000003416 antiarrhythmic agent Substances 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000012458 free base Substances 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 230000036390 resting membrane potential Effects 0.000 description 6
- HNJWKRMESUMDQE-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-n-methylethanamine Chemical compound CNCCC1=CC=C(OC)C(OC)=C1 HNJWKRMESUMDQE-UHFFFAOYSA-N 0.000 description 5
- INUNLMUAPJVRME-UHFFFAOYSA-N 3-chloropropanoyl chloride Chemical compound ClCCC(Cl)=O INUNLMUAPJVRME-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 238000013019 agitation Methods 0.000 description 5
- 239000003937 drug carrier Substances 0.000 description 5
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 description 5
- 239000012280 lithium aluminium hydride Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 238000001665 trituration Methods 0.000 description 5
- 230000002861 ventricular Effects 0.000 description 5
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 4
- 229910010084 LiAlH4 Inorganic materials 0.000 description 4
- 239000007832 Na2SO4 Substances 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 230000000004 hemodynamic effect Effects 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- IVEAXRWEGVPLPF-UHFFFAOYSA-N 3-chloro-n-(3,4-dichlorophenyl)propanamide Chemical compound ClCCC(=O)NC1=CC=C(Cl)C(Cl)=C1 IVEAXRWEGVPLPF-UHFFFAOYSA-N 0.000 description 3
- WXMWLNAPEHYULF-UHFFFAOYSA-N 3-chloro-n-(4-fluorophenyl)propanamide Chemical compound FC1=CC=C(NC(=O)CCCl)C=C1 WXMWLNAPEHYULF-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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- 238000004458 analytical method Methods 0.000 description 3
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- VQRALEUIKWLGLG-UHFFFAOYSA-N n'-[2-(3,4-dimethoxyphenyl)ethyl]-n'-methyl-n-(3,4,5-trimethoxyphenyl)propane-1,3-diamine Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCNC1=CC(OC)=C(OC)C(OC)=C1 VQRALEUIKWLGLG-UHFFFAOYSA-N 0.000 description 3
- ZXLABRSLOUVIII-UHFFFAOYSA-N n-(3,4-dimethoxyphenyl)-n'-[2-(3,4-dimethoxyphenyl)ethyl]-n'-propan-2-ylpropane-1,3-diamine Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C(C)C)CCCNC1=CC=C(OC)C(OC)=C1 ZXLABRSLOUVIII-UHFFFAOYSA-N 0.000 description 3
- ZBMZVLHSJCTVON-GFCCVEGCSA-N n-[4-[(1s)-1-hydroxy-2-(propan-2-ylamino)ethyl]phenyl]methanesulfonamide Chemical compound CC(C)NC[C@@H](O)C1=CC=C(NS(C)(=O)=O)C=C1 ZBMZVLHSJCTVON-GFCCVEGCSA-N 0.000 description 3
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- NYDBTRCGHOXYLR-UHFFFAOYSA-N 4-[3-[2-(3,4-dimethoxyphenyl)ethyl-methylamino]propylamino]-2-methoxyphenol Chemical compound C1=C(O)C(OC)=CC(NCCCN(C)CCC=2C=C(OC)C(OC)=CC=2)=C1 NYDBTRCGHOXYLR-UHFFFAOYSA-N 0.000 description 2
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- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 description 2
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
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- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
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- CTDNMKOBWPJMOM-UHFFFAOYSA-N n'-[2-(3,4-dimethoxyphenyl)ethyl]-n-[3,4-di(propan-2-yloxy)phenyl]-n'-methylpropane-1,3-diamine Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCNC1=CC=C(OC(C)C)C(OC(C)C)=C1 CTDNMKOBWPJMOM-UHFFFAOYSA-N 0.000 description 2
- LARAMROHGGPQHV-UHFFFAOYSA-N n'-cyclopropyl-n-(3,4-dimethoxyphenyl)-n'-[2-(3,4-dimethoxyphenyl)ethyl]propane-1,3-diamine Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C1CC1)CCCNC1=CC=C(OC)C(OC)=C1 LARAMROHGGPQHV-UHFFFAOYSA-N 0.000 description 2
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- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
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- 239000002687 nonaqueous vehicle Substances 0.000 description 1
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- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 230000001536 pro-arrhythmogenic effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- FKRCODPIKNYEAC-UHFFFAOYSA-N propionic acid ethyl ester Natural products CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 238000000718 qrs complex Methods 0.000 description 1
- 150000003254 radicals Chemical group 0.000 description 1
- 230000002336 repolarization Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
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- 238000007789 sealing Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 229920000260 silastic Polymers 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- ZBMZVLHSJCTVON-UHFFFAOYSA-N sotalol Chemical compound CC(C)NCC(O)C1=CC=C(NS(C)(=O)=O)C=C1 ZBMZVLHSJCTVON-UHFFFAOYSA-N 0.000 description 1
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- 230000000699 topical effect Effects 0.000 description 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- 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
-
- 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
- A61P9/08—Vasodilators for multiple indications
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- This invention relates to a novel treatment and in particular to a novel treatment for arrhythmia and to certain novel compounds and compositions used in such treatment .
- Antiarrhythmic drugs have been grouped according to the pattern of electrophysiological effects they produce and/or their presumed mechanism of action. A classification in four groups has been originally proposed by Naughan Williams in 1970. At the molecular level, class I compounds act on ⁇ a + currents; class II compounds possess b-adrenoceptor blocking activity; class III drugs block K + channels; and class IV drugs target Ca ++ channels.
- European Patent Application, Publication Number 0233762 discloses compounds of formula (I) therein which are stated to have cardiovascular activity, including use in the treatment of angina.
- cardiodepressive activity in ischaemic myocardium are also considered to be effective against atrial fibrillation and flutter.
- the present invention provides a method for the treatment of arrhythmia in human or non-human mammals, which method comprises the administration of an effective, non-toxic amount of a compound of formula (I):
- R 1 and R 4 are independently phenyl optionally substituted by one, two or three of halogen, C 1-4 alkoxy, C 1-4 alkyl, cyano, hydroxy, nitro, NR 5 R 6 or O 2 SNR 5 R 6 wherein R 5 and R 6 are independently hydrogen or C 1-6 alkyl or together are C 3-6 polymethylene, or disubstituted at adjacent carbon atoms by C 1-2 alkylenedioxy and optionally further substituted by one of the above groups;
- R 2 is selected from (CH 2 ) z CN where z is O or an integer from 1 to 4, C 1-12 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-4 alkyl, phenyl C 1 -4 alkyl, pyridyl, pyridyl C 1-4 alkyl, COR 7 , COCH 2 COR 7 , SO 2 R 7 , CO 2 R 7 , CONHR 7 and CSNHR 7 , where R 7 is selected from C ⁇ -12 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1 -4 alkyl, phenyl and phenyl C 1-4 alkyl, any alkyl moiety in R 7 optionally substituted by hydroxy or C 1-4 alkanoyloxy, any pyridyl or phenyl moiety in R 2 optionally substituted as defined for R 1 and R 4 and any cycloalkyl moiety in R 2 optionally
- R 3 is hydrogen, C 2-6 alkyl, C 2-6 alkene or C 3-8 cycloalkyl
- A represents C 2-5 alkylene
- B represents C 1 -4 alkylene.
- the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment of arrhythmia.
- the invention further provides a pharmaceutical composition for the treatment of arrhythmia, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof and a pharmaceutically acceptable carrier therefore.
- Arryhthmia particularly includes cardiac arrhythmia and ischaemic rhythm disorders, especially cardiac arrhythmia.
- Suitable values for R 1 and R 4 include phenyl, phenyl di-substituted by methylenedioxy and optionally further substituted by chloro, or phenyl substituted by one of fluoro, chloro or bromo or by one, two or three of methoxy, ethoxy, n- or iso-propoxy. methyl, ethyl, n - or iso-propyl. cyano, hydroxy or amino optionally substituted by one or two methyl groups.
- R 1 and R 4 are preferably the same group, most preferably
- R 1 and R 4 are halophenyl, especially 4-halophenyl, dihalophenyl, especially 3,4-dihalophenyl, dialkylphenyl, especially 3,4-dialkoxyphenyl, (hydroxy, alkoxy )phenyl such as (3-alkoxy,4-hydroxy)phenyl and trialkoxyphenyl such as 3,4,5-trialkoxyphenyl.
- R 1 and R 4 examples include 4-fluorophenyl, 3,4-dichlorophenyl, 3,4-dimethoxyphenyl, (3-methoxy, 4-hydroxy)phenyl and 3,4,5-trimethoxyphenyl.
- Phenyl moieties in R 2 include phenyl, 2-, 3- and 4-nitrophenyl,
- Suitable values for alkylene moieties in R 2 include -CH 2 -, -CH(CH 3 )- -CH 2 CH 2 CH 2 - and -CH 2 CH 2 -. Suitable values for R 2 when alkyl include n-pentyl.
- Suitable values for alkyl R 7 in R 2 includes C 1_6 alkyl, such as methyl, ethyl, n- and iso- C 3 H 7 , n-C 4 H 9 , n-C 5 H 11 , nC 6 H 13 , nC 7 H 15 , nC 8 H 17 and nC 11 H 23 .
- Suitable values for pyridyl moieties in R 2 include 2-and 4 - pyridyl.
- Suitable values for optional substituents on alkyl moieties in R 7 include acetoxy.
- Suitable values for z in R 2 include 0 or 1.
- Suitable values for C 1-4 alkyl groups in R 2 include methyl and ethyl.
- Suitable values for R 3 include hydrogen, methyl, ethyl, n- and iso-propyl. and n, iso -, sec- and t-butyl.
- R 3 is methyl
- Suitable values for A and B include -(CH 2 ) 2 - and -(CH 2 ) 3 -.
- A is -(CH 2 ) 3- .
- B is -(CH 2 ) 2- .
- R 2 1 is CONHR 7 or CSNHR 7 where R 7 is as defined in formula (I), and the remaining variables are as defined in formula (I).
- R 2 2 is COR 7 where R 7 is as defined in formula (I), and the remaining variables are as defined in formula (I).
- pharmaceutically acceptable salts thereof and/or a pharmaceutically acceptable solvate thereof are class III antiarrhythmic agents, and hence can be used as such, for example they are effective against ventricular fibrillation.
- R 7 is optionally substituted phenyl, optional substituents being selected from one halogen atom, especially a chlorine atom, and one, two or three of cyano, hydroxy, nitro and NR 5 R 6 wherein R 5 and R 6 are independently hydrogen (especially)or C 1-6 alkyl; a preferred substituent is a nitro group, especially a 4-nitro group.
- R 7 is optionally substituted phenyl, optional substituents being selected from one halogen atom, especially a chlorine atom, and one, two or three of cyano, hydroxy, nitro and NR 5 R 6 wherein R 5 and R 6 are independently hydrogen (especially)or C 1-6 alkyl, or pharmaceutically acceptable salts thereof and/or a pharmaceutically acceptable solvates thereof, are combined class III and class IV antiarrhythmic agents and hence can be used as such, for example they are particularly effective against ventricular fibrillation, they are also considered to be effective against atrial fibrillation and flutter.
- the compound of formula (I) is that compound wherein R 1 represents 3,4-dimethoxyphenyl, R 2 represents a 4-nitrobenzoyl group, R 3 represents methyl, R 4 represents 3,4-dimethoxyphenyl, A represents (CH 2 ) 3 and B represents (CH 2 ) 2 : i.e.the compound of example 50 of EP 0233762.
- the invention extends to all such stereoisometric forms, including enantiomers of the compounds of formula (I) and to mixtures thereof, including racemates.
- the different stereoisomeric forms may be separated or resolved one from the other by the usual methods or any given isomer may be obtained by stereospecific or asymmetric syntheses.
- alkyl, alkene and alkylene includes straight- and
- Pharmaceutically acceptable salts include acid addition salts with conventional acids such as hydrochloric, hydrobromic, boric, phosphoric, sulphuric and pharmaceutically acceptable organic acids such as acetic, tartaric, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, a-keto-glutaric, a-glycerophosphoric, and glucose-1-phosphoric acids.
- acid addition salt is a hydrochloride; this is conveniently prepared by treating the relevant compound with HCl in a solvent such as diethylether.
- Pharmaceutically acceptable salts also include quaternary salts.
- quaternary salts include such compounds quaternised by compounds such as R 8 -T wherein R 8 is C 1-6 alkyl, phenyl-C 1-6 alkyl or C 5-7 cycloalkyl, and T is a radical corresponding to an anion of an acid.
- R 8 include methyl, ethyl and n- and iso- propyl; and benzyl and phenethyl.
- Suitable T include halide such as chloride, bromide and iodide.
- Pharmaceutically acceptable salts also include pharmaceutically acceptable N-oxides, and the invention extends to these.
- the compounds of the formula (I) and their pharmaceutically acceptable salts may also form solvates with pharmaceutically acceptable solvates and the invention extends to these.
- salts of the compounds of the formula (I) which are not pharmaceutically acceptable may be useful as intermediates in the preparation of pharmaceutically acceptable salts of compounds of the formula (I) or the compounds of the formula (I) themselves, and as such form an aspect of the present invention.
- R 1 , R 2 , A, B and R 4 are as defined in relation to formula (I), and R' 3 represents C 2-6 alkene or C 3-8 cycloalkyl.
- the invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula (IC) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier.
- the invention also provides a compound of formula (IC) or a
- the invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising a Novel Compound or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier.
- the invention also provides a Novel Compound or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance, in particular for use in the treatment of arrhythmia.
- Pharmaceutically acceptable salts include conventional salts such as those disclosed in EP-A-0233762, but in particular the hydrochloride:
- Pharmaceutically acceptable solvates include hydrates.
- the compounds of formula (I), pharmaceutically acceptable salts thereof and/or a pharmaceutically acceptable solvates thereof may be prepared according to known methods including those methods disclosed in EP-A-0233762.
- the compound wherein R 1 represents 3,4-dimethoxyphenyl, R 2 represents a 4-nitrobenzoyl group, R 3 represents methyl, R 4 represents 3,4-dimethoxyphenyl, A represents (CH 2 ) 3 and B represents (CH 2 ) 2 may be prepared according to methods disclosed in Example 50 of EP-A-0233762.
- EP-A-0233762 also discloses certain intermediates for preparing the compounds of formula (I) which intermediates have the formula (II):
- R 1 - NH - A - NR 3 - B - R 4 (II) wherein R 1 , A, R 3 , B and R 4 are as defined in relation to formula (I).
- the present invention also provides a pharmaceutical
- composition comprising a compound of the above defined formula (II) and a pharmaceutically acceptable carrier therefor.
- the invention also provides a compound of formula (II) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use as a therapeutically active compound.
- the invention provides a compound of formula (II) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use in the treatment of arrhythmia.
- the present invention provides a method for the treatment of arrhythmia in human or non-human mammals, which method comprises the administration of an effective, non-toxic amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof.
- the invention also provides the use of a compound of formula (II) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment of arrhythmia.
- Active compounds or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof is normally administered in unit dosage form.
- an amount effective to treat the disorder hereinbefore described depends upon such factors as the efficacy of the active compounds , the particular nature of the pharmaceutically acceptable salt or pharmaceutically acceptable solvate chosen, the nature and severity of the disorders being treated and the weight of the mammal.
- a unit dose will normally contain 0.1 to 500 mg for example 2 to 50 mg, of the compound of the invention.
- Unit doses will normally be administered once or more than once a day, for example 2,3,4,5 or 6 times a day, more usually 2 to 4 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 0.1 to 2500 mg, more usually 50 to 2000 mg, for example 10 to 75mg, that is in the range of approximately 0.002 to 35 mg/kg/day, more usually 1 to 30 mg/kg/day, for example 0.15 to 1 mg/kg/day.
- the active compound may be administered by any suitable route, e.g. by the oral, parenteral or topical routes.
- the compound will normally be employed in the form of a pharmaceutical composition in association with a human or veterinary pharmaceutical carrier, diluent and/or excipient, although the exact form of the composition will naturally depend on the mode of
- compositions are prepared by admixture and are suitably adapted for oral, parenteral or topical administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, pastilles,
- reconstitutable powders injectable and infusable solutions or suspensions, suppositories and transdermal devices.
- Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use.
- Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents.
- the tablets may be coated according to well known methods in the art.
- Suitable fillers for use include cellulose, mannitol, lactose and other similar agents.
- Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate.
- Suitable lubricants include, for example, magnesium stearate.
- Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
- solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
- Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
- Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose,
- non-aqueous vehicles which may include edible oils
- preservatives for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
- fluid unit dose forms are prepared containing a compound of the present invention and a sterile vehicle.
- the compound depending on the vehicle and the concentration, can be either suspended or dissolved.
- Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing.
- adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle.
- the composition can be frozen after filling into the vial and the water removed under vacuum.
- Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
- a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active compound.
- the composition may be in the form of a transdermal ointment or patch for systemic delivery of the active compound and may be prepared in a conventional manner, for example, as described in the standard textbooks such as 'Dermatological Formulations' - B.W. Barry (Drugs and the Pharmaceutical Sciences - Dekker) or Harrys Cosmeticology (Leonard Hill Books).
- compositions may contain further active agents such as anti-hypertensive agents and diuretics.
- compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.
- the mixture was then cooled to room temperature and quenched with 0.30 ml water, then washed with 0.30 ml of 15% aqeous NaOH and 0.60 ml water, then diluted with
- reaction mixture was concentrated to dryness. 200 ml of ethyl acetate were added and the solution was washed with 100 ml water.
- the resulting crude product was purified by flash chromatography on silica gel using 95:5 methylene chloride:methanol, affording 1 g (12%) of an amorphous solid.
- the product was then disolved in 5 ml of ethyl acetate and 5.5N anhydrous HCl in diethyl ether was added dropwise.
- the resulting amorphous solid was triturated in anhydrous diethyl ether and afforded 0.9 g (85%) of the title compound as yellow cristals.
- ⁇ 1.85-2.25 (m,2H,CH 2 ); 2.50-3.50 (m,13H,(CH 2 )x5,NCH 3 ); 3.50-3.85 (m,14H, (OCH 3 )x4,CH 2 ); 6.40-7.00 (m,6H,Ar); 7.30-7.65 (m,2H,Ar); 8.10-8.35 (m,2H,Ar); 10.45-10.75 (m,1H,exch.D 2 O,NH) ppm.
- the compound was purified as free base twice by chromatography on silica gel using first 97/3, then 98/2 methylene chloride/methanol, and as hydrochloride by trituration in diethyl ether.
- Surgical preparation Dogs were anesthetized using 30 mg/kg i.v. sodium pentobarbital. A tracheal cannula was placed for artificial respiration with room air (Harvard 613 pump). A catheter was inserted into the right femoral artery to measure the systemic arterial pressure (Statham P23 ID, GOULD). A 5F Millar microtip catheter pressure transducer was inserted into die left carotid artery and advanced into the left ventricular lumen to measure the left ventricular pressure (LVP) and its first positive derivative dP/dt. Peripheral venous and arterial catheters were placed for drug administration and blood samples collection, respectively. Electrocardiographic variables were measured via a standard lead II ECG.
- a CV5RL precordial lead of ECG was measured as previously described (Koerner et al. J.,Cardiovascular Pharmacol. Vol. 16, p.383-393, 1990).
- the heart was suspended in a pericardial cradle.
- the left circumflex coronary artery (LCX) was isolated close to its origin and a silk suture was placed around it for later occlusion.
- Ventricular arrhythmias were analyzed during die preischemic period, during ischemia and during die first hour of reperfusion.
- Ventricular premature beats (VPBs) were defined as identifiable premature QRS complexes and salvos as more than 2 consecutive VPBs.
- Ventricular tachycardia was defined as 4 or more consecutive VPBs.
- Ventricular fibrillation (VF) was diagnosed when total irregularity of rhythm occurred and when a rate could no longer be measured. If defibrillation was required a DC shock was given.
- Heart rate was calculated from the ECG.
- Guinea pigs (300-350 g) were anesthetized by intravenous injection of sodium pentobarbital (60 mg/kg). After thoracotomy die heart was rapidly excised and placed in oxygenated Tyrode solution. Papillary muscles were removed from the right ventricle. Preparations were then fixed to die silastic base of a 5 ml organ bath and superfused with oxygenated Tyrode solution maintained at 37 ⁇ 1 °C.
- the modified Tyrode solution (pH 7.35) contained die following (mM): NaCl 125, KCl 4.0, MgCl 2 0.5, CaCl 2 1.8, NaHCO 3 24, NaH 2 PO40.9 and glucose 5.5. The solution was equilibrated with a gas mixture of 95% O 2 - 5% CO 2 .
- transmembrane action potentials were recorded witii conventional microelectrodes (10 MOhm) connected to a high input impedance amplifier (BIOLOGIC VF 180). External stimuli were delivered to die preparation with bipolar platinum electrodes placed at one end of die muscle. The pulse duration was 1 ms and die amplitude was twice threshold. The basic cycle length was 1000 ms (PULSAR 6i stimulator). The signals were monitored on a storage oscilloscope (GOULD 1602) and simultaneously recorded on a digital tape recorder (BIOLOGIC DTR 1200) for further analysis.
- RMP resting membrane potential
- APA action potential amplitude
- APD30, APD50 and APD90 action potential durations at 30, 50 and 90% repolarization
- Ischemia and reperfusion-induced arrhythmias The effects of Compound I (0.3 and 1 mgKg) were compared to those of D-sotalol (3 and 10 mg/kg). Ventricular arrhythmias were analyzed during ischemia, maintained for 45 min, and again during die first 60 min of die reperfusion period. The effects of Compound I and D-sotalol on the incidence of ventricular fibrillation observed during these period were summarized in figure 1. The results show that 66.7 % of the control dogs (8 out of 12 dogs) exhibited ventricular fibrillation during either ischemia (2 dogs) or reperfusion (4 dogs).
- Table 1 Effect of Compound I and d-Sotalol on electrocardiographlc parameters measured in anesthetized dog. n Before drug After drug Ischemia reperfusion
- RMP resting membrane potential, APA; action potential amplitude, APD30, APD50 and APD90; action potential durations at 30, 50 and 90 % of the repofarizatfon respectively.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Emergency Medicine (AREA)
- Pain & Pain Management (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
Abstract
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP98200466A EP0852142A1 (fr) | 1992-05-14 | 1993-05-14 | Diamines pour le traitement de l'arythmie |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR9205855 | 1992-05-14 | ||
FR9205855A FR2691064B3 (fr) | 1992-05-14 | 1992-05-14 | Nouveau medicament pour le traitement de l'arythmie. |
PCT/EP1993/001177 WO1993023024A1 (fr) | 1992-05-14 | 1993-05-14 | Diamines pour le traitement de l'arythmie |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP98200466A Division EP0852142A1 (fr) | 1992-05-14 | 1993-05-14 | Diamines pour le traitement de l'arythmie |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0639973A1 true EP0639973A1 (fr) | 1995-03-01 |
Family
ID=9429783
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP98200466A Withdrawn EP0852142A1 (fr) | 1992-05-14 | 1993-05-14 | Diamines pour le traitement de l'arythmie |
EP93909965A Withdrawn EP0639973A1 (fr) | 1992-05-14 | 1993-05-14 | Diamines pour le traitement de l'arythmie |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP98200466A Withdrawn EP0852142A1 (fr) | 1992-05-14 | 1993-05-14 | Diamines pour le traitement de l'arythmie |
Country Status (14)
Country | Link |
---|---|
EP (2) | EP0852142A1 (fr) |
JP (2) | JP2779269B2 (fr) |
KR (1) | KR950701517A (fr) |
AP (1) | AP410A (fr) |
AU (2) | AU677190B2 (fr) |
CA (1) | CA2135612A1 (fr) |
FR (1) | FR2691064B3 (fr) |
HU (1) | HUT72634A (fr) |
IL (1) | IL105690A0 (fr) |
MX (1) | MX9302832A (fr) |
SG (1) | SG47098A1 (fr) |
TW (1) | TW366283B (fr) |
WO (1) | WO1993023024A1 (fr) |
ZA (1) | ZA933376B (fr) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2691064B3 (fr) * | 1992-05-14 | 1996-01-12 | Beecham Laboratoires | Nouveau medicament pour le traitement de l'arythmie. |
FR2694557B1 (fr) * | 1992-08-05 | 1994-09-23 | Synthelabo | Dérivés de tétrahydronaphtalène, leur préparation, et leur application en thérapeutique. |
FR2710065B1 (fr) * | 1993-09-13 | 1996-10-04 | Smithkline Beecham Labo Pharma | Nouveaux composés, leur procédé de préparation et leur utilisation en tant que médicaments. |
AU1949795A (en) * | 1995-03-08 | 1996-09-23 | Smithkline Beecham Laboratoires Pharmaceutiques | Heterocyclycarboxamides and other compounds for the treatment of the cardiac arrhythmias |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3242344A1 (de) * | 1982-11-16 | 1984-05-17 | Dr. Karl Thomae Gmbh, 7950 Biberach | Neue alkylendiaminoderivate, ihre herstellung und diese verbindungen enthaltende arzneimittel |
US4751327A (en) * | 1985-06-28 | 1988-06-14 | Xerox Corporation | Photoconductive imaging members with unsymmetrical squaraine compounds |
GB8603765D0 (en) * | 1986-02-15 | 1986-03-19 | Beecham Wuelfung Gmbh & Co Kg | Compounds |
CA2060326C (fr) * | 1989-07-25 | 2003-10-21 | Jackson Boling Hester, Jr. | Amino-alcenyl-phenylalcanesulfonamides, agents antiarythmiques |
US5051422A (en) * | 1989-09-15 | 1991-09-24 | Schering Ag | 2-substituted-1(4)-aryl piperazines and the process for their preparation |
FR2691064B3 (fr) * | 1992-05-14 | 1996-01-12 | Beecham Laboratoires | Nouveau medicament pour le traitement de l'arythmie. |
-
1992
- 1992-05-14 FR FR9205855A patent/FR2691064B3/fr not_active Expired - Lifetime
-
1993
- 1993-05-13 IL IL105690A patent/IL105690A0/xx not_active IP Right Cessation
- 1993-05-13 AP APAP/P/1993/000527A patent/AP410A/en active
- 1993-05-14 CA CA002135612A patent/CA2135612A1/fr not_active Abandoned
- 1993-05-14 ZA ZA933376A patent/ZA933376B/xx unknown
- 1993-05-14 JP JP5519876A patent/JP2779269B2/ja not_active Expired - Lifetime
- 1993-05-14 SG SG1996007170A patent/SG47098A1/en unknown
- 1993-05-14 EP EP98200466A patent/EP0852142A1/fr not_active Withdrawn
- 1993-05-14 HU HU9403242A patent/HUT72634A/hu unknown
- 1993-05-14 EP EP93909965A patent/EP0639973A1/fr not_active Withdrawn
- 1993-05-14 KR KR1019940704080A patent/KR950701517A/ko not_active Application Discontinuation
- 1993-05-14 AU AU40670/93A patent/AU677190B2/en not_active Ceased
- 1993-05-14 WO PCT/EP1993/001177 patent/WO1993023024A1/fr not_active Application Discontinuation
- 1993-05-14 MX MX9302832A patent/MX9302832A/es unknown
- 1993-05-15 TW TW082103828A patent/TW366283B/zh active
-
1996
- 1996-06-18 JP JP8156724A patent/JPH09118635A/ja active Pending
-
1997
- 1997-02-21 AU AU14851/97A patent/AU1485197A/en not_active Abandoned
Non-Patent Citations (1)
Title |
---|
See references of WO9323024A1 * |
Also Published As
Publication number | Publication date |
---|---|
AU1485197A (en) | 1997-05-15 |
JPH07506824A (ja) | 1995-07-27 |
SG47098A1 (en) | 1998-03-20 |
AP9300527A0 (en) | 1993-07-31 |
AU677190B2 (en) | 1997-04-17 |
FR2691064A1 (fr) | 1993-11-19 |
CA2135612A1 (fr) | 1993-11-25 |
IL105690A0 (en) | 1993-09-22 |
EP0852142A1 (fr) | 1998-07-08 |
JP2779269B2 (ja) | 1998-07-23 |
HUT72634A (en) | 1996-05-28 |
TW366283B (en) | 1999-08-11 |
KR950701517A (ko) | 1995-04-28 |
MX9302832A (es) | 1994-07-29 |
WO1993023024A1 (fr) | 1993-11-25 |
ZA933376B (en) | 1995-02-14 |
JPH09118635A (ja) | 1997-05-06 |
FR2691064B3 (fr) | 1996-01-12 |
AU4067093A (en) | 1993-12-13 |
AP410A (en) | 1995-09-28 |
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