IL43552A - Derivatives of 2-n-phenyl-n-aminoalkyl(or aminoalkanoyl)-aminoindanes their preparation and pharmaceutical compositions them - Google Patents
Derivatives of 2-n-phenyl-n-aminoalkyl(or aminoalkanoyl)-aminoindanes their preparation and pharmaceutical compositions themInfo
- Publication number
- IL43552A IL43552A IL43552A IL4355273A IL43552A IL 43552 A IL43552 A IL 43552A IL 43552 A IL43552 A IL 43552A IL 4355273 A IL4355273 A IL 4355273A IL 43552 A IL43552 A IL 43552A
- Authority
- IL
- Israel
- Prior art keywords
- formula
- phenyl
- group
- aminoindane
- compound
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title description 49
- 150000001875 compounds Chemical class 0.000 claims description 92
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 61
- 238000000034 method Methods 0.000 claims description 34
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 18
- -1 diethylamino- Chemical class 0.000 claims description 16
- 150000001412 amines Chemical class 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 11
- LMHHFZAXSANGGM-UHFFFAOYSA-N 2-aminoindane Chemical class C1=CC=C2CC(N)CC2=C1 LMHHFZAXSANGGM-UHFFFAOYSA-N 0.000 claims description 10
- 239000004480 active ingredient Substances 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 7
- XJEVHMGJSYVQBQ-UHFFFAOYSA-N 2,3-dihydro-1h-inden-1-amine Chemical compound C1=CC=C2C(N)CCC2=C1 XJEVHMGJSYVQBQ-UHFFFAOYSA-N 0.000 claims description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 4
- 159000000000 sodium salts Chemical class 0.000 claims description 4
- 238000011282 treatment Methods 0.000 claims description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 3
- 206010003119 arrhythmia Diseases 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 3
- 230000006793 arrhythmia Effects 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims 5
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims 4
- 238000004519 manufacturing process Methods 0.000 claims 1
- 150000003141 primary amines Chemical class 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 46
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 40
- 238000004458 analytical method Methods 0.000 description 39
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 33
- 239000000243 solution Substances 0.000 description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- 239000000203 mixture Substances 0.000 description 23
- 239000000155 melt Substances 0.000 description 20
- 239000000047 product Substances 0.000 description 19
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 17
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
- 238000001953 recrystallisation Methods 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 12
- 238000002844 melting Methods 0.000 description 12
- 230000008018 melting Effects 0.000 description 12
- 239000003208 petroleum Substances 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- XFSBVAOIAHNAPC-XTHSEXKGSA-N 16-Ethyl-1alpha,6alpha,19beta-trimethoxy-4-(methoxymethyl)-aconitane-3alpha,8,10alpha,11,18alpha-pentol, 8-acetate 10-benzoate Chemical compound O([C@H]1[C@]2(O)C[C@H]3[C@@]45C6[C@@H]([C@@]([C@H]31)(OC(C)=O)[C@@H](O)[C@@H]2OC)[C@H](OC)[C@@H]4[C@]([C@@H](C[C@@H]5OC)O)(COC)CN6CC)C(=O)C1=CC=CC=C1 XFSBVAOIAHNAPC-XTHSEXKGSA-N 0.000 description 7
- XFSBVAOIAHNAPC-UHFFFAOYSA-N Aconitin Natural products CCN1CC(C(CC2OC)O)(COC)C3C(OC)C(C(C45)(OC(C)=O)C(O)C6OC)C1C32C4CC6(O)C5OC(=O)C1=CC=CC=C1 XFSBVAOIAHNAPC-UHFFFAOYSA-N 0.000 description 7
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 7
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 7
- 229940039750 aconitine Drugs 0.000 description 7
- STDXGNLCJACLFY-UHFFFAOYSA-N aconitine Natural products CCN1CC2(COC)C(O)CC(O)C34C5CC6(O)C(OC)C(O)C(OC(=O)C)(C5C6OC(=O)c7ccccc7)C(C(OC)C23)C14 STDXGNLCJACLFY-UHFFFAOYSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 229960004592 isopropanol Drugs 0.000 description 7
- 230000010412 perfusion Effects 0.000 description 7
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 6
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- REQCZEXYDRLIBE-UHFFFAOYSA-N procainamide Chemical compound CCN(CC)CCNC(=O)C1=CC=C(N)C=C1 REQCZEXYDRLIBE-UHFFFAOYSA-N 0.000 description 5
- 229960000244 procainamide Drugs 0.000 description 5
- SDRILVPHSGGIDI-UHFFFAOYSA-N 1-methoxy-n-phenyl-2,3-dihydro-1h-inden-2-amine Chemical compound C1C2=CC=CC=C2C(OC)C1NC1=CC=CC=C1 SDRILVPHSGGIDI-UHFFFAOYSA-N 0.000 description 4
- VQVMIKIZBPAVAO-UHFFFAOYSA-N 2,3-dihydro-1h-inden-4-amine;hydrochloride Chemical compound Cl.NC1=CC=CC2=C1CCC2 VQVMIKIZBPAVAO-UHFFFAOYSA-N 0.000 description 4
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000003416 antiarrhythmic agent Substances 0.000 description 4
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N benzocyclopentane Natural products C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 229940093499 ethyl acetate Drugs 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 229960004194 lidocaine Drugs 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 239000006187 pill Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- UJOCWOHUQOVJCC-UHFFFAOYSA-N 1-ethoxy-2,3-dihydro-1h-inden-2-ol Chemical compound C1=CC=C2C(OCC)C(O)CC2=C1 UJOCWOHUQOVJCC-UHFFFAOYSA-N 0.000 description 3
- DNPRLLUKCXIQLF-UHFFFAOYSA-N 1-ethoxy-n-phenyl-2,3-dihydro-1h-inden-2-amine Chemical compound C1C2=CC=CC=C2C(OCC)C1NC1=CC=CC=C1 DNPRLLUKCXIQLF-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 3
- 239000008119 colloidal silica Substances 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 3
- ZHWPZRVYPHGXSF-UHFFFAOYSA-N 1-methoxy-2,3-dihydro-1h-inden-2-ol Chemical compound C1=CC=C2C(OC)C(O)CC2=C1 ZHWPZRVYPHGXSF-UHFFFAOYSA-N 0.000 description 2
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical compound C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 2
- QEYMMOKECZBKAC-UHFFFAOYSA-N 3-chloropropanoic acid Chemical compound OC(=O)CCCl QEYMMOKECZBKAC-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 229910018954 NaNH2 Inorganic materials 0.000 description 2
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical group C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- GGFOZRQCNXQCLO-UHFFFAOYSA-N aniline;methanesulfonic acid Chemical compound CS(O)(=O)=O.NC1=CC=CC=C1 GGFOZRQCNXQCLO-UHFFFAOYSA-N 0.000 description 2
- MMCPOSDMTGQNKG-UHFFFAOYSA-N anilinium chloride Chemical compound Cl.NC1=CC=CC=C1 MMCPOSDMTGQNKG-UHFFFAOYSA-N 0.000 description 2
- 230000003288 anthiarrhythmic effect Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
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- 239000008120 corn starch Substances 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 230000000994 depressogenic effect Effects 0.000 description 2
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- LIWAQLJGPBVORC-UHFFFAOYSA-N ethylmethylamine Chemical compound CCNC LIWAQLJGPBVORC-UHFFFAOYSA-N 0.000 description 2
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- 150000003840 hydrochlorides Chemical class 0.000 description 2
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- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000002028 premature Effects 0.000 description 2
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- VILMUCRZVVVJCA-UHFFFAOYSA-M sodium glycolate Chemical compound [Na+].OCC([O-])=O VILMUCRZVVVJCA-UHFFFAOYSA-M 0.000 description 2
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- RXTJLDXSGNEJIT-UHFFFAOYSA-N 2,3-dihydro-1h-inden-4-amine Chemical compound NC1=CC=CC2=C1CCC2 RXTJLDXSGNEJIT-UHFFFAOYSA-N 0.000 description 1
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
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- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
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- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 229940101006 anhydrous sodium sulfite Drugs 0.000 description 1
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- 230000002763 arrhythmic effect Effects 0.000 description 1
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- NIQQIJXGUZVEBB-UHFFFAOYSA-N methanol;propan-2-one Chemical compound OC.CC(C)=O NIQQIJXGUZVEBB-UHFFFAOYSA-N 0.000 description 1
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- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C35/48—Halogenated derivatives
- C07C35/52—Alcohols with a condensed ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- Chemical & Material Sciences (AREA)
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- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- General Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Description
¾niN o' 'aan ninpn » *« m New derivatives of 2- ~phenyl-N-aminoalkyl (or aminoalkanoyl)-aminoindanesj their preparation and pharmaceutical compositions containing them A. CHRISTIAENS SOCIETE ANONYME CJ- 41686 43552/3 This invention relates to new derivatives of 2-aminoindane, the preparation and use thereof.
French Patent Specification No. 2,081,383 discloses related 2-aminoindane derivatives which are unsubstituted in the l-position. The new compounds according to the invention surprisingly show better pharmacological activity than the corresponding compounds known from said French patent specification.
The new derivatives of 2--am.inoJndane according to th s invention are the compounds of formula : in wh O group alkyl group containing 1 to 3 carbon atoms, may also represent hydrogen, and and R2 may also form with the attached nitrogen atom a saturated nitrogenous heterocyclic nitrogenous heterocyclic ring, as well as the acid addition salt of said compounds of formula I. The saturated nitrogenous heter cyclic ring or rings of the new derivatives of formula I may b selected among piperidino, pyrrolidino and morphollno rings. 43552/1 The preferred compounds of the "formula I are those In which and R2 represent a methyl or ethyl group, those in which R.j also represents a hydrogen atom and those wherein and R2 form together with the attached nitrogen atom a piperidino or pyrrolidino group, as well as the acid^ addition salts thereof such as the hydrochlorides, fumarates, oxalates, etc.
This invention relates also to pharmaceutical compositions containing, as active ingredient, at least one compound of general formula I, together with a pharmaceutically acceptable carrier.
Finally, the invention relates to processes for preparing the new compounds of formula I.
Examples of preferred compounds of formula I are as follows : 1-methoxy-2-^N-phenyl-N-(diethylaminopropyl 7-aminoindane (formula I : R1 = R2 = C2H5 ; n = 2 ; A = OCH^ ; B = phenyl Z = CH2) . 1 -methoxy-2-^-phenyl-N- (diethylaminopropionyl 7-aminoindane (formula I : R1 = R2 = C2H(- ; n = 2 ; A = OCH^ ; B = phenyl Z = CO). 1 -ethoxy-2-H-phenyl-N-(diethylaminopropyljy-aminoindane (formula I : = R2 = C2H5 ; n = 2 ; A = 0C2H5 ; B = phenyl J Z = CH2). 1-methoxy^-^-phenyl-N- (dimethylaminopropyl)7-aminoindane (formula I : R1 = R2 = CH^ ; n = 2 ; A = OCH^ ; B = phenyl ; Z = CH2). 1 -methoxy-2-^J-pheny1-N-diethylaminoacetyl7-aminoindane (formula I : R^ = R2 = C2H5 ; n = 1 ; A = OCH^ ; B = phenyl Z = CO). 1 -methoxy-2-^/TT-phenyl-N-(diethylaminoethyl 7-aminoindane (formula I : R^ = R2 = C2H5 ; n = 1 ; A = OCH^ ; B = phenyl Z = CH2). 1-methoxy-2- (N-phenyl-N-piperidinoacetyl)-aminoindane (for- 1 -methoxy-2-^!-phenyl-N-(piperidinoethyl^T-aminoindane (for¬ 1 -dimethylamino-2-JT-phenyl-N-( Y-diethylaminopropylVJ-amino-indane (formula I : = R2 = CgH^ ; n = 2 A = dimethyl-amino ; B = phenyl J Z = CH2) o 1 -dimethylamino-2- l!T-phenyl-N-( Y-dimethylaminopropyl^Z-amino indane (formula I : R^ = R2 = CH^ ; n = 2 \ A = dimethylami-no } B = phenyl ; Z = CH2) . 1-diethylamino-2-jTT-phenyl-N-( Y-diethylaminopropylJT-amino-indane (formula I : R^ = R2 = C2H5 ; n = 2 ; A = diethyl-amino ; B = phenyl ; Z = CH2) «, 1 -diethylamino-2-/I-phenyl-N- (p-dimethylaminoHethyl J-amino-indane (formula I : R^ = R2 = CH^ ; n = 1 ; A = diethylami-no ; B = phenyl ; Z = CH2)« 1 -methoxy-2- E7-phenyl-N-(diethylaminoethyl_V7-aminoindane (formula I : R1 = R2 = C2H5 ; n = 1 ; A = OCH^ ; B = phenyl Z = CH2), 1-ethoxy-2-^f-phenyl-N-(diethylaminoacetyl 7-aminoindane (formula I : R1 ■ R2 = C2H5 ; n = 1 ; A = 0C2H5 ; B = phenyl ; Z = CO) . 1 -ethoxy-2-^I-phenyl-N- (diethylaminoethyl 7-aminoindane (formula I : R1 = R≥ = C2H5 ; n = 1 ; A = 0C2H5 % B = phen¬ 1-ethoxy-2-^T-phenyl-N-( β-diethylaminopropionyl 7-aminoin-dane (formula I : R1 = R2 = C2H5 ; n » 2 ; A = OC2H5 ; B = phenyl | Z = CO), 1-ethoxy-2- CT-phenyl-N-( -dlethylaminopropyl27-aminoindane (formula I : R^ = R2 = CgH^ \ n = 2 j A = 0C2H^ ; B = phen 1 -methoxy-2-iIT-phenyl-N-(piperidinopropyljy-aminoindane hydrochloride (formula I : B = phenyl ; N, i = piperi-dino \ n o 2 ; A = OCH3 } Z = CH2) . 2 1-methoxy-2-^-phenyl-Ν-β- ( ' -methylpiperazino )propionyl7- ; B = phenyl ; n = 2 ; CO) . 1-methoxy-2- E7-phenyl-N-( Y-methylpiperazinopropyl27-amino- indane phenyl ; A = OCH, n = 2 ; CH«) 1-ethoxy-2-^TT-phenyl-N- ( β-ργΓΓθϋά1ηορΓορ1ο^ΐ 7-βπι1ηο1η- 1-ethoxy-2-^J-phenyl-N- (pyrrolidinopropyl 7-aminoin.dt:ne hydrochloride (formula I : A = OC9H,- ; i = pyrroli-dino ; n = 2 ; B = phenyl ; Z = CH2 ) « 1-methoxy-2-^f-phenyl-N- ( β^methylaminopropionyl 7-amino-indane hydrochloride (formula I : A = OCH^ ; = H ; R2 = CH3 ' B = *16*1^1 » n = 2 ; Z = CO) . 1-methoxy-2-^iT-phenyl-N- (meth laminopropy 1 )7~aminoinciane (formula I : A = OCH^ ; R1 = H ; R2 = CH^ ; B = phenyl \ n = 2 ; Z = CH2 ) . 1-methoxy-2- H-phenyl-N-( P-ethylaminopropionylJT-aminoin-dane hydrochloride (formula I : A = OCH^ ; R^ = H j R2 = C2H5 ; B = phenyl ; n = 2 ; Z = CO) β 1-methoxy-2-j!I--phenyl-N-( -ethylaminopropyl7-aminoindane hydrochaoride (formula I : A = OCH^ ; R1 = H ; R2 = C2H5 j B = phenyl ; n *= 2 ; Z = CH2) . 1 -ethoxy-2-^T-phenyl-N-( β-eth laminopropionyl 7-aminoi -dane hydrochloride (formula I : A = OCgH^ ; = H ; R2 = C2H5 ; B = phenyl ; n = 2 ; Z = CO) . 1 -ethoxy-2-^T-phenyl-N- ( Y-ethylaminopropyl7-aminoindane hydrochloride (formula I : A = OC2H5 ; R^ = H ; R2 = C2H5 B = phenyl ; n = 2 ; Z = CH2) „ -ethoxy-2-^T-phenyl-N- (ethylaminoacetyl27-aminoindane fumarate (formula I : A = 0C2H5 ; = H 5 R2 = CgH^ ; B = phenyl ; n = 1 ; Z = CO) . 1 -ethoxy-2- fT-phenyl-N- ( p-ethylaminoethyl 7-aminoindane hydrochloride (formula I : A = 0C2H5 ; R^ = H ; R2 = C2H5 B = phenyl ; n = 1 ; Z = CH2) . -methoxy-2-^-phenyl-N- ( Y-methylethylaminopropyl^J-amino-indane hydrochloride (formula I : A = OCH^ ; R,| = CH^ ; R2 = C2 5 » n = 2 ; Z = CH2 ; B = phenyl). 1-methoxy-2-iIT-phenyl-N-( -ιηοΓρ οΙΙηο ΓορΙο^Ι^-βπιΙηο-indane hydrochloride (formula I : A = OCH, ; B = phenyl ; . 1 -methoxy-2-^-phenyl-N-( -pyrrolidinopropionylJ ~amino"" indane hydrochloride (formula I : A = OCH, ; B = phenyl 5 O) . 1 -ethoxy-2-^-phenyl-N-( -piperidinopropionyl^T-aminoindane -hydrochloride (formula I : A = 0C2H^ ; B = phenyl ; n = 2 ; ' = piperldlno % Z = .C0). 1 -methoxy-2-R~phenyl-N-(Y-piperidinobutyroyl 7-aminoindane hydrochloride (formula I : A = OCH, ; B = phenyl ; n = 3 » ; It has been surprisingly found that the compounds of the general formula I where Z represents a CO or a CHg group are very active for the treatment of heart arrhythmia.
Said compounds can be used for the treatment of various heart diseases such as premature heart contractions, ventricular and supraventricular tachycardias either idio-pathic or subsequent to a cardiopathia or to a coronary disease, cardiac arrhythmias due to digitalin intoxication, as well as atrial fibrillation and flutter, particularly in the early stage.
It is known (see Koch-Weser, J. Arch. Int. Med. 1 9? 763, 1972) that none of the presently available antiarrhythmic agents are satisfactory for the prophylaxis of tachycardias and fibrillation of ventricular origin.
The oral activity of the known antiarrhythmic agents, such as procainamide or lidocaine, is either too short, leading to multiple day and night administration (for example with procainamide) or too low to be of some practical utility (for example with lidocaine) or their therapeutic activity is conjugated with frequent and dangerous side effects, such as hypotension (with procainamide), sudden death, agranulocytosis or idiosyncrasy.
The compounds of general formula I according to this Invention are very active when orally administered, although they may also be administered parenterally. They have also a long activity duration and are not depressant for the myocardial function.
Applicants do not know any orally active antiarrhythmic agent which does not act at the same time as a depressant of the myocardial function.
The oral antiarrhythmic activity of the compounds of formula I has been proved by tests on rats using aco-nitine which is a compound causing premature heart contractions and death of the animals .
The method used for these tests is described hereafter : Animals : Male or female rats with a body-weight ranging from 380 to 450 ge Aconltine solution ; 3e12 μ aconltine nitrate/1 ml physiological salinee Solution of the compound to be tested : 0.75 % in distilled water.
Method : Six random selected animals are required for each compound to be tested. The compound is administered by oral route at the dose of 75 mg/kg (1 ml of the 0.75 % solution/100 g of body-weight) 75 minutes before the intravenous perfusion of the aconitine solution is initiated.
Control groups of animals are treated only with distilled water (1 ml/100 g) .
Sixty minutes after the administration of the compound to be tested, the animals are anesthesized by an intraperitoneal injection of Pentobarbital (50 mg/kg) and the jugular vein is dissected.
A catheter is introduced in the vein and fixed by a ligature .
The ECG (D II derivation) is then continuously recorded.
The perfusion of the aconitine solution is started 75 minutes after the administration of the compound to be tested.
The volume delivered by the injection device being 0.287 ml/minute, the dose of aconitine nitrate administered is 0.895 /minute (0,20-0.24 g/100 g/minute according to the minimal and maximal weight of the animals).
The experience is stopped as soon as the first extrasystoles are appearing and the time elapsed from the beginning of the perfusion is noted.
The results are expressed as the mean total dose of aconitine injected in a group of animals.
The relative activity between a tested compound and a V_/ reference substance (lidocaine, procainamide) is< computed in the following way : A (x) = τ " x 100 K - ϋ where A(x) = activity of tested compound X (in %) 7. = mean dose of aconitine in the animals treated by compound X ϋ = mean dose of aconitine Injected in the untreated animals (controls) .
E => mean dose of aconitine injected in the animals treated by the reference substances.
The following table gives the results of the evaluation of the antiarrhythmic activity by oral route of a great number of acid addition salts of compounds of formula I, compared to the activity of two well known antiarrhythmic agents (procainamide and lidocaine) „ TABLE 1 The compounds of the formula I may be administer^ ed orally or parenterally.
Oral preparations may be administered under the form of capsules, tablets, pills and the like. Each capsu-le, tablet or pill may contain from 10 to 200 mg of a compound of formula I as active ingredient, together with pharmaceutically acceptable excipients or carriers .
Parenteral preparations may consist in a solution for perfusion or for intravenous or intramuscular injection, Such a solution may contain from 0.2 per thousand to 2 per thousand of a compound of formula I.
The parenteral preparation may be either a solution which may be directly used for the perfusion and contains a proportion of the active ingredient within the above limits, or a concentrated solution containing 1 to 10 % of the active ingredient, said concentrated solution being diluted when administered to a patient.
The initial dose of active ingredient may be of 200 to 800 mg per day during 2 or 3 days, the maintenance dose being of about 25 mg to 300 mg per day.
If a single dose is sufficient for obtaining the therapeutic effect, this dose is generally comprised between 50 and 300 mg.
The active ingredient may be administered at the same time by the parenteral route (for example by perfusion) and by the oral route.
This invention relates also to processes for preparing the new compounds of formula I0 According to this invention, the compounds of formula I may be prepared from a compound of the following formula : A in which A and B have the above meanings, by the three following processes : First process : This process involves the preparation of a sodium salt of a compound of formula II by means of sodium amide and the reaction of the obtained sodium salt with a halo-genated amine of the formula : in which Hal represents a halogen atom, preferably a chlorine atom, whereas n, and have the above meanings „ Second process : This process involves the acylation of a compound of formula II with an acid chloride of the formula : in which n = , 2 or 3, so as to obtain an acylated compound of the formula : the subsequent reduction of the acylated compound of formula V by means of aluminum lithium hydride into a compound of the following formula : in which n, A and B have the above meanings, the obtained compound of formula VI being finally alkylated by means of a primary or secundary amine of the formula : in which R^ and R2 have the above meanings .
Third process : This process involves the acylation of a compound of formula II with an acid chloride of the formula s CI (CH2)n C0C1 (IV) in which n = 1, 2 or 3, so as to obtain an acylated compound of the formula : (V) the subsequent N-alkylation of the acylated compound of formula V with a primary or secondary amine of the formu-la : in which and R2 have the above meanings, so as to obtain a compound of the formula : which is a compound of formula I wherein Z represents a CO group* The latter compound can be finally reduced into a compound of formula I wherein Z represents CH2, by means of aluminum lithium hydride* The compounds of formula II used as starting materials in the three preceding processes according to this invention may be prepared by reacting a compound of the following formula : or a compound of the following formula : with aniline.
The compounds of formula IX may be prepared from compounds of the following formula : by reaction of the latter compounds with the chloride of methane sulfonic acid.
The compounds of the formula X may be prepared by reacting compounds of the following formula : in which and have the. above .meanings, with thionyl chloride.
The compounds of. formula XI and XII may be obtained from 2-bromo-indanol-1 of formula : ' said 2-bromo-indanol-1 being obtained from indene by the method described by W. Treibs and Schroth ; Ann. 639, 204 (1961).
When 2-bromo-indanol-1 of the formula XIII is i treated by means of an alcohol, such as methanol or ethanolj in the presence of an alcoholate, an 1-alkoxy-indanol-2 of | formula XI is obtained. This reaction may be effected by ' the method described by W. Treibs and Schroth ; Ann. 639, ; 204 (1961).
When 2-bromo-indanol-1 of the formula XIII is treated by means of an amine of the formula VII, a compound of the formula XII is obtained. The method used for this reaction is as described by J. Sam, Th. C. Snapp, Jr. in Journal of Pharmaceutical Sciences p'. 1364 (1964) or by o Levin, B.E. Graham, H.G. Kolloff in J.O.C. 9, 380 (1944) The following examples 1 to 39 illustrate the ] preparation of the new compounds of formula I. i EXAMPLE 1 Preparation of 1-methoxy-2-/H-phenyl-N- (diethylaminopro-pyl)7-aminoindane (formula I : = = ; n = 2 { A = OCH, ; B - phenyl ; Z = CH9). 1 ) Preparation of mesylate of 1-methoxy-2-hydroxyindane (formula IX : A = OCH^) . 82 grams (0.5 mol) of 1-methoxy-2-hydroxyindane (formula IX , A = OCH^) are dissolved in 250 ml of pyridine. The solution is cooled at 0°C and 45 ml (0.55 mol) of chloride of methane sulfonic acid are added drop by drop to said solution, while maintaining the temperature between 0 and 5°C. The reaction mixture is then stirred during one hour at room temperature and subsequently poured onto ice. After filtration and drying, 113 grams of the desired mesylate melting at 55-75°C are obtained. The product is recrys tallized from petroleum ether.
Yield : 91 % Analysis : % calculated : C 54,54 j H 5,82 % found : C 54,67 ? H 5,82 2) Preparation of 1-methoxy-2-phenylaminoindane (formula II : A = OCH^ ; B = phenyl). 60.5 grams of the mesylate obtained in section 1 and 125 ml of aniline are heated during 3 hours at 150°C, The reaction mixture is then cooled and extracted by means of 150 ml of ether. After separation of the precipitated aniline mesylate by filtration, the ether is removed from the filtrate and the filtrate is distilled. The desired product distils at 1650C/0.05 mm. The distilled product becomes solid and is recrystallized from isopropanol.
Melting point : 53-54°C.
Analysis of the hydrochloride melting at 182-184°C and recrystallized from acetone. % calculated : C 69.68 ; H 6.58 ; N 5.07 ; CI 12.85 % found ; C 69 o65 ; H 6.55 J N 5.18 ; CI 12.68 3) Preparation of 1-methoxy~2-/H-phenyl-N-(diethylamlno n = 2 ; A = OCH^ °, B = phenyl ; Z = CH2) .
A mixture of 1.2 grams (0.03 mol) of Na H2, 30 ml of toluene and 0.015 mol of 1-methoxy-2-phenylamino-indane is boiled during 30 minutes. 3.75 grams of Y-chloro propyldiethylamine are then added and the mixture is re-fluxed during three hours. After cooling and addition of 50 ml of water, the toluene phase is separated, dried and concentrated, so as to obtain a residue (6.3 grams) which is treated with 2 grams of ,n fumaric acid and 50 ml of water. The obtained solution is evaporated under vacuum and the residue is treated by means of 50 ml of ether. A solid product is obtained. After recrystallization from acetone or a mixture of acetone and methanol, 4.4 grams of a product melting at 138-1 0°C are obtained.
Yield : 63 %.
Analysis : % calculated : C 69.2 ; H 7.74 ; N 5.97 % found : C 69.2 °, H 7.38 ; N 6.12 Another method for preparing the desired compound is described in Example 7.
EXAMPLE 2 Preparation of 1-ethoxy-2-/Tf-phenyl-N- (diethylaminopropyl)7-amlnoindane (formula I : = R2 = ^2^5 » n = 2 ; A = O^CjH^ B = phenyl ; Z = CH2) . 1 ) Preparation of 1-ethoxy-2-hydroxyindane (formula XI : A = 0C2H5). 5 grams of Na are dissolved in 140 ml of ethanol. To the obtained solution, 42.3 grams of 1-hydroxy-2-bromo-indane are addedβ The mixture is refluxed during 19 hours under nitrogen. 100 ml of ethanol are removed by distillation and 200 ml of ether are added* After cooling, the sodium bromide is separated by filtration and the ether is evaporated. The desired product is obtained by distillation at 87-90°C/0.05 mm. Yield : 25.4 grams (71 %) . 2) Preparation of the mesylate of 1-ethoxy-2-hydroxy- indane (formula IX : A = 0C2H5). 0.07 mol of 1-ethoxy-2-hydroxyindane and 0.105 mol (10.6 grams) of distilled triethylamine are dissolved in 60 ml of anhydrous dichloromethane . 0.077 mole (8.82 grams) of CH^SO^l are then added drop by drop to the solution which has previously been cooled to -5°C. The mixture is then stirred during 30 minutes at room temperature. The reaction mixture is diluted with 60 ml of dichloro-raethane and the obtained solution is successively washed with 10 % hydrochloric acid (100 ml at 0°C), with a saturated solution of sodium bicarbonate (30 ml at 0°C) and with a saturated aqueous solution of sodium chloride (50 ml at 0°C)e The organic phase is then dried and evaporated," 16,17 grams (94 %) of a residue melting at 56-57°C after recrystallization from isopropanol are obtained,, Analysis- : % calculated : C 56.23 ; H 6.29 °, S 12,51 % found : C 56.6 ; H 6,27 5 S 12.42 3) Preparation of 1-ethoxy-2-phenylamlnoindane (formula II : A = OC^ \ B = phenyl). 60.5 grams of the mesylate obtained in section 2 of Example 2 and 125 ml of aniline are heated during 45 minutes at 150°C. After cooling, the mixture is treated with 150 ml of ether and the formed aniline mesylate is separated by filtration. The ether is removed from the filtrate and the excess of aniline is distilled. The residue of this distillation is treated with 6-N-hydrochloric acid, so as to obtain the hydrochloride which is extracted by means of chloroform. The obtained solution is dried on sodium sulfate, filtered and concentrated to dryness. By addition of acetone, 19.77 grams (yield = 56 %) of the hydrochloride melting at 172-173°C are obtained. After recrystallization from a mixture of acetone and methanol, the hydrochloride melts a 176°C.
Analysis of the hydrochloride : % calculated : C 70.45 ; H 6.96 ; N 4.83 ; CI 12.24 % found : C 70,85 ; H 6.88 ; N 5.0 ; CI 12,1 The free base melts at 71-72°C and is recrystallized from isopropanol.
Analysis of the base : % calculated : C 80.59 ; H 7.56 ; N 5.53 % found : C 80.35 ; H 7.42 2 N 5.41 4) Preparation of 1~ethoxy-2-/I?-phenyl-N-(diethylamino- propyl ) 7~aminoindane (formula I : R.j = R2 = ^ ^ * A = 0C2H5 ; n = 2 ; B = phenyl ; Z = CH2) .
This compound is prepared by the method used in section 3 of Example 1, using 1-ethoxy-2-phenylaminoindane instead of 1-methoxy-2-phenylaminoindane . The duration of the reaction is 22 hours and the yield of 20 , The oxalate recrystallized from isopropanol melts at 133-134°C.
Analysis : °/o calculated : C 68.39 J H 7.95 ; N 6.14 % found : C 68.2 2 H 7.74 ; N 6.05 EXAMPLE 3 Preparation of 1~methoxy-2- IT~phenyl-N-(dlmethylaminopro-pyl )7-amlnoindane (formula I : = R2 = CH^ 2 n = 2 ; A a OCH^ B = phenyl ; Z = CH2).
This compound is prepared by the method described in the Example 1, section 3, using Y-chloropropyldimethyl-amine instead of Y-chloropropyldiethylamine. The duration of the reaction is of 4 hours. Yield : 80 %e The fumarate of the desired compound is recrystallized from acetone. Melting point : 149-151 °C.
Analysis : % calculated : C 68.16 j H 7.32 j N 6.36 % found : C 68.00 2 H 7.20 2 N 6.43 EXAMPLE 4 Preparation of 1-methoxy-2-/T?-phenyl-N-diethylaminoacetyl7 amlnoindane (formula I : = R2 = C2H^ ; n = 1 ; A = OCH^ B = phenyl 5 Z = CO) . 1 ) Preparation of 1-methoxy-2-(N-phenyl-N-chloracetyl)°- aminoindane (formula V : n = 1 ; A = OCH^ ; B = phenyl) 0.04 mol of 1-methoxy-2-phenylaminoindane and 0.06 mol of C1C0-CH2C1 are refluxed in benzene (50 ml) during 90 minutes. After cooling, the benzene is removed. The residue is washed with 20 ml of petroleum ether and recrystallized from petroleum ether. Melting point 104-105°C. Yield : 95 %.
Analysis : °/o calculated : C 68.46 ; H 5.74 ; N 4,43 ; CI 11.23 % found : C 69.11 ? H 5.59 ; N 4.65 ; CI 11.47 2) Preparation of 1-methoxy-2-/T7-phenyl-N-diethylamino- acetyl7-aminoindane (formula VIII : = R2 = C^H^ ; n = 1 ; A = OCH^ ; B = phenyl j formula I : Z = CO) . 5.8 grams of 1-methoxy-2-(N-phenyl-N-chlorace-tyl)-aminoindane and 2.63 grams of diethylamine are dissol ved in 50 ml of anhydrous ethanol. The solution is refluxed during 24 hours, but after 6 hours 1,32 grams of further diethylamine are ^a^iii- added, when the reaction is finished, the alcohol is removed and the residue is treated with diluted hydrochloric acid. The obtained solution is made alkaline and extracted by means of chloroform. After removal of the chloroform, a residue of 6 grams is obtained.
After recrystallization from acetone, the hydrochloride melts at 188-190°C.
Analysis : % calculated : C 67-94 ; H 7,51 ; N 7.20 ; CI 9.11 % found : C 68 ; H 7.48 ; N 6,98 ; CI 9.28 EXAMPLE 5 Preparation of 1-methoxy-2-/H-phenyl-N- (diethylaminoethyl)7 aminoindane (formula I : = R2 = C2H^ » n = 1 » A = OCH^ B = phenyl ; Z = CH2) .
The compound prepared in Example 4, section.2, is reduced by means of aluminum lithium hydride by a known method. The hydrochloride of the desired compound melts at 145-147°C. Another method for preparing the same compound is described in example 14.
EXAMPLE 6 Preparation of 1-methox —y-2~/T-~p~henyl-N-(j piiethylaminopro- ionyl)7-aminoindane (formula I : = R2 = ; n = 2 ; A = OCH^ ; B = phenyl ; Z = CO) . 1 ) Preparation of 1-methoxy-2--(N-phenyl~N-3-chloropropion- y1)-aminoindane (formula V : n = 2 ; A = OCH^ ; B = phenyl) .
This compound is prepared as described in Example 4, section 1, using the chloride of β-chloropropionic acid instead of the chloride of chloroacetic acid. Yield : 90 %, The desired product melts at 117-118°C after recrys-tallization from petroleum ether (60-80°C), Analysis : % calculated : C 69.19 ; H 6.11 ; N 4.25 ; CI 10.75 % found : C 69.47 ; H 6.29 ; N 4.3 J CI 10.60 2) Preparation of 1-methoxy-2-(N-phenyl-N-diethylaminopro- plonyl)-aminoindane (formula VIII : = = gH^ ; n = 2 ; A = OCH^ % B = phenyl).
Starting from 1-methoxy-2-(N-phenyl-N- -chloro-propionyl)-aminoindane, this compound is prepared in the manner described in Example 4, section 2. Melting point : 146-147°C (CgHg).
Analysis : % calculated : C 68.56 ; H 7.76 ; N 6.95 ; CI 8.80 % found : C 68.54 ; H 7.74 j N 6.84 ; CI 8.63 EXAMPLE 7 Preparation of 1-methoxy-2-(N-phenyl-N-diethylaminopropyl)-aminoindane (formula I : = R2 = C2^5 » n = 2 » A = 0CH^ B = phenyl j Z = CH2) .
This compound is prepared by reduction of 1-meth-oxy-2-(N-phenyl-N-diethylaminopropionyl)-aminoindane by means of aluminum lithium hydride.
EXAMPLE 8 Preparation of 1-methoxy-2-(N-phenyl-N-piperidinoacetyl)-aminoindane (formula VIII : y = piperidino j n = 1 ; B = phenyl % A = OCH^ ; formula Ί : Z = CO) .
This compound is prepared in the manner described in Example 4, section 2, except that piperidine is used instead of diethylamine . The obtained free amine melts at 85-86°C. Yield : 75 %. The hydrochloride of the amine recrystallized from acetone melts at 216-218°C.
- -S6 - Analysis of the hydrochloride : C H N CI % calculated : 68. 7 .29 6 .98 8.84^ % found : 69 * 07 7.03 7 20 8.96 EXAMPLE 9 ■ Preparation of 1-met oxy-2- ~(N-phenyl-N-(piperidinoethyl)7- A = 0CH3 ; B=phenyl > Z = CH2).
This compound is prepared from 1 -methoxy-2-(N-phenyl-N-piperidinoacetyl)-aminoindane by reduction by means of aluminium lithium hydride. The fumarate recrystallized from ethyl acetate melts at 140-142 °C .
Analysis s C H N % calculated : 69.5 7.34 6 % found . 69 o 7 7 .22 5.93 Another method for preparing the same compound is described in Example 15 .
EXAMPLE 10 .
Preparation of l-dimethylamlno-2-/ (N-phenyl-N-(Y-diethylamino-propyl7~aminoindan e (formula I : R1=R2=C2H^; n = 2 ; A = dime-thylamino : B = phenyl^ Z = CH2). 1 ) Preparation of 1 -^dimethylamirio-2-phenylaminoind,ane (formula II : A = dimethylamino ; B = phenyl) 1 1 .2 grams of -dimethylamino-2-chloroindane hydrochloride :are stirred during 2 hours at room temperature in 40 ml of aniline. The reaction mixture is treated by means of 75 ml of chloroformr and the aniline hydrochloride is separated by filtration. The filtrate is evaporated to dryness, so as to remove the excess of,, aniline 0 The residue is treated with 250 ml of water., After addition of charcoal, the solution is filtered— and made alkaline,, By cooling in a refrigerator, the desired amine is obtained (11.5 grants, yield s 95%) » After recrystalll- zation from petroleum ether (60«80°C ) the product melts at 90 - 92°C o . .
Analysis % C H N % calculated % 80 c 91 7 .93 1 1 . 1 % found 5 81 .40 7 c91 11 .25 Analysis o the fumarate s G H N % calculated : · 68.46 6.56 7.6 % found · g 68.84 6.61 7.57 2)- Preparation of 1-dimethylamiho-2 N-phenyl-N( Y-diethylami- T.opT^ i!^- mino nd¾ng^ ; n = 2; -■ A β dimethylamino ; B « phenyl; Z ■ CH2).
This- compound- is prepar-ed from 1 -dlmethylamino-2-phenylaminoin-dane in the manner described in example 1, section 3, except that the oxalate of the desired compound is prepared instead of the fu»arat thereof.
Yield -K< 7 96 Af*er -recTtystallization from ethanol, the oxalate -melts at 195 - 197°C0 Analysis ; (for 1 squrroieni^^. the f ee'funine and 1.5 equivalents of oxali© acid; molecular~weight s 500.63 - % calculated g - 64v7? 7.65 8.39 % found - ·?:. 64.66 - 7.73 8.05 - " ' EXAMPLE- 1 Preparation of 1 -dimethylamino-2- "N~phenyl-N-( T-dimethylamino- 56- This- compound is prepared in the manner described in example 1 , section 3 , from 1-dimethylamino-2-phenyl-aminoin- dane by using Y-chloropropy-ldimethylamine as alkylating agent „ The prepared oxalate (yield ; 80%) melts at 193-195°C, From the purified oxalate, the free amine is prepared and converted into difumarate which melts at 167-1699C after recrystallization from acetone and methanol „ Analysis s Molecular weight 569,66 G '"·=■ H % calculated s 63.25 6.9 7 o 37 % found S' 63.21 7 o 19 7.38 EXAMPLE 12 Preparation of 1 -diethylamino-"2- "N-phenyl- -(Y-diethylamino- 1 ) Preparation of -diethylamlno-2-phenylaminoindane (formula II : A = diethylamino, B = phenyl) 24,-5 grams (0.094 -mol.) of 1-diethylamino-2-chlor0iridan^e and 100 ml aniline are stirred during 1 hour at room temperature. After addition of 100 ml of chloroform, the aniline hydrochloride is separated by filtration and the filtrate is evaporated to dryness. The residue is extracted with 200 ml of water, made alkaline and extracted with ether. After drying on potassium carbonate and filtration, the solvents are removed and the product is distilled. The fraction distilling at 65 C/0.4 mm is collected. 20.6 grams (yield ; 80%) of a pro- _ £9 _ duct melting at 37-39°C after recrystallization from petroleum ether (40 - 60°C) are obtained„ Analysis s ". . . C H % calculated s 81 038 8„62 9o99 ved in 150 ml of toluene, in the presence of 3,51.grams of NaNH2(0009 mol) o After refluxlng during 20 minutes 0.076 mol of Y-chloropropyldiethylamine are added, the mixture being then further refluxed during 1 hour0 After cooling and addi- tion. of 100 ml of water, the mixture is decanted and extracted by means of 100 ml of toluene 0 The toluene phase is extracted by means of 1 N hydrochloric acido The acid extract is made alkaline and extracted with benzene „ After drying of the benzene phase on potassium carbonate, the benzene is evaporated and the product distilled. The fraction distilling at 210°C/0c9 mm is collected. 1408 grams (yield s 33%) of the desired product are obtained0 Analysis § .. ·. :■:. ' C H N % calculated i - 79»33 9»99 10o67 % found ; 79o43 9°93 10.5Q EXAMPLE 1 .
Preparation of 1-diethylamino-2- ~N-phenyl-N-(8-dimethylamino- diethl amino ; B = phenyl? Z = CH2) This compound is prepared by the method described in example 12 , section 2 , except that β- chloroetihyldimethylami- ne is used instead of Y-chloropropyldiethylamine0 Yield 80%ο The dlhydrochloride obtained after recrystallizatipn from ace- , tone and methanol melts at 2Q9-210°C.
Analysi's s C H N CI % calculated s 65 08 8 o 31 9o89 16.7 % found : 6409 8.27 9=78 16 ,4 B = phenyl? Z = CH2 9 «6 grams of 1-methoxy-2-phenylaminoindar e, 204 grams of NaNH2 and 100 ml of benzene are refluxed during 30 minutes o 7 grams of -chloroethyldiethylamine are then added o The mixture is refluxed during 48 hours» After cooling,. 100 ml of water are added to the reaction mixture which is then acidified ό The aqueous phase is separated, made alkaline and extracted with chloroform0 The chloroform phase is dried and the solvent is removed therefrom, -the mixture being then distilled , The fraction distilling at 174 - 177°C/0, 1 mm is collected ( 10, 3 grams) « The hydrochloride of the -desired product is prepared in aqueous solution at a pH of 5 ° 3 The aqueous solution is evaporated and dried with benzene (azeotropic distillation) » --3 - . -to 9o7 grams of the desired hydrochloride are obtained. After re-crystallization from ethylacetate , this hydrochloride melts Ana-lysis ; C H CI % calculated 70o46 8033 7°47 9 6 % found s 70o38 8o33 7<>63 9.28 EXAMPLE 15 Preparation of 1 ~methoxy-2 ~ -phenyl-N-( β~Ν ' -piperidinoethyl Tr aminoindane (formula I : = piperidino ; n = 1 ; B » phenyl-; Z = CH2) This compound is prepared in the manner described in e ample 14, except that β-chloroethylpiperidlne is ;used instead of β-chloroethyldlethylamineo Yield 50%„ The fumarate of the desired product melts at 140-142°C after recrystalliza-tion from ethylacetate.
-V" Analysis ; C H N % calculated : 69» 0 7° 34 6.00 % found i 69o70 7=22 5=93 EXAMPLE .16 Preparation of ; l-ethoxy^2-( -pti^ indane (formula I s R1=R2 = C2H^ ; n=?1 ; A= 0C2Hj. ; B=phenylj Z = CO) dane^(formula V s n =1 ; A=0C2H^ ; B=phenyl)0 . . 2o53 grams of 1 -ethoxy-2-phenylaminoindane , 205 ml of the chloride of chloracetic acid and 15 ml of benzene are refluxed during 30 minutes. The mixture is evaporated to dryness and the residue is extracted with petroleum ether. Yield 91#o The desired product melts at 142 143°C after recrystal lization from benzene and cyclohexane.
Analysis s C H J CI % calculated ; 69.19 6.1t 4,25 10.75 % found ί 69.19 5.90 4.07 11.1 2 1 -ethoxy-2-/~ ~phehyl-N-(dlethylamlnoacetyi)7-amlnolhdane (formula VIII ; A , = R2"C2H5 ) (formula I : Z = CO) This compound is prepared by the method described in Example 4, section 2.
Melting point : 195 - 196?C after recrystallization from acetone C H 68.55 7.75 EXAMPLE 17 Preparatio of 1 -'ethoxy-2- ~N-phenyl-N-diethyl-amlnoethylj7-aminolndane (formula I ; R1 = R2 = C^H^ ; n = 1 ; A=0C2H^ ; B = phenyl ; Z » CH2) This compound is obtained by reduction of the preceding compound of Example 16 by means of AlLiH^ in ether m.p. 137 - 138°C( in ethylacetate) , Analysis s C H N CI % calculated i 71.02 8.55 7o20 9.12 % found : 70.99 8.31 7.27 9.21 EXAMPLE 18 -Preparat±on~ of -ethoxy~2- ~N-phenyl-N-(i3 -diethylaminopropib-* -^' nyl 7~aminoindane (formula I ; R1=R2=C2H^ ; n = 2; A = 0C2H^ ; B = phenyl; Z = CO) 1) Preparation of 1-ethoxy-2- ~N-phenyl-N-(3-chloropropionyl 7- aminoindarie ( ormula V : n = 2; A=0C2H^ ; B = phenyl) "" . 2.53 grams of 1 -ethoxy-2-phenylaminoindane , 205 ml of the chloride of β-chloropropionic acid and 15 ml of benzene are. re- fluxed during 30 minutes„ The mixture is then evaporated to dryness and the residue is extracted with petroleum ether (40 -60°C). 2o84 grams (yield 85%) of the desired product are ob-tainedo After recrystallization from petroleum -ether (40 - 60°C), this product melts at 92 - 93°C.
Analysis ; C H N CI % calculated ; 69.86 6.45 4,07 10.31 % found : 69.89 6.0 3.9 10.2 . (formula I ; Z = CO) 1-ethoxy-2- ~N-phenyl~N-( -chloropropionyl 7aminoindane is reacted during 24 hours with diethylamine at 100°C in an autoclave m0p0 : 105-110° C (oxalate recrystallized from acetone) Analysts ; , „. C H % calculated; ; 66.360 7«28 5»95 % found ; 66,01 7.29 6o20 _ 5-- EXAMPLE 19 Preparation of 1-ethoxy-2-(N-phenyl-N-(dieth^ aminoindane (formula Ϊ ; k1 = R2=G2H^ ;. n = 2 ; A= 02¾ » B«phenyl; Z = CH2) This product is prepared from 1-ethoxy-2-(N- phenyl-N-p-chloropropionyl)-aminoindane by reduction thereof by means of aluminium lithium hydride, so as to obtain 1~etho- xy-2- *N-phenyl-N-chlpropropyl)-aminoindane (formula VI s n = 2 ; A=dC2H^ ; B = phenyl), the latter compound being treated With diethylamineo The oxalate of the desired compound recrystallized from iso- propanol melts at 33-134°C o Analsd-S s C H N % calculated 68 « 39 7» 95 6„ 14 % found 68 o2 7°74 6 o05 EXAMPLE 20 Preparation of 1-metfaoxy-2- ~N-phenyl-N-(piperidto^ 10 g of 1-methoxy-2^ ~N-phenyl-N-(p-chloropro» prepared as described in example 6 , section 1 ) , are dissolved in a solution of piperidine in ethanolo The reaction mixture is refluxed during 24 hours0 After removal of the aLcohol, the residue is treated with diluted hydrochloric acido The obtained solution is made alkaline and extracted by means of chloroform0 The residue of the chloroform extract: is dissolved in diluted hydrochloric acid and carefully dried under vacuum0 The residue is treated with acetone and the obtained solution is filtered,, By r¾crystallization from a mixture of * acetone and methanol the desired hydrochloride is obtained.
Analysis of the base ι C H N % calculated s 76. 15 7 - 98 7.40 % found s 75.96 7 o 9 7.54 Analysis of the hydrochloride CI % calculated s 8„ 54 % found § 806O EXAMPLE 21 Preparation of 1-methoxy-2'- ~N-phenyl--N-(piperidinopropyl 7-aminoindane hydrochloride, (formula I . A = OCHj ; B = phenyl; N '; » piperidino; n = 2 ; Z = CH2) To a solution of 1-methoxy-2-(N-phenyl-N-piperi-' dinopropionyl)-aminoindane in ether, a suspension of 2 g of lithium aluminium hydride in 100 ml of ether is continously ;'; " h added o The obtained mixture is refluxed during 2 ^ours. After cooling with ice water, ice and water are added to the mixture, which is then decanted and dried.
The obtained oil is treated with diluterjhydro-chloric acid and the pH is then brought to 60 After extraction with chloroform, the organic phase is dried and distilled under vacuum 0 The residue is treated with 100 ml of acetone and heated until a precipitate is obtained „ By recrystallization from a mixture of methanol and acetone, the desired ^product melting at 173-174°C is obtained.
Analysis : C H N CI % calculated 7.1 .88 · 8.29 6.98 8.84 % found s 72c04 8„20 7 = 01 8e64 , EXAMPLE 22 i ; This compound is prepared from the acylated derivative described in Example 18 Section 1)follo ing the procedure described in Example 18 Section 2, the amine being here pyrrolidine 175° - 177° C (isop-iOpanolJ Analysis s C H N CI % calculated 69c 6 7c53 6c75 8o55 % found 69 c 52 7o51 6o51 8o35 EXAMPLE 25 Preparation of 1=ethoxy=-2 "N=-phenyl=N=(pyrrolidinopropyl 7 The preceding compound described in Example 24 is reduced by means of AlLiH^ following the procedure described in E o 19o m.p„: 189=190° C (methanol - acetone) Analysis s C H N CI % calculated 71 c88 8c29 6o99 8o84 % found 71 c46 8,28 6086 8.98 EXAMPLE 26 Preparation of 1 -methoxy"2== ~N-phenyl~N-=(B"-methylaminoproplonyl 7 -aminoindane hydrochloride (formula I s A = me hoxy? R,j ■-- Hj R2 = CHjj B = phenyl n = 25 Z = CO 10 g of -methoxy~2=(N-phenyl-Ν-β-chloropropio-nyl-aminoindane are dissolved in 70 ml of a 33% solution of methylamine in ethanolo The mixture is refluxed during 24 hours e The ethanol is then removed and the mixture is treated with diluted hydrochloric acido The obtained solution is made alkaline and extracted with chloroforme The residue of the chloroform solution is dissoved in diluted hydrochloric acido After removal of water under reduced pressure, the residue is treated with acetone and filtered. - 3& - The product is recrystallized from a mixture of methanol and acetone, m„p, I 210=215° C, Analysis s C H N CI Calculated % 66,55 6 ο 9θ 7 , 76 9 o 82 Found % 66,65 6 , 93 7 c 87 10.00 EXAMPLE 27 Preparation of l-methoxy-^-.fN-phenyl-N-Cmethylaminopropyl)" aminoindane (formula I : A = met 2.% Z = CHp; β = phenyl) To a solution of 1 methylaminopropionylJTT-aminoindane in 80 ml of anhydrous ether, a suspension of 2g of lithium aluminum hydride in 00 ml of ether is added. The obtained mixture is refluxed during 2 hours and thencooled with ice water. After decaxitation and drying, the obtained oil is treated with diluted hydrochloric acid.
The pH of the solution is brought to 6 and the solution is extracted by means of chloroform. The organic phase ic dried and distilled under reduced pressure. The mixture is treated with 100 ml of acetone and heated until a precipitate is obtained.
The desired hydrochloride is recrystallized from a mixture of methanol and acetone, m.p.: 139-1 0° C, Analysis Y C H N CI Calculated % 69,24 7.84 8,04 10,22 Found % 69,50 7,74 8,05 10.20 3
Preparation of the -methoxy-2 ~N-phenyl-N (Ύ-methylethylamino pyls-aminoindane hydrochloride (formula I : A = m^thoxy; R1 = CH^; R2 = C2H5. n = 2 ; Z = CH2; B = phenyl) This substance is obtained from the acylated compound described in example 6 sectio 1 by reacting said compound with methylethylamine as amine, and reducing the thus obtained compound of formula VU1 by means of AlLiH^ in ether. m.p.: 1 75-176° C (acetone) Analysis : C H N CI ^calculated 70.46 8.33 7.47; 9.46 % found 70.20 8.33 7.50 9.48 EXAMPLE 35 This compound is prepared by the method of 20 except that morpholine is used instead of piperidine . d,p,: 184-185° C. (isopropanol) Analysis s C H N CI % Calculated 66.25 7o01 6o72 8c50 % Found 66o10 7.15 6c88 8c30 EXAMPLE ?6.
This compound is prepared by the method of Example 20 except that pyrrolidine is used instead of piperidine m.p.: 180-181° C. (isopropanol) Analysis ; C H N CI % Calculated 68090 7o29 6.99 8.84 % Found 68.70 7o25 6.84 8o76 EXAMPLE 37 Preparation -aminoidane piperidino, This substance is prepared from the acylated derivative described in Example 18, section 1 following the procedure described in Example 18 section 2, except that piperidine is used instead of diethylamine. m.p.s 185-187° C (methanol - ethylacetate) Analysis ; C . H N CI % Calculated 69,99 7.75 6.53 8,27 % Found 69.40 7o84 . 6.96 8.30 EXAMPLE 38 Preparation of the 1-methoxy-2- ~N-phenyl-N-(Y piperidino- A o Preparation of 1 -methoxy-2- ~N-phenyl-N- Ύ chloro.bu tyroyl7-aminoindane (formula V; 'nL= 3; A = OCH^; B = phenyl) This compound is prepared as described in example 4 section 1 , using the chloride of"A-ctil'o^d ^yric acid instead of the chloride of chloroacetic acid0 The desired product melts at 68-70° C after recrystallisation from petroleum ether (60-80° ) 0 Analysis ; C H N CI % Calculated 69o85 6.44 4o 07 1 0.31 % Found 69 c 70 6.43 4o 1 0 10.32 B . Preparation of the desired end product.
This compound is prepared from the acylated derivative described in part A of this example following the procedure described in example 20. m.p. ; 157-1 59° C. (benzene) i Analysis : C H N CI % Calculated 69.99 7.75 6.53 8.27 % Found 69.47 7.69 6.62 8.38 EXAMPLE 39 - 44> - U3 - 1-diethylamino~2»phenylaminoindane ( Example 12 section 1) is acylated by means of C1-C0(CH2)2 C1 as described in example 6, section 1 „ The product thus obtained is thus reacted with pipe ridine applying the method of Example 200 m.p. 192=193° C0 (ethanol) Analysis : C H N % Calculated 68 « 7o71 8<, 24 % Found 68«15 7.66 8 2 The following examples 40-43 illustrate pharma- ceutical compositions of this invention for he , treatment of1 ia heart arrhythmic , EXAMPLE 40 ; CAPSULE Active ingredient of formula I 100 mg ' Lactose 120 mg Rice starch 30 mg Corn starch 30 mg Colloidal silica 1 mg for one capsule EXAMPLE 41 TABLET Active ingredient of formula I 200 mg Potato starch 1 20 mg Lactose 80 mg Starch sodium glycollate 30 mg Colloidal silica 15 mg Magnesium stearate 5 mg Hydroxy propylcellulose 4 mg Stearic acid „ Λ ■ „ , 2 mg for one tablet EXAMPLE 42 PILLS Core ; e Active ingiT&ient of formula I 50„0 mg Lactose 67 5 mg Microcrystalline cellulose 3200 mg Starch sodium glycollate 8„2 mg Colloidal silica 0o4 mg Magnesium stearate 0„9 mg Coating ; Shellac 1,0 mg Sandarac 0.2 mg Castor oil 0„3 mg Gum arable 7«0 mg Talc 11.2 mg Corn starch 1,0 mg Titanium oxide 1,3 mg Dyestuff 4„0 mg Sucrose 142*8 mg White wax / carnauba wax 0„2 mg for one pill EXAMPLE 43 Solution for perfusion Active ingidient of formula I . , ., , 200 mg Anhydrous sodium sulfite 60 mg Anhydrous sodium metabisulfite 140 mg Sodium chloride 1.7 mg Water for injection ad 200 ml It should be understood that the invention is not exclusively limited to the embodiments described hereinabove and that many modifications may be brought thereto by the man skilled in the art without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (3)
1. 43552/2 1. Derivatives of 2-aminoindane of the general form in which n is equal to 1, 2, 3, Z represents a CH2 or CO .-roup, R1 and.R2 represent each a lower alkyl or hydroxyalkyl group containing 1 to 3 carbon atoms, and R1 may also represent hydrogen, R1 and R2 also may form with the attached nitrogen atom a saturated nitrogenous heterocyclic ring, B represents an unsubstituted ph group or a group each represent a attached nitrogen atom a saturated nitrogenous heterocyclic ring, as well as the acid addition salts of said compounds of formula I.
2. Derivatives of 2-aminoindane according to Claim 1, in which Z represents a CH^ group and n, R^, R^,. A and B have the above meanings .
3. Derivatives of 2-aminoindane according to claim 1, in which Z represents a CO group and n, ^, R^ t A and B have the above meanings; 4. Derivatives of 2- aminoindane according to claim 2, in which n is equal to 1 and 2, R^ and R^ each represent a methyl. or ethyl group, with the proviso that R^ and R^ may be different and R^ may also represent a hydrogen atom, aminoindane and the acid addition salts thereof, 7c' Derivatives of 2-aminoindane according to claim 3> in which n is equal to 1, .2 or 3» R1 and R2 each represent an ethyl group with the proviso that R^ may also · represent a hydrogen atom, R1 and R2 may also form with the ^_atjta^hjed_nitrogen atom a piperidino group, B represents ¾n unsubstituted. henyl group and A represents a methoxy or ethoxy group, and the acid addition salts thereof, 8, j Derivatives, of 2-aminoindane according to claim 7 selected from 1 -methoxy-2- ~N-phenyl-N-(piperidinopr0-0 pionyl 7-aminoindahe and the acid addition salts thereof. . 9, j Derivatives of 2-aminoindane. according to claim.7 selected from 1~methoxy-2- ~N-phenyl-N=(diethylamino-' propionyljjamihoindane, 1- methoxy-2f- ~N^henyl-N-(diethylamino- and the acid addition salts of said compounds 10, Pharmaceutical compositions particularly for •the treatment of heart arrhythmia containing, as active ingredient, d n to an one of the recedin 43552/2 11o A process for preparing new derivatives 2-aminoindane of the general .formula in which n is equal to 1 , 2, 3» Z represents a CH2 or CO group Rj and R2 represent each a lower alkyl or hydroxyalkyl group containing 1 to 3 carbon atoms, and R-. may also represent hydrogen, R1 and R2 also may form with the attached nitrogen saturated atom a/nitrogenous heterocyclic ring, B represents an unsubsti tuted phenyl group, A repres group or a group of the formula N; each represent a methyl or ethyl group or may form with the attached saturated nitrogen atom a/nitrogenous heterocyclic ring, as well as the acid addition , said process comprising the la either with sodium amide so as to obtain the sodium salt of said compound of formula (II), this sodium salt being then reacted, with a halogenated amine of the formula (III) in which Hal represents a halogen atom and n, R1 and R2 have the above-indioated meanings*, or with an acid chloride of the formula CI (CH2)n -C0C1 (IV) in which n has the above meanings, so as to obtain an acylated compound of said acylated compound being reduced into a compound of the formula in which n, A and B have the above meanings, said compound o of formula (VI) being then reacted with a primary or sticjlnd amine of the formula wherein R., and R2 have the above meanings, or the a acylated compound of formula V may also be reacted with an amine of formula VII to give a compound of formula I in which 2 represent a - CO- group, the latter compound being reduced, if desired, into a compound of formula I in which Z represents a -CH2~ group 12o A process according to claim 11, in which a primary amine of the formula I^NRgf in which has the above meanings, is used when a compound of formula I, in which R represents hydrogen, whereas represents a lower alkyl or hydroxyalkyl group, has to be prepared. A process according to claim 11, in which a secundary amine of the formula wherein R1 and R2 have the above meanings, except that R1 does not represent hydrogen, is used when a compound of the formula I in which R_| and R~ represent each a lower alkyl or hydroxyalkyl . . - - .. . . k 43552/3 group or form together with the attached nitrogen atom a saturated nitrogenous heterocyclic ring, has to be prepared. ' , 14. A procecs according to any of claims 11 to 13, wherein reduction of a CO group into a CH2 group is effected by means of lithium aluminum hydride. 15. A process according to claim 11, substantially described in anyone of the Examples 1 - 39. 16. Pharmaceutical compositions substantially as described in anyone of the Examples 40-43. 17. l-Ethoxy-2-[N-phenyl-N-(ethylaminoacetyl)]-aminoindane. 18. l-Ethoxy-2-[N-phenyl-N-(diethylaminoacetyl) ]-aminoindane . 19. l-Sthoxy-2-[N-phenyl-N-( -ethylnminopropionyl)]- I arainoindane . " \ 20. l-Ethoxy-2-[N-pheny1-N-( β-diethylaminopropiony1) ]■ aminoindane .
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB5109472 | 1972-11-06 | ||
| GB1030573*[A GB1423839A (en) | 1972-11-06 | 1973-03-02 | Derivatives of 2-aminoindane |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL43552A0 IL43552A0 (en) | 1974-03-14 |
| IL43552A true IL43552A (en) | 1977-08-31 |
Family
ID=26247434
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL43552A IL43552A (en) | 1972-11-06 | 1973-11-02 | Derivatives of 2-n-phenyl-n-aminoalkyl(or aminoalkanoyl)-aminoindanes their preparation and pharmaceutical compositions them |
Country Status (13)
| Country | Link |
|---|---|
| JP (2) | JPS546551B2 (en) |
| AR (2) | AR206999A1 (en) |
| CA (1) | CA999007A (en) |
| CH (2) | CH594596A5 (en) |
| DD (2) | DD111288A5 (en) |
| DE (1) | DE2355039A1 (en) |
| FR (1) | FR2205332B1 (en) |
| GB (1) | GB1423839A (en) |
| HU (1) | HU167575B (en) |
| IL (1) | IL43552A (en) |
| LU (1) | LU68744A1 (en) |
| NL (1) | NL7315187A (en) |
| YU (1) | YU287673A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH073878A (en) * | 1993-06-14 | 1995-01-06 | Natl House Ind Co Ltd | Bay window device |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE760018A (en) * | 1969-12-19 | 1971-06-08 | Christiaens Sa A | NEW DERIVATIVES OF 2-AMINO-INDANE, THEIR PREPARATION AND THEIR USE |
-
1973
- 1973-01-01 AR AR250867A patent/AR206999A1/en active
- 1973-03-02 GB GB1030573*[A patent/GB1423839A/en not_active Expired
- 1973-10-30 CA CA184,594A patent/CA999007A/en not_active Expired
- 1973-11-02 IL IL43552A patent/IL43552A/en unknown
- 1973-11-03 DE DE19732355039 patent/DE2355039A1/en not_active Withdrawn
- 1973-11-05 HU HUCI1420A patent/HU167575B/hu unknown
- 1973-11-05 FR FR7339260A patent/FR2205332B1/fr not_active Expired
- 1973-11-05 CH CH25177A patent/CH594596A5/xx not_active IP Right Cessation
- 1973-11-05 LU LU68744A patent/LU68744A1/xx unknown
- 1973-11-05 CH CH1553473A patent/CH594598A5/xx not_active IP Right Cessation
- 1973-11-06 JP JP12486073A patent/JPS546551B2/ja not_active Expired
- 1973-11-06 NL NL7315187A patent/NL7315187A/xx not_active Application Discontinuation
- 1973-11-06 YU YU02876/73A patent/YU287673A/en unknown
- 1973-11-06 DD DD177891*A patent/DD111288A5/xx unknown
- 1973-11-06 DD DD174480A patent/DD108972A1/xx unknown
-
1975
- 1975-01-01 AR AR258190A patent/AR207142A1/en active
-
1978
- 1978-01-12 JP JP260878A patent/JPS53121752A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| DE2355039A1 (en) | 1974-05-16 |
| DD111288A5 (en) | 1975-02-12 |
| CH594598A5 (en) | 1978-01-13 |
| LU68744A1 (en) | 1974-01-18 |
| CH594596A5 (en) | 1978-01-13 |
| DD108972A1 (en) | 1974-10-12 |
| JPS576419B2 (en) | 1982-02-04 |
| AU6206773A (en) | 1975-05-01 |
| HU167575B (en) | 1975-11-28 |
| JPS53121752A (en) | 1978-10-24 |
| JPS49132057A (en) | 1974-12-18 |
| YU287673A (en) | 1981-04-30 |
| GB1423839A (en) | 1976-02-04 |
| JPS546551B2 (en) | 1979-03-29 |
| IL43552A0 (en) | 1974-03-14 |
| CA999007A (en) | 1976-10-26 |
| AR207142A1 (en) | 1976-09-15 |
| FR2205332B1 (en) | 1977-04-22 |
| AR206999A1 (en) | 1976-09-09 |
| FR2205332A1 (en) | 1974-05-31 |
| NL7315187A (en) | 1974-05-08 |
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