DE8718021U1 - Condensed bis-(3,4-dihydro-1-pyridiny1)methanes, processes for their preparation and pharmaceutical compositions containing these compounds - Google Patents
Condensed bis-(3,4-dihydro-1-pyridiny1)methanes, processes for their preparation and pharmaceutical compositions containing these compoundsInfo
- Publication number
- DE8718021U1 DE8718021U1 DE8718021U DE8718021U DE8718021U1 DE 8718021 U1 DE8718021 U1 DE 8718021U1 DE 8718021 U DE8718021 U DE 8718021U DE 8718021 U DE8718021 U DE 8718021U DE 8718021 U1 DE8718021 U1 DE 8718021U1
- Authority
- DE
- Germany
- Prior art keywords
- alkyl
- compound
- hydrogen
- independently
- compound according
- 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.)
- Expired - Lifetime
Links
- 150000001875 compounds Chemical class 0.000 title claims description 60
- 238000000034 method Methods 0.000 title claims description 9
- 230000008569 process Effects 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- 239000001257 hydrogen Substances 0.000 claims description 30
- -1 amino, thiomethyl Chemical group 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 239000004480 active ingredient Substances 0.000 claims description 8
- 125000001544 thienyl group Chemical group 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000001054 5 membered carbocyclic group Chemical group 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 150000002431 hydrogen Chemical group 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000005948 methanesulfonyloxy group Chemical group 0.000 claims description 6
- 125000004008 6 membered carbocyclic group Chemical group 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- 235000005985 organic acids Nutrition 0.000 claims description 3
- 238000011282 treatment Methods 0.000 claims description 3
- JSBRRBMLENGMKZ-UHFFFAOYSA-N 1-[1-(6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-ylidene)ethyl]-4-hydroxy-6,7-dimethoxy-2H-isoquinolin-3-one Chemical compound COC1=CC2=C(C=C1OC)C(NCC2)=C(C)C1=NC(O)=C(O)C2=CC(OC)=C(OC)C=C12 JSBRRBMLENGMKZ-UHFFFAOYSA-N 0.000 claims description 2
- 206010000891 acute myocardial infarction Diseases 0.000 claims description 2
- 125000005605 benzo group Chemical group 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 208000029078 coronary artery disease Diseases 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 230000004927 fusion Effects 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 230000002152 alkylating effect Effects 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 43
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 16
- 239000000203 mixture Substances 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 229920002261 Corn starch Polymers 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 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 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- 238000009835 boiling Methods 0.000 description 6
- 239000008120 corn starch Substances 0.000 description 6
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 6
- 239000008101 lactose Substances 0.000 description 6
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 5
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 5
- 238000007363 ring formation reaction Methods 0.000 description 5
- 229940127291 Calcium channel antagonist Drugs 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- HGDSYZMHRDLVDE-UHFFFAOYSA-N 1-(3,4-dihydro-2h-pyridin-1-ylmethyl)-3,4-dihydro-2h-pyridine Chemical class C1CCC=CN1CN1CCCC=C1 HGDSYZMHRDLVDE-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000003293 cardioprotective effect Effects 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 229940098779 methanesulfonic acid Drugs 0.000 description 3
- 230000002107 myocardial effect Effects 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 206010021143 Hypoxia Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 229910001424 calcium ion Inorganic materials 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
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- 239000008273 gelatin Substances 0.000 description 2
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- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229960001317 isoprenaline Drugs 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
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- 239000000047 product Substances 0.000 description 2
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 2
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
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- USKBWPLFXNWFKF-UHFFFAOYSA-N 1-[1-(6,7-dimethoxy-3,4-dihydro-2h-isoquinolin-1-ylidene)pentyl]-6,7-dimethoxy-3,4-dihydroisoquinoline Chemical compound COC1=C(OC)C=C2C(C(=C3C4=CC(OC)=C(OC)C=C4CCN3)CCCC)=NCCC2=C1 USKBWPLFXNWFKF-UHFFFAOYSA-N 0.000 description 1
- BOHURVXQPCBRSC-UHFFFAOYSA-N 1-[1-(6,7-dimethoxy-3,4-dihydroisoquinolin-1-yl)pentylidene]-6,7-dimethoxy-2-methyl-3,4-dihydroisoquinoline Chemical compound CN1CCC2=CC(OC)=C(OC)C=C2C1=C(CCCC)C1=NCCC2=CC(OC)=C(OC)C=C12 BOHURVXQPCBRSC-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- MCRZWYDXIGCFKO-UHFFFAOYSA-N 2-butylpropanedioic acid Chemical compound CCCCC(C(O)=O)C(O)=O MCRZWYDXIGCFKO-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
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- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
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- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
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- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 1
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- WRIRWRKPLXCTFD-UHFFFAOYSA-N malonamide Chemical compound NC(=O)CC(N)=O WRIRWRKPLXCTFD-UHFFFAOYSA-N 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
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- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical group C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 231100000816 toxic dose Toxicity 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
- C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
- C25B13/00—Diaphragms; Spacing elements
- C25B13/04—Diaphragms; Spacing elements characterised by the material
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B22—CASTING; POWDER METALLURGY
- B22F—WORKING METALLIC POWDER; MANUFACTURE OF ARTICLES FROM METALLIC POWDER; MAKING METALLIC POWDER; APPARATUS OR DEVICES SPECIALLY ADAPTED FOR METALLIC POWDER
- B22F3/00—Manufacture of workpieces or articles from metallic powder characterised by the manner of compacting or sintering; Apparatus specially adapted therefor ; Presses and furnaces
- B22F3/10—Sintering only
- B22F3/11—Making porous workpieces or articles
- B22F3/1103—Making porous workpieces or articles with particular physical characteristics
- B22F3/1118—Making porous workpieces or articles with particular physical characteristics comprising internal reinforcements
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B22—CASTING; POWDER METALLURGY
- B22F—WORKING METALLIC POWDER; MANUFACTURE OF ARTICLES FROM METALLIC POWDER; MAKING METALLIC POWDER; APPARATUS OR DEVICES SPECIALLY ADAPTED FOR METALLIC POWDER
- B22F3/00—Manufacture of workpieces or articles from metallic powder characterised by the manner of compacting or sintering; Apparatus specially adapted therefor ; Presses and furnaces
- B22F3/18—Manufacture of workpieces or articles from metallic powder characterised by the manner of compacting or sintering; Apparatus specially adapted therefor ; Presses and furnaces by using pressure rollers
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- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Manufacturing & Machinery (AREA)
- Mechanical Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Electrochemistry (AREA)
- Materials Engineering (AREA)
- Metallurgy (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Die Erfindung betrifft neue kondensierte Bis-(3,4-dihydro-1-pyridinyl)methane, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel.The invention relates to novel condensed bis-(3,4-dihydro-1-pyridinyl)methanes, processes for their preparation and pharmaceuticals containing these compounds.
Die neuen Verbindungen besitzen die allgemeine Formel IThe new compounds have the general formula I
limlim
A und B unabhängig voneinander einen Benzo- oder Thienorest bedeuten;A and B independently represent a benzo or thieno radical;
R1 Wasserstoff, (C -C,_)Alkyl, Phenyl, Phenyl =R 1 hydrogen, (C -C,_)alkyl, phenyl, phenyl =
1 1 1U1 1 1U
(C -C )alkyl, (C -C )Alkoxy oder -NHCOX (worin X (C -C )Alkyl ist) bedeutet;(C -C )alkyl, (C -C )alkoxy or -NHCOX (wherein X is (C -C )alkyl);
R Wasserstoff, (C -C )Alkyl oder Hydroxymethyl bedeutet;R is hydrogen, (C -C )alkyl or hydroxymethyl;
R0, R_, R£ und R unabhängig voneinanderR 0 , R_, R £ and R independently
&Dgr; i b IΔ i b I
Wasserstoff oder (C -C )Alkyl bedeuten oder R mit R und/oder R mit R und dem jeweiligenhydrogen or (C -C )alkyl or R with R and/or R with R and the respective
3 6 73 6 7
Kohlenstoffatom, an das sie gebunden sind, einen 5- oder 6-gliedrigen Carbocyclus bedeuten;Carbon atom to which they are attached represents a 5- or 6-membered carbocycle;
R und R unabhängig voneinander (C -C )Alkyl, Halogen (F, Cl, Br, J), Hydroxy, (C -C )Alkoxy, Amino, Thiomethyl, Methansulfonyloxy oder Methansulfonamido bedeuten, oder zwei benachbarte Substituenten R beziehungsweise R zusammen -O-CH -O- oder -O-CH -CH-O- sind;R and R independently of one another are (C -C )alkyl, halogen (F, Cl, Br, I), hydroxy, (C -C )alkoxy, amino, thiomethyl, methanesulfonyloxy or methanesulfonamido or two adjacent substituents R or R together are -O-CH -O- or -O-CH -CH-O-;
m und &eegr; unabhängig von einander O, 1, 2 oder 3 bedeuten, wenn A beziehungsweise B ein Benzorest ist, und O, 1 oder 2 bedeuten, wenn A beziehungsweise B ein Thienorest ist;m and η independently of one another are O, 1, 2 or 3 if A or B is a benzo radical and are O, 1 or 2 if A or B is a thieno radical;
und ihre pharmazeutisch annehmbaren Salze mit anorganischen und organischen Säuren;and their pharmaceutically acceptable salts with inorganic and organic acids;
ausgenommen ist die Verbindung der Formel 1, worin R ,except for the compound of formula 1, wherein R ,
R_, R_, R1-. R und R, Wasserstoff bedeuten und A 2 3 5 6 /R_, R_, R 1 -. R and R, are hydrogen and A 2 3 5 6 /
und B den Restand B the rest
CH3O. CH3O .
CH3O CH3O
bedeuten.mean.
Verbindungen der Formel I, worin R Wasserstoff ist, bilden Tautomere der Formeln Ia und Ib,Compounds of formula I in which R is hydrogen form tautomers of formulas Ia and Ib,
(R19) 12 &eegr;(R 19 ) 12 &eegr;
worin R ebenfalls Wasserstoff ist. Die Definition der Formel I umfaßt auch die genannten Tautomeren.where R is also hydrogen. The definition of formula I also includes the tautomers mentioned.
Von Kobar, Jeno wurde in Szegedi Tonarkepzo Foiskala Ind. Kozl. 1985, Seiten 145-153 (vgl. Chem. Abstr. &Egr;&Ggr;7; 134980Z) eine Verbindung der vorstehenden allgemeinen Formel I beschrieben, worin R1, R_, R., R., R, und R„A compound of the above general formula I was described by Kobar, Jeno in Szegedi Tonarkepzo Foiskala Ind. Kozl. 1985 , pages 145-153 (cf. Chem. Abstr. �Egr;&Ggr;7; 134980Z), wherein R 1 , R_, R., R, R, and R„
1 Z &ogr; b &ogr; /1 Z ϳ b ϳ /
Wasserstoff bedeuten und A und B den Resthydrogen and A and B represent the rest
bedeuten.Diese Publikation enthält keine Angaben über physiologische Wirkungen dieser Verbindung.This publication does not contain any information on physiological effects of this compound.
Es wurde überraschenderweise gefunden, daß die neuen Bis-(3,4-dihydro-1-pyridinyl)-methane der allgemeinen Formel I sowohl als Basen als auch in Form ihrer Salze wertvolle therapeutische Eigenschaften besitzen.It was surprisingly found that the new bis-(3,4-dihydro-1-pyridinyl)-methanes of the general formula I have valuable therapeutic properties both as bases and in the form of their salts.
Von den Verbindungen der Formel I können folgende als besonders interessant hervorgehoben werden:Of the compounds of formula I, the following can be highlighted as particularly interesting:
-) Verbindungen (I), worin R Wasserstoff, (C -C )Alkyl, PhenyKC -C )alkyl oder -NHCOX (worin X (C -C )Alkyl ist) bedeutet;-) Compounds (I) wherein R is hydrogen, (C -C )alkyl, phenylKC -C )alkyl or -NHCOX (wherein X is (C -C )alkyl);
R und R unabhängig voneinander (C -C )Alkyl, Hydroxy, (C-C4)AIkOXy, Methansulfonyloxy oder Methansulfonamido bedeuten, oder zwei benachbarte Substituenten R beziehungsweise R zusammen -O-CH -O- oderR and R independently of one another are (C -C )alkyl, hydroxy, (CC 4 )alkOXy, methanesulfonyloxy or methanesulfonamido, or two adjacent substituents R or R together are -O-CH -O- or
-O-CH -CH -O- sind;
2 2-O-CH -CH -O-;
2 2
-) Verbindungen (I), worin R Wasserstoff, (C -C )Alkyl oder -NHCOX (worin X (C -C )Alkyl ist) bedeutet;-) Compounds (I) wherein R is hydrogen, (C -C )alkyl or -NHCOX (wherein X is (C -C )alkyl);
R-. R-, - Rr und R-7 unabhängig von einander 2 3 6 7R-. R -, - R r and R -7 independently of each other 2 3 6 7
Wasserstoff bedeuten oder R mit R und/oder Rhydrogen or R with R and/or R
2 3 62 3 6
mit R und dem jeweiligen Kohlenstoffatom, an das sie gebunden sind, einen 5- oder 6-gliedrigen Carbocyclus bedeuten;with R and the respective carbon atom to which they are attached represent a 5- or 6-membered carbocycle;
R und R unabhängig voneinander Hydroxy, (C -C )Alkoxy, Methansulfonyloxy oder Methansulfonamido bedeuten, oder zwei benachbarte Substituenten R beziehungsweise R zusammen -O-CH -O- oder -O-CH -CH -O- sind;R and R independently of one another are hydroxy, (C -C )alkoxy, methanesulfonyloxy or methanesulfonamido, or two adjacent substituents R or R together are -O-CH -O- or -O-CH -CH -O-;
Ct L·, C*Ct L·, C*
-) insbesondere Verbindungen, worin R Wasserstoff,-) in particular compounds in which R is hydrogen,
(C -C )Alkyl, oder -NHCOCH bedeutet und/oder 16 3(C -C )alkyl, or -NHCOCH and/or 16 3
R Wasserstoff, Methyl oder Hydroinethyl bedeutet und/oderR is hydrogen, methyl or hydroethyl and/or
Ro' R-> - R/r und R-7 unabhängig voneinander R o' R -> - R /r and R -7 independently
2 3 6 7
Wasserstoff bedeuten oder R mit R und/oder R mit R und dem jeweiligen Kohlenstoffatom, an das
sie gebunden sind, einen 5-gliedrigen Carbocyclus bedeuten und/oder2 3 6 7
hydrogen or R with R and/or R with R and the respective carbon atom to which they are attached, represent a 5-membered carbocycle and/or
R und R unabhängig voneinander Hydroxy, Methoxy, Methansulfonyloxy oder Methansulfonamido bedeuten, oder zwei benachbarte Substituenten R beziehungsweise R zusammen -O-CH -O- sind.R and R independently of one another are hydroxy, methoxy, methanesulfonyloxy or methanesulfonamido, or two adjacent substituents R or R together are -O-CH -O-.
Bevorzugt sind Verbindungen (I), worin m und/oder &eegr; 2 bedeuten, insbesondere solche in denen A und/oder B ein Benzorest ist, wobei vorzugsweise die beiden Substituenten R und/oder R in meta- beziehungsweise para-Posit ion zu den Fusionspunkten des Restes A beziehungsweise B stehen.Preference is given to compounds (I) in which m and/or η is 2, in particular those in which A and/or B is a benzo radical, with the two substituents R and/or R preferably being in meta- or para-position to the fusion points of the radicals A and B respectively.
Hervorzuheben sind Verbindungen, worin R und R Methoxy sind.Of particular interest are compounds in which R and R are methoxy.
Beispiele spezifischer Verbindungen gemäß der Erfindung sind in den Tabellen 1 bis 3 angeführt, hervorzuheben ist 1-(3,4-Dihydroxy-6,7-dimethoxy-isochinolin-l-yl)-l-(3,4-dihydro-6,7-dimethoxy-isochinolin-l-yliden)-ethan oder ihr physiologisch unbedenkliches Salz.Examples of specific compounds according to the invention are given in Tables 1 to 3, with particular emphasis being given to 1-(3,4-dihydroxy-6,7-dimethoxy-isoquinolin-l-yl)-l-(3,4-dihydro-6,7-dimethoxy-isoquinolin-l-ylidene)-ethane or its physiologically acceptable salt.
Die erfindungsgemäßen Verbindungen können in an sich bekannter Weise hergestellt werden.The compounds according to the invention can be prepared in a manner known per se.
In Gegenwart eines Kondensationsmittels kann ein Amid der allgemeinen Formel 11,In the presence of a condensing agent, an amide of the general formula 11,
IIII
worin A, R , R , R , R , R , R11, R.. und m 1 L 3 6 7 11 12where A, R , R , R , R , R , R 11 , R.. and m 1 L 3 6 7 11 12
wie oben definiert sind, Ar Phenyl oder Thienyl bedeutet und n' O, 1, 2 oder 3 bedeutet wenn Ar Phenyl ist, und O, 1 oder 2 bedeutet, wenn Ar Thienyl ist, und R Wasserstoff oder (C -C )Alkyl bedeutet, zu eineras defined above, Ar is phenyl or thienyl and n' is O, 1, 2 or 3 when Ar is phenyl, and O, 1 or 2 when Ar is thienyl, and R is hydrogen or (C -C )alkyl, to a
1 41 4
entsprechenden Verbindung (I) cyclisiert werden.corresponding compound (I) can be cyclized.
Als Kondensationsmittel eignen sich starke Lewis-Säuren, wie z.B. Phorphoroxychlorid, Phosphorpentachlorid, Phosphor trichlorid, Phosphorpentoxid, Titantetrachlorid, Bortrifluorid, Zinntetrachlorid, aber auch anorganische Säuren, wie z.B. Polyphosphorsäure, Schwefelsäure,Strong Lewis acids are suitable as condensing agents, such as phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, phosphorus pentoxide, titanium tetrachloride, boron trifluoride, tin tetrachloride, but also inorganic acids, such as polyphosphoric acid, sulfuric acid,
Fluorsulfonsäure und Fluorwasserstoffsäure, oder Gemische von Kondensationsmitteln wie z.B. ein Gemisch von Phosphoroxychlorid und Phosphorpentachlorid, oder ein Gemisch von Phosphorpentoxid und (C-C ) Alkylsulfonsäure z.B. mit einem P O -Anteil von ca. 10 Gewichtsprozenten.Fluorosulfonic acid and hydrofluoric acid, or mixtures of condensing agents such as a mixture of phosphorus oxychloride and phosphorus pentachloride, or a mixture of phosphorus pentoxide and (C-C) alkylsulfonic acid e.g. with a P O content of approx. 10 percent by weight.
Wird eine Verbindung II, worin R Wasserstoff ist, in Gegenwart des Gemisches von Phosphorpentoxid und (C -C )Alkylsulfonsäure cyclisiert, so erhält man neben der entsprechenden Verbindung I, in der RIf a compound II, in which R is hydrogen, is cyclized in the presence of the mixture of phosphorus pentoxide and (C -C )alkylsulfonic acid, one obtains in addition to the corresponding compound I, in which R
5 Wasserstoff ist, auch die analoge Verbindung I, in der R (C -C )Alkyl ist. Vorzugsweise wird diese Verfahrensvariante mit Methansulfonsäure ausgeführt.5 is hydrogen, also the analogous compound I in which R is (C -C )alkyl. Preferably, this process variant is carried out with methanesulfonic acid.
Die Cyclisierung kann in Gegenwart oder Abwesenheit eines Lösungsmittels durchgeführt werden. Geeignet sind alle inerten Lösungsmittel, soweit sie eine ausreichende Löslichkeit für die Reaktionspartner besitzen und einen ausreichend hohen Siedepunkt aufweisen, beispielsweise Benzol, Alkylbenzole (z.B. Toluol, Xylol), Chlorbenzole, Chloroform, Acetonitril, Dekalin. Eine bevorzugte Variante des Verfahrens besteht darin, das Kondensationsmittel, beispielsweise Phosphoroxychlorid oder ein (C-C )AlkylsuIfonsäure-/Phosphorpentoxid-Gemisch, ohne Zusatz von Lösungsmittel zu verwenden.The cyclization can be carried out in the presence or absence of a solvent. All inert solvents are suitable, provided they have sufficient solubility for the reactants and a sufficiently high boiling point, for example benzene, alkylbenzenes (e.g. toluene, xylene), chlorobenzenes, chloroform, acetonitrile, decalin. A preferred variant of the process consists in using the condensation agent, for example phosphorus oxychloride or a (C-C)alkylsulfonic acid/phosphorus pentoxide mixture, without the addition of solvent.
Bevorzugt erfolgt die Cyclisierung mit Phosphoroxychlorid oder in schwierigen Fällen mit einem Gemisch von Phosphorpentoxid und (C -C )Alkylsulfonsäure (bevorzugt Methansulfonsäure).The cyclization is preferably carried out with phosphorus oxychloride or, in difficult cases, with a mixture of phosphorus pentoxide and (C -C )alkylsulfonic acid (preferably methanesulfonic acid).
Die Umsetzung kann innerhalb eines großen Temperaturbereichs, vorzugsweise unter Erwärmen oder Erhitzen auf BO0C bis etwa dem Siedepunkt des Reaktionsgemisches, durchgeführt werden.The reaction can be carried out within a wide temperature range, preferably by warming or heating to B0 0 C up to about the boiling point of the reaction mixture.
Die erforderliche Reaktionsdauer liegt je nach Ausgangsverbindung II zwischen mehreren Tagen und mehreren Stunden.The required reaction time is between several days and several hours, depending on the starting compound II.
Die Verbindungen der oben definierten allgemeinen Formel II sind neue Verbindungen. Sie können durch Cyclisieren des entsprechenden Malonsäurediamids der allgemeinen Formel IIIThe compounds of the general formula II defined above are new compounds. They can be prepared by cyclizing the corresponding malonic acid diamide of the general formula III
?2 fl
C-CH2-NHCO-CH-CO-NH-CH2-C-(Ar ?2 fl
C-CH 2 -NHCO-CH-CO-NH-CH 2 -C-(Ar
hergestellt werden, in der R , R , R , R., R ,are manufactured in which R , R , R , R., R ,
L Z &ogr; b /L Z γ b /
R und R wie oben definiert sind, Ar Phenyl oder Thienyl bedeutet und m' und n' unabhängig voneinander O, 1, 2 oder 3 bedeuten, wenn Ar Phenyl ist, und O, 1 oder bedeuten, wenn Ar Thienyl ist.R and R are as defined above, Ar is phenyl or thienyl and m' and n' independently of one another are O, 1, 2 or 3 when Ar is phenyl and O, 1 or when Ar is thienyl.
Die Umsetzung erfolgt wie oben für die Cyclisierung der Verbindung II zu Verbindung I beschrieben ist. Wird die Reaktion mit dem Gemisch von Phosphorpentoxid und (C -C )Alkylsulfonsäure ausgeführt so erhält man neben der entsprechenden Verbindung II, worin R Wasserstoff ist, auch die analoge Verbindung II, worin R (C -C )Alkyl ist.The reaction is carried out as described above for the cyclization of compound II to compound I. If the reaction is carried out with the mixture of phosphorus pentoxide and (C -C )alkylsulfonic acid, in addition to the corresponding compound II, in which R is hydrogen, the analogous compound II, in which R is (C -C )alkyl, is obtained.
Die Uflt.sotzung, bei der von Verbindung III ausgegangen wird, kann ohne Isolierung der Zwischenverbindung II in situ bis zur Herstellung der Verbindung I geführt werden. Da bei manchen Verbindungen sich der Isochinolin- bzw. Thienopyridinring nur sehr schwer schließt, kann man, The reaction starting from compound III can be carried out in situ without isolating the intermediate II to produce compound I. Since in some compounds the isoquinoline or thienopyridine ring closes only with great difficulty,
falls erforderlich oder erwünscht, die während der Cyclisierungsreaktion sich bildende Zwischenverbindung der allgemeinen Formel II oder deren Tautomeres isolieren, die Base freisetzen und diese der zweiten Cyclisierungsreaktion unterwerfen. In diesem Fall arbeitet man in der ersten Stufe bevorzugt mit Phosphoroxychlorid unter gelindem Erwärmen. In der zweiten Stufe schließt man den Ring mit Phorphorpentachlorid, einem Gemisch aus Phosphoroxychlorid und Phorphorpentachlorid oder mit einem Methansulfonsäure-VPO-Gemisch.if necessary or desired, isolate the intermediate compound of general formula II or its tautomer formed during the cyclization reaction, release the base and subject it to the second cyclization reaction. In this case, the first step is preferably carried out with phosphorus oxychloride with gentle heating. In the second step, the ring is closed with phosphorus pentachloride, a mixture of phosphorus oxychloride and phosphorus pentachloride or with a methanesulfonic acid-VPO mixture.
Die Verbindungen der allgemeinen Formel III sind im wesentlichen bekannte Verbindungen und können nach an sich bekannten Verfahren hergestellt werden.The compounds of general formula III are essentially known compounds and can be prepared by processes known per se.
Verbindungen der Formel 1, worin R Wasserstoff ist, werden gegebenenfalls N-alkyliert. Für die N-Alkylierung eignen sich im Prinzip alle bekannten Alkylierungsmittel, soweit sie eine ausreichende Reaktivität besitzen, z.B. aktive Alkylester, wie Dialkylsulfat, Toluolsulfonsäure= alkylester oder Fluormethansulfonsäurealkylester. Die Reaktion erfolgt bei Temperaturen bis zum Siedepunkt des Reaktionsgemisches (Alkyl steht hier für (C -C) Alkyl).Compounds of formula 1 in which R is hydrogen are optionally N-alkylated. In principle, all known alkylating agents are suitable for N-alkylation, provided they have sufficient reactivity, e.g. active alkyl esters such as dialkyl sulfate, toluenesulfonic acid = alkyl ester or fluoromethanesulfonic acid alkyl ester. The reaction takes place at temperatures up to the boiling point of the reaction mixture (alkyl here stands for (C -C) alkyl).
Die N-Hydroxymethylierung erfolgt unter den Bedingungen der Aminoalkylierung nach Leuckart-Wallach (Ber. dtsch. Chem. Ges. IJi^ (188S) 2341) oder Eschweiler-Clarke (Teilheimer 2, (1948) Nr. 352; i (1950) Nr. 378). Im allgemeinen wird die Substanz mit einer z.B. 30%-igen Formalinlösung in Gegenwart von Ameisensäure bei Raumtemperatur behandelt.The N-hydroxymethylation is carried out under the conditions of aminoalkylation according to Leuckart-Wallach (Ber. dtsch. Chem. Ges. IJi^ (1885) 2341) or Eschweiler-Clarke (Teilheimer 2, (1948) No. 352; i (1950) No. 378). In general, the substance is treated with a 30% formalin solution in the presence of formic acid at room temperature.
Die Überführung der freien Base der allgemeinen Formel I in ihre Säureadditionssalze erfolgt in an sich bekannter Weise.The conversion of the free base of general formula I into its acid addition salts takes place in a manner known per se.
Zur Salzbildung geeignete Säuren sind beispielsweise Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Phosphorsäure, Salpetersäure, Essigsäure, Propionsäure, Buttersäure, Oxalsäure, Malonsäure, Bernsteinsäure, Maleinsäure, Fumarsäure, Milchsäure, Weinsäure, Zitronensäure Apfelsäure, Benzoesäure, Zimtsäure, Ascorbinsäure, Methansulfonsäure.Acids suitable for salt formation include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, butyric acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, malic acid, benzoic acid, cinnamic acid, ascorbic acid, methanesulfonic acid.
Die neuen Bis-(3,4-dihydro-l-pyridinyl)-methane der allgemeinen Formel I besitzen, wie eingangs erwähnt, sowohl, als Basen als auch in Form ihrer Salze wertvolle therapeutische Eigenschaften. Insbesondere weisen diese Substanzen eine deutliche cardioprotektive Wirkung auf, die wie folgt bestimmt wurde:As mentioned at the beginning, the new bis-(3,4-dihydro-l-pyridinyl)-methanes of the general formula I have valuable therapeutic properties both as bases and in the form of their salts. In particular, these substances have a significant cardioprotective effect, which was determined as follows:
Bekanntlich ist der myocardiale Ca(2+)-Gehalt ein Maß für die hypoxische bzw. durch toxische Catecholamindosen hervorgerufene Herzschädigung (Higgins et al., Mol. Cell. Cardiol. IjD, 427-438, 1984; Nakanishi et al., Am. J. Physiol. 242, 437-449, 1982; Fleckenstein, A. Vorträge der Erlanger Physiol. Tagung 1970, Edit. Keidel, Springer Verlag Berlin, Heidelberg, New York, 1971). Umgekehrt ist die Inhibition der hypoxischen oder Isoprenalin-bedingten myocardialen Calciumaufnähme ein Maß für die cardioprotektive Effektivität von Calciumantagonisten (Fleckenstein, s.o.), von Calmodulininhibitoren (Higgins) und anderen Pharmaka, z.B. Betaadrenolytika (Arndts, Arzneimittelforschung 2S_, 1279-1284, 1975). Die cardioprotektive Wirkung wurde an wachen Ratten nach subcutaner oder peroraler Wirkstoffabgabe anhand der von Arndts (s.o.) beschriebenen Methode festgestellt und die Wirkungsstärke der Testsubstanzen als H -Wert angegeben. Dieser Wert entspricht der Dosis, die die durch eine Gabe von 30 mg/kg s.c. Isoprenalin bedingte myocardiale Radiocalciumaufnähme zu 50 % hemmt.It is known that the myocardial Ca(2+) content is a measure of the cardiac damage caused by hypoxia or by toxic doses of catecholamines (Higgins et al., Mol. Cell. Cardiol. IjD, 427-438, 1984; Nakanishi et al., Am. J. Physiol. 242 , 437-449, 1982; Fleckenstein, A. Proceedings of the Erlanger Physiol. Conference 1970, Edit. Keidel, Springer Verlag Berlin, Heidelberg, New York, 1971). Conversely, the inhibition of hypoxic or isoprenaline-induced myocardial calcium uptake is a measure of the cardioprotective effectiveness of calcium antagonists (Fleckenstein, see above), of calmodulin inhibitors (Higgins) and other drugs, e.g. beta-adrenolytics (Arndts, Arzneimittelforschung 2S_, 1279-1284, 1975). The cardioprotective effect was determined in conscious rats after subcutaneous or oral administration of the active substance using the method described by Arndts (see above) and the potency of the test substances was given as the H value. This value corresponds to the dose that inhibits by 50% the myocardial radiocalcium uptake caused by an administration of 30 mg/kg sc isoprenaline.
Hier erwiesen sich die untersuchten neuen Verbindungen als bis zu fünfmal wirksamer als das bekannte Handelsprodukt Propranolol.Here, the new compounds investigated proved to be up to five times more effective than the well-known commercial product propranolol.
In vitro-Untersuchungen an der glatten Muskulatur (Aortenstreifen) haben ergeben, daß es sich bei den erfindungsgemäßen Verbindungen um Calciumantagonisten mit einem neuen Wirkungsmechanismus handelt:In vitro studies on smooth muscle (aortic strip) have shown that the compounds according to the invention are calcium antagonists with a new mechanism of action:
Calciumantagonisten hemmen den transmembranären Calciumioneneinstrom in die Zelle. Diese Hemmung betrifft den spannungsabhängigen (langsamen) Calciumkanal in der Zellmembran. Die Bestimmung transmembraner Calciumionenströme an Gewebestreifen unter Kaiiumdepolarisation nach der von van Breemen beschriebenen Methode weist Calciumantagonisten eindeutig nach (van Breemen et al., Chest. 7_8, 157 S - 165 S, 1980; van Breemen et al., Am J. Cardiol. 4_9, 507 - 510, 1982; Casteels et al. Pflügers Arch. 392, 139 - 145, 1981; Deth. und van Breemen, J. Membrane Biol. 3JD> 363 - 380, 1977).Calcium antagonists inhibit the transmembrane influx of calcium ions into the cell. This inhibition affects the voltage-dependent (slow) calcium channel in the cell membrane. The determination of transmembrane calcium ion currents on tissue strips under potassium depolarization according to the method described by van Breemen clearly detects calcium antagonists (van Breemen et al., Chest. 7_8, 157 p. - 165 p., 1980; van Breemen et al., Am J. Cardiol. 4_9, 507 - 510, 1982; Casteels et al. Pflügers Arch. 392 , 139 - 145, 1981; Deth. and van Breemen, J. Membrane Biol. 3JD> 363 - 380, 1977).
Aufgrund dieser Befunde kommen die Verbindungen der allgemeinen Formel I bzw. ihre Säureadditionssalze als Wirkstoffe für Arzneimittel zur Behandlung der koronaren Herzkrankheit und des akuten Myocardinfarktes in Frage.Based on these findings, the compounds of general formula I or their acid addition salts are suitable as active ingredients for drugs for the treatment of coronary heart disease and acute myocardial infarction.
Ein weiterer Gegenstand der Erfindung sind Arzneimittel, welche die Substanzen der allgemeinen Formel I sowie ihre Salze mit anorganischen oder organischen Säuren enthalten. Die Arzneimittel sind für orale oder parenterale Verabreichung geeignet. Als Arzneimittelformen dienen vorwiegend Tabletten, Dragees, Ampullen und Saftzubereitungen. Die Einzeldosis zu diesen Arzneimittelformen beträgt zwischen 1,0 und 200 mg, vorzugsweise 20 und 50 mg pro 75 kg Körpergewicht. Je nach der Schwere des Falles sind täglich im allgemeinen 1 bis Einzeldosen zu verabreichen.The invention also relates to medicaments which contain the substances of general formula I and their salts with inorganic or organic acids. The medicaments are suitable for oral or parenteral administration. The drug forms used are mainly tablets, dragees, ampoules and juice preparations. The individual dose for these drug forms is between 1.0 and 200 mg, preferably 20 and 50 mg per 75 kg of body weight. Depending on the severity of the case, 1 to 2 individual doses are generally administered daily.
Die folgenden Beispiele sollen die Erfindung näher erläutern:The following examples are intended to illustrate the invention in more detail:
l-(3,4-Dihydro-6,7-dimethoxy-isochinolin-l-yl)-l-(l,2,3,4-tetrahydro-6,7-dimethoxy-isochinolin-l-yliden)-pentan undl-(3,4-dihydro-6,7-dimethoxy-isoquinolin-l-yl)-l-(l,2,3,4-tetrahydro-6,7-dimethoxy-isoquinolin-l-ylidene)-pentane and
1-(3,4-Dihydro-6,7-dimethoxy-isochinolin-l-yl)-1-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-N-methyl-isochinolin-l-yliden)-pentan 1-(3,4-Dihydro-6,7-dimethoxy-isoquinolin-l-yl)-1-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-N-methyl-isoquinolin-l-ylidene)-pentane
4,9 g n-Butylmalonsäure-di-N-[2-(3,4-dimethoxy-phenyl)-ethyl]-amid werden in 20 ml eines Methansulfonsäure-P O -Gemisches (10 Gewichtsprozent P O -Anteil) 1-2 Stunden auf 1000C erhitzt. Nach beendeter Umsetzung (Dünnschichtchromatographie-Kontrolle) wird das Reaktionsgemisch auf Eis gegossen, mit gesättigter Sodalösung alkalisch gestellt und mit Methylenchlorid extrahiert. Die organische Phase wird mit Wasser gewaschen, über Natriumsulfat getrocknet, im Vakuum eingedampft und der Rückstand an Kieselgel (Eluent: Methylenchlorid: Methanol = 100:5, V:V) aufgetrennt. Dabei wird zuerst die N-&EEgr;-Verbindung eluiert.4.9 g of n-butylmalonic acid di-N-[2-(3,4-dimethoxy-phenyl)-ethyl]-amide are heated in 20 ml of a methanesulfonic acid-P O mixture (10 percent by weight PO content) at 100 ° C for 1-2 hours. After the reaction is complete (thin layer chromatography control), the reaction mixture is poured onto ice, made alkaline with saturated sodium carbonate solution and extracted with methylene chloride. The organic phase is washed with water, dried over sodium sulfate, evaporated in vacuo and the residue is separated on silica gel (eluent: methylene chloride: methanol = 100:5, V:V). The N-�EEgr; compound is eluted first.
N-H-Verbindung: Fp. = 158-159°C (Hydrochlorid)N-H compound: mp = 158-159°C (hydrochloride)
N-CH -Verbindung: Fp. = 136-137°C (Hydrochlorid)N-CH compound: mp = 136-137°C (hydrochloride)
l-(3,4-Dihydro-6,7-dimethoxy-isochinolin-l-yl)-l-(3,4-dihydro-6,7-dimethoxy-2-N-methyl-isochinolin-l-yliden)-pentan-hydrochlor idl-(3,4-dihydro-6,7-dimethoxy-isoquinolin-l-yl)-l-(3,4-dihydro-6,7-dimethoxy-2-N-methyl-isoquinolin-l-ylidene)-pentane hydrochloride
1 g des nach Beispiel l dargestellten
1-(3,4-Dihydro-6,7-dimethoxy-isochinolin-l-yl)-l-(1,2,3,4-tetrahydro-6,7-dimethoxy-isochinolin-l-yliden)-pentan
werden in 2 ml frisch destilliertem Dimethylsulfat 6 Stunden zum Sieden erhitzt. Nach der üblichen
Aufarbeitung wird an Kieselgel (Eluent: CH Cl : MeOH = 100:5, V:V) chromatographiert, das Hydrochlorid gebildet
und aus Ethanol/Ether kristallisiert.1 g of the product prepared according to Example 1
1-(3,4-Dihydro-6,7-dimethoxy-isoquinolin-l-yl)-l-(1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinolin-l-ylidene)-pentane is heated to boiling in 2 ml of freshly distilled dimethyl sulfate for 6 hours. After the usual
After work-up, the residue is chromatographed on silica gel (eluent: CHCl:MeOH = 100:5, V:V), the hydrochloride is formed and crystallized from ethanol/ether.
Das Produkt ist mit dem nach Beispiel 1 hergestellten
identisch.The product is the same as that prepared according to Example 1.
identical.
l-(3 , 4-Dihydro-6 ^-dimethoxy-isochinolin-l-yD-l-OM-dihydro-6,7-dimethoxy-1-N-hydroxymethyl-isochinolin-1-yliden)-ethan-hydrochlorid l-(3,4-Dihydro-6 ^-dimethoxy-isoquinolin-l-yD-l-OM-dihydro-6,7-dimethoxy-1-N-hydroxymethyl-isoquinolin-1-ylidene)-ethane hydrochloride
12 g 1-(3,4-Dihydro-6,7-dimethoxy-isochinolin-1-yl)-&Igr;&Ogr;
,4-dihydro-6,7-dimethoxy-isochinolin-l-yliden)-ethan
werden in einem Gemisch bestehend aus 20 ml 30 %iger
Formalinlösung und 10 ml Ameisensäure (98 %ig) 20 Stunden
bei Raumtemperatur stehengelassen. Es wird im
Wasserstrahlvakuum zur Trockne eingedampft, das
Umsetzungsprodukt in CH Cl aufgenommen, mit
verdünnter Sodalösung und nachfolgend mit Wasser
gewaschen, die organische Phase über Na SO
getrocknet, das Lösungsmittel im Vakuum abgezogen, der Rückstand in der eben ausreichenden Menge Ethanol
aufgenommen und unter Zugabe von etherischer Salzsäure als Hydrochlorid gefällt. Fp = 155°C12 g of 1-(3,4-dihydro-6,7-dimethoxy-isoquinolin-1-yl)-�IΩ,4-dihydro-6,7-dimethoxy-isoquinolin-l-ylidene)-ethane are dissolved in a mixture consisting of 20 ml of 30 %
Formalin solution and 10 ml formic acid (98 %) for 20 hours at room temperature.
Water jet vacuum evaporated to dryness, the
Reaction product taken up in CH Cl, with
diluted soda solution and then with water
washed, the organic phase over Na SO
dried, the solvent removed in vacuo, the residue in just sufficient amount of ethanol
and precipitated as hydrochloride with the addition of ethereal hydrochloric acid. Mp = 155°C
&agr;-(3,4-Dihydro-6,7-dimethoxy-isochinolin-l-yl)-l,2,3,4-tetrahydro-6,7-dimethoxy-l-benzyliden-isochinolin α-(3,4-dihydro-6,7-dimethoxy-isoquinolin-l-yl)-l,2,3,4-tetrahydro-6,7-dimethoxy-l-benzylidene-isoquinoline
4,9 g 1,2,3,4-Tetrahydro-6,7-dimethoxy-l-a -£2-(3,4-diemethoxyphenyl)-ethyl]-aminocarbonylj-benzyl-isochinolin werden in 20 ml frisch destilliertem Phosphoroxychlorid 4 Stunden zum Sieden erhitzt. Nach beendeter Umsetzung (Dünnschichtchromatographie-Kontrolle) wird überschüssiges POCl abdestilliert, der Rückstand zwischen CH Cl und verdünnter Sodalösung verteilt, die organische Phase wird mit Wasser gewaschen, über Na SO getrocknet und eingeengt. Der Rückstand wird an Kieselgel (Eluent: CH Cl :MeOH = 100:10, V:V) chromatographiert. Die rasch laufende gelbe Fraktion liefert &agr;-(3,4-Dihydro-6,7-dimethoxy-isochinolin-l-yl)-l,2,3,4-tetrahydro-6,7-dimethoxy-1-benzyl iden-2-N-phosphono- isochinolin (Fp. > 2700C (Hydrochlorid)), die nachfolgende rote Zone die N-H-Verbindung (Fp = 95-1000C), die im Titel angegeben ist.4.9 g of 1,2,3,4-tetrahydro-6,7-dimethoxy-la-[2-(3,4-di-methoxyphenyl)-ethyl]-aminocarbonylj-benzyl-isoquinoline are heated to boiling in 20 ml of freshly distilled phosphorus oxychloride for 4 hours. After the reaction is complete (thin layer chromatography check), excess POCl is distilled off, the residue is partitioned between CH Cl and dilute sodium carbonate solution, the organic phase is washed with water, dried over Na SO and concentrated. The residue is chromatographed on silica gel (eluent: CH Cl :MeOH = 100:10, V:V). The rapidly migrating yellow fraction yields α-(3,4-dihydro-6,7-dimethoxy-isoquinolin-l-yl)-l,2,3,4-tetrahydro-6,7-dimethoxy-1-benzylidene-2-N-phosphono-isoquinoline (m.p. > 270 0 C (hydrochloride)), the subsequent red zone the NH compound (m.p. = 95-100 0 C) which is indicated in the title.
(4,5-Dihydro-thieno[2,3-c]pyrid in-1-yl)-4,5,6,7-tetrahydrol-methyliden-thieno[2,3-c]pyrid in(4,5-Dihydro-thieno[2,3-c]pyridin-1-yl)-4,5,6,7-tetrahydrol-methylidene-thieno[2,3-c]pyridin
19 g Malonsäure-di-N-[2-(3-thieno-)ethyl]amid werden in 25 ml Phosphoroxychlorid 3 Stunden zum Sieden erhitzt. Sobald kein Ausgangsmaterial mehr nachweisbar ist, wird wie üblich aufgearbeitet, das Reaktionsprodukt an Al O neutral, Aktivitätsstufe III (Fa. Woelm) (EluenstCH Cl ) gereinigt und das Hydrochlorid gebildet. (Fp. = 233-235°C)19 g of malonic acid di-N-[2-(3-thieno-)ethyl]amide are heated to boiling in 25 ml of phosphorus oxychloride for 3 hours. As soon as no more starting material can be detected, the reaction product is processed as usual, the reaction product is purified on Al O neutral, activity level III (Woelm) (eluent CH Cl ) and the hydrochloride is formed. (Mp. = 233-235°C)
Beispiele erfindungsgemäßer Verbindungen werden in den folgenden Tabellen 1-3 zusammengefaßt.Examples of compounds according to the invention are summarized in the following Tables 1-3.
RiRi
Fp°C/SalzrormFp°C/Salt
CH3SO2NH CH3SO2NH
-0-CH3O -0- CH3O
-0 CH2--0 CH2 -
CH2- CH2 -
CH3O CH3O
CH3O CH3O
CH3O CH3O
CH3O CH3O
CH3O CH3O
CH3O CH3O
CH3O CH3O
CH3O CH3O
CH3SO, CH3SO ,
CH3O CH3O
CH3O CH3O
CH3O CH3O
CH3O CH3O
CH3O CH3O
CH3O CH3O
CH3O CH3O
CH3O CH3O
-0-CH3O -0- CH3O
-0--0-
H
HH
H
CH3 CH3
CHsCHs
CH3 CH3
n-CsHnn-CsHn
C2H5 C2H5
CeHsCeHs
CHsCHs
C2HsC 2 Hs
C2HsC 2 Hs
CH3CONHCH 3 COCH
CeHsCeHs
- (CH2)4-- ( CH2 )4-
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
HH
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H H H H H H H H H H H H H H H H H H HH H H H H H H H H H H H H H H H H H H
CH3 CH3
CH3 CH3
CH3 CH3
CH3 CH3
CH2OH CH2OH
CH3 CH3
CH3 CH3
CH3O CH3O
CH3O CH3O
CH3O CH3O
CH3O CH3O
CHsOCHsO
CH3O CH3O
CH3SO2O CH3SO2O
CH3O CH3O
HOHO
CH3O CH3O
CH3O CH3O
CH3O CH3O
CH3O CH3O
-0 CH2--0 CH2 -
-0 CH2--0 CH2 -
CH3O CH3O
-0 CH2--0 CH2 -
-0 CH2--0 CH2 -
CH3O CH3O
CH3SO2NH CH3SO2NH
CH3O CH3O
CH3O CH3O
CH3O CH3O
CH3O CH3O
HOHO
CH3O CH3O
CH3O CH3O
CH3O CH3O
CH3O CH3O
CH3O CH3O
CH3O
-0-
-0- CH3O
-0-
-0-
CH3O
-0— CH3O
-0—
CH:CH:
CH3O
—0-—0- CH3O
—0-—0-
CH3O
— 0- CH3O
— 0-
H H H H H H H H H H H H H H H H H H HH H H H H H H H H H H H H H H H H H H
H H H H H H H H H H H H H H H H H H HH H H H H H H H H H H H H H H H H H H
119/BS119/BS
233-238 (Z)/BS 136-137/C1233-238 (Z)/BS 136-137/C1
180/C1180/C1
177/BS177/BS
]82-186/BS]82-186/BS
138-140/BS138-140/BS
222-225/BS222-225/BS
155/C1155/C1
75-79(amorph)/BS75-79(amorphous)/BS
80 (amorph)/BS80 (amorphous)/BS
95-100/BS95-100/BS
156-158/C1156-158/C1
148-155/C1148-155/C1
177-179/C1177-179/C1
251 253/C1251 253/C1
251-253(Z)/C1251-253(Z)/C1
171-172/C1171-172/C1
191-195/BS191-195/BS
BS = Base
Cl = Chlorid
Z = ZersetzungBS = Base
Cl = chloride
Z = decomposition
Sa 1 &zgr; f&ogr; rmSa 1 &zgr;f&ogr; rm
Fp(0C)Fp( 0 C)
218-222218-222
239-235239-235
Sa 1 2 f&ogr; rmSa 1 2 f&ogr; rm
Fp(0C)Fp( 0 C)
162-172162-172
237-239237-239
250-253250-253
a) Drageesa) Coated tablets
1 Drageekern enthält:1 tablet core contains:
Wirkstoff der allgemeinen Formel I 30,0 mgActive ingredient of general formula I 30.0 mg
Milchzucker 100,0 mgLactose 100.0 mg
Maisstärke 75,0 mgCorn starch 75.0 mg
Gelatine 3,0 mgGelatin 3.0 mg
Magnesiumstearat 2,0 mgMagnesium stearate 2.0 mg
210,0 mg210.0mg
Die Mischung der Wirksubstanz mit Milchzucker und
Maisstärke wird mit einer 10%-igen wässerigen
Gelatinelösung durch ein Sieb mit 1 mm Maschenweite granuliert, bei 400C getrocknet und nochmals durch ein
Sieb gerieben. Das so erhaltene Granulat wird mit
Magnesiumstearat gemischt und verpreßt. Die so erhaltenen Kerne werden in üblicher Weise mit einer Hülle überzogen,
die mit Hilfe einer wässerigen Suspension von Zucker, Titandioxyd, Talkum und Gummi arabicum aufgebracht wird.
Die fertigen Dragees werden mit Bienenwachs poliert.The mixture of the active substance with lactose and
Corn starch is mixed with a 10% aqueous
Gelatin solution is granulated through a sieve with a mesh size of 1 mm, dried at 40 0 C and rubbed through a sieve again. The granulate thus obtained is mixed with
Magnesium stearate and pressed. The cores thus obtained are coated in the usual way with a shell, which is applied using an aqueous suspension of sugar, titanium dioxide, talcum and gum arabic. The finished dragees are polished with beeswax.
-2D--2D-
b) Tabletten b) Tablets
Wirkstoff der allgemeinen Formel I 30,0 mgActive ingredient of general formula I 30.0 mg
Milchzucker 100,0 mgLactose 100.0 mg
Maisstärke 70,0 mgCorn starch 70.0 mg
löslich Stärke 7,0 mgsoluble starch 7.0 mg
Magnesiumstearat 3,0 mgMagnesium stearate 3.0 mg
210,0 mg Herstellung 210.0 mg Production
Wirkstoff und Magnesiumstearat werden mit einer wässerigen Lösung der löslichen Stärke granuliert, das Granulat getrocknet und innig mit Milchzucker und Maisstärke vermischt. Das Gemisch wird sodann zu Tabletten von 210 mg Gewicht verpreßt.The active ingredient and magnesium stearate are granulated with an aqueous solution of the soluble starch, the granules are dried and thoroughly mixed with lactose and corn starch. The mixture is then pressed into tablets weighing 210 mg.
c) Kapseln c) Capsules
Wirkstoff gemäß Anspruch 1 20,0 mgActive ingredient according to claim 1 20.0 mg
Milchzucker 230,0 mgLactose 230.0 mg
Maisstärke 40,0 mgCorn starch 40.0 mg
Talk 10,0 mgTalc 10.0 mg
300,0 mg300.0mg
Wirkstoff, Milchzucker und Maisstärke werden zunächst in einem Mischer und dann in einer Zerkleinerungsmaschine vermengt. Das Gemisch wird nochmals in den Mischer gegeben, gründlich mit dem Talk vermengt und maschinell in Hartgelatinekapseln abgefüllt.The active ingredient, lactose and corn starch are first mixed in a mixer and then in a shredding machine. The mixture is put back into the mixer, thoroughly mixed with the talc and machine-filled into hard gelatin capsules.
In diesen Beispielen kann als Wirkstoff z.B.In these examples, the active ingredient can be e.g.
l-(3,4-Dihydroxy-6,7-dimethoxyisochinolin-l-yl)-l- (3,4-dihydro-6,7-dimethoxyisochinolin-l-yliden)-ethan verwendet werden.l-(3,4-Dihydroxy-6,7-dimethoxyisoquinolin-l-yl)-l-(3,4-dihydro-6,7-dimethoxyisoquinolin-l-ylidene)-ethane can be used.
Claims (17)
R in meta- beziehungsweise para-Position zu den
Fusionspunkten des Restes A beziehungsweise B stehen.11) A compound according to claim 10, wherein, when A and/or B is a benzo radical, the two substituents R and/or
R in meta- or para-position to the
Fusion points of the remainder A or B.
unbedenkliches Salz.13) A compound according to claim 1, namely 1-(3,4-dihydroxy-6,7-dimethoxyisoquinolin-l-yl)-l-(3,4-dihydro-6,7-dimethoxyisoquinolin-l-ylidene)-ethane or its physiologically
harmless salt.
eine Verbindung (II),14) Process for the preparation of a compound according to one of claims 1 to 13, characterized in that
a compound (II),
1 4(C -C )alkyl means,
1 4
Priority Applications (1)
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DE8718021U DE8718021U1 (en) | 1987-04-24 | 1987-04-24 | Condensed bis-(3,4-dihydro-1-pyridiny1)methanes, processes for their preparation and pharmaceutical compositions containing these compounds |
DE3813743A DE3813743A1 (en) | 1988-04-23 | 1988-04-23 | METHOD AND DEVICE FOR PRODUCING DIAPHRAGMS |
Publications (1)
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1987
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