NO872672L - PROCEDURE FOR PREPARING CONDENSED DIHYDROPYRIDINES. - Google Patents
PROCEDURE FOR PREPARING CONDENSED DIHYDROPYRIDINES.Info
- Publication number
- NO872672L NO872672L NO872672A NO872672A NO872672L NO 872672 L NO872672 L NO 872672L NO 872672 A NO872672 A NO 872672A NO 872672 A NO872672 A NO 872672A NO 872672 L NO872672 L NO 872672L
- Authority
- NO
- Norway
- Prior art keywords
- alkyl
- stands
- hydrogen
- phenyl
- hydroxy
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 9
- -1 alkyl radicals Chemical class 0.000 claims description 107
- 229910052739 hydrogen Inorganic materials 0.000 claims description 45
- 239000001257 hydrogen Substances 0.000 claims description 43
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 35
- 150000001875 compounds Chemical class 0.000 claims description 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 21
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 20
- 125000000623 heterocyclic group Chemical group 0.000 claims description 17
- 125000001424 substituent group Chemical group 0.000 claims description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 10
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 7
- 150000007513 acids Chemical class 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 6
- 101100294102 Caenorhabditis elegans nhr-2 gene Proteins 0.000 claims description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 5
- 235000011054 acetic acid Nutrition 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 5
- 125000002837 carbocyclic group Chemical group 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 5
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 5
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 5
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- WWYDYZMNFQIYPT-UHFFFAOYSA-N ru78191 Chemical class OC(=O)C(C(O)=O)C1=CC=CC=C1 WWYDYZMNFQIYPT-UHFFFAOYSA-N 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- VNZLQLYBRIOLFZ-UHFFFAOYSA-N 1-(2-methoxyphenyl)piperazine Chemical compound COC1=CC=CC=C1N1CCNCC1 VNZLQLYBRIOLFZ-UHFFFAOYSA-N 0.000 claims description 4
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 4
- IQXXEPZFOOTTBA-UHFFFAOYSA-N 1-benzylpiperazine Chemical compound C=1C=CC=CC=1CN1CCNCC1 IQXXEPZFOOTTBA-UHFFFAOYSA-N 0.000 claims description 4
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 4
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000004122 cyclic group Chemical group 0.000 claims description 4
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 4
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 claims description 4
- LIWAQLJGPBVORC-UHFFFAOYSA-N ethylmethylamine Chemical compound CCNC LIWAQLJGPBVORC-UHFFFAOYSA-N 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 150000003222 pyridines Chemical class 0.000 claims description 4
- 238000007363 ring formation reaction Methods 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 3
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 3
- 230000005961 cardioprotection Effects 0.000 claims description 3
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 3
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims description 3
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 2
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 2
- WNWVKZTYMQWFHE-UHFFFAOYSA-N 4-ethylmorpholine Chemical group [CH2]CN1CCOCC1 WNWVKZTYMQWFHE-UHFFFAOYSA-N 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 150000001735 carboxylic acids Chemical class 0.000 claims description 2
- 239000008139 complexing agent Substances 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 claims description 2
- 150000002475 indoles Chemical class 0.000 claims description 2
- RPAWVEMNAJPPEL-UHFFFAOYSA-N morpholine;thiomorpholine Chemical compound C1COCCN1.C1CSCCN1 RPAWVEMNAJPPEL-UHFFFAOYSA-N 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 14
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims 1
- KKSXPIZEAGEAMG-UHFFFAOYSA-N 3-amino-3-oxo-2-phenylpropanoic acid Chemical compound NC(=O)C(C(O)=O)C1=CC=CC=C1 KKSXPIZEAGEAMG-UHFFFAOYSA-N 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound 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 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 230000003293 cardioprotective effect Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-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
- 239000013543 active substance 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
- 238000000576 coating method Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000002156 mixing Methods 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
- 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
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229940127291 Calcium channel antagonist Drugs 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-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
- 206010021143 Hypoxia Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 2
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 2
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 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
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 230000001146 hypoxic effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 229960001317 isoprenaline Drugs 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000002107 myocardial effect Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- FYADHXFMURLYQI-UHFFFAOYSA-N 1,2,4-triazine Chemical compound C1=CN=NC=N1 FYADHXFMURLYQI-UHFFFAOYSA-N 0.000 description 1
- JIHQDMXYYFUGFV-UHFFFAOYSA-N 1,3,5-triazine Chemical compound C1=NC=NC=N1 JIHQDMXYYFUGFV-UHFFFAOYSA-N 0.000 description 1
- KVGZZAHHUNAVKZ-UHFFFAOYSA-N 1,4-Dioxin Chemical compound O1C=COC=C1 KVGZZAHHUNAVKZ-UHFFFAOYSA-N 0.000 description 1
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 1
- CPSUAFUQJBJMPO-UHFFFAOYSA-N 2-phenylpropanediamide Chemical compound NC(=O)C(C(N)=O)C1=CC=CC=C1 CPSUAFUQJBJMPO-UHFFFAOYSA-N 0.000 description 1
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 1
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-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
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical group OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 102000000584 Calmodulin Human genes 0.000 description 1
- 108010041952 Calmodulin Proteins 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical class OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- 244000126014 Valeriana officinalis Species 0.000 description 1
- 235000013832 Valeriana officinalis Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 150000004996 alkyl benzenes Chemical class 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 230000003185 calcium uptake Effects 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 229940096529 carboxypolymethylene Drugs 0.000 description 1
- 230000003683 cardiac damage Effects 0.000 description 1
- 230000003177 cardiotonic effect Effects 0.000 description 1
- 150000003943 catecholamines Chemical class 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940109275 cyclamate Drugs 0.000 description 1
- 150000001925 cycloalkenes Chemical class 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229960005150 glycerol Drugs 0.000 description 1
- 238000009499 grossing Methods 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- 125000004836 hexamethylene group Chemical class [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- PBMIETCUUSQZCG-UHFFFAOYSA-N n'-cyclohexylmethanediimine Chemical compound N=C=NC1CCCCC1 PBMIETCUUSQZCG-UHFFFAOYSA-N 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000004817 pentamethylene group Chemical class [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 229940075065 polyvinyl acetate Drugs 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000004805 propylene group Chemical class [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Natural products C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 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
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000003396 thiol group Chemical class [H]S* 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 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
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000016788 valerian Nutrition 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 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
- 239000000080 wetting agent Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/18—Aralkyl radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Toxicology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Hydrogenated Pyridines (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Description
Fra EP-A 37 934 er det kjent dihydroisokinoliner med den generelle formel Ia. Forbindelsene som der er nevnt har kardioton virkning og oppviser en kontraktilitets-økende og blod-trykkspåvirkende virkning. De er foreslått anvendt til forbedring av vevsgjennomblødningen og til oksygenforsyningen av vevet. From EP-A 37 934, dihydroisoquinolines of the general formula Ia are known. The compounds mentioned there have a cardiotonic effect and exhibit a contractility-increasing and blood-pressure-influencing effect. They have been proposed to be used to improve tissue perfusion and to supply oxygen to the tissue.
Det har nå overraskende vist seg at forbindelsene med den generelle formel I og II har en bemerkelsesverdig beskyttende virkning på hjertet og utgjør en fullstendig ny type av Ca-antagonistiske forbindelser. It has now surprisingly been shown that the compounds of the general formula I and II have a remarkable protective effect on the heart and constitute a completely new type of Ca-antagonistic compounds.
Oppfinnelsen angår således forbindelser med karbocykliskThe invention thus relates to compounds with carbocyclic
og heterocyklisk anellerte dihydropyridiner med formeland heterocyclic fused dihydropyridines of formula
samt deres tautomere former II, hvor følgende sammenfattende betegnelser står for cis- og trans-formene II' og II": as well as their tautomeric forms II, where the following summary designations stand for the cis- and trans-forms II' and II":
hvor X står for ORi ; NHR2 ; NR3 R4 where X stands for ORi; NHR2; NR3 R4
og and
Ri for hydrogen, Ci-C4-alkyl; Ci-C4-alkoksyalkylR 1 is hydrogen, C 1 -C 4 alkyl; C 1 -C 4 -Alkoxyalkyl
R2for hydrogen; C3-C6-alkenyl; C3-Ce-alkinyl; C3-C6-cykloalkyl; R 2 for hydrogen; C3-C6 alkenyl; C 3 -C 6 alkynyl; C3-C6 cycloalkyl;
C3-C6-cykloalkenyl; C3-C6 cycloalkenyl;
rettkjedet eller forgrenet Ci-C6-alkyl som eventuelt kan være substituert med én eller flere av de nevnte substituenter av gruppene a) til c), som kan være like eller forskjellige: a) halogen; cyano; hydroksy; merkapto; Ci- Ca-alkoksy; straight-chain or branched Ci-C6 alkyl which may optionally be substituted with one or more of the aforementioned substituents of the groups a) to c), which may be the same or different: a) halogen; cyano; hydroxy; mercapto; C 1 -C 6 alkoxy;
Ci-C4-alkyltio; amino; mono-Ci-C4-alkylamino; di-Ci-C4-alkylamino (hvor alkylradikalene kan være like eller forskjellige) C 1 -C 4 alkylthio; amino; mono-C 1 -C 4 alkylamino; di-Ci-C4-alkylamino (where the alkyl radicals may be the same or different)
b) fenyl; eventuelt substituert med én eller flere like eller forskjellige substituenter valgt blant gruppene b) phenyl; optionally substituted with one or more identical or different substituents selected from the groups
halogen, Ci-C4-alkoksy, hydroksy, merkapto, Ci-C4-alkyltio, Ci-C4-alkyl, amino, mono-Ci-C4-alkylamino, di-Ci-C4-alkylamino (hvor alkylrestene kan være like eller forskjellige), C2-C3-acylamino, C2-C3-acyloksy samt gruppen -0-(CH2)n-0 (med n = 1 eller 2) visinalt bundet til fenylsystemet halogen, C1-C4-alkyl, hydroxy, mercapto, C1-C4-alkylthio, C1-C4-alkyl, amino, mono-C1-C4-alkylamino, di-C1-C4-alkylamino (where the alkyl residues may be the same or different) , C2-C3-acylamino, C2-C3-acyloxy as well as the group -0-(CH2)n-0 (with n = 1 or 2) vicinally bonded to the phenyl system
c) en 5- eller 6-leddet mettet eller fullstendig eller delvis umettet monocyklisk heterocyklus med opp til 3 c) a 5- or 6-membered saturated or fully or partially unsaturated monocyclic heterocycle with up to 3
heteroatomer fra gruppen N, 0, S; samt som bicyklisk heterocyklus, indol (hvor de tidligere nevnte heterocykler kan være substituert med én eller flere Ci-C4-alkylgrupper, heteroatoms from the group N, O, S; as well as bicyclic heterocycle, indole (where the previously mentioned heterocycles may be substituted with one or more Ci-C4 alkyl groups,
C3-Ce-cykloalkyl; Cs- eller C6-cykloalkenyl; C 3 -C 6 cycloalkyl; C 5 - or C 6 -cycloalkenyl;
C2-C3-acyl; Ci-C4-alkylsulfonyl; eller fenylC2-C3 acyl; C 1 -C 4 alkylsulfonyl; or phenyl
(som på sin side kan ha opp til 3 substituenter som (which in turn can have up to 3 substituents such as
angitt under b)).stated under b)).
R3og R4uavhengig av hverandre, for Ci-C4-alkyl som eventuelt kan være fenylsubstituert, idet fenylsubstituenten på R 3 and R 4 independently of each other, for C 1 -C 4 alkyl which may optionally be phenyl substituted, the phenyl substituent on
sin side kan være substituert som angitt under b) eller its side may be substituted as indicated under b) or
R3og R4sammen med nitrogenatomet som de er bundet til, for en fullstendig eller delvis mettet heterocyklisk 5-eller 6-ring (som dessuten kan inneholde opp til ytterligere 2 heteroatomer fra gruppen N, 0, S), hvor R 3 and R 4 together with the nitrogen atom to which they are attached, for a fully or partially saturated heterocyclic 5- or 6-ring (which may also contain up to 2 further heteroatoms from the group N, 0, S), where
den således oppnådde heterocyklus kan være substituert med Ci-C4-alkyl, hydroksy eller (CføJp-Rs (med p = 0 the heterocycle thus obtained can be substituted with C1-C4-alkyl, hydroxy or (CføJp-Rs (with p = 0
eller 1)or 1)
og and
Rs for et fenylradikal, som eventuelt er substituert som Rs for a phenyl radical, which is optionally substituted as
angitt under b).specified under b).
A står for de anellerte ringsysterneneA stands for the annelated ringsisters
hvor where
Rs står for hydrogen; Ci-C4-alkyl; eller Ci-C4-alkoksy R6og R7som kan være like eller forskjellige, for hydrogen; R s stands for hydrogen; C 1 -C 4 alkyl; or C 1 -C 4 alkoxy R 6 and R 7 which may be the same or different, for hydrogen;
hydroksy; Ci-C4-alkyl; Ci-C4-alkoksy; amino; metansulfonylamino; hydroxy; C 1 -C 4 alkyl; C 1 -C 4 -Alkoxy; amino; methanesulfonylamino;
elleror
R6og R7sammen står for -0-(CH2)n-0- (med n = 1 eller 2)R6 and R7 together stand for -0-(CH2)n-0- (with n = 1 or 2)
R9for hydrogen; Ci-C4-alkylR 9 for hydrogen; C 1 -C 4 alkyl
Rio for hydrogen; eller 2-fenyl-2-etoksykarbonylacetyl samt deres salter med fysiologisk akseptable syrer, baser eller kompleksdannere for kardioproteksjon. Rio for hydrogen; or 2-phenyl-2-ethoxycarbonylacetyl as well as their salts with physiologically acceptable acids, bases or complexing agents for cardioprotection.
Foretrukket er anvendelsen av karbocyklisk og heterocyklisk anellerte dihydropyridiner med formel samt deres tautomere former med formel Preferred is the use of carbocyclic and heterocyclic fused dihydropyridines of formula as well as their tautomeric forms of formula
hvor X står for ORi NHR2 ; NR3 Ra where X stands for ORi NHR2; NR3 Ra
Ri for metyl eller etylRi for methyl or ethyl
R2for hydrogen, rettkjedet eller forgrenet usubstituert Ci - R2 for hydrogen, straight-chain or branched unsubstituted Ci -
Cs-alkyl; allyl; propargyl; C3-C6-cykloalkyl; 3-klorfenyl; C 6 -alkyl; allyl; propargyl; C3-C6 cycloalkyl; 3-chlorophenyl;
2-metyl-3-klorfenyl; eller Ci-C3-alkyl, som er enkelt-substituert med en av de senere nevnte substituenter innen gruppene d) til f); 2-methyl-3-chlorophenyl; or C1-C3-alkyl, which is single-substituted with one of the later-mentioned substituents within the groups d) to f);
d) cyano, hydroksy, metoksy, dimetylamino,d) cyano, hydroxy, methoxy, dimethylamino,
e) fenyl, 3,4-metylendioksyfenyl, 2,4-dimetoksyfenyl, 4-metoksyfenyl, 3,4-dimetoksyfenyl, 2-metoksyfenyl, 3-metoksy-4-hydroksyfenyl, 3,4,5-trimetoksyfenyl, 3-hydroksy-4-metoksyfenyl, f) morfolino, pyridin-2-yl, indol-3-yl, furan-2-yl, tiofen-2-yl, pyridin-3-yl, pyridin-4-yl, e) phenyl, 3,4-methylenedioxyphenyl, 2,4-dimethoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 2-methoxyphenyl, 3-methoxy-4-hydroxyphenyl, 3,4,5-trimethoxyphenyl, 3-hydroxy- 4-methoxyphenyl, f) morpholino, pyridin-2-yl, indol-3-yl, furan-2-yl, thiophen-2-yl, pyridin-3-yl, pyridin-4-yl,
R3og R4uavhengig av hverandre, for metyl; etyl; 3-cyanopropyl; R 3 and R 4 independently of each other, for methyl; ethyl; 3-cyanopropyl;
benzyl; eller 3,4,5-trimetoksyfenetyl ellerbenzyl; or 3,4,5-trimethoxyphenethyl or
R3og R4sammen med nitrogenatomet som de er bundet til, for morfolin; tiomorfolin; pyrrolidin; piperazin; 4-metylpiperazin; 4-benzylpiperazin; eller 4-(2-metoksyfenyl)piperazin; R 3 and R 4 together with the nitrogen atom to which they are attached, for morpholine; thiomorpholine; pyrrolidine; piperazine; 4-methylpiperazine; 4-benzylpiperazine; or 4-(2-methoxyphenyl)piperazine;
og and
A for de anellerte ringsystemene A for the annelated ring systems
hvor where
Re står for hydrogen eller metoksyRe stands for hydrogen or methoxy
R6for metoksy; hydroksy; hydrogen; amino; eller R6 for methoxy; hydroxy; hydrogen; amino; or
metansulfonylaminomethanesulfonylamino
R7for hydrogen; metoksy; eller hydroksy; R7 for hydrogen; methoxy; or hydroxy;
R9for metyl; R9 for methyl;
Rio for 2-fenyl-2-etoksykarbonylacetyl; eller hydrogen; samt deres salter med fysiologisk akseptable syrer for kardioproteksjon. Rio for 2-phenyl-2-ethoxycarbonylacetyl; or hydrogen; as well as their salts with physiologically acceptable acids for cardioprotection.
Oppfinnelsen angår således dihydroisokinoliner med formel The invention thus relates to dihydroisoquinolines of formula
dihydro-tieno[3,2-c]pyridiner med formel dihydro-pyrrolo[3,2-c]pyridiner med formel og dihydro-pyrido[3,4-b]indoler med formel dihydro-thieno[3,2-c]pyridines of formula dihydro-pyrrolo[3,2-c]pyridines of formula and dihydro-pyrido[3,4-b]indoles of formula
samt deres tautomere former Ila', Ilb', lic' og Ild' og deres E/Z-isomere former Ila", Ilb", Ile" og Ild". as well as their tautomeric forms Ila', Ilb', lic' and Ild' and their E/Z isomeric forms Ila", Ilb", Ile" and Ild".
Forbindelsene med formel Ia-Id er chirale. Oppfinnelsen omfatter også de to R- og S-enantiomere former av forbindelsen med formel I, hvor restene X, Re , R7, Rs , R9og Rio har de tidligere angitte betydninger. The compounds of formula Ia-Id are chiral. The invention also encompasses the two R- and S-enantiomeric forms of the compound of formula I, where the residues X, Re, R7, Rs, R9 and R1o have the previously indicated meanings.
Substansene som er ført opp i de etterfølgende tabeller 1 til 11 foreligger fortrinnsvis i den tautomere form I eller II. The substances listed in the subsequent tables 1 to 11 are preferably present in the tautomeric form I or II.
Den foretrukne tautomere form er betegnet med I, resp. II i kolonnen merket Struktur. The preferred tautomeric form is denoted by I, resp. II in the column labeled Structure.
Her skal anføres følgende forbindelse med I i den tautomere form I, resp. II. The following compound with I in the tautomeric form I, resp. II.
I definisjonene benyttet i teksten, kan de enkelte rester og grupper være like eller forskjellige, dvs. når en av de tidligere nevnte substituenter forekommer flere ganger i et bestemt molekyl, kan de respektive betydninger velges fritt innen rammen av definisjonen. In the definitions used in the text, the individual residues and groups can be the same or different, i.e. when one of the previously mentioned substituents occurs several times in a particular molecule, the respective meanings can be chosen freely within the framework of the definition.
Med alkyl menes Ci-Ce-alkyl og Ci-C4-alkylradikaler som selv kan være substituert, eller som alkylradikaler, utgjøre en del av en funksjonell gruppe så som alkoksy eller alkyltio. Alkylradikalene omfatter metyl-, etyl-, n-propyl-, isopropyl-, n-butyl-, sek-butyl-, isobutyl-, tert-butylradikaler, samt de forskjellige isomere pentyl- og heksylradikaler så som isopentyl-, neopentyl-, n-pentyl- og n-heksylradikalet. By alkyl is meant Ci-Ce-alkyl and Ci-C4-alkyl radicals which may themselves be substituted, or as alkyl radicals, form part of a functional group such as alkoxy or alkylthio. The alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl radicals, as well as the various isomeric pentyl and hexyl radicals such as isopentyl, neopentyl, n -pentyl and n-hexyl radicals.
De ovenfor angitte definisjoner gjelder således også når alkylradikalet selv er substituert og/eller selv utgjør en del av en alkoksyalkyl-, alkoksykarbonyl-, alkoksy-, alkyltio-, alkylsulfonyl-, monoalkylamino-, alkylmetyl-, alkyltiometyl-, dialkylaminogruppe, eller alkylradikalet er bundet som substituent til et aromatisk heterocyklisk eller karbocyklisk system. The above-mentioned definitions thus also apply when the alkyl radical itself is substituted and/or itself forms part of an alkoxyalkyl-, alkoxycarbonyl-, alkoxy-, alkylthio-, alkylsulfonyl-, monoalkylamino-, alkylmethyl-, alkylthiomethyl-, dialkylamino group, or the alkyl radical is bonded as a substituent to an aromatic heterocyclic or carbocyclic system.
Halogener er fluor, klor, brom og jod, fortrinnsvis fluor, klor og brom og dernest jod. Halogens are fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine and then iodine.
C3-C6-cykloalkyl er cyklopropan, cyklobutan, cyklopentan og cykloheksan. C3-C6 cycloalkyl is cyclopropane, cyclobutane, cyclopentane and cyclohexane.
Cs-C6-cykloalken er f.eks. cyklopenten, cykloheksen og cykloheksadien. Cs-C6 cycloalkene is e.g. cyclopentene, cyclohexene and cyclohexadiene.
C2- og C3-acylradikalet står for acetyl- og propionyl-radikalet. The C2 and C3 acyl radicals stand for the acetyl and propionyl radicals.
C3-C6-alkiner er de isomere heksiner, pentiner, butiner og propiner, fortrinnsvis propargyl. C3-C6 alkynes are the isomeric hexynes, pentynes, butynes and propynes, preferably propargyl.
C3-C6-alkener er de isomere heksener, pentener, butener og propener, fortrinnsvis allyl. C3-C6 alkenes are the isomeric hexenes, pentenes, butenes and propenes, preferably allyl.
Blant umettede heterocykler kan nevnes:Unsaturated heterocycles include:
furan, pyran, pyrrol, pyrazol, imidazol, pyridin, pyrazin, pyrimidin, pyridazin, tiofen, tiazol, oksazol, 1,2,4-triazol, 1,2,3-triazol, 1,2,4-triazin, 1,3,5-triazin, indol. furan, pyran, pyrrole, pyrazole, imidazole, pyridine, pyrazine, pyrimidine, pyridazine, thiophene, thiazole, oxazole, 1,2,4-triazole, 1,2,3-triazole, 1,2,4-triazine, 1, 3,5-triazine, indole.
Som 5- eller 6-leddede helt eller delvis mettede mono-cykliske heterocykler kan bl.a. nevnes: imidazolidin, pyrazolidin,, pyrrolidin, piperidin, piperazin, morfolin, tiomorfolin, tetrahydrofuran, tetrahydrotiofen, 1,4-dioksin, imidazolin, pyrazolin, pyrrolin, etc. As 5- or 6-membered fully or partially saturated mono-cyclic heterocycles, i.a. are mentioned: imidazolidine, pyrazolidine,, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, tetrahydrofuran, tetrahydrothiophene, 1,4-dioxin, imidazoline, pyrazoline, pyrroline, etc.
Forbindelsene med formel I resp. II, er baser og kan på vanlig måte overføres i forskjellige fysiologisk akseptable addukter (salter) med uorganiske eller organiske syrer samt med salt- og kompleksdannere. The compounds of formula I or II, are bases and can normally be transferred in various physiologically acceptable adducts (salts) with inorganic or organic acids as well as with salt and complex formers.
Syrer egnet for saltdannelsen er eksempelvis saltsyre, hydrogenbromidsyre, hydrogenjodidsyre, hydrogenfluoridsyre, svovelsyre, fosforsyre, salpetersyre, eddiksyre, propionsyre, smørsyre, kapronsyre, valeriansyre, oksalsyre, malonsyre, ravsyre, maleinsyre, fumarsyre, melkesyre, vinsyre, sitronsyre, eplesyre, benzosyre, p-hydroksybenzosyre, ftalsyre, kanelsyre, salicylsyre, askorbinsyre, metansulfonsyre og lignende. Acids suitable for salt formation are, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, butyric acid, caproic acid, valerian acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, malic acid, benzoic acid, p-hydroxybenzoic acid, phthalic acid, cinnamic acid, salicylic acid, ascorbic acid, methanesulfonic acid and the like.
Det har nå overraskende vist seg at forbindelser med formel I resp. II, har kardioprotektiv virkning. It has now surprisingly been shown that compounds of formula I resp. II, has a cardioprotective effect.
Den kardioprotektive virkning bestemmes som beskrevet i det følgende. The cardioprotective effect is determined as described below.
Som kjent er myokardiets Ca<+2->innhold et mål for den hypoksiske hjerteskade som også kan forårsakes av toksiske katekolamindoser (Higgins et al., Mol. Cell. Cardiol. 1JD: 427-438, 1984; Nakanishi et al., Am. J. Physiol. 242, 437-449, As is known, the myocardial Ca<+2-> content is a measure of the hypoxic heart damage which can also be caused by toxic catecholamine doses (Higgins et al., Mol. Cell. Cardiol. 1JD: 427-438, 1984; Nakanishi et al., Am . J. Physiol. 242, 437-449,
1982; Fleckenstein, A., Vortråge der Erlanger Physiol. Tagung 1970, Ed. Keidel, Springer Verlag Berlin, Heidelberg, New York, 1971). Omvendt er hemmingen av det hypoksiske eller isoprenalin-betingede kalsiumopptak av myokardiet et mål for den kardioprotektive effektivitet av kalsiumantagonister (Fleckenstein, 1982; Fleckenstein, A., Vortråge der Erlanger Physiol. Tagung 1970, Ed. Keidel, Springer Verlag Berlin, Heidelberg, New York, 1971). Conversely, the inhibition of hypoxic or isoprenaline-induced calcium uptake by the myocardium is a measure of the cardioprotective effectiveness of calcium antagonists (Fleckenstein,
se ovenfor), av calmodulin-hemmere (Higgins) og andre farmaka, f. eks. (3-adrenoly tika (Arndts, Arzneimittelf orschung 25_: 1279-1284, 1975). see above), of calmodulin inhibitors (Higgins) and other pharmaceuticals, e.g. (3-adrenolysis (Arndts, Arzneimittelf orschung 25_: 1279-1284, 1975).
Den kardioprotektive virkning ble fastslått på bevisste rotter etter subkutan eller peroral administrasjon av virkestoff etter fremgangsmåten beskrevet av Arndts (se ovenfor), og testsubstansenes effekt angitt som Hao-verdi. Denne verdi tilsvarer den dose som gir en 50% hemming av myokardiets opptak av radioaktivt kalsium etter administrasjon av 30 mg/kg s.c. isoprenalin. The cardioprotective effect was determined in conscious rats after subcutaneous or oral administration of the active substance according to the method described by Arndts (see above), and the effect of the test substances indicated as Hao value. This value corresponds to the dose which produces a 50% inhibition of the myocardial uptake of radioactive calcium after administration of 30 mg/kg s.c. isoprenaline.
Herunder har de undersøkte nye forbindelsene vist seg virksomme. In vitro-undersøkelser på glatt muskulatur (aorta-strimler; C. van Breemen, P. Aarenson, R. Lautzen heiser, K. Meisheri, Chest 78: 157S-165S (1980); R. Casteels og G. Droogman, J. Physio. 317: 263-279 (1981) har vist at det her er tale om kalsiumantagonister med en ny virkningsmekanisme. Below, the investigated new compounds have proven to be effective. In vitro studies on smooth muscle (aortic strips; C. van Breemen, P. Aarenson, R. Lautzen heiser, K. Meisheri, Chest 78: 157S-165S (1980); R. Casteels and G. Droogman, J. Physio. 317: 263-279 (1981) has shown that these are calcium antagonists with a new mechanism of action.
Ut fra disse funn er forbindelser med den generelle formel I, resp. II, og deres salter med syrer, baser eller kompleksdannere, verdifulle virkestoff i legemidler med kardioprotektiv virkning og kan blant annet benyttes til behandling av hjerte-infarkt og i profylaksen og terapien ved ischemiske hjerte-sykdommer . Based on these findings, compounds with the general formula I, resp. II.
Egnede administrasjonsformer er f.eks. tabletter, kapsler, stikkpiller, oppløsninger, safter, emulsjoner, aerosoler og dispergerbare pulvere. Passende tabletter kan eksempelvis oppnås ved å blande virkestoff(ene) med kjente hjelpestoffer som f.eks. inerte fortynningsmidler som kalsiumkarbonat, kalsium-fosfat eller melkesukker, sprengmidler som maisstivelse eller alginsyre, bindemidler som stivelse eller gelatin, glattemidler som magnesiumstearat eller talk og/eller midler for å oppnå depotvirkninger så som karboksypolymetylen, karboksymetyl-cellulose, celluloseacetatftalat eller polyvinylacetat. Tablettene kan også bestå av flere lag. Tilsvarende kan drasjeér fremstilles ved overtrekking av kjerner, oppnådd på tilsvarende måte som tablettene, med vanlige midler som inngår i drasjeéovertrekk, f.eks. kollidin eller skjell-lakk, gummi arabicum, talk, titandioksyd eller sukker. For å oppnå en depotvirkning eller for å hindre uforlikelighet, kan kjernen også bestå av flere lag. Likeledes kan drasjeringen også bestå av flere lag for å oppnå en depotvirkning, idet hjelpestoffene omtalt i forbindelse med tablettene benyttes. Suitable forms of administration are e.g. tablets, capsules, suppositories, solutions, juices, emulsions, aerosols and dispersible powders. Suitable tablets can, for example, be obtained by mixing the active substance(s) with known excipients such as e.g. inert diluents such as calcium carbonate, calcium phosphate or milk sugar, disintegrants such as corn starch or alginic acid, binding agents such as starch or gelatin, smoothing agents such as magnesium stearate or talc and/or agents to achieve depot effects such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets can also consist of several layers. Correspondingly, dragées can be produced by coating cores, obtained in a similar way to the tablets, with common agents included in dragée coatings, e.g. collidine or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve a depository effect or to prevent incompatibility, the core can also consist of several layers. Likewise, the coating can also consist of several layers to achieve a depot effect, as the excipients mentioned in connection with the tablets are used.
Safter av virkestoffet fremstillet i henhold til oppfinnelsen, resp. virkestoffkombinasjoner, kan i tillegg tilsettes et søtningsmiddel som sakkarin, cyklamat, glycerol eller sukker så vel som smaksforbedrende midler, f.eks. aromastoff som vanillin eller appelsinekstrakt. De kan dessuten inneholde suspenderingshjelpestoffer eller fortykningsmidler som natriumkarboksymetylcellulose, fuktemidler, eksempelvis kondensasjonsprodukter av fettalkoholer med etylenoksyd, eller konserveringsmidler som p-hydroksybenzoat. Juices of the active substance produced according to the invention, resp. active ingredient combinations, a sweetener such as saccharin, cyclamate, glycerol or sugar can also be added as well as taste-enhancing agents, e.g. flavoring agent such as vanillin or orange extract. They may also contain suspending aids or thickeners such as sodium carboxymethyl cellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoate.
Injeksjonsoppløsninger fremstilles på vanlig måte, f.eks. under tilsetning av konserveringsmidler, som p-hydroksybenzoater eller stabilisatorer som alkalisalter av etylendiamintetra-eddiksyre, og påfylles injeksjonsflasker eller ampuller. Injection solutions are prepared in the usual way, e.g. with the addition of preservatives, such as p-hydroxybenzoates or stabilizers such as alkali salts of ethylenediaminetetraacetic acid, and are filled into injection bottles or ampoules.
Kapsler som inneholder ett eller flere virkestoff resp. virkestoffkombinasjoner, kan for eksempel fremstilles ved at virkestoffet blandes med inerte bæremidler som melkesukker eller sorbitt, og innkapsles i gelatinkapsler. Capsules containing one or more active ingredients or active ingredient combinations, for example, can be prepared by mixing the active ingredient with inert carriers such as milk sugar or sorbitol, and encapsulating in gelatin capsules.
Egnede stikkpiller lar seg eksempelvis fremstille ved blanding av bæremidler for formålet, f.eks. nøytralfett eller polyetylenglykol eller derivater derav. Suitable suppositories can, for example, be produced by mixing carriers for the purpose, e.g. neutral fat or polyethylene glycol or derivatives thereof.
Forbindelsene med formel Ib, Ic og Id samt deres tautomere former Ilb", Ilb", lic', lic", Ild' og Ild" er nye. Tallrike forbindelser med formel Ia samt deres tautomere former Ia' og Ia" (som f.eks. de hvor X = ORi) er likeledes nye. The compounds of formula Ib, Ic and Id as well as their tautomeric forms Ilb", Ilb", lic', lic", Ild' and Ild" are new. Numerous compounds of formula Ia as well as their tautomeric forms Ia' and Ia" (such as those where X = ORi) are also novel.
Oppfinnelsen angår således også de nye forbindelser med formel The invention thus also relates to the new compounds of formula
hvor A og X er som tidligere angitt, med den reservasjon at forbindelser med formel Ia ikke innbefattes når where A and X are as previously indicated, with the reservation that compounds of formula Ia are not included when
Re og R? står for OCH3 , Ra for hydrogen ogR and R? stands for OCH3, Ra for hydrogen and
i) R2står for indol-3-yletyl; morfolin; pyridin-3-yl; 2-metyl-4-metoksyfenetyl; 4-metoksyfenetyl; fenetyl; i) R2 stands for indol-3-ylethyl; morpholine; pyridin-3-yl; 2-methyl-4-methoxyphenethyl; 4-methoxyphenethyl; phenethyl;
cykloheksyl; 3,4-metylendioksyfenyl; n-propyl; n-butyl; allyl; propargyl; metyl; etyl; 2-hydroksyetyl; cyclohexyl; 3,4-methylenedioxyphenyl; n-propyl; n-butyl; allyl; propargyl; methyl; ethyl; 2-hydroxyethyl;
2-metoksyetyl; 3-metoksypropyl; 2-metylpropyl; 3- 2-methoxyethyl; 3-methoxypropyl; 2-methylpropyl; 3-
dimetylaminopropyl; 2-metoksyfenetyl; 3,4-dimetoksy-fenetyl; 2-(morfolin-4-yl)etyl; furan-3-ylmetyl; dimethylaminopropyl; 2-methoxyphenethyl; 3,4-dimethoxyphenethyl; 2-(morpholin-4-yl)ethyl; furan-3-ylmethyl;
cyklopropyl; isopropyl; tert-butyl; n-pentyl; 1-metylpropyl; 3-metylbutyl; 2-hydroksypropyl; 2-dimetylaminoetyl; 2-(pyridin-2-yl)etyl; 2,4-dimetoksy-fenetyl; cyclopropyl; isopropyl; tert-butyl; n-pentyl; 1-methylpropyl; 3-methylbutyl; 2-hydroxypropyl; 2-dimethylaminoethyl; 2-(pyridin-2-yl)ethyl; 2,4-dimethoxyphenethyl;
elleror
ii) R3og Ra sammen med nitrogenatomet som de er bundet til, ii) R 3 and Ra together with the nitrogen atom to which they are attached,
står for dietylamino; dimetylamino; pyrrolidin; 4-metylpiperazin; 4-benzylpiperazin; tiomorfolin; 4-(2-metoksyfenyl)piperazin eller di(3,4,5-trimetoksyfenetyl)amino; stands for diethylamino; dimethylamino; pyrrolidine; 4-methylpiperazine; 4-benzylpiperazine; thiomorpholine; 4-(2-methoxyphenyl)piperazine or di(3,4,5-trimethoxyphenethyl)amino;
elleror
når R6står for metoksy og R7for OH og Re for hydrogen og i) R2står for pyridin-3-yl; fenetyl; n-butyl; allyl; 2-metylpropyl;2-(4-morfoliny1)etyl; 2-(2-pyridiny1)etyl; when R6 stands for methoxy and R7 for OH and Re for hydrogen and i) R2 stands for pyridin-3-yl; phenethyl; n-butyl; allyl; 2-methylpropyl; 2-(4-morpholinyl)ethyl; 2-(2-pyridinyl)ethyl;
3-klorfenyl; 4-hydroksy-3-metoksyfenetyl; isopropyl; 3-chlorophenyl; 4-hydroxy-3-methoxyphenethyl; isopropyl;
n-pentyl; 3-klor-2-metylfenyl; eller pyridin-2-yl eller n-pentyl; 3-chloro-2-methylphenyl; or pyridin-2-yl or
ii) R3og R4sammen med nitrogenatomet som de er bundet til, ii) R3 and R4 together with the nitrogen atom to which they are attached,
står for morfolin eller for N-benzyl-N-2-cyanoetylstands for morpholine or for N-benzyl-N-2-cyanoethyl
elleror
når R6står for hydroksy, R7for metoksy og Re for hydrogen ii) R3og R4sammen står for etyl when R6 stands for hydroxy, R7 for methoxy and Re for hydrogen ii) R3 and R4 together stand for ethyl
elleror
når R6 , R7og Rs står for metoksywhen R 6 , R 7 and R s stand for methoxy
i) R2står for benzyl; 2,3,4-trimetoksyfenetyl; i) R 2 is benzyl; 2,3,4-trimethoxyphenethyl;
eller pyridinyl-4or pyridinyl-4
elleror
ii) R3og Ra sammen med nitrogenatomet som de er bundet til, ii) R 3 and Ra together with the nitrogen atom to which they are attached,
står for metyletylaminstands for methylethylamine
elleror
når Re og R7sammen står for -0-CH2-0- og Re for Hwhen Re and R7 together stand for -0-CH2-0- and Re for H
i) R2står for 2-(morfolin-4-yl)etyl; 2-( 3-isokinolinyl)etyl; i) R2 is 2-(morpholin-4-yl)ethyl; 2-(3-isoquinolinyl)ethyl;
eller 2-(3,4-metylendioksyfenyl)etylor 2-(3,4-methylenedioxyphenyl)ethyl
ii) R3og Ra sammen med nitrogenatomet som de er bundet til, ii) R 3 and Ra together with the nitrogen atom to which they are attached,
står for morfolin; eller pyrrolidinstands for morpholine; or pyrrolidine
elleror
når R6står for metoksy, R7og Re for H,when R6 stands for methoxy, R7 and Re for H,
i) R2står for benzyl; 3-metoksy-fenetyl; metyl eller etyl eller i) R 2 is benzyl; 3-methoxy-phenethyl; methyl or ethyl or
ii) R3står for metyl og R4for etyl.ii) R3 stands for methyl and R4 for ethyl.
Forbindelsene med formel I eller II kan fremstillesThe compounds of formula I or II can be prepared
a) analogt med fremgangsmåten fra EP-A 00 37 934 ved cyklisering av et fenylmalonsyrediamid med den generelle formel a) analogous to the method from EP-A 00 37 934 by cyclization of a phenylmalonic acid diamide with the general formula
III, hvor A og X er som tidligere definertIII, where A and X are as previously defined
i nærvær av et kondensasjonsmiddel in the presence of a condensing agent
elleror
b) ved å gå ut fra karbonsyrer eller karbonsyrehalogenider med formel IV, hvor A er som tidligere definert og Y står for OH eller halogen, ved omsetning med alkoholer resp. aminer, med den generelle formel VI, hvor X er som tidligere definert b) by starting from carboxylic acids or carboxylic acid halides with formula IV, where A is as previously defined and Y stands for OH or halogen, by reaction with alcohols or amines, of the general formula VI, where X is as previously defined
i nærvær av et egnet kondensasjonsmiddel. in the presence of a suitable condensing agent.
Egnede kondensasjonsmidler for fremgangsmåte a) er en lang rekke Lewis-syrer, som f.eks. fosforoksyklorid, bortrifluorid, tinntetraklorid eller titantetraklorid eller sterke mineralsyrer som svovelsyre, fluorsulfonsyrer, hydrogenfluoridsyre eller polyfosforsyre. De anvendes vanligvis i overskudd. Fosforoksyklorid foretrekkes. Suitable condensing agents for method a) are a wide range of Lewis acids, such as e.g. phosphorus oxychloride, boron trifluoride, tin tetrachloride or titanium tetrachloride or strong mineral acids such as sulfuric acid, fluorosulfonic acids, hydrofluoric acid or polyphosphoric acid. They are usually used in excess. Phosphorus oxychloride is preferred.
Cykliseringsreaksjonen kan utføres med eller uten opp-løsningsmiddel. Alle inerte oppløsningsmidler med tilstrekkelig løselighet for reaktantene og tilstrekkelig høyt kokepunkt, kan benyttes. Eksempler er benzen, alkylbenzener, klorbenzen, dekalin, kloroform, metylenklorid, acetonitril og lignende. En fremgangsmåtevariant består i at kondensasjonsmidlet, eksempelvis fosforoksyklorid, selv benyttes som oppløsningsmiddel. The cyclization reaction can be carried out with or without a solvent. All inert solvents with sufficient solubility for the reactants and a sufficiently high boiling point can be used. Examples are benzene, alkylbenzenes, chlorobenzene, decalin, chloroform, methylene chloride, acetonitrile and the like. A method variant consists in the condensing agent, for example phosphorus oxychloride, itself being used as a solvent.
For reaksjonstemperaturen gjelder ingen spesielle betingelser. Omsetningen i henhold til oppfinnelsen kan utføres innenfor et stort temperaturområde, fortrinnsvis under svak eller sterkere oppvarming helt opp til oppløsningsmidlets kokepunkt. Forestrings- resp. amideringsreaksjonen b) kan prinsipielt foretas under de samme betingelsene som reaksjon a). Som kondensasjonsmidler kan ytterligere nevnes karbodiimider som cykloheksylkarbodiimid eller karbonyldiimidazol. No special conditions apply to the reaction temperature. The reaction according to the invention can be carried out within a large temperature range, preferably under weak or stronger heating right up to the boiling point of the solvent. Esterification resp. the amidation reaction b) can in principle be carried out under the same conditions as reaction a). Carbodiimides such as cyclohexylcarbodiimide or carbonyldiimidazole can also be mentioned as condensation agents.
Fenylmalonsyrene og dihydropyridinyl-eddiksyrene medThe phenylmalonic acids and the dihydropyridinyl acetic acids with
formel IV som tjener som utgangsforbindelser ved begge fremgangsmåter, er likeledes nye forbindelser og utgjør verdifulle mellomtrinn for syntesen av produktene I resp. II. formula IV, which serve as starting compounds in both methods, are likewise new compounds and constitute valuable intermediate steps for the synthesis of the products I resp. II.
Oppfinnelsen angår således også fenylmalonsyrer med formel The invention thus also relates to phenylmalonic acids with formula
hvor A og X er som tidligere definert med det forbehold at kombinasjonen Re = R7= OCH3 , Re = H, X = NH-CH2 CH3 , N(CH2CH3)2og Re = OCH3 , R? = Re = H, X = N(CH3)2 ikke er innbefattet. where A and X are as previously defined with the proviso that the combination Re = R7= OCH3 , Re = H, X = NH-CH2 CH3 , N(CH2CH3)2 and Re = OCH3 , R? = Re = H, X = N(CH3)2 are not included.
Videre angår oppfinnelsen dihydropyridinyleddiksyrer med formel samt deres tautomere former Furthermore, the invention relates to dihydropyridinyl acetic acids of formula and their tautomeric forms
hvor Y står for OH eller halogen, fortrinnsvis for fluor, klor eller brom, og A er som tidligere definert. where Y stands for OH or halogen, preferably for fluorine, chlorine or bromine, and A is as previously defined.
Fenylmalonsyrene med formel III kan fremstilles analogt med de fremgangsmåter som er kjent fra EP-A 00 37 934. The phenylmalonic acids of formula III can be prepared analogously to the methods known from EP-A 00 37 934.
Dihydropyridinyleddiksyrer med formel IV, resp. V, kan fremstilles analogt med den generelle fremgangsmåte a) ved cyklisering av tilsvarende substituerte fenylmalonsyrer. Dihydropyridinyl acetic acids of formula IV, resp. V, can be prepared analogously to the general procedure a) by cyclization of correspondingly substituted phenylmalonic acids.
Eksempel 1 Example 1
1- [benzyl-a-(4-metyl-piperazin-l-yl-karbonyl]-3,4-dihydro-5, 6, 7- trimetoksy- isokinolin- hydroklorid 1- [Benzyl-α-(4-methyl-piperazin-1-yl-carbonyl]-3,4-dihydro-5, 6, 7- trimethoxy- isoquinoline hydrochloride
37,8 g a-(4-metylpiperazin-l-yl)karbonyl)-fenyleddiksyre-2- [(3,4,5-trimetoksyfenyl)etyl]amid ble oppløst i 120 ml acetonitril og tilsatt 18 ml fosforoksyklorid. Reaksjons-blandingen ble kokt under tilbakeløpskjøling i 2 timer og ble 37.8 g of α-(4-methylpiperazin-1-yl)carbonyl)-phenylacetic acid-2-[(3,4,5-trimethoxyphenyl)ethyl]amide was dissolved in 120 ml of acetonitrile and 18 ml of phosphorus oxychloride was added. The reaction mixture was boiled under reflux for 2 hours and was
deretter inndampet, hvorpå residuet ble tatt opp i 200 ml metylenklorid og gjort alkalisk ved innrøring i en isvann-kaliumkarbonatoppløsning. Etter den vanlige opparbeidning - utristing med metylenklorid, tørking av den organiske fase over Na2 SCm , avdampning av oppløsningsmidlet, etc, ble produktet renset over en kiselgelsøyle (CH2Cl2/MeOH = 100/1 100/2. Den frie base av tittelforbindelsen ble derved isolert. then evaporated, after which the residue was taken up in 200 ml of methylene chloride and made alkaline by stirring in an ice-water potassium carbonate solution. After the usual work-up - shaking off with methylene chloride, drying the organic phase over Na2 SCm , evaporation of the solvent, etc, the product was purified over a silica gel column (CH2Cl2/MeOH = 100/1 100/2. The free base of the title compound was thereby isolated .
For fremstilling av hydrokloridet ble basen oppløst i minst mulig etanol og tilsatt etanolisk saltsyre. Hydrokloridet ble brakt til krystallisasjon ved dråpevis tilsetning av abs. eter og petroleter, kp. 40-80° (1:1). To prepare the hydrochloride, the base was dissolved in as little ethanol as possible and ethanolic hydrochloric acid was added. The hydrochloride was brought to crystallization by dropwise addition of abs. ether and petroleum ether, bp. 40-80° (1:1).
Det ble isolert 16,5 g av tittelforbindelsen som krystaller med smp. 233° . 16.5 g of the title compound were isolated as crystals with m.p. 233°.
PA analog måte kan følgende forbindelser fremstilles: In an analogous way, the following compounds can be prepared:
Claims (11)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO901627A NO170486C (en) | 1986-06-26 | 1990-04-10 | ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE DIHYDRO-PYRROLO (3,2-C) PYRIDINES |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19863621413 DE3621413A1 (en) | 1986-06-26 | 1986-06-26 | USE OF CARBOCYCLIC AND HETEROCYCLICALLY FURNISHED DIHYDROPYRIDINE AS A CARDIOPROTECTIVE AGENT AND NEW HETEROCYCLIC AND CARBOCYCLICALLY FURNISHED DIHYDROPYRIDINE, METHOD FOR THE PRODUCTION THEREOF AND ITS ADDITIONAL PRODUCTS |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NO872672D0 NO872672D0 (en) | 1987-06-25 |
| NO872672L true NO872672L (en) | 1987-12-28 |
Family
ID=6303756
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO872672A NO872672L (en) | 1986-06-26 | 1987-06-25 | PROCEDURE FOR PREPARING CONDENSED DIHYDROPYRIDINES. |
Country Status (18)
| Country | Link |
|---|---|
| EP (1) | EP0251194B1 (en) |
| JP (1) | JPS63258458A (en) |
| KR (2) | KR890000480A (en) |
| AU (1) | AU598558B2 (en) |
| DD (1) | DD264429A5 (en) |
| DE (2) | DE3621413A1 (en) |
| DK (1) | DK323887A (en) |
| ES (1) | ES2053471T3 (en) |
| FI (1) | FI872827A (en) |
| GR (1) | GR3007545T3 (en) |
| HU (1) | HU203752B (en) |
| IE (1) | IE59546B1 (en) |
| IL (1) | IL82995A0 (en) |
| NO (1) | NO872672L (en) |
| PL (1) | PL159840B1 (en) |
| PT (1) | PT85169B (en) |
| YU (1) | YU46216B (en) |
| ZA (1) | ZA874587B (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2623810B2 (en) * | 1987-02-17 | 1992-01-24 | Sanofi Sa | ALPHA SALTS- (TETRAHYDRO-4,5,6,7 THIENO (3,2-C) PYRIDYL-5) (2-CHLORO-PHENYL) -THETHYL ACETATE DEXTROGYRE AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
| IL86131A0 (en) * | 1987-04-24 | 1988-11-15 | Boehringer Ingelheim Kg | Benzo-and thieno-3,4-dihydropyridine derivatives,their preparation and pharmaceutical compositions containing them |
| DE3827727A1 (en) * | 1988-08-16 | 1990-02-22 | Boehringer Ingelheim Kg | ANALYZED TETRAHYDROPYRIDINE IGNESE DERIVATIVES, METHOD FOR THE PRODUCTION AND USE OF SUCH CONNECTIONS FOR CARDIRO PROTECTION |
| GB8921304D0 (en) * | 1989-09-20 | 1989-11-08 | Wyeth John & Brother Ltd | New method of treatment and heterocyclic compounds used therein |
| DE9017900U1 (en) | 1990-12-22 | 1993-01-28 | Boehringer Ingelheim Kg, 55218 Ingelheim | 3,4-Dihydro-1-benzyl-6,7-dimethoxy-α-[di-2-(2,3,4-trimethoxyphenyl)ethyl] aminocarbonyl-isoquinoline |
| KR100291706B1 (en) * | 1992-06-22 | 2001-10-24 | 베링거 인겔하임 카게 | Closed dihydropyridine, preparation method thereof and pharmaceutical composition comprising the same |
| CN1056832C (en) * | 1992-06-22 | 2000-09-27 | 贝林格尔·英格海姆公司 | Carbocyclic and heterocyclic annelleted dihydropyridine and application of same in preparation of pharmaceutical |
| DE4343683A1 (en) * | 1993-12-21 | 1995-06-22 | Boehringer Ingelheim Kg | Anellated dihydropyridines and their use for the preparation of pharmaceutical preparations |
| FR2724384B1 (en) * | 1994-09-14 | 1999-04-16 | Cemaf | NOVEL 3,4-DIHYDRO BETA-CARBOLINE DERIVATIVES OF MELATONIN AGONISTS, PROCESS FOR THEIR PREPARATION AND THEIR USE AS MEDICAMENTS |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2417512A1 (en) * | 1978-02-17 | 1979-09-14 | Parcor | THIENO (3,2-C) AND THIENO (2,3-C) PYRIDINES, THEIR PREPARATION PROCESS AND THEIR APPLICATION IN THERAPEUTICS |
| DE3013906A1 (en) * | 1980-04-11 | 1981-10-15 | C.H. Boehringer Sohn, 6507 Ingelheim | SUBSTITUTED (ALPHA) -AMINOCARBONYL-L-BENZYL-3,4-DIHYDRO-ISOCHINOLINE, METHOD FOR THE PRODUCTION AND USE THEREOF |
| DE3309596A1 (en) * | 1982-08-05 | 1984-04-05 | Basf Ag, 6700 Ludwigshafen | 2-SUBSTITUTED 1- (3'-AMINOALKYL) -1,2,3,4-TETRAHYDRO-SS-CARBOLINE, THEIR PRODUCTION AND USE AS MEDICINAL PRODUCT |
-
1986
- 1986-06-26 DE DE19863621413 patent/DE3621413A1/en not_active Ceased
-
1987
- 1987-06-24 DD DD87304137A patent/DD264429A5/en not_active IP Right Cessation
- 1987-06-24 EP EP87109110A patent/EP0251194B1/en not_active Expired - Lifetime
- 1987-06-24 DE DE8787109110T patent/DE3785093D1/en not_active Expired - Fee Related
- 1987-06-24 PL PL1987266416A patent/PL159840B1/en unknown
- 1987-06-24 ES ES87109110T patent/ES2053471T3/en not_active Expired - Lifetime
- 1987-06-25 DK DK323887A patent/DK323887A/en not_active Application Discontinuation
- 1987-06-25 KR KR1019870006443A patent/KR890000480A/en not_active Application Discontinuation
- 1987-06-25 PT PT85169A patent/PT85169B/en not_active IP Right Cessation
- 1987-06-25 ZA ZA874587A patent/ZA874587B/en unknown
- 1987-06-25 HU HU872890A patent/HU203752B/en not_active IP Right Cessation
- 1987-06-25 IE IE168987A patent/IE59546B1/en not_active IP Right Cessation
- 1987-06-25 NO NO872672A patent/NO872672L/en unknown
- 1987-06-25 YU YU119887A patent/YU46216B/en unknown
- 1987-06-25 IL IL82995A patent/IL82995A0/en not_active IP Right Cessation
- 1987-06-26 JP JP62159558A patent/JPS63258458A/en active Pending
- 1987-06-26 FI FI872827A patent/FI872827A/en not_active Application Discontinuation
- 1987-06-26 AU AU74775/87A patent/AU598558B2/en not_active Ceased
- 1987-07-01 KR KR1019870006891A patent/KR930006639B1/en not_active IP Right Cessation
-
1993
- 1993-04-01 GR GR930400694T patent/GR3007545T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IE59546B1 (en) | 1994-03-09 |
| PT85169B (en) | 1990-03-30 |
| HU203752B (en) | 1991-09-30 |
| DE3785093D1 (en) | 1993-05-06 |
| PL266416A1 (en) | 1988-09-01 |
| AU598558B2 (en) | 1990-06-28 |
| YU119887A (en) | 1988-10-31 |
| FI872827A (en) | 1987-12-27 |
| DE3621413A1 (en) | 1988-01-07 |
| KR890000480A (en) | 1989-03-14 |
| PT85169A (en) | 1987-07-01 |
| NO872672D0 (en) | 1987-06-25 |
| JPS63258458A (en) | 1988-10-25 |
| YU46216B (en) | 1993-05-28 |
| ZA874587B (en) | 1989-02-22 |
| FI872827A0 (en) | 1987-06-26 |
| EP0251194B1 (en) | 1993-03-31 |
| EP0251194A1 (en) | 1988-01-07 |
| DK323887D0 (en) | 1987-06-25 |
| HUT47932A (en) | 1989-04-28 |
| IL82995A0 (en) | 1987-12-20 |
| GR3007545T3 (en) | 1993-08-31 |
| KR930006639B1 (en) | 1993-07-22 |
| ES2053471T3 (en) | 1994-08-01 |
| AU7477587A (en) | 1988-01-07 |
| DD264429A5 (en) | 1989-02-01 |
| IE871689L (en) | 1987-12-26 |
| DK323887A (en) | 1987-12-27 |
| PL159840B1 (en) | 1993-01-29 |
| KR890002144A (en) | 1989-04-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP4394960B2 (en) | Akt activity inhibitor | |
| JP4783532B2 (en) | Pyrazole compositions useful as inhibitors of ERK | |
| EP3538519B1 (en) | Indazole derivatives as alpha v integrin antagonists | |
| JP7191826B2 (en) | tricyclic RHO kinase inhibitor | |
| EP1603908B1 (en) | Quinazoline derivatives as tgf-beta inhibitors | |
| AU2018222073A1 (en) | O-aminoheteroaryl alkynyl-containing compound, preparation method therefor, and use thereof | |
| CZ211696A3 (en) | Tetracyclic derivatives, processes of their preparation, their use and pharmaceutical compositions containing thereof | |
| KR20190017931A (en) | 3-sulfonylpyridin-2 (1H) -one as an APJ receptor agonist | |
| JP2013529196A (en) | Pyrazolopyridines as inhibitors of kinase LRRK2 | |
| WO2001083481A1 (en) | Imidazopyridine derivatives | |
| JP2000256358A (en) | Pyrazole derivative | |
| CN111601807B (en) | Exo-azaspiro inhibitors of MENIN-MLL interactions | |
| BRPI1013999B1 (en) | AZABICYCLE COMPOUND AND A SALT OF THIS, PHARMACEUTICAL PRODUCT AND PHARMACEUTICAL COMPOSITION UNDERSTANDING THIS COMPOUND AND USE OF THE SAME TO TREAT CANCER | |
| AU2003301958A1 (en) | Indole, azaindole and related heterocyclic 4-alkenyl piperidine amides | |
| KR20060021811A (en) | Composition and antiviral activity of substituted azaindoleoxoacetic piperazine derivatives | |
| CA2431326A1 (en) | Pyrrolo (2.1-a) dihydroisoquinolines and their use as phosphodiesterase 10a inhibitors | |
| TW201041876A (en) | Carboxamide compounds and their use as calpain inhibitors | |
| NO872672L (en) | PROCEDURE FOR PREPARING CONDENSED DIHYDROPYRIDINES. | |
| JP2005538962A (en) | Phenylaminopyrimidine and its use as a Rho-kinase inhibitor | |
| CA2547347C (en) | Diazaindole-dicarbonyl-piperazinyl antiviral agents | |
| US11236083B2 (en) | Compounds and pharmaceutical compositions for modulating SGK activity, and methods thereof | |
| AU2017220984A1 (en) | Substituted amino six-membered nitric heterocyclic ring compound and preparation and use thereof | |
| WO2016205460A1 (en) | Polycyclic derivatives targeting ral gtpases and their therapeutical applications | |
| KR100227953B1 (en) | New 3,4-dihydroisoquinoline derivatives and new pharmaceutical use of carbocyclically and heterocyclically annulated dihydropyridines | |
| JP2009513580A (en) | Tyrosine kinase inhibitor |