US3169968A - Esters of ajmaline and related compounds - Google Patents
Esters of ajmaline and related compounds Download PDFInfo
- Publication number
- US3169968A US3169968A US193313A US19331362A US3169968A US 3169968 A US3169968 A US 3169968A US 193313 A US193313 A US 193313A US 19331362 A US19331362 A US 19331362A US 3169968 A US3169968 A US 3169968A
- Authority
- US
- United States
- Prior art keywords
- acid
- ajmaline
- acetyl
- quaternary ammonium
- compounds
- 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 25
- 229960004332 ajmaline Drugs 0.000 title description 20
- CJDRUOGAGYHKKD-UHFFFAOYSA-N Iso-ajmalin Natural products CN1C2=CC=CC=C2C2(C(C34)O)C1C1CC3C(CC)C(O)N1C4C2 CJDRUOGAGYHKKD-UHFFFAOYSA-N 0.000 title description 14
- CJDRUOGAGYHKKD-RQBLFBSQSA-N 1pon08459r Chemical compound CN([C@H]1[C@@]2(C[C@@]3([H])[C@@H]([C@@H](O)N42)CC)[H])C2=CC=CC=C2[C@]11C[C@@]4([H])[C@H]3[C@H]1O CJDRUOGAGYHKKD-RQBLFBSQSA-N 0.000 title description 10
- 244000061121 Rauvolfia serpentina Species 0.000 title description 10
- 150000002148 esters Chemical class 0.000 title description 9
- -1 aliphatic monocarboxylic acid Chemical class 0.000 description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 150000003839 salts Chemical class 0.000 description 23
- 239000002253 acid Substances 0.000 description 18
- 238000000034 method Methods 0.000 description 17
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 125000001931 aliphatic group Chemical group 0.000 description 10
- 239000007858 starting material Substances 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 8
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 8
- 230000032050 esterification Effects 0.000 description 8
- 238000005886 esterification reaction Methods 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000001589 carboacyl group Chemical group 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 125000001453 quaternary ammonium group Chemical group 0.000 description 6
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 6
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 5
- 150000001335 aliphatic alkanes Chemical class 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 5
- JLUFXYAXVHAFTF-FOYGJLHASA-N Ajmalidine Natural products O=C1[C@H]2[C@@H]3[C@H](CC)[C@@H](O)N4[C@H]([C@@H]5N(C)c6c(cccc6)[C@@]15C[C@@H]24)C3 JLUFXYAXVHAFTF-FOYGJLHASA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- CJDRUOGAGYHKKD-JZQIZOIBSA-N Isoajmaline Chemical compound CN1C2=CC=CC=C2[C@@]2([C@@H](C34)O)[C@@H]1[C@@H]1C[C@H]3[C@@H](CC)[C@H](O)N1[C@H]4C2 CJDRUOGAGYHKKD-JZQIZOIBSA-N 0.000 description 4
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 4
- JLUFXYAXVHAFTF-UHFFFAOYSA-N ajmalidine Chemical class C1=CC=C2C3(C(C45)=O)CC4N4C(O)C(CC)C5CC4C3N(C)C2=C1 JLUFXYAXVHAFTF-UHFFFAOYSA-N 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 150000004820 halides Chemical class 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- 239000000155 melt Substances 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical class S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 3
- 239000012346 acetyl chloride Substances 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 150000001340 alkali metals Chemical class 0.000 description 3
- 150000001336 alkenes Chemical class 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
- 229960004132 diethyl ether Drugs 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-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
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 2
- PLUBXMRUUVWRLT-UHFFFAOYSA-N Ethyl methanesulfonate Chemical compound CCOS(C)(=O)=O PLUBXMRUUVWRLT-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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 150000003973 alkyl amines Chemical class 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 238000005349 anion exchange Methods 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 2
- 229910001863 barium hydroxide Inorganic materials 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- LJOODBDWMQKMFB-UHFFFAOYSA-N cyclohexylacetic acid Chemical compound OC(=O)CC1CCCCC1 LJOODBDWMQKMFB-UHFFFAOYSA-N 0.000 description 2
- 150000005690 diesters Chemical class 0.000 description 2
- DENRZWYUOJLTMF-UHFFFAOYSA-N diethyl sulfate Chemical compound CCOS(=O)(=O)OCC DENRZWYUOJLTMF-UHFFFAOYSA-N 0.000 description 2
- 229940008406 diethyl sulfate Drugs 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000003456 ion exchange resin Substances 0.000 description 2
- 229920003303 ion-exchange polymer Polymers 0.000 description 2
- 239000007788 liquid Substances 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
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- JDRMYOQETPMYQX-UHFFFAOYSA-N monomethyl succinate Chemical compound COC(=O)CCC(O)=O JDRMYOQETPMYQX-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- 229940107700 pyruvic acid Drugs 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229910001923 silver oxide Inorganic materials 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 150000003460 sulfonic acids Chemical class 0.000 description 2
- KQTIIICEAUMSDG-UHFFFAOYSA-N tricarballylic acid Chemical compound OC(=O)CC(C(O)=O)CC(O)=O KQTIIICEAUMSDG-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- CJDRUOGAGYHKKD-XMTJACRCSA-N (+)-Ajmaline Natural products O[C@H]1[C@@H](CC)[C@@H]2[C@@H]3[C@H](O)[C@@]45[C@@H](N(C)c6c4cccc6)[C@@H](N1[C@H]3C5)C2 CJDRUOGAGYHKKD-XMTJACRCSA-N 0.000 description 1
- HFVMEOPYDLEHBR-UHFFFAOYSA-N (2-fluorophenyl)-phenylmethanol Chemical compound C=1C=CC=C(F)C=1C(O)C1=CC=CC=C1 HFVMEOPYDLEHBR-UHFFFAOYSA-N 0.000 description 1
- 239000001124 (E)-prop-1-ene-1,2,3-tricarboxylic acid Substances 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
- RESZKUYVAVEVII-ONEGZZNKSA-N (e)-2-ethoxybut-2-enedioic acid Chemical compound CCO\C(C(O)=O)=C\C(O)=O RESZKUYVAVEVII-ONEGZZNKSA-N 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- BZCOSCNPHJNQBP-UPHRSURJSA-N (z)-2,3-dihydroxybut-2-enedioic acid Chemical compound OC(=O)C(\O)=C(\O)C(O)=O BZCOSCNPHJNQBP-UPHRSURJSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- QXQAPNSHUJORMC-UHFFFAOYSA-N 1-chloro-4-propylbenzene Chemical compound CCCC1=CC=C(Cl)C=C1 QXQAPNSHUJORMC-UHFFFAOYSA-N 0.000 description 1
- SPXOTSHWBDUUMT-UHFFFAOYSA-N 138-42-1 Chemical compound OS(=O)(=O)C1=CC=C([N+]([O-])=O)C=C1 SPXOTSHWBDUUMT-UHFFFAOYSA-N 0.000 description 1
- VUAXHMVRKOTJKP-UHFFFAOYSA-N 2,2-dimethylbutyric acid Chemical compound CCC(C)(C)C(O)=O VUAXHMVRKOTJKP-UHFFFAOYSA-N 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-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
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 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 1
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 1
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 1
- MYMNBFURSYZQBR-UHFFFAOYSA-N 5-ethoxy-5-oxopentanoic acid Chemical compound CCOC(=O)CCCC(O)=O MYMNBFURSYZQBR-UHFFFAOYSA-N 0.000 description 1
- ONMOULMPIIOVTQ-UHFFFAOYSA-N 98-47-5 Chemical compound OS(=O)(=O)C1=CC=CC([N+]([O-])=O)=C1 ONMOULMPIIOVTQ-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- XLYMOEINVGRTEX-ARJAWSKDSA-N Ethyl hydrogen fumarate Chemical compound CCOC(=O)\C=C/C(O)=O XLYMOEINVGRTEX-ARJAWSKDSA-N 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- 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 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 238000003436 Schotten-Baumann reaction Methods 0.000 description 1
- 229910021607 Silver chloride Inorganic materials 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 206010047281 Ventricular arrhythmia Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229940091181 aconitic acid Drugs 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 229960004909 aminosalicylic acid Drugs 0.000 description 1
- 229940107816 ammonium iodide Drugs 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 1
- 230000003440 anti-fibrillation Effects 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- SLUNEGLMXGHOLY-UHFFFAOYSA-N benzene;hexane Chemical compound CCCCCC.C1=CC=CC=C1 SLUNEGLMXGHOLY-UHFFFAOYSA-N 0.000 description 1
- WAMGVVQHTXUAFV-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1 WAMGVVQHTXUAFV-UHFFFAOYSA-N 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- NDKBVBUGCNGSJJ-UHFFFAOYSA-M benzyltrimethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)CC1=CC=CC=C1 NDKBVBUGCNGSJJ-UHFFFAOYSA-M 0.000 description 1
- 125000002527 bicyclic carbocyclic group Chemical group 0.000 description 1
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 1
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 1
- 235000014121 butter Nutrition 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- GTZCVFVGUGFEME-IWQZZHSRSA-N cis-aconitic acid Chemical compound OC(=O)C\C(C(O)=O)=C\C(O)=O GTZCVFVGUGFEME-IWQZZHSRSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical class C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000909 electrodialysis Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 description 1
- 238000006266 etherification reaction Methods 0.000 description 1
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 1
- 229960003750 ethyl chloride Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229940114124 ferulic acid Drugs 0.000 description 1
- 230000002600 fibrillogenic effect Effects 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- XLYMOEINVGRTEX-UHFFFAOYSA-N fumaric acid monoethyl ester Natural products CCOC(=O)C=CC(O)=O XLYMOEINVGRTEX-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 230000008570 general process Effects 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 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
- 238000004519 manufacturing process Methods 0.000 description 1
- PVBQYTCFVWZSJK-UHFFFAOYSA-N meldonium Chemical compound C[N+](C)(C)NCCC([O-])=O PVBQYTCFVWZSJK-UHFFFAOYSA-N 0.000 description 1
- 229960002937 meldonium Drugs 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 125000005395 methacrylic acid group Chemical group 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 description 1
- 229940050176 methyl chloride Drugs 0.000 description 1
- 150000002762 monocarboxylic acid derivatives Chemical class 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- HVAMZGADVCBITI-UHFFFAOYSA-N pent-4-enoic acid Chemical compound OC(=O)CCC=C HVAMZGADVCBITI-UHFFFAOYSA-N 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-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
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000006748 scratching Methods 0.000 description 1
- 230000002393 scratching effect Effects 0.000 description 1
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 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
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- GTZCVFVGUGFEME-UHFFFAOYSA-N trans-aconitic acid Natural products OC(=O)CC(C(O)=O)=CC(O)=O GTZCVFVGUGFEME-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 208000003663 ventricular fibrillation Diseases 0.000 description 1
- NLVXSWCKKBEXTG-UHFFFAOYSA-N vinylsulfonic acid Chemical compound OS(=O)(=O)C=C NLVXSWCKKBEXTG-UHFFFAOYSA-N 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/22—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 systems contains four or more hetero rings
Definitions
- This invention relates to and has for its object the proviin which R represents the acyl radical of a carboxylic acid of aliphatic character, the quaternary ammonium derivatives and the salts of these compounds as Well as process for manufacturing them.
- the acyl radical R represents primarily that of an aliphatic, cycloaliphatic, cycloaliphatioaliphatic, araliphatic or heterocyclyl-aliph-atic carboxylic acid containing up to carbon atoms, such, for example, as the acyl radical of a lower aliphatic monocarboxylic acid, particularly a lower alkane monocarboxylic acid, e.g. formic, acetic, propionic, butyric, pivalic, caproic, 2,2-dimethyl-butyric acid and the like, a lower alkene monocarboxylic acid, e.g.
- a lower alkane dicarboxylic acid cg. oxalic, malonic, succinic, dimethylsuccinic, glutaric, a,a-dimethyl glutar-ic, o-methylglutaric acid and the like, a lower alkane dicarboxylic acid half ester with a lower alkanol, e.g. succinic acid monomethyl ester, glu taric acid monoethylester and the like, a low er'alkene dicarboxylic acid, cg.
- a lower aliphatic tricarboxylic acid for example, a lower alkane tricarboxylic acid, cg. tricarballylic acid and the like, a lower alkene tricarboxylic acid, e.g. aconitic acid and the like, a hydroxy-lower alkane tricarboxylic acid, eg. citric acid and the like, a cycloaliphatic monoearboxylic acid, such as a cycloalkane monocarboxylic acid, in which cycloalkane has from five to seven carbon atoms as ring members, e.g.
- a cycloaliphatic-aliphatic monocarboxylic acid such as cycloalkyl-lower alkane monocarboxylic acid, in which cycloalkyl has from five to seven carbon atoms as ring members, e.g. fi-cyclopentylpropionic, cyclohexylacetic acid and the like
- a monocyclic or bicyclic carbocyclic aryl-aliphatic carboxylic acid e.g.
- a lower alkyl lower alkane sulfonate e.g. methyl or ethyl methane sulfonate or ethane sulfonate and the like
- Salts of the new compounds of this invention are particularly pharmaceutically acceptable, non-toxic acid addition salts, especially those with inorganic acids or organic carboxylic or sulfonic acids having from one to fifteen carbon atoms, such as with those described hereinafter. Also included are the corresponding quaternary ammonium salts, in which the anion is derived from an inorganic acid other than hydrohalic or sulfuric acids, or an organic carboxylic acid, such as one of those furnishing the acyl radical previously mentioned.
- the new compounds of this invention have antifibrillatory properties and are virtually free from toxic and unwarranted side effects at the pharmacologically effective doses. They can, therefore, be used for the treatment of cardiac irregularities, such as auricular or ventricular arrhythmias or fibrillation.
- R stands for lower alkanoyl, preferably for acetyl, but also for formyl, propionyl, butyryl, pivaloyl, caproyl, 2,2-dimethyl-butyryl and the like, or for lower alkanoyl substituted by lower alkoxy groups, preferably for tri-(methoxymethyl)-acetyl, but also for methoxy-acetyl, ethoxy-acetyl, B-methoxy-propionyl and the like, and their pharmaceutically acceptable, non-toxic acid addition salts and quaternary lower alkylarnmonium salts.
- the new compounds of this invention may be prepared by esterifying ajmaline compounds containing a free 17- and 2l-hydroxyi group with a carboxylic acid of aliphatic character or a reactive functional derivative thereof and isolating the 21-O-acyl compounds formed or converting in 2l-O-R-ajmaline compounds in which R represents the acyl radical of a carboxylic acid of aliphatic character, and containing in the 17-position a group convertible into a hydroxyl group, this group into a free l7-hydroxyl group and/ or, if desired, converting a resulting salt into the free compound or into another salt, and/or, if desired, converting a resulting free compound into a salt or quaternary ammonium compound thereof, and/or, if desired, converting a resulting quaternary ammonium com pound into another quaternary ammonium compound.
- the esterification procedure may be carried out in an acidic, a neutral or, surprisingly, even in an alkaline medium according to the Schotten-Baumann procedure for esterifying alcohols.
- the latter modification of the esterification procedure can successfully be applied, though it is well known in the art that the complex ring structure of ajmaline compounds is destroyed by the action of alkaline agents. 7
- the reaction may be performed, for example, by treating the ajmaline compound with a carboxylic acid of aliphatic character or a reactive functional derivative thereof, for example with a halide, e.g. the chloride or "3 3 bromide, an anhydride, e.g. the normal or mixed anhydride or ketene, or an ester, such as a lower alkyl or aralkyl ester, e.g. the methyl, ethyl, propyl, butyl, benzyl, p-nitro-benzyl ester and the like.
- the esterification may be carried out in the presence of an inert diluent, for example a hydrocarbon, such as an alkane, e.g.
- a monocyclic carbocyclic aromatic hydrocarbon e.g. benzene, toluene, xylene and the like
- a halo genated hydrocarbon such as a halogenated aliphatic hydrocarbon, e.g. methylene chloride, chloroform, ethylene chloride and the like
- an ether such as diethylether, tetrahydrofurane, dioxane and the like, or mixtures thereof or any other suitable diluent, or in the absence of a solvent or diluent, for example by treating the ajmaline compound with a corresponding acid anhydride.
- Esterification with the free acid is preferably performed in the presence of a strong mineral acid, such as sulfuric acid and the like, that with an acid halide preferably in the presence of an alkaline agent, for example an alkali metal or alkaline earth metal hydroxide, carbonate or bi carbonate, such as sodium, potassium or barium hydroxide, potassium or calcium carbonate, sodium bicarbonate and the like, or an organic base, for example a tri-lower alkylamine, e.g. trimethylamine, triethylamine and the like, or a heterocyclic base, e.g. pyridine, eollidine and the like.
- a strong mineral acid such as sulfuric acid and the like
- an acid halide preferably in the presence of an alkaline agent, for example an alkali metal or alkaline earth metal hydroxide, carbonate or bi carbonate, such as sodium, potassium or barium hydroxide, potassium or calcium carbonate, sodium bicarbonate and the like
- an organic base for example a
- transesterification catalysts such for example as alkali metal alcoholates, e.g. sodium methylate and the like, alkali metal cyanides, e.g. potassium cyanide and the like, quaternary 17-hydroxyl group can be formed without affecting the 21-O-acyl group.
- Preferred groups convertible into a free 17-hydroxyl group are, for example, the 0x0 group, acyloxy radicals of carbonic acid half esters, such as the benzyloxycarbonyloxy, tertiary butyloxycarbonyloxy group and the like, or benzyloxy radicals, such as the benzyloxy or u-phenylethoxy radical.
- a l7-oxo group present, for example, in 21-O-acyl ajmalidine or isoajmalidine compounds, may also be converted into a 17-hydroxyl group, whose configuration is opposite to that in ajmaline or isoajmaline, by treatment with a complex light metal hydride, such as an alkali metal borohydride, e.g. sodium borohydride.
- a complex light metal hydride such as an alkali metal borohydride, e.g. sodium borohydride.
- the above reactions are preferably carried out in the presence of inert diluents, for example in those described hereinbefore.
- the starting material used in the above procedure can be obtained, for example, by esterifying ajmalidine compounds with a reactive functional derivative of a carboxylic acid of aliphatic character or by protecting both, the 17- and 2l-hydroxyl group of ajmaline compounds, for
- the starting materials used are preferably compounds of the Formula I in which R represents hydrogen, such as ajmaline or isoajmaline.
- Starting materials containing in the 17- and/or 21-position a hydroxyl group opposite to the configuration in ajmaline as is the case, for example, in sandwicine can be prepared from 17-O-R and/or 21-O-R -ajmaline or -isoajmaline, in which R stands for the acyl radical of an organic sulfonic acid, such as an aliphatic or aromatic sulfonic acid, containing up to 15 carbon atoms, e.g.
- a tertiary amine such as a tri-lower alkylamine, e.g. triethylamine and the like.
- the l7,21-di-O-R -ajmaline or -isoajmaline may be prepared according to the procedure of Anet et al., J. Chem. Soc., 1954, p.
- Sandwicine and 17-epiisoajmaline may also be prepared by reduction of ajmalidine or isoajmalidine, for example with catalytically activated hydrogen or with sodium borohydride. Both methods, the hydrolysis and reduction, may be applied in order to obtain the appropriate starting material.
- the new compounds are prepared by conversion of a group present in the 1'7-position of Zl-O-acyl ajmaline compounds into a free 17-hydroxyl group
- the obtained di-esters can be easily hydrolysed into the 17-O-rnonoacylates, for example by heating an acid addition salt, such as the monohydrochloride, of the di-esters in water on a steam bath for a short time, for example about 5 to 45 minutes.
- the aforementioned dibenzylethers may be partially hydrogenolyzed, for example With the stoichiometric amount of catalytically activated hydrogen.
- the free 21-hydroxyl group may be esterificd with a reactive functional derivative of a carboxylic acid of aliphatic character by methods in themselves known.
- the new compounds are obtained in the free form or in the form of their salts.
- the salts of the new compounds may be converted into the free bases in a manner known per se, for example by reaction with a basic agent, for example aqueous ammonia, an alkali metal hydroxide, moist silver oxide and the like, or an ion exchange resin.
- a resulting salt may be converted into another salt, for example, by treatment with a metal salt of an acid, preferably with such a metal salt of which the metal forms with the anion of the ajmaline compound an insoluble salt, or with an ion exchange resin.
- the free bases may be converted into acid addition salts of inorganic or organic, pharmaceutically acceptable, nontoxic acids, if desired in the presence of a suitable solvent or diluent.
- Acids of the aforementioned kind are for example mineral acids, such as hydrochloric, hydrobromic, sulfuric, phosphoric, nitric or perchloric acid or organic carboxylic or sulfonic acids, such as formic, acetic, propionic, oxalic, succinic, glycollic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, dihydroxymaleic or pyruvic acid; phenylacetic, benzoic, para-aminobenzoic, anthranilic, para-hydroxybenzoic, salicylic or para-aminosalicylic acid; methane sulfonic, ethane sulfonic, hydroxyethane sulfonic or ethylene sulfonic acid; toluene
- Quaternary ammonium derivatives of the compounds of this invention may be obtained by reacting a resulting free compound with a quaternating agent, preferably a lower alkyl halide, sulfate or sulfonate, such for example as, methyl or ethyl-chloride, -bromide or -iodide, dimethyl or diethyl sulfate, methyl or ethyl-methane sulfonate, -ethane sulfonate or -p-toluene sulfonate and the like.
- a quaternating agent preferably a lower alkyl halide, sulfate or sulfonate, such for example as, methyl or ethyl-chloride, -bromide or -iodide, dimethyl or diethyl sulfate, methyl or ethyl-methane sulfonate, -
- a resulting quaternary ammonium compound may be converted into another quaternary ammonium compound, such as a quaternary ammonium hydroxide, for example,
- quaternary ammonium halide by reacting a quaternary ammonium halide ,with silver oxide, by treating a quaternary ammonium sulfate with barium hydroxide, or a quaternary ammonium salt with an anion exchange preparation, or by electrodialysis. From a resulting quaternary ammonium hydroxide, there may be formed a quaternary ammonium salt by treating it with an acid.
- Quaternary ammonium salts may be converted directly into other quaternary ammonium salts, for example, a quaternary ammonium iodide, when reacted with silver chloride or withhydrogen chloride in methanol, yields a quaternary ammonium chloride; a corresponding conversion may also be achievedby treating a quaternary ammonium salt with a suitable anion exchange preparation, for example, with those outlined hereinbefore as being useful for the preparation of acid. addition salts.
- the invention also comprises any modification of the general process, wherein a compound obtainable as an intermediate at any stage of the'process is used as the starting material and the remaining step(s) of the process is (are) carried out; orthe process is discontinued at any stage, or inwhich the starting materials are formed in the course of the reaction or used in the form of their salts.
- any new intermediates such, for example, as compounds of the Formula I, in whichR'represents the acyl radical of an organic sulfonic acid or 21-O-R -ajmalidine and 2l-O-R isoajmalidine, in which R represents the acyl radical of a carboxylic acid of aliphatic character or of an organic sulfonic acid. Examples for theseacyl radicals are given hereinbefore.
- the compounds of this invention may be used in the form of pharmaceutical preparations for enteral or parenteral use, which contain the new compounds, particularly the salts thereof in-admixture with a pharmaceutical organic or inorganic, solid or liquid carrier.
- a pharmaceutical organic or inorganic, solid or liquid carrier for making up the preparations there can be employed substances which do not react with the new compounds, such as water, gelatine, lactose, starches, stearic acid, magnesium stearate, stearyl alcohol, talc, vegetable oils, benzyl alcohol, gums, propylene glycol, polyalkylene glycols, cholesterol or any other known carrier for pharmaceutical preparations.
- the latter may be in solid form, for example, as tablets, dragees, capsules and the like, or in liquid form, for example, as solutions, suspensions, emulsions and the like. If desired, they may contain auxiliary substances, such as preserving, stabilizing, wetting, emulsifying agents and the like, salts for varying the osmotic pressure, butters, etc. They also may contain, in combination, other useful substances.
- Example 1 To a mixture of 2.00 g. of ajmaline and 20 ml. of tetrahydrofuran, rapidly stirred in a flask cooled in an ice bath, is added dropwise and simultaneously ml. of a IO-nsolution of aqueous sodium hydroxide and a solution of 4 ml. of acetyl chloride in ml. of tetrahydrofuran over a period of 1% hours at such a rate that the solution is always alkaline.
- Example 3 The mixture of 933 mg. of 21-O-acetyl-ajmaline, 15 ml. methylene chloride and 3 ml. methyliodide is allowed to stand overnight atroom temperature. An oil, representing the 2l-O-acetyl-ajmaline methiodide, settles out, which doesnot crystallizefrom a number of solvents.
- Example 4 The mixture of 244 mg. of 2l-O-acetyl-isoajmaline, 10 ml. methylene chloride and 2 ml. of methyliodide is allowed to stand at room temperature overnight. The oil separated crystallizes on scratching. There are obtained 285 mg. of 2l-O-acetyl-isoajmaline methiodide which melts at 254-256 and after recrystallization from methanol at 259-261".
- Example 5 The mixture of 22 g. of ajmaline and 100ml. of acetic acid anhydride is heated on the steam bath for 10 minutes.
- Example 9 The mixture of 300 mg. of 21-O-acetyl-ajmalidine and 10 ml. of methanol is shaken in an atmosphere of hydrogen in the presence of 50 mg. of pro-reduced platinum oxide. catalyst is filtered oil and the solution concentrated to dryness.
- the so obtained 21-O-acetyl sandwicine (21-O- acetyl-17-epi-ajmaline) is an amorphous substance, 11 :1742 cmr- Its hydrochloride, prepared according to the method given in Example 8 melts at 250251 with decomposition.
- the starting material can be prepared in the following manner:
- Example 10 250 mg. of sandwicine in 4 ml. of benzene are heated briefly on the steam bath with 250 mg. of acetyl chloride. The 21-O-acetyl-sandwicine hydrochloride crystallizes out and is filtered off; M.P. 250-251 (dec.). The free base generated from th salt is amorphous but showes the carbonyl band in the infra-red spectrum at 1738 cm.-
- the starting material may be prepared as follows:
- ajmalidine dissolved in 10 ml. of methanol are catalytieally reduced as in shown in Example 9.
Description
United States Patent ()fifice 3,169,968 ESTERS F ALFMALHNE AND RELATED CUMPOUNDS Merrill Frederick Bartlett, Warren Township, and William Irving Taylor, Summit, Null, assignors to Ciha Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed May 3, 1962, Ser. No. 193,313 Claims. (Ci. zen-494.3
This invention relates to and has for its object the proviin which R represents the acyl radical of a carboxylic acid of aliphatic character, the quaternary ammonium derivatives and the salts of these compounds as Well as process for manufacturing them.
The acyl radical R represents primarily that of an aliphatic, cycloaliphatic, cycloaliphatioaliphatic, araliphatic or heterocyclyl-aliph-atic carboxylic acid containing up to carbon atoms, such, for example, as the acyl radical of a lower aliphatic monocarboxylic acid, particularly a lower alkane monocarboxylic acid, e.g. formic, acetic, propionic, butyric, pivalic, caproic, 2,2-dimethyl-butyric acid and the like, a lower alkene monocarboxylic acid, e.g. acrylic, methacrylic, crotonic, 3-butene carboxylic acid and the like, a hydroxy-lower alkane monocarboxylic acid, e.g. glycolic, lactic acid and the like, a lower alkoxylower alka'ne monocarboxylic acid, e.g. methoxy-acetic, ethoxy-acetic, fi-methoxy-propionic, tri-(methoxymethyl)- acetic acid andthe like, a lower alkanoyl-lower alkane monocarboxylic acid, e.g. acetoacetic, pyruvic acid and I 3,169,968 Patented 7 Feb. 16, 1965 cyclic or bicyclic heterocyclic aryl-aliphatic carboxylic acid, cg. 3-pyridyl-aoetic, 4-pyridyl-acetic, Z-thienyl-acetic fate, e.g. dimethyl sulfate, diethyl sulfate and the like,
the like, a lower aliphatic dicarboxylic acid, for example,
a lower alkane dicarboxylic acid, cg. oxalic, malonic, succinic, dimethylsuccinic, glutaric, a,a-dimethyl glutar-ic, o-methylglutaric acid and the like, a lower alkane dicarboxylic acid half ester with a lower alkanol, e.g. succinic acid monomethyl ester, glu taric acid monoethylester and the like, a low er'alkene dicarboxylic acid, cg. itaconic, maleic, citraconic, pyrocinchonic, xeronic, fumaric acid and the like, a lower alkene dicarboxylic acid half ester with a lower alkanol, e.g. maleic acid monoethyl ester and the like, a hydroxy-lower alkane dicarboxylic acid, e. g. malic, tartaric acid and the like, as well as the optically active forms thereof, a lower alkoXy-lowei' alkane dicarboxylic acid, e. g. a,[3-dimethoxy-succinic acid and the like, a lower alkoxy-lower alkene dicarboxylic acid, eg. ethoxymaleic acid and the like, a lower aliphatic tricarboxylic acid, for example, a lower alkane tricarboxylic acid, cg. tricarballylic acid and the like, a lower alkene tricarboxylic acid, e.g. aconitic acid and the like, a hydroxy-lower alkane tricarboxylic acid, eg. citric acid and the like, a cycloaliphatic monoearboxylic acid, such as a cycloalkane monocarboxylic acid, in which cycloalkane has from five to seven carbon atoms as ring members, e.g. cycle-hexane carboxylic acid and the like, a cycloaliphatic-aliphatic monocarboxylic acid, such as cycloalkyl-lower alkane monocarboxylic acid, in which cycloalkyl has from five to seven carbon atoms as ring members, e.g. fi-cyclopentylpropionic, cyclohexylacetic acid and the like, a monocyclic or bicyclic carbocyclic aryl-aliphatic carboxylic acid, e.g. phenylacetic, ,8 phenylpropionic, (3,4,5 trimethoxyphenyD-acetic, cinnamic, mandelic, 4-methoxy-cinnamic, fer-ulic, o-ethoxycarbonyl-ferulic acid and the like, a monowith a lower alkyl lower alkane sulfonate, e.g. methyl or ethyl methane sulfonate or ethane sulfonate and the like, a lower alkyl carbocyclic aryl sulfonate, e.g. methyl p-toluene sulfonate and the like, or any other suitable reactive ester of an alcohol with a strong acid.
Salts of the new compounds of this invention are particularly pharmaceutically acceptable, non-toxic acid addition salts, especially those with inorganic acids or organic carboxylic or sulfonic acids having from one to fifteen carbon atoms, such as with those described hereinafter. Also included are the corresponding quaternary ammonium salts, in which the anion is derived from an inorganic acid other than hydrohalic or sulfuric acids, or an organic carboxylic acid, such as one of those furnishing the acyl radical previously mentioned.
The new compounds of this invention have antifibrillatory properties and are virtually free from toxic and unwarranted side effects at the pharmacologically effective doses. They can, therefore, be used for the treatment of cardiac irregularities, such as auricular or ventricular arrhythmias or fibrillation.
Particularly outstanding antiiibrillartory properties are exhibited by 2l-O-R -ajmaline, 21-O-R -isoajmaline and 2 1O-R -sandwicine (i.e. 2l-O-R -17-epi-ajma: line), in which R stands for lower alkanoyl, preferably for acetyl, but also for formyl, propionyl, butyryl, pivaloyl, caproyl, 2,2-dimethyl-butyryl and the like, or for lower alkanoyl substituted by lower alkoxy groups, preferably for tri-(methoxymethyl)-acetyl, but also for methoxy-acetyl, ethoxy-acetyl, B-methoxy-propionyl and the like, and their pharmaceutically acceptable, non-toxic acid addition salts and quaternary lower alkylarnmonium salts.
The new compounds of this invention may be prepared by esterifying ajmaline compounds containing a free 17- and 2l-hydroxyi group with a carboxylic acid of aliphatic character or a reactive functional derivative thereof and isolating the 21-O-acyl compounds formed or converting in 2l-O-R-ajmaline compounds in which R represents the acyl radical of a carboxylic acid of aliphatic character, and containing in the 17-position a group convertible into a hydroxyl group, this group into a free l7-hydroxyl group and/ or, if desired, converting a resulting salt into the free compound or into another salt, and/or, if desired, converting a resulting free compound into a salt or quaternary ammonium compound thereof, and/or, if desired, converting a resulting quaternary ammonium com pound into another quaternary ammonium compound.
The esterification procedure may be carried out in an acidic, a neutral or, surprisingly, even in an alkaline medium according to the Schotten-Baumann procedure for esterifying alcohols. The latter modification of the esterification procedure can successfully be applied, though it is well known in the art that the complex ring structure of ajmaline compounds is destroyed by the action of alkaline agents. 7
The reaction may be performed, for example, by treating the ajmaline compound with a carboxylic acid of aliphatic character or a reactive functional derivative thereof, for example with a halide, e.g. the chloride or "3 3 bromide, an anhydride, e.g. the normal or mixed anhydride or ketene, or an ester, such as a lower alkyl or aralkyl ester, e.g. the methyl, ethyl, propyl, butyl, benzyl, p-nitro-benzyl ester and the like. The esterification may be carried out in the presence of an inert diluent, for example a hydrocarbon, such as an alkane, e.g. hexane and the like, a monocyclic carbocyclic aromatic hydrocarbon, e.g. benzene, toluene, xylene and the like, a halo genated hydrocarbon, such as a halogenated aliphatic hydrocarbon, e.g. methylene chloride, chloroform, ethylene chloride and the like, an ether, such as diethylether, tetrahydrofurane, dioxane and the like, or mixtures thereof or any other suitable diluent, or in the absence of a solvent or diluent, for example by treating the ajmaline compound with a corresponding acid anhydride. Depending on the method used for the esterification procedure, several reaction accelerators may be applied. Esterification with the free acid is preferably performed in the presence of a strong mineral acid, such as sulfuric acid and the like, that with an acid halide preferably in the presence of an alkaline agent, for example an alkali metal or alkaline earth metal hydroxide, carbonate or bi carbonate, such as sodium, potassium or barium hydroxide, potassium or calcium carbonate, sodium bicarbonate and the like, or an organic base, for example a tri-lower alkylamine, e.g. trimethylamine, triethylamine and the like, or a heterocyclic base, e.g. pyridine, eollidine and the like. Using an ester as the reactive functional derivative of the acid, several transesterification catalysts may be applied, such for example as alkali metal alcoholates, e.g. sodium methylate and the like, alkali metal cyanides, e.g. potassium cyanide and the like, quaternary 17-hydroxyl group can be formed without affecting the 21-O-acyl group. Preferred groups convertible into a free 17-hydroxyl group are, for example, the 0x0 group, acyloxy radicals of carbonic acid half esters, such as the benzyloxycarbonyloxy, tertiary butyloxycarbonyloxy group and the like, or benzyloxy radicals, such as the benzyloxy or u-phenylethoxy radical. These groups can be converted into a hydroxyl group in known manner, for example by treatment with hydrogenating agents, such, for example, as catalytically activated hydrogen. A l7-oxo group present, for example, in 21-O-acyl ajmalidine or isoajmalidine compounds, may also be converted into a 17-hydroxyl group, whose configuration is opposite to that in ajmaline or isoajmaline, by treatment with a complex light metal hydride, such as an alkali metal borohydride, e.g. sodium borohydride. The above reactions are preferably carried out in the presence of inert diluents, for example in those described hereinbefore.
The starting material used in the above procedure can be obtained, for example, by esterifying ajmalidine compounds with a reactive functional derivative of a carboxylic acid of aliphatic character or by protecting both, the 17- and 2l-hydroxyl group of ajmaline compounds, for
' example by esterification with the halide of a carbonic acid ammonium bases, e.g. benzyl-trimethylammonium hydroxide and the like. The above reactions may be carried out under cooling, at normal or elevated temperature, in an open or closed vessel and/ or if necessary in the atmosphere of an inert gas, e.g. nitrogen.
In order to obtain the desired new compounds in optimum yields, mild esterification conditions should be ap plied. Reacting the ajmaline compounds for example with an acid anhydride, it is sufficient to heat the reaction mixture on the steam bath for few minutes only. Using acid halides in the presence of alkaline agents for the esterification, the latter should be carried out below or at room temperature. The new compounds formed, may be isolated in known manner, for example by crystallization, precipitation or chromatography.
The starting materials used are preferably compounds of the Formula I in which R represents hydrogen, such as ajmaline or isoajmaline. Starting materials containing in the 17- and/or 21-position a hydroxyl group opposite to the configuration in ajmaline as is the case, for example, in sandwicine, can be prepared from 17-O-R and/or 21-O-R -ajmaline or -isoajmaline, in which R stands for the acyl radical of an organic sulfonic acid, such as an aliphatic or aromatic sulfonic acid, containing up to 15 carbon atoms, e.g. methane sulfonic, ethane sulfonic, p-toluene sulfonic, 4-bromo-benzene sudfonic, 3 or 4-nitro-benzene sulfonic acid and the like, by hydrolysis, if necessary in the presence of a tertiary amine, such as a tri-lower alkylamine, e.g. triethylamine and the like. The l7,21-di-O-R -ajmaline or -isoajmaline may be prepared according to the procedure of Anet et al., J. Chem. Soc., 1954, p. 1242, whereas the corresponding monoacylates are obtainable according to the method described above and hereinbelow. Sandwicine and 17-epiisoajmaline may also be prepared by reduction of ajmalidine or isoajmalidine, for example with catalytically activated hydrogen or with sodium borohydride. Both methods, the hydrolysis and reduction, may be applied in order to obtain the appropriate starting material.
In case the new compounds are prepared by conversion of a group present in the 1'7-position of Zl-O-acyl ajmaline compounds into a free 17-hydroxyl group, those com: pounds preferably used as starting material,.in which the half ester, such as carbobenzoxy-chloride and the like or by etherification with benzyl halides, such as benzylchloride and the like. The obtained di-esters can be easily hydrolysed into the 17-O-rnonoacylates, for example by heating an acid addition salt, such as the monohydrochloride, of the di-esters in water on a steam bath for a short time, for example about 5 to 45 minutes. The aforementioned dibenzylethers may be partially hydrogenolyzed, for example With the stoichiometric amount of catalytically activated hydrogen. In the so obtained compounds containing a protected l7-hydroxyl group, the free 21-hydroxyl group may be esterificd with a reactive functional derivative of a carboxylic acid of aliphatic character by methods in themselves known.
Depending on the procedure used, the new compounds are obtained in the free form or in the form of their salts. The salts of the new compounds may be converted into the free bases in a manner known per se, for example by reaction with a basic agent, for example aqueous ammonia, an alkali metal hydroxide, moist silver oxide and the like, or an ion exchange resin.
A resulting salt may be converted into another salt, for example, by treatment with a metal salt of an acid, preferably with such a metal salt of which the metal forms with the anion of the ajmaline compound an insoluble salt, or with an ion exchange resin.
The free bases may be converted into acid addition salts of inorganic or organic, pharmaceutically acceptable, nontoxic acids, if desired in the presence of a suitable solvent or diluent. Acids of the aforementioned kind are for example mineral acids, such as hydrochloric, hydrobromic, sulfuric, phosphoric, nitric or perchloric acid or organic carboxylic or sulfonic acids, such as formic, acetic, propionic, oxalic, succinic, glycollic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, dihydroxymaleic or pyruvic acid; phenylacetic, benzoic, para-aminobenzoic, anthranilic, para-hydroxybenzoic, salicylic or para-aminosalicylic acid; methane sulfonic, ethane sulfonic, hydroxyethane sulfonic or ethylene sulfonic acid; toluene sulfonic, naphthalene sulfonic or sulfanilic acid; methionine, tryptophan, lysine or arginine.
Quaternary ammonium derivatives of the compounds of this invention may be obtained by reacting a resulting free compound with a quaternating agent, preferably a lower alkyl halide, sulfate or sulfonate, such for example as, methyl or ethyl-chloride, -bromide or -iodide, dimethyl or diethyl sulfate, methyl or ethyl-methane sulfonate, -ethane sulfonate or -p-toluene sulfonate and the like.
A resulting quaternary ammonium compound may be converted into another quaternary ammonium compound, such as a quaternary ammonium hydroxide, for example,
8 i by reacting a quaternary ammonium halide ,with silver oxide, by treating a quaternary ammonium sulfate with barium hydroxide, or a quaternary ammonium salt with an anion exchange preparation, or by electrodialysis. From a resulting quaternary ammonium hydroxide, there may be formed a quaternary ammonium salt by treating it with an acid. Quaternary ammonium salts may be converted directly into other quaternary ammonium salts, for example, a quaternary ammonium iodide, when reacted with silver chloride or withhydrogen chloride in methanol, yields a quaternary ammonium chloride; a corresponding conversion may also be achievedby treating a quaternary ammonium salt with a suitable anion exchange preparation, for example, with those outlined hereinbefore as being useful for the preparation of acid. addition salts.
The above reactions, for example the salification or quaterin a closed vessel and/ or in the atmosphere of aninert gas,
e.g. nitrogen.
The invention also comprises any modification of the general process, wherein a compound obtainable as an intermediate at any stage of the'process is used as the starting material and the remaining step(s) of the process is (are) carried out; orthe process is discontinued at any stage, or inwhich the starting materials are formed in the course of the reaction or used in the form of their salts. Also included Withinthe scope of the invention are any new intermediates, such, for example, as compounds of the Formula I, in whichR'represents the acyl radical of an organic sulfonic acid or 21-O-R -ajmalidine and 2l-O-R isoajmalidine, in which R represents the acyl radical of a carboxylic acid of aliphatic character or of an organic sulfonic acid. Examples for theseacyl radicals are given hereinbefore.
In the process of this invention such starting materials are preferably used which lead to final products mentioned in the specification as preferred embodiments of the invention. t
The compounds of this invention may be used in the form of pharmaceutical preparations for enteral or parenteral use, which contain the new compounds, particularly the salts thereof in-admixture with a pharmaceutical organic or inorganic, solid or liquid carrier. For making up the preparations there can be employed substances which do not react with the new compounds, such as water, gelatine, lactose, starches, stearic acid, magnesium stearate, stearyl alcohol, talc, vegetable oils, benzyl alcohol, gums, propylene glycol, polyalkylene glycols, cholesterol or any other known carrier for pharmaceutical preparations. The latter may be in solid form, for example, as tablets, dragees, capsules and the like, or in liquid form, for example, as solutions, suspensions, emulsions and the like. If desired, they may contain auxiliary substances, such as preserving, stabilizing, wetting, emulsifying agents and the like, salts for varying the osmotic pressure, butters, etc. They also may contain, in combination, other useful substances.
The following examples illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade Example 1 To a mixture of 2.00 g. of ajmaline and 20 ml. of tetrahydrofuran, rapidly stirred in a flask cooled in an ice bath, is added dropwise and simultaneously ml. of a IO-nsolution of aqueous sodium hydroxide and a solution of 4 ml. of acetyl chloride in ml. of tetrahydrofuran over a period of 1% hours at such a rate that the solution is always alkaline. Stirring is continued 30 minutes and then the reaction mixture is extracted with benzene, the extract is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue (2.40 g.) yields after recrystallization from benzenehexane 1.04 g. of 21-O-acetyl ajmaline, which melts 5 first at 117, resolidifies and remelts at l87-l.88; [a] =+100 (in methanol), pk -=14 methyl-Cellosolve) Example 2 1.3 89 g. of isoajmaline are acetylated with acetylchloride in tetrahydrofuran and in the presence of sodium hydroxide using the sameprocedure as described inExample 1. There are obtained 500 mg. of ZI-O-acetyl-isoajmaline melting at 210-211"; [a] =+36.5 (in methanol), pk =4.9 (80% .methyl-Cellosolve).
Example 3 The mixture of 933 mg. of 21-O-acetyl-ajmaline, 15 ml. methylene chloride and 3 ml. methyliodide is allowed to stand overnight atroom temperature. An oil, representing the 2l-O-acetyl-ajmaline methiodide, settles out, which doesnot crystallizefrom a number of solvents.
Example 4 The mixture of 244 mg. of 2l-O-acetyl-isoajmaline, 10 ml. methylene chloride and 2 ml. of methyliodide is allowed to stand at room temperature overnight. The oil separated crystallizes on scratching. There are obtained 285 mg. of 2l-O-acetyl-isoajmaline methiodide which melts at 254-256 and after recrystallization from methanol at 259-261".
Example 5 The mixture of 22 g. of ajmaline and 100ml. of acetic acid anhydride is heated on the steam bath for 10 minutes.
Thereupon, the acetic acid anhydride is removed under reduced pressure and the residue crystallized from diethyl ether. There are obtained 9 g. of 2l-O-acetyl-ajmaline melting at l191.
Example .6
The mixture of 1.00 g. of isoajmaline and 5 ml. acetic acid anhydride is heated on the steam bath for 5 minutes and then evaporated under reduced pressure. The residue crystallizes on addition of diethyl ether and yields 184 mg. of 2l-O-acetyl-isoajmaline melting at 210-212".
Example 7 7 Example 8 139 mg. of 21-0- [tri- (methoxymethyl) -acetyl] -ajmaline dissolved in 1 ml. of methanol is treated with a diethylether-solution of hydrogen chloride. The solvents are partly removed and the residue again treated with ethereal hydrogen chloride. The precipitated ZI-O-[tri-(methoxymethyl) -acetyl] -ajmaline monohydrochloride is filtered oil and recrystallized from methanol-diethylether; MP. 278-280" [a] =+87.4 (in methanol).
Example 9 The mixture of 300 mg. of 21-O-acetyl-ajmalidine and 10 ml. of methanol is shaken in an atmosphere of hydrogen in the presence of 50 mg. of pro-reduced platinum oxide. catalyst is filtered oil and the solution concentrated to dryness. The so obtained 21-O-acetyl sandwicine (21-O- acetyl-17-epi-ajmaline) is an amorphous substance, 11 :1742 cmr- Its hydrochloride, prepared according to the method given in Example 8 melts at 250251 with decomposition.
When the uptake of hydrogen has ceased, the
The starting material can be prepared in the following manner:
The mixture of 375 mg. ajmalidine, 4 ml. of benzene and 0.4 ml. of acetic anhydride is briefly heated on the steam bath. The cooled solution is Washed with dilute aqueous ammonia, dried over anhydrous sodiumsulfate and evaporated to dryness. The 21-O-acetyl-ajma1idine formed (400 mg.) is recrystallized from ethanol and melts at 180182; 11 :1745 emf (broad band).
Example 10 250 mg. of sandwicine in 4 ml. of benzene are heated briefly on the steam bath with 250 mg. of acetyl chloride. The 21-O-acetyl-sandwicine hydrochloride crystallizes out and is filtered off; M.P. 250-251 (dec.). The free base generated from th salt is amorphous but showes the carbonyl band in the infra-red spectrum at 1738 cm.-
The starting material may be prepared as follows:
300 mg. of ajmalidine dissolved in 10 ml. of methanol are catalytieally reduced as in shown in Example 9. The obtained amorphous sandwicine (300 mg.) has the expected properties, for example [a] =175 (in chloroform), the infra-red spectrum shows no absorption in the carbonyl region.
What is claimed is:
1. A member selected from the group consisting of a compound of the Formula I in which R is lower alkanoyl substituted by lower alltoxy, a lower alkyl quaternary ammonium compound thereof,
. and a non-t0xic acid addition salt of such compound.
2. ZI-O-R -ajmaline, in which R is lower alkanoyl substituted by lower alkoxy.
3. 21-O-R -isaojmaline, in which R is lower alkanoyl substituted by lower alkoxy.
4. 21-O-R -sandwicine, in which R is lower alkanoyl substituted by lower alkoxy. 5. 21-O -[tri-(methoxymethyl)-acetyl]-ajmaline.
References Cited in the file of this patent Siddiqui et al.: J. Indian Chem. Soc., vol. 9, (1932), pages 539, 540.
Anet et al.: J. Chem. Soc. (1954), pages l2421260.
Gorman et al.: Tetrahedron, v01. 1 (1957), pages
Claims (1)
1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA I
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US3392173A (en) * | 1964-03-09 | 1968-07-09 | Lilly Co Eli | Novel acyl derivatives of desacetyl-vincaleukoblastine and processes for their preparation |
US3414577A (en) * | 1962-01-10 | 1968-12-03 | Boehringer Sohn Ingelheim | Quaternary ammonium salts of ajmaline |
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US3414577A (en) * | 1962-01-10 | 1968-12-03 | Boehringer Sohn Ingelheim | Quaternary ammonium salts of ajmaline |
US3392173A (en) * | 1964-03-09 | 1968-07-09 | Lilly Co Eli | Novel acyl derivatives of desacetyl-vincaleukoblastine and processes for their preparation |
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