CH544070A - N-phenethyl amides with pharmacodynamic activity - esp as hypotensive antipyretics and anti-parkinson agents - Google Patents
N-phenethyl amides with pharmacodynamic activity - esp as hypotensive antipyretics and anti-parkinson agentsInfo
- Publication number
- CH544070A CH544070A CH369273A CH369273A CH544070A CH 544070 A CH544070 A CH 544070A CH 369273 A CH369273 A CH 369273A CH 369273 A CH369273 A CH 369273A CH 544070 A CH544070 A CH 544070A
- Authority
- CH
- Switzerland
- Prior art keywords
- oxo
- formula
- hypotensive
- antipyretics
- esp
- Prior art date
Links
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical class NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 title claims description 7
- 208000001953 Hypotension Diseases 0.000 title description 2
- 230000001754 anti-pyretic effect Effects 0.000 title description 2
- 239000000939 antiparkinson agent Substances 0.000 title description 2
- 239000002221 antipyretic Substances 0.000 title description 2
- 208000021822 hypotensive Diseases 0.000 title description 2
- 230000001077 hypotensive effect Effects 0.000 title description 2
- 229940125688 antiparkinson agent Drugs 0.000 title 1
- 229940125716 antipyretic agent Drugs 0.000 title 1
- 230000003285 pharmacodynamic effect Effects 0.000 title 1
- -1 phenylsulphonyl Chemical group 0.000 claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims description 11
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 8
- 239000007858 starting material Substances 0.000 claims description 8
- 125000003170 phenylsulfonyl group Chemical class C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 abstract 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 abstract 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 229960003638 dopamine Drugs 0.000 description 4
- 239000000155 melt Substances 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- JXPQMHIXNPWEEK-UHFFFAOYSA-N 2-[3,4-bis(phenylmethoxy)phenyl]ethanamine Chemical compound C=1C=CC=CC=1COC1=CC(CCN)=CC=C1OCC1=CC=CC=C1 JXPQMHIXNPWEEK-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000006264 debenzylation reaction Methods 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000000706 filtrate 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
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 1
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 1
- VHSFUGXCSGOKJX-UHFFFAOYSA-N 5-oxo-1-phenylmethoxycarbonylpyrrolidine-2-carboxylic acid Chemical compound OC(=O)C1CCC(=O)N1C(=O)OCC1=CC=CC=C1 VHSFUGXCSGOKJX-UHFFFAOYSA-N 0.000 description 1
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-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
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- KLGIPMFLWJDMDH-UHFFFAOYSA-N N-[2-(3,4-dihydroxyphenyl)ethyl]-1-phenylmethanesulfonamide Chemical compound C(C1=CC=CC=C1)S(=O)(=O)NCCC1=CC(O)=C(O)C=C1 KLGIPMFLWJDMDH-UHFFFAOYSA-N 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000000648 anti-parkinson Effects 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- KCIDZIIHRGYJAE-YGFYJFDDSA-L dipotassium;[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] phosphate Chemical compound [K+].[K+].OC[C@H]1O[C@H](OP([O-])([O-])=O)[C@H](O)[C@@H](O)[C@H]1O KCIDZIIHRGYJAE-YGFYJFDDSA-L 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229960001149 dopamine hydrochloride Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 229940117803 phenethylamine Drugs 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000007787 solid 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
- 239000000126 substance Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension 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
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
- C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Title amides are of formula (Ie (where R is lower t-alkoxycarbonyl, pyroglutamyl, opt lower alkyl-substd. phenylsulphonyl or nitro-substd. phenylthio) and their salts.
Description
Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung von Phenäthylamiden der allgemeinen Formel
EMI1.1
in der R t-Alkoxycarbonyl, 5-Oxo-2-pyrrolidincarbonyl oder gegebenenfalls alkylsubstituiertes Phenylsulfonyl darstellt, sowie von Salzen dieser Verbindungen.
Die vorstehend genannten aliphatischen Reste können sowohl geradkettig als auch verzweigt sein. Die Alkylreste enthalten bevorzugt bis zu 7 Kohlenstoffatome, wie z. B. Methyl, Isopropyl, n-Hexyl oder n-Heptyl. Die t-Alkoxycarbonylgruppen enthalten bevorzugt bis 8 Kohlenstoffatome, wie z. B. die t-Butoxycarbonyl- oder t-Heptyloxycarbonylgruppe.
Die Verbindungen der Formel I bilden mit Basen Salze.
Solche Salze sind z. B. das Dinatrium-, Dikalium- und Diammoniumsalz.
Interessante Vertreter der erfindungsgemässen Phen äthylamide der Formel I sind: - N-(t-Butoxycarbonyl)-dopamin [N-(t-Butoxycarbonyl)
N'-(3,4-dihydroxyphenäthyl) -amin] - N-(3,4-Dihydroxyphenäthyl)-5-oxo-L-2-pyrrolidincarb- oxamid und Salze hiervon - N-(p-Toluolsulfonyl)-dopamin sowie auch Salze dieser Verbindungen.
Das erfindungsgemässe Verfahren zur Herstellung der Phenäthylamide der Formel I und deren Salze ist dadurch gekennzeichnet, dass man eine Verbindung der allgemeinen Formel II
EMI1.2
in der R' t-Alkoxycarbonyl, 5-Oxo-2-pyrrolidincarbonyl, N-B enzyloxycarbonyl-5-oxo-2-pyrrolidincarbonyl oder gegebenenfalls alkylsubstituiertes Phenylsulfonyl darstellt, debenzyliert
EMI1.3
worauf man erwünschtenfalls ein erhaltenes Produkt in ein Salz überführt.
Die Herstellung der Ausgangsverbindungen der Formel II kann in der Weise erfolgen, dass man 3,4-bis-(Benzyloxy)phenäthylamin oder ein Salz hiervon mit einem die Gruppe R' abgebenden Mittel behandelt. Diese Reaktion kann unter den für Acylierungsreaktionen üblichen Bedingungen durchgeführt werden. Beispielsweise setzt man 3,4-bis-(Benzyloxy)-phenäthylamin mit dem entsprechenden Säurehalogenid, vorzugsweise mit dem Chlorid, oder auch mit dem entsprechenden Säureazid um. Für den Fall, dass R' 5-Oxo-2-pyrrolidincarbonyl oder N-B enzyloxycarbonyl5 -oxo-2-pyrrolidin- carbonyl darstellt, kann das 3 ,4-bis-(B enzyloxy)-Phen- äthylamin auch mit einem aktivierten Ester behandelt werden.
Beispielsweise verwendet man einen Ester der 5-Oxo2-pyrrolidincarbonsäure oder der N-Benzyloxycarbonyl-5oxo-2-pyrrolidincarbonsäure mit N-Hydroxysuccinimid, N Hydroxyphthalimid oder p-Nitrophenol. Diese Reaktionen werden vorzugsweise in organischen Lösungsmitteln, wie z. B. Pyridin, Tetrahydrofuran, Dimethylformamid, Dioxan, gegebenenfalls in Gegenwart eines basischen Mittels, wie z. B. Triäthylamin oder Pyridin, durchgeführt. Für den Fall, dass R' 5-Oxo-2-pyrrolidincarbonyl oder N-Benzyloxycarb onyl-5-oxo-2-pyrrolidincarbonyl darstellt, kann 3,4-bis-(Benzyloxy)-phenäthylamin oder ein Salz hiervon auch direkt mit der entsprechenden Carbonsäure oder einem Salz davon in Gegenwart eines wasserabspaltenden Mittels, wie z. B.
Dicyclohexylcarbodiimid oder Carbonyldiimidazol, gegebenenfalls in Gegenwart eines basischen Mittels wie Triäthylamin oder Pyridin, zu den Ausgangsverbindungen der Formel II umgesetzt werden.
Die erfindungsgemässe Debenzylierung der Ausgangsverbindung der Formel II kann beispielsweise hydrogenolytisch mit Wasserstoff und einem Hydrierungskatalysator, wie Platin, Nickel oder Palldium, gegebenenfalls in Verbindung mit einer Trägersubstanz, wie Kohle oder Bariumsulfat, durchgeführt werden. Vorzugsweise arbeitet man in eineminertenLösungsmittel,z. B. in einem niederen Alkanol, z. B. in Äthanol, oder in Tetrahydrofuran, Dimethylformamid, Dimethylsulfoxid oder in einer niederen Alkancarbonsäure, z. B. in Essigsäure. Die Hydrierungstemperatur liegt vorzugsweise im Bereich von etwa 0 bis 80 C.
Für den Fall, dass R' 5-Oxo-2-pyrrolidincarbonyl, N Benzyloxycarbonyl-5-oxo-2-pyrrolidincarbonyl oder p-To luolsulfonyl darstellt, kann die Debenzylierung auch durch Behandeln mit Trifluoressigsäure bei einer Temperatur zwischen etwa 200 C und dem Siedepunkt des Reaktionsgemisches durchgeführt werden.
Eine vorhandene N-B enzyloxycarbonyl-5-oxo-2-pyrro- lidincarbonylgruppe R' wird bei der Debenzylierung der Verbindungen der Formel II in die 5-Oxo-2-pyrrolidincarbonylgruppe übergeführt.
Die nach der Durchführung des erfindungsgemässen Verfahrens erhaltenen Phenäthylamide der Formel I enthalten einen Säurerest R, welcher unter stark sauren Bedingungen, insbesondere bei höheren Temperaturen, abgespalten werden kann. Diese Säureempfindlichkeit gilt insbesondere für die t-Alkoxycarbonylgruppen, z. B. für die t-Butoxycarbonylgruppe. Es soll deshalb mit Rücksicht auf die erwähnten Säurereste R bei der Aufarbeitung des Endproduktes darauf geachtet werden, dass das Produkt nicht stark angesäuert bzw. stark angesäuert und erhitzt wird, weil stark saure Bedingungen, besonders in Verbindung mit erhöhten Temperaturen, zu einer teilweisen oder völligen Abspaltung dieser Gruppen R führen kann, was eine Verringerung der Ausbeute zur Folge hat.
Die neuen Phenäthylamide der Formel I und deren Salze sind pharmakodynamisch wirksam. Sie zeichnen sich durch vielfältige Wirkungen auf das Nervensystem aus. Sie besitzen insbesondere hypotensive, antipyretische bzw. Antiparkinson-Eigenschaften.
Die Phenäthylamide der Formel I können als Heilmittel, z. B. in Form pharmazeutischer Präparate Verwendung finden, welche diese Verbindungen oder ihre Salze in Mischung mit einem für die enterale oder parenterale Applikation geeigneten pharmazeutischen, organischen oder anorganischen inerten Trägermaterial, wie z. B. Wasser, Gelatine, Gummiarabicum, Milchzucker, Stärke, Magnesiumstearat, Talk, pflanzliche Öle, Polyalkylenglykole, Vaseline usw. enthalten. Die pharmazeutischen Präparate können in fester Form, z. B. als Tabletten, Dragees, Suppositorien, Kapseln, oder in flüssiger Form, z. B. als Lösungen, Suspensionen oder Emulsionen, vorliegen. Die Präparate sind gegebenenfalls sterilisiert und/oder enthalten Hilfsstoffe, wie Konservierungs-, Stabilisierungs-, Netz- oder Emulgiermittel, oder Salze zur Veränderung des osmotischen Druckes oder Puffer.
Sie können auch noch andere therapeutisch wertvolle Stoffe enthalten.
Eine Dosierungseinheit der pharmazeutischen Präparate kann zweckmässig etwa 10 bis etwa 1000 mg Wirkstoff enthalten.
Die pro Tag zu verabreichende Wirkstoffmenge richtet sich nach dem jeweiligen Fall. Im allgemeinen wird bei oraler Verabreichung eine Wirkstoffmenge von etwa 0,1 bis etwa 4 g, insbesondere von etwa 1,5 bis etwa 3 g, anzuwenden sein.
Bei intravenöser Applikation kann die pro Tag verabreichte Wirkstoffmenge zwischen etwa 10 mg und etwa 2 g, insbesondere bei etwa 1 g, liegen.
Die Applikation erfolgt zweckmässig in Einzeldosen über den Tag verteilt.
Wie Versuche an Ratten gezeigt haben, werden die erfindungsgemässen Verbindungen oral resorbiert und u. a. zu Dopamin metabolisiert. Die erfindungsgemässen Verbindungen sind deshalb dazu geeignet, in der Humanmedizin auftretende Erkrankungen, welche auf Dopaminmangel beruhen, wie z. B. Morbus Parkinson, günstig zu beeinflussen.
Beispiel 1
5,6 g 1 -B enzyloxycarbonyl-N-[3 ,4-bis-(benzyloxy)- phenäthyl]-5-oxo-L-2-pyrrolidincarboxamid werden in Gegenwartvon 2 g 5 XOigem Pd/Cin 100 ml absolutem Methanol bei Normalbedingungen hydriert. Das nach Abfiltrieren des Katalysators und Eindampfen des Filtrates bei 30 C/ 12 torr zurückbleibende 2,5 g N-(3,4-Dihydroxyphenäthyl)5-oxo-L-2-pyrrolidincarboxamid schmilzt bei 185 bis 186 C.
Die Ausgangsverbindung kann wie folgt hergestellt werden:
Ein Gemisch von 7,4 g 3,4-Dibenzyloxydopaminhydrochlorid, 8,9 g N-carbobenzoxy-L-pyroglutaminsäure-dicyclohexylaminsalz und 4,12 g Dicyclohexylcarbodiimid in 120 ml absolutem Tetrahydrofuran und 80 ml Methylenchlorid wird 15 Stunden bei Raumtemperatur gerührt. Der entstandene Dicyclohexylharnstoff wird abfiltriert. Das Filtrat wird bei 40 C/12 torr eingedampft. Der Rückstand wird in Essigester/Methylenchlorid 1:1 aufgenommen und durch 150 g Kieselgel filtriert. Das aus dem Eluat isolierte 1-Benzyloxy carbonyl-N-[3 ,4 -bis-(benzyloxy)-phenäthyl]-5-oxo-L-2-pyrrolidincarboxamid schmilzt nach dem Umkristallisieren aus Äther bei 144-145" C.
Beispiel 2
14,8 g O,O'-Dibenzyl-N-toluolsulfonyldopamin werden in Gegenwartvon3 gPalladiumkohle [5%] in 300 ml absolutem Methanol bei Normalbedingungen hydriert. Das aus der Hydrierlösung isolierte N-Toluolsulfonyldopamin schmilzt bei 128-129 .
Die Ausgangsverbindung kann wie folgt hergestellt werden:
Eine Lösung von 3,7 g O,O'-Dibenzyl-dopamin-hydrochlorid in 80 ml Pyridin wird bei 0 C tropfenweise mit einer Lösung von 2,3 g p-Toluolsulfochlorid in 30 ml absolutem Dioxan versetzt. Das Gemisch wird 12 Stunden bei Raumtemperatur gerührt, dann auf Eis gegossen, mit konzentrierter Salzsäure congosauer gestellt und mit Essigester extrahiert.
Das aus dem Extrakt gewonnene O,O'-Dibenzyl-N-toluolsulfonyldopamin wird in Äther aufgenommen und durch 30 g Kieselgel filtriert. Die reine Verbindung schmilzt bei 101 bis 103"C.
The present invention relates to a process for the preparation of phenethylamides of the general formula
EMI1.1
in which R represents t-alkoxycarbonyl, 5-oxo-2-pyrrolidine carbonyl or optionally alkyl-substituted phenylsulfonyl, and salts of these compounds.
The abovementioned aliphatic radicals can be either straight-chain or branched. The alkyl radicals preferably contain up to 7 carbon atoms, such as. B. methyl, isopropyl, n-hexyl or n-heptyl. The t-alkoxycarbonyl groups preferably contain up to 8 carbon atoms, such as. B. the t-butoxycarbonyl or t-heptyloxycarbonyl group.
The compounds of the formula I form salts with bases.
Such salts are e.g. B. the disodium, dipotassium and diammonium salts.
Interesting representatives of the inventive phenethylamides of the formula I are: - N- (t-butoxycarbonyl) dopamine [N- (t-butoxycarbonyl)
N '- (3,4-dihydroxyphenethyl) amine] - N- (3,4-dihydroxyphenethyl) -5-oxo-L-2-pyrrolidinecarboxamide and salts thereof - N- (p-toluenesulfonyl) dopamine as well Salts of these compounds.
The process according to the invention for preparing the phenethylamides of the formula I and their salts is characterized in that a compound of the general formula II
EMI1.2
in which R 'is t-alkoxycarbonyl, 5-oxo-2-pyrrolidinecarbonyl, N-B is enzyloxycarbonyl-5-oxo-2-pyrrolidinecarbonyl or optionally alkyl-substituted phenylsulfonyl, debenzylated
EMI1.3
whereupon, if desired, a product obtained is converted into a salt.
The starting compounds of the formula II can be prepared in such a way that 3,4-bis (benzyloxy) phenethylamine or a salt thereof is treated with an agent which donates the group R '. This reaction can be carried out under the usual conditions for acylation reactions. For example, 3,4-bis (benzyloxy) phenethylamine is reacted with the corresponding acid halide, preferably with the chloride, or with the corresponding acid azide. In the event that R 'represents 5-oxo-2-pyrrolidine carbonyl or NB enzyloxycarbonyl5 -oxo-2-pyrrolidine carbonyl, the 3,4-bis (B enzyloxy) -phenethylamine can also be treated with an activated ester .
For example, an ester of 5-oxo2-pyrrolidinecarboxylic acid or of N-benzyloxycarbonyl-5oxo-2-pyrrolidinecarboxylic acid with N-hydroxysuccinimide, N-hydroxyphthalimide or p-nitrophenol is used. These reactions are preferably carried out in organic solvents, such as. Example, pyridine, tetrahydrofuran, dimethylformamide, dioxane, optionally in the presence of a basic agent such as. B. triethylamine or pyridine carried out. In the event that R 'is 5-oxo-2-pyrrolidine carbonyl or N-benzyloxycarb onyl-5-oxo-2-pyrrolidine carbonyl, 3,4-bis (benzyloxy) phenethylamine or a salt thereof can also be used directly with the corresponding Carboxylic acid or a salt thereof in the presence of a dehydrating agent, such as. B.
Dicyclohexylcarbodiimide or carbonyldiimidazole, optionally in the presence of a basic agent such as triethylamine or pyridine, are converted to the starting compounds of the formula II.
The debenzylation according to the invention of the starting compound of the formula II can, for example, be carried out hydrogenolytically using hydrogen and a hydrogenation catalyst such as platinum, nickel or pallium, optionally in conjunction with a carrier such as carbon or barium sulfate. It is preferred to operate in an inert solvent, e.g. B. in a lower alkanol, e.g. B. in ethanol, or in tetrahydrofuran, dimethylformamide, dimethyl sulfoxide or in a lower alkanecarboxylic acid, e.g. B. in acetic acid. The hydrogenation temperature is preferably in the range from about 0 to 80 C.
In the event that R 'represents 5-oxo-2-pyrrolidine carbonyl, N benzyloxycarbonyl-5-oxo-2-pyrrolidine carbonyl or p-toluenesulfonyl, the debenzylation can also be carried out by treating with trifluoroacetic acid at a temperature between about 200 ° C. and the boiling point of the reaction mixture can be carried out.
An existing N-B enzyloxycarbonyl-5-oxo-2-pyrrolidine carbonyl group R 'is converted into the 5-oxo-2-pyrrolidine carbonyl group in the debenzylation of the compounds of the formula II.
The phenethylamides of the formula I obtained after carrying out the process according to the invention contain an acid radical R which can be split off under strongly acidic conditions, in particular at elevated temperatures. This acid sensitivity applies in particular to the t-alkoxycarbonyl groups, e.g. B. for the t-butoxycarbonyl group. With regard to the acid residues R mentioned, care should therefore be taken when working up the end product that the product is not strongly acidified or strongly acidified and heated, because strongly acidic conditions, especially in connection with elevated temperatures, lead to partial or total Cleavage of these groups R can lead, which results in a reduction in the yield.
The new phenethylamides of the formula I and their salts are pharmacodynamically active. They are characterized by a variety of effects on the nervous system. In particular, they have hypotensive, antipyretic or anti-Parkinson properties.
The Phenäthylamide of formula I can be used as remedies, for. B. in the form of pharmaceutical preparations use which these compounds or their salts in a mixture with a pharmaceutical, organic or inorganic inert carrier material suitable for enteral or parenteral administration, such as. B. water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, etc. contain. The pharmaceutical preparations can be in solid form, e.g. B. as tablets, coated tablets, suppositories, capsules, or in liquid form, e.g. B. as solutions, suspensions or emulsions. The preparations are optionally sterilized and / or contain auxiliaries such as preservatives, stabilizers, wetting agents or emulsifiers, or salts for changing the osmotic pressure or buffers.
They can also contain other therapeutically valuable substances.
A dosage unit of the pharmaceutical preparations can expediently contain about 10 to about 1000 mg of active ingredient.
The amount of active ingredient to be administered per day depends on the respective case. In general, in the case of oral administration, an amount of active ingredient from about 0.1 to about 4 g, in particular from about 1.5 to about 3 g, will have to be used.
In the case of intravenous administration, the amount of active ingredient administered per day can be between about 10 mg and about 2 g, in particular about 1 g.
The application takes place expediently in single doses distributed over the day.
As tests on rats have shown, the compounds according to the invention are orally absorbed and u. a. metabolized to dopamine. The compounds according to the invention are therefore suitable for treating diseases which occur in human medicine and which are based on dopamine deficiency, such as, for. B. Parkinson's disease to influence favorably.
example 1
5.6 g of 1 -B enzyloxycarbonyl-N- [3, 4-bis- (benzyloxy) phenethyl] -5-oxo-L-2-pyrrolidinecarboxamide are added to 100 ml of absolute methanol in the presence of 2 g of 5% Pd / Cin under normal conditions hydrogenated. The 2.5 g of N- (3,4-dihydroxyphenethyl) 5-oxo-L-2-pyrrolidinecarboxamide that remains after filtering off the catalyst and evaporating the filtrate at 30 ° C./12 torr melts at 185 to 186 ° C.
The starting compound can be made as follows:
A mixture of 7.4 g of 3,4-dibenzyloxydopamine hydrochloride, 8.9 g of N-carbobenzoxy-L-pyroglutamic acid dicyclohexylamine salt and 4.12 g of dicyclohexylcarbodiimide in 120 ml of absolute tetrahydrofuran and 80 ml of methylene chloride is stirred for 15 hours at room temperature. The resulting dicyclohexylurea is filtered off. The filtrate is evaporated at 40 C / 12 torr. The residue is taken up in ethyl acetate / methylene chloride 1: 1 and filtered through 150 g of silica gel. The 1-benzyloxy carbonyl-N- [3, 4 -bis- (benzyloxy) -phenethyl] -5-oxo-L-2-pyrrolidinecarboxamide isolated from the eluate melts after recrystallization from ether at 144-145 "C.
Example 2
14.8 g of O, O'-dibenzyl-N-toluenesulfonyldopamine are hydrogenated in the presence of 3 g of palladium carbon [5%] in 300 ml of absolute methanol under normal conditions. The N-toluenesulfonyldopamine isolated from the hydrogenation solution melts at 128-129.
The starting compound can be made as follows:
A solution of 3.7 g of O, O'-dibenzyl-dopamine hydrochloride in 80 ml of pyridine is treated dropwise at 0 ° C. with a solution of 2.3 g of p-toluenesulfonyl chloride in 30 ml of absolute dioxane. The mixture is stirred for 12 hours at room temperature, then poured onto ice, made congo acidic with concentrated hydrochloric acid and extracted with ethyl acetate.
The O, O'-dibenzyl-N-toluenesulfonyldopamine obtained from the extract is taken up in ether and filtered through 30 g of silica gel. The pure compound melts at 101 to 103 "C.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH369273A CH544070A (en) | 1970-10-30 | 1970-10-30 | N-phenethyl amides with pharmacodynamic activity - esp as hypotensive antipyretics and anti-parkinson agents |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH369273A CH544070A (en) | 1970-10-30 | 1970-10-30 | N-phenethyl amides with pharmacodynamic activity - esp as hypotensive antipyretics and anti-parkinson agents |
| CH1604470A CH540230A (en) | 1970-10-30 | 1970-10-30 | Process for the production of phenethylamides |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH544070A true CH544070A (en) | 1973-11-15 |
Family
ID=4414026
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH369273A CH544070A (en) | 1970-10-30 | 1970-10-30 | N-phenethyl amides with pharmacodynamic activity - esp as hypotensive antipyretics and anti-parkinson agents |
| CH1604470A CH540230A (en) | 1970-10-30 | 1970-10-30 | Process for the production of phenethylamides |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1604470A CH540230A (en) | 1970-10-30 | 1970-10-30 | Process for the production of phenethylamides |
Country Status (10)
| Country | Link |
|---|---|
| AU (1) | AU3357971A (en) |
| BE (1) | BE774674A (en) |
| CA (1) | CA958020A (en) |
| CH (2) | CH544070A (en) |
| DE (1) | DE2153825A1 (en) |
| FR (1) | FR2111950B1 (en) |
| GB (1) | GB1307028A (en) |
| IL (1) | IL37702A (en) |
| NL (1) | NL7113513A (en) |
| ZA (1) | ZA716133B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010534691A (en) * | 2007-07-30 | 2010-11-11 | ラルフ ローゼル | Substances for the protection of cells and / or tissues |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4443473A (en) * | 1981-06-30 | 1984-04-17 | The Procter & Gamble Company | Carbamate derivatives |
-
1970
- 1970-10-30 CH CH369273A patent/CH544070A/en unknown
- 1970-10-30 CH CH1604470A patent/CH540230A/en not_active IP Right Cessation
-
1971
- 1971-09-13 ZA ZA716133A patent/ZA716133B/en unknown
- 1971-09-13 IL IL37702A patent/IL37702A/en unknown
- 1971-09-16 AU AU33579/71A patent/AU3357971A/en not_active Expired
- 1971-10-01 NL NL7113513A patent/NL7113513A/xx unknown
- 1971-10-22 CA CA125,840A patent/CA958020A/en not_active Expired
- 1971-10-28 DE DE19712153825 patent/DE2153825A1/en active Pending
- 1971-10-28 FR FR7138782A patent/FR2111950B1/fr not_active Expired
- 1971-10-29 BE BE774674A patent/BE774674A/en unknown
- 1971-10-29 GB GB5033171A patent/GB1307028A/en not_active Expired
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010534691A (en) * | 2007-07-30 | 2010-11-11 | ラルフ ローゼル | Substances for the protection of cells and / or tissues |
Also Published As
| Publication number | Publication date |
|---|---|
| CH540230A (en) | 1973-08-15 |
| FR2111950A1 (en) | 1972-06-09 |
| FR2111950B1 (en) | 1975-04-18 |
| IL37702A (en) | 1975-02-10 |
| DE2153825A1 (en) | 1972-05-04 |
| BE774674A (en) | 1972-05-02 |
| NL7113513A (en) | 1972-05-03 |
| ZA716133B (en) | 1972-06-28 |
| CA958020A (en) | 1974-11-19 |
| GB1307028A (en) | 1973-02-14 |
| AU3357971A (en) | 1973-03-22 |
| IL37702A0 (en) | 1971-11-29 |
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