CH496701A - 4-substd-1-4-oxo-4-phenylbutyl-piperidines - Google Patents
4-substd-1-4-oxo-4-phenylbutyl-piperidinesInfo
- Publication number
- CH496701A CH496701A CH99668A CH99668A CH496701A CH 496701 A CH496701 A CH 496701A CH 99668 A CH99668 A CH 99668A CH 99668 A CH99668 A CH 99668A CH 496701 A CH496701 A CH 496701A
- Authority
- CH
- Switzerland
- Prior art keywords
- formula
- addition salts
- piperidines
- acid addition
- oxo
- Prior art date
Links
- 239000002253 acid Substances 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 4
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000000460 chlorine Chemical group 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- -1 1- (3-benzoylpropyl) -4- (3-hydroxyphenyl) -4-propionylpiperidine Chemical compound 0.000 claims description 2
- WLTFPYVGECWXFO-UHFFFAOYSA-N 1-phenyl-4-piperidin-1-ylbutan-1-one Chemical class C=1C=CC=CC=1C(=O)CCCN1CCCCC1 WLTFPYVGECWXFO-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 230000029936 alkylation Effects 0.000 claims 2
- 238000005804 alkylation reaction Methods 0.000 claims 2
- GJVNIMXPNFBEDC-UHFFFAOYSA-N 4-[4-acetyl-4-(3-hydroxyphenyl)piperidin-1-yl]-1-(4-bromophenyl)butan-1-one Chemical compound BrC1=CC=C(C(=O)CCCN2CCC(CC2)(C(C)=O)C2=CC(=CC=C2)O)C=C1 GJVNIMXPNFBEDC-UHFFFAOYSA-N 0.000 claims 1
- 229940100198 alkylating agent Drugs 0.000 claims 1
- 239000002168 alkylating agent Substances 0.000 claims 1
- FFSAXUULYPJSKH-UHFFFAOYSA-N butyrophenone Chemical compound CCCC(=O)C1=CC=CC=C1 FFSAXUULYPJSKH-UHFFFAOYSA-N 0.000 claims 1
- 229910052757 nitrogen Inorganic materials 0.000 claims 1
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 1
- 125000003386 piperidinyl group Chemical group 0.000 claims 1
- 239000011541 reaction mixture Substances 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 abstract description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 4
- 230000000202 analgesic effect Effects 0.000 abstract description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 abstract description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 abstract description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 abstract description 2
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 abstract 2
- XNEFVTBPCXGIRX-UHFFFAOYSA-N methanesulfinic acid Chemical compound CS(O)=O XNEFVTBPCXGIRX-UHFFFAOYSA-N 0.000 abstract 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 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
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- LXKNAUOWEJWGTE-UHFFFAOYSA-N 2-(3-methoxyphenyl)acetonitrile Chemical compound COC1=CC=CC(CC#N)=C1 LXKNAUOWEJWGTE-UHFFFAOYSA-N 0.000 description 2
- GHEFQKHLHFXSBR-UHFFFAOYSA-N 4-chloro-1-phenylbutan-1-one Chemical compound ClCCCC(=O)C1=CC=CC=C1 GHEFQKHLHFXSBR-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
- 238000006243 chemical reaction Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- KDRKQBSWSBMTHQ-UHFFFAOYSA-N 1-[4-(3-hydroxyphenyl)piperidin-4-yl]ethanone Chemical compound C(C)(=O)C1(CCNCC1)C1=CC(=CC=C1)O KDRKQBSWSBMTHQ-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- UKCHLVFIVJBCKE-UHFFFAOYSA-N 4-chloro-1-(4-chlorophenyl)butan-1-one Chemical compound ClCCCC(=O)C1=CC=C(Cl)C=C1 UKCHLVFIVJBCKE-UHFFFAOYSA-N 0.000 description 1
- 125000000242 4-chlorobenzoyl group Chemical group ClC1=CC=C(C(=O)*)C=C1 0.000 description 1
- DMCVVFIWYIKAEJ-UHFFFAOYSA-N 4-phenylpiperidine-4-carbonitrile Chemical class C=1C=CC=CC=1C1(C#N)CCNCC1 DMCVVFIWYIKAEJ-UHFFFAOYSA-N 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 238000005661 deetherification reaction Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 150000004658 ketimines Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 150000003053 piperidines Chemical group 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
- C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
(A) 4-Substd.-1-(4-oxo-4-phenylbutyl)-piperidines of formula: (I) where R1 = H, F, Cl, Br, OH, CH3 or CH3O; R2 = 1-4C alkyl or phenyl; R3 = H, Cl, Br, CH3 or CH3O; (B) Acid addn. salts of I. Strong analgesic activity. II (R1 = 3-OH; R2 = CH3) (13.2g., 0.06 mole), NaHCO3 (7.6g.) and II (R3 = 4-Cl) (19.5g., 0.09 mole) were refluxed in a mixture of DMF (70cc.) and THF (175.cc.) with NaI (0.3g.) for 24 hrs. Mixture was added to water (500cc.), crude base collected, washed with water and dried to give I (R1 = 3-OH; R2=CH3; R3 = 4-Cl) (21g. 87%). This was treated with warm soln. of methanesulphinic acid (5.1g.) in ethanol (50cc.), and ether added to ppte. the methanesulphonate (24.5g.). Recrystn. from ethanol/ether gave 23g. product with m.p. 164 deg.C.
Description
Verfahren zur Herstellung von neuen in 4-Stellung substituierten
1-(4- Oxo 4-phenyl-butyl) -piperidinen
Die Erfindung betrifft die Herstellung von neuen in 4-Stellung substituierten 1 - (4 - Oxo4-phenyl-butyl)-pi- peridinen der Formel
EMI1.1
worin R1 eine Alkylgruppe mit 1 bis 3 Kohlenstoffatomen und R Wasserstoff, Chlor, Brom, Methyl oder Methoxy bedeuten sowie von deren Säureadditionssalzen.
Erfindungsgemäss werden die neuen Verbindungen durch Umsetzung der entsprechenden sekundären Piperidine der Formel
EMI1.2
mit einem 4-Chlor-butyrophenon der Formel
EMI1.3
hergestellt.
Die Umsetzung erfolgt vorzugsweise in Gegenwart eines geeigneten organischen Lösungsmittels und einer schwachen Base, beispielsweise Natriumhydrogencarbonat, zweckmässig bei Temperaturen zwischen 30 und 150ob. Die Reaktionspartner können hierbei im Molverhältnis 1:1 eingesetzt werden, vorzugsweise wird jedoch das entsprechende 4-Chlorbutyrophenon im Überschuss angewendet. Zur Reaktionsbeschleunigung können geringe Mengen Alkalijodid zugesetzt werden. Als Lösungsmittel werden Alkohole oder ein Gemisch aus Dimethylformamid und Tetrahydrofuran bevorzugt.
Die erhaltenen Verbindungen der Formel I können in ihre physiologisch unbedenklichen Säureadditionssalze umgewandelt werden, beispielsweise durch Behandlung mit einer anorganis'chen oder organischen Säure wie Mineralsäuren, Essigsäure, Propionsäure, Capronsäure, Methansulfonsäure, Weinsäure, Fumarsäure, Maleinsäure, Citronensäure oder Ascorbinsäure.
Die neuen Verbindungen besitzen wertvolle, pharmakodynamische Eigenschaften. Sie weisen insbesondere eine starke, nichtnarkotische analgetische Wirksamkeit auf. Überraschenderweise wirken sie wesentlich stärker analgetisch als konstitutionell ähnliche Verbindungen der USA-Patentschrift, wie sich aus dem Vergleich der Writhingtest-Werte ergibt [E. Siegmund, R. Cadmus, G.
Lu, Proc. Soc. Exptl. Biol. and Med. 95 (1957) 729-7311:
EMI2.1
umgesetzt. Das entstehende in 1-Stellung tosylierte Ketimin kann entsprechend den zitierten Literaturstellen enttosyliert und zum Keton verseift werden.
Die folgenden Beispiele dienen zur Erläuterung der Erfindung:
Beispiel 1 1 - [3-(4-Chlor-benzoyl)-propylj-4-(3-hydroxy-phenyi)- -4-acetylpiperidin-methansulfonat
13,2 g (0,06 Mol) 4-(3-Hydroxy-phenyl)-4-acetyl-pi- peridin, 7,6 Natriumhydrogencarbonat und 19,5g (0,09 Mol) 4,4'-Dichlor-butyrophenon werden in 70 ml Dimethylformamid und 175 ml Tetrahydrofuran unter Zusatz von 0,3 g Natriumjodid 24 Stunden unter Rückfluss gekocht. Anschliessend wird am Rotationsverdampfer eingeengt und in 500 ml Wasser eingegossen. Dabei scheidet sich die Rohbase in fester Form ab. Sie wird abgesaugt, mit Wasser gewaschen und getrocknet (21 g ¯ 87% d.Th.). Die Base wird mit der berechneten Menge Methansulfonsäure (5,lg) in ca. 50ml Äthanol unter Erwärmen gelöst und die Lösung mit Äther bis eben zur Trübung versetzt.
Es kristallisieren 24,5 g Methansulfonat des 1 - [3-(4-Chlor-benzoyl)-propyl-4-(3-hydro- xy-phenyl)-4-acetyl-piperidin-methansulfonat mit einem Schmelzpunkt von 162 - 163,50C. Nach dem Umkristal
USA-Patentschrift Erflndungsgemäss
Writhingtest Writhingtest Rl R Rs ED5o R1 R2 R3 EDso mg/kg mg/kg H CH3 NOCH, 16 OH CH3 OCH 3,5 H CH3 Br 14,5 OH CH3 Br 0,57 H C3H7 Cl ¯ OH CM Cl 27
Die neuen Verbindungen lassen sich zu allen für pharmazeutische Zwecke üblichen Zubereitungsformen verarbeiten, zum Beispiel kann man daraus Pillen, Dra genes, Tabletten, Suppositorien,
Emulsionen, Lösungen und Injektionslösungen herstellen.
Die Ausgangsstoffe können nach bekannten Methoden hergestellt werden. Beispielsweise kann ein Arylacetonitril mit einem Amid der Formel
EMI2.2
in welcher X eine 3-Halogenäthylgruppe bedeutet, nach Eisleb, Chem. Ber. 74 (1941) 1433, unter Ringschluss umgesetzt werden. Der Ringschluss zur Herstellung der Ausgangsverbindung erfolgt mit dem 3-Methoxy-benzylcyanid. Anschliessend wird eine Ätherspaltung durchgeführt (vgl. deutsche Patentschrift Nr. 679 281, Schweizer Patent Nr. 236 312).
Grignard-Reaktionen von 4-Phenyl-4-cyan-piperidinen sind mehrfach in der Literatur beschrieben (z.B. DB 679281). Auf analoge Weise wurden zur Herstellung der Ausgangsstoffe l-Tosyl-4-phenyl-4-cyan-piperidine lisieren aus Äthanol/Äther werden 23 g reine Substanz vom Schmelzpunkt 163 - 1640C erhalten.
Analog der in Beispiel 1 angegebenen Arbeitsweise wurden die folgenden Endprodukte erhalten: Beispiel R1 R2 Smp. C
2 CH3 Cl Hydrochlorid
229-230
3 CH3 Br Hydrochlorid
207-209
4 CH3 H Hydrochlorid
192-193
5 CH3 CH3 Hydrochlorid
180-181
6 CH3 OCH Hydrochlorid
163-165
7 CM7 Cl Hydrochlorid
158-161
8 C3H7 CH3 Hydrochlorid
168-171
9 CM H Hydrochlorid
111-112 10 CM5 OCH Hydrochlorid
182-184
Process for the preparation of new ones substituted in the 4-position
1- (4- Oxo 4-phenyl-butyl) -piperidines
The invention relates to the preparation of new 4-substituted 1 - (4 - Oxo4-phenyl-butyl) -piperidines of the formula
EMI1.1
where R1 is an alkyl group having 1 to 3 carbon atoms and R is hydrogen, chlorine, bromine, methyl or methoxy and of their acid addition salts.
According to the invention, the new compounds are obtained by reacting the corresponding secondary piperidines of the formula
EMI1.2
with a 4-chloro-butyrophenone of the formula
EMI1.3
manufactured.
The reaction is preferably carried out in the presence of a suitable organic solvent and a weak base, for example sodium hydrogen carbonate, expediently at temperatures between 30 and 150ob. The reactants can be used in a molar ratio of 1: 1, but the corresponding 4-chlorobutyrophenone is preferably used in excess. Small amounts of alkali iodide can be added to accelerate the reaction. Alcohols or a mixture of dimethylformamide and tetrahydrofuran are preferred as solvents.
The compounds of the formula I obtained can be converted into their physiologically acceptable acid addition salts, for example by treatment with an inorganic or organic acid such as mineral acids, acetic acid, propionic acid, caproic acid, methanesulfonic acid, tartaric acid, fumaric acid, maleic acid, citric acid or ascorbic acid.
The new compounds have valuable pharmacodynamic properties. In particular, they have a strong, non-narcotic analgesic activity. Surprisingly, they have a much stronger analgesic effect than constitutionally similar compounds of the USA patent, as can be seen from the comparison of the writhing test values [E. Siegmund, R. Cadmus, G.
Lu, Proc. Soc. Exptl. Biol. And Med. 95 (1957) 729-7311:
EMI2.1
implemented. The resulting ketimine tosylated in the 1-position can be de-tosylated and hydrolyzed to the ketone in accordance with the literature references cited.
The following examples serve to illustrate the invention:
Example 1 1 - [3- (4-Chloro-benzoyl) -propylj-4- (3-hydroxyphenyi) -4-acetylpiperidine-methanesulfonate
13.2 g (0.06 mol) 4- (3-hydroxyphenyl) -4-acetyl-piperidine, 7.6 g sodium hydrogen carbonate and 19.5 g (0.09 mol) 4,4'-dichloro-butyrophenone are refluxed for 24 hours in 70 ml of dimethylformamide and 175 ml of tetrahydrofuran with the addition of 0.3 g of sodium iodide. It is then concentrated on a rotary evaporator and poured into 500 ml of water. The raw base separates out in solid form. It is filtered off with suction, washed with water and dried (21 g ¯ 87% of theory). The base is dissolved with the calculated amount of methanesulfonic acid (5, lg) in approx. 50 ml of ethanol while warming and ether is added to the solution until it becomes cloudy.
24.5 g of methanesulphonate of 1 - [3- (4-chloro-benzoyl) -propyl-4- (3-hydroxyphenyl) -4-acetyl-piperidine methanesulphonate with a melting point of 162-163 crystallize, 50C. After the recrystalline
USA patent according to the invention
Writhing test Writhing test Rl R Rs ED5o R1 R2 R3 EDso mg / kg mg / kg H CH3 NOCH, 16 OH CH3 OCH 3.5 H CH3 Br 14.5 OH CH3 Br 0.57 H C3H7 Cl ¯ OH CM Cl 27
The new compounds can be processed into all forms of preparation customary for pharmaceutical purposes, for example pills, dra genes, tablets, suppositories,
Prepare emulsions, solutions and injection solutions.
The starting materials can be produced by known methods. For example, an arylacetonitrile can be combined with an amide of the formula
EMI2.2
in which X is a 3-haloethyl group, according to Eisleb, Chem. Ber. 74 (1941) 1433, are implemented with ring closure. The ring closure for the preparation of the starting compound takes place with 3-methoxy-benzyl cyanide. An ether cleavage is then carried out (cf. German patent specification No. 679 281, Swiss patent No. 236 312).
Grignard reactions of 4-phenyl-4-cyano-piperidines are described several times in the literature (e.g. DB 679281). In an analogous manner, l-tosyl-4-phenyl-4-cyano-piperidines were lized from ethanol / ether to produce the starting materials, 23 g of pure substance with a melting point of 163-1640C are obtained.
The following end products were obtained analogously to the procedure given in Example 1: Example R1 R2 Mp. C
2 CH3 Cl hydrochloride
229-230
3 CH3 Br hydrochloride
207-209
4 CH3 H hydrochloride
192-193
5 CH3 CH3 hydrochloride
180-181
6 CH3 OCH hydrochloride
163-165
7 CM7 Cl hydrochloride
158-161
8 C3H7 CH3 hydrochloride
168-171
9 CM H hydrochloride
111-112 10 CM5 OCH hydrochloride
182-184
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEB0090912 | 1967-01-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH496701A true CH496701A (en) | 1970-09-30 |
Family
ID=6985550
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH99668A CH496701A (en) | 1967-01-26 | 1968-01-23 | 4-substd-1-4-oxo-4-phenylbutyl-piperidines |
Country Status (11)
| Country | Link |
|---|---|
| BE (1) | BE709966A (en) |
| CH (1) | CH496701A (en) |
| DE (1) | DE1670187A1 (en) |
| DK (1) | DK120192B (en) |
| ES (1) | ES349732A1 (en) |
| FR (2) | FR7256M (en) |
| GB (1) | GB1148427A (en) |
| IL (1) | IL29374A (en) |
| NL (1) | NL6800967A (en) |
| SE (1) | SE333569B (en) |
| YU (1) | YU18068A (en) |
-
1967
- 1967-01-26 DE DE19671670187 patent/DE1670187A1/en active Pending
-
1968
- 1968-01-23 NL NL6800967A patent/NL6800967A/xx unknown
- 1968-01-23 CH CH99668A patent/CH496701A/en not_active IP Right Cessation
- 1968-01-25 DK DK29968A patent/DK120192B/en unknown
- 1968-01-25 YU YU18068A patent/YU18068A/en unknown
- 1968-01-25 ES ES349732A patent/ES349732A1/en not_active Expired
- 1968-01-25 IL IL2937468A patent/IL29374A/en unknown
- 1968-01-26 BE BE709966D patent/BE709966A/xx unknown
- 1968-01-26 SE SE106068A patent/SE333569B/xx unknown
- 1968-01-26 GB GB431968A patent/GB1148427A/en not_active Expired
- 1968-01-26 FR FR137661A patent/FR7256M/fr not_active Expired
- 1968-01-26 FR FR1568084D patent/FR1568084A/fr not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| IL29374A (en) | 1971-07-28 |
| DK120192B (en) | 1971-04-26 |
| ES349732A1 (en) | 1969-11-01 |
| FR1568084A (en) | 1969-05-23 |
| BE709966A (en) | 1968-07-26 |
| DE1670187A1 (en) | 1971-01-21 |
| FR7256M (en) | 1969-09-08 |
| NL6800967A (en) | 1968-07-29 |
| SE333569B (en) | 1971-03-22 |
| YU18068A (en) | 1973-10-31 |
| GB1148427A (en) | 1969-04-10 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PL | Patent ceased |