DE1545597C - 1 (Cyclohex 2 enyl) 4 (3 hydroxyphenyl) piperidines, their acid addition salts and processes for their preparation - Google Patents
1 (Cyclohex 2 enyl) 4 (3 hydroxyphenyl) piperidines, their acid addition salts and processes for their preparationInfo
- Publication number
- DE1545597C DE1545597C DE19651545597 DE1545597A DE1545597C DE 1545597 C DE1545597 C DE 1545597C DE 19651545597 DE19651545597 DE 19651545597 DE 1545597 A DE1545597 A DE 1545597A DE 1545597 C DE1545597 C DE 1545597C
- Authority
- DE
- Germany
- Prior art keywords
- hydroxyphenyl
- cyclohex
- enyl
- acid addition
- addition salts
- 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
Links
- 239000002253 acid Substances 0.000 title claims description 7
- 150000003839 salts Chemical class 0.000 title claims description 7
- 239000011780 sodium chloride Substances 0.000 title claims description 7
- FHEPZBIUHGLJMP-UHFFFAOYSA-N cyclohexene Chemical group [CH]1CCCC=C1 FHEPZBIUHGLJMP-UHFFFAOYSA-N 0.000 title description 5
- 238000002360 preparation method Methods 0.000 title description 4
- 238000000034 method Methods 0.000 title description 3
- YNLRDTBLEOQPQL-UHFFFAOYSA-N 3-piperidin-1-ylphenol Chemical class OC1=CC=CC(N2CCCCC2)=C1 YNLRDTBLEOQPQL-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 9
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- 208000007101 Muscle Cramp Diseases 0.000 description 8
- 206010028334 Muscle spasms Diseases 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 230000000202 analgesic Effects 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 229960005301 pentazocine Drugs 0.000 description 6
- AJKDUJRRWLQXHM-UHFFFAOYSA-N 3-bromocyclohexene Chemical compound BrC1CCCC=C1 AJKDUJRRWLQXHM-UHFFFAOYSA-N 0.000 description 4
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- VOKSWYLNZZRQPF-UHFFFAOYSA-N Talwin Chemical compound C1C2=CC=C(O)C=C2C2(C)C(C)C1N(CC=C(C)C)CC2 VOKSWYLNZZRQPF-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- VOKSWYLNZZRQPF-GDIGMMSISA-N (1R,9R,13R)-1,13-dimethyl-10-(3-methylbut-2-en-1-yl)-10-azatricyclo[7.3.1.0^{2,7}]trideca-2,4,6-trien-4-ol Chemical compound C1C2=CC=C(O)C=C2[C@@]2(C)[C@@H](C)[C@@H]1N(CC=C(C)C)CC2 VOKSWYLNZZRQPF-GDIGMMSISA-N 0.000 description 3
- -1 3-methyl- but-2-en-yl Chemical group 0.000 description 3
- 229940035676 ANALGESICS Drugs 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 230000003042 antagnostic Effects 0.000 description 3
- 239000000730 antalgic agent Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 150000003053 piperidines Chemical class 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N (E)-but-2-enedioate;hydron Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- BJTDPLRIKDSWIS-UHFFFAOYSA-N 1-[4-(3-hydroxyphenyl)piperidin-4-yl]propan-1-one Chemical compound C=1C=CC(O)=CC=1C1(C(=O)CC)CCNCC1 BJTDPLRIKDSWIS-UHFFFAOYSA-N 0.000 description 2
- LNGQLHZIYFQUIR-UHFFFAOYSA-N 3-chlorocyclohexene Chemical compound ClC1CCCC=C1 LNGQLHZIYFQUIR-UHFFFAOYSA-N 0.000 description 2
- 206010003591 Ataxia Diseases 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N Hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N al2o3 Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 230000000985 convulsing Effects 0.000 description 2
- 230000002920 convulsive Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 230000029058 respiratory gaseous exchange Effects 0.000 description 2
- 230000036387 respiratory rate Effects 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 229960000583 Acetic Acid Drugs 0.000 description 1
- 229910018072 Al 2 O 3 Inorganic materials 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- KDRKQBSWSBMTHQ-UHFFFAOYSA-N C(C)(=O)C1(CCNCC1)C1=CC(=CC=C1)O Chemical compound C(C)(=O)C1(CCNCC1)C1=CC(=CC=C1)O KDRKQBSWSBMTHQ-UHFFFAOYSA-N 0.000 description 1
- NJPGUZKNRHMQBA-UHFFFAOYSA-N C1(C=CCCC1)N1CCC(CC1)(C(=O)OC)C1=CC(=CC=C1)O Chemical compound C1(C=CCCC1)N1CCC(CC1)(C(=O)OC)C1=CC(=CC=C1)O NJPGUZKNRHMQBA-UHFFFAOYSA-N 0.000 description 1
- FVXXNBFJYNWSTF-UHFFFAOYSA-N C1(C=CCCC1)N1CCC(CC1)(C(CC)=O)C1=CC(=CC=C1)O Chemical compound C1(C=CCCC1)N1CCC(CC1)(C(CC)=O)C1=CC(=CC=C1)O FVXXNBFJYNWSTF-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N Carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- HRYZWHHZPQKTII-UHFFFAOYSA-N Chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 1
- NXAGXWTVITWDJE-UHFFFAOYSA-N Cl.OC=1C=C(C=CC1)C1(CCNCC1)C(=O)OC Chemical compound Cl.OC=1C=C(C=CC1)C1(CCNCC1)C(=O)OC NXAGXWTVITWDJE-UHFFFAOYSA-N 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 206010013663 Drug dependence Diseases 0.000 description 1
- 229960002598 Fumaric acid Drugs 0.000 description 1
- ALFGKMXHOUSVAD-UHFFFAOYSA-N Ketobemidone Chemical compound C=1C=CC(O)=CC=1C1(C(=O)CC)CCN(C)CC1 ALFGKMXHOUSVAD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- BQJCRHHNABKAKU-KBQPJGBKSA-N Morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 1
- ZGUZCSYMWJLWDZ-UHFFFAOYSA-N OC=1C=C(C=CC1)C1(CCNCC1)C(=O)OC Chemical compound OC=1C=C(C=CC1)C1(CCNCC1)C(=O)OC ZGUZCSYMWJLWDZ-UHFFFAOYSA-N 0.000 description 1
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N Pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 1
- 229960001412 Pentobarbital Drugs 0.000 description 1
- XADCESSVHJOZHK-UHFFFAOYSA-N Petidina Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Vitamin C Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 230000037005 anaesthesia Effects 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
- 239000011230 binding agent Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000003001 depressive Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- XWVZJLCKVYUBJC-UHFFFAOYSA-N ethyl 4-(3-hydroxyphenyl)piperidine-4-carboxylate Chemical compound C=1C=CC(O)=CC=1C1(C(=O)OCC)CCNCC1 XWVZJLCKVYUBJC-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 239000001530 fumaric acid Substances 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
- 229960003029 ketobemidone Drugs 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 229940098779 methanesulfonic 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
- 239000000203 mixture Substances 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 229930014694 morphine Natural products 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000003533 narcotic Effects 0.000 description 1
- 239000004081 narcotic agent Substances 0.000 description 1
- 230000001264 neutralization Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 229960000482 pethidine Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003389 potentiating Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000000241 respiratory Effects 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 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
- 238000005406 washing Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Description
HOHO
IOIO
(D(D
2020th
in der R eine Methyl-, Äthyl-, Methoxy- oder Äthoxygruppe bedeutet, sowie deren Säureadditionssalze. in which R denotes a methyl, ethyl, methoxy or ethoxy group, as well as their acid addition salts.
2. Verfahren zur Herstellung der Verbindungen gemäß Anspruch 1, dadurch gekennzeichnet, daß man in an sich bekannter Weise ein Piperidinderivat der allgemeinen Formel II2. Process for the preparation of the compounds according to claim 1, characterized in that a piperidine derivative of the general formula II is used in a manner known per se
HOHO
(H)(H)
3535
4040
in der R die obige Bedeutung hat, entweder mit 3-Chlor- oder 3-Brom-cyclohexen in Gegenwart eines säurebindenden Mittels umsetzt und gegebenenfalls die so erhaltene Verbindung in ihre Säureadditionssalze überführtin which R has the above meaning, either with 3-chloro- or 3-bromo-cyclohexene in the presence of an acid-binding agent and, if appropriate, converts the compound thus obtained into their Acid addition salts transferred
3. Pharmazeutische Zubereitung, bestehend aus einer Verbindung gemäß Anspruch 1 und üblichen Hilfsstoffen.3. A pharmaceutical preparation consisting of a compound according to claim 1 and customary Auxiliary materials.
5050
Es wurde gefunden, daß Piperidinderivate der allgemeinen Formel IIt has been found that piperidine derivatives of the general Formula I.
HOHO
(I)(I)
HOHO
(II)(II)
in der R die oben angegebene Bedeutung besitzt, entweder mit 3-Chlor- oder 3-Brom-cyclohexen erhalten werden.in which R has the meaning given above, either can be obtained with 3-chloro- or 3-bromo-cyclohexene.
Die Umsetzung erfolgt vorzugsweise in Gegenwart eines geeigneten organischen Lösungsmittels und einer schwachen Base, beispielsweise Natriumbicarbonat, zweckmäßig bei Temperaturen zwischen 50 und 150° C. Die Reaktionspartner können hierbei im Molverhältnis 1:1 eingesetzt werden; vorzugsweise wird jedoch das Alkylierungsmittel im Überschuß angewendet Als Lösungsmittel werden Alkohole oder ein Gemisch aus Dimethylformamid und Tetrahydrofuran bevorzugt The reaction is preferably carried out in the presence of a suitable organic solvent and a weak base, for example sodium bicarbonate, expediently at temperatures between 50 and 150 ° C. The reactants can here in a molar ratio Can be used 1: 1; however, the alkylating agent is preferably used in excess Alcohols or a mixture of dimethylformamide and tetrahydrofuran are preferred as solvents
Gewünschtenfalls kann eine Verbindung der allgemeinen Formel I in ein physiologisch unbedenkliches Säureadditionssalz umgewandelt werden, z. B. durch Behandlung mit einer anorganischen oder organischen Säure, wie Mineralsäuren, Essigsäure, Methansulfonsäure, Weinsäure, Fumarsäure, Maleinsäure, Zitronensäure, Ascorbinsäure, Capronsäure oder Propionsäure.If desired, a connection to the general Formula I can be converted into a physiologically acceptable acid addition salt, e.g. B. by treatment with an inorganic or organic acid, such as mineral acids, acetic acid, Methanesulfonic acid, tartaric acid, fumaric acid, maleic acid, Citric acid, ascorbic acid, caproic acid or propionic acid.
Die Herstellung der als Ausgangsverbindungen dienenden sekundären Piperidinderivate erfolgt nach bekannten Methoden, wie sie beispielsweise in den Chemischen Berichten, Bd. 74, S. 1433 (1941), der deutschen Patentschrift 679 281, der schweizerischen Patentschrift 236 312 oder der USA.-Patentschrift 3 004 877 beschrieben sind.The secondary piperidine derivatives used as starting compounds are prepared according to known methods, as for example in the Chemical Reports, Vol. 74, p. 1433 (1941), the German patent specification 679 281, the Swiss patent specification 236 312 or the USA patent specification 3 004 877 are described.
Zur Herstellung der erfindungsgemäßen Endprodukte können beispielsweise die folgenden Ausgangsverbindungen verwendet werden.The following starting compounds, for example, can be used to produce the end products according to the invention be used.
I 4-(3-Hydroxyphenyl)-4-acetyl-piperidin, 205° C
II 4-(3-HydroxyphenyI)-4-propionyl-piperidin,
223°CI 4- (3-hydroxyphenyl) -4-acetyl-piperidine, 205 ° C
II 4- (3-hydroxyphenyl) -4-propionyl-piperidine,
223 ° C
III 4-{3-Hydroxyphenyl)-4-methoxycarbonylpiperidin · HCl, 244° CIII 4- (3-hydroxyphenyl) -4-methoxycarbonylpiperidine · HCl, 244 ° C
IV 4-(3-Hydroxyphenyl)-4-äthoxycarbonylpiperidin-HCL 192°CIV 4- (3-hydroxyphenyl) -4-ethoxycarbonylpiperidine HCl 192 ° C
Die neuen Piperidinderivate zeichnen sich durch eine starke morphinantagonistische Wirkung aus; einige der Verbindungen besitzen darüber hinaus eine ausgeprägte analgetische Wirkung. Die neuen Substanzen können daher in der Humanmedizin als nicht suchtmachende Analgetika bzw. als Zusätze zu suchtmachenden Analgetika, beispielsweise Morphin, Pethidin . oder Ketobemidon, Verwendung finden.The new piperidine derivatives are characterized by a strong morphine-antagonistic effect; some of the compounds also have a pronounced analgesic effect. The new Substances can therefore be used in human medicine as non-addictive analgesics or as additives addictive analgesics, for example morphine, pethidine. or ketobemidone.
Sie lassen sich zu allen für pharmazeutische Zwecke üblichen Zubereitungsformen verarbeiten.They can be processed into all forms of preparation customary for pharmaceutical purposes.
VergleichsversQche A. AnalgesicSettlement VersQche A. Analgesic
Die in der Tabelle aufgeführten Verbindungen wurden auf ihre analgetische Wirksamkeit nach der Methode der »heißen Platte« (vgL J. PhannacoL Exp.The compounds listed in the table were tested for their analgesic effectiveness after Method of the »hot plate« (see L. J. PhannacoL Exp.
Therap-, 80 [1944], 300) untersucht. Bei diesem Versuch werden Mäuse auf eine 55° C heiße Platte gesetzt und die Zeit gemessen, die bis zum Auftreten von Schmerzsymptomen (Lecken der PfÖtchen, Fluchtversuch) verstreicht. Als ED100 wird diejenige Dosis bezeichnet, die eine Reaktionszeit-Verlängerung um 100% bewirkt.Therap-, 80 [1944], 300) examined. In this experiment, mice are placed on a 55 ° C hot plate and the time measured before pain symptoms appear (licking the paws, attempting to escape). The ED 100 is the dose that causes a reaction time extension of 100%.
l-(Cyclohex-2-enyi)-4-{3-hydroxyphenyl)-4-methoxycarbonyl- piperidin l- (Cyclohex-2-enyi) -4- {3-hydroxyphenyl) -4-methoxycarbonyl- piperidine
l-(Cyclohex-2-eny])-4-{3-hydroxyphenyl)-4-äthoxycarbonyl- piperidin l- (Cyclohex-2-eny]) - 4- {3-hydroxyphenyl) -4-ethoxycarbonyl- piperidine
l-(Cyclohex-2-enyl)-4-{3-hydroxyphenyl)-4-propionyl-piperidin 1- (Cyclohex-2-enyl) -4- {3-hydroxyphenyl) -4-propionyl-piperidine
Pentazocin [1^3,4^,6-Hexahydro-6,1 l-dimethyl-3-(3-methyl- but-2-en-yl)-2,6-methano-3-benzazocin-8-or] Pentazocin [1 ^ 3,4 ^, 6-hexahydro-6,1 l-dimethyl-3- (3-methyl- but-2-en-yl) -2,6-methano-3-benzazocin-8-or]
4,54.5
8,0 4A8.0 4 A
Bis 100 mg/kg keine Wirkung festgestellt in Übereinstimmung mit der Literatur (vgl. N. B. Eddy und E.L. May, Synthetic Analgesics, Part Π Β, Tabelle S. 169, Verbindung 5220)Up to 100 mg / kg no effect found in accordance with the Literature (see N. B. Eddy and E.L. May, Synthetic Analgesics, Part Π Β, table p. 169, connection 5220)
Pentazocin (NIH 7958, UM 381) wird im Addendum zum Report der 24. Tagung des »Comittee on Drug Dependence and Narcotics« (1962), Tabelle 1-4 als »not an antagonist« klassifiziert.Pentazocin (NIH 7958, UM 381) is included in the addendum to the report of the 24th session of the »Committee on Drug Dependence and Narcotics "(1962), Table 1-4 classified as" not an antagonist ".
Demgegenüber wird l-(Cyclohex-2-enyl-4-(3-hydroxyphenyl) - 4 -methoxycarbonyl- piperidin (NIH 8285, UM 659) im Addendum 1 zum Report derIn contrast, l- (Cyclohex-2-enyl-4- (3-hydroxyphenyl) -4-methoxycarbonyl-piperidine (NIH 8285, UM 659) in Addendum 1 to the report of
29. Tagung des gleichen Comittees als »Nalorphine-. like antagonist, about 80 times less potent« bezeichnet.29th meeting of the same committee as "Nalorphine-. like antagonist, about 80 times less potent ”.
l-(Cyclohex-2-enyl)-4-(3-hydroxyphenyl)-4-meth-l- (Cyclohex-2-enyl) -4- (3-hydroxyphenyl) -4-meth-
oxy-carbonyl-piperidin und Pentazocin wurden aduloxy-carbonyl-piperidine and pentazocine were adul ten Kaninchen in steigenden Dosen s. c. injiziert undten rabbits in increasing doses s. c. injected and das Verhalten der Tiere beobachtet. Die Ergebnisseobserved the behavior of the animals. The results sind in der folgenden Übersicht zusammengestellt:are compiled in the following overview:
Nr.No.
Nr.No.
Die erfindungsgemäße Verbindung wird von den Kaninchen besser als Pentazocin vertragen, die krampferzeugende Wirkung von l-(Cyclohex-2-enyl)-4-{3-hydroxyphenyl)-4-methoxy-carbonyl-piperidin ist deutlich geringer.The compound according to the invention is better tolerated by the rabbits than pentazocine, the Convulsive effect of l- (Cyclohex-2-enyl) -4- {3-hydroxyphenyl) -4-methoxycarbonyl-piperidine is significantly lower.
l-(Cyclohex-2-enyl)-4-(3-hydroxyphenyl)-4-methoxy-carbonyl-piperidm: Unter Pentobarbital-Narkose1- (Cyclohex-2-enyl) -4- (3-hydroxyphenyl) -4-methoxycarbonyl-piperidm: Under pentobarbital anesthesia wurde die Atemfrequenz registriert. 1 bis 10 mg/kg beeinflussen bei Lv.-Injektion nicht die Atemfrequenz, 30 mg/kg Lv. erhöhen die Atemfrequenz um 20 bis 64%.the respiratory rate was registered. 1 to 10 mg / kg do not affect the respiratory rate with LV injection, 30 mg / kg Lv. increase breathing rate by 20 to 64%.
Pentazocin: Die atemdepressive Wirkung ist literaturbekannt (vgL L. S. Harris, Arch. Exp. PathoL Pharmao, 248, 426 [1964]).Pentazocine: The respiratory depressive effect is known from the literature (see L. S. Harris, Arch. Exp. PathoL Pharmao, 248, 426 [1964]).
Die folgenden Beispiele sollen die Herstellung der erfindungsgemäßen Verbindungen näher erläutern:The following examples are intended to explain the preparation of the compounds according to the invention in more detail:
l-(Cyclohex-2-enyl)-4-(3-hydroxyphenyl)-4-methoxycarbonyl-piperidin-hydrocblorid 1- (Cyclohex-2-enyl) -4- (3-hydroxyphenyl) -4-methoxycarbonyl-piperidine hydrochloride
2,72 g (0,01MoI) 4-(3-Hydroxyphenyl)-4-methoxycarbonyl-piperidin-hydrochlorid, 2,1 g (0,025 Mol) Natriumbicarbonat und 1,8 g (0,011 Mol) 3-Bromcyclohexen werden in 10 ml Dimethylfonnamid und 25 ml Tetrahydrofuran 6 Stunden unter Rückfluß gekocht. Darauf wird das Lösungsmittel im Vakuum entfernt und der Rückstand mit Chloroform und Wasser ausgeschüttelt. Die wäßrige Schicht wird abgetrennt, nochmals mit Chloroform ausgeschüttelt und die vereinigten Chlorofonnlösungen mit Wasser gewaschen und mit Natriumsulfat getrocknet. Nach dem Verdampfen des Lösungsmittels hinterbleibt die Rohbase, die als solche kristallisiert oder in ein Salz übergeführt werden kann.2.72 g (0.01MoI) 4- (3-hydroxyphenyl) -4-methoxycarbonyl-piperidine hydrochloride, 2.1 g (0.025 mole) sodium bicarbonate and 1.8 g (0.011 mole) 3-bromocyclohexene are refluxed in 10 ml of dimethylformamide and 25 ml of tetrahydrofuran for 6 hours cooked. The solvent is then removed in vacuo and the residue with chloroform and Water shaken out. The aqueous layer is separated off and extracted again with chloroform and the combined chloroform solutions washed with water and dried with sodium sulfate. To the evaporation of the solvent leaves the crude base, which crystallizes as such or in a salt can be transferred.
Zweckmäßiger ist aber eine vorherige Reinigung durch Filtration über Aluminiumoxyd (neutrales Aluminiumoxyd der Aktivität II). Hierzu wird die rohe Base in 20 ml Chloroform gelöst und die Lösung unter Nachwaschen mit Chloroform über eine Chromatographiersäule mit 75 g Al2O3 filtriert. Das Filtrat enthält die reine Base, die kristallisiert oder in ein Salz verwandelt wird. Zur Bereitung des Hydrochloride geht man z. B. folgendermaßen vor: Der Verdampfuhgsrückstand des Chloroformfiltrats wird mit 20 ml Äthanol gelöst, die Lösung mit 4 ml 2,5normaler äthanolischer Salzsäure angesäuert und mit Äther bis zur Trübung versetzt Es kristallisiert das Hydrochlorid, welches nach Kühlen abgesaugt undHowever, it is more expedient to clean it beforehand by filtration through aluminum oxide (neutral aluminum oxide of activity II). For this purpose, the crude base is dissolved in 20 ml of chloroform and the solution is filtered through a chromatography column with 75 g of Al 2 O 3 , washing with chloroform. The filtrate contains the pure base which is crystallized or turned into a salt. To prepare the hydrochloride one goes, for. B. proceed as follows: The evaporation residue of the chloroform filtrate is dissolved with 20 ml of ethanol, the solution is acidified with 4 ml of 2.5 normal ethanolic hydrochloric acid and ether is added until it becomes cloudy. The hydrochloride crystallizes, which is suctioned off after cooling and
mit Äther gewaschen wird. Die Ausbeute beträgt 2,4 g = 71% der Theorie. Nach Umkristallisation aus Äthanol/Äther erhält man die analysenreine Substanz vom Fp. 215° C.washed with ether. The yield is 2.4 g = 71% of theory. After recrystallization the analytically pure substance with a melting point of 215 ° C. is obtained from ethanol / ether.
H2-Cydohex-2-enyl)-4-(3-hydroxvphenyl)-4-propionyl-piperidin-hydrochlorid H2-Cydohex-2-enyl) -4- (3-hydroxyphenyl) -4-propionyl-piperidine hydrochloride
2,33 g (0,01 Mol) 4-{3-Hydroxyphenyl)-4-propionylpiperidin, 1,56g (0,015 Mol) Soda und 1,8g (0,011 Mol) 3-Bromcyclohexen werden in 35 cm Äthanol 6 Stunden unter Rückfluß gekocht. Die Aufarbeitung erfolgt analog Beispiel 1.2.33 g (0.01 mol) 4- {3-hydroxyphenyl) -4-propionylpiperidine, 1.56g (0.015 mol) of soda and 1.8g (0.011 mol) of 3-bromocyclohexene are in 35 cm of ethanol for 6 hours refluxed. The work-up is carried out in the same way as in Example 1.
Ausbeute: 2,05g = 58% der Theorie vom Fp. 2020C.Yield: 2.05 g = 58% of theory, mp 202 0 C..
Analog der vorstehend beschriebenen Arbeitsweise wurden die folgenden Verbindungen hergestellt:The following compounds were prepared analogously to the procedure described above:
BeispielAnalogue
example
0CFp.
0 C
% derprey
% the
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEB0082611 | 1965-06-29 | ||
| DEB0082611 | 1965-06-29 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE1545597A1 DE1545597A1 (en) | 1969-08-07 |
| DE1545597C true DE1545597C (en) | 1973-08-16 |
Family
ID=
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