SE190892C1 - - Google Patents
Info
- Publication number
- SE190892C1 SE190892C1 SE190892DA SE190892C1 SE 190892 C1 SE190892 C1 SE 190892C1 SE 190892D A SE190892D A SE 190892DA SE 190892 C1 SE190892 C1 SE 190892C1
- Authority
- SE
- Sweden
- Prior art keywords
- phenyl
- piperidine
- pethidine
- formula
- ethyl
- Prior art date
Links
- 230000000202 analgesic effect Effects 0.000 claims description 11
- 150000003053 piperidines Chemical class 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- -1 alkyl radical Chemical class 0.000 description 14
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 10
- 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 10
- 229960000482 pethidine Drugs 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229960005181 morphine Drugs 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- LECMBPWEOVZHKN-UHFFFAOYSA-N 2-(2-chloroethoxy)ethanol Chemical compound OCCOCCCl LECMBPWEOVZHKN-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- KJTKYGFGPQSRRA-UHFFFAOYSA-N Etoxeridine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(CCOCCO)CC1 KJTKYGFGPQSRRA-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000000490 cinnamyl group Chemical group C(C=CC1=CC=CC=C1)* 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 230000002433 effect on respiration Effects 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 210000005224 forefinger Anatomy 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229940068938 morphine injection Drugs 0.000 description 1
- QKHMFBKXTNQCTM-UHFFFAOYSA-N norpethidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCNCC1 QKHMFBKXTNQCTM-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000000286 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
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Description
KLASS INTERNATIONELLSVENSK C 07 d12 p:1/01 PATENT- OCH REGISTRERI NGSVERKET Ans. 10 21011957 inkom den 11111 1957 zitlagd den 28/12 1963 H MORREN, FOREST-BRYSSEL, BELGIEN San all framstailla piperidinderivat med analgetisk verkan Prioritet begard frcin den 16 november 1956 (Belgien) Morfin och 1-mety14-feny1-4-karbetoxi-piperidin, numera benamnt »petidin», ha som bekant analgetiska egenskaper. CLASS INTERNATIONAL SWEDISH C 07 d12 p: 1/01 PATENT AND REGISTRATION AGENCY Ans. 10 21011957 received on 11111 1957 dated 28/12 1963 H MORREN, FOREST-BRUSSELS, BELGIUM San all manufacture piperidine derivatives with analgesic effect Priority requested frcin on 16 November 1956 (Belgium) Morphine and 1-methyl-pheny1-4-carbethoxy-piperidine , now called «pethidine», have known analgesic properties.
Man har sokt framstalla foreningar, vilka likna petidin, for att erhalla starkare analgetika. Salunda beskriva 0. J. Beaenden, N. B. Eddy och H. Halbach, Bull. World Health Org. 13, 1955, sid. 937-998 och N. B. Eddy, J. Org. Chem. 21, 1956, sid. 125-126, emnen med den allmanna formeln: C,IL\ /Cl2CH2 nnr/CNcT_T er4 l41-,2%,“2 i vilken R betecknar en lagre alkylradikal och R' betecknar en vateatom eller en etyl-, propyl-, alkyl-, cyklohexyl-, 2-hydroxietyl-, amino-, 2-(dietylamino)-etyl- eller 2-hydroxi-3-fenyl-propylradikal. Efforts have been made to produce compounds, which are similar to pethidine, in order to obtain stronger analgesics. Salunda describe 0. J. Beaenden, N. B. Eddy and H. Halbach, Bull. World Health Org. 13, 1955, p. 937-998 and N. B. Eddy, J. Org. Chem. 21, 1956, p. 125-126, the substances of the general formula: C 1 IL 2 / Cl 2 CH 2 nnr / CNcT_T er4 141-, 2%, "2 in which R represents a lower alkyl radical and R 'represents a hydrogen atom or an ethyl, propyl, alkyl , cyclohexyl, 2-hydroxyethyl, amino, 2- (diethylamino) ethyl or 2-hydroxy-3-phenyl-propyl radical.
Ingen av dessa foreningar har emellertid starkare analgetisk verkan an petidin. Man har tvart om kunnat observera en lagre aktivitet. However, none of these compounds has a stronger analgesic effect than pethidine. On the contrary, it has been possible to observe a lower activity.
Vidare liar J. Weijlard och medarbetare, J. Am. them. Soc. 78, 1956, sidorna 2342-2343, framstallt en forening enligt den oven angivna formeln, i vilken R' betecknar 2-(p-aminofeny1)- etyl. De ha funnit, att denna forening har starkare analgetisk verkan an petidin, och att dess aktivitet vid djurfOrsok narmar sig morfinets. Furthermore, J. Weijlard and co-workers, J. Am. them. Soc. 78, 1956, pages 2342-2343, prepared a compound of the above formula, in which R 'represents 2- (p-aminophenyl) ethyl. They have found that this compound has a stronger analgesic effect than pethidine, and that its activity in animal research approaches that of morphine.
F. Elpern och medarbetare, Abstr. Papers 130th Meeting of Am. chem. Soc., september 1956, 7 N no. 11, ha framstallt forefinger enligt den allmanna formeln I, i vilken R' betecknar flagon av radikalerna fenyletyl, fenylpropyl, fenylbutyl, sub stituerad fenyletyl, pyridyletyl, cinnamyl, osv. Vissa av dessa fOreningar ha starkare analgetisk verkan On petidin, sarskilt om R' betecknar en cinnamylradikal. F. Elpern and employees, Abstr. Papers 130th Meeting of Am. chem. Soc., September 1956, 7 N no. 11, having prepared forefinger according to the general formula I, in which R 'represents the flag of the radicals phenylethyl, phenylpropyl, phenylbutyl, substituted phenylethyl, pyridylethyl, cinnamyl, etc. Some of these compounds have stronger analgesic effects on pethidine, especially if R 'represents a cinnamyl radical.
FOreliggande uppfinning hanfOr sig till framstallning av ett medel med starkt analgetisk verkan genom att 4-feny1-4-karbalkoxi-piperidin med formeln C61-1CFL—CIL »s\ ,C,,NH ROOC/ U-12 CH2/ i vilken R Or en lagre alkylradikal, omsattes med ett halogenderivat med formeln lx—(CH2)2—OH I vilken Hal representerar en halogenatom och x Or 1 eller 2, till bildning av ett piperidinderivat med den allmanna formeln C,IL\ /CIL—CIL\ N RO 0 \ CH 2 — CH/ dar R liar oven angiven betydelse och R' representerar radikalen —[(CH2)2-01x—(CH2)2 OH, i vilken x har oven angiven betydelse. Det har visat sig att foreningar med denna struktur ha en analgetisk verkan, vilken Or flera ganger starkare On petidinens och narmar sig morfinets. Dessa foreningar Or vidare mindre giftiga vid samma aktivitet och medfora icke de biverkningar, som observeras vid kande. analgetika. The present invention relates to the preparation of an agent having a strong analgesic action by substituting 4-phenyl-4-carbalkoxy-piperidine of the formula C61-1CFL-CIL »s \, C ,, NH ROOC / U-12 CH2 / in which R Or a lower alkyl radical, is reacted with a halogen derivative of the formula Ix- (CH2) 2-OH in which Hal represents a halogen atom and x Or 1 or 2, to form a piperidine derivative of the general formula C, IL \ / CIL-CIL \ N RO 0 \ CH 2 - CH / dar R has the meaning given above and R 'represents the radical - [(CH2) 2-01x— (CH2) 2 OH, in which x has the meaning given above. It has been shown that compounds with this structure have an analgesic effect, which Or several times stronger On pethidine and approaches morphine. Furthermore, these compounds are less toxic in the same activity and do not cause the side effects observed in the pitcher. analgesics.
Det var fullstandigt omOjligt att forutse, att enb art ersattning av petidinens metylgrupp med en alifatisk radikal innehallande en eterfunktion skulle kunna Oka den analgetiska verkan i sadan utstrackning. It was completely impossible to predict that simply replacing the methyl group of the pethidine with an aliphatic radical containing an ether function could increase the analgesic effect to such an extent.
Dessa foreningar ha icke endast starkare analgetisk verkan On petidin utan Oven lagre toxicitet och lag depressiv verkan pa andningen. These compounds not only have stronger analgesic effect on pethidine but also lower toxicity and low depressant effect on respiration.
Jamforande, farmakologiska experiment utforda pa ratter med en av foreningarna enligt uppfinningen, namligen 1-[2-(2-hydroxietoxi)-ety11-4- feny1-4-karbetoxipiperidin (produkt A), samt med petidin och morfin ha visat, att fiireningarna enligt uppfinningen ha dubbelt sa stark aktivitet som morfin. Resultaten fran dessa forsiik framga av foljande tabell, i vilken de angivna vardena svara mot den erforderliga mangden i mg per kg 2— — av djurets (ratta) kroppsvikt for astadkommande av analgetisk verkan resp. mot dodlig dos. Comparative pharmacological experiments challenge in association with one of the compounds of the invention, namely 1- [2- (2-hydroxyethoxy) -ethyl] -4-phenyl] -4-carbethoxypiperidine (product A), and with pethidine and morphine have shown that the compounds according to the invention have twice as strong activity as morphine. The results of these experiments are shown in the following table, in which the values given correspond to the required amount in mg per kg 2— - of the animal's (steering wheel) body weight for achieving analgesic effect resp. against lethal dose.
Produkt A Petidin Aktivitet vid subkutan Morfin injektion 1 2 Aktivitet vid buccal administrering 8 8 Toxicitet per os 200 100 ± 500 Toxicitet vid subkutan injektion 300 600 ±400 Exempel 1. Framstallning av 1-[2-(2-hydroxietoxi)-ety1]-4-feny1-4-karbetoxipiperidin. Product A Pethidine Activity by subcutaneous Morphine injection 1 2 Activity by buccal administration 8 8 Toxicity per os 200 100 ± 500 Toxicity by subcutaneous injection 300 600 ± 400 Example 1. Preparation of 1- [2- (2-hydroxyethoxy) -ethyl] - 4-phenyl-4-carbethoxypiperidine.
OH—(CH2)2-0— /CH2CH2\ /C 00C `CH,CF12/ En losning av 34,5 g 4-feny1-4-karbetoxipiperidin, 50 g 2-(2-kloretoxi)-etanol och 30 ml trietylamin halles 30 h vid 60° C under omroring. OH- (CH2) 2-O- / CH2CH2 \ / C 00C `CH, CF12 / A solution of 34.5 g of 4-phenyl-4-carbetoxypiperidine, 50 g of 2- (2-chloroethoxy) -ethanol and 30 ml of triethylamine kept for 30 hours at 60 ° C with stirring.
Efter kylning tillsattes 30 ml bensen, varefter blandningen filtreras och filtratet extraheras med utspddd saltsyra. Den sura losningen gores basisk med natronlut och de salunda frigjorda, basiska anmena extraheras med bensen. BensenlOsningen torkas Over natriumhydrwdd och losningsmedlet avdrives. Atersto den rektifieras forsiktigt i vakuurn. Forst erhalles 9,8 g joke omvandlad 4-feny1-4- karbetoxipiperidin och sedan 28 g 1-[2-(2-hydroxietoxi)-ety1]-4-feny1-4-karbetoxipiperidin. Basens kokpunkt Or 170° C/0,02 mm Hg. After cooling, 30 ml of benzene were added, after which the mixture was filtered and the filtrate was extracted with dilute hydrochloric acid. The acidic solution is made alkaline with sodium hydroxide solution and the thus liberated, basic anemene is extracted with benzene. The benzene solution is dried over sodium hydride and the solvent is evaporated. Atersto it is carefully rectified in the vacuum. First, 9.8 g of joke converted 4-phenyl-4-carbetoxypiperidine and then 28 g of 1- [2- (2-hydroxyethoxy) ethyl] -4-phenyl-4-carbetoxypiperidine are obtained. Base boiling point Or 170 ° C / 0.02 mm Hg.
Motsvarande hydroklorid framstalles genom behandling av alkohollOsning av basen med ett ringa overskott av med eter blandad saltsyra. Hydrokloriden kristalliserar ur en blandning av alkohol och eter. Hydrokloridens smaltpunkt är 115°C. The corresponding hydrochloride is prepared by treating the alcoholic solution of the base with a slight excess of hydrochloric acid mixed with ether. The hydrochloride crystallizes from a mixture of alcohol and ether. The melting point of the hydrochloride is 115 ° C.
Exempel 2. Framstallning av 1-(242-(2-hydroxietoxi) -etoxi] -ety1)-4-fenyl- 4-karbetoid-piperidin. Example 2. Preparation of 1- (242- (2-hydroxyethoxy) -ethoxy] -ethyl) -4-phenyl-4-carbetoid-piperidine.
OH—(CH2)2-0— m/CH,CH, /C00C21-1 —4CH2)2-0—(CH2) 2-J-1 \ `CH2CH2/ \C61-1 En losning av 16,7 g 4-feny1-4-karbetoxipiperidin, 15 ml trietylamin, 100 ml vattenfri toluen och 12,2 g 242-(2-hydroxietoxi)-etwd]-1-kloretan Mlles 20 h vid 150° C i en autoklav. Framstallningen slutfores pa det i exempel 1 beskrivna sattet, varvid man slutligen erhaller 1-(242-(2- hydroxietoici)-etwd]-ety1)-4-feny1-4-karbetoxipiperidin med ett utbyte av 60 %. Basens kokpunkt dr 205° C/0,01 mm Hg. Motsvarande hydroklorid framstalles p. det i exempel 1 beskrivna sdttet. OH- (CH2) 2-0— m / CH, CH, / C00C21-1 —4CH2) 2-0— (CH2) 2-J-1 \ `CH2CH2 / \ C61-1 A solution of 16.7 g 4 -phenyl-4-carbethoxypiperidine, 15 ml of triethylamine, 100 ml of anhydrous toluene and 12.2 g of 242- (2-hydroxyethoxy) -ethylo] -1-chloroethane Melt for 20 hours at 150 ° C in an autoclave. The preparation is completed in the manner described in Example 1, finally obtaining 1- (242- (2-hydroxyethoxy) -ethyl] -ethyl) -4-phenyl-4-carbethoxypiperidine in a yield of 60%. The boiling point of the base is 205 ° C / 0.01 mm Hg. The corresponding hydrochloride is prepared by the method described in Example 1.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE190892T |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| SE190892C1 true SE190892C1 (en) | 1964-01-01 |
Family
ID=41977459
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SE190892D SE190892C1 (en) |
Country Status (1)
| Country | Link |
|---|---|
| SE (1) | SE190892C1 (en) |
-
0
- SE SE190892D patent/SE190892C1/sv unknown
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5627211A (en) | Cyclohexyl amine derivatives and their use as tachykinin antagonists | |
| JP6182594B2 (en) | New compounds | |
| JP5486928B2 (en) | Cyclic urea and carbamate inhibitors of 11β-hydroxysteroid dehydrogenase 1 | |
| DE19525137C2 (en) | 6-Dimethylaminomethyl-1-phenyl-cyclohexane compounds as intermediates for the preparation of pharmaceutical agents | |
| DE68914488T2 (en) | 2- (2-Hydroxy-3-phenoxypropylamino) ethylphenoxyacetamide, process and intermediates for their preparation. | |
| US20130059871A1 (en) | Pyrimidine derivatives for the treatment of amyloid-related diseases | |
| US7728020B2 (en) | Amino acid derivatives | |
| AU2004257277B2 (en) | Substituted arylthiourea derivatives useful as inhibitors of viral replication | |
| US11667606B2 (en) | Thyromimetics | |
| AU2014212465A1 (en) | S1P modulating agents | |
| CS197300B2 (en) | Method of producing new 1-/isoquinoline-1-one-2-yl and 1,2,3,4-tetrahydrobenzazepine-1-one-2-ylalkyl/ phenyl-et | |
| US7700623B2 (en) | Arylamidine derivative, salt thereof, and antifungal containing these | |
| RU2145599C1 (en) | Piperidine derivatives, methods of their synthesis and pharmaceutical preparation based on thereof | |
| UA116542C2 (en) | UREA COMPOUNDS AND THEIR APPLICATIONS AS ENZYME INHIBITORS | |
| US8680279B2 (en) | Compounds for the treatment of neurological disorders | |
| HU178126B (en) | Process for preparing 4-spectinomycylamines and physiologocally tolerable salts thereof | |
| CA2565293C (en) | Tetrahydroisoquinoline sulfonamide derivatives, the preparation thereof, and the use of the same in therapeutics | |
| SE190892C1 (en) | ||
| US20100204275A1 (en) | N-piperidin-4-ylmethyl-amide derivatives and their use as monoamine neurotransmitter re-uptake inhibitors | |
| JPS5982378A (en) | 3-aminopropoxyphenyl derivative, manufacture and medicine | |
| US2723269A (en) | Piperidino tertiary amino alcohols | |
| AU2002221632B2 (en) | 5-amino-1-pentene-3-ol substituted derivatives | |
| US3576009A (en) | Amphetamine derivatives | |
| US3058986A (en) | N-ammoalkyl-x-phenyl-x-lower alkyl-z- | |
| RU2822624C1 (en) | 1,3,4-oxadiazole derivatives as histone deacetylase 6 inhibitor and pharmaceutical composition containing thereof |