DE301498C - - Google Patents
Info
- Publication number
- DE301498C DE301498C DENDAT301498D DE301498DA DE301498C DE 301498 C DE301498 C DE 301498C DE NDAT301498 D DENDAT301498 D DE NDAT301498D DE 301498D A DE301498D A DE 301498DA DE 301498 C DE301498 C DE 301498C
- Authority
- DE
- Germany
- Prior art keywords
- alcohol
- cephaelin
- emetine
- ether
- propyl
- 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.)
- Active
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- AUVVAXYIELKVAI-CKBKHPSWSA-N Emetine Chemical compound N1CCC2=CC(OC)=C(OC)C=C2[C@H]1C[C@H]1C[C@H]2C3=CC(OC)=C(OC)C=C3CCN2C[C@@H]1CC AUVVAXYIELKVAI-CKBKHPSWSA-N 0.000 claims description 8
- 229960002694 emetine Drugs 0.000 claims description 8
- DTGZHCFJNDAHEN-OZEXIGSWSA-N cephaeline Chemical compound N1CCC2=CC(O)=C(OC)C=C2[C@H]1C[C@H]1C[C@H]2C3=CC(OC)=C(OC)C=C3CCN2C[C@@H]1CC DTGZHCFJNDAHEN-OZEXIGSWSA-N 0.000 claims description 7
- 230000002152 alkylating Effects 0.000 claims 1
- 239000012435 aralkylating agent Substances 0.000 claims 1
- 230000001035 methylating Effects 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 235000019441 ethanol Nutrition 0.000 description 9
- AUVVAXYIELKVAI-UWBTVBNJSA-N emetine Natural products N1CCC2=CC(OC)=C(OC)C=C2[C@H]1C[C@H]1C[C@H]2C3=CC(OC)=C(OC)C=C3CCN2C[C@H]1CC AUVVAXYIELKVAI-UWBTVBNJSA-N 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000000095 emetic Effects 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- NJGIRBISCGPRPF-KXQOOQHDSA-N (2-aminoethoxy)[(2R)-2-(icosanoyloxy)-3-(pentadecanoyloxy)propoxy]phosphinic acid Chemical compound CCCCCCCCCCCCCCCCCCCC(=O)O[C@@H](COP(O)(=O)OCCN)COC(=O)CCCCCCCCCCCCCC NJGIRBISCGPRPF-KXQOOQHDSA-N 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N Benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- DENRZWYUOJLTMF-UHFFFAOYSA-N Diethyl sulfate Chemical compound CCOS(=O)(=O)OCC DENRZWYUOJLTMF-UHFFFAOYSA-N 0.000 description 1
- POLCUAVZOMRGSN-UHFFFAOYSA-N Dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 description 1
- 208000001848 Dysentery Diseases 0.000 description 1
- PVWOIHVRPOBWPI-UHFFFAOYSA-N N-Propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 1
- OOEWZEXEJQEFJO-UHFFFAOYSA-N O.[I] Chemical compound O.[I] OOEWZEXEJQEFJO-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- 229940008406 diethyl sulfate Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- -1 propyl ether chlorohydrate Chemical compound 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
- C07D455/06—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine containing benzo [a] quinolizine ring systems
- C07D455/08—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine containing benzo [a] quinolizine ring systems having an isoquinolyl-1, a substituted isoquinolyl-1 or an alkylenedioxyisoquinolyl-1 radical linked through only one carbon atom, attached in position 2, e.g. emetine
Description
KAISERLICHESIMPERIAL
PATENTAMT.PATENT OFFICE.
Aus dem Journal of the Chemical Society, Bd. 105 [1914], S. 1591 {vgl. auch die britischen Patentschriften 14677 und 17483 vom Jahre 1913) ist es bekannt, daß bei der Methylierung des Cephaelins neben anderen Verbindungen auch Emetin ,gebildet wird. Es wurde nun gefunden, daß durch Einführung anderer Alkylreste und auch von Aralkylresten in das Molekül des Cephaelins nach den übliehen Methoden Homologe des Emetins gewonnen werden können. Diese weisen vor dem Emetin wesentliche Vorzüge auf. So ist ihre Toxizität gegenüber derjenigen des Emetins bedeutend herabgesetzt. Für das Äthylhomolöge beträgt die tötliche Dosis bei der Maus z.B. nur 2/3, bei der Propyl verbindung sogarFrom the Journal of the Chemical Society, Vol. 105 [1914], p. 1591 {cf. also the British patents 14677 and 17483 from 1913) it is known that emetine is formed in addition to other compounds during the methylation of cephaelin. It has now been found that by introducing other alkyl radicals and also aralkyl radicals into the molecule of cephaelin according to the usual methods, homologues of emetins can be obtained. These have significant advantages over emetine. Their toxicity compared to that of emetine is significantly reduced. For the Äthylhomolöge the lethal dose in mice, for example, is only 2/3, connection to the propyl even
; nur 1Z8 derjenigen des Emetins selbst. Auch die Brechwirkung, die sich bekanntermaßen bei der Emetin therapie außerordentlich störend macht, ist bei den Homologen stark abgeschwächt. Versuche beim Hund führten zum Ergebnis, daß z. B. das Äthylhomologe bedeutend geringere Brechwirkung auslöst, während diese beim Propylhomologen überhaupt nur noch andeutungsweise vorhanden ist. ; only 1 line 8 of that of emetine itself. The emetic effect, which is known to be extremely disruptive in emetine therapy, is also greatly weakened in the homologues. Experiments in dogs have led to the result that, for. B. the ethyl homologue triggers a significantly lower emetic effect, while this is only hinted at in the propyl homologue.
Die neuen Verbindungen sollen therapeutisch, besonders gegen Ruhr und ähnliche Krankheiten, Verwendung finden.The new compounds are said to be therapeutic, especially against dysentery and the like Diseases, find use.
i. 4,7 g wasserfreies Cephaelinchlorhydrat werden in 20 ecm absolutem Äthylalkohol gelöst, mit einer Lösung von 0,87 g Natrium in Alkohol und 1,15 g Diäthylsulfat im Rohr 5 bis 6 Stunden auf 58 bis 6o° erwärmt. Am nächsten Tage wird der Alkohol abdestilliert und der Rückstand mit kaltem Wasser angerieben. Die weitere Aufarbeitung erfolgt wie bei der Herstellung von Emetin (vgl. Journ. of the Chem. Soc. a. a. 0.). Die Reinigung des Cephaelinäthyläthers kann, wie dort beschrieben, über das Jodhydrat erfolgen. Dieses kristallisiert aus Alkohol in rein weißen Drusen und schmilzt langsam erhitzt bei etwa 211 bis 2140. Der Schmelzpunkt des Cephaelinäthyläthers selbst liegt etwas tiefer als der des Emetins, nämlich bei 68 bis 71 °.i. 4.7 g of anhydrous cephaelin chlorohydrate are dissolved in 20 ecm of absolute ethyl alcohol and heated to 58 to 60 ° in the tube with a solution of 0.87 g of sodium in alcohol and 1.15 g of diethyl sulfate for 5 to 6 hours. The next day the alcohol is distilled off and the residue is rubbed with cold water. The further work-up takes place as in the production of emetine (cf. Journ. Of the Chem. Soc. Loc. Cit.). The purification of the cephalic ethyl ether can, as described there, take place via the iodine hydrate. This crystallizes from alcohol in pure white drusen and melts slowly heated at about 211 to 214 0 . The melting point of cephalic ethyl ether itself is somewhat lower than that of emetine, namely 68 to 71 °.
2. 5,6 g wasserfreies Cephaelinchlorhydrat in 20 ecm absolutem Alkohol werden mit einer Lösung von 1 g Natrium in Alkohol und 1,71g Propyljodid versetzt und die Mischung im Rohr 8 Stunden auf 57 bis 60° erwärmt. Hierauf wird die Hauptmenge des Alkohols destilliert, der Rückstand mit kaltem Wasser angerieben, mit Natronlauge alkalisch gemacht und ausgeäthert. Die ätherische Schicht wird auf dem Wasserbade verdunstet und der Rückstand mit wenig Kubikzentimeter verdünnter Salzsäure angerieben. Noch ehe er sich darin vollständig aufgelöst hat, beginnt schon das Chlorhydrat des Cephaelinpropyläthers auszukristallisieren. Nach kurzer Zeit ist ein dicker Brei von Kristallnadeln abgeschieden. Diese werden aus heißem Wasser umkristallisiert. So erhält man das Cephäelinpropylätherchlorhydrat in weißen filzigen Nadeln, die in kaltem Wasser schwer, in warmem Wasser leicht löslich sind. Es schmilzt bei2. 5.6 g of anhydrous cephaelin chlorohydrate in 20 ecm of absolute alcohol are mixed with a Solution of 1 g of sodium in alcohol and 1.71 g of propyl iodide are added and the mixture heated in the tube to 57 to 60 ° for 8 hours. This is where the bulk of the alcohol is distilled, the residue rubbed with cold water, made alkaline with sodium hydroxide solution and etherified. The ethereal layer is evaporated on the water bath and the The residue rubbed with a few cubic centimeters of dilute hydrochloric acid. Before he did has completely dissolved in it, the hydrochloric acid of cephaelin propyl ether begins crystallize out. After a short time, a thick paste of crystal needles is deposited. These are recrystallized from hot water. This is how one obtains the cephelic propyl ether chlorohydrate in white felty needles that are difficult to dissolve in cold water and easily soluble in warm water. It melts at
202 bis 205 °. Die aus dem Salz gewonnene Base zeigt den unscharfen Schmelzpunkt von 58 bis 60 °.202 to 205 °. The base obtained from the salt shows the fuzzy melting point of 58 to 60 °.
3. 5,71 g Cephaelinchlorhydrat in Alkohol gelöst, werden mit einer Lösung von 1 g Natrium in wenig Alkohol und 1,73 g Benzylchlorid versetzt und im Rohr 6 Stunden auf j 58° erwärmt. Hierauf wird der Alkohol abdestilliert, der Rückstand mit Wasser angerieben, alkalisch gemacht und ausgeäthert. Beim freiwilligen Verdunsten der Ätherlösung bleibt der Cephaelinbenzyläther als weiße amorphe Masse zurück. Die Salze mit den Halogenwasserstoffsäuren sind sehr schwer löslich und konnten bisher nicht kristallisiert gewonnen werden. Die Verbindung ist leicht löslich in Alkohol und Äther, unlöslich in Alkalien.3. 5.71 g of cephaelin chlorohydrate dissolved in alcohol are mixed with a solution of 1 g of sodium in a little alcohol and 1.73 g of benzyl chloride and in the tube for 6 hours on j 58 ° heated. The alcohol is then distilled off, the residue rubbed with water, made alkaline and etherified. When the ether solution evaporates voluntarily what remains is the cephalin benzyl ether as a white amorphous mass. The salts with the Hydrogen halide acids are very sparingly soluble and have not yet been obtained in crystallized form will. The compound is easily soluble in alcohol and ether, insoluble in alkalis.
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