DE2065956C3 - p-Acyloxime-phenoxyacetic acids and derivatives, processes for their preparation and pharmaceutical agents - Google Patents
p-Acyloxime-phenoxyacetic acids and derivatives, processes for their preparation and pharmaceutical agentsInfo
- Publication number
- DE2065956C3 DE2065956C3 DE19702065956 DE2065956A DE2065956C3 DE 2065956 C3 DE2065956 C3 DE 2065956C3 DE 19702065956 DE19702065956 DE 19702065956 DE 2065956 A DE2065956 A DE 2065956A DE 2065956 C3 DE2065956 C3 DE 2065956C3
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- water
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- alcohol
- acyloxime
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/12—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines
- C07C259/18—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines having carbon atoms of hydroxamidine groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/353—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by isomerisation; by change of size of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/76—Unsaturated compounds containing keto groups
- C07C59/90—Unsaturated compounds containing keto groups containing singly bound oxygen-containing groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C23—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; CHEMICAL SURFACE TREATMENT; DIFFUSION TREATMENT OF METALLIC MATERIAL; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL; INHIBITING CORROSION OF METALLIC MATERIAL OR INCRUSTATION IN GENERAL
- C23C—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; SURFACE TREATMENT OF METALLIC MATERIAL BY DIFFUSION INTO THE SURFACE, BY CHEMICAL CONVERSION OR SUBSTITUTION; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL
- C23C8/00—Solid state diffusion of only non-metal elements into metallic material surfaces; Chemical surface treatment of metallic material by reaction of the surface with a reactive gas, leaving reaction products of surface material in the coating, e.g. conversion coatings, passivation of metals
- C23C8/06—Solid state diffusion of only non-metal elements into metallic material surfaces; Chemical surface treatment of metallic material by reaction of the surface with a reactive gas, leaving reaction products of surface material in the coating, e.g. conversion coatings, passivation of metals using gases
- C23C8/08—Solid state diffusion of only non-metal elements into metallic material surfaces; Chemical surface treatment of metallic material by reaction of the surface with a reactive gas, leaving reaction products of surface material in the coating, e.g. conversion coatings, passivation of metals using gases only one element being applied
- C23C8/10—Oxidising
- C23C8/12—Oxidising using elemental oxygen or ozone
- C23C8/14—Oxidising of ferrous surfaces
-
- C—CHEMISTRY; METALLURGY
- C23—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; CHEMICAL SURFACE TREATMENT; DIFFUSION TREATMENT OF METALLIC MATERIAL; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL; INHIBITING CORROSION OF METALLIC MATERIAL OR INCRUSTATION IN GENERAL
- C23C—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; SURFACE TREATMENT OF METALLIC MATERIAL BY DIFFUSION INTO THE SURFACE, BY CHEMICAL CONVERSION OR SUBSTITUTION; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL
- C23C8/00—Solid state diffusion of only non-metal elements into metallic material surfaces; Chemical surface treatment of metallic material by reaction of the surface with a reactive gas, leaving reaction products of surface material in the coating, e.g. conversion coatings, passivation of metals
- C23C8/80—After-treatment
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Materials Engineering (AREA)
- Mechanical Engineering (AREA)
- Metallurgy (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Hydrogenated Pyridines (AREA)
Description
in der bedeuten:in which:
R H oder CH3 undRH or CH 3 and
R' OH1 NHOH, Morpholino, Piperidino oder Hexamethylenimino.R 'OH 1 NHOH, morpholino, piperidino or hexamethyleneimino.
2. p-Acetyloxim-phenoxyessigsäure-morpholinamid der Formel2. p-Acetyloxime-phenoxyacetic acid-morpholine amide the formula
IOIO
1515th
NOHNOH
3. Verfahren zur Herstellung der Verbindungen nach Anspruch 1 und 2, dadurch gekennzeichnet, daß in an sich bekannter Weise Chloressigsäure mit einem p-Acylphenol der allgemeinen Formel3. A method for the preparation of the compounds according to claim 1 and 2, characterized in that in a manner known per se, chloroacetic acid with a p-acylphenol of the general formula
R-CR-C
Il οIl ο
OHOH
3030th
mit R wie in Anspruch 1with R as in claim 1
durch Kochen am Rückfluß in Gegenwart von Natriumhydroxid zur entsprechenden p-Acyl-phenoxyessigsäure der allgemeinen Formelby refluxing in the presence of sodium hydroxide to give the corresponding p-acyl-phenoxyacetic acid the general formula
R-CR-C
O —CH2-C —OHO-CH 2 -C -OH
4040
umgesetzt wird, die anschließend, gegebenenfalls nach Oberführung der Carboxylgruppe in die entsprechende Carbonsäureamidgruppe über einen entsprechenden Ester oder das Säurechlorid, mit Hydroxylamin-hydrochlorid am Rückfluß in das Oxim übergeführt wird.is implemented, which then, optionally after conversion of the carboxyl group into the corresponding carboxamide group via a corresponding ester or the acid chloride, with Hydroxylamine hydrochloride is converted into the oxime under reflux.
4. Pharmazeutische Mittel, dadurch gekennzeich- w net, daß sie die Verbindungen nach Anspruch 1 als Wirkstoff neben üblichen Hilfs- und Trägerstoffen entfalten.4. Pharmaceutical agents, marked thereby- w net that they use the compounds according to claim 1 as an active ingredient in addition to customary auxiliaries and carriers unfold.
■>■>■> ■>
Die Erfindung betrifft den Gegenstand der Ansprüche. The invention relates to the subject matter of the claims.
Im folgenden wird die Herstellung von Zwisehenver' to bindungen erläutert, Über die die erfindungsgemäßen Verbindungen hergestellt werden können.The production of Zwisehenver 'to bonds explained, via which the compounds according to the invention can be produced.
Die entsprechende p'Acylphenoxyessigsäure kann nach üblichen Veresterungsverfahren in schwefelsaurem Medium mit einem Alkohol in den einsprechenden Ester übergeführt werden.The corresponding p'Acylphenoxyacetic acid can according to the usual esterification process in a sulfuric acid medium with an alcohol in the corresponding Ester are converted.
Der Ester kann seinerseits durch Kochen am Rückfluß in Gegenwart eines entsprechenden Amins inThe ester can in turn by boiling on Reflux in the presence of an appropriate amine in
das entsprechende Amid übergeführt werden.the corresponding amide can be converted.
Das Amid kann ferner auch aus der entsprechenden Säure über die nach an sich bekannten Verfahren hergestellte Zwischenstufe des Säurechlorids hergestellt werden.The amide can also be obtained from the corresponding acid by methods known per se prepared intermediate of the acid chloride are prepared.
Die Ester oder Oxime können ihrerseits durch Kochen am Rückfluß in Äthanol mit Hydroxylamin und Soda in die entsprechende Phenoxymethylcarbohydroxamsäure überführt werden.The esters or oximes can in turn by refluxing in ethanol with hydroxylamine and Soda can be converted into the corresponding phenoxymethylcarbohydroxamic acid.
Die erfindungsgemäBen Verbindungen, die über die vorstehend erwähnten Zwischenprodukte herstellbar sind, zeichnen sich besonders durch ihre pharmakologische Wirksamkeit aus, aufgrund deren sie z. B. als Wirkstoffe in Mitteln gegen Husten geeignet sind.The compounds according to the invention, which via the Above-mentioned intermediates can be prepared, are characterized in particular by their pharmacological Effectiveness, due to which they z. B. are suitable as active ingredients in anti-cough agents.
Die erfindungsgemäßen Verbindungen und ihre Herstellung werden nachstehend anhand von Ausführungsbeispielen näher erläutert.The compounds according to the invention and their preparation are illustrated below with the aid of working examples explained in more detail.
Herstellung von p-Acyloximphenoxyessigsäuren
und ihren DerivatenProduction of p-acyloximphenoxyacetic acids
and their derivatives
1. Herstellung von p-Acylphenoxyessigsäuren1. Production of p-acylphenoxyacetic acids
0,6 mol Natriumhydroxid, 0,3 mol p-Hydroxybenzaldehyd oder p-Hydroxyacetophenon sowie 03 mol Chloressigsäure werden in einem Gefäß mit 600 ml Wasser vorgelegt0.6 mole sodium hydroxide, 0.3 mole p-hydroxybenzaldehyde or p-hydroxyacetophenone and 03 mol of chloroacetic acid are placed in a vessel with 600 ml Submitted water
Die Lösung wird 8 Stunden am Rückfluß zum Sieden erhitzt Nach Abkühlung wird mit 12n-Salzsäure auf pH 3 angesäuert Die ausgefallene Säure wird abfiltriert, in Äther wieder gelöst und mit verdünnter Säure extrahiert Die Säure wird aus Wasser durch Abkühlen auf Umgebungstemperatur umkristallisiertThe solution is refluxed for 8 hours. After cooling, it is made up with 12N hydrochloric acid pH 3 acidified. The precipitated acid is filtered off, redissolved in ether and diluted with dilute acid The acid is recrystallized from water by cooling to ambient temperature
Die mittlere Ausbeute dieser Verfahrensweise liegt bei etwa 65%.The average yield of this procedure is about 65%.
Diese Verfahrensweise gestattet die Herstellung von p-Formyl-phenoxyessigsäure und p-Acetyl-phenoxyessigsäure. This procedure allows the production of p-formyl-phenoxyacetic acid and p-acetyl-phenoxyacetic acid.
2. Veresterung2. Esterification
10 g einer nach 1. erhaltenen Säure werden in 150 ml Methanol oder Äthanol gelöst. Hierzu werden 150 ml wasserfreies Benzol und 1 ml 36 n-Schwefelsäure zugesetzt Nach 2 Stunden Kochen am Rückfluß wird das azeotrope Benzol-Alkohol-Gemisch abdestilliert, bis das ganze Benzol entfernt ist.10 g of an acid obtained according to 1. are in 150 ml Dissolved methanol or ethanol. For this purpose 150 ml of anhydrous benzene and 1 ml of 36 N sulfuric acid are added added After 2 hours of refluxing, the azeotropic benzene-alcohol mixture is distilled off, until all of the benzene is removed.
Die alkoholische Lösung wird dann im Vakuum eingeengt Das abgeschiedene öl .vird in 200 ml Äthyläther aufgenommen, worauf die Ätherlösung mit Wasjer gewaschen und dann über Natriumsulfat getrocknet wird. Nach Eindampfen der Ätherlösung im Vakuum wird der Ester je nach dem Derivat in Form eines gelben Öls oder kristallin erhalten.The alcoholic solution is then concentrated in vacuo. The separated oil .vird in 200 ml Ethyl ether added, whereupon the ethereal solution was washed with water and then over sodium sulfate is dried. After evaporation of the ethereal solution in vacuo, the ester becomes in shape depending on the derivative of a yellow oil or obtained in crystalline form.
3. Herstellung der Amide
3.1 aus den Estern3. Preparation of the amides
3.1 from the esters
8 g eines nach 2. erhaltenen Esters werden in etwa 25 ml eines vorher über Kaliumcarbonat getrockneten Amins gelöst. Diese Lösung wird 3 Stünden am Rückfluß zum Sieden erhitzt Das entsprechende Amid kristallisiert Im allgemeinen durch einfaches Abkühlen oder nach Zusatz einer geringen Menge Wasser ausi Die vollständige Ausfällung geschieht durch langsamen Zusatz Von 200 bis 300 ml Wasser. Die Reinigung erfolgt durch Umkristallisieren in einer Mischung aus Alkohol und Wasser.8 g of an ester obtained according to 2. are dried in about 25 ml of one beforehand over potassium carbonate Amine dissolved. This solution is refluxed for 3 hours. The corresponding amide generally crystallizes out by simple cooling or after adding a small amount of water Complete precipitation occurs by slowly adding 200 to 300 ml of water. The cleaning takes place by recrystallization from a mixture of alcohol and water.
3,2 aus den Säurechloriden3.2 from the acid chlorides
Es ist ferner möglich, zunächst in üblicher Weise die Chloride der entsprechenden Säuren herzustellen, die dann unter denselben Bedingungen wie in 3.1 in Gegenwart eines Amins zum entsprechenden Amid umgesetzt werden.It is also possible first of all to prepare the chlorides of the corresponding acids in the customary manner then under the same conditions as in 3.1 in the presence of an amine to give the corresponding amide implemented.
Hierzu kann beispielsweise wie folgt verfahren werden:This can be done, for example, as follows:
a) Das Morpholinamid der p-Formyl-phenoxyessigsäure (1 -(p-Formyl-phenoxyacetyl)-morphoIin) wird erhalten durch die vorstehend unter 3.1 oder 32 erwähnte Verfahrensweise. Die Ausbeute beträgt 65%. Das Amid ist in Alkohol löslich und in Wasser unlöslich. F. 116° C.a) The morpholine amide of p-formyl-phenoxyacetic acid (1 - (p-formyl-phenoxyacetyl) -morphoIin) is obtained by the procedure mentioned under 3.1 or 32 above. The yield is 65%. The amide is soluble in alcohol and insoluble in water. 116 ° C.
b) Das Morpholinamid der p-Acetyi-phenoxyessigsäure (l-(p-Acetyl-phenoxyacetyl)-morpholin) wird nach 3.1 erhalten; es ist löslich in Alkohol und unlöslich in Wasser und Petroläther. Ausbeute 60%; F. 112°C.b) The morpholine amide of p-Acetyi-phenoxyacetic acid (l- (p-Acetyl-phenoxyacetyl) -morpholine) is obtained after 3.1; it is soluble in alcohol and insoluble in water and petroleum ether. yield 60%; 112 ° C.
c) Das !-(p-Acetyl-phenoxyacetylJ-hexamethylenimin wird nach 3.1 in einer Ausbeute von 50% erhalten. Es ist löslich in Alkohol und Äther und unlöslich in Wasser; F. 780C.c) The - (p-acetyl-phenoxyacetylJ-hexamethyleneimine obtained after 3.1 in a yield of 50% It is soluble in alcohol and ether, and insoluble in water;! 0 C. F. 78.
d) Das Piperidinamid der p-Formyl-phenoxyessigsäure wird durch die Verfahrensweise gemäß 3.1 oder 32 erhalten. Man erhält ein kristallines Produkt, das in Äther, Alkohol und in den meisten organischen Lösungsmitteln löslich und in Petroläther und Wasser unlöslich ist Die Ausbeute beträgt etwa 60%; F. 96" C.d) The piperidinamide of p-formyl-phenoxyacetic acid is obtained by the procedure according to 3.1 or 32 . A crystalline product is obtained which is soluble in ether, alcohol and most organic solvents and insoluble in petroleum ether and water. The yield is about 60%; F. 96 "C.
e) Das Piperidinamid der p-Acctyl-phenoxyessigsäure wird nach 3.1 als kristallines Produ' ί erhalten; die Ausbeute beträgt etwa 60%. Das Produkt ist in Alkohol und den meisten organischen Lösungsmitteln löslich und in Wasser, Äther und Petroläther unlöslich. F. 97°C.e) The piperidine amide of p-Acctyl-phenoxyacetic acid is obtained as a crystalline ί to 3.1 Produ '; the yield is about 60%. The product is soluble in alcohol and most organic solvents and insoluble in water, ether and petroleum ether. 97 ° C.
4. Herstellung der Oxime4. Manufacture of the oximes
0,1 mol eines nach 3. hergestellten Amids wird in ml absolutem Äthanol gelöst Hierzu werden 7 g Hydroxylamin-hydrochlorid und 4,8 g Soda hinzugefügt, worauf diese Mischung 3 Stunden am Rückfluß zum Sieden erhitzt wird.0.1 mol of an amide prepared according to 3. is in ml of absolute ethanol dissolved 7 g of hydroxylamine hydrochloride and 4.8 g of soda are added, whereupon this mixture is refluxed for 3 hours.
Nach Zusatz von 100 ml Wasser und Eindampfen im Vakuum kristallisiert das Oxim in der Wasser-AJkohol-Lösung aus. Nach Filtration wird das Oxim durch Umkristallisieren in einer Alkohol-Wasser-Mischung gereinigtAfter adding 100 ml of water and evaporating in vacuo, the oxime crystallizes in the water-alcohol solution the end. After filtration, the oxime is recrystallized from an alcohol-water mixture cleaned
AusführungsbeispieleWorking examples
a) Das p-Formyloxim-phenoxyessigsäure-piperMinamid wird unter den vorstehenden Bedingungen erhalten. Das kristallisierte Oxim fällt in einer Ausbeute von etwa 70% an; F. 135°C Es ist löslich in Alkohol und unlöslich in Wasser.a) The p-formyloxime-phenoxyacetic acid-piperMinamide is obtained under the above conditions. The crystallized oxime falls in a Yield of about 70%; F. 135 ° C. It is soluble in alcohol and insoluble in water.
b) Das p-Formyloxim-phenoxyessigsäure-morpholinamid wird unter den gleichen Bedingungen erhalten. Es ist löslich in Alkohol und unlöslich in Wasser; F. 169° C. Die Ausbeute beträgt 60%.b) The p-formyloxime-phenoxyacetic acid-morpholine amide is obtained under the same conditions. It is soluble in and insoluble in alcohol Water; M.p. 169 ° C. The yield is 60%.
c) Die p-Acetyloxim-phenoxyessigsäure wird ebenfalls unter den vorstehend genannten Bedingungen bei einem nahezu alkalischen pH-Wert, wie er beim Piperidin vorliegt durch Einsatz einer äquimolaren Menge an Hydroxylamin-hydrochlorid erhalten. Das Produkt fällt mit einer Ausbeute von 55% an; F. 177° C. Es ist löslich in Alkohol und wäßriger Bicarbonatlösung und unlöslich in Wasser.c) The p-acetyloxime-phenoxyacetic acid is also under the above-mentioned conditions at an almost alkaline pH value, as in Piperidine is obtained by using an equimolar amount of hydroxylamine hydrochloride. The product is obtained with a yield of 55%; 177 ° C. It is soluble in alcohol and water Bicarbonate solution and insoluble in water.
d) Das p-Acetyloxim-phenoxyessigsäure-piperidinamid wird durch Koxidensation des entsprechenden Amids mit Hydroxylamin-hydrochlorid in Alkohol in Gegenwart von Soda durch Kochen am Rückfluß und anschließende Reinigung erhalten. Die Ausbeute beträgt 70%. Das Produkt ist in Alkohol löslich und in Wasser unlöslich; F. 168°Cd) The p-acetyloxime-phenoxyacetic acid-piperidinamide is made by co-oxidizing the corresponding Amides with hydroxylamine hydrochloride in alcohol in the presence of soda by refluxing and subsequent cleaning. The yield is 70%. The product is in alcohol soluble and insoluble in water; M.p. 168 ° C
e) Das p-Acetyloxim-phenoxyessigsäure-morphoIinamid wird nach der gleichen Verfahrensweise in einer Ausbeute von 70% erhalten. Das Produkt ist löslich in Alkohol und unlöslich in Wasser. F. 145° C.e) The p-acetyloxime-phenoxyacetic acid-morphoIinamid is obtained by the same procedure in a yield of 70%. The product is soluble in alcohol and insoluble in water. F. 145 ° C.
f) Das p-Acetyloxim-phenoxyessigsäure-hexamethylenimid wird in einer Ausbeute von 60% erhalten. Es ist löslich in Alkohol und unfösHch in Wasser. F. 134° C.f) The p-acetyloxime-phenoxyacetic acid-hexamethyleneimide is obtained in a yield of 60%. It is soluble in alcohol and insoluble in water. 134 ° C.
Pharmakologische UntersuchungenPharmacological studies
Die erfindungsgemäßen Oxime zeichnen sich durch günstige pharmakologische Wirkung gegen Husten aus.The oximes according to the invention are distinguished by a favorable pharmacological action against coughing.
Die Wirksamkeit gegen Husten sowie die akute Toxizität wurden an Mäusen untersucht Als Vergleichssubstanz diente Codein. Die erhaltenen Ergebnisse sind in der Tabelle angegeben.The effectiveness against cough and the acute toxicity were investigated in mice. Codeine was used as the comparison substance. The results obtained are indicated in the table.
R-CR-C
IlIl
NOH
VerbindungNOH
link
Ο —CH2-C-R'Ο —CH 2 -C-R '
Il οIl ο
Wirksamkeit gegen HustenEfficacy against cough
EDi0 prozentualeEDi 0 percentage
Verringerung
der Hustenzahl
() = Dosisreduction
the number of coughs
() = Dose
(mg/kg per os) (mg/kg)(mg / kg per os) (mg / kg)
Akute Toxizität
LDacute toxicity
LD
(mg/kg per os)(mg / kg per os)
CH3 CH 3
CHjCHj
3030th
-50% (30)-50% (30)
-56% (75)-56% (75)
LD50 = 750LD 50 = 750
LD50 = 700LD 50 = 700
LD
(mg/kg per os)acute toxicity
LD
(mg / kg per os)
RR.
ED50 prozentuale
Verringerung
der Hustenzahl
O = Dosis
(mg/kg per os) (mg/kg)Efficacy against cough
ED 50 percent
reduction
the number of coughs
O = dose
(mg / kg per os) (mg / kg)
CodeinCodeine
Aus den Ergebnissen geht die günstige Wirkung bei therapeutischen Index gegenüber Codein als besonders Husten bei gleicher ED50 wie für Codein sowie die günstig: demgegenüber signifikant verringerte Toxizität der 25From the results, the beneficial effect at therapeutic index compared to codeine goes as special Cough with the same ED50 as for codeine as well as the favorable: in contrast, significantly reduced toxicity of the 25th
erfindungsgemäßen Verbindungen hervor. p-Acetyloxim-phenoxyessigsäure-morpholinamidcompounds according to the invention. p-Acetyloxime-phenoxyacetic acid-morpholine amide
Al=CH3 R'=N 6\ erweist sich dabei aufgrund seines vorteilhaftenAl = CH 3 R '= N 6 \ proves to be advantageous because of its advantages
p-Acetyloxim-phenoxyessigsäure- .,,-„p-Acetyloxim-phenoxyacetic acid-. ,, - "
morpholinamid: —— = 25,0morpholinamide: - = 25.0
Codein: ~ = 7,3Codeine: ~ = 7.3
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19702065956 DE2065956C3 (en) | 1969-01-31 | 1970-01-27 | p-Acyloxime-phenoxyacetic acids and derivatives, processes for their preparation and pharmaceutical agents |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH151769A CH515873A (en) | 1969-01-31 | 1969-01-31 | Phenoxyacetic acid derivs |
| CH1302269A CH543472A (en) | 1969-01-31 | 1969-08-28 | Process for the preparation of phenoxyalkylcarboxylic acids |
| DE19702065956 DE2065956C3 (en) | 1969-01-31 | 1970-01-27 | p-Acyloxime-phenoxyacetic acids and derivatives, processes for their preparation and pharmaceutical agents |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DE2065956A1 DE2065956A1 (en) | 1977-07-14 |
| DE2065956B2 DE2065956B2 (en) | 1980-06-04 |
| DE2065956C3 true DE2065956C3 (en) | 1981-02-19 |
Family
ID=27173033
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19702065956 Expired DE2065956C3 (en) | 1969-01-31 | 1970-01-27 | p-Acyloxime-phenoxyacetic acids and derivatives, processes for their preparation and pharmaceutical agents |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE2065956C3 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT389105B (en) * | 1988-02-23 | 1989-10-25 | Gerot Pharmazeutika | NEW AROMATIC ALDEHYDE, THEIR PRODUCTION AND USE |
| WO2008035359A2 (en) * | 2006-06-12 | 2008-03-27 | Cadila Healthcare Limited | Oximinophenoxyalkanoic acid and phenylalkanoic acid derivatives |
-
1970
- 1970-01-27 DE DE19702065956 patent/DE2065956C3/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| DE2065956A1 (en) | 1977-07-14 |
| DE2065956B2 (en) | 1980-06-04 |
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| Date | Code | Title | Description |
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| OGA | New person/name/address of the applicant | ||
| C3 | Grant after two publication steps (3rd publication) |