DE1937515C3 - N- (2'-PyiToIidinylmelhyl) -2-methoxy-4-hydroxy-5-chlorobenzamides, their salts, processes for their preparation and pharmaceuticals - Google Patents
N- (2'-PyiToIidinylmelhyl) -2-methoxy-4-hydroxy-5-chlorobenzamides, their salts, processes for their preparation and pharmaceuticalsInfo
- Publication number
- DE1937515C3 DE1937515C3 DE1937515A DE1937515A DE1937515C3 DE 1937515 C3 DE1937515 C3 DE 1937515C3 DE 1937515 A DE1937515 A DE 1937515A DE 1937515 A DE1937515 A DE 1937515A DE 1937515 C3 DE1937515 C3 DE 1937515C3
- Authority
- DE
- Germany
- Prior art keywords
- methoxy
- hydroxy
- salts
- preparation
- compound
- 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.)
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Links
Classifications
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
- C07C45/54—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition of compounds containing doubly bound oxygen atoms, e.g. esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
- C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 radicals, substituted by hetero atoms, attached to ring carbon atoms
- C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
Description
Die Erfindung betrifft N-(2'-PyrrolidinyImethyl)-2-methoxy^-hydroxy-S-chlorbenzamide der allgemeinen Formel IThe invention relates to N- (2'-pyrrolidinyimethyl) -2-methoxy ^ -hydroxy-S-chlorobenzamides of the general formula I.
I OCH,
OHI OCH,
OH
Π)Π)
in der R die Äthylgruppe ist, einschließlich der linksdrehenden Form dieser Verbindung, oder in der R die Allylgruppe ist sowie deren Additionssalze mit Säuren.in which R is the ethyl group, including the levorotatory form of this compound, or in R is the allyl group and their addition salts with acids.
Die Addilionssalze können mit anorganischen oder organischen Säuren wie Salzsäure. Bromwassers'off, Phosphorsäure. Citronensäure. Weinsäure. Milchsäure oder Essigsäure gebildet werden.The addition salts can be mixed with inorganic or organic acids such as hydrochloric acid. Hydrogen bromide, Phosphoric acid. Citric acid. Tartaric acid. Lactic acid or acetic acid are formed.
Die Verbindungen der Erfindung können in an sich bekannter Weise dadurch erhalten werden, daß man 2'Methöxy'5-chlof-benzoesäure in das Säurechlorid oder den Ester Überführt und mit NÄthyl· oder Allyl^aminomethylpyrroiidin amidiert Und die so erhaltenen Verbindungen gegebenenfalls mit pharma' zeutisch unbedenklichen Säuren in ihre Salze überführt.The compounds of the invention can be obtained in a manner known per se by 2'Methöxy'5-chloro-benzoic acid into the acid chloride or the ester and converted with ethyl · or Allyl ^ aminomethylpyrroiidin amidiert And the compounds thus obtained, if necessary with pharma ' Zeutisch harmless acids converted into their salts.
Die Verbindungen der Erfindung besitzen interessante pharmakologische Eigenschaften und können beispielsweise als antiemetische, spasmogene öder" analge* tische Mittel therapeutisch verwendet werden.The compounds of the invention have interesting pharmacological properties and can, for example as antiemetic, spasmogenic, or "analge * Table means can be used therapeutically.
Die Erfindung betrifft auch Arzneimittel, die aus den erfindungsgemäßen Verbindungen und den üblichen Hilfs- und Trägerstoffen bestehen.The invention also relates to medicaments consisting of the compounds according to the invention and the customary Auxiliary and carrier materials exist.
Die Hersteilung der Verbindungen der Erfindung wird im folgenden an Hand von Ausführungsbeispielen erläutert.The preparation of the compounds of the invention is described below on the basis of exemplary embodiments explained.
N-(I '-Äthyl-2'-pyrrolidinyImethyl)-2-methoxy-4-hydroxy-5-ch!orbenzamid N- (I '-ethyl-2'-pyrrolidinyimethyl) -2-methoxy-4-hydroxy-5-chlorobenzamide
Stufe ALevel a
2-Hydroxy-4-benzyloxybenzoesäuremethyIester
In einen 31-Kolben mit abgedichtetem Rührer, Rückflußkühler und Thermometer gibt man 251 g (1,5
Mol) 2,4-Dihydroxybenzoesäuremethylest°r und 1100 ml Aceton. Man erhält eine Lösung, welcher man
20 g Benzylchlorid hinzufügt. Man erwärmt auf 40°C
und fügt langsam 220 g Kaliumcarbonat hinzu. Man beobachtet eine leichte Erwärmung, wobei die Temperatur
bis auf etwa 52° C ansteigt Man fügt dann 21 g Natriumiodid hinzu und erwärmt 133 Stunden lang
unter Rückfluß. Nach beendeter Reaktion destilliert man 800 ml Aceton ab und löst den Rückstand mit 3,5
Liter Wasser wieder auf. Die Mineralsalze lösen sich, und das Benzoylderivat fällt aus. Es wird abgesaugt, mit
Wasser gewaschen und getrocknet. Man erhält 382 g (99%) 2-Hydroxy-4-benzyloxybenzoesäuremethylester
(Smp.:103°C).2-Hydroxy-4-benzyloxybenzoic acid methyl ester
251 g (1.5 mol) of methyl 2,4-dihydroxybenzoate and 1100 ml of acetone are placed in a 31 flask equipped with a sealed stirrer, reflux condenser and thermometer. A solution is obtained to which 20 g of benzyl chloride are added. The mixture is warmed to 40 ° C. and 220 g of potassium carbonate are slowly added. Slight warming is observed, the temperature rising to about 52 ° C. 21 g of sodium iodide are then added and the mixture is refluxed for 133 hours. When the reaction has ended, 800 ml of acetone are distilled off and the residue is redissolved with 3.5 liters of water. The mineral salts dissolve and the benzoyl derivative precipitates. It is filtered off with suction, washed with water and dried. 382 g (99%) of methyl 2-hydroxy-4-benzyloxybenzoate are obtained (melting point: 103 ° C.).
Stufe BLevel B.
2-Methoxy-4-benzyloxybenzoesäuremethylester2-methoxy-4-benzyloxybenzoic acid methyl ester
In einem 31-Kolben mit abgedichtetem Rührer, Rückflußkühler und Thermometer löst man 299 g (1,2 Mo!) 2-Hydroxy-4-benzyI-oxybenzoesäuremethylester in 80OmI Aceton in der Wärme auf und fügt 190 g Dimethylsulfat, 191 g Kaliumcarbonat und 17 g Natriumjodid hinzu. Man erhitzt unter Rückfluß, bis 0,2 ml der klaren Lösung, mit 2 ml Alkohol verdünnt, nur eine sehr schwache Färbung mit einer Spur von Eisenchlorid oder überhaupt keine Färbung ergeben. Die Reaktion dauert 4 Stunden.In a 31 flask with a sealed stirrer, 299 g (1.2 Mo!) Of methyl 2-hydroxy-4-benzyI-oxybenzoate are dissolved in the reflux condenser and thermometer in 80OmI acetone in the heat and adds 190 g of dimethyl sulfate, 191 g of potassium carbonate and 17 g of sodium iodide added. Heat under reflux until 0.2 ml of the clear solution, diluted with 2 ml of alcohol, only one very faint coloration with a trace of ferric chloride or no coloration at all. The reaction takes 4 hours.
Man destilliert dann 600 ml Aceton ab und nimmt den Rückstand mit 2 Liter Wasser auf. Die Mineralsalze lösen sich, und der methylierte Ester kristallisiert. Er wird ausgeschleudert, mit Wasser gewaschen und getrocknet. Man erhält 283 g (90%) 2-Methoxy-4-benzyloxybenzoesäuremethy!ester(Smp.:91°C). 600 ml of acetone are then distilled off and the residue is taken up in 2 liters of water. The mineral salts dissolve and the methylated ester crystallizes. It is spun out, washed with water and dried. 283 g (90%) of 2-methoxy-4-benzyloxybenzoic acid methyl ester (melting point: 91 ° C.) are obtained.
'.n Stufe C'.n level C
2-Methoxy-'*-hydroxybenzoesäuremethylester2-methoxy - '* - hydroxybenzoic acid methyl ester
Das in Stufe B erhaltene Produkt wird in einem Autoklav in Alkohol mit Raney-Nickel als Katalysator hydriert. Die Hydrierung wird bei 5P°C durchgeführt Und dauert 2'/2 Stunden. Man kühlt ab, saugt das Nickel ab und destilliert den Alkohol im Vakuum ab. Der gebildete 2-Methoxy-4-hydroxybenzoesäuremethylester kristallisiert und wird in dieser Form für die folgende Stufe Verwendet. Das Produkt weist einen Schmelzpunkt von 150--1510CaUf.The product obtained in stage B is hydrogenated in an autoclave in alcohol with Raney nickel as a catalyst. The hydrogenation is carried out at 5P ° C and lasts for 2 '/ 2 hours. It is cooled, the nickel is filtered off with suction and the alcohol is distilled off in vacuo. The methyl 2-methoxy-4-hydroxybenzoate formed crystallizes and is used in this form for the following step. The product has a melting point of 150-151 0 CaUf.
Stufe D
2'Melhoxy'4'hydroxy-'5-chlorbenzoesäuremethylesterLevel D
2'Melhoxy'4'hydroxy-'5-chlorobenzoic acid methyl ester
In einen 1 I'Kolben mit Rührer Und Thermometer gibt man 55 g (0r3 Möl) 2'Methoxy4-hydroxybenzoesäuremethylester und 300 ml Essigsäure, Man erwärmt auf 60In a 1 I'Kolben with stirrer and thermometer is added 55 g (0 r 3 Möl) 2'Methoxy4-hydroxybenzoic acid methyl ester and 300 ml of acetic acid is heated to 60
bis 7O0C1 um alles aufzulösen, und kühlt auf 35° C ab. Der Ester rekristallisiert Man fügt 40 g Chlorsuccinimid in Portionen hinzu und erwärmt dann auf 50 bis 55° C. Es löst sich alles auf, und anschließend kristallisiert der chlorierte Ester. Die Mischung wird etwa 20 Stunden lang auf 50 bis 55°C gehalten. Es bleiben dann nur noch Spuren des Chlorsuccinimids in Lösung. Man kühlt ab, fügt 3 Liter Wasser hinzu, schleudert aus, wäscht mit Wasser und trocknet. Man erhält 59 g (90%) 2-Methoxy-'t-hydroxy-S-chlorbenzoesäuremethylester mit einem Schmelzpunkt von 197 bis 1980C.to 7O 0 C 1 to dissolve everything, and cools down to 35 ° C. The ester is recrystallized. 40 g of chlorosuccinimide are added in portions and the mixture is then heated to 50 to 55 ° C. Everything dissolves and the chlorinated ester then crystallizes. The mixture is held at 50 to 55 ° C for about 20 hours. Only traces of the chlorosuccinimide then remain in solution. It is cooled, 3 liters of water are added, the product is centrifuged, washed with water and dried. 59 g (90%) of methyl 2-methoxy-'t-hydroxy-S-chlorobenzoate with a melting point of 197 to 198 ° C. are obtained.
Stufe ELevel E.
N-(l'-ÄthyI-2'-pyrroIidinyImethyl)-2-methoxy-4-hydroxy-5-chlorbenzamid N- (1'-EthyI-2'-pyrrolidinyimethyl) -2-methoxy-4-hydroxy-5-chlorobenzamide
In einen 500 ml-Kolben mit einer 40 cm-Vigreux-Kolonne gibt man 57 g (0,25 Mol) 2-Methoxy-4-hydroxy-5-chlorbenzoesäureinethyIester, 200 ml Xylol und 67 g (2 χ 0,26 Mol) i-Äihyi-2-aminomethylpyrroiidin. Nach vollständiger Auflösung beobachtet man eine leichte Rekristallisation. Man erwärmt und destilliert schonend bei 64°C den Methylalkohol in Form eines mit dem Xylol gebildeten Azeotrops ab. In einer Stunde destilliert man 12 ml des azeotroper? Gemisches und während einer weiteren Stunde bei 13O0C ein wenig Xylol. Insgesamt erhält man 47 ml Destillat, das 9 ml Alkohol enthält Das überschüssige Xylol und Amin werden dann im Vakuum abdestilliert Man erhält 139 g einer braunen Flüssigkeit Das erhaltene Produkt wird in 150 ml warmem Wasser wieder aufgelöst und mit 65 ml konzentrierter HCl angesäuert Beim Abkühlen kristallisiert das Hydrochlorid. Es wird bei etwa 100C abgesaugt und mit 30 ml Eiswasser gewaschen. Man erhält 80 g (98%) N-(l'-Äthy[-2'-pyrroIidinyImethyl)-2-methoxy-4-hydroxy-5-chIorbenzamid-HydrochIorid (Smp.:207-208°C).57 g (0.25 mol) of 2-methoxy-4-hydroxy-5-chlorobenzoic acid, 200 ml of xylene and 67 g (2 χ 0.26 mol) are placed in a 500 ml flask with a 40 cm Vigreux column. i-Äihyi-2-aminomethylpyrroiidine. After complete dissolution, a slight recrystallization is observed. The mixture is heated and the methyl alcohol is gently distilled off at 64 ° C. in the form of an azeotrope formed with the xylene. In one hour, 12 ml of the azeotropic? Mixture and for a further hour at 13O 0 C a little xylene. A total of 47 ml of distillate is obtained, which contains 9 ml of alcohol. The excess xylene and amine are then distilled off in vacuo. 139 g of a brown liquid are obtained. The product obtained is redissolved in 150 ml of warm water and acidified with 65 ml of concentrated HCl the hydrochloride. It is suctioned off at about 10 ° C. and washed with 30 ml of ice water. 80 g (98%) of N- (l'-ethyl [-2'-pyrrolidinyimethyl) -2-methoxy-4-hydroxy-5-chlorobenzamide hydrochloride (melting point: 207-208 ° C.) are obtained.
Linksdrehendes N-(I '-Äthyl^'-pyrrolidinylmethyl)-2-methoxy-4-hydroxy-5-chlorbenzamid Left-handed N- (I '-ethyl ^' - pyrrolidinylmethyl) -2-methoxy-4-hydroxy-5-chlorobenzamide
Die Stufen A bis D sind identisch mit denen des Beispiels 2.Levels A to D are identical to those of Example 2.
Stufe ELevel E.
In einen 500 njI-Kolben mit einer 40 cm-Vigreux-Ko-Ionne gibt man 32 g (0,15 Mol) 2-Metboxy-4-hydroxy-5-chlorbenzoesäuremethylester, 120 ml Xylol und 23 g linksdrehendes l-ÄthyI-2-aminomethylpyrrolidon und erwärmt sanft Man erhält eine Lösung. Man desti'Uert dann den Methylalkohol als azeotropes Gemisch Methanol-Xylol bei 60 bis 62° C etwa eine Stunde langInto a 500 njI flask with a 40 cm Vigreux column 32 g (0.15 mol) of methyl 2-metboxy-4-hydroxy-5-chlorobenzoate are added, 120 ml of xylene and 23 g of levorotatory l-EthyI-2-aminomethylpyrrolidone and heat gently. A solution is obtained. One destined then the methyl alcohol as an azeotropic mixture of methanol-xylene at 60 to 62 ° C for about one hour
ίο ab. Nach Beendigung der Reaktion destilliert man noch 10 ml Xylol bei 1350C ab. In dem Destillat erhält man 5 ml Alkohol gegenüber 6 ml der Theorie.ίο off. After completion of the reaction, a further 10 ml of xylene is distilled off at 135 0 C. In the distillate, 5 ml of alcohol are obtained compared to 6 ml of theory.
Das überschüssige Xylol und Amin werden dann im Vakuum abdestilliert Der feste Rückstand wird mit 600 ml Wasser aufgenommen, ausgeschleudert bis zur Neutralität gegen Phenolphthalein gewaschen und bei 45° C getrocknet Dieses Produkt wird in 130 ml absolutem Alkohol aufgelöst und mit einer Lösung von 4,9 g wasserfreier Salzsäure in 30 ml Alkohol und 4 ml Wasser versetzt Das Hydrochloric des linksdrehenden N-( 1 '-ÄthyI-2'-pyrroIidinylmethyl)-2-methoxy-4-hydroxy-5-chIorbenzamids kristallisiert Es wird abgesaugt und mit Alkohol gewaschen. Es handelt sich um einen farblosen Feststoff (44 g; 89%), (Smp.: 217-220°C); [λ]ο= -8° C (5% Wasser).The excess xylene and amine are then distilled off in vacuo. The solid residue is taken up with 600 ml of water, centrifuged, washed to neutrality against phenolphthalein and dried at 45 ° C. This product is dissolved in 130 ml of absolute alcohol and mixed with a solution of 4.9 g of anhydrous hydrochloric acid in 30 ml of alcohol and 4 ml of water are added. The hydrochloric acid of the levorotatory N- (1'-ethyl-2'-pyrrolidinylmethyl) -2-methoxy-4-hydroxy-5-chlorobenzamide crystallizes. It is filtered off with suction and washed with alcohol. It is a colorless solid (44 g; 89%), (melting point: 217-220 ° C.); [λ] ο = -8 ° C (5% water).
N-(l'-AllyI-2'-pyrroIidinylmethyl)-2-methoxy-4-hydroxy-5-chlorbenzamid N- (1'-AllyI-2'-pyrrolidinylmethyl) -2-methoxy-4-hydroxy-5-chlorobenzamide
Diese Verbindung kann in der in Beispiel 2 beschriebenen Weise, jedoch unter Verwendung von l-Allyl-2-aminomethyl-pyrrolidin erhalten werden. Die freie Base schmilzt bei 134°C, ihr Hydrochlorid bei 1970C.This compound can be obtained in the manner described in Example 2, but using 1-allyl-2-aminomethyl-pyrrolidine. The free base melts at 134 ° C, its hydrochloride at 197 0 C.
Einige pharmakologische Eigenschaften der Verbindungen der Erfindung wurden mit denen des N-(Di-Some pharmacological properties of the compounds of the invention were compared with those of the N- (Di-
äthylaminoäthyl)-2-methoxy-4-amino--> chlorbenzamids verglichen, welches unter dem internationalen Freinamen Metoclopramid als Antiemetikum bekannt istethylaminoethyl) -2-methoxy-4-amino -> compared to chlorbenzamids, which is known as an anti-emetic under the international non-proprietary name metoclopramide is
Die bei den durchgeführten Vergleichsversuchen erhaltenen Toxizitäts- und antiemetischen Wirkungsdaten sind in der folgenden Tabelle zusammengefaßtThe toxicity and antiemetic effect data obtained in the comparative tests carried out are summarized in the following table
3030th
3535
4040
Verbindunglink
Toxizität DL50 (mg/kg; Maus)Toxicity DL50 (mg / kg; mouse)
p.O.p.O.
Antiemetische
WirkungAntiemetic
effect
Hund)Dog)
Aus der DE-AS 15 95 915, Beispiel 2, ist die Verbindung Ν'[1'*Α^^ΓΓοΜίιψΙ;(2')-^εΐΙψΓ]-2-ηιεΐηο^- 4-amittö-5-chlörberizamid bekannt. Auch diese Verbin^ dung wurde mit den Verbindungen der Beispiele 1 und 2 der folgenden Anmeldung verglichen, Es zeigte sich jedoch bei Versuchen zur Ermittlung der Barbituratpo^ tentialisicrung, daß die vorbekarinte Verbindung eine wesentlich stärker sedierende Wirkung hat und daher zuFrom DE-AS 15 95 915, Example 2, the connection Ν '[1' * Α ^^ ΓΓοΜίιψΙ ; (2 ') - ^ εΐΙψΓ] -2-ηιεΐηο ^ - 4-amittö-5-chlörberizamid known. This compound was also compared with the compounds of Examples 1 and 2 of the following application. However, experiments to determine the barbiturate potential showed that the compound prepared beforehand had a significantly more sedative effect and was therefore too
Dies läßt sich
schließen:Comparison purposes
This can be
conclude:
aus den folgendenis not suitable
from the following
ErgebnissenResults
Der Potentialisierungseffekt der Verbindung des Beispiels 2 der DE-AS 15 95 915 beträgt 1,45 bei der Verabreichung von 20 mg/kg der Verbindung (Maus;!, p.).The potentialization effect of the connection of the Example 2 of DE-AS 15 95 915 is 1.45 when 20 mg / kg of the compound is administered (Mouse;!, P.).
5 65 6
Z Annähernd der gleiche Effekt wird bei der fekt auf. Das gleiche gilt auch bezüglich derZ Almost the same effect is achieved with the fekt on. The same also applies to the
Verabreichung der Verbindung des Beispiels 2 der Verbindung 1 der Anmeldung.
Anmeldung erhalten, jedoch erst bei einer vierfachAdministration of the compound of Example 2 of Compound 1 of the application.
Registration received, but only after a quadruple
höheren Dosis (80 mg/kg; Maus; i.p,). Die Vergleichsverbindung zeigt daher eine starkhigher dose (80 mg / kg; mouse; i.p.). The comparative compound therefore shows a strong
3. Die Verbindung 2 der Anmeldung weist bei 5 sedierende Wirkung; dieser Effekt fehlt bei den3. Compound 2 of the application has a sedating effect at 5; this effect is absent in the
20 mg/kg, d. h. bei der Dosierung, bei der der Effekt Verbindungen der Erfindung vollkommen. Dies ist als20 mg / kg, i.e. H. at the dosage at which the effect of the compounds of the invention is complete. This is as
unter der obigen Ziffer 1 geroessen wurde, Vorteil anzusehen, denn bei den meisten Medikamentenunder the above paragraph 1 was found to be beneficial, for most drugs
überheupt keinen meßbaren Potentiaiisierungsef- ist eine sedierende Wirkung unerwünschtWith no measurable potentiating effect, a sedative effect is undesirable
Claims (3)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR161593A FR7707M (en) | 1968-08-01 | 1968-08-01 | |
| FR171761 | 1968-10-29 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DE1937515A1 DE1937515A1 (en) | 1970-07-02 |
| DE1937515B2 DE1937515B2 (en) | 1980-06-12 |
| DE1937515C3 true DE1937515C3 (en) | 1981-02-19 |
Family
ID=26182167
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19691966215 Withdrawn DE1966215A1 (en) | 1968-08-01 | 1969-07-23 | Process for the preparation of heterocyclic benzamides |
| DE1937515A Expired DE1937515C3 (en) | 1968-08-01 | 1969-07-23 | N- (2'-PyiToIidinylmelhyl) -2-methoxy-4-hydroxy-5-chlorobenzamides, their salts, processes for their preparation and pharmaceuticals |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19691966215 Withdrawn DE1966215A1 (en) | 1968-08-01 | 1969-07-23 | Process for the preparation of heterocyclic benzamides |
Country Status (22)
| Country | Link |
|---|---|
| JP (1) | JPS4837267B1 (en) |
| BE (1) | BE736560A (en) |
| BG (1) | BG17299A3 (en) |
| BR (1) | BR6911217D0 (en) |
| CA (1) | CA955949A (en) |
| CH (1) | CH507938A (en) |
| DE (2) | DE1966215A1 (en) |
| DK (1) | DK142844B (en) |
| ES (1) | ES369930A1 (en) |
| FI (1) | FI52214C (en) |
| GB (1) | GB1234118A (en) |
| IE (1) | IE33541B1 (en) |
| IL (1) | IL32712A (en) |
| LU (1) | LU59176A1 (en) |
| MC (1) | MC806A1 (en) |
| NL (1) | NL142410B (en) |
| NO (1) | NO131834C (en) |
| OA (1) | OA03889A (en) |
| PH (1) | PH11002A (en) |
| RO (1) | RO55778A (en) |
| SE (1) | SE359830B (en) |
| YU (1) | YU34289B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5212117U (en) * | 1975-07-15 | 1977-01-27 | ||
| IL52645A (en) * | 1976-08-05 | 1980-02-29 | Synthelabo | Optically active 1 substituted 2 aminomethyl pyrrolidines stereospecifics synthesis thereof and process for the preparation of optically active 2 methoxy n pyrrolidylmethyl benzamides |
| SE8101536L (en) * | 1981-03-11 | 1982-09-12 | Astra Laekemedel Ab | Benzamide derivative |
| SE8205135D0 (en) * | 1982-09-09 | 1982-09-09 | Astra Laekemedel Ab | Benzamido-DERIVATIVES |
-
1969
- 1969-07-21 CH CH1115769A patent/CH507938A/en not_active IP Right Cessation
- 1969-07-23 DE DE19691966215 patent/DE1966215A1/en not_active Withdrawn
- 1969-07-23 OA OA53680A patent/OA03889A/en unknown
- 1969-07-23 DE DE1937515A patent/DE1937515C3/en not_active Expired
- 1969-07-24 IE IE1027/69A patent/IE33541B1/en unknown
- 1969-07-24 SE SE10434/69A patent/SE359830B/xx unknown
- 1969-07-25 MC MC834A patent/MC806A1/en unknown
- 1969-07-25 BE BE736560D patent/BE736560A/xx not_active IP Right Cessation
- 1969-07-26 ES ES369930A patent/ES369930A1/en not_active Expired
- 1969-07-26 BG BG12749A patent/BG17299A3/xx unknown
- 1969-07-27 IL IL32712A patent/IL32712A/en unknown
- 1969-07-28 LU LU59176D patent/LU59176A1/xx unknown
- 1969-07-28 GB GB1234118D patent/GB1234118A/en not_active Expired
- 1969-07-29 FI FI692247A patent/FI52214C/en active
- 1969-07-29 YU YU1965/69A patent/YU34289B/en unknown
- 1969-07-30 CA CA058,341*7A patent/CA955949A/en not_active Expired
- 1969-07-31 NL NL696911713A patent/NL142410B/en not_active IP Right Cessation
- 1969-07-31 NO NO3148/69A patent/NO131834C/no unknown
- 1969-07-31 JP JP44060979A patent/JPS4837267B1/ja active Pending
- 1969-07-31 DK DK414169AA patent/DK142844B/en not_active IP Right Cessation
- 1969-07-31 BR BR211217/69A patent/BR6911217D0/en unknown
- 1969-08-01 RO RO60706A patent/RO55778A/ro unknown
-
1973
- 1973-05-02 PH PH14575A patent/PH11002A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NL6911713A (en) | 1970-02-03 |
| MC806A1 (en) | 1970-07-30 |
| NO131834C (en) | 1975-08-13 |
| DE1937515B2 (en) | 1980-06-12 |
| FI52214C (en) | 1977-07-11 |
| DE1937515A1 (en) | 1970-07-02 |
| DE1966215A1 (en) | 1972-01-27 |
| DK142844C (en) | 1981-09-28 |
| SE359830B (en) | 1973-09-10 |
| BG17299A3 (en) | 1973-07-25 |
| IL32712A (en) | 1973-06-29 |
| CH507938A (en) | 1971-05-31 |
| YU34289B (en) | 1979-04-30 |
| PH11002A (en) | 1977-10-20 |
| RO55778A (en) | 1974-02-01 |
| BR6911217D0 (en) | 1973-02-15 |
| BE736560A (en) | 1970-01-26 |
| NO131834B (en) | 1975-05-05 |
| GB1234118A (en) | 1971-06-03 |
| CA955949A (en) | 1974-10-08 |
| JPS4837267B1 (en) | 1973-11-09 |
| FI52214B (en) | 1977-03-31 |
| YU196569A (en) | 1978-10-31 |
| OA03889A (en) | 1975-08-14 |
| IE33541B1 (en) | 1974-08-07 |
| ES369930A1 (en) | 1973-02-01 |
| IL32712A0 (en) | 1969-09-25 |
| DK142844B (en) | 1981-02-09 |
| IE33541L (en) | 1970-02-01 |
| NL142410B (en) | 1974-06-17 |
| LU59176A1 (en) | 1970-01-28 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C3 | Grant after two publication steps (3rd publication) |