DE2924011A1 - Pyrrolidin-2-one-1-yl alkyl carboxylic acid amide(s) - esp. 2,6-di:methyl anilide of pyrrolidinone acetic acid used to treat cerebral oxygenation insufficiency, migraine etc. - Google Patents

Pyrrolidin-2-one-1-yl alkyl carboxylic acid amide(s) - esp. 2,6-di:methyl anilide of pyrrolidinone acetic acid used to treat cerebral oxygenation insufficiency, migraine etc.

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Publication number
DE2924011A1
DE2924011A1 DE19792924011 DE2924011A DE2924011A1 DE 2924011 A1 DE2924011 A1 DE 2924011A1 DE 19792924011 DE19792924011 DE 19792924011 DE 2924011 A DE2924011 A DE 2924011A DE 2924011 A1 DE2924011 A1 DE 2924011A1
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Prior art keywords
methyl
pyrrolidin
insufficiency
pref
opt
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DE19792924011
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German (de)
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DE2924011C2 (en
Inventor
Hans Dipl Chem Dr Betzing
Juergen Dipl Chem D Biedermann
Carsten Dipl Chem Dr Materne
Volker Dr Neuser
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Daiichi Pharmaceutical Co Ltd
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A Natterman und Cie GmbH
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Priority to DE19792924011 priority Critical patent/DE2924011C2/en
Priority to IT21464/80A priority patent/IT1141287B/en
Priority to US06/155,952 priority patent/US4341790A/en
Priority to FR8012840A priority patent/FR2458544A1/en
Priority to GB8019199A priority patent/GB2053909B/en
Publication of DE2924011A1 publication Critical patent/DE2924011A1/en
Application granted granted Critical
Publication of DE2924011C2 publication Critical patent/DE2924011C2/en
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    • 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
    • C07D207/18—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 one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—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 one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • 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
    • C07D207/18—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 one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—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 one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms

Abstract

Pyrrolidin-2-one-1-yl-alkylcarboxylic acid amides of formula (I) and their acid addition salts are new. In (I) R = H or hydroxy; R1 = H or methyl and R2 = pyridyl or phenyl substd. by 1-3 independently chosen substituents. Pref. substituents are CF3, halo, nitro, acetyl, 1-4C opt. branched alkyl, 1-4C alkoxy, 1-7C opt. branched alkylthio, -5-(CH2)n-CHR3R4 (II), -SO2R5 (III) or -COO-(CH2)2-NR6R7 (IV); n = 1 or 2; R3 = H or methyl; R4 = hydroxy or -NR8R9 (V); R5 = -NH2 or 1-3C alkyl; R6,R7 independently = H, methyl or ethyl; R8 = H or methyl; R9 = methyl or opt. substd. benzyl or R8 and R9 together with the N atom form a substd. pyrrolidino gp. e.g. 2-oxo-pyrrolidino. (I) have central vasoactive and metabolism regulating properties, they inhibit agglutination of thrombocytes and have tranquillising activity. They may be used prophylactically or therapeutically to treat cerebro-ischemic or atrophic troubles, such as organic psychic syndrome and migraine, and to treat cerebral irrigation insufficiency, cerebral aging etc. The cpds. may be administered enterally in doses of 1-1000 mg, pref. 10-100 mg, or parenterally in doses of 0.1-100 mg, pref. 1-20 mg.

Description

Titel. Pyrrolidin (2)-on (1 ylessigsäure-2, 6-dimethyl-Title. Pyrrolidin (2) -one (1-ylacetic acid-2,6-dimethyl-

anilid, Verfahren zur Herstellung und Arzneimittel, welche diese Verbindung enthalten Beschreibung Die Erfindung betrifft Pyrrolidin-(2)-on-(1)-ylessigsäure-2,6-dimethylanilid, ein neues Arzneimittel mit zerebralprotektiver Wirkung. anilide, method of manufacture and medicines containing them Connection included Description The invention relates to pyrrolidin- (2) -one- (1) -ylacetic acid-2,6-dimethylanilide, a new drug with a cerebral protective effect.

Die Pharmakoprophylaxe sowie die Therapie von Krankheiten infolge zerebraler Mangeldurchblutung, hirnatrophischer Krisen sowie zerebraler Alterungsvorgänge gewinnen in letzter Zeit immer mehr an Bedeutung, und es hat bis heute nicht an Versuchen gefehlt, vasotrope und stoffwechselregulierende Verbindungen aufzufinden, die die hier angesprochenen Krankheiten im gewünschten Sinne beeinflussen. Doch konnte durch medikamentöse Behandlung mit Nootropica, zentralen Vasotropica u.a. Therapeutica eine entscheidende Verbesserung nicht erreicht werden.The pharmacoprophylaxis as well as the therapy of diseases as a result cerebral insufficient blood flow, brain atrophic crises and cerebral aging processes are gaining more and more importance lately, and it has not continued to this day No attempt is made to find vasotropic and metabolic regulating compounds which influence the diseases mentioned here in the desired sense. Indeed could through drug treatment with nootropics, central vasotropics, etc. Therapeutica a decisive improvement cannot be achieved.

Es wurde nun überraschenderweise gefunden, daß Pyrrolidin-(2-)-on-(l)-ylessigsäure-2,6-dimethylanilid vasoaktive und stnffwechselregulierende Eigenschaften in sich vereinigt, die es zur Behandlung zerebraler Durchblutungsstörungen bis hin zur Migräne, hirnatropischer Krisen snwie zerebraler Alterungsvorgänge und anderen zerebralen Erkrankungen geeignet macht.It has now been found, surprisingly, that pyrrolidine- (2 -) - one- (1) -yl acetic acid 2,6-dimethylanilide vasoactive and metabolism-regulating properties combined in one, which is used to treat cerebral circulatory disorders up to and including migraines, cerebral atropic Crises such as cerebral aging processes and other cerebral diseases are suitable power.

Dies ist um so überraschender, als das in der Literatur (Brit.This is all the more surprising as that in literature (Brit.

Pat. 1.039.113) bekannte Pyrrolidin-(2)-on-(l)-ylessigsäureanilid keine dieser Wirkungen zeigt.Pat. 1.039.113) known pyrrolidin- (2) -one- (1) -ylacetic anilide shows none of these effects.

Die erfindungsgemäße Verbindung wird erhalten, indem man in an sich bekannter Weise Pyrrolidin-(2)-on-(1)-ylessigsäure und 2,6-Dimethylanilin zusammen mit N,N-Dicyclohexylcarbndiimid in organischen Lösungsmitteln, wie Chloroform, Dichlnrmethan, Tetrahydrofuran, Acetnnitril, Essigsäureäthylester bei Temperaturen 0 zwischen 0 C und der Siedetemperatur des jeweiligen Lösungsmittels umsetzt.The compound of the invention is obtained by in per se known way pyrrolidin- (2) -one- (1) -ylacetic acid and 2,6-dimethylaniline together with N, N-dicyclohexylcarbndiimide in organic solvents such as chloroform, dichloromethane, Tetrahydrofuran, Acetnnitril, ethyl acetate at temperatures 0 between 0 C and the boiling point of the respective solvent.

Ferner eignen sich zur Gewinnung der erfindungsgemäßen Verbindung die üblichen Herstellungsverfahren für Amide, wie z.B. das Verfahren über gemischte Anhydride unter Verwendung vnn Chlnraeisensäureester, snwie die Verwendung aktivierter Ester der Pyrrolidin-(2)-nn-(2)-ylessigsäure, wie z.B. Nitrophenylester, Cyanbethylester nder Trichlorphenylester, nder auch die Verwendung des Pyrrnlidin-(2)-nn-(1)-ylessigsäurechlnrids.They are also suitable for obtaining the compound according to the invention the usual manufacturing processes for amides, such as the process via mixed Anhydrides using chloroic acid esters, like the use of activated ones Esters of pyrrolidine- (2) -nn- (2) -ylacetic acid, such as, for example, nitrophenyl ester, cyano ethyl ester The trichlorophenyl ester, also the use of pyrrolidine- (2) -nn- (1) -ylacetic acid chloride.

Zur Untersuchung der pharmakodynamischen Eigenschaften der erfindungsgemäßen Verbindung wurden folgende Methoden verwendet: 1. Verlängerung der zerebralen Überlebenszeit unter NaN02-evozierter Hypoxämie.To study the pharmacodynamic properties of the invention Compound the following methods were used: 1. Extension of the cerebral survival time under NaN02-evoked hypoxemia.

Ausgehend von den Ergebnissen von Gibson und Blass (J.Neurochemistry 27, 1976) wird bei männlichen Mäusen mit NaNO2 (225 mg/kg s.c.) eine zerebrale Hypoxie erzeugt. Die zerebrale Hypoxie-Periode wird durch charakteristisches Krampfverhalten gekennzeichnet und endet mit dem Tod der Versuchstiere. Gemessen wird, ob sich die Überlebenszeit unter zerebral-hypoxischen Bedingungen durch Prämedikation signifikant verlängert. Based on the results of Gibson and Blass (J.Neurochemistry 27, 1976), cerebral hypoxia develops in male mice with NaNO2 (225 mg / kg s.c.) generated. The cerebral hypoxia period is characterized by characteristic convulsive behavior marked and ends with the death of the laboratory animals. It is measured whether the Survival time under cerebral hypoxic conditions due to premedication was significant extended.

2. Verlängerung der zerebralen Überlebenszeit bei Unterdruckevnzierter Hypoxie.2. Extension of the cerebral survival time in negative pressure patients Hypoxia.

Es ist bekannt, daß Tiere unter abnehmendem Sauerstnffdruck charakteristisches neuropathologisches Verhalten zeigen. It is known that animals under decreasing oxygen pressure characteristic show neuropathological behavior.

Dieses neuropathologische Verhalten wird bei männlichen Mäusen durch progredienten Druckabfall in der Beobachtungskammer auf 26,66 k Pa ausgelöst und dient als Indikator der zerebralen Hypoxie-Periode. Sie endet mit dem Tod des Versuchstieres. Untersucht wird, ob sich die Überlebenszeit unter zerebral-hypoxischen Bedingungen durch Prämedikation signifikant verlängert. This neuropathological behavior is evident in male mice progressive pressure drop in the observation chamber to 26.66 k Pa triggered and serves as an indicator of the cerebral hypoxia period. It ends with the death of the test animal. It is examined whether the survival time under cerebral-hypoxic conditions significantly extended by premedication.

3. Schutz vor Elektroschock-induzierter Amnesie.3. Protection against electric shock-induced amnesia.

Ausgehend von den Ergebnissen von Taber und Banuazizi (Psychopharmakologia 9, 1966), läßt man männliche Mäuse erlernen, zur Vermeidung eines Elektroschocks ein bestimmtes Käfigkompartiment nicht zu begehen. Das Erlernte wird über Kopfelektroden mit Elektroschock extingiert (Elektroschock-Amnesie). Based on the results of Taber and Banuazizi (Psychopharmakologia 9, 1966), male mice are trained to avoid electric shock not to enter a certain cage compartment. What is learned is carried out via head electrodes Extinged with electric shock (electric shock amnesia).

Es wird untersucht, ob sich die Verweilzeit im elektroschockfreien Kompartiment des Käfigs als Maß für das Erinnerungsvermögen der Versuchstiere durch Prämedikation signifikant verlängert. It is examined whether the dwell time in the electroshock Compartment of the cage as a measure of the memory of the test animals Premedication significantly extended.

Als Referenzsubstanzen dienten in allen Versuchen: Papaverin, Cinnarizin, Meclofenoxat, Piracetam, Vincamin, Propranolol, Pyritinol und Pyrrolidin-(2)-on-(1)-ylessigsäureanilid.The following were used as reference substances in all experiments: papaverine, cinnarizine, Meclofenoxate, piracetam, vincamine, propranolol, pyritinol and pyrrolidin- (2) -one- (1) -ylacetic anilide.

In der nachfolgenden Tabelle werden die in den aufgeführten Versuchsmodellen erarbeiteten pharmakologischen Wirkqualitäten der erfindungsgemäßen Verbindung mit den handelsüblichen Referenzsubstanzen verglichen.The following table shows the experimental models listed elaborated pharmacological properties of the compound according to the invention with compared to the commercially available reference substances.

Substanz Appl. NaNO2- Unterdruck- Amnesie--Art Hypoxie- Hypoxie- Modell Modell Modell .Substance appl. NaNO2 negative pressure amnesia - type hypoxia-hypoxia model Model model.

DZL 221 p.o. + + + PA 2) p.o.DZL 221 p.o. + + + PA 2) p.o.

Papaverin i.v. + Cinnarizin p.o.Papaverine i.v. + Cinnarizine p.o.

Meclofenoxat p.o.Meclofenoxate p.o.

Piracetam p.o. - + + Vincamin p.o. ~ + + Propranolol p.o. + - + Pyritinol p.o. - - + I + = signifikante, therapeutisch nützliche Wirkung = = erfindungsgemäße Verbindung (DZL 221) Pyrrolidin-(2)-on-(1)-ylessigsäure-2, 6-dimethylanilid 2) = Verbindung aus Brit. Pat. 1.039.113 (PA) Pyrrolidin-(2)-on-(1)-ylessigsäureanilid Wie aus der Tabelle ersichtlich, zeigt die erfindungsgemäße Verbindung ein völlig neuartiges, zerebral-protektives Wirkprofil, da sie im Gegensatz zu den Referenzsubstanzen in allen drei Testverfahren wirksam ist.Piracetam p.o. - + + vincamine p.o. ~ + + Propranolol p.o. + - + pyritinol p.o. - - + I + = significant, therapeutically useful effect = = according to the invention Compound (DZL 221) pyrrolidin- (2) -one- (1) -ylacetic acid-2,6-dimethylanilide 2) = Connection from Brit. Pat. 1.039.113 (PA) pyrrolidin- (2) -one- (1) -ylacetic anilide As can be seen from the table, the compound according to the invention shows a completely novel, cerebral-protective action profile, as it is in contrast to the reference substances is effective in all three test procedures.

Die erfindungsgemäße Verbindung zeigt eine ausgezeichnete Wirkqualität sowie eine gute Verträglichkeit bei einer sehr geringen Toxizität: DL50: 1766 mg/kg - Maus p.o.The compound according to the invention shows an excellent quality of action as well as a good tolerance with a very low toxicity: DL50: 1766 mg / kg - mouse p.o.

DL50: 421 mg/kg - Maus i.v. DL50: 421 mg / kg - mouse i.v.

Die ausgezeichnete Wirkqualität und die gute Verträglichkeit, verbunden mit einer thrombozytenaggregationshemmenden Eigenschaft, wie sie für diesen Indikationsbereich erwünscht ist, machen die Substanz zur Behandlung von Krankheiten des zerebro-ischämischen wie zerebro-atrophischen Formenkreises incl. des organischen Psychosyndroms und der Migräne hervorragend geeignet.The excellent quality of action and the good tolerability, combined with a platelet aggregation-inhibiting property, as it is for this indication area is desirable to make the substance for the treatment of diseases of cerebro-ischemic such as cerebro-atrophic forms including the organic psychosyndrome and ideal for migraines.

Darüberhinaus zeigt die Verbindung eine gute tranquilisierende Eigenschaft.In addition, the compound shows good tranquilizing properties.

Der neue Wirkstoff kann in bekannter Weise in die üblichen Darreichungsformen, wie Tabletten, Kapseln, Dragees, Pillen, Emulsionen, Suspensionen und Lösungen übergeführt werden unter Verwendung pharmazeutisch geeigneter Lösungsmittel oder Trägerstoffe.The new active ingredient can be used in a known manner in the usual dosage forms, such as tablets, capsules, coated tablets, pills, emulsions, suspensions and solutions are made using pharmaceutically suitable solvents or carriers.

Als Hilfsstoffe seien beispielsweise aufgeführt: Nichttoxische, organische LMsungsmittel, wie pflanzliche Öle (z.B. Erdnußöl, Sojaöl), Alkohole (z.B. Polyäthylenglykol, Glycerin), feste Trägerstoffe, wie z.B. Gesteinsmehle (Kaoline, Talkum, Silikate), Zucker (z.B. Milchzucker, Traubenzucker), Emulgiermittel (z.B. Fettsäureester, Fettalkoholäther), Dispergiermittel (z.B. Methylcellulose, Stärke) und Gleitmittel (z.B. Talkum, Stearinsäure, Kakaobutter).Examples of auxiliaries are: Non-toxic, organic Solvents such as vegetable oils (e.g. peanut oil, soybean oil), alcohols (e.g. polyethylene glycol, Glycerine), solid carriers such as rock flour (kaolins, talc, silicates), Sugar (e.g. milk sugar, grape sugar), emulsifying agents (e.g. fatty acid esters, fatty alcohol ethers), Dispersants (e.g. methyl cellulose, starch) and lubricants (e.g. talc, stearic acid, Cocoa butter).

Die Applikation erfolgt üblicherweise enteral mit Dosen von 1-1000 mg, bevorzugt 10-100 mg, oder parenteral von 0,1 -100 mg, insbesondere 1-20 mg.The application is usually carried out enterally with doses of 1-1000 mg, preferably 10-100 mg, or parenterally from 0.1-100 mg, in particular 1-20 mg.

Die Erfindung wird im folgenden Beispiel erläutert Beispiel: DZL 221 Pyrrolidin-(2)-on-(1)-ylessigsäure-2,6-dimethylanilid 14,3 g (0,1 Mol Pyrrolidin-(2)-on-(1)-ylessigsäure C6HgrJ03 NO und 12,1 g (0,1 Mol) 2,6-Dimethylanilin 6 9 3 143,1J C8N11N (121, 21 werden in 100 ml Chloroform abs. mit 20,6 g (0,1 Mol), N,2-Diclyclohexylcarbodiimid C13H22N2 206, 3 3 Stunden unter Rückfluß erhitzt. Nach dem Abkühlen wird vom ausgefallenen N,N-Dicyclohexyl-harnstoff abgesaugt, das Filtrat eingeengt und der Rückstand umkristallisiert.The invention is illustrated in the following example: DZL 221 pyrrolidin- (2) -one- (1) -ylacetic acid-2,6-dimethylanilide 14.3 g (0.1 mol of pyrrolidin- (2) -one- (1) -ylacetic acid C6HgrJ03 NO and 12.1 g (0.1 mol) 2,6-dimethylaniline 6 9 3 143.1J C8N11N (121, 21 are dissolved in 100 ml of absolute chloroform with 20.6 g (0.1 mol) of N, 2-diclyclohexylcarbodiimide C13H22N2 206, 3 Heated under reflux for 3 hours After cooling, the precipitated N, N-dicyclohexylurea is filtered off with suction, the filtrate is concentrated and the residue is recrystallized.

Ausbeute: 18,7 g (76 % d. Theorie) C14H18N202 [246,3J Schmelzpunkt: 1530C (Wasser) Elementaranalyse: C14H18N202 246,3; be. : C = 68,27% H = 7,37% N = 11,37% 0 = 12,99% gef. C = 68,12% H = 7,37% N = 11,39% 0 = 12,94% C = 68,09% H = 7,42% N = 11,34% 0 = 13,09% IR-Spektrum: Gerät: Perkin-Elmer Modell 257 (KBr): NH:3260cm 1650 -1700cm-1 CO (Ring, Amid)' (überlagerte Banden) H-NMR-Spektrum: Gerät: Hitachi Perkin-Elmer, 60MHz, Modell R-24 Lösungsmittel: CDCL3(TMS intern g = 0) NH 7,85 (5), arom.7,0 (s), CH2 4,1 (s), CH2 3,6 (t), CH2 - CH2 2,2 (m), CH2 2,1 (s).Yield: 18.7 g (76% of theory) C14H18N202 [246.3J melting point: 1530C (water) Elemental analysis: C14H18N202 246.3; be. : C = 68.27% H = 7.37% N = 11.37% 0 = 12.99% found. C = 68.12% H = 7.37% N = 11.39% 0 = 12.94% C = 68.09% H = 7.42% N = 11.34% 0 = 13.09% IR spectrum: Device: Perkin-Elmer model 257 (KBr): NH: 3260cm 1650-1700cm-1 CO (ring, amide) '(superimposed bands) H-NMR spectrum: Device: Hitachi Perkin-Elmer, 60MHz, Model R-24 Solvent: CDCL3 (TMS internal g = 0) NH 7.85 (5), arom.7.0 (s), CH2 4.1 (s), CH2 3.6 (t), CH2 - CH2 2.2 (m), CH2 2.1 (s).

MS-Spektrum: Gerät: Varian Mat 311 A; Elektronenenergie 70eV, 200 Ionenquellentemperatur 2000C, Festprobenverdampfung bzw.MS spectrum: device: Varian Mat 311 A; Electron energy 70eV, 200 Ion source temperature 2000C, solid sample evaporation or

Gas einlaß für die Referenzsubstanz PFK, Scankontrolle sowie Datenerfassung und -verarbeitung über ein Finnigan-Incos-System; M+: m/e 246 (60 %) Dünnschichtchromatographie: DC-Fertigplatten Kieselgel 60 F254 (Merck) Sprühreagenz: Bromkresolgrün (0,05, Merck) Rf = 0,83 Laufmittel: Chloroform/Methanol/Ammoniak (25%) 70 26 4 (V/V/V) Rf = 0,36 Laufmittel: Chloroform/Methanol 190 10 (V/V) Gas inlet for the reference substance PFK, scan control and data acquisition and processing via a Finnigan Incos system; M +: m / e 246 (60%) Thin layer chromatography: TLC ready-to-use plates silica gel 60 F254 (Merck) spray reagent: bromocresol green (0.05, Merck) Rf = 0.83 mobile phase: chloroform / methanol / ammonia (25%) 70 26 4 (V / V / V) Rf = 0.36 Mobile phase: chloroform / methanol 190 10 (V / V)

Claims (1)

P a t e n t a n s p r ü c h e 1. Pvrrolidin-(2)-on-(l )-yle ssigs äure-2, 6-dimethylanllid 2. Verfahren zur Herstellung der Verbindung gemäss Anspruch 1 dadurch g e k e n n z e i c h n e t X dass man in an sich bekannter Weise Pyrrolldin-(2)-on-(l) ylessigsäure und 2, 6-Dimethylanilin zusammen mit N,§-Dicyclohexylcarbodiimid in einem organischen Lösungsmittel umsetzt, 3. Arzneimittel, enthaltend die Verbindung gemäss Anspruch 1 und übliche pharmazeutische Hilfsstoffe. P a t e n t a n s p r ü c h e 1. Pvrrolidin- (2) -on- (l) -yle ssigs äure-2,6-dimethylanllid 2. A process for the preparation of the compound according to claim 1 as a result of the fact that in a known manner Pyrrolldin- (2) -on- (l) ylacetic acid and 2,6-dimethylaniline together with N, §-dicyclohexylcarbodiimide in an organic solvent converts, 3. medicament containing the compound according to claim 1 and customary pharmaceutical auxiliaries.
DE19792924011 1979-06-13 1979-06-13 Pyrrolidin- (2) -one- (1) -ylacetic acid-2,6, -dimethylanilide, process for the preparation and medicaments containing this compound Expired DE2924011C2 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
DE19792924011 DE2924011C2 (en) 1979-06-13 1979-06-13 Pyrrolidin- (2) -one- (1) -ylacetic acid-2,6, -dimethylanilide, process for the preparation and medicaments containing this compound
IT21464/80A IT1141287B (en) 1979-06-13 1980-04-17 PYROLIDIN ACIDS AMIDS- (2) -ON- (1) -ILALKYL-CARBOXYLS, PROCEDURE FOR THEIR PREPARATION AND MEDICINAL PRODUCTS CONTAINING THEM
US06/155,952 US4341790A (en) 1979-06-13 1980-06-03 Pyrrolidinylalkylcarboxylic acid amide derivatives, their preparation and pharmaceutical compositions containing them
FR8012840A FR2458544A1 (en) 1979-06-13 1980-06-10 NOVEL PYRROLIDIN- (2) -ON- (1) -YLALCOYL-CARBOXYLIC ACID AMIDES, PROCESS FOR THEIR PREPARATION AND THEIR USE AS MEDICAMENTS
GB8019199A GB2053909B (en) 1979-06-13 1980-06-12 Pyrrolidinylalkycarboxylic acid amide derivatives their preparation and pharmaceutical compositions containing them

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DE19792924011 DE2924011C2 (en) 1979-06-13 1979-06-13 Pyrrolidin- (2) -one- (1) -ylacetic acid-2,6, -dimethylanilide, process for the preparation and medicaments containing this compound

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DE2924011C2 DE2924011C2 (en) 1982-04-08

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4476308A (en) * 1981-07-24 1984-10-09 Hoffmann-La Roche Inc. 1-Pyrrolidine acetamides
DE3336024A1 (en) * 1983-10-04 1985-04-18 Boehringer Ingelheim KG, 6507 Ingelheim 4-AMINO-L-BENZYL-PYRROLIDINONE AND ITS ACID ADDITION SALTS, METHOD FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS
US6423739B1 (en) 2000-02-23 2002-07-23 Daiichi Pharmaceutical Co., Ltd. Method for aiding cerebral recovery following neurodegeneration
EP1274423A1 (en) * 2000-04-11 2003-01-15 Virginia Commonwealth University Intellectual Property Foundation Medicine for treating traumatic brain injury and other neuronal disorders

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4476308A (en) * 1981-07-24 1984-10-09 Hoffmann-La Roche Inc. 1-Pyrrolidine acetamides
US5034402A (en) * 1981-07-24 1991-07-23 Hoffmann-La Roche Inc. Methods and pharmaceutical compositions using pyrrolidine derivatives
DE3336024A1 (en) * 1983-10-04 1985-04-18 Boehringer Ingelheim KG, 6507 Ingelheim 4-AMINO-L-BENZYL-PYRROLIDINONE AND ITS ACID ADDITION SALTS, METHOD FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS
US6423739B1 (en) 2000-02-23 2002-07-23 Daiichi Pharmaceutical Co., Ltd. Method for aiding cerebral recovery following neurodegeneration
EP1274423A1 (en) * 2000-04-11 2003-01-15 Virginia Commonwealth University Intellectual Property Foundation Medicine for treating traumatic brain injury and other neuronal disorders
EP1274423A4 (en) * 2000-04-11 2006-09-06 Univ Virginia Commonwealth Medicine for treating traumatic brain injury and other neuronal disorders

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Free format text: WUESTHOFF, F., DR.-ING. FRHR. VON PECHMANN, E., DIPL.-CHEM. DR.RER.NAT. BEHRENS, D., DR.-ING. GOETZ, R., DIPL.-ING. DIPL.-WIRTSCH.-ING. HELLFELD VON, A., DIPL.-PHYS. DR.RER.NAT. BRANDES, J., DIPL.-CHEM. DR.RER.NAT., PAT.-ANWAELTE WUERTENBERGER, G., RECHTSANW., 8000 MUENCHEN