DE2462963C2 - Derivatives of 2-phenyl-3-aminopyrrole, their salts and pharmaceutical preparation containing them - Google Patents
Derivatives of 2-phenyl-3-aminopyrrole, their salts and pharmaceutical preparation containing themInfo
- Publication number
- DE2462963C2 DE2462963C2 DE2462963A DE2462963A DE2462963C2 DE 2462963 C2 DE2462963 C2 DE 2462963C2 DE 2462963 A DE2462963 A DE 2462963A DE 2462963 A DE2462963 A DE 2462963A DE 2462963 C2 DE2462963 C2 DE 2462963C2
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- Prior art keywords
- phenyl
- aminopyrrole
- derivatives
- salts
- pharmaceutical preparation
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Classifications
-
- 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
- C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
- C07D207/34—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 two double bonds between ring members or between ring members and non-ring members 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
- C07D207/36—Oxygen or sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
- C07D207/34—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 two double bonds between ring members or between ring members and non-ring members 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Rheumatology (AREA)
- Pharmacology & Pharmacy (AREA)
- Pain & Pain Management (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Furan Compounds (AREA)
Description
2020th
2525th
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Die Erfindung betrifft den Gegenstand der Ansprüche. The invention relates to the subject matter of the claims.
Die beiden erfindungsgemäßen Verbindungen können erhalten werden, indem man zunächst 2-Amino-2-phenylacetonitril oder ein Säureanlagerungssalz desselben in einer 1. Verfahrensstufe mit einer Verbindung der allgemeinen Formel IlThe two compounds of the invention can be obtained by first adding 2-amino-2-phenylacetonitrile or an acid addition salt thereof in a 1st process stage with a compound of general formula II
IlIl
CCH3
^CH3 CCH 3
^ CH 3
(H)(H)
4040
45 S-amino^-carbomethoxy-S-carbamoylpyrrol, kann erhalten werden, indem man das 2-Phenyl-3-amino-4,5-dicarbomethoxypyrrol aus der 1. Verfahrensstufe mit Ammoniakgas umsetzt 45 S-amino ^ -carbomethoxy-S-carbamoylpyrrole can be obtained by reacting the 2-phenyl-3-amino-4,5-dicarbomethoxypyrrole from the 1st process stage with ammonia gas
Die erwähnten Anlagerungssalze der erfindungsgemäßen Verbindung des Beispiels 2 mit pharmazeutisch zulässigen Säuren werden im wesentlichen repräsentiert durch das Hydrochloride Hydrobromid, Hydrojodid, Sulfat, Phosphat, Benzoat, Oxalat, Acetat, Methansulfonat und Cyclohexylsulfonat. Sie werden leicht erhalten, indem man die Verbindung in Form der freien Base mit der gewünschten pharmazeutisch zulässigen Säure behandelt. Andererseits ist es möglich, die freie Base aus dem entsprechenden Säuresalz wieder herzustellen, indem man letzteres mit mindestens einer äquimolaren Menge eines basischen Stoffs umsetztThe mentioned addition salts of the compound according to the invention of Example 2 with pharmaceutical Permissible acids are essentially represented by the hydrochloride hydrobromide, hydroiodide, Sulfate, phosphate, benzoate, oxalate, acetate, methanesulfonate and cyclohexyl sulfonate. They are easily obtained by using the compound in free base form the desired pharmaceutically acceptable acid treated. On the other hand, it is possible to choose the free base to restore the corresponding acid salt by mixing the latter with at least one equimolar Amount of a basic substance converts
Die erfindungsgemäßen Verbindungen besitzen eine beträchtliche entzündungshemmende Wirkung bei geringer ulcerogener Nebenwirkung.The compounds of the invention have a significant anti-inflammatory effect with little ulcerogenic side effect.
Die erfindungsgemäßen Verbindungen sowie Phenylbutazon, Indomethacin Γ, 1-(p-Chlorbenzoyl)-5-methoxy-2-methylindol-3-yl-essigsäure] und die aus der DD-PS 70 880, Tab. 1, bekannte 1-Cinnamoyl-2-methyl-5-methoxy-3-indolylessigsäure als Vergleichssubstanz wurden im Carrageenintest (vgl. C. A. Winter u. a., Proc. Soc. Exptl. Biol. Med„ Bd. 111, Seite 544 [1962]) hinsichtlich ihrer entzündungshemmenden Wirkung untersucht.The compounds according to the invention and phenylbutazone, indomethacin Γ, 1- (p-chlorobenzoyl) -5-methoxy-2-methylindol-3-yl-acetic acid] and the 1-cinnamoyl-2-methyl-5-methoxy-3-indolylacetic acid known from DD-PS 70 880, Tab. 1 in the carrageenin test (cf. C. A. Winter et al., Proc. Soc. Exptl. Biol. Med "Vol. 111, page 544 [1962]) with regard to investigated their anti-inflammatory effects.
Die Toxizitäten LD50 wurden nach der Methode von Lichtfield und Wilcoxon, J. Pharm. Exp. Ther., Bd. 96, Seite 99 (1949), bestimmt.The toxicities LD50 were determined by the method of Lichtfield and Wilcoxon, J. Pharm. Exp. Ther., Vol. 96, Page 99 (1949), determined.
Zum Vergleich wurde auch für die beiden erstgenannten Vergleichssubstanzen u. a. ihre Fähigkeit bestimmt, das ödem bei Dosierungen herabzusetzen, die etwa einem Fünftel ihrer Toxizität, ausgedrückt als LD50, entsprechen. In der Tat werden im allgemeinen höhere Dosierungen in der Praxis deshalb nicht berücksichtigt, weil sie zu nahe der toxischen Dosis liegen würden, und mit der Entstehung von unerwünschten Nebeneffekten zu rechnen wäre, wie nachfolgende Tests belegen.For comparison, the first two were also mentioned Comparative substances, inter alia. determines their ability to lower the edema at dosages that are approximately one fifth of their toxicity, expressed as LD50, correspond. In fact, higher doses are generally not taken into account in practice, because they would be too close to the toxic dose, and with the development of undesirable side effects to be expected, as the following tests show.
Der Vergleich zwischen den Vergleichssubstanzen und den erfindungsgemäßen Substanzen erfolgt daher zwar nicht aufgrund der therapeutischen Indices, jedoch ist er durchaus gültig, indem man nach gleichen Kriterien erhaltene Ergebnisse gegenüberstellt.The comparison between the comparison substances and the substances according to the invention is therefore made Although not based on the therapeutic indices, however, it is entirely valid by looking for the same Compares the results obtained with the criteria.
Die Versuchsergebnisse sind in nachfolgender Tabelle A enthalten:The test results are given in Table A below:
worin X die Gruppe -C = C- oder -CH2-CO-darstellt,
deren -CH2-AnIeH an den Acetylrest
gebunden ist. z. B. mit Acetylaceton, bzw. mit Dicarbotnethoxyacetylen,
in an sich bekannter Weise zu
2-Phenyl-3-amino-4-acetyl-5-methylpyrrolwherein X is the group -C = C- or -CH 2 -CO-whose -CH 2 -AnIeH is bonded to the acetyl radical. z. B. with acetylacetone, or with Dicarbotnethoxyacetylen, in a conventional manner
2-phenyl-3-amino-4-acetyl-5-methylpyrrole
(vgl. DE-OS 24 39 284, Bsp. 1) bzw.
2-Phcnyl-3-amino-4.5-dicarbomethoxypyrrol(cf. DE-OS 24 39 284, Ex. 1) or
2-Phenyl-3-amino-4,5-dicarbomethoxypyrrole
umsetzt.implements.
2-Phenyl-3-amino-4-acetyl-5-methylpyrrol wird sodann in einer 2. Verfahrensstufe durch Methylierung der 3ständigen Aminogruppe mit einem Meihylierungsmittel wie z. B. Dimethylsulfat in an sich bekannter Weise in2-Phenyl-3-amino-4-acetyl-5-methylpyrrole is then in a 2nd process stage by methylation of the 3-position amino group with a methylating agent such as B. dimethyl sulfate in a known manner in
2-Phenyl-3-dimcthylamino-4-acetyl-5-met.hylpyrrol
übergeführt, das in einer 3. Stufe am Ringstickstoffatom mit einem p-Chlorbcnzylhalogenid in Gegenwart eines
stark basischen Mittels, wie z. B. eines Alkalimetalls oder -hydrids. substituiert wird, wobei man die
erfindungsgemäße Verbindung 1-(p-Chlorbenzyl)-2-phcnyl-)dimethylamino-4
acctylS-mcthylpyrrol erhält.2-phenyl-3-dimethylamino-4-acetyl-5-methyl-ethylpyrrole
transferred, which in a 3rd stage on the ring nitrogen atom with a p-Chlorbcnzylhalogenid in the presence of a strongly basic agent, such as. B. an alkali metal or hydride. is substituted, the compound according to the invention 1- (p-chlorobenzyl) -2-phcnyl-) dimethylamino-4-acctylS-methylpyrrole being obtained.
Die andere erfindungsgemäße Verbindung, 2-Phenyl-The other compound of the invention, 2-phenyl-
Fortsetzungcontinuation
erfindungsgemäßen Verbindungen berücksichtigt wird, hat man die folgende Situation:connections according to the invention is taken into account, one has the following situation:
Verbindung des
BeispielsConnection of the
Example
LD50 DosisLD 50 dose
(mg/kg) (mg/kg)(mg / kg) (mg / kg)
p.o. p.o.p.o. p.o.
Maus RatteMouse rat
l-Cinnamoyl-2- 500 12l-cinnamoyl-2- 500 12
ti- müthyl-5-methoxy-3-indolylessigsäure
(!Vergleich)**)
Phenylbutazon 390tri-methyl-5-methoxy-3-indolylacetic acid
(!Comparison)**)
Phenylbutazone 390
(3. Vergleich)(3rd comparison)
des induacceptance
of the indu
**) vgl. DD-PS 70 880, Tab. 1**) see DD-PS 70 880, Tab. 1
In Anbetracht der Tatsache, daß eine prozentuale Hemmung von 3P -ind mehr unter pharmakologischem Gesichtspunkt bedeutungsvoll ist, ergibt sich, daß Indomethacin das ödem auf ungefähr 30% vermindert, wenn es annähernd bei Ve seiner (sehr hohen) Toxizität verabreicht wird, während die bei Verabreichung von geringeren Dosen (S'/io der LD50-Werte) der erfindungsgemäßen Substanzen beobachteten prozentualen ödemabnahmen größer als 38 sind.In view of the fact that a percentage inhibition of 3P -ind is more pharmacologically significant, it turns out that indomethacin reduces the edema to about 30% when it is administered near its (very high) toxicity, while that at Administration of lower doses ( 1/2 of the LD 50 values) of the substances according to the invention, the percentage edema reductions observed are greater than 38.
Wenn die Wirkung bei den höchsten Dosen der Gegenüber i-Cinnamoyl^-methyl-S-methoxyO-indoiylessigsäure (und das Gleiche gilt gegenüber Indomethacin) zeigen die erfindungsgemäßen Verbindungen den großen Vorteil, daß sie eine sehr geringe gastroulcerogene Wirkung aufweisen, wie es sich aus der nachfolgenden Tabelle B ergibt. Dieser Vorteil kommt insbesondere bei einer Dauertherapie, wie sie z. B. bei der Behandlung von Arthritis notwendig ist, zum tragen. Die gasiroulcerogene Wirkung von Indomethacin und den neuen Pyrrolderivaten wurde jeweils nach der von Thuillier und Mharb., Chim. Therap., Bd. 3, Seite 53 (1968), beschriebenen Methode untersucht. Als Parameter wurde der «Durchschnittliche UIcerationsgradx berücksichtigt, der djrch folgendes Verhältnis ausgedrückt wird:If the effect at the highest doses is compared to i-Cinnamoyl ^ -methyl-S-methoxyO-indoiylacetic acid (and the same applies to indomethacin) show the compounds according to the invention the great advantage that they have a very low gastroulcerogenic effect, as can be seen from Table B below shows. This advantage comes especially with long-term therapy like her z. B. in the treatment of arthritis is necessary to wear. The gasiroulcerogenic effect of Indomethacin and the new pyrrole derivatives were each after that of Thuillier and Mharb., Chim. Therap., Vol. 3, page 53 (1968), investigated the method described. “Average UIcerationsgradx taken into account, the following Ratio is expressed:
T-v ·. u -..ι tu .· α Summe der »Einzelnen Ulcerationsgrade«Tv ·. u - .. ι tu. · α Sum of the "individual degrees of ulceration"
Durchschnittl. Ulcerationsgrad = —— —: Average Degree of ulceration = —— - :
Anzahl der VersuchstiereNumber of test animals
wobei man unter »Einzelnem Ulc./"ationsgrad« den Ulcerationsgrad des Magens jedes einzelnen Versuchstieres (im allgemeinen Ratten) verste'it, und sich die Anzahl der \ jrsuchstiere pro Bestimmung jeweils auf 7 bei ift.eluting under "single Ulc./"ationsgrad" of each individual test animal verste'it the Ulcerationsgrad of the stomach (generally rat), and the number of \ jrsuchstiere per determination in each case to 7 at ift.
Der »Einzelne Ulcerationsgrad« wird ermittelt, indem man der Art der im Magen jeder einzelnen Ratte beobachteten UIcerbildung eine willkürliche Wertung zuschreibt, die innerhalb einer Skala von aufsteigenden Wertungen zu wählen ist: je höher die Wertung ist, desto schwerer ist die UIcerbildung. Die Wertungen liegen zwischen 0 und 4, wobei Null die Abwesenheit jedweder UIcerbildung, und 4 perforierte Geschwüre bezeichnet.The "individual degree of ulceration" is determined by looking at the type of stomach in each individual rat observed ulcer formation ascribing an arbitrary rating within an ascending scale Valuations should be chosen: the higher the valuation, the more difficult the UIcer formation. The ratings range from 0 to 4, with zero indicating the absence of any ulcer formation, and 4 perforated ulcers designated.
3535
4040
4545
5050
5555
6060
6565
Somit erwiesen sich die beiden erfindungsgemäßen Verbindungen gegenüber den Vergleichssubstanzen 1 und 2 hinsichtlich dieser sehr unerwünschten Nebenwirkung als überlegen, da es sich ergibt, daß bei ersteren, auch wenn sie den Ratten bei den höchsten berücksichtigten Dosen von 200 mg verabreicht werden, der »Durchschnittliche Ulcerationsgrad« nie größer als 0,79 ist, was praktisch Abwesenheit oder Entstehung von nur geringfügigen Ulcerbildungen bedeute'.. Im Gegensatz hierzu ist der »Durchschnittliche Ulcerationsgrad« von Indomethacin und der 2. Vergleichssubstanz 3,10 bzw. 2,90, wenn man auf den jeweiligen EDw-Wert abstellt: dies heißt aber, daß bei einigen Ratten auch perforierte Geschwüre zu beobachten waren.The two compounds according to the invention were thus found to be compared with comparison substances 1 and 2 as superior with regard to this very undesirable side effect, since it appears that with the former, even when administered to rats at the highest considered doses of 200 mg, the "Average degree of ulceration" is never greater than 0.79, which is practically the absence or occurrence of only minor ulcerations mean '.. In contrast the "average degree of ulceration" of indomethacin and the second comparison substance is 3.10 or 2.90 if the respective EDw value is used: but this means that perforated ulcers were also observed in some rats.
Die bevorzugten Verabreichungsarten sind der orale und rektale Weg, jedoch ist auch parenteral Verabreichung möglich. Zur oialen Verabreichung werden die Verbindungen zu pharmazeutischen Dosierungsformen formuliert, zum Beispiel zu Tabletten, Kapseln, Elixieren, Lösungen und dergleichen. Die Dosiseinheit kann die üblichen Streckmittel wie zum Beispiel Stärke, Gummis, Fettsäuren, Alkohole oder Zucker enthalten. Zur rektalen Verabreichung werden die Verbindungen in Form von Suppositorien verabreicht, und zwar in Gemisch mit konventionellen Trägern wie zum Beispiel Kakaobutter, Wachs, Walrat oder Polyoxymethylenglycolen. Die Dosis liegt zwischen etwa 0,05 und etwa 2,00 g pro Tag und wird vorzugsweise in Teilmengen verabreicht.The preferred modes of administration are the oral and rectal routes, however parenteral administration is also possible possible. For oral administration, the compounds become pharmaceutical dosage forms formulated, for example, into tablets, capsules, elixirs, solutions and the like. The dose unit can contain the usual extenders such as starch, gums, fatty acids, alcohols or sugars. For rectal administration, the compounds are administered in the form of suppositories, specifically in Mixture with conventional carriers such as cocoa butter, wax, whale rat or polyoxymethylene glycols. The dose is between about 0.05 and about 2.00 grams per day and is preferably used in aliquots administered.
1-(p-Chlorbenzyl)-2-phenyl-3-dimethylamino-4-acetyl-5-mcthylpyrrol 1- (p-Chlorobenzyl) -2-phenyl-3-dimethylamino-4-acetyl-5-methylpyrrole
a) Eine Lösung von 2 g (0,015 Mol) 2-Amino-2-phenylacetonitril und 1.4 g (0,014 Mol) Acetylaceton ina) A solution of 2 g (0.015 mol) of 2-amino-2-phenylacetonitrile and 1.4 g (0.014 mol) of acetylacetone in
30ml wasseiiiwiem Benzol "<ird 2 Stunden auf einem ölbad in Gegenwart von 100 mg p-Toluolsulfonsäure unter Rückfluß erwärmt. Nach dem Abkühlen wird das Reaktionsgemisch nitriert, Ja.in wird das Lösungsmittel abgedampft, wobei man ■"' einen öligen Rückstand erhält. Dieser Rückstand wird sodann in wasserfreiem Äthanol geluvt. Diese Lösung wird zu einer Lösung von 0,4 g Natrium in 15 ml wasserfreiem Äthanol zugetropft, und das Gemisch wird bei Raumtemperatur 4 Stunden stehengelassen. Nach dem Durchleiten von trockener.· i' borwasserstoff durch die Äthanoliösung bildet sich ein Niederschlag, der abfiltriert und aus Äthanol-Diäthyläther umkristallisiert wird. Hierbei werden 2,0 g i-Phenyl-S-amino^-acetyl-S-methyl- '5 pyrrol-hydrochlorid erhalten; F. 242°C (Zers.) [vgl. DE-OS 24 39 284, Bsp. I].30ml water-like benzene is left on for 2 hours an oil bath in the presence of 100 mg of p-toluenesulfonic acid heated to reflux. After cooling, the reaction mixture is nitrated, Ja.in the solvent is evaporated to give an oily residue. This residue is then luv in anhydrous ethanol. These Solution is added dropwise to a solution of 0.4 g of sodium in 15 ml of anhydrous ethanol, and that The mixture is left to stand at room temperature for 4 hours. After passing through dry. i 'hydrogen boride through the ethanol solution A precipitate forms, which is filtered off and recrystallized from ethanol-diethyl ether. Here 2.0 g of i-phenyl-S-amino ^ -acetyl-S-methyl- '5 pyrrole hydrochloride obtained; M.p. 242 ° C (decomp.) [Cf. DE-OS 24 39 284, Ex. I].
Zu einer Lösung von 5 g (0,0278 Mol) der letztgenannten Verbindung in 40 ml Pyridin wer- a) den unter Rühren 0,0228 MoI Dimethylsulfat bei 00C zugegeben. Nach 1 stündigem weiteren Rühren wird die Lösung über Nacht bei 0°C stehengelassen. Das Reaktionsgemisch wird in 10%ige wäßrige Salzsäure eingegossen, der entstandene Niederschlag abfiltriert, eine wäßrige Lösung desselben mit 5%iger NaOH alkalisch gemacht, mit Chloro- b) form extrahiert und aus Chloroform umkristallisiert. The added to a solution of 5 g (0.0278 mol) of the latter compound in 40 ml of pyridine advertising a) with stirring 0.0228 MoI dimethyl sulfate at 0 0 C. After stirring for a further 1 hour, the solution is left to stand at 0 ° C. overnight. The reaction mixture is poured into 10% aqueous hydrochloric acid, the resulting precipitate is filtered off, an aqueous solution of the same is made alkaline with 5% NaOH, extracted with chloroform and recrystallized from chloroform.
Hierbei wird in 68%iger Ausbeute 2-Phenyl-3-dimethylamino-4-acetyl-5-methylpyrrol, F. 3"In this case, 2-phenyl-3-dimethylamino-4-acetyl-5-methylpyrrole, F. 3 "
153 -155° C, erhalten.153-155 ° C.
Eine Lösung von 0,00467 Mol der zuletzt genannten bindung in 25 ml Dimethylformamid v.rc) zu
einer kaiien Suspension von Naui'umhydrid in
10 ml Dimethylformamid zugetropi?.
Dac erhaltene Gemisch v.v-d Ij Mifititsn bei eiwa 0
bis 50C gerührt, wonach 0,0161 Mol p-Chlo;t>enzylchlorid
zugesetzt werden. Nach jeweils 30minütigem Rühren bei etwa 0°C und bei Raumtemperatur
wird mit 150 ml Wasser versetzt und sodsnn mit
Diäthyläther extrahiert. Aus der organisches* Phase wird das Lösungsmittel abgedampft, und der
Rückstand wird aus Hexan umkristallisiert Hierbei wird die gewünschte Verbindung in S2%iger
Ausbeute erhalten; F. 118- 119°C.A solution of 0.00467 mol of the last-mentioned bond in 25 ml of dimethylformamide v.rc) is added dropwise to a kaiien suspension of sodium hydride in 10 ml of dimethylformamide.
Dac resulting mixture vv-d Ij Mifititsn stirred at Eiwa 0 to 5 0 C, after which 0.0161 mol of p-Chlo; be t> enzylchlorid added. After stirring for 30 minutes at about 0 ° C. and at room temperature, 150 ml of water are added and the mixture is extracted with diethyl ether. The solvent is evaporated from the organic * phase and the residue is recrystallized from hexane. The desired compound is obtained in S2% yield; 118-119 ° C.
2-Pheny!-3-amino-4-caΓbomethoxy-5-carbamoylpyrrol 2-Pheny! -3-amino-4-caΓbomethoxy-5-carbamoylpyrrole
Nach dem Verfahren des Beispiels 1, Teil a), wird unter Verwendung von Dicarbomethoxyacetylen
anstelle von Acetylaceton in 39°/oiger Ausbeute 2-Phenyl-3-amino-4,5-dicarb' ;.;iethoxypyrrol hergestellt;
F. des Hydrochloric 205-2070C (aus Methanol/Diäthyläther), F. der freien Base
142- 143° C (aus Diäthyläther).
Eine Lösung von 5 g (0,0161 Mol) der in Stufe a) erhaltenen Verbindung wird mit Ammoniakgas
gesättigt, dann läßt man das Reaktionsgemisch 2 Tage stehen. Es kristallisiert die gewünschte
Verbindung aus, die abfiltriert wird. Ausbeute: 2,8 g; F. 177-179° C (aus Methanol/Wasser).Following the procedure of Example 1, part a), 2-phenyl-3-amino-4,5-dicarb ';.; Iethoxypyrrole is prepared in 39% yield using dicarbomethoxyacetylene instead of acetylacetone; F. Hydrochloric of 205-207 0 C (from methanol / diethyl ether), F. the free base 142- 143 ° C (from diethyl ether).
A solution of 5 g (0.0161 mol) of the compound obtained in step a) is saturated with ammonia gas, then the reaction mixture is left to stand for 2 days. The desired compound crystallizes out and is filtered off. Yield: 2.8 g; Mp 177-179 ° C (from methanol / water).
Claims (2)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB3979073A GB1427945A (en) | 1973-08-22 | 1973-08-22 | Aminopyrrole derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE2462963C2 true DE2462963C2 (en) | 1982-12-02 |
Family
ID=10411528
Family Applications (4)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE2462966A Expired DE2462966C2 (en) | 1973-08-22 | 1974-08-16 | Derivatives of 3-amino-4-acetyl-5-methylpyrrole and pharmaceutical preparations containing them |
| DE2462967A Expired DE2462967C2 (en) | 1973-08-22 | 1974-08-16 | Derivatives of 3-amino-5-methyl-2-phenyl-pyrrole, their salts and pharmaceutical preparations containing them |
| DE2462963A Expired DE2462963C2 (en) | 1973-08-22 | 1974-08-16 | Derivatives of 2-phenyl-3-aminopyrrole, their salts and pharmaceutical preparation containing them |
| DE2439284A Expired DE2439284C2 (en) | 1973-08-22 | 1974-08-16 | 2-Phenyl-3-amino-4-acetyl-5-methylpyrrole, its salts and pharmaceutical preparation containing these compounds |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE2462966A Expired DE2462966C2 (en) | 1973-08-22 | 1974-08-16 | Derivatives of 3-amino-4-acetyl-5-methylpyrrole and pharmaceutical preparations containing them |
| DE2462967A Expired DE2462967C2 (en) | 1973-08-22 | 1974-08-16 | Derivatives of 3-amino-5-methyl-2-phenyl-pyrrole, their salts and pharmaceutical preparations containing them |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE2439284A Expired DE2439284C2 (en) | 1973-08-22 | 1974-08-16 | 2-Phenyl-3-amino-4-acetyl-5-methylpyrrole, its salts and pharmaceutical preparation containing these compounds |
Country Status (27)
| Country | Link |
|---|---|
| JP (1) | JPS5328914B2 (en) |
| AR (3) | AR210246A1 (en) |
| AT (1) | AT336600B (en) |
| BE (1) | BE819088A (en) |
| CA (1) | CA1050556A (en) |
| CH (1) | CH605741A5 (en) |
| CS (1) | CS188201B2 (en) |
| DD (1) | DD113756A5 (en) |
| DE (4) | DE2462966C2 (en) |
| DK (1) | DK156391C (en) |
| ES (3) | ES429446A1 (en) |
| FI (1) | FI61879C (en) |
| FR (1) | FR2241308B1 (en) |
| GB (1) | GB1427945A (en) |
| HU (1) | HU169728B (en) |
| IE (1) | IE40290B1 (en) |
| IL (1) | IL45368A (en) |
| IN (1) | IN140329B (en) |
| LU (1) | LU70764A1 (en) |
| NL (1) | NL7411092A (en) |
| NO (1) | NO143845C (en) |
| PL (2) | PL96806B1 (en) |
| RO (3) | RO70534A (en) |
| SE (1) | SE394429B (en) |
| SU (1) | SU843738A3 (en) |
| YU (1) | YU36926B (en) |
| ZA (1) | ZA744754B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1492663A (en) * | 1975-02-20 | 1977-11-23 | Lepetit Spa | 4-amino-3-pyrrole carboxamides |
| GB1548398A (en) * | 1975-06-05 | 1979-07-11 | Lilly Industries Ltd | Acylamino pyrroles furans and thiophenes |
| DE3212591A1 (en) * | 1982-04-03 | 1983-10-13 | Gödecke AG, 1000 Berlin | 2-PYRROLIN-3-CARBONITRIL DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THE SAME |
| JPH0216740U (en) * | 1988-07-21 | 1990-02-02 | ||
| EP0390739B1 (en) * | 1989-03-28 | 1995-08-09 | Ciba-Geigy Ag | Substituted aminopyrroles as stabilisers in chlorinated polymers |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1148908A (en) * | 1965-04-19 | 1969-04-16 | Sumitomo Chemical Co | Indole derivatives and processes for making them |
| GB1187903A (en) * | 1967-09-29 | 1970-04-15 | Sumitomo Chemical Co | Glucuronides of 3-Indolylaliphatic Acid Derivatives and Processes for Producing them |
-
1973
- 1973-08-22 GB GB3979073A patent/GB1427945A/en not_active Expired
-
1974
- 1974-07-27 ZA ZA00744754A patent/ZA744754B/en unknown
- 1974-07-29 IL IL45368A patent/IL45368A/en unknown
- 1974-08-01 YU YU2141/74A patent/YU36926B/en unknown
- 1974-08-08 IE IE1672/74A patent/IE40290B1/en unknown
- 1974-08-08 NO NO742862A patent/NO143845C/en unknown
- 1974-08-16 DE DE2462966A patent/DE2462966C2/en not_active Expired
- 1974-08-16 DE DE2462967A patent/DE2462967C2/en not_active Expired
- 1974-08-16 DE DE2462963A patent/DE2462963C2/en not_active Expired
- 1974-08-16 DE DE2439284A patent/DE2439284C2/en not_active Expired
- 1974-08-16 DD DD180545A patent/DD113756A5/xx unknown
- 1974-08-19 RO RO7491734A patent/RO70534A/en unknown
- 1974-08-19 RO RO79830A patent/RO72882B/en unknown
- 1974-08-19 RO RO7491735A patent/RO70535A/en unknown
- 1974-08-20 IN IN1864/CAL/1974A patent/IN140329B/en unknown
- 1974-08-20 NL NL7411092A patent/NL7411092A/en unknown
- 1974-08-20 LU LU70764A patent/LU70764A1/xx unknown
- 1974-08-21 CA CA207,472A patent/CA1050556A/en not_active Expired
- 1974-08-21 SE SE7410636A patent/SE394429B/en not_active IP Right Cessation
- 1974-08-21 CH CH1142674A patent/CH605741A5/xx not_active IP Right Cessation
- 1974-08-21 JP JP9600974A patent/JPS5328914B2/ja not_active Expired
- 1974-08-21 HU HULE754A patent/HU169728B/hu not_active IP Right Cessation
- 1974-08-21 DK DK445974A patent/DK156391C/en active
- 1974-08-21 FI FI2462/74A patent/FI61879C/en active
- 1974-08-21 SU SU742055571A patent/SU843738A3/en active
- 1974-08-22 AT AT684774A patent/AT336600B/en not_active IP Right Cessation
- 1974-08-22 PL PL1974189700A patent/PL96806B1/en unknown
- 1974-08-22 FR FR7428894A patent/FR2241308B1/fr not_active Expired
- 1974-08-22 BE BE147818A patent/BE819088A/en not_active IP Right Cessation
- 1974-08-22 PL PL1974173617A patent/PL95235B1/pl unknown
- 1974-08-22 CS CS745833A patent/CS188201B2/en unknown
- 1974-08-22 ES ES429446A patent/ES429446A1/en not_active Expired
- 1974-08-27 AR AR255253A patent/AR210246A1/en active
-
1976
- 1976-06-03 AR AR263502A patent/AR210132A1/en active
- 1976-06-03 AR AR263503A patent/AR210133A1/en active
- 1976-07-01 ES ES449425A patent/ES449425A1/en not_active Expired
- 1976-07-01 ES ES449426A patent/ES449426A1/en not_active Expired
Non-Patent Citations (1)
| Title |
|---|
| NICHTS-ERMITTELT * |
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