DE3217446A1 - Substituted thiocarbamoylthenoylacetonitriles, process for their preparation and pharmaceutical preparations containing them - Google Patents
Substituted thiocarbamoylthenoylacetonitriles, process for their preparation and pharmaceutical preparations containing themInfo
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- DE3217446A1 DE3217446A1 DE19823217446 DE3217446A DE3217446A1 DE 3217446 A1 DE3217446 A1 DE 3217446A1 DE 19823217446 DE19823217446 DE 19823217446 DE 3217446 A DE3217446 A DE 3217446A DE 3217446 A1 DE3217446 A1 DE 3217446A1
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- thiocarbamoyl
- thiol
- chloro
- acetonitrile
- salts
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
- C07D333/28—Halogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
- C07D333/30—Hetero atoms other than halogen
- C07D333/32—Oxygen atoms
Abstract
Description
Titel: Substituierte Thiocarbamoyl-thenoyl-Title: Substituted Thiocarbamoyl-thenoyl-
acetonitrile, Verfahren zu ihrer Herstellung und diese enthaltende pharma-. acetonitriles, process for their preparation and containing them pharmaceutical.
zeutische Präparate. chemical preparations.
Beschreibung Die vorliegende Erfindung betrifft neue, substituierte Thiocarbamoyl-thenoylacetonitrile, Verfahren zu ihrer Herstellung sowie ihre Verwendung als Wirkstoff in Arzneimitteln.Description The present invention relates to new, substituted ones Thiocarbamoyl-thenoylacetonitrile, process for their preparation and their use as an active ingredient in pharmaceuticals.
Die erfindungsgemäßen Verbindungen entsprechen der allgemeinen Formel I worin R¹ ein Wasserstoff- oder Halogenatom, eine Niederalkyl-oder Niederalkoxygruppe sein kann während R2 eine Cycloalkylgruppe mit 3-6 C-Atomen, unsubstituiertes Phenyl, eine durch einen oder zwei gleiche oder verschiedene Substituenten der Gruppe Halogen, Niederalkyl, Niederalkoxy, Niederalkylmercapto oder Trifluormethyl substituierte Phenylgruppe, einen Benzyl-oder Furfurylrest bedeutet. Darin enthalten sind auch die tautomeren Verbindungen der Mercapto- und Hydroxy-Formen der Formel I sowie ihre Mono-S-alkylether und Di-S>O-alkylether oder ihre Salze mit Basen.The compounds according to the invention correspond to the general formula I. wherein R¹ can be a hydrogen or halogen atom, a lower alkyl or lower alkoxy group while R2 is a cycloalkyl group with 3-6 C atoms, unsubstituted phenyl, one by one or two identical or different substituents from the group halogen, lower alkyl, lower alkoxy, lower alkylmercapto or trifluoromethyl substituted phenyl group, benzyl or furfuryl radical. This also includes the tautomeric compounds of the mercapto and hydroxy forms of the formula I and their mono-S-alkyl ethers and di-S> O-alkyl ethers or their salts with bases.
Für den Rest R1 kommen insbesondere in Betracht ein Wasserstoff- oder Chloratom, eine Methyl~ oder Methoxygruppeu Für R² kommen insbesondere in Betracht eine Cyclopropyl-, Cyclopentyi-, Cyclohexyl-, Phenyl-, Chlorphenyl-, Fluorphenyl-, Methylphenyl-, Methylmercaptbphenyl -, Methoxyphenyl-, Trlfluormethylphenyl-, Chlor-methoxyphenyl-, Chlor-methylphenyl-, Dimethoxyphenyl-, Dimethylphenyl-, Furfuryl- oder Penzylgruppe.For the radical R1 are in particular a hydrogen or Chlorine atom, a methyl or methoxy group are particularly suitable for R² a cyclopropyl, cyclopentyi-, cyclohexyl, phenyl, chlorophenyl, fluorophenyl, Methylphenyl-, methylmercaptobphenyl-, methoxyphenyl-, trlfluoromethylphenyl-, chloromethoxyphenyl-, Chloromethylphenyl, dimethoxyphenyl, dimethylphenyl, furfuryl or penzyl group.
Besonders günstige Eigenschaften besitzen solche Verbindungen der Formel I, bei denen R1 ein Chloratom ist, während R2 eine Phenyl-, 4-Chlorphenyl- oder Furfurylgruppe bedeutet. Such compounds have particularly favorable properties Formula I in which R1 is a chlorine atom, while R2 is a phenyl, 4-chlorophenyl or means furfuryl group.
Erfindungsge9.äße Verbindungen sind beispielsweise: α-<4-Chlorphenyl -thiocarbamoyl )-5-chlor-2-thenoyl-acetonitril α-(Furfuryl-thiocarbamoyl)-5-chlor-2-thenoyl-acetonitril, α-(Cyclohexyl-thiocarbamoyl )-5-chlor-2-thenoyl-acetonitril α-(4-Fluorphenyl-thiocarbamoyl)-5-chlor-2-thenoyl-acetonitril, α-(4-Chlorphenyl-thiocarbamoyl)-5-methoxy-2-thenoyl-acetonitril, α-(Benzyl-thiocarbamoyl)-5-chlor-2-thenoyl-acetonitril, α-(Phenyl-thiocarbamoyl)-5-chlor-2-thenoyl-acetonitril, α-(Furfuryl-thiocarbamoyl)-5-chlor-2-thenoyl-acetonitril-mono-Natriumsalz, α-(4-Chlorphenyl-thiocarbamoyl3-5-methyl-2-thenoyl-acetonitril, α-(4-Chlorphenyl-thiolcarbamoyl)-2-thenoyl-acetonitril, α-(p-Tolyl-thiocarbamoyl-5-chlor-2-thenoyl-acetonitril, t -(Cyclopropyl-thiocarbamoyl)-5-chlor-2-thenoyl-acetonitril. Compounds according to the invention are, for example: α- <4-chlorophenyl -thiocarbamoyl) -5-chloro-2-thenoyl-acetonitrile α- (furfuryl-thiocarbamoyl) -5-chloro-2-thenoyl-acetonitrile, α- (Cyclohexyl-thiocarbamoyl) -5-chloro-2-thenoyl-acetonitrile α- (4-fluorophenyl-thiocarbamoyl) -5-chloro-2-thenoyl-acetonitrile, α- (4-chlorophenyl-thiocarbamoyl) -5-methoxy-2-thenoyl-acetonitrile, α- (benzyl-thiocarbamoyl) -5-chloro-2-thenoyl-acetonitrile, α- (Phenyl-thiocarbamoyl) -5-chloro-2-thenoyl-acetonitrile, α- (Furfuryl-thiocarbamoyl) -5-chloro-2-thenoyl-acetonitrile monosodium salt, α- (4-chlorophenyl-thiocarbamoyl3-5-methyl-2-thenoyl-acetonitrile, α- (4-chlorophenyl-thiolcarbamoyl) -2-thenoyl-acetonitrile, α- (p-Tolyl-thiocarbamoyl-5-chloro-2-thenoyl-acetonitrile, t - (cyclopropyl-thiocarbamoyl) -5-chloro-2-thenoyl-acetonitrile.
r)ie tautomeren Mercapto- und Hydroxyformen von Verbindungen der Formel I sind genügend sauer. Dementsprechend können in Abhännigkeit vom pH-Wert der Lösungen mit Basen 2 Reihen von Salzen, Mono- und Di-Salze hergestellt werden. Insbesondere die schwach basischen Mono-Salze sind therapeutisch verwendbar. Diese Salze werden mit anorganischen und organischen Basen gebildet. Beverzugt kommen als Basen zur Salzbildung Alkali- und Erdalkali-Hydroxide in Betracht. Die therapeutisch verwendbaren Salze können z.B. mit wässrigen Alkalimetallhydroxiden, vorzugsweise in Gegenwart eines Alkohols als Lösungsmittel, hergestellt werden.r) ie tautomeric mercapto and hydroxy forms of compounds of the formula I am pissed off enough. Accordingly, depending on the pH of the solutions with bases 2 series of salts, mono- and di-salts can be prepared. In particular the weakly basic mono-salts can be used therapeutically. These salts are formed with inorganic and organic bases. Beverzugt are used as bases Salt formation alkali and alkaline earth hydroxides into consideration. The therapeutically useful ones Salts can, for example, with aqueous alkali metal hydroxides, preferably in the presence an alcohol as a solvent.
Aus den alkoholischen Lösungen können die Salze mit Ethern ausgefällt werden. Die wässrigen Lösungen der Salze können in allen Fällen durch behandlung mit Säuren in die freten Ausganqsverbindungen umgewandelt werden. Die Salze sind mit Alkylantien in Mono-S-Ether und Di-S,O-Ether überführbar.The salts can be precipitated with ethers from the alcoholic solutions will. The aqueous solutions of the salts can be used in all Cases can be converted into the free starting compounds by treatment with acids. The salts can be converted into mono-S-ethers and di-S, O-ethers with alkylating agents.
Die erfindungsgemäßen Verbindunsen besitzen wertvolle pharmakologische Eigenschaften. Aufgrund ihrer antiphlogistischen, antiarthritischen und Immunmodulatorischen Wirksamkeit sind sie gut geeignet zur Behandlung von Erkrankungen des rheumatischen Formenkreises.The compounds according to the invention have valuable pharmacological ones Properties. Because of their anti-inflammatory, anti-arthritic and immunomodulatory Efficacy they are well suited for the treatment of diseases of the rheumatic Shape circle.
Die erfindungsgemäßen Verbindungen werden nach an sich bekannten Verfahren hergestellt (Houben-Weyel, Methoden der oreanischen Chemie, Bd. 9, S. 881). Vorzugsweise besteht das erfindungsgemäße Verfahren in der Addition eines Isothiocyanats der Formel R2-N=C=S an substituierte Thenoylacetonitrile der Formel II wobei R1 und R2 die in Formel I angegebenen Bedeutungen haben.The compounds according to the invention are prepared by processes known per se (Houben-Weyel, Methods of Organic Chemistry, Vol. 9, p. 881). The process according to the invention preferably consists in the addition of an isothiocyanate of the formula R2-N = C = S onto substituted thenoylacetonitriles of the formula II where R1 and R2 have the meanings given in formula I.
Das erfindungsgemäße Verfahren wird vorzugsweise durch Umsetzung des Thenoylacetonitrils mit dem Isothiocyanat in geeigneten Lösungsmitteln wie aromatischen Kohlenwasserstoffen, z.B. Toluol, Ethern, z.B. Dimethoxyethan, Amiden, z.R. Dimethxlformamid oder Sulfoxiden, z.B. Dimethylsulfoxid, in Gegenwart von Basen wie Triethylamin oder Natriumhydrid unter 2-24stündigem Rühren bei Raumtemperatur durchgeführt.The inventive method is preferably by implementing the Thenoylacetonitrile with the isothiocyanate in suitable solvents such as aromatic Hydrocarbons, e.g. toluene, ethers, e.g. dimethoxyethane, amides, e.g. Dimethylformamide or sulfoxides, e.g. dimethyl sulfoxide, in the presence of bases such as triethylamine or sodium hydride with stirring for 2-24 hours at room temperature.
Die als Ausgangsverbindungen verwendeten 2-Thenoyl-acetonitrile der allgemeinen Formel II werden entweder konventionell nach W.S.Emerson und T.H.Patrick (J.Org.Chem. 13, 722-8, 1948) durch Acylierung der entsprechenden Thiophene nach Friedel-Crafts, Bromierung in Eisessig und nucleophilen Austausch des Broms h@rgestellt oder nach S.A.Lang und E.Cohen (J.Med.Chem. 18, 441, 1975) durch saure Hydrolyse von B-Amino-2-thienyl-acryl-nitri- len der allgemeinen Formel I I Ì die durch Kondensation von entsprechend substituierten Thiophennitrilen mit Acetonitril in Gegenwart starker Basen aewonnen werden.The 2-thenoyl-acetonitriles of the general formula II used as starting compounds are either conventionally according to WSEmerson and THPatrick (J.Org.Chem. 13, 722-8, 1948) by acylation of the corresponding thiophenes according to Friedel-Crafts, bromination in glacial acetic acid and nucleophiles Exchange of the bromine is made or according to SALang and E. Cohen (J.Med.Chem. 18, 441, 1975) by acid hydrolysis of B-amino-2-thienyl-acryl-nitriles of the general formula II Ì which are obtained by condensation of appropriately substituted thiopheneditriles with acetonitrile in the presence of strong bases.
Die Isothiocyanate werden, soweit sie nicht zur Verfugung stehen, durch Thiophosgenierunq der entsprechenden Amine hergestellt.The isothiocyanates are, if they are not available, produced by thiophosgenation of the corresponding amines.
Die vorliegende Erfindung betrifft ebenfalls pharmazeutische Präparate, welche Verbindungen der Formel 1 enthalten. Bei den erfindungsgemäßen pharmazeutischen Präparaten handelt es sich um solche zur enteralen, wie oralen oder rektalen sowie parenteralen Verabreichung, welche die pharmakologischen Wirkstoffe allein oder zusammen mit einem üblichen, pharmazeutisch anwendbaren Trägermaterial enthalten. Vorteilhafterweise liegt die pharmazeutische Zubereitung des Wirkstoffes in Form von Einzeldosen vor, die auf die gewünschte Verabreichung abgestimmt sind, wie z.B. Tabletten, Dragees, Kapseln, Suppositorien, Granulate, Lösungen oder Suspensionen.The present invention also relates to pharmaceutical preparations, which compounds of formula 1 contain. In the pharmaceutical according to the invention Preparations are those for enteral, such as oral or rectal as well parenteral administration, which the pharmacologically active ingredients alone or together with a conventional, pharmaceutically acceptable carrier material. The pharmaceutical preparation of the active ingredient is advantageously in the form of single doses which are tailored to the desired administration, e.g. Tablets, coated tablets, capsules, suppositories, granules, solutions or suspensions.
Die Herstellung der erfindunssgemäßen Verbindungen wird durch die folgenden Beispiele näher erläutert.The production of the compounds according to the invention is carried out by the the following examples are explained in more detail.
Beispiel 1 α -(4- Chlorphenyl-thiocarbamoyl )-5-chlor-2-thenoylacetonitril Zu einer Mischung aus 3,7g (0902 Mol) 5-Chlor-2-thenoyl -acetonitril, 2,4g (0,024 Mol) Triethylamin und 60 ml trockenem Toluol gibt man unter Rühren bei Raumtemperatur portionsweise 3,49 (0,02 Mol) 4-Chlorphenyl-isothiocyanat. Es wird 14 Stunden bei Raumtemperatur gerührt und 2 n Salzsäure zugegeben.Example 1 α - (4-chlorophenyl-thiocarbamoyl) -5-chloro-2-thenoylacetonitrile To a mixture of 3.7 g (0902 mol) 5-chloro-2-thenoyl-acetonitrile, 2.4 g (0.024 Mol) triethylamine and 60 ml of dry toluene are added with stirring at room temperature 3.49 (0.02 mol) 4-chlorophenyl isothiocyanate in portions. It will be 14 hours at Stirred at room temperature and added 2N hydrochloric acid.
Man erhält einen gelben Niederschlag, der gut mit Wasser gewaschen und im Vakuum getrocknet wird. Das Produkt wird mit Toluol und Ether verrieben und ergibt 6,8q hell gelbe Kristalle vom F. 2060-2080C.A yellow precipitate is obtained which is washed well with water and dried in vacuo. The product is triturated with toluene and ether and results in 6.8q light yellow crystals with a temperature of 2060-2080C.
Das als Ausgangsmaterial verwendete 5-Chlor-2-thenoylacetonitril wird wie folgt erhalten: Zu einer eisgekühlten Lösung von 19g (0,29 Mol) Kaliumcyanid in 100 ml Wasser gibt man unter Rühren eine Lösung von 349 (0,14 Mol) 5-Chlor-2-bromacetyl-thiophen in 300 ml Ethanol.The 5-chloro-2-thenoylacetonitrile used as the starting material is Obtained as follows: To an ice-cold solution of 19 g (0.29 mol) of potassium cyanide a solution of 349 (0.14 mol) of 5-chloro-2-bromoacetylthiophene is added to 100 ml of water with stirring in 300 ml of ethanol.
Dabei wird die Temperatur unter 20°C gehalten. Die Lösung, die nach 30 Minuten klar wird, läßt man 12 Stunden bei 40C im Kühl raum stehen. Es wird mit 160 ml Wasser und 2 ml 10%iqcr Natronlauge versetzt und zweimal mit je 100 ml Toluol extrahiert. Nach vorsichtigem Ansäuern mit halbkonzentrierter Salzsäure wird der gebildete Niederschlag abgesaugt und getrocknet. Umkristallisation aus Ethanol liefert 22g hell braune Kristalle von 5-Chlor-2-thenoyl-acetonitril vom F.113-116 0C.The temperature is kept below 20 ° C. The solution that after If it becomes clear for 30 minutes, it is left to stand in the refrigerator at 40C for 12 hours. It will be with 160 ml of water and 2 ml of 10% sodium hydroxide solution are added and twice with 100 ml of toluene each time extracted. After careful acidification with half-concentrated hydrochloric acid, the The precipitate formed is filtered off with suction and dried. Recrystallization from ethanol provides 22g light brown crystals of 5-chloro-2-thenoyl-acetonitrile with a melting point of 113-116 ° C.
Beispiel 2 α -(Furfuryl-thiocarbamoyl)-5-chlor-2-thenoyl-acetonitril.Example 2 α - (Furfuryl-thiocarbamoyl) -5-chloro-2-thenoyl-acetonitrile.
Eine Mischung aus 1,9g (0,01 Mol) 5-Chlor-2-thenoyl-acetonitril 1,2g (0,012 Mol) Triethylaminfi 1,4g (0,01 Mol) Furfurylisothiocyanat und 30 ml Toluol wird 24 Stunden bei Raumtemperatur unter Stickstoff gerührt. Die Lösung wird mit verdünnter Salzsäure angesäuert und der ausgeschledene Niederschlag nach kurzem Stehen abfiltriert, gut mit Wasser verrieben, mit Aceton gewaschen und im Vakuum getrocknet. Man erhält 1,7g qelbe Kristalle vom F. 149°-150°C.A mixture of 1.9 g (0.01 mol) of 5-chloro-2-thenoyl-acetonitrile 1.2 g (0.012 mol) triethylamine fi 1.4 g (0.01 mol) furfuryl isothiocyanate and 30 ml toluene is stirred for 24 hours at room temperature under nitrogen. The solution is with acidified with dilute hydrochloric acid and the precipitated precipitate after a short time Standing filtered off, triturated well with water, washed with acetone and in vacuo dried. 1.7 g yellow crystals with a melting point of 149 ° -150 ° C. are obtained.
Oben eingesetztes Furfurylisothiocyanat wird durch Thiophosqenierung aus Furfurylamin in 827 Ausbeute hergestellt. Die Substanz ist nur ca. 2 Tage beständig und färbt sich unter Polvmerisation dunkel.Furfuryl isothiocyanate used above is thiophosphorized made from furfurylamine in 827 yield. the Substance is Resistant only for approx. 2 days and turns dark when polymerized.
Beispiel 3 α-(Cyclohexyl-thiocarbamoyl)-5-chlor-2-thenoyl-acetonitríl Eine Suspension von O,Sg (0,016 Mol) 50%igem Natriumhydrid in Mineralöl (mit Petrolether gewaschen) in 40 ml Dimethoxyethan wird mit 2,4a (0>013 Mol) 5-Chlor-2-thenoyl-acetonitril und 2,8e (0,02 Mol) Cyclohexylisothiocyanat versetzt. Nach 12stündigem Rühren bei Raumtemperatur gibt man weitere 1,49 Cyclohexylisothiocyanat zu und läßt 12 Stunden stehen. Das Lösungsmittel wird abdestilliert, der Rückstand in Wasser aufgenommen und mit Ether extrahiert. Die wässrige Phase wird mit 2 n Salzsäure angesäuert und mit Chloroform ausgeschüttelt. Die oruanische Phase ergibt, gewaschen, getrocknet und eingeengt, 5,2g Ruckstand der aus Essipester umkristallisiert wird.Example 3 α- (Cyclohexyl-thiocarbamoyl) -5-chloro-2-thenoyl-acetonitrile A suspension of O, Sg (0.016 mol) 50% sodium hydride in mineral oil (with petroleum ether washed) in 40 ml of dimethoxyethane is mixed with 2.4a (0> 013 mol) of 5-chloro-2-thenoyl-acetonitrile and 2.8e (0.02 mol) of cyclohexyl isothiocyanate are added. After stirring for 12 hours at At room temperature, a further 1.49 cyclohexyl isothiocyanate is added and the mixture is left for 12 hours stand. The solvent is distilled off and the residue is taken up in water and extracted with ether. The aqueous phase is acidified with 2N hydrochloric acid and extracted with chloroform. The oruan phase gives, washed, dried and concentrated, 5.2g residue which is recrystallized from ethyl acetate.
Ausbeute: 1,lg hellgelbe Kristalle vom F. 154-155°C.Yield: 1.1 g of light yellow crystals with a melting point of 154-155 ° C.
Beispiel 4 Salzbi Idung 1,8g (0,005 Mol) g α-(4-Chlorphenyl-thiocarbamoyl)-5-chlor-2-thenoyl-acetonitril werden mit einer äquivalenten Menge Natronlauge behandelt. Die Lösung wird blank filtriert und zur Trockne eingedampft. Der Rückstand wird in wenig Ethanol aufgenommen und mit Ether versetzt. Man erhä-lt nach Filtration und Trocknung 1,6 α-(4-Chlorphenyl-thiocarbamoyl)-5-chlor-2-thenoyl-acetonitril-mono-Natrium-Salz vom F. 275°-277°C.Example 4 Salt Formation 1.8 g (0.005 mol) g of α- (4-chlorophenyl-thiocarbamoyl) -5-chloro-2-thenoyl-acetonitrile are treated with an equivalent amount of sodium hydroxide solution. The solution becomes blank filtered and evaporated to dryness. The residue is taken up in a little ethanol and mixed with ether. After filtration and drying, 1,6 α- (4-chlorophenyl-thiocarbamoyl) -5-chloro-2-thenoyl-acetonitrile monosodium salt is obtained from m.p. 275 ° -277 ° C.
Das Di-Natrium-Salz wird mit 2 Äquivalenten Natriumhydroxid erhalten. Aus den wässrigen Lösungen der Salze wird die Ausgangssubstanz durch Ansäuern mit Salzsäure wieder zurückgewonnen.The di-sodium salt is obtained with 2 equivalents of sodium hydroxide. The starting substance is made from the aqueous solutions of the salts by acidification with Hydrochloric acid recovered.
Beispiel 5 Mono- und Dialkylierung von α-(4-Chlorphenyl-thiocarbamoyl)-5-chlor-2-thenoyl-acetonitri 1 α-(4-Chlorphenyl-methylthio-carbimidoyl)-5-chlor-2-thenoylacetonitril 1g (0,002 Mol) α-(Chlorphenyl-thiocarbamoyl)-5-chlor-2-thenoylacetonitril-mono-Natrium-Salz in 10 ml Methanol wird unter Rühren mit 0,49 (0,002 Mol). Methyljodid versetzt und 12 Stunden gerührt. Das Lösungsmittel wird abgezogen und der Rückstand zwischen Chloroform und Wasser verteilt. Die Chloroformphase wird nacheinander mit in Natronlauge und Wasser gewaschen, getrocknet und eingeengt. Das Öl kristallisiert unter Ether/Petrolether und liefert 0,7g hellgelbe Kristalle vom F. 128-1290C.Example 5 Mono- and dialkylation of α- (4-chlorophenyl-thiocarbamoyl) -5-chloro-2-thenoyl-acetonitrile 1 α- (4-chlorophenyl-methylthio-carbimidoyl) -5-chloro-2-thenoylacetonitrile 1g (0.002 moles) α- (chlorophenyl-thiocarbamoyl) -5-chloro-2-thenoylacetonitrile monosodium salt in 10 ml of methanol is added with stirring at 0.49 (0.002 mol). Methyl iodide added and Stirred for 12 hours. The solvent is removed and the residue between Distributed chloroform and water. The chloroform phase is successively mixed with sodium hydroxide solution and water, dried and concentrated. The oil crystallizes from ether / petroleum ether and provides 0.7 g of pale yellow crystals with a melting point of 128-1290C.
o-(4-Chlorphenyl-methylthio-carbimidoyl )-5-chlor-2-thienyl-ßmethoxy-acryl ni tri l .o- (4-Chlorophenyl-methylthio-carbimidoyl) -5-chloro-2-thienyl-β-methoxy-acryl ni tri l.
3,6g Di-Natrium-Salz, mit 2 Äquivalenten Methyljodid umgesetzt, ergibt 1*1g hellgelbe Kristalle vom F. 120°-121°C.3.6 g of di-sodium salt, reacted with 2 equivalents of methyl iodide, results 1 * 1g light yellow crystals with a melting point of 120 ° -121 ° C.
Beispiel 6 Nach den Verfahren der Beispiele 1-4 werden aus den entsprecherden Ausgangsprodukten die folgenden Verbindungen hergestellt: a) t-(4-Fl uorpheny.l-thiocarbamoyl-2-thenoyl-acetonitrils F. 218°-220°C.Example 6 Following the procedures of Examples 1-4, the appropriate earths Starting materials produced the following compounds: a) t- (4-Fl uorpheny.l-thiocarbamoyl-2-thenoyl-acetonitrils Mp 218-220 ° C.
b) 4 α-(4-Chlorphenyl-thiocarbamoyl)-5-methoxy-2-theonylacetonitril, F. 215°-217°C.b) 4 α- (4-chlorophenyl-thiocarbamoyl) -5-methoxy-2-theonylacetonitrile, M.p. 215-217 ° C.
c) t -(Benzyl-thiocarbamoyl)-5-chlor-2-thenoyl-acetonitril, F. 144°-147°C.c) t - (Benzyl-thiocarbamoyl) -5-chloro-2-thenoyl-acetonitrile, mp 144 ° -147 ° C.
d) 4 α-(Phenyl-thiocarbamoyl)-5-chlor-2-thenoyl-acetonitril, F. 186°-187°C e) α -(Furfuryl-thiocarbamoyl)-5-chlor-2-thenoyl-actonitrilmono-Natrium-Salz,F. 220°-222°C.d) 4 α- (phenyl-thiocarbamoyl) -5-chloro-2-thenoyl-acetonitrile, F. 186 ° -187 ° C e) α - (Furfuryl-thiocarbamoyl) -5-chloro-2-thenoyl-actonitrile monosodium salt, F. 220 ° -222 ° C.
f) α-(4-Chlorphenyl-thiocarbamoyl)-5-methyl-2-thenoyl-aceton -tril, F. 219°-221°C.f) α- (4-Chlorophenyl-thiocarbamoyl) -5-methyl-2-thenoyl-acetone -tril, m.p. 219-221 ° C.
g) α -(4-Chlorphenyl-thiocarbamoyl)-2-thenoyl-acetonitril, F. 212°-214°C.g) α - (4-chlorophenyl-thiocarbamoyl) -2-thenoyl-acetonitrile, F. 212 ° -214 ° C.
h) α -(Tolyl-thiocarbamoyl)-5-chlor-2-thenoyl-acetonitril, F. 213°-214°C i) α-(Cyclopropyl-thiocarbaomyl)-5-chlor-2-thenoyl-acetonitril F. 152°-154°C.h) α - (Tolyl-thiocarbamoyl) -5-chloro-2-thenoyl-acetonitrile, F. 213-214 ° C i) α- (Cyclopropyl-thiocarbaomyl) -5-chloro-2-thenoyl-acetonitrile 152-154 ° C.
Claims (7)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19823217446 DE3217446A1 (en) | 1982-05-08 | 1982-05-08 | Substituted thiocarbamoylthenoylacetonitriles, process for their preparation and pharmaceutical preparations containing them |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19823217446 DE3217446A1 (en) | 1982-05-08 | 1982-05-08 | Substituted thiocarbamoylthenoylacetonitriles, process for their preparation and pharmaceutical preparations containing them |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE3217446A1 true DE3217446A1 (en) | 1983-11-24 |
Family
ID=6163152
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19823217446 Withdrawn DE3217446A1 (en) | 1982-05-08 | 1982-05-08 | Substituted thiocarbamoylthenoylacetonitriles, process for their preparation and pharmaceutical preparations containing them |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE3217446A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0326107A1 (en) * | 1988-01-26 | 1989-08-02 | Bristol-Myers Squibb Company | Antiarthritic beta-cycloalkyl-beta-oxopropionitriles |
| EP0372470A2 (en) * | 1988-12-08 | 1990-06-13 | Ciba-Geigy Ag | Novel alpha-cyano-beta-oxopropionamides |
| US4975462A (en) * | 1988-07-29 | 1990-12-04 | Bristol-Myers Company | Antiarthritic α-arylcarbamoyl cyanoacetic acid derivatives |
-
1982
- 1982-05-08 DE DE19823217446 patent/DE3217446A1/en not_active Withdrawn
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0326107A1 (en) * | 1988-01-26 | 1989-08-02 | Bristol-Myers Squibb Company | Antiarthritic beta-cycloalkyl-beta-oxopropionitriles |
| US4888357A (en) * | 1988-01-26 | 1989-12-19 | Bristol-Myers Company | Antiarthritic β-cycloalkyl-β-oxopropionitriles |
| US4975462A (en) * | 1988-07-29 | 1990-12-04 | Bristol-Myers Company | Antiarthritic α-arylcarbamoyl cyanoacetic acid derivatives |
| EP0372470A2 (en) * | 1988-12-08 | 1990-06-13 | Ciba-Geigy Ag | Novel alpha-cyano-beta-oxopropionamides |
| EP0372470A3 (en) * | 1988-12-08 | 1991-07-10 | Ciba-Geigy Ag | Novel alpha-cyano-beta-oxopropionamides |
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