WO1993004035A1 - Neue 3,5-di-tert.butyl-4-hydroxyphenyl-derivate, verfahren zu ihrer herstellung und arzneimittel - Google Patents

Neue 3,5-di-tert.butyl-4-hydroxyphenyl-derivate, verfahren zu ihrer herstellung und arzneimittel Download PDF

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WO1993004035A1
WO1993004035A1 PCT/EP1992/001821 EP9201821W WO9304035A1 WO 1993004035 A1 WO1993004035 A1 WO 1993004035A1 EP 9201821 W EP9201821 W EP 9201821W WO 9304035 A1 WO9304035 A1 WO 9304035A1
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compounds
aryl
formula
group
radical
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PCT/EP1992/001821
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English (en)
French (fr)
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Bruno Dreckmann-Behrendt
Reinhard Heck
Alois Dresel
Helmut Michel
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Boehringer Mannheim Gmbh
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Priority to DE59205041T priority Critical patent/DE59205041D1/de
Priority to EP92917133A priority patent/EP0600949B1/de
Priority to JP5504071A priority patent/JPH06510030A/ja
Publication of WO1993004035A1 publication Critical patent/WO1993004035A1/de

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    • 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
    • C07D207/32—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
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    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to new di-tert-butyl-hydroxyphenyl derivatives (BHT derivatives) of the general formula I.
  • a valence a straight or a branched alkyl chain with 1 to 5 carbon atoms
  • R represents a hydrogen atom or a C1-C4-alkyl radical
  • a straight-chain or branched, saturated or unsaturated hydrocarbon chain with 1 to 6 carbon atoms which can be substituted by an aryl, hetaryl aryloxy or arylthio radical
  • a C 3 -Cg cycloalkyl or an aryl radical represents, the respective aryl or hetaryl radical in each case one to three times in all possible positions on the ring by CN, hydroxymethyl, methylenedioxy, halogen, trifluoromethyl, C ⁇ _-C4-alkyl, amino, C1-C4- Acylamino, di- (C ⁇ _-C 4 ) -alkylamino, hydroxy, -C ⁇ C 4 -alko, carboxyl, oxyacetic acid ethyl ester or nitro can be substituted
  • the "bridge” A is preferably the -CH -, -CH 2 -CH 2 -, - (CH 2 ) 3 -,
  • R preferably represents a hydrogen atom or a methyl group.
  • the benzyl, phenethyl, styryl, phenyl and naphthyl radicals are preferred, the aromatics of which in turn are one to three times in all positions, preferably by CN, fluorine, chlorine, hydroxymethyl, methyl, trifluoromethyl, methoxy, nitro, hydroxy, dimethylamino, Methylenedioxy, oxyacetate, carboxyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridazyl, pyrimidinyl, pyrazyl or 2-indolyl may be substituted.
  • the preferred hetaryl radical is 2-furyl, 2-thienyl, 2-pyrryl, 2-pyridyl and 3-indolyl radical.
  • Structurally analogous compounds are used as additives in polymerization reactions (cf. US Pat. 4,152,319, US Pat. 3,780,103) 3,5-Di-tert-butyl-4-hydroxyacetanilide (ZA 7401080) is known as antihyperlipidae.
  • the compounds I of the present invention have strong antioxidant activity.
  • the lipophilicity of this group of antioxidants means that the compounds accumulate in the atherogenic low-density lipoprotein (LDL) and effectively protect the sensitive components of the LDL against reactive oxygen species.
  • LDL low-density lipoprotein
  • Antioxidants are substances that - generally speaking - cause a considerable delay in the oxidative processes in a product to be protected.
  • a potent anti-atherosclerotic antioxidant is Probucol R , which has a hypolipidemic effect in various animal species and in humans. It is a sterically hindered alkylphenol that accumulates in the LDL. Animal experiments have shown that probucol blocks the oxidative modification of LDL in the arterial wall and prevents atheroma formation directly due to the antioxidant activity (D. Steinberg et al., Amer. J. Cardiol. 57, 16 M (1986).
  • Probucol R Disadvantages of Probucol R are the low absorption of the substance and the extremely long residence time in body tissue; Probucol is excreted mainly via the faeces (cf. MN Cayen, Pharmacol. Ther. 29, 157 (1985)).
  • compounds of the formula I lower the plasma lipids by blocking the intestinal cholesterol absorption, consequently reducing the intrahepatic pool of free cholesterol and correspondingly reducing the secretion of the food-dependent lipoproteins from the liver into the plasma.
  • the inhibition of cholesterol absorption is based on an inhibition of the acyl-coenzyme A: cholesterol transferase (ACAT) reaction.
  • ACAT cholesterol transferase
  • the substances have good absorption and inhibit the ACAT-dependent esterification of free cholesterol not only in the enterocytes, but also in the cells of the atheroma itself. They thereby prevent their foam cell degeneration as a result of overloading with cholesterol esters.
  • Di-tert-butylphenol derivatives of the formula I can be obtained by synthesis processes known per se, for example by reacting an amine of the formula II with a carboxylic acid or a derivative of a carboxylic acid of the general formula III
  • A, R and Y have the meaning given in formula I and Z represents hydroxyl, halogen, C 1 -C 4 alkoxy or azide.
  • the reaction is usually carried out in an inert solvent, such as a hydrocarbon, dimethylformamide, dichloromethane or in ether.
  • an inert solvent such as a hydrocarbon, dimethylformamide, dichloromethane or in ether.
  • Equimolar amounts of amine and carboxylic acid are preferably used in the presence of equimolar amounts of a base such as a tert. organ.
  • A in, preferably triethylamine, alkali bicarbonate, hydroxide or carbonate.
  • the acid halide, azide, anhydride or ester can serve as derivatives of the carboxylic acid (formula III).
  • the presence of POCI 3 , S0C1 2 or PCI 3 is generally necessary for the reaction of a carboxylic acid ester with the amine, a basic catalyst, preferably an alkali alcoholate.
  • the reaction of the carboxylic acid with an amine in a solvent such as, for example, xylene is also possible by heating under reflux on a water separator.
  • an inert solvent e.g. Toluene, obtained (see Houben-Weyl, Vol. VIII, p. 157).
  • the compounds of the formula I are used as medicaments, in particular as antiatherosclerotics.
  • the crude products can be purified by crystallization or column chromatography.
  • salts with physiologically compatible organic or inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, methylglucamine, morpholine, triethylamine or ethanol-a in
  • the compounds of formula I can be reacted with the corresponding bases.
  • Mixtures of the acidic compounds with a suitable alkali metal carbonate or hydrogen carbonate are also suitable.
  • the compounds of general formula I are mixed in a manner known per se with suitable pharmaceutical carriers, flavorings, flavors and colors and shaped, for example, as tablets or dragées or with the addition of appropriate auxiliaries in water or oil, such as e.g. Olive oil, suspended or dissolved.
  • the substances of the general formula I can be administered orally and parenterally in liquid or solid form.
  • Water is preferably used as the injection medium, which contains the stabilizers, solubilizers and / or buffers customary for injection solutions, ethanol, dimethyl sulfoxide, complexing agents (such as ethylenediaminetetraacetic acid), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation or polyethylene derivatives of sorbitol ⁇ anhydrides.
  • Solid carriers are, for example, starch, lactose, mannitol, methyl cellulose, talc, highly disperse silica, higher molecular fatty acids (such as stearic acid), gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats or solid high molecular polymers (such as polyethylene glycols) .
  • Preparations suitable for oral administration can optionally contain flavorings and sweeteners.
  • the dosage administered depends on the age, health and weight of the recipient, the extent of the disease, the type of further treatments which may be carried out at the same time, the frequency of the treatments and the type of effect desired.
  • the daily dose of the active compound is usually 0.1 to 10 mg / kg body weight.
  • the mixture is poured into cold 1N hydrochloric acid for 14 hours, the phases are separated and the organic phase is shaken twice with 100 ml of water each time.
  • aqueous phase is separated off, the organic phase with a little HC1 conc. offset and connect i.Vak. constricted. Any water still present is dragged out azeotropically with toluene. The remaining residue is triturated with a little ether / ligroin and suction filtered. 25.8 g of brownish crystals, mp: 200-203'C.
  • the azide is solidly introduced into 100 ml of tetrahydrofuran solution of 20 mmol of 3,5-di-tert-butyl-4-hydroxybenzylamine (prepared as described in Example 3) and stirred for 2 minutes at room temperature.
  • 300 ml of water and extracting with ethyl acetate 10 g of the isobutoxycarbonyl compound are obtained.
  • 75 ml of tetrahydrofuran By dissolving with 75 ml of tetrahydrofuran and adding 25 ml of conc.
  • the ester is saponified with ammonia.
  • the solution is distilled off, dissolved in water and ethyl acetate, the organic phase is dried over Na 2 SO 4 and in vacuo. away. After rubbing and suctioning off, 2.6 g of almost colorless crystals, mp. 205-208-C, are obtained.
  • Acrylic derivatives are always (E) configured
  • the ethyl acetate residue is purified on a silica gel column (KG 60) with isohexane / ethyl acetate. After rubbing with ether, colorless crystals of mp 172-173 ° C. remain.

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Abstract

Verbindungen der Formel (I), in der A Valenz, eine gerade oder eine verzweigte Alkylkette mit 1 bis 5 C-Atomen; X eine -NR-CO-(Amid) oder eine -NR-CO-NR-(Harnstoff) Gruppe, in der R ein Wasserstoffatom oder einen C1-C4-Alkylrest darstellt, und Y eine geradkettige oder verzweigte, gesättigte oder ungesättigte Kohlenwasserstoffkette mit 1 bis 6 C-Atomen, die durch einen Aryl-, Hetaryl-,Aryloxy- oder Arylthio-Rest substituiert sein kann, einen C3-C6-Cycloalkyl-, oder einen Arylrest darstellt, wobei der betreffende Aryl- bzw. Hetarylrest jeweils ein bis dreifach in allen möglichen Positionen am Ring durch CN, Hydroxymethyl, Methylendioxy-, Halogen, Tri-fluormethyl, C1-C4-Alkyl, Amino, C1-C4-Acylamino, Di-(C1-C4)-alkylamino, Hydroxy, C1-C4-Alkoxy, Carboxyl, Oxyessigsäureethylester oder Nitro substituiert sein kann, bedeuten, mit der Maßgabe, daß Y nur unsubstituiertes Phenyl bedeutet, wenn A eine andere Bedeutung als -CH2- oder -CH2-CH2- hat, sowie deren pharmakologische unbedenkliche Salze, Verfahren zu ihrer Herstellung und Arzneimittel, die diese Verbindungen enthalten, zur Behandlung von Stoffwechselerkrankungen.

Description

Neue 3,5-Di-t rt.butyl-4-hydroxyphenyl-Derivate, Verfahren zu ihrer Herstellung und Arzneimittel
Die vorliegende Erfindung betrifft neue Di-tert.-butyl-hydroxy- phenyl-derivate (BHT-Derivate) der allgemeinen Formel I
Figure imgf000003_0001
in der
A Valenz, eine gerade oder eine verzweigte Alkylkette mit 1 bis 5 C-Atomen
X eine -NR-CO- (A id) oder eine -NR-CO-NR-(Harnstoff)
Gruppe, in der R ein Wasserstoffatom oder einen C1-C4- Alkylrest darstellt,
und
eine geradkettige oder verzweigte, gesättigte oder unge¬ sättigte Kohlenwasserstoffkette mit 1 bis 6 C-Atomen, die durch einen Aryl-, Hetaryl- Aryloxy-, oder Arylthio-rest substituiert sein kann, einen C3-Cg-Cycloalkyl-, oder einen Arylrest darstellt, wobei der betreffende Aryl- bzw. Hetarylrest jeweils ein bis dreifach in allen möglichen Positionen am Ring durch CN, Hydroxymethyl, Methylendioxy- , Halogen, Tri-fluormethyl, Cτ_-C4-Alkyl, Amino, C1-C4- Acylamino, Di-(Cτ_-C4)-alkylamino, Hydroxy, Cι~C4-Alko , Carboxyl, Oxy-essigsäureethylester oder Nitro subsitutiert sein kann,
bedeuten,
mit der Maßgabe, daß Y nur unsubstituiertes Phenyl bedeutet, wenn A eine andere Bedeutung als -CH2- oder -CH2-CH2- hat,
sowie deren pharmakologische unbedenkliche Salze, Verfahren zu ihrer Herstellung und Arzneimittel, die diese Verbindungen enthalten.
Als "Brücke" A steht bevorzugt, die -CH -, -CH2-CH2-, -(CH2)3-,
-CH2-CH-, bzw. die -CH2-C(CH3)2-Gruppe.
CH3
In der Carbonamidgruppe, in welcher der Hydroxyphenylrest über die "Brücke" A mit dem A idstickstoff verbunden ist, bzw. in der Harnstoffgruppierung X stellt R bevorzugt ein Wasserstoff¬ atom bzw. eine Methylgruppe dar.
Für Y ist der Benzyl, Phenethyl, Styryl-, der Phenyl und der Naphthylrest bevorzugt, deren Aromaten ihrerseits in allen Positionen ein bis dreifach, bevorzugt durch CN, Fluor, Chlor, Hydroxymethyl, Methyl, Trifluormethyl, Methoxy, Nitro, Hydroxy, Dimethylamino, Methylendioxy, Oxyessigsäureethylester, Carboxyl, 2-Pyridyl, 3-Pyridyl, 4-Pyridyl, Pyridazyl, Pyrimidinyl, Pyrazyl oder 2-Indolyl substituiert sein kann. Als bevorzugter Hetarylrest gilt der 2-Furyl, 2-Thienyl, 2-Pyrryl, 2-Pyridyl, sowie der 3-Indolylrest.
Strukturell analoge Verbindungen finden als Zusätze bei Polymerisationsreaktionen Anwendung (vgl. U.S.-Pat. 4,152,319, U.S.-Pat. 3,780,103) Als antihyperlipidae isch ist 3,5-Di-tert.butyl-4-hydroxy- acetanilid (ZA 7401080) bekannt.
Ebenso sind die konstitutionsisomeren Amide in dem EP-A 407 200 als Antihyperlipidae ica beschrieben.
Figure imgf000005_0001
Weitere antioxidativ wirkende Verbindungen sind in dem EP-A 407 200 beschrieben.
Bekannt ist bereits das N-(3,5-Di-tert.-butyl-4-hydrox )- phenethyl-benzoesäureamid, J.A .Chem.Soc. 84; 1629 (1962), jedoch sind in dieser Arbeit nur physikalisch-chemische Eigenschaften der genannten Verbindung beschrieben.
Verbindungen mit zwei BHT-Resten, die ebenfalls antioxidativ wirken, sind in EP-A 404 039 beschrieben.
In einer russischen Arbeit ist der N-(3,5-Di-tert.butyl-4- hydroxy)methyl-N'-phenylharnstoff als Treibstoffzusatz beschrieben, Nefthekhimiya 22(5), 703.
Die Verbindungen I der vorliegenden Erfindung verfügen über eine starke Antioxidantienaktivität. Die Lipophilie dieser Antioxidantiengruppe bedingt, daß die Verbindungen sich im atherogenen low-density lipoprotein (LDL) anreichern und die sensitiven Bestandteile des LDL wirksam gegen reaktive Sauer¬ stoffspezies schützen. Damit wird aber der LDL-Influx in die akrophagozytaren Schaumzellen deutlich abgebremst; denn die pathologisch gesteigerte Aufnahme von atherogenem LDL in den Atheromzellen setzt dessen oxidative Modifikation voraus.
Antioxidantien sind Substanzen, die - allgemein gesehen - eine erhebliche Verzögerung der oxidativen Vorgänge bei einem zu schützenden Produkt bewirken. Ein potent antiatherosklerotisch wirksames Antioxidans ist Probucol R, das eine hypolipidämische Wirkung bei verschiedenen Tierspezies und am Menschen hat. Es ist ein sterisch gehindertes Alkylphenol, das im LDL akkumu¬ liert. Im Tierversuch wurde gezeigt, daß Probucol die oxidative Modifikation von LDL in der Arterienwand blockiert und die Atherombildung direkt aufgrund der Antioxidansaktivität verhin¬ dert (D. Steinberg et al., Amer. J. Cardiol. 57, 16 M (1986).
Nachteile von Probucol R liegen in der geringen Resorption der Substanz, sowie in der extrem langen Verweildauer im Körper¬ gewebe; die Ausscheidung von Probucol erfolgt hauptsächlich über die Faeces (vgl. M.N. Cayen, Pharmacol. Ther. 29, 157 (1985)) .
Ferner senken Verbindungen der Formel I die Plasmalipide indem sie die intestinale Cholesterinresorption blockieren, in Konse¬ quenz den intrahepatischen Pool des freien Cholesterins reduzieren und die Sektretion der nahrungsabhängigen Lipo- proteine aus der Leber in das Plasma entsprechend vermindern. Die Inhibition der Cholesterinresporption beruht auf einer Hemmung der Acyl-Coenzym A: -cholesterintransferase (ACAT) Reaktion. In den Enterozyten katalysiert ACAT die Veresterung des Cholesterins, die notwendig ist, um Cholesterin in Chylo- mikronen einzupacken und über Darmlymphe und den Ductus thoracicus in das zirkulierende Blut einzuführen. Die Substanzen verfügen über eine gute Resorption und inhibie¬ ren die ACAT abhängige Veresterung des freien Cholesterins nicht nur in den Enterozyten, sondern auch in den Zellen des Atheroms selbst. Sie verhindern dadurch deren schaumzellige Degeneration infolge Überladung mit Cholesterinester.
Di-tert.butyl-Phenolderivate der Formel I können nach an sich bekannten Syntheseverfahren erhalten werden, beispielsweise durch Umsetzung eines Amins der Formel II mit einer Carbon- säure, bzw. eines Derivats einer Carbonsäure der allgemeinen Formel III
Figure imgf000007_0001
II III
in denen A, R und Y die in Formel I angegebene Bedeutung haben und Z Hydroxyl, Halogen, C1-C4-Alkoxy oder Azid darstellt.
Die Umsetzung erfolgt in der Regel in einem inerten Lösungs¬ mittel, wie einem Kohlenwasserstoff, Dimethylformamid, Dichlor- methan oder in Ether.
Vorzugsweise verwendet man äquimolare Mengen an Amin und Carbonsäure in Gegenwart äquimolarer Mengen einer Base wie einem tert. organ. A in, bevorzugt Triethylamin, Alkalibi- carbonat, -Hydroxyd oder - Carbonat.
Als Derivate der Carbonsäure (Formel III) können das Säure- halogenid, -azid, -anhydrid oder -ester dienen. Für die Umsetzung der freien Carbonsäure ist in der Regel die Anwesenheit von POCI3, S0C12 oder PCI3 erforderlich für die Umsetzung eines Carbonsäure-Esters mit dem Amin ein basischer Katalysator, bevorzugt ein Alkalialkoholat. In vielen Fällen gelingt auch die Reaktion der Carbonsäure mit einem Amin in einem Lösungsmittel wie z.b. Xylol durch Erwärmen unter Rück¬ fluß am Wasserabscheider.
Die Harnstoff-Derivate der allge . Formel I (X = -NR-C-NR-) werden vorzugsweise durch Addition eines Isocyanats IV an ein Amin der Formel II, durchgeführt in einem inerten Lösungsmittel z.B. Toluol, erhalten (vgl. Houben-Weyl, Bd. VIII S. 157).
II + -A-NH-C-tlH-Y
Figure imgf000008_0001
IV
Die Verbindungen der Formel I finden aufgrund ihrer stabilisie¬ renden Wirkung auf Lipoproteine Verwendung als Arzneimittel, insbesondere als Antiatherosclerotica.
Desweiteren wirken sie antiinflammatorisch, cytoprotektiv sowie antiasthmatisch. Sie können aber auch als Inhibitoren der reperfusionsabhängigen Lipidperoxidation und als Stabilisatoren des "lung surfactant factor" eingesetzt werden.
Falls einzelne Reaktionsprodukte nicht in genügender Reinheit anfallen, kann die Reinigung der Rohprodukte durch Kristalli¬ sation oder Säulenchromatographie erfolgen. Zur Herstellung von Salzen mit physiologisch verträglichen organischen oder anorganischen Basen wie beispielsweise Natriumhydroxid, Kaliumhydroxid, Calciumhydroxid, Ammonium¬ hydroxid, Methylglucamin, Morpholin, Triethylamin oder Ethanol- a in können die Verbindungen der Formel I mit den entsprechenden Basen umgesetzt werden. Auch Mischungen der sauren Verbindungen mit einem geeigneten Alkalicarbonat bzw. - hydrogencarbonat kommen in Betracht.
Zur Herstellung von Arzneimitteln werden die Verbindungen der allgemeinen Formel I in an sich bekannter Weise mit geeigneten pharmazeutischen Trägersubstanzen, Aroma-, Geschmacks- und Farbstoffen gemischt und beispielsweise als Tabletten oder Dragees ausgeformt oder unter Zugabe entsprechender Hilfsstoffe in Wasser oder öl, wie z.B. Olivenöl, suspendiert oder gelöst.
Die Substanzen der allgemeinen Formel I können in flüssiger oder fester Form oral und parenteral appliziert werden. Als Injektionsmedium kommt vorzugsweise Wasser zur Anwendung, welches die bei Injektionslösungen üblichen Stabilisierungs¬ mittel, Lösungsvermittler und/oder Puffer, Ethanol, Dimethyl- sulfoxid, Komplexbildner (wie Ethylendiamintetraessigsäure) , hochmolekulare Polymere (wie flüssiges Polyethylenoxid) zur Viskositätsregulierung oder Polyethylen-Derivate von Sorbit¬ anhydriden.
Feste Trägerstoffe sind z.B. Stärke, Lactose, Mannit, Methyl- cellulose, Talkum, hochdisperse Kieselsäure, höhermolekulare Fettsäuren (wie Stearinsäure) , Gelatine, Agar-Agar, Calcium- phosphat, Magnesiumstearat, tierische und pflanzliche Fette oder feste hochmolekulare Polymere (wie Polyethylenglykole) . Für die orale Applikation geeignete Zubereitungen können gewünschtenfalls Geschmacks- und Süßstoffe enthalten. Die verabreichte Dosierung hängt vom Alter, der Gesundheit und dem Gewicht des Empfängers, dem Aussmaß der Krankheit, der Art gleichzeitiger gegebenenfalls durchgeführter weiterer Behand¬ lungen, der Häufigkeit der Behandlungen und der Art der gewünschten Wirkung ab. üblicherweise beträgt die tägliche Dosis der aktiven Verbindung 0.1 bis 10 mg/kg Körpergewicht.
Die nachfolgenden Beispiele zeigen einige Verfahrensvarianten, die zur Synthese der erfindungsge äßen Verbindungen verwendet werden können. Sie sollen jedoch keine Einschränkung im Sinne des Erfindungsgedanken darstellen.
Beispiel 1
N-C3,5-Di-tert.butyl-4-hvdroxybenzyl)-3-(4-chlor- phenyl)acrylamid
Zu einer Lösung von 10.0 g (42 mmol) 3,5-Di-tert.butyl-4- hydroxybenzylamin. HC1 (z.B. analog Houben-Weyl, Bd. 11/1,
S. 502) und 5.4 ml Triethylamin in 100 ml absolutem Toluol tropft man 40 mol 4-Chlorzimtsäurechlorid (aus 7.3 g (40 mmol)
4-Chlorzimtsäure, analog Houben-Weyl Bd.8, S. 464) gelöst in
30 ml Toluol innerhalb 1 Stunde bei Raumtemperatur. Nach
14 Stunden Rühren gießt man den Ansatz in kalte 1 n Salzsäure, trennt die Phasen und schüttelt die organische Phase zweifach mit je 100 ml Wasser.
Nach Trocknen der Toluolphase über MgSθ4 wird das Lösungsmittel i.Vak. entfernt, der Rückstand mit wenig Ligroin angerieben und abgesaugt.
8.7 g fast farblose Kristalle, Fp: 175°C. Beispiel 2
a) N-Methyl-f3 ,5-di-tert.butyl-4-hvdroxylphenylethylamin.HCl
Ein Gemisch aus 30.0 g (0.12 mol) 3 ,5-Di-tert.butyl-4- hydroxyphenethyla in und 13.4 ml (0.13 mol) Benzaldehyd in 200 ml absolutem Toluol wird am Wasserabscheider am Rück¬ fluß erhitzt, bis sich kein Reaktionswasser mehr abschei¬ det. Anschließend engt man i.Vak. ein, löst erneut in 100 ml absolutem Toluol und versetzt diese Lösung mit 12.6 ml (0.13 mol) Dimethylsulfat. Nach 3 Stunden Erwärmen wird abgekühlt, 150 ml Wasser zugegeben, erneut 1 Stunde auf 120°C erwärmt und wieder abgekühlt. Die wässrige Phase wird abgetrennt, die organische Phase mit wenig HC1 conc. versetzt und anschließen i.Vak. eingeengt. Noch vorhande¬ nes Wasser wird mit Toluol azeotrop herausgeschleppt. Der verbleibende Rückstand wird mit wenig Ether/Ligroin ver¬ rieben und abgesaugt. 25.8 g bräunliche Kristalle, Fp: 200-203'C.
b) N-2-f3.5-di-tert.butyl-4-hvdroxylphenyl) ethγl-N-methγl-3- (4-chlorphenyl) acrylamid
Ein Gemisch aus 4.0 g (15.6 mmol) des unter a) erhaltenen Amins, 2.6 ml (36 mmol) Pyridin und 100 ml Dichlormethan wird bei Raumtemperatur innerhalb 30 min mit einer Lösung von 16 mmol 4-Chlorzimtsäurechlorid (aus 2.9 g (16 mmol) 4-Chlorzimtsäure, analog Houben-Weyl Bd. 8, S. 464) in 20 ml Dichlormethan versetzt.
Nach 6 Stunden Rühren gießt man in kalte In HC1, trennt die Phasen und schüttelt die organische Phase zweifach mit Wasser aus. Nach Trocknen des Dichlormethans über Na2S04 wird das Lösungsmittel i.Vak. entfernt. Nach Anreiben mit Ligroin/Toluol erhält man ein kristallines Produkt. 1.6 g farblose Kristalle, Fp: 156"C.
LATT Beispiel 3
N-(3 ,5-Di-tert.butyl-4-hydroxybenzyl)-3-(3,4-methylendioxy- phenyl)acrylamid
Zu einer Lösung von 2.7 g (10 mmol) 3.5-Di-tert.butyl-4- hydroxybenzylamin Hydrochlorid (hergestellt analog: Houben- Weyl, Bd. 11/1, S. 502 aus 3,5-Di-tert.butyl-4- hydroxybenzaldoxim) in 50 ml Tetrahydrofuran gibt man 4.2 ml Triethylamin und saugt nach 2 Stunden Rühren das gebildete Triethylamin Hydrochlorid ab. Zur Lösung der Base werden 2.2 g (10 mmol) 3,4-Methylendioxyphenyl-acrylsäureazid in 50 ml Tetrahydrofuran unter Eiskuhlung zugetropft und über Nacht bei Raumtemperatur rühren lassen. Nach Eindampfen der Tetrahydrofuranlösung wird in Wasser und Essigester aufgenom¬ men, trennt die organische Phase ab und schüttelt noch 2 mal mit Essigester. Nach Trocknen der Essigesterphase über Na2≤θ4 wird abdestilliert und der Rückstand mit Ether/Isohexan verrie¬ ben und abgesaugt. Es verbleiben 1.4 g farblose Kristalle, Fp. 194-197°C.
Beispiel 4
N-2-(3,5-Di-tert.butγl-4-hvdroxyphenyl)ethyl-N'-phenyl-harn- stoff
Eine Lösung von 2.0 g (8 mmol) 3,5-Di-tert.butyl-4-hydroxy- phenethylamin (z.B. nach J.A .Chem.Soc. 4, 1629 (1962) in 30 ml Toluol wird tropfenweise mit 0.87 ml (8 mmol) Phenyliso- cyanat versetzt. Nach 2 Stunden Rühren wird das Lösungsmittel weitgehend entfernt, der Rückstand abgesaugt und aus Ethanol/Toluol (1:3) umkristallisiert. 2.8 g farblose Kristalle, Fp: 181-83°C. Beispiel 5
N-C3.5-Di-tert.butyl-4-hvdroxybenzyl)-3-(4-hvdroxy- phenyl)acrylamid
4.9 g (30 mmol) trans-4-Hydroxyzimtsäure werden in 50 ml wasserfreiem Aceton suspendiert und mit 12.6 ml (90 mmol) Triethylamin versetzt. Man kühlt im Eisbad auf etwa 5°C ab und tropft eine Lösung von 11.7 g (90 mol) Isobutylchloroformat in 12 ml Aceton zu. Nach 2 Stunden Rühren unter Eiskühlung wird eine Lösung von 6.3 g (96 mmol) Natriumazid in 24 ml Wasser zugetropft und noch weitere 2 Stunden ohne Kühlung weiterge¬ rührt. Man verdünnt mit etwa 300 ml Wasser und extrahiert das gebildete Azid mehrmals mit Essigester. Nach Eindampfen wird ein kristallines Produkt vom Fp. 74-76βC erhalten.
Das Azid wird fest zu 100 ml Tetrahydrofuranlösung von 20 mmol 3,5-Di-tert.butyl-4-hydroxybenzylamin (bereitet wie in Bei¬ spiel 3 beschrieben) eingetragen und 2 min bei Raumtemperatur gerührt. Durch Zugabe von 300 ml Wasser und Extrahieren mit Essigester erhält man 10 g der Isobutoxycarbonylverbindung. Durch Lösen mit 75 ml Tetrahydrofuran und Zugabe von 25 ml conc. Ammoniak wird der Ester verseift. Die Lösung wird ab- destilliert in Wasser und Essigester gelöst, die organische Phase über Na2S0 getrocknet und im Vak. entfernt. Nach Anrei¬ ben und Absaugen erhält man 2.6 g fast farblose Kristalle, Fp. 205-208-C.
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000016_0001
Beispiel 6
r-4—r (3 ,5-Di-tert.butyl-4-hvdroχyphenyl)methvπamino-(3-oxo-1- propenyl)phenoxylessigsäureethylester
5.6 g (15 mmol) N-(3,5-Di-tert.butyl-4-hydroxybenzyl)-3-(4- hydroxyphenyl)acrylamid werden in 150 ml Aceton gelöst, 4.2 g Kaliumcarbonat zugegeben und mit 3.4 ml (30 mmol) Bro essig- säureethylester versetzt. Nach 24 Stunden Rühren bei Raumtempe¬ ratur wird i. Vak. eingeengt, in Wasser und Essigester gelöst, die Essigesterphase abgetrennt mit Na2Sθ4 getrocknet und ab¬ destilliert. Der feste Rückstand wird mit Ether verrieben und abgesaugt. Es verbleiben 4.5 g farblose Kristalle, Fp. 144- 147°C. Beispiel 7
N-(3 ,5-Di-tert.butyl-4-hγdroxybenzyl)-3-(4-dimethylamino- phenyl)acrylamid
3.8 g (20 mmol) 4-Dimethylaminozimtsäure werden in 75 ml Tetra¬ hydrofuran gelöst, 0.4 ml (60 mmol) Triethylamin zugegeben und unter Kühlung bei ca. 5βC 2.9 ml (22 mmol) Chlorameisensäure- isobutylester zugetropft. Man läßt noch 1 Stunde im Eisbad und 1 Stunde bei Raumtemperatur nachrühren. Anschließend werden 2.8 g (10 mmol) 3,5-Di-tert.butyl-4-hydroxybenzylamin Hydro¬ chlorid bei Raumtemperatur fest eingetragen und 24 Stunden weiter rühren lassen. Nach Zugabe von 300 ml Wasser wird 3 mal mit Essigester extrahiert. Die organische Phase mit Na2S04 getrocknet und abdestilliert. Der verbleibende Rückstand wird über eine Kieselgel 60 Säule (60x600 mm) mit
Isohexan/Essigester 1:1 gereinigt. Die Fraktion mit der reinen Verbindung werden abdestilliert, der Rückstand mit Ether ver¬ rieben und abgesaugt. Es verbleiben 2.6 g farblose Kristalle, Fp. 195-197'C.
Beispiel 8
In analoger Weise wie in Beispiel 1 beschrieben werden die folgenden Verbindungen hergestellt:
Figure imgf000017_0001
- -
Figure imgf000018_0002
Beispiel 9
In analoger Weise wie in Beispiel 4 beschrieben werden die folgenden Verbindungen hergestellt:
Figure imgf000018_0001
- -
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0002
+ungesätt. Acrylderivate sind stets (E)-konfiguriert
Beispiel 10
In analoger Weise wie in Beispiel 1 beschrieben werden die folgenden Verbindungen hergestellt:
Figure imgf000023_0001
Figure imgf000023_0003
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0002
Beispiel 11
In analoger Weise wie in Beispiel 2 beschreiben werden die folgenden Verbindungen hergestellt:
Figure imgf000030_0001
Figure imgf000031_0001
Beispiel 12
N-(3,5-Di-tert.butyl-4-hydroxybenzyl)-3-(4-phenoxyessig- säure)acrylamid
5.8 g (0.0124 mol) N-(3,5-Di-tert.butyl-4-hydroxybenzyl)-3-(4- phenoxyessigsäureethylester)acrylamid (Beispiel 6) werden in 50 ml Ethanol und 50 ml Wasser mit 1.06 g (0.019 mol) KOH 24 h bei Raumtemperatur gerührt. Man destilliert den Alkohol ab, säuert mit verd. Salzsäure an und extrahiert mit Essigester. Nach Ver¬ dampfen des Essigester kristallisiert das Produkt aus Ether/Isohexan (1:1) aus. Man erhält 1.1 g vom Fp. 125-126°C.
Analog erhält man:
12.1 N-(3,5-Di-tert.buty1-4-hydroxybenzyl)-3-(3, -dihydroxy- phenyl)acrylamid fast farblose Kristalle, Fp. 233-235'C aus N-(3,5-Di-tert.butyl-4-hydroxybenzyl-3-(3,4-diacetoxy- phenyl)aryla id (Beisp. 5.7)
12.2.N-(3.5-Di-tert.butyl-4-hydroxybenzyl)-3-(4- hydroxycarbonyl-phenyl)acrylamid aus N-3,5-Di-tert.butyl- 4-hydroxybenzyl)-3-(4-ethoxycarbonylphenyl)acrylamid (Beisp. 10.55)
Beispiel 13
N-(3,5-Di-tert.butyl-4-hydroxybenzyl)-3-(4-pivaloyl- henyl)acrylamid
3.8 g (10 mmol) N-(3,5-Di-tert.butyl-4-hydroxybenzyl)-3-(4- hydrσxypheny1)acrylamid (Beisp. 5) werden in 100 ml■ Tetrahydro¬ furan gelöst und 2.8 ml (20 mmol) Triethylamin zugegeben. Unter Kühlung werden zwischen 5β und 10°C 1.5 ml (12 mmol) Pivalin- säurechlorid in 5 ml Tetrahydrofuran gelöst, zugetropft. Nach 24 h rühren bei Raumtemperatur wird mit Wasser verdünnt und mit Essigester extrahiert. Der Essigesterrückstand wird über eine Kieselgelsäule (KG 60) mit Isohexan/Essigester gereinigt. Es verbleiben nach Anreiben mit Ether farblose Kristalle vom Fp. 172-173"C.
Beispiel 14
N-(3,5-Di-tert.butyl-4-hydroxybenzyl)-3-(4-amino- phenyl)acrylamid
4.1 g (10 mmol) N-(3,5-Di-tert.butyl-4-hydroxybenzyl)-3-(4- nitrophenyl)acrylamid (Beisp. 10.17) werden in 250 ml Ethanol gelöst und mit 6.5 g (100 mmol) Zink-Staub versetzt. Innerhalb 1 h werden unter kräftigem Rühren 100 ml 2 molare Salzsäure zugetropft. Nach 3 stündigem Rühren ist die Reaktion beendet. Es wird abgesaugt, das Filtrat abdestilliert und in Essigester und Wasser aufgenommen. Der Essigesterrückstand wird über eine Kieselgelsäule (KG 60) gereinigt. Es werden 1.5 g Produkt vom Fp. 80°C (sintern) nach Anreiben mit Isohexan erhalten. Beispiel 15
N-(3,5-Di-tert.butyl-4-hydroxybenzyl)-4-hydroxy-phenoxyessig- säureamid
1.5 g 3.2 mmol N-(3,5-Di-tert.butyl-4-hydroxybenzyl)-4- benzyloxy-phenoxyessigsäureamid (Beisp. 10.50) werden in 50 ml Methanol gelöst, mit 0.5 g lOproz. Pd-Kohle versetzt und 3 h bei Raumtemperatur und Normaldruck hydriert. Nach Absaugen des Katalysators und Eindampfen des Lösungsmittels werden 1.2 g farblose Kristalle vom Fp. 114-116"C erhalten.
Analog Beispiel 15 erhält man:
Figure imgf000034_0001
Figure imgf000034_0002
Beispiel 16
N-(3,5-Di-tert.butyl-4-hydroxybenzyl)-3-(4-hydroxymethyl- phenyl)acrylamid
2.7 g 6 mmol N-(3,5-Di-tert.butyl-4-hydroxybenzyl)-3-(4-ethoxy- carbonyl-phenyl)acrylamid (Beisp. 10.55) werden mit Li BH4 (hergestellt aus 1.4 g NaBH4 37 mmol und 1.6 g LiCl 37 mmol) in 100 ml Ethylenglycoldimethylether 24 h bei Raumtemperatur und anschließend 4 h bei 50°C gerührt. Der Reduktionskomplex wird mit Wasser und 2 mol Schwefelsäure zersetzt und das Produkt mit Essigester extrahiert. Nach Einengen der Essigesterphase und Anreiben mit Ether/Isohexan werden 1.1 g farblose Kristalle vom Fp. 177-179"C erhalten.

Claims

Patentansprüche
Verbindungen der Formel I
Figure imgf000036_0001
in der
A Valenz, eine gerade oder eine verzweigte Alkylkette mit 1 bis 5 C-Atomen
X eine -NR-CO- (A id) oder eine -NR-CO-NR-(Harnstoff) Gruppe, in der R ein Wasserstoffatom oder einen Cτ_- C4-Alkylrest darstellt,
und
eine geradkettige oder verzweigte, gesättigte oder ungesättigte Kohlenwasserstoffkette mit 1 bis 6 C- Atomen, die durch einen Aryl-, Hetaryl- Aryloxy-, oder Arylthio-Rest substituiert sein kann, einen C3- Cg-Cycloalkyl-, oder einen Arylrest darstellt, wobei der betreffende Aryl- bzw. Hetarylrest jeweils ein bis dreifach in allen möglichen Positionen am Ring durch CN, Hydroxymethyl, Methylendioxy-, Halogen, Trifluormethyl, Cι~C4-Alkyl, Amino, C1-C4-Acylamino, Di-(Cτ_-C4) -alkylamino, Hydroxy, Cι-C4-Alkoxy, Carboxyl, Oxyessigsaureethylester oder Nitro substituiert sein kann, bedeuten ,
mit der Maßgabe, daß Y nur unsubstituiertes Phenyl bedeutet, wenn A eine andere Bedeutung als -CH2- oder -CH2-CH2- hat, sowie deren pharmakologische unbedenkliche Salze.
2. Verfahren zur Herstellung von Verbindungen der Formel I
Figure imgf000037_0001
in der
A Valenz, eine gerade oder eine verzweigte Alkylkette mit 1 bis 5 C-Atomen
X eine -NR-CO- (A id) oder eine -NR-CO-NR-(Harnstoff) Gruppe, in der R ein Wasserstoffatom oder einen Cτ_- C4-Alkylrest darstellt,
und
eine geradkettige oder verzweigte, gesättigte oder ungesättigte Kohlenwasserstoffkette mit 1 bis 6 C- Atomen, die durch einen Aryl-, Hetaryl- Aryloxy-, oder Arylthio-Rest substituiert sein kann, einen C3- Cg-Cycloalkyl-, oder einen Arylrest darstellt, wobei der betreffende Aryl- bzw. Hetarylrest jeweils ein bis dreifach in allen möglichen Positionen am Ring durch CN, Hydroxymethyl, Methylendioxy-, Halogen, Trifluormethyl, Cτ_-C4-Alkyl, Amino, C1-C4-Acylamino, Di-(C1-C4) -alkylamino, Hydroxy, Cτ_-C4-Alkoxy, Carboxyl, Oxyessigsäureethylester oder Nitro substituiert sein kann,
bedeuten,
mit der Maßgabe, daß Y nur unsubstituiertes Phenyl bedeutet, wenn A eine andere Bedeutung als -CH - oder -CH2-CH2- hat,
sowie deren pharmakologische unbedenkliche Salze, dadurch gekennzeichnet, daß man in an sich bekannter Weise
a) für den Fall, daß X eine -CO-NR-Gruppe darstellt, eine Verbindung der Formel II
Figure imgf000038_0001
in der A und R die angegebene Bedeutung haben, mit einer Verbindung der Formel III
Y-C-Z (III)
in der Y die angegebene Bedeutung hat und Z Hydroxyl, Halogen, C]_-C4-Alkoxy oder Azid darstellt,
umsetzt, und
b) für den Fall, daß X eine -NR-CO-NR-Gruppe darstellt,
eine Verbindung der Formel II
Figure imgf000039_0001
in der A und R die angegebene Bedeutung haben,
mit einem Isocyanat der Formel IV umsetzt
0=C=f7-y (IV)
in der Y die angegebene Bedeutung hat,
und anschließend gewünschtenfalls die erhaltenen Verbindungen der Formel I durch geeignete Maßnahmen in andere Verbindungen der Formel I umwandelt oder die Verbindungen in pharmakologisch unbedenkliche Salze überführt.
3. Arzneimittel, enthaltend eine Verbindung gemäß Anspruch 1, neben üblichen Träger- und Hilfsstoffen.
4. Verwendung von Verbindungen gemäß Anspruch 1 zur Behand¬ lung von StoffWechselerkrankungen.
PCT/EP1992/001821 1991-08-13 1992-08-10 Neue 3,5-di-tert.butyl-4-hydroxyphenyl-derivate, verfahren zu ihrer herstellung und arzneimittel WO1993004035A1 (de)

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NZ553329A (en) 2004-07-22 2010-09-30 Ptc Therapeutics Inc Thienopyridines for treating hepatitis C
DE102005062985A1 (de) * 2005-12-28 2007-07-05 Grünenthal GmbH Substituierte bis(hetero)aromatische N-Ethylpropiolamide und ihre Verwendung zur Herstellung von Arzneimitteln
KR20230163603A (ko) * 2022-05-23 2023-12-01 재단법인 대구경북첨단의료산업진흥재단 페닐프로핀 유도체를 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물

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EP1000935A1 (de) * 1997-07-25 2000-05-17 TSUMURA & CO. Pyridylacrylamid-derivate und arzneimittel gegen nephritis und inhibitoren des transformierenden wachstumsfaktors beta die diese derivate enthalten
EP1000935A4 (de) * 1997-07-25 2001-03-21 Tsumura & Co Pyridylacrylamid-derivate und arzneimittel gegen nephritis und inhibitoren des transformierenden wachstumsfaktors beta die diese derivate enthalten
AU737018B2 (en) * 1997-07-25 2001-08-09 Tsumura & Co. Pyridylacrylamide derivatives and nephritis remedies and TGF-beta inhibitors containing the same
US6313153B1 (en) * 1997-07-25 2001-11-06 Tsumura & Co. Compositions and methods for treating nephritis and inhibiting TGF -β related conditions using pyridylacrylamide derivatives
WO2003086396A1 (fr) * 2002-04-02 2003-10-23 Tsumura & Co. Inhibiteur de phosphodiesterase iv contenant un derive de pyridylacrylamide
WO2004052890A1 (en) * 2002-12-06 2004-06-24 Affinium Pharmaceuticals, Inc. Heterocyclic compounds, methods of making them and their use in therapy
US8895545B2 (en) 2006-07-20 2014-11-25 Debiopharm International Sa Acrylamide derivatives as Fab I inhibitors
US9862737B2 (en) 2007-02-16 2018-01-09 Debiopharm International Sa Salts, prodrugs and polymorphs of fab I inhibitors
US8901105B2 (en) 2012-06-19 2014-12-02 Debiopharm International Sa Prodrug derivatives of (E)-N-methyl-N-((3-M ethylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide
US10035813B2 (en) 2012-06-19 2018-07-31 Debiopharm International Sa Prodrug derivatives of (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide
US10751351B2 (en) 2016-02-26 2020-08-25 Debiopharm International S.A. Medicament for treatment of diabetic foot infections
CN116284642A (zh) * 2023-05-18 2023-06-23 平原倍斯特化工有限公司 一种耐黄变异氰酸酯组合物及其制备方法

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EP0600949A1 (de) 1994-06-15
TW203039B (de) 1993-04-01
MX9204622A (es) 1993-04-01
DE4126662A1 (de) 1993-02-18
CA2115349A1 (en) 1993-03-04
ZA926049B (en) 1994-02-14
EP0600949B1 (de) 1996-01-10
EP0527458A1 (de) 1993-02-17
IL102772A0 (en) 1993-01-31
ATE132849T1 (de) 1996-01-15
AU2418692A (en) 1993-03-16
JPH06510030A (ja) 1994-11-10

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