EP0000220B1 - Dihydrouracils, process for their preparation and pharmaceuticals containing them - Google Patents

Description

The present invention relates to dihydrouracils including their salts, processes for their preparation and medicaments which contain these compounds as active ingredients.

Piperazine compounds are already known from German laid-open specification 2,242,382 which, in addition to a trifluoromethylphenyl group, can also carry a dihydrouracil radical. However, nothing is reported about their pharmacological effects. The analog succinimide compounds described there only have appetite-inhibiting properties. It was therefore not foreseeable that derivatives of such dihydrouracils which do not carry a trifluoromethyl group on the phenyl ring and which have alkyl substituents on the dihydrouracil ring show completely different pharmacological effects.

It is known that, like methysergide, pizotifen is used as an antimigraine agent due to its serotonin-antagonistic action (H. Heyck "Med. Welt" Volume 25, (1974) pages 1853 to 1874). Successes in migraine treatment with the vascular therapeutic Bencyclan have recently been reported (M. Abel, "Med. Welt" Volume 27, (1976) pages 1509 to 1512), which besides a weak serotonin antagonism in particular has the property of increasing the aggregation of platelets inhibit.

worin

• R¹ Alkyl mit 1 bis 2 C-Atomen,
• R² bis R⁵ Wasserstoff oder Alkyl mit bis zu 2 C-Atomen, wobei R² bis R⁵ gleich oder verschieden sind,
• R⁶ Wasserstoff, einen anellierten Benzolring oder 1 bis 3 Substituenten der Gruppe Alkoxy mit 1 bis 3 C-Atomen, Halogen oder Alkyl mit 1 bis 4 C-Atomen,
• A eine Einfachbindung oder die Gruppe
  
• Q unverzweigtes oder verzweigtes Alkylen mit 2 bis 6 C-Atomen, wobei mindestens 2 C-Atome zwischen den beiden Stickstoffatomen stehen, oder die 2-Hydroxy-1,3-propylen-Gruppe
• X Sauerstoff oder Schwefel und
• Z Stickstoff oder eine Gruppe
  
  neben anderen wertvollen pharmakologischen Eigenschaften bei guter Verträglichkeit vor allem hochwirksame Serotoninantagonisten und gleichzeitig starke Thrombozytenaggregationshemmer darstellen. Sie kommen deshalb besonders für die Migränetherapie in Betracht.

It has now been found that dihydrouracils of the formula I

wherein

• R ¹ alkyl with 1 to 2 carbon atoms,
• R ² to R ^{5 are} hydrogen or alkyl having up to 2 carbon atoms, where R ² to R ^{5 are} identical or different,
• R ^{6 is} hydrogen, a fused-on benzene ring or 1 to 3 substituents from the group alkoxy with 1 to 3 C atoms, halogen or alkyl with 1 to 4 C atoms,
• A is a single bond or the group
  
• Q unbranched or branched alkylene with 2 to 6 carbon atoms, at least 2 carbon atoms between the two nitrogen atoms, or the 2-hydroxy-1,3-propylene group
• X oxygen or sulfur and
• Z nitrogen or a group
  
  in addition to other valuable pharmacological properties with good tolerability, are above all highly effective serotonin antagonists and at the same time strong platelet aggregation inhibitors. They are therefore particularly suitable for migraine therapy.

The invention thus relates to compounds of the formula (I), including their addition salts, with physiologically tolerated acids.

In addition to the valuable pharmacological properties already mentioned, the compounds according to the invention exhibit antihistaminic activity, an increase in erythrocyte fluidity, in some cases also psychotropic activity, a weak bradykinin antagonism and hypotensive effects.

• R' Alkyl mit 1 bis 2 C-Atomen,
• R²,R³ Wasserstoff oder Alkyl mit 1 bis 2 C-Atomen,
• _R ⁴,R⁵ Wasserstoff,
• R⁶ Wasserstoff oder Halogen,
• A eine Einfachbindung,
• Q eine unverzweigte Alkylenkette mit 2 bis 3 C-Atomen,
• X Sauerstoff oder Schwefel und
• Z Stickstoff bedeuten.

Compounds of the formula (1) in which

• R 'alkyl with 1 to 2 carbon atoms,
• R ² , R ^{3 are} hydrogen or alkyl having 1 to 2 carbon atoms,
• _R ⁴ , R ^{5 are} hydrogen,
• R ^{6 is} hydrogen or halogen,
• A a single bond,
• Q is an unbranched alkylene chain with 2 to 3 carbon atoms,
• X oxygen or sulfur and
• Z is nitrogen.

Of these, those are particularly preferred in which R 'is methyl, one of the radicals R ² and R ^{3 is} methyl and the other is hydrogen and R ^{6 is} hydrogen or fluorine in the 4-position, such as compounds Nos. 8, 10 and 14 to 16 of the Table IV.

sind beispielsweise Phenyl, 2-, 3- oder 4-Tolyl, 2,6- oder 3,4-Dimethylphenyl, 2-, 3- oder 4-Methoxyphenyl, Naphthyl, Fluorphenyl, Chlorphenyl, Bromphenyl oder Diphenylmethyl.Suitable groupings

are, for example, phenyl, 2-, 3- or 4-tolyl, 2,6- or 3,4-dimethylphenyl, 2-, 3- or 4-methoxyphenyl, naphthyl, fluorophenyl, chlorophenyl, bromophenyl or diphenylmethyl.

sind beispielsweise 5,6- oder 6,6-Dimethyl-dihydrouracil-3-yl; 5,6- oder 6,6-Dimethyl-2-thio-dihydrouracil-3-yl; 1,6,6-Trimethyl-2-thio-dihydrouracil-3-yl; 1,6,6-Trimethyl-dihydrouracil-3-yl; 6-Methyl-dihydrouracil-3-yl.Suitable groupings

are, for example, 5,6- or 6,6-dimethyl-dihydrouracil-3-yl; 5,6- or 6,6-dimethyl-2-thio-dihydrouracil-3-yl; 1,6,6-trimethyl-2-thio-dihydrouracil-3-yl; 1,6,6-trimethyl-dihydrouracil-3-yl; 6-methyl-dihydrouracil-3-yl.

Suitable bridge members Q are, for example, ethylene, propylene, butylene, pentylene, hexylene and 2-hydroxypropylene, it being possible for the radicals with at least 3 C atoms to be branched off, so that at least 2 C atoms are still in the chain.

in der R¹ bis R⁶, A, Q, Z und X die oben genannten Bedeutungen haben und OR⁷ Hydroxyl oder eine Alkoxygruppe mit 1 bis 4 C-Atomen bedeutet, unter Abspaltung von R⁷0H cyclisiert und gewünschtenfalls die Verbindungen der Formel I als solche isoliert oder mit Säuren in ihre physiologisch verträglichen Säureadditionssalze umwandelt.The invention also relates to a process for the preparation of dihydrouracils of the formula (1), in which a compound of the formula II

in which R ¹ to R ⁶ , A, Q, Z and X have the meanings given above and OR ^{7 is} hydroxyl or an alkoxy group having 1 to 4 carbon atoms, cyclized with elimination of R ⁷ 0H and, if desired, the compounds of the formula I. isolated as such or converted with acids into their physiologically acceptable acid addition salts.

The cyclization of the compound II can be carried out in various ways by conventional condensation methods, especially in a suitable solvent and / or in the presence of mineral acids and / or by heating the reaction mixture obtained in the synthesis of the compound II or the pure substance II isolated therefrom. Compounds in which R ^{7 represents} hydrogen can often be cyclized particularly well with the aid of mineral acids, such as sulfuric acid or hydrohalic acids, preferably hydrochloric acid or hydrobromic acid, in an alcohol such as methanol, ethanol, propanol or isopropanol. However, the cyclization can, which is preferred, be achieved by heating the pure substances with elimination of water or without addition of solvent and acid by means of suitable dehydrating agents, such as acetyl chloride or acetic anhydride. It is advisable to work at the boiling point of the corresponding solvent or condensing agent.

The cyclization of compounds in which R ^{7 is} alkyl is preferably carried out in a suitable solvent and / or in the presence of mineral acids, for example the abovementioned acids and alcohols. For compounds in which X is sulfur, cyclization in solvents without the addition of mineral acids is particularly preferred. It is also possible to use compounds of the formula II in which R ^{7 is} alkyl having 1 to 4 carbon atoms, first hydrolyzing with an alkali metal hydroxide to give a compound of the formula II in which R ^{7 is} hydrogen, and then cyclizing it. This hydrolysis can advantageously be carried out in aqueous or aqueous-acetone or aqueous-alcoholic medium, the alcohol advantageously having 1 to 3 carbon atoms.

• a) durch Umsetzung eines Amins der Formel lll
  
  mit einem 3-lsocyanato- bzw. 3-Isothiocyanato-alkancarbonsäureester der Formel IV
  
  oder Verbindungen der Formel ll, in denen R⁵ Wasserstoff oder Alkyl bedeutet, indem man
• b) ein Amin der Formel lll zuerst mit einer Verbindung der Formel V
  
  zu einer Verbindung der Formel VI
  
  und diese anschließend nach oder vorzugsweise ohne Zwischenisolierung mit einem 3-Amino-alkancarbonsäureester der Formel VII
  
  als solchem oder in Form eines Säureadditionssalzes umsetzt, oder
• c) ein Amin der Formel lll mit einem Carbamoylhalogenid der Formel VIII
  
  worin Hal vorzugsweise Chlor ist, zu einem Hydrohalogenid einer Verbindung der Formel II umsetzt.

The starting substances of formula II can be represented in various ways. So you get compounds where R ^{5 is} hydrogen

• a) by reacting an amine of the formula III
  
  with a 3-isocyanato or 3-isothiocyanato alkane carboxylic acid ester of the formula IV
  
  or compounds of the formula II in which R ^{5 is} hydrogen or alkyl by
• b) an amine of the formula III first with a compound of the formula V.
  
  to a compound of formula VI
  
  and then, after or preferably without intermediate isolation, with a 3-aminoalkane carboxylic acid ester of the formula VII
  
  as such or in the form of an acid addition salt, or
• c) an amine of formula III with a carbamoyl halide of formula VIII
  
  wherein Hal is preferably chlorine, converted to a hydrohalide of a compound of formula II.

Suitable starting materials of the formula (III) are, for example, 1-phenyl-4- (3-aminopropyl) piperazine, 1- (2-methylphenyl) and 1- (3-methylphenyl) -4- (3-aminopropyl) piperazine, 1- (2-methoxyphenyl) -1- (3-methoxyphenyl) - and 1- (4-methoxyphenyl) -4- (3-aminopropyl) piperazine, 1- (3-dimethylphenyl) - and 1- (2.6 -Dimethylphenyl) -4- (3-aminopropyl) piperazine, 1- (1-naphthyl) - and 1- (4-fluorine phenyl) -4- (3-aminopropyl) piperazine, 1-phenyl-4- (2-aminoethyl) piperazine, 1- (2-methoxyphenyl) -4- (2-aminoethyl) piperazine, 1- (4- Methoxyphenyl) -4- (5-aminopentyl) piperazine, 1-diphenylmethyl-4- (3-aminopropyl) piperazine, 4-phenyl-1- (3-aminopropyl) piperidine, 1-phenyl-4- (4- aminobutyl) piperazine, 1-phenyl-4- (5-aminopentyl) piperazine, or 4-phenyl-1- (2-aminoethyl) piperidine.

Suitable 3-isocyanato- or isothiocyanatoalkanecarboxylic acid esters of the formula (IV) are, for example, 3-isocyanato-isovaleric acid methyl ester and ethyl ester, 3-isocyanato-isovaleric acid n-and isopropyl ester, the various 3-isocyanato-isovaleric acid butyl ester, 3-isocyanato-isoisoisoisalerate ester, and isopropyl ester, the various 3-isothiocyanatoisovaleriansäurebutylester, 2-methyl-3-isocyanatobuttersäuremethyl- and 2-methyl-3-isothiocyanatobuttersäuremethylester.

Suitable 3-aminoalkanecarboxylic acid derivatives of the formula (VII) are, for example, those which correspond to the isocyanato compounds mentioned above and which contain an amino group in the 3-position instead of the isocyanato group, such as 3-aminoisovaleric acid methyl ester, 3-amino-2-methylbutyric acid methyl ester and 3 -Methylaminoisovaleriansäuremethylester.

Procedure a) is advantageously carried out in solvents which are inert to the reactants, such as xylene, toluene, mesitylene, benzene, methylene chloride or chloroform, preferably at the boiling point of the solvent; however, the reaction can also be carried out at room temperature, the reaction mixture generally warming itself. Then the solvent is removed, advantageously under reduced pressure, and the intermediate compound II either after purification by recrystallization or directly as a crude product - as described above - in aqueous or aqueous-alcoholic medium, preferably at its boiling point, in the case of X = oxygen, preferably in Cyclized presence of mineral acids. In the case of X = sulfur, it is generally not necessary to add an acid. Cyclization by heating to temperatures above 150 ° C., preferably around 200 ° C. and under protective gas is also possible.

Process variants b) and c) can generally be carried out at room temperature and expediently as a one-pot process. In process (b), which proceeds particularly well in tetrahydrofuran, the further reaction and the cyclization described above are advantageously carried out at the boiling point of the reaction mixture after addition of compound VII. Compounds of formula II; in which R ^{7 is} hydrogen are preferably - after they are isolated in pure form - cyclized by heating without solvent; and advantageously at temperatures above 150 ° C, preferably at about 200 ° C and under protective gas. When compounds of the formula VII which are only sparingly soluble in the reaction mixture are used, the addition of a polar solvent which is inert to the reaction participants, such as dimethylformamide, is expedient in order to achieve the desired conversion, so that a homogeneous solution is obtained.

Physiologically compatible mineral or sulfonic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid and cyclohexylsulfamic acid, are suitable for the preparation of the mono- or bisaddition salts, which is carried out by the generally customary methods.

The stability of the compounds obtained according to the invention, which are generally crystalline, allows the preparation of pharmaceutical preparations for oral, parenteral and rectal administration. The preparation of these preparations can be made according to the usual practice by admixing suitable and compatible auxiliaries, such as starch, milk sugar, cellulose derivatives, stearic acid or its salts, solvents, solubilizers, suppository mass, carriers such as chlorides, phosphates and carbonates in the usual way to form powders, tablets, dragees , Capsules, suppositories, solutions, pastes or suspensions. It is also possible to administer the pure substances in the form of microcapsules and also to combine them with other active substances.

Your dosage in humans is 0.1 to 50 mg, preferably 0.5 to 10 mg, in particular 0.5 to 3 mg per os per day.

Pharmacological testing and results 1. Serotonin antagonistic effect

• Test a: Versuchsanordnung nach Konzett und Rössler (Arch. exp. Path. Pharmak. 195 (1940) 71): Albino-Meerschweinchen aus hauseigener Zucht werden mit 1,25 g/kg Urethan intraperitoneal (i.p.) narkotisiert. Die Registrierung des Bronchialwiderstandes erfolgt bei geöffnetem Thorax über ein Aufnahmegerät ("Broncho-transducer") der Firma Ugo Basile (Mailand); die Atem-frequenz wird durch künstliche Beatmung mit einer Frequenz von 58 Huben/min konstant gehalten, der Aufblasdruck beträgt 9 cm H₂0-Säule. Zur Erzeugung der Bronchospasmen injiziert man alle 15 min 5 bis 10 µg/kg Serotonin (als Serotonin-kreatinin-sulfat) in einem Volumen von 0,1 ml/kg Körpergewicht (KG) in eine der Jugularvenen. Die Prüfsubstanzen werden in einem Volumen von 1 ml/kg entweder intravenös innerhalb von 30 s 2 min vor der Erzeugung des Serotoninspasmus oder aber intraduodenal bzw. oral mittels Schlundsonde 15 min vor dem Spasmus verabreicht Der ED₅₀-Wert entspricht der Dosis, durch die ein Serotonin-Spasmus 2 min nach i.v.-Injektion bzw. 15 min nach oraler oder intraduodenaler Gabe des Präparates um 50% gehemmt wird (seihe Tabelle 11.,

The following pharmacological test models were used to characterize the serotonin-antagonistic effect:

• Test a: Experimental arrangement according to Konzett and Rössler (Arch. Exp. Path. Pharmak. 195 (1940) 71): Albino guinea pigs from in-house breeding are anesthetized with 1.25 g / kg urethane intraperitoneally (ip). The bronchial resistance is registered with the thorax open using a recording device ("broncho-transducer") from Ugo Basile (Milan); the breathing frequency is kept constant by artificial ventilation with a frequency of 58 strokes / min, the inflation pressure is 9 cm H ₂ 0 column. To produce the bronchospasm, 5 to 10 µg / kg serotonin (as serotonin creatinine sulfate) in a volume of 0.1 ml / kg body weight (KG) is injected into one of the jugular veins every 15 min. The test substances are administered in a volume of 1 ml / kg either intravenously within 30 s 2 min before the generation of the serotonin spasm or intraduodenally or orally using a pharyngeal tube 15 min before the spasm.The ED ₅₀ value corresponds to the dose by which a Serotonin spasm 2 min after iv injection or 15 min after oral or intraduodenal Administration of the preparation is inhibited by 50% (see Table 11.

• Weibliche Sprague-Dawley-Ratten mit einem Gewicht von 180 bis 240 g erhalten zur Erzeugung des Oestrus 24 Stunden vor der Uterusentnahme 2 mg/kg Oestromon (Firma Merck, Darmstadt) intraperitoneal. Das auf 22°C gehaltene Organbad enthält eine Tyrode-Lösung mit spezifischer Zusammensetzung. Das Präparat wird in wäßriger Lösung mit einem Gesamtvolumen von 0,1 ml in das Bad appliziert. Die verabreichte Serotonin-Konzentration beträgt 10-⁸ g/ml Bad. Der ED₅₀-Wert entspricht der Dosis, durch die ein Serotonin-Spasmus um 50% gehemmt wird (siehe Tabelle 1).

Test b: Serotonin antagonism on the isolated uterus of the rat according to Robert A. Turner: Screening Methods in Pharmacology, Academic Press 1965 (New York and London):

• Female Sprague-Dawley rats weighing 180 to 240 g receive 2 mg / kg of oestromon (Merck, Darmstadt) intraperitoneally to produce the oestrus 24 hours before the uterus is removed. The organ bath, kept at 22 ° C, contains a Tyrode solution with a specific composition. The preparation is applied to the bath in aqueous solution with a total volume of 0.1 ml. The administered serotonin concentration is 10- ⁸ g / ml bath. The ED ₅₀ corresponds to the dose by which a serotonin spasm is inhibited by 50% (see table 1).

• Eine einmalige Gabe von 5-Hydroxy-L-tryptophan bewirkt bei Mäusen eine starke Erhöhung der Defakation aufgrund der gesteigerten Biosynthese von Serotonin aus der exogen zugeführten Aminosäure. Durch Serotoninantagonisten läßt sich dieser Defäkationseffekt vermindern. Die Prüfsubstanzen werden 45 min vor der Tryptophan-Gabe oral verabreicht. Die Tryptophan-Dosis beträgt 40 mg/kg i.p.

Test c: 5-hydroxyl-L-tryptophan antagonism in the mouse:

• A single administration of 5-hydroxy-L-tryptophan causes a large increase in the defection in mice due to the increased biosynthesis of serotonin from the exogenously supplied amino acid. This defecation effect can be reduced by serotonin antagonists. The test substances are administered orally 45 minutes before the tryptophan is administered. The tryptophan dose is 40 mg / kg ip

The assessment is made 1 hour after administration of the preparation by measuring the amount of faeces excreted. A reduction of this amount by <25% of the empty check is given depending on the result with 0 or (+), from 25 to 50% with +, from 50 to 75% with ++ and _> 75% with +++ (see table I).

The serotomine-antagonistic effect of the following compounds was determined using the Konzett-Rössler model (test a) and the LD ₅₀ values on the mouse:

2. Antiplatelet effect

according to G.V.R. Born, Nature 4832, 927-929 (1962) and K. Breddin et al., Klin. Wschr. 53, 81-89 (1975)

In platelet-rich plasma (PRP) of Beagle dogs by in vitro administration of adenosine diphosphate (ADP) to a final concentration of 2.5 x 10- ⁶ g / ml experimentally a platelet aggregation induced with the aid of a Universalaggregometers of B. Braun / Melsungen is measured. An Eppendorf photometer registers the change in the optical density of the plasma.

• 1) Der Winkel a zwischen der Tangente am Anfangsteil der kurve udn der waagerechten Tangente
• 2) Die Zeit Tr vom Beginn der Rotation (Aggregation) bis zur völligen Desaggregation
• 3) Die Maximalamplitude (Ma) der Aggregationskurve als Differenz zwischen der Ausgangstransmission und der maximalen Transmission.
  

The following parameters are recorded:

• 1) The angle a between the tangent at the beginning of the curve and the horizontal tangent
• 2) The time Tr from the start of rotation (aggregation) to complete disaggregation
• 3) The maximum amplitude (Ma) of the aggregation curve as the difference between the initial transmission and the maximum transmission.
  

3. Acute toxicity

For some compounds, the toxicity determined in mice and rats in intraperitoneal and intravenous administration via mortality occurring within 7 days as the LD ₅₀ and LD ₅₀ range are given in Table III.

Wie aus den vorstehenden Tabellen hervorgeht, sind die erfindungsgemäß erhaltenen Verbindungen größtenteils dem Vergleichspräparat Pizotifen-HCI überlegen. Darüber hinaus haben tierexperimentelle Untersuchungen weitere Vorzüge gegenüber Pizotifen-HCI in der Weise gezeigt, daß a) die Wirkung wesentlich schneller eintritt, b) im therapeutischen Dosisbereich keine Sedation hervorgerufen und c) keine unerwünschte Appetitstimulation bewirkt wird.

As can be seen from the tables above, the compounds obtained according to the invention are largely superior to the comparative preparation Pizotifen-HCl. In addition, animal experiments have shown further advantages over Pizotifen-HCI in such a way that a) the effect occurs much faster, b) no sedation is caused in the therapeutic dose range and c) no unwanted appetite stimulation is caused.

A particular application of the compounds of formula (1) and their salts obtained according to the invention is in the combination with other suitable active ingredients, such as analgesics, ergotamine preparations, other serotonin antagonists, spasmolytics, vasodilatants, β-sympatholytics, antemetics, antihistamines, sedatives, tranquillizers , Caffeine, nicotinic acid derivatives, vitamins and estrogens.

example 1 3 - [3 - (4 - phenyl - piperazino) - propyl] - 6,6 - dimethyl - dihydrouracil - hydrochloride (Table IV, No. 8)

A) 11.0 g (0.05 mol) of 1-phenyl-4- (3-aminopropyl) piperazine and 7.85 g (0.05 mol) of methyl 3-isocyanatoisovalerate are dissolved in 50 ml of toluene according to process variant a) , mixed together and briefly heated to boiling. After cooling, the solvent is distilled off under reduced pressure and the oily residue is taken up in ether. After adding petroleum ether and rubbing with a glass rod, compound II is obtained in crystalline form. It can be recrystallized from a mixture of acetone and petroleum ether. Melting range 75 to 77 ° C; Yield 15.1 g (80.0% of theory).

For the conversion into the hydrochloride, the base is dissolved in acetone and the equimolar amount of 1N hydrochloric acid is added. The solvent is removed under reduced pressure at a maximum of 30 ° C. and the residue is recrystallized from dioxane, whereby the intermediate 3 - [3 - (3 - {4 - phenyl - piperazino) - propyl) - ureidoJ - isovaleric acid methyl ester - hydrochloride in pure Takes shape. Yield quantitative; Melting range 168 to 170 ° C; C ₂₀ H ₃₃ CIN ₄ 0 ₃ ; Molecular weight 412.96.

For the cyclization, the compound is dissolved in about 10 times the amount of 12% hydrochloric acid and boiled under reflux for two hours, about half of the solvent being distilled off under normal pressure within the last hour. It is evaporated under reduced pressure, the residue is dissolved in water and an excess of aqueous sodium hydroxide solution is added. The precipitated base is taken up in methylene chloride, dried over sodium sulfate and, after evaporation, recrystallized from a mixture of methanol and diisopropyl ether. Melting range 135 to 136 ° C. The cyclization can also be carried out by mixing 5.65 g (0.015 mol) of 3- [3- (3- {4-phenyt-piperazino) propyl) ureido] isovaleric acid methyl ester under a nitrogen atmosphere at 200 ° C. for 1.5 hours heated. The course of the cyclization is followed by thin layer chromatography. After the reaction has ended, the solidified melt is rubbed with diisopropyl ether, purified on a chromatography column and recrystallized from methanol-diisopropyl ether. Yield: 2.5 g (48% of theory); Melting range: 134 to 136 ° C.

For the conversion into the monohydrochloride, the base is dissolved in methanol and the calculated amount of 1N hydrochloric acid is added. After evaporation under reduced pressure, the residue is recrystallized from methanol or water. Melting range 236 to 242 ° C; Molecular formula C ₁₉ H ₂₉ CIN ₄ 0 ₂ ; Molecular weight: 380.92.

B) The same substance can also be produced as follows:

A solution of 21.9 g (0.1 mol) of 1-phenyl-4- (3-aminopropyl) piperazine in 100 ml of toluene is, according to procedure a), with stirring, with a mixture of 15.7 g (0.1 mol ) 3-Isocyanatoisovaleriansäuremethylester and 100 ml of toluene. The mixture is briefly heated to boiling, cooled to room temperature, evaporated to dryness and the residue is dissolved in about 1 liter of acetone. After adding 100 ml (0.1 mol) of 1N sodium hydroxide solution, the reaction mixture is stirred for 20 hours at room temperature. 100 ml (0.1 mol) of 1N hydrochloric acid are then added, the mixture is evaporated to dryness, the residue is recrystallized from an acetone / petroleum ether mixture and the free 3- [3- (3- {4- Phenyl-piperazino} -propyl) -ureido] -isovaleric acid. Yield: 23.9 g (66% of theory); Melting range: 139 to 140 ° C; Molecular formula: C ₁₉ H ₃₀ N ₄ 0 ₃ ; Molecular weight 362.47.

The intermediate product thus obtained is heated to 180-200 ° C for 1 hour. After cooling, the solidified base is purified by column chromatography and recrystallized from a mixture of methanol and diisopropyl ether. Melting range: 135 to 136 ° C.

As a further variant, the cyclization of the open-chain carboxylic acid to the corresponding 5,6-dihydrouracil can be carried out by heating in aqueous-alcoholic hydrochloric acid, acetyl chloride or acetic anhydride for two hours. After removing the corresponding condensing agent (dehydrating agent) under reduced pressure, the residue is dissolved in water and excess potassium hydroxide solution is added. The precipitated base is taken up in methylene chloride, dried over sodium sulfate and, if necessary, purified by column chromatography after evaporating the extractant.

Example 2 3 - [3 - (4-Diphenylmethyl-piperazino) propyl] - 6,6-dimethyl-dihydrouracil (Table IV, entry 26).

9.0 g (0.029 mol) of 1-diphenylmethyl-4- (3-aminopropyl) piperazine are dissolved in 30 ml of toluene and, according to process variant a), with a mixture of 4.6 g (0.029 mol) of 3-isocyanatovaleric acid methyl ester and 20 ml Toluene added with stirring. The mixture is heated to 70 ° C. for 30 minutes, evaporated to dryness under reduced pressure and the oily residue is rubbed in after the addition of diethyl ether. The 3- (1-diphenylmethylpiperazino-propylureido) isovaleric acid methyl ester thus obtained is pure by thin layer chromatography.

• Ausbeute: 7,1 g (77,8% der Theorie)
• Schmelzbereich: 183-185°C
• Summenformel: C₂₆H₃₄N₄0₂
• Molekulargewicht: 434,58
  
  

9.8 g (0.021 mol) of the isolated ester are dissolved in about 150 ml of methanol, 30 ml of concentrated hydrochloric acid are added and the mixture is heated under reflux for 2 hours. After removing the solvent under reduced pressure, the oily residue is dissolved in water and the base is released with aqueous potassium hydroxide solution. It is shaken out with chloroform, the organic phase is dried over sodium sulfate and evaporated. The crystalline residue is washed several times with ether.

• Yield: 7.1 g (77.8% of theory)
• Melting range: 183-185 ° C
• Molecular formula: C ₂₆ H ₃₄ N ₄ 0 ₂
• Molecular weight: 434.58
  
  

The compound can then be converted into the salts desired in each case by the customary methods.

Example 3 3 - [2 - (4 - phenyl - piperazino) - ethyl] - 5,6 - dimethyl - dihydrouracil - hydrochloride (Table IV, No. 20)

20.5 g (0.1 mol) of 1-phenyl-4- (2-aminoethyl) piperazine and 15.7 g (0.1 ml) of 3-isocyanato-2-methylbutyric acid methyl ester are obtained according to process variant a) in 125 ml each Toluene dissolved, mixed together at room temperature and refluxed for 5 minutes. The mixture is concentrated under reduced pressure, 200 ml of 3N hydrochloric acid are added and the mixture is boiled for 1 hour. Towards the end of the reaction time, about half of the hydrochloric acid is distilled off under atmospheric pressure; the rest is then removed under reduced pressure. The residue crystallizes after trituration with methanol and is recrystallized several times from methanol-water. Yield: 21.5 g (58.7% of theory); Melting range 265 to 273 ° C; Molecular formula C ₁₈ H ₂₇ CIN ₄ 0 ₂ ; Molecular weight 366.89.

Example 4 3 - [3 - (4 - phenyl - piperazino) - 6,6 - dimethyl - 2 - thiodihydrouracil - hydrochloride (Table IV, No. 14)

According to process variant a), a solution of 21.9 g (0.1 mol) of 1-phenyl-4- (3-aminopropyl) piperazine in 100 ml of toluene is stirred with a mixture of 17.3 g (0.1 mol ) 3-Isothiocyanatoisovaleriansäuremethylester and 100 ml of toluene. The reaction mixture is refluxed for 15 minutes and then freed from the solvent under reduced pressure.

The evaporation residue is purified on a silica gel 60 column (E. Merck) (diameter: 6 cm, height: 70 cm) with a chloroform-methanol mixture (volume ratio 9: 1). Yield 19.1 g (53% of theory)

Melting range: 150―151 ° C.

For conversion into the hydrochloride, the previously obtained 19.1 g of base are dissolved in methanol and 53 ml of N hydrochloric acid are added. After evaporation, a solid crystalline residue is obtained, which can be recrystallized from methanol.

Melting range 200-217 ° C, empirical formula C ₁₉ H ₂₉ CIN ₄ OS, molecular weight 396.98

Example 5

3 - [2 - (4 - phenyl - piperazino) - ethyl] - 6,6 - dimethyl - 2 - thio - dihydrouracil - hydrochloride (Table IV, No. 16)

According to process variant b), a solution of 25.8 g (0.145 mol) of N, N'-thiocarbonyldi-imidazole in 500 ml of anhydrous tetrahydrofuran is 29.8 g (0.145 mol) of 1-phenyl-4- (2-aminoethyl) piperazine drop in 125 ml of anhydrous tetrahydrofuran within 90 minutes with stirring added wisely. The mixture is stirred for 90 minutes and then 24.3 g (0.145) mol) of anhydrous 3-aminoisovaieric acid methyl) ester hydrochloride are also added with stirring. The clear solution is refluxed for 120 minutes. After cooling to room temperature, a solution of 3.33 g (0.145 gram atom) of sodium in 200 ml of methanol is added and stirring is continued for 15 minutes. The solvent is removed under reduced pressure and the crystalline residue is washed several times with water. After drying, the base is washed with diethyl ether and recrystallized from ethanol.

Yield: 35.7 g (71% of theory) melting range. 185-188 ° C.

To prepare the monohydrochloride, the base is dissolved in methylene chloride and an excess of ethanolic hydrochloric acid is added. After adding diethyl ether, a colorless crystalline substance is obtained, which is recrystallized twice from ethanol and which is monohydrochloride. The pH of a 0.1% aqueous solution is 4.3. Melting range 239 to 240 ° C; Molecular formula: C ₁₈ H ₂₇ CIN ₄ OS; Molecular weight 382.95.

To prepare the dihydrochloride hydrate, the base is dissolved in a little water-containing methanol and an excess of alcoholic hydrochloric acid is added. After precipitation with diethyl ether, the desired compound is obtained, which is freed from adhering hydrochloric acid under reduced pressure at room temperature and dried over calcium chloride. The pH of a 10% aqueous solution is 1.8. Melting range 238 to 247 ° C with decomposition; Molecular formula C ₁₈ H ₃₀ CI ₂ N ₄ O ₂ S; Molecular weight 437.42.

Example 6

3 - [3 - (4 - phenyl - piperazino) - propyl] - 1,6,6 - trimethyl - dihydrouracil - hydrochloride (Table IV, No. 23)

A solution of 16.2 g (0.1 mol) of N, N'-carbonyl-di-imidazole in 500 ml of anhydrous tetrahydrofuran is converted to 21.9 g (0.1 mol) of 1-phenyl-4- ( 3-aminopropyl) -piperazine in 150 ml of anhydrous tetrahydrofuran was added dropwise over the course of 90 minutes with stirring. The mixture is stirred for a further 30 minutes and 18.1 g (0.1 mol) of methyl 3-methylaminoisovaleric acid hydrochloride and 100 ml of anhydrous dimethylformamide are also added with stirring. After refluxing for 180 minutes, the mixture is cooled to room temperature, a solution of 2.29 g (0.1 gram atom) of sodium in 50 ml of methanol is added and the mixture is stirred for a further 15 minutes. After removing the solvent under reduced pressure, the oily residue is taken up in diethyl ether. Undissolved parts are filtered off, the ethereal solution is evaporated under reduced pressure and a little methanol is added to the residue, whereupon the desired base separates out in crystalline form. The compound can be recrystallized from methanol. Yield: 24.7 g (68.9% of theory).

• Summenformel: C₂₀H₃₁CIN₄O₂
• Molekulargewicht: 394,94
  
  
  
  

For the conversion into the hydrochloride, the base is dissolved in acetone and the equivalent amount of 1N hydrochloric acid is added. After evaporation under reduced pressure, the crystalline residue from methanol is reprecipitated with diethyl ether. The pH of a 0.1% solution is 3.0. Melting range: 188-195 ° C

• Molecular formula: C ₂₀ H ₃₁ CIN ₄ O ₂
• Molecular weight: 394.94
  
  
  
  

Claims (10)

1. Dihydrouracils of formula I

wherein

R' represents alkyl with up to 2 carbon atoms,

R² to R⁵ each represent hydrogen or alkyl having up to 2 carbon atoms whereby R² to R⁵ are identical or different,

R⁶ represents hydrogen, an anellated benzene nucleus or 1 to 3 substituents from the group consisting of alkoxy groups having from 1 to 3 carbon atoms, halogen or alkyl having from 1 to 4 carbon atoms;

A represents a single bond or a

group;

Q represents alkylene with 2 to 6 carbon atoms at least two carbon atoms being between the two nitrogen atoms or the 2-hydroxy-1,3-propylene group

X is an oxygen or sulphur atom; and

Z is nitrogen or the group

and the physiologically acceptable acid addition salts thereof.

2. Compounds as claimed in claim 1 in which

R' represents an alkyl group having up to 2 carbon atoms;

R² and R³ each represent hydrogen or an alkyl with up to 2 carbon atoms;

R⁴ and R⁵ each represent hydrogen;

R⁶ represents hydrogen or halogen;

A represents a single bond;

Q represents a straight-chained alkylene group having 2 to 3 carbon atoms;

X represents an oxygen or sulphur atom; and

Z represents a nitrogen atom.

3. Compounds as claimed in claim 2 wherein R' represents a methyl group; one of R² and R³ represents a methyl group and the other hydrogen; and R⁶ represents hydrogen or fluor in the 4- position.

4. 3 - 13 - (4 - {4 - Fluorphenyl} - 1 - piperazinyl) - propyl] - 6,6 - dimethyl - dihydrouracil - hydrochloride hydrate as claimed in claim 1.

5. 3 - [3 - (4 - Phenyl - 1 - piperazinyl) - propyl] - 6,6 - dimethyl - dihydrouracil - hydrochloride as claimed in claim 1.

6. 3 - [3 - (4 - Phenyl - 1 - piperazinyl) - propyl] - 6,6 - dimethyl - 2 - thio - dihydrouracil - hydrochloride as claimed in claim 1.

7. 3 - [3 - (4 - Phenyl - 1 - piperazinyl) - propyl] - 5,6 - dimethyl - dihydrouracil - hydrochloride as claimed in claim 1.

8. 3 - [2 - (4 - Phenyl - 1 - piperazinyl) - ethyl] - 6,6 - dimethyl - 2 - thio - dihydrouracil - hydrochloride as claimed in claim 1.

9. A process for the preparation of dihydrouracils as claimed in claim 1, characterised in cyclising a compound of formula II

wherein R¹ to R⁶, A, Q, Z and X represent the meanings as mentioned in claim 1 or OR⁷ represents hydroxy or an alkoxy group with 1 to 4 carbon atoms, by elimination of R⁷0H and isolating the compounds of formula I as such, if desired, or converting them with acids into their physiologically acceptable acid addition salts.

10. Medicament containing at least one compound as claimed in claim 1 either alone or in combination with usual additives.