EP0000220A1 - Dihydrouracils, process for their preparation and pharmaceuticals containing them - Google Patents

Abstract

New hexahydropyrimidines of the formula (I) in which: R 1 is hydrogen, alkyl having up to 2 C atoms, phenyl or tolyl, R 2 to R 5 hydrogen or alkyl having up to 2 C atoms, where R 2 to R 5 are the same or different, R 6 is hydrogen, a fused-on benzene ring or 1 to 3 identical or different substituents from the group alkoxy with 1 to 3 C atoms, halogen, nitro, hydroxy or alkyl with 1 to 4 C atoms, which is unsubstituted or is substituted by at least one halogen atom, a single bond or the group C6H5-CH Q a single bond or alkylene with n = 2 to 6 C atoms, where at least 2 C atoms are between the two nitrogen atoms, or such an alkylene, which is substituted with at most (n-2) hydroxyl groups, the OH group being in a position other than geminal to nitrogen, oxygen or sulfur and nitrogen or the groups -CH including the acid addition salts of the compounds of the formula (I), process for their preparation and drugs containing these compounds.

Description

The present invention relates to novel hexahydropyrimidines including their salts, processes for their preparation and pharmaceutical t-hold these novel compounds as active ingredients, e _n.

1- (3-Trifluoromethylpoenyl) -4-ethyl- or -propyl-piperazines, which are ω-substituted in the alkyl part, are described as anorectics, derivatives of the general definition also containing 2,4-dioxo-3- hexahydropyrimidinyl group in the ω position, but without C ^5- and / or C ⁶ -bonded substituents, but without such compounds being disclosed (German Offenlegungsschrift 22 42 382).

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

• R¹ Wasserstoff, Alkyl mit 1 bis 2 C-Atomen, Phenyl oder Tolyl,
• R² bis R⁵ Wasserstoff oder Alkyl mit bis zu 2 C-Atomen, wobei R² bis R⁵ glejch oder verschieden sind
• R⁶ Wasserstoff, einen anellierten Benzolring oder 1 bis 3 gleiche oder verschiedene Subs-tituenten der Gruppe Alkoxy mit 1 bis 3 C-Atomen, Halogen, Nitro, Hydroxy oder Alkyl mit 1 bis 4 C-Atomen, das unsubstituiert oder mit mindestens einem Halogenatom substituiert ist, wobei das Halogen jeweils Fluor, Chlor, Brom und/oder Jod ist,
• _A eine Einfachbindung oder die Gruppe ^C ₆ ^H ₅-^CH,
• Q eine Einfachbindung, unverzweigtes oder verzweigtes Alkylen mit n = 2 bis 6 C-Atomen, wobei mindestens 2 C-Atome zwischen den beiden Stickstoffatomen stehen , oder ein solches Alkylen, das mit höchstens (n-2) Hydroxylgruppen substituiert ist, wobei die OH-Gruppen in anderer als geminaler Stellung zu Stickstoff stehen,
• X Sauerstoff oder Schwefel und
• Z Stickstoff oder eine Gruppe -CH

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.Surprisingly, it has now been found that the completely differently structured, new hexahydropyrimidines of the general formula (1) (see formula sheet), in which:

• R ^{1 is} hydrogen, alkyl having 1 to 2 carbon atoms, phenyl or tolyl,
• R ² to R ^{5 are} hydrogen or alkyl having up to 2 carbon atoms, where R ² to R ^{5 are the} same or different
• R ^{6 is} hydrogen, a fused benzene ring or 1 to 3 identical or different substituents from the group alkoxy with 1 to 3 C atoms, halogen, nitro, hydroxy or alkyl with 1 to 4 C atoms, which is unsubstituted or with at least one halogen atom is substituted, the halogen in each case being fluorine, chlorine, bromine and / or iodine,
• _{A is} a single bond or the group ^C ₆ ^H ₅ - ^CH,
• Q is a single bond, unbranched or branched alkylene with n = 2 to 6 carbon atoms, where at least 2 carbon atoms are between the two nitrogen atoms, or such an alkylene which is substituted by at most (n-2) hydroxyl groups, the OH Groups are other than geminal to nitrogen,
• X oxygen or sulfur and
• Z nitrogen or a group -CH

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 acid addition salts with suitable inorganic and / or organic 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.

Hiervon sind solche besonders bevorzugt, in denen R¹ Methyl, einer der Reste R² und R³ Methyl und der andere Wasserstoff und R⁶ Wasserstoff oder Fluor in 4-Stellung bedeutet, wie die Verbindungen Nr. 9, 11 und 16 bis 18 der Tabelle IV.Compounds of the formula (I) in which, on their own or preferably combined, are particularly interesting.

Of these, those are particularly preferred in which R ^{1 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. 9, 11 and 16 to 18 of the Table IV.

If R ^{6 represents} a 3-position CF ₃ group, one of the radicals R ¹ to R is preferably also different from hydrogen or is AC ₆ H ₅ -CH or Q is a single bond or has at least 4 C atoms or is X is a sulfur atom or Z is -CH =.

sind beispielsweise Phenyl, 2-, 3- oder 4-Tolyl, 2,6- oder 3,4-Dimethylphenyl, 2-, 3- oder 4-Methoxyphenyl, Naphthyl, Fluorphenyl, Chlorphenyl, Bromphenyl, Trifluornethylphenyl 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, trifluoromethylphenyl or diphenylmethyl.

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

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

Suitable bridge members Q are, in addition to a single bond, for example ethylene, propylene, butylene, pentylene, hexylene, 2-hydroxypropylene or butylene, where the radicals can also be branched with at least 3 carbon atoms, so that at least 2 carbon atoms in the Chain stand. Any OH groups should not be geminal to a nitrogen atom.

The invention also relates to a process for the preparation of the abovementioned compounds of the formula (I), which is characterized in that a compound of the formula (II) (see formula sheet) in which R ^{7 is} hydrogen or alkyl having 1 to 4 C - Atoms means, with elimination of R ⁷ OH to the compound I cyclized or a compound of formula (III) (see formula sheet) with. a 3-isocyanato- or 3-isothiocyanato-alkanecarboxylic acid halide of the formula (IV) (see formula sheet) or a dihalide of the formula (IVa) (see formula sheet), in each case the chloride being preferred, with the escape of hydrogen halide to give a hexahydropyrimidine of the formula (I) implements.

The cyclization can be carried out in various ways by conventional condensation methods. For example, it can be carried out in a suitable solvent and / or in the presence of mineral acids and / or by heating the reaction mixture obtained in the synthesis of 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 in a suitable solvent and / or in the presence of mineral acids, e.g. B. the above acids and alcohols performed. For compounds in which X is sulfur, cyclization in solvents without the addition of mineral acids is particularly preferred. It is also possible to hydrolyze compounds of the formula (II) in which R ^{7 is} alkyl having 1 to 4 carbon atoms, first with an alkali metal hydroxide to give a compound of the formula (II) in which R is hydrogen, and then hydrolyzing them to cyclize. This hydrolysis can advantageously be carried out in an aqueous or aqueous-acetone or aqueous-alcoholic medium, the alcohol advantageously having 1 to 3 carbon atoms.

The reaction of the halides of the formulas (IV) and (IVa) is advantageously carried out in solvents which are inert to the reaction participants under the reaction conditions, such as methylene chloride, chloroform, toluene or xylene, preferably in the presence of tertiary amines such as triethylamine, tributylamine or pyridine, or even only in the pure tertiary amines or in strongly polar aprotic solvents such as dimethylformamide, the mixture being expediently cooled at the beginning of the reaction and heated to the boil towards the end.

Preference is given to the preparation of the compounds (I) according to the invention using the intermediates corresponding to formula (II), which can be obtained in various ways. For example, compounds of the formula (II) in which R ^{5 is} hydrogen are obtained,
a) by reacting an amine of the general formula (III) (see formula sheet) with a 3-isocyanato- or 3-isothiocyanatoalkane carboxylic acid ester of the formula (V) (see formula sheet) or.

Compounds of formula (II) in which R ^{5 represents} hydrogen or alkyl by
b) an amine of the formula (III) first with a compound of the formula (VI) (see formula sheet) to give an imidazole of the formula (VII) (see formula sheet) and then afterwards or preferably; as intermediate or without isolation with a 3-aminoalkanecarboxylic acid derivative of the formula (VIII) (see formula sheet) as such or in the form of one of its acid addition salts, or
c) reacting an amine of the formula (III) with a carbamoyl halide of the formula (IX) (see formula sheet), in which Hal is preferably chlorine, to give a hydrohalide of a compound of the 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- (3,4-dimethylphenyl) - and 1 - (2,6-dimethylphenyl) -4- (3-aminopropyl) piperazine, 1- (3-trifluoromethylphenyl) -, 1- (1-maphtyl) - and 1- (4-fluorophenyl) -4- (3- aminopropyl) piperazine, 1-phenyl-4- (2-aminoethyl) piperazine, 1- (2-methoxyphenyl) -4- (2-aminoethyl) piperazine, 1- (4-1-methoxyphenyl) -4- ( 5-aininopentyl) piperazine, 1- (3-trifluoromethylphenyl) -4- (4-aminobutyl) piperazine, 1-diphenylmeihyl-4- (3-aminopropyl) piperazine, 4-phenyl-1- (3-amino- propyl) piperidine, 1-phenyl-4- (4-aminobutyl) piperazine, 1-phenyl-4- (5-aminopentyl) piperazine, 1-phenyl-4-aminopiperazine or 4-phenyl-1- (2- aminoethyl) piperidine. Suitable 3-isocyanato- or isothiocyanatoalkane carboxylic acid esters of the formula (V) are, for example, 3-isocyanatoisovaleric acid methyl ester and ethyl ester, 3-isocyanatoisovaleric acid n-and isopropyl ester, the various 3-isocyanatoisovalerianic acid butyl ester, 3-isocyanatooisoisoisyl ester and 3-isothiothio-ethanoate ester - And isopropyl ester, the various 3-isothiocyanatoisovaleriansäurebutylester, 2-methyl-3-isocyanatobuttersäuremethylester, 2-methyl-3-isothiocyanatobuttersäuremethylester, 3-phenyl-3-isocyanatopropionic acid methyl ester and 3-isocyanatopropionic acid methyl

Suitable 3-aminoalkanecarboxylic acid derivatives of the formula (VIII) 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 -Aminopropionic acid methyl ester, furthermore 3-methylaminoisovaleric acid methyl ester.

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. The solvent is then 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 an aqueous or aqueous-alcoholic medium is preferred as cyclized at its boiling point, in the case of X = oxygen, preferably in the 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 variant b) can in general be carried out particularly well in tetrahydrofuran at room temperature and advantageously as a one-pot process. After addition of compound VIII, the further reaction and cyclization described above is advantageously carried out at the boiling point of the reaction mixture. Compounds of the formula (II) in which R ^{7 is} hydrogen are preferably - after they have been isolated in pure form - cyclized by heating without solvent, advantageously at temperatures above 150 ° C., preferably at about 200 ° C. and under protective gas . When compounds of the formula (VIII) 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 reaction, 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 cyclohexylsulfarainic acid, are suitable for the preparation of the mono- or bisaddition compounds, which is carried out by the generally customary methods.

The stability of the compounds according to the invention, which are generally crystalline, allows the preparation of pharmaceutical preparations for oral, parenteral and rectal administration. According to customary practice, these preparations can be prepared by admixing suitable and compatible auxiliaries, such as starch, lactose, cellulose derivatives, stearic acid. or their salts, solvents, solubilizers, suppositories, carriers such as chlorides, phosphates and carbonates in the usual way to form powders, tablets, dragees, capsules, suppositories, solutions, pastes or suspensions. Administration of the pure substances in the form of microcapsules is also possible, as is a combination with other active substances.

Your dosage can be in Henschen z. B. 0.1 to 50 mg, preferably 0.5 to 10 mg, in particular 0.5 to 3 mg per os per day and Hensch.

Pharmacological testing and results 1. Serotonin antagonistic effect

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 intraperitoneally (ip) with 1.25 g / kg urethane. The bronchial resistance is registered with the chest open via a recording device ("bronchotransducer") from Ugo Basile (Milan); the respiratory rate is kept constant by artificial ventilation with a frequency of 58 strokes / min, the inflation pressure is 9 cm H ₂ O-pillar. To produce the bronchospasm, 5 to 10 µg / kg serotonin (as serotonin creatinine sulrate) 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 NG 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 corresponds to the dose; by which a serotonin spasm is inhibited by 50% 2 min after iv injection or 15 min after oral or intraduodenal administration of the preparation (see Table I).

Test b: Serotonin antagonism on the isolated uterus of the rat according to Robert A. Turner: Screening Hethods in Pharmacology, Academic Press 1965 (New York and London): Female Sprague-Dawley rats weighing 180 to 240 g obtained to produce the oestrus 24 Hours before the uterus removal 2 mg / kg oestromon (Merck, Darmstadt) intraperitoneally. 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 scrotonin concentration is 10 ^-8 g / ml bath. The EC ₅₀ corresponds to the dose by which a serotonin spasm is inhibited by 50% (see Table 1).

Test c: 5-hydroxy-L-tryptophan antagonism in the mouse:. A single administration of 5-hydroxy-L-tryptophan causes a strong increase in defecation 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 i.p ..

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 control 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 ):

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) from beagle dogs, platelet aggregation is experimentally induced by 5 in vitro administration of adenosine diphosphate (ADP) at a final concentration of 2.5 × 10 ^-6 g / ml, which is carried out with the aid of a universal aggregometer from B. Braun / Melsungen is measured. An Ependorf photometer registers the change in the optical density of the plasma.

• 1) Der Winkel α zwischen der Tangenete am Anfangsteil der Kurve und 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 α between the tangenete 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

In Table III, the toxicity determined for mice and rats in intraperitoneal and intravenous administration via the mortality occurring within 7 days as the LD ₅₀ or ID ₅₀ range is given.

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

A particular application of the compounds according to formula (I) according to the invention and their salts 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 estrogenic.

Example

1. 3- [3- (4-phenyl-1-piperazinyl) propyl] -6,6-dimethyl-5,6-dihydrouracil hydrochloride (Table IV, No. 9)

A) 11.0 g (0.05 mol) of 1-phenyl-3- (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 conversion into the hydrochloride, the base is dissolved in acetone and the equimolar amount of N 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-1-piperazinyl> -propyl) -ureido] -isovaleric acid methyl ester- receives hydrochloride in pure form. Yield quantitative; Melting range 168 to 170 ° C; C ₂₀ H ₃₃ ClN ₄ O ₃ ; Molecular weight 412.96.

Analyse: berechnet: _C 58,17 H 8,05 N 13,57 gefunden: _C 58,07 H 7,97 N 13,46

Analysis: Calculated: _C 58.17 H 8.05 N 13.57 Found: _C 58.07 H 7.97 N 13.46

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. Nan evaporates under reduced pressure, dissolves the residue in water and adds an excess of aqueous sodium hydroxide solution. The precipitated Ease 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-phenyl-1-piperazinyl) propyl) -ureido] isovaleric acid methyl ester under a nitrogen atmosphere for about 1.5 hours to 200 ° C heated. The course of the cyclization is monitored by thin-layer chromatography. When the reaction is complete, 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 conversion into the monohydrochloride, the base is dissolved in methanol and the calculated amount of N 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 ClN ₄ O ₂ ; Molecular weight: 380.92.

Analysis: Calculated: 59.91 H 7.67 Cl 9.31 N 14.71 Found: C 60.28 H 7.75 C ^l 9.39 N 14.73

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

A solution of 21.9 g (0.1 mol) of 1-phenyl-4- (3-aninopropyl) 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 added. 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 sodium hydroxide solution, the reaction mixture is stirred for about 20 hours at room temperature. 100 ml (0.1 mol) of N hydrochloric acid are then added, the mixture is evaporated to dryness, the residue is recrystallized from an acetone / petroleum ether mixture and the intermediate 3- [3- (3- <4-phenyl -1-piperazinyl> -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 O ₃ ; Molecular weight 362.47.

Analysis: Calculated: C 62.96 H 8.34 N 15.46 Found: _C 62.93 H 8.30 N 15.30

The intermediate product thus obtained is heated to 180-200 ° C. for about 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 - 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 evaporation of the extractant.

2. 3- [3- (4-Diphenylmethyl-1-piperazinyl) propyl] -6,6-diryl-5,6-dihydrouracil (Table IV, No. 30)

Ausbeute: 9;8 g (72 % der Theorie)9.0 g (0.029 mol) of 1-diphenylmethyl-4- (3-aminopropyl) piper in 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-isocyanatoisovaleric acid yl ester and 20 ml of toluene are added with stirring. The mixture is heated to 30 ° C. to about 70 ° C. and evaporated to dryness under reduced pressure, and the oily residue is rubbed in after the addition of diethyl ether. The 3- (1-diphenylmethylpiperazin-4-ylpropylureido) isovaleric acid methyl ester obtained is pure by thin layer chromatography.

Yield: 9.8 g (72% of theory)

9.8 g (0.021 mol) of the isolated ester are dissolved in about 15 nl of methanol, crosslinked with 30 ml of concentrated hydrochloric acid and heated under reflux for 2 hours. After removal of the solvent under reduced pressure, the oil, a residue is dissolved in water and the base is liberated with aqueous potassium hydroxide. It is shaken out with chloroform, the org is dried; ische phase 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 O ₂

Molecular weight: 434.58

Analysis: Calculated: C 71.86 H 7.89 N 12.89 Found: C 71.85 H 8.05 N 13.02

The compound can then be converted into the desired salts in accordance with the usual method a.

3. 3- [2- (4-phenyl-1-piperazinyl) ethyl] -5,6-dimethyl-5,6-dihydrouracil hydrochloride (Table IV, No. 22)

20.5 g (0.1 mol) of 1-phenyl-4- (2-aminoethyl) piperazine and 15.7 g (0.1 mol) of methyl 3-isocyanato-2-methylbutyrate are obtained in each case according to process variant a) in 125 ml 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 about 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 ClN ₄ O ₂ ; Molecular weight 366.89.

Analysis: Calculated: C 58.93 H 7.42 Cl 9.66 N 15.27 Found: C 58.73 H 7.53 Cl 9.70 N 15.16

4. 3- [3- (4-Phenyl-1-piperazinyl) ―propyl] -6,6-dimethyl-2-thio-5,6-dihydrouracil hydrochloride (Table IV, No. 16).

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 added. The reaction mixture is refluxed for 15 minutes and then freed from the solvent under reduced pressure.

The evaporation residue is on a silica gel 60 column

(E. Merck company) (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.

Analyse: berechnet: C 57,49 H 7,36 C1 8,93 N 14,11 S 8,08 gefunden: C 57,71 H 7,46 Cl 8,96 N 14,10 S 8,22For 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; Molecular formula C ₁₉ H ₂₉ ClN ₄ OS; Molecular weight: 396.98.

Analysis: Calculated: C 57.49 H 7.36 C1 8.93 N 14.11 S 8.08 Found: C 57.71 H 7.46 Cl 8.96 N 14.10 S 8.22

5. 3- [2- (4-phenyl-1-piperazinyl) ethyl] -6,6-dimethyl-2-thio-5,6-dihydrouracil hydrochloride (Table IV, Rr. 18)

A solution of 25.8 g (0.145 mol) of N, N'-thiocarbonyl-di-imidazole in 500 ml of anhydrous tetrahydrofuran is, according to process variant b), 29.8 g (0.145 mol) of 1-phenyl-4- (2-aminoethyl) -piperazine in 125 ml of anhydrous tetrahydrofuran added dropwise within 90 minutes with stirring. The mixture is stirred for 90 minutes and then 24.3 g (0.145 mol) of anhydrous methyl 3-aminoisovaleric acid 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 gramactom) sodium in 200 ml methanol is added and the mixture is stirred 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 the manohydrochloride. The pH of a 0.1% solution is 4.3. Melting range 239 to 240 ° C; Molecular formula: C ₁₈ H ₂₇ ClN ₄ OS; Molecular weight: 382.95.

Analysis: Calculated: C 56.46 H 7.11 Cl 9.26 N 14.63 S 8.37 Found: C 56.48 H 7.11 Cl 9.60 N 14.62 s 8.67

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 Cl ₂ N ₄ O ₂ S; Molecular weight 437.42

Analysis: Calculated: C 49.43 H 6.91 Cl 16.21 N 12.81 S 7.33 Found: C 49.94 H 6.95 Cl 16.71 N 12.90 S 7.35

6. 3- [3- (4-phenyl-1-piperazinyl) propyl] -1,6,6-trimethyl-5,6-dihydrouracil hydrochloride (Table IV, No. 26)

A solution of 16.2 g (0.1 mol) of N, N'-carbonyl-di-imidazole in 500 ml of water-free 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 90 minutes while stirring. The mixture is stirred for 30 minutes and, while stirring, 18.1 g (0.1 mol) of methyl 3-methylaminolsovalerate hydrochloride and 100 ml of anhydrous dimethylformamide are added. 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. Unfiltered 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. Compound 1 can be recrystallized from methanol.

Extensions: 24.7 g (68.9 of theory)

To convert it to the hydrochloride, the base is dissolved in acetone and the equivalent amount of N 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 ClN ₄ O ₂

Molecular weight: 394.94

Analysis: Calculated: C 60.82 H 7.91 Cl 8.98 N 14.19 Found: C 60.39 H 7.87 Cl 9.80 N 13.69

7. 3- [3- (4-phenyl-1-piperazinyl) propyl] -5,6-dihydrouracil dihydrochloride (Table IV, No. 32)

21.9 g (0.1 mol) of ethyl 3-isocyanatopropionate and 14.3 g (0.1 mol) of 1-phenyl-4- (3-aminopropyl) piperazine are dissolved in 100 ml of toluene, according to process variant a), with one another mixed and heated briefly to boiling. After evaporation, the residue is triturated with diethyl ether, washed out and recrystallized from diethyl ether, whereby the ethyl 3- [3- (3- <4-Phenyl-1-piperazinyl> -propyl) -ureido] -propionate is obtained.

Yield: 19.2 g (53% of theory) (a further portion of the desired product can be isolated from the mother liquor).

Melting range: 66 to 69 ° C

19.0 g (0.0524 mol) of this este

dissolved in 250 ml of acetone and mixed with 2.4 ml of N sodium hydroxide solution. The mixture is stirred at room temperature for 18 hours, 52.4 ml of N hydrochloric acid are added, the mixture is evaporated and the residue is recrystallized from methanol, whereby the 3- [3- (3- <4-P enyl-1-piperazinyl> - propyl) - ureido] propionic acid.

Yield: 15.9 g (90% of theory)

Melting range: 169 - 171 ° C

2.5 g of 3- [3- (3- <4-phenyl-1-piperazi 1) -propyl) -urcido] -propionic acid are refluxed in 35 ml of acetic acid hydride for about two hours. It is evaporated, the residue is digested with diethyl ether and the whole is dissolved in methanol. After the addition of ethereal hydrochloric acid, an xrystallizate is obtained, which is isolated and then boiled in ethanol until thin-layer chromatography in acetyl derivative is more detectable. The compound is then recrystallized from methanol.

Yield: 1.5 g (51.5% of theory

Melting range: 192 - 216 ° C with 2 reduction

Molecular formula: C ₁₇ H ₂₆ Cl ₂ N ₄ O ₂

Molecular weight: 389.32

Analysis: Calculated: C 52.45 H 6.73 Cl 18.21 N 14.39 Found: C 52.48 H 6.84 Cl 18.37 N 14.56

Claims (9)

1. New hexahydropyrimidines of the formula (I) (see formula sheet) in which:

including the acid addition salts of the compounds of formula (I).

3. A compound according to claim 2, characterized in that R ^{1 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. 4. A compound according to claim 1 or 2, characterized in that pure trifluoromethyl is in the 3-position, wherein a) one of the radicals R ¹ to R ^{5 has} a meaning other than hydrogen or b) A

is or c) Q is a single bond or alkylene with at least 4 carbon atoms or d) X is sulfur or e) Z the group

is. 5. Compounds according to one or more of claims 1 to 3 of the formulas 3- [3- (4- <4-fluorophenyl) -1-piperazinyl) propyl] -6,6-dimethyl-5,6-dihydrouracil hydrochloride hydrate, 3- [3- (4-phenyl-1-piperazinyl) propyl] -6,6-dimethyl-5,6-dihydrouracil hydrochloride, 3- [3- (4-pheayl-1-piperazinyl) propyl ] -6,6-dimethyl-2-thio-5,6-dihydrouracil hydrochloride, 3- [3- (4-phenyl-1-piperazinyl) propyl] - 5,6-dimethyl-5,6-dihydrouracil- hydrochloride, 3- [2- (4-phenyl-1-piperazinyl) ethyl] -6,6-dimethyl-2-thio-5,6-dihydrouracil hydrochloride. 6. A process for the preparation of compounds of formula (I) according to one or more of claims 1 to 5, wherein R ¹ to R ⁶ , A, Q, X and Z have the meaning given above, characterized in that
a compound of the formula (II) (see formula sheet) in which R ^{7 is} hydrogen or alkyl having 1 to 4 carbon atoms, cyclized to give the compound (I) with elimination of R ⁷ 0H or a compound of the formula (III) (see formula sheet ) with a 3-isocyanato- or 3-isothiocyanato-alkane carboxylic acid halide of the formula (IV) (see formula sheet) or a dihalide of the formula (IVa) (see formula sheet) with the escape of hydrogen halide to give a hexahydropyrimidine of the formula (I), and that the compounds are isolated as such or reacted with suitable acids to form non-toxic acid addition compounds. 7. The method according to claim 6, characterized in that the reaction of the halides (IV) or (IVa) is carried out in a solvent which is inert towards the reaction participants under the reaction conditions in the presence of tertiary amines or in strongly polar aprotic solvents. 8. The method according to claim 6, characterized in that the compounds (I) are prepared using the intermediates (II) which, when R ⁵ in formula (II) is hydrogen, a) by reacting an amine of the formula (II) with a 3-isocyanato- or 3-isothiocyanatoalkane carboxylic acid ester of the formula (V) (see formula sheet), or if R ⁵ in formula (II) is hydrogen or alkyl, b) by reacting an amine of the formula (III) first with a compound of the formula (VI) (see formula sheet) to give an imidazole of the formula (VII) (see formula sheet), which is then reacted with a 3-aminoalkane carboxylic acid derivative of the formula (VIII ) (see formula sheet) as such or in the form of one of its acid addition salts, or c) by reacting an amine of the formula (III) with a carbamoyl halide of the formula (IX) (see formula sheet)
receives,
where in the above formulas R ¹ to R ^T , A, Q, X and Z have the aforementioned meaning. 9. Medicament consisting of at least one or containing at least one compound according to claims 1 to 5 or at least one compound prepared by the method according to claims 6 to 8 alone or in combination with conventional additives and / or other active ingredients. 10. Medicament according to claim 9 for the treatment of migraines.

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