EP0000718B1 - Quinazoline derivatives, process for their preparation, pharmaceutical preparations and their preparation - Google Patents

Description

worin R' und R² Wasserstoff, C_1-6-Alkyl, Hydroxy, C_1-6-Alkoxy, Hydroxy-C_1-6-alkyl, C_1-6-Alkoxy-C_1-6-alkyl, Halogen, Phenyl, Phenoxy, Amino, C_1-6-Alkylamino oder di-C_1-6-Alkylamino, und R¹ und R² an benachbarten Kohlenstoffatomen auch gemeinsam Methylendioxy; R³ Wasserstoff, C_1-6-Alkyl oder Phenyl; und R⁴ C_1-6-Alkyl, Hydroxy-C_1-6-alkyl, C_1-6-Alkoxy-C_1-6-alkyl, Aryl-C_1-6- alkyl oder Aryl bedeuten,
deren Tautomere und Salze solcher Verbindungen. Im Gegensatz zu den aus der DE-A-2305575 bekannten Imidazochinazolinen enthalten die vorliegenden Imidazochinazoline einen Substituenten in 3-Stellung.The present invention relates to new tricyclic compounds, namely imidazo-quinazolines of the formula

wherein R 'and R ^{2 are} hydrogen, C _1-6 alkyl, hydroxy, C _1-6 alkoxy, hydroxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkyl, halogen, phenyl , Phenoxy, amino, C _1-6 alkylamino or di-C _1-6 alkylamino, and R ¹ and R ^{2 together} on adjacent carbon atoms also methylenedioxy; R ^{3 is} hydrogen, C _1-6 alkyl or phenyl; and R ^{4 is} C _1-6 alkyl, hydroxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkyl, arylC _1-6 alkyl or aryl,
their tautomers and salts of such compounds. In contrast to the imidazoquinazolines known from DE-A-2305575, the present imidazoquinazolines contain a substituent in the 3-position.

Alkyl and alkoxy radicals preferably contain 1-4 carbon atoms. Alkyl radicals can be straight-chain or branched. Examples of alkyl radicals are: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and hexyl. Aryl means in particular phenyl or phenyl substituted by halogen, C _1-6 -alkyl, hydroxy and / or C _1-6 -alkoxy.

• D-6-Chlor-1,5-dihydro-3-methyl-imidazo[2,1-b]chinazolin-2(3H)-on und deren Salze bevorzugt. Beispiele von Verbindungen der Formel 1 sind
• D-1,5-Dihydro-3,6-dimethyl-imidazo[2,1-b]chinazolin-2(3H)-on,
• D-7-Brom-1,5-dihydro-3-methyl-imidazo[2,1-b]chinazolin-2(3H)-on,
• L-6-Chlor-1,5-dihydro-3-hydroxymethyl-imidazo[2,1-b]chinazolin-2(3H)-on,
• L-6-Chlor-1,5-dihydro-3-phenyl-imidazo[2,1-b]chinazolin-2(3H)-on,
• L-6-Chlor-1,5-dihydro-3-isobutyl-imidazo[2,1-b]chinazolin-2(3H)-on,
• L-3-Benzyl-6-chlor-1,5-dihydro-imidazo[2,1-b]chinazolin-2(3H)-on und deren Salze.

Among the compounds of the formula are

• D-6-chloro-1,5-dihydro-3-methylimidazo [2,1-b] quinazolin-2 (3H) -one and their salts are preferred. Examples of compounds of formula 1 are
• D-1,5-dihydro-3,6-dimethyl-imidazo [2,1-b] quinazolin-2 (3H) -one,
• D-7-bromo-1,5-dihydro-3-methylimidazo [2,1-b] quinazolin-2 (3H) -one,
• L-6-chloro-1,5-dihydro-3-hydroxymethyl-imidazo [2,1-b] quinazolin-2 (3H) -one,
• L-6-chloro-1,5-dihydro-3-phenyl-imidazo [2,1-b] quinazolin-2 (3H) -one,
• L-6-chloro-1,5-dihydro-3-isobutyl-imidazo [2,1-b] quinazolin-2 (3H) -one,
• L-3-benzyl-6-chloro-1,5-dihydro-imidazo [2,1-b] quinazolin-2 (3H) -one and their salts.

The invention further relates to a process for the preparation of the compounds mentioned and pharmaceutical preparations based on the compounds mentioned.

The compounds of formula I can exist in various tautomeric forms. The invention is therefore not limited to compounds of the formula I shown above, but also includes the tautomers, for example those of the formula

The compounds of formula I and their tautomers, e.g. la and Ib can also be in the form of racemates or in optically active form, all of which are the subject of the invention.

Examples of physiologically compatible salts are mineral acid salts, such as hydrochlorides, hydrobromides, sulfates and phosphates; Salts of organic sulfonic acids such as alkyl sulfates and aryl sulfonates; and carboxylic acid salts such as succinates, citrates, tartrates and maleates.

• a) eine Verbindung der Formel
  
  worin R'-R⁴ die obige Bedeutung haben und R⁵ C_1-6-Alkyl darstellt,
  mit Bromcyan umsetzt, oder
• b) eine Verbindung der Formel
  
  worin R'-R⁵ die obige Bedeutung haben,
  mit Ammoniak behandelt.

According to the invention, the compounds of the formula I and their tautomers can be prepared by

• a) a compound of the formula
  
  wherein R'-R ⁴ are as defined above and R ^{5 is} C _1-6 alkyl,
  reacted with cyanogen bromide, or
• b) a compound of the formula
  
  in which R'-R ^{5 have} the above meaning,
  treated with ammonia.

The reaction of a compound of formula II with bromo-cyan is conveniently carried out with heating in a solvent such as a lower alcohol, e.g. Ethanol performed. The reaction of a compound of formula III with ammonia is conveniently carried out with heating in a solvent such as a lower alcohol, e.g. Ethanol, and water.

A compound of the formula I in which R ¹ and / or R ^{2 is} hydrogen can be halogenated in a manner known per se. For example, a solution of a compound which is unsubstituted in positions 6, 7, 8 and 9 in acetic acid can be reacted with bromine to give the 7-bromo compound.

The compounds of the formula in which R ¹ and R ² are different from an optionally alkylated amino group can be prepared according to formula scheme I given below, in which Y is chlorine or bromine, R ¹¹ and R ^{21 have} the same meanings as R ¹ and R ² with the exception of optionally alkylated amino and R ³ and R ^{4 have the} above meaning.

The compounds of the formula I can furthermore be prepared according to the formula scheme given below, in which Z represents oxygen or sulfur, M ammonium, potassium or sodium and the remaining symbols have the above meaning.

The compounds of formula II are new.

The starting compounds of the formulas II and III can be prepared according to the formula III given below, in which X represents halogen and the remaining symbols have the meaning given above, or in analogy to the methods given in the examples.

The compounds of the formula I, their tautomers and physiologically tolerable salts of such compounds are to be used as medicaments. They inhibit e.g. platelet aggregation and can therefore be used to prevent thrombosis. They are also effective for the circulation. Because of their positive inotropic effect, they can be used without significant tachycardia for the treatment and prophylaxis of heart failure and heart failure.

The compounds of the formula and their tautomers can be used as medicaments e.g. in the form of pharmaceutical preparations which they or their salts are mixed with a pharmaceutical, organic or inorganic inert carrier material suitable for enteral, percutaneous or parenteral administration, such as e.g. Contain water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, Vaseline @, etc. The pharmaceutical preparations can be in solid form, e.g. as tablets, dragees, suppositories, capsules; in semi-solid form, e.g. as ointments; or in liquid form, e.g. as solutions, suspensions or emulsions. If necessary, they are sterilized and / or contain auxiliary substances, such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers. They can also contain other therapeutically valuable substances. Oral administration of the compounds according to the invention is preferred. For adults, an oral daily dose of 0.5 to 30 mg / kg and a parenteral daily dose of 0.05 to 10 mg / kg are possible.

The aggregation-inhibiting effect was demonstrated by the aggregometer method of BORN [Nature 194, 927 (1962)] and MICHAL and BORN [Nature 231, 220 (1971)]. The maximum rate of aggregation was taken as the test parameter and the effective concentration (EC ₅₀ ) was determined from dose-response curves.
@ Trademark

Human plasma was obtained from venous blood decomposed with citrate (10.6 mM) by centrifugation. 0.18 ml of plasma were mixed with 10 μl of aqueous suspension of the test compounds, incubated for 10 minutes at 37 ° C., whereupon the aggregation was initiated by adding 10 μl of collagen-fibril suspension.

Rabbit plasma was obtained from arterial blood decomposed with citrate (9 mM) by centrifugation. 1 ml of plasma was mixed with 10 μl of test solution and incubated for 1 minute at 37 ° C., whereupon 8 μl of collagen fibril suspension or 10 μl of adenosine diphosphate (ADP) in 10 ⁻⁴ M saline solution were added. Plasma incubated with dimethyl sulfoxide was used as a control value.

The results are shown in Table I below.

The positive inotropic effect was measured after oral administration of the test substances to awake German shepherds. For this purpose, the animals are equipped with an implanted pressure telemetry system, the pressure sensor being fixed in the left ventricle. The left ventricular pressure is transmitted from the animal via the implanted radio transmitter and received, demodulated and amplified via a suitable antenna and receiver system. By differentiating the increasing leg of the left ventricular pressure (LVP), the maximum pressure rise rate (dLVP / dt _max ) is calculated, which is considered a contractility parameter. At the same time, the heart rate is recorded on a cardiotachograph. The percentage change (Δ%) of dLVP / dt and the duration of action in minutes (min) are given under inotropy. The percentage changes in heart rate (Δ%) after administration of the test substance and the duration of action in minutes (min) are given under tachycardia. The results are shown in Table II below.

The following examples illustrate the invention. The temperatures are given in ° C.

example 1

A solution of 5.3 g of cyanogen bromide in 10 ml of ethanol was added to a solution of 11.8 g of ethyl N- (2-amino-3-methylbenzyl) -L-alanine in 30 ml of ethanol at room temperature with stirring. The reaction mixture was heated to reflux for 1 hour and then evaporated to dryness under reduced pressure. The residue was mixed with 100 ml of water and made alkaline by adding 3 N ammonium hydroxide with stirring. The mixture was then stirred for a further 30 minutes and extracted three times with 100 ml of methylene chloride each time. The organic extracts were washed twice with 150 ml of water, dried over sodium sulfate and evaporated. The residue was recrystallized from ethanol and gave L-1,5-dihydro-3,9-dimethylimidazo [2,1-b] -quinazolin-2 (3H) -one, melting point 259-261 °, [α] _D + 15 , 5 ° (C = 1% in methanol).

By recrystallization of the base thus obtained from 1 N hydrochloric acid and acetonitrile (3: 1), the hydrochloride with a melting point of 272-275 ° (decomp.) Was obtained.

• Zu einer Lösung von 91,8 g L-Alanin-äthylester-hydrochlorid in 300 ml absolutem Aethanol wurde innerhalb von 30 Minuten eine Lösung von 120 Triäthylamin in 200 ml absolutem Aethanol getropft. Das Reaktionsgemisch wurde auf 60° erwärmt, wobei eine klare Lösung entstand. Zu dieser Lösung wurde innerhalb 1 Stunde eine Lösung von 55,5 g 3-(Chlormethyl)-2-nitrotoluol in 300 ml absolutem Aethanol getropft. Danach wurde die Temperatur auf 80° erhöht und das Reaktionsgemisch über Nacht bei dieser Temperatur gerührt. Danach wurde unter vermindertem Druck zur Trockene eingedampft und der Rückstand in 600 ml Wasser gelöst. Die Lösung wurde dreimal mit Methylenchlorid extrahiert und die Extrakte wurden nacheinander mit Wasser und mit gesättigter Natriumchloridlösung gewaschen, getrocknet und eingedampft. Das so erhaltene Rohprodukt wurde durch Chromatographie an Kieselgel mit Methylenchlorid/5% Methanol als Laufmittel gereinigt. Man erhielt N-(3-Methyl-2-nitrobenzyl)-L-alanin-äthylester als gelbes Oel, [α]_D - 36° (C = 1 % in Methanol).

The starting material was produced as follows:

• A solution of 120 triethylamine in 200 ml of absolute ethanol was added dropwise to a solution of 91.8 g of L-alanine ethyl ester hydrochloride in 300 ml of absolute ethanol within 30 minutes. The reaction mixture was heated to 60 °, a clear solution being formed. A solution of 55.5 g of 3- (chloromethyl) -2-nitrotoluene in 300 ml of absolute ethanol was added dropwise to this solution within 1 hour. The temperature was then raised to 80 ° and the reaction mixture was stirred at this temperature overnight. The mixture was then evaporated to dryness under reduced pressure and the residue was dissolved in 600 ml of water. The solution was extracted three times with methylene chloride and the extracts were washed successively with water and with saturated sodium chloride solution, dried and evaporated. The crude product thus obtained was purified by chromatography on silica gel using methylene chloride / 5% methanol as the eluent. N- (3-methyl-2-nitrobenzyl) -L-alanine ethyl ester was obtained as a yellow oil, [α] _D - 36 ° (C = 1% in methanol).

A solution of 26.6 g of ethyl N- (3-methyl-2-nitrobenzyl) -L-alanine in 100 ml of absolute ethanol was hydrogenated in the presence of 2 g of 10% Pd / C. 6.7 l of hydrogen were taken up in 5 hours. After the hydrogenation had ended, the catalyst was filtered off and the filtrate was evaporated to dryness. N- (2-Amino-3-methylbenzyl) -L-alanine ethyl ester was obtained as a yellow oil, [α] _D - 52.6 ° (C = 1% in methanol).

• aus 3-(Chlormethyl)-2-nitrotoluol und D-Alanin-äthylester-hydrochlorid der N-(3-methyl-2-nitrobenzyl)-D-alanin-äthylester, gelbes Oel, [a]_o + 31,4° (c = 1 % in Methanol);
• aus a^3-Chlor-4-nitro-m-xylol und L-Alanin-äthylester-hydrochlorid der N-(5-Methyl-2-nitrobenzyl)-L-alanin-äthyles_ter, rotes Oel, [a]p - 12,6° (c = 1% in Methanol);
• aus a^3-Chlor-4-nitro-m-xylol und D-Alanin-äthylester_-hydrochlorid der N-(5-Methyl-2-nitrobenzyl)-D-alanin-äthylester, rotes Oel, [α]_D + 11,4° (c = 1% in Methanol);
• aus a^2-Chlor-3-nitro-o-xylol und L-Alanin-äthylester-hydrochlorid der N-(2-Methyl-6-nitrobenzyl)-L-alanin-äthylester, rotes Oel, [α]_D + 35,8° (c = 1 % in Methanol);
• aus a^2-Chlor-3-nitro-o-xylol und D-Alanin-äthylester-hydrochlorid der N-(2-Methyl-6-nitrobenzyl)-D-alanin-äthylester, rotes Oel, [α]_D - 34° (c = 1 % in Methanol);
• aus a2-Chlor-3-nitro-o-xylol und L-Serin-äthylester-hydrochlorid der N-(2-Methyl-6-nitrobenzyl)-L-serin-äthylester, rotes Oel,
  
  ;
• aus a^2-Chlor-3-nitro-o-xylol und D-a-Phenylglycin-äthylester-hydrochlorid der N-(2-Methyl-6-nitrobenzyl)-D-a-phenylglycin-äthylester, rotes Oel,
  
  ;
• aus 2-Nitrobenzylchlorid und L-Alanin-äthylester-hydrochlorid der 2-Nitrobenzyl-L-alanin- äthylester, dunkelrotes Oel, [a]_D - 5,4° (c = 1 % in Aethanol);
• aus 2-Nitrobenzylchlorid und D-Alanin-äthylester-hydrochlorid der (2-Nitrobenzyl)-D-alanin- äthylester, rotes Oel, [α]_D + 5,4° (c = 1% in Aethanol);
• aus N-3-Methyl-2-nitrobenzyl-D-alanin-äthylester der N-(2-Amino-3-methylbenzyl)-D-alanin- äthylester, hellgelbes Oel, [α]_D +51 ° (c = 1% in Methanol);
• aus N-(5-Methyl-2-nitrobenzyl)-L-anilin-äthylester der N-(2-Amino-5-methylbenzyl)-L-alanin- äthylester, [α]_D - 45° (c = 1 % in Methanol);
• aus N-(5-Methyl-2-nitrobenzyl)-D-alanin-äthylester der N-(2-Amino-5-methylbenzyl)-D-alanin- äthylester, rotes Oel, [α]_D + 34,2° (c = 1% in Methanol);
• aus N-(2-Methyl-6-nitrobenzyl)-L-alanin-äthylester der N-(2-Amino-6-methylbenzyl)-L-alanin- äthylester, gelbes Oel, [α]_D- 34,7° (c = 1 % in Methanol);
• aus N-(2-Methyl-6-nitrobenzyl)-D-alanin-äthylester der N-(2-Amino-6-methylbenzyl)-D-alanin- ä_thylester, rötliches Oel, [a]_D + 36,8° (c = 1 % in Methanol);
• aus N-(2-Methyl-6-nitrobenzyl)-L-serin-äthylester der N-(2-Amino-6-methylbenzyl)-L-serin-äthylester, rotes Oel, n²⁴ _D = 1,5468;
• aus N-(2-Methyl-6-nitrobenzyl)-D-a-phenylglycin-äthylester der N-(2-Amino-6-methylbenzyl)-D-α-phenylglycin-äthylester, gelbes Oel,
  
  ;
• aus (2-Nitrobenzyl)-L-alanin-äthylester der 2-Aminobenzyl-L-alanin-äthylester, rotes Oel, [α]_D - 55,1 ° (c = 1% in Aethanol);
• aus 2-Nitrobenzyl-D-alanin-äthylester der 2-Aminobenzyl-D-alanin-äthylester, dunkelrotes Oel, [α]_D + 57,2° (c = 1 % in Aethanol).

The following connections were made analogously:

• from 3- (chloromethyl) -2-nitrotoluene and D-alanine ethyl ester hydrochloride the N- (3-methyl-2-nitrobenzyl) -D-alanine ethyl ester, yellow oil, [a] _o + 31.4 ° ( c = 1% in methanol);
• from a ^3- chloro-4-nitro-m-xylene and L-alanine ethyl ester hydrochloride the N- (5-methyl-2-nitrobenzyl) -L-alanine ethyl _t er, red oil, [a] p - 12.6 ° (c = 1% in methanol);
• from a ^3- chloro-4-nitro-m-xylene and D-alanine ethyl ester _- hydrochloride the N- (5-methyl-2-nitrobenzyl) -D-alanine ethyl ester, red oil, [α] _D + 11, 4 ° (c = 1% in methanol);
• from a ^2- chloro-3-nitro-o-xylene and L-alanine ethyl ester hydrochloride the N- (2-methyl-6-nitrobenzyl) -L-alanine ethyl ester, red oil, [α] _D + 35, 8 ° (c = 1% in methanol);
• from a ^2- chloro-3-nitro-o-xylene and D-alanine ethyl ester hydrochloride the N- (2-methyl-6-nitrobenzyl) -D-alanine ethyl ester, red oil, [α] _D - 34 ° (c = 1% in methanol);
• from a2-chloro-3-nitro-o-xylene and L-serine ethyl ester hydrochloride the N- (2-methyl-6-nitrobenzyl) -L-serine ethyl ester, red oil,
  
  ;
• from a ^2- chloro-3-nitro-o-xylene and da-phenylglycine ethyl ester hydrochloride the N- (2-methyl-6-nitrobenzyl) -da-phenylglycine ethyl ester, red oil,
  
  ;
• from 2-nitrobenzyl chloride and L-alanine ethyl ester hydrochloride the 2-nitrobenzyl L-alanine ethyl ester, dark red oil, [a] _D - 5.4 ° (c = 1% in ethanol);
• from 2-nitrobenzyl chloride and D-alanine ethyl ester hydrochloride the (2-nitrobenzyl) -D-alanine ethyl ester, red oil, [α] _D + 5.4 ° (c = 1% in ethanol);
• from N-3-methyl-2-nitrobenzyl-D-alanine ethyl ester of N- (2-amino-3-methylbenzyl) -D-alanine ethyl ester, light yellow oil, [α] _D +51 ° (c = 1% in methanol);
• from N- (5-methyl-2-nitrobenzyl) -L-aniline ethyl ester of N- (2-amino-5-methylbenzyl) -L-alanine ethyl ester, [α] _D - 45 ° (c = 1% in Methanol);
• from N- (5-methyl-2-nitrobenzyl) -D-alanine ethyl ester of N- (2-amino-5-methylbenzyl) -D-alanine ethyl ester, red oil, [α] _D + 34.2 ° ( c = 1% in methanol);
• from N- (2-methyl-6-nitrobenzyl) -L-alanine ethyl ester of N- (2-amino-6-methylbenzyl) -L-alanine ethyl ester, yellow oil, [α] _D - 34.7 ° ( c = 1% in methanol);
• of N- (2-methyl-6-nitrobenzyl) -D-alanine ethyl ester of N- (2-amino-6-methylbenzyl) -D-alanine ä _th yl ester, reddish oil, [a] _D + 36.8 ° (c = 1% in methanol);
• from N- (2-methyl-6-nitrobenzyl) -L-serine ethyl ester the N- (2-amino-6-methylbenzyl) -L-serine ethyl ester, red oil, n ²⁴ _D = 1.5468;
• from N- (2-methyl-6-nitrobenzyl) -Da-phenylglycine-ethyl ester of N- (2-amino-6-methylbenzyl) -D-α-phenylglycine-ethyl ester, yellow oil,
  
  ;
• from (2-nitrobenzyl) -L-alanine ethyl ester of 2-aminobenzyl-L-alanine ethyl ester, red oil, [α] _D - 55.1 ° (c = 1% in ethanol);
• from 2-nitrobenzyl-D-alanine ethyl ester of 2-aminobenzyl-D-alanine ethyl ester, dark red oil, [α] _D + 57.2 ° (c = 1% in ethanol).

Example 2

In analogy to Example 1, N- (2-amino-3-methylbenzyl) -D-alanine ethyl ester was used to convert D-1,5-dihydro-3,9-dimethylimidazo [2,1-b] quinazolin-2 (3H ) -On hydrochloride obtained. Melting point 270-275 ° (dec.). The free base melts at 262-265 ° ..

Example 3

Analogously to Example 1, N- (2-amino-5-methylbenzyl) -L-alanine ethyl ester became the L-1,5-dihydro-2,7-dimethyl-imidazo [2,1-b] quinazolin-2 Obtained (3H) -one hydrochloride. Light yellow crystals, melting point 173-176 °. The free base melts with decomposition above 300 °.

Example 4

In analogy to Example 1, N- (2-amino-5-methylbenzyl) -D-alanine ethyl ester became D-1,5-dihydro-3,7-dimethyl-imidazo [2,1-b] quinazolin-2 Obtained (3H) -one hydrochloride. Light yellow crystals, melting point 173-176 ° (dec.). The free base melts with decomposition at 310-314 °.

Example 5

In analogy to Example 1, N- (2-amino-6-methylbenzyl) -L-alanine ethyl ester became L-1,5-dihydro-3,6-dimethyl-imidazo [2,1-b] quinazolin-2 Obtained (3H) -one hydrochloride. Colorless crystals with a melting point of 285-288 ° (dec.). The free base melts above 340 ° with decomposition.

Example 6

In analogy to Examples 1, N- (2-amino-6-methylbenzyl) -D-alanine ethyl ester became D-1,5-dihydro-3,6-dimethyl-imidazo [2,1-b] quinazolin-2 Obtained (3H) -one hydrochloride. Light yellow crystals with a melting point of 287-290 ° (dec.). The free base melts above 340 °.

Example 7

In analogy to Example 1, N- (2-amino-6-methylbenzyl) -L-serine ethyl ester became L-1,5-dihydro-3-hydroxymethyl-6-methylimidazo [2,1-b] quinazoline Obtained -2 (3H) -one hydrochloride. Yellow crystals with melting point 320-325 ° (dec.).

Example 8

Analogously to Example 1, N- (2-amino-6-methylbenzyl) -D-α-phenylglycine ethyl ester was used to convert D-1,5-dihydro-3-phenyl-6-methylimidazo [2,1-b ] Quinazolin-2 (3H) -one hydrochloride obtained. Light yellow crystals with a melting point of about 320 ° (dec.).

Example 9

In analogy to Example 1, the L-1,5-dihydro-3-methylimidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride was obtained from 2-amino-benzyl-L-alanine ethyl ester . Brown crystals with a melting point of 223-226 °. The free base melts at 300-305 ° with decomposition.

Example 10

Analogously to Example 1, the D-1,5-dihydro-3-methylimidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride was obtained from 2-amino-benzyl-D-alanine ethyl ester . Yellow crystals with a melting point of 225-227 °. The free base melts at about 300 ° with decomposition.

Example 11

A solution of 5 g of cyanogen bromide in 20 ml of ethanol was added dropwise to a solution of 11.9 g of N- (2-amino-6-chlorobenzyl) -L-alanine ethyl ester in 20 ml of ethanol at room temperature with stirring. The reaction mixture was then boiled under reflux for 1 hour, evaporated to dryness, 150 ml of water were added to the residue and the mixture was made alkaline with 3N NH ₄ 0H while stirring. After stirring for 30 minutes, the precipitate was filtered off and recrystallized from 1N HCl and acetonitrile. 9.1 g (68% of theory) of L-6-chloro-1,5-dihydro-3-methylimidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride were obtained as yellow crystals of Mp 260-263 °, [α] _D + 34.2 ° (DMSO).

D-6-chloro-1,5-dihydro-3-methylimidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride was analogously made from N- (2-amino-6-chlorobenzyl) -D-alanine -ethyl ester obtained, mp. 263-266 °, [α] _D -23.9 ° (DMSO); Mp of the free base 275-280 °.

• 18,24 g L-Alaninäthylester-hydrochlorid in 60 ml Aethanol wurde eine Mischung von 25 ml_Triäthylamin in 60 ml Aethanol zugetropft und das Gemisch auf 80° erhitzt. Der entstandenen Lösung wurde bei dieser Temperatur eine Lösung von 15 g a-Brom-2-chlor-6-nitrotoluol in 60 ml Aethanol zugetropft. Das Gemisch wurde über Nacht bei 80° gerührt und dann zur Trockene eingedampft, der Rückstand mit 150 ml ionenfreiem Wasser versetzt und zweimal mit 100 ml Methylenchlorid extrahiert. Die Methylenchloridextrakte wurden mit Wasser gewaschen, getrocknet und eingedampft. Das so erhaltene Produkt wurde durch Chromatographie an Kieselgel mit Methylenchlorid/5% Methanol gereinigt. Man erhielt 15,75 g (91% d.Th.) N-(2-Chlor-6-nitrobenzyl-L-alaninäthylester,
  
  .

The starting material can be produced as follows:

• A mixture of 25 ml of triethylamine in 60 ml of ethanol was added dropwise to 18.24 g of L-alanine ethyl ester hydrochloride in 60 ml of ethanol, and the mixture was heated to 80 °. A solution of 15 g of a-bromo-2-chloro-6-nitrotoluene in 60 ml of ethanol was added dropwise to the resulting solution at this temperature. The mixture was stirred at 80 ° overnight and then evaporated to dryness, 150 ml of ion-free water were added to the residue and the mixture was extracted twice with 100 ml of methylene chloride. The methylene chloride extracts were washed with water, dried and evaporated. The product thus obtained was purified by chromatography on silica gel with methylene chloride / 5% methanol. 15.75 g (91% of theory) of ethyl N- (2-chloro-6-nitrobenzyl-L-alanine,
  
  .

.N- (2-chloro-6-nitrobenzyl) -D-alanine ethyl ester was obtained analogously from ethyl D-alanine and a-bromo-2-chloro-6-nitrotoluene,

.

A solution of 14.3 g of N- (2-chloro-6-nitrobenzyl) -L-alanine ethyl ester in 50 ml of absolute ethanol was hydrogenated in the presence of 1 g of Raney nickel. After the hydrogenation had ended, the catalyst was filtered off and the filtrate was evaporated to dryness. This gave 12.6 g (99% of theory) of N- (2-amino-6-chlorobenzyl) -L-alanine, n2 ² 1.5430.

.N- (2-amino-6-chlorobenzyl) -D-alanine ethyl ester was obtained analogously by hydrogenation of N- (2-chloro-6-nitrobenzyl) -D-alanine ethyl ester,

.

Example 12

• D-6,7-Dichlor-1,5-dihydro-3-methylimidazo[2,1-b]chinazolin-2(3H)-on-hydrochlorid, Smp. >280°,
• L-6,7-Dichlor-1,5-dihydro-3-methylimidazo[2,1-b]chinazolin-2(3H)-on-hydrochlorid, Smp. _>290°,
• D-7-Brom-1,5-dihydro-3-methylimidazo[2,1-b]chinazolin-2(3H)-on-hydrochlorid, Smp. 268-270°,
• L-7-Brom-1,5-dihydro-3-methylimidazo[2,1-b]chinazoiin-2(3H)-on-hydrochlorid, Smp. 280-284° (Zers.),
• L-6-Chlor-7-methoxy-1,5-dihydro-3-methylimidazo[2,1-b]chinazolin-2(3H)-on-hydrochlorid, Smp. >280°.

The following compounds were prepared in a manner analogous to Example 11:

• D-6,7-dichloro-1,5-dihydro-3-methylimidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride, mp.> 280 °,
• L-6,7-dichloro-1,5-dihydro-3-methylimidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride, mp. _> 290 °,
• D-7-bromo-1,5-dihydro-3-methylimidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride, mp. 268-270 °,
• L-7-bromo-1,5-dihydro-3-methylimidazo [2,1-b] quinazoiin-2 (3H) -one hydrochloride, mp. 280-284 ° (dec.),
• L-6-chloro-7-methoxy-1,5-dihydro-3-methylimidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride, mp> 280 °.

Example 13

• aus N-(2-Chlor-6-nitrobenzyl)-3-phenyl_-D-alanin-äthylester, [α]_D - 21,2° (c = 1 % in Aethanol) über N-(2-Amino-6-chlorbenzyl)-3-phenyl-D-alanin-äthylester, [α]_D + 40,7° (c = 1% in Aethanol), das D-3-Benzyl-6-chlor-1,5-dihydroimidazo[2,1-b]chinazolin-2(3H)-on-hydrochlorid Smp. 260-265° (Zers.); Smp. der Base 270-275° (Zers.);
• aus N-(2-Chlor-6-nitrobenzyl)-D-leucin-äthylester über N-(2-Amino-6-chlorbenzyl)-D-leucin- äthylester, [α]_D + 8,5° (c = 1% in Aethanol) das D-6-Chlor-1,5-dihydro-3-isobutylimidazo[2,1-b]-chinazolin-2(3H)-on-hydrochlorid, Smp. 290-293°; Smp. der Base 280-285°:
• aus N-(2-Chlor-6-nitrobenzyl)-D-serin-äthylester, [α]_D 2,7° (c=1% in Aethanol), über N-2-(Amino-6-chlorbenzyl)-D-serin-äthylester, Smp. 73­-75°, [a]_D + 65,5° (c = 1% in Aethanol) das D-6-Chlor-3-hydroxymethyl-1,5-dihydroimidazo[2,1-b]chinazolin-2(3H)-hydrochlorid, Smp. der Base _>300° (Zers.);
• aus D-N-(2-Chlor-6-nitrobenzyl)-2-phenylglycin-äthylester, [α]_D - 21° (c = 1 % in Aethanol), über D-N-(2-Amino-6-chlorbenzyl)-2-phenylglycin-äthylester, [α]_D - 4,5° (c = 1% in Aethanol) das D-6-Chlor-3-phenyl-1,5-dihydroimidazo[2,1-b]chinazolin-2(3H)-on-hydrochlorid, Smp. _>300° (Zers.); Smp. der Base 260-265° (Zers.).

The following compounds were prepared in a manner analogous to Example 11:

• from N- (2-chloro-6-nitrobenzyl) -3-phenyl _- D-alanine ethyl ester, [α] _D - 21.2 ° (c = 1% in ethanol) over N- (2-amino-6- chlorobenzyl) -3-phenyl-D-alanine ethyl ester, [α] _D + 40.7 ° (c = 1% in ethanol), the D-3-benzyl-6-chloro-1,5-dihydroimidazo [2, 1-b] quinazolin-2 (3H) -one hydrochloride mp 260-265 ° (dec.); Mp 270-275 ° (dec.);
• from N- (2-chloro-6-nitrobenzyl) -D-leucine ethyl ester via N- (2-amino-6-chlorobenzyl) -D-leucine ethyl ester, [α] _D + 8.5 ° (c = 1 % in ethanol) the D-6-chloro-1,5-dihydro-3-isobutylimidazo [2,1-b] -quinazolin-2 (3H) -one hydrochloride, mp. 290-293 °; Base 280-285 °:
• from N- (2-chloro-6-nitrobenzyl) -D-serine ethyl ester, [α] _D 2.7 ° (c = 1% in ethanol), via N-2- (amino-6-chlorobenzyl) -D -serine-ethyl ester, mp. 73-75 °, [a] _D + 65.5 ° (c = 1% in ethanol) the D-6-chloro-3-hydroxymethyl-1,5-dihydroimidazo [2,1- b] quinazoline-2 (3H) hydrochloride, mp. of the base _> 300 ° (dec.);
• from DN- (2-chloro-6-nitrobenzyl) -2-phenylglycine ethyl ester, [α] _D - 21 ° (c = 1% in ethanol), via DN- (2-amino-6-chlorobenzyl) -2- phenylglycine ethyl ester, [α] _D - 4.5 ° (c = 1% in ethanol) the D-6-chloro-3-phenyl-1,5-dihydroimidazo [2,1-b] quinazoline-2 (3H) -on-hydrochloride, mp. _> 300 ° (dec.); Mp of base 260-265 ° (dec.).

Example 14

A mixture of 6 g of ethyl-D-2,5-dichloro-α-methyl-3- (4H) -quinazoline acetate, 20 ml of absolute ethanol and 25 ml of 5% alcoholic ammonia was heated to 110 ° in a pressure tube overnight . The pressure tube was cooled in an ice bath and opened. The resulting crystal slurry was filtered off and washed with cold ethanol. The crystals obtained were dissolved in 1N hydrochloric acid and filtered. The filtrate was evaporated to dryness and the residue from 1N hydrochloric acid and acetonitrile as D-6-chloro-1,5-dihydro-3-methyl-imidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride recrystallized (4.3 g, 74% of theory), mp. 275-278 °.

• Einem Gemisch von 18, 24 g D-Alaninäthylester-hydrochlorid in 60 ml Aethanol wurde ein Gemisch von 25 ml Triäthylamin in 60 ml Aethanol zugetropft und das Reaktionsgemisch auf 80° erhitzt. Der entstandenen Lösung wurde bei dieser Temperatur eine Lösung von 15 g 2-Chlor-6-nitrobenzylbromid in 60 ml Aethanol zugetropft. Das Gemisch wurde über Nacht bei 80° gerührt, dann zur Trockene eingedampft, der Rückstand mit 150 ml ionenfreiem Wasser versetzt und zweimal mit 100 ml Methylenchlorid extrahiert. Die Methylenchloridextrakte wurden mit Wasser gewaschen, über Natriumsulfat getrocknet und eingedampft. Das so erhaltene Produkte wurde durch Chromatographie an Kieselgel mit Methylenchlorid/5% Methanol gereinigt. Man erhielt 16 g (93% d.Th.) N-(2-Chlor-6-nitrobenzyl)-D-alaninäthylester,
  
  ; [α]_D - 6,9° (c = 1 %, C₂H₅OH).

The starting material can be produced as follows:

• A mixture of 25 ml of triethylamine in 60 ml of ethanol was added dropwise to a mixture of 18.24 g of D-alanine ethyl ester hydrochloride in 60 ml of ethanol, and the reaction mixture was heated to 80.degree. A solution of 15 g of 2-chloro-6-nitrobenzyl bromide in 60 ml of ethanol was added dropwise to the resulting solution at this temperature. The mixture was stirred at 80 ° overnight, then evaporated to dryness, 150 ml of ion-free water were added to the residue and the mixture was extracted twice with 100 ml of methylene chloride. The methylene chloride extracts were washed with water, dried over sodium sulfate and evaporated. The product thus obtained was purified by chromatography on silica gel with methylene chloride / 5% methanol. 16 g (93% of theory) of N- (2-chloro-6-nitrobenzyl) -D-alanine ethyl ester were obtained,
  
  ; [α] _D - 6.9 ° (c = 1%, C ₂ H ₅ OH).

A solution of 14.3 g of N- (2-chloro-6-nitrobenzyl) -D-alanine ethyl ester in 50 ml of ethanol was hydrogenated in the presence of 1 g of Raney nickel. 3.35 l of hydrogen were taken up in 2 hours. The catalyst was then filtered off and the filtrate was evaporated to dryness. This gave 12.6 g (99% of theory) of ethyl N- (2-amino-6-chlorobenzyl) -D-alanine, ng ³ 1.5405, [α] _D + 55.8 ° (c = 1% , C ₂ H ₅ OH).

(c = 1 %, C₂H₅OH).52 g of N, N'-carbonyldiimidazole were added in portions to a solution of 71.75 g of N- (2-amino-6-chlorobenzyl) -D-alanine ethyl ester in 400 ml of dry tetrahydrofuran while gassing with nitrogen and stirring. The mixture was stirred for 2 hours and refluxed for 18 hours and evaporated to dryness and the residue extracted with 1500 ml of methylene chloride, the organic phase washed with twice 400 ml of 1N hydrochloric acid and then with 400 ml of water, dried and evaporated. The oil thus obtained was purified by chromatography on silica gel with methylene chloride / 5% methanol. Yield: 79 g (99% of theory) of ethyl D-5-chloro-1,4-dihydro-cr-methyl-2-oxo-3 (2H) quinazoline acetate,

(c = 1%, C ₂ H ₅ OH).

50.9 g of ethyl D-5-chloro-1,4-dihydro-α-methyl-2-oxo-3 (2H) -quinazoline acetate were dissolved in 135 ml of phosphorus oxychloride and heated to 110 ° for 3 hours with stirring. After cooling, the reaction mixture was evaporated to dryness, the residue was dissolved in 250 ml of chloroform, the solution was diluted with 300 ml of ice water and adjusted to pH 7-8 by dropwise addition of 40% sodium hydroxide. The chloroform phase was separated, dried and evaporated. The product was purified by chromatography on silica gel with methylene chloride / 5% methanol. Yield: 37.4 g (70% of theory) of ethyl D-2,5-dichloro-a-methyl-3 (4H) -quinazoline acetate, np ² 1.5775.

Example 15

A solution of 5 g of D-1,5-dihydro-3-methylimidazo [2,1-b] quinazolin-2 (3H) -one in 80 ml of glacial acetic acid. 1.5 ml of bromine are added dropwise. The mixture is stirred for 1 1/2 hours at room temperature, diluted with 100 ml of water, concentrated to 30 ml, diluted again with 100 ml of water, made alkaline with _3N ammonium hydroxide, washed and filtered. The precipitated product is washed with water and recrystallized from 100 ml of 2N HCl. 3.9 g (56%) of D-7-bromo-1,5-dihydro-3-methylimidazo [2,1-b] quinazoine-2 (3H) -one-hydrochloride, mp. 268-270 °.

Example 16

In a manner analogous to Example 15, 4.7 g of L-1,5-dihydro-3-methylimidazo [2,1-b] quinazolin-2 (3H) -one are converted into 4.2 g (64%) of L-7- Bromine-1,5-dihydro-3-methyl-imidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride, mp 280-284 ° (dec.) Brominated.

Example 17

Tablets of the following composition are produced in the usual way:

Example 18

Gelatin capsules of the following composition are produced in the usual way:

Example 19

A solution for injection of the following composition is prepared in the usual way:

Claims (9)

1. Compounds of the formula

wherein R¹ und R² signify hydrogen, C_1-6-alkyl, hydroxy, C -alkoxy, hydroxy-C_1-6-alkyl, C_1-6- alkoxy-C_1-6-alkyl, halogen, phenyl, phenoxy, amino, C_1-6-alkylamino or di-C_1-6-alkylamino, and R¹ and R² on adjacent carbon atoms also together signify methylenedioxy; R³ signifies hydrogen,

C_1-6-alkyl, C_1-6-alkoxy-C_1-6-alkyl, aryl-C_1-6-alkyl or aryl, and their tautomers as well as salts of such compounds.

2. D-6-Chloro-1,5-dihydro-3-methylimidazo[2,1-b]quinazolin-2(3H)-one and salts thereof.

3. A compound according to claim 1 or 2 as an agent for inhibiting blood platelet aggregation or for intensifying the heart contraction without substantial tachycardia.

4. Process for the manufacture of compounds of the formula

wherein R' und R² signify hydrogen, C_1-6-alkyl, hydroxy, C_1-6-alkoxy, hydroxy-C_1-6-alkyl, C_1-6- alkoxy-C_1-6 alkyl, halogen, phenyl, phenoxy, amino, C_1-6-alkylamino or di-C_1-6-alkylamino, and R¹ and R² on adjacent carbon atoms also together signify methylenedioxy; R³ signifies hydrogen, C_1-6-alkyl or phenyl; and R⁴ signifies C_1-6-alkyl, hydroxy-C_1-6-alkyl, C_1-6-alkoxy-C_1-6-alkyl, aryl-C_1-6-alkyl or aryl,
and their tautomers as well as of salts of such compounds, characterized by

a) reacting a compound of the formula

wherein R¹-R⁴ have the above significance and R⁵ represents C_1-6-alkyl, with cyanogen bromide, or

b) treating a compound of the formula

wherein R'-R⁵ have the above significance, with ammonia.

5. Process according to claim 4 for the manufacture of D-6-chloro-1,5-dihydro-3-methylimidazo[2,1-b]quinazolin-2(3H)-one and salts thereof.

6. Pharmaceutical preparation, characterized by a content of a compound of formula I in accordance with the definition in claim 1, a tautomer thereof or a physiologically compatible salt of such a compound.

7. Process for the manufacture of pharmaceutical preparations, characterized by mixing a compound of formula I in accordance with the definition in claim 1, a tautomer thereof or a physiologically compatible salt of such a compound as the active ingredient with non-toxic, inert, solid and liquid carriers which are usual in such preparations and which are suitable for therapeutic administration.