Quinazoline derivatives, process for their preparation, pharmaceutical preparations and their preparation

0001The present invention relates to new tricyclic compounds, namely imidazo-quinazolines of the formula<chemistry id="chem0001" num="0001"><img file="EP0000718B1_D0001.tif" /></chemistry>wherein R 'and R² 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 at adjacent carbon atoms also methylenedioxy together; R³ Hydrogen, C_1-6-Alkyl or phenyl; and R⁴ C._1-6-Alkyl, hydroxy-C_1-6-alkyl, C_1-6-Alkoxy-C_1-6-alkyl, aryl-C_1-6- mean 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.

0002Alkyl 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 by halogen, C._1-6-Alkyl, hydroxy and / or C._1-6-Alkoxy substituted phenyl.

0003Among the compounds of the formula are<ul id="ul0001" list-style="none"><li>D-6-chloro-1,5-dihydro-3-methyl-imidazo [2,1-b] quinazolin-2 (3H) -one and their salts are preferred. Examples of compounds of formula 1 are</li><li>D-1,5-dihydro-3,6-dimethyl-imidazo [2,1-b] quinazolin-2 (3H) -one,</li><li>D-7-bromo-1,5-dihydro-3-methylimidazo [2,1-b] quinazolin-2 (3H) -one,</li><li>L-6-chloro-1,5-dihydro-3-hydroxymethyl-imidazo [2,1-b] quinazolin-2 (3H) -one,</li><li>L-6-chloro-1,5-dihydro-3-phenyl-imidazo [2,1-b] quinazolin-2 (3H) -one,</li><li>L-6-chloro-1,5-dihydro-3-isobutyl-imidazo [2,1-b] quinazolin-2 (3H) -one,</li><li>L-3-benzyl-6-chloro-1,5-dihydro-imidazo [2,1-b] quinazolin-2 (3H) -one and its salts.</li></ul>

0004The invention further relates to a process for the preparation of the compounds mentioned and pharmaceutical preparations based on the compounds mentioned.

0005The 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<chemistry id="chem0002" num="0002"><img file="EP0000718B1_D0002.tif" /></chemistry>

0006The compounds of the formula I and their tautomers, for example la and Ib, can furthermore be present in the form of racemates or in optically active form, all of which are the subject of the invention.

0007Examples of physiologically acceptable 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.

0008According to the invention, the compounds of the formula I and their tautomers can be prepared by<ul id="ul0002" list-style="none"><li>a) a compound of the formula<chemistry id="chem0003" num="0003"><img file="EP0000718B1_D0003.tif" /></chemistry>wherein R'-R⁴ have the above meaning and R⁵ C._1-6Represents alkyl, reacted with cyanogen bromide, or</li><li>b) a compound of the formula<chemistry id="chem0004" num="0004"><img file="EP0000718B1_D0004.tif" /></chemistry>wherein R'-R⁵ have the above meaning treated with ammonia.</li></ul>

0009The reaction of a compound of formula II with bromo-cyan is conveniently carried out with heating in a solvent such as a lower alcohol, for example ethanol. The reaction of a compound of formula III with ammonia is expediently carried out with heating in a solvent, such as a lower alcohol, for example ethanol, and water.

0010A compound of formula I, wherein R¹ and / or R² Is hydrogen, can be halogenated in a conventional manner. For example, a solution of a compound unsubstituted in positions 6, 7, 8 and 9 in acetic acid can be reacted with bromine to give the 7-bromo compound.

0011The compounds of the formula wherein R¹ and R² differ from an optionally alkylated amino group, can be prepared according to the formula scheme I given below, wherein Y represents chlorine or bromine, R¹¹ and R²¹ have the same meanings as R¹ and R² with the exception of optionally alkylated amino and R³ and R⁴ have the above meaning.

0012The 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.<chemistry id="chem0005" num="0005"><img file="EP0000718B1_D0005.tif" /></chemistry><chemistry id="chem0006" num="0006"><img file="EP0000718B1_D0006.tif" /></chemistry>

0013The compounds of formula II are new.

0014The 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.<chemistry id="chem0007" num="0007"><img file="EP0000718B1_D0007.tif" /></chemistry>

0015The compounds of the formula I, their tautomers and physiologically tolerable salts of such compounds are to be used as medicaments. For example, they inhibit platelet aggregation and can therefore be used to prevent thrombosis. They are also effective in 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.

0016The compounds of the formula and their tautomers can be used as medicaments, for example 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 water, gelatin, Gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, Vaseline @, etc. included. The pharmaceutical preparations can be in solid form, for example as tablets, dragees, suppositories, capsules; in semi-solid form, for example as ointments; or in liquid form, for example 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.

0017The 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 (EC₅₀) determined from dose-response curves. @ Trademark

0018Human 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., after which the aggregation was initiated by adding 10 μl of collagen-fibril suspension.

0019Rabbit 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 were added. Plasma incubated with dimethyl sulfoxide was used as a control value.

0020The results are shown in Table I below.

0021The 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) calculates what counts as 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. Tachycardia shows the percentage changes in heart rate (Δ%) after administration of the test substance and the duration of action in minutes (min). The results are shown in Table II below.<tables id="tabl0001" num="0001"><img file="EP0000718B1_D0008.tif" /></tables><tables id="tabl0002" num="0002"><img file="EP0000718B1_D0009.tif" /></tables>

0022The following examples illustrate the invention. The temperatures are given in ° C.

example 1

0023A 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).

0024By 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.

0025The starting material was produced as follows:<ul id="ul0003" list-style="none"><li>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).</li></ul>

0026A 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).

0027The following connections were made analogously:<ul id="ul0004" list-style="none"><li>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);</li><li>from a^3-Chloro-4-nitro-m-xylene and L-alanine ethyl ester hydrochloride of N- (5-methyl-2-nitrobenzyl) -L-alanine ethyl_ter, red oil, [a] p - 12.6 ° (c = 1% in methanol);</li><li>from a^3-Chloro-4-nitro-m-xylene and D-alanine ethyl ester_-hydrochloride of N- (5-methyl-2-nitrobenzyl) -D-alanine ethyl ester, red oil, [α]_D + 11.4 ° (c = 1% in methanol);</li><li>from a^2-Chloro-3-nitro-o-xylene and L-alanine ethyl ester hydrochloride of N- (2-methyl-6-nitrobenzyl) -L-alanine ethyl ester, red oil, [α]_D + 35.8 ° (c = 1% in methanol);</li><li>from a^2-Chloro-3-nitro-o-xylene and D-alanine ethyl ester hydrochloride of N- (2-methyl-6-nitrobenzyl) -D-alanine ethyl ester, red oil, [α]_D - 34 ° (c = 1% in methanol);</li><li>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, <maths id="math0001" num=""><img file="EP0000718B1_D0010.tif" /></maths>;</li><li>from a^2-Chloro-3-nitro-o-xylene and da-phenylglycine ethyl ester hydrochloride of the N- (2-methyl-6-nitrobenzyl) -da-phenylglycine ethyl ester, red oil, <maths id="math0002" num=""><img file="EP0000718B1_D0011.tif" /></maths>;</li><li>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);</li><li>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);</li><li>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);</li><li>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);</li><li>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);</li><li>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);</li><li>from N- (2-methyl-6-nitrobenzyl) -D-alanine ethyl ester of N- (2-amino-6-methylbenzyl) -D-alanine_thylester, reddish oil, [a]_D + 36.8 ° (c = 1% in methanol);</li><li>from N- (2-methyl-6-nitrobenzyl) -L-serine ethyl ester the N- (2-amino-6-methylbenzyl) -L-serine ethyl ester, red oil, n²⁴_D = 1,5468;</li><li>from N- (2-methyl-6-nitrobenzyl) -Da-phenylglycine-ethyl ester the N- (2-amino-6-methylbenzyl) -D-α-phenylglycine-ethyl ester, yellow oil, <maths id="math0003" num=""><img file="EP0000718B1_D0012.tif" /></maths>;</li><li>from (2-nitrobenzyl) -L-alanine ethyl ester of 2-aminobenzyl-L-alanine ethyl ester, red oil, [α]_D- 55.1 ° (c = 1% in ethanol);</li><li>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).</li></ul>

Example 2

0028Analogously 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

0029Analogously to Example 1, N- (2-amino-5-methylbenzyl) -L-alanine ethyl ester became 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

0030Analogously 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

0031In analogy to example 1, N- (2-amino-6-methylbenzyl) -L-alanine ethyl ester became the 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

0032In 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

0033Analogously 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

0034In analogy 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

0035Analogously 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

0036In analogy 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

0037A 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. Then the reaction mixture was boiled under reflux for 1 hour, evaporated to dryness, 150 ml of water were added to the residue and, with stirring, 3N NH₄0H made alkaline. 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).

0038D-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 free base 275-280 °.

0039The starting material can be produced as follows:<ul id="ul0005" list-style="none"><li>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) were obtained,<maths id="math0004" num=""><img file="EP0000718B1_D0013.tif" /></maths>.</li></ul>

0040N- (2-chloro-6-nitrobenzyl) -D-alanine ethyl ester was obtained analogously from ethyl D-alanine and a-bromo-2-chloro-6-nitrotoluene, <maths id="math0005" num=""><img file="EP0000718B1_D0014.tif" /></maths>.

0041A 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, n2² 1,5430.

0042N- (2-amino-6-chlorobenzyl) -D-alanine ethyl ester was obtained analogously by hydrogenation of N- (2-chloro-6-nitrobenzyl) -D-alanine ethyl ester, <maths id="math0006" num=""><img file="EP0000718B1_D0015.tif" /></maths>.

Example 12

0043The following compounds were prepared in a manner analogous to Example 11:<ul id="ul0006" list-style="none"><li>D-6,7-dichloro-1,5-dihydro-3-methylimidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride, mp> 280 °,</li><li>L-6,7-dichloro-1,5-dihydro-3-methylimidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride, m.p. _>290°,</li><li>D-7-bromo-1,5-dihydro-3-methylimidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride, mp. 268-270 °,</li><li>L-7-bromo-1,5-dihydro-3-methylimidazo [2,1-b] quinazoiin-2 (3H) -one hydrochloride, mp. 280-284 ° (dec.),</li><li>L-6-chloro-7-methoxy-1,5-dihydro-3-methylimidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride, mp> 280 °.</li></ul>

Example 13

0044The following compounds were prepared in a manner analogous to Example 11:<ul id="ul0007" list-style="none"><li>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.);</li><li>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 °:</li><li>from N- (2-chloro-6-nitrobenzyl) -D-serine ethyl ester, [α]_D 2.7 ° (c = 1% in ethanol), over 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.);</li><li>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] quinazolin-2 (3H) -one hydrochloride, mp. _>300 ° (dec.); Mp of base 260-265 ° (dec.).</li></ul>

Example 14

0045A 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 ° overnight in a pressure tube . 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 °.

0046The starting material can be produced as follows:<ul id="ul0008" list-style="none"><li>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,<maths id="math0007" num=""><img file="EP0000718B1_D0016.tif" /></maths>; [α]_D - 6.9 ° (c = 1%, C₂H₅OH).</li></ul>

0047A 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 N- (2-amino-6-chlorobenzyl) -D-alanine ethyl ester, ng³ 1.5405, [α]_D + 55.8 ° (c = 1%, C₂H₅OH).

004852 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,<maths id="math0008" num=""><img file="EP0000718B1_D0017.tif" /></maths> (c = 1%, C₂H₅OH).

004950.9 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, np² 1,5775.

Example 15

0050A 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, with_3N Ammonium hydroxide made alkaline, 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

0051In 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

0052Tablets of the following composition are produced in the usual way:<tables id="tabl0003" num="0003"><img file="EP0000718B1_D0018.tif" /></tables>

Example 18

0053Gelatin capsules of the following composition are produced in the usual way:<tables id="tabl0004" num="0004"><img file="EP0000718B1_D0019.tif" /></tables>

Example 19

0054A solution for injection of the following composition is prepared in the usual way:<tables id="tabl0005" num="0005"><img file="EP0000718B1_D0020.tif" /></tables>