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="EP0000718A2_D0001.tif" /></chemistry>where R¹ and _R² Hydrogen, lower alkyl, hydroxy, lower alkoxy, hydroxy lower alkyl, lower alkoxy lower alkyl, halogen, phenyl, phenoxy, amino, lower alkylamino or di-lower alkylamino, and R¹ and R² at adjacent carbon atoms also methylenedioxy together; R is hydrogen, lower alkyl or phenyl; and R 4 is lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, aryl lower alkyl or aryl, their tautomers and salts of such compounds.

0002The term "lower" used here preferably refers to residues with 1-6, in particular 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, lower alkyl, hydroxy and / or lower alkoxy.

0003Among the compounds of formula I, those which are in D-form are preferred. Also preferred are 3 the compounds of formula I, wherein R and R are hydrogen, R² Halogen in the 6- or 7-position or lower alkyl in the 6-position, in particular 6-chlorine, 7-bromo or 6-methyl, and _R⁴ lower alkyl, especially methyl, are preferred.

0004Are particularly preferred<ul id="ul0001" list-style="none"><li>D-6-chloro-1,5-dihydro-3-methyl-imidazo [2,1-b] chinazolin-2 (3H) -one,</li><li>D-1,5-dihydro-3,6-dimethyl-imidazo [2,1-b] quinazolin-2 (3H) -one,</li><li>D-7-bromo-l, 5-dihydro-3-methyl-imidazo [2, lb] chinazolin-2 (3H) -one</li></ul>and their salts.

0005Examples of compounds of formula I are<ul id="ul0002" list-style="none"><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] chinazolin-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</li></ul>and their salts.

0006The invention further relates to a process for the preparation of the compounds mentioned and pharmaceutical preparations based on the compounds mentioned.

0007The 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="EP0000718A2_D0002.tif" /></chemistry>and<chemistry id="chem0003" num="0003"><img file="EP0000718A2_D0003.tif" /></chemistry>

0008The compounds of the formula I and their tautomers, for example Ia 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.

0009Examples 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.

0010According to the invention, the compounds of the formula I and their tautomers can be prepared by<ul id="ul0003" list-style="none"><li>a) a compound of the formula<chemistry id="chem0004" num="0004"><img file="EP0000718A2_D0004.tif" /></chemistry>4th where R - _R⁴ have the above meaning and _R⁵ represents lower alkyl, reacted with cyanogen bromide, or</li><li>b) a compound of the formula<chemistry id="chem0005" num="0005"><img file="EP0000718A2_D0005.tif" /></chemistry>where R - _R⁵ have the above meaning treated with ammonia.</li></ul>

0011The reaction of a compound of formula II with cyanogen bromide is expediently 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.

0012A 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.

0013The compounds of formula I, 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 _R¹and _R² with the exception of optionally alkylated amino and R³ and R⁴ have the above meaning.

0014The compounds of the formula I can furthermore be prepared according to the formula scheme II given below, in which Z represents oxygen or sulfur, M ammonium, potassium or sodium and the remaining symbols have the above meaning.<chemistry id="chem0006" num="0006"><img file="EP0000718A2_D0006.tif" /></chemistry><chemistry id="chem0007" num="0007"><img file="EP0000718A2_D0007.tif" /></chemistry>

0015The compounds of formula II are new and as such are also the subject of the present invention.

0016The starting compounds of the formulas II and III can be according to the formula III given below, in which X represents halogen and the remaining symbols above _Bhave e-interpretation, or be prepared in analogy to the methods given in the examples.<chemistry id="chem0008" num="0008"><img file="EP0000718A2_D0008.tif" /></chemistry>

0017The compounds of the formula I, their tautomers and physiologically tolerable salts of such compounds are to be used as medicaments. For example, they inhibit the aggregation of blood platelets 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.

0018The compounds of the formula I 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, petroleum jelly, etc. contain. 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.

0019The aggregation-inhibiting effect was determined by the aggregometer method of BORN [Nature 194, 927 (1962)] and MICHAL and BORN [Nature 231, 220 <img file="EP0000718A2_D0009.tif" />proven. The maximum rate of aggregation was taken as the test parameter and the effective concentration (EC₅₀) determined from dose-response curves.

0020Human 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.

0021Rabbit 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.

0022The results are shown in Table I below.

0023The 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 rate of pressure rise (dLVP / dtmax) is calculated, which is considered a contractility parameter. At the same time, the heart rate is recorded on a cardiotachograph. Inotropy is the percentage. Change (Δ%) in dLVP / dt_Max and the duration of action in minutes (min). 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="EP0000718A2_D0010.tif" /></tables><tables id="tabl0002" num="0002"><img file="EP0000718A2_D0011.tif" /></tables>

0024The following examples illustrate the invention. The temperatures are given in ° C.

example 1

0025A solution of 5.3 g of cyanogen bromide in 10 ml of ethanol was added to a solution of 11.8 g of N- (2-amino-3-methylbenzyl) -L-alanine ethyl ester 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).

0026By 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.

0027The starting material was produced as follows:<ul id="ul0004" list-style="none"><li>A solution of 120 ml of 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>

0028A 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).

0029The following connections were made analogously:<ul id="ul0005" 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, [α]_D + 31.4 ° (c = 1% in methanol);</li><li>from α³-Chlor-4-nitro-m-xylene and L-alanine ethyl ester hydrochloride of N- (5-methyl-2_-nitrobenzyl) -L-alanine ethyl ester, red oil, [α]_D -12.6 ° (c = 1% in methanol);</li><li>from α³-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 α²-Chlor-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 α²-Chlor-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 α²-Chlor-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="EP0000718A2_D0012.tif" /></maths>;</li><li>from α-chloro-3-nitro-o-xylene and da-phenylglycine ethyl ester hydrochloride the N- (2-methyl-6-nitrobenzyl) -daphenylglycine ethyl ester, red oil, <maths id="math0002" num=""><img file="EP0000718A2_D0013.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-alaniri-ethyl ester hydrochloride the (2-nitrobenzyl) -D-alanine-ethyl ester, red oil, [a]_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-alanine ethyl ester of N- (2-amino-5-methylbenzyl) -L-alanine ethyl ester, [a]_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, [a]_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 ethyl ester, reddish oil, [α]_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, <maths id="math0003" num=""><img file="EP0000718A2_D0014.tif" /></maths>;</li><li>from N- (2-methyl-6-nitrobenzyl) -D-α-phenylglycine ethyl ester the N- (2-amino-6-methylbenzyl) -Da-phenylglycine ethyl ester, yellow oil, <maths id="math0004" num=""><img file="EP0000718A2_D0015.tif" /></maths>;</li><li>from (2-nitrobenzyl) -L-alanine ethyl ester of 2-aminobenzyl-L-alanine ethyl ester, red oil, [a]_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, [a]_D +57,2⁰ (c = 1% in ethanol).</li></ul>

Example 2

0030Analogously 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

0031Analogously to Example 1, N- (2-amino-5-. Methylbenzyl) -L-alanine ethyl ester was converted into L-1,5-dihydro-2,7-dimethyl-imidazo [2, lb] quinazolin-2 ( 3H) -one hydrochloride obtained. Light yellow crystals, melting point 173-176 °. The free base melts with decomposition above 300 °.

Example 4

0032In analogy to Example 1, N- (2-amino-5-methylbenzyl) -D_-alanine-ethyl ester obtained the D-1,5-dihydro-3,7-dimethyl-imidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride. Light yellow crystals, melting point 173-176⁰ (Dec.). The free base melts with decomposition at 310-314 °.

Example 5

0033Analogously to Example 1, N- (2-amino-6-methylbenzyl) -L-alanine ethyl ester was converted into L-1,5-dihydro-3,6-dimethyl-imidazo [2, lb] quinazolin-2 (3H ) -On hydrochloride obtained. Colorless crystals with a melting point of 285-288 ° (dec.). The free base melts above 340 ° with decomposition.

Example 6

0034Analogously to Example 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

0035Analogously 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 -2 (3H) -one hydrochloride obtained. Yellow crystals with melting point 320-325 ° (dec.).

Example 8

0036In analogy to Example 1, N- (2-amino-6-methylbenzyl) -Da-phenylglycine ethyl ester became the D-1,5-dihydro-3-phenyl-6-methyl-imidazo [2,1-b] quinazoline Obtained -2 ​​(3H) -one hydrochloride. Light yellow crystals with a melting point of about 320 ° (dec.).

Example 9

0037In analogy to Example 1, 2-amino-benzyl-L-alanine ethyl ester became L-1,5-dihydro-3-methyl-imidazo [2,1-b] -quinazolin-2 (3H) -one hydrochloride receive. Brown crystals with a melting point of 223-226 °. The free base melts at 300-305 ° with decomposition.

Example 10

0038In analogy to Example 1, 2-amino-benzyl-D-alanine ethyl ester became D-1,5-dihydro-3-methyl-imidazo [2,1-b] -quinazoline-2 (3H) -one hydrochloride receive. Yellow crystals with a melting point of 225-227 °. The free base melts at about 300 ° with decomposition.

Example 11

0039A 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 NH₄OH 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).

0040D-6-chloro-1,5-dihydro-3-methylimidazo [2,1-b] chinazolin-2 (3H) -one hydrochloride was analogously made from N- (2-amino-6-chlorobenzyl) -D -alanine ethyl ester obtained, mp. 263-266 °, [a]_D -23.9 ° (DMSO); Mp of free base 275-280 °.

0041The starting material can be produced as follows:<ul id="ul0006" 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="math0005" num=""><img file="EP0000718A2_D0016.tif" /></maths>.</li></ul>

0042N- (2-chloro-6-nitrobenzyl) -D-alanine ethyl ester was obtained analogously from ethyl D-alanine and a-bromo-2-chloro-6-nitrotoluene, <maths id="math0006" num=""><img file="EP0000718A2_D0017.tif" /></maths>.

0043A 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. 12.6 g (99% of theory) of N- (2-_Amino-6-chlorobenzyl) -L-alanine ethyl ester, <maths id="math0007" num=""><img file="EP0000718A2_D0018.tif" /></maths>.

0044N- (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="math0008" num=""><img file="EP0000718A2_D0019.tif" /></maths> .

Example 12

0045The following compounds were prepared in a manner analogous to Example 11:<ul id="ul0007" 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, mp.> 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] quinazolin-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

0046The following compounds were prepared in a manner analogous to Example 11:<ul id="ul0008" 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, [a]_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 ethyl N- (2-chloro-6-nitrobenzyl) -D-serine, [a]_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-l, 5-dihydro-imidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride, mp the base> 300 ° (dec.);</li><li>from DN- (2-chloro-6-nitrobenzyl) -2-phenylglycine ethyl ester, [a]_D -21 ° (c = 1% in ethanol), via DN- (2-amino-6-chlorobenzyl) -2-phenylglycine ethyl ester, [a]_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

0047A mixture of 6 g of ethyl-D-2,5-dichlor_-a-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-methylimidazo [2,1-b] -quinazolin-2 (3H) -one hydrochloride recrystallized (4.3 g, 74% of theory), mp. 275-278 °.

0048The starting material can be produced as follows:<ul id="ul0009" 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 °. 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 left at 80 overnight⁰ stirred, then evaporated to dryness, the residue was mixed with 150 ml of ion-free water and 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="math0009" num=""><img file="EP0000718A2_D0020.tif" /></maths>; [a]_D -6.9 ° (c = 1%, C₂H₅OH).</li></ul>

0049A 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. 12.6 g (99% of theory) of N- (2-amino-6-chlorobenzyl) -D-alanine ethyl ester were obtained,<maths id="math0010" num=""><img file="EP0000718A2_D0021.tif" /></maths> , [α]_D + 55.8 ° (c ⁼ 1%, C₂H₅OH).

005052 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-a-methyl-2-oxo-3 (2H) -quinazoline acetate,<maths id="math0011" num=""><img file="EP0000718A2_D0022.tif" /></maths> -40.8 ° (c = 1%, C₂H_SOH).

005150.9 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-α-methyl-3 (4H) -quinazoline acetate,<maths id="math0012" num=""><img file="EP0000718A2_D0023.tif" /></maths>.

Example 15

00521.5 ml of bromine are added dropwise to a solution of 5 g of DI, 5-dihydro-3-methylimidazo [2, lb] quinazolin-2 (3H) -one in 80 ml of glacial acetic acid. 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] quinazolin-2 (3H) -one hydrochloride, mp. 268-270 °.

Example 16

0053In 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] chinazolin-2 (3H) -one hydrochloride, mp. 280-284 ° (dec.) Brominated.

Example 17

0054Tablets of the following composition are produced in the usual way:<tables id="tabl0003" num="0003"><img file="EP0000718A2_D0024.tif" /></tables>

Example 18

0055Gelatin capsules of the following composition are produced in the usual way:<tables id="tabl0004" num="0004"><img file="EP0000718A2_D0025.tif" /></tables>

Example 19

0056A solution for injection of the following composition is prepared in the usual way:<tables id="tabl0005" num="0005"><img file="EP0000718A2_D0026.tif" /></tables>