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

Start of patent duration: 1981 01 15 Longest possible duration:

@ Issued on: 1981 08 10 (72) Inventors:

@) Dependency: '

AT 363 479 @ pamphlets considered to delineate the prior art:

AT-PS 310758 DE-OS 2508543 DE-OS 2402454

- 2 No. 363479

The invention relates to a process for the preparation of novel tricyclic compounds, namely imidazo-quinazolines of the formula

<img file="AT363479B_D0001.tif" />

wherein 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 on adjacent carbon atoms also together methylenedioxy; R³

Hydrogen, lower alkyl or phenyl; and R "are lower-alkyl, hydroxy-lower-alkyl, lower-alkoxy-lower-alkyl, aryl-lower-alkyl or aryl, their tautomers and salts of such compounds.

The term "lower" as used herein preferably refers to radicals having 1 to 6, in particular 1 to 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 is in particular phenyl or phenyl substituted by halogen, lower-alkyl, hydroxy and / or lower-alkoxy.

Among the compounds of formula (I), those in D-form are preferred.

Preference is further given to the compounds of formula (I) wherein R is¹ and R³ Hydrogen, R² Halogen in the 6- or 7-position or lower-alkyl in the 6-position, in particular 6-chloro, 7-bromo or 6-methyl, and R¹* lower alkyl, especially methyl, are preferred.

Particularly preferred

D-6-Chloro-1, 5-dihydro-3-methyl-imidazo [2,1-b] quinazolin-2 (3H) -one

Dl, 5-Dihydro-3,5-dimethylimidazo [2,1-b] quinazolin-2 {3H) -one D-7-bromo-1,1,5-dihydro-3-methylimidazo [2,1- b] quinazolin-2 (3H) -one and its salts.

Examples of compounds of formula fl) are

L-6-chloro-1,5-dihydro-3-hydroxymethyl-imidazo [2,1-b] quinazolin-2 (3H) -one

L-6-chloro-l, 5-dihydro-3-phenyl-imidazo [2,1-b] quinazolin-2 (3H) -one L-6-chloro-1,5-dihydro-3-isobutyl-imidazo [2,1-b] quinazoline-2 (3H) -one L-3-benzyl-6-chloro-1,5-dihydro-imidazo [2,1-b] quinazolin-2 (3H) -one and its salts.

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

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

<img file="AT363479B_D0002.tif" />

(la) (lb)

- 3 No. 363479

The compounds of the formula (I) and their tautomers, for example (Ia) and (Ib), may furthermore be present in the form of racemates or in optically active form, all of which forms the subject of the invention.

Examples of physiologically acceptable salts are mineral acid salts such as hydrochlorides, hydroxides, 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.

The compounds of the formula (I) and their tautomers can be prepared according to the invention by reacting a compound of the formula

<img file="AT363479B_D0003.tif" />

wherein R¹ to R¹* have the above meaning and R⁵ If desired, a 6-, 7-, 8- and 9-unsubstituted compound of the formula (I) obtained is halogenated and, if desired, the compounds of the formula (I) thus obtained are converted into their salts.

The reaction of a compound of formula (II) with cyanogen bromide is conveniently carried out with heating in a solvent such as a lower alcohol, eg ethanol.

A compound of formula (I) wherein R is¹ and / or R² Is hydrogen, can be halogenated in a conventional manner. Thus, for example, a solution of a unsubstituted in the positions 6, 7, 8 and 9 compound in acetic acid with bromine to 7-bromine compound implement.

The starting compounds of the formula (II) can be prepared as shown below

Formula scheme I, wherein X is halogen and the remaining symbols have the above meaning, or are prepared in analogy to the methods given in the examples.

- 4 No. 363479

Formula Scheme I

<img file="AT363479B_D0004.tif" />

CHNHCHCOOR⁵

R³ R "

(II)

The compounds of the formula (I), their tautomers and physiologically tolerable salts of such compounds are to be used as medicaments. They inhibit, for example, the aggregation of platelets and can therefore be used to prevent thrombosis. In addition, they are 5 effective in circulation. Thus, due to their positive inotropic action, they can be used without significant tachycardia for the treatment and prophylaxis of heart failure and cardiac insufficiency.

The compounds of the formula (I) and their tautomers can be used as remedies, for example in the form of pharmaceutical preparations containing them or their salts in admixture with a suitable for enteral, percutaneous or parenteral administration pharmaceutical, organic 10 or inorganic inert carrier material, such as Water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, vaseline, etc. included. The pharmaceutical preparations may be in solid form, for example as tablets, dragees, suppositories, capsules; in semi-solid form, eg as ointments; or in liquid form, for example as solutions, suspensions or emulsions. If appropriate, they are sterilized and / or contain auxiliaries, such as preservatives, stabilizers, wetting agents or emulsifiers, Salts for changing the osmotic pressure or buffer. They may also contain other therapeutically valuable substances. Oral administration of the compounds of 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, (1962)] and Michal and Born [Nature 231, 220 (1971)]. The maximum aggregation rate was taken as the experimental parameter and the effective concentration (ED₅₀) out

- 5 No. 363479

Dose-response curves determined.

Human plasma was obtained from citrated (10.6 mM) decomposed venous blood by centrifugation. 0.18 ml of plasma were mixed with 10 μl of aqueous suspension of the test compounds, incubated at 37 ° C. for 10 minutes, whereupon the aggregation was initiated by addition of 10 μl of collagen-fibril 5 suspension.

Rabbit plasma was obtained from citrated (9 mM) decomposed arterial blood by centrifugation. 1 ml of plasma was spiked with 10 μl of test solution and incubated for 1 min at 37 ° C., after which 8 μl of collagen-fibril-suspenison or 10 μl of adenosine diphosphate (ADP) in 10 "¹¹ M saline solution was added. The control value was plasma incubated with dimethyl sulfoxide.

The results are shown in Table I below.

The positive inotropic effect was measured after oral administration of the test substances to awake sheep dogs. The animals are equipped for this purpose with an implanted pressure-telemetry system, wherein the pressure transducer is fixed in the left ventricle. Left ventricular pressure is transmitted from the animal via the implanted radio transmitter and received, demodulated and amplified via a suitable antenna 15 and receiver system. By differentiating the rising leg of left ventricular pressure (LVP), the maximum rate of pressure rise (dLVP / dt_Max), which is considered a contractility parameter. At the same time, the heart rate is recorded via a cardiotachograph. Under inotropy, the percentage change (Δ%) of dLVP / dt_Max and the duration of action is given in minutes. Tachycardia is the percentage change in heart rate (Δ%) after administration of the test substance and the duration of action in minutes. The results are given in Table II below.

Table I

Collagen and ADP-induced platelet aggregation

<td rowspan="2">connection</td><td colspan="2">Rabbit plasma</td><td>human plasma</td>

<td>collagen EC 50 pM</td><td>ADP EC 50 pM</td><td>collagen EC 50 pM</td>

<td>D1, 5-Dihydro-3,9-dimethyl-imidazo [2, 1b] quinazolin-2 (3H) -one hydrochloride</td><td>3.0</td><td>32</td><td>26</td>

<td>L1, 5-dihydro-3,9-dimethyl-imidazo [2,1-b] quinazoline-2 (3H) -one hydrochloride</td><td>18</td><td>60</td><td>49</td>

<td>Dl, 5-dihydro-3,7-dimethyl-imidazo [2,1-b] quinazolin-2 (3H) -one-hy dro chloride</td><td>3.1</td><td>19</td><td>3.4</td>

<td>Ll, 5-dihydro-3,7-dimethyl-imidazo [2, 1b] quinazolin-2 (3H) -one hydrochloride</td><td>22</td><td>77</td><td>33</td>

<td>D1, 5-Dihydro-3,6-dimethyl-imidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride</td><td>0.19</td><td>2.2</td><td>2.3</td>

<td>Ll, 5-dihydro-3,6-dimethyl-imidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride</td><td>0.93</td><td>11</td><td>6.2</td>

<td>Ll, 5-dihydro-3-hydroxymethyl-6-methylimidazo [2,1b] quinazolin-2 (3H) -one hydrochloride</td><td></td><td></td><td>14</td>

- 6 No. 363479

Table II

<td rowspan="2">connection</td><td rowspan="2">dose mg / kg</td><td colspan="2">Inotropie</td><td colspan="2">heart rate</td>

<td>Δ%</td><td>min</td><td>Δ%</td><td>min</td>

<td>D-6-chloro-1,1,5-dihydro-3-methyl-imidazo [2,1-b] quinazolin-2 (3H) -one-hydrochloride</td><td>5</td><td>93</td><td>145</td><td>28</td><td>115</td>

<td>Dl, 5-dihydro-3,6-dimethyl-imidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride</td><td>10</td><td>82</td><td>440</td><td>63</td><td>480</td>

<td>Ll, 5-dihydro-3,9-dimethyl-imidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride</td><td>10</td><td>43</td><td>120</td><td>16</td><td>100</td>

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

Example 1: 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, a solution of 5.3 g of cyanogen bromide in 10 ml of 5 ethanol given. The reaction mixture was heated at reflux for 1 h and then evaporated to dryness under reduced pressure. The residue was mixed with 100 ml of water and made alkaline by addition of 3N ammonium hydroxide while stirring. The mixture was then stirred for an additional 30 min and extracted three times with 100 ml each of methylene chloride. The organic extracts were washed twice with 150 ml of water, dried over sodium sulfate and evaporated. The residue was recrystallized from ethanol to afford LI, 5-dihydro-3,9-dimethylimidazo [2,1-b] quinazolin-2 (3H) -one, mp 259-261 °;

[A]_D + 15.5 ° (c = 1% in methanol);

Yield 88%.

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

The starting material was prepared as follows:

To a solution of 91.8 g of L-alanine ethyl ester hydrochloride in 300 ml of absolute ethanol was added dropwise within 30 min, a solution of 120 ml of triethylamine in 200 ml of absolute ethanol. The reaction mixture was heated to 60 ° to give a clear solution. To this solution was added dropwise within 1 h a solution of 55.5 g of 3- (chloromethyl) -2-nitrotoluene in 300 ml of absolute ethanol. Thereafter, the temperature was raised to 80 ° and the reaction mixture was stirred overnight at this temperature. It 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 with methylene chloride / 5% methanol as eluent. N- (3-methyl-2-nitrobenzyl) -L-alanine ethyl ester was obtained as a yellow oil;

[α] θ -36 ° (c = 1% in methanol).

A solution of 26.6 g of N- (3-methyl-2-nitrobenzyl) -L-alanine ethyl ester in 100 ml of absolute 30% ethanol was hydrogenated in the presence of 2 g of 10% Pd / C. In 5 hours, 6.7 liters of hydrogen were taken up. After completion of the hydrogenation, 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] θ -52.6 ° (c = 1% in methanol).

The following compounds were prepared analogously:

from 3- (chloromethyl) -2-nitrotoluene and D-alanine ethyl ester hydrochloride, the N- (3-methyl-2-nitrobenzyl) -D-alanine ethyl ester, yellow oil;

[α] θ + 31.4 ° (c = 1% in methanol);

from α ³Chloro-4-nitro-molybdenum and L-alanine ethyl ester hydrochloride of N- (5-methyl-2-nitroben7 no.363479 cyl) -L-alanine ethyl ester, red oil;

-12.6 ° (c - 1% in methanol);

from a³Chloro-4-nitro-m-xylene and D-alanine ethyl ester hydrochloride of N- (5-methyl-2-nitrobenzyl) -D-alanine ethyl ester, red oil;

⁵ ["] P + 11.4 ° (c = 1% in methanol);

from a²Chloro-3-nitro-o-xylene and L-alanine ethyl ester hydrochloride of N- (2-methyl-6-nitrobenzyl) -L-alanine ethyl ester, red oil;

[Α]_θ + 35.8 ° (c = 1% methanol);

from a²Chloro-3-nitro-o-xylene and D-alanine ethyl ester hydrochloride of N- (2-methyl-6-nitrobenzyl) -D-alanine ethyl ester, red oil;

[α] θ -34 ° (c = 1% in methanol) from α ²Chloro-3-nitro-o-xylene and L-serine ethyl ester hydrochloride of N- (2-methyl-6-nitrobenzyl) -L-serine ethyl ester, red oil;

ng = 1.5474;

from a ²Chloro-3-nitro-o-xylene and D-α-phenylglycine ethyl ester hydrochloride of N- (2-methyl-6-nitrobenzyl) -da-phenylglycine ethyl ester, red oil;

ng = 1.5261;

from 2-nitrobenzyl chloride and L-alanine ethyl ester hydrochloride, the 2-nitrobenzyl-L-alanine ethyl ester, dark red oil;

²⁰ [«]])" 5,4 ° (c = 1% in ethanol);

from 2-nitrobenzyl chloride and D-alanine ethyl ester hydrochloride of (2-nitrobenzyl) -D-alanine ethyl ester, red oil;

[α] θ + 5.4 ° (c = 1% in ethanol);

N-3-methyl-2-nitrobenzyl-D-alanine ethyl ester 25 ethyl ester, pale yellow oil;

+ 51 ° (c = 1% in methanol);

N- (2-amino-3-methylbenzyl) -D-alanine N- (2-amino-5-methylbenzyl) -L-alanine N- (2-amino-5-methylbenzyl) -D-alanine N- (2 -amino-6-methylbenzyl) -L-alanine^LJD of N- (5-methyl-2-nitrobenzyl) -L-alanine ethyl ester-ethyl ester;

[α] θ -45 "(c = 1% in methanol);

from N- (5-methyl-2-nitrobenzyl) -D-alanine ethyl ester

ethyl ester, red oil;

[α] θ + 34.2 ° (c = 1% in methanol); N- (2-methyl-6-nitrobenzyl) -L-alanine ethyl ester ethyl ester, yellow oil;

[o] -37.7 ° (c = 1% in methanol);

N- (2-methyl-6-nitrobenzyl) -D-alanine ethyl ester ethyl ester, reddish oil;

[A]_D + 36.8 ° (c = 1% in methanol);

N- (2-methyl-6-nitrobenzyl) -L-serine ethyl ester of N- (2-amino-6-methylbenzyl) -L-serine ethyl-ethyl ester, red oil;

ng = 1.5468;

N- (2-methyl-6-nitrobenzyl) -D-α-phenylglycine ethyl ester of N- (2-amino-6-methylbenzyl) -Da-phenylglycine ethyl ester, yellow oil;

ng = 1.5665;

from (2-nitrobenzyl) -L-alanine ethyl ester of 2-aminobenzyl-L-alanine ethyl ester, red oil;

[a] p -55.1 ° (c = 1% in ethanol);

from 2-nitrobenzyl-D-alanine-ethyl ester of 2-aminobenzyl-D-alanine-ethyl ester, dark red oil;

[α] θ + 57.2 ° (c = 1% in ethanol).

Example 2; In analogy to Example 1, from N- (2-amino-3-methylbenzyl) -D-alanine ethyl ester the Dl, 5-dihydro-3,9-dimethyl-imidazo [2,1-b] quinazolin-2 ( 3H) -one hydrochloride.

Melting point 270 to 275 ° (decomp.). The free base melts at 262 to 265 °.

Example 3: In analogy to Example 1, from N- (2-amino-5-methylbenzyl) -L-alanine ethyl ester the Ll, 5-dihydro-2,7-dimethyl-imidazo [2,1-b] quinazoline 2 (3H) -one hydrochloride. Hellder N- (2-amino-6-methylbenzyl) -D-alanine8

No. 363479 yellow crystals, melting point 173-176 °. The free base melts with decomposition over 300 °.

Example 4 In analogy to Example 1, N, N-2-amino-5-methylbenzyl-D-alanine ethyl ester was converted into the diol-5-dihydro-3,7-dimethylimidazo [2,1-b] quinazoline. 2 (3H) -one hydrochloride. Pale yellow crystals, mp 173 to 176 "(Zers.). The free base melts with decomposition

310 to 314 ".

Example 5: In analogy to Example 1, N, N-2-amino-6-methylbenzyl-L-alanine ethyl ester was converted into the LI, 5-dihydro-3,6-dimethylimidazo [2,1-b] quinazoline. 2 (3H) -one hydrochloride. Colorless crystals of melting point 285 to 288 "(Zers.). The free base melts above 340 "with decomposition.

Example 6: Analogously to Example 1, N, N-2-amino-6-methylbenzyl-D-alanine ethyl ester was converted into the di, 5-dihydro-3,6-dimethylimidazo [2,1-b] quinazoline. 2 (3H) -one hydrochloride. Pale yellow crystals of melting point 287 to 290 ° (decomp.). The free base melts above 340 ".

Example 7: In analogy to Example 1, from N- (2-amino-6-methylbenzyl) -L-sero-ethyl ester the Ll, 5-dihydro-3-hydroxymethyl-6-methyl-imidazo [2,1-b ] quinazolin-2 (3H) -one hydrochloride.

Yellow crystals of melting point 320 to 325 ° (dec.).

Example 8 In analogy to Example 1, N, N-2-amino-6-methylbenzyl-D-phenylglycine ethyl ester was converted into the di, 5-dihydro-3-phenyl-6-methylimidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride. Pale yellow crystals of melting point about 320 "(decomp.).

Example 9 In analogy to Example 1 was from 2-amino-benzyl-L-alanine-ethyl ester the

Ll, 5-dihydro-3-methyl-imidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride. Brown crystals of melting point 223 to 226 ". The free base melts at 300 to 305 "with decomposition.

Example 10 In analogy to Example 1, from 2-amino-benzyl-D-alanine-ethyl ester, the D, 5-dihydro-3-methyl-imidazo [2,1-b] quinazolin-2 (3) -one hydrochloride receive. Yellow crystals of melting point 225 to 227 ". The free base melts at about 300 ° with decomposition.

Example 11: To a solution of 11.9 g of N- (2-amino-6-chlorobenzyl) -L-alanine ethyl ester in ml of ethanol at room temperature with stirring, a solution of 5 g of cyanogen bromide in 20 ml of ethanol was added dropwise. The reaction mixture was refluxed for 1 h, evaporated to dryness, the residue was admixed with 150 ml of water and, while stirring with 3N NH_U OH alkaline. After stirring for 30 minutes, the precipitate was filtered off and recrystallised from IN 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 the mp 260-263 ";

[α] +34.2 "(DMSO).

D-6-Chloro-1, 5-dihydro-3-methyl-imidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride was prepared analogously from N- (2-amino-6-chlorobenzyl) -D alanine ethyl ester, m.p. 263-266 ";

[_O]_D -23.9 "(DMSO);

Mp. Of the free base 275 to 280 ".

The starting material can be prepared as follows:

18.24 g of L-alanine ethyl ester hydrochloride in 60 ml of ethanol was added dropwise to a mixture of 25 ml of triethylamine in 60 ml of ethanol and the mixture heated to 80 ". The resulting Lö 40 solution was added dropwise at this temperature, a solution of 15 g of α-bromo-2-chloro-6-nitrotoluene in 60 ml of ethanol. The mixture was stirred overnight at 80 ° and then evaporated to dryness, the residue was added 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 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 N- (2-chloro-6-nitrobenzyl-L-alanine ethyl ester; n "1.5267) were obtained.

N- (2-chloro-6-nitrobenzyl) -D-alanine ethyl ester was obtained analogously from D-alanine ethyl ester and α-Br om-2-chloro-6-nitrotoluene;

ng 1.5247.

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 completion of the hydrogenation was from

Catalyst filtered off and the filtrate evaporated to dryness. 12.6 g (99% of theory) were obtained.

N- (2-amino-6-chlorobenzyl) -L-alanine ethyl ester;

n "1.5430.

Nr.363479

- 9 N- (2-amino-6-chlorobenzyl) -D-alanine ethyl ester was analogously hydrogenated by

N- (2-chloro-6-nitrobenzyl) -D-alanine ethyl ester;

ng 1.5405.

Example 12 In an analogous manner to Example 11, the following compounds were prepared:

D-6,7-dichloro-l, 5-dihydro-3-ethyl-imidazo [2,1-b] quinazolin-2 (3) -one hydrochloride, m.p.> 280 °,

L-6,7-dichloro-l, 5-dihydro-3-methyl-imidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride, mp> 290⁰.

D-7-bromo-1,1,5-dihydro-3-methylimidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride, m.p. 268-270 °,

L-7-bromo-1,1,5-dihydro-3-methyl-imidazo [2, lb] quinazolin-2 (3H) -one hydrochloride, m.p. 280-284 ° (dec.),

L-6-chloro-7-methoxy-l, 5-dihydro-3-rriethyl-imidazo [2, lb] quinazolin-2 (3H) -one hydrochloride, m.p.

> 280 °.

Example 13 In an analogous manner to Example 11, the following compounds were prepared:

from N- (2-chloro-6-nitrobenzyl) -3-phenyl-D-alanine ethyl ester, [α] θ -21.2 ° (c = 1% in ethanol) over N- (2-amino-6- chlorobenzyl) -3-phenyl-D-alanine ethyl ester, [α] + 40.7 ° (c = 1% in ethanol) containing 15 D-3-benzyl-6-chloro-1,5-dihydro-imidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride, m.p. 260-265 ° (dec.); Mp. Of the base 270 to 275 ° (dec.);

from N- (2-chloro-6-nitrobenzyl) -D-leucine ethyl ester over N- (2-amino-6-chlorobenzyl) -D-leucine ethyl ester, [a]_D + 8.5 ° (c = 1% in ethanol) the D-6-chloro-l, 5-dihydro-3-isobutyl-imidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride, mp 290 up to 293 °; M.p. of the base 280-285 °;

from N- (2-chloro-6-nitrobenzyl) -D-serih-ethyl ester, [a] p 2.7 ° (c = 1% in ethanol), via N-2- (amino-6-chlorobenzyl) -D -serine ethyl ester, mp 73-75 °, [α] θ + 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. Of the base> 300 ° (dec.);

from DN- (2-chloro-6-nitrobenzyl) -2-phenylglycine ethyl ester, [α] θ-21 ° (c = 1% in ethanol)

DN- (2-amino-6-chlorobenzyl) -2-phenylglycine ethyl ester, [α] θ-4.5 ° (c = 1% in ethanol) the D-6-chloro-3-phenyl-l, 5- dihydro-imidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride, m.p.> 300 ° (dec.); Mp. Of the base 260-265 ° (dec.).

Example 14: To a solution of 5 g of Dl, 5-dihydro-3-methylimidazo [2,1-b] quinazolin-2 (3H) -one in 80 ml of glacial acetic acid is added dropwise 1.5 ml of bromine. The mixture is stirred for 1 1/2 h at room 30 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. This gives 3.9 g (56%)

D-7-bromo-1,1,5-dihydro-3-methyl-imidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride, m.p. 268-270 °.

Example 15 In an analogous manner to Example 14, 4.7 g of Ll, 5-dihydro-3-methylimidazo35 [2,1-b] quinazolin-2 (3H) -one are converted into 4.2 g (64%) of L -7-bromo-1,1,5-dihydro-3-methyl-imidazo [2,1-b] quinazoline-2 (3H) -one hydrochloride, m.p. 280-284 ° (dec.) Brominated.

PATENT CLAIMS:

1. A process for the preparation of novel imidazo-quinazolines of the formula

<img file="AT363479B_D0005.tif" />

wherein 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 on adjacent carbon atoms also together methylenedioxy; R³

Hydrogen, lower alkyl or phenyl; and R "are lower-alkyl, hydroxy-lower-alkyl, lower-alkoxy-lower-alkyl, aryl-lower-alkyl or aryl, and their tautomers and salts thereof

- 10 No. 363479

Compounds, characterized in that a compound of the formula

<img file="AT363479B_D0006.tif" />

NH _z

CHNHCHCOOR⁵

R³ R "in which R 'to R ​​* have the above meaning and R^s lower alkyl, reacting with cyanogen bromide, if desired, halogenated a thus obtained 6-, 7-, 8- and 9-unsubstituted compound of formula (I) and, if desired, converting the thus obtained compounds of formula (I) into their salts.

2. The method according to claim 1, characterized in that starting from a compound of formula (II) in D-form.

3. The method according to claim 1 or 2, characterized in that starting from a compound of formula (II) wherein R * and R³ Hydrogen, R² Halogen in the 6- or 7-position or lower-alkyl in the 6-position and R "lower alkyl represent.

4. The method according to claim 1, 2 or 3, characterized in that one of a compound of formula (II), wherein R^l and R³ Hydrogen, R² 6-chloro, 7-bromo or 6-methyl and R * methyl.

5. Method according to one of