3-substituted-1,5-dihydroimidazo(2,1-b)quinazolin-2(3h)-one derivatives,their preparation and pharmaceutical compositions containing them

The present invention relates to tricyclic compounds.

More particularly, the invention is concerned with imidazoquinazoline derivatives, a process for the manufacture thereof and. pharmaceutical preparations containing same.

The imidazoquinazoline derivatives provided by the present invention are compounds of the general formula

<img file="IL55183A_D0001.tif" />

(I)

2 , wherein R and R each represent a hydrogen or halogen atom or a lower alkyl or lower alkoxy group and

R represents a lower alkyl, hydroxy-(lower alkyl)., phenyl-(lower alkyl) or phenyl group, tautomers thereof and salts of such compounds.

The imidazo[2,1-b]quinazolin-2(3H)-ones of formula I are structurally different from those described in British Patent Specification No. 1,418,822 and U.S. Patent Specifications Nos. 3,932,407 and 3,988,340, in that, in contradistinction to the latter, they are substituted in position 3. Furthermore, the compounds of formula I are superior to the prior art compounds in that the administration of the former results in a substantially lower increase of the heart frequency (lower tachycardia) than the latter compounds, whereas the positive

<img file="IL55183A_D0002.tif" />

inotropic activity is of the same order of magnitude for the compounds of formula I and the prior art compounds.

The term ״lower used herein refers in particular to groups containing 1-6, especially 1-4, carbon atoms. Alkyl groups can be straight-chain or branched-chain. Examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and hexyl.

a

Among the compounds of formula I there are preferred those which exist in the D-form. In addition, there are preferred compounds of formula I in which represents a hydrogen atom, R represents a halogen atom in the 6- or 7-position or a lower alkyl group in the 6-position, especially a chlorine atom in the 6-position, a bromine atom in the 7-position or a methyl group in the

6-position, and R⁴ represents a lower alkyl group, especially a methyl group.

Especially preferred imidazoquinazoline derivatives provided by the present invention are:

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

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

D-7-bromo-l,5-dihydro-3-methy1-imidazo[2,1-blquinazolin-2(3H)-one and their salts.

Examples of other imidazoquinazoline derivatives provided by the present invention are:

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

L-6-chloro-1,5-dihydro-3-pheny1-imidazo[2,1-b jquinazolin-2(3H)-one,

L-6-chloro-l, 5-dihydro^3-isobutyl-imidazo.[2,1-b] quinazolin-2(3H)-one /

L-3-benzyl-6-chloro-l,5-dihydro-imidazo[2,l-b]quinazolin-2(3H)-one and their salts.

The compounds of 'formula I can exist in various tautomeric forms. The invention is therefore not restricted to compounds of formula I reproduced hereinbefore, but also includes the tautomers, for example those of the formulae and

<img file="IL55183A_D0003.tif" />

(lb)

4 ר ו wherein IT, κ and R have the significance given earlier

The compounds of formula I and their tautomers (e.g. of formulae la and lb) can exist in the form of racemates or in optically active form. All of these forms form part of the present invention.

Examples of salts of the compounds provided by the present invention are physiologically compatible salts; for example, mineral acid salts such as hydrochlorides, hydrobromides, sulphates and phosphates, salts formed with organic sulphonic acids such as alkylsulphates and arylsulphonates and carboxylic acid salts such as succinates, citrates,tartrates and maleates.

According to the process provided by the present invention, the imidazoquinazoline derivatives aforesaid (i.e. the compounds of formula I, tautomers thereof and salts of such compounds) are manufactured by (a) reacting a compound of the general formula

<img file="IL55183A_D0004.tif" />

<img file="IL55183A_D0005.tif" />

- ־ 4 2 1 , wherein R , R and R have The significance given earlier and R⁵represents a lower alkyl group, with cyanogen bromide, .

or (b) treating a compound of the general formula

<img file="IL55183A_D0006.tif" />

2 4 5 , wherein R , R , R . and R have the significance given earlier, with ammonia, and, if desired, converting a resulting compound of formula I or tautomer thereof into a salt.

The reaction of a compound of formula II with cyanogen 15 bromide according to embodiment (a) of the process is conveniently carried out while warming in a solvent such as a lower alcohol (e.g. ethanol).

The treatment of a compound of formula III with ammonia according to embodiment (b) of the process is conveniently carried out while warming in a solvent such as a lower alcohol (e.g. ethanol) and water.

2

A compound of formula I in which R and/or R rep— resents a hydrogen atom can be halogenated in a manner known per se. Thus, for example, a solution of a compound of formula I,, which is unsubstituted in the 6-, 7-, 8־ and 9-positions, in acetic acid can be reacted with bromine to give a 7-bromo compound of formula I.

The compounds of formula I can Be manufactured according to Formula Scheme I hereinafter in which Y 1 2 4 represents a chlorine or bromine atom, R , R and R have the significance given earlier.

The compounds of formula'I can also be manufactured according to Formula Scheme II hereinafter in which Z represents an oxygen or sulphur atom, M represents ammonium, potassium or sodium and R , R and R have the significance given earlier.

Formula Scheme I

<img file="IL55183A_D0007.tif" />

H-/Pt, Pd or Raney Ni

י «£

<img file="IL55183A_D0008.tif" />

e.g. in C,H-OH M- J

(.

Bran in

e.g C-H-OH

<img file="IL55183A_D0009.tif" />

Y—CH —COY

e.g. in THF O°-1OO°C

<img file="IL55183A_D0010.tif" />

nh₂

Formula Scheme II ί

<img file="IL55183A_D0011.tif" />

M-.Z—CN

<img file="IL55183A_D0012.tif" />

Acetic acid or pyridine 25°1־OO°C

<img file="IL55183A_D0013.tif" />

(IV)

ORI/K-CO«9 aw«

THF, 20°-100°C

<img file="IL55183A_D0014.tif" />

H₂/Pt, Pd or

Raney Ni e.g. in c₂h₅oh

<img file="IL55183A_D0015.tif" />

<img file="IL55183A_D0016.tif" />

NHg in H₂0, C₂H₅OH or pyridine

20°C - reflux

1-50 atm.

sch₃

<img file="IL55183A_D0017.tif" />

<img file="IL55183A_D0018.tif" />

H״/Pt, Pd or A

Raney Ni

e.g. in C₂Hj.OH

<img file="IL55183A_D0019.tif" />

NH₃ in C₂H₅OH or pyridine 20°-100°C, 1-50 atm.

<img file="IL55183A_D0020.tif" />

The starting materials of formula II are novel and also form part of the present invention.

The starting materials of formulae II and III can be prepared according to Formula Scheme III hereinafter in

4 2 ך which X represents a halogen atom and R ! R , R_ and ~ .R⁵ have the significance given earlier or in analogy to the methods given in the Examples.

<img file="IL55183A_D0021.tif" />

Formula Scheme III

<img file="IL55183A_D0022.tif" />

<img file="IL55183A_D0023.tif" />

<img file="IL55183A_D0024.tif" />

(III)

-n- ₍

The compounds of formula I, their tautomers and physiologically compatible salts of such compounds should find use as medicaments. They inhibit, for example, the aggregation of blood platelets and can therefore be used for the prophylaxis of thromboses. Moreover, they are active on the circulatory system. On the basis of their positive inotropic activity without substantial tachycardia, they can bfe used for the treatment and prophylaxis of cardiac, insufficiency and cardiac failure.

The compounds of formula I, their tautomers and physio־־ logically compatible salts of such compounds can be used as medicaments; for example, in the form of pharmaceutical preparations which contain them in association with a compatible pharmaceutical carrier material. This carrier material can be an organic or inorganic inert carrier material which is suitable for enteral, percutaneous or parenteral administration such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, poly alkylene[gly cols, petroleum jelly etc. The pharmaceutical preparations can be made up in a solid form (e.g. as tablets, dragees, suppositories or capsules), in a semi-solid form (e.g. as salves) or in a liquid form (e.g. as solutions, suspensions or emulsions). The pharmaceutical preparations may be sterilised and/or may contain adjuvants such as preserving, stabilising, wetting or emulsifying agents, salts for varying the osmotic pressure or buffers. They can also contain still other thera12 peutically valuable substances. The compounds provided by the present invention are preferably administered orally.

In the case of adults, a daily dosage of 0.5 mg/kg to 30 mg/kg may be administered orally and a daily dosage of 0.05 mg/kg to 10 mg/kg may be administered parenterally.

The aggregation-inhibiting activity was demonstrated according to the aggregometer method of BORN [Nature 194, 927 (1962)] and MICHAL and BORN [Nature 231, 220 (1971)]. The maximum aggregation velocity was taken as the test parameter and the effective concentration (EC_5Q) was ascertained from dosage-activity curves.

Human plasma was obtained by centrifugation from venous blood treated with citrate (10.6 mM). 0.18 ml of plasma . was treated with 10 μΐ of an aqueous suspension of the test substance and the mixture was incubated at. 37°C for 10 minutes, whereupon the aggregation was initiated by the addition of 10 μΐ of collagen-fibril suspension.

Rabbit plasma was obtained by centrifugation from arterial blood treated with citrate (9 mM). 1 ml of plasma was treated with 10 μΐ of test solution and the mixture was incubated at 37°C for 1 minute, whereupon 8 μΐ of collagen-fibril suspension or 10 μΐ of adenosine diphosphate (ADP) in 10⁴־ N sodium chloride solution were added. Plasma incubated with dimethyl sulphoxide served as the control.

The results are given in the Table I hereinafter.

The positive inotropic activity was measured after the oral administration of the test substances to conscious sheepdogs. For this purpose, the animals are provided with an implanted pressure-telemetry system, whereby the pressure receiver is fixed in the left ventricle. The left ventricular pressure is sent from the animal via the implanted radio transmitter and received via a suitable antenna and receiver, system, demodulated and amplified. By differentiation of the ascending side of the left ventricular pressure (LVP) there is calculated the maximum pressure increase rate (dLVP/dt ) which represents the contractility parameter. Simultaneously, the heart frequency is recorded via a cardiotachograph. Under inotropy there are indicated the percentage variation (Δ%) of dLVP/dt and the duration of activity in minutes (min). max

Under tachycardia there are indicated the percentage variations of the heart frequency (Δ%) after administration of the test substance and the duration of activity in minutes (min). The results are given in Table II hereinafter.

Table

Collagen- and ADP-induced blood platelet aggregation

<td rowspan="2"> 5</td><td rowspan="2"> Test substance (imidazoquinazoline derivative)</td><td colspan="2"> Rabbit plasma.</td><td> Human plasma</td>

<td> Collagen EC 50 μΜ</td><td> ADP EC 50 μΜ</td><td> Collagen EC 50 μΜ</td>

<td> 10</td><td> D-l,5-Dihydro-3,9-dimethyl-imidazo[2,1-b]quinazolin-2(3H)-one hydrochloride</td><td> 3.0</td><td> ב3</td><td> 6ב</td>

<td></td><td> L-l, 5-Dihydr0T3,9־-dimethyl-imidazo[2,1-b]quinazolin-3) בH)-one hydrochloride</td><td> 18</td><td> 60</td><td> 49</td>

<td> 15</td><td> Drl,5-Dihydro-3, 7-dimethy !-imidazo [2,1-b]quinazolin-2(3H)-one hydrochloride</td><td> 3.1</td><td> 19</td><td> . 3.4</td>

<td></td><td> L-l, 5-Dihydro-3,7-dimethy1-imidazo[2,1-b]quinazolin-3)בH)-one hydrochloride</td><td> 22</td><td> 77</td><td> . 33</td>

<td> 20</td><td> D-l, 5-Dihydro-3, 6-dimethy !-imidazo [1, ב-b]quinazolin-3)בH)-one hydrochloride</td><td> 0.19</td><td> ב.ב</td><td> 3.ב</td>

<td> 25</td><td> L-l,5-Dihydro-3, 6-dime thy !-imidazo[1, ב-b]quinazolin^(3H)-one hydrochloride</td><td> 0.93</td><td> 11</td><td> ב.6</td>

<td></td><td> L-l,5-Dihydro-3-hydroxymethy1-6-methy1-imi da z 0[2,1-b] quinazolin-2.(3H) -one hydrochloride</td><td></td><td> Μ</td><td> 14</td>

Table II

<td rowspan="2"> 5</td><td rowspan="2"> Test substance (imidazoquinazoline derivative)</td><td rowspan="2"> Dosage mg/kg</td><td colspan="2"> Inotropy.</td><td colspan="2"> Heart frequency</td>

<td> Δ%</td><td> Min</td><td> Δ%</td><td> Min</td>

<td> 10</td><td> D-6-Chloro-l,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></td><td> D-l, 5-Dihydr0r-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> 15</td><td> L-l, 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 process provided by the present invention:

Example 1

A solution of 5.3 g of cyanogen bromide in 10 ml of ethanol was added at room temperature while stirring to a solution of 11.8 g of N-(2-amino-3-methy !benzyl) ־L-alanine ethyl ester in 30 ml of ethanol. The mixture was heated to reflux for 1 hour and then evaporated to dryness under reduced pressure. The residue was treated with 100 ml of water and made alkaline by the addition of 3-N ammonium hydroxide while 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 each time, dried over sodium sulphate and evaporated. The residue was recrystallised from ethanol and yielded L-l,5-dihydro-3,9-dimethylimidazo[2,l-b]quinazolin-2(3H)-one of melting point 259°-261°C; [a)_D = +15.5° (c 1% ־ in methanol).

/

By recrystallisation of the thus-obtained base from 1-N hydrochloric acid/acetonitrile (3:1) there was obtained the hydrochloride of melting point 272°-275°C (decomposition).

The starting material was prepared as follows:

A solution of 120 ml of triethylamine in 200 nil of absolute ethanol was added dropwise over a period of 30 minutes to a solution of 91.8 g of L-alanine ethyl ester hydrochloride in 300 ml of absolute ethanol. The mixture was warmed to 60°C, a clear solution resulting. To this solution was added dropwise within 1 hour a solution of 55.5 g of 3-(chloromethyl)-2-nitrotoluene in. 300 ml of absolute ethanol. Thereafter, the temperature was increased to 80°C and the mixture was stirred at this temperature overnight. Thereafter, the mixture was 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 thus-obtained crude product was purified by chromatography on silica gel using methylene chloride/5% methanol for the elution. There was obtained N-(3-methyl-2-nitrobenzyl)-L-alanine ethyl ester in the form of a yellow oil; Cal_D = -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 ethanol was hydrogenated in the presence of 2 g of 10% palladium/carbon. 6.7 litres of hydrogen were taken up in 5 hours. After completion of the hydrogenation, the catalyst was filtered off and the filtrate was evaporated to dryness. There was obtained N-(2-amino-3-methy!benzyl)-L-alanine ethyl ester in the form of a yellow oil, [a]^ ⁼ ”52.6° (c = 1% in methanol).

In an analogous manner, from 3-(chloromethyl)-2-nitrotoluene and D-alanine ethyl ester hydrochloride there was obtained N-3-(methyl-2-nitrobenzyl)-D-alanine ethyl ester in the form of a yellow oil; [a!_D = +31.4° (c 11 ־־ in methanol)., from a³-chloro-4-nitro-m-xylene and L-alanine ethyl ester hydrochloride there was obtained N-(5-methyl-2-nitrobenzyl)-L-alanine ethyl ester in the form of a red oil; [a]_D = -12.6° (c = 1% in methanol);

from a³-chloro-4-nitro-m-xylene and D-alanine ethyl ester hydrochloride there was obtained N-(5-methyl-2-nitrobenzyl)-D-alanine ethyl ester in the form of a red oil;

[a] 11.4°+ =־ (c = 1% in methanol);

from a^-chloro-3-nitro-o-xylene and L-alanine ethyl ester hydrochloride there was obtained N-(2-methyl-6-nitrobenzyl)-L-alanine ethyl ester in the form of a red oil; [a]_D 35.8°+ =־ (c = 1% in methanol);

from a -chloro-3-nitro-o-xylene and D-alanine ethyl ester hydrochloride there was obtained N-(2-methyl-6-nitrobenzyl)-D-alanine ethyl ester in the form of a red oil;

[a]_D = -34° (c = 1% in methanol);

from a -chloro-3-nitro-o-xylene and L-serine ethyl ester hydrochloride there was obtained N-(2-methyl-6-nitrobenzyl)-L-serine ethyl ester in the form of a red oil;

nJ⁴ = 1.5474;

from a²-chloro^3-nitro-o-xylene and D-a-phenylglycine ethyl ester hydrochloride there was obtained N-(2-methyl-6-nitrobenzyl)-D-a-phenylglycine ethyl ester in the form of a red oil» n_D = 1.5261;

from 2-nitrobenzyl chloride and L-alanine ethyl ester hydrochloride there was obtained 2-nitrobenzyl-L-alanine ethyl ester in the form of a dark red oil; [a]_D = -5.4° (c = 1% in ethanol);

from 2-nitrobenzyl chloride and D-alanine ethyl ester hydrochloride there was obtained (2-nitrobenzyl)-D-alanine ethyl ester in the form of a red oil; [a]-_D = +5.4° (c = 1% in ethanol);

from N-3-methyl-2-nitrobenzyl-D-alanine ethyl ester there was obtained N-(2-amino-3-methy!benzyl)-D-alanine ethyl ester in the form of a light yellow oil; [a]_D = +51° (c = 1% in methanol);

from N-(5-methyl-2-nitrobenzyl)-L-alanine ethyl ester there was obtained N-(2-amino-5-methy!benzyl)-L-alanine ethyl ester; [a] = -45° (c = 1% in methanol);

from N-(5-methyl-2-nitroben2yl)-D-alanine ethyl ester there was obtained N-(2-amino-5-methylbenzyl)-D-alanine ethyl ester in the form of a red oil; [a]^ = +34.2° (c = 1% in methanol);

from N-(2-methyl-6-nitrobenzyl)-L-alanine ethyl ester there was obtained N-(2-amino-6-methyIbenzyl)-L-alanine ethyl ester in the form of a yellow oil; [a]_D = -34.7° (c = 1% in methanol);

.from N-(2-methyl-6-nitrobenzyl)-D-alanine ethyl ester there was obtained N~(2-amino-6-methyIbenzyl)-D-alanine ethyl ester in the form of a reddish oil, [a]_D = +36.8° (c = 1% in methanol);

from N-(2-methyl-6-nitrobenzyl)-L-serine ethyl ester there was obtained N-(2-amino-6-methylbenzyl)-L-serine ethyl ester in the form of a red oil; n_D = 1.5468;

from N-(2-methyl-6-nitrobenzyl)-D-a-phenylglycine ethyl ester there was obtained N-(2-amino-6-methylbenzyl)-מ-a-phenylglycine ethyl ester in the form of a yellow oil; n²⁴ 5665 .1 ־ ;

from (2-nitrobenzyD-L-alanine ethyl ester there was obtained 2-aminobenzyl-L-alanine ethyl ester in the form of a red oil; [a]_D - -55.1° (c = 1% in ethanol); and from 2-nitrobenzyl-D-alanine ethyl ester there was obtained 2-aminobenzyl-D-alanine ethyl ester in the form of a dark red oil; [a]_D = +57.2° (c = 1% in ethanol).

Example 2

In a manner analogous to that described in Example 1, from N-(2-amino-3-methy!benzyl)-D-alanine ethyl ester there was obtained D-l,5-dihydro-3,9-dimethylimidazo[2,l-b]quinazolin-2(3H)-one hydrochloride of melting point 270°-275°C (decomposition). The free base melts at 262°-265°C.

Example 3

In a manner analogous to that described in Example 1, from N-(2-amino-5-methy!benzyl)-L-alanine ethyl ester there

- J־ was obtained L-l, 5-dihydro-^, 7.-dimethylimidazo [2,1-b] quinazolin-2(3H)-one hydrochloride in. the form of light yellow crystals of melting point 173°-176°C. The free base melts above 300°C with decomposition.

Example 4

In a manner analogous to that described in Example 1, from N-(2-amino-5-me.thy!benzyl)-D-alanine ethyl ester there was obtained D-l,5-dihydro-3,7-dimethylimidazo[2,l-b]quinazolin-2(3H)-one hydrochloride in the form of light yellow crystals of melting point 173^O°C (decomposition). The free base melts at 31O°-314°C with decomposition.

Example 5

In a manner analogous to that described in Example 1, from N-(2-amino-6-methylbenzyl)-L-alanine, ethyl ester there was obtained L-l,5-dihydro-3,6-dimethylimidazo[2,l-b]quinazolin-2(3H)-one hydrochloride in the form of colourless crystals of melting point 285°-288°C (decomposition). The free base melts above 34O°C with decomposition.

Example 6

In a manner analogous to that described in Example 1, from N-(2-amino-6-methylbenzyl)-D-alanine ethyl ester there was obtained D-l,5-dihydro-3,d-dimethylimidazo[2,l-b]- ץ - 22 quinazolin-2(3H)-one hydrochloride in the form of light yellow crystals of melting point 287°-29O°C (decomposition).

The free base melts above. 34O°C.

Example 7

In a manner analogous to that described in Example 1, from N-(2-amino-6-methy!benzyl)-L-serine ethyl ester there was obtained L-l,5-dihydro-3-hydroxymethyl-6-methyl-imidazo[2,l-b]guinazolin-2(3H)-one hydrochloride in the form of yellow crystals of melting point 32O°-325°C (decomposition).

Example 8

In a manner analogous to that described in Example 1, from N-(2-amino-6-methylbenzyl)-D-a-phenylglycine ethyl ester there was obtained D-l,5-dihydro-3-phenyl-6-methyl-imidazo [2,1-b]quinazolin-2(3H)-one hydrochloride in the form of light yellow crystals of melting point about 32O°C (decomposition).

Example 9

In a manner analogous to that described in Example 1, from 2-amino-benzyl-L-alanine ethyl ester there was obtained L-l, 5-dihydro-3-methy1-imidazo[2,1-b]quinazolin-2(3H)-one hydrochloride in the form of brown crystals of melting point 223°-226°C. The free base melts at. 300°-305°C with decomposition

Example 10

In a manner analogous to that described in Example 1, from 2-amino-benzyl-D-alanine ethyl ester there was obtained D-l,5-dihydro-3-methyl-imidazo[2,1-b]quinazolin-2(3H)-one hydrochloride in the form of yellow crystals of melting point 225°-227°C. The free base melts at about 300°C with decomposition.

Example 11

A solution of 5 g of cyanogen bromide in 20 ml of ethanol was added dropwise at room temperature while stirring to a solution of 11.9 g of N-(2-amino-6-chlorobenzyl)-L-alanine ethyl ester in 20 ml of ethanol. The mixture was then boiled at reflux for 1 hour and evaporated to dryness. The residue was treated with 150 ml of water and made alkaline with 3-N ammonium hydroxide while stirring. After stirring for 30 minutes, the precipitate was filtered off and recrystallised from 1-N hydrochloric acid and acetonitrile. There were obtained 9.1 g (68% of theory) of L-6-chloro-l,5-dihydro-3-methyl-imidazo[2,l-b]quinazolin-2(3H)-one hydrochloride in the form of yellow crystals of melting point 26O°-263°C, ⁼ +34.2° (in dimethyl sulphoxide).

In an analogous manner, from N.-(2-amino-6-chlorobenzyl)-D-alanine ethyl ester there was obtained D-6-chloro -1,5-dihydro-3-methyl-imidazo [2,1-b] quinazolin-2.( 3H) -one hydrochloride of melting point 263°-266°Cj [a]_D = -23.9° (in dimethyl sulphoxide); melting point of the free base 275°-280°C.

The starting material can be prepared as follows:

18.24 g of L-alanine ethyl ester hydrochloride in 60 ml of ethanol were added dropwise to a mixture of 25 ml of triethylamine in 60 ml of ethanol and the mixture was heated to 80°C. The resulting solution was added dropwise at this temperature to a solution of 15 g of a-bromo-2-chloro-6-nitrotoluene in 60 ml of ethanol. The mixture was stirred at 80°C overnight and then evaporated to dryness. The residue was treated with 150 ml of deionised water and extracted twice with 100 ml of methylene chloride The methylene chloride extracts were washed with water, dried and evaporated. The resulting product was purified by chromatography on silica gel with methylene chloride/5% methanol. There were obtained 15.75 g (91% of theory) of N-(2-chloro-6-nitrobenzyl)-L-alanine ethyl ester; n^° ־־ 1.5267.

N-(2-Chloro-6-nitrobenzyl)-D-alanine ethyl ester (n^S =1,5247 ־) was obtained in an analogous manner from D-alanine ethyl ester and a-bromo-2-chloro-6-nitroto.luene.

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, the catalyst was filtered off and the filtrate was evaporated to dryness. There were obtained 12.6 g (99¾ of theory) of N-(2-amino-6-chloro22 benzyl)-L-alanine ethyl ester; n_D 1.5430 =־.

N-(2-Amino-6-chlorobenzyl)-D-alanine ethyl ester (n³³ = 1.5405) was obtained in an analogous manner by hydrogenating N-(2-chloro-6-nitrobenzyl)-D-alanine ethyl ester.

Example .12

In a manner analogous to that described in Example 11 there were obtained:

D-6,7-Dichloro-l,5-dihydro-3-methyl-imidazo[2,1-b] quinazolin-2(3H)-one hydrochloride of melting point above 280°C,

L-6,7-dichloro-l,5-dihydro-3-methyl-imidazo[2,1-b]quinazolin-2(3H)-one hydrochloride of melting point above 29O°C,

D-7-bromo-l, 5-dihydro-3-methy1-imidazo[2,1-b]quinazolin-2(3H)-one hydrochloride of melting point 268°-27O°C,

L- 7-bromo-1,5-dihydror. 3-methy1-imidazo [ 2,1-b ] quinazolin-2(3H)-one hydrochloride of melting point 280°-284°C (decomposition), and

L-6-chloro-l,5-dihydr0r3-methy1-7-methoxy-imidazo[2,1-b]quinazolin-2(3H)-one hydrochloride of melting point above 28O°C.

Example 13

In a manner analogous to that described in Example 11, from N-(2-chloro-6-nitrobenzyl)-3-phenyl-D-alanine ethyl ester /[a]_D = -21.2° (c = 1% in ethanol)_7 there was obtained, via N-(2-amino-6-chlorobenzyl)-3-phenyl-D-alanine ethyl ester / [a]_D = +40.7° (c = 1% in ethanol)_7_׳ D-3-benzyl-6-chloro-l,5-dihydro-imidazo[2,l-b]quinazolin-2(3H>-one hydrochloride of melting point 26O°-265°C (decomposition)j melting point of the base 270°-275°C (decomposition);

from N-(2-chloro-6-nitrobenzyl)-D-leucine ethyl ester there was obtained, via N-(2-amino-6-chlorobenzyl)-D-leucine ethyl ester /”[a]_D = +8.5° (c = 1% in ethanol)_7, D-6-chloro-l,5-dihydro-3-isobutyl-imidazo[2 ,l-b]quinazolin-2(3H)-one hydrochloride of melting point 290°-293°Cj melting point of the base 280°-285°C;

from N-(2-chloro-6-nitrobenzyl)-D-serine ethyl ester /~[a]_D = 2.7° (c = 1% in ethanol)_7 there was obtained,, via N-(2-amino-6-chlorobenzyl)-D-serine ethyl ester ^”melting point 73°-75°C; [a] = +65.5° (c = 1% in ethanol)_7, D-627 -chloro:-3-hydroxyme thy 1-1, 5-dihydro-imidazo [2,1-b] quinazolin-2.(3H)-one hydrochloride; melting point of the base above 300°C (decomposition); and ' from D-N-(2-chloro-6-nitrobenzyl)-2-phenyIglycine ethyl ester /”[a]_D = -21° (c = 1% in ethanol)_7 there was obtained, via D-N-(2-amino-6-chlorobenzyl)-2-pheny1glycine ethyl ester /”[a]_D =-4.5° (c = 1% in ethanol)_7, D-6-chloro-3-phenyl-l, 5-dihydro-imidazo[2,1-b]quinazolin-2.(3H)-one hydrochloride of melting point above 300°C

«י (decomposition); melting point of the base 26O°-265°C (decomposition). ״

Example 14

A mixture of 6 g of ethyl D-2,5-dichloro-a-methyl-3(4H)-quinazolinacetate, 20 ml of absolute ethanol and 25 ml of 5% alcoholic ammonia was heated to 110°C overnight in a pressure tube. The pressure tube was cooled in an ice-bath and opened. The resulting crystal slurry was filtered off under suction and washed with cold ethanol. The crystals obtained were dissolved in 1-N hydrochloric the ,solution־ acid and/flltered. The filtrate was evaporated to dryness and the residue was recrystallised from 1-N hydrochloric acid and acetonitrile to give 4.3 g (74% of theory) of D-6-chloro-1,5-dihydro-3-methy1-imidazo[2,1-b]quinazolin-2(3H)-one hydrochloride of melting point 275°-278°C.

The starting material can be prepared as follows:

A mixture of 18.24 g of D-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 resulting mixture was heated to 80°C. The solution obtained was added dropwise at this temperature to a solution of 15 g of 2-chloro-6-nitrobenzyl bromide in 60 ml of ethanol. The mixture was stirred at 80°C overnight and then evaporated to dryness. The residue was treated with 150 ml of deionised water and extracted twice with 100 ml of methylene chloride. The methylene chloride extracts were washed with water, dried over sodium sulphate and evaporated. The resulting product was purified by chromatography on silica gel with methylene chloride/5% methanol. There were obtained 16 g (93% of theory) of 25 N-(2-chloro-6-nitrobenzyl)-D-alanine ethyl ester! η_β = 1.5247., [al_D = -6.9° (c = 1% in ethanol).

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 litres of hydrogen were taken up in 2 hours. The catalyst was then filtered off and the filtrate was evaporated to dryness. There were obtained 12.6 g (99% of theory) of N-(2-amino-623 -chlorobenzyl)-D-alanine ethyl ester! η_β = 1.5405! [α]_β = +55.8° (c = 1% in ethanol).

g of N,Ν'-carbonyldiimidazole were added portionwise while gassing with nitrogen and stirring, to a solution of 71.75 g of N-(2-amino-6-chlorobenzyl)-D-alanine ethyl ester in 400 ml of dry tetrahydrofuran. The mixture was stirred for 2 hours, heated under reflux for 18 hours and evaporated to dryness. The residue was extracted with 1500 ml of methylene chloride, the organic phase was washed twice with 400 ml of 1-N hydrochloric acid and then with 400 ml of water, dried and evaporated. The resulting oil was purified by chromatography on silica gel with methylene chloride/5% methanol. There were obtained 79 g (99% of theory) of ethyl D-5-chloro-l,4-dihydro-a-methyl-2-oxo-2)נH)-quinazolinacetate; [a]_D = -40.8° (c = 1% in ethanol) .

50.9 g of ethyl D-5-chloro-l,4-dihydro-a-methyl-2-oxo-3(2H)-quinazolinacetatewere dissolved in 135 ml of phosphorus oxychloride and heated to 110°C for 3 hours while stirring. After cooling, the 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 the 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. There were obtained 37.4 g (70% of theory) of ethyl D-2,5-di22 chloro-a-methyl-3(4H)-quinazolinacetate; ηθ = 1.5775.

Example 15

1.5 ml of bromine were added dropwise to a solution . 30 of 5 g of D-l,5-dihydro-3-methyl-imidazo[2,l-b]quinazolin-2.(3H)-one in 80 ml of glacial acetic acid. The mixture was stirred at room temperature for 1.5 hours, diluted with 100 ml of water, concentrated to 30 ml, again diluted with 100 ml of water, made alkaline with. 3-N ammonium hydroxide, washed and filtered. The separated product was washed with water and recrystallised from 100 ml of 2-N hydrochloric acid. There were obtained 3.9 g (56% of theory) of D-7-bromo-l,5-dihydro-3-methyl-imidazo[2,1-b]quinazolin-2(3H)-one hydrochloride of melting point 268°-270°C.

Example 16

In a manner analogous to that described in Example 15, 4.7 g of L-l,5-dihydro-3-methyl-imidazo[2,l-b]quinazolin-2(3H)-one were brominated to give 4.2 g (64% of

י theory) of L-7-bromo-l,5-dihydro-3-methyl-imidazo [2,1-b]quinazolin-2(3H)-one hydrochloride of melting point 28O°-284°C (decomposition).

The following Examples illustrate pharmaceutical preparations containing the imidazoquinazoline derivatives provided by the present invention:

Example A

Tablets containing the following ingredients were manufactured in the usual manner:

D-6-Chloro-l, 5.-dihydr0T3 ־-me thyl-

<td> -imidazo[2,1-b]quinazolin-2(3H) -one hydrochloride</td><td> 184.6 mg</td>

<td> Lactose</td><td> 15.0 mg</td>

<td> Maize starch</td><td> 37.9 mg</td>

<td> Water-soluble polyvinylpyrrolidone</td><td> 10.0 mg</td>

<td> Magnesium stearate</td><td> 2.5 mg</td>

<td> Total weight per tablet</td><td> 250.0 mg</td>

Example B

Interlocking gelatin capsules containing the following ingredients were manufactured in the usual manner:

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

<td> -one hydrochloride</td><td> 200.0 mg</td>

<td> Water-soluble polyvinyIpyrrolidone י</td><td> 2.0 mg</td>

<td> Maize starch</td><td> 43.0 mg</td>

<td> Talc</td><td> 4.5 mg</td>

<td> Magnesium stearate</td><td> 0.5 mg</td>

<td> Total weight per capsule</td><td> 250.0 mg</td>

Example C

An injection solution containing the following ingredients was manufactured in the usual manner:

-. 32 D-6-Chloro-l5_׳-dihydro-3-methyl-

<td> -imidazo[2,1-b]quinazolin-2(3H)-one hydrochloride</td><td> 114.16 mg</td>

<td> Glycerinformal</td><td> 2.4 ml</td>

<td> 5 Water</td><td> 4.0 ml</td>

55183/2 .