Process for preparing new imidazoquinazolines

The present invention relates to novel tricyclic compounds, i.e., imidazoquinazolines of formula I

H

<img file="CS203014B2_D0001.tif" />

in which

R⁴ represents a C1-C4 alkyl group, a hydroxymethyl group, a benzyl group or a phenyl group, their tautomers and salts thereof.

The alkyl radicals may be straight-chain or branched. Examples of alkyl radicals include: methyl, ethyl, propyl, isopropyl, butyl and isobutyl.

Among the compounds of formula I, those occurring in the D-form are preferred. Preferred are the compounds of formula I wherein R is hydrogen, R is chlorine or bromine at the 6-position or at the 7-position or the methyl group at the 6-position, especially 6-chloro, 7-bromo or 6-methyl, and R⁴ is C1-C4alkyl, especially methyl.

Particularly preferred are:

D-6-chloro-1,5-dihydro-3-methylimidazo [2,1-b] quinazolin-2 (3H) -one,

D-115-dihydro-3,6-dimethylimidazo [2,1-b] quinazolin-2 (3H) -one,

D-7-bromo-1,5-dihydro-3-methylimidazo [2,1-b] quinazolin-2 (3H) -one, and salts thereof.

Examples of compounds of formula I include:

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

L-6-chloro-1,5-dihydro-3-phenylimidazo [2,13b] quinazolin-2 (3H) 3-one,

Ь-6-γ-1,5-dihydro-3'-isobutylimidazo [2,1-b] quinazolin-2 (ЗЮ-one,

L-3-benzyl-6-chloro-1_&gt;5-dihydro-imidazo [2,1-b] quinazoline-4-carboxylic acid and their salts.

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

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

<img file="CS203014B2_D0002.tif" />

(Ia) (Ib)

H

The compounds of formula (I) and tautomers thereof, for example of formula (Ia) and (Ib), may furthermore exist in the form of racemates or in optically active form, all of which forms are within the scope of the invention.

Exemplary physiologically acceptable salts include those with a mixed acid such as hydrides, hydrobromides, sulfates, and phosphates; organic sulfonic acid salts such as alkyl sulfates and aryl sulfonyl salts; and salts of carboxylic acids such as succinates, citrates, tartrates and maleates.

The compounds of the formula I and their tautomers are prepared according to the invention by the formation of a compound of the formula II -

<img file="CS203014B2_D0003.tif" />

CH.NHCHCOOR⁵ in which ^r1 and^{ž r4} maaí s^hor as defined above, and

R 6 represents an alkyl group having 1 to 6 carbon atoms, (II) is treated with cyanogen bromide, and the compound of formula I obtained. is isolated in this form or in the form of a tautomer or in the form of a salt. The reaction of the compound of Formula II with cyanogen bromide is conveniently carried out by heating in a solvent such as a lower alcohol such as ethanol.

2 ‘ ⁱⁿ

A compound of formula I wherein R¹ and / or π is hydrogen, it may be halogenated in a manner known per se. Thus, for example, a solution of a compound which is not substituted at the 6, 7, 8 and 9 positions in acetic acid can be reacted with bromine to form the 7-bromo derivative.

Compounds of formula I may be prepared according to Reaction Scheme I shown below, ^pspeech^of Chlor Chlorine no^bO ^brom, and R⁴ has s^horn.

Compounds of formula (I) may be further prepared according to Flow Diagram II below, wherein Z is oxygen or sulfur, M is ammonium, potassium or sodium, and the remaining symbols are as defined above.

R1

R²

<img file="CS203014B2_D0004.tif" />

, wo₂

CH₂IMH₂

Hg / Pt, Pd or Raney-rNi, for example, in C 8 H 11 OH

<img file="CS203014B2_D0005.tif" />

<img file="CS203014B2_D0006.tif" />

Y-CH-COY

4-E - for example in tetrahydrofuran 0-100 ° C

<img file="CS203014B2_D0007.tif" />

R1 r2

<img file="CS203014B2_D0008.tif" />

^ch₂NHCHCOOR^WITH

R⁴

MZ-CN

-----------------&gt;

acetic acid or pyridine 25-100 ° C

<img file="CS203014B2_D0009.tif" />

(TV)

<img file="CS203014B2_D0010.tif" />

ch₃i / k₂what₃ tetrahydrofuran 20-100 ° C

<img file="CS203014B2_D0011.tif" />

H₂/ Pt, Pd or Raney / Ni e.g.

<img file="CS203014B2_D0012.tif" />

<img file="CS203014B2_D0013.tif" />

NH₃ v H₂O, C 8 H 4 OH or pyridine

20 ° reflux under 0.1 to 5 MPa

H₂/ Pt, Pd or Raney-Ni

-----------------------------&gt;

for example in C₂H, OH

<img file="CS203014B2_D0014.tif" />

NH₃ v C₂H₅Or pyridine

20-100 ° C, 0.1-5 MPa

<img file="CS203014B2_D0015.tif" />

(AND)

The compounds of formula II are novel.

The starting materials of formula II can be prepared according to Scheme III below, in which X is halogen and the remaining symbols are as described above, optionally analogously to the methods given in the examples.

<img file="CS203014B2_D0016.tif" />

<img file="CS203014B2_D0017.tif" />

Reaction Scheme III

H₂NCHCOOR

<img file="CS203014B2_D0018.tif" />

R1

R²

<img file="CS203014B2_D0019.tif" />

no₂ ^ CHnNHCHCOOR⁵and.

R¹R2

<img file="CS203014B2_D0020.tif" />

nh₂ ch₂nhchcoor⁵

I4 (II)

The compounds of formula I, their tautomers and physiologically useful salts of such compounds are used as medicaments. These substances suppress platelet aggregation and can therefore be used to prevent thromboses. In addition, they are effective for blood circulation. Thus, by virtue of their positive inotropic effect, these substances can be used without substantial tachycardia for the treatment and prophylaxis of heart failure and cardiac weakness.

The compounds of the formula I and their tautomers can be used as medicaments, for example in the form of pharmaceutical preparations containing these compounds or their salts in admixture with a pharmaceutical, organic or inorganic inert carrier material suitable for enteral, percutaneous or parenteral administration such as water, gelatin , gum arabic, lactose, starch, magnesium stearic acid, talc, vegetable oils, polyalkylene glycols, vaseline std.

The pharmaceutical preparations may be in solid form, for example in the form of tablets, dragees, suppositories, capsules; in a semi-solid state, for example in the form of ointments, or in a liquid state, for example in the form of solutions, suspensions or emulsions, these preparations optionally being sterilized and / or containing auxiliaries such as preservatives, stabilizers, wetting agents or emulsifiers or buffers. They may also contain other therapeutically valuable substances. Oral administration of the compounds of the invention is preferred. For adult patients an oral daily dose of 0.5 to 30 mg / kg and a parenteral daily dose of 0.05 to 10 mg / kg are suitable.

The effect of suppressing platelet aggregation was demonstrated by the method using the aggregator of Borne Nature 194. 927 (1962) and Michael and Borne Nature 231. 220 (1971)]. The maximum aggregation rate was determined as the tested parameter and the effective concentration (ΕΟ ^ θ) was determined from the dose-response curves.

Human plasma was obtained by centrifugation from venous blood disrupted by citrate (10.6 mmol). 10 µl of an aqueous suspension of test compounds was added to 0.18 ml of plasma for 10 minutes and incubated at 37 ° C, followed by aggregation by adding 10 µl of collagen fibril suspension.

20301-4

Calcium plasma was obtained by centrifugation from arthropod blood decomposed with citrate (9 mol). To 1 ml of plasma, add 10 µl of test solution, then incubate for 1 minute at 37 ° C, then add 8 µl of a suspension of fibrils of collagen or 10 µl of adenoindine phosphate (ADP) in¹⁰⁴ mnol rozto^towith hair^dNo^hPlasma was used to control the tulle^yiincubated with dimethylsulfoxide. &gt;

The results are shown in Table I below.

The pootive inotropic effect is measured after oral administration of test substances on the watchful Schafer dogs. For this purpose, the animals are equipped with an implanted telemetry system for measuring the pressure, the pressure sensor being fixed in the left ventricle. The left ventricular pressure is transmitted from the animal, by means of an implanted radio transmitter, and is captured through a suitable antenna and receiver system, demooling and amplifying.

By derivating the rising left ventricular pressure arm (LVP), the maximum rate of pressure increase is calculated. (dLVP /^dt_m ), which value serves as a cooactivity parameter. At the same time, the heart rate is recorded using a cardiotachograph. Inotropy was given the percent change (delta%) of dLVV / dt_max and duration of action in minutes (min). Tactycaaddis are reported as percent changes in heart rate (delta%) after administration of test substance and duration of action in minutes (min). The results are shown in the table below.

Ta table 1

Platelet Aggregation Induced by Collagen 'and Adenooindiphosphate (ADP)

<td>Compound</td><td>Shouting</td><td>plasma</td><td>Human plasma</td>

<td></td><td>collagen</td><td>ADP</td><td>collagen</td>

<td></td><td>^EC50</td><td>ec₅0</td><td>ec₅0</td>

<td></td><td>/ Umal</td><td>/ imol</td><td>/ unol</td>

<td>D-1.5 ~^dity йго-З.Э- ^ те ttylimidazo] ^ 1,1-b] c^hinazolin-2 (3H) -one dihydrochloride</td><td> 3,0</td><td> 32</td><td> 26</td>

<td>L-1,5-^dyou too^dro-3^,9-^dimettylimidazz^O2,1-b] chiNazolin-2 (3H) -one-iddoolhoride</td><td> 18</td><td> 60</td><td> 49</td>

<td>D-115-dity^dro-3,7-dimettyllml^dazoo2,1-b] quinazolin-2 (3H) -one-tydoomide</td><td> 3,1</td><td> 19</td><td> 3,4</td>

<td>L-1,5-ditydro-3,7-dimethylimidazzo-2,1-bquinazoline- -2 (3H) -one^drochlorid ·</td><td> 22</td><td> 77</td><td> 33</td>

<td>D-l15-ditydrz-3,6-dimettylimidazzo-2,1-b '] quin- zolin-2 (3H) -one-tyrosyl) iodide</td><td> 0,19</td><td> 2,2</td><td> 2,3</td>

<td>L-1, S-dihydro-1,6-di-ethyl-imidazo (2,1-b) quinazolin-2 (3H) -one-tyrocyclone</td><td> 0,93</td><td> 11</td><td> 6,2</td>

<td>L-1,5-^dyou too^ddz-3-Hyddoxyneethyl-6-methylimidazo [2,1-b] quinazolin-2 (3H) -one-tydrocM-Zdid</td><td></td><td></td><td> 14</td>

Table II

<td rowspan="2">Compound</td><td rowspan="2">Dose mg / kg</td><td colspan="2">Inotropy</td><td rowspan="2">Heart Delta%</td><td rowspan="2">frequency min</td>

<td>delta%</td><td>min</td>

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

<td>D-1,5-Dihydro-3,6-dimethylimidazo [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>L-1,5-dihydro-3,9-dimethylimidazo [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. Temperatures are given in degrees Celsius.

Example 1

To a solution of 11.8 g of N- (2-amino-3-methylbenzyl) -L-alanine ethyl ester in 30 ml of ethanol is added at room temperature with stirring a solution of 5.3 g of cyanogen bromide in 10 ml of ethanol. The reaction mixture was heated at reflux for 1 hour and then evaporated to dryness under reduced pressure. 100 ml of water are added to the residue and the mixture is rendered alkaline by stirring with 3N ammonium hydroxide solution.

The mixture was then stirred for an additional 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 sulfate and evaporated. The residue was recrystallized from ethanol to give L-1,5-dihydro-3,9-dimethylimidazo [2,1-b] quinazolin-2 (3H) -one, m.p. 259 DEG-261 DEG C. (.alpha.)_D = + 15.5 ° (c = 1%, in methanol).

Recrystallization of the base thus obtained from a 1N solution of hydrochloric acid and acetonitrile (ЗИ) gives the hydrochloride, m.p. 272 ​​DEG-275 DEG (decomposition).

The starting material is prepared as follows:

To a solution of 91.8 g of L-alanine ethyl ester hydrochloride in 300 ml of absolute ethanol, a solution of 120 ml of triethylamine in 200 ml of absolute ethanol is added dropwise over 30 minutes. The reaction mixture was heated to 60 ° to give a clear solution. To this solution was added dropwise a solution of 55.5 g of 3- (chloromethyl) -2-nitrotoulene in 300 ml of absolute ethanol over 1 hour. The temperature was then raised to 80 ° and the reaction mixture was stirred at this temperature overnight. It is then evaporated to dryness under reduced pressure and the residue is dissolved in 600 ml of water. This solution is extracted three times with methylene chloride and the extracts are washed successively with water and saturated sodium chloride solution, dried and evaporated. The crude product thus obtained is purified by chromatography on silica gel using a mixture of methylene chloride and 5% methanol as the solvent system. N- (3-methyl-2-nitrobenzyl) -L-alanine ethyl ester was obtained as a yellow oil. / alpha /_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 is hydrogenated in the presence of 2 g of 10% palladium on carbon. It is consumed within 5 hours

6.7 liters of hydrogen. After completion of the hydrogenation, the catalyst was filtered off and the filtrate was evaporated to dryness. There was thus obtained N- (2-amino-3-methylbenzyl) -L-alanine ethyl ester as a yellow oil (alpha)._D = -52.6 ° (»» 1% in methanol).

The following compounds were prepared in an analogous manner:

from 3- (chloromethyl) -2-nitrotoluene and D-alanine ethyl ester hydrochloride to give N- (3-methyl-2-nitrobenzyl) -D-alanine ethyl ester, a yellow oil. / alpha /_D = + 31.4 ° (с = 1% in methanol):

starting from α-chloro-4-nitro-m-xylene and ethyl L-alanine ethyl ester, ethyl ester of NO-meth / 1α-nitrobenzyl-L-elenine, a red oil, was obtained. [.alpha.] D -12.6 DEG (c = 1% in methanol): from alpha^P4-nitro-xplene and the ester of D-alanine ethyl ester are obtained^th^yyN- (5-tetulol-2-onltrobenzyl) -Daniline, red oil. [.alpha.] D = + 11.4 DEG (c = 1% in ethanol):

starting from .alpha.-chloro-1-nitro-o-xylene and ethyl ester of L-alanine ethyl ester, ethyl N- (2-ethyl-nitrobenzyl) -L-alanine is obtained; red oil, [.alpha.] D = + 35.8 DEG (c = 1% in cenamide);^forlf^and2^ochl^rr-3on^andtro-o-з^yof ethylene and the D-alanine ethyl ester hydrocM-orine are recovered^andwith^ká N- (2-methyl-16-nitro-benzyl) -D-alanine ethyl ester, red oil, [.alpha.] D = -34 DEG (c = 1% in ethanol);

from α-chloro-1-nitro-o-xylene and ethyl ester of L-serine hydrochloride to give ethyl 9A ^N- (2-meehy.)^l-L^-6nitrobθnz^zl)-^L-8θг^andnu^, red oil, n ^ = ¹,5⁴⁷⁴⁾ from alumino-4-oxo-oxo-ene and hydrochloride^idfor ethyl D-alpha^-^^^^^^ se ^gainsethyl ester ^N- (2-meet.)^hl16 - nitrobenzyl) - D-alpha red oil, n^2P = ^{1 ,}5²61;

from 2-nitrobenzyl chloride and hy^droch^lorThe ethyl ester of L-alanine gave ethyl 2-benzyl-L-alanine ethyl ester, dark red oil, [.alpha.] D @ -5.4 DEG (c = 1% in ethanol);

from 2-nitrobenzyl halide and D-alanine ethyl ester hydrochloride to give 4-nitrobenzyl-4-alanine ethyl ester, a red oil, [.alpha.] D @ + + 5.4 DEG (c = 1% in ethanol);

from ethyl N-3-ethyl-11-nitrobenzyl-D-alanine to give N- (2-a-ino-3-ethyl-4-benzyl-D-alanine ethyl ester, pale yellow oil) .alpha.^0,(c = 1% in Ethiopia);

from ethyl N- (5-meeth122-nitroben)^ofyl) .alpha.-L-alanine yields ethyl N- (4-a-ino-5-ethoxybenzyl) -L-alanine, [.alpha.] D -45 DEG (c = 1% in ethanol);

from N- (5-menthyl-12-nitrobenzyl) -Do ethyl ester_andl_andn-N-5-ethylbenzyl-D-alanine ethyl ester, red oil, [.alpha.] D = 34.2 DEG (c = 1% in ethanol);

starting from N- (2-amino-6-methylbenzyl) -L-alanine ethyl ester, N-02-methyl-6-nitrobenzyl) -L-alanine, yellow oil, [.alpha.] D -34.7 DEG (c = 1) % in eethianol);

from N- (2-meeth16-nitro-benzyl) -D- ethyl ester^andLanine gives N- (2α-amino-6-ethylbut-4-N-anaine) ethyl ester, reddish oil, [α] D + 36.8 ° (c = 1% in ethanol);

starting from N- (2-menthyl-11,6-nitro-benzyl) -L-serine ethyl ester, ethyl N- (4-α-ino-6-benzothiazole) -L-serine ethyl ester was obtained, red oil, np⁴ = 1,5468;

starting from N- (2-methoxyl) -naphthylbenzyl-L-D-α-phenynyl glycine ethyl ester to give N- (2-oxo-ethyl) -ethyl ester⁶-meehy^lbbnn^ylL-D-olfa-fe^nylgl^lC^andnu^{, of}lu^tolej oil, np^P = ^1,5665; from (2-nitrobenzyl) -L-alanine ethyl ester to give 2-aminobenzyl-L-alanine ethyl ester, red oil, [.alpha.] D @ 20 = 55.1 DEG (c = 1% in ethanol);

starting from 2-nitrobenzyl-D-alanine ethyl ester to give 2- [alpha] -inobenzyl-D-alanine ethyl ester, a light red oil, [.alpha.] D + 57.2 DEG (c = 1% in ethanol).

Example 2

Analogous to the procedure of Example 1, [eta] &amp; lt; 15 &amp; gt; -15-dihydro-3,9-diethylidazo [eta] &amp; lt; 1 &amp; gt;²1ob] hhinazolin-2 (3H) -hydrochloride. Melting point 270-275 ° (decomposition). The free base melts at 262-265 °.

Example d 3

In an analogous manner to that described in Example 1, L-1,5-dihydro-3,7-diethyl-imidazo [2,1-b] quinazole-22-ol was obtained from N- (2-a-ino-5-ethyl-benzyl) -o-alanine ethyl ester. 3H) o-hydroxyl chloride.

Light yellow crystals, m.p. 173-176 °. The free base melts above 300 ° with decomposition.

Example 4

In analogy to Example 1, D-1,5-dihydro-3,7-dimethylimidazo [2,1-blquinazolin-2 (3H) - was obtained from N- (2-amino-5-methylbenzyl) -D-alanine ethyl ester. on-hydrochloride. Light yellow crystals, m.p. 173-176 ° (dec.). The free base melts with decomposition at 310 to 314 °.

Example 5

In analogy to Example 1, L, 5-dihydro-3,6-dimethylimidazo [2,1-b] quinazoline-2 (3H) was obtained from N- (2-amino-6-methylbenzyl) -L-alanine ethyl ester. -one hydrochloride. Colorless crystals, m.p. 285 DEG-288 DEG (decomposition). The free base melts above 340 ° with decomposition.

Example 6

In an analogous manner to that described in Example 1, D-1,5-dihydro-3,6-dimethylimidazo [2,1-b] quinazoline is obtained from N- (2-amino-6-methylbenzyl) -D-alanine ethyl ester. -2 (3H) -one hydrochloride. The pale yellow crystals had a melting point of 287-290 ° (decomposition). The free base melts above 340 °.

♦

Example 7

Analogously to Example 7, L-1,5-dihydro-3-hydroxymethyl-6-methylimidazo [2,1-b] quinazoline-2 is obtained from N- (2-amino-6-methylbenzyl) -L-serine ethyl ester. (3H) -one hydrochloride. The yellow crystals have a melting point of 320 to 325 ° (decomposition).

Example 8

Analogously to Example 1, D-1,5-dihydro-3-phenyl-6-methylimidazo [2,1-b] quinazoline is obtained from N- (2-amino-6-methylbenzyl) -D-alpha-phenylglycine ethyl ester -2 (3H) -one hydrochloride. Light yellow crystals щцр! melting point about 320 ° (decomposition).

Example 9

Analogous to Example 1, L-1,5-dihydro-3-methylimidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride was obtained from 2-aminobenzyl-L-alanine ethyl ester. Brown crystals, m.p. 223-226 °. The free base melts at 300 to 305 ° with decomposition.

Example 10

Analogously to Example 1, D1,5-dihydro-3-methylimidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride was obtained from 2-aminobenzyl-D-alanine ethyl ester. Yellow crystals, m.p. 225-227 °. 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 20 ml of ethanol is added dropwise a solution of 5 g of cyanogen bromide in 20 ml of ethanol at room temperature with stirring. The reaction mixture was then refluxed for 1 hour, evaporated to dryness, water (150 ml) was added to the residue and basified with 3 N ammonium hydroxide solution with stirring. After stirring for 30 minutes, the precipitate was filtered off and recrystallized from 10% HCl solution. 9.1 g (68% of theory) of L-6-chloro-1,5-dihydro-3-methylimidazo [2,1-bquinazolin-2 (3H) -one-hydro203014 chloride are obtained in the form of yellow crystals, m.p. 260 DEG-263 DEG, [.alpha.] D @ + 34.2 DEG (dim^su1f-oxide).

D-6-chloro-1,5-dihydro-3-methylimidazo [2,1-b] quinazolin-2 (3H) -one-hycidochloride was obtained in an analogous manner from N- (2-amino-6-chloro-benzyl) -D ethyl ester -alanine. Melting point 263 DEG-266 DEG C., [.alpha.] D -23.9 DEG. Melting point of the free base^O.

The starting material can be cc^r° bit as follows:

To 18.24 g of L-alanine ethyl ester hydrochloride in 60 ml of ethanol was added dropwise a mixture of 25 ml of triethylamine in 60 ml of ethanol and the mixture was heated to 80 °. The resulting solution was added dropwise at this temperature to a solution of 15 g of 2-methyl-2-carboxylic acid. The mixture was stirred overnight at 80 DEG C. and then evaporated to dryness, the residue was treated with 150 ml of deionized water and extracted twice with 100 ml of methyl ether, the methylene chloride extracts were washed with water, dried and evaporated. se. The product thus obtained is purified by chromatography on -ethanol chloride and 5% methanol. 115.75 g (91% of theory) of N- (2-chloro-6-nitroitnyyl) -L-alanine ethyl ester are obtained. n = 1.5267.

N- (2-Chloro-6-nitro-ynyl) -D-alanine ethyl ester was obtained in an analogous manner from D-alanine ethyl ester and alia-2-chloro-6-nitrotoluene. = 1.5247.

A solution of 14.3 ethyl N- (2-chloro-6-nitrsitnyyl) -L-alanine ethyl ester in 50 mL of absolute ethanol was hydrogenated in the presence of 1 g of Raneeynikl. After completion of the hydrogenation, the catalyst was filtered off and the filtrate was evaporated to dryness. 12.6 g of N- (2-amino-6-chloro-benzyl) -L-alanine ethyl ester are obtained, m.p.² = 1.5430. VThe yield corresponds to 99% of theory.

N- (2-Amino-6-chloro-phenyl) -D-alanine ethyl ester is obtained in an analogous manner by hydrogenation of ethyl 4-N (2-chloro-6-nitrosienyl) -D-alanine, np = 1.5405.

Example 12

The following compounds were prepared analogously to Example 11 as described in Example 11:

D-6,7-dichloro-1,5-dihydno-3-methyllimido [2,1-b] clino-2-2H (2 H) -os-hexyl chloride, m.p. &amp; gt; 280 DEG;

L-6,7-dichloro-1,5-dihyfro-3-methylimidazo [2,1-b] pyridin-3-ylamino-2 (3H) -one-1-chlorobutyl, m.p. &amp; gt; 290 DEG,

D-7-Bromo-1,5-dilydro-3-methyl-imidimido [2,1-i] quinolin-2 (3H) -one-lyroside chloride, m.p. 268 DEG-270 DEG.

280 DEG-284 DEG C. (decomposition), m.p. 280 DEG-284 DEG (decomposition), m.p. 280 DEG-284 DEG (decomposition), m.p.

L-6-chloro-7-eths: α-115-dihydro-3-meth^,Quinazoline-2 (3H) -sn-ldrocClorif, m.p. &amp; gt; 280 °.

Example 13

The following compounds were prepared in an analogous manner to that described in Example 11:

from N- (2-chloro-6-nitrsienyyl) -3-ienyl-D-alanine, ethyl, β-ester, [α] D -21.2 ° (c =&gt; 1% in ethanol) via N- (2-ethyl ester) α-ω-6-chlorosyl-3-phenyl-D-alanine, [α] D + 40.7 ° (c = 1% in ethanol) gave D-3-diethyl-6-chloro-1 5-dilydrsi-ida [2,1-i] clolinolin-2 (ЗH) -one-lydro-ΛΓΛ ^then^{í 260} up to · ²⁶5° ⁽rozkla^d). Pulse^pota t^ánand ^band^ofE ²⁷⁰ and²75° ^(rozkland^(d)· From N- (2-chloro-6-nitrobenzyl) -D-leucine ethyl ester via N- (2-amino-6-chlorobenzyl) -D-leucine ethyl ester, (alpha)_D + 8.5 ° (s = 1% in ethanol) gave D-6-chloro-1,5-dihydro-3-isobutylimidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride, m.p. 290-293 ° . The melting point of the base is 280-285 °.

from N- (2-chloro-6-nitrobenzyl) -D-serine ethyl ester, [.alpha.] D @ 20 = 2.7 DEG (1% in ethanol) through N-2- (amino-6-chlorobenzyl) -D- ethyl ester serine, melting point 73-75 °, (alpha)_D + 65.5 ° (с = 1% in ethanol) gave D-6-chloro-3-hydroxymethyl-1,5-dihydroimidazole-2,1-bquinazolin-2 (3H) -one hydrochloride, m.p.&gt; 300 ° (decomposition).

from DN- (2-chloro-6-nitrobenzyl) -2-phenylglycine ethyl ester, [.alpha.] D -21 DEG (c = 1% in ethanol), via D-N- (2-amino-6-chlorobenzyl) ethyl ester - 2-phenylglycine, [.alpha.] D @ -4.5 DEG (s = 1% in ethanol) affords D-6-chloro-3-phenyl-1,5-dihydroimidazo [2,1-b] quinazoline-2 (3H) - on hydrochloride, m.p. &amp; gt; 300 DEG (decomposition). 260 DEG-265 DEG (decomposition).

Example 14

To a solution of 5 g of D-1,5-dihydro-3-methylimidazo (2,1-b) quinazolin-2 (3H) -one in 80 ml of glacial acetic acid was added dropwise 1.5 ml of bromine. hours at room temperature, then diluted with 100 ml of water, concentrated to a volume of 30 ml, diluted again with 100 ml of water, basified with 3 N ammonium hydroxide solution, washed and filtered The product precipitated was washed with water and recrystallized from 100 ml. 2 N hydrochloric acid. 3.9 g (56%) of D-7-bromo-1,5-dihydro-3-methyl-imidazo [2,1-b) quinazolin-2 (3H) -one hydrochloride are obtained, m.p. 268-270. °.

Example 15

In analogy to Example 14, 4.7 g of L-1,5-dihydro-3-methylimidazo [2,1-b] quinazolin-2 (3H) -one is brominated to 4.2 g (64%) of L-7- bromo-1,5-dihydro-3-methyl-imidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride, m.p. 280-284 ° (dec.).

Example 16

Tablets of the following composition are prepared in a conventional manner:

<td>D-6-chloro-1,5-dihydro-3-methylimidazo-</td><td></td><td></td>

<td>[2,1-b] quinazolin-2 (3H) -one hydrochloride</td><td> 184,6</td><td>mg</td>

<td>lactose</td><td> 15,0.</td><td>mg</td>

<td>cornstarch</td><td> 37,9</td><td>mg</td>

<td>νθ water-soluble polyvinylpyrrolidone</td><td> 10,0</td><td>mg</td>

<td>magnesium stearic acid salt</td><td> 2,5</td><td>mg</td>

<td>total weight per 1 tablet</td><td> 250,0</td><td>mg</td>

<td>Example 17</td><td></td><td></td>

Gelatin insert capsules of the following composition are prepared in a conventional manner:

<td>D-6-chloro-1,5-dihydro-3-methylimidazo-</td><td></td><td></td>

<td>[2,1-b] quinazolin-2 (3H) -one hydrochloride</td><td> 200,0</td><td>mg</td>

<td>water-soluble polyvinylpyrrolidone</td><td> 2,0</td><td>mg</td>

<td>cornstarch</td><td> 43,0</td><td>mg</td>

<td>talc</td><td> 4,5</td><td>mg</td>

<td>magnesium stearic acid salt</td><td>. M</td><td></td>

<td>total weight per capsule</td><td> 250,0</td><td>mg</td>

An injection solution of the following composition is prepared in the usual manner:

Example 18

D-Clhor-1,5-dihydro-3-methylimidazo [2,1-b] quinazolin-2 (3H) -one hydrochloride glycerirformal water

4.16 mg

2.4 ml

4.0 ml