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

MINISTRY OF INDUSTRY AND ENERGY

Industrial Property Registry

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<img file="ES471981A1_D0002.tif" />

SPAIN

Granted the Register of agreement @ with those listed in the pre · _6&amp;»Te d ^ crypto and. according to the oon · had of the attached Memory.

(RAN 4044 / 50-000)

INVENTION PATEWTE

HUMERUS

one 98 1 © Al

<td>θ PRIORITIES? ^ NUMBER</td><td>θ DATE</td><td>(know</td>

<td> 77.829</td><td>July 25 '1,977</td><td>Luxembourg</td>

<td> 5776/78</td><td>May 26, 1978</td><td>Switzerland</td>

<td>θ TECHA OE PUBLICITY _________________</td><td>(^ INTERNATIONAL CLASSIFICATION</td><td>θ OUE PATENT IS DIVISIONARY</td>

<td colspan="3"> // ✓</td>

θ TITLE OF THE INVENTION

A PROCEDURE FOR THE PREPARATION OF IMIDAZOQUINAZOLINE DERIVATIVES θ APPLICANT (YES

F. HOFFMANN-LA ROCHE &amp; CIE., SA

APPLICANT'S ADDRESS

BASEL (Switzerland) ____ © inventor teai

Madhukar Underlines Chodnekar - Ado Kaiser @ TITULAIS IESI

F. HOFFMANN-LA ROCHE &amp; CIE., SA

θ REPRESENTATIVE

Mr. JAIME ISERN CUYAS, Official Agent of Industrial Property.

UNC A · 4 MOO. 9100

BE USED AS THE FIRST MEMORY PAGE

DESCRIPTIVE MEMORY

The present invention relates to tricyclic compounds, More particularly the invention relates to imidazoquinazoline derivatives, a process for their preparation and the pharmaceutical preparations containing them,

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

<img file="ES471981A1_D0003.tif" />

where

R.

and R each represent a hydrogen or halogen atom or a group of lower alkyl, hydroxy, lower alkoxy, hydroxy- (lower alkyl), (lower alkoxy) - (lower alkyl), phenyl, phenoxy, araino , lower alkylamino or di '(lower alkyl) amino or 2 and R in adjacent carbon atoms together represent a methylenedioxy group, represents a hydrogen atom or a lower alkyl or phenyl group and

- 3 R 'represents a group of lower alkyl, hydroxy- (lower alkyl), (lower alkoxy) - (lower alkyl), aryl- (lower alkyl) or aryl, their tautomers and the salts of these compounds.

The lower term "used herein refers, in particular, to groups containing 1-6 carbon atoms, especially 1-4. The alkyl groups may be straight chain or branched chain.

Examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and hexyl »The term" aryl "denotes, in particular, the phenyl group or a phenyl group substituted by halogen, lower alkyl, hydroxyl and / or lower alkoxy.

Among the compounds of formula-1, those that exist in the D form are preferred. In addition, compounds of the formula I are preferred wherein R each represents a hydrogen atom, R represents a halogen atom at position 6 or 7 or a lower alkyl group at position 6, especially a Chlorine atom in position 6, a bromine atom in position 7 or a methyl group in position 6, and represents a lower alkyl group, especially a methyl group.

Especially preferred imidazoquinazoline derivatives provided by the present invention are: D-ó-chloro-1,5-dihydro-3-methyl-imidazo [2,1-bjquinazolin-2 (3H) -one,

Dl, 5-dihydro-3,6-diethyl-imidazo £ 2, l-bJquinasolin-2 (3H ~ or.a, 5 D-7-bromo-1,5-dihydro-3-methyl-imidazo [2, l -blquinazolin

-2 (3H) -one, and its salts.

Examples of other imidazoquinazoli na derivatives provided by the present invention are:

L-6-chloro-l, 5-dihydro-3-hydroxymethyl-imidazo £ 2, l-bj ~ quinazolin-2 (3H) one,

L-6-chloro-l, 5-dihydro-3-phenyl-imidazo [2, lb} quinazolin2 (3H) -onaj

L-6-chloro-l, 5-dihydro-3-isobutyl-imidazoC2 »l ~ b] .- quinazolin ~ 15-2 (3H) -one,

L-3-benzyl-6-chloro-l, 5-dihydro-imidazo [2, l-blquinazolin-2 (3H) -one and its salts.

The compounds of the formula I can be found in various tautonic forms. Accordingly, the invention is not limited to the compounds of the formula I set forth above, but also includes the tautomers, for example those of the formulas

<img file="ES471981A1_D0004.tif" />

where . 12 3 4

R, R, R, and R have the meaning indicated above »

The compounds of the formula I and their tautonomists (for example of the formulas la and Ib) can be in the form of racemates or in optically active form, all 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, salts of mineral acid such as hydrochlorides, hydrobromides, sulfates and phosphates, salts formed with organic sulfonic acids such as alkyl sulfates and arylsulfonates and salts of carboxylic acids such as succinates, citrates, tartrates and maleates.

According to the process provided by the present invention, the aforementioned imidazoquinazoline derivatives S (ie the compounds of the formula I, their tautomers and the salts of these compounds) are prepared (a) by reacting a compound of the general formula

<img file="ES471981A1_D0005.tif" />

(XI) where

3Δ

R, R, R and R have the meaning indicated above, and r5 represents a lower alkyl group, with cyanogea bromide, or (b) treating a compound of the general formula

<img file="ES471981A1_D0006.tif" />

(III) where

two 3 Λ 5

R, R, R, R'and R have the meaning indicated above, with ammonia, and, if desired, converting a resulting compound of the respective formula I or tautomer into a salt.

The reaction of a compound of the formula II with cyanogen bromide according to the method (a) of the process is conveniently carried out while heating in a solvent such as a lower alcohol (for example ethanol).

The treatment of a compound of the formula III with ammonia according to the modality (b) of the process

- »4 Λ is conveniently carried out while a solvent such as a lower alcohol (for example ethanol) and water is heated in 15.

A compound of the formula I wherein R ^. And / or

- R represents a hydrogen atom can be halogenated. In a manner known per se. So, for example, nail-so »3 · a»:

A solution of a compound of the formula I, which is unsubstituted in positions 6,7,8 and 9, in acetic acid can be reacted with bromine to obtain a compound

7-bromine of the formula I,

The compounds of the formula I, where

2

R and R have a different meaning of an amino, lower alkylamino or cli (lower alkyl) amino group can be prepared in accordance with reaction scheme I below, where Y represents a chlorine or bromine atom 11 21

R and R have any of the agreed values ​​for

R '' and R ^ described above with the exception of amino, lower alkyl and di (lower alkyl) amino and R have the meaning indicated above.

Additionally, the compounds of the formula I can be prepared according to the reaction scheme II that follows, wherein Z represents an oxygen or azure atom 3 3 fre, M represents ammonium, potassium and sodium and R, R, R and Λ

R 'have the meaning indicated above.

<img file="ES471981A1_D0007.tif" />

-9- Reaction scheme I

5.

<img file="ES471981A1_D0008.tif" />

^ / Pt, Pd or Ni ñaney for ex. in c_H „OH £» or

<img file="ES471981A1_D0009.tif" />

BrCN for Ex in ^C2^H5^OH

<img file="ES471981A1_D0010.tif" />

Y — CH — COY l ·

M By e3.in THE O ° -1OO ° C

Reaction Scheme II

Κλ

<img file="ES471981A1_D0011.tif" />

acetic acid or 'pyridine 25 ° -l00 ° C

Jt-Z-CN

V

<img file="ES471981A1_D0012.tif" />

<img file="ES471981A1_D0013.tif" />

: h ch₃i / k₂co₃

THF, 2O ° -1OO ° C

SCHq

<img file="ES471981A1_D0014.tif" />

: h

25.

-10Hg / Ρΐ, 0 Ni Raney for example in CoH ^ OK

10.

<img file="ES471981A1_D0015.tif" />

Q] 1 ^ 2 ^ 3 * C2H5OH or pyridine

20 ° C - reflux 1-50 atm.

<img file="ES471981A1_D0016.tif" />

e.g. in ^C2^H5^OH

Hj / Pt, Pd o -'i Raney

-í&gt;

Y

<img file="ES471981A1_D0017.tif" />

15.

KH, in CH OH oj 25 pyridine

2O ° -lC0^orC,

1—50 &amp; l «u ·

<img file="ES471981A1_D0018.tif" />

20 «• The starting materials of formulas II and III can be prepared according to reaction scheme III below, where X represents a halogen atom and 1 2 3 4 5

R, R ~, R^j, Ií and R have the meaning indicated above or in analogy to the methods set forth in the examples.

Reaction Scheme III

<img file="ES471981A1_D0019.tif" />

<img file="ES471981A1_D0020.tif" />

<img file="ES471981A1_D0021.tif" />

R '

R

<img file="ES471981A1_D0022.tif" />

(III)

The compounds of the formula I, their tauthorics and physiologically compatible salts of these compounds are used as medicaments. These inhibit, for example, the aggregation of blood platelets and, consequently, can be used for thrombosis prophylaxis. They are also active on the circulatory system.

Based on their positive inotropic activity without substantial tachycardia, they can be used for the treatment and prophylaxis of heart failure and heart failure.

The compounds of the formula I, their tautonomists and physiologically compatible salts of these compounds can be used as drugs, for example, in the form of pharmaceutical preparations containing them in association with a compatible pharmaceutical carrier material. This carrier material may be an organic or inorganic inert carrier material that is suitable for enteral, percutaneous or parenteral administration such as, for example, water, gelatin, gum arabic, lactose, aluminum, magnesium stearate, talc, oils polyalkylene glycol vegetables, petrolatum, etc.

Pharmaceutical preparations can take a solid form (for example of pills, dragees, suppositories or capsules), semi-solid form (for example of ointments) or liquid form (for example of solutions, suspensions or emulsions) · Pharmaceutical preparations can be sterilized and / or may contain adjuvants such as preservatives, stabilizers, wetting agents or emulsifiers, salts for varying osmotic pressure or tarapones. They may also contain other therapeutically valuable substances. The compounds provided by the present invention are preferably administered orally. In the case of adults, a daily dose of 0.5 mg / kg at 30 mg / kg can be administered orally and • a parenteral dose can be administered daily from 0.05 mg / kg to 10 mg / kg *

Aggregation inhibition activity was demonstrated according to the method of the BORN aggregometer [lJa ture 194, 927 (1962)] and MECHAl and BORÍJ [llature. 231,

220 (1971)] · As the test parameter the maximum aggregation speed and effective concentration (EC ^_that) was determined from the dose activity curves.

Human plasma was obtained by centrifugation from venous blood treated with citrate (10.6 πύΐ),

0.18 cc of plasma was treated with 10 microliters of an aqueous suspension of the test substance and the mixture was incubated at 37 for 10 minutes, after which aggregation was started by adding 10 microliters of fibril suspension collagen

Rabbit plasma was obtained by centrifugation from citrate-treated arterial blood (9 raM), 1 ml of plasma was treated with 10 microliters of test solution and the azure was incubated at 37^fiC for 1 minute, after which 8 microliters of collagen fibrils suspension were added to 10 microliters of adenosine diphosphate (ADP) in sodium chloride solution 10 As a control, plasma incubated with dimethyl sulfoxide was used.

The results are shown in table I 'below.

Positive inotropic activity was measured after oral administration of the test substances to conscious shepherd dogs. For this purpose the animals were provided with an implanted pressure-telemetry system, whereby the pressure receptor is fixed in the left ventricle. The left ventricular pressure is sent from the animal through the implanted radio transmitter and received through an appropriate antenna and receiver system, demodulated and amplified. With the differentiation of the ascending lateral of the left ventricular pressure (LVP), the maximum pressure increase speed (DLVP / dt ^^) that represents the contractility parameter is calculated. Simultaneously, the heart rate is recorded through a cardiotacograph. The percentage variation (/ \ of dLVP / dty the duration of the activity in minutes (min) is indicated under innotropy. Under max tachycardia, the percentage variations of the heart rate are indicated (after administration of the test substance and the duration of the activity in minutes (min). The results are expressed in Table II below.

Table I

Blood platelet aggregation induced by genus tail and by ADP - ·

<td rowspan="2">Test substance (imidazo quinazoline derivative</td><td colspan="2">Rabbit plasma</td><td>Plasma, human</td>

<td>Collage- do not EC 50 ¿iM</td><td>ADP EC 50 ¿iM</td><td>Collagen EC $ 0 pM.</td>

<td>Dl hydrochloride, 5-dihydro</td><td></td><td></td><td></td>

<td>-3,9-dimethyl-imidazo / 2,1-b /</td><td></td><td></td><td> - -</td>

<td>quinazolin-2 (3H) -one</td><td> 3,0</td><td> 32</td><td> 26</td>

<td>L-1,5-dihydro -3,9-dimethyl-imidazo / 2,1-b / quina zolin-2 (3H) -one hydrochloride</td><td> 18</td><td> 60</td><td> 49</td>

<td>Dl hydrochloride, 5-dihydro</td><td></td><td></td><td></td>

<td>-3,7-dimethyl-imidazo / 2,1-b / quinazolin-2 (3H) -one</td><td> 3,1</td><td> 19</td><td> 3,4</td>

Table I (continued)

<td></td><td>Ll hydrochloride, 5-dihydro -3 »7-dimethyl-imide zo2 _t lb / quinazolin-2 (3K) -one</td><td>í 22</td><td> 1 ¹ 77</td><td> - 33</td>

<td> 5</td><td>Dl hydrochloride, 5-dihydro '-3 and 6-dimethyl-imidazo / 2, lb / quinazolin-2 (3H) -one</td><td> 0,19</td><td> 1 2, 2</td><td> 2,3</td>

<td></td><td>Ll Hydrochloride, 5-dihydro-3 _F6-dimethyl-imidazo / 2, lb / quinazolin-2 (3H) -one</td><td> 0,93</td><td> 11</td><td> 6,2</td>

<td>1Ó</td><td>Ll hydrochloride, 5-dihydro-3-bidroxiaethyl-or-methyl-imide l zo / 2, l-b7quinazolin-2 (3H) ~ one i</td><td> -</td><td> 1</td><td> 14</td>

Table II

15.

<td rowspan="2">Test substance (imidazoquinazoline derivative)</td><td rowspan="2">Dose mg / kg</td><td colspan="2">Inotropia</td><td colspan="2">Heart rate</td>

<td colspan="2">% Min</td><td>Δ</td><td>Min</td>

<td>D-6-Chloro1 hydrochloride, S-dihydro-S-methyl-iraida zo2, l-b7quinazolin-2 (3H) one</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 ~ b7quinazolin-2 (3H) -one hydrochloride</td><td> 10</td><td> 32</td><td> 440</td><td>or⁶ 3 -,·</td><td>CO OR</td>

<td>Ll hydrochloride, 5-dihydro-3,9-dimethyl-imide zo ¿2, l-b7quinazolin-2 (3H) -one</td><td> 10</td><td> 43</td><td> 120</td><td> 16</td><td> 100</td>

- 17 The following examples illustrate the procedure provided by the present invention.

EXAMPLE 1,

A solution of 5.3 g of cyano-5 bromide in 10 ml of ethanol was added at room temperature and with stirring to a solution of 11.8 g of ethyl ester of U- (2-amino-3-raethylbenzyl) -L-Alanine in 30 cc of ethanol. The mixture was heated under reflux for 1 hour and then; go evaporated to dryness under reduced pressure. The residue was treated with 100 ml of water and made alkaline with the addition of 3 ~ H 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 co of water each time, dried over sodium sulfate and evaporated.

The residue was recrystallized from ethanol and gave Ll, 5-d ± hydro-3,9-dimethylimidazo [2, lb} quinazolin-2 (3H) -one melting point 259⁸-2612Cj [alfal ^ "+15.5⁸ (c &lt;= »1% in methanol).

With the recrystallization of the base ”thus obtained from 1-N hydrochloric acid / acetonitrile (3? 1) melting point hydrochloride 2722-275 was obtained⁸C. (decomposition).

The starting material was prepared as follows

A solution of 120 cc of triethylamine in

200 cc of absolute ethanol was instilled, during a period of

- 18 30 minutes, to a solution of 91.8 g of L-alanine ethyl ester hydrochloride in 300 ml of absolute ethanol.

The mixture was heated to 60SC, resulting in a clean solution. To this solution, a solution of 55.5 g of 3- (chloronethyl) -2-nitrotoluene in 300. ml of absolute ethanol was instilled for 1 hour. The temperature was then increased to SOSO and the 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 / methanol at __ to elution. N- (3-methyl-2-nitrobeacyl) -L-alanine ethyl ester was obtained in the form of a yellow oil; [alpha} _ = -362 (_c »1% in methanol)»

A solution of 26.6 g of N- (3-methyl-2-nitrobenzyl) -L-alanine ethyl ester in 100 ce of absolute ethanol was hydrogenated in the presence of 2 g of $ 10 palladium carbon. In 5 hours 6.7 liters of hydrogen were collected. After completion of the hydrogenation, the catalyst was filtered off and the filtrate was evaporated to dryness. Ethyl ester of IT- (2-amino19 -

-3-methylbenzyl) -L-alanine in the form of a yellow oil) [alpha] ^ w -52.62 (c »1 $ in methanol).

Similarly:

from 3- (chloronethyl) -2-nitrotoluene and ethyl ester hydrochloride of D- * alanine, ethyl ester of I-3 ~ (methyl ~ 2-nitrobenzyl) -D-alanine was obtained in the form of a yellow oil) [ alpha] ^ »+ 3l₉4e (1% in methanol) and from L-alanine alpha-chloro-4-nitro-ra-xylene and ethyl ester hydrochloride, N- (5-methyl-2-nitrobenzyl) ethyl ester was obtained - L-alanine in the form of a red oil) [alphaj ^ "-12.62 (c« 1 $ in methanolj from alpha-chloro-4-nitro-ni-xylino and D-alanine ethyl ester hydrochloride was obtained ethyl ester of II- (5-raethyl-2-nitrobenzyl) -D-alanine in the form of a red oil) [alpha] ^ - +11.4^S (c - 1 $ in methanol ·)) 'from alpha-chloro-3-nitro-o-xiIeno and L-alanine ethyl ester hydrochloride was obtained

Λ Ethyl ester of IJ- (2-methyl-6-nitrobenzyl) -L-alaniria in the form of a red oil) [alpha] = + 35.8® (c “l ^ in net, ·» nol) from alpha-chloro-3-nitro-o-xylene and D-alanine ethyl ester hydrochloride was obtained ethyl ester of H- (2-methyl-6-nitrobenzyl) -D-alanine in the form of a red oil falfa '^ =

-34^and (c »1 $ in methanol) from alpha-chloro-3-nxtro-o-xxlene and L-serine ethyl ester hydrochloride was obtained N- (2-methyl ~ 6-nxtrobenzyl) -L- ethyl ester U-shaped serine 24 red oil n ^ - 1,5474?

from N-(2-methyl-6-nitrobenzyl) -D-alpha 24 N-(2-methyl-6-nitrobenzyl) -D-alpha 24 ethyl ester was obtained from alpha-clcro-3-nitro-o-xylene and ethyl ester hydrochloride

-phenylglycine in the form of a red oil n ^ = 1, 526lj from 2-nitrobenzyl chloride and L-alanine ethyl ester hydrochloride, 2-nitrobenzyl-L-alanine ethyl ester was obtained in the form of a dark red oilj [alphaj ^ = -5.4^S (or "1% in ethanol) from 2-nitrobenzyl chloride and D-alanine ethyl ester hydrochloride, (2-nitrobenzyl) -D-alanine ethyl ester was obtained in the form of a red oil Calm} jj = + 5.4^and (c ~ 1% ⁱⁿ ethanol) From ethyl de-3-methyl-2-nxtrobenzyl-D-alanxna ethyl ester, ethyl ester of N- (2-amino-3-methylbenzyl) -D-alanine was obtained in the form of a light yellow oil [ alpha ^ - +51^s (c-1% in methanol) From ethyl ester of Ii- (5-methyl-2-aitrobenzyl) -L-alanine, ethyl ester of iT- (2 ~ amino-5-methylbenzyl) -L-alanine was obtained [alphaj ^ = -45^s(c = Ifi in methanol) From ethyl ester of IJ- (5-methyl-221-nitrobenzyl) -D-alanine, N- (2-aoi-, non-5-motylbonzyl) -D- ethyl ester was obtained alanine in the forage of a red oil; [alfal_D = +34,22 (_c «1% in methanol);

from 1- (2-amino-6-methylbenzyl) -L-alanine ethyl ester was obtained from N- (2-raethyl-6-nitrobenzyl) -L-alanine ethyl ester as a yellow oil; [alfal ^ = -34.7^and (c = 1% in methanol);

from ethyl ester of U- (2-methyl-6-nitrobenzyl) -D-alanine, ethyl ester of II- (2-amino-6-nethylbenzyl) -D-alanine was obtained in the form of a reddish oil; [alfajjj = + 3ó, 8s (_c «1% in methanol);

Ethyl ester was obtained from II- (2-nethyl-6-ni tr obenzyl) -L-serine ethyl ester; of.-11- (2-amino-6-methylbenzyl) -L-serine in the form of a red oil; n *⁴» 1,5468;

From ethyl ester of ll ~ ('2 ~ methyl-6-nitrobenzyl) -D-alpha-phenylglycine, ethyl ester of {- (2 ~ amino-6 ~ methylbenzyl) -D-alpha-phenylglycine was obtained in form of a yellow oil; n ^ '= 1.5665; 'from 2' aminobenzyl-L-alanine ethyl ester from. '(^ nitrobenyl) -L-alanine was obtained in the form of a red oil; [alfal_D = -55.1® (c »1% in ethanol);

and from 2-nitrobenzyl-D-alanine ethyl ester, 2-aminobenzyl ^ D-alanine ~ ethyl ester was obtained in the form of a dark red oil; [alpha] ^ «= +57.22. (c = 1% in ethanol) »

EXAMPLE 2

Analogously to that described in Example 1, Dl hydrochloride was obtained from ..H- (2-amino-3-methylbenzyl) -D-alanine ethyl ester₃5-dihydro-3,9-dimethylinidazo [2, l-bl-quina3olia-2 (3K) -one melting point 27O2-275^gC (decomposition) «The free base melts

2622-26520.

EXAMPLE 3

Analogously to that described in Example 1, from Ll- 5-dihydro hydrochloride, N-(2-amino-5-methylbenzyl) ~ -L-alanine hydrochloride was obtained. "? 2 ', 7-dimethylimidazo [2, l-b3-quinazolin-2 (3H) -one in the form of cris *

«T such light yellow melting point 173^G-176^fiC · The free base melts above 3002C with decomposition.

EXAMPLE 4

Analogously to that described in example 1, starting from ethyl ester of H- (2-amino-5-methylbeneyl) -D-alanine, Dl, 5-dihydro-3,7-diraethylimidazo hydrochloride [2, 1- b3quinazolin-2 (3H) one in the form of light yellow crystals of melting point 173²-17 or 2C (decomposition). Free base melts at 31O^S-314^SC with composition.

- 23 EXAMPLE 5

Analogously to that described in Example 1, from Ll- 5-dihydro ~ 3,6-dinethyl * inidazo hydrochloride [2, 1] was obtained from H- (2-amino-6-methylbenzyl) -Lalanine hydrochloride -b3quinazolin-2 (3H) -one in the form of colorless crystals of melting point 285^S-2882C (decomposition).

The free base melts above 3402C with decomposition.

EXAMPLE 6

Analogously to that described in Example 1, Dl, 5-dih ± dro-3,6-dimethylimidazo C2 hydrochloride was obtained from the ethyl ester of í- (2-arr.ino-6-methylbenzyl) ~ D-alanine , l-bJquinanolin-2 (3H) -one in the form of light yellow crystals of melting point 2872-2 ^ 020 (decomposition). The free base melts above \ 3402C.

EXAMPLE 7

Analogously to that described in example 1, starting from ethyl ester of Ii- (2-amino ~ 6-methylbenzyl) -L-serine, Ll.5-dihydro-3-hydroxymethyl hydrochloride * «HH hydrochloride was obtained

-6-methyl-imidazoL2, l ~ bj, quinazolin-2 (3H) -one in the form of such melting pinito yellows 32O2-325^SC (decomposition.)

EXAMPLE 8

Similar to that described in Example 1, Dl, 5-dihydrochloride was obtained from N- (2-amino-6-aethylbenzyl-D-alpha-phenylglycine ethyl ester)

-3-phenyl-6-methyl-imidazo [2, l-blquinazolin-2. (3H) -one in the form of light yellow crystals of melting point around 32O2C (decomposition) i

EXAMPLE . 9

Analogously to that described in example 1, from Li-5-dihydro-3-methyl-imidazo hydrochloride [2-amino-benzyl-L-alanine ethyl ester [2]_íl-b ']. -quinazolin-2 (3H) -one in the form of brown crystals of melting point 223^S-2262C. The free base melts at 30023O52C with decomposition,

EXAMPLE 10,

Analogously to that described in Example 1, Dl, 5 ~ dihydro-3-methyl-imidazo £ 2,1-bjquinazolin-2 (3H) hydrochloride was obtained from 2-amino-beacyl-D-aIanine ethyl ester ) -one in the form of yellow crystals; melting point 225^and-227 ^SC »The free base melts at around 30020 with decomposition. '· EXAMPLE 11' '7

A solution of 5 g of cyanogen bromide in 20 ml of ethanol was instilled at room temperature and with stirring to a solution of 11.9 g of ethyl ester of IJ- (2-amino-6-chlorobenzyl) - L-Alanine in 20 cc of ethanol. The mixture was then boiled under reflux for 1 hour and evaporated to dryness. The residue was treated with 150 ml of water and made alkaline with 3-U ammonium hydroxide while stirring. After stirring for 30 minutes, the precipitate was filtered off and recrystallized from 1-N hydrochloric acid and acetonitrile. 9.1 g (68 $ of theory) of L-6-chloro-l, 5-dihydro-3-methyl-iraidazo hydrochloride [2, l ~ b} quinazolin-2 (3H) -one was obtained as crystals melting point yellows 2OO2-2ó3^andCj [alfalp »+34.22 (in diraethyl sulfoxide),

Similarly, from D- 6-chloro-1, 5-dihydro-3-methyl-imidazo [2-amino-6-chloro-benzyl-D-alanine ethyl ester, [2] , 1-bl quinazolin-2 (3H) -one of melting point 2 or 3^and-2662Cj [alfal ^ = -23.9^fi(in dinethyl sulfoxide); melting point of the free base 275S-28O2C,? , The starting material can be prepared as follows: ''

18.24 g of ester hydrochloride were instilled

-Ί ethyl of L-alanine in 60 ml of ethanol to a mixture of cc of triethylamine in 60 ml of ethanol and the

Λ * mix up to 8O2C, The resulting solution was instilled, to is&gt; 3.

*. * ta temperature, in a solution of 15 g of alpha-bromo-2-chloro-6-nitrotoluene in 60 ml of ethanol. The mixture was stirred at 802C overnight and then evaporated to dryness. The residue was treated with 150 ml of deionized water and extracted twice with 100 ml of methylene chloride.

The extracts of methylene chloride were washed with water, dried and evaporated. The resulting product was purified by chromatography on silica gel with 5% methylene chloride / methanol · 15.75 S (91 $ of theory) of ethyl ester of U- (2-chloro-or-nitrobenzyl) - L20

-alanine) n ^ = 1.5207 »

<img file="ES471981A1_D0023.tif" />

from ethyl ester of D-alanine and alpha-bromo-2-chloro-6-nitrotoluene

A solution of 14.3 g of ethyl ester of

N- (2-Chloro-6-nitrobenzyl) -L-alanine in 50. cc of absolute ethanol was hydrogenated in the presence of 1 g of Raney nickel. After completion of the hydrogenation, the catalyst was removed by filtration and the filtrate was evaporated to dryness.

tf M

12.6 g (99% of the teroria) of ethyl ester 22 were obtained ^UJ of ii- (2-amino-6-chlorobenzyl) -L-alanine jn ^ = 1.5430.,

Similarly, ethyl ester of

<img file="ES471981A1_D0024.tif" />

generating the ethyl ester of IJ- (2-chloro-6-nitrobenzyl * 1) ~ Dalanine.

EXAMPLE 12

Similar to that described in the example, we obtained:

D-6,7-dichloro-X hydrochloride, 5-dihydro-3-methyl-imidazo · j2, lb] quinazolin-2 (3H) -one melting point higher than

280fiC, L-ó, 7-dichloro-1 hydrochloride, 5-dihydro-3-methyl-imidazo [2, l-blquinazolin-2 (3H) -one melting point higher than 2902C, D-7- hydrochloride Bromo-1,5-dihydro ~ 3-methyl-imidazo [2, lb], quinazolin-2 (3H) -one melting point 2682-2702C, L-7-bronorl hydrochloride, 5-dihydro-3-methyl ~ imidazo [2, l ~ bl i

quinazolin-2 (3H) -one melting point 28O £ -284^fiC (decomposition), and L-6-chloro-l, 5-dihydro-3-methyl-7-methoxy-imidazo hydrochloride [2, lb / kina zolin-2 (3H) -one melting point higher than 28OSC.

EXAMPLE 13 * '

Analogously to that described in example 11, from N- (2-chloro-6-nitrobenzyl) -3- ethyl ester

<img file="ES471981A1_D0025.tif" />

obtained, through N- (2-anino ~ 6-chlorobenzyl) -3-phenyl-D-alanine / £ alfal ethyl ester_D =&gt; + 40.7- (c - 1% in ethanol) D-3 ~ benzyl-6 ~ chloro hydrochloride «, 5 ~ dihydro-imiazo [2, lb} quinazolin-2 (3H) -one point melting 260.2C-265²C (decomposition); melting point of base 2702-275²C (decomposition);

from ethyl ester of li- (2-chloro-6-nitrobenzyl) -D-leucinn oe obtained, through ethyl ester

<img file="ES471981A1_D0026.tif" />

- 28 10 +8,5^S (c “1% in ethanol) / ^ D-6-chloro-l hydrochloride, 5 ·

-dihydro-3-isobutyl-imidazo [2, l-bjquinazolin-2 (3H) -one, melting point 2902-293^SC; melting point of the base

28O2-2852C;

from ethyl ester of M- (2-chloro-onitrobenzyl) -D-serine / ~ [alpha3._D = 2,7^S (c-1 / £ in ethanol) / was obtained, through the ethyl ester of IT- (2-amino-6-clo robenzyl) -D-serine [melting point 73²-75^sC; [alphaj ^ = +65.5² (c ^and 1% in ethanol O / ^, D-6-chloro-3 hydroxymethyl-1,5-dihydro-inidazo hydrochloride [2,1-blquinazolin-2 (3H) -basin base melting point higher than 3002C (decom position),; and from the ethyl ester of D-II- (2-.-chloro-6-nitrobenzyl) -2-phenylglycine = - 212 (c&gt; = 1% in ethanol) ^ / was obtained, through ethyl ester of D- II (2-amino ~ 6 ~ chlorobenzyl) ~ 2-phenylglycine ^ / [alfal ^ - -4.5²(c = 1% in ethanol) ^, D-6-chloro-3-phenyl-l hydrochloride, 5 "dibydro-iraidazoC2, l-b'J, quinazolin-2 (3K) -one of higher melting point at 3002c (decomposition); melting point of base 2OO2-265²C (decomposition). )

EXAMPLE 14

Heated to 1102 overnight, in a pressure tube, a mixture of 6 g of D-2,5-dichloro-alphamethyl-3 (4H) -quinazine ethyl acetate, 20 ml of absolute ethanol and 25 ml of ammonia 5% alcoholic, The pressure tube was cooled in an ice bath and opened. The resulting crystalline suspension was filtered off with suction and washed with cold ethanol. The crystals obtained were dissolved in 1-N hydrochloric acid and filtered rum. The filtrate was evaporated to dryness and the residue recrystallized from 1-N hydrochloric acid and acetonitrile, which gave 4.3 G (78% of the teroria) of D-6-chloro-1,5-dihydro- hydrochloride. 3-methyl-imidazo [2,1-b} quinazolin-2 (3H) -one melting point 275^S-278²C.

The starting material can be prepared as follows:

A mixture of 18.24 g of D-alanine ethyl ester odor in 60 ml of ethanol was instilled in a mixture of 25 ml of triethylamine in 60 ml of ethanol and the resulting mixture was heated to 8O2C. The solution obtained was instilled at this temperature in a solution of 15 g of 2-chloro-6-nitrobenzyl bromide in 60 ml of ethanol. The mixture was stirred at 80²C overnight and then evaporated to dryness. The residue was treated with 150 ml of deionized water and extracted twice with 10 * 0 ml of methylene chloride. The methylene chloride extracts were washed with water, dried over sodium sulfate and evaporated. The resulting product was purified by chromatography on silica gel with 5% methylene chloride / methanol. 16 g (93% of theo) were obtained

-.

est.) of N- (2-eloro-6-nitrobenzyl) -D-alanine ethyl ester; xip = 1.5247; Calfal. ^ - -6.9^S (c - 1% in ethanol).

A solution of 14.3 3 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. In hours, 3.35 liters of hydrogen were collected. The catalyst was then filtered off and the filtrate was evaporated to dryness. 12.6 g (99% of theory) of iJ- (2-awino-6-chlorobenzyl) -D-alanine ethyl ester were obtained; η ^ 3 = l, 54O5j [alfal_D = +55,8^S (c = 1% in ethanol).

g of Ν, Ν'-carbonyldiiraidazole were added in portions, while gassing with nitrogen and stirring, to a solution of 71.75 g of N- (2-amino-or-chlorobenzyl) -D-alanine ethyl ester in 4-00 cc dry tetrahydrofuran. The marrow was stirred for 2 hours: it was 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 5% methylene chloride / methanol. 79g (99% of theory) of D-5chloro-1,4-dihydro-alf a-methyl-2-oxo-3 (2H) -quinazolineacetate 2c ethyl were obtained; [alfal ^ "-40.82 (_c = 1% in ethanol).

50.9 g of D-5-chloro-l, 4 dihydro-alpha-methyl-2-o3io-3 (2H) -quinazoline ethyl acetate were dissolved in 135 ml of phosphorus oxychloride and heated to 1102C 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 cc of ice / water and adjusted to pH 7 ** 8 by instilling 4θ sodium hydroxide ·

The chloroform phase was separated, dried and evaporated. The product was purified by chromatography on silica gel with 5 ^ methylene chloride / methanol

37.4 g (7% of theory) of D-2.5 ~ dichloro22 were obtained

-alpha-raethyl-3 (4H) -quinazolineacetyl ethylj n ^ »1.5775. EXAMPLE 15

1.5 cc of bromine was instilled into a solution of

5 g of Dl, 5-dihydro ~ 3-methyl-imidazo [2, lb -], quinazolin-2 (3H) -one in 80 ml of glacial acetic acid. The mixture was stirred at room temperature for 1 hour and a half, diluted with 100 ml of water, concentrated to 3 ml, • diluted again with 100 ml of water, alkanized with ammonium hydroxide • 3-H, washed and filtered. The product, separated, was washed with water and recrystallized from 100 ml of 2-IJ hydrochloric acid. 3.9 g (56% of theory) of D-7-bromo-l, 5-dihydro-3-methyl-imidazo hydrochloride [2, l-blquinazolin-2 (3H) -one, were obtained from the point of fusion 2682-27O2C.

EXAMPLE

Analogously to that described in Example 15, 4.7 g of Ll, 5 ~ dihydro-3-methyl-imidazo [2, lb] quinazolin-2 (3H) -one were brominated to obtain 4.2 g (64 # of the theory) of L-7-bromo-l hydrochloride, 5 "dihydro-3-methyl-imidazo— [2, l, b} quinazolin-2 (3H) -one of melting point 2802-284^fiC (decomposition).

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

EXAMPLE A

In the usual way pills were prepared having the following ingredients:

D-6-Chloro-l, 5-dihydro-3- hydrochloride

<td>-methyl-imidazoC 2,1-b} quinazolin-2 (3H) -</td><td></td>

<td>-ona</td><td>184.6 mg</td>

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

<td>Cornstarch</td><td>37.9 mg</td>

<td>Aqueous soluble polyvinyl pyrrolidone</td><td>1Q., 0 mg</td>

<td>Magnesium stearate</td><td>2-, 5 * mg</td>

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

EXAMPLE . B

In the usual way interconnected gelatin capsules containing the ingredients si 'were prepared. guientes:

D-6 ~ chloro-l, 5-hydrochloride-3 - &lt;»ethyl hydrochloride

<td>-imidazoC 2, l ~ bJquinazolin-2 (3H) -one</td><td> 200,0</td><td>mg</td>

<td>Aqueous soluble polyvinyl pyrrolidone</td><td> 2,0</td><td>mg</td>

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

<td>talcum powder</td><td> 4,5</td><td>mg</td>

<td>Magnesium stearate</td><td> 0,5</td><td>mg</td>

<td>Total hit per capsule</td><td> 250,0</td><td>mg</td>

BJEMPLO

In the usual way, a solution for injection was prepared containing the following ingredients: D-6-Chloro-l, 5-dihydro ~ 3 * -methyl-imidazo [2,1-b} quinazolin-2 (3H) -one hydrochloride 114.16 mg

2.4 Glycerinformal

Aeua 4 »θ cc