CS231970B2 - Manufacturing process of the 4-amino-2-peperidinochinazoline derivatives - Google Patents

Description

The invention relates to the preparation of novel 4-amino-2-piperidinoquinazoline derivatives, in particular those substituted with an alkoxy group at the 4-position of the piperidine ring. These agents are therapeutically effective as cardiovascular regulators and, in particular, are effective in the treatment of hypertension.

These novel compounds have the general formula I

in which

R is (C 1 -C 4) alkyl or benzyl, R ¹ is (C 1 -C 4) alkyl,

X stands for —CH (phenyl JCH2 -, —CH2CH (phenyl) - or —CH2C (Cnz) phenyl and

R ² represents hydrogen, (C - C4) alkyl or phenyl.

and pharmaceutically acceptable acid addition salts thereof.

The pharmaceutically acceptable acid addition salts of the non-toxic salts include suitable anions such as hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or hydrogen phosphate, acetate, maleate, lactate, tartrate, citrate, gluconate, saccharate or p-toluenesulfonate.

Compounds of the invention containing one or more asymmetric centers exist in the form of one or more pairs of einantiomers, and these pairs or individual enantiomers may be separated by physical methods such as fractional crystallization of suitable salts. The invention includes separate pairs as well as mixtures thereof, racemic mixtures, or as separate d- and 1-optically active isomeric forms.

The C 3 -C 4 alkyl and alkoxy groups may be straight or branched.

R is preferably C, C 2 H 5, benzyl.

Preferably R ¹ is N 2.

Preferably, R ² is H, N ^2, C ² H 5 or phenyl.

Compounds of formula (II) are prepared by reacting a quinazoline of formula (II)

where

R, R ¹ and Q are as defined above, with a piperidine of formula III ^HN ^ _ / ~ OR ^OX-Z (where nn

X and R ² are as defined above.

If desired, the compounds of formula (I) obtained are converted into pharmaceutically acceptable acid addition salts.

In a typical process according to the invention, the reactants are heated together for example at a temperature of 70 to 130 ° C, preferably under reflux in an inert organic solvent, for example n-butanol, for up to about 48 hours. The product is isolated and purified by conventional means.

The intermediates of formulas II and III are either known compounds or can be prepared by methods similar to those known in the art. The preparation of many intermediates of formula III is exemplified in the preparations below.

Pharmaceutically acceptable acid addition salts may be prepared by conventional methods, for example by mixing the free base with the appropriate acid in a suitable solvent, for example isopropanol, followed by filtration and, if necessary, recrystallization to the desired purity.

The antihypertensive activity of the compounds of the invention is demonstrated by their ability to lower the blood pressure of spontaneously hypertensive rats and renally hypertensive dogs at doses up to 5 mg / kg.

The compounds of the invention may be administered alone, but are generally administered in admixture with a pharmaceutical carrier selected with respect to the intended route of administration and conventional pharmaceutical practice.

For example, they may be administered in the form of tablets containing such excipients as starch or lactose, or in the form of capsules containing the active ingredient alone or a mixture thereof with the excipients, or in the form of elixirs or suspensions containing flavoring and coloring agents. They may be administered in parallel by an injectable route, for example, intramuscularly, intravenously or subcutaneously. For parenteral administration, these are best used in the form of a sterile aqueous solution which may contain other solutes, for example, sufficient salts or glucose to render the solution isotonic.

Accordingly, the invention provides pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.

The compounds of the invention may be administered in human medicine for the treatment of hypertens from either the oral or oral route. Orally, they can be administered at a dose ranging from about 1 to 50 mg / day for an average adult patient (70 kg) in a single dose or in divided doses up to 3 doses. Intravenous doses are expected to be about ^x / sec to V10 of the daily oral dose. Thus, for the average patient (adult), individual oral doses in the form of tablets or capsules will generally range from 1 to 50 mg of the active ingredient. Depending on the weight and condition of the patient to be treated and the route of administration, there will be various variations in administration known to those skilled in the art.

The invention also provides a method of treating animals, including humans having hypertension, which comprises administering to said animals an antihypertensive amount of a compound of Formula I or a pharmaceutically acceptable salt thereof as defined above.

The process according to the invention is illustrated by the following examples.

Example 1

Preparation of 4-amino-6,7-dimethoxy-2- [4- (2-ethoxy-1-phenylethoxy) piperidino] quinazoline hydrochloride

2.6 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline and 3.0 g of 4- (2-ethoxy-1-phenylethoxy) piperidine in 100 ml of n-butanol are boiled under reflux for 22 hours. The solution was then cooled, filtered and the filtrate evaporated in vacuo. The residue was triturated with diethyl ether and recrystallized twice from isopropanol to give 2.0 g of 4-amino-6,7-dimethoxy-2- (4- (2-ethoxy-1-phenylethoxy) piperidino) quinazoline hydrochloride, m.p. 230 DEG.

For C 25 H 32 N 4 O 4 HCl

calculated:

% C, 61.4;% H, 6.8;% N, 11.5;

found:

% C, 61.0;% H, 6.9;% N, 11.5.

Example 2

Production of 4-amino-6,7-dimethoxy-2- [4- [2-phenoxy-1-phenylethoxy) piperidino] quinazoline hydrochloride hydrate

Ηθοοκθ

CH 2 OPh

1.44 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline and 2.0 g of 4- (2-phenoxy-1-phenylethoxy) piperidine in 100 ml of n-butanol are boiled under reflux. hours. The solvent was then evaporated in vacuo, the residue triturated with ether and crystallized from isopropanol. The solid was partitioned between chloroform and aqueous sodium carbonate solution, the chloroform solution was dried with magnesium sulfate, and the solvent was evaporated in vacuo. The residue was chromatographed on silica (100 g) eluting with chloroform and then with chloroform / methanol (20: 1). The product-containing fractions were combined, the solvent was evaporated in vacuo and the residue converted to the hydrochloride salt by treatment with a chloroform solution with ethereal hydrogen chloride.

The solid hydrochloride is collected and recrystallized from isopropanol to give -0.85 g of 4-amino-6,7-dimethoxy-2- [4- (2-phenoxy-1-phenylethoxy) piperidino] quinazoline hydrochloride hydrate, m.p. 202 to 204 ° C.

For C29H32N.1O4.HCl.H2O calculated:

62.8% C, 6.4% H, 10.1% N;

found:

% H, 6.1%; N. 10.1%.

Examples - 3 to 6

The following compounds were prepared analogously to the previous examples using 4-amino-2-chloro-6,7-dimethoxyquinazoline and the appropriate piperidine, with the product of Example 3 being prepared analogously to Example 1 and the products of in Examples 4, -5 and 6 were prepared analogously to Example 2, but the product in Example 5 was not converted to the hydrochloride salt.

Example R5

R ² Isolated form a tt (° C)

Analysis (%) of the theoretical value in brackets C Η N

3 H H hydrochloride 59.7 6.3 12.0 Mp 241-243 ° C (59.9 6.3 12.2) 4 H C2H5 ^; hydrocíilorid 61.3 6.7 11.0 Mp 234-235 ° C (61.4 6.8 11,5)

Example R5 R2 Isolated form Analysis (%) and -t. t (° C) theoretical values - in brackets C Η N

5 CHs H monohydrate - free base, 63.0 6.8 12.2 Mp 146-148 ° C (63.1 7.1 12.3 6 CH3 C2H5 Hydrochloiride 61.9 7.0 11.1 (62.1 7.0 11.1)

Example 7

Preparation of 4-Amino-6-cyclopropylmethoxy-2- [4- (2-ethoxy-1-phenyl-ethoxy) -piperidino] -7-methoxy-quinazoline D (+) Tartrate

0.75 g of 4-amino-2- [4- (2-ethoxy-1-phenylethoxy) piperidino] -6-hydroxy-7-methoxychmazoline hydrochloride in 50 ml of dimethylformamide and 1 ml of 5 N sodium hydroxide is stirred at room temperature under nitrogen atmosphere for 40 minutes in the dark. 0.27 g of cyclopropylmethyl bromide are then added and the solution is stirred under nitrogen for 20 hours. 4 mg of potassium iodide and another 0.27 g of cyclopropylmethyl bromide are then added and stirring is continued for two hours at room temperature. The solvent was evaporated in vacuo, the residue was taken up in 50 ml of water, basified to pH 12 with 2 N sodium hydroxide and extracted three times with 100 ml of chloroform. The combined chloroform fractions were dried with sodium sulfate and the solvent was evaporated in vacuo to give a semi-solid. The product is chromatographed on 7 g of silica gel, eluting with chloroform. The product containing fractions were combined and the solvent was evaporated in vacuo. The residue was converted to the tartrate by treating its chloroform solution with D (+) tartaric acid in ether. The resulting solid was filtered, washed with ether and dried under reduced pressure to give 115 mg of 4-amino-6-cyclopropylmethoxy-2- [4- (2-ethoxy-1-phenylethoxy) piperidino] -7-methoxyquinazoline D (+) tartrate mp 142-145 ° C.

For C28H36N4O4.C4H6O6 calculated:

% C, 59.8;% H, 6.6;% N;

found:

% H, 6.5%; N. 8.9%.

Example 8

Preparation of 4-amino-6-ethoxy-2- [4- (2-ethoxy-1-phenylethoxy) piperidino] -7-methoxyquinazoline

The title compound was prepared analogously to Example 7 using 4-amino-2- [4- (2-ethoxy-1-phenylethoxy) piperidino] -6-hydroxy-7-methoxyquinazoline and ethyl iodide as starting materials in the presence of sodium hydroxide.

Example 9

Preparation of 4-amino-6-benzyloxy-2- (4- (2-ethoxy-1-phenylethoxy) piperidino) -7-methoxyquinazoline hydroxide

0) 72 g of 4-amino-6-benzyloxy-2-chloro-7-methoxyquinazoline (J. Med. Chem. 1977,

20, 146) and 0.57 g of 4- (2-ethoxy-1-phenylethoxy) piperidine in 50 ml of n-butanol are boiled under reflux for 30 hours. The solvent was evaporated in vacuo and the residue was triturated with ether to give a solid which was recrystallized from isopropanol / diisopropyl ether to give 740 mg of 4-amino-6-benzyloxy-2- [4- (2-ethoxy-1-phenylethoxy) hydrochloride piperidino] -7-methoxyquinazoline. A sample recrystallized from ethanol has a melting point of 238-240 ° C.

For C51H36N4O4.HCl calculated:

% C, 65.9;% H, 6.6;% N, 9.9%;

found:

% C, 65.5;% H, 10.0%.

The following preparations illustrate the preparation of certain starting materials.

Preparation

Preparation of 4- (2-hydroxyphenethyloxy) piperidine

5.0 g of N-acetyl-4-hydroxypiperidine in 50 ml of tetrahydrofuran (THF) was added to a stirred suspension of 1.84 g of sodium hydride (50% dispersion in mineral oil) in 25 ml of tetrahydrofuran (THF) under a nitrogen atmosphere. When effervescence has ceased, 4.6 g of styrene oxide in 25 ml of THF are added, then the reaction mixture is diluted with 25 ml of dimethylformamide (DMF) and stirred at 60 ° C for 18 hours. After addition of isopropanol to the cooled solution, the solvent is removed in vacuo, the residue is treated with water, the pH is adjusted to 4 with 2 N hydrochloric acid and extracted with chloroform. The chloroform extract was dried over sodium sulfate and the solvent was evaporated in vacuo to give N-acetyl-4- (2-hydroxyphenethyloxy) piperidine. This product was refluxed for three hours with 50 mL of ethanol and 100 mL of 5 N sodium hydroxide. The solvent was then removed in vacuo, the residue taken up in water, extracted with chloroform, dried and the solvent evaporated in vacuo. The product in chloroform was converted to the hydrochloride by treatment with ethereal hydrogen chloride and evaporation of the solvent.

The residue was taken up in methanol, treated with ether, and the precipitated solid was collected and recrystallized from isopropanol to give 0.6 g of 4- (2-hydroxyphenethyloxy) piperidine hydrochloride, m.p. 174-175 ° C.

P; C 13 H 19 NO 2 .HCl calculated:

H, 7.8; N, 5.4;

found:

60.1% С, 7.8% Η, 5.2% Ν.

Preparation В

Preparation of 4- (2-ethyoxyphenethyloxy) piperidine

8.0 g of N-acetyl-4- (2-hydroxyphenethyloxy) piperidine, prepared as in Preparation A, and 0.3 g of 1,2-dimethoxyethane in 50 ml of dry DMF are added dropwise to a stirred suspension of 2.96 g of hydride sodium (50% dispersion in mineral oil) in 50 ml dry DMF. The suspension was stirred at room temperature for 3.5 hours, cooled to 0-5 ° C, and 9.6 g of a solution of ethyl iodide in 25 mL of DMF was added dropwise. The temperature of the mixture was allowed to rise to room temperature (23 degrees Celsius) and then stirred at room temperature for 2 hours. 75 ml of isopropanol are added, the solvent is removed in vacuo and the residue is partitioned between chloroform and water. The chloroform layer was dried and the solvent was evaporated in vacuo to give 5.2 g of N-acetyl-4- (2-ethoxyphenethyloxy) piperidine.

This product was refluxed in 50 mL of ethanol and 50 mL of 5 N sodium hydroxide for 3.5 hours. The organic solvent was removed in vacuo and the aqueous residue was extracted with chloroform. The organic extract was dried over sodium sulfate, evaporated in vacuo and then partitioned between 2N hydrochloric acid and ether. The aqueous phase was then basified with sodium carbonate solution and extracted with chloroform. The chloroform extract is dried over sodium sulfate, the solvent is evaporated off under vacuum and then the residue is taken up in ether and further in the form of the oxalate salt. Recrystallization from isopropanol gave 1.6 g of 4- (2-ethoxyphenethyloxy) piperidine oxalate salt, m.p. 136-137 ° C.

For C15H23NO2.C2H2O4 calculated:

H, 7.4; N, 4.1;

found:

60.3% C, 7.4% H, 4.1% N.

Preparation C

Preparation of 4- (2-ethoxy-1-phenylethoxy) piperidine

OH

1. N ^ H

AND

AND

CH 2

В rCHCOJ-f

3. EtOH · CHC

GChCh ^ OC ^ H 1. ₅ VR-H

H <-

OCHCH3OH

I ^Z

The organic extracts were removed. The pH of the aqueous phase was adjusted to 12 with sodium hydroxide, extracted three times with 100 ml of ether, the ether layers were combined, dried with magnesium sulfate and the solvent evaporated in vacuo to give 3.55 g of 4- (2-phenoxy-1-phenylethoxy) piperidine as oils. The sample is converted to the oxalate salt, which is recrystallized from isopropanol and has a melting point of 170-172 ° C.

For C19H25NO2.C2H2O4 calculated:

65.1% С, 6.5%

3,6, 3.6% Ν;

found:

3,8, 3.8% Ν.

Preparation Ε

Preparation of 4- [2-hydroxy-2-phenyl-n-propoxy) piperidine

Сн _э

(1)

N-acetyl-4- (2-phenylallyloxy) piperidine

13.6 g of N-acetyl-4-hydroxypiperidine in 50 ml of DMF is added dropwise to a stirred suspension of 10 g of sodium hydride (50% dispersion in mineral oil) in 50 ml of DMF under nitrogen. The mixture was stirred at room temperature for 3 hours, then 20 g of α- (bromomethyl) styrene in 50 ml of DMF was added dropwise. The mixture was stirred at room temperature for 4 hours, then diluted with water and extracted 3 times with 200 ml of chloroform. The combined chloroform extracts were dried over sodium sulfate, evaporated in vacuo and distilled to give 25 g of N-acetyl-4- (2-phenylallyloxy) piperidine, bp 170-180 ° C / 49 Pa with NMR spectrum consistent with this structure.

N & Он (СН _ъ Он у / 3 _t

(П)

4- (2-Hydroxy-2-phenyl-n-propoxy) piperidine

4.0 g of N-acetyl-4- (2-phenylallyloxy) piperidine in 60 ml of dry THF was added dropwise to a stirred solution of 6.35 g of mercuric acetate in 60 ml of water and the solution was stirred at room temperature for 1 hour. 40 ml of 3 N sodium hydroxide solution and 0.75 g of sodium borohydride in 40 ml of 3 N sodium hydroxide solution are then added dropwise to the stirred solution at 0 ° C. The gray suspension was stirred at 0 ° C for 1 hour, ice-acetic acid was added to adjust the pH to 6, then the suspension was filtered and the filtrate was extracted with 3X 150 mL chloroform. The combined organic extracts were dried with copper sulfate and evaporated in vacuo to give 2.1 g of N-acetyl-4- (2-hydroxy231970 (i)).

Α- (N-Acetyl-4-piperidinoxy) phenylacetic acid ethyl ester

27.5 g of N-α-ethyl-4-hydroxypiperidine in 100 ml of dry DMF are slowly added to a stirred suspension of 25 g of sodium hydride (50% dispersion in mineral oil) in 159 ml of DMF and 10 ml of 1,2-dimethoxyethane.

The suspension was stirred at room temperature for 3 hours. Subsequently, 45 g of .alpha.-bbomphenylodic acid in 250 ml of DMF are slowly added under cooling with ice water. The mixture was stirred at room temperature for 20 hours, isopropanol was added and the solvent was evaporated in vacuo. The residue is taken up in water, acidified to pH 1 with 2N hydrochloric acid and extracted four times with 300 ml of chloroform. The combined chloroform extracts were washed with water and brine, dried over magnesium sulfate, and the solvent was evaporated in vacuo. The residue in 450 ml of anhydrous ethanol was refluxed with 9 ml of concentrated sulfuric acid for 8 hours. The cooled solution was carefully neutralized with aqueous sodium carbonate solution and the organic solvent was evaporated in vacuo. The aqueous residue is adjusted to pH 10 with sodium carbonate solution and extracted twice with chloroform. The combined chloroform extracts were dried over magnesium sulfate and evaporated in vacuo. Distillation of the residue gave 37.2 g of ethyl [alpha] - (N-acetyl-4-piperidino [4- (4-yl)] phenyl] acetic acid, b.p. 190 DEG-194 DEG C./0.2 mbar.

For C17H23NO4 calculated:

% C, 66.9;% H, 7.6;% N;

found:

66.4% C, 7.8% H, 4.5% N.

(ii)

N-Acetyl-4- (2-hydroxy-1-phenylethoxy) piperidine

3.24 g of lithium horohnoid are added portionwise to a solution of 11.2 g of α- (N-acetyl-4-piperidino) phenylacetic acid ethyl ester in 200 ml of dry THF. When the evolution of hydrogen ceased, the reaction mixture was refluxed for 4 hours. Water was added to the cooled solution, the solvent was evaporated in vacuo, then the residue was taken up in 200 ml of chloroform and washed with dilute hydrochloric acid, water and brine. The chloroform extract was dried over magnesium sulfate and the solvent was evaporated in vacuo. Thin layer chromatography showed that the reduction was incomplete. Therefore, the product was treated with an additional 3.24 g of lithium borohydride in 100 mL of THF and refluxed for 4 hours. 9.5 g of N-acetyl-4- (2-hydroxy-1-phenylethoxy) piperidine are obtained as an oil which solidifies on standing. A sample crystallized from ether has a melting point of 92-94 ° C.

For C15H21NO3 calculated:

C 68.4%, H 8.1%, N 5.3%;

found:

68.1% C, 8.1% H, 5.7% N.

(iii)

4- [2-Ethoxy-1-phenylethoxy) piperidine

This compound was prepared in analogy to Preparation B using N-acetyl-.alpha.-hydroxy-1-phenolphhoxy) piperidine (prepared as in part (ii)) and ethyl iodide as starting materials followed by basic hydrolysis of the N-acetyl group. was characterized as the oxalate salt, m.p. 137-139 ° C.

For C15H23NO2.C2H2O4 calculated:

% C, 60.2;% H, 7.4;% N;

found:

% H, 7.4%; N. 4.0%.

Preparation D

4- (2-Phenoxy-1-phenylphenyl) piperidine

5.25 g of N-acphyl-4- (2-indoxin-1-phenylethoxine) pipfoidine (prepared as in Preparation C (ii), 4.2 g of diethyl azodicarboxylate, 6.3 g of triphenylphosphine and 2.25 g of phenol are stirred in 100 ml of dry tetrahydrofuran at 0 ° C for two hours and then left at room temperature for 48 hours The solvent is evaporated off in vacuo, the residue is taken up in 59 ml of refluxing diethyl ether and left in the refrigerator overnight The precipitated biproducts are filtered off and the filtrate is evaporated The residue is treated again with ether, cooled and the precipitated solid is filtered off, the ether filtrate is evaporated to dryness and the residue is boiled in 50 ml of methanol and 30 ml of 5 N sodium hydroxide at reflux for 5 hours.

The organic solvent is removed in vacuo, the aqueous residue is acidified: to pH 3 with 2 N hydrochloric acid and extracted with two

-2-phenyl-n-propoxy) piperidine. This product was refluxed in 30 ml of methanol with 20 ml of 5 N sodium hydroxide for 4 hours. The organic solvent was evaporated and the aqueous solution was extracted with 3X 20 mL of chloroform, dried over sodium sulfate and the solvent was evaporated in vacuo to give 1.8 g of 4- (2-hydroxy-2-phenyl-n-propoxy) piperidine as an oil. characterized as the oxalate salt which recrystallized from ethyl acetate has a melting point of 132-134 ° C.

of sodium hydroxide under reflux for 11 hours. The organic solvent was then evaporated and the aqueous solution was extracted with chloroform (3.times.30 ml). The combined chloroform extracts were dried over sodium sulfate and the solvent was evaporated in vacuo to give 3.8 g of 4- (12-ethoxy-2-phenyl-n-propoxy) piperidine as an oil. The sample was converted to the oxalate silane, which after recrystallization twice from ethyl acetate and then acetone had a melting point of 126-127 ° C.

For C 14 H 21 NO 2. C2H2O4

For C 16 H 25 NO 2. C2H2O4. 1 / 4H2O calculated:

% C, 59.1;% H; 7.1;% N;

% H, 7.1%; N. 4.8%.

Preparation F

Preparation of 4- [2-ethoxy-2-phenyl-n-propoxy) piperidine

7.0 g of N-acetyl-4- (2-phenylallyloxy) piperidine (prepared as in Preparation E) in 10 ml of ethanol are added to a stirred suspension of 9.2 g of mercuric acetate in 50 ml of ethanol at room temperature. The mixture was stirred at room temperature for 1 hour, then cooled to 0 ° C. To the stirred suspension is added 20 ml of 5 N sodium hydroxide solution and then 1.03 g of sodium borohydride in 20 ml of 5 N sodium hydroxide solution, and after 10 minutes glacial acetic acid is added to adjust the pH to 6. The suspension is filtered, the filtrate is concentrated and the residue was partitioned between chloroform and water. The organic layer was dried over sodium sulfate and the solvent was evaporated in vacuo. GLC indicated incomplete conversion of the desired product, therefore, the oxymercuration process was as described above to give 7.4 g of N-acyl-4- (2-ethoxy-2-phenyl-n-propoxy) piperidine, 84%. purity determined by GLC. This product is boiled in 100 ml of ethanol with 30 ml of the solution calculated:

60.4% C, 7.3% H, 3.9% N, n o] p in ωγ) Π

H, 7.6; N, 4.1%.

Preparation G

Preparation of 4-amino-2- [4- (2-ethoxy-1-phenylethoxy} piperidino] -6-hydroxy-7-methoxyquinazoline hydrochloride hydrate

0.9 g of 4-amino-6-benzyloxy-2- [4- (2-ethoxy-1-phenylethoxy) piperidino] -7-methoxyquinazoline hydrochloride in 150 ml of dry ethanol is hydrogenated to 5% Pd / C at room temperature and a pressure of 105 kPa for 2 hours. The catalyst was filtered off and the filtrate was evaporated to dryness in vacuo. The residue was triturated with ether to give 0.55 g of a white solid. A 200 mg sample recrystallized from isopropanol provides 71 mg of 4-amino-2- [4- (2-ethoxy-1-phenylethoxy) piperidino] -6-hydroxy-7-methoxyquinazoline hydrate hydrochloride, m.p. 141-144 ° C.

For C 24 H 30 N 4 O 4. HCl. H2O calculated:

58.5% C, 6.8% H, 11.4% N,

Пд1р7рлП ·

% H, 6.5%; N. 11.5%.

Claims (5)

ADD ADD A process for the preparation of 4-amino-2-pipeiridinoquinazoline derivatives of the general formula I Л / Нд where R is (C 1 -C 4) alkyl or benzyl, R ¹ is (C 1 -C 4) alkyl, X stands for —CH (phenyl) CH2—, —СНзСН (phenylj— or - СНгС (СНз) (beny.1) and R ² is hydrogen, (C 1 -C 4) alkyl or phenyl, or a pharmaceutically acceptable acid addition salt thereof, characterized in that the quinazoline of formula (II) is reacted wherein: R 1 and R ² are as defined in 1 and R 1 is (C 1 -C 4) alkyl, or a pharmaceutically acceptable acid addition salt thereof, characterized in that the quinazoline of formula (II) is reacted R and R 1 are as defined above and Q represents an easily cleavable group such as chlorine, thunder,. iodo, [(C 1 -C 4) alkyl] thio or [(C 1 -C 4) alkyl] sulfonyl, with piperidine of formula III OX-OR ² (III) where X and R 2 are as defined above and, if desired, the compound is converted. or a pharmaceutically acceptable addition salt thereof. with an acid by reaction with a non-toxic acid. 2. Method. A compound according to claim 1, characterized in that compounds of the formulas II and III are used as starting compounds, in which R is CH 3 or benzyl, R 1 is CH 3, R 2 is H, methyl, R 3. ethyl or. phenyl and X are as defined in 1. 3. The process of item 1, for the preparation of 4-amino-2-piperidinoquinolinium derivatives of the general formula Γ wherein: R 1 and R 2 are as defined above and Q is as defined in item 1, with piperidine. and wherein, if desired, the compound obtained is converted to a pharmaceutically acceptable non-toxic acid addition salt thereof. 4. The process of claim 3 wherein the starting compounds are compounds. ΙΓ and formula III, wherein R .and R 1 are CH, X is -CH [phenyl) CH _2, R2 is C2H5, and Q is Cl. 5. A process according to claim 3, wherein R @ 1 and R @ ¹ are CH3, X is --CH2 CH (phenyl) -, R @ 2 is H and Q is Cl.