NO793009L - PROCEDURE FOR THE PREPARATION OF NEW N- (1- (4-AMINO-2-CHINAZOLINYL) -3- OR -4-PIPERIDYL-LACTAMES - Google Patents

Description

Process for the production of new N-[1-(4-amino-2-quinazolinyl)-3- or -4-piperidyl lactams.

According to US patent no. 3-511,836, 1-[4-amino-2-quinazolinyl)-piperidines and their derivatives which in the 4-position of the piperidine contain alkyl, alkoxy, hydroxy,

hydroxyalkyl, phenyl, benzyl and 4-phenyl-4-carboxylic acid lower alkyl esters, hypotensive agents. It is surprising that the compounds according to the invention which contain the lactam nitrogen atoms in the 3- or 4-position of the piperidine exhibit superior hypotensive and antihypertensive effects on the basis of an α-blocking mechanism.

The invention relates to new N-[1-(4-amino-2-quinazolinyl)-3- or -4-piperidyl-lactams of the general formula I

in which Ph means a 1,2-phenylene residue which may optionally be substituted with a maximum of 3 substituents selected from lower alkyl and lower alkoxy and a lower alkylenedioxy at each of the symbols m and n means an integer from 1 to 3, where m + n = 4,

X means 2 hydrogen atoms or oxo and A means lower alkylene,

4 to 7 ring-membered cycloalkylene, cycloalkyllower alkylene

and spirocycloalkane-lower alkylene, HPh-lower alkylene or Ph, as well as acid addition salts s particularly therapeutically useful acid addition salts of these compounds.

A 1,2-phenylene group Ph present in the quinazoline and/or lactam part of the compound is preferably mono-, di- or tri-substituted with lower alkyl, e.g. methyl, ethyl, n- or i-propyl or -butyl, or lower alkoxy, e.g. methoxy, ethoxy, n- or i-propoxy or -butoxy, or monosubstituted with lower alkylenedioxy, e.g. methylenedioxy, 1,1- or 1,2-ethylenedioxy. The said substituents appear preferably in the 4,5- or 4,5,6-position of the said phenylene group.

The alkylene groups CmH2mog CnH2n, which separate the nitrogen atom from the methine group by 1 to 3 carbon atoms, preferably mean each ethylene, but also methylene and 1,3-propylene.

A lower alkylene residue "A" is preferably ethylene, 1,3-propylene, 2,2-di-(methyl, ethyl, n-propyl or n-butyl)-ethylene or 2,2-di-(methyl, ethyl, n- propyl- or n-butyl)-1,3-propylene, 2,3- or 1,4-butylene.

Each of the cycloalkylene, cycloalkyl-lower alkylene or spirocycloalkane-lower alkylene residues has 4 to 7 ring carbon atoms and means e.g. 1,2-cyclobutylene, 1,2- or 1,3-(cyclopentylene, cyclohexylene or cycloheptylene), 1- or 2-(cyclopentyl or cyclohexyl)-ethylene or 1- or 2-(cyclopentyl or cyclohexyl)-1,3 -propylene, 1- or 2-spirocyclo-(butane, pentane or hexane)-ethylene or 1- or 2-spirocyclo-(butane, pentane or hexane)-1,3-propylene.

The phenyl lower alkylene or 1,2-phenylene residue, especially the HPh lower alkylene residue or the Ph residue "A" is preferably unsubstituted or monosubstituted in the ring with the above-mentioned alkyl, alkoxy or alkylenedioxy groups. The symbol "A" therefore means e.g. 1-phenyl-ethylene, 2-phenylene-1,3-propylene, 1- or 2-(tolyl or anisyl)-ethylene or 1- or 2-(tolyl or anisyl)-1,3-propylene, 1,2- phenylene, 3- or 4-(methyl or methoxy)-1,2-phenylene or 4,5-methylenedioxy-1,2-phenylene.

The term "lower" defines in the above

and the following organic residues or compounds thereof with a maximum of 8, preferably 4, especially 1 or 2 carbon atoms.

The basic compounds of formula I form acid addition salts. Preferred are the therapeutically applicable acid addition salts, e.g. such of the below-mentioned acids. The compounds according to the invention show valuable pharmacological properties, e.g. hypotensive, antihypertensive and vasodilating effect. These pharmacological properties can be demonstrated in animal experiments, preferably on mammals, e.g. rats, cats or dogs as test subjects. The animals can be normotensive or hypertensive, e.g. genetically or renally hypertensive rats or dogs. The new compounds can be administered enterally or parenterally, preferably orally, subcutaneously, intravenously, intraperitoneally or intraduodenally, e.g. in the form of gelatin capsules or in the form of starch-containing suspensions or aqueous solutions. The dose used can be in a range from about 0.1 to 100 mg/kg/day, preferably about 1 to 75 mg/kg/day, especially between 5 to 50 mg/kg/day. The blood pressure-lowering effect is recorded either directly with a catheter such as is introduced into the caudal artery of a rat or into the femoral artery of a dog, and indicates with a transfer instrument the blood pressure before and after the administration of the active substance in mm/Hg or is determined indirectly by sphygmomanometry, e.g. on a rat's tail. Thus, e.g. 1-[4-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidyl]-pyrrolidine-2,5-dione or its therapeutically applicable salts as typical representatives of compounds according to the invention strongly antihypertensive effective 1 the aforementioned trials. The compound according to the invention can therefore be used as antihypertensive agents, which have no or only minimal effect on the heart rate for the treatment or management of essential or renal hypertension and/or of congestive or chronic heart disorders in mammals. They can also be used as intermediates for the production of other valuable, particularly pharmacologically active compounds or preparations.

Preferred compounds are those of formula I where Ph means a 1,2-phenylene residue which may optionally be substituted with a maximum of 3 substituents selected from alkyl or alkoxy with a maximum of 4 carbon atoms and an alkylenedioxy with a maximum of 2 carbon atoms, each of the symbols m and n means a integer from 1 to 3, where m + n = 4, X means 2 hydrogen atoms or oxo and A means lower alkylene, 4 to 7 ring-membered cycloalkylene, cycloalkyl-lower alkylene, spirocycloalkane-lower alkylene, HPh-lower alkylene or Ph as well as their therapeutic

applicable acid addition salts.

Further compounds of formula I are preferred, in which Ph means 1-,2-phenylene, mono-, di- or tri-(alkyl or alkoxy.)-1,2-phenylene or alkylenedioxy-1,2-phenylene, in which alkyl, Alkoxy or alkylene contains a maximum of 2 carbon atoms, where each of the groups cmH2m°S cnH2n means etvlenjx means two hydrogen atoms or oxo and A means lower alkylene,

5 or 6 ring membered 1,2-cycloalkylene or (cycloalkyl, spirocycloalkane or phenyl)-alkylene, each of the latter containing three residues of a total of a maximum of 8 carbon atoms and their therapeutically useful acid addition salts. Especially to highlight are connections with that gene real formula II

in which each of the symbols R and R' means methoxy or together means methylenedioxy, X means two hydrogen atoms or oxo, CpH2p-q means alkylene, phenyl-alkylene or spirocycloalkane-alkylene, where p means an integer from 2 to 8 and q means the numbers 0, 2 or 8 and 2p-q is positive, as well as their therapeutically useful acid addition salts.

Further compounds of formula II are preferred, in which each of the symbols R and R' means methoxy, X means oxo and the symbol CpH2p-q means ethylene, phenylethylene or 1,3-propylene and their therapeutically applicable acid addition salts.

The compounds according to the invention are produced according to methods known per se, e.g. by condensing compounds of the formulas III and IV, in which Y means halogen or lower alkylthio and M means hydrogen or an alkali metal atom and, if desired, a formed compound of formula I is converted with another compound according to the invention.

The halogen atom Y is preferably chlorine or bromine.

A lower alkylthio group Y is primarily methylthio. The alkali metal atom M is preferably sodium or potassium.

The aforementioned condensation is carried out at temperatures above room temperature, e.g. between about 100 and about 200°C and/or in the presence of condensing agents which form the acids formed. Such agents are alkali metal carbonates or hydrogen carbonates or tertiary amines, e.g. tri-lower alkylamines, pyridines resp. lower alkylated pyridines.

Formed free bases can be prepared in corresponding acid addition salts, preferably using acids which give therapeutically useful acid addition salts or with corresponding anion exchangers. Formed acid addition salts can be transferred into the corresponding free bases, e.g. by treatment with a base such as a metal hydroxide, basic salt, ammonia, amine or a cation exchanger, e.g. an alkali metal hydroxide or carbonate. Acids that give therapeutically useful acid addition salts are e.g. inorganic acids such as hydrohalic acid, e.g. hydrochloric or hydrobromic acid, or sulphurous, phosphoric, nitric or perchloric acid, or organic acids such as aliphatic or aromatic carboxylic acids and sulphonic acids, e.g. formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, 4-aminobenzoic acid, anthranilic acid, 4-hydroxybenzoic acid, salicylic acid, 4-aminosalicylic acid, pamoic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylene-sulfonic acid, halobenzenesulfonic acid, toluenesulfonic acid, naphthalene-sulfonic acid, sulfanilic acid or cyclohexylsulfamic acid or ascorbic acid.

These or other salts, e.g. the picrates can

also used in the purification of the free bases. The bases are transferred in their salts, the salts are separated and the bases are released from the salts. Due to the close relationship between the new for-

bonds in free form and in the form of their salts, in the foregoing and the following are understood as free compounds and salts also possibly the corresponding salts resp. free connections.

The starting substances with the formulas III and IV are known, or if they are new, they can be prepared according to methods known per se, e.g. as shown in the examples. Known starting materials and their advantages also e.g. mentioned in US patents no. 3,511,836, 3-769,286 and 4,000,287, but also

in references set forth in these patents.

The final product with formula I, which is a mixture of isomers, can be prepared according to methods known per se, e.g. by fractional distillation, crystallization and/or chromatography, are divided into the individual isomers. Racemic products can be poured into the optical antipodes, e.g. by rinsing their diastereomeric salts, e.g. by fractional crystallization of the d- or 1-tatrates.

The above-mentioned reactions are carried out in a manner known per se in the presence or absence of diluents, preferably in those which are inert towards the reagents and dissolve them, catalysts, condensation agents or other mentioned agents and/or in an inert atmosphere under cooling, at room temperature or at elevated temperatures, preferably at the boiling point of the solvent used, at normal or elevated pressure.

The invention also relates to changes to the present method according to which an intermediate is used as a starting material at one or another stage of the process and the remaining process steps are carried out or the process is interrupted at one or another stage or according to which starting material is formed under the reaction conditions or in which a starting material: in the form of a salt or an optically pure antipode.

In the method according to the invention, such starting materials are preferably used which lead to the compounds mentioned at the outset as particularly valuable, especially those with formula II.

The pharmacologically usable compounds according to the invention can be used for the production of pharmaceutical preparations containing an effective amount of the active substance together or in admixture with carriers suitable for enteral or parenteral administration. Preferably, tablets or gelatin capsules are used which contain the active substance together with diluents, e.g. lactose, dextrose, cane sugar, mannitol, sorbitol, cellulose and/or glycine and lubricants, e.g. diatomaceous earth, talc, stearic acid or salts thereof such as magnesium or calcium stearate and/or polyethylene glycol, tablets also contain binders e.g. magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone and, if desired, explosives, e.g. starches, agar, alginic acid or a salt thereof, enzymes and the binders and/or fizzy mixes or adsorbents, colourings, flavorings and sweeteners. Injectable or inhalable preparations are preferably isotonic aqueous solutions or suspensions and suppositories primarily fat emulsions or suspensions. The pharmacological preparations may be sterilized and/or contain excipients, e.g. preservatives, stabilizers, wetting agents and/or emulsifiers, solubility mediators, salts for regulating the osmotic pressure and/or buffers. The present pharmaceutical preparations which, if desired, can contain further pharmacologically valuable substances are prepared in a manner known per se, e.g. by usual mixing, granulation or coating methods, contains from approx. 0.1$ to approx. 75$, especially from approx. 1% to approx. 50% of the active substance.

The invention shall be explained by means of some examples. The temperatures are indicated in degrees Celsius and the indications above parts refer to parts by weight. If nothing else is mentioned, evaporation of the solvents is carried out under reduced pressure, i.e. between about 1 and 100 mm Hg.

Example 1

A mixture of 8.66 g of 4-amino-2-chloro-6,7-dimethoxy-quinazoline, 6.6 g of 1-(4-piperidyl)-pyrrolidine-2,5-dione, 9.4 g of diisopropylethylamine and 100 ml of dimethylformamide is stirred in a nitrogen atmosphere at 150°C for 8 hours. The reaction mixture is evaporated, the residue is triturated with aqueous sodium carbonate solution and extracted with ethyl acetate. The extract is washed, dried, evaporated and the residue recrystallized from ethanol. The crystals are dissolved in a mixture of ethanol-acetone and the solution is neutralized with methanesulfonic acid. The precipitate formed is filtered off, dried and recrystallized from aqueous ethanol. One obtains ly[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidyl]-pyrrolidine-2,5-dione-monomethanesulfonate with the formula

which melts during decomposition at 331°C.

The starting material is prepared as follows: A mixture of 20 g of succinic anhydride, 19 g of 4-aminopyridmn and 450 ml of xylene is stirred under stirring for 24 hours. The reaction mixture is cooled to room temperature, the solid material is separated and extracted three times with 200 ml of methylene chloride under reflux. The combined extracts are evaporated and the residue is recrystallized from ethanol. 1-(4-pyridyl)-pyrrolidine-2,5-dione is obtained. .11.36 g of the latter compound are hydrogenated at 60°C in a minimal amount of glacial acetic acid over 8 g of 10% palladium-on-charcoal catalyst at 2.7 atmospheres. The reaction mixture is filtered and evaporated. The residue is made basic with aqueous sodium carbonate solution, extracted with chloroform and the extract evaporated. 1-(4-piperidyl)-pyrrolidine-2,5-dione is obtained which melts at 133-134°C.

Example 2

A mixture of 6.7 g of 4-amino-2-chloro-6,7-dimethoxy-quinazoline, 5.5 g of 1-(4-piperidyl)-piperidine-2,6-dione, 7.2 g of diisopropylethylamine and 75 ml of dimethylformamide is stirred in a nitrogen atmosphere for 8 hours at 150°C. The reaction mixture is cooled to room temperature, filtered and the filtrate is evaporated. The residue is triturated with ethanol, filtered again and the two precipitates are combined. This solid material is taken up in aqueous sodium carbonate solution, the mixture is extracted with acetic acid ethyl ester, the extract is washed with water, dried and evaporated. The residue is taken up in hot ethanol, the solution is acidified with methanesulfonic acid, the precipitate formed is filtered off and recrystallized from aqueous ethanol. 1-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidyl]-piperidine-2,6-dione-monomethanesulfonate is obtained which melts at 333-334°C.

The starting material is prepared as follows: A mixture of 34.2 g of glutaric anhydride, 28.2 g of 4-amino-pyridine and 650 ml of xylene is boiled with stirring for 6 hours under reflux. The reaction mixture is cooled to room temperature, the precipitate is filtered off and extracted twice with 200 ml of chloroform under reflux. The combined extracts are evaporated and the residue recrystallized twice from acetic acid ethyl ester. 1-(4-pyridyl)-piperidine-2,6-dione is obtained which melts at 153-155°C.

8.1 g of the latter compound are hydrogenated in 100 ml of glacial acetic acid over 6.3 g of 10% palladium-on-charcoal catalyst at 60° C. and 2.9 atmospheres. The reaction mixture is filtered off, the filtrate is evaporated and the residue is treated with aqueous sodium carbonate solution. The mixture is extracted several times with methylene chloride and the combined extracts are evaporated. 1-(4-piperidyl)-piperidine-2,6-dione is obtained as solvated material with a low melting point.

Example 3

A mixture of 4.79 g of 4-amino-2-chloro-6,7-dimethoxy-quinazoline, 4.49 g of 4,4-dimethyl-1-(4-piperidyl)-piperidine-2,6-dione, 4 .24 g of anhydrous sodium carbonate and 75 ml of dimethylformamide are stirred in a nitrogen atmosphere for 6 hours at 150°C. The reaction mixture is filtered off, the filtrate is evaporated, the residue is dissolved in acetic acid ethyl ester, the solution is washed with aqueous sodium carbonate solution and water. The solution is dried, evaporated, the residue triturated with isopropanol, filtered and the solid material sieved. The filtrate is strongly acidified with hydrogen chloride, the precipitate is filtered off and triturated with 175 ml of boiling methanol. 1-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidyl]-4,4-dimethyl-piperidine-2,6-dione-mono-hydrochloride is obtained which melts under cleavage at 279-280°C.

The starting material is prepared as follows: A mixture of 19.3 g of 3,3-dimethylglutaric anhydride, 12.55 g of 4-amino-pyridine and 350 ml of xylene is boiled using a water rinser for 60 hours with stirring and reflux. The hot xylene solution is decanted from the syrup-like residue, cooled to room temperature, filtered and the residue recrystallized from ethanol. 4,4-dimethyl-1-(4-pyridyl)-piperidine-2,6-dione is obtained which melts at 225-226°C.

20 g of the latter compound are dissolved in

200 ml of glacial acetic acid at 60°C and hydrogenates it over 15 g of 10% palladium-on-charcoal catalyst at 3.1 atmospheres. The reaction mixture is filtered, evaporated, the residue is taken up under cooling in 6N aqueous sodium hydroxide solution and the mixture is extracted with methylene chloride. The extract is evaporated and the residue is recrystallized from a mixture of benzene and hexane. 4,4-dimethyl-1-(4-piperidyl)-1-piperidine-2,6-dione is obtained,

which melts at l62-l63°C.

Example 4

A mixture of 70 g of 4-amino-2-chloro-6,7-dimethoxy-quinazoline, 73.2 g of 8-(4-piperidyl)-8-azaspiro, 4,5]decane-7,9-dione, 62 .1 g of anhydrous sodium carbonate and 800 ml of dimethylformamide are stirred in a nitrogen atmosphere at 135°C for 8 hours. The reaction mixture is allowed to cool to room temperature, filtered and the filtrate evaporated. The residue is poured into 300 ml of water while stirring and cooling, the mixture is diluted with 1400 ml of water and filtered. The solid material is triturated with 1600 ml of acetic acid ethyl ester and 10 ml of saturated aqueous sodium carbonate solution. The organic layer is separated, dried, evaporated and the residue is dissolved in 1000 ml ethyl acetate. The solution is acidified with hydrogen chloride, the precipitate is filtered off and recrystallized from aqueous methanol. 8-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidyl]-8-aza-spiro[4,5]decane-7,9-dione hydrochloride is obtained which melts under cleavage at 277-279°C

5 g of the latter compound are suspended in 100 ml of water and 10 ml of 6N aqueous sodium hydroxide solution and the mixture is extracted with chloroform. The extract is washed with water, dried, evaporated and the residue is dissolved in 50 ml of ethanol while heating. The solution is mixed with 0.94 g of methanesulfonic acid, the precipitate is separated and recrystallized from aqueous ethanol. The corresponding monomethanesulfonate is obtained which melts at 307-308°C.

The starting material is prepared as follows: A mixture of 100 g of 3,3-tetramethylene-glutaric anhydride, 57 g of 4-amino-pyridine and 1500 ml of xylene is stirred and boiled using a water rinser for 3 days under reflux. The reaction mixture is cooled slightly, the xylene solution is decanted from a small amount of an oily material and cooled in an ice bath. The precipitate formed is separated, dissolved in 1500 ml of boiling ethanol and the solution cooled to 5°C, filtered and the residue dried. 8-(4-pyridyl)-8-azaspiro[4,5]decane-7,8-dione is obtained which melts at 208-211°C.

A solution of 58 g of the latter compound

in 580 ml of glacial acetic acid is hydrogenated over 45 g of 10%-lg palladium-on-charcoal catalyst at room temperature and 3.1 atmospheres. After absorption of the theoretical amount of hydrogen, the mixture is filtered and evaporated. The residue is made basic with 6N aqueous sodium hydroxide solution and the mixture is extracted with chloroform. The extract is washed with saturated aqueous sodium chloride solution, dried, evaporated and the residue dissolved in 325 ml of hot toluene. The solution is filtered, diluted with 400 ml of hexane, cooled and filtered. 8-(4-piperidyl)-8-azaspiro-[4,5]decane-7,9-dione is obtained, which melts at 141-142°C.

Example 5

A mixture of 5.39 g of 4-amino-2-chloro-6,7,8-;tri-methoxy-quinazoline, 5.25 g of 8-(4-piperidyl)-8-azaspirote4,5]decane-7,9- dione, 4.24 g of anhydrous sodium carbonate and 75 nil of dimethylformamide are stirred for 8 hours at 150°C. The reaction mixture is filtered after cooling to room temperature, the filtrate is evaporated, the residue is dissolved in acetic acid ethyl ester and the solution is washed with aqueous sodium bicarbonate solution and water. The solution is dried, evaporated, the residue is dissolved in 75 ml of acetic acid ethyl ester and set aside for crystallisation. The crystals are dissolved in 50 ml of hot isopropanol and the solution is adjusted with hydrogen chloride to a pH value of 1. The formed precipitate is filtered off. 8-[1-(4-amino-6,7,8-trimethoxy-2-quinazolinyl)-4-piperidyl]-8-azaspiro[4,5]decane-7,9-dione-mono- hydrochloride, which melts at 225-227°C.

Example 6

A mixture of 2.39 g of 4-amino-2-chloro-6,7-dimethoxy-quinazoline, 2.64 g of 3-(4-piperidyl)-3-azaspiro[5,5]undecane-2,4-dione , 2.1 g of anhydrous sodium carbonate and 25 ml of dimethylformamide are stirred in a nitrogen atmosphere for 10 hours at 150°C. The reaction mixture is filtered, the filtrate is evaporated, and the residue is dissolved in methylene chloride. The solution is washed with aqueous sodium carbonate solution, dried, filtered and evaporated. The residue is triturated with 50 ml of isopropanol, the remaining material is taken up in isopropanol and acidified with hydrogen chloride. 3-[1-(4-amino-6,7_dimethoxy-2-quinazolinyl)-4-piperidyl]-3-azaspiraL5,5]undecane-2,4-dione monohydrochloride is obtained, which melts during cleavage at 290 °C.

The starting material is prepared as follows: A mixture of 25 g of 1,1-cyclohexane-diacetic anhydride, 12.92 g of 4-amino-pyridine and 400 ml of xylene is boiled using a water rinse for 25 hours under reflux. The hot xylene solution mentioned above is decanted from an oily precipitate (which is discarded), cooled, filtered and the residue recrystallized from ethanol. 3-(4-pyridyl)-3~azaspiro[5,5]undecane-2,4-dione is obtained which melts at 213-215°C.

13.8 g of the latter compound are dissolved in

150 ml of glacial acetic acid and hydrogenates it over 10 g of 10% palladium-on-charcoal catalyst at 50-60°C and 1.7 atmospheres. The mixture is filtered and the residue is worked up according to the example

4. 3_(4-piperidyl)-3-azaspiro[5,5]undecane-2,4-dione is obtained, which melts after recrystallization from benzene-hexane at 148-149°C

Example 7

A mixture of 5.72 g of 4-amino-2-chloro-6,7-dimethoxy-quinazoline, 5.65 g of 2-(4-piperidyl)-2-azaspiro[4,4]nonane-1,3-dione , 6.16 g of diisopropylethylamine and 75 ml of dimethylformamide are stirred in a nitrogen atmosphere for 8 hours at 150°C. The reaction mixture is evaporated, the residue is distributed between ethyl acetate and aqueous sodium carbonate solution, the organic solution is washed with water, dried and evaporated. The residue is taken up in ethanol and adjusted with methanesulfonic acid to a pH value of 1. The precipitate formed is filtered off and crystallized first from methanol and then from aqueous ethanol. 2-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidyl]-2-azaspiro-[4, 4]nonane-1,3-dione-monomethanesulfonate is obtained which melts at 278-280°C .

The starting material is prepared as follows: A mixture of 21.8 g of tetramethylene-succinic anhydride (prepared from the corresponding dicarboxylic acid by refluxing with acetic anhydride), 12.2 g of 4-amino-pyridine and 300 ml of xylene is boiled using a water rinser for 9 hours round-to-back race. The hot solution is filtered, cooled to 5°C

and the residue is recrystallized from ethanol. 2-(4-pyridyl)-2-azaspiro[4,4]nonane-1,3-dione is obtained which melts at 100-103°C.

16.76 g of the latter compound are hydrogenated over 12 g of 10% palladium-on-charcoal catalyst in 180 ml of glacial acetic acid at 60°C and 3.2 atmospheres. The mixture is filtered, evaporated, the residue made basic with aqueous sodium carbonate solution and extracted several times with chloroform. The extracts are dried and concentrated. 2-(4-piperidyl)-2-aza-spiro[4,4]nonane-1,3-dione is obtained which melts at 119-120°C.

Example 8

A mixture of 4.8 g of 4-amino-2-chloro-6,7-dimethoxy-quinazoline, 5.17 g of 1-(4-piperidyl)-3-phenyl-pyrrolidine-2,5-dione, 5.2 g of diisopropylethylamine and 75 ml of dimethylformamide are stirred in a nitrogen atmosphere for 8 hours at 150°C. The reaction mixture is evaporated, the residue is distributed between ethyl acetate and aqueous sodium carbonate solution, the organic layer is separated, dried and evaporated. The residue is dissolved in hot ethanol and the solution is adjusted with methanesulfonic acid to a pH value of 1. The precipitate formed after cooling is separated and recrystallized from aqueous ethanol. One obtains 1-[1-(4-amino-6,7_dimethoxy-2-quinazolinyl)-4-piperidyl]-3-phenyl-pyrrolidine-2,5-dione-monomethanesulfonate which melts during decomposition at 239-244°C.

The starting material is prepared as follows: A mixture of 20.2 g of phenylsuccinic anhydride, 10.7 g of 4-amino-pyridine and 300 ml of xylene is boiled using a water rinser for 6 hours under reflux. The hot solution is decanted and some gummy precipitate. After cooling, a precipitate is obtained which is filtered off and recrystallized from ethanol. 3-phenyl-1-(4-pyridyl)-pyrrolidine-2,5-dione is obtained, which melts at 146-147°C

20.6 g of the latter compound are hydrogenated

in 200 ml of glacial acetic acid over 14 g of 10% palladium-on-charcoal catalyst at 60°C and 3 atmospheres. The mixture is filtered off, evaporated and the residue is dissolved in 575 nil of water. The solution is made basic with sodium carbonate and extracted several times with ethyl acetate. The extract is washed with aqueous sodium carbonate solution, dried and evaporated. The residue is recrystallized from a mixture of toluene-hexane. One obtains 1-(4-piperidyl)-3-phenyl-pyrrolidine-2,5-dione which melts at 119-124°C.

Example 9

A mixture of 5S39g 4-amino-2-chloro-6,7,8-tri-methoxyquinazoline, 4.32g 2-(4-piperidyl)-isoindolin-1-one, 4.24g anhydrous sodium carbonate and 75 ml of dimethylformamide is stirred in a nitrogen atmosphere for 16 hours at 125-130°C. The reaction mixture is filtered, the filtrate is evaporated, the residue is taken up in methylene chloride and the solution is washed with aqueous sodium bicarbonate solution. The organic layer is separated, dried and evaporated. The residue is suspended in refluxing isopropanol and adjusted with hydrogen chloride to pH 1. The formed precipitate is filtered off and triturated with hot ethanol. 2-[1-(4-amino-6,7,8-trimethoxy-2-quinazolinyl)-4-piperidyl]-isoindolin-1-one monohydrochloride is obtained,

which melts during decomposition at 234°C.

In an analogous way, by reacting 2.4 g of 4-amino-2-chloro-6,7-dimethoxy-quinazoline, 2.2 g of 2-(4-piperidyl)-isoindolin-1-one and 2 g of anhydrous sodium carbonate in 20 ml of dimethylformamide give 2-[1-(4-amino-6,7_dimethoxy-2-quinazolinyl)-4-piperidyl]-isoindolin-1-one monohydrochloride which melts on cleavage at 288-289°C.

The starting material is prepared as follows: A mixture of 2-formyl-benzoic acid, 8532 g of 4-amino-pyridine and 2800

ml of toluene is stirred using a water rinser for 2 hours and refluxed and stirring is continued at room temperature overnight. The reaction mixture is filtered and the residue is washed with toluene. 1-(4-pyridyl-amino)-3-oxo-phthalan is obtained, which melts at 215-220°C. (In an analogous way, 1-(3-pyridylamino)-3-oxo-phthalan is obtained starting from 3-amino-pyridine, melting point 150-155°C).

A suspension of 278 g of the compound melting at 215-220°C in 4700 ml of anhydrous ethanol is mixed portionwise with stirring at 18°C with 96 g of sodium borohydride over 105 minutes. Stirring is continued overnight at room temperature. The mixture is filtered, the filtrate is concentrated to a volume of 1200 ml, cooled and the precipitate formed is separated. 2-(4-pyridylaminomethyl)-benzoic acid is obtained, which melts at over 250°C.

One takes 180 g of the latter compound

1400 ml of concentrated sulfuric acid over 40 minutes with stirring and allowing the temperature to rise to about 67°C. The mixture is stirred for one hour at approximately 95°C, cooled to 25°C and slowly poured onto 4000 g of ice. The mixture is neutralized with approximately 450 ml of aqueous ammonia, the precipitate formed is filtered off and taken up in 2300 ml of isopropanol and 600 ml of chloroform. The mixture is boiled for 30 minutes under reflux, filtered hot, the filtrate is cooled and the precipitate formed is separated. 2-(4pyridyl)-isoindolin-1-one is obtained.

A mixture of 30 g of the latter compound,

400 ml of glacial acetic acid and 30 g of 10% palladium-on-charcoal catalyst are hydrogenated at approximately 65°C and 3 atmospheres to absorb the theoretical amount of hydrogen. The mixture is cooled to room temperature, filtered and evaporated. The residue is taken up in 6N aqueous sodium hydroxide solution, the mixture is extracted with chloroform, the extract is washed with saturated aqueous sodium chloride solution, dried and evaporated. 2-(4-piperidyl)-isoindolin-1-one is obtained, which melts at 144-146°C.

Example 10

A mixture of 4.4 g of 4-cyclohexyl-1-(4-piperidyl)-piperidine-2,6-dione, 3.4 g of 4-amino-2-chloro-6,7-dimethoxy-quinazoline and 100 ml of isoamyl alcohol boiled with stirring for 20 hours under reflux. The reaction mixture is left for 18 hours at room temperature, filtered, the residue is washed with isoamyl alcohol and diethyl ether, dried and dissolved in aqueous sodium carbonate solution. The solution is extracted with methylene chloride, the extract is evaporated and 7 g of the residue is dissolved in 75 ml of ethanol. The solution is first mixed with 1.4 g of methanesulfonic acid, then with 125 ml of ethanol, the precipitate formed is filtered off and recrystallized from aqueous ethanol. 1-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidyl]-4-cyclohexyl-piperidine-2,6-dione-monomethanesulfonate is obtained, which melts at 277-279°C

The starting material is prepared as follows: A mixture of 22.4 g of 3-(p-chlorophenyl)-glutaric anhydride, 10.3 g of 4-amino-pyridine, 350 ml of xylene and 1.5 g of methanesulfonic acid is stirred using a water separator for 4 days and boil under reflux. After the first day, the reaction mixture is mixed with 0.5 g of methanesulfonic acid and at the end the hot solution is decanted from any gummy material. The crystals formed after cooling are filtered off, triturated with hot ethanol, cooled, filtered again and dried. 4-(p-chlorophenyl)-1-(4-pyridyl)-piperidine-2,6-dione is obtained, which melts at 204-206°C.

A mixture of 11 g of the latter compound, 5.5 g of 10% palladium-on-charcoal catalyst and 150 ml of glacial acetic acid is hydrogenated for 10 hours at 120-140°C and 3 atmospheres. The solution is filtered off, after cooling it is evaporated and the residue is dissolved in a minimal amount of water. The solution is made basic with a 2N aqueous sodium hydroxide solution and extracted with methylene chloride. The extract is washed with water and evaporated. 4-Cyclohexyl-1-(4-piperidyl)-piperidine-2,6-dione is obtained, the hydrochloride of which melts during decomposition at 284-285°C.

Example 11

A mixture of 4.57 g of 4-amino-2-chloro-6,7-dimethoxy-quinazoline, 5.95 g of 3-(p-methoxyphenyl)-1-(4-piperidyl)-pyrrolidine-2,5 -dione and 125 ml of isoamyl alcohol are boiled for 24 hours under reflux. The reaction mixture is left for 2 days at room temperature, filtered, the residue is washed with isoamyl alcohol and diethyl ether, dried and dissolved in aqueous sodium carbonate solution. The solution is extracted with methylene chloride and the extract is evaporated. 8.1 g of the residue is dissolved in 175 ml of ethanol while heating and 1.5 g of methanesulfonic acid is added thereto. The precipitate formed is recrystallized from aqueous ethanol. One obtains 1-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidyl]-3_(p-methoxyphenyl)-pyrrolidine-2,5-dione-monomethanesulfonate which melts at 189-192 °C.

In an analogous manner (or according to example 2), 1-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidyl ]-J>-(3,4-dimethoxyphenyl)-pyrrolidine-2 ,5-dione-monomethanesulfonate,

which melts at 'l80-l82°C.

The starting material is prepared as follows: A mixture of 57.9 g of 2-(p-methoxyphenyl)-succinic anhydride, 26.3 g of 4-amino-pyridine and 500 ml of xylene is boiled using a water separator with stirring for 6 hours under backflow.

The hot solution is decanted, cooled, filtered and the residue recrystallized from ethanol. 3-(p-Methoxyphenyl)-1-(4-pyridyl)pyrrolidine-2,5-dione is obtained, which melts at 179-180°C. The analogous 3,4-dimethoxy compound melts at 172-174°C.

A mixture of 36 g of the p-methoxy compound,

22 g of 10% palladium-on-charcoal catalyst and 400 ml of glacial acetic acid are hydrogenated at 100°C and 1.7 atmospheres to absorb the theoretical amount of hydrogen. The reaction mixture is cooled, filtered and evaporated. The residue is dissolved in 100 ml of water, the solution is made basic with sodium carbonate, extracted with methylene chloride and the extract is evaporated. 3-(p-methoxyphenyl)-1-(4-piperidyl)-pyrrolidine-2,5-dione is obtained, the hydrochloride of which melts at 244-246°C. The hydrochloride of the analogous 3,4-dimethoxy compound melts at 238-240°C.

Example 12

A mixture of 6 g of 3-methyl-3-phenyl-1-(4-piperidyl)-pyrrolidine-2,5-dione, 4.79 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline and 200 ml of isoamyl alcohol is boiled for 9 hours under reflux, cooled and acidified with anhydrous hydrogen chloride in ethyl acetate. The reaction mixture is filtered, the residue is washed with isoamyl alcohol and diethyl ether, triturated with 95

% aqueous ethanol and absorbed in aqueous sodium carbonate solution. The solution is extracted with acetic acid ethyl ester and the extract is evaporated and the residue taken up in 100 ml of ethanol. The solution is mixed with 1.6 g of methanesulfonic acid, the precipitate formed is filtered off and recrystallized from aqueous ethanol. 1-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidyl]-3~methyl-3-phenyl-pyrrolidine-2,5-dione-monomethanesulfonate is obtained, which melts at 286 -288°C.

The starting material is prepared as follows: A mixture of 68.6 g of 2-methyl-2-phenyl-succinic anhydride, 34 g of 4-amino-pyridine and 675 ml of xylene is stirred using a water rinser and refluxed for 7 hours. The reaction mixture is cooled to 40°C, filtered, cooled to 0°C and filtered again. The other residue is recrystallized from isopropanol-hexane. 3-methyl-3-phenyl-1-(4-pyridyl)-pyrrolidine-2,5-dione is obtained, which melts at 90-92°C.

A mixture of 57.8 g of the latter compound, 22.5 g of 10% palladium-on-charcoal catalyst and 500 ml of glacial acetic acid is hydrogenated at 120°C and approximately 1.7 atmospheres. The reaction mixture is cooled, filtered and the residue taken up in aqueous sodium carbonate solution and ethyl acetate. The organic solution is washed with water, dried and evaporated. 3-methyl-3-phenyl-1-(4-piperidyl)-pyrrolidine-2,5-dione is obtained, whose hydrochloride after recrystallization from ethanol melts at 212-214°C.

Example 13

A mixture of 6.16 g of 3-methyl-1-(4-piperidyl)-pyrrolidine-2,5-dione, 6.71 g of 4-amino-2-chloro-6,7-dimethoxy-quinazolin and 125 ml of isoamyl alcohol boiled with stirring for 18 hours under reflux. The reaction mixture is cooled, filtered, the solid material is washed with isoamyl alcohol and diethyl ether, triturated with hot 90% aqueous ethanol and, after cooling, the crystalline product is filtered off. This is dissolved in a 10% aqueous sodium carbonate solution and the solution is extracted with ethyl acetate. The extract is washed with aqueous sodium carbonate solution and water, dried and evaporated. The residue is dissolved in 100 ml of anhydrous ethanol while heating, mixed with 2.14 g of methanesulfonic acid and cooled. The product formed is filtered off and recrystallized from 66% aqueous ethanol. 1-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidyl]-3-methyl-pyrrolidine-2,5-dione-monomethanesulfonate is obtained which melts during cleavage at 325-326 °C.

The starting material is prepared as follows: A mixture of 28.5 g of 2-methylsuccinic anhydride, 23.5 g of 4-aminopyridine and 350 ml of xylene is stirred using a water rinser for 3 hours and boiled under reflux. The hot solution is decanted from any gummy residue, cooled and filtered. The residue is suspended in 100 ml of boiling isopropanol and filtered again. 3-methyl-1-(4-pyridyl)-pyrrolidine-2,5-dione is obtained which melts at 119-120°C.

A mixture of 34.6 g of the latter compound,

9 g of 10% palladium-on-charcoal catalyst and 400 ml of glacial acetic acid are hydrogenated at 110°C and approximately 1.7 atmospheres to absorb the theoretical amount of hydrogen. j The reaction mixture is filtered, evaporated and the residue taken up in water. The mixture's pH value is set with sodium carbonate between 9 and 10 and'

the liberated base is extracted with methylene chloride. The extract is dried and evaporated. 3-methyl-1-(4-piperidyl)-pyrrolidine-2,5-dione is obtained, which is used without further purification.

Example 14

A mixture of 4.6 g of 4-phenyl-1-(4-piperidyl)-piperidine-2,6-dione, 3.64 g of 4-amino-2-chloro-6,7-dimethoxy-quinazoline and 100 ml of isoamyl alcohol is boiled with stirring for 22 hours under reflux. The reaction mixture is cooled and acidified with anhydrous hydrogen chloride in ethyl acetate. The solid material formed is filtered off and washed with isoamyl alcohol and diethyl ether. The product is triturated with 90%-lg aqueous ethanol and then taken up in aqueous sodium carbonate solution. The mixture is extracted with chloroform and the extract is evaporated. The residue is taken up in 75 ml of ethanol and mixed with 0.58 g of methanesulfonic acid. The resulting suspension is filtered and the residue is recrystallized from aqueous ethanol. 1-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidyl]-4-phenyl-piperidine-2,6-dione-monomethanesulfonate is obtained, which melts during decomposition at 292-295 °C.

1-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidyl]-4-(p-methoxy-phenyl)-piperidine-2,6-dione-monomethanesulfonate is also obtained in an analogous manner , which melts during cleavage at 305-307°C.

The starting material is prepared as follows: A mixture of 19 g of 3-phenylglutaric anhydride, 10.3 g of 4-amino-pyridine, 350 ml of xylene and 2.5 g of methanesulfonic acid is boiled using a water separator with stirring for 2 days under reflux. The hot solution is decanted from any insoluble material, cooled and filtered. The residue is triturated with hot isopropanol. 4-phenyl-1-(4-pyridyl)-piperidine-2,6-dione is obtained which melts at 229-230°C. The analogously prepared 4-(p-methoxyphenyl)-1-(4-pyridyl)-piperidine-2,6-dione melts at 168-169°C.

A mixture of 14.6 g of 4-phenyl-1-(4-pyridyl)-piperidine-2,6-dione, 12.3 g of 10% palladium-on-charcoal catalyst and 200 ml of glacial acetic acid is hydrogenated at 100° C and 1.7 atmospheres for 8 hours. After cooling, the reaction mixture is filtered, evaporated, the residue is dissolved in a minimal amount of water and the solution is made basic with sodium carbonate. The solution is extracted with acetic acid ethyl ester and the extract is evaporated. The residue is crystallized by trituration with 75 ml diethyl ether-hexane (3:1) and recrystallized from 50 ml isopropanol. 4-Phenyl-1-(4-piperidyl)-piperidine-2,6-dione is obtained which melts at 182-189°C. The analogous p-methoxy-phenyl compound melts at 127-129°C.

Example 15

Production of 10,000 tablets each containing 2.5 mg of the active substance:

Approach:

All powdered ingredients are sieved with a sieve of 0.6 mm mesh size. The active substance is then mixed with milk sugar, talc, magnesium stearate and with semi- part of the starch in a suitable mixer. The other half of the starch is suspended in 45 ml of water and the suspension is brought to a boiling solution of polyethylene glycol in 180 ml of water. The resulting paste is made into powders and possibly granulated with the addition of a further amount of water. The granulate is dried overnight at 35°C, passed through a sieve of 1.2 mm mesh and pressed into tablets of 7.1 mm diameter which have a breaking drill.

Production of 10,000 capsules each containing 5 mg of the above-mentioned active substance:

Approach:

All powdered components are sieved with a sieve of 0.6 mm mesh size. The active substance is then homogenised first with talc and then with milk sugar in a suitable mixer. Capsules No. 2 are filled each time with 300 mg of the mixture with a spring machine.

In an analogous manner, tablets or capsules are prepared which contain another compound prepared according to the invention, e.g. one such according to the previous example.

Example 16

A mixture of 4.79 g of 4-amino-2-chloro-6,7-dimethoxy-quinazoline, 5.2 g of 2-(4-piperidyl)-hexahydroisoindole-1,3-dione and 100 ml of isoamyl alcohol is boiled in a nitrogen atmosphere with stirring for 20 hours under reflux. The reaction mixture is cooled and acidified with a solution of anhydrous hydrogen chloride in acetic acid ethyl ester. The precipitate formed is filtered off, washed with ethanol, triturated with anhydrous sodium carbonate solution and extracted with ethyl acetate. The extract is washed with water, dried and evaporated. The residue is dissolved in anhydrous ethanol, the solution is neutralized with methanesulfonic acid,

the precipitate formed is filtered off and recrystallized from aqueous ethanol. 2-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidyl]-hexahydroisoindole-1,3-dione-monomethanesulfonate is obtained, which melts at 303-305°C.

The starting material is prepared as follows: A mixture of 23.5 g of 4-amino-pyridine, 38.5 g of cis-1,2-cyclohexane-dicarboxylic acid anhydride and 400 ml of xylene is stirred and refluxed using a water separator for 42 hours . After the first half hour and after 18 hours, the reaction mixture is mixed with 1 ml of methanesulfonic acid each time. The hot reaction mixture is filtered. The crystals formed during cooling are filtered off and recrystallized from isopropanol.

2-(4-pyridyl)-hexahydroisoindole-1,3-dione is obtained, which melts at 165-168°C.

A mixture of 38.7 g of the latter compound, 10 g of 5% rhodium catalyst on aluminum oxide and 400 ml of glacial acetic acid is hydrogenated at 75-105°C for 3 hours at 3 atmospheres. After cooling, the reaction mixture is filtered, evaporated, the residue is treated with saturated aqueous sodium carbonate solution and extracted with methylene chloride. The extract is washed with water and evaporated. 2-(4-piperidyl)-hexahydroisoindole-1,3-dione is obtained. Its hydrochloride melts at 24l-243°C

Example 17

A mixture of 2.2 g of 8-amino-6-chloro-1,3-dioxolo-[4,5_g]-quinazoline, 2.2 g of 1-(4-piperidyl)-pyrrolidine-2,5-dione and 60 ml of isoamyl alcohol is boiled with stirring for 20 hours under reflux. The reaction mixture is cooled, filtered, the solid material formed is washed with isoamyl alcohol and diethyl ether and dried. The product is triturated with a 10% aqueous sodium carbonate solution and extracted with ethyl acetate. The extract is washed with aqueous sodium carbonate solution and water, dried and evaporated. The residue is dissolved under heating in anhydrous ethanol and neutralized with methanesulfonic acid. After cooling, the product is filtered off and recrystallized from aqueous ethanol. One obtains 1-[1-(8-amino-1,3-dioxolo[4,5-g]-6-quinazolinyl)-4-piperidyl]-pyrrolidine-2,5-dione-monomethanesulfonate, which melts during cleavage at 348-350°C.

In an analogous manner, preferably according to examples 1, 12 and 13, 1-[1-(4-amino-6,7_dimethoxy-2-quinazolinyl)-4-piperidyl]-3 j 3-dimethyl-pyrrolidine-2,5- dione-monomethanesulfonate (melting point 267-268°C) and 1-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidyl]-3,4-dimethyl-pyrrolidine-2,5-dione- monomethane sulfonate (melting point 3l4-315°C).

Claims (9)

1. Process for the preparation of N-[1-(4-amino-2-quinazolinyl)-3- or -4-piperidyl-lactams of the general formula I in which Ph means a 1,2-phenylene residue which can optionally be substituted with a maximum of 3 substituents selected from lower alkyl and lower alkoxy and a lower alkylenedioxy, each of the symbols m and n means an integer from 1 to 3S, where m + n = 4, X means 2 hydrogen atoms or oxo, and A means lower alkylene, 4 to 7 ring-membered cycloalkylene, cycloalkyl-lower alkylene and spirocycloalkane-lower alkylene, HPh-lower alkylene or Ph as well as their acid addition salts characterized in that compounds with the formulas III and IV is condensed, in which Y means halogen or lower alkylthio and M means hydrogen or an alkali metal atom, and if desired, a formed compound of formula I is converted into another compound according to the invention and/or if desired, a formed free compound is transferred in an acid addition salt or an acid addition salt in the free compound or in another salt and/or if desired, split a formed mixture of isomers or racemates in the individual isomers or racemates and/or if desired, the formed racemates are resolved in the optical antipodes. 2. Process according to claim 1, characterized in that starting substances of formulas III and IV are used, in which Y means chlorine, bromine or methylthio and M means sodium or potassium. 3. Method according to one of claims 1 and 2, characterized in that one uses an intermediate product formed in one or another step of the method as starting material and carries out the remaining method steps or interrupts the method at one or other step or forms a starting material under the reaction conditions or uses the in the form of a salt or optically pure antipode. 4. Process according to one of claims 1-3, characterized in that compounds of the general formula I are prepared, where Ph means a 1,2-phenylene residue which can optionally be substituted with a maximum of 3 substituents selected from alkyl or alkoxy with a maximum of 4 carbon atoms and an alkylenedioxy with a maximum of 2 carbon atoms, each of the symbols m and n means an integer from 1 to 3, where m + n = 4, X means 2 hydrogen atoms or oxo and A means lower alkylene, 4 to 7 ring membered cycloalkylene, cycloalkyl-lower alkylene , spirocycloalkane-lower alkylene, HPh-lower alkylene or Ph as well as their acid addition salts. 5« Process according to one of claims 1-3, characterized in that compounds of the general formula I are prepared, where Ph means 1,2-phenylene, mono-, di- or tri-(alkyl or alkoxy)-1,2- phenylene or alkylenedioxy-1,2-phenylene, in which alkyl, alkoxy or alkylene maxi- malt has 2 carbon atoms, each of the groups C H„ and C H„ means j & m 2m & n 2n J ethylene, X means 2 hydrogen atoms or oxo and A means lower alkylene, 5 or 6 ring-membered 1,2-cycloalkylene or (cycloalkyl, spirocycloalkane or phenyl)-alkylene, each of the latter three residues containing a sum of a maximum of 8 carbon atoms as well as their acid addition salts. 6. Method according to claims 1-3, characterized in that compounds are prepared with the general formula II where each of the symbols R and R' means methoxy or together methylenedioxy, X means 2 hydrogen atoms or oxo, CpH2 p- q is the thiety alkylene, phenyl-alkylene or spirocycloalkane-alkylene, where p means an integer from 2 to 8, q means the number 0, 2 or 8 and 2p-q are positive as well as their acid addition salts. 7. Method according to one of claims 1 to 3, characterized in that compounds of the general formula II are prepared, in which each of the symbols R and R' means methoxy, X means oxo and the symbol C p H means ethylene, phenylethylene or 1,3 -propylene as well as their acid addition salts. 8. Method according to one of claims 1 to 3, characterized in that compounds are prepared with the formula II shown in claim 6, in which each of the symbols R and R' means hydrogen, methoxy or together methylenedioxy, X means 2 hydrogen atoms or oxo, the symbol cnH? means alkylene or spirocycloalkane-alkylene, where p means an integer from 2 to 8, q means the numbers 0 or 2 and their acid addition salts. 9. Method according to one of claims 1 to 3, characterized in that 1-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidyl]-pyrrolidine-2,5-dione is prepared and they t-s acid addition onsalt.