CS210700B2 - Manufacturing process of newly n-(l1-(l4-amino-2-quinazolinyl)p-3- or -4-piperidyl) plaktanes - Google Patents

Description

The present invention relates to a process for the preparation of novel N- [1 - ((4α-mimido) -4- (2-quinazolinyl) -3- or -4-piperidyl] lactams.

According to U.S. Pat. No. 3,518,336 are 1- [4-amino-2-quinazollnyl] piperldines and derivatives thereof containing at the 4-position of piperidine an alkyl, alkoxy, hydroxy, hydroxyalkyl, phenyl, benzyl and lower alkyl-4-phenyl residue. -4-carboxylic acids, by hypotensive means.

It is surprising that the compounds of the invention which contain a lactam nitrogen atom at the 3 or 4-position of piperidine have higher hypotensive and antihypertensive effects due to the blocking mechanism.

The present invention relates to a process for the preparation of the novel N- [1- (44a, 4- (2-quinazolinyl) -4- or -4-piperidyl] lactams of formula (I).

is optionally substituted with - at most 3 substituents selected from the group consisting of (C 1 -C 4) alkoxy and alkylenedioxy of up to - 4 carbon atoms, each of m - and n being an integer from - 1 to 3, wherein m - -j- n = '4,

X represents 2 atoms - hydrogen - or oxo - and

A - represents an alkylene - group having at most 8 carbon atoms, a cycloalkenyl group, a cycloalkylalkylene group and a spirocycloalkanalkylene group, an HPh-alkylene group or a - Ph group, wherein the cycloalkylene, cycloalkyl and spirocycloalkane group contain 4 to 7 ring carbon atoms and Contains up to 8 carbon atoms and their acid addition salts, in particular the therapeutically useful acid addition salts of these compounds.

The 1,2-phenylene Ph present in the quinazoline and / or lactam moiety of the compound is preferably mono-, di- or trisubstituted by C 1 -C 4 alkoxy, for example -methoxy, ethoxy, n- or iso-propoxy, or -alkyloxydioxo-C4-C4alkyloxy, e.g., 1,1-methylenedioxy or 1,2-ethylenedioxy. Said substituents are preferably in the 4,5- or 4,5,6 position of said phenylene group.

in which i

Ph is 1,2-phenylene, kte210700

The alkylene groups C _m H 2 _m and C n H ₂ n, which separate the nitrogen atom from the methine group having 1 to 3 carbon atoms, are preferably in each case ethylene or also methylene and 1,3-propylene.

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

Each of the cycloalkylene, cycloalkylalkylene or spirocycloalkanalkylene radicals contains 4 to 7 ring carbon atoms and is, for example, 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 alkylene moiety or the 1,2-phenyl moiety, i.e. the HPh-alkylene moiety or the Ph-moiety "A", is preferably in the ring unsubstituted or mono-substituted with the abovementioned alkoxy or alkylenedioxy groups. Thus, the symbol "A" means, for example, 1-phenylethylene, 2-phenyl-1,3-propylene, 1- or, 2-anisylethylene or 1- or, 2-anisyl-1,3-propylene; 1,2-phenylene, 3- or 4-methoxy-1,2-phenylene or, 4,5-methylene-1, oxy-1,2-phenylene. .....

The term " lower " in the following organic radicals or compounds defines radicals or compounds with a maximum of 8, preferably 4, in particular 1, or 2, carbon atoms.

The basic compounds of formula I form acid addition salts. Preferred are the therapeutically useful acid addition salts, for example, salts with the acids listed below.

The compounds of the invention exhibit valuable pharmacological properties, for example, hypotensive, antihypertensive, and vascular dilatation properties. These pharmacological properties can be demonstrated by experiments on animals, preferably mammals, for example on rats, cats or dogs, as experimental animals. These animals may be normotensive or hypertensive, for example, genetically or renally hypertensive rats or dogs. The novel compounds can be administered to these animals enterally or parenterally, preferably orally, subcutaneously, intravenously, intraperitoneally or intraduodenally, for example in the form of gelatin capsules or, in the form of suspensions or aqueous solutions, containing starch.

The dosage used may range from about 0.1 to 100 mg / kg / day, preferably from about 1 to 75 mg / kg / day, in particular from 5 to 50 mg / kg / day. The blood pressure lowering effect is registered either directly, by means of a catheter which is introduced, for example, into the caudal artery of the rat or into the femural artery of the dog and, by means of a special device, measures blood pressure before and application of the active substance in mmHg or indirectly , stygmomanometrically, for example on the tail of a rat.

Thus, 1- [4- (4-amino-6,7-dimethoxy-2-quinazolyl) -4-piperidinyl] pyrrolidine-2,5-dione or, therapeutically useful salts thereof, as typical representatives of the compounds of the invention are strongly antihypertensive effective in the above experiments. The compounds of the invention may be used as antihypertensive agents that have no effect on heart rate or have minimal effect on heart rate, for the treatment or management of essential or renal hypertension and / or congestive or chronic cardiac disorders in mammals. These compounds can also be used as intermediates for the production of other valuable, earthly pharmacologically active compounds or preparations.

Preferred are compounds of formula I wherein Ph is 1,2-phenyl, mono-, di-, or trialkoxy-1,2-phenylene or an alkylenedioxy-1,2-phenylene group in which alkoxy or alkylene is preferred. contains not more than 2 carbon atoms, each of CmH2m and ύηΗ2 _Ί represent an ethylene group, X represents 2 hydrogen atoms or an oxo group, and A represents an alkylene group having at most 8 carbon atoms, 5 or 6 ring members containing 1,2-cycloalkylene or a (cycloalkyl, spirocycloalkane or phenyl) alkylene group, each of the 3 radicals containing a total of at most 8 carbon atoms, and therapeutically useful acid addition salts thereof.

Particularly preferred are compounds of formula II,

·. ... N'V. From ^R w7 ^r 'r +

(i) in which each of the symbols R and R 'represents a methoxy group, or' together 'means a methylenedioxy group,

X 'represents 2 hydrogen atoms or' xixo- '. pin,

CpH2p. _q is an alkylene, phenylalkylene or spirocycloalkanalkylene group, wherein p is an integer from 2 to 8, q is 0, 2 or, 8, and 2p-q is a positive value; and a therapeutically useful acid addition salt thereof.

Preference is further given to compounds of the general formula II in which each of the symbols represents

R and R 'are methoxy, X is oxo, and C ₍ H 2 Pt _{) ;} an ethylene group, a phenylethylene group, or an X + propylene group, and therapeutically useful acid addition salts thereof.

The compounds of the present invention are prepared by methods known per se, for example by: compounds of formulas III and IV,

NH.

(Ν (lil)

in which

Y is halogen and

Ph, -m,, η, X and A are as defined above, condense - and optionally convert the free compound obtained into an acid addition salt or convert the acid addition salt into the free compound or another salt, and / or- the resulting mixture of isomers or racemates · optionally separated into the individual isomers or .racemáty ^1, and / or racemates obtained respectively. splits into optical atipodes.

The halogen atom Y is preferably chlorine or bromine.

Said condensation. is carried out at temperatures above room temperature, - for example. between about 100 - and about - 200 ° C, and / or. in the presence of condensing agents which bind the resulting acids. Such agents are - alkali metal carbonates or - alkali metal acid carbonates or tertiary-amines, for example - - tri (lower alkylamines, - pyridines or pyridines substituted with - lower-alkyl groups).

The free bases obtained can be converted into the corresponding acid addition salts, preferably using acids which provide therapeutically - useful - addition salts - with acids, or - with corresponding - ion exchangers - - - ( anion exchanger). The acid addition salts obtained may be converted into the corresponding free base, for example. by treatment with a base, such as hydroxide, metal, basic salt, ammonia, amine or ion exchanger (cation exchanger), e.g. - alkali hydroxide or carbonate. - metal.

Acids that. provide therapeutically useful acid addition salts - are - inorganic acids, such as hydrohalic acids, - for example - hydrochloric or hydrobromic acid, - or sulfuric acid, - phosphoric acid, - nitric acid, or -chloristou; or - organic acids, such as - aliphatic or aromatic - carboxylic and sulphonic acids, such as formic acid, -acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, - maleic, hydroxymaleinic, pyruvic, phenylacetic benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, 4-aminosalicylic, pamoic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic,. ethylene sulfone, halobenzene sulfone, toluene sulfone, naphthalene sulfone, -sulfanil or cyclohexylsulfame, or ascorbic acid. and

These. or other salts, such as picrates, can also be used to purify the free bases. The bases are converted into their salts, the salts separated and the base released from the salts. Due to the close relationship between the new compounds in free form and in the form of their salts, in the foregoing, the following free compounds and salts are to be understood as meaning and purpose, and optionally also the corresponding salts or free compounds.

The starting materials of formulas III and IV are known or, if new, can be prepared by methods known per se, for example as illustrated in the examples. Known starting materials and intermediates thereof are also described, for example, in U.S. Patent Nos. 3,511,836, 3,769,286 and 4,000,287, but also in the literature cited therein.

The reaction products of formula I, which are mixtures of isomers, can be separated into the individual isomers by methods known per se, for example by fractional distillation, crystallization and / or chromatography. Racemic products can be separated into optical antipodes, for example, by resolution of their diastereomeric salts, for example, by fractional crystallization of d- or 1- artrate.

The above reactions are carried out by methods known per se. in the presence - or - in the absence of diluents, preferably those which are inert to the reaction components and dissolve the reactants, catalysts, condensation agents and / or. other - said reagents, and / or in an inert atmosphere, with cooling,. at temperature. room - or at elevated temperatures, preferably. at the boiling point used. solvents, at atmospheric or - elevated pressure.

When. . of the process according to the invention. - preferably uses such-. the starting substances - which they lead. to the - compounds described above as particularly valuable, especially to the compounds of formula II.

The pharmacologically usable compounds of the invention can be used for the manufacture of pharmaceutical compositions containing an effective amount of the active ingredient together or in admixture with carriers suitable for enteral or parenteral administration. Preferably, tablets or gelatin capsules are used which contain the active ingredient together with diluents, for example lactose, dextrose, cane sugar, mannitol, sorbitol, cellulose and / or glycine, lubricants, for example silica gel talc, stearic acid or its salts, such as magnesium or calcium stearic acid, and / or with polyethylene glycol.

Tablets also contain binders such as magnesium aluminum silicate, paste starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or - potyvinylpyrrolidone, and optionally with tablet disintegrants such as starches, agar, alginic acid or a salt thereof, binder enzymes and / or foaming mixtures, or adsorbents, colorants, flavors and sweeteners. Injectable preparations are preferably isotonic aqueous solutions or suspensions, and suppositories are preferably emulsions or fat suspensions. The pharmacological compositions may be sterilized and / or contain adjuvants, for example preservatives, wetting agents and / or. emulsifiers, co-solvents, salts for regulating the osmotic pressure and / or buffers. Said pharmaceutical preparations, which may optionally contain other pharmaceutically valuable substances, are prepared in a manner known per se, for example by means of conventional mixing, granulating or coating processes, and comprise from about 0.1 to about 75%, in particular from about 1 to about 75%. Up to about 50% of the active ingredient.

The following examples serve to illustrate the invention. Temperatures are given in degrees Celsius and parts data refer to parts by weight. Unless otherwise stated, the solvents are evaporated under reduced pressure, for example between about 133.3 and 13330 Pa.

Example 1

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

-piperidyl] pyrrolidine-5S-dione monomethanesulfonate of formula O Λη γ yy N Ct \ O o _ΝΗ Ζ -сн ^ н

which melts at 331 ° with decomposition.

The starting material is prepared as follows:

A mixture of 20 g of succinic anhydride, 19 g of 4-aminopyridine and 450 ml of xylene is stirred under heating for 24 hours. The reaction mixture was cooled to room temperature, the solid product collected and extracted three times with 200 ml of methylene chloride at reflux. The combined extracts were evaporated and the residue was recrystallized from ethanol.

1- (4-Pyridyl) pyrrolidine-2,5-dione is obtained.

11.36 g of the latter are hydrogenated at 60 DEG C. in a minimum amount of glacial acetic acid in the presence of 8 g of 10% palladium on carbon catalyst and at a pressure of 0.27 MPa. The reaction mixture is filtered and evaporated. The residue was basified with aqueous sodium carbonate solution, extracted with chloroform, and the extract was evaporated. 1- (4-Plperidyl) pyrrolidine-2,5-dione is obtained, which melts at 133-134 °.

Example 1 a d 2

A mixture of 6.7 g of 4-camino-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 for 8 hours. The reaction mixture was cooled to room temperature, filtered and the filtrate was evaporated, the residue was triturated with ethanol, filtered again and the two precipitates were combined and the solid was taken up in aqueous sodium carbonate solution. The mixture is extracted with ethyl acetate, the extract is washed with water, dried and evaporated, the residue is taken up with hot ethanol, the solution is acidified with methanesulfonic acid, the resulting precipitate is filtered off and recrystallized from aqueous ethanol to give 1- [1- (4-amino-6, C-dimethoxy-2-quinazol-1-yl) -4-piperidyl] piptridin-2,6-dione monomethane ^; sulfonate melting at 33-334 ° C ^;

The starting material is prepared as follows:

A mixture of 34.2 g glutaric anhydride,

28.2 g of 4-aminopyridine and 650 ml of xylene are refluxed under stirring for 6 hours. The reaction mixture is cooled to room temperature, the precipitate is filtered off and extracted twice with 200 ml of chloroform at reflux. The combined extracts were evaporated and the residue was recrystallized twice from ethyl acetate. 1- (4-Pyridyl) piperidine-2,6-dione is obtained, which melts at 153-155 ° ^C.

8.1 g of the above compound is hydrogenated in 100 ml of glacial acetic acid in the presence of 6.3 g of 10% palladium on carbon catalyst at 60 DEG C. and at a pressure of 0.29 MPa. The reaction mixture was filtered, the filtrate was evaporated and the residue treated with aqueous sodium carbonate solution. The mixture was extracted several times with methylene chloride. and the combined extracts are evaporated. 1- (4-piperidyl) piptridine-2,6-dione is obtained as a low melting solvating product.

Example 3

A mixture of 4.79 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline, 4.49 g of 4-dimethyl-1- (4-piperidyl) piperidine-2,6-dione, 4.24 g of anhydrous. sodium carbonate. and 75 ml of DMF were stirred at 150 DEG C. under nitrogen for 6 hours. The reaction mixture was filtered, the filtrate was evaporated, the residue was dissolved in ethyl acetate and the solution was washed with aqueous sodium carbonate solution and water. This solution was dried, evaporated, the residue triturated with isopropanol, filtered and the solid product was set aside. The filtrate was strongly acidified with hydrogen chloride, the precipitate was filtered off and triturated with 175 ml of boiling methanol. 1- [1-44-Amino-6,7-dimethoxy-2-quinazolinyl] -4-piperidyl] -4,4-dimethylpiperidine-2,6-dione monohydrochloride melting at 276-280 with decomposition Deň: 32 ° C.

The starting material is prepared as follows:

A mixture of 3,3-dimethylglutaric anhydride (19.3 g), 4-aminopyridine (12.55 g) and xylene (350 ml) was refluxed under stirring for 60 hours. The hot xylene solution is separated by decantation from the syrup-like residue, which is cooled to room temperature, filtered and the residue is recrystallized from ethanol. It is obtained

4,4-dimethyl-1- (4-pyridyl) piperidine-2,6-dione, melting at 225-226 °.

g of the latter compound is dissolved in 200 ml of glacial acetic acid and this solution is hydrogenated in the presence of 15 g of 10% palladium on carbon catalyst at 0.31 Pa. The reaction mixture was filtered, the filtrate was evaporated, the residue was taken up in 6N aqueous sodium hydroxide solution with cooling, and the mixture was extracted with methylene chloride. The extract was evaporated and the residue was recrystallized from benzene / hexane. 4,4-dimethyl-1- (4-piperidyl) -1-piperidine-N-dione melting at 162-163 ° is obtained.

Example 4

A mixture of 70 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline, 73.2 g of 8- (4-piperidyl-4-piperidinyl) -dione, 62.1 g of anhydrous sodium carbonate and 800 ml of dimethylformamide The reaction mixture was allowed to cool to room temperature, filtered, and the filtrate was evaporated. The residue was poured into 300 ml of water with stirring and cooling, diluted with 1600 ml. The solid filtrate was triturated with 1600 ml of ethyl acetate and 10 ml of saturated aqueous sodium carbonate solution. The organic layer was separated, dried, evaporated and the residue was dissolved in 100 ml of ethyl acetate. hydrochloric acid, the precipitate was filtered off and recrystallized from aqueous methanol to give 8- [1- (4-amino-4 - [(4-dimethoxy-2- [4] quinazolinyl] -8-azaspiro]] - [4]. 5] decane-7,9-dlonone hydrochloride, which melts at 277-279 ° with decomposition.

g of the latter compound is suspended in 100 ml of water and 10 ml of 6N aqueous sodium hydroxide solution and extracted with chloroform. The extract was washed with water, dried, evaporated and the residue was dissolved in 50 ml of ethanol with heating. A solution of 0.94 g of methanesulfonic acid is then added, the precipitate is collected and recrystallized from aqueous ethanol. The corresponding monomethanesulfonate melts at 307-308 °.

The starting material is prepared as follows:

A mixture of 100 g of 3,3-tetramethyleneglutaric anhydride, 57 g of 4-aminopyrrolidine and 1500 xylene is stirred and refluxed for 3 days using a water separator. The reaction mixture was cooled somewhat, the xylene solution was separated by decantation from a small amount of oily material and cooled in an ice bath. The precipitate obtained is separated, dissolved in 1500 ml of boiling ethanol, the solution is cooled to 5, filtered and the residue is dried. There was obtained 8l (4-pyridyl) -8-aza-triazole (α-decane-ZAdioTi) melting at 208-211 °.

A solution of 58 g of the latter compound in 580 ml of glacial acetic acid is hydrogenated in the presence of 45 g of 10% palladium on carbon catalyst at room temperature and at a pressure of 50 psig. After the theoretical amount of hydrogen had been consumed, the mixture was filtered and the filtrate was evaporated. The residue was basified with 6N aqueous sodium hydroxide solution and the mixture was extracted with chloroform. The extract was washed with saturated aqueous sodium chloride solution, dried, evaporated and the residue was dissolved in 325 ml of hot toluene. The solution was filtered, diluted with 400 mL of hexane, cooled and filtered. There was thus obtained 8- (4-piperidyl) 18-azaspiro [4.5] decane-7,9-dione melting at 141-14.2 °.

Example 5

A mixture of 5.39 g of 4-amino-2-chloro-6,7,8 trimethoxyquinazoline, 5.25 g of 8l (4-piperidyl) -8-azaspiro [4.5] decane-7,9-dione, 4.24 g of anhydrous sodium carbonate and 75 ml of dimethylformamide were stirred at 150 degrees for 8 hours. After cooling to room temperature, the reaction mixture is filtered, the filtrate is evaporated, the residue is dissolved in ethyl acetate and the ethyl acetate solution is washed with aqueous sodium bicarbonate solution and water. The solution is dried, evaporated, the residue is dissolved in 75 ml of ethyl acetate and allowed to crystallize. The crystals are dissolved in 50 ml of hot isopropanol and the solution is acidified with hydrochloric acid, to pH 1. The precipitate obtained is filtered off. There was obtained 8l (11 (4-amino-6,7,8-trimethoxy-2-quinolinyl) -4-piperidyl] -8-azaspiro [4,5] decane-7,9-dione manohydrochloride melting at 225 ° C. to 227 °.

Example '6

A mixture of 2.39 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline, 2.64 g of 3- (4-piperidyl) -3-aza210700 spiro [5.5] _undec: an 2,4-dione 2 1 g of anhydrous sodium carbonate and 25 ml of dimethylformamide were stirred at 150 DEG C. under nitrogen for 10 hours. The reaction mixture was filtered, the filtrate was evaporated and the residue was dissolved in methylene chloride. The solution was 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 with isopropanol and the solution is acidified with hydrogen chloride. 3- [1- (4-Amino-6,7-dimethoxy-2-quinazolin-4-yl) -4-piperidyl] -3-aza-piperazin [5.5] unane dee was obtained. The hydrochloride, which melts with decomposition at 290 degrees.

The starting material is prepared as follows:

A mixture of 1,1-cyclohexanediacetic acid anhydride (25 g), 4-aminopyridine (12.92 g) and xylene (400 ml) was refluxed for 25 hours using a water trap. The hot xylene solution, which forms the upper layer, is decanted from the oily precipitate (set aside), cooled, filtered and the residue recrystallized from ethanol to give 3- (4-pyridyl) -3-azaspiro [ 5,5] undecane-2,4-dione, which melts at 213-215 °.

13.8 g of the latter are dissolved in 150 ml of glacial acetic acid and the solution is hydrogenated in the presence of 10 g of 10% palladium on carbon catalyst at a temperature of 50 to 60 ° C and at a pressure of 1 bar. The mixture was filtered and the residue was worked up as described in Example 4. 3- (4-Piperidyl] -3-azaspiro [5,5] undecane-2,4-dione was obtained, which after recrystallization melted from a mixture of benzene and hexane at 148 ° C. to 149 °.

Example 7

A mixture of 5.72 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline, 5.65 g of 2- (4-piperidyl) -2-azase, piro [4,4] nonane-1,3-dione, 6 16 g of diisopropylethylamine and 75 ml of dimethylformamide were stirred at 150 DEG C. for 8 hours under a nitrogen atmosphere. The reaction mixture was evaporated, the evaporation residue was partitioned between ethyl acetate and aqueous sodium carbonate solution, the organic solution was washed with water, dried and evaporated. The residue is taken up in ethanol and adjusted to pH 1 by addition of methanesulfonic acid. The precipitate obtained is filtered off and recrystallized first from methanol and then from aqueous ethanol. 2- (1- (4-Amino-6,7-dinethoxy-2-quinazolinyl) -4-piperidyl] -2-azaspiro [4.4] nonane-1,3-dione-monomethyl ether) was obtained. The ulphonate melts at 278 DEG-280 DEG.

The starting material is prepared as follows:

A mixture of 21.8 g of tetra-methylene succinic acid (made from the corresponding dicarboxylic acid by refluxing with acetic anhydride), 12.2 g of amminopydinine and 300 ml of xylene is boiled using a water trap for 9 hours under reflux. The hot solution was filtered, the filtrate was cooled to 5 ° and the residue was recrystallized from ethanol. 2- (4-Pyridyl) -2-azaspiro [4.4] nonane-1,3-dione melting at 100-103 ° C is obtained.

16.76 g of the latter compound are hydrogenated in the presence of 12 g of 10% palladium on carbon catalyst in 180 ml of glacial acetic acid at 60 DEG C. and 0.32 MPa. The mixture was filtered, evaporated, the residue basified with aqueous sodium carbonate solution and extracted again with chloroform. The extracts were dried and concentrated. 2- (4-Piperidyl] -2-azaspiro [4.4] nonane-1,3-dione melting at 119-120 ° C is obtained.

Example 8

A mixture of 4.8 g of 4-amino-4- (4-piperidinyl) -3- (4-piperidyl) -3-phenylpyrrolidin-2-yl, 5,17 g of 1- (4-piperidyl) -3-phenylpyrrolidine diisopropylethylamine (5.2 g) and dimethylformamide (75 ml) were stirred at 150 DEG C. under nitrogen for 8 hours. The reaction mixture was evaporated, the residue was partitioned between ethyl acetate and aqueous sodium carbonate, organic The residue was dissolved in warm ethanol and adjusted to pH 1 by addition of methanesulfonic acid solution. The precipitate obtained after cooling was collected and recrystallized from aqueous ethanol to give 1- [C- ( C-amino-6,7-dimelhoxy-2-quinazolin-4-piperidyl] -3-phenylpyrrolidine-2,5-dione-one-one-ethanesulfonate, melting at 239-244 °.

The starting material is prepared as follows:

A mixture of 20.2 g of phenyl succinic anhydride, 10.7 g of 4-aminopyridine and 300 ml of xylene is refluxed for 6 hours. The hot solution was separated by decantation from a small amount of gummy precipitate. After cooling, a precipitate is obtained, which is filtered off and recrystallized from ethanol. There was thus obtained 3-phenyl-1- (4-pyridyl) pyrrolidine-2,5-dione melting at 146-147 degrees.

20.6 g of the latter are hydrogenated in 200 ml of glacial acetic acid in the presence of 14 g of 10% palladium-on-carbon catalyst at 60 DEG C. and at a pressure of 0.3 MPa. The mixture is filtered, the filtrate is evaporated and the residue is dissolved in 75 ml of water. The solution was basified with sodium carbonate and extracted several times with ethyl acetate. The extract was washed with aqueous sodium carbonate solution, dried and evaporated.

The residue was recrystallized from toluene / hexane. 1- (4-Piperidyl) -3-phenylpyrrolidine-2,5-diamide is obtained, which melts at 119-124 °.

Example 9

A mixture of 5.39 g of 4-amino-2-chloro-6,7,8-trimethoxyquinazoline, 4.32 g of 2- (4-piperidyl-isoindolin-1-one), 4.24 g of anhydrous sodium carbonate and 75 ml of dimethylformamide was added in The reaction mixture was filtered, the filtrate was evaporated, the residue was taken up in methylene chloride and the solution was washed with aqueous sodium bicarbonate solution. The organic layer was separated, dried and evaporated. in isopropanol boiling under reflux and hydrogen chloride, the pH is adjusted to 1. The precipitate obtained is filtered off and triturated with warm ethanol to give 2- [1- (4-amino-6,7,8-trimethoxy-2-quinazolinyl)]. 4-piperidyl] isoindolin-1-one monohydrochloride melting at 234 ° with decomposition.

In an analogous manner, the reaction of 2.4 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline, 2.2 g of 2- (4-piperidyl) isoindolin-1-one and 2 g of anhydrous sodium carbonate ¹ in 20 ml of dimethylformamide 2- (1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4-piperidyl] isoindolin-1-one monohydrochloride melting at 288-289 ° C decomposes.

The starting material is prepared as follows:

A mixture of 2-formylbenzoic acid, 85.2 g of 4-aminopyridine and 28 * 00 ml of toluene was stirred for 2.5 hours using a water separator and refluxed and stirring was continued at room temperature overnight. The reaction mixture was filtered and the residue was washed with toluene. 1- (4-Pyridylamino) -3-oxo-phthalate melts at 215-220 ° C. [Analogous to give 1- (3-pyridylamino) -3-oxophthalane from 3-aminopyridine, m.p. 150-155 ° C.

To a suspension of 278 g of the compound melting at 215-220 ° in 4700 ml of anhydrous ethanol, 96 g of sodium borohydride are added in portions over a period of 105 minutes with stirring at 18 °. 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 obtained is collected. 2- (4-Pyridylaminomethyl) benzoic acid is obtained, which melts above 250 °.

180 g of the latter are added to 1400 ml of concentrated sulfuric acid over 40 minutes with stirring and the temperature is allowed to rise to approximately 67 °. The mixture is stirred at about 95 ° for one hour, cooled to 25 ° and slowly poured onto 4000 g of ice. The mixture is neutralized with about 4500 ml of aqueous ammonia, the precipitate obtained is filtered off and taken up with 2300 ml of isopropanol and 600 ml of chloroform. The mixture is refluxed for 30 minutes, filtered while hot, the filtrate is cooled and the precipitate obtained is collected. 2- (4-pyridyl) isolndolin-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-carbon catalyst is hydrogenated at about 65 ° and 0.3 MPa until the theoretical amount of hydrogen has been consumed. The mixture was cooled to room temperature, filtered and evaporated. The residue was taken up in 6N aqueous sodium hydroxide solution, extracted with chloroform, washed with saturated aqueous sodium chloride solution, dried and evaporated. 2- (4-piperidyl) isoindolin-1-one is obtained, which melts at 144-146 °.

Example 10

A mixture of 4.4 g of 4-cyclohexyl-1- (4-piperidyl) piperidine-2,6-dione, 3.41 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline and 100 ml of isoamyl alcohol is boiled with stirring. hours under reflux. The reaction mixture is left to stand 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. This solution was extracted with methylene chloride, the extract was evaporated and 7 g of the residue was dissolved in 75 ml of ethanol. To this solution is first added 1.4 g of methanesulfonic acid, then 125 ml of ethanol, the precipitate obtained is filtered off and recrystallized from aqueous ethanol. 1- [1- (4-Amino-6,7-dimethoxy-2-quinazolinyl) -4-piperidyl] -4-cyclohexylpiperidine-2,6-dione monomethanesulfonate is obtained, which melts at 277-279 °.

The starting material is prepared as follows:

A mixture of 22.4 g of 3- (p-chlorophenyl) glutaric anhydride, 10.3 g of 4-aminopyridine, 350 ml of xylene and 1.5 g of methanesulfonic acid was stirred and refluxed for 4 days using a water separator. After the first day, 0.5 g of methanesulfonic acid is added to the reaction mixture and finally a small amount of gum is separated from the hot solution by decanitization. After cooling, the crystals obtained are filtered off, triturated with hot ethanol, cooled, filtered again and dried. There was thus obtained 4- (p-chlorophenyl) -1- (4-pyridyl) piperidine-2,6-dione melting at 204-206 °.

A mixture of 11 g of the latter compound, 5.5 g of 10% palladium on carbon catalyst and 150 ml of glacial acetic acid is hydrogenated for 10 hours at a temperature of 120-140 [deg.] And at a pressure of 0.3 MPa. After cooling, the solution is filtered, the filtrate is evaporated and the residue is dissolved in a minimum amount of water. This solution was basified with 2N aqueous solution; sodium hydroxide and extracted with methylene chloride. The extract was washed with water and evaporated. 4-Cyclohexyl-1- (4-piperidyl) piperidine-2,6-dione is obtained, the hydrochloride of which melts at 284 DEG-285 DEG with decomposition.

Example 11

A mixture of 4.57 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline, 5.95 g of 3- (p-methoxyphenyl) -1- (4-piperidyl) -pyrrolidine-2,5-dione and 125 ml of isoamyl alcohol is refluxed for 24 hours. The reaction mixture is allowed to stand at room temperature for 2 days, filtered, the residue is washed with isoamyl alcohol, dried and dissolved in aqueous sodium carbonate solution. This solution was extracted with methylene chloride and the extract was evaporated.

8.1 g of the residue were dissolved in 175 ml of ethanol with heating and 1.5 g of methanesulfonic acid was added. The precipitate obtained is recrystallized from aqueous ethanol. There was obtained 1- (1- (4-amino-6,7-dimethoxy) -2-quinazolinyl) -4-piperidyl] -3- (p-methoxyphenyl) pyrrolidine-2,5-dione monomeithanesulfonate which was melts at 189-192 °.

Analogously (or according to Example 2), 1- [1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4-piperidyl] -3- (3,4-dimethoxyphenyl) pyrrolidine- 2,5-dione monomethanesulfonate melting at 180-182 ".

The starting material is prepared as follows:

A mixture of 57.9 g of 2- (p-methoxyphenyl) succinic anhydride, 26.3 g of 4-aminopyridine and 500 ml of xylene is refluxed under stirring for 6.5 hours. The hot solution was decanted, cooled, filtered and the residue recrystallized from ethanol. 3- (p-methoxyphenyl) -1- (4-pyridyl) pyrrolidine-2,5-dione melting at 179-180 DEG C. Analogous 3,4-dimethoxy derivative melts at 172-174.

A mixture of 36 g of the p-methoxy derivative, 22 g of 10% palladium on carbon catalyst and 400 ml of glacial acetic acid is hydrogenated at 100 DEG and 50 psi until the theoretical amount of hydrogen has been consumed. The reaction mixture was cooled, filtered and the filtrate was evaporated. The residue was dissolved in 100 ml of water, basified with sodium carbonate, extracted with methylene chloride and the extract was evaporated. 3- (p-methoxyphenyl) -1- (4-piperidyl) pyrrolidine-2,5-dione is obtained, the hydrochloride of which melts at 244-246 °. Analogous hydrochloride

The 3,4-dimethoxy derivative melts at 238-240 °.

Example 12

A mixture of 6 g of 3-ethyl-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 9. The reaction mixture was cooled and acidified with anhydrous hydrogen chloride in ethyl acetate. The reaction mixture was filtered, the residue was washed with isoamyl alcohol and diethyl ether, triturated with 95% ethanol (aqueous) and dissolved in aqueous sodium carbonate solution. The solution was extracted with ethyl acetate, the extract was evaporated and the residue taken up in 100 ml of ethanol.

1.6 g of methanesulfonic acid are added to the solution, and the precipitate obtained is filtered off and recrystallized from aqueous ethanol. 1- (1- (4-Amino-6,7-dimethoxy-2-quinazolinyl) -4-piperidyl) -3-methyl-3-phenylpyrrolidine-2,5-dione monomethanesulfonate is obtained, which melts at 286 DEG-288 DEG.

The starting material was prepared as follows; as follows:

A mixture of 2-methyl-2-phenylsuccinic anhydride (68.6 g), 4-aminopyridine (34 g) and xylene (675 ml) was refluxed using a water trap and stirred for 7 hours. The reaction mixture was cooled to 40 °, filtered, cooled to 0 ° and filtered again. The second residue was recrystallized from isopropanol / hexane. 3-Methyl-3-phenyl-1- (4-pyridyl) pyrrolidine-2,5-dione melting at 90-92 ° is obtained.

A mixture of 57.8 g of the latter compound,

22.5 g of 10% palladium-on-carbon catalyst and 500 ml of glacial acetic acid are hydrogenated at about 12.0 ° under a pressure of about 100 psig. The reaction mixture was cooled, filtered and the residue was taken up in aqueous sodium carbonate solution and ethyl acetate. The organic solution was washed with water, dried and evaporated. 3-Methyl-3-phenyl-1- (4-piperidyl) pyrrolidine-2,5-dione is obtained, the hydrochloride of which melts at 21.2 to 214 ° after recrystallization from ethanol.

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-dimethoxyquinazoline and 125 ml of isoamyl alcohol is boiled under stirring. hours under reflux. cooler. The reaction mixture is cooled, filtered, the solid residue is washed with isoamyl alcohol and diethyl ether, triturated with hot 90% aqueous ethanol and, after cooling, the crystalline product is filtered off.

This product was dissolved in a 10% aqueous sodium carbonate solution and extracted with ethyl acetate. The extract was washed with aqueous sodium carbonate solution and water, dried and evaporated. The residue was dissolved in 100 ml of anhydrous ethanol with heating, 2.14 g of methanesulfonic acid was added and cooled. The product obtained is filtered off and recrystallized from 66% aqueous ethanol. 1- [1- (4-Amino-6,7-dimethoxy-2-quinazolinyl) -4-piperidyl] -3-methylpyrrolidine-2,5-di-one-monomethyl ethanesulfonate is obtained, which melts on decomposition at 325-326 °.

The starting material is prepared as follows:

A mixture of 2-methylsuccinic anhydride (28.5 g), 4-aminopyridine (23.5 g) and xylene (350 ml) was refluxed with a water trap for 3.5 hours.

The hot solution was separated from the small amount of gum by decanting, cooled and filtered. The residue is suspended in 100 ml of boiling isopropanol and filtered again. 3-Irethyl-1- (4-pyridyl) pyrrolidine-2,5-dione is obtained, which melts at 119-120 °.

A mixture of 34.6 g of the latter compound, 9 grams of 10% palladium on carbon catalyst and 400 ml of glacial acetic acid is hydrogenated at 110 ° C and about 100 psi until the theoretical amount of hydrogen is consumed.

The reaction mixture was filtered, the filtrate was evaporated and the residue was dissolved in water. The pH of the mixture was adjusted between 9 and 10 by the addition of sodium carbonate and the liberated base was extracted with methylene chloride. The extract was dried and evaporated. This gave 3-methyl-1- (4-piperidyl) pyrrolidine-2,5-dione which was used without further purification.

Example 14

A mixture of 4.6 g of 4-phenyl-1 ((4 (yiperidyl) piperidine-2,6-dione, 3.64 g of 2-amino-2-chloro-6,7-dimethoxyquinazoline and 100 ml of isoamyl alcohol is boiled under stirring for 22 hours). The reaction mixture was cooled and acidified with anhydrous hydrogen chloride in ethyl acetate, the solid obtained was filtered off, washed with isoamyl alcohol and diethyl ether, the product was triturated with 90% aqueous ethanol and then taken up in aqueous sodium carbonate solution. The residue is taken up in 75 ml of ethanol and 0.58 g of methanesulfonic acid is added, the suspension obtained is filtered and the residue is recrystallized from aqueous ethanol to give 1-tert-amino-B, [eta] < 5 > dimethoxy-2- (4-methyl-4-azolinyl) -4- (4-phenyl) -4-phenylpiperidine-4-dione monomethanesulfonate, which melts on decomposition on decomposition 292-295 '.

Similarly, 1- [1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4-piperidyl] -4- (p-methoxyphenyl) piperidine-2,6-dione monomer is also obtained: ethanesulfonate melting at 305-307 ° with decomposition.

The starting material is prepared as follows:

A mixture of 3-phenylglutaric anhydride (19 g), 4-aminopyridine (10.3 g), xylene (350 ml) and methanesulfonic acid (2.5 g) was refluxed for 2 days using a water separator and stirring. The hot solution was separated by decantation from a small amount of insoluble material, cooled and filtered. The residue was triturated with hot isopropanol. There was thus obtained 4-phenyl- (4-pyridyl) piperidine-2,6-dione melting at 229-230 °.

4- (p-Methoxyphenyl) -1- (4-pyridyl) piperidine-2,6-dione, prepared in an analogous manner, melts at 168-169 °.

A mixture of 14.6 g of 4-phenyl-4- (4-yyridyl) yeridine (

-2.6-dione, 12.3 g of 10% palladium-on-carbon catalyst and 200 ml of glacial acetic acid are hydrogenated at 100 DEG C. and a pressure of 100 psig for 8 hours. After cooling, the reaction mixture was filtered, evaporated, the residue dissolved in a minimal amount of water and the solution basified with sodium carbonate. This solution was extracted with ethyl acetate and the extract was evaporated. The residue was crystallized by trituration with 75 ml of a mixture of diethyl ether and hexane (3: 1) and recrystallized from 50 ml of isoyloroyl alcohol. There was obtained 4-phenyl-1 ((4 (yeridyl) piyeridine (-2,6-dione), melting at 182-189). Analogous γ (methoxyphenyl derivative) melts at 127-129 °.

Example 15

Production of 10'000 'tablets containing always

2,5 mg of active substance:

Folders:

1- (1- (4-Amino-6,7-dimethoxy-2-quinazolinyl) -4- (pyrrolidin-1-yl) -pyrrolidine (2,5 (dione (mon.metha.n (sulfonate 25 g lactose 1956 g corn) starch 90g yolyethyltglycol 6000 6000g talcum powder 90g magnesium stearate salt 24g purified water as needed

Method:

All powder components are passed through a sieve with a mesh size of 0.6 mm. The active ingredient is then mixed in a suitable mixer with lactose, talc, magnesium stearate and half of the starch. The other half of the starch is suspended in 45 ml of water and this suspension is added to a boiling solution of polyethylene glycol in 180 ml of water. The paste obtained is added to the powder fractions and optionally granulated with the addition of additional water. The granulate is dried overnight at 35 ° and passed through a sieve with a mesh size

1.2 mm and then compressed into 7.1 mm diameter tablets which are scored.

Production of 10,000 capsules each containing 5 mg of the above active ingredient:

Folders:

the above monornethanesulfonate 50 g lactose 2350 g talc powder 150 g

Method:

All powder components are sieved through a 0.6 mm sieve. Thereafter, the active ingredient is mixed in a suitable blender first with talc and then with lactose until a homogeneous mixture is obtained. In each case 300 'mg of this' blend' is filled with size 2 capsules on a filling machine.

Tablets or capsules containing another compound are prepared in an analogous manner

21U70U according to the invention, for example any of the above examples.

Example 16

A mixture of 4.79 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline, 5.2 g of 2- (4-piperidyl) hexahydroisoindole-1,3-dione and 100 ml of isoamyl alcohol is boiled under nitrogen atmosphere with stirring under The reaction mixture was cooled and acidified with a solution of anhydrous hydrogen chloride in ethyl acetate, and the precipitate obtained was filtered off, washed with ethanol, triturated with aqueous sodium carbonate solution and extracted with ethyl acetate. The residue was dissolved in anhydrous ethanol, the solution was neutralized with methanesulfonic acid, the resulting precipitate was filtered off and recrystallized from aqueous ethanol to give 2- [1- (4-amino-6,7-dimethoxy-2). (quinazolinyl) -4-piperidyl] hexahydroisoindole-1,3-dione monomethanesulfonate melting at 303-305 °.

The starting material is prepared as follows:

A mixture of 4-aminopyridine (23.5 g), cis-1,2-cyclohexanedicarboxylic anhydride (38.5 g) and xylene (400 ml) was stirred and refluxed for 42 hours using a water trap. After the first half hour and after an additional 18 hours, 1 ml of methanesulfonic acid was added to the reaction mixture. The hot reaction mixture was filtered. The crystals obtained by cooling ¹ are filtered off and recrystallized from isopropanol. There was thus obtained 2- (4-pyridyl) hexahydroisoindole-1,3-dione melting at 165-169 °.

A mixture of 38.7 g of the latter compound, 10 g of 5% rhodium on alumina catalyst and 400 ^l ml of glacial acetic acid is hydrogenated at 75-105 ° C for 3 hours at 0.3 MPa. After cooling, the reaction mixture is filtered, the filtrate is evaporated, the residue is treated with a saturated aqueous sodium carbonate solution and extracted with methylene chloride. The extract was washed with water and evaporated. 2- (4-Piperidyl) hexahydroisoindole-1,3-dione hydrochloride melts at 241-243 °.

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 added. The reaction mixture was cooled, filtered, washed with isoamyl alcohol and diethyl ether and dried, triturated with 10% aqueous sodium carbonate solution and extracted with ethyl acetate. aqueous sodium carbonate solution and water, dried and evaporated, the residue was dissolved in anhydrous ethanol with heating, and this solution was neutralized with methanesulfonic acid, and after cooling the product was filtered off and recrystallized from aqueous ethanol to give 1- { 1- (8-amino-1,3-dioxolo [4,5-g] -6-quinazolinyl) -4-piperidyl} pyrrolidine-2,5-dione monomethanesulfonate, melting at 348-350 ° with decomposition.

In an analogous manner, preferably according to Examples 1, 12 and 13, 1- (1- (4-amino-6H-dimethoxy-2-quinazolinyl) -4-piperidyl) -3,3-dimethylpyrrolidin-2 is also obtained. 5-dione-monom-than-sulfonate (m.p. 267 DEG-2613 DEG); and 1- [1- (3-methyl-6,7-triazol-2-yl) naphtholinyl] -4-piperidyl] -3, 4-dimethylpyrrolidine-2,5-dione monomethanesulfonate (mp 314-315 °).

Example 18

A mixture of 3.75 g of 8- (3-piperidyl) -8-azaspiro [4.5] decane-7,9-dione, 3.59 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline and 100 ml The reaction mixture was cooled to 20 ° and the solid was filtered off, washed with isoamyl alcohol and diethyl ether and recrystallized from a mixture of 160 ml of ethanol and 110 ml of water to give 8- [1]. (4-Amino-6,7-dimethoxy-2-quinolinyl-3-piperidyl) -8-azaspiro (4,5) decane, 9-dione hydrochloride, melting at 311-312 ° (with decomposition).

5.4 g of the above compound are suspended in 10 ml of water and the suspension is made alkaline with a 10% aqueous sodium carbonate solution. The mixture is extracted with methylene chloride, the extract is dried, evaporated and the residue is dissolved in 50 ml of ethanol with heating. Methanesulfonic acid (1.1 g) was added and the precipitate was collected. 8- (1- (4-Amino-6,7-dimethoxy-2-quinazolinyl) -3-piperidyl) -8-azaspir d [4,5,5] decane-4-diene monornethanesulfonate yields. monohydrate melting at 195 to 199 ° C.

The starting material is prepared as follows:.

A mixture of 3,3-Cetram: ethylene glutaric anhydride (16.8 g), 3-aminopyridine (9.4 g) and xylene (225 ml) was refluxed under stirring for 48 hours while the resulting water was separated. The reaction mixture is cooled in a refrigerator, the precipitate obtained is filtered off and recrystallized from a mixture of 300 ml of ethanol and hexane. 8- (3-pyridyl) -8C-azaspiro [4,5] decane-7,9-one is obtained, melting at 153-154 °.

A solution of 14.7 g of the above compound in 150 ml of glacial acetic acid is hydrogenated in the presence of 11 g of 10% palladium on carbon catalyst at 50 psi at 60 DEG C. until the calculated amount of hydrogen is consumed. The mixture was cooled to 20 °, filtered and then the filtrate was evaporated. The residue is taken up in 6N aqueous sodium hydroxide solution and the mixture is extracted with methylene chloride. The extract was washed with a saturated aqueous sodium chloride solution, dried and evaporated. The oil obtained as a residue is dissolved in 50 ml of isopropanol and then. the solution is acidified with hydrogen chloride. The mixture was cooled in an ice bath, the precipitate obtained. was filtered, dried, and the hydrochloride (pulse lota point 245-248 °) was 10 působením- vodného- ^1% sodium carbonate-Sodium · převede- free base. The product was extracted with methylene chloride to give 8- (3-piperidyl) -8-a ^; zaspiro <[4,5.] decane-7,9 ^: -dione in the form of a viscous oil.

Claims (7)

SUBJECT OF THE INVENTION A process for the preparation of the novel N- (1- (4-amino-2-chlorosolinyl) -3- or -4-piperidyl) lactams of the general formula I, in which: Ph is 1,2-phenyl-optionally substituted with no more than 3 substituents selected from the group consisting of C 1 -C 4 alkoxy and C 1 -C 4 alkylenedioxy, each of m and n being an integer from 1 to 3, wherein: m + n - = '4, X is 2-hydrogen atoms or oxo-a A represents an alkylene group having at most 8 carbon atoms, a cycloalkylene group, a cycloalkylalkylene group and a spirocycloalkalkylene group, an HPh-alkylenoyl group or a Ph group, wherein the cycloalkylene, cycloalkyl and spirocycloalkane group contains 4-7 carbon atoms in the ring and "alkylene" contains up to 8 carbon atoms, and their salts with acids -adičních and further comprising, by condensing compounds of the formulas III and IV / CO _s ⁴ CX ^Z (IV) Nina converted to an acid addition salt or -adiční the acid salt is converted into the free compound or another salt, and / or the mixture of isomers or racemates obtained is optionally separated into individual isomers or racemates, and / or the racemates obtained are optionally resolved into optical antipodes. 2. The process according to claim 1, wherein the starting materials are compounds of the general formula III in which Y is chlorine or bromine and Ph is as defined in point 1. 3. The process of any one of items 1 and 2 for the preparation of compounds of formula I wherein: Ph represents a 1,2-phenyl group, a mono-, di- or -tralkoxy-1,2-phenylene group, or an alkyldioxy-1,2-phenylene group, wherein the alkoxy and alkylene moieties - contain - not more than 2 carbon atoms, each of the groups C _m H2m and C _n H2 _n represent an ethylene group, X is 2-hydrogen atoms or oxo, and A represents an alkylene group having at most 8 carbon atoms, a 1,2-cychoalkylene group having 5 or 6 ring carbon atoms, a (cycloalkyl-, -spirocycloalkane- or phenyl) alkylene group, each of said three groups comprising a total of at most 8 atoms The compounds of formulas III and IV are condensed, wherein Y is a halogen atom and the remaining symbols are as defined above. 4. A process according to one of items 1 and 2 for the preparation of compounds of the general formula II, N — C0 CXCH ^ (II) wherein each of R and R 'is a mothoxy group, or both together are methylenedioxy, X is 2 hydrogen atoms or oxo, CpH2p. _q represents an alkylene group, a phenylalkylene group or a spirocycloalkanalkylene group, wherein p is Y is halogen and Ph, m, η, X - and A are as defined above, whereupon the optionally obtained free compound 210700 is an integer of 2 to 8, q is the number · 0, 2 or 8, and 2p-q has a positive value, and their addition salts with acids, characterized in that the starting materials of the formulas IIIa and IVa are condensed; Y represents a halogen atom and the remaining symbols have the meanings given above. ' 5. A process according to any one of items 1 and 2 for the preparation of compounds of formula (II) as defined in item 4, wherein each of R and R ' is methoxy, X is oxo and C _is H2 _pq ethylene, phenylethylene or 1,3- propylene, and their acid addition salts, characterized in that the starting materials of the formulas IIIa and IVa mentioned in point 4 are condensed, wherein Y is halogen and the remaining symbols are as defined above. 6. A process according to any one of items 1 and 2 for the preparation of compounds of formula II as defined in item 4, wherein each of R and R 'is hydrogen, methoxy or together represents methylenedioxy, X is 2 hydrogen atoms or oxo, C _p H 2 ' _pq means alkylene or spirocycloalkanalkylene, wherein p is an integer from 2 to 8 and q is 0 or 2, and their acid addition salts, characterized in that the compounds of formulas IIIa and IVa, which are mentioned in 4 wherein Y is halogen and the remaining symbols are as defined above. 7. The process according to one of items 1 and 2 for producing 1- [1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4-piperidyl] pyrrolidine-2,5-dione and its addition salts with acids, characterized in that 4-amino-2-halo-6,7-dimethoxyquinazoline is reacted with 1- [4-piperidyl) pyrrolidine-2,5-dione.