DE2121031A1 - Base-substd quinazolines - thrombocyte aggregation inhibitors - Google Patents

Abstract

Cpds. of formula (I), and their acceptable acid addn. salts. where one of R1 or R2 = (thio) morpholino, thiomorpholino 1-oxide, -1, 1-dioxide, all opt. substd. by 1 or 2 lower alkyl gps; and the other gp. = dialkylanolamino (where the OH may be etherified by a 1-3C alkyl) or a 1-6C alkyl -2-6C alkanolamino, or a cyclic diamino gp. of formula where R'=H, opt. OH substd. lower alkyl, acyl, aryl, or aralkyl; R"=H, loer alkyl; n, m=1,2); R3, R4 = independently H, halo, lower alkyl, lower alkoxy, nitro, amino, acylamino or together methylene dioxy.

Description

New Basically Substituted Quinazolines and Processes for Their Production The present invention relates to new base substituted quinazolines of the general formula and their physiologically acceptable acid addition salts and processes for their preparation.

In the above general formula I one of the radicals R1 or a morpholino, thiomorpholino, thiomorpholino-1-oxide or thiomorpholino-1,1-dioxide radical, where the solid can be substituted by 1 or 2 lower alkyl radicals, and the other of the radicals R1 or R2 is a dialkanolamino radical, where the hydroxyl group of an alkanol radical can be etherified by an alkyl radical with 1-3 carbon atoms, or an alkylalkanolamino radical in which the alkano radical has 2-6 carbon atoms and the alkyl radical 1-6 carbon atoms may contain, or a cyclic diimine of the general formula in which R 'represents a hydrogen atom, a lower alkyl radical optionally substituted by a hydroxyl group, an acyl, aryl or aralkyl radical, R ″ represents a hydrogen atom or a lower alkyl radical and the symbols n and m represent the number 1 or 2, and R3 and R4> which can be identical or different, hydrogen atoms, halogen atoms, lower alkyl or alkoxy radicals, nitro, amino or acylamino groups, or R3 and R1 together represent the methylenedioxy group.

The new compounds of general formula I have valuable pharmaicological properties, they show a small effect on the circulatory system in particular a very good platelet aggregation-inhibiting effect.

The new basic substituted quinazolines of the general formula I can be prepared by the following processes: a.) Reaction of a compound of the general formula in which R3 and R4 are as defined at the outset and one of the radicals A1 or A2 is an exchangeable radical such as a halogen atom, a mercapto group or a hydroxy, mercapto, sultinyl or sulfonyl group substituted by an alkyl, benzyl or phenyl radical, and the other of the radicals A1 or A2 has the meanings mentioned for R1 or R2 at the beginning, with an amine of the general formula H - R1 or H - R2 III in which R1 and R2 are defined as initially, preferably at elevated temperatures, for example at temperatures between 30 and 250 ° C.

The reaction is expediently carried out in the presence of an acid-binding agent by means of, e.g. B. in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine in a solvent, for example in acetone, dioxane, dioxane / water, dimethylformamide or in an alcohol. However, a corresponding excess of an amine is preferably the general Formula III used simultaneously as a solvent and as an acid-binding agent. In some cases, the addition of a reaction accelerator, preferably one Copper salt or a salt of the amine used, or the work in a closed vessel

b. For the preparation of compounds of the general formula I in which one of the radicals R1 or R2 is a cyclic diamine in which R 'denotes a hydrogen atom: cleavage of a protective radical from a compound of the general formula in which R3 and R4 are as defined at the outset, one of the radicals R11 or R2 'has the meanings mentioned for R1 or R2 at the beginning and the other of the radicals R1' or R2 'is a cyclic diamine of the general formula in which nn and m are as defined at the outset and 2 R '''represents a protective radical for an amino group, for example the benzyl or any acyl radical.

If R '' 'is any acyl radical, the cleavage takes place this protective radical is preferably hydrolytically, e.g.

in the presence of an acid such as hydrochloric acid or an inorganic base like potassium hydroxide in a solvent like isopropanol and at temperatures up to the boiling point of the solvent used.

In a compound of the general formula IV, means one of the radicals R11 or R2, one optionally substituted by 1 or 2 lower alkyl radicals Morpholino radical and R '' ', for example, the benzyl radical, this can be split off Protective residue also by means of hydrogen in the presence of a catalyst such as palladium / animal charcoal in a solvent such as methanol or glacial acetic acid and preferably at slightly elevated levels Temperatures, for example at 600C, can be carried out.

c.) For the preparation of compounds of the general formula I in which one of the radicals R1 or R2 represents a thiomorpholino-1-oxide or thiomorpholino-1,1-dioxide radical optionally substituted by one or two lower alkyl radicals and the other represents the R1 or R2 radicals as defined at the outset are oxidation of a compound of the general formula in which R3 and R4 are as defined at the outset and one of the radicals R1 "or R2," has the meanings mentioned for R1 or R2 at the beginning and the other radical R1 "or R2" is optionally substituted by 1 or 2 lower alkyl radicals Represents thiomorpholino radical.

Oxidation is preferred with a common oxidizing agent in a solvent such as water, methanol, glacial acetic acid or acetic anhydride is expedient carried out at room temperature.

Hydrogen peroxide, potassium permanganate, Sodium metaperiodate or an organic peracid can be considered.

If by a process a-c a compound of the general formula I is obtained, in which R1 and R2 are as initially defined, R3 and / or R4 nitro groups represent, these can, if desired, by reduction, e.g. by means of catalytic activated hydrogen, can be converted into the corresponding amino compound.

The starting materials used in the process a-c of the general Formulas II-V are obtained by processes known from the literature. This is how you get the Implementation of a corresponding 2,4-dichloro-quinazoline with an amine of the general Formula III a corresponding 2-chloro-4-amino compound at low temperatures of the general formula II (see J. Gen. Chem. 32, 3263 (1962)).

By mild hydrolysis of an appropriately substituted 2,4-dichloro-quinazoline with 1 equivalent of alkali metal hydroxide at low temperatures one obtains a corresponding one 2-chloro-4-hydroxy compound, which is then used at higher tempatures a corresponding chimney is implemented. The obtained 2-amino-4-hydroxy compound is then converted into the corresponding 2-amino-4-halogen compound of the general Formula II transferred.

A halogen compound of the general formula II can with a corresponding Mercapto or hydroxy compound in the presence of a base into a corresponding substituted one Nercapto or hydroxy compound of the general formula II are converted to a obtained mercapto compound of the augemoinen formula II can furthermore by means of oxidation converted into a corresponding sulfinyl or sulfonyl compound.

The starting compounds of the formulas IV and V are obtained in a z-stretched manner according to method a of the present application.

The compounds of general formula I obtained can be physiologically with Compatible inorganic or organic acids are converted into their salts. Hydrochloric acid, hydrobromic acid, sulfuric acid, Phosphoric acid, lactic acid, citric acid, tartaric acid or maleic acid as suitable proven.

As already mentioned at the beginning, the new connections have the general formula I valuable pharmacological properties. In particular, own they have a very strong inhibitory effect with a small effect on the circulatory system platelet aggregation. This inhibitory effect on platelet aggregation leaves for example according to the method of Born and Cross (J. Physiol. 170, 397 (1964)) or Morris (E. Deutsch E. Gerlach and K. Moser: 1st International Symposium on Metabolism and membrane permeability of erythrocytes and thrombocytes Vienna 1969; Georg Thieme Verlag Stuttgart) or K.

Breddin (Switzerland. Med. Wschr. 95, 655-660 (1965)) on the human Examine plasma or blood. The circulatory effect was tested on dogs (Eckenhoff, Amer. J. Physiol. 148, 582 (1947)).

The following compounds show a particularly good inhibitory effect on the Platelet aggregation: 2- (N-methylpiperazino) -4-morpholino-quinazoline 2-piperazino-4- (thiomorpholino-1-oxide) -quinazoline 2- (Thiomorpholino-1-oxide) -4-piperazino-quinazoline 2-Piperazino-4-morpholino-quinazoline 2-Dipropanolamino-4-morpholino-quinazoline 2-Piperazino-4-thiomorpholino-quinazoline The following examples are intended to explain the invention in more detail: example 1 2- (N-methylpiperazino) -4-morpholino-quinazoline 10.0 g (0.04 mol) 2-chloro-4-morpholino-quinazoline (M.p. 115-117 ° C, made from 2,4-dichloro-quinazoline and morpholine in dioxane Room temperature) are refluxed for one hour with 90 ml of N-methylpiperazine heated. When the reaction mixture is taken up in about 250 ml of water, 2- (N-methylpiperazino) -4-morpholino-quinazoline falls as viscous oil au:;. After solidification, it is filtered off with suction, washed with water and dried.

Yield: 10.6 g (89% of theory). 114-1150C (from ethyl acetate) Zur The free base is converted into dns dihydrochloride in about 25-30 ml absolute Dissolve ethanol and add about 10 ml of ethanolic hydrochloric acid. It is being cooled and finally the crystalline precipitated salt with a little absolute ethanol and. Diethyl ether washed and dried. The 2- (N-methylpiperazino = -4-morpholino-quinazoline dihydrochloride) obtained in this way melts at 298 ° C with decomposition.

Example 2 2- (N-methylpiperazino) -4-morpholino-quinazoline 2.6 g (0.01 Moles) 4-chloro-2- (N-methylpiperazino) -quinazoline (m.p. 86-87 ° C, prepared from 4-hydroxy-2- (N-methylpiperazino) -quinazoline by heating with phosphorus oxychloride in the presence of N, N-dimethylanil @@@@ ter reflux) are refluxed with 5 ml of morpholine in about 50 ml of acetone for 15 hours.

The reaction mixture is largely concentrated. When recording de remaining residue in about 80 ml of water falls 2- (N-methylpiperazino) -4-morpholino-quinazoline initially smeary. After standing in a hurry, it is filtered off with suction and washed with water and dried.

Yield: 2.6 g (83% of theory), mp 114-115 ° C. (from ethyl acetate).

The same compound is produced analogously by reacting 4-ethylthio-2- (N-methylpiperazino) quinazoline obtained by heating with morpholine at about 2000C for several hours under pressure.

Example 3 2- (N-Methylpiperazino) -4-morpholino-quinazoline 2.0 g (0.005 Mol) 4-Benzyloxy-2- (N-methylpiperazino) quinazoline dihydrochloride (no melting point up to 300 ° C, made from 4-chloro-2- (N-methylpiperazino) quinazoline and sodium benzylate in benzyl alcohol at 100 ° C) with 20 ml of morpholine for 5 hours in a pressure tube heated to about 200 ° C. The reaction mixture is taken up in methanol and then largely concentrated in vacuo. The remaining residue is mixed with gasser, the reaction product is filtered off with suction after standing for a while, washed with water and dried.

Yield: 1.3 g (83% of theory). After cleaning a silica gel column (Mobile solvent: ethyl acetate / methanol = 3/1) and recrystallization from ethyl acetate melts 2- (N-methylpiperazino) -4-morpholino-quinazoline at 113-115 ° C.

The same substance is produced in an analogous manner by reacting vr'.n 4-ethoxy-2- (N-methylpiperazino ) -quinazoline obtained with morpholine in the presence of copper sulfate.

Example 4 4-Morpholino-2-piperazino-quinazoline 2.5 g (0.01 mol) of 2-chloro-4-morpholino-quinazoline or 3.1 g (0.01 mol) of 2-ethylsulfonyl-4-morpholino-quinazoline (m.p. 175-177 ° C) from 2-thylthio-4-morpholino-quinazoline in 0, n-hydrochloric acid by passing in chlorine at about 5 ° C) with 10 g of piperazine hexahydrate in 50 ml of dioxane for one hour heated under reflux for a long time. The solvent and excess amine will be largely distilled off in vacuo. After taking up the remaining residue 4-Morpholino-2-piperazino-quinazoline separates out as colorless in about 50 ml of water Precipitation from. Do vacuuming, washing and drying, the yield is 2.7-2.9 g (90-97% of theory). For cleaning, the substance is dissolved in 0.5 N hydrochloric acid, the solution adjusted to pH 6 with 2N ammonia, a small amount of precipitate separated and finally by adding 8N sodium hydroxide solution to pH 14 4-morpholino-2-piperazino-quinazoline precipitated from F. 146-1490C.

Example 5 4-Morpholino-2-piperazino-quinazoline 2.8 g (0.01 mol) of 2-ethylthio-4-morpholino-quinazoline (F. 113 -1150C; made from 2-chloro-4-morphol ino-quinazoline and sodium mercaptide in dioxane under reflux) with 20 g of piperazine in the presence of piperazine hydrochloride heated in a closed vessel to about 2000C for 4 hours. The reaction mixture is taken up in acetone and largely concentrated in vacuo.

The remaining residue is taken up in about 60 ml of water and the reaction product is filtered off with suction after standing for a short time, washed with water and dried.

Yield: 2.2 g (73% of theory). After cleaning on a silica gel column (Mobile solvent: methanol / conc. Ammonia = 9/1) and recrystallization from benzene / petroleum ether 4-Morpholino-2-piperazino-quinazoline melts at 146-149 ° C.

Example 6 2- (N-Methylpiperazino) -4-thiomorpholino-quinazoline 2.6 g (0.01 mol) of 4-mercapto-2- (N-methylpiperazino) quinazoline (m.p. 172-174 ° C.) from 4-chloro-2- (N-methylpiperazino) quinazoline and sodium hydrogen sulfide in acetone / water = 9/1 by heating to 100 ° C. under pressure) with 25 ml of thiomorpholine for 5 hours heated to about 1300 C for a long time. The excess thiomorpholine is distilled off in vacuo. When the remaining residue is taken up in about 50 ml of water, it separates 2- (N-Methylpiperazino) -4-thiomorpholino-quinazoline initially as a greasy precipitate away. It is immediately recrystallized once from methanol / water 1/3, mp 123-125 ° C.

Yield: 2.2 g (67% of theory).

The same compound is produced analogously by reacting 4-benzylthio-2- (N-methylpiperazino) quinazoline or from 2- (N-methylpiperazino) -4-phenylthio-quinazoline with thiomorpholine at about 200 ° C under pressure or 2-chloro-4-thiomorpholino-quinazoline by heating with N-methylpiperazine obtained under reflux.

Example 7 2-Piperazino-4-thiomorpholino-quinazoline 7.8 g (0.03 mol) 2-chloro-4-thiomorpholino-quinazoline (m.p. 145-147 ° C, made from 2,4-dichloro-quinazoline and thiomorpholine in dioxane in the presence of an aqueous sodium bicarbonate solution at room temperature) with 13 g (0.15 mol) of piperazine in 180 ml of dioxane for one hour heated under reflux for a long time. Most of the solvent is distilled off in vacuo. After the remaining residue has been taken up in about 150 ml of water, it separates the reaction product as a colorless, finely crystalline precipitate. It is sucked off, washed with water and dried.

Yield: 7.7 g (81% of theory).

After a single reprecipitation from 0.5 N hydrochloric acid by means of conc.

Ammonia melts 2-piperazine-4-thiomorpholino-quinazoline at 153-155 ° C.

Example 8 2-piperazino-4-thiomorpholino-quinazoline 1.5 g (0.005 Mol) 2-Ethylthio-4-thiomorpholino-quinazoline (mp 118-119 ° C, prepared from 2-chloro-4-thiomorpholino-quinazoline and sodium ethyl mercaptide in dioxane under reflux) with 10 g of piperazine in Presence of piperazine hydrochloride in the pressure pipe for about 5 hours at 210 ° C heated. After the reaction mixture has been taken up in about 50 ml of water, the procedure is analogous Example 7 worked up.

Yield: 0.9 g (57% of theory), mp 153-155 ° C.

Example 9 2- (N-methylpiperazino) -4- (thiomorpholino-1-oxide) quinazoline 3.1 g (0.01 mol) of 4-bromo-2- (N-methylpiperazino) quinazoline (m.p. 92-93 ° C) from 4-hydroxy-2- (N-methylpiperazino) quinazoline by heating with phosphorus oxybromide) are refluxed with 5 g of Thiomprpholino-1-oxide in 50 ml of dioxane for about 5 hours heated. The solvent is distilled off in vacuo.

When taking up the remaining residue in about 50 ml of water 2- (N-methylpiperazino) -4- (thiomorpholino-1-oxide) -quinazoline initially falls in a greasy manner the end. It is immediately once from 0.2 N hydrochloric acid using conc. Ammonia reprecipitated.

Yield: 2.3 g (67% of theory), mp 133-136 ° C.

The same substance is produced analogously by reacting 4-chloro-2- (N-methylpiperazino) -quinazoline with thiomorpholine-1-oxide that of 2-chloro-4- (thiomorpholino-1-oxide) -quinazoline with N-methylpiperazine obtained.

Example 10 2- (N-methylpiperazino) -4- (thiomorpholino-1-oxide) quinazoline 3.2 g (0.01 mol) of 2- (N-methypiperazino) -4-phenoxy-quinazoline (m.p. 93-96 ° C) from 4-chloro-2- (N-methylpiperazino) quinazoline and sodium phenolate in phenol 100 ° C) are heated to 130 ° C for about 4 hours with 20 g of thiomorpholine-1-oxide.

After taking up in about 150 ml of water, work-up is carried out analogously to Example 9.

The same compound is produced analogously by reacting 4-ethylsulfonyl-2- (N-methylpiperazino) quinazoline obtained with thiomorpholine oxide.

Example 11 2- (N-methylpiperazino) -4- (thiomorpholino-1-oxide) quinazoline 3.0 g (0.01 mol) of 4-ethylsulfinyl-2- (N-methylpiperazino) quinazoline (mp 214-216 ° C) or 3.7 g (0.01 mol) of 4-benzylsulfinyl-2- (N-methylpiperazino) quinazoline (m.p. 204 -206 ° C) or 3.5 g (0.01 mol) 2- (N-methylpiperzino) -4-phenylsulfinylquinazoline (F. 169-172 ° C) are implemented analogously to Example 10.

Yield: 60-70% of theory, mp 133-136 ° C. The starting substances used are oxidized to the corresponding 2- (N-methylpiperazino) -4-mercapto-quinazoline using sodium metaperiodate in methanol / water at room temperature or slightly increased Maintain temperatures.

Example 12 2-Piperazino-4- (thiomorpholino-1-oxide) -quinazoline 14.1 g (0.05 mol) 2-chloro-1 + - (thiomorpholino -? - oxide) -quinazoline (mp 190-192 ° C, prepared from 2,4-dichloro-quinazoline and thiomorpholine-1-oxide in acetone in the presence of a aqueous sodium bicarbonate solution) are in a slightly warmed solution of 48.5 g (0.25 mol) of piperazine hexallydrate slowly introduced into 250 ml of dioxane and then Reflux for 1 hour. The solvent is largely in vacuo distilled off and the remaining residue taken up in 150-200 ml of water.

The 2-piperazino-4- (thiomorpholino- 1 -oxide) -quinazoline is suctioned off, washed with water and dried.

Yield: 16.1 g (97% of theory), mp 223-2250C To the Purification, the substance is dissolved in about 180 ml of 0.5N hydrochloric acid, the solution in the middle] 2 N ammonia adjusted to pH 7-8 and after some standing a less precipitated one Separated precipitate. Finally, sodium hydroxide is added to the filtrate by adding 8N up to pH 14 2-piperazino-4- (thiomorpholino-1-oxide) quinazoline as colorless crystalline Get precipitation.

Yield: 14.3 g (86% of theory), mp 225-227 ° C. For conversion the base iii about 1N hydrochloric acid is dissolved in the hydrochloride. After adding conc. Ammonia up to about pH 10 separates the 2-piperazino-4- (thiomorpholino-1-quinazoline hydrochloride as a crystalline precipitate with a temperature of 192-197 ° C.

2-piperazino-4- (thiomorpholino-1-oxide) -quinazoline-maleinate vom F. 181-185 ° C. falls from a warm solution of the base in dioxane after the addition of nalein acid (dissolved in dioxane) as a colorless precipitate.

Example 13 2-piperazino-4- (thiomorpholino-1-oxide) quinazoline 3,4 g (0.01 mol) of 2-phenoxy-4- (thiomorpholino-1-oxide) quinazoline (m.p. 236-2380C) from 2-chloro-4- (thiomorpholino-1-oxide) quinazoline by heating with sodium phenolate in phenol to about 120 ° C.) are heated to 130 ° C. for 2 hours with 20 g of piperazine. Working up takes place analogously to Example 12.

Yield: 2.2 g (66% of theory), melting point 224-2260C the The glcicho compound is produced analogously by heating 4-ethylsulfinyl-2-piperazino-quinazoline obtained with thiomorpholino-1-oxide.

Bfistil. 14 2-piperazino-4- (thiomorpholino-1-oxide) quinazoline 3.1 g (0.01 mol) of 2-ethylthio-4- (thiomorpholino-1-oxide) quinazoline (m.p. 64-66 ° C, prepared from 2-chloro-4- (thiomorpholino-1-oxide) quinazoline and sodium mercaptide in dioxane under reflux) are full of piperazine hydrochloride with 20 g of piperazine in the presence of heated in the pressure tube to about 2000C for 5 hours. The reaction mixture is in Dioyan added and then the solvent and excess piperazine largely removed in vacuo. After taking up the remaining residue approximately 50 ml of water becomes 2-piperazino-4- (thiomorpholino-1-oxide) quinazoline after some Standing vacuumed, washed with water and dried.

Yield: 1.9 g (58% of theory), mp 224-226 ° C. (purification on a silica gel column, Mobile phase: methanol / ammonia = 9/1).

The same substance is produced analogously by reacting 2-phenylthio-4- (thiomorpholino-1-oxide) quinazoline or obtained from 2-benzylthio-4- (thiomorpholino-1-oxide) quinazoline with piperazine.

Example 12 2-piperazino-4- (thiomorpholino-1-oxide) quinazoline 3.2 g (0.01 mol) 2-ethylsulfinyl-4- (thiomorpholino-1-oxide) quinazoline (m.p. 1600C under Decomposition, produced from 2-ethyl thio-4- (thiomorpholino-1-oxide) -quinazoline by Oxidation by means of sodium metaperiodate in methanol-water under reflux) heated with 10 g of piperazine hexahydrate in 50 ml of dioxane for 8 hours at about 600C. Isolation and purification are carried out analogously to Example 12.

Yield: 2.6 g (79% of theory), mp 225-227 ° C.

The same substance is produced analogously from 2-Bei.'zylsulfinyl-4- (thiomorpholino-1-oxide) -quinazoline or 2-phenylsulfinyl-4- (thiomorpholino-1-oxide) -quinazoline by heating with Piperazine obtained under reflux in dioxane.

Example 16 2- (N-methylpiperazino-4- (thiomorpholino-1,1-dioxide) quinazoline 3.2 g (0.01 mol) 2-ethylthio-4- (thiomorpholino-1,1-dioxide) quinazoline (mp 144-146 ° C, made from 2-chloro-4- (thiomorpholino-1,1-dioxide) quinazoline and sodium ethyl mercaptide in dioxane under reflux) with 20 ml of N-methylpiperazine in the presence of N-methylpiperazine hydrochloride Heated for 4 hours in a pressure tube to about 200 ° C. When taking up the reaction mixture 2- (N-methylpiperazino) -4- (thiomorpholino-1,1-dioxide) -quinazoline separates in about 120 ml of water as a colorless precipitate.

It is once from 0.5 N hydrochloric acid by means of conc. Ammonia reprecipitated and recrystallized once from methanol-water (1: 3).

Yield 2.2 g (6'1% of theory), m.p. 165-1670C.

The same substance is produced analogously also by heating 4-bromine or 4-chloro-2- (N-methylpiperazino) -quinazoline with thiomorpholine-1,1-dioxide to about 120 ° received.

Example 17 2-Piperazino-4- (thiomorpholino-1,1-dioxide) quinazoline 3.0 g (0.01 mol) 2-chloro-4- (thiomorpholino-1,1-dioxide) -quinazoline (mp 227-230 ° C, made from 2,4-dichloro-quinazoline and thiomorpholine-1,1-dioxide in dioxane under Warming) are in a heated to about 1000C solution of 4 g of piperazine in 50 ml of dioxane entered and then heated under reflux for one hour. The resulting reaction solution is poured into about 100 ml of water, whereupon the reaction product separates out as a colorless crystalline precipitate. After several hours Standing is suctioned off, washed with water and dried.

Yield: 3.0 g (86% of theory). After a single reprecipitation at 0.1 n-hydrochloric acid using conc. Ammonia melts 2-piperazino-4- (thiomorpholino-1; 1-dioxide) quinazoline at 213-215 ° C.

Example 18 2-Piperazino-4-thiomor (holino-11-dioxide) quinazoline 3.4 g (0.01 mol) 2-ethylsulfinyl-4- (thiomorpholino-1,1-dioxide) quinazoline (m.p. 167-170 ° C) or 3.6 g (0.01 mol), 2-ethylsulfonyl-4- (thiomorpholino-1,1-dioxide) quinazoline (F. 213-215 ° C, obtained from 2-ethylthio-4-thiomorpholino-quinazoline by oxidation with potassium permanganate in 0.2 N hydrochloric acid at 0-50C) with 5 g of piperazine in Heated 50 ml of dioxane under reflux for 2 hours.

After working up as in Example 17, 2.5-2.7 g (72-78 % of theory) 2-piperazino-4- (thiomorpholino-1,1-dioxide) with a mp of 213-215 ° C The same substance is produced in an analogous manner by reacting 2-benzylsulfonyl-4- (thiomorpholino-1,1-dioxide) quinazoline or of 2-phenylsulf6nyl-4- (thiomorpholino-1,1-dioxide) quinazoline with piperazine obtain.

Example 19 4- (2-Methylmorpholino) -2- (N-methylpiperazino) -quinazoline 5.2 g (0.02 mol) of 2-chloro-4- (2-methylmorpholino) quinazoline (m.p. 65-67 ° C.) from 2,4-dichloro-quinazoline and 2-methylmorpholine in acetone at Raumtempetaur) with 5 g (0.05 mol) of N-methylpiperazine in 50 ml of dioxane for one hour under reflux heated. Most of the solvent is distilled off in vacuo, the remaining one Residue taken up in water. After standing for several hours, the meanwhile froze Sucked off precipitate, washed with water and dried.

Yield: 6.1 g (93% of theory), melting point 112-114 ° C.

After recrystallization from petroleum ether, the substance melts at 114-1160C.

Example 20 4- (2,6-Dimethylmorpholino) -2- (N-methylpiperazino) -quinoline Made from 2-chloro-4- (2,6-dimethylmorpholino) -quinazoline (F. 142-1440C) and N-methylpiperazine analogous to Example 19.

Yield: 77% of theory, mp 125-126 ° C. (from ethyl acetate).

Example 21 4- (2-Methylmorpholino) -2-piperazino-quinazoline Prepared from 2-chloro-4- (2-methylmorpholino) quinazoline and piperazine analogously to Example 12.

Yield: 82% of theory, temperature: 138-141 ° C.

Example 22 4- (2,6-Dimethylmorpholino) -2-piperazino-quinazoline Prepared from 2-chloro-4- (2,6-dimethylmorpholino) quinazoline and piperazine analogously to the example 12th

Yield: 73% of theory; Resin, Rf value; 0.6-0.7 (TLC prefabricated plate Kieselgel F, Merck, mobile phase: methanol / conc. Ammonia = 9/1).

Example 23 2- (N-methylpiperazino) -4- (2-methylthiomorpholino-1-oxide) quinazoline Made from 2-chloro-4- (2-methylthiomorpholino-1-oxide) -quinazoline (F. 138-1410C) and N-methylpiperazine analogous to Example 7.

The purification is carried out on a silica gel column (mobile phase: methanol / conc. lernmoniac = 9/1).

Yield: 71 Vo of theory; Resin, Rf value: about 0.7 (DC-Fe: rtigplatte Kieselgel F, Merck, mobile phase: methanol / conc. unioniak = 9/1).

Example 24 4- (2-methylthiomorpholino-1-oxide) -2-piperazino-quinazoline Made from 2-chloro-4- (2-methylthiomorpholino-1-oxide) quinazoline and piperazine analogous to example 23.

Yield: 68 V of theory; Resin, Rf value: 0.6 (TLC prefabricated silica gel plate F, Merck, mobile phase: methanol / conc. Ammonia = 9/1) Example 25 2- [2 (3) -Methylpiperazino] -4- (thiomorpholino-1-oxide) -quinazoline Made from 2-chloro-4- (thiomorpholino-1-oxide) -quinazoline and. 2-methylpiperazine analogous to example 12.

Yield: 93% of theory; M.p. 163-165 ° C (from ethyl acetate) Example 26 2- (2,5-Dimethylpiperazino) -4- (thiomorpholino-1-oxide) -quinazoline Manufactured from 2-chloro-4- (thiomorpholino-1-oxide) quinazoline and 2,5-dimethylpiperazine analogous to the example 12th

Yield: 53% of theory, m.p. 95-980C.

Example 27 2-Homop ip eraz ino-4-morpholino-chinaz olin Prepared from 2-chloro-4-morpholino-quinazoline and homopiperazine analogously to Example 4.

Yield: 83% of theory, m.p. 64-660C.

J3eirpiel 28 2-homopiperazino-4- (thiomorpholino-1-oxide) quinazoline Made from 2-chloro-4- (thiomorpholino-1-oxide) quinazoline and homopiperazine analogously Example 12.

Yield: 81% of theory, mp 119-121 ° C.

Example 29 7-Chloro-2-homopiperazino-4-morpholino-quinazoline Manufactured: ellt from 2,7-dichloro-4-morpholino-quinazoline (mp 167-169 ° C.) and homopiperazine analogously Example 4.

Yield: 78.4 theory, m.p. 43-480C.

Example 30 4-Piperazino-2-thiomorpholino-quinazoline 2.7 g (0.01 mol) 4-chloro-2-thiomorpholino-quinazoline (F. 85-880C, made from 4-hydroxy-2-thiomorpholino-quinazoline by heating with phosphorus oxychloride in the presence of dimethylaniline under reflux) are refluxed for 1 hour with 4.3 g of piperazine in 100 ml of dioxane. The solvent is distilled off in vacuo and the residue that remains in absorbed about 50 ml of water. The reaction product falls as slightly greasy Precipitate from, which sucked off after solidification, washed with water and is dried.

Yield: 2.7 g (86% of theory). After reprecipitation from 0.2N hydrochloric acid means of can. Ammonia melts 4-piperazino-2-thiomorpholino-quinazoline at 124-1260C.

Example 31 2-Morpholino-4-piperazino-quinazoline Prepared from 4-chloro-2-morpholino-quinazoline (F. 117-1190C) and piperazine analogous to example 30.

Yield: 88% of theory, mp 140-1430C.

Example 32 4- (N-Methylpiperazino) -2-thiomorpholino-quinazoline 5.3 g (0.2 mol) of 2-chloro-4- (N-methylpiperazino) -quinazoline (mp 85-87 ° C, prepared from 2,4-dichloro-quinazoline and N-methylpiperazine in dioxane at room temperature) are heated to about 1200C for one hour with 10 g of thiomorpholine. When recording of the reaction mixture in about 100 ml of water separates 4- (N-methylpiperazino) -2-thiomorpholino-quinazoline as a somewhat greasy precipitate. After it has solidified, it is suctioned off with water washed and recrystallized once from methanol / water (1/3).

Yield: 5.6 g (85% of theory), mp 112-1140C.

Example 33 4- (N-Methylpiperazino) -2-morpholino-quinazoline Prepared from 2-chloro-4- (N-methylpiperazino) quinazoline and morpholine analogously to Example 32.

Yield: 82% of theory, m.p. 88-900C.

Example 34 2- (2-Methylmorpholino) -4- (N-methylpiperazino) -quinazoline Made from 2-chloro-4- (N-methylpiperazino) -quinazoline and 2-methylmorpholine analogous to Example 32, yield: 69% of theory; Resin, Rf value: 0.7-0.8 (TLC prefabricated plate Kieselgel F, Merck, mobile phase: methanol / conc. Ammonia = 9/1).

Example 2- (2,6-Dimethylmorpholino) -4- (N-methylpiperazino) -quinazoline Made from 2-chloro-4- (N-methylpiperazino) -quinazoline and 2,6-dimethylmorpholine analogous to example 32.

Yield: 78% of theory, m.p. 122-1250C.

Example 36 4- (N methylpiperazino) -2- (thiomorpholino-1-oxide) quinazoline Made from 2-chloro-4- (N-methylpiperazino) -quinazoline and thiomorpholine-1-oxide analogous to example 32.

Yield: 67% of theory, mp 165-167 ° C.

Example 37 6-Chloro-4- (N-methylpinerazino) -2-morpholino-china inches Made from 2,6-dichloro-4- (N-methylpiperazino) -quinazoline (F. 130-1310C) and Morpholine analogous to Example 32.

Yield: 66% of theory; 124-126 ° C.

Example 38 7-Chloro-4- (N-methylpiperazino) -2-morpholino-quinazoline Made from 2,7-dichloro-4- (N-methylpiperazino) -quinazoline (m.p. 162-163 ° C) and Morpholine analogous to Example 32.

Yield: 75 94 of theory, m.p. 131v1330C.

Example 39 4-Piperazino-2- (thiomorpholino-1-oxide) quinazoline In a Solution of 3.2 g (0.01 mol) of 4-piperazino-2-thiomorpholino-quinazoline in 150 ml of methanol a solution of 2.2 g (0.01 mol) of sodium metaperiodate is poured into about 15 ml of water, a colorless crystalline precipitate quickly separates out. He will after about 6 hours of standing vacuumed. The filtrate is concentrated in vacuo, the 4-piperazino-2- (thiomorpholino-1-oxide) quinazoline remains as a slightly greasy precipitate. He freezes with the digestion Ethyl acetate, is filtered off, washed and dried.

Yield: 2.4 g (72% of theory).

After recrystallization from ethyl acetate / nethanol = 4/1, the melts Substance at 158 - 1600C.

The same compound is also made from 4-chloro-2- <thiomorpholino-1-oxide) quinazoline and piperazine obtained analogously to Example 30.

Example 40 2-Piperazino-4- (thiomorpholino-1-oxide) -quinazoline Manufactured from 2-piperazino-4-thiomorpholino-quinazoline by oxidation with sodium tetaperiodate analogous to Example 39. After reprecipitation once from OJ5 N hydrochloric acid using 8 N sodium hydroxide solution the yield is 69 O / u of theory, mp 225-2270C.

Example 41.

2- (N-Methylpiperazino) -4- (thiomorpholino-1-oxide) -quinazoline In a Solution of 1.7 g (0.005 mol) of 2- (N-methylpiperazino) -4-thiomorpholino-quinazoline in 50 ml. 0.5 N hydrochloric acid are stirred at room temperature 6 ml of a 3% aqueous hydrogen peroxide solution was slowly added dropwise. After a total of 4 hours Stirring, the reaction solution is largely concentrated in vacuo and the remaining solution Residue from 0.2 N hydrochloric acid using conc. Ammonia reprecipitated.

Yield: 0.9 g (52% of theory), melting point 132-1350C.

Example 42 4- (N-methylpiperazino) -2- (thiomorpholino-1,1-dioxide) - quinazoline In a solution of 3.3 g (0.01 mol) 4- (N-methylpiperazino) -2-thiomorpholino-quinazoline in 100 ml of 0.5N hydrochloric acid, a solution of 1.6 g is obtained while cooling with ice and stirring (0.01 mol) of potassium permanganate in 50 ml of water added dropwise so that the temperature of the reaction mixture does not exceed 50C. Then another 30 minutes touched. The brown reaction solution is made using saturated sodium bisulfite solution discolored and after filtering the 4- (N-methylpiperazino) -2- (thimorpholino-1,1-dioxide ) -quinazoline by adding conc. Ammonia precipitated as a colorless precipitate. After a one-off Reprecipitation from 0.5 N hydrochloric acid using conc. Ammonia and one-time recrystallization from ethyl acetate the substance melts at 227-229 ° C.

Yield: 1.9 g (53% of theory.

Example 43 4-Piperazino-2- (thiomorpholino-1,1-dioxide) quinazoline Made from 4-piperazino-2-thimorpholino-quinazoline by means of oxidation Potassium permanganate analogous to Example 42. After reprecipitation from 0.2 N hydrochloric acid means conc. Ammonia, the yield is 55% of theory, mp 202-204 ° C.

Example 44 4-Morpholino-2- (N-propylpiperazino) quinazoline Prepared from 2-chloro-4-morpholino-quinazoline and N-propylpiperazine analogously to Example 7.

Yield: 85 according to theory, mp 121-122 ° C.

Example 45 2- (N-Benzylpiperazino) -4-morpholino-quinazoline Prepared from 2-chloro-4-morpholino-quinazoline and N-benzylpiperazine analogously to Example 7.

Yield: 82% of theory, mp 107-1090C example 46 2- (N-Benzylpiperazino) -4- (thiomorpholino-1-oxide) -quinazoline Prepared from 2-chloro-4- (thiomorpholino-1-oxide) -quinazoline and N-benzylpiperazine analogous to Example 7.

Yield: 76% of theory, mp 167-168 ° C. Example 47 4-Morpholino-2- (N-phenylpiperazino) quinazoline Manufactured from 2-chloro-4-morpholino-quinazoline and N-phenylpiperazine analogous to the example 7th

Yield: 69% of theory, F. 128-1300C0 Bs game 48 2- (N-Hydroxyäthylpiperazino) -4-morpholino-quinazoline Manufactured from 2-chloro-4-morpholino-quinazoline and N-hydroxyethylpiperazine analogously Example 7.

Yield: 82% of theory, mp 275-2770C 1 Example 49 2- (N-HydroxyäthylPi-perazino) -4-thiomorpholino-quinazoline Made from 2-chloro-4-thiomorpholino-quinazoline and N-hydroxyethylpiperazine analogous to Example 7e yield: 78% of theory, mp 107-1090C example 50 2- (N-Hydroxyäthylpiperazino) -4- (thiomorpholino-1-oxide) -quinazoline Manufactured from 2-chloro-4- (thiomorpholino-1-oxide) quinazoline and N-hydroxyethylpiperazine analogously Example 7.

Yield: 67% of theory, m.p. 134-1360C.

Example 51 2- (N-Hydroxyethylpiperazino) -4- (thiomorpholino-1,1-dioxide) quinazoline Made from 2-chloro-4- (thiomorpholino-1, 1-dioxide) quinazoline and N-hydroxyethylpiperazine analogous to example 7.

Yield: 77% of theory, mp 115-118 ° C.

Example 52 2- [N- (2-Hydroxypropyl) piperazino] -4-morpholino-quinazoline Manufactured from 2-chloro-4-morpholino-quinazoline and N- (2-hydroxypropyl) piperazine analogously to the example 7th

Yield: 92% of theory, mp 130-132 ° C.

Example 53 2- [N- (2-Hydroxypropyl) piperazino] -4- (thiomorpholino-1-oxide) quinazoline Made from 2-chloro-4- (thiomorpholino-1-oxide) -quinazoline and N- (2-hydroxypropyl) -piperazine analogous to example 7.

Yield: 72% of theory; 153-155 ° C.

Example 54 2- (N-Carbethoxypiperazino) -4- (thiomorpholino-1-oxide) quinazoline Made from 2-chloro-4- (thiomorpholino-1-oxide) -quinazoline and 1-carbäthoypiperazine analogous to example 7.

Yield: 83% of theory, m.p. 185-1860C.

Example 55 2- (N-Formylpiperazino) -4- (thiomorpholino-1-oxide) quinazoline Prepared from 2-chloro-4- (thiomorpholino-1-oxide) quinazoline and 1-formylpiperazine analogous to example 7.

Yield: 77% of theory, m.p. 291-2930C (decomp.) Example 56 2- (N-Acetylpiperazino) -4- (thiomorpholino-1-oxide) -quinazoline Made from 2-chloro-4- (thiomorpholino-1-oxide) -quinazoline and 1-acetylpiperazine analogous to example 7.

Yield: 74% of theory, mp 192-1930C.

Example 57 2- (N-Benzoylpierazino) -4- (thiomorpholino-1-oxide) quinazoline Made from 2-chloro-4- (thiomorpholino-1-oxide) -quinazoline and 1-benzoylpiperazine analogous to example 7.

Yield: 73% of theory, mp 93-97 ° C.

Example 58 2- (N-Carbethoxypiperazino) -4-morpholino-quinazoline Prepared from 2-chloro-4-morpholino-quinazoline and 1-carbethoxypiperazine analogously to Example 7.

Yield: 92% of theory, mp 147-1490C.

Example 59 2-piperazino-4- (thiomorpholino-1-oxide) quinazoline 4 g (0.01 mol) 2- (N-carbethoxypiperazino) -4- (thiomorpholino-1-oxide) quinazoline (. 185-1860C) are mixed with 3.5 g of finely ground potassium hydroxide in about 200 ml of isopropanol for 15 hours lallg heated under reflux. The solvent is largely distilled off in vacuo and the residue taken up in about 80 ml of water. After some standing the 2-piperazino-4- (thiomorpholino-1-oxide) quinazoline is suctioned off with water washed and dried.

Yield: 2.1 g (63% of theory).

After a single reprecipitation from 0.5 N hydrochloric acid using 4 N sodium hydroxide solution the substance melts at 225-227 ° C.

Analogously, from 2- (N-formylpiperazino) -4- (thiomorpholino-1-oxide) quinazoline, 2- (N-acetylpiperazino) -4- (thiomorpholino-1-oxide) quinazoline or 2- (N-benzoylpiperazino ) -4- (thiomorpholino-1-oxide) quinazoline by refluxing for 4-10 hours 2-piperazino-4- (thiomorpholino-1-oxide) quinazoline of m.p. 225-2270C.

Example 60 2-Piperazino-4- (thiomorpholino-1-oxide) quinazoline 2 g (0.005 moles) 2- (N-carbethoxypiperazino) -4- (thiomorpholino-1-oxide) quinazoline with 100 ml of 20% hydrochloric acid for 2-3 hours under reflux - heated. The solution is concentrated to dryness in vacuo and the residue is taken up in 30 ml of water.

After filtering, the 2-piperazino-4- (thiomorpholino-1-oxide) quinazoline becomes precipitated by means of 4N sodium hydroxide solution.

Yield: 0.3 g (18 o ', o of theory). M.p. 224-226 ° C Example 61 4-Morpholino-2-piperazino-quinazoline 3.9 (0.01 mol) 2- (N-Benzylpiperazino) -4-morpholino-quinazoline (m.p. 107-1090C) from 2-chloro-4-morpholino-quinazoline and N-benzylpiperazine at 1200C) are in 20 ml of glacial acetic acid and 200 ml of methanol in the presence of palladium / carbon (10, 4) with hydrogen Shaken for about 4 hours at 600 C and 50 atm. The catalyst is filtered off and the solvent is then distilled off in vacuo. The remaining residue is taken up in about 80 ml of water and the solution obtained using 8N sodium hydroxide solution adjusted to about pH 7. After standing for a while, the 4-morpholino-2-piperazino-quinazoline separates as an almost colorless precipitate. It is filtered off with suction and washed with a little water and dried.

Yield: 1.3 g (43% of theory), mp 148-150 ° C. (from benzene / petroleum ether).

Example 62 4-Morpholino-2-piperazino-quinazoline Prepared from 2- (N-carbethoxypiperazino) -4-morpholino-quinazoline (F. 147-1490C) by heating with potassium hydroxide in isopropanol as in the example 59.

Yield: 67% of theory, mp 146-1490C.

Example 63 2-Dipropanolamino-4-morpholino-quinazoline 5.0 g (0.02 Mol) 2-chloro-4-morpholino-quinazoline are mixed with 20 ml of dipropanolamine for 1 hour heated to 120 0C. The still warm reaction mixture is standardized in about 150 ml of water, where the 2-Dipropanolamino-4-morpholino-quinazoline as a greasy precipitate separates. After solidification, it is filtered off with suction, washed with water and dried.

Yield: 5.4 g (78 Vo of theory) Hydrochloric acid melts by means of ammonia and one recrystallization from benzene the substance at 93-950C.

The same compound is made analogously by reacting 2-ethylsulfinyl-4-morpholino-quinazoline or 2-EthylsulSonyl-4-morpholino-quinazoline obtained with dipropanolamine.

Example 64 4-Dipropanolamino-2-morpholino-quinazoline 3.0 g (0.01 Mol) 2-chloro-4-dipropanolamino-quinazoline (m.p. 96-970C, made from 2,4-dichloro-quinazoline and dipropanolamine in dioxane at about 400C) are mixed with 15 ml of morpholine for 30 minutes heated to 1000C for a long time. The excess morpholine is distilled off in vacuo. When the residue obtained is taken up in about 50 ml of water, 4-dipropanolamino-2-morpholino-quinazoline falls as a greasy precipitate. It is made once from 0.5N hydrochloric acid using 2N ammonia fell over. The still greasy precipitate is digested with acetone fixed. After vacuuming, washing and drying, the substance melts at 99-101 C.

Yield: 2.4 g (69% of theory) Example 65 2- (2-Hydroxyethyl-3-methoxypropylamino) -4-morpholino-quinazoline Made from 2-chloro-4-morpholino-quinazoline and 2-hydroxyethyl-3-methoxypropylamine analogous to example 63.

Yield: 75% of theory; Resin, Rf value: 0.6-0.7 (TLC ready-made plate Kieselgel F, Merck; Mobile phase: acetone / benzene = 1/1).

Example 66 2-Dipropanolamino-4-thiomorpholino-quinazoline Prepared from 2-chloro-4-thiomorpholino-quinazoline and dipropanolamine analogously to Example 63.

Yield: 83% of theory, mp 122-124 ° C.

Manufactured at s67 2-Dipropanolamino-4- (thiomorpholino-1-oxide) -quinazoline from 2-chloro-4- (thiomorpholino-1-oxide) quinazoline and dipropanolamine analogous to the example 63.

Yield: 57% of theory; F. 130-1320C.

Example 68 2-Dipropanolamino-4- (thiomorpholino-1,1-dioxide) quinazoline Made from 2-chloro-4- (thiomorpholino-1,1-dioxide) -quinazoline and dipropanolamine analogous to example 63.

Yield: 66 o / o of theory, m.p. 116-118oC.

Example 69 2-Methylethanolamino-4-morpholino-quinazoline Prepared from 2-chloro-4-morpholino-quinazoline and methylethanolamine analogously to Example 63.

Yield: 87% of theory, m.p. 60-630C.

Example 70 2-Diethanolamino-4-morpholino-quinazoline Prepared from 2-chloro-4-morpholino-quinazoline and diethanolamine analogous to Example 63.

Yield: 82% of theory, m.p. 95-980C.

Example 71 2-Methylpentanolamino-4-morpholino-quinazoline Prepared from 2-chloro-4-morpholino-quinazoline and methylpentanolamine analogously to Example 63.

Yield: 79% of theory, m.p. 64-660c.

Example 72 2-Ethylbutanolamino-4-morpholino-quinazoline Prepared from 2-chloro-4-morpholino-quinazoline and ethylbutanolamine analogously to Example 63.

Yield: 67,96 of theory; Resin, Rf value: about 0.8 (TLC prefabricated plate Silica gel F, Merck, mobile phase: ethyl acetate / methanol = 3: 1).

Example 73 Prepared 2-ethanolpropanolamino-4-morpholino-quinazoline from 2-chloro-4-morpholino-quinazoline and ethanolpropanolamine analogously to Example 63.

Yield: 69% of theory, mp 102-104 ° C example 74 2-Ethanolisopropanolamino-4-morpholino-quinazoline Manufactured from 2-chloro-4-morpholino-quinazoline and ethanol isopropanolamine analogous to Example 63.

Yield: 66% of theory, mp 90-94 ° C.

Example 75 2-Ethanolbutanolamino-4-morpholino-quinazoline Prepared from 2-chloro-4-morpholino-quinazoline and ethanolbutanolamine analogously to Example 63.

Yield: 65 Vo of theory, E. 77-80 ° C.

Example 76 2- (Ethanol-tert-butanolamino) -4-morpholino-quinazoline Manufactured from 2-chloro-4-morpholino-quinazoline and ethanol tert-butanolamine analogously Example 63.

Yield: 52% of theory, melting point 81-83 ° C.

Example 77 4-Morpholino-2-propanolisopropanolamino-quinazoline Prepared from 2-chloro-4-morpholino-quinazoline and propanol isopropanolamine analogously to the example 63.

Yield: 49% of theory; Resin, Rf value: 0.7-0.8 (TLC prefabricated plate Keiselgel F, Merck, mobile phase: ethyl acetate / methanol = 3: 1).

Example 78 2-Hexanolpentanolamino-4-morpholino-quinazoline Prepared from 2-chloro-4-morpholino-quinazoline and hexanolpentanolamine analogously to Example 63.

Yield: 43% of theory; Resin, Rf value: about 0.8 (TLC prefabricated plate Kieselgel F, Merck; Mobile phase: methanol / conc. Ammonia = 9/1).

Example 79 8-Chloro-2-dipropanolamino-4-morpholino-quinazoline Prepared from 2,8-dichloro-4-morpholino-quinazoline and dipropanolamine analogously to Example 63.

Yield: 76% of theory, mp 137-139 ° C. Example 80 7-Chloro-2- (N-methylpiperazino) -4-morpholino-quinazoline Manufactured as 2,7-dichloro-4-morpholino-quinazoline (m.p. 167-1690 C) and N-methylpiperazine analogous to example 1.

Yield: 84% of theory, mp 133-135 ° C. Example 81 6-Methyl-2- (N-methylpiperazino) -4-morpholino-quinazoline Made from 2-chloro-6-methyl-4-morpholino-quinazoline (mp 135-136 ° C) and N-methylpiperazine analogous to example 1.

Yield: 78% of theory, mp 71-74 ° C Example 82 8-chloro-2- (N-methylpiperazino) -4-morpholino-quinazoline Made from 2,8-dichloro-4-morpholino-quinazoline (F. 145-147 ° C) and N-methylpiperazine analogous to Example 1.

Yield: 75% of theory, m.p. 168-1700C Example 83 6-Chloro-2- (N-methylpiperazino) -4-morpholino-quinazoline Made from 2,6-dichloro-4-morpholino-quinazoline (mp 170-172 ° C) and N-methylpiperazine analogous to example 1.

Yield: 67% of theory, mp 106-1080 ° C. Example 84 5-Chloro-2- (N-methylpiperazino) -4-morpholino-quinazoline Made from 2,5-dichloro-4-morpholino-quinazoline (F. 117-1190C) and N-methylpiperazine analogous to example 1.

Yield: 64% of theory, mp 106-107 ° C. Example 85 6,8-Dibromo-2- (N-methylpiperazino) -4-morpholino-quinazoline Made from 6,8-dibromo-2-chloro-4-morpholino-quinazoline (F. 187-1890C) and N-methylpiperazine analogous to example 1.

Yield: 87% of theory; F. of monohydrochloride: 291-2920C (under Decomposition). By reprecipitation from dilute hydrochloric acid using conc. Ammonia is the Obtain free compound with a melting point of 102-105 ° C (from methanol).

Example 86 6,8-Dichloro-4-morpholino-2-piperazino-quinazoline Prepared from 2,6,8-trichloro-4-morpholino-quinazoline (melting point 181-183 ° C.) and piperazine analogously to the example 4th

Yield: 85% of theory, mp 153-155 ° C.

Example 87 7-Chloro-4-morpholino-2-piperazino-quinazoline Prepared from 2,7-dichloro-4-morpholino-quinazoline and piperazine analogously to Example 4.

Yield: 72% of theory, mp 162-164 ° C.

Example 88 7-Fluoro-2- (N-methylpiperazino) -4- (thiomorpholino-1-oxide) quinazoline Made from 2-chloro-7-fluoro-4- (thiomorpholino-1-oxide) -quinazoline (F.95-980C) and N-methylpiperazine analogous to Example 1.

Yield: 83% of theory, m.p. 103-1050C; F. of the hydrochloride: 229-231 ° C Example 89 7-Fluoro-2-piperazino-4- (thiomorpholino-1-oxide) quinazoline Prepared from 2-chloro-7-fluoro-4- (thiomorpholino-1-oxide) quinazoline and piperazine analogously to the example 12th

Yield: 72% of theory, mp 188-191 ° C.

Example 90 7-Chloro-2-piperazino-4-thiomorpholino-quinazoline Prepared from 2,7-dichloro-4-thiomorpholino-quinazoline (mp 160-162 ° C) and piperazine analogously Example 7.

Yield: 77% of theory, mp 161-163 ° C.

Example 91 7-Chloro-2-piperazino-4- (thiomorpholino-1-oxide) quinazoline Made from 2,7-dichloro-4- (thiomorpholino-1-oxide) -quinazoline (M.p. 193-195 ° C) and Piperazine analogous to example 12.

Yield: 82% of theory, mp 211-213 ° C.

Example 92 6-Methyl-2-piperazino-4- (thiomorpholino-1-oxide) quinazoline Made from 2-chloro-6-methyl-4- (thiomorpholino-1-oxide) -quinazoline (mp 115-118 ° C) and piperazine analogous to Example 12.

Yield: 87% of theory, mp 190-192 ° C.

Example 93 6-Methyl-2- (N-methylpiperazino) -4- (thiomorpholino-1-oxide) quinazoline Made from 2-chloro-6-methyl-4- (thiomorpholino-1-oxide) -quinazoline and N-methylpiperazine analogous to example 1.

Yield: 64% of theory, mp 158-160 ° C.

Example 94 6,7-Dimethoxy-2- (N-methylpiperazino) -4-morpholino-quinazoline Made from 2-chloro-6,7-dimethoxy-4-morpholino-quinazoline (m.p. 215-216 ° C) and N-methylpiperazine analogous to example 1.

Yield: 78% of theory, mp 128-130 ° C.

Example 95 6,7-methylenedioxy-4-morpholino-2-piperazino-quinazoline Made from 2-chloro-6,7-methylenedioxy-4-morpholino-quinazoline (M.p. 198-200 ° C) and piperazine analogous to Example 4.

Yield: 79 of theory, m.p. 153-1560C.

Example 96 6,7-methylenedioxy-2- (N-methylpiperazino) -4- (thiomorpholino-1-oxide) quinazoline Made from 2-chloro-6,7-methyl-dioxy-4- (thiomorpholino-1-oxide) -quinazoline (F. 225-227 ° C) and N-methylpiperazine analogous to Example 1.

Yield: 59% of theory, mp 203-205 ° C.

Example 97 7-Nitro-2-piperazino-4- (thiomorpholino-1-oxide) quinazoline Made from 2-chloro-7-nitro-4- (thiomorpholino-1-oxide) -quinazoline (F.232-2330C, Decomposition) and piperazine analogous to Example 7.

Yield: 93% of theory, m.p. 236-2380C.

Example 98 7-Amino-2-piperazino-4-thiomorpholino-quinazoline Prepared from 7-amino-2-chloro-4-thiomorpholino-quinazoline (mp 185-186 ° C) and piperazine analogously Example 12.

Yield: 79% of theory, mp 201-203 ° C.

Example 99 7-Amino-2-piperazino-4- (thiomorpholino-1-oxide) quinazoline Made from 7-amino-2-piperazino-4-thiomorpholino-quinazoline and sodium metaperiodate analogous to example 39.

Yield: 49% of theory, m.p. 255-2570C (decomposition) example 100 7-Amino-2- (N-methylpiperazino) -4- (thiomorpholino-1-oxide) -quinazoline from 7-amino-2- (N-methylpiperazino) -4-thiomorpholinoquinazoline and sodium metaperiodate analogous to example 39.

Yield: 58% of theory, mp 253-255 ° C. (decomposition). Example 101 7-Acetylamino-2-piperazino-4- (thiomorpholino-1-oxide) -quinazoline hydrochloride manufactured from 7-acetylflmino-2 chloro-4 "(thiomorpholino-1-oxide) quinazoline (mp. 254-256 ° C, Decomposition) and piperazine analogous to Example 12.

Yield: 82% of theory, m.p. 284-2860C (decomposition) Example 102 2- (N-methylpiperazino) -4-morpholino-7-nitro-quinazoline 2.9 g (0.01 mol) of 2-chloro-4-morpholino-7-nitro-quinazoline (F.171-1730C) are refluxed with 20 ml of N-methylpiperazine for 30 minutes heated. When the reaction mixture is taken up in water, the 2- (N-methylpiperazino) -4-morpholino-7-nitro-quinazoline falls as a crystalline precipitate. After vacuuming, bottle and drying amounts the yield 3.3 g (92 76 of theory); F. 190-1920C (from ethanol).

Example 103 7-Amino-2- (N-methylpiperazino) -4-morpholino-quinazoline A suspension of 3.6 g (0.01 mol) of 2- (N-methylpiperazino) -4-morpholino-7-nitro-quinazoline in 100 ml of absolute ethanol is in the presence of Raney nickel with hydrogen im closed vessel shaken under pressure for about 3 hours at room temperature. To The solvent is stopped and the catalyst is removed by filtration largely distilled off in vacuo, and the remaining residue consists of benzene-cyclohexane recrystallized.

Yield: 2.1 g (64% of theory); Mp 149-150 ° C.

The compounds of the formula I and their salts can be per se known methods also in combination with other active ingredients in customary pharmaceuticals Incorporate preparations. The single dose for adults is 5 to 100 mg, preferably 10 to 50 mg, the daily dose 100 mg to 200 mg.

Example I Tablets containing 30 mg of 2-piperazino-4- (1-oxidothiomorpholino) quinazoline Composition: 1 tablet contains: active substance 30.0 mg milk grower 38.0 mg potato starch 26.0 mg polyvinylpyrrolidone 5.0 mg magnesium stearate 1.0 mg 100.0 mg Manufacturing process: The active ingredient mixed with milk sugar and potato starch is treated with a 20 % ethanol solution of polyvinylpyrrolidone evenly moistened through granulated a sieve with a mesh size of 1.5 mm, dried at 45 ° C. and passed through again Beat a sieve with a mesh size of 1.0 mm.

The granules obtained in this way are mixed with magnesium stearate and added Compressed tablets.

Tablet weight: 100 ng Punch: 7 mm, flat example II Deagées with 15 mg 2-piperazino-4- (1-oxidothiomorpholino) -quinazoline Composition: 1 tablet core contains: active substance 15.0 mg lactose 14.0 mg corn starch 8.0 mg Polyvinylpyrrolidone 2.5 mg Magnesium stearate 0.5 mg 40.0 mg Manufacturing process: The active ingredient mixed with milk sugar and corn starch is mixed with a 20% Ethanol solution of polyvinylpyrrolidone evenly moistened by a Sieve with a mesh size of 1.5 mm, granulated, dried at 450 C and through again Beat a sieve with a mesh size of 1.0 mm.

The granules obtained in this way are mixed with magnesium stearate and added Pressed tablet cores.

Core weight: 40.0 mg Stamp: 5.0 mm, domed The manufactured in this way Dragee cores are coated with a shell according to known methods, which essentially consists of sugar and talc. The finished coated tablets are made with the help of beeswax polished.

Drag weight: 70.0 mg Example III ampoules with 10 mg 2-piperazino-4- (1-oxidothiomorpholino) -quinazoline Composition: 1 ampoule contains: active substance 10.0 mg polyethylene glycol 600 100.0 mg distilled water ad 2.0 ml Manufacturing process: In boiled and cooled under nitrogen gas distilled water, the polyethylene glycol and the Active ingredient dissolved. The solution is given with pretreated water Volume made up and sterile filtered. All work steps must be in diffuse light take place.

Filling: In brown 2 ml ampoules under nitrogen gas.

Sterilization: 20 minutes at 1200C.

Example IV Drops containing 10 mg of 2-piperazino-4- (1-oxidothiomorpholino) quinazoline Composition: 1 ml dropping solution contains: active substance 10.0 mg cane sugar 350.0 mg sorbic acid 1.0 mg cocoa essence 50.0 mg ethyl alcohol 0.2 ml polyethylene glycol 600 0.1 ml of distilled water to 1.0 ml Production method: The sorbic acid is dissolved in alcohol and the same amount of water is added. In this the active substance is dissolved (solution 1).

The sugar is dissolved in the remaining water (solution 2).

Solution 2, polyethylene glycol 600 and the cocoa essence are added to the solution 1 added with stirring. Filter through a suitable filter.

1 ml drop solution 6 10 mg active ingredient manufacture, filling and The solution must be stored under nitrogen gas and protected from light.

Claims (1)

P a t e n t a n s p r ü c h e 1.) New basic substituted quinazolines of the general formula in which one of the radicals R1 or R2 is a morpholino, thiomorpholino, thiomorpholino-1-oxide or thiomorpholino-1,1-dioxide group optionally substituted by 1 or 2 lower alkyl radicals, the other of the radicals R1 or R2 is a dialkanolamino radical, wherein the hydroxyl group of an alkanol radical can be etherified by an alkyl group with 1-3 carbon atoms or an alkyl-alkanolamino radical in which the alkanol radical can contain 2-6 carbon atoms and the alkyl radical 1-6 carbon atoms, or a cyclic diamine general formula in which R 'represents a hydrogen atom, a lower alkyl radical optionally substituted by a hydroxyl group, an acyl, aryl or aralkyl radical, R ″ a hydrogen atom or a lower alkyl radical and the symbols n and m represent the number 1 or 2, R3 and R4 , which can be the same or different, hydrogen atoms, halogen atoms, lower alkyl or alkoxy radicals, nitro, amino or acylamino groups or R3 and R4 together mean the methylenedioxy group, and their salts with physiologically compatible inorganic or organic acids. 2.) Today basic substituted quinazolines of the above general @ one Formula I in which one of the radicals R1 or R2 is optionally lower by 1 or 2 Alkyl radicals substituted morpholino, thiomorpholino, thiomorpholino-1-oxide or Thiomorpholino-1,1-dioxide group, the other of the radicals R1 or R2, if appropriate Piperazino radical substituted by one or two alkyl radicals with 1-3 carbon atoms, R3 and R4 mean hydrogen atoms, and their salts with physiologically compatible inorganic or organic acids. 3.) 2-Piperazino-4- (thiomorpholino-1-oxide) -quinazoline and its acid addition salts 4.) 2- (Thiomorpholino-1-oxide) -4-piperazino-quinazoline and its acid addition salts 5.) 2-piperazino-4-morpholino-quinazoline and its acid addition salts. 6.) 2-Piperazino-4-thiomorpholino-quinazoline and its acid addition salts . 7.) 2-Dipropanolamino-4-morpholino-quinazoline and its acid addition salts. 8.) Medicinal products containing a compound of the general formula I in addition to one or, if necessary, several generally customary carriers or Thinners. 9.) Process for the preparation of the new basically substituted quinazolines of the general formula I according to claim 1 and of their salts with physiologically acceptable inorganic or organic acids, characterized in that a) a compound of the general formula in which R3 and R4 are as defined at the outset, one of the radicals A1 or A2 is an exchangeable radical such as a halogen atom, a mercapto group or a hydroxy, mercapto, sulfinyl or sulfonyl group substituted by an alkyl, benzyl or phenyl radical, and the other of the radicals A1 or A2, which have meanings mentioned at the beginning for R1 or R2, with an amine of the general formula H - R1 or H - R2. . III in which R1 and R2 are as defined at the outset, is reacted at elevated temperatures or b) for the preparation of compounds of the general formula I in which one of the radicals R1 or R2 is a cyclic diamine, in which R 'is a hydrogen atom, of a compound of the general formula in which R3 and R4 are as defined at the outset, one of the radicals R1 'or R2' has the meanings mentioned for R1 or R2 at the beginning and the other of the radicals R1 'or R2' is a cyclic diamine of the general formula in which R '' n and m are as defined at the outset and R '''represents a protective radical for an amino group such as benzyl or any acyl radical, the radical R' is split off or c) for the preparation of compounds of the general formula I, in which one of the radicals R1 or R2 is a thiomorpholino-1-oxide or thiomorpholino-1,1-dioxide group optionally substituted by one or two lower alkyl radicals and the other of the radicals R1 or R2 is as defined above, a compound of general formula in which R3 and R4 are as defined at the outset and one of the 'radicals R1''orR2' has the meanings mentioned for R1 or R2 at the beginning and the other of the radicals R1 "or R2" is optionally substituted by 1 or 2 lower alkyl radicals Thiomorpholino radical means being oxidized in a solvent and if desired. if a compound of general formula I in which R3 and / or R4 represent nitro groups is obtained according to process ac, this is reduced to the corresponding amino compound of general formula 1 and / or a obtained compound of general formula 1 in its salt is converted with a physiologically compatible inorganic or organic acid0 10.) Process according to claims 9a and 9b, characterized in that the reaction is carried out in a solvent. 11.) Method according to claim 9a and 10, characterized in that the reaction in the presence of a seedling agent or in the presence of a Excess of an amine of the general formula III used is carried out. 12.) Method according to Anspnlch 9a, 10 and 11, characterized in that that the reaction is carried out at temperatures between 300 and 250 ° C. 13.) Method according to claim 9b and 10, characterized in that the cleavage of the radical R '' 'hydrolytically in the presence of an acid or base and carried out at temperatures up to the boiling point of the solvent used will. 14.) Method according to claim 9b and 10, characterized in that splitting off with hydrogen in the presence of a catalyst such as palladium / animal charcoal is carried out if R '' 'is the benzyl radical and one of the radicals R1 or R2 is optionally morpholino substituted by 1 or 2 lower alkyl radicals. 15.) The method according to claim 9c, characterized in that the Oxidation with hydrogen peroxide, potassium permanganate, sodium metaperiodate or one Peracid is carried out.