EP0000538A1 - 6,7-Dihydro-5H,13H-quinazolino(3,2-a)(1,4)benzodiazepine-5,13-diones, process for their preparation and their use as medicaments. - Google Patents

Abstract

in welcher

• R¹ und R⁵ für 1,2,3 oder 4 Substituenten aus der Gruppe Wasserstoff, Alkyl, Hydroxy, Acyloxy. Alkoxy Nitro, Amino, Alkylamino, Dialkylamino, Acylamino, Acylalkylamino, Alkoxycarbonylamino Halogen, Trifluoromethyl, Cyan, Carboxy, Alkoxy carbonyl, Aminocarbonyl, Alkylaminocarbonyl. Dialkylaminocarbonyl, Aminosulfonyl, Alkylami nosulfonyl, Dialkylaminosulfonyl, Alkylaminocarbonylamino und Dialkylaminocarbonylamino steht,
• R² für Wasserstoff, gegebenenfalls substituiertes Alkyl, Aralkyl, Aryl oder für Heterocycloalkyl, Acyl oder Alkoxycarbonyl steht und
• R' und R⁴ für gleiche oder verschiedene Substituenten aus der Gruppe Wasserstoff, gegebenenfalls substituiertes Alkyl, gegebenenfalls im Arylteil substituiertes Aralkyl, gegebenenfalls substituiertes Aryl oder Heteroaryl steht

sowie ihre Verwendung als Arzneimittel, vorzugsweise als auf das Zentralnervensystem wirkende Stoffe, insbesondere als cerebralatiischemische, antiamnetische, lern-, leistungsund gedächtnisverbessernde, tranquillisierende, analgetische und antipyretische Wirkstoffe.6,7-dihydro-5H, 13H-quinazolino (3,2-a) (1,4) benzodiazepine-5,13-dione of the general formula (I)

in which

• R ¹ and R ⁵ for 1,2,3 or 4 substituents from the group hydrogen, alkyl, hydroxy, acyloxy. Alkoxy nitro, amino, alkylamino, dialkylamino, acylamino, acylalkylamino, alkoxycarbonylamino halogen, trifluoromethyl, cyan, carboxy, alkoxy carbonyl, aminocarbonyl, alkylaminocarbonyl. Dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylaminocarbonylamino and dialkylaminocarbonylamino,
• R ^{2 represents} hydrogen, optionally substituted alkyl, aralkyl, aryl or heterocycloalkyl, acyl or alkoxycarbonyl and
• R 'and R ^{4 represent} identical or different substituents from the group hydrogen, optionally substituted alkyl, optionally substituted aralkyl in the aryl part, optionally substituted aryl or heteroaryl

and their use as medicaments, preferably as substances acting on the central nervous system, in particular as cerebralatic, antiamnetic, learning, performance and memory-improving, tranquilizing, analgesic and antipyretic active substances.

The compounds are prepared by reacting a 2-alkyl-3-aryl-4H-quinazolin-4-one with H ₂ NR ² or NH

Description

The present invention relates to new 6,7-dihydro-5H, 13H-quinazolino [3,2-a] [1,4] benzodiazepin-5,13-dione, a process for their preparation and their use as a medicament, preferably as substances that act on the central nervous system, in particular as cerebral anti-ischemic, antiamnetic, learning, performance and memory-improving, tranquilizing, analgesic and antipyretic active substances.

in welcher

• R¹ und R⁵ für 1, 2, 3 oder 4 Substituenten aus der Gruppe Wasserstoff, Alkyl, Hydroxy, Acyloxy, Alkoxy, Nitro, Amino, _Aikylamino, Dialkylamino, Acylamino, Acylalkylamino, Alkoxycarbonylamino, Halogen, Trifluormethyl, Cyan, Carboxy, Alkoxycarbonyl, Aminocarbonyl, Alkylaminocarbonyl, Dialkylaminocarbonyl, Aminosulfonyl, Alkylaminosulfonyl, Dialkylaminosulfonyl, Alkylaminocarbonylamino und Dialkylaminocarbonylamino steht,
• _R ² für Wasserstoff, gegebenenfalls substituiertes Alkyl, Aralkyl, Aryl oder für Heterocycloalkyl, Acyl oder Alkoxycarbonyl steht und
• _R ³ und _R ⁴ für gleiche oder verschiedene Substituenten aus der Gruppe Wasserstoff, gegebenenfalls substituiertes Alkyl, gegebenenfalls im Arylteil substituiertes Aralkyl, gegebenenfalls substituiertes Aryl oder Heteroaryl steht,

sowie ihre pharmakologisch unbedenklichen Salze mit anorganischen oder organischen Säuren.The invention relates to new 6,7-dihydro-5H, 13H-quinazolino [3,2-a] [1,4] benzodiazepine-5,13-diones of the general formula (I)

in which

• R ¹ and R ⁵ for 1, 2, 3 or 4 substituents from the group hydrogen, alkyl, hydroxy, acyloxy, alkoxy, nitro, amino, _A ikylamino, dialkylamino, acylamino, acylalkylamino, alkoxycarbonylamino, halogen, trifluoromethyl, cyano, carboxy, Alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylaminocarbonylamino and dialkylaminocarbonylamino,
• _R ^{2 represents} hydrogen, optionally substituted alkyl, aralkyl, aryl or heterocycloalkyl, acyl or alkoxycarbonyl and
• _R ³ and _R ^{4 represent} identical or different substituents from the group hydrogen, optionally substituted alkyl, optionally substituted aralkyl in the aryl part, optionally substituted aryl or heteroaryl,

as well as their pharmacologically acceptable salts with inorganic or organic acids.

in welcher

• _R ³ und _R ⁴ die oben angegebene Bedeutung haben,
• R¹ und R⁵ für 1, 2, 3 oder 4 Stubstituenten aus der Gruppe Wasserstoff, Alkyl, Hydroxy, Acyloxy, Alkoxy, Nitro, Dialkylamino, Acylamino, Acylalkylamino, Alkoxycarbonylamino, Halogen, Trifluormethyl, Cyan, Alkoxycarbonyl, Dialkylaminocarbonyl, Aminosulfonyl, Alkylaminosulfonyl, Dialkylaminosulfonyl und Dialkylaminocarbonylamino steht,
• R⁶ für Wasserstoff, Alkyl, Aralkyl oder Aryl steht und
• X für eine leicht nucleophil substituierbare Abgangsgruppe wie Halogen oder Alkylsulfo, Aralkylsulfo oder Arylsulfo steht,

mit Ammoniak oder primären Aminen der allgemeinen Formel (III)

in welcher

• _R ² für gegebenenfalls substituiertes Alkyl, Aralkyl, Heterocycloalkyl oder Aryl steht,
  • oder mit deren Salzen mit anorganischen oder organischen Säuren oder Basen
  • in Gegenwart von inerten organischen Lösungsvermittlern und gegebenenfalls in Gegenwart von Säurebindern bei Temperaturen zwischen 20 und 250°C umsetzt
  • und gegebenenfalls anschließend in an sich bekannter Weise in einem weiteren Reaktionsschritt Nitrogruppen oder Acylaminogruppen als Substituenten R¹ und/oder R in Aminogruppen oder

It was found that 6,7-dihydro-5H, 13H-quinazolino [3,2-a] [1,4] benzodiazepine-5,13-diones of the formula (1) are obtained when 2-alkyl-3 -aryl-4H-quinazolin-4-ones of the general formula (II)

in which

• _R ³ and _R ^{4 have} the meaning given above,
• R ¹ and R ^{5 represent} 1, 2, 3 or 4 substituents from the group hydrogen, alkyl, hydroxy, acyloxy, alkoxy, nitro, dialkylamino, acylamino, acylalkylamino, alkoxycarbonylamino, halogen, trifluoromethyl, cyano, alkoxycarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl , Dialkylaminosulfonyl and dialkylaminocarbonylamino,
• R ^{6 represents} hydrogen, alkyl, aralkyl or aryl and
• X represents an easily nucleophilically substitutable leaving group such as halogen or alkylsulfo, aralkylsulfo or arylsulfo,

with ammonia or primary amines of the general formula (III)

in which

• _R ^{2 represents} optionally substituted alkyl, aralkyl, heterocycloalkyl or aryl,
  • or with their salts with inorganic or organic acids or bases
  • in the presence of inert organic solubilizers and optionally in the presence of acid binders at temperatures between 20 and 250 ° C.
  • and optionally subsequently in a manner known per se in a further reaction step, nitro groups or acylamino groups as substituents R ¹ and / or R in amino groups or

Acylalkylamino groups in alkylamino groups or alkoxycarbonyl groups in carboxy groups or alkoxycarbonyl groups and / or cyano groups in aminocarbonyl or alkylaminocarbonyl groups or amino groups in alkylaminocarbonylamino groups, or
in the case of reaction with ammonia (R ² = hydrogen), the NH group is subsequently acylated with carboxylic acid, sulfonic acid chlorides or carbonic acid ester chlorides or with carboxylic acid anhydrides or with pyrocarbonates.

The reaction of the 2-alkyl-3-aryl-4H-quinazolin-4-ones of the formula (II) with ammonia or primary amines of the formula (III) to give the 6,7-dihydro-5H, 13H-quinazolino [3.2 -a] [1,4] benzodiazepine-5,13-diones of the formula (I) proceeds in two reaction steps via intermediates IV and / or V, which can optionally be isolated:

The benzodiazepine derivatives of the formula (I) according to the invention surprisingly show very strong effects on the central nervous system, in particular very good cerebral anti-ischemic, antiamnetic, learning, performance and memory-improving, tranquilizing, analgesic and antipyretic properties and thus represent an enrichment of the pharmaceutical industry.

Beispiele für gegebenenfalls anschließende weitere Reaktionsschritte:

The following reaction scheme shows examples of reactions of individual reaction partners that can be used according to the invention:

Examples of subsequent reaction steps which may follow:

In the formulas (I) and (II), R ¹ and R ⁵ preferably represent one or two substituents from the group hydrogen, alkyl, hydroxy, alkoxy, nitro, amino, dialkylamino, acylamino, alkoxycarbonylamino, halogen, trifluoromethyl, carboxy, alkoxycarbonyl , Aminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, dialkylaminosulfonyl, where halogen in particular represents fluorine, chlorine and bromine and the alkyl, alkoxy and acyl radicals mentioned contain 1 to 4 carbon atoms, in particular 1 or 2 carbon atoms.

• R³ steht vorzugsweise für Wasserstoff und R⁴ vorzugsweise für Wasserstoff, Alkyl mit 1 bis 16, insbesondere 1 bis 8, Kohlenstoffatomen, Aralkyl mit 1 bis 6 Kohlenstoffatomen im Alkylteil, insbesondere Benzyl oder Phenyläthyl, Aryl in Form von Phenyl und Heteroaryl in Form eines 5- bis 6-gliedrigen heterocyclischen Systems mit 1 bis 3 Heteroatomen aus der Gruppe Stickstoff, Sauerstoff und/oder Schwefel. Mögliche Substituenten im Arylteil von Aralkyl und von Aryl sind Halogen, insbesondere Brom und Chlor, Trifluormethyl, Hydroxy, Alkoxy und Nitro.
• _R ⁶ steht vorzugsweise für Alkyl mit 1 bis 2 Kohlenstoffatomen, für Benzyl und Phenyl und
• X steht vorzugsweise für Halogen, insbesondere Brom und Chlor und für Methylsulfo, Phenylsulfo und 4-Methylphenylsulfo.

The alkyl radicals in dialkylamino can also be closed in themselves or via a hetero atom from the group O, S or via an NH or K alkyl group to form a 4- to 7-membered ring.

• R ³ preferably represents hydrogen and R ⁴ preferably represents hydrogen, alkyl having 1 to 16, in particular 1 to 8, carbon atoms, aralkyl having 1 to 6 carbon atoms in the alkyl part, in particular benzyl or phenylethyl, aryl in the form of phenyl and heteroaryl in the form of a 5- to 6-membered heterocyclic system with 1 to 3 heteroatoms from the group nitrogen, oxygen and / or sulfur. Possible substituents in the aryl part of aralkyl and of aryl are halogen, in particular bromine and chlorine, trifluoromethyl, hydroxy, alkoxy and nitro.
• _R ⁶ preferably represents alkyl having 1 to 2 carbon atoms, benzyl and phenyl and
• X preferably represents halogen, especially bromine and chlorine and methylsulfo, phenylsulfo and 4-methylphenylsulfo.

The 2-alkyl-3-aryl-4H-quinazolin-4-ones of the formula II to be used as starting materials are known or can be prepared by known processes (cf. J.Amer.Chem. Soc. 68 (1946), 542 / J.org.Chem. 14 (1949), 967 / J.Gen. Chem. (Engl. Trans.) 30 (1960), 2333 and 34 (1964), 848 / Chem.Abstr. 52 (1958), 9147 / J.pr.Chem. (4) 14 (1961), 84 / drug research 13 (1963) 688 / J.Med.Chem. 20 (1977), 379 / Synthesis 1977, 309).

• 2-Chlormethyl-3-(2-methoxycarbonyl-phenyl)-4H-chinazolin-4-on, 2-Brommethyl-3-(2-methoxycarbonyl-phenyl)-4H-chinazolin-4-on, 2-Chlormethyl-3-(2-äthoxycarbonyl-phenyl)-6-chlor-4H-chinazolin-4-on,
• 2-Bromnethyl-3-(2-carboxy-phenyl)-4H-thinazolin-4-on, 2-Chlormethyl-3-(2-methoxycarbonyl-5-bhlor-phenyl)-7-chlor-4H-chinazolin-4-on,
• 2-Methylsulfomethyl-3-(2-äthoxycarbonyl-phenyl)-6-trifluormethyl-4H-chinazolin-4-on,
• 2-Phenylsulfomethyl-3-(2-methoxycarbonyl-phenyl)-8-methoxy-4H-chinazolin-4-on,
• 2-Fluormethyl-3-(2-methoxycarbonyl-phenyl)-6-fluor-4H-chinazolin-4-on,
• 2-Chlormethyl-3-(2-äthoxycarbonyl-phenyl)-6,7-dimethoxy-4H-chinazolin-4-on,
• 2-Brommethyl-3-(2-butoxycarbonyl-phenyl)-6,7,8-trichlor-4H-chinazolin-4-on,
• 2-(1-Chloräthyl )-3-(2-methoxycarbonyl-phenyl)-6-dimethylamino-4H-chinazolin-4-on,
• 2-(α-Brombenzyl)-3-(2-carboxy-phenyl)-6-aminosulfonyl-7-chlor-4H-chinazolin-4-on,
• 2- (α.-Bromfurfuryl) -3- (2-benzyloxycarbonyl-4,6-dichlor-phenyl)-4H-chinazolin-4-on,
• 2-(2-Brompropyl)-3-(2-methoxycarbonyl-4-trifluormethyl-phenyl)-6-nitro-4H-chinazolin-4-on.

The following are examples:

• 2-chloromethyl-3- (2-methoxycarbonyl-phenyl) -4H-quinazolin-4-one, 2-bromomethyl-3- (2-methoxycarbonyl-phenyl) -4H-quinazolin-4-one, 2-chloromethyl-3- (2-ethoxycarbonyl-phenyl) -6-chloro-4H-quinazolin-4-one,
• 2-bromomethyl-3- (2-carboxy-phenyl) -4H-thinazolin-4-one, 2-chloromethyl-3- (2-methoxycarbonyl-5-chlorophenyl) -7-chloro-4H-quinazolin-4- on,
• 2-methylsulfomethyl-3- (2-ethoxycarbonyl-phenyl) -6-trifluoromethyl-4H-quinazolin-4-one,
• 2-phenylsulfomethyl-3- (2-methoxycarbonyl-phenyl) -8-methoxy-4H-quinazolin-4-one,
• 2-fluoromethyl-3- (2-methoxycarbonyl-phenyl) -6-fluoro-4H-quinazolin-4-one,
• 2-chloromethyl-3- (2-ethoxycarbonyl-phenyl) -6,7-dimethoxy-4H-quinazolin-4-one,
• 2-bromomethyl-3- (2-butoxycarbonyl-phenyl) -6,7,8-trichloro-4H-quinazolin-4-one,
• 2- (1-chloroethyl) -3- (2-methoxycarbonyl-phenyl) -6-dimethylamino-4H-quinazolin-4-one,
• 2- (α-bromobenzyl) -3- (2-carboxyphenyl) -6-aminosulfonyl-7-chloro-4H-quinazolin-4-one,
• 2- (α.-bromofurfuryl) -3- (2-benzyloxycarbonyl-4,6-dichlorophenyl) -4H-quinazolin-4-one,
• 2- (2-bromopropyl) -3- (2-methoxycarbonyl-4-trifluoromethyl-phenyl) -6-nitro-4H-quinazolin-4-one.

In the formulas (I) and (III), R ² preferably represents an optionally substituted alkyl radical having 1 to 10, in particular 1 to 6, carbon atoms, an optionally substituted aralkyl radical having 1 to 6 carbon atoms in the alkyl part, in particular benzyl or phenethyl, an optionally substituted one Phenyl radical, a heterocycloalkyl radical with 1 to 6 carbon atoms in the alkyl part and 4 to 8 ring members and 1 to 3 heteroatoms from the group consisting of nitrogen, oxygen and / or sulfur in the heteroaryl part, to which a phenyl ring can also be fused.

Possible substituents in R ² = alkyl are hydroxy, alkoxy, amino, alkylamino, dialkylamino, acylamino, alkoxycarbonylamino, trifluoromethyl, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, Alkylaminocarbonylamino and sulfo groups, where carboxy and sulfo groups can also be present in the form of salts with inorganic and organic acids. The alkyl radicals in dialkylamino groups can also be closed in themselves or via a hetero atom from the group consisting of oxygen, sulfur or via an NH, N-alkyl, N-acyl or _N- alkoxycarbonyl group to form a 4- to 8-membered ring. Alkyl, alkoxy and acyl radicals mentioned in the possible substituents preferably contain 1 to 4, in particular 1 to 2, carbon atoms.

Possible substituents in R ² = aralkyl and phenyl are in respective aryl part halogen, in particular chlorine and bromine, trifluoromethyl, hydroxy, alkoxy, nitro and alkyl.

The primary amines of Fornel (III) to be used as starting materials are known or can be prepared by known processes.

The following are examples:

Methylamine, isobutylamine, 2-ethylhexylamine, 4-methylcyclohexylamine, 2-norbornylamine, allylamine, propargylamine, propylenediamine, 1-amino _- 2-diethylaminoethane, ethanolamine, 3-atoxypropylamine, aminoacetic acid ethyl ester, aminopropionitrylamine, aminopropyl aminomethylamine, aminopropionitrylamine, 2,4-dichlorobenzylamine, 4-chlorophenylethylamine, 3-ethoxyaniline, 4-diethylaminoaniline, 2-aminomethylfuran, 4-aminomethylpyridine, N-aminoethyl-N'-methylpiperazine, N-aminobutylthiomorpholine-1,1-dioxide, 1 Aminomethylisoquinoline, 1-aminopropyl-1,2,3-triazole.

In the formulas (I), (II) and (III) and correspondingly also (IV) and (V), alkyl represents, for example, methyl, ethyl, n- and isopropyl, n-, iso- and tert-butyl, h- and iso-hexyl, decyl, hexadecyl, allyl, propargyl, cyclohexyl.

Alkoxy stands for example for methoxy, ethoxy, n- and iso _- propoxy, n-, iso- and tert-butoxy, allyloxy, cyclobutyloxy.

Alkylamino and dialkylamino are, for example, methylamino, dimethylamino, ethylamino, diethylamino, methylethylamino, n- and iso-propylamino, n-, iso- and tert-butylamino, n- and iso-dipropylamino, n-, iso- and tert-dibutylamino, allylamino, diallylamino - dialkylamino also for pyrrolidino, piperidino, cyclohexylimino, morpholino, thiomorpholino, piperazino, N-methylpiperazino, tetrahydroquinolino,.

Acylamino stands for example for formylamino, acetylamino, propionylamino, n- and iso-butyrylamino, valeroylamino, iso-valeroylamino, pivaloylamino.

Alkoxycarbonyl stands for example for methoxycarbonyl, ethoxycarbonyl, n- and iso-propoxycarbonyl, n-, iso- and tert-butoxycarbonyl, allyloxycarbonyl, cyclohexyloxycarbonyl.

Aralkyl stands for example for benzyl, 4-chlorobenzyl, 2,6-dichlorobenzyl, 3-bromobenzyl, 2-methoxybenzyl, 3-hydroxybenzyl, 2,4,6-trimethylbenzyl, phenylethyl, 4-chlorophenylethyl, phenylpropyl, phenylbutyl.

Aryl stands for example for phenyl, 2-chlorophenyl, 2,4-dichlorophenyl, 3-nitrophenyl, 3-trifluoromethylphenyl, 2-trifluoromethyl-4-chlorophenyl, 2-methylphenyl, 4-xthylphenyl, 3,4-dimethylphenyl, 3-hydroxyphenyl , 2-methoxyphenyl,; 4-ethoxyphenyl, 2-methoxy-5-chlorophenyl, 2,5-diethoxyphenyl, 4-aminosulfonylphenyl, 3-dimethylaminophenyl, 3-xthylaminophenyl, 3-ethylamino-4-methylphenyl.

Heteroaryl stands for example for furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, pyrazole, imidazole, triazole, pyridine, pyrimidine, thiazine, indole, benzimidazole, benzoxazole, benz thiazole, indazole, quinoline, isoquinoline, quinazoline, cninoxaline, benzotriazine, phthalazine.

All organic solvents which are inert to the respective reactants are suitable as solubilizers. These preferably include aliphatic alcohols such as methanol, ethanol, isopropanol or butanol, ethers such as tetrahydrofuran, dioxane, ethylene glycol monomethyl ether, ethylene glycol diethyl ether, glycols such as ethylene glycol, propylene glycol, diethylene glycol and corresponding ethers with aliphatic alcohols such as diethylene glycol, xylene alcohol, tolylene glycol, xylene alcohol, tolylene glycol, xylene alcohol, tolylene alcohol, tolylene glycol, xylene glycol, xylene glycol, ethyl ether, tolylene alcohol, tolylene alcohol, tolylene glycol, xylene alcohol, tolylene glycol, xylene glycol, xylene glycol Halogenated hydrocarbons such as chloroform, carbon tetrachloride, chlorobenzene, dichlorobenzenes, nitriles such as acetonitrile, propionitrile, carboxamides such as dimethylformamide, dimethylacetamide, heterocyclic bases such as pyridine, picoline, collidines, quinoline or isoquinoline, as well as commercially available technical mixtures of these solvents.

The reaction can be carried out at normal pressure but also at elevated pressure. In particular when using ammonia or low-boiling primary amines as the reaction partner, increased pressure may be required for the reaction.

The reaction temperatures can be varied within a wide range. In general, temperatures between 20 and 250 ° C, preferably between 20 and 18 ₀ ^o _C , especially between 40 and 150 ° C.

All customary acid binders can be used as acid binders. These include inorganic bases such as alkali and alkaline earth hydroxides, e.g. Sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, alkali or alkaline earth carbonates such as sodium carbonate, potassium carbonate, calcium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, amides such as sodium amide and organic bases such as tertiary amines, e.g. Triethylamine, N, N-dimethylaniline, pyridines, quinolines and isoquinolines. Instead of one of the customary acid binders, an excess of the reactant ammonia or primary amine can also advantageously be used in the reaction.

When carrying out the process according to the invention, 1 mol of 2-alkyl-3-aryl-4H-quinazolin-4-one of the formula (II) is at least 1 mol of ammonia or primary amine of the formula (III) and at least 1 mol of one of the acid binders mentioned.

In the course of the reaction according to the invention, the starting materials generally go completely or partially into solution, while the end products crystallize out. The deposition of the end products can be accelerated by cooling and / or by adding precipitants such as water, lower aliphatic ethers such as diethyl ether or dibutyl ether or lower aliphatic hydrocarbons such as petroleum ether or mineral spirits.

• Rund R gleich oder verschieden sind und jeweils für 1 oder 2 Substituenten aus der Gruppe Wasserstoff, Halogen, Nitro, Cyano, Trifluormethyl, Amino, Alkyl mit 1 bis 4 Kohlenstoffatomen oder Alkoxy mit 1 bis 4 Kohlenstoffatomen stehen,
• _R ² für Wasserstoff, Alkyl mit 1 bis 6 Kohlenstoffatomen, wobei die Alkylgruppe gegebenenfalls durch Phenyl, Pyridyl, Halogen, Alkoxy oder Dialkylamino substituiert sein kann und wobei die Alkyl- und Alkoxysubstituenten 1 bis 4 Kohlenstoffatome enthalten, oder für eine Alkoxycarbonylgruppe mit 1 bis 4 Kohlenstoffatomen im Alkoxyrest, steht und
• R und _R ⁴ gleich oder verschieden sind und für Wasserstoff, Alkyl mit 1 bis 4 Kohlenstoffatomen oder Phenyl stehen.

Of particular interest are 6,7-dihydro-5H, 13H-quinazolino [3,2-a] [1,4] benzodiazepine-5,13-diones of the formula (I), in which

• R are the same or different and each represents 1 or 2 substituents from the group hydrogen, Halogen, nitro, cyano, trifluoromethyl, amino, alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms,
• _R ^{2 represents} hydrogen, alkyl having 1 to 6 carbon atoms, where the alkyl group can optionally be substituted by phenyl, pyridyl, halogen, alkoxy or dialkylamino and the alkyl and alkoxy substituents contain 1 to 4 carbon atoms, or an alkoxycarbonyl group having 1 to 4 Carbon atoms in the alkoxy radical, stands and
• R and _R ^{4 are the} same or different and represent hydrogen, alkyl having 1 to 4 carbon atoms or phenyl.

The following may be mentioned as new active ingredients: 6,7-dihydro-5H, 13H-quinazolino [3,2-a] [1,4] benzodiazepine-5,13-dione, 1-chloro-6,7-dihydro-, 2-chloro ..., 3-chloro, 4-chloro, 9-chloro, 10-chloro, 11-chloro, 12-chloro, 1,3 _- dichloro, 1,4-dichloro -, 9,11-dichloro, 9,12-dichloro-, 1,2,3-trichloro-, 9,10, 11-trichloro-, 1,2,3,4-tetrachloro-, 9,10,11, 12-tetrachloro, 3-bromo, 11-bromo, 1,3-dibromo, 9,11-dibromo, 3-fluoro, 11-fluoro, 1,3-diiodo, 9,11- Diiodine, 1-trifluoromethyl, 2-trifluoromethyl, 3-trifluoromethyl, 4-trifluoromethyl, 9-trifluoromethyl, 10-trifluoromethyl, 11-trifluoromethyl, 12-trifluoromethyl, 1-methyl, 2- Methyl, 3-methyl, 9-methyl, 10-methyl, 11-methyl, 2,4-dimethyl, 10,12-dimethyl, 1-ethyl, 9-ethyl, 1-methoxy -, 3-methoxy, 4-methoxy, 9-methoxy, 11-methoxy, 12-methoxy, 2,3-dimethoxy, 10,11-dimethoxy, 2-xthoxy, 10-ethoxy , 1-hydroxy, 2-hydroxy, 9-hydroxy, 10-hydroxy, 1-nitro, 2-nitro, 3-nitro, 4-nitro, 9-nitro, 10-nitro , 11-nitro, 12-nitro, 1,3- Dinitro, 9,11-dinitro, 1-nitro-3-chloro, 9-nitro-11-chloro, 9,11-dinitro-12-chloro, 1-bromo-3-nitro, 9- Bromine-11-nitro, 1-amino, 2-amino, 3-amino, 4-amino, 9-amino, 10-amino, 11-amino, 12-amino, 1,3 -Diamino-, 9,11-diamino-, 10-acetylamino-, 11-acetylamino-, 2-ethoxycarbonylamino-, 3-ethoxycarbonylamino-, 11-ethoxycarbonylamino-, 10-dimethylamino-, 10-N-ethyl-N-formyl -amino-, 10-pyrrolidino-, 10-piperidino-, 10-morpholino-, 10-N-methyl-piperazino-, 10-ethylamino-, 10-isopropoxycarbonylamino-, 2-carboxy-, 3-carboxy-, 4- Carboxy, 2-methoxycarbonyl, 3-ethoxycarbonyl, 4-butoxycarbonyl, 2-aminocarbonyl, 3-butylaminocarbonyl, 4-morpholinocarbonyl, 10-aminosulfonyl, 11-aminosulfonyl, 10-chloro-11-aminosulfonyl -, 11-methylaminosulfonyl-, 11-diethylaminosulfonyl-, 9-methoxy-11-chloro-12-methyl-, 9-chloro-12-ethyl-, 3,10-dichloro-, 3,11-dichloro-, 2- Chloro-11-trifluoromethyl-, 4-chloro-10-trifluoromethyl-, 3,11-bistrifluoromethyl-, 6-methyl-, 6-butyl-, 6- (2-ethoxymethyl) -, 6- (3 _- dimethyla minoethyl) -, 6- (2-diethylaminoethyl) -, 6- (2-diethylaminopropyl) -, 6-ethoxycarbonylmethyl-, 6-piperidino- ethyl-, 6- (4-methylpiperidinoethyl) -, 6- (N-methylpiperazino- propyl) -, 6-morpholinoethyl, 6-benzyl, 6- (4-chlorobenzyl) -, 6- (2,4-dichlorobenzyl) -, 6- (3-hydroxybenzyl) -, 6-phenylethyl, 6- (4-methoxyphenylethyl) -, 6-acetyl, 6-ethoxycarbonyl, 6- (picolyl-2) -, 6- (picolyl-4) -, 7-methyl, 7-phenyl, 7- (3- Chlorophenyl) -, 7-thienyl-, 7-methyl-7- (4-chlorophenyl) -, 7- (furyl-2) -10-chloro, 3-chloro-6-benzyl-7-methyl-, 4- Chloro-6-ethyl-7-phenyl-11-trifluoromethyl-6,7-dihydro-6H, 13H-quinazolino [3, 2-a] [1, 4] -benzodiazepine-5,13-dione.

The new compounds according to the invention are substances which can be used as medicaments. You can use it be administered, for example intravenously, intramuscularly, subcutaneously, orally or intravaginally.

The new active compounds can be converted in a known manner into the customary formulations, such as tablets, capsules, dragées, pills, granules, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents. Here, the therapeutically active compound should in each case be present in a concentration of approximately 0.5 to 90% by weight of the total mixture, i.e. in amounts sufficient to achieve the dosage range indicated.

The formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, e.g. if water is used as the diluent, organic solvents can optionally be used as auxiliary solvents.

Examples of auxiliary substances are:

Water, non-toxic organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. peanut / sesame oil), alcohols (e.g. ethyl alcohol, glycerin), glycols (e.g. propylene glycol, polyethylene glycol), solid carriers such as natural rock powder (e.g. kaolins, clays, talc, chalk), ground synthetic minerals (for example highly disperse silica, silicates), sugars (for example sucrose, lactose and glucose), emulsifiers such as nonionic and anionic emulsifiers (for example, polyethylene fatty acid ester, polyoxyethylene. ettalkoholäther _F, alkylsulfonates and Arylaulfonate) Dis Pergiermittel (eg lignin, methyl cellulose, starch and polyvinylpyrrolidone) and lubricants (eg magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

The application is carried out in the usual way, preferably orally or parenterally.

In the case of oral use, tablets can of course also contain additives such as sodium citrate, calcium carbonate and calcium phosphate together with various additives such as starch, preferably potato starch, gelatin and the like, in addition to the carriers mentioned. Lubricants such as magnesium stearate, sodium lauryl sulfate and talc can also be used for tableting. In the case of aqueous suspensions and / or elixirs which are intended for oral applications, the active ingredients can be mixed with various flavor enhancers or colorants in addition to the abovementioned auxiliaries.

In the case of parenteral use, solutions of the active ingredients can be used using suitable liquid carrier materials. The fact that the compounds according to the invention are able to form readily soluble salts in water has proven to be particularly advantageous in the case of parenteral use. These salts are obtained if the compounds according to the invention are combined in a suitable solvent with the equimolar amount of a non-toxic inorganic or organic base. Examples include: caustic soda, potash lye, ethanolamine, diethanolamine, triethanolamine, aminotris hydroxymethyl methane, glucosamine, N-methylglucosamine. Such salts can also be of greater importance for the oral use of the compounds according to the invention, in that they accelerate or delay the absorption as desired. In addition to the salts already mentioned above, examples may be mentioned: magnesium salts, calcium salts, aluminum salts and iron salts.

In general, it has proven to be advantageous to administer amounts of approximately 0.05 to 200 mg / kg, preferably approximately 0.1 to 50 mg / kg of body weight per day in the case of parenteral administration in order to achieve effective results, and in the case of oral administration it is Dosage about 0.1 to 500 mg / kg, preferably 0.5 to 100 mg / kg body weight per day.

Nevertheless, it may be necessary to deviate from the quantities mentioned, depending on the body weight of the test animal or the type of application route, but also on the basis of the animal species and its individual behavior towards the medication or the type of its formulation and the time or date Interval at which the administration takes place. In a few cases it may be sufficient to make do with less than the aforementioned minimum quantity, while in other cases the above upper limit must be exceeded. In the case of application of larger quantities, it may be advisable to distribute them in several single doses throughout the day.

This information applies both to the use of the compounds according to the invention in veterinary and in human medicine. :

Manufacturing example example 1

• a) Das Reaktionsprodukt des Beispiels 1' erhält man auch bei der Umsetzung von 32,9 g (0,6 Mol) 2-Chlormethyl-3-(2-methoxycarbonyl-phenyl)-4H-chinazolin-4-on und 80 ml flüssigen Ammoniaks in 200 ml Athylenglykolmonomethyl- äther in einem Autoklaven in 5 Stunden bei 120°C in 69 %- iger Ausbeute.
  2-Chlormethyl-3-(2-methoxycarbonyl-phenyl)-4H-chinazolin-4-on (Schmelzpunkt: 197-199°C, umkristallisiert aus Toluol) wurde analog J. Chem. (4) 14 (1961), 84 aus N-Chloracetyl-anthranilsäure und Anthranilsäuremethylester hergestellt.
• b) Das Reaktionsprodukt des Beispiels 1 erhält man auch durch 2 stündiges Einleiten von gasförmigem Ammoniak in eine Lösung von 0,05 Mol 2-Chlormethyl-2-(2-methoxycarbonyl-phenyl)-4H-chinazolin-4-on in 250 ml Dimethylformamid bei 20-25° und 12 stündiges Stehenlassen des Ansatzes in 81 %iger Ausbeute.

14.7 g (0.05 mol) of 2-bromomethyl-3- (2 (methoxycarbonyl-phenyl) -4H-quinazolin-4-one and 25 ammonia in 100 ml of ethylene glycol monomethyl ether are heated to 100 ° C. in an autoclave for 5 hours. After cooling, the colorless crystals are filtered off with suction and washed several times with methanol, giving 6.1 g (44 of the dihydro-5H, 13H-quinazolino [3, 2-a] [1, 4] benzodiazepine-5,13-dione Melting point: 313-315 ° C (from dimethylformamide).

• a) The reaction product of Example 1 'is also obtained in the reaction of 32.9 g (0.6 mol) of 2-chloromethyl-3- (2-methoxycarbonyl-phenyl) -4H-quinazolin-4-one and 80 ml of liquid Ammonia in 200 ml of ethylene glycol monomethyl ether in an autoclave in 5 hours at 120 ° C in 69% yield.
  2-Chloromethyl-3- (2-methoxycarbonyl-phenyl) -4H-quinazolin-4-one (melting point: 197-199 ° C, recrystallized from toluene) was analogous to J. Chem. (4) 14 (1961), 84 from N-chloroacetyl-anthranilic acid and anthranilic acid methyl ester produced.
• b) The reaction product of Example 1 is also obtained by introducing gaseous ammonia into a solution of 0.05 mol of 2-chloromethyl-2- (2-methoxycarbonyl-phenyl) -4H-quinazolin-4-one in 250 ml of dimethylformamide for 2 hours at 20-25 ° and leaving the batch for 12 hours in 81% yield.

Example 2

18,9 g (0,05 Mol) 2-Chlormethyl-3-(2-äthoxycarbonyl-phenyl)-6-chlor-4H-chinazolin-4-on und 50 ml flüssigen. Ammoniaks in 150 ml Äthylenglykolmonoäthylläther werden in einem Autoklaven 3 Stunden auf 60°C erhitzt. Nach dem Erkalten saugt man die farblosen Kristalle ab und wäscht mehrfach mit Methanol. Man erhält 13 g (33 ' der Theorie) 11-Chlor-6,7-dihydro-5H, 13H-chinazolino [3,2-a][1,4] benzodiasepin-5,13-dion. Schmelzpunkt: 286-288°C (aus Dimethylformamid/Äthanol 1:1).

18.9 g (0.05 mol) of 2-chloromethyl-3- (2-ethoxycarbonyl-phenyl) -6-chloro-4H-quinazolin-4-one and 50 ml of liquid. Ammonia in 150 ml of ethylene glycol monoethyl ether are heated in an autoclave at 60 ° C for 3 hours. After cooling, the colorless crystals are filtered off and washed several times with methanol. 13 g (33 'of theory) of 11-chloro-6,7-dihydro-5H, 13H-quinazolino [3,2-a] [1,4] benzodiasepine-5,13-dione are obtained. Melting point: 286-288 ° C (from dimethylformamide / ethanol 1: 1).

2-chloromethyl-3- (2-ethoxycarbonyl-phenyl) -6-chloro-4H-quinazolin-4-one (melting point: 195-197 ° C, recrystallized from toluene) was prepared analogously to J.Amer.Chem.Soc. 68 (1946), 542 from N-chloroacetyl-5-chloroanthranoic acids and anthranilic acid ethyl ester.

Example 3

Analog Beispiel 1 a) erhält man aus 18 g (0,05 Mol) 2-Chlormethyl-3- (2-methoxycarbonyl-phenyl)-7-chlor-4H-chinazolin-4-on (Schemlzpunkt: 150-152°g aus Äthanol)und 50 ml flüssi- gen Ammoniaks in 150 ml Äthylenglykolmonomethyläther in 5

Analogously to Example 1 a), 2-chloromethyl-3- (2-methoxycarbonylphenyl) -7-chloro-4H-quinazolin-4-one is obtained from 18 g (0.05 mol) (melting point: 150-152 ° g) Ethanol) and 50 ml liquid ammonia in 150 ml ethylene glycol monomethyl ether in 5

Hours at 80 ° C 10 g (65 of theory) 10-chloro-6,7-dihydro-5H, 13H-quinazolino [3, 2-a], [1,4] benzodiazepine-5,13-dioz. Melting point: 290-292 ° C (from dimethylformamide).

Example 4

Analogously to Example 1 a), 18 g (0.05 Mcl) of 2-chloromethyl-3- (2-methoxycarbonyl-5-chlorophenyl) -4H-quinazolin-4-one (melting point: 151-152 ° C.) are obtained Ethanol) and 50 ml of liquid ammonia in 150 ml of ethylene glycol monomethyl ether in 5 hours at 80 ° C 9.5 g (61% of theory) 2-chloro-6,7-dihydro-5H-13H-quinazolino [3,2- a] [1,4] benzodiazepine-5,13-dione. Melting point: 330-333 ° C (from dimethylformamide).

Example 5

Analogously to Example 1 a), 13-g (0.05 mol) of 2-chloromethyl-3- (2-methoxycarbonyl-4-chlorophenyl) -4H-quinazolin-4-one is obtained (melting point: 135-136 ° C. from toluene) and 50 ml of liquid ammonia in 150 ml of ethylene glycol monomethyl ether in 5 hours at 80 ° C 13 g (84 of theory) 3-chloro-6,7-dihydro-5H, 13H-quinazolino [3,2-a] [1,4] benzodiazepine-5,13-dione. Melting point 294-296 ° C (from dimethylformamide)

Example E

16.4 g (0.05 mol) of 2-chloromethyl-3- (2-methoxycarbonyl-phenyl) -4H-quinazolin-4-one and 10 ml of liquid methylamine in 100 ml of ethylene glycol monomethyl ether are in an autoclave at 40 ° C for 2 hours heated. After cooling, the colorless crystals are filtered off and washed several times with ethanol. 12 g (82.3 g of theory) of 6-methyl-6,7-dihydro-5H, 13H-quinazolino [3,2-a] [1,4] benzodiazepine-5,13-dione are obtained. Melting point: 204-206 ° C (from ethanol).

Example 7

Analogously to Example 6, 32.9 g (0.1 mol) of 2-chloromethyl-3- (2-methoxycarbonyl-phenyl) -4H-quinazolin-4-one and 75 ml of n-butylamine in 200 ml of ethylene glycol monomethyl ether are obtained in 5 hours at 120 ° C 7 g (21% of theory) 6-n-butyl-6,7-dihydro-5H, 13H-quinazolino [3,2-a] [1,4] benzodiazepine-5,13-dione . Melting point: 125-127 ° C (from ethanol).

Example 8

16.4 g (0.05 mol) of 2-chloromethyl-3- (2-methoxycarbonylphenyl) -4H-quinazolin-4-one and 12.8 g (0.11 mol) of 1-amino-2-dimethylamino- ethane in 100 ml of ethylene glycol monomethyl ether are heated to 120 ° C for 5 hours. The solvent is evaporated off on a Rotavapor and the oil residue is mixed with 50 ml of ethanol. A clear solution is formed and after a short time, colorless crystals separate out. Sucking off and washing with ethanol and water gives 12.4 g (66% of theory) of analytically pure 6-diethylaminoethyl-6,7-dihydro-5H, 13H-quinazolino [3,2-a] [1,4] benzodiazepine 5,13-dione. Melting point: 117-119 ° C.

Example 9

16.4 g (0.05 mol) of 2-chloromethyl-3- (2-methoxycarbonyl-phenyl) -4H-quinazolin-4-one and 14.3 g (0.11 mol) of 1-amino-3-diethylamino-propane in 100 ml Äthylenqlykolmonomethyläther are heated to 120 ° C for 5 hours. The solvent is evaporated off on a Rotavapor and the oil residue is mixed with 50 ml of water and 100 ml of chloroform. After the chloroform phase has been separated off in a separating funnel, it is shaken with water, dilute sodium hydroxide solution and again with water, dried over sodium sulfate and the chloroform is evaporated off on a rotavapor. The oil residue is dissolved in ethanol and hydrogen chloride is introduced until it is saturated. 6-Diethylaminopropyl-6,7-dihydro-5H, 13H-quinazolino [3,2-a] [1,4] benzodiazepine-5,13-dione hydrochloride (15.1 g, 71% of theory ). Melting point: 237-238 ⁰ C.

Example 10

Analogously to Example 1 a), 30 g (0.091 mol) of 2-chloromethyl-3- (2-methoxycarbonyl-phenyl) -4H-quinazolin-4-one and 50 ml of benzylamine in 200 ml of ethylene glycol monomethyl ether are obtained in 5 hours at 120 ° C. 29.5 g (88% of theory) 6-benzyl-6,7-dihydro-5H, 13H-quinazolino [3,2-a) [1,4] benzodiazepine-5,13-dione. Melting point: 171-173 ° C.

Example 11

16.4 g (0.05 mol) of 2-chloromethyl-3- (2-methoxycarbonyl-phenyl) -4H-quinazolin-4-one and 12.1 g (0.1 mol) of 2-phenylethylamine are dissolved in 100 ml of ethylene glycol monomethyl ether . Heated to 100 ° C for 5 hours. The solvent is evaporated off on a Rotavapor and 100 ml of water are added to the semi-solid residue. The colorless crystals are filtered off and washed with hot methanol. 5.8 g (30.5% of theory) of 6- (2-phenylethyl) -6,7-dihydro-5H, 13H-quinazolino [3,2-a] [1,4) benzodiazepine-5,13 are obtained -dion. Melting point: 208-210 ° C.

Example 12

16.4 g (0.05 mol) of 2-chloromethyl-3- (2-methoxycarbonyl-phenyl) -4H-quinazolin-4-one and 12 g (0.11 mol) of 2-aminomethylpyridine in 100 ml of ethylene glycol monomethyl ether are used for 5 hours heated to 120 ° C. The solvent is evaporated off on a rotavapor and the solid residue is recrystallized from methanol. After suction filtration, it is washed with methanol and water, 10 g (54.5% of theory) of 6- (pyridyl- (2) -methyl) -6,7-dihydro-5H, 13H-quinazolino [3,2-a ] [1,4] benzodiazepine-5,13-dione can be obtained. Melting point: 202-2 ₀ 3 ° _C.

Example 13

8 g (0.029 mol) of the reaction product from Example 1 are heated in 30 ml of diethyl pyrocarbonate at 120 ° C. for 15 minutes, while the ethanol that forms is continuously distilled off via a descending condenser. You evaporate ethanol and excess diethyl pyrocarbonate on a Rotavapor and add another 50 ml of ethanol to the oil residue. Colorless crystals form which are washed with ethanol after suction. 6.4 g (63.5% of theory) of 6-ethoxycarbonyl-6,7-dihydro-5H, 13H-quinazolino [3,2-a] [1,4] benzodiazepine-5,13-dione are obtained. Melting point: 185-187 ° C.

Example 14

Analogously to Example 1 a), 0.05 mol of 2-chloromethyl-3- (2-methoxycarbonylphenyl) -8-methyl-4H-quinazolin-4-one (mp. 206-208 °) and 50 ml of liquid ammonia are obtained in 150 ml Äthylenglykoldiäthyläther in 3 hours at 60 ⁰ 76% d. Th. 9-Methyl-A. *) Mp 273-274 ° (from n-butanol).

*) The abbreviation A used in most examples is: 6,7-dihydro-5H, 13H-quinazolino 3,2-a 1,4 benzodiazepine-5,13-dione Example 15

Analogously to Example 1 a), 0.05 mol of 2-chloromethyl-3- (2-methoxycarbonyl-phenyl) -8-methoxy-4H-quinazolin-4-one (mp. 208-210 °) and 50 ml of liquid ammonia are obtained in 150 ml of n-butanol in 3 hours at 60 ° 52% of theory ., Th 9-methoxy-A * mp 290 -. 292 ⁰ (n-butanol).

Example 16

Analogously to Example 1 a), 0.135 mol of 2-chloromethyl-3- (2-methoxycarbonyl-phenyl) -6-fluoro-4H-quinazolin-4-one (mp. 213-215 °) in 400 ml of ethylene glycol and 140 ml liquid ammonia in 3 hours at 60 ° 85% d. Th. 11-Fluor-A. Mp 275 - 277 ° (from ethylene glycol monomethyl ether).

Example 17

Analogously to Example 1 a), 0.05 mol of 2-chloromethyl-3- (2-methoxycarbonylphenyl) -6-bromo-4H-quinazolin-4-one (mp. 235-237 °) and 50 ml of liquid ammonia are obtained in 150 ml pyridine in 5 hours at 60 ° 88% of theory Th. 11-bromo-A. 300 - 303 °.

Example 18

Analogously to Example 1 a), 0.025 mol of 2-chloromethyl-3- (2-methoxycarbonylphenyl) -8-chloro-4H-quinazolin-4-one (mp. 205-208 °) and 20 ml of liquid ammonia in 50 ml of ethylene glycol monoethyl ether in 3 hours at 50 ⁰ 71% d. Th. 9-chloro-A. Mp 255-258 °.

Example 19

Analogously to Example 1 a), 0.05 mol of 2-chloromethyl-3- (2-methoxycarbonylphenyl) -5-chloro-4H-quinazolin-4-one (mp. 177 ° -178 °) and 50 ml of liquid ammonia are obtained in 150 ml of ethylene glycol dimethyl ether in 3 hours at 60 ° 60% of theory Th. 12-chloro-A. Mp 308-310 ° (from dimethylformamide).

Example 20

Analogously to Example 1 a) are obtained from 0.05 mole of 2-chloromethyl-3- (2-methoxycarbonyl-phenyl) -6-trifluoromethyl-4H-quinazolin-4-one (m.p. 169 -. 170 ⁰⁾ and 50 ml of liquid ammonia in 150 ml dioxane in 3 hours at 50 ° 36 th. 11-trifluoromethyl-A. Mp 190-192 ° (from toluene).

Example 21

Analogously to Example 1 a) are obtained from 0.05 mole of 2-chloromethyl-3- (2-methoxycarbonyl-5-nitro-phenyl) -4H-quinazolin-4-one (mp 158 -. 159 ⁰⁾ and 50 ml of liquid ammonia in 150 ml of o-dichlorobenzene in 3 hours at 60 ° 35% of theory Th. 2-nitro-A. Mp 276 - 277 ° dec. (from glacial acetic acid).

Example 22

Analogously to Example 8, 0.05 mol of 2-methoxymethyl-3- (2-methoxycarbonyl-phenyl) -4H-quinasolin-4-one (mp. 134-137 °, prepared from 2-bromomethyl-3- (2- methoxycarbonyl-phenyl) -4H-quinazolin-4-one and methanol analogous to J. Med. Chem. 20, 379 (1977)) and 20 ml 2-methoxyethylamine in 100 ml xthanol in 3 hours at 50 ° 40% of theory 6-Methoxyethyl-A.Schmp. 127 - 130 ° (from ethanol).

Example 23

Analogously to Example 9, 0.05 mol of 2-chloromethyl-3- (2-ethoxycarbonyl-phenyl) -4H-quinazolin-4-one and 10 g of 3-dimethylaminopropylamine in 100 ml of ethylene glycol monoethyl ether are obtained in 5 hours at 120 ° 67% of theory . Th. 6-Dimethylaminopropyl-A-dihydrochloride. Mp 198 - 200 ° (from ethanol).

Example 24

Analogously to Example 9, 0.05 mol of 2-chloromethyl-3- (2-ethoxycarbonyl-phenyl) -4H-quinazolin-4-one and 17 g of N- _A minopropyl-4-methyl-1,2,5,6 are obtained -tetrahydro-pyridine in 100 ml tetralin in 5 hours at 120 ⁰ 45% d. T. 6- (4-methyl-1,2,4,6-tetrahydro-pyridino-propyl) -A-dihydrochloride. Mp 112-115 ° (from ethanol).

Example 25

Analogously to Example 13, from 0.05 mol of the reaction product from Example 5 and 60 ml of pyrocarbonate in 20 minutes at 120-130 ⁰ 80% d. Th. 6-Athoxycarbonyl-3-chloro-A. M.p. 189-191 ⁰ (also ethanol).

Example 26

Analogously to Example 13, from 0.015 mol of the reaction product from Example 2 and 20 ml of ethyl pyrocarbonate, 94% d, Th. 6-ethoxycarbonyl-11-chloro-A in 30 minutes at 130-135 °. _S chmp. 258 - 260 ° (from ethanol).

Example 27

0.05 mol of the reaction product from Example 1 are heated in 1 ₀₀ ml of acetic anhydride and 10 ml pyridine 8 hours to 120 °. After cooling, the clear solution is poured onto water and the precipitated crystals are suctioned off. You get 44% of theory. Th. 6-acetyl-A. Mp 189-191 ° (from ethanol).

Example 28

Analogously to Example 1 a), 0.03 mol of 2-chloromethyl-3- (2-methoxycarbonyl-5-chlorophenyl) -4H-quinazolin-4-one. And 25 ml of isopropylamine (65% solution in water) are obtained. in 100 ml isopropanol in 3 hours at 50 ⁰ 48% of theory 2-chloro-6-isopropyl-A. (Mp 193 - 195 ° (from ethanol).

Example 29

Analogously to Example 1a), 0.03 mol of 2-chloromethyl-3- (2-methoxycarbonyl-5-chlorophenyl) -4H-quinazolin-4-one and 15 ml of allylamine in 100 ml of toluene are obtained in 3 hours at 50 ° 89% of theory 6-allyl-2-chloro-A. 155-157 °.

Example 30

Analogously to Example 8, 0.035 mol of 2-chloromethyl-3- (2-methoxycarbonyl-phenyl) -8-methoxy-4H-quinazolin-4-one and 15 ml of ethanolamine in 100 ml of propylene glycol are obtained in 5 hours at 80 ° 80.5 % d. _T h. 6-hydroxyethyl-9-methoxy-A. Mp 233-235 °.

Example 31

Analogously to Example 8, 0.035 mol of 2-chloromethyl-3- (2-methoxycarbonyl-phenyl) -8-methoxy-4H-quinazolin-4-one and 15 ml of cyanoethylamine in 100 ml of ethanol are obtained in 5 hours at 80 ° 51% of theory .Th. 6-cyanoethyl-9-methoxy-A. Mp 198-200 ° (from ethanol).

Example 32

Analogously to Example 8, 0.03 mol of 2-chloromethyl-3- (2-methoxycarbonyl-phenyl) -8-methyl-4H-quinazolin-4-one and 15 ml of 2-norbornylamine in 100 ml of ethylene glycol monomethyl ether are obtained in 5 hours at 80 ° 62% of theory 6-norbornyl- (2) -9-methyl-A. M.p. 168-169 ⁰ (from methanol).

Example 33

Analogously to Example 8, 0.03 mol of 2-chloromethyl-3- (2-methoxycarbonyl-phenyl) -8-methyl-4H-quinazolin-4-one and 0.07 mol of 1-aminoadamantane in 100 ml of ethylene glycol monoethyl are obtained ether in 5 hours at 125-130 ° 90% of theory 6-Adamantyl- (1 9-methyl-A. Mp 204-206 °.

Example 34

Analogously to Example 8, 0.03 mol of 2-chloromethyl-3- (2-methoxycarbonyl-phenyl) -8-methyl-4H-quinazolin-4-one and 15 ml of n-hexylamine in 100 ml of n-butanol are obtained in 5 hours at 80 ° 88.5% of theory 6-hexyl-9-methyl-A. 138-139 °.

Example 35

Analogously to Example 8 from 0.05 _M ol 2-chloromethyl-3- (2-methoxycarbonyl-phenyl) -6-bromo-4H-quinazolin-4-one and 20 ml of cyclohexylamine in 100 ml of ethylene glycol in 5 hours at 125 ° 43% of theory 11-bromo-6-cyclohexyl-A. Mp 276-279 °.

Example 36

0.06 mol of the reaction product from Example 21 are hydrogenated in 150 ml of dimethylformamide in the presence of 5 g of Raney nickel at 60 °. After filtering off the catalyst, the solution is evaporated (Rotavapor) and the residue is extracted hot with ethylene glycol monomethyl ether. On cooling, pure 2-amino-A crystallizes out. Yield 50% of theory, mp> 340 °.

Example 37

0.015 mol of the reaction product from Example 36 are heated in 80 ml of ethanol with 10 g of pyrocarbonate for 12 hours at 80 °. After cooling, suction and washing with ethanol, 89% of theory are obtained. 2-ethoxycarbonylamino-A. Mp 335 ⁰ dec.

Claims (6)

1) 6,7-dihydro-5H, 13H-quinazolino [3,2-a] [1,4] benzodiazepine-5,13-diones of the general formula (I)

in which R and R ⁵ for 1, 2, 3 or 4 substituents from the group hydrogen, alkyl, hydroxy, acyloxy, alkoxy, nitro, amino, alkylamino, dialkylamino, acylamino, acylalkylamino, alkoxycarbonylamino, halogen, trifluoromethyl, cyan, carboxy, alkoxycarbonyl, Aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylaminocarbonylamino and dialkylaminocarbonylamino, R represents hydrogen, optionally substituted alkyl, aralkyl, aryl or heterocycloalkyl, acyl or alkoxycarbonyl and R ³ and R ^{4 represent} identical or different substituents from the group hydrogen, optionally substituted alkyl, optionally substituted aralkyl in the aryl part, optionally substituted aryl or heteroaryl,
as well as their pharmacologically acceptable salts with inorganic or organic acids. 2) Process for the preparation of 6,7-dihydro-5H, 13H-quinazolino [3,2-a,] [1,4] benzodiazepine-5,13-diones of the general formula (I), characterized in that 2 -Alkyl-3-aryl-4H-quinazolin-4-ones of the general formula (II)

in which _R ³ and _R ^{4 have} the meaning given above, _R ¹ and R ⁵ for 1, 2, 3 or 4 substituents from the group hydrogen, alkyl, hydroxy, acyloxy, alkoxy, nitro, dialkylamino, acylamino, acylalkylamino, alkoxycarbonylamino, halogen, trifluoromethyl, cyano, alkoxycarbonyl, dialkylaminocarbonyl) aminosulfonyl, alkylaminosulfonyl , Dialkylaminosulfonyl and dialkylaminocarbonylamino, R ^{6 represents} hydrogen, alkyl, aralkyl or aryl and X represents an easily nucleophilically substitutable leaving group such as halogen or alkylsulfo, aralkylsulfo or arylsulfo,
with ammonia or primary amines of the general formula (III)

in which R represents optionally substituted alkyl, aralkyl, heterocycloalkyl or aryl,
or with their salts with inorganic or organic acids or bases in the presence of inert organic solubilizers and optionally in the presence of acid binders at temperatures between 20 and 250 ° C. and optionally subsequently in a manner known per se in a further reaction step, nitro groups or acylamino groups as substituents R ¹ and / or R ⁵ in amino groups or Acylalkylamino groups in alkylamino groups or Alkoxycarbonyl groups in carboxy groups or Alkoxycarbonyl groups and / or cyano groups in aminocarbonyl or alkylaminocarbonyl groups or Amino groups converted into alkylaminocarbonylamino groups, or in the case of reaction with ammonia (R ² = hydrogen), the NH group is subsequently acylated with carboxylic acid, sulfonic acid or carbonic acid ester chlorides or with carboxylic acid anhydrides or with pyrocarbonates. 3) Compounds according to formula (I) in claim 1, in which the substituents _R ¹ and _R ^{5 are the} same or different and each represents 1 or 2 substituents from the group hydrogen, halogen, nitro, cyano, trifluoromethyl, amino, alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms, R ^{2 represents} hydrogen, alkyl having 1 to 6 carbon atoms, where the alkyl group can optionally be substituted by phenyl, pyridyl, halogen, alkoxy or dialkylamino and the alkyl and alkoxy substituents contain 1 to 4 carbon atoms, or an alkoxycarbonyl group having 1 to 4 Carbon atoms in the alkoxy radical, stands and R ³ and R ^{4 are the} same or different and are hydrogen, alkyl having 1 to 4 carbon atoms. or phenyl. 4) Medicament containing compounds according to claim 1. 5) Process for the preparation of medicaments, characterized in that at least one 6,7-dihydro-5H, 13H-quinazolino [3,2-a] [1,4] benzodazepine-5,13-dione according to claim 1 with conventional Auxiliaries and carriers mixed. 6) Use of 6,7-dihydro-5H, 13H-quinazolino [3,2-a] [1,4] benzodiazepine-5,13-diones according to claim 1 for the treatment of the central nervous system.