DE2221506A1 - PROCESS FOR THE PRODUCTION OF 4-PHENYL AND 4- (2'-THIENYL) -6,7-METHYLENDIOXY-2 (LH-QUINAZOLINONES OR -3,4-DIHYDRO-2 (LH) QUINAZOLINONES OR -2 (LH) -QUINAZOLINTHIONES OR -3,4-DIHYDRO- 2 (LH) -CHINAZOLINONS - Google Patents

Description

SANDOZ AG.

Basel ' Case 600-6333 / F

Pafehfanwlte

Diph-Fng. P. WirA

Dr.V.Schmic-d-ifcv / crzik

DipUng. G. Dcrcc-r.bsrg

Pr. P. WeinhoU, Dr. P. Gudel

Bfrankfuri / M., Gr. Eschenheiinec S6.-3 &

A process for preparing o n v ~ 4-phenyl or 4- (2'-ThienylVe _y 7-methylenedioxy-2 (IH) -chinazolinonen or -3-f 4 d ihydr o-2 (IH) -chinazolinonen and -2 (IH) -quinazolinethiones or -3,4-aihydro-2 (IH) -quinazolinethiones

The invention relates to a method of manufacture of 4-phenyl- or 4- (2'-thieny £ h6,7-methylenedioxy-2 (IH) quinazolinones or -3,4-dihydro-2 (IH) -quinazolinones or -2 (IH) -quinazolinethiones or -3,4-dihydro-2 (IH) quinazolinethiones of formula I,

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where X is oxygen or sulfur, R is alkyl with -1-5 carbon atoms, cycloalkyl with 3-6 Carbon atoms or cycloalkylalkyl with a total of 4-7 carbon atoms, the cycloalkyl Has 3-6 carbon atoms and the alkyl is straight chain and contains 1-3 carbon atoms, and χ y stands for a group C = N or CH-NH, in 1 Ί

which either R, a phenyl radical of the formula II

Z Z,

II

denotes in which Z and Z are identical or different and denote hydrogen, fluorine, chlorine, alkyl or alkoxy with 1-3 carbon atoms each, nitro or trifluoromethyl, but denotes at most one of the substituents Z and Z, trifluoromethyl or nitro, or in which Z and Z. are on adjacent carbon atoms and together represent methylenedioxy, or in which R _{1 is} a thienyl radical of the formula III

III

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means in which Z_ hydrogen, fluorine, chlorine or Alkyl of 1-3 carbon atoms.

Of the compounds of the above formula I are those of the formula In

In

Av Jl k

new, in which χ y has the above meaning and R 'and X ^{1 have} the same meaning as R and X, with the exception that X ^{1 is} sulfur if R ^{1 is} alkyl with 1-5 carbon atoms.

The inventive method for the preparation of compounds of the formula I is characterized in that one

a) for the preparation of 4-phenyl- or 4- (2'-thienyl) -6,7-methylenedioxy-2 (IH) -quinazolinones or -2 (IH) quinazolinethiones of the formula Ia.

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wherein R, R. and X have the above meanings, 2-amino-4,5-methylenedioxy-benzophenonimines or 2-amino-4,5-methylenedioxy- (2'-thenoylimine) of the formula IV,

IV

where R and R have the above meaning, with phosgene or Thiophosgene of formula V,

Cl-C-Cl

Jj ^ ^{C ± 1} V

wherein X has the above meaning, cyclizes, or

) for the production of 4-phenyl-'bzw. 4- (2'-thienyl) -6,7-methylenedioxy-2 (IH) -quinazolinones of formula Ib,

Ib

where R. has the above meaning and R ¹ 'has the same meaning as R, with the exception that it is not for tert. Alkyl can stand in which the tert. Carbon atom is bonded directly to the ring nitrogen atom, 2-amino-4,5-methylenedioxy-benzophenonimine or 2-amino-4,5-methylenedioxy- (2'-thenoylimine) of the formula IVa,

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y \

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. ■ χ

wherein R ¹ 'and R _{T have the} above meaning / with

1) ^c -i_2 alky! Chlorocarbonates,

2j CL "alkyl carbamates at temperatures of at least 14O ° C, or

3) Ι, Ι'-carbonyldiimidazoles
cyclized, or

c) for the preparation of 4-phenyl- or 4- (2'-thienyl) -6,7-methylenedioxy-2 (IH) -quinazolinones the formula Ib, 2-amino-4,5-methylenedioxy-benzophenone or 2-Amino-4,5-methylenedioxy- (2'-thenoyle) of the formula VIa,

■ VIa

wherein R ¹ 'and R _{1 have the} above meaning, with

1) ^c i_5 alkyl carbamates at temperatures of at least 14O ° C and in the presence of a catalytic amount of Lewis acid,

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Urea or -r- 6OO-6333 / P Carbamy chloride 222 2) 3)

reacts at elevated temperature, or

d) for the preparation of 4-phenyl- or 4- (2'-thienyl) -6,7-methylenedioxy-2 (IH) -quinazolinones or -2 (IH) -quinazolinethiones of the formula Ia already mentioned, 2-amino-4,5-methylenedioxy-benzophenone or 2-amino-4,5-methylenedioxy- (2'-thenoyle) of formula VI,

VI.

^R l

wherein R and R have the above meaning, with isocyanic acid or isothiocyanic acid of the formula VIII,

HN = C = X VIII _;

wherein X has the above meaning, cyclizes, or

e) for the preparation of 4-phenyl- or 4- (2'-thienyl) -6,7-methylenedioxy-3,4-dihydro-2 (IH) -quinazolinones or -2 (IH) -quinazolinethiones of the formula Ic,

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Ic

where R, R ₁ and X have the above meanings, 2- (N-carbamoylamino) - or 2- (N-thiocarbamoylamino) -4,? - iaethylendioxy-benzhydroles or - (2'-thenoylhydroles)

the formula

IX

wherein R, R, and X have the above meanings, by dehydration cyclized, or

f) for the preparation of 4-phenyl- or 4- (2'-thienyl) -6,7-methylenedioxy-3,4-dihydro-2 (IH) -quinazolinen or -2 (IH) -quinazolinethiones of the formula Id,

Id

where R and R have the above meaning and R 'has the same meaning as R, but not phenyl substituted by nitro, 6,7-methylenedioxy-2 (IH) -quinazolinone or 6 _? 7-methylenedioxy-2 (IH) quinazolinediones of the formula X,

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wherein R and X have the above meaning, with lithium phenylene or phenyl magnesium halides or .mit Lithium thienylene or thienyl magnesium halides of the formula XI,

XI

where R 'has the above meaning and Q is lithium or a radical -MgY ¹ ', in which Y ¹ 'is chlorine or bromine, is reacted in the presence of an inert organic solvent and the reaction product is hydrolyzed, or

g) for the preparation of 4-phenyl- or 4- (2'-thienyl) -6,7-methylenedioxy-3,4-dihydro-2 (IH) -quinazolinones or -2 (IH) -quinazolinethiones of the formula Ic already mentioned, 4-phenyl- or 4- (2'-thienyl) -6,7-methylenedioxy-2 (IH) -quinazolinones or -2 (IH) -quinazolinthione of the formula Ia already mentioned, or

h) for the preparation of 4-phenyl- or 4- (2'-thienyl) -6,7-methylenedioxy-2 (IiI) -quinazolinones or -2 (IH) -quinazolinethiones of the formula Ie,

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2121S0S

h ■

Wherein R ' ¹ , R. and X have the above meaning, l-Mkali-4-

> or l ^ alkali ^ 4-i2 ^l -thienyl) -6 _/ 7-m quinazolinone or -2 (iHj-fehinäzölinthionfe of the formula XII,

r - ■ .- ■ ■■ .- ■ ■■ ·

wherein R and X have the above meaning and M ^{1 is} alkali, with halides of the formula XIII,

R "-Y ¹ XIiI

wherein R ^{11 has the} above meaning and Y 'is chlorine, bromine or iodine, is reacted in the presence of an inert organic solvent, or

i) for the production of 1-Methy1-4-phenyl- or »l-methyl-4- (2 '· thiehyl} -6,7-methylenedioxy-2 (iH) -ehirtazoliiionen der Formei

If

vjoriu Ej has the above meaning, IHi-Ie.thyl-4-phenyl.- bzv ;.

2 [ι :) «-B 2 / \ I ¹ J P:

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l-methyl-4- (2'-thienyl) -6,7-methylenedioxy-1,2-dihydro * - quinazolinium halosenide of the formula XlV,

/ S ^ ir ί ·. XiY

wherein R 'and Y ^{1 have the} above meaning, or

1-methyl-4-phenyl- or 1-methyl-4- (2 -thienyl) -6,7-methylenedioxy-1,2,3,4-tetrahydroquinazolines formula XV,

wherein R ^{1 has the} above meaning, oxidizes, or

j) for the preparation of 4-phenyl- or 4- (2'-thienyl) -6,7-methyiendioxy-2 (III) quinasolinones of the formula Ib, 2- (Π -riihaloacetylamino) -4, '5 -methyLunctioxy-bunEöphenone b?; w _t - (2'- thenoyle) of the formula XVI,

R "OY
I /

^k C = 0

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in which R. and R ¹ 'have the above meanings and Y is fluorine, chlorine or bromine, reacts with ammonia, or

k) for the preparation of 4-phenyl- or 4- (2'-thienyl) -6,7-methylenedioxy-2 (IH) -quinazolinones of the formula Ig,

Ig

wherein R and R have the above meaning, 4-phenyl- or • 4- (2'-thienyl) -6,7-methylenedioxy-2 (IH) -quinazolinethxones of the formula Ih, _p

You

wherein R and R _{1 have the} above meaning, hydrolyzed at temperatures between 10 and 150 ° C, or

1) for the preparation of 4-phenyl- or 4- (2'-thienyl) -6,7-methylenedioxy-2 (IH) -quinazolinones of the formula Ig, 4-phenyl- or 4- (2'-thienyl) -6,7-methylenedioxy-3,4-dihydro-2 (IH) -quinazolinthxone of formula Ii,

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wherein R and R have the above meaning, oxidized, or

m) for the preparation of 4-phenyl- or 4- (2'-thienyl) -6,7-methylenedioxy-2 (IH) -quinazolinones or -2 (IH) -quinazolinethiones of the formula Ij,

R ¹ -. .

wherein R ¹ , R. and X ^{1 have the} above meanings, 4-phenyl- or 4- (2'-thienyl) -6,7-methylenedioxy-3,4-dihydro-2 (IH) -quinazolinones or -2 (IH) -chinazolinthione of the formula Ik,

in which R ¹ , R and X ^{1 have the} above meanings, oxidized in an inert organic solvent, operating under practically anhydrous conditions if the compound of the formula Ik is a thione, or

n). for the preparation of 4-phenyl- or 4- (2'-thienyl) -6,7-methylenedioxy-3,4-dihydro-2 (IH) -quinazolinones or -2 (IH) -quinazolinethiones of the formula Ik, 3,4-methylenedioxyphenyl ureas or

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3,4-methylenedioxyphenyl thioureas of the formula XVII,

XVII

wherein R ¹ and X ^{1 have the} above meaning, with aldehydes of the formula XVIII,

R-CHO XVIII

wherein R- has the above meaning at elevated temperature under practically anhydrous conditions and cyclized in the presence of an acid catalyst, or

o) for the preparation of 4-phenyl- or 4- (2'-thienyl) -6,7-methylenedioxy-2 (IH) -quinazolinethionene Formula Ih already mentioned, 4-phenyl- or 4- (2'-thienyl) -6,7-methylenedioxy-2 (IH) -quinazolinone of the aforementioned formula Ig with phosphorus pentasulfide at elevated temperature and in the presence of an inert organic solvent converts, or

p) for the preparation of 4-phenyl- or 4- (2'-thienyl) -6,7-methylenedioxy-3,4-dihydro-2 (IH) -quinazolinethiones of the formula Ii already mentioned, 2-amino-4,5-methylenedioxy-benzohydroles or -U'-thienylhydroles) of the formula XIX,

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XIX

wherein R and R, have the above meaning, with isothiocyanic acid cyclized, or

q) for the preparation of 4-phenyl- or 4- (2'-thienyl) -6,7-methylenedioxy-2 (IH) -quinazolinones of the formula Ig, N - [(3,4-methylenedioxy-6-benzoyl ) phenyl] N ¹ -acy! ureas or N- [3,4-methylenedioxy-6-thenoyl) r phenyl] -N'-acy! ureas of the formula XXXIII,

XXXIII

wherein R and R, have the above meaning and R is one Acid residue of an acid chloride or acid bromide of Formula XXXIV

R COY ¹

XXXIV

corresponds, in which Y ^{11 has the} above meaning, hydrolyzed under alkaline conditions.

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Process a) is expediently carried out at temperatures between 0 ° and 50 ° C., preferably 10 ° and 30 ° C. The reaction can be carried out in an inert organic solvent, conveniently an aromatic hydrocarbon such as toluene, xylene or, preferably, benzuene. The 'molar ratio from compounds of formula V to compounds of formula IV is not particularly critical, one used but preferably a fair excess of

bonds of the formula V. The process can optionally be carried out in the presence of an acid binder, for example an inorganic Ease, such as sodium or potassium carbonate, or a tert. Amine, such as trialkylamine or pyridine, with triethylamine being preferred.

In the process b) i), are wherein compounds of the formula IVa with methyl chlorocarbonate or Aethylchlorcarbonat, preferably with Aethylchlorcarbonat reacted, is conveniently carried out at temperatures between 30 ° and 150 ⁰ C, preferably 60 ° and 100 ⁰ C. The reaction can in In the presence of an inert organic solvent, conveniently an aromatic hydrocarbon such as toluene, xylene or preferably benzene. Another suitable solvent is pioxane. The molar ratio of the chlorocarbonate to the compound of the formula IVa is not critical, but the reaction is preferably carried out using a substantial excess of chlorocarbonate.

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The reaction time can be 0.5 to 10 hours, and it is conveniently 1-4 hours. The cyclization with the chlorocarbonate can optionally be carried out in The presence of an acid binder can be made, for example an inorganic base such as sodium carbonate or potassium carbonate, or a tert. Amine, such as trialkylamine or pyridine, with triethylamine is preferred.

The process b) 2) is expediently carried out at temperatures between 140 ° and 200 ⁰ C, preferably at 160 ° to 180 ° C. The molar ratio of alkyl carbamate, preferably urethane, to the compound of formula IVa is not critical. According to a preferred procedure, a considerable excess of carbamate is used, which at the same time serves as the preferred solvent for the reaction. Other high-boiling inert organic solvents can optionally or additionally also be used. The reaction time is, for example, 0.5 to 10 hours and it is expediently between 1 and 4 hours. The cyclization with the carbamate is optionally and preferably carried out in the presence of a Lewis acid as reaction catalyst. The amount of Lewis acid used is preferably between 5 and 20%, based on the amount by weight of compounds of the formula IVa present in the reaction mixture. Zinc chloride is preferred as the catalyst.

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Process b) 3) is expediently carried out at temperatures between 20.degree. And 120.degree. C., preferably 60 ° and 90 ° C. The reaction is preferably carried out in an inert organic solvent, conveniently an aromatic hydrocarbon, such as Toluene, xylene or especially benzene. An excess of 1,1 'carbonyldiimidazole is preferably used,

In the case of process c) i), it is expedient to work with Temperatures between 140 ° and 200 ° C. The preferred Lewis acid is zinc chloride and is used as the carbamate one preferably uses ethyl carbamate. If desired, can you can also work in the presence of an inert organic solvent, for example o-dichlorobenzene, what however, this is not absolutely necessary, since an excess of carbamate can also be used for this purpose. can. Depending on the particular reaction conditions, a suitable reaction time is between about 30 minutes and about 4 hours.

The process c) 2) is a known implementation and can, for example, analogously to that in the the operation described in Japanese Patent Publication No. 3097/67. The procedure will expediently carried out at temperatures between 140 ° and 220 ° C, preferably 180 ° and 20 ° C, as well as in the absence of additional solvent ..

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Optionally and preferably, the process can be carried out in the presence of a carboxylic acid having 2-4 carbon atoms and using at least 3 moles of urea per mole of compound of the formula VIa. The molar ratio of urea to the compound of the formula VIa is expediently between 3: 1 and 20: 1, preferably between 4: 1 and 15: 1, and in particular between 5: 1 and 10: 1. It is expedient to use acetic acid or propionic acid, preferably glacial acetic acid, namely about 2 moles, preferably 4 to 12 moles, of acid per mole of urea. In this manner, one can at temperatures between 80 ° and 160 ⁰ C working, preferably between 100 ° and 130 ° C, and especially at the reflux temperature of the reaction mixture. Other reactants, such as p-toluenesulfonic acid, can also expediently be added to the reaction mixture. The process is best continued until the total amount of compounds of the formula VIa has been consumed, which can be determined, for example, by thin layer chromatography. The reaction time can be, for example, between 1 and 20 hours. \

Process c) 3) can be carried out in a manner similar to that described for process c) 2) first embodiment.

In process d) one works expediently at temperatures between 50 ° and 150 ° C, preferably

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100 ° and 14O ° C. Since the compounds of Formula VIII are known to be unstable, they do best made in situ. For this purpose, the process can be carried out in an acidic medium using a Perform salt of formula VII. The connection of the. Formula VII is preferably an alkali salt such as sodium or Potassium salt, or especially the ammonium salt. As an acid for. in situ formation of the desired isocyanic acid from the compound of the formula VII, a lower carboxylic acid is preferably used, expediently acetic acid, which can also be used as a solvent for the reaction.

Process e) is preferably carried out at elevated temperatures and under acidic conditions. Suitable temperatures are, for example, between 80 and 150 ⁰ C, preferably 95 ° and 120 ⁰ C. For the elimination of water are used suitably a strong inorganic acid such as sulfuric or hydrochloric acid, or an organic acid such as acetic acid, which is preferred. The reaction can be carried out in water as the sole reaction medium, although numerous other solvents can also be used, such as ethanol, if this is desired or necessary for optimum "solubility".

Process e) is a method known per se and is described, for example, in J.Chem.Soc. 1959 , 3555.

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The process f) is conveniently carried out at temperatures between -40 ° and + 5O ⁰ C, preferably +15 ⁰ C and +35 ⁰ C, and especially at room temperature (20 ⁰ C). The inert organic solvent used is preferably an organic acyclic or cyclic ether, such as diethyl ether, dimethoxyethane, tetrahydrofuran or dioxane, or a mixture of these ethers, and in particular an acyclic ether, such as tetrahydrofuran. The molar ratio of compounds of formula XI to compounds of formula X is not particularly critical. According to a preferred procedure, an excess of magnesium halide or lithium compound is used, so that a molar ratio between about 3: 1 and 30: 1, in particular between 5: 1 and 20: 1, results. Lithium compounds are preferred as compounds of the formula XI. The reaction time can be, for example, 15 minutes to 5 hours. The reaction is expediently carried out under anhydrous conditions, which is then followed by a hydrolysis known per se. The hydrolysis can be carried out, for example, by adding water to the reaction mixture.

The above procedure is particularly interesting as it is good practice. Yield compounds of the Formula Id can produce although an on or thione function is present in the starting compounds of the formula X. is, with which one normally under the applied working conditions a reaction of the arylmagnesium

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halide or the aryl lithium compound of the formula XI would expect.

The reduction in process g) can be carried out, for example, with a borohydride, preferably an alkali borohydride, such as sodium borohydride, with lithium aluminum hydride or by hydrogenation in the presence of Raney nickel, platinum or palladium. The reduction is conveniently carried out at temperatures between 0 ° and 80 ⁰ C, preferably 15 ° and 30 ⁰ C. As the organic solvent used is preferably a lower alkanol such as methanol or preferably ethanol. If desired, other solvents such as methylene chloride, chloroform or water can also be added. If R. in the compounds of the formula Ia is phenyl substituted by nitro, one must of course make a certain selection among the reducing agents and / or reducing conditions so that the nitro group is not hydrogenated at the same time as the double bond of the nucleus. This is not the case, for example, when using metal borohydrides.

The process h) is conveniently about 20 ⁰ C) is carried out at room temperature (or at elevated temperature up to about 100 ⁰ C. Suitable inert organic solvents are dimethylacetamide, diethylacetamide, dimethylformamide, Dimethylfulfoxid or dioxane are suitable. A sodium or potassium salt is preferably used as the compound of the formula XII, and an iodide is preferably used as the compound of the formula XIII.

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The process i) is expediently carried out in an inert organic solvent which is at least partially miscible with water, such as dioxane or acetone, which is best carried out at room temperature (about 20 ^° C.), and as an oxidizing agent, for example, alkali permanganate, such as sodium permanganate or potassium permanganate , preferably used in aqueous solution.

In the method j) is conveniently bulky enough, at temperatures between 0 ° and 50 ⁰ C, preferably 15 ° and 30 ° C. It is best to work in the presence of an inert organic solvent, for example a lower alkanol such as methanol or ethanol.

The method k) is preferably carried out by alkaline hydrolysis of compounds of the formula Ih at temperatures between 50 ° and 150 ⁰ C, preferably 80 ° and 120 ° C. Alkali hydroxides, such as sodium or potassium hydroxide, are preferably used for this purpose. The reaction is conveniently carried out in an aqueous solvent medium which contains water and a water-miscible inert organic solvent, for example a lower alkanol, such as ethanol, or a cyclic ether, such as dioxane, which is preferred.

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The process k) may further by oxidative hydrolysis of compounds of Formula Ih can be made, and indeed in an aqueous alkaline medium at temperatures between 10 ° and 80 ⁰ C, preferably 15 ° and 60 ° C. The oxidative hydrolysis is preferably carried out in an alkaline medium using a peroxide, preferably a hydroperoxide, and in particular hydrogen peroxide. The peroxide is preferably used in a moderate excess, for example an excess of about 1.5 to 4 mol. An alkali metal hydroxide, such as sodium or potassium hydroxide, is expediently used to form the alkaline medium, preferably in a substantial excess. The alkaline oxidative hydrolysis is best carried out in an aqueous solvent medium consisting of water and an inert organic solvent such as a lower alkanol or a cyclic ether.

In the method 1) is conveniently carried out in an inert organic solvent and at temperatures between 0 ° and 60 ⁰ C, preferably 15 ° and 40 ° C. The process is preferably carried out in an aqueous medium, an aqueous solution of an alkali permanganate, such as sodium or potassium permanganate, being used as the oxidizing agent, the latter being preferred. The organic solvent used can be, for example, an aromatic solvent, such as benzene, or an acyclic or cyclic ether, such as dioxane, a lower alkanol, such as ethanol, or

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a lower ketone such as acetone.

The method m) is zweckrnässigerwexse carried out at temperatures between 0 ° and 120 ⁰ C, which might best at temperatures between 15 ° and 100 ⁰ C, if the starting product is an on-compound, and at temperatures between 0 ° and 150 ° C , preferably 20 ° and 60 ° C, if the starting product is a thione compound. To carry out the process, any oxidizing agent can be used which is suitable for converting an organic amino function into an imino function, for example an alkali permanganate such as sodium or potassium permanganate, manganese dioxide or mercury acetate.If the starting product is an on compound, an alkali permanganate is preferably used. If, on the other hand, the starting product is a thione compound, manganese dioxide, which is practically anhydrous, is preferably used. Suitable solvents are lower alkanols such as methanol or ethanol, aromatic solvents such as benzene, and cyclic and acyclic ethers such as dioxane.

In process n) one works expediently at elevated temperatures between 30.degree. And 120.degree. C., preferably 50 ° and 100 ° C. The reaction is carried out in the presence of an acid as a catalyst and agent Elimination of water which, however, does not otherwise react with the compounds of the formulas XVII and XVIII, for example an inorganic mineral acid, oxalic acid, or an arylsulfonic acid or alkylsulfonic acid,

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such as benzenesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid. The amount of acid catalyst is advantageously kept low so that it is practically not more than about one mole, based on the amount of compounds of the formula XVII, and it is preferably between 0.005 and 0.5 mol, based on the amount used Urea. The process is conveniently carried out in an inert organic solvent, preferably an aromatic solvent such as benzene or toluene. The reaction time can be between 1 and 50 hours. (Please insert page 25a here) The process q) is carried out by treating the compounds of the formula XXXIII with a strong base at elevated temperature. This treatment is expediently carried out at temperatures between and 100 ^° C. and in the presence of an alkali metal, for example sodium or potassium hydroxide, and in an aqueous solvent medium which contains water and an inert organic solvent, for example a cyclic ether such as dioxane.

The compounds of the formula I can be known per se Way to be isolated and purified.

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The process ο) is expediently carried out at temperatures between 70 and 180 ^° C., preferably between 100 and 130 ^° C., and in particular at the reflux temperature of the reaction mixture. It is advisable to work in an inert organic solvent, for example toluene, xylene or, preferably, pyridine. The reaction time can be 1 to 50 hours, and it is usually 10 to 30 hours.

In the case of process p), it is expedient to work in an acidic aqueous medium and at temperatures between 70 and 110 ° C. The isothiocyanic acid is on best prepared in situ by running the reaction in an acidic medium as well as using a Alkali metal isothiocyanate, for example sodium isothiocyanate, an alkaline earth metal isothiocyanate, for example Calcium isothiocyanate, or preferably ammonium isothiocyanate. The acid used is expediently a strong inorganic acid, for example sulfuric acid, or nitric acid, preferably Hydrochloric acid. If desired, a further inert organic solvent can be used in addition to water can also be used, for example methanol / ethanol or dioxane. The implementation time is for example between 10 minutes and 5 hours and it is usually between 15 and 60 minutes.

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The 2-amino-4,5-methylenedioxy-benzophenone imines used as starting materials for process a) and process b) or 2-amino-4,5-methylenedioxy- (2'-thenoylimines) of the formula IV can be reached by

1) 2-Amino-4,5-methylenedioxy-benzophenone or 2-amino-4,5-methylenedioxy- (2'-thenoyle) der already mentioned formula VI cyclized with ammonia, or

2) for the production of 2-amino-4 _f 5-methylenedioxybenzophenonimines or 2-amino-4,5-methylenedioxy (2'-thenoylimines) of the formula IVb,

IVb

wherein R and Rl have the above meaning, 2-amino * 4,5-methylenedioxy-benzonitrile of the formula XX,

XX

C = N-

where R has the above meaning with lithium phenylene or lithium thienylene or with phenyl magnesium halides bzv /. Thienylmagnesium halides of the formula XXI already mentioned and the obtained Hydrolyzed reaction products in a manner known per se.

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Process 1) can be carried out in a manner known per se: The operation here is expediently carried out in a closed reaction vessel under anhydrous conditions and at elevated temperature and pressure. The reaction temperature conveniently lies between 100 ° and 200 ⁰ C, preferably 100 ° and 150 ° C. It is advantageous to use a catalyst, for example a Lewis acid, such as zinc chloride. The process is expediently carried out using an excess of ammonia as the solvent, but a suitable further solvent can also be used, such as dioxane.

Process 2) is preferably carried out at room temperature in an inert organic solvent, like diethyl ether. A lithium compound is preferably used as the compound of the formula XI. The received The reaction mixture is conveniently hydrolyzed directly in a manner known per se, for example by the reaction mixture is simply poured onto ice.

The compounds of the formula IV obtained can be isolated and purified in a manner known per se.

The compounds of the formula VI used as starting materials for process c) and for process d) are known or can be produced in a manner known per se.

The 2- (N-carbamoylamino) or 2- (N-thiocarbamoylamino) -4,5-methylenedioxy-benzhydrols used as starting materials for process e) or - (2'-thenoylhydrclen) of the formula IX can be used

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get by adding 2-amino-4,5-methylenedioxy-benzhydrols or 2-amino-4/5-methylenedioxy-thenoYlhydrols of the Formula XIX already mentioned with isocyanic acid or isothiocyanic acid of the formula VIII already mentioned.

The process is conveniently carried out in an aqueous acidic medium and at temperatures between O and 8O ⁰ C / 15 ° and preferably 35 ° C. The compounds of the formula VIII are best prepared in situ by carrying out the reaction in an acidic medium and using a salt of the formula VII already mentioned. An alkali metal salt, for example sodium or potassium salt, an alkaline earth metal salt, for example calcium salt, or the ammonium salt is expediently used as the compound of the formula VII, a potassium salt being preferred. The acid used to create the acidic conditions and to prepare the desired compounds of formula VIII in situ can be, for example, sulfuric acid or hydrochloric acid, or an organic acid such as acetic acid, which is preferred.

The compounds of the formula IX obtained can be isolated and purified in a manner known per se.

The 4-phenyl- or 4- (2 ^I- thienyl) -6,7-methylenedioxy-3,4-dihydro -2 (1H) -quinazolinones or -2 (IH) used as starting materials for process f) -quinazolinethionen of the formula X already mentioned can be obtained by adding '2-amino-4, * 5-methylendioxy ™ benzaldehyde

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Formula XXI,

XXI

wherein R has the above meaning with urea or thiourea of the formula XXII,

NH ₀ -C-. NH XXII

¹ Il *
X

wherein X has the above meaning, cyclized at elevated temperature.

The reaction is conveniently carried out at temperatures between 50 ° and 250 ° C, preferably 100 ° and 200 ° C, carried out. The process can expediently be carried out in the absence of a solvent or in an inert atmosphere, as under nitrogen, 'can be carried out. If so desired however, you can also work in the presence of an inert organic solvent, for example an aromatic solvent such as benzene or toluene.

The compounds of the formula X obtained can in an can be isolated and purified in a known manner.

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The 4-phenyl- or 4- (2'-thienyl) -6,7-methylenedioxy-2 used as starting materials for process h) (IH) -quinazolinones or -2 (IH) -quinazolinethiones of Formula XII already mentioned can be obtained by using corresponding quinazolinones which are unsubstituted in position 1 or quinazolinthione with alkali hydrides, such as sodium hydride, or alkali alkoxides, such as sodium or Potassium methoxide or ethoxide, treated in a manner known per se.

The process is conveniently carried out at room temperature carried out in an inert organic solvent such as dimethylformamide, dimethyl sulfoxide or dioxane. It is best to use the same solvent for the subsequent process h).

The compounds of the formula XII obtained can be isolated and purified in a manner known per se.

The quinazolinones unsubstituted in position 1 and used for the preparation of compounds of the formula XII and Chinazolinthione are new. They can be produced in a manner known per se, for which purpose, for example start from a corresponding 2-aminobenzophenone and analogously to the processes c) and d) already mentioned can work.

The starting materials used for process i)

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of Formula XIV - can be prepared by adding Ver compounds of the formula XXIII,

XXIII

wherein R ^{1 has the} above meaning, with compounds of the formula XXIV,

CH ₃ Y ¹ XXIV

wherein Y ^{1 has the} above meaning, at temperatures between about room temperature (2O ⁰ C) up to about 45 ° C. You can either work with an excess of compounds of the formula XIV or use an inert organic solvent as the reaction medium, such as chloroform or acetone. The process is preferably started at room temperature, for example 1-4 hours, and then continued at the reflux temperature, using an excess of methyl iodide. If the compounds of the formula XXIV are gaseous under the reaction conditions used, for example at room temperature, an organic solvent should of course be used as the reaction medium.

The compounds of the formula XIV obtained can be isolated and purified in a manner known per se.

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Those used as starting materials for process i) Compounds of the formula XV can be obtained by reducing compounds of the formula XIV already mentioned. The reduction is expediently carried out using a borohydride such as sodium borohydride as a reducing agent so / ie in an inert

organic solvent, for example a lower alkanol such as methanol or ethanol, or a mixture of a lower alkanol and methylene chloride, chloroform or water. The reaction temperature may be between about room temperature and about 8O ⁰ C.

The compounds of the formula XV obtained can in an can be isolated and purified in a known manner. In general, however, the compounds of formula XV somewhat unstable, so it's best to get them as soon as possible processed according to procedure i).

The 2- (N-trihaloacetylamino) -4,5-methylenedioxy-benzophenones or ~ (2 '~ thenoyle) of the formula XVI used as starting products can be prepared by adding 2-amino-4,5- methylenedioxy-benzophenone or 2-amino-4,5-methylenedioxy (2 ¹ - thenoyle) of the formula VI with trihaloacetic acid of the formula XXV

Y-C-COOH XXV

I.
Y

wherein Y has the above meaning, or reacts with a reactive derivative thereof.

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The process is expediently carried out at temperatures between -20 ° and + 2O ⁰ C and in an inert organic solvent, for example an aromatic solvent such as benzene.

The compounds of the formula XVI obtained can be isolated and purified in a manner known per se.

The 3,4-methylenedioxyphenyl ureas or 3,4-methylenedioxyphenyl ureas used as starting materials for process n)
3,4-Methylenedioxyphenyl-thioureas of the formula XVII already mentioned can be obtained by

3) for the production of 3,4-methylenedioxyphenyl ureas of formula XVIIa,

XVIIa

wherein R ¹ ″ has the same meaning as R, but cannot represent alkyl with 1-5 carbon atoms, 3,4-methylenedioxyanilines of the formula XXVIa,

, 11 I.

XXVIa

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.Worin R ¹ ' ^{1 has the} above meaning, reacts with isocyanic acid or nitrourea, or

4) for the production of 3,4-methylenedioxy-t thioureas of formula XVIIb,

wherein R has the above meaning, 3,4-methylenedioxythioureas of formula XXVII,

XXVII

wherein R above, has meaning and A stands for an acid radical of an acid halide, alkaline hydrolysis at elevated temperatures between 50 ° and 14O ⁰ C.

If isocyanic acid is used in process 3), then so they are preferably prepared in situ by carrying out the reaction under acidic conditions and using of an alkali isocyanate. To form the acidic conditions, it is expedient to use a lower one aliphatic carboxylic acid, preferably acetic acid. The process is conveniently carried out at

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Temperatures between 10 ° and 50 ° C as well as in an organic Solvent, conveniently an excess of lower carboxylic acid, for example Acetic acid. If one uses for the procedure 3) nitrourea or nitrothiourea, then it is expedient to work at temperatures between 80 ° and 120 ° C and in an inert organic solvent, preferably a lower alkanol such as ethanol.

Process 4) is expediently carried out using an alkali hydroxide, preferably sodium or potassium hydroxide, and preferably at Temperatures between 80 ° and 120 ° C. The process is expediently carried out in an inert medium, preferably a mixture of water and an inert, water-miscible organic solvent, for example a cyclic ether, preferably dioxane.

The compounds of formula XVII obtained can in.an can be isolated and purified in a known manner.

To those used as starting materials for process p) and for the preparation of compounds of the formula IX Compounds of the formula XIX can be obtained in a manner known per se, for example by adding compounds of the formula VI already mentioned with sodium borohydride in an inert organic solvent hydrogenated. (G.N. Walker, J.Org.Chem. 27, 1929 [1962]).

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The starting materials used for process q) Compounds of the formula XXXIII can be prepared by adding compounds of the formula VI mentioned above with Compounds of the formula XXXIV already mentioned. as well as compounds of the formula VII,

VII

where M is alkali, alkaline earth or ammonium and X has the above meaning, or with the reaction product of compounds of the formula already mentioned XXXIV and compounds of the formula VII already mentioned are cyclized.

The reaction van compounds of the formula VI with compounds of formula XXXIV and VII or their reaction products can be carried out * wherein one operates at temperatures between 10 and 8Q ⁰ Cj, preferably 70 ⁰ C in a convenient manner in an inert organic solvent. As already said, the process can be carried out by reacting compounds of the formula VI with the reaction products of compounds of the formulas XXXIV and VII, in general preferably first reacting the compounds of the formulas XXXIV and VII, and the reaction mixture then with the compounds of formula VI admixed * the reaction of compounds of formula XXXIV and VII is exothermic and "preferably started at temperatures between 10 ° and 30 ⁰ C. of course, should the

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acid halides used do not carry any substituents or functional groups that interfere with the process. Suitable acid halides are acetyl chloride or, preferably, benzoyl chloride. Be best of course Compounds of the formula VII used which react most easily with compounds of the formula XXXIV.

The compound "of the formula VII is expediently used an alkali salt, for example sodium or potassium salt, and preferably an ammonium salt. As a solvent lower alkanols, ketones and cyclic ethers are suitable, acetone being preferred.

Those used as starting materials for process 2) 2-Amino-4,5-methylenedioxy-benzonitriles of the formula XX can be prepared in a manner known per se by tosylation, alkylation (or cycloalkylation or Cycloalkylalkylation) and ■ Detosylation of 2-amino-4,5-methylenedioxy-benzonitrile of formula XXVIII

XXVIII

The 2-araino-4,5-methylenedioxybenzonitriles of the formula XXa,

XXa

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was in R · a branched alkyl of 3-5 carbon atoms means in which the carbon atom attached to the nitrogen atom is branched, however, are preferred produced by 2 ~ amino-4,5-methylenedioxy-benzonitrile of the formula XXVIII already mentioned with alkyl halides of the formula XXIX,

R ^IV - Y '·' XXIX

where R has the above meaning and Y ¹ ″ stands for bromine or iodine.

The reaction is conveniently carried out in the presence of a base, preferably an inorganic base such as an alkali metal carbonate, in order to bind the hydrogen halide formed in the reaction. The reaction can be carried out in an inert organic solvent, for example dioxane, benzene or toluene. However, it is not necessary to use a solvent. Instead, there is preferably used an excess of compounds of the formula · XXlXo expediently carried out at elevated temperatures, which are not particularly critical, however, but preferably between 60 ° and 140 ⁰ C, in particular 70 ° and 110 ° C, are.

The compounds of the formula XX obtained can be isolated and purified in a manner known per se.

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2-Amino-4,5-methylenedioxy-benzonitrile of the formula XXVIII is known.

Compounds of the formula XXI used to prepare compounds of the formula X can be prepared in a manner known per se. They can be prepared, for example by reduction of compounds of the abovementioned formula XX using a conventional catalyst, for example Raney nickel / aluminum, in the presence of an acid, for example formic acid, zwischem at temperatures 40 ° and 100 ⁰ C and in a liquid medium, for example an excess of acid.

The compounds of the formula XXIII used for the preparation of compounds of the formula XIV can be get by, for example, compounds of the formula XXX,

XXX

where R 'has the above meaning, analogously to process i) already described in a manner known per se oxidized.

The compounds of the formula XXX can be prepared by using the compound of the formula XXXI,

XXXI

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with compounds of the formula XI already mentioned implemented analogously to method f) already described.

The compound of the formula XXXI is known.

To the starting products used for process 4) of the formula XXVII can be obtained by adding compounds of the formula XXVI,

XXVI

wherein R has the above meaning with compounds of the formula VIIa,

M-N = C = S VIIa

where M has the above meaning, and an acid halide, preferably an acid chloride, or with the reaction product of compounds of the formula Vila and the acid halide implements. .

The method can be analogous to the method already described d) 1). The compounds of the formula XXVII obtained can be known per se Isolate and clean wise, however they are best done right after procedure 4) without isolation

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further processed. The reaction mixture obtained can contain varying amounts of compounds of the formula JXVII

contain.

The process 3) as well as for the production of connections of the formula XXVII compounds of the formula XXVI used are known or in a manner known per se manufacturable. They are preferably prepared by using the compound of the formula XXXII,

XXXIl

provided with a protective group, for example tosylated or reacted with a trialkyl orthoformate, and then treated with a strong acid such as sulfuric acid, cycloalkylated or cycloalkylalkylated and finally the protective group is split off in a manner known per se, for example by detosylation. Those connections of the formula XXVI, in which R is cycloalkyl or branched alkyl, where the branching is on the carbon atom bonded to the nitrogen atom is present, are, however, preferably by direct reaction of compounds of the formula XXXII with a corresponding one Cycloalkyl halide or a branched alkyl halide.

The compounds of the formula XXXII can be prepared in a manner known per se, for example by

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Nitration of methylenedioxybenzene and catalytic reduction of the 3,4-methylenedioxynitrobenzene obtained by means of hydrogen, platinum oxide or palladium on activated carbon. ''.

The compounds of the formula I are pharmacologically active and can therefore be used as medicaments. she have an anti-inflammatory effect in particular, so that they can be used as anti-inflammatory agents.

The amount to be administered daily is, for example, between about 60 and 2000 mg for compounds of the formula Ia, where X is oxygen, between about 90 and 2000 mg for compounds of the formula Ia, where X is Sulfur stands. In the case of compounds of the formula Ic in which X is oxygen, the amount to be administered daily is Amount about 140-2000 mg, and it is included in compounds of the formula Ic in which X is sulfur about 200-2500 mg. The doses given above are preferably administered in several aliquots between about 15 and 1000 mg, etv / a 25 and 1000 mg, about 35 and 1000 mg, and about 50 and 1250 mg, two to four times a day or in sustained release form.

The compounds of the formula I, in particular the compounds of the formula Ia, also have an analgesic effect, so that they can be used as analgesics and antipyretics. The here to be administered daily Amounts are the same as for anti-inflammatory effects.

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The compounds of the formula XVII are also pharmacologically active and can therefore also be used as medicaments will. They have anti-inflammatory effects in particular, so they are used as anti-inflammatory agents can be. The daily doses to be administered here correspond to those given above for the compounds of the formula Ic are given in which X is oxygen.

The compounds of the formula IV, IX, X, XII, XV, XVI, XIX, XX, XXI and XXIII are pharmacologically active.

The compounds of the formula I can be administered orally or parenterally and can be used to prepare Process dosage forms with the usual auxiliaries and additives. A suitable capsule is fixed, for example from 50 parts by weight of a compound of the formula I, e.g. l-isopropyl-4-phenyl-6,7-methylenedioxy-2 (IH) -quinazolinone, or of the formula IV, and 200 parts by weight of an inert, solid diluent, for example kaolin.

Of the compounds of the formula I, those of the formula Ia are preferred because of their pharmacological action, and in particular those in which R is isopropyl, for example 1-isopropyl-4-phenyl-6,7-methylenedioxy-2 (IH) -quinazolinone, 1-Isopropyl-4- (fluorophenyl) -6,7-methylenedioxy-2 (IH) -quinazolinone and 1-isopropyl-4-phenyl-6,7-methylenedioxy-2 (IH) -quinazolinethione.

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Example -1 ; l-Isopropyl-4-phenyl-6 _/ 7-methylenedioxy 2 (IH) -quinazolinone [method c) 1)]

A flask equipped with a stirrer and a Dean-Stark water separator is charged with 53 g of benzoin, 51 g of 3,4-methylenedioxyaniline, 2.5 g of p-toluenesulfonic acid and 300 ml of xylene are charged. The mixture will take 10 hours Stir heated to reflux. After cooling to room temperature, 1500 ml of chloroform are added and the organic layer is washed twice with 150 ml of 10% sulfuric acid .. The organic layer is then treated with activated charcoal, filtered and in vacuo concentrated to about 500 ml. When left to stand, 2,3-diphenyl-5,6-methylenedioxyindole separates out, which occurs at 187-188 ° C melts.

A flask equipped with a stirrer, reflux condenser, funnel and thermometer is charged with 31.3 g of 2,3-diphenyl-5/6-methylenedioxyindole, 600 ml of acetic acid and 0.30 g of ammonium molybdate dissolved in 30 ml of water. ¹ The mixture is heated to 60 - 65 ° C while stirring and then 30 ml of 40% hydrogen peroxide are added dropwise (about 15 minutes). The reaction mixture is kept at 65 ^° C. for about 2 hours and then treated with 150 ml of water.

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filtered and recrystallized from chloroform to give · for 2-Benzoylamino-4,5-methylendioxybenzophenon of mp. 195-197 ⁰ C passes.

c) 2-Amino-4 _i 5-methy _> lendioxy_benzo £ henon

A flask equipped with a stirrer and reflux condenser is filled with 40 g of 2-benzoylamino-4,5-methylenedioxybenzophenone, 150 ml of ethanol and 100 ml of 50% sodium hydroxide are charged. The mixture is stirred for 2 hours Heated to reflux. The solution is treated with 400 ml of water, whereupon the solid obtained from 2-Amino-4,5-methylenedioxybenzophenone was filtered off. It melts at 160-161 ° C.

A flask equipped with a stirrer and reflux condenser is filled with 80 g of 2-amino-4,5-methylenedioxybenzophenone, 600 ml Isopropyl iodide and 80 g of anhydrous potassium carbonate are added. The mixture is refluxed with stirring for about 48 hours, then cooled to room temperature, filtered and concentrated in vacuo on a rotary evaporator. The residue is dissolved in 1: 1 chloroform / hexane dissolved and chromatographed through a silica gel (500 g) column with the same solvent system. That 2-Isopropylamina-4,5-methylenedioxybenzophenone obtained is recrystallized from ethanol and melts at 77-78 ° C.

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-Jf- 600-6333 / P • 2221506

quinazolinone

A flask equipped with a stirrer and a distillation head is mixed with 28 g of 2-isopropylamino-4,5-methylenedioxybenzophenone, 50 g of ethyl carbamate and 4.5 g of anhydrous zinc chloride. The mixture is heated under stirring to obtain 45 minutes 160-165 ⁰ C, 45 minutes 175-180 ⁰ C and finally 1 hour at 185-19O ° C erhitzt.Hierbei a distillate from ethanol and Aethylcarbamat. The cooled residue is treated with about 250 ml of chloroform and 25 g of activated charcoal. The mixture is filtered and the filtrate is concentrated in vacuo. The residue is dissolved in 1: 1 chloroform-hexane, and the solution is then chromatographed through a silica gel column (150 g) with the same solvent system. The l-isopropyl-4-phenyl-6,7-methylenedioxy-2 obtained (IH) -quinazolinone melting at 194 to 194.5 ⁰ C.

Example 2 ; l-isopropyl-4-phenyl-6,7-methylenedioxy-

3,4-dihydro-2 (IH) -quinazolinone [method e)]

One equipped with a stirrer and a reflux condenser Flask is filled with 5.09 g of 2-isopropylamino-4,5-methylenedioxybenzophenone and 125 ml of methanol are added. To the

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2.5 g of sodium borohydride are added in portions (about 15 minutes) to the solution with stirring. The resulting mixture is stirred for about 12 hours at room temperature and then concentrated in vacuo. The residue is mixed with 100 ml of water treated and then extracted twice with 50 ml of methylene chloride each time. The organic layer becomes anhydrous with Dried sodium sulfate, filtered and concentrated. The 2-isopropylamino-4,5-methylenedioxy obtained in this way Benzhydrol is recrystallized from ether and melts at 78-80 ° C.

A flask equipped with a stirrer is filled with 1.5 g of 2-isopropylamino-4,5-methylenedioxybenzhydrol and 7.5 ml 2N hydrochloric acid added. The solution is stirred and in one portion with 0.78 g of sodium cyanate in 15 ml of water treated. The mixture is stirred for about 18 hours at room temperature, the solid obtained is filtered off and crystallized from ether, with 2- (N-carbamoylisopropylamino) 4,5-methylenedioxybenzhydrol from Emp. 145-15O ° C (ether) got.

The reaction mixture obtained in process step b) (before filtering) is refluxed for 2 hours, resulting in 1-isopropyl-4-phenyl-6,7 ~ methylenedioxy-

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3,4-dihydro-2 (IH) -quinazolinone passes, which melts after recrystallization from a mixture of ether and isopropanol at 165-168 ⁰ C.

Example 3 ; l-isopropyl-4-phenyl-6,7-methylenedioxy-

3,4-dihydro-2 (IH) -quinazolinone [method g)]

A flask equipped with a stirrer and reflux condenser is mixed with 10.29 g of 1-isopropyl-4-phenyl-6 _f 7-methylenedioxy-2 '(1H) quinazolinone and 250 ml of methanol. The solution is stirred and 5.0 g of sodium buohydride are added in portions (approx. 30 minutes). The reaction mixture is stirred for 5 hours at room temperature and then under vacuum ^in: a rotary evaporator. The residue is treated with 200 ml of water and then twice. extracted with methylene chloride. The organic layer is dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The 1-isopropyl-4-phenyl-6,7-methylenedioxy-3,4-dihydro-2 (IH) -quinazolinone obtained in this way melts at 161-163 ° C. after recrystallization from ether.

Example 4 ; l-Isopropyl ^ -phenyl-e ^ -methylenedioxy-2 (IH) -quinazolinone [method j)]

dioxy_benzo £ henon
One with stirrer, thermometer, drip funnel and one with

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scr

Dry tube filled with anhydrous calcium chloride is provided in the flask with 3.0 g of 2-isopropylamino-4,5-methylenedioxybenzophenone, 1.43 g of triethylamine and 30 ml of dry toluene. The solution is stirred and cooled to an internal temperature of about 10 ^° C., a solution of 2.4 g of trifluoroacetic anhydride in 10 ml of toluene being added dropwise so that the internal temperature is 10 ^° C.-5 ^° C. The mixture is then left to stand until it has reached room temperature, and after about 12 hours it is washed with 100 ml of water, dried with anhydrous magnesium sulfate, filtered and concentrated. The 2- (N-trifluoroacetylisopropylamino) -4,5-methylenedioxybenzophenone obtained in this way melts at 100 ° -12O ° C. after crystallizing from ether.

A mixture of 1.0 g of 2- (N-trifluoroacetylisopropylamino) -4,5-methylenedioxybenzophenone and 50 ml of tetrahydrofuran saturated with anhydrous ammonia becomes 40 Stirred for hours at room temperature. The solvent is then drawn off in vacuo and crystallized from isopropanol to, resulting in l-isopropyl-4-phenyl-6,7-methylenedioxy-2 (IH) -quinazolinone of m.p. 189-19O ° C reached.

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Example 5 : 1-Isopropyl-4-phenyl-6,7-methylenedioxy-2 (IB) -quinazolinethione [method o)]

A mixture of 5 g of 1-isopropylM-phenyl-6, 7-methylenedioxy-2 (IH) -quinazolinone, 10 g of phosphorus pentasulfide and 75 ml of pyridine is refluxed for 5 hours. The mixture is then further stirred overnight at room temperature and filtered. The filtrate is poured into water and the resulting mixture is extracted with chloroform. The chloroform is evaporated, wor.a; if man. sends the solids obtained through a column filled with silica gel. The fraction obtained by eluting with methylene chloride is urakristailisiert from ethyl acetate, and leads to as 1-isopropyl ~ 4-phenyl-G ^ -methylendioxy-Z (IH) -chinazolinthion of mp. 202-205 ⁰ C.

Example 6 ; l-Is op ropy l - ^ - pheny l-e, 7-m ethylenedioxy ~ '3,4- dihydro-2 (1H) -quin azoiinthione [method g)]

A solution of 0.5 g of 1-isopropyl-4-phenyl-6,7-methylehdioxy-2 (IH) -quinazolinethione, 50 ml of ethanol and 0.57 g of sodium borohydride is refluxed for 4 hours. The reaction mixture is then cooled and ^filtered: wherein one of l-isopropyl - passes phenyl-e ^ -methylendioxy-3,4-dihydro-2 (IH) -chinazolinthion which melts at 213-222 ° C - ^.

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Sl

Example 7: l -Isopro pyl-4- phenyl-6,7-methylene dioxy- 3, 4-dihydro: -2 (IU) -quinazolinethione [method n)]

150 ml of concentrated nitric acid, which are ^{cooled to 0} ° C. and kept at this temperature, are admixed dropwise with 100 g of methylenedioxybenzene with vigorous stirring. After the addition is complete, the reaction mixture is diluted with several volumes of water, whereupon the precipitated solids are recovered by vacuum filtration and washed several times with water. After recrystallization of the crude solids from methanol, l-nitro-3,4-methylenedioxybenzene, which melts at 138 ° -141 ° C., is obtained.

b) l-amino-3,4-methy_lendioxy_benzene

A solution of 38 g of 1-nitro-3,4-methylenedioxybenzene in 75 ml of absolute ethanol is mixed with 1.5 g of 5% palladium / carbon. The resulting reaction mixture is at about 4 atm. Hydrogenated under hydrogen pressure and room temperature for 4 hours. The catalyst is then filtered off and the filtrate is added in vacuo . concentrated in a syrup. By treating the syrup with petroleum ether (boiling point 30-60 ° C.), a precipitate forms, which is recrystallized from the same solvent and thus leads to 1-amino-3, 4-mel.hy lc? .Ndioxybenzene, which 37 ⁰ C melts

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A solution of 197 g of 1-amino-3,4-methylenedioxybenzene 110.3 ml of isopropyl iodide and 154.8 ml of triethylamine are added to 1500 ml of methanol. The solution obtained is refluxed for 32 hours, after which the solvent is removed under reduced pressure. That so The oil obtained is extracted repeatedly with diethyl ether. The extracts are combined, filtered through Celite, and freed from ether, resulting in N-isopropylamino 3,4-methylenedioxybenzene arrives in the form of an oil.

A solution of 16.3 g of benzoyl isothiocyanate, prepared by boiling 136 g of dry sodium isothiocyanate with 17 g of benzoyichloride in 30 ml of benzene under reflux, is slowly added at room temperature with 28 g of N-isopropylamino 3,4-methylenedioxybenzene in 150 ml of benzene . The reaction mixture is stirred at 20 ° C. for 30 minutes, after which the solid formed is recrystallized from benzene and thus N-isopropyl-N- (3,4-methylenedioxyphenyl) --N'-benzoyl-thiourea is obtained, which is obtained at 152-152 ⁰ C melts. ν

■ j 0

- jfjS - 600-6333 / P

si

e) N-Iso £ rogYlHN -_ (3, ^ l ^

27 g of sodium hydroxide are added to a solution of 45 ml of dioxane and 200 ml of water, the mixture being stirred until it has completely dissolved. 17 g of N-isopropyl-N- ( ^{3,4-methylenedioxyphenyl) -N 1} -benzoylthiourea are added to the solution. The mixture obtained is heated to reflux for 48 hours and then cooled to 15 ^° C. This gives a white solid which, after recrystallization from benzene, gives the title compound, which melts at 149-151 ° C.

A solution of 30 g of N-isopropyl-N- (3,4-methylenedioxyphenyl) thiourea, 27.6 ml of benzaldehyde and 2 ml of methanesulfonic acid in 500 ml of toluene is refluxed for 4 hours under a Dean-Stark water separator, with 2 ml of water must be collected. The solution is filtered and then evaporated to a powder. The product obtained is then crystallized from dioxane and water, giving 1-isopropyl-4-phenyl-6,7-methylenedioxy-3,4-dihydro-2 (1H) -quinazolinethione, which is obtained at 215-218 ⁰ C melts.

Example % : 1-1fioprcpy 1-4-phenyl-6/7-irethylenedioxy-2 _i

[Method m)]

t:! in Gaiai.r.ch from 2 g of 1-isopr: opyl.-4-phenyl-6 _/ 7-! r.oL-.liylen ~

600-6333 / P

dioxy-3,4-dihydro-2 (IH) -quinazolinethione, 100 ml methylene chloride and 4 g of manganese dioxide is stirred for 48 hours at room temperature. The precipitated solids are grounded filtered off, and the filtrate is concentrated to dryness in vacuo. The residue is as ethyl acetate and then off Recrystallized methanol, and finally eluted with benzene from a silica gel column, whereby the 1-Isopropyl ~ 4 ~ phenyl-6,7 ~ methylenedioxy-2 (IH) -quinazolinethione obtained, which melts at 2Ο2-2Ό5 ° C.

Bei Piel 9; l-isopropyl-4-phenyl-l -6,7-met hyl endioxy ~ 2 (IH) - [d method)] chinazolinthion

A solution of 5.6 g of 2-isopropylamino-4,5-methylene-dioxybene-phenone in 50 ml of acetic acid is mixed with 1.5 g of aminenium thiocyanate. The mixture is refluxed for 3 hours and then concentrated to dryness. A sample of the residue is examined by thin layer chromatography (absorbent ι silicon dioxide, 20% ethyl acetate / chloroform). The substance with a Rf value of 0.5 is separated in manner known per se to give gelanqt the title compound of mp. 202-204 ⁰ C.

-β, 7-itieth ylend ioxy-

2-i 4-dihydro ■ -2 (IH) -quinazolinethione [method p). ]

A solution of 1 g of 2-isopropylamino-4,5-mathylendioxybenkhydrol in 28 ml ice vinegar is mixed with 2 g Airanoniuiath'io-

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cyanate added. The mixture is stirred for 24 hours
Room temperature, whereupon the solid precipitate obtained is filtered off. The filtrate is concentrated to dryness, and the residue is taken up in chloroform. the

Solution is washed with water, dried and added to the ■ j

ι Concentrated to dryness. The solid obtained is from '. \

Recrystallized ethyl acetate, whereby one for the titlever-:

binding of m.p. 214-218 ° C reached. ,

i Example 11; [Method c) i) or j)].

Analogously to Examples 1 or 4 and using suitable ones
Starting products can be obtained in appropriate quantities
to the following connections:

a) 1-isopropyl-4- (m-fluorophenyl) -6,7-methylenedioxy- -; 2 (1H) -quinazolinone, m.p. 16 9-17O ° C,

b) l-Isopropyl-4- (m-methoxyphenyl) -6,7-methylenedioxy-.: 2 (1H) -quinazolinone, m.p. 189-191 ° C,

c) l-isopropyl-4- (p-methylphenyl) -6,7-methylenedioxy-

2 (IH) -quinazolinone, m.p. 188-19O ° C, ί

d) l-isopropyl-4- (o-nitrophenyl) -6,7-methylenedioxy-2 (lH) -quinazolinone, M.p. 148-15O ° C,

e) l-Isopropyl-4- (5'-chloro-2-thienyl) -6,7-methylen- \ dioxy-2 (1H) -quinazolinone, m.p. 192-2O1 ° C,

f) l-Isopropyl-4- (3,4-methylenedioxyphenyl) -6,7-methylenedioxy-2 (IH) -quinazolinone, m.p. 234-235 ^o C,

g) l-isopropyl-4- (m-nitrophenyl) -6,7-methylenedioxy-2 (IH) -quinazolinone, M.p. 23O-232 ° C,

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h) l-isopropyl-4- (o-methylphenyl) -6,7-methylenedioxy-2 (lH) -quinazolinone, M.p. 155-157 ° C,

i) 1-isopropyl-4- (p-fluorophenyl) -6,7-methylenedioxy-2 (1H) -quinazolinone _/ m.p. 238-24O ⁰ C,

j) 1-isopropyl-4- (3,4-dichlorophenyl) -6,7-methylenedioxy-2 (IH) -quinazolinone ,. Mp. 239-242 ⁰ C.

k) 1-methyl-4-phenyl-6 _/ 7-methylenedioxy-2 (IH) -quinazolinone, 257-260 ° C _f

1) 1-Cyclopropylmethyl-4-phenyl-6 _/ 7-methylenedioxy-2 (IH) -quinazolinone.

Example 12 ; [Method e) or g)]

The following compounds are obtained analogously to Examples 2, 3 or 6 and using suitable starting materials in appropriate amounts:

a) l-Isopropyl - ^ - phenyl-e ^ -methylenedioxy-S ^ -dihydro 2 (IH) -quinazolinone, m.p. 165-168 ° C (only analogous to Example 6), ■

b) l ~ isopropyl-4-phenyl-6,7-methylenedioxy-3 _/ 4-dihydro 2J [IH) -quinazolinethione, melting point 218-222 ° C (only analogous to Example 2 or 3)

c) l-isopropyl-4- (m-fluorophenyl) -6 _/ 7-methylenedioxy-3,4-dihydro-2 (IH) -quinazolinone, mp. 165-167 ⁰ C.

d) 1-Isopropyl-4- (m-methoxyphenyl) -6,7-methylenedipxy-3,4-dihydro * 2 (IH) -quinazolinone, M.p. 167-168 ° C

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e) l-isopropyl-4- (p-methylphenyl) -6,7-methylenedioxy-3,4-dihydro-2 (1H) -quinazolinone, M.p. 192-194 ° C,

f) l-Isopropyl-4- (o-nitrophenyl) -6,7-methylenedioxy-3,4-dihydro-2 (IH) -quinazolinone, mp. 202-205 ⁰ C.

g) l-Isopropyl-4- (5'-chloro-2-thienyl) -6,7-methylenedioxy-3,4-dihydro-2 (IH) -quinazolinone, mp. 162-164 ⁰ C.

h) l-isopropyl-4- (3,4-methylenedioxyphenyl) -6,7-methylene- _{'dioxy-3/4-dihydro-2} (IH) -quinazolinone, mp. 145-147 ⁰ C.

i) l-isopropyl-4- (m-nitrophenyl) -6,7-methylendloxy-3,4-dihydro-2 (IH) -quinazolinone, mp 218-22O. ° C _r

j) l-isopropyl-4- (o-methylphenyl) -6,7-methylenedioxy-3 _/ 4-dihydro-2 (IH) -quinazolinone, melting point 172-174 ° C,

k) 1-Isopropyl ~ 4- (p-fluorophenyl) -6,7-methylenedioxy-3,4-dihydro-2 (IH) -quinazolinone, M.p. 163-166 ° C,

1) l-isopropyl-4- (3,4-dichlorophenyl) -6,7-methylene

dioxy-3,4-dihydro-2 (IH) -quinazolinone, m.p. 155-157 ° C,

m) l-methyl-4-phenyl-6,7-methy1endioxy-3,4-dihydro-2 (IH) -quinazolinone, mp. 233.-232 ⁰ C,

n) l-Cyclopropylmethyl-4-phenyl-6 ', 7-methylenedioxy- \ 3,4-dihydro-2 (IH) -quinazolinone,

o) l-isopropyl-4- (m-fluorophenyl) -6,7-methylenedioxy-3,4-dihydro-2 (IH) -quinazolinethione, M.p. 200-2O3 ° C,

p) l-isopropyl-4- (p-isopropylphenyl) -6,7-methylenedioxy-3,4-dihydro-2 (IH) -chinazolinthion, mp. 155-157 ⁰ C.

q) l-Isopropyl-4- (p-fluorophenyl) -6,7-methylenedioxy-3,4-dihydro-2 (1H) -quinazolinethione, M.p. 198-199 ° C,

r) l-isopropyl-4- (m-nitrophenyl) -6,7-methylenedioxy-3,4-dihydro-2 (IH) -quinazolinethione, M.p. 115-117 ° C.

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Example 13: [Procedure ο)]

Analogous to example 5 and using a suitable output products arrives in appropriate quantities

one to the following connections:

a) l-Isopropyl-4- (πί-fluorophenyl) -6,7-methylenedioxy-2 (1H) -quinazolinethione, m.p. 210-214 ⁰ C,

b) 1-isopropyl-4- (p-isopropylphenyl) -6,7-methylenedioxy-2 (IH) -quinazolinthione, Siup. 167-17O ° G,

c) l-isopropyl-4- (p-fluorophenyl) -6,7 ~ methylenedioxy-2 (IH) chinazolinthion, mp. 220-223 ⁰ C.

d) l-isopropyl-4- (m-nitrophenyl) -6,7-methylenedioxy-2 (IH) chinazolinthion, mp. 199-202 ⁰ C.

Example 14 ; [Method n)]

Analogous to Example 7 and using suitable starting materials the following compounds are obtained in appropriate quantities:

a) l-Cyclopropylmethyl-4-phenyl-6,7-methylenedioxy-3,4-dihydro-2 (1H) -quinazolinone,

b) l-isopropyl-4- (m-fluorophenyl) -6,7-methylenedioxy-3,4-dihydro-2 (1H) -quinazolinethione, M.p. 200-2O3 ° C,

c) l-isopropyl-4- (p - isopropylphenyl) -6,7-methylenedioxy ~ 3,4-dihydro-2 (1H) -quinazolinethione _/ melting point 155-157 ° C,

d) l-isopropyl-4- (p-fluorophenyl) -6 / 7-methylenedioxy-3,4-dihydro-2 (1H) -quinazolinethione _/ m.p. 198-199 ⁰ C,

e) 1-Isopropyl-4- (m ~ nitrophenyl) -6,7-methylenedioxy-3, A- dihydro-2 (1H) -quinazolinethione _{/ m.p.}

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Example 3.5; [Method m)] j

Analogous to Example 8 and using suitable 1

common products in suitable quantities one arrives at \

the following connections: i

a) l-cyclopropylmethyl-4-phenyl-6 _/ 7-methylenedioxy-; 2 (IH) -quinazolinone,

b) l-isopropyl-4- (m-fluorophenyl) ~ 6,7-methylenedioxy-2 (IH) -quinazolinethione, m.p. 210-214 ⁰ C,

c) l-isopropyl-4- (p-isopropylphenyl) -6,7-methylenedioxy-2 (IH) -quinazolinethione, M.p. 167-17O ° C,

d) l-isopropyl-4- (p-fluorophenyl) -6,7-methylenedioxy-2 (IH) -quinazolinethione, M.p. 220-223 ° C,

e) l-isopropyl-4- (m-nitrophenyl) -6,7-methylenedioxy-2 (IH) -quinazolinethione, M.p. 199-2O2 ° C.

Example 16 : [method d)]

Analogously to Example 9 and using suitable starting materials in corresponding quantities one arrives at | following connections:!

a) 1-Isopropyl-4-phenyl-6,7-methylenedioxy-2 (IH) -quina- ) zolinone, m.p. 2O2-2O5 ° C _f .

b) l-Isopropyl-4- (m-fluorophenyl) -6,7-methylenedioxy-: * 2 (1H) -quinazolinone, m.p. 169-17O ° C;

c) l-isopropyl-4- (m-methoxyphenyl) -6,7-methylenedioxy- / 2 (1H) -quinazolinone, m.p. 189-191 ° C, /

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ά) l-Isopropyl-4- (p-methylphenyl) -6,7-methylenedioxy-2 (IH) -quinazolinone, m.p. 188-19O ⁰ C,

e) l-Isopropyl-4- (o-nitrophenyl) -6, 7-methylenedioxy-2 (IH) -quinazolinone, m.p. 148-15O ⁰ C,

f) l-Isopropyl-4- (5'-chloro-2-thienyl) -6,7-methylenedioxy-2 (IH) -quinazolinone, m.p. 192-201 ⁰ C,

g) l-isopropyl-4- (3,4-methylenedioxyphenyl) -6,7-methylenedioxy-2 (lH) -quinazolinone _/ mp. 234-235 ⁰ C.

h) 1-Isopropyl-4- (m-nitrophenyl) -6,7-methylenedioxy-2 (IH) -quinazolinone M.p. 23O-232 ° C,

i) l-Isopropyl-4- (o-methylphenyl) -6,7-methylenedioxy-2 (1H) ~ quinazolinone, M.p. 155-157 ° C,

j) 1-isopropyl-4- (p-fluorophenyl) -6,7-methylenedioxy-2 (1H) -quinazolinone, m.p. 238-24O ⁰ C,

k) l-isopropyl-4- (3,4-dichlorophenyl) -6,7-methylenedioxy-2 (1H) -quinazolinone, M.p. 239-242 ° C,

1) l-methyl-4-phenyl-6,7-methylenedioxy-2 (IH) quinazolinone, M.p. 257-260 ° C,

m) l-Cyclopropylmethyl-4-phenyl ~ 6,7-methylenedioxy-2 (IH) -quinazolinone,

n) l7lsopropyl-4- (m-fluorophenyl) -6,7-methylenedioxy-2 (IH) chinazolinthion, mp. 210-214 ⁰ C.

o) l-isopropyl-4- (p-isopropylphenyl) -6,7-methylenedioxy-2 (IH) -quinazolinethione, M.p. 167-17O ° C,

p). l-isopropyl-4- (p-fluorophenyl) -6,7-methylenedioxy-2 (IH) chinazolinthione, m.p. 22O-223 ° C,

q) l-Isopropyl-4- (m-nitrophenyl) -6,7-methylenedioxy-2 (IH) quinazolinthione, m.p. 199-2O2 ° C

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Example 17 ; [Method p)]

Analogously to Example 10 and using appropriate starting materials in suitable amounts, one arrives at following connections:

a) l-Isopropyl-4- (m-fluorophenyl) -6 _/ 7-methylenedioxy-3,4 dihydro-2 (1H) -quinazolinethione, m.p. 200-203 ⁰ C,

b) l-isopropyl-4- (p-isopropylphenyl) -6,7-methylenedioxy-3,4-dihydro-2 (lH) -chinazolinthion _/ mp. 155-157 ⁰ C.

c) l-isopropyl-4- (p-fluorophenyl) -ö ^ - dihydro-2 (1H) -quinazolinthione, m.p. 198-199 ° C,

d) 1-Isopropyl-4- (m-nitrophenyl) -6,7-methylenedioxy-3,4 dihydro-2 (1H) -quinazolinthione, m.p.

Example 18 ; 1-methyl-4-phenyl-6,7-methylenedioxy-2 (IH) quinazolinone [method h)]

A mixture of 10 g of 2-amino-4 _/ 5-methylenedioxybenzophenone, 24.6 g of urea and 160 ml of glacial acetic acid is refluxed for 3 hours. The mixture is then cooled and the resulting solids filtered off, washed sequentially with water and methanol, slurried in methanol for about 1 hour, filtered and dried under reduced pressure to give the title compound, melting above 300 ° C.

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b) l-Meth ^ l-4-phenyl-6,7-methylenedioxy-2JlH) _2China7.oliDQQ

A suspension of 2.6 g of 4-phenyl-6,7-methylenedioxy-2 (IH) -quinazolinone in 80 ml of dimethylformamide, 0.6 g of sodium hydride is added and the mixture becomes 2 Stirred for hours at room temperature, the 1-sodium derivative being obtained. The mixture is then with 4.5 g of methyl iodide are added, 2 hours at room temperature stirred and filtered. The filtrate is concentrated to about half its volume under reduced pressure, and then poured onto ice-water. The precipitated solid is collected and poured over a silica gel column chromatographed, eluting with chloroform The fraction collects, evaporated and recrystallized from ethyl acetate to give the title compound of mp. 263-265 ° C.

Example 19 : ■ l-Isopropyl-4-phenyl-6,7-methylenedioxy -

3,4-dihydro-2 (IH) -quinazolinone [method f)]

a) l-IsogrogYl-ö ^ rm ^ ithYlendioxY ^ (IH) -quinazolinone

A mixture of 7 g of 2-isopropylamino- ^{4,5-methylenedioxy- i} · benzaldehyde and 7 g of urea is heated to 165 ° C. with stirring and nitrogen and kept at this temperature overnight. The reaction mixture is then cooled and the Solids are taken up in chloroform and washed with water, the chloroform is evaporated under reduced pressure to give the crude title compound.

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2iiii) _- quinazolinone

A solution of 5 g of crude 1-isopropyl-6,7-methylenedioxy 2 (IH) -quinazolinone, obtained in process step a), in about 250 ml of anhydrous tetrahydrofuran is mixed with 25 ml of a 2M lithium phenyl solution in hexane. The temperature is kept at about 20 ^° C. during the addition. The reaction mixture is then treated with water and extracted with chloroform. The chloroform extract is washed several times with saturated sodium chloride solution and dried over sodium sulfate; and evaporated. The solid residue is recrystallized from ethyl acetate, giving the title compound with a melting point of 172-175 ° C.

Example 20 ; l-Isopropyl-4-phenyl-6,7-methylenedioxy-2 (IH) -c hinazolinon [method q)]

Nj_-benzoy_lurstoff f

7 g of 2 ~ isopropylamino-4,5-methylenedioxybenzophenone become added to a solution of 5 g of benzoyl isocyanate in 60 g of dry benzene, the temperature being raised to about 20.degree holds. The solid obtained is filtered off and washed with benzene, whereby the title compound is obtained, which melts at 183-184 ° C.

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b) l-isopropyl-4-phenyl ~ 6,7-methylenedioxy-2 (IH) -

W BB * Mt * · ■ A ^ M VBB BHV 4BJ% as «BV BBI ■ * ■> BBp Vhv · ■ · ■■ ^ MV4 BBB BBP * BP ^ fc") * ■ MP · * · ■ * · PP " J ■ ·! ■ · ■ * ■■ ^^ Λ ^^ Φ 9 ^ m ^^ B ^^ A BBV ΊΒΒ4 BPB] WHV BBB BVB. AMB BHBi «BB Mh)

quinazolinone.

A mixture of 13 ml of dioxane and 3 ml of water is mixed with 4.3 g of 1-isopropyl-N - [(3,4-methylenedioxy-6-benzoyl) phenyl] -N'-benzoylurea and 0.6 g of sodium hydroxide are added. The reaction mixture is refluxed for 24 hours and the intestines are concentrated in a vacuum. The residue will dissolved in chloroform and washed three times with water. The chloroform is evaporated and the residue off Recrystallized ethyl acetate, giving the title compound with a melting point of 186-192 ° C.

Example 21 ; l-Isopropyl-4-phenyl-6,7-methylenedioxy-2 (IH) -quinazolinone [method c) 2)]

A mixture of 1 g of 2-isopropylamino-4,5-methylenedioxybenzophenone and 0.5 g of urea is heated ^{to about 195 ° C. for about half an hour.} The melt is cooled to room temperature and taken up in chloroform. The solution obtained in this way is then processed further by thin-layer chromatography in chloroform. The corresponding band is extracted with methanol and the resulting mixture is evaporated. After recrystallization of the residue from ethyl acetate, the title compound, which melts at 187-189 ° C., is obtained.

Example 22 : 1-Isopropyl-4-phenyl-g _y 7-methylenedioxy-2 (IH) -quinazolinone [method c) 2)]

A mixture of 3.408 kg of 2-N-isopropylamino-4,5-methylene

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dioxybenzophenone, 5.28 kg of urea and 30.6 kg of glacial acetic acid is refluxed (115 ° C) for 4.5 hours. The reaction mixture is evaporated in vacuo until no more acetic acid escapes, then cooled to 50 ° C and finally in 15 , 6 kg of chloroform dissolved. It is finally cooled to room temperature and washed with water. The chloroform layer is washed with water and evaporated in vacuo to an oil, from which, after recrystallization from ethyl acetate, 2.75 kg of 1-isopropyl-4-phenyl-6,7-methylenedioxy-2 (IH) -quinazolinone is obtained -189 ⁰ C melts. The filtrate is concentrated, cooled and washed with water, whereby an additional 0.17 kg of the title compound is obtained.

Example 23 ; l-Isopropyl-4-phenyl-6,7-methylenedioxy-2 (IH) -quinazolinone [method c) 2)]

A mixture of 14.2 g of 2-N-isopropylamino-4,5-methylenedioxybenzophenone, 25 ml of glacial acetic acid, 12.3 g of urea and 2.3 g of p-toluenesulfonic acid are refluxed for as long heated until benzophenone can no longer be detected by thin-layer chromatography. After removing the Acetic acid is added to the reaction mixture with water and chloroform, and finally with ammonium hydroxide made alkaline. The chloroform layer is washed with water, followed by evaporation of chloroform and so on arrives at an oily residue, which after recrystallization from ethyl acetate and washing with ether to the 1-Isopropyl-4-phenyl-6,7-methylenedioxy-2 (IH) -quinazolinone of m.p. 187-189 ° C.

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Example 24 : 1-Isopropyl-4-phenyl-6,7-methylenedioxy-2 (IH) quinazolinone [method a)]

^a ) ^ I ^ IsogrogYlaminoj ^^ S ^ meth ^ lendioxYbenzonitrile

A mixture of 8.1 g of 2-amino-4,5-methylendloxybenzonitrii, 174 g of isopropyl iodide and 15 g of potassium carbonate are refluxed for 48 hours. The mixture is then cooled and filtered, whereupon the solvent was removed under reduced pressure and a reddish oil was obtained. The OeI is in Dissolved chloroform and washed with water. The chloroform is stripped off in vacuo and the residue is crystallized one arrives at the title compound with a melting point of 77 ° -78 ° C. from cyclohexane.

A solution of 7.9 g of bromobenzene, 80 ml of benzene and 85 g Diethyl ether is mixed with 21 g of butyllithium solution (23%) in hexane for a period of about half Hour shifted. The mixture obtained is added over a period of about half an hour 4.1 g of 2-isopropylamino-4,5-methylenedioxybenzonitrile given in 10 ml of benzene. The solution is then poured onto about 8.0 ml of ice-water, resulting in 2 ~ isopropylaroino-4,5-methylenedioxybenzophenoneimine got. The organic layer is separated over sodium sulfate dried and treated with 7.4 g of triethylamine. the

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The solution is then saturated with phosgene while cooling. The reaction mixture obtained is stirred overnight and finally evaporated under reduced pressure. The residue is recrystallized from ethyl acetate, whereby the title compound is obtained, which melts at 185-187 ° C.

Example 25 : {procedure h) or a)]

Analogous to example 18 or 22 and using suitable starting materials in appropriate amounts one arrives at to the compounds a) to q) from Example 16.

Example 26 ; [Method f)]

Analogously to Example 19 and using suitable starting materials in appropriate amounts, one arrives at to compounds a) to r) of Example 12.

Example 27 ; [Method c) 2)]

Analogously to Examples 21, 22 or 23 and using suitable starting materials in corresponding amounts lead to compounds a) to 1) des Example 11.

Example 28 ; [Method q)]

Analogous to Example 20 and using suitable starting materials Compounds a) to m) of Example 16 are obtained in corresponding amounts.

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Example 29 ; ' l-Isopropylamino-4-phenyl-6,7-methylene-

dioxy-2 (IH) -quinazolinone [method b) i>]

A solution of 4 g of 2-isopropylamino-4,5-methylenedioxybenzonitrile in 10 ml of anhydrous benzene is added dropwise to a solution of lithium phenyl, the is prepared in a manner known per se from 7.9 g of bromobenzene and 21 g of 23% strength n-butyllithium solution in hexane. The mixture is stirred for about half an hour and then poured into ice-water. The organic layer will separated, dried and evaporated to give the title compound in the form of a crude yellow oil.

A solution of 7 g of 1-isopropylamino-4,5-methylenedioxybenzophenone imine and S ml of ethyl chloroformate in 50 ml of dry benzene is refluxed for about 4 hours heated. The reaction mixture is cooled, washed with water, dried and evaporated. The ones left behind Treat the syrup with ethyl acetate, and recrystallizes from isopropanol, giving the title compound with a melting point of 189-191 ° C.

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Example 30 ; l-Isopropyl-4-phenyl-6,7-methylenedioxy-2 (IH) -quinazolinone [method b) 3)]

1-Isopropyl'amino-4,5-methylenedioxybenzophenonimine is ^{reacted with N, N 1} -carbonyldiimidazole in back-measuring benzene, giving the compound with a melting point of 188-19O ° C.

Example 31 ; l-Isopropyl ^ -phenyl-e ^ -methylenedioxy-2 (IH) -quinazolinone [method b) 2)]

A mixture of 5 g of 2-isopropylamino-4,5-methylenedioxybenzophenoneimine and 15 g of urethane is melted together and ^{heated to about 180 °} C. for 3 hours. The reaction mixture is cooled and the solid mass obtained is taken up in 75 ml of chloroform. The chloroform solution is washed with water, filtered to remove insoluble residue, dried and evaporated. The residue is recrystallized from isopropanol, giving the title compound with a melting point of 188-19O ° C. _x

Example 32; l-Isopropyl-4-phenyl-6,7-methylenedioxy-2 (IH) -quinazolinone [method k)]

A mixture of 21 g of l-isopropyl-4-phenyl-6,7-methylenedioxy-2 (IH) -quinazolinethione, 11 g of sodium hydroxide, 15 ml of water and 50 ml of p-dioxane are refluxed for about 0.5 hours. The mixture is at reduced

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The pressure is concentrated, whereupon the residue is extracted several times with chloroform. The chloroform extracts are washed with water, dried and evaporated. The residue is treated with ethyl acetate and, after the solid obtained has been recrystallized from isopropanol, the title compound has a melting point of -188-19O ⁰ C ₁

Example 33 ; l-Isopropyl-4- (3'-fluorophenyl) -6,7-methylenedioxy-2 (IH) -quinazolinone [method e)]

A solution of 4 g of sodium permanganate in 75 ml of water is added dropwise to a solution of 2 g of 1-isopropyl-3,4-dihydro-4- (3'-fluorophenyl) -6,7-methylenedioxy-2 (IH) quinazolinethione in 130 ml of p-dioxane was added. The mixture is stirred for about 2 hours and then through the cellite bed filtered and the filtrate is evaporated to dryness under reduced pressure. After recrystallizing the The title compound with a melting point of 169 ° -17O ° C. is obtained after the residue from ethyl acetate.

Example 34 ; [Method b) 1), b) 2), b) 3), k) or I)]

Analogously to Examples 29-33 and using suitable starting materials in appropriate amounts one arrives at the connections a) - q) of the example

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Claims (1)

- 600-6333 / P Patent claims: Process for the preparation of 4-phenyl- or 4- (2'-thienyl) -6,7-methylenedioxy-2 (IH) -quinazolinones or -3 _/ 4-dihydro-2 (IH) -quinazolinones or -2 ( IH) -quinazolinethiones or -3,4-dihydro-2 (IH) -quinazolinethiones of the formula I, where X is oxygen or sulfur, R is alkyl with 1-5 carbon atoms, cycloalkyl with 3-6 j Carbon atoms or cycloalkylalkyl with total j together with 4-7 carbon atoms, the cyclo-. alkyl has 3-6 carbon atoms and the alkyl J is straight-chain and contains 1-3 carbon atoms, and χ y stands for a group C = N or CH-NH, in k K I which either R, a phenyl radical of the formula II means in which Z and Z are identical or different and represent hydrogen, fluorine, chlorine, alkyl or alkoxy with 1-3 carbon atoms each, nitro or trifluoromethyl, 209882/1156 600-6333 / P but at most one of the substituents Z and Z, trifluoromethyl or nitro means.t, or where Z and 1
are on adjacent carbon atoms and together stand for methylenedioxy, or in v / elcher R. one
Thienyl radical of the formula III means, in v / elcher Z “hydrogen. Fluorine, "chlorine or Alkyl with 1-3 carbon atoms, characterized by that he a) for the production of 4-phenyl- or 4- (2'-thienyl) 6, 7 ^ -methylenedioxy-2 (IH) -quinazolinones or ~ 2 (IH) quinazolinethion of the formula Ia, 209882/1156 600-6333 / P wherein R, R- and X have the above meaning, 2-amino ^ 4,5-methylenedioxy-benzophenonimines or 2-amino-4,5-methylenedioxy- (2 ¹ -thenoylimines) of the formula IV, wherein R and R _{1 have the} above meaning, with phosgene or thiophosgene of the formula V, ^cl - I - ^ci ν wherein X has the above meaning, cyclizes, or b) for the preparation of 4-phenyl ~ or 4- (2'-thienyl) -6,7-methylenedioxy-2 (IH) -quinazolinones of formula Ib, Ib wherein R _{1 has the} above meaning and R ^r · has the same meaning; like R, except that it is not for tert. Alkyl can stand in which the tert. Carbon atom is bonded directly to the ring nitrogen atom, 2 ~ Ainirio ~ 4,5-methylenedioxy-benzophenonimine or 2-amino-4,5-methylenedioxy- (2'-thenoylimine) of the formula IVa, 209882/1156 - * f ~ 6OO ~ 6333 / P IVa wherein R ¹ '"and -R. have the above meaning, with 1) C _1-9 alkyl chlorocarbonates / 2) C "_ alkyl carbamates at temperatures of at least 140 ⁰ C, or 3) Ι, Ι'-carbonyldiimidazoles
cyclized, or c) for the preparation of 4-phenyl- or 4- (2'-thienyl) -6, 7-methylenedioxy-2 (IH) -quinazolinones of the formula Ib ₇ 2-Air _l ino-4 _/ 5-methylenedioxy already mentioned -benzophenone or 2-amino-4 _/ 5-methylenedioxy- (2'-thenoyle) of the formula VIa ₇ R " Via wherein R ¹ 'and R have the above meaning, with 1) ^c t_5 alkyl carbamates at temperatures of at least 14O ° C and in the presence of a catalytic amount of Lewis acid, 209882/1 166 600-6333 / P 2) urea or 3) carbamyl chloride reacts at elevated temperature, or d) for the preparation of 4-phenyl- or 4- (2'-thienyl) -6,7-methylenedioxy-2 (IH) -quinazolinones or -2 (IH) -quina- · zolinethiones of the formula Ia already mentioned, 2-amino-4,5-methylenedioxy-benzophenones or 2-amino ~ 4,5-methylenedioxy- (2'-thenoyle) of formula VI, VI. wherein R and R _{1 have the} above meaning, with isocyanic acid or isothiocyanic acid of the formula VIII, H-N = C = X VIII wherein X has the above meaning, cycles, or e) for the preparation of 4-phenyl- or 4- (2'-thienyl) -6,7-methylenedioxy-3,4-dihydro-2 (IH) -quinazolinones or -2 (IH) -quinazolinethiones of the formula Ic, 209882/1 156 600-6333 / P. Ic where R / R, and X have the above meaning, 2- (N-carbamoylamino) ^{- or 2- {N-thiocarbamoylamino) ~ 4} ,? - methylenedioxy-benzhydroles or - (2'-thenoylhydroles) the formula IX wherein R _r R ₁ and X have the above meaning, cyclized by elimination of water, or f) for the preparation of 4-phenyl- or 4- (2'-thienyl) -6,7-methylenedioxy-3,4-dihydro-2 (1H) -quinazolinen or -2 (IH) -quinazolinethiones of the formula Id, Id where R and R have the above meaning and Rj 'has the same meaning as R ₁ , but not phenyl substituted by nitro, 6,7-methylenedioxy-2 (IH) -quinazolinone or 6,7-methylenedioxy-2 (IH ) chinazolinthione of formula X, 209882/1156 600-6333 / P wherein R and X have the above meaning with lithium phenylene or Phenylmagnesiumhalogeniden or .mit Lithiumthienylen or Thienylmagnesiumhalogeniden der Formula XI, R- [Q XI where Ri has the above meaning and Q is lithium or a radical -MgY ¹¹ , in which Y ^{11 is} chlorine or bromine, reacted in the presence of an inert organic solvent and hydrolyzed the reaction product, or g) for the preparation of 4-phenyl- or 4- (2'-thienyl) -6,7-methylenedioxy-3,4-dihydro-2 (IH) -quinazolinones or -2 (IH) -quinazolinethiones of the formula Ic already mentioned, 4-phenyl- or 4- (2-th'ienyl) -6; 7-methylenedioxy-2 \ (1H) quinazolinone or -2 (IH) -quinazolinediones of the already mentioned formula Ia reduced, or h) for the preparation of 4-phenyl- or 4 ~ (2 ¹ -thienyl) -6,7-methylenedioxy-2 (IH) -quinazolinones or. -2 (IH) -quinazolinethiones of the formula Ie, 209882/1156 600-6333 / P Ie ' wherein R ¹¹ , R. and X have the above meaning, l-alkali-4-phenyl- or l-alkali-4- (2 · thienyl) -ö ^ -methylenedioxy-? (IH) quinazolinone or -2 (IH) -quinazolinthione of the formula XII wherein R, and X have the above meaning and M 'stands for alkali, with halides of the formula XIII, R ¹¹ - Y ¹ XIII wherein R ¹ 'has the above meaning and Y ^{1 is} chlorine, bromine or iodine, is reacted in the presence of an inert organic solvent, or i) for the preparation of l-methyl-4-phenyl- or l-methyl ~ 4 - '("2'-thienyl) -6,7-methylenedioxy-2 (IH) -quinazolinones of the formula If. If where Rl has the above meaning, l * -Methyl-4-phenyl- or, 209882/1156 600-6333 / P tv 1-methyl-4- (2-thienyl) -6,7-methylenedioxy-1,2-dihydroquinazolinium halides of the formula XIV ₇ XIV wherein Rj and Y ^{1 have the} above meaning, or l-methyl-4-phenyl- or l-methyl-4- (2'-thienyl) -6,7-methylenedioxy-1, 2,3,4-tetrahydroquinazolines of the formula XV, j XV wherein R ^{1 has the} above meaning, oxidizes, or j) for the production of 4-phenyl- or 4- (2'-thienyl) - j 6,7-irtethylendioxy-2 (IH) -quinazolinonen of the already j mentioned formula Ib, 2- (N-Trihalogenacetylamino) - \ 4,5-methylenedioxy-benzophenone or - (2 ¹ - thenoyle)
formula XVI, XVI 209882/115 6 «4 600-6333 / P wherein R, and R ¹ 'have the above meaning and Y is fluorine, chlorine or bromine, reacts with ammonia, or k) for the preparation of 4-phenyl- or 4- (2'-thienyl) -6,7-methylenedioxy-2 (IH) -quinazolinones of the formula Ig, wherein R and R .. have the above meaning, 4-phenyl- or • 4- (2'-thienyl) -6,7-methylenedioxy-2 (IH) -quinazolinethiones of the formula Ih, _R v ■■■■■■■■ ■■ · i. ■ ^C Ä wherein R and R _{1 have the} above meaning, hydrolyzed at temperatures between 10 and 150 ° C, or 1) for the preparation of 4-phenyl- or 4- (2'-thienyl) -6,7-methylenedioxy-2 (IH) -quinazolinones the already mentioned, Fprmel Ig, 4-phenyl- or 4- (2'-thienyl) -6.7 methylenedioxy-3,4-dihydro-2 (IH) -quinazolinthione der Formula Ii, 2 0 9 8 8 2/1156 600-6333 / Ρ wherein R and R. have the above meaning, oxidizes, or m) for the preparation of 4-phenyl- or 4- (2'-thienyl) -6,7-methylenedioxy-2 (IH) -quinazolinones or. -2 (IH) -quinazolinethioneh the formula wherein R ¹ , R ₁ and X ^{1 have the} above meaning / 4-phenyl- or 4- (2'-thienyl) -S / V- 2 (IH) -quinazolinone or. -2 (IH) -chinazolinthione der Formula Ik, V7orin R ¹ , R ₁ and X ^{1 have the} above meaning, oxidized in an inert organic solvent, working under practically water-free conditions if the compound of the formula Ik is a thione, or n) for the preparation of 4-phenyl- or 4- (2 ^1- thienyl) -6,7-methylenedioxy-3,4-dihydro-2 (IH) -quinazolinones or -2 (IH) -quinazolinethion of the formula already mentioned Ik, 3,4-methylenedioxyphenyl ureas or 2098 82/1156 600-6333 / P 3,4-methylenedioxypheny! -Thioureas of the formula XVII, XVII v / orln R ¹ and X ^{1 have the} above meaning, with aldehydes of the formula XVIII, R CHO XVIII wherein R _{1 has the} above meaning, cyclized at elevated temperature under practically anhydrous conditions and in the presence of an acid catalyst, or o) for the preparation of 4-phenyl- or 4- (2'-thienyl) -6,7-methylenedioxy-2 (IH) -quinazolinethionene Formula Ih already mentioned, 4-phenyl- or 4- (2'-thienyl) -6,7-methylenedioxy-2 (IH) -quinazolinone of the aforementioned formula Ig with phosphorus pentasulfide at elevated temperature and in the presence of an inert organic solvent converts, or p) for the production of 4-phenyl- * or 4- (2'-thienyl) ~ 6,7-methylenedioxy-3,4-dihydro-2 (IH) -quinazolinethiones of the formula Ii already mentioned, 2-amino-4,5-methylenedioxy-benzohydroles or - (2'-thienylhydroles) of the formula XIX, - 209882/1166 600-6333 / P XEC wherein R and R. have the above meaning, cyclized with isothiocyanic acid, or q) for the production of 4 ^ -phenyl- or 4- (2'-thienyl) -6,7- ' methylenedioxy-2 (IH) -quinazolinonender already used: named formula Ig, N - [(3,4-methylenedioxy-6-benzoyl) phenylj- i N'-acylureas or N- [3,4-methylenedioxy-6-thenoyl) r \ phenyl] -N'-acy! ureas of the formula XXXIII, XXXIII wherein R and R. have the above meaning and R- one
Acid residue of an acid chloride or acid bromids of formula XXXIV R ₃ COY ¹¹ . XXXIV corresponds, in which Y ¹ 'has the above meaning, alkaline
hydrolyzed. 209882/1156 SOO-6333 / P 2. Process for the preparation of 2-amino-4,5-methyl.endioxy-benzophenonimines or »2-amino-4,5-methylenedioxy- (2'-thenoylimines) the formula IV mentioned in claim 1, characterized in that one 1) 2-Amino ~ 4,5-methylenedioxy-benzophenone or 2-Amino-4,5-methylenedioxy- (2'-thenoyle) of the in Claim 1 mentioned formula VI cyclized with ammonia, or· 2) for the production of 2-amino-4,5-methylenedioxybenzophenonimines or 2-amino-4,5-methylenedioxy (2'-thenoYlimines) of formula IVb, IVb wherein R and R 'have the above meanings, 2-amino-4,5-methylenedioxy-benzonitrile of formula XX, XX where R has the above meaning with lithium phenylene or lithium thienylene or with phenylmagnesium halides or thienylmagnesium halides of the formula XXI already mentioned and the resulting Reaction products hydrolyzed in a manner known per se. · · · 209882/1156 600-6333 / P 3. Process for the preparation of 2- (N-carbamoylamino) - or, 2- (N-thiocarbamoylamino) -4,5-methylenedioxybenzhydrols or - (2'-thenoylhydrolen) of the formula IX mentioned in claim 1, characterized in that that 2-amino-4,5-methylenedioxy-benzhydrols or 2-amino-4,5-methylenedioxy-thenoylhydrols of the in Claim 1 mentioned formula XIX with isocyanic acid or isothiocyanic acid of the formula VIII mentioned in claim 1 implements. 4. Process for the preparation of 4-phenyl- or 4- (2'-thieny1) -6,7-methylenedioxy-3,4-dihydro-2 (IH) quinazolinones or -2 (IH) -quinazolinethiones of the formula X mentioned in claim 1, characterized in that that 2-amino-4,5-methylenedioxy-benzaldehydes of the formula XXI, XXI wherein R has the above meaning, with urea or thiourea of the formula XXII, / NH ₀ '-C- NH ₀ XXII ^A \ * X wherein X has the above meaning, cyclized at elevated temperature. 209882/1156 - $ fi - 600-6333 / P 5. Process for the production of 4-phenyl resp. 4- (2'-thienyl) -6,7-methylenedioxy-2 (IH) -quinazolinones or -2 (IH) -quinazolinethiones of those mentioned in claim 1 Formula XII, characterized in that corresponding quinazolinones unsubstituted in position 1 are used or quinazolinediones treated with alkali hydrides or alkali alkoxides in a manner known per se. 6. Process for the preparation of 2- (N-trihaloacetylamino) -4,5-methylenedioxy-benzophenones or - (2'-thenoylene) of the formula mentioned in claim 1 XVI, characterized in that 2-amino-4,5-methylenedioxy-benzophenone or 2-amino-4,5-methylenedioxy- (2'-thenoyle) the formula VI mentioned in claim 1 with trihaloacetic acid of the formula XXV, ■ T ■ '. Y-C-COOH XXV wherein Y has the above meaning, or reacts with a reactive derivative thereof. ?. Process for the preparation of 3,4-methylenedioxyphenyl ureas and 3,4-methylenedioxyphenylthioureas, respectively of the formula XVII mentioned in claim 1, characterized in that one 20 98 82/1156 600-6333 / P 3) for the production of 3,4-methylenedioxyphenyl ureas of formula XVIIa, XVIIa. wherein R " ^{1 has} the same meaning as R, but cannot represent alkyl having 1-5 carbon atoms, 3,4-methylenedioxyanilines of the formula XXVIa, XXVIa v / orin R ¹ ″ has the above meaning, reacts with isocyanic acid or nitrourea, or 4) for the production of 3,4-methylenedioxy-thioureas of the formula XVIIb, ' XVIIb wherein R has the above meaning, 3,4-methylenedioxythiourea of the formula XXVII, 209 88 2/1156 wherein R has the above meaning and A stands for an acid radical of an acid halide, alkaline hydrolysis at elevated temperatures between 50 ° and 140 ⁰ C. ' 8. Process for the preparation of 4-phenyl- or 4- (2 · -thienyl) -6, T-methylenedioxy-S, 4-dihydro-2 (IH) quinazolinethiones of the formula XIX mentioned in claim 1, characterized in that 2-amino-4/5-methylenedioxy-benzophenone or 2-amino-4,5-methylenedioxy- (2'-thenoyle) the formula VI mentioned in claim 1 is hydrogenated in a manner known per se. 9. Process for the preparation of 2-amino-4,5-methylenedioxy-benzonitriles of the formula XX mentioned in claim 2, characterized in that one 5) 2-Amino-4 _/ 5-methylenedioxy-benzonitrile of the formula XXVIII XXVIII "C = N tosylated, alkylated or cycloalkylated or cycloalkylalkylated and detosylated in a manner known per se, or 209 8 82/1156 600-6333 / P 6) for the preparation of 2-amino-4 _/ 5-methylenedioxy benzonitriles of the formula XXa, XXa C = N where R is a branched alkyl with 3-5 carbon atoms, in which the carbon atom lying on the nitrogen atom is branched, 2-amino-4 _/ 5-methylenedioxy-benzonitriles of the formula XXVIII already mentioned with alkyl halides of the formula XXIX, TV
R - Y '·' XXIX wherein R has the above meaning and Y ^{111 is} . Bromine or iodine. ■ 209882/1156 600-6333 / P Germany 10. 4-phenyl- or 4- (2'-thienyl) -6,7-methylenedioxy-2 (IH) -quinazolinore or -3,4-dihydro-2 (IH) -quinazolinone, respectively. -2 (IH) -quinazolinthione or -3,4-dihydro-2 (IH) -quinazolinethione formula In, In wherein χ y have the meaning given in claim 1 and R * and X 'have the same meaning as the substituents R and X defined in claim 1, with the exception that X ^{1 is} sulfur if R' is alkyl with 1-5 Carbon atoms. 11. Pharmaceutical preparation, characterized by a content of compounds of the Formal In according to Claim 10. 12. 3,4-methylenedioxyphenyl ureas or 3,4-methylenedioxyphenyl thioureas of the formula XVII mentioned in claim according to claim 7. 13. Pharmaceutical preparation, characterized in that it contains compounds of the formula XVII according to claim 12. 209 88 2/1156 600-6333 / P I. Germany 14. Compounds of the formulas IV, IX, XII, XVI or XIX according to claim 1 or the formula XX according to claim 2. 37OO / SP / GD The patent attorney: 209882/1156