NO129906B - - Google Patents

Description

Procedure for manufacturing new ones

4-phenyl-2(1H)-quinazolinones.

The present invention relates to a process for the production of new, β-phenyl-2(1H)-quinazolinones with the general formula I

where either n stands for 1,

R means alkyl with 1 - 5 carbon atoms, alkoxy or alkylthio with each 1 - k carbon atoms, nitro, cyano, acetamido or trifluoromethyl,

R^ stands for alkyl with 1 to 5 carbon atoms, allyl or propargyl, but only means isopropyl if R stands for cyano or acetamido, and

R 2 means, phenyl or substituted phenyl of formula II

in which Y stands for fluorine, chlorine, bromine, alkyl or alkoxy with each 1 - h carbon atom or trifluoromethyl, and

Y1 means hydrogen, fluorine, chlorine, bromine, alkyl or alkoxy with every 1 - h carbon atoms,

or where n stands for 2.

R means alkyl with 1 - 5 carbon atoms, alkoxy with

1 - h carbon atoms, fluorine, chlorine or bromine,

R1 stands for alkyl with 1 - 5 carbon atoms, allyl or

propargyl, but not isopropyl, and

R2 has the above meaning.

The peculiarity of the method according to the invention is that a compound of formula III in which R, n, R. and R.sub.1 have the above meaning is reacted with phosgene.

For the turnover, the compounds of formula III are disposed of appropriately

in an inert organic solvent, e.g. an aromatic hydrocarbon, such as benzene, toluene or xylene, preferably benzene, and the solution obtained is added, optionally in the presence of an acid-binding agent such as e.g. triethylamine, at temperatures between 0 and 50°C, preferably between 10 and 30°C, a solution of phosgene 1 the same or in another inert organic solvent. The molar ratio between the compounds of formula III and phosgene is

not critical, but it is beneficial to use an excess of phosgene, as this results in higher yields of the final product. The compounds of formula III which can be prepared according to the method can be isolated from the reaction mixture in a manner known per se, e.g. by evaporation of the reaction mixture, distribution of the residue between an aqueous sodium carbonate solution and an inert organic solvent, e.g. methylene chloride and evaporation of this organic solvent and can be purified in a manner known per se, e.g. by recrystallization, e.g. from ethyl acetate.

The starting products with formula III are either known or can be prepared in a manner known per se. These compounds are usually prepared by reacting correspondingly substituted 2-aminobenzophenones with ammonia, suitably in an autoclave under anhydrous conditions at temperatures between 100 and 200°C, preferably between 110 and 150°C and at elevated pressure. The reaction is preferably carried out in the presence of a catalyst, e.g. a Lewis acid, such as zinc chloride, in ammonia as a solvent, as additional solvents can be used, such as e.g. dioxane. Other known methods consist of tosylating a correspondingly substituted o-aminobenzonitrile, the tosylated amino group is alkylated, the tosyl group is cleaved off and the obtained o-alkylaminobenzonitrile is reacted with a corresponding phenylmagnesium halide or phenyllithium. However, the last method cannot be used when R means nitro, cyano or acetamido.

The compounds of formula I which can be prepared by the method according to the invention have particularly favorable pharmacodynamic properties. In particular, these compounds, which can be demonstrated by the results from the carrageenan-induced edema test in rats, have a beneficial anti-inflammatory effect. The daily dose should be between 10 and 1,000 mg, preferably administered in several doses

(2 - 4) daily doses of 3 - 500 mg or in slow-release form. The compounds of formula I also have analgesic, antipyretic and antibradykinin activity. The doses required for the analgesic or antipyretic use correspond to the doses needed for the anti-inflammatory use.

For the application that anti-inflammatory agents have due to

the above-mentioned samples show the compounds with the general formula I to be particularly suitable, in which R^ means methyl, ethyl/isopropyl, tert-butyl, allyl or propargyl, especially ethyl, isopropyl and tert-butyl, and then especially isopropyl, and R 2 means an unsubstituted phenyl group. If R, Y and Y1 stand for an alkyl group, this should preferably contain 1-3 carbon atoms and, if R, Y or Y1 stand for an alkoxy group, this should preferably contain 1 or 2 carbon atoms. If R stands for an alkylthio group, this should preferably contain 1 or 2 carbon atoms.

A beneficial effect, however, also has compounds in which n stands for 2, compounds in which n stands for 1 and R means alkyl, alkoxy, thioalkyl or trifluoromethyl, as well as compounds in which R means cyano, nitro (especially when R stands for tert.-butyl) or acetamido.

The compounds and their salts which can be prepared by the method according to the invention can be used as drugs in themselves or in corresponding preparation forms for oral or parenteral administration. For the production of suitable preparation forms, the compounds are processed with inorganic or organic, pharmacologically indifferent excipients.

As excipients, e.g.

for tablets and dragees: Milk sugar, starch, talc,

stearic acid, etc.

for syrups: caster sugar, invert sugar,

glucose solutions etc.

Por injection preparations are used: Water, alcohols, glycerol,

vegetable oil is o.1.

Furthermore, the preparations may contain suitable preservatives, stabilisers, wetting agents, release agents, sooting

and dyes, flavorings, etc.

The method according to the invention shall be illustrated in the following by means of preferred and exemplary embodiments.

Example 1: 1-tert.-butyl-6-nitro-4-phenyl-2(1H)-clnazolinone

a) 5-nitro-2-tert-butylaminobenzophenone

To a solution of 20 g of 2-chloro-5-nitrobenzophenone, 20 ml of ethanol

and 30 ml of tert,-butylamine are added to 1.5 g of copper powder and 1.5 g of copper chloride. The resulting mixture is heated for 5 days under reflux and stirring, the separated crystallized product is filtered off and washed with ethanol whereby 5-nitro-2-tert-butyl-aminobenzophenone is obtained in the form of yellow crystals with a melting point of 157 - 158°C.

b) 5-nitro-2-tert-butylaminobenzophenonimine

A mixture of 2 g of 5-nitro-2-tert-butylaminobenzophenone, 15 ml

anhydrous ammonia (with a small moisture content) and 20 mg of zinc chloride are heated in an autoclave for 3 dbgn at a temperature of 110 - 120°C. Excess ammonia is evaporated and the residue is recrystallized from ethanol, 5-nitro-2-tert-butylaminobenzophenonimine being obtained in the form of yellow crystals with a melting point of 146°C.

c) 1-tert.-<butyl>yl-6-nitro-4-phenyl-2(1H)-quinazolinone To a solution of 1.3 g of 5-nitro-2-tert.-butylaminobenzophenonimine

and 5 ml of triethylamine in 30 ml of benzene is added to 25 ml of a 12% phosgene solution in benzene at a temperature between 5 and 20°C. The resulting solution is allowed to stand for 15 minutes at room temperature and is then evaporated to dryness in a vacuum. The residue is divided between one of 50 ml of an aqueous 0.5 N sodium carbonate solution and 50 ml

methylene chloride compound liquid system followed by a further extraction of the aqueous phase with 30 ml of methylene chloride. The combined methylene chloride solutions are filtered over anhydrous sodium sulfate, evaporated to dryness in vacuo and the residue recrystallized from ethyl acetate, 1-tert-butyl-6-nitro-4-phenyl-2(1H)-quinazolinone being obtained in the form of pale yellow needles with melting point 206°C.

Example 2:

Analogous to the method described in example 1 c), the following final compounds are obtained by reacting equivalent amounts of the starting compounds described below with phosgene:

Example 3:

In an analogous manner to what is stated in the preceding examples, the following compounds are prepared using corresponding starting products: a) 4-phenyl-1,6,7-trimethyl-2(1H)-quinazolinone with a melting point of 204 - 206°C. b) 6,7-dimethyl-4-phenyl-1-propargyl-2(1H)-quinazolinone with melting point 202 - 205°C. c) 1-ethyl-6-nitro-4-phenyl-2(1H)-quinazolinone with melting point 214 - 215°C. d) 6-acetamido-1-isopropyl-4-phenyl-2(1H)-quinazolinone with melting point 278 - 280°C. e) 6-cyano-1-isopropyl-4-phenyl-2(1H)-quinazolinone with melting point 125 - 128°C. f) 1-ethyl-6-methyl-4-phenyl-2(1H)-quinazolinone with melting point 180°C. g) 6-methylthio-1-ethyl-4-phenyl-2(1H)-quinazolinone with melting point 150 - 151°C.

h) 1-ethyl-7-methyl-4-phenyl-2(1H)-quinazolinone with melting point

160 - 162°C.

i) 1-ethyl-7-nitro-4-phenyl-2(1H)-quinazolinone with m.p

200 - 203°C.

k) 1-ethyl-6,7-dimethoxy-4-phenyl-2(1H)-quinazolinone with melting point

175°C.

1) 1,7-dimethyl-4-phenyl-2(1H)-quinazolinone with melting point

171 - 172°C.

m) 1-methyl-6,7-dimethoxy-4-phenyl-2(1H)-quinazolinone with melting point

197 - 198°C.

n) 1,7-dimethyl-4-(p-methoxyphenyl)-2(1H)-quinazolinone with melting point 150 - 152°C.

o) 1,7-dimethyl-4-(m-trifluoromethylphenyl)-2(1H)-quinazolinone with

melting point 180 - 183°C.

p)< 1,7-dimethyl-4-(p-methylphenyl)-2(1H)-quinazolinone with melting point 153 - 155°C.

Claims (1)

q) 1,7-dimethyl-if-(p-fluorophenyl)-2(1H)-quinazolinone with. melting point 2^3 - 21+6 °C. PATENT CLAIMS Process for the preparation of new h-phenyl-2(1H)-quinazolinones of the general formula I where either n stands for 1, R means alkyl with 1-5 carbon atoms, alkoxy or alkylthio with each 1 - h carbon atoms, nitro, cyano, acetamido or trifluoromethyl, R1 stands for alkyl with 1 - 5 carbon atoms, allyl or propargyl, but means only isopropyl if R stands for cyano or acetamido, and R 2 means phenyl or substituted phenyl with formula II in which Y stands for fluorine, chlorine, bromine, alkyl or alkoxy with every 1 - k carbon atoms or trifluoromethyl, and Y1 means hydrogen, fluorine, chlorine, bromine, alkyl or alkoxy with every 1 - h carbon atoms, or in which n stands for 2, '.R means alkyl with 1 - 5 carbon atoms, alkoxy with 1 - h carbon atoms, fluorine, chlorine or bromine,