DE1168435B - Process for the preparation of 4-oxo-3, 4-dihydroquinazolines - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY Internat. KL: C§7d

GERMAN

PATENT OFFICE

EDITORIAL

German KL: 12ρ-7 / θ1

Number.
File number:
Registration date:
Display day:

K45400 IVd / 12p
December 9, 1961
April 23, 1964

The invention relates to a process for the preparation of 4-oxo-3,4-dihydroquinazolines of the general formula

NO"

in which R 'is an alkyl radical having 1 to 3 carbon atoms and R "is optionally replaced by a or a plurality of methyl groups substituted pyridyl radicals, and salts thereof with inorganic ones and organic acids, which is characterized in that in a manner known per se either

a) an acylanthranil of the general formula

with an amine of the general formula R "- NH2 in the presence or absence of Solvents heated or

b) an o-aminobenzoic acid amide of the general formula

CO —NH-R "
NH ₂

Process for the production of
4-oxo-3,4-dihydrochmazolines

Applicant:

Kali-Chemie Aktiengesellschaft,

Hanover, Hans-Böckler-ADee 20

Named as the inventor

Dr. Wilhelm Kaupmann, Hanover-Kleefeld,

Dr. Siegfried Funke, Hanover-Kirchrode

c) an o-acylamino-benzoic acid of the general formula

-COOH
NH-CO —R '

with a carboxylic anhydride of the general formula

R '- CO

R '- CO

or an anhydrous carboxylic acid of the general formula R '- COOH heated or

with an amine of the general formula R "- NH2 in the presence of phosphorus halides or phosphorus oxyhalides heated in inert solvents, with in all formulas R 'and R "have the meanings given above, and optionally subsequently bases obtained converted into their salts with acids. The salts that can be prepared according to the invention 4-Oxo-3,4-dihydro-quinazolines can be mixed with inorganic and organic acids Manufacture according to the usual procedures.

It is known that 2-alkyl-3-aryl-substituted 4-oxo-3,4-dihydroquinazolines are physiologically active are. For example, shows 2-methyl-3-o-tolyl-4-oxo-3,4-dihydro-quinazoline a hypnotic effect (I. R. Boissier, C. Dumont and C. Malen, Therapy, 13, pp. 30 to 45 [1958]). Other compounds from the series of 4-oxo-3,4-dihydroquinazolines, z. B. those that carry a / I-halogenoethyl radical in the 3-position show antipyretic and anti-inflammatory effectiveness (cf. German Auslegeschrift 1 102 755).

It has been found that the compounds which can be prepared by the claimed process have valuable therapeutic properties and are well tolerated. In animal experiments, they show a clear attenuation of the central nervous functions. Z. B. the pharmacological effect of 2-methyl-3-pyridyl- (2 ^/ ) -4-oxo-3,4-di-

409 560/425

hydrochinazolins does not have the characteristic effect of common hypnotics. At a pharmacological one Comparison of 2-methyl-3-pyridyl- (2 ') -4-oxo-3,4-dihydroquinazoline with the well-known centrally damping 2-methyl-3-o-tolyl-4-oxo-3,4-dihydroquinazoline and the commercially available psychosedativum 2-methyl-2-propyl-1,3-propanediol dicarbamate on white mice it was found that 2-methyl-3-pyridyl- (2 ') -4-oxo-3,4-dihydroquinazoline these known compounds in the acute toxicity, in the depressant effect on spontaneous motility, in the ability to prolong anesthesia with S-zli-cyclohexenyl-l ^ -dimethylbarbituric acid and in the protective effect against the convulsive dose of pentamethylenetetrazole is at least equivalent. An essential one The difference compared to the comparison substances mentioned is that this is a clear one Exercise general anesthetic or hypnotic effect, while 2-methyl-3-pyridyl- (2 ') - 4-oxo-3,4-dihydroquinazoline is almost ineffective in this regard and, in tolerable doses, never leads to the lateral position. From the experiments ίο it can be concluded that the latter substance is significantly more suitable as a daytime sedative than the two known preparations.

The test results are compiled in the following table:

LD ₅₀ oral

II

Medium

Side position dose,

oral III

Attenuation of the

Spontaneous motility,

orally

IV

Extension of anesthesia with

5- / 1'-Cyclohexenyl-1,5-dimethyl-barbituric acid

antagonism

opposite to

Pentamethylene

tetrazole, oral

2-methyl-3-o-tolyl-4-oxo-3,4-dihydroquinazoline ....

2-methyl-2-propyl-1,3-propanediol dicarbamate

2-methyl-3-pyridyl- (2 ') -4-oxo-3,4-dihydroquinazoline ....

992 mg / kg 1090 mg / kg 1180 mg / kg

331 mg / kg 312 mg / kg 50 mg / kg

> 200 mg / kg

50 mg / kg

25 mg / kg
75 mg / kg
25 mg / kg

75 to 100 mg / kg 75 to 100 mg / kg 75 to 100 mg / kg

The attenuation of spontaneous motility was determined in the tremor cage test.

2-methyl -3 - [6'-methyl-pyridyl - (2 ')] - 4-oxo-3,4-dihydroquinazoline was 131 to 133 ° C.

For example example 3

2-Methyl-3-pyridyl- (2 ') -4-oxo-3,4-dihydroquinazoline ³⁵ 2-Methyl-3-pyridyl- (2') -4-oxo-3,4-dihydroquinazoline

28.2 g of 2-amino-pyridine were mixed with 48.6 g Acetanthranil and heated for 4 hours in an oil bath to a temperature of 120 ⁰ C in the flask. The viscous melt was triturated with water, the oily base solidifying. The sucked off crude 2-methyl-3-pyridyl- (2 ') -4-oxo-3,4-dihydroquinazoline was recrystallized for purification from benzene or from aqueous ethanol and showed a melting point of 167 to 169 ^° C. The hydrochloride of the base could be obtained by dissolving the same in methanol, passing in hydrogen chloride gas and adding ether to the solution. It has a melting point of 254 to 260 ^° C. (indistinct with decomposition).

Example 2

2-methyl-3- [6'-methyl-pyridyl- (2 ')] -4-oxo-3,4-dihydroquinazoline

By catalytic reduction of 2- (o-nitrobenzoylamino) -6-methyl-pyridine at room temperature and in the presence of Raney nickel at a hydrogen pressure of 140 atm. became that as a starting material Serving 2- (o-aminobenzoylamino) -6-methyl-pyridine obtained, which has a melting point of 92 to 94 ° C. 6 g of this 2- (o-aminobenzoylamino) -6-methyl-pyridine were refluxed with 30 ecm acetic anhydride for 3 hours heated, then the reaction mixture was evaporated in vacuo and the crystalline residue purified by recrystallization from benzene and aqueous ethanol. The melting point of the obtained In a suspension of 17.9 g of N-acetyl-anthranilic acid and 9.4 g of 2-aminopyridine in 100 ecm of toluene was added dropwise with stirring to a solution of 4.6 g of phosphorus trichloride in 25 ecm of toluene and then the mixture under for 2 hours further stirring and kept at the boil under reflux. After cooling it was made with soda solution until the reaction is clearly alkaline and the toluene is distilled off under reduced pressure. After standing overnight, the separated 2-methyl-3-pyridyl- (2 ') -4-oxo-3,4-dihydroquinazoline became sucked off. After recrystallization from aqueous ethanol, it had a melting point of 167 to 169 ° C.

Example 4 2-methyl-3-pyridyl- (2 ') -4-oxo-3,4-dihydroquinazoIine

10.7 g of 2- (o-aminobenzoylamino) pyridine were heated for 3 hours in the bath at 120 ⁰ C with 10 cc of acetic anhydride, the cooled reaction mixture was triturated with dilute sodium carbonate solution and the resulting crystalline deposited 2-methyl-3-pyridyl (2 ') -4-oxo-3,4-dihydroquinazoIin recrystallized from a benzene-ligroin mixture. The melting point of the product obtained is from 167 to 169 ^° C.

Example 5 2-Ethyl-3-pyridyl- (2 ') -4-oxo-3,4-dihydroquinazoline

10.7 g of 2- (o-aminobenzoylamino) pyridine were treated with 24 ecm propionic anhydride for 5 hours in

The bath was ^{heated to 175 °} C., and the excess propionic anhydride was distilled off in vacuo. The initially oily residue solidified on standing. For purification, it was recrystallized from cyclohexane and from 50% strength aqueous ethanol. The 2-ethyl-3-pyridyl- (2 ') -4-oxo-3,4-dihydroquinazoline obtained in this way has a melting point of 92 to 94 ° C.

Example 6
2-methyl-3-pyridyl- (4 ') -4-oxo-3,4-dihydroquinazoline

10.7 g of the starting material 4- (o-aminobenzoylamino) -pyridine of melting point 151 to 153 ⁰ C, which by catalytic reduction of 4- (o-nitrobenzoylamino) -pyridine at room temperature in the presence of Raney nickel and at a Hydrogen pressure of 120 atm. was obtained, 10.2 g of acetic anhydride were heated ^{to 120 ° C. in an oil bath for 3 hours.} The cooled melt was treated with dilute soda solution and the undissolved crude 2-methyl-3-pyridyl- (4 ') -4-oxo-3,4-dihydroquinazoline was filtered off. It was purified by recrystallization from a ligroin-benzene mixture. The pure substance had a melting point of 153 to 155 ° C. The hydrochloride of the base was obtained by dissolving the same in methanol, introducing hydrogen chloride gas and adding ether to the solution. The hydrochloride of 2-methyl-3-pyridyl- (4 ') -4-oxo-3,4-dihydroquinazoline obtained in this way has a melting point of 268 to 27 ° C.

The production of the starting materials is not claimed here.

Claims (1)

Claim: Process for the preparation of 4-oxo-3,4-dihydroquinazolines the general formula NO" in which R 'is an alkyl radical having 1 to 3 carbon atoms and R "is optionally replaced by a or a plurality of methyl groups substituted pyridyl radicals, as well as their salts with inorganic and organic acids, characterized in that either in a known manner a) an acylanthranil of the general formula
O with an amine of the general formula R "- NH2 in the presence or absence of Solvents heated or b) an o-aminobenzoic acid amide of the general formula CO - NH - R " NH ₂ with a carboxylic anhydride of the general formula R'- CO R'- CO or an anhydrous carboxylic acid of the general formula R '- COOH or c) an o-acylamino-benzoic acid of the general formula COOH NH - CO - R ' with an amine of the general formula R "- NH2 in the presence of phosphorus halides or phosphorus oxyhalides heated in inert solvents, where in all formulas R 'and R "are the above have given meaning, and optionally subsequently obtained bases with acids converted into their salts.