DE1280874B - 2-methyl-3- (2-dimethylaminophenyl) -8-amino-3H-quinazolone- (4) - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. Cl .:

C07d

A 61k

German class: 12 ρ-7/01
30 h-2/36

Number: 1 280 874

File number: P 12 80 874.1-44 (B 73447)

Filing date: September 9, 1963

Opening day: October 24, 1968

The invention relates to 2-methyl-3- (2-dimethylaminophenyl) -8-amino-3 H-quinazolone- (4) of the formula

N (CHj) ₂

NH,

as well as its physiologically acceptable acid addition salts and processes for the preparation thereof. The preparation of the new compound of the formula I takes place according to the following per se known Methods:

a) Reduction of quinazolones of the general formula

2-methyl-3- (2-dimethylaminophenyl) -8-amino-3H-quinazolone- (4)

Applicant:

C. H. Boehringer Sohn, 6507 Ingelheim

Named as inventor:

Dr. Alex Heusner,

Dr. Karlzeile, 6507 Ingelheim

as well as organic acids. The following acids may be mentioned as examples: hydrochloric acid. Hydrobromic, phosphoric, sulfuric, acetic, lactic, salicylic, tartaric, methanesulphonic, benzoic acid. The nitro or nitrosoquinazolones of the formula II used as starting materials are, for example by condensation of a nitro or nitrosoacetylanthranilic acid of the general formula

II

N (CH ₃ J ₂

in which R is a nitro or nitroso group, with catalytically excited hydrogen or with hydrogen in statu nascendi, or b) hydrogenolytic cleavage of the radical Z from Compounds of the general formula

O

IV

N (CH ₃ ),

NH-Z

in which Z denotes the carbobenzoxy or benzyl radical, or

c) Condensation of 2-acetylamino-3-aminobenzoic acid with 2-dimethylaminoaniline in the presence dehydrating agents.

The compound of the formula I can be converted into its physiologically tolerated salts in a customary manner. For salt formation are both inorganic

COOH

NH - COCH,

in which R is a nitro or nitroso group, with 2-dimethylaminoaniline in the presence of dehydrating agents Means made.

The preparation of the starting compounds of the formula IV can, for. B. by condensation of N-protected aminoacetylanthranilic acids of the general formula

COOH

NH - COCH ₃

NH-Z

in which Z has the abovementioned meaning, with 2-dimethylaminoaniline in the presence of dehydrating agents Means done.

The quinazolone of the formula I according to the invention is distinguished by valuable pharmacological properties Properties. In particular, it has a strong sedating effect with low toxicity. Especially over-

- «(" - 6? 8 167f

surprising is the fact that, in contrast to known compounds of the prior art the compound according to the invention does not have any central excitation component.

The 2-methyl-3- (2-dimethylaminophenyl) according to the invention - 3 H - 8 - amino - quinazolone - (4) was known for its sedative effect with the 2 - Methyl - 3 - (2 - methylphenyl) - 3 H - chinazolone) (Methaqualone) and the one from the British Patent specification 916 139 known 2-methyl-3- (2-methylphenyl) -3 H-o-amino-quinazolone- ^) compared. The patent specification says nothing about a sedative effect of the last-mentioned compound noted.

The "atactic dose" (AD50) at which the movements of the test animals are no longer coordinated, and the "corrective reflex dose" (SD50) at which the animals the side position can no longer stand on their own feet, as well as the lethal dose (LD50) certainly. The therapeutic range (T) was expressed as a quotient

LD

^r 50

V ₂ (AD ₅₀ + SD ₅₀ )

calculated. The substances were given orally in an oil-water emulsion, as test animals Mice. The following values were obtained:

link AD ₃₀ SD ₅₀ LD ₅₀ T mg / kg mg / kg mg / kg Methaqualone 145 580 2100 5.7 2-methyl-3- (2-methyl- phenyi) -3 H-6-amino- quinazolone- (4) (British Patent 916 139) 115 400 2050 7.9 2-methyl-3- (2-dimethyl- aminophenyl) - 3 H-8-animo-chin- azolone (4) 66 470 2646 10

45

With regard to the anticoavulsive effectiveness for the quinazotone according to the invention Methaqualone has a surprisingly great superiority:

Methaqualone ED »

2-methyl-3- {2-dimethyl-

aminopbenyi) -

3 H-8-ammo-chin-

azoIon- (4) ED50

154 mg / kg mouse

30 mg / kg mouse

⁵⁵

It was not foreseeable that the Compound such pronounced sedative and surprisingly also anticonvulsant properties in the absence of a central excitation component.

Experience in the synthesis of substituted barbituric acids (B. D ο r a η, Barbituric acid hypnotics, Medicinical Chemistry, Vol. IV, p. 34, Verlag Wiley and Sons, New York 1959) on the contrary, one might expect that the introduction of a basic residue would reduce the edifying effect would be.

example

10.8 g of 2 - methyl - 3 - (2 - dimethylaminophenyl} -8-nitro-3 H-quinazolone- (4) are hydrogenated with about 10 g of Raney nickel in 200 ml of dioxane at room temperature and atmospheric pressure; the hydrogen uptake is after The solution freed from the catalyst is evaporated in vacuo, the hydrogenation product remaining in crystalline form; yield almost quantitative; melting point after recrystallization from ethanol-water 189 to 190 ^° C.

The nitro compound used as the starting product. Melting point 214 to 216 ^° C., can be obtained in the usual way by reacting 3-nitroacetylanthranilic acid with o-amino-dimethylaniline in the presence of dehydrating agents, such as phosphorus oxychloride or phosphorus trichloride, or by direct reaction of 3-nitroacetylanthraniI with 2-dimethylaminoaniline.

Claims (3)

Patent claims: 1. 2 - methyl - 3 - (2 - dimethylaminophenyl) -8-amino-3 H-quinazoIon- (4) and its physiologically compatible acid addition salts. 2. Process for the preparation of the compound according to claim 1, characterized in that that one in a known manner a) Chinazolones of the general formula in which R is a nitro or nitroso group, reduced with catalytically excited hydrogen or with hydrogen m statu nasendi or that one
b) from quinazolones of the general formula N (CH ₃ ); 3) 2 IV NH-Z in which Z denotes the carbobenzoxy or benzyl radical, the radical Z is split off hydrogenolytically or that one
c) 2 - Acetyiamino - 3 - aminobenioesäure is condensed with 2-dimethylaminoaniline in the presence of dehydrating agents and that the compound obtained is optionally converted into its physiologically acceptable acid addition salts. Considered publications:
British Patent No. 916 139. Legacy Patents Considered:
German «Patent No. 1 232 152.