CS269461B1 - Ketone derivatives of 4 / 3H / -quinazolinone - Google Patents

Abstract

The solution concerns ketonic derivatives of 4/3H/-quinazolinone, substituted in position 3 by an oxoethyl or oxopropyl group, the carbonyl of which is bound to an aromatic residue. The substances are prepared by alkylation of 4/3H/-quinazolinone with the corresponding halogen ketones in dimethylformamide in the presence of sodium hydride or with Mannich bases in aqueous methyl alcohol. The compounds were tested for analgesic activity and one of the series of prepared substances, 3-(2-oxo-2-(4- -biphenylyl)ethyl)-4/3H-quinazolinone, showed the same analgesic activity and lower toxicity in a comparative test with aminophenazone compared to the standard.

Description

The invention relates to ketone derivatives of 4(3H)-quinazolinone of the general formula I

/1/ in which n represents 1 or 2 and R represents 4-isopropylphenyl, 4-isobutylphenyl, 3,4-dimethoxyphenyl, 2,4-dichlorophenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-biphenylyl and 2*4'-difluoro-4-biphenylyl.

These new compounds were tested for analgesic efficacy and in comparative tests with aminophenazone /1-phenyl-2,3-dimethyl-4-dimethylamino-5-pyrazolone/, some of them showed significant analgesic activity and mostly significantly lower toxicity compared to the standard.

The invention also relates to a process for the production of compounds of general formula I. According to the invention, they are prepared, for example, by alkylating 4(3H)-quinazolinone with a haloketone of general formula II

RCO/CH ₂ / _n X /11/, in which R has the same meaning as in formula I, X represents a chlorine or bromine atom, in an inert solvent environment, such as dimethylformamide, at a temperature of 90 to 110 °C, or the compounds of formula I in which n represents 2 can also be prepared by alkylation of 4/3H/-chloroazolinone with Mannich bases of the general formula III rcoch ₂ ch ₂ N\__/111/, in which R has the same meaning as in formula I, in an aqueous methanol environment at a temperature of 90 to 100 °C.

All intermediates, with the exception of 4-(2,4-difluorophenyl)-bromoacetophenone and 4-(3-piperidinopropionyl)-2,4-difluoro-4-biphenyl, are known and have been prepared by known methods. Both of these previously undescribed compounds were obtained from 4-(2,4-difluorophenyl)-acetophenone by known procedures.

In the pharmacological evaluation of ketones of general formula I, the substance 3-/2-oxo-2-/4-biphenylyl/ethyl-4/3H/-quinazolinone in particular showed a significant analgesic effect. The substances were evaluated in the acute oral toxicity test in mice and the analgesic efficacy was evaluated in the intraperitoneal irritation test after oral administration and is expressed in % pain inhibition. The results are shown in Table 1.

Table 1

Substance

LD 50 mg/kg p.o.

% pain inhibition dose 100 mg/kg p.o.

3-(2-oxo-2-(4-biphenylyl)ethyl)-4-(3H)-quinazolinone greater than 1000 aminophenazone

804

Aminophenazone, which has been used as a standard in analgesic tests, has a number of undesirable side effects. For this reason, its use is increasingly restricted and in many countries it has been completely excluded from human medicine.

CS 269461 Bl

The method of producing the compounds of general formula I and the previously undescribed compounds of formulas II and III is described in more detail in the following examples.

Example 1

To a solution of 5.84 g of 4/3H/-quinazolinone in 80 ml of dimethylformamide is added gradually 1.24 g of 80% sodium hydride at an initial temperature of 25 °C, the mixture is heated for 15 min. to 100 °C and after cooling to 50 °C, a solution of 11 g of 4-phenyl-^-bromoacetophenone in 25 ml of dimethylformamide, heated to 40 to 45 °C, is added. The mixture is then kept at 98 to 105 °C for 2 h. After cooling to 20 to 25 °C, it is diluted with water, the crude product is filtered off with suction and recrystallized from nitromethane.

10 g of the desired substance are obtained, mp 186-187°C.

In the same way, 3-(2-oxo-2-(2,'4'-difluoro-4-biphenylyl)ethyl-4(3H)-quinazolinone was prepared, m.p. 222-223 °C (nitromethane). By the same alkylation, but using chloroketones of formula II, in which n is 2, compounds 1 to 4 were obtained, listed in Table 2.

Example 2

A mixture of 7.1 g of 4-(3-piperidinopropionyl)-2,'4'-difluorobiphenyl hydrochloride, 3.1 g of 4(3H)-quinazolinone, 18 ml of methyl alcohol and 26 ml of water is heated to boiling under stirring for 2 h. After cooling, the crude product is filtered off with suction and recrystallized from 2-propanol. 3.8 g of the desired substance is obtained, m.p. 149-151 °C.

In the same way, compounds 5 to 7, listed in Table 2, were obtained.

Table 2

Substance R n Φ ₍ . t. °C 1 4-/CH ₃ / ₂ CHC ₆ H ₄ 2 109 until 110 2 4-/CH ₃ / ₂ CHCH ₂ C ₆ H ₄ 2 104 until 105 3 4-CH^0C.H> 3 0 4 2 138 until 13» 4 4-ClC ₆ H ₄ 2 149 until 150 5 4-C ₆ V ₆ H ₄ 2 186 until 187 6 3,4-/CH ₃ O/ ₂ C ₆ H ₃ 2 163 until 164 7 2,4 _{- CL2C6H3} 2 114 until 115 Substance 5 was crystallized from nitromethane, all others from 2-propanol,

Example 3

Preparation of 4-[2'4'-difluorophenyl-N^-bromoacetophenone

To a solution of 22.4 g of 4-/2,4-difluorophenyl/acetophenone in 105 ml of acetic acid, 15.4 g of bromine are gradually added dropwise with stirring at a temperature of 30 to 40 °C. The mixture is kept for 2 h with stirring at 20 to 25 °C, cooled to 10 to 15 °C and stirred with ice water. The product is filtered off with suction, washed with water and, after drying, recrystallized from n-hexane. 16.4 g of the desired substance are obtained, m.p. 82 to 84 °C.

CS 269461 Bl

Example 4

Preparation of 4-(3-piperidinopropionyl)-2,*4*-difluorobiphenyl

A mixture of 24.4 g of piperidine hydrochloride, 9 g of paraformaldehyde, 60 ml of ethyl alcohol, 0.5 ml of concentrated hydrochloric acid and 46.5 g of 4-/2^4'-difluorophenyl/acetophenone is heated to boiling for 1 h, another 6 g of paraformaldehyde are added and heating to boiling is continued for another 2 h. After the reaction is complete, 500 ml of acetone is added to the hot mixture and, after cooling to 20 to 22 °C, the crude product is filtered off with suction and recrystallized from a mixture of ethyl alcohol:acetone /2:4/. 38.8 g of the hydrochloride of the desired Mannich base are obtained, m.p. 215 to 217 °C. .

Claims (3)

SUBJECT OF THE INVENTION 1. Ketone derivatives of 4/3H/-quinazolinone of general formula I 2. A method for producing ketonic derivatives of 4/3H/-quinazolinone according to point 1 of general formula I, characterized in that 4/3H/-quinazolinone is alkylated with helegone ketone of general formula II RC0/CH ₂ / _n X /11/, in which R has the same meaning as in formula I, X represents a chlorine or bromine atom, in the presence of sodium hydride in an inert solvent environment, such as dimethylformamide, at a temperature of 90 to 110 °C. ₂ / _n C0R /1/, in which n represents 1 or 2 and R 4-isopropylphenyl, 4-isobutylphenyl, 3,4-dimethoxyphenyl, 2,4-dichlorophenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-biphenylyl and 2,'4'-difluoro-4-biphenylyl. 3. A method for producing ketonic derivatives of 4(3H)-quinazolinone according to point 1 of general formula I, where n is 2, characterized in that 4(3H)-quinazolinone is alkylated with Mannich bases of general formula III rcoch ₂ ch ₂ n^ /111/, in which R is the same as in formula I, in an aqueous methanol environment at a temperature of 90 to 100 °C.