CS208131B2 - Method of making the new derivatives of the 1,3-benzoxazine-2,4-dione - Google Patents

Description

(54) A process for the preparation of new 1,3-benzoxazine-2,4-dione derivatives

The present invention relates to a process for the preparation of novel 1,3-benzoxazine-2,4-dione derivatives of the general formula I

(I) in which ~

R is C1-C4alkyl, o-phenoxyphenyl, o-thiophenoxyphenyl, benzyl, furfuryl or 2-pyridyl;

R 'represents a hydrogen, chlorine, bromine or methoxyl radical;

R is hydrogen, chlorine or methyl;

R 'represents a hydrogen, chlorine or bromine atom.

The derivatives of the formula I have valuable pharmacological properties.

According to the invention, the derivatives of the formula I are obtained by reaction of a salicylamide derivative of the formula II

(II) wherein R, R *, R **, R *, have the same meanings as in Formula I, with ethyl chloroformate.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The preparation of certain derivatives of formula (I) is described in detail below by way of examples, but these examples do not limit the invention in any way.

He did

Preparation of 6-chloro-3-methyl-1,3-benzoxazine-2,4-dione

To a solution of 18.6 g (0.1 mol) of 5-chloro-N-methylsalicylamide in pyridine was slowly added (over half an hour) 37 ml (0.375 mol) of ethyl chloroformate. The mixture was refluxed for 7 hours, allowed to cool, diluted with water, filtered and washed with distilled water. Recrystallized from chloroform, washed with methanol cooled to 5 ° C to give 6-chloro-3-methyl-1,3-benzoxazine-2,4-dione, m.p. 151-153 ° C (see Table I).

Examples 2 to 17

Analogous to Example 1, for example, derivatives can be obtained whose physicochemical constants, such as solvents for crystallization, melting points, and characteristic IR bands are given in Table I.

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Analgesic efficacy

The analgesic activity of the compounds of formula (1) was evaluated in male mice weighing between 20 and 25 g. The volume of solution administered is 25 ml / kg and the concentration of test substance varies according to the dose administered.

Pain was induced in animals by intraperitoneal injection of 0.2 ml / 20 g of a 0.32 mg / ml acetylcholine bromide solution. Five minutes before administration of the test substance, acetylcholine is injected into a group of 5 mice. The test substance is then administered and acetylcholine is re-injected at 20, 40, 80, 120 and 160 ml intervals. The number of abdominal wall contractions induced by acetylcholine injection over 5 minutes is counted.

The analgesic potency is calculated using the following formula:

It »100 - (Nt / No) .100 = 100 (1-Nt / No) where It = pain relief after t minutes,

Number of abdominal wall contractions prior to administration of test substance, and

Nt = number of abdominal wall contractions at t minutes after test substance administration.

Multiple doses of each agent are administered to determine the dose that will cause analgesia (DA-50) in 50% of the animals.

For each of these doses, It is calculated over a time interval of 20, 40, 80, 120 and 160 minutes. The mean of the five It values for each dose is taken as an analgesic effect. The analgesic effects are plotted as the logarithmic function of the dose in question.

This curve yields an analgesic dose of fifty, i.e., a dose that produces an analgesic effect in 50% of the animals.

By way of example, the results obtained for certain derivatives of the invention of general formula I are given in Table II below.

Acute toxicity

Acute oral toxicity is determined in mice weighing 20-25 g using groups of 6 animals each. Multiple doses rising in a geometric series are administered. The observation period is 72 hours. The 50% death dose (LD-50) is calculated graphically using log-probit paper.

By way of example, Table II shows the results obtained for some of the derivatives of the invention of formula (I).

Table II

Example # Substance Dose in m / ki DA-50 DL-50 1 β-chloro-3-oettyl-1,3-benzoxaine-2,4-dione 30 233 2 6-Bromo-4- (4-ethoxy) -3,3-benzoxaazin-2,4-dione 90 717 3 .alpha.-chloro-3-propyl-1,3benaoxaine-2,4-dione 240 > 650 8 .alpha.-chloro-3-l-1,3benaoxaine-2,4-dione 280 > 550 9 б-chloro-3- (o-phenoxyphenrl) - 1,3-benzoxazine-2,4-dione 675 > 750 10 6-cis-3- (o-thoophene) fenfl-1,3-benzoxaine-2,4-dione 650 > 1,500 12 6-chloro-3-ethyl-1,3-benzoxaine-2,4-yne 172 > 250

Anti-inflammatory activity

Anti-inflammatory activity was assessed in male Sprague-Dawley rats. It is induced in the paw by subplantar injection of 1% cerragenine solution. The paw volume is measured before oral administration and after two and five hours using a plethome meter. Anti-inflammatory-

The efficacy is calculated from the control group. They are given as an example below in Table III results obtained for Example 1. T a b u 1 k a III Example Substance Dose Anti-inflammatory activity (ms / ke) 2 hours 5 hours 1 .alpha.-chloro-3-oetyl-1 I.3- -benzoxaain-2, A-dione 100 ALIGN! 26% 30%

Because of their good pharmacodynamic properties, the compounds of the formula I are suitable for use in hummus medicine and / or veterinary medicine as analgesic, antipyrotic and anti-inflammatory drugs.

Pharmaceutical compositions which contain, in addition to a pharmaceutically acceptable carrier, at least one derivative of the general formula I according to the invention have a very wide field of therapeutic use and can be used in particular in the pharmaceutical composition. Surgery, rheumatology, odontostomatology, oto-rhino-laryngooooii, pneumonia, cardiology, gynecology and urology. These pharmaceutical compositions will be used to treat a variety of manifestations of diabetes, such as headache, toothache. Nevuragia, οοη ^ ™ο^ boooooooooooooooooooooooooooooooooo booooooooooooooooooooooooooooooooooooooooooo reoo reooooooo reoo re re re re re re re re re re re re re re re re re re re re re re re re re re re re re re re re re re re re re re re re.

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In human therapy, a dose of the compounds of the invention of between about 100 and 300 m / d, for example in the form of tablets, wafers or suppositories, is suggested.

The three general ileic derivatives of the present invention are exemplified below.

Tablet composition example

6-chloro-3-methyl-1,3-benzoxazine-2,4-dione 100mg microcrystalline, partially depolymerized cellulose (avicel pH-102) 100mg carboxymethylated Starch (Primojel) 10mg colloidal silicon dioxide (Herosil-200) 1mg magnesium stearate 2mg

Weight tablet 213mg

Example of wafer composition

6-chloro-3-methyl-1,3-benzoxazine-2,4-dione 100 lactose 75 microcrystalline, partially depolymerized cellulose (Avicel pH-102) 25 colloidal silicon dioxide (Aerosil-200) 1 magnesium stearate __ £

Weight of wafer 203

Example of suppository composition

6-chloro-3-methyl-1,3-benzoxazine-2,4-dione 0.2 g semisynthetic natural fatty acid triglycerides (Monolen) 1.8 g

Suppository weight 2.0 g

Claims (1)

SUBJECT OF THE INVENTION Process for the preparation of the novel 1,3-benzoxazine-2,4-dione derivatives of the general formula I R ^{, / z} (I) wherein R is C1-C4alkyl, o-phenoxyphenyl, o-thiophenoxyphenyl, benzyl, furfuryl or 2-pyridyl; R * represents a hydrogen, chlorine, bromine atom or a methoxy radical; R is hydrogen, chlorine or methyl; R ^z is hydrogen, chlorine or bromine, characterized by reacting a derivative of salicylamide of formula II O (II) wherein R, R ', R **, R ^{/ z} * are as defined for Formula I, with ethyl chloroformate.