CA1128511A

CA1128511A - Preparation and pharmaceutical applications of 1,3-benzoxazine-2,4-dione derivatives

Info

Publication number: CA1128511A
Application number: CA334,287A
Authority: CA
Inventors: Antonio Esteve-Subirana
Original assignee: Provesan SA
Current assignee: Provesan SA
Priority date: 1978-08-25
Filing date: 1979-08-22
Publication date: 1982-07-27
Also published as: FI68818B; GB2031410B; SE446865B; GR69619B; FR2434158A1; PL217893A1; SU797576A3; IL58096A0; CS208131B2; PT70107A; RO78156A; HU182916B; YU207379A; ATA568379A; AR222494A1; AT373591B; FI68818C; CH643548A5; IL58096A; GB2031410A

Abstract

Nouveaux dérivés de 1,3-benzoxazine-2,4-dione, leur préparation et leur application en tant que médicaments PROVESAN, S.A. DESCRIPTIF La présente invention concerne de nouveaux dérivés de 1,3-benzoxazine-2,4-dione, leur préparation et leur application en tant que médicaments. Les dérivés selon l'invention répondent à la formule générale I (I) dans laquelle R représente un radical alkyle, notamment un radical alkyle inférieur de préférence en C1 à C4, un groupe ortho-phénoxy-phényle, ortho-thiophénoxy-phényle, benzyle, furfuryle ou bien 2-pyridyle ; R' représente un atome d'hydrogène, de chlore, de brome ou radical méthoxyle ; R" représente un atome d'hydrogène, de chlore ou un radical méthyle, et R"' représente un atome d'hydrogène, de chlore ou de brome. Application notamment en tant qu'agent analgésique.New derivatives of 1,3-benzoxazine-2,4-dione, their preparation and their use as medicaments PROVESAN, SA DESCRIPTION The present invention relates to new derivatives of 1,3-benzoxazine-2,4-dione, their preparation and their application as drugs. The derivatives according to the invention correspond to the general formula I (I) in which R represents an alkyl radical, in particular a lower alkyl radical preferably in C1 to C4, an ortho-phenoxy-phenyl, ortho-thiophenoxy-phenyl, benzyl group. , furfuryle or 2-pyridyle; R 'represents a hydrogen, chlorine, bromine or methoxyl radical; R "represents a hydrogen, chlorine or methyl radical, and R" 'represents a hydrogen, chlorine or bromine atom. Application in particular as an analgesic agent.

Description

5~
La présen-te illvention concerne de nouveaux dérivés de 1,3~benzoxazina-2,4-dione, leur preparation et leur ap~lica-tion en -tant que ~édicamentsO
Les nouveaux dérivés, objet de la présente inven-tion, répondent à la formule générale I

\ ~ N ~ (I) ~0 0 R
R"' dans laquelle R représente un radical alkyle, notamment un radiGal alkyle in~érieur de préférence en C1 à CL~ un groupe ortho--phénoxy-phényle, ortho-thiophénoxy-phényl~, benzyle, furfuryle ou bien 5 ~
The present invention relates to new derivatives of 1,3 ~ benzoxazina-2,4-dione, their preparation and their ap ~ lica-tion as ~ edicamentsO
The new derivatives, the subject of this invention, meet the general formula I

N ~ (I) ~ 0 0 R
R "' in which R represents an alkyl radical, in particular an alkyl radiGal in ~ érieur preferably in C1 to CL ~ an ortho-phenoxy- group phenyl, ortho-thiophenoxy-phenyl ~, benzyl, furfuryl or else

2-pyridyle ;
R' représente un atome d'hydrogène, de chlore, de brome ou un rad.ioal méthoxyle ;
R" représente un atome d'hydrogène, de chlore ou un radical méthyle, et R"' représente un atome d'hydrogène, de chlore ou de brome.
La présente invention se rapporte également aux sels d'addition d'acides physiologiquement acceptables~ tels ~ue les halogénohydrates et en particulier les chlorhydrates, des dérivés de ~ormule générale I.
Les dérives de formule generale I se sont reveles posseder de précieuses propr;etes p~armacolo~ues. La presente inYention se rapporte donc egalement ~ l'application de ces composes en tant que medicaments~, ainsi qu'aux compositions pharmaceutiques les contenant ~ titre de principe actif.

-~;
'., ' ~1;285~
La pré,sente invention se rapporte également à la prépa-ration des dérivés de formule générale I. Selon l'invention, on obtient c~s déri.vés de formule générale I :
a) par réact:ion d'un dérivé de salicylamide de formllle générale II
o ~ (II) R" OH
R"' dans laquelle R,R',R" et R"' ont les significations indiquées à propos de la formule générale I, avec du chloroformiate d'éthyle, ou bien b) par réaction d'u~ dérivé d'acide salicylique de ~ormule genérale III

R' ~ ~ - OH
l ll (III) ,~, R" ¦ OH
~"' dans laquelle R',R" et R"' ont les significations indiquées à 2-pyridyl;
R 'represents a hydrogen, chlorine, bromine atom or a rad.ioal methoxyl;
R "represents a hydrogen, chlorine atom or a radical methyl, and R "'represents a hydrogen, chlorine or bromine atom.
The present invention also relates to the salts addition of physiologically acceptable acids ~ such ~ eu halohydrates and in particular hydrochlorides, derived from ~ general formula I.
The derivatives of general formula I are revealed own valuable properties; etes p ~ armacolo ~ ues. The current inYention therefore also relates to the application of these compounds as medicaments ~, as well as compositions pharmaceuticals containing them as active ingredient.

-~;
'.,' ~ 1; 285 ~
The present invention also relates to the preparation ration of derivatives of general formula I. According to the invention, we obtain c ~ s drift of general formula I:
a) by reaction: ion of a salicylamide derivative of general formllle II
o ~ (II) R "OH
R "' in which R, R ', R "and R"' have the meanings indicated about the general formula I, with ethyl chloroformate, or b) by reaction of u ~ salicylic acid derivative of ~ ormule general III

R '~ ~ - OH
l ll (III) , ~, R "¦ OH
~ "' in which R ', R "and R"' have the meanings indicated in

3~ propos de la formule générale I, avec un isocyanate de formule générale IV
` O - C = N - R (IV) dans laquelle R a la signification donnée à propos de la formule générale I.

~2~
On décrira ci-après plus en détail, à titre de simple exemple non limitatif, la préparation de quelques derivés ~e formule générale I.

Exemple 1 = _ = = =
Préparation du 6-chloro-3-méth~l-1.3-benzoxazine-2,4-dione On ajoute lentement (1/2 heure) 37 ml (0,375 mole) de chloroformiate d'éthyle à une solution de 18,6 g (0,1 mole) de 5-chloro-N-méthylsalicylamide dans la pyridine. On laisse à
reflux pendant 7 heures, on laisse refroidir, on dilue avec de l'eau, on filtre et on lave avec de l'eau distillée. On recris~
tallise avec du chloroforme, on lave avec du méthanol à 5C et on obtient le 6-chloro-3-méthyl-1,3-benzoxazine-2,4-dione de point de fusion 151-153C (voir tableau I).

Exemple 2 ~ = = -- = _ = _ = =
`~
Préparation du_6-bromo-3~m-thyl-1~3-benzoxazine-2,4-dione .
On ajoute 7J5 ml (0,12 mole) d'isocyanate de méthyle et 5 ml de triéthylamine à une solution de 21,7 g (0,1 mole) dlacide 5-bromosalicylique dans 150 ml de benzène~ ~;
On agi-te le mélange pendant 1 heure à temperature ambian--te et on laisse ensuite à reflux pendant 6 heuresO On évapore à sec, on recristallise avec du méthanol et on obtient le 6-bromo-3-méthyl-1,3-benzoxazine-2~4-dione de point de fusion 186 (voir tableau I).

Exemples 3 à 1~
--==o__a==_=a==_ En opérant comme indiqué précédemment aux exemples 1 et 2, on peut par exemple obtenir les dérivés dont un certain nombre de constantes physico-chimiques, tels que les sol~ants de cristallisation, les points de fusion et les bandes carac-téristiques du spectre infra rouge, sont mentionnés au tableau I cl-eprès.

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Activit anal~és aue L'a~tivité analgésique des dérivés de formule générale I
a été déterminée chez la souris mâle d'un poids compris entre 20 et 25 g. Le produit à tester s'administre en suspension dans la gomme arabique à 5 % par voie orale au moyen d'une sonde oesophagique. ~e volume de la solution administrée est de 25 ml/kg et l'on change la concentration du produit essayé selon la dose administrée~
On provoque la douleur chez les animaux moyennant une injection intrapéritonéale de Ot2 ml/20 g de solution de bromure d'acétylcholine d'une concentration de 0,32 mg/mlO Cinq minutes avant l'administration du produit testé, on injecte l'acétyl-choline a un lot de 5 souris. On administre ensuite le produit ~ tester, on effectue à nouveau l'injection d'ac~tylcholine après 20,40,80,120 et 160 minutes. On compte toujours le nombr~
de contorsions par injection d'acétylcholine pendant 5 minutes.
On calcule l'activité analgésique au moyen de la formule suivante :
It , 100 -(Nt/No),100 , 10() (1-Nt/No3 ou It _ inhibition de la douleur après t minutes No - nombre de contorsions avant l'administration du produit Nt = nombre de contorsions après t minutes de 1'admi-nistration du produit.
On administre plusieurs doses de chaque produit pour pouvoir déterminer la dose analgésique cinquante pour cent ~DA-50~.
Avec chacune de ces doses on calcule It aux temps 20, 40,80,120 et 160 minutesO On prend comme effet analgésique la moyenne de ces cinq valeurs de It pour chaque dose. On repré-sente graphiquement les ef~ets analgésiques en fonc-tion du logarithme de la dose correspondante.
A partir de cette courbe on obtient la dose analgésique cinquante, c'est-à-dire la dose qui produit un e~fet analgé-3~ ~ique cinquante pour cent.
A titre d'exemple on a indiqué dans le tableau II ci-après les résultats obtenus pour quelques dérivés de ~ormule I selon l'invention, 195~9.
Tox~cité aigue ~.
On ~étermine la toxicité aiguë par voie orale chez des souris de 20 à 25 g de poids 9 en employant des lots de 6 animaux.
On administre plusieurs doses en progression géométrique, Le temps d'observation est de 72 heures. La dose léthale cinquante pour cent (DL-50) se calcule graphiquement au moyen de papier logarithmique-probalistique.
A titre d'exemple on a indiqué dans le tableau II ci-aprè~ les résultats obtenus pour quelques dérivés de formule I
selon l'invention.
TABLEAU II
. _ _ _ . . . .. ... ~
Exemple Dérivé Doses en mg/kg N . .

_ . _ _ _ _ ....
1 6-chloro-3-méthyl-1,3- O
benzoxazine-2,4-dione 3 33 ~ .
2 6-bromo-3-méthyl-1,3- O
benzoxa2ine-2,4-dione 9 7 7 3 6-chloro-3-propyl-1,3- 240 ~' 650 benzoxazine-2,4-dione ~ . . _ _ 8 6-chloro-3-furfuryl-1,3- 280 550 benzoxazine-2,4-dione ~
. ,.. , .,_v. ,,,,,, 9 6~chloro-3~(o-phénoxyphényl ) 6 _ _ -1,3-benzoxazine-2,4-dione . _ > 750 6-chloro-3-(o-thiophénoxy-phényl)-1,3-benzoxazine- 650 ~1 500 2,4-dione _ _ _ 12 6-chloro-3-éthyl-1,3- 1' ~
. benz~azine 2,4-d~-De ~ 2~0 ~L~Z~3Sll Activité anti-inila~Jmato e On détermine l'activi-t2 anti~inflammatoire chez le rat mâle de souche Sprague-Dawley. On provoque un oedème dans la patte par injection subplantaire d'une solution de carraghénine 1 %. On mesure le volume de la patte avant l'administration du produit par voie orale après deux et cinq heures avec un pléthysmomètre. L'activité anti-inflammatoire est calculée par rapport à un lot témoin. A titre d'exemple on indiquera dans le tableau III ci-après les résultats obtenus pour le dérivé de l'exemple 1.
TABLEAU III
.. . . .... ..
Exemple ~érivé Dose Activité anti-inflam-(mg/kg) matoire 2 heures 5 heures _ _ . ..
1 6-chloro-3-méthyl-1,3~benzoxazine- 100 26 % 30 %
_.... _ 2,4-dlone _ _ .

Compte -tenu de leurs bonnes propriétés pharmacodynamiques, les dérivés de formule générale I sont donc susceptibles d'~tre utilisés en médecine humaine et/ou vétérinaire, en tant qu'a-gents analgésiques, antipyrétiques et anti-inflammatoires.
Les compositions pharmaceutiques qui contiennent selon l'invention, outre un support pharmaceutiquement acceptable, au moins un déri~é de formule générale I ont un champ d'application thérapeuti~ue très vaste et peuvent être utili~s~notamment en traumatologie, chirurgie, rhumatologie, odonstostomatologie,-oto-rhino-laryngologie, pneumologie, cardiologie, gynécologie et urologie. Ces compositions pharmaceutiques seront, par exem- -~
ple, utilisées pour le traitement de diverses manifestations douloureuses, de céphalées, de migraines, de rages de dents, de névralgies, de douleurs mens-truelles, de rhumatismes inflam-- matoires, de douleurs arthrosiques~ d'états fébriles, de rhumes, de grippes e-t d'infec-tions saisonnières, En thérapeutique humaine, la dose proposée des dérivés de la présente invention est environ comprise entre 100 et 300 mg/jour, par exemple administrée sous la forme de comprimes~
de gélules ou de suppositoires.
On indiquera ci-après, à titre d'exe~ples, trois formes galléniques particulières des déri~és, obje~s de la présente inventionO

Exemple de formule par comprimé

6 chloro-3-méthyl-1,3-benzoxazine 2,4-dione .... 0..... 100 mg .. 10 Avicel1pH~102 .......... ,....... ,............ 0~ . 100 mg Primoje~ ................ 0.. ,.O............... ......,. 10 mg Aérosil~200 ~ s~o~ mg Stéarate de magnésium ...... .~................ ....,.,. 2 mg Poicls comprimé ... , 213 mg Exemple de formule par ~élule 6-c~oro-3-méthyl-1,3-benzoxazine-2,4-dione .................. ,0.~ 100 mg Lactose .................................. ~...... ~........... ...~ 75 mg Avicel pH-102 ....... .,,....... "................. ,.,..... ,... ..., 25 mg A~rosil-200 ,... ,~... ,,,.0,,......... ,,,.. O...... ..,,,O...... ..., 1 mg 2~ Stéarate de magnésium ......... ,........... ...~,... ,.,,. 2 mg Poids gélule ............................. 203 mg 1::
6-chloro-3-méthyl-1,3-benzoxazine-294-dione ,.,...0~ 0,2 g Monolène ....... ,.. ,.. 0........ .,O.. 1,8 g Poids suppositoire .... 2,0 g 3 ~ about the general formula I, with an isocyanate of general formula IV
`O - C = N - R (IV) in which R has the meaning given about the general formula I.

~ 2 ~
We will describe below in more detail, by way of simple nonlimiting example, the preparation of some derivatives ~ e general formula I.

Example 1 = _ = = =
Preparation of 6-chloro-3-meth ~ l-1.3-benzoxazine-2,4-dione Slowly added (1/2 hour) 37 ml (0.375 mole) of ethyl chloroformate to a solution of 18.6 g (0.1 mole) of 5-chloro-N-methylsalicylamide in pyridine. We leave to reflux for 7 hours, allow to cool, dilute with water, filter and wash with distilled water. We're recruiting ~
tallises with chloroform, washed with 5C methanol and 6-chloro-3-methyl-1,3-benzoxazine-2,4-dione is obtained from melting point 151-153C (see table I).

Example 2 ~ = = - = _ = _ = =
`~
Preparation of 6-bromo-3 ~ m-thyl-1 ~ 3-benzoxazine-2,4-dione .
75 ml (0.12 mol) of methyl isocyanate are added and 5 ml triethylamine to a solution of 21.7 g (0.1 mole) 5-bromosalicylic acid in 150 ml of benzene ~ ~;
The mixture is stirred for 1 hour at room temperature--te and then allowed to reflux for 6 hours O evaporated when dry, recrystallized from methanol and the 6-bromo-3-methyl-1,3-benzoxazine-2 ~ 4-dione of melting point 186 (see Table I).

Examples 3 to 1 ~
- == o__a == _ = a == _ By operating as indicated previously in examples 1 and 2, one can for example obtain the derivatives of which a certain number of physicochemical constants, such as sol ~ ants of crystallization, melting points and characteristic bands of the infrared spectrum, are mentioned in the table I will next.

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Anal activity The analgesic activity of the derivatives of general formula I
was determined in male mice weighing between 20 and 25 g. The product to be tested is administered in suspension in 5% gum arabic orally using a probe esophageal. ~ e volume of the solution administered is 25 ml / kg and the concentration of the product tested is changed according to the dose administered ~
Pain is caused in animals with intraperitoneal injection of Ot2 ml / 20 g bromide solution acetylcholine at a concentration of 0.32 mg / mlO Five minutes before administering the tested product, acetyl-choline has a lot of 5 mice. We then administer the product ~ test, the injection of ac ~ tylcholine is carried out again after 20,40,80,120 and 160 minutes. We always count the number ~
contortions by injection of acetylcholine for 5 minutes.
The analgesic activity is calculated using the formula next :
It, 100 - (Nt / No), 100, 10 () (1-Nt / No3 or It _ pain inhibition after t minutes No - number of contortions before administration of product Nt = number of contortions after t minutes of administration product administration.
Several doses of each product are administered to ability to determine analgesic dose fifty percent ~ DA-50 ~.
With each of these doses we calculate It at times 20, 40,80,120 and 160 minutes O The analgesic effect is taken average of these five It values for each dose. We represent graphically feel the analgesic effects according to the logarithm of the corresponding dose.
From this curve we obtain the analgesic dose fifty, that is to say the dose which produces an analgesic effect 3 ~ ~ ique fifty percent.
By way of example, it is indicated in table II below.
after the results obtained for some derivatives of ~ ormule I according to the invention, 195 ~ 9.
Tox ~ acute city ~.
Acute oral toxicity is determined in mice of 20 to 25 g of weight 9 using lots of 6 animals.
We administer several doses in geometric progression, The observation time is 72 hours. Fifty lethal dose percent (DL-50) is calculated graphically using paper logarithmic-probalistic.
By way of example, it is indicated in table II below.
after ~ the results obtained for some derivatives of formula I
according to the invention.
TABLE II
. _ _ _. . . .. ... ~
Example Derivative Doses in mg / kg NOT . .

_. _ _ _ _ ....
1 6-chloro-3-methyl-1,3- O
benzoxazine-2,4-dione 3 33 ~.
2 6-bromo-3-methyl-1,3- O
benzoxa2ine-2,4-dione 9 7 7 3 6-chloro-3-propyl-1,3-240 ~ '650 benzoxazine-2,4-dione ~. . _ _ 8 6-chloro-3-furfuryl-1,3-280,550 benzoxazine-2,4-dione ~
. , ..,., _ v. ,,,,,, 9 6 ~ chloro-3 ~ (o-phenoxyphenyl) 6 _ _ -1,3-Benzoxazine-2,4-dione. _> 750 6-chloro-3- (o-thiophenoxy-phenyl) -1,3-benzoxazine- 650 ~ 1,500 2,4-dione _ _ _ 12 6-chloro-3-ethyl-1,3- 1 '~
. benz ~ azine 2,4-d ~ -De ~ 2 ~ 0 ~ L ~ Z ~ 3Sll Anti-inila activity ~ Jmato e Anti ~ inflammatory activity is determined in the rat male of Sprague-Dawley strain. We cause edema in the leg by subplant injection of carrageenan solution 1%. The volume of the leg is measured before administration oral product after two and five hours with a plethysmometer. Anti-inflammatory activity is calculated compared to a control batch. As an example we will indicate in Table III below the results obtained for the derived from example 1.
TABLE III
... . .... ..
Example ~ erected Dose Anti-inflammatory activity (mg / kg) 2 hours 5 hours _ _. ..
1 6-chloro-3-methyl-1.3 ~ benzoxazine- 100 26% 30%
_.... _ 2,4-dlone _ _ .

Given their good pharmacodynamic properties, the derivatives of general formula I are therefore likely to be used in human and / or veterinary medicine, as a analgesic, antipyretic and anti-inflammatory gents.
Pharmaceutical compositions which contain according to the invention, in addition to a pharmaceutically acceptable carrier, minus a derivative of general formula I have a field of application very broad therapy and can be used especially in traumatology, surgery, rheumatology, odonstostomatology, -otolaryngology, pneumology, cardiology, gynecology and urology. These pharmaceutical compositions will, for example- - ~
ple, used for the treatment of various manifestations painful, headache, migraines, toothaches, neuralgia, monthly pain, inflamed rheumatism - pain, arthritis pain ~ feverish states, colds, seasonal flu and infections, In human therapy, the proposed dose of derivatives of the present invention is approximately between 100 and 300 mg / day, for example administered in the form of tablets ~
capsules or suppositories.
Three forms will be indicated below, by way of example.
Gallenic particulars of the drifts, obje ~ s of the present inventionO

Example of formula per tablet 6 chloro-3-methyl-1,3-benzoxazine 2,4-dione .... 0 ..... 100 mg .. 10 Avicel1pH ~ 102 .........., ......., ............ 0 ~. 100 mg Primoje ~ ................ 0 .., .O ............... ......,. 10 mg Aerosil ~ 200 ~ s ~ o ~ mg Magnesium stearate ....... ~ ................ ....,.,. 2 mg Poicls tablet ..., 213 mg Example of formula by ~ elule 6-c ~ oro-3-methyl-1,3-benzoxazine-2,4-dione .................., 0. ~ 100 mg Lactose .................................. ~ ...... ~ ....... .... ... ~ 75 mg Avicel pH-102 ........ ,, ....... ".................,., ....., .. . ..., 25 mg A ~ rosil-200, ..., ~ ... ,,,. 0 ,, ......... ,,, .. O ...... .. ,,, O .. .... ..., 1 mg 2 ~ Magnesium stearate ........., ........... ... ~, ...,. ,,. 2 mg Capsule weight ............................. 203 mg 1 ::
6-chloro-3-methyl-1,3-benzoxazine-294-dione,., ... 0 ~ 0.2 g Monolene ......., .., .. 0 ........., O .. 1.8 g Suppository weight .... 2.0 g

Claims

The realizations of the invention on the subject of-which an exclusive property right or privilege is claimed, are defined as follows:

1. Process for the preparation of new derivatives of 1,3-benzoxazine-2,4-dione with the formula general I:

(I) in which:
R represents a lower alkyl radical in C1 to C4, an orthophenoxyphenyl group, a orthothiophenoxyphenyl group, a group benzyl, a furfuryl group, and R 'represents a chlorine or bromine atom, characterized in that one reacts A) a salicylamide derivative of general formula II:
(II) in which R and R 'have the meanings indicated previously, with ethyl chloroformate, or B) a salicylic acid derivative of general formula III:

(III) with an isocyanate of general formula IV:
O = C = N - R (IV) in which R and R 'have the meanings indicated previously.

2. Process for the preparation of 6-chloro-3-methyl-1,3-benzoxazine-2,4-dione, characterized in that 5-chloro-N-methylsalicylamide is reacted with ethyl chloroformate and the product is recovered longed for.

3. Process for the preparation of 6-chloro-3-ethyl-1,3-benzozazine-2,4-dione, characterized in that 5-chloro-N-ethylsalicylamide is reacted with the ethyl chloroformate and the product is recovered longed for.

4. Process for the preparation of 6-chloro-3-propyl-1,3-benzoxazine-2,4-dione, characterized in that 5-chloro-N-propylsalicylamide is reacted with ethyl chloroformate and the product is recovered longed for.

5. Process for the preparation of 6-chloro-3-furfuryl-1,3-benzoxazine-2,4-dione, characterized in that we react with 5-chloro-N-furfurylsalicylamide with ethyl chloroformate and the desired product.

6. Process for the preparation of 6-chloro-3-(o-phenoxyphenyl) -1,3-benzoxazine-2,4-dione, characterized in that reacting 5-chloro-N- (o-phenoxy-phenyl) salicylamide with ethyl chloroformate and the desired product is recovered.

7. Process for the preparation of 6-chloro-3-(o-thiophenoxyphenyl) -1,3-benzoxazine-2,4-dione, carac-terized by reacting 5-chloro-N- (o-thiophenoxyphenyl) salicylamide with chloroformate ethyl and the desired product is recovered.

8. Process for the preparation of 6-bromo-3-methyl-1,3-benzoxazine-2,4-dione, characterized in that 5-bromo-N-methylsalicylamide is reacted with ethyl chloroformate and the product is recovered longed for.

9. Process for the preparation of 6-chloro-3-methyl-1,3-benzoxazine-2,4-dione, characterized in that the methyl isocyanate is reacted with the acid 5-chlorosalicylic acid and the desired product is recovered.

10. Process for the preparation of 6-chloro-3-ethyl-1,3-benzoxazine-2,4-dione, characterized in that ethyl isocyanate is reacted with 5- acid chlorosalicylic acid and the desired product is recovered.

11. Process for the preparation of 6-chloro-3-propyl-1,3-benzoxazine-2,4-dione, characterized in that propyl isocyanate is reacted with 5- acid chlorosalicylic acid and the desired product is recovered.

12. Process for the preparation of 6-chloro-3-furfuryl-1,3-benzoxazine-2,4-dione, characterized in that is reacted with furfuryl isocyanate with 5-chlorosalicylic acid and the product is recovered longed for.

13. Process for the preparation of 6-chloro-3-(o-phenoxyphenyl) -1,3-benzoxazine-2,4-dione, characterized in that the o-phenoxy isocyanate is reacted phenyl with 5-chlorosalicylic acid and we recover the desired product.

14. Process for the preparation of 6-chloro-3-(o-thiophenoxyphenyl) -1,3-benzoxazine-2,4-dione, carac-terized in that the isocyanate is reacted with thiophenoxyphenyl with 5-chlorosalicylic acid and the desired product is recovered.

15. Process for the preparation of 6-bromo-3-methyl-1,3-benzoxazine-2,4-dione, characterized in that methyl isocyanate is reacted with 5- acid bromosalicylic acid and the desired product is recovered.

16. New derivatives of 1,3-benzoxazine-2,4-dione corresponding to general formula I:

(I) in which:
R represents a lower alkyl radical in C1 to C4, an orthophenoxyphenyl group, a orthothiophenoxyphenyl group, a group benzyl, a furfuryl group, and R 'represents a chlorine or bromine atom, when prepared by the process of claim 1 or by an equivalent chemical process.

17. 6-chloro-3-methyl-1,3-benzoxazine-2,4-dione, when prepared by the process of the claim-tion 2 or 9 or by an equivalent chemical process.

18. 6-chloro-3-ethyl-1,3-benzoxazine-2,4-dione, when prepared by the process of the claim-tion 3 or 10 or by an equivalent chemical process.

19. 6-chloro-3-propyl-1,3-benzoxazine-2,4-dione, when prepared by the process of the claim-tion 4 or 11 or by an equivalent chemical process.

20. 6-chloro-3-furfuryl-1,3-benzoxazine-2,4-dione, when prepared by the process of the claim cation 5 or 12 or by an equivalent chemical process.

21. 6-chloro-3- (o-phenoxyphenyl) -1,3-benzoxazine-2,4-dione, when prepared by the process of claim 6 or 13 or by a chemical process equivalent.

22. 6-chloro-3- (o-thiophenoxyphenyl) -1,3-benzoxazine-2,4-dione, when prepared by the process of claim 7 or 14 or by a chemical process equivalent.

23. 6-bromo-3-methyl-1,3-benzoxazine-2,4-dione, when prepared by the process of the claim-tion 8 or 15 or by an equivalent chemical process.