CH643548A5 - 1,3-BENZOXAZINE-2,4-DIONE DERIVATIVES, THEIR PREPARATION AND MEDICAMENTS CONTAINING THEM - Google Patents
1,3-BENZOXAZINE-2,4-DIONE DERIVATIVES, THEIR PREPARATION AND MEDICAMENTS CONTAINING THEM Download PDFInfo
- Publication number
- CH643548A5 CH643548A5 CH773579A CH773579A CH643548A5 CH 643548 A5 CH643548 A5 CH 643548A5 CH 773579 A CH773579 A CH 773579A CH 773579 A CH773579 A CH 773579A CH 643548 A5 CH643548 A5 CH 643548A5
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- Prior art keywords
- benzoxazine
- dione
- formula
- chloro
- derivatives
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
- C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
- C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D265/24—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in positions 2 and 4
- C07D265/26—Two oxygen atoms, e.g. isatoic anhydride
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Description
La présente invention concerne des dérivés de 1,3-benzoxazine-2,4-dione en tant que nouveaux composés chimiques, leur préparation et leur utilisation à titre de médicaments. The present invention relates to 1,3-benzoxazine-2,4-dione derivatives as new chemical compounds, their preparation and their use as medicaments.
Les nouveaux dérivés, objet de l'invention, répondent à la formule générale I: The new derivatives which are the subject of the invention correspond to the general formula I:
(i) (i)
ai) have)
30 dans laquelle 30 in which
R représente un radical alkyle, un groupe orthophénoxyphényle, orthothiophénoxyphényle, benzyle, furfuryle ou bien 2-pyridyle; R represents an alkyl radical, an orthophenoxyphenyl, orthothiophenoxyphenyl, benzyl, furfuryl or else 2-pyridyl group;
R' représente un atome d'hydrogène, de chlore, de brome ou un radical méthoxyle; R 'represents a hydrogen, chlorine, bromine atom or a methoxyl radical;
35 R" représente un atome d'hydrogène, de chlore ou un radical méthyle, et 35 R "represents a hydrogen or chlorine atom or a methyl radical, and
R'" représente un atome d'hydrogène, de chlore ou de brome. R '"represents a hydrogen, chlorine or bromine atom.
Les dérivés préférés de l'invention sont ceux de la formule I, dans laquelle R est un radical alkyle inférieur, de préférence en Ci à C4. 40 La présente invention se rapporte également aux sels d'addition d'acides physiologiquement acceptables, tels que les halogénohydra-tes et en particulier les chlorhydrates, des dérivés de formule générale I. The preferred derivatives of the invention are those of formula I, in which R is a lower alkyl radical, preferably from C1 to C4. The present invention also relates to the addition salts of physiologically acceptable acids, such as the halohydra-tes and in particular the hydrochlorides, of the derivatives of general formula I.
Les dérivés de formule générale I se sont révélés posséder de pré-45 cieuses propriétés pharmacologiques. La présente invention se rapporte donc également à l'utilisation de ces dérivés à titre de médicaments. En cas d'utilisation, on administre généralement les dérivés de formule I ou leurs sels d'addition d'acides physiologiquement acceptables sous forme de compositions pharmaceutiques, qui contien-50 nent les dérivés selon l'invention à titre de principe actif. The derivatives of general formula I have been found to have valuable pharmacological properties. The present invention therefore also relates to the use of these derivatives as medicaments. In case of use, the derivatives of formula I or their physiologically acceptable acid addition salts are generally administered in the form of pharmaceutical compositions, which contain the derivatives according to the invention as active principle.
La présente invention se rapporte également à la préparation des dérivés de formule générale I. Selon l'invention, on obtient ces dérivés de formule générale I: The present invention also relates to the preparation of the derivatives of general formula I. According to the invention, these derivatives of general formula I are obtained:
a) par réaction d'un dérivé de salicylamide de formule générale a) by reaction of a salicylamide derivative of general formula
55 II: 55 II:
(III) (III)
60 60
C - N C - N
R R
(il) (he)
"H "H
3 3
643 548 643,548
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'un dérivé d'acide salicylique de formule générale III: in which R, R ', R "and R'" have the meanings indicated with respect to the general formula I, with ethyl chloroformate, or else b) by reaction of a salicylic acid derivative of general formula III :
0 0
R R
R R
R"1 R "1
dans laquelle R', R" et R'" ont les significations indiquées à propos de la formule générale I, avec un isocyanate de formule générale IV : in which R ', R "and R'" have the meanings indicated with regard to the general formula I, with an isocyanate of general formula IV:
0=C=N—R (IV) 0 = C = N — R (IV)
dans laquelle R a la signification donnée à propos de la formule générale I. in which R has the meaning given in relation to the general formula I.
On décrira ci-après plus en détail, à titre de simple exemple non limitatif, la préparation de quelques dérivés de formule générale I. The preparation of some derivatives of general formula I will be described below in more detail, by way of simple non-limiting example.
Exemple 1: Example 1:
Préparation du 6-chloro-3-méthyl-I,3-benzoxazine-2,4-dione Preparation of 6-chloro-3-methyl-I, 3-benzoxazine-2,4-dione
On ajoute lentement ( lA h) 37 ml (0,375 mol) de chloroformiate d'éthyle à une solution de 18,6 g (0,1 mol) de 5-chloro-N-méthyIsali-cylamide dans la pyridine. On laisse à reflux pendant 7 h, on laisse refroidir, on dilue avec de l'eau, on filtre et on lave avec de l'eau distillée. On recristallise avec du chloroforme, on lave avec du métha-nol à 5°C et on obtient le 6-chloro-3-méthyl-l,3~benzoxazine-2,4-dione de point de fusion 151-153°C (voir tableau I). 37 ml (0.375 mol) of ethyl chloroformate are slowly added (1 h) to a solution of 18.6 g (0.1 mol) of 5-chloro-N-methylisali-cyclamide in pyridine. The mixture is left to reflux for 7 h, allowed to cool, diluted with water, filtered and washed with distilled water. We recrystallize with chloroform, wash with metha-nol at 5 ° C and we obtain 6-chloro-3-methyl-1,3 ~ benzoxazine-2,4-dione with melting point 151-153 ° C ( see table I).
Exemple 2: Example 2:
Préparation du 6-bromo-3-méthyl-l,3-benzoxazine-2,4-dione Preparation of 6-bromo-3-methyl-1,3-benzoxazine-2,4-dione
On ajoute 7,5 ml (0,12 mol) d'isocyanate de méthyle et 5 ml de triéthylamine à une solution de 21,7 g (0,1 mol) d'acide 5-bromosali-cylique dans 150 ml de benzène. 7.5 ml (0.12 mol) of methyl isocyanate and 5 ml of triethylamine are added to a solution of 21.7 g (0.1 mol) of 5-bromosali-cyclic acid in 150 ml of benzene.
On agite le mélange pendant 1 h à température ambiante et on laisse ensuite à reflux pendant 6 h. On évapore à sec, on recristallise avec du méthanol et on obtient le 6-bromo-3-mêthyl-l,3-benzoxazi-ne-2,4-dione de point de fusion 186°C (voir tableau I). The mixture is stirred for 1 h at room temperature and then left to reflux for 6 h. Evaporated to dryness, recrystallized from methanol and obtained 6-bromo-3-methyl-1,3-benzoxazi-ne-2,4-dione with melting point 186 ° C (see Table I).
Exemples 3 à 17: Examples 3 to 17:
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, telles que les solvants de cristallisation, les points de fusion et les bandes caractéristiques du spectre infrarouge, sont mentionnées au tableau I ci-après. By operating as indicated previously in Examples 1 and 2, it is possible, for example, to obtain the derivatives of which a certain number of physicochemical constants, such as the solvents of crystallization, the melting points and the bands characteristic of the infrared spectrum, are mentioned in Table I below.
( Voir pages suivantes ) (See following pages)
Activité analgésique Analgesic activity
L'activité 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 œsophagique. Le volume de la solution administrée est de 25 ml/kg et l'on change la concentration du produit essayé selon la dose administrée. 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 gum arabic at 5% orally by means of an esophageal probe. The volume of the solution administered is 25 ml / kg and the concentration of the product tested is changed according to the dose administered.
On provoque la douleur chez les animaux moyennant une injection intrapéritonéale de 0,2 ml/20 g de solution de bromure d'acétyl-choline d'une concentration de 0,32 mg/ml. 5 min avant l'administration du produit testé, on injecte l'acétylcholine à un lot de 5 souris. On administre ensuite le produit à tester, on effectue à Pain is caused in animals by an intraperitoneal injection of 0.2 ml / 20 g of acetylcholine bromide solution with a concentration of 0.32 mg / ml. 5 min before the administration of the test product, acetylcholine is injected into a batch of 5 mice. The product to be tested is then administered,
nouveau l'injection d'acétylcholine après 20,40, 80,120 et 160 min. On compte toujours le nombre de contorsions par injection d'acétylcholine pendant 5 min. again acetylcholine injection after 20.40, 80.120 and 160 min. We always count the number of contortions by acetylcholine injection for 5 min.
On calcule l'activité analgésique au moyen de la formule suivante: The analgesic activity is calculated using the following formula:
It = 100~(Nt/No)-100 = 100 (1 — Nt/No), où It = 100 ~ (Nt / No) -100 = 100 (1 - Nt / No), where
It — inhibition de la douleur après t min; It - pain inhibition after t min;
No = nombre de contorsions avant l'administration du produit, et No = number of contortions before administration of the product, and
Nt = nombre de contorsions après t min de l'administration du produit. Nt = number of contortions after t min of product administration.
On administre plusieurs doses de chaque produit pour pouvoir déterminer la dose analgésique 50% (DA 50). Several doses of each product are administered in order to determine the 50% analgesic dose (DA 50).
Avec chacune de ces doses, on calcule It aux temps 20, 40, 80, 120 et 160 min. On prend, comme effet analgésique, la moyenne de ces cinq valeurs de It pour chaque dose. On représente graphiquement les effets analgésiques en fonction du logarithme de la dose correspondante. With each of these doses, It is calculated at times 20, 40, 80, 120 and 160 min. As an analgesic effect, the average of these five It values is taken for each dose. The analgesic effects are represented graphically as a function of the logarithm of the corresponding dose.
A partir de cette courbe, on obtient la dose analgésique cinquante, c'est-à-dire la dose qui produit un effet analgésique 50% From this curve, the analgesic dose fifty is obtained, that is to say the dose which produces an analgesic effect 50%
A titre d'exemple, on a indiqué, dans le tableau II ci-après, les résultats obtenus pour quelques dérivés de formule I selon l'invention. By way of example, the results obtained for a few derivatives of formula I according to the invention are indicated in table II below.
Toxicité aiguë acute toxicity
On détermine la toxicité aiguë par voie orale chez des souris de 20 à 25 g de poids en employant des lots de 6 animaux. On administre plusieurs doses en progression géométrique. Le temps d'observation est de 72 h. La dose létale 50% (DL 50) se calcule graphiquement au moyen de papier logarithmique-probalistique. Acute oral toxicity was determined in mice 20-25 g in weight using batches of 6 animals. Several doses are administered in geometric progression. The observation time is 72 h. The lethal dose 50% (LD 50) is calculated graphically using logarithmic-probalistic paper.
A titre d'exemple, on a indiqué, dans le tableau II ci-après, les résultats obtenus pour quelques dérivés de formule I selon l'invention. By way of example, the results obtained for a few derivatives of formula I according to the invention are indicated in table II below.
Tableau II Table II
Exemple N° Example No.
Dérivé Derivative
Doses (mg/kg) Doses (mg / kg)
DA 50 DA 50
DL 50 DL 50
1 1
6-Chloro-3-méthyl-l ,3-benz-oxazine-2,4-dione 6-Chloro-3-methyl-1,3-benz-oxazine-2,4-dione
30 30
233 233
2 2
6-Bromo-3-méthyl-l ,3-benz-oxazine-2,4-dione 6-Bromo-3-methyl-1,3-benz-oxazine-2,4-dione
90 90
717 717
3 3
6-Chloro-3-propyl-1,3-benz-oxazine-2,4-dione 6-Chloro-3-propyl-1,3-benz-oxazine-2,4-dione
240 240
>650 > 650
8 8
6-Chloro-3-furfuryl-l,3-benz-oxazine-2,4-dione 6-Chloro-3-furfuryl-1,3-benz-oxazine-2,4-dione
280 280
>550 > 550
9 9
6-Chloro-3-(o-phénoxyphén-yl)-1,3-benzoxazine-2,4-dione 6-Chloro-3- (o-phenoxyphen-yl) -1,3-benzoxazine-2,4-dione
675 675
>750 > 750
10 10
6-Chloro-3-(o-thiophénoxy-phényl)-1,3-benzoxazine-2,4-dione 6-Chloro-3- (o-thiophenoxy-phenyl) -1,3-benzoxazine-2,4-dione
650 650
>1500 > 1500
12 12
6-Chloro-3-éthyl-l,3-benzox-azine-2,4-dione 6-Chloro-3-ethyl-1,3-benzox-azine-2,4-dione
172 172
G G
>250 > 250
Activité anti-inflammatoire Anti-inflammatory activity
On détermine l'activité anti-inflammatoire chez le rat mâle de souche Sprague-Dawley. On provoque un œdème 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 The anti-inflammatory activity was determined in the male rat of the Sprague-Dawley strain. Edema is caused in the paw by subplant injection of a 1% carrageenan solution. The volume of the leg is measured before the administration of the product by
5 5
10 10
15 15
20 20
25 25
30 30
35 35
40 40
45 45
50 50
55 55
60 60
65 65
Exemple Example
R R
R' R '
R" R "
R"' R "'
Point de fusion Fusion point
(°cj (° cj
Solvant de Solvent
Rendement Yield
IR IR
Analyse (%) Analysis (%)
n° n °
cristallisation crystallization
(%) (%)
(cm"1) (cm "1)
C VS
H H
Cl Cl
Br n Br n
1 1
ch3 ch3
Cl Cl
H H
H H
151-3 151-3
CHC13 CHC13
93 93
1300, 1350 1690,1770 1300, 1350 1690.1770
Calculé Trouvé Calculated Found
51,12 51,20 51.12 51.20
2,86 2,79 2.86 2.79
16,76 16,70 16.76 16.70
— -
6,63 6,57 6.63 6.57
2 2
ch3 ch3
Br Br
H H
H H
186 186
ch3oh ch3oh
19 19
1300, 1350 1690,1750 1300, 1350 1690.1750
Calculé Trouvé Calculated Found
42,23 42,15 42.23 42.15
2,36 2,41 2.36 2.41
— -
31,14 31,27 31.14 31.27
5,47 5,32 5.47 5.32
3 3
ch2ch2ch3 ch2ch2ch3
Cl Cl
H H
H H
118 118
ch3oh ch3oh
52 52
1340 1340
1700, 1770 1700, 1770
Calculé Trouvé Calculated Found
55,17 55,25 55.17 55.25
4,21 4,15 4.21 4.15
14,80 14,73 14.80 14.73
— -
5,85 5,97 5.85 5.97
4 4
CH(CH3)2 CH (CH3) 2
Cl Cl
H H
H H
167-9 167-9
ch3oh ch3oh
24 24
1330 1330
1700,1770 1700.1770
Calculé Trouvé Calculated Found
55,17 55,08 55.17 55.08
4,21 4,32 4.21 4.32
14,80 14,86 14.80 14.86
— -
5,85 5,80 5.85 5.80
5 5
ch2ch2ch2ch3 ch2ch2ch2ch3
Cl Cl
H H
H H
103 103
ch3ch2oh ch3ch2oh
12 12
1300 1300
1700,1770 1700.1770
Calculé Trouvé Calculated Found
56,87 56,79 56.87 56.79
4,75 4,81 4.75 4.81
14,00 13,92 14.00 13.92
— -
5,52 5,46 5.52 5.46
6 6
(CH2)15CH3 (CH2) 15CH3
Cl Cl
H H
H H
97 97
ch3coch3 ch3coch3
67 67
1350 1350
1700,1770 1700.1770
Calculé Trouvé Calculated Found
68,31 68,42 68.31 68.42
8,60 8,56 8.60 8.56
8,40 8,35 8.40 8.35
— -
3,32 3,25 3.32 3.25
7 7
c"j -<s> c "j - <s>
Cl Cl
H H
H H
152-5 152-5
ch3oh ch3oh
42 42
1340 1340
1710, 1770 1710, 1770
Calculé Trouvé Calculated Found
62,60 62,55 62.60 62.55
3,51 3,57 3.51 3.57
12,33 12,28 12.33 12.28
— -
4,87 4,97 4.87 4.97
8 8
-, _ÇJ -, _ÇJ
Cl Cl
H H
H H
178-80 178-80
EtOH/Me2CO EtOH / Me2CO
46 46
1320 1320
1700,1770 1700.1770
Calculé Trouvé Calculated Found
56,27 56,14 56.27 56.14
2,90 2,87 2.90 2.87
12,77 12,69 12.77 12.69
— -
5,05 4,98 5.05 4.98
9 9
Cl Cl
H H
H H
167 167
EtOH EtOH
70 70
1360 1360
1710,1770 1710.1770
Calculé Trouvé Calculated Found
65,73 65,81 65.73 65.81
3,30 3,34 3.30 3.34
9,70 9,77 9.70 9.77
— -
3,83 3,95 3.83 3.95
10 10
Cl Cl
H H
H H
150 150
EtOH EtOH
98 98
1360 1360
1710, 1770 1710, 1770
Calculé Trouvé Calculated Found
62,90 63,02 62.90 63.02
3,17 3,09 3.17 3.09
9,29 9,34 9.29 9.34
— -
3,67 3,80 3.67 3.80
11 11
ch3 ch3
H H
Cl Cl
H H
192-4 192-4
ch3oh ch3oh
10 10
1300, 1360 1690,1760 1300, 1360 1690.1760
Calculé Trouvé Calculated Found
51,11 50,98 51.11 50.98
2,86 2,93 2.86 2.93
16,78 16,89 16.78 16.89
— -
6.62 6.62
6.63 6.63
12 12
ch2ch3 ch2ch3
Cl Cl
H H
H H
120-2 120-2
CC14 CC14
51 51
1340, 1350 1700, 1770 1340, 1350 1700, 1770
Calculé Trouvé Calculated Found
53,27 53,15 53.27 53.15
3,58 3,63 3.58 3.63
15,72 15,74 15.72 15.74
— -
6,22 6,15 6.22 6.15
5 5
643 548 643,548
S S
I £ I £
Analyse (%) Analysis (%)
Z Z
5,69 5,75 5.69 5.75
4,86 4,79 4.86 4.79
(N r-r-; t-; en en (N r-r-; t-; en en
6,77 6,85 6.77 6.85
7,33 7,40 7.33 7.40
(H (H
0Q 0Q
! !
1 1
42,39 42,53 42.39 42.53
1 1
I I
Ö Ö
28,82 28,91 28.82 28.91
24,61 24,57 24.61 24.57
1 1
1 1
i i
33 33
2,05 1,98 2.05 1.98
3,85 3,91 3.85 3.91
2,94 3,01 2.94 3.01
OO es en OO es en
4,75 4,70 4.75 4.70
U U
43,94 44,05 43.94 44.05
50,00 49,87 50.00 49.87
38,23 38,32 38.23 38.32
58,02 57,91 58.02 57.91
62,89 62,97 62.89 62.97
Calculé Trouvé Calculated Found
Calculé Trouvé Calculated Found
Calculé Trouvé Calculated Found
Calculé Trouvé Calculated Found
Calculé Trouvé Calculated Found
o o
1300, 1360 1690, 1770 1300, 1360 1690, 1770
1340 1340
1700,1770 1700.1770
1350 1350
1690, 1770 1690, 1770
1300, 1355 1690, 1760 1300, 1355 1690, 1760
1300, 1370 1690, 1760 1300, 1370 1690, 1760
Rendement (%) Yield (%)
SO SO
\o "S" \ o "S"
OO OO
m m (N m m (N
(N (NOT
Solvant de cristallisation Solvent of crystallization
AcoEt AcoEt
33 O 33 O
n not
33 U 33 U
EtOH EtOH
O O
(S (S
33 33
K O K O
fO fO
33 U 33 U
33 O 33 O
n not
33 U 33 U
Point de fusion (°C) Melting point (° C)
159-63 159-63
106-8 106-8
139 139
138-40 138-40
VO VO
û4 û4
U U
U U
UH « UH "
33 33
33 33
& &
33 33
X X
X X
33 33
fO fO
33 U 33 U
Ü Ü
Ö Ö
u oa u oa
O O
33 O 33 O
33 33
X X
o n we
33 U 33 U
M M
33 U 33 U
N NOT
X X
O O
N NOT
X X
u f) u f)
X X
U U
r) r)
X U X U
N NOT
33 U 33 U
N NOT
3! U 3! U
X X
u u
X U X U
Exemple N° Example No.
m m
2 2
VO VO
r- r-
voie orale après 2 et 5 h avec un pléthysmomètre. L'activité antiinflammatoire 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. orally after 2 and 5 h with a plethysmometer. The anti-inflammatory activity is calculated relative to a control batch. By way of example, the results obtained for the derivative of Example 1 will be indicated in Table III below.
Tableau III Table III
io io
15 15
Exemple N° Example No.
Dérivé Derivative
Dose (mg/kg) Dose (mg / kg)
Activité antiinflammatoire Anti-inflammatory activity
2 h (%) 2 h (%)
5 h (%) 5 h (%)
1 1
6-Chloro-3-méthyl-1,3-benzoxazine-2,4-dione 6-Chloro-3-methyl-1,3-benzoxazine-2,4-dione
100 100
26 26
30 30
20 Compte tenu de leurs bonnes propriétés pharmacodynamiques, les dérivés de formule générale I sont donc susceptibles d'être utilisés en médecine humaine et/ou vétérinaire, en tant qu'agents analgésiques, antipyrétiques et anti-inflammatoires. Given their good pharmacodynamic properties, the derivatives of general formula I are therefore capable of being used in human and / or veterinary medicine, as analgesic, antipyretic and anti-inflammatory agents.
25 Les compositions pharmaceutiques qui contiennent selon l'invention, outre un support pharmaceutiquement acceptable, au moins un dérivé de formule générale I ont un champ d'application thérapeutique très vaste et peuvent être utilisées notamment en traumatologie, chirurgie, rhumatologie, odontostomatologie, oto-rhino-30 laryngologie, pneumologie, cardiologie, gynécologie et urologie. Ces compositions pharmaceutiques seront, par exemple, utilisées pour le traitement de diverses manifestations douloureuses, de céphalées, de migraines, de rages de dents, de névralgies, de douleurs menstruelles, de rhumatismes inflammatoires, de douleurs arthrosiques, d'états fé-35 briles, de rhumes, de grippes et d'infections saisonnières. The pharmaceutical compositions which, according to the invention contain, in addition to a pharmaceutically acceptable carrier, at least one derivative of general formula I have a very wide field of therapeutic application and can be used in particular in traumatology, surgery, rheumatology, odontostomatology, oto- rhino-30 laryngology, pneumology, cardiology, gynecology and urology. These pharmaceutical compositions will, for example, be used for the treatment of various painful manifestations, headache, migraines, toothaches, neuralgia, menstrual pain, inflammatory rheumatism, arthritis pain, feverish states , colds, flu and seasonal infections.
En thérapeutique humaine, la dose proposée des dérivés de la présente invention est environ comprise entre 100 et 300 mg/d, par exemple administrée sous forme de comprimés, de gélules ou de sup-4o positoires. In human therapy, the proposed dose of the derivatives of the present invention is approximately between 100 and 300 mg / d, for example administered in the form of tablets, capsules or positive sup-4o.
On indiquera ci-après, à titre d'exemples, trois formes galléni-ques particulières des dérivés, objets de la présente invention. Three specific gallenic forms of the derivatives which are the subject of the present invention will be indicated below, by way of examples.
45 45
Exemple de formule par comprimé Example of formula per tablet
6-Chloro-3-méthyl-1,3-benzoxazine-2,4-dione Avicel pH-102 Primojel 50 Aérosil-200 6-Chloro-3-methyl-1,3-benzoxazine-2,4-dione Avicel pH-102 Primojel 50 Aerosil-200
Stéarate de magnésium Magnesium stearate
Poids du comprimé: Weight of the tablet:
100 mg 100 mg 10 mg 100 mg 100 mg 10 mg
1 mg 1 mg
2 mg 213 mg 2 mg 213 mg
55 Exemple de formule par gélule 55 Example of formula per capsule
6-Chloro-3-méthyl-l,3-benzoxazine-2,4-dione 100 mg 6-Chloro-3-methyl-1,3-benzoxazine-2,4-dione 100 mg
Lactose 75 mg Lactose 75 mg
Avicel pH-102 25 mg Avicel pH-102 25 mg
Aérosil-200 1 mg Aerosil-200 1 mg
60 60
Stéarate de magnésium 2 mg Magnesium stearate 2 mg
Poids de la gélule: 203 mg Capsule weight: 203 mg
Exemple de formule par suppositoire Example of a suppository formula
6-Chloro-3-méthyl-1,3-benzoxazine-2,4-dione 0,2 g 6-Chloro-3-methyl-1,3-benzoxazine-2,4-dione 0.2 g
Monolène 1,8 g Monolene 1.8 g
Poids du suppositoire : 2,0 g Suppository weight: 2.0 g
R R
Claims (4)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7824674A FR2434158A1 (en) | 1978-08-25 | 1978-08-25 | NOVEL 1,3-BENZOXAZINE-2,4-DIONE DERIVATIVES, THEIR PREPARATION AND THEIR APPLICATION AS MEDICAMENTS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH643548A5 true CH643548A5 (en) | 1984-06-15 |
Family
ID=9212085
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH773579A CH643548A5 (en) | 1978-08-25 | 1979-08-24 | 1,3-BENZOXAZINE-2,4-DIONE DERIVATIVES, THEIR PREPARATION AND MEDICAMENTS CONTAINING THEM |
Country Status (25)
| Country | Link |
|---|---|
| JP (1) | JPS5533484A (en) |
| AR (1) | AR222494A1 (en) |
| AT (1) | AT373591B (en) |
| BE (1) | BE878395A (en) |
| BG (1) | BG30929A3 (en) |
| CA (1) | CA1128511A (en) |
| CH (1) | CH643548A5 (en) |
| CS (1) | CS208131B2 (en) |
| DD (1) | DD145534A5 (en) |
| DE (1) | DE2934166A1 (en) |
| EG (1) | EG14355A (en) |
| ES (1) | ES481856A1 (en) |
| FI (1) | FI68818C (en) |
| FR (1) | FR2434158A1 (en) |
| GB (1) | GB2031410B (en) |
| GR (1) | GR69619B (en) |
| HU (1) | HU182916B (en) |
| IL (1) | IL58096A (en) |
| NL (1) | NL7906408A (en) |
| PL (1) | PL116771B1 (en) |
| PT (1) | PT70107A (en) |
| RO (1) | RO78156A (en) |
| SE (1) | SE446865B (en) |
| SU (1) | SU797576A3 (en) |
| YU (1) | YU40849B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4224566B2 (en) | 2000-12-18 | 2009-02-18 | 株式会社医薬分子設計研究所 | Inflammatory cytokine production release inhibitor |
| WO2003103665A1 (en) | 2002-06-06 | 2003-12-18 | 株式会社医薬分子設計研究所 | Antiallergic |
| AU2003242118B2 (en) * | 2002-06-06 | 2008-09-11 | Institute Of Medicinal Molecular Design, Inc | O-substituted hydroxyaryl derivatives |
| CN108658887B (en) * | 2018-06-20 | 2022-04-05 | 中南大学 | Benzo [ d ] [1,3] oxazine-2, 4(1H) -diketone derivative and synthetic method and application thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2476559A (en) * | 1946-10-01 | 1949-07-19 | Gen Aniline & Film Corp | Oxazine diones |
| DE1153375B (en) * | 1960-05-25 | 1963-08-29 | Thomae Gmbh Dr K | Process for the preparation of benzoxazine- (1, 3) -dione- (2, 4) |
| GB1069367A (en) * | 1964-10-01 | 1967-05-17 | Aspro Nicholas Ltd | Improvements in or relating to the production of 1:3-benzoxazine-2:4-dione |
| CH459211A (en) * | 1965-01-25 | 1968-07-15 | Robapharm Ag | Process for the preparation of new basic derivatives of dihydro-1,3-benzoxazine-2,4-dione |
-
1978
- 1978-08-25 FR FR7824674A patent/FR2434158A1/en active Granted
-
1979
- 1979-06-06 ES ES481856A patent/ES481856A1/en not_active Expired
- 1979-08-21 DD DD79215096A patent/DD145534A5/en not_active IP Right Cessation
- 1979-08-22 RO RO7998518A patent/RO78156A/en unknown
- 1979-08-22 PL PL1979217893A patent/PL116771B1/en unknown
- 1979-08-22 HU HU79PO694A patent/HU182916B/en not_active IP Right Cessation
- 1979-08-22 GR GR52886A patent/GR69619B/el unknown
- 1979-08-22 CA CA334,287A patent/CA1128511A/en not_active Expired
- 1979-08-22 GB GB7929266A patent/GB2031410B/en not_active Expired
- 1979-08-22 BG BG7944725A patent/BG30929A3/en unknown
- 1979-08-23 YU YU2073/79A patent/YU40849B/en unknown
- 1979-08-23 IL IL58096A patent/IL58096A/en not_active IP Right Cessation
- 1979-08-23 JP JP10764779A patent/JPS5533484A/en active Pending
- 1979-08-23 FI FI792632A patent/FI68818C/en not_active IP Right Cessation
- 1979-08-23 PT PT70107A patent/PT70107A/en unknown
- 1979-08-23 DE DE19792934166 patent/DE2934166A1/en not_active Ceased
- 1979-08-23 BE BE0/196852A patent/BE878395A/en not_active IP Right Cessation
- 1979-08-23 SU SU792804596A patent/SU797576A3/en active
- 1979-08-23 AT AT0568379A patent/AT373591B/en not_active IP Right Cessation
- 1979-08-23 AR AR277829A patent/AR222494A1/en active
- 1979-08-24 CS CS795769A patent/CS208131B2/en unknown
- 1979-08-24 SE SE7907067A patent/SE446865B/en not_active IP Right Cessation
- 1979-08-24 CH CH773579A patent/CH643548A5/en not_active IP Right Cessation
- 1979-08-24 NL NL7906408A patent/NL7906408A/en not_active Application Discontinuation
- 1979-08-27 EG EG520/79A patent/EG14355A/en active
Also Published As
| Publication number | Publication date |
|---|---|
| YU207379A (en) | 1983-02-28 |
| BE878395A (en) | 1980-02-25 |
| GR69619B (en) | 1982-07-06 |
| PL116771B1 (en) | 1981-06-30 |
| IL58096A0 (en) | 1979-12-30 |
| SU797576A3 (en) | 1981-01-15 |
| DE2934166A1 (en) | 1980-02-28 |
| FR2434158A1 (en) | 1980-03-21 |
| GB2031410A (en) | 1980-04-23 |
| SE446865B (en) | 1986-10-13 |
| EG14355A (en) | 1983-12-31 |
| CA1128511A (en) | 1982-07-27 |
| AR222494A1 (en) | 1981-05-29 |
| PT70107A (en) | 1979-09-01 |
| JPS5533484A (en) | 1980-03-08 |
| AT373591B (en) | 1984-02-10 |
| FI68818C (en) | 1985-11-11 |
| FI68818B (en) | 1985-07-31 |
| HU182916B (en) | 1984-03-28 |
| YU40849B (en) | 1986-06-30 |
| PL217893A1 (en) | 1980-04-21 |
| BG30929A3 (en) | 1981-09-15 |
| ATA568379A (en) | 1983-06-15 |
| RO78156A (en) | 1982-02-01 |
| IL58096A (en) | 1982-12-31 |
| DD145534A5 (en) | 1980-12-17 |
| FR2434158B1 (en) | 1985-05-03 |
| SE7907067L (en) | 1980-02-26 |
| FI792632A (en) | 1980-02-26 |
| ES481856A1 (en) | 1980-02-16 |
| GB2031410B (en) | 1982-12-01 |
| CS208131B2 (en) | 1981-08-31 |
| NL7906408A (en) | 1980-02-27 |
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| PL | Patent ceased |