SE446865B - NEW DERIVATIVES OF 1,3-BENZOXAZINE-2,4-DION, PROCEDURE FOR PREPARING THEREOF, AND PHARMACEUTICAL COMPOSITIONS - Google Patents

Description

15 20 25 30 35 446 865 2 0 R U RI. Q - Nííc fl (II) OH wherein R- and R 'have the meanings given in the general formula I, with an ethyl chloroformate, or b) a salicylic acid derivative of the general formula III is reacted.

R '- OH (III) OH wherein R' has the meaning given in the general formula I, with an isocyanate of the general formula IV O = C = N - R (IV) r wherein R has the meaning given by given in the general formula I.

In the following, the preparation of some derivatives of the general formula I is described in more detail by means of non-limiting examples.

EXAMPLE 1 Composition of 6-chloro-3-methyl-1,3-begggazazine-2,4-digg 37 ml (0.37S mol) of ethyl chloroformate were slowly added (1/2 mol) to a solution of 18.6 g ( 0.1 mol) of 5-chloro-N-methylsalicylamide in pyridine. They were refluxed for 15 hours and cooled and predicted with water, filtered and washed with distilled water. It was recrystallized from chloroform and washed with methanol at s ° c. One obtained s-claer-s-n-ethyl-1,1a-benzexezln-z, fl-aien with the melting point 1sl-1s3 ° c (see Table 1).

EXAMPLE 2 Preparation of 6-bromo-3-methyl-11β-benzyl: 2 ml: 7.5 ml (0.2 mol) of methyl isocyanate and 5 ml of triethylamine were added to a solution of 21.7 g (0.1 mol) of 5-bromosalicylic acid in 150 ml of benzene. The mixture was stirred for 1 hour at room temperature and then refluxed for 6 hours. Evaporated to dryness and recrystallized from methanol to give 6-bromo-3-methyl-1,3-benzoxazine-2,4-dione, m.p. C (see Table I).

EXAMPLES 3-13 Work was carried out as indicated above in Examples 1 to 2, and derivatives were obtained for which a number of physicochemical constants, such as crystallization solvent 1, melting points and characteristic bands in the IR spectrum, are mentioned in the following Table 1. 446 865 @ «.M Nm.m ~« w. <@ ~. @ Mu @ === @ oßß fl .ooß fi ~ mm 1 oo. «~ M ~.« ~ W. @ Mu «= xm ~ @ m Oona NH mo ~ mun = u mo fl av mm0 ~ = u ~ = o ~ = um ow.m @m. «H ~ m.« @ o.nm ~ @ === m oßß fl .ocß fl mm.m 1 ow. ~ m.m n>. «H mH.« m ~ .mm ßwaøøm oßß fi .ooß fl m @ .m | ow. «~ H ~. <~ H.mm mumuxmuwm o« m fl ~ m mamma »ÄH Au m = o ~: u ~ = um ~ nm -, Hn h ~«. ~ m ~. ~ «» w == = w omß fl .omw fi W ~ «.m« H. ~ n 1 @ n. ~ n ~. ~ «umnxmuwm omn fl .Oona mä mommu ewa nu mmu ~ ßm. @ o ~. @ ~ m ~. ~ o ~. ~ mu @ === m oßß fi .om @ H nw. @ | @ ~. @ H @ w. ~ ~ H. ~ m »~ = 1w ~ wm omm fi .oon fl mm m fl umu mm ~ | ~ mH Hu n = u H z um fi u = 0. fifi uauv @u> wu = w fi wwmwwß »x == @ mm Hmm> êë ä NWWLNWH: mä oLuu% \\ o ~ Tz .m O ~ AAmm 446 865 ê fi ää fi .EEZH 0% ... äá moá 3.3» wëš EZ. SS w, Û © S6 | 2. m D .m om. S äšäuwm 03 A w m: så 02 8 O / w \ m ... än t; .so 8.2 own ES .22 Qá .. E; 8; 2.3 änš fi ... S2 2 šä Sd 8 w ä; SJ .. EJ Sim .ääå 85 .85 ~. T fi q ~ mOwm I ßß-NH Om.N ßwaøm uw fi åwuwm. ONnH we OO UZÉæOH-W Oæ fi lwß fi .Ü m0 ß E; 3.2 S6 ... QS 353 .., 25 .S5 m N, å ... 2.2 1.2 3.3 äšmuwm 32 S- ä ä ... S134 S @ | ä w ß z ... å .nu ._ I u ATEUV »N uß fifl m u: T .ä .E š 3 .En på fl wmöa Låwsw à m 1 :; H 4 lwwcwcwwq. Läxl 446 865 ~ ß.m nm. ~ «Ho.n ~ n.wn u« === m ohß fl .oaø fl ~>. «Mn.N« | «M. ~ M ~ .æm uwußmuwm omm fl wm: cum» MH pm mmuwmu fl muwmu MH m ~. «~ M.« ~ H ° .m ~ w. @ «» ~ === @ oßß fi. ° 0- @w. «1 H @.« ~ M @ .n oo.om uwnxmuwm o «n fl Q: = ø ~ = u wo ~ | @ o ~ Hu ~ = u ~ mu ~ = u ~ = u NH mßfm H @. @ ~ wm.H mo. <«U« === m íøßß fi. ° @@ ~ @@. m | ~ w.w ~ w °. ~ «m.n« umnamuwn owm fi .oon fl Q um ° u <n @ ~ | @ m ~ Mu. mao fifi mH. @ «> .m ~ m @ .mn ~ .nm ~ @ === @ cßß fl .ooß fl _ -. @ - -.mH wm. ~ -.mm ~ m = xm» «m omm fi .oqm fl Hm §HuQ -H | ø ~ H Hu n: U ~ = @ OH 2 pm Hu m 0 ¶ ^ Hu = uv N WMWMMMWM ~ x == @ Hc MH wu> @ u = »ou Hwvwe fu fi wsw .MM _ fi m fl wåüïë ... mmn fi øwoq. lemxm ^ .mU ~ ° wv M q4mm <~ 10 15 20 25 30 35 446 865 Analgesic activity- The analgesic activity of the derivatives of the general formula I was determined on male mice weighing between 20 and 25 g. The test compound was administered in 5% suspension in gum arabic orally by the esophagus. It administered 25 ml / kg and the concentration of the test compound was changed concentrically by means of a probe in accordance with the dose administered.

Pain was induced in the animals with an intraperitoneal injection of 0.2 ml / 20 g solution of acetylcholine bromide at a concentration of 0.32 mg / ml. Five minutes before the administration of the test compound, the acetylcholine was injected into a group of 5 mice. The test compound was then administered and a new acetylcholine injection was made after 20, 40, 80, 120 'and 160 minutes. The number of grimaces per injection of acetylcholine was always counted for 5 minutes.

The average analgesic activity was calculated by the following formula: where It = 100 - (nT / No). 100 = 100 (1-Nt / N6) wherein It = inhibition of pain after t minutes No = number of grimaces before administration of the product Nt = number of grimaces after t minutes after administration of the product Several doses of each product were administered to be able to determine the dose that provides pain relief in 50% (ADSO).

For each of these doses, It was calculated at the time of 20, 40, 80, 120 and 160 minutes. As analgesic activity, the mean value of 5 was taken for each dose. The analgesic effects were represented graphically as a logarithmic function of the corresponding dose.

Based on this curve, ADSO was obtained, ie the dose which gives an analgesic effect in 50%. 10 15 446 865. By way of example, Table 2 shows the results obtained for some derivatives of formula I according to the invention.

Acute toxicity Acute toxicity was determined orally for mice weighing 20 to 25 g and groups of 6 animals were used. Several doses were administered in geometric series. The observation time was 72 hours. The LDSO was calculated graphically using a probabilistic logarithmic paper. by way of example, Table 2 below shows the results obtained with some grade derivatives of formula I according to the invention.

TABLE 2 Exem- _. Dose 1 mg / kg pel Derivat _ ~ ____.__ T ---- M šnr A050 _ LDso 1 6-chloro-3-methyl-1,3-benzoxazine-233 zin-2,4-dione '2 6- bromo-3-methyl-1,3-benzoxa-90,717-zin-2,4-dione E3 6-chloro-3-propyl-1,3-benzoxa-240> 65O: in-z, 4-alon ' 7 6-chloro-3-furfuryl-1,3-benz-280> 550 in oxazine-2,4-dione in 6 6-chloro-3- (o-phenoxyphenyl) -1,3-675> 75O-benzoxazine- 2,4-dione 9 6-chloro-3- (o-thiophenoxyphenyl) -650> 1500. -1,3-benzoxazine-2,4-dione '6-chloro-3-ethyl-1,3-benzoxazine-172> 250 -2,4-dione. 10 15 20 '25 30 35 4-46 865 9 Anti-inflammatory activity The anti-inflammatory activity of male rats belonging to the Sprague-Dawley strain was determined.

Edema in the paw was induced by injection in the underside of the paw of 1% carrageenan solution. The volume of the paw was measured before the administration of the product orally and after 2 and 5 hours with a plethysmometer. The anti-inflammatory effect was calculated in relation to a control group. By way of example, Table 3 below shows the results obtained with the derivative of Example 1.

TABLE 3 ___.___ (Example Derivative 'Dose Anti-inflammatory r (mg / kg) activity 2 h 5 h 1 6-chloro-3-methyl-1,3- z -benzoxazine 100 26% § 30% i Due of their good pharmacodynamic properties, the derivatives of the general formula I are suitable for use in human medicine and / or in veterinary medicine such as analgesic, anti-pyretic and anti-inflammatory agents.

The pharmaceutical compositions of the invention, which in addition to an acceptable pharmaceutical carrier, contain at least one derivative of the general formula I, have a very wide therapeutic field of application and can be used in traumatology, surgery, rheumatology, odontostomatology, otorhinolaryngology , pneumology, cardiology, gynecology and urology. The pharmaceutical compositions can be used, for example, for the treatment of various painful conditions, headaches, migraines, acute dental problems, neuralgias, menstrual pains, inflammatory rheumatism, arthritis pains, febrile conditions, colds, influenza. and infections.

In human therapy, the proposed dose for compounds of the invention is between about 100 and 300 mg / day and the compounds are administered in the form of tablets, capsules or suppositories.

The following are exemplified by three particular Gallenic forms of the derivatives of the invention.

Example of tablet preparation. 6-Chloro-3-methyl-1,3-hensoxazine-2,4-dione Avicel pH-102 Primojel Aerosil-200 magnesium stearate d Example of capsule preparation 6-chloro-3-methyl-1,3-benzoxazine -2,4-dione Lactose Avicel pH-102 Aerosil-200 magnesium stearate Example of suppository preparation V 6-chloro-3-methyl-1,3-benzoxazine-2,4-dione Monolen 100 mg 100 mg 10 mg ”213 mg 100 mg 75 mg 25 mg 2 mg 203 mg

Claims (4)

1. Derivatives of 1,3-benzoxazine-2,4-dione of the general formula I n '_ / OÅO lu) wherein R represents an alkyl group having 1 to 4 carbon atoms , an orthophenoxyphenyl group, an orthothiophenoxyphenyl group, a benzyl group or a furfuryl group and R 'represents a chlorine atom or a bromine atom. A derivative of the general formula I according to claim 1, which is selected from 6-chloro-3-methyl-1,3-benzoxazine-2,4-dione, 6-chloro-3-ethyl-1,3-benzoxazine-2 , 4-dione 6-chloro-3-propyl-1,3-benzoxazine-2,4-dione 6-chloro-3-furfuryl-1,3-benzoxazine-2,4-dione, 6-chloro-3- ( o-phenoxyphenyl) -1,3-benzoxazine-2,4-dione 6-chloro-3- (o-thiophenoxyphenyl) -1,3-benzoxazine-2,4-dione and 6-bromo-3-methyl-1 , 3-benzoxazine-2,4-dione. 3. A process for the preparation of derivatives of the general formula IR '/// R Mg, m 6 446 see wherein R represents an alkyl group having 1 to 4 carbon atoms, an orthophenoxyphenyl group, an orthothiophenoxyphenyl group, a benzyl group or a furfuryl group and R 'represents a chlorine atom or a bromine atom, characterized in that a) is reacted with salicylamide derivative of the general formula II / R "N \\\ HO == ° RI" OH (II) wherein R and R 'have the meaning given above, with ethyl chloroformate, or b) react a salicylic acid derivative of the general formula III' 0 _ 'I. Wherein R 'has the meaning given above, with an isocyanate of the general formula IV O = C = N - R wherein R has the meaning given above. (IV) 4. Pharmaceutical composition having analgesic, antipyretic and anti-inflammatory action, characterized in that it contains, in addition to a known pharmaceutically acceptable carrier, at least one derivative of the general formula IV -V ...___ .. ~~ »~ __- (R) wherein R represents an alkyl group having 1 to 4 carbon atoms, an orthophenoxyphenyl group, an orthothiophenoxyphenyl group, a benzyl group or a furfuryl group and R 'represents a chlorine atom or a bromine atom. '