FI68818B - REFERENCE TO A FRAMEWORK FOR THERAPEUTIC TREATMENT OF 1,3-BENZOZAZINE-2,4-DIONER - Google Patents

Description

rr75 £ zrn ....... advertisement publication ^ 11 UTLÄG G NI NG SSKRI FT 608I8 C (45) Titon Ui -Pushed 11 11 1985 (51) Kv.lk. * / lnt.CI. 'C 07 D 265 / 26 £ q | ^ | | ___ p | l ^ j | _ ^ \ | ^ φ (21) Patent application - Patentansökning 792632 (22) Application date - Ansökningsdag 23. θ8.79 (F ·) (23) Start date - Giltighetsdag 23.08.79 (41) Has become public - Blivit offentlig 26.02.80

National Board of Patents and Registration (44) Date of publication and date of publication. -, ·. 07 gc

Patent and registration authorities '' Ansökan utlagd och utl.skriften publlcerad Ρ I .U / .Op (32) (33) (31) Privilege requested - Begärd priority 25.08.78 France-France (FR) 782 ^ + 67 ^ + (71) Provesan SA, 1, Place St. Gervais, 1211 Geneva, Switzerland-Switzerland (CH) (72) Antonio Esteve-Subirana, Barcelona, Spain-Spain (ES) (7 * 0 Oy Kolster Ab (5 * 0 Process for the preparation of therapeutically useful new 1,3-benzoxazine-2,4-diones - For the preparation of new 1,3-benzoxazine-2,4-diones

The invention relates to a process for the preparation of therapeutically useful 1,3-benzoxazine-2,4-diones of formula (I)

O

JCoX, wherein R is alkyl of 1 to 3 carbon atoms, ortho-phenoxy-2,63818 phenyl, ortho-thiophenoxyphenyl or furfuryl and X is chlorine or bromine, and physiologically acceptable acid addition salts thereof.

The invention is characterized in that a) salicylamide of formula (II) 0 X ^ J (II)

^ OH

wherein R and X have the same meaning as above, are reacted with ethyl chloroformate C1-COOC „Hc, or 1 o b) a salicylic acid derivative of formula (III) 0

X C-OH

Il (i11)

OH

wherein X is as defined above, is reacted with an isocyanate of formula (IV) O = C = N-R (IV) wherein R is as defined above, and that the resulting compound is, if desired, converted into an acid addition salt.

Analgesic effect

The analgesic effect of the derivatives of general formula I was determined in male mice weighing 20-25 g. The test substance was administered orally as a 5% gum arabic suspension using an esophacial probe. The amount of solution administered was 25 ml / kg and the concentration of test substance varied according to the dose administered.

Il 3 60818

The animals were in pain by intraperitoneal injection of 0.2 ml / 20 g of an acetylcholine bromide solution at a concentration of 0.32 mg / ml. 5 min. before administration of the test substance, acetylcholine was injected into 5 batches of mice. The test substance was then administered and again injected with acetylcholine at 20, 40, 80, 120 and 160 min. The number of seizures caused by acetylcholine injection over 5 min was always counted.

The analgesic effect is calculated according to the following formula:

It = 100 - (Nt / No) · 100 = 100 (1-Nt / No) where It = inhibition of pain after t min

No = number of seizures before administration

Nt = number of seizures t min after administration.

Several doses of each agent were administered to prescribe a 50% analgesic dose (AD-50).

It was calculated at 20, 40, 80, 120 and 160 min for each dose. The analgesic effect is considered to be the average of these five It values at each dose. The analgesic effects were plotted as a function of the logarithm of the corresponding dose.

This curve gives AD-50, i.e. a dose that produces a 50% analgesic effect.

Table II shows, by way of example, the results obtained with some of the new derivatives of formula I.

Acute toxicity

Acute toxicity was determined orally in mice weighing 20-25 g using groups of 6 animals. Several doses were given as a geometric series. The observation time was 72 h. A 50% lethal dose (LD-50) was calculated graphically using logarithmic probability paper. The results are shown in Table II.

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Table II

Eg Derivative Doses mg / kg No. DA-50 DL-50 1 6-chloro-3-methyl-1,3-benzoxazine-2,4-dione 30 233 2 6-bromo-3-methyl-1 1,3-benzoxazine-2,4-dione 90,717 3 6-chloro-3-propyl-1,3-benzoxazine-2,4-dione 240,650 8 6-chloro-3-furfuryl-1,3 -Benzoxazine-2,4-dione 280,550,9 6-chloro-3- (o-phenoxyphenyl) -1,3-benzoxazine-2,4-dione 675,750 10 6-chloro-3- (o-thiophenoxyphenyl) -1,3 - benzoxazine-2,4-dione 650 1500 12 6-chloro-3-ethyl-1,3-benzoxazine-2,4-dione 172 250

Anti-inflammatory effect

The anti-inflammatory effect was determined in a male mouse of the Sprague-Dawley breed. Edema was induced in the paw by injecting a 1% solution of carrageenan into the sole of the foot. Paw volume was measured before and 2 or 5 h after oral administration using a plethysmometer. The anti-inflammatory effect was calculated by comparison with the control group. Table III shows the results obtained with the derivative of Example 1 by way of example.

Table III

Eg Derivative Dose Anti-inflammatory effect No. (mg / kg) 2 h 5 h 1 6-chloro-3-methyl-1,3-benzoxazine-2,4-100 26% 30% dioni

Thus, due to their good pharmacodynamic properties, the derivatives of the general formula I can be used in human and / or veterinary medicine as analgesic, antipyretic and anti-inflammatory agents.

5,68818

Pharmaceutical compositions according to the invention, with the exception of a pharmaceutically acceptable carrier, at least one derivative of the general formula I, have a very wide therapeutic field and can be used in particular in traumatology, surgery, rheumatology, Odon dentistry, ortho-rhinolaryngology, pneumology. , cardiology, gynecology and urology. These pharmaceutical compositions can be used, for example, for the treatment of various pain conditions, such as headache, migraine, neuralgia, toothache, menstrual cramps, rheumatoid arthritis, osteoarthritis, fever, colds and influenza, and various infections.

The proposed dose of the derivatives of this invention for humans is about 100-300 mg / d, administered, for example, as tablets, capsules or suppositories.

Pharmacological comparative tests

Male non-white rabbits weighing 1.5 to 2.5 kg were used to determine the change in mean bleeding time (TMS).

The method originally developed by Roskan »(1) and modified by Laporte (2) was used. Prior to test substance administration, a control reading was taken from the right ear as follows: each animal was placed in a frame to prevent head movement and four sets of five incisions were made in the outer ear in the area between the artery and the peripheral vein. Bleeding time was measured from each incision from a wound sprayed with distilled water at 38 ° C.

Test compounds were administered orally by esophageal probe as a 4% suspension in acacia. Final readings were taken 2 hours after test compound administration. The left ear of each animal underwent the same operation as the right ear under the same conditions. The difference between the two readings was calculated as the percentage decrease in bleeding time (TMS). The results are shown in the following table.

(1) Roskam, J.

1'Hemostase spontanee, MASSON ET CIE: PARIS, 1951 (2) Laporte, J.

Chemotherapy (1961) 3, 62-80 6 68818

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1 63818

The preparation of some derivatives of general formula I is described in more detail below.

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

37 ml (0.375 moles) of ethyl chloroformate are slowly added (1/2 h) to a solution of 18.6 g (0.1 moles) of 5-chloro-N-methylsalicylamide in pyridine. Maintained under a condenser for 7 h, allowed to cool, diluted with water, filtered and washed with distilled water. Recrystallized from chloroform, washed with methanol at 5 ° C to give 6-chloro-3-methyl-1,3-benzoxazine-2,4-dione, m.p. 151-153 ° C (see Table I).

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

7.5 ml (0.12 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 at ambient temperature for 1 h and then allowed to reflux for 6 h. Evaporated to dryness, recrystallized from methanol to give 6-bromo-3-methyl-1,3-benzoxazine-2,4-dione, m.p. 186 ° C (see Table I).

Examples 3-9

When worked as described in Examples 1 and 2 above, derivatives were obtained whose physicochemical constants such as crystallization solution, melting point and characteristic lines of the infrared spectrum are shown in Table I.

8 68818

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Claims (4)

9 6381 8 A process for the preparation of therapeutically useful 1,3-benzoxazine-2,4-diones of formula (I) 0 (I) wherein R is alkyl of 1 to 3 carbon atoms, ortho-phenoxy-phenyl, ortho-thiophenoxyphenyl or furfuryl, and X is chlorine or bromine, and for the preparation of their physiologically acceptable acid addition salts, characterized in that a) salicylamide of the formula (II) OI! / RX CN ^ I (II) wherein R and X are as defined above is reacted with ethyl chloroformate Cl-COCX ^ H, - or b) a salicylic acid derivative of formula (III) OX C-OH ΥΎ wherein X is the same as above, is reacted with an isocyanate of formula (IV) 10 6381 80 = C = NR (IV) wherein R is as defined above, and that the compound obtained is, if desired, converted into an acid addition salt. Process for the preparation of 6-chloro-3-methyl-1,3-benzoxazine-2,4-dione according to Claim 1, characterized in that 2-hydroxy-5-chloro-N-methylbenzamide is used as the starting material of the formula (II). 11 6381 8 A process for the preparation of therapeutically active 1,3-benzoxazine-2,4-dione with the formula (I) 0 X ^ R ^ 1 I (I) O o color R är alkyl rned 1-3 cholatomers, ortho- f enoxyphenyl, ortho-thiophenoxyphenyl or furfuryl and X and chlorine or bromine, as well as physiologically acceptable syrup addition, some of which are salicylamide with formula (II) 0 Il / RX> ^ c-nXh | (II) color R and X is an angettable form of the compound, which is selected from the group consisting of ethyl chloroformates b or CC) X that isocyanat med formeln (IV)