DD145534A5 - PROCESS FOR THE PREPARATION OF 1,3-BENZOXAZINE-2,4-DION DERIVATIVES - Google Patents

Description

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Process for the preparation of 1,3-benzoxazine-2 _f 4-dione derivatives

¹ '* .1 »

A nwendu ngsgeb iet the He-making

The invention relates to novel 1,3-enzoxazine-2,4-dione derivatives and to processes for their preparation. The novel compounds find use as or in drugs as well as pharmaceutical compositions containing them.

Characteristic of the known technical solutions

There are no known technical solutions known.

Zi el de r invention

The aim of the invention is the provision of new drugs with analgesic, antipyretic and anti-inflammatory activity.

Explanation of the essence of the invention

The invention has for its object to provide a process for the preparation of new l, 3-Eenzoxazin-2,4-dione derivatives.

Such 1,3-benzoxazine-2,4-dione derivatives of the general formula are prepared according to the invention

"ι ') if«; -Ι α Λ r, \ ο'" · ^Λ <'> r- <\ I I. οίίίι. ΙΟ *. ' ί <"<.)». * ί '.. ·''> .ζ ·

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0 R ^"s

in which * mean:

R is an alkyl radical, in particular a lower alkyl radical having preferably 1 to 4 carbon atoms, an o-phenoxyphenyl group, an o-thiophenoxyphenyl group, a benzyl group, a furfuryl group or a 2-pyridyl group,

R 'eiif hydrogen atom' is a chlorine atom, a bromine atom or a methoxy radical,

R "is a hydrogen atom, a chlorine atom or a methyl radical and

R '"is a hydrogenatora, a chloroengine or a bromine atom, giving these derivatives of general formula (I)

a) by reacting a salicylamide derivative of the general formula

pt I ^ "

^R C - N

H II

wherein R ₁ R ', R "and R"' have the meanings given above with respect to the general formula (I), with ethyl chloroformate or

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b} by reaction of a salicylic acid derivative of the general formula,

C-OH

wherein R ¹ , R "and R" ^{B have} the meanings given above with respect to the general formula (I), with an isocyanate of the general formula

0 = C = M - R IV

wherein R has the meaning given above with respect to the general formula (I).

Because of their good phrarmacodynamic properties, the derivatives of the general formula (I) according to the invention can be used in human medicine and / or in veterinary medicine as analgesics * antipyretics and as anti-inflammatory agents.

Pharmaceutical agents which contain, in addition to at least one pharmaceutically acceptable carrier, at least one derivative of the general formula (I) and / or at least one pharmaceutically acceptable acid addition salt thereof, have a very wide range of therapeutic uses and, in particular, in the field of omatology. Surgery,

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Iheuiiiatologie, Odontostomatologie, Otorhinolaryngology »are used in pulmonology, cardiology, gynecology and urology. These pharmaceutical agents can be used, for example, for the treatment of various pain conditions, headaches, migraines, toothaches, neuralgia, menstrual boils, rheumatic inflammation, arthritic pain, fevers, rheumatism, influenza and seasonal infections.

In the following, the preparation of some derivatives of the general formula (I) in the farm of their free base is explained in more detail by means of simple examples; however, it will be understood by those skilled in the art that they are by no means limited thereto, but that in many respects they may be altered and modified without departing from the scope of the present invention.

Earthing example

Example 1 .

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

To a solution of 18.6 g (0.1 mol) of 5-chloro-N-methylsalicylamide in pyridine is added slowly (within 2 hours) 37 ssl (0.375 mol) of ethyl chloroformate. Refluxed for 7 hours, allowed to cool, diluted with iSasser, filtered and washed with distilled water. It is recrystallized from chloroform, washed with methanol of 5 ⁰ C and receives the 6 ~ chloro-3-methyl-i _J 3-benzoxazin- »2 _!! 4 '»dione _i F. 151 to 153 ^° C. (cf. the following Table I).

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Example 2 Preparation of 6-8romo-3-methyl-1,3-benzoxazine-2 _/ 4-dione

To a solution of 2ΐγ ~ 7 g (0.1 mol) of 5-bromosalicylic acid in 150 nil benzene are added to 1.5 ml (0.12 mol) of methyl isocyanate and 5 ml of triethylamine. The mixture is stirred for one hour at ambient temperature and then allowed to reflux for 6 hours. The mixture is evaporated to dryness, recrystallized from methanol and the 6-Bro: n-3-methyl-l, 3-benzoxazine-2,4-dione, mp 186 ° C (see the following Table I).

· « Examples 3 to 17

If one operates as indicated in the above Seispielen 1 and 2, one can, for example, produce the derivatives, of which a certain number of physicochemical constants, never z. For example, the crystallization solvents, the Schrslzpunkte (F.) and the characteristic bands of the infrared spectrum, are given in Table I below.

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Tabelie I

TSnHnMaamt T-i In game R CH ₃ R ' Cl R "" R ' " F- ( ⁰ C) Crystallization solvent Yield (SS) IR (cm " ¹ ) CH ₃ br H H 151-3 ' CHCl ₃ 93 1300, 1350 1690, 1770 2 CH ₂ CH ₂ CH ₃ Cl H H 186 CH ₃ OH 19 1300, 1350 1690, 1750 3 CH (CH ₃ ) g Cl H H 118 OH 52 1340 1700, 1770 4 CHGCHGCHGCH ₃ Cl H H 167-9 CH ₃ OH 24 1330 1700, 1770 5 (CHg) ₁₅ CH ₃ Cl H H 103 CH ₃ CHgOH 12 1300 1700, 177 (3 5 H H 97 CH ₃ COCH ₃ 67 1350 1700, 1770

Ι CQ ro N nf CM in cn in η CM ω CM in J I KD in in ro co in CD ω in nf ro CM J I ID ID in in in in in in ro ro I CM O I I ro I I I I ro to O ω O O r ^ O "η O CM O in > · I ω CO co O nf ro co KO IO T-I nf nf nf ro CX) ω C X vi 1.0 * "* in T-I V-I r-l KO ro rh τ-! rh CM in  H O ω fv, nf CM ft! CM ro fs. CD VD LO Ü ν " CM a * nf β " OJ CM ro CM in NT nf nf ω OD CM O CM LO CM cn rn CM <H CM CM per cent IO ' τ-! O CO ro Ni  H r-i nf CM in UT in ir " (.0 KO ω CO in m LD LO m in LT) UJ β • 1_ M- Q) (I)   r S S Xi

Table I (continued)

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At play N « R R '. · R " R ¹ " P- ( ⁰ Cj Crystallization solvent Yield (%) IR (cm " ¹ ) 7 ^CH 2- <O> Cl H H 152-5 CH ₃ OH 42 1340 1710, 1770 8th ^CH 2 Jg. Cl H H 178-80 KtOH / M © ₂ GO 46 1320 1700, 1770 9 Cl H H 167 EtOH 70 1360 1710, 1770 10 Cl H H 150 EtOH. 98 1360 1710, 1770 11 CH ₃ H Cl H 192-4 CH ₃ OH 10 1300, 1360 1690, 1760 12 CH ₀ CH, Cl H H 120-2 C Cl ₄ 51 1340, 1350 1700, 1770 13 CH ₇ Cl H Cl 159-63 AccÄt 6 1300, 1360 1690, 1770 14 CH ₂ CH ₂ CH ₂ CH ₃ Cl H Cl 105-8 CH ₃ OH 46 1340 1700, 1770 I

 ζ ω cn on CX) K) in VD O Oil a K) CJ in cn m VO cn  <* O cn CO cn K) CO VD co VD OJ VD r ^ ω L, in K) K) K) vD r- vD VD vD LO in ω ι I vD I I I rh I I K) co cn 0 K) OJ m O CM "J. v.0 G) C \ l OJ per cent per cent co ο OJ OJ VD r ^ O ¹ I K) co ω co cn V.0 in per cent OJ CV cn cn cn OJ vD in in ω co XJ ro rh  H OJ OJ OJ OJ C r-I N per cent LO LO O O r-i rn K) ω m ω LO K) K) co K) K) K) O LO O ^ to ·. O cn CO cn O m OJ K) K) O K) OJ K) to OJ to K) VD in K) σ " OJ OT in in OJ Oil OJ -H co 0.1 O cn OJ cn O O ω HO iO LO LO VD K) η K) ro K) O cn CD C) m LO vO vO <0 in in in m S3 D)

Table I (continued)

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At game no. R .Ri. R " R "' F. (° C) Crystallization solvent yield IR (cm- ¹ ) 15 CH ₂ CH ₂ CH ₂ CH ₃ br H br 139 EtOH 38 1350 1690, 1770 16 ^CH 3 CH ₃ O H H 138-40 CH ₃ UH / H ₂ O. 23 1300, 1355 1690, 1760 17 CH, I H ^CH 3 H 164th CH ₃ OH 12 1300, 1370 1690, 1750

- ΑΛ-

 ζ CM N Ό ω K) - Γ "* O Γ ^ K) - ^ Μ " K! ro. CTi ι_ σ " K) I CO ω K) m CM ·. I 1.0 CM OJ O co i-t • ί ο σ I ίθ I 1 C  ίθ CM O • Ε 01 ο CM K) : Ο r-l O IO CM CO 01 CM K)  ιη CTi CO CO _ C \! K) K) (1) V Χ}

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Anaesthetic activity

The analgesic activity of the derivatives of the general formula (I) was determined in a male mouse weighing between 20 and 25 g. The product to be tested was administered in the form of a $ 5 P-9 ^en suspension in gum arabic by the oral route by means eioer Ösophag probe. The volume of solution administered was 25 ml / kg and the concentration of the product tested was changed according to the dose administered.

By intraperitoneal injection of 0.2 ml of acetylcholine bromide solution eiaer concentration of 0.32 mg / rnl per 20 g pain hex caused the animals. Five minutes prior to administration of the tested product, acetylchine was injected into a group of 5 mice. Then, the under examination P ^r was administered oduct was being carried out again after 20, AQ., 80, 120 and 160 minutes, an acetylcholine injection '. The number of painkillers per acetylcholine injection was counted within 5 minutes.

Using the formula given below, the analgesic activity was calculated:

It = 100 - (Nt / No). 100 = 100 (I-Nt / No)

in which: It = sclimeric inhibition after t minutes

No = number of pain bends before

Administration of the product Nt = number of aches and bends after t

Minutes of administration of the product »

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Several doses of each product were administered to determine the analgesic 50% ^D sis (DA-50).

With each of these doses It was calculated at times 20, 40, 80, 120 and 160 minutes. As an analgesic effect, the mean of these 5 values of It is taken for each dose. The analgesic effects were plotted as a function of the logarithm of the appropriate dose.

From this curve, the analgesic 50/0 dose is obtained, ie the dose giving an analgesic effect of 50 % . In the following Table II, the results are given by way of example, which were obtained for some derivatives of the formula (I) according to the invention.

Acute Tox i ζ it t

Oral toxicity was determined in mice weighing 20 to 25 g using groups of 6 animals. "Several geometrically increasing doses were administered. The observation time was 72 hours. The Lethal 50% Dooe (DL-50) was calculated graphically using logarithmic paper.

In Table II the results are shown as an example, which were obtained in some derivatives of the invention of formula (1).

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Table II example

derivative

Doses in mg / kg DA-50 DL-50

1 2 3 8

IO

12

benzoxazine-2,4-dione

6-Br, ffl-3-methyl-1,3-benzoxazine-2,4-dione

ppy benzoxazine-2- _t 4-dione

6-Chloro ~ 3-furfuryl

1,3-benzoxazin-2,4 ~ dione

6 ~ chloro-3- (o-phenoxyphenyl) -l, 3-benzoxazin-2,4-Êîìóñ

6-ChI.GT-3- (o -thiophenoxyphylnyl) -1S-bzin-2 "4-dione

30 233 90 717 240 Ύ 650 280 > 550

y benzoine: azine-2 ₁ 4-dione

675

650

172

> 750

7 1500 y 250

Anti .-- iη f 1 at; natori specific Ak. tiνität

It vvarde determined the anti-inflamatory activity in a male rat of the strain Sprague-Dawley. In the Pf-ote dor rat, edema was induced by subplantar injection of a 1% carrageenin solution. The volume of the paw before administration of the product was determined by oral route to ζκβϊ and five hours by means of a plethysmometer. The anti-inflammatory activity was determined by reference to a comparison group.

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expects. In the following Table III are given by way of example the results obtained for the derivative of Example 1.

Table ίίΐ

Example No. Derivative Dose Anti-inflammatori ·

(mg / kg) activity

2 hours 5 hours

6 "chloro-3-methyl-

1,3-benzoxazin-100 26% _30/0

2,4-dione. ·

In human therapy, is the suggested dose for this invention derivatives of between about 100 and about 300 mg / day, administered for example in the form of tablets, capsules or suppositories.

In the following, three preferred galenic forms of the derivatives according to the invention will be described in more detail by way of example.

Formulation example for tablets

G-chloro-S-iTiethyl-1,3-benzoXQ2in-2,4-dione 100 mg

Avicel pH-102 100 mg

PrifDoiel 10 mg

Aerosil-200 1 mg

Magnesium stearate 2 mg

Weight of the table 213 mg

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Formulation example of a capsule

6-Chloro-3-methyl-1- _J 3-benzoxazine-2,4-dione 100 mg

Lactose 75 mg

Avicel pH-102 25 mg

Aerosil-200 1 mg

Magnesium stearate 2 mg

Weight of the capsule 203 mg

Formulation example for a suppository

6-Chloro-3-methyl-1,3-benzoxazine-2,4-dione 0.2 g

Monol 1.8 g

Weight for the suppository 2.0 g

Claims (3)

1, Process for the preparation of l, 3-benzoxazine-2,4-dione derivatives of the general formula OR ¹ (I) R ¹ " £ ± r \ mean: R is an alkyl rust, in particular a lower alkyl radical having preferably 1 to 4 carbon atoms, an o ~ pherioxyphenyl group _t o-thiophenoxyphenyl group, benzyl group, furfuryl group or 2-pyridyl group> R * is a hydrogen atom, a chlorine atom, a bromine atom or a hethoxy radical, R "is a hydrogen atom, a chlorine atom or a methyl radical and 'ti'"is a hydrogen atom, a chlorocitome or a dromatome, characterized by doB man '*' · a) a Salicylamiddorivat the general formula 01/22/1980 AP C 07 D / 215 55 652/12 (II) wherein R ₁ R '_# R "and R ¹¹ ' have the meanings given in items 1 and / or 2,
reacted with ethyl chloroformate .or b) a salicylic acid derivative of the general formula (III) R " ¹ in which R ¹ , R "and R" * have the abovementioned meaning, with an isocyanate of the general formula 0 = C = η - R (IV) where R also has the above given meaning. 2. The method according to item 1, characterized in that one 6 ~ chloro-3-methyl ~ l _1, 3-benzoxazine-2,4-dione, 6-chloro-3-ethyl ~ l, 3-benzox3zin ~ 2,4-dione, 01/22/1980 , AP C 07 Ρ / 215 096 21 .5-09 6. ^ _ 55 652/12 ö-chloro-o-propyl-1, S- 6-Chloro-3-fur uryl-1,3-benzoxazine-2,4-dione, 6-Ghloro-3- (o -phenoxyphenyl) -1,3-benzoxazine-2,4-dione, 6α-chloro-3- (o-t-phenophenoxyphenyl) -1, S-benzoxazine-4/4 dione 6-bromo-3-methyl-1,3-ben2oxazine-2,4-dione.