LU83054A1 - NOVEL HETEROCYCLIC COMPOUNDS USEFUL AS ANTIALLERGIC AGENTS - Google Patents

Description

I * - 1 - t "4 I 'i The invention relates to new antiallergic agent and, more particularly, new heterocyclic compounds, which are useful by virtue of their antiallergic activity"! 5 Oxadiazolones with the structure s are known in the literature

% -NH

6 \ 10 as well as analogous heterocycles, in which O is replaced by S, NH or CH ^, with or without substituents in place of H "

Pyridyl-oxadiazolones, quinolyl-oxadiazolones, furyl-oxadiazolones and thienyl-oxadiazolones are described in JAC * S "76, 2208 (1954), pyridazyl-oxadiazolone is described in Khim" Geterosikl, Svedin, 556 (1973), la nitroimidazolyl-oxadiazolone is described as antibacterial in patent DE 2,045,789, indolyl-oxadiazolone in Tet "Let" 3235 (1973) and methyl-isoxazolyl-oxadiazolone, in leprosy agent, in J "Org" Chem "26 , 1514 (1961) "'i The novel heterocyclic compounds of the invention * are benzoheterocycles corresponding to the formula i' y '20'% - <\ | (A) '25 a Rj.

in which the dotted line indicates that the double bond can be in either position, R represents H, an alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, hydroxyl, alkoxyl, alkenyl-oxyl, alkynyloxyl group , aryloxyl or aralkyloxyl, a halogen atom, a cyano, nitro, carboxyl, formyl, carbalkoxyl, carbaryloxyl, hydroxyalkyl, amine, alkylamine "trifluoromethyl, mercaptan, trifluoromethoxy, alkylthio // '' t 4 - 2 - or aminoalkyl, Y represents N, NR ^ · or CR ^, R ^ representing H or an alkyl or aryl group, with the proviso that, when Y represents NH, (R) does not represent H, ci 5 â is an integer from 1 to 4, X and Z each represent O, S, NR ^ or CR ^, R ^ meeting the definition above, with the proviso that, when 'Y represents NR ^, X does not represent CR ^, and R ^ represents H or an alkyl, aryl, acyl, carbaΙ-ΙΟ coxyl or carbaryloxyl group · The invention also relates to the acid addition salts of these compounds ·

The total number of carbon atoms in each of the hydrocarbyl substituents represented by R, R ^, R ^, Z 15 and X can range up to approximately 10 · The preferred compounds are those in which these hydrocarbyl radicals contain at most approximately 7 carbon atoms, when they are aliphatic, and a maximum of 10 carbon atoms, when they are aromatic, such as phenyl and naphthyl · 20 It is also understood that the aryl, aralkyl and alkaryl radicals also include the heterocyclic rings known such as furan, thiophene, thiazole, pyridine, pyrimidine, piperidine, oxazole etc ··· as well as benzo-heterocycles like benzothiophene and benzofuran · 25 Although up to four substituents are indicated in the definition of ( R) (a »1 to 4), it is preferable that the benzene fragment does not carry more than two substituents ·

The preferred compounds are those in which X and Z both represent an oxygen atom and Y a nitrogen atom and those in which X represents ΝΉ, N-alkyl or N-aryl, Z represents 0 and Y represents N · 1 The new compounds of the invention can be prepared by known methods, starting from known compounds ·

Examples of cyclization methods for the preparation of benzoheterocydic oxadiazolones include cyclization of the following compounds s / y.

* - 3 - f <r) "" CO-0 ^ 000 "

5 I II

^ 0 Cl .s Cl (R) 40 ^> C-0 (R) “" O> C> 00

a XNH “NH a NH-NH

i

10 III IV

*

15 V VI

in which "Et" denotes the ethyl radical # and which can be prepared by known methods # for example i

. I

NH-NHCOOAnd Γ 20 <«," K>, ^ “CC13 - * -> 1

VII

r * ·

NiUNHCOOEt

25 (R) a Ί3> 1 p ~ cc! ° Et - -7 H

VIII

'NH2NHC00And 1 ° “’ -τδίΑ ->: j

1 IX

0/0 Cl-C-Cl

35 (R) 44-)> c '-> III

Ä vNHNH2 «* 9 / <<> V ^ Xk β Cl-C-Cl /“ -f§Q <_, - * "μ! ** // 1 f

I I

- 4 -, ΝΗ NH NHCOOEt '<RÎatO Cv - ----> 5 ° CH3

XII

ΛγΛ, o hnnh

(R) a T \ _j | y c ~ CH2Coast “- ^ VA

10 XIII

By similar methods "analogous heterocycles can be formed" in which Z is other than O *

Substituents can be introduced onto the oxadiazolone ring either by using a suitably substituted hydrazine in the cyclization reaction, or by alkylation or acylation reactions of the already formed ring.

Aromatic ring substituents which are reactive and which would interfere with cyclization reactions are preferably introduced by common subsequent reactions, for example by reduction of a nitro group to the amine group or hydrolysis of a cyano group to the amide or acid group .

By the methods described "a wide variety of heterocyclics can be prepared" as follows: I · '<R) * <R) a Y X Z Rx

30 H N, S ___________ 0 H

5- CH3 N „CH2 0 CH3

6- CH3 N CH (CôH5> S H

5- C1 N NCH3 NH. ’H

6- OCH3 N NH 0} 35 6-0CH3 N O 0 H, /

5-C6H5 N <S 0 H / A

I <»» - 5 - (R) a Y X 2 5-CF3 N NC6H5 ° ^ 3 5- OC3H5 N "CH2 0 COOCH3

6- OC6H5 N NH CHCH3 CH3CO

5 H N CH2 S H

6-OH N NCH2C6H5 O COOCgHg 6-C4H9 N O NCH3 COOC2H5 6-CH2OH N S CHC6H5 C6H5

5- NH2 N O CHCH2C6H5 C3H? CO

10 5-NHCH3 N 0 0 H

d6-SH N. 0 O CH3 '6-SC3H7 N S H C10H7

'6-C.H, M O O COOH

4 7

6- N02 N 0 0 H

15 6-C6H5CH20 N. 0 P H

6-OCF3 N O O H

6-C2H4NH2 N 0 0 H

H CH 0 0 H

H CH * CH O H

• 8 PM CH S 0 H

The present novel heterocyclic compounds are useful therapeutically as such or may be used in the form of salts, due to their basic nature. Thus, these esters form salts with a wide variety of mineral and organic acids, including therapeutically acceptable acids. The therapeutically acceptable acid salts are, of course, useful in the preparation of compositions which it is desired to make water-soluble. Salts of therapeutically unacceptable acids are particularly useful for the isolation and purification of the novel esters of the invention. Therefore, all the acid salts of the new esters are contemplated by the invention.

The pharmaceutically acceptable acid addition salts are particularly useful in therapy. / 35 They include the salts of mineral acids such as ///

(I

(»T I

I - 6 - hydrochloric, hydroiodic, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, as well as the salts of organic acids such as tartaric, acetic, citric, malic, benzoic, glycolic, gluconic, succinic, arenesifonic acids , for example p-toluenesulfonic acid etc. ·· The pharmaceutically unacceptable acid addition salts, while not being useful in therapy, are useful in the isolation and purification of new substances. In addition, they are useful in the preparation of pharmaceutically acceptable salts. In this group, the most common salts include those formed with hydrofluoric and perchloric acids · Hydrofluorides are particularly useful in the preparation of salts pharmaceutically. Acceptable, for example hydrochlorides, by dissolution in hydrochloric acid and crystallization of the hydrochloride formed. The perchloric acid salts are useful for purifying and crystallizing new products.

As therapeutic agents, the novel heterocyclic compounds according to the invention are particularly useful as antiallergic agents, acting by inhibiting the release of mediators. They are active by the oral route in the control of passive cutaneous anaphylaxis and they inhibit the release of histamine by the mast cells of the passively sensitized rat. The therapeutic agents of the invention can be administered alone or in combination with pharmaceutically acceptable vehicles, the proportion of which is determined by the solubility and the chemical nature of the compound, the chosen route of administration and current pharmaceutical practice. For example, they can be administered orally in the form of tablets or capsules containing excipients such as starch, lactose, certain types of clay, etc. They can be administered orally / in the form of solutions. which contain dyes // and flavorings or parenterally, ie intramuscularly intravenously or subcutaneously. For . parenteral administration "they can be used in the form of a sterile solution containing other solutes" for example enough physiological saline or glucose 5 to make the solution isotonic ·

The doctor will determine the most appropriate dosage which will vary according to the mode of administration and the compound chosen and will also vary according to the patient to be treated * Generally "he will prefer to start treatment with 10 small dosages" markedly lower than the optimal dose of compound, and increase the dosage in small increments until the optimal effect under the circumstances considered is achieved. It will generally be found that when the composition is administered orally, larger amounts of the active agent are required to produce the same effect as a smaller amount administered parenterally. The compounds are useful in the same way as other antiallergic agents and the dosage is of the same order of magnitude as that generally used for these agents. The dosage will generally be 10 to 750 mg per day and more, although this dose can be administered in multiple doses. Tablets containing 10 to 250 mg of active agent are particularly useful.

The following examples further illustrate the invention. <EXAMPLE 1 (2-benzoxazovl) -hvdrazinecarboxvlate eth • •. : t

Method A

A mixture of 15 g of 3-chloro-1,4-benzoxazine-2-one and,, 4 g of ethyl carbazate in 80 ml of dioxane and 12 ml of triethylamine is stirred at ambient temperature for 4 hours. · The organic solvent is evaporated // - 8 - and 100 ml of water are added to the residue with stirring · The solid obtained is filtered and dried · By recrystallizing from acetonitrile, white crystals are obtained, melting point 175-176 ° C.

5 Method B

A mixture of 106 mg of methyl benzoxazole-2-carboxylate and 68.5 mg of ethyl carbazate in dioxane is heated at reflux overnight. The organic solvent is evaporated and the residue is extracted with hexane 10. and hot ether to remove the unaltered ester. Recrystallization from acetonitrile gives the pure body, melting point 175 to 176 ° C. · 2 "(2-OXO-3H-1,3,4-oxadiazole-5-vl) -benzoxazole A 250 ml of" Dôwtherm A "between 230 and 240 ° C., 12 g of the product prepared according to process A · 20 are added with stirring. After heating: for 1 hour, the mixture is cooled, filtered and the solid product is washed with hexane · Recrystallization from acetonitrile gives an analytical sample, melting point 220 at 223 ° C.

In the same way as above, using suitable raw materials and reagents, the following compounds are prepared: 5-chloro-2- (2-oxo-3H-1,3,4-oxadiazole-5- yl) -benzoxazole, melting point 263 at 266 ° C, 5-carbomethoxy-7-methoxy-2- (2-oxo-3H-1,3,4-oxadiazole— 5-yl) -benzoxazole, fusion 247 at 248 ° C, 'i 6-methyl-2- (2-OXO-3H-1,3,4-oxadiazole-5-yl) -benzoxazole, melting point 245 at 248 ° C,! 5-carbethoxy-2- (2-oxo-3H-1,3,4-oxadiazole-5-yl) -benzoxazole, melting point 218 at 219 ° C, 35! 4-methyl-2- (2-oxo-3H-1,3,4-oxadiazole-5-yl) -benzoxazole? / melting point 247 at 251 ° C, / - 9 - - 5-methyl-2 - (2-oxo-3H-l, 3,4-oxadiazole-5-yl) -benzoxazole, melting point 207 at 210 ° C, 2- (2-oxo-3H-l, 3,4-oxadiazole- 5-yl) -benzothiazole, melting point 235 at 236 ° C.

5 EXAMPLE 2 2- (2-oxo-3-acetvl-3H-l, 3.4-oxadiazole-5-vl) -benzoxazole - t

Heated at 100 ° C for 1 hour 5.0 g of 2- (2-oxo-3H-1,3,4-oxadiazole-5-yl) ~ benzoxazole in 50 ml of acetic acid containing 5 ml of anhydride acetic · The mixture is poured into water and the crystalline product is filtered · 15 By recrystallizing from acetonitrile, a melting point of 231 at 232 ° C. is obtained ·

In the same way as above, using suitable raw materials and reagents, the following compounds are prepared: 2- (2-oxo-3-carbethoxy-3H-1,3,4-oxadiazole-5) yl) -benzoxazole, melting point 189 at 190 ° C,

Ile 2- (2-oxo-3-carbethoxy-3H-l, 3,4-oxadiazole-5-yl) -6-methyl-benzoxazole, melting point 164 at 166 ° C, 2- (2-oxo- 3-carbethoxy-3H-1,3,4-oxadiazole-5-yl) -1-raethyl-25 benzimidazole, melting point 179 at 181 ° C, 2- (2-oxo-3-acetyl-3H-1 , 3,4-oxadiazole-5-yl) -1-methyl-benzimidazole, melting point 220 at 222 ° C. EXAMPLE 3 (1-methvl-2-benzimidazovl) -hvdrazinecarboxvlate of ethyl.

CH3 C-NH-NH-COOC2H5 Î A mixture of .24.9 g (0.1 mol) of 1-methyl-2-trichloromethylbenzimidazole is heated under reflux for 1 hour. // / - 10 - 10.4 g (0.1 mol) of ethyl carbazate, 100 ml of acetonitrile, 100 ml of water and 33.6. g (0/8 mol) of sodium bicarbonate · After cooling, the mixture is diluted with 200 ml of methylene chloride. The organic phase is separated, washed with water # it is dried over MgSO 4 and concentrated to obtain a solid, melting point 190 at 193 ° C # l-methvl-2- (1.3.4-oxadiazol ~ 2 (3H) ~ one-5-vl) -benzimidazole T3 0 0 10

A suspension of 10 g (0.046 mol) of the easesple 3 product in 30 ml of "Dowtherm" is heated at 180 ° C. for 30 mixed. The mixture is filtered hot. After cooling, the precipitate is washed. with ether and recrystallized from acetone, melting point 300 ° C, EXAMPLE 4 1-methvlbenzimidazole-2-carbQXVj "± g of methvl CH3

A solution of 249.5 g (1 mol) of 1-methyl-2-trichlic3nethylbenzimidazole in 1.0 liter of methanol is heated at reflux for 2 days. We concexr * the mixture under

Ivide and add 200 ml of water. The suspension obtained is neutralized with 250 g of bicarbonate of ir ~ -m and extracted with chloroform (3 times 200 if), fc separates the organic phase, it is dried over MgSC 4 and concentrated to /

2 ° obtain a solid, melting point fei at 99.5 ° C.

r - 11 - 2- (l-methvl-2-benzimidazovl) —hvdrazjner '. f1 * To a solution of 95 g (Of5 mol) of methyl 1-methylbenzimidazole-2-carboxylate in 500 ml of isopropanol, we>. 190 ml of an 85% aqueous hydrazine solution are added. The mixture is heated at 60 ° C. for 1 hour and then cooled to 0 ° C. The precipitate obtained is filtered, washed with ether. and dried, melting point 156 to 159 ° C · l-methvl-2- (1.3 * 4-oxadiazole-2 (3H) -one-5-vl) -benzimidazole I 3 15

Phosgene gas is slowly dispersed, until saturation, in a suspension of 95 g (0.5 mol) of, 2- (1-methyl-2-benzimidazolyl) -hydrazine in 300 ml of methylene chloride · After having stirred for 1 hour, the precipitate is filtered, washed with methylene chloride and dried · The solid obtained is the hydrochloride (melting point 253 at 261 ° C with decomposition), which can be converted into free base ( melting point 300 ° C) treating it with aqueous sodium bicarbonate.

In the same way as above, the 3-chlorobenzo (b) thiophene-2-carboxylic acid hydrazide is reacted with phosgene to obtain 3-chloro-2- (2-oxo-3H-1). , 3,4-oxadiazole-5-yl) -benzo (b) thiophene, melting point 218 at 220 ° C.

Similarly, ethyl indene-2-carboxylate is reacted with hydrazine and phosgene to obtain / 2- (2-oxo-3H-1,3,4-oxadiazole-5-yl) -indene. . / /:. ψ - 12 - EXAMPLE 5 l-methvl-2- (1,3 »4-triazole-2 (1H, 3H) -one-5-vl) -benzImidazole

fs H

:

A mixture of 23.7 g (0.1 mol) of 1-methyl-2-trichloromethylbenzimidazole, 7.5 g (0.1 mol) of seraicarbazide, 50 ml of triethylamine, 100 ml is heated at reflux for 5 hours. of water and 200 ml of acetonitrile · The mixture is filtered while hot and 4.1 g of crude product are obtained · It is purified by treating it with methanol at reflux for 1/2 hour and filtered while hot to obtain a white solid, melting point 293 at 296 ° C.

! EXAMPLE 6 2- (2-ΟΧΟ-3Η-1 »3; 4-oxadiazole-5-vl) -benzofuran I · O *

20 (oQ

To a solution of 45 g (0.25 mol) of 2-chlorocarbonyl-benzofuran in 500 ml of acetonitrile is added 27 g '(0.26 mol) of ethyl carbazate · After heating at reflux for 1 hour, the mixture is cooled to 0 ° C * for 18 hours · The precipitate is filtered, washed with ether and dried to obtain ethyl (2-benzofuranoyl) -hydrazinecarboxylate, melting point 137 at 138 ° C. 4.0 g (16 mmol) of this product is heated to 240 ° C for 4 hours in "Dowtherm A". After cooling, we

filter the mixture · The product is purified by high-pressure liquid chromatography using a 3/1 hexane / acetone mixture to obtain a white powder, melting point 202-203 ° C. AL

\ T

EXAMPLE 7 2- (1, 3, 4-triazole-2- (1H, 3H) -one-5-vl) -benzoxazole. mit

8.0 g of methyl benzo-xazole-2-imidate and 5.2 g of ethyl carbazate are heated overnight to 110 ° C. overnight.> After evaporation of the solvent, the residue is suspended in 45 ml. of "Dowtherm A" and heated at 220 ° C for 15 minutes · The precipitated product is filtered, washed with CH ^ Cl ^ and CH ^ OH and dried to obtain 3.6 g of solid, higher melting point at 300 ° C. EXAMPLE 8 15 2- (2-oxo-3H-1. 3,4-thiadiazole-5-vl) -indene: ma! 17.4 g (0.1 mol) of indene-2-carboxylic acid ethylhydrazide in 200 ml of carbon disulfide are treated with 22 g (0.1 mol) of phosphorus pentasulfide and the mixture is stirred with reflux for 24 hours · The mixture is extracted with 3 portions of 10% sodium hydroxide solution 25, the organic phase is dried and concentrated to obtain a solid. The thiohydrazide thus obtained is reacted with the phosgene, as indicated in Example 4, to obtain the product indicated by the title · EXAMPLE 9 30 2- (Pvrazole-5- (1H.4H) -one-3-vl) -benzoxazole ·. ! r

V

- 14 -

5.28 g (0.11 mol) of 50% sodium hydride in mineral oil are washed with heptane twice and suspended in 100 ml of dry tetrahydrofuran * 9.68 are added g (0.11 mol) of ethyl acetate and the mixture is stirred at reflux for 4 hours * 18.2 g (0.1 mol) of 2-chlorocarbonylbenzo-furan are then added dropwise * Stirred the mixture at room temperature for 16 hours, diluted with water and the tetrahydrofuran is removed by distillation * The aqueous phase is extracted with chloroform and the chloroform phase is concentrated to obtain a gum * It is taken up in 100 ml of ethanol, treated with 5.0 g of 85% hydrazine hydrate and the solution is heated to reflux for 4 hours.

The mixture is concentrated to a gum which crystallizes on rubbing and which is recrystallized from ethanol to obtain the product indicated by the title.

!

The compounds of the invention have great activity of inhibiting papule formation when used in the control of passive anaphylaxis in rats, as described by I. Mot a, Life Sciences , 2.465 (1963) and Z * Ovary et al., Proceedings of Society of Experimental Biology and Medicine, 81, 584 (1952).

In addition, the compounds of the invention have potent activity as inhibitors of histamine release from mast cells of the passively sensitized rat, according to the method described by E. Kusner et al. Journal of Pharmacology / and Experimental Therapeutics · /} /, ·:: V / •. -: l ‘. t · I 'f i. ... ,.

Claims (18)

1. Antiallergic compound corresponding to the formula tsu> a - ^ CKX in which the dotted line indicates that the double bond can be in one or the other position, R represents H, an alkyl, alkenyl, alkynyl, aryl group, aralkyl, araleenyl, hydroxyl, alkoxyl, alkenyl-10 oxyl, alkynyloxyl, aryloxyl or aralkyloxyl, halogen atom, cyano, nitro, carboxyl, formyl, carbalkoxyl, carbaryloxyl, hydroxyalkyl, amine, alkylamine, trifluoromethyl, mercaptan, mercaptan , alkylthio or aminoalkyl, 15. represents N, NR ^ or CR ^, R2 represents H or an alkyl or aryl group, with the proviso that, when Y represents NH, (R) does not represent H, Û £ is an integer from 1 to 4, X and Z each represent O, S, NR ^ or CR ^, corresponding to the definition above, with the proviso that, when Y represents NR ^, X does not represent CR ^ # and R ^ represents H or an alkyl, aryl, acyl, carbalkoxyl or carbaryloxyl group, as well as the salts of a corresponding acid addition · 25 2 · - Antiallergic compound corresponding to the formula t in which the dotted line indicates that the double bond 30 may be in one or the other position, R represents H, an alkyl or alkenyl group, alkynyl, aryl, aralkyl, araleenyl, hydroxyl, alkoxyl, alkenyl oxyl, alkynyloxyl; aryloxyl or aralkyloxyl, halogen atom, cyano, nitro, carboxyl, formyl, carbalkoxyl, carbaryloxyl, hydroxyalkyl, amine, alkylamine, trifluoromethyl, mereaptan, trifluororaethoxyl, alkylthicT / • · - 16 - or aminoalkyl, Y represents N , NR ^ or CR ^, R ^ representing · H or an alkyl or aryl group, with the proviso that, when 'Y represents NH, (R) does not represent H, 5. is an integer from 1 to 4, X represents O, S, NR ^ or CR ^ "meeting the definition above, with the proviso that, when Y represents NR ^, X does not represent CR ^, and R ^ represents H or an alkyl, aryl, acyl group , 10-carbalco xyl or carbaryloxyl, and the corresponding acid addition salts · 3. Antiallergic compound corresponding to formula t; '»'" • 'CCKX • I where R represents H, an alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, hydroxyl, alkoxyl, alkenyl-oxyl, alkynyloxyl, aryloxyl or aralkyloxyl, halogen atom, cyano, nitro, carboxyl, formyl, carbalcoxyl, carbaryloxyl, hydroxyalkyl, amine, alkylamine, trifluoromethyl, mercaptan, trifluoromethoxyl, alkylthio or aminoalkyl,, a is an integer from 1 to 4, 25. represents O, S, NH, or an N-alkyl or N-aryl group, and R ^ represents H or an alkyl, aryl, acyl, carbal-coxyl or carbaryloxyl group, as well as the corresponding acid addition salts · i 4 · “Antiallergic compound according to the claim 3, characterized in that R represents an alkyl group, that y * h that X represents 0 and that R ^ represents H · l 5 · - Compound according to claim 3, characterized! in that R represents H, that X represents 0 and that R ^ represents an alkyl group · j 35 - 6 · - Compound according to claim 3, character sé J I by the fact that R represents Cl, that y * 1, that X represents? / i: /// "i - / jp i 17" 0 and that R ^ represents H, 7 · - Compound according to claim 3 # characterized in that R represents H, that X represents N-alkyl and that represents an acyl group * 8. A compound according to claim 2, characterized in that R represents H, that X represents N-alkyl and that represents H. 9 · - Compound according to claim 3 # characterized in that R represents H, that X represents S and 10 that R ^ represents H. 10 · - Compound according to claim 2 "characterized in that X represents CH # that Y represents 0 and that R represents an alkyl group. 11 · - 2- (2-OXO-3H-1,3,4-oxadiazol-5-yl) -benzoxazole · 12 12 - - L-raethyl-2- (2-oxo-3H-l # 3, 4-oxadiazol-5-yl) - benzimidazole. 13 · - 5-chloro-2- (2-oxo-3H-l, 3,4-oxadiazol-5-y1) - benzoxazole · 14 · - 6-methyl-2- (2-oxo-3H-l, 3,4-oxadiazol-5-yl) -20 benzoxazole · 15 · - 2- (2-oxo-3H-l, 3,4-oxadiazol-5-yl) -benzothiazole · 16 · - 2- (2-oxo-3-aaetyl-3H-1,3,4-oxadiazol-5-yl) -1-methylbenzimidazole · 17.- 2- (2-OXO-3H-1,3,4-oxadiazol-5-yl) -benzofuran · 18 18 - Acid addition salt of the compound according to claim 8 · 19 · - acid addition salt of the compound according to claim 10 · 20 · - Acid addition salt of the compound according to claim 15 · 21 · - A pharmaceutical composition comprising a compound according to claim 1 in a pharmaceutically acceptable excipient · 22 · - Process for the preparation of a compound according to J f 35 claim 1 # characterized in that one cyclizesV £ - 18 -. compounds corresponding to the formulas t! '"· -COxr“ lLr “I 5 I II! RXVsr ^ \ /? C1 C1! (R) a TOT M / °“ ° (R, a {Ol ÿ% / C- ° t NH-NH NH-NH I III IV <R) * tQTM, cooEt "KiQLH nh-nh nn-nh2 V VI to form the oxadiazolone structure of formula A, which, optionally, are applied to the product of the substitution reactions by methods in themselves known, that, optionally, converting substituents already present on the ring structures of the compound formed into other substituents by transformation reactions in themselves known and / or that, optionally, the addition salt is formed. acid of the basic product · 23 · - Method according to claim 22, characterized in that the compounds of formulas I to VI are derived, by methods known per se, from corresponding compounds 25 corresponding to the formulas "(r> * 0013 VII < κ> β -0 ^ -c ° oEt fl vin h - 19 - '"·. IX ^ νηνη2 X ♦ 4 (" i.-tôjrV'C,. Ν / ^ Υ ΝΗΝΗ0 m * ΐ' · 5. 'XI j ^ ΝΗ 15. och3 XII (R) ay ^ "CH ^ COOEt 20 Ss ^ V *! XIII i ·! Drawings: ....,. plates 'JLA— pages of which ....... A ....... cover page' _. * LH ....... p'rgcs cb description jp; -. ~ es of claims I —AJL short description Luxemhcuro, le - Le v '“'" 'Charles München; ”