FR2472569A1 - Hexa:hydro-4-hydroxy-di:benzofuran derivs. - useful as intermediates for analgesic 4-amino cpds. - Google Patents

Abstract

Dibenzofuran derivs. of formula (I) are new: (R1, R2, R3 and R4 are each H, halo, lower alkyl or alkoxy, or trifluoromethyl). (I) are pref. prepd. by yielding an opt. substd. 2-(cyclohexen-2-yl) phenol (II) in a single stage with an organic peracid. Pref. the acid is m-chloroperbenzoic (III) and is added in small portions to a soln. of (II) in e.g. CH2Cl2 at 0 deg.C. The mixt. is then stirred at room temp. for about 4 hr. Pref., the phenolic gp. in (II) is protected by reaction with acetyl chloride, then the prod. reacted with (III) to give an epoxide which is cyclised with alcoholic alkali alkoxide. (I) are converted to 4-amino derivs. (a) by oxidn. to ketone then reaction with amine, or (b) reaction with hydroxylamine then redn. of the oxime formed.

Description

 The subject of the present invention is substituted 1, 2, 3, 4, 4a, 9b-hexahydro-4-hydroxy-dibenzofurans, which are new chemical compounds making it possible in particular to synthesize compounds that can be used in human therapy, such as, for example, derivatives. -amino with analgesic activity.

 The invention also relates to the particular process which makes it possible to synthesize the abovementioned compounds.

Many amino derivatives of dibenzofuran are already known, synthesized and studied therapeutically because of their structural relationship with morphine. WINTERNITZ and
Coll. Bull. Soc. Chim. France 1817 (1956) 7 described the structural compound

GODEFROI and SIMANYL gJ. Org. Chem. 28, 1112 (1963) 7 have described compounds of general structure

More recently, other dibenzofuran derivatives have been described in patents; this is the case, for example, of the following derivatives

In all cases, these compounds result from very specific syntheses, which make it possible to obtain on the tricyclic backbone only the precisely described substitutions.

dans laquelle les substituants R1, R2, R3, R4 sont identiques ou différents et représentent un atome d'hydrogène, un atome d'halogène, un radical alkyle ou alcoxy inférieur, ou le radical trifluorométhyle.It has now been discovered that new substitutions on dibenzofuran are possible if 1, 2, 3, 4, 4a, 9b-hexahydro-4-hydroxy dibenzofurans are used as the starting material, having the following general formula:

wherein the substituents R1, R2, R3, R4 are the same or different and represent a hydrogen atom, a halogen atom, an alkyl or lower alkoxy radical, or the trifluoromethyl radical.

 The invention thus concerns as new chemical compounds the compounds of formula (I); it also relates to their preparation process, which will be described later.

dans laquelle les substituants R1, R2, R3, R4 ont les significations indiquées pour la formule (I) et les substituants
R5 et R6 du groupement aminé

représententindé- pendamment l'un de l'autre, un atome d'hydrogène, un radical alkyle ou cycloalkyle, un radical aralkyle ou un radical alcoxyalkyle, ou, ensemble avec l'atome d'azote auquel ils sont liés1 un reste aminé cyclique pouvant contenir un autre hétéro-atome d'oxygène ou d'azote.The invention also relates to the application of compounds (I) for the synthesis of 4-amino derivatives of general formula

in which the substituents R1, R2, R3, R4 have the meanings indicated for the formula (I) and the substituents
R5 and R6 of the amino group

independently of one another, a hydrogen atom, an alkyl or cycloalkyl radical, an aralkyl radical or an alkoxyalkyl radical, or, together with the nitrogen atom to which they are bonded, a cyclic amine residue may contain another hetero atom of oxygen or nitrogen.

 The invention relates ultimately to the amine compounds (II) and their therapeutic application, in particular because of their analgesic activity.

1, 2, 3, 4, 4a, 9b-hexahydro-4-hydroxy-dibenzofurans (compounds of formula I) are prepared in one stage from 2- (cyclohexenyl-2) -phenols substituted with groups R1, R2, R3 , R4 appropriate according to the following reaction scheme

To carry out this reaction, the organic peracid is introduced in small portions into a three-necked flask equipped with a stirrer and containing a 2- (cyclohexenyl-2) phenol previously dissolved in an organic solvent, such as ethyl acetate, ethyl acetate and the like. methylene chloride or ethyl ether; the reaction medium is maintained at 0 ° C. during the addition of peracid. When the addition is complete, the stirring is continued at ambient temperature for about 4 hours, then the reaction medium is brought to pH 7, the phase is separated and dried. The organic solvent is evaporated off and the product is purified by distillation under reduced pressure.

According to a variant of the process, it may be necessary, depending on the nature of the substituents R.sub.1, R.sub.2, R.sub.3, R.sub.4.sub.w, to protect the -OH function before acting on the organic peracid. The reaction then proceeds in three steps, according to the following schema

 The first step is to treat a 2 (2-cyclohexenyl) phenol, for example by acetyl chloride, in an anhydrous solvent (pyridine, mixture of triethylamine and chloroform or methylene chloride), or by any other suitable mode of protection of the -OH function.

 In the second step, the epoxidation of the previously obtained compound is carried out by means of an organic peracid; For example, metachloro peroxybenzoic acid is used, for example, by taking methylene chloride as a solvent.

 In a last step, cyclization of the compound obtained in the preceding step is carried out by causing sodium alcoholate to act on the product previously dissolved in an alcohol; for example, sodium methoxide is used for this purpose, using absolute ethanol as the solvent.

 The 2- (cyclohexenyl) phenols used as raw material in the process according to the invention can be prepared by known means from substituted phenols, for example by acting on them in a first stage 1,2-dibromocyclohexane - - GoGEK & Coll. / case.

J. Chem. 29, 938 (1951) 7 - then by subjecting in a second stage the (cyclohexenyl-2) -phenyl ether obtained in a Claisen-GRIPENBERG & Coll. jacta Chem.

Scand. 20 (6) 1561 (1966)
In order to obtain the corresponding 1, 2, 3, 4, 4a, 9b-hexahydro-4-amino-dibenzofurans (compounds of formula II), the following reaction steps are used according to known means.

 In a first step, the oxidation of the alcohol of formula I is carried out by means of a weakly acidic pH oxidizing agent; this oxidation is effected for example by means of pyridinium chlorochromate in the presence of sodium acetate, or by means of N, N'-dicyclohexylcarbodiimide (DCC) in the presence of anhydrous orthophosphoric acid and DMSO (dimethylsulfoxide).

en présence d'un reducteur; ia reaction peut s'etrectuer, par exemple, en présence d'un borohydrure de sodium, ou d'un cyanoborohydrure de sodium.In a second step, the ketone previously obtained is treated with an amine

in the presence of a reducer; the reaction may be carried out, for example, in the presence of sodium borohydride, or sodium cyanoborohydride.

According to a variant of the process, it is possible to obtain the compounds of the invention of formula II for which R5 = R6 = H by treating the ketone obtained in the first step with hydroxylamine hydrochloride and then reducing the oxime. obtained by lithium aluminum hydride, which corresponds to the following reaction scheme

The compounds thus obtained also make it possible to prepare, by conventional means, the other compounds of the invention for which R5 or R6 = H; for example, a compound having a = NH 2 group as above may be treated with a suitable organic acid chloride and then reduced, by lithium aluminum hydride, the carbonyl function thus introduced.

 According to a second variant, the compounds of the invention of formula II can also be obtained by treating the ketone synthesized in the first stage with a mixture consisting of formic acid and formamide or an N-alkylformamide.

 The method of preparation of compounds I and II is described in more detail with reference to the following examples which more concretely illustrate the invention without limiting it.

EXAMPLE 1 8-fluoro 1, 2,3,4a, 9b-hexahydro-4-hydroxy dibenzofuran
In a flask containing 6 liters of methylene chloride, 368 g (1.92M) of 4-fluoro-2- (2-cyclohexenyl) phenol were introduced, then 513 g (2.97 M) was slowly added with stirring. metachloroperoxybenzoic acid. Then stirring was continued at room temperature for about 1 hour. The meta-chlorobenzoic acid formed was removed by filtration.

 The filtrate was washed with carbonated water and then with water. After separation, the organic phase was dried over sodium sulfate and the solvent was removed under vacuum.

 The oily residue was then distilled under reduced pressure to give 218 g of the title product, boiling point E1 = 1350 ° C.

EXAMPLE 2 1,234a. 9b-hexahydro 4-hydroxy dibenzofuran
In a 2-liter flask 87.12 g (0.5 M) of 2- (2-cyclohexenyl) phenol was dissolved in 250 g of anhydrous pyridine, then 47.1 g (0.6 g) was added dropwise. M) acetyl chloride while maintaining the temperature at 60 ° C. When the reaction was complete, 750 ml of ice water, acidified with HCl, was added and the methylene chloride ester was extracted.

 After washing with a slurry, drying over sodium sulfate, filtration and evaporation of the solvent, the product was distilled under reduced pressure.

 99.4 g of 1- (cyclohexenyl-2) -2- (acetyloxy) benzene having a boiling point of E015 = 1250 ° C. were obtained.

 In a second step, 90.8 g (0.42M) of the ester obtained above were dissolved in 1 liter of chloroform at ambient temperature, and then 86.8 g (0.50 M) of metachloroperoxybenzoic acid were gradually added; the reaction was allowed to continue stirring for 8 to 10 hours.

 After removal of metachlorobenzoic acid by filtration, washing and drying over sodium sulfate, the solvent was evaporated and 97.5 g of 2- (2-acetyloxyphenyl) -7-oxabicyclo [4.10 g] were obtained. heptane.

 In a last step, 97.5 g (0.42 M) of the preceding epoxide, dissolved in 100 ml of absolute ethanol, was slowly added to a solution of 34 g (0.63M) of sodium methoxide. in 50 ml absolute ethanol; the addition was carried out under a current of nitrogen, maintaining the temperature at 60 ° C., and the reaction was allowed to continue for 4 hours.

When the reaction was complete, the solvent was removed by evaporation and the formed product taken up in water. The reaction medium was then treated with
HC1, then brought back to slightly basic pH.

 The product of the titrera was then extracted with chloroform and dried over sodium sulfate. After evaporation of the solvent, the product was distilled under reduced pressure.

 80 g of 1,2,3,4,4a, 9b-hexahydro-4-hydroxy-dibenzofuran having a boiling point E1 = 1330 ° C. were obtained.

Applying the same process to raw materials obtained from substituted phenols, the following compounds were also prepared: 8-chloro-1,2,3,4,4a, 9b-hexahydro-4-hydroxy-dibenzofuran (E0.5 = 1650C 6-chloro-1,2,3,4,4a, 9b-hexahydro-4-hydroxy-dibenzofuran 8-methyl-1,2,3,4,4a, 9b-hexahydro-4-hydroxy-dibenzofuran 8-methoxy-1,2, 3,4,4a, 9b-hexahydro-4-hydroxy dibenzofuran (eg, 1,180C) 8-isopropyl 1,2,3,4,4a, 9b-hexahydro-4-hydroxy-dibenzofuran 7-trifluoromethyl 1,2,3, 4,4a, 9b-hexahydro 47,9-dichloro-1,2,3,4,4a-9b-hexahydro-4-hydroxy-dibenzofuran 6,8-dichloro-1,2,3,4,4a, 9b-hexahydro-4-hydroxy-dibenzofuran
(F = 690C) 6-methoxy-1,2,3,4,4a, 9b hexahydro-hydroxy-dibenzofuran 8-fluoro-1,2,3,4,4a, 9b-hexahydro-4-hydroxy-dibenzofuran
(F = 65C)
EXAMPLE 3 1,2,3,4,4a, 9b-hexahydro-4-methylamino dibenzofuran
In a 2-liter reactor containing 1.3 liters of methylene chloride, 1,2,3,4,4a, 9b-hexahydro-4-hydroxydibenzofuran, prepared according to US Pat. Example 2, 13.12 g (0.16 M) of sodium acetate and 170 g (0.79 M) of pyridinium chlorochromate. After allowing the reaction to proceed for 6 hours, the reaction medium was concentrated and the ketone formed was extracted with ether, the solvent removed and distilled off under reduced pressure.

45 g of 1,2,3,4,4a, 9b-hexahydro-4-oxo-dibenzofuran having boiling point were thus obtained.
E0.5 = 1500C.

 In a second step, 4 g (0.021 M) of the ketone previously obtained was dissolved in 40 ml of methanol; 4 ml of methylamine in 33% solution in absolute ethanol were then added. The mixture was left in contact for 5 minutes, then 1.6 grams of sodium borohydride was added in small portions and stirring was maintained for 1 hour 30 minutes. When the reaction was complete, the solvents were removed. taken up in water, extracted with chloroform and dried over sodium sulphate.

 After filtration and evaporation of the ether, the product was taken up in anhydrous ethyl acetate and crystallized as hydrochloride by bubbling a stream of dry hydrochloric gas. The precipitate obtained was filtered, washed with ethyl acetate and dried.

 3 g of title product having melting point F = 235 + 20C was obtained.

EXAMPLE 4 8-Methoxy-1,2,3,4,4a, 9b-hexahydro-4-pyrrolidino dibenzofuran
In a reactor containing 350 ml of DMSO, 32 g (0.145 M) of 8-methoxy-1,2,3,4,4a, 9b-hexahydro-4-hydroxybenzofuran were prepared according to the method explained in Examples 1 or 2, then 7.2 g (0.0725 M) of anhydrous orthophosphoric acid was added. N, N'-dicyclohexylcarbodiimide (90 g, 0.143 M) was then added and the mixture was stirred at room temperature for about 3 hours. The precipitate was removed by filtration and the ketone formed was extracted with acetone, re-taken with sodium chloride, and then recrystallized from isopropyl ether.

 21 g of 8-methoxy-1,2,3,4,4a, 9b-hexahydro-4-oxo-dibenzofuran were obtained having a melting point of F = 103.50 ° C.

 In a flask provided with a stirring system, 6.9 g (0.0316 M) of the previously obtained ketone and 6.7 g (0.094 M) of pyrrolidine were introduced; the mixture was left in contact for a few minutes at 400 ° C. until the ketone was dissolved, and then 70 ml of methanol were added. The reaction medium was stained red. 1.2 g (0.032 M) of sodium borohydride were then added in small portions; when the reaction was complete, the methanol was removed, taken up in water and extracted with chloroform.

 The organic phase was washed with water, dried over sodium sulfate, then, after removal of chloroform, the residue was taken up in acetone.

 The title product was extracted as the hydrochloride salt by passing a stream of dry hydrogen chloride gas through the solution.

 There was thus obtained 7 μg of product having mp = 2190 ° C.

EXAMPLE 5 8-Fluoro-1,2,3,4,4a, 9b-hexahydro-4-N-morpholino dibenzofuran
Starting from the starting material whose synthesis is described in Example 1, 8-fluoro-1,2,3,4,4a, 9b-hexahydro-4-oxo-dibenzofuran was first prepared by applying the method indicated in US Pat. the first step of Example 4. There was thus obtained a crystallized product having mp = 830C.

 In the last step, 8.7 g (0.1 M) of orphan base and 12.3 g (0.1 M) of morpholine hydrochloride in 250 ml of methanol were first dissolved at room temperature. 20.6 g (0.1 M) of the previously prepared ketone were then added. After allowing the mixture to contact for about 1/4 hour, 6.3 g (0.1 M) of sodium cyanoborohydride was added. The reaction was allowed to proceed with stirring for 3 hours, then the solvent was evaporated, taken up in 150 ml of 20% sodium hydroxide, extracted with ether, dried over anhydrous sodium sulphate and filtered. After removing the last traces of moisture by passing a stream of xylene, the ether was evaporated, and the residue redissolved in acetone. The title product was then extracted as the hydrochloride salt by passing a stream of gaseous HCl.

 After filtration, rinsing and drying, 20.5 g of product having melting point F = 2010C were obtained.

EXAMPLE 6 1.2 3.4, 4a 9b-hexahydro 4-amino dibenzofuran
In a 21 ml soybean flask, 21.8 g (0.1158 M) of 1,2,3,4,4a, 9b-hexahydro-4-dibenzofuran (prepared as indicated in the first step of the example) were dissolved. 3) in the ethanol minimum at 950, then 12.6 g (0.181M) of hydroxylamine hydrochloride dissolved in 30 ml of water were added with stirring. 23.2 g (0, 6 M) of powdered sodium hydroxide, and the mixture was refluxed for 15 minutes. After concentrating the reaction medium by half, 1.5 l of water containing 50 ml of concentrated hydrochloric acid were poured into it. The precipitate of 1,2,3,4,4a, 9b-hexahydro-4-hydroxypropane Amino dibenzofuran formed was filtered, washed with water, dried in a vacuum oven at 500C, and then used in the next stage.

 In a 1-liter flask equipped with a stirrer, traversed by a stream of nitrogen, and protected by a guard with calcium chloride, 19 g of the compound prepared in the preceding stage, dissolved in approximately 700 ml of ethyl ether, were introduced. anhydrous. 7.7 g (0.203 M) of lithium hydride was then added and brought to light reflux until the oxime had disappeared.

 After removal of excess hydride by hydrolysis, the title product was extracted with ether, then dried and the ether removed in vacuo. The residue was taken up in ethyl acetate and the product was isolated as hydrochloride by bubbling dry hydrogen chloride gas.

 8 g of product having melting point F = 249 OC was obtained.

EXAMPLE 7 1,2,3,4,4a, 9b-hexahydro-4-dimethylamino dibenzofuran
In a first step, 8fluoro 1,2,3,4,4a, 9b-hexahydro-4-oxo dibenzofuran was prepared according to the same method as that described for the first step of Example 3.

 In a second step, 10 g (0.048 M) of the previously obtained ketone was dissolved in 30 ml of dimethylformamide, then 5 ml of formic acid was added and the mixture was refluxed for 4 hours. After the dimethylformamide was evaporated, the residue was taken up with sodium hydroxide solution and extracted with ether. The ether phase was washed with water, dried over sodium sulfate and then concentrated to dryness. The residual oil was taken up with acetone, and the title product was precipitated as hydrochloride by bubbling dry hydrogen chloride gas. After filtration, rinsing with acetone and drying at 800C under vacuum, there was obtained 5g of title product having mp = 2160C.

 Using other amines in the second step, the compounds whose characteristics are summarized in Table I below were also prepared.

TABLE I

<tb><SEP> obfuscated <SEP> R1 <SEP> R2 <SEP> R4 <SEP> - <SEP> N <SEP> R5 <SEP>. <SEP> F0C
<tb><SEP> Compound <SEP> R1 <SEP> R2 <SEP> R3 <SEP>: <SEP> R4 <SEP>: <SEP> FC <SEP> R <SEP>: (chiorhy-:
<tb> N <SEP> - <SEP>: <SEP>: <SEP>: <SEP>: <SEP> R6t <SEP> drate):
<tb><SEP> drate)
<tb>: <SEP> 1 <SEP>: <SEP> H <SEP>: <SEP> Cl <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> -NH- CH3 <SEP> 2230C
<tb><SEP>.<SEP>.<SEP>.<SEP>.<SEP>.<SEP> / CH3 <SEP> 2700C
<tb><SEP> ~ <SEP> CH
<tb>: <SEP> 2 <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> -NH- CH <SEP> \ <SEP>. <SEP> 2700C
<tb><SEP> 3
<Tb>
TABLE I (continued)

<tb><SEP> R
<tb>: <SEP> R3 <SEP> R4 <SEP>. <SEP>. <SEP>. <SEP> FOC
<tb><SEP> asked:
<tb>: Compound: <SEP> R1 <SEP>: <SEP> R2 <SEP>: <SEP> R <SEP>: <SEP> Rq <SEP>: <SEP> (chlorhy-:
<tb><SEP>:<SEP> N <SEP>: <SEP> 1
<tb>: <SEP>: <SEP>: <SEP>: <SEP>: <SEP>: <SEP>: <SEP> drate) <SEP>:
<tb> 3 <SEP> 3 <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> -NH- (CH2) 3-CH3 <SEP>: <SEP> 2090C
<tb><SEP>.<SEP>.<SEP>.<SEP>.<SEP>.<SEP>.
<Tb>

4 <SEP> ≈ <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> -NH-CH, - CHZ1 <SEP>: <SEP> 2490C
<tb><SEP> o
<tb><SEP>.<SEP>.
<Tb>

<SEP>. <SEP>. <SEP>. <SEP>. <SEP>. <SEP>.
<Tb>

: <SEP> 5 <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> -NH-CH2 <SEP ><<SEP>:<SEP> 910C
<tb><SEP> L
<tb><SEP>.<SEP>.<SEP>.<SEP>.<SEP>.<SEP>.
<Tb>

: <SEP> 6 <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> - <SEP> NH- CH3 <SEP>: <SEP> 2350C
<tb>: (exem- <SEP>: <SEP>. <SEP>. <SEP>. <SEP>.
<Tb>

: <SEP> ple <SEP> 3): <SEP>: <SEP>: <SEP>: <SEP>:
<tb>: <SEP> 7 <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> -CH2- CH2-OCH3 <SEP>: <SEP> 1400C
<tb>: <SEP> 8 <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> -NH <SEP><<SEP>:<SEP> 206 "C
<tb><SEP>:<SEP>:<SEP>:<SEP>:<SEP>:<SEP>:<SEP>:
<tb>: <SEP> 9 <SEP>: <SEP> H <SEP>: <SEP> C1 <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> -NH- CH2-CH3 <SEP>: <SEP> 252 "C
<tb>: <SEP> 10 <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> -NH- CH2-CH3 <SEP> t <SEP> 2740C
<tb>: <SEP> 11 <SEP>: <SEP> H <SEP>: oye3 <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> - <SEP> NH- CH3 <SEP>: <SEP> 252 "C
<tb><SEP> J <SEP>
<tb><SEP>.<SEP>.<SEP> $ <SEP> s
<tb>: <SEP> 12 <SEP>: <SEP> H <SEP>: <SEP> C1 <SEP>: <SEP> H <SEP>: <SEP> Cl <SEP>: <SEP> KH-CH3 <SEP>: <SEP> 3000C
<tb>: <SEP> 13 <SEP>: <SEP> C1 <SEP>: <SEP> H <SEP>: <SEP> C1 <SEP>: <SEP> H <SEP>: <SEP> - <SEP > NH-CH3 <SEP>: <SEP> 246 ° C
<tb><SEP>:
<tb>: <SEP> 14 <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> C1 <SEP>: <SEP> -NH- CH3 <SEP>: <SEP> 265 "C
<tb>: <SEP> 15 <SEP>: <SEP> H <SEP>: <SEP> F <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> -NH- CH3 <SEP>: <SEP> 172 "C
<tb>: <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> CF3: <SEP> H <SEP>: <SEP> -NH-CH3 <SEP>: <SEP > 2520C
<Tb>
TABLE I (continued)

<tb> R
<tb>: Compound: <SEP> R1 <SEP>: <SEP> R2 <SEP>: <SEP> R3 <SEP>: <SEP> R4 <SEP>: <SEP> N / Rg: I <SEP>: <SEP> F0C
<tb><SEP> L <SEP>: <SEP>. <SEP>. <SEP> R6s <SEP> (chlorhy-:
<tb><SEP> drate)
<tb> 17 <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: CF3: <SEP> H <SEP>. <SEP> - <SEP> NH- <SEP> CH2CH3 <SEP> 219 "C
<tb>: <SEP> 18 <SEP>: <SEP> H <SEP>: CH30: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> - <SE> 219 "C
<tb>: (exem- <SEP>: <SEP>: <SEP>: <SEP>: <SEP>:
<tb>: <SEP> ple <SEP> 4): <SEP>: <SEP>:
<tb>: <SEP>: <SEP>: <SEP>: <SEP>: <SEP> ~, <SEP> CH3 <SEP>: <SEP>:
<tb>: <SEP> 19 <SEP>: <SEP> H <SEP>: <SEP> F <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> -NH- CH / I <SEP>: <SEP> 236 "C
<tb><SEP> CHQ <SEP>
<tb>: <SEP> 20 <SEP> H <SEP> H <SEP> CH30 <SEP> H <SEP>: <SEP> H <SEP>: <SEP> -NH-CH3 <SEP> 2170C
<tb>: <SEP> 21 <SEP>: <SEP> H <SEP>: <SEP> F <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> - <SEP ><SEP> 218 "C
<tb>: <SEP> / CH3
<tb><SEP> T
<tb>: <SEP> 22 <SEP>: <SEP> H <SEP>: <SEP> F <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> -N- <SEP>: <SEP> 216 "C
<tb>: (exem- <SEP>: <SEP>: <SEP>: <SEP>: <SEP>: <SEP> Nai3
<tb>: ple <SEP> 7) <SEP>: <SEP> 3
<tb>: <SEP> 23 <SEP>: <SEP> H <SEP>: <SEP> F <SEP>: <SEP> H <SEP>: <SEP> H <SEP>:
<tb>: (exem- <SEP>: <SEP>: <SEP>: <SEP>: <SEP>: <SEP> -N <SEP> O <SEP>: <SEP> 201 "C
<tb>: ple <SEP> 5) <SEP>: <SEP>: <SEP>:
<tb>: <SEP> 24 <SEP>: <SEP> H <SEP>: <SEP> F <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> NH2 <SEP >. <SEP> 279 "C
<tb>: <SEP> 25 <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: OCH3: <SEP> -NH-CH3 <SEP>: <SEP> 249 "C
<tb>: <SEP> 26 <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> H <SEP>: <SEP> -NH2 <SEP> 2490C
<tb>: (exem- <SEP>: <SEP>: <SEP>: <SEP>.
<Tb>

: <SEP> ple6) <SEP>: <SEP>: <SEP>: <SEP>
<Tb>
The compounds of the general formula II have proved useful as analgesics, because of their activity with respect to the thermal stimulus and the chemical stimulus, as determined in the mouse according to the following tests.
Thermal stimulus
According to EDDY NB, LEIMBACH D. - J. Pharmacol. Exp.

Ther., 107, 385-393, (1953)] The ED 50 is the dose of oral product, expressed in mg / kg, which increases by 50% the reaction time of the treated animals compared to that of the group of control animals.

Chemical stimulus
[SIEGMUND E., CADMUS R., GO LU - Proc. Soc. exp.

Biol. Med. 95, 729-731, (195i). The ED 50 is the dose of oral product, expressed in mg / kg, which inhibits by 50% the number of abdominal cramps compared to that of the group of control animals.

The LD 50 toxicity of these compounds was evaluated in mice orally, according to the method of BEHRENS and
KARBER [Arch. Exp. Path. Pharm. 177, 379 (1935) 7.

These results are summarized in Table II below
TABLE II

<tb>: Compound: Stimulus <SEP> thermi: Stimulus <SEP> Chemical <SEP>: <SEP> DL <SEP> 50
<tb><SEP> N <SEP>: that <SEP> DE <SEP> 50 <SEP> (mg / kg: DE <SEP> 50 <SEP> (mg / kg <SEP> PO): <SEP> ( mg / Rg <SEP> PO <SEP>)
<tb><SEP> PO) <SEP>
<tb>: <SEP> 1 <SEP>: <SEP> 22.7 <SEP>: <SEP> 24 <SEP>: <SEP> 180
<tb>: <SEP> 2 <SEP>: <SEP>><SEP> 50 <SEP>><SEP>><SEP> 50 <SEP>: <SEP> 250
<tb>. <September>
<Tb>

: <SEP> 3 <SEP>: <SEP>><SEP> 50 <SEP>:><SEP> 50 <SEP>: <SEP> 120
<tb>: <SEP>4> 100 <SEP>: <SEP> 46.8 <SEP>:
<tb>: <SEP> 5 <SEP>: <SEP>><SEP> 50 <SEP>:> 50 <SEP>: <SEP> 300
<tb>: <SEP> 6 <SEP>: <SEP> 50 <SEP>: <SEP>> 50 <SEP>: <SEP> 340
<tb>: <SEP> 7 <SEP>:><SEP> 50 <SEP>> 50 <SEP>: <SEP> 480
<tb>: <SEP> 8 <SEP>> 50 <SEP>: <SEP> 50 <SEP>. <SEP> 340
<Tb>
TABLE II (continued)

<tb>: Compound: Stimulus <SEP> thermi: Stimulus <SEP> Chemical <SEP>: <SEP> DL <SEP> 50
<tb>: <SEP> NO <SEP>: <SEP> DE <SEP> 50 <SEP> (mg / kg: DE <SEP> 50 <SEP> (mg / kg <SEP> PO): <SEP> (mg / kg <SEP> PO) <SEP>
<tb><SEP> PO) <SEP>
<tb>: <SEP> 9 <SEP>: <SEP> 21.3 <SEP>> 50 <SEP>: <SEP> 340
<tb>:><SEP> 50 <SEP>: <SEP>><SEP> 50 <SEP>: <SEP> 240
<tb>: <SEP> 11 <SEP> 11 <SEP>: <SEP>><SEP> 50 <SEP> 50 <SEP>: <SEP>><SEP> 50 <SEP>: <SEP> 400
<tb> 12 <SEP>: <SEP>> 50 <SEP>: <SEP> 32.5 <SEP>: <SEP> 500
<tb>: <SEP> 13 <SEP>> 50 <SEP> 50 <SEP>: <SEP>><SEP> 50 <SEP>: <SEP> 960
<tb>: <SEP> 14 <SEP>: <SEP> 39.7 <SEP>: <SEP>><SEP><SEP> 50 <SEP>: <SEP> 480
<tb> 15 <SEP>: <SEP> 43 <SEP>: <SEP> 7 <SEP> 50 <SEP>: <SEP> 340
<tb>: <SEP> 16 <SEP>> 50 <SEP>: <SEP> 15.2 <SEP>: <SEP> 340
<tb>: <SEP> 17 <SEP>: <SEP> 21 <SEP>:> 50 <SEP>: <SEP> 300
<tb>: <SEP> 26 <SEP> 26 <SEP>: <SEP> 44.4 <SEP>: <SEP>) <SEP> 50 <SEP>: <SEP> 340
<Tb>
The compounds which present the most interesting activities are the compounds 1, 9, 17, 16, 14, 15. They can be recommended for their application in human therapy, associated with the usual pharmaceutical excipients, for the treatment of pain syndromes, to daily doses of between 100 and 500 mg.

Claims (4)

 1. Derivatives of dibenzofuran, characterized in that they correspond to the formula

 wherein R1, R2, R3 and R4 are the same or different and represent a hydrogen atom, a halogen atom, an alkyl or lower alkoxy radical, or the trifluoromethyl radical.  2. Process for obtaining compounds according to claim 1, characterized in that the cyclization of a 2- (cyclohexenyl-2-phenol) substituted by groups R1, R2, R3 and R4 appropriate, in a single step. by means of an organic peracid.  Process according to Claim 2, characterized in that the hydroxy function of the substituted 2- (cyclohexenyl-2-phenol) phenol is first inactivated by means of acetyl chloride, then treated with the organic peracid and, finally, causes a sodium alkoxide to act to achieve the cyclization.  4. Method according to one of claims 2 or 3, characterized in that the peracid used is metachloroperoxybenzoic acid.