CH617654A5 - Process for the preparation of new benzophenone derivatives - Google Patents

Abstract

A benzophenone derivative, comprising at least one and at most three ethyl substituents on a hydroxyphenyl ring or an alkyl- or phenylcarbonyloxyphenyl ring of benzophenone, is prepared by reacting, under Friedel-Crafts acylation conditions, an acid of formula A-COOH or a functional derivative of the latter with a compound HAr or else an acid of formula Ar-COOH or a functional derivative of the latter with a compound HA in which A represents a hydroxyphenyl ring or an alkyl- or phenylcarbonyloxyphenyl ring substituted by one to three ethyl groups. The compounds thus obtained can be used as an active substance of antiallergic medicaments.

Description

The present invention relates to processes for the preparation of novel benzophenone derivatives suitable for the preparation of pharmaceutical compositions useful for the treatment of allergic conditions.

There is an abundant literature on the subject of benzophenones, their preparation and their use. However, it had not yet been realized that o-hydroxybenzophenones and their derivatives can be used for the treatment of allergic conditions.

The invention relates first of all to a process for the preparation of a compound of formula:

1

H

in which the different symbols R1, R2, R3, R5 and Ar have the meanings indicated above starting from the compound (la) in which Z represents H by acylating the compound (la) with a corresponding R5 derivative in order to form the compound (the).

As an illustration of a Friedel and Crafts acylation reaction as described above, mention may be made of the reaction of a compound of formula ArCOX and of a compound of formula:

R

Ar

(the)

R OZ

in which R1, R2 and R3 represent hydrogen or ethyl, at least one of the substituents R1, R2 and R3 being ethyl, Ar is a phenyl group optionally substituted by one to three groups chosen from chlorine, fluorine, methyl, carboxy , COOR5 and trifluoromethyl provided that the phenyl group is not substituted only by one to three methyl groups; Z is hydrogen or COR5, R5 representing Cm alkyl or phenyl, provided that when R1 is ethyl, R2 and R3 are hydrogen and the meaning 2,4- or 3,4-dichlorophenyl, 2- or 3- chlorophenyl or 4-fluorophenyl is excluded for Ar, characterized in that an acid of formula A-COOH or a functional derivative thereof is reacted under Friedel and Crafts acylation conditions with a HAr compound or else a acid of formula Ar-COOH or a functional derivative thereof with a compound HA in which A represents:

1

R

Z 'being hydrogen or a protective group such as methyl.

The reaction can be represented by the following reaction scheme:

P1

ArCOX

Ar

R

The invention further relates to a process for the preparation of a compound of formula:

R

(Ib)

R "OZ

in which the various symbols R1, R2, R3, Z and Ar have the meaning indicated above starting from the compound (la) by putting this compound in reaction with hydroxylamine in the presence of a base to form the oxime corresponding to formula (Ib).

According to the invention, it is also possible to prepare a compound of formula:

R 'OZ'

wherein X is a halogen or hydroxyl atom. When X is halogen, the reaction can be carried out using a Lewis acid such as an aluminum halide (for example chloride) as catalyst in a suitable inert solvent such as 1,1,2, 2-tetrachloroethane or carbon disulfide.

45 When X is hydroxyl, boron trifluoride or

(CF3CO) are preferred catalysts which are used in the presence. or in the absence of a suitable solvent.

When Z 'is a protective group, it can be removed in situ or later, when it is desired to form a compound of' so formula (I) in which Z 'is hydrogen.

The reduction in the formation of one or more unwanted isomers can be obtained by a suitable choice of reaction conditions, the temperature control being particularly important. Ideally, the reaction temperature 55 varies from 20 ° C to the reflux temperature and preferably from 80 ° C to the reflux temperature.

Similarly, benzophenones can be prepared by the following reaction scheme:

1

Ar

(the)

COX + HAr

OCOR "

OZ '

617,654

4

OZ *

similar reaction conditions being applicable.

In the case of the reaction of a compound of formula ArCOX, an initial reaction product (A) indicated below can be obtained and isolated. This can be subjected to a Fries rearrangement using similar catalytic conditions:

25

COAr

(I)

as described above using for example aluminum chloride.

Another example of an acylation reaction using an A-COOH derivative is the use of the compound Ar-CN as an acylating agent. This modified process is known as the Houben-Hoesch reaction, which takes place as indicated below:

R1

ArCN +

Lewis acid p. ex. ZnCl

COAr

OH

When a protected hydroxyl group Z ′ is used in the above reactions, it can be transformed into the desired hydroxyl group by cleavage using for example HBr, BF3, AlCb or HI.

As indicated above, the preparation of ketone derivatives such as oxime can be carried out by reacting a solution of the ketone, for example an aqueous or alcoholic solution with a derivative, preferably the hydrochloride of a hydroxylamine in the presence of a base, for example sodium or potassium hydroxide.

As indicated previously, the preparation of the acyl derivatives of the o-hydroxyl groups can be carried out by various methods, for example by treating o-hydroxybenzophenone in a basic solution (for example a solution of pyridine or an aqueous solution of a hydroxide of group IA such as sodium or potassium hydroxide) with an anhydride or an acid halide (preferably chloride) or with a solution of an acylating acid in the presence of acid anhydride with a trace of catalyst (for example 70% perchloric acid) or by reflux of o-hydroxybenzophenone with an acylating agent.

The o-hydroxybenzophenones and derivatives thereof according to the present invention have shown activity in one or more of the four tests commonly used to detect anti-allergic activity. Two of these tests are in vitro tests, tests on minced guinea pig or human lungs and involve direct measurement of mediators, histamine and slow-reacting substance in anaphylaxis (SRS-A) which have been reported to be were released from the asthmatic human lung. For compounds of the type according to the present invention, a compound is considered active when an inhibition of at least 30% of the release of SRA-A in the test of the minced guinea pig lung is obtained at a dose of 10 ng / ml or less. Depending on the absorption, distribution and metabolism of the drug under study, the activity in the test of the chopped lung at this level indicates in vivo dosages varying from 0.5 to about 100 mg / kg orally.

The other two tests are in vivo tests known as the Herxheimer test and rat peritoneal anaphylaxis and reflect oral activity in two species. In the Herxheimer test, sensitized guinea pigs are protected against the bronchial spasm produced by an aerosol or an antigen, while in the rat peritoneal anaphylaxis test, the SRS-A, the release of which is caused, is measured directly. When the active compound is tested in in vivo tests, activity at a dose of 300 mg / kg or less is normally obtained.

The compounds of the invention exhibit activity in one or more of the foregoing tests (the broadest spectrum compounds being those which exhibit antiallergic activity in all four tests) and are therefore useful in the prophylactic and therapeutic treatment of diseases immediate hypersensitivity including asthma and to avoid asthmatic state (status asthmaticus). In some cases, the compounds have been found useful in diseases causing excessive release of prostaglandins and as a respiratory stimulant. The products have low toxicity.

The compounds or compositions of the present invention can be administered by several routes and for this purpose can be presented in different forms. Thus, the compounds or compositions can be administered orally or rectally, topically, parenterally, for example by injection or by continuous or discontinuous intra-arterial infusion, in the form for example of tablets, diamonds, sublingual tablets, sachets , cachets, elixirs, suspensions, aerosols, on-55 guents which contain for example from 1 to 10% by weight of the active compound in a suitable base, soft or hard gelatin capsules, suppositories , injection solutions or suspensions in physiologically acceptable media and in the form of powder packed under sterile conditions 60 adsorbed on a support to make injection solutions. Advantageously, for this purpose, the compounds can be supplied in the form of a unit dosage, each dosage unit containing from 5 to 500 mg (from 5.0 to 50 mg in the case of parenteral administration, from 5.0 to 50 mg in the case of inhalation and 25 to 500 mg 65 in the case of oral or rectal administration) of a compound of formula (I).

As indicated in the tests to which reference is made above, dosages of the order of about 0.5 to 300 mg / kg

5

617,654

daily, preferably 0.5 to 20 mg / kg of the active compound can be administered. It will however be understood that the quantity of compound or compounds of formula (I) actually administered will be determined by the doctor taking into account the circumstances in question, including the condition to be treated, the choice of the compound which is administered and the choice of the route of administration and therefore the preferred dosage range does not in any way limit the scope of the present invention.

In the description, the expression unit dosage form is used to refer to a discrete physical unit containing an individual amount of the active component, generally in admixture with a pharmaceutical diluent or in another way in association with a pharmaceutical carrier, the the amount of the active component being such that one or more units are normally necessary for a single therapeutic administration or, in the case of units which can be fragmented, for example grooved tablets, at least a fraction such as half or a quarter of a fragmentable unit being necessary for a single therapeutic administration.

The compositions of the present invention will normally consist of at least one compound of formula (I) in combination with a pharmaceutically acceptable carrier for it, that is to say in mixture with a carrier or diluted with a carrier or alternatively wrapped or encapsulated in a support that can be ingested in the form of a capsule, sachet, seal, paper or other packaging or in a disposable packaging such as an ampoule. A carrier or diluent can be a solid, semi-solid or liquid material serving as a vehicle, excipient or medium for the therapeutically active substance.

Examples of diluents or carriers which can be used in the pharmaceutical compositions of the present invention consist of lactose, dextrose, sucrose, sorbital, mannitol, propylene glycol, liquid paraffin, white soft paraffin, kaolin, smoked silicon dioxide, microcrystalline cellulose, calcium silicate, silica, polyvinylpyrrolidone, ketostearic alcohol, starch, modified starches, gum acacia, calcium phosphate, cocoa butter, ethoxylated esters, theobromine oil,

peanut oil, alginates, tragacanth, gelatin, BP syrup, methylcellulose, polyoxyethylene sorbitan monolaurate, ethyl lactate, methyl and propyl hydroxybenzoate, trioleate sorbitan, sorbitan sesquioleate and oleic alcohol as well as propellants such as trichloromonofluoromethane, dichlorodifluoromethane and dichlorotetrafluoroethane. In the case of tablets, a lubricant may be incorporated to prevent the powdered components from sticking or binding to the molds and punches of the tablet making machines. For this purpose, it is possible to use, for example, aluminum, magnesium or calcium stearates, talc or mineral oil.

The examples which follow will serve to illustrate the invention in more detail.

Example 1:

2-hydroxy-5-methyl-4'-chlorobenzophenone oxime (syn and anti).

a) 13.5 g (0.055 mole) of 2-hydroxy-5-methyl-4'-chlorobenzo-phenone are stirred with a solution of 44 g of potassium hydroxide in 150 ml of water and then 17 is added, 4 g (0.25 mole) of hydroxylamine hydrochloride while cooling with ice. After stirring overnight at room temperature, 100 ml of water is added and the mixture is acidified with 5N hydrochloric acid to give 14.7 g of a white precipitate which is filtered, washed and dried.

Recrystallization of the product from benzene gives 7 g of 2-hydroxy-5-methyl-4'-chlorobenzophenone oxime, m.p. 163 ° C. (This is the stereo-isomer in which the group

—OH and the 4'-chlorophenyl group are in the syn position with respect to each other.)

b) The preceding procedure is repeated, this time using 192 g (0.78 mole) of the benzophenone used in a). The benzene solution gives a second and a third crop of crystals. The second crop (31.5 g) is a mixture of the two forms of oxime while the third crop (1.9 g) is the stereoisomer in which the hydroxyl oxime group and the 4'-chlorophenyl group are in anti position relative to each other. (The melting point of the product was 145-147 ° C).

Microanalysis C, H, N, C1 for each isomer was satisfactory.

c) Diacetate of 4'-chloro-2-hydroxy-5-methyl-benzophenone oxime.

26.2 g of the oxime produced in a) above are dissolved in 50 ml of hot acetic anhydride and a solid is separated by cooling. This is filtered and the filtrate is evaporated to dryness, leaving a residue which is crystallized from ethanol to give the diacetate as a second crop (m.p. 136 ° C).

Example 2:

4'-Chloro-5-ethyl-2-hydroxybenzophenone.

267 g of aluminum chloride are added in parts over 30 min to a stirred solution of 122.1 g of 4-ethylphenol and 140 ml of 4-chlorobenzoyl chloride in 800 ml of 1,1,2,2-tetra- chloroethane. The mixture is heated at 105 ° C for 22 h with stirring and cooling, a mixture of 600 g of ice and concentrated hydrochloric acid is added slowly. A violent reaction occurs and some material is lost. The remaining material is separated, the aqueous fraction is extracted twice with 200 ml of chloroform and the combined organic layers are evaporated to give a dark oil which is distilled in vacuo giving two main fractions: B (17.4 g) 150- 160 ° C under 0.3 mm Hg; C (110.8 g) 160-168 ° C under 0.3 mm Hg.

The title compound is crystallized by cooling to -20 ° C and recrystallization from n-hexane at 0 ° C to give a yellow crystalline solid, m.p. 35-38 ° C.

Microanalysis for C15H13CIO2:

Calculated: C69, l H 5.0 Cl 13.6%

Found: C69.0 H 5.0 Cl 13.9%

Example 3:

4'-chloro-5-ethyl-2-hydroxybenzophenone oxime.

65.2 g of 4'-chloro-5-ethyl-2-hydroxybenzophenone and 170 g of potassium hydroxide in 700 ml of water and 150 ml of ethanol are treated with 70.0 g of hydroxylamine hydrochloride, while cooling, and the resulting mixture is stirred for 18 h at room temperature. Dissolution occurs during this time. The solution is acidified with 5N hydrochloric acid and then extracted with 3 x 200 ml of ether. The combined solutions in ether are washed with 2 x 200 ml of a 10% aqueous sodium carbonate solution and evaporated to dryness to give a whitish solid. This solid is recrystallized from 40% benzene / petroleum ether at 60-80 ° C to give a white crystalline solid (29.9 g), second harvest (14.5 g), m.p. 117 ° C.

Microanalysis for C15H14CINO2:

Calculated: C65.3 H 5.1 N5, l Cl 12.9%

Found: C65.3 H 4.9 N5, l Cl 12.9%

[Stereoisomer as in Example 1 a).]

Example 4:

2-Hydroxy-3-methyl-4'-chlorobenzophenone.

78.79 g (71.6 ml = 0.7 mole) of chlorobenzene and 14 g

5

10

15

20

25

30

35

40

45

50

55

60

65

617,654

6

(0.105 mole) of AlCb are mixed, stirred and treated with a solution of 12 g (0.07 mole) of 2-hydroxy-3-methylbenzoic acid chloride in 20 ml of chlorobenzene. The mixture is stirred and heated to 100 ° C overnight. The cooled mixture is added to 10 ml of concentrated HCl and ice, extracted with ether and the ether is washed with a saturated sodium bicarbonate solution, dried (Na2SC> 4), filtered, the filtrate is distilled to give (after removal of the ether) a main fraction of 2-hydroxy-3-methyl-4'-chlorobenzophenone, PE 148-152 ° C / 0.5 mm Hg (8.18 g) which solidifies under form of yellow microchips, mp 55-58 ° C.

Microanalysis for C14H11CIO2:

Calculated: C 68.16 H 4.49 Cl 14.37%

Found: C 68.23 H 4.71 Cl 14.61%

Example 5:

4-Ethyl-4'-fluoro-2-hydroxybenzophenone.

24.4 g of 3-ethylphenol and 34.9 g of 4-fluoro-benzoyl chloride are reacted with each other as in Example 2 to give three main fractions:

B (11.4 g) 126-129 ° C under 0.07 mm Hg;

C (7.9 g) 129-132 ° C under 0.06 nun Hg;

D (5.9 g) 132-150 ° C under 0.06 mm Hg;

which contain about 80% of the desired isomer. B (4.0 g)

are separated by preparative thin film chromatography to give the title compound (2.6 g), m.p. 44-48 ° C. The same compound was obtained using the method of Example 4.

Example 6:

Oxime of 4-ethyl-4'-fluoro-2-hydroxybenzophenone.

21.0 g (80% purity) of 4-ethyl-4'-fluoro-2-hydroxybenzo-phenone are treated with 24.0 g of hydroxylamine hydrochloride in a similar manner to that of Example 3 to give after recrystallization in benzene the title compound in the form of a white crystalline solid (10.7 g), mp 130-132 ° C.

Microanalysis for C15H14FNO2:

Calculated: C69.5 H 5.4 N5.4 F 7.3%

Found: C69.2 H 5.5 N5.2 F 7.2%

Example 7:

2-hydroxy-3-methyl-4'-chlorobenzophenone oxime.

7.5 g (0.03 mole) of the ketone of Example 4 in 18 ml of ethanol are added with stirring to a solution of 20.74 g (0.3 mole) of 85% potassium hydroxide in 85 ml of water at 10 ° C., this colloidal solution being treated with 8.54 g (0.12 mole) of hydroxylamine hydrochloride and stirred overnight. The solution is acidified with 5N HCl to give a solid which is filtered, washed with water and stirred for 45 min and then treated with 30.5 ml of Na2CC solution> 3 to 5%, to remove the stereo- unwanted oxime isomer, filtered, washed with 100 ml of Na2CC solution> 3 to 5% and then with water until no alkali is present. The dried solid has a m.p. 175-177 ° C. Recrystallization from 54% benzene / light petroleum fraction (m.p. 60-80 ° C) gives the oxime, m.p. 178 ° C (bound isomer) 5.45 g.

Microanalysis for C14H12CICO2:

Calculated: C 64.25 H 4.6 Cl 13.55 N5.35%

Found: C 64.25 H 4.79 CI 13.41 N5.3%

Example 8:

2-Hydroxy-3-ethylbenzophenone.

44.67 g of this compound are prepared from 172 g (2.2 mole) of benzene and 63.15 g (0.34 mole) of 2-hydroxy-3-ethylbenzoic acid chloride, using the same conditions as in Example 4. The boiling point of the compound

was 123-126 ° C / 0.14 mm Hg, T | d22 1.6081, v max. (movie)

1630 cm -1. The same compound can be obtained using the method of Example 2.

Example 9:

2 ', 4'-Dichloro-3-ethyl-2-hydroxybenzophenone.

26.7 g of aluminum chloride are added in parts to a stirred mixture of 12.2 g of 2-ethylphenol and 23.1 g of 2,4-dichlorobenzoyl chloride in 100 ml of 1,1,2,2 -tetrachloroethane and then the mixture is heated under reflux for 21 h. After cooling, the solution is poured into 100 ml of concentrated hydrochloric acid cooled by 200 g of ice. The organic fraction is separated and added to 2 additional washes with chloroform of the aqueous fraction, and then washed twice with a 10% aqueous sodium carbonate solution, dried over magnesium sulfate monohydrate and evaporated until obtained 30.0 g of a dark viscous oil. This oil is distilled under vacuum, the first fraction (156-172 ° C at 0.06 mm Hg) containing 85% of the desired product. (With a solution of ferric chloride, a purple coloration is obtained indicating the presence of an o-hydroxyketone.) The ketone product is purified by chromatography on a column of silica rio22 1,6163. The same product is obtained using the method of Example 4.

Example 10:

4-Ethyl-3'-fluoro-2-hydroxybenzophenone.

This compound is prepared from 12.2 g of 3-ethylphenol, 17.5 g of 3-fluorobenzoyl chloride and 26.7 g of aluminum chloride in 75 ml of 1,1,2,2-tetrachloroethane in using the same conditions as in Example 2 but heating at reflux, and not at 105 ° C. The product is purified by chromatography on a silica column. M.p. between 0 and 20 ° C. r) o22 1,5962. The same product is obtained using the method of Example 4.

Example 11:

1.35 g (0.0077 mole) of 4-chlorobenzoyl chloride are added dropwise to a solution of 0.86 g (0.0070 mole) of

4-ethylphenol in 5.6 ml of an aqueous 2.5N sodium hydroxide solution. The mixture is stirred vigorously for

15 min, which causes the separation of a light brown solid. The mixture is diluted with 10 ml of water and the solid is separated by filtration, washed with 3 x 20 ml of water and dried. The solid is recrystallized twice from n-hexane to give pale brown crystals of 4-ethylphenyl 4-chlorobenzoate, m.p. 66.5-67 ° C.

2.6 g of the above ester are heated with 1.33 g of aluminum chloride in tetrachloroethane for 6 h at 125 ° C. A sample taken at the end of this period is added to dilute hydrochloric acid and the organic matter is extracted with chloroform. Analysis by vapor phase chromatography of this solution does not reveal any remaining ester and comparison with an authentic sample indicates that the product is 4'-chloro-5-ethyl-2-hydroxybenzophenone.

Similarly, we prepared:

5-ethyl-2-hydroxy-4'-methylbenzophenone, m.p. 49-51 ° C and 4'-chloro-3,5-diethyl-2-hydroxybenzophenone, m.p. 188 ° C at 1.4 mmHg.

Example 12:

2-Benzoyloxy-5-ethyl-4'-chlorobenzophenone.

5 g (0.019 mole) of 2-hydroxy-5-ethyl-4'-chlorobenzophenone are vigorously stirred in a solution of 7.5 g (0.187 mole) of NaOH in 75 ml of water and benzoyl chloride is added dropwise drop by drop in 5 min. The temperature rises to around 50 ° C. The mixture is stirred for 1 hour at

5

10

15

20

25

30

35

40

45

50

55

60

65

7

617,654

at room temperature and is then extracted with ether, the ether is washed with saturated NaCl solution, dried (Na2S (> 4), filtered and evaporated to give the product which has been recrystallized from n-hexane to give white crystals of the desired product, mp 79-81 ° C. s

Example 13:

2-Acetoxy-4'-Chloro-5-ethylbenzophenone.

3 g of 2-hydroxy-5-ethyl-4'-chlorobenzophenone in 10 ml of acetic anhydride and 1 ml of acetic acid are refluxed for VA h, after which cooling is allowed. The mixture is poured into a dilute NaOH solution and extracted with chloroform. The chloroform is washed with 50 ml of a NaHCC solution> 3 at 10%, dried (MgSC> 4) and evaporated to leave an oil which is distilled; M.p. 160-165 ° C under 3.5 mm Hg 15 to give 2.3 g of the desired product.

Example 14:

5-Ethyl-2-hydroxy-4'-trifluoromethylbenzophenone.

20

0.6 g (0.004 mole) of aluminum chloride are stirred in 2 ml of dichloromethane and treated with 1 g (0.0048 mole) of 4-trifluoromethylbenzoyl chloride (cooling in an ice bath) and then 0.6 g (0.0044 mole) of 4-ethylanisole in 1 ml of dichloromethane are added. The mixture is stirred at room temperature overnight and is then poured into ice and concentrated hydrochloric acid and extracted with chloroform. The chloroform solution is washed with 100 ml of a 10% NaHCO 3 solution, dried (MgSC> 4), filtered and

evaporated to leave 1.2 g of 5-ethyl-2-methoxy-4'-trifluoro-methylbenzophenone in the form of a yellow oil. The latter is heated in 27.5 ml of 55% aqueous hydrogen bromide at 110-120 ° C for 5 h. The mixture is evaporated to dryness to give the desired product.

Example 15:

5-Ethyl-2-hydroxy-3'-carboxy- and 3'-carbomethoxybenzo-

phenone.

39.9 g (0.3 mole) of aluminum chloride are stirred in 133 ml of dichloromethane and treated with 59.5 g (0.3 mole) of 3-carbomethoxybenzoyl chloride (cooling in the ice bath) for the H. 40.8 g (0.3 mole) of 4-ethylanisole in 70 ml of dichloromethane are added to the cooled and stirred mixture and stirring is continued at room temperature overnight. The reaction mixture is treated as in Example 14 to give 5-ethyl-2-methoxy-3'-carbomethoxy-benzophenone. This is heated in 500 ml of a 55% aqueous hydrogen bromide solution at 110-120 ° C for 5 h. The mixture is evaporated to dryness to give 5-ethyl-2-hydroxy-3'-carboxybenzophenone which is characterized by a correct C, H and N microanalysis. This carboxylic acid is then refluxed overnight in 500 ml of methanol containing 5 ml of concentrated sulfuric acid, poured into 11 of water and extracted with ether. The combined ether extracts are then washed with saturated NaHCC> 3 solution, dried (MgSCU), filtered and evaporated to give the desired ester which gives a satisfactory microanalysis.

r

Claims (8)

617,654 2 1. Process for the preparation of a compound of formula: 1 (the) the compound (la) in which Z represents H is prepared from a compound A in which Z also represents H according to the method of claim 1 and the compound (la) is acylated with a corresponding R5 derivative. 4. Method according to claim 1, characterized in that a compound of formula Ar-CN or ArCOX in which X is halogen, is reacted with a compound of formula: Ar in which R1, R2 and R3 represent hydrogen or ethyl, at least one of the substituents R1, R2 and R3 being ethyl, Ar is a phenyl group optionally substituted by one to three groups chosen from chlorine, fluorine, methyl, carboxy, COOR5 and trifluoromethyl provided that the phenyl group is not substituted only by one to three methyl groups; Z is hydrogen or COR5, R5 representing C1-4 alkyl or phenyl, provided that when R1 is ethyl, R2 and R3 are hydrogen and the meaning 2,4- or 3,4-dichlorophenyl, 2- or 3-chloro-phenyl or 4-fluorophenyl is excluded for Ar, characterized in that an acid of formula A-COOH or a functional derivative thereof is reacted under Friedel and Crafts acylation conditions with a compound HAr or else an acid of formula Ar-COOH or a functional derivative thereof with a compound HA in which A represents: R 5. Method according to claim 1, characterized in that a compound of formula: 1 R R COX R R 3 OZ 2. Process for the preparation of a compound of formula: 1 R 30 in which X is halogen, is reacted with a substituted benzene of formula Ar-H. 6. Method according to claim 1, characterized in that the catalyst for the Friedel and Crafts acylation is a Lewis acid. 7. Method according to claim 6, characterized in that the Lewis acid is an aluminum halide. 8. A process for the preparation of a compound of formula (la), in which the substituents have the meaning indicated in claim 1, Z being hydrogen, characterized in that it is reacted under conditions of acylation of Friedel and Crafts, a functional derivative of formula Ar-COX, in which X is a halogen, with a compound of formula HA in which A represents: in which the different symbols R1, R2, R3, Z and Ar have the meaning indicated in claim 1, characterized in that the compound (la) is prepared according to the method of claim 1 and that this compound is put in reaction with hydroxylamine in the presence of a base to form the oxime. 3. Process for the preparation of a compound of formula: OH so as to obtain an intermediate compound of formula: .1 R Ar (the) 60 Û.CO.Ar in which the different symbols R1, R2, R3, R5 and Ar have the meaning indicated in claim 1, characterized in that "S and then subject this intermediate compound to a Fries rearrangement. 3 617,654