CH619951A5 - Process for the preparation of condensed pyrimidines - Google Patents

Abstract

New 4-(3H)-oxopyrimidino[4,5-b]quinoline-2-carboxylic acids and their esters, compounds substituted by at least one acyloxy group, in particular acetoxy, or hydroxy in position 7 or 8, are obtained by reaction of a corresponding 2-amino-3-carboxamidoquinoline with a dialkyl oxalate. The esters obtained can be hydrolysed to give the free acid or one of its pharmaceutically acceptable salts. The new compounds are useful as medicaments against allergies, in particular against allergic bronchial asthma.

Description

The invention relates to the preparation of fused heterocyclic rings in which a quinoline ring system is condensed to a pyrimidine-4 (3H) -one-2-carboxylic acid or to one of its esters, and their use as antiallergic agents. It relates more particularly to the preparation of pyrimido [4,5-b] -quinoline-4 (3H) -one-2-carboxylic acids of their pharmaceutically acceptable esters and salts which are useful as inhibitors of allergic reactions and, in particular , allergic bronchial asthma.

Similar compounds have already been proposed according to a prior right which exposes the state of the art.

It has now been found that, in addition to the type of compound already proposed, the following condensed pyrimidines corresponding to the formulas:

and their pharmaceutically acceptable cationic salts also exert potent anti-allergic effects in mammals, including humans, by an intal-like mechanism. Unlike Tintai, many of these compounds are effective intraperitoneally and orally, as well as by inhalation and intravenously.

In the above formulas:

R ° is chosen from hydroxy and C1 to Gt alkoxy groups;

R3 and R4 are chosen from (a) hydrogen, groups, C1 to C4 alkoxy and benzyloxy, (b) hydroxy and C1 to C1 alkanoyloxy, preferably acetoxy; provided that at least one of the groups R3 and R4 and Rs are chosen from group (b).

"0 The term" pharmaceutically acceptable cationic salts "means salts such as the alkali metal salts, such as sodium and potassium; alkaline earth metal salts such as calcium and magnesium; aluminum salts; ammonium salts; and salts with organic bases

6s ques, for example amines such as triethylamine, tri-n-butylamine, piperidine, triethanolamine, diethylaminoethylamine, N-N-dibenzyl-ethylenediamine and Pyrrolidine.

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The following compounds are of particular interest in the invention:

Formula I: R3 and R4 are hydrogen, hydroxy, or alkoxy; provided that when R3 or R4 is a hydroxy group, the other is an alkoxy group.

The following compounds of formula I are of special interest:

R3

R4

OH

OCH3

OCH3

OH

The compounds of Formula I, in which R ° is alkoxy are also valuable intermediates for the preparation of compounds in which R ° is a hydroxy group.

The compounds in which any of the groups R3 and R4 is a benzyloxy group serve as intermediates for the preparation of compounds in which the group R3 or R4 is a hydroxy group.

The anti-allergic power of the compounds of the invention is evaluated by the passive skin anaphylaxis test (PCA)

(Ovary, J. Immun. 81, 355, 1958). In the PCA test, normal animals receive an intradermal injection (i.d.) of antibodies contained in serum obtained from actively sensitized animals. The animals are then subjected intravenously to the antigen mixed with a dye such as Evans Blue. The increase in capillary permeability caused by the antigen-antibody reaction results in the dye escaping from the site of the antibody injection. The test animals are then asphyxiated and the intensity of the reaction is determined by measuring the diameter and the intensity of the blue coloration which appears on the internal face of the skin of the animals.

The compounds of formula I are prepared by reaction of a compound of formula in which R3 and R4 correspond to the definition above, with a dialkyl oxalate; and when any of the groups R3 and R4 is a benzyloxy group, the benzyl ether is debenzylated, if desired.

The ester obtained, having the group -COR0 (R ° = C1 to Ct alkyl) can be saponified to give the acid (R ° = H) and its salts.

It should be noted that the compounds prepared according to the invention are similar to those of the prior law. The technical data appearing therein are applicable to carrying out from the chemical point of view, the preparation of condensed compounds, although, moreover, the particular compounds obtained according to the present invention and their properties are not necessarily achievable from the data appearing in the description of the prior right.

A catalyst is often used to facilitate condensation. Suitable catalysts are ammonia, primary, secondary and tertiary amines such as n-butylamine, diethylamine, triethylamine, pyridine, piperidine, Pyrrolidine, alcoholates and alkali metal fluorides, stannous fluoride and basic ion-exchange resins of the amine type, such as Amberlite IR-45 (weakly basic polystyrene with polyamine groups, supplied by Rohm & Haas Co.) and De-Acidite G (polystyrene resin carrying diethylamino groups, supplied by Permutit Co., Ltd, London).

The amount of catalyst used is not decisive, and it can vary within wide limits, namely from about 0.1% to about 100% by weight relative to the starting carbocylic aldehyde. The preferred concentration range for the catalyst is from about 10% to about 30% by weight of the starting carbocyclic aldehyde.

The reaction can be carried out at a temperature ranging from approximately 0 ° C. to approximately 50 ° C., and generally around ambient temperature for a period ranging from approximately a quarter of an hour to five hours. The reaction products generally separate from the reaction mixture as solids, and are collected by filtration. Those which do not separate out as solids are collected by evaporation of the solvent or by pouring it into a large volume of non-solvent for the final product.

The dialkyl oxalate of the operation provides the single carbon fragment necessary to complete the condensed pyrimidine nucleus.

The process involves using the appropriate 2-amino-3-carboxamide (Formula II) as a reactant which is condensed with the dioxalic ester which provides only the single carbon moiety to complete the pyrimidine nucleus.

The reaction of the 2-aminoquinoline-3-carboxylic acid derivative with dialkyl Oxalate is preferably carried out in a solvent inert with respect to the reaction medium, and preferably a single solvent allowing the elimination , by distillation, alcohol and water formed as by-products. As solvents representative of the solvents which can be used for this cycli-sation, mention will be made of aromatic hydrocarbons such as xylene, toluene, benzene; an excess of the dialkyl oxalate chosen as reactant; tetralin and decaline.

It is easy to determine, by experimentation, which solvents are suitable. A preferred solvent is an excess of the dialkyl oxalate, given its ability to dissolve the reagents and to allow simple removal of the alcohol and water formed as by-products. Although the reaction temperature is not critical, the reaction is generally carried out at elevated temperature to facilitate removal of the alcohol and water. When a dialkyl oxalate is used as the solvent, it can be operated at temperatures from about 150 ° C to about 185 ° C. It is sometimes advantageous to end with a melting or heating period to achieve maximum cyclization and obtain the pyri-midoi [4,5-b] quinoline-4 (3H) -one-2-carboxylic acid derivative desired. . The addition of a small amount of a base such as sodium hydride or alkali metal alcoholates is frequently useful to promote cyclization.

The transformation is carried out by oxidation using chromic anhydride in pyridine (Sarett reagent) or chromic anhydride-pyridine-water (Cornforth reagent). The latter reagent is preferred for its ease of preparation and handling over the Sarett reagent. Subsequent oxidation of 2-carboxaldehyde, for example, by chromic anhydride-sulfuric acid, at about 30 ° -50 ° C gives 2-carboxylic acid.

The compounds of Formula I in which any of the groups R3 and R4 is a benzyloxy group, serve as intermediates for the preparation of the corresponding hydroxylated compounds. Debenzylation is conveniently carried out by treating the benzyl ether with trifluoroacetic acid. Debenzylated products are obtained in the form of their tri-fluoride acetates. The hydroxylated compounds, for their part, are intermediates for the preparation of the corresponding alkanoyloxylated and benzoyloxylated derivatives, by acylation, using the appropriate acid anhydride, for example acetic anhydride. In general, a catalytic amount of p- acid is used.

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toluene sulfonic to accelerate the reaction.

The products of the invention and their pharmaceutically acceptable cationic salts are useful for the suppression (prophylactic and therapeutic treatment) of allergic symptoms and reactions in mammals and can be administered either as isolated therapeutic agents or as a mixture of therapeutic agents. , for example with theophylline or with sympathomimetic amines, by the oral, parenteral or inhalation routes. They can be administered alone, but they are generally administered with a pharmaceutical support chosen taking into account the route of administration adopted and current pharmaceutical practice.

Typical methods of administration and butylene compositions are described in more detail in the aforementioned patent application.

It is necessary that the active ingredient forms a proportion of the composition such that an appropriate dosage form is obtained. Obviously, several unit doses can be administered at approximately the same time. Although compositions containing less than 0.005% by weight of active ingredient can be used in some cases, it is preferred to use compositions containing not less than 0.005% of active ingredient, otherwise the amount of carrier becomes excessive. The activity increases with the concentration of the active ingredient. The composition may contain 10, 50, 75, 95% or even more by weight of the active ingredient.

The procedure of the PCR test used to evaluate the compounds of the invention shows an excellent correlation between the activity of the compounds in this test and their usefulness for the treatment of allergic asthma. The ability of agents to interfere with PCR reactions is measured in Charles River Wistar rats, 170-210 g. The reactin antisera are prepared according to Mota, Immunology, 7, 681 (1964) using chicken egg albumin and B. pertussis. The hyperimmune antiserum to chicken egg albumin is prepared according to Orange et al., J. Exptl. Med., 127, 767 (1968). 48 hours before exposure to the antigen, the reaction antiserum is injected intradermally (i.d.) into the shaved skin of the back of a normal rat; five hours before exposure, the hyperimmune antiserum is also injected; five hours later, in a third place, 60 meg of hista-mine dihydrochloride (i.d.) is added as a check on antihistamic and non-specific blocking types; the compounds of the invention or physiological serum are then administered intravenously, then immediately, 2.5 mg of Evan blue dye and 5 mg of oval-bumine in physiological serum. In the case of oral administration, Evan's blue and ovalbumin are administered five minutes after the drug. Thirty minutes later, the animals are asphyxiated with chloroform, the back skin is removed and turned over to examine it. A score is given at each injection site, equal to the product of the diameter of the site in mm and a factor of 0.1, 0.5.1, 2, 3 or 4 proportional to the intensity of the coloring. The scores are summed for a given injection site for each group of eight animals and compared to the controls treated with physiological saline. The difference is expressed in percent blocking of the compound used.

Representative compounds of the invention are tested by the above procedure and the activities obtained are expressed in degree (%) of protection.

N-H

Table I

Antiallergic activity of pyrimido [4,5-b] quinoline-4 (3H) -one-2-carboxylic acid derivatives (Formula I).

Intravenous use * Oral use *

R

R3

R4

mg / kg

%

mg / kg

%

COOC2H5

CH3COO

OCHs

3

0.003

100 53

10

40

COOC2H5

OH

OCH3

0.03 0.01 0.003 0.0003

97

98 94 38

30

6

COOH

OH

OCH3

3

0.01 0.003

100 86 90

COO-

OH

OCH3

3

100

10

67

(n-C; H9)

0.003

52

COO-

CHsCOO

OCH3

3

100

10

36

(n-C4Hs)

COOC2H5

OH

H

0.3

92

10

13

0.03

21

3

4

COOH

OH

H

3

0.03 0.003

100 91 4

COOC2H5

OCHs

OH

0.003

0.3

3.0

0

100 100

* The numbers above the line indicate that a particular value is the average of two or more determinations.

It is estimated that an effective daily oral dose of the compounds of the invention in humans of about 10 to about 1,500 mg per day, the preferred range being from about 10 to about 600 mg per day, in a single dose or in fractional doses, or from about 0.2 to about 12 mg / kg of body weight, effectively relieves broncho-constriction. These values are given by way of example and there may, of course, be special cases justifying ranges of higher or lower doses.

When administered intravenously or by inhalation, the effective daily dose is from about 0.5 to about 400 mg per day, and preferably from about 0.25 to 200 mg / day, or from about 0.005 to 4 mg / kg bodyweight in a single dose or in fractional doses.

Example 1

Ethyl 7-benzyloxy-8-methoxy pyrimido [4,5-b] quinoline-4 (3H) -one-2-carboxylate

A) a-cyano-p- (2-nitro-4-methoxy-5-benzyloxyphenyl) -acrylamide

Piperidine (2.1 g, 0.0237 mole) and 2-cyanoacetamide (22.0 g, 0.263 mole) are added to a suspension of 3-benzyloxy-4-methoxy-6-nitrobenzaldehyde (0.237 mole). ) in methanol (500 cm3). The mixture is heated under reflux for 2 hours, then cooled in an ice bath and filtered. The bright yellow filter cake is washed with cold isopropanol (300 cm3), then air-dried. Yield: 45 g; melting point: 157-158 ° C.

Following the above procedure, but using the appropriate substituted alkoxy nitrobenzaldehyde, the compounds below are prepared:

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CONH

CN

R2

R3

R4

Rs m.p. (° C)

Yield

%

H

OC2H5

OC7H7

H

167-167.5 (dec.)

73

H

OCH3

OC7H7

H

182-3

52

H

OC7H7

H

H

125-6

47

B) 6-benzyloxy-7-methoxy-2-aminoquinoline-3-carboxamide

Iron powder (65.2 g, 1.22 moles) is added over a period of half an hour to a suspension of the product of procedure A (0.271 mole) in a 50% solution of acetic acid and N, N-di-dimethylformamide (750 cm3) at 75 ° C. When the addition of the iron powder is complete, the mixture is heated to 90 ° C for 4 hours and filtered while it is hot. The filter cake is washed with hot acetic acid (150 cm3). The dark red filtrate is gradually added to IN hydrochloric acid (1,500 cm 3), the pink precipitate is collected by filtration and it is recrystallized from an excess (10%) of aqueous sodium hydroxide. The solid is filtered, washed with cold isopropanol and dried, giving the desired product in the form of yellow crystals. Yield = 80%, melting point 264-266 ° C.

By repeating procedure B above, but using the appropriate α-cyano-P- (2-nitrophenyl) acrylamide, obtained by procedure A, the compounds below are prepared:

r3

r4

mp (° C)

Yield

%

OC2H5

OC7H7

279-80 (dec.)

73

OCHs

OC7H7

282-3 (dec.)

95

OC7H7

H

238-9

94

C) ethyl 7-benzyloxy-8-methoxy pyrimido 4,5-b quinoline-4 (3H) -one-2-carboxylate

In a round bottom flask, equipped with a stirrer, a reflux condenser and a Dean-Stark apparatus, and containing a mixture of diethyl oxalate (50 cm3) and xylene (80 cm3) under reflux , the product of procedure B (0.012 mol) is added. The xylene, water and ethanol are distilled off and collected over a four hour period. When all the xylene is removed, the reaction mixture is brought to 185 ° C., it is cooled to approximately 100 ° C., then it is slowly poured into chloroform (300 cm 3). The chloroform solution is cooled and the brown precipitate is separated by filtration. The filtrate is discolored with charcoal, concentrated, and cooled, giving a crystalline mass. The crystals are taken up in hot chloroform, the solution is treated with charcoal, filtered and concentrated, which gives pale yellow crystals, yield: 25%, m.p. 274-275 ° C.

Then heated under reflux, for 3 days, a mixture of 6,7-dimethoxy-2-aminoquinoline-3-carboxamide (0.5 g, 2 millimoles), ethyl cyanoformate (0.43 g, 44 millimoles) and benzene (30 cm3). The mixture is then cooled, filtered and the solid is extracted with chloroform. By concentration of the chloroform extract, the desired product is obtained which is recrystallized from chloroform.

By following procedure C above, but using the appropriate alkoxy-substituted 2-aminoquinoline-3-carboxamide, obtained by procedure B above and the appropriate ester of oxalic acid, the compounds are prepared. this-

below:

-H

HORN

r °

R3

r4

m.p.

(° C)

Yield

%

OC2H5

OC2H5

OC7H7

241-2

(Dec.)

41

OC2H5

OCH3

OC7H7

254-5

(Dec.)

8

O-n-C-tHs

OC7H7

OCHs

261-2

(Dec.)

13

OC2H5

OC7H7

H

256-7

(Dec.)

32

D) 7-ben2yloxy-8-methoxy pyrimido [4,5-b] quino-leine-4 (3H) -one-2-carboxylic acid

Stirred, at room temperature, for 20 hours, ethyl 7-benzyloxy-8-methoxy pyrimido [4,5-b] quinoline-4 (3H) -one-2-carboxylate (7.4 mA-) in 5% aqueous sodium hydroxide (37.5 cm3). The ester dissolves in ten minutes, and a light colored precipitate gradually appears. The reaction mixture is acidified by the slow addition of 10% aqueous hydrochloric acid (13 cm3). The light colored precipitate dissolves and a yellow precipitate is formed. The acid mixture is stirred for 45 minutes, then filtered. The filter cake is washed with water, then dried under vacuum.

The other products of Example I-C are hydrolyzed according to procedure D, giving the corresponding acids.

Example 2

Ethyl 7-benzyloxy-8-ethoxy pyrimido [4,5-b] quinoline-4 (3H) -one-2-carboxylate

A) a-cyano-ß - (2-nitro-4-benzyloxy-5-ethoxyphenyl) -acrylamide

Heated, under reflux, in a boiling water bath, for 2 hours, a mixture of 3-ethoxy-4-benzyloxy-6-nitrobenzaldehyde (0.0592 mole), 2-cyanoacetamide (5.24 g 0, 0622 mole), piperidine (0.37 g, 4.36 millimoles) and ethanol (92 cm3). It is cooled in an ice bath. The product precipitates and is collected by filtration, washed with cold ethanol and dried.

It is pure enough to be used in the next operation.

B) 6-ethoxy-7-benzyloxy-2-aminoquinoline-3-carboxamide

Iron powder is gradually added (8.52 g, 0.152

mole) over a period of 40 minutes, to a suspension of the product obtained by procedure A (0.034 mole) in acetic acid (100 cm3) at 85 ° C. When the addition of the s

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iron powder is complete, the mixture is heated to 95-100 ° C for 1.5 hours, then filtered hot through diatomaceous earth. The filtrate is cooled in an ice bath, then filtered, which gives a yellow-brown crystalline solid. The solid is partitioned between ethyl acetate and water, the organic phase is separated, dried over anhydrous sodium sulfate, and concentrated, which gives the desired amide in the form of yellow crystals .

C) ethyl 7-benzyloxy-8-methoxy pyrimido [4,5-b] quinoline-4 (3H) -one-2-carboxylate

A mixture of diethyl oxalate (57.2 g, 0.392 mole) and product of procedure B (0.0261 mole) is heated for 160 hours at 160 ° C., under a nitrogen atmosphere, and allowed to cool. at room temperature. Hexane (300 cm3) is added, the mixture is stirred and filtered, which gives the desired product. It is washed with hexane and dried.

Example 3

7-hydroxy-8-methoxy pyrimido [4,5-b] quinoline-4 (3H) -one-2-ethyl carboxylate (trifluoroacetate) (debenzylation) A solution of 7- is refluxed for 2.5 hours ethyl benzyloxy-8-methoxy pyrimido- [4,5-b] -quinoline-4 (3H) -one-2-carboxylate (250 mg, 0.618 millimole) in trifluoroacetic acid (5 cm3). (The mixture can also be stirred at room temperature for three days). The reaction mixture is then poured into ether (25 cm 3) and the bright yellow precipitate of trifluoroacetate obtained is collected by filtration, washed with ether and dried.

Yield = 194 mg, 72%; m.p. 279 ° C.

Composition for C15H13N3CF5COOH 1/2 H2O:

C H N

Calculated: 46.58% 3.42% 9.58%

Found: 46.81% 3.41% 9.21%

By repeating the above procedure, but using the corresponding n-butyl ester (862 mg, 0.199 millimole) in place of the ethyl ester, the result is with 8 cm 3 of trifluoroacetic acid and a reflux time of 3.5 hours, 7-hydroxy-8-methoxy-pyrimido trifluoroacetate] 4,5-b] quino-lein-4 (3H) -one-2-n-butyl carboxylate (0.67 g, 74% ); m.p. 240 ° C (dec).

Composition for C17H17O5N3CF3COOH:

C H N F

Calculated: 49.89% 3.96% 9.18% 12.46%

Found: 49.93% 3.97% 8.79% 11.17%

Debenzyl in the same way, ethyl 7-benzyloxypyri-mido [4,5-b] quinoline-4 (3H) -one-2-carboxylate, which gives a yield of 74% in hemitrifluoroacetate of 7-hydroxypyrimido [4,5-b] quinoline-4 (3H) -one-2-ethyl carboxylate; m.p. 274-175 ° C (dec).

Composition for C14H11P4N31 / 2 CF3COOH:

C H N.

Calculated: 57.43% 3.66% 13.39%

Found: 57.75% 4.05% 13.65%

Example 4

7-hydroxy-8-methoxypyrimido acid [4,5-b) quinoline-

4 (3H) -one-2-carboxylic A slurry is formed with the trifluoroacetate hemihydrate of 7-hydroxy-8-methoxypyrimido [4,5-b] quinoline-4 (3H) -

ethyl one-2-carboxylate (200 mg, 0.456 millimole) in 0.1N sodium hydroxide (5 cm3) and 15% sodium hydroxide is added dropwise, stirring until that the dissolution is complete. The mixture is stirred at room temperature for 18 hours, then strongly acidified by the addition of trifluoroacetic acid. The precipitate which forms is separated by filtration, washed with water, then with isopropyl alcohol and dried in air. Yield = 114 mg; m.p. 281 ° C (dec.)

Composition for C13H9O5N32H2O:

C H N

Calculated: 48.29% 4.02% 13.00%

Found: 47.30% 3.32% 12.73%

The hemitrifluoroacetate of 7-hydroxy-pyrimidino [4,5-b] quinoline-4 (3H) -one-2-carboxylate (210 mg) is likewise transformed into 7-hydroxypyrimido acid [4,5-b ] quinoline-4 (3H) -one-2-carboxylic. Yield = 191 mg, 91%; m.p. 340 ° C (dec.).

Example 5

7-methoxy-8-hydroxy pyrimido [4,5-b] quinoline-4 (3H) -one-2-carboxyIate A solution of 7-methoxy-8-benzyloxypyrimido- is stirred at room temperature for 8 days [4,5-b] -quinoline-4 (3H) -one-2-ethyl carboxylate (198 mg, 0.488 millimole) in trifluoroacetic acid (4 cm3). Ether (15 cm 3) is added and the yellow precipitate which forms is separated by filtration. The precipitate is taken up in chloroform and the solution is filtered through diatomaceous earth, to remove a small amount of insoluble matter present. The filtrate is discolored on charcoal and concentrated under reduced pressure to a small volume. The solid which forms is filtered and dried. Yield: 9 mg, 6%; m.p. 265-266 ° C (dec.).

Example 6

7-acetoxy-8-methoxy pyrimido [4,5-b] quinoline-4 (3H) -one-2-ethyl carboxylate (p-toluenesulfonate) A mixture of 24 hours at 100 ° C. acetic anhydride (4 cm3), trifluoroacetate of 7-hydroxy-8-methoxy-pyrimido [4,5-b] quinoline-4 (3H) -one-2-carboxylate ethyl hemihydrate (250 mg, 0.572 millimole) and p-toluenesulfonic acid monohydrate (100 mg, 0.572 millimole). The acetic anhydride is then extracted under vacuum from the reaction mixture. The solid residue is dissolved in hot chloroform, and the solution is discolored over activated carbon. Benzene (4 volumes) is added to the discolored solution which is then cooled in ice. The crystals which separate are collected by filtration and then dried in air. Yield = 174 mg, 58%; m.p. 215-217 ° C.

Composition for C17H15O6N3C7H8O3S:

C H N

Calculated: 54.43% 4.37% 7.98%

Found: 53.74% 4.28% 7.24%

The above procedure is repeated, but using the corresponding trifluoroacetate of the n-butyl ester (200 mg, 0.437 millimole) in place of the trifluoroacetate of the ethyl ester. The product is collected by concentration of the chloroform solution to one third of its volume and filtration of the solid which precipitates rather than by precipitation with benzene. Yield = 30 mg, 18%; m.p. 260-261 ° C (dec.).

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Claims (8)

619,951 2 CLAIMS 1. Process for the preparation of compounds of formula (I) and their pharmaceutically acceptable salts, in which: R ° is a C1 to Gt alkoxy group, and R3 and R4 are independently selected from (a) hydrogen, C1 to Gt alkoxy and benzyloxy (b) hydroxy and C1 to Ca alkanoyloxy, at least one substituent R3 and R4 being chosen from group (b), characterized in that a compound of formula is reacted 0 R4 is a benzyloxy group, at a debenzylation to obtain the —OH group. 4. Method according to claim 1, characterized in that one of R3 and R4 is a hydroxy group. 5. Method according to claim 2, characterized in that one of R3 and R4 is a hydroxy group. 6. Method according to claim 4, characterized in that the other of the radicals R3 and R4 is a C1 to Ci alkoxy group. 7. Method according to claim 1, characterized in that R ° is a butoxy group, Rs is a group -OH, and R4 is a group -OCH3. 8. Method according to claim 1, characterized in that R ° is an ethoxy group, R3 is a -OCH3 group, and R4 is a -OH group. with a dialkyl oxalate. 2. Process for the preparation of a compound of formula I, in which R ° is a radical -OH, characterized in that a compound is prepared by the process according to claim 1 and that the compound obtained is subjected to hydrolysis to ester. 3. Method according to claim 1, characterized in that a compound obtained in the formula of which R3 and / or is subjected 40