SI9010206A - Ethers of 1-benzyl-3-hydroxymethyl-indazole with aliphatic 2-hydroxy acids - Google Patents

Abstract

Compounds having a formula (I) A-CH2-O-CRR'-COOR''' are assured by the invention, where A means a 1-benzyl-indazol-3-yle nucleus; R and R' which may be the same or different represent hydrogen or C1-5 alkyl; R''' means hydrogen or the rest of aliphatic saturated alcohol with 1-4 carbon atoms, and in case R''' is hydrogen, their salts with pharmaceutically acceptable bases. The process is assuring also intermediates and procedures for preparation of compounds having the formula (I) according to the following reaction schemes: (II), (III) , or (IV), where Me represents alkali metal, X a leaving group such as halogen or the rest of sulphonic acid, and R a C1-5 alkyl. The compounds with the formula (I) and their salts with pharmaceutically acceptable bases may be used for instance as antiinflammatory agents or analgetics.

Description

ETRI 1-BENZYL-3-HYDROXYMETHYL-INDDAZOLA WITH ALIPHATIC 2-HYDROXIC ACIDS

The present invention relates to ethers of 1-benzyl-3-hydroxymethyl-indazole with aliphatic 2-hydroxy acids, to their salts with pharmaceutically acceptable bases / to intermediates and methods for their production, and to pharmaceutical preparations containing them.

Closer, the first object of the present invention is to provide compounds of the formula: '

A-CH ₂ -O-CRR'-COOR 'in which A represents 1-benzyl-indazol-3-yl core of formula (I)

f / \

R and R 'may be the same or different and represent H or C 1-6 alkyl, R' is hydrogen or a saturated aliphatic alcohol of 1-4 carbon atoms; and, when R 'is H, their salts with pharmaceutically acceptable bases.

It is clear that when R and R 'are different, the compound of formula (I) may occur either as a single enantiomer or as a racemic mixture. The present invention therefore encompasses both racemic mixtures and certain enantiomers that can be obtained either by separation of the racemic mixture using known techniques or by stereospecific synthesis. Unless otherwise indicated, the starting compounds in the examples having an asymmetric carbon atom were used in the form of racemic mixtures.

Bendazac is a known compound of the formula:

¹ '·' $ '· i ·. ·

A-O-CH-COOH (BZ) , _; j * · *> ·. f where A has the meaning defined above which has an anti-inflammatory effect (US patent 3,470,194). Continuous study of the compound over several years has shown that bendazac and its salts with pharmaceutically acceptable bases are active in the treatment of some dyslipemias (US patent 4,352,813), retinitis pigmentosis (EP-B-131,317) and cataracts (US patent 4,451,477 bandazac and its salts have finally been found to prevent contact lens blurring (EP-A-255,967);

The present invention is essentially based on the finding that the addition of a methylene group (—-CH ^ -) between the 1-benzyl-indazol-3-yl nucleus (A) and the side sequence (-0-CH ^ -COOH) alters the pharmacological properties bendazac so that, in contrast to bendazac itself, the compounds of formula (I) also have an analgesic effect (Example 5). _<

Another object of the present invention is to provide a process for the preparation of a compound of formula (I). The procedure involves:. Y. · ·.

i) (a) reacting, in accordance with conventional techniques, compounds of the formula:

A — CH ₂ —Y (Ila) in which A has the meaning defined above and Y is hydroxy, with an alkali metal or a suitable derivative thereof, to give an alcoholate of the formula:

A — CH ₂ —OMe (Ilb) in which A has the meaning defined above and Me is an alkali metal atom, after which the compound of formula (Ilb) reacts with the compound of the formula:

I »

X-CRR'-COOR (purple) in which R and R 'are as defined hereinbefore Eligible mountains meanings, X is a leaving group with the following from halogen atoms and radicals of the formula Z-SC> ₂ -0-, Where the

Z is aryl or alkyl, and R is C 1-6 alkyl to give the ether of the formula:

A-CH ₂ -O-CRR'-COOR (1a) in which A, R, R 'and R have the meanings defined above; or · and (b) reacting, in accordance with conventional techniques, compounds of formula: ii β

A — CH ₂ —X (Ilc) A in which A and X have the meanings defined above, with an alcohol of the formula:

MeO-CRR'-COOR (IHb) in which R, R ', R and Me have the meanings defined above to give the ether of formula (Ia); or (cj reaction, according to conventional techniques, of a compound of formula (Ila) with ketone and chloroform in the presence of an alkaline hydroxide according to the ' ^r ' following reaction scheme: 'A'! ·

A — CH ₂ —Y + CHC1 ₃ + R — CO — R '-> A — CH ₂ —0 — CRR' ^: —COOH '(Ila) (I) where A and Y have the meanings defined above and R and R 'may be Buddhist or different and represent C 1-6 alkyl; .

ii) optionally hydrolyzing the ester of formula (Ia) to give the corresponding acid of formula (I) according to conventional techniques, and iii) optionally, obtaining (a) a salt of said acid of formula (I) with a pharmaceutically acceptable base or ( b) an ester of said acid of formula (I) with saturated aliphatic alcohol 1; 1 and 1a ~ 4 carbon atoms, in accordance with conventional techniques.

Phases (i) (a) and (i) (b) may be subjected to a process for the production of asymmetric ethers according to Williamson (J. March Advanced Organic Chemistry,

3rd edition, p. 342 to 344, reactions 0-14 and 0-16) and are preferably carried out in the presence of a suitable solvent, at room temperature to the boiling point of the reaction mixture, for 15 minutes to 48 hours. Examples of suitable solvents are aprotic solvents. Typical examples of preferred solvents are tetrahydrofuran, dimethylformamide, toluene, and mixtures thereof.

The alcoholates (Ila) and (Ilb) are conveniently prepared starting from metallic sodium, potassium metal or sodium hydride, in the presence of a suitable solvent, at room temperature to the boiling point of the reaction mixture, for 15 minutes to 48 hours. Examples of suitable solvents are aprotic solvents. Typical examples of preferred solvents are tetrahydrofuran, dimethylformamide, toluene, and mixtures thereof.

- 4 Preferred meanings for X are chlorine, bromine 1 Z — SO ^ —0— where Z is p-methylphenyl, phenyl and methyl. '

Phase (i) (c) is preferably carried out at. boiling point of the reaction mixture for 30 minutes to 12 hours.

Stage (11) is preferably carried out with an aqueous or aqueous / alcoholic alkali solution at room temperature to the boiling point of the reaction mixture for 1 to 48 hours. '

Typical examples of pharmaceutically acceptable inorganic bases suitable for use in step (iii) (a) are alkali and alkaline earth metal bases; nearer, sodium, potassium, and calcium. Typical examples of organic pharmaceutically acceptable bases are primary and secondary amines which are optionally substituted by hydroxy and / or carboxy groups. Specific examples of such organic bases are: methylamine, isopropylamine, hexylamine, diethylamine, ethanolamine, 2-hydroxymethyl-2-aminoT, 3-propanediol, glycine, glipin, alanine, valine, leucine, isoleucine, serine, tr.eonine, aspartic acid , glutamic acid, arginine, lysine, chistin, cysteine, methioin, phenyl alanine, tyrosine, tryptophores and histidine. T

Typical examples of preferred alcohols for use in step (iii) (b) are straight-line alcohols.

It is a further object of the present invention to provide intermediate compounds of formula:.

A — CH ₂ —W (II) where A is a 1-benzyl-indazol-3-yl nucleus, W represents OH, OMe (where Me is an alkali metal atom) or a leaving group selected from halogens and radicals of the formula Z-S0 ₂ - 0 - wherein Z represents aryl or alkyl.

Preferred leaving groups are chromo, chloro and Z-S0 ₂ --0 where Z is p-methylphenyl, phenyl or methyl.

An alcohol of formula (II) (A-CH ₂ -OH) may be obtained by reduction of an acid of the formula:

A — COOH (IV) where A has the meaning defined above, or an aliphatic ester thereof, according to conventional techniques. Preferably, the reduction of said ester is effected with a suitable reducing agent such as lithium aluminum hydride, sodium bis (2-methylethoxy) aluminum hydride (70% in toluene) or calcium tetra (isopropoxy) -alanate (70% in toluene), in the presence of a suitable solvent, at ¹ O - T temperature of 0 C to the boiling point of the reaction mixture, for 30 minutes to 12 hours. Examples of suitable solvents are diethyl ether, tetrahydro- and furan, toluene and mixtures thereof. f ¹ t,

Appropriate alcohols (W = OMe), halides (W = halogen) and sulfone esters' (W = O-SO2-Z) can also be obtained easily, in accordance with conventional techniques.

For practical use in therapy, the compounds of the present invention and their pharmaceutically acceptable salts may be administered per se, but preferably administered in the form of pharmaceutical preparations.

Said preparations are another object of the invention and consist of an effective amount of one or more compounds of formula (I) or salts thereof with pharmaceutically acceptable organic or inorganic bases, together with liquid or solid pharmaceutical excipients suitable for systemic administration, such as oral. oral, rectal and parenteral administration, or for topical administration, such as aerosol administration or ophthalmic administration.

The pharmaceutical compositions of the present invention may be in solid form as tablets, pills, capsules and light-release forms, then in a semi-solid form such as suspensions, creams and ointments, and in liquid form such as solutions, suspensions and emulsions.

In addition to the usual excipients, the preparations may also contain additives suitable for pharmaceutical use, such as preservatives, stabilizers, emulsifiers, osmotic pressure regulating salts, buffers, as well as coloring agents and flavors.

When required by a particular therapy, the compositions of the present invention may contain other compatible active ingredients whose simultaneous administration is therapeutically useful.

For practical applications in therapy, the effective amount of the compounds of the present invention may vary widely depending on known factors such as the particular therapy required, a pharmaceutical preparation;

- 6 - I. .., (

the route of administration as well as the efficacy of the particular compound of the present invention and the invention used. However, the optimum effective amount can easily be determined by simple, routine procedures. . .

.. and J's ..

Pharmaceutical preparations can be obtained by the following common pharmacist techniques, such as mixing, granulating and compressing when required; 'ί C-r *! - ·.

bno, or variously mixing and dissolving the ingredients, in a manner that is ·, suitable to obtain the desired end product.

In principle, in the case of systemic administration, the daily dose of the compounds of formula (I) i

-5 -3 will preferably be determined such that a tissue level of 10 to 10 M is achieved in the tissue; ' this level will usually be reached at doses of 0.5 to 100 mg / kg. Local administration will, in turn, require administration of pharmaceutical preparations (drops of ^ creams, ointments, etc.) containing from 0.1 to 5% by weight of the compounds of formula (I) and or an appropriate amount of a pharmaceutically acceptable salt thereof. '

Lastly, it is another object of the present invention to provide a method of treatment comprising a compound that provides an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need of such treatment.

To better illustrate the invention, the following examples are given:

Example 1

a) 1-Benzyl-3-hydroxymethyl-indazole. ..

To a suspension of 2 g of lithium aluminum hydride in 50 ml of diethyl ether was added dropwise a solution of 12.5 g of ethyl ester.l-benzyl-3-indazole-carboxylic acid (Von Auwers Schaich, Chem. Ber., 54, 1756). (1921)) in 30 ml of anhydrous tetrahydrofuran.

Upon completion of the addition, the reaction mixture was refluxed for 90 minutes.

After cooling, the reaction mixture was treated in the usual manner and the precipitate obtained was filtered off and the residue obtained after evaporation of the solvent was recrystallized from isopropyl alcohol. 1-Benzyl-3-hydroxymethyl-indazole (Compound Ila) is thus obtained. T.t. 85-86 ° C.

b) 1-Benzyl-3-hydroxymethyl-indazole ether with glycolic acid

2.4 g of Sodium hydride (60% suspension in oil) was added to a solution of the entire amount of the 1-benzyl-3-hydroxymethyl-indazole obtained above in 70 ml of tetravol;

- 7 hydrofuran, and the reaction mixture is heated to reflux in an inert stream

F gas (nitrogen). A solution of 3.5 g of hydrobromic acid in 40 ml · d of tetrahydrofuran was added to the mixture and the reaction was refluxed for 90 minutes. After cooling, the reaction mixture is treated as usual and acidified. The product obtained is recrystallized from isopropanol. The ether of 1-benzyl- is thus obtained

3-hydroxymethyl-indazole with glycolic acid (Compound I, R = R '

R '= H), m.p. Mp 136-138 ° C. J

Example 2 'j

a) 1-Benzyl-3-chloromethyl-indazole, j · J '' _v · ·> - i

A solution of 11 g of 1-benzyl-3-hydroxymethyl-indazole (obtained as opi

l '* ..., ·, 1 sano in Example 1a) and 11.9 g of thionyl chloride in 100 ml of toluene was heated at reflux for 4 hours. The solid residue obtained by evaporation of the solvent consists of crude 1-benzyl-3-chloromethyl-indazole (Compound II, W = Cl) and used in step (b) without further purification. The sample recrystallized from hexane melts at 89-91 ° C.

b) L-benzyl-3-chloromethyl-indazole ether with lactic acid, and its ethyl ester

2.7 g of sodium hydride (60% suspension in oil) was added portionwise over a minute to a solution of crude 1-benzyl-3-chloromethyl-indazole obtained as described above and 53 g of ethyl lactate in 100 ml of dimethylformamide. at reflux temperature. After complete addition, the reaction mixture was refluxed for another 30 minutes and then cooled and diluted with water; The separating oil was extracted with ethyl acetate.

The residue obtained by evaporation of the solvent consists of crude ethyl ester (Compound I, R = H, R '= CH 2, R' = C ₂ H ₂ ) and dissolved in 560 g of an alcohol / water solution (1: 1) containing 3.4 g NaOH. After 4 hours of boiling, most of the alcohol is evaporated and the remaining aqueous solution is acidified and the resulting solid is recrystallized from a mixture of hexane and ethyl acetate. ;

Thus, l-benzyl-3-chloromethyl-indazole ether with lactic acid was obtained (Compound I, R = R '' = H, R '= CH2, mp 126-128 ° C.

Alternatively, NaH is added at room temperature and the reaction mixture is heated to 40-50 ° C upon completion of the addition.

- 8 By the procedure described in Example 2 (b), but using methyl 2-hydroxy-butyrate, methyl 2-ethyl-2-hydroxy-butyrate and methyl 2-hydroxycaproate instead of ethyl lactate, the compounds of formula (I) can be obtained )

·. i

. 'fr', and · '

in which R, R 'and R' have next meanings: R = H; R '= ^C 2 ^H 5 ' R '= CH ₃ (ester) i H (acid) R = ^C 2 ^H 5 ^; R '= ^C 2 ^H 5 ' R '= CH ₃ (ester) i H (acid) R - ^H 5 R '= ^C 4 ^H 9 ^; R '= CH ₃ (ester) i H (acid).

Example 3

1-Benzyl-3-hydroxymethyl-indazole ether with 2-hydroxy-2-methyl-propionic acid

To the round bottom balloon, equipped with a vigorous stirrer, were added one after the other 1.9 g of NaOH, 10 g of acetone and 2.38 g of 1-benzyl-3-hydroxymethyl-indazoyl obtained as described above. 1.6 g of chloroform (exothermic reaction) are then added and the mixture is heated for two hours in a water bath. Water was then added, the reaction mixture was washed with ethyl acetate, and the aqueous solution acidified. The residue was recrystallized from a mixture of hexane and ethyl acetate (1: 1). Thus, 1-benzyl-3-hydroxymethyl-indazole 'ether with 2-hydroxy-2methyl-propionic acid was obtained (Compound I, R = R' = CH _3> R ' ⁼ H), mp 132-134 ° C.

Example 4.

1-Benzyl-3-hydroxymethyl-indazole ether with 2-hydroxy-2-ethyl-propionic acid

A solution of 6 ml of chloroform and 6.8 ml of methyl ethyl ketone was added dropwise over a period of about 30 minutes to a suspension of 5.9 g of 1-benzyl-3-hydroxymethyl-indazole obtained as described above, 12 g of NaOH and 35 ml of methyl ethyl ketone. Upon completion of the addition of ·, the reaction mixture was heated to reflux. After 60 minutes, the reaction mixture was cooled, water was added, and the aqueous phase was separated and acidified. The resulting oil was extracted with diethyl ether and the solvent was evaporated to give a curing oil which was crystallized from hexane / ethyl acetate (1: 1). Thus, 1-benzyl-3-hydroxymethyl-indazole ether with 2-hydroxy-2-ethyl-propionic acid was obtained (Compound I, R = CH ^, R '= ^ 2 ^ 5'

R '= H), m.p. 115-116 ° C.

By the procedure as described in Example 4, but. using 2- and 3-pentanone, 2- and 3-hexanone, 2-, 3- and 4-heptanone, 3-octanone, 5-nonanone and 6-undecanone instead of methyl ethyl ketone yields compounds of formula (I) in which R, r 'and R' ”have the following meanings:

R = CHg R ' 1 ^C 3 ^H 7 R ' = H R = C _o H _c R ' - C_H _c R ' H 2 5 2 5 R ^CH 3 R ' = ^C 4 ^H 9 R ' = H R ₌ C _n H _r R ' C-H-, R ' _s H 2 5 3 7 R CH_ R ' C.H ,, R ' ss H 3 5 11 R s C_H _r R ' - C.H. R ' - H 2 5 4 9 R = C „R., R ' s C "H" R ' - H 3 7. 3 7 R C „H _c R ' SS C _c H ,, R ' = H 2. 5 5 11 R = C.H „ R ' ss C, H. R ' . = H 4 9. 4 9 R = C.H., R ' s C.H ,, R ' H 5 11 · 5 11

Example 5

The analgesic effect of the compounds of the present invention may be evaluated using the hot plate test and the phenol quinone stretch test in mice.

'. A. Hot plate

Analgesic action was tested according to the method of Woolfe and MacDonald (J., Pharmacol. Exp. Ther. 80, 300, 1944), Eddy et al. (J. Pharmacol.

Exp. Ther. 98, 121, 1950) and Janssen and Jagenean (J. Pharm. Pharmacol.

9, 381, 1957), with modifications.

1. Hot plate equipment, Cat. 7250 is from Ugo Basile (Cornerio Varese - Italy)

The aluminum plate is electrically heated through an element that provides heat to the entire test surface. The temperature controller records the temperature of the board and controls the supply voltage to avoid overheating. The potentiometer allows the desired temperature to be set within the range of 45-62 ° C (± 0.2 ° C).

2. Induction of discomfort ·.

. Place one mouse on a plate heated to 55 ± 0.2 ° C. To keep the animal on the test surface, a transparent plexiglass cylinder 1.9 cm in diameter and 13 cm in height is used. The animal po10 indicates that it is uncomfortable in one of the following ways (Eddy 1 et al., J. Pharmacol. Exp. Ther. 98, 121, 1950):

- kicking with the hind legs (S),

- baldness by circumference of the cylinder (D), _ή

- 1 lap hind limb (L) swirled,

- raising one of the hind paws and keeping it close to the body (A); this last reaction is usually shown when the analgesic action of the drug begins to weaken,

- jumping and trying to jump out of cylinder (J).

3. Measurement of reaction time. '·

The reaction time is measured using a split split electronic stopwatch - ·. of 0.1 sec, starting with the foot switch. Stopwatch starts t

the moment the mouse is placed on the board and stops when the animal shows one of the above reactions. Immediately after the reaction, the animal is removed from the hot plate and time in seconds is recorded in the rubric for time, while the reaction type is recorded in the corresponding rubric by the symbol (S; D; L; A; J) (see section 2).

4. Measurement times

- Basic measurement: two measurements are made 20 or 10 minutes before treatment. The mean of these two measurements is Normal t

reaction time (Janssen and Jagenean, J. Pharm. Pharmacol., 9, 381, 1957).

- Post-treatment measurements: performed at 10-20-30-40-50-60-90-120 minutes after treatment.

- Length of measurement: the maximum observation time should not exceed 30 seconds to avoid any lesions on the paws of animals.

After this time, if no reaction occurs, the animal is removed from the plate and the reaction time is recorded as> 30; the number 30 is used in the calculation (Eddy and Leimbach, J. Pharm. Exp. Ther. 107, 385, 1953).

/ - ^lL—

5. Positive reactions

This parameter represents the end point for calculating Εϋ ^ θ and is defined as follows (Janssen and Jegenean, J. Pharm.Pharmacol., £, 381, 1957): the reaction is considered positive when the reaction time is at least once> 30, or when in at least 3 readings the reaction time is three times longer than the normal reaction time.

JI Γ

6. Experimental groups and treatments

Groups of two animals are formed for each product and each dose, up to a maximum of 14 mice. Treatment is generally performed by intraperitoneal or subcutaneous administration.

B. Phenolquinone stretch test. ai '· j - <.

The test is performed on mice, according to the method of Henderson and Forsaith (J. Pharmacol. Exp. Ther. 125, 237, 1959), with modifications and

- Algogenic agent: 0..08Z (20 mg / 25 ml) of phenylquinone (2-phenyl-1,4-benzoquinone) suspended in corn germ oil according to Loux, Smith and Salem (Arzneim, Forsch. 28, 1644, 1978). 7> f. .

- Experimental groups and administration of phenylquinone: Experimental groups of 4 mice (20-30 g) are formed, with each animal being labeled with picric acid (saturated solution in alcohol). All animals in each group were treated intraperitoneally with phenylquinone (10 ml / kg for each animal weighing more than 25 g and ??? 0.25 ml for each animal weighing less than 25 g), placed in a transparent plastic cage (23.5 x 13.7 x 13.1 cm ) and the experimenter! they are observed for 20 minutes after administration of phenylquinone.

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Stretches are classified as follows:

- full stretching = contraction of the abdomen, periodic twisting of the torso, stretching of the hind legs;

- half stretching = abdominal contraction and a few twist of the torso.

Every two half stretches are registered as one complete.

- Treatments: Products are given orally (axis) or subcutaneously (sc) for 30 or 20 minutes before phenylquinone. Three animals from each group are treated with different products and the fourth one is treated with a carrier only.

The effects of the compounds of Example 3 and reference drugs on the reaction of mice in hot plate and phenylquinone assays are given in the following Table.

-? 2 TABLE

Product i 1 1 1 1 1 Dose] mg / kg j— 1 l 1 1 1 Phenyl quinone Hot plate Number mice Z Stretching inhibitions Number mice With the rise time latencies 1 1 1 25 os J 14 22 ___ Compound] from example] 50 os J 24 23 (1) - - ³ i 100 os] 24 38 (2) - '- 400 os j - - 8 0 Acetyl { 1 30 os { 11 ·· 0 salicylic J acid j 60 os j 1 13 '25 (1) - - 1 120 os] 11 43 (2) -. . 1 240 os] 1 13 56 (2) * · 8 0 1 1 1 I 0.5 sc] ' 9 52 (2) 8 .42 (1) Morphine] 1 sc J 1 10 89 (2) 8 94 (2) Bendazac ^] 1 1 100 os j 11 5 - 200 os j -1_ - - 8 0

Statistical value compared to control (Student's t-test and graph splitting method): (1) p 0.05; (2) p 0.01 = not tested.

1¾

Claims (16)

PATENT APPLICATIONS A compound having the formula: A-CH ₂ -O-CRR'-COOR '"(I) in which A represents a 1-benzyl-indazol-3-yl nucleus; R and R 'may be the same or different and represent hydrogen or C _1-5 alkyl; R '' is hydrogen or a residue of an aliphatic saturated alcohol having from 1 to 4 carbon atoms and, when R '' represents hydrogen, salts thereof with pharmaceutically acceptable bases. Compound of formula (I) according to claim 1, characterized in that both, R and R 'are methyl and R' 'is hydrogen. 3. A process for the preparation of a compound of the formula: A-CH ₂ -O-CRR'-COOR '' (I) in which A represents a 1-benzyl-indazol-3-yl nucleus; R and R 'may be the same or different and represent hydrogen or C _1-5 alkyl; R '' is hydrogen or a residue of an aliphatic saturated alcohol having from 1 to 4 carbon atoms; and, when R '' represents hydrogen, salts thereof with pharmaceutically acceptable bases, characterized in that it comprises the reaction of a compound of formula: A-CH-Y (Ila) wherein A is as defined above and Y is hydroxy, with an alkali metal or a corresponding derivative thereof, to give an alcoholate of the formula: A-CH ₂ -OMe (Ilb) wherein A is as defined above and Me is an alkali metal atom, and then a compound of formula (Ilb) is reacted with a compound of formula: X-CRR'-COOR '(lilac) where R and R' are as defined above, X is a leaving group selected from halogens and radicals of the formula Z-SO ₂ -O-, where Z is aryl or alkyl and R " represents C ₁₅ alkyl to give an ether of the formula: A-CH - O-CRR'-COOR '(la) in which A, R, R' and R 'have the meanings as defined above; or that it comprises the reaction of a compound of the formula: A-CH ₂ -X (Ilc) wherein A and X are as defined above with an alcoholate of the formula: MeO-CRR'-COOR '(Hib) where R, R', R 'and Me have the meanings as defined above to give the ether of formula (Ia); or that it comprises reacting a compound of formula (Ila) with ketone and chlorophyll in the presence of an alkali metal hydroxide according to the formula: A-CH ₂ -Y + CHC1 ₃ + R-CO-R'-► A-Ctt, -O-CRR'-COOH (Ila) (I) where A and Y are as defined above and R and R can be 'are the same or different and represent C _1-5 alkyl and, if necessary, hydrolyzed the ester of formula (Ia) to give the corresponding acid of formula (I); and to obtain, if necessary, an acid salt of formula (I) with a pharmaceutically acceptable base, or an ester of said acid of formula (I) with a saturated aliphatic alcohol having from 1 to 4 carbon atoms. Process according to claim 3, characterized in that the reaction phase of the compound of formula (Ila) with an alkali metal and then the compound of formula (Ilb) with the compound of formula (lila) or the reaction phase of the compound of formula (Ilc) with the compound s formula (Illb) is carried out in the presence of a suitable solvent, at room temperature to the boiling point of the reaction mixture, for a period of 15 minutes to 48 hours. 5. A process according to claim 4, wherein the solvent is aprotic. A process according to claim 4, characterized in that the solvent is selected from the group consisting of tetrahydrofuran, dimethylformamide, toluene and mixtures thereof. Ί. Process according to any one of claims 3 to 6, characterized in that the alcoholates of formulas (Ilb) and (Illb) are obtained from metallic sodium, metallic potassium or sodium hydride, in the presence of a suitable solvent, at room temperature to the boiling point of the reaction mixture , over a period of 15 minutes to 48 hours. Process according to claim 7, characterized in that the solvent is aprotic in nature. Process according to claim 7, characterized in that the solvent is selected from the group consisting of tetrahydrofuran, dimethylformamide, toluene and mixtures thereof. A process according to any one of claims 3 to 9, characterized in that X represents chlorine, bromine or a group, Z-SO ₂ -O-, wherein Z represents p-methylphenyl, phenyl or methyl. Process according to claim 3, characterized in that the reaction phase of the compound of formula (Ila) with ketone and chlorophyll is carried out at the boiling point of the reaction mixture for a period of 30 minutes to 12 hours. Process according to any one of claims 3 to 11, characterized in that the hydrolysis phase of the compound of formula (Ia) is carried out in an aqueous or aqueous / alcoholic solution of the base, at room temperature to the boiling point of the reaction mixture, for a period from 1 to 48 ur. 13. A pharmaceutical composition comprising an effective amount of a compound of the formula: A-CH ₂ -O-CRR'-COOR '"(I) in which A represents a 1-benzyl-indazol-3-yl nucleus; R and R 'may be the same or different and represent hydrogen or C ₁₅ alkyl; R '' is hydrogen or a residue of an aliphatic saturated alcohol having from 1 to 4 carbon atoms, or, when R '' is hydrogen, salts thereof with a pharmaceutically acceptable base; together with a pharmaceutically acceptable excipient. 14. An intermediate compound having the formula: A — CH ₂ —W (II) in which A represents a 1-benzyl-indazol-3-yl nucleus and W is OH, OMe, where Me is an alkali metal atom, or a leaving group selected from halogens and radicals of formula Z— SO _{2 is} —O—, where Z is aryl or alkyl. An intermediate compound according to claim 14, characterized in that the leaving group represents chloro, bromo or Z-SO ₂ -O-, wherein Z is methyl, phenyl or p-methylphenyl. A process for the preparation of an intermediate compound of formula (II) according to claim 14 or 15, characterized in that a compound of formula (II) in which W represents hydroxy is obtained by reduction of an acid of formula: A-COOH (IV) in which A is as defined above, or an aliphatic ester thereof, with a reducing agent selected from lithium aluminum hydride, sodium bis (2methoxyethoxy) aluminum hydride (70% in toluene) or calcium tetra (isopropoxy) - alanate (70% in toluene), in the presence of a suitable solvent, at a temperature from 0 ° C to the boiling point of the reaction mixture, for a period of 30 minutes to 12 hours. Process according to claim 16, characterized in that the solvent is selected from the group consisting of diethyl ether, tetrahydrofuran, toluene and mixtures thereof.