LT5282B - Intermediates in producing phenoxyacetic acid derivatives and method of using the same - Google Patents

Abstract

The present invention provides novel intermediates represented by general formula (I) etc. for preparing a phenoxyacetic acid derivative represented by general formula (X) or a pharmaceutically acceptable salt thereof, which has beta-3-adrenoceptor stimulating activity and are useful for treating or preventing obesity, hyperglycemia, diseases caused by intestinal hypermotility, pollakiuria, urinary incontinence, depression or biliary calculus. The present invention also provides a process for preparing said intermediates and a method of using said intermediates.

Description

The inventors have intensively investigated a novel intermediate which can be converted into a phenoxyacetic acid derivative of the general formula (X) or a pharmaceutically acceptable salt thereof in a suitable and high yield, and discovered that the phenoxyacetic acid derivative (X) can be obtained in very high yield from a new hemiacetal compound. expressed by the general formula (I). In addition, the inventors have discovered a method for preparing the hemiacetal compound (I) from 2,5-xylene in convenient ways. Based on these discoveries, the present invention was made.

Thus, the present invention provides:

(1) A compound represented by the general formula (I):

wherein each of R ¹ and R ^{2 is} independently lower alkyl;

(2) a compound according to the above (1), wherein R ¹ and R ² are ethyl;

(3) of the compound represented by the general formula (I):

wherein each of R ¹ and R ^{2 is} independently a lower alkyl group, the process comprising the steps of:

(a) Compound of Formula (II):

R ³ Q (ii) Exposure to a compound represented by the general formula (III)

-CHO

R ³ O '

(III) wherein R ³ is a lower alkyl group to give a compound represented by the general formula (IV):

wherein R ³ is as defined above;

(b) the effect of said compound represented by the general formula (IV) with the compound represented by the general formula (V):

ZCH ² CO ² R ¹ (V) wherein Z is a chlorine, bromine or iodine atom and R ¹ is as defined

wherein R ¹ and R ² are as defined above;

(c) reducing said compound represented by general formula (VI) to obtain a compound represented by general formula (VII):

(VII) wherein R ¹ and R ³ are as defined above;

(d) hydrolyzing said compound of general formula (VII) to obtain a compound of general formula (VIII):

wherein R ¹ is as defined above; and (e) reacting said compound of general formula (VIII) with R ² -OH wherein R ² is as defined above;

(4) the method according to the above (3), wherein R ¹ and R ² are ethyl and R ³ is methyl;

(5) a compound represented by the general formula (IV):

(IV) wherein R ³ is lower alkyl;

(6) a compound according to the above (5), wherein R ³ is a methyl group;

(7) compound represented by the general formula (VI):

(VI) wherein each of R ¹ and R ^{3 is} independently lower alkyl;

(8) a compound represented by the general formula (VII):

wherein each of R ¹ and R ^{3 is} independently lower alkyl;

(9) a compound according to (7) or (8) above, wherein R ¹ is ethyl and R ³ is methyl;

(10) a compound represented by the general formula (VIII):

(VII)

(VIII) wherein R ¹ is lower alkyl;

(11) The compound of claim 10, wherein R ¹ is ethyl;

(12) a compound represented by the general formula (X):

(X) wherein R ¹ is a lower alkyl group, or a pharmaceutically acceptable salt thereof, which process comprises the preparation of a compound represented by the general formula (I):

wherein R ¹ is as defined above and R ² is a lower alkyl group, by the action of the compound represented by formula (IX):

a step, in the presence of a reducing agent, and optionally forming a pharmaceutically acceptable salt of said compound (X);

(13) A process according to the above (12), wherein R ¹ and R ² are ethyl.

In the present invention, the term "lower alkyl group" means a straight or branched chain alkyl group containing from 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and the like.

BEST MODE FOR CARRYING OUT THE INVENTION

The compound of the present invention represented by the general formula (I) may be obtained in steps (a) to (e) as depicted in the following scheme:

wherein R ¹ , R ² , R ³ and Z are as defined above.

(Tier a)

The phenol derivative represented by the general formula (IV) may be obtained by the action of 2,5-xylenol represented by the formula (II), a compound represented by the general formula (III) in the presence of an aqueous alkali metal hydroxide such as aqueous sodium hydroxide. The amount of compound (III) and alkali metal hydroxide used ranges from about 1 to about 3 molar equivalents on average, based on 1 mol of 2,5-xylene (II). The reaction is carried out on average at about 10 to about 70 ° C for a period of from 1 to 10 hours. After the completion of the reaction, the reaction solution is neutralized with dilute acid such as dilute hydrochloric acid. The precipitated crystals are then filtered and dried to give the phenol derivative of general formula (IV).

(Step b)

The phenol derivative (IV) is treated with a haloacetic acid ester of the general formula (V) in the presence of a base in an inert solvent to give the compound represented by the general formula (VI). Inert solvents used in the reaction include ethers such as tetrahydrofuran or the like, ketones such as acetone, methyl ethyl ketone or the like, acetonitrile, N, N-dimethylformamide, Ν, Ν-dimethylacetamide or the like. Solvents can be used singly or as a mixture of two or more solvents. The base used in the reaction includes sodium carbonate, potassium carbonate, cesium carbonate and the like. Haloacetic acid ester (V) includes CICH2CO2R ^1, BrCH2, CO 2 R ¹ or R ₂ ICH2CO ^first The amount of haloacetic acid (V) and base used is on average from about 1 to about 5 molar equivalents based on 1 mol of phenolic derivative (IV). The haloacetic acid ester (V) and base are used in equimolar proportions on average, but any of these can be used in excess. The reaction is carried out on average at about 0 to about 100 ° C for a period of from 1 to 24 hours. Upon completion of the reaction, extraction of the reaction mixture and subsequent concentration in a conventional manner affords the compound of general formula (VI).

(Step c)

Reduction of compound (VI) using a reducing agent in an inert solvent enables the acetal derivative of general formula (VII) to be obtained. Inert solvents used in the reaction include ethers such as tetrahydrofuran, 1,2-dimethoxyethane, dioxane or the like, organic carboxylic acid esters such as ethyl acetate or the like, acetonitrile or the like. Solvents can be used singly or as a mixture of two or more solvents. Reducers used in the reaction include sodium iodide / trialkylchlorosilane such as chlorthrimethylsilane, chlorthriethylsilane, t-butyldimethylchlorosilane, or the like, which are used in an amount ranging from about 2 to about 6 molar equivalents on average per mole of compound (VI). The reaction is run on average from about -30 to about

30 ° C for 10 minutes to 12 hours. Upon completion of the reaction, the reaction mixture is extracted and then concentrated in a conventional manner to afford the acetal derivative of general formula (VII).

(Step d)

Hydrolysis of the acetal derivative (VII) using an acid in a suitable solvent affords the aldehyde derivative represented by the general formula (VIII). The solvent used in the hydrolysis reaction includes ethers such as tetrahydrofuran,

1,2-dimethoxyethane, dioxane or the like, ketones such as acetone or the like, acetonitrile or the like. Solvents can be used singly or as a mixture of two or more solvents. Solvents can also be used in combination with water. The acid used in the reaction comprises 5-20% perchloric acid 1-10% hydrochloric acid 1-10% sulfuric acid ptoluenesulfonic acid trifluoroacetic acid, or the like, in an amount ranging from about 0.1 to about 2.5 molar equivalents on average per mol. acetal derivative (VII). The hydrolysis reaction is carried out at an average temperature of about 0 to about 50 ° C for a period of from 0.5 to 24 hours. Upon completion of the reaction, extraction of the reaction mixture and subsequent concentration in the usual manner affords the aldehyde derivative (VIII).

(Tier e)

The hemiacetal derivative of the present invention represented by the general formula (I) may be obtained by reacting the aldehyde (VIII) with R ² OH, optionally in the presence of an acid such as acetic acid or the like. The additional reaction of R ² OH to the aldehyde derivative (VIII) proceeds rapidly and subsequent crystallization from a suitable solvent enables the hemiacetal derivative of general formula (I) to be obtained. The amount of R ² OH used ranges, on average, from about 1 to about 10 molar equivalents, based on 1 mol of aldehyde (VIII). In the case where an acid is used, the amount of acid used ranges on average from about 0.01 to about 0.1 molar equivalents based on 1 mol of aldehyde (VIII). Crystallization solvents include a mixed solvent of R ² OH in combination with n-hexane, n-heptane, cyclohexane or the like. The hemiacetal derivative (I) has good crystalline properties and can be stored under certain conditions such as below 10 ° C for a long period. Accordingly, hemiacetal is suitable for commercial production.

The process for preparing a phenoxyacetic acid derivative of the general formula (X) which is suitable for use as a medicament using the hemiacetal derivative of the general formula (I) is detailed in the following scheme:

(ix) wherein R ¹ and R ² are as defined above.

The phenoxyacetic acid derivative represented by the general formula (X) may be obtained by the action of a hemiacetal derivative of the general formula (I) on an amine of the formula (IX) in the presence of a reducing agent in an inert solvent. Inert solvents used in the reaction include ethers such as tetrahydrofuran, 1,2-dimethoxyethane, dioxane or the like, halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane or the like, organic carboxylic acids such as acetic acid or the like, hydrocarbons such as toluene. or the like, alcohols such as methanol, ethanol or the like, acetonitrile or the like. Solvents can be used singly or as a mixture of two or more solvents. Reducers used in the reaction include alkali metal hydroboranes such as NaBFU, NaBH ₃ CN, NaBH (OAc) ₃ , NaBH (0Me) 3 or the like, boranes such as BH ₃ · pyridine, BH ₃ · Ν, Ν-diethylaniline or the like. If necessary, these reducing agents may be used optionally in the presence of an acid such as acetic acid, p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid, hydrochloric acid, or a base such as triethylamine or the like. Alternatively, the reaction may be carried out in a hydrogen atmosphere in the presence of a metal catalyst such as 5-10% palladium on carbon, Raney-Ni, platinum oxide, palladium on carbon, 10% platinum on carbon (sulfide) or the like. In the case of alkali metal hydroboranes or boranes as reducing agents, the amount of such reducing agent used will on average vary from about 0.5 to about 5 molar equivalents based on 1 mol of the hemiacetal derivative (I). The reaction is carried out at an average temperature of about 0 to about 60 ° C for a period of from 1 to 48 hours. After completion of the reaction, insoluble materials, if required, are filtered off and the reaction mixture is extracted and then concentrated in a conventional manner to afford the phenoxyacetic acid derivative of general formula (X). Alternatively, the reaction may be carried out by reacting the amine (IX) with an aldehyde of general formula (VIII) instead of the hemiacetal derivative (I).

The phenoxyacetic acid derivative (X) can optionally be converted into its pharmaceutically acceptable acid addition salt by conventional means. Examples of such salts include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid and the like; acid addition salts with organic acids such as formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, malic acid, acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid and the like.

The amine represented by formula (IX) may be obtained by optional separation of a commercially available mixture of amino enantiomers by conventional means. Alternatively, the amine (IX) can be obtained by the methods described in “J. Med. Chem. 1997, 20 (7), p. 978-981 ".

The compound of the present invention represented by the general formula (I), its intermediates (IV), (VI), (VII) and (VIII) as well as the phenoxyacetic acid derivative of the general formula (X) can be optionally isolated or purified, by standard isolation or purification techniques such as solvent extraction, recrystallization, chromatography, and the like.

EXAMPLES

The following examples illustrate the invention in more detail. However, this does not mean that they are intended to limit the scope of the present invention.

EXAMPLE

4- (1-hydroxy-2,2-dimethoxyethyl) -2,5-dimethylphenol

A suspension of 5.2% sodium hydroxide (630g), 2,5-xylene xenol (100g) in water, 60% glyoxal dimethylacetal (213g) in water and water (200g) was heated at 55 ° C for 5 hours with stirring. The reaction mixture was cooled in an ice bath and acetanitrile (90g) and 7.4% hydrochloric acid (380g) were added successively. The precipitated crystals were filtered to give 4- (1-hydroxy-2,2-dimethoxyethyl) -2,5-dimethylphenol (150 g). ¹ H-NMR (DMSOd ₆ ) δ min. d: 2.06 (3H, s), 2.15 (3H, s), 3.08 (3H, s), 3.35 (3H, s), 4.23 (1H, d, J = 6) , 7Hz), 4.55 (1H, dd, J = 6.7, 4.4Hz), 4.96 (1H, d, J = 4.4Hz), 6.49 (1H, s), 7.03 (1H, s), 8.96 (1H, s).

EXAMPLE

Ethyl 2- [4- (1-hydroxy-2,2-dimethoxyethyl) -2,5-dimethyl-phenoxy] acetate

4- (1-Hydroxy-2,2-dimethoxyethyl) -2,5-dimethylphenol (20, Og), potassium carbonate (15.8g), and ethyl chloroacetate ( 12.4g). The mixture was stirred at room temperature for 1 hour and then stirred at 71 ° C for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure and a mixture of ethyl acetate and hexane was added to the residue. The precipitated crystals were collected by filtration to give ethyl 2- [4- (1-hydroxy-2,2-dimethoxyethyl) -2,5-dimethylphenoxy] acetate (21.3 g).

¹ H-NMR (CDCl ₃ ) δ min. d: 1.28 (3H, t, J = 7.1Hz), 2.26 (3H, s), 2.32 (3H, s), 2.54 (1H, d, J = 2.3Hz) , 3.22 (3H, s), 3.50 (3H, s), 4.27 (2H, q, J = 7.1Hz), 4.32 (1H, d, J = 6.6Hz), 4 , 61 (2H, s), 4.80 (1H, dd, J = 6.6, 2.3Hz), 6.48 (1H, s), 7.25 (1H, s).

EXAMPLE

Ethyl 2- [4- (2,2-dimethoxyethyl) -2,5-dimethylphenoxy] acetate

Ethyl 2- [4- (1-hydroxy-2,2-dimethoxyethyl) -2,5-dimethylphenoxy] acetate (50g) acetonitrile was added dropwise to a stirred suspension of sodium iodide (72g) and chlorotrimethisilane (52g) in acetonitrile (180g). 80g) in an ice-salt bath solution. The mixture was stirred for 30 minutes and then toluene (400g) and pyridine (25g) were added. The reaction mixture was washed successively with aqueous sodium thiosulfate solution, aqueous citric acid solution, aqueous sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give ethyl 2- [4- (2,2-dimethoxyethyl) -2,5-dimethylphenoxy] acetate (43g).

¹ H-NMR (CDCl ₃ ) δ min. d: 1.30 (3H, t, J = 7.1Hz), 2.24 (3H, s), 2.27 (3H, s), 2.82 (2H, d, J = 5.6Hz) , 3.33 (6H, s), 4.27 (2H, q, J = 7.1Hz), 4.47 (1H, t, J = 5.6Hz), 4.60 (2H, s), 6 , 50 (1H, s), 6.97 (1H, s).

EXAMPLE

Ethyl 2- [4- (2-formylmethyl) -2,5-dimethylphenoxy] acetate

Ethyl 2- [4- (2,2-dimethoxyethyl) -2,5-dimethylphenoxy] acetate (23.7g) was dissolved in acetonitrile (110g) with stirring and 10% perchloric acid (120g) was added and the mixture was stirred for one hour. at room temperature. The reaction mixture was partitioned between toluene (190g) and water (120g). The organic layer was washed successively with water, aqueous sodium bicarbonate solution and brine, and dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. After dissolving the precipitate in ethanol (96g), the solvent was removed under reduced pressure. The residue was redissolved in ethanol (96g) and removal of the solvent under reduced pressure gave ethyl 2- [4- (2-formylmethyl) -2,5-dimethylphenoxy] acetate (20.8g).

¹ H-NMR (CDCl ₃ )? Ppm: 1.30 (3H, t, J = 7.1Hz), 2.20 (3H, s), 2.25 (3H, s), 3.59 (2H, d, J = 2.4Hz), 4.27 (2H, q, J = 7.1Hz), 4.62 (2H, s), 6.56 (1H, s), 6.94 (1H , s), 9.66 (1H, t, J = 2.4Hz).

EXAMPLE

Ethyl 2- [4- (2-ethoxy-2-hydroxyethyl) -2,5-dimethylphenoxy] acetate

Ethyl 2- [4- (2,2-dimethoxyethyl) -2,5-dimethylphenoxy] acetate (43g) was dissolved in acetonitrile (190g) with stirring. To the resulting solution was added 10% perchloric acid (216g) and the mixture was stirred for one hour at room temperature. The reaction mixture was partitioned between toluene (340g) and water. (200g). The organic layer was washed successively with water, aqueous sodium bicarbonate solution and brine, and dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The precipitate was dissolved in ethanol (180g) and the solvent was removed under reduced pressure. The precipitate was dissolved with hexane (86g) and ethanol (37g). After the addition of crystallizers, the solution was stirred at 0 - 10 ° C for 2 hours. Hexane (220g) was added and the resulting suspension was stirred at 0-10 ° C for 2 hours. The precipitated crystals were filtered to give ethyl 2- [4- (2-ethoxy2-hydroxyethyl) -2,5-dimethylphenoxy] acetate (21 g).

¹ H-NMR (DMSO-d _e) 6 min. d: 1.06 (3H, t, J = 7.0Hz), 1.21 (3H, t, J = 7.1Hz), 2.11 (3H, s), 2.19 (3H, s) , 2.50-2.80 (2H, m), 3.20-3.40 (1H, m),

3.60-3.70 (1H, m), 4.16 (2H, q, J = 7.1Hz), 4.50-4.70 (1H, m), 4.73 (2H, s),

5.98 (1H, d, J = 7.6Hz), 6.59 (1H, s), 6.93 (1H, s).

EXAMPLE

Ethyl (-) - 2- [4- [2 - [[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] -2,5-dimethylphenoxy] acetate

Ethyl 2- [4- (2-ethoxy-2-hydroxyethyl) -2,5-dimethylphenoxy] acetate (5.4g), 10% Palladium Carbon (50% Humidity, 1.4g), (1R, 2S) - A suspension of 2-amino-1- (4-hydroxyphenyl) propan-1-ol (3.0g) and tetrahydrofuran (30g) was stirred under a hydrogen atmosphere at 40 ° C for 3 hours. After the catalyst was removed by filtration, the filtrate was concentrated under reduced pressure. The precipitate was dissolved in toluene and washed successively with water, aqueous sodium bicarbonate, and brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give ethyl (-) - 2- [4- [2 - [[(1S, 2R) -2-hydroxy-2- (4-hydroxy-phenyl)]. -1-methylethyl] amino] ethyl] -2,5-dimethylphenoxy] acetate (7.3 g).

¹ H-NMR (CDCl ₃ ) 6 min. d: 0.98 (3H, d, J = 6.4Hz), 1.34 (3H, t, J = 7.1Hz),

2.18 (3H, s), 2.22 (3H, s), 2.60 - 3.00 (5H, m), 4.31 (2H, q, J = 7.1Hz), 4.49 ( 1H, d, J = 5.6Hz), 4.62 (2H, s), 6.41 (1H, s), 6.69 (2H, d, J = 8.5Hz), 6.78 (1H, s), 7.05 (2H, d, J = 8.5Hz).

EXAMPLE

Ethyl (-) - 2- [4- [2 - [[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethylamino] ethyl] -2,5-dimethylphenoxy] acetate hydrochloride

Ethyl 2- [4- (2-ethoxy-2-hydroxyethyl) -2,5-dimethylphenoxy] acetate (68.7 g),

A suspension of 10% palladium-carbon (50% humidity, 17g), (1R, 2S) -2-amino-1- (4-hydroxyphenyl) propan-1-ol (38.0 g) and tetrahydrofuran (380g) was stirred under a hydrogen atmosphere at 40 ° C. ° C for 5 hours. After removal of the catalyst by filtration, the filtrate was concentrated under reduced pressure. The precipitate was dissolved in toluene and washed successively with water, aqueous sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The precipitate was dissolved in toluene (200g) and ethanol (21g) and added dropwise to 20% w / w hydrogen chloride in ethanol (37.3g). The precipitated crystals were filtered to give ethyl (-) - 2- [4- [2 - [[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] -2. 5-dimethylphenoxy] acetate hydrochloride (70.2 g).

¹ H-NMR (DMSO-d ₆ ) δ million. d: 0.96 (3H, d, J = 6.6Hz), 1.21 (3H, t,

J = 7.1 Hz), 2.15 (3H, s), 2.25 (3H, s), 2.8 - 3.2 (4H, m), 4.16 (2H, q, J = 7 , 1Hz),

4.76 (2H, s), 4.9-5.1 (1H, m), 5.8-6.0 (1H, m), 6.68 (1H, s), 6.76 (2H, d, J = 8.5Hz), 6.96 (1H, s), 7.17 (2H, d, J = 8.5Hz), 8.5-9.0 (2H, br), 9.41 (1H, s) ..

INDUSTRIAL ADAPTATION

The commercially useful 2,5-xylenol via the hemiacetal derivative represented by the general formula (I) of the present invention can, in conventional manner, provide a high-purity phenoxyacetic acid derivative of the general formula (X) or a pharmaceutically acceptable salt thereof. Thus, said hemiacetal derivative (I) is useful as an intermediate in the manufacture of a medicament for the treatment or prevention of obesity, hyperglycemia, diseases caused by intestinal hyperkinesia, polycuria, urinary incontinence, depression or gallstones.

Claims (13)

DEFINITION 1. A compound represented by the general formula (I): wherein each of R ¹ and R ^{2 is} independently lower alkyl. 2. A compound according to claim 1, characterized in that R ¹ and R ² is an ethyl group. 3. Compound represented by the general formula (I): wherein each R ¹ and R ^{2 is} independently a lower alkyl group, the process comprising the steps of: (a) Compound of Formula (II): (II) R ³ O, the effect of the compound represented by the general formula (III): -CHO (III) R ³ O 'wherein R ³ is a lower alkyl group to give a compound represented by the general formula (IV): , 3 / V ° ^H OH (IV) wherein R ³ is as defined above; (b) the effect of said compound represented by the general formula (IV) with the compound represented by the general formula (V): ZCH ₂ CO ₂ R ¹ (V) wherein Z is a chlorine, bromine or iodine atom and R ¹ is as defined above to give the compound represented by the general formula (VI): wherein R ¹ and R ³ are as defined above; (c) reducing said compound represented by general formula (VI) to obtain a compound represented by general formula (VII): wherein R ¹ and R ³ are as defined above; (d) hydrolyzing said compound of general formula (VII) to obtain a compound of general formula (VIII): wherein R ¹ is as defined above; and (e) reacting said compound represented by general formula (VIII) with R ² -OH wherein R ² is as defined above. 4. A process according to claim 3 wherein R ¹ and R ² are ethyl and R ³ is methyl. ⁵ 5. Compound represented by the general formula (IV): wherein R ³ is lower alkyl; 6. A compound according to claim 5 wherein R ³ is methyl. 7. Compound represented by the general formula (VI): .CL. CO ₂ R ¹ (VI) wherein each of R ¹ and R ^{3 is} independently lower alkyl. 8. Compound represented by the general formula (Vii): .CL. / C0 ₂ R ¹ (VII) wherein each of R ¹ and R ^{3 is} independently lower alkyl. 9. A compound according to claim 7 or 8 wherein R ¹ is ethyl and R ³ is methyl. 10. Compound represented by the general formula (VIII): OO ₂ R ¹ (VIII) wherein R ¹ is a lower alkyl group. 11.Junginys according to claim 10, characterized in that R ¹ is an ethyl group. 12. Compound of general formula (X): wherein R ¹ is a lower alkyl group, or a pharmaceutically acceptable salt thereof, characterized in that it comprises the steps of: a compound represented by the general formula (I): (f) wherein R ¹ is as defined above and R ² is a lower alkyl group represented by the formula (IX): HO OH NH ₂ (IX) in the presence of a reducing agent and then optionally forming a pharmaceutically acceptable salt of said compound (X). 13. The process of claim 12, wherein R ¹ and R ² are ethyl.