MXPA02005823A - Process for the preparation of arylethanolamine derivatives having an anti obesity and anti diabetic properties - Google Patents

Abstract

A process for the preparation of a compound of Formula (IA) or a pharmaceutically acceptable salt thereof:wherein R1 is an aryl, pyridyl, thiazolyl, phenoxymethyl, or pyrimidyl group, optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C1 6alkoxy, C1 6alkyl, hydroxymethyl, trifluoromethyl, NR6R6, and NHSO2R6, where each R6 is independently hydrogen or C1 4alkyl;R2 is hydrogen or C1 6alkyl;R3 is CO2R7 where R7 is hydrogen or C1 6alkyl;R4 and R5 are independently hydrogen, C1 6alkyl, or CO2C1 6alkyl;and Y is N or CH comprising the step of preparing a diamide of Formula (II) or a pharmaceutically acceptable salt thereof:wherein R1 is an aryl, pyridyl, thiazolyl, phenoxymethyl, or pyrimidyl group, optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C1 6alkoxy, C1 6alkyl, hydroxymethyl, trifluoromethyl, NR6R6, and NHSO2R6, where each R6 is independently hydrogen or C1 4alkyl;R2 is hydrogen or C1 6alkyl;R3 is CO2R7 where R7 is C1 6alkyl;R4 and R5 are independently hydrogen, C1 6alkyl, CO2C1 6alkyl;and Y is N or CH.

Description

PROCEDURE FOR THE PREPARATION OF ARILETANOLAMINE DERIVATIVES THAT HAVE ANTIOBESITY PROPERTIES AND ANTIDIABETICS FIELD OF THE INVENTION This invention relates to a method for the preparation of certain biaryl derivatives.

BACKGROUND OF THE INVENTION It is known that there are certain atypical beta-adrenoceptors in adipose tissue and the gastrointestinal tract. It has been found that atypical beta-adrenoceptor agonists are particularly useful as anti-obesity thermogenic agents and as antidiabetic agents. Compounds having atypical beta-adrenoceptor agonist activity have also been described as being useful in the treatment of hyperglycemia, as promoters of animal growth, as inhibitors of platelet aggregation in blood, as positive inotropic agents and as antiatherosclerotic agents. , and are useful in the treatment of glaucoma. A United Kingdom patent application filed on June 13, 1998 as GB 9812709.5 (and the international patent application) AÁá.! t? & í - »- Sa¿i ^ - ^ -. ^ > JA-aa ^ > i, corresponding gff WO99 / 65877), describes the compounds of the formula (I) and the pharmaceutically acceptable derivatives thereof: (wherein R1 is an aryl, pridyl, thiazolyl, phenoxymethyl or primidyl group, optionally substituted by one or more substituents selected from the group Which consists of halogen, hydroxy, C-i-β alkoxy, C 1-6 alkyl, nitro, cyano, hydroxymethyl, trifluoromethyl, -NR 6 R 6, and -NHSO 2 R 6, wherein each R 6 is independently hydrogen or C 1-4 alkyl; R2 is hydrogen or C? -6 alkyl, -X is oxygen, NH, or NC-C- alkyl; R3 is cyano, tetrazol-5-yl or CO2R7 wherein R7 is hydrogen or Ci-β alkyl; R4 and R5 are Independently of hydrogen, C1-6 alkyl, -CO2H, -CO2.alkyl of C? 6. > cyano, tetrazol-5-yl, halogen, trifluoromethyl or Ci-β alkoxy, or when R4 and R5 are bonded to adjacent carbon atoms, R4 and R5 can, together with the carbon atoms to which they are attached, form a 5- or 6-membered ring, which optionally contains one or two atoms of nitrogen, oxygen or sulfur; and Y is N or CH. : - .... - - j ^ '- • ífe .aaato¿te- i BRIEF DESCRIPTION OF THE INVENTION Briefly, in one aspect, the present invention provides a process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof: (IA) wherein R 1 is an aryl, pyridyl, thiazolyl, phenoxymethyl or pyrimidyl group, optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, Ci-β alkoxy, C 1-6 alkyl, hydroxymethyl, trifluoromethyl, - NR6R6, and -NHSO2R6, each R6 is independently Hydrogen or C 1-4 alkyl, is R 2 is hydrogen or C 1-6 alkyl; R3 is CO2R7 wherein R7 is hydrogen or Ci-β alkyl; R4 and R5 are independently hydrogen, C1-6alkyl-CO2- C6_6alkyl; and Y is N or CH which comprises the step of preparing a diamide of the formula (II) or a pharmaceutically acceptable salt thereof: (II) - "• W • 1? ?? .. ..Í. K? * Fít- _. ** -» *. «" Wherein R 1 is an aryl, pyridyl, thiazolyl, phenoxymethyl, or pyrimidyl group, optionally substituted by one or more substituents of the group consisting of halogen, hydroxy, C6-6 alkoxy, C6-6 alkyl) hydroxymethyl, trifluoromethyl, -NR6R6, and -NHSO2R6, wherein each R6 is independently hydrogen or CM alkyl; R2 is hydrogen or C alquilo .6alkyl; R3 is CO2R7 wherein R7 is C alquilo _6alkyl; R4 and R5 are independently hydrogen, C1.6alkyl -CO2C?-6, Ci alquilo alquiloalkyl, and Y is N or CH.

In an alternative aspect, the invention provides a process for the preparation of a compound of the formula (IA): (IA) in R 1 is an aryl, pyridyl, thiazolyl, phenoxymethyl, or pyrimidyl group, optionally substituted by one or more substituents of the group consisting of halogen, hydroxy, C 1-6 alkoxy, C 1-6 alkyl, hydroxymethyl, trifluoromethyl , -NR6R6, and -NHSO2R6, wherein each R6 is independently hydrogen or C-alkyl; R 2 is hydrogen or C 1-6 alkyl; R3 is CO2R7 wherein R7 is hydrogen or C-? 6 alkyl; R 4 and R 5 are independently hydrogen, C 1-6 alkyl-CO 2 C 1-6, C-t-β alkyl; and Y is N or CH; or a pharmaceutically acceptable salt thereof; comprising the reduction of a compound of the formula (II): (ll) wherein R 1 is an aryl, pyridyl, thiazolyl, phenoxymethyl, or pyrimidyl group, optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C 1-6 alkoxy, C 1 .6 alkyl hydroxymethyl , trifluoromethyl, -NR6R6, and -NHSO2R6, wherein each R6 is independently hydrogen or CM alkyl; R2 is hydrogen or C6.6 alkyl; R3 is CO2R7 wherein R7 is alkyl of d.6; R 4 and R 5 are independently hydrogen, C 1, 6 -CO 2 -C 6 alkyl, C 1 alkyl; and Y is N or CH, or a pharmaceutically acceptable salt thereof, and optionally the step of hydrolysis of the resulting ester group R7 in the formula (IA) to produce a compound of the formula (IA), wherein R7 is H.

Another aspect of the present invention provides a compound of the formula (II), wherein R 1 is an aryl, pyridyl, thiazolyl, methoxymethyl or pyrimidyl group, optionally substituted by one or more selected substituents of the group consisting of halogen, hydroxy, C1.6 alkoxy, C1-6 alkyl, hydroxymethyl, trifluoromethyl, -NR6R6, and -NHSO2R6, wherein each R6 is independently hydrogen or CM alkyl; R2 is hydrogen or alkyl of C? .6; R3 is CO2R7 wherein R7 is C6-6 alkyl; R4 and R5 are independently hydrogen, C1.6-CO2C1.6 alkyl, C6.6 alkyl; and Y is N or CH, or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION As used herein, the terms "alkyl" and "alkoxy" mean an alkyl group or straight or branched alkoxy group respectively, which contains the indicated number of carbon atoms. For example, alkyl of C-? -6 means a straight or branched alkyl containing at least 1, and at most 6 carbon atoms. As used herein, the term "aryl" means aromatic, monocyclic or bicyclic carbocyclic groups, such as phenyl and naphthyl. Preferably, R1 is phenoxymethyl or phenyl optionally substituted by 1, 2 or 3 substituents selected from halogen, hydroxy, C6.6 alkoxy > alkyl of C-i-β, hydroxymethyl and trifluoromethyl. More preferably, R1 is phenoxymethyl or phenyl substituted by a chlorine, fluorine or bromine atom, or a methyl or trifluoromethyl group, said atom or group is preferably located in the meta position. More preferably R1 is phenyl substituted by a chlorine atom which is located in the meta position. Preferably, R2 is hydrogen or methyl. More preferably R2 is hydrogen.

Preferably, R3 is attached to the metacarbon atom to the attached phenyl ring. In a compound of the formula (1A), R3 is preferably CO2H. In a compound of the formula (II) R3 is preferably CO2CH3. Preferably, at least one of R4 and R5 is hydrogen. More preferably, both R4 and R5 are hydrogen. Preferably Y is CH. Particularly preferred compounds, or process compounds, of the invention, include those in which each variable is selected from preferred groups for each variable. Even more preferred compounds of the invention include those wherein each variable is selected from the most preferred or most preferred groups for each variable. Reagents for the transformation of a compound of the formula (II) into a compound of the formula (I) include any reagent suitable for the reduction of amide-carbonyl bonds, for example the compounds of borane-ether, borane-sulfide, borane -amine and also borane-forming conditions in situ (e.g., sodium borohydride and iodine or sulfuric acid). Suitable solvents include hydrocarbons, for example toluene or ethers, for example tetrahydrofuran. The reaction can be conveniently carried out on a solid substrate, such as a bed or standard substrate that is used in the solid phase synthesis. For example, a compound of the formula (II) can be coupled to the solid substrate through the group R3, ie solid substrate of -CO2-.

To form a compound of the formula (1A) wherein R7 is hydrogen, the reduction step of a compound of the formula (II) must be followed by the hydrolysis of the resulting ester group R7. A compound of the formula (II) can be prepared by the reaction of a compound of the formula (III) with a compound of the formula (IV): (III) (IV) using any suitable method to form an amide bond, for example suitable coupling agents include diimide, for example diisopropylcarbodiimide, dicyclohexylcarbodiimide, or carbonyldiimidazole, hydroxytriazoles and equivalents, or chloroformates, while suitable solvents include esters, for example ethyl acetate, ethers , halogenated solvents, N-methylpyrrolidinone, acetonitrile or trifluorobenzene. As a further aspect of the present invention, there is provided a compound of the formula (IV) wherein R 2 is hydrogen or C 6 alkyl R 3 is CO2 R 7 wherein R 7 is C 1 6 alkyl; R4 and R5 are independently hydrogen, C1-6 alkyl, -CO2-C6-alkyl; and Y is N or CH, or a pharmaceutically acceptable salt thereof.

The compounds of the formula (III) are commercially available or can be prepared by standard methods, for example, as described in the examples herein. The compounds of the formula (IV) can be prepared from compounds of the formula (V): (V) using any suitable method to form an amide bond. For example, a compound of the formula (V) can be treated with a compound of the formula (VIII): (VIII) using standard coupling methods, for example, diimide coupling agents, for example diisopropylcarbodiimide, dicyclohexylcarbodiimide or carbonyldiimidazole with a suitable glycine compound, for example, N-Boc-glycine, in a suitable solvent such as esters, for example ethyl acetate , ethers or hydrocarbons. P2 is a standard protective group for a nitrogen, for example butoxycarbonyl.

* A * -kAau * * a ^ ..¿ ». ^ Áká, i ** ~. * .. .. .. ......, ._..... - ^ - i .a ^ j- ^ - J- -maSfe- ± A? Ú The compounds of the formula (V) can be prepared by the reaction of a compound of the formula (VI) with a compound of the formula (VII) according to Thompson's method, (J. Org. Chem. 1984. 49, 5237), (VI) (Vil) wherein Z is halogen or triflate, using suitable boronic acid coupling conditions, for example palladium on carbon and sodium carbonate or Pd (PPh3) 4 (tetrakis (triphenylphosphine) palladium (0)), followed by reduction of the nitro group using standard methods, for example under hydrogen using a suitable catalyst, such as palladium or carbon, in a suitable solvent such as an alcohol, tetrahydrofuran, DME, ethyl acetate, toluene, iso-octane, cyclohexane or water, or mixtures thereof, optionally at elevated temperature. The compounds of the formula (V) can also be conveniently prepared using a reaction of a two step crucible starting from the reaction of a compound of the formula (VI) with a compound of the formula (VII), under the conditions described above, that is, in the presence of a palladium on carbon catalyst, followed by reduction of the nitro group under hydrogen, using the reagents described above. Í? F. yes'if *. !fa*. HE HAS. iJ ^ jí ^^? mtjÉ? tl? a? + a ^ a &? k ** ^ * ... * ^! .- !!. *, ^. . The compounds of the formula (V) can also be prepared with the reaction of a compound of the formula (VII) with a compound of the formula (VII). formula (IX) using the standard boronic acid coupling methods described above.

(IX) EXAMPLES The invention is further illustrated by the following intermediates and examples. All temperatures are in degrees centigrade. The mass spectra (ms) were obtained using electroaspersion analysis (positive or negative ion). 3'-Methyl amino-1'-biphenin-3-carboxylate Method 1 A mixture of 3-nitrobenzanboronic acid (20 g), methyl 3-bromobenzoate (27 g), sodium carbonate (14 g) and 10% palladium on carbon (50% wet pulp, 1 g) in methanol (120 ml) was heated under reflux for 2 hours. The mixture was removed from reflux, diluted with isopropyl acetate (240 ml) and cooled to room temperature. The mixture is stirred under a hydrogen atmosphere until the uptake ceases, water (80 ml) is added and the suspension is filtered. The filtrate is separated and the organic phase is washed with salt water. The organic solution is concentrated by distillation to a low volume, treated with cyclohexane and filtered to yield the title compound as a light brown solid (24.5g). Mass spectrum M + H = 228 (electroaspersion).

Method 2 A mixture of 3-aminophenyl boronic acid emisulfate (0.5 g), methyl 3-bromobenzoate (0.61 g), sodium carbonate (0.57 g) and 10% palladium on carbon (50% wet paste, 30 mg) ), in methanol (5.4 ml) was heated under reflux for 14 hours. The mixture was extracted from the reflux, diluted with ethyl acetate (20ml) and filtered through a Celite pad, rinsed well with ethyl acetate. The filtrate was washed with water (10ml) and with saturated salt water (10ml). The organic phase was dried over sodium sulfate and concentrated in vacuo to yield the title compound as a dark oil, which solidifies slowly (0.58g). ie '•' * i < * Ji A-fa- * »i¿iÍ-ii-J ~» Aii-tÁaie .. - - - ^ * ?? L * .M *. - ^ - ^^ * < w i i. .- .. - ^. ^^, - á .. ^^ - «- ^ .. * < ^ r? i¿kM iiái 31-amino-1,11-biphenyl-3-carboxlate-methyl-hydrochloride A mixture of 3-nitrobenxenobenonic acid (20 g), methyl 3-bromobenzoate (27 g), sodium carbonate (14 g) and 10% palladium on carbon (50% wet paste, 1 g) in methanol (120 ml) was heated under reflux for 2 hours. The mixture was extracted from the reflux, diluted with isopropyl acetate (240ml) and cooled to room temperature. The mixture was stirred under a hydrogen atmosphere until the uptake ceased, water (80ml) was added and the suspension was filtered. The filtrate was separated and the organic phase was washed with salt water. The organic solution was concentrated by distillation and treated with anhydrous hydrochloric acid (prepared from acetyl chloride (19ml) and isopropanol (82ml) to yield the title compound as a white solid (29.5g). 31-r (amynoacetyl) aminoip. 11-biphenin-3-carboxlate-methyl chlorohydrate Method 1 A mixture of methyl 31-amino [1,1-biphenyl] -3-carboxlate (4.0g), N-tert-butoxycarbonylglycine (3.24g) and dicyclocarbodiimide (3.81 g) in ethyl acetate (48ml) was stirred at room temperature for 1 hour, cooled to 5 ° C and filtered. The solid was washed with ethyl acetate (8ml) and the combined organic layers were washed with aqueous sodium bicarbonate and then water. The organic solution was treated with concentrated hydrochloric acid (3.5ml), stirred overnight and the mixture was filtered to give the title compound as a white solid (4.4g). 1 H NMR (400MHz, DMSO) d ppm: 3.84 (broad s); 3.90 (s); 7.45 (ddd); 7.49 (dd); 7.66 (dd); 7.68 (ddd); 7.93 (ddd); 7.98 (ddd); 8.00 (dd); 8.17 (dd); 8.32 (broad peak); 10.97 (s).

Method 2 A mixture of 3-nitrobenxenobenonic acid (20g), methyl 3-bromobenzoate (27g), sodium carbonate (14g) and 10% palladium on carbon (50% wet pulp, 1g) in methanol (120ml) was heated under reflux for 2 hours. The mixture was extracted from reflux, and diluted with isopropyl acetate (240g) and cooled to room temperature. The mixture was stirred under a hydrogen atmosphere until the uptake ceased, water (80ml) was added and the suspension was filtered. The filtrate was separated and the organic phase was washed with salt water. The organic solution was concentrated by distillation at a low volume, cooled to room temperature and then treated sequentially with N-tert-butoxycarbonylglycine (21g) and 1,3-diisopropylcarbodimide (19ml) at less than 30 ° C. The mixture was stirred for one hour, filtered and the solid was washed with additional isopropyl acetate. The combined filtrates were washed with 2M aqueous sodium carbonate and then water. The organic solution was treated with concentrated hydrochloric acid (35ml), stirred overnight and the mixture was filtered to give the title compound as a white solid (33g). 31-rr (2S) -2- (3-chlorophenyl) -2-hydroxyethanoamino) acetyl) aminoirri. 11-biphenin-3-carboxylic acid methyl A suspension of 31 - [(aminoacetyl) amino] [1, Methyl 11-biphenyl] -3-carboxlate-hydrochloride (50g) in ethyl acetate (350g) is treated with 1M aqueous sodium carbonate (250ml) at room temperature. The lower aqueous phase is discarded, 1-hydroxybenzotriazole hydrate (10g) and then dicyclohexylcarbodiimide (30.6g) are added to the organic phase and the mixture is cooled to about 10 ° C. This mixture is treated with a solution of (R) -3-chloromandelic acid (5.8 g) in ethyl acetate (40 ml) for about 1 hour. The mixture is stirred for several hours and then filtered. The filtrate is washed with 6% w / w aqueous sodium bicarbonate and water, and the organic phase is concentrated at low volume. Isopropanol is added and the organic solution is further concentrated at low volume. The organic solution is heated to 70 ° C, treated with water, cooled to room temperature and the mixture is filtered to give the title compound (60g). Mass spectrum M + H = 453/455 (electrospray). 3'-r (2- (I (2R) -2- (3-chlorophenin-2-hydroxyethylamino) ethyl) aminoip. 1'-biphenip-3-carboxylate-methyl chloridrate Method 1 A solution of 3 '- [(2- {[[2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl) amino] [1,1' -biphenyl] Methyl -3-carboxylate (10 g) in tetrahydrofuran (40 ml) is heated to 40-60 ° C and treated with a solution of 1 M borane-tetrahydrofuran complex in tetrahydrofuran (51 ml) for 15 to 60 minutes . The mixture is heated at this temperature for about 2 hours, then treated with more than 1M of the borane-tetrahydrofuran complex in tetrahydrofuran (6.7 ml). After about 2 more hours, 1M of the borane-tetrahydrofuran complex in tetrahydrofuran (4.4 ml) is added. The reaction is stirred overnight at this temperature, and then methanol (13 ml) is added. A solution of hydrogen chloride (prepared from acetyl chloride (4.7 ml) and methanol (50 ml) is added to the mixture, and the resulting suspension is concentrated at low volume, diluted with ethyl acetate, cooled to 0-5 ° C and filtered to yield the title compound as a white solid (8.2 g).

Method 2 A suspension of 3 '- [( { [(2s) 2- (3-chlorophenyl) -2-hydroxyethanol] amino.} Acetyl) amino] [1,1'-biphenyl] -3- Methyl carboxylate (10 g) in toluene (44 ml) is heated to 100 ° C and treated with a solution of the complex . »? Uk **: j-jffiíftk áÉ? Á, & I of borane-dimethylsulfide (4.9 mf) for 60 to 120 minutes. The mixture is heated for an additional 1 to 4 hours, cooled and treated with ethanol (44 ml). Concentrated hydrochloric acid (5.6 ml) is added, the suspension is stirred for 2 to 20 hours and filtered to give the title compound as a white solid (6.6 g). Mass spectrum M + H = 425/427 (elctroasperción). 3'-r (2-W2R) -2- (3-chlorophenin-2-hydroxyethynamino) ethyl) amino1 [1,1'-biphenip-3-carboxylic acid hydrochloride A suspension of 3 '- [(2- { [(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino} ethyl) amino] [1, r-biphenyl] -3-carboxylic acid methyl ester (10 g) and methanol (67 ml) ) at 40-50 ° C is treated with 1.5N of aqueous sodium hydroxide (60 ml) and kept at this temperature for at least 1 hour. This solution is added to a solution of concentrated hydrochloric acid (10 ml) in water (20 ml) and methanol (33 ml) at 50 ° C. The resulting suspension is cooled to room temperature and filtered to give the title compound (8 g). Mass spectrum M + H = 411/413 (electroaspersion). H1 NMR (400MHz, DMSO) d ppm: 3.06 (dd); 3.17 (t); 3.25 (dd): 3.52 (t); 5.07 (d); 6.10 (broad peak); 6.36 (broad peak); 6.70 (d); 6.92 (s); 7.23 (dd); 7.38 (m, peak); 7.47 (s); 7.57 (dd); 7.86 (d); 7.92 (d); 8.14 (s); 9.03 (broad peak); 9.41 (1 broad peak); 13.04 (broad peak).

Claims (11)

NOVELTY OF THE INVENTION CLAIMS

1. - A process for the preparation of a compound of the formula (1A) or a pharmaceutically acceptable salt thereof:

(IA) wherein R 1 is an aryl, pyridyl, thiazolyl, phenoxymethyl or pyrimidyl group, optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, Ci-β alkoxy, C 1-6 alkyl, hydroxymethyl, trifluoromethyl, -NR6R6, and -NHS02R6, wherein each R6 is independently hydrogen or CM alkyl; R2 is hydrogen or C6.6 alkyl; R3 is C02R7 wherein R7 is hydrogen or Ci-β alkyl; R4 and R5 are independently hydrogen, C1-6alkyl, or -CO2-C1.6alkyl; and Y is N or CH, which comprises the step of preparing a diamide of the formula (II) or a pharmaceutically acceptable salt thereof: (ll) wherein R 1 is an aryl, pyridyl, thiazolyl, phenoxymethyl or pyrimidyl group, optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C 1-6 alkoxy, hydroxymethyl, trifluoromethyl, -NR 6 R 6, and - NHSO2R6, wherein each R6 is independently hydrogen or CM alkyl; R2 is hydrogen or d-e alkyl; R3 is C02R7 wherein R7 is C6.6 alkyl; R4 and R5 are independently hydrogen, C? -6 alkyl, or -C? 2-alkyl of CI-T; and Y is N or CH. 2. A process for the preparation of a compound of the formula (1A):

(THE) wherein R 1 is an aryl, pyridyl, thiazolyl, phenoxymethyl or pyrimidyl group, optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C-? 6 alkoxy, C-t-β alkyl, hydroxymethyl, ..l Ét? fk. *? v * Jlu * ¡flt ^ s? ^ & Jk * .... * ~ x ^. - jp * > * t f,. ^, _ _. n ^^^^^^ trifluoromethyl, -NR6R6, and -NHSO2R6, wherein each R6 is independently hydrogen or CM alkyl; R2 is hydrogen or C6.6 alkyl; R3 is CO2R7 wherein R7 is hydrogen or C-? 6 alkyl; R 4 and R 5 are independently hydrogen, C 6 alkyl, > -C 2 -alkyl; and Y is N or CH, or a pharmaceutically acceptable salt thereof, comprising the reduction of a compound of the formula (II): (ll) wherein R 1 is an aryl, pyridyl, thiazolyl, phenoxymethyl or pyrimidyl group, optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C 1-6 alkoxy, C 1-6 alkyl, hydroxymethyl, trifluoromethyl, -NR6R6, and -NHSO2R6, wherein each R6 is independently hydrogen or CM alkyl; R2 is hydrogen or d-e alkyl; R3 is C02R7 wherein R7 is d6 alkyl; R4 and R5 are independently hydrogen, C6-alkyl, or -CO2-alkyl of d.6; and Y is N or CH, or a pharmaceutically acceptable salt thereof, and optionally the step of hydrolysis of the resulting ester group R7 in the formula (1A) to produce a compound of the formula (1A) wherein R7 is H 3. The process according to claim 1 or 2, further characterized in that R1 represents phenoxymethyl or phenyl optionally substituted by one, two or three substituents selected from halogen, hydroxy, C? -6 alkoxy, d-6 alkyl; hydroxymethyl and trifluoromethyl.

4. The process according to claim 3, further characterized in that R1 represents phenoxymethyl or phenyl substituted by a chlorine, fluorine or bromine atom or a methyl or trifluoromethyl group.

5. The process according to any of claims 1 to 4, further characterized in that R2 is hydrogen or methyl.

6. The method according to any of claims 1 to 5, further characterized in that at least one of R4 10 and R5 is hydrogen.

7. The method according to any of claims 1 to 6, further characterized in that said compound of the formula (IA) is selected from the group consisting of: acid (R) -5- [3 - [[2- [[ [2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] phenyl] -3-pyridinecarboxylic acid; 3 '- [[2R-15 [[2- (3-chlorophenyl) -2R-hydroxyethyl] amino] propyl] amino] - [1,1'-biphenyl] -2,4-dicarboxylic acid; (R) -3 [2 - [(2-hydroxy-3-phenoxypropyl) amino] ethyl] amino- [1,1'-biphenyl] -3-carboxylic acid; (R) -3 '- [[2 - [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1,1'-biphenyl] -2'-methyl-5-carboxylic acid; (R) -3 '- [[2- [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] - [1,1'-biphenyl] -3-carboxylic acid; and pharmaceutically acceptable salts thereof.

8. A compound of the formula (II) or a pharmaceutically salt thereof: - - > (ll) wherein R1 is an aryl, pyridyl, thiazolyl, phenoxymethyl or pyrimidyl group, optionally substituted by one or more substituents selected from the group which consists of halogen, hydroxy, C? .6 alkoxy, C? .6 alkyl, hydroxymethyl, trifluoromethyl, -NR5R5, and -NHS02R6, wherein each R6 is independently hydrogen or CM alkyl; R2 is hydrogen or alkyl of Ci-ß; R3 is -C02-C1.6alkyl; R4 and R5 are independently hydrogen, Ci-β alkyl or -C ?2-C de6 alkyl; and Y is N or CH.

9. A process for the preparation of a compound of the formula (II) comprising the reaction of a compound of the formula (III) with a compound of the formula (IV): (III) (IV)

10. - The method according to claim 9, further characterized in that it also comprises preparing a compound of the formula (V) using a reaction of a crucible in which a compound of í * í > Aii < ? .. Í ..i ^ í - - ^ - "~? &,. * T. * !?., I, .il? I? R ,," - *? the formula (VI) reacts with a compound of the formula (VII) in the presence of a palladium on carbon catalyst, and is then reduced under hydrogen: (VI) (Vil) wherein Z is halogen or triflate.

11. A compound of the formula (IV) or a pharmaceutically acceptable salt thereof: (IV) wherein: R2 is hydrogen or C-I-T alkyl; R3 is -C02-d-β alkyl; R4 and R5 are independently hydrogen, C1-6 alkyl or -C02-Ci-β alkyl; and Y is N or CH.