MXPA06008019A - Piperazine derivatives which exhibit activity as serotonin and noradrenaline re-upatke inhibitors - Google Patents

Abstract

A compound of formula (I), wherein R1 is H;R2 is aryl, het, C3-8cycloalkyl, C1-6alkyl, (CH2)zaryl or R4, wherein each of the cycloalkyl, aryl, het and R4 groups is optionally substituted by at least one substituent independently selected from C1-6alkyl, C1-6alkoxy, OH, halo, CF3, OCF3, OCHF2, O(CH2)yCF3, CN, CONH2, CON(H)C1-6alkyl, CON(C1-6alkyl)2, hydroxy-C1-6alkyl, Cl-4alkoxy-C1-6alkyl, C1-4alkoxy-C1-4alkoxy, SCF3, C1-6alkyISO2, C1-4alkyl-S-Cl-4alkyl, C1-4alkyl-S-, C1-4alkyINR10R11 and NR10R11;or R1 and R2, together with the carbon atom to which they are bound, form a 5- or 6-membered carbocycle or a 5- or 6-membered heterocycle containing at least one N, O or S heteroatom;R3 is aryl, het or R4, each optionally substituted by at least one substituent independently selected from C1-6alkyl, C1-6alkoxy, het, OH, halo, CF3, OCF3, OCHF2, O(CH2)yCF3, CN, CONH2, CON(H)C1-6alkyl, CON(C1-6alkyl)2, hydroxy-Cl-6alkyl, C1-4alkoxy-C1-6alkyl, C1-4alkoxy-C1-4alkoxy, SCF3, C1-6alkyISO2, C1-4alkyl-S-C1-4alkyl, C1-4alkyl-S-, C1-4 alkylNR10R11and NR10R11;R4 is a phenyl group fused to a 5- or 6- membered carbocycle, or a phenyl group fused to a 5- or 6-membered heterocycle containing at least one N, O or S heteroatom;R5 is H or C1- 6alkyl;R10 and R11 are the same or different and are independently H or C1-4alkyl;A is a C1-3alkylene chain which is optionally substituted by OH, C1-4alkyl or C1-4alkoxy;x is an integer from 1 to 3;y is 1 or 2;z is an integer from 1 to 3;aryl is phenyl, naphthyl, anthracyl or phenanthryl;and het is an aromatic or non-aromatic 4-, 5- or 6-membered heterocycle which contains at least one N, O or S heteroatom, optionally fused to a 5- -or 6-membered carbocycle or a second 4-, 5- or6-membered heterocycle which contains at least one N, O or S heteroatom.

Description

P1PERAZINE DERIVATIVES PRESENTING ACTIVITY AS SEROTONIN AND NORADRENALINE REABSORINATION INHIBITORS DESCRIPTIVE MEMORY This invention relates to novel amine compounds that inhibit the reabsorption of monoamine, to processes for preparation, to pharmaceutical compositions containing them and to their use in medicine. The compounds of the invention exhibit activity as inhibitors of both serotonin and noradrenaline reuptake and therefore have utility in a variety of therapeutic areas. For example, the compounds of the invention are used in the treatment of disorders in which regulation of the function of the monoamine transporter is involved; very particularly disorders in which the inhibition of resorption of serotonin and noradrenaline is involved; and especially disorders in which the inhibition of both serotonin and noradrenaline, such as urinary incontinence, is involved. According to a first aspect, the invention provides a compound of the formula I, as defined below in entity 1.

Entity 1 and pharmaceutically and / or veterinarily acceptable derivatives thereof, wherein: R1 is H; R2 is aryl, het, C3.8 cycloalkyl, C-? 6 alkyl, (CH2) zaryl or R4, wherein each of the cycloalkyl, aryl, het and R4 groups is optionally substituted by at least one substituent independently selected from C? -6 alkyl, C? -6 alkoxy, OH, halogen, CF3, , OCHF2, O (CH2) and CF3l CN, CONH2) CON (H) -alkyl of C -? - 6, CON (C? -6 alkyl) 2, hydroxy-C? -6 alkyl, C 1-4 alkoxy- C.sub.1 -C.sub.1 -C.sub.1 -C.sub.1 -C.sub.1 alkoxy, SCF.sub.3 alkyl, C.sub.6.6.sub.2 SO.sub.2 -C.sub.4 alkyl C.sub.4 -C.sub.1 alkyl C.sub.1 -C.sub.1 alkyl -4-S-, alkyl of C-, 4NR10R11 and NR10R11; or R1 and R2, together with the carbon atom to which they are attached, form a 5- or 6-membered carbocyclic ring or a 5- or 6-membered heterocyclic ring containing at least one N, O or S heteroatom; where R1 and R2 are different, * represents a chiral center; R 3 is aryl, het or R 4, each optionally substituted by at least one substituent independently selected from C 1 -alkyl. e, C 1-6 alkoxy, het, OH, halogen, CF 3, 3, OCHF 2, O (CH 2) and CF 3, CN, CONH 2, CON (H) C 1-6 alkyl, CON (C 1-6 alkyl) 2 , hydroxyC1-6alkyl, C- [alpha] 4alkyl-C6-6alkyl, C1- [alpha] -alkoxy] alkoxy, SCF3, Ci-alkyl. 6SO2, C- [alpha] 4-S-C 1-4 alkyl, C- [beta] alkyl. -S-, alkyl of R 4 is a phenyl group fused to a 5 or 6 membered carbocyclic group, or a phenyl group fused to a 5- or 6-membered heterocyclic group containing at least one N, O or S heteroatom; R5 is H or C? -6 alkyl; R 0 and R 11 are the same or different and are independently H- or C 1-4 alkyl; A is an alkylene chain of C -? 3 which is optionally substituted by OH, C? _ Alkyl or C1-4 alkoxy; x is an integer from 1 to 3; and it is 1 or 2; z is an integer from 1 to 3; aryl is phenyl, naphthyl, anthracyl or phenanthryl; and het is an aromatic or non-aromatic 4, 5 or 6-membered heterocycle containing at least one N, O or S heteroatom, optionally fused to a 5 or 6 membered carbocyclic group or a second 4, 5 or 6 heterocyclic group. members containing at least one heteroatom N, O or S, provided that when R1 is H, R2 is phenyl, A is CH2 and x is 1, R3 is not 3-hydroxyphenyl or 3- (C1-4alkoxy) phenyl .

Alternative embodiments of the invention are referred to below with reference to entities 2 through 23. Entity 2 provides a compound in accordance with entity 1, wherein R1 is H. Entity 3 provides a compound in accordance with entity 1 or entity 2, wherein R2 is aryl, het or C3-8 cycloalkyl, each optionally substituted as indicated in entity 1. Entity 4 provides a compound in accordance with entity 3, wherein R2 is aryl, het or C3-6 cycloalkyl, each optionally substituted as indicated in entity 1. Entity 5 provides a compound in accordance with entity 4, wherein R2 is aryl or het, each optionally substituted as indicated in entity 1. Entity 6 provides a compound in accordance with entity 5, wherein R2 is aryl, optionally substituted as indicated in entity 1. Entity 7 provides a compound in accordance with entity 6, wherein R2 is phenyl, optionally substituted as indicated in entity 1. Entity 8 provides a compound according to any of entities 1 to 7, wherein R2 is optionally substituted by at least one substituent independently selected from C? _6 alkyl, C1-6 alkoxy, OH, halogen, CF3, CN, when R2 contains a cycloalkyl, aryl or het group. Entity 9 provides a compound in accordance with any of entities 1 to 8, wherein R3 is aryl or R4 each optionally substituted by at least one substituent independently selected from C -? - alkyl, C? - alkoxy 6, OH, halogen, CF3l OCF3, OCHF2, O (CH2) and CF3, CN, CONH2, CON (H) C- alkyl ,. 6, CON (C-α-6 alkyl) 2, d-β hydroxyalkyl, C? .4-alkyloxy-C -? Alquiloalkyl, C C ---Cal-4alkoxy alco alco alkoxy, SCF3, C1-6SO2 alkyl and C4-S-alkyl of C? -. Entity 10 provides a compound in accordance with entity 9, wherein R3 is optionally substituted by at least one substituent independently selected from C1-6 alkyl, C-i alkoxy. 6, OH, halogen, CF3, OCF3l OCHF2, O (CH2) and CF3, CN, CONH2, CON (H) C? -6 alkyl, CON (C1-6 alkyl) 2, hydroxyC? , C 1-4 alkoxy-C 1-6 -alkyl, C? -4 -alkoxy-C-4-alkoxy. Entity 11 provides a compound in accordance with entity 10, wherein R3 is optionally substituted by at least one substituent independently selected from C1-6alkyl of C-i alkoxy. 6, OH, halogen, CF3. Entity 12 provides a compound in accordance with any of entities 9 to 11, wherein R3 is aryl, optionally substituted as indicated in any of entities 9 through 11. Entity 13 provides a compound in accordance with entity 12, wherein R3 is aryl, optionally substituted by C-? 3 alkoxy or halogen. Entity 14 provides a compound in accordance with entity 12 or entity 13, wherein R3 is phenyl, optionally substituted as indicated in any of entities 9 through 13. Entity 15 provides a compound in accordance with any of the entities 1 to 14, wherein R5 is H or C- | 3 alkyl. Entity 16 provides a compound in accordance with entity 15, wherein R5 is H, Me or Et. Entity 17 provides a compound in accordance with entity 16, wherein R5 is H. Entity 18 provides a compound in accordance with any of entities 1 to 17, wherein A is an optionally substituted C1-3 alkylene chain by OH. Entity 19 provides a compound in accordance with entity 18, wherein A is a methylene group (-CH2-) optionally substituted by OH. Entity 20 provides a compound in accordance with entity 19, wherein A is an unsubstituted methylene group. Entity 21 provides a compound in accordance with any of entities 1 through 20, where x is 1. Entity 22 provides a compound in accordance with any of entities 1 through 21, where y is 1.

The entity 23 provides a compound according to any of entities 1 to 22, wherein z is 1. The substituent R4 is defined in the above entities as a phenyl group fused to a carbocyclic group of 5 or 6 members, or a group phenyl fused to a 5- or 6-membered heterocyclic group containing at least one heteroatom N, O or S. However, in certain embodiments, or in connection with any of the aforementioned entities, this definition may be limited to one group phenyl fused to a 6-membered carbocyclic group, or a phenyl group fused to a 5- or 6-membered heterocyclic group containing at least one N or O heteroatom. In any of the foregoing entities, the term "aryl" means phenyl, naphthyl, anthracyl or phenanthryl. However, in certain embodiments, or in connection with any of the aforementioned entities, the definition of "aryl" may be limited to phenyl or naphthyl. The term "het" is defined in the above entities as an aromatic or non-aromatic 4, 5 or 6-membered heterocyclic containing at least one N, O or S heteroatom, optionally fused to a 5 or 6 membered carbocyclic group or a second heterocyclic of 4, 5 or 6 members containing at least one heteroatom N, O or S. However, in certain embodiments of the invention, or in connection with any of the aforementioned entities, this may be limited to a 5 or 6 membered aromatic or non-aromatic heterocycle containing at least one N or O heteroatom, optionally fused to a 5 or 6 membered carbocyclic group or a 5 or 6 membered heterocycle containing at least one heteroatom N or O OR; or an aromatic or non-aromatic 5- or 6-membered heterocycle containing at least one N heteroatom, optionally fused to a 5 or 6 membered carbocyclic group or a 5 or 6 membered heterocycle containing at least one N heteroatom. In the above definitions, the second heterocycle, to which the first heterocycle may be fused, may be either aromatic or non-aromatic. In embodiments wherein R1 and R2 are different, * represents a chiral center and may be of either the stereochemical R or S configuration. Racemic mixtures of chiral compounds according to the invention may be produced and are within the scope of the invention as it is claimed. A further embodiment of the invention provides a compound of the formula la as defined below: and pharmaceutically and / or veterinarily acceptable derivatives thereof, wherein: R2 is as defined above with respect to formula 1; and R6 and R7 are the same or different and are independently selected from H, C-? 6 alkyl, d-6 alkoxy, OH, halogen, CF3, OCF3, OCHF2, 0 (CH2) and CF3, CN, CONH2l CON ( H) C 1-6 alkyl, CON (C 1-6 alkyl) 2, hydroxy C 1-6 alkyl, C 1-4 alkoxy C 1-6 alkyl, C 1- alkoxy C 1-6 alkoxy 4, SCF3, C? .6S02 alkyl, C 1-4 alkyl-S-C 1-4 alkyl, C 1-4 alkyl-S-, C 1-4 alkyl R 10 R 11 and NR 10 R 11, wherein R 10 and R 11 are as defined earlier with respect to formula 1; or R6 and R7 together represent a 5- or 6-membered aromatic or non-aromatic carbocyclic ring fused to the phenyl group; or R6 and R7 together represent an aromatic or non-aromatic heterocycle of 4, 5 or 6 members fused to the phenyl group, wherein the heterocycle contains at least one heteroatom N, O or S. It should be noted that there may be more than one substituent R6 and / or more than one R7 substituent. Therefore, the phenyl ring can be substituted by up to 4 substituents which can be the same or different, provided that each one is selected from the list of possible previous groups. Therefore, R6 and R7 can be read as (R6) ny (R7) m respectively, where the sum of m + n is not greater than 4. In the compounds of the formula la, R2 can be optionally substituted so less by a substituent independently selected from C1-6alkyl, C6-6alkoxy, OH, halogen, CF3, CN, when R2 contains a cycloalkyl, aryl or het.

Alternatively, R 2 can be aryl, a 5- or 6-membered aromatic or non-aromatic heterocycle group containing at least one N or O heteroatom, C-6 alkyl, C 3-6 cycloalkyl or - (CH 2) zaryl, wherein z is an integer from 1 to 3 and aryl is as defined above. In certain embodiments in relation to the formula la, R6 and R7 may be the same or different and are independently selected from H, C- | 6 alkyl, C-6 alkoxy, OH, halogen, CF3, OCF3, OCHF2, 0 (CH2) and CF3, CN, CONH2, CON (H) C1-6alkyl, CON (C1-6alkaryl) 2, hydroxyC1-6alkyl, C1-6alkyl-C1alkyl -6 and C 4 -alkoxy-C 4 alkoxy; or R6 and R7 together represent a 5- or 6-membered aromatic or non-aromatic carbocyclic ring fused to the phenyl group; or R6 and R7 together represent a 5- or 6-membered aromatic or non-aromatic heterocycle fused to the phenyl group, wherein the heterocycle contains at least one N or O heteroatom. A further embodiment of the invention provides a compound of the formula Ib as It is defined below: and pharmaceutically and / or veterinarily acceptable derivatives thereof, wherein: R6 and R7 are the same or different and are independently selected from H, C1-6 alkyl, C6-6 alkoxy, OH, halogen, CF3, OCF3, OCHF2, O (CH2) and CF3, CN, CONH2, CON ( H) C 1-6 alkyl) CON (C-? 6 -alkyl) 2, hydroxy-C 1-6 -alkyl, C 1-4 -alkoxy-C 1-6 -alkyl, C 1-4 -alkoxy-alkoxy C- | , SCF3, C? -6SO2 alkyl and C? -4-S- C1- alkyl-; or R6 and R7 together represent a 5- or 6-membered aromatic or non-aromatic carbocyclic ring fused to the phenyl group; or R6 and R7 together represent a 5- or 6-membered aromatic or non-aromatic heterocycle fused to the phenyl group, wherein the heterocycle contains at least one N, O or S heteroatom; and R8 and R9 are the same or different and are independently selected from H, C? -6 alkyl, C1-6 alkoxy, OH, halogen, CF3, OCF3, OCHF2, O (CH2) and CF3, CN, or R8 and R9 together represent a 5- or 6-membered aromatic or non-aromatic carbocyclic ring fused to the phenyl group; or R8 and R9 together represent a 4, 5 or 6-membered aromatic or non-aromatic heterocycle fused to the phenyl group, wherein the heterocycle contains at least one N, O or S heteroatom. It should be noted that there may be more than one R6 substituent and / or more than one R7 substituent. Therefore, the phenyl ring can be substituted by up to 4 substituents which can be the same or different, provided that each one is selected from the list of possible previous groups. Therefore, R6 and R7 can be read as (R6) ny (R7) m respectively, where the sum of m + n is not greater than 4. The same is true for R8 and R9, which can also be read as (R8) p and (R9) q, where the sum of p + q is not greater than 4. In certain embodiments in relation to the compounds of the formula Ib, R6 and R7 may be the same or different and are independently selected from H, Ci-β alkyl, Ci-β alkoxy, OH, halogen, CF3, OCF3, OCHF2, and O (CH2) and CF3; or R6 and R7 together represent a 5- or 6-membered aromatic or non-aromatic carbocyclic ring fused to the phenyl group or R6 and R7 together represent a 5- or 6-membered aromatic or non-aromatic heterocycle fused to the phenyl group, wherein the heterocycle contains at least one heteroatom N or O; and R8 and R9 are the same or different and are independently selected from H, C- | .6 alkyl, C-? -6l OH alkoxy, halogen, CF3, OCF3, OCHF2 and O (CH2) and CF3; or R8 and R9 together represent a 5- or 6-membered aromatic or non-aromatic carbocyclic ring fused to the phenyl group; or R8 and R9 together represent a 5- or 6-membered aromatic or non-aromatic heterocycle fused to the phenyl group, wherein the heterocycle contains at least one N or O heteroatom. In a specific embodiment, the invention provides a compound of the formula Ib , wherein R6 is OEt and R7, R8 and R9 are each H. In particular, R6 can be 2-ethoxy. Exemplary compounds within the scope of the invention are the following: Ditrifluoroacetate of 1 -. { 1-phenyl-2- [2- (trifluoromethoxy) pheny] ethyl} -piperazine, Ditrifluoroacetate 1-. { 1-phenyl-2- [2-chloro-6-fluorophenyl] ethyl} piperazine Ditrifluoroacetate 1-. { 1-phenyl-2- [2-chlorophenyl] ethyl} piperazine 1-. { 1- (3-Fluorophenyl) -2- [2- (trifluoromethoxy) phenyl] ethyl} piperazine, 1 -. { 2- [2- (Difluoromethoxy) phenyl] -1-phenylethyl} piperazine, 1-. { 1- (4-Fluorophenol) -2- [2- (trifluorometho? I) phenyl] ethyl} piperazine, 1-. { 1- (2-Fluorophenyl) -2- [2- (trifluoromethoxy) phenyl] etl} piperazine, 1-dihydrochloride. { 2- [2- (difluoromethoxy) phenyl] -1-phenylethyl} piperazine, 1- [2- (2-chlorophenyl) -1-phenylethyl] piperazine dihydrochloride, 1- [2- (2-methoxyphenyl) -1-phenylethyl] piperazine dihydrochloride, and 1- [2- (2-dihydrochloride -ethoxyphenyl) -1-phenylethyl] piperazine Additional embodiments of the invention include the following compounds: 1 -. { 2- (3-methoxyphenyl) -1 - [3- (trifluoromethyl) phenyl] ethyl} piperazine 1 - [2- (2-ethoxyphenyl) -1-pyridin-3-ylethyl] piperazine 1- [2- (3-chlorophenyl) -1-phenylethyl] piperazine 1 - [2- (2-ethoxyphenyl) -1 - phenylethyl] piperazine 1 - [2- (2,5-dichlorophenyl) -1-phenylethyl] piperazine 1- [2- (2,3-dichlorophenyl) -1-phenylethyljpiperazine 1- [2- (2,3-dichlorophenyl) - 1-pyridin-3-ylethyl] piperazine 1 -. { 1-phenyl-2- [2- (trifluoromethyl) phenyl] ethyl} piperazine 1 - [2- (2-chlorophenyl) -1 - (4-fluorophenyl) ethyl] piperazine 1 - [2- (2-chlorophenyl) -1 - (3-fluorophenyl) ethyl] piperazine 1 - [2- (2 -bromophenyl) -1-phenylethylpiperazine 1 - [2- (2-chlorophenyl) -1 - (2-fluorophenyl) ethyl] piperazine 1- [2- (2,3-dichlorophenol) -1-pyridin-4-ylethyl ] piperazine 1 -. { 1-phenyl-2- [2- (trifluoromethoxy) phenyl] ethyl} piperazine 1 - [2- (2-ethoxyphenyl) -1 - (3-fluorophenyl) ethyl] piperazine 1- [2- (2-ethoxyphenyl) -1- (4-fluorophenyl) ethyl] piperazine 1 - . 1 - . 1 - [2- (2-Ethoxyphenyl) -1 - (2-trifluorophenyl) ethyl] piperazine 1 - [1- (4-fluorophenyl) -2- (2-methoxyphenyl) ethyl] piperazine 1 - [1 - ( 3-fluorophenyl) -2- (2-methoxyphenyl) ethyl] piperazine 1 - [1 - (2-fIuophenyl) -2- (2-methoxyphenyl) ethyl] piperazine 1- [2- (2-methylphenyl) -1-phenylethyl ] piperazine 1- [1- (4-chlorophenyl) -2- (2-methoxyphenyl) ethyl] piperazine 1- [1- (3-chlorophenyl) -2- (2-methoxyphenyl) ethyl] piperazine 1- [1-phenyl] -2- (2-propoxyphenyl) ethyl] piperazine 1 -. { 2- [2- (2-methoxyethoxy) phenyl] -1-phenylethyl} piperazine 1- (1-benzyl-2-phenylethyl) piperazine 1 -. { 2- [2- (methoxymethyl) phenyl] -1-phenylethyl} piperazine 1 - [2- (2-ethylphenyl) -1-phenylethyl] piperazine 1-. { 1'-phenyl-2- [2- (2,2,2-trifluoroethoxy) phenyl] ethyl} piperazine 1 - [2- (2,6-dichlorophenyl) -1-phenylethylpiperazine 1 -. { 2- [2- (Cyclopropylmethoxy) phenyl] -1-phenylethyl} piperazine 1- [4- (2-chlorobenzyl) tetrahydro-2H-pyran-4-yl] piperazine 2- [2- (4-fluorophenyl) -2-piperazin-1-ylethyl] phenol 2- (2-phenyl-2) -piperazin-1-ethyl) phenol 1 - [2- (2-methoxyphenyl) -1-phenylethyljpiperazine 1- [2- (2-chlorophenyl) -1- (1,3-thiazol-5-yl) ethyl] piperazine 1 - [2- (2-Ethoxyphenyl) -1- (3-methylphenyl) ethyl] piperazine 1 - [2- (2-ethoxyphenyl) -1 - (3-methoxyphenyl) ethyl] piperazine 2- (2-phenyl-2- piperazin-1-ylethyl) benzonitrile 1 - [2- (2-ethoxyphenyl) -1 - (4-methylphenyl) ethyl] piperazine 1- [2- (2-ethoxyphenyl) -1- (1,3-thiazole- 5-yl) ethyl] piperazine 1- [2- (2-ethoxyphenyl) -1- (1,3-taizol-2-yl) etl] piperazine 4- [2- (2-chlorophenyl) -1 -piperazin-1-ethylhexbenzonitrile 1- [1- (2-ethoxybenzyl) cyclopentyl] piperazine 1 - [1 - (2-chlorobenzyl) cyclopentyl] piperazine 3- [2- (2-ethoxyphenyl) -1-piperazine -1-Ethyl-benzonitrile (2S) -1 - [2- (2-ethoxyphenyl) -1-phenylethyl] -2-methylpiperazine 3- [2- (2-chlorophenyl) -1-piperazin-1-ethyl) benzonitride Io 1 - [2- (2-methoxyphenyl) -1-pyridin-3-ylethyl] piperazine 1- [2- (2-chlorophenyl) -1-pyridin-3-ylthyl] piperazine 1 - [1 - (2-chlorobenzyl) -3-methylbutyl] -piperazine 1 - [1 - (2-methoxybenzyl) - 3-methylbutyl] piperazine 1 - [2- (2-chlorophenyl) -1 - (6-methylpyridin-3-yl) ethyl] piperazine 1 - [2- (2-ethoxyphenyl) -1 - (6-methylpyridin-3- il) ethyl] piperazine 1 - [2- (2-methoxyphenyl) -1 - (6-methylpyridin-3-yl) ethyl] piperazine 1 -. { 2- [2- (difluoromethoxy) phenyl] -1-pyridin-3-ylethyl} piperazine 1 - [2- (3-fluoro-2-methoxyphenyl) -1-phenylethyljpiperazine 1 - [2- (2-ethoxy-3-fluorophenyl) -1-phenylethyl] piperazine 1- [2- [2- (difluoromethoxy) phenyl] -1- (3-fluorophenyl) ethyl] piperazine 1- [2- [2- (difluoromethoxy) phenyl] -1- (2-fluorophenyl) ethyl] piperazine 1- [2- [2- (difluoromethoxy) phenyl] -1- (4-fluorophenyl) etl] piperazine 1- [2- [3- (difluoromethoxy) phenyl] -1-phenylethyl] piperazine 1 - [2- (2-Cyoprophenyl) -1 - (2-fluorophenyl) ethyl] piperazine 1 - [2- (2-fluoro-6-methoxyphenyl) -1-phenylethyl] piperazine 1 -. { 2- [2- (difluoromethoxy) -6-fluorophenyl] -1-phenylethyl} piperazine 1-. { 2- [2-fluoro-6- (trifluoromethyl) phenyl] -1-phenylethyl} piperazine 1 -. { 1- (3-fluorophenyl) -2- [2- (trifluoromethyl) phenyljetyl} piperazine 1 - [2- (2-isopropoxyphenyl) -1-phenylethyl] piperazine 1-. { 1- (4-chlorophenyl) -2- [2- (difluoromethoxy) phenyl] ethyl} piperazine (1S, 2S) -1- (2-methoxyphenyl) -2-phenyl-2-piperazin-1-yl-ethanol 1-. { 1- (3-chlorophenyl) -2- [2- (difluoromethoxy) phenyl] ethyl} piperazine 1 -. { 1- (2-chlorophenyl) -2- [2- (difluoromethoxy) phenyl] ethyl} piperazine 1-. { 1- (4-fluorophenyl) -2- [2- (trifluoromethyl) phenyl] ethyl} piperazine 1 -. { 2- [2- (cyclopropyloxy) phenyl] -1-phenylethylpiperazine (1S, 2S) -1- (2,3-dichlorophenyl) -2-phenyl-2-piperazin-1-ylethanol (1S, 2S) -1 - (2-chlorophenyl) -2-phenyl-2-piperazin-1-ylethanol (1 S, 2S) -1 - (2-ethoxyphenyl) -2-phenyl-2-piperazin-1-yl-ethanol 1 - [2- ( 2-chlorophenyl) -1-phenylethyl] -1,4-diazepane-1- (1,3-diphenylpropyl) piperazine. In accordance with a further aspect of the invention, one or more metabolites of the compounds of formula I, la or Ib are provided when they are formed in vivo. In particular, it is believed that the compounds of the formula I can be metabolized to a compound of the formula II, wherein R1, R2, R3, R5 and A are all defined with respect to the formula I above: The metabolites of formula II are also considered to constitute one aspect of the present invention. By pharmaceutically and / or veterinarily acceptable derivative is meant a salt, solvate, prodrug (e.g., ester or amide) pharmaceutically and / or veterinarily acceptable, or salt or solvate of said drug (e.g., a salt or solvate of an ester or amide), of the compounds of the formula I, the or Ib or any other compound that when administered to the recipient is capable of providing (directly or indirectly) a compound of the formula I, the or Ib. For pharmaceutical or veterinary use, the aforementioned salts will be the pharmaceutically and / or veterinarily acceptable salts, but other salts may be used, for example in the preparation of compounds of the formula I, I or Ib and the salts pharmaceutically and / or veterinarily acceptable from them. The aforementioned pharmaceutically and / or veterinarily acceptable salts include the acid and basic addition salts thereof. Suitable acid addition salts are formed from acids that form non-toxic salts, examples include the salts of acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, camsylate, citrate, edisilate, hemiedisilate, esylate, fumarate , gluceptate, gluconate, glucuronate, hibietyate, hydrochloride / chloride, hydrobromide / bromide, iodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylisulfate, 2-napsylate, nicotinate, nitrate, orotate, pamoate, acid phosphate / phosphate / diacid phosphate, saccharate, stearate, succinate, tartrate and tosylate. Suitable basic salts are formed from bases that form non-toxic salts. Examples include aluminum salts, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc. For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). A pharmaceutically acceptable salt of a compound of formula I, or Ib can be prepared easily by mixing together the solutions of the compound and the desired acid or base, as appropriate. The salt can be precipitated from the solution and collected by filtration or recovered by evaporation of the solvent. The degree of ionization in the salt can vary from completely ionized to almost non-ionized. The pharmaceutically acceptable solvates according to the invention include hydrates and solvates of the compounds of the formula I, la, or Ib. Also within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes where, unlike the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included in this invention are complexes of the pharmaceutical drug containing two or more organic and / or inorganic components that may be in stoichiometric or non-stoichiometric amounts. The resulting complexes can be ionized, partially ionized or non-ionized. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 of Haleblian (August 1975). The compounds of the formula I, la or Ib can be modified to provide pharmaceutically and / or veterinarily acceptable therefor in any of the functional groups in the compounds. Examples of such derivatives are described in: Drugs of Today, volume 19, number 9,1983, pp 499-538; Topics in Chemistry, chapter 31, pp 306-316; and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, chapter 1 (the descriptions in the documents are incorporated herein by reference) and include: esters, carbonate esters, hemi-esters, phosphate esters, nitro-esters , sulfate esters, sulfoxides, amides, sulfonamides, carbamates, azo compounds, phosphamides, glycosides, ethers, acetals and ketals. In addition, those skilled in the art will appreciate that certain portions, known in the art as "pro-portions", for example, as described in H. Bundgaard in "Design of Prodrugs" (ibid) can be placed in appropriate functionalities when said Functionalities are present within compounds of the invention. The compounds of formula I, la or Ib may contain one or more chiral centers, for example by virtue of the asymmetric carbon atom defined by certain meanings of R1 and R2. Such compounds exist in a number of stereoisomeric forms (e.g., in the form of a pair of optical isomers, or enantiomers). It is to be understood that the present invention encompasses all isomers of the compounds of the invention, including all geometric, tautomeric and optical forms, and isomeric mixtures thereof (e.g., tautomeric or racemic mixtures). The compounds of the invention can exist in one or more tautomeric forms. All tautomers and mixtures thereof are included within the scope of the present invention. For example, a claim for 2-hydroxypyridinyl would also cover its tautomeric form a-pyridonyl. It is to be understood that the present invention includes radiolabelled compounds of the formula I, la or Ib. The compounds of formula I, la or Ib and their pharmaceutically and / or veterinarily acceptable derivatives thereof may also exist in more than one crystal form, a characteristic known as polymorphism. All those polymorphic forms ("polymorphs") are encompassed within the scope of the invention. Polymorphism can usually occur as a response to changes in temperature or pressure or both, and can also result from variations in the crystallization process. The polymorphs can be distinguished by various physical characteristics, and typically the X-ray diffraction patterns, solubility behavior, and melting point of the compound are used to distinguish polymorphs. Unless otherwise indicated, any alkyl group may be straight or branched chain and is 1 to 8 carbon atoms, such as 1 to 6 carbon atoms or 1 to 4 carbon atoms, for example a methyl group, ethyl n-propyl, α-propyl, n-butyl, i-butyl, s-butyl or t-butyl. Where the alkyl group contains more than one carbon atom, it can be unsaturated. Thus, the term "C alquilo?-6 alkyl" includes C 2-6 alkenyl and C 2-6 alkynyl. Similarly, the term "C?-8 alkyl" includes C 2-8 alkenyl and C 2-8 alkynyl. , and the term alkyl of C -? - 4 includes C2-4 alkenyl and C2-4 alkynyl. The term halogen is used to represent fluorine, chlorine, bromine or iodine. Unless otherwise indicated, the term "het" includes any aromatic, saturated or unsaturated 4-, 5- or 6-membered heterocyclic containing up to 4 heteroatoms selected from N, O and S. Examples of such heterocyclic groups include furyl, thienyl, pyrrolyl pyrrolinyl, pyrrolidinyl, imidazolyl, dioxolanyl, oxazolyl, thiazolyl, imidazolyl, imidazolidyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyranyl, pyridyl, piperidinyl, dioxan, morpholino, dithianyl, thiomorpholino, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, sulfolanyl, tetrazolyl, triazinyl, azepinyl, oxazapinyl, thiazepinyl, diazepinyl and thiazolinyl. In addition, the term "heterocycle" includes fused heterocyclic groups, for example, benzimidazolyl, benzoxazolyl, imidazopyridinyl, benzoxazinyl, benzothiazinyl, oxazolopyridinyl, benzofuranyl, quinolinyl, quinazolinyl, quinoxalinyl, dihydroquinazdinyl, benzothiazolyl, phthalimido, benzodiazepinyl, indolyl and isoindolyl. The terms het, heterocyclyl and heterocyclic should be considered as similar. For the avoidance of doubt, unless otherwise indicated, the term "substituted" means substituted by one or more defined groups. In the case where the groups can be selected from a number of alternative groups, the groups selected may be the same or different. In addition, the term "independently" means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different. Hereinafter, the compounds of formula I, la and Ib, and their pharmaceutically and / or veterinarily acceptable derivatives, the radiolabelled analogues of the foregoing, the isomers of the foregoing, and the polymorphs of the foregoing, are referred to as " compounds of the invention ". In one embodiment of the invention, "compounds of the invention" are those pharmaceutically and / or veterinarily acceptable derivatives of compounds of formula I, la or Ib, such as pharmaceutically and / or veterinarily acceptable salts or solvates of compounds of the formula I, la or Ib, (eg, pharmaceutically and / or veterinarily acceptable salts of compounds of the formula I, la or I. b). In a further embodiment of the invention, there is provided a compound of the formula I, or Ib which is a resorption inhibitor of monoamine serotonin and / or noradrenaline, having Ki values of SRI or NR1 of 200 nM or less. In a further embodiment, the compound has SRI or NRl Ki values of 100 nM or less. In a further embodiment, the compound has Ki values of SRI or NR1 of 50 nM or less. In a further embodiment, the compound has Ki values of SRI or NR1 of 50 nM or less. In a further embodiment, the compound has Ki values of SRI or NRl of 25 nM or less. In accordance with scheme 1, the compounds of formula I can be prepared by analogy with the methods of Nishimura et. to the. DE 2610433 or Natsuka et. to the. J. Med. Chem. 1987.30, 10, 1779-1787. Alternatively, the compounds of the formula I can be prepared according to the methods of scheme 1 shown below, when R1 represents H and A is unsubstituted, and R2, R3 and x are as defined above.

SCHEME 1 (lll) PG represents a suitable nitrogen protecting group, typically Boc, benzyl or CBz, and preferably Boc. M represents a suitable reactive metal, such as Zn or Mg, and Hal represents a halogen, typically Br or Cl and preferably Cl. The compounds of the formula (II) and (IV) are either commercially available, or can be prepared from commercial materials using standard chemical transformations.

Step (a) - Mannich reaction The preparation of the compound of the formula (III) can be achieved by reaction of benzotriazole, a suitable protected cyclic amine, and an aldehyde (R2CHO), in equimolar amounts in a suitable solvent, such as benzene , THF or toluene, at elevated temperature and with concomitant water removal (e.g., using an appropriate drying agent, or under Dean and Stark conditions). Preferred conditions are: 1 eq of benzotriazole, 1 eq of cyclic protected amine, 1 eq aldehyde in toluene under reflux under Dean and Stark conditions for about 5 hours.

Step (b) - The compounds of the formula (V) can be prepared by reaction of the benzotriazole adduct of the formula (III) with a suitable organometallic reagent (R3MHal), in a suitable solvent such as toluene or THF, by analogy with the method of Katritzky et. to the. (Tetrahedron, 199, 47, 2683 or Chem. Soc. Rev. 363 (1994) and references therein). Preferred conditions when M represents Zn are: 2eq R3-A-ZnCl (IV) (optionally generated in-situ), in THF and toluene at room temperature for 2-18 hr. When M represents Mg: 2.0-2.1 eq R3-A-MgCI (optionally generated in situ) in THF, optionally with toluene as a co-solvent, at -70 ° C to 0 ° C for about 2 hr. Optionally steps (a) and (b) can be carried out in a "one container" reaction.

Step (c) - Deprotection of N-protecting group Deprotection of compound (V) to provide the compound of formula (I) is carried out using standard methodology, as described in "Protecting Groups in Organic Synthesis" by TW Greene and P. Wutz. PG is preferably Boc. Typical conditions for deprotection are treatment with a strong acid (e.g., HCl or TFA) in a suitable solvent, such as DCM, dioxane or ether at between 0 ° C and room temperature. The preferred conditions are: TFA: DCM (1: 10 to 1: 1 by volume) at between 0 ° C and room temperature up to 18 hr, OR, Aqueous HCl in toluene or THF at 0 ° C to room temperature until 48 hr, or 4M HCl in dioxane and DCM at room temperature for 18 hr. The compounds of the formula (I), wherein A is represented as the C C3 alkylene chain substituted by OH and R2, R3 and x are as defined above, can be prepared according to scheme 2.

SCHEME 2 (VI) (Vil) (VIII) (I) LG represents a suitable residual group, such as halogen or mesylate, typically bromine or chlorine and preferably bromine. a represents 0, 1 or 2. The compounds of the formula (VI) are either commercially available or can be prepared by analogy with the method of Shimokawa et. to the. (J. Med. Chem. 1979.22, 1.58-63).

Step (d) - Amination The compounds of the formula (VII) can be prepared from the compounds of the formula (VI) by reaction with an excess of suitable protected cyclic amine, in the presence of a base (e.g. K2CO3, or 3 ° amine base such as Et3N, NMM, Hunig base) in a suitable solvent, such as THF, MeCN, DMF or EtOH at between room temperature and about 70 ° C, for up to 72 hours. The preferred conditions are: 1-1. 1eq Boc-piperazine, 3eq Et3N, in EtOH at 60 ° C for about 3 hrs, or 1 eq Boc-piperazine, 1.5-3eq K2CO3 in THF or DMF at room temperature for 18-72 hrs.

Step (e) -Reduction The compounds of the formula (VII) can be reduced, using a suitable reducing agent such as NaBH 4 or LiAlH in a suitable solvent at room temperature to provide the alcohol of the formula (VIII). The preferred conditions are: 2eq NaBH, in MeOH at room temperature for 18 hr. The compounds of the formula (I) can be obtained by deprotection of the N-protecting group of the compounds of the formula (VIII), using the methods of step (c), as described above in scheme 1. The compounds of the Formula (VII) can be prepared alternatively, wherein A represents an alkylene chain of C C3 substituted by OH, as described in scheme 3.

SCHEME 3 (IX) (X) (Xl) (XII) (Vil) Ralq represents an alkyl group of C6-6 or benzyl, typically a group of C1-4 and preferably Me. L represents an alkali metal, preferably Na. a represents 0, 1 or 2 LG is a suitable residual group, such as halogen or mesylate, preferably Br. The compounds of the formula (IX) are commercially available. The compounds of the formula (X) can be prepared from the compounds of the formula (IX) by reaction with a suitable protected cyclic amine, preferably Boc-piperazine, in accordance with the method of step (d) as described above in scheme 2.

Step (f) - Formation of carboxylate The compounds of the formula (X) can be treated with a suitable strong base, such as an alkali metal hydroxide (e.g., NaOH, LiOH, KOH) in aqueous solvent to give the compounds of the formula (XI). Preferred conditions are: 1 eq NaOH, H 2 O: MeOH (1: 1 by volume) at room temperature for 18 hr.

Step q) - Weinreb Amide Formation The reaction of the compounds of the formula (XI) with CH3NHOCH3 in the presence of a conventional coupling agent (e.g., WSCDI, DCC), optionally in the presence of HOBT or HOAT, with a Acid acceptor excess (e.g., Et3N, Hunig's base) in a suitable solvent (e.g., EtOAc, THF, DCM) at room temperature provides the compounds of the formula (Xll). Preferred conditions are: 1.1 eq of CH3NHOCH3, 1.2 eq of WSCDI, 1.5 eq of HOBT, 3.5 eq of Et3N in DCM for 18 hr at room temperature.

Step (h) - Ketone Formation The compounds of the formula (VII) can be prepared by reaction of the compounds of the formula (Xll) with a suitable organometallic reagent (typically BuLi) followed by treatment with R3Hal, (Hal is typically Br or I and preferably 1) The preferred conditions are: 2. 05 eq of n-BuLi, 2 eq of R3I in THF at -78 ° C and 5 room temperature for approximately 2 hr. The compounds of the formula (vil) can be prepared alternatively in accordance with the methods described in scheme 4.

SCHEME 4 (Xül) (XIV) (XV) (VIII) 0 a represents 0, 1 or 2. The compounds of the formula (Xlll) can be obtained by treating the compounds of the formula (XI) with aqueous acid under standard conditions.

Step (i) - Reduction of carboxylic acid The compounds of the formula (XIV) can be prepared by reduction of the compounds of the formula (Xlll) using a suitable reducing agent, such as a metal hydride or borane reducing agent (v. .gr. DIBAL, LiAIH4, BH3) in a suitable solvent (eg THF, toluene) at -78 ° C to room temperature or by hydrogenation with a copper chromite catalyst in a suitable solvent at high temperature and pressure . The preferred conditions are: 2eq BH3 in THF at between 0 ° C and room temperature up to 18 hr.

Step (i) - Alcohol oxidation The oxidation of the alcohol of the formula (XIV) can be achieved using a suitable light oxidizing agent such as Dess-Martin periodinane as described in J. Am. Chem. Soc. 113.7277, 1991, or tetra-n-propylammonium perruthenate (VII) / NMO as described in Synthesis 639,1994 or under Swern conditions as described in Org. Synth Coll. 7.258, 1990 to give the aldehyde of the formula (XV). The preferred conditions are: 1.5 eq (COCI) 2, 2.5 eq DMSO, 5 eq Hunig base, in DCM between -78 ° C and room temperature.

Step (k) - Grignard Reaction The reaction of the compounds of the formula (XV) with a suitable Grignard reagent (R3MgHal, Hal represents Cl or Br), optionally generated in-situ, in a suitable solvent such as THF or ether it can give the compounds of the formula (VIII). The preferred conditions are: 1.2-2.2 eq R3MgBr, in THF at between 0 ° C and room temperature for 18 hr. The compounds of the formula (I), wherein A is substituted by OH and R2, R3 and a are as defined above can also be prepared from by analogy with the methods of Bolli and Ley (J. Chem. Soc. Perkin Trans. 1, 1998, 2243-46). Those skilled in the art will appreciate that the compounds of the formula (I) wherein A is substituted by CC alkoxy, can be obtained from the compounds of the formula (I) (or (VIII) when a targeting strategy is required. protective group), wherein A is replaced by OH using standard alkylation conditions. For example, treatment of the compound (VIII) with a suitable base, such as NaH, followed by treatment with a suitable alkylating agent, C C4Hal. The compounds of the formula (I) wherein R 1 and R 2 together with the carbon atom to which they are attached, form a 5- or 6-membered ring, can be prepared according to the methods described in scheme 5.

SCHEME 5 (XVII) (XVIII) - d) p represents 1 or 2. Z represents N, O or S. The compounds of the formula (XVI) are commercially available.

Step (I) - Enamine Formation The compound of the formula (XVII) can be prepared by reaction of the ketone (XVI) with the protected cyclic amine by analogy with the Yamamoto method (J. Org. Chem. 1998,63, 377-378). Preferred conditions are: 1.2 eq of protected cyclic amine, cat. Mei, 1-1.5 eq of BSA in hexane at between 50-75 ° C for about 4 hr.

Step (m) - Amine Formation The compounds of the formula (XVIII) can be prepared from the compounds of the formula (XVII) by treatment with benzotriazole, followed by reaction with a suitable R3-A-Mhal (M is typically Zn or Mg, and Hal is typically Cl or Br), by analogy with the method of Katritzky et. to the. Synthesis, 1992,1295. Preferred conditions are: 1.34 eq of benzotriazole in THF for 15 min-1 hr, followed by 2 eq of R3-A-ZnCl for 18 hr at room temperature. Treatment of the compound of the formula (XVIII) as described above in step (c), provides the compound of the formula (I). Unless otherwise provided herein: CDI means N, N'-carbonyldiimidazole; WSCDI means 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; DCC means N.N'-dicyclohexylcarbodiimide; HOAT means 1-hydroxy-7-azabenzotriazole; HOBT means 1-hydroxybenzotriazole hydrated; Hunig base means N-ethyldiisopropylamine; Et 3 N means triethylamine; NMM means N-methylmorpholine; DIBAL means diisobutylammonium hydride; Dess-Martin periodinane means 1, 1, 1-triacetoxy-1,1-dihydro-1, 2-benziodoxol-3 (1 H) -one; BSA means N, 0-Bis (trimethylsilyl) acetamide; Boc means tert-butoxycarbonyl; CBz means benzyloxycarbonyl; MeOH means methanol; EtOH means ethanol; EtOAc means ethyl acetate; THF means tetrahydrofuran; DMSO means dimethyl sulfoxide; DCM means dichloromethane; DMF means N, N-dimethylformamide; AcOH means acetic acid; and TFA means trifluoroacetic acid. Certain intermediates described above are novel compounds and it is understood that all novel intermediates herein are for additional aspects of the present invention. The racemic compounds can be separated either using preparative CLAP and a column with a chiral stationary phase, or can be resolved to give individual enantiomers using methods known to those skilled in the art. In addition, the chiral intermediates can be resolved and used to prepare chiral compounds of the invention. The compounds of the invention are useful because they have pharmacological activity in mammals, including humans. Therefore, they are useful in the treatment or prevention of disorders in which the regulation of the function of the monoamine transporter is involved, very particularly disorders in which the inhibition of serotonin and noradrenaline reuptake is involved, and especially those in the which the inhibition of reuptake of serotonin and noradrenaline is involved. Accordingly, the compounds of the invention are useful in the treatment of urinary incontinence, such as genuine stress incontinence (GSI), urinary stress incontinence (SUI) or urinary incontinence in elderly adults.; Overreactive bladder (OAB), including idiopathic detrusor instability, detrusor overreactivity secondary to neurological diseases (eg, Parkinson's disease, multiple sclerosis, spinal cord injury and stroke) and detrusor overreactivity secondary to outflow obstruction of the bladder (eg, benign prostatic hyperplasia (BPH), narrowing or stricture of the urethra); nocturnal enuresis; urinary incontinence due to a combination of the above conditions (e.g., genuine stress incontinence associated with overactive bladder); and urinary symptoms, such as frequency and urgency. In view of their aforementioned pharmacological activity, the compounds of the invention are also useful in the treatment of depression, such as major depression, recurrent depression; single-episode depression, subsyndromal symptomatic depression, depression in cancer patients, depression in patients with Parkinson's, depression due to post-myocardial infarction, pediatric depression, depression induced by child abuse, depression in infertile women, post-partum depression, premenstrual dysphoria and the bad old man's syndrome. In view of their aforementioned pharmacological activity, the compounds of the invention are also useful in the treatment of cognitive disorders such as dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntington's chorea, Parkinson's disease and Creutzfeldt-Jakob disease) and vascular dementia (including dementia due to multiple infarction), as well as dementia associated with lesions that occupy intracranial space, trauma, infections and related conditions (including HIV infection), metabolism, toxins, anoxia and deficiency of vitamins; mild cognitive impairment associated with aging, particularly memory impairment associated with age (AAMI), amnestic disorder and cognitive decline associated with age (ARCD); psychotic disorders, such as schizophrenia and mania; anxiety disorders, such as generalized anxiety disorder, phobias (eg, agoraphobia, social phobia and simple phobias), panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, anxiety and depression combined; personality disorders such as avoidance personality disorder and attention deficit hyperactivity disorder (ADHD); sexual dysfunction, such as premature ejaculation, male erectile dysfunction (MED) and female sexual dysfunction (FSD) (eg, female sexual arousal disorder (FSAD)); Premenstrual syndrome; seasonal affective disorder (SAD); eating disorders, such as anorexia nervosa and bulimia nervosa; obesity; suppression of appetite; chemical dependencies resulting from addiction to drugs or substances of abuse, such as addictions to nicotine, alcohol, cocaine, heroin, phenobarbital and benzodiazepines; Withdrawal syndromes, such as those that may arise from the aforementioned chemical dependencies; cephalic pain, such as migraine, cluster headaches, chronic paroxysmal hemicrania, headache associated with vascular disorders, headache associated with chemical dependencies or abstinence syndromes resulting from chemical dependencies, and tension headache; pain; Parkinson's diseases, such as dementia in Parkinson's disease, neuroleptic-induced Parkinsonism and tardive dyskinesias); endocrine disorders, such as hyperprolactinaemia; vasospasm, such as in the cerebral vasculature; cerebellar ataxia; Tourette syndrome; trichotillomania; kleptomania; emotional lability; pathological crying; sleep disorder (cataplexy); and shock. In view of their aforementioned pharmacological activity, the compounds of the invention are also useful in the treatment of a number of other conditions or disorders, including hypotension; disorders of the gastrointestinal tract (involving changes in mobility and secretion) such as irritable bowel syndrome (IBS), ileus (eg, post-operative ileus and ileus during sepsis), gastroparesis (eg, diabetic gastroparesis), peptic ulcer, gastroesophageal reflux disease (GORD, or its synonym GERD), flatulence, and other functional bowel disorders, such as dyspepsia (eg, non-ulcerative dyspepsia (NUD)) and non-cardiac chest pain (NCCP); and fibromyalgia syndrome. In view of its aforementioned pharmacological activity, the compounds of the invention are also useful in the treatment of pain. For example, sprained / dislocated pain, post-operative pain (pain after any type of surgical procedure), post-traumatic pain, burns, myocardial infarction, acute pancreatitis, and renal colic. Also acute pain syndromes related to cancer commonly due to therapeutic interactions such as chemotherapy toxicity, immunotherapy, hormonal therapy and radiotherapy. Additional examples include tumor-related pain (e.g., bone pain, headache and facial pain, visceral pain) or associated with cancer therapy (e.g., post-chemotherapy syndromes, chronic postsurgical pain syndromes, syndromes of post-radiation), back pain that may be due to herniated or ruptured intervertebral discs or abnormalities of the lumbar facet joints, sacroiliac joints, paraspinal muscles or the posterior longitudinal ligament. In addition, the compounds of the invention may be useful in the treatment of neuropathic pain. This is defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system (definition of 1ASP). Damage to nerves can be caused by trauma and disease and therefore the term 'neuropathic pain' encompasses many disorders with diverse etiologies. These include but are not limited to diabetic neuropathy, post-herpetic neuralgia, back pain, cancer neuropathy, chemotherapy-induced neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, chronic alcoholism, hypothyroidism, trigeminal neuralgia, uremia, trauma-induced neuropathy or vitamin deficiencies Other types of pain include but are not limited to: - Inflammatory pain, such as arthritic pain, including rheumatoid arthritis (RA) and osteo-arthritis (OA), and inflammatory bowel disease (IBD); - Musculoskeletal disorders including but not limited to myalgia, fibromyalgia, spondylitis, sero-negative (non-rheumatoid) arthropathies, non-articular rheumatism, dystrophinopathy, glycogenolysis, polymyositis, pyomyositis; - Central pain or 'thalamic pain' as defined by pain caused by injury or dysfunction of the nervous system including but not limited to central pain after stroke, multiple sclerosis, spinal cord injury, Parkinson's disease and epilepsy; - Cardiac and vascular pain including but not limited to angina, myocardial infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, sclerodoma, skeletal muscle ischemia; - visceral pain, and gastrointestinal disorders, including pain associated with dysmenorrhea, pelvic pain, cystitis and pancreatitis; - Headache including but not limited to migraine, migraine with aura, migraine without aura, cluster headache, tension-type headache; and - Orofacial pain including but not limited to dental pain, temporomandibular myofascial pain. Disorders of particular interest include urinary incontinence, such as mixed incontinence, GSI and USI; pain; depression; anxiety disorders, such as obsessive-compulsive disorder and post-traumatic stress disorder; personality disorders, such as ADHD; sexual dysfunction; and dependencies of chemical substances and withdrawal syndromes that result from dependencies of chemical substances. Therefore, in accordance with additional aspects, the invention provides: i) a compound of the invention for use in human or veterinary medicine; I) a compound of the invention for use in the treatment of a disorder in which regulation of the function of the monoamine transporter is involved, such as urinary incontinence; iii) the use of a compound of the invention in the manufacture of a medicament for the treatment of a disorder in which the regulation of the function of the monoamine transporter is involved; iv) a compound of the invention for use in the treatment of a disorder in which the regulation of serotonin or noradrenaline is involved; v) the use of a compound of the invention in the manufacture of a medicament for the treatment of a disorder in which the regulation of serotonin and noradrenaline is involved; vi) a compound of the invention for use in the treatment of urinary incontinence, such as GSI or SUI; vii) the use of a compound of the invention in the manufacture of a medicament for the treatment of urinary incontinence, such as GSI or SUI; viii) a compound of the invention for use in the treatment of depression; ix) the use of a compound of the invention in the manufacture of a medicament for the treatment of depression; x) a method of treating a disorder in which regulation of the function of the monoamine transporter is involved, comprising administering a therapeutically effective amount of a compound of the invention to a patient in need of such treatment; xi) a method of treating a disorder in which serotonin or noradrenaline regulation is involved which comprises administering a therapeutically effective amount of a compound of the invention to a patient in need of such treatment; xii) a method of treating a disorder in which the regulation of serotonin and noradrenaline is involved, comprising administering a therapeutically effective amount of a compound of the invention to a patient in need of such treatment; xiii) a method of treating urinary incontinence, such as GSI or SUI, which comprises administering a therapeutically effective amount of a compound of the invention to a patient in need of such treatment; and xiv) a method of treating depression, which comprises administering a therapeutically effective amount of a compound of the invention to a patient in need of such treatment. It is to be appreciated that all references herein for treatment include curative, palliative and prophylactic treatment, unless otherwise explicitly stated. The compounds of the invention can be administered alone or as part of a combination therapy. If a combination of therapeutic agents is administered, then the active ingredients can be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. Examples of suitable agents for adjunctive therapy include: an estrogen agonist or selective estrogen receptor modulator (e.g., HRT or lasofoxifene therapies); an alpha-adrenergic receptor agonist, such as phenylpropanolamine or R-450; an alpha-adrenergic receptor antagonist (e.g., phentolamine, doxazasin, tamsulosin, terazasin and prazasin), including a selective alpha-adrenergic antagonist (e.g., example 19 of W098 / 30560); a beta-adrenergic agonist (e.g., clenbuterol); a muscarinic receptor antagonist (e.g., tolterodine or oxybutynin), including a muscarinic M3 receptor antagonist (e.g., darifenacin); a Cox inhibitor, such as a Cox-2 inhibitor (eg celecoxib, rofecoxib, valdecoxib parecoxib or etoricoxib); a tachykinin receptor antagonist, such as a neurokinin antagonist (e.g., an antagonist of NK1, NK2 or NK3); a beta 3 receptor agonist; a 5HT ligand? (e.g., buspirona); a 5HT? agonist, such as a triptan (e.g., sumatriptan or naratriptan); a dopamine receptor agonist (e.g., apomorphine, teachings on the use thereof as a pharmaceutical substance can be found in US-A-5945117), including a dopamine receptor agonist (e.g., premiprixal, compound from Pharmacia Upjohn number PNU95666; or ropinirole); a melanocortin receptor agonist (e.g., melanotan II); a PGE receptor antagonist; a PGE1 agonist (e.g., alprostadil); an additional monoamine transport inhibitor, such as a noradrenaline reuptake inhibitor (e.g., reboxetine), a serotonin reuptake inhibitor (e.g., sertraline, fluoxtin, or paroxetine), or a dopamine reuptake inhibitor; a 5-HT3 receptor antagonist (e.g., ondansetron, granisetron, tropisetron, azasetron, dolasetron or alosetron); a phosphodiesterase (PDE) inhibitor, such as an inhibitor of PDE2 (e.g., erythro-9- (2-hydroxyl-3-nonyl) -adenine or example 100 of EP 0771799, incorporated herein by reference) and in particular a PDE5 inhibitor (e.g., sildenafil; - { [3- (3,4-Dihydro-5-methyl-4-oxo-7-propylimidazo [5,1-fJ-as-trazin-2-yl) -4-ethoxy-phenyl] sulfonyl}. -4-ethylpiperazine, ie, vardenafil, also known as Bayer BA 38-9456; or Icos Lilly's IC351, see structure below). 1C351 (icos Lilly) - Therefore, the invention provides, in a further aspect, a combination comprising a compound of the invention together with an additional therapeutic agent. For human use, the compounds of the invention can be administered alone, but in human therapy they will generally be administered in admixture with a suitable excipient, diluent or pharmaceutical carrier, selected with respect to the intended route of administration and standard pharmaceutical practice. For example, the compounds of the invention can be administered orally, buccally or sublingually in the form of tablets, capsules (including soft gelatin capsules), ovules, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, for applications of immediate, delayed, modified, sustained, double, controlled or pulsed release. The compounds of the invention can also be administered by intracavemose injection. The compounds of the invention can also be administered by rapid dispersion or rapid dissolution dose forms. Said tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine and starch (preferably corn starch, potato or tapioca), disintegrants such as sodium starch glycolate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. In addition, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc can be included. Solid compositions of a similar type can also be used as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols. For aqueous suspensions and / or elixirs, the compounds of the invention, and their pharmaceutically acceptable salts, can be combined with various sweetening or flavoring agents, coloring material or dyes, with emulsifying and / or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof. The dose doses of modified and pulsatile release may contain excipients such as those detailed for immediate release dosage forms together with additional excipients which act as release rate modifiers, these being applied as a coating and / or included in the body of the device . Release rate modifiers ncluyenBut not exclusively limited to, hydroxypropylmethylcellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, polyethylene oxide, xanthan gum, carbomer copolymer, ammonio methacrylate hydrogenated castor oil, carnauba wax, paraffin wax , cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, methacrylic acid copolymer and mixtures thereof. The modified and pulsatile release forms may contain one or a combination of release rate modifying excipients. Release rate modifying excipients may be present within the dosage form, ie, within the matrix, and / or on the dosage form, ie, on the surface or coating. Dose formulations Fast dispersing or dissolving (FDDFs) may contain the following ingredients: aspartame, acesulfame potassium, citric acid, croscarmellose sodium, crospovidone, diascorbic acid, ethyl acrylate, ethyl cellulose, gelatin, hydroxypropylmethyl cellulose, magnesium stearate, mannitol, methyl methacrylate, mint flavoring, polyethylene glycol, fumed silica, silicon dioxide, sodium starch glycolate, sodium stearyl fumarate, sorbitol, xylitol. The terms dispersion or dissolution, as used herein to describe FDDFs, depend on the solubility of the drug substance used, ie, wherein the drug substance is insoluble, a rapid dispersion dose form can be prepared and wherein the substance of drug is soluble a fast dissolving dose form can be prepared. The compounds of the nvención can also be administered parenterally, e.g., intravenously, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ntraesternal, intracranially, intramuscularly or subcutaneously, or administered by infusion techniques . For parenteral administration they can best be used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with the blood. The aqueous solutions should be adjusted at their pH appropriately (preferably at a pH of 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is easily accomplished by standard pharmaceutical techniques well known to those skilled in the art. For oral and parenteral administration to human patients, the daily dose level of the compounds of the invention or salts or solvates thereof will generally be from 10 to 500 mg (in single or divided doses). Thus, for example, tablets or capsules of the compounds of the invention or salts or solvates thereof may contain from 5 mg to 250 mg of active compound to be administered individually or two or more at a time, as appropriate . The doctor in any case will determine the actual dose that will be most suitable for any individual patient and will vary with the age, weight and response of the particular patient. The above doses are illustrative of the average case. Of course, there may be individual cases where higher or lower dose ranges are required and those are within the scope of this invention. The person skilled in the art will also appreciate that, in the treatment of certain conditions (including PE), the compounds of the invention can be taken as a single dose on a "as required" basis (ie, as needed or desired). ).

Example tablet formulation In general, a tablet formulation would typically contain between about 0.01 mg and 500 mg of a compound according to the present invention (or a salt thereof) while the tablet filling weights may vary from 50 mg to 1000 mg. An exemplary formulation for a 10 mg tablet is illustrated: Ingredient% w / w Free base or compound salt 10,000 * Lactose 64,125 Starch 21,375 Croscarmellose sodium 3,000 Magnesium stearate 1,500 * This amount is typically adjusted in accordance with the activity of the drug and is based on the weight of the free base. The compounds of the invention can also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurized container, pump, spray or nebulizer with the use of a propellant. suitable, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1-tetrafluoroethane (HFA 134A [trademark]) or 1, 1, 1, 2,3,3,3-heptafluoropropane (HFA 227EA [trademark]), carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dose unit can be determined by providing a valve to supply a measured quantity. The pressurized container, pump, spray or nebulizer may contain a solution or suspension of the active compound, e.g., using a mixture of ethanol and the propellant as the solvent, which may also contain a lubricant, v.gr, sorbitan trioleate . Capsules and cartridges (made, for example, of gelatin) for use in an inhaler or insufflator can be formulated to contain a powder mixture of a compound of the invention and a suitable powder base such as lactose or starch. The aerosol or dry powder formulations are preferably arranged in such a way that each measured dose or "inhalation" contains from 1 to 50 mg of a compound of the invention to be delivered to the patient. The general daily dose with an aerosol will be in the range of 1 to 50 mg that may be administered in a single dose or, more usually, in divided doses throughout the day. The compounds of the invention can also be formulated to be delivered by an atomizer. The formulations for atomizing devices may contain the following ingredients as solubilizers, emulsifiers or suspending agents: water, ethanol, glycerol, propylene glycol, low molecular weight polyethylene glycols, sodium chloride, fluorocarbons, polyethylene glycol ethers, sorbitan trioleate, oleic acid. Alternatively, the compounds of the invention may be administered in the form of a suppository or pessary, or they may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or fine powder. The compounds of the invention can also be administered dermally or transdermally, for example, by the use of a skin patch. They can also be administered through the eye, lung or rectal routes. For ophthalmic use, the compounds can be formulated as micronized suspensions in sterile, isotonic saline, adjusted in pH, or preferably, as solutions in sterile isotonic saline, adjusted in their pH, optionally in combination with a preservative such as sodium chloride. benzylalkonium Alternatively, they can be formulated in an ointment such as petrolatum. For topical application to the skin, the compounds of the invention can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum , propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, they can be formulated as a suitable, suspended or dissolved lotion or cream, for example, in a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters, wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The compounds of the invention can also be used in combination with a cyclodextrin. It is known that cyclodextrins form inclusion complexes and without inclusion with drug molecules. The formation of a drug-cyclodextrin complex can modify the solubility, dissolution rate, bioavailability and / or stability property of a drug molecule. Drug-cyclodextrin complexes are generally useful for most dosage forms and routes of administration. As an alternative to direct complex formation with the drug, the cyclodextrin can be used as an auxiliary additive, e.g., as a carrier, diluent or solubilizer. Alpha-, beta- and gamma-cyclodextrins are most commonly used and suitable examples are described in WO-A-91/11172, WO-A-94/02518 and WO-A-98/55148. For oral or parenteral administration to human patients, the daily dose levels of the compounds of the formula (I), and their pharmaceutically acceptable salts, will be from 0.01 to 30 mg / kg (in single or divided doses) and will preferably be in the range from 0.01 to 5 mg / kg. Therefore, the tablets will contain 1 mg to 0.4 g of compound to be administered individually or two or more at a time, as appropriate. The doctor in any case will determine the actual dose that will be most suitable for any individual patient and will vary with the age, weight and response of the particular patient. The above doses are, of course, only illustrative of the average case and there may be individual cases where higher or lower doses are required, and those are within the scope of the invention. Oral administration is preferred. For veterinary use, a compound of the invention is administered as a suitably acceptable formulation in accordance with normal veterinary practice and the veterinary surgeon will determine the dosage and administration regimen that will be most appropriate for a particular animal. Therefore, in accordance with a further aspect, the invention provides a pharmaceutical formulation containing a compound of the invention and a pharmaceutically acceptable adjuvant, diluent or carrier. The combinations referred to above may also conveniently be presented for use in the form of a pharmaceutical formulation and therefore pharmaceutical formulations containing a combination as defined above together with a pharmaceutically acceptable adjuvant, diluent or carrier comprise a further aspect of the invention. The individual components of such combinations can be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. When a compound of the invention is used in combination with a second therapeutic compound, the dose of each compound may differ from that when the compound is used alone. The appropriate doses will be readily appreciated by those skilled in the art. The invention is illustrated by the following non-limiting examples in which the following abbreviations and definitions can be used: APCI chemical ionization at atmospheric pressure Arbacel® broad filter agent BOC tert-butoxycarbonyl CDI carbonyldiimidazole d chemical shift d doublet? heat DCCI dicyclohexylcarbodiimide DCM dichloromethane DMF N, N-dimethylformamide DMSO dimethyl sulfoxide ES + positive ionization scintillation by electrospray ES "negative scintillation by electrospray hr hours HOAT 1 -hydroxy-7-azabenzotriazole HOBT 1 -hydroxybenzotriazole CLAP high performance liquid chromatography pressure m / z peak mass spectrum min minutes EM mass spectrum NMM N-methylmorpholin NMR nuclear magnetic resonance q quadriplete singlet t triplet TBTU tetrafluoroborate 2-H-benzotriazol-1-yl) -1, 1, 3,3 tetramethyluronium Tf trifluoromethanesulfonyl TFA trifluoroacetic acid THF tetrahydrofuran CCD thin layer chromatography TS + positive ionization scintillation by thermal spraying WSCDI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride The preparations and examples that follow illustrate the invention but they do not limit the invention in any way. All temperatures are in ° C. Flash column chromatography was carried out using Merck silica gel 60 (9385). Solid phase extraction chromatography (SPE) was carried out using Varian Mega Bond Elut (Si) cartridges (Anachem) under a vacuum of 15 mmHg. Thin layer chromatography (CCD) was carried out on 60 Merck silica plates (5729). The melting points were determined using a Gallenkamp MPD350 apparatus and were not corrected. NMR was carried out using a Varian-Unity Inova 400MHz NMR spectrometer or a 400 MHz Varian Mercury NMR spectrometer. Mass spectroscopy was carried out using a Finnigan Navigator individual electrospray mass spectrometer or a Finnigan mass spectrometer aQa APCI. Conveniently, the compounds of the invention are isolated following treatment in the form of the free base, but pharmaceutically acceptable acid addition salts of the compounds of the invention can be prepared using conventional means. Solvates (e.g., hydrates) of a compound of the invention can be formed during the treatment process of one of the aforementioned process steps. Where the compounds were prepared in the manner described for a previous example, one skilled in the art will appreciate that however it may be necessary or desirable to use different treatment or purification conditions.

PREPARATION 1 4-f1fí-1,2,3-benzotriazol-1-yl (phenyl) methyl-1-piperazine-1-carboxylic acid tert-butyl ester A solution of benzaldehyde (5 ml, 50 mmol), benzotriazole (6 g, 50 mmol) and 1-tert-butyl piperazinecarboxylate (9.3 g, 50 mmol) in toluene (280 ml) was heated at 140 ° C for 5 hours , with concomitant removal of water under conditions of Dean and Stark. The reaction was then stirred for an additional 18 hours at 110 ° C, and the mixture was allowed to cool. The volume of the solution was made up to 280 ml with toluene, and the title compound was stored as a solution in toluene.

PREPARATIONS 2 TO 4 The following preparations of the general formula: were prepared from benzotriazole, tert-butyl 1-piperazinecarboxylate and the appropriate benzaldehyde, R2COH, following a method similar to that described in Preparation 1.

PREPARATION 5 4-f2- (2-chlorophenyl) -1-phenylethylpiperazin-1-tert-butylcarboxylate A solution of the compound of preparation 1 (28 ml, 5 mmol) was added dropwise to a solution of 2-chlorobenzyl zinc chloride (0.5M in tetrahydrofuran, 20 ml, 10 mmol) and the reaction was stirred at room temperature for 2 hours. The reaction was quenched by the addition of 0.88% ammonia (10 ml) and the mixture was partitioned between ethyl acetate and water. The layers were separated, the organic phase was washed with 1N sodium hydroxide solution and brine, then dried (MgSO 4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of cyclohexane: ethyl acetate (100: 0 to 80:20) to provide the title compound as a colorless oil, 1.94 g. 1 H NMR (CDCl 3, 400 MHz) d: 1.40 (s, 9 H), 2.50 (m, 4 H), 2.90 (m, 1 H), 3.40 (m, 4 H), 3.60 (m, 1 H), 3.68 (m , 1 H), 6.74 (d, 1 H), 6.96 (m, 1 H), 7.03 (m, 1H), 7.12 (m, 2H), 7.18-7.30 (m, 5H). LRMS: m / z (ES +) 401 [MHf PREPARATION 6 4-. { 1-phenyl-2- [2- (trifluoromethoxy) phenyl-1-ethyl} piperazin-1-tert-butyl carboxylate 1,2-Dibromoethane (0.05 ml, 0.58 mmol) was added to a suspension of zinc (490 mg, 7.5 mmol) in tetrahydrofuran (15 ml) and the mixture was heated to reflux for 2 minutes, then allowed to cool. Chlorotrimethylsilane (0.13 ml, 1 mmol) was added, the mixture was sonicated and a solution of 2- (trifluoromethoxy) benzyl bromide (1.28 g, 5 mmol) in tetrahydrofuran (10 ml) was added dropwise over 5 minutes. . Sonication was continued for an additional 30 minutes, and the mixture was then stirred for one hour. A solution of the compound of preparation 1 (14 ml, 2.5 mmol) was added and the reaction was stirred for 2 hours. The reaction was quenched by the addition of 0.88% ammonia solution (8 ml) and the mixture was partitioned between ethyl acetate (20 ml) and water (20 ml). The layers were separated, the organic phase was washed with 1 M sodium hydroxide solution, dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of pentane: ethyl acetate (95: 5 to 84:16) to give the title compound as a colorless oil, 859 mg. 1 H NMR (CDCl 3, 400 MHz) d: 1.42 (s, 9 H), 2.43 (m, 4 H), 2.88 (dd, 1 H), 3.38 (m, 4 H), 3.45 (dd, 1 H), 3.58 (dd) , 1 H), 6.86 (d, 1 H), 7.00 (m, 1 H), 7.10 (m, 4H), 7.20 (m, 3H). LRMS: m / z (ES +) 473 [MNa] + PREPARATIONS 7 TO 10 The following compounds of the general formula shown below: were prepared as described in Preparation 6 using the compounds of Preparations 1, 2 and 4 and the appropriate benzyl bromides a- isolated without column chromatography.

PREPARATION 11 4-. { 1- (3-fluorophenyl) -2-f2- (trifluoromethoxy) phenylethyl} tert-butyl piperazin-1-carboxylate 2- (Trifluoromethoxy) benzyl bromide (20.5 g, 80.5 mmol) was added to a cooled solution (-25 ° C) of Rieke® zinc (90 mL, suspension of 5.0 g of Zn in 100 mL of tetrahydrofuran, 68.8 mmol) , and the mixture was stirred for 1 hour. This solution was added in portions to a solution of the compound of preparation 3 (220 ml, 0.15 M in toluene, 32.2 mmoles) and the reaction was stirred at room temperature for 18 hours. The reaction was quenched by the addition of 0.88% ammonia (100 ml) and the mixture was diluted with water (350 ml) and ethyl acetate (200 ml) and the phases were separated. The organic layer was dried (MgSO4) and evaporated under reduced pressure to give the title compound as a brown oil. 1 H NMR (CDCl 3, 400 MHz) d: 1.42 (s, 9 H), 2.42 (m, 4 H), 2.82 (m, 1 H), 3.36-3.50 (m, 5 H), 3.58 (m, 1 H), 6.82 -7.30 (m, 8H). LRMS: m / z APCf 469 [MH] + PREPARATION 12. 1 - (Chloromethyl) -2-ethoxybenzene Thionyl chloride (115 ml, 1.48 moles) was added dropwise to a solution of 2-ethoxybenzyl alcohol (214 g, 1.41 mol) in dichloromethane (1.3 I) and once the addition was complete, the reaction was heated under reflux for 3 hours. The cooled mixture was concentrated under reduced pressure and the residue was azeotroped with tetrahydrofuran. The crude product was purified by distillation to give the title compound as a colorless oil, 190 g. (e.g., 80 ° C to 2 mmHg). 1 H NMR (CDCl 3, 400 MHz) d: 1.45 (t, -3 H), 4.10 (q, 2 H), 4.70 (s, 2 H), 6.85 (d, 1 H), 6.90 (dd, 1 H), 7.25 ( dd, 1 H), 7.35 (d, 1 H).

EXAMPLE 1 1- Difluoroacetate. { 1-phenyl-2-f2- (trifluoromethoxy) phenylethyl} piperazine Trifluoroacetic acid (1.9 ml) was added to a solution of the compound of preparation 6 (859 mg, 1.91 mmol) in dichloromethane (10 ml) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was azeotroped with toluene. The solid was triturated with ether, to give the title compound as a white powder, 296 mg. 1 H NMR (CD 3 OD, 400 MHz) d: 2.86 (m, 4 H), 3.12 (dd, 1 H), 3.22 (m, 4 H), 3.56 (dd, 1 H), 3.95 (dd, 1 H), 7.08 ( m, 2H), 7.18-7.35 (m, 7H). LRMS: m / z (ES +) 351 [MH] + EXAMPLES 2 TO 3 The following examples of the general formula: were prepared from the appropriate protected piperidines following the method described in example 1. a- 1: 1 ratio of volume of trifluoroacetic acid and dichloromethane used.

EXAMPLE 4 1-. { 1- (3-Fluorophenyl) -2-r2- (trifluoromethoxy) phenylethyl} piperazine Trifluoroacetic acid (16.4 ml, 213.5 mmol) was added dropwise to an ice-cooled solution of the compound of preparation 11 (10.0 g, 21.3 mmol) in dichloromethane (110 ml) and the solution was stirred at room temperature for 18 hours . The reaction mixture was concentrated under reduced pressure and the residue was azeotroped with toluene and dichloromethane.

The product was partitioned between ether (300 ml) and sodium hydroxide solution (500 ml, 2M) and the layers were separated. The organic phase was dried (MgSO) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of ethyl acetate: pentane: dichloromethane: methanol: 0.88% ammonia (20: 80: 0: 0: 0 to 0: 0: 90: 10: 1) to give the title compound as a brown oil, 3.5 g. 1 H NMR (CDCl 3, 400 MHz) d: 2.79 (m, 5 H), 3.18 (m, 4 H), 3.40 (dd, 1 H), 3.62 (dd, 1 H), 6.82 (m, 3 H), 6.90 (m , 1 H), 7.02 (m, 1 H), 7.19 (m, 3H). LRMS: m / z APCf 369 [MHf EXAMPLE 5 1 2-r 2 - (Difluoromethoxy) fenin-1-phenylethyl > piperazine Trifluoroacetic acid (47 ml) was added dropwise to an ice-cooled solution of the compound of preparation 8 (26.4 g, 61 mmol) in dichloromethane (50 ml) and the reaction was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure and the residue was azeotroped with toluene and dichloromethane. The product was triturated with ether and the resulting solid was filtered and dried. The solid was partitioned between dichloromethane (200 ml) and saturated sodium bicarbonate solution (100 ml), then sodium hydroxide (6 M) was added until complete dissolution occurred, and the layers were separated. The aqueous phase was extracted with dichloromethane (100 ml) and the combined organic solutions were dried (Na2SO4) and evaporated under reduced pressure. The residual gum was dissolved in dichloromethane, the solution was cooled on ice, and ethereal hydrochloric acid was added. The solution was evaporated under reduced pressure, the residue was azeotroped with dichloromethane and the product was recrystallized from ethanol. This product was partitioned between sodium hydroxide solution (6M) and dichloromethane, the layers were separated and the organic phase was dried (Na2SO4) and evaporated under reduced pressure to give the title compound as an oil, 12 g. 1 H NMR (CDCl 3, 400 MHz) d: 2.45 (m, 4 H), 2.84 (m, 5 H), 3.45 (m, 2 H), 6.23 (t, 1 H), 6.83 (m, 3 H), 7.10 (m, 3 H) ), 7.22 (m, 3H). LRMS: m / z APCI + 333 [MHf EXAMPLE 6 1-. { 1- (4-Fluorophenifl) -2-F2- (trifluoromethoxy) phenyl-1-ethyl} piperazine The title compound was obtained as a gum in a 21% yield from the compound of preparation 10, following a general procedure to that described in example 5, except that the compound was further purified by column chromatography on silica gel using dichloromethane: methanol: 0.88% ammonia (90: 10: 1). 1 H NMR (CDCl 3, 400 MHz) d: 2.16 (br s, 1 H), 2.45 (m, 4 H), 2.80 (m, 1 H), 2.90 (m, 4 H), 3.47 (m, 2 H), 6.85 (m , 3H), 7.03 (m, 3H), 7.15 (m, 2H). LRMS: m / z APCf 369 [MHf EXAMPLE 7 1- (1- (2-Fluoro-phenyl) -2-f2- (trifluoromethoxy) phenyl] ethyl) piperazine The title compound was obtained from the title compound of preparation 9 following a general procedure to that described in example 6. 1 H NMR (CDCl 3, 400 MHz) d: 2.12 (br s, 1 H), 2.50 (m, 4H), 2.84 (m, 1 H), 2.98 (m, 4H), 3.42 (m, 2H), 4.10 (m, 1 H), 6.90 (dd, 1 H), 7.10 (m, 6H), 7.53 (m, 1 H) ). LRMS: m / z APCI + 369 [MHf EXAMPLE 8 (-) - 1- (2-f2- (Difluoro-methoxy) phenan-1-phenylethyl} -piperazine dihydrochloride.

A portion of the compound of Example 5 was further purified by CLAP using a Chiralcel OD 250 column and isopropyl alcohol: hexane: diethylamine (10: 90: 0.2) to provide enantiomer 1. Additional elution gave the second enantiomer. The product was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88% ammonia (95: 5: 0.5) as eluent to give the free base of the title compound. This gum was dissolved in dichloromethane, the solution was cooled in ice and treated with ethereal hydrochloric acid. The solution was evaporated under reduced pressure to give the title compound as a white solid. 1 H NMR (CD 3 OD, 400 MHz) d: 3.40-3.58 (m, 4 H), 3.62 (m, 4 H), 3.82 (dd, 1 H), 4.63 (m, 1 H), 6.68-7.01 (m, 3 H) , 7.06 (m, 1 H), 7.19 (dd, 1 H), 7.40 (m, 3H), 7.52 (d, 2H). LRMS: m / z APCI + 333 [MHf [a] D = -58.67 (c = 0.1, methanol) Microanalysis found: C, 54.17; H, 5.87; N, 6.53.

C19H22F2N2O: 2HCl: H2O requires C, 53.91; H, 6.19; N, 6.82%.

EXAMPLES 9 AND 10 (-) and (+) - 1-f2- (2-chlorophenyl) -1-phenylethylpiperazine dihydrochloride The compound of Example 3 (1.2 g) was dissolved in methanol and the solution was treated with 1 M sodium hydroxide solution (20 ml), the solution was stirred at room temperature for 30 minutes, then concentrated under reduced pressure. The aqueous solution was extracted with ethyl acetate (x2), the combined organic extracts were washed with sodium hydroxide solution 1 N, brine, then dried (Na2SO) and evaporated under reduced pressure. The residual yellow oil was further purified by CLAP using a chiralcel OJ 250 column and hexane: ethanol: diethylamine (80: 20: 0.2) as eluent to provide the free base of Example 9. This was purified by column chromatography on silica gel using dichloromethane: methanohamonic at 0.88% (100: 0: 0 to 90: 10: 1) to give a colorless oil. This was dissolved in dichloromethane (4 ml) and the solution was treated with ethereal hydrochloric acid (10 ml, 1 M), the solution was stirred for 30 minutes, then evaporated under reduced pressure to give the title compound of example 9 as a white solid, 320 mg. 1 H NMR (CD 3 OD, 400 MHz) d: 3.32 (m, 2 H), 3.48 (m, 2 H), 3.66 (m, 5 H), 3.95 (dd, 1 H), 4.75 (dd, 1 H), 6.94 (d , 1 H), 7.00 (dd, 1 H), 7.15 (dd, 1 H), 7.30 (d, 1 H), 7.41 (m, 3H), 7.57 (m, 2H). LRMS: m / z (ES +) 301 [MHf Microanalysis found: C, 56.01; H, 6.16; N, 7.09. C18H2iCIN2; 2HCI; 0.15CH2Cl2 requires C, 56.40; H, 6.08; N, 7.25%. [α] D = -88.22 (c = 0.2, methanol) Additional elution of chiralcel column OJ gave the free base of example 10. This was treated as described for example 9 to provide the title compound of example 10. 1H NMR (CD3OD, 400 MHz) d: 3.34 (m, 2H), 3.45 (m, 2H), 3.62 (m, 5H), 3.95 (dd, 1 H), 4.75 (dd, 1 H), 6.94 (d, 1 H), 7.00 (dd, 1 H), 7.15 (dd, 1 H), 7.30 (d, 1 H), 7.40 (m, 3H), 7.57 (m, 2H). LRMS: m / z (APCI +) 301 [MHf Microanalysis found: C, 56.79; H, 6.21; N, 7.17. C18H2? CIN2; 2HCI; 0.10CH2Cl2 requires C, 56.87; H, 6.12; N, 7.33%. [a] D = +87.32 (c = 0.2, methanol) EXAMPLE 11 1-f2- (2-methoxyphenyl) -1-phenylethylpiperazine dihydrochloride A crystal of iodine was added to a suspension of magnesium filings (2.43 g, 100 mmol) in tetrahydrofuran (120 ml) and the mixture was heated to reflux for 10 minutes. The mixture was diluted with additional tetrahydrofuran (80 ml) and a solution of 2-methoxybenzyl chloride (11.73 g, 75 mmol) in tetrahydrofuran (20 ml) was added dropwise through a dropping funnel by pressure equalization during 1 hour, to maintain the reaction at reflux. The reaction was heated under reflux for an additional hour, then allowed to cool to room temperature. This solution was cooled to -70 ° C, and a solution of the compound of preparation 1 (140 ml, 0.25M in toluene, 35 mmol) was added dropwise over 20 minutes. The reaction was stirred for an additional 15 minutes, then warmed to 0 ° C for 30 minutes and emptied into a mixture of ice (300 g) and concentrated hydrochloric acid (100 ml). This mixture was stirred for 2 hours, additional concentrated hydrochloric acid (200 ml) was added and the mixture was stirred for an additional hour. The mixture was filtered, washing thoroughly with ether (2x250 ml) and the filtrate was separated. The aqueous layer was carefully basified using 0.88% ammonia and this solution was extracted with dichloromethane (4x250 ml) and the combined organic extracts were dried (MgSO) and evaporated under reduced pressure. The product was dissolved in ethyl acetate (300 ml) and washed with 20% potassium carbonate solution (3x200 ml), then dried (MgSO) and evaporated under reduced pressure. The residual yellow oil was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol: 0.88% ammonia (95: 5: 0.5 to 90: 10: 1) to give a pale orange oil, in addition to a yellow oil (product with minor impurity). A sample of this product was converted to the dihydrochloride salt to provide the title compound of Example 11. 1 H NMR (D 2 O, 400 MHz) d: 3.22-3.68 (m, 10 H), 4.60 (m, 1 H), 6.58 (m, 1 H), 6.84 (m, 2H), 7.14 (dd, 1 H), 7.36 (m, 5H). LRMS: m / z (ES +) 297 [M + 2Hf EXAMPLE 12 (") -1-r2- (2-methoxyphenyl) -1-phenylethylpiperazine dihydrochloride The free base of Example 11 was dissolved in dichloromethane, treated with trifluoroacetic acid and the solution was evaporated under reduced pressure. The solid was triturated with water and the resulting crystals were dried and recrystallized from hot ethyl acetate. These white crystals were partitioned between ethyl acetate (70 ml) and 1 N sodium hydroxide solution (150 ml), the organic phase was washed with 1 N sodium hydroxide solution (20 ml), then dried (MgSO 4). and evaporated under reduced pressure. The product was purified by CLAP using a Chiralcel OD 250 column (20mm) and hexane: isopropyl alcohol: diethylamine (80: 20: 0.3) as eluent, to provide the enantiomer 1. Additional elution gave the enantiomer 2, which was returned to purify by column chromatography on silica gel using dichloromethane: methanol: 0.88% ammonia (90: 10: 1). The resulting gum was dissolved in methanol (4 ml), the solution was treated with 1 N hydrochloric acid (2 ml) and then evaporated under reduced pressure to provide the title compound of example 12. 1 H NMR (D 2 O, 400 MHz) d : 3.19 (m, 1 H), 3.32 (m, 2H), 3.41 (m, 4H), 3.56 (dd, 1 H), 4.57 (m, 1 H), 6.58 (dd, 1 H), 6.78 (m, 2H), 7.01 (dd, 1 H), 7.24 (m, 5H). LRMS: m / z (APCI +) 297 [MHf Microanalysis found: C, 61.07; H, 7.11; N, 7.44. C18H2? CIN2; 2HCI; 0.2H2? requires C, 61.19; H, 7.14; N, 7.51%. [a] D = -105.0 (c = 0.112, methanol) EXAMPLES 13 AND 14 (+) and (-) - 1-f2- (2-ethoxyphenyl) -1-phenylethyl piperazine-dihydrochloride A crystal of iodine was added to a suspension of magnesium filings (13.5 g, 0.56 mol) in tetrahydrofuran (200 ml) and the mixture was heated to reflux until discoloration occurred. The mixture was diluted with additional tetrahydrofuran (200 ml) and a solution of benzyl chloride from preparation 12 (85.25 g., 0.5 mol) in tetrahydrofuran (400 ml) was added dropwise through a dropping funnel for 2 hours, to maintain the reaction at reflux. The reaction was heated under reflux for a further 2 hours, then allowed to cool to room temperature. This solution was cooled to -78 ° C, and a solution of the compound of preparation 1 (98.37 g, 0.25 mol) (prepared by evaporation under reduced pressure of the solution of preparation 1) in tetrahydrofuran (800 ml) was added dropwise. drop for 35 minutes, to keep the temperature below -65 ° C. The reaction was stirred for an additional 30 minutes, then warmed to 0 ° C for 1 hour and slowly emptied into a mixture of ice (500 g), concentrated hydrochloric acid (100 ml) and toluene (1.5 I), so that the temperature remained below 15 ° C. Further concentrated hydrochloric acid (650 ml) was added portionwise with cooling and once the addition was complete, the mixture was stirred at room temperature for 42 hours. The mixture was separated and the aqueous layer was washed with toluene (2x750 ml), cooled in an ice bath, then basified carefully using 0.88% ammonia (520 ml). This solution was extracted with dichloromethane (3x1 I, 3x750 ml) and the combined organic extracts were washed with water (1 L) and evaporated under reduced pressure. The residual brown oil was dissolved in ethyl acetate (1.2 L), and the solution was washed with 20% aqueous potassium carbonate solution (4x500 ml), dried (MgSO4) and evaporated under reduced pressure. The product was dissolved in ethanol (700 ml), 1M ethereal hydrochloric acid (700 ml) was added and the solution was evaporated under reduced pressure to give an orange solid. This was recrystallized from hot ethanol to provide the racemate of the title compound as a white solid, obtained in three crops, 105.3 g in total. A portion of this compound was further purified by CLAP using a chiralcel OD column and hexane: isopropyl alcohol: diethylamine (70: 30: 0.3) as eluent to give the free base of example 13. This was further purified by gel column chromatography. of silica using dichloromethane: methanol: 0.88% ammonia (90: 10: 1) as eluent. The product was treated with ethereal hydrochloric acid and dried at 70 ° C to provide the title compound of example 13. 1 H NMR (D 2 O, 400 MHz) d: 1.36 (t, 3 H), 3.26-3.45 (m, 4 H) , 3.51 (m, 4H), 3.67 (m, 2H), 3.95 (m, 1 H), 4.05 (m, 1 H), 4.60 (m, 1 H), 6.65 (m, 1 H), 6.84 (m , 2H), 7.08 (m, 1 H), 7.32 (m, 5H). LRMS: m / z (APCI +) 311 [MHf Microanalysis found: C, 62.01; H, 7.48; N, 7.19. C20H26N2O; 2HCl; 025H2O requires C, 61.93; H, 7.41; N, 7.22%. [α] D = +84.22 (c = 0.2, methanol) Additional elution of the chiralcel OD column gave the free base of example 14. This was further purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia % (90: 10: 1) As eluent, the product was treated with 1 M ethereal hydrochloric acid and dried at 70 ° C to provide the title compound of Example 14. 1 H NMR (D 2 O, 400 MHz) d: 1.37 (t , 3H), 3.24-3.38 (m, 4H), 3.50 (m, 4H), 3.61 (m, 2H), 3.96 (m, 1 H), 4.07 (m, 1 H), 4.55 (m, 1 H) , 6.66 (m, 1 H), 6. 85 (m, 2H), 7.08 (m, 1 H), 7.32 (m, 5H). LRMS: m / z (APCf) 311 [MHf [a] D = -97.02 (c = 0.2, methanol) Microanalysis found: C, 61.22; H, 7.47; N, 7.11. C2oH26N2O; 2HCI; 0.5H2O requires C, 61.22; H, 7.45; N, 7.14%. A portion of this compound, (257 mg, 0.65 mmol) was dissolved in sodium hydroxide solution (20 ml, 1 M) and the solution was extracted with dichloromethane (3x15 ml). The combined organic extracts were dried (MgSO4) and evaporated under reduced pressure to give a gum. This was dissolved in methanol (20 ml), and a solution of succinic acid (77 mg, 0.65 mmol) in methanol (5 ml) was added. The solution was stirred until homogeneous and then evaporated under reduced pressure. The residue was triturated with ethyl acetate (10 ml) and the resulting solid was dried to give a white solid. This solid was recrystallized twice from acetone to give the succinate salt of example 14. 1 H NMR (DMSO-de, 400 MHz) d: 1.38 (t, 3H), 2.23 (m, 4H), 2.48 (m, 4H), 2.85 (m, 4H), 3.22 (m, 2H), 3.78 (m, 1 H), 3.88-4.02 (m, 2H), 6.64 (dd, 1 H), 6.81 (d, 1 H), 6.85 (d, 1 H), 7.02 (dd, 1 H), 7.18 (m, 3H), 7.24 (m, 2H).

EXAMPLE 15 The NR1 Ki and SRI Ki values of the compounds of Examples 1, 2, 5, 8 and 14 were determined as follows. The results are shown below in table 1.

Biological activity The compounds were tested for biological activity for their ability to compete with, and inhibit, the binding of [3 H] Nisoxetine to the human noradrenaline transporter, [3 H] Citalopram to the human serotonin transporter and [3H] WIN-35428 to the transporter of human dopamine as follows. (i) Membrane preparation Human embryonic kidney cells (HEK-293) stably transfected with the human serotonin transporter (hSERT), noradrenaline transporter (hNET) or dopamine transporter (hDAT) were cultured under standard cell culture techniques (cells were grown at 37 ° C and 5% CO2 in Dulbecco's Modified Eagle's Medium (DMEM) culture medium supplemented with 10% dialysate fetal calf serum (FCS), 2 mM L-glutamine and 250 μg / ml of geneticin (hSERT and hNET cells) or DMEM culture medium supplemented with 5% FCS, 5% newborn calf serum, 2 mM L-glutamine and 2.5 mg / ml puromycin (hDAT cells)). The cells were harvested, compressed into pellets by centrifugation and resuspended in ice-cold membrane preparation buffer. The cell suspension was then homogenized, the large particulate material was removed by low speed centrifugation and the supernatant was recentrifuged (35,000 x g, 30 minutes at 4 ° C). The membrane pellets were resuspended in pH regulator of membrane preparation, protein concentrations were measured (Sigma protein team) and the membrane suspension was stored under freezing in aliquots. (ii) Determination of inhibitor potency Prior to testing, the membranes containing the respective human carrier protein were pre-coupled to proximity test spheres by appropriate scintillation (SPA), i.e. PVT spheres WGA SPA (Amersham) for hNET and hDAT and spheres of YSi WGA SPA (Amersham) for hSERT, to minimize ligand depletion and maximize the test window for the corresponding ligand [3H]. SPA spheres were resuspended (-50 mg / ml) in test pH regulator (1.5x) were pre-coupled with membranes (typically 5-40, μg membrane per mg sphere) incubating with gentle shaking for 2 hours. hours at 4 ° C. After coupling, the spheres / membranes were collected by centrifugation and washed and re-suspended in test pH buffer (1.5x) with gentle agitation at the concentration required for the test (typically 5-40 mg spheres / ml) . Also before the test, each ligand [3H] was diluted in test pH regulator (1.5x) to give an impact concentration of 3x the final test concentration (typical final concentrations = 12 nM [3H] Nisoxetine (Amersham), 2.5 nM [3H] ] Citalopram (Amersham) and 10 nM [3H] WIN-35428 (Perkin Elmer), which was confirmed by scintillation counting). Finally, all the test compounds were dissolved in 100% DMSO at 4 mM and diluted in 1% DMSO in water to give appropriate test concentrations. The tests were carried out on 384-well NBS plates (Costar). For each test, 20 μl of the appropriate dilution of any test compound, a standard inhibitor (positive control) or compound vehicle (DMSO in water); the final concentration of DMSO was 0.25% in each test well) was added to 20 μl of the appropriate [3H] ligand supply. 20 μl of the corresponding sphere / membrane preparation was then added and the plate was sealed before the incubation with shaking for 1 hour. The test plates were then incubated at room temperature for at least 6 additional hours (to achieve equilibrium) with dark adaptation, prior to direct scintillation counting. The potency of the test compounds was quantified as Cl50 values (concentration of test compound required to inhibit specific binding of radiolabelled ligand to the respective carrier protein by 50% relative to maximum responses (compound carrier only) and minimal (complete inhibition by standard inhibitor)). The Ki value was derived for each compound by conversion of the IC50 value using the Cheng-Prusoff equation and the experimentally measured free ligand concentration and Kd for the membrane lot used in the test (typical Kd values: -30 nM Nisoxetine, -8 nM Citalopram and -15 nM WIN-35428). (iii) HEPES membrane preparation pH regulator (20 mM) HEPES 1 tablet of complete protease inhibitor (Roche) / 50ml at pH 7.4 at room temperature, storage at 4 ° C Test pH regulator (1.5x concentration) test) HEPES (30 mM) NaCl (180 mM) pH 7.4 at room temperature, storage at 4 ° C (iv) (iv) Summary of test parameters TABLE 1

Claims (6)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A compound according to formula I: and pharmaceutically and / or veterinarily acceptable derivatives thereof, wherein: R1 is H; R2 is aryl, het, C3-8 cycloalkyl, C6-6 alkyl, (CH2) zaryl or R4, wherein each of the cycloalkyl, aryl, het and R4 groups is optionally substituted by at least one substituent independently selected from C 1-6 alkyl, C 1-6 alkoxy, OH, halogen, CF 3, OCF 3, OCHF 2, O (CH 2) and CF 3, CN, CONH 2, CON (H) - C 1-6 alkyl, CON (C? -6 alkyl) 2, C? .6 hydroxy alkyl, d-4-alkyl alkoxy of Ci. 6, C 1-4 alkoxy, C 1-4 alkoxy, SCF 3, C 1-6 alkyl-SO 2 -, alkyl-alkyl of C 1-4 C 1-4 alkyl- S-, C 1-4 alkyl R 10 R 11 and NR 10 R 11; or R1 and R2, together with the carbon atom to which they are attached, form a 5- or 6-membered carbocyclic ring or a 5- or 6-membered heterocyclic ring containing at least one N, O or S heteroatom; where R1 and R2 are different, * represents a chiral center; R3 is aryl, het or R4, each optionally substituted by at least one substituent independently selected from C- | 6 alkyl, C 1-6 alkoxy, het, OH, halogen, CF3, OCF3, OCHF2, 0 (CH2 ) and CF3, CN, CONH2, CON (H) C6-6 alkyl) CON (d-6-alkyl) 2, hydroxy-C-6 alkyl, d-alkoxy. -alkyl of C ?. 6, C 1-4 alkoxy-C 4 -alkoxy, SCF 3, C? -6SO 2 alkyl, C? - S-alkyl of d.4, C 1-4 alkyl-S-, C 1-4 alkyl 4NR10R11 and NR10R11; R 4 is a phenyl group fused to a 5 or 6 membered carbocyclic group, or a phenyl group fused to a 5- or 6-membered heterocyclic group containing at least one N, O or S heteroatom; R5 is H or C1-6 alkyl; R10 and R11 are the same or different and are independently H- or C1- alkyl; A is an alkylene chain of C? -3 which is optionally substituted by OH, d-4 alkyl or alkoxy of d.4; x is an integer from 1 to 3; and it is 1 or 2; z is an integer from 1 to 3; aryl is phenyl, naphthyl, anthracyl or phenanthryl; and het is an aromatic or non-aromatic 4, 5 or 6-membered heterocycle containing at least one N, O or S heteroatom, optionally fused to a 5 or 6 membered carbocyclic group or a second 4, 5 or 6 heterocyclic group. members containing at least one heteroatom N, O or S, provided that when R1 is H, R2 is phenyl, A is CH2 and x is 1, R3 is not 3-hydroxyphenyl or 3- (alkoxy of d-4) phenyl.
2. 2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, further characterized in that R1 is H.
3. 3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or claim 2, characterized further, because R2 is aryl, het, or C3-8 cycloalkyl, each optionally substituted by at least one substituent independently selected from C1-6alkyl, C-? -6alkoxy, OH, halogen, CF3, OCF3, OCHF2 , 0 (CH2) and CF3, CN, CONH2, CON (H) alkyl of d. 6, CON (C 1-6 alkyl) 2, hydroxy C 1-6 alkyl, C 1-4 alkoxy of d 6, C 4 -4 alkoxy of d 6, SCF 3, alkyl of d-6SO2 and C 1-4 alkyl-S-C? -4 alkyl.
4. 4. The compound or a pharmaceutically acceptable salt thereof according to claim 3, further characterized in that R2 is aryl optionally substituted by at least one substituent independently selected from C1-6 alkyl, d-6 alkoxy, OH, halogen, CF3, OCF3, OCHF2, O (CH2) and CF3, CN, CONH2, CON (H) alkyl of d. 6, CON (C 1-6 alkyl) 2, hydroxy-alkyl of d-6, C 1-4 alkoxy of d-6 alkyl, C 1 alkoxy-C 1-4 alkoxy, SCF 3, alkyl of d -6S02 and C 4 -4 -alkyl alkyl.
5. 5. The compound or a pharmaceutically acceptable salt thereof according to claim 4, further characterized in that R2 is phenyl optionally substituted by at least one substituent independently selected from C? -6 alkyl, d-6 alkoxy, OH , halogen, CF3, OCF3, OCHF2, O (CH2) and CF3, CN, CONH2l CON (H) d6 alkyl, CON (C 1-6 alkyl) 2, hydroxy C 1-6 alkyl, C? 4 alkoxy C 1-6 alkyl, C? - alkoxy x alkoxy of d-, SCF 3, C alkyl? -6SO2 and C- (C) -alkyl alkyl. 6. The compound or a pharmaceutically acceptable salt thereof according to any of the preceding claims, further characterized in that R3 is aryl or R4, each optionally substituted by at least one substituent independently selected from C1-6alkyl, alkoxy of C1-6, OH, halogen, CF3, OCF3, OCHF2, 0 (CH2) and CF3, CN, CONH2, CON (H) alkyl of d.6, CON (alkyl of .6) 2, hydroxy-alkyl of C? -6, C? -alkyl-C6-alkoxy, C-] -4-alkoxy-d-4-alkoxy, SCF3, C? -6S02 alkyl and C? -4-S-alkyl C? -4. The compound or a pharmaceutically acceptable salt thereof according to claim 6, further characterized in that R3 is phenyl optionally substituted by at least one substituent independently selected from C? -6 alkyl, d-b, -alkoxy, OH , halogen, CF3, OCF3, OCHF2, 0 (CH2) and CF3, CN, CONH2, CON (H) C- alkyl ,.
6. 6, CON (C? -6 alkyl) 2, C? .6 hydroxy-alkyl, d-4-alkoxy of C? -6 alkyl, C 1-4 alkoxy-C- alkoxy, SCF3, d ^ SOa and C 1-4 alkyl-S-alkyl of -4. 8. The compound or a pharmaceutically acceptable salt thereof according to any of the preceding claims, further characterized in that R5 is H or alkyl of d-6. 9. The compound or a pharmaceutically acceptable salt thereof according to any of the preceding claims, further characterized in that x is 1. 10. The compound or a pharmaceutically acceptable salt thereof according to claim 1, further characterized in that is (+) or (-) - 1- [2- (2-ethoxyphenyl) -1-phenylethyl] piperazine. 11. The compound or a pharmaceutically acceptable salt thereof according to claim 1, further characterized in that it is 1 -. { 1-phenyl-2- [2- (trifluoromethoxy) phenyl] ethyl} piperazine; 1 -. { 1-phenyl-2- [2-chloro-6-fluorophenyl] ethyl} piperazine; 1-. { 1-phenyl-2- [2-chlorophenyl] ethyl} piperazine; 1-. { 1- (3-fluorophenyl) -2- [2- (trifluoromethoxy) phenyl] ethyl} piperazine; 1-. { 2- [2- (Difluosomethoxy) -phenyl] -1-phenylethyl} piperazine; 1-. { 1- (4-fluorophenyl) -2- [2- (trifluoromethoxy) phenyl] ethyl} -piperazine; 1-. { 1- (2-fluorophenyl) -2- [2- (trifluoromethoxy) phenyl] ethyl} piperazine; and 1- [2- (2-methoxyphenyl) -1-phenylethyl] piperazine. 12. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any of claims 1 to 11 and a pharmaceutically acceptable adjuvant, diluent or carrier. 13. The compound or a pharmaceutically acceptable salt thereof according to any of claims 1-11 for use as a medicament. 14. The use of a compound or a pharmaceutically acceptable salt thereof according to any of claims 1-11 in the manufacture of a medicament for the treatment of a disorder in which the regulation of serotonin or norepinephrine is involved. in mammals. 15. The use as claimed in claim 14, wherein the regulation of serotonin or noradrenaline is involved. 16. The use of a compound or a pharmaceutically acceptable salt thereof as claimed in claim 15, in the manufacture of a medicament for the treatment of urinary disorders, depression, pain, premature ejaculation, ADHD or fibromyalgia in mammals. 17. The use of a compound or a pharmaceutically acceptable salt thereof as claimed in claim 16, for the treatment of urinary incontinence, such as GSI or USI, in mammals. 18. A process for preparing a compound or a pharmaceutically acceptable salt thereof according to any of claims 1-11 which comprises reacting a compound of the formula III. (di) wherein R2 and x are as defined in any one of claims 1 to 11 and PG is a protective group; with a compound of formula IV K MHal (IV) wherein R3 and A are as defined in any of claims 1 to 11, M is a metal selected from Zn and Mg and Hal is a halogen atom selected from chlorine, bromine and iodine; and deprotecting the resulting compound. SUMMARY OF THE INVENTION A compound of the formula (I): wherein: R1 is H; R2 is aryl, het, C3-8 cycloalkyl, C6-6 alkyl, (CH2) zaryl or R4, wherein each of the cycloalkyl, aryl, het and R4 groups is optionally substituted by at least one substituent independently selected from C 1-6 alkyl, C 1-6 alkoxy, OH, halogen, CF 3, OCF 3, OCHF 2, 0 (CH 2) and CF 3, CN, CONH 2, CON (H) -C 1-6 alkyl) CON (C-alkyl) ? -6) 2, hydroxyalkyl of d-6, C? -alkoxy of d-6, C? -4 alkoxy of C 1-4 alkoxy, SCF3, alkyl of C -? - 6-S02 -, alkyl of d-4-S-C 1-4 alkyl, C 1-4 alkyl- S-, C 1-4 alkyl R 10 R 11 and NR 10 R 11; or R1 and R2, together with the carbon atom to which they are attached, form a 5- or 6-membered carbocyclic ring or a 5- or 6-membered heterocyclic ring containing at least one N, O or S heteroatom; R3 is aryl, het or R4, each optionally substituted by at least one substituent independently selected from C1-6 alkyl, d-6 alkoxy, het, OH, halogen, CF3, OCF3, OCHF2, 0 (CH2) and CF3 , CN, CONH2, CON (H) alkyl of d_6, CON (alkyl of d-6) 2, hydroxy-alkyl of C-? -6, alkoxy of d. -alkyl of C-? -6, C- -alkoxyl-alkoxy of C? _4, SCF3, d6S? -alkyl, C4-S-alkyl of C? alkyl, C1-4-S- alkyl, C1-4NR10R11 alkyl and NR10R11; R4 is a phenyl group fused to a 5 or 6 membered carbocyclic group, or a phenyl group fused to a 5- or 6-membered heterocyclic group containing at least one N, O or S heteroatom; R5 is H or alkyl of d-6; R10 and R11 are the same or different and are independently H- or C? .4 alkyl; A is an alkylene chain of C -? - 3 which is optionally substituted by OH, C 1-4 alkyl or d-4 alkoxy; x is an integer from 1 to 3; and it is 1 or 2; z is an integer from 1 to 3; aryl is phenyl, naphthyl, anthracyl or phenanthryl; and het is an aromatic or non-aromatic 4, 5 or 6-membered heterocycle containing at least one N, O or S heteroatom, optionally fused to a 5 or 6 membered carbocyclic group or a second 4, 5 or 6 heterocyclic group. members containing at least one heteroatom N, O or S, 9B / cgt * P06 / 1049F